• TABLE OF CONTENTS
HIDE
 Title Page
 Preface
 Table of Contents
 Introduction
 A survey of the problem
 Synthesis and characterization...
 Amino alcohol derivatives
 Summary
 Bibliography
 Acknowledgement
 Biographical sketch
 Copyright














Title: Derivatives of piperazine. XII
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Table of Contents
    Title Page
        Page i
    Preface
        Page ii
    Table of Contents
        Page iii
        Page iv
    Introduction
        Page 1
        Page 2
    A survey of the problem
        Page 3
        Page 4
        Page 5
        Page 6
        Page 7
        Page 8
        Page 9
        Page 10
    Synthesis and characterization of 1-arylpiperazines
        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
        Page 24
        Page 25
        Page 26
        Page 27
        Page 28
        Page 29
        Page 30
    Amino alcohol derivatives
        Page 31
        Page 32
        Page 33
        Page 34
        Page 35
        Page 36
        Page 37
        Page 38
        Page 39
        Page 40
        Page 41
        Page 42
        Page 43
        Page 44
        Page 45
        Page 46
        Page 47
        Page 48
        Page 49
        Page 50
        Page 51
        Page 52
        Page 53
        Page 54
        Page 55
        Page 56
        Page 57
        Page 58
        Page 59
        Page 60
        Page 61
        Page 62
        Page 63
        Page 64
        Page 65
    Summary
        Page 66
        Page 67
        Page 68
        Page 69
    Bibliography
        Page 70
        Page 71
        Page 72
    Acknowledgement
        Page 73
    Biographical sketch
        Page 74
        Page 75
    Copyright
        Copyright
Full Text












Derivatives of Piperazine. XII. Synthesis of

1-Arylpiperazines and Amino Alcohol Derivatives










By
THOMAS H. WICKER, JR.


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
June, 1951
















P.fAACO


The subject matter of this dissertation is presented in

two sections to facilitate handling the survey of the literature.

In the first section the synthosis of 1-arylpiperazineo is present-

ed. Amino r-lcohol derivatives of these piperanines are discussed

in the second section. The preparation of individual compounces

is presented in detailed form so that future investigators may easi-

ly duplicate the "or:t.

The ri.nnor of listing tecmhica~l worhs is the customary one

used by journals of the American Chemical Society. The abbrevia.tl

of Journals iae those adopted as official by Chemical Abstracts.

All temperatures are reported in degrees centigrade, and

the contirade eoybol is omitted. All melting points and boiling

points are corrected and were determined with thermometers calibrated

against a set of thermometers corrected by the Barea of Starndards.

Yields of 1-arylpiperazines are based on either the diethanol-

amine or the substituted diethanol~nine %which was used in the synthesis.

In the case of the amino alcohol derivatives, the percentage yields

are based on the larylpiperazine used.













TABL1 OF CO0Ti.'TS


Chapter


PIRZACE . . ... . .

11fOiCTOION ...... ....

A SURVEr OF SH PROBLDI . . .

Review of the Literature .

Discussion .. . . .

SYlT.-SIS AfD CHKAACTMRIZATIOIT O0


Page

. . . . . . ii

. . . .. .

. . . . . . 3

. . . . . . 3

. . . . .. . 9

1-ARYLPIJ..A2IInES 11


I





























IV


Z.xporimental ork . . . . . . . .

1-(4-4ethylphonyl)piperaine . .

3-((3- Iethylplhonyl)piperazine .. .. .

l-(2-,e thylphenyl)piperaz ne .

1-(.-Chloropheay1)piperazine . . . . .

1-(3-Chlorophlenl)piperazpine . . . . .

1-(2-Chlorophenyl)piparazine . . . .

l-Phenyl-2-mothylpiperaino . . .

l-Mhenyl3-sethylpiperazine . . . . .

Discussion of Exerimental Reaults . . . .

AIIIlTO ALCOHOL DERIVATIVES . . . . . .

Review of the Literatiue . . . . . .

Experimental Work . . . . . . . .

1-(4-tetbylpheBln)-4-(2-hydarosy-3-.
nethio~propyl)pipeanzine . . . . .

1-(3-Methylphenyl)-.4(2-hydrozy-3-
nethoizypropyl)piperaaine ., .

ilI












TAEE 0F CO0T0ITS (Continued)


1-(2-Methylphenyl) -4-(2-hy&ro37-3.-
nethoqypropy1)p3lperazine . . .

1-(4-chlor ophonyl) 4-(2-hydroxy-3-
methosp3ropyl)piperazine . . .

1.(3-Chlorophsayl)-J4..(2-bydro3y-3-
methopvpropyl)plperasine .. . .

1-(2-ChIorophbeyl)-4-(2-hydro y-3-
nethob3propyl)piperasne i

l-Petenyl-2pethyl-n.-(2.. .hro y-3-
aetyhoypropel)pipes rie . .

1.(4-.eihylphenal) -4-(2-hydro3y-
ethyl)piperaine.. . .

1.(3J1f thylphonyl)-'iL-(2-hydro y-
ethyl)piperSalne. . . . . .

1-(2-Hethylphonyl).4-(2-hydr*sy.-
ethyl)piperazine. . . . . .

1-(4-Chlorophenyl)-4-(2-.hydro -
ethyl)piperasine. . . . .

1-(3-ChLorophonyl)J4-(2-hydro3!-
ethyl)piperaaine. . . . .


$ 9


* 9 9


* 4 9


* 4 *


* 9 *


4 9 *


* 4. 9


* 9 *


* 9 9


* 4 9


Pa.ge


39


X-Phenyl-2-maethyl-.4. (2-hydcro gethyl)ipernz Ino.

1-Phelnyl-3 ethyl--(2-hydroayettyl)piporasin .

1.(2-ChlorophBnyl)J~- (2-hydroz~-
ethyl)piperaine . . .... ..

Discussion of Esxerimental Results . . . *

V Sult(IA .... .. . . . . *. .

BIIiLIOGRAPHTI . .. . . ... . ..... .

ACTJllO DGill2TS. . ., . . . . .

BIOGAPHICAL DATA. . .... . -* .


Chapter












CHAPTER I


ITRQODUCTIMO

The recent, wide-spread search for anti-histamines, or hista-
mine antagonists, has caused nmch interest in the field of piperazine
chemistry. From examination of the structures below, it is apparent
that, in many respects, piperazlne (1) may be likened either to a
subatitnted ethylenediamins (II) or to a substituted dimethylamino
group (III):




(I)




(II) (IXI)

Pyribensaaine, a product of Ciba Pharmacentical Products, Inc., is a
substituted ethylenediamine:





Benadryj, a product of Parke-Davis & Company, is the other formed by
condensing benshydryl bromide with 2-dimethylaminoethandol


O\
u\r










2

If ethylene oxide or one of its derivatives were condense with a

1-subbtituted piperazine, a compound containing a substantial por-

tion of both the Pyribenzamine and Ben.dryl molecules would be

formed:




Thic di".crtation is concerned with the preparation of conmounds in

which I represents a phenyl or substituted phenyl radical.

The work of Albro, Baltzby and Philllps and of Salt zby,

Du3reoil, Ide and Lorz9 shoved that N-methyl-NI-benzhydry1pipera-

sines exhibited. ronounced anti-histaminic activity, particularly

when the ~r~ position of the benzhydry group was substituted.

Hamlin, Ye-tton, Yischer and Michaels prepared a number of 1-

apt 1,4- Aisubstituted derivatives of piperazine as potential hieta-

mine antagon its. Of those prepared, 1-(i-chlorebenshydryl)-4-methyl-

piperazine was the most active compound.

This dissertation describes the preparation of certain 1-

arylpiperasinen and their derivatives. The purpose of the project

was not only to synthesize potential -uti-histaminic agents but also

to Investigate the synthesis of piperazines with a view of determin-

ing limiting factors in tho reaction if any were present.













CWAPTR 1


A SURt OF TIM PXROSIMi


Reviewv th Literattr r


Pip rablnp, as a compound, has been rnognizeL& since 1853-

MSooPeer, substituted iperasines are less well known, and their

preparation is tmisll:y very difficult In fact, very few methods

have beon devised by which a desired r~.ontituent may be -placed at

a desired po-ition in the pinerazine ring.
Several general methods for the synthesis of piperasine have

been developed. The first method by which oiperzaine was prepared

was the reaction of alcoholic ammonia with ethylene chloride or

othylenr bromide. This method, which was discwered by Clo'r13 and

was also used by Natansoa and Homann,20.21 left much to be desired

as a procedure for synthesis since piperazine was formed in small

quantities. Sieber treated ethylenediamine with ethylene bromide

and obtains3 an oil which was identified as piperazine.

An adaptation of the alkylation of ammonia is the reaction

of two malee of a cormooand, lR-~, with two moles of an ethylene

dihalide and the subsequent removal of the | groups by various means.
Ths B lor prepare e-10en)per e
Thus Bischlor prepared 1, PT-j(Z-nitrosophenyl)piperazine and









4
removed the nitroeophenyl groups with alcoholic potassium hydroxide:


4 3r- C H NagCO












Amerou' modifteations of this method are recorded in the literature.
Harok3al3 patented a proceee which required the alkylation

of an ar'yl sulfonamide with an ethylene dihalide followed by hydrolysis:
40 0 _












0 0
Q^{ 2 o)V-1 + 2 0y>( M)S









srahe redufo action of ha isx-me d bere r ordod ini he nitrogen in
the 1- andr 4a pition te ha provide a oih r eqie of pi tr alkin. An
Se early exlpl of a reaction of this type iB the redfotion of hydroyine
+ "oK CRZ--CR2i*r .0 -N5

0 0











to pipera8ine, using seatim and ethanol, by Wolff. Steehw2 pro-
S2-motrelpuction o a i by the bredut ion of the corroaponding t
the 1- and 4- positions has provided a. eoujre osf piperaeino An
early example of a reaction of this type is the reduction of 7)yrezlne
to piperazine, using sdlttfa and ethanol, by Wolff.kb Stoahr4 pro
dueA 2-mnothylpiip razino lyy the reduction of the corresponding









5
pyrazine. Abderhalden and co-rvorere prepared piperazine b~ the

reduction of glycine azbhtride, 2,5-diketopiperazine, and isobutyl-

piperazine by reduction of leniylglycine anbydride. *rede, Bruch

and Ketl4 used electrolytic reduction to prepare piperazine from

2,55-iketopipera ine.

A more direet methba for the synthesis of piperastne is

fomun in the work of Garelli and Raeeit6 who reported a 90-95 per

cent yield from the siMple dehydration of ethanolamine with 90 per

cent sulfuric acid. Hoevere, Rollins and Calderwood8 stated that

the only product of the reaction was 2-m nnoethyl7flftric acid.

Groseb.eg7 has been granted a patent for the preparation of

piperazine by the reaction between ethylenediazine sa an ethylene-

glycol ester of the formula N0DCH2f 2R; denotes either an inorganic

or an organic acid ravdcal. The mixture was heated to 200-300e in

the presence of a suitable catalyst.

Reactions which involve the inter- or intra- molecular

splitting of aaaonia have been used to synthesize piperazines. Laden-

bare identified, the product obtained by distillation of the hybro-

chloride of etblenedisaine as piperazine by means of its benoyl

derivative. Raefdsfi22 av that piperazine was also a product of

the strong heating of the hydrochlorides of diethylenetria ino or

triethylenetetraaidne. It has also been foxmd that ethylenedim ine

hydrochloride will yield piperazine, but not with the same ease.

Recently WilsonL5 was granted a patent which described the prepara-

tion of piperasine by heating diethylene triamine and one of its









6

hydrohalides under pressure to at least 2200. Kyrides28 has been

granted a patent for the preparation of piperasine from ethylene-

diaminea polyethylene polyanines, or their mixtures. In this process

the amines were heated to 200-3000 in the presence of a metal bydro-

genation catalyst, such as reduced nioakel, so that amsonia was

liberated.
The inter- or intra- molecular splitting of water has also

been utilized to synthesis piperasines. Poppenberg and Mayer4 were

granted a German patent which described the preparation of piperasines

from comeipouinds of the foraMla R-CH2.CH,-T- C 2-CFg-11 in which repre-

sents an On group and R' an 0O or group. These compounds were

heated to a high temperature in the optional presence of an nmonium

salt to yield piperasine. Thus, monoethanolethylenedisaine was heated

to 200.3000 in the presence of anonia chloride to give piperasine.

Pollard and Kitchean2 were granted a patent which describee the cata-

lytic dehydration of 2-.ydroqethylethylenediamine in the presence

of an anhydroue solvent at 195-200O in an autoclave to give an ydrous

piperasine, Vilkets0 has recently been granted a patent, very simi-
lar t that of Pollard and Kitchen, which describes the Mdition to

the reaction mixture of hydrogen, which is supposed to raise the

yields and eliminate side reactions.

1-AryCpiperasineu may be prepared by adaptation of some of

the methods used for the preparation of piperazine. In effect, the

synthesis involves the splitting of water or hydrogen halide between
an aromatic amine and a dialtkaol amino or its halogen derivative.
Bowever, chmsidt and Wiebhaman 9 report that an oil, probably 1.phenrl









7

piperauine, wa& obtained as one of the products in the reaction between

bromobonzeno and piperazine. They also report that 1-(E-nitrophonyl)-

piperarine is obtained when piperazine is heated with gl-chloronitro-

bonzene at 150*. Xn both cases, however, the dai-ubatitute& derivative

was obtained almost exclusively.
The first preparation of l-phenylpipera-ino in which physical

proportion were listeawas reported by Prolog and DriSa.3 These in-
restigators refliued bi.-(2-chloroethyl)amine, (01- E-CH2 2)2MnH, with
aniline in nmthyl alcohol for sixteen hours


Q Ma2 +- -Hl CH -2)0* 2H01
01-CC3 2 J -C2-H2


Prelog and Blasei extended this synthesis to include other aryl

amine and. their derivatives. With steam-volatile amines, one molo

of the hy3robromide of bi.-(2-bromoothyl)anine was hoatod with two
moles of the amine in methyl or butyl alcohol under reflxi for twelve
hours. Then one mole of sodium carbonate was added and the excean
amine volatilized; the residue was acidified ,with hydrobromic acid

and concentrated to crystallization. If the amines were not volatile

with steam one mole of the lqdrobromide salt of bj.e(2-bromoethyl)-

amine and one nole of the amine were heated under the same conditions

for six hours. Then one-half mole of sodium carbonate was added and
the mixture was kept at boiling toemrrature for three to six hours.

The compounds were separated as crystalline solids and were usually

recryntallized from methyl alcohol.









8

Pollard and MacDowell reported a new synthesis of 1-phenyl-

piperaine in which they heated together aniline hydrochloride and

diethanolamine hydrochloride for a period of six to eight hours at

220-240o to produce the hydrochloride of l-phenylpiperazine. Then

1-phenylpiperanine was obtained from the resulting reaction mass

by treatment with concentrated soadiu hydroxide*33 Ban 6 reported

an attempt to synthesize l-phenyl-2,6-dimethylpiperazine by this

method. However, he did not prepare the desired compound in suffi-

cient quantity to determine any physical constants or prepare deriva-

tives.

Bain and Pollard applied the catalytic alkylation method,

using copener*chromita oxide catalyst, to the preparation of pipera-

sines from amines and amino alcohols. F6 or example, 1-cyclohoxy1-
2,6-dimethyl-4-2-tolylpiperasine was prepared from cyclohaxylamine

and N-2-tolyldiisopropanolamine:






C 2-


CeIl)Pr()OR3 +220
HC2 2)0 H\ '- 20

CH,


The yoilds usually raSed from 15 to 20 per cent.









9
214
HowardF has recently obtained an American tent covering

the preparation of l-alkylpiperaaines by con4ensinr diethanolamine

or its alkyl derivatives with prin.ry alkyl anines in inert solvents

nnd in the nreoence of dohyd.ration eat.lyt's at about 250*. Thus,

l-mnthylni-erazine was prepared by refluxing diethanolamine with

methyl nine for three hours in the presence of an alumina-nickel

catalyst.

Discussion

From a consideration of the literature, it tnpeared that the

method reported by Pollard and. "icDowell3' would be most suitable

for the preparation of large quantities of l-arylpiporatines. The
7,8
catalytic method of Bain and Pollarid requires a considerable

Volume of diluent, and this appreciable reduction of the charge of

reacting materials which can be used in the autoclave available made

it less suitable for this project.

Several objectionable features of the reaction by Pollard

and MacDovell3 have been noted. The formation of mornholine by

the internal dehydration of diethanolamine is one of these:




H 2R E0 I -+ ---- + 2
-OHg2-OH ^ -^C2-
1351









10

In addition, the formation of bj~-(2-phenylaminoethy1)amIne is possible



+ 2 -I 2)ja + 2NO



Also, the formation of 1,l4-i_.(2-hyaroxyethyl)piperatine should be em-
pected:



%11 + W>-oR 2

2 HgO 4 HOH3HCHi2W("2n)1GCOK24OH


It is seen that the reaction is by no means clear-.ut; there-

fore high yields should not be expected. Actually, it was found that
a considerable increase In yield of the substitutel piperazine could
be effected by using a slight excess of the arom atie amine.
The purpose of this investigation has been to synthesize
various 1-arylpiperagines and some of their amino alcohol derivatives.
Derivatives for the characterization of the prperasines also were

prepared.












CAPUefR III


SY1NTDgSIS AD CRRACOTRIZATION OF 1-AR.YiPIP3RAZInES


Sbxoerimental VWro


The intermediates wied in the synthesoe were com-mrcial pro-

duats with the exception of two amino alcohols. The method of Cottle

and co-workers was used for the preparation of N-(2-hydroxyethyl)-l-

amine-2*projaaol and N-(2-hydroxyethyl)-2-*aino-l-'butanol. The first

compound, N-(2-hydroxyethyl)-l-aino-2-propanol, vwa prepared by re-

acting propylene oxide with a large excess of a cold aqueous solution

of 2-aminoethanol. The preparation of N-(2-hydroxyethyl)-2-amino-l-

butanol was carried out by reacting ethylene oxide with a large ex-

cess of 2-aminobutanol-l in a cold, 60 per cent aqueous solution.

Honranto Chemical Company gratuitously provided samples of k-chloro-

aniline, g-chloroaniline, and 2-chloroaniline.

The general method for synthesis of the arylpiperasines con-

sisted of heating the mixed hydrochlorides of a substituted aromatic

amine and diethanolamine or a C-alkyl derivative of diethanolamnie.

The heating of the hydrochlorides appeared to have the effect of

splitting two moles of water between the aromatic amine and diethanol-

amine. The water was removed from the reaction mixture either through

a short air condenser or by use of a distilling trap-reflux condenser

combination in which the liquid was removed through a stopcock in the










12

arm of the distilling trap. The second method was need in all of the

preparations except one in order that cono idea of the degree of eom-

pleteneas of the reaction could be er.cortained, The first preparation

merely provided proof that tho synthesis described by Pollard and Mar-

Dowell33 could be extended to substituted phenylpiperasines.

Characterization derivatives have been prepared in all cases

to insure duplication of the work by future investigators.

The crude pinerazinen were purified by aistillation through

a 50-centimeter column packed with one-eighth inch Berl saddled and

provided with an electrically heated outer jacket.

All syntheees are described individually in the following

pages, and each description is followed by a data sheet which tabulates

some prop-rties of the compound.










13

1-(4-4ethyl)henyl)piterasine and Charactertiation Derivatives

In a two-liter, three-necked flask provided with a mechanical

stirrer, air condenser, and thermometer were placed 428.6 g. (4 moles)

of -toluidine and 4220.56 g. (4 moles) of diethanolamine. These amines

were carefully neutralized with 700 ml. of concentrated hydrochloric

acid (37% C1, ep. gr. 1.19). As soon as neutralization was complete

heating of the reaction mass with an electric heating mantle was begun.

Water wae allowed to aistill from the reaction flask through the air

condenser as rapidly as possible. Finally the temperature climbed to

200-210* and was maintained in this range for ten hours. At the end

of this period the temperature was allowed to fall about 1100, and the

reaction mass was neutralized with an excess of concentrated sodium

hydroxide solution. The oil which separated was first subjected to

distillation under water-pnp vacaau to remove low-boiling materials,

and then 1-(4-methylphenyl)piperazine was collected at 150.9-152.5; at

10 mm. The yield was 179.8 g. (or 25.5%).

The bentoyl derivative of 1-(4-sethylphenyl)piperazine was pre-

pared by shaking the piperazine with a slight excess of bensoyl chloride

in the presence of excess 10 per cent sodium hydroxide solution. The

derivative was reerystallized from ethanol. Given though the reaction

mixture was basic, the compound precipitated as the monohydrochloride.
In order to prepare l-acetyl-4-(4-nethylphenyl)piperazine, 1-
(4-methylphenyl)piperazine was refluxed with a three-fold excess of
acetic anhydride for thirty minutes. This mixture was poured into lOO1 ,
of ice water and made basic with solid sodium carbonate. The crude 1-
aef*tyl-4-(4-methylphenyl)piperazine was recrystallized from boiling water.











Equation for Synthesis:


930 -0 2 + 4.-a + 2 g0o --,

00J2. 2) 2 0 saH
CH52 ^-

,c.0-C 2 -E + 2 oa01 + 2 20


Molecular ror=mla . . . . . . . . . 0 2

Molecular Weight. . . . . ... . . . .176.2$8
Boiling Point ..... . . . 10.9-15. 5/110 an.
Tield of Parified Prodant, . .. . . . . 25.5
Analysis Nitrogena t
Calculated . . . . . . 3.89
Foun. . . . . . . . . 16.00

Charaoterisation Derivatives
l-Aeetyl-4*(4-BmetThylphenttlperasaansm
Meltaig Point 3 . . . . . 109.5-110.5"
Analysis Nitrogen, :
Calculate. . . . . . .1283
round..... . . . .v... 12.99
1-Sensoyl-4-(4-methylphenyl)piperasine monobydroahloride:
Melting Point . . . . . . . . . 201.6-203.6*
Analysie Nitrogen, %f
calctlated . . .. .,*, .8.84
Pound.9 v . . . . . .8.85
Analysis Chlorine, t,
Cal1ulated . . . . 11.19
Found.. ................ 11.36








15

I-(3 -Tthynhyanyl) i rrazing and. 01ractc ri zaton Derivativen

In a one-liter, three-necked flask equipped with a ochanical

ctirror, tharmonotor, and a distilling trzp-reflux condenser combination

were placed 214.3 g. (2 noles) of m-toluidine and 210.3 g. (2 moles) of

diethanolamine. This mixture was carefully neutralized with 350 ml. of

concentrated hydrochloric acid (37 BH01, sp.gr. 1.19), and hooting of

the flask with an electric heating mantle was then started. Water was

collected in the arm of the di.tillinc trap, drained off, and measured.

The total volume of iater removed, 330 ml., indicated that the reaction

was approximately complete since, if reaction occur as supposed, about

340 ml, should have been removed. The reaction mass was then noutraliz-

ed with 180 g. of rndium hydroxide dissolved in 300 ml, of water. The

oily layer which neparatod was first distilled under slightly lowered

prossuro to remove low-boiling materials, and l-(3-methylghenyl)pi5pera-

sine was then collected at 154.2-156.20 at 10 am. The yield was 80.2 g.

(pr 22.8 ).
The benzoyl derivative was prepared by shalding a alight excess

of benroyl chloride with the l-(3-nothylyhcnyl)piperazinc in the presence

of excess 10 per cent asodiu hydroxide solution. The monohydroohloride

which was produced was recrystallized from othanol.

The acetyl derivative was prepared by rofluxing a small quantity

of l-(3-methylphenyl)piperazine with a three-fold excess of acetic anhy-
drite for a half-hour. The mixture was poured into ice water, stirred
well, and made basic with sodium carbonate. An oil separated and was taken
up in ether. The solution was dried over anhydrous potassium carbonate,
the ether evaporated, and the product rocrystallized from boiling heptane.














Equation for Synthesis:


+ H)N + 2 Hal -
)-/ ~ O-CH^-CH2


+ 2 O0


% o -c-R
-)*E *- 2 H01 + 2 10
A Ir +21
C"!


+ 2 1aC1


molecular Fornmla .. .
Molecular Weight. ....
Boiling Point . . ..
n25D 4 4 4 4 9
121 . . .
Hield of Purified Produet,
Analysis Nitrogen, t%


* 4 4 4 4 4r
* 4 4 4 4 4 4 0 4 0 -
* 4 4 4 4 4 4 4 4
* 0 4 9 4 4 4 4 4

4 4 0 4 4 4I 4 4


Calculated.. .
Poua, . . .


. . . C 11
. . . .176.258
.154.2-156,2/10 / a.
. . . . 1.5744
. . 1.0383
. . . . 22.8


4 4 4 4
* 4 4 4


S. . 15.89
. . 15.67


Chaeratorizatiop Derivatives

1-Acetyl-4-(3-methylphonyl)piperazine:
Molting Point . . . . . 4 4.. 6.7-48.2.
Analysis -- fttrogon, %:
Calculateed... . . . .. . 12.83
Pound . *,, . .. . ,12.76

1-Senoyl,-4-(3-mehthylphenyl)pip oratine monohydrochloride:
Melting Point . . . 202.6 204. 6(ad.)
Analysis -- Nitrogen, %:
Calculated . . . .... . 8.84
FoUtnd . .. . . . .. 8.73

Analysis -- Chlorine, %t
Calculatod . . . . . 11.19
Found. . . 1 . .. ... 11.32


----I I









17

l-(2-Tlthylnhonyl)r-n-rge.ine r-."' Cihract~ritration Prrivwtivv s

In a one-liter, threo-necked flask fitted with thermometer,

mechanical stirrer, and distilling traP-reflux condenser combination

were placed 2 moleo (214.3 g.) of g-toliuiline and 2 moles (210.28 g.)

of diethanolanine. After careful neutralization vith 350 mi. of con-

centrated hydrochloric acid (37A HC1, sp.gr. 1.19), heating of the

flask was so regulated that water distilled continuously into the arm

of the distilling trap. The water removed by means of the stopcock,

334 ml. in volume, corresponded very closely to the theoretical amount

of about 340 ml. Finally the reaction mass was neutralized with con-

centrated sodium hydroxide solution. The oil which separated was

first distilled under water pump vacuum to remove low-boiling materials,

and l-(2-methylphonyl)piperazine was then collected at 136.5-137.50 at

10 mm.

The bensoyl derivative of l-(2-imethylphonyl)piPerazine was

prepared by shaking a slight excess of benzoyl chloride with 1-(2-

methylphenyl)piperazine in the -rescnce of excess 10 per cent sodium

hydroxide solution. The product was recrystallized from ethanol.

The acetyl derivative was prepared by refluxing 1-(2-methyl-

phonyl)pireratine with a three-fold excess of acetic anhydride for

thirty minutes. The mixture was poured into 100 ml. of cold water,

and the solution made basic with sodium carbonate. The oil which separ-

ated was extracted with ether, the ethereal solution was dried over =k-

hydrous potassium carbonate, and the ether was evaporated. The 1-

acetyl-4-(2-nethylnhenyl)piperazine was recry tallied from heptane.











18

*(2-Mrtthyl1henyl)j'i- era ine


equation for Synthesis


L+ 0E"i-C1+ + 62 +201 -


Nao0


*2 CI + 2 20


+ 2 NaOC1+ 2 H2


Molecular Forsala . . .

Molecular eight . . .
willing Point . . . .
D . . . . . .
,454 . . . . . .
Yield of Purified Product, %
Analysis Nitrogen, %:
Calculated..
Found . .


0 . 0 .


. ... .s1 6N2


136.5-137.5*/10 maa
S. . . . .5600
. . . 1.0261
. . . .. 26.5


* S 5 4 S S S V
* S S 4 V S


. ..15.89
. ..15.66


Charact eri zati on Dorivativen

l-Acetyl-4-(2-methylphenyl)piperasinet
Voting Point . . . . . . .
Analysis *- Nitrogen, %t
Calculated . ... . .
Found. . . . . . .

1-Benzoyll-4-(2-mothylphenyl)piperazine:
Melting Point . . . . . .
Analysis Nitrogen, %:
Calculated. . . . . ..
ou d . . . . . .


. . ... 55.9-57.9


. . . . 12.83
S. . . . 12.90


6 .


*. . 9.99


122.5-123.5*









19

1-(4-Chloroheny1)Dpierazine and Characterization Derivatives

In a one-liter, three-necked flask fitted tith a thermometer,

mechanical stirrer, and distilling trap-reflux condenser combination

were placed 280.6 g. (2.2 moles) of 2-chloroaniline and 210.3 g. (2

moles) of diethanolamine. The mixture of these two amines was care-

fully neutralized with 375 ml. of concentrated hydrochloric acid

(3% H0C1, sp.gr. 1.19). As soon as the addition of the hydarchloric

acid had been completed, heating with an electric mantle was begun

and was so regulated that water distilled continuously. Practically

the theoretical quantity of water was collected in the arm of the

distilling trap and removed. The reaction mass was neutralized with

180 g. of sodiUm hydroxide dissolved in 300 ml. of water. The oily

layer which separated was first distilled under water-pamp vaetm to
remove low-boiling constituents, and 1-(0-chlorophenyl)piperazine was

then collected at 155.7-157.2* at 5 mm. The yield was 205 g. (or 52.3,)2

)istillation was complicated by the fact that the product solidified on

cooling.

l-Benzoyl-4-(4-chlorophenyl)piperazine was prepared by shaking

a slight excess of benzoyl chloride with the piperazine in a flask in

the presence of an excess of 10 per cent sodium hydroxide solution.

This derivative was recrystallized from ethanol.

Preparation of l-acetyl-4-(4-chlorophenyl)piporazine was accom-

plished by reacting 1-(4-chlorophenyl)piperazine with a three-fold ex-

cese of acetic anhydride fof thirty minutes. The reaction mixture was

poured into 100 ml. of ice water and then was neutralized with solid
sodium carbonate. The solid product was recrystallized from ethanol.











I-Q (4-Chl*rothenyl)-sjeradnAtse


Equation for Synthesiso
-i BD-( -O-C) 2 OCHTHR

+ 01 rH + 2 HOI 01 1 2 2




CM 04 -0I ~) I 2 + 2 WaCI + 2 H20
0i -C 2


Molecular Formula . .
Molecular Vaeiht. . *.
Boiling Point . . .
Melting Point . . .
Tield of Purified Product,%
Analyel BNitrogen, %:


* 6 9 * 9 3 3 3
* 6 9 9 3
* -. 3 9 3 . 9
* 9 9 9 9
* 3 6 9 9 3


. . 010 i201
. . .196.677
. 155 ;.157.2,/5 mm.
. . ,71.5-73.5
. . . . 52.3


Caleulated . . . . 14.24
Fontl l .... . . . ..14.27

Chazaeterisatina Derivative

1-Acety1-~.-(4-chlorophenril)piperSaine

Melting Point... . . .... . . 99.5-101..5
Analysis Ntrogen, %s
Calculated. .. . . . . .11.73
Foand .......... ..... .11.88

1-Benzoyl-4- (4-chlorophonyl)piperazine


Melting Point. . . . . . . ..
Analysis -- Nitrogen, St
Calculate, .. . . . .
pound . .... . .


128.0-129.5"


. 9,31
. . 9.11









21

I-(3-Chlorophenyl)pipera.ine and Characterisation Derivatives

In a one-liter, three-necked flask fitted vith thermometer,

mechanical stirrer, and a distilling trap-reflux condenser combination

wore placed 255 g. (2 moles) of n-chloroaniline and 210.3 g. (2 moles)

of diethanolamine. These aninoe were carefully neutralized with 350 ml.

of concentrated hydrochloric acid. Heating of this mixture was so regu-

lated that water distilled continaously into the arm of the distilling

trap. After a volume of approximately 334 ml. of water had been re-

moved, the reaction mass turned dark-brown and the odor of hydrogen

chloride was apparent. The reaction mixture was neutralise& with 180 g.

of sodium hydroxide dissolved in 300 ~l. of water. The oil which separ-

ated was distilled under water-pump vactum to remove low-boiling mater-

tal, and 1(3-chlorophenyl)piperaeine was collected at 157.2-158.20

at 5 mo.

The bensoyl derivative ws prepared by shaking a slight excess

of ben=oyl chloride with 1-(3-chlorophenyl)piperazine in the presence

of excess 10 per cent sodium hydroxide solution. Although the final

solution was basic to litmus, the product precipitated as the mono-

hydrochloride and was recrystallised from ethanol.

The acetyl dorivative was prepared by refluxing 1-(3-chloro-

phenyl)piporarine with a three-fold excess of acetic anhydride for

thirty ninmtes. This mixture was poured into 100 ml, of ice water

and made basic with sodium carbonate. The oil was extracted with ether,

the ethereal extract dried over anhydrous potassium carbonate, and the

ether evaporated. 1-Acetyl-14-(3-chlorophonyl)piporazine was recrystalliz-
ed from heptane.










22

1- Chloraonhonv yl)-, rat in

Tlqution for rynthfoist


p-2 +


*2 El + 2 Hp


+ 2 IUO + 2 20


Molecular eFormulh . . . . . .


BolIline Point . . . . . .. .
S . . . . . . . . . . . .
a25 . . . . . . . .
Yinld of Tarified Product, . .. .
Anrlysir -- TitroCon, $t


. .0 1301

. 196.677
157.2-158.2'/5 mm.
S. . . 1.5985
. . 1.1897
S* . 304


Caloulatod .
ounda . 4

Charactori nation


c* 4 *4
* a 4 a a


. . . . 14,24
. .. . 14.15


13cnsayl-4I-(3h-chlo ropin.nyl)p in.ra ine nonhydrochlorides

1!olting Point . . . . . . *
Annlycis *- Nitrogen, %"


Calculated . a
Found. .. .
1-Acet yl-4J- (-chlorophcnyl~pip eras ina

lioltliv Point . . . . .
Annlynin *) Tttrogen, ;t


Cleculato. .* * .
Found. . . . .


158.3-159.8*


. . 8.31
. . .* 8.50


. . 142.2-44.2'


. a 1.70
. . 11.70


- -- I--' "I


) H/ 'CH.0C1 2








23
l-(2-.Chlorohtaenyl)piperagi6 an&d Charasterization Derivatives

in a one-liter, three-necked flaskL fitted with thermometer,
powerful mechanical stirrer, and distilling tBpvwith reflux condenser
were placed 280.6 g. (2.2 moles) of o-chloroanilino and 210.3 g. (2

moles) of diethanolamine. These mines were neutralizese with 420 ml,
of concentrated hydrochlorie aeid (3?% 01, sp.gr. 1.19). Heating was

so regulated that water distilled continuously into the distilling
trap; a total of 392 al, was removed (calculated V~lXme, approximately

405 al.). The hydroehlorides in this synthesis were not rntual3y sel.
uble~ therefore more care than usual was necessary to prevent super-
heating. The reaction mixture was neutralizedL with 180 g. of sodium

hydroxide dissolved in 300 ml. of water. Whe oil which separated was
distilled under water-wpump vacm to remove low-boilingt materials, and
l-(2..chlorophenyl)plperazine me collected at 133.9-134.90 at 5 mn.

The benzoyl derivative was prepared by shaking l-(2-.hloro-

pheayl)piperazine with a slight excess of benzoyl chloride in the pres-
ence of excess 10 per cent sodium hydroxide solution. l-Benzoyl-4-(2-
chlorophenyl)piperazine was recrystalli ed. from ethanol*
The acetyl derivative was prepared by refltuing l-(2-chloro-
phenyl)piperasine with a three-fold excess of acetic anhydride for thir-
ty minutes. This mixture vae poured, into 100 ml, of ice water and made
basic with sodium carbonate. The oily layer was extracted with ether,

the ethereal solution dried. over anhydrous potassiue carbonate, and the
ether evaporated. The product was reerystallized from boiling heptane6













I-( 2-Chlorot~heaxwlnierasitn

equation for Synthesias


2 + H -O+ 2 HOl C-* 2( ( IT-1* 28X1 + 2 %0
E^ 2 O^^0 \-f(


+ 2 aN&O + 2 H20


Molecular Foratla . . .. . * *

Molocul,.r Weight .
Boiling Point. . . . . . . . . .
n25 . . . . . . . . . . .
n25
, . . . . . . . .
Yield of Purifiod Prodtet, % . . . ...
Analysis -- Nitrogen, %


Calculated.
Found. .


ft t t t t f f f f
ft t t t t f f f f


S.. O^10H3N201

S* ., 196.677
133.9-134.90/5 man
. . . 1.5794
... . 1.1763
* 32.7


. . . 14.24
. .. 14.04


Characterization Dorivatives

-Acetyl-4- (2-chlorophonyl)piperazinot

Melting Point .* . . . ..
Analysis -- fitrogon, %:


Calculated .
Found. .


1-Benzoyl-4-(2-hlorophenyl)piperasinet

Melting Point . . . . . .
Analysis -- Nitrogen, %:
Calculated .
Pound. .


ft ft ft ft f


ft t t t f f f
ft t t t f f f



ft t t t f f f


. 65.5-67


S. 11.73
. 11.86



130.5-132*


. . . . 9.32
. . . 9.43









25
1-PhA11-2-tetlyb1iteratie and ChaMaterization Derivatives

In a two-liter, three-neledb flask fitted with thcronooter, me.

chanical stirrer, and distilling trap with reflux condenser were placed

204.8 C. (2.2 moles) of aniline end 238.3 g. (2 noles) of IT-(2-hydroxy-

ethyl)-l-amino-2-propanol. This mixture was stirred thoroughly an&

neutralized with 350 al. of concentrated hydrochloric acid. Then heating

of the reaction mass with an electric mantle vas started and was so rega-

lated that vater distillle continuously Wattor vas rcnoved at intervals

through a stopcock in the distilling trap; the volume removed, 322 al.,

corresponded very well with the theoretical quantity of atproxiM tely

340 ml. The temperature was maintained between 200-2300 for six hours.
The reaction mass was then neutralised with concentrated. sodium hydrox-
ade solution. The oil which separated was first distilled under water.

puVp vacmun to remove low-boiling materials; l-phenyl-2-mcthylpiperaeine
was collected at 138,5-140.50 at 10 t The yield was 108 g.(or 30.7?).
The phenylthioarea of l-phenayl4.aethylpiperasine was prepared

by heating a small amount of phenylleothiocyanate with an equal volvae

of l-phenyl-2.-ethblpiperazine on a stea 'bath for fifteen minute.

The phenilthiourea was reorystallised from ethanol.

lAe-etyl-3netbyl-.phonas lpipersBtne vas prepared by refluxing
l-phenrl-2-met1hlpiperazine with a three-fold excess of acetic anhy&ride

for thirty minutes, The reaction mixture was poured into 100 ml, of

ice water and then was neutralized with solid sodium carbonate. The

oil which separated was takon up in ether, the ethereal solution dried,

and the ether evaporated. The residue was reorystallized from heptane.










26

l-Phenyl-2-Me thylspiora1n1ne


equation for Synthesis:



+ N-H + 2 HOI -
H&sCHi-0 E2


: 2 HC1 + 2 TO

I


+ 2 Na1I + 2 H20


Molecular Forula . . .

Molecular eight . .
boiling Point . . .
n25D . . . . .


Tield of Purified Product,$
Analysis -- nitrogen, %:


S # 0 # a 4 4 4


..1 .. 1162

. . ... 176.258
.138.5-10.5*/1 an.
. . . 1.5723


. . .. 30.7


gharacteri zat on Deriv-.tive
l-Ace tyl-3-methyl-4-phenylpiperazine:

Melting Point . . . . . . .
Analysis Nitrogen, %:


. 0 *


Calculated . ..
'ound. . . .

1-(N-Phwylthiocarbanyrl)-3-nethyl-4-phenylpiperazinet

Iolting Point . . ..... . .
Analysis -- Nitrogen, %t
Calculate . . .
Found. . . . .


15.89
15.95


57.4-59.4'


* 4 4
* 4 4


12.83
12.95


156.2-157.20


S. 13.49
. .. 3.65


Calculated.
Pouna .


* 9 9 4 4 4 9 9 *
* 4 4 9 9 9 4 4


- - - 1









27

laPhrMogl3e tlhypiperasine and Characterizatio Derivative

In a one-liter, three-necked flask equipped with thermometer,

mechanical stirrer, and distilling trap-reflux condenser woablaMation

were placed 186.24 g. (2 moles) of aniline and 266.4 g. (2 moles) of

H-(2-bydroxyethyl)-2-aaino--l.atanol, and the mixture was stirred

thoroughly. 'hen 350 ml. of concentrated hydrochloric acid (37 C01,

sp.gr. 1,19) vere added in such a manner that the heat of neatralisa-

tion did not cause boiling. Heating of the reaction mixture with an

electric heating mantle was started and was so regulated that water

distilled continuously and was collected in the distilling trap. At

intervals the water was drained off anl measured a total of 338 ml.

of liquid was removed. When this quantity of water had been removed,

the temperature reached 2300. The oil which separated was first

distilled under water-pump vacuum to remove lowv.boiling constituents,

and l-phenyl-3-ethylpiperatine was then collected at 147.8-149.80

at 10 am. The yield was 20.3 per cent of theoretical.

In order to provide a characterization derivative, the phenyl-
thiourea of l-phenyl-3-ethylpiperazine was prepared by heating a asall

qu.itity of pheayiaothioeyanate with an equal volume of l-phenyl-3-
ethylpiperasine on a steam bath for fifteen nihrates. The phenyl-

thiouroa wat reorystallized three times from boiling ethanol.









28

l-Pheny!-I-thylrieprznin


Equation for Synthocict

r )B 2C2H .


+ N-H + 2 (01 HN-H2 U01 + 2 H20


2 20


Molecular Formula .. . .

Ilolecular Velght. . . . .
Boiling Point . . . .
25D . . . . . . .
25e.
d . . . v . .
Yield of Purified Product, .
Analysis -- Nitrogen, :


a 9 v 0 *


Calculated . . .
Found. ... ...


& . ... a X1802

. ... . 190.284
147.8-1.49.8l.10 ,nm.
. . . 1.5635
. . . 1.0327
. . . 20.3


. . . 14.72
. . .0 14.66


Caracteruixsaton erivattve


14l.-Phonylthiocarbanyl) -2- othyl-4-phanylpiperazlne i

Melting Point ...... . . 184-185*,5
Analysis Hlitrogon, %t
Caleulated.... . . . 12.91
Found . . .. . . . 12.99


NaOH


SI









29
Diseusion of Eertiental Results

It was noted in the discussion that the synthesis of aryl

pipcracinoe is not new. However, tho nrthod of synthesis prosentc

here has beon applied og to the synthesis of l.phevylpiperazine.

Prelog and 3laze76 used the reaction between salts of 2,2*-aihrlo-

diethylanines end aromatic amines to synthesis 1.-metjbhlphen)y)-

piperazine and 1-(2.methylpheAyl)piperazine. The other eomponds

synthesized are new to the literature. This Investigation marks the

first successful attempt to introduce alkyl substituents on one of the

carbon atoms of the piperazine nucleus in a l-arylpiperazine by the

route outlined. Bain and Pollardl reported that the synthesis of

Pollard and MKacDovel133 could not be extended conveniently to the

preparation of 0-substituted piperazinee from arylamines and di-

isopropanolanine.

In the preparation of 1-(1-.chloropheny)piperazine and 1-(2-

chlorophonyl)piperazine, the ratio of aroimatic amine to diethanolamine

was 1.1 to 1 as compared with a 1 to I molar ratio with the other

mines used. In the case of l-(4.chlorophen~l)piperaizne, in particu-

lar, the yield is much higher, 52.3 per cent, than for the other

piperasznes prepared. However, 1.(h'-chlorophenyl)piperazine is ex-

tremely insoluble in water, and it therefore may be more easily iso-

lated. Since larger quantities of several of the piperazines were

required, some preparations using an excess of arofmatic amine and

the method described for 1-(4-methylphenyl)piperasine were carried

out. The results are summarized in Table I.









30

TABLE I

Comparison of Percentage Yields in Syntheses with Excess of Aromatic
Amines andl Without Excess of Aromatic Aninee

Moles of Holes of I Yiell, %
Amine Used Aromatic Diethan- Using Not Using
AMne olamine Excess Bxeeaa

_-Soluidine 4.2 4 42.2 26.5
M-Toluidine 3.35 2.96 55.6 22.8
hyChloroaniline 4.2 4 51.3 38.4


In all of these preparations removal of water was as rapid as

possible and rwLpired approximately five hours heating at 215-225.

Thus, it wuld seem that best yields of the substituted phenylpipera-

sines are obtained when a light excess of aromatic amine is used and

when the heating time is kept at the minimum.
The effect of introducing substitu ats on the dieth~nolamine

nucleus is illustrated very amply. In the case of l-phenyl-3-ethyl-

piperazine the yield is especially low. However, the yield of 1-phenyl-

2-methylpiperazine is comparable uith that obtained for the methyl-

phenylpiperaaines using the same method of synthesis.
Attempts to extend this synthesis, by use of the method outlin-

ed, to include cyclohealamine, methylamine, ethylamine, and 2-amino.
24
pyridine were not successful. In view of the fact that Howard has

recently been granted a patent for the preparation of alkylpiperazines

by condensing diethanolomine or its alkyl derivatives with a primary al.

lqr amine in the presence of dehydration catalysts at about 2500, it is

possible that under the proper conditions the reaction could be achieved.












clAPUM-n IV


AlirO ALCOHOL T0,' VAT'I7ES

Revi -of the Literatbay


The preparation of alkanol aminese by the reaction of mines
or amionia with a 1,2-epoxide is a wellaknovn process in synthetic

organic chonistry. The reaction of an aqueaos solution of ammonia
vith ethylene oxide was first investigated try Vtqtz XtZis e23 also

investigatUd the reaction anda in 1897 reported that ethanolamine,
diethanolanine, and triethanolamine were formed in relative quanti-

ties dependent upon the concentration of the ammonia employed.
From first observation it would appear that an =asynmetrieal

1,2-epoxide wvold be capable of reacting with camonia to give two
products:



\ t/ N R-ca-Ca
0 A

Kraasousn 6 after investigating this reaction an& several others

very similar to it, formulated a rule in which he said Unsymetricai
1,2-epoxides combine with armonia to form amino alcohols in which the
hydroxyl rouip is attached to the carbon nton which, in the original

compound., was associated with the least unnber of hydrogen atoms.
PTrther asibatnntiation of the work of Krassaonky is found in

the reaction of benylethylene oxide and amnonia reported by Castro

31








32

and 1oller.,1 these investigators feoud that the product of the re-

action between benzylethylene oaide anz ammonia is Identical vith that

formed by the condensation of phenylacetaldehyde with nitronethane

and therefore is 1-nino2.-ydr.oxy-3-phleny propane.
The presence of water in a reaction mixture of amonia or

amine and 1,2.-pozide has usually been considered essential for

reaction. ~KorrZ observed. that although aamonia, methylomine, or
etbyleamne may often act violently upon ethylene oxiCde, they react

with it only very slovly or not at all when quite dry. Whitmorew3

stated that diathylainie and asaonia did not unite when dry but that

they react readily in anhyidrous nethawol at 40.6o0. traseouske6
observed that 2-metbyl-2,3-epo3ybutaa e did not react with anhyro

amonia but did react in sealed tubes at 1000 vith a 33 per cent

solution of ammonia. Schwoeglet0 has described a process in which

a substantially anhydrous aliphatic primary or secondary amine was

heat. to 18-0-2000 and an equivalent amount of a substantially an-
hydrous alkylene oxide vae a6ded in such a manner that it reacted

as rapidly as added and thereby avoided a material increase in temper-

ature. n'-ms, it would seee that water may be necessary for the re-
aetion unless high temperature is employee
Several synthetic routes are available for the preparation

of amino alcohols derived from phenylpiperasines. Prelog and 3laaek7

reported the synthesis of 1-pheyl..-(2-hyd.rozpethyl)pipertaine tb

treating 1-phenylpiperazine solvedd in methyl alcohol with ethylene

oxide. Adelson and Pollard2 prepared the same compound by reduction











of N.-phenylpiperazino-s'-ethyl p.ceRs.to with soditm and a-butyl alco-

hol, A unique method for the synthesis of l-phenyl-4-(2-hydroxy-

ethyl)piperazine is found in the method of Kremoer27 wio mixed. tri-

ethanolaaine and aniline in molecular proportions and caused dehydra-

tion to the piperazine ring by treatment with sulfuric aoid. Anderson

and Pollard have synthesized a series of L-phonyl-4-(4*-hydo"Walkyl)-

piperazinee in which the alIky group contained from four to ten carbon

atoms by reacting 1-phenylpiperazine with the correponding 6 a-

chlorohydrin in the presence of excess ~1phenylpiperasine. Cerkovni-

koa and Stern2 have eyntheetsed a number of derivatives by starting

with 4-phenylmorpholine, opening the ring with hydrobroeic acid in a

sealed-tibe reaction, and finally reacting the 2,2'-dibromodiethyl-

aminobensene with ethanolamine or any other desired. sbstituent:








Sz 2HBr
(D--O.Cr .- ,CH2 2


Bachman and Mayhemw report the re tiont of l-phenalpiperazine with

ethylene oxide, propylene oxdde, and epiahlorohydria.
naeinmeh as several 1,2-epoxides are commercially available,

the reaction between the piperasine and the desired epoxide was used

to syntheetse the amino alcohol herein reported. The ethylene oxide

used was a commercial product and was obtained from a large cylinder

immediately before use. The preparation of l,2-epoxy-3-methoxypropane









34

as described by Flores-'allardo and Pollard,15 was from 1-chloro-2-

hydroxy-3-methoaypropane which had been prepared by reaction between

epichlorohydrin and excess methanol in the presence of sulfuric acid

as catalyst,

Since several investigators have described the use of water

for its catalytic influence in reactions of ethylene oxide ~ith amines,

small Pmounts of water have been used in some of the reactions. Horne

and Shriner23 report that in the reaction of diethylsmino with othylono

oxide methanol is the best solvent because it is rost easily separatod.

It also has the added advantage of boiling: just above the optime

temperature ascertain. for the reaction, 45-10E .


ExPeritentala Wor

Syntheses of the amino alcohols prepared urging the course of

this research are described individually in the following pages; each

description is accompanied by a data sheet which tabulates some proper-

ties of the compound.









35

1.4-11etylphenyl).4.(2 hyd roxy3-methohypropyl)piaperin

In a 200 jal., throo-neclced flash : fitted with reflux condenser,

tneraometer, and mechanical stirrer were placed 35.25 g, (0.2 mole) of
1-(4-methylphenyl)piperasine and I ml. of water. This mixture was

heated to approximately 600, and 17.6 g. (0.2 mole) of 1,2-sposy-3-

methoxypropane were added dropvise during a period of one-hlf hour.
The reaction temperature climbed during addition and was maintained

between 100-140 for five hours. At the end of this time the reaction
mass was allowed to cool a few minutes and then was poured into a

beaker. The product solidified on cooling and was recryotnllizoa
twice from boiling heptane. Daring the second recrystallization
the heptane solution was decolorized with WxTorite", a decolorizing

charcoal. The yield of purified product was 32.2 g. (or 61%).

The product, which was dried in a dea-icator before analysis, melts

at 77.5-79












36

-( -MetgyL^hayg3).(2hyd^roz3y-3-methoaUpropyl)piporazine

Equation for Synthesis:






HOH




30-04CA'!


Holeoular Formla a . . . . . .

Molecular Weight. .. . . .

Melting Point . . . . .

Yield of Purified Prodnct, *. . .

Analysis -- Nitrogen, :


* 9 9

* 9 .*

9 9 9 9 9

* 9 9 9


C05H241202

. 264.362

* 77,5-79

. 61


Calculated 4 ... 9 . 104+59

Pound* . . . . . 10.45


Solubilitiest






Ether . * . . , .

Acetone . . . . . . .

Benzene . . .

Heptane [Recrystallization Solvent] .


* 9 9


* 9 *

9 9 9

* 9

* 9 9


. Insoluble

. Soluble

. . Soluble

. . Soluble

S. . Soluble

.,. Insoluble










37
1-(3-Methylphengl)-4-(2-hydroxy-3-nemth33propyl) pi2cragine


In a 200 ml., three-necked flask fitted with mechanical

stirrer, reflux condenser, ana-thermometer were placed 35.25 a. (0.2

mole) of l.(3-methylphenyl)piperazine and 0.5 ml. of water. This
well-stirred mixture was heated to 680 vith an electric heating mantle,
the he-ting vas discontinued, and 17.6 g. (0.2 mole) of 1,2-epoxy-3-
n-thoxyproppne were added dropwise through the reflux condenser.

Addition required 25 minutes, and the heat of reaction caused the
temperature to rise to 1000. The temperature was naint.ined at
110-1150 for one and one-half hours. Finally the mixture was cooled
aliritlyS and poured into a beaker. On cooling the product solidified
and was recrystallized from boiling heptane. The yield was 23.6 g.
(or 44.6%). The product, which was dried in a vacuum dessicator
over solid potassium hydrozide, melts at 56.5-57.5.










38

l.(^3rlethylphenyl) .4(2.. droo -3-methoxypropyl)piporazine


EqDiation for Synthesis;



C,- I- /0\
01-z 0s a
CL^^


Molecular formla , ,, . . . . . .

Molecular Weight. . . . ..

Melting Point , . . . . ..

Yield of Purified Product, . .. . %

Analysis -- Nitrogen, %:


C15124 T202
. 264.362

56.5-57.e
* . k-4.6


Calculated . . . 10.59

found. #. . q . . . . . 10.40


Solubilitie;s


Water .
Ethanol

Ether .

Acetone

Benzene

Reptane


. . . . .9 . . . . . Insolble

, , . . . . . . . . .Soluble

, 9 9 9 . . . . . . . Soluble

. . . . . . . . . ... .. . Soluble

* 9 4 . 9 . 9 . . 9 9 . Soluble

[Recrystallization Solvent) . . Slightly soluble










39

l-("2iHthylphenyl)- l(2-hUyIro$xy^-i:tgn h ropyl)piperagine


In a 200 ml., three-necked flask fitted with reflux conden-

ser, mechanical ctirrer, and thermometer were placed 35.25 g. (0.2

mole) of 1.(2-methylphenyl)piperazine and 0.5 ml. of water. This
mixture was her.ted to 57 by inmeana of an electric her.tinr mantle, and

17.6 g. (0*2 mole) of 1,2-epoxy-3-methoxypnropano were added dropvise
through the top of the reflux condenser. Addition required 25 minutes,
and at the end of the addition period the temperature had climbed to

118. The reaction mixture was maintained at 115-1200 for a period
of one hour and fifteen minutes. Then the mixture was cooled to 70
pnnd poured into a beaker. The product did not solidify on continued

cooling and was therefroe distilled through a short, unliected Vigrerux

column. Distillation yielded 24.7 g. (46.7%) of product boiling at
161-1650 at I um, The compound was a super-conled liquid and solidi-
fled after the bottle in which it was stored was shaken. The melting
point is 38-39o.










(yO

1-( 2-1ethglphgn0i).4-(2Lh.droa*3-maethouro )ip ine


Equation for Synthesis:


/0\
+ 0 2-CK-CH2-c!


S03
MolecularSoyffla . . F o r t . . 5a 20,


Sj 4 j 4 *4


Hloleedwar Velht. .

boiling Point P o n t *

Yield of Purified Prod=t, . .

AnaPlysis -- Nitrogen, %:


Calculated .

Found. 4 .


* . 264.362

161-16501 sUM;

* ; 46*1


* 9 9 9 9 9 4 9 9 10.59


Solubilities:

ater . .

Ethanol .

Ether . .

Acetone .

Benzene . .

Heptane .


.Insoluble

. Soluble

S Soluble

SSoluble

* Soluble

. Soluble










41

l-f 4.Chloropho1g). -(- 2.hyroxy^-^3ethoxpropyW)Diperazin


In a 500 Ml., three-neeoed flask fitted with reflux condenser,

mechanical stirrer, and dropping funnel were placed 19.66 (. (0.1 mole)

of 1-(4-chlorophenyl)piperazine dissolved in 100 al. of c ~crrcial

methanol. Then 8.8 g. (0.1 hole) of 1,2-epos-3-nethoypropane were

added to the well-stirred mixture of l-(4l-chlorophonyl)piperazino and

methanol during a period of fifteen minutes, After the addition iad

been completed the mixture was refluxed for a period of three hours

by ILrtinrl the reaction vessel with an electric heating mantle. At

the end of thi time the nothcnol vas removed under water pup vacuum

and the residue was cooled. The solid which separated was recryst-llis-

ed from boiling hioptanc and yielded 13.5 -. (47.5;) of product. The

compound, vhich was dried over solid potassium hydroxide in a vaeuma

doesicator, melts at 78-79.5.










42

1-(4 -Ohloropheyl).(2fetho rop) eraine


Equation for Synthesis:











,3+CM -(""SH2 -O^-CH-OHH2
,2

Molecular Formula .. . . . .


* 0 0 v 0 *


v e21 220


Molecular Welght . . . .

Melting Point. . . . . .

Yield of Purified Product, % .

Analysis -- Nitrogen, %I

Calculated

around. .



Water . . . .

Ethanol .... .

Ether . . . . .

Acetone . . . . .


Sensene . . . . .


. . . . . . 284.781

. . . . . 78-79,5*

. . . . . . . 47.5


. . 9.84

. . 9.56


. . . . .. Insoluble

. . . A . Soluble

, . .. . . Soluble

. . . . . Soluble

. .. . . Soluble


Heptane (Recryctnlliration Solvent] . ., .Insoluble (cold)












1-(3-Chlorophenyl)-4A(2-hydroxr3.othorrropyl)pipeiBra! ine

In a 200 sa., three-nelc~d flask fitted with ne hanical

stirrer, reflux condenser, -ud thernoneter were placed 39,3 g.

(0.2 mole) of l-(3-chlorophcnyl)piperazine and 0.5 ml. of water,
This well-stirre& reaction mixture was heated to 780 with an elec-
trio heating nontle, and 17.6 6. (0.2 mole) of 1,2-epozy-3-nmthoxy-

propano ware addod dropwise during a period of thirty minutes.
HeatinC was discontinucd during the addition, but the temperature

after completion of the addition was 1150. After the temneraturo
hal been maintained at 110-1200 for two hours the mixture was cooled
slightly and poured into a beaker to solidify. the crude material,
recrystallized from boiling heptane, yielded 19.5 g. of product (or

34.4~). The purified product, which was dried in a vacumn dessicator
over solid potassium hydroxide, melts at 58.8-59.80.


















Equation for Synthesist





2 %


08


"on--rIH
1W-C,
r^ ^^"2 3


1iolocular Formla . . .

Molecular Voight. .

Molting Point . . . .

Yield of Purified Product, e

Analysis -- Nitrogen, 1t


Calculated.

Found .


Solubilities:

Water . .

Ethanol .

Ether . *

Acetone .


9 4 4 9 9 '4 9 . '* '* '



.0 2 '4 '


. 9 .4 9 * 4 0 0 *


* * 9 9 * 9 0 4


4 0

494)


9 p 9 .4 4 .0 4 9


9 4 .4 i .4 4 *4 .4 49


Ben2ene V, . .4 0 0 9 9 .&


. 14T-21h02C1


. 284.781

58.8-59.86

* 34.4



S.. 9.84

*. 9.81


. . Innoluble

*. . Soluble

* 4 Soluble

S. .* Soluble

.. Soluble


Heptane [Recryetrllization Solvent] .


9 9 # & *94 *0'0 4 p .&


1-(3-Chloroghetl)-4-(2-~byroxy-3-mehoxpropy 1 iperz2Yn


. . Insoluble (cold)













1-(2-OhlooMThenyl)-4-(2-hyd'roxy-3-m'thonytroy ^ioorazine

In a 200 ml., three-necked flask fitted with reflux condenser,

mechanical stirrer, and thermometer were placed 39.3 g. (0.2 mole) of

1-(2-cllorophenyl)pimraz3ne and 0.5 ml. of water. This well-stirred

mixture was heated to 55* by means of an electric hosting mantle and

17.6 g. (0.2 mole) of 1,2-epoxy-3-ncth -ypropene were added dropwise

during a period of 20 minutes. Dnrin~ addition the temperature

climbed to 1400. After addition was conmloted the h.e-ting wans o

adjusted that the tenmprature remained between 125-1300 for a period

of one hour and fifteen minutes. Then the mixture was allowed to cool

to 750 and finally was poured into a beaker, The product solidified

in the beaker and was recrystallized four times from boiling heptano.

The compound was extremely insoluble in heptane and did not go into

solution easily unless boiled. The yield of purified product was

40 g, (or 70.4 ). For purposes of analysis, the compound was dried

over solid sodi'a hydroxide in a vacima deanicator. The melting

point is 90-91l.50











46

1-(2-Chlorohoenyl)-4-(2-hy roxy-3-methoxproroyl)iperaRzin


Squation for Synthesist


21) + C-0H2-Oii-O- -

01
OH
*-"t /C L -CIU

( HJ J ^H,^C^-<^-


Molecular Formula . .. .

Molecular Weight. . .

Melting Point .. ... .

Tiel of Purifie& Product, % .

Analysis Nitrogen, %:

Calculate ed.

touhd .

Solubilitiest

Vater . . . . .

.tlhenol . .

otherr . . . *

Acetone .. . . *

Bensene . . *

Hoptane . . . .


* *


*








4.'


*0 1421 '201

*. 284.781

S*. 90-91.5e

.* .. 70.4


* .9.84

* .9.59


. . Innoluble

.Slightly soluble

. . Soluble

. Soluble

*. Soluble

. Insoluble












1-Phenyl-24.thy-4-,(2-h droxy-3-n tho- ronyl) ie raz ne

In a 200 ml., three-necked flask fitted with reflux condenser,

mechanical stirrer, and thermometer were placed 35.25 g. (0.2l ole)

of 1-phenyl-2-methylpiperazlne and 1.0 ml. of water. This well-stirred

nizture was heated to 60-70, and 17.6 ~. (0.2 mole) of 1,2-opoxy-3-

methoxypropane were added dropwie dauing a period of twenty minutes.

During addition the mixture started refsuxing, but it stopped later

as the reaction progressed. Heating of the reaction mixture at a

temperature of about 110-1300 vas continued for six hours after
comnletion of the addition. The mixture was then poured into a beaker

and allowed to cool. The product did not solidify after continued

cooling; therefore it was distilled froma Claieen flask. Distilla-

tion yielded 29.6 g. ($6% yield) of product boiling between 170-

180 at 1.3 em. Efforts to prepare the hydrochlori& of this compound
for analysis were not successful. Therefore the sample was redictilled,

and the fraction boiling at 151.5-153.5* at about 0.3 mm. was used

for analysis.











48

1-Pherny1.2-met yl-4J(2- yaoxyo3-?mnrtho. ropy1)piperasine


Equation for Synthesis:




0H.C-CH2 A
( __ __ )*.g c -- -0-015


W 6 # * *4


1oleecular Weietht. .. . . .

Boiling roint. ... .. ,. ., . .


n25E


. 4 4, 1 4 a 4 0


S. . . . . . .

Yield of Purifiea Produet, . .

Analysis -- TJitroen,, :

Calculated.

Poun.l ., .


6 4 4

* . .

. ; .


. 15* 4 202


. ... . .. 264.362

. 15.5-53.5 f o0.3 rn.

. . . . .1.5435


. .1.0704

* 56


.. 10.59

. 10.39


Solutilities:

i'ater .

Ethnnol ...

:the . .

Acetone . .

Benzene . ..


*, 4 4 4. 4 4 4 4 4

4 4 4 4 4 4 4


Insoluble

. Soluble

. Soluble

. Soluble

. Soluble


. *4 0 4 0 4 &


S. .Slightly soluble


HITCetne ,


Uoleeular Form ula a .. . ..


4 .


Ci











-(le thlhe-nyl)-(2ithl)pieras ine


In a 500 al., three-ncked fa fakfitted with nochanic1

ntirror, rrflux c-ndenser, and a Cas inlet-tube which e-tended to

the bott'n of the flask end did not interfere with the stirrer ac-

tion vore -laced 0.2 mole (35.25 g.) of l-(4-mth;lphenya)plperslne

dissolved in 75 ml. of commercial methanol. Into this well-stirred

mixture a slight esxess (actual requirement for complete reaction

was 8.81 r.) of ethylene oxide w:n rllowed to distill slowly enou~)l

that the reaction mixture did not boil. Althoth he temperature

of the reaction mixture increased, no external cooling was used.

After naditton of the ethylem oxice had been completed the reaction

mixture was stirred for several hours at room temperature. Finally

the methanol was removed under water-pump vrnaun. The residue was

placed in an ice room here it solidified. This crude materi-J. ,:as

discolved in boiling heptane, and slow cooling gave beautiful needles

of 1-(4t-methylpionyl)J4-(2-hydroxyethyl)piperasine. Several recrys-

tllizn tions were necessary to tive the ,olting point of 51.5-52.50.

The yield of pnuriflied product, which was driod in a vacuan dessicator

over solid potassiun hydroxido, was 35.5 per cent.










50

1-(4-liothylpheag l). (2-hydaroxyathyl)piperaziAe.


equation for Synthesis:








+ -OH j-'- C2--
-?~ ~ v"-' 'a,"2)

S-o-/ )-^( 'P"IMH~C ry-^s
:? -. YI ff-O1E


Holecula-r oronmla ..


. 4 0 4 0


* .... 3 2020


!Iolecular Yoicit. . * *

Kelting Point . 4 . 4 4

Yield of r~-ified Produet, % .

Analysis -- Hitrogon, ft


* . . . . . 220.31

. . . . .. 51.-52.50

. . . . * * e 35 5


Calculated.

Found . .


Solubilitiesa

WVator . .

EthanOl . . . .

Ether ... ..

Acetone . .


. 12.72

S. 12.67



Insoluble

. Soluble

. Soluble

, Soluble

* Soluble


Moncone . . . . * * *


Aeptrae [Recrystallization Solvent] . . .. . Insoluble










51



3n a 500 ml., three-necked flank fitted with reflux condenser,

mechanical stirrer, and a tube for introducing a gas near the bottom

of the flask aere placed 35.25 g. (0.2 mole) of l-(3-methylphenyl)-

piperazine, 0.5 m of water, and 150 al. of commercial ethanol.

Into this well-stirred mixture a slight excess (0.2 mole is 8.81 g,

of ethylene oxide was allowed to distill in a manner that did not

cause the mixture to .boil. Otirring was continued for an hour nfter

completion of the addition, and then the methanol was removed under

roducef pressure. Mhe residue was placed in the ice room. After it

had been seeded with a small crystal obtained by carefully drying and

cooling a small portion of the reaction mixture the material became

solid, and several recrystallizations from boiling heptano yielded

a product which melts at 67-68.5. The product vae T ried in a

vacuamn dessiator over solid potassium hydroxide before analysis.

The yield of purified compound was 31.8 per cent.











52

1-(3*etylThenyl) -in


Equation for Synthesist


o\+
+ ong2oIa


4 p


E-H2-OH~


Molecular Formula . ..

Molecular Weight. .

IMelting Point . . .

Yinld of Purified Product, % .

Analytie Nitrogen, 5s


4 0 4 4 4 0 *


ound.. . . .


Solubilitiee:


Vater . .

Sthanol . .

Ether . . .

Aeetone . .

Berzene . .


. a . ..01 20 12


. .220.31

67-68. 5

. .31.8



. 12.7

. 12.65



Insoluble

. Soluble

. Soluble

* Soluble

. Soluble


Heptane [Recrystallisation Solvent] .


. Insoluble (old)










53
l-(2-Methlph i).-4(2.hydroyetyl)pipraine

In a 500 ml., three-necked flask fitted with reflux condenser,
roc~lanical stirrer, and a tube which allowed a gas to be introduced
near the bottom of the flask were placed 35-25 g. (0.2 mole) of 1-

(2-methylphenyl)piperazine, 150 mal of commercial r~ithanol, rnd 0.5

ml. of rater. To the well-stirred mixture of these materials a slight
excess of ethylene oxide a added in a msnner that minimized hosting

of the reaction mixture. Stirrin- tas continued for an hour after

the addition had been completed. The nethmnol waS then nlloved to

evaporate on the steam bath. Since the resist~ was still liquid after

Being cooled in the ice room, the reaction mixture was distilled.

The product boils at 146-1&90 at 1.5 ma.; the yield was 28.9 g. (or

65. 6).
The dihydrochloride of 1-(2-methylphenyl)-4.(2.hydroxyethyl)-

piperazine was prepared by diasolving the compound in enhydrous ether

and precipitating the hyd-rochloride with pron:molic hydrogen chloride.
The hydrochloride was filtered off, recryrtallized from absolute

etihnol, and dried in a vacuum dessicator over sulfuric acid. The

melting point of the purified dihydrochloride is 158.3-159.8.












54

l-(2-ethyl'thnyl)4*(2-hylro3ytthyl)'piperaain


Equation for Synthesis;


S 0\
+ -OH2g0


Molecular Forma . . .

Molecular Weight. . . .

Boiling Point . . . .

n25 . . . . . . .
25
a25 9 . . . 9 .

Yield of Purlfie Product, % .

Solubilities:

Water.. .....

Ethanol* . . ..

Ether, i . .

Acetone . . . .

Bensne? . . . .

Reptane. .


9 9 9 * a p a

9 p 9 9 9

a a a a

a p 9 p a a 9 9

* 9 p 9 P 9 9

a 9 9 9 9


.. WrO20

. . .. 220.31

1.6-49/1.5 am.

. .. 1.5530

*. . 1,0660

. . . 65.6


S. . ......... Insoluble

. . . . . . . . Soluble

. . . . . . . Soluble

. . . .. . Soluble

. . .. 9 . . . . Soluble

. . . . . .Slightly soluble


1-(2jMethrbjiehnprt) 2-harQoethy)i,,,rasine d1 roohloride

Melting Point . . . . . . 15;8.3-159.8

Analysis Jitrogen, %:
calculated. a956
Calculate.. . .. . .. .. 9.5
Pound . . . . . . . . . . . 9.58










55

1-( -Chlorophenyl) -4- (2-bhylrp o thyl) oinc razing

In a 500 m., three-necked fla k fitted with reflux condonser,

mechanical stirrer, and a tube which allowed the introduction of a

gas near the bottom of the flask vere placed 19.66 g. (0.1 mole)

of l-(4-chloropheMyl)piperaSine dissolved in 100 nl. of irthanol.

Into this well-stirred mixture a slight excess (actual requironent

is 0.1 mole or /.405 g.) of ethylene oxide was elloved to clistill

in such a manner that the nisture did not boil. No oxternal hoating

of the nthylene oxide was necessary. Aftor addition of tlie thylene

oxide had been completed the mixture w as stirred sovorcl hours at

room temperature, and finally the r-thnaol was evaporated on the

otem "oath. The residue vas solid after cooling, auml rocrystallisa-

tion from heptane gave 19.5 g. (or 81.2% yila) of l.(L-chlorophenyl)-

4-(2-hy1roxyethyl)pipcraxine. ror analytical purpoos the compound

wat dried in a vaemum desseictor over solid potassium hydroxide.

Small pieces of paraffin were also placed in the dessicator to remove

heptano from the compound.










56

l-4*(hnalorophegl),n4t2-e3roxyethyl)ier


Equation for Synthesis



ODnCCzpc"z)14- + aOH2 ---
UJ <3B2^B2


Molecular Porila .. . ..

Molecular Ieight. . . . . .

eolting Point . . . .

Yiela of Purifiea Prod&ctb % .

Analysai Nitrogen, P


Caleulat~.a

S S Sd


Solubilition:

Water . . . . . . *

lithpnol . . . . .

Ether . . * . *

Acetone . . . . . .

Benzene ... . . .

Reptane (P.eerystallisation Solvent)


. . * . . O.. 20C0

. . . . . 0 . 2~0.733

S. .. . . . 107-.108.5

. . . . . . 81.2


. 11.64

. 11.86


. . Insoluble

. . . Soluble

. . Soluble

. . Soluble

. . Soluble
Insoluble (col4)










57

l (3 a-Clerophiagl ) -C2-hycdrozyethylwiperaz sine

In a 500 ml., three-necked flask fitted with reflux conden-

ser, nechanical stirrer, and an inlet tn'be through which a gas wold
be introduced near the bottom of the flask were placed 39.3 g. (0.2

mole) of 1-(3.-chlrophenyl)piperazine dissolved in 150 ml. of commer-
cial methanol. A small 'ount of water (0.5 ml.) was added for its
possible catalytic influence on the reaction of the ethylIne oxide

with the mine. Then a slight excess of etihlene oxide (actual re-

quirement was 8.81 g.) was allowed to distill into the flask so slow.

ly that the heat of reaction in the flask did not csase the contents
to boll. No external heating of the cthylone oxide container was

necessary. After the ethylene oxide had been added the reaction
mixture was stirred for an hour at roon temperature. Finally the

methanol was removed under reduced pressure. The residue was solidi-
fled by cooling in the ice room and was dissolved in butanol-1. In
order to recover the compound it was necessary to "seed"' the b~utanol

solution with a crystal obtained by evaporating and cooling a srnll

portion of the butanso olntion. Since recovery of product from
butanol was not satisfactory, subsequent purification was from heptcne.

The product, which was xdied in a vacum dessioator over solid potassium

hydroxide, melts at 97.5-98.5o, and the yield was 15.8 g. (or 33%).












58

1-(3-Chloroher nyl}- -(2. droxrthyl)pierati e


Equation for Synthasia:



S2-9 + -CH, ----


Molecular formula . . ,,


Molecular Weight . . .

Melting Point . ... . .

Yield of Parified Produet,

Analysis -- Nitrogen, %:


Calculated.

Pounds. .


Solubilitiest

fatr .

ethaoel



Acst one


ft t f


ft t f


Senzene *

YTotana CUse :


t f .t .t t ft f f


* f f f f

ft t t f f


C1Wf 17N001

. 240.733

97.5-98.5*

. . 33



S. 11.64

11.63


. .. . . . . . f . Insoluble

. . . . . . . . . . Soluble

. . . . . . . Fairly soluble

. . . . .t . .. .... . Soluble

. . . . ... . . .f .. .. Soluble

for final reorystalligation]. . In-oluble


nttenol (Recrytaallization Solvent]. f .Very lightly aoluble


ft t t t t t t f f f f f f f

ft t t t t t t f f f f f f f

ft t t t t t t f f f f f f f









59

1.Pheql-24Methyrl-J(2*hydreothyl)tiperas

In a 500 ml., three-necked flask fitted. with reflux conden-

ser, mechanical stirrer, and an inlet tube which permitted gas to

be introduced near the bottom of the flask wore placed 35.25 g.

(0.2 mole) of l.henyl-Ziaethblpiperazine dissolved in 80 ml. of

methanol to which 0.5 ml, of water had been added for its possible

catnlytic effect. Into this well-stirred mixture a slight excess

of ethylene oxide (actual rerequirent was 0.2 nole or 8.81 g.) was

allowed to distill. ?No external heating of the ethylene oxide gener-

ator was necessary. After addition of the ethylene oxide had been

completed the mixture was stirred several hours at room temperature.

Finally the methanol was removed under water pump vacuum. Since

the residue did not solidify on continued coolitn, it was distilled

from a Claieen flask. The prod et boils at 167-1720 at I am.; the

yield was 32.7 g. (or 7?).

The dihydrochloride of this compound was prepared by passing

anhydrous hydrogen chloride through a solution of the compound dissolved

in anhydrous ether. The compound was filtered as soon as precipitation

was complete and was recryotallized from anhydrous ethanol. The com-

pound, which was dried in a vacuva dessicator over sulfuric acid,

nolte at 235.2-236.50.












60

heony1-2-Mathtl^Yl-^(2-h-yroxyethyl )pierazinje


Equation foy Synthe~sfa



)-% + CHH


Molecular Formula

Molecular Weight.

Boiling Point .

25 . . .

25 . . .

Yield of Purifled

Solubilitiest

lVatr .

thanol .

Mother .

Acetone .

Benzene


* a u



Preauct


Hentano a *


l-Phenyl-2-me thyl

Meltittn Point . .


*

*


* * 01320 2

....** 220.31

.167-1?2*/1 mm.

S. . 1.5618

. .. .1.0741

. . . .74


. . . *. . . a a * Insoluble

. . . . a . . . Soluble

. . . *. . Soluble

S.. .. .. .* a . .* . .* Soluble

. .. . . . **Fairly soluble

.. . . . . . Slightly soluble


-4- (2-hyr.rozyethyli )n)pnera e thrd.rociLorid- e

. . a a a a . a . .235.2-236.50


Analysis -- Eitrogen, %:
Calculated.. .. . .
found .. .. . .


. . .* 9.56
Sa a 9*.3










61
lPhenyl-3-ethyl (2.ay1roetyl)piprain

In a 500 ml., three-neaoed flask fitted with reflux condemn.

ser, mechanical stirrer, and an inlet tube which permitted a gas to

be introduced beneath the surface of the reaction mixture were placed

38 (0.2 mole) of l-phenyl-3-etbylpiperasine dissolved in 150 ml.

of methanol. Into this well-stirred reaction mixture a light ex-

oaes of ethylene oxide (0.2 mole is 8.81 g.) was allowed to distill.

No external heating of the ethylene oxide generator was necessary.

After addition of the ethylene oxide had been completed the reaction

mixture was stirred several hours at room temperature. Then the

methanol was evaporated on the steam bath,. Since the residue did

not crystallize, it was fractionated at reduce pressure. The first

distillation of the crude material through a Vigreaxz column yielded

31.4 g. (or 67 yield) of material. Since the nitrogen analysis of

this material did not correspond closely enough with the theoretical

valtta, the product was redistilled through a 50 an. colmim packed
with one-eighth inch Serl seddles. The product boils at 156.7.158.20

at 2.2 m.












62

l-Phfhnyl-"3-ethyl-4-4(2-hydroxyethXyl)vieragine


equation for Synthesis$


A
le
+ o n,- asS, --*




r^j~ ?"CI -CF -OS
^ C OBj-JI 2


Molecular Formula .


*S 0 w


Molecular Weight. . .

Moiling Point . . ..



25D . . . . .


Yield of Purified Product, %

Analysta -- itrogen, %I


* S *


* 9 5 9 5

959r 9 9

9 4 9 5 9

* 9 9 9 9

9 9 *- 9


S. . 234*336
....* * * *55.6

. 54.7-158.2*/2.2 mn.

. . . .1.5567

. ... ,. .1.0584

* . . * .67


Calculated.

Fonnd. . .


Solubilitiest

Vater . .. .

rthanol . .

Fthler *. .. .

Acetono . .

Dcn"ocne .


*. 9

9...

* 9

9..

* *


Insoluble




* Soluble

. Soluble
. Soluble


. . . ...* ..Slightly noluble


*. 1.73


Heptane . . . .










63

1l(2*Chloropheayl).! ( hlydroxyethylV)vperaste

In a 500 at., three-neched flask fitted with mechanical

stirrer, reflux condenser, and an inlet tube which permitted a

gas to be introduced near the bottom of the flask were placed 39.3 g.

(0.2 mole) of 1-(2-chloropheWny)piperazine dissolved in 150 ml. of
conmercinl methanol to which 0.5 ml. of water had been added, Into
this well-stirred mixture a slight excels of ethylene oxide (actual

requirement was 0.2 mole or 8.81 g.) was allowed to distill slowly.

No external her-ting of the ethylene oxide generator was necessary.

After addition of the ethylene oxide had been completed the reaction

nizture was stirred for as hour. The methanol was then evaporated

under uater-puap vacuum,- and the residue was cooled in an attempt to

produce a solid product. Since it would not solidify the residue

was distilled through a short Vigreaux eolumt. There was a yield

of 26.5 g. (or 55%) of product which boils at 166-169 at 2.3 mm.
The nonohydrochloride was prepared by dissolving the compound

in anhydrous ether and precipitating the hydrochloride in anhydrous

propanole hydrogen chloride. The nonohydrochloride was filtered

off, recrystallized from anhydrous ethanol, and dried over st1furic

acid in a vacaon dessicator. The melting point of the purified

monohydrochloride is 154.2-155.7*,













64

1-(2-Chlorophenyl)-4-(2-hyiroxyethyl)vierasine

.aqnation for Synthesis:




+ 1H ---CR2
W.-CH'MIT


.-OH


Molecular Pormula ..

ITolecular Weight. .

Boiling Point .



d 25
a5 . . . .

Yield of iPurified Produc

Solubilitiest

Water *

thalnol . ..

Cthpr. .

Acetone . .

Benzene.. .

ieptane . .


* a * 4 4 4

* 4 9 * 4 4 .*

* 4 4 4 9

* 9 4 4 a

* 4 44 4 4 9

* 4 9 4 4


* S 0 & 4 4 4 4 4 4


S. 012172001



.166-169912.3 mn.

. . . 1.537

. . 1.1C75

. 4 4 . 4 55



, . InSoluble



, . . Soluble

S* * GSoluble

.* . Soluble

Slightly colublo


1-( 2-Chl or ohe ngyl) -4- ( 2-hy roxyethyl) in era ine nionohy r ochl orid

Melting Point ., *. . . . . 15!-.2-155.7

Analysis -- Nitrogen, ;t

Calculated. . . . 10.11

Found . * 10,26











65

Piscuesion of Eapcrinontal Resultc


Iy reacting l,2-epoxides with 1-arylpiperarlnos, several

new compounds have been synthesized. As a result of this series

of reactions a norber of general observations have been made which

might give better yields. Briefly, these are:

1. Use of a more suitable solvent for reerystallization

if one eould be found

2. Use of lowered reaction temperaturee in reactions with

ethylene oxide

3. Variation of proportions of 1,2-epoxides used

4. Preliminary purifieation of low-melting solids by vauomn

distillation

Since the purpose of this phase of the research was to synthe-

aise compounds for physiological testing, no reaction was carried out

a number of times in order to .ascertain conditions for zaaziMm possible

yields.













7;APTrT 'V


SUM M ARY


As a result of this investigation eight l-arylpiperazines

have been synthosized. These compounds, with the exception of

l-(L-mcthylphenyl)piperazino aca 1-(2-mitthylphonyl)pirperazine which

were synthesized be Prolog and S3lazek,'6 are new to the literature.

Data on these compounds are presented in Table II. Characterization

ioriv:tivee for all of these compounds are reported on the individual

lata sheets for the compounds.

The 1-erylpiperazines reported in Table II have been reacted

with 1,2-eposidea to give fifteen new rmino alcohol derivatives.

Those derivatives prepared by reacting cthylono oxide with l-aryl-e

pinorazines are reported in Table III. Data obtained on compounds

obtained by reacting 1,2-epoxy-53-m.ethoaypropene with the 1-a.yl-

piperazines are presented in Table IV.















Where H2


TAKBIS II
DATA CONCRNIfG I-ARTIPIPT '.AZIT.S OF T:' TYFP




Is 8, 01, or CHi; R, tis H or CSI ; and. R2 is


3 or 02Rq


y field, .1 25 .5 molecular Molecular P,
Componma ..C. a. 4 PorU- 9a eCale. PFomd

1-(4-nethylphenyl)piperazine 25.5 150.9-152.5 10 ..... ..... C 2 176.258 15.89 16.00
1-(3-Methylphenyl)piperazlne 22.8 154.2-156.2 10 1.0383 1.5744 011i1612 176.258 15.89 15.67
1-(2-Athylphenyl)plpera2lno 26.5 136.5-137.5 10 1.0261 1.5600_ 01l 162 176.258 15.89 15.66
1-(4-Ohlorophonyl)piperazina 52.3 155 7-157.2 5 ..... ..... Co 10 01 196.677 14.24 14.27
l-(3-Chloronhenyl)piperazine 38.4 357.2-158.2 5 1.1897 1.5985 010.O32C1 196.677 14.24 14.15
1-(2-Chlorophnnyl)piperazine 32.7 133.9-134.9 5 1.1763 1.5794 o010o132C1 196.677 14..24 14.04
1-Phanyl-2-maethylpiperasine 30.7 138.5-140.5 10 1.0410 1.5723 11 16 2 176.258 15.89 15.95
1-Phenyl-3-othylpiperazine 20.3 147.8-149,8 10 1.0327 1.5635 012.I 2 190.284 14.72 14.66








TAB~r III

DATA O COMPOUNDS OF TIM TYP


*BWz ^13

htre r is Ha. C1. or : S is i or C,; and. M is H or 0 2

.Yield, Iolecular Molecular y.
Sut uns Mopormla eight 1alel .on.d Other Data
l RI # 1 ), ,.1ll -i I t I i I i ii L E .,I -- I -


1-( -o thylphenyl)-

1-(3-Rethylphony1l)-
1-(2-Rethylphearl)-

1-(4-Chlorophenyl)-
1-(3-Chloro-hanyl)*
1-(2-Chloro-honyl)-

1-Phe nyl-3-mnthyl-
-Eshcnmy-3-othyl-


35.5

31,8
65.6
81,2

33

55

74
67


51.5-52.5
67-68.5


107 -108.5

97.5-98.5


....T.


W13 R202
C 13"zo'20

a13 o20 2

a 121 01



a VJW2z0
cl32n~


220.31.
220.31

220.31

240.733
240,733

240.733
220,31.

234.336


12,72
12,72

9.56!'

11.64

11.64

10.11

9.56e

11.95


12.67
12.65

9.58

11.86

11,63

10.26

9.53
11.73


b.4 146-"1490
ai-BOl m.158.3-159.8



b2.3 166-1690
ante-HC1 a, 154.2-155.r7
b1 167-1720
di-HOl m. 235.2-236.5*
b2.2 156.7-15C.2


CCalm-lated for dihydrochloride.


aCalculated for dihyrochloride. COalc ~lted for monohydrochloride.


- "~~" "~


,+- ..... + .. .... + .. .. ..... ... .. ... . . . ....







TABLE IV
DATA OIT coIPOUNDS OF V-i T YP3
2]h i-
NE -41


.'horo 1 Is 01, or C ,; 2 a or M and is N or
yia, .Iolfcular Molecular .,%
Piprazine ied, arromula Veight
Pi-. 0. Calc .Found

1-(4-TMothylr henyl) -4-(2-hydroxy-6-7thox6yropy1: 61 77.5-79 015 O 2440 264.362 10.59 10.45
l-(3-(-mthylphanyl)-4-(2-hdroy-3-mthoypropl) 44.6 56.5-57.5 0152 s202 264.362 10.59 10.40
1-(2-Hnthyl-honyl)-4-(2-hylrox 3-3-acthoyproPyl) 6.7 38-39 C1. 4202 264.362 10.59 10.51
1-(4-Chlorophnnyl)-4-(2-hydroxy-3-methonypropyl) 47.5 78-79.5 0o121021O 1 284.781 9.84 9.56
1-(3-Chorophenyl)-4-(2-hydrojy-3-motho.ypropyl) 34.4 58.8-59.8 C01H2o1202C1 284.781 9.84 9.81
1-(2-Chlorohenyl)-4-(2-hydro-3-thayo3proyl) 70.4 90-91.5 014H2102021 284.781 9.84 9.59
1-Phinyl-2-mothyl-'4-(2-hy.rox -3-mctho rpy) 56....... O 264.362 10.59 10.39



*B. P. 151.5-153.5*o .3 saa.













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ACKKOWEiEDINSTS


h te author wishes to express his sincere appreciation to

Dr. C. 3. Pollard, Ch0irnan of the candidate's Special Supervisory

Committee. Dr. Pollard.s patience, assistance, atviee, and encourage-

ment have helped the author immeasurably.

A portion of this work vasS done under a Parke, Davis & Com-

pany research grant. The author extends his thanks for financial

assistance, chemicals, and supplies.

Finally, the author dishes to thaies his fellow-etudents

for making this work as pleasant as possible.











BIOGRAPIOAL ITUF


Thomas H. Wicker, Jr., was bora November 19, 1923, in

Orlando, Florida. He was graduated from the Umatilla, Florida,

High School in May, 1941. He attended the University of Florida

from 1941 to May, 1944, at which time he received the degree of

Bachelor of Science in Chemistry, with honors. The period from

1944 to 1946 was spent in service in the United States Army.

Mr. Wicker entered the Graduate School of the University of Florida

in 1946 and received the Master of Science degree in June, 1948.

Mr. Vicker is the holder of the Parke-Davis Research Fellow-

ship at the University of Florida. Since 1943 he has been, in

succession, a student assistant, a graduate assistant, and the

holder of a graduate fellowship in the oDpartment of Chemistry,

He is a member of Phi Kappa Phi, the American Chemical Society,

and the Society of American Bacteriologists.











Committee Rooort


This dis.ertation was rtepared under the direction of the
Chairman of the candidate's Supervinory Committee and has beon approv-
ed. by all members of the Coamitteo. It was submitted to the Craduate
Council and was a~roved as partial fulfilment of the requirements
for the degree of Doctor of Philosophy.


IDate_____-_I______i


Dean

SUPMsVISCIR COM-IITT :I:



Chairman










^A i^










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TITLE: Derivatives ofpiperazine. XII (record number: 554269)
PUBLICATION DATE: 1951


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