Chemoselective Schmidt reaction mediated by triflic acid: Selective synthesis of nitriles from aldehydes

Article abstract of DOI:10.1021/jo3008258

An excellent utility of Schmidt reaction of aldehydes to access corresponding nitriles in an instantaneous reaction is demonstrated. The reaction of aldehydes with NaN₃ and TfOH furnishes the corresponding nitriles in near quantitative yields and tolerates a variety of electron-withdrawing and electron-donating substituents on the substrates. Formanilides, a common side product in Schmidt reaction, is not observed in this reaction. Besides these advantages, the salient feature of this reaction is that it exhibits a remarkable chemoselectivity, as acid and ketone functionalities are well tolerated under the reaction conditions. The reaction is easily scalable, high yielding, and nearly instantaneous.

Full text of DOI:10.1021/jo3008258

Article
pubs.acs.org/joc
Chemoselective Schmidt Reaction Mediated by Triflic Acid: Selective
Synthesis of Nitriles from Aldehydes
Balaji V. Rokade and Kandikere Ramaiah Prabhu*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India
*
S Supporting Information
ABSTRACT: An excellent utility of Schmidt reaction of aldehydes to access
corresponding nitriles in an instantaneous reaction is demonstrated. The
reaction of aldehydes with NaN and TfOH furnishes the corresponding
3
nitriles in near quantitative yields and tolerates a variety of electron-
withdrawing and electron-donating substituents on the substrates. Formani-
lides, a common side product in Schmidt reaction, is not observed in this
reaction. Besides these advantages, the salient feature of this reaction is that it
exhibits a remarkable chemoselectivity, as acid and ketone functionalities are
well tolerated under the reaction conditions. The reaction is easily scalable,
high yielding, and nearly instantaneous.
INTRODUCTION
this report, to the best of our knowledge, utility of Schmidt
■
reaction for selective transformation of aldehyde to one of the
The Schmidt reaction of carbonyl compounds is a well
7
1
two possible products in Schmidt reaction is scarce. Hence, it
addressed reaction. It is well-known that under the Schmidt
is desirable to develop a method to access either nitrile or
formanilide selectively using Schmidt reaction protocol.
Nitriles are important structural motifs in organic synthesi-
reaction conditions, ketones and carboxylic acids are converted
2
3
into their corresponding amides and amines respectively,
whereas aldehydes furnish a mixture of formanilides and
8a−g
4
s,
which are valuable intermediates that are easily amenable
nitriles. Therefore, there is a great surge in the utility and
2
3
to their corresponding acids, esters, amines, amides, aldehydes,
applications of Schmidt reactions of ketones and acids, while
Schmidt reactions of aldehydes are limited because of the
formation of mixtures of corresponding formanilides and
8
h,i
benzamidines, and nitrogen-containing heterocycles.
In
continuation of our work to develop simple synthetic strategies
9
4
to accomplish nitriles, in this paper we present an efficient
nitriles (Scheme 1). Interestingly, pioneering work of Aube
́
utility of the Schmidt reaction for a selective transformation of
aldehydes to their nitriles using triflic acid (TfOH) (Scheme 1).
Scheme 1
RESULTS AND DISCUSSION
We began the current study by employing 4-nitrobenzaldehyde
a and a variety of Bronsted acids. A number of Bronsted acids
■
1
were screened to optimize the reaction conditions by reacting
4
-nitrobenzaldehyde 1a and NaN (Table 1). The reactions
3
were performed using several acids (3 equiv) such as acetic
acid, methanesulfonic acid, p-toluenesulfonic acid (p-TSA),
sulfuric acid, and trifluoroacetic acid (TFA) (Table 1, entries
2
1
−6) in CH CN at room temperature. As can be seen in Table
3
, most these reactions failed to produce the expected product
even after prolonged reaction (24 h), and the starting material
was intact. Interestingly, perchloric acid (HClO ) in a reaction
on intramolecular Schmidt reaction of carbonyl compounds,
particularly ketones, with alkyl azides unraveled excellent
methods to accomplish amides, lactams, oxazolines, and their
4
with aldehyde 1a and NaN3 (1.5 equiv) furnished the
corresponding nitrile 2a in low yield (6%, 24 h, Table 1,
entry 7). Although this reaction has produced a low yield of the
nitrile, it furnished only the corresponding nitrile, and the
formation of formanilide was not observed. Further, this
5
application to synthesize natural products. Addition of azides
to olefins in the presence of Bronsted acid to activate olefin to
6
get aziridines is also reported. In this context, in 1952 McEwen
et al. revealed that in the Schmidt reaction of aldehyde with
HN , the product ratio of nitrile to formanilide depends upon
the amount of sulfuric acid employed in the reaction. Besides
Received: April 24, 2012
3
4
©
XXXX American Chemical Society
A
dx.doi.org/10.1021/jo3008258 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Table 1. Optimization of Reaction Conditions
yields without forming other regiomer, N-substituted for-
mamides (Table 2). Benzaldehydes bearing electron-donating
and electron-withdrawing groups underwent smooth con-
version to furnish their corresponding nitriles regioselectively
in good to excellent yields (Table 2, entries 1−22).
Benzaldehyde reacted smoothly to furnish benzonitrile in
82% (Table 2, entry 1). Similarly, benzaldehyde substituted
with a variety of substituents such as alkyl, methoxy, hydroxyl,
allyloxy, propargyloxy, benzyloxy, phenyl, halo, amide, ester,
and nitro groups underwent a facile reaction to produce
corresponding nitriles in excellent yields (Table 2). Further-
more, it was found that the methodology is general and works
well with cinnamaldehyde to furnish the corresponding
cinnamonitrile in excellent yield (Table 2, entry 23). Similarly,
p-nitrocinnamaldehyde and p-methoxycinnamaldehyde reacted
smoothly to furnish their corresponding nitriles 3b and 3c in
almost quantitative yields (Table 2, entries 24−25). Alicyclic
α,β-unsaturated aldehyde, 2-bromocyclohex-1-enecarbaldehyde,
reacted smoothly under the standard reaction conditions to
furnish the nitrile, 2-bromocyclohex-1-enecarbonitrile, 3d in
b
entry
Bronsted acid
solvent
yield (%)
1
2
3
4
5
6
7
8
9
none
CH CN
nr
nr
nr
nr
nr
nr
6
3
AcOH
CH CN
3
CH SO H
CH CN
3
3
3
p-TSA
CH CN
3
H SO
2
CH CN
4
3
TFA
CH CN
3
HCIO (70%)
CH CN
4
3
c
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
TfOH
CH CN
99
3
d
CH CN
6
3
e
10
11
12
13
14
15
16
17
18
CH CN
66
3
THF
nr
21
nr
nr
nr
75
nr
nr
CHCl3
CH Cl
2
2
6
0% yield (Table 2, entry 26). In most of the reactions, the
DMF
product obtained was NMR pure; therefore, further purification
was not necessary.
Et O
2
EtOAc
After successful attempts to convert benzyl and cinnamyl
aldehydes to their corresponding nitriles, we attempted
selective reaction of aldehydes in the presence of ketone and
acid functionalities, hoping that ketone or carboxylic acid
groups would be inert under the reaction conditions. It is well-
known that aryl ketones and acids undergo a facile Schmidt
toluene
MeOH
a
Reactions were performed with 1a (1 mmol), NaN (1.5 mmol), and
Bronsted acid (3 mmol), solvent (2 mL) for 24 h at room
temperature. Refers to H NMR yield. nr = no reaction. Reaction
completed in 2 min. TfOH (1.5 equiv). TfOH (2 equiv).
3
b
1
c
d
e
2
3
reaction to furnish their corresponding amides and amines,
respectively, which have been well exploited in organic
synthesis. To test this hypothesis, 4-acetylbenzaldehyde was
subjected to standard reaction conditions to obtain the
corresponding 4-acetylbenzonitrile 2x in almost quantitative
yield (98%, Scheme 2). Similarly, 4-formylbenzoic acid under
the similar reaction conditions furnished the corresponding 4-
formylbenzonitrile 2y in 99% yield (Scheme 2). The selectivity
observed in the formation of nitrile in the presence of keto- and
carboxylic functionality was further confirmed by performing an
intermolecular reaction of a mixture of 4-methoxybenzaldehyde
and 4-methoxyacetophenone. As expected, 4-methoxybenzal-
dehyde reacted to yield the corresponding nitrile 2d (99%),
whereas 4-methoxyacetophenone was intact during the reaction
condition (Scheme 3). Similarly, under the similar reaction
conditions, an intermolecular reaction of 4-methoxybenzalde-
hyde and 4-methoxybenzoic acid resulted in the formation of 4-
methoxybenzonitrile 2d in almost quantitative yield (99%),
while 4-methoxybenzoic acid was intact during the reaction
conditions (Scheme 3). These reactions reiterate that the
Schmidt reaction using TfOH is selective for the transformation
of aldehydes to their nitriles in the presence of ketones or
carboxylic acid functionalities (Schemes 2 and 3).
To examine the application of this methodology in large
scale, the reaction of 1a was carried out in 10 mmol scale. As
expected, the product 2a was obtained in 95% yield after
purification (Scheme 4), which is comparable to the yield
obtained in small-scale reaction (1 mmol, entry 8, Table 1).
We believe that the selective formation of nitriles from the
corresponding aldehyde goes through the expected pathway of
Schmidt reaction. Hydazoic acid attacks the aldehyde to form
the corresponding azido alcohol, which loses water to furnish
the intermediate I. Further, the intermediate I loses nitrogen to
afford the corresponding nitrile (Scheme 5). It appears that
reaction indicated that it is necessary to use stronger Bronsted
acids to achieve the better results such as HClO (Table 1,
4
entry 7). Encouraged by the outcome, a reaction of 1a and
NaN using TfOH was performed. In this reaction, it was
3
pleasing to find that 4-nitrobenzonitrile 2a was formed, almost
instantaneously, in near quantitative yield (99%, Table 1, entry
8
), and side products were not observed even in trace
4
amounts. It is worthwhile to note that the similar reaction of
p-nitrobenzaldehyde, H SO , and NaN in benzene resulted in
2
4
3
the formation of a mixture of corresponding nitrile and
4
formanilide. On the basis of these inputs, further screening
studies were carried out using 1a as a precursor. Decreasing the
amount of TfOH to 1.5 or 2 equiv resulted in the formation of
the product in low yield (6 and 66% respectively, Table 1,
entries 9−10). Solvent screening studies revealed that solvents
such as CHCl or EtOAc are not suitable for this reaction, as
3
the reactions in these solvents have produced a mixture of
products along with unreacted starting material. Similarly, the
reaction in diethyl ether, CH Cl , THF, toluene, and DMF did
2
2
not proceed, as the starting material was recovered unaltered.
Further, MeOH as a solvent resulted in the formation of
10
corresponding dimethyl acetal as the product. Nevertheless,
the most satisfactory results were obtained by using CH CN as
3
1
1
solvent. Although CH CN is known to react with TfOH, it is
used as solvent in several organic reactions. Therefore, we
3
12
carried out further reactions with NaN (1.5 equiv), TfOH (3
3
equiv) using CH CN as solvent at room temperature.
3
With the optimized reaction conditions, we explored the
scope and limitation of the reaction with a variety of aldehydes,
and results are compiled in Table 2. In general, it was noticed
that under the optimal conditions, a variety of aldehydes were
converted into their corresponding nitriles in good to excellent
B
dx.doi.org/10.1021/jo3008258 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Table 2. Substrate Scope for Schmidt Reaction ,
a b
a
b
Reaction conditions: aldehyde (1 mmol), NaN (1.5 mmol), TfOH (3 mmol), CH CN (2 mL) at rt for 2 min. Isolated yields.
3
3
migration of hydrogen atom is preferred over phenyl group
migration and has no other preferences, as substrates with
electron-withdrawing or electron-donating groups are under-
going a facile reaction under the reaction conditions to furnish
the corresponding nitrile as the sole product. The plausible
mechanism of this reaction is shown in Scheme 5, wherein
TfOH first reacts with NaN to form HN , which further reacts
3
3
with aldehyde in the presence of TfOH followed by
13
dehydration to form intermediate I, which yields nitrile.
Scheme 2. Intramolecular Chemoselective Transformation
of Aldehyde to Nitrile
CONCLUSION
a
■
In conclusion, we have shown an excellent utility of Schmidt
reaction of aldehydes to obtain corresponding nitriles. This
reaction is almost instantaneous and furnishes the correspond-
ing nitriles in near quantitative yields and tolerates electron-
withdrawing and electron-donating substituents. Additionally,
side product formanilide is not observed. Besides these
advantages, the salient feature of this reaction is the remarkable
selectivity seen in the reaction of aldehyde functionality in the
presence of carboxylic acid and ketone functionalities under the
reaction conditions. Further work to explore the scope of this
reaction is underway in our laboratory.
a
Reaction conditions: 1a (1 mmol), NaN , (1.5 mmol), TfOH (3
3
mmol), CH CN (2 mL) at rt for 2 min.
3
C
dx.doi.org/10.1021/jo3008258 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Scheme 3. Intermolecular Chemoselective Transformation of Aldehyde to Nitrile
a
Reaction conditions: 1a (1 mmol), NaN , (1.5 mmol), TfOH (3 mmol), CH CN (2 mL) at rt for 2 min
3
3
1
3
Scheme 4. Scaling-up Experiment
MHz, CDCl ) δ 7.66−7.59 (m, 3H), 7.49−7.45 (m, 2H); C NMR
3
(
100 MHz, CDCl ) δ 132.7, 132.0, 129.0, 118.8, 112.3.
3
4-Methylbenzonitrile (2c). Prepared as described in the general
experimental procedure. White solid: yield 71% (83.0 mg); mp 27−29
1
5
−1
°
2
=
C (lit. 26−28 °C); R (15% EtOAc/hexane) 0.7; IR (KBr, cm )
1
f
226; H NMR (400 MHz, CDCl ) δ 7.54 (d, J = 8 Hz, 2H), 7.27 (d, J
3
8.4 Hz, 2H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl ) δ 143.6,
3
1
32.0, 129.8, 119.1, 109.2, 21.8; HRESI-MS (m/z) Calculated for
C H N (M + H) 118.0657, found (M + H) 118.0654.
8
7
4-Methoxybenzonitrile (2d). Prepared as described in the
general experimental procedure. Colorless solid: yield 97% (129.0
9
b
mg); mp 55−57 °C (lit. 56−57 °C); R (25% EtOAc/hexane) 0.50;
f
−1
1
IR (KBr, cm ) 2218; H NMR (400 MHz, CDCl ) δ 7.57 (d, J = 8.4
Hz, 2H), 6.94 (d, J = 8.0 Hz, 2H), 3.86 (s, 3H); C NMR (100 MHz,
EXPERIMENTAL SECTION
General Experimental Methods. NMR spectra were recorded on
3
■
13
CDCl ) δ 162.8, 133.8, 119.1, 114.6, 103.8, 55.4; HRESI-MS (m/z)
3
in CDCl ; tetramethylsilane (TMS; δ = 0.00 ppm) served as internal
3
Calculated for C H NO (M + Na) 156.0425, found (M + Na)
1
8
7
standards for H NMR; chemical shifts (δ) are reported in ppm
1
56.0427.
,4-Dimethoxybenzonitrile (2e). Prepared as described in the
relative to TMS. The corresponding residual nondeuterated solvent
3
13
signal (CDCl : δ = 77.00 ppm) was used as internal standards for
C
3
general experimental procedure. Colorless solid: yield 97% (158.1
mg); mp 63−65 °C (lit. 65−66 °C); R (25% EtOAc/hexane) 0.50;
IR (KBr, cm ) 2223; H NMR (400 MHz, CDCl ) δ 7.29 (d, J = 8.4
NMR. High-resolution mass spectra were obtained using a TOF
spectrometer using simultaneous electrospray (ESI). Column
chromatography was conducted on silica gel 230−400 mesh
9b
f
−1
1
3
Hz, 1H), 7.08 (s, 1H), 6.91 (d, J = 8.4 Hz, 1H), 3.94 (s, 3H), 3.91 (s,
(
Merck), and preparative thin-layer chromatography was carried out
3
1
H); 13C NMR (100 MHz, CDCl ) δ 152.8, 149.1, 126.4, 119.2,
3
using silica gel GF-254.
13.8, 111.1, 103.8, 56.1, 56.0; HRESI-MS (m/z) Calculated for
Typical Experimental Procedure, Synthesis of Nitriles from
Aldehydes. Triflic acid (3 mmol) was added to a well-stirred solution
C H NO (M + Na) 186.0531, found (M + Na) 186.0533.
9
9
2
3,4,5-Trimethoxybenzonitrile (2f). Prepared as described in the
of aldehyde (1 mmol), sodium azide (1.5 mmol) in CH CN (2 mL),
3
general experimental procedure. Colorless solid: yield 97% (187.2
mg); mp 93−95 °C (lit. 92−94 °C); R (25% EtOAc/hexane) 0.50;
IR (KBr, cm ) 2226; H NMR (400 MHz, CDCl ) δ 6.87 (s, 2H),
and the mixture was stirred at room temperature until the reaction was
completed (monitored by TLC, ∼ 2 min.). After removal of the
solvent under reduced pressure, the residue was extracted with EtOAc
9
b
f
−
1
1
3
3
1
.90 (s, 3H), 3.88 (s, 6H); 13C NMR (100 MHz, CDCl ) δ 153.5,
(
3 × 15 mL), and the combined organic extract was washed with
3
42.3, 118.9, 109.4, 106.7, 61.0, 56.3; HRESI-MS (m/z) Calculated for
water, dried over anhydrous Na SO , and purified by silica gel column
2
4
C H NO (M + Na) 216.0637, found (M + Na) 216.0637.
(
in most of the reactions, the product obtained was NMR pure; further
10 11
3
1,3-Benzodioxole-5-carbonitrile (2g). Prepared as described in
purification was not necessary).
1
4
4
-Nitrobenzonitrile (2a). Prepared as described in the general
the general experimental procedure. White solid: yield 99% (145.5
9
b
experimental procedure. White solid: yield 99% (146.5 mg); mp 148−
mg); mp 83−85 °C (lit. 90−93 °C); R
f
(15% EtOAc/hexane) 0.8;
IR (KBr, cm ) 2223; H NMR (400 MHz, CDCl ) δ 7.21 (d, J = 8.0
Hz, 1H), 7.03 (s, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.07 (s, 2H);
NMR (100 MHz, CDCl ) δ 151.5, 148.0, 128.2, 118.8, 111.3, 109.1,
9
a
−1
1
1
49 °C (lit. 148−149 °C); R (25% EtOAc/hexane) 0.5; IR (KBr,
3
f
−1
1
13
cm ) 2222; H NMR (400 MHz, CDCl ) δ 8.37 (d, J = 8.9 Hz, 2H),
C
3
7
1
.90 (d, J = 8.9 Hz, 2H); 13C NMR (100 MHz, CDCl ) δ 150.0, 133.4,
3
3
+
24.2, 118.3, 116.8; MS (m/z) 148 (M ).
Benzonitrile (2b). Prepared as described in the general
104.9, 102.2; HRESI-MS (m/z) Calculated for C H NO (M + Na)
170.0218, found (M + Na) 170.0218.
8 5 2
9
a
experimental procedure. Colorless liquid: yield 82% (84.4 mg); R
2-Hydroxy-3-methoxybenzonitrile (2h). Prepared as described
f
−1
1
(10% EtOAc/hexane) 0.80; IR (Neat, cm ) 2225; H NMR (400
in the general experimental procedure. Solid: yield 97% (144.5 mg);
Scheme 5. Plausible Mechanism
D
dx.doi.org/10.1021/jo3008258 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
6
mp 55−57 °C (lit. 56−57 °C); R (15% EtOAc/hexane) 0.6; IR
4-Chlorobenzonitrile (2q). Prepared as described in the general
experimental procedure. Purified on a silica gel column (EtOAc/
f
−1
1
(
KBr, cm ) 2220; H NMR (400 MHz, CDCl ) δ 8.69 (s, 1H), 7.30−
3
13
22
7
.21 (m, 2H), 6.99 (s, 1H), 4.05 (s, 3H); C NMR (100 MHz,
hexane, 6:94). White solid: yield 73% (100.0 mg); mp 91−92 °C (lit.
−
1
1
CDCl ) δ 152.9, 146.3, 144.5, 124.9, 123.1, 113.3, 111.0, 56.3; HRESI-
MS (m/z) Calculated for C H NO (M + H) 150.0555 found (M +
90−92 °C); R (15% EtOAc/hexane) 0.7; IR (KBr, cm ) 2226 ; H
3
f
8
7
2
NMR (400 MHz, CDCl ) δ 7.60 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.4
3
Hz, 2H); 13C NMR (100 MHz, CDCl ) δ 139.5, 133.3, 129.7, 117.9,
H) 150.0550.
-Hydroxybenzonitrile (2i). Prepared as described in the general
experimental procedure. Solid: yield 99% (117.8 mg); mp 108−110
3
4
110.8; MS (m/z) 137.
2-Bromobenzonitrile (2r). Prepared as described in the general
1
7
°
C (lit. 107−109 °C); R (15% EtOAc/hexane) 0.65; IR (KBr,
experimental procedure. Solid: yield 93% (169.2 mg); mp 52−55 °C
f
−1 1
22
−1
cm ) 2233; H NMR (400 MHz, CDCl ) δ 7.55 (d, J = 8.8 Hz, 2H);
(lit. 53−54 °C); R (25% EtOAc/hexane) 0.6; IR (KBr, cm ) 2225;
3
f
.94 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl ) δ 160.5, 134.3,
1
6
H NMR (400 MHz, CDCl ) δ 7.70−7.66 (m, 2H), 7.49−7.41 (m,
2H); C NMR (100 MHz, CDCl ) δ 134.3, 133.8, 133.2, 127.6,
3
3
1
19.3, 116.5, 102.5; HRESI-MS (m/z) Calculated for C H NO (M +
H) 120.0449 found (M + H) 120.0452.
-Hydroxy-3,5-dimethoxybenzonitrile (2j). Prepared as de-
scribed in the general experimental procedure. Solid: yield 93% (166.4
13
7
5
3
1
25.3, 117.1, 115.9; MS (m/z) 183 (M + H).
E)-Methyl 3-(2-Cyanophenyl)prop-2-enoate (2s). Prepared as
4
(
described in the general experimental procedure. White solid: yield
1
8
mg); mp 105−106 °C (lit. 107−109 °C); R (15% EtOAc/hexane)
23
f
55% (102.8 mg); mp 94−96 °C (lit. 94 °C); R (25% EtOAc/
f
−1
1
0
2
1
.6; IR (KBr, cm ) 2226; H NMR (400 MHz, CDCl ) δ 6.87 (s,
−1
1
3
hexane) 0.5; IR (KBr, cm ) 2223; H NMR (400 MHz, CDCl ) δ
3
H), 6.02 (s, 1H), 3.92 (s, 6H); 13C NMR (100 MHz, CDCl ) δ
3
7.98 (d, J = 16.0 Hz, 1H), 7.72 (t, J = 8.0 Hz, 2H), 7.63 (t, J = 7.6 Hz,
47.1, 139.3, 119.3, 109.2, 102.2, 56.5; HRESI-MS (m/z) Calculated
for C H NO (M + Na) 202.0480 found (M + Na) 202.0480.
-(Prop-2-en-1-yloxy)benzonitrile (2k). Prepared as described
in the general experimental procedure. Colorless solid: yield 99%
157.4 mg); mp 43−46 °C (lit. 43−44 °C); R (25% EtOAc/hexane)
.5; IR (KBr, cm ) 2218; H NMR (400 MHz, CDCl ) δ 7.57 (d, J =
.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 6.08−5.98 (m, 1H), 5.42 (d, J =
7.2 Hz, 1H), 5.33 (d, J = 10.4 Hz, 1H), 4.59 (dd, J = 0.8 Hz, J = 5.2
Hz, 2H); C NMR (100 MHz, CDCl ) δ 161.8, 133.9, 132.0, 119.1,
18.4, 115.4, 104.0, 68.9; HRESI-MS (m/z) Calculated for C H NO
M + Na) 182.0582, found (M + Na) 182.0580.
-(Prop-2-yn-1-yloxy)benzonitrile (2l). Prepared as described in
the general experimental procedure. White solid: yield 61% (95.7 mg);
1
H), 7.48 (t, J = 7.6 Hz, 1H), 6.61 (d, J = 16.0 Hz, 1H), 3.84 (s, 3H);
13
9
9
3
C NMR (100 MHz, CDCl ) δ 166.2, 139.6, 137.3, 133.5, 132.9,
3
4
1
30.1, 126.9, 122.6, 117.1, 112.7, 52.0; HRESI-MS (m/z) Calculated
for C H NO (M + Na) 210.0531 found (M + Na) 210.0533.
9c
11
9
2
(
f
4
-Cyano-N,N-diethylbenzamide (2t). Prepared as described in
the general experimental procedure. Purified on a silica gel column
EtOAc/hexane, 30:70). White solid: yield 92% (185.8 mg); mp 77−
−1
1
0
8
1
3
(
7
1
2
24
8 °C (lit. 79−80 °C); R (50% EtOAc/hexane) 0.35; IR (KBr,
13
f
3
−1 1
cm ) 2231; H NMR (400 MHz, CDCl ) δ 7.71 (d, J = 8.0 Hz, 2H),
3
1
10 9
7
1
1
.48 (d, J = 8.0 Hz, 2H), 3.55 (br, 2H), 3.20 (br, 2H), 1.26 (br, 3H),
(
.11 (br, 3H); 13C NMR (100 MHz, CDCl ) δ 169.2, 141.4, 132.4,
3
4
27.0, 118.1, 113.0, 43.2, 39.4, 14.2, 12.8; HRESI-MS (m/z)
9
c
Calculated for C12
H N O (M + Na) 225.1004 found (M + Na)
14 2
mp 109−111 °C (lit. 113−114 °C); R (15% EtOAc/hexane) 0.4; IR
f
−1
1
225.1003.
(
KBr, cm ) 2222; H NMR (400 MHz, CDCl ) δ 7.61 (d, J = 8.8 Hz,
3
Methyl 4-Cyanobenzoate (2u). Prepared as described in the
general experimental procedure. Purified on a silica gel column
2
H), 7.04 (d, J = 8.8 Hz, 2H), 4.75 (d, J = 2.0 Hz, 2H), 2.57 (t, J = 2.0
Hz, 1H); C NMR (100 MHz, CDCl ) δ 160.6, 133.9, 118.9, 115.6,
04.9, 76.7, 76.5, 55.9; HRESI-MS (m/z) Calculated for C H NO (M
Na) 180.0425, found (M + Na) 180.0425.
-(Phenylmethyl)benzonitrile (2m). Prepared as described in
the general experimental procedure. Colorless solid: yield 88% (183.9
mg); mp 93−95 °C (lit. 94−96 °C); R (25% EtOAc/hexane) 0.5; IR
KBr, cm ) 2217 ; H NMR (400 MHz, CDCl ) δ 7.58 (d, J = 8.8
Hz, 2H), 7.41−7.35 (m, 5H), 7.01 (d, J = 8.8 Hz, 2H), 5.11 (s, 2H);
C NMR (100 MHz, CDCl ) δ 161.9, 135.6, 134.0, 128.7, 128.4,
27.4, 119.1, 115.5, 104.1, 70.2; HRESI-MS (m/z) Calculated for
C H NO (M + Na) 232.0738, found (M + Na) 232.0736.
-Phenoxybenzonitrile (2n). Prepared as described in the
general experimental procedure. Purified on a silica gel column
EtOAc/hexane, 10:90). Light yellow oil: yield 71% (138.4 mg); R
15% EtOAc/hexane) 0.75; IR (Neat, cm ) 2232 ; H NMR (400
13
3
(
6
2
(
EtOAc/hexane, 10:90). White solid: yield 94% (151.3 mg); mp 67−
1
10 7
25
−1
8 °C (lit. 67−69 °C); R (15% EtOAc/hexane) 0.4; IR (KBr, cm )
f
+
1
231; H NMR (400 MHz, CDCl ) δ 8.14 (d, J = 8.4 Hz, 2H), 7.75
3
4
13
d, J = 8.4 Hz, 2H), 3.96 (s, 3H); C NMR (100 MHz, CDCl ) δ
3
9c
166.4, 133.8, 132.2, 130.0, 117.9, 116.3, 52.7; HRESI-MS (m/z)
f
−1
1
Calculated for C H NO (M + H) 162.0555, found (M + H)
9
7
2
(
3
1
62.0552.
4-Hydroxy-3-nitrobenzonitrile (2v). Prepared as described in
the general experimental procedure. Yellow solid: yield 94% (154.1
1
3
3
1
2
6
mg); mp 141−143 °C (lit. 142−145 °C); R (15% EtOAc/hexane)
0.55; IR (KBr, cm ) 2228; H NMR (400 MHz, CDCl ) δ 10.90 (br,
f
1
4
3
11
−1
1
1
9
3
1
H), 8.48 (s, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H);
1
3
C NMR (100 MHz, CDCl ) δ157.8, 139.5, 133.5, 130.1, 121.7,
3
(
(
f
−1
1
116.6, 104.5; MS (m/z) 164.
-Hydroxy-(1,1-biphenyl)-3-carbonitrile (2w). Prepared as
described in the general experimental procedure. Solid: yield 51%
4
MHz, CDCl ) δ 7.43−7.34 (m, 4H), 7.25−7.18 (m, 3H), 7.02 (d, J =
.0 Hz, 2H); C NMR (100 MHz, CDCl ) δ 158.1, 155.4, 130.6,
30.2, 126.3, 124.7, 122.7, 121.0, 119.7, 118.3, 113.4; HRESI-MS (m/
3
13
8
3
2
7
(
99.4 mg); mp 193−194 °C (lit. 195 °C); R (15% EtOAc/hexane)
1
f
−1
1
0
1
2
1
.6; IR (KBr, cm ) 2225; H NMR (400 MHz, CDCl ) δ 8.77 (s,
z) Calculated for C H NO (M + Na) 218.0582, found (M + Na)
3
1
3
9
H), 7.91 (s, 1H), 7.82 (d, 1H), 7.70 (d, 1H), 7.61 (d, 2H), 7.50 (t,
2
18.0581.
-(N,N-Dimethylamino)benzonitrile (2o). Prepared as described
in the general experimental procedure. Solid: yield 98% (143.0 mg);
H), 7.41 (t, 1H); 13C NMR (100 MHz, CDCl ) δ 161.8, 146.4,
4
3
40.3, 137.7, 130.0, 128.9, 127.5, 127.4, 122.0, 120.0, 109.9; HRESI-
20
MS (m/z) Calculated for C H NO (M + H) 196.0762, found (M +
mp 73−75 °C (lit. 74−75 °C); R (15% EtOAc/hexane) 0.6; IR
13
9
f
−1
1
(
KBr, cm ) 2211; H NMR (400 MHz, CDCl ) δ 7.46 (d, J = 9.2,
H) 196.0760.
3
2
H), 6.64 (d, J = 9.2 Hz, 2H), 3.03 (s, 3H); 13C NMR (100 MHz,
4-Ethanoylbenzonitrile (2x). Prepared as described in the general
CDCl ) δ 154.4, 133.3, 120.7, 111.3, 97.3, 39.9; HRESI-MS (m/z)
Calculated for C H N (M + Na) 169.0742 found (M + Na)
experimental procedure. White solid: yield 98% (142.1 mg); mp 56−
3
9
a
−1
57 °C (lit. 56−58 °C); R
(15% EtOAc/hexane) 0.5; IR (KBr, cm )
2227; H NMR (400 MHz, CDCl ) δ 8.04 (d, J = 8.4 Hz, 2H), 7.78
3
9
10
2
f
1
1
69.0745.
4
13
-Phenylbenzonitrile (2p). Prepared as described in the general
(d, J = 8.4 Hz, 2H), 2.64 (s, 3H); C NMR (100 MHz, CDCl
3
) δ
experimental procedure. White solid: yield 85% (152.1 mg); mp 82−
196.5, 139.9, 132.5, 128.7, 117.9, 116.4, 26.7; MS (m/z) 145.
4-Cyanobenzoic Acid (2y). Prepared as described in the general
21
−1
8
2
7
1
3 °C (lit. 83−84 °C); R (15% EtOAc/hexane) 0.7; IR (KBr, cm )
f
1
226; H NMR (400 MHz, CDCl ) δ 7.73−7.66 (m, 4H), 7.58 (d, J =
experimental procedure. Yellow solid: yield 99% (145.5 mg); mp 208−
3
13
28
.2 Hz, 2H), 7.50−7.40 (m, 3H); C NMR (100 MHz, CDCl ) δ
209 °C (lit. 209−211 °C); R (25% EtOAc/hexane) 0.1; IR (KBr,
f
3
−
1
1
45.6, 139.1, 132.5, 129.0, 128.6, 127.7, 127.2, 118.9, 110.8; HRESI-
cm ) 2231; H NMR (400 MHz, CDCl ) δ 13.51 (br, 1H), 8.07 (d, J
3
= 8.0 Hz, 2H), 7.97 (d, J = 8.0 Hz, 2H); 1 C NMR (100 MHz, CDCl3)
3
MS (m/z) Calculated for C H N (M + Na) 202.0633, found (M +
13
9
Na) 202.0632.
δ 166.4, 135.3, 133.1, 130.3, 118.6, 115.4; MS (m/z) 147.
E
dx.doi.org/10.1021/jo3008258 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
9
a
(
E)-3-Phenylprop-2-enenitrile (3a). Prepared as described in
(3) Datta, S. K.; Grundmann, C.; Bhattacharyya, N. K. J. Chem. Soc. C
1970, 2058.
(4) McEwen, W. E.; Conrad, W. E.; Vanderwerf, C. A. J. Am. Chem.
the general experimental procedure. Colorless liquid: yield 98% (126.4
mg); R (15% EtOAc/hexane) 0.7; IR (Neat, cm ) 2218; H NMR
−1
1
f
(
400 MHz, CDCl ) δ 7.45−7.37 (m, 6H), 5.88 (d, J = 16.8 Hz, 1H);
Soc. 1952, 74, 1168.
3
1
3
C NMR (100 MHz, CDCl ) δ 150.5, 133.4, 131.2, 129.1, 127.3,
(5) (a) Liu, R.; Gutierrez, O; Tantillo, D. J.; Aube,
2012, 134, 6528 and references cited therein. (b) Chaudhry, P.;
Schoenen, F.; Neuenswander, B.; Lushington, G. H.; Aube, J. J. Comb.
Chem. 2007, 9, 473. (c) Forsee, J. E.; Aube, J. J. Org. Chem. 1999, 64,
4381. (d) Frankowski, K. J.; Golden, J. E.; Zeng, Y.; Lei, Y.; Aube, J. J.
Am. Chem. Soc. 2008, 130, 6018. (e) Iyengar, R.; Schildknegt, K.;
Morton, M.; Aube, J. . J. Org. Chem. 2005, 70, 10645.
(6) Moheney, J. M.; Smith, C. R.; Johnston, J. R. J. Am. Chem. Soc.
2005, 127, 1354.
(7) (a) Pavlov, P. A. Chem. Heterocycl. Compd. 2001, 37, 1199 and
references cited therein. (b) Suzuki, H.; Nakaya, C. Synthesis 1992,
́
J. J. Am. Chem. Soc.
3
1
18.1, 96.2; HRESI-MS (m/z) Calculated for C H N (M + H)
9 7
1
30.0657, found (M + H) 130.0653.
E)-3-(4-Methoxyphenyl)prop-2-enenitrile (3b). Prepared as
described in the general experimental procedure. White solid: yield
́
(
́
́
2
9
9
8% (155.8 mg); mp 63−65 °C (lit. 62−65 °C); R (25% EtOAc/
f
−1 1
hexane) 0.65; IR (KBr, cm ) 2213; H NMR (400 MHz, CDCl ) δ
́
3
7
2
.39 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 16.8 Hz, 1H), 6.91 (d, J = 8.8 Hz,
H), 5.71 (d, J = 16.4 Hz, 1H), 3.84 (s, 3H); 13C NMR (100 MHz,
CDCl ) δ 162.0, 150.0, 129.0, 126.3, 118.7, 114.5, 93.3, 55.4; HRESI-
MS (m/z) Calculated for C H NO (M + Na) 182.0582, found (M +
Na) 182.0585.
E)-3-(4-Nitrophenyl)prop-2-enenitrile (3c). Prepared as de-
scribed in the general experimental procedure.Yellowish solid: yield
3
10
9
641. (c) Suzuki, H.; Hwang, Y. S.; Nakaya, C.; Matano, Y. Synthesis
1993, 1218. (d) Nishiyama, K.; Watanabe, A. Chem. Lett. 1984, 13,
773. (e) Nishiyama, K.; Oba, M.; Watanabe, A. Tetrahedron 1987, 43,
(
3
0
9
9% (172.2 mg); mp 198−200 °C (lit. 200−201 °C); R (25%
f
693.
−1 1
EtOAc/hexane) 0.56; IR (KBr, cm ) 2217; H NMR (400 MHz,
(8) (a) The Chemistry of the Cyano Group; Rappoport, Z., Ed.;
CDCl ) δ 8.28 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 8.8 Hz, 2H), 7.48 (d, J
=
CDCl ) δ 149.0, 147.7, 139.1, 128.1, 124.3, 117.0, 101.0; MS (m/z)
3
Interscience: New York, 1970. (b) Arseniyadis, S.; Kyler, K. S.; Watt,
D. S. In Organic Reactions; Dauben, W. G., Ed.; Wiley: New York,
1984; Vol. 31, p 1. (c) Fatiadi, A. J. In Preparation and Synthetic
Applications of Cyano Compounds; Patai, S., Rappaport, Z., Eds.; Wiley:
New York, 1983. (d) Larock, R. C. Comprehensive Organic Trans-
formations; VCH: New York, 1989. (e) Kleemann, A.; Engel, J.;
Kutscher, B.; Reichert, D. Pharmaceutical Substance: Synthesis Patents,
Applications, 4th ed.; Georg Thieme: Stuttgart, 2001. (f) Miller, J. S.;
Manson, J. L. Acc. Chem. Res. 2001, 34, 563. (g) Smith, M. B.; March,
J. March’s Advanced Organic Chemistry: Reactions, Mechanisms, and
Structure, 6th ed.; Wiley: Hoboken, NJ, 2007. (h) Kobayashi, Y.;
Kamisaki, H.; Yanada, R.; Takemoto, Y. Org. Lett. 2006, 8, 2711.
13
16.8 Hz, 1H), 6.07 (d, J = 16.8 Hz, 1H); C NMR (100 MHz,
3
1
74.
-Bromocyclohex-1-enecarbonitrile (3d). Prepared as de-
scribed in the general experimental procedure. Colorless liquid: yield
2
−1
1
6
0% (111.6 mg); IR (Neat, cm ) 2211; H NMR (400 MHz, CDCl )
3
C
13
δ 2.62−2.59 (m, 2H), 2.35−2.32 (m, 2H), 1.79−1.69 (m, 4H);
NMR (100 MHz, CDCl ) δ 138.3, 118.1, 113.7, 36.2, 29.5, 23.2, 20.7;
3
HRESI-MS (m/z) Calculated for C H BrN (M + Na) 207.9738, found
7
8
(
M + Na) 207.9737.
Typical Procedure for Gram Scale Synthesis of 4-Nitro-
benzonitrile (2a). Triflic acid (30 mmol, 2.63 mL) was added
dropwise during 10 min (Caution! reaction is exothermic) to a well-
stirred solution of aldehyde (10 mmol, 1.51 g), sodium azide (975 mg,
(
i) Kobayashi, Y.; Harayama, T. Org. Lett. 2009, 11, 1603.
9) (a) Lamani, M.; Prabhu, K. R. Angew. Chem., Int. Ed. 2010, 49,
622. (b) Lamani, M.; Devadig, P.; Prabhu, K. R. Org. Biomol. Chem.
012, 10, 2753. (c) Rokade, B. V.; Malekar, S. K.; Prabhu, K. R. Chem.
(
6
2
1
5 mmol) in CH CN (10 mL), and the mixture was stirred at room
3
temperature until the reaction was completed (monitored by TLC, ∼2
min.). After removal of the solvent under reduced pressure, the residue
was extracted with EtOAc (3 × 30 mL), and the combined organic
extract was washed with water, dried over anhydrous Na SO , and
Commun. 2012, 48, 5506.
10) The reaction of 4-nitrobenzaldehyde, NaN , and TfOH in
(
3
MeOH produced the corresponding dimethyl acetal along with
unreacted starting material.
2
4
purified by silica gel column using EtOAc/hexane (10:90) to furnish
colorless solid 2a (1.40 g, 95%).
(
11) Solvent screening studies with solvents such as CHCl , CH Cl ,
3 2 2
THF, toluene, EtOAc, MeOH, or DMF are carried out for only for 2
min, and the reactions were worked up. This is due to the reason that
the reaction of 4-nitrobenzaldehyde, NaN , and TfOH in CH CN was
ASSOCIATED CONTENT
■
3
3
*
S
Supporting Information
complete almost instantaneously.
1
13
Characterization data (including H and C NMR spectra) for
all products. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) (a) Salnikov, G. E.; Genaev, A. M.; Vasiliev, V. G.; Shubin, V. G.
Org. Biomol. Chem. 2012, 10, 2282. (b) Hojo, M.; Ueda, T.; Ike, M.;
Okamura, K.; Sugiyama, T.; Kobayashi, M.; Nakai, H. J. Chem. Eng.
Data 2010, 55, 1986.
(
13) In the control experiments, it was observed that the reaction of
AUTHOR INFORMATION
■
triflic acid with aldehyde 1a in CH CN is almost instantaneous (1
min) to furnish the product 2a in quantitative yield. However, the
same reaction of 1a with other acids including concentrated H SO in
CH CN did not furnish the nitrile 2a (see entries 2−7, Table 1).
Therefore, we believe that acidity of acids used in this reaction plays a
major role. Hence, triflic acid, which is a stronger acid than all other
acids (pK is ∼ −15), works well for this reaction to form only the
nitrile.
3
Corresponding Author
Telephone: +91-80-22932887. Fax: +91-80-23600529. E-mail:
prabhu@orgchem.iisc.ernet.in.
*
2
4
3
Notes
The authors declare no competing financial interest.
a
ACKNOWLEDGMENTS
(
14) Kim, J.; Choi, J.; Shin, K.; Chang, S. J. Am. Chem. Soc. 2012, 134,
■
2
528.
The authors thank Indian Institute of Science and CSIR for
financial support of this investigation and Dr. A. R. Ramesha for
useful discussions. B.V.R. thanks CSIR for a fellowship.
(15) Ali-Akbar, P. Synthesis 1983, 717.
(
16) Stanislav, R.; Petr, H.; Jitka, U.; Petr, V.; Ivan, K. Collect. Czech.
Chem. Commun. 2000, 65, 280.
17) Molander, G. A.; Cavalcanti, L. N. J. Org. Chem. 2011, 76, 623.
(
REFERENCES
■
(18) Magano, J.; Chen, M. H.; Clark, J. D.; Nussbaumer, T. J. Org.
Chem. 2006, 71, 7103.
(19) Soula, G. J. Org. Chem. 2011, 76, 623.
(20) Ishii, G.; Moriyama, K.; Togo, H. Tetrahedron Lett. 2011, 52,
2404.
(
1) (a) Schmidt, K. F. Z. Angew. Chem. 1923, 36, 511. (b) Schmidt,
K. F. Chem. Ber. 1924, 57, 704. (c) Koldobskii, G. I.; Ostrovskii, V. A.;
Gidaspov, B. V. Russ. Chem. Rev. 1978, 47, 1084.
(
2) Smith, P. A. S.; Horwitz, J. P. J. Am. Chem. Soc. 1950, 72, 3718.
F
dx.doi.org/10.1021/jo3008258 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(
21) Fan, X.-H.; Yang, L.-M. Eur. J. Org. Chem. 2011, 8, 1467.
(
22) Lee, Y. M.; Moon, M. E.; Vajpayee, V.; Chi, K.-W.; Filimonov,
V. D. Tetrahedron 2010, 66, 7418.
(
(
(
23) Elvidge, J. J. Chem. Soc. C 1967, 2059.
24) Ecanow, G. J. Am. Pharm. Assoc. 1957, 46, 315.
25) Ren, Y.; Wang, W.; Zhao, S.; Tian, X.; Wang, J.; Yin, W.; Cheng,
L. Tetrahedron Lett. 2009, 50, 4595.
26) Lok, R.; Leone, R. E.; Williams, A. J. J. Org. Chem. 1996, 61,
289.
(
3
(
27) Mathur. J. Sci. Ind. Res., Sect. B 1960, 19, 351.
(28) Li-Qian, C.; Kai, L.; Chi, Z. Org. Biomol. Chem. 2011, 9, 2258.
(29) Qin, C.; Jiao, N. J. Am. Chem. Soc. 2010, 132, 15893.
(30) Zhou, W.; Xu, J.; Zhang, L.; Jiao, N. Org. Lett. 2010, 12, 2888.
G
dx.doi.org/10.1021/jo3008258 | J. Org. Chem. XXXX, XXX, XXX−XXX