Group Title: addition of heterocyclic amines to cinnamete esters
Title: The addition of heterocyclic amines to cinnamete esters
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Title: The addition of heterocyclic amines to cinnamete esters
Physical Description: 76 leaves : ; 28 cm.
Language: English
Creator: Mattson, Guy Charles, 1927-
Publisher: University of Florida
Place of Publication: Gainesville Fla
Gainesville, Fla.
Publication Date: 1955
Copyright Date: 1955
 Subjects
Subject: Esters   ( lcsh )
Amines   ( lcsh )
Chemistry thesis Ph. D
Dissertations, Academic -- Chemistry -- UF
Genre: bibliography   ( marcgt )
non-fiction   ( marcgt )
 Notes
Bibliography: Bibliography: leaves 74-75.
General Note: Manuscript copy.
General Note: Dissertation (Ph.D.) - University of Florida, 1955.
General Note: Biography.
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Bibliographic ID: UF00098420
Volume ID: VID00001
Source Institution: University of Florida
Holding Location: University of Florida
Rights Management: All rights reserved by the source institution and holding location.
Resource Identifier: alephbibnum - 000546216
oclc - 13200823
notis - ACX0177

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THE ADDITION OF HETEROCYCLIC AMINES

TO CINNAMATE ESTERS











By 5
GUY C." MATTSON











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











UNIVERSITY OF FLORIDA
August, 1955

















ACKNOWLEDGMENTS


The author wishes to express his sincere appreciation

to Dr. C. B. Pollard, Chairman of the candidate's Supervisory

Committee, under whose direction this work was performed.

Dr. Pollard's guidance, advice, and encouragement have been

a great help.

The author thanks Dr. A. H. Gropp for his many sug-

gestions and advice on certain phases of this work.

For her support and encouragement the author wishes

to express his gratitude to his wife, Jean.
















PREFACE


The experimental work described in this disserta-

tion is purposely presented in detailed form to facilitate

duplication by future investigators. Every synthesis is

reported in detail, even though the basic procedure in a

given series is essentially the same.

Throughout this dissertation all melting points

reported are corrected values. The thermometers used were

calibrated against a set of thermometers standardized by

the Bureau of Standards. In conformity with present prac-

tice, all temperatures reported refer to the Centigrade

scale; the symbol is omitted.

The manner of listing references is the customary

one for technical reports. Journal abbreviations are those

used by Chemical Abstracts.














TABLE OF CONTENTS


Page


ACINOWLEDGMSNTS . . . . . .

PREFACE . . . . . . .

LIST OF TABLES. . . . . . .

LIST OF FIGURES . . . . . .

Chapter

I. INTRODUCTION. . . . .

II. DISCUSSION OF THE REACTION. .

III. EXPERIMENTAL. . . . .

Part 1: The Preparation of
cyclic)-2-phenyl-propionate

Part 2: The Preparation of


2-(N-Hetero-
Esters. . .

Intermediates .


Part 3: A Study of the Reaction of Hetero-
cyclic Amines with Cinnamate Esters . . .

IV. SUMIMARY . . . . . . . . . .

BIBLIOGRAPHY. . . . . . . . . . . .

BIOGRAPHICAL NOTES. . . . . . . . . .
















LIST OF TABLES

Table Page

1. Cinnamate Esters . . . . . . . ... 53

2. Ethyl 2-(H-Heterocyclic)-2-phenyl-propionate
Hydrochlorides . . . . . . . .... . 69

3. Alkyl 2-(l-Piperidyl)-2-phenyl-propionate
Hydrochlorides . . . . . . . .... . 70

L4. Esters of 2-(l-Piperidyl)-2-phenyl-propionic
Acid Hydrochloride . . . .... . ... . 72















LIST OF FIGURES


Fig. No. Page

1. Relationship between reaction time and yield
of product. Heptane solution, no catalyst. 59

2. Relationship between reaction time and yield
of product. Toluene solution, tetramethyl-
ammonium hydroxide catalyst . . . . . 61

3. Refractive Indices vs. Time . . . .... . 67















CHAPTER I


INTRODUCTION

For many years a search has been under way for a

synthetic drug which possesses an analgesic potency similar

to that of morphine (I) but lacks the undesirable side ef-

fects and addiction liabilities of this alkaloid. One of

the milestones in this search was the synthesis of ethyl

l-methyl-4-phenylpiperidine-4-carboxylate (II) in 1937 by
1
Eisleb and Schaumann.


OH o OH
r^ C-O-CH2CH,

0HH C CC

CH,
CH3

I II

(a)
Under the name Demerol this drug has found wide

clinical use in recent years. Although a less potent anal-

getic than morphine, Demerol is less toxic and causes less
2
euphoria and sedation. It has been found to cause definite


(a)
Other names: Meperidine, Pethidine, Dolantin, Iso-
nipecaine












true addiction, but the withdrawal symptoms are milder than

those caused by morphine.3

In 1944 an analog of Demerol in which the 3- instead

of the 4-position of the piperidine is substituted was syn-

thesized by Bergel et al. It has been reported that this

compound (III), ethyl 1-methyl-3-phenylpiperidine-3-car-

boxylate, retains the analgetic action of Demerol, but

causes less sedation.5 This would indicate that substi-

tution in the 4-position is not essential to analgetic

activity in piperidine derivatives.

The object of the present research was to synthe-

size ester derivatives of piperidine of the general form

IV in the hope of obtaining a clinically useful analgesic.


CH-CHa-COOR


CH,-


It was decided to attempt the formation of these

compounds by the addition of heterocyclic secondary amines

to cinnamate esters.


O CH=CH-COOR + H-N R


N /CH-CH,-COOR


OR'












The addition of amines to acrylate esters consti-

tutes a useful method of synthesizing N-substituted beta-

amino propionate esters. However, there are few literature

reports of the reaction of amines with the less reactive

substituted acrylate esters such as the cinnamate esters.

There is no reference in the literature to a successful

addition of a secondary amine to a cinnamate ester.















CHAPTER II


DISCUSSION OF THE REACTION


The Addition of Amines to Olefinic Esters


Amines do not generally react with olefins under

ordinary conditions. However, in many cases they add
6
readily to conjugated olefins such as acrylonitrile,
7 8
beta-keto olefins, and the acrylate esters to form the

beta-amino compounds.

The mechanism of this addition reaction is thought

to be a nucleophilic attack by the amine or amine anion

upon a carbonium ion. Considering the reaction of piperi-

dine with ethyl acrylate, this mechanism can be illustrated

in the following manner:
0
CBH=CH-C-0-C2He

CH2-CH=-CH O-C2H, + H-CH= -O-C',H



1N-CHs-CH,-C-O-CHe

It is probable that a secondary amine reacts with a

cinnamate ester according to a similar scheme. However, in

this case there are three additional, nonreactive resonance

4













forms which could tend to make the olefin less reactive by

decreasing the positive charge on the beta-carbon atom.

+ 0" 0
Q CH-CH=C-0-CaH, + HN ) --- ( CH -C-O-CaH,

Reactive Form N

+ 0





0
\}=CH-CH=C-0-C2H6




+ =CH-C=C-0-CsH ---- Non-reactive, Competing
Forms



)=CH-CH=C-0-CSHe




The Michael reaction, in which the anion of an

active hydrogen compound adds to the beta-carbon atom of

an unsaturated ester, is believed to proceed by the same
9
type of mechanism. C. K. Ingold, in his discussion on

the effect of structure on equilibrium in this reversible

reaction, states that beta-aryl groups are thermodynamically

inhibitory towards addition due to conjugation with the
10
double bond. In addition, steric effects may also tend

to decrease the reactivity of the beta-substituted olefinic
11
esters.












This decreased reactivity of substituted acrylic

esters can be illustrated by considering the yields of

beta-amino esters obtained by the reaction of piperidine

with various esters:


C5H,,NH+ CH2=CH-COOCa2He- CGeHN-CH-CHCOOOCBH, 88%12

CH, CH,
CsHIoNH + CHa=0-COOC2H0 -- CBHioN-CH2-CH-COOCH, 833


CHioNH + CH,-CH=OH-COOCOH -CHoN-CH-CHaCOOCH, 60

CH 14CH
CH1,NH + C=CH-COOCzHe CeHIoN\-C-HaC000CHe 0%14
CH3 CH,


The products of the reactions of ammonia and amines

with ethyl cinnamate have been studied by Karl Morsch.15

The yields of beta-amino ester isolated from the reaction

mixtures are listed below:


NH, + OQ CH=CH-COOC2H, -9- O CH-CHOOCH, 13%
NH2

CHMNHa + 1CH=GH-COOCGHe -* O CH-CHsCOOC2He 18%
H-N-CH5

(C2H),2NH + CCH=CH-COOCHe CH-CH2COOC2He (O
N(CEH,)

The only product obtained from the reaction of diethylamine

with ethyl cinnamate was the amide, N,N-Diethylcinnamide,

in 39.9% yield.











Evidence of the reversibility of the reaction of
amines with unsaturated esters is provided by the work of
McElvain and Stork.16

In addition to the reaction of the amine with the
olefinic bond, it is also possible for ammonolysis of the

ester group to occur. This competing reaction is known
to take place, and under certain conditions the amide is
the only product isolated.


O


H=CCH=-COORNo +RO


Q-CH-CHOCOOR


CN-H +

















CHAPTER III


EXPERIMENTAL


Part 1: The Preparation of 2-(N-Heterocyclic)-

2-phenyl-propionate Esters


The reaction of heterocyclic amines with cinnamate

esters was effected by refluxing equimolar quantities of

the reactants with or without a solvent. The method used

to isolate the product was basically the same in all cases.

The reaction mixture was first washed with distilled water

to remove unchanged amine. The solution was then extracted

with a dilute acid solution to remove the product from the

reaction mixture. This acid solution was then made basic,

causing the product to separate out as an oil. This oil

was taken up in ether and the ether solution was dried.

The product was isolated from the ethereal solutions by

precipitation as the hydrochloride salt. This method of

working up the products was employed because it was found

that vacuum distillation of the reaction mixture led to

formation of the corresponding amide.












The percentage yields of products are based upon

the molar quantity of cinnamate ester used. Unless other-

wise noted, they refer to purified product.

All of the products were analyzed for carbon and

hydrogen content. These microanalyses were done by Geller

Laboratories.












Methyl 2-(l-Piperidyl)-2-phenyl-propionate Hydrochloride


CH=CH-COOCH, + H-N CH- CH2\ CH, H -CH-CCOOCHa
\CHC,-CH^,/
CH2 CH2
I I

CH,

Sixteen and two-tenths grams of methyl cinnamate

and 8.5 g. of piperidine were dissolved in 30 ml. of hep-

tane, and the solution was refluxed for eight hours. After

the solution had cooled to room temperature, it was washed

with three 30-m1l. portions of distilled water. The organic

layer was then extracted with two 30-ml. portions of cold

3 N hydrochloric acid. These acid aqueous extracts were

combined and made basic to pH 8 by the addition of granu-

lar potassium carbonate. The resultant oil was then ex-

tracted with two 50-ml. portions of ether. The ethereal

extracts were combined and dried over anhydrous calcium

sulfate. The dry ether solution was then treated with

dry hydrogen chloride until acid to Congo Red paper. The

precipitated white solid was recrystallized three times

from propanol-2. Yield: 4.6 g., or 18.6%.













Methyl 2-(l-Piperidyl)-2-phenyl-propionate Hydrochloride



CH-CHg-C-OCH,
SI. HC1

CH2 CH,
I I
CH2 CH2
CH,


Molecular Formula. . . . . . ... C .1 CHsN O0C1

Molecular Weight. . . . . . . . ... .283.80

Melting Point. . . . . . . ... .190.5 191.5

Recrystallizing Solvent. . . . . .... . Propanol-2

Analyses:

Carbon, %

Calculated. . . . .63.47

Found . . . . .63.34

Hydrogen, %

Calculated. . . . 7.82

Found . . . . . 7.95

Solubilities:

Water. . . .Very Soluble

Ethanol. . . . Soluble

Acetone. . . Insoluble

Benzene. . .... Insoluble












Ethyl 2-(l-Piperidyl)-2-phenyl-propionate Hydrochloride


CH=CH-COOH, + H-N /C,-CH, ->. C-CH-CH-COOCH,
0CH 1--CH2/ -

CH2 CH2
I I

CH2

Seventeen and six-tenths grams of ethyl cinnamate

and 8.5 g. of piperidine were dissolved in 30 ml. of hep-

tane, and the solution was refluxed for eight hours. After

the solution had cooled to room temperature, it was washed

with three 30-mi. portions of distilled water. The organic

layer was then extracted with two 30-ml. portions of 3 N

hydrochloric acid. These acid aqueous extracts were com-

bined and made basic to pH 8 by the addition of granular

potassium carbonate. The resultant oil was then extracted

with two 50-mi. portions of ether. The ethereal extracts

were combined and dried over anhydrous calcium sulfate.

The dry ether solution was then treated with dry hydrogen

chloride until acid to Congo Red paper. The precipitated

white solid was recrystallized three times from propanol-2.


Yield: 6.0 g., or 20.1%.













Ethyl 2-(l-Piperidyl)-2-phenyl-propionate Hydrochloride


CH-CHa-C-O-CHe



CH, CH,
CH2


Molecular Formula. . . . . . . . .CiH2sN 02C01

Molecular Weight. . . . . . . . . . 297.82

Melting Point. . . . . . . ... . 195 195.5

Recrystallizing Solvent. . . . . . . .Propanol-2

Analyses:

Carbon, %

Calculated. . ... .64.52

Found. . . . . 64.36

Hydrogen, %

Calculated. . . . 8.12

Found. . . ... . 8.22

Solubilities:

Water. . . .Very Soluble

Ethanol. . . . Soluble

Acetone. . . Insoluble

Benzene. . .... Insoluble













n-Propyl 2-(l-Piperidyl)-2-phenyl-propionate Hydrochloride


-CH=CH-COOCH, + H-N CCH -p- ( C-CH0COOCaHY
\CH2-CH2/ -6 a
CH2 CH2
CHa CH,
CH2

Nineteen grams of n-propyl cinnamate and 8.5 g. of

piperidine were dissolved in 30 ml. of heptane and the

solution was refluxed for eight hours. After the solution

had cooled to room temperature, it was washed with three

30-ml. portions of distilled water. The organic layer was

then extracted with two 30-ml. portions of cold 3 N hydro-

chloric acid. These acid aqueous extracts were combined and

made basic to pH 8 by the addition of granular potassium

carbonate. The resultant oil was then extracted with two

50-mi. portions of ether. The ethereal extracts were com-

bined and dried over anhydrous calcium sulfate. The dry

ether solution was treated with hydrogen chloride until

acid to Congo Red paper. The precipitated white solid was

then recrystallized from propanol-2.


Yield: 7.0 g., or 22.14.













n-Propyl 2-(l-Piperidyl)-2-phenyl-propionate Hydrochloride


-C-CHa-C-0-CHCH,-CH,

N
CH, CH, *HC1

CHa CH,
CHa

Molecular Formnula . . . . . . .C17H2sN 02C01

Molecular Weight. . . . . . . . . . 311.85

Melting Point. . . . . . . . . ... . 200.5

Recrystallizing Solvent. . . . . ... .Propanol-2

Analyses:

Carbon, %

Calculated. . . 65.47

Found. . . .65.83

Hydrogen, %

Calculated. . ... .8.42

Pound. . . . . 8.55

Solubilities:

Water . .. Very Soluble

Ethanol. . .... .Soluble

Acetone. . . .Insoluble

Ether. . ... .Insoluble







15













n-Butyl 2-(l-Piperidyl)-2-phenyl-propionate Hydrochloride


-CH=CH-COOC4,H + H-N CH CH, -> -CH-CHs-COOC4He


I I
CH, CH,
CHa


Thirty-five and six-tenths grams of n-butyl cinna-

mate and 15.0 g. of piperidine were dissolved in 30 ml. of

heptane, and the solution was refluxed for eight hours.

After the solution had cooled to room temperature, it was

washed with three 30-ml. portions of distilled water. The

organic layer was then extracted with two 30-ml. portions

of 3 N hydrochloric acid. These acid aqueous extracts were
combined and made basic to pH 8 by the addition of granular

potassium carbonate. The resultant oil was then extracted

with two 50-ml. portions of ether. The ethereal extracts

were combined and dried over anhydrous calcium sulfate.

The dry ether solution was treated with hydrogen chloride

until acid to Congo Red paper. The precipitated white

solid was recrystallized twice from propanol-2.


Yield: 8.9 g., or 15.6%.













n-Butyl 2-(l-Piperidyl)-2-phenyl-propionate Hydrochloride



CH-CH,-C-O-CHCHCHaCHa

SN" *HC1l
CH2, CH,
CH CHe
CH,

Molecular Formula. . . . . . . .C1jH2aN 0,01

Molecular Weight. . . . . . . . ... . 32$.87

Melting Point. . . . . . . . . 169 170

Recrystallizing Solvent. . . . . . . .Propanol-2

Analyses:

Carbon, %

Calculated.. . .. .66.33

Found. . . . . 66.44

Hydrogen, %

Calculated. . . . 8.67

Found. . . .... . .8.85

Solubilities:

Water.. .. .Very Soluble

Ethanol. . . . Soluble

Acetone. .Slightly Soluble

Ether. . . . Insoluble













n-Amyl 2-(l-Piperidyl)-2-phenyl-propionate Hydrochloride

CH=CH-COOCBH11 + H-N CHCHa\ CH-, -CH-CH-COOCeHiI


CH, CH,
I I
CH, CH,
CH,

Thirty-seven grams of n-amyl cinnamate and 16.0 g.

of piperidine were dissolved in 30 ml. of heptane, and the

solution was refluxed for eight hours. After the solution

had been cooled to room temperature, it was washed with

three 30-ml. portions of distilled water. The organic

layer was then extracted with two 30-ml. portions of 3

N hydrochloric acid. These acid aqueous extracts were

combined and made basic to pH 8 by the addition of granu-

lar potassium carbonate. The resultant oil was then ex-

tracted with two 50-mi. portions of ether. The ethereal

extracts were combined and dried over anhydrous calcium

sulfate. The dry ether solution was treated with hydrogen

chloride until acid to Congo Red paper. The precipitated

white solid was recrystallized from a mixture of propanol-

2 and acetone.


Yield: 7.3 g., or 12.2%.













n-Amyl 2-(l-Piperidyl)-2-phenyl-propionate Hydrochloride


-CH-CH,-C-O-CH ,-CHr-CH2-CHa

-"" *HC1
CH, C r
CH, CH2
CH2


Molecular Formula. . .

Molecular Weight . .

Melting Point. . . .

Recrystallizing Solvent.

Analyses:


. . . . . . .CeHoN 0,C01

* . . . . . . .339.90

. . . . . . 171.5 172.5

. . . . Propanol-2, Acetone


Carbon, %

Calculated. . . . 67.13

Found. . . .. .... . 67.24

Hydrogen, %

Calculated. . . . . . 8.91

Found. . . . . .... . .8.76

Solubilities:


Water. .

Ethanol.

Acetone.

Ether. .


. .. . ..Very Soluble

. . . . . Soluble

S. . . Slightly Soluble

. . . . . Insoluble













n-Hexyl 2-(l-Piperidyl)-2-phenyl-propionate Hydrochloride

-CB=CH-COOCH, + H-N CH-C H2 -- / CH-CH2-COOC6H13

CHH-C
I I
CH2 CH2
CH2

Twenty-three and one-tenth grams of n-hexyl cinna-

mate and 8.5 g. of piperidine were dissolved in 30 ml. of

heptane, and the solution was refluxed for twenty-four hours.

After the solution had been cooled to room temperature, it

was washed with three 30-ml. portions of distilled water.

The organic layer was then extracted with two 30-ml. por-

tions of cold 3 N hydrochloric acid. These acid aqueous

extracts were combined and made basic to pH 8 by the addi-

tion of granular potassium carbonate. The resultant oil

was then extracted with two 50-ml. portions of ether. The

ethereal extracts were combined and dried over anhydrous

calcium sulfate. The dry ether solution was treated with

hydrogen chloride until acid to Congo Red paper. The

precipitated white solid was recrystallized from benzene.


Yield: 2.8 g., or 7.9%.













n-Hexyl 2-(l-Piperidyl)-2-phenyl-propionate Hydrochloride


-CH-CH,- -0-CHCH,-CII,-CH,-CH,-CHa
Ns *HC1
CHs CHZ

CH2 CH,
CH,


Molecular Formula . . . . .. . . .CoHN 0,C01

Molecular Weight. . . . .. . . . . 353.93

Melting Point. . . . . . . . . 131 132

Recrystallizing Solvent. . . . . . Benzene

Analyses:

Carbon, %

Calculated. . . . .67.86

Found. . . . . . 67.76

Hydrogen, %

Calculated. . . . ... 9.13

Found. . . . . .. . 9.22

Solubilities:

Water. . . . . Soluble

Ethanol. . . . . Soluble

Acetone. . . .Slightly Soluble

Ether. . . . . Insoluble













1-Methylpropyl 2-(1-Piperidyl)-2-phenyl-proplonate
Hydrochloride

SHCH 2 -GH-\
J CH C=H-COOEH-CH2-CH, + H-CH CH, --i
H, CH,-CH,


-CH-CHs-OOCH-CH2-CH3

CHs HH,
IC I
CH2 CH,
CH,

Thirty grams of 1-methylpropyl cinnamate and

12.5 g. of piperidine were dissolved in 30 ml. of heptane,

and the solution was refluxed for twenty hours. After the

solution had been cooled to room temperature, it was washed

with three 30-ml. portions of distilled water. The organic

layer was then extracted with two 30-ml. portions of cold

3 N hydrochloric acid. These acid aqueous extracts were

combined and made basic to pH 8 by the addition of granular

potassium carbonate. The resultant oil was then extracted

with two 50-ml. portions of ether. The ethereal extracts

were combined and dried over anhydrous calcium sulfate.

The dry ether solution was treated with hydrogen chloride

until acid to Congo Red paper. The precipitated white

solid was recrystallized twice from propanol-2.


Yield: 3.0 g. or 6.3%.













1-Methylpropyl 2-(l-Piperidyl)-2-phenyl-propionate
Hydrochloride



CH-CH,-CO-CH-CH,-CH,


CH, CH, HC1
I I HCl
CH, CH,
CH,


Molecular Formula. . . . . . . . C1,H,,N 0201

Molecular Weight. . . . . . . . . .325.87

Melting Point. ................ .189.5 190

Recrystallizing Solvent. . . . . .... . Propanol-2

Analyses:

Carbon, %

Calculated. . . 66.33

Found. . ... .66.48

Hydrogen, %

Calculated. . . .8.67

Found. ....... 8.57

Solubilities:

Water. . . ... .Soluble

Ethanol . . .... Soluble

Acetone. .Very Slightly Soluble

Ether. . . .... .Insoluble












2-Methylpropyl 2-(1-Piperidyl)-2-phenyl-propionate
Hydrochloride

O=\ /CH,-CH,\
-CH=CH-COO-CH,-CH-CH, + H-k CH, -H--
CH, CH,-CH,

G--CH-CHO-CHOO-CH-CH-CHa
N, CH,

I I
CHa CH,
CH,




Thirty grams of 2-methylpropyl cinnamate and

12.5 g. of piperidine were dissolved in 30 ml. of heptane,

and the solution was refluxed for twenty hours. After

the solution had been cooled to room temperature, it was

washed with three 30-ml. portions of distilled water. The

organic layer was then extracted with two 30-ml. portions

of cold 3 N1 hydrochloric acid. These acid aqueous extracts

were combined and made basic to pH 8 by the addition of

granular potassium carbonate. The resultant oil was then

extracted with two 50-ml. portions of ether. The ethereal

extracts were combined and dried over anhydrous calcium

sulfate. The dry ether solution was treated with hydrogen

chloride until acid to Congo Red paper. The precipitated

white solid was recrystallized twice from propanol-2.

Yield: 3.1 g., or 6.5%.













2-Methylpropyl 2-(1-Piperidyl)-2-phenyl-propionate
Hydrochloride



-CH-CH0-O-CH-CHCH-
HN CH
CH, CH, HC1
I I

CH,

Molecular Formula. . . . . . . . ..C1Ha2N 0,01

Molecular Weight. . . . . . . . .... . 32.87

Melting Point. . . . . . . . . . 160 161

Recrystallizing Solvent. . . . . . . .Propanol-2

Analyses:

Carbon, %

Calculated. . . 66.33

Found. . . . .66.16


Hydrogen, %

Calculated. . . .8.67

Found. . . ... 8.55

Solubilities:

Water. . . ... .Soluble

Ethanol. . . ... .Soluble

Acetone. . Slightly Soluble

Ether. . . ... .Insoluble













1-Methylbutyl 2-(l-Piperidyl)-2-phenyl-propionate
Hydrochlori de

Q/-c 0Ho -CHa\

CH CH



Q H-CH-CH-COOCH-CH2CH2-CH,

CH2 CH,
I I
CH, CH,

CH,



Thirty-five grams of 1-methylbutyl cinnamate and

14 g. of piperidine were dissolved in 30 ml. of heptane,

and the solution was refluxed for twenty hours. After the

solution had been cooled to room temperature, it was

washed with three 30-ml. portions of distilled water. The

organic layer was then extracted with two 30-ml. portions

of cold 3 N hydrochloric acid. These acid aqueous extracts

were combined and made basic to pH 8 by the addition of

granular potassium carbonate. The resultant oil was ex-

tracted with two 50-ml. portions of ether. The ethereal

extracts were combined and dried over anhydrous calcium

sulfate. The dry ether solution was treated with hydrogen

chloride until acid to Congo Red paper. The precipitated

white solid was recrystallized three times from propanol-2.

Yield: 2.0 g., or 3.7%.













1-Methylbutyl 2-(l-Piperidyl)-2-phenyl-propionate
Hydrochloride


H-CH,--O-CEH-CH,-CH,-CH,
N 0CH,,
CH, CH,
S II 'HC1
CH, CH,

CH,


Molecular Formula. . . . . . CeHaoN 02CI01

Molecular Weight. . . . . . . ... . .339.90

Melting Point. . . . . . . . ... .167 168

Recrystallizing Solvent. . . . . .... . Propanol-2

Analyses:

Carbon, %

Calculated. . . . 67.13

Found . . . . 67.10

Hydrogen, %

Calculated . . . 8.91

Found . . . .... . 8.87

Solubilities:

Water. . . . . Soluble

Ethanol . . ... .Soluble

Acetone. . .Slightly Soluble

Ether. . . ... Insoluble












Cyclohexyl 2-(1-Piperidyl)-2-phenyl-propionate
Hydrochloride

O /CH2-CH2 CHg-CHA
-CH=CH-COO-CH H, + H-H CH, -:-
\CHa-CH, CH,-CH2



-CH-CHg-COOCH CH
0 \CHg-CH,/

CH2 CHs
I I
CHa CH,
CH,



Forty grams of cyclohexyl cinnamate and 15.0 g.

of piperidine were dissolved in 30 ml. of heptane, and the

solution was refluxed for twenty hours. After the solution

had been cooled to room temperature, it was washed with

three 30-ml. portions of distilled water. The organic

layer was then extracted with two 30-ml. portions of cold

3 N hydrochloric acid. These acid aqueous extracts were
combined and made basic to pH 8 by the addition of granu-

lar potassium carbonate. The resultant oil was extracted

with two 50-ml. portions of ether. The ethereal extracts

were combined and dried over anhydrous calcium sulfate.

The dry ether solution was treated with hydrogen chloride

until acid to Congo Red paper. The precipitated white solid

was recrystallized twice from propanol-2.

Yield: 6.0 g., or 9.9%.












Cyclohexyl 2-(l-Piperidyl)-2-phenyl-propionate Hydrochloride

0 ,CHC-CH2\
-CH-CH,-C-O-CH CH,
1 'CH,-CH,/

CHa C 2
CH CH,
CH,


Molecular Formula. . . . . . . . .C2,aoN OCl

Molecular Weight. . . . . . . . . . 351.91

Melting Point. . . . . . . . . 182.3 182.5

Recrystallizing Solvent. . . . . . . Propanol-2

Analyses:

Carbon, %

Calculated. . . .68.26

Found. . . . 68.00

Hydrog en, %

Calculated. . . 8.59

Found. . . . 8.45

Solubilities:

Water. . . . . .Soluble

Ethanol . . . . Soluble

Acetone. . Slightly Soluble

Ether. . . . .Insoluble








29


_^J












Benzyl 2-(l-Piperidyl)-2-phenyl-propionate Hydrochloride


CH=CH-COOGH + H-N CH2 --H -
Y_/ ^-y CHa-CHa/


QG -CH-CHa-COO-CHoa
N
CH, CH,
I I
CH, CH,
CH,


Twenty-three and eight-tenths grams of benzyl

cinnamate and 8.5 g. of piperidine were dissolved in 30 ml.

of heptane, and the solution was refluxed for eight hours.

After the solution had been cooled to room temperature, it

was washed with three 30-ml. portions of distilled water.

The organic layer was then extracted with two 30-ml. portions

of cold 3 N hydrochloric acid. These acid aqueous extracts

were combined and made basic to pH 8 by the addition of

granular potassium carbonate. The resultant oil was then

extracted with two 50-ml. portions of ether. The ethereal

extracts were combined and dried over anhydrous calcium

sulfate. The dry ether solution was then treated with

hydrogen chloride until acid to Congo Red paper. The

precipitated white solid was recrystallized three times

from propanol-2.


Yield: 7.3 g., or 20.3%.













Benzyl 2-(l-Piperidyl)-2-phenyl-propionate Hydrochloride




CH1 H .N
CH, CH2 'HC1


CH2



Molecular Formula. . . . . . . . .CaHa26N OaC1

Molecular Weight. . . . . . . . . . 359.88

Melting Point. . . . . . . .... . 191.5 192

Recrystallizing Solvent Propanol-2

Analyse s:

Carbon, %

Calculated. . .. ..70.08

Found. . . . 69.72

Hydrogen, %

Calculated. . . 7.28

Found. . . . .7.32

Solubilities:

Water. . . . .. ..Soluble

Ethanol. . . .... .Soluble

Acetone. . Slightly Soluble

Ether. . ..... .Insoluble












1-Phenylethyl 2-(1-Piperidyl)-2-phenyl-propionate
Hydrochloride

O.. /CHa-CH2\
CH=CH-COO-CH-CH, + H-N\ ---
O CH2-CH2


CH-CH,-COO-CII-CH1


I I
.- -
CHs CH,
CH,

Thirty-three grams of 1-phenylethyl cinnamate and

11.2 g. of piperidine were dissolved in 30 ml. of heptane,

and the solution was refluxed for twenty hours. After the

solution had been cooled to room temperature, it was washed

with three 30-ml. portions of distilled water. The organic

layer was then extracted with two 30-ml. portions of cold

3 N hydrochloric acid. These acid aqueous extracts were
combined and made basic to pH 8 by the addition of granu-

lar potassium carbonate. The resultant oil was extracted

with two 50-ml. portions of ether. The ethereal extracts

were combined and dried over anhydrous calcium sulfate.

The dry ether solution was treated with hydrogen chloride

until acid to Congo Red paper. The precipitated white

solid was recrystallized three times from propanol-2.


Yield: 6.8 g., or 13.5%.













1-Phenylethyl 2- (l-Piperidyl)-2-phenyl-propionate Hydrochloride


CH-C-CH-C-O-CH-CHa

i I
CHI O(3H.2

CHs


Molecular Formula. . . . . . . .CaeN OC01

Molecular Weight. .................. 385.92

Melting Point. . . . . . . .... . 182.3 182.8

Recrystallizing Solvent. . . . . ... .Propanol-2

Analyses:

Carbon, %

Calculated. .. .70.66

Found....... 70.65

Hydrogen, %

Calculated. . . 7.55

Found. . . . .7.65
Solubilities:

Water. ........ .Soluble

Ethanol. . . .... .Soluble

Acetone. . ... .Insoluble

Ether. . . ... .Insoluble













p-Bromobenzhydryl 2-(l-Piperidyl)-2-phenyl-propionate
Hydrochloride

O ^ V-Br /CH2-CH,\
CH=CH-C0 CH + H-N CH2 --CH
c \ ^CH,-CH,/

Br

G CH-CH,-COOCH

CH, CH,

CH, CH,
CH,

Fifteen grams of p-bromobenzhydryl cinnamate and

5.0 g. of piperidine were dissolved in 30 ml. of heptane,

and the solution was refluxed for twenty hours. After the

solution had been cooled to room temperature, it was washed

with three 30-ml. portions of distilled water. The organic

layer was then extracted with two 30-ml. portions of cold

3 N hydrochloric acid. These acid aqueous extracts were
combined and made basic to pH 8 by the addition of granular

potassium carbonate. The resultant oil was then extracted

with two 50-ml. portions of ether. The ethereal extracts

were combined and dried over anhydrous calcium sulfate.

The dry ether solution was treated with hydrogen chloride

until acid to Congo Red paper. The precipitated white

solid was recrystallized twice from propanol-2.


Yield: 4.8 g., or 24.4%.













p-Bromobenzhydryl 2- (1-Pipe ridyl) -2-phenyl-propionate
Hydro chloride




CH-CHS,--O-CH


CH, C -HHC1
CH^ C0H2 11


CH2


Molecular Formula.

Molecular Weight .

Melting Point. . .

Analyses:

Carbon, %


Calculated. .

Found . .

Hydrogen, %

Calculated.

Found . .


S. . . CH,,N 0,C01 Br

. . . . . .514.89

S. . . 179.5 180.5


. . .62.97

* . .62.53



. .- 5.68

. . 5.67


Solubilities:


Water. . .

Ethanol. . .

Acetone . .

Ether. . .


. . Soluble

. . Soluble

. . Insoluble

. . Insoluble













9-Fluorenyl 2-(l-Piperidyl)-2-phenyl-propionate
Hydrochloride


,CB0-CH,\
Q CH=H-C000-CH + H-N CH --1 *
\-- 01 G\CH,-CH,/




aN C-CHj-C OO-CH

CH, CH,
I I
CH, CH2
CH,


Fifteen and six-tenths grams of 9-fluorenyl cinna-

mate and 4.25 g. of piperidine were dissolved in 30 ml. of

heptane, and the solution was refluxed for twenty hours.

After the solution had been cooled to room temperature, it

was washed with three 30-ml. portions of distilled water.

The organic layer was then extracted with two 30-ml.

portions of cold 3 N hydrochloric acid. These acid aqueous

extracts were combined and made basic to pH 8 by the addi-

tion of granular potassium carbonate. The resultant oil

was then extracted with two 50-mi. portions of ether. The

ethereal extracts were combined and dried over anhydrous

calcium sulfate. The dry ether solution was treated with

hydrogen chloride until acid to Congo Red paper. The

precipitated white solid was recrystallized from propanol-2.


Yield: 3.0 g., or 13.8%.













9-Fluorenyl 2- (1-Piperidyl) -2-phenyl-propionate Hydrochloride


it -
CH-CH2-C-0-C

"N' s HC1
I H2 C H2
CH, CH,

CH,



Molecular Formula. . . . . . . .. C0,H,,N OgCl

Molecular Weight . . . . . . . . 433.96

Melting Point. ................. .192.5 193

Recrystallizing Solvent. . . . . Hexane-Propanol-2

Analyses:

Carbon, %

Calculated. . 74.72

Found. . ... .74.79

Hydrogen, %

Calculated. ... .6.50

Found. . . . 6.69

Solubilities:

Water. . . .... Soluble

Sthanol. . . . Soluble

Acetone. . .Slightly Soluble

Ether. . . .... Insoluble












Tetrahydrofurfuryl 2-(l-Piperidyl)-2-phenyl-propionate
Hydrochloride

H -OCH /CH,-CHH\
CH=CH-COO-CHa-CH CHa + H-N CH2 --*
0 PCHH-CHs/


O CHa- CH,
-YH-CH,-COO-CH,-CH CH,
N '0
CH2 CH2
I I
CH, CH,
CH,

Fifteen grams of tetrahydrofurfuryl cinnamate and

5.5 g. of piperidine were dissolved in 30 ml. of heptane,
and the solution was refluxed for twenty hours. After the

solution had been cooled to room temperature it was washed

with three 30-ml. portions of distilled water. The organic

layer was then extracted with two 30-ml. portions of cold

3 N hydrochloric acid. These acid aqueous extracts were
combined and made basic to pH 8 by the addition of granu-

lar potassium carbonate. The resultant oil was extracted

with two 50-ml. portions of ether. The ethereal extracts

were combined and dried over anhydrous calcium sulfate.

The dry ether solution was treated with hydrogen chloride

until acid to Congo Red paper. The precipitated white

solid was then recrystallized three times from propanol-2.


Yield: 4.8 g., or 13.5%.













Tetrahydrofurfuryl 2- (1-Pipe ridyl) -2-phenyl-propionate
Hydrochloride

1 9 CHa- CH,
CH-CH,-C-0-CH,-CH CH,
0
N HC
CH, CH,
I I
CH, CH,

CH,


Molecular Formula . . . . . . . Ca.12aN 0,C1

Molecular Weight. . . . . . . . . . 353.88

Melting Point. . . . . . . .... . 156.7 157.5

Recrystallizing Solvent. . . . . ... .Propanol-2

Analyses:

Carbon, %

Calculated. . .64.46

Found. . . . 64.10

Hydrogen, %

Calculated. . ... 7.98

Found. . . .. .8.16

Solubilities:

Water. . . . ... .Soluble

Ethanol. . . ... .Soluble

Acetone. . . Slightly Soluble

Ether. . . . . Insoluble












Ethyl 2- (1-Pyrrolidyl)-2-phenyl-propionate Hydrochloride



CQO =CH-COO-COHS + H-N I -I 0 C H7CHO-COOC0HB


CH, CH,
I i
CH- CH2


Thirty-five and two-tenths grams of ethyl cinnamate

and 14.2 g. of piperidine were dissolved in 30 ml. of toluene

and the solution was refluxed for twenty hours. After the

solution had been cooled to room temperature, it was washed

with three 30-ml. portions of distilled water. The organic

layer was then extracted with two 60-ml. portions of cold

3 N hydrochloric acid. These acid aqueous extracts were

combined and made basic to pH 8 by the addition of granu-

lar potassium carbonate. The resultant oil was then ex-

tracted with two 50-mi. portions of ether. The ethereal

extracts were combined and dried over anhydrous calcium

sulfate. The dry ether solution was treated with hydrogen

chloride until acid to Congo Red paper. The precipitated

white solid was recrystallized twice from propanol-2.


Yield: 10.3 g. or 18.2%.













Ethyl 2-(l-Pyrrolidyl)-2-phenyl-propionate Hydrochloride


QC -CHC-C-0-CH,CHa


I I
CH, c~H *HC1

CHr--CH2


Molecular Formula. . . . . . .... . .C,,eHN OaC1

Molecular Weight. . . . . . . . .... . 283.80

Melting Point. . . . . . . . . 175.5 176

Recrystallizing Solvent. . . . . ... .Propanol-2

Analyses:

Carbon, %

Calculated. . . 63.62

Found. . . ... .63.28

Hydrogen, %

Calculated. . . .7.82

Found. . . . . 7.76

Solubilities:

Water. . ... .Very Soluble

Ethanol. . . ... Soluble

Acetone. . . . Insoluble

Ether. . . . . Insoluble













Ethyl 2-(4-Morpholinyl)-2-phenyl-propionate Hydrochloride


Q CH=ICH-COO-CaHe + H-N 10H 0 --




QG H-CH-CHsOO-CSH

CH2 CH2
I I
CH2 CH,



Seventeen and six-tenths grams of ethyl cinnamate

and 8.7 g. of morpholine were dissolved in 30 ml. of toluene,

and the solution was refluxed for twenty hours. After the

solution had been cooled to room temperature it was washed

with three 30-ml. portions of distilled water. The organic

layer was then extracted with two 30-mi. portions of cold

3 N hydrochloric acid. These acid aqueous extracts were

combined and made basic to pH 8 by the addition of granular

potassium carbonate. The resultant oil was extracted with

two 50-mi. portions of ether. The ethereal extracts were

combined and dried over anhydrous calcium sulfate. The

dry ether solution was treated with hydrogen chloride until

acid to Congo Red paper. The precipitated white solid was

recrystallized three times from propanol-2.


Yield: 6.0 g. or 20%.













Ethyl 2-(4-morpholinyl)-2-phenyl-propionate Hydrochloride


S-H-CH,-C-O-CHe

CH, CH, C
I CI

0


Molecular Formula . .

Molecular Weight. . .

Melting Point . . .

Recrystallizing Solvent

Analyses:

Carbon, %


Hydrogen, %


Calculated. .

Found . .



Calculated. .

Found . .


. .C,,HaeN OsC

. . .299.80

S. . . 201

. .Propanol-2


. . 60.09

. . 60.43



. . .7.40

. . .7.49


Solubilities:


Very Soluble

. .Soluble

. *Insoluble

.Insoluble


Water. .

Ethanol.

Acetone.

Ether. .












Ethyl 2- [ 1-(4-Methyl)-piperidyl] -2-phenyl-propionate
Hydrochloride


(vD^CH=CH-COO-CgHB + H-N CIH-CH, --
^U-V-Y Y" CH,



CH-CH-C-COO-CaHe


CHa CH2
I I
CH, CH,
CH
CHa

Seventeen and six-tenths grams of ethyl cinnamate

and 9.9 g. of piperidine were dissolved in 30 ml. of hep-

tane, and the solution was refluxed for eight hours.

After the solution had been cooled to room temperature,

it was washed with three 30-ml. portions of distilled

water. The organic layer was then extracted with two

30-ml. portions of cold 3 N hydrochloric acid. These

acid aqueous extracts were combined and made basic to

pH 8 by the addition of granular potassium carbonate.

The resultant oil was extracted with two 50-ml. portions

of ether. The ethereal extracts were combined and dried

over anhydrous calcium sulfate. The dry ether solution

was treated with hydrogen chloride until acid to Congo

Red paper. The precipitated white solid was recrystal-

lized from propanol-2.

Yield: 5.3 g., -or 17%.













Ethyl 2-[ l-(4-Methyl)-piperidyl] -2-phenyl-propionate
Hydrochloride



( CH-CH-C-O-CH2CH,

/NC

C H,2 C H,


OH
CH,


Molecular Formula . . .

Molecular Weight. . . .

Melting Point . . . .

Recrystallizing Solvent

Analyses:

Carbon, %


Hydrogen, %


.H. . . . . .C1HsN OC1

. . . . . . 311.85

S. . . . . 215- 216

. . . . . .Propanol-2


Calculated.

Found . .



Calculated.

Found . .


65.47

. 65.42



. .8.42

. .8.40


Solubilities:


. . Very Soluble

. . . Soluble

. . . Insoluble

. . Insoluble


Water. .

Ethanol.

Acetone.

Ether. .













Ethyl 2-(1-Piperidyl)-2-(4-nitrophenyl)-propionate
Hydrochlor ide

/CHH-CH2\




NO,-- -CH-CH,-COO-CHe

CH, CHs
I I
CHO CH,
CH,

Fifteen and six-tenths grams of ethyl 4-nitro-

cinnamate and 6.0 g. of piperidine were dissolved in 30

ml. of heptane. To this solution was added 1 ml. of a

10% solution of tetramethylammonium hydroxide. The solu-

tion was refluxed for eight hours. After the solution had

been cooled to room temperature, it was washed with three

30-ml. portions of distilled water. The organic layer was

then extracted with two 30-mi. portions of cold 3 N hydro-

chloric acid. These acid aqueous extracts were combined

and made basic to pH 8 by the addition of granular potas-

sium carbonate. The resultant oil was extracted with two

50-ml. portions of ether. The ethereal extracts were com-

bined and dried over anhydrous calcium sulfate. The dry

ether solution was treated with hydrogen chloride until

acid to Congo Red paper. The precipitated white solid

was recrystallized twice from propanol-2.


Yield: 6.6 g., or 27.3%.













Ethyl 2-(1-Piperidyl)-2-(4-nitrophenyl)-propionate
Hydrochloride


NO,- -CHCH-CH-C-0-CHCH


CH2 CH2 *HC1
I I
CH, CH,
CH,


Molecular Formula . .

Molecular Weight. . .

Melting Point . . .

Recrystallizing Solvent

Analyses:

Carbon, %


Hydrogen, %


Calculated .

Found. . .



Calculated

Found. .


* ..C18H2NON204C

. . . .342.82

* . 191 192

S. . Propanol-2


. . .56.06

. .. .55.98



.* *. 676

. . 6.69


Solubilities:


Water. . .

Ethanol . .

Acetone . .

Ether. . .


* . .Soluble

* . Soluble

. Insoluble

. .Insoluble












1-Cinnamylpiperidine


a0/C1-CHs0T__
CH=OH-COOCHs + H-N HCH,
\-H,-CHC/

/=\ i O/CH,-CH,\
CH=CH-C-N CH, + CH,0H
Q- \OH0-CH,/


A mixture of 52.8 g. of ethyl cinnamate and

25.5 6g of piperidine was refluxed for seventy hours.

The unchanged reactants and ethanol were then removed by

distillation at 0.50 mm. Hg. When the temperature reached

800 the distillation was discontinued. After cooling to

room temperature the material in the pot solidified. This

was recrystallized twice from ethanol and washed with

petroleum ether.


Yield: 46.5 g., or 71.3.L















1-Cinnamylpiperidine


Molecular Formula . .

Molecular Weight . .

Melting Point . . .

Recrystallizing Solvent

Analyses:

Carbon, %


Hydrogen, %


Calculated. . .

Found . . . .



Calculated. . .

Found . . . .


. Ca4He8N 0

* . .215.29

* 118 119.5

* . Ethanol


78.14

78.23



7.97

8.03


Solubilities:


Water .

Ethanol

Acetone

Ether .


.. . . .Insoluble

. . . .Soluble

. . . .Soluble

. . . .Soluble


O B /CH,-CHg
-CE=CHs-C5-N CH2
\CH,-CH2


. . . . . .

. . . . . .

. . . . . .

. . . . . .
















Part 2: The Preparation of Intermediates


Amines

The piperidine used in this investigation was

practical grade material obtained from Matheson, Coleman,

and Bell Company. It was redistilled before use. The

fraction boiling at 1060 was collected.

The morpholine used was obtained from Carbide and

Carbon Chemicals Company. It was redistilled before being

used. The fraction boiling at 128 to 1290 was collected.

The pyrrolidine was purchased from the Brothers

Chemical Company. It was redistilled; the fraction boiling

at 86 to 87 was collected.

The 2-methylpiperidine, 3-methylpiperidine, and

4-methylpiperidine were formed by reduction of the cor-

responding methylpyridines. The freshly distilled methyl-

pyridine was reduced under 4000 lbs. pressure of hydrogen

at 2000 for eight hours, using a Raney nickel catalyst.

After the products had been decanted from the catalyst they

were distilled at atmospheric pressure. The 2-methyl-

piperidine boiled at 118-1190; the 3-methylpiperidine at

125-1260; the 4-methylpiperidine at 125-1260.












The 2-ainylpiperidine was obtained by the reduction

of 2-amylpyridine. The 2-amylpyridine was prepared by the

reaction of 2-methylpyridine and n-butyl chloride with

sodamide according to the method of Vaughn et al. The

2-amylpyridine boiled at 117-1200 at 40 nmm. Hg. It was

reduced at 2000 under a pressure of 2000 lbs. of hydrogen,

using a Raney nickel catalyst. The 2-amylpiperidine was

distilled at 40 mm. Hg.; it boiled at 115.5 to 1170. The

overall yield was 63.5%.

The di(n-butyl)amine was obtained from the Hooker

Electrochemical Company and was used without further puri-

fication.


Cinnamate Esters

The ethyl cinnamate was obtained from Brothers

Chemical Company. It was redistilled before using. The

fraction boiling at 128-1300 at 6.0 mm. Hg. was collected.

The beta-substituted cinnamate esters were prepared

by the Reformatsky reaction according to the method de-

scribed in "Organic Reactions," Volume I.18 Ethyl 2-ethyl-

cinnamate boiled at 106-1080 at 1.5 mm. Hg. Ethyl 2-phenyl-

cinnamate boiled at 153-1570 at 2.0 mm. Hg.

Ethyl 2-nitrocinnamate was prepared by the nitration

and esterification of cinnamic acid.19 The melting point of

this compound was 137-1380.













The unsubstituted cinnamate esters, other than the

ethyl ester, were prepared by reacting'cinnamyl chloride

with the corresponding alcohol in the presence of pyridine.

The cinnamyl chloride was formed by refluxing a benzene

solution of cinnamic acid and thionyl chloride for eight

hours. The solvent was then removed on the steam bath

under water pump vacuum. The cinnamyl chloride was then

used without further purification.

All of the unsubstituted cinnamate esters were

synthesized according to the same procedure. Two-tenths

of a mole of cinnamyl chloride was added portionwise, with

ice bath cooling, to a solution of 0.2 moles of the alcohol

and 0.2 moles of pyridine in 100 ml. of benzene. The

reaction mixture was allowed to stand at room temperature

for twenty-four hours. It was then extracted with three

50 ml. portions of distilled water. The organic layer was

separated and dried over anhydrous calcium sulfate. The

solvent was then removed by distillation on the steam bath

under water-pump vacuum. The residue was vacuum distilled.

The yields and physical constants of the products are listed

in Table 1.


















0 0 & -'N n





So G o N CM r\ 0A m aco
,A 0 o^ oo 11; A 4 A; o A;
L'- r- >l- r- co I-- co 'D Ir\ 'o


le
0




0

a



10
+I

I






0B
rl


(Da
kS:
0
ci-
p;


r H
r00 ri
cl^


o 0 lf\ 0 \ 0 0 0
U'A Vt\ rrl M N A \0
o O 0 0 0 0 0 0


0
-d o
IT ro

Ca 0'


co a'

co (rj
I I
c) a


0 o H


o r H


Irl

4-,
pip
H H )



S I 1 1 C4M rl S
a+ F [ o a o a P
-0 I I 0 C I 0 I 0 I
S CfI i n .H li CT sl p rl


r H


H- r-I i-A l-f


H f




























co r~- 0 _Y Or
CO O cGo -
L- co Q o ri


v\ -
~at
Eas
SCO


co
* CO
*0


a,
a4,
r-, -| 0





H
H "0 0

;4 0 a, 0 r



0 Pl N E- C
0 0. 0 N EI N


o
a,
0


a)

Hrl
Sa,
*<


a,



Va,


a,















Part 3: A Study of the Reaction of Heterocyclic
Amines with Cinnamate Esters


The experimental work described in this section was

undertaken to study various means of increasing yields of

2-(N-heterocyclic)-2-phenyl-propionate esters, and to in-

vestigate the nature of the reaction of a heterocyclic

amine with a cinnamate ester.

The effects of various solvents, catalytic sub-

stances, molar proportions of reactants, and reaction

times upon the yield were determined. In all of the work

on this phase of the problem ethyl cinnamate and piperidine

were used as the reactants. Unless otherwise noted, all

yields reported in this section refer to crude, unrecrystal-

lized product.

There are very few reports in the literature to the

reaction of amines with cinnamate esters. Some of the work

described here tends to clarify the chemistry of the reaction.

Data is presented which indicates the reversible nature of

the reaction. Secondary amines and cinnamate esters which

did not react are discussed because they tend to define the

scope and limitations of the reaction.













Percent Conversion


A solution of 17.6 g. (0.1 mole) of ethyl cinnamate,

8.5 g. (0.1 mole) of piperidine and 1 ml. of a 10% solution

of tetramethylammonium hydroxide in 30 ml. of toluene was

refluxed for twenty hours. After the solution had been

cooled, it was washed with three 30-ml. portions of distilled

water. The solution was then extracted with two 30-ml.

portions of 3 N hydrochloric acid. The organic layer was

separated, dried over anhydrous calcium sulfate and dis-

tilled under vacuum. Eight and nine-tenths grams of ethyl

cinnamate (n28 1.5593) boiling at 78-790 at 1.10 mm. Hg

were recovered. The aqueous acid extract was cooled, made

basic with granular potassium carbonate and extracted with

ether. The dry ethereal solution was treated with dry

hydrogen chloride, yielding 14.2 g. of ethyl 2-(l-piperidyl)-

2-phenyl-propionate hydrochloride.

Moles of ester used: 0.100

Moles of ester recovered: 0.0ol

Moles of ester reacted: 0.049

Moles of product isolated: 0.048

Percentage Yield: 48%

Percentage Conversion: 98%


~












The Effect of Various Solvents Upon Yield


Ethyl cinnamate and piperidine were refluxed in

various solvents for twenty hours. No catalysts were used.

The product was isolated as described on the preceding page.


Solvent

Toluene

Heptane

n-Butanol

None


Percentage Yield

26.5

20.1

20.8

23.4


The Effect of Catalysts Upon Yield


Two series of tests were run, one using heptane

as a solvent, the other using toluene. In each case the

substance was employed in the form of a 10% aqueous solu-

tion. One milliliter of the solution containing the cata-

lyst was added to a solution of 0.1 mole of each reactant

in 30 ml. of solvent.


Heptane, refluxed 8 hours:


Catalyst

Tetramethylammonium Hydroxide

Tetramethylanmonium Bromide

Sodium Hydroxide

None


Percentage Yield

32.9

11.1

8.7

8.5












Toluene, refluxed 20 hours:


Catalyst

Tetranethylammonium Hydroxide

Water

None


Percentage
Yield

47.7

26.9

26.5


The Effect of Reaction Time Upon Yield


Two series of tests were made, one using heptane

as the solvent, the other using toluene. In both cases

equimolar quantities of reactants were employed. The

product was isolated in the manner described on page 56.

The first test was run on a heptane solution of

the reactants, containing no catalyst. The temperature

was the reflux temperature of the solution.


Time in Hours

3

7
10

14
22

31

50.5

58

75


Percentage Yield

3.9

7.2

8.3

10.3

141.7

16.5

20.5

22.8

25.8




























C





\o o


0

\ 0 0 0

\ o0





P, OP
an >
*\ 4>




\ 0




\ oo
\0 .0
S0 0


-0 *0
HO





rl
0

0 5- OT 0

PIG-2x %
\ r^ -^o












The second test was run on a toluene solution of

the reactants, containing 5 ml. of a 10% solution of tetra-

me thylanmonium hydroxide. The temperature was the reflux

temperature of the solution.

Time in Hours Percentage Yield

5 20.3
10 36.0

15 40.5

20 45.1

25 43.2

The relationship of yield to reaction time for

these two runs is expressed graphically in Figures 1 and 2.



The Effect of Employing Excess Piperidine
Upon Yield

These tests were run in toluene solution, with no

catalyst. The solutions were refluxed for twenty hours.

Moles of Piperidine per Percentage Yield
Mole of Ethyl Cinnamate Crude Recrystallized

1 26.5 16.7

3 75.2 47.3







































































o5 Ott oc oz
PTOTL %


0

C O
0Hx




ao 4t
m *H





o o






A-H
H m

*H 0



E-i OE


o


*H

0 0




-p

0T 0
or +3












Negative Reactions


The pairs of substances listed below did not react

when refluxed eight to twenty hours in heptane or toluene

solution. The unchanged amine was isolated in each case.


(a) ethyl 2-phenylcinnamate and piperidine

(b) ethyl 2-phenylcinnamate and pyrrolidine

(c) ethyl 2-phenylcinnamate and 4-methylpiperidine

(d) ethyl 2-phenylcinnamate and morpholine

(e) ethyl 2-phenylcinnamate and 2-methylpiperidine

(f) ethyl 2-phenylcinnamate and 2-amylpiperidine

(g) ethyl 2-ethylcinnamate and piperidine

(h) ethyl 2-ethylcinnamate and pyrrolidine

(i) ethyl 2-ethylcinnamate and morpholine

(j) ethyl 2-ethylcinnamate and 4-nethylpiperidine

(k) ethyl 2-ethylcinnamate and 2-methylpiperidine

(1) ethyl 2-ethylcinnamate and 2-amylpiperidine

(m) ethyl cinnamate and 2-nethylpiperidine

(n) ethyl cinnamate and 2-amylpiperidine

(o) ethyl cinnamate and 1-phenylpiperazine

(p) ethyl cinnamate and di(n-butyl)amine


The expected beta-amino ester was not isolated when

the pairs of substances listed below were refluxed in toluene

solution for twenty hours. The unchanged olefinic ester was

recovered in each case.












(a) 2-(diethylanino)ethyl cinnamate and piperidine

(b) 2-(dimnethylamino)ethyl cinnamate and piperidine

(c) 3-(diethylamino)propyl cinnamate and piperidine

(d) 2- (2-methoxyethoxy) -ethyl cinnamate and piperidine


The following pairs of substances, when reacted,

yielded only viscous oils which could not be crystallized.


(a) ethyl cinnamate and 3-methylpiperidine

(b) ethyl cinnamate and 4-ethylpiperidine .

(c) p-methoxybenzyl cinnamate and piperidine

(d) benzhydryl cinnamate and piperidine

(e) p-methylbenzhydryl cinnamate and piperidine

(f) 1-phenylpropyl cinnanate and piperidine


Ethyl 2-phenylcinnamate and ethyl 2-ethylcinnamate

did not react with any of the heterocyclic amines. It is

probable that this is due to resonance and steric effects.

Because two phenyl groups are conjugated with the olefinic

bond in the 2-phenylcinnamate ester six nonreacting, com-

peting resonance forms are possible. Similarly in the case

of the 2-ethylcinnamate ester steric hindrance and resonance

effects due to hyperconjugation would tend to decrease the

reactivity of the ester.

Piperidines which are substituted in the alpha-

position do not react with cinnamate esters. Since the













electronic effects of such substitutions should tend to

increase the reactivity of the amine, the lack of reaction

must be due to steric causes.

The failure of 1-phenylpiperazine to react with

ethyl cinnamate is not surprising. Pollard and Robbins

found that 1-arylpiperazines did not react with 2-methyl-
25
acrylate esters, which could be expected to be more

reactive than the cinnamate esters.

The only aliphatic secondary amine used, di(n-butyl)-

amine, did not react. It has been stated that aliphatic

secondary amines in general give lower yields than the
8
heterocyclic amines when reacted with acrylate esters.

It may be that this general trend.applies to the reaction

of amines with cinnamate esters.

The failure to isolate any product from the reaction

of the dialkylaminoalkyl cinnamate esters with piperidine

may be due to the method of. working up the reaction mixture

rather than a lack of reactivity of the ester. Because the

product could not be separated from the cinnamate ester

by extraction with an acid solution, isolation was attempted

by vacuum distillation. Piperidine has the lowest boiling

point of any of the substances in the equilibria which is

probably involved. This could have shifted the equilibrium

in the direction of the reactants during the distillation.













In summary, a few generalizations can be made:

(1) Cinnamate esters which are substituted in the beta-

position with an alkyl or aryl group do not react with

heterocyclic amines. (2) Heterocyclic amines which are

substituted in the alpha-position do not react with cinna-

mate esters.


Stability of Products


In all cases the 2-(N-heterocyclic)-2-phenyl-

propionate esters were stable in the form of their hydro-

chloride salts. There was no evidence of decomposition in

aqueous solution or in boiling propanol-2. Pollard and
26
Stewart report that 4-chalcone morpholine is unstable

in the form of its hydrochloride salt.

Attempts to form quarternary salts of ethyl 2-

(1-piperidyl)-2-phenyl-propionate resulted in decomposition.

When methyl iodide was reacted with this compound at room

temperature N,N-dimethylpiperidinium iodide was formed.

This substance was identified by melting point and mixed

melting point with an authentic sample.


Evidence of the Reversibility

of the Reaction

An equimolar mixture of ethyl cinnamate and piperi-

dine was refluxed without a solvent. Periodically the re-

fractive index of this mixture was measured.

65












A sample of ethyl 2-(l-piperidyl)-2-phenyl-propionate
was refluxed without a solvent. The refractive index was
measured periodically.
A plot of refractive indices against time (Figure 3)
indicates that the two curves approach each other. That the
situation is more complex than a simple equilibrium can be
seen by the fact that the curves do not become constant at
a refractive index between that of the two starting materials.
The sharp upward break of the two curves could be considered
as an indication of formation of a third substance, 1-cinna-

mylpiperidine. This substance was isolated from both reac-
tion mixtures. Identification was made by melting point
and mixed melting point with an authentic sample of N-
cinnamylpiperidine.
This evidence would apparently indicate that the
reaction of heterocyclic amines with cinnamate esters in-
volves the following equilibria:




SCH=CH-C-0l Q + ROH


Q-CH=CH-COOR + H-NQ



V-C-CH,-C-OR


0
66



























0 ;1 0
p, n Nj
P, cd
S 'd 0 co
*j *- l H
I0
SHF-I
04) P -o
0 0



I d Hi
t o Cl






E- bO


co











00010






o0 0 0
o 0\ i f) 0 lrz
' (M r-H H 0
V\IIA If\ )\ Ij


xGpUi: GAT4qo1BJOIj


o o
0 0\
o m
* *
H H


















CHAPTER IV


SUMMARY


The addition of heterocyclic amines to cinnamate

esters has been shown to be a practical method of synthe-

sizing 2-(N-heterocyclic)-2-phenyl-propionate esters. The

effects of various conditions upon the yield have been

studied. Evidence has been obtained which indicates the

nature of the equilibria involved in this reaction. The

preparation of nineteen new 2-(N-heterocyclic)-2-phenyl-

propionate esters has been described in detail. The

properties of these compounds are summarized in Tables 2,

3, and 4.



























0





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BIBLIOGRAPHY


1. Otto Eisleb and 0. Schaumann, Deut. med. Wochschr. 65,
967-8, (1939).

2. Frederick F. Yonkman, Ann. N. Y. Acad. Sci. $1, 59,
(1948).

3. Victor A. Drill, "Pharmacology in Medicine," McGraw-
Hill Book Company, Inc., New York, 1954, page 19/8.

4. F. Bergel, N. C. Hindley, A. L. Morrison and H. Rinder-
knecht, J. Chem. Soc., 1944, 269.

5. A. D. McDonald, G. Woolfe, F. Bergel, A. L. Morrison,
and H. Rinderknecht, Brit. J. Pharmacol. Chemotherapy,
1, 4, (1946).
6. "The Chemistry of Acrylonitrile," American Cyanamid
Company, Synthetic Organic Chemicals Department,
30 Rockefeller Plaza, New York 20, N.Y., 1951, page 31.

7. "The Monomeric Acrylic Esters," 3rd Edition, Rohm and
Haas Company Washington Square, Philadelphia 5, Pa.,
1951, page 24.

8. N. H. Cromwell, Chem. Revs. 38, 83 (1946).

9. Elliot R. Alexander: "Principles of Ionic Organic
Reactions," John Wiley and Sons, Inc., New York, 1950,
page 149.

10. C. K. Ingold, "Structure and Mechanism in Organic
Chemistry," Cornell University Press, Ithaca, New
York, 1953, page 693.
11. C. K. Ingold and W. J. Powell, J. Chem. Soc., 119,
1976 (1921).

12. D. W. Adamson, J. Chem. Soc. 1949, Supplement Number 1,
page S-144.

13. C. A. Weisel, R. B. Taylor, H. S. Mosher and F. C.
Whitmore, J. Am. Chem. Soc. 67, 1071 (1945).












14. Ernst Philippi and Eberhard Gatter, Monatsh, 51, 253,
(1929).

15. Karl Morsch, Monatsh. 61, 299, (1932).

16. S. M. McElvain and Gilbert Stork, J. Am. Chem. Soc., 68,
1049 (1946).

17. T. H. Vaughn, R. R. Voght and J. A. Nieuwland, J. Am.
Chem. Soc. 56, 2121, (1934).

18. Organic Reactions Vol. I, Ralph L. Shriner, John Wiley
and Sons, Inc., New York, (1942), page 1.

19. C. L. Muller, Ann. Chem., Justus Leibigs 212, 126,
(1882).

20. Felix Weger, Ann. Chem., Justus Liebigs, 221, 74-6,
(1883).
21. Vorlander and Walter, Z. physik. Chem. 118, 13, 17.

22. J. J. Sudborough, K. J. Thompson, J. Chem. Soc., 83,
676.
23. Kalle and Company, German Patent, D. R. P., 127, 649,
(1902).
24. H. Gilman, L. C. Heckort, A. P. Hewlett and J. B.
Dickey, Iowa State Ceoll. J. Sci. 7, 419-28 (1933).

25. C. B. Pollard and R. Robbins, unpublished work.

26. C. B. Pollard and V. E. Stewart, unpublished work.
















BIOGRAPHICAL NOTES


Guy C. Mattson was born in Glenridge, New Jersey,

on January 3, 1927.

Mr. Mattson received the Degree of Bachelor of

Science at Union College, Schenectady, New York, in June,

1949. He attended Columbia University on a part-time basis

from September, 1949, to June, 1950. He was enrolled as a

part-time student in the Graduate School of The Polytechnical

Institute of Brooklyn, from September, 1950, to June, 1951.

He entered the University of Florida in June, 1952.

From September, 1949, to June, 1952, Mr. Mattson

was employed by the Warner-Chilcott Laboratories, as a

research chemist.

Mr. Mattson is a member of Kappa Sigma, a social

fraternity; a senior member of the American Chemical

Society; and a member of Gamma Sigma Epsilon, an honorary

chemical fraternity. He has held a Graduate Assistant-

ship from 1952 to 1954 and a Teaching Assistantship from

1954 to 1955 at the University of Florida.


















This dissertation was prepared under the direction

of the chairman of the candidate's supervisory committee

and has been approved by all members of the committee. It

was submitted to the Dean of the College of Arts and

Sciences and to the Graduate Council and was approved as

partial fulfillment of the requirements for the degree of

Doctor of Philosophy.


August, 1955




Dean, College of Arts and Sciences



Dean, Graduate School
SUPERVISORY COMMITTEE:


Chairman















































UNIVERSITY OF FLORIDA


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