Some piperazino analogues of methadone and related ketones: a novel conversion

of an N-carbethoxy to a triethylmethyl group

School of Pharmacy, Chelsea College of Science and Technology, University of London, London, S. W. 3, England
Received November 21, 1968

A number of derivatives of methadone and related compounds have been prepared, where the di-
methylamino group has been replaced by a 4-substituted piperazino function. The preparation of
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these compounds involved the reaction of N-w-cyanoalkyl-N'-carbethoxy piperazines with ethyl mag-
nesium bromide, and various products were obtained. These included replacement of the N'-carbethoxy
group by a triethylmethyl function and cleavage of the carbethoxy group. In some cases the w-cyano
group reacted to give the corresponding ketone. Reactions of 1-benzyl-4-carbethoxy piperazine with
ethyl magnesium bromide and phenyl magnesium bromide gave no evidence for the formation of the
triethylmethyl group. However, cleavage of the carbethoxy group occurred and there was evidence
for the formation of the corresponding amide.
Canadian Journal of Chemistry, 47, 2413 (1969)

Introduction and also because of the possibility of subsequent

Structural modifications of the narcotic anal- replacement of N'-C0,Et in the ketone 3 by a
gesic methadone (la) involving replacement of variety of R substituents. It was recognized that
the terminal dimethylamino group by an alicyclic the N'-C0,Et group in the cyanide 2 might pro-
t-basic function have led to several potent com- vide a further point of Grignard attack but this
pounds, two of which, namely dipipanone (lb) was not considered a disadvantageous com-
and phenadoxone (lc), have been used clinically plication since it could lead directly to the N'H
(1, 2). The N'-methylpiperazino analogue ( I d ) analogue of 3. Other piperazino cyanides sub-
has also been examined and is significantly active jected to the same reaction sequence were the
as an analgesic being half as potent as methadone trimethylene analogue 4 and the branched chain
in mice (3). In analgesics based upon 4-phenyl- derivatives 5a and 5b. The latter pair both re-
piperidine (e.g. pethidine) and those in which sulted when diphenylacetonitrile was alkylated
this structural unit forms part of a polycyclic with N-2-chloropropll-N'-carbethoxypiperazine
molecule (e.g., dromoran), substitution of N- and their structures were established by con-
methyl by arylalkyl functions such as 2-phen- verting one member to the corresponding N'-
ethyl and 3-phenpropyl generally yields a more methyl derivative, previously prepared by an
potent product (2), while oxygenated functions unambiguous route (5).
[e.g. (CH,),OH and (CH,),OEt] effectively Reaction of the cyanides 2, 4, and 5 with
raise the activity of pethidine (4). ethyl magnesium bromide (excess of reagent in
In the light of these findings, it was considered benzene at the reflux temperature) led in all
of interest to examine piperazino analogues of cases to basic mixtures from which crystalline
methadone and related compounds which car- products could in some instances be isolated as
ried aryl-alkyl and oxygenated-alkyl N'-sub- hydrochloride salts. Further evidence of reaction
stituents. pathways was provided by the nature of prod-
The general route used to prepare the desired ucts obtained from the uncrystallizable residues
methadone analogues is illustrated for one series after hydrolysis and N1-alkylation procedures.
in Scheme 1. N'-Carbethoxy intermediates (2) With the exception of the highly hindered cya-
rather than those unsubstituted at this position nide 5b, all substrates suffered attack at the cyano
were chosen on account of the need to avoid function and were converted to corresponding
active hydrogen sites in certain of the reactions, ethyl ketones. These were isolated as the N'-
alkylated products required for pharmacological
evaluation. Direct evidence of the removal of
'Correspondence should be addressed to this author.
Present address: College of Pharmacy, University of the N'-C0,Et group was only obtained in the
Saskatchewan, Saskatoon, Saskatchewan. case of cyanide 4, through the isolation of the
 CANADIAN JOURNAL O F CHEMISTRY. VOL. 47, 1969

X-CHMeCH2CPh2COEt
1
n
3 C
X = a) NMe2; 6) N ; c) N 0 ; d ) -N uNMe
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I ) Hydrolysis A
-\ n.. + EtCCPh2(CH2)2N YR

(2) The 60 MHz proton magnetic resonance

(p.m.r.) spectrum of the salt demonstrates the
presence of three identical C-ethyl groups (a
9 proton deformed triplet near 9 7 and a 6 pro-
ton multiplet near 8.25 7). Their identity is sup-
ported by the fact that these signals were not
further resolved when a spectrum was recorded
at 100 MHz (Fig. 1).
(3) The mass spectrum of the hydrochloride
showed a peak of highest mle ratio at 403, corre-
sponding with the dihydrochloride monohydrate
of 7a. Prominent peaks consistent with likely
fragments were found at 374 (loss of Et), 304
(loss of CEt,), 192 ,(due
- to NCCPh,), and 112
/
(due to CH,CH,N . N),
. while a peak at 99
w
(CEt,) was also recorded.
(4) Elemental analysis of the salt supported
the dihydrochloride monohydrate structure 7a.
sec-amine 6 as a hydrochloride, while an unex- Evidence for water of crystallization was pro-
pected reaction between the N-carbethoxy group vided by a loss on drying determination and
and ethyl magnesium bromide, namely its con- infrared characteristics (broad band near 3500
version to a triethylmethyl function, was detected cm-') of the salt.
in two cases. Structural evidence for the cyanide A dihydrochloride monohydrate, isolated from
2-ethyl Grignard reaction product 7a is detailed the cyanide 4-ethyl Grignard reaction product,
below: was similarly assigned the N-triethylmethyl
(I) The cyano group of this product is intact structure 7b on the basis of analytical and infra-
because the infrared spectrum of the free base red spectroscopic evidence. Its N'-substituent
shows a typical v G N band at 2280cm-' could be removed under acid conditions (18 %
(obscured in the salt by the broad vN'H band); HCl-H,O at the reflux temperature) giving the
the N'-C0,Et group has been modified, how- sec-base 6 , and this unusual result (most N-alkyl
ever, since the pronounced v C - 0 band near derivatives are stable towards acids) may be
1700 cm-' of the precursor cyanide is absent, as attributed to resonance stabilization of the tri-
are other bands in the carbonyl stretching region ethyl carbonium ion 8;. a likely reaction inter-
(1800-1620 cm-'). mediate. N-Alkyl fission of certain benzhydryl-
 DIMMOCK ET AL.: PIPEFZAZINO ANALOGUES O F METHADONE AND RELATED KETONES 2415

amines with water or mineral acid represents an together with the impure N'-propionyl amide
analogous example (6). (infrared evidence). No evidence for pathway
Literature data upon the fate of an N-carbeth- (a) was obtained in either reaction of the simpler
oxy group following attack by an organo- piperazine derivative. Although Scheme 2 de-
metallic reagent is sparse [chemically N-car- picts N'-C02Et loss via the amide 10, the secon-
bethoxy piperazines are substituted urethanes, a dary amine l l b might also form upon initial
class to which no reference is made in standard Grignard attack through cleavage of the N-C
works on the Grignard reaction (7, 8)], and a rather than 0-C bond within the complex 9.
tentative reaction mechanism for (a) its con- However, amides have already been shown to
version to a triethylmethyl function and (b) its react with Grignard reagents to yield t-alkyl
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removal is given below (Scheme 2). amines (9) and secondary amines (10) analogous
Although the amide 10, proposed as a com- to l l a and l l b respectively.
mon intermediate for both pathways, was not A number of compounds described in this
detected in reactions involving 3 and 4, the work were evaluated for analgesic activity after
analogous benzamide was isolated in 28 % yield subcutaneous injection in mice by a pinch tail
from the analogous reaction between phenyl method and a modification of the hot plate
magnesium bromide and N-benzyl-Nf-carbeth- method described by Janssen and Jageneau (1 1).
oxy piperazine. Treatment of this N-benzyl deriv- Only three compounds showed activity at a dose
ative with ethyl magnesium bromide gave range of 100 mg/kg, namely 12, 20, and 21
N-benzyl piperazine (loss of the N'-C02Et group) (Table I), with approximately 10-15% of the

Et Et
n EtMgBr A 1- A I
R.N N-C-OEt R.N N-C-OEt A R.N N-C
II
o " jbMgBr o11

n Et
R N N= ~ M ~ B ,

(-1 (+)
Et MgBr

at llb
lla
Can. J. Chem. Downloaded from cdnsciencepub.com by 65.109.204.245 on 03/14/24

CANADIAN JOURNAL OF CHEMISTRY. VOL. 47, 1969

 DIMMOCK ET AL.: PIPERAZINO ANALOGUES OF METHADONE AND RELATED KETONES 2417
I'""''"I";:';:
, ' 1 . I I l i < 4 I , I : I " ' : :
' 3 ' ::::
3-(4-Carbethoxypiperazino)-1,l-diphenylpropyl
(
Cyanide (2)
Sodamide (8.6 g) was added to a solution of diphenyl-
2W IW
acetonitrile (37.6 g) in dry benzene (280 ml) under nitro-
gen. The mixture was stirred for 1 h and heated under
reflux for 4.5 h during which time a further 230 ml of
benzene were added. On cooling, a solution of 1-(2-chloro-
ethyl)-4-carbethoxy piperazine (38.5 g) in dry benzene
(100 ml) was added and the mixture heated under reflux
for 5.5 h. After standing overnight, the excess. of soda-
mide was decomposed with water and the organic extract
separated; removal of benzene gave an oil which solidi-
fied on trituration with petroleum ether (b.p. 40-60 "C)to
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give the aminocyanide 2 as yellow crystals (70 g). An

analytical sample, melted at 111.5-112.5 "C.
Anal. Calcd. for C23H27N30z(equiv., 377): C, 73.1;
H, 7.3. Found (equiv., 372): C, 73.5; H, 7.3.
It gave a hydrochloride m.p. 176.5-178 "C.
I
Anal. Calcd. for CZ3H2,C1N,O2 (equiv., 414): C,
66.7; H, 6.8; C1, 8.6; N, 10.2. Found (equiv., 413): C,
66.6; H, 6.9; C1, 8.5; N, 10.3.
4-(4-Carbethoxypiperazino)-1,I-diphenylbutyl
Cyanide (4)
Reaction between diphenylacetonitrile and 1-(3-chloro-
propy1)-4-carbethoxy piperazine using the method de-
scribed in the previous experiment gave the aminocyanide
4, as pale-yellow crystals, m.p. 139 "C.

i
Anal. Calcd. for C24H29N302(equiv., 391): C, 73.6;
H, 7.5; N, 10.7. Found (equiv., 390): C, 73.6; H, 7.5;
N, 10.9.
Preparation and Proof of Structure of the Isomeric
Cyanides 5a and 56

< 8 7 9
Diphenylacetonitrile (37.6 g) was condensed with 1-(2-
chloropropy1)-4-carbethoxy piperazine (41.3 g) using the
method described previously to give an oil (72.0 g), which
yielded pale-yellow crystals (40.0 g) from ethanol, m.p.
FIG. 1. The 100 MHz proton magnetic resonance 119-122 OC. Recrystallization gave sa, m.p, 122 OC.
spectrum of 7a in DMSO-d6.
Anal. Calcd. for CZ4HZ9N3O2 (equiv., 391): C, 73.7;
H, 7.4; N, 10.7. Found (equiv., 392): C, 74.4; H, 7.4;
activity of methadone. None of the cyanides N, 10.8.
possessed analgesic activity. The hydrochloride melted at 177-178 "C.
Anal. Calcd. for C24H3~C1N302(equiv., 427.5): C,
67.4; H, 7.0; C1, 8.3; N, 9.8. Found (equiv., 428): C,
Experimental 67.1; H, 7.2; C1, 8.2; N, 9.3.
All melting points and boiling points are uncorrected. Evaporation of the combined ethanolic mother liquors
The infrared spectra were determined on Unicam SP 100 gave an oil (28.0 g) which could not be crystallized. A
and Unicam SP 200 spectrophotometers. The proton solution of the oil in a mixture of equal parts of benzene
magnetic resonance (p.m.r.) spectra were recorded on and petroleum ether (b.p. 40-60 "C) waschromatographed
Perkin-Elmer R 10 and Varian HA-100 instruments in on alumina, followed by elution with petroleum ether
dimethyl sulfoxide, operating at 60 and 100 MHz/s containing increasing concentrations of benzene gave the
respectively with TMS as standard. Equivalent weights isomeric cyanide 56 (23.0g), m.p. 113-114 OC from
of bases and salts were determined by titration with ethanol. It gave a hydrochloride, m.p. 124-125.5 "C.
0.02 N perchloric acid in glacial acetic acid with Oracet Anal. Calcd, for C24H30CIN302 (equiv., 427.5): C,
Blue B as indicator. Microanalyses were performed by 67.4; H, 7.0; Cl, 8.3. Found (equiv., 430): C, 66.8; H,
Mr. G. S. Crouch, School of Pharmacy, University of 7.1; C1, 8.3.
London, Dr. G. Weiler and Dr. F. B. Strauss, 5a (15.0 g) was heated under reflux for 6 h with 20 %
Microanalytical Laboratory, Oxford, and Mr. M. alcoholic potassium hydroxide solution (100 ml). After
Ellison, Chesterford Park Research Station, Saffron removal of the alcohol the reaction product was extracted
Waldon, Essex. All organic extracts were washed several with chloroform to give 3-piperazino-1,l-diphenylbutyl
times with water and dried over anhydrous sodium sul- cyanide (11.0 g), the picrate crystallizing from acetone
fate prior to removal of the solvent. Unless otherwise as solvated needles, m.p,. 208-210 "C.
stated, compounds were recrystallized from ethanol or Anal. Calcd. for Cz,Hz,N3 .2C6H3N307. C3H60 : C,
96 % ethanol. 51.7; H, 4.5; N, 15.1. Found: C, 52.0; H, 4.6; N, 15.9.
 2418 CANADIAN JOURNAL OF (ZHEMISTRY. VOL. 47. 1969

This cyanide (3.2 g), 90 % formic acid (1.2 g) and 36 % Further alkylated derivatives together with compounds
formaldehyde solution (0.5 g), were heated under reflux isolated from the aminocyanides 4, 5a, and 5b were pre-
for 6 h after which time hydrochloric acid was added pared by similar procedures. Relevant analytical and
and the formic acid and formaldehyde removed by dis- physical data are given in Table I.
tillation. Basification of the reaction mixture and ex-
traction with chloroform gave an oil which solidified on Reaction of Ethyl Magnesium Bromide with 4-(4-Carbeth-
titration with petroleum ether (b.p. 40-60 "C) to give a oxypiperazino)-1,l-diphenylbrrtylCyanide (4)
solid (3.3 g) which on recrystallization from petroleum Ethyl magnesium bromide (prepared from 65.4 g ethyl
ether (b.p. 8&100 "C) gave 3-(4-methy1piperazino)-1,l- bromide and 14.6 g magnesium) was reacted with 4
diphenylbutyl cyanide, m.p. 107 'C, lit. m.p. 108-110 "C (58.6 g) using the conditions described previously.
The product (55 g) was acidified with ethanolic hydro-
(5). gen chloride and fractionally crystallized from ethanol
Calcd. for CZZHZ7N3: equiv., 166.5. Found: equiv.,
168. to give
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(i) 4-piperazino-I,I-diphe~lylbutylcyanide dihydro-

Reaction of Ethyl Magr~esiumBromide with chloride (6) (5.0 g), m.p. 26&261 "C from ethanol.
3-(4-Carbethoxypiperazino) -I ,I-dipheny[propyl Anal. Calcd. for CzlHz7CIzN3(equiv., 196): C, 64.2;
Cyanide (2) H, 6.9; C1, 18.1; N, 10.7. Found (equiv., 198): C, 64.2;
A solution of 2 (12.0 g) in dry benzene (100 ml) was H, 6.8; C1, 18.4; N, 10.9.
added to a solution of ethyl magnesium bromide (pre- (ii) 4-(4-triethylmethy[piperazi11o)-I,I-diphenylbutyl
cy-
pared from 13.9 g of ethyl bromide and 3.05 g of mag- anide dilgvdrochoride moilohydrate (7b) m.p.. 180-182 "C.
nesium) in ether (90 ml). After removal of the ether the Anal. Calcd. for CZ8H41C12N3~H20 (equiv., 254): C,
mixture was stirred at room temperature for 4 h and 66.1; H, 8.6; N, 8.3. Found (equiv., 256): C, 66.3; H,
then heated under reflux for 16 h. On cooling the product 8.4; N, 8.5. Its infrared spectrum was similar to that
was decomposed with ice and dilute hydrochloric acid of 7a.
and the benzene layer was separated. Basification of the A mixture of 7b (30.0 g) and 18% hydrochloric acid
aqueous phase followed by extraction with ether and (300 ml) was heated under reflux for 6 h. The free base,
subsequent evaporation of the solvent gave an oil (12.2 g) recovered as usual, was acidified with ethanolic hydro-
which could not be crystallized. The oil (9.05 g) was dis- chloric acid to give 4-piperazino-1,l-diphenylbutylcy-
solved in ethanol and treated with ethanolic hydrochloric anide dihydrochloride, m.p. and mixture m.p. 260-
acid and stored one month at 1 "C when 7a separated as 261 "C.
the dihydrochloride monohydrate (2.8 g), m.p. 190 "C Hydrolysis of residues from the mother liquors of the
from ethanol. Grignard reaction product, carried out as before, gave
Anal. Calcd. for C27H39C1ZN3.Hz0(equiv., 247): C, an oil from which 7-piperazino-4,4-diphenylheptan-3-one
65.6; H, 8.4; C1, 14.3; N, 8.5. Found (equiv., 245): C, dihydrochloride monohydrate m.p. 105-110 "C was ob-
65.8; H, 8.3; C1, 14.1; N, 8.7. Loss of H,O at 120 "C. tained.
Anal. Calcd. for 1 HzO: 3.6. Found: 3.85. Anal. Calcd. for Cz3H3zCIzNzO~Hz0 (equiv., 220):
~(Nujol): 3450 (OH), 670,710 (monosub., aromatic) C, 62.6; H, 7.8; N, 6.3; C1, 16.0. Found (equiv., 222): C,
cm-' ; v(neat, free base), 2280 (CN) cm-' : p.m.r. charac- 62.5; H, 8.2; N, 6.3; C1, 15.5.
teristics in DMSO-d6: 9.03 (deformed triplet, 9H), 8.23 v(Nuj01): 3350(Hzo), 1700(CO) cm-'.
(multiplet, 6H), 6.90 (triplet, 2H), 2.56 (multiplet, 10H).
Prominent m/e peaks: 403(7a), 374[loss of C2H5], 304 Reaction of Ethyl Magnesium Bromide with 3-(4-Carbeth-
[loss of C(CzH5)31, 192[due to NC.C. (C6H5),], 112 oxypiperazino)-I,]-diphenylbutylCyanide 5a

[due to CH~CH~I\~\
-
/ 7
$1, 99[due to C(CzH5)3].
Reaction between the cyanide 5a (39 g) and ethyl
magnesium bromide (prepared from 43.1 g of ethyl
bromide and 8.8 g magnesium) gave an oil (35.0 g) from
The residue (30 g) from the mother liquors of several which an unidentified solid A (11 g) separated as a
batches was heated under reflux with 18% hydrochloric hydrochloride. This salt was hydrolyzed with 18 % hydro-
acid (300 ml) for 5.5 h. The free base recovered from the chloric acid as usual and the product alkylated with 2-
aqueous phase was an oil A which could not be crystal- phenylethyl bromide to give 3-[4-(2-phenylethylpipera-
lized or converted to a solid salt. It was characterized zino)]-1,l-diphenylbutyl cyanide dihydrobromide m.p.
by alkylation as follows. 282 "C, undepressed by an authentic sample of the salt
2-Phenylethyl Bromide prepared in the following manner. The carbethoxy group
A mixture of the oil A (5.3 g), 2-phenylethyl bromide of 5a (15.0 g) was hydrolyzed with 20 % alcoholic potas-
(1.6 g), sodium bicarbonate (2.0 g), and ethanol (25 ml) sium hydroxide solution (100 ml) and the product alky-
was heated under reflux for 5.5 h. After removal of the lated.
inorganic matter by filtration, the ethanol was removed Anal. Calcd. for C29H35Br~N3 (equiv., 292): C, 59.5;
and the resultant oil basified with ammonia and ex- H, 6.0; Br, 27.3; N, 7.2. Found (equiv., 294): C, 59.6;
tracted with ether. Evaporation of the solvent gave an H, 6.1; Br, 27.4; N, 7.1.
oil which when treated with ethanolic hydrochloric acid Hydrolysis of the residues from the mother liquors
gave 3-[4-(2-phenylethylpiperazino)]-l,l-diphenylpropyl remaining after solid A had separated (18.0g) with
cyanide dihydrochloride (2.5 g), m.p. 264266 "C. An excess 18 % hydrochloric acid gave 6-piperazino-4,4-
analytical sample melted at 266267 "C. diphenylheptan-3-one (14.0 g)' identified as the picrate,
Anal. Calcd. for CZ8H33C1ZN3 (equiv., 241): C, 69.7; m.p. 259-260 "C (from acetone).
H, 6.9; N, 8.7. Found (equiv., 244): C, 69.0; H, 7.0; Anal. Calcd. for Cz3H30Nz0.2C6H3N307:C, 51.9;
N, 9.0. H, 4.5; N, 13.8. Found: C, 50.6; H, 4.6; N, 13.5.
 DIMMOCK ET AL.: PIPERAZINO ANALOGUES OF METHADONE AND RELATED KETONES 2419
Reaction of Ethyl Magnesium Bromide with 3-(4-Carbeth- with ethyl magnesium bromide (from 9.36 g ethylbromide
oxypiperazino)-1 ,I -diphenyl-2-met/1ylpvyl and 2.07 g of magnesium) under the conditions of the
Cyanide 56 previous experiment to give a golden oil (8.01 g). Treat-
Ethyl magnesium bromide (prepared from 4.4g of ment of the oil with ethanolic hydrochloric acid gave a
ethyl bromide and 1.0 g of magnesium) was reacted with solid which was fractionally crystallized from ethanol and
56 (3.9 g) using the method described previously to give ether-ethanol to give
an oil B (3.6 g) which failed to solidify or form a crystal- ( i ) 1-benzyl piperazine dihydrochloride (1.79 g),
line salt. 239 "C decom~.).An analytical sample melted at 256 "C
(lit. m.p. 2 5 3 " ~(12)). -
Hydrolysis of the Oil B Anal. Calcd. for CllHlSCIzNz: C, 53.0; H, 7:3. Found:
Hydrolysis of B (3.4g) with 18% hydrochloric acid C, 53.0; H, 7.3.
(30 ml) gave another oil C (2.7 g) which similarly failed (it) l-benzyl-4-carbethoxy piperazine hydrochloride
to solidify or give a crystalline derivative. (2.15g) m.p. 210-212 "C. Recrystallization raised the
Can. J. Chem. Downloaded from cdnsciencepub.com by 65.109.204.245 on 03/14/24

Alkylation of the Oil C m.p. to 215.5-217.5 "C, undepressed when mixed with
Alkylation of C (2.0 g) with 2-phenylethyl bromide an authentic
gave 3-[4-(2-pheny]ethyl)piperazino]-l,l-diphenyl-2-me- (iii) a fawn (2.40g). The infrared spectrum
thylpropyl cyanide dihydrobromide (2.8 g) m.p. 297- (Nujol) indicated the presence of 1-benzyl-4-carbethox~
299 "C. piperazine hydrochloride (vCO, 1710 cm-') and a small
Anal. Calcd. for C,,H,,B~,N, (equiv., 293): C, 59.5; peak at 1650 cm-' (tertiary amide) indicated the presence
H, 6.0; B ~ 27.3;
, N, 7.2. Found (equiv., of l-benzyl-4-~ro~ion~l piperazine hydrochloride.
. . . 294): C, 59.7;
H; 6.2; ~ r 27.2;
, N, 7.1.
The compound was also prepared from 5b by hydroly-
sis and subsequent alkylation with 2-phenylethyl bromide Acknowledgments
by the methods described previously.
We should like to thank Mr. R. F. Branch of
Reaction of Phenyl Magnesium Bromide with I-Benzyl-4- the School of Pharmacy. -,
Chelsea College of
carbethoxy Piperazine
I-Benzyl-4-carbethoxy piperazine (12.5 g) and phenyl
Science and Technology, and Professor A. 5.
magnesium bromide (from 17.5 g phenyl bromide and E1vidge of the Uni-
2.6 g of magnesium) were reacted under conditions de- versity of Surrey for profitable discussions. We
scribed previously, except that the time of heating under are grateful to Smith. Kline & French Labora-
reflux was 4 h. Treatment of the crude reaction product tori& who undertook the pharmacological test-
with ethanolic hydrobromic acid gave a solid, fraction-
ally crystallizing from ethanol to give ing and provided samples of the cyanides 2, 4,
( i ) 1-benzyl-4-benzoyl piperazine hydrobromide (1.35 and 5. Dr. D. H. Williams of the University
g) m.p. 250 "C. An analytical sample, melted at 257-259 Chemical Laboratories, Cambridge, kindly de-
"C, undepressed when mixed with an authentic sample termined the 100 MHz proton magnetic reson-
prepared below. ance spectrum.
Anal. Calcd. for ClsHzlBrNzO (equiv., 361): C, 59.8;
H, 5.9; Br, 22.1; N, 7.8. Found (equiv., 370): C, 60.4;
H, 6.2; Br, 21.7; N, 8.1. Benzoylation of 1-benzyl
piperazine gave 1-benzyl-4-benzoyl piperazine hydro- 1. 0.J. BRAENDEN, N. B. EDDY,and H. HALBACH.Bull.
World Hlth. Organ. 13, 937 (1955).
chloride m.p. 247.5-248.5 "C (lit. m.p. 245 "C (12)). 2. A. H. BECKETTand A. F. CASY. Progress in medi-
Calcd. for Cl~HzlCIN20: equiv., 315.5. Found: equiv., cinal chemistry. Editors. G. P. Ellis and G. B. West.
317. Vol. 2. Buttenvorth and Co. Ltd., London. 1962. p.
Liberation of the free base followed by treatment with 43.
ethanolic hydrobromic acid yielded an authentic sample 3. J. OMERMAN-CRAIG, R. J. HARRISSON, M. E. TATE,
of 1-benzyl-4-benzoyl piperazine hydrobromide. R. H. THORP,and R. LADD. Australian J. Chem. 9,
(ii) 1-benzyl-4-carbethoxy piperazine hydrobromide 89 (1956).
(0.94 g) m.p. 215.5-217 "C. Recrystallization raised the 4. D. 'G. HARDY,R. E. LISTER,and E. S. STERN. J.
Med. Chem. 8, 847 (1965).
m.p. to 219.5-220.5 "C, undepressed when mixed with 5. J. REDELand A. BOUTEVILLE. Bull. Soc. Chim.
an authentic sample prepared below. France, 1411 (1955).
Calcd. for C14HZ1BrN202: equiv., 329. Found: equiv., 6. R. CANTAREL.Compt. Rend. 226, 931 (1948).
325. 7. M. S. KHARASCH and 0. REINMUTH.Grienard re-
1-Benzyl-4-carbethoxy piperazine, prepared from an actions of non-metallic substances. ~ o n s G b l eand
authentic sample of the hydrochloride, on treatment with Co., Ltd., London. (1954).
ethanolic hydrobromic acid gave an authentic sample of 8. F. RUNGE. Organo-metallverbindungen. 2nd ed.
the salt, m.p. 227-227.5 "C. Found: equiv., 327. Wissenschaftlich&,VerlagsgesellschaftM.G.H., Stutt-
Evaporation of the ethanolic mother liquors gave an
. gart. (1944).
9. M. MONTAGNE.Compt. Rend. 183, 216 (1926).
oil (1.62 g) from which no further crystalline material 10. M. B u s c ~and M. FLEISCHMANN. Chem. Ber. 43.
could be isolated.
11. P: A. J. JANSSEN and A. JAGENEAU.J. Pharm. Phar-
Reaction between Ethyl Magnesium Bromide and I-Benzyl- macol. 9, 381 (1957).
4-carbethoxy Piperazine 12. R. BALTZLY, J. S. BUCK,E. LORZ,and W. SCHON.
1-Benzyl-4-carbethoxy piperazine (9.64 g) was reacted J. Am. Chem. SOC.66, 263 (1944).