Organic Syntheses, Vol. 79, pp. 209-215
Submitted by Stéphane Caron
1, Jill M. Wojcik, and Enrique Vazquez.
Checked by Li Dong and Marvin J. Miller.
1. Procedure
2-(2-Methoxyphenyl)-2-methylpropionitrile.
A
300-mL, three-necked, round-bottomed flask equipped with
a
reflux condenser and a
Teflon-coated magnetic
stir bar is placed under a
nitrogen atmosphere and
charged with
2-fluoroanisole (10.00
g, 79.28 mmol) (Note
1),
100 mL of tetrahydrofuran (THF,
Note 2) and
potassium
hexamethyldisilylamide (KHMDS, 23.72 g, 118.92 mmol)
(Note
3).
Isobutyronitrile
(28.8 mL, 316.71 mmol) (Note
4)
is added via syringe. The reaction mixture is heated to 60°C for 23 hr (Note
5).
After the solution is cooled to room temperature, it is transferred to a
1000-mL
separatory funnel containing
300 mL
of methyl tert-butyl ether (Note
6)
and
300 mL of 1 N hydrochloric
acid (HCl). The organic layer is separated and washed successively
with 300 mL of water and
200 mL of brine.
The organic phase is dried over
anhydrous magnesium
sulfate (MgSO4), filtered, and concentrated to provide
the desired product as a tan oil (
13.75 g,
99%) (Notes
7,
8 and
9).
2. Notes
1.
2-Fluoroanisole
was purchased from Aldrich Chemical Co., Inc., and
used without further purification.
2.
Anhydrous tetrahydrofuran
was purchased from Aldrich Chemical Co., Inc., in
a Sure/Seal™ bottle.
3.
Potassium hexamethyldisilylamide
was purchased from Aldrich Chemical Co., Inc., and
used without further purification. The solid was weighed on a balance without special
protection from air.
4.
Isobutyronitrile
was purchased from Aldrich Chemical Co., Inc., and
used without further purification.
5. The reaction can be monitored by HPLC (Hewlett-Packard 1100 HPLC,
Kromasil C18 column (4.6 × 150 mm), 50/50 MeCN/0.2% H
3PO
4, 1.0
mL/min, product = 7.8 min) or by TLC analysis (
2-fluoroanisole
R
f = 0.67, product R
f = 0.51,
ethyl
acetate/hexanes 20/80).
7.
1H NMR and
13C NMR indicate reasonably pure
product. The HPLC analysis of the crude product showed a purity >97% (same conditions
as Note
5) and satisfactory elementary analysis
(calculated for C
11H
13NO: C, 75.40; H, 7.48; N, 7.99. Found:
C, 75.01; H, 7.35; N, 8.07).
8. The product shows the following physical properties:
1H NMR (CDCl
3,
300 MHz) δ: 1.80 (s, 6), 3.96 (s, 3), 6.97-7.02
(m, 2), 7.29-7.39 (m, 2);
13C NMR δ: 27.00, 34.43,
55.51, 112.02, 120.76, 124.80,
125.92, 128.62, 129.39, 157.30.
IR cm
−1: 2980,
2235, 1493, 1462, 1437, 1253,
1027, 756.
9. If material of greater purity is necessary, the product can be
purified by chromatography on
silica gel (100 g)
using
ethyl acetate/hexanes 20/80 (900
mL) as the eluant. When 100-mL fractions were collected, fractions
#2 to #5 contained the desired product in >99% purity (
12.31g,
89%
yield)
Waste Disposal Information
All toxic materials were disposed of in accordance with "Prudent Practices in the
Laboratory;" National Academy Press; Washington, DC, 1995.
3. Discussion
Tertiary benzylic nitriles are useful synthetic intermediates, and have been used
for the preparation of amidines,
2 lactones,
3 primary amines,
4
5 pyridines,
6 aldehydes,
7
8
carboxylic acids,
9 and esters.
10
11 The
general synthetic pathway to this class of compounds relies on the displacement of
an activated benzylic alcohol or benzylic halide with a cyanide source followed by
double alkylation under basic conditions. For instance,
2-(2-methoxyphenyl)-2-methylpropionitrile
has been prepared by methylation of
(2-methoxyphenyl)acetonitrile
using
sodium amide and
iodomethane.
12
In the course of the preparation of a drug candidate,
13 the submitters discovered that
the nucleophilic aromatic substitution of aryl fluorides with the anion of a secondary
nitrile is an effective method for the preparation of these compounds.
14
The reaction was studied using
isobutyronitrile
and
2-fluoroanisole. The
submitters first showed that KHMDS was the superior base for the process when carried
out in either THF or
toluene
(Table I). For example, they found that the preparation of
2-(2-methoxyphenyl)-2-methylpropionitrile
could be accomplished in near quantitative yield in a single operation. Several other
substrates were studied as summarized in Table II. The reaction proceeds using either
electron-rich or electron-poor arenes (entries 1-11) as well as cyclic nitriles (entries
12-14). The reaction requires an excess of nitrile, which can self-condense under
the reaction conditions, as well as a slight excess of base. The submitters obtained
the best results when using about 1.5 equiv of base in conjunction with 4 equiv of
the nitrile. The acidic work-up removes most of the impurities generated in the reaction
and, in the case of a low boiling starting nitrile, the excess reagent is evaporated
with the solvent to provide a crude material of high purity.
TABLE I
NUCLEOPHILIC AROMATIC SUBSTITUTION OF (2-METHOXYPHENYL)-ACETONITRILE
WITH ISOBUTYRONITRILE
|
Entry |
Base |
Solvent |
T |
Time |
Yielda |
|
(1.5 equiv) |
|
(°C) |
(h) |
(%) |
|
1 |
LiHMDS |
THF |
60 |
23 |
3 |
2 |
NaHMDS |
THF |
60 |
23 |
49 |
3 |
KHMDS |
THF |
60 |
23 |
95 |
4 |
KHMDS |
Toluene |
60 |
18 |
95 |
5 |
KHMDS |
DMSO |
75 |
24 |
No rxn |
6 |
KHMDS |
i-Pr2O |
75 |
24 |
3 |
7 |
KHMDS |
NMP |
75 |
24 |
1 |
|
a) Yields <5% indicates the conversion observed
by HPLC analysis after the time shown. The yields of entry 2,3 and 4 are isolated
yields.
|
TABLE II
SNArOF ARYL FLUORIDES WITH SECONDARY
NITRILES AND KHMDS
|
Entry |
Fluoride |
Nitrile |
Solvent |
T |
Time |
Yield |
|
|
(equiv) |
|
(°C) |
|
(%) |
|
1 |
2-OMe |
1 (4.0) |
Toluene |
60 |
18 h |
99 |
2 |
3-OMe |
1 (4.1) |
Toluene |
100 |
3 h |
69 |
3 |
4-OMe |
1 (4.0) |
THF |
60 |
50 h |
66 |
4 |
3,5-OMe |
1 (4.0) |
Toluene |
70 |
48 h |
85 |
5 |
3,4-OMe |
1 (4.0) |
THF |
80 |
4 h |
28 |
6 |
2-Cl |
1 (4.0) |
Toluene |
60 |
45 min |
77 |
7 |
4-Cl |
1 (4.0) |
THF |
75 |
2 h |
72 |
8 |
H |
1 (4.0) |
THF |
75 |
14 h |
69 |
9 |
3-Me |
1 (4.0) |
THF |
75 |
14 h |
71 |
10 |
4-CN |
1 (4.0) |
Toluene |
60 |
40 min |
83 |
11 |
4-CF3 |
1 (3.3) |
Toluene |
60 |
40 min |
94 |
12 |
2-OMe |
2 (4.0) |
Toluene |
75 |
48 h |
47 |
13 |
2-OMe |
3 (4.0) |
THF |
75 |
24 h |
67a |
14 |
2-OMe |
4 (4.0) |
THF |
75 |
15 h |
70a |
|
a) Provided exclusively the 2(S) isomer (exo-aryl).
|
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
2-(2-Methoxyphenyl)-2-methylpropionitrile: Hydratroponitrile,
o-methoxy-α-methyl- (8); Benzeneacetonitrile, 2-methoxy-α,α-dimethyl-
(9); (13524-75-9)
2-Fluoroanisole: Anisole, o-fluoro-
(8); Benzene, 1-fluoro-2-methoxy- (9); (321-28-8)
Potassium hexamethyldisilylamide: Aldrich: Potassium-(bis(trimethylsilyl)amide:
Silanamine, 1,1,1-trimethyl-N-(trimethylsilyl)-, potassium salt
(9); (40949-94-8)
Isobutyronitrile (8): Propanenitrile, 2-methyl-
(9); (78-82-0)
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