Notes
J . Org. Chem., Vol. 64, No. 12, 1999 4517
Sch em e 3
Sch em e 4
overall yield (ca. 60%) starting from inexpensive com-
mercially available materials. Involvement of the oxime
5 in such a preparation opens up two possible path-
ways: (a) removing the byproducts of the aromatic
coupling in a very simple manner followed by dehydration
to the nitrile or (b) achieving the whole synthesis in a
one-pot process and purification by distillation, which
make the overall procedure a suitable candidate for
industrial application.
Ta ble 1. Deh yd r a tion of 5 in to 2c
purified
yield
conversion
Exp er im en ta l Section
entry
reagent
solvent
THF
conditions
20 °C, 1h
of 5 (%)
of 2c (%)
All quantifications of reaction constituents were achieved on
GC using a known quantity of dry dodecane as reference
standard. Oven temperature rampings were chosen to obtain
“baseline” separation of all components in a mixture. NMR
spectra were run in CDCl3 solutions. Proton spectra were
recorded at 200 MHz and carbon spectra at 50 MHz. Chemicals
shifts (δ) are reported in ppm. IR spectra were recorded in CCl4
solutions. Solvents were purified and dried by standard tech-
niques8 before use. Solids were dried over P2O5 under vacuum.
Syn th esis of 4′-Meth ylbip h en yl-2-ca r ba ld eh yd e (2a ). To
a solution of 3a (15.7 g, 70.8 mmol) in dry refluxing THF (79
mL) under nitrogen, containing 1.34 g of MnCl2 (10.6 mmol, 0.15
mol equiv), was slowly added 66 mL of a 1.6 M solution of
Grignard reagent in anhydrous THF (106 mmol, 1.5 mol equiv).
After completion of the addition, reflux was maintained for 1 h,
and the brown mixture then carefully quenched into an ice-
water bath (200 mL) containing 3 mL of 2-(diethylamino)ethanol
(2.7 g, 22.6 mmol). The mixture was extracted with 3 × 100 mL
of dichloromethane, and the combined organic layers were dried
with anhydrous magnesium sulfate, filtered, and evaporated in
vacuo to give 16.3 g of a viscous brown oil. The oil was eluted
on silica with petroleum ether/dichloromethane to provide pure
2a as a pale yellow oil (10.1 g, 51.3 mmol, 72% yield): MS: m/e
196 (M•+). IR: 1697 cm-1. 1H NMR (CDCl3) δ 2.44 (s, 3H), 7.26-
7.28 (m, 4H), 7.42-7.52 (m, 2H), 7.59-7.64 (m, 1H), 8.00-8.05
(m, 1H), 10.00 (s, 1H); 13C NMR (CDCl3) δ 21.21, 127.56, 128.95,
129.19, 129.87, 130.06, 130.81, 133.53, 133.80, 134.84, 138.04,
146.01, 192.51.
1
2
P2O5 (10eq.)
Zeolite HY 10, Toluene 120 °C, 16h
(3 mmol/g)
DCC (1 equiv) THF
DCC (1 equiv) THF
DCC (1 equiv) CH2Cl2 20 °C, 24h
100
30
92
-
3
4
5
6
7
20 °C, 16h
90 °C, 4h
5
100
100
40
-
90
N-methylpyrrolidinone 126 °C, 16h
-
91
formic acid, 99%
126 °C, 1h
100
as no cine substitution occurred. A more subtle directive
effect, involving chelation at the nitrogen, is certainly
operating, since 2-chlorobenzaldehyde dimethyl acetal
and oxime were found unreactive under the same condi-
tions. In the latter case, the nitrogen would not be
available any longer for chelation following deprotonation
of the oxime moiety.
Conversion of aldehyde 2a into the corresponding
nitrile 2c was subsequently attempted following Streith’s
methodology.7 Treatment of 2a with 1.5 mol equiv of
hydroxylamine-O-sulfonic acid in semiaqueous media
(THF/water 1/1 or CH3CN/water 1/1) at 65 °C for 2 h led
to a mixture of the desired product 2c with the corre-
sponding oxime 5 and some unreacted aldehyde 2a in a
molar ratio (5/2/3) as determined by GC-MS.
It is worth noting that the crude imines 4a ,b, on
treatment with a 3-fold excess of hydroxylamine-O-
sulfonic acid at reflux in THF/water 1/1 for 1 h, were
quantitatively transformed into a mixture of 2c and 5 in
a 3/1 ratio. Since 5 gave 2c only very slowly under such
experimental conditions, the oxime must be considered
more as a byproduct rather than as an intermediate of
the reaction. The workup of the aromatic coupling was
therefore modified to obtain the oxime 5 in a one-pot
process (Scheme 3).
The crude crystalline mixture of 5 and bis-tolyl was
then triturated in cold petroleum ether (fraction 30-40
°C) to provide after filtration the oxime as a white powder
in 71% isolated yield for the three steps. Recrystallization
from CH2Cl2/petroleum ether afforded 5 as white, sharp-
melting needles, mp ) 119-120 °C.
Syn th esis of 4′-Meth ylbip h en yl-2-ca r boxim e (5). To a
solution of 3a (15.7 g, 70.8 mmol) in dry refluxing THF (79 mL)
under nitrogen, containing 1.34 g of MnCl2 (10,6 mmol, 0.15
molar equivalent), was slowly added 66 mL of a 1.6 M solution
of Grignard reagent in anhydrous THF (106 mmol, 1.5 mol
equiv). After completion of the addition, reflux was maintained
for 1 h, and the brown mixture then carefully quenched into 150
mL of an ice-cold solution of hydroxylamine sulfate (23.4 g, 0.14
mol) containing 3 mL of 2-(diethylamino)ethanol (2.7 g, 22.6
mmol). The biphasic mixture was then vigorously stirred at room
temperature for 1 h. Workup as above gave 11.0 g of white
needles. Trituration in cold petroleum ether and filtration
provided 5 (10.6 g, 50.2 mmol, 71% yield) as white needles which
were recrystallized from dichloromethane/petroleum ether.
mp: 119-120 °C. MS: m/e 211 (M•+). IR: 3596 cm-1. H NMR
1
(CDCl3) δ 2.45 (s, 3H), 7.28 (large m, 4H), 7.43 (large m, 3H),
7.95 (m, 1H), 8.22 (large s, 1H), 9.27 (large s,1H); 13C NMR
(CDCl3) δ 21.22, 126.20, 127.53, 129.15, 129.59, 129.69, 129.84,
Various dehydration reagents listed in Table 1 proved
to be efficient for conversion of 5 into 2c (entries 1, 4, 5,
and 7) (Scheme 4). As it only needs an aqueous workup,
the one involving formic acid (entry 7) seems to be the
most convenient for industrial scale-up.
130.37, 136.56, 137.42, 142.36, 149.85. Anal. Calcd for C14H13
-
NO: C, 79.58; H, 6.20; N, 6.63. Found: C, 79.69; H, 6.29; N, 6.71.
Syn th esis of 4′-Meth ylbip h en yl-2-ca r bon itr ile (2c). A
suspension of 5 (0.54 g, 2.56 mmol) in formic acid (5 mL) was
refluxed for 1 h. The solution was then cooled to room temper-
In conclusion, nitrile 2c, a key intermediate in angio-
tensin II antagonists synthesis, has been prepared in fair
(8) Vogel’s Textbook of Practical Organic Chemistry, 5th ed.; Long-
man, London, 1989; pp 395-413.
(7) Streith, J .; Fizet, C.; Fritz, H. Helv. Chim. Acta 1976, 59, 2786.