SYNTHESIS OF A SUBSTITUTED CENTRALITE
by Robert Young Moir
A Thesis submitted to the Faculty of Graduate
Studies and Research at McGill University, in partial
fulfilment of the requirements for the Degree of Doctor of Philosophy.
McGill University
August, 1946.
ACKNOWLEDGEMENT
It is a pleasure to thank Dr Purves for directing the research. and the National Research Council
for providing the necessary financial aid.
1~
espec-
ial thanks are also due to Miss Marie Anderson, of
Guelph, for performing the microanalyses reported
in this work and for assistance in the preparation
of the manuscript.
Chemistry
Ph.D.
R.Y.Moir
ABSTRACT
(1) This research is part of N.R.C. project XR-79,a
search for desirable stabilizers for guncotton. Three substituted ureas, N,N'-diethyl-N,N'-bis-(3,4-dimethoxyphenyl)·
urea, N-ethyl-N,N'-bis-(3,4-dimethoxyphenyl)-urea, and
N,N'-bis-{3,4-dimethoxyphenyl)-urea were synthesized. These
compounds are analogues of the
co~mon
stabilizer, centralite.
Tho first two were new compounds, and were characterized;
the third was synthesized by a new method.
(2) The necessary intermediate, 4-athylwAinoveratrola,
was synthesized in four ways, and characterized by derivatives.
The benzenesulfonyl and acetyl derivatives were also employed in the purification of the compound. Practical methods of
hydrolyzing these derivatives were discovered.
{3) In addition to those already mentioned, the following new compounds ware prepared in pure form and analyzed:
4-bromoacetylguaiacol, N-benzenesulfonyl-3,4-dimethoxyaniline,
N-ethyl-N-benzenesulfonyl-3,4-dimethoxyanilina, N-othyl-3,4dimethoxyacetanilide, and N-ethyl• N-3,4-dimethoxyphenylcarbamyl chloride.
CLADI TO ORIGINAL RESEARCH
(1) This research is part of N.R.c. project XR-79,
a searoh for desirable stabilizers for guncotton. Three
substituted ureas, N,N'·diethyl-N,N'-bis-(3,4-dimethoxyphenyl)-urea, N•ethyl-N,N'-bis-(3,4-dimethoxyphenyl)urea, and N,N'-bis-(3,4-dimethoxyphenyl)-urea, were synthesized. These compounds are analogues of the common
stabilizer, centralite. The first two are new compounds,
and were characterized; the third was synthesized by a new
method.
(2) The necessary intermediate, 4-ethylaminoveratrole,
was synthesized in four ways, and characterized by deriv"
atives. The benzenesulfonyl and acetyl derivatives were
also employed in the purification of the compound. Practical methods of hydrolyzing these derivatives were diecovered.
(3) In addition to those already mentioned, the foll-
owing new compounds were prepared in pure form and anal ...
yzed:
4-bromoacetylguaiacol,N•benzenesulfonyl-3,4~dimeth­
oxyaniline,
N-ethyl~•-benzenesulfonyl-3,4-dimethoxyan.iline,
t
N-ethyl-3,4-dimethoxyacetanilide, and
methoxyphenylcarbamyl chloride.
N-ethyl~•-3,4-di­
TABLE OF CONTENTS
Subject
Page
GENERAL INTRODUCTION
1
DISCUSSION OF SYNTHETICAL 1ffiTHODS AND
3
EXPERIMENTAL RESULTS
Characteristics of a Satisfactory Stabilizer
3
Ethylaminoveratrole from Vanillin
4
Ethylaminoveratrole from Guaiacol
10
Condensation of the Amine with Phosgene
18
INTRODUCTION TO THE EXPERIMENTAL SECTION
25
EXPERIMENTAL
26
Veratraldehyde
26
Veratraldoxime
26
Veratronitrile
26
Veratramide
26
4-Aminoveratrole
26
Its formanilide analogue
27
Dimethoxy-N-ethylformanilide.Ethyl Bromide Method
27
Direct Ethylation of Aminoveratrole
29
Hydrochloride of Bthylaminoveratrole
29
Rinsberg Separation of the Amines
30
Benzenesulfonyl-dimethoxyaniline
32
N-Ethyl-benzenesulfonyl-dimethoxyaniline
33
Its Preparation by the Direct Method
35
Its Attempted Alkaline Hydrolysis
36
N-Ethyl-dimethoxyacetanilide from Hinsberg Method
39
Ethyl-dimethoxyformanilide and -acetanilide.
40
Ethyl sulfate Method
TABLE OF CONTENTS (CTD.)
Subject
Pa~e
4-Bromoguaiacol
42
Acetylguaiacol
43
4-Bromoacetylguaiacol
43
5-Bromoacetylguaiacol
44
4-Bromoveratrole from 4-Bromoguaiacol
46
Cuprous Catalyst Suspensions
46
Ethylaminoveratrole and its Acetyl Derivative
48
Pure Samples of the Acetyl Derivative
52
Recovery of the Acetyl Derivative
53
Hinsberg Method of Analysis of Ethylaminoveratrole
54
Ethyl-dimethoxyphenyl-carbamyl Chloride
56
Its Recovery
61
Pure Ethyl-dimethoxyphenyl-carbamyl Chloride
62
Hydrolysis of Ethyldimethoxyacetanilide
63
Tetramethoxycarbanilide;Ethyltetramethoxycarbanilide 66
Diethyl-bis-dimethoxyphenyl-urea
70
SUMMARY
75
LITERATURE REFERENCES
77
SYNTHESIS OF A
SUBSTil~TED
CENTRALITE
General Introduction
The research described in this thesis is part of the oonfidential N.R.C. war project XR - 79, the object of which is
to discover efficient stabilizers more compatible than
cent~
ralite with nitrocelluloses, which are the principal ingredient of many military explosives. Since centralite (sym-di·
ethyldiphenyl urea) is known to be an efficient stabilizer,
it was thought likely that the substitution of ethoxy or methoxy groups into the phenyl nuclei would increase the compatibility with nitrocellulose& without decreasing the stabilizing
effect. This task was undertaken in this laboratory by Dr
J. A. F. Gardner (1), who succeeded in preparing bis-(3-meth-
oxy-4-ethoxyphenyl)-diethylurea (I), albeit with difficulty
and in rather low yield, from a readily accessible substance,
vanillin. The object of the present work was to synthesize
the 3,4-dimethoxy analog II, a new compound, preferably from
the same source, and to discover the most convenient methods
for the synthesis. The preparation of the new stabilizer II in
amounts large enough to permit assessment of its stabilizing
action was not an object of this research.
Substituted ureas are classically synthesized in three ways;
by the action of an amine on urea; by the action of an amine,
or water, upon an isocyanate; and by the action of phosgene or
a carbamyl chloride upon an amine. No reference to a direct
alkylation of ureas could be discovered in the literature.
2.
Only the phosgene route is applicable to the synthesis of compounds such as I and II. The synthesis of II
therefore depended on the condensation of one molecule
of phosgene with two molecules of N-cthylaminoveratrole
( III) •
The main difficulty encountered in the wotk was the
production in quantity, from vanillin or guaiacol, of
pure N-ethylaminoveratrole (III). Much of the thesis
is concerned with the difficulties surrounding the synthesis of this compound.
The subject of the thesis is unusual in that it
involves no general theoreti.a discussion. The only
object of the research was the synthesis of one single
compound, and the work consisted entirely in the application of published experimental methods to the synthesis of this compound and six other new compounds in the
veratrole series. The standard thesis form has therefore not been followed; it has been found more convenient to include references to previous and analogous
employment of the synthetical methods in the sections
entitled, "Discussion of Synthetical Methods and Ex-
3.
perimental Results" and "Experimental."
Discussion of aynthetioal Methods
~d
!!Perimental Results
Characteristics of a Satisfactory Stabilizet
Previous work, summarized by Dr Gardner (l), showed
that stabilizers for nitrocellulose& should possess the
following properties:
a) Contain groupings, usually amino groups. that combine readily with the oxides of nitrogen responsible for
oatalyzing the decomposition of nitrocelluloses.
b) Not be basic in reaction(and therefore cause decomposition of the explosive on their own account.)
c) Be compatible with technical nitrooelluloses so
that proper working of the mix gives a permanently homogeneous system.
d) Be low in vapor pressure, lest they evaporate
slowly from the blend.
e) Be inaoluble in water, tt avoid slow leaching from
the blend by aoceas of moisture.
f) Have a low melting-point, oertainlJ below 100°, so
that blending with nitrocellulose can be carried out with
the molten stabilizer dispersed in warm water.
The close structural similarity between the customary
and fairly satisfactory stabilizer, centralite, and structures I and II, makes it very likely that the latter would
fulfil requirements a} and b). The presence of alkoxyl sub-
4.
stituents might well improve compatibility with nitrocell•
uloses (requirement c)). Requirements d) and e) are also
fulfilled by I and II. The compound II, synthesized in this
research, has the same melting-point, 79°, as has centralita. For this reason, G&rdner•s analog I, of m.p. 51°, might
be preferred.
As already mentioned, practical tests of stabilizing
action must await the synthesis of compound I on a scale
somewhat lafrger then is convenient in the laboratory.
Byptheses of
N-Ethylamino~veratrole
(III) from Vanillin
At the present time, vanillin (VIII) is a somewhat
expensive chemical available from the commercial pint of view
only in rather small amounts. Today, however, much vanillin
is obtained by the high pressure oxidation of waste sulfite
liquor from the wood pulp industry. Since the liquor is
available in millions of tons, the output of vanillin is
J
now limited by the manufacturing capacity, and when this
can be expanded, the output of vanillin will be limited by
the moderate demand rather than by any difficulties in pro•
duction. If large new uses for the substance lead to its
production on the full industrial scale, the cost per unit
would no doubt be greatly decreased. These considerations
~~stify
the use of vanillin as a possible starting mater-
ial for the synthesis of new industrial chemicals such as
stabilizers for the explosives industry.
6.
As mentioned in the General Introduction, the most
practical route for the synthesis of substituted sy.mN,N'-diethyldiphenylureas of the centralite type is
the condensation of phosgene with the corresponding amines.
The related primary amines are obtained, for the syn•
theses used in this laboratory, from vanillin by a series
of standard reactions described in "Organic Syntheses"
(2), which only need to be mentioned briefly here. For
example, the 4-aminoveratrole (VII) used in the present
work was obtained in the following manner. Vanillin(VIII)
·o::.
cc.
OC:H.3
OCa.Hs
III
IV
tt- "'- c:~o
ooeH3
oc.zHs
V
was methylated to give veratric aldehyde (IX); the oxint.e
(X) of the latter compound was then dehydrated to yield
veratronitrile (XI). HJdroljsis of the nitrile pro•
duoed veratramdde (XII), and the action of sodium hypo-
chlorite upon XII gave the desired 4-aminoveratrole (VII).
O
lll(~:~s
OCH
3
o c2. H 5
VI
VII
VIII
IX
C':: NOH
OO~H3
OCH
X
3
c oAI H,
e:N
Oo~H,
Oo~H3
oeH 3
OCH 0
XI
- X:ri
The conversion of a primary to a secondary amine, such
as III or IV, 1n high yield is still a difficult matter,
since direct alkylation tends to yield a mixture of sec•
ondary, tertiary, and unchanged primary amines. These
mixtures are difficult to separate.
Dr Gardner (1) Sinthesized N-ethyl-3-methoxy-4-ethoxy-
aniline (IV) in two ways: by the action of ethyl bromide
on 3-methoxy-4-ethoxyformanilide {V) in aqueous solution,
and by the action of ethyl sulfat e on V in dioxane. The
first method yielded a mixture of V and
N-ethyl-3-methoxy~
4-ethoxyformanilide (VI) Which could not be separated by
fractional crystallization. The second method gave a pure
preparation of VI, and from this derivative the pure amine
{IV) was readily obtained by hydrolysis. Much leas satisfactory results were obtained in the present research when
these methods were used to prepare N-ethylft4-aminoveratrole
(III). The necessary 4-aminoveratrole was prepared as
already described. It was formylated in good yield to give
3,4-dimethoxyformanilide (XIII). The preparation of this
compound and Gardner 1 s preparation and analysis of V are
interesting in view of the fact that Fetsoher and Bogert (3)
were not able to find any method for successfully formyl-
7.
ating 4-aminoveratrole. When 3,4-dimethoxyformanilide
(XIII) was treated with ethyl bromide, or when 4-aminoform~
veratrole was treated with ethyl bromide and then
ylated, no crystalline compound could be obtained. When
the crude mixture of formanilides was hydrolyzed and converted to the. hydrochlorides, a highly crystalline mixture of amine hydrochloride& resulted which could not be
separated by fractional crystallization. Finally, the
hydrochlorides were condensed with benzenesulfonyl chloride and by Hinsberg's method readily gave two new compounds,
N-benzenesulfonyl-3,4-dimethoxyaniline (XIV) and N•
ethyl·N-benzenesulfonyl-3,4~dimethoxyaniline
H -N- SOtCbHS
Oc.H
XIII
oocH3
3
Octi
3
XIV
(XV). These
.,cz.H5
N'SOzCbH5
O
OCH
3
oc.t-4 3
XV
two compounds were readily separated because the former,
but not the latter, was soluble in alkali.
Since this method of synthesis did not give satisfactory results, a regular Hinsberg synthesis from 4-aminoveratrole was attempted and found to be satisfactory.
The action of ethyl sulfate on XIV, which could be prepared from 4-aminoveratrole and ethylated without being
isolated, gave good yields of XV. The difficulty in the
s.
method lay in the hydrolysis of XV to give the desired
n-ethyl-4-&llinovera. trole
Ordinary sulfonarailles
(Ill) •
are not hydrolyzed by alkalies (4) 1 but are hydrolyzed
in good yields by heating with hydrochloric acid (5).
The compound XV was found to be resistant to alkali;
acid hydrolysis gave low yields because of extensive
demethylation. However, it was found that much better
yields were obtained when a mixture of hydrochloric acid
and dioxane was used for the hydrolysis - perhaps the
dioxane protected theCher groups from attack by the
acid. The method finally developed gave fair yields
and the period of hydrolysis was not unduly long. A pure
product was readily obtained, since unhydrolyzed starting material was easily separated by its insolubility in
acid, and demethylated products by their solubility in
alkali.
Dr Gardner's seoona method for the production of
IV was now applied to the preparation of III. A relatively low yield of crystalline N-ethyl-3,4-dimethoxyformanilide (XVI) 1 together with some oily amine which presumably
_, CaWs
(1"0::3
OC.H"3
XVI
OCOCH5
a~~~!
ocH 3
OC. H~
nl....-c2. H5
OC.H:,
XVII
oc.t-t3
XVIII
9.
arose from the saponification of XIII ef XVI, was obtained.
The N-othyl-3,4-dimethoxyformanilide {XVI), a new compound
was not purified; instead it was hydrolysed and converted
to N-ethyl-3,4-dimethoxyacetanilide (XVII), which was
obtain~
ed as a pure crystalline material. This acetyl derivative,
a new compound, was also prepared from the amine (III) obtained from the Hinsberg reaction, in an analytically pure
condition, and the two preparations were shown to be identical. It is possible that milder conditions would have given better yields; if so, this method would be a desirable
one because XVI appears to be very easily hydrolysed to
give N-ethylaminoveratrole (III).
The main features of a desirable synthe*ia of III may
now be summarized. To be successful, tne method must yield
substantially pure III.
This requirement means that, if any
by-products are formed, they must be easily separable from
III, or if nothing better can be done, that difficultly
separable by-products be formed in very small amount. The
primary amine VII , and the tertiary amine XVIII fall in the
latter category. In such a case it is necessary to purify
Ill through one of its derivatives, since Ili is non-crystalline and since fractional distillation is not practical.
The synthetical methods discussed so far belong to the last
class - the crux of these methods is to prepare satisfactory
derivatives. A satisfactory derivative would be one which is
easily formed, readily separated from its impurities, and
...ily decomposed to give the purified original material in
good yield. Four derivatives of III were tried; the
hydro~
10.
chloride, the benzenesulfonyl derivative, the formyl derivative, and the acetyl derivative. The hydrochloride was readily formed and decomposed, but could not be separated from
its impurities. The benzenesulfonyl derivative (XV) was
readily formed and very easily purified; its decomposition
was difficult and gave only a moderate yield, although it
did offer a satisfactory route to pure III. The formyl derivative {XVI) was readily formed and decomposed, but, judging from Dr Gardner•s {l) work for his corresponding compound 1VI), it probably could not be separated from its
impurities if they were present in considerable amounts.
The compound XVI was not prepared in a pure condition in
this research. The acetyl derivative was readily formed, but
its purification was difficult and somewhat wasteful. Its
decomposition also gave considerable difficulty, but a method
giving good yields was eventually discovered. The use of
the benzenesulfonyl and acetyl derivatives, then, offered
satisfactory ways of purifying III.
synthesis of N-ethzlaminoveratrole from Guaiacol
No method is known by Which pure secondary amines
n~y
be obtained directly, although some methods yield secondary
&mines with only small amounts of impurities; an example
is Dr Gardner's second method of synthesizing IV {1). It
was therefore decided to seek a method in which the byproducts are all easily separated from the desired product
III. The synthesis attempted is summarized in formulae XIX
ll.
to
xxv.
This synthesis offered the following advantages:
o::
5
H3
oett3
III
er
ooeH3
oeocH3
XXIV
it required only three steps from guaiacol (XIX} which was
available, compared with the respective eleven, seven, and
eight steps from vanillin required in the three previous
syntheses; the expected by-products, XXI and XXV, would be
readily separable from the desired product III.
The synthes-
is toolt: place readily, and compari tively large a.mo unts of
III were made without much la.bor.
However, the overall yield
was only moderately good, because the bromination of guaiacol (XIX) and the ethylamination of 4-bromoveratrole (XXI)
had yields of only about 60% each.
The necessity of using
bromine and guaiacol also added to the expense of the synthesis.
From the laboratory stand-point, however, there was
no doubt about the superiority of the present method.
4-Bromoguaiacol (XX) has been reported only occasionally.
A German patent (6 ) gives a m.p. of 46 0 -46 0 for the product
made by brominating guaiacol in the cold. The method used
in this work was that due to Robertson (7) 1 who brominated
guaiacol in cold glacial acetic acid in the presence of
sodium acetate. Robertson claimed that XX was the only monobromoguaiaool produced in the reaction. His product did not
solidify when cooled with an ice-salt mixture. The product
made in this investigation did solidify in the refrigerator,
but it was not further purified. It was evident from the
boiling-points of the fractions obtained that the mono-bromo
compound was accompanied by guaiacol and by dibromoguai•
acol, which accounted for the rather low yield. The acetyl
derivative of XX, 4-bromoaoetylguaiaool (XXIV) has not been
prepared before. It was obtained in the present research as
a pure solid, and analyzed. For comparison, the known
5~
bromoacetylguaiaool (XXIII) was made by the method of HindmarshKnigh t, and Robinson ( 8) 1 by brom.ina ting acetylpa!aool
(XXII) (which in turn was made easily enough from guaiacol)
in cold carbon tetrachloride. The two compounds were shown
to be different.
~b2~
v-OCH3
OC H 3
V
OCH3
oc.H 3
There are four important methods available in the
lit~
13.
erature for preparing 4-bromoveratrole (XXI). The first,
not used in the present research, involves the diazotization
of ._aminoveratrole (VII), followed by the action of copper
and hJCrogen bromide (9). This method offers a possible route
for preparing XXI from vanillin, which is known to yield the
necessary intermediate VII (2). Other preparations of XXI
are: from bromocatechol and methyl iodide (10); from 4• or
5-bromo-3-aminoveratrole (11); and from veratrole by
brom~
ination (12). In this investigation, 4-bromogu.aiacol was
directly methylated with methyl sulfate
~
the yield was
satisfactory (So%). The compound also was made by hydrolysis and methylation of 5-bromoacetylguaiacol {XXIII).
The last step in the synthesis, the conversion of 4•
bromoveratrole to 4-ethylaminoveratrole (III), involved a
reaction whose tJ.pe has been studied to a surprisingly small
extent. The conversion of alkyl halides to amines occurs
readily and is a
well~known
reaction, but the conversion of
phenyl halides to &mines is much more difficult and has
been studied only in the simplest oases. There are only
two methods available, the action of metallic amides on
aryl halides in liquid ammonia or other solvent, and the
action of amines on aryl halides at high temperatures ,nd
pressures in the presence of a catalyst.
The first method has been discussed recently by
~rg­
strom, et al (13), but ammonia was the only amine used by
these authors. Organic metallic amides have been used very
occasionally. Horning and Bergstrom ( 14) caused lithium, an
14.
aryl or alkyl halide 1 and a secondary amine to react and
form a tertiary amine in 21%- 66% yield. Gilman and Kyle
(15) showed that diethyllitha.mide and o-bromo-dimethylaniline gave m-dimethyldiethylphenylenediamine. an example
of a general rearrangement reaction. It will be seen that
the technique is quite difficult and expensive. The yields
obtained by previous authors were only moderate, and the
method would have to be extended well
beJ~d
its known
applications to be useful in the present synthesis.
~he
second method is the basis for the well-known cat-
alytic process for the production of aniline from chlorobenzene. This process is covered by American patents, the
abstracts of which reveal surprisingly little of the information necessary for carrying out the reaction. The only detailed experimental work published is that of Vorozhtzov
and Kobelev (16). Although the abstract available to the
writer does not give sufficient information. the work of
these authors has fortunately been reviewed by Groggins and
Stirton (17). The important facts are that ouprous chloride
at high temperature and pressure catalyzes the reaction of
phenyl halides with amines. that aryl bromides are much more
reactive than aryl chlorides, and that the correct conditions
may be derived from a recipe quoted from a patent by Mills
(18) for the production of
p~methylaminochlorobenzene
from
methylamine and p•chlorobromobenzene. This recipe was followed quite closely for the reaction used in the present synthesis, except that much longer heating ttqew and slightly
15.
lower temperatures had to be used. The yield was moderate,
but there was sane recovery of original material.
The method, although easy and direct, failed in its main
purpose of providing ethylaminoveratrole {III) free from aminoveratrole (VII). One of the runs was analyzed by the
Hinsberg method. This is not the best method for the quantitative analysis of mixtures of amines, but it had the important advantage in the present case of making it possible
to identify the constituents present.
~
its aid, the crude
amine was found to contain about 90% of N-ethyl-4-aminoveratrole (III), about 7% of
4~aminoveratrole
1% of tertiary amine. About
(VII}, and about
2% of the total fraction was
not accounted for. The source of the 4-aminoveratrole is
unknown; it might have arisen from ammonia present as an impurity in the ethylamime. Since the latter was used in great
excess, a small trace of ammonia might be sufficient to create
the observed amount of 4-aminoveratrole. Another possibility
was that the ethylamine or the ethylaminoveratrole might have
decomposed on the catalyst. The small amount of tertiary amine
found perhaps told against this possibility. The Hinsberg analysis
of the product from the ethylamination reaction yielded the
benzenesulfonyl derivatives XIV and XV, showing that the
ethylaminoveratrole was the same as that produced by the
other methods of synthesis. This fact was also shown by
converting the crude amine from the ethylamination reaction
to its acetyl derivative. The purified derivative (XVII)
was identical with that derived from the amine made by the
16.
previous methods.
Ethylaminoveratrole (III) was found to be a very easily oxidizable subs;tance, and to preserve it, nearly all
was converted to the acetyl derivative (XVII) as soon as
it was formed. Ethylaminoveratrole could also be preserved
in the cold under nitrogen without deterioration. Unfortunately, the reaction product was impure, and could not be
purified by crystallization. For this reason it was still
necessary to form a derivative for purposes of purification.
The compound N-ethyl-3,4-dimethoxyacetanilide (XVII) deserves
some attention because it was extensively used in the research
for the purification of the amine. Purification of the acetyl
derivative was quite tedious owing to its low melting-point,
ita tendency to form oils, and its high solubility in
nearly all solvents. The substance appeared to be mora soluble in cold water than in hot water. The material readily
formed a hydrochloride which was insoluble in ether but
soluble in water. The conventional method of separating
acetamines from basic ajdnes, by virtue of the insolubility
of the former in aqueous acid, therefore could not be
applied with any confidence in the present case.Evidence,
to be presented later, Shows that such methods did however
lead to some. separation. Moreover, after being heated for
twenty-seven hours in caustic soda, 14% of the acetpl derivative was recovered in a pure, crystalline state. This unexpectedly high resistance to saponification made the regeneration of the free amine difficult. Acid hydrolysis of the
17.
acetyl compound was avoided for a long time because it was
feared 'that extensive demethylation would occur, but when
the substance was boiled for three hours with 25% sulfuric
acid, the desired amine was obtained in 94% yield; the low
boiling-point, low viscosity, and failure of the product
to yield any crystalline acetyl compound, Showed that it
contained little, if any, unchanged starting-material. This
greater ease of hydrolysis with acids than with bases seems
to be typical of this series of
oompo~da;
Burton (19)
hydrolyzed N-methyl"3,4-dimethoxyacetanilide by boiling it
for twenty-four hours with an excess of alcoholic potassium
hydroxide, while Heidelberger and Jacobs (20) hydrolyzed
3-•etho~-4-ethoxy-acetanilide
by boiling it for fifty-five
minutes with 25% sulfuric acid.
To sum up, four methods for the production of N-ethyl3,4-dimethoxyaniline were investigated. All the methods
yielded the product (III); the best being the condensation
of ethylamine with 4-bromoveratrole (XXI). The crude amine
could be purified either through its benzenesulfonyl derivative or through its acetyl compound. The benzenesulfonyl
derivative was superior to the other in that it was much
more quickly obtained pure and with less loss; it was inferior because on hydrolysis it regenerated a somewhat lower
yield than the hydrolysis of the acetyl derivative; the
two hydrolyses were best performed under almost exactly the
same conditions.
Other methods for synthesizing secondary amines are
18.
available. Eesides the methods he used, Gardner (1) con4idered
the following: (1) Action of an alkyl halide or sulfate on
an amine {this method was tried in the present research).
(2) Purification of the secondary amine through its nitroso
derivati•e• (3) High temperature reaction of an alcohol and
an amine (or its salt). (4) Reduction of the corresponding
Schiff's base, which works well for higher aldehydes and ketones but only poorly for the lower members. {6) Alkylation of
a Schiff's base, but Gardner found that the method was not
valid for the preparation of ethylaniline. (6) Alkylation of
amides, as in the Hinsberg and the formanilide methods. To
this list might be added: (7) the reaction of an amine with an
alcohol in the presence of Raney nickel (21), and {S) the reduction of a nitro, nitroso, or azo compound in the presence
of an aldehyde, ketone or alcohol.
A few substances similar to N-ethylaminoveratrole have
been prepared previously. The acetyl derivative of VII has been
made frequently (3). lUrton (19) synthesized
3,~dimethoxr~l~
methylaniline by treating the sodium derivative of 4-acetaminoveratrole with methyl iodide. Parys (22) made compounds
such as XXVI {where R is an alkyl group) by treating
4,5-dinitro~
veratrole with a primary amine. The Index of Chemical Abstracts
is in error when it states that Young and Robinson (23) made
3,4-methylenedioXJ-1-ethylaniline.
Condensation of N-ethylaminoveratrole with Phosgene
The action of phosgene on
~tiallJ
hydrolyzed XVII yielded
crude N-ethyl-3,4-dimethoxy-phenylcarbamyl chloride (XXVII),
19.
a new compound. Three preparations of the substance were made.
the first two from partially hydrolysed XVII which was badly
contaminated with the primary amine (VII), and the third
from a pure preparation of XVII which had been subjected to
a much longer period of hydrolysis. Nevertheless, the first
two preparations gave products of greater purity and in higher
yield than the third. The reason for this anomaly was that in
the first two preparations, but not in the third, an attempt
had :first been
L~
.made to separate the amine to be used in the
experiment from its contaminating
N-ethyl-3,4-dimethoxyacet~
anilide (XVII) by partitioning the mixture between hydrochloric acid and ether. Thus the conventional method of separating
these substances did succeed to some extent at least. The
carbamyl chloride (XXVII) was a remarkably stable substance.
Its benzene solution could be extracted with concentrated
alkalies or acids without much loss of material; incidentally
very little purification resulted from this treatment. The
substance could be crystallized from a mixture of water and
dioxane. There was some loss, but this procedure was found to
be by far the best and speediest method of obtaining the pure
material. An analytioally pure sample was also obtained by
recrystallizing the substance from inert solvents, but the
process was very long and tedious. It should be noted that the
product was obtained from this reaction in a lees pure state
and in lower yield than the corresponding product (XXVIII)
made by Dr Ge.rdner (l). The reason for this difference seems
clear. In this research, an impure amine (III) resulting from
20.
N(~~~:
O
ocH 3
OCz.I-IS
XXVII
XXVI
the alkaline h1drolyais of
.XXVIII
N•ethyl~3,4~dimetho~aoetanilide
(XVII) was used in all the preparations; this method was
later shown to lead to very incomplete hydrolysis. The use
of the pure amine resulting from the acid hydrolysis of pure
XVII would in all probability give almost pure carbamyl chloride (XXVII) in high yields.
The action of 4-aminoveratrole (VII) upon crude N•ethyl3,4-dimethoXJPhenylcarbamyl chloride yielded not only the
expected
N•ethyl-N,N 1 •bis~(3,4-d1methoxyphenyl)-urea
XXIX
(XXIX),
XXXI
but also N,N 1 -bis-(3,4-d1methoxyphenyl)-urea (XXX) in aaounts
-·
which Showed that the carbamyl Chloride (XXVII) was contaminated with at least 20% of
N-3,4-dtMetho~phenylcarbamyl
chlor-
ide (XXXI). These two substituted ureas were obtained as
pure crystals and analyzed. An interesting circumstance was
that they could not be distinguished by analysis alone from
21.
such compounds as XXXII and XXXIII, which have practically
the same elementary compositions as XXIX and XXX, respectively. The determ.ination of the molecular weights left no
doubt that the compounds obtained were the latter pair.
XXXII
The substituted urea XXIX was a new compound, but the
symmetrical urea XXX has been made twice before. Brunner and
Wohrl (24) obtained it by the action of water upon 3,4-di•
methoxyphenylisocyanate (XXXIV); its structure is therefore
well established. The melting-point of their preparation was
215 0 ; of the one in this research, 2130 -214.0 It would
XXXIV
there~
XXXV
fore seem certain that Fetsoher and Bogert (3) made a mistake
in their preparation. They allowed the hydrochloride of 4amtneveratrole {VII) to react with urea and water and obtained three products: 3,4-dimethoxyphenylurea (m.p. 210°)
22.
1n 50% yield; a product (m.p. 219°) agreeing in analysis with
formula XXX, in 10% yield; and a product (m.p. 313°), also
agreeing in analysis with formula XXX, in 5% yield. They
decided that the product of m.p. 313~ obtained in
5%
yield,
was XXX and that the product of m.p. 219~ obtained in 10%
yield, was asymmetrical-bis-{3,4-dimethoxyphenyl)-urea (XXXV),
because they felt strongly that the symmetrical compound
should have the higher melting-point. It is obvious that in
all probability the compound of m.p. 219°, obtained in the
higher yield, was actually the symmetrical urea (XXX), because its melting-point is in close agreement with that
Brunner and WOhrl (24) and with the product of this research.
The present results would seem to place its structure beyond
any doubt. The writer also suggests that the compound of m.p.
313° was perhaps not the asymmetrical urea XXXV, but was
B,B-bis•(N•3,4•dimethoXJPhenylaminofor~l)-4-aminoveratrole
(XXXIII). This substance certainly would be expected to have
a higher melting-point. The two compounds could scarcely be
distinguished by their elementary analyses.
When impure N-ethyl-3,4-dimethoxyphenylcarbamyl chloride
(XXVII) was allowed to r ..ot with crude
N-ethyl-3,4-dimethoxy~
aniline {III)t small amounts of N,N'•diethyl-N,N'·bis-(3,4-dimethoxyphenyl)-urea (II) and of N-ethyl-N,N'•bis-(3,4-dimethoxyphenyl)-urea (XXIX) were obtained. When the
p~e
carbamyl
chloride (XXVII) was caused to react with the pure amine (III),
only the desired stabilizer II resulted, in an analytically
pure condition and in a yield of 41%. The solubilities of the
23.
stabilizer (II) and the reactant (XXVII) were so similar, and
the reaction of III and XXVII so sluggish, that it was necessary to use a very large excess of the free amine (III) to ensure that no carbamyl aaloride (XXVII) would remain in the
product.
The synthesis of the desired stabilizer (II) was therefore completed successfully. The only poor step now remaining in the synthesis is the formation of the intermediate
carbamJl chloride (XXVII). It is believed that this difficulty
has already been solved, and was caused by a now abandoned
method of hydrolyzing the intermediate compound XVII.
All the substituted ureas (II, XXIX, and XXX) obtained in
the research are very easily separated from each other because
their solubilities differ wilely. It might be thought that
the purification of III, a difficult and wasteful process,
might be avoided, the crude amine used in the syntheses, and
the mixture of ureas separated at the end. Unfortunately, since
a large excess of
~ine
is needed in the final reaction with
the carbamyl chloride, and since the primary amine reacts so
much faster than the secondary amine, only low yields of the
desired urea II could be obtained by this method of
s~aration.
Similarly, the use of the carbamyl Chloride (XXVII) as a
means of purifying III could not succeed - the compound itself
is too difficult to purify.
Table I lists the melting-points of the 3,4-dimethoxyphenyl
compounds obtained in this research together with the corresponding 3-methoxy-4-ethoxy derivatives synthesized by GBrdner(l}.
24.
The alternating increase and decrease caused by the replacement of the methoxyl for the ethoxyl is interesting, although
no explanation is advanced for the phenomenon. Centralite
(N,N'-diethyldiphenylurea)- melts at 79~
T.ARtE I
Meltins-Points of Corresponding 3,4-Dimetho;rand 3,4-Metho;yetho;y-Phenzl Derivatives
Compound
3 1 4-dimethorz series
(a
3-metho~-4-etho!l
ser es
88°
55°
(XIII, V)
91°
103°
Acetanilide a (3) (20)
133°
150°
Ethylformanilides(XVI,VI)
---
80°
Ethylaoetanilides(XVII)
61°
Ethylamines (III,IV)
oil
Primary amines (V.II.il$)
~o:rmanilides
Carbamyl chlorides(XXVII,
--43°
86°
85°
.XXVIII)
0
Ureas (X::XX,sim)
214
Bthylureas (XXIX,sim)
159°
127°
79°
51°
Diethylureas (II,I)
209°
(a) The series of the present research.
(b) The series investigated by Dr Gardner (l).
(b)
25.
Introduction to the Experimental Section
All temperatures are uncorrected. All pressures are
unoorrelted, and are expressed in millimetres of mercury,
unless otherwise stated. The carbon, hydrogen, and
nitrogen determinations, and the (Rast) molecular weight
determinations are mioroanalyses performed by Miss
1~rie
Anderson of the Dominion Rubber Company.
EXPERIMENTAL
Veratraldehyde (25)
This shorter method of methylating vanillin with dimethyl sulfate and alkali has been found perfectly satisfactory.
Veratraldoxime (26)
The yields of the crude oxime in three preparations
were, respectively, 61%, 99% (the oxime was wet), and 86%,
calculated on vanillin.
Veratronitrile (26}
The yields of the crude nitrile in three preparations,
calculated on the oxime, were respectively 77%,m.p. 64.5°660), 49% (m.p. 65.5°- 66.5° ~an additional 19% was recovered from the
mother-liq~ora),
and 60%. At least one factor
in the low yields is therefore the solubility of the product in the diluted reaction-mixture.
Veratramide (2)
The yields of the crude amide in three preparations,
calculated
on the nitrile, were respectively 93% (m.p.
163.5°- 165°), 81% (m.p. 164°- 165°}, and 91% (m.p.l65°165.5°. Buck and Ide (2) give a m.p. of 162.5°- 163.5°.
~Aminoveratrole
(2)
In three preparations, a total of 79.4 g. of distilled
4•aminoveratrole was made. The respective yields, calculated on the amide, were 79% (b.p. 163°- 166°/13- after re•
27.
crystallizing from 40 cc of benzene, the yield was 74%, the
m.p. 87.5°- 89°), 76% (b.p. 166°- 170°/14), and 81% (b.p.
165°/13 - 11). BUck and Ide (2) give a m.p. of 87.5° - 88~
3 4-Dimethoxyformanilide (1) 1
1
4-Aminoveratrole (crude, distilled, 18.0 g.) was gently
heated under reflux for half an hour with formic acid (90%,
~5cc).
Cooled in the refrigerator overnight, the mixture set
to a solid mass which was then broken up, transferred to a
Buchner, well washed with water, then with 6 cc of ether, and
air-dried. Yield of crude bluish powder, 21.3 g. or lOO%.
1.3 g. of this crude product was recrystallized from
a mixture of petroleum ether, benzene, and acetone, with char·
coal. Yield, 0.7 g., of material of m.p. 90° - 91~
In another preparation, the yield of crude product was
83%.
3,4•Dimethoxy-N-ethyl-formanilide.Ethyl Bromide Method (1}.
3,4-dimethoxyformanilide (20.0 g.) was dissolved in boiling alcohol (30 cc) in a 3-necked, 500cc flask fitted with
a reflux condenser and two dropping-funnels. From one funnel,
a solution of potassium hydroxide (USP, 7.3 g.) in alcohol
(75 cc) and from the other a solution of ethyl bromide (13.2 g.)
in alcohol (50 cc) were slowly added at equivalent rates over
1
The reference to Dr Gardner's work here, and in other parts
of the Experimental Section, signifies that the preparation
in question was based on a similar preparation of Dr Gardner's
in the 3-methoxy-4-ethoxy series.
28.
a period of 45 minutes. During the addition. the mixture was
kept gently boiling; potassium bromide slowly settled out.
After the addition of the reagents had finished, the mixture
was heated under reflux for 1.25 hours longer, and then
allowed to cool. Next morning, the mixture was made slightly
acid with hydrochloric acid, the precipitate was removed by
filtration and washed with two portions of boiling ethanol.
The filtrate was diluted with about 50 eo of water, and
evaporated to small volume under reduced pressure. The resulting syrup did not crystallize, and the following operations were
designed to obtain a crystalline product. The syrup was first
hydrolyzed by heating under reflux for four hours with a very
slight excess of aqueous alcoholic potassium hydroxide, the
free amine extracted with ether and distilled. The mixed amines
ware a yellow oil, b.p. 165°/14, yield, 11.1 g. This oil was
reconverted to the formyl derivative with formic acid (as for
4-aminoveratrole), but again, only an uncrystallizable oil was
obtained. Accordingly, the oily formanilide was re-ethylated
by adding alcohol (50 eo) and ethyl bromide (3.6 g. in 10 cc
of alcohol). Then, while the mixture was gently heated under
reflux, potassium hydroxide (1.8 g.) in alcohol (20 eo) was
added from a dropping-funnel over a period of 26 minutes. Heating was continued for an additional 155 minutes. When the product was worked up in the usual manner, an uncrystallizable
oil was again obtained {Product A).
Another preparation of this compound is given in a later
section.
Direct Ethylation of 4-Aminover.atrole
4•Aminoveratrole (11.2 g.) in ethanol (25 eo) was
ethylated by adding ethyl bromide (10.6 g.) in alcohol {30 cc)
and potassium hydroXide (4.7 g.) in alcohol (50 eo} at equivalent rates, over a period of 45
minutes~
the reaction mix-
ture being gently heated under reflux. After the addition
had been completed, heating was continued for two hours more.
The pH was now 6 - 7. Product A (as
above~
dissolved in 26 eo
of alcohol} was now added to the mixture, and the whole was
heated under reflux for 4 hours with a solution of potassium
hydroxide (8.3 g.) in water {100 eo). The product was diluted
with water, extracted with ether, and the isolated amines
distilled, a yellow oil, b.p. 155
0
being collected. The last few drops
0
- 163 /10, yield 16.4 g.,
crystallized~
but not the
main body.
Hzdroohloride of 3,4-Dimetho!l{-N-Ethylaniline
Gaseous hydrogen chloride (4.6 g.) was dissolved in ether
(30 cc) and the solution added to a cold solution of the yellow
oil (obtained as described just above) in ether. After a short
time, a vigorous reaction occurred, and a gummy precipitate
formed which gradually crystallized. After thorough
cooling~
the precipitate was recovered and washed with two portions of
ether. Yield, 20.1 g. or 9~, m.p. 120° - 145~ Recrystallization from alcohol gave a pure white product, yield 11.6 g., of
m.p. 141° - 168~ a small amount being unmelted from 146°. Another recrystallization from a mixture of benzene and methanol
0
gave 6.1 g. of crystals, melting above 143. The crystals were
30.
dissolved in ethanol and precipitated with ether. White
crystals with a slight purple encrustation were obtained
in 4.8 g. yield. This hydrochloride, though it amounted to less
than 25%
o~
the original product and had been reorystallised
four times, was still ver,v impure, as shown by its
Hins~
berg separation, which is described below.
(From the
mother-li~ors
of the reorystallisations,
9.0 g. of the hydrochloride was recovered).
Hinsberg
separa~,ion
of tae Amine Hydrochloride&
(a)Bensenesulfonation: The reoryatallized amine hydrochloride
(4.8 g.) was treated with a solution of potassium hydroxide (7.8
g.) in water (50 eo); while the mixture was mechanically stirred
benzenesulfonyl chloride (5 cc} was added; stirring was
then continued for 2 hours. The mixture was then heated to
0
93 and the stirring continued for 1.25 hours longer. The
alkaline mixture was now made distinctly aoid with hydrochlor•
ic acid and cooled. The precipitate was recovered, ground
fine and extracted with dilute hydrochloric acid, well
washed with. water, and dried in vacuo. Yield, 7.2 g.
(b) Tertiarz Amine:The acid filtrate was worked up as usual
for &mines, but no crystalline amine hydrochloride was obtained.
(c) Hydrolzsis of
Dibenzenesul~opYl
Derivative of
Primary Amine: The crystalline precipitate obtained in (a)
part
w~s
dissolved in boiling alcohol (30 cc), and a solution
of sodium (3.7 g.} in alcohol (70 cc) was added, the clear
solution heated under reflux for 15 minutes, diluted with
200 cc of water, and the mixture distilled under reduced press-
31.
ure until 185 cc of distillate had collected. The residue
was made acid with hydrochloric acid, cooled thoroughly,
and filtered. The precipitate was well washed with water
and dried !!! vacuo.
(d) Separation of the BenzenesulfOAfl Derivatives of
Primarz and Secondary Amines: The dried precipitate of (c)
part was then dissolved in 500 cc of dry ether and 1.5 g.
of sodium wire was added; the mixture was then heated under
reflux for 6.5 hours. Another 1.6 g. of sodium wire was
added, and the mixture heated for 8 hours more and allowed to stand overnight - the second portion of sodium was
practically unattacked. The ether was removed by filtration
and the residue extracted by heating it under reflux for
several minutes with three large portions of dry ether. The
filtered extracts were added to the previous filtrate.
The insoluble residue, consisting of sodium and the
sodium salt of the benzenesulfonyl derivative of 4-sminoveratrole, was treated with lOO eo of alcohol, and then with
300 cc of water.
~
distillation under reduced pressure,
250 cc of the solvents were removed. On acidification of
the residue, a scanty (0.1 g.) precipitate formed, which
was recovered and washed.
The ether filtrates were evaporated, and 6.5 g. of
crude crystalline material were obtained. This material was
washed with dilute hydrochloric acid, then with water, and
then extracted twice with dilute sodium hydroxide solution,
and well washed with water. The united caustic and (post-
37.
-
twice with ethanol, and dried in vacuo. The white crystals
weighed 4.2 g., and had a m.p. of 93.2°- 94.0°. They were
therefore unchanged starting-material.
Acid Hzdrolzsis of
N-Ethzl-B~benzensulfopYl-3,4~dimetha;J·
Aniline
(1) N-ethyl-N-benzenesulfonyl-3 1 4-dimethoxyaniline (4.2 g.,
reclaimed from the above alkaline hydrolysis) was heated under
reflux in an atmosphere of washed illuminating gas for 11.75
hours with a solution of concentrated hydrochloric acid (16
cc) and water {9 cc). On cooling, the solution was filtered
from some tar, Which was waShed with dilute hydrochloric
acid. The combined filtrates were then made very alkaline
with sodium hydroxide (20 g.) and water (20 cc), ice being
added to keep the mixture cool. The mixture was then extracted
thoroughly with ether, then once with benzene, and the combined
extracts, after drying over caustic, were distilled. A
yellow oil, most of it boiling between 153° - 160°/10 1 yield
0.6 g. or 27%, was obtained. On forcing of the distillation,
a few more drops distilled, the temperature rising rapidly to
215°; this portion solidified in the side-tube, and no
attempt was made to collect it. Probably it was a demethylated
product.
(2) N-Ethyl-N-benzenesulfonyl-3,4-dimethoxyaniline (5.5
g., recrystallized) was heated under reflux for 5 hours with
a solution of dioxane (15 cc} and concentrated hydrochloric
38.
acid (15 cc) in an atmosphere of washed illuminating gas. The
mixture was then evaporated almost to dryness under reduced
pressure. After being cooled and triturated with dilute
hydro~
chloric acid, the syrup solidified. It was then partitioned
between dilute hydrochloric acid and ether. On evaporation,
the ether extract yielded 1.1 g. of brown crystals, probably
impure starting-material, a yield of 20%. The acid aqueous
layer was made strongly alkaline with sodium hydrOBide solution
in the cold, ice being added. A precipitate formed which
could not be separated by filtration. The solution rapidly
turned dark blue, another indication of demethylation. The
solution,was then extracted with several portions of ether,
the combined ether extracts dried over sodium hydroxide and
distilled. An oil, b.p. 145° - 155°/9 - 12, was collected.
The yield was 1.0 g. or 32%.
The products collected in the two hydrolyses just described were assumed to be N-ethyl-3,4-dimetaoxyaniline, probably
contaminated with higher-boiling, partially demethylated pro•
ducts. Both samples oXidized very rapidly 'o brown gums, even
'
in the refrigerator.
(3) N-Ethyl-N•benzenesulfonyl-3,4-dimethoxyaniline (20.0
g., reorystallized) was heated under reflux for 3 hours with a
solution of dioxane (60 cc) and concentrated hydrochloric
acid {60 oo) in an atmosphere of washed illuminating gas. The
reaction-mixture was then evaporated almost to dryness under
reduced pressure and as before partitioned between ether and
dilute hydrochloric acid (the ether layer was discarded).
The acid aqueous layer was made strongly alkaline in the
cold with sodium hydroxide, and was immediately and thoroughly extracted with ether; the aqueous layer darkened rapid•
ly during the extraction, no doubt dQe to the presence of
aminophenols. The ether extracts were dried over sodium
hydroxide and distilled. A very slightly yellow oil, b.p.
145° - 151° {the major portion at 1500)/8 ·6 was collected,
yield 7.6 g. or 67%, assumed to be practically pure N-ethyl·
3,4-dimethoxyaniline.
3,4-Dimethoxy-N-ethylaoetanilide from the
Hinsber~
Synthesis
N-Ethyl-3,4-dimethoxyaniline (prepared in the third acid
hydrolysis described above, 4.4 g.) was allowed to stand
45 minutes in solution with acetone (25 eo) and acetic
anhydride (9 ea) at room temperature. The solvents were then
evaporated very thoroughly under vacuum, the last traces of
anhydride being flushed out with water, benzene, and ether,
,, each being added and distilled away in succession. On
being cooled
and~dedwith
a crystal obtained from a pre-
liminary experiment, the residue crystallized, yield 5.5 g.
or 101%. An attempt was made to reorystallize the substance
from water (55 eo) -however it seemed to be more soluble in
cold than in hot water, and did not crystallize from the
solution in the cold. Accordingly the aqueous solution was
evaporated in vacuo, the last of the water being flushed out
with benzene (which of course was distilled away) and the
syrup crystallized by seeding. After many months, the product
40.
was distilled, a light brown, very viscous oil, b.p. 123°
- 1320/28 mic., yield 3.2 g., being collected. This oil
waa crystallized from petroleum ether; the resulting crystals weighed 2.7 g. and melted at 60°- 62°. On reorystallization with charcoal from. 230 cc of petroleum ether, colorless
crystals were obtained, yield 1.7 g. !wo determinations of
the m.p. were made: 1) 60.5°- 62.5° 2)60.0°- 61.2°.
Found:O - 64.67%, 64.47%; R • 7.64%, 7.66%; N - 6.44%,
6.27%.
c1 zal 7o3N requires
64.57% 0; 7.62% HJ 6.28% N.
N-Ethil-3 1 4-dimethoxyformanilide; N-ethil-3 1 4-dimethoxyaoetanilide. Diethyl Sulfate Method. {1)
3,4-Bimethoxyformanilide {crude, 13.2 g.) was dissolved
in dioxane (92 eo) contained in a three-necked flask equipped
with condenser, mechanical stirrer, and two dropping-funnels,
and heated with a water-bath. With the temperature of the
water-bath at 90°- 950, diethyl sulfate (28 oo} was added to
the solution from one funnel; a solution of potassium hydroxide (17 g.) in water (17 oo) from the other. The alkali
was added somewhat more slowly than and somewhat after the
ethyl sulfate - all the ethyl sulfate was added in 50 minutes; the last of the alkali
wa~dded
10 minutes later. The
different rates of addition were adjusted to keep the solution at approximate neutrality; at first, the oolor of the
solution was a guide to the acidity, but not later; pH test
paper was not very reliable either. After the addition was
complete, the solution was heated 15 minutes, then allowed to
cool to 80°, and then rapidly cooled to 200. Water (200 cc)
was added. The pH was now about 9. After cooling thoroughly
in the cold room, the solution was thoroughly
extrac~ed
with
ether. The ether extract was then extracted first with dilute
hydrochloric acid and then with water (the united acid and
water extracts were made alkaline with sodium hydroxide in
the cold and extracted thoroughly with ether. On standing,
a small quantity of brown needles separated from the ether.
The ether solution on evaporation yielded a brown oil, thought
to be impure N-ethyl-3,4-dimethoxyaniline, yield 4.1 g. or 31%).
The acid-extracted ether solution was now treated with sodium
bicarbonate and the filtered ethereal solution evaporated.
Crude N-ethyl-3,4-dimethoxyformanilide crystallized from the
residue on standing in the cold, yield 3.9 g. or 26%. The
crude material was heated under reflux with ethanol (25 cc),
water (5 eo), and potassium hydroxide (2.0 g.) for 1 hour,
cooled, and diluted with water (lOO eo). The mixture was then
repeatedly extracted with small portions of ether, the solvent
removed from the ether extracts, and the residue treated with
acetone (8 oa) and acetic anhydride
(8
cc). The mixture became
warm. Next morning, the mixture was distilled, a pale yellow
oil, b.p. 121° - 125°/12 mic., yield 2.2 g., being collected.
This oil was recrystallized from petroleum ether. Yield
1.2 g., m.p. 50°- 59° (probably the material was contaminated
with the acetyl derivative of the primary amine). Recrystall"
ized from petroleum ether (140 cc) with charcoal, the crystals
weighed 0.5 g., m.p. 59°-61~ They were then recrystallized
from methylcyolohexane {15 eo). Yield of colorless crystals
0.2 g., m.p. (two determination&): 1) 60.5°- 62.5° 2) 60°-
42.
0
61 ; mixed m.p. with a pure sample fro• the Hinsberg reaction
(two determinations): 1) 60.2°- 61.3° 2) 60.2°- 61.1~
4-Bromosuaiaool (7}
Glacial acetic acid (300 eo), guaiacol (Merck,
~ight
brown in color, 110 cc), and sodium acetate (probably the
trihydrate, 136 g.) were placed in a flask cooled in an icesalt bath. Then While the mixture was mechanically stirred,
a solution of bromine (51 cc in 102 cc of glacial acetic
acid) was slowly added from a funnel, the temperature of the
reaction-mixture not being allowed to rise above 4~ The addition
required 1.5 hours; the solution was stirred 45 minutes longer,
then poured into 3 1. of water, and the mixture extracted with
two large portions of ether. The combined ether extracts were
washed repeatedly with water, and then distilled. A yellow oil,
b.p. 115°- 141°/14 was collected as product, yield 141.2 g. The
consider~ble
low- and high- boiling fractions were discarded,
and the main fraction was refractionated through a small col-
umn, the following
~raotions
being collected: a) up to 100°/13,
mostly at 92°, probably principally guaiaool, 11.2 g. (discarded b) 100°- 129°/13, major part above 125°, 7.9 g.
c) 129°- 132°/13, a colorless oil quickly turning yellow in the
receiver, 99.6 g. or 49% of theory on guaiacol l)residues
(discarded}.
The fraction c) solidified partially after several days in
the refrigerator.Robertson•s material (7) (yield not stated}
boiled at 180° - 182°/60, and did not solidify in a freezingmixture.
Aoe,tzlguaiaool ( 28)
Guaiacol (Merck, 31 eo), acetic anhydride (Shawinigan
Chemicals, 35 cc), and concentrated sulfuric acid (2 drops}
were mixed in a flask. The temperature tmmediately began to
rise rapidly and was kept below 80° by external cooling. After
the temperature began to fall of its own accord, the mixture
was heated on the steam-bath for 25 minutes, allowed to cool,
and neutralized with sodium acetate (2 g.). The mixture was
filtered through a perforated filter-disk. and the filtrate
was fractionated twice, the following fractions being collected
in the first distillation: a) up to 100°/20 (discarded)
b) 100°- 117°/20. 21, 7.5 g. o) 117°- 123°/21- 19, 7.5 g.
d) 123°- 122°/19, 20.2 g. All the fractions were colorless
oils. In the second distillation, the following fractions were
collected: a) up to 11S 0/l2, 7.6 g. (discarded) b) 118°1200/12, 4.4 g. c) 120°- 121°/12 1 20.6 g. or 44% of theory
on guaiacol.
4-Bromoacetylguaiaool
4-Bromoguaiaool (b.p. 129°- 132°/13, as above, 4.6 g.),
acetic anhydride (5 oc), and concentrated sulfuric acid ( 1
drop) were heated on the steam-bath for 95 minutes, allowed to
cool at room temperature for 24 hours, diluted with 30
cc~f
ether, and extracted with a solution of potassium hydroXide
(oa. 5 g.) in 40 cc of water (and sufficient ice to keep the
mixture cool). The ethereal solution was then washed with watel'
and distilled. A faintly yellow oil, b.p. 135°- 151°/12 and
44.
nearly all at 143°- 148°/12, collected in the receiver,
yield 3.9 g. or 70%. The product soon solidified in the
refrigerator, and
~as
then recrystallized with charcoal
from 15 cc of petroleum ether; the white crystals were recovered, washed with petroleum ether, and air-dried; m.p.
45.3°- 47.5°. The product was now dissolved in 15 cc of petroleum ether, filtered, and the solution chilled. The large
~hite
crystals were recovered, crushed, washed with petrol-
eum ether, and dried over paraffin and sulfuric acid at a pressure of 100 mm.; m.p. 48.3° - 49.2°.
Found:1.:. C • 44.37%, 44.27%; H - 3.86%, 3.92%. CgHg03 Br
requires 44.08%-'UJ; 3.67% H.
5-Bromoacetylguaiacol (8)
Acetylguaiacol
( b.p.
1200 - 1210112, as above, 20.2 g. )
was dissolved in carbon tetrachloride (100 cc), cooled in an
ice-salt bath, and mechanically stirred while a solution of
bromine (7.2 cc) in carbon tetrachloride {20 cc) was added
over a period of one hour, the temperature being kept below
3°, and nearly always at -5°. The mixture was stirred and
cooled for half an hour longer, then it was washed three
times with 200 cc portions of
calcium chloride, and the
~ater,
dried by shaking with
carbon~etrach1oride
was then re-
moved on the steam-bath ( a considerable amount of free bromine also distilled). The residue was fractionated, the
fractions collected being: a) 115°- 150°/12, a slightly
yellow oil, 3.4 g. (discarded) b) 150°- 1540/12, nearly all
at 152°- 1540/12, a colorless oil which solidified in the
45.
refrigerator, yield 16.3 g. or 65%. o) a considerable residue, which was discarded.
A portion of the main fraction was recrystallized, with
filtering and chilling, from petroleum ether (30 eo). The
crystals were recovered, washed twice with petroleum ether, and
air-dried• m.p. 61.5°- 63o5°.The crystals were again reorystallized from 30 cc of petroleum ether, charcoal being used.
The glistening white crystals obtained melted at 63.4
0
-
64.0°; mixed m.p. with the purified 4-bromoaoetylguaiaool
described above (1:1): 28°- 43°, nearly all melted at 32°.
(Hindmarsh, Knight, and Robinson (8) give a m.p. of 62° 63° for their product).
4-Bromoveratrole (from 4-Bromoguaiaool}
4-Bromoguaiaool (b.p. 129°- 132°/13, as above, 70.2 g.}
was heated on a boiling water-bath while from separate funnels
potassium hydroxide solution (33.7 g. of alkali in 50 cc of
water) and dimethyl sulfate (tech., 41.5 cc) were added at
approximately equivalent rates over a period of 20 minutes,
the reaction mixture being mechanically stirred. stirring and
heating were continued half an hour after the addition was
completed; the mixture was then cooled, diluted with 400 eo
of water, extracted twice with ether, and the ether extracts
washed with water and distilled. A colorless oil was collected
as the product, b.p. 130.5° - 1390/16 - 15, yield 59.7 g. or
8o%.
4-Bromoveratrole (from 5-bromoacetylguaiacol)
5-bromoacetylguaiacol (b.p. 150°- 154°/12, as above,
46.
10.3 g.) was placed in a three-necked flask. Sodium hydroxide (USF, 6 g.) was dissolved in 20 cc of water. Water
(20 cc) and about half the caustic solution were now
added to the 5-bromoacetylguaiacol. The mixture was warmed
and mechanically stirred. With the temperarure kept between
70° and 80°, solution was complete in 5 minutes. Then dimethyl sulfate (tech., 6 cc) was added over a period of
10 minutes; the rest of the alkali was added in portions,
the stirring was continued, and the temperauture kept at
70° - 80°, during this time. For half and hour after the
addition of reagents was complete, the stirring was contin-
o
ued, and the temperature kept at 80 - 1000. The very alkaline reaction-mixture was then cooled and extracted with
three portions of ether. The ether extract was then distilled
~ vacuo, a oolorless but somewhat wet liquid, b.p. 130° 131°/14- 11, being collected. Yield, 6.6 g. or 72%.
Cuprous Catalyst Suspensions
Catalyst I: Sodium sulfite {presumably the heptahydrate,
38.4 g.) was dissolved in water (100 cc) in a stoppered flask.
In a beaker, copper sulfate (anhydrous, 21.0 g.) and common
salt (43.5 g.) were dissolved in water (180 cc}; the solution was heated, filtered, and reheated to boiling. The
copper-sulfate-salt solution was now added to the sulfite
solution. There was no precipitate. Then common salt (40 g.)
was added to the solution, and the mixture brought to a pH
of 6 with hydrochloric acid and caustic potash. The resulting
precipitate
w~s
orange rather than white
~
color, and there-
47.
fora contained some cuprous oxide. The carefully stoppered
mixture was cooled, allowed to settle, decanted, washed with
a large volurde of water, decanted after settling, and stored
under nitrogen in a small, stoppered flask. The total volume
of the suspension was about 60 cc.
Catalyst II: In a flask, copper sulfate (anhydrous, 20.1
g.) and common salt (32.4 g.) were dissolved in water (lOO eo)
and to this solution was added a boiling solution of sodium
sulfite
(.~H o?
2
16.0 g.), potassium hydroxide (7.0 g.), and
common salt (21.7 g.) in water (130 eo). The green calor of
the cupric salt was not totally discharged. The flask was
stoppered, the precipitate allowed to settle, and washed by
deoantation (the mixture could not be filtered). Of final
volume 60 - 70 eo, this suspension was stored under nitrogen
in a small flask. It still contained some cupric copper and
so was green in oolor.
Catalyst III: In one flask was placed copper sulfate
(anhydrous, 3.0 g.), common salt (5 g.), and water (16 eo);
in another, sodium bisulfite (1.0 g.), sodium hydroxide (1.1
g.~,
common salt (3.3 g.) and water (20 eo). The contents of the
two flasks were heated and the second added to the first. The
precipitate was brown. A few drops of hydrochloric acid were
added, but the oolor did not change. The supernatant liquid
was decanted after the mixture had cooled and settled; the
precipitate was then washed twice by ·decantation.
All the suspensions were thoroughly shaken just before use 9
48.
N-Ethyl-4-Aminoveratrole and 3,4-Dimetho!Y-N•etpylaoetanilide
The method is sL1ilar to that used by lUlls (18) for
the preparation of methylamino-ohlor-benzene.
Note: All the apparatus and reagents used in charging
the bomb, and the bomb itself, were chilled thoroughly before
these experiments were commenced, to avoid loss of the volatile ethylamine.
Run I:
4-Bromoveratrole (b.p. 130.5°- 139°/16- 15,
as above, 20.1 g.), ethylamine (liquid,Eastman, 36 cc}, and
catalyst I (10 eo) were placed in a 100 oo beaker and se.led
in a steel bomb (oa. 250 oo capacity) which was then heated
on the steam-bath for 7 hours. The maximum temperature reached
was 97°. The bomb was then thoroughly chilled, opened, its
contents rinsed into a beaker with ether and water. An attempt
to remove the excess ethylamine with a stream of air was unsuccessful. The mixture was then made strongly acid with concentrated hydrochloric acid (50 cc), cooled by adding ice,
and twice extracted with ether. This ether extract gave on
0
disti11ation a 1ight brown oi1 1 b.p. 120- 142°/11, yield
14.3 g., a recovery of 71% of bromoveratrole.
The acid aqueous layer form the ether extraction was
treated with ice and made strongly alkaline with a solution
of potassium hydroxide (60 g. in 60 cc of water), and then
extracted with three portions of ether - the aqueous layer was
filtered after the second
extrao1io~
to break the emulsion.
The ether extracts were dried over potassium hydroxide and
distilled, the product being collected as a light brown oil,
49.
b.p. 150°- 163°/12; the yield of crude ethylaminoveratrole
was 2.6 g. or 16%. The oil on cooling began to crystallize.
The product was dissolved in acetone (20 cc) and treated with
acetic anhydride (4.5 cc). The mixture became warm and turned
first blue, then purple. After three hours at room temperature and two days in the refrigerator, the mixture was distilled, crude ethyldimethoxyacetanilide being collected as a
very viscous, yellow oil, b.p. 120°- 130°/35 mic., yield 1.2 g.
or 37% on the crude amine. A filtered solution of this oil in
petroleum ether (15 cc} on cooling depos1led an oil which crystallized. After recovery, washing with petroleum ether, grinding in a mortar, and drying in vacuo over paraffin and sulfur~o acid, the product melted at 55°- 58°, yield 0.7 g.
Run II:
As above, using 4-bromoveratrole (20.0 g.),
ethylamine (37. 5
cc}, and catalyst II (15 cc). The mixture
was heated in the bomb for 25 hours, the temperature usually
being 101°. On opening the bomb, after tharough cooling, the
observer noted the presence of metallic copper (this was
also seen in the subsequent runs). Before acidification, the
ether, excess ethylamine, and about half the water were removed under reduced pressure - this procedure made it possible to use much less alkali and acid in the isolation of the
product.
The acid-insoluble extract yielded 3.4 g. of a brown oil,
b.p. 110° - 132°/12, a recovery of bromoveratrole of 17%.
The acid-soluble, alkali-insoluble extract gave a brown
oil, b.p. 142°- 163°/11, nearly all above 154°, yield 8.4 g.
50.
or 50%. The crude amine was dissolved in acetone (50 cc), and
treated with acetic anhydride (15 cc}. The mixture became
warm, but the oolor change noted in Run I was absent. After
standing at room temperature for 2. hours and in the refrigerator for 24 hours, the oily mixture was distilled, crude
ethyldimethoxyacetanilide being collected as
~iscous,
light
brown oil, b.p. 125°- 131°/20- 18 mic., yield 8.4 g. or
81% on the crude amine. The oil was recrysta11ized with filtering from 120 cc of petroleum ether. An oil separated which
slowly crystallized. The recovered crystals were washed with
benzene, finely powdered, and dried. Yield, 7.? g •• m.p.
54.5°- 58°; mixed m.p. with a corresponding sample from Run I
(1:1): 54.5°- 58.5°. The products from the two runs were now
mixed.
Run III: As above, using 4-bromoveratrole (19.6 g.), ethylamine (36 cc), and cuprous catalyst II (15 eo). The mixture
· was heated for 38.6 hours on the steam-bath. During the isolation of the product, it was noticed that some oil codistilled with the water in the first distillation.
The recovered 4-bromoveratrole was worked up with that
of Run IV.
The crude ethylaminoveratrole was obtained as a brown
oil, b.p. 145° - 1600/11, yield 8.7 g. or 53%. From the crude
amine, the acetyl compound was obtained as before, a yellow
oil, b.p. 120°- 130°/15 mic., yield 8.3 g. or 77% on the
crude amine. The product was recrystallized with filtering
61.
from 105 oc of petroleum ether; it had to be seeded to induce
crystallization. After redovery, two washings with petroleum
ether, fine grinding,and drying, the crystals weighed 6.9
g., m.p. 52° - 68°.
Run
IV: As above, using 4-bromoveratrole (recovered
from the first two runs of this section, 17.1 g.), ethylamine (44 eo), and catalyst II (15 cc). The mixture was heated for 41 hours. The acid-insoluble ether extracts from this
run and from Run III were united, washed with dilute hydrochloric acid, then with dilute potassium hydroxide, and
distilled. A colorless oil, b.p. 110° - 126°/11, was collected. Yield, 4.2 g., a recovery of bromoveratrole of 11%.
The crude amine was obtained as a brown oil, b.p. 150°
-162°/12, yield 8.4 g. or 59%. It was converted to the acetyl
.
0
derivative which was obtained as an oil, b.p. 112° - 131 /12
mic., yield 9.5 g. or 92% on the crude amine. The product was
reorystallized from petroleum ether,seeding being necessary,
yield, 8.3 g., m.p.52°- 58°; mixed m.p. (1:1) with the product from Bun III; 53° - 58°; with the mixea products from
Runs I and II: 52° - 59.5°. All four products were now mixed.
Run V: 4-Bromoveratrole (from 5-bromoacetylguaiaool, and
that recovered from Runs III and IV of this section, 10.3 g.
in all) was placed in a 25 cc flask, together with catalyst
III. The flask was then placed in the bomb, and in the bomb,
but outside the flask, was placed ethylamine(49 cc). The
product was isolated as before; the heating-time was 44 hours.
The rejovered 4-bromoveratrole was discarded; the crude amine
62.
was obtained as a brown oil, b.p. 1500- 155°/8, yield 2.0
g. or 23%. An attempt to recrystallize it from petroleum
ether was unsuccessful; the mixture was again distilled,
the product being a very viscous, pale yellow oil, b.p.
150° - 160°/10, yield 1.8 g. This material, stored under
nitrogen in the refrigerator, had not darkened in color
after three weeks.
Pure Samples of N-Ethll-3,4-dimethoxyacetanilide from the
Ethylamination Reaction
(1) From Runs I - IV: The crude compound (from the mixed
products I - IV from 4-bromoveratrole, 2.7 g.) was recrystallized from petroleum ether with charcoal, then from
p•~rol­
eum ether (150 cc). After being powdered and dried, the
crystals melted at
~a.so
- 620, yield o.a g. A reorystalliz-
ation from methyloyolohexane (12 eo) yielded 0.7 g., m.p.
60°- 61°. The substance was then dissolved at room temperature in a mixture of ether and petroleum ether (1:2); the
solution was chilled, and the crystals recovered. M.p. (two
determinatione}: 1) 59°- 61° 2)60°- 62°, yield 0.4 g. The
crystals were now redissolved in butyl ether (7 eo), the
solution filtered and chilled. The oolorless crystals which
were obtained, m.p. 60°- 62°,aeighed 0.2 g. Mixed m.p. with
a purified sample from the ilnsberg reaction (1:1): 60.0°0
61:.1, mixed m.p. (1:1) with a purified sample from the ethylation of 3,4-dimethoxyformanilide: 60.3°- 61.30.
From Run V from 4-bromoveratrole: To 0.297 g. of the
crude distillate (Run V, b.p. 150°- 160°/10, as above) was
added acetone (4 cc) and acetic anhydride (l cc). The mixture
was kept half an hour at
roo1~
temperature, then chilled. Next
day, the solution was evaporated to a syrup, and the remaining acetic anhydride removed first by washing the residue with
pot~ssium
carbonate solution and extracting, and then by heat-
ing the residue
~vacuo
at 200°. The residue was then dissolved
in ether (3 co) and petroleum ether (2 cc) and chilled and
seeded. The browm crystals were recovered, washed, and dried.
Crystals were also obtained from the mother-liquor.
~he
mixed
crystals, which melted at 53°- 62°, were treated with a
mixture of petroleum ether, ether, and ethyl acetate. A small
amount of residue, still solid at 70°, did not dissolve. It
was perhaps the acetyl derivative of the primary amine. Char•
coal was added, and the solution filtered hot, the filtrate
evaporated and the residue recrystallized from petroleum
ether (25 cc) {a few crystals did not dissolve). The pure white
crystals obtained melted at 58.0° - 60.9°. The pure sample of
N-ethyl-3,4-dimethoxyacetanilide from the Hinsberg reaction
now.melted at 59.7°- 61.5°; its mixed m.p. with the present
sample {1:1) was 60.0° - 6lo3°.
Reooverl of N-Ethyl-3,4-dimethoxyacetanilide
The available residues from all sources were united,
treated with acetic anhydride (20 cc) and after 2 weeks distilled. A light brown oil, b.p. 110°- 131°/ca. 20 mic., yield
13.2 g., was obtained. It was dissolved in ether (40 cc) and
petroleum ether (80 eo), and the selution chilled and seeded.
54.
The colorless crystals were recovered, washed twice with
petroleum ether, and dried
~vacuo.
Yield, 7.2 g., m.p.
59° - 60°; mixed m.p. with a purified sample from the Hinsberg
reaction {1:1): 590. 61°.
At a later date, the accumulated residues were again
distilled, a light brown oil, b.p. 114°- 132°/20 mic.,
yield 7.5 g., being collected. !his was dissolved in ether
(13 cc), treated with charcoal for 80 minutes, and filtered.
To the filtrate was added ether (5 cc) and petroleum ether
.
(25 cc), the mixture chilled and seeded. The rather
grey~
ish crystals were washed twice with petroleum ether, then
with a mixture of ether and petroleum ether, and air-dried.
Yield 2.3 g., m.p. 56°- 60°.
The two portions of the product were then united,
re~
crystallized from methylcyclohexane, rejecting the least
soluble portion, then twice from mixtures of ether and
petroleum ether. The white crystals obtained weighed 7.2.g.;
0
0
m.p. 59.0 - 60.9 • The crystals were warmed to 45
0
with
50 eo of methyloyolohexane, a few crystals being left undis"
solved so that the product did not separate as an oil on
being chilled. The white crystals which were deposited by
the chilled solution were recovered as usual, yield 6.9 g.,
0
0
m.p. 59.2 - 61.0.
Analysis by the Hinsberg Method of the Product from the
~thylamination
Reaction
Crude 4-ethylaminoveratrole (Run V, b.p. 150°- 160°/10,
as above, 0.812 g.) was treated with a cold solution of pot"
assium hydroxide (1.8 g. in 15 cc of water) and benzenesul-
55.
fonyl chloride (1.0 cc). The mixture was stirred 10 minutes
at 40°- 50°, 10 minutes at 50°- 60°, then heated slowly to
95° and allowed to cool with stirring. The product solidified at about 65°. After thorough cooling, the mixture was
filtered, and the almost white crystals were washed thoroughly with water. These crystals ware the derivative of the
secondary amine.
The filtrate was extracted once with ether (20 oo). This
ether extract was called the tertiary amine extract. The
aqueous layer was acidified with 4 cc of concentrated hydrochloric acid, and cooled. The precipitated oil soon solidified
and was recovered, washed with water,and air-dried. Yield,
0.106 g., m.p. 128.2°- 130.5°. This experiment showed that
the original crude amine contained at least 6.8% of the prim"
ary amine, 4-aminoveratrole. The crystals were recrystallized
from dilute ethanol, washed with petroleum ether, and dried
!£vacuo; yield 0.042 g., m.p. (two daterminations): 131°1320 and 130.9° - 131.9°. The analyti•al sample of N-banzenesul£onyl-3,4-dimethoxyaniline now was found to melt at 132.0°
- 132.5°; its mixed m.p. with the present sample (1:1) was
131.0° - 132.0°.
The derivative of the secondary amine was dissolved in
the tertiary amine extract, plus 20 cc of ethyl acetate. This
solution was extracted with dilute hydrochloric acid (2 cc
of concentrated acid in 30 cc of water). The aqueous phase
was called the solution of the tertiary amine. The organic
phase was now evaporated
1E
vacuo in a current of air to a
syrup which soon crystallized. The product was transferred
56.
with a little solvent to a small beaker, and dried, first
in air, then~ vacuo. Yield 1.292 g., m.p. 88°~92°. Hence
the original crude amine contained at least 9o% of the
secondary amine, 4-ethylaminoveratrole. After recrystallization from ethanol and drying
~
vacuo, the crystals
weighed 1.005 g., and melted at 93.0° -. 94.0°. The analytical sample of N-ethyl-N-benzenesulfonyl-3,4-dimethoxyaniline was now found to melt at 93.8° • 94.5°; its mixed
m.p. with the present sample (1:1) was 93.2°- 94.5°.
The solution of the tertiary amine was made strongly
alkaline with potassium hydroxide and extracted with three
10 cc portions of ether. On evaporation, the ether extract
left a somewhat wet syrup, yield 10 mg., which was discarded.
Thus the original crude amine contained about 1% of a tertiary
amine, probably B,I-diethyl-4-aminoveratrole.
About
2%
of the original amine was not accounted for.
~~~-Dimethoxyphenyl-N-ethllcarb!ffill
Ohloride (1)
Run 1:3,4-Dimethoxy-J:J-ethylacetanilide (from the ethylamination reaction, once
crysta~lized,
8.3 g.) was heated
under reflux on the steam-bath with a solution of potassium
hydroxide {3.0 g.) in water (20 cc) and alcohol (40 cc} for
1 hour. The extract was then cooled, diluted with water (200
cc) and extracted five times with ether (230 cc in all). The
ethereal extracts were now distilled, a viscous yellow oil,
b.p. 168°- 188°/10, being collected. The high b.p. suggested
that hydrolysis was incomplete; accordingly the distillate and
residue were again heated under reflux on the steam-bath
with potassium hydroxide (3 g.), alcohol (20 cc) and water
(10 cc) for 5 hours longer; the mixture was then cooled,
diluted with 100 cc of water, made strongly acid with 10
cc of concentrated hydrochloric acid and extracted three
times with a total of 80 cc of ether. The aqueous phase was
then made strongly alkaline with 7 g. of potassium hydroxide
in water and was extracted with a total of 90 cc of ether
in three extractions. The solvent was removed from this
ether extract by
distillation~
vacuo (the amine was not
distilled) and the residue (2.0 g.) was dissolved in benzene
(stook, 30 cc), placed in a ground-glass apparatus, and treated with a solution of phosgene in benzene(2o%, made by Dr
Pepper, 8 eo), with shaking. The mixture was warmed on the
water-bath until about 1 cc had distilled and condensed in
the receiver. Then pyridine (stook, 5 eo) was added to the
residue (a precipitate formed immediately), a reflux condenser
was attached to the flask, and the mixture was gently boiled
for 35 minutes on the W$.ter-bath. The mixture became very
dark. The water-bath was then removed, and the mixture allowed to cool overnight. Next morning, the reaction-mixture was
diluted with benzene (20 eo) and extracted once with a 6%
solution of sulfurio acid (lOO eo), then twice with 50 cc
portions of water; the final emulsion was extracted with a
little benzene, The combined yellow benzene extracts were
dried with sodium sulfate, the benzene distilled in vacuo,
----
68.
and the residue (1.9 g., 21% on the original acetyl com•
pound, 70% on the crude amine), a brown syrup, was crystallized from 50 cc of
petrole~
ether with charcoal. Yellow
crystals, m.p. 74°- 75.5°, were obtained in 1.1 g. (or 41%)
yield. They were recrystallized from petroleum ether with
charcoal, and collected. Yield, 1.0 g. of a light yellow solo
0
id, m.p. 75.5 - 77 • A small portion of this substance slowly
produced a turbidity when warmed with a solution of silver
nitrate in dilute nitric acid.
In
an attempt to purify this compound, 0.463 g. (m.p.
75.5°- 770) were dissolved in 5 cc of ethyl ether and 10 ea
of petroleum ether, and the solution was chilled. Crystals
(0.139 g., m.p. 77° - 79°) were deposited and were reorystallized from butyl ether (7 cc). The crystals (called lfl)
ob~
tained melted at 81°- 82.5°. (The ether-petroleum ether mother
liquor did not deposit any crystals when diluted
wit~f&trol•
eum ether and chilled.) The crystals lfl were reorystallized
from butyl ether (1 eo). The crystals obtained, washed with
butyl ether and dried !a vacuo, melted at 82.3°- 83.0°.
Run II: N-Ethyl-3,4-diuethoxyaoetanilide (from the ethylamination reaction, once crystallized, 6.0 g.) was heated
under reflux on the steam-bath with a solution of potassium
hydroxide (6.2 g.) in water (20 cc) and ethanol (40 cc) for
9 hours; the mixture was then diluted with 200 cc of water,
acidified with concentrated hydrochloric acid (15 cc), and
extracted with three portions of ether. The aqueous layer
was now made very alkaline with potassium hydroxide (8 g. in
water), and was extracted with five 30cc portions of ether.
This ether extract was concentrated in vacuo until all the
solvent had been removed; the residue (3.2 g., a yield of
66%) was dissolved in benzene (50 cc) and in the same way
as before treated with a 2o% solution of phosgene in benzene {13.5 cc). The mixture was boiled gently for a few
minutes to remove the excess phosgene; then pyridine (tech.,
8 cc) was added. A precipitate formed. The mixture was heated
under reflux on the water bath for 35 minutes {the mixture
grew dark, a tar was deposited), and then quickly cooled,
diluted with benzene (25 cc), and extracted with dilute
hydrochloric acid (1:6, 175 cc), then with three 50 cc portions of water. The final emulsion was extracted with a little
benzene, the combined benzene extracts dried with sodium
sulfate, and the solvent removed
~
vacuo. The dark-colored
residue (3.0 g., a yield of 70% on the crude amine) was
crystallized from petroleum ether (90 cc) and charcoal.
The yellow crystals melted at 79° - 80°, yield 2.3 g. or 53%.
They were recrystallized from petroleum ether (lOO cc) with
charcoal; the yield of lemon-yellow crystals, m.p. 80.5
0
.
-
83°, was 1.9 g. Mixed m.p. with a ssmple from Run I (m.p.
75.5°- 77°): 76°- 80°.
In an attempt to purify this material, 0.481 g. was
dissolved in 5 cc of ether and 2.5 cc
o~etroleum
ether; the
solution was chilled, and the lemon-yelJaworystals recovered.
Yield, 0.266 g., m.p. 82.50- 83°. They were recrystallized
from butyl ether (9 cc). From this recrystallization, crystals
were obtained whiwh melted at 84.00- 84.lo. They were again
60.
crystallized, with filtering, from 2.2 eo of butyl ether.
The crystals obtained were the analytical sample of N-ethyl3,4-dimethoxyphenylcarbamyl chloride.
They were very light
yellow in color, and melted at 84.5°-85.9°.
C11H140 3 NCl requires 54.21% C; 5.75% H; 5.75% N.
Found: C " 54.15%, 54.03%;
H - 5.89%, 5.57%;
N - 5.82%.
The ether-petroleum ether mother-liquors of the preceding paragraph were diluted with petroleum ether and chilled.
A few very large crystals, called 2f2, and melting at 81.2°82.00, were obtained.
Run III:
Crude N-ethyl-3,4-dimethoxyaniline (from the
alkaline hydrolysis under nitrogen of N-ethyl-3,4-dimethoxyacetanilide, b.p. 109°-136°/40-30 mic., described in a following section, 1.6 g,) was heated under reflux for a minute
with benzene (25 cc) and a 20% solution of phosgene (in benzene, 8.5 cc); then pyridine (4 cc) was added down the condenser, and the heating continued for 35 minutes.
The mixture
was then cooled, diluted with benzene (25 cc), and extracted
with dilute hydrochloric acid (1:6, 125 cc), then with three
30 eo portions of water; the final emulsion was extracted
with a little benzene, the combined benzene extracts dried
over sodium sulfate and then evaporated !£vacuo to a syrup.
The syrup was crystallized from petroleum ether (75 cc) with
charcoal.
The lemon yellow crystals which were recovered,
washed with petroleum ether and dried, weighed 0.8 g. or
37%, m.p. 71.5°-72o.
The crystals were recrystallized as
usual from 4 eo of ether plus 2 eo of petroleum wther,
yield 0.7 g., m.p. 72.0°-74.0°.
They were again dissolved
61.
in 3 cc of ether plus 3 cc of petroleum ether; the solution
was cooled until about 0.1 g. of
yello~
crystals had depos-
ited; the solution was decanted from these crystals and
chilled; it yielded a crop of bright yellow crystals. The
lass soluble crystals had a m.p. of 73.0°- 74 9 5°; the more
soluble crystals a m.p. of 72.50- 74.7°, yield 0.4 g. Thus
there was practically no separation occurring. The two fractions
were combined, dissolved in benzene (20 cc), extracted with
dilute hydrochloric acid (4 cc of concentrated acid in 10 cc
of water), then with water, dilute sodium bicarbonate solution,
and finally twice with water. The yellow color remained wholly
in the benzene solution. The benzene solution was now dried
over sodium sulfate, evaporated to a syrup
~
vacuo, the
syrup crystallized from 15 cc of petroleum ether. The bright
yellow crystals, m.p. 73.3°- 76.3°, weighed 0.4 g., after
being recovered as usual. They were dissolved in 1 eo of
pure dioxane (from !tr Foxlee) plus 1 cc of water; the solution
was chilled and seeded. The light yellow crystals were recovered, well washed with water (the filtrate was violet)
and dried. Yield, 0.2 g., m.p. 83.0°- 83.8°. Finally' this
crop of crystals was recrystallized from 1 cc of butyl ether,
the recovered crystals washed with butyl ether and then with
petroleum ether. The pale yellow crystals melted at 84.0°
-85.0°, and weighed 0.15 g.
Recovery of
N-Ethyl-3,4-dimethoxyphen~lcarbamll
Ghloride
The combined residues of the compound were distilled, a
brown oil, b.p. 125°- 145°/20 - 120 mic., which rBpidly solil-
63.
pure dioxane plus 1 cc of water.
The almost white crystals
were recovered, well washed with water, and dried; the filtrate was purple.
Yield of crystals, 0.4 g., m.p. 83.0°-
84.00; mixed m.p. (1:1) with the product (m.p. 84.00-85.0°)
from Run 111 above,
83.8°~85.0°.
The two fractions of
crystals were now combined and recrystallized with filtering
:from 20 cc of petroleum ether.
The fine, pale yellow crystals
which were obtained weighed 0.6 g., m.p. 84.00-85.0°.
The
analytical sample of N-ethyl-3,4-dimethoxyphenylcarbamyl
chloride now melted at 84.8°-85.7°; its mixed m.p. (1:1)
with the present sample was 84.20-85.2°.
Further Experiments on the HydrolNsis of 3,4-DimethoxNN-ethylacetanilide
(1) 3,4-Dimethoxy-N-ethylacetanilide (from the ethylamination reaction, once crystallized, 3.0 g.) was heated
under reflux with a solution of potassium hydroxide (4.0 g.)
in water (10 cc) and alcohol (20 cc) for 27 hours. The solution
was cooled, diluted with water (lOO cc), and acidified with
concentrated hydrochloric acid (11 cc) and extracted with
three small portions of ether. The aqueous phase was then
made strongly alkaline with a solution of potassium hydroxide
(7 g.) in water, and extracted with four small portions o:f
ether. This ether extract was then distilled, a pale yellow
oil, b.p. 200°~ 210°/9- 8 being collected as product, yield
1.7 g. or 70%. However, the b.p. was high enough to suggest a
very incomplete hydrolysis, although the viscosity was much
less than that of the pure acetyl compound. The liquid distillate was dissolved in ether (5 cc) and petroleum ether
64.
(10 cc) and the solution chilled, but even on long standing,
no crystals formed. The mixture was now treated with acetic
anhydride and returned to the residues.
The acetyl compound itself was now tested for solubility.
It was found to be readily soluble in water. Moreover, a small
amount, dissolved in ether,was treated with a solution of
hydrogen chloride in ether, and gave a heavy precipitate
which was insoluble in neutral ether, but very soluble in
water.
(2) It was thought that the high b.p. of the hydrolyzed
products might have been due to oxidation which had occurred
during the long periods of hydrolysis. Accordingly, N-ethyl3,4-dimethoxyacetanilide (recovered from the residues, m.p.
59.2°- 61.0°, as above, 4.0 g.) was heated under reflux in
a copper vessel in an atmosphere of nitrogen with a solution
of potassium hydroxide (5 g.) in water {15 eo) and alcohol
(6 cc) for 27 hours; the temperature, howev·er, fell to 75
0
during the night. The mixture was then cooled (an oil had
separated), extracted with three 20 cc portions of
et~er,
the ether extract dried over sodium sulfate under an atmosphere of nitrogen, and then distilled. A viscous yellow oil,
b.p. 109°- 136°/40 - 30 mio., yield 3.0 g. or 93%, was
collected. The b.p., however, resembled that of the acetyl
compound. The product was stored under nitrogen in the
re~
frigerator. Of this material, 1.6 g. was used in a preparation of the carbamyl chlorid.e; the residue (1.4 g.} on stand-
65.
ing for several days crystallize<"l. slovJly and partially.
The crystals were recovered, with considerable loss due
to the oily nature of the impurity, well washed with
petroleum ether, pressed dry, dissolved in 5 cc of petroleum ether, the solution chilled, and the almost white
crystals recovered as usual. They were recrystallized from
10 cc of petroleum ether with charcoal, crystallization
being induced
by scratching. The white crystals were
recovered, washed with petroleum ether, and dried in
0
0
vacuo; m.p. 59.0 - 61.5 , mixed m.p. with a pure sample
of
N~ethyl-3,4-dimethoxyacetanilide
from theBinSberg re•
action (m.p. 60.2°- 61.1°) (1:1): 59.3°- 61.0°; yield
0.193 g. This yield shows that the hydrolyzed product contained at least 14% of the unchanged acetyl compound;
the actual amount present was undoubtedly much larger,
since considerable losses were sustained in the isolation
and purification of the acetyl derivative.
(3) N-Ethyl-3,4-dimethoxyacetanilide (recovered from
the residues, m.p. 59.2°- 61.0°, as above, 2.9 g.) was
treated with 12 eo of water and 2.4 eo of concentrated
sulfuric acid. The solid dissolved easily in the warm acid
and was not reprecipitated when the solution was cooled.
The solution was now heated under reflux under a stream of
nitrogen for 3 hours; the light-colored mixture was then
cooled and allowed to stand overnight in an atmosphere of
nitrogen. No crystals separated. The strongly acid solution
66.
was now treated with ice and potassium hydroxide (8 g.}; an
oil and a solid separated. The mixture was extracted with
three 20 cc portions of ether, the ether extracts dried
over
sodit~
aq~eous
hydroxide under nitrogen. The highly alkaline
phase rapidly turned to a beautiful blue color dur"
ing the extraction, indicating that some demethylation had
occurred. The ether extract was then distilled, a brown oil,
b,p, 950- 113°/15 mic., yield 2.2 g. or 94%, being collected.
The material was stored in the refrigerator under nitrogen.
Note: In the preparation Lnm.ediately preeeding this one, conditions during the distillation favored superheating, so that
the b.p. recorded is not very reliable. In the present preparation, mora care was taken to reduce superheating. The
pro~
duct from the present preparation was much mora mobile than
that from the previous preparation. The product was inocul-
ated with a few of the crystals which had appeared in the
previous hydrolysis, but no further crystallization occurred
even after the mixture had stood for several days in the
cold.
N,N'-bis-(3 1 4-dimethoxyphenyl)-urea and N-Ethyl-N,N 1 -bis(3,4-dimethOX]phen;l)-urea
(1)
First Method: Potassium carbonate (Merck reagent, 0.172
g.), 4-aminoveratrole (as above, 0.371 g.),
N~athyl-3,4-
dimethoxyphanylcarbamyl chloride (Run II as above, m.p.
80.5°- 83°, its present m.p. was 79.9°- 80.90, 0.502 g.),
and water (10 cc) were mixed together in a small flask. The
flask was heated on the steam-bath and the contents mechanically stirred for 40 minutes; it was then rapidly cooled,
67.
and the stirring continued. The brown, oily phase solidified
in a few minutes. The gummy precipitate was crushed, washed with
water, and then with 15 ea of 1 - 2% hydrochloric acid, then
thoroughly with water, and air-dried. Yield, 0.3 g. The substance was recrystallized without filtration from ether (10
cc) plus ethyl acetate (25 cc) - it did not all dissolve in the
hot solvent. The mixture was chilled and the precipitate reoov·ered and washed with petroleum ether. The filtrate was
called Ul, the precipitate, U2. The latter melted at 209°2120. A small amount of U2 gave a negative test for chloride
with silver nitrate. The remainder was recrystallized without filtering fmwm butyl ether (6 cc) plus ethanol (9 eo}.
The wl1ite needles obtained weighed 0.044 g. and ware later
shown to be N,N'-bis-(3,4-dimathoxyphenyl)-uraa. Therefore
the ethyldimethoxyphenylcarbamyl chloride contained at least
5.7% of 3,4-dimethoxyphenyloarbamyl chloride. The needles
melted at 213.0°- 213.2°. Further work on this compound is
described under the Second Method.
Ul and the
ated to dryness
mother-liq~urs
~
from U2 were united and evapor-
vaouo.The crystalline residue was recryst-
allized without filtering from hot ethanol (5 cc). The
slightly brown crystals obtained, m.p. 158.5°- 159.1°, weighed
0.196 g., a yield of N-ethyl-N,N'-bis-(3,4-dimethoxyphenyl)urea of 26% from the carbamyl chloride. The crystals were recrystallized without filtration from ethanol (3 cc); the
white powder obtained melted at 158.3°- 159.1~ yield 0.173 g.
See the next Method for further work on this compound. The
68.
aqueous filtrates of the reaction-mixture were made slightly
alkaline with sodium bicarbonate and evaporated to dryness
~
vacuo; the residue was extracted with hot ethyl acetate and
then with benzene. The extracted residue dissolved completely in 4 cc of water, and was discarded. The solvent extract was
evaporated to a syrup which was treated with petroleum ether
{14 cc) and ethyl acetate (2.5 cc), the hot solution decanted
from a small amount of tar and chilled. The dark-brown crystala obtained dissolved completely in dilute hydrochloric acid;
extracted in the usual way from this solution, they were recrystallized from petroleum ether. Brown needles were obo
0
tained, m.p. 83 - 86 , probably crude 4-aminoveratrole, which
when pure melts at 88°. The mother-litJOrs from this substance
yielded no pure products.
Second Method: Potassium carbonate (0.092 g.), 4-aminoveratrole (0.566 g.}, and N-ethyl-N-3,4-dimethoxyphenyl-carbamyl
chloride (Run 2 as above, 0.301 g.) were placed in a testtube; toluene (3 eo) was added and the mixture heated under
reflux £or 4.5 hours. The white orystala which were recovered
by filtration were washed with two 2co portions of hot toluene (the toluene filtrate4 were united and called TF), and then
three times with water; the first water-wash caused an effervescence, suggesting that the
potassi~~
carbonate had not re-
acted in the toluene solution. The aqueous filtrates were
slightly alkaline.
The precipitate, a light blue solid, melted at about 190°
- 200°, with extensive decomposition. It was treated with butyl
ether (6 cc) plus ethanol (14 cc}
M
the substance did not
all dissolve - the hot solution was decanted from the precipitate and on cooling deposited 0.043 g. of slightly
pinkish crystals, m.p. 212°- 213°. The precipitate from
the decantation was recrystallized from water (1 cc) and
ethanol (8 eo) and yielded White crystals, m.p. 212.8°,
weighing 0.051 g. The total yield of bis-(3,4-dimethoxyphenyl)-urea of Oe094 g. showed that the N-athyl-3,4-dimethoxy"
phenyloarbamyl chloride contained at least 20% of 3,4-dimethoxyphenylcarbamyl chloride. These two fractions of crystals
were combined with the fraction U2 described above in the
First Method. The combined crystals (Ml) melted at 212.7°213.00. They were recrystallized with filtering from ethanol
(40 cc). The long white needles (with a faint pinkish
t inge } ,a ft er drying in vacuo, melt ed a t 212.7 0- 214. 00 •
Found: C - 61.21%; H- 6.11%; N - 8.5~fo; molecular
weight - 341, 318.
c17H20o5N2
requires 61.45% C; 6.02% H;
8.43% N; molecular weight - 332.
The filtrate TF was chilled, the white crystals recovered,washed with water, then with dilute hydrochloric
acid, and then with water. The dried, light-blue crystals
melted at 148°- 154°. They were extracted with cold ethanol
and then recrystallized from ethanol, without filtering. The
almost white powder ~btained, m.p. 157.2°- 158.3°, weighed
0.081 g., a yield of N-athyl-N,N'-bis-(3,4-dimethoxyphenyl)urea of 18%. The crystals were again extracted with a little
70.
water, then with ethanol, and recrystallized without filtering fromRthanol (2 cc). The White powder obtained had a m.p.
of 158.7°- 159.0°, yield 0.066 g. The powder was now mixed
with the fraction U1 obtained by the first method described;
the mixed fraction(Ul)me1ted at 158.7°- 158.9°, and was recrystallized, with filtering, from hot toluene (6 cc). After
being
dried~
vacue, the white powder obtained had a m.p.
of 158.3° - 159.0°.
Found: C - 63.09%; H - 6.73%; 1~ - 7 .81%; molecular weight
- 336.
c19n24o5N2
reqnires 63.33% C; 6.68% H; 7.78% N; mol-
ecular weight - 360.
No pure products could be obtained from the remaining
filtrates and mother-liquors.
N,N'-Diethyl-N,N'-bis-(3,4-dimethoxyphenll)-urea (1)
(l) In a 250 cc flask was placed potassium carbonate
(anhyd., 0.221 g.), 4-ethylaminoveratrole (Run V from 4bromoveratrole, b.p. 150°- 160°/10, as above, 0.548 g.),
3,4-dimethoxyphenyl-N-ethylcarbamyl chloride (Run 2, m.p.
0
0
0
80.5 - 83 , as above, 0.615 g., and Run I, m.p. 75.5 -
77°, as above, 0.119 g., 0.734 g. in all), and toluene
(30 cc). A reflux condenser was attached, and the mixture
gently boiled for 17.5 hour•• The mixture was cooled, and,
as the potassium carbonate appeared to be unchanged, 4 drops
of water were added and the mixture thoroughly shaken. Refluxion was now continued for 6.5 hours longer; the reactionmixture was then filtered hot, the precipitate washed with
hot toluene (10 cc). The precipitate was then found to be
soluble in 5 cc of cold water (except for about 2 mg of tar)
n.
- this fraction was then discarded. The toluene filtrate
was evaporated to a syrup, dissolved in
petrole~
ether,
and chilled. Tarry crystals (RFl) separated and were recovered from the mother-liquor (RF2). The crystals were
extracted with ether (10 cc).
The~her
extract was called
RF4. The ether-insoluble crystals were reorystallized
from ethanol (1.5 oo) without filtering. The product was
a light-brown powder, m.p. 153.5°- 156°, yield 0.035 g.
The product was now recrystallized with charcoal and filtering from ethanol (2.6 oo). The grey crystals obtained
were recrystallized with filtering from ethanol (3 eo). The
white powder obtained weighed 0.012 g., and had a m.p. of
153 9 8° - 154.5°; mixed m.p. with a pure sample of N-ethyl"
N,N'-bis-{3,4-dimethoxyphenyl}-urea: 166.20- 158.2°.
The fraction RF4 was extracted with dilute hydrochloric
acid (the acid aqueous extract being highly oolored) and
then with water. The ether layer was evaporated to a syrup
which was dissolved in
petrole~
ether (10 oo). After the
mixture had been seeded with N-ethyl-3,4•dimethoxyphenyloarbamyl chloride, and had stood for a very long time, a
few crystals appeared.
The fraction RF2 was evaporated in vacuo to a brown oil.
This oil was taken up in a little ether and extracted with
dilute hydroohlorid acid (the aqueous layer beiame highly
oolored). The ether extract was again evaporated to a syrup,
which could not be induced to crystallize under the most
prolonged treatment, even when seeded with
N-ethyl-3,4-di~
methoxyphenyldarbamyl chloride. The fraction accordingly was
72.
distilled
!£ vacuo; 2 or 3 drops of a brown oil were obtained
which turned opaque on cooling, showing it to be a mixture.
The oil would not crystallize, so it was dissolved in ether
(2 eo) and chilled. A few crystals appeared- on recovery
from the
mother-liq~or
they were found to amount to about
0.1 mg. The filtrate was concentrated under reduced pressure.
A few crystals appeared, but did not noticeably increase in
weight when the fraction was Chilled. A small sample of the
oily crystals was kept; the rest of the proiuct was dissolved
in boiling petroleum ether (8 eo). After several months in the
refrigerator, this solution deposited a crop of crystals.
These crystals (RF2) were recovered from the filtrate, dissolved
in petroleum ether (8 cc), the solution decanted from a little
tar, cooled, seeded with a little crude RF2, and chilled.
Vfuite crystals with brown centres separated; they were recovered,washed, and dissolved in 5 cc of petroleum ether.The
solution was decanted from the first crystals which formed
and chilled. The light brown crystals were recovered from
the chilled solution as usual; m.p., approximately, 74° aoo. The crystals were recrystallized from 15 eo of petroleum ether with charcoal. Pure white crystals were obtained,
m.p. 77.9°- 78.1°, yield 0.132 g.; this represents a yield
of N,N'-diethyl-N,N'-bis~,4-dimethoxyphenyl)-urea of 11%.
Various small samples of RF2, less than 10 mg in all, which
had been kept for seeding, were now found all to have crystallized after very prolonged standing.
73.
(2) Potassium bicarbonate (Merak reagent, finely
grounl, 0.135 g.), N-ethyl-3,4-dimethoxyphenyloarbamyl
chloride (m.p. 84.0°- 85.0°, 0.317 g.), N-ethyl-3,4dimethoxyaniline (from the acid hydrolysis of the
purified acetyl derivative, b.p. 950- 113°/15 mic., as
above, 0.946 g.), and toluene (Merck reagent, 3 ea)
were heated together under reflux in an atmosphere of
nitrogen for 24.75 hours; the mixture was then cooled
and filtered and the precipitate washed with two hot
portions of benzene. (This precipitate, small in amount,
was all dissolved in 2 oc of hot water and acidified
with nitric acid. The solution turned reddish-brown,
showing the presence of organic matter. A solution of
silver nitrate was now added to the acidified solution
- there was a heavy precipitate, showing that at least
some reaction had occurred). The combined organic
filtrates were extracted with dilute hydrochloric acid
(3 ac of concentrated acid in 17 ac of water), then
with water, then with 25 cc of 2% potassium hydroxide
solution, and finally with two portions of water. The
faintly colored organic solution was now dried over sodium sulfate, evaporated
~
vacuo to a syrup, and the
syrup dissolved in 15 oo of petroleum ether. The solution
was allowed to cool slowly, seeded with a very small
amount of the fraction RF2 from the previous experiment,
and chilled. The deposited oil crystallized slowly; the
74.
white crystals with reddish-brown nuclei were recovered,
washed with petroleum ether, and then recrystallized
with charcoal from 20 cc of petroleum ether; the
sol~
ution had to be seeded with a small amount of the crude
material and chilled. The White crystals were recovered,
washed with petroleum ether, and dried
~vacuo;
m.p.
77.0°- 80.5° (only 3 specks, probably bubbles, were left
above 78°). The crystals were recrystallized with filtering from 20 cc of petroleum ether - this time they crystallized spontaneously without first separating as an oil.
The fine, colorless needles were recovered, washed with
petroleum ether, and dried~ v.acuo; m.p. 78.4°- 79.oo,
mixed m.p. with the fraction RF2 (m.p. 77.9°- 78.1°) from
the previous experiment (1:1}, 77.20- 78.5°; mixed m.p.
with N-ethyl-3,4- dimethoxyphenylcarbamyl chloride (m.p.
84.0°- 85.0°) (1:1), 64°- all but a speck melted at 70°
0
- 79 , possibly one or two points not melted. The yield
o• analytically pure
N,N 1 -diet~l~I,N 1 -bis-{3 1 4-dimethoxy­
phenyl}-urea was 0.214 g., or 41%.
c21H28 o5N2
requires 64.95% C; 7.22% H; 7.22% N. Found:
C - 65.04%, 65.24%, 65.14%; H - 7.42%, 7.54%, 7.39%; N -
7.11%.
76.
SilliO\IARY
1) This research was part of N.R.c. project XR-79,
a search for desirable stabilizers for guncotton. Three
substituted ureas, N,N'-d.iethyl-N,N'-bis-(3,4-dimetho:x:yphenyl)-urea, N-ethyl-N,N'•bis-(3,4-dimethoxyphenyl)urea, and N,N'-bis-(3,4-dimethoxyphenyl)-urea, all analogues of the common stabilizer centralite, have been
synthesized.
2) The main problem encountered in the research was
to find satisfactory methods of obtaining the necessary
intermediate, 4-ethylaminoveratrole, a new compound. Of
the four methods of synthesis investigated, the most satisfactory used guaiacol as starting-material. Guaiacol
was converted by Robertson's method to 4-bromoguaiacol
in 49% yield; the bromo compound was methylated in SO%
yield to 4-bromoveratrole. The bromoveratrole was then
allowed to react under pressure at 100° with excess
ethylamine; the yield of ethylaminoveratrole was 69%. An
alternative synthesis from vanillin was found less satisfactory because it required many more steps and the
yields were lower. Vanillin was converted to 4-aminoveratrole by known methods and the latter by a conventional Hinsberg synthesis gave 4-ethylamtnoveratrole.
3) The
ethylaminover~trole
obtained from guaiacol was
found to be about 9o% pure. Since a better product was
required for the preparation of the stabilizer, the oily
76.
amine was purified either through its benzeneaulfonyl
derivative ot through its acetyl derivative. The former
was formed quantitatively from the amine, and purified
in high yield; on decomposition it gave a 67% yield of
the secondary amine. The
co~esponding
yields for the
acetyl compound were found to be: formation, 92%; purif"
!cation, about 7o%; and hydrolysis, 94%. The purification
of the benzeneaulfonyl derivative was much more rapidly
accomplished than the purification of the acetyl compound.
The latter was found to be unexpectedly soluble in water
and especially in aqueous acids.
4) In the course of the work, the following new compounds were prepared and characterized. The melting-point
is given in brackets after the name of eawh compound:
4~bromo­
acetylguaiacol (49°), N-benzenesulfonyl-3,4-dimethoxyaniline
(132°), N-ethyl·N-benzenesulfonyl-3,4-dimethoxyaniline (94°),
N-ethyl-3,4-dimethoxyacetanilide (610), N-ethyl-3,4-dimethoxyphenyloarbamyl chloride (86°}, N-ethyl•N,N'-bis-(3,4-dimethoxyphenyl)-urea (1590), and
N,N'~diethyl-N,N'-bis-{3,~
dimethoxyphenyl)-urea (79°).
5) sym-bia-(3,4-dimethoxyphenyl)-urea was made by a new
method. A mistake in the literature in regard to its identity
was pointed out.
77.
LITERATUitE
(1) Gardnar:
REFER]ll~CES
N.R.C. Report, McG111 University (1945).
(2) Buak and Ide: Organic Syntheses, Co11. Vol. II, P• 44
(Wiley and Sons, New York, 1943}.
-
( 3) Fetscher and Bogert: J. Org. Chem. 4 71 (1939).
-
(4} Schreiber and Shriner: J. Am. Chem.. Soc. 56 114 (1934).
(5) Sohreiber and Shriner: J. Am.. Chem.. Soc. 56 1618 (1934).
(6) Chem. Zentr.
~
II 1079 (A German Patent).
(7) Robertson: J. Cham.. Soc., 93 791 (1908).
(8) Hindmarsh, Knight, and Robinson: J. Chem.. Soc. 111 941
(1917).
(9) Moureu: Compt. Rend.
~
477 (1896).
(10) Jona: Beilstein, Vol VI, Supp., P• 390 (Ed. 1931, Berlin).
(11) Simonsen and Rau: J. Cham. Soo.
~
786 (1918).
(12} Several references in Bei1stein.
(13) Bergstrom et al: J. Org. Chem.
!
170 and 179 (1936).
(14) Horning and Bergstrom: J. Am.. Chem. Soo. §! 2111 {1945).
(15} Gilman, Kyle, at al: J. Am.. Chem.
Soc.~
(16) Vorozhtzov and Kobelev: Chem. Abs.
~
143 (1946).
6706 (1934).
{17) Groggins and Stirton: Ind. and Eng. Cham. 29 1353 (1937).
{18) Mills:
u.s.
Patent 1,935,515 {1933).
(19) Burton: J. Cham. Soc. P• 549 (1932}.
-
( 20) Heidelberger and Jaaobs: J. Am. Chem. Soa. 41
(1919).
1461
(21) Winans and Adkins: J. Am. Chem. Soo. 54 306 (1932).
(22) Parys: Reo. Trav. Chim. !2 17
(1930), etc.
(23) Young and Robinson: J. Chem. Soa. P• 275 (1933).
76.
Literature References (Ctd.)
(24)Brunner and Wohr1: Monatsh.
~
374 (1933).
(25) Johnson and Stevenson: Organic Syntheses, Co11.Vo1· • II,
P• 620.
{26} Buck and Ide: Organic Syntheses, Co11. Vol. II, p.622.
(27) Kind1er and Peschke: Arch. der Pharm. 269 604 (1931).
(28) Freyss: Chem. Zentr.
~
I 835.