Note: Descriptions are shown in the official language in which they were submitted.
7~86
Case 4920-Plus
NUCLEOPHILIC SUBSTITUTION PROCESSES AND PRODUCTS
This invention relates to processes for pre-
paring nitroaralkyl cyanides~and derivatives thereof.
There are known techniques of preparing profen-
5. type pharmaceuticals.and other materials having arelatively complex aryl group attached to the alpha-
-carbon of a substituted.or unsubstituted acetic acid.
For example, U, S. patents 3,755,427 (Adams et al.),
: 3,959,364 ~Armitage et al.), and 4,278,516 (Zaiko et
10 al.) disclose processes for converting various starting
makerials into flurbiprofen, i.e., 2-(2-fluoro-4-
biphenylyl)propionic acid, and similar compounds having
anti-inflammatory, analgesic, and anti-pyretic
properties; Carney et al., "A Potent Non-Steroidal
15 Anti-Inflammatory Agent: 2-[3-Chloro-4-(3-pyrrolinyl)-
phenyl]propionic Acid," ~E~ Vol. 29, page 938
(1973) teach, inter alia, the preparation of their
anti-inflammatory agent - also known as pirprofen - via
an ethyl 2-(3-chloro-4-nitrophenyl)propionate inter
20 mediate; U. S. Patent 4,239,901 ~Rainer) shows that
pyrazol-l-ylphenyl and pyrazolin-l-ylphenylacetic acids
having anti-inflammatory properties can be synthesized
~'
~ ~7t~
from various intermediates, including po'lychloronitro-
-phenylacetic acid esters; and it is known that
indoprofen, i.e., 2-[4-(1,3-dihydro-1-oxo-2H-isoindol-
2-yl)phenyl]propionic acid, and indobufen, i.e.,
- ' - 5 '2-~4-(1',3-dihydro-1-oxo-2H-isoindol-2-yl)phenyl]butyric
acid, can be prepared from the appropriate
2-(4-nitrophenyl)-alpha-alkylacetic acids.
: - . ; . .
Nitroarylacetic acids and their esters and
nitriles, as well as the amino derivatives thereof,
10 have been found to be particularly useful intermediates
for the synthesis of thes-e pharmaceuticals. Eowever,
in the past, a disadvantage of employing them as
pharmaceutical intermediates has been the difficulty of
preparing them by conventional techniques. Even the
15 preferred procedures for preparing them have proven to
be difficult, tedious, and time-consuming, as evidenced
by Example 23 of U. S. Patent 3,868,391 (Carney et al.
II) and Example 16 of 'Rainer, both of which show the
use of days of reEluxing to acco~plish only a portion
20 of their syntheses.
It would obviously be a welcome contribution to
the art to provide a method of synthesizing nitrophenyl-
alkyl cyanides and analogs and derivatives thereof in a
simple and straightforward manner.
An object of this invention is to provide
processes for preparing nitroaralkyl cyanides in
moderate-to-~ood yield with high selectivity in a simple
and straightforward manner.
Another object is to provide novel, improved
processes for preparing derivatives of the cyanides.
A further object is to provide novel cyanides
useful as intermediates Eor the preparation of
pharmaceuticals.
. . ~
These and other objects are attained by (A)
reacting a nitroaromatic comp~und with an alpha,
10 alpha-disubstituted acetonitrile in a substantially
anhydrous aprotic solvent and in the presence of a base
so that the nitrile undergoes a nucleophilic
substitution on an unsubstituted ring carbon of the
nitroaromatic compound during which an alpha-
15 substituent functions as a leaving group, therebyforming a nitroarylacetonitrile and (B~ when
appropriate, converting the nitroarylacetonitrile to a
desired derivative thereof.
Nitroaromatic compounds utilizable in the
20 practice of the invention include a variety oE ~uch
compounds - the chieE requirements Eor their utility
being that (1) they bear at least one nitro substituent
on an aromatic ring, (2) they contain at least one
replaceable hydrogen on an aromatic ring to which a
25 nitro group is attached, and (3) they be devoid of
substituents which would interfere with the desired
~ ~'7'~
nucleophilic substitution reaction, e.g., substituents
-bearing an acidic proton, such as -NH2, -OH, -Sl~,
-NHR, etc.
Thus, the utilizable nitroaromatic compounds
- 5- include compounds having one or more simple or fused
aromatic rings containing five or six members and
either bearing no substituents other than nitro
. ~ : . ,, -. -. .
substituents or also bearing any of a variety of inert
substituents, i.e., substituents that do not inter~ere
10 with the desired nucleophilic substitution reaction,
such as halo, alkyl, alkbxy,.alkylmercapto, trifluoro~
methyl, dialkylamino, dialkanoylamino, cyano, dialkyl~
carbamoyl, alkylsulfonyl, dialkylsulfamoyl,
alkoxyalkyl, haloalkyl, cycloalkyl, halocycloalkyl,
15 etc. - any alkyl chains in the substituents generally
being lower alkyl chains. When the nitroaromatic
compound contains more than one ring, any such inert
substituent may be on the same ring as the ring bearing
a nitro substituent and/or on a ring which is directly
20 or indirectly attached to the ring bearing a nitro
substituent.
When the aromatic ring bearing the required
nitro substituent is a six-membered ring, there will be
at least one replaceable hydrogen in a position para or
25 ortho to the carbon bearing the nitro substituent; and
it is preferred that there be a replaceable hydrogen in
~.~7"7~?~3~
the para position. Nitroaromatic compounds having a
five-membered ring should have a replaceable hydrogen
on a carbon adjacent to, or separated by two ring atoms
Erom,.the carbon bearing the nitro substituent.
: 5 In accordance with one embodiment of the
invention, the nitroaromatic compound is a compound
which is devo.id of halogen on the aromatic ring bearing
.
the required nitro group. Illustrative of such
compounds are heterocyclic co~pounds which.preferably
10 contain five or six-membered rings having aromatic
character, such as nitropyridine-N-oxide,
5-nitroisoquinoline, 5- and 6-nitroquinolines,
2-nitrothiophene9 etc.; fused-ring aromatic compounds,
such as the 1- and 2-~itronapthalenes, etc.; aro~atic
15 compounds containing a plurality of simple rings, such
as the 2-, 3-, and 4-nitrobiphenyls, the 2-, 3-, and
4-benzylnitrobenzenes, 2-nitrodiphenyl ether, etc.; and
aromatic compounds containing a single simple ring,
such as nitrobenzene, 2-methylnitrobenzene, the 2,3-,
20 2,5-, and 3,5-dimetllylnitrobenzenes, the 2,4- and
2,6-diethylnitrobenzenes, 3,4-dibutylnitrobenzene, the
1,2- and 1,3-dini~robenzenes, 2,6-dinitrotoluene, the
1,2,3- and 1,2,4-trinitrobenzenes, 2-nitro-N,N-diethyl-
aniline, 4-nitro-N-e~hylacetanilide9 2-nitrobenzyl-
25 cyanide, 2-nitrophenyl acetate, etc.
-- 5
.~l'7'7~3~
In accordance with another embodiment of the
-invention, the nitroaromatic compound is a compound
which bears at least one halo substituent on the
aromatic ring bearing the required nitro group.
5iExemplary of such compounds are the 2-, 3-, and
4-chloronitrobenzenes; the 2,3-, 2,4-, 2,5-, 2,6-,
3,4-, and 3,5-dichlor~nitrobenzenes; the various
- . ; . . . . .
trichioronitrobenzenes; the corresponding fluoro,
bromo, and iodo compounds; the various dimethyl-,
10 diethyl-, and dibutylnitrobenzenes, nitrobiphenyls,
benzylnitrobenzenes, nitronaphthalenes, di- and
trinitrobenzenes, nitro-N,N-diethylanilines,
nitrodiphenyl esters, nitro-N-ethylacetanilides,
nitrobenzylcyanides, nitrophenyl acetates, nitro-
15 pyridine-N-oxides, nitroquinolines, nitroisoquinolines,
nitrothiophenes, and the like bearing one or more
ar-chloro, fluoro, bromo, or iodo substituents and
containing at least one replaceable hydrogen in an
appropriate position.
In some cases, polynitroaromatic reactants may
undergo substitution reactions whereby one of the nitro
groups is replaced by the nitrile reactant. Therefore,
the possibility of this competitive reaction should be
kept in mind when selecting a polynitroaromatic
25 reactant for use in the process.
In each of the aforementioned embodiments of the
invention, the preferred nitroaromatic compounds are
nitrobenzenes having a replaceable hydrogen in the
position para to thc nitro group, since the
- 5 nucleophilic substitution reaction of the invention
tends to be highly selèctive on the para position, and
the use of such compounds therefore leads to the
.
production o~ nitrophenylacetonitrlles which are
ideally suited for the synthe~is of anti-inflammatory
10 agents of the type described in the aforementioned
references. Even more preferred in the case of the
halonitrobenzenes are such nitrobenzenes having a halo
substituent in a position ortho to the nitro group.
Halonitrobenzenes which are especially pre~erred are
15 2-chloronitrobenzene and 2-fluoronitrobenzene which are
readily converted wi~h high selectivity into such
products as 2-[3-chloro-4-(3-pyrrolinyl)phenyl~propionic
acid, 2-(2-fluoro-4-biphenylyl)propionic acid, and
related anti-inÉlammatory agents. A non-halogenated
20 nitroaromatic compound that is particularly preferred
is nitrobenzene, which is readily converted with high
selectivity into pharmaceutically-active agents such as
2-~4-(1,3-dihydro-l-oxo-2~-isoindol-2-yl)phenyl]-
propionic acid, 2-[4-(1,3-dihydro-1-oxo-2~1-isoindol-
25 2-yl)phenyl]butyric acid, and analogs thereof.
~ 76~ ~
The alpha, alpha-disubstituted acetonitriles that
can be used in the practice of the invention also in~
clude a variety of such compounds, which - in general -
may be represented by the formula:
- 5 -~ -~ L
/ CHCN
R
wherein L is a leaving group and R is halo (preferably
chloro) or, mQre preferably, a hydrocarbyl (e.g.,
10 alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
aryl, aralkyl, etc.) or hydrocarbyloxyhydrocarbyl
(e.g., alkoxyalkyl, aryloxyalkyl, alkoxyaryl, alkoxy-
cycloalkyl, etc.) group which most preferably contains
up to about 10 carbons.
Exemplary leaving groups, L, include halo,
aryloxy, haloaryloxy, alkylthio, cycloalkylthio,
arylthio, aralkylthio, haloalkylthio, halocyclo-
alkylthio, haloarylthio, haloaralkylthio, or, less
preferably, alkoxy, cycloalkoxy~ aralkoxy, haloalkoxy,
20 halocycloalkoxy, haloaralkoxy, and the like, as well as
other suitable leaving groups which have been described
in the literature, e.g., in Golinski et al.,
"'Vicarious' Nucleophilic Substitution oE Hydrogen in
Aromatic Nitro Compounds,"Tetrahedron_Letters," Vol.37,
25 pp. 3495-8 (1978) and in Makosza et al., "Vicarious
-- 8 --
Substitution of Hydrogen in Aromatic Nitro Compounds
with Acetonitrile Derivatives," Jou~
~hemistry, Vol. 45, pp. 1534-5 (1980).
When the leaving group is an organic group, it
5 is generally preferred that it contain not more than
about 10 carbons, although organic leaving groups
having an even higher carbon content are satisfactory
.,, . . ~ .
in the pr~ctice of the invention. Preferably the
leaving group is halo, i.e., chloro, bromo, fluoro, or
10 iodo; and it is more preferably chloro or bromo, most
preferably chloro.
It is notable that acetonitriles ha~ing a single
alpha-substituent do not appear to be equivalent to the
aforementioned alpha, alpha-disubstituted acetonitriles
15 in the preparation of nitroaralkyl cyanides by a
nucleophilic substitution reaction. For example,
attempts to prepare substitution products by reacting
alpha-chloroacetonitrile with nitrobenzene have not
been successful thus far, and Makosza et al. teach that
20 they were also unsuccessful in reacting alpha-chloro-
acetonitrile with 4-nitrobiphenyl, although that
nitrile did react with l-nitronaphthalene and 4-chloro-
nitrobenzene to form the corresponding alpha-nitroaryl-
acetonitriles.
A few examples of alpha, alpha-disubstituted
acetonitriles that can be used in the practice of the
~ '7~
invention are 2-chloropropionitrile, 2-chlorobutyro-
nitrile, 2-chlorovaleronitrile, 2-chlorocapronitrile,
2-chloro-4-pentenenitrile, 2-chloro-3,3-dimethylbu~yro-
nitrile, 2-chloro-2-phenylacetonitrile, 2-chloro-2-
5 cyclohexylacetonitrile, 2-chloro-3-(3-chloro-o-tolyl)-
propionitrile, 2-chloro-3-phenylpropionitrile, the
corresponding bromo and iodo compounds, and the like.
The alpha-halo-alpha-hydrocarbylacetonitriles, i.e.,
alpha-haloalkyl cyanides containing at least three
10 carbons - particularly 2-chloropropionitrile and
2-bromopropionitrile - are e~specially preferred,
although similar cyanides in which the alpha-halo
substituent is replaced by one of the other leaving
groups mentioned above are also highly desirable.
`In another highly desirable embodiment of the
invention, the alpha, alpha-disubstituted acetonitrile
is an alpha, alpha~dihaloacetonitrile, most preferably
an alpha, alpha-dichloroacetonitrile, which leads to
the formation of a product having a reactive halo
20 substituent in the alpha-position, e.g., a product
corresponding to the formula:
Xn N~2
H~C-CN
- 10 -
~ 3~
wherein X is halo, preferably chloro, and n is an
integer of 1 to 3. Such products enable facile
synthesis of a variety of end products. Most
preferably the nitro group is in the position para to
- 5 the ni~rile subs~ituent, although it may be located in
an ortho position.
Illustrative aprotlc solvents which may be
employed in the process of the invention include ethers
such as diethyl ether, dibutyl ether, l-ethoxyhexane,
10 tetrahydrofuran, 1,4-dioxane, 1,3-dioxolane, diglyme,
1,2-diethoxyethane, anisole, etc.; tertiary amines such
as pyridine, N-ethylpiperidine, triethyl amine,
tributyl amine, N,N-diphenyl-N-methyl amine, N,N-
dimethylaniline, etc.j and other solvents. However,
15 the preferred aprotic solvents are dipolar aprotic
solvents such as dimethyl sulfoxide, N,N-dimethyl-
formamide, N,N-dimethylacetamide, dimethyl sulfone,
tetramethylene sulfone, N-methylpyrrolidone, and the
like.
Bases useful in the practice of the invention
include all bases strong enough to activate the nitrile
reactant, e.g., alkaline earth metal compounds such as
calcium oxide, calcium hydride, calcium hydroxide,
barium oxide, barium hydroxide, magnesium hydroxide,
25 zinc hydroxide, etc. However, the base is preferably
an alkali metal compound, e.g., an organoalkali metal
- 11 -
'7~3~ ~
. compound, alkali metal hydride, alkali metal hydroxide,
-alkali metal oxide, alkali metal amide, or alkali metal
alcoholate, such as butyllithium, phenyllithium,
ethylsodium, amylsodium, butylpotassium,
5 benzylpotassium, sodium dimsylate (i.e., the sodium
salt of diethylsulEoxide), sodium hydride, potassium
hydride, sodium hydrox-ide, potassium hydroxide, sodium
oxide, potassium oxide, sodium amide, potassium amide,
lithium diisopropylamide, sodium methoxide, potassium
10 t-butoxide, the sodium salt of the monomethylether of
ethylene glycol, sodium phenoxide, and the likeO
Ordinarily the use of sodium hydride or potassium
hydride will be found most convenient and economical.
Use of an alkali metal compound as the base
15 permits the alternatives of using the alkali metal
compound alone or in conjunction with a phase transfer
catalyst, such as a quaternary ammonium salt, ethylene
glycol, or a suitable crown ether. When a phase
transfer catalyst is employed (1) the alkali metal
20 compound may be any of the alkali metal compounds
generically or specifically indicated above, although
the type of alkali metal compound being used determines
the type of crown ether that is preferably utilized -
lithium bases generally calling for the use of a
25 12-crown-4 ether, sodium bases usually calling for the
use of a 15-crown-5-ether, and potassium bases
- 12 -
generally calling for the use ~f an 18-crown-6-ether,
and (2) the reaction medium may be any of the aprotic
solvents mentioned above, or it may be an inert liquid
hydrocarbon such as benzene, toluene, xylene, hexane,
5 heptane, isooctane, or the lIke.
When an alkali metal hydride, especially a highly
pure alkali metal hydride, is employed as the base, it
is desirable to include a small amount of a transfer
agent such as water, alcohol, or the like in the system.
10 It is believed that the transfer agent activates the
hydride by reacting therewith to form a small amount of
the alkali metal hydroxide or alcoholate.
The nitroaralkyl cyanide synthesis of the
invention is conducted in a substantially anhydrous
15 reaction system, and accordingly, except when a small
amount of water (which is itself consumed by reaction
with the alkali metal hydride) is employed as a
transfer agent, the components of the reaction sy~tem
should be brought together and maintained under a dry
20 inert atmosphere. Thus, while it is possible to
conduct the process in the presence of air, it is
desirable to maintain the reaction system under an
atmosphere of dry nitrogen or the like. Since the
reaction itself is normally an exothermic reaction,
25 with its initiation readily ascertainable by noting the
exotherm produced, the reactants are ordinarily brought
- 13 -
together at ambient temperatures, although the
temperature may be raised or lowered to suit the needs
of the occasion i~ desired.
The nitroaromatic compound and alpha,alpha-
5 disubstituted acetonitrile may be used in amounts suchas to provide a stoichiometric excess of either of the
reactants or the stoichiometric amount of each. How-
ever, when a stoichiometric excess of the nitroaromatic
compound is employed, the quantity of product
10 obtainable will be limited by the quantity of nitrile
used, so it is desirable to utilize a stoichiometric
excess of the nitrile; The amount of base employed is
preferably such as to provide at least two molar
equivalents of base per mol of nitroaromatic compound,
lS since the use of smaller amounts - although permitting
the reaction to occur - makes ths base the limiting
reagent.
The mode of addition of the ingredients oE the
reaction system is not particularly critical. Accord-
2~ ingly, it is convenient to add the nitroaromaticcompound to a mixture of the other materials, add the
base to a mixture of the other materials, add the
reactants to a mixture of the base and aprotic solvent,
introduce all four ingredients simultaneously into the
25 reaction zone, or the like~ Since the reaction
ordinarily proceeds very rapidly, long reaction times
- 14 -
are not required. The reaction will usually be
completed within a ma~ter of minutes or a few hours at
ambient temperatures.
When derivatives of the nitroaralkyl cyanides
5 are desired, they may be prepared by employing
conventional techniques to convert to the desired
derivatives the nitroaralkyl cyanides made in
.
accordance with the present invention. Thus, for
example:
(A) 2-(4-nitrophenyl)propionitriIe synthesized
by the process of the invention may be hydrolyzed to
2-(4-nitrophenyl)propionlc acid, which in turn may be
hydrogenated to 2-(4-aminophenyl)propionic acid,
reacted with phthalic anhydride to form 2-(4-phthal-
15 imidophenyl)propionic acid, and reduced to indoprofen,
(B) 2-(4-nitrophenyl)propionitrile synthesized
by the process of the invention may be hydrogenated to
2-(4-amino-phenyl)propionitrile, hydrolyzed to
2-(4-aminophenyl)propionic acid, reacted with phthalic
20 anhydride to form 2-(4-phthalimidophenyl)propionic
acid, and reduced to lndoprofen,
(C) 2-(4-nitrophenyl)propionitrile synthesized
by the process of the invention may be hydrogenated to
2-(4-aminophenyl)propionitrile, reacted with phthalic
25 anhydride to form 2-(4-phthalimidophenyl)propionitrile,
and hydrolyzed and reduced (in either order) to
indoprofen,
~ ~ 7'7~
(D) 2-(4-nitrophenyl)bu~yronitrile synthesized
by the process of the invention may be-subjected to the
same reactions to prepare indobu:Een or indobufen
intermediates,
.5 (E) 2-(3-chloro-4-nitrophenyl)propionitrile
synthesized by tbe process of the invention may be
reduced to 2-(4-ami~o-3-chlorophenyl)propionitrile,
reacted witb a 1,4-dihalo-2-butene to form
~-[3-ch.loro-4-(3-pyrrolinyl)phenyl]propionitrile, and
lO then converted into 2-[3-chloro-4-(3-pyrrolinylphenyl]-
propionic acid, and
(F) 2-(3-fluoro-4-nitrophenyl)propionitrile
synthesized by the process of the invention may be
reduced to 2-(4-amino-3-fluorophenyl)propionitrile,
15 converted into (2-fluoro~4-biphenylyl)propionitrile by
means of a Gomberg-Bachmann reaction with benzene, and
then converted into 2-(2-fluoro-4-biphenylyl)propionic
acid.
The particular conventional techniques used to
20 convert the nitroaralkyl cyanides into their various
derivatives are not critical. It may sometimes be
desirable to use certain particular techniques for the
preparation of the derivatives, e.g., (a) the reduction
and/or hydrolysis techniques taught in March, Advanced
25 Organic Chemistry, McGraw-Hill, New York, 1977, pages
809-10, 1125~6, and the references cited
- 16 -
~ ~t~7~ ~ ~
therein; (b) the Gomberg-Bachmann techniques taught in
March, pages 653-4, and in Organic Reactions, Vol. 2,
page 224 (1944); JournaL of_the American Chemical
y, Vol. 46, page 2339 (1924); Chemical RevO ~ Vol.
~ 5 57, page 77 (1957), an~ Journal of_the Ch~mical
Society~ Vol. D 1971, page 4il, and (c) the techniques
taught in Adria Laboratories, Inc.'s NDA on Indoprofen
Capsules, Section No. 8~c), pages 2-11, which is on
file with the Federal Drug Administration. However,
- 10 the overall processes for preparing the derivatives are
simplified and made more efficient and economical by
the present simplification of the synthesis of the
nitroaralkyl cyanides regardless of the particular
techniques used to convert them into their various
15 derivatives.
As indicated above, the present invention is
particularly advantageous in providing a readier and
more economical route to the synthesis of pharma-
ceuticals and other chemica:L products that can be
20 prepared from nitroaralkyl cyanides. Such products
include, not only those mentioned above, but a variety
of products, such as products disclosed in U.S. Patents
3,641,040, 3,657,230, 3,767,805, 3,868,391., 3,936,467,
3,993,763, 3,997,669, 4,010,274, 4,118,504 9 ~ ~ 126,691,
25 4,163,788, and 4,239,901.
1~7~7~
The following examples are giver- to illus~rate
the invention and are not intended as a limitation
thereo~.
~e~
' 5^' 'Into a flame dried flask under nitrogen was
placed 1.3 grams (0.026 mol) of NaH (50% dispersion in
mineral oil). This was washed twice'with 10 ml
portions of petroleum ether (b.p. 35-60C) and dried
in a ni,trogen stream. Then 25 ml of N,N-dimethyl-
10 formamide (DMF; dried over 3 Angstrom molecular sieves)was added followed by dropwise addition (over 20
minutes) of a solution of 2.2 ml (0.021 mol) of
2-fluoronitrobenzene and 1.9 ml (0.023 mol) of 2-chloro-
propionitrile in lO ml of DMF. The mixture became red
15 and hot during the dropwise addition. A small portion
of the reaction mixture was worked up by partitioning
between lN HCl and diethyl ether, and analysis of the
ether layer by gas chromatography (GC) indicated some
starting material had not reacted. A second (0.40 g,
20 0.008 mol) and third (0.80 g, 0.017 mol) portion oE 50%
NaH were added so that workup of a reaction mixture
sample Eollowed by GC analysis indicated that no
starting material remained. The reaction mixture was
poured into 250 ml of lN HCl and extracted with six
25 200 ml portions of ether. The ether layers were
combined, dried (MgS04), and concentrated to give a
- 18 -
black oil which was adsorbed on 15 g of Silica Gel 60
(230-400 mesh) and loaded on a column of 150 g Silica
Gel 60 packed in 40% CH2C12/60% petroleum ether (bp
35-60C). Elution with the same solvent mixture
5 afforded four fractions which, by GC area %, contain
1.8 g (44%) of 2-(3-fluoro-4-nitrobenzene)propionitrile.
This compound was characterized by NMR, IR, and mass
. .
spectrometry.
A slurry of 240 mg (5.0 mmols) of NaH (50% in
mineral oil) in 2 ml of pyridine was treated dropwise,
under nitrogen, with 0.26 ml (0.35 g, 2.5 mmols) of
2-fluoronitrobenzene followed by 0.22 ml (0.23 g, 2.6
mmols) of 2-chloropropionitrile. The purple reaction
15 mixture was stirred at room temperature under nitrogen
for 15 minutes, then was poured into an equal volume of
5% HCl and extracted with an equal volume of
CH2C12. The organic phase was shown by gas
chromatography-mass spectral analysis tGC-MS) to0 contain 2-(3~Eluoro-4-nitrobenzene)propionitrile.
Example Ill
A solution of 0.61 g (3.1 mmol) of
2-(3-fluoro-4-nitrobenzene)propionitrile in lO ml of
absolute ethanol was treated with 0.03 g of 7%
25 palladium on carbon and hydrogenated at 45 psi of
hydrogen (Parr apparatus) for 1 hour. The reaction
- 19 -
~ ~7~7~ ~ ~
mixture was Eiltered and concentrated to give 0.54 g of
an oil which darkened on standing. A portion of this
oil was purified on 1 mm silica gel plates (developed
with CH2C12) to give 2-(4-amino-3-fluorobenzene)-
5 propionitrile, which was characterized by NMR, IR, andmass spectrometry.
Example_IV
A solution of 1.2 g (6.2 mmol) of 2-(3-fluoro-4-
nitrobenzene)propionitrile in 24 ~1 of absolute ethanol
10 was treated with 0.06 g of 7% palladium on carbon and
hydrogenated at 40-45 psi hydrogen pressure (Parr
apparatus) for 1 hour. Th~e reaction mixture was
filtered and the filtrate was shown to contain, by GC
analysis (area percent) 99% 2-(4-amino-3-fluorobenzene)-
15 propionitrile. Removal of the solvent in a rotaryevaporator gave 1.1 gram of a yellow oil which quickly
darkened on standing.
A solution oE 25 mg (0~15 mmol) of 2-(4-amino-3-
20 fluorobenzene)propionitrile, 0.2 ml of benzene, and
0.03 ml (0.25 mmol) of isoamyl nitrite was heated at
reflux for 1.5 hours. GC analysis ~area percent) of
the reaction mixture indicated the presence of 23%
unreacted starting material and 60% of a product which
25 was identified by GC-MS to be 2-(2-fluoro-4-biphenylyl)-
propionitrile.
- 20 -
~. ~'7'7~
To a slurry of 0.50 g (1~ mmols) of NaH (50~/~
dispersion in mineral oil) in 2 ml of NJN-dimethyl-
formamide (DMF, dried over 3 Angstrom moIecular sieves)
5 under nitrogen was added dropwise1 over a period of 10
minutes, a solution of 0.60 ml (5.1 mmols) of 2-chloro-
nitro~enzene and 0.42 ml (5.1 mmols) of 2 chloro~
- ., , - .
propionitrile in 1 ml of DMF~ During the addition, the
mixture became purple and an exotherm was-observed.
10 The reaction mixture was stirred under nitrogen for 15
minutes, poured into 30 ml of lN HCl and extracted with
four 30 ml portions of diethyl ether. The organic
layers were combined, dried using MgS04, and
concentrated to give 1.2 g of a black oil. Preparative
15 thin layer chromatography of 0.20 g of this oil (one
2mm silica gel plate developed with 50% CH2C12/50%
petroleum ether) afforded 0.088 gram of
2-(3-chloro-4-nitrobenzene)ptopionitrile which was
characterized by means oE N~R and mass spectrometry.
EXAMPLE VII
_ _ _ _
Into a flask under nitrogen was placed 4.0 g oE
60% sodium hydride in mineral oil (0.10 mole). The
sodium hydride was washed with three 10 ml portions of
petroleum ether (b.p. 35-60C) and was slurried in
25 50 ml of N,N-dimethylformamide (DMF). A solution of
12.3 g of nitrobenzene (0.10 mole) and 9.0 g of
- 21 -
~ 7 7!C~
. 2-chloropropionitrile (O,10 mole) in 10 ml of DMF was
added dropwise to the slurry. An ice water bath was
applied to the mixture periodically so that the
temperature did not exceed 45C. After the addition
- 5 was complete (30 minutes) the purple m;xture was
allowed to react for 30 minutes and was poured into 200
ml of cold 10% HCl. The aqueous mixture was extracted
with three 100 ml portions of diethyl ether and the
ether layers were combined, dried (MgSO~), and
10 concentrated to give a dark oil. Excess nitrobenzene
and DMF were removed From thls oil at 50C (at 1 mm
pressure) and the residue was chromatographed on a
column of 400 g o silica gel which was eluted with
dichloromethane. A fraction was collected containing
15 2.9 g of 2-(4-nitrobenzene)propionitrile (16.5% yield).
EXAMPLE VIII
Into a flame dried flask under nitrogen was
placed 500 mg of 60% sodium hydride in mineral oil
(12.5 mmole). The sodium hydride was washed with three
20 5 ml portions of petroleum ether (b.p. 35-60C) and
was slurried in 4 ml of N,N-dimethylformamide (D~IF).
One drop of a solution of 770 mg of nitrobenzene (6.25
mmole) and 600 mg of 2 chloropropionitrile (6.70 mmole)
in 1 ml of DMF was added to the sodium hydride slurry
25 to give a deep purple solution. After one minute the
mixture was placed in an ice water bath and the rest of
- 22 -
~'7~7~g8~
the reactant solution was added dropwise. The
resulting mixture was stirred at 0C for 15 minutes
and was poured into 50 ml of lN HCl. The aqueous
mixture was extracted with three 40 ml portions of
5 dlethyl ether and the ether layers were combined, dried
(MgSO4), and concentrated to give 880 mg of black
oil. Purification of 208 mg of this oil on one 2 mm
silica gel plate eluted with 50% dichloromethane/50%
petroleum ether afforded 51.2 mg (20% yield) of
lO 2-(4-nitrobenzene)propionitrile.
- EXAMPLE IX
Into a flame dried flask under nitrogen was
placed 176 mg of potassium tert-butoxide (1.57 mmoles) J
23 mg of dibenzo 18-crown-6 ether (0.064 mmole), and
15 l.O ml of toluene, While this mixture was vigorously
stirred in a room temperature water bath a solution of
106 mg of 1,3-dinitrobenzene (0.631 mmole) and 71 mg of
2-chloropropionitrile (0.79 mmole) in 0.5 ml oE toluene
was added dropwise. The resulting purple mixture was
20 stirred for 15 minutes and poured into 20 ml of lN
HCl. The aqueous mixture was extracted with three 20
ml portions of diethyl ether and the ether layers were
combined, dried (MgS04), concentrated, and placed on
one 2 mm silica gel TLC plate. One development with
25 50% petroleum ether (bp35-60C~/50~/o dichloromethane
afforded 10 mg of 1,3-dinitrobenzene (9% recovery) and
:~ a~7¢~
25 mg of 2-(2~4-di-nitrobenzene)propionitrile (18V/o
yield).
The preceding examples demonstrate the utility
of alpha, alpha-disubstituted acetonitriles in the
5 preparation of nitroaralkyl cyanides. The following
example shows that similar results are not achieved
when an acetonitrile having only one alpha-sub5tituent` ` is substituted for the alpha,alpha-disubstituted
acetonitriles.
COMPARATIVE EXAMPLE
Into a flame dried fl~sk under nitrogen was
placed 500 mg of 60% sodium hydride in mineral oil
(12.5 mmole). The sodium hydride was washed with three
5 ml portions of petroleum ether (b.p. 35-60C),
15 slurried in 4 ml of N,N-dimethylformamide (DMF), and
cooled in an ice water bath. A solution of 770 mg of
nitrobenzene (6.25 mmole) and 500 mg of chloro-
acetonitrile (6.62 mmole) in 1 ml of DMF was added
dropwise. The resulting brown mixture was stirred at
20 0C for 15 minutes and was poured into 50 ml of lN
HCl. The aqueous mixture was extracted with three 40
ml portions of diethyl ether and the ether layers were
combined, dried (MgSO4), and concentrated to give
1.02 g of black oil. Thin layer chromatographic
25analysis of this o;l revealed no substitution product;
only nitrobenzene and an immobile brown spot were
observed.
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