• TABLE OF CONTENTS
HIDE
 Title Page
 Acknowledgement
 Table of Contents
 List of Tables
 List of Figures
 Introduction
 Results and discussion
 Experimental
 Summary
 Bibliography
 Biographical sketch
 Copyright














Title: synthesis of 2-phenylpiperazine and some derivatives.
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Title: synthesis of 2-phenylpiperazine and some derivatives.
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Table of Contents
    Title Page
        Page i
    Acknowledgement
        Page ii
    Table of Contents
        Page iii
        Page iv
    List of Tables
        Page v
    List of Figures
        Page vi
    Introduction
        Page 1
        Page 2
        Page 3
        Page 4
    Results and discussion
        Page 5
        Page 6
        Page 7
        Page 8
        Page 9
        Page 10
        Page 11
        Page 12
        Page 13
        Page 14
        Page 15
        Page 16
        Page 17
        Page 18
        Page 19
        Page 20
        Page 21
        Page 22
        Page 23
    Experimental
        Page 24
        Page 25
        Page 26
        Page 27
        Page 28
        Page 29
        Page 30
        Page 31
        Page 32
        Page 33
        Page 34
        Page 35
        Page 36
        Page 37
        Page 38
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        Page 40
        Page 41
        Page 42
        Page 43
        Page 44
        Page 45
        Page 46
        Page 47
    Summary
        Page 48
        Page 49
    Bibliography
        Page 50
        Page 51
    Biographical sketch
        Page 52
        Page 53
    Copyright
        Copyright
Full Text
THE SYNTHESIS OF 2-PHENYLPIPERAZINE AND SOME DERIVATIVES
By
HOWARD JEAN PLATTE
A DISSERTATION PRESENTED TO THE GRADUATE COUNCIL OF
THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY
UNIVERSITY OF FLORIDA June, 1962


ACKNOWLEDGMENT
Sincere thanks are extended to the chairmnn of his committee, Dr. Wo R. Roderick, whose unfailing and impeccable guidance, criticism and teachings have been immeasurably valuable throughout the research and preparation of this dissertation. The author is also grateful to the late Professor C. B. Pollard who initiated this research, to Commander N L. Smith (Ret.) for his moral support, to Professor R. V. Krumm for his able counsel in searching the literature and to the many graduate students that made graduate study at the University of Florida a rewarding experience.
The author wishes to thank the members of his committee for their interest and advice. He is also indebted to Parke, Davis & Company for the financial support which enabled him to pursue the research. In addition, the effort and patience contributed by Mrs. P. Ansell in typing this dissertation is sincerely appreciated.
Finally, without the encouragement and many sacrifices of his wife, Edna Dee, this work could not have been'completed.


TABLE OF CONTENTS
Page
ACKNOWLEDGMENTS ii
LIST OF TABLES v
LIST OF FIGURES vi
I INTRODUCTION 1
II RESULTS AND DISCUSSION 5
Studies of the cyclodehydration with
Raney nickel 5
A successful new synthetic route to 2-phenylpiperazine 8
An attenipt to prepare 2- (o-6ubst ituted-phenyl)piperazine6 11
Unsuccessful attempts to prepare 2-phenylpiperazine utilizing N-(p -hydroxy-P-phenylethyl)ethylenediamine 15
Unsuccessful attempts to prepare 2-phenyl-piperazine utilizing ., p -substituted ethylbenzenes 19
Unsuccessful attempts to prepare 2-(o-substitutedphenyl)piperazines 19
Unsuccessful attempts to prepare 3,5-
diketo-2-phenylpiperazine from ethyl
N- (<%-carboxamidobenzyl)glycinate or
N-(-carboxamidobenzyl)glycinamide 22
III EXPERIMENTAL 24
Studies related to the new synthesis of 2-phenylpiperazine 24
Preparation of l-alkyl-3-keto-2-phenyl-
piperazines 28
Preparation of l-alkyl-2-phenylpiperazines 31


TABLE OF CONTENTS Continued
Page
Preparation of 4-alkyl-2-phenylpiperazines 32
Preparation of l,4~dialkyl-2-phenyl-
piperazines 34
Studies related to the preparation of
2- (o_-substitutedphenyl)piperazine 35
Preparation of 2-phenylpiperazine by the
Pollard and Kitchen method 40
Unsuccessful attempts to prepare 2-phenylpiperazine by a new method 43
IV SUMMARY 48
BIBLIOGRAPHY 50
BIOGRAPHICAL SKETCH 52


LIST OF TABLES
Table Page
1 DERIVATIVES OF 3-KET0-2-PHENYLPIFERAZINE
AND 2-PHENYLPIFERAZINE 12


LIST OF FIGURES
Figure Pngc
1 A MECHANISM FOR THE CYCLIZATION OF COMPOUND
IX WITH SODIUM HYDRIDE 14
2 THE MECHANISM OF THE ALKYLATION OF ANILINE BY
BENZYL ALCOHOL IN THE PRESENCE OF BASE 18
3 THE MECHANISM OF THE ALKYLATION OF ANILINE BY
BENZYL ALCOHOL IN THE PRESENCE OF RAHEY NICKEL 18


I. INTRODUCTION
Among the vast spectrum of nitrogen-containing heterocyclic compounds, piperazine derivatives are in wide use as pharmaceuticals and to some extent in the preparation of nylon type polymers. Piperazine derivatives have exhibited useful applications as anthelmintics, as antihistamines, as tuberculostatic compounds, and as antimotion sickness compounds. The many useful applications of piperazine derivatives indicate the value of continued study.
The preparation of piperazine derivatives in the chemistry laboratories at the University of Florida has been carried out for the past thirty years under the able direction of the late Professor C. B. Pollard. In the forties work was initiated to develop a general method for the preparation of C-substituted piperazines. The thesis of Leland B. Kitchen,* later published in the Journal of the American Chemical Society, formed the basis of a patent covering the preparation of alkyl and aryl C-substituted piperazines. The synthesis, for the first time, of 2-phenylpiperazine provided a molecule of decided interest. Within the structure of 2-phenylpiperazine is a p -phenylethylamine unit, which is often responsible for sympathomimetic actions:


HN /NH)
4/''
v. /
The structural formulas of the following sympathomimetic compounds illustrate briefly some of the versatile combinations known to be of pharmaceutical value.
CH
CH
/
Q
H
N-CU
C---N
,CH0
H
amphetamine
iproniazid
HO
CHCH
NH
CH-
CH30---C H
.CH-
ephedrine
methylphenidate


CH3
"NH ' NH
/CH2-C^ / CH3
CH2CH2CH2CH2
\ /
methylaminoheptane phenmetrazine
A listing of several structural features of these compounds, with some further subdivision, will provide a general review of structures that have been useful:
lo An aromatic nucleus: phenyl, pyridyl, indyl,
naphthyl, monosubstituted phenyl, disubstituted phenyl, and trisubstituted phenyl, (Exceptions to the need for an aromatic nucleus are found in a few derivatives where the aromatic nucleus has been replaced by cyclopentyl, cyclohexyl, n-butyl, or iso-butyl groups.)
2. Basic nitrogen: primary, secondary, and tertiary amines.
3. Separation of the aromatic nucleus from the basic nitrogen: a two carbon unit or a carbon-nitrogen unit.
The purposes of this research can be divided into two areas: I. Preparation of 2-phenylpiperazine by improvements
on the Pollard and Kitchen method or by a more facile
new route.


2. Preparation of three series of compounds: 1-alkyl-, 4-alkyl-, and 1,4-dialkyl-2-phenylpiperazines, where the alkyl groups are methyl, ethyl, n-propyl and benzyl.
The derivatives of 2-phenylpiperazine and related compounds prepared during the course of this research were submitted to Parke, Davis & Co. for pharmacological screening.


II. RESULTS AND DISCUSSION
Studies of the cycle-dehydration with Raney nickel
Before serious consideration was given to a new synthetic route to 2-phenylpiperazine, the Pollard and Kitchen synthesis was repeated. The preparation of 2-phenylpiperazine by this method involves a sequence of two reactions:
r H2N
HO
C6H5 + H2N-CH2-CH2-NH2 ~-*" C6H5 nickel HN NH
NH
/
HN K
C6H5
The first step, the preparation of N- -hydroxy- -phenyl-ethyl)ethylenediamine, consisted of adding one mole of styrene oxide in methanol to two moles of ethylenediamine in methanol. After the addition was completed, the temperature rose sufficiently to cause the methanol to reflux. A precipitate (designated as by-product) which formed during the reaction period was removed after the temperature of the solution returned to room temperature. The methanol was then removed by distillation at atmospheric pressure leaving an orange, oily liquid. This liquid was distilled at reduced pressure giving an orange-yellow product which solidified as it was collected. The solid, representing a 60% yield based on the amount of styrene oxide used, was purified by recrystallization from benzene rather than from a


mixture of hexane and absolute ethanol as employed by Pollard and Kitchen.
Benzene was chosen after some experimentation because of several factors. After noting that N-(p -hydroxy-> -phenylethyl)-ethylenediamine was very hygroscopic, it seemed difficult to rationalize the use of a hydrophilic solvent like absolute ethanol. When the hexane and absolute ethanol mixture was used, an oily layer separated from the main body of the solution; it was difficult to initiate crystallization and to filter the recrystallized product when it was obtained The gummy product obtained from the first recrystallization had to be recrystallized several more times before pure N-( -hydroxy-p -phenylethyl)ethylenediamine was obtained. The problem of purification could have been the result of a tenacious impurity which was removed only after a series of treatments. However, since relatively small amounts of water could have been responsible for the persistent gumminess of impure preparations of this compound, the product from the vacuum distillation was dissolved in benzene and any water removed by azeotropic distillation. Small amounts of water were found and when the solution was cooled slowly to room temperature, well-defined crystals formed. The product from this first recrystallization was slightly yellow, but the color could be removed by a second or at most a third recrystallization.
The by-product from the reaction of styrene oxide with ethylenediamine was recrystallized from N,N-dimethylformamide, giving a pure, shiny, flake-like substance. Analytical data were consistent with a bisG^ydroxyphenylethyl) adduct of ethylenediamine. Since it would be most unlikely for two hydroxyphenylethyl units to be on the


same nitrogen of ethylenediamine, only three reasonable structures (I, II, III) can be drawn:
oh oh
c6h51hch2nh-ch2ch2nhch2chc6h5
I
oh c6h5
c6h5chch2nhch2CH2nh-chch2oh
II
?6H5 HOCILjCHNH-CHgCHjNHCHCHgOH
III
Steric effects encountered by ethylenediamine in its attack on the
molecule of styrene oxide, indicate attack at the beta carbon would
be favored over attack at the alpha carbon.^ If the reaction path is
controlled by steric factors, the major product would have the
structure I. No further characterization was attempted.
The purified N-(p -hydroxy-^ -phenylethyl)ethylenediamine
5,6
dissolved in dioxane was mixed with a slurry of Raney nickel in dioxane and sealed in an autoclave. The autoclave was filled with hydrogen to 500 psi., heated, and then finally cooled. The spent catalyst was removed by filtration while the dioxane and water formed during the reaction were distilled. The residual orange liquid was fractionated at reduced pressure giving 2-phenylpiperazine and a sizeable recovery of N-(p -hydroxy-p -phenylethyl)ethylenedianvine. The yield of 2-phenylpiperazine in several preparations ranged from


20-30%, while 50-70% of N-(p -hydroxy-p -phenylethyl)ethylenediamine was recovered. Since the formation of 2-phenylpiperazine may be governed by an equilibrium between itself and N-(|i -hydroxy-^ -phenylethyl)ethylenediamine, an attempt was made to remove water from the reaction by having anhydrous sodium sulfate present in the reaction mixture. The yield (21.2%) of 2-phenylpiperazine obtained from this treatment, however, was the lowest obtained in any of the Raney nickel catalyzed reactions. Apparently the sodium sulfate reduced the activity of the catalyst. Further study of the Pollard and Kitchen synthesis was abandoned, since only 7rl5% overall yields of pure 2-phenylpiperazine could be expected from this long, tedious process. Therefore, consideration was given to the development of a new synthetic route.
A successful new synthetic route to 2-phenylpiperazine
Ethyl ct-bromophenylacetate (IV) was prepared'' and allowed to react with ethylenediamine^ in order to obtain ethyl crt-(p-amino-ethylamino)phenylacetate (V). The pyrolysis of this compound should cause ring closure to the lactam (VI), which on reduction with lithium aluminum hydride would give 2-phenylpiperazine (VII). Interestingly, the lactam (VI) formed directly in the reaction of IV with ethylene-diamine. The reduction of VI with lithium aluminum hydride proceeded smoothly to the desired product, VII.
Preparation of 2-phenylpiperazine (VII) by this new method was much easier to carry out in the laboratory than the original synthesis developed by Pollard and Kitchen. It eliminated the use of pressure apparatus, gave purer or more easily purified products, and


resulted in an overall yield of 2-phenylpiperazine two to three times greater than that obtained by Pollard and Kitchen.
V VI
HN NH
\ /
C6H5
VII
However, a more subtle development was derived from the new synthesis. In order to prepare the two mono N-substituted derivatives of 2-phenylpiperazine using 2-phenylpiperazine, a major difficulty is called to attention. Obviously, if 2-phenylpiperazine were alkylated by an alkyl halide, the alkyl group would preferentially attack one reaction site over the other. Because of the steric blocking imposed on the 1-position by the phenyl group, it is reasonable to assume that this position would be attacked only after the 4-position had been substituted. For example, it has been shown that 2-methylpiperazine


is substituted initially in the 4-position and then finally substituted in the 1-position.9 However, proving this unequivocally is another matter. The following set of equations illustrates how both mono-substituted derivatives could be prepared.
-6n5
0
hn
NCOEt
J
1. RX 2
base
1. RX
2. base
HN
/ \
c6h5
-6n5
NR
Since the infrared spectra of the two monosubstituted derivatives would probably not have great enough differences for identification purposes, some unequivocal synthesis is needed to prepare at least one if not both monosubstituted derivatives. The lactam, 3-keto-2-phenylpiperazine (VI),* avoids this problem by providing an internal protecting group for the 4-nitrogen atom. Alkylation of VI can take place only at the one basic amine nitrogen.
*The naming of compound VI presents a problem. Since the keto function takes precedence over the phenyl group, the name should be 2-keto-3-phenylpiperazine. In order to maintain the "2-phenyl" nomenclature throughout, VI will bear the name 3-keto-2-phenyl-piperazine.


The resulting alkyl derivatives were reduced with lithium aluminum hydride to produce unequivocally the l-alkyl-2-phenylpiperazines. Preparation of the raonoalkyl-2-phenylpiperazines from 2-phenylpiperazine gave different compounds, which were assigned the 4-alkyl-2-phenylpiperazine structure. It was also shown that the 4-nitrogen of VII was almost completely alkylated before the 1-nitrogen. When a Bolution of equimolar amounts of VII and alkylating reagent was refluxed, the final product did not show the presence of the dialkyl derivative. In the cases where the alkyl halides were methyl iodide or ethyl iodide, a small amount of dialkyl product was detected. The l,4-dialkyl-2-phenylpiperazines were prepared using two or three equivalents of alkylating reagent. Table 1 shows the various compounds prepared, their melting points or boiling points and per cent yields. An attempt to prepare 2-(q-substitutedphenyppiperazines
Since much of the pharmacological activity of many aromatic compounds has been attributed to polysubstitution of the aromatic nucleus, it seemed reasonable to study possible synthetic routes to the phenyl-substituted 2-phenylpiperazines.
During the course of this investigation several routes were followed without appreciable success. However, one route, as outlined in the sequence below, showed some promise. If 2-phenylpiperazine could be prepared by the following sequence of reactions, it seemed reasonable that replacement of benzaldehyde with suitably substituted benzaldehydes might lead to many 2-(substitutedphenyl)piperazines.


Table 1
DERIVATIVES OF 3-KETO-2-PHENYLPIPERAZINE AND 2-PHENYLPIPERAZINE
R
m.p.,C. Yield, 7. b.p. (m.p.) ,C. Yield, 7. b.p. (m.p.),C. Yield, 7. b.p. (m.p.),C. Yield, 7.
CH~- 130- -132 20.0 78-80/0.1 mm. 49.7 95/0.4- 50.5 88/0.5 mm. 59.6
0.5 mm.
CH^CI^ 99. -101 80.7 90/0.5 mm. 65.2 91-93/0.7- 81.6 93- 95/0.3- 82.5
0.8 mm. 0.4 mm.
CHjCiLyCiL^ 89.5- 92.0 71.4 (61.5-66.5) 82.7 91-94/0.3- 64.8 106- 110/0.7- 68.0
0.4 mm. 0.9 mm.
C6H5CH2- 224- 226 d. 82.1 (101.5-102.5) 61.4 110/1.5 mm. 62.5 (109 .5-110.5) 65.3
(55-63)
C6H5CH2CH2-^0 CH3C-" 144- 145 50.0
161- 162 54.4


IX X VII
The formation of VIII10*11,12 and its conversion to the 13
ester-amide IX havebeea reported. The ester-nitrile was prepared by ultraviolet irradiation of a mixture of ethyl glycinate hydrochloride, benzaldehyde, and potassium cyanide in diethyl ether with a small amount of water present. Several attempts to prepare VIII were made before success was realized. The somewhat vague nature of the report of the original preparation of VIII caused difficulties in deciding upon the most ideal method. The use of an artificial ultraviolet source greatly reduced the reaction time reported by Stadnikoff, who had to depend upon sunlight as his source of ultraviolet radiation. The impure VIII waB added slowly to concentrated sulfuric acid giving a deep red-brown solution which was allowed to stand for


twelve hour6 and then was neutralized with a solution of ammonia in absolute ethanol.
Of the many experiments run in order to cyclize IX to form X, the most favorable results were obtained when IX was subjected to the action of sodium hydride. The reaction using sodium hydride was attempted on the basis of the mechanism outlined in Fig. 1 and also since sodium hydride has been useful in the preparation of N-substituted amides from simple amides.1^
salt of X
FIG. 1. A MECHANISM FOR THE CYCLIZATION OF COMPOUND IX WITH SODIUM
HYDRIDE
This proposed cyclization was applied to the formation of X where two equivalents of sodium hydride for each equivalent of IX were mixed in xylene which had been freshly distilled from sodium hydride. The mixture was refluxed for twenty hours and then treated with glacial acetic acid to convert all the sodium salts present to sodium acetate.


Large amounts of decomposition during the reaction reduced the yield
of products to approximately 507. The product was crystallized
from xylene and washed with diethyl ether to remove absorbed
xyleneo A small crystalline residue was obtained from the ether
washings which, surprisingly, had a somewhat different spectrum than
the original product. Since the infrared spectrum of the major
product indicated the presence of an imide, a sample of this material
was subjected to the action of lithium aluminum hydride*-*^ in diethyl
ether giving some oils interspersed with crystalline materials. An
infrared spectrum of this impure substance contained the major bands
found in the infrared spectrum of 2-phenylpiperazine and also contained
a carbonyl band.
The above studies presented in this dissertation have provided
a new synthesis of 2-phenylpiperazine which is an improvement over the
previously known preparation of 2-phenylpiperazine and also have
provided a practical method for preparing the two mono-N-alkyl-
substituted derivatives of 2-phenylpiperazine. An additional new
synthetic route has been explored which is potentially a general
method for the preparation of 2-(substitutedphenyl)piperazines.
Unsuccessful attempts to prepare 2-phenylpiperazine utilizing N--hydroxy-y9 -phenylethyl)ethylenediamine)
Since large amounts of N--hydroxy-yfl -phenylethyl)ethylene-diamine (XI) were readily prepared, several reaction paths were investigated to obtain 2-phenylpiperazine (VII).
The use of thionyl chloride in an attempt to obtain XII gave conflicting results and no indication of the desired products.


B2 ,m S0C12 "2" /"' i. heat
V
J
C6K5
HO / -CI / 2. b
XI
>ase
VII
The difficulty may involve the reaction of primary and secondary
amines with thionyl chloride.1^
RNH2 + S0C12 > RN=S=0 R2NH + S0C12 > K2NSMR2
By heating XI in various solvents which form azeotropes with water, it was thought possible to cause ring closure by removing water as it formed No evidence for the formation of water was ever obtained, and extreme decomposition during reflux in nitrobenzene made the isolation of identifiable products impossible.
Attempted oxidation of the alcohol (XI) to the corresponding ketone (XIII) was unsuccessful as far as the experiments were pursued.


VII
XIII XIV
When nitric acid was used as the oxidizing agent, the starting
material XI was recovered with some decomposition. When a mixture
of potassium dichromate and sulfuric acid was used, benzaldehyde,
benzoic acid, and starting material were obtained. Since the recovery
of starting material in this case wa6 high and no other fragments but
benzoic acid and benzaldehyde were found, it appeared that the
oxidation*^ either proceeded all the way to benzaldehyde and benzoic
acid or did not occur at all.
Another approach was suggested by the alkylation of amines by 20-25
alcohols. It was shown that the Raney nickel U6ed in these
alkylations could often be replaced by a strong base such as alkoxide ion. For example, benzyl alcohol was treated with potassium to obtain the benzyloxy ion. Benzaldehyde was present in the benzyl alcohol in small but significant enough quantities to allow the formation of benzalaniline by its condensation with aniline. The benzalaniline then removed hydride from the benzyloxy ion and hydrogen ion from benzyl alcohol to form respectively benzaldehyde and benzyloxy ion, while the benzalaniline was converted into the final product, benzylaniline (Fig. 2).


C6H5CH2OH -!2L>. C6H5CHO (catalytic amount)
C6H5CH0 + H2NC6H5--^ CgHgCH-NCgHj +
0 0
C6H5CH=NC6H5 + C^CH^ -- CgHgC^NC^ + C6H5CHO
.
CgHjCHjjjjCgHg + C6H5CH2OH -> CgHgCHgNHCgHj + C^C^Q:
Net result:
C6H5CH2OH + HgNCg^ --> CgHgCHgNHCgHg + HgO
FIG. 2. THE MECHANISM OF THE ALKYLATION OF ANILINE BY BENZYL ALCOHOL
IN THE PRESENCE OF BASE
Fig. 3 illustrates the proposed function of Raney nickel in an oxidation-condensation-reduction type of sequence.
C^CHgOH + Ni -C6H5CHO + Nitf^)
CgHgCHO + HjNCgHg ->- C6H5CH=NC6H5 4- HgO
C6H5CH=NC6H5 + Ni(H2) -> CgHjCHgNHCgHg + Ni
FIG. 3. THE MECHANISM OF THE ALKYLATION OF ANILINE BY BENZYL ALCOHOL
IN THE PRESENCE OF RANEY NICKEL
Since Pollard and Kitchen successfully utilized Raney nickel to convert N-(p -hydroxy-^ -phenylethyl)ethylenediamine into 2-phenylpiperazine, it seemed reasonable to ascertain whether the nickel catalyst could be replaced by a base. Refluxing the alkoxide ion of N- (> -hydroxy-(5 -phenylethyl) ethylenediamine in toluene gave no 2-phenylpiperazine so an imine was introduced into the reaction mixture in order to initiate the formation of the desired carbonyl compound. Again, no 2-phenylpiperazine was obtained.


Unsuccessful attempts to prepare 2-phenylpiperazlne utilizing sc. p-substituted ethylbenzen.es
cC,p -substituted ethylbenzene derivatives were also considered as possible intermediates to VII.
C6H5 C CRjBr + (NHjCI^ XV
C6H5CHBrCHjBr + (NIL^CH^ ->- VII
XVI
C6H5CHCICI^I + (NHgCHpg -*- VII
XVII
The reaction of phenacyl bromide with ethylenediamine was studied in detail but appeared useless in the eventual preparation of 2-phenylpiperazine (VII). There was a problem in identifying the products of the reaction, since polymeric substances seemed to predominate. If XV were less reactive than demonstrated, XIV would have been an expected product, which would undergo reduction to VII. The reaction of The diacetyl derivative of VII was subjected to a direct nitration. A mixture of cupric nitrate and acetic anhydride was


chosen because nitrations with this mixture have been shown to proceed preferentially at the -position of mono-alkyl substituted benzene derivativeso '
No isolable product could be found when the reaction mixture was worked up.
Coumaranone (XIX) was prepared by fusing o-hydroxyphenyl-acetic acid 02N


When o-nitrophenylacetic acid (XXI) was allowed to react, as
shown in the following sequence, to form ethyl et-bromo(o-nitrophenyl^ 31
acetate (XXII), extensive decomposition gave a brown, tarry mass. Since isolation of a product at this point was unsuccessful, the brown, tarry mass was subjected to the reaction of ethylenediamine. Again, a pure substance could not be isolated.


1. S0C1,
2. Br2
3. 100% EtOH
I
.CHBr-COEt H2N.
XXI
XXII
[H]
Unsuccessful attempts to prepare 3,5-diketo-2-phenylpiperazine from ethyl N-( q--carboxamidobenzyl)glyclnate or N-(^-carboxamidobenzyl)-glyclnamlde
r
-OEt
HN
r
HN
\
C6H5 \>
06%
IX
0
-NHr
I
-NH2
XXIII
Pyrolysis of IX at reduced pressure resulted only in its sublimation, and no other products were detected. Treatment of IX with concentrated ammonia solution gave a substance the infrared spectrum of which indicated that hydrolysis of the ester group had taken place and no imide (X) had formed. However, pyrolysis of this unidentified material at reduced pressure only caused decomposition and gave no identifiable product. The attempted cyclization of IX


in a solution of concentrated hydrobromic acid and glacial acetic
acid gave no isolable product. This apparent loss of product may
33
be attributed to the ease of hydrolysis of six-membered imides.
The hydrolysis of the expected imide (X) or even of IX would give
an amino acid, and Zwitterion formation would produce an ionic
species the isolation of which would be extremely difficult. Success-
34 35
ful conversion of IX to XXIII gave a compound which could possibly be pyrolyzed to form the imide (X). Pyrolysis of XXIII gave a large amount of decomposition; a small amount of starting material sublimed.


III. EXPERIMENTAL*
Studies related to the new synthesis of 2-phenylplperazine
Preparation of <*-bromophenylacetic acid.--The method of Bruce and Sutcliffe was employed with some modifications. A solution of 572 ml. of 487. hydrobromic acid and 141 ml. of concentrated sulfuric acid was placed in a 2000 ml. round-bottom, standard taper flask fitted with a reflux condenser. A solution of 397 g. (2.61 moles) of mandelic acid in 141 ml. of concentrated sulfuric acid was added slowly while the solution in the flask was stirred with a magnetic stirring bar. After the addition was completed, the mixture was refluxed (125-130) for three hours. The mixture was then cooled to about 10 and poured into 2 1. of crushed ice. The product was extracted with diethyl ether. The ether was removed and the crude product was distilled at 152/3.0 mm. Decomposition at a pot temperature of 170 gave a sudden release of hydrogen bromide causing the yield of distilled acid to be only 307..
The same procedure was repeated through the addition of the reaction mixture to crushed ice. The resulting orange oil was removed, washed with four 250 ml. portions of water and set aside to recrystal-lize. The solid produced was washed with three 100 ml. portions of
*Melting points and boiling points are not corrected. Analyses were performed by Drs. Weiler and Strauss, Oxford, England, and by the Galbraith Microanalytical Laboratories, Knoxville, Tennessee.


hexane. This removed all oils and gave the product in a 74% yield.
Very little product was obtained from the oils extracted by the hexane.
37
Preparation of -bromophenylacetamide. -Bromophenyl-acetyl chloride was prepared by refluxing 21.5 g. (0.1 mole) of Preparation of ethyl a.-bromophenylacetate.A solution of 408 g. (3.0 moles) of phenylacetic acid and 291 ml. (4.0 moles) of thionyl chloride and 250 ml. of benzene were placed in a 2000 ml., round-bottom, three-neck, standard taper flask. For this part of the reaction a reflux condenser was set up in the center neck and the other two necks were stoppered. After the mixture was refluxed for two hours, one of the stoppers was replaced with an addition funnel containing 161 ml. (3.15 moles) of bromine. The bromine was added dropwise, since the bromination reaction was vigorous enough to cause a gentle reflux and a strong evolution of hydrogen bromide. The bromine was added over a two hour period and then the gentle reflux was maintained by heating for one more hour. The reaction mixture stood for twelve hours and then was added cautiously to 875 ml. (15.0 moles) of absolute ethanol. This mixture, after standing two hours, was poured into 500 ml. of distilled water and extracted with five 150 ml. portions of ether. The combined ether extracts were


Z6u
washed with water, then with a 5% sodium bicarbonate solution, and finally with water. The ether extract was dried over anhydrous sodium sulfate, and the ether was removed under aspirator vacuum leaving an orange-brown residue. This was distilled under vacuum and the product was collected from 89.5-93.0/0,3-0.4 mm. to give 630 g. (93.3% yield) of purified ethyl a-bromophenylacetate. Caution must be exercised toward the end of the distillation, since decomposition occurs releasing hydrogen bromide. Also noteworthy of mention is the fact that ethyl *-bromophenylacetate is not only a lachrymator but is also a powerful vesicant.
Preparation of 3-keto-2-Phenvlpiperazine.~A solution of 68 ml. (1.0 mole) of ethylenediamine and 750 ml. of absolute ethanol was placed in a 2000 ml. round-bottom, single neck, standard taper flask fitted with a reflux condenser topped by an addition funnel which contained 121.5 g. (0.5 mole) of ethyl -bromophenylacetate. The addition was made dropwise as the solution below was stirred with a magnetic stirrer. After the addition was completed, a sodium ethoxide solution, prepared by adding 11.5 g. (0.5 mole) of Bodium to 100 ml. of absolute ethanol, was added as the reaction mixture was stirred. The unchanged ethylenediamine and ethanol solvent were removed on a steam bath under aspirator pressure. As the volume of solution decreased, precipitation occurred, when most of the solvent and ethylenediamine had been removed, leaving a light yellow-orange residue. Treatment of this with five 100 ml. portions of boiling acetone extracted the 3-keto-2-phenylpiperazine and small amounts of sodium bromide. The 3-keto-2-phenylplperazine was purified by recrystallization instead of distillation since it showed marked


decomposition at the boiling point 190-200/1.0 mm. Recrystallization from benzene removed the sodium bromide, and finally recrystallization again from acetone gave a fairly pure product which melted at 139.0-139.5.
The somewhat unsatisfactory analysis could not be satisfactorily explained. When the lactam was further recrystallized three times from water and two times from acetone, the analysis (C, 68.44; H, 7.02; N, 15.62.) was in better agreement with the calculated values. Furthermore, the N-alkyl derivatives all gave satisfactory analyses. It appeared, therefore, that the product was the expected lactam with a small amount of some impurity. Possible by-products which might have been formed are indicated below:
Anal. Calcd. for C]_oHi20N2: C, 68.16; H, 6.86; N, 15.90.
Found: C, 67.62; H, 6.90; N, 15.40.
C6H5
C6%
C12H1802N2
C22H284N2
C12H20ON4
C, 64.84 H, 8.16 N, 12.60
C, 68.72 H, 7.34 N, 7.29
C, 60.99 H, 8.53 N, 23.71


C10H142N2
C, 61.83 H, 7.27 N, 14.42
Of these, the first, is the mo6t likely impurity since it is probably an intermediate in the cyclization to the lactam. A mixture of 90% 3-keto-2-phenylpiperazine and 10% of this compound, ethyl N-(>-aminoethyl)- <^--aminophenylacetate would have a composition (C, 67.80; H, 6.98; N, 15.40) approximating that observed.
As the crude 3-keto-2-phenylpiperazine was extracted from the inorganic bromide, the acetone mother liquor turned progressively darker as it stood at room temperature. Since this seemed to lower the yield of 3-keto-2-phenylpiperazine, recrystallization was carried out rapidly. When the mother liquor was evaporated, a dark brown viscous residue was obtained from which no 3-keto-2-phenylpiperazine was ever recovered. A solution of purified 3-keto-2-phenylpiperazine in acetone did not develop a color on standing. Further study to ascertain the cause of the original coloration during the purification procedure was not attempted.
Preparation of l-alkyl-3-keto-2-phenylpiperazines
l-Methyl-3-keto-2-phenylpiperazine.--Methylation of 3-keto-2-
38
phenylpiperazine utilizing a mixture of formaldehyde and formic acid gave poor results (approximately 20% yield). The poor yield was attributed to the fairly high solubility of the product in water.


The 3-keto-2-phenylpiperazine, 17.5 g. (0.0996 mole), was refluxed four hours with 8.92 g. (0.11 mole) of 37% formalin and 12,25 g. (0.20 mole) of 77.5% formic acid in 100 ml. of water. After the reflux period, 9.42 ml. (0.11 mole) of concentrated hydrochloric acid was added resulting in a precipitate which was removed. Recrystallization of this solid from benzene gave 3.85 g. (approximately 20% yield) of colorless crystals, m.p. 130-132.
The aqueous formalin, foamic, acid, hydrochloric acid
solution was not treated further to obtain more product. This
solution should have been worked up, since the product was found to
be quite soluble in water.
Anal. Calcd. for CnRu0H2: C, 69.44; H, 7.42; N, 14.73.
Found: C, 69.50; H, 7.44; N, 15.05.
l-Ethvl-3-keto-2-phenylpjperazine.A slurry composed of
8.75 g. (0.05 mole) of 3-keto-2-phenylpiperazine, 4.45 ml. (0.055
mole) of ethyl iodide, 100 ml. of acetone and 3.40 g. (0.10 mole)
of sodium bicarbonate was refluxed for six hours. The insoluble
portion was removed and the solution was evaporated to dryness.
Recrystallization from hexane gave 8.23 g. (80.7% yield) of colorless
needles, m.p. 99-101.
Anal. Calcd. for C^H^Ol^: C, 70.56; H, 7.90; N, 13.72.
Found! C, 70.27; H, 7.71; N, 13.69.
l-n-Propyl-3-keto-2-phenylpiperazine.This derivative was
prepared by the same method used in the preparation of l-ethyl-3-keto-
2-phenylpiperazine, except that 20.9 ml. (0.150 mole) of triethyl-
amine was used instead of sodium bicarbonate and 100 ml. of toluene
was used instead of acetone. After the reflux, the insoluble solids


were removed and the oily residue obtained from the evaporation of the toluene was extracted with ether giving 2.28 g. (71.4% yield) of colorless needles, m.p. 89.5-92.0 d., which tended to turn yellow within a few days. This product was somewhat difficult to purify, but recrystallization from acetone by slow cooling in an acetone-dry ice bath and finally from diethyl ether at room temperature, produced fine needles melting at 87-90 with no decomposition.
Anal. Calcd. for Cj.3H180N2: C, 71.52; H, 8.31; N, 12.83.
Found: C, 71.60; H, 8.35; N, 13.01.
l-Benzyl-3-keto-2-phenylpiperazine.This preparation was
executed in a manner similar to the preparation of the preceding
derivatives using 6.51 ml, (0.055 mole) of benzyl bromide, 8.75 g.
(0.050 mole) of 3-keto-2-phenylpiperazine and 8.33 ml. (0.060 mole)
of triethylamine. After a reflux period of one hour, the product was
isolated and recrystallized from acetone giving 10.91 g. (82.1% yield)
of needlelike colorless crystals, m.p., 224-226 d.
Anal. Calcd. for C17H18ON2: C, 76.66; H, 6.81; N, 10.52.
Found: C, 76.61; H, 6.89; N, 10.34.
l-Acetyl-3-keto-2-phenylpiperazine.--A 8.75 g. (0.050 mole)
sample of 3-keto-2-phenylpiperazine in 100 ml. acetone was acetylated
with 5.65 ml. (0.06 mole) of acetic anhydride by heating the mixture
on a steam bath for 15 minutes. The acetone was evaporated leaving
a residue which was recrystallized from hot water giving 5.94 g.
(54.5% yield) of platelike colorless crystals, m.p., 161-162.
Since this derivative was easily prepared in a short time, it is
ideal for the characterization of 3-keto-2-phenylpiperazine.
Anal. Calcd. for C12H1402N2: C, 66.03; H, 6.46; N, 12.83.
Found: C, 66.04; H, 6.53; N, 13.03.


1-(|S -Phenylethyl)-3-keto-2-phenylpiperazine.--A solution
composed of 12.27 g. (0.0696 mole) of 3-keto-2-phenylpiperazine,
10.2 ml. (0.075 mole) of {3-phenylethylbromide, 20.9 ml. (0.150
mole) of triethylamine and 100 ml. of acetone was refluxed for three
days giving 10.0 g. (approximately 507. yield) of colorless crystals
from acetone-water, m.p., 144-145.
Anal. Calcd. for C18H200N2: C, 77.11; H, 7.19; N, 9.99.
Found: C, 77.33; H, 7.15; N, 9.60.
Preparation of l-alkyl-2-phenylpiperazines
These derivatives were prepared in essentially the same way as 2-phenylpiperazine was prepared by the reduction of 3-keto-2-phenylpiperazine with lithium aluminum hydride. The reductions were carried out by refluxing for 24 hours a solution of 250 ml. of ether containing 0.0158 mole of lactam and 0.063 mole of lithium aluminum hydride, i.e., a 1:4 molar ratio. In the preparations from the 1-methyl- and l-ethyl-3-keto-2-phenylpiperazines, the solubilities in diethyl ether were low enough to necessitate the use of a Soxhlet extractor or to permit the use of the slurry method.
l-Methyl-2-phenylpiperazine.1.38 g. (49.7% yield) of colorless liquid, b.p., 78-80/0.1 mm.
Anal. Calcd. for CnH16N2: C, 74.95; H, 9.15; N, 15.90.
Found: C, 74.91; H, 9.17; N, 15.76.
l-Ethyl-2-phenylpiperazine.2.50 g. (65.2% yield) of colorless liquid, b.p., 90/0.5 mm.
Anal. Calcd. for C^R^: C, 75.74; H, 9.54; N, 14.72.
Found: C, 75.75; H, 9.51; N, 14.83.


l-n-Propyl-2-phenylpiperazine.--1.10 g. (82.7% yield of crude
product). Recrystallization was difficult; sublimation at 60/1.5 mm.
gave white needles, m.p., 61.5-66.5.
Anal. Calcd. for C13H20N2: C, 76.42; H, 9.87; N, 13.71.
Found: C, 76.59; H, 9.98; N, 13.60.
l-Benzyl-2-phenylpiperazlne.--3.56 g. (61.4% yield) recrystallized from acetone-water as colorless needles, m.p., 104-106.
Anal. Calcd. for C^H^ryH^O: C, 75.52; H, 8.22; N, 10.36.
Found: C, 75.65; H, 8.19; N, 10.36.
Vacuum desiccation of a weighed sample of the monohydrate in an
Abderhalden pistol containing phosphorus pentoxide and heated by
refluxing benzene confirmed the presence of monohydrate as indicated
by its loss in weight. The m.p. of the resulting product was 101.5-
102.5.
Anal. Calcd. for C17H20N2: C, 80.91; H, 7.99; N, 11.10.
Found: C, 81.03; H, 8.06; N, 11.23.
Preparation of 4-alkyl-2-phenylpiperazines
4-Methyl-2-phenylplperazine.--A solution composed of 5.00 g.
(0.0309 mole) of 2-phenylpiperazine, 2.76 g. of 37% formalin, 4.17 g.
of 77.5% formic acid and 100 ml. of water was refluxed in a 250 ml.
round-bottom, single-neck, standard taper flask. After a four hour
reflux period, 3.00 ml. of concentrated hydrochloric acid was added
and the solution was evaporated almost to dryness. At this point a
20% sodium hydroxide solution was added to pH 11, and all low boiling
fractions were removed by distillation leaving a residue which on
vacuum distillation gave about a 50% yield of product as a colorless
liquid, b.p., 76-86/0.4-0.5 mm. Since the analysis indicated the
presence of mono- and disubstituted 2-phenylpiperazines, the derivative


was made by direct methylation with methyl iodide. A solution of
0.050 mole of 2-phenylpiperazine, 0.050 mole of methyl iodide and
0.150 mole of triethylamine in benzene was refluxed for six hours.
The product, 4.80 g. (50.57. yield), distilled at 95/0.4-0.5 mm.
Anal. Calcd. for CnH16N2: C, 74.95; II, 9.15; N, 15.90.
Found: C, 74.81; H, 8.96; N, 15.83.
4-Ethvl-2-phenvlpiperazine.A solution of 5.00 g. (0.0309
mole) of 2-phenylpiperazine, 2.50 ml. (0,0310 mole) of ethyl iodide
and 13.9 ml. (0.100 mole) of triethylamine in benzene was refluxed
for nine hours giving 4.79 g. (81.67. yield) of colorless liquid,
b.p., 91-93/0.7-0.8 mm.
Anal. Calcd. for C12H18N2: C, 75.74; H, 9.54; N, 14.72.
Found: C, 75.36; H, 9.46; N, 15.10.
4-n-Propyl-2-phenylpiperazine.This derivative prepared by
the same method used for the preceeding compound resulted in 4.10 g.
(64.87. yield) of a colorless liquid, b.p., 91-94/0.3-0.4 ram.
Partial solidification was noted at room temperature, (27).
Anal. Calcd. for C!3H20N2: C, 76.42; H, 9.87; N, 13.71.
Found: C, 76.24; H, 9.95; H, 13.83.
4-Benzyl-2-pheaylpiperazine.The 4-benzyl derivative was prepared by dropwise addition of 3.65 ml. (0.0309 mole) of benzyl bromide to a stirred solution of 5.00 g. (0.0309 mole) of 2-phenylpiperazine, 13.9 ml. (0.100 mole) of triethylamine and 150 ml. of acetone. The mixture was refluxed for twelve hours and worked up to give an orange-red oily residue. Distillation gave 5.26 g. (62% yield) of purified material, which solidified in a few hours. Recrystallization of this material was unsatisfactory;


sublimation at 110/lo5 mm. was utilized resulting in the collection
of colorless prisms, m.p., 55-63.
Anal. Calcd. for C17H20N2: C, 80.91; H, 7.99; N, 11.10.
Found: C, 80.79} H, 7.76; N, 11.15.
Since the melting point of the product has such a wide range and since the analytical results are in good agreement with the proposed product, it appeared that a mixture of l-benzyl-2-phenylpiperazine and 4-benzyl-2-phenylpiperazine might be present. However, a comparison of the infrared spectrum of l-benzyl-2-phenylpiperazine with the infrared spectrum of the supposed 4-phenyl-2-phenylpiperazine shows that there is quite a difference and that none of the distinguishing bands of the 1-benzyl derivative are present in the spectrum of the 4-benzyl derivative. Therefore, the wide m.p. range was left unexplained. Preparation of l,4-dialkyl-2-phenylpiperazines
l,4-Dimethyl-2-phenylpiperazine.--A 5.00 g. (0.0309 mole) sample of 2-phenylpiperazine was methylated with a mixture of formalin and formic acid, the ratio of 2-phenylpiperazine to formaldehyde to formic acid being 1:2:4. After a twelve-hour reflux and the subsequent work up, the product was obtained as a colorless liquid, 3.50 g. (59.67. yield), b.p., 88/0.5 mm.
Anal. Calcd. for C12HiaN2: C, 75.74; H, 9.54; N, 14.72.
Found: C, 75.76; H, 9.56; N, 14.50.
l,4-Diethyl-2-phcnylpiperazine.--A mixture of 8.10 g. (0,050 mole) of 2-phenylpiperazine, 12.1 ml. (0.150 mole) of ethyl iodide, 20.8 ml. (0.150 mole) of triethylamine, and 100 ml. of benzene was refluxed for four hours. The precipitate of triethylamine hydroiodide that formed during this time was removed, and the benzene was evaporated


leaving a residue which was distilled giving 9.00 g. (82.5% yield)
of a colorless liquid, b.p., 93-95/0.3-0.4 mm.
Anal. Calcd. for C^h^V- C, 77.01; H, 10.16; N, 12.83.
Found: C, 77.07; H, 10.05; N, 13.01.
1,4-Di-n-propyl-2-phenylpiperazlna.This derivative was prepared by using the same molar quantities as described for the previous derivative, but toluene was used in place of benzene. Distillation of the crude product gave 5.17 g. (68.0% yield) of a colorless liquid, b.p., 106-110/0.7-0.9 mm.
Anal. Calcd. for Ci6H26N2: C, 77.99; H, 10.64; N, 11.56.
Found: C, 77.75; H, 10.36; N, 11.37.
1.4-Dibenzvl-2-phenylpiperazine.--Using the same molar quantities as mentioned in the two previous preparations, recrystallization of the crude product from acetone gave 6.98 g. (65.3% yield) of colorless needles, m.p., 109.5-110.5.
Anal. Calcd. for C24H26N2: C, 84.17; H, 7.65; N, 8.18.
Found: C, 84.26; H, 7.86; N, 8.19.
Studies related to the preparation of 2-(o-substitutedphenyl)piperazine o_-Hydroxyphenylacetic acid and subsequent reactions.--Pyrolysis
of o-hydroxyphenylacetic acid gave 2-coumaranone in 75% yield.
During the pyrolysis, water distilled off followed by 2-coumaranone
which was collected at 92-94/0.4 mm. Bromination of 1.34 g. (0.010
mole) of coumaranone with 1.52 g. (0.0095 mole) of bromine in 100 ml.
of benzene caused large scale decomposition and no isolable products. A mixture of 0.010 mole of 2-coumaranone and 1.78 g. (0.010
mole) of N-broraosuccinimide in 100 ml. carbon tetrachloride was refluxed
for eight hours showing no evidence of a reaction.


o-Nitrophenylacetic acid and subsequent react ions.--When
-------------- . . ------- .------------ .......-
9.05 g. (0.050 mole) of o_-nitrophenylacetic acid was refluxed with 10.0 ml. (0.138 mole) of thionyl chloride, a large amount of decomposition was observed. Continuation of the sequence to 3-keto-2-(o-nitrophenyl)piperazine by reaction with bromine followed by the addition of absolute ethanol gave no isolable product. However, the crude reaction mixture was subjected to the action of ethylenediamine. The desired product, 3-kcto-2-(o-nitrophenyl)piperazine, was not isolated.
Direct nitration of 2-phenylpiperazine.A solution composed of 12.08 g. (0.050 mole) of cupric nitrate trihydrate, 21.6 ml. (0.250 mole) of acetic anhydride and 12.6 ml. (0.200 mole) of glacial acetic acid was used to nitrate 0.050 mole of l,4-diacetyl-2-phenylpiperazine. A very slight rise in temperature was observed upon mixing the react-ants. After the reaction mixture stood overnight it was poured into ice-water, and when no precipitate was observed, the water was distilled as the benzene-water azeotrope and the benzene solution filtered. Since no isolable product was found in the benzene, this study was discontinued.
Preparation of ethyl N- ( x-cyanobenzvDElycjnate (ester-nitrilc XV).--A slurry of 13.96 g. (0.100 mole) of ethyl glycinate hydrochloride, 10.2 ml. (0.100 mole) of benzaldehyde and 200 ml. of ether were mixed thoroughly, and a solution of 6.51 g. (0.100 mole) of potassium cyanide in 10.0 ml. of water was added. Instead of allowing the mixture to stand in the sunlight for 7 days, as suggested by Stadnikoff, artificial ultraviolet radiation for 12 hours was used by inserting an ultraviolet irradiation lamp into a water-cooled, Vycor tube which was immersed into the continuously stirred solution of the


reactants. The colorless solution turned light yellow within one hour and finally an orange-yellow toward the end of the twelve hour irradiation. After the irradiation period, the mixture was filtered, dried over anhydrous sodium sulfate for 30 minutes, filtered again and the ether removed leaving 19.71 g. (90.4% yield) of the crude ester-nitrile. Since this material could not be purified by distillation, it was used directly in the next reaction to convert the nitrile to the amide.
Preparation of ethyl N-(a-carboxamidobenzypglycinate (ester-amide XXVI).--A 5.00 g. sample (0.0229 mole) of the ester-nitrile was added dropwise with constant stirring to 21.8 ml. (0.408 mole) of concentrated sulfuric acid. The sulfuric acid turned a deep red-brown and an amorphous lump appeared, which finally dissolved 30 minutes after the addition was completed. The resulting red-brown viscous solution was set aside for twenty hours and then added dropwise to 50.0 ml. of absolute ethanol, previously cooled to 0, making sure that the temperature did not exceed 15. This solution was added to 250 ml. of absolute ethanol, cooled to 0, containing enough ammonia to neutralize the sulfuric acid. The temperature during addition was kept below 15, and after the addition was completed more ammonia was added if the solution was acidic. The ammonium sulfate formed during the neutralization was removed and the ethanol was distilled leaving a residue of crude ester-amide. The crude product was recrystallized from acetone giving 2.83 g. (52.4% yield) of needlelike colorless crystals, m.p., 133.5-134.0.


Attempts to convert the ester-amide to 3.5-diketo-2-phenyl-pjperazine.A solution of 0.5 g. (0.00212 mole) of ester-amide in 10 ml. of concentrated ammonium hydroxide wa6 refluxed for four hours. A deep blue solution formed which turned red on cooling. The ammonia and water were distilled. The infrared spectrum of the residue showed the absence of the ester carbonyl band and indicated the possibility of an acid-amide or ammonium salt-amide. Since this material could not be purified, it was pyrolyzed at 200/1 mm. The sample decomposed and no sublimate was obtained.
Another attempt to prepare 3,5-diketo-2-phenylpiperazine by refluxing the ester-amide with hydrobromic acid in glacial acetic acid was unsuccessful. A 0.100 g. (0.000424 mole) sample of ester-amide was heated on a steam bath with 5.0 ml. of 48% hydrobromic acid and 10.0 ml. of glacial acetic acid. The solution was neutralized with 5% sodium bicarbonate and extracted with benzene. When no residue was found on evaporation of the benzene, ether was tried with no success. Therefore, the reaction mixture was evaporated to dryness and the solid residue wa6 extracted with acetone, but again no product could be isolated.
Simple heating of the ester-amide resulted in the sublimation of the ester-amide unchanged.
Preparation of N-(o^-carboxamidobenzyl)Rlycinamide.A solution of 0.5 g. (0.00212 mole) of eBter-amide in 200 ml. of absolute ethanol was saturated with ammonia at 25. At 25 the concentration of ammonia is about 0.680 mole/200 ml. of solution. The heat of solution when the ammonia was first introduced caused the temperature to rise to 43. The solution was set aside for two days after which the ethanol


was evaporated leaving a residue. Recrystallization from 95% ethanol gave 0.36 g. (82% yield) of well-defined colorless needles, m.p., 154-155.
Anal. Calcd. for C10H13O2N3: C, 57.96; H, 6.32; N, 20.28.
Found: C, 57.74; H, 6.59; N, 19.98.
A 50 mg. sample of diamide wa6 pyrolyzed at 175. The melt turned green and then darkblue. When the temperature was raised to 200/1.0 mm., a sublimate of the diamide was collected. The residue from the pyrolysis also showed the presence of the unchanged diamide.
Preparation of 3f5-diketo-2-phenylpiperazine.--A solution of 3.94 g. (0.0167 mole) of e6ter-amide in 50.0 ml. of xylene, freshly distilled from sodium hydride, was added to a round-bottom flask containing 0.80 g. (0.0334 mole) of sodium hydride. This sodium hydride was prepared for the reaction by washing with pentane to remove the mineral oil preservative, centrifuging, decanting, and repeating the process several more times. The sodium hydride was then transferred to the reaction fla6k with pentane and the pentane was evaporated in a stream of nitrogen. The mixture, protected from atmospheric moisture, was refluxed in an atmosphere of nitrogen for twenty hours. At the end of the reflux period, 1.91 ml. (0.0334 mole) of glacial acetic acid was added to convert any excess sodium hydride or sodium salt of the product to sodium acetate. The solution was then heated to about 100 and filtered. Crystals formed in the xylene, were filtered off and washed with ether to remove residual xylene. These crystals, 0.80 g., melted at 121-124 and had an infrared spectrum indicating the presence of an imide. Strangely enough the residue from the ether, 0.05 g., while it melted at 128-129 had an infrared


spectrum with several different bands and bands of different intensity as compared with the spectrum of the 0.80 g. sample from xylene. No explanation could be offered for these two variant spectra.
Preparation of 2-phenylpiperazine.Since the material from xylene (the 0.80 g. sample) appeared to have a spectrum in agreement with the spectra of other imides, an 0.1 g. sample was placed in a Soxhlet extraction apparatus fitted into the neck of a 100 ml. round-bottom flask containing 0.090 g. of lithium aluminum hydride in 50.0 ml. ether. The ether solution was refluxed for eight hours; water was added to remove excess lithium aluminum hydride; the solution was filtered and was evaporated to dryness leaving an oily residue (approximately 50 mg.) which started to crystallize after two hours. An infrared spectrum of the oil and crystals showed all the major bands of 2-phenylpiperazine with an additional carbonyl band.
Further experimental studies were not carried out to definitely establish that the imide, 3,5-diketo-2-phenylpiperazine had formed. Preparation of 2-phenylpiperazine by the Pollard and Kitchen method
Preparation of N-(ft -hydroxy-ft -phenvlethvl)ethylenediamine. A solution of 270 g. (2.25 moles) of styrene oxide in 500 ml. of methanol was added slowly to a stirred solution of 255.5 ml. (4.5 moles) of ethylenediamine and 500 ml. methanol in a 3000 ml, round-bottom, three-neck, standard taper flask fitted with a condenser, thermometer, and stirrer. After the addition of the styrene oxide solution was complete, stirring was discontinued. The mixture stood for four hours, during which the temperature rose quite rapidly to a reflux and a white precipitate formed. This by-product (38 g.) was


removed after the four hour standing period, washed with methanol and dried. The melting point without further purification was 210-215.
The reflux condenser was replaced with a simple column packed with 10 cm. of coarse, stainless steel wool and fitted with a Claisen head, thermometer, and condenser with a receiving vessel. The methanol and unchanged ethylenediamine were removed by distillation until the pot temperature reached 200. The remaining orange-brown residue was allowed to cool to 40 and then distilled at reduced pressure. The main fraction was collected at 151-160/0.8-1.0 ram. as a light yellow-orange liquid which solidified as it was collected. The major portion of the distillate came over at 156.
The yield of crude N-(B-hydroxy- -phenylethyl)ethylene-diamine was 242 g. (59.8% yield) with about 70 g. of dark brown residue. Benzene, as mentioned earlier, was found to be a satisfactory solvent for recrystallization and was utilized to obtain the purified N-(j3 -hydroxy-(3 -phenylethyl)ethylenediamine which melted at 88.5-91.0.
The by-product, 38 g. (11.3% yield based on the styrene oxide used), formed during the preparation of N-(j3 -hydroxy-^-phenylethyl)-ethylenediamine was undoubtedly N,N'-bis-(p-hydroxy- fi>-phenylethyl)-ethylenediamine. Attempts to purify this material by recrystallization from water, benzene, hexane, ethanol, chloroform, ether, or dioxane proved useless. However, recrystallization from N,N-dimethylformamide gave white flakes, m.p., 230-232. The purified product was soluble in 5% hydrochloric acid, gave a test for nitrogen, and showed the presence of no primary amine by the Hinsberg Test.


Anal. Calcd. for C^O HjS C, 71.97; H, 8.05; N, 9.33.
Found: C, 72,42; H, 8.18; N, 9.00.
Preparation of 2-phenvlPiperazine.--A solution of 132 g. N-(p -hydroxy- ^-phenylethyl)ethylenediamine in 600 ml. of dioxane was placed in a 1500 or 2000 ml. capacity autoclave. About 20 g. of Raney nickel catalyst was transferred to the autoclave, which was then sealed, fitted with a 1000 psi. capacity pressure gauge and charged with 500 psi. of hydrogen gas. The mixture was heated to 200 and maintained at this temperature for four hours, during which time the autoclave was continuously rocked; the pressure reading reached a maximum of 825 psi. After the treatment was completed, the autoclave was cooled by carefully lowering it into cool, circulating water. After 15 minutes in contact with the cool, circulating water, the hydrogen was slowly bled off. The catalyst residue was removed by filtration and the remaining solution was placed in a 1000 ml. round-bottom, three-neck, standard taper flask fitted with a typical arrangement for distillation.
The water produced during the ring closure was conveniently removed as the dioxane-water azeopcape. (b.p,, 88, with a composition of 18% water82% dioxane). The distillation temperature rose slowly to 101, the boiling point of pure dioxane. Further distillation removed most of the dioxane. The crude mixture of 2-phenylpiperazine and N-(^ -hydroxy--phenylethyl)ethylenediamine was fractionally distilled at reduced pressure. The 2-phenylpiperazine was collected at 110-130/4 mm. and finally the unchanged starting material at 170-175/4 mm. The yield of 2-phenylpiperazine ranged from 25-30% while the recovery of the starting material ranged from 50-70%. The


2-phenylpiperazine was further purified by two or three recrystal-lizations from n,-hexane.
Only one attempt was made to shift the apparent equilibrium in favor of 2-phenylpiperazine. The autoclave reaction was repeated in the same manner as described with the addition of one mole of anhydrous sodium sulfate for each mole of N-(ft-hydroxy-$-phenylethyl)-ethylenediamine. This reaction produced only a 21.2% yield of 2-phenylpiperazine.
unsuccessful attempts to prepare 2-phenylpiperazine by a new method
The reaction of N-(p-hydroxy-p-phenylethyl)ethylenediamine with thionyl chloride.Addition of thionyl chloride to N-(j3-hydroxy-
-phenylethyl)ethylenediamine was carried out at 10 to avoid the decomposition found in one exploratory run at room temperature. The precipitate that formed during the reaction was difficult to purify. As a result, establishing whether the conversion of hydroxyl to chloro had taken place was never realized.
The reaction of N--hydroxy- ft-phenvlethvl)ethylenediamine with oxidising agents.To a 50.0 ml. solution of 2 M nitric acid was added 5.00 g. (0.028 mole) of N-(6-hydroxy-(3 -phenylethyl)ethylene-diamine, and the mixture was refluxed for two hours. The mixture was then cooled to room temperature and 20% sodium hydroxide solution was added to pH 11. Benzene was added and all the water present was removed by distillation as the benzene-water azeotrope. An infrared spectrum of the organic material from the benzene solution indicated the presence of only N-((3 -hydroxy-6 -phenylethyl)ethylenediamine.
The next oxidative treatment utilized a mixture of potassium dichromate and sulfuric acid. With continuous stirring, 10.0 g. of


N-( {5-hydroxy-(3-phenylethyl)ethylenediamine in 10,0 ml. of water, was treated with 4.79 ml. of concentrated hydrochloric acid to form the dihydrochloride followed by the addition of 2.94 g. of potassium dichromate. This solution was cooled below 20 and a cold solution composed of 4.84 ml. concentrated sulfuric acid, 14.8 ml. of water, and an additional 2.94 g. of potassium dichromate was added slowly keeping the temperature below 20. During the addition of the acid and dichromate, the solution turned brown. After eighteen hours of standing at room temperature, the precipitate that formed was removed. This precipitate plus more material obtained by ether extraction of the reaction mixture was found to be benzoic acid. A trace of benzaldehyde was found and identified as the 2,4-dinitro-phenylhydrazone. All chromium (VI) was removed by the addition of 47 g. of ferrous ammonium sulfate and the resulting solution was refluxed with benzene into a Dean-Stark trap to remove all water. When all the water had been distilled, the inorganic substances were removed by filtration, leaving the dry benzene solution. Only N-(6 -hydroxy- f> -phenylethyl) ethylenediamine was found in the benzene layer. The results of this experiment showed that 657. of the N-( -hydroxy-(3 -phenylethyl)ethylenediamine was recovered unchanged while 157. was oxidized to benzoic acid.
The reaction of N-([3-hydroxy-(3-phenylethyl)ethylenediamine with strong bases in place of Raney nickel.--A 2.0 g. (0.050 mole) sample of potassium was reacted with 18,0 g. (0,10 mole) of N-((5-hydroxy-(3 -phenylethyl)ethylenediamine in 100 ml. of xylene and then 1.80 g. (0.010 mole) of benzalaniline added after all the potassium had been consumed. The mixture was refluxed in a set-up which included


a Dean-Stark trap to remove water that might be formed if the expected reaction took place. Only Email amounts of water were found, and the starting material was recovered. A few other runs were made in which the benzalaniline concentration was increased to as high as 0.50 mole and the potassium was decreased to 0.10 mole. An increase in benzalaniline concentration supposedly would increase the rate of the reaction while a decrease in potassium would reduce the amount of decomposition during the reflux treatment. No 2-phenylpiperazine was found after 24 to 36 hours of reflux.
Attempted ring closure of N-(p-hydroxy-S -phenylethyl)-ethylenediamine by azeotropic removal of water.--Several solvents that form azeotropes with water were chosen for this series of experiments. A 10.0 g. sample of N-(^ -hydroxy-p-phenylethyl)ethylene-diamine wa6 dissolved in 150.0 ml. of solvent in a 250 ml, round-bottom, single-neck, standard taper flask fitted with a Dean-Stark trap and a reflux condenser. The refluxing was extended over periods of 24 to 72 hours. When benzene, toluene, or xylene were used, no conversion to 2-phenylpiperazine was found, and refluxing in n-octanol (b.p., 195) gave no appreciable amount of water. However, in the experiment using nitrobenzene (b.p., 210.9) as the solvent, water appeared to distill from the mixture, but decomposition was so great that no 2-phenylpiperazine or starting material were found.
The reaction of 1,2-dibrpmoethyl benzene with ethylenediamine. The 1,2-dibromoethyl benzene was conveniently prepared by slowly adding, with vigorous stirring, 52 ml. (1.015 mole) of bromine to a solution composed of 125 ml. (1.00 mole) of styrene and 500 ml. glacial acetic acid. Fifteen minutes after the addition of bromine, the


mixture was cooled to 15 and poured into 1500 ml. of water also at 15. The crude product precipitated, was removed by filtration, dried in a vacuum oven at 40 for two hours and recrystallized from 95% ethanol. The yield of purified 1,2-dibromoethylbenzene was 201.5 g. (76.2%).
Several reactions of 1,2-dibromoethylbenzene were attempted but none gave indication of producing 2-phenylpiperazine. A 0.1 mole sample of the dibromo compound dissolved in 50 ml. of solvent was added to either 0.2 mole of 0.1 mole of ethylenediamine in 150 ml. of solvent. Benzene and chlorobenzene were used as solvents and in a few reactions an additional base, 0.3 mole of triethylamine, was present. The hydrobromide salts of ethylenediamine were found when it was the only base present. When triethylamine was used only triethylamine hydrobromide was found. Decomposition during these reactions caused difficulty in isolating any other products. However, a liquid was obtained the boiling point and infrared spectrum of which indicated the presence of jb -bromostyrene.
The reaction of l-chloro-2-iodoethylbenzene with ethylene-diamine.A 200 ml. portion of a 5% solution of iodine monochloride39 (0.098 mole) in carbon tetrachloride was added to 10.0 ml. (0.096 mole) of styrene with vigorous stirring. The violet color of iodine remaining after the addition was removed with a saturated aqueous solution of sodium bisulfite. After the carbon tetrachloride was evaporated under aspirator vacuum, the crude product^ was recrystallized from 95% ethanol giving the pure l-chloro-2-iodoethylbenzene, m.p., 39.5-40.5. When 2.655 g. (0.10 mole) of l-chloro-2-iodoethyl-benzene was treated with 0.73 ml. (0.11 mole) of ethylenediamine in


dry ether, extensive decomposition was observed. The resulting reaction mixture was evaporated to dryness and neutralized with aqueous potassium hydroxide. Water was removed by azeotropic distillation with benzene. No 2-phenylpiperazine was found in the benzene after removal of the inorganic materials.
The reaction of phcnacvl bromide with ethylenediamine.--Usually 0.1 mole of phenacyl bromide in 50 ml.of solvent was added dropwise to a stirred solution of 0.2 mole of ethylenediamine in 150 ml. of solvent. The solvents chosen for these reactions were toluene, benzene, and diethyl ether, and in one reaction 0.15 mole of triethylamine was present in the diethyl ether. The hydrobromide salts of ethylenediamine and a brown tarry mass were obtained. Attempts to isolate pure materials from this brown tar were unsuccessful. Small portions of the brown tar were chromatographed, but no crystalline fractions were obtained, and a plot of fraction residue weights against volume of eluent showed no separations. When the reaction was run in an atmosphere of nitrogen, the color did not develop from the usual pale yellow to red-brown. On exposure to air, the deep coloration appeared immediately.


IV. SUMMARY
The preparation of 2-phenylpiperazine developed by Pollard and Kitchen was re-investigated in order to increase the overall yield of 2-phenylpiperazine. New. synthetic routes were examined when several studies of the Pollard and Kitchen method did not reveal a worth-while improvement on the yield of 2-phenylpiperazine, The main course of study was directed to the development of a new synthesis of 2-phenylpiperazine.
Ethyl a-bromophenylacetate was allowed to react with ethylenediamine giving 3-keto-2-phenylpiperazine (50% yield) which was reduced with lithium aluminum hydride to 2-phenylpiperazine (95% yield).
The 3-keto-2-phenylpiperazine molecule provided a way of producing unequivocally the l-alkyl-2-phenylpiperazines. The internal protecting group for the 4-nitrogen provided by the lactam structure of 3-keto-2-phenylpiperazine allowed alkylation with alkyl halides to proceed only at the 1-nitrogen. Subsequent reduction of the 1-alkyl-3-keto-2-phenylpiperazines with lithium aluminum hydride gave the l-alkyl-2-phenylpiperazines.
The 4-alkyl-2-phenylpiperazines were prepared by direct alkylation of 2-phenylpiperazine, and the 1,4-dialkyl-2-phenyl-piperazines were prepared by using an excess of alkylating reagent. Alkyl groups introduced into 3-keto-2-phenylpiperazine and 2-phenylpiperazine were methyl, ethyl, n-propyl, and benzyl.


Preparation of 2-(o-substitutedphenyl)piperazines was attempted using the corresponding -substitutedphenylacetic acids. When the desired product could not be obtained, another approach was investigated. Ethyl glycinate hydrochloride, potassium cyanide, and benazaldehyde undergo a condensation to ethyl N-(cc-carboxamido-benzyl)glycinate. N-(c-Carboxamidobenzyl)glycinate appeared to cyclize to 3,5-diketo-2-phenylpiperazine in the presence of sodium hydride, and subsequent reduction of the supposed 3,5-diketo-2-phenylpiperazine gave a compound which had the major infrared spectral bands of 2-phenylpiperazine. Since the available evidence from these reactions indicates the presence of 2-phenylpiperazine it might be possible to replace benzaldehyde of the first reaction with an o-substituted benzaldehyde and carry through the suggested sequence ending with a 2-(o-substitutedphenyl)piperazine.


BIBLIOGRAPHY
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BIOGRAPHICAL SKETCH
Howard Jean Platte was born in New York City on March 4, 1933. In 1950 he graduated from White Plains Senior High School, White Plains, New York, and entered St. Lawrence University, Canton, New York. After receiving his Bachelor of Science degree from that institution in 1954, he attended Bucknell University, and he entered the University of Florida in 1958.
From September, 1958, through June, 1961, he held a Graduate Teaching Assistantship in the Department of Chemistry. From June, 1961, to June, 1962, he held a Research Fellowship sponsored by Parke, Davis & Company.


This dissertation was prepared under the direction of the chairman of the candidate's supervisory committee and has been approved by all members of that 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.
Dean, Graduate School
Supervisory Committee:


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TITLE: The synthesis of 2-phenylpiperazine and some derivatives, (record
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