Transition Metal-Free Carbonylation of Amines to Formamides

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Transition Metal-Free Carbonylation of Amines to Formamides
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Gerack, Ciera Jane
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Doctorate ( Ph.D.)
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University of Florida
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Chemistry
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Mcelwee-White, Lisa Ann
Committee Members:
Castellano, Ronald K
Christou, George
Miller, Stephen Albert
Hagelin, Helena Ae

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amines -- carbonylation -- formamides
Chemistry -- Dissertations, Academic -- UF
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Chemistry thesis, Ph.D.
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Abstract:
Base-mediated carbonylation of amines provides an alternative to current methods of synthesizing formamides, which can involve high temperatures, metal catalysts, or stoichiometric equivalents of formic acid. The conditions for this reaction include potassium carbonate as base, an amine, and methanol as solvent in a vessel charged with CO. Optimization was done for base identity, time, promoter identity, pressure, and base quantity. It was determined that neither the promoter nor oxidant was necessary for this reaction. The optimal conditions for formamide synthesis from amines were amine, 35 atm CO, 3 equiv of K2CO3 as base, methanol as solvent, 7 h, and room temperature. Isotopic labeling experiments were conducted to determine the source of the formyl hydrogen and the carbonyl moiety, indicating that methanol oxidation is not the source of the carbonyl in the product. The functional group compatibility was examined using para-substituted benzyl amines. Substrates with electron-donating groups produced higher yields than substrates with electron-withdrawing groups. The scope of the reaction was examined using primary and secondary cyclic and acyclic aliphatic amines. Control experiments led us to propose a base mediated mechanism, proceeding through methyl formate as an intermediate.
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by Ciera Jane Gerack.
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Thesis (Ph.D.)--University of Florida, 2013.
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Adviser: Mcelwee-White, Lisa Ann.
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1 TRANSITION METAL FREE CARBONYLATION OF AMINES TO FORMAMIDES By CIERA JANE GERACK A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF D OCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2013

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2 2013 Ciera Jane Gerack

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3 To my parents, for everything.

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4 ACKNOWLEDGMENTS I am very grateful for all of the support I have received while completing my gr aduate work. I have been most fortunate to have Professor Lisa McElwee White as an advisor. She is an excellent mentor, always available for discussions when I needed insight and for encouragement when I was feeling unsure. I appreciate all of her valua ble guidance. I also thank my committee members, Dr. Ron Castellano, Dr. Steven Miller, Dr. George Christou, and Dr. Helena Haeglin Weaver for their time spent. I am appreciative of the entire McElwee White research group, past and present members. I than k Dr. Phil Shelton for introducing me to this project and for the training he supplied. I would like to acknowledge assistance I received by Lilli Carpo, a recent undergraduate, for her work on early optimization of this project. I thank Joseph anything and Kelsea Johnson for her ever present willingness to help and excellent has been a source of unwavering friendship. I also must acknowledge Jim Dale for his constant companionship as I completed hours of lab work. I truly doubt I would have been ab le to persevere without him. I thank my parents, Gary and Belinda Gerack. I thank my mother for our daily conversations that helped me maintain my sanity. I thank my father for being an inexhaustible source of support. I also thank my sisters Brittany a nd Kelsey. I am Special thanks go to my non UF chemist friends. I thank Anna Dawsey for being a source of constant encouragement and the best friend I could ever ask for. I thank

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5 Greg Goschy for his desire to help troubleshoot my problems even when I was just hoping to forget about chemistry. Last but certainly not least, I thank Clayton Hall for participating in this crazy journey with me. I thank him for being with me th ough the easy times, for supporting me though the hard times, and for challenging the way I think about everything.

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6 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............ 8 LI ST OF FIGURES ................................ ................................ ................................ .......... 9 LIST OF ABBREVIATIONS ................................ ................................ ........................... 12 ABSTRACT ................................ ................................ ................................ ................... 13 CHAPTER 1 I NTRODUCTION ................................ ................................ ................................ .... 15 General Formylation ................................ ................................ ............................... 15 Transition Metal Catalyzed Formylation ................................ ................................ .. 30 Conclusions ................................ ................................ ................................ ............ 44 2 CARBONYLATION USING TUNGSTEN CATALYSTS ................................ .......... 45 Initial Urea Formation ................................ ................................ .............................. 45 Urea Formation Using W(CO) 6 Catalyst ................................ ................................ 46 Cyclic Ureas ................................ ................................ ................................ ............ 48 Complex Targets ................................ ................................ ................................ .... 50 Ureas from Amino Alcohols ................................ ................................ .................... 52 Hydantoins ................................ ................................ ................................ .............. 53 Dihydrouracils ................................ ................................ ................................ ......... 53 Diarylureas ................................ ................................ ................................ ..... 54 Metal Free Carbonylation ................................ ................................ ....................... 55 Conclusions ................................ ................................ ................................ ............ 56 3 TRANSITION METAL FREE CARBONYLATION OF AMINES TO FORMAMIDES ................................ ................................ ................................ ....... 57 Early Optimization ................................ ................................ ................................ ... 57 Control Experiments ................................ ................................ ............................... 59 Isotopic Labeling Experiments ................................ ................................ ................ 59 A New Perspective ................................ ................................ ................................ 61 Conclusions ................................ ................................ ................................ ............ 62 4 BASE MEDIATED CARBONYLATION ................................ ................................ ... 63 Optimization ................................ ................................ ................................ ............ 63 Substituent Effects ................................ ................................ ................................ .. 64

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7 Other Amines ................................ ................................ ................................ .......... 67 Proposed Mechanism ................................ ................................ ............................. 69 Conclusions ................................ ................................ ................................ ............ 70 5 EXPERIMENTAL SECTION ................................ ................................ ................... 71 General Methods ................................ ................................ ................................ .... 71 General Procedure for Carbonylation of Amines to Formamides ............................ 71 Procedure A ................................ ................................ ................................ ..... 71 Procedure B ................................ ................................ ................................ ..... 72 Procedure C ................................ ................................ ................................ ..... 73 Procedure D ................................ ................................ ................................ ..... 74 Carbonylation Products ................................ ................................ ........................... 74 N (Methoxybenzyl)formamide d, p CH 3 OC 6 H 4 CH 2 NHCDO (44 d) ................... 74 N (4 Nitrobenzyl)formamide (68). ................................ ................................ ..... 75 N ( 4 Methylbenzyl)formamide (46). ................................ ................................ .. 75 N (4 Vinylbenzyl)formamide (48). ................................ ................................ ..... 75 N (4 Fluorobenzyl)formamide (52). ................................ ................................ .. 76 N (4 Iodobenzyl)formamide (54). ................................ ................................ ..... 76 N (4 Bromobenzyl)formamide (56). ................................ ................................ .. 77 N (4 Chloroben zyl)formamide (58). ................................ ................................ .. 77 Methyl 4 (formamidomethyl)benzoate (60). ................................ ...................... 77 N (4 Formamidomethyl)benzoic acid (62). ................................ ....................... 78 N (4 (Trifluromethyl)benzyl)formamide (64). ................................ .................... 78 N (4 Cyanobenzyl)formamide (66). ................................ ................................ .. 79 N Formylpyrrolidine (82). ................................ ................................ .................. 79 N Formylmorpholine (86). ................................ ................................ ................. 79 N Propylformamide (70). ................................ ................................ .................. 80 N Isopropylformamide (72). ................................ ................................ .............. 80 N Isobutylformamide (76). ................................ ................................ ................ 80 N Tertbutylformamide (78). ................................ ................................ .............. 80 N Cyclohexylformamide (80). ................................ ................................ ........... 81 LIST OF REFERENCES ................................ ................................ ............................... 82 BIOGRAPHICAL SKETCH ................................ ................................ ............................ 87

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8 LIST OF TABLES Table page 3 1 Selection of base for conversion of 42 to 44 ................................ ....................... 58 3 2 React ion time for conversion of 42 to 44 ................................ ........................... 58 3 3 Examination of promoter identity for the conversion of 42 to 44 ......................... 62 4 1 Time optimi zation for the conversion of 42 to 44 ................................ ................ 63 4 2 Base quantity optimization for the conversion of 42 to 44 ................................ .. 63 4 3 Pressure optim ization for 7 h reaction time for the conversion of 42 to 44 ........ 63 4 4 Pressure optimization for 24 h reaction time for the conversion of 42 to 44 ...... 63 4 5 Carbonylatio n of 4 substituted benzylamines ................................ ..................... 65 4 6 Carbonylation of 4 substituted benzylamines with NaIO 4 present ...................... 67 4 7 Carbonylation of primary amines to formamides ................................ ................ 68 4 8 Carbonylation of secondary amines to formamides ................................ ............ 68

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9 LIST OF FIGURES Figure pag e 1 1 Formylation using 1 ................................ ................................ ............................ 15 1 2 Formylat ion of amines using formic acid ................................ ............................ 16 1 3 Formylation of a sterically hindered amine ................................ ......................... 17 1 4 Formylation of aromatic amines using form ic acid and polyethylene glycol ........ 18 1 5 One step preparation of formamides by method A at reflux or met hod B via microwave irradiation ................................ ................................ .......................... 19 1 6 Pathway of formamide formation from formic acid an d 3 ................................ .... 19 1 7 General reactio n of MTSA catalyzed formylation ................................ ................ 20 1 8 Proposed reaction mechanism for MTSA catalyzed formylation ......................... 20 1 9 General formylation by formic acid in ammonium formate ................................ .. 21 1 10 Formylation of 5 without racemization of chiral center s ................................ ...... 21 1 11 Reaction of amine with triethyl orthoformate in water ................................ ......... 22 1 12 Formylation of amines by methyl formate and catalyst ................................ ....... 22 1 13 Amberlite IR 120 catalyzed formylation. F igure adapted from reference 25 ....... 23 1 14 Mechanism of I 2 catalyzed formylat ion ................................ ............................... 24 1 15 Solvent free formylation catalyzed by 9 ................................ .............................. 25 1 16 Proposed mechanistic pathway of formamide production with 9 ........................ 25 1 17 Silica supported acid catalyzed N formylation ................................ .................... 26 1 18 TBD based IL examined for catalytic activity towards N formylation .................. 27 1 19 Optimized conditio ns for IL catalyzed formylation ................................ ............... 27 1 20 Mechanistic p athway for formamide production ................................ .................. 27 1 21 Formylation of amines using CO catalyzed by 13 ................................ ............... 28 1 22 N formylation of secondary amines ................................ ................................ .... 29

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10 1 23 General mechanism of the formylation via the Reimer Tiemann reaction. F igure adapted from reference 30 ................................ ................................ ...... 29 1 24 Indium catalyzed formylation of amines ................................ .............................. 30 1 25 ZnO catalyzed formyla tion of amines with formic acid ................................ ........ 31 1 26 Solvent free formylation of amines using ZnCl 2 catalyst ................................ ..... 31 1 27 Formylation of amines by formic acid ................................ ................................ 32 1 28 Amine formylation from formic acid catalyzed by TiO 2 P25 or TiO 2 SO 4 2 .......... 33 1 29 Mechanism of TiO 2 P25 catalyzed formylation ................................ ................... 33 1 30 N formylation of amines with formic acid and sulfated tungstate catal yst ........... 34 1 31 N formylation catalyzed by FSG Hf[N(SO 2 C 8 F 17 ) 2 ] 4 ................................ ........... 35 1 32 Electronic assistance for nucleophilic attack of amine on formic acid ................. 35 1 33 Iridium catalyzed formylation of amines with paraformaldehyde ......................... 36 1 34 Formylation of dimethylamine wi th formaldehyde mediated by oxygen atoms on metallic surfaces. F igure adapted from reference 52 ................................ .... 37 1 35 N formylation of amines with methanol by nanogold particles ............................ 38 1 36 Ru NHC catalyzed methanol activation and formylation of amines .................... 39 1 37 Mechanism for Ru catalyzed methanol dehydrogenation followed by cross coupling with amine to produce the formamide ................................ .................. 40 1 38 N formylation of amines with for maldehyde by nanogold particles ..................... 41 1 39 Ruthenium ca talyzed carbonylation of amines ................................ ................... 42 1 40 Tungsten dimer catalyst ................................ ................................ ..................... 44 2 1 Phos gene and examples of derivatives ................................ .............................. 45 2 2 Carbonylation of amines using tungsten dimer ................................ ................... 46 2 3 Carbonylation of primary amines to ureas using W(CO) 6 /I 2 ................................ 46 2 4 Formation of 22 from secondary amines ................................ ............................ 48 2 5 Consumption of four equiv of ami ne to produce one equiv of urea ..................... 48

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11 2 6 Carbonylation of primary (R=H) and secondary (R=Me, Et, i diamines to form 22 ................................ ................................ ............................ 49 2 7 Carbonylation of 26 to form cyclic u rea 27 and tetrahydropyrimidine 25 ............ 49 2 8 Functionalized diamines ................................ ................................ ..................... 50 2 9 Carbonylation of diamines with protected alcohols to form 30 the core structure of 28 and 29 ................................ ................................ ......................... 50 2 10 Diamine substrates forming 30 by catalytic carbonylation ................................ .. 51 2 11 Comple x targets ................................ ................................ ................................ 51 2 12 Preparation of biotin derivatives (X=O, N Boc, CH 2 CH 3; R 1 =H, CH 3 ; R 2 =H, CH 3 (CH 2 ) 4 CH 3 ) ................................ ................................ ................................ 52 2 13 Selective carbonylation of amino alcohols to 34 ................................ ................. 52 2 14 Formation of hydantoins ( 37 ) ................................ ................................ .............. 53 2 15 Formation of dihydrouracils from unsubs tituted amino amides ........................... 54 2 16 Formation of 40 instead of 39 substituted amino amides were carbonylated ................................ ................................ ................................ ....... 54 2 17 Carbony diphenylurea ( 41 ) ................................ ............. 54 2 18 Oxidative carbonylation of 42 forming 43 and 44 ................................ ................ 56 2 19 Optimized condit ions for urea synthesis using NaIO 4 and NaI ........................... 56 3 1 Initial use of methanol solvent to form 44 from 42 ................................ .............. 57 3 2 Possible outcom es for incorporation of 13 C from labeled methanol .................... 60 3 3 Incorporation of deu terium from deuterated methanol ................................ ........ 60 4 1 Proposed mechanism for the base mediated pathway to formamides ............... 69

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12 LIST OF ABBREVIATIONS AFA Acetic formic anhydride atm Atmospheres CDI Carbonyldiimidazole CDMT 2 Chloro 4,6 dimethoxy[1,3,5]triazine DBU 1,8 Diazabicyclo[5.4.0]undec 7 ene DCC Dicyclohexylcarbodiimide DCE Dichloroethane DCM Dichloromethane DMAP 4 (Dimethylamino)pyridine DMDTC Dimethyldithiocarbamate DMF Dimethylformamide DMSO Dimethylsulfoxide IL Ionic liquid LA Lewis acid MTSA Melamine trisulfonic acid MW Microwave i rradiation NHC N Heterocyclic carbene NMM N Methylmorpholine ppm Parts per million Pyr Pyridine SEM [2 (Trimethylsilyl)ethoxy]methyl TBD 1,5,7 Triazabicyclo[4.4.0]dec 5 ene TEMPO (2,2,6,6 Tetramethyl piperidin 1 yl)oxyl TLC Thin layer chromatography

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13 Abst ract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy TRANSITION METAL FREE CARBONYLATION OF AMINES TO FORMAMIDES By Ciera Jane Gerack August 2013 Chair: Lisa McElwee White Major: Chemistry Base mediated carbonylation of amines provides an alternative to current methods of synthesizing formamides, which can involve high temperatures, metal catalysts, or stoichiometric equivalent s of formic acid. The conditions for this reaction include potassium carbonate as base, an amine, and methanol as solvent in a vessel charged with CO. Optimization was done for base identity, time, promoter identity, pressure, and base quantity. It was determined that neither a halide promoter nor an oxidant was necessary for this reaction. The optimal conditions for formamide synthesis from amines were amine, 35 atm CO, 3 equiv of K 2 CO 3 as base, methanol as solvent, 7 h, and room temperature. Isotopic labeling experiments were conducted to determine the source of the formyl hydrogen and the carbonyl moiety, indicating that methanol oxidation is not the source of the carbonyl in the product. The functional group compatibility was examined using para sub stituted benzyl amines. Substrates with electron donating groups produced higher yields than substrates with electron withdrawing groups. The scope of the reaction was examined using primary and secondary cyclic and acyclic aliphatic

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14 amines. Control exp eriments led us to propose a base mediated mechanism, proceeding through methyl formate as an intermediate.

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15 CHAPTER 1 INTRODUCTION Interest in the preparation of formamide derivatives has been driven by their variety of uses. Formamides serve as intermed iates in pharmaceutical syntheses, 1 4 precursors to fungicides, 3 5 intermediates in isocyanate, formamidine, and nitrile formation, reagents in functional group conversion, 6 and reagents in the Vilsmeier formylation reaction. 7 Formamides can also be used in allylation 8 and hydrosilation 9 of carbo nyl compounds. General Formylation In order to install the CHO group on a molecule, formylating agents are often used. These include chloral, formic acid, formaldehyde, and formates. One of the earliest of these reports comes from Blicke in 1952. He rep orted the formylation of amines with chloral ( 1 ) (Figure 1 1). 10 This method produced excellent yields with strong organic bases, occurred at low temperature, and the only byproduct was chloroform. Amines that were formylated by this method include primary amines, diamines, cyclic secondary amines, and sterically hindered secondary amines. Figure 1 1. Formylation using 1 Formic acid can be used alone to achieve formylation. This method was reported by Choi and required the use of a Dean Stark trap (Figure 1 2). 11 The amine and formic acid were dissolved in toluene a nd the solution was refluxed. The trap was used to collect the water produced by the condensation of the two reactants. By

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16 refluxing, the formamide product was produced in high yields without the need of a catalyst. This allowed the monitoring of the re action to take place via thin layer chromatography, and the absence of a metal catalyst allowed for easier isolation of the product. Figure 1 2. Formylation of amines using formic acid. Another example of N formylation b y formic acid was reported by Hajra. 12 This reaction employed solvent free and catalyst free conditions. Amine and formic acid were heated to 80 C until the reaction reached completion. Reaction time ranged from 25 480 min. This reaction required no specialized glassware. Formamide products were obtained from substituted aromatic amines as well as primary and secondary alkyl amines in good to excellent yields. Hydroxyl substituents remained intact after formylation of the amine. Additionally, no isolable side products were observed. When a mixture of primary and secondary amines was exposed to the reaction conditions, the primary amines were selectively formylated. There are many examples of N formylation by acetic formic anhydride (AFA), a mixture of formic acid with acetic anhydride. 13 One such example was seen by Krishnamurthy who reported a one pot procedure for N monomethylation of primary amines that proceeds through N formylation followed by reduction. 14 Amines were allowed to react with excess formic acid and acetic anhydride at 20 C (Figure 1 3). T he reaction reached completion for most amines in less than 15 min and took no longer than 3 h for any amine. The resultant formamides were isolated in yields

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17 between 97 100%. High yields were achieved for simple alkyl, aromatic, multifunctional, and ste rically hindered amines, such as 2 Figure 1 3. Formylation of a sterically hindered amine. Formylation is often used as a means of protecting amino groups in peptide synthesis. du Vigneaud reported a procedure for formy lating the N terminus of amino acids in 1932 by the use of formic acid and acetic anhydride. 15 This method was used as a way to resolve dl cystine from inactive cystine. The product dl diformylcystine was able to be readily removed from the product mixture by forming the strychnine salt. However, the yield reported for the dl diformylpeptide was only moderate. This method of formylating amino acids was applied by Yang as a means of protecting the amino group of many individual amino acids. 16 When parent amino acids instead of peptides were exposed to t he reaction conditions, the procedure yielded the formamides in yields between 85 90%. tert Butyl esters of amino acids are unable to be protected by AFA without racemization occurring. Meienhofer reported a modification that allows the formylation of ter t butyl amino acid esters with minimal or no racemization. 17 This method combined formic aci d with dicyclohexylcarbodiimide (DCC). This mixture was added to solutions of tert butyl amino acid esters. The protected amino acid esters were produced in high yields.

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18 Formic acid in polyethylene glycol has been shown to formylate anilines (Figure 1 4) 18 This reaction can be done at room temperature at relatively moderate reaction times, 4 6 h. The conditions are tolerant of various functional groups such as nit ro, halogen, ester, ketone, and alkyl groups. This formylation only takes place under inert atmosphere. Attempts to formylate the oxygen of phenols with these conditions were unsuccessful. Figure 1 4. Formylation of aro matic amines using formic acid and polyethylene glycol. Formylation with formic acid and 2 chloro 4,6 dimethoxy[1.3.5]triazine (CDMT) ( 3 ) was reported by Giacomelli. 19 Amines and amino acid esters were formylated in dichloromethane (DCM) at reflux (method A) or under microwave irradiation (method B) (Figure 1 5). Formamides were produced in a one step process. In method A, dry formic acid and the amine were treated with 3 and 4 (dimethylamino)pyridine (DMAP) as a catalyst. N methylmorpholine (NMM) and DCM were added, and the solution was refluxed. This reaction required 5 20 h to reach completion. However, with the use of microwave irradiation in method B, the reaction produced the formamides in high yields after only 3 6 min. The yields from this reaction were nearly quantitative. Slightly lowered yields were observed when more sterically hindered amines were used. The proposed mechanistic pathway involved the formation of a formate ester intermediate composed of formic acid and 3 which then is attacked by the amine to form the formamide (Figure 1 6). When chiral amino acid esters were used, optical puri ty was

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19 maintained. This indicated that the chiral center is not involved in the reaction, which is consistent with the proposed pathway. Figure 1 5. One step preparation of formamides by method A at reflux or method B via microwave irradiation. Figure 1 6. Pathway of formamide formation from formic acid and 3 In a procedure reported by Yang, melamine trisulfonic acid (MTSA) ( 4 ) catalyzed formylation with formic acid in solvent free cond itions (Figure 1 7). 20 The amine, two equiv formic acid, and 3 mol% 4 were stirred at 60 C until completion of the reaction (40 90 min). Substituted aniline derivatives were examined and all produced excellent

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20 yields of formamides regardless of electron donating or electro n withdrawing substituents. Primary and secondary amines also produced formamides in high yields. A proposed mechanism suggests that formic acid is protonated by 4 followed by nucleophilic attack of the amine Subsequent elimination of water produced t he formamide (Figure 1 8). Figure 1 7. General reaction of MTSA catalyzed formylation. Figure 1 8. Proposed reaction mechanism for MTSA catalyzed formylation. Ammonium formate has been s hown to formylate both anilines and secondary amines in good to excellent yields (Figure 1 9). Primary amines produced alkyl formate salts instead of the expected products. Benzylamine was an exception, and it successfully produced the formamide in 88% y ield. To produce formamides, the amine was dissolved in acetonitrile, ammonium formate was added, and the solution was refluxed between 6 15 h. These conditions are also applicable as protecting groups for chiral molecules. The benzyl ester of L proline ( 5) was successfully formylated to 6 in 75% yield without any observed racemization (Figure 1 10). When hydroxyl groups

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21 were present, ammonium formate selectively formylated the nitrogen, leaving the hydroxyl group intact. Figure 1 9. General formylation by formic acid in ammonium formate. Figure 1 10. Formylation of 5 without racemization of chiral centers. Swaringen previously reported that amines and triethyl orthoformate produced th e corresponding N ethyl formamides in the presence of sulfuric acid at high temperature. 21 Using a similar method, Kaboudin reported simple N formylation without an alkyl shift onto the nitrogen (Figure 1 11). 22 primary amines took place in water with triethyl orthoformate in the absence of base, acid, or catalyst in moderate to good yields. No secondary amines were examined. A number of solvents were examined inclu ding ethanol, ethyl acetate, DCM, chloroform, dimethylformamide (DMF), dimethylsulfoxide (DMSO), and water. However, water was chosen as the optimal solvent. Two methods were employed. In method A, the components were refluxed in water, and method B inc luded microwave irradiation at 90 C. The reaction times associated with method A ranged between 24 48 h. When MW was used reaction times were between 2 3 h.

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22 Figure 1 11. Reaction of amine with triethyl orthoformate in water. Deutsch reported formylation of amine s by methyl formate and a molecular catalyst (Figure 1 12). 23 Amidine and guanidine catalysts were examined in the formylation of morpholine and tert butylamine at room temperature. The best catalyst for this reaction was 1,5,7 triazabicyclo[4.4.0]dec 5 ene (TBD) ( 7 ). Figure 1 12. Formylation of amines by methyl formate and catalyst. Formic acid and a catalytic amount of sodium formate have been reported to produce formamides from amines at room temperature in solvent free conditions. 24 Functionalized anilines, primary amines, cyclic secondary amines, and sterically hindered secondary amine s all produced good to excellent yields of formamides. Reactions reached completion between 0.33 8 h. When either phenol or benzyl alcohol was exposed to the reaction conditions, no O formylated products were formed. Additionally, when hydroxyl groups w ere present on the amines, they remained intact when the products were formed. The sodium formate used in the reaction could be isolated from the reaction mixtures and reused up to four times without a loss of activity. N formylation of anilines and simpl e primary amines in solvent free conditions by the use of formic acid with a reusable resin was reported by Pasha. 25 Amberlite IR

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23 120[H + ], a heterogeneo us catalyst, was aided by microwave irradiation to formylate amines in excellent yields. Amberlite IR 120 and the amine were combined and formic acid was added. The substrates were exposed to microwave irradiation for 20 s intervals until all starting ma terial was consumed. All conversions were complete between 60 120 s regardless of amine or substituents. A control was done in which the amine and formic acid were combined and irradiated without Amberlite IR 120. No formamide product was produced after 180 s. Once the catalyst was added to this trial, the product formed in 60 s. At the end of each reaction the resin was easily reisolated. Further study showed that after thorough washing with ethyl acetate and drying, the resin was reusable up to five times without a loss in activity. The proposed mechanistic pathway involved coordination to the resin through hydrogen bonds (Figure 1 13). The amine and formic acid coordinated to the resin, attack occurred at the carbonyl by the amine, and through a re arrangement the formamide was produced leaving water coordinated to the resin. Figure 1 13. Amberlite IR 120 catalyzed formylation. Figure adapted from reference 25. Jang reports N formylation in solvent free conditions with molecular iodine (I 2 ) as a catalyst. 26 After optimization studies done on aniline, it was determined that aniline, 5

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24 mol% I 2 and tw o equiv of formic acid produced formanilide in excellent yield after 2 h at 70 C. Several factors caused the yield to decrease including higher reaction temperature, less formic acid, and use of acetonitrile as solvent. After optimization was completed, several aniline derivatives as well as primary and secondary amines were subjected to the reaction conditions and produced formamides in good to excellent yields. Reaction times were adjusted to ensure completion. All trials were between 2 8 h. The rol e of I 2 was then examined. As it is known that I 2 reacts with formic acid to produce HI, 27 it was assumed that HI was the active catalytic species, generated in situ. Protonated formic acid is attacked by the amine, followed by proton transfer to provide 8 and finally through elimination of water and a proton, the formamide is formed (Figure 1 14). Figure 1 14. Mechanism of I 2 catalyzed formylation. Complex molecular catalysts may also be used for N formylation. Hu reported the use of thiamine hydrochloride ( 9 ) as a catalyst to produce formamides fr om amine and formic acid in solvent free conditions (Figure 1 15). 28 This method was successfully applied to aromatic and aliphatic amines. Yields rang ed from 88 96%. When other carboxylic acids were used in place of formic acid, the corresponding amides were produced using this catalytic method. While the mechanistic pathway is not known, a

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25 proposed mechanism suggests that the catalyst activates formi c acid through hydrogen bonding, after nucleophilic attack of the amine at the carbonyl of formic acid, and the formamides were produced through the elimination of water (Figure 1 16). Figure 1 15. Solvent free formylatio n catalyzed by 9 Figure 1 16. Proposed mechanistic pathway of formamide production with 9 Other solvent free, acid catalyzed methods have been reported. Hajela reported silica supported perchloric acid (HClO 4 SiO 2 ) cat alyzed N formylation of aromatic and cyclic secondary amines (Figure 1 17). 29 When substrates with hydroxyl groups were

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26 exposed to this reaction, formylation occurred selectively at the am ino position. Other silica supported acids including sulfuric (H 2 SO 4 ), fluoroboric (HBF 4 ), and trifluoroacetic (TFA) acids were examined but all produced lower yields of products. The catalyst was easily removed at the completion of the reaction and afte r washing and drying, could be used up to three times without a loss in activity. Figure 1 17. Silica supported acid catalyzed N formylation. Ionic liquids (IL) have recently been reported to catalyze formylation. IL ar e attractive because of their stability, ease of removal, and easy synthesis. Baghbanian reports that amine, formic acid, and TBD based ionic liquids produced formamides from aromatic, alkyl, and heteroaromatic amines as well as amino alcohols in good to excellent yields. 30 Three related ionic liquids were examined ( 10 11 and 12 ) with 10 being the preferred IL (Figure 1 18). In optimization studies, 5 mol% 10 1.3 equiv formic acid, a nd 10 min were chosen as the reaction conditions (Figure 1 19). This is a solvent free method and when solvent was used yields decreased. The IL was easily separated from the product and reused up to six times without a loss in activity. A proposed mech anism indicated that the reaction was mediated through hydrogen bonding with the catalyst (Figure 1 20).

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27 Figure 1 18. TBD based IL examined for catalytic activity towards N formylation. F igure 1 19. Optimized conditions for IL catalyzed formylation. Figure 1 20. Mechanistic pathway for formamide production.

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28 Another example of IL catalyzed formylation was reported by Lee. 31 In this case CO was used as the carbonyl source without formic acid. Amine, IL and 40 atm CO produced formamides from primary and secondary amines in moderate to excellent yields. A selection of IL and a selection of counterions were examined. Optimization studies were performed and 1 butyl 3 methylimidazolium carbonate ( 13 ) was chosen as the best IL to catalyze N formylation. Other optimized conditions include 40 atm CO, methanol solvent, 140 C, and 1 mol% 13 (Figure 1 21). No urea products were observed in the reaction mixtures. Recyclability of 13 was examined. The catalyst could be used for five trials with no loss in selectivity and only a 20% reduction in activity. Figure 1 21. Formylation of amines using CO catalyzed by 13 A method has emerged recently that uses the Reimer Tie mann (R T) reaction to produce formamides from secondary amines (Figure 1 22). 32 Alkyl, cyclic, and N methylaniline derivatives all produced formamides in good to excellent yields. The best yields were obtained with cyclic amines. Reduced yields were seen for open chain aliphatic amines, suggesting that steric bulk may have been an issue. A mechanistic pathway consistent with the Reimer Tiemann reaction was proposed (Figure 1 23). First, chloroform reacted with sodium ethoxide to form the chloro form carbanion ( 14 ). The carbanion was readily converted into dichlorocarbene ( 15 ). Then 15 reacted with the amine and through the R T reaction produced the formamide product.

PAGE 29

29 Figure 1 22. N formylation of secondary ami nes. Figure 1 23. General mechani sm of the formylation via the R e i mer T i e mann reaction. Figure adapted from reference 30. Group 3 metals have also been reported to catalyze formylation of amines. Jang reported solvent f ree conditions in which amine, formic acid, and 10 mol% indium at 70 C produced formamide in moderate to excellent yields (Figure 1 24). 33 Without indium, these conditions did not produce as high a yield. The reaction times vary between 1 24 h depending on the electronics and sterics of the amine. Aniline derivatives, primary amines, secondary amines, and amino alcohols were all successfully formylated in these solvent free condi tions. These conditions were then applied to protect the a mino

PAGE 30

30 amino acid esters. The formylation proceeded successfully in good yields. Additionally, no racemization was observed. Figure 1 24. Indium catalyzed formylation of amines. Transition Met al Catalyzed Formylation In addition to simple formylating agents, transition metals have been used to formylate amines using stoichiometric amounts of formic acid or another formylating agent. Transition metal catalysts have also been used to formylate a mines using CO as the carbonyl source. 34 42 When CO is used as the carbonyl source, formamide products are much less commonly obtained than ureas. 43 45 A variety of transition metal Lewis acids have been reported to N formylate amines. ZnO was reported by Hosseini Sarvari as a Lewis acid catalyst for the solvent free fo rmylation of amines with formic acid. 46 Optimal conditions of this reaction are 3 equiv of formic acid, 50 mol% catalyst, 70 C, and 10 720 mi n (Figure 1 25). Aromatic, primary and secondary amines were formylated in good to excellent yields. The progress of the reaction was monitored by TLC, and longer reaction times were necessary for aromatic amines containing electron withdrawing groups as well as for secondary amines. Decreased yield was not observed when the reaction was scaled up from 1 mmol amine to 100 mmol amine. O formylation of alcohols was not observed. Amines containing hydroxyl groups were selectively formylated at the amino g roup. When a mixture of primary and secondary amines was subjected to the reaction conditions, primary amines were selectively formylated. ZnO was easily filtered out of

PAGE 31

31 the reaction mixture at the completion of the reaction. The catalyst was washed wit h DCM and could be successfully recycled up to three times. Figure 1 25. ZnO catalyzed formylation of amines with formic acid. Similar, Lewis acid (LA) catalyzed, solvent free conditions for formylation were reported by R ao. 47 A Lewis acid catalyst and formic acid were used an d produced high yields of the desired formamide products (Figure 1 26). Lewis acids such as FeCl 3 AlCl 3 and NiCl 2 worked well, but ZnCl 2 produced the best results. The optimum conditions are 10 mol% catalyst, 3 equiv of formic acid, 70 C, and 10 900 m in. The reaction was monitored by TLC and required longer reaction times for electron poor aromatic amines as well as secondary amines. This catalyst, ZnCl 2 is inexpensive, environmentally friendly, and tolerated a variety of functional groups such as nitro, halogen, ester, ketone, and alkyl. The proposed reaction mechanism is similar to other acid catalyzed reactions of formic acid catalyzed formylation and yet Rao did not cite the previous work and incorrectly claimed that their conditions were the first report of Lewis acid catalyzed N formylation of amines with formic acid. Figure 1 26. Solvent free formylation of amines using Z nCl 2 catalyst.

PAGE 32

32 Heydari reports a catalyst for the formylation of amines with formic acid. 48 Sulfonic acid supported on hydroxyapatite (HAp) encapsulated Fe 2 O 3 nanocrystallites catalyze formylation of aromatic, primary, and secondary amines (Figure 1 27). No O f ormylation occurred on amines containing hydroxyl groups. Optimum conditions are amine, 1.2 equiv of formic acid, 0.9 mol% SO 3 Fe 2 O 3 @ HAp SO 3 H), and room temperature. The reaction was monitored by TLC and required 15 60 min to reach completion. This is a magnetic, solid state catalyst with no air/moisture sensitivity. The catalyst was easily removed from the reaction mixtures by attaching an external magnet to the vessel and decanting the reaction solutions. After washing and drying the catalyst co uld be reused for four consecutive trials without a loss in activity. In order to ascertain whether acid was detaching from the particles and catalyzing the reaction homogenously, the reaction was performed for 10 min, the catalyst was removed by an exter nal magnet, and the reaction was allowed to continue for 3 h. At the end of this time, no significant amount of product had formed. Figure 1 27. Formylation of amines by formic acid Formylation of amines with formic aci d and TiO 2 P25 or sulfated titania was reported by Swaminathan. 49 This was an extension of their resea rch on semiconductor photocatalysts. They found that at room temperature either TiO 2 P25 or TiO 2 SO 4 2 catalyzed formylation of amines with formic acid in short reaction times (Figure 1 28). This method was applied to substituted aromatic amines as well as primary and

PAGE 33

33 secondary aliphatic amines. In all cases studied, TiO 2 SO 4 2 produced better yields, ranging from moderate to excellent. In recyclability tests, TiO 2 SO 4 2 could be reused up to five times without a loss in activity, while TiO 2 P25 suffer ed a 50% drop in activity during the second trial. A proposed mechanism suggests that the reaction is similar to other acid catalyzed formylations (Figure 1 29). The catalyst is a Lewis acid and coordinates formic acid in order to facilitate nucleophilic attack of the amine on the carbonyl. Then through loss of water and rearrangement, the formamide product is produced. This was the first example of a semiconductor oxide heterogeneous catalyst employed in N formylation at room temperature. Figure 1 28. Amine formylation from formic acid catalyzed by TiO 2 P25 or TiO 2 SO 4 2 Figure 1 29. Mechanism of TiO 2 P25 catalyzed formylation.

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34 Another easily removed and recycled transition metal cat alyst was reported by Akamanchi. 50 Sulfated tungstate ( 15 ) catalyzed the reaction of amines with formic acid to produce formamides in solvent free conditions (Figure 1 30). The optimized conditions are 10 mol% 15 70 C, 1.2 equiv of formic acid, and 10 45 min. The catalyst was easily isolated after the reaction and could be reused up to four times without experiencing any loss of activity. A broad scope was examined including primary, secondary, aromatic, heteroaroma amino acids. Yields ranged from 85 99%. Studies were done to understand the interaction between the catalyst and the reagents. They indicated that formic acid was adsorbed onto the catalyst, but amine was not adsorbed. This suggests a mechanism in which the catalyst activates the formic acid followed by nucleophilic attack, similar to other acid catalyzed formylations. Figure 1 30. N formylation of amines with formic acid and sulfated tungstate catalyst. More recently Hong reported another Lewis acid, a fluorous silica gel supported hafnium (IV)bis(perfluoroocatanesulfonyl)imide complex (FSG Hf[N(SO 2 C 8 F 17 ) 2 ] 4 ), that formylated amines in aqueous formic acid (Figure 1 31). 51 Optimum conditions were 1 mol% catalyst, 70 C, and 3 equiv of formic acid. The catalyst could be reused for up to three cycles without loss of activity.

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35 Aromatic amines produce d the desired formamides in high yields regardless of substituent. However, when electron withdrawing groups were present, longer reaction times were necessary. Aliphatic n butylamine and secondary diphenylamine produced good yields. Hong proposed that the catalyst and the higher loading of formic acid provided electronic assistance to the reacting formic acid carbonyl, which allowed for more facile nucleophilic attack by the amine (Figure 1 32). Figure 1 31. N formylat ion catalyzed by FSG Hf[N(SO 2 C 8 F 17 ) 2 ] 4 Figure 1 32. Electronic assistance for nucleophilic attack of amine on formic acid. Williams reported N formylation of amines with paraformaldehyde by an iridium catalyst. 52 Optim al conditions of this reaction were amine, paraformaldehyde (3 equiv of the monomer), 1 mol% [Cp*IrI 2 ] 2 as catalyst, water as solvent, reflux, and 5 10 h (Figure 1 33). Primary amines produced the expected formamides in high yields. Secondary amines prod uced the expected formamides in moderate to excellent yields. When an

PAGE 36

36 enantiomerically pure amine was reacted, the formamide product retained most but not all of its enantiomeric purity. Primary anilines did not afford product under these conditions. Th e acyclic secondary aniline examined produced the formamide in only 46% yield, but indoline, a cyclic secondary aniline, produced the formamide in 91% yield. Figure 1 33. Iridium catalyzed formylation of amines with paraf ormaldehyde. Formylation of dimethyl amine with formaldehyde was studied collaboratively by Madix and Friend on silver and gold surfaces. 53 54 Oxygen assisted formylation of dimethylamine on metallic silver surfaces was reported by Madix. 53 The proposed mechanistic pathway involves molecular oxygen dissociating on the silver surface, coordination and deprotonation of the amine occurs, formaldehyde is introduced and hydride elimination occurs to produce the formamide (Figure 1 34). A similar mechanism was proposed by Friend when gold is used with oxygen (Figur e 1 34). 54 One important distinction between these two mechanisms is that gold requires ozone (O 3 ) to introduce adsorbed oxygen, wh ile silver can employ oxygen (O 2 ). These are examples in which the catalyst interacts with the amine directly during reaction with a formylating agent.

PAGE 37

37 Figure 1 34. Formylation of dimethylamine with formaldehyde mediate d by oxygen atoms on metallic surfaces. Figure adapted from reference 52. Gold nanoparticles were reported by Sakurai to catalyze the formylation of amines with methanol or formaldehyde. 55 Gold nanoclusters stabilized by poly( N vinyl 2 pyrrolidione) (Au:PVP) acte d as the catalyst in aerobic oxidation conditions. Optimum conditions for this reaction when methanol was used as the formyl source were 10 atom% catalyst, 200 mol% LiOH as base, 1:2 methanol:water solvent, 80 C (reflux), and 8 h (Figure 1 35). When the se conditions were applied to N methylaniline, two pro ducts were formed: 94% yield of N methylanilide 16 and 5% yield of anilide 17 Methanol oxidation leads to formaldehyde, formic acid, methyl formate, and carbon dioxide. In order to ascertain which in termediate was reacting with the amine, formylative agents were used in place of methanol. The solvent system used was ethanol:water, the reaction time was reduced to 1 h, and the temperature was reduced

PAGE 38

38 to 50 C. Without methanol or a formylating agent no reaction occurred. When formaldehyde was used in place of methanol as a 37% solution, 16 was formed in 81% yield. When either methyl formate or formic acid was used in place of methanol, no reaction occurred. Optimum conditions for this reaction when formaldehyde was used as the formyl source were 1.5 equiv of formaldehyde, 1 atom% catalyst, 100 mol% NaOH as base, 1:2 ethanol:water solvent, 27 C, and 9 h. A wide selection of amines was subjected to these new conditions. Yields were best for aromati c amines. Sterically hindered and electon poor aromatic species produced little to no product. Aromatic, primary, and secondary alkyl amines produced high yields of formamides. Figure 1 35. N formylation of amines with methanol by nanogold particles. Glorius reported N formylation of amines by methanol activation catalyzed by a ruthenium N heterocyclic carbene complex ( 18 ) (Figure 1 36). 56 This complex was also reported to catalyze amide synthesis. The optimized conditions for the amide synthesis were initially applied to the activation of methanol. These conditions were 1 mol% 18 1.5 eq uiv of alcohol, toluene solvent, inert atmosphere, at reflux, and 24 h. When these conditions produced only trace amount of the formamide, the amount of methanol was increased to 3.3 equiv. Attempted optimizations of equiv of reactants, concentration, sol vent identity, and temperature did not increase the yield. When the reaction was run in a sealed container, the yield was lower and a build up of gas was observed. This was presumed to be hydrogen gas and thus the introduction of a sacrificial hydrogen

PAGE 39

39 a cceptor was added to shift the equilibrium towards product. Styrene was chosen as this acceptor, and with this additive 96% conversion of starting material to formamide was observed. Figure 1 36. Ru NHC catalyzed methano l activation and formylation of amines. A) Catalyst 18 B) Optimum conditions. The scope was examined using primary, secondary, tertiary, and benzyl amines. Overall yields ranged from 27 99%. The lowest yields corresponded to bulkier substrates and ele ctron poor benzyl amines. Aromatic amines did not react. When optically pure phenylethylamine was reacted, the reaction produced a 77% yield and no loss of enantiomeric purity was observed. During the examination of the reaction scope the catalyst 18 wa s formed in situ from the pre catalyst Ru(cod)(2 methylallyl) 2 the HCl salt of the NHC ligand, and base (Figure 1 36). To ensure this reaction was not base catalyzed, the catalyst was prepared and isolated before the reaction and then introduced with the NHC ligands attached. The yield of the reaction did not decrease. When excess base was introduced the reaction yield decreased. The NHC used was ICy. The identity of the NHC was examined but other NHCs achieved lowered conversion of starting material. The pre catalyst without NHC ligands did not catalyze the reaction. Through examination of the reaction with NMR studies, a possible mechanism was proposed (Figure 1 37). First, methanol is deprotonated and

PAGE 40

40 Hydride eli mination occurs and produces coordinated formaldehyde. The carbonyl of formaldehyde undergoes nucleophilic attack by the amine, then hydrogen (H 2 ) is lost as the amine is deprotonated. A second hydride elimination occurs to form the formamide product. The formamide product may be exchanged with methanol and a second H 2 is liberated as the original methoxide complex is formed, beginning the catalytic cycle again. Figure 1 37. Mechanism for Ru catalyzed methanol dehydro genation followed by cross coupling with amine to produce the formamide. Reddy reported formylation of primary and secondary amines by the catalytic oxidation of methanol in solution by copper salts. 57 This transformation was achieved in the presence of hydrogen peroxide (H 2 O 2 ) and basic co pper hydroxyl salts (Figure 1

PAGE 41

41 38). Optimized conditions for the formylation of amines were amine, 30 mol% CuCl 2 2 O, methanol solvent, 3.4 equiv of 6.0% w/w H 2 O 2 room temperature, and 45 90 min. All amines were selectively converted to formamides. Prim ary and secondary amines were formylated in 63 80% yields. The mode of H 2 O 2 addition was very important to the reaction. When slow addition of H 2 O 2 occurred, formylated product was instantly formed. When the same amount of H 2 O 2 was added as two equal po rtions, reaction times were longer and more H 2 O 2 was necessary as decompositio n of the peroxide was observed. Figure 1 38. N formylation of amines with formaldehyde by nanogold particles. Saegusa reported formylation of a mines by copper complexes and carbon monoxide. 58 Various metal complexes were examined. The most a ctive of these complexes was CuCl. This reaction selectively formed formamides with only trace amounts of urea observed. This reaction was found to be accelerated in water. This was attributed to the fact that the CuCl CO complex is favored in water sol vent. Aliphatic amines were subjected to this reaction and secondary amines proved more facile to formylation than primary amines. Aromatic amines did not react with CuCl catalyst but they were formylated when chloroauric acid (HAuCl 4 2 O) was used as ca talyst. Remple reported a ruthenium catalyst that produced formamides from cyclic secondary amines using only 1 atm of carbon monoxide gas at 75 C (Figure 1 39). 36 The mild conditions in this reaction required long reaction times (20 200 h) to ensure

PAGE 42

42 completion. These conditions were unsuccessful formylating primary or acyclic secondary amines. Figure 1 39. R uthenium catalyzed carbonylation of amines. Watanabe reported triruthenium dodecacarbonyl (Ru 3 (CO) 12 ) catalyzed formylation of amines using CO as the carbonyl source. 59 Different ruthenium and rhodium catalysts were examined. The rhodium based catalysts produced significant amounts of urea. The best catalytic activity toward formamide production was shown by Ru 3 (CO) 12 Optimum conditions were 0.17 mol% catalyst, 40 atm CO, benzene as solvent, 120 180 C, and 6 h. Primary aliphatic amines successfully produced formamide products in these conditions. Carbonylation of piperidine produced the formamide in only moderate yield due to formation of urea. This catalyst worked best for basic primary amines. Jenner reported that ruthenium compounds catalyzed primary and secondary amines with CO as the carbonyl source. 34 Ruthenium trichloride trihydrate (RuCl 3 2 O) showed the highest activity and selectivity towards the formation of formamides from primary amines. Two other catalysts were tested, Co(OAc) 2 2 O and RhCl 3 2 O. The cobalt catalyst showed low conve rsion, and the rhodium catalyst showed high activity but low selectivity towards the formamide product. Only primary hydrogen were carbonylated. This may be indicative the pathway of formamide formation, or it could be a steric issue. C yclic secondary amines were carbonylated to the corresponding formamides. However a competing reaction was the

PAGE 43

43 transalkylation which forms a trialkyl amine and a primary amine from two equiv of secondary amine. The newly formed primary amine was also car bonylated to the formamide product. Cobalt ruthenium catalysts improved the selectivity for formylation of dialkylformamides from secondary amines. Adjustments of temperature and/or pressure increased the selectivity of reaction toward formamide products The primary formamide and urea products were byproducts of these reactions. In related work, Jenner reported the effect of solvent on carbonylation of amines with RuCl 3 2 O. 35 Solvents with varying dielectric constants were examined. No correlation between the yield of formamide and dielectric constant was found. Methanol was the best solvent for ruthenium catalyzed carbonylation. In water, dependin g upon the amine identity, either more urea was formed or the conversion of amine was sharply decreased. The previously examined cobalt ruthenium catalyst produced selectivity for formamide in methanol similar to that of the ruthenium catalyst with no sig nificant improvement. Higher pressure, 750 atm, and high temperature, 180 C, suppressed the urea formation and increased formamide selectivity. The best conversion and selectivity were observed when excess methanol was present, which indicated that the alcohol was stoichiometrically involved in the reaction. The proposed reaction pathway for this reaction was initial formation of methyl formate from methanol and CO, followed by attack from the dialkylamine forming the formamide and regenerating methanol This reaction was successfully applied to dialkylamines and aromatic amines. However, aromatic amines still show lower conversion and selectivity than alkylamines. Sterically hindered amines such as tert butylamine, which was unreactive without methan ol,

PAGE 44

44 underwent selective formylation in the presence of ruthenium catalyst and methanol solvent. McElwee White reported a tungsten catalyst ( 19 ) that produced formamides (Figure 1 40). 38 This catalyst selectively formed formamides from secondary amines and ureas from primary amines. This method will be discussed in Chapter 2. Figure 1 40. Tungsten dimer catalyst. Conclusions There are many m ethods of formylating amines. Formylating agents, such as formic acid, alkyl formates, formaldehyde, and paraformaldehyde, can produce formamides with the aid of molecular and transition metal catalysts in a variety of conditions. Many types of amines ca n be formylated in excellent yields: primary, acyclic secondary, cyclic secondary, and aromatic amines as well as amino acids. Enantiomeric purity can be maintained during formylation. Catalysts can also perform N formylation with CO as the carbonyl sour ce with molecular or transition metal catalysts. Disadvantages of these methods include the requirement of stoichiometric amounts of formylating agents, expensive or complex catalysts, high temperatures, and high CO pressures.

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45 CHAPTER 2 CARBONYLATION USI NG TUNGSTEN CATALYSTS Industrial scale carbonylation generally uses phosgene or one of its derivatives as a carbonyl source (Figure 2 1). These are unattractive options due to the toxicity of phosgene and atom economy of the derivatives. 60 The McElwee White research group has been studying carbonylation as an alternative to phosgene for many years. A variety of conditions have been used to produce products such as ureas, formamides, hydantoins, and dihydrouracils. These moieties have been formed most commonly using carbon monoxide gas with W(CO) 6 as catalyst, oxidant, and base. 43 In the most recent method, the tra nsition metal catalyst has been eliminated completely creating a greener method for synthesis of carbonyl compounds. 61 62 Figure 2 1. Phosgene and examples of derivatives. A) Phosgene. B) DMDTC. C) CDI. Initial Urea Formation The W(CO) 6 catalyzed carbonylation began when a dimer tungsten complex ( 19 ) was found to produce f ormamides and ureas from secondary and primary amines respectively (Figure 2 2). 38 Using this method, secondary amines selectively form formamides ( 20 ) in yields ranging from 8 61% and primary amines selectively form ureas ( 21 ) in yields ranging from 56 105% with no added carbon monoxide gas (yields calculated per equiv of tungsten).

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46 Figure 2 2. Carbonylation of amines using tungsten dimer. A) Secondary amines react to form 20 B) Primary amines react to form 21 Urea Formation Using W(CO) 6 Catalyst When the tungsten dimer is used without any added carbon monoxide gas, turnover numbers (TON) of up to 12 per dimer can be achieved forming the carbonylated products. 63 When 100 atm of carbon monoxide gas was added to the reaction, TON were able to reach 25 per dimer. Carbonylation of amines by the t ungsten dimer with iodine (I 2 ) added as an oxidant suggested that other tungsten carbonyl complexes may also afford these transformations. The inexpensive and readily available metal complex W(CO) 6 was chosen as a precatalyst. This complex afforded no p roduct without I 2 present. But when the precatalyst (W(CO) 6 ), oxidant (I 2 ) and base (K 2 CO 3 ) were present with 100 atm of added carbon monoxide gas, the process yielded 39 TON per tungsten (Figure 2 3). Figure 2 3. Carbon ylation of primary amines to ureas using W(CO) 6 /I 2

PAGE 47

47 As carbonylation of primary amines by W(CO) 6 was probed further, many variables such as catalyst, temperature, pressure, equiv of base, and solvent were optimized. 64 Similar group 6 metal catalysts, Mo(CO) 6 and Cr(CO) 6 were examined for efficiency. Both metal com plexes produced lower yields than tungsten carbonyl which was surprising as third row metals are usually less effective catalysts. Optimized conditions include a higher temperature (90 C), 80 atm CO pressure, and 1.5 equiv of base (K 2 CO 3 ). Many solvents polar and non polar, halogenated and non halogenated, organic and aqueous were examined. DCM was the best single solvent disubstituted ureas. In some cases a biphasic solvent system increased yields. For primary amines such as n pr opylamine, n butylamine, or i propylamine, the yields were highest in DCM. For the wide range of benzylamines examined, the DCM:water biphasic solvent system increased nearly all of the yields of ureas. During the reaction each equiv of urea produced als o formed two equiv of the amine hydroiodide as the amines forming urea were deprotonated. These amine salts have lowered solubility in DCM so the addition of water allows them to be deprotonated by the base in aqueous solution. The amines can then reente r the organic layer and participate in urea formation. During the examination of substituted benzylamines, it was found that a wide range of substituents will tolerate these carbonylation conditions. This includes halogen containing compounds, ether and t hioether compounds, and amines with unprotected alcohols. Ureas are also formed in the presence of carboxylic acids, esters, cyano, and nitro groups.

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48 These newly optimized conditions were then applied to secondary amines. 65 In the previous reactions of secondary amines, formamide products were selectively formed. However, using these newly optimized conditions only trace a mounts of formamides were observed and the major products were tetrasubstituted ureas ( 22 ) (Figure 2 4). Yields were low to moderate. This was attributed to the inability of any of the bases examined to deprotonate the amine salt ( 23 ) that is formed as 2 2 forms. As one urea molecule is formed, four equiv of amine are consumed, two become part of 22 and two act as a sacrificial base to deprotonate each of the amines that react (Figure 2 5). This method is still an attractive, alternative method for the f ormation of tetrasubstituted ureas from secondary amines. Figure 2 4. Formation of 22 from secondary amines. Figure 2 5. Consumption of four equiv of amine to produce one equiv of urea. Cyclic Ureas diamines. These molecules were studied for their ability to be converted into cyclic ureas. 66 This was the first example of transition metal catalysis using carbon monoxide to form cyclic ureas ( 24 ) from both diamines (Figure 2 6). Primary diamines formed 24 in yields ranging from 38 51% and secondary diamines formed 24 in yields ranging from

PAGE 49

49 10 5 2% (yields calculated per equiv of amine). In both cases high dilution conditions were necessary to prevent oligomers from forming. Formamides were not observed in either diamine case. Figure 2 6. Carbonylation of prima ry (R=H) and secondary (R=Me, Et, i diamines to form 22 This process was then optimized to produce better yields. 67 The pressure was reduced from 100 atm to 80 atm, and in some cases the temperature was raised from 25 C to 90 C In addition, the amount of W(CO) 6 was increased f rom 1 mol% to 4 mol% for primary amines and from 0.7 mol% to 4 mol% for secondary amines, and a number of secondary amines used a biphasic DCM:water solvent system. Yields for primary amines were increased to 33 80%. Secondary amine yields did not see a n overall improvement and remained between 10 52%. The best results were achieved when the N alkyl substituent is a methyl group. During the reaction of secondary diamines, the tetrahydropyrimidine derivatives (such as 25 ) were also observed (Figure 2 7) Control experiments showed that the tetrahydropyrimidine derivative also forms without the presence of the catalyst or CO. This side product may be responsible for the lowered yields observed. Figure 2 7. Carbonylatio n of 26 to form cyclic urea 27 and tetrahydropyrimid in e 25

PAGE 50

50 Complex Targets To illustrate the utility of this new method, these conditions were applied towards the formation of complex target molecules. 68 The core structures of DMP 323 ( 28 ) and DMP 450 ( 29 ), two HIV protease inhibitors, contain a tetrasubstituted urea moiety (Figure 2 8). The previously reported method of installing the urea moiety involved using phosgene or a phosgene derivative. The yields of urea formed by W(CO) 6 /CO are comparable to those obtained by using CDI. In both methods the yields vary substantially with the identity of the protecting group used (Figure 2 9). Figure 2 8. Functionalized diamines. A) DMP 323 ( 28 ). B) DMP 450 ( 29 ). Figure 2 9. Carbonylation of diamines with protected alcohols to form 30 the core structure of 28 and 29 A) Catal ytic carbonylation. 68 B) Carbonylation via the phosgene derivative CDI. 69

PAGE 51

51 Additional substrates were tested using this methodology (Figure 2 10). 70 The reaction conditions were optimized by increasing the temperature to 80 C and using dich loroethane (DCE) as the solvent. The urea ( 30 ) was formed under these conditions and in some cases the alcohols did not require protecting groups. Figure 2 10. Diamine substrates forming 30 by catalytic carbonylation. An other extension of this methodology includes the application to forming biotin (Vitamin H) derivatives. 71 The attempts to synthesize biotin ( 31 ) were unsuccessful but may be due to the low solubility of the diamine substrate (Figure 2 11). The precursor to the methyl ester of biotin was soluble in organic solvents and when carbonylated yielded the derivative ( 32 ) in 84% yield. Figure 2 11. Complex targets. A) Biotin ( 31 ). B) Methyl ester derivative of Biotin ( 32 ). Other derivatives of biotin ( 33 ) were also examined (Figure 2 12). Yields produced using W(CO) 6 and CO were comparable to those obtained when using CDI. Yields were moderate to good with a large dependence upo n the solubility of the

PAGE 52

52 diamine and urea in DCM. This method provides an alternative to phosgene or phosgene derivatives in the preparation of 32 and 33 Figure 2 12. Preparation of biotin derivatives (X=O, N Boc, CH 2 CH 3 ; R 1 =H, CH 3 ; R 2 =H, CH 3 (CH 2 ) 4 CH 3 ). Ureas from Amino Alcohols Amino alcohols were studied using the tungsten catalyst to examine the selectivity between forming ureas or carbamates. 72 Examples of 1,2 1,3 1,4 and 1,5 amino alcohols with various substitut ions were examined. In the W(CO) 6 catalyzed conditions the acyclic urea ( 34) was selectively formed over the cyclic carbamate ( 35 ) in all cases, and the acyclic carbamate ( 36 ) was not observed (Figure 2 13). These conditions do not require the use of a p rotecting group on the alcohol. These results were compared to carbonylation from DMDTC and CDI, phosgene derivatives. The phosgene derivatives show varied selectivity between 34 and 35 formation making the tungsten catalyst an attrac tive option for urea formation. Figure 2 13. Selective carbonylation of amino alcohols to 34

PAGE 53

53 Hydantoins The next class of molecules examined was hydantoins. 73 These molecules contain a cyclic urea moiety. The effectiveness of the W(CO) 6 catalytic conditions to install this carbonyl wa amino amides (Figure 2 14). Hydantoins ( 37 ) were formed in these conditions with yields ranging from 11 75%. The conditions needed to be modified to produce a high yield, but this synthesis was successfully applied to the pharmaceutica l phenytoin ( 38 ), a commonly prescribed anticonvulsive (Figure 2 14). Figure 2 14. Formation of hydantoins ( 37 ). A) General hydantoin reaction. B) Phenytoin ( 38 ). Dihydrouracils Another class of molecules that can by sy nthesized in these conditions is dihydrouracils. 74 These molecules are of interest for their biological activity. By employing the conditions used to form hydantoins, the di hydrouracil ( 39 ) was produced in 88% yield (Figure 2 position, symmetrical ureas ( 40 ) were formed and no cyclic product was present (Figure 2 16). methyl substituted amino amide 39 was formed in <10% yield. For all other substitutions, only DBU salts were formed at the completion of the reaction. Other conditions may need to be employed to make this an attractive synthesis of 39

PAGE 54

54 Figure 2 15. Form ation of dihydrouracils from unsubstituted amino amides. Figure 2 16. Formation of 40 instead of 39 substituted amino amides were carbonylated. Diarylureas In previous works aniline, an aryl amine, was unable to produce urea when K 2 CO 3 was used as the base. 64 When other bases were screened it was found that while DBU and pyridine only produced the urea in trace amounts, the use of DMAP increased the yi eld to 81% (Figure 2 17). 75 The optimal conditions for urea formation from aromatic amines were 40 C, 80 atm CO, 1 equiv I 2 2 equiv DMAP, 8 h, and DCM as solvent. A large number of p substituted aryl amines were subjected to these diarylureas, such as 41 Yields ranged from moderate to good for functional groups such as halogens, ethers, thioethers nitro, cyano, and esters. Vinyl, hydroxyalkyl, and carboxylic acid substituted a rylamines produced no product. Figure 2 diphenylurea ( 41 ).

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55 Unsymmetrical ureas were then examined und er these conditions. In some cases the unsymmetrical urea was the primary product and in others the symmetric ureas dominated. By altering the ratios of the aryl amines, it was possible to force more unsymmetrical urea to form. The reaction mechanism was probed with N methylaniline. It was previously thought that an isocyanate may form from the amine and CO which is then attacked by a second amine to form ureas. If this is the only pathway, a N substituted arylamine should not form any urea. Using thes e conditions, it was found that no urea formed from the N methylaniline alone. However, when aniline was combined with excess N methylaniline, the trisubstituted urea was the major product with only trace diphenylurea observed. Other aniline derivatives were examined with N methylaniline and all produced trisubstituted arylureas. These results are consistent with an isocyanate intermediate. Metal Free Carbonylation During control experiments done on the W(CO) 6 catalyzed method, it was discovered that wit hout the metal catalyst, a NaIO 4 /NaI oxidant and promoter system would cause the transformation of 4 methoxybenzylamine ( 42 ) to 1,3 bis(4 methoxylbenzyl)urea ( 43 ) in high yields (72 96%). 61 Initia lly, the formamide product ( 44 ) was also observed in the product mixture (Figure 2 18 ). However, when the promoter identity was changed from I 2 to NaI, only the 43 was observed, optimizing away from 44 In order to increase yields, the solvent system was changed to a biphasic DCM:water system and the base was changed to DMAP from potassium carbonate (Figure 2 19). These optimized conditions were applied to a variety of substituted benzyl amines.

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56 Figure 2 18. Oxidative ca rbonylation of 42 forming 43 and 44 Figure 2 19. Optimized conditions for urea synthesis using NaIO 4 and NaI. Conclusions Tungsten hexacarbonyl is a very useful catalyst for carbonylating amines. di a tetra substituted ureas, cyclic ureas, hydantoins, diarylureas have all been successfully formed using W(CO) 6 in a variety of conditions. The core structures of complex target molecules like biotin and DMP 450 were al so successfully produced with this catalyst. This work was further developed when metal free conditions were found that formed ureas from oxidative carbonylation of primary amines.

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57 CHAPTER 3 TRANSITION METAL FREE CARBONYLATION OF AMINES TO FORMAMIDES In c onjunction with previous work carbonylating amines to ureas in the absence of a transition metal catalyst, which used NaIO 4 as an oxidant and NaI as a promoter, the effect of solvent was examined. 61 Using similar conditions, it was found that amines could be converted to formamides in methanol solvent without formation of urea. During our studies of NaIO 4 induced carbonylation of amines to ureas, fo rmamide derivatives were also observed as byproducts. In the course of our optimization studies, the reaction was carried out in methanol instead of the standard biphasic DCM:water solvent mixture. In methanol, only 44 was produced from the carbonylation of 42 without 43 detected in the reaction mixtures (Figure 3 1). These new conditions were then examined to maximize the yield of the formamide. Figure 3 1. Initial use of methanol solvent to form 44 from 42 Early O ptimization The initial observation of formamides in the product mixtures involved DMAP as the base in the reaction because it was the preferred base in the urea synthesis. However, incomplete separation of product and base during flash chromatography of the reaction mixtures containing DMAP led to low yields of formamides. Other bases were examined to determine their efficacy for formamide synthesis. The bases studied were DBU, potassium carbonate and pyridine. All three resulted in formation of the for mamide product (Table 3 1). The highest yields were obtained from DBU and

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58 K 2 CO 3 with K 2 CO 3 preferred due to its much lower cost and ease of removal during aqueous workup. Table 3 1. Selection of base for conversion of 42 to 44 Entry a Base Yield (%) 1 DMAP Trace b 2 DBU 73 3 K 2 CO 3 78 4 Pyr 31 a Conditions: 4.0 mmol amine, 4.0 mmol NaI, 6.4 mmol NaIO 4 16 mmol K 2 CO 3 45 atm CO, 60 mL CH 3 OH, 24 h, 90 C. b Product observed spectroscopically. Preliminary optimization experiments addressed reaction time (Table 3 2). After 8 h, the reaction yields stabilized, indicating that the product does not decompose under the reaction conditions. This is different than the urea reactions where longer reaction times led to decreased yields and decomposed products. The last preliminary optimization was temperature. When 44 was first observed, the temperature of the reaction was 90 C. The temperature was increased from that of the optimized temperature for urea synthesis under similar conditions (25 C) due to the lack of solubility of the oxidant and base in methanol. However, when the reaction was run at room temperature in attempts to utilize a multi chamber vessel for small scale reactions, the yield did not decrease. Future experiments were run without heatin g. Table 3 2. Reaction time for conversion of 42 to 44 Entry Time (h) Yield (%) 1 2 32 2 4 64 3 8 79 4 24 80 5 48 75 Conditions: 4.0 mmol amine, 4.0 mmol NaI, 6.4 mmol NaIO 4 16 mmol K 2 CO 3 45 atm CO, 60 mL CH 3 OH, 90 C.

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59 Control Experiments After a suitable base was selected and an initial time study was completed, various control experiments were conducted. A concern of these conditions is the possibility that the formyl group in the products could be derived from the oxidation of methanol by pe riodate, not from the carbon monoxide. Control experiments with methanol oxidation products but without carbon monoxide were run to investigate the origin of the carbonyl group during formylation of 42 When either formic acid or 37% w/w formaldehyde/wate r was used as the solvent with no addition of carbon monoxide, no 44 was detected by IR or 1 H NMR analysis The reaction was also run using ethanol as a solvent instead of methanol. If alcohol oxidation to the aldehyde were occurring and reacting with th e amine, we would expect the amide product to form. However, 44 was produced in a 40% yield Isotopic Labeling Experiments Another method to examine possible methanol incorporation is to label the methanol. An isotopic labeling experiment in which the me thanol solvent was 50% 13 CH 3 OH produced 44 with 13 C in only natural abundance as determined by mass spectrometry (Figure 3 2). This result confirms that the source of the carbonyl is carbon monoxide and not the methanol solvent. Although the 13 C labeling experiments establish that the formyl carbonyl is not derived from methanol, the formyl hydrogen could be incorporated from the methyl group by H abstraction or from the hydroxyl group by proton transfer (Figure 3 3) The carbonylation reaction of 42 was run in CD 3 OH, to look for incorporation of deuterium label at the formyl position of 44 as a result of radical abstraction from the labeled methyl group. However, the IR spectra of the products obtained in CH 3 OH and CD 3 OH

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60 were identical as were the integr ations of the formyl hydrogen peak in the 1 H NMR spectra. Figure 3 2. Possible outcomes for incorporation of 13 C from labeled methanol. Figure 3 3. Incorporation of deuterium from deuterated methanol. In contrast, running the experiment in CH 3 OD resulted in incorporation of deuterium 1 in 44 to 1624 cm 1 in 44 d Presence of the label was confirmed by a decreased relative integration value of the formamide proton at 8.1 ppm in the 1 H NMR spectrum of 44 d to 0.1 H from it s original value of 1.0 H in the spectrum of 44 The 2 H NMR spectrum of 44 d shows a formyl deuterium peak at 8.1 ppm, the same chemical shift as the

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61 hydrogen in the 1 H NMR. The mass spectrum of formamide 44 d also confirms the presence of the deuterium label. These labeling experiments identify the methanol hydroxyl proton as the source of the formyl hydrogen A New Perspective Periodate is known to gener ate radical species. 76 Thus, based upon bond energies and resonance stabilization, if the reaction proceeded by a radical mechanism, it was expected that the hydrogen incorporating into the formamide product would be the results of a hydrogen abstraction from the methyl portion of the solvent, not from the proton attached to the oxygen. The reaction was run with TEMPO, a known radical trap (1:1 NaIO 4 :TEMPO) in order to ascertain the presence of a long lived radical species. The yield of this reaction was 79%, not the decreased yield expected of a radical pathway. Additi onally, no amine adduct was observed. This result, coupled with the result of the deuterium labeling study, led us to believe that the reaction was not going through a radical pathway. Thus, a further examination of the role of periodate and of the react ion mechanism began. New control experiments addressed the necessity of each piece of the reaction. An examination of the promoter identity was done ( Table 3 3 ) 1 Various iodide salts with different counterions were examined. The yields were not affecte d by the counterion identity. However, when the yield of the reaction did not change with the removal of the promoter, it was determined that the promoter was not necessary. In further experiments NaI was left out of the reaction conditio ns. 1 Promoter study performed by Lilli Carpo.

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62 Table 3 3. Examination of promoter identity for the conversion of 42 to 44 Ent ry Promoter Yield (%) 1 NaI 63 2 (NBu 4 )I 67 3 KI 68 4 I 2 68 5 None 70 Conditions: 3.0 mmol amine, 3.0 mmol promoter, 4.8 mmol NaIO 4 12 mmol K 2 CO 3 45 atm CO, 45 mL CH 3 OH, 24 h, 90 C. When NaIO 4 was present but the base was removed, no product formed. When the base and NaIO 4 were both removed, no product formed. When NaIO 4 was removed but the base was still present the reaction achieved the same yields as previously observed. Th us unlike urea formation, this carbonylation is not oxidative but possibly base mediated. The reaction was run without any base and no product formed. The reaction was run in water instead of methanol with base and NaIO 4 and while the product was observe d by TLC, the yield was too small to isolate, <1%. This is a drastic difference than the 78% yield that is obtained when methanol is the solvent. When the reaction was run in water with base but no NaIO 4 the product was not observed at all. Conclusions C arbonylation of amines in methanol selectively produces formamides. Potassium carbonate was chosen as the optimal base for this conversion. Sodium iodide and NaIO 4 were discovered to be unnecessary. The only necessary components in this reaction are ami ne, base, carbon monoxide, and methanol. Further optimizations were performed on this reaction without NaIO 4 present.

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63 CHAPTER 4 BASE MEDIATED CARBONYLATION Optimization Optimization studies were conducted on 4 methoxybenzylamine beginning with the most r ecent conditions sans oxidant. These conditions consisted of 1 equiv (0.004 mol) amine, 4 equiv K 2 CO 3 60 mL methanol, 24 h, 25 C, and 45 atm carbon monoxide. Conditions were then optimized for time (Table 4 1), base quantity (Table 4 2), and pressure (T able 4 3 and Table 4 4). Table 4 1. T ime optimization for the conversion of 42 to 44 Entry Time (h) Yield (%) 1 2 49 2 4 63 3 7 78 4 8 81 5 24 81 Conditions: 4 mmol amine, 16 mmol K 2 CO 3 45 atm CO, 60 mL CH 3 OH 25 C Table 4 2. B ase quantity opt imization for the conversion of 42 to 44 Entry K 2 CO 3 (equiv) Yield (%) 1 1.1 72 2 2 76 3 3 81 4 4 78 Conditions: 4 mmol amine, 45 atm CO, 60 mL CH 3 OH, 8 h, 25 C. Table 4 3. P ressure optimization for 7 h reaction time for the conversion of 42 to 44 Entry Pressure CO (atm) Yield (%) 1 15 44 2 25 60 3 35 78 4 45 78 Conditions: 4 mmol amine, 12 mmol K 2 CO 3 60 mL CH 3 OH 7 h, 25 C. Table 4 4. P ressure optimization for 24 h reaction time for the conversion of 42 to 44 Entry Pressure CO (atm) Yie ld (%) 1 25 79 2 35 80 3 45 84 Conditions: 4 mmol amine, 8 mmol K 2 CO 3 60 mL CH 3 OH 24 h, 25 C.

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64 It was difficult to decide on a set of optimized conditions because there is a delicate balance between reaction time, equiv of base, and pressure. The r eaction reached completion in 7 h when 45 atm of CO and four equiv of K 2 CO 3 were used. At 8 h reaction time, only 3 equiv of base were needed to get the standard yield of product. Using 3 equiv of base at 7 h, we see that the pressure can be reduced to 3 5 atm. However, if lower pressure is desired, the reaction can be extended to 24 h and use only 25 atm CO with 2 equiv of base to achieve the same yield. This reaction is able to reach achieve similar yields when higher pressures or higher concentration of base are used. It is also important to note that there is a significant dependence upon the stirring of the reaction. Yields dropped 10 20% in different sets of conditions when a smaller stir plate was used for the reaction. This problem was identifie d and all reactions were done on large, stronger stir plates that resulted in more vigorous stirring. Substituent Effects The optimization reactions were all conducted using 42 as star t ing material. We next wanted to examine the effect of the para substit uent on the benzylamines as well as the functional group tolerance of this method. A selection of benzyl amines with different functional groups at the para position were tested (Table 4 5). para valu es. This value is effectively a measure of the donating or withdrawing effect of the substituent when it is on the para position of the benzene ring. These values take into account both inductive effects of the substituent as well as resonance effects. Negative values indicate a substituent is overall electron donating and positive values indicate that the substituent is overall electron withdrawing.

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65 Table 4 5. Carbonylation of 4 substituted benzylamines. Entry Amine para Product Yield a (%) 1 b 0.27 78 2 b 0.17 61 3 c 0.02 71 4 b 0 49 5 b 0.06 67 6 c 0.18 33 d 7 b 0.23 48 8 b 0.23 47 9 c n/a (CO 2 Et = 0.40) 27 d 10 b 0.45 25 a Isolated yield per equiv of amine. b Conditions: 4 mmol amine, 12 mmol K 2 CO 3 35 atm CO 60 mL CH 3 OH 7 h, 25 C. c Conditions: 2 mmol amine, 6 mmol K 2 CO 3 35 atm CO, 30 mL CH 3 OH, 7 h, 25 C. d One extra equiv of base was added because the amine was an HCl salt.

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66 Table 4 5. Continued. Entry Amine para Product Yield a (%) 11 c 0.54 23 12 b 0.66 17 d a Isolated yield per equiv of amine. b Conditions: 4 mmol amine, 12 mmol K 2 CO 3 35 atm CO, 60 mL CH 3 OH, 7 h, 25 C. c Conditions: 2 mmol amine, 6 mmol K 2 CO 3 35 atm CO, 30 mL CH 3 OH, 7 h, 25 C. d One extra equiv of base was added because the amine was an HCl salt. The yields of the formamides produced by their correspondi ng amines follow a trend that better electron donating groups on the ring produce higher yields. This is consistent with nucleophilic attack of the amine on the carbonyl species present. The yields of formamides produced by the electron poor species are rather low. For comparison purposes, the conditions used in this study were optimized using an electron rich species and were not changed. Using the same conditions facilitates seeing the trend based upon electron density. A previous examination of subs trate scope was done before NaIO 4 was eliminated from the reaction conditions (Table 4 6). These previous conditions employed higher pressure and more equiv of base. Yields of many of these substituted formamides are higher but that is believed to be a r esult of the higher pressure and additional base.

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67 Table 4 6. Carbonylation of 4 substituted benzylamines with NaIO 4 present. Entry Amine Product Yield a (%) 1 b 80 2 c 68 3 d 61 4 b 79 5 e 36 f 6 b 86 7 b 92 8 b 7 f a Iso lated yield per equiv of amine. b Conditions: 4.0 mmol amine, 6.4 mmol NaIO 4 16 mmol K 2 CO 3 60 mL CH 3 OH, 25 C. c Conditions: 2.5 mmol amine, 4.0 mmol NaIO 4 9.9 mmol K 2 CO 3 40 mL CH 3 OH, 8 h, 25 C d Conditions : 4.0 mmol amine, 4.0 mmol NaI, 6.4 mmol NaIO 4 16 mmol K 2 CO 3 60 mL CH 3 OH, 90 C e Conditions : 1.5 mmol amine, 1.5 mmol NaI, 2.4 mmol NaIO 4 6.0 mmol K 2 CO 3 20 mL CH 3 OH, 90 C f One extra equiv of base was added because the amine was an HCl salt. Other Amines A variety of other amines was al so subjected to these reaction conditions (Table 4 7, Table 4 8). The conditions optimized for 42 at 24 h reaction time were used for primary amines (Table 4 7) and the conditions optimized at 7 h reaction time were used for the cyclic secondary amines (T able 4 8) It was unknown how acyclic secondary

PAGE 68

68 amines would react, so longer reaction times were employed. Previous work had shown that cyclic secondary amines produced good results in short reaction times. Table 4 7. Carbonylation of primary amine s to formamides Entry Amine Product Yield a (%) 1 b 40 2 b 37 3 b 76 4 c 61 5 b Trace 6 c 71 a Isolated yield based on equiv of amine. b Conditions : 1 mmol amine, 4 mmol K 2 CO 3 25 atm CO, 15 mL CH 3 OH, 24 h, 25 C. c Conditions: 2 mmol amine, 4 mmol K 2 CO 3 25 atm CO, 15 mL CH 3 OH, 24 h, 25 C. Table 4 8. Carbon ylation of secondary amines to formamides Entry a Amine Product Yield b (%) 1 39 2 78 3 66 d Condi tions: 4 mmol amine, 12 mmol K 2 CO 3 35 atm CO, 7 h, 25 C. b Isolated yield based on equiv of amine. n Butylamine, i butylamine, and cyclohexylamine were formylated in good yield but amines with shorter alkyl groups exhibit lower yields. This may be attr ibuted to the solubility of the formamides in water which inhibits their isolation during the reaction

PAGE 69

69 workup. Cyclic secondary amines produced the formamides in moderate to good yields. Proposed Mechanism A possible reaction mechanism involves base media ted carbonylation through a methyl formate intermediate (Figure 4 1 ). This mechanism is consistent with our experimental data. There is literature precedent for the formation of methyl formate when base, methanol, and carbon monoxide are mixed at high pr essures. 77 Jogunola reported the formation of methyl formate when potassium methoxide was combined with carbon monoxide followed by proton transfe r from methanol, thereby regenerating methoxide. Figure 4 1 Proposed mechanism for the base mediated pathway to formamides.

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70 Similar to our experimental results, Jogunola reported a relationship between stirring rate and methyl formate concentration. The faster stirring speeds produced a marked increase in methyl formate concentration due to the increased mass transfer area of the gas bubbles, which led to increased gas absorption. We saw a strong relationship between y ield and stirring. Smaller stir plates did not produce yields as high as when the reaction was performed on a larger, more vigorous stir plate. Methyl formate, amine 42 and K 2 CO 3 and were stirred at room temperature until starting material was no longer observed via TLC 2 This yielded 44 in quantitative yield. This control was repeated with the addition of NaIO 4 to determine whether the pathway would proceed with periodate present. The product 44 was produced again in quantitative yield. These result s are consistent with the reaction occurring via formation of methyl formate from methanol and CO, followed by nucleophilic displacement of meth anol by the amine. Conclusions Two sets of optimized conditions were identified. For a shorter reaction time of 7 h, 35 atm CO and 3 equiv of base are necessary. When the reaction is run for 24 h, 25 atm CO and 2 equiv of base are sufficient. Product formation is sensitive to stirring. Substituted benzylamines are formylated in moderate to good yields. Primary and secondary amines were formylated in a range of yields depending upon the structure of the amine. We propose a base mediated mechanistic pathway leading through methyl formate as an intermediate. 2 Methyl formate control experiments performed by Jennifer Johns.

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71 CHAPTER 5 EXPERIMENTAL SECTION General Methods Startin g materials and reagents were purchased from Sigma Aldrich or Acros Organics and used without further purification unless specified. 4 Methoxybenzylamine was purified by distillation under reduced pressure. Carbon monoxide was purchased from Airgas. 1 H and 13 C NMR spectra were obtained on Varian Gemini 300, VXR 300, and Mercury 300 MHz spectrometers. 2 H NMR spectra were obtained on an Inova 500 MHz spectrometer. Infrared spectra were measured on a Perkin Elmer 1600 FTIR either as pure solid or as neat oil. Elemental analysis was performed at the University of Florida. High resolution mass spectrometry (HRMS) was performed by the University of Florida analytical service. General Procedure for Carbonylation of Amines to Formamides Procedure A N (4 Methoxybenzyl)formamide ( 44 ). To a 300 mL glass liner for a Parr high pressure vessel were added methanol (60 mL), NaI (0.600 g, 4.00 mmol), NaIO 4 (1.37 g, 6.40 mmol), potassium carbonate (2.21 g 16.0 mmol) and amine 42 (0.631 g, 4.06 mmol). The liner was placed in the vessel and methanol was added to the space between the liner and vessel. The vessel was then closed, charged to 45 atm with carbon monoxide, heated to 90 C and stirred for 24 h. At the completion of the reacti on the solution was placed in a separatory funnel. Saturated sodium sulfite was added to the solution and mixed thoroughly. Water was added to dissolve the solid salt

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72 present and the mixture was extracted with DCM (3 x 25 mL). The organic layers were co mbined and the solvent was removed via rotary evaporation leaving an off white solid residue. The solid was purified via column chromatography using silica gel and ethyl acetate/hexanes as the eluent (50:50 ethyl acetate: hexanes shifted to pure ethyl ace tate) to provide 44 as a white solid (0.604 g, 80% yield). The compound was identified by comparison with literature data. 78 1 H NMR (DMSO d 6 8.10 (s, 1 H), 7.19 (d, J = 8.5 Hz, 2 H) 6.88 (d, J = 8.5 Hz, 2 H), 4.23 (d, J = 6.0 Hz, 2 H), 3.73 (s, 3 H); 13 C NMR (DMSO d 6 IR (solid) 1641 cm 1 ; HRMS (ESI): Calcd for C 9 H 11 NO 2 [M+Na] + 188.0682, found 188.0690. Procedure B N (Benzyl)formamide ( 50 ) To a 300 mL glass liner for a Parr high pressure vessel were added methanol (60 mL), potassium carbonate (1.66 g, 1 2.0 mmol), and amine 49 (0.429 g, 4.00 mmol). The liner was placed in the vessel. The vessel wa s then closed, charged to 35 atm with carbon monoxide, and stirred for 7 h. At the completion of the reaction the solution was placed in a separatory funnel. Water was added to dissolve any solid base and to achieve separation between methanol and DCM. The mixture was extracted with DCM (3 x 25 mL). The organic layers were combined and the solvent was removed via rotary evaporation leaving an off white solid residue. The solid was purified via column chromatography using silica gel and ethyl acetate/he xanes as the eluent (50:50 ethyl acetate: hexanes shifted to pure ethyl

PAGE 73

73 acetate) to provide 50 as a white solid (0.268 g, 49% yield). The compound was identified by comparison with literature data. 48 1 H NMR (DMSO d 6 8.14 (s, 1 H), 7.42 7.13 (m, 5 H), 4.30 (d, J = 6.1 Hz, 2 H); IR (solid) 1638 cm 1 Procedure C N Formylpiperidine ( 84 ) To a 300 mL glass liner for a Parr high pressure vessel were added methano l (60 mL), potassium carbonate (1 .66 g, 12.0 mmol) and amine 83 (0.325 g, 3.82 mmol). The liner was placed in the vessel. The vessel was then closed, charged to 35 atm with carbon monoxide, and stirred for 7 h. At the completion of the reaction the solu tion was placed in a separatory funnel. Water was added to dissolve any solid base and to achieve separation between methanol and chloroform. The mixture was extracted with chloroform (3 x 25 mL). The organic layers were combined and the solvent was rem oved via rotary evaporation leaving a slightly yellow oil residue. The oil was purified via column chromatography using silica gel and CHCl 3 /CH 3 OH as the eluent (CHCl 3 shifted to 100:5 CHCl 3 /CH 3 OH) to provide 84 as a colorless oil (0.335 g, 78% yield). T he compound was identified by comparison with literature data. 32

PAGE 74

74 Procedure D N Butylformamide ( 74 ) To a 25 mL glass vial for a multi chamber Parr high pressure vessel were added methanol (15 mL), potassium carbo nat e (0.553 g, 4.00 mmol) and amine 73 (0.0788 g, 1.08 mmol). The liner was placed in the vessel. The vessel was then closed, charged to 25 atm with carbon monoxide, and stirred for 24 h. At the completion of the reaction the solution was acidified with 3.0 M HCl to approximately pH 2 and placed in a separatory funnel. Water was added to achieve separation between methanol and DCM. The mixture was extracted with DCM (3 x 10 mL). The organic layers were combined and the solvent was removed via rotary e vaporation to afford 74 as a colorless oil (0.0828 g, 77% yield). The compound was identified by comparison with literature data. 79 Carbonylation Products N (Methoxybenzyl)formamide d, p CH 3 OC 6 H 4 CH 2 NHCDO (44 d) Proced ure A was used at 25 C with amine 42 (0.285 g, 2.077 mmol), NaIO 4 (0.6845 g, 3.200 mmol), potassium carbonate (1.11 g, 8.00 mmol) and 20 mL CH 3 OD. The product was identified by comparison with literature data. 78 1 H NMR (DMSO d 6 8.10 (s, 0.1 H), 7.19 (d, J = 8.5 Hz, 2 H), 6.88 (d, J = 8.5 Hz, 2 H), 4.23 (d, J = 6.0 Hz, 2 H), 3.73 (s, 3 H); 2 H NMR (DMSO d 6 ) 8.10 (s); IR (solid) 2186, 2171, 1623 cm 1 ; HRMS (DART): Calcd for C 9 H 10 DNO 2 [M+H] + 167.0925, found 167.0928.

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75 N (4 Nitrobenzyl)formamide ( 68 ). Procedure A was used with the HCl salt of amine 67 (0.755 g, 4.01 mmol). The procedure was altered to include an additional purification via column chromatography using silica gel and 7:3 ethyl acet ate: DCM. The product was afforded in a 7% yield and was identified by comparison to literature data. 80 N (4 Methylbenzyl)formamide ( 46 ). Procedure B was used with amine 45 (0.483 g, 3.99 mmol) and afforded the product in a 61% yield. 1 H NMR (DMSO d 6 7.02 (m, 4 H), 4.25 (d, J = 6.0 Hz, 2 H), 2.27 (s, 3 H); 13 C NMR (DMSO d 6 135.9, 128.8, 127.3, 40.5, 20.7; IR (solid) 1650 cm 1 ; HRMS ( ESI ): Calcd for C 9 H 12 NO [M+H] + 150.091 3 found 150.0915 ; A nal. Calcd for C 9 H 11 NO: C, 72.46; H, 7.43; N, 9.39; found: C, 72.64; H, 7.62; N, 9.31 N (4 Vinylbenzyl)formamide ( 48 ). Procedure B was altered to use methanol (30 mL), potassium carbonate (0.829 g, 6.00 mmol), and amine 4 7 (0. 263 g, 1.97 mmol) to afford the product in a 7 1% yield. 1 H NMR (DMSO d 6

PAGE 76

76 J = 7.9 Hz, 2 H), 6.71 (dd, J = 10.8, 17.7 Hz, 1 H), 5.80 (d, J = 17.7 Hz, 1 H), 5.23 (d, J = 10.8 Hz, 1 H), 4.29 (d, J = 5.8 Hz, 2 H) ; 13 C NMR (DMSO d 6 13 5.5, 127.2, 125.8, 113.7, 40.2 ; IR (solid) 1651 cm 1 ; HRMS ( ESI ): Calcd for C 10 H 1 2 NO [M+H] + 1 62 .0913, found 1 62 .09 13 ; Anal. Calcd for C 10 H 11 NO: C, 7 4 51 ; H, 6 88 ; N, 8 69; found: C, 74.40; H, 7.31 ; N, 8.3 5 N (4 Fluorobenz yl)formamide ( 52 ). Procedure B was used with amine 51 (0.501 g, 4.00 mmol) and afforded the product in a 67% yield. The solid was identified by comparison with literature data. 81 N (4 Iodobenzyl)formamide ( 54 ). Procedure B was altered to use methanol (30 mL), potassium carbonate (1.11 g, 8.03 mmol) and the HCl salt of amine 53 (0.538 g, 1.82 mmol) to afford the product in a 33% yield. 1 H NMR (DMSO d 6 J = 8.3 Hz, 2 H), 7.07 (d, J = 8.2 Hz, 2 H), 4.24 (d, J = 6.3 Hz, 2 H); 13 C NMR (CDCl 3 137.2, 129. 6, 93.1, 41.6; IR (solid) 1648 cm 1 ; HRMS (APCI): Calcd for C 8 H 9 INO [M+H] + 261.9723, found 261.9723; Anal. Calcd for C 8 H 8 INO: C, 36.81; H, 3.09; N, 5.37; found: C, 37.06; H, 3.03; N, 5.13.

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77 N (4 Bromobenzyl)formamide ( 56 ) Procedure B was used with amine 55 (0.753 g, 4.05 mmol) and afforded the product in a 48% yield. 1 H NMR (DMSO d 6 J = 8.0 Hz, 2 H), 7.22 (d, J = 8.0 Hz, 2 H), 4.27 (d, J = 6.0 Hz, 2 H); 13 C NMR (DMSO d 6 ): 1 ; HRMS (APCI ): Calcd for C 8 H 9 BrNO [M+H] + 213.9862, fou nd 213.9867; Anal. Calcd for C 8 H 8 BrNO: C, 44.89, H, 3.77; N, 6.54; found: C, 44.87; H, 3.77; N, 6.54. N (4 Chlorobenzyl)formamide ( 58 ). Procedure B was used with amine 57 (0.566 g, 3.99 mmol) and afforded the product in a 47% yield. The solid was identified by comparison with literature data. 81 Methyl 4 (formamidomethyl)benzoate ( 60 ). Procedure B was altered to use methanol (30 mL), potassium carbonate (1.11 g, 8.03 mmol) and the HCl salt of amine 59 (0.396 g, 1.96 mmol) to afford the product in a 27% yield. 1 H NMR (DMSO d 6 J = 7.7 Hz, 2 H), 7.40 (d, J = 7.7 Hz, 2 H), 4.38 (d, J = 6.0 Hz, 2 H), 3.84 (s, 3 H); 13 C NMR (DMSO

PAGE 78

78 d 6 cm 1 ; HRMS ( ES I ): C alcd for C 10 H 12 NO 3 [M+H] + 194.081 2 found 194.0809 ; Anal. Calcd for C 10 H 11 NO 3 : C, 62.17; H, 5.74; N, 7.25 ; found: C, 62.39; H, 5.71; N, 6.96 N (4 Formamidomethyl)benzoic acid ( 62 ). Procedure B was used with amine 61 (0.603 g, 3.99 mol). The procedure was altered in the following way, before extraction the pH was adjusted to 1 with 3.0 M HCl, after which no further purification was necessary. The product was obtained in a 25% yield. 1 H NMR (DMSO d 6 J = 7.7 Hz, 2 H), 7.37 (d, J = 7.7 Hz, 2 H), 4.37 (d, J = 6.0 Hz, 2 H); 13 C NMR (DMSO d 6 ): 3 127.2, 40.5 ; IR (solid) 1687, 1653, 1630 cm 1 ; HRMS ( ESI ): Cal cd for C 9 H 10 NO 3 [M H] 1 78 .0 510 found 178.0514 ; Anal. Calcd for C 9 H 9 NO 3 : C, 60.33; H, 5.06; N, 7.82; found : C, 60.28; H, 5.41; N, 7.00 N (4 (Trifluromethyl)benzyl)formamide ( 64 ). Procedure B was altered to use methanol ( 30 mL), potassium carbonate (0.829 g, 6.00 mmo l) and amine 63 (0.351 g, 2.01 mmol) and afforded the product in a 23% yield. The solid was identified by comparison with literature data. 81

PAGE 79

79 N (4 Cyanobenzyl)formamide ( 66 ). Procedure B was altered to use the HCl salt of amine 65 (0.674 g, 4.00 mmol) and potassium carbonate (2.21 g, 16.0 mmol). The product was afforded in a 17% yield. 1 H NMR (DMSO d 6 J = 7.9 Hz, 2 H), 7.45 (d, J = 7.9 Hz, 2 H), 4.38 (d, J = 6.0 Hz, 2 H); 13 C NMR (DMSO d 6 132.3, 128.0 118.8, 109.6, 40.5; IR (solid) 2229, 1651 cm 1 ; HRMS ( ESI ): Calcd for C 9 H 9 N 2 O [M+H] + 161.07 0 5, found 161.0709 ; Anal. Calcd for C 9 H 8 N 2 O: C, 67.49 ; H, 5.03; N, 17.49; found: C,67.50; H, 4.81; N, 17.11. N Formylpyrrolidine ( 82 ). Procedure C was used with amine 81 (0.285 g, 4.01 mmol) and afforded the product in a 39% yield. The oil was identified by comparison with literature data. 32 N Formylmorpholine ( 86 ). Procedure C was used with amine 85 (0.350 g, 4.02 mmol) and afforded the product in a 66% yield. The oil was identified by comparison to literature data. 82

PAGE 80

80 N Propylformamide ( 70 ). Procedure D was used with amine 69 (0.0543 g, 0.919 mmol) and afforded the product in a 40% yield. The oil was identified by comparison t o literature data. 83 N Isopropylform amide ( 72 ). Procedure D was used with amine 71 (0.0564 g, 0.954 mmol) and afforded the product in a 37% yield. The oil was identified by comparison to literature data. 83 N Isobutylformamide ( 76 ). Procedure D was used with amine 75 (0.1470 g, 2.01 mmol) and afforded the product in a 61% yi eld. The oil was identified by comparison to literature data. 84 N Tertbutylformamide ( 78 ). Procedure D was used with amine 77 (0.0793 g, 1.08 mmol).. Trace amounts of product were tentatively identified spectroscopically by comparison to literature data. 48

PAGE 81

81 N Cyclohexylformamide ( 80 ). Procedure D was used with amine 79 (0.1 974 g, 1.99 mmol) and afforded the product in a 7 1% yield. The oil was identified by comparison to literature data. 85

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87 BIOGRAPHICAL SKETCH Ciera Jane Gerack was raised in Greenville, SC. Her love of learning began at a very young age. However, her passion for chemistry came later during her junior year of high school, and she has not stopped studying the subject ever since. At the age of eighteen Ciera began attending the College of Charleston in Charleston, SC. In May of 2008, she earned her B.S. in chemistry. In August of the same year, Ciera began graduate school at the Unive rsity of Florida. After five full years that were filled with learning, teaching, laughter, and tears, she earned her Ph.D., specializing in organic chemistry. She plans to continue her career in the world of academics, as teaching is her particular pass ion.