Jan.

, 1940

AMINESRELATED
TO 2,5-DWTHOXYFENETIYLAMINE

161

TABLE
I
M. p., o c .

Compound

(corr.)

Nitrogen, %
Calcd.
Founds

Formula

CiaHiaNaOaS
14.42
14.60
226-227
CiiHiiNaOzS
16.86
16.68
190-191
CisHisNaOsS
14.42
14.14
3-N4-Acetylsulfanilamidopyridine
272-275 dec.
CiiHiiNaOiS
16.86
16.61
3-Sulfanilamidop yridine
248-251 dec.
C16Hlt.N,O&
16.09
15.81
5-N4-Acetylsulfanilamido-2-acetylaminopyridine
288-291 dec.
CiiHizNLhS
21.20
20.94
5-Sulfanilamido-2-aminop yridine
210-211
CIVHI~N~OSS 12.31
12.23
3-N4-Acetylsulfanilamidoquinoline
250-253 dec.
CisHisNaOzS
14.04
14.20
3-Sulfanilamidoquinoline
185-186 dec.
CiiHisNsOsS
12.31
12.52
5-N4-AcetylsulfanilamidoquinolineC
256-258
CiaHisNaOzS
14.04
14.15
5-Sulfanilarnidoq~inoline~
228-230
CnHi~NaoaS
12.31
12.12
6-N4-AcetylsulfanilamidoquinolineC
285-287
6-N~-Acetylsulfanilamidoquinoline
hydrochloride
238-240
CirHi&lNaOsS
11.12
11.06
CisHiaNaOaS
14.04
13.86
202-204
6-SulfanilamidoquinolineC
Ci7HibNsOaS
12.31
12.02
8-N~-Acetylsulfanilamidoquinoline~d
193-194
CiaHiaNsOzS
14.04
13.87
8-Sulfanilamidoquinolinecvd
194-195
Dumas.
Nomenclature according t o Crossley, Northey and Hultquist, THISJOURNAL,
60, 2217 (1938).
PreviPreviously prepared by A. D. Choudhury, et al., J . Ind. Chem. SOC.,14,733 (1937).
ously prepared by Bobranski.2
2-N4-Acet ylsulfanilamidop yridine
2-Sulfanilamidop yridine

chloric acid. After refluxing for twenty minutes, the reaction mixture was diluted with water and made basic
with ammonium hydroxide. It was recrystallized from
ethanol; yield, 0.67 g. (75%).
5 N4 Acetylsulfanilamido 2 acetylmhopyridine.Using the same procedure as above, 3.0 g. of 5-amino-2acetylaminopyridine and 4.0 g. of acetyl sulfanilyl chloride gave 6.0 g. (94%) of crude 5-N4-acetylsulfanilamido-2acetylaminopyridine. This was converted to 5-sulfanilamido-2-aminopyridine by the same procedure used below
for 3-sulfanilamidoauinoline.
3-Sulfanilamidoquinoline.-3-Aminoquinoline (2.5 g.)
and acetylsulfanilyl chloride (4.0 g.) were dissolved in 30
cc. of dry pyridine. After heating for two hours on the
steam-bath, the reaction mixture was poured into 400 cc.
of cold water. The product separated as a white crystalline mass weighing 5.4 g. when dry. For analysis a small

- -

[CONTRIBUTION FROM

THE

amount was washed successively with water and ethanol

and dried a t 100. One gram of the crude acetyl
compound was boiled for a half hour with 25 cc. of 12%
hydrochloric acid. Upon cooling and neutralizing with
ammonium hydroxide, the sulfonamide was obtained;
yield 0.8 g. (91%). It was recrystallized from ethanol.

Summary
An improved method of preparation of the 5, 7,
and 8-aminoquinolines as well as the preparation
of certain sulfanilamido derivatives of pyridine
and quinoline amines is described.
The
obtained by Bobranski2 are confirmed.
NEW YORK,N . Y .

BURROUGHS
WELLCOME & CO.u.

RECEIVEDOCTOBER
31, 1939

s. A. EXPERIMENTAL
RESEARCH
LABORATORIES]

Amines Related to 2,5-Dimetho~yphenethylamine.~

I
BY RICHARD
BALTZLY
AND JOHANNES
S. BUCK
Preliminary pharmacological work has indicated
that some amines containing the 2,5-dimethoxyphenyl group show activity comparable with that
of similar phenolic amines, and also that they
probably will be active orally. It therefore became important to prepare, for pharmacological
examination, as complete a series as possible of
amines (as hydrochlorides) containing the 2,5-dimethoxyphenethyl grouping, the optimal C-C-N
side chain being present in all cases.
(1) This work is part of a joint research being carried out in collaboration with a pharmacological group at t h e above laboratories.

Six series of 2,5-dimethoxyphenethylamines

were prepared, in each series the primary, secondary, tertiary and quaternary compounds being
made. Included in the series are the analogs of
practically all the known pharmacologically active amines containing the phenethyl group (that
is, containing the C-C-N side chain).
The present paper deals with the preparation
and properties of the amines with no hydroxyl
group in the side chain. One hydrochloride has
been described previously.
The formulas of the primary amines are

162

RICHARD BALTZLY AND JOHANNES

s"'

s. BUCK

VOl. 62
@CH(C;;NH~
OCHs

CH(CH3)CHtNHs

OCHa
2,5-Dimethoxyphenethylamine

OCHa
XI
8-(2,5-Dimethoxyphenyl)-propylamine

OCHs
(3-(2,5-Dimethoxyphenyl)-isopropylamine

The syntheses of the first primary amine (I) ride to an ether solution of the amine, forms lustrous
and of the corresponding secondary amine have leaflets, melting a t 139".
Anal. Calcd. for CI0H16O2NC1: C, 55.15; H , 7.41.
been described.2 The starting material for the
Found: C, 55.19; H, 7.37.
P-phenylpropylamine (11) was obtained by a
2,5-Dimethoxyphenethylmethylamine Hydrochloride.Reformatzky reaction (2,5-dimethoxyacetophe- This has been described previously.2
none and ethyl bromoacetate). The remaining
2,5-Dimethoxyphenethyldmethylamine
Hydrochlostages of the synthesis paralleled those of the ride.-The above primary amine was converted into the
first amine. The 2,j-dimethoxy-a-methylhydro- tertiary amine by a modified Eschweiler reacti~n.~,'jS
cinnamic acid required for the third, P-phenyliso- Nine grams of primary amine, 40 cc. of 36% formaldehyde
solution and 0.1 cc. formic acid were heated for three hours
propylamine, was obtained by two methods, (a) at 125" in a sealed tube. The tertiary amine, b. p. 159"
by condensation of 2,5-dimethoxybenzaldehyde (23 mm.), was isolated in good yield and converted into
with ethyl a-bromopropionate, followed by reduc- the hydrochloride by adding alcoholic hydrogen chloride
tion, and (b) by condensation of 2,5dimethoxy- to the ether solution. The hydrochloride forms small,
benzaldehyde with diethyl malonate] followed by colorless plates, melting a t 148",and is rather hygroscopic.
Anal. Calcd. for C12H2o02NCl: C, 58.63; H, 8,21.
reduction, methylation] saponification and de- Found: C, 58.79; H, 8.25.
carboxylation. Inaccessibility of the starting
2,5-Dimethoxyphenethyltrimethylammonium Chloride.
aldehyde deterred the authors from using the -The foregoing tertiary amine was converted, in ether
Claisen condensation with ethyl propionate, as solution, into the methiodide, which was filtered off, disthis condensation in similar cases is wasteful and solved in water, and allowed t o stand with silver chloride.
troublesome. The method of Bogert and David- After filtration, evaporation in vacuo and recrystallization,
the chloride forms very hygroscopic lustrous plates, meltson3 also was avoided, as in the authors' hands i t ing a t 184-185".
gave discouraging results with dialkoxybenzaldeAnal. Calcd. for C13H~202NCl: C, 60.06; H, 8.54.
hydes.
Found: C, 60.28; H , 8.79.
2,5-Dimethoxy-(3-methylcinnamic Acid.-2,5-l)imethSecondary amines were obtained from the primary amines by the method of
The oxyacetophenone and ethyl bromoacetate were condensed
tertiary amines were prepared from the primary by the Reformatzky method, using a zinc-copper alloy.
The resulting 8-hydroxybutyric ester was dehydrated by
(or, better, secondary) amines by an adaptation phosphorus oxychloride t o the 8-methylcinnamic
of the Eschweiler reaction. Quaternary chlorides which was distilled, b. p. 140-143" (1.0 mm.). Saponificawere obtained by the action of silver chloride. on tion yielded the acid which crystallized from aqueous alrnhol in slender prisms, melting at 113.5".
the methiodides of the tertiary amines.

Experimental
2,5-Dimethoxybenzaldehyde (gentisic aldehyde dimethyl ether) was prepared by the Gattermann method.6
Amine hydrochlorides were all recrystallized, until pure,
from absolute alcohol-ether mixture, sometimes with the
addition of ethyl acetate. The solubilities of the hydrochlorides are all very similar, the compounds being readily
soluble in water, alcohol, and methanol, and practically
insoluble in less polar solvents. The melting points were
determined on material dried for several hours a t 100'
in vacuo. All melting points are corrected.
2,5-Dimethoxyphenethylamine Hydrochloride.-The
amine has been described previously.* The hydrochloride,
made by the addition of absolute alcoholic hydrogen chlo(2) Buck, THISJOURNAL,
64, 3661 (1932).
(3) Bogert and Davidson, ibid.. 64, 334 (1932).
(4) Decker and Becker, Ann., 896, 362 (1913).
(5) Kauffmann and Burr, Bey., 40, 2352 (1907).

Anal. Calcd. for C12H1401: C, 64.83; H, 6.3d. Found:

C, 64.82; H, 6.69.
,%(2,5-Dimethoxyphenyl)-butyric Acid.-The ester described above was reduced (platinum oxide and hydrogen)
and then saponified. The resulting acid forms irregular
crystals from ether-petroleum ether, melting at 7'3".
Anat. Calcd. for ClnH~sOa:C, 64.27; H,7.20. F o u n d :
C, 64.62; H, 7.40.
(3-(2,5-Dimethoxyphenyl)-butyramide.---The foregoing
acid was heated in a stream of ammonia, a t 220-230", for
two hours. Recrystallized from benzene the amide forms
columnar prisms melting a t 121".
(6) Cf. Decker and Becker, ibid., 46, 2404 (1912); An?$.,396, 342
(1913).

(7) For an alternative method see Buck, Baltzly and Ide, THIS
JOURNAL,
60, 1789 (1938).
( 8 ) The adaptation of Clarke and Gillespie, ibid., 65, 4571 (1933),
appears to give some substitution with certain dimethoxp derivatives.
(9) Cf. Lindenbaum, &r., 60, 1270 (1917).
(10) CI.Woodruff and Pierson, THISJOURNAL, 60, 1075 (1938).

Jan., 1940

AMINESRELATED
TO 2,~-DIMETHOXYPHENETHYLAMl"

Anal. Calcd. for C12H1703N: C, 64.54; H , 7.68.

Found: C, 64.76;H, 7.88.
p (2,5 Dimethoxyphenyl) propylamine Hydrochloride.-The amine was obtained from the amide, in 45%
yield, by the usual Hofmann procedure, using sodium
hypochlorite. It boiled a t 114' (1.0 mm.) and was converted into the hydrochloride by adding alcoholic hydrogen
chloride to the ether solution. After recrystallization the
hydrochlorite forms fine, colorless, felted needles melting
a t 149-1.50".
Anal. Calcd. for C11Hls02NCl: C, 56.99; H , 7.83.
Found: C, 57.11;H , 8.03.
p (2,5 Dimethoxyphenyl) propylmethylamine Hydrochloride.-The above primary amine was converted into
the hydriodide of the secondary amine (m. p. 131') by
the Decker method (v. s.). The base, liberated from the
hydriodide, was converted directly into the hydrochloride,
which crystallizes in fine, colorless needles, melting a t 146".
Anal. Calcd. for C12H2002NCl: C, 58.63; H, 8.21.
Found: C, 58.82; H, 8.07.
p (2,5 Dimethoxyphenyl) propyldimethylamine
Hydrochloride.-The tertiary amine may be prepared from
the primary amine (or, better, from the secondary amine)
by the Eschweiler methylation (v. s.). The amine was
purified as the hydrochloride, which forms slender prisms,
melting a t 182-183".
Anal. Calcd. for C~H2202NCl: C, 60.06; H, 8.54.
Found: C, 60.33; H , 8.60.
p (2,5 Dimethoxyphenyl) propyltrimethylammonium
Chloride.-p - (2,5 - Dimethoxyphenyl) - propyldimethylamine (above) was treated with methyl iodide in ether solution to give the quaternary iodide (i. e., the methiodide).
Silver chloride converted the iodide (m. p. 139") into the
required chloride, which crystallizes in hygroscopic slender
prisms. It forms a stable monohydrate, melting at 92'.
Aftei thorough drying, the chloride melts a t 159-161 with
discoloration.
Anal. Calcd. for ClrH2402NCl: C, 61.37; H, 8.84.
Found: C, 61.48; H , 9.18.
Diethyl 2,5-Dimethoxybenzalmalonate.-Diethyl malonate was condensed with 2,5-dimethoxybenzaldehydein the
presence of piperidine." Saponification of a portion
yielded an acid crystallizing in faint yellow leaflets from
alcohol-benzene mixture. The acid melts at 183" (dec.).
Kauffmann and Burr6 prepared this acid by another
method and gave the m.p. as 188" (dec.).
Anal. Calcd. for Cl2Hl208: C, 57.12;H, 4.80. Found:
C, 57.10;H , 5.13.
Diethyl 2,5-Dimethoxybenzylmalonate.-Catalytic reduction of the preceding ester yielded a nearly colorless oil,
which was identified by saponifying a portion. The acid
obtained, recrystallized from benzene, gave rhombic prisms
melting a t 156.5"(dec.).
Anal. Calcd. for Cf2H1406: C, 56.68; H, 5.55. Found:
C, 57.03;H. 5.43.
2,5-Dimethoxybenzylmethylmalonic Acid.-The
foregohg ester was methylated in the usual way (methyl iodide
and sodium ethylate) and the product saponified. The re-

(11)

Cf.Knoevwgel, E#., 81,2586 (1888).

163

sulting acid after crystallization from hexane forms fine,

colorless crystals, melting a t 143' (dec.).
Anal. Calcd. for ClaHleOe: C, 58.19;H, 6.02. Found:
C, 58.35; H , 5.87.
a-Methyl-2,5-dimethoxyhydrocinnamicAcid.-This was
obtained by heating the corresponding malonic acid
(above) a t 150'. After crystallization from ether-hexane
mixture it forms a cream-colored powder melting a t

59.5".
Anal. Calcd. for C12H1604: C, 64.27;H, 7.20. Found:
C, 64.39;H, 7.14.
a-Methyl-2,5-dimethoxyhydrociamide.-The
amide
was obtained by heating the corresponding hydrocinnamic
acid (above) in a stream of ammonia a t 220-230" for two
hours. Recrystallized from benzene it forms a finely
crystalline powder melting a t 99 '.
Anal. Calcd. for C12H1703N: C, 64.54; H, 7.68.
Found: C, 64.58;H, 7.91.
The same amide was prepared, in poor yield by condensing ethyl bromopropionate with 2,5-dimethoxybenzaldehyde (Reformatzky method with ordinary zinc), dehydrating the resulting ester with phosphorus oxychloride, reducing the unsaturated ester catalytically, and then saponifying, and, finally, amidating the acid produced. The dehydration with phosphorus oxychloride or the subsequent
distillation resulted in extensive polymerization, the yield
of unsaturated ester being only about 20%.
p-(2,5-Dimethoxyphenyl)-isopropylamine Hydrochloride.-The Hofmann reaction on the foregoing amide was
carried out as usual except that the amide was added dissolved in dioxane to the hypochlorite solution.12 The
yield of distilled amine (b. p. 137-140" (3mm.)) was 70%.
The hydrochloride, prepared in the usual way (v. s.),
crystallizes in fine prisms melting a t 117.5'.
Anal. Calcd. for C11Hls02NC1: C, 56.99; H , 7.83.
Found: C, 57.25; H , 7.89.
The same hydrochloride was also prepared, in very poor
yield, by the catalytic reduction, in strongly acid alcohol,
of 2,5-dimethoxynitropropenylbenzene.l3 The compound
was isolated via the hydriodide, which forms prismatic
needles, m. p. 138".
Anal. Calcd. for CllHls02NI: C, 40.86; H , 5.62.
Found: C, 40.94;H , 5.94.
0 (2,5 Dimethoxyphenyl) isopropylmethylamine
Hydrochloride.-The primary amine (v. s.) was readily converted into the secondary amine by the Decker
The hydrochloride crystallizes in needle prisms, melting
at 98.5'.
Anal. Calcd. for C12H2002NCl: C, 58.63; H, 8.21.
Found: C, 58.52;H , 8.46.
fi (2,5 Dimethoxyphenyl) isopropyldmethylmnine
Hydrochloride.-The tertiary amine, b. p. 118-121 (0.5
mm.), was obtained by the Eschweiler methylation (v. s.)
of the primary amine. The hydrochloride forms needles
melting a t 138-139 '.

(12) The use of dioxane to dissolve amides (using about one-third

of the volume of the hypochlorite solution) greatly improves matters
in cases where the amide is of low solubility. Cf. Woodruff and
Conger. Tars JOURNAL, 0,466 (1988).
(la) aufftnann. BW., so, 680 (1917).

RICHARD
BALTZLY
AND JOHANNES S. BUCK

164

Anal. Calcd. for CI~HZZOZNC~:

C, 60.06; H , 8.54.
Found:

of considerable amounts of 2,5-dimethoxybenzaldehyde.

C, 60.17; H, 8.39.
8 (2,s Dimethoxyphenyl) isopropyltrimethylammonium Chloride.-The preceding tertiary amine was converted, in ether solution, into the methiodide (m. p. 142 ),
which on treatment with silver chloride gave the quaternary chloride. After crystallization, the chloride forms
very hygroscopic, tiny, colorless prisms. After thorough
drying (finally a t 120 in vacuo) it melts a t 203 .
Anal. Calcd. for C1~HzrOzNCl: C, 61.37; H, 8.84.
Found: C, 61.63; H, 8.81.

Vol. 62

Summary
As part of a series of 2,5-dimethoxyphenylalkyland alkanolamines, 2,5-dimethoxyphenethylamine hydrochloride, &(2,5-dimethoxyphenyl)propylamine hydrochloride and p- (2,5-dimethoxyphenyl)-isopropylamine hydrochloride, together
with the corresponding secondary and tertiary
amine hydrochlorides and the quaternary chlorides, have been prepared.

The authors wish to thank Mr. W. S. Ide for

the many micro-analyses carried out during this
work, and Dr. C. W. Ferry for the preparation

TUCKAHOE,
NEWYORK

RECEIVED
OCTOBER
20, 1939

u. s. A. EXPERIMENTAL
RESEARCH
LABORATORIES]
Amines Related to 2,5-D imethoxyphenethylamine I1

[CONTRIBUTION FROM

THE

BURROUGHS
WELLCOME

BY

82

CO.

RICHARD
BALTZLY
AND

The work described below is a continuation

JOHANNES

made.

s. BUCK

The primary amines have the formulas

@ T ) C H z T
OCHs

F O H C T
OCHs
@-(2,5-Dimethoxyphenyl)8-hy droxyethylamine

@ O H r a
0CH.y

I11
6-(2,5-Dimethoxyphenyl)-

@-(2,5-Dimethoxyphenyl)8-hydroxypropylamine

and completion of that described in Part I.2

The amines have the same structure as in the
previous work but possess, in addition, a /3-hydroxy group. As before, the primary, secondary, tertiary and quaternary compounds were

8-hydroxyisopropylamine

Secondary amines are denoted by a, tertiary

by b, and quaternary salts by c. The primary and secondary hydroxyethylamines and
hydroxypropylamines (I, Ia, 11, IIa) were prepared by the following series of reactions:

(R = 2,5-dimethoxyphenyl, Bz = benzyl)
(CH~~NI
PtOz
Hz
RCOCH3
RCOCHzBr
RCOCHzNH2___) RCHOHCH2NHz
(1)
CHIBrCOOCzHs
NHzNHz
HNOz
RCHO _____) RCHOHCHZCOOCZHS
RCH0HCHzCONzH.y e
HC1
[RCHOHCHzCONa] --f RCHCHZ
RCHOHCHzNHz (1)

____f

____f

__f

6-CO-NH
BzNHCHs

PtOz

Hz
RCOCHzBr(v.s.)
RCOCH2NCH8Bz
RCHOHCH2NHCH8
CHlBrCOOCzHs
NHzNHz
HNOz
RCOCH,
RC(0H) (CHa)CHzCOOCzHs___) RC(OH)(CHa)CHsCONsHa_ic
___f

(14

0-CO-NH
CHsMgI
PtOz
R C O C H Z N C H ~ ~ Z ( V___.)
.S.)
RC(0H) (CHa)CHzNCHaBz
(1) This work is part of a joint research being carried out in collaboration with a pharmacological group at the above laboratories.
(2) Bdtzly and Buck, Tars JOURNAL, 82, 161 (1840).

+ Ha

RC(OH)(CH.y)CHzNHCHa (IIa)

The corresponding tertiary amines and quaternary

salts were prepared as follows: