<%BANNER%>

Synthesis and Characterization of Alkylzirconium Complexes For The Fabrication of Low Work Function Materials and Synthe...

Permanent Link: http://ufdc.ufl.edu/UFE0041070/00001

Material Information

Title: Synthesis and Characterization of Alkylzirconium Complexes For The Fabrication of Low Work Function Materials and Synthesis of Hydantoins and Dihydrouracils From Amino Amides
Physical Description: 1 online resource (140 p.)
Language: english
Creator: Dumbris, Seth
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2010

Subjects

Subjects / Keywords: carbonylation, dihydrouracil, hydantoin, organic, propargyl, zirconium
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: SYNTHESIS AND CHARACTERIZATION OF ALKYLZIRCONIUM COMPLEXES FOR THE FABRICATION OF LOW WORK FUNCTION MATERIALS AND SYNTHESIS OF HYDANTOINS AND DIHYDROURACILS FROM AMINO AMIDES By Seth Michael Dumbris December 2009 Chair: Lisa McElwee-White Major: Chemistry Alkylzirconium compounds have been studied as precursors for the chemical vapor deposition of ZrC for application as low work function materials in devices such as field emitter arrays. Tetraneopentylzirconium and trineopentylzirconium monochloride were synthesized to test the decomposition pathways using mass spectrometry to help further understand the thermal decomposition under deposition conditions. The initial decomposition step of tetraneopentylzirconium was determined to occur through a mixture of ?- and ?-hydride elimination processes resulting in a complex mass spectrum. The homoleptic alkylzirconium complex tetra-?3(phenylpropargyl)zirconium was synthesized. It exhibited interesting bonding resulting in a D2d symmetric, 16 electron complex that was characterized with X-ray crystallography. The bonding was further analyzed by computational analysis, which determined the HOMO-LUMO gap to be 5.2 eV and showed the highly delocalized bonding of the phenylpropargyl ligands to the zirconium center. The synthesis of ureas has traditionally been accomplished using stoichiometric amounts of phosgene or its derivatives, which results in various environmental, safety, and health issues. Due to the prevalence of urea moieties in molecules of interest in the pharmaceutical industry, catalytic alternative routes that employ CO as the carbonyl source have been found. W(CO)6-catalyzed oxidative carbonylation provides an alternative to using phosgene or isocyanates to yield ureas. A series of ?- and ?-amino amides were synthesized and successfully carbonylated using a W(CO)6/I2 system resulting in hydantoins and 5,6-dihydrouracils, respectively. The effects of sterics on the system are seen as steric bulk of the N-alkyl substituent increases, yield of the corresponding product decreases. Secondary amides also have been shown to afford the products in moderate to good yields.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Seth Dumbris.
Thesis: Thesis (Ph.D.)--University of Florida, 2010.
Local: Adviser: McElwee-White, Lisa A.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2012-04-30

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2010
System ID: UFE0041070:00001

Permanent Link: http://ufdc.ufl.edu/UFE0041070/00001

Material Information

Title: Synthesis and Characterization of Alkylzirconium Complexes For The Fabrication of Low Work Function Materials and Synthesis of Hydantoins and Dihydrouracils From Amino Amides
Physical Description: 1 online resource (140 p.)
Language: english
Creator: Dumbris, Seth
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2010

Subjects

Subjects / Keywords: carbonylation, dihydrouracil, hydantoin, organic, propargyl, zirconium
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: SYNTHESIS AND CHARACTERIZATION OF ALKYLZIRCONIUM COMPLEXES FOR THE FABRICATION OF LOW WORK FUNCTION MATERIALS AND SYNTHESIS OF HYDANTOINS AND DIHYDROURACILS FROM AMINO AMIDES By Seth Michael Dumbris December 2009 Chair: Lisa McElwee-White Major: Chemistry Alkylzirconium compounds have been studied as precursors for the chemical vapor deposition of ZrC for application as low work function materials in devices such as field emitter arrays. Tetraneopentylzirconium and trineopentylzirconium monochloride were synthesized to test the decomposition pathways using mass spectrometry to help further understand the thermal decomposition under deposition conditions. The initial decomposition step of tetraneopentylzirconium was determined to occur through a mixture of ?- and ?-hydride elimination processes resulting in a complex mass spectrum. The homoleptic alkylzirconium complex tetra-?3(phenylpropargyl)zirconium was synthesized. It exhibited interesting bonding resulting in a D2d symmetric, 16 electron complex that was characterized with X-ray crystallography. The bonding was further analyzed by computational analysis, which determined the HOMO-LUMO gap to be 5.2 eV and showed the highly delocalized bonding of the phenylpropargyl ligands to the zirconium center. The synthesis of ureas has traditionally been accomplished using stoichiometric amounts of phosgene or its derivatives, which results in various environmental, safety, and health issues. Due to the prevalence of urea moieties in molecules of interest in the pharmaceutical industry, catalytic alternative routes that employ CO as the carbonyl source have been found. W(CO)6-catalyzed oxidative carbonylation provides an alternative to using phosgene or isocyanates to yield ureas. A series of ?- and ?-amino amides were synthesized and successfully carbonylated using a W(CO)6/I2 system resulting in hydantoins and 5,6-dihydrouracils, respectively. The effects of sterics on the system are seen as steric bulk of the N-alkyl substituent increases, yield of the corresponding product decreases. Secondary amides also have been shown to afford the products in moderate to good yields.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Seth Dumbris.
Thesis: Thesis (Ph.D.)--University of Florida, 2010.
Local: Adviser: McElwee-White, Lisa A.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2012-04-30

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2010
System ID: UFE0041070:00001


This item has the following downloads:


Full Text

PAGE 1

1 S YNTHESIS AND C HARACTERIZATI O N OF ALKYLZIRCONIUM C OMPLEXES FOR THE FABRICATION OF L OW W ORK F UNCTION M ATERIALS AND S YNTHESIS OF H YDANTOINS AND D IHYDROURACILS FROM A MINO A MIDES By SETH MICHAEL DUMBRIS A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 20 10

PAGE 2

2 2010 Seth Michael Dumbris

PAGE 3

3 To SDG and to my loving wife, Molly

PAGE 4

4 ACKNOWLEDGMENTS I would like to thank my parents Alan and Linda Dumbris, and siblings for their encouragement over the years. I would also like to thank my colleagues whom I have worked with in the McElwee White laboratories, especially Phillip Shelton, Ampofo Darko, and Jennifer Johns. I would also like to thank Dr. Khalil Abboud and J rgen Kohler for their assistance with the X ray crystallography and Demps e y Hyatt for computational assistance.

PAGE 5

5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 8 LIST OF FIGURES ................................ ................................ ................................ .......... 9 LIST OF ABBREVIATIONS ................................ ................................ ........................... 12 ABSTRACT ................................ ................................ ................................ ................... 15 CHAPTER 1 THIN FILM DEPOSITON OF ZrC FOR THE FABRICATION OF LOW WORK FUNCTION MATERIALS ................................ ................................ ........................ 17 Introduction ................................ ................................ ................................ ............. 17 Physical Vapor Deposition (PVD) of ZrC ................................ .......................... 17 Conventional Chemical Vapor Deposition (CVD) of ZrC ................................ .. 19 Metal Organic Chemical Vapor Deposition (MOCVD) of ZrC ........................... 22 High Brightness Electr on Devices ................................ ................................ ........... 24 2 SYNTHESIS, CHARACTERIZATION, AND COMPUTATIONAL ANALYSIS OF ALKYLZIRCONIUM COMPLEXES ................................ ................................ ......... 27 Background ................................ ................................ ................................ ............. 27 Mechanistic Analysis of ZrNp 4 Decomposition ................................ ........................ 27 Propargyl/Allenyl Zirconium Complexes ................................ ................................ 31 Synthesis of Alkylzirconium Complexes ................................ ................................ .. 34 Results and Discussion ................................ ................................ ........................... 36 Tetraneope ntylzirconium (ZrNp 4 ) Studies ................................ ......................... 36 Characterization of 3 Tetra( 3 phenylpropargyl)zirconium ............................. 37 Computational Analysis of 3 Tetra( 3 phenylpropargyl)zirconium .................. 40 Conclusions ................................ ................................ ................................ ............ 46 3 TRANSITION METAL CATALYZED OXIDATIVE CARBONYLATION OF AMINES TO UREAS ................................ ................................ ............................... 47 Introduction and Background ................................ ................................ .................. 47 Transition Metal Catalysts ................................ ................................ ................ 49 Palladium Catalyzed Oxidative Carbonylation of Amines ................................ 49 Heterogenous carbonylations of amines to ureas ................................ ...... 50 Mechanistic studies ................................ ................................ .................... 51 Other Late T ransition Metal Catalysts ................................ .............................. 53 Nickel catalyzed oxidative carbonylation ................................ ................... 53

PAGE 6

6 Ruthenium catalyzed oxidative carbonylation ................................ ............ 54 Cobalt and rhodium catalyzed oxidative carbonylation ............................. 55 Gold catalyzed oxidative carbonylation ................................ ...................... 59 Tungsten Catalyzed Oxidative Carbonylation of Amines ................................ 60 Carbonylation of primary amines ................................ ............................... 60 Carbonylation of primary and secondary diamines to cyclic ureas ............. 63 Conclusions ................................ ................................ ................................ ............ 73 4 CATALYTIC OXIDATIVE CARBONYLATION OF AMINO AMIDES TO PRODUCE HYDANTOIN DERIVATIVES ................................ ............................... 74 Background ................................ ................................ ................................ ............. 74 Classic Ways to Synthesize Hydantoins ................................ ................................ 74 Solution Phase Syntheses ................................ ................................ ................ 76 Solid Phase Syntheses ................................ ................................ ..................... 78 Synthesis of Amino Amides ................................ ................................ ................. 79 Results and Discussion ................................ ................................ ........................... 82 Conclusion s ................................ ................................ ................................ ............ 87 5 CATALYTIC OXIDATIVE CARBONYLATION OF AMINO AMIDES TO PRODUCE 5,6 DIHYDROURACIL DERIVAT IV ES ................................ ................ 88 Background ................................ ................................ ................................ ............. 88 Synthetic Routes to Form Dihydrouracils ................................ ................................ 88 Solution Phase Methods ................................ ................................ ................... 89 Solid Phase Organic Chemistry (SPOC) ................................ .......................... 93 Synthesis of Amino Amides ................................ ................................ ................. 95 Results and Discussion ................................ ................................ ........................... 97 Conclusion s ................................ ................................ ................................ .......... 101 6 EXPERIMENTAL SECTION ................................ ................................ ................. 103 Synthesis of Alkylzirconium Complexes ................................ ................................ 1 03 General ................................ ................................ ................................ ........... 103 Synthesis of ZrNp x Cl y Complexes ................................ ................................ .. 103 Neopentylmagnesium chloride ................................ ................................ 103 Tetraneopentylzirconium (2) ................................ ................................ .... 103 Tris neopentyl zirconium monochloride (10) ................................ ............. 104 Synthesis of Propargylzirconium Complexes ................................ ................. 105 Phenylpropargyl bromide ................................ ................................ ......... 105 Phenylpropargylmagnesium bromide ................................ ....................... 105 Tetra 3 (phenylpropargyl) zirconium (11) ................................ ................. 106 Structure determination for 11 ................................ ................................ .. 106 Computational Analysis of 11 ................................ ................................ ... 107 Me thylpropargylmagnesium bromide ................................ ....................... 107 (Methylpropargyl) n zirconium (12) ................................ ............................. 108 Synthesis of and Amino Amides for Oxidative Carbonylation ........................ 108

PAGE 7

7 General Procedures ................................ ................................ ....................... 108 General Procedure for the Synthesis of Amino Amides 78 82 .................... 109 General Preparation of Amino Amide 82 by MAC ................................ ....... 110 Synthesis of Amino Amide 83 ................................ ................................ ..... 111 Boc Protection of Diphenylglycine to 84 ................................ ................... 112 N Benzyl Diphenylglycamide (85) ................................ ............................ 112 Diphenylglycamide (86) ................................ ................................ ............ 113 Procedure A for Carbonylation of Amino Amide 78 ................................ ..... 114 (S) 5 Benzyl 3 methylimidazolidine 2,4 dione (78a) ................................ 114 (S) 5 Benzyl 3 ethylimidazolidine 2,4 dione (79a) ................................ ... 114 (S) 5 Benzyl 3 benzylimidazolidine 2,4 dione (81a) ................................ 115 (S) 3 Benzyl 5 (hydroxymethyl)imidazolidine 2,4 dione (82a) ................. 115 Procedure B for Carbonylation of Amino Amide 8 6 ................................ ..... 116 Hydantoin 83a ................................ ................................ .......................... 116 3 Benzyl 5,5 diphe nylimidazoidine 2,4 dione 85a ................................ ... 117 Phenytoin, 86a ................................ ................................ ......................... 117 General Procedure C for N Boc Protection of Amino Acids to Form 100 .... 117 3 (( tert butoxycarbonyl)amino) 3 phenylpropanoic acid 101 .................... 118 3 (( tert butoxycarbonyl)amino) 4 phenylbutanoic acid 102 ...................... 118 3 (( tert butoxycarbonyl)amino) 4 methylpenta noic acid 103 .................... 119 General Procedure D for Mixed Anhydride Coupling of Amino Acid 99 to Form 104 ................................ ................................ ................................ ..... 119 3 (( tert butoxycarbonyl)amino) N benzyl butanamide 105 ....................... 120 3 (( tert butoxycarbonyl)amino) N benzyl 3 phenyl propanamide 106 ...... 120 3 (( tert butoxycarbonyl)amino) N benzyl 4 phenyl butanamide 107 ........ 120 3 (( tert butoxycarbonyl)amino) N benzyl 4 methyl pentanamide 108 ...... 121 General Procedure E for Deprotection of N Boc Amino Amide 104 to Form 109 ................................ ................................ ................................ ..... 121 3 amino N benzyl butanamide 110 ................................ .......................... 122 3 amino N benzyl 3 phenyl propanamide 111 ................................ ......... 122 3 amino N benzyl 4 phenyl butanamide 112 ................................ ........... 123 3 amino N benzyl 4 methyl pentanamide 113 ................................ ......... 123 General Procedure F for Carbonylation of Amino Amides 109 112 to Form 109a 112a ................................ ................................ .......................... 123 Urea 110a ................................ ................................ ................................ 124 Urea 111a ................................ ................................ ................................ 125 Urea 112a ................................ ................................ ................................ 125 APPENDIX A CRYSTALLOGRAPHIC DATA AND STRUCTURE REFINEMENT OF 11 ........... 126 LIST OF REFERENCES ................................ ................................ ............................. 127 BIOGRAPHICAL SKETCH ................................ ................................ .......................... 140

PAGE 8

8 LIST OF TABLES Table page 2 1 Selected bond angles and distances for 11 ................................ ........................... 39 2 2 Bond dis tances ( ) in crystal structure 14 ................................ .............................. 39 3 1 Oxidative carbonylation of primary amines to ureas under optimized conditions ... 62 3 2 Tungsten catalyzed oxidative carbonylation of substituted primary diamines ........ 65 3 3 Catalytic carbonylation of substituted benzylamines to ureas ................................ 67 3 4 Tungsten catalyzed oxidative carbonylation of 44 46 to ureas 47 49 ............... 69 3 5 Carbonylatio n of amino alcohols to ureas and carbamates ................................ .... 71 3 6 Yield of bicyclic ureas from diamines 57 60 ................................ ........................ 73 4 1 Synthesis of amino amides 78 81 ................................ ................................ .... 79 4 2 Carbonylation conditions for amino amide 78 to form 78a ................................ .. 82 4 3 Catalytic carbonylation of amino amide substrate s ................................ ................ 83 4 4 Optimization of carbonylation of 86 ................................ ................................ ........ 85 4 5 Comparison of carbonylation conditions for 83 85 86 ................................ .......... 86 5 1 Optimization of carbonylation conditions for 109 to form 109a ............................... 98 5 2 Carbonylation of amino amides to acyclic ureas 110a 113a .......................... 100

PAGE 9

9 LIST OF FIGURES Figure page 1 1 Comparison of conformal vs. non conformal substrate coverage ........................ 18 1 2 Morphologies of ZrC films deposited from a ZrCl 4 CH 4 H 2 Ar system .................. 20 1 3 Tetraalkyl zirconium compounds ................................ ................................ ......... 23 1 4 Spindt t ype field emitter cathode array ................................ ................................ 24 1 5 FEA device failure ................................ ................................ ................................ 25 2 1 Thermal desorption following adsorption of ZrNp 4 on a nickel foil after annealing at 275 K prior to spectrum collection ................................ ................... 28 2 2 Initial decomposition pathways of MNp 4 and ZrNp 4 d 8 ................................ ......... 30 2 3 Tautomerization of a metal allenyl and a metal propargyl complex ..................... 31 2 4 Synthetic routes to 3 al lenyl/propargyl metal complexes ................................ .... 32 2 5 Bonding modes of 3 al lenyl/propargyl metal complexes ................................ ..... 33 2 6 Synthesis of ZrNp 4 and ZrNp 3 Cl ................................ ................................ .......... 34 2 7 Synthesis of alleny l/propargyl zirconium complexes ................................ ............ 35 2 8 Other p roparylzirconium complexes ................................ ................................ ..... 37 2 9 Thermal ellipsoid drawing of 11 ................................ ................................ ........... 38 2 1 0 Ti pentalene complex 15 ................................ ................................ ...................... 40 2 11 Molecular orbital diagram of 15 ................................ ................................ ............ 40 2 12 3 Dimensional stick model of 16 ................................ ................................ .......... 41 2 13 Molecular orbital diagram of 16 ................................ ................................ ............ 42 2 14 Degenerate HOMO orbitals of 16 ................................ ................................ ........ 43 2 15 LUMO and LUMO+1 orbitals of 16 ................................ ................................ ....... 44 2 16 Degenerate LUMO+2 orbitals of 16 ................................ ................................ ..... 45 3 1 Oxidative carbonylation of alkylamines using a PdI 2 and KI system .................... 50

PAGE 10

10 3 2 Oxidative c arbonylation of phenylacetylene ................................ ......................... 51 3 3 Postulated Pd catalytic cycle for Eq. 3 1 ................................ .............................. 52 3 4 Synthesis of NPY5RA 972 using Pd ca talyzed oxidative carbonylation ............... 53 3 5 Nickel catalyzed ox idative carbonylation of amines ................................ ............. 54 3 6 Oxidative carbonylation of arylamines using ruthenium catalysts ........................ 55 3 7 Cobalt (salen) catalyzed oxidat ive carbonylation of arylamines ........................... 56 3 8 Co(salen) and modified Co(salen) complexes 31 35 ................................ ........... 57 3 9 Rh catalyzed oxidative carbonylation of aniline to DPU ................................ ....... 58 3 10 Polymer supported Au catalyzed carbonyl ation of amines ................................ .. 60 3 11 Mechanistic studies using 38 ................................ ................................ ............... 61 3 12 W(CO) 6 catalyzed oxidative carbonylation of diamines ................................ ....... 63 3 13 W(CO) 6 catalyzed carbonylat ion of substituted benzylamines ............................. 66 3 14 St ructures of DMP 323 and D MP 450 ................................ ................................ .. 68 3 15 Carbonylation of 44 46 ................................ ................................ ......................... 69 3 16 Carbonylation of amino alc ohols to form cyclic carbamates ................................ 70 3 17 Synthesis of the biotin methylester 56 ................................ ................................ 72 3 18 Carbonylation of heterocycles 57 60 ................................ ................................ .... 72 4 1 Numbe ring system for hydantoin rings ................................ ................................ 74 4 2 Synthetic approaches to hy dantoins ................................ ................................ .... 75 4 3 Preparation of sorbinil ( 67 ) ................................ ................................ ................... 76 4 4 Synthesis of hydantoin 70 ................................ ................................ .................... 76 4 5 Synthesis of thiohydantoin 72 ................................ ................................ .............. 77 4 6 Synthesis of hydantoin 75 ................................ ................................ .................... 77 4 7 SPOS (solid phase organic synthesis) of 76 ................................ ........................ 78 4 8 Proposed synthetic approach to using the W(CO 6 )/I 2 system to yield hydantoins ................................ ................................ ................................ ........... 79

PAGE 11

11 4 9 Synthesis of amino amides 78 81 ................................ ................................ ..... 79 4 10 Synthesis of 82 from serine methyl ester ................................ ............................. 80 4 11 MAC synthesis of 82 ................................ ................................ ............................ 80 4 12 MAC synthesis of 80 and 81 ................................ ................................ ................ 80 4 13 Synthesis of 83 ................................ ................................ ................................ .... 81 4 14 Synthetic scheme for 84 86 ................................ ................................ ................. 81 4 15 W(CO) 6 catalyzed carbonylation of 78 to hydantoin 78a ................................ ..... 82 4 16 General carbonyl ation of amino amide substrates ................................ ............... 83 5 1 5,6 Dihydrouracil ................................ ................................ ................................ .. 88 5 2 Synthesis of 5,6 dihydrouracils using unsaturated carboxylic acids .............. 89 5 3 Synthesis of 5,6 dihydroura cils using isobutyric anhydride ................................ .. 89 5 4 Proposed mechanism of 5,6 dihydrouracil formation ................................ ........... 90 5 5 Conversion of diamides to 5,6 dihydrou racils by reaction with Pb(OAc) 4 ............ 91 5 6 Hydrogenation of uracil to 5,6 dihydrouracil ................................ ......................... 91 5 7 L selectride reduction of ura cils to form 5,6 dihydrouracils ................................ .. 92 5 8 Synthesis of dihydrouracils from amino acid derivatives ................................ ... 93 5 9 SPOC synthesis of 5,6 dihydrou racils ................................ ................................ .. 93 5 10 N Boc protection of amino acids to generate 100 103 ................................ ......... 95 5 11 MAC reaction to yield 104 108 ................................ ................................ ............. 96 5 12 Deprotection of N Boc amino amides to afford 109 113 ................................ ...... 97 5 13 W(CO) 6 catalyzed carbonylation of 109 ................................ ............................... 98 5 14 Carbonylation of substrates 110 113 to form 110a 113a using optimized conditions from 109a ................................ ................................ ............................ 99

PAGE 12

12 LIST OF ABBREVIATION S AA MOCVD aerosol assisted metal organic chemical vapor deposition amu atomic mass unit Bn benzyl group Boc tert butyl carb onyl group BtOH 1 hydroxy 1H benzotriazole Cat. any catalyst Cbz carbobenzyloxy group CDI 1,1 carbonyldi i midazole CI MS chemical ionization mass spectrometry Cmpd compound CVD chemical vapor deposition DABCO 1,4 diazabicy c lo[2.2.2]octane DBU 1,8 diazabicyclo[5.4.0]undec 7 ene DCB 1,4 dichloro 2 butene DCE 1,2 dichloroet hane DCM dichloromethane DMA dimethylacetamide DMAP 4 dimethylaminopyridine DMDTC dimethyl dithiocarbamate DMF dimethylformamide DMP DuPont Merck Pharmaceuticals DMSO dimethyl sulfoxide DPT di 2 pyridylthiocarbonate DPU N,N diphenylurea

PAGE 13

13 E a activation ener gy EDCI 1 ethyl 3 (3 dimethylaminopropyl)carbodiimide EI MS electrical ionization mass spectrometry Equiv. equivalent Et ethyl group EtOAc ethyl acetate EtOH ethanol eV electron volt FEA field emission array FT IR Fourier transform infrared spectroscopy GLC gas liquid chromatography h hour HIV Human I mmunodeficiency V irus HOMO highest occupied molecular orbital HPLC high pressure liquid chromatography i Pr isopropyl group L any ligand LCMS liquid chromatography mass spectrometry LMCT ligand to metal charge transfer LUMO lowest unoccupied molecular orbital M any metal MAC mixed anhydride coupling Me methyl group MEM meth oxyethoxymethyl ether MeOH methanol

PAGE 14

14 MO molecular orbital MOCVD metal organic chemical vapor deposition MS mass spectrometry NMM N methymorpholine NMP N methylpyrrolidinone NMR nuclear magnetic resonance spectroscopy Np neopentyl group PG protecting group PVD p hysical v apor d eposition Py. pyridine rt room temperature SEM (trimethylsilyl)ethoxy] methyl acetal SPOC solid phase organic chemistry SPOS solid phase organic synthesis TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TMAH tetramethylammonium hydroxide UHV ultra high vacuum X any halide

PAGE 15

15 Abstract of Dissertation Presented to the Graduate S chool of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy SYNTHESIS AND CHARACTERIZATI O N OF ALKYLZIRCONIUM COMPLEXES FOR THE FABRICATION OF LOW WORK FUNCTION MATERIALS AND SYNTHESI S OF HYDANTOINS AND DIHYDROURACILS FROM AMINO AMIDES By Seth Michael Dumbris M ay 20 1 0 Chair: Lisa McElwee White Major: Chemistry Alkylzirconium compounds have been studied as precursors for the chemical vapor deposition of ZrC for application as low work function materials in devices such as field emitter arrays. Tetraneopentylzirconium and t rineopentylzirconium mono chloride were s ynthesized to test the decomposition pathways using mass spectrometry to help further understand the thermal decomposition under deposition conditions. The initial decomposition step of tetraneopentylzirconium was determined to occur through a mixture of and hydride elimination proces s e s resul ting in a complex mass spectrum. The homoleptic alkylzirconium complex tetra 3 (phenylpropargyl)zirconium was synthesized It exhibited interesting bonding resulting in a D 2d symmetric, 16 electron complex tha t was characterized with X r ay crystallography. The bonding was further analyzed by computational analysis, which determined the HOMO LUMO gap to be 5.2 eV and showed the highly delocalized bonding of the phenylpropargyl ligands to the zirconium center

PAGE 16

16 T he synthesis of ureas has traditionally been accomplished using stoichiometric amounts of phosgene or its derivatives, which results in various environmental, safety, and health issues. Due to the prevalence of urea moieties in molecules of interest in th e pharmaceutical industry catalytic alternative routes that employ CO as the carbonyl source have been found. W(CO) 6 catalyzed oxidative carbonylation provides an alternative to using phosgene or isocyanates to yield ureas. A series of and amino am ides were synthesized and successfully carbonylated using a W(CO) 6 /I 2 system resulting in hydantoins and 5,6 dihydrouracils, respectively. The effects of sterics on the system are seen as steric bulk of the N alkyl substituent increases, yield of the corr esponding product decreases. Secondary amides also have been shown to afford the products in moderate to good yields.

PAGE 17

17 CHAPTER 1 THIN FILM DEPOSITON OF Z r C FOR THE FABRICATIO N OF LOW WORK FUNCTION MATERIALS Introduction Metal carbide coatings have been of interest lately because their thermal and electrical conductivities are similar to those of pure metals. In addition, they possess high ha rdness values, high melting temperature high s trength at elevated temperature and stability. 1 T hey have been incorporated into a number of applications including corrosion resistant materials, energy production applications, components for aircraft and rockets, high heat resistant materials, and wear resistant technologies. Zirconium carbide (ZrC) has been of particular interest as it has been shown to enhance the corrosion resistance of carbon steels 2 improve beam confinement and emission stability on the cathodes of field emitters 3 and control wear and friction in engineering materials 4 It is also used in atomic fuel particles due to its low neutron cross section 5 and use d in high brightness electron sources 6 Thin films of ZrC ca n be deposited on a variety of substrates through many methods that center around two main types; p hysical v apor d eposition (PVD) and c hemical v apor d eposition (CVD). CVD itself can be further divided into two main types : conventional and m etal o rganic ( MOCVD). While both PVD and CVD are successful in depositing ZrC in a controlled manner, there are intrinsic differences between the two methods that can result in differences in morphology, film thickness, rate of deposition, atomic ratio of Zr to C, and temperatures and pressures needed for deposition. Physical Vapor Deposition (PVD) of ZrC P hysical v apor d eposition is a method that employs vacuum to deposit thin films by the condensation of a gaseous form of a specific material onto a substrate. This is

PAGE 18

18 conducted in a directional, line of sight manner through numerous methods, one of which is evaporative deposition. In this method the material to be deposited i s heated under vacuum on one side of the reactor and is distributed on the substrate o pposite it This can be assisted by an inert carrier gas to help transfer or not. The substrate is then coat ed on any surface that is exposed to the flow of gas /deposited material Other PVD methods that have been successfully employed for the depositio n of ZrC include e beam bombardment 6 pulsed laser ablation 7 laser cladding 8 and magnetron sputtering. 9 These methods have proven successful at depositing ZrC onto many substrates including steel, silica, molybdenum, tungsten, and graphite Figure 1 1. Comparison of conformal vs. non conformal substrate c overage. Left) Conformal coverage of film on substrate. Right) Non conformal coverage of film on substrate. These methods also tend to be fairly mild to the substrate as the temperature needed often do es not exceed 300 C. This i s not always the case, however, as laser cladding superficially melts the surface of the substrate. 8 While this generally does not affect the mechanical properties of the material, it could potentially a ffect the substrate if it has more than one layer. In addition as this is a line of sight deposition method at low pressure a substrate that is not smooth will not have conformal coverage. A reas have thicker coverage on the direction facing the gas/depo sited material flow while the face

PAGE 19

19 opposite would receive less. Achieving conformal coverage on an inset substrate area would also not be vi able (Figure 1 1) Conventional Chemical Vapor Deposition (CVD) of ZrC Conventional CVD uses binary metal halide pr ecursors, such as ZrCl 4 and methane (CH 4 ) as the carbon source under a reducing H 2 atmosphere to achieve deposition of ZrC. The metal source, ZrCl 4 is heated under reduced pressure and is transported to the substrate which is heated to 1000 2000 C T he zirconium halide and CH 4 react to generate ZrC on the surface As the reaction does not occur until the reactants reach the substrate, conformal coverage is much easier to obtain. Control parameters such as temperature, pressure, carbon source, and flux of gas precursors have been thoroughly examined. 10 12 A n in depth thermodynami c analysis predicted that, at equilibrium, it would be easy to manipulate the exact molecular composition of the solid deposited by controlling the input partial pressure of CH 4 with a constant ZrCl 4 feed. 13 These pressure ranges at 1900 K are 5x10 3 torr < P CH 4 <10 2 torr and 10 2 torr


PAGE 20

20 reaction kinet ics should be dominated by deposition of Zr or C, or the reaction of the two to form carbide. Independently t he decomposition E a of CH 4 was found t o range from 280 380 kJ/mol in an experiment involving the deposition of pyrocarbon using CH 4 as the carbon source under similar experimental controls as in the ZrC system. 17 In addition, the pyrocarbon studies showed that gaseous hydrocarbons tend to decompose into a complex mixture of organic molecules in the form of liquid or plastic like droplets. Figure 1 2. Morphologies of ZrC films deposited from a ZrCl 4 CH 4 H 2 Ar s ystem. a) Film grown at 1573 K. b) Film grown at 1673 K. 14

PAGE 21

21 Th e s e studies help to explain the very different morphologies obtained from the deposition of ZrC (Figure 1 2) When the temperature is 1573 K or lower, the deposited films show column ar growth Each column terminates in a tip and grows larger towards its base. In c ontrast fil ms grown at 1673 K show an isotropic cauliflo wer like shape. The grain size of films grown above 1573 K are considerabl y larger than those which are gro wn below it. 14 This observation is consistent with morphologies of deposited carbon and its isotropic forms at these temperatures. 18 These observations seem consistent with others 19 that the growth rate of ZrC appears to be limited by the carbon deposition rate at temperatures above 1573 K. The observed morphologies can more readily be understood using this model. At 1573 K the CH 4 first decompose d to form plastic like droplets of C on the substrate surface. The droplets tend to be more dispersed as the temperature wa s not high enough for neighboring droplets to fuse to gether. This result ed in column ar growth as the zirconium or reduced ZrCl 4 then react ed at the carbon droplet. It wa s also believed that the needle tip of the column was then where more liquid droplets deposit, continuing the film growth at this temperat ure resulting in a slower growth rate. When the temperature is greater at 1673 K, CH 4 can decompose more readily a nd result ed in more plastic like droplets per unit area on the substrate surface Droplets could then also fuse together while some form of reduced zirconium dissolve d and react ed in the droplets. This wa s not a step wise proce ss, like a tomic l ayer d eposition. B oth the decomposition of CH 4 and reaction of zirconium happen ed simultaneously. P article size s tend to enlarge as the film growth r ate is much higher at elevated temperatures

PAGE 22

22 resulting in more of the materials coming into contact with one another more quickly via an increased transport rate 14 The results showed that the films grown from a Zr Cl 4 CH 4 H 2 system can be made much more conformal in coverage at temperatures higher tha n 1523 K. Conventional CVD of ZrC requires relatively high growth temperatures and thus limits the number of substrates that can tolerate such high temperature One su ch example is silica, which is used to make high brightness electron sources. It s melting temperature is 1414 C, too low for ZrC to be effectively deposited under conventional conditions. 20 In addition, ZrCl 4 or other halogen bearing sources of zirconium a re most often utilized as the zirconium source T hese halogens have a tendency to be incorporated into the film and can limit device effi ci ency. 21,22 L arge amount s of acidic halide waste are also generated under these conditions four equivalents of HCl for every mole of ZrCl 4 used, which can be hazardous on a large scale to humans, equipment, and the environment Thus, an alternative approach was sought to overcome these limitations. Metal Organic Chemica l Vapor Deposition ( MO CV D ) of ZrC The use of a single source precursor that contains only the requisite metal, carbon, and hydrogen is advantageous for CVD. The precursor only contains the desired atoms, so problems associated with halide contamination ar e eliminated. In MOCVD, the precursor i s carried through the deposition system either in a gaseous state or part as of an aerosolized mixture. The precursor is delivered to the substrate, which is heated to the requisite deposition temperature needed to decompose the precursor. The organic portion of the molecule then thermally decomposes leaving on ly the desired film behind on the substrate. The decomposition reaction itself is

PAGE 23

23 initiated at the substrate surface, which results in conformal coverage and does not have line of sight issues as in PVD. As with conventional CVD, gr owth rates are also a function of a variety of factors including identit y of the precursor, deposition temperature flow rate and carrier g as, and reactor design There are limitat ions on the metal organic precursors that can be used for the deposition of ZrC. Alkyl ligands placed on the zirconium center cannot contain any hydrogen atoms as hydride elimination occurs readily at room temperature from early transition metals. H e teroatoms in the ligands are avoided, as they can be incorporated into the film. The compound must also be sufficiently stable to be handled Tetramethyl zirconium, Zr(CH 3 ) 4 meets the criteria o f no hydrogens and no heteroatoms, however it cannot be used for deposition of ZrC as it readily decomposes at 20 C. 23 Tetraallyl zirconium is also known and does have hydrogens, b ut does not have the necessary geometry to eliminate them. It is also unable to be utilized for CVD as it decompose s re adily at temperatures above 20 C The most heavily studied alkylzirconium compound that meet s the c riteria above is tetraneopentyl zir conium Zr[CH 2 C(CH 3 ) 3 ] 4 (ZrNp 4 ) Figure 1 3 1,23 27 Figure 1 3. Tetraalkyl z irconium c ompounds. a) Tetramethyl zirconium. b) Tetraallylzirconium. c) Tetraneopentylzirconium. ZrC has been successfully deposited from ZrNp 4 under various conditions. Deposition using u ltra high vacuum has been done with so lid ZrNp 4 and applying heat and a base pressure of around 10 10 torr. 1 This was done as the vapor pressure of

PAGE 24

24 ZrNp 4 itself is very low, which makes it difficult to volatilize. Another route to overcome low volatility is to dissolve the material in a high boiling temperature organic solvent The solvent can be nebulized and carried to the deposition reactor in a process called aerosol assisted metal organic CVD (AA MOCVD). The carrier solvent then is removed under vacuum while traveling through the reactor, delivering an aerosol of ZrNp 4 to the substrate. 28 High Brightness Electron D evices Electron sources based on vacuum tubes have been around for many years, with the use of thermionic emission technology used for the last 30 years in high brightness electron sources. The Department of Defense currently operates over 170,000 of thes e tubes which are utilized in 272 applications in various fields. Devices such as the SPY 1 cross field amplifier system, high speed data communications in submarines, radar, sonar, and other electronic warfare systems make use of these vacuum tubes. The devices operate by the electrical generation of heat reaching a threshold temperature at which the flow of electrons across the system i s possible. Figure 1 4. Spindt t ype f ield e mitter c athode a rray Due to this parameter, the devices require high p ower consumption and have a emission technology is highly reliable, there exists a strong demand to decrease both

PAGE 25

25 the size of the devices and their power consumption. O ne p ossible alternative to this technology is the use of gated field emission arrays (FEAs) (Figure 1 4) 29 Gated FEAs provide a good alternative in that they have a near instant on capability and do not require time to heat prior to use. The units themselves operate cold and give off little heat of their own, consequently requiring much less heat dissipation equipment and lowering the overall size of the device. This results in space/weight savings over devices that employ vacuum tubes. Higher anode current is also possible from these devices while using less power overall. These reasons result in substantial savings over currently employed thermionic emission technology. Figure 1 5. FEA d evice f ailure. a) Arcing damage to tips and gate electrode. b) Dulling of e mitter t ips d ue to i on b ombardment. T he reliability of FEAs needs to be improved before the technology can be of general use. Some of the problems to be overcome are illustrated in Figure 1 5 29 In the first the gate film has melted and vapori zed, exposing the underlying SiO 2 film, thereby destroying the tips around the area. This cathode destruction can result in a partial or complete loss of system voltage from the array as a whole. Ion bombardment is also a problem attributed to ions being formed by electron beam ionization. These ions are accelerated and impact the field emitter surface, which can dull the emitter tip or lead to a nanopr otrusion on its surface. A nano protrusion is then capable of

PAGE 26

26 generating a large local emission field, which if intense enough, can cause a vacuum arc to occur and damage the cathode. Reliability of devices can be improved by lowering the operational voltage of the system, as this reduces the likelihood of the previously mentioned problems from occurring. This is done by either fabricating cathodes out of, or by coating conventional electrodes with a thin film of a low work function material. Certain carbides, borides, nitrides, and carbon based thin films have low work functions ranging from 2 3.5 eV. 30 When these materials are incorporated into a high brightness electron source, emission currents can be increased by a factor of 100, as shown in the use of conventional Si and Mo systems. This operational system w as successfully able to have its work function lowered from 4 eV to 3 eV, resulting in an overall current density increase from the system. 30 Of these low work function materials, ZrC is a promising candidate. Its bulk work function is between 2.0 2.2 eV and it has been demonstrated to lower the operational work function from 4.85 eV to 3.15 eV on a Si ( 100 ) tip array r esult ing in a voltage reduction of about 23% while maintaining the same current 6 When a Mo( 100 ) tip array was coated with ZrC its work function was lowered from 4.60 eV to 3.58 eV, resulting in a voltage reduct ion of 44 % while maintaining the same current In addition to the power savings, ZrC is also much more durable than many substrates, like Si. The melting point of ZrC is more than twice that of Si. 20 Its durability and wear resistance are profound with hardness values as high as 30.2 35.6 GPa. 7,9 Lastly, the resistivity of ZrC is around 10 4 lower than that of Si making it a very good candidate for incorporation into high brightness electron sources. 20

PAGE 27

27 CHAPTER 2 SYNTHESIS, CHARACTER IZATION, AND COMPUTA TIONAL ANALYSIS OF ALKYLZIRCON IUM COMPLEXES Background One of the most studied complexes for the MOCVD of ZrC is ZrNp 4 The molecule contains no hydrogens, is stable at temperatures reasonable for deposition, is reasonably volatile, and contains no heter o atoms which might contaminat e the deposited film. I t is a homoleptic compound containing only one type of ligand, the neopentyl group. The inclusion of only one type of ligand makes its decomposition study easier as fragmentation has limited options. Due to this, its stability and relative ease of synthesis, it has been the focus of decomposition studies conducted with the hope that knowledge of the decomposition mechanism can give insight into the MO CVD process. This may also lead to development of a new type of alkylzirconiu m compound as decomposition may lead to better understanding of ligand design A particular issue that has been of interest is how the final film Zr/C ratio is not 1:1 as expected; rather ratios of 1:2 to 1:5 have been reported. 1,26 28,31 Mechanis tic Analysis of ZrNp 4 Decomposition Early studies indicated that at a deposition temperature of 500 C, ZrC could be deposited in stable crystalline thin films as confirmed by XRD and XPS data. However AES data indicated that the Zr/C ratio was 1:2, despite efforts to lower it by controlling deposition parameters. 25 To help better understand this observed result ZrC was deposited on Ni substrates and further studies conducted The surface of these samples was then exposed to a set amount of ZrNp 4 below 125 K, to prevent premature ZrNp 4 decomposition. The films were then annealed at 275 K to remove the ZrNp 4 multilayers, achieving monolayer coverage 1

PAGE 28

28 The films were then placed in a n u ltrahigh vacuum (UHV) chamber and heated to higher temperatures while monitoring the effluent gas by MS. Around 410 K a simultaneous mass loss of 29, 41, and 57 amu wa s observed with mass loss of 15 and 16 amu occurring near 500 K (Figure 2 1) as measured by mass spectrometry 1 Figure 2 1. Thermal d esorption f ollowi ng a dsorption of ZrNp 4 on a n ickel f oil a fter a nnealing at 275 K p rior to s pectrum c ollection. 1 As the films have already undergone desorption, this can only be attributed to hydrocarbon cracking in the mass spectrometer, most likely from a single desorbing hydrocarbon. No direct peak of m/z 56, correspo nding to isobutylene, could be observed, making methyl elimination unlikely. Also, no Zr containing fragments were detectable. This makes the loss of fragments m/z 29, 41, and 57 likely to have come mostly from the loss of neopentane itself. This was very likely as surface IR confirmed

PAGE 29

29 the presence of surface bound neopentane. Loss of fragments of 15 and 16 amu has previously been attributed to loss of adsorbed methyl groups as well as smaller fragments from previous hydrocarbon cracking. One diffic ulty in using this UHV study as a direct correlation to the CVD of ZrC itself is that this study utilized a Ni substrate on to which a ZrC film was deposited with a Zr/C ratio of 4:1, while the samples obtained using a Si substrate had a ratio of 2:1. 1 It was shown that surface chemistry has at least some effect on the Zr/C surface stoichiometry. While not directly observing the loss of neopentane, the study indicated loss of neopentane appears to be necessary for further hydrocarbon cracking. Similar studies using TiNp 4 did report direct loss of neopentane and the deco mposition resulted in a Ti/C ratio of 1:0.93. 32 34 This raises the possibility that the decomposition of ZrNp 4 might undergo a different thermolysis mechanism than TiNp 4 2 3 Of specific interest is the initial decomposition step of the two complexes, which could occur by either or hydride abst raction. Computations conducted on TiNp 4 showed that hydrogen abstraction was favored over by an E a of 8 kcal/mol. 35 Experimental and further computational data were sought to identify t he initial decomposition step. To determine if the decomposition of ZrNp 4 proceeded by elimination, 2 and 3 were synthesized and used to deposit ZrC by CVD (Figure 2 2) Volatiles were collected by vacuum and analyzed by EI MS, 1 H NMR, and 13 C NMR. 23 Complex 2 was determined to generate neopentane and isobutene in a 2.3:1 ratio per mol of starting material. The deuterated isotopologues of neopentane evolved from 3 were determined to be 15% d 0 14% d 1 59% d 2 and 12% d 3 giving a ratio of 4.9:1 between the d 2 and d 3 species. The two possible unimolecular pathways that can give rise to a d 2 product are

PAGE 30

30 hydride elimination or a radical process generating Np 3 Zr and Np. However, there was no evidence for Np Np formation in the CVD of 3 This does not rule out the possibility of radical formation, but simply makes it a less likely candidate. Computations showed that the Zr C bond length is 0.15 longer than that of a Ti C bond in MNp 4 where M is Zr and Ti respectively. The shorter bond length was expected when comparing a first row metal complex to a second row. In addition, it was hydrogen abstraction was 5.2 kcal/mol lower in activation energy than hydrogen abstraction computationally. 23 Figure 2 2. Initial d ecomposition p athways of MNp 4 and ZrNp 4 d 8

PAGE 31

31 The large amount of Np d 2 present after deposition, absence of a Np Np dimer, hydrogen abstraction is the predominant pathway for initial decomposition of ZrNp 4 Lastly, overall 70.4% to 29.6 % molar amounts of neopentane and isobutene w ere found for the decomposition of 2 and that the ratio holds within experimental error for 3 suggesting that the two compounds undergo similar decomposition pathways. 23 Both major studies on the deposition decomposition pathway have focused on following the deposition of ZrC from ZrNp 4 by experimentally examining the gases after deposition has occurred and with computational analysis reinforci ng experimental results. Propargyl/Allenyl Zirconium Complexes The design and use of other alkylzirconium complexes that can potentially be used for MOCVD of ZrC has also been o f interest. The inability to have ligands with a hydrogen or the presence of heteroatoms severely limits the functionality that can be incorporated into the se molecule s One ligand group that had not received much examination is that of a propargyl group. Propargyl groups cannot undergo hydride elimination as they are completely unsaturated in the position. They also have unique structural and bonding characteristics that makes their potential usage chemically interesting. 36 A tautomerization exists between the allenyl and propargyl forms allowing for different modes of bonding to metals (Figure 2 3) 36 F igure 2 3. Tautomerization of a metal alle nyl and a metal propargyl c omplex.

PAGE 32

32 The ligands are capable of donating four electrons to the metal system through various of formation values of 42.2 kcal/mol for 2 C=C=CH 2 show that the free propargyl species is slightly more stable than the allenyl, 37 but studies have shown that the M allenyl bonds are stronger than the corresponding prop argyl metal interaction. In general, the allenyl tautomer is favored when placed on a metal system. 38 Several synthetic strategies 3 allenyl/propargyl metal complexes. 36 Figure 2 4. Synthetic r outes to 3 allenyl/propargyl m etal c omplexes. In Figure 2 4 ( Eq. 2 1 1 propargyl to the 3 allenyl/propargyl produc t via abstraction of a coordinated halide. This method has been applied to generate Pt(II) and Pd(II) complexes. 39 Equation 2 2 is a variant of this

PAGE 33

33 by abstraction of a 2 acetylene ligand 40 Another technique 2 propargyl alcohol or ether complex with a Lewis acid ( Eq. 2 3). 39 Lastly, equation 2 4 shows how reactions of early transition metal halide complexes with Grignard or related reagents hav e proven use ful 3 allenyl/propargyl complexes X r ay crystallography has been used to determine the structures of several 3 allenyl/propargyl metal complexes and some significant features are associated with attachment to the metal center (F igure 2 5 ). 36 In general, metal complexes with an 3 allenyl/propargyl ligand have a large distortion in the ligand with the C C C angle bent between 146 156 as compared to a linear fr ee alkyne moiety or a n 3 allenyl ligand angle of 120 36 This disparity is expected due to the electronic distortion at the centr al carbon Another difference is shown in 4 a versus 4 b In 4 a the metal is virtually coplanar with the three carbon skeleton compared to the 3 allenyl ligand being out of plane with the metal center in 4 b Figure 2 5. Bonding modes of 3 allenyl/propargyl metal complexes.

PAGE 34

34 The C 1 C 2 and C 2 C 3 bond lengths in ligands of the type in 6 are between 1.34 1.40 and 1.22 1.28 respectively different than that of the free alkyne in 5 which has distances of 1.47 and 1.20 41 respectively Complexes 7 8 9 illustrate the three possible 1 and 3 b o ndings of the allenyl/propargyl ligand itself. The bond l engths mentioned for 6 reduce the canonical structures to primarily those depicted in 7 and 9 36 Sy n thesis of Alkylzirconium Complexes The synthesis of alkyl substituted zirconium complex es was achieved using ZrCl 4 and the requisite Grignard or lithium reagents resulting in a series of alkyl halogen transmetalation react ions. Controlling stoichiometry of the alkylating reagent allow s for the synthesis of mono through tetra substituted complexes, depending on the desired molecule. The synthese s of the alkyl zirconium complexes utilized are outlined in Figure 2 6 42,43 and Figure 2 7 44 46 Figure 2 6. Synthesis of ZrNp 4 and ZrNp 3 Cl. Synthesis of 2 (Eq. 2 5) was achieved by literature procedures starting with the conversion of neopentyl chloride to the correspondin g Grignard which was then reacted with 0.25 equivalents of ZrCl 4 to afford the product in 70% yield. 42 The purified product

PAGE 35

35 was a white to off white air and moisture sensitive solid after sublimation. Complex 10 (Eq. 2 6) was sy nthesized by two methods. The literature method used neopentylmagnesium chloride in a 3:1 mixture with ZrCl 4 43 The resulting yield was poor, due to th e large amount s of impurities and separation was difficult. A second pathway used 2 as the starting material which was reacted with 0.33 equiv alents ZrCl 4 in ether overnight. 42 A bright yellow solid was obtained in 87% yield and was extr emely sensitive to light, air, and moisture. Figure 2 7. Synthesis of a llenyl/ p ropargyl z irconium c omplexes. Complex 11 was obtained in 74% yield based on ZrCl 4 from the synthesis shown in Figure 2 7 Phenylpropargyl alcohol was treated with PBr 3 to phenylpropargyl bromide 44 which was then converted to the corresponding Grignard 45 and reacted with 0.25 equiv alents of ZrCl 4 The product wa s a crystalline white solid that proved to be air and moisture sens itive Attempts to prepare c ompound 12 i n similar fashion (Eq. 2 8), 46 resulted only in a non isolable, air and m oisture sensitive compound.

PAGE 36

36 Results and Discussion Tetraneopentylzirconium (ZrNp 4 ) Studies In order to generate alkylzirconium precursors that can successfully deposit ZrC by MO CVD, it is helpful to understand how the precursor decomposes under deposition conditions. The insight provided by the isotopologue analysis from Xue 23 is very helpful in exa mining the decomposition of 2 and 3 experimentally and comparing it with computational data. It suggest ed that the initial decomposition step of 2 wa s hydrogen abstraction. However, the method employed collected and analyzed gasses from the entire depo sition experiment, not just the initial decomposition. Another way to analyze these compounds is the use of mass spectrometry. 47 49 CVD is a thermal process whereas mass spectrometry is ionic, and care must be taken to not rely too heavily upon such data to p redict CVD behavior as smaller fragments are not necessarily derived from larger ones. Mass spectrometry can however provide good insight into the relative fragmentation patterns of various single source organometallic precursors. 48,49 A CI MS of 2 w as obtained and the spectrum indicated a complex mixture of peaks that could not be assigned to appropriate decomposition pathways In addition, oxidized Zr alkyl peaks were also visible in the spectrum preventing accurate assignment. Compound 10 was synthesized with the hope that a similar MS analysis could be conducted on the compound to yield insight into a similar decomposition pa thway. However, 10 proved to be more sensitive tha n 2 as both light and the presence of solvents rapidly decomposed the complex rendering analysis impossible.

PAGE 37

37 Characterization of 3 Tetra( 3 p henylpropargyl) z irconium The characterization of the phenylpr opargyl compound 11 has yielded very interesting results. 1 H NMR data consisted of a single aliphatic methylene peak at 3.23 ppm. Comparisons can be made between 11 and 13 and 14 (Figure 2 8 ) 39,50 Figure 2 8 Other p roparylzirconium c omplexes. It was experimentally determined by variable temperature 1 H NMR that 13 contained two phenylpropargyl ligands on the zi r conocene with one being coordinated in an 1 fashion while the other exhibited an 3 mode of coordination The 1 H NMR spectrum of 13 had one signal for the CH 2 group at 2.80 ppm from 223 303 K. At 180 K, the signal decoalesces into two equal intensity peaks at 3.3 and 1.9 ppm, which were assigned to 3 and 1 coordination respectively. Confirmation of this was subsequently obtained with 14 as it only has one resonance at 3.37 ppm, corresponding to an 3 pro pargyl ligand Based on these chemical shifts, it seemed probable that the lone resonance i n the 1 H NMR spectrum of 11 corresponded to an 3 coordination of the phenylpropargyl ligand. While the reaction to synthesize 11 was conducted in a 4:1 ratio of Grignard reagent to ZrCl 4 the number of ligands on the zirconium center could theoretically be from four to six ( ZrR n=4 6 ) Any number n above four would result in an ate complex,

PAGE 38

38 with Mg 2+ as the counter ion. Also, formation of Zr dimers could have also been possible. The structure of 11 was determined by X ray crystallography to be a tetra( 3 phenylpropargyl)zirconium complex (Figure 2 9) The structure itself contains high symmetry, belonging to the D 2d point group. All four ligands are bound in an 3 fashion and are four electron donors, resulting in a 16 electron complex. Bond lengths for compari son to 14 are provided (Table 2 1 Table 2 2 ). Figure 2 9 Thermal e llipsoid d rawing of 11 Hydrogen atoms are omitted for clarity. Complexes 11 and 14 show structural similarities in that the C C C bond angles are 145.38(16) and 155.4(3) respectively. The Zr C1 bond length in 11 is shorter than that of 14 (Table 2 2) while the Zr C2 is about the same in both structures and Zr C3 is slightly longer in 14 A point of interest is that all Zr propargyl bond lengths in 11 are approximately the same length, differing by a net 0.09 overall, whereas those in 14 differ by a much larger value, 0.297 This is possibl y due to the large structural

PAGE 39

39 differences between the two as 1 1 has an electron count of 16, while 14 has an electron count of 18 and the phenylpropargyl ligand is sterically encumbered by two cyclopentadiene rings. This could rationalize the shorte r bond length along Zr C1 in 11 as the metal must rely more on the donation to gain electron density as it does n ot have the cyclopentadienyl system to draw upon. Table 2 1. Selected bond angles and distances for 11 Bond Angle ( ) C2 C1 Zr 70.08(9) C3 C2 C1 154.38(2) C3 C2 Zr 77.01(1) C4 C3 Zr 137.87(1) Zr C1 H1A 116.60(0) C2 C1 H1A 116.60(0) Bond Distance ( ) Zr C1 2.4955(2) Zr C2 2.4043(1) Zr C3 2.4474(2) C1 C2 1.3760(2) C2 C3 1.2490(2) C3 C4 1.4500(2) Table 2 2. Bond d istances ( ) in c rystal s tructure 14 C1 C2 C2 C3 Zr C1 Zr C2 Zr C3 1.344(5) 1.259(4) 2.658(4) 2.438(3) 2.361(3) *Uses the n umbering system as in compound 11 Data are taken from ref. 50 Complex 11 represents, to the best of the knowledge of the author, the first example of a homoleptic proparg y lzirconium complex and is also the first homoleptic propargyl metal complex synthesized to date. The interesting structural features

PAGE 40

40 present in the X r ay structure needed further exploration to determine the full extent of the system interaction with the metal center. Computational Analysis of 3 Tetra( 3 p henylpropargyl) z irconium Figure 2 10. Ti pentalene complex 15 Figure 2 11. Molecular orbital diagram of 15 51

PAGE 41

41 Group IV D 2d metal complexes with conjugated systems are known in the literature. 51 53 The pentalene complex 1 5 ( Figure 2 1 0 ) ha s a unique type of bonding that suggested an electron count of 20 for the metal. Calculations showed that was not actually the case, due to a folding distortion of the pentalene ring that resulted in an overall electron count of 18. 51 A molecular orbital (MO) diagram was generated from the computational analysis (Figure 2 1 1 51 ). Figure 2 12. 3 Dimensional stick model of 16 This interest led to preparation of the Zr and Hf versions of the bispentalene sandwich complex. 52,54 Isolation of the Zr(C 8 H 6 ) 2 complex was difficult as

PAGE 42

42 decomposition readily occurred at room temperature. 13 C NMR suggested an overall staggered structure of the two rings, but this could not be confirmed by X r ay analysis. 52 The complex system seen in 11 was analyzed by density functional theory (DFT) calculations (B3LYP/ LANL 2 DZ ) to better understand t he bonding shown in the X ray crystal st ructure. 55 58 Initial calculations were performed on 11 but the contribution of the phenyl rings complicated the results by delocalizing the molecular orbitals to such an extent that visualization of them was difficult. To help simplify the visualization, the phenyl rings were replaced with hydrogen to give 16 which is also of D 2d symmetry (Figure 2 1 2 ). Figure 2 13. Molecular orbital diagram of 16

PAGE 43

43 The molecular orbital diagram in Figure 2 1 3 was generated from the computational results The calculated HOMO LUMO gap was 5.2 eV. This was considerably larger than th at obtained for D 2d symmetric 15 which had a calculated band gap of 1.93 eV, 51 presumabl y due to the extensive conjugation in the molecule Such a large HOMO LUMO gap for 16 also helps explain the lack of color of the solid state in 11 which is a transparent to transluce nt white depending on the degree of crystallinity in the solid Figure 2 14. Degenerate HOMO orbitals of 16 The orbital contributions a nd images were also obtained. Select contributions are given below with the percent contribu tion listed in parentheses. The HOMO comprised of two degenerate orbitals, contains the p orbitals of the terminal carbons of the propargyl ligand that intersect the yz plane due to the interaction from the d zy orbital on Zr (20.7%) (Figure 2 1 4 ) The o ther degenerate orbital uses d xz of Zr (20.7%) instead. The HOMO 2 (not pictured) is mainly comprised of dz 2 on Zr (21.3%) and the xy plane of the p orbitals on the propargyl ligand

PAGE 44

44 The LUMO of 16 is mainly composed of many small interactions but has the strongest p orbital contributions from the central carbon in the propargyl groups. The largest contributions of Zr are s (14.2%) and dz 2 (6.2%) (F igure 2 15 ) The LUMO+1 is mainly comprised of the d xy orbital of Zr (76.1%). The LUMO+2 is comprised of two degenerate orbitals, one is composed primarily of d xz (25.3%) and the other d yz (25.3%), ( Figure 2 16 ) Figure 2 15. LUMO and LUMO+1 orbitals of 16 Left) LUMO. Right) LUMO+1. The somewhat mi nor contributions from the orbitals are to be expected as this compound has a large system which disperses electron density. However, this does give excellent insight as to which orbitals are involved in the bonding and allows for an intellectual constr uct to help better understand the orbital interactions. It is interesting that this early transition metal 16 electron complex does not have an empty coordination site due to its symmetry. Complex 11 was also crystallized from THF with vapor diffusion of pentanes and did not show any coordinated THF in either the 1 H NMR or the

PAGE 45

45 X ray crystal structure. It is also possible that the large steric bulk afforded by the phenyl rings helps to exclude coordinating solvents. Figure 2 16. Degenerate LUMO+2 orbit als of 16 An electronically similar system is found in tetra 3 allylzirconium. Although the complex was first reported in 1966 59 the complex is not well characterized owing to its ready decomposition at temperatures above 20 C. Spectroscopic 1 H NMR studies indicate d that the allyl ligands do undergo internal rotation about the methylene carbon at temperature s above 70 C The material itself is a bright red solid, indicating that the HOMO LUMO gap in the substance is low enough to allow LMCT. Compared with 11 which is a white solid at room temperature, the HOMO LUMO gap in tetra 3 allylzirconium must be c onsiderably lower. A solid state comparison between the two is not possible as tetra 3 allylzirconium decomposes when placed on a microscope slide even when kept cool. 60

PAGE 46

46 Conclusions Attempts at gaining insight in the decomposition mechanism of ZrNp 4 toward deposition of ZrC were undertaken with the synthesis of 2 and 10 however a suitable mass spectral analysis was unable to be obtained due to the high sensitivity of the compounds to air and moisture. The synthesis of 11 has yielded the first known example of a homoleptic propargylzirconium complex. The X r ay analysis has shown this complex to be structurally interesting with D 2d symmetry The extent of the system in bonding was investigated by computational analysis and indicated that the molecu le had an exceptionally large HOMO LUMO gap of 5.3 eV The high symmetry enabled wide dispersion of electron density greatly stabilizing the molecule. The HOMO was found to be comprised of two degenerate orbitals and the main orbital interactions with Zr are d yz and d x z respectively. The LUMO was found to be mainly focused around the central carbons in the propargyl ligands and comprised of s and dz 2 interactions with Zr. The LUMO +1 was found to be comprised of and d xy orbitals. The LUMO+2 was found to be degenerate and comprised of d xz and d zy orbitals.

PAGE 47

47 CHAPTER 3 TRANSITION METAL CATALYZED OXIDATIVE CARBONYLATION OF AMI NES TO UREAS Introduction and Background The presence of urea moieties in molecules of interest in a w ide range of fields and applications has stimulated interest in their synthesis. Much development into the synthesis of this particular functional group has occurred as it is seen in pharmaceutical s 61 65 agrochemical s precursors of resins, dyes and additives to both petrochemicals and polymers. 66 Of particular interest has been their usage as non protein based HIV protease inhibitors, CCK B receptor antagonists, and endothelin antagonists. 63, 67 70 Ureas themselves can also be synthons for other bulk chemicals by thermal cracking to yield isocyanates 71 or rea cting with alcohols to yield carbamates. 72 The traditional synthesis of ureas has been accomplished with th e nucleophilic attack of amines on phosgene and its derivatives or isocyanates 73,74 Phosgene is very reactive with both primary and secondary amines, and arrives at the product urea very well. However, phosgene is a highly toxic and corrosive gas that requires special handling and equipment. This has greatly discouraged its use in the laboratory setting. The production of phosgene on an industrial scale also includes serious risks to bo th safety of personnel and the environment in its usage, storage, and transportation. 75 Derivatives of phosgene are safer in all three of the above mentioned categories and include 1,1 car b onyl d i i midazole, triphosgene, and many others. These are more common f or use in laboratory scale synthesis than in industrial applications as each equivalent of phosgene derivative used produces two equivalents of the leaving group. The generatio n of a large waste stream of byproducts is problematic with phosgene

PAGE 48

48 derivativ es on an industrial scale, but not with phosgene itself as only aqueous chloride is produced Other synthetic methods employed to convert amines to ureas include reaction with isocyanates and chloroformates. Isocyanates themselves are mainly derived from phosgene and are very toxic. Phenyl c hloroformate has also been used but has drawbacks as DMSO is the required solvent. In both laboratory and industrial scales, DMSO poses large risks to its potentially carcinogenic nature and because of its high boili ng point making solvent removal very difficult. Synthesis of ureas with phosgene also poses other synthetic problems due to its high reactivity. Unwanted side reactions involving nucleophilic functional groups, such as hydroxyl groups, can be a problem an d require extensive protection/ d eprotection steps to avoid. Alternative routes have actively been sought that utilize either CO or CO 2 as the source of the carbonyl moiety. 75 These do not have the same problems of functional group compatibility and are genera lly safer to conduct especially upon scale up 76,77 The desire for catalytic systems as an alternative to stoich iometric reagents is evident and has been explored. Catalytic systems are also attractive from an atom economy 78 standpoint as catalytic oxidative carbonylation systems only employ amine, carbon monoxide, and some form of oxidant, which in turn only produces the reduced form of the oxidant and protons. 79,80 With this in mind, the McElwee White group reported the catalytic oxidative carbonylation of amines using a system comprised of W(CO) 6 as the catalyst, I 2 as the oxidant, and some form of base. This has been shown to convert primary amines 81 secondary amines 82 diamines, 83 and amino alcohols to the corresponding ureas in the

PAGE 49

49 presence of CO. 77 These reactio n conditions tend to be relatively mild and have been shown to be highly tolerant of various functional groups. 84 The use of the W(CO) 6 /I 2 system is advantageous as the reagents are readily available commercially and are easy to handle. It provides an excellent laboratory scale alternat ive to urea synthesis from phosgene and its derivatives given its compatibility with functional groups. The remainder of this work will focus on the applications of the W(CO) 6 /I 2 catalyzed carbonylation system to complex substrates. Transition Metal Catal ysts New synthetic methods for preparing carbonyl nitrogen bond moieties utilizing the metal catalyzed carbonylation of amines are numerous and extensively studied. Mono and dicarbonylation of amines have been reported as catalyzed by complexes of Mn, 85,86 Fe, 87 Co, 88 92 Ni, 93,94 Ru, 71,95 98 Rh, 89,98,99 Pd, 71,100 112 W 76,77,81 84,113 Pt, 114 Ir, 114 and Au. 115,116 The products of these carbonylations include ureas, 71,86,89,90 ,93,98 urethanes, 9 2,117 oxamides, 118 formamides, 119 123 and oxazolidinones. 92,124 The conditions reported for these, in general, include elevated temperatures and moderate to high pressures of CO. Highlighted advances in transition metal catalyzed oxidative carbonylation of amines will be presented in this section. Palladium Catalyzed Oxi dative Carbonylation of Amines The Tsuji group first reported Pd catalyzed carbonylation of amines in 1966. 109 Since then it has been extensively studied and recently reviewed. 71,80 Methods for oxidative carbonylation utilizing copper oxidant s or O 2 as the terminal oxidant and CuX or CuX 2 mediating have been utilized effectively with PdCl 2 to form ureas, 125 127 carbamates, 100,128 and oxamides. 100,129 131 Non metal oxidants have also been used effectively including desyl chloride to generate carbamates from In based alkylating

PAGE 50

50 reagents and PdC l 2 and phosphine ligands 111 The use of 1,4 dichloro 2 butene (DCB) as oxidant with the catalyst PdCl 2 (PPh 3 ) 2 has been found to affo rd ox amides while using the oxidant I 2 yield ed ureas from primary and secondary amines. 118 Heterogenous c arbonylations of a mines to u r eas The first oxidative carbonylations of alkylamines using Pd/C as a catalyst were reported by Fukuoka 132 and Chaudhari 133 The reactions were successful in the presence of promoter iodide salts and O 2 to afford ureas and carbamates in good yields. Simil arly, Gabriele reported the use of PdI 2 and O 2 for the formation of ureas and cyclic carbamates from amines 134 high yields and turnover numbers over 4900 were obtained ( Figure 3 1 ) 103,135 Figure 3 1. Oxidative c arbonylation of a lkylamines u sing a PdI 2 and KI s ystem. 103 Primary aliphatic amines (Eq 3 1, R = alkyl) were carbonylated at 100 C under elevated pressure with an atmosphere comprised of a 4:1:10 mixture of CO:air:CO 2 in the presence of a catalytic system comprised of PdI 2 utilizing KI as a promoter. The presence of CO 2 proved crucial to obtain higher yields. Solvent choice also dictated selectivity observed in the reaction. Urea for mation was favored by using di oxane and glyme, while the oxa mide predominated in much more polar solvents including N,N dimet h ylacetamide (DMA) or N methylpyrrolidinone (NMP). 135 It was postulated that the more polar solvents favored the formation of the intermediate Pd(CONHBu) 2 which then underwent reducti ve elimination to form the ox amide. Primary aromatic amines were also tested and found to be less reactive than their alkyl counterparts, unless

PAGE 51

51 electron donating groups were present on the aromatic ring increasing their nucleophilic i ty. When attempting to employ a similar system to the syn thesis of carbonates from phenylacetylene and MeOH, Whiting found the system too difficult to effectively control ( Figure 3 2) 112 While conditions were different than th ose for amines they found that product dis tribution and yield could be affected by concentration, stirring speed, and grain size and loading of PdI 2 Combined product yields only approached 52% and ineffectively produced four different products. Overall, the method could not be adapted effective ly to yield carbonates. Figure 3 2. Oxidative c arbonylation of p henylacetylene. Mechanistic s tudies The carbonylation of amines is generally thought to be carried out by a Pd(II) complex that is usually reduced to Pd(0) in the process. 71 Only a single case of the formation of a Pd(IV) complex has been reported. 136 It has been shown that direct oxidation of Pd(0) by O 2 is possible, but is too slow to prevent precipitation of metallic Pd under carbonylation conditions. 137 This necessitates that a co cata lyst be used to act as an oxidation catalyst for Pd. Shimizu and Yamamoto conducted a mechanistic study focusing on the role of reoxidation of the Pd(0) species formed in the principal catalytic cycle to electrophilic Pd(II) ( 17 ) during the selective carbonylation of amines to oxamides and ureas. 118 It was found t hat using DCB afforded oxamides and I 2 resulted

PAGE 52

52 in the formation of ureas selectively. The independent generation of the carbamoyl palladium complex 18 as a model species also generated further i nsight into the catalytic cycle ( Figure 3 3 ) 135 Figure 3 3. Postulated Pd c atalytic c ycle for Eq. 3 1 The study discussed two possible mechanisms for the conversion of primary amines to u reas by Pd catalyzed carbonylation. The first proposed mechanism involves the reductive elimination of a carbamoyl or amido ligand to generate the urea, in conjunction with work by Alper. 129 The second possible route is crucially dependant upon the formation of the alkyl isocyanate from the carbamoyl palladium species 18 The urea is then generated through nucleophilic attack by either a primary or secondary amine on the i ntermediate isocyanate to generate either a symmetric or unsymmetrically substituted urea, as based on work by Gabriele on a similar system. 135 It was found that diethylamine, dibutylamine, and morpholine, all secondary amines, were unreactive under the same conditions as their primary counterparts. 118 This supports the isocyanate pathway as secondary amines are unable to form tetra

PAGE 53

53 substituted ureas. Further support comes from tri substituted ureas being synthesized u pon carbonylation of mixtures of both primary and secondary amines. Lastly, trace isocyanates have been detected with GLC, TLC, and GLC/MS in the reaction mixtures of low conversion experiments. 135 Dire ct catalytic preparation of tri substituted ureas i n high selectivity is difficult, but made possible under th ese conditions by carbonylation of the primary amine in large excess of the less reactive secondary amine. 103 This prove d effective for many urea type derivatives, especially cyclic ureas from pr imary diamines and N N bis(meth oxyca rbonylalkyl)ureas from primary amino esters. The synthesis of 19 the neuropeptide Y5 receptor antagonist NPY5RA 972 was showcased utilizing this method ( Figure 3 4 ). 103 Figure 3 4. Synthesis of NPY5RA 972 u sing Pd c atalyzed o xidative c arbonylation. Other Late Transition Metal Catalysts Nickel c atalyzed o xidative c arbonylation Based on previous development of Pd catalyzed oxidative carbonylations, efforts were m ade to use Ni as an inexpensive alternative. Nickel complexes ha ve already been shown to yield stable carbamoyl derivatives upon carbonylation, suggesting that they could make potentially good candidates for oxidative carbonylation of amines. 93 Rather than the expected oxamides, 94 Giannoccaro obtained N N dialk y lureas from the

PAGE 54

54 reaction of primary amines with the nickel amine complexes NiX 2 (RNH 2 ) 4 (X = Cl, Br; R = alkyl). At temperatures above 50 C side reactions became competitive Figure 3 5. Nickel c atalyzed o xidative c arbonylation of a mines. At l ower temperatures the reductive elimination of the oxamide did not occur S electivity between urea and ox amide was accomplished by controlling the amount of water present in the reaction. The presence of water afforded urea formation and anhydr ous conditions yielded oxamide ( Figure 3 5 ) 93 It was suggested that under aqueous conditions, water could coordinate to the Ni cente r and prevent more than one carbamoyl from form ing This intermediate would then be susceptible to nucleophilic attack from free amine, yielding the urea. Without the presence of water, two carbamoyls can form and reductively eliminate to form the oxamid e. 93 Ruthenium c atalyzed o xidative c arbonylation The oxidative carbonylation of aniline catalyzed by [Ru(CO) 3 I 3 ]N Bu 4 utilizing NiI as the promoter forms N,N diphenylurea (DPU) 99% selectively, as shown by Gupte 98 The key step ( Figur e 3 6 ) is the formation of the carbamoyl ruthenium intermediate 24

PAGE 55

55 Loss of CO from the catalyst precursor [Ru(CO) 3 I 3 ] 20 generates the ruthenium dicarbonyl intermediate 21 which then become s susceptible to nucleophilic attack by aniline to form the amino rut henium dicarbonyl species 22 and HI. Addition of CO to produce 23 is followed by insertion to afford the carbamoyl complex 24 This then reacts with aniline to form both the product urea and the hydrido carbonyl species 25 Addition of aniline yields 26 which is oxid ized by O 2 to regenerate the active species. 98 Similar r esults utilizing alkylamines have also been reported. 133,138 Figure 3 6. Oxidative c arbonylation of a rylamines u sing r uthenium c atalysts. 97 Cobalt and r hodium c atalyzed o xidative c arbonylation The synthesis of acyclic and cyclic ureas from primary aromatic amines was accomplished by Rindone using N N bis(salicylidene)ethylenediaminocobalt(II)

PAGE 56

56 [Co(salen)] as catalyst. 90 No single set of reaction conditions could be obtained that w a s effective for multiple substrates. The pressure of O 2 a ffect ed the yield of urea as high pressures worked well for 4 methylaniline but considerably lower pressures were more effective for 4 fluoroaniline. In general, electron withdrawing groups in the para position lowered conversion of the starting amine. It was also found that electron donating groups in the ortho position increased conversion as 2 aminophenol was more reactive than other amines. 139 Fi gure 3 7. Cobalt ( s alen) c atalyzed o xidative c arbonylation of a rylamines. The proposed mechanism ( Figur e 3 7 ) involved the planar salen complex 27 being in equilibrium with the Co(III) amido complex 28 Carbon monoxide can then insert into either complex generating another equilibrium mixture between 29 and 30 The trans geometry between the carbamoyl and the amine ligands could then lead to either free isocyanate or carbamates from 29 The non planar species 30 has a cis relationship between carbamoyl and amine ligands, which could then lead to urea formation.

PAGE 57

57 Figure 3 8. Co(salen) and m odified Co(salen) c omplexes 3 1 35 Further studies on Co(salen) complexes led to the development of many new ligands to yield complexe s capable of oxidative carbonylation. Compounds 3 1 and 3 2 were both found to yield diphenylurea and 3 2 even does so 100% selectively in the presence of butanol 140 The phenanthroline derivative 3 3 also was found to give 94% selectivity for the urea. Sun and Xia recently used 3 1 to produce cyclic carbamates in high yields from corresponding amino alcohols, but the substrates were limited to using aliphatic functionality only. 92 By using 3 4 they were also successfully able to cyclize substrates containing isopropyl groups in 91% yield, which has been shown to be difficult under other circumstances. 83 Recently, i n an effort to better increa se catalyst

PAGE 58

58 recovery, Co(salen) catalysts were covalently bonded to a silica matrix via a sol gel process. 88 The het erogeneous catalyst 3 5 was used for the oxidative carbonylation of carbamates from aniline and methanol. While the reaction only produced a 60% yield of carbamate, it was able to be recovered five times with only a small drop in catalytic activity to stil l afford the product in 50% yield Figure 3 9. Rh c atalyzed o xidative c arbonylation of a niline to DPU. 141 Investigations of rhodium catalyzed carbonylation of amines to ureas have been sparse recently. Chaudhari initially used Rh/C NaI to make carbamates, but found some conditions that favored formation of ureas. 142 However, DMF was required as solvent to achieve urea synthesis, and all other sol vents tested gave the carbamate product Giannoccaro found that materials containing simple Rh 3+ salts worked well for carbonylation of aniline to form DPU. The catalytic system worked better when inter calated with titanium phosphate to make a heterogeneous system. A mechanism was postulated ( Figure 3 9 ) and the key intermediate appears to be the Rh 3+ carbamoyl

PAGE 59

59 complex 3 6 which reacts with I 2 to form the iodoformate intermediate 3 7 Another molecule of aniline then reacts with 3 7 to form DPU. 141 Attempts t o further increase reactivit y led to a bimetallic system. As heterogeneous catalysts with rhodium worked better than homogenous, a Co 2 Rh 2 /C complex was made The strategy behind this was to immobilize nanoparticles of the metals in close proximity to one another for the oxidative c arbonylation of amines using molecular oxygen as the oxidant 89 This relied on the high surface area to volume ratio that makes nanoparticles very reactive in these catalytic systems The product urea s of aliphatic amines were obtained in good yields with butylamine giving 84% isolated urea and benzylamine generating 74%. Primary aromatic amines were also successful with aniline yielding 81% urea. Para substituted anilines were well tolerated, with p tert butyl giving 80% isolated product Even allyl amine could be tolerated and was carbonylated in 44%. Recyclability of the heterogenous catalyst proved problematic as the yield of di n butylurea dropped to 31% after the fourth attempt. As less than 0 .2% of the metals on a molar basis were found to have le a ched, the loss of activity could not be adequately explained. 89 A different mechanism also appears to be operative from traditi onal Co oxidative carbonylation but has not yet bee n determined. Gold c atalyzed o xidative c arbonylation Gold catalysts for the oxidative carbonylation of amines have also been investigated and recently reviewed 115,116,143 Simple Au I salts formed carbamates from aniline, but aliphatic amines could be used to generate ureas. 115 Better results were obtained with polymer immobilized gold catalysts using arylamines to generate their methyl carbamates in the pres ences of methanol. 116 Ureas could be obtained only in the absence of methan ol. The polymeric catalyst also showed enhanced activity and

PAGE 60

60 ease of separation from the product compared to those gold catalysts previously reported. It was later shown that this reaction is capable of forming dialkylureas in high yield with high turnov er frequencies, and worked in the presence of CO 2 as reactant ( Figure 3 10 ). 143 The exact mechanism for this reaction is still unknown. Figure 3 10. Polymer s upported Au c atalyzed c arbonylation of a mines. Tungsten Catalyzed Oxidative Carbonylation of Amines Carbonylation of p rimary a mines Examples of Group 6 metal complexes for the catalytic carbonylation of amines are rare. The initial report by McElwee White utilized primary amines for catalytic oxidative carbonylation using the iodo bridged tungsten dimer [(CO) 2 W(NPh)I 2 ] 2 ( 3 8 ) as the precatalyst (F igure 3 11) 81 Those studies showed that primary aromatic and aliphatic amines could be carbonylated to the corresponding disubstituted u rea, while secondary amines yielded modest amounts of formamides. Mechanistic studies determine d that primary amines reacted stoichiometrically with dimer 3 8 to yield the amine complexes (CO) 2 I 2 W(NPh)(NH 2 R), 3 9 In the presence of an oxidant, t hese unde rgo nucleophilic attack by excess free amine to give the ureas. 81 The carbonyl ligand in 40 is susceptible to nucleophilic attack followe d by proton abstraction from a second equivalent of amine to afford 41 The reaction mixture w as tested by FT IR and indicated the presen ce of a carbamoyl species, as precedented from results from Angelici on the carbonylation of methylamine by [( 5 C 5 H 5 )W(CO) 4 ]PF 6 144 I n that case, i t was shown that the first step is conversion of [( 5

PAGE 61

61 C 5 H 5 )W(CO) 4 ] + to the carbamoyl complex ( 5 C 5 H 5 )W(CO) 3 (CONHCH 3 ) after reaction with two equivalents of CH 3 NH 2 Figure 3 11. Mechanistic s tudies u sing 3 8 Assignmen t of the next step as oxidation was also supported by IR spectra showing the disappearance of the carbamoyl stretches upon exposure of the reaction mixture to air. Oxidation of 41 is expected to make the carbamoyl proton more acidic, thus enabling excess amine to deprotonate it to afford in the isocyanate complex 42 Free amine woul d then be able to nucleophilical ly attack either coordinated or free

PAGE 62

62 isocyanate to afford the disubs tituted urea and also the coordinatively unsaturated complex 43 Addition of CO would then regenerate the cationic species 40 and complete the catalytic cycle. These results suggested that other tungsten carbonyl iodide complexes might also serve as catal yst s The choice to test W(CO) 6 as precatalyst was simple as it is commercially available, inexpensive, and air stable. Preliminary reactions using W(CO) 6 100 equivalents of n butylamine, 50 equivalents of iodine, and 100 equivalents of K 2 CO 3 in a 125 m L Parr high pressure autoclave pressurized with 100 atm CO produced di n butylurea in 80% yield with respect to amine, corresponding to 39 turnovers per equivalent of W(CO) 6 Table 3 1. Oxidative c arbonylation of primary a mines to u reas u nder o p t imized c onditions Amine Product %Yield in CH 2 Cl 2 90 84 53 55 72 0 The W(CO) 6 /I 2 system was subsequently optimized with n propylamine and it was found that N N disubstituted ureas could be obtai ned in good to excellent yields ( Table

PAGE 63

63 3 1 ) 70 After determining that a 2 mol% catalyst loading was ideal, other variables were examined. Overall optimal conditions were found to be 90 C, 80 atm CO, 1.5 equivalents of K 2 CO 3 and chlorinated solvents such as CH 2 Cl 2 or CHCl 3 Aniline could not be successfully converted to DPU under any conditions tested, presumably due to its lower nucleophilicity as an aryl amine. Carbonylation of p rimary and s econdary d iamines to c yclic u reas Known methods for converting diamines to the corresponding cyclic ureas generally involve use of stoichiometric reagents based on nucleophilic attack of amines on phosgene and its derivatives. 73,74 The tr ansition metal catalyzed synthesis of cyclic ureas has not received much attention. The use of Mn 2 (CO) 10 for the catalytic carbonylation of diamines to cyclic ureas from H 2 N(CH 2 ) n NH 2 was successful only when n = 3, to make the six membered ring, and in on ly 6% yield. This lack of success with other systems lead to the use of the W(CO) 6 /I 2 system using high pressure CO as the carbonyl source as an alternative Primary and secondary diamines were both examined and found to yield the corresponding N N disubstituted cyclic ureas. Figure 3 12. W(CO) 6 c atalyzed o xidative c arbonylation of d iamines. When using primary diamines, five six and seve n membered cyclic ureas could be fo rmed in moderate to good yields (Figure 3 12) 83 The highest isolated yields were for six membered cyclic ureas, with only trace amounts of the eight membered ring compound being detected in the reaction mixt ure. This was not surprising as there are

PAGE 64

64 no reports in the literature of the preparation of this compound from 1,5 pentanediamine. A 2 i midazolidinone derivative could be synthesized using this method from (+) (1 R ,2 R ) 1,2 diphenyl 1,2 ethanediamine in 4 6% yield. Secondary diamines of the form RNHCH 2 CH 2 NHR ( Figure 3 12 R Me, Et, i Pr, Bn) under similar conditions resulted in the formation of the corresponding N N disubstituted cyclic ureas. The formation of oligomers upon carbonylation of both primary and secondary diamines was problematic, but could be overcome by employing high dilution. This strategy also been reported in the use of phosgene and its derivativ es with diamines. 145 An examination of steric effects on the ring closure was also undertaken using N N dimethyl, diethyl, diisopropyl, and dibenzyl diamines under the standard conditions yielding both the dimeth yl and diethyl cyclic ureas in nearly identical yields. The use of benzyl groups had only a minor lowering effect on the yield, but the use of isopropyl groups drastically lowered the yield of the imidazolidinone to only 10%. These steric effects could not be overcome by raising reaction temperatures. An interesting competition experiment yielded that when N methylpropanediamine was reacted under the oxidative carbonylation conditions the corresponding monosubstituted N methyl cyclic urea was formed in preference to acyclic urea formation through the much more reactive primar y amine 83 Further optimization of the carbonylation cond ition s for the conversion of diamines to cyclic ureas used propane 1,3 diamine, W(CO) 6 as catalyst, and I 2 as the oxidant for tests of solvent effects and temperature variation. 70 Additional experiments on the effect of alkyl substituents in the linker of p rimary diamines were conducted ( Table 3 2 ) 83

PAGE 65

65 Table 3 2. Tungsten catalyzed oxidative carbonylation of substituted primary diamines Amine Product % Yield 52 80 70 48 50 33 38

PAGE 66

66 Simple n alkyl substitution had dramatic effects on cyclic urea formation. 2,2 D ialkyl 1,3 propanediamines gave increased yields as compared to the parent propane 1,3 diamine as a result of the Thorpe Ingold effect 146 and the enhanced solubility of the product resulting in simplification of the reaction workup. The carbonylation of N N dialkyl 2,2 dimethylpropane 1,3 diamines afforded tetrasubstituted ureas, but only in modest yields. Tetr ahydropyrimidine byproducts were formed in significant amounts when the N alkyl substituents were larger tha n methyl. When compared to the results obtained with carbonylations of secondary diamines to form five membered cyclic ureas, the effects of the di methyl substitution on ring size and those of the N substituents are complex. As cyclic ureas could be synthesized from the corresponding diamines, more complex synthetic targets were considered. However, no experiments on functional group tolerance had b een conducted, and this tends to be an issue with early transition metals. Functional group compatibility was examined using a series of substitute d benzylamines (Figure 3 13 ). 84 Figure 3 13. W(CO) 6 c atalyzed c arbonylation of s ubstituted b enzylamines. The groups tested (Table 3 3 84 ) demonstrated that the oxidat ive carbonylation of amines using the W(CO) 6 /I 2 system was tolerant of a wide variety of functional groups. Amines containing s ubstit uents such as halides, esters, alkenes, and nitriles on the benzyl amine were successfully carbonylated to the correspondi ng ureas in moderate to good yields.

PAGE 67

67 Table 3 3. Catalytic carbonylation of substituted benzylamines to ureas Amine % Yield [a] Yield [b] Amine % Yield [a] % Yield [b] 63 73 36 55 35 77 0 37 30 77 41 69 39 70 41 69 47 70 37 68 24 81 28 14 5 58 17 20 0 0 a Reaction conditions: amine (7.1 mmol), W(CO) 6 (0.14 mmol), I 2 (3.5 mmol), K 2 CO 3 (10.7 mmol), CH 2 Cl 2 (20 mL), 70 C, 80 atm CO, 24 h. b The solvent was CH 2 CH 2 (21 mL) plus H 2 O (3 mL). Other conditions are as in footnote a. 84 The presence of u nprotected alcohols had been shown to be a problem using phosgene derivatives, 84 however this was not the case in the tungsten system. Changing the reaction medium to using a biphasic solvent system produced a dramatic change in the yields of these functionalized ureas. This system pr ovided solubility for

PAGE 68

68 the starting amine, catalyst, the hydroiodide salt of the start ing material formed from proton scavenging, and the K 2 CO 3 base. Phase transfer conditions provided with this system then allowed for the amine salt to be deprotonated by aqueous carbonate, re forming the free amine and allowing it to return to the organic phase for carbonylation. After it was determined that the W(CO) 6 /I 2 catalyzed system was tolerant of a broad range of functional groups in the conversion of amines to ure as, 84 use of this methodology to install the urea moiety into the core structure of the HIV protease inhibitors DMP 3 23 and DMP 450 was investigated (Figure 3 14 ). 147,148 Due to the large amount of literature present on the two synthetic targets, a direct comparison of the known routes using phosgene derivatives w ith the W(CO) 6 /I 2 catalyzed system was possible Figure 3 14. Structures of DMP 323 and DMP 450. The use of an O protected diamine diol to install the urea moiety of DMP 323 and DMP 450 by reaction with phosgene or its derivative had been reported. Sma ll scale syntheses for initial testing were carried out using the phosgene derivative 1,1 carbonyldiimidazole (CDI) followed by N alkylation as appropriate. 148 151 On a practical scale, preparation of DMP 4 50 involves the reaction of a secondary diamine with phosgene to form the cyclic urea, as t he use of stoichiometric CDI is cost prohibitive

PAGE 69

69 As using both phosgene and CDI required protection of the diol, much effort h as been put into studying protecting groups in the stoichiometric reactions 149,152 As a comparison O protecting groups acetonide, MEM ether, and SEM ether were tested in the catalytic carbonylation of diamine diols ( Figure 3 15 ) 76 The oxidative carbonylation of substrates 44 46 to cyclic ureas 47 49 by the W(CO) 6 catalyzed process allow e d for a direct comparison to reactions conducted with the stoichiome tric reagent CDI. Yields of the product were dependent on the identity of the protecting group in both the catalytic system and the stoichiometric one ( Table 3 4 ) 76 These results show that the tungsten system can be used in preparation of complex targets. Figure 3 15. Carbonylation of 44 46 Table 3 4. Tungsten c atalyzed o xidative c arbonylation of 44 46 to u reas 47 49 Diamine Reagent Solvent Urea % Yield Ref. 44 CDI CH 3 CN 15 149 44 CDI TCE 67 149 44 W(CO) 6 /CO CH 2 Cl 2 /H 2 O 38 76 44 W(CO) 6 /CO CH 2 Cl 2 23 76 45 CDI CH 2 Cl 2 62, 76 148,150,153 45 W(CO) 6 /CO CH 2 Cl 2 /H 2 O 49 76 46 CDI CH 2 Cl 2 52, 93 148,150 46 W(CO) 6 /CO CH 2 Cl 2 /H 2 O 75 76

PAGE 70

70 The formation of oxazolidinones 51 and 52 resulted from the tungsten catalyzed carbonylation of the unprotected diamine diol 50 ( Figure 3 16 ). 77 While previous results on substituted benzyl amines had indicated the stability of unprotected OH groups, this was not observed in the synthesis of DMP 323 or DMP 450. However, t he formation of oxazolidinone as t he major product was also reported in the reaction of 50 with both CDI and phosgene. 154 During the functional group tolerance experiments, the formation of carbamates was not possible due to geometric constraints owing to the 1 ,4 substitution pattern thus favoring urea formation only. 84 With this constraint removed in 50 oxazolidinone formation was preferred over that of the urea. Figure 3 16. Carbonylation of a mino a lcohols to f orm c yclic c arbamates. To further understand the limitations of the W(CO) 6 /I 2 catalyzed system, 1,2 1,3 1,4 and 1,5 amino alcohol substrates were subjected to W(CO) 6 catalyzed oxidative carbonylation to see if carbonate, carbamates, or urea formation was preferred (Table 3 5) 77 The varying su bstitution patterns and tether lengths al so made it possible to probe whether formation of cyclic or acyclic ureas was preferred. A direct comparison to phosgene derivatives was sought with stoichiometric reagents CDI and dimethyl dithiocarbamate (DMDTC). 77 The carbonylation of amino alcohols using the W(CO) 6 /I 2 catalyzed system favored urea formation over that of the cyclic carbamates, even in the presence of

PAGE 71

71 unprotected OH groups, with respect to all tether sizes and sub stitution patterns tested. Neither acyclic carbonates or carbamates were detected as products In comparison, carbonylation using the phosgene derivatives CDI and DMDTC resulted in variable selectivities between ureas and cyclic carbamates in the case of 1,2 and 1,3 amino alcohols Optimized conditions for the W(CO) 6 /I 2 catalyzed carbonylation of amino alcohols to ureas involved the use of pyridine as the base removing the need for the biphasic solvent system originally utilized in the functional group compatibility experiments. 84 Table 3 5. Carbonylation of a mino a lcohols to u reas and c arbamates 77 Substrate Reagent Urea (%) Cyclic Carbamate (%) W(CO) 6 /CO CDI DMDTC 64 80 45 2 Trace 0 W(CO) 6 /CO CDI DMDTC 93 70 93 0 Trace 0 W(CO) 6 /CO CDI DMDTC 95 36 30 Trace 60 8 W(CO) 6 /CO CDI DMDTC 72 49 34 14 30 47 W(CO) 6 /CO CDI DMDTC 60 55 32 5 28 29 W(CO) 6 /CO CDI DMDTC 78 18 72 10 22 Trace W(CO) 6 /CO CDI DMDTC 79 30 73 14 52 Trace Other synthetic targets that were prepared using the W(CO) 6 /I 2 catalyzed carbonylation methodology included biotin and related heterocyclic ureas. More commonly known as Vitamin H, biotin is produced on an industrial scale as a n additive

PAGE 72

72 to the diet of poultry and swine Synthesis of biotin has been extensively studied, 155 and the reports commonly employ the formation of the urea moiety by the reaction of phosgene with a diaminotetrahydrothiophene derivative. Biotin itself could not be obtained directly from the parent carboxylic acid, 53 but t he biot in methyl ester was obtained in 84% yield upon W(CO) 6 catalyzed oxidative carbonylation of substrate 54 (Figure 3 17) 156 Figure 3 17. Synthesis of the b iotin methylester 56 Heterocycles related to biotin, ( 57 60 Figure 3 18 ) 156 were also prepared via the W(CO) 6 catalyzed pathway and compared to reaction of the same substrates with CDI. Solubility of the diamine in dichloromethane appears to have a direct effect upon conversion of the diamine to the corresponding urea resulting in moderate to good yields of the product (Table 3 6) 156 Figure 3 18. Carbonylation of h eterocycles 57 60

PAGE 73

73 Table 3 6. Yield of b icyclic u reas f rom d iamines 57 60 Amine Urea W(CO) 6 /I 2 % Yield CDI % Yield 57 61 Trace 20 58 62 47 67 59 63 46 37 60 64 57 56 Conclusions The use of transition metal catalyzed carbonylation of amines offers efficient methodology to selectively synthesize ureas using mild reaction conditions. Being able to utilize CO as the carbonyl source directly, in the presence of both a catalyst and an oxidant, provides an effective alternative to traditional synthetic methods that employ stoichiometric reagents such as phosgene or phosgene derivatives while maintaining selectivi ty, or even increasing it, for the formation of ureas from amines. T he replacement of phosgene and the minimization of the waste streams associated wi th phosgene derivatives result in a greener alternative having less environmental impact Many transition metal complexes have successfully been employed in the carbonylation reactions, such as those of Pd, Ni, Co, Rh, and Au These catalysts have been sho wn to afford ureas from amines, in both homogeneous, and more recently developed, heterogeneous processes Tungsten catalyzed oxidative carbonylation of functionalized amines has also been shown to be effective in the synthesis of complex targets such as the core structure of DMP 323 and DMP 450 and biotin.

PAGE 74

74 CHAPTER 4 CATALYTIC OXIDATIVE CA RBONYLATION OF AMINO AMIDES TO PROD UCE HYDANTOIN DERIVATIVE S Background Considerable attention has been given to the synthesis of hydantoins and cyclic ureas as they are frequently found as crucial moieties in many biologically active molecules with pha rmaceutical relevance. Hydantoi ns substituted at the C 5 position (Figure 4 1) are important to medicinal chemistry as the heterocyclic derivatives are associated with a wide range of biological properties including anticonvulsant, 157 antidepressant, 158,159 antiviral, 158,159 and platelet inhibitory activities. 160 Figure 4 1. Numbering s ystem for h ydantoin r ings. Classic Ways to Synthesize Hydantoins Various synthetic methods exist to prepare hydantoins from diverse starting materials. Reference s to solution phase syntheses and polymer bound solid phase organic synthesis can be found in the literature. 161 165 Different strategies have been employed to prepare the core structure including the use of urea s cyanates, and phosgene reagents (Figure 4 2). 166 Hydantoins can be prepared from ureas and carbonyl compounds as reported by Beller 167 utilizi ng methodology developed by Blitz (Figure 4 2a) The reaction of carbonyl compounds with inorganic cyanide incorporates the second nitrogen a nd carbonyl units to afford the hydantoin in the Bucherer Bergs route (Figure 4 2b). The

PAGE 75

75 Read type reaction uses amino acid derivative s with inorganic isothiocyanate (Figure 4 2c) to yield hydantoins with hydrogen only at N 3. The use of alkyl or aryl iso(thio)cyanates (Figure 4 2d) allows for substituents at N 3. Amino amides can be used to introduce the last carb onyl, C 1, into a substrate already containin g two carbons and two nitrogens (Figure 4 2e) with phosgene Lastly, using halo amides and inorganic isothiocyanates can also afford a substituent at N 1 (Figure 4 2f) 166 Figure 4 2. Synthetic approaches to h ydantoins.

PAGE 76

76 Solution P hase S yntheses The Bucherer Bergs synthetic method is commonly used in the synthesis of hydantoins to yield a 5 substituted ring employing aldehydes and ketones. This route uses potassium cyanide and ammonium carbonate with the requisite carbonyl compound as shown in the preparation of the aldose reductase inhibitor sorbinil ( 67 ) in which the absolute stereochemistry of the product is set using the alkaloid b rucine ( Figure 4 3 ). 161 Figure 4 3. Preparation of s orbinil ( 67 ) For the synthesis of both hydantoins and thiohydantoins, the Read synthesis is also frequently used, as illustrated by Smith in the synthesis of a silicon containing hydantoin startin g from the silylated amino acid 68 Treatment with potassium cyanate in pyridine followed by subsequent acid cyclization afforded hydantoin derivative 70 ( Figur e 4 4 ). 162 Figure 4 4. Synthesis of h ydantoin 70 Both the Bucherer Bergs and Read type methodologies have long been applie d to the synthesis of hydantoins, but as more hydantoin derivatives have show n biological

PAGE 77

77 activity, alternative methods have been of increasing interest Among these is the synthesis of thiohydantoins. 163 The product thiohydantoin was afforded from an amino acid amide and reaction with a carbon sulfide. Amino amide 71 was treated with di 2 pyridylthiocarbonate (DPT) in THF at room temperature to yield the disubstituted hydantoin 72 ( Figure 4 5 ). Figure 4 5. Synthesis of t hiohydantoin 72 1,5 D isubstituted hydantoins ca n also be produced from other heterocyclic compounds. Aziridinone 73 can be used with cyanamide to yield the iminohydantoin intermediate 74 which is then treated with HNO 2 to a fford the disubstituted product 75 ( Figure 4 6 ). 168 Figure 4 6. Sy nthesis of h ydantoin 75 Phosgene and its derivatives have also been employed in the synthesis of carbonyldiimidazole (CDI) to yield several enantiomer i cally pure hydantoins from amino amides derived from amin o esters 165

PAGE 78

78 Solid P hase S yntheses The development of solid support systems capable of synthesizing str ucturally challenging heterocycl es bearing one or more nitrogen atoms has received much attention in the last decade. A recent review by Gutschow addresses some of the more recent examples in this area that synthe size hydantoins via solid phase organic synthesis (SPOS). 166 A rather complex example of SPOS was shown in the a ssembl y of trisubstituted hydantoins from multiple components as demonstrated utilizing Ugi/De Boc/Cyclization methodology. 164 The five starting materials used in this reaction include aldehydes or ketones, amines, isonitriles, methanol, and CO 2 to yield hydantoin s 76 ( Figure 4 7 ). Figure 4 7. SPOS ( s olid p hase o rganic s ynthesis) of 76 B ased on success in utilizing W(CO) 6 /I 2 catalytic oxidative carbonylation as an alternative to phosgene and phosgene derivatives, it was anticipated that this methodology could be extended to hydantoin targets. In theory, formation of the five membered ring fr om an amino amide should be kinetically favored over bimolecular

PAGE 79

79 acyclic urea formation Therefore, the synthesis of a series of hydantoins was undertaken to better understand the scope of the catalytic system. A range of amino amides with differing substitution patterns was synthesized to determine the effect upon cyclization using the W(CO) 6 /I 2 system (Figure 4 8) Figure 4 8. Proposed s ynthetic a pproach to u sing the W(CO 6 ) /I 2 s ystem to y ield h ydantoins. Synthesis of Amino Amides Figure 4 9. Synthesis of amino amides 78 81 Table 4 1. Synthesis of amino amides 78 81 Entry R Produc t t Yield (%) 1 CH 3 78 90 2 CH 2 CH 3 79 82 3 CH(CH 3 ) 2 80 40 4 CH 2 Ph 81 45 A series of seven disubstituted amino amides containing various aromatic and aliphatic side chains on either the amido or amino nitrogen was synthesized Compounds 78 81 were synthesized by treatment of the corresponding amino acid

PAGE 80

80 methyl ester hydrochloride with the requisite amine in anhydrous methanol ( Figure 4 9 Table 4 1 ). 165 A n attempt at using a serine methyl ester ( Figure 4 10 ) under similar circumstances using analogous methodology 169 as for 78 was conducted but the product amide 82 could only be obtained in 35% yield. Thus an alternative approach was sought to obtain 82 using a mixed anhydride coupling procedure (MAC) followed by deprotection of the Cbz group by hydrogenation ( Figure 4 11 ). 170 Figure 4 10. Synthesis of 82 from s erine m ethyl e ster. Figure 4 11. MAC synthesis of 82 Figure 4 12. MAC synthesis of 80 and 81 The yields of both 80 and 81 using the procedure in Figure 4 9 were poor owing to difficulty in purification, presumabl y due to the 10 equivalen ts of amine used. The MAC

PAGE 81

81 procedure was then extended to synthesize them from the commercially available N Boc protected amino acid in overall yields of 75% and 84%, respec tively ( Figure 4 1 2 ). The secondary amino amide 83 was obtained from the condensation of L phenylalanamide with benzaldehyde followed by reduction with NaBH 4 in accordance with literature precedent ( Figure 4 1 3 ) 171 Figure 4 13. Synthesis of 83 The Boc protection of commercially available diphenylglycine was carried out by adaptation of a literature procedure to give 84 172 The benzotriazol e mediated coupling of 84 with benzylamine gave 85 in overall 81% yield. 172 Figure 4 14. Synthetic s cheme for 84 86 It was envisioned that 86 could be synthesized by the hydrogenation of 85 but no conditions could be found for removing the benzyl unit from the amide, including 80

PAGE 82

82 mol% Pd catalyst, and 80 atm H 2 at 100 C for 24 hours. Instead 86 was derived from treat ment of 84 with SOCl 2 and saturated NH 3 in THF as adapted from the literature. 173 This proved fortuitous as i t also resulted in the removal of the Boc group without needi ng a second deprotection step to afford the product in 88% yield Results and Discussion Figure 4 15. W(CO) 6 catalyzed carbonylation of 78 to hydantoin 78 a Initial carbonylations of 78 were conducted under conditions optimized for the conversion of amino alcohols to ureas, 77 but the reaction did not produce the hydantoin and starting material was recovered. Table 4 2. Carbonylation conditions for amin o amide 78 to form 78 a Entry Time (h) Pressure (atm) Temp ( C) Base/equiv. Solvent % Yield 1 18 80 40 Py/2 CH 2 Cl 2 0 2 24 80 45 Py/2 CH 2 Cl 2 0 3 36 90 55 Py/2 CH 2 Cl 2 40 4 45 80 25 Py/2 CH 2 Cl 2 0 5 36 90 55 K 2 CO 3 CH 2 Cl 2 /H 2 O 20 6 42 90 45 DMAP/2 CH 2 Cl 2 0 7 36 85 45 DMAP/3 Toluene 0 8 36 85 45 DMAP/3 CH 2 Cl 2 /H 2 O 50 9 36 85 45 DMAP/4 CH 2 Cl 2 /H 2 O 50 10 48 85 45 DMAP/4 CH 2 Cl 2 /H 2 O Trace 11 36 80 45 DBU/4 DCE 7 3 The solution concentration of Entry 1 was 4.0 M, (0.87 mL of solvent), all others were conducted at 0.031 M (35 mL of solvent). 174

PAGE 83

83 As the amide is considerable less nucleophilic than the amines pr esent in the amino alcohol substrates, this was not surprising. A series of carbonylations testing different bases, higher temperatures, and longer reaction times was conducted using 78 ( Figure 4 15 Table 4 2 174 ). The best conditions are described in Entry 11. The lower amide nucleophilicity is compensated by use of a stronger base. In addition, time was also a factor as 36 hours was optimal for these conditions. At longer reaction times, the product began to decompose. Figure 4 16. General c arbonylation of a mino a mide s ubstrates. Table 4 3. Catalytic c arbonylation of a mino a mide s ubstrates Entry Cmpd R 1 R 2 R 3 R 4 Product Yield (%) 1 78 CH 2 Ph H H CH 3 78 a 73 2 79 CH 2 Ph H H CH 2 CH 3 79 a 61 3 80 CH 2 Ph H H CH(CH 3 ) 2 80 a Trace 4 81 CH 2 Ph H H CH 2 Ph 81 a 75 5 82 CH 2 OH H H CH 2 Ph 82 a 50 6 83 CH 2 Ph H CH 2 Ph H 83 a 10 7 85 Ph Ph H CH 2 Ph 85 a Trace 8 86 Ph Ph H H 86 a 7 Starting with the conditions described in Table 4 2 Entry 11, the carbonylation of the other substrates was attempted ( Figure 4 16 Table 4 3). Compounds 78 81 illustrate the effect of steric variation at the amid e nitrogen on ring closure. The yields were highest for compounds 78 79 and 81 (R 4 = Me, Et, and Bn respectively), which

PAGE 84

84 have no branching at the carbon of the substituent. The effect of the secondary alkyl substituent is seen in 80 ( R 4 = i Pr ) where the hydantoin product 80 a was only observed in trace quantities. This is not surprising as similar effects have been found in the carbonylation of secondary diamines containing these N alkyl substituents. 83,84 The substrate with the free OH group, 82 yield ed the hydantoin product 82 a in 50% yield and no carbamate was observed. What was intriguing is that substrates 83 85 and 86 yielded almost no product under these conditions. Since hydantoin 86 a is the a nticonvulsant diphenylhydantoin ( Dilantin TM ) and thus one of the more interesting targets, other conditions for successful carbonylation of 86 were sought The results of the reaction conditions tested in the carbonylation of 86 to form diphenylhydantoin 86 a ( Table 4 4 ) show the complexity of this system Lack of nucleophilicity rendered this substrate less reactive and stronger bases such as DABCO ( entry 4) and DBU (entry 7) were required H owever, the excess base also could have a deleterious effect upon the reaction as 1.1 equiv alents of DBU (entry 8) gave 35% yield and 2.2 equiv alents DBU (entry 13) lowered the yield to 12%. Utilizing either anh ydrous solvent (entries 8 and 9) or high dilution (entry 12) also seemed to have no effect upon yield. Anhydrous solvents were examined because one of the ma jor products was benzophenone which presumably arises via hydroly sis but the decomposition occur red regardless of the presence of adventitious water in the solvent or other reagents Choice of solvent and temperature appeared to make the largest impact upon the system. When using 1,2 dichloroethane (DCE) the reaction mixture appeared often to undergo a coupling oligomerization as evidenced by a viscous dark orange solution following c arbonylation. When dichloromethane was substituted, the

PAGE 85

85 oligomerization was not observed Although amines are known to react with chlorinated solvents, 175 no products of reaction with DCE were observed. Optimized results were obtained using DCM with 1.1 equivalents o f DBU as base for 24 hours at 35 C (entry 20). The higher yields of hydantoins in DCM, as compared to DCE, are attributed to the higher solubility of the substrate. Table 4 4. Optimization of c arbonylation of 86 Entry Base (equiv.) Temp ( C) Time (h) Yield 1 a Py (1.1) 60 24 Trace 2 Py (2) rt 48 Trace 3 Py (7) 60 48 0 4 a DABCO (1.1) rt 24 5 5 DBU (1.1) rt 24 9 6 DMAP (4) 60 24 0 7 DBU (1.1) 45 24 5 8 DBU (1.1) 60 24 35 9 a DBU (1.1) 60 24 31 10 DBU (1.1) 60 36 0 11 DBU (1.1) 70 24 Trace 12 a,b DBU (2.2) 60 24 11 13 DBU (2.2) 60 24 12 14 DBU (4) 60 24 Trace 15 DBU (4) 60 36 0 16 b DBU (4) 60 36 0 17 DBU (4) 60 48 0 18 DBU (4) rt 60 0 19 c DBU (1.1) 35 12 51 20 c DBU (1.1) 35 24 64 21 c DBU (1.1) 35 36 12 a A nhydrous solvent and reagents b Conducted at half concentration, 0.028 M, all others at 0.056 M c Dichloromethane as solvent, all others are 1,2 dichloroethane. The CO pressure for all reactions was held constant at 80 atm.

PAGE 86

86 Substrates 83 and 85 were then carbonylated using the optimized conditions for 86 (Eq. 4 6) The yields improved greatly over those obtained using the conditions optimized for the methyl amide 78 but still are low to moderate (Table 4 5) Substrate 83 the constitutional isomer of 81 was only able to affo rd the hydantoin product in 41% yield whereas 81 a was obtained in 75%. This illustrates the effect that steric bulk on the amine nitrogen has on the system. Compound 85 underwent competitive decomposition to benzophenone during the formation of 85 a as w as observed in reactions of 86 It appears in the case of 85 the relative rate of decomposition into benzophenone is faster than that of the relative rate of carbonylation. One possible route to explain the low yields from 83 a and 86 a is that primary am ides are less nucleophilic than their secondary counterparts, and as a result the rate of carbonylation is slower making decomposition pathways possible. Table 4 5. Comparison of carbonylation conditions for 83 85 86 Substrate Hydantoin %Yield a %Yield b 83 83 a 10 41 85 85 a Trace 11 86 86 a 7 64 a Conditions optimized for 78 a b Conditions optimized for 86 a W hen substrates 78 81 are carbonylated under the optimum conditions for phenytoin, the yield of the corresponding hydantoins drops to less than 15% for all amino amides This could be d ue to differences in solubility of substrates in DCM versus DCE, the fewer equivalen ts of ba se present, or that both reaction time s and temperature s were lower.

PAGE 87

87 Conclusions W(CO) 6 /I 2 oxidative catalytic carbonylation of amino amides results in moderate to good yields of hydantoins. Steric hindrance at the nitrogen in the substrate has an effect on the yield and decomposition of the substrate is competitive with product formation in a few cases. The use of this methodol ogy provides an alternative to previous existing synthetic pathways to hydantoins.

PAGE 88

88 CHAPTER 5 CATALYTIC OXIDATIVE CARBONYLATION OF AMINO AMIDES TO PROD UCE 5,6 DIHYDROURACIL DERIVA T IV ES Background The synthesis of 5,6 dihydrouracils ha s been of in terest in organic chemistry due to their importance in the biochemistry of cells and their potential as biologically active molecules. 176 Long known to be intermedia tes in the catabolism of uracils, 5,6 dihydrouracils have been studied for their biological significance. 177,178 The applications of this class of molecules are anticancer, 179,180 antifungal agents 181 and herbicides, 182 and inhibitors of HIV 1 integrase 183 5 ,6 D ihydro 5 fluorouracil is a potential pro drug form of 5 fluorouracil, which is a widely prescribed antineoplastic drug used in the treatment of breast and colorectal cancers. 184 Synthetic Routes to Form Dihydrouracils While 5,6 dihyrouracils (Figure 5 1) have been heavily investigated for their biological effects and have been of spec troscopic interest for their conformational characteristics, 185 187 the synthetic methods to yield these compounds have not been been explored, mainly utilizing isocyanates or hydrogenat ions of p arent uracils to their 5,6 dihydr ouracil products. There has also been recent interest in the application of solid phase organic chemistry (SPOC) to synthesize these compounds Figure 5 1. 5,6 Dihydrouracil.

PAGE 89

89 Solution Phase Methods The condensa tion of unsaturated carboxylic acids with ureas has been an effective way to synthesize 5,6 dihydrouracils ( Figure 5 2 ). 187,188 Initially, this synthesis was applicable only on large, multi molar scales and tended to only give moderate yields of products, around 45% 188 Figure 5 2. Synthesis of 5,6 d ihydrouracils u sing u nsaturated c arboxylic a cids. Scaling the method down proved problematic as urea decomposition occurred readily at the reaction temperature in the presence of air. To overcome th is limitation a millimolar amount of reactant could be sealed in a 40 mL steel tube a nd heated to the appropriate temperature for 1 2 hours. 187 The reaction is still limited in that it could only use matched alkyl groups on the ureas (Eq. 5 1 R 3 =H, Me) to yield symmetrically 80% depending on the substituents present on the alkene. Figure 5 3. Synthesis of 5,6 d ihydrouracils u sing i sobutyric a nhydride. More recently, a variant of this reaction using N 3 substituted 3 thioureidopropanoic acids combined with isobutyric anhydride resulted in the formation of 5,6 dihydrouracils ( Figure 5 3 ). 189 This was a serendipitous discovery in an attempt

PAGE 90

90 to generate 2 amino 4,5 dihydro 1,3 thiazin 6 ones. Instead of the intended compound a dihydrouracil was obtained Upon further exploration of the reaction it was determined that the ur e ido N substituent generally could only be an activated benzene. Deactivated aryl rings were found to give poor yields and the presence of aryl halogens resulted in inseparable mixtures. When the reaction was conducted at 80 C, samples analyzed by HPLC after 15 minutes indicated that characterizable quantities of products and other intermediates were present in the reaction mixture ( Figure 5 4 ). 189 Compounds 89 91 were all discrete compounds, each identified by NMR and/or LCMS. Only 5% of the dihydrouracil had been formed at this point and the mixture was comprised of 9% 89 52% 90 and 10% 91 The r emainder of the mixture was unidentifiable. The identity of the compounds led them to postulate a mechanism that rationalized the products formed. Figure 5 4. Proposed m echanism of 5,6 dihydrouracil formation Usi ng lead tetraacetate to oxidize substituted succinamides has also been successful in regiosel e ct iv e ly furnishing dihydrouracils ( Figure 5 5 ). 190 The yield s of 92

PAGE 91

91 and 93 approach 90%. However, if the aceto xy group is placed in the 3 position as opposed to the 4 position the molecule loses AcOH upon reaction with Pb(OAc) 4 to produce the uracil derivative in 70% yield. The reaction has limited scope as lead tetraacetate is not compatible with most function al groups. Figure 5 5. C onversion of d iamides to 5,6 d ihydrouracils by reaction with Pb(OAc) 4 The hydrogenation of uracil derivatives ( Figure 5 6 ) has also been demonstrated to yield 5,6 dihydrouracils but has proven problematic in some regards. Established methodology includes use of hydrogen with a Rh Al amalgam Pd/C or NaBH 4 191 Problems often encountered with these methods are low yields, epimerization at C5, or complete removal of the N1 alkyl group. 192 Newer techniques using ammonium formate as an H 2 source in methanol do not epimerize C5 although yields still are moderate ( 39 50% depending on water content of the solve nt ) 193 Figure 5 6. Hydrogenation of u racil to 5,6 d ihydrouracil. A milder reduction pathway utilizing l ithium tri sec butyl borohydride (L selectride) was found by Kundu to reduce substituted uracils to their 5,6 dihydrouracil adducts in yields of 72 94% (Figure 5 7 ) 176 The reaction tolerates a range of alkyl groups ( H, propargyl, methyl, and benzyl ) The propargyl group is not reduced under these

PAGE 92

92 conditions, showing chemo selectivity. The limitat ion to the reaction is that N H bonds a re incompatible with L selectride, and the reaction was successful only where R = Me and aryl 194 The requirement for matched alkyl substituents on the nitrogens limits applicability of the reaction to varied substrates. Figure 5 7. L s electride r eduction of u racils to f orm 5,6 d ihydrouracils. The most common pathway seen in solution phase organic chemistry is the combination of a amino acid derivative with an alkyl isocyanate or alkyl isothiocyanate to afford the 5,6 dihydrourac il or 5,6 dihydro thione adduct ( Figure 5 8 ) The reaction of an amino nitrile with an isothiocyanate was shown to yield the thione derivative after treatment with acid ( Eq. 5 6). 195 Similarly the reaction of a n alkyl isocyanate with an amino nitrile afford ed the 5,6 dihydrouracil after cyclization of an isolable urea intermediate (Eq. 5 7) 196 While not a 5,6 dihydrouracil, the product in Eq. 5 8 comes from the condensation of a n amino ester and either an alkyl isocyanate or isothiocyanate, but this time from a base induced cyclization. 197 These reactions give between 50 86% yield and are compatible with R = alkyl, aryl, and substituted aryl groups. These reactions do not have wide applicability as the isocyanates u sed are very reactive with some functional groups and do not work well with a primary amino nitrogen 196 A lso t he starting material in Eq. 5 8 is not commercially available.

PAGE 93

93 Figure 5 8. Synthesis of dihydrouracils from amino acid derivatives. Solid Phase Organic Chemistry (SPOC) Figure 5 9. SPOC s ynthesis of 5,6 d ihydrouracils. The use of combinatorial ch emistry to prepare nitrogen containing heterocyclic compounds by SPOC has seen tremendous growth in the last decade. 181 Synthesis of

PAGE 94

94 r ing systems including imidazoles, 198 pyrazoles, 199 isoxazoles, 199 pyridines, 200 and isoquinlines 201 are all well described. Pyrimidinone derivatives ha ve also been formed using solid phase three component process 202 but are rarer. Hamper reported a successful system that was capable of generatin g 5,6 dihydrouracil systems in moderate to good yields (Figure 5 9) 181 The reaction employed a Wang resin which is initially reacted with acryloyl chloride in the presence of triethyl amine to afford the acrylate resin 94 Michael addition of a substituted amine yielded 95 a aminoester, which when combined with a 2:1 molar excess of an alkyl isocyanate afford ed the urea moiety, 96 Initial attempts at using TFA to cyclize the ureido ester 96 to form the desired 5,6 dihydrouracil 98 instead formed a mixture of ureido acid 9 7 and 98 More consistent results were obtained using HCl as the acid source in toluene to afford 98 in a hydrolysis yield of 95 99% When either aqueous 6 N HCl or HCl in dry ethanol were employed the yields obtained were only 10% and 60%, respectively. Overall yields for the four step synthesis were 13 76% and tended to be lower when resonance delocalizing groups like phenyl and allyl were employed. This system was expanded later by Janusz to include thio derivatives of the uracil product. 203 Current methodologies for preparation of 5,6 dihydrouracils h ave much room for improvement on both yields and toleranc e to alkyl/aryl substituents. In addition, synthetic strategies of using condensation of ureas with unsaturated carboxylic acids are difficult to scale down to a laboratory level, and systems us ing SPOC are difficult to scale up to an industrial level. Hydrogenation methods suffer from inability to obtain good yields, scrambling of stereochemistry, and non compatibility with acidic

PAGE 95

95 hydrogens. Use of isocyanates has a negative environmental impa ct, which makes their reaction with amino acids difficult on a large scale. As we were able to employ the W(CO) 6 /I 2 system in the synthesis of hydantoins, it was a natural extension to attempt the synthesis of dihydrouracil s While not as kinetically favored as formation of a 5 membered ring in the hydantoin case it was theorized that these products could be formed in good yields as we had shown with t he carbonylation of 1,4 diamino butanes. Synthesis of Amino Amides A series of five amino amides with various alkyl and aryl substituents to the carbonyl was synthesized to explore the effect of the substituent on cyclization. P revious results with hydantoins suggested the use of a benzyl group on the amide moiety as they tended to afford highe r yields Alkyl substitution specifically was examined due to the difficulty in incorporating it after cyclization has occurred, giving rise to products that would not have been readily available through other synthetic methods. Figure 5 10. N Boc protection of amino acids to generate 100 103 Different synthetic methodology to afford amino amides was required compared to the synthesis of the amino amides used in the preparation of hydantoins.

PAGE 96

96 Commercially available alkyl substituted a mino acids were employed. As most were not available in N protected form, protection was required initially. The N Boc protected amino acid was then subjected to a m ixed a nhydride c oupling (MAC) reaction to afford the protected amino amide. Deprotection with HCl afforded the final amino amide. Compound 99 was commercially available as the N Boc derivative Initially the amino acid to afford 101 was protected through a protocol de veloped for the synthesis of 84 using acetonitrile and tetrabutylammonium hydroxide with Boc 2 O However this gave yields of only 56% so a new method 204 was sought and proved to be more successful (Figure 5 10 ) Figure 5 11. MAC reaction to yield 104 108 Once the N Boc protected amino acid was synthesized, it was converted to the N Boc protected amino amide through a previously employed MAC reaction (Figure 5 11) 170 Even though the literature procedure employed u tilized Cbz protected amino acids, it was found that the Cbz protected form of 101 gave less than 1 0% yield of the resulting amide due to poor solubility of the starting amino acid when the MAC reaction

PAGE 97

97 was attempted using the same methodology Boc protected substrates proved to be more successful and were th en exclusively utilized for further reacti ons Deprotection using 4.0 M HCl in dioxane proved to be slightly problematic as widely different times were needed to complete the reaction ( Figure 5 1 2 ) Constant monitoring by TLC was needed to determine deprotection reaction time as the material wo uld decompose into an intractable yellow oil if left for times over two hours. Figure 5 12. Deprotection of N Boc a mino a mides to a fford 109 113 Results and Discussion Initially chosen for carbonylation was substrate 109 as it was the simplest amino amide (Figure 5 13) Optimized conditions for the carbonylation of 86 to hydantoin 86 a 35 C, 1.1 equivalents of DBU, and 24 h ou rs with dichloromethane (DCM) as solvent, were tested as a starting point, howe ver no dihydrouracil was fo rmed. Even when the temperature was increased to 60 C, no product could be found. C arbonylation conditions were then more extensively examined and the base concentration, identity, temperature, and time were optimized ( Table 5 1 )

PAGE 98

98 Figure 5 13. W(CO) 6 c atalyzed c arbonylation of 109 Table 5 1. Optimization of carbonylation conditions for 109 to form 109a Entry Time (h) Temperature ( C) Base (Equiv.) Solvent %Yield 109 a 1 24 35 DBU (1.1) DCM 0 2 24 60 DBU (1.1) DCM 0 3 24 35 DBU (1.1) DCE 48 4 24 30 DBU (2.5) DCE 27 5 24 30 D BU (4.0) DCE 8 6 24 30 Pyridine (1.1) DCE 13 7 8 30 DBU (1.1) DCE 5 8 12 30 DBU (1.1) DCE 45 9 36 30 DBU (1.1) DCE 7 10 24 45 DBU (1.1) DCE 88 11 24 60 DBU (1.1) DCE 13 It is important to note that the molar amounts of 109 W(CO) 6 I 2 and solvent volume were held constant for the optimization experiments The best system was found in Entry 10 with 45 C, 24 hours, and 1.1 equivalents of DBU using 1,2 dichloroethane (DCE ) as solvent. The choice of solvent proved critical again for the carbonylation system, as was seen with the formation of hydantoins. When using DCM, starting material decomposed forming no product (Entry 1), but upon switching to DCE (Entry 3) the 5,6 d ihydrouracil was isolated in 48% yield. Not as much effort was placed into analyzing base identity as the compared to the amino amides used to form hydantoins. DBU was found to be

PAGE 99

99 necess ary for high yi elds, as when pyridine was used (Entry 6) the yield dropped significantly Longer reaction times were also found to decompose the product and the optimum reaction time was determined to be 24 hours. Product identification was based preliminarily on 1 H and 13 C NMR along with IR data indicating a new carbonyl peak at 1726 cm 1 The new CO stretch is within the range of reported values for 5,6 dihydrouracil compounds 205 and the structure of 109 a was confirmed by comparison to literature data. 206 Using the optimized con ditions for 109 to form dihydrouracil 109 a the remaining amino amides were carbonylated ( Figure 5 14, Table 5 2 ). While 109 formed the corresponding dihydrouracil in good yield, the alkyl substituted substrates resulted in acyclic urea formation N ew CO stretches were found around 1640 cm 1 in the IR data to corroborate this conclusion These new CO stretches are sharply lower than reported v alues for 5,6 dihydrouracil by 8 0 cm 1 and are consistent with those reported for acyclic ureas 70,205 Structur e confirmation was obtained from MS data ( vide infra ) Figure 5 14. Carbonylat ion of substrates 110 113 to form 110a 113a using optimized conditions from 109a

PAGE 100

100 Table 5 2 Carbonylation of amino amides to acyclic ureas 110a 113a Amino Amide R Group % Yield of Acyclic Urea 110 CH 3 86 111 Ph 7 112 CH 2 Ph 29 113 i Pr 0 The highest yield of acyclic urea formed w as obtained with the substituent being methyl afford ing 86% yield of 110 As the size of the substituent increases, the yield drops significantly. Th e substrate tested with the most steric hind rance was the i Pr amino amide 113 from which no carbonylated product s could be detected and complete decomposition of starting material was observed When the substituent wa s phenyl ( 111 ) the reaction produce d very low yield presumably due to oxidation of the amino nitrogen Similar degradation pathways may also exist for the i Pr variant 113 which would explain both the lack of products and observed degradation of the starting material When the phenyl group is shifted a CH 2 unit further from the amino nitro gen ( 112 ) the carbonylation yielded significantly higher amounts of the acyclic urea product compared to that seen from phenyl substrate 111 Understanding t he effect of sterics on the formation of acyclic ureas is difficult with this system as seen in the formation of 110 a and 112 a The benzyl group in 112 is not much sterically larger than the methyl group in 110 but the yield is significantly less. The A value for CH 2 Ph is 1.68 kcal/mol while that for CH 3 is 1.74 kcal/mol, 207 predicting that sterically the benzyl substituted 112 would be the easier substrate to carbonylate, while the o pposite trend is observed The electron withdrawing effect of the phenyl group in 112 is now two carbons removed from the amino nitrogen, which should make

PAGE 101

101 the nucleophilicity of the amino nitrogens approximately the same in 112 and 100 The interplay between sterics and electronics of this system is very complex. An attempt to carbonylate substrate 110 under high dilution condit ions was also examined with a substrate concentration of 0.0028 M (compared to 0.028 M for opti mi zed conversion of 109 to 109a and 0.055 M used in the formation of 86a ) in DCE. After the 24 hour reaction time, only complete degradation of the starting material was observed. Neither acyclic urea nor 5,6 dihydrouracil formation was detected in the reaction mixture. A direct compa rison of product ratios is available between substrates 81 and 1 1 1 as they are constitutional isomers. Hydantoin 81a forms in 75% yield from the carbonylation of 81 whereas 1 1 1 forms the acyclic urea in only 7%. It appears that the relative rate of cyclization is significantly faster for the formation of the five membered hydantoin ring over the relative rate of formation for the acyclic urea In the case of formation of 5,6 dihydrouracils, the opposite trend is seen. While not surprising that the relative rate of five membered ring formation is faster than that of the six it is interesting that even a small alkyl substituent, like a methyl group, can slow down the relative rate of cyclization enough to favor acyclic urea formation over cycl ization of the dihydrouracil. This was demonstrated in the ability of 109 to carbonylate to form 5,6 dihydrouracil 109a in 88% yield, while as methyl substituted 110 only forms the acyclic urea. Conclusions The oxidative carbonylation of amino amides using the W(CO) 6 /I 2 system has only proven effective to form 5,6 dihydrouracil 109 a which has no alkyl substituent When alkyl substituents are added in the position, the carbonylation of the amino

PAGE 102

102 amide affords acyclic urea preferentially over forma tion of the 5,6 dihydrouracil The interplay between sterics and electronics brought about by the alkyl substituent is not fully understood, but has a large effect upon the yield s of acyclic urea s This methodology provides a synthetic route to form 5,6 dihydrouracils although it is limited in scope

PAGE 103

103 CHAPTER 6 EXPERIMENTAL SECTION Synthesis of Alkylzir conium Complexes General All manipulations were carried out using standard Schlenk and glove box techniques under an inert atmosphere of argon o r nitrogen. All solvents, unless otherwise noted, were purchased from Fisher and passed through an M. Braun MB SP solvent purification system or were distilled from sodium/benzophenone prior to use. All 1 H and 13 C NMR spectra were obtained on a VXR 300 MH z spectrometer. Mass spectrometry services were provided by the University of Florida analytical service. Synthesis of ZrNp x Cl y Complexes Neopentylmagnesium c hloride A mixture of 9.00 mL (73 .0 mmol) freshly distilled neopentyl chloride and 1.2 1 mL (14 .0 mmol) 1,2 dibromoethane were placed in an addition funnel and added dropwise to a three neck Schlenk flask containing 3.65 g (151 mmol) activated Mg turnings and 50 mL ether over a 1 hour period, in accordance with literature procedure. 42 Th e resulting mixture was refluxed overnight and filtered through a 1 cm pad of Celite (previously dried and evacuated) to afford a pale yellow product. Yield: 57 mL of 1.0 M solution, 78%. 1 H NMR (C 6 D 6 ) 0.89 0 (s, 9 H), 1.18 (s, 2H). 42 Tetraneopentylzirconium ( 2) Neopentylmagnesium chloride concentration was determined 208 and 8.1 mL of 1.0 M (8.1 mmol) of the Grignard reagent in ether was measure d into an addition funnel

PAGE 104

104 and added dropwise to a three neck Schlenk flask containing 0.629 g (2.7 0 mmol) ZrCl 4 slurried in 60 mL ether at 0 C over a 1 hour period. The mixture was then allowed to warm to room temperature and stirred vigorously overnight. Volatiles were then removed via reduced pressure and the resulting brown solid was extracted with hexan es and filtered through a 1 cm Celite pad (previous ly dried and evacuated). Volatiles were removed again to leave a pale brown solid which was sublimed (75 C, 0.02 mmHg) to produce ZrNp 4 as a white solid. Yield 0.523 g, 70%. The product was identified based on literature values. 42 1 H NMR ( C 6 D 6 ) 1.15 (s, 9H), 1.55 (s, 2H) Trisneopentyl z irconium m onochloride ( 10 ) A three neck Schlenk flask with 0.721 g (1.92 mmol) of 2 was dissolved in 40 mL ether and added at 0 C to 0.149 g (0.64 0 mmol) ZrCl 4 dropwise over a one hour period. The reaction temperature was maintained at 0 C overnight and resulted in a bright yellow solution. Volatiles were then removed leaving a bright yellow solid. The solid was then stored at 30 C in the dark. Yield 0.75 5 g, 87%. Decomposition can be seen at room temperature by darkening of the product. The p roduct was identified based on literature values. 43 1 H NM R (C 6 D 6 ) 1.15 (s, 9H), 1.55 (s, 2H).

PAGE 105

105 Synthesis of Propargylzirconium Complexes Phenylpropargyl b romide A 50 mL Schlenk flask containing 5 mL ether and 4.78 g (0.037 0 mol) phenylpropargyl alcohol and 1 g pyridine was cooled to 0 C and 5.0 g (0.18 mol) to which phosphorus tribromide was added dropwise over a 45 minute period with strong stirring under nitrogen in accordance with literature procedure. 44 The resul ting mixture was added to 25 mL of ice to deactivate the excess PBr 3 and extracted three times with 25 mL ether. The ether was then washed with sodium bicarbonate and dried over MgSO 4 Ether was removed by reduced pressure. Yield 6.0 g, 83%. 1 H NMR (C 6 D 6 ) 4.1 (s, 2H), 7.4 (m, 5H) 13 C NMR (CDCl 3 ) 15.3, 84.2, 86.6, 121.9, 128.1, 128.7, 131.7. Phenylpro pargylmagnesium b romide An addition funnel was charged with 12.0 g (61.6 mmol) phenylpropargyl bromide and 30 mL ether and the mixture was added dro pwise to a three neck flask cooled to 0 C containing 1.80 g (75 .0 mmol) activated Mg turnings with a few crystals of HgCl 2 in ether over a four hour period in accordance with literature preparation. 45 After the addition, the reaction was refluxed for 1 hour. The resulting mixture was filtered through a 1 cm pad of Celite (previously dried a nd evacuated) and yielded a dark yellow solution. Yield 30 mL of 1.85 M product, 90.1%. 1 H NMR (C 6 D 6 ) 2.11 (s, 2H), 6.8 (m, 5H).

PAGE 106

106 Tetra 3 (phenylpropargyl) z irconium ( 11) An addition funnel was charged with 20.0 mL of 1.85 M phenyl propargyl magnesium bromide (37 .0 mmol) and added dropwise to a three neck flask containing 2.16 g (9.25 mmol) ZrCl 4 slurried in 100 mL ether over a one hour period and stirred overnight at room temperature. Volatiles were removed via reduced pressure and a brown solid remai ned. The solid was extracted with 150 mL toluene and filtered through a fine glass frit. The filtrate was then condensed and crystallized with hexanes. The recrystallized product was tan in color and was subjected to repeated vapor diffusion recrystalli zation using THF and pentane s until a colorless to white solid remained. Yield 3.77 g, 74%. 1 H NMR (C 6 D 5 CD 3 ) 3.22 (s, 2H), 6.95 (m, 5H) Structure determination for 11 X ray experimental d ata for 11 were collected at 173 K on a Siemens SMART PLATFORM equipped with A CCD area detector and a graphite monochromator utilizin g MoK scan method (0.3 frame widt h). The first 50 frames were re measured at the end of data collection to monitor instrument and crystal stability (maximum correction on I was < 1 %). Absorption corrections by integration were applied based on measured indexed crystal faces. The struct ure was solved by the Direct Methods in SHELXTL6, 209 and refined using full matrix least squares. The non H atoms were treated anisotropically, whereas

PAGE 107

107 the hydrogen atoms were calculated in ideal positions and were riding on their respective carbon atoms. The complexes are located on 2 fold rotation axes; thus a half complex occupies the asymmetric unit. A total of 168 parameters were refined in 2.44% and 6.76%, respectively. Refinement was done using F2. Computational Analysis of 11 Geometry optimizations and single point calculations were performed using the DFT B3LYP functional and the LANL 2 DZ basis set utilized in the Gaussian 03 210 program package. 55 58 Compositions o f molecular orbitals were calculated using the AOMix program. 211,212 Molecular orbital pictures were generated from Gabedit. Computational resources and support were provided by the University of Florida High Performance Computing Center. Methylpropargylmagnesium b romide An addition funnel was charged with 6.61 mL (75.5 m mol) freshly distilled 1 bromo 2 butyne was diluted with 20 mL ether and added dropwise to a three neck flask containing a 20 mL ether suspension of 2.0 2 g (83. 1 mmol) activated Mg turnings and a few crystals of HgCl 2 cooled to 0 C over a 1 hour period. After addition, the reaction was allowed to warm to room temperature and stirred overnight. The resulting cloudy green yellow solution was filtered through a 1 cm pad of Celite (previously dried and evacuated) and yielded a bright yellow solution. Yield e d 50 mL of a 0.792 M solution, overall 83.6%. 1 H NMR (C 6 D 6 ) 1.68 (t, 3H) 1.8 (q, 2H)

PAGE 108

108 (Methylpropargyl) n z irconium ( 12) An addition funnel was charged with 20. 0 mL of 0.792 (15.8 mmol) methylpropargylmagnesium bromide was a dded dropwise to a flask conta ining 0.923 g (3.95 mmol) ZrCl 4 slurried in 100 mL ether over a 1 hour period. The mixture was then stirred overnight at room temperature. Volatiles were removed by reduced pressure and the resulting brown solid was extracted with 150 mL toluene. The ex tract was then filtered through a fine glass frit and condensed and recrystallized with hexanes. The resulting air and moisture sensitive brown solid showed a myriad of peaks in the 1 H NMR spectrum and was unable to be further purified. Synthesis of and Amino Amides f or Oxidative Carbonylation General Procedures All experiments, unless otherwise noted, were carried out under an inert argon atmosphere with oven dried glassware. Solvents for carbonylation reactions were passed through a solvent p urification system ( vide supra ) prior to use or were distilled from CaH 2 Commercially available substrates were used without further purification. All column chromatography was conducted with 270 400 mesh silica. All 1 H and 13 C NMR spectra were obtained on a Varian Gemini 300 MHz, VXR 300 MHz, or Mercury 300 MHz spectrometer. Infrared spectra were recorded on a Perkin Elmer 1600 FT IR. High resolution mass spectrometry was performed by the University of Florida analytical servi c e.

PAGE 109

109 General Proce dure f or the Synthesis of Amino Amides 78 82 The amino acid methyl ester hy drochloride (4 .0 mmol) and the alkylamine (40 mmol) were dissolved in anhydrous methanol (20 mL) and stirred at room temperature for 3 days in accordance with literature protoc ol 165 The reaction mixture was concentrated, and the residue was purified by column chromatography using EtOAc/MeOH (96:4) as eluant affording the amino amides 78 82 in yields reported in Table 4 1. Product ide ntification was made from literature comparison. 165,170 ( S ) 2 Amino N methyl 3 phenylpropionamide ( 78) 1 H NMR (CDCl 3 ) 2 ), 2.67 (dd, 1H, CH 2 CHCO), 2.84 (d, 3H, N H CH 3 ), 3.48 (d, 2H, PhCH 2 ), 7.22 7.30 (m, 5H, C 6 H 5 ). ( S ) 2 Amino N ethyl 3 phenylpropionamide (79) 1 H NMR (CDCl 3 2 ), 2.65 (t, 3H, N H CH 2 CH 3 ), 2.71 (dd, 1H, CH 2 CHCO), 3. 3 1 (m, 2H, NCH 2 CH 3 ), 3.64 (d, 2H, PhCH 2 CH), 7.25 7.34 (m, 5H, C 6 H 5 ). ( S ) 2 Amino N isopropyl 3 phenylpropionamide ( 80 ) 1 H NMR (CDCl 3 2 ), 2.43 (d, 6H, NHCH(CH 3 ) 2 ), 2.59 (dd, 1H, CH 2 CHCO), 3.17 (m, 1H, NCH(CH 3 ) 2 ), 3.46 (d, 2H, PhCH 2 CH), 7.21 7.30 (m, 5H, C 6 H 5 ).

PAGE 110

110 ( S ) 2 Amino N benzyl 3 phenylpropionamide ( 81 ) 1 H NMR (CDCl 3 2 ), 2.72 (dd, 1H, CH 2 CHCO), 3.37 (d, 2H, PhCH 2 CH), 3.51 (d, 2H, NHCH 2 Ph), 7.25 7.38 (m, 10H, aromatics). General Preparation of Amino Amide 82 by MAC A two step procedure, as described in the literature, 170 was followed starting with commercially available Cbz serine. A 25 mL solution of dry THF containing carbobenzy loxy DL serine (2.00 g, 8. 4 0 mmol) was cooled to 78 C and then 4 methylmorpholine (1. 29 g 10.5 mmol) was added and stirred for 5 minutes. Isobutyl chloroformate (1.4 6 g 10.5 mmol) was then added and the reaction mixture was strirred for 15 minutes after which benzylamine (1. 08 g 10.5 mmol) was added. The reaction was then stirred for 15 minutes at 78 C, before allowing to warm to room temperature where it continued to stir for one hour. The reaction mixture was filtered and the filtrate evaporated by reduced pressure. The concentrated residue was suspended in ether (75 mL) and filtered again. The crude product was purified by column chromatography with 5% MeOH/DCM eluent. A 1.95 g amount of product was isolated, a 74% yield. The hydrogenation of the Cbz protecting group was then accomplished. A flask containing 1.71 g (5.44 mmol) amount of the purified benzamide ( vide supra ) was combined with 0.286 g of Pd/C (10% w/w) and slurried in 50 mL anhydrous MeOH. The reaction was stirred under a n atmosphere of H 2 for 3 hours af ter which the mixture was filtered through a 2 cm pad of Celite. The filtrate was condensed by reduced pressure. The crude residue was purified by column chromatography using 7.5% MeOH/DCM as eluent affording 0.951 g of 82 in a yield of 90%. The product was identified by comparison to literature values. 170 1 H NMR (DMSO) 2H, N H 2 ), 3.23 (t, 1H, CH 2 C H CO), 3.41 (m, 2H, C H 2 OH ), 4.25 (d, 2H, NHC H 2 Ph), 4.76 (broad s, 1H, O H ),

PAGE 111

111 7.18 7.31(m, 5H, C 6 H 5 ), 8.36 (broad s, 1H, N H ). Substrates 80 and 81 were also alternatively made using this synthetic protocol. Synthesis of Amino Amide 83 According to t he literature 171 L Pheny lalanamide (3.05 mmol) and benzaldehyde (3.05 mmol) were dissolved in 40 mL anhydrous benzene in a round bottom flask equipped with a Dean Stark trap and condenser. The mixture was then refluxed for 3 hours and the benzene/water aze o trope was removed as needed. Solvent was then removed via reduced pressure and replaced with 20 mL MeOH to which 1.1 0 mmol of NaBH 4 was added and stirred for 1 hour. Solvent was removed and the resulting solid was triturated in hexanes to afford an oily solid. Column chroma tography with 95/5 (DCM:MeOH) was then used to complete the purification. The product was obtained in 72% yield and was identified by comparison to literature values 171 1 H NMR (CDCl 3 ) 1.77 (broad s, 1H, N H ), 2 78 (t, 1H, CH 2 C H CO), 3.34 (dd, 2H, PhC H 2 CH), 3.65 (dd, 2H, PhC H 2 NH), 5.83 (broad s, 2H, CON H 2 ), 7.10 7.31 (m, 10H, aromatics).

PAGE 112

112 Boc Protection of Diphenylglycine to 84 The commercially available diphenylglycine (2.26 g, 10 .0 mmol) was slurried in 80 mL acetonitrile and dissolved using a minimum amount of 25% (w/w) tetramethylammonium hydroxide in H 2 O. Di tert butyldicarbonate (5.00 g, 25 .0 mmol) was added over a three day period and allowed to s tir for a total of four days until TLC indicated that the reaction was complete. The reaction mixture was then concentrated under reduced pressure and dissolved in 150 mL EtOAc and acidified to pH 3 4 using 1.0 N HCl. The organics were then separated and the aqueous material extracted twice with EtOAc. The organics were then combined and washed with brine, then dried over MgSO 4 The product was obtained in 92% yield following flash column chromatography using 97/3 (DCM:MeOH). The product was identified by comparison to literature data. 172 1 H NMR (CDCl 3 3 ) 3 5.1 (broad s, 1H, NH), 7.2 7.35 (m, 10 H, C 6 H 5 ). 13 C NMR (CDCl 3 8.5, 148.2, 155.2, 172.9. N B enzyl D iphenylglycamide ( 85 ) The N Boc protected amino acid 84 was converted to the amino amide via benzotriazole mediated coupling. 172 After wo rkup, the mixture was taken without purification and deprotected using 5 molar equivalents of 4.0 M HCl in dioxane and stirred overnight. The resulting mixture was purified by flash column chromatography with a solvent gradient shift from DCM to 90/10 (DC M:MeOH). Yield 72% The product

PAGE 113

113 was identified by comparison to literature data. 172 1 H NMR (CDCl 3 NHCH 2 Ph), 4.36 (broad s, 1H, NHCO) 4.82 (broad s, 2H, NH 2 ), 7.2 5 7.35 (m, 15H, C 6 H 5 ). 13 C NMR (CDCl 3 145.1, 173.4. Diphenylglycamide ( 86 ) The N Boc protected amino acid 84 (1.00 g, 3.18 mmol) was dissolved in 20 mL anhydrous DCM and brought to reflux, according to literature procedure. 173 Then SOCl 2 (1.13 g, 9.54 mmol) was added, and the mixture continued to reflux for 3 hours. After cooling, the acid chloride solution was evaporated in vacuo and 50 mL of THF saturated in ammonia was slowly added and the mixture was stirred overn ight. The excess ammonia was removed by sparging with N 2 and the concentrate dissolved in DCM and washed once with water. The organics were separated and dried over MgSO 4 The resulting residue was purified by flash column chromatography with 95/5 (DCM: MeOH) to afford 86 in 95% yield. The compound was identified by comparison to literature data. 213 1 H NMR (CDCl 3 NH 2 ), 6.05 (broad s, 1H, CONH 2 ), 7.02 (broad s, 1H, CONH 2 ), 7.25 7.43 (m, 10H, C 6 H 5 ). 13 C NMR (CDCl 3 127.4, 128.3, 144.7, 176.8.

PAGE 114

114 Procedure A f or Carbonylation of Amino Amide 78 To a 300 mL glass lined Parr high pressure vessel containing 35 mL of 1,2 dichloroethane were added amino amide 78 (400 mg, 2.2 0 mmol), W(CO) 6 (56 mg, 0.16 mmol), I 2 (396 mg, 1.56 mmol), and DBU (1.3 6 mL, 8.96 mmol). The vessel was then charged with 80 atm CO and heated to 60 C for 36 hours with constant stirring. After cooling, the pressure was released and 15 mL water was added. The organics were then separated and washed successively with Na 2 SO 3 and 0.1 M HCl. The aqueous layer was then extracted with EtOAc (20 mL x 4). The combined organic layers were then dried over MgSO 4 filtered and concentrated. The resulting residue was purified via flash column chromatography using DCM/EtOAc (80:20) to afford hydantoin 78 a The same procedure was applied to prepare hydantoins 79 a 82 a The products were identified by comparison to literature data. 165,214,215 (S) 5 Benzyl 3 methylimidazolidine 2,4 dione ( 78 a) The hydantoin was synthesized through carbonylation procedure A. 1 H NMR (CDCl 3 ) 2.80 (t, 1H CH 2 C H ), 3.0 (s, 3H ,NCH 3 ), 3.32 (dd, 1H PhCH 2 ), 4.25 (dd, 1H PhCH 2 ), 5.19 (broad s, 1H NH ), 7.21 7.40 (m, 5H, C 6 H 5 ); 13 C NMR (CDCl 3 ) 25.8, 41.0, 56.4, 126.7, 128.6, 129.2, 174,4; IR (neat) CO 1772, 1709 cm 1 (S) 5 Benzyl 3 ethylimidazolidine 2,4 dione ( 79 a) The hydantoin was synthesized through carbonylation proc edure A. 1 H NMR (CDCl 3 ) 1.19 (t, 3H, CH 2 C H 3 ), 2.82 (dd, 1H, C H 2 CH 3 ), 3.24 (dd, 1H, C H 2 CH 3 ), 3.43

PAGE 115

115 3.60 (m, 2H, C H 2 Ph), 4.21 (dd, 1H, CH 2 C H CO), 7.19 7.39 (m, 5H, C 6 H 5 ); 13 C NMR (CDCl 3 ) 12.0, 33.9, 38.1, 58.1, 127.0, 130.0, 131.2, 134.5, 157.5, 172.4. IR (neat) CO 1770, 1714 cm 1 (S) 5 Benzyl 3 benzylimidazolidine 2,4 dione ( 81 a) The hydantoin was synthesized through carbonylation procedure A. 1 H NMR (CDCl 3 ) 2.82 (dd, 1H, C H 2 Ph), 3.24 ( dd, 1H, C H 2 Ph), 4.22 (s, 2H, C H 2 Ph), 4.60 (t, 1H, CH 2 C H CO), 5.38 (broad s, 1H, N H ), 7.23 7.42 (m, 10H, C 6 H 5 ); 13 C NMR (CDCl 3 ) 38.4, 43.9, 61.7, 125.8, 126.7, 126.9, 127.7, 128.9, 135.5, 135.7, 158.5, 169.5. IR (neat) CO 1775, 1716 cm 1 (S) 3 Benzyl 5 (hydroxymethyl)imidazolidine 2,4 dione ( 82 a) The hydantoin was synthesized through carbonylation procedure A. 1 H NMR (DMSO) 3.46 (dd, 1H, C H 2 Ph), 3.53 (dd, 1H, C H 2 Ph), 4.26 (t, 1H, CH 2 C H CO), 4.48 (d, 2H, C H 2 OH), 4.77 (broad s, 1H, O H ), 7. 21 7.30, (m, 5H, C 6 H 5 ). IR CO 1765, 1708 cm 1

PAGE 116

116 Procedure B f or Carbonylation of Amino Amide 86 To a 300 mL glass lined Parr high pressure vessel containing 20 mL of dichloromethane were added amino amide 86 (250 mg, 1.1 mmol), W(CO) 6 (29 mg, 0.081 mmol), I 2 (195 mg, 0.77 0 mmol), and DBU ( 18 7 mg 1.22 mmol). The vessel was then charged with 80 atm CO and heated to 35 C for 24 hours with constant stirring. After cooling, the pressure was released and 20 mL of 95/5 (DCM:MeOH) was added The organics were then washed immediately with Na 2 SO 3 and separated. The aqueous layer was then extracted with ethyl acetate (2 x 20 mL). The combined organic layers were then dried with MgSO 4 filtered, and concentrated. The resulting residue was th en purified via flash column chromatography using DCM/EtOAc (80:20) to afford hydantoin 86 a also known as phenytoin The same procedure was applied to prepare hydantoins 83 a and 85 a Phenytoin was identified by comparison to a commercially available sam ple. Other p roducts were identified by comparison to literature data. 216,217 Hydantoin 83 a The hydantoin was synthesized through carbonylation procedure B. 1 H NMR (CDCl 3 /CD 3 H CO), 4.3 3 (d 2H, PhC H 2 CH), 6.78 (d, 2H, PhC H 2 N), 7.21 7.47(m, 10H, C 6 H 5 ), 8.98 (broad s, 1H, N H ) 7.2 4 7. 45 (m, 10H, C 6 H 5 ). 13 C NMR (CDCl 3 /CD 3 CO 173 8 165 1 cm 1

PAGE 117

117 3 Benzyl 5,5 diphenylimidazoidine 2,4 dione 85 a The hydantoin was synthesized through carbonylation procedure B. 1 H NMR (CDCl 3 /CD 3 26 (s, 2H, PhC H 2 N), 7.15 7.60 (m, 15 H, C 6 H 5 ), 7.88 (broad s, 1H, N H CO 1734, 1650 cm 1 Phenytoin, 86 a The hydantoin was synthesized through carbonylation procedure B. 1 H NMR ( 7.15 7.60 (m, 1 0 H, C 6 H 5 ), 9.30 (broad s, 1H, N H ) 10.54 CO 17 29 16 6 0 cm 1 13 68.4, 122.3, 123.5, 124.3, 137.5, 164.1, 172.6. IR (solid) CO 1732, 1654 cm 1 General Procedure C f or N Boc Protection of Amino A cid s to F orm 100 In a 100 mL round bottom flask, 10 .0 mmol of ( ) 3 aminobutanoic acid (1.03 g) was slurried in 10 mL tert butanol and 10 mL 1.0 N NaOH then cooled to 0 C in accordance with literature procedure. 204 Then 11 .0 mmol Boc 2 O (2.40 g) was added in one portion str ired at 0 C for 10 minutes, then allowed to warm to room temperature. The pH of the reaction mixture was adjusted continuously to pH 9 10 by adding 4.0 N NaOH. The reaction stirred for a total of 3 hours, after which the mixture was concentrated to appro ximately 15 mL by reduced pressure. The remaining aqueous

PAGE 118

118 layer was covered with EtOAc and cool ed to 0 C where it was then acidified to pH 1 2 using 5.0 N HCl. The organics were separated and the aqueous layer extracted with EtOAc three times with 25 mL The organics were combined and dried over MgSO 4 filtered and volatiles were then removed by reduced pressure. The resulting oil was purified by column chromatography starting with 3% MeOH/DCM and gradient shifting to 5% MeOH/DCM after 500 mL, resultin g in 1.78 g of amino acid 100 Yield 88%. Product identification was made by comparison to literature data. 204 1 H NMR (CDCl 3 ) 1.21 (d, 3H, C H 3 ), 1.40 (s, 9 H, C(C H 3 ) 3 ), 2.42 (d 2 H, C H 2 ), 3.96 ( m, 1 H, C H CH 3 ), 5.2 ( broad s, 1 H, BocN H ). 13 C NMR (CDCl 3 ) 20.9, 28.6, 43.0, 43.8, 70.6, 155.7, 170.9. 3 ( ( tert butoxycarbonyl)amino) 3 phenylpropanoic acid 101 The procedure followed was the same as described in general procedure C to afford compound 100 1 H NMR (CDCl 3 ) 1.40 (broad s, 9H, C(C H 3 ) 3 ), 2.84 (broad s, 2H, C H 2 ), 5.09 (broad s, 1H, C H Ph), 5.54 (broad s, 1H, N H Boc), 7.25 7.36 (m, 5H, C 6 H 5 ), 9.90 (broad s, 1H, COO H ). 13 C NMR (CDCl 3 ) 21.1, 28.5, 31.8, 7 1.2, 126.4, 127.7, 128.8, 155.2, 164.8, 181.8. HRMS [M+Na] + calcd 288.1206, found 288.1193. 3 ( ( tert butoxycarbonyl)amino) 4 phenylbutanoic acid 102 The procedure followed was the same as d escribed in general procedure C to afford compound 100 1 H NMR (CDCl 3 ) 1.41 (s, 9H, C(C H 3 ) 3 ), 2.53 ( d, 2H,

PAGE 119

119 CHC H 2 COOH), 2.86 (m, 1H, NHC H CH 2 ), 4.18 (d, 2H, PhC H 2 ), 7.20 7.32 (m, 5H, C 6 H 5 ). 13 C NMR (CDCl 3 ) 21.5, 28.4, 39.3, 43.8, 72.4 126.7, 128.0, 129.5, 138.3, 155.2, 170.9. 3 ( ( tert butoxycarbonyl)amino) 4 methylpentanoic acid 103 The procedure followed was the same as described in general procedure C to afford compound 100 1 H NMR (CDCl 3 ) 0.92 (d, 6H, C H (C H 3 ) 2 ), 1.44 (s, 9H, C(C H 3 ) 3 ), 1.86 (m, 1H, C H (CH 3 ) 2 ), 2.55 (d, 2H, CH 2 COOH), 3.76 (m, 1H, CHNHC H CH 2 ). 13 C NMR (CDCl 3 ) 18.7, 19.6, 28.6, 31.9, 37.4, 6 3.1, 155.9, 177.3. General Procedure D f or Mixed An h ydride Coupling of Amino A cid 99 to F or m 104 Into a 100 mL round bottom flask were placed 5.29 mmol of N Boc alanine (1.00 g) and 6.6 mmol N methylmorpholine (0. 66 g ). The flask was cooled to 78 C and 6.61 mmol isobutylchloroformate (0.8 8 g ) was added and stirred for 5 minutes. Then 6.61 mmol benzylamine (0.7 1 mL) was added a nd stirred for 10 minutes before allowing the flask to warm to room temperature. The reaction then stirred for one and a half hours after which solid was removed and washed with hexanes. The filtrate was concentrated by reduced pressure then re suspended in hexanes and filtered again. The solids were combined and purified by column chromatography 95/5 (DCM:MeOH). Isolated 1.37 g,

PAGE 120

120 93% yield of 104 1 H NMR (CDCl 3 ) 1.42 (s, 9H, C(C H 3 ) 3 ), 2.45 (t, 2H, C H 2 CONHBn) 3.42 (t, 2H, C H 2 NHBoc), 5.21 (broad s, 1H, N H ), 6.15 (broad s, 1H, N H ), 7.24 7.33 (m, 5H, C 6 H 5 ) 13 C NMR (CDCl 3 ) 20.5, 31.3, 36.1, 44.1, 63.7, 126.7, 127.1, 128.2, 137.4, 155.4, 173.9. HRMS [M+Na] + calcd 301.1523, found 301.1515. 3 ( ( tert butoxycarbonyl)amino) N benzyl butanamide 105 The pr ocedure followed was the same as described in general procedure D to afford compound 10 4 1 H NMR (CDCl 3 ) 1.23 (d, 3H, CHC H 3 ), 2.42 (t, 2H, CHC H 2 CO), 3.97 (sextet, 1H, NHBocC H ), 4.42 (d, 2H, NHC H 2 Ph), 5.21 (broad s, 1H, N H ), 6.25 (broad s, 1H, N H ), 7.26 7.34 (m, 5H, C 6 H 5 ). 13 C NMR (CDCl 3 ) 20.7, 26.8, 28.4, 33.7, 43.5, 79.4, 127.5, 127.7, 128.7, 138.1, 155.4, 170.6. HRMS [2M+Na] + calcd 607.3466, found 607.3454. 3 ( ( tert butoxycarbonyl)amino) N benzyl 3 phenyl propanamide 106 The procedure followed was the same as described in general procedure D to afford compound 10 4 Compound 106 was u nable to be purified so the crude product was carried to the deprotection step and used without purification 3 ( ( tert butoxycarbonyl)amino) N benzyl 4 ph enyl butanamide 107 The procedure followed was the same as described in general procedure D to afford compound 10 4 1 H NMR (CDCl 3 ) 1.39 (s, 9H, C(C H 3 ) 3 ), 2.46 (d, 2H,

PAGE 121

121 CHC H 2 CO), 4.12 (m, 1H, C H NHBoc), 4.40 (d, 2H, NHC H 2 Ph), 4.47 (d, 2H, PhC H 2 CH), 5.42 (broad s, 1H, N H), 5.94 (broad s, 1H, N H), 7.15 7.34 (m, 10H, aromatics). 13 C NMR (CDCl 3 ) 20.1, 28.6, 33.7, 43.8, 49.8, 59.6, 126.7, 127.7, 128.0, 128.7, 129.0, 129.5, 138.2, 138.6, 155.7, 170.9. 3 ( ( tert butoxycarbonyl)amino) N benzyl 4 met hyl penta namide 108 The procedure followed was the same as described in general procedure D to afford compound 10 4 1 H NMR (CDCl 3 ) 0.91 (d, 6H, CH(C H 3 ) 2 ), 1.39 (s, 9H, C(C H 3 ) 3 ), 1.83 (m, 1H, C H (CH 3 ) 2 ), 2.46 ( d 2 H, NHC H C H 2 ), 3.67 (m, 1H, NHC H CH 2 ), 4.41 (d, 2H, NHC H 2 Ph), 5.07 (broad s, 1H, NH), 6.47 (broad s, 1H, NH). 13 C NMR (CDCl 3 ) 19.4, 28.3, 32.1, 39.5, 43.6, 53.4, 63.1, 127.4, 127.7, 128.6, 138.2, 163.4, 166.7. General Procedure E f or Dep ro tection of N Boc Amino Amide 104 to Form 109 Compound 104 4.91 mmol (1.36 g), was placed in a round bottom flask and dis solved in 10 mL DCM. Then 24.6 mmol (6.13 mL) of 4.0 M HCl in dioxane was added and stirred for 18 hours. After reaction time, the excess HCl was removed by sparging with N 2 The resulti ng solid was purified via column chromatography using 5% MeOH in DCM and gradient shifting 2.5% MeOH increases per 400 mL eluent used until a final percentage of 15% MeOH/DCM was achieved. Isolated 109 0.832 g, 95% yield

PAGE 122

122 1 H NMR (CDCl 3 /CD 3 OD) 2.55 (t, 2 H, CH 2 C H 2 CO), 3.04 (t, 2H, NH 2 C H 2 CH 2 ), 4.22 (s, 2H, NHC H 2 Ph) 7.08 7.20 (m, 5H, C 6 H 5 ). 13 C NMR (CDCl 3 /CD 3 OD) 31.0, 35.8, 42.9, 126.8, 127.0, 128.0, 137.4, 170.2. HRMS [M+H] + calcd 179.1179, found 179.1175. 3 amino N benzyl butanamide 110 The procedure followed was the same as described in general procedure E to afford compound 10 9 1 H NMR (CDCl 3 /CD 3 OD) H 3 ), 2.50 (d, 2H, CHC H 2 CO), 3.51 (m, 1H, CH 3 C H CH 2 ), 4.25 ( s 2H, NHC H 2 Ph), 7.13 7.20 (m, 5H, C 6 H 5 ). 13 C NMR (CDCl 3 /CD 3 OD) 164.7. 3 amino N benzyl 3 phenyl propanamide 111 The procedure followed was the same as described in general procedure E to afford compound 10 9 1 H NMR (CDCl 3 /CD 3 OD) H C H 2 CO ), 4.10 (d, 2H, NHC H 2 Ph), 4.81 (t, 1H,PhC H CH 2 ), 7.15 7.35 (m, 10H, aromatics). 13 C NMR (CDCl 3 /CD 3 39.3, 44.2, 48.4, 127.1, 127.6, 127.9, 128.2, 128.7, 129.1, 135.4, 137.2, 171.9.

PAGE 123

123 3 amino N benzyl 4 phenyl butanamide 112 The procedure followed was the same as described in the general procedure to afford compound 10 9 1 H NMR (CDCl 3 /CD 3 OD) H 2 CO), 2.99 (dd, 1H, PhC H 2 CH), 3.29 (dd, 1H, PhC H 2 CH), 3.88 (m, 1H, PhCH 2 C H CH 2 ), 7.10 7.525 (m, 10H, aromatics). 13 C NMR (CDCl 3 /CD 3 OD) 127.7, 128.6, 128.9, 129.5, 135.9, 137.7, 174.9. HRMS [M+H] + calcd 269.1648, found 269.1639. 3 amino N benzyl 4 methyl pentanamide 113 The procedure followed was the same as described in general procedure E to afford compound 10 9 1 H NMR (CDCl 3 /CD 3 OD) H 3 ) 2 ), 1.87 (m, 1H, C H (CH 3 ) 2 ), 2.48 (d, 2H, CHC H 2 CO), 3.17 (m, 1H, NH 2 C H CH 2 ), 4.23 (d, 2H, NHC H 2 Ph), 7.10 7.17 (m, 5H, C 6 H 5 ). 13 C NMR (CDCl 3 /CD 3 OD) 5, 127.1, 127.8, 128.2, 137.4, 173.3. HRMS [M+H] + calcd 221.1648, found 221.1656. General Procedure F f or Carbonylation of Amino Amides 109 112 to Form 109 a 112 a To a 300 mL glass lined Parr high pressure vessel containing 20 mL of 1,2 dichloroethane were added amino amide 109 (99 mg, 0.55 mmol), W(CO) 6 (14 mg, 0.04 mmol), I 2 (98 mg, 0.39 mmol), and DBU (0.09 4 g 0.61 mmol). The vessel was then charged with 80 a tm CO and heated to 45 C for 24 hours with constant stirring.

PAGE 124

124 After cooling, the pressure was released and 20 mL of 95/5 (DCM:MeOH) was added. The organics were then washed immediately with Na 2 SO 3 and separated. The aqueous layer was then extracted wit h 3:1 CHCl 3 /EtOH solution (3 x 20 mL). The combined organic layers were then dried with MgSO 4 filtered, and concentrated. The resulting residue was then purified via flash column chromatography using DCM/EtOAc (80:20) to afford 3 benzyl dihydropyrimidin e 2,4(1 H ) dione 109 a 1 H NMR (CDCl 3 /CD 3 OD) 2.49 (t, 2H, CH 2 C H 2 CONCH 2 Ph), 3.53 (q, 2H, NHC H 2 CH 2 ), 4.39 (d, 2H, NC H 2 Ph), 7.19 7.34 (m, 5H, C 6 H 5 ). 13 C NMR (CDCl 3 /CD 3 OD) 128.3, 137.9, 159.0, 170.9. CO 1726 167 8 cm 1 The product was identified by comparison to literature values. 206 Urea 110 a The procedure followed was the same as described in general procedure F to afford compound 1 10 a 1 H NMR (DMSO) H 3 ), 2.31 (d, 2H, CHC H 2 CO), 3.92 (m, 1H, CH 3 C H CH 2 ), 4.25 (d, 2H, NCH 2 Ph), 7.21 7.29 (m, 5H, C 6 H 5 ), 8.33 (s, 1H, NH). 13 C NMR (DMSO) 31.8, 32.3, 57.9, 127.4, 127.9, 128.9, 134.8, 154.2, 171.0. CO 1651, 1687 cm 1

PAGE 125

125 Urea 111 a The procedure followed was the same as described in general procedure F to afford compound 1 11 a 1 H NMR (DMSO) H 2 CO), 4.21 (t, 1H, PhC H CH 2 ), 5.10 (d, 2H, NC H 2 Ph), 7.13 7.28 (m, 10 H, C 6 H 5 ). 13 C 43.9, 50.4, 126.2, 126.7, 126.9, 127.1, 127.6, 128.8, 132.1, 133.6, 153.0, 178.4. IR CO 1665, 1698 cm 1 Urea 112 a The procedure followed was the same as described in general procedure F to afford compound 1 12 a 1 H NMR (CDCl 3 /CD 3 OD) H 2 CO), 2.81 (d, 2H, PhC H 2 CH), 4.14 (quintet, 1H, PhCH 2 C H CH 2 ), 4.36 (d, 2H, NC H 2 Ph), 7.12 7.34 (m, 10H, aromatics), 7.71 (broad s, 1H, N H ). 13 C NMR (CDCl 3 /CD 3 OD) 53.2, 130.5, 131.4, 131.7, 132.4, 132.7, 133.4, 142.1, 142.3, 162.2, 175.9 IR (solid) CO 1637, 1684 cm 1 HRMS [M+H] + calcd 563.3017, found 563.3013.

PAGE 126

126 APPENDIX A CRYSTALLOGRAPHIC DAT A AND STRUCTURE REFI NEMENT OF 11 Empirical formula C 36 H 28 Zr Formula weight 551.80 Temperature 173(2) K Wavelength 0.71073 Crystal system Monoclinic Space group C2/c Unit cell dimensions Volume 2808.1(3) 3 Z 4 Density (calculated) 1.305 Mg/m 3 Absorption coefficient 0.413 mm 1 F(000) 1136 Crystal size 0.19 x 0.11 x 0.04 mm 3 Theta range for data collection 2.18 to 27.50 Index ranges Reflections collected 9334 Independent reflections 3226 [R(int) = 0.0272] Completeness to theta = 27.50 99.8 % Absorption correction Integration Max. and min. transmission 0.9861 and 0.9103 Refinement method Full matrix least squares on F 2 Data / restraints / parameters 3226 / 0 / 168 Goodness of fit on F 2 1.065 Final R indices [I> 2sigma(I)] R1 = 0.0244, wR2 = 0.0676 [2730] R indices (all data) R1 = 0.0312, wR2 = 0.0700 Largest diff. peak and hole 0.300 and 0.346 e. 3 o | |F c o | wR 2 = [ [ w ( F o 2 F c 2 ) 2 ] / [ o 2 2 ]] 1/2 o 2 F c 2 ) 2 ] / (n p)] 1/2 w= 2 (F o 2 )+(m*p) 2 +n*p], p = [max(F o 2 ,0)+ 2* F c 2 ]/3, m and n are constants.

PAGE 127

127 LIST OF REFERENCES 1 Parmeter, J. E.; Smith, D. C.; Healy, M. D. J. Vac. Sci. Technol., A 1994 12 2107 2113. 2 He, X. M.; Shu, L.; Li, H. B.; Weng, D. J. Mater. Res. 1999 14 615 618. 3 Mackie, W. A.; Xie, T. B.; Davis, P. R. J. Vac. Sci. Technol. B 1995 13 2459 2463. 4 Holmberg, K.; Matthews, A. Coatings Tribology: Properties, Techniques, and Applications i n Surface Engineering ; Elsevier: Amsterdam, 1994. 5 Reynolds, G. H. J. Nucl. Mater. 1974 50 215 216. 6 Xie, T.; Mackie, W. A.; Davis, P. R. J. Vac. Sci. Technol., B. 1996 14 2090. 7 D'Alessio, L.; Santagata, A.; Teghil, R.; Zaccagnino, M.; Zaccardo, I.; Marotta, V.; Ferro, D.; De Maria, G. Appl. Surf. Sci. 2000 168 284 287. 8 Zhang, Q.; He, J.; Liu, W.; Zhong, M. Surf. Coat. Technol. 2003 162 140 146. 9 Chen, C. S.; Liu, C. P.; Tsao, C. Y. A. Thin Solid Films 2005 479 130 136. 10 Hollabaugh, C. M.; Wahman, L. A.; Reiswig, R. D.; White, R. W.; Wagner, P. Nucl. Technol. 1977 35 527 535. 11 Ogawa, T.; Ikawa, K.; Iwamoto, K. J. Mater. Sci. 1979 14 1 25 132. 12 Wagner, P.; Wahman, L. A.; White, R. W.; Hollabaugh, C. M.; Reiswig, R. D. J. Nucl. Mater. 1976 62 221 228. 13 Ducarroir, M.; Salles, P.; Bernard, C. J. Electrochem. Soc. 1985 132 221 228. 14 Liu, Q.; Zhang, L.; Cheng, L.; Wang, Y. J. Coat. Technol. Res. 2009 6 269 273. 15 Pattanaik, A. K.; Sarin, V. K. In Chemical Vapor Deposition ; Park, J. H., Ed.; ASM International: Materials Park, 2001; Vol. 2, p 23. 16 Samoilenko, V. G.; Pereselentseva, L. N. Powder Metall. Met. Ceram. 1975 14 725 728. 17 Brggert, M.; Hu, Z.; Httinger, K. J. Carbon 1999 37 2021 2030. 18 Pierson, H. O. Handbook of Chemical Vapor Deposition (CVD): Principles, Technology, and Ap p lications ; William Andrew Publishing: New York, 1992.

PAGE 128

128 19 Ogawa, T.; Ikawa, K.; Iwamoto, K. J. Nucl. Mater. 1981 97 104 112. 20 Scussel, H. J. ASM Handbook ; ASM Int.: New York, 1992; Vol. 18. 21 Glass, J. A., Jr.; Palmisiano, N., Jr.; Welsh, R. E. Mater. Res. Soc. Symp. Proc. 1999 555 185 190. 22 Blair, H. T.; Carroll, D. W.; Matthews, R. B. AIP Conf. Proc. 1991 217 1052 1058. 23 Wu, Y. D.; Peng, Z. H.; Chan, K. W. K.; Liu, X. Z.; Tuinman, A. A.; Xue, Z. L. Organometallics 1999 18 2081 2090. 24 Girolami, G. S.; Jensen, J. A.; Gozum, J. E.; Pollina, D. M. Mater. Res. Soc. Symp. Proc. 1988 121 429 438. 25 Smith, D. C.; Rubiano, R. R.; Healy, M. D.; Springer, R. W. Proc. Electrochem. Soc. 1993 93 2 417 424. 26 Won, Y. S.; Varanasi, V. G.; Kryliouk, O.; Anderson, T. J.; McElwee White, L.; Perez, R. J. J. Cryst. Growth 2007 307 302 308. 27 Won, Y. S.; Kim, Y. S.; Varanasi, V. G.; Kryliouk, O.; Anderson, T. J.; Sirimanne, C. T.; McElwee White, L. J. Cryst. Growth 2007 304 324 332. 28 S irimanne, C. T.; McElwee White, L.; Won, Y. S.; Kryliouk, O.; Anderson, T. J. Abstr. Pap. Am. Chem. Soc. 2005 230 U2024 U2025. 29 Polk, J. An Overview of JPL's Advanced Propulsion Concepts Research Program 2001. 30 Temple, D. Mater. Sci. Eng., R. 1999 24 185 239. 31 Smith, D. C.; Rubiano, R. R.; Healy, M. D.; Springer, R. W. Mater. Res. Soc. Symp. Proc. 1993 282 643 649. 32 Girolami, G. S.; Jensen, J. A.; Pollina, D. M.; Williams, W. S.; Kaloyeros, A. E.; Allocca, C. M. J. Am. Chem. Soc. 19 87 109 1579 1580. 33 Cheon, J.; Rogers, D. M.; Girolami, G. S. J. Am. Chem. Soc. 1997 119 6804 6813. 34 Cheon, J.; Dubois, L. H.; Girolami, G. S. J. Am. Chem. Soc. 1997 119 6814 6820. 35 Wu, Y. D.; Peng, Z. H.; Xue, Z. L. J. Am. Chem. Soc. 1996 118 9772 9777.

PAGE 129

129 36 Wojcicki, A. Inorg. Chem. Commun. 2002 5 82 97. 37 Pedly, J. B.; Naylor, R. D.; Kirby, S. P. Thermochemical Data for Organic Compunds ; Chapman and Hall: London, 1986. 38 Doherty, S.; Corrigan, J. F.; Carty, A. J.; Sappa, E. Adv. Organomet. Chem. 1995 37 39 130. 39 Blosser, P. W.; Schimpff, D. G.; Gallucci, J. C.; Wojcicki, A. Organometallics 1993 12 1993 1995. 40 Casey, C. P.; Yi, C. S. J. Am. Chem. Soc. 1992 114 6597 6598. 41 Dewar, M. J. S.; Thiel, W. J. Am. Chem. S oc. 1977 99 4907 4917. 42 Hughes, A. K.; Kingsley, A. J. J. Organomet. Chem. 1997 539 109 114. 43 McAlexander, L. H.; Li, L.; Yang, Y.; Pollitte, J. L.; Xue, Z. Inorg. Chem. 1998 37 1423 1426. 44 Lai, T. Y. Bull. Soc. Chim. Fr. 1933 53 1533. 45 Lappin, G. R. J. Am. Chem. Soc. 1949 71 3966 3968. 46 Gaudemar, M. Ann. Chim. 1956 1 190 202. 47 Lewekebandara, T. S.; Sheridan, P. H.; Heeg, M. J.; Rheingold, A. L.; Winter, C. H. Inorg. Chem. 1994 33 5879 5889. 48 Interrante, L. V.; Sigel, G. A.; Garbauskas, M.; Hejna, C.; Slack, G. A. Inorg. Chem. 1989 28 252 257. 49 Bchir, O. J.; Green, K. M.; Hlad, M. S.; Anderson, T. J.; Brooks, B. C.; Wilder, C. B.; Powell, D. H.; McElwee White, L. J. Organomet. Chem. 2003 684 338 350. 50 Blosser, P. W.; Gallucci, J. C.; Wojcicki, A. J. Organomet. Chem. 2000 597 125 132. 51 Costuas, K.; Saillard, J. Y. Chem. Commun. 1998 18 2047 2048. 52 Gleiter, R.; Bethke, S.; Okubo, J.; Jonas, K. Organometallics 2001 20 4274 4278. 53 Bendjaballah, S.; Kahlal, S.; Costuas, K.; Bvillon, E.; Saillard, J. Y. Chem. -Eur. J. 2006 12 2048 2065.

PAGE 130

130 54 Summerscales, O. T.; Cloke, F. G. N. Coord. Chem. Rev. 2006 250 1122 1140. 55 Becke, A. D. J. Chem. Phys. 1993 98 5648 5 652. 56 Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988 37 785 789. 57 Vosko, S. H.; Wilk, L.; Nusair, M. Can. J. Phys. 1980 58 1200 1211. 58 Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. J. Phys. Chem. 1994 98 11623 11627. 59 Becconsall, J. K.; O'Brien, S. Chem. Commun. 1966 302 303. 60 Jennings, J. R. J. Mol. Catal. 1990 58 95 105. 61 Chrusciel, R. A.; Strohbach, J. W. Curr. Top. Med. Chem. 2004 4 1097 1114. 62 De Lucca, G. V.; Lam, P. Y. S. Drugs Future 1998 23 987 994. 63 Semple, G.; Ryder, H.; Rooker, D. P.; Batt, A. R.; Kendrick, D. A.; Szelke, M.; Ohta, M.; Satoh, M.; Nishida, A.; Akuzawa, S.; Miyata, K. J. Med. Chem. 1997 40 331 341. 64 Dragovich, P. S.; Barker, J. E.; French, J.; Imbacuan, M.; K alish, V. J.; Kissinger, C. R.; Knighton, D. R.; Lewis, C. T.; Moomaw, E. W.; Parge, H. E.; Pelletier, L. A. K.; Prins, T. J.; Showalter, R. E.; Tatlock, J. H.; Tucker, K. D.; Villafranca, J. E. J. Med. Chem. 1996 39 1872 1884. 65 vonGeldern, T. W.; Ke ster, J. A.; Bal, R.; WuWong, J. R.; Chiou, W.; Dixon, D. B.; Opgenorth, T. J. J. Med. Chem. 1996 39 968 981. 66 Vishnyakova, T. P.; Golubeva, I. A.; Glebova, E. V. Russ. Chem. Rev. (Engl. Transl.) 1985 54 249 261. 67 DeLucca, G. V.; Liang, J.; Aldrich, P. E.; Calabrese, J.; Cordova, B.; Klabe, R. M.; Rayner, M. M.; Chang, C. H. J. Med. Chem. 1997 40 1707 1719. 68 Lam, P. Y. S.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.; De, L. G. V.; Rodgers, J. D. WO Patent 941 9329, 1994 69 Lam, P. Y. S.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.; Ru, Y.; Bacheler, L. T.; Meek, J. L.; Otto, M. J.; Rayner, M. M.; Wong, Y. N.; Chang, C. H.; Weber, P. C.; Jackson, D. A.; Sharpe, T. R.; Erickson Viitanen, S. Science 1994 263 380 384.

PAGE 131

131 70 Qian, F.; McCusker, J. E.; Zhang, Y.; Main, A. D.; Chlebowski, M.; Kokka, M.; McElwee White, L. J. Org. Chem. 2002 67 4086 4092. 71 Ragaini, F. Dalton Trans. 2009 6251 6266. 72 Giannoccaro, P.; Tommasi, I.; Aresta, M. J. Organomet. Che m. 1994 476 13 18. 73 Sartori, G.; Maggi, R. In Science of Synthesis ; Ley, S. V., Knight, J. G., Eds.; Thieme: Stuttgart, 2005; Vol. 18, pp 665 758. 74 Hegarty, A. F.; Drennan, L. J. In Comprehensive Organic Functional Group Transformations ; Katritzky, A. R., Meth Cohn, O., Rees, C. W., Eds.; Pergamon: Oxford, 1995; Vol. 6, pp 499 526. 75 Bigi, F.; Maggi, R.; Sartori, G. Green Chem. 2000 2 140 148. 76 Hylton, K. G.; Main, A. D.; McElwee White, L. J. Org. Chem. 2003 68 1615 1617. 77 Daz, D. J.; Hylton, K. G.; McElwee White, L. J. Org. Chem. 2006 71 734 738. 78 Trost, B. M. Angew. Chem. Int. Edit. Engl. 1995 34 259 281. 79 Klausener, A.; Jentsch, J. D. In Applied Homogeneous Catalysis with Organometallic Compounds (2nd Edition ) ; Cornils, B., Herrmann, W. A., Eds.; VCH: Weinheim, 2002; Vol. 1, pp 164 182. 80 Gabriele, B.; Salerno, G.; Costa, M. In Catalytic Carbonylation Reactions ; Beller, M., Ed.; Springer: Heidelberg, 2006, pp 239 272. 81 McCusker, J. E.; Logan, J.; McElwe e White, L. Organometallics 1998 17 4037 4041. 82 McCusker, J. E.; Qian, F.; McElwee White, L. J. Mol. Catal. A Chem. 2000 159 11 17. 83 McCusker, J. E.; Grasso, C. A.; Main, A. D.; McElwee White, L. Org. Lett. 1999 1 961 964. 84 McCusker, J. E.; Main, A. D.; Johnson, K. S.; Grasso, C. A.; McElwee White, L. J. Org. Chem. 2000 65 5216 5222. 85 Li, K. T.; Peng, Y. J. J. Catal. 1993 143 631 634.

PAGE 132

132 86 Srivastava, S. C.; Shrimal, A. K.; Srivastava, A. J. Organomet. Chem. 1991 414 65 69. 87 Dombek, B. D.; Angelici, R. J. J. Catal. 1977 48 433 435. 88 Li Juan, C.; Fu Ming, M.; Guang Xing, L. Catalysis Communications 2009 10 981 985. 89 Park, J. H.; Yoon, J. C.; Chung, K. Y. Adv. Synth. Catal. 2009 351 1233 1237. 90 Bassoli, A.; Rindone, B.; Tollari, S.; Chioccara, F. J. Mol. Catal. 1990 60 41 48. 91 Benedini, F.; Nali, M.; Rindone, B.; Tollari, S.; Cenini, S.; Lamonica, G.; Porta, F. J. Mol. Catal. 1986 34 155 161. 92 Liu, J. M.; Peng, X. G.; Liu, J. H.; Zhen g, S. Z.; Sun, W.; Xia, C. G. Tetrahedron Lett. 2007 48 929 932. 93 Giannoccaro, P.; Nobile, C. F.; Mastrorilli, P.; Ravasio, N. J. Organomet. Chem. 1991 419 251 258. 94 Hoberg, H.; Faans, F. J.; Riegel, H. J. J. Organomet. Chem. 1983 254 267 2 71. 95 Kondo, T.; Kotachi, S.; Tsuji, Y.; Watanabe, Y.; Mitsudo, T. Organometallics 1997 16 2562 2570. 96 Kotachi, S.; Kondo, T.; Watanabe, Y. Catal. Lett. 1993 19 339 344. 97 Mulla, S. A. R.; Gupte, S. P.; Chaudhari, R. V. J. Mol. Catal. 1991 67 L7 L10. 98 Mulla, S. A. R.; Rode, C. V.; Kelkar, A. A.; Gupte, S. P. J. Mol. Catal. A Chem. 1997 122 103 109. 99 Durand, D.; Lassau, C. Tetrahedron Lett. 1969 2329 2330. 100 Alper, H.; Vasapollo, G.; Hartstock, F. W.; Mlekuz, M.; Smith, D. J. H.; Morris, G. E. Organometallics 1987 6 2391 2393. 101 Chiarotto, I.; Feroci, M. J. Org. Chem. 2003 68 7137 7139. 102 Choudary, B. M.; Rao, K. K.; Pirozhkov, S. D.; Lapidus, A. L. Synth. Commun. 1991 21 1923 1927. 103 Gabriele, B.; Salerno, G.; Mancuso, R.; Costa, M. J. Org. Chem. 2004 69 4741 4750.

PAGE 133

133 104 Imada, Y.; Mitsue, Y.; Ike, K.; Washizuka, K.; Murahashi, S. Bull. Chem. Soc. Jpn. 1996 69 2079 2090. 105 Ozawa, F.; Soyama, H.; Yanagihara, H.; Aoyama, I.; Takino, H.; Izawa, K.; Yamamoto, T.; Yamamoto, A. J. Am. Chem. Soc. 1985 107 3235 3245. 106 Ozawa, F.; Sugimoto, T.; Yuasa, Y.; Santra, M.; Yamamoto, T.; Yamamoto, A. Organometallics 1984 3 683 692. 107 Shi, F.; Deng, Y. Q.; SiMa, T. L.; Yang, H. Z. Tetrahedron Lett. 2001 42 2161 2163. 108 Ozawa, F.; Yamamoto, A. Chem. Lett. 1982 865 868. 109 Tsuji, J.; Iwamoto, N. Chem. Commun. 1966 380. 110 Ronchin, L.; Vavasori, A.; Amadio, E.; Cavinato G.; Toniolo, L. J. Mol. Catal. 2009 23 23 30. 111 Zhao, Y.; Jin, L.; Peng, L.; Lei, A. J. Am. Chem. Soc. 2008 130 9429 9433. 112 Grosjean, C.; Novakovic, K.; Scott, S. K.; Whiting, A.; Willis, M. J.; Wright, A. R. J. Mol. Catal. 2008 284 33 39. 113 McCusker, J. E.; Abboud, K. A.; McElwee White, L. Organometallics 1997 16 3863 3866. 114 Fukuoka, S.; Chono, M.; Kohno, M. J. Org. Chem. 1984 49 1458 1460. 115 Shi, F.; Deng, Y. Q. Chem. Commun. 2001 443 444. 116 Shi, F.; Deng, Y. Q. J. C atal. 2002 211 548 551. 117 Waller, F. J. EP Patent 195515, 1986 118 Hiwatari, K.; Kayaki, Y.; Okita, K.; Ukai, T.; Shimizu, I.; Yamamoto, A. Bull. Chem. Soc. Jap. 2004 77 2237 2250. 119 Bitsi, G.; Jenner, G. J. Organomet. Chem. 1987 330 429 435. 120 Byerley, J. J.; Rempel, G. L.; Takebe, N.; James, B. R. J. Chem. Soc. D. 1971 1482 1483. 121 Jenner, G.; Bitsi, G. Appl. Catal. 1987 32 293 304.

PAGE 134

134 122 S ss Fink, G.; Langenbahn, M.; Jenke, T. J. Organomet. Chem. 1989 368 103 109. 123 Tsuji, Y.; Ohsumi, T.; Kondo, T.; Watanabe, Y. J. Organomet. Chem. 1986 309 333 344. 124 Chiusoli, G. P.; Costa, M.; Gabriele, B.; Salerno, G. J. Mol. Catal. A Chem. 1999 143 297 310. 125 Giannoccaro, P. J. Organomet. Chem. 1987 336 271 278. 126 Gupte, S. P.; Chaudhari, R. V. J. Catal. 1988 114 246 258. 127 Sheludyakov, Y. L.; Golodov, V. A. Bull. Chem. Soc. Jpn. 1984 57 251 253. 128 Alper, H.; Hartstock, F. W. J. Chem. Soc. Chem. Commun. 1985 1141 1142. 129 Pri Bar, I.; Alper, H. Can. J. Chem. Rev. Can. Chim. 1990 68 1544 1547. 130 Murahashi, S.; Mitsue, Y.; Ike, K. J. Chem. Soc. Chem. Commun. 1987 125 127. 131 Tam, W. J. Org. Chem. 1986 51 2977 2981. 132 Fukuoka, S.; Chono, M.; Kohno, M. J. Chem. Soc. Chem. Commun. 1984 399 400. 133 Kelkar, A. A.; Kolhe, D. S.; Kanagasabapathy, S.; Chaudhari, R. V. Ind. Eng. Chem. Res. 1992 31 172 176. 134 Gabriele, B.; Salerno, G.; Brindisi, D.; Costa, M.; Chiusoli, G. P. Org. Lett. 2000 2 625 627. 135 Gabriele, B.; Mancuso, R.; Salerno, G.; Costa, M. Chem. Commun. 2003 486 487. 136 Aresta, M.; Giannoccaro, P.; Tommasi, I.; Dibenedetto, A.; Lanfredi, A. M. M.; Ugozzoli, F. Organometallics 2000 19 3879 3889. 137 Stahl, S. S. Angew. Chem. Int. Ed. 2004 43 3400 3420. 13 8 Kanagasabapathy, S.; Gupte, S. P.; Chaudhari, R. V. Ind. Eng. Chem. Res. 1994 33 1 6. 139 Bolzacchini, E.; Meinardi, S.; Orlandi, M.; Rindone, B. J. Mol. Catal. A Chem. 1996 111 281 287.

PAGE 135

135 140 Orejn, A.; Castellanos, A.; Salagre, P.; Castilln, S.; Claver, C. Can. J. Chem. 2005 83 764 768. 141 Giannoccaro, P.; De Giglio, E.; Garganno, M.; Aresta, M.; Ferragina, C. J. Mol. Catal. A Chem. 2000 157 131 141. 142 Presad, K. V.; Chaudhari, R. V. J. Catal. 1994 145 204 215. 143 Shi, F.; Zhang, Q.; Ma, Y.; He, Y.; Deng, Y. J. Am. Chem. Soc. 2005 127 4182 4183. 144 Jetz, W.; Angelici, R. J. J. Am. Chem. Soc. 1972 94 3799 3802. 145 Davies, S. G.; Mortlock, A. A. Tetrahedron Lett. 1991 32 4791 4794. 146 Smith, S. W.; Newman, M. S. J. Am. Chem. Soc. 1968 90 1249 1253. 147 De Lucca, G. V. J. Org. Chem. 1998 63 4755 4766. 148 Lam, P. Y. S.; Ru, Y.; Jadhav, P. K.; Aldrich, P. E.; DeLucca, G. V.; Eyermann, C. J.; Chang, C. H.; Emmett, G.; Holler, E. R.; Daneker, W. F.; Li, L. Z.; Confalone, P. N.; McHugh, R. J.; Han, Q.; Li, R. H.; Markwalder, J. A.; Seitz, S. P.; Sharpe, T. R.; Bacheler, L. T.; Rayner, M. M.; Klabe, R. M.; Shum, L. Y.; Winslow, D. L.; Kornhauser, D. M.; Jackson, D. A.; EricksonViitanen, S.; Hodge, C. N. J. Med. Chem. 1996 39 3514 3525. 149 Confalone, P. N.; Waltermire, R. E. In Process Chemistry in the Pharma ceutical Industry ; Gadamasetti, K. G., Ed.; Marcel Dekker: New York, 1999, pp 201 219. 150 Lam, P. Y.; Jadhav, P. K.; Eyermann, C. J.; Hodge, C. N.; De Lucca, G. V.; Rodgers, J. D. US Patent 5,610,294, 1997 151 Nugiel, D. A.; Jacobs, K.; Worley, T.; Pa tel, M.; Kaltenbach, R. F.; Meyer, D. T.; Jadhav, P. K.; DeLucca, G. V.; Smyser, T. E.; Klabe, R. M.; Bacheler, L. T.; Rayner, M. M.; Seitz, S. P. J. Med. Chem. 1996 39 2156 2169. 152 Rossano, L. T.; Lo, Y. S.; Anzalone, L.; Lee, Y. C.; Meloni, D. J.; Moore, J. R.; Gale, T. M.; Arnett, J. F. Tetrahedron Lett. 1995 36 4967 4970. 153 Hodge, C. N.; Aldrich, P. E.; Bacheler, L. T.; Chang, C. H.; Eyermann, C. J.; Garber, S.; Grubb, M.; Jackson, D. A.; Jadhav, P. K.; Korant, B.; Lam, P. Y. S.; Maurin, M. B.; Meek, J. L.; Otto, M. J.; Rayner, M. M.; Reid, C.; Sharpe, T. R.; Shum, L.; Winslow, D. L.; EricksonViitanen, S. Chem. Biol. 1996 3 301 314. 154 Pierce, M. E.; Harris, G. D.; Islam, Q.; Radesca, L. A.; Storace, L.; Waltermire, R. E.; Wat, E.; Jadha v, P. K.; Emmett, G. C. J. Org. Chem. 1996 61 444 450.

PAGE 136

136 155 DeClercq, P. J. Chem. Rev. 1997 97 1755 1792. 156 Zhang, Y.; Forinash, K.; Phillips, C. R.; McElwee White, L. Green Chem. 2005 7 451 455. 157 Mehta, N. B.; Diuguid, C. A. R.; Soroko, F. E. J. Med. Chem. 1981 24 465 468. 158 Gutschow, M.; Hecker, T.; Eger, K. Synthesis 1999 410 414. 159 Wessels, F. L.; Schwan, T. J.; Pong, S. F. J. Pharm. Sci. 1980 69 1102 1104. 160 Caldwell, A. G.; Ha rris, C. J.; Stepney, R.; Whittaker, N. J. Chem. Soc. Perkin Trans. 1 1980 495 505. 161 Sarges, R.; Bordner, J.; Dominy, B. W.; Peterson, M. J.; Whipple, E. B. J. Med. Chem. 1985 28 1716 1720. 162 Smith, R. J.; Bratovanov, S.; Bienz, S. Tetrahedron 1997 53 13695 13702. 163 LeTiran, A.; Stables, J. P.; Kohn, H. Bioorg. Med. Chem. 2001 9 2693 2708. 164 Hulme, C.; Ma, L.; Romano, J. J.; Morton, G.; Tang, S. Y.; Cherrier, M. P.; Choi, S.; Salvino, J.; Labaudiniere, R. Tetrahedron Lett. 2000 41 1889 1893. 165 Zhang, D.; Xing, X. C.; Cuny, G. D. J. Org. Chem. 2006 71 1750 1753. 166 Meusel, M.; Gutschow, M. Org. Prep. Proced. Int. 2004 36 391 443. 167 Beller, M.; Eckert, M.; Moradi, W. A.; Neumann, H. Angew. Chem. Int. Ed. 1999 38 1454 1457. 168 Talaty, E. R.; Yusoff, M. M.; Ismail, S. A.; Gomez, J. A.; Keller, C. E.; Younger, J. M. Synlett 1997 683 684. 169 Choi, D.; Stables, J. P.; Kohn, H. J. Med. Chem. 1996 39 1907 1916. 170 Andurkar, S. V.; Stables, J. P.; Kohn, H. Tetrahedron: Asymm. 1998 9 3841 3854. 171 Bailey, P. D.; Bannister, N.; Bernad, M.; Blanchard, S.; Boa, A. N. J. Chem. Soc., Perkin Trans. 1 2001 3245 3251. 172 Wolin, R. L.; Venkatesan, H.; Tang, L.; Santillan Jr., A.; Barclay, T.; Wilson, S.; Lee, D. H.; Lovenberg, T. W. Bioorg. Med. Chem. 2004 12 4477 4492. 173 Zhao, M. X. W. S. M. Tetrahedron: Asymm. 2002 13 1695 1702.

PAGE 137

137 174 Diaz, D. J. PhD Dissertation, Department of Chemistry, University of Florida, 2007 175 Mills, J. E.; Maryanoff, C. A.; Cosgrove, R. M.; Scott, L.; McComsey, D. F. Org. Prep. Proced. Int. 1984 16 97 114. 176 Hannon, S. J.; Kundu, N. G.; Hertzberg, R. P.; Bhatt, R. S.; Heidelberger, C. Tetrahedron Lett. 1980 21 1105 1108. 177 Chaudhuri N. K.; Mukherjee, K. L.; Heidelberger, C. Biochem. Pharmacol. 1959 1 328 341. 178 Mukherjee, K. L.; Heidelberger, C. J. Biol. Chem. 1960 235 433 437. 179 Suto, A.; Kubota, T.; Fukushima, M.; Ikeda, T.; Takeshita, T.; Ohmiya, H.; Kitajima, M. Oncolo. Rep. 2006 15 1517 1522. 180 LaFrate, A. L.; Katzenellenbogen, J. A. J. Org. Chem. 2007 72 8573 8576. 181 Kolodziej, S. A.; Hamper, B. C. Tetrahedron Lett. 1996 37 5277 5280. 182 Takano, M.; Mishima, H. Patent EP 1095935, 2001 183 Embr ey, M. W.; Wai, J. S.; Funk, T. W.; Homnick, C. F.; Perlow, D. S.; Young, S. D.; Vacca, J. P.; Hazuda, D. J.; Felock, P. J.; Stillmock, K. A.; Witmer, M. V.; Moyer, G.; Schleif, W. A.; Gabryelski, L. J.; Jin, L.; Chen, I. W.; Ellis, J. D.; Wong, B. K.; Lin J. H.; Leonard, Y. M.; Tsou, N. N.; Zhuang, L. Bioorg. Med. Chem. Lett. 2005 15 4550 4554. 184 Bocci, G.; Danesi, R.; Allegrini, G.; Innocenti, F.; Di Paolo, A.; Falcone, A.; Conte, P. F.; Del Tacca, M. Eur. J. Clin. Pharmacol. 2002 58 593 595. 185 Katritzky, A. R.; Nesbit, M. R.; Kurtev, B. J.; Lyapova, M.; Pojarlieff, I. G. Tetrahedron 1969 25 3807 3824. 186 Rouillier, P.; Delmau, J.; Duplan, J.; Nofre, C. Tetrahedron Lett. 1966 7 4189 4194. 187 Lee, C. K.; Shim, J. Y. Bull. Korean Che m. Soc. 1991 12 343 347. 188 Zee Cheng, K. Y.; Robins, R. K.; Cheng, C. C. J. Org. Chem. 1961 26 1877 1884. 189 Delpiccolo, C. M. L.; Albericio, F.; Schiksnis, R. A.; Michelotti, E. L. Tetrahedron 2007 63 8949 8953.

PAGE 138

138 190 Bhat, K. S.; Rao, A. S. Org. Prep. Proced. Int. 1983 15 303 312. 191 Kondo, Y.; Witkop, B. J. Am. Chem. Soc. 1969 91 5264 5270. 192 Duschinsky, R.; Pleven, E.; Heidelberger, C. J. Am. Chem. Soc. 1957 79 4559 4560. 193 Paryzek, Z.; Tabaczka, B. Org. Prep. Proced. Int. 2001 33 400 405. 194 Kundu, N. G.; Sikdar, S.; Hertzberg, R. P.; Schmitz, S. A.; Khatri, S. G. J. Chem. Soc. Perkin Trans. 1 1985 1295 1300. 195 Yamamoto, I.; Fukui, K. I.; Yamamoto, S.; Ohta, K.; Matsuzaki, K. Synthesis 1985 686 688. 196 Deck, L M.; Papadopoulos, E. P. J. Heterocyclic Chem. 2000 37 675 686. 197 Guemmout, F. E.; Foucaud, A. Synth. Commun. 1993 23 2065 2070. 198 Zhang, C.; Moran, E. J.; Woiwode, T. F.; Short, K. M.; Mjalli, A. M. M. Tetrahedron Lett. 1996 37 751 754. 19 9 Marzinzik, A. L.; Felder, E. R. Tetrahedron Lett. 1996 37 1003 1006. 200 Gordeev, M. F.; Patel, D. V.; Gordon, E. M. J. Org. Chem. 1996 61 924 928. 201 Goff, D. A.; Zuckerman, R. J. J. Org. Chem. 1995 60 5748 5749. 202 Wipf, P.; Cunningham, A. Tetrahedron Lett. 1995 36 7819 7822. 203 Wu, S.; Janusz, J. M. Tetrahedron Lett. 2000 41 1165 1169. 204 Yang, T.; Lin, C.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2005 7 4781 4784. 205 Pretsch, E.; Buhlmann, P.; Badertscher, M. Structure Determination of Organic Compounds ; 4th ed.; Springer: Berlin, 2009. 206 Beckwith, A. L. J.; Hickman, R. J. J. Chem. Soc. C. 1968 2756 2759. 207 Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic Compounds ; Wiley Interscience: New York, 1994. 208 Vogel, A. I.; Tatchell, A. R.; Furnis, B. S.; Hannaford, A. J.; P.W.G., S. Vogel's Textbook of Practical Organic Chemistry ; 5th ed.; Wiley: New York, 1996. 209 SHELXTL6 ; Bruk er AXS:Madison, Wisconsin, 2000

PAGE 139

139 210 Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Menn ucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniel s, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox D. J.; Keith, T.; Al Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, Revision B.04 2004 211 Gorelsky, S. I.; Lever, A. B. P. J. Organomet. Chem. 2001 635 187 196. 212 Gorelsky, S. I. AOMix: Program for Molecular Orbital Analysis ; University of Ottawa, 2009 213 Edward, J. T.; Lantos, I. Can. J. Chem. 1967 1925 1934. 214 Lazarus, R. A. J. Org. Chem. 1990 15 4755 4757. 215 Pham, T. Q.; P yne, S. G.; Skelton, B. W.; White, A. H. J. Org. Chem. 2005 16 6369 6377. 216 Sanders, M. L.; Donkor, I. O. Synthetic Commun. 2002 7 1015 1021. 217 Banjac, N.; Uscumlic, G.; Valentic, N.; Mijin, D. J. Solution Chem. 2007 36 869 878.

PAGE 140

140 BIOGRAPHICAL SKETCH Seth M. Dumbris was born in Evansville, Indiana February 22, 1982. He graduated from Model Laboratory High School in 2000. His undergraduate studies were conducted at Western Kentucky University as he was awarded a B.S. in chemistry i n May of 2004.