Efficient methods for the synthesis of arylacetonitriles

Article abstract of DOI:10.1055/s-0030-1257871

Various approaches to [2-fluoro-4-(trifluoromethyl)phenyl]acetonitrile were investigated. Two of these methods were selected and applied to a variety of electron-deficient substrates, thereby expanding the scopes of the procedures.

Full text of DOI:10.1055/s-0030-1257871

3332
PAPER
Efficient Methods for the Synthesis of Arylacetonitriles
Efficient
S
ynth
e
eses of
A
r
d
ylacetonitrile
e
s
rica Stazi, William Maton, Damiano Castoldi, Pieter Westerduin, Ornella Curcuruto, Sergio Bacchi*
GlaxoSmithKline Spa, Chemical Development Department, Via Fleming 4, 37135 Verona, Italy
Fax +39(045)8218117; E-mail: sergio.k.bacchi@gsk.com
Received 20 April 2010; revised 24 June 2010
dimethyl sulfoxide8 gave undesired products resulting
from the homocoupling of the starting chloride. As a re-
sult of the discouraging results of this preliminary reaction
and the toxicity of potassium cyanide, we decided to in-
vestigate an alternative approach.
Abstract: Various approaches to [2-fluoro-4-(trifluoromethyl)phe-
nyl]acetonitrile were investigated. Two of these methods were se-
lected and applied to a variety of electron-deficient substrates,
thereby expanding the scopes of the procedures.
Key words: nitriles, nucleophilic aromatic substitutions, decarbox-
ylations, Wittig reactions, reductions
R
CHO
F
a
F
Arylacetonitrile derivatives are synthetically interesting
and useful compounds. The active methylene moiety pro-
vides an entry to the synthesis of heterocyclic compounds,
whereas the cyano group can be involved in a number of
transformation, e.g. dipolar cycloadditions reactions.1
Among the methods for the synthesis of this class of com-
pound are the classical reaction of benzyl halides3 or
sulfonates3,4 with the cyanide ion; the dehydration of
arylacetaldoximes2,3,5,6 or primary amides,2–4 and the
more-recent synthesis based on b-(N,N-dimethylami-
no)styrenes containing electron-withdrawing substituent
on the benzene ring.7 During a phase of process develop-
ment, we found it necessary to synthesize [2-fluoro-4-(tri-
fluoromethyl)phenyl]acetonitrile on a multi-gram scale.
We identified an efficient process for the synthesis of this
compound and we utilized the results in optimizing a gen-
eral method for the synthesis of electron-deficient aryl-
acetonitriles that can be applied to a variety of substrates.
A retrosynthetic analysis, involving two disconnections (a
and b) based on the commercial availability of starting
materials, is shown in Figure 1.
a
a
NC
CF3
CF3
b
2a R = OH
2b R = CHO
3
F
b
X
CF3
1
F
CF3
4a R = Br
4b R = F
Figure 1 Retrosynthetic approach to the synthesis of [2-fluoro-(4-
trifluoromethyl)phenyl]acetonitrile (1)
OH
Cl
CN
CHO
F
F
F
F
(a)
(b)
(c)
CF3
CF3
2a
CF3
CF3
The first approach (disconnection a; Figure 1) involves
the reduction of aldehyde 3 followed by activation of the
primary alcohol and cyanide substitution, or aldehyde ho-
mologation through formation of an oxime and subse-
quent dehydration. In the second approach (disconnection
b; Figure 1), the cyanomethyl group is introduced onto the
benzene ring by a palladium-catalyzed coupling reaction
of bromide 4a or through nucleophilic substitution of flu-
oride 4b, followed by decarboxylation.
3
5
1
Scheme 1 Reagents and conditions: (a) NaBH4, EtOH, 0 °C to 20
°C, 1 h (quant.); (b) SOCl2, 80 °C, 3 days (91%); (c) KCN, KI,
DMSO, 20 °C, 3 h.
Treatment of aldehyde 3 with (methoxymethyl)(triphe-
nyl)phosphonium chloride and a 0.5 M solution of potas-
sium hexamethyldisilazide in toluene at room temperature
gave the corresponding vinyl ether, which was hydrolyzed
with a 2 M solution of hydrogen chloride in refluxing
acetone to give the homologated aldehyde 2b.10 The com-
pound 2b was then converted into the corresponding
oxime derivative 6 as a mixture of cis- and trans-isomers
(Scheme 2, method A).11
In our first attempt (Scheme 1), we reduced aldehyde 3
with sodium borohydride to give the corresponding ben-
zyl alcohol 2a quantitatively.8 This was converted into the
benzyl chloride derivative by treatment with thionyl chlo-
ride at 80 °C over three days.9 Unfortunately, the substitu-
tion with cyanide by treatment with potassium cyanide in
Oxime
6 was submitted to various dehydration
conditions12 (Table 1) in attempts to obtain the desired
arylacetonitrile 1. The best results were achieved by slow
addition of a solution of thionyl chloride in tetrahydrofu-
SYNTHESIS 2010, No. 19, pp 3332–3338
x
x.
x
x
.
2
0
1
0
Advanced online publication: 30.07.2010
DOI: 10.1055/s-0030-1257871; Art ID: T09110SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Efficient Syntheses of Arylacetonitriles
3333
ment with 4 M hydrochloric acid in ethanol at 80 °C for
48 h, but the results were unsatisfactory. We then attempt-
ed a Krapcho decarboxylation,15 which gave a cleaner
compound within 18 h. The crude mixture was purified as
previously described to give a pale yellow liquid in 82%
overall yield. However, the final compound 1 was con-
taminated with 5% of its regioisomer 9, formed during the
aromatic nucleophilic substitution. Purification of com-
pound 1 from its regioisomer 9 proved to be extremely
challenging. We therefore shifted our attention to the pu-
rification of the precursor compound 7 of its regioisomer
8; intermediates 7 and 8 were treated with potassium tert-
butoxide to give the corresponding potassium salts 10 and
11, respectively. At this point, 10 could be selectively pre-
cipitated and purged of impurities. After acidification and
Krapcho decarboxylation, product 1 was obtained in 70%
overall yield (Scheme 5) and in better than 98% purity.
For the sake of clarity, this modification of method B is re-
ferred to as method C.
method A
(b)
CHO
F
OH
(c)
CN
CHO
N
F
F
F
(a)
CF3
3
CF3
2b
CF3
CF3
6
1
Scheme
2
Reagents and conditions: (a) Ph3P(CH2OMe)Cl,
KHMDS, toluene, 20 °C, 3 h, then 2 M HCl, acetone, reflux, 12 h; (b)
NH2OH·HCl, Et3N, EtOH, reflux, 2 h; (c) see Table 1 for conditions.
Table 1 Conditions for Dehydration of Oxime 6
Conditions
Results
Ph3P, I2, CH2Cl2, r.t.
complete conversion, but difficulties
in removal of (O)PPh3
RuCl2(p-cymene)2, 4-Å MS,
incomplete conversion
MeCN, 80 °C
PvCl, pyridine, reflux
wet AcOH, reflux
KF, Al2O3
complex mixture
no reaction
method B
EtO2C
CN
F
F
CO2Et
CN
F
F
no reaction
(a)
+
Burgess reagent, THF, reflux complex mixture
SOCl2, THF, <20 °C complete conversion
CF3
CF3
CF3
4b
7
8
CN
ran while the internal temperature was kept below 20 °C.
After distillation under reduced pressure, 1 was isolated as
a colorless liquid in a 33% overall yield.
F
F
(b)
CN
+
Initially, we envisaged a synthesis of intermediate 7 by
palladium-catalyzed coupling13 of halide 4a with ethyl
cyanoacetate (Scheme 3). Various sources of palladium
[tris(dibenzylideneacetone)dipalladium or dichloro-
bis(triphenylphosphine)palladium] and ligands [tributyl-
phosphine, 2,2¢-bis(diphenylphosphino)-1,1¢-binaphthyl
(BINAP), or (2-biphenyl)di-tert-butylphosphine] were
tested without success.
CF3
CF3
1
9
Scheme 4 Reagents and conditions: (a) EtO2CCH2CN, K2CO3,
BnN+Et3Cl–, DMSO, 90 °C, 19 h; (b) NaCl, DMSO, 110 °C, 18 h
(82% overall).
method C
EtO2C
CN
F
CO2Et
CN
F
EtO2C
CN
CN
Br
F
F
(b)
(a)
F
F
F
(a)
+
CF3
CF3
CF3
CF3
CF3
CF3
4b
8
7
4a
7
1
K+
O–
K+
O–
Scheme
3
Reagents and conditions: (a) Pd source, ligand,
OEt
CN
CN
CN
F
EtO
EtO2CCH2CN, K3PO4, toluene, 90 °C, 12 h.
F
F
(c)
+
To overcome this problem, we attempted the nucleophilic
aromatic substitution14 of fluoride 4b with ethyl cyan-
oacetate and potassium carbonate in the presence of a cata-
lytic amount of benzyltriethylammonium chloride in
dimethyl sulfoxide at 90 °C (Scheme 4, method B); this
gave intermediate 7 with complete conversion. We first
attempted to perform the decarboxylation step by treat-
CF3
11
CF3
10
selective precipitation
CF3
1
Scheme 5 Reagents and conditions: (a) EtO2CCH2CN, K2CO3,
BnN+Et3Cl–, DMSO, 90 °C, 19 h; (b) t-BuOK, CH2Cl2; (c) i. 1 M HCl,
CH2Cl2; ii. NaCl, DMSO, 110 °C, 18 h (70% overall).
Synthesis 2010, No. 19, 3332–3338 © Thieme Stuttgart · New York

3334
F. Stazi et al.
PAPER
for protons and at 100.52 MHz or 150.8 MHz, respectively, for car-
bon-13. MS were recorded on an Agilent 1100 series instrument.
HRMS measurements within 5 ppm were performed on a Waters
UPLC coupled with a Waters LCT Premiere XE mass spectrometer
equipped with an electrospray ion source operating in negative-ion
mode.
When method C was performed on a multi-gram scale,
arylacetonitrile 1 was obtained in a high yield and high
purity, thereby proving the efficiency of the methodology.
Because of the good results obtained with methods B and
C, we decided to expand the scope of these procedures.
Four electron-deficient aryl fluorides were converted into
the corresponding arylacetonitriles in good-to-excellent
yields (Table 2). Both methods could be easily applied,
but method C could be advantageous when there are prob-
lems of purification, as in entry 1, or when the scale is so
small that the use of distillation to purify the final product
could be technically challenging.
Method A
[2-Fluoro-4-(trifluoromethyl)phenyl]acetaldehyde (2b)
A 0.5 M soln of KHMDS in toluene (23.7 mL, 11.9 mmol, 1.2
equiv) was added dropwise over 10 min to a suspension of
MeOCH2P+Ph3Cl– (3.9 g, 11.4 mmol, 1.15 equiv) in toluene (40
mL) at 0 °C under N2. The soln was stirred for 30 min at 25 °C then
cooled to 0 °C. A soln of 2-fluoro-4-(trifluoromethyl)benzaldehyde
(1.9 g, 9.89 mmol, 1 equiv) was added dropwise, and the resulting
mixture was stirred for 3 h at 25 °C. H2O (50 mL) was added, and
the phases were separated. The organic layer was washed succes-
sively with H2O (50 mL), 20 wt% NH4Cl (50 mL), and brine (50
mL) then dried (Na2SO4). The suspension was filtered through a
plug of silica gel that was then washed with cyclohexane (350 mL).
The filtrate was concentrated under reduced pressure to give an oil
(1.26 g) that was dissolved in acetone (20 mL) and treated with 4 M
aq HCl (10 mL). The mixture was stirred overnight at reflux, and
then the solvent was partially removed, the residue was diluted with
MTBE (20 mL), and the phases were allowed to separate. The aque-
ous layer was extracted with MTBE (20 mL). The combined organ-
ic phases were washed with H2O (16 mL) and brine (16 mL) then
dried (Na2SO4), filtered, and concentrated under reduced pressure to
give an oil; yield: 1.04 g. This was used in the next step without fur-
ther purification.
Table 2 Formation of Arylacetonitriles from Aryl Fluorides
Entry ArF
ArCH2CN
Yield
Method B Method C
CN
F
F
F
1
82%a
79%
70%
CF3
F
CF3
CN
O2N
O2N
2
quant
1H NMR (600 MHz, CDCl3): d = 9.79 (m, 1 H), 7.43 (d, J = 7.7 Hz,
1 H), 7.38 (d, J = 9.2 Hz, 1 H), 7.35 (t, J = 7.7 Hz, 1 H), 3.84 (s, 2
H).
CF3
CF3
13C NMR (151 MHz, CDCl3): d = 196.59 (s), 160.73 (d, J = 248.5
Hz), 132.37 (d, J = 4.6 Hz), 131.85 (qd, J = 33.4, 8.1 Hz), 123.79
(d, J = 17.3 Hz), 121.27 (q, J = 3.5 Hz), 123.15 (qd, J = 272.6, 2.3
Hz), 112.96 (dq, J = 25.3, 3.5 Hz), 43.65 (s).
HRMS (ESI): m/z [M – H]– calcd for C9H6F4O: 205.0277; found:
205.0282.
CN
F
O2N
3
58%
37%
54%
56%
O2N
NC
CN
F
NC
4
(E/Z)-[2-Fluoro-4-(trifluoromethyl)phenyl]acetaldehyde
Oxime (6)
The aldehyde 2b was dissolved in EtOH (5.4 mL) and treated suc-
cessively with NH2OH HCl (0.7 g, 10.07 mmol) and Et3N (1.56 mL,
11.19 mmol). The mixture was then stirred at reflux for 1 h. The sol-
vent was removed, and the mixture was diluted with H2O (10 mL)
and MTBE (15 mL). The biphasic system was separated, and the
aqueous phase was further extracted with MTBE (15 mL). The
combined organic layers were washed with 3 M HCl (15 mL), H2O
(15 mL), and brine (15 mL) then dried (Na2SO4), filtered, and con-
centrated under reduced pressure; yield: 0.96 g. The product was
used in the next step without further purification.
CN
N
F
5
50%
–
N
CF3
CF3
a Contaminated with 5% of regioisomer 9
1H NMR (600 MHz, DMSO-d6): d = 11.23 (s, 1 H), 10.74 (s, 1 H),
7.58 (m, 6 H), 7.47 (t, J = 5.3 Hz, 1 H), 6.83 (t, J = 5.3 Hz, 1 H),
3.71 (d, J = 5.3 Hz, 2 H), 3.59 (d, J = 5.3 Hz, 2 H).
13C NMR (151 MHz, DMSO-d6): d = 160.2 (d, J = 247.1 Hz, 1 C),
161.0 (d, J = 247.1 Hz, 1 C), 146.3 (s, 1 C), 145.9 (s, 1 C), 132.4 (d,
J = 5.1 Hz, 1 C), 132.3 (d, J = 5.1 Hz, 1 C), 129.4 (d, J = 15.1 Hz,
2 C), 129.3 (m, 2 C), 121.3 (m, 2 C), 123.4 (qd, J = 272.4, 3.0 Hz,
2 C), 112.6 (m, 2 C), 28.9 (d, J = 2.0 Hz, 1 C), 24.8 (d, J = 2.0 Hz,
1 C).
To summarize, two slightly different approaches for the
synthesis of arylacetonitriles from aryl fluorides were de-
veloped and demonstrated on a multi-gram scale. Further-
more, these methods were demonstrated on various
electron-deficient substrates, and gave yields ranging
from 38 to 99%, and produced products with a purity of
more than 98%.
All materials were purchased from commercial suppliers and were
used without purification. 1H NMR and 13C NMR spectra were re-
corded at 25 °C on a Varian INOVA 400 MHz or a 600 MHz NMR
spectrometer operating at 399.7 MHz or 599.7 MHz, respectively,
19F NMR (376 MHz, acetone-d6): d = –116.66 (s, 1 F), –63.10 (s, 3
F).
MS (ESI): m/z [M + H]+ = 222.
Synthesis 2010, No. 19, 3332–3338 © Thieme Stuttgart · New York

PAPER
Efficient Syntheses of Arylacetonitriles
3335
HRMS (ESI): m/z [M – H]– calcd for C9H7F4NO: 220.0386; found:
220.0380.
Ethyl Cyano[2-nitro-4-(trifluoromethyl)phenyl]acetate
K2CO3 (325 mesh; 3.3 g, 23.88 mmol) and BnN+Et3Cl– (21.6 mg,
0.10 mmol) were added to a soln of 1-fluoro-2-nitro-4-(trifluorom-
ethyl)benzene (1.8 g, 8.61 mmol) and EtO2CCH2CN (853 mL,
8.02 mmol) in DMSO (4.5 mL) at r.t. under N2, and the mixture was
heated to 90 °C and stirred for 12 h. The mixture was then cooled to
r.t., diluted with EtOAc (10 mL), and poured into a cooled 6 M HCl
(20 mL). The biphasic system was separated, and the aqueous phase
was extracted with EtOAc (15 mL). The combined organic layers
were washed with H2O, dried (Na2SO4), and concentrated under re-
duced pressure to give ethyl cyano[2-nitro-4-(trifluoromethyl)phe-
nyl]acetate as an oil; yield: 2.7 g (>99%; uncorrected).
[2-Fluoro-4-(trifluoromethyl)phenyl]acetonitrile (1)
The oxime 6 was dissolved in THF (19.2 mL), and SOCl2 (1.48 mL,
17.08 mmol) was slowly added while the temperature was kept be-
low 20 °C. The soln was stirred at r.t. for 1 h and then concentrated
under reduced pressure. The residue was dissolved in MTBE and
the soln was filtered through a silica plug, which was washed with
additional MTBE. The filtrate was concentrated under reduced
pressure to give the required product; yield: 0.8 g (40%).
1H NMR (400 MHz, DMSO-d6): d = 4.22 (s, 2 H), 7.66–7.71 (m, 1
H), 7.74 (t, J = 7.71 Hz, 1 H), 7.80 (m, 1 H).
13C NMR (151 MHz, DMSO-d6): d = 159.7 (d, J = 249.0 Hz), 131.6
(d, J = 3.7 Hz), 130.6 (qd, J = 33.0, 8.6 Hz), 123.7 (d, J = 16.5 Hz),
123.1 (qd, J = 272.2, 2.4 Hz), 121.9 (quin, J = 3.7 Hz), 117.5 (s),
113.1 (dq, J = 24.4, 3.7 Hz), 17.1 (d, J = 3.7 Hz).
1H NMR (400 MHz, DMSO-d6): d = 1.22 (t, J = 7.03 Hz, 3 H), 4.25
(q, J = 7.03 Hz, 2 H), 6.41 (s, 1 H), 8.04 (m, 1 H), 8.34 (d, J = 7.03
Hz, 1 H), 8.58 (m, 1 H).
13C NMR (100.52 MHz, DMSO-d6): d = 13.76, 40.94, 63.25,
114.76, 123.26, 129.61, 131.63, 134.53, 147.28, 163.48.
19F NMR (376 MHz, DMSO-d6): d = –113.96, –61.20.
MS (ESI): m/z [M + H]+ = 202.
19F NMR (376 MHz, DMSO-d6): d = –61.68 (s, 3 F).
HRMS (ESI): m/z [M – H]– calcd for C12H9F3N2O4: 301.0436;
found: 301.0437.
HRMS (ESI): m/z [M – H]– calcd for C9H5F4N: 202.0280; found:
202.0285.
[2-Nitro-4-(trifluoromethyl)phenyl]acetonitrile
A soln of ethyl cyano[2-nitro-4-(trifluoromethyl)phenyl]acetate
(2.7 g, 8.93 mmol) in a mixture of DMSO (4 mL) and brine (1 mL)
was heated at 120 °C until the reaction was complete (7 h), then
cooled to r.t. The resulting mixture was diluted with EtOAc (20 mL)
and H2O (5 mL), and the biphasic system was separated. The organ-
ic layer was washed successively with H2O (5 mL) and brine (5
mL), then dried (Na2SO4) and concentrated under reduced pressure.
The resulting brown oil was purified by column chromatography
[cyclohexane–EtOAc (85:15)] to give an orange oil; yield: 1.6 g
(79%).
1H NMR (400 MHz, DMSO-d6): d = 4.47 (s, 2 H), 7.98 (d, J = 8.10
Hz, 1 H), 8.23 (dd, J = 8.10, 1.17 Hz, 1 H), 8.46 (d, J = 1.17 Hz, 1
H).
13C NMR (100.52 MHz, DMSO-d6): d = 21.62, 117.32, 122.56,
122.79, 129.81, 130.87, 130.99, 132.99, 148.06.
19F NMR (376 MHz, DMSO-d6): d = –61.48 (s, 3 F).
MS (ESI): m/z [M + H]+ = 231.
HRMS (ESI): m/z [M – H]– calcd for C9H5F3N2O2: 229.0225;
Method B
Ethyl Cyano[2-fluoro-4-(trifluoromethyl)phenyl]acetate (7)
A suspension of 3,4-F2C6H3CF3 (100 g, 549 mmol, 1.1 equiv),
EtO2CCH2CN (53.2 mL, 500 mmol, 1 equiv), BnN+Et3Cl– (11.4 g,
50 mmol, 0.1 equiv) and K2CO3 (325 mesh; 207 g, 1.5 mol, 3 equiv)
in DMSO (300 mL) was stirred at 90 °C under N2 for 20 h. The mix-
ture was then cooled to 20 °C, diluted with EtOAc (500 mL), and
further cooled to 5 °C. 6 M aq HCl (500 mL) was added dropwise,
leading to precipitation of a white solid. The resulting suspension
was stirred for 30 min until the solid completely dissolved. The bi-
phasic system was separated, and the organic layer was washed with
H2O (2 × 300 mL) and brine (300 mL). The organic layer was mixed
with DMSO (200 mL) and then concentrated under reduced pres-
sure to give a brown soln of 7 in DMSO that was used without fur-
ther treatment.
1H NMR (400 MHz, DMSO-d6): d = 1.21 (t, J = 7.12 Hz, 3 H), 4.26
(q, J = 7.12 Hz, 2 H), 6.11 (s, 1 H), 7.72–7.83 (m, 2 H), 7.90 (dd,
J = 10.25, 1.27 Hz, 1 H).
13C NMR (100.52 MHz, DMSO-d6): d = 13.72, 37.45, 63.23,
113.73, 115.16, 122.26, 122.98, 123.29, 131.90, 132.33, 159.73,
163.87.
found: 229.0028.
Ethyl Cyano(2-nitrophenyl)acetate
19F NMR (376 MHz, DMSO-d6): d = –112.65 (m, 1 F), –61.41 (s, 3
F).
HRMS (ESI): m/z [M – H]– calcd for C12H9F4NO2: 274.0491;
found: 274.0499.
K2CO3 (325 mesh; 3.3 g, 23.88 mmol) and BnN+Et3Cl– (21.6 mg,
0.10 mmol) were added to a soln of 1-fluoro-2-nitrobenzene (1.2 g,
8.50 mmol) and EtO2CCH2CN (853 mL, 8.02 mmol) in DMSO (4.5
mL) at r.t. under N2. The resulting mixture was heated to 90 °C and
stirred for 12 h, then cooled to r.t.. The soln was then diluted with
EtOAc (10 mL) and poured into cooled 6 M HCl (20 mL). The bi-
phasic system was separated, and the aqueous phase was extracted
with EtOAc (15 mL). The combined organic layers were washed
with H2O, dried (Na2SO4), and concentrated under reduced pressure
to give an oil; yield: 2.08 g (>99%; uncorrected).
[2-Fluoro-4-(trifluoromethyl)phenyl]acetonitrile (1)
Brine (100 mL) was added to the previously obtained brown soln of
7, and the resulting mixture was stirred at 107 °C under N2 for 18 h.
The mixture was allowed to cool down to 20 °C then diluted with
EtOAc (500 mL) and H2O (200 mL). The mixture was then stirred
at 20 °C for 30 min and then the biphasic system was separated. The
organic layer was washed successively with H2O (100 mL) and
brine (100 mL) then concentrated under reduced pressure (50 mbar,
35 °C) to give a brown oily residue that was purified by distillation
under reduced pressure (bp 84–92 °C, 6 mbar) to give [2-fluoro-(4-
trifluoromethyl)-phenyl]acetonitrile (1) as a pale yellow liquid;
yield: 91.4 g (82%; purity ~ 95% by NMR). The product was con-
taminated with ~5% of the isomeric nitrile 9.
1H NMR (400 MHz, DMSO-d6): d = 1.19 (t, J = 7.12 Hz, 3 H), 4.22
(qd, J = 7.12, 1.10 Hz, 2 H), 6.25 (s, 1 H), 7.78 (m, 2 H), 7.92 (dt,
1 H), 8.29 (dd, J = 8.10, 1.27 Hz, 1 H).
13C NMR (100.52 MHz, DMSO-d6): d = 13.77, 41.23, 62.89,
115.37, 125.67, 126.02, 131.17, 133.18, 135.27, 146.72, 164.02.
HRMS (ESI): m/z [M – H]– calcd for C11H10N2O4: 233.0562; found:
233.0561.
Synthesis 2010, No. 19, 3332–3338 © Thieme Stuttgart · New York

3336
F. Stazi et al.
PAPER
(2-Nitrophenyl)acetonitrile
tracted with EtOAc (2 × 50 mL). The combined organic layers were
dried (Na2SO4), filtered, and concentrated under reduced pressure.
The resulting material was dried under a high vacuum for several
hours to give a reddish oil; yield: 9.5 g (>99%; uncorrected).
1H NMR (600 MHz, CDCl3): d = 1.33 (t, J = 7.2 Hz, 3 H), 4.31 (q,
J = 7.2 Hz, 2 H), 4.88 (s, 1 H), 7.80 (d, J = 8.1 Hz, 1 H), 8.07 (dd,
J = 8.1, 1.5 Hz, 1 H), 8.82 (d, 1.5 Hz, 1 H).
A soln of ethyl cyano(2-nitrophenyl)acetate (1.87 g, 7.99 mmol) in
a mixture of DMSO (4 mL) and brine (1 mL) was heated at 120 °C
until the reaction was complete (7 h), then cooled to r.t. The result-
ing mixture was diluted with EtOAc (20 mL) and H2O (5 mL), and
the biphasic system was separated. The organic layer was washed
successively with H2O (5 mL) and brine (5 mL) then dried (Na2SO4)
and concentrated under reduced pressure. A brown solid was ob-
tained that was purified by precipitation in EtOAc (6 mL) and cy-
clohexane (10 mL) to give a yellow solid; yield: 0.75 g (58%).
13C NMR (100.52 MHz, CDCl3): d = 13.81, 41.02, 64.22, 114.03,
120.87, 121.06, 129.27, 137.10, 148.90, 149.34, 163.40.
19F NMR (376 MHz, CDCl3): d = –68.12 (s, 3 F).
MS (ESI): m/z [M + H]+ = 259.
HRMS (ESI): m/z [M – H]– calcd for C11H9F3N2O2: 257.0538;
1H NMR (400 MHz, DMSO-d6): d = 4.35 (s, 2 H), 7.66 (ddd, 1 H),
7.71–7.76 (m, 1 H), 7.83 (dt, 1 H), 8.16 (dd, 1 H).
13C NMR (100.52 MHz, DMSO-d6): d = 21.54, 117.85, 125.41,
126.36, 129.68, 131.70, 134.60, 147.63.
MS (ESI): m/z [M + H]+ = 163.
HRMS (ESI): m/z [M – H]– calcd for C8H6N2O2: 161.0351; found:
found: 257.0544.
[6-(Trifluoromethyl)pyridin-3-yl]acetonitrile
A soln of ethyl cyano[6-(trifluoromethyl)pyridin-3-yl]acetate (9.5
g, 36.79 mmol) in DMSO (100 mL) was treated with brine (50 mL).
The resulting orange soln was heated to 110–120 °C. After 2 h, the
mixture was cooled to 25 °C, diluted with EtOAc (100 mL), and
washed successively with H2O (100 mL) and brine (100 mL). The
organic layer was dried (Na2SO4), filtered, and concentrated under
reduced pressure to give an oil that was purified on silica gel
(EtOAc–cyclohexane, 1:1); yield: 3.42 g (50%).
1H NMR (600 MHz, CDCl3): d = 3.89 (s, 2 H), 7.75 (d, J = 8.1 Hz,
1 H), 7.94 (dd, J = 8.1, 1.7 Hz, 1 H), 8.70 (d, 1.7 Hz, 1 H).
13C NMR (150.81 MHz, CDCl3): d = 21.15, 115.93, 120.76 (q,
J = 2.6 Hz), 120.77 (q, J = 274.0 Hz), 129.31, 136.92, 148.17 (q,
J = 34.8 Hz), 149.27.
161.0350.
Ethyl Cyano(2-cyanophenyl)acetate
K2CO3 (325 mesh; 3.3 g, 23.88 mmol) and BnN+Et3Cl– (21.6 mg,
0.10 mmol) were added to a soln of 2-fluorobenzonitrile (1.1 g, 9.08
mmol) and EtO2CCH2CN (853 mL, 8.02 mmol) in DMSO (4.5 mL)
at r.t. under N2, and the resulting mixture was heated to 90 °C and
stirred for 12 h. The mixture then was cooled to r.t., diluted with
EtOAc (10 mL), and poured into cooled 6 M HCl (20 mL). The bi-
phasic system was separated, and the aqueous phase was extracted
with EtOAc (15 mL). The combined organic layers were washed
with H2O then dried (Na2SO4) and concentrated under reduced pres-
sure to give an oil; yield: 1.6 g (82%).
1H NMR (400 MHz, DMSO-d6): d = 1.23 (t, J = 7.12 Hz, 3 H), 4.26
(q, J = 7.16 Hz, 2 H), 6.07 (s, 1 H), 7.65–7.72 (m, 2 H), 7.81–7.87
(m, 1 H), 8.00–8.03 (m, 1 H).
13C NMR (100.52 MHz, DMSO-d6): d = 13.74, 41.63, 63.25,
111.84, 115.36, 116.35, 130.05, 130.25, 133.82, 134.16, 134.23,
163.97.
MS (ESI): m/z [M + H]+ = 187.
HRMS (ESI): m/z [M – H]– calcd for C8H5F3N2: 185.0327; found:
185.0325.
Method C
Potassium (E,Z)-2-cyano-1-ethoxy-2-[2-fluoro-4-(trifluoro-
methyl)phenyl]ethylenolate (10):
HRMS (ESI): m/z [M – H]– calcd for C12H10N2O2: 213.0664; found:
A suspension of 3,4-F2C6H3CF3 (100 g, 549 mmol, 1.1 equiv) and
EtO2CCH2CN (53.2 mL, 500 mmol, 1 equiv), BnN+Et3 Cl– (11.4 g,
50 mmol, 0.1 equiv), and K2CO3 (325 mesh; 207 g, 1.5 mol, 3
equiv) in DMSO (300 mL) was stirred at 90 °C under N2 for 19 h.
The mixture was allowed to cool to 20 °C, diluted with EtOAc (500
mL), and then further cooled to 5 °C. 6 M HCl (500 mL) was added
dropwise, leading to precipitation of a white solid. The resulting
suspension was stirred for 30 min until the precipitate completely
dissolved. The biphasic system was separated, and the organic layer
was washed with H2O (2 × 300 mL) and brine (300 mL). The organ-
ic layer was dried (Na2SO4), filtered, and evaporated to dryness.
MTBE (300 mL) was added followed by t-BuOK (47 g, 418 mmol,
0.8 equiv) in small portions while the temperature was kept below
30 °C. The mixture was then concentrated under vacuum to give a
thick slurry. MeCN (500 mL) was added and the mixture was con-
centrated to 250 mL. The slurry was cooled at 5–8 °C and stirred for
10–12 h. The solid was filtered off, washed with MeCN (50 mL),
and dried under vacuum at 40 °C to give a pale yellow solid; yield:
143.4 g (96%).
213.0662.
2-(Cyanomethyl)benzonitrile
A soln of ethyl cyano(2-cyanophenyl)acetate (1.6 g, 7.47 mmol) in
DMSO (4 mL) and brine (1 mL) was heated at 120 °C until the re-
action was complete (7 h), then cooled to r.t. The resulting mixture
was diluted with EtOAc (20 mL) and H2O (5 mL), and the biphasic
system was separated. The organic layer was washed successively
with H2O (5 mL) and brine (5 mL) then dried (Na2SO4) and concen-
trated under reduced pressure. A brown solid was obtained that was
purified by precipitation in EtOAc (6 mL) and cyclohexane (10 mL)
to give a yellow solid; yield: 0.392 g (37%).
1H NMR (400 MHz, DMSO-d6): d = 4.35 (s, 2 H), 7.66 (ddd, 1 H),
7.71–7.76 (m, 1 H), 7.83 (dt, 1 H), 8.16 (dd, 1 H).
13C NMR (100.52 MHz, DMSO-d6): d = 21.54, 117.85, 125.41,
126.36, 129.68, 131.70, 134.60, 147.63.
MS (ESI): m/z [M + H]+ = 143.
HRMS (ESI): m/z [M – H]– calcd for C9H6N2: 141.0453; found:
1H NMR (400 MHz, DMSO-d6): d = 1.15 (t, J = 7.12 Hz, 3 H), 3.95
(q, J = 7.12 Hz, 2 H), 7.07–7.18 (m, 2 H), 8.25 (m, 1 H).
141.0450.
Ethyl Cyano[6-(trifluoromethyl)pyridin-3-yl]acetate
13C NMR (151 MHz, DMSO-d6): d = 168.1 (s), 154.7 (d, J = 243.6
Hz), 134.7 (d, J = 9.7 Hz), 125.9 (s), 125.4 (br. s), 124.5 (qd,
J = 269.7, 2.9 Hz), 119.8 (m), 118.2 (qd, J = 32.9, 7.7 Hz), 111.2
(dq, J = 26.1, 3.9 Hz), 56.6 (s), 50.3 (s), 15.1 (s).
19F NMR (376 MHz, DMSO-d6): d = –113.19 (m, 1 F) –59.41 (s, 3
F).
K2CO3 (11.3 g, 81.76 mmol) and BnN+Et3Cl– (0.68 g, 2.98 mmol)
were added to a soln of 5-fluoro-2-(trifluoromethyl)pyridine (5 g,
30.29 mmol) and EtO2CCH2CN (3.5 mL, 32.91 mmol) in DMSO
(50 mL). The resulting mixture was heated to 90 °C for 3 h then
cooled to r.t. The slurry was then diluted with EtOAc (50 mL) and
slowly treated with 6 M HCl (50 mL). The aqueous layer was ex-
Synthesis 2010, No. 19, 3332–3338 © Thieme Stuttgart · New York

PAPER
Efficient Syntheses of Arylacetonitriles
3337
MS (ESI): m/z [M + H]+ = 314
HRMS (ESI): m/z [M – K]– calcd for C12H8F4KNO2: 274.0491;
8.50 mmol) and EtO2CCH2CN (853 mL, 8.02 mmol) in DMSO (4.5
mL) at r.t. under N2. The resulting mixture was heated to 90 °C,
stirred for 12–18 h, and then cooled to r.t., diluted with EtOAc (10
mL), and poured into cooled 6 M HCl (20 mL). The biphasic system
was separated, and the aqueous phase was extracted with EtOAc (15
mL). The combined organic layers were washed with H2O, dried
(Na2SO4), and concentrated under reduced pressure to give an oil;
yield 2.1 g. This residue was dissolved in MTBE (5.6 mL), and t-
BuOK (760 mg, 6.77 mmol) was added portionwise. The resulting
mixture was stirred for 2 h at r.t., treated with CH2Cl2 (2 mL), and
then stirred for 30 min at r.t. The solvent was removed to give a pur-
ple solid that was used in the next step without further purification;
yield: 1.5 g (65%).
1H NMR (400 MHz, DMSO-d6): d = 1.10 (t, J = 7.03 Hz, 3 H), 3.87
(q, J = 7.03 Hz, 2 H), 6.75 (ddd, J = 8.25, 6.98, 1.37 Hz, 1 H), 7.26
(ddd, J = 8.30, 6.93, 1.56 Hz, 1 H), 7.41–7.52 (m, 2 H).
13C NMR (151 MHz, DMSO-d6): d = 167.3, 144.3, 136.1, 130.6,
127.3, 126.3, 124.7, 118.6, 56.7, 54.3, 15.2.
found: 274.0490
[2-Fluoro-4-(trifluoromethyl)phenyl]acetonitrile
The solid obtained above (143.4 g, 527 mmol) was dissolved in H2O
(215 mL) and the pH was adjusted to 7 with concd HCl (44 mL)
while the temperature was kept below 30 °C. DMSO (300 mL) was
added followed by NaCl (40 g, 684 mmol, 1.4 equiv), and the mix-
ture was heated at 110 °C for 12–15 h until conversion was com-
plete. The mixture was then cooled at 25 °C, and CH2Cl2 (450 mL)
was added, followed by H2O (330 mL). The phases were separated.
The aqueous phase was back-extracted with CH2Cl2 (300 mL). The
combined organic phases were washed with H2O (3 × 500 mL),
dried (Na2SO4), filtered, and evaporated to dryness. The product
was purified by distillation under reduced pressure to give a color-
less liquid; yield: 74.9 g [70%; purity: ~99% (NMR)].
Potassium (E,Z)-2-Cyano-1-ethoxy-2-[2-nitro-4-(trifluoro-
methyl)phenyl]ethylenolate
MS (ESI): m/z [M + H]+ = 273.
HRMS (ESI): m/z [M – K]– calcd for C11H9KN2O4: 233.0562;
K2CO3 (325 mesh, 3.3 g, 23.88 mmol) and BnN+Et3Cl– (21.6 mg,
0.10 mmol) were added to a soln of 1-fluoro-2-nitro-4-(trifluoro-
methyl)benzene (1.8 g, 8.61 mmol) and EtO2CCH2CN (853 mL,
8.02 mmol) in DMSO (4.5 mL) at r.t. under N2. The resulting mix-
ture was heated to 90 °C, stirred for 12 h, cooled to r.t., diluted with
EtOAc (10 mL), and poured into a cooled 6 M HCl (20 mL). The
biphasic system was separated, and the aqueous phase was extract-
ed with EtOAc (15 mL). The combined organic layers were washed
with H2O, dried (Na2SO4), and concentrated under reduced pressure
to give an oil. This residue (1.9 g, 6.29 mmol) was dissolved in
MTBE (5.6 mL), and t-BuOK (760 mg, 6.77 mmol) was added por-
tionwise. The resulting mixture was stirred overnight at r.t., and
then evaporated to give a purple oil (yield: 1.23 g, 42%) that was
used in the next step without further purification.
found: 233.0562
(2-Nitrophenyl)acetonitrile
The suspension of the potassium salt obtained above (1.5 g, 5.51
mmol) in CH2Cl2 (28 mL) was treated with a 1 M HCl soln (14 mL).
The biphasic system was stirred until complete dissolution and al-
lowed separating. The aqueous layer was extracted with CH2Cl2
(2 × 30 mL). The combined organic layers were washed with brine,
dried (Na2SO4) and concentrated under reduced pressure to oil. The
oil was dissolved in DMSO (4 mL) and treated with a brine soln.
The mixture was stirred at 115 °C for 12 h. After cooling to r.t., the
resulting mixture was diluted with EtOAc (30 mL) and H2O (15
mL). The biphasic system was separated and the aqueous layer was
extracted with EtOAc (15 mL). The combined organic layers were
washed with H2O dried (Na2SO4) and concentrated under reduced
pressure affording (2-nitrophenyl)acetonitrile; yield: 0.892 g
(54%).
1H NMR (600 MHz, DMSO-d6): d = 7.74 (s, 1 H), 7.67 (d, J = 8.6
Hz, 1 H), 7.50 (dd, J = 8.6, 1.6 Hz, 1 H), 3.92 (q, J = 7.2 Hz, 2 H),
1.12 (t, J = 7.2 Hz, 3 H).
13C NMR (151 MHz, DMSO-d6): d = 166.9 (s), 142.1 (s), 140.3 (s),
127.1 (s), 126.5 (m), 124.5 (s), 122.3 (q, J = 4.6 Hz), 124.2 (q,
J = 270.4 Hz), 117.2 (q, J = 33.4 Hz), 57.7 (s), 57.3 (s), 15.0 (s).
19F NMR (376 MHz, DMSO-d6): d = –60.01 (s, 3 F).
HRMS (ESI): m/z [M – K]– calcd for C12H8F3KN2O4: 301.0436;
Potassium (E,Z)-2-Cyano-2-(2-cyanophenyl)-1-(ethoxy)ethyle-
nolate
K2CO3 (325 mesh, 3.3 g, 23.88 mmol) and BnN+Et3Cl– (21.6 mg,
0.10 mmol) were added to a soln of 2-fluorobenzonitrile (1.1 g, 9.08
mmol) and EtO2CCH2CN (853 mL, 8.02 mmol) in DMSO (4.5 mL)
at r.t. under N2. The resulting mixture was heated to 90 °C, stirred
for 12–18 h, was cooled to r.t., diluted with EtOAc (10 mL), and
poured into cooled 6 M HCl (20 mL). The biphasic system was sep-
arated, and the aqueous phase was back-extracted with EtOAc (15
mL). The combined organic layers were washed with H2O, dried
(Na2SO4), and concentrated under reduced pressure to give an oil.
The residue (1.5 g) was dissolved in MTBE (5.6 mL) and t-BuOK
(760 mg, 6.77 mmol) was added portionwise. The resulting mixture
was stirred for 2 h at r.t. to give a suspension that was treated with
CH2Cl2 (2 mL) and stirred for 30 min at r.t. The slurry was filtered
to give a solid that was washed with CH2Cl2 (3 × 5 mL) and dried
in an oven at 40 °C under reduced pressure; yield: 1.41 g (62%).
found: 301.0438.
[2-Nitro-4-(trifluoromethyl)phenyl]acetonitrile
A suspension of the potassium salt obtained above (1.22 g, 3.58
mmol) in CH2Cl2 (28 mL) was treated with 1 M HCl (14 mL), and
the resulting biphasic system was stirred until complete dissolution
occurred and then allowed to separate. The aqueous layer was ex-
tracted with CH2Cl2 (2 × 30 mL), and the combined organic layers
were washed with brine, dried (Na2SO4), and concentrated under re-
duced pressure to give an oil. The oil was dissolved in DMSO (4
mL) and treated with brine. The mixture was stirred at 115 °C for
12 h then cooled to r.t. The resulting mixture was diluted with
EtOAc (30 mL) and H2O (15 mL). The biphasic system was sepa-
rated, and the aqueous layer was extracted with EtOAc (15 mL).
The combined organic layers were washed with H2O, dried
(Na2SO4), and concentrated under reduced pressure to give [2-nitro-
4-(trifluoromethyl)phenyl]acetonitrile; yield: 0.823 g (quantita-
tive).
1H NMR (400 MHz, DMSO-d6): d = 1.15 (t, J = 7.12 Hz, 3 H), 3.94
(q, J = 7.12 Hz, 2 H), 6.78 (td, J = 7.47, 1.27 Hz, 1 H), 7.21–7.30
(m, 1 H), 7.34–7.39 (m, 1 H), 7.60–7.73 (m, 1 H).
13C NMR (151 MHz, DMSO-d6): d = 167.7, 145.4, 133.2, 131.0,
126.9, 126.1, 119.7, 119.6, 105.6, 56.6, 54.8, 15.2.
MS (ESI): m/z [M + H]+ = 253.
HRMS (ESI): m/z [M – K]– calcd for C12H9KN2O2: 213.0664;
Potassium (E,Z)-2-Cyano-1-ethoxy-2-(2-nitrophenyl)ethyleno-
late
K2CO3 (325 mesh, 3.3 g, 23.88 mmol) and BnN+Et3Cl– (21.6 mg,
0.10 mmol) were added to a soln of 1-fluoro-2-nitrobenzene (1.2 g,
found: 213.0664.
Synthesis 2010, No. 19, 3332–3338 © Thieme Stuttgart · New York

3338
F. Stazi et al.
PAPER
(3) Friedrich, K.; Wallenfels, K. In The Chemistry of Cyano
2-(Cyanomethyl)benzonitrile
A suspension of the potassium salt obtained above (1.41 g, 5.59
mmol) in CH2Cl2 (28 mL) was treated with 1 M HCl (14 mL). The
biphasic system was stirred until complete dissolution occurred and
then separated. The aqueous layer was extracted with CH2Cl2
(2 × 30 mL). The combined organic layers were washed with brine,
dried (Na2SO4), and concentrated under reduced pressure to give an
oil. This residue was dissolved in DMSO (4 mL) and treated with
brine. The mixture was stirred at 115 °C for 12 h then cooled to r.t.
The resulting mixture was diluted with EtOAc (30 mL) and H2O (15
mL). The biphasic system was separated and the aqueous layer was
extracted with EtOAc (15 mL). The combined organic layers were
washed with H2O, dried (Na2SO4), and concentrated under reduced
pressure; yield: 0.445 g (56%).
Group; Rappoport, Z., Ed.; Wiley-Interscience: New York,
1970, Chap. 2, 67–122.
(4) Harrison, I. T.; Harrison, S. In Compendium of Organic
Synthetic Methods, Vol. 1; Wiley: Interscience New York,
1971, Chap. 13, 457–478.
(5) Metzger, H. In Methoden der Organischen Chemie
(Houben–Weyl), Vol. 10, Part 4; Müller, E., Ed.; Thieme:
Stuttgart, 1968, 217–282.
(6) Naumov, Y. A.; Grandberg, I. I. Russ. Chem. Rev. 1966, 35,
9.
(7) Starosotnikov, A. M.; Lobach, A. V.; Shevelev, S. A.
Synthesis 2005, 2830.
(8) Mano, T.; Stevens, R. W.; Ando, K.; Kawai, M.; Kawamura,
K.; Nakao, K.; Okumura, Y.; Okumura, T.; Sakakibara, M.;
Miyamoto, K.; Tamura, T. Chem. Pharm. Bull. 2005, 53,
965.
Acknowledgment
(9) Konkel, J. T.; Fan, J.; Jayachandran, B.; Kirk, K. L.
J. Fluorine Chem. 2002, 115, 27.
(10) Clive, D. L. J.; Wang, J. J. Org. Chem. 2004, 69, 2773.
(11) Poschalko, A.; Welzig, S.; Treu, M.; Nerdinger, S.; Mereiter,
K.; Jordis, U. Tetrahedron 2002, 58, 1513.
We are grateful to Alcide Perboni for useful advice, and to Damiano
Cancogni for help with the synthesis. The authors would like to
thank Stefano Provera and Lucilla Turco for their NMR support.
We are also grateful to Zhang Tongqiang, Asymchem Laboratories
Inc. for their excellent synthetic support.
(12) (a) Narsaiah, A. V.; Sreenu, D.; Nagaiah, K. Synth.
Commun. 2006, 36, 137. (b) Yang, S. H.; Chang, S. Org.
Lett. 2001, 3, 4209. (c) Narsaiah, A. V.; Nagaiah, K. Adv.
Synth. Catal. 2004, 346, 1271. (d) Löwe, W.; Witzel, S.;
Tappmeyer, S.; Albuschat, R. J. Heterocycl. Chem. 2004,
41, 317. (e) Movassagh, B.; Shokri, S. Synth. Commun.
2005, 35, 887. (f) Miller, C. P.; Kaufman, D. H. Synlett
2000, 1169. (g) Lutz, A. W.; Diehl, R. E. US 4288385, 1981;
Chem. Abstr. 1981, 96: 103821.
(13) (a) Beare, N. A.; Hartwig, J. F. J. Org. Chem. 2002, 67, 541.
(b) Stauffer, S. R.; Beare, N. A.; Stambuli, J. P.; Hartwig, J.
F. J. Am. Chem. Soc. 2001, 123, 4641.
(14) Kowalczyk, B. A. Synthesis 1997, 1411.
(15) Padmavathi, V.; Balaiah, A.; Reddy, B. J. M.; Padmaja, A.
Heterocycl. Commun. 2003, 9, 599.
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Synthesis 2010, No. 19, 3332–3338 © Thieme Stuttgart · New York