Studies in the chemistry of cyclic and acyclic nitrogen compounds

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Title:
Studies in the chemistry of cyclic and acyclic nitrogen compounds
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vii, 179 leaves : ill. ; 29 cm.
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White, Roslyn Lorraine, 1967-
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Subjects / Keywords:
Organonitrogen compounds   ( lcsh )
Chemistry thesis, Ph. D
Dissertations, Academic -- Chemistry -- UF
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non-fiction   ( marcgt )

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Thesis:
Thesis (Ph. D.)--University of Florida, 1995.
Bibliography:
Includes bibliographical references (leaves 170-178).
Statement of Responsibility:
by Roslyn Lorraine White.
General Note:
Typescript.
General Note:
Vita.

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Full Text













STUDIES IN THE CHEMISTRY OF
CYCLIC AND ACYCLIC NITROGEN COMPOUNDS











By

ROSLYN LORRAINE WHITE


A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY

UNIVERSITY OF FLORIDA

1995



























To my husband, Abdul, for his loving support














ACKNOWLEDGEMENTS


First and foremost, I would like to give praises to the Almighty God,


whom al


without


life would not be possible.


Secondly, I would like to thank my supervisor, Dr. Alan R Katritzky, for allowing


me the opportunity to become a member of his research group.


gratitude for his guidance during my stay here.


I would also like to express


I would especially like to thank him for


challenging me, for it is those challenges which have pushed me to look deep within myself

and to strive to become a better, stronger chemist.

For the time spent and helpful suggestions given, I would like to express sincere


thanks to my supervisory committee members, Dr


James A.


Deyrup, Dr.


William R.


Dolbier


Vaneica Young and Dr. Jonathan F. K. Earle.


I would also like to express special thanks to Dr. Richard A.


Barcock and Dr.


Steven M. Allin for their help over the years.


Also special


thanks go to


Elena S.


Ignatchenko.

It has been a rather unique experience working with the members of the Katritzky

Research Group and these memories will remain with me always.

I am truly grateful to my entire and extended family and friends for their love and

support.


Finally,


forever


indebted


husband,


Abdul


whose


love,


understanding, support and encouragement has been a constant source of inspiration.










TABLE OF CONTENTS


page


ACKNOWLEDGEMENTS.

ABSTRACT.


CHAPTERS


GENERAL INTRODUCTION.


General Introduction to Nitrogen Compounds.
Introduction. .


FIRST DEMONSTRATION OF SPECIFIC C-C BOND SCISSION
OF THE PYRIDINE RING: REACTIONS OF PIPERIDINE, PYRIDINE
AND SOME OFTHEIR METHYLDERIVATIVES.


Introduction. .
Synthesis of Compounds.
Results.
General Discussion.
Conclusions.
Experimental. .


REACTIONS OF VARIOUS ALIPHATIC AMINES WITH FORMIC
ACID: 1-OCTYLAMINE, DI-1-OCTYLAMINE, N,N-DIMETHYL-
OCTYLAMINE, 1-DODECYLAMINE AND N,N-DIMETHYL-1-
DODECYLAMINE.. . .


Introduction.
Synthesis of Compounds.
Results.
General Discussion.
Conclusions.
Experimental. .










IV BENZOTRIAZOLE-1-CARBOXAMIDINIUM TOSYLATE:
ANALTERNATIVE METHOD FOR THE CONVERSION OF AMINES
TO GUANIDINES.. . . . 76

Introduction . . . 76
Results and Discussion. . 81
Conclusions. . 86
Experimental.. . . . 87

V INVESTIGATIONS OF 4-AMINO-1,2,4-TRIAZOLE: APPROACHES
TO THE DEVELOPMENT OF A NEW ELECTROPHIIC AMINATING
AGENT & METHODOLOGY FOR THE PREPARATION OF
4-(ALKYLAMINO)- 1,2,4-TRIAZOLES. . 93

Introduction. . . . . 93
Results and Discussion. 99
Conclusions. . 117
Experimental. . . 119


APPENDICES

A MASS SPECTRAL FRAGMENTATION PATTERNS OF
PIPERIDINE PRODUCTS. . . 126

B MASS SPECTRAL FRAGMENTATION PATTERNS OF
ALIPHATIC PRODUCTS. . . . 144

C X-RAY CRYSTAL STRUCTURE OF
BENZOTRIAZOLE-1-CARBOXAMIDINIUMTOSYLATE. . 166


REFERENCES. . 170


BIOGRAPHICAL SKETCH. . . 179













Abstract 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

STUDIES IN THE CHEMISTRY
OF CYCLIC AND ACYCLIC NITROGEN COMPOUNDS


By

Roslyn Lorraine White


May


Chairman:


1995


Alan R. Katritzky, FRS


Major Department: Chemistry


Formic acid variously acts as a formylating, methylating, reducing and oxidizing

agent in its reactions with piperidine, pyridine and some of their methyl derivatives under


aquathermolysis conditions.


Both pyridine and piperidine are converted in significant


amounts into 1-methyl-,


1-ethyl-,


1-propyl-


and 1-pentyl-piperidines.


1-alkyl


groups, isotopic labelling shows that only 1-methyl derives from the formic acid, while the

1-ethyl and 1-propyl arise from heterocyclic ring C-C bond fission by retro-vinylogous-

bis-aza-Aldol reactions. Detailed analysis of the products for pyridine, piperidine, and their

4-methyl derivatives, reacted separately and mixed, supports mechanisms in which a


piperidine adds 1


to a pyridinium cation, or to a di-


or tetra-hydropyridine, to initiate


reaction sequences leading to the product slates found.


Two primary aliphatic amines (1-octylamine,


1-dodecylamine),


one secondary


aliphatic amine (di-1-octylamine) and two tertiary aliphatic amines (N


,N-dimethyl-1-









dominant reaction pathways viz., (i) N-formylation with subsequent reduction to give N-
methyl- and N,N-dimethyl-alkylamines, and (ii) elimination of NH3 and smaller amines to


the corresponding alkenes followed by partial double bond isomerization.


The secondary


amine mainly underwent conventional N-formylation with subsequent reduction to the N-


methyl derivative.


Tertiary amines underwent reductive cleavages to secondary and


primary amines, which subsequently followed the reaction sequences seen for primary

amines.

Benzotriazole-1-carboxamidinium tosylate was synthesized from benzotriazole,


cyanamide and


p-toluenesulfonic acid.


This tosylate salt underwent nucleophilic


displacement of the benzotriazole anion by various primary and secondary amines to

generate substituted guanidines under mild conditions.

Two derivatives of 4-amino-l,2,4-triazole were synthesized and their chemistries


investigated.


Condensation of 4-amino-l,2,4-triazole and fluorenone led to N-(1


triazol-4-yl)fluorenimine.


aminating agent.


This novel imine was investigated as a potential electrophilic


4-(Benzotriazol-l-ylmethylamino)-1,2,4-triazole was synthesized by the


condensation of 4-amino-l,2,4-triazole and hydroxymethylbenzotriazole.


This adduct


undergoes nucleophilic displacement by Grignard reagents to generate 4-(alkylamino)-

1,2,4-triazoles.














CHAPTER I
GENERAL INTRODUCTION



General Introduction to Nitrogen Compounds


Nitrogen is one of the principal elements in all living creatures.


Therefore, nitrogen


containing compounds are ubiquitous in nature.


A large number of


medically and


biologically important compounds are N-compounds--in particular various amines and


amino acids.


Many of these compounds have powerful physical and psychological effects.


Nitrogen compounds are also important industrially.


The petrochemical industry provides


raw materials for liquid petroleum and natural gas feed stocks in the form of amines, nitro-


compounds, heterocyclic N-compounds, dyes, drugs etc.


Due to the importance of


nitrogen to the growth of plants and animals, it is not surprising that nitrogen compounds

(particularly fertilizers) rank very high in total annual commercial production. The

objective of this dissertation is to investigate the chemistry of cyclic and acyclic nitrogen

compounds, for which the results will be reported in the following four chapters.



Introduction


Chapters II and III deal with the aquathermolysis


of various classes of nitrogen


compounds.


Chapter II focuses upon the aquathermolysis of piperidine,


pyridine and


some of their methyl derivatives,


while chapter III deals with the aauathermolvsis


-a





2


can be used to remove the deleterious nitrogen compounds found in crude petroleum and

synthetic oils. Normally, organic compounds do not react with water under standard

reaction conditions. However, organic molecules which are unreactive in liquid water can

be subjected to many chemical reactions when the temperature of water is raised to 250 *C -


350 oC.


Compounds such as ethers (1


-001) and esters (1


-002) undergo cleavage and


hydrolysis,


respectively, with ease [90EF488] (Scheme 1


the above reactions):


catagenesis, takes place in nature.


An analogous process (to


Catagenesis, is the process by


which cross-linked macromolecular structures (solid petroleum kerogens) are converted in


source rock into liquid petroleum.


In nature, catagenesis has a time frame of millions of


years, and occurs at temperatures less than 200 *C,


in aqueous environments at about


61MPa of pressure [91SCI231].


HO


-O-R1
-001


- 3500C


R-H


+ HO


cleavage products


H20


-0-


- 350C


-OH


+ "OR1


-002


hydrolysis
products


RC-


Scheme 1-1


When water is heated at elevated temperatures significant changes in its physical

and chemical properties take place. As the temperature of water is increased from 25 to 350

*C the following changes take place:
/\; ,'m.A j4, gf ^,f ,4.., /l/^. ^ /,Fn, <-/^-. f\ rw7 *- / ,'1I l-- -^ to1 jr rT ,-n


-R1


-R1





3


The physical changes allow water at 300 C to behave similar to acetone at


[91SCI231],


creating an environment for ionic reactions.


Chapter IV discusses the synthesis of benzotriazol


e- 1-carboxamidinium tosylate


and the related application of benzotriazole methodology in the synthesis of guanidines


from amines.


A useful synthetic auxiliary, benzotriazole (1


-003) and its chemistry has


been exploited within the Katritzky research laboratories and has also found favorable use


industrially.


The N-N double bond of benzotriazole has strong electron-withdrawing


ability which enhances the acidic properties and therefore transforms the benzotriazole


anion into an excellent leaving group.


A wide variety of organic compounds including


primary,


secondary


tertiary


amines,


hydroxylamines,


hydrazines,


amides,


polyfunctional amino compounds, ethers and esters have been synthesized [91T2683].


N-N

N
I
NH2


-003


The structurally related 4-amino-1,2,4-triazole (1


-004


-004) has also been investigated.


This amino-triazole can be condensed with ketones to generate the corresponding imine. In

addition, this triazole can also be condensed with benzotriazole and formaldehyde to


generate the corresponding benzotriazole-triazole adduct.


Chapter VI deals with the


derivatization of 4-amino-l,2,4-triazole and its application in the attempted synthesis of


imines and 4-(alkylamino)-1


,4-triazoles.















CHAPTER II
FIRST DEMONSTRATION OF SPECIFIC C-C BOND SCISSION OF THE PYRIDINE
RING: REACTIONS OF PIPERIDINE, PYRIDINE AND SOME OF THEIR METHYL
DERIVATIVES IN AQUEOUS FORMIC ACID



Introduction


Nitrogen, sulfur and oxygen are among the heteroatoms which are found in coals


[92EF439].


In order to convert solid coals and oil shale kerogens to liquids which can be


used as synthetic fuels (the) cross-links of the above mentioned heteroatoms need to be


broken. This process of the liquification of coal normally requires a variety of catalysts

[89EF160]. Unfortunately, a specific catalyst is required for the removal of a specific


heteroatom and can become quite costly.


Liquids derived from N-containing coals often contain large amounts of N-

impurities [84MI]. Compounds which contain nitrogen are detrimental for the following

three reasons:-

(i) they poison and deactivate catalyst used later in refining processes,

(ii) they form toxic nitrogen oxides upon combustion, and

(iii) they confer instability on the product fuel, causing discoloration and other

detrimental reactions [92EF439, 93TL4739].

The nitrogen-containing compounds found in petroleum or synthetic oils include both

heterocycles, for example pyridines and pyrroles, and non-heterocycles such as aliphatic


amines


With N-heterocvcles. the normal mode of removal has been denitrogenation


r
I


~~l.





5


hydrogenolysis of strong aromatic C-N bonds which subsequently requires significant

prehydrogenation of the heteroaromatic and/or aromtic rings [92EF439].

Extensive investigations have been carried out within the Katritzky Research Group

on nitrogen removal from heterocyclic nitrogen model compounds in aqueous systems


[92EF439, 92EF450].


Formally, we have been investigating the aquathermolysis2.1


- i.e.


thermal transformations of organic compounds in aqueous environments


- of a variety of


N-compounds.


Recently, we found that at 350 *C,


49% aqueous formic acid induces the


hydrogenation of the pyridine ring to piperidine in significant amounts and also induces the


scission of the pyridine ring [93TL4739].


Over the last 50 years, much evidence has


accumulated that the common heterocycles can undergo (often reversibly) ring opening


under a variety of conditions.


However, all examples involve the scission of heteroatom-


carbon


bonds;


the analogy


been


made of heterocycles as carbon chains


with


heteroatoms as padlocks which enable opening by a suitable key.

We set out to propose appropriate mechanistic pathways for the various products of

pyridine ring scission, by synthesizing authentic compounds and investigating their


authentic mass spectral


fragmentation


pathways to


confirm


products


aquathermolysis runs.


2.2,2.3 Therefore, we studied the effect of 49% aqueous formic acid


on piperidine (2-004)2.4


, 1-methylpiperidine (2-007),


4-methylpiperidine (2-008),


pyridine (2-005) and 4-methylpyridine (2-012) (Scheme


The work to be described


had its origin in our extensive studies [92EF439, 92EF450] of hydrodenitrogenation of

2.1 This project formed part of a joint collaboration between the Katritzky Research Group at the
University of Florida and groups at Exxon Research and Engineering Co.
2.2 All aquthermolysis reactions were conducted jointly by Mamudai Balasubramanian, Richard A.


Barcock and Elena S.


Ignatchenko at the University of Florida.


A.-- L


~ll..,rt,~. ,E,,,,,..,1, ,,~ ...I,, ,.,,I,,,,,, _-~-1 1~~.~-Il__rl_.__!.~ .._1_.~~1 d









heteroaromatic models of compounds found in fuel resource streams.


In addition to


reporting the unique behavior of these compounds under aquathermolysis conditions, we


now


disclose


first examples of


specific


C-C-bond


scission


unactivated


heterocyclic system of pyridine,


and demonstrate how the long-studied


ndustrially


important processes by which pyridine rings are formed from C1,


2 and C3 aldehydes are


in principle reversible.


2-004


2-005


2-007


2-008


2-012


Scheme


The gas chromatographic (GC) behavior (retention times) of all the compounds

employed in this study (starting materials and products) are summarized in Table 2-1.2.5


Tables

results.


Table


, and 2-4 contain the compiled mass spectral data for the analysis of the

.-2 contains the sources and purities of the starting materials used and have


been compiled based upon the direct comparison of the GC retention times, and of the mass


spectral (MS) fragmentation patterns with those of the authentic compounds.


Table 2-3


contains compounds which have been compared with literature mass spectral data for the


same compound.


Those compounds for which no suitable literature MS data were


available


have


been


identified


fragmentation


patterns (obtained from


aquathermolysis runs) and have been compiled in Table 2-4.


Further explanation of the


Tables


--2-4


given


in section


Experimental.


results


from


from










Table 2-1.


Structure and Identification of Starting Materials and Products.


tR (min)


Structure


Eq. Wt


Basis a


Factor b


2-001

2-002

2-003

2-004

2-005

2-006

2-007

2-008

2-009

2-010

2-011

2-012


potenne

3-methyl- 1-pentene

pentyiamine

pperidine

pyridine

1-(13C)-methylpiperidine

1-methylpiperidine

4-methylpiperidine

N,N-dimethylpentylamine

1,4-dimethylpiperidine

1-ethylpiperidine

4-methylpyridine


Table 2-2

Table 2-2

Table 2-2

Table 2-2

Table 2-2

Table 24

Table 2-2

Table 2-2

Table 24

Table 2-2

Table 2-2

Table 2-2


2-013


N,N-dimethyl-2-
methylpentylamine


Table 24


2-014

2-015


l-ethyl-4-methylpiperidine


Table 24

Table 2-4


1 -propylpiperidine


2-016


1-popyl-4-methylpiperidine


2-017


l-butylpiperidine


2-018


1-butyl-4-methylpiperidine


2-019

2-020

2-021


1-(2-methylbutyl)piperidine

1-pentylpiperidine

1-(pent-4-en-yl)piperidine

1-(13C)-formylpiperidine

1-formylpipezidine


2-022

2-023


Table 2-4


Table 2-3


Table 24


Table 2-4

Table 2-3

Table 24


Table 2-4

Table 2-2





8




Table 2-- 1 continued


tR (min)


Structure


Eq. Wt


Basis a


Factor b


2-027


1-formyl-4-methylpiperidine


Table 2-4


2-028


l-(3-methylpentyl)-4
-methylpiperidine


2-029

2-030


Table 2-4


1-(5aminopentyl)piperidine

1-acetyl-4-methylpiperidine


Table 2-4

Table 2-4


2-031


1-(3-methyl-5-aminopentyl)-4
-methylpiperidine


Table 24


tR (min)


Retention time in minutes. MW = molecular weight. Eq. Wt = equivalent weight.


a = Identification Basis, see appropriate tables. b = Response Factor, see ref [89TCM17].










Table


Authentic Compounds Used as Starting Materials and for the Identification
of Products.


Compound


Purity


m/z (% relative intensity)


Ref. b
spectra#


2-001


pentene


70(35); 55(60); 42(100); 41(45);
39(35)


2-002

2-003

2-004


2-005


2-007


2-008


3-methyl-l-pentene


pentylamine

piperidine


84(30); 69(80); 55(100); 41(80)

87(5); 70(3); 55(2); 42(3); 30(100)

85(55); 84(100); 70(10); 56(40);
55(45)


pyridine


79(60); 55(20); 52(100); 50(60);
44(70)


1-methylpiperidine


99(35); 98(100); 84(10); 70(30);
58(10)


4-methylpiperidine


99(60); 98(95); 84(40); 70(10);
56(100)


67826


68696


68691


2-009


N.N-dimethyl
pentylamine


115(6); 58(100); 44(4); 42(10)


2-010

2-011


1,4-dimethylpiperidine

1-ethylpiperidine


113(10); 112(100); 98(5); 70(20)

113(25); 112(20); 98(100); 84(10)


80481

3071


2-012


4-methylpyridne


93(100); 66(50); 65(25);


51915)


68420


2-013


N,N-dimethyl-
2-methylpentylamine


129(5); 100(5); 86(10); 58(100)


2-019


-(2-methylbutyl)-


piperidine


155(7); 98(100); 84(10); 70(6); 56(10)


2-023


1 -formylpiperidine


13(100); 112(50); 103(30); 98(50)


2-024


1-(3-methylpentyl)-


piperidine


2-026


1-acetylpiperidine


MW = molecular weight. a A


1690); 154(9); 98(100); 84(5); 70(4)


127(100); 112(20); 84(45); 70(25);
56(30)


= Aldrich, S = synthesized authentic compound (see experimental section).


b spectral numbers of the mass spectral data for the compounds found from a search of the Wiley











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11




Table 2-4. Identification of Piperidines from Mass Spectral Fragmentation Patterns


1iperidine
Substituent


Fragmentation Pattern m/z (% rel. intensity,
structure of fragment ion)


2-006


1-(13C)-methyl-


100(75, M+); 99(100, M-H); 71(25, M-Et); 70(10);
58(10, C3HgN); 43(30, C2H5N)


2-014


1-ethyl-4-methyl-


127(20, M+);


112(100, M-CH3); 84(20, C5H10N+); 80(15);


70(40); 52(25); 42(60); 33(99)


2-015


2-016


2-018


1-propyl-


M+); 126(20, M-H); 98(100, M-Et); 57(5, C3H7N)


1-propyl-4-methyl-


1-butyl-4-methyl-


141(5, M+); 112(100, M-Et); 70(25); 55(10); 44(30);
42(30)


155(10, M+); 112(100, M-Pr); 98(10); 70(35); 55(20);
44(60); 33(95)


2-021


1-(pent-4-en-1-yl)-


153(1,


M+); 98(100, M-C4H7); 84(4); 70(12)


2-022


14-13C)-formyl-


114(100, M+);113(35, M-H); 98(30, M-CH);
84(20, M-13CHO); 70(15, M-C3H6)


2-025


l-pentyl-4-methyl-


169(5, M+); 112(100, M-C4H9); 84(5); 70(30); 55(5);
44(30)


2-027


1-formyl-4-methyl-


128(100, M+


27(10, M+); 126(5); 112(25, M-CH3);


98(10, M-CHO); 84(10, C5H1 N+)


2-028


1-(3-methylpentyl)-


4-methyl-


2-029


2-030


183(5, M+); 112(100, M-C5H11); 70(
55(5); 44(20); 42(10); 41(15)


1 -(5-aminopentyl)-


l-acetyl-4-methyl-


M-C7H15N);


170(40, M+); 140(10, M-CH2=NH2+); 112(5); 98(100);
84(10); 70(20); 58(15); 41(15); 42(35)


142(100, M+ + 1); 141(25, M+); 140(10, M-H);


126(35, M-CH3); 98(35,


M-COCH3); 84(30)


2-031


1-(3-methyl-5-amino-
pentyl)-4-methyl-


198(1


M+); 197(5); 196(15); 112(100); 70(15); 55(10);


44(20); 42(15); 41(20)


+ 1); 1





12


percentages of moles of starting material as described in detail previously [90EF493] and


have been corrected with regard to their response factors [89TCM17].


demonstrates the percentages of


Table


the various simple N-alkylpiperidines formed from


pyridine and their 4-methyl derivatives, singly and admixed.


Structures and proposed


mechanistic pathways for the formation of these products (which are justified later in this


chapter) are given in Schemes 2-3,


2-8--2-


In these reaction Schemes, numbers greater


than 2-


100 are used for postulated intermediates not detected by the GC/MS analyses.


Synthesis of Compounds


project


outlined


above


undertaken


our


laboratories


on the


aquathermolysis of piperidine, pyridine and some of their methyl derivatives in 49%


aqueous formic acid solutions,


we were speculating upon


the formation of


some


alkylpiperidines and tertiary aliphatic amine derivatives as the aquathermolysis reactions


progressed.


However, the gas chromatographic/mass spectral data was inconclusive for


the compounds were hitherto unknown.

various 1-alkylpiperidines and N, N-din


Thus, we were interested in synthesizing these


lethylalkylamines and determining their authentic


mass spectral fragmentation pathways, to confirm the identity of these products in the

aquathermolyses, as well as giving us an idea about the identity of similar derivatives.

The compounds synthesized were authentic samples of two tertiary amines, N,N-


dimethylpentylamine (2-009) and N,N-dimethyl-2-methylpentylamine (2


-013), and three


1-alkylpiperidines, 1-(2-methylbutyl)piperidine (2-019), 1-(3-methylpentyl)piperidine (2-


024) and 1-(4-methylpentyl)piperidine (2-032) (Scheme 2-2).


(2-019,


The novel cyclic amines


2-024) and the known cyclic amine (2-032) were prepared in respectable yields









N


RN
R2


R3MgBr


Et20O


R3CH-N'
R2


2-033R1
2-034R'


= -(CH,)5-


2-009, 2


-Me


2-019,


-013,


2-024,


2-032


Compound


2-033
2-034


(%) yield


-(CH2)5-


2-009


CH2CH2CH2CH2


2-013


CH3CH2CH2(CH3)CH


2-019


-(CH2)5-


2-024


2-032


CH3CH2(CH3)CH

CH3CH2CH(CH3)CH2

(CH3)2CHCH2CH2


H-C-H


EtOH


+ H-NF
R


N
N


R2


2-033R1
2-034 R1


= -(CH2)5-


-Me


Scheme


-(CH2)5-


-(CH2)5-


_R2





14


bromobutane, 1-bromo-2-methylbutane and 1-bromo-3-methylbutane, respectively.


The tertiary, acyclic amines (2-009,


2-013) were prepared by the reaction of 1-(N,N-


dimethylaminomethyl) benzotriazole (2-034) with the corresponding Grignard reagents of

n-butyl bromide and 2-bromopentane, respectively (see section 2.6 Experimental).


1-(Piperidinomethyl)benzotriazole (2-033)


[52JA3868,


87JCS(P1)799] and


(N,N-dimethylaminomethyl)benzotriazole (2-034)


[46JA2496,


92JOC4932


were


prepared in high yields employing literature procedures.


The benzotriazole adduct 2-033


was synthesized by condensation of benzotriazole formaldehyde and piperidine, while

adduct 2-034 was synthesized by the condensation of benzotriazole, formaldehyde and


dimethylamine (Scheme 2.2).


Further discussion of the mass spectral identification and


interpretation of the amines


is covered in the Discussion (2.4),


Experimental (


6) and


Appendix.


Results


Piperidine (2-004).


On heating with aqueous 49% HCO2H at 350


*C for


piperidine (2


-004) was completely consumed (Table 2-5).


The major product was


formylpiperidine (2-023,


93.9%)


together


with


an appreciable


amount


methylpiperidine (2-007


However, 1-ethyl-


(2-011


0.3%),


1-propyl-


(2-015,


0.8%) and 1-acetyl-piperidine (2-026, 0.8%) were all detected as minor products along


with traces of 1-pentylpiperidine (2-020, 0.1%).


After 8 h at 350 *C in 49% HCO2H, the


yield of 1-formylpiperidine (2-023) was roughly halved (42.4%) and the aforementioned


1-alkylpiperidines, noticeably 1-pentylpiperidine (2-020, 19.3


) were all formed in larger


amounts.


1-(2-Methylbutyl)piperidine (2


-019) was formed in trace amount (0.6%).


clear that


1-formylpiperidine (2


-023)


initially


formed


later converted


later


converted






15


Table 2-5. Products Obtained from 1-Methylpiperidine (1-MePip), 4-Methylpiperidine (4-MePip),
Piperidine (Pip).


Mech


1-MePip


4-MePip


Additive


(see text)


Time (h)
No. Structure


2-001
2-003
2-004
2-005
2-007
2-009
2-010
2-011
2-013


2-014
2-015
2-016
2-017
2-018
2-019
2-020


2-021
2-023
2-025
2-026
2-027
2-028


2-029
2-030
2.ilT 1


pentene
pentylamine
piperidine


pyridine


(25.6)+


1-methylpiperidine


23.2 3.9


N, N-dimethylpentylamine
1,4-dimethylpiperidine


1ethylpiperidine


1.5 4.8


0.9 0.6


NN-dimethyl-2-methyl-
pentyamine
1-ethyl-4-methylpiperidine


1-propylpiperidine


2.4 0.5


1-propyl-4-methylpiperidine
1-butylpiperidine
1 -butyl-4-methylpiperidine
1-(2-methylbutyl)piperidine


1 -pentylpiperidine


19.3 0.1


1-(pent-4en-1-yl)piperidine


1-formylpiperidine


42.4 94.9


1 -pentyl-4-methylpiperidine
1-acetylpiperidine
1-formyl-4-methylpiperidine
1-(3-methylpentyl)-4-methyl
piperidine


1-(5-aminopentyl)piperidine
1 -acetyl-4-methylpiperidine
1 -.-mathvl- gmltnrmowntulk









Piperidine (2-004) plus 1-pentene (2-001).


The same reaction of piperidine was


carried out in the presence of 1-pentene (2-001) (1 equivalent) in 49% HCQ2H at 350 oC


2 h and gave the same slate of products as in the absence of pentene, i.e. 1-methyl-(2-


,3.9%) and 1-formyl-piperidine (2-023, 94.9%),


products.


together with the same minor


In particular, no significant increase in 1-pentylpiperidine (2-020) was found


this run, suggesting that olefins are not intermediates in these reactions.


1-Methvlpiperidine (2-007).


This


compound showed a 46.


conversion after


just 0.5 h at 350 *C in 49% HCO2H.


29.0%).


The major product was 1-formylpiperidine (2-023,


This product is probably formed via the N-formylation of 1-methylpiperidine


with the subsequent elimination of a methyl cation probably assisted by the format ion.


Other products included piperidine (2-004,


1.8%),


and small quantities of 1-ethyl-


, 1.5%),


1-propyl-


(2-015,


0.9%),


1-butyl-


(2-017


1.6%) and 1-pentylpiperidine


(2-020, 3.7%).


Extending the reaction time to 2 h yielded a similar product slate,


although a higher conversion (52.1%) was observed.


formylpiperidine (2- 0 2 3, 28.3 %).


The major product was again 1-


The N-alkylpiperidines observed in the above reaction


(350 *C, 0.5 h) were again seen here,


but in increased amounts (see Table


Extending


the reaction time further to 4 h, led to a 48.3


conversion, which is only slightly lower


than that observed for the


2h run.


The major product here is again 1-formylpiperidine (2-


023, 1


, N-Dimethyl-2-methylpentylamine (2-013) was formed in trace amount


(0.3%), while N


, N-dimethylpentylamine (2


-009) was observed slightly higher (2.


2%).


However, it seems likely that during the extended time of this reaction, some of the 1-


formylpiperidine is reduced


hydride


from


formic


acid


to return


to 1-


methylpiperidine (2-007)


in view


the increased amounts of


the same higher N-


alkylpiperidines which were observed (see Table 2-5).


On heating at 350 OC for 8 h with









and 1-pentyl-piperidine (2-020,


4.8%).


,N-Dimethylpentylamine (2-009) was formed


in 23.1


After 8 h,


1-formylpiperidine (2-023) was present only in a small amount


(2.4%).


4-Methvlpiperidine (2-008).


This compound underwent complete conversion after


h(see


Table 2-5) and the major products were 1,4-dimethylpiperidine (2


1-formyl-4-methylpiperidine (2-027,


70.1


-010, 27.5%),


1-(3-methyl-5-aminopentyl)-4-


methylpiperidine (2-031,


2.3%).


A trace amount of 1-ethyl-4-methylpiperidine (2-014,


) was also seen.


At 350 *C


for 8 h


n 49% HCO2H,


4-methylpiperidine (2-008)


underwent a complete conversion to give


1,4-dimethylpiperidine (2-010,


38.0%),


formyl-4-methylpiperidine (2-027, 33.3%),


together with smaller amounts of 1-ethyl-


014, 6.9%),


1-propyl-


-016


1-butyl-


(2-018, 0.


) and 1-pentyl-


(2-025,


1-(3-methylpentyl)-4-methylpiperidines (2-028,


7.0%).


demonstrated that the N-alkyl groups on the nitrogen-functionality are now derived from

the 4-methylpiperidine (2-008) ring.


4-Methvlpiperidine (2-008) plus 3-methvl-1-pentene (2-002).


This


run was


carried out to determine whether or not 3-methyl-1-pentene (2-002) is an intermediate in


the formation of 2-028 from 2-008.


HCO2H at 350 *C for


002),


4-Methylpiperidine (2-008) on heating with 49%


2 h, in the presence of one equivalent of 3-methyl-l-pentene (2-


underwent a 100% conversion with the major products being 1,4-dimethylpiperidine


(2-010, 13.


) and 1-formyl-4-methylpiperidine (2-027


83.1%).


The product slate


from this


run (Table 2-5) suggests that 3-methy


1-pentene (2-002) does not play a


significant role in the generation of the products, especially as

methylpiperidine(2-028), was not seen in increased amounts.


Pvridine (2-005).


1-(3-methylpentyl)-4-


Pyridine (2-005) on heating with 49% HCO2H 350 *C for












Table 2-6.


Products Obtained from 4-Methylpyridine (4-MePy), Pyridine (Py).


Mech


Additive
Time (h)
No.


2-004
2-005
2-006
2-007
2-010
2-011
2-012
2-014
2-015
2-016
2-017
2-018
2-019
2-020


4-MePy


(see text)


Structure


piperidine

pyridine


1-(3C)Q-methylpiperidine
1-methylpiperidine
1,4-dimethylpiperidine


14.9 0.4


1-ethylpipridine
4-methylpyridine


1 -ethyl-4-methylpiperidine
1-propylpiperidine
1-propyl-4-methylpiperidine
1-butylpiperidine
1-butyl-4-methylpiperidine
1 -(2-methylbutyl)piperidine


1 -pentylpiperidine


11.7 6.7


2-022
2-023
2-024
2-025
2-026
2-027
2-028


2-029
2-030


1-(13C)-fonnylpieridine


1 -formylpiperidine


1-(3-methylpentyl)piperidine
1-pentyl-4-methylpiperidine


1-acetylpiperidine


1-formyl-4methylpiperidine
1-(3-methylpentyl)-4-methyl
piperidine
1-(n5aminopentyl)piperidine
1-acetyl-4-methylpiperidine





19


16% to 59.7% and produced all the foregoing products in much increased quantities,


together with


1-acetylpiperidine (2-026,


2.1%), 1-(2-methylbutyl)piperidine (2-019,


1.8%) and 1-(5-aminopentyl)-piperidine (2


-029,


1%).


On heating in 100% H13CO2H at 350 *C for


2 h, pyridine (2-005) showed a


conversion into a similar slate of products (but in increased amounts, probably


facilitated by the use of 100% HCO2H


- see Table 2-6) as seen for the run in 49% HCO2H


at 350 *C for


Significantly, only the 1-methylpiperidine (2-006,


1.9%) and the


1-formylpiperidine (2-022, 19


) were labelled, and each contained just one C label.


The fact that 1-ethyl-


(2-011,


1-propyl- (2-015,


1%),


1-pentyl-piperidine


(2-020, 6.7%) produced simultaneously had no 13C labelled carbons shows conclusively


that the ethyl, propyl and pentyl groups in 2-011,


2-015 and 2


-020, respectively, are all


derived completely from pyridine carbon atoms and not from carbons of the formic acid.


4-Methvlpvridine (2-012).


4-Methylpyridine (2-012) on heating in 49% HCO2H


at 350 *C for


2 h showed a 59.6% conversion into


1,4-dimethyl-


(2-010,


14.9%),


formyl-4-methyl-


-027


) and


-methylpentyl)-4-methyl-piperidine (2-028,


together with


smaller amounts


1-ethyl-


(2-014,


1.4%)


-butyl-4-


methylpiperidine (2-018,


) (Table 2-6).


Evidently,


the ethyl and butyl groups


required for the N-alkylation of 4-methylpiperidine were derived by fragmentation of 4-


methylpyridine molecules.


amount (0.3%).


1-(3-Methylpentyl)piperidine (2-024) was observed in trace


4-Methylpyridine (2-012) on heating in 49% HCO2H at 350 *C for 6 h


underwent a 64.6% conversion to 1,4-dimethylpiperidine (2-010,


18.2%),


1-formyl-4-


methylpiperidine (2-027,


30. 1


and 1-(3-methylpentyl)-4-methylpiperidine (2-028,


9.7%).


Other products included small amounts of 1-ethyl-


-014), 1-propyl-


(2-016),


-butyl-


(2-018),


1-pentyl-


(2-025)


2-acetyl-


(2-030) -4-methylpiperidines.









4-Methylpiperidine (2-008) plus pvridine (2-005).


To understand the types of


intermediates involved in the C-C and C-N bond cleavages, we ran an aquathermolysis of

4-methylpiperidine (2-008) mixed with pyridine (2-005) (1 mole equivalent) in 49%


HCO2H at 350 *C for


2 h (Table 2-5).


4-Methylpiperidine (2-008)


underwent a 100%


and pyridine a


74.6% conversion


under these conditions.


Various


N-substituted


piperidines (2-007


2-011


2-015


, 2-019,


2-020,


2-023 and


2-029) were formed


together with the following N-substituted-4-methylpiperidines


1,4-dimethyl-


(2-010,


7%),


methyl-


1-ethyl-4-methyl-


(2-025,


(2-014, 1.1


1-propyl-4-methyl-


1-(3-methylpentyl)-4-methyl-


(2-016, 1.9%), 1-pentyl-4-


(2-028,


1-(3-methyl-


aminopentyl) -4-methyl-


(2-031,


2.3%


1-formyl-4-methylpiperidine (2-027


4-Methvlpvridine (2-012) plus piperidine (2-004).


This reaction was carried out


in order to compare the results with those obtained from the 4-methylpiperidine (2-008)

plus pyridine (2-005) run. 4-Methylpyridine (2-012) showed a 58.9% conversion with
49% HCO2H at 350 oC for 2 h and the same slate of products was seen as in the case of 4-


methylpiperidine (2-008) plus pyridine (2-005) (Table 2-6).


The long list of products


can be classified


nto two groups:


(i) N-substituted piperidines (2-007,


2-011


, 2-015,


2-017


, 2-020,


2-023


2-024


and 2-026) and (ii) 4-methyl-N-substituted piperidines


(2-010,


2-014,


2-016, 2-018,


2-028,


2-030).


No piperidine (2-004) or 4-


methylpiperidine (2


-008) (reduction product of 4-methylpyridine {2-012}) was left in the


reaction mixture which indicates that they were completely consumed in further reactions.



General Discussion








from the ring carbon atoms.


The fact that piperidine (2-004) forms a rather similar slate of


products to that obtained from pyridine (2


-005), suggest that formic acid acts not only as a


reducing, but also evidently toward piperidine (2-004) as an oxidizing agent, although we


have been unable to find literature precedence for this.


We believe that most of the


products formed can be explained by four types of mechanistic routes:

(i) Conventional reactions where the formic acid is behaving as a hydride ion donor
and as a formylating agent

(ii) Retro-vinylogous-bis-aza-aldol reactions of products formed by the addition of

piperidines to dihydropyridines.

(iii) Simple ring-opening of amidine or aminal type intermediates formed by addition of

piperidine to dihydro- or tetrahydro-pyridines followed by reduction.

(iv) Ring-opening of isomers of products formed by addition of piperidines to a

quaternized pyridinium cation.

We now discuss each of these mechanistic pathways in turn.


(i) Conventional formic acid reduction/formvlation.


Formic acid reductions of


quaternary salts of pyridine and of 1-methylpyridinium cation to the corresponding fully


hydrogenated products, viz. piperidine (2


-004) and 1-methylpiperidine (2-007), are well


documented [55ZOK1947


57ZOK3021


, 65CCC1700, 65MI1058]


The mechanistic


pathway [38CCC66, 47CCC71] to these compounds (Scheme 2-3) involves formic acid


(or format anion) donating hydride ion to the C-4 of the pyridinium cation (2-


101)


resulting in 1,4-dihydropyridine (2-


102).


Further successive protonations and attacks of


hydride ion at C-6 and C


yield piperidines (2-004


2-008).


Piperidine (2-004)


undergoes


formylation


to 1-formylpiperidine (2-023)


which


reduced


methylpiperidine(2-007) in the presence of formic acid as shown in Scheme 2-3.


In the












HCO2H


2-005R


2-012


=H
=Me


101)


2-004
2-008


-H
=Me


102)


103)


CH3
2-007R


HCOH


HCO2H


2-010

R :


=Me


2H,
2 H+


CHO


CHO


CHO


104)


105)


2-023
2-027


-Me


Scheme


Retro-vinvlogous-bis-aza-Aldol reaction route.


The Aldol reaction [680R1]


and its reverse, the retro-Aldol reaction [89MI 199], are among the most important reactions


in organic chemistry.


Mono-aza-Aldol reactions are also well known [68AG(E)7].


Although the self-condensation of nitriles (Scheme 2-4) is a well known "named reaction"


(Thorpe-reaction) [06JCS 1906],


we have been unable to find any example of the similar








which should thus involve the fragmentation of a 3-amino-imine (2-


109 and 2-


111) into two imines


110) also appears to be unknown (Scheme 2-5).


RCH2CN


RCH2CN


R-CH2,-


NHCN
I %PC


106)


107)


108)


alkyl,


Scheme 2-4


H i"
RC-C-R
R5


R'HN
R2-C-
R3


C-R7


R2, R3


109)


R'-R7


=alky


110)


111)


,aryl


Scheme


As regards vinylogs of the Aldol reaction, although the reactions of aldehydes at the


y-position of an a,j-unsaturated ketone (Scheme 2-6) is well known [680R1],


we have


been unable to find any example when this reaction stops at the intermediate hydroxy

compound.


RCHO + R'CH2CH=CHCOR


112)


113)


C-CR
H


= alkyl,


R-C=C-C=C-CR2


R H-
FI I


R.R1


u L









Aza analogs of


vinylogous Aldol reactions also appear to be uninvestigated


although such reactions are almost certainly involved in the commercially important


preparation of pyridines from aliphatic aldehydes and ammonia (see later).


Based on the


previous arguments, 6.amino-y6-unsaturated imines could be expected to undergo retro-


vinylogous-bis-aza-Aldol (RVBAA) reactions cf 2-115


-> 2-116 & 2-


(Scheme


R
'NH
I 4-
R-3C r>


R
R N
-_ II 7
-C-C-R


R,
-N R
II I
R~r^_r^-


R F~IHR
+ C=C-R
R


115)


= H, alkyl


116)


117)


Scheme


Compounds of type 2-


115 are tautomers of 6-bis-imines, and the related cations


(cf 2-


120) are capable of formation by ring-opening of the addition products (2-


a secondary amine (R2NH) to a 1,4-(or


) dihydropyridine (2-


119) of


118) (see Scheme 2-8).


The RVBAA reaction of 2-


120 thus causes scission into protonated acrylaldehyde imine


122) and the N-vinyl derivative (2-


vinyl compound (2-


123) of the original secondary amine.


123) is rapidly converted by successive H+


This N-


and H- addition (both


supplied by formic acid) into the corresponding N-ethyl derivative (2-


129).


In addition,


intermediate 2-


120 can undergo proton loss and proton addition to give the isomeric 6-


amino-y6-unsaturated imine cation 2-


121.


RVBAA


reaction


of 2-


121 affords


vinylamine 2-124


and the unsaturated imine cation 2-


the latter which is converted


rapidly, by successive additions of


H-, H+


and H-


, into the propyl derivative 2-


127 of


the wnri oinal snomndarv marine


Ths narstpfl AnriVtihni 7.


1 r an 9alar n f,, ,wr-mn- f,-m,,m i


. FL










R2N H


NR+
NR2


118)


119)


120)


121)


HCQCH2

H2N 22)
(2-12 2)


OfH2


123)

H+


CH2
fCH
H2N


124)


CH

NR
125)


9H3
HCR +
NR,


126)


CH3CH2NR2


CH3CH2CH2NR2


127)


H20,-2H/
CH3


129)


"NR2
128)


Scheme 2-8


The formation of 1-ethyl- (2


-011)


and 1-propyl-piperidine (2


-015)


from


reaction of pyridine (2-005), (and of piperidine {2-004}) with formic acid are thus


explained by the transformation of Scheme


Moreover, it would be expected that 4-














2-005


118)


130)


H2N


134)


131)


R


HN:
(2-


132)


-1H2N


135)


2-011


2-014R


=Me
R


133)
H20


136)


2-015R


2-016


2-026
2-030


=H
=Me


=H
= Me


Scheme 2-9


Further evidence for the mechanism proposed can be derived from the selected data


of Tables


5 and 2-6 which have been abstracted into


Table


This compares the


H










Table


Comparison of the Percentages of some of the N-Alkvlpiperidines formed


from Pyridine (Py) and Piperidine (Pip) and their 4-Methyl Derivatives, Singly and
Admixed in 49% HCO2H at 350 C for 2 h.
----------------l-----it ------------------l-l-i----.--l----l-----l 4-------- --i---- i------ ------nBe--l-- I 1-I i---i---I- ---l l -- Il I Illl ll Il IDql I d*i Il 10 --


Entry No.


Piperidine
Product
Substituent


Origin of t


4-MePy


4-MePy 4-MePip


N-alkyl


4-MePip Py


2-011


1-ethyl-


Either


2-014


2-015

2-016


2-017

2-018


2-020

2-024


2-025


2-028


1-ethyl-
4-methyl-


Either


1-propyl-

1-propyl-
4-methyl-


1-butyl-

1-butyl-
4-methyl


1-pentyl-

l-(3-methyl-
pentyl)-


N-pentyl-
4methyl-


1-(3-methyl
pentyl)-4-methyl-


2-011, 015, 017, 020, 024*

2-014, 016, 018, 025, 028*


2-015, 016, 020, 025*

2-017, 018, 024, 028*


Either


Either


Either

Either


i---" -" -----i --eI---l--B--i-.-----------------"-1-i-1----l---0- ---#ii ..---i1 ---.-e --. ---ii ---.---l -


t H is from Py or Hp; Me is from 4-MePy or 4-MePip


* = total for compounds listed.


1--1111 M-mumh ~-_II ICI~-II-CIY-~I-









amounts


simple


N-alkylpiperidines


formed


from


piperidine (2-004)


methylpiperidine (2-008),


those from the two mixed runs.


pyridine (2-005),


Table


and 4-methylpyridine (2-012) alone with


7 demonstrates very clearly that the products


expected from the mechanistic routes discussed, and only the expected products, are

formed in the runs from a single substrate.

Furthermore, Table 2-7 provides good evidence for the mechanism postulated from


the nature, and the proportions of the products formed in the mixed runs.


Thus, when 4-


methylpiperidine (2-008)


pyridine


(2-005)


were


reacted


together,


methylpiperidine (2-008) predominately provided the ring component of the piperidines


formed (compare 3.


to 1.5%


Entries xii and xi


, respectively),


whereas pyridine


predominately provided the piperidine N-alkyl substituent (compare


9% to 0.5%


Entries


xiii and xiv, respectively).


methylpyridine (2


Conversely, when a mixture of piperidine (2-004) and 4-


-012) was reacted a total of 3.9% of products formed was derived from


piperidine (2


-004) reacting as the amine HNR2,


compared


with 3.7%


from


the 4-


methylpyridine (2-012) reacting as HNR2.


Again, the N-alkyl groups of the piperidine


products


were


formed


from


the starting piperidine and 3.5%


from


methylpyridine.


This is in good agreement with the mechanism proposed in Scheme 2-9 in


which the saturated secondary amine adds to a dihydropyridine in a key step.


Addition to 23,4,5-tetrahvdropvridinium cations.


addition of R2NH to a 2,3,4,5-tetrahydropyridinium ring (2-


A simpler sequence of

137) followed by ring-


opening and reduction leads to amines of type R2N(CH2)5NH2 and this explains the


formation of 2-029 and 2-031 (Scheme


2-10).


Ring opening of isomers of products of addition of pioeridines to auaternized


ovridines


Addition of a secondary amine to a ouaternized nvridine (2-


1421 will Five


.








converts 2-


145 into the saturated product 2-


146.


We believe mechanisms of these types


to be involved in the formation of products 2-020, 2-024, 2-025,


2-028, and 2


-029


(Scheme 2-12).


140)


H

Me


H


137)


138)


NH2


NH2


141)


139)


NH2


NH2


2-031


=Me


2-029


Scheme


















142)


143)


144)


4H+


146)


= alkyl,


NR1

145)


= H, alkyl


Scheme
















150)


H

Me


101)


147)


151)


148)


152)

I 4H+


4H+


2-025


2-028 R


= Me


2-020


149)
S2H,
\2H


2-021


R=H


2-024 R


Scheme






32


Conclusions


Formic acid variously acts as a formylating, methylating, reducing and oxidizing

agent when it reacts with piperidine, pyridine and some of their methyl derivatives under

aquathermolysis conditions. In similar reactions both piperidine and pyridine are converted


to significant amounts of 1-alkylpiperidines, namely 1-methyl-,


1-ethyl-,


1-propyl- and 1-


pentyl-piperidines

aquathermolyses.


1-(4-Methylpentyl)piperidine was not observed as product from the


Through the use of isotropic labelling it has been demonstrated that only


the 1-methyl-


derivative originated from formic acid.


That is


, during the course of the


reactions piperidine and pyridine were both formylated and then subsequently reduced to


the 1-methyl derivatives.


The 1-ethyl- and 1-propyl derivatives arise from the heterocyclic


rng C-C bond fission by retro-vinylogous-bis-aza-Aldol reactions.


These unique C-C


bond scissions show for the first time that heterocyclic rings are susceptible to opening


other than at the heteroatoms.


Other reaction pathways elucidated during the course of this


work include conventional


formic acid reduction/formylation, addition


to 2,3


,4,5-


tetrahydropyridinium cations and ring opening of isomers of products formed by addition

of piperidines to a quaternized pyridinium cation.

It has been shown that formic acid at 350 *C converts pyridine and piperidine into a


defined


mixture


specific


N-alkylpiperidines.


4-Methylpyridine


methylpiperidine


similarly


converted


corresponding


1-alkyl-4-


methylpiperidines.


It has been demonstrated that al


1-alkyl groups (except for 1-


methyl) arise from a second molecule of the heterocyclic ring compound and not from the


formic acid.


The formation of all products can be rationalized by addition of a piperidine


mninletnll tnr a nn-din nr i rnr tnf _hirnrn-r;rA;nn oinol nn





33


synthesis of pyridine involves the formation of the Cs unit in situ by one or more base-


catalyzed condensation reactions.

cyclization is usually spontaneous.


With ammonia or an amine as the condensing agent,

On the industrial scale, self condensation of simple


aldehydes with ammonia lead to a variety of pyridines [79MI64].


Perhaps, the mechanistic


pathways may be viewed as cleavage into two molecules of aldehyde, the subsequent

intermediate can enable retro-aldol cleavage of the pyridines.


Experimental


1H NMR spectra were recorded either on a Varian VXR 300 (300 MHz) or a


General Electric QE 300 (300 MHz) spectrometer.


13C NMR spectra were recorded at 75


MHz on the same spectrometers. Chemical shifts are reported in parts per million (ppm)


downfield from tetramethylsilane (TMS) used as the internal standard.


(J values) are reported in Hz.

using oven dried apparatus.


Coupling constants


All Grignard reactions were run under an inert atmosphere

Solvents and anhydrous liquid reagents were dried prior to


use: diethyl ether was distilled over sodium benzophenone ketyl.


Analytical thin layer


chromatography (TLC) was performed using pre-coated silica gel 60 F 254 plastic plates

(0.2 mm thick) using iodine as indicator.


I-(Piperidinomethvl)benzotriazole (2-033) was prepared by applying the literature


procedure [87JCS(P1)799].


Benzotriazole (5.0 g, 42 mmol) was dissolved in EtOH (50.0


mL).


Next was added 37% aqueous formaldehyde (6.60 mL, 64.0 mmol)


and piperidine


mL, 42.0 mmol) and the reaction was stirred vigorously at room temperature (18 h).


Precipitation was induced by addition of HO (2 mL).


The product obtained was washed









4H, J


7.0) (piperidine),


5.43 (s,


2H) (CH2),


7.4 (m, 1H) (Bt),


(Bt),


2 (d,


1H, J


= 8.0) (Bt).


13C NMR (CDCl3)


: 6 23


70.1


110.1


118.2


119.7


123.7


126.3


127.3.


1-(N,N-Dimethvlaminomethvl)benzotriazole (2


-034) was prepared according to


the literature procedure [92JOC4932].


Benzotriazole (5.13 g,


43 mmol) was dissolved in


EtOH (42.0 mL).


Next was added 37% aqueous formaldehyde (6.60 mL, 64.0 mmol).


The mixture was stirred vigorously and cooled to 0 *C.


After the initial precipitate formed,


, N-dimethylamine (6.4 mL, 129 mmol) was added dropwise via an addition funnel and


the reaction was allowed to warm up to room temperature (18 h).

crude product was induced by cooling the mixture to -18 *C. The


filtered and washed with EtOH (20 mL).


Crystallization of the


Crude white solid was


Recrystallization from ethanol yielded white


prisms (6.3 g,


M.p. 95-97 *C (lit.[52JA3868]


m.p. 99-100.5 *C).


1H NMR


(CDC13):


(Bt),


6 2.4 (s,


7.7 (d, 1H,


6H) (2CH3),


= 8.2) (Bt),


5.4 (s,


2H) (CH2),


8.1 (d, 1H,


7.4 (m, 1H) (Bt),


7.3) (Bt).


(t, 1H, J


13C NMR (CDCl3) 6:


42.3,


69.8, 109.8, 119.5, 123.7,


127.3,


133.76, 145.


General procedure for the synthesis of N-alkvlpioeridines


1 -(2-Methvlbutvl)piperidine (2-019)


. Mg


metal


(1.7


mmol)


was


suspended with an iodine chip in Et20 (20 mL).


2-Bromobutane (9.5 g, 69.4 mmol) was


dissolved in Et20 (50 mL) and added dropwise to the Mg metal.


After the addition was


complete,


mixture


was


heated


under


reflux


stirred


(Piperidinomethyl)benzotriazole (5.0 g, 23.0 mmol)


was


- -Y - a V m


Soxhlet


then


added


via a









removed in vacuo to yield a crude yellow oi


, which was purified by Kugelrohr distillation.


A colorless oil (


20 g, 62


) was isolated: B.p. 65 *C/0.65 mm


1H NMR (CDCl3):


6 0.8 (d,


3H, J


= 8.0) (CH3),


0.9 (t, 3H, J


= 8.0) (CH3), 1.0-1.1 (m,


1H) (CH), 1


4H) (2CH2 [ring]),


1.6 (quintet,


= 6.0, 8.0) (CH2N aliphaticc]),


4H, J


2-2.4 (br m,


= 8.0) (CH2 [ring]),


4H) (CH2N [ring]).


1.0-2.1 (d of d, 2H,
13C NMR (CDC13):


6 11.3


, 24.6, 26.1,


27.9,


66.4.


HR MS (70 eV


1666 (7) [M+],


98(100) [CSH11N+];


C10H21N requires 155.1674.


1-(3-Methvlpentvl)piperidine (2-024).


This product was obtained as a crude


yellow oil and was purified by Kugelrohr distillation to give a colorless oil (3.0 g, 76%);


*C/0.


mm Hg


1H NMR (CDC13):


6 0.8-0.9 (d & t, 6H, J


= 8.0) (2CH3),


.2 (quintet, 1H, J


(CH2 [ring]),
aliphaticc]), 2.


= 8.0) (CH),


(quintet,


-2.4 (br


.2-1.4 (m,


= 8.0)


s, 4H) (CH2N [ring])


4H) (2CH2 aliphaticc]),


2CH2


[ring]),


13C NMR (CDCl3):


1.4-1


.5 (m,


(CH2N


611


26.0, 29.6, 33.3,

(100) [C5H 11N+]


54.7.


HR MS (70 eV


169.1827 (7),


C11H23N requires 169.1830.


1-(4-Methvlpentvl)piperidine (2


-032).


This product was obtained as a crude


yellow oil and was purified by Kugelrohr distillation to give a pale yellow oil (2


B.p. 65 *C/0.1 mm Hg;


1H NMR (CDCl3):


6 0.9 (d, 6H, J


= 8.0) (2CH3),


.2 g, 57%);
.2 (quintet,


2H, J


= 9.0) (CH2),


.5 (m,


4H) (piperidine),


4H) (piperidine),


(t, 2H, J


7.0) (CH2 [ring]),


2.4 (br.


s, 3H) aliphaticc).


13C NMR (CDCI3):


6 22.2


24.7


9, 36.8, 54.5, 59.8.


HR MS (70 eV


169.1


98 (100)


[CsH 11N+1


Ci1HnoN requires 169.1830.


[M+],


.5 (m,


[M+],





36


General procedure for the synthesis of acvclic amines


N,N-Dimethvlentvlamine (2- 009).


n-Buty


bromide (11.68 g, 85.2


mmol) was


dissolved in Et20 (65 mL) and added dropwise to Mg metal (2.05 g,


85.2


mmol) in the


presence of an iodine chip. After the addition was complete, the mixture was heated under


gentle


reflux


stirred


0.5 h.


After


period


time


dimethylaminomethyl)benzotriazole (5.0 g, 28.4 mmol) was added via Soxhiet extractor.


The mixture was stirred and refluxed for 18 h.


aqueous NaOH (30 mL).


The reaction was cooled and quenched with


The bulk of the Et20O was decanted from the solid and the


remainder filtered through celite, dried (MgSO4) and concentrated in vacuo to give a crude


yellow oil


- GC yield 79%.


The crude product was purified by Kugelrohr distillation to


give a colorless oil (27%


*C/0.9 mm Hg (lit. [46MI165] b.p.


122-123 "C/760


mm Hg).


1H NMR (CDCl3):


6 0.9 (t, 3H, J


= 6.0) (CH3),


1.50-1.60 (m, 6H) (3CH2),


2.20 (s,


6H) (2CH3N),


2.30 (d, 2H,


= 6.0) (CH2N).


13C NMR (CDCl3)


6 13.9,


22.5,


, 29.6,


59.7.


HR MS (70 eV


EI): ml


(%) 11


1364 (8%) [M+],


(100) [C5H11N+]


C7H17N requires 11


1361.


N,N-Dimethvl-2-methvlpentvlamine (2-013).


This product was obtained crude as


a yellow oil which was purified by Kugelrohr distillation to give a colorless oil (1.02 g,


28%


*C/2 mm Hg (lit.[50CCC512]


*C/760 mm Hg).


1H NMR


(CDCl3):


6 0.7-0.8 (t, 3H,


= 6.0) (CH3 [terminal]),


0.9 (d, J


= 6.0)3H) (CH3),


1.02-


= 6.0) (CHa),


.2 (d, 1H, J


= 6.0) (CHb),


1.4 (m,


2H) (CH2),


1.7-1.8


1H) (CH [CH3]),


.4 (d of d, 6H, J


= 6.0, 6.0) (CH2N),


2.4 (s, 6H) (2CH3N).


13C NMR (CDCIj):


6 14.3


-- ---- -


,30.8, 37.8,


45.9, 67.4.


HR MS (70 eV


-(N,N-


1.1 (q, 1H,









Aquathermolysis: General2.7


All starting materials were checked by GC prior to use;


purified to >98%.


where necessary they were


49% Aqueous formic acid was deoxygenated with argon for 1 h prior to


use. The model compound (1 g) and the formic acid (7 mL) were charged into a nitrogen-

blanketed 1" Swagelok stainless steel bomb (plug and cap) which was then sealed. The

reactor was then kept, without agitation, in a fluidized sand bath (model SBS-4) set at 350

*C using a Techne temperature controller (TC-8D) for the specified time period. The


temperature profile was measured by a Barnant 115

placed in the sandbath adjacent to the reaction vessel.


thermocouple thermometer (type J)

After the reaction period, the reactor


was immediately cooled with a stream of cold air and then quenched i

reaction mixture was then worked up as previously described [90EF493],


n dry ice.


and subjected to


GC analyses on a Hewlett Packard 5890 instrument (flame ionization detector, [FID]) with

a 15 m capillary column (SPB-1) and a temperature program of 10 *C min-1 from 50-250


GC/MS


analyses


compounds


were


performed


on a Varian 3400 gas


chromatograph and a Finnigan MAT 700 ion trap detector.


Product identification.


The GC behavior of all the compounds in this chapter


(starting material and products) are collated in Table


earlier papers [90EF493]).


1 (in the format as explained in


Within the reaction mixtures, the identities of all the starting


materials and some of their reaction products [2-001--2-005,


2-007--2-013, 2-019,


023, 2-024, 2-026] were confirmed by direct comparisons of retention times and mass

spectral fragmentation patterns with those of the authentic compounds, under essentially the


same mass spectral operating conditions.


Table 2-2 records the major features of the mass


spectra together with a literature reference to the MS of the compounds (where available).


Table 2-3 recnrds the man. enar.tral fraomentatinn nattomo rnf nrmlnteo (


n.n '7


'- nA'


i





38


the reference spectrum is always given and the major features of both the experimental and


the reference spectrum are recorded.


Table 2-4 records the MS patterns of products [2-


006, 2


-014--2-016, 2-018, 2-021,


2-022,


2-025


2-027--2


-031] for which no


published MS data could be


found.


These products were assigned from


their MS


fragmentation patterns, together with a consideration of the reaction conditions, starting


materials

materials,


, and a reasonable mechanistic pathway for their formation from the starting

p Also, the mass spectral fragmentation patterns for the synthesized compounds


(see Appendix A) 2-009,


2-013


,2-019, and 2-024 are represented.














CHAPTER III
REACTION OF VARIOUS ALIPHATIC AMINES WITH FORMIC ACID:
1-OCTYLAMINE, DI-1-OCTYLAMINE, N,N-DIMETHYL- 1-OC'TYLAMINE,
1-DODECYLAMINEAND N,N-DIMETHYL-1 -DODECYLAMINE



Introduction


As stated in Chapter


, nitrogen is among the heteroatoms


found in coals


[92EF439].


Due to the deleterious effects of N impurities (as mentioned in Chapter II),


remaining in synthetic oils


it is highly economical to remove them easily and cost


effectively.


Normal


mode


purification


involve


denitrogenation


hydrodenitrogenation


[92EF439,


93TL4739].


Aquathermolysis,


thermal


transformation of organic compounds in aqueous environments, holds potential economic

incentive as an alternative purification method for the conversion and purification of fossil

fuels such as coal.3.1


Denitrogenation can


a costly


process


removal


nitrogen form


heterocyclic nitrogen containing compounds due to the large excess of hydrogen needed to


afford hydrogenolysis of the heterocyclic ring (as mentioned in Chapter II),


but aliphatic


amines should undergo denitrogenation quite rapidly since there is no need to use excess


hydrogen.


With six-membered heterocycles, progressive decarboxylation and C-C, C-N


bond cleavages occur, leading to the generation of alkane chains [92EF439].


The aliphatic


amine already contains the alkane chain, and would therefore undergo fragmentation









directly.


There would be no need for significant prehydrogenation of the system.


Aliphatic


amines are among the nitrogen compounds found in petroleum or synthetic oils.


Our main objective was to uncover the general


pattern of


reactivity under


aquathermolysis3


functional groups.


3.3 conditions of some common, naturally occurring amine-related

Literature reports have shown that formic acid at temperatures ranging


from 100


-200 *C


, readily reduces basic N-heterocyclic rings.


Thus pyridine, quinoline,


isoquinoline and acridine can be easily reduced to piperidine, 1,2,3,4-tetrahydroquinoline,


1,2,3,4-tetrahydroisoquinoline, and 9,10-dihydroacridine respectively.


The analogous


salts


yield


the corresponding N-substituted compounds


[65CCC 1700,


65CLI1058,


55ZOK1947, 57ZOK3021].


More recently, it has been demonstrated in our laboratories


that formic acid induces the hydrogenation of the pyridine ring and subsequently leads to its

scission [93TL4739].

As previously stated, it was demonstrated in our laboratories [93TL4739] that in


49%


aqueous


formic


at 350


pyridine


was


converted


predominantly


formylpiperidine accompanied by several N-alkylpiperidines as minor products.


connection with


elucidation


mechanism


formation


alkylpiperidines,


we have also studied the effect of


49%


aqueous


formic acid on


representative primary [1-octylamine (3


-008)3 .4, 1-dodecylamine (3


-023)],


secondary


[di-1-octylamine (3


-033)]


tertiary


, N-dimethyl--1-octylamine (3


-013)


dimethyl- 1-dodecylamine (3-028)] alkylamines (Scheme 3-1).


3.2 All synthetic work and mass spectral investigations
White at the University of Florida.


All nna thennrmonvli reritinm w rnne nrwn/,,tp hr fenaf


interpretations were performed by Rolsyn L.


Tnn !anatnlnnlrn at t1a T Tn4,onrtrr nIf fLji.-Al










CeH17NH2
3.008


CeH17NMe2


3.013


12H25NH2
3.023


C12H2sNMe2
3.028


(CsH17)2NH
3.033


Scheme 3-1


The gas chromatographic (GC) behavior of al


study and the products are recorded in Table 3


the compounds employed for this


Table 3-2, 3-3 and 3-4 contain the


compiled mass spectral data for the analysis of results.


Table 3


contains the sources and


purities of the starting materials used and have been compiled based upon the direct

comparison of the GC retention times and of the mass spectral (MS) fragmentation pattern


with those of the authentic compound.


Table 3-3 contains compounds which have been


identified by comparison of MS patterns with literature MS data for the same compound.

Those compounds for which no suitable literature MS data were available have been

identified by their MS fragmentation patterns (obtained from the aquathermolysis runs) and

have been compiled in Table 3-4. A more detailed explanation of Tables 3-2--3-4 is given


in section 3


.5 Experimental.


The results from the aquathermolyis of each amine are


collected in Tables 3-5--3-11


All product yields (molar %) are represented as a percentage


of moles as described in detail previously [90EF493] and have been corrected with regard

to their response factors [89TCM17].3.6


Structures and proposed reaction pathways for the formation of these products


given in Schemes 3-6--3-9 (see section 3.4 Discussion).


numbers


In these reaction Schemes,


> 3-100 are used for postulated intermediates not detected by the GC/MS


analyses.










Table 3-1.


Structure and Identification of Starting Materials and Products


tR(min)


Compound


Eq. W


Basisa


Factor


3-001
3-002
3-003
3-004
3-005
3-006
3-007
3-008
3-009
3-010
3-011
3-012
3-013
3-014
3-015
3-016
3-017
3-018
3-019
3-020
3-021


3-022
3-023
3-024
3-025
3-026
3-027
1-ton


N,N-dimethyl- 1-butylamine


1-hexanol


N, N-dimethy-1 -hexylamine
N-methyldi-1 -butylamine


2-octamone


N,N-dimethyl-2-ethyl- 1-hexylamine
N-methyl-N-1 -butylformamide


1-octylamine


N, N-dimethyl-3-octylamine


1-octanol


N-methyl-3-octylamine
N-methyl-1-octylamine
N,N-dimethyl-1 -octylamine


Table 3-2
Table 3-3
Table 3-2
Table 3-4
Table 3-2
Table 3-3
Table 3-4
Table 3-2
Table 3-3
Table3-2
Table 34
Table 3-3
Table 3-2
Table 3-3
Table 3-3
Table3-2
Table 3-3
Table 34
Table 3-3
Table 3-3
Table34


tri-1-butylamine


10.73
10.87
10.94
11.03
11.10
11.57
12.06
14.52
14.64
14.84


2-todecee


N-methyl-N-1-hexylformamide


N, N-di-l-butylformamide
N-methyldi-1 -hexylamine


N- l-octylfarmamide


14odecylamine


N-methyl-N-1 -octylfonnamide


N-1-otylacetaritde


15.06
15.18
.e -'


1-dodecanl


N-methyl-1 -dodecylamine


-* I nri a' sr.hn ,h.a.Aj A.a u U' r *


Table 3-3
Table 3-2
Table 34
Table 34
Table 3-2
Table 3-4


I Af


3-dodeceexa










Table 3-1 continued


tR(min)


Compound


Eq.W


Basisa


Factor


3-032
3-033
3-034
3-035
3-036
3-037
3-038
3-039
3-040
3-041
3-042
3-043
3-044


18.12
18.41
18.76
19.54
19.99
20.56
21.43
21.44
22.37
22.62
24.58
28.91
29.26


N-methyldi-1 -octylamine


di-l-oaylamine


127.5
120.5
134.5


N- l-octyl-N-3-octylformamide


N-l-odec4yfonamide


N-methyl-N- 1-dodecylfonnamide
N-methyl-N-1dodecylaetamide
N-acetyl-N-1-dodecylfomamide
N-methyl-N-3-octyl- 1-octylamine


N,N-dil-octylfomamide
N,N-di- 1-octylactamide


127.5
134.5
141.5
117.7
183.5
176.5


tri-1-octylamine


di-odecylaminem


Table 3-3
Table 3-2
Table 34
Table 3-2
Table 34
Table 3-4
Table3-4
Table 3-4
Table 3-3
Table 3-3
Table 3-3
Table34
Table 3-3


tR(min)


= Retention time in minutes.


= molecular weight.


= equivalent weight.


a = Identification


Basis, see appropriate table. b = Response Factor, see ref [89TCM17].


N-methyldi-1 -dodecylamine






44


Table 3-2. Properties of Authentic Compounds used as Starting Materials and for the
Identification of Products


Compound


a Purity


m/z (% relative intensity)


Spectra#


3-001

3-003

3-005

3-008


3-010


3-013


N,N-dimethyl- -butylamine

N, N-dimethyl-1 -hexylamine

2-octanone

1-octylamine


1-octanol


A 99

A 99

K 97

A >99


A 97


N, N-dimethyl-1.-octylamine


A 95


101(9); 72(1); 58(100); 44(5); 42(12)

129(7); 114(1); 84(1); 58(100); 42(9)

128(12); 113(5); 85(9); 58(96); 43(100)

129(2); 100(3); 86(5); 58(6); 45(8);
41(10); 30(100)


112(2); 84(43); 83(46); 70(69); 56(100);
55(89)


157(6);
42(6)


118158

6209

120848

120973


121161


143(2); 59(4); 58(100); 44(41);


3-016


A 99


170(8); 85(46); 71(64); 57(100); 56(22);
55(18)


126002


3-023


3-026


-dodecyamine


F 99


l-dodecano


A 98


185(2); 184(1); 55(9); 44(10); 43(10);
41(15); 30(100)


168(1); 140(8); 97(43); 83(65); 69(81);
55(100)


28046


127402


3-028


N,N-dimethyl-1-
dodecyamine


A 97


213(4); 212(1); 84(2); 59(4); 58(100)


40885


3-033


di-1-octylamine


A >99


241(5)
44(36)


143(10); 142(100); 57(7); 56(4);


53027


3-035


N-1-dodecyifomamide


213(18)
44(19)


184(15); 72(39); 59(100); 58(68);


34318


3-042


tri-1-octylamine


A 98


353(2); 352(2); 256(2); 255(19); 254(100);
156(8)


135035


aA = Aldrich, F


Fluka, K


= Eastman Kodak; L


Lancaster, S = synthesized authentic compound (see


experimental section). b = spectral numbers of the mass spectral data for the compounds found from a search of the
Wiley. 138L / MSP. c = no spectra available.


dodeane






45





rO s-4r I
T ... -a ..o i n** c
(N -8' 4 ..
4- *. ci S o I'^ --S S S f
N^ C S .. r h- .
n ^o 8 h oS fS
IQ S: -n s ''E & ^ S ^
'8 -
-g S 4-' *
o' ^*~ ci C iS r fi -'
a C .4. c I Sr l


aNI 2 v 1 0 4/.0 0 -0 -s N^ N N' "l
-* -t l- tl '




5S I^ 'o %; ^ SS EEEI E5M ^0
o3 Vn
U NNN

I S
45i n '3 o



Qc a
'S~~~ =tc'-


00 N NO



L*I ^S ^~- 4' 4 N ..r^c ^v S
*.
-a '4 lat ta tat -



.24~t~ -o
10 S a S''
OI~yI
S ^ y p~ggl~r i~s






g. g EZ' a a .ai 8 I
Vj> ^ lQ'& ^ .^ ^ ^ y


0 .~




^SSf N ff4r S S) ^ ^ ;'B
S 8'"y'^' do s^' r^ t' -^ -i ^- r^S
.0 9 I ^ '^^ ^ ^'^ ^ S'^ ^ ^ r
ISd





II ('D( (' *S*' ^ ^ * *t *l
'-~~~~L E0 rPa 00^ t ^ i ^ ^ ^ ^ lN f f
sa~~h >i g r 3 ?(i% 8^
^~ S '5

^ a 1
~~^ o8-, 'laIll'
'S~~~ *s. 11 *ci *
"{ F*&: S t a






I IinJ 1t
1~h I






o I .
I
Us "
j'i I
h h ~ hy ~y gVs




















h rl

- N



- t
-
U
E


+ +


- *a


00


*



-
" i0
J








U 8
ar
C r







- as
-
^ e4
* aS
N^
is
'o6
*


MAl


r 00
c^ w
3 -' h




v^
+2'r
&?^
aa





47


Synthesis of Compounds


After extensive mass spectral interpretation and subsequent identification of all the

products/unknowns obtained from the aquathermolysis runs there were several compounds


whose formation remained obscure.


Therefore


, five compounds were selected to


synthesized. They included N-1-octylacetamide (3


-025) N


, N-dimethyl-3-octylamine (3-


009),


, N-dimethyl-2-octylamine (3


-045), 2-dodecylamine (3


-049) and 3-dodecylamine


(3-050).


Amine 3-025 was chosen because it appeared to be an unlikely product based


upon the expected reaction pathways,


while amines 3


-009 and 3


-045 were chosen


because no direct mechanistic pathway for their formation could be suggested.


primary amines (3-049, 3


-050) were synthesized to investigate whether or not amination


of the alkenes formed during aquathermolysis was occurring.


N-1-Octylacetamide (3-025) was synthesized using


1-octylamine (3-008) and


acetic anhydride and was isolated as a clear oil in 68% yield (Scheme 3-2).


Analysis of the


MS fragmentation pattern of our authentic N-l-octylacetamide (3-025) shows that its


pattern is identical


to that of the literature (see Table 3-3) and suggests that amide 3-025


could be a product from the aquathermolysis of 1-octylamine (3-008).


C8H17NH2


acetic anh.


50 *C


C8H17NHCOCHa


3-008


3-025


Scheme 3


, N-Dimethyl-3-octylamine (3


[94TL2401].


-009) was synthesized using a literature method


This method uses titanium (IV) isopropoxide [Ti(OiPr)4] and sodium





48


is thought that the Ti(OiPr)4 functions as a Lewis acid catalyst as well as a water scavenger


(Scheme 3-

octanone (3


5).


3-Octylamine (3-046) was prepared from the corresponding ketone, 3-


-047) using the literature method [83JCS(P1)3027] (Scheme 3-3).


3-046


(HCHO)n

Ti(OiPr)4
diglyme


a


+ CH2
HN


NaBH4


Me2


3-009


NH2


NaBH3CN


3-047


NH4OAc,
reflux


EtOH


3-046


Scheme 3-3


Mass


spectral


analysis


the authentic N


, N-dimethyl-3-octylamine (3-009)


revealed that the MS fragmentation pattern is identical to that of the literature (see Table 3-3)


and suggests that amine 3-009 could be a product from N


, N-dimethyl-1-octylamine (3-


013).


The proposed compound (i.e.


from the fragmentation found in the aquathermolysis


runs),


the library match and the synthesized compound are identical (see Table 3-3).


, N-Dimethyl-2-octylamine (3


-045)


was


also synthesized


using


the above


literature procedure [94TL2401] from 1-methylheptylamine (3-048) (Scheme 3-4).


suggested that the compound proposed to be N


It was


, N-dimethyl-2-ethyl-1-hexylamine (3-006)











NH2


3-048


(HCHO)n
Ti(OiPr)4
diglyme


H -
+N=
)N=CH2


NaBH4


NMe2


3-045


Scheme 3-4


2-Dodecylamine(3-049) and 3-dodecylamine (3


corresponding


-050) were synthesized from the


and 3-dodecanone using a literature method [83JCS(P1)3027] (Scheme


As with amine 3-046, the ketone is reductively aminated to the corresponding


amine.


These primary amines were synthesized to tell whether the 2-dodecene (3


-017)


and 3-dodecene (3-019) formed (see section 3.3 Results) were being converted back to the


corresponding amines.


This hypothesis


was disproven, as neither of the amines (3-049


nor 3-050) were observed as products.


Further discussion of these and the above


compounds will be covered in the Discussion (section 3.4).


0
CH3(CH 2)0C- CH3


NaBHaCN


N H4OAc,
reflux


EtOH


!JH2
CH3(CH2)9-CHCH,
3-049


0
CH3(0H2)8C- CH2CH3


NaBH3CN


NH4OAc, EtOH
reflux


CH3(CH 2)8-CHCH 2CH3
3-050


3-5).


-- .=





50




Results


-1-Octvlamine (3


-008) (Table 3-5).


The reaction of 1-octylamine (3


-008) with


49% aqueous formic acid (HCO2H) at 350 C for 0.5 h showed a 50.4% conversion to the


major products N-1-octylformamide (3-022,


17.5%),


1-octylamine (3-033,


11.6%).


Other minor products included 1-octanol (3-010,


7%),


N-methyl-1 -octylamine


-012, 5.4%),


N-methyl-N- 1-octylformamide (3-024, 3.0%),


N- 1-octylacetamide (3-


025,


N-methyldi- 1 -octylamine (3


-032, 1.0%) and N


, N-di-1-octylformamide (3-


040,


3.7%).


,N-Dimethyl-1-octylamine (3-013,


0.3%),


N-methyl-N-3-octyl-1-


octylamine (3-039, 0.


) and tri-1-octylamine (3-042, 0.


) were formed in trace


amounts.


Extending the reaction time to


2 h resulted in a 60.1


conversion with N-1-


octylformamide (3-022,


10.4%),


-octylamine


(3-033,


N-di-1-


octylformamide (3-040,


7.9%)


1-octylamine (3


-042,


2.7%


as the major


products.


Similar minor and trace products were observed as in the 0.5 h reaction.


Reactions at lower temperature gave significant formamide product formation.


250 *C in 49% aqueous HCO2H for 0.


1-octylamine (3


-008) underwent a 98.1


conversion to products with N-l1-octylformamide (3-022, 91.5%) as the major product


along with N-methyl-N-1-octylformamide (3-024,


) and N-l-octylacetamide (3-


025,


Increasing the reaction time to


2 h gave a somewhat lower conversion


(90.9%) to the major products N-l-octylformamide (3-022,


N-methyl-N-l-


octylformamide (3


-024, 9.8%) and N-l-octylacetamide(3-025,


6%).


N, N-Dimethyl-


-octylamine


-013)


N-acetyl-N- 1-octylformamide


-030)


N,N-di-1-


octylformamide (3-040) were each observed in less than


1-Octanol (3-010),


-


_ I
















I
r*
i**


0
I
-*


'0
S*


\0
fl


'6
* *


I
I S









N-methyl-N-1-octylformamide (3-024,


10.5%), di-


1-octylamine (3


-033,


9.7%)


,N-di-l-octylformamide (3


-040, 1


0%) as major products.


A similar slate of minor


products as seen previously was also observed.


The product slate suggests that formylation of 3


-008 yields N-l-octylformamide


-022) which can subsequently undergo reduction to furnish N-methyl-1-octylamine (3-


012).


Similarly,


, N-dimethyl- 1-octylamine (3


-013) can be derived from N-methyl-l-


octylamine (3-012),


but this conversion appears to occur in small amounts.


Di-1-


octylamine (3-033) can be obtained by further reaction of 3


-013 with 1-octylamine (3-


008).


Reaction


di-1-octylamine


(3-033)


with


HCO2H


leads


to N


N-di-1-


octylformamide (3-040) which can be subsequently reduced to N-methyldi-1-octylamine


(3-032).


Tri-1-octylamine (3


-042) can be obtained by reaction of 3


-033 with 3-013.


The increasing amount of 1-octylamine (3


-008) remaining with increasing reaction


time and temperature is unexpected.


Since reaction at 250


"C 0.5


h indicates 98.1


conversion, it appears that with increasing time and temperature all the 1-octylamine (3-

008) is converted to the observed products, some of which revert to starting material.


Di-1-octvlamine (3-033) (Table 3-6).


After 0.5 h, the reaction of di-1-octylamine


(3-033) with 49% aqueous HCO2H at 350 C showed 75.


conversion to 1-octylamine


(3-008, 3.9%),


1-octanol (3


-010, 2.4%),


N-methyldi-1 -octylamine (3


-032,


,N-di-1-octylformamide (3-040,


18.5%) and tri-1-octylamine (3


-042


Methyl-


1-octylamine


-012),


- 1-octylformamide


(3-022)


N-methyl-N-l-


octylformamide (3-024) and N


,N-di-1 -octylacetamide (3


-041) were formed in less than


Trace


amounts


octylformamide (3-034) were observed.


, N-dimethyl-1-octylamine (3-013)


Heating with 49% HCO2H for


N-l-octyl-N-3-

2 h led to the


formation of i-octvlamine (3


A 1\


--o u- J 'I *f .-


-n. l


Ao\


1-netannl (3


nin


A/-methvldi-1


. ..


-













,-

I*


-4
rl


-4

Vd
v


'I


0
I ni


0:


, C ,


00








t Co









were each observed in less than


Traces of N


, N-dimethyl- 1-octylamine (3-013) and


N-l-octyl-N-3-octylformamide (3-034) were observed in <0.1


and 0.8%, respectively.


The first step in the reaction sequence could be the cleavage of di-1-octylamine (3-


033) to give 1-octylamine (3-008).


1-Octylamine (3


-008) thus obtained,


could further


react to give a similar product slate to that discussed.


Once again, formamide formation was dominant at lower temperatures.


At 250


reaction


time


to N-methyldi-1-octylamine (3


-032,


6.8%),


N-di-1-


octylformamide (3-040, 82.


2%) and tri-1-octylamine (3-042, 3.0%) as major products.


The following four compounds were identified, each in less than 1


1-octylamine (3-


00 8),


, N-dimethyl-1-octylamine (3


-013),


N- 1-octyl-N-3-octylformamide (3


-034) and


N-methyl-N-3-octyl- 1-octylamine (3


-039).


Extending the reaction time to


2 h gave N-


methyldi- 1-octylamine (3


-032,


10.0%),


, N-di-1-octylformamide (3


-040,


70.7%) and


tri-1-octylamine (3-042,


4.8%) with an 88.3


conversion to products,


while the


10 h


reaction gave N-methyldi-1-octylamine (3-032,


, N-di-1-octylformamide (3-


040,


41.6%)


tri-1-octylamine (3-042,


with


an 81.3%


conversion


products. Again, there appears to be some equilibrium reversion to starting material.


2 h reaction also gave a small amount of N-l-octyl-N-3-octylformamide (3-034,


trace amounts of


1-octylamine (3-008),


1-octanol


(3-010)


N, N-dimethyl-1-


octylamine (3-013),


N-1-octylformamide (3-022)


024),

039).


N-methyl-N- 1-octylacetamide (3-029)

Similarly, the 10 h reaction gave small


and N-methyl-N-3-octyl-l-octylamine (3-


amounts of N-1-octylformamide (3-022,


N-methyl-1-octylformamide (3


-024,


0%),


N-l -octyl-N-3-octylformamide (3-


034, 1


) and N


, N-di- 1-octylacetamide (3


-041


,1.6%),


and traces of 1-octylamine (3-


n008f


1 -octanol


(3-010m


v t -- -


.N-dimethvl- 1-octvlamine (3


-013).


N-methyl-N-1-


N-methyl-N-1-octylformamide (3-









N. N-Dimethvl- 1-octvlamine (3-013) (Table 3-7).


At 350 *C in HCO2H for 10 h,


, N-dimethyl-1-octylamine (3


-013) showed a 64.0% conversion.


Products observed


include


1-octanol (3-010,


octylamine (3


N-methyldi-1-octylamine (3


-033, 10.2%) and tri-l-octylamine (3-042,


were identified in lesser amounts:


2-octanone (3-005,


4.6%).

4.3%),


-032,


.6%),


The following products

1-octylamine (3-008,


2.0%),


N-methyl-N-l -octylformamide (3


-024, 3


.2%),


and N


, N-di- 1-octylformamide (3-


040,


0%), with N-methyl-l-octylacetamide (3


-029) and N-l-octyl-N-3-octylamine (3-


031) in traces.


At lower temperatures N


,N-dimethyl-1-octylamine (3-013) was not very reactive


with 49% aqueous HCO2H.


At 250 *C for


2h, a


25.8


% conversion led to N-methyl-N-1-


octylformamide (3-024, 10.8%) as the major product.


Other products identified include


, N-dimethyl-2-ethyl- 1-hexylamine (3


-006


,1.8%),


, N-dimethyl-3-octylamine (3-011,


-032


- 1-octylformamide


After 10 h a 19.9% conversion led to N-methyl-3-octylamine (3


-011


(3-049,


) and


N-methyldi- 1-octylamine (3


-032,


7.5%


N-methyl- 1-octylformamide (3


-024,


3.2%


, N-dimethyl-3-octylamine (3-009, 1.4%) and 1-octylamine (3


-008,


<0.1


1-Dodecvlamine (3-023)


(Table


3-8).


1-Dodecylamine (3-023)


was


very


reactive in 49% aqueous formic acid. A 97.1% conversion was observed after 0.


six major products were 1-dodecanol (3


-026, 6.1


, N-dimethyl- 1-dodecylamine (3-


028, 8.6%),


-036,


N- 1-dodecylformamide (3


11.9%),


-035


,19.3%),


N-methyldi-1-dodecylamine (3


N-methyl-N-1 -dodecylformamide


-043, 20.0%)


and di-1-dodecylamine


-044,


9%).


Minor products observed were dodecane (3-016, 6.1%),


2-dodecene


(3-017,


0.3%),


1-dodecanol (3


-026


, 6.1%),


N-methyl-N-1-dodecylacetamide (3-037


1.4%) and N-acetvl-N- 1-dodecvlformamide (3


-.ia


A4AOt\


A ftPr


--UU 'tU / i. f LU!


10 hI a significant


N-methyldi- 1-octylamine (3




















N
lb*


, ,


00
I r-


I *


00
I
-4


0
Sci


-4





I I





1 cn
~W








FH


00
I *
N


0
* ri


F*













vi


' d


0,
I *
ci


'0
I 00


r-


I
I


,I
V3


I;
I *


* *r









The major products were 1-dodecanol (3


-026, 14.3%),


N-methyl-N-1 -dodecylformamide


(3-036,


10.0%),


N-methyldi-1-dodecylamine (3-043,


and di-1-dodecylamine


(3-044, 30.0%).


Also minor amounts of three isomers of dodecene (3-015,


3-017


019) were observed.


Lower temperature runs also showed moderate to high reactivity.


After 1 h, in


49% HCO2H at 150


dodecylformamide (3


*C, 1-dodecylamine (3


-035


-023) showed 58.2


) and a trace of di-1-dodecylamine (3


conversion to N-1-


-044,


After 0.5 h at 250 *C an 88.6% conversion was observed with N-1-dodecylformamide (3-


) and N-methyl-N-1-dodecylformamide (3


-036,


7.5%


as products.


conversion was observed after 10 h with N


, N-dimethyl- 1-dodecylamine (3


-028,


7.6%),


N-1-dodecylformamide (3


-035


N-methyl-N- 1-dodecylformamide


(3-036, 34.7%) as the major products.


Minor products identified were N-methyl-N-l-


dodecylacetamide (3


-037


, 2.1%),


N-acetyl-N-1-dodecylformamide (3


-038,


1.6%),


methyldi- 1-dodecylamine (3


-043, 3.3%) and di-1-dodecylamine (3


', N-Dimethvl- 1-dodecvlamine (3


-028) (Table 3-9).


-044,


A 46.0% conversion was


observed after reacting N


, N-dimethyl- 1-dodecylamine (3-028)


with


aqueous


HCO2H for


2 h at 350


The major products observed were


1-dodecanol (3-026,


14.8


N-methyldi-


1-dodecylamine (3


-043,


27.8


N-Methyl-N-l-


dodecylformamide (3


-036),


1-dodecene (3


-015) and dodecane (3


-016) were formed in


minor amounts.


Extending the reaction time to 10 h led to a 57.8% conversion with a


significant number of


minor products


- dodecane (3-016,


N-methyl-N-1-


dodecylacetamide (3


-037


, 0.4%) and di-


1-dodecylamine (3


-044,


The major


product was again N-methyldi- 1-dodecylamine (3


-043, 39.5%).


Two isomeric dodecenes


(3-015, 3-017) were also formed in this run in minor amounts.


























00








Irl


t*i


00









, N-Dimethyl-1-dodecylamine (3-028)


was much less reactive at 250 *C in


HCO2H for 0.5


Only a 7.3% conversion was observed with 1-dodecanol (3


-026,


), and N-methyl-N-1-dodecylformamide (3


-036,


as the


major products.


Traces of 1-dodecene (3-015,


0.4%),


dodecane (3-016, 0.


2-dodecene (3-017,


2%) and 3-dodecene (3


-019, 0.1%) were also identified.


Extending the reaction time to


10 h showed a 28.9% conversion with 1-dodecanol (3-026,


N-methyl-N-1-


dodecylformamide (3-036,


8%) and N-methyldi-1-dodecylamine (3


-043,


the only products (Table 3-9).


Since a clear mechanistic pathway (see


Discussion) could not be proposed for the


formation of


the rearranged product 3-009,


two additional


aquathermolyses were


performed to see whether similar rearranged products would be formed and whether a clear


mechanistic pathway could be determined.


butylamine (3-001) and N


The amines of choice were N


, N-dimethyl- 1 -hexylamine (3-003).


, N-dimethyl-1-


These two tertiary amines


were heated at 250 *C for 2 h in 49% HCO2H since these were the conditions under which

N, N-dimethyl-3-octylamine(3-009) was observed.


, N-Dimethvl-1 -butvlamine (3-001) (Table 3-10).


On heating with aqueous 49%


HCO2H


at 250


2 h, N


, N-dimethyl-1-butylamine (3


-001)


showed


a 63.1


conversion (Table 3-10).


The two major products were N-methyldi-1-butylamine (3-004,


32.3%) and N-methyl-N- 1-butylformamide (3


-007


2%).


Tri-1-butylamine (3-014,


1.1%) and N


,N-di- 1-butylformamide (3-020,


1.5%) were detected in minor amounts.


There was no detection of any rearranged product, that is, no N


, N-dimethyl-2-butylamine.








Table 3-10.


Products from N


, N-Dimethyl-1-butylamine (3-001) 49% HCO2H


Temp.(*C)
Time(h)


Compound


Identification


3-001
3-004
3-007
3-014
3-020


N, N-dimethyl- 1-butylamine
N-methyldi- 1-butylamine
N-methyl-N- 1-butylformamide


tri-1-butylamine


, N-di-1-butylformamide


Table 3-2
Table 3-4
Table 3-4
Table 3-3
Table 3-3


36.9
32.3
28.2


= molecular weight


. N-Dimethvl-1-hexvlamine (3


-003) (Table 3-11).


, N-Dimethyl- 1-hexylamine


-003) showed a 37.5% conversion after 2 h at 250 *C in 49% aqueous HCO2H (Table


3-11).


The major product was N-methyl-N-1-hexylformamide (3


-018, 23.9%).


Other


products included


1-hexanol (3-002,


2.8%)


N-methyldi-1-hexylamine (3-021,


10.8%).


There was no detection of any rearranged products.


Table 3-11.


Products from N


, N-Dimethyl-1-hexylamine(3-003) 49% HCO2H


Temp.(*C)
Time(h)


Compound


Identification


3-002
3-003
3-018
3-021


1-hexanol


Table 3-3


N, N-dimethyl- 1-hexylamine
N-methyl-N-1 -hexylformamide
N-methyldi-1 -hexylamine


Table 3


Table 3-4
Table3-4


62.5
23.9
10.8


- mal1 nn* n1rt fnt





62


General Discussion


The aliphatic primary amines showed the dominant reaction


formylation with subsequent reduction to give N-methyl and N


pathway as N-


N, -dimethylalkylamines.


That is, under the above mentioned aquathermolysis conditions the aliphatic amines are

involved in conventional reactions where the formic acid is behaving as a hydride donor


and as a formylating agent.


In the case of 1-dodecylamine (3


-023), in addition to the


above mentioned pathway, elimination of NH3 and HNMe2 to the corresponding alkene


was also observed; which could then undergo isomerization.


The secondary amine, di-1-


octylamine (3-033) underwent conventional N-formylation and subsequent reduction to


the N-methyl derivative.


Also, formation of the mono- and tri-


1-octyl derivatives is


representative of a cleavage process.


The tertiary amines underwent reductive cleavages to


primary and secondary amines, which subsequently followed the reaction sequences seen

for the primary amines.

Formation of N-l-octylformamide (3-022) and subsequent reduction products


was the major reaction pathway for 1-octylamine (3-008) (Scheme 3-6).


It is evident that


ower temperatures


there


is significant formamide


product


formation as well.


Subsequent reduction of the N-formylation product is supported by the presence of N-


methyl-1 -octyamine (3-012) and N


, N-dimethyl- 1-octylamine (3


-013).


Amine 3-012,


the reduced product of formamide 3-022 underwent a second formylation to give N-


methyl-N- 1-octylformamide (3-024).


Subsequent reduction of amide 3


-024


eads to


N, N-dimethyl- 1-octylamine (3-013).


Tri-1-octylamine (3-042) can be formed by the


reaction of amine 3-013 with di-1-octylamine (3-033).


In this process, amine 3-013


undergoes loss of N.N-dimethvlamine.


Di- 1-octvlamine (3


-033) is the product of self






















0
I c
0(3


V r
(I
++z
I I


0


I +
I


O
II


I I
I


+
I


p p


N
I I

0 .
I

XN *
O
LI
'a
0"
pII


I
0

z i
I




o+o
Iur

Ir


O= O
I
0=0
(0,

0o


CM
. n
2 ?2
Z 03
I
zo

0


I


N
1
o 5
I

I
CO


I
z
^N
I A
10









N-l-Octylacetamide (3


-025)


may have been produced under aquathermolysis


conditions via a rearrangement of N-methyl-N-1-octylformamide (3-024) (Scheme 3-6),

although we have been unable to find an example of an acid promoted rearrangement of a


formamide to an acetamide.


The other acetyl derivatives would have been formed from


further reaction of 3-025.


N-Acetyl-N- 1-octylformamide (3


-030) is produced from the


N-formylation of acetamide 3-025.


Subsequently, reduction of amide 3-030 would


generate N-methyl-N- 1-octylacetamide (3-029) (Scheme 3-6).


Similarly,


other primary


amine,


-dodecylamine


(3-023)


gave


N-l-


dodecylformamide (3


-035) as the main product under all reaction conditions,


subsequent reduction was supported by formation of the various N-methyl derivatives.


contrast to implied formation of 1-octene, formation of 1-dodecene is observed as well as


and 3- isomer (Scheme 3-7).


Under


aquathermolysis


conditions


1-dodecylamine


-023)


underwent


conventional N-formylation to

Subsequent reduction of amide 3


give N-1-dodecylformamide (3-035)

-035 generates the N-methyl derivative 3


(Scheme


-027


3-7).


. Loss of


methylamine from 3-027 results in the formation of 1-dodecene (3-015).


alkene 3


Alternately,


-015 may be generated either by the loss of ammonia from 1-dodecylamine (3-


023) or by the loss of N


, N-dimethylamine from N


, N-dimethyl-1-dodecylamine (3-028).


In turn, the amine 3


-028 is generated from the reduction of N-methyl-N-1-octylformamide


(3-036) which is produced by the N-formylation of N-methyl-1-dodecylamine (3-027).


1-Dodecene can undergo isomerization to both the


(3-017) and the 3-


(3-019)


derivative (Scheme 3-7).


Reduction of either of these alkenes would lead to dodecane (3-


016).


In addition, loss of ammonia from 1-dodecylamine (3


-023) and a formic acid


catalyzed reaction


with


water generated


1-dodecanol


(3-026). N


.N-Dimethvl-1-


_ _~~____




















I
0
I


NO
"O
0 I
No


BI
IO
O

O


o
4-z
10
I-z
I
Cu
I
CM
0


(O "
* S


CZ
I
z


N
I



9,
ri
5
A


IC
I0
o0


+


C


CO

ff ^
f0,
C o
a '

O
c'0


I4
I









The acetyl derivatives may


justified


amide 3-036,


though


corresponding N-1-dodecylacetamide (3-


108) was not detected by the GC/MS analysis


(Scheme 3-7).


N-Acetyl-N- 1-dodecylformamide (3


-038)


be explained via


formylation


3-108,


with


subsequent


reduction


leading


N-methyl-N-l-


dodecylacetamide (3-037).


Again, there is no literature precedence for the formation of


acetamide 3 -


108 from the formamide 3


-036.


As expected di-1-octylamine (3


-033)


underwent N-formylation.


a simple


reduction were the only possible reaction pathway, then N-methyldi-1-octylamine (3


would be the only next logical product.

takes place (on the starting amine), du


-032)


However, it is apparent that reductive cleavage

e to the presence in the product slate of similar


products to those obtained from 1-octylamine (3-008) (Scheme 3-6). Formation of N-1-

octyl-N-3-octylformamide (3-034) and N-methyl-N-3-octyl- 1-octylamine (3 -03 9) appear

to be from the isomerization of the octyl moiety before the formulation and reduction take

place (Table 3-9).

Since the tertiary amine could not undergo N-formylation directly, N-formyl and

subsequent reduction products would have to be formed after reductive cleavage of the


starting amine.


Reductive cleavage explains


methyldialkylamine major products from


both N


formation


alcohol


, -dimethyl-1-octylamine (3


-013)


(Scheme 3-6) and N, N-dimethyl-1-dodecylamine (3


N, -Dimethyl- 1-octylamine (3


-028) (Scheme 3-7).


-013) may be reductively cleaved to amine 3-008


and/or amine 3-012, which can each undergo the reaction pathways outlined in Scheme 3-


As shown in Chapter II,


formic acid may act both as a reducing and as an oxidizing


agent.


Its role as an oxidizer may explain the formation of octanone (3


-005).


Again the


rearranged derivatives 3


-006


,3-009, 3-011 and 3


-031 (Table 3-7) may be from the





67


tertiary amine 3-001 would undergo reductive cleavage to the primary amine before


formylation took place.


However, the corresponding primary amine, 1-butylamine (3-


109) was not detected by GC/MS.


, N-methyl-N-l-butylformamide (3


-007) does


support the above pathway, since its (3-007) formation may be viewed through the


formylation of 3-


109, to form 3-


112, which would subsequently be reduced to 3-


finally,


formylated once again


to give


amide


3-007.


Likewise


N, N-di-1-


butylformamide (3-020) is formed via formylation of 3-


. The intermediate 3-


111 is


generated from condensation of 3-


110 and 3-


109 accompanied by the loss of N


dimethylamine.


Tri-1-butylamine (3


-014) is a self condensation product via intermediate


3-109.


Simple reduction of 3


-020 leads to N-methyldi-1l-butylamine (3


-004) (Scheme


3-8).


The products from N


,N-dimethyl- l1-hexylamine (3


-003) are formed similarly to


those of amine 3


-001 (Scheme 3-9).


As seen with amine 3-001


, formation of N-methyl-


N-1-hexylformamide suggests the presence of intermediates 3-


114,


3-115 and 3-


116,


though they were not detected by the GC/MS analysis.


N-Formylation of intermediate 3-


114 would give 3-


115, which could undergo reduction to 3-


116.


Subsequent reduction


of intermediate 3-

not detected (3-1


116 would generate formamide 3-018.


14--3-


Since these intermediates were


116), this may suggest that they are being consumed within the


reactions.


N-Methydi-1-hexylamine (3-021) may be explained similarly, via formylation


and reduction of 3-


119 and


3-120, respectively.


As with


1-octylamine (3-008),


formation of 1-hexanol (3-002) implies the presence of an alkene


- 1-hexene (3-


117)


(Scheme 3-9).

























I
O
O
I
0

I
O
I
0




O


I
O
I
Z
oP
0


U.
0


0
I

z
0


CM
I
z0
I
O


0 2


'.
~^ c


Z
-a
'^s


CM
Cr


t
0o







































(U)
I
ro

0)

I '
co'

0
*p


I
a
I
O
0
Z4
z'


0)
I
cc


O
I

CM
I
0
Ii


z0
I
OI
0
r
0.


p
0
0
I
z
C,--
I
<0
p p


I I
CM
I
C)
cu e
0 T
~e .


I t
CM~
I:

r
I'
^'c
O0


I
0
o
II
I
o
0
02

.0
or
7
o


CM

i s
z o

I
_-CO


rC-





70


Conclusions


The general trend observed from the results obtained is that N-formylation is the


dominant reaction pathway.


Under the above mentioned aquathermolysis conditions the


aliphatic amines were involved in conventional reactions where the formic acid behaved


both as a hydride donor and as a formylating agent.


The aliphatic primary amines showed


the dominant reaction pathway as N-formylation with subsequent reduction to give N-


methyl and N


, N-dimethylalkylamines.


In addition to the above mentioned pathway,


there


was


also elimination of simple amines to yield the corresponding alkene which could


further undergo isomerization.


The secondary amine also underwent conventional N-


formylation and subsequent reduction to the N-methyl derivative, with formation


mono- and tri-1-octyl


of the


derivatives is representative of a reductive cleavage process.


tertiary amines underwent reductive cleavages to primary and secondary amines, which

subsequently followed the reaction sequences seen for the primary amines.


1-Octylamine (3-008)


displayed


significant amounts


N-formylation and


subsequent reduction products.


This trend was observed at 350 *C as well as at


ower


temperatures.


There was also some self condensation products


- di-1-octylamine (3


-033)


and tri- 1-octylamine (3-042).


Synthesis of authentic N-1-octylacetamide (3


-025) and investigation of its MS


pattern suggest that it could be a plausible product under the aquathermolysis conditions.

However, since the suggested pathway for its formation lacks literature precedence and is


an anomaly, amide 3


-025 may be alternately explained as an obscure impurity


1-Dodecylamine (3


-023)


gave significant N-formylation.


In addition,


formation of alkenes was observed via the 1


oss of ammonia and N, N-dimethylamine.









Di-1-octylamine (3-033),


also gave N-formylation, but it was not significant.


This secondary amine also underwent reductive cleavage and subsequent reduction, with


products similar to those from 1-octylamine (3


-008).


Both tertiary amines (3


-013, 3


-028) were, as expected, less reactive than the


primary and secondary amines.


Most products were generated from a primary or


secondary amine, which was produced by reductive cleavage of the corresponding tertiary

amine.


A number of rearranged products were identified, but may well be inadvertent


impurities.


Though, MS investigations indicate N


,N-dimethyl-3-octylamine (3-009) as a


possible product, aquathermolysis of N


, -dimethyl-1-butylamine (3-001)


and N


dimethyl- 1-hexylamine (3


-003) revealed no rearranged products similar to amine 3-009


and therefore could shed no light on a possible rearrangement pathway.


It is very likely


that the rearranged amine 3


-009


might


have


been


an impurity.


appears


rearrangement is not a normal pathway under the reaction conditions.


Experimental


1H NMR spectra were recorded either on a Gemini 300 (300 MHz) Varian VXR


300 (300 MHz) or a General Electric QE (300 MHz) spectrometer.


13C NMR spectra were


recorded at 75 MHz on the same spectrometers. Chemical shifts are reported in parts per

million (ppm) downfield from tetramethylsilane (TMS) used as an internal standard.


Coupling constants (J values)


are reported in


hertz


(Hz).


Analytical


layer


chromatography (TLC) was performed using pre-coated silica gel 60 F254 plastic plates

(0.2 mm thick) using iodine as an indicator to visualize the product compounds.









General procedure for the synthesis of N


.N-dimethvloctvlamines


, N-Dimethvl-3-octvlamine (3-009)


. 3-Octylamine (1 eq.,


2.4 g,


18.8 mmol),


formaldehyde (4 eq.,


3 g, 75.0 mmol) and titanium tetraisopropoxide (2 eq.


10.4 g,


mmol) was refluxed in diglyme (


0 ml) at 70


After


2 h the reaction was cooled to


room temperature and sodium borohydride (1.


reaction was then stirred at room temperature (7 h).


reaction was diluted with Et20 (


5 eq, 1.1 g, 28.1 mmol) was added.


After cooling to room temperature, the


mL) and aqueous ammonium hydroxide was added to


precipitate the inorganic product, which was filtered and washed with excess Et2O.


organic layer was dried over Na2SO4 and concentrated in vacuo.


Dyglime was removed by


distillation in vacuo.


A pale colored oil (1.6 g, 57%) was isolated.


1H NMR (CDCI3):


0.9 (t, 3H, J


= 6.5) (CHtCH2),


1.0 (t, 3H, J


= 7.0) (CHICH2CH),


.2 (s,


8H) (4CH2),


1.4 (m, 2H) (CH3CH2CH),


2.3 (s,


6H) (NMe2),


6 (m, 1H) (CH).


13C NMR (CDCI3):


13.9


0, 31


58.9.


= m/z


(C10H23N); base peak


m/z 86 (C5H12N).


,N-Dimethvl-2-octvlamine (3


-045).


This product was obtained as an off-white


oil which solidified upon cooling.


1H NMR (CDCl3)


6 0.9 (t, 3H, J


= 7.0) (CHCH2),


1.1 (d, 3H, J


= 6.7) (CH_3CH),


1.3 (s,


8H) (4CH2),


1.7 (m, 2H) (Ci2CH),


2 (S,


(NMe2),


2.9 (m, 1H) (CH).


13C NMR (CDCl3):


6 13.9,


6, 23


26.0, 29.4, 29.6,


31.8, 39.5, 54.9.


LR MS M+


= m/z 157 (C10H23N)


base peak


= m/z 72 (C4HIoN).


N-1-Octvlacetamide (3-025).


-Octylamine (iml)


was dissolved


n acetic


anhydride (2.


7 mL) and warmed for about 0.5 h.


The mixture was then cooled to room









7.4),


0 (s, 3H),


(q, 2H, J


= 6.7),


6.3 (s,


13C NMR (CDCl3): 6


13.9,


,26.8, 29.1


29.4, 31.7,


39.6,


170.2.


LR MS M+


= m/z 171


(CloH21NO);


base peak


= m/z 30 (CH4N)


N- 1-Dodecvlformamide (3-03 5)


1-Dodecylamine (10.0 g, 54 mmol)


was


suspended in an excess of aqueous formic acid (88%) (


48 g, 108 mmol).


The mixture


was refluxed in benzene (150 mL) under Dean-Stark conditions for the azeotropic removal


of water.


The reaction was refluxed for 18 h; cooled to room temperature and the solvent


removed in vacuo.


The pale yellow solid was recrystallized from petroleum ether to give


the title compound as white flakes (9.70 g, 84%) (m.p.


33.5-35


C) (Lit. [59MI388] m.p.


35-36 "C)


1H NMR (CDCl3): 6


0.9 (t, 3H, J


= 7.0), 1.3 (s,


18H),


.5 (t, 2H, J


= 7.0),


2 (q,


2H, J


7.0),


7 (br.


s, 1H), 8.2


(s, 1H); 13C NMR (CDCI3): 6 14.1,


.6, 26.8,


29.5


(2C),


6, 29.7,


31.8, 38.


161.1


HR MS m/z


213.2090 (M+


, C13H27NO requires


213.2090).


General procedure for the synthesis of orimarv anmines


3-Octvlamine(3-046).


Sodium cyanoborohydride (7.0 eq, 17.8 g, 273


mmol)


was suspended in absolute EtOH (100 mL) and 3-octanone (1.0 eq,


absolute EtOH (50 ml) was added dropwise via addition funnel.


39.1 mmol) in


Ammonium acetate (10.0


eq, 30.1 g, 390.1 mmol) was then added and the mixture was allowed to reflux at 70 *C.


After

to pH


5 h the reaction mixture was cooled to room temperature, acidified with cone.


then basified with 20% NaOH.


The aqueous layer was then extracted with CHCl3


..1 -


dried over Na-SOa and concentrated to give a nale fellow viscous oil (3.1 .


lm)X(1( 3 X)


I jk VV .at[









2H) (NH2).


13C NMR (CDC13):


22.8,


, 27.0, 31


32.8, 35.0, 58.9.


LR MS M+


129 (CgH19N),


base peak


= m/z 58 (C3H2N).


2-Dodecylamine(3- 049).


This compound was obtained crude as a pale yellow


viscous oil by the procedure outline above for 3

Kugelrohr distillation to produce a colorless oil (:


-046.


The sample was then purified by


0 g, 66%).


1H NMR (CDC13):


6 0.9


(t, 3H, J


(CI-!CH),


= 6.3) (CHICH2),


1.3 (s,


1.0 (t, 3H, J


16H) (8CH2),


1.7 (s,


= 6.9) (C.H3CH2),


2H) (CH),


1.1 (d of d, 3H, J


3 (d, 1H, J


7.0) (CH).


= 6.4, 6.3)

13C NMR


(CDCl3):


6 14.0,


23.7, 26.3, 29.


29,5


2C),


29.6, 31.8,


40.0,


46.8.


HR MS


185.2167 (M+


0.5%


, C12H27NO requires 185.


2167).


3-Dodecvlamine (3-050).


This compound was obtained crude as a pale yellow


viscous oil by the procedure outline above for 3


-046.


The sample was then purified by


Kugelrohr distillation to produce a colorless oil (07 g, 68%).


1H NMR (CDCl3):


60.9


6H) (NCH3CH2


CH3CH2),


1.0 (t, 3H,


= 6.9) (CH3CH2),


1.3 (s,


16H) (8CH2),


1.4 (m, 2H) (CHCH_2),


2H) (NH2),


6 (m,


1H) (CH).


13C NMR (CDCl3):


, 14.0,


6, 23.7


29,5,


29.6, 29.8, 30.6, 31.8, 37


52.6.


HR MS


m/z 185.2158 (M+


0.5%


, C2H27NO requires 185.2


158).


Aquathermolvsis: General.3 7


The purities of all starting materials


were checked by GC prior to use


Aqueous formic acid was deoxygenated with argon for


h prior to use.


49%


The model


compound (1 g) and the acid (7 mL) were charged into a nitrogen blanketed stainless steel


bomb which was then sealed.


The reactor was then kept without agitation in a fluidized


= m/


.5 (m,









The reaction mixture was then worked up as previously described [90EF493],


subjected to GC analyses on a Hewlett Packard 5890 instrument (flame ionization detector,


FID) fitted with a 15 m capillary column (SPB-


1) and an oven temperature program of 10


*C/min from 50


-250 C.


Gas chromatographic/mass spectral analyses were obtained on a


Hewlett Packard 5890 Series II Gas Chromatograph with a HP 5972A Mass Selective

Detector (MSD).


Product identification.


Within the reaction mixtures, the identities of all the starting


materials, and some of the products [3-005


3-006, 3-008, 3


-009, 3-010, 3


-012--3-


024, 3


-026, 3-027


,3-028, 3


-032, 3-033, 3-035,


3-040--3


-042 and 3


-044] were


confirmed by comparison of their retention times and mass spectral fragmentation patterns

with those of the authentic compounds, commercially available or prepared independently.


Table 3


-2 records the source and mass spectral fragmentation patterns of the authentic


compounds used, either as starting materials or for the identification of products.


For some


other products [3-006, 3-009,


3-012,


3-015,


3-017--3


-022,


3-026,


3-032,


040, 3-041 and 3


-044 for which authentic samples were not available, identification was


by comparison of their mass spectral (MS) fragmentation patterns with published mass


spectra (Table 3-3).


The structure for the remaining products (Table 3-4) [3


-011


,3-024,


3-025


3-027


3-029--3


-031


,3-034, 3


-036--3


-039 and 3


-043] were assigned by


consideration of their mass spectral fragmentation patterns together with the starting

materials, reaction conditions and reasonable mechanistic pathways for their formation


from the starting materials.


Tables 3-3 and 3-4


record the mass spectral fragmentation


pattern of those compounds for which authentic samples were not available


the structural


assignments of these were based either on the fragmentation pattern of that same compound


reported in the literature (Table 3-3IL


or deduced from the fragmentation nhberved and















CHAPTER IV
BENZIOTRIAZOLE- 1-CARBOXAMIDINIUMTOSYLATE: AN ALTERNATIVE
METHOD FOR THE CONVERSION OF AMINES TO GUANIDINES



Introduction


Much research has been directed toward the synthesis of guanidines as many


biologically active compounds contain guanidine moieties.


Established methods for the


preparation of guanidines include the use of cyanamide [04CB 1681, 50CB1260, 270S46,


46HCA324,


50JOC884,


50JOC890


, 51CJC718,


51JCS1252,


71JA5542],


alkylthiouronium salts and derivatives [430S345,


63JMC275

92TL5933


550S440, 58CJC1541, 62RTC69,


74JOC1166, 87JOC1700, 89SC1787, 90JCS(P1)311, 91MI425, 92MI119,


, 93TL7677, 94SC321, 94TL977],


aminoiminosulfonic acids [86JOC1882,


87S777


, 88TL3183,


90SC3433],


3,5-dimethylpyrazole-1 -carboxamidine nitrate


[58CJC1541,


90JCS(P1)311,


91MI425,


94SC321],


pyrazole- 1-carboxamidine


hydrochloride [92JOC2479, 93SC3055, 93TL3389] and N, N'-bis(tert-butyloxycarbonyl)-

and N, N'-bis(benzyloxycarbonyl)thiourea [94TL977].

Historically, preparation of guanidines has been accomplished using cyanamide (4-


001)


[04CB 1681


46HCA324,


4270S46,


50CB1260,


50JOC884,


50JOC890,


50CJC718, 51JCS1252, 71JA5542].


The cyanamide methodology has usually been used


to synthesize aromatic guanidines such as phenylguanidine, dibenzoylphenylguanidine and


n-methvlnhenvliruanidine nitrate l04CR 16R11


fGurlnidine nlhatitntedp with elertrnn-





77


p-nitrophenylguanidine, a, a-diphenylguanidine, phenylbenzoylguanidine and m- and p--


nitrophenylbenzoylguanidine [50CB 1260].

been moderate to good (50--80%) but t


Reaction yields of this cyanamide process have


the reaction conditions have often been harsh


involving refluxing at high temperatures for long periods of time [50JOC884, 50JOC890,


51CJC718].


Even more harsh conditions involve fusion at 200


-260


*C [51JCS1252].


These conditions were used to prepare aliphatic guanidines in moderate yields.


Compound


4-001 has also been used to prepare guanidines from amino acids--but long reaction times

(several days) are required [71JA5542] with the products isolated as pirates.


H2N


4-001


S-Alkylthiouronium halides or salts have been used effectively to synthesize


guanidines [58CJC 1541


63JMC275,


71JA5542, 92TL5933].


More specifically


ethylthiourea hydrogen bromide (4-002)


(which requires synthesis from thiourea)


[550S440] has been used to convert glycine to guanidinoacetic acid in 80


- 90% yield.


Methylthiourea sulfate/hydrogen sulfate (4-003)


[430S345,


62RTC69,


74JOC1166,


90JCS(P1)311,


92MI119, 94SC321] has been used to generate a variety of compounds.


Compound 4-003 has been used in the synthesis of dicyanodiamide [430S345] and to

generate monosubstituted guanidines [90JCS(P1)311] (reaction time 48 h).


H2N


NH*HBr


H2N' NH*H2SO4


4-002


4-003


S/\









guanidino group.


Guanylation of the aminomethyl derivatives of azepines [94SC321] has


also been accomplished using this methodology.

Aminoiminomethanesulfonic acid (4-004) and its phenyl derivatives [86S777,

86JOC1882, 88TL3183] have been used to generate guanidines at ambient temperature


within a matter of minutes.

purified by crystallization.


Products precipitate from the reaction mixture and can be

Formamidinesulfinic acid which is used to generate the


aminoiminosulfinic acids may be used as a guanylating reagent [88TL3183].


acid derivatives are crystalline and are stable over a few weeks.


The sulfonic


Displacement of the


HSO3-


groups


takes


place


more easily


than


the alkylmercaptan anion of


kylthioureas


classical


synthetic


procedures


[88TL3183].


Ethylaminoethyliminomethanesulfonic acid (4-005) has been used in the amidination of

lysine [90SC3433] of which the amidination is known to occur regiospecifically.


SOaH


H2N


EtHN


SOaH

NEt


4-004


4-005


Literature searches thus far have revealed two pyrazole reagents for the conversion


amines to guanidines:


i) 3,5-dimethylpyrazole-1-carboxamidine nitrate (4-006)


[63JA2


86S777


, 90JCS(P1)311


91MI425


94SC32


pyrazole-1-


carboxamidine hydrochloride (4-007).


Both reagents have been used effectively with


amines and are improvements over the existing methods.


However, 4-006 requires a


strongly basic medium and/or heat when used in the formation of guanidines [86S777].









C


H2N


NH*HNO3


H2N


NH*HCI


4-006


4-007


Compound 4-006 is a convenient reagent for the synthesis of monosubstituted


guanidines [90JCS(P1)311].
room temperature (2 days) d<


Reactions are normally carried out at 40


pending on the substrate.


*C (about 4 h) or


This guanylnitrate reagent has also


been


used in


the synthesis of


analogs of


the antihypersensitive agent


guanetidine


[94SC321],


but with low isolated yields.


Products were isolated as nitrates.


A more versatile reagent is pyrazole-1-carboxamidine hydrochloride (4-007)


[92JOC2497, 93SC3055, 93TL3389].


Pyrazole 4-007 reacts with primary and secondary


amines to produce guanidine hydrochlorides in good yields, and is also a useful reagent for
peptide synthesis when standard methods for the conversion of amines to guanidines are


not practical [92JOC2497].


for short periods of time and


The gaunylpryazole 4-007 can be stored in aqueous solution


used in stoichiometric amounts at room temperature.


pyrazole by-product is soluble in ether and can be easily removed [92JOC2497].


This is a


welcomed advantage over 4-006 which requires refluxing and two equivalents of the

amine.


Protection of 4


-007 [93SC3055, 93TL3389] is known to enhance its reactivity.


, N-bis-(tert-Butyloxycarbonyl)- 1-carboxamidinepyrazole (4-008a)


N' -bis-


(benzyloxycarbonyl)-l-carboxamidinepyrazole(4-008b) have been used for mild and
efficient preparation of monosubstituted guanidines [93TL3389] and in peptide synthesis


[93SC3055].


The bis-urethane protected (Boc, Cbz) derivatives 4-008a and 4-008b










N


ZHN


4-008a
4-008b


=Boc
=Cbz


Slight modification of the guanyl reagent allows for the generation of (protected)


guanidines


which are


more soluble


in organic solvents.


Acyl-


[92TL5933]


cyanothioureas [89TL7313] have been used for the preparation of


monosubstituted


guanidines.


Normally, this


occurs as a one pot, two stage procedure.


Also, bis-protection


of the guanidine reagent with tert-butoxycarbonyl (Boc) or benzyloxycarbonyl (Cbz)


enhances


reactivity.


,N-bis(tert-B utoxycarbonyl)thiourea


(4-009)


methylisothiourea (4-010)


[87JOC1700, 92MI 119, 93TL7677, 94TL977] and N, N'


bis(benzyloxycarbonyl)thiourea (4-011) [87JOC 1700, 92MI 119, 94TL977] have been
used to synthesize protected guanidines which are easy to purify.


BocHN


NHBoc


BocN


NHBoc


CbzHN


NHCbz


4-009


4-010


4-011


Kozikowski and co-workers have used these protected guanidine reagents (4-009-

-4-011) [94TL977] to synthesize guanidines in excellent yields starting from alcohols,

while Kim and co-workers have enhanced the reactivity of highly deactivated amines and


the bis-Boc protected guanidines by treatment with HgC12 or CuCl2


[93TL7677].


usefulness of benzotriazole


(4-012)


as a synthetic


auxiliary


well





81


of benzotriazole adducts, and (ii) it's anion is an especially good leaving group which can


be displaced by various types of nucleophiles.


report a novel,


In extending this latter property we now


effective and convenient reagent for the mild and efficient conversion of


amines


to guanidines utilizing benzotriazole methodology.


Our approach


utilizes


benzotriazole- 1-carboxamidinium tosylate (4-013) to generate substituted guanidines from

amines.


H2N


NH+
NH2


TsO'
4-013


Results and Discussion


Benzotriazole-1-carboxamidinium tosylate (4


-013) was conveniently prepared in


good yield by modification of a procedure previously reported for the preparation of


pyrazole-1-carboxamidine hydrochloride (4-007) [92JOC2497]:


benzotriazole, cyanamide and p-toluenesulfonic acid (p-TsOH)


dioxane (Scheme 4-1).


molar equivalents of


were refluxed in


The amidinium tosylate 4-013 preciptated from the reaction during


reflux, and could be filtered from the reaction mixture.


Recrystallization gave pure


benzotriazole- 1-carboxamidinium tosylate (4-013) (77%) as stable, non-hygroscopic, fine

white needles.

The reaction for the formation of guanidines from benzotriazole- 1-carboxamidinium
.- 1 at-n- A A lll "\ .- ..... I C-... _--.. .-- .-.. .. __ ___- ... ..








(DIEA) at room temperature, (ii) in CH3CN or (iii) in the absence of solvent.


Product


isolation is facile as the precipitated guanidine can be filtered from the ether soluble


benzotriazole by-product when DMF is used as solvent.


When CH3CN is employed the


product precipitates during the reaction, while in the absence of solvent the product can be

isolated chromatographically (Scheme 4-2, Table 4-1).


p-TsOH


-CEN


1,4-dioxane,


reflux


| N
- N
+
H2N~ N2


TsO'


4-001


4-012


4-013


Scheme 4-1


RN, R'
+NH
H2NO-NH
TsO"


50 C


R-N,


15 mins


H2N


4-015d


NH+
NH2


DMF
DIEA
rt


R, R1
N


H2N


NH2


TsO"


TsO'


4-013


4-014a-


4-015


= n-Bu


DMF


cR, R1
b R.R1


=Me
= -(CH2)5-


RN


gR, R1


= -[(CH2)21-
= -(CH,2)s-


H2N


TsO"
4-015


cR, R1
e R.R1


= MeOCeH4


=C6H


Scheme 4-2


- C6H1








Table 4-1


Products of the Reaction of Benzotriazole-1-carboxamidinium Tosylate (4-
013) with Primary and Secondary Amines


Entry


Amine


4-014a-h


Guanidine
4-015a-h


Yield(%)a


NHI
(i) Me2NH MeNH2N2 69b


NNH2


MeO NH2


MeO


H NH2 Ts


C4HQNH


C4HgNH2


/


NH2
NHTsO
NHo'5


H2
NH2
NH2 TsO"


NH2
NH2


0 I


NH2


TsO'


(viii)


C6H13NH2 CH13NH


NH2
NH2 TsO


aReported yields for purified compounds, reaction time 4-5 h,


Reaction time 24 h, performed in the


absence of DIEA (diisopropylethylamine), reaction time 15 min in the absence of solvent, reaction time
days, performed in CH3CN in the absence of DIEA, reaction time 24 h.


-4


--4





84



Formation of the guanidines 4-015a-b, and 4-015f-h was carried out in DMF in


the presence of DIEA (Scheme 4-


Table 4-1).


In these reactions DIEA serves to


neutralize 4-013 and make it more miscible with organic solvents.


amine 4-014h


Use of the primary


and the secondary amines 4-014a and 4-014f-g afforded the desired


guanidines easily.


However, when the secondary amine, N


, N-diethylamine (4


-0141) was


used, this resulted in the formation of the tosylate salt 4-016 and not the desired guanidine


(Scheme 4-3).


This may be because N


, N-diethylamine is a sterically hindered, more basic


secondary amine.


DMF


4-013 + EtN ,H

H


4-0141


DIEA


EtN ;Et

H TsO


4-016


Scheme 4-3


4-Methoxyaniline- 1-carboxamidinium


tosylate


(4-015c)


aniline-l-


carboxamidinium tosylate (4-015e) were both prepared from 4-013 in DMF in the


absence of DIEA.


reaction.


With primary aromatic amines, the absence of DIEA does not hinder the


Guanidine 4-015e could also be synthesized in CH3CN after five days stirring


at room temperature.


Attempts were made to generate various other phenyl substituted


guanidines under the above conditions, but resulted in the recovery of unreacted starting

materials (Scheme 4-4).


4-013


R,'N'


DMF


No Reaction


4-014


*.... t ._ ...


SA -,,1


& LA A I


* | i


**
a a





85


Since previous attempts to generate n-butylamine-1-carboxamidinium tosylate (4-

015d) by the standard procedure using 4-013 in DMF with DIEA resulted either in poor


yield (34%) or isolation of the corresponding n-butylamine tosylate salt (4-017),


prepared in the absence of solvent.


it was


Guanidine 4-015d was prepared by heating 4-013


4-014d


at 50


minutes.


product


was


purified


column


chromatography.


The poor yield isolated in the standard procedure may be due to


reversible formation of the desired product, which can then decompose to starting materials

and undergo formation of the tosylate salt at a much faster rate (Scheme 4-5).


slow


4-013 +


r 4-015d


C4H9


4-014d

fast


C4H9N H3+ TsO'
4-017
Scheme 4-5


Comparisons of the existing literature methods for the preparation of guanidines

from amines suggest that the pyrazole-1-carboxamidine (4-007) [92JOC2497] approach


is superior to the other literature methods previously mentioned.


Some of the advantages


include mild reaction conditions, the ease of preparation and product isolation and the

extended shelf-life of the parent amidine.

We therefore compared benzotriazole-1 -carboxamidinium tosylate (4-013) with the


pyrazole derivative 4-007 and concluded that 4-013,


while similar in ease of preparation









from pyrazole-1-carboxamidine hydrochloride (4-007) [92JOC2497].


We now report a


yield


84%


using


4-013.


Preparation


hydrochloride


derivative of


methoxyaniline-1-carboxamidinium tosylate (4-015c)


using


pyrazole-1-carboxamidine


hydrochloride (4-007) [92JOC2497], required a reaction time of 21 h to give a yield of


58%.


Using the benzotriazole methodology, an improved yield of 68% was isolated after a


reaction time of 24 h.


The benzotriazole derivative 4-013 is more reactive than 4-007


which is


as expected,


since


benzotriazole is a better leaving group than pyrazole


[91T2683].


The hydrochloride analog of the phenylguanidine salt 4-015e was prepared


previously from aniline using 4-007 [92JOC2497],


in nitrobenzene.


but the procedure involved refluxing


The use of 4-013 afforded 4-015e in dimethylformamide or acetonitrile


after 5 days at room temperature.


Conclusions


In summary, benzotriazole methodology has been extended in the preparation of an

alternative reagent for the preparation of guanidines from primary aliphatic and aromatic


amines and secondary aliphatic and cyclic amines.


Guanidines can be conveniently


prepared and isolated in a one pot sequence as the corresponding tosylate salts.


This


eliminates the step of converting the guanidine to an isolable compound such as a pirate.


Under mild conditions,


benzotriazole- 1-carboxamidinium


tosylate


(4-013)


gives


guanidines in moderate to good yields, and offers advantages such as increase yields and

reactivity over the existing procedure employing pyrazole-1-carboxamidine hydrochloride


(4-007).


Benzotriazole-1-carboxamidinium tosylate (4-013) can be easily prepared and


purified and stored over lone periods of time.





87


Experimental


General.


Melting points were obtained using a Thomas Hoover capillary melting


point apparatus and are uncorrected.


VXR 300 (300 MHz),


1H NMR spectra were recorded either on a Varian


Gemini (300 MHz) or General Electric QE 300 (300 MHz)


spectrometer.


l3C NMR were recorded at 75 MHz on the same instruments.


Chemical


shifts (6) are reported in parts per million (ppm) downfield from tetramethylsilane (TMS)


as the internal standard.


Coupling constants (J values) are reported in Hz.


All reactions


were performed in an inert atmosphere using oven-dried glassware.


Elemental analyses


and high resolution mass spectrometry were performed on site at the analytical facility.

Benzotriazole, ether and piperidine were purchased from Fisher and used as


supplied.


Cyanamide,


DMF, also purchased from Fisher,


dimethylamine, n-butylamine,


was dried over


4A molecular sieves.


pyrrolidine, n-hexylamine and DIEA


were


purchased from Aldrich and used as supplied. Aniline (Aldrich) was distilled prior to use.


4-Methoxyaniline (Aldrich) was recrystallized from hexane prior to use.


(Fluka) was used as supplied.


Morpholine


TLC was performed on pre-coated silica gel F254 plates


which were developed using hexane:ether (70:30) and were visualized with UV light and

iodine.


Benzotriazole- 1-carboxamidinium Tosvlate (4-013).


A mixture of benzotriazole


(11.9 g, 0.1 mol),


cyanamide (4.2


g, 0.1 mol) and p-toluenesulfonic acid (19.2 g, 0.1


mol) was refluxed in 1,4-dioxane (150 mL) for 24 h.


heating.


A white precipitate formed upon


The reaction was then cooled to room temperature, diluted with Et20 (200 mL)


and stirred vigorously for several hours.


The solid was filtered under vacuum


allowed to


.









8.0 (d, 1H, J


= 8.4),


8.3 (d, 1H, J


= 8.2),


10.1 (br


s, 4H).


13C NMR


(DMSO-d6):


20.9, 112.9,


120.4,


126.7


, 128.4,


130.6,


130.7


, 138.4,


144.6,


145.8,


152.0.


Further confirmation was accomplished by single x-ray crystallography (see Appendix C).



General procedure for the formation of substituted guanidines


, N'-Dimethvlamine- 1-carboxamidinium tosvlate (4-015a).


To a mixture of


dimethylamine (40% wt. soln.


in water) (100 pL, 90 mg,


2.0 mmol),


benzotriazole-1-


carboxamidinium tosylate (666 mg,


2.0 mmol) and diisopropylethylamine (DIEA) (347


mg, 2.0 mmol) was added DMF (10 mL).


The reaction was stirred at room


temperature and monitored by TLC.


After


5 h the reaction mixture was diluted with Et20


(20 mL),


stirred and the crude precipitate collected,


washed with Et20O and


dried.


Recrystallization from EtOH afforded white prisms (356 mg, 69%),


mp 173-175 *C (lit.


[51JCS1252] mp 179


1H NMR (DMSO-d6):


= 2.3 (s,


3H),


2.9 (s,


6H),


2H, J


= 8.0),


7.3 (s,


4H),


7.5 (d, 2H, J


= 8.1).


13C NMR (DMSO-d6):


= 20.9, 37.8,


128.4, 138.4, 144.7


156.9.


Piperidine-1 -carboxamidinium tosvlate (4- 015 b).


mg, 3.0 mmol),


DIEA (


Treatment of piperidine (296


benzotriazole-1-carboxamidinium tosylate (1.0 g, 3.0 mmol) and


1 pL, 387 mg, 3.0 mmol) as described for compound 4-015a gave the crude


product after 4 h.


Crystallization from EtOH gave fine white needles (753 mg, 84%),


183-184 *C.


1H NMR


(DMSO-d6):


1.4-1


.5 (m, 6H),


2.3 (s,


3H),


3.4 (t,


4H, J


2 (d, 2H, J


= 8.4),


7.3 (s,


4H),


7.5 (d, 2H, J


= 8.2).


13C NMR (DMSO-d6):


20.8, 2


- -


46.2, 125.5. 128.3.


138.4. 144.8. 1


5. C1IH1iNtOtS requires:









4-Methoxvaniline- 1-carboxamidinium tosvlate (4-015c).


Treatment of


methoxyaniline (393 mg, 3.0 mmol) and benzotriazole-1-carboxamidinium tosylate (1.0 g,


3.0 mmol) as described for compound 4-015a gave


the crude product after 24 h.


Crystallization from MeOH/Et20 gave fine white needles (884 mg, 68%),


mp 143-144


1H NMR (DMSO-ds):


(s, 3H),


3.8 (s, 3H), 6.9 (d, 2H, J


= 4.4),


= 4.4),


7.3 (s,


4H),


5 (d, 2H, J


= 3.7),


13C NMR (DMSO-d6):


= 20.9,


114.9,


128.4,


144.6,


156.3


158.1.


(C14Hi9N304S, FAB):


(M+H)+


= 166.0910.


CgH12N3 (calcd as free base) requires


166.0980.


n-Butvlamine- 1-carboxamidinium


tosylate


(4-015d).


Benzotriazole- 1-


carboxamidinium tosylate (3.0 g, 9.0 mmol),


n-butylamine (887 pL, 657 mg, 9.0 mmol)


and DIEA (1.56 mL, 1.16 g, 9.0 mmol) were heated (50 *C) with stirring for 15 minutes.

The viscous, pale-yellow crude material was cooled to room temperature, dissolved in a


minimal amount of THF and purified by flash column chromatograghy using Et20,


THF


EtOH


consecutively


as eluents.


hygroscopic white solid obtained


upon


evaporation of the EtOH fractions


was suspended in CHC13 to precipitate the pure


hygroscopic white solid (1.4 g,


55%


mp 135 *C (decomposition).


1H NMR


(DMSO-


0.9 (t, 3H, J


= 5.4),


1.3 (septet, 2H, J


= 7.5),


1.4 (septet, 2H, J


7.1),


2.3 (s,


3H),


3.1 (q,


2H, J


= 6.4),


7.1 (d, 2H, J


7.6 (d, 2H, J


= 7.2),


NH protons not


observed.


13C NMR


(DMSO-d6):


20.8, 30.4,


40.5, 125.4,


138.3


144.3


156.8.


HR MS (C12H21N303S,


FAB)


(M+H)+


= 116.1186.


CsH13N3


(calcd as free base) requires 116.1187.





90


filtered and recrystallized from EtOH/Et20 to yield a fine white powder (417 mg, 68%),


mp 150-151 *C.


1H NMR


(DMSO-d6):


= 2.3


3H),


7.1 (d, 2H, J


7.3),


2H, J


= 8.0),


7.3 (d,


2H, J


7.4),


7.4, (t, 1H, J


7.1) 7


(d, 2H, J


= 8.2) 9.7 (s,


1H),


NH2 not observed.


13C NMR


(DMSO-d6):


= 20.9,


124.4,


126.4,


128.4,


129.7


138.4


, 144.6,


(C14H17N303S,


FAB):


(M+H)+


136.0854.


C7H10N3 (calcd as free base) requires 136.0874.


Aniline- 1-carboxamidinium tosylate (4-015e).


Treatment of benzotriazole-1-


carboxamidinium tosylate (666 mg,


0 mmol) and aniline (182 pL, 186 mg,


0 mmol) in


CH3CN as described for compound 4-015a gave the crude product after


5 days (392 mg,


64%).


HR MS (C14H17N303S,


FAB)


(M+H)+


= 136.0854.


C7H10N3 (calcd as free


base) requires 136.0874.


Morpholine-4-carboxamidinium tosvlate (4-015 f).


Treatment of morpholine (174


HL, 174 mg, 2.0 mmol),


benzotriazole-1-carboxamidinium tosylate (666 mg,


2.0 mmol)


and DIEA (347 yL, 258 mg,


2.0 mmol) in DMF (3 mL) as described for compound 4-


014a gave the crude product after 24 h.

crystalline, white powder (520 mg, 86%),


Crystallization from EtOH/Et20 gave a fine


mp 165-167 *C.


1H NMR


(DMSO-d6):


, 3H), 3.6 (t,


SJ = 4.8),


3.9 (t,


4H, J


7.4 (d, 2H, J


= 8.3),


7.8 (d &


6H Jd


8.2).


13C NMR


(DMSO-d6):


= 20.8,


65.3


128.4,


138.4,


144.7


156.4.


HR MS (C12H19N304S, FAB):


(M+H)+


130.0973.


C5H12N30 (calcd


as free base) requires 130.0981.


Pvnnrolidine-1-carboxamidinium tnsvlate (4-.01 Yl


TrePatment nf nvrrnlidina (1i









yellow needles (404 mg, 71%),


mp 185-187 "C.


1H NMR (DMSO-d6):


1.9 (t,


4H, J


= 6.6),


2.3 (s, 3H), 3.3 (t,


4H, J


= 6.6),


7.2 (d &


,6H, Jd


= 8.0),


7.5 (d,


= 8.0).


13C NMR


(DMSO-d6):


= 20.8,


24.7


46.9


, 125.4,


128.3


144.8,


154.3.


C12H 19N303S requires:


H, 6.71


14.73.


Found:


C, 50.


H, 6.70


HR MS (C12H19N304S,


FAB):


(M+H)+


= 114.1025.


CsH12N3 (calcd as free


base) requires 114.1031.


n-Hexvlamine- 1-carboxamidinium tosvlate (4- 015 h).


Treatment of n-hexylamine


(264 yL, 202 mg,


mmol) and DIEA (347 pL,


4-015a gave the crude product after 24 h.


2.0 mmol), benzotriazole-1-carboxamidinium tosylate (666 mg,


0 mmol) in DMF (3 mL) as described for compound


Crystallization from EtOHIEt20 gave fine


white, crystalline flakes (420 mg, 67%),


mp 1


1H NMR (DMSO-d6):


(t, 3H, J


= 6.6),


.2 (br


s, 6H),


1.4 (q,


2H, J


= 6.3),


(s, 3H), 3.1


2H, J


= 6.5),


7.2 (d &


7H,Jd


8.2),


7.6 (d, 2H, J


= 8.3).


13C NMR (DMSO-d6):


13.9, 20.8,


28.3


(C14H25N303S,


30.8


FAB):


40.8


(M+H)+


138.4


= 144.1431


156.8.


. C7H18N3 (calcd as free base) requires


130.1501.


N. N-Diethvlamine tosvlate salt (4- 016).


Treatment of N


, N-diethylamine (197uL,


146 mg, 2.0 mmol),


benzotriazole-1-carboxamidinium tosylate (666 mg,


0 mmol) and


DIEA (287 4L, 258 mg, 2.0 mmol)


gave the crude product after 24 h.


n DMF (5 mL) as described for compound 4-015a

Crystallization from EtOH/Et20 gave fine white,


crystalline flakes (470 mg, 82


), mp 96-98


1H NMR (DMSO-d6):


1.0 (t, 6H, J


= 7.3),


7 (a


4H.J


7.3).


7.1 (d. 2H. J


'.9L 7.4 (d. 2H J.


7.8g 8R


3 H)


. .. .


-


n









n-Butvlamine tosvlate salt (4-017).


Treatment of n-butylamine (197uL, 146 mg,


0 mmol),


benzotriazole-1-carboxamidinium tosylate (666 mg, 2.0 mmol) and DIEA (287


yL, 258 mg,


0 mmol) in DMF (5


mL) as described for compound 4-015a gave the


crude product after 24 h.


Crystallization from EtOH/Et20 gave fine white, crystalline


flakes (380 mg, 68%), mp 80-82


1H NMR (DMSO-d6):


= 0.9 (t, 6H, J


= 9.0),


(m, 2H),


.5 (m


3H),


7 (t, 2H, J


= 8.5),


7.1 (d, 2H,


= 8.5),


7.5 (d,


2H, 8.5),


3H).


13C NMR


(DMSO-d6):


13.8,


, 29.4, 39.08,


9, 128.6,


145.4.


2H,),














CHAPTER V
INVESTIGATIONS OF 4-AMINO-1,2,4-TRIAZOLE:
APPROACHES TO THE DEVELOPMENT OF A NEW ELECTROPHILIC
AMINATING AGENT & METHODOLOGY FOR THE PREPARATION OF
4-(ALKYLAMINO)- 1,2,4-TRIAZOLES



Introduction


4-Amino-1,2,4-triazole (5-001)


was


first


obtained


Curtius


Lang


[1888JPR531].


Later in 1906, Bulow and co-workers demonstrated that triazole 5-001


reacts with 1,4-dicarbonyl compounds to afford the corresponding pyrrole derivatives


[06CB2618, 06CB4106].


This reaction is characteristic for most primary amines.


Triazole


5-001 was also synthesized from the self-condensation of formhydrazide at 150-250 *C


[440S12].


The formhydrazide was made from ethyl format and hydrazine.


The amino


group of the triazole 5-001 is weakly basic [71JPR795, 89JOC731], therefore it is


alkylated and aminated only at the ring nitrogen atom [89S69].


N-Alkylaminotriazdoles


have been synthesized by the reduction of the corresponding Schiff bases with sodium

borohydride and lithium aluminium hydride [88JOC3978].


-N

INH
NH2


5-001


This chapter, which focuses upon investigations of 4-amino-l,2,4-triazole will be