Synthesis of Nitriles from Primary Amides or Aldoximes under Conditions of a Catalytic Swern Oxidation

Article abstract of DOI:10.1021/acs.joc.8b02190

The preparation of nitriles from primary amides or aldoximes was achieved by using oxalyl chloride with a catalytic amount of dimethyl sulfoxide in the presence of Et₃N. The reactions were complete within 1 h after addition at room temperature. A diverse range of cyano compounds were obtained in good to excellent yields, including aromatic, heteroaromatic, cyclic, and acyclic aliphatic species.

Full text of DOI:10.1021/acs.joc.8b02190

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Note
Synthesis of Nitriles from Primary Amides or Aldoximes
under Conditions of a Catalytic Swern Oxidation
Rui Ding, Yongguo Liu, Mengru Han, Wenyi Jiao, Jiaqi Li, Hongyu Tian, and Baoguo Sun
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02190 • Publication Date (Web): 21 Sep 2018
Downloaded from http://pubs.acs.org on September 21, 2018
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Synthesis of Nitriles from Primary Amides or Aldoximes under Conditions of a Catalytic
Swern Oxidation
Rui Ding, Yongguo Liu, Mengru Han, Wenyi Jiao, Jiaqi Li, Hongyu Tian* and Baoguo Sun*
Beijing Advanced Innovation Center for Food Nutrition and Human Health, Beijing Key
laboratory of Flavor Chemistry, Beijing Technology and Business University, Beijing, China,
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100048
Telephone and Fax: +8610 68984545
Eꢀmail Address: tianhy@btbu.edu.cn and sunbg@btbu.edu.cn
ABSTRACT: The preparation of nitriles from primary amides or aldoximes was achieved by
using oxalyl chloride with a catalytic amount of dimethyl sulfoxide in the presence of Et N. The
3
reactions were complete within 1 h after addition at room temperature. A diverse range of cyano
compounds were obtained in good to excellent yields, including aromatic, heteroaromatic, cyclic
and acyclic aliphatic species.
O
R
N
(COCl)
2
S
Me
Me
1 mol %
OH
H
Me
O
N
S
Cl
2
CO + CO
Me Cl-
R
NH
2
R
From amides, 16 examples, 76-96% yield
From aldoximes, 6 examples, 87-95% yield
Nitriles are important organic compounds either as versatile precursors in synthesis or as
valuable end products. The cyano group can be easily converted to other functional groups, such
1
as carboxyl derivatives, amines, ketones and various heterocycles. Many cyanated compounds
2
display attractive applications as pharmaceuticals, agrochemicals, or fragrances. A plethora of
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methods for the synthesis of nitriles has been developed over the past century, which can be
divided into two classes, one involving introduction of a cyano group with inorganic or organic
3
cyanating reagents and the other involving creation of a cyano group by chemical transformation
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of other functional groups.
The dehydration of amides or aldoximes is the most commonly used approaches for the
creation of a cyano group by far. A wide variety of reagents have been described for the
5
transformation of primary amides or aldoximes to nitriles. However, many of these existing
methods suffer from more or less drawbacks, such as drastic reaction conditions, limited substrate
scope, not readily available reagents, poor yields and long reaction time. Several attractive
methods have been reported recently, in which the dehydration of primary amides or aldoximes
6
could be achieved via catalysis under mild conditions. It is worth highlighting that a highly
efficient catalytic Appelꢀtype dehydration of amides to nitriles has been developed by Malkov and
Rubtsov using oxalyl chloride and triethylamine along with triphenylphosphine oxide as a
6b
catalyst.
The combination of DMSO and oxalyl chloride has been used widely in the oxidation of
7
primary and secondary alcohols since Swern reported this method at first in 1978. In addition, it
was also very efficient for other transformations, such as methylthiomethyl esterification of
8
9
carboxylic acids and dehydration of primary amides. In our recent work, novel application of the
combined reagents of R
2
SO (R = Me or Ph) and (COX)
2
(X = Cl or Br) has been developed, such
1
0
11
as sulfenllactonization and chlorolactonization of alkenoic acids, bromination of alkenes,
12
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alkynes and ketones, and preparation of α,βꢀunsaturated γꢀlactones. We noticed that primary
amides could be dehydrated to afford nitriles under Swern oxidation conditions, however DMSO
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and (COCl) were used in stoichiometric amounts and the reactions needed to be carried out at ꢀ78
2
o
9
C. Obviously, it is very inconvenient to run reactions at such a low temperature. The work of
6b
Malkov and Rubtsov inspired us that the dehydration of amides or aldoximes may be able to be
achieved under conditions of a catalytic Swern oxidation at room temperature. Herein, we report
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the successful results of the dehydration of amides or aldoximes to afford nitriles with (COCl)
2
and a catalytic amount of DMSO in the presence of Et N at room temperature (Scheme 1).
3
O
2
(COCl) (1.2 equiv)
Et N (2.5 equiv)
3
R
NH
2
DMSO (1 mol %)
or
R
N
OH
MeCN, rt
N
From amides,
76-96% yield
R
H
From aldoximes, 87-95% yield
Scheme 1. Dehydration of Amides or Aldoximes to Nitriles by a Catalytic Swern Oxidation
The investigation started with employing benzamide (1a) as a model substrate (Table 1). First,
the experiment was carried out under the conditions mimicking those in the protocol from amides
6
b
to nitriles developed by Malkov and Rubtsov, in which 2 equiv of oxalyl chloride in anhydrous
MeCN was added dropwise to the solution of 1a, 1 mol % DMSO, and 3 equiv of Et N in
3
anhydrous MeCN at rt (entry 1). The reaction was complete in 10 min to produce benzonitrile (2a)
almost quantitatively. A reaction was also carried out in the absence of Et
benzonitrile (2a) was detected by GCMS even stirring for 24 h at rt (entry 2). Another experiment
was performed under the conditions similar to those in entry 1 except that 3 equiv of Et N was
3
N, in which only trace
3
added to the reaction mixture at last (entry 3). The conversion of benzonitrile (2a) was only 1%
after stirring for 24 h at rt, which was similar to that in entry 2. These results indicated that it was
feasible that the dehydration of an amide was carried out under the conditions of a catalytic Swern
3
oxidation at rt, in which Et N was needed to be added to the reaction mixture in advance. One
2 3
more experiment was carried out to optimize the amounts of (COCl) and Et N, in which they
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were reduced to 1.2 equiv and 2.5 equiv respectively (entry 4). It was observed that the reaction
underwent slightly slower than that in entry 1, but produced the desired nitrile 2a in a very close
yield. The reaction was also tried in the absence of DMSO, but no product was detected (entry 5).
This result indicated that DMSO is indispensable for the reaction, which is consistent with that
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reported by Nakajima and Ubukata. In addition, two more bases were examined to see if they
could promote this reaction. No product was obtained in the presence of DBU (entry 6), whereas
the reaction gave the desired nitrile in 58% yield in the presence of NMM (entry 7). In comparison,
Et
3
N is the most effective base for this conversion.
Table 1. Optimization of the Reaction Conditions of Dehydration of amides
O
N
NH2
1
a
2a
Entry DMSO (COCl)
2
base (equiv)
Time
Yield
(%)
(
equiv) (equiv)
a
1
2
3
4
5
6
7
0.01
0.01
0.01
0.01
0
2.0
2.0
2.0
1.2
1.2
1.2
1.2
Et
3
N (3.0)
0
10 min
24 h
92
b
1
b,c
Et
3
3
N (3.0)
N (2.5)
24 h
1
a
Et
40 min
24 h
90
b
Et N (2.5)
3
0
b
0.01
0.01
DBU (2.5)
NMM (2.5)
24 h
0
b
24 h
58
a
b
Isolation yield after chromatographic purification. Determined
c
by GCMS. The only difference against the conditions of entry
1 was that Et N was added at last.
3
The dehydration of more amides was explored under the conditions the same as those in
entry 4 of Table 1. The results were shown in Table 2. Three benzamides with substituted groups
on the phenyl ring (1bꢀd) were converted to the corresponding benzonitriles (2bꢀd) in good to
excellent yields, regardless of whether they bore electronꢀwithdrawing group (2b, 2d) or
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electronꢀdonating group (2c). Among the aromatic amides, 1d with two electronꢀwithdrawing
nitro groups on the phenyl ring afforded the nitrile in the lowest yield of 80%. Two heterocyclic
amides 1e and 1f was then investigated. 2ꢀCyanothiophene 2e and 3ꢀcyanopyridine 2f were
obtained in 89% and 90% yields respectively. The dehydration of 2ꢀnaphthamide 1h gave
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5
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0
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9
0
1
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9
0
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8
9
0
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2
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9
0
1
2
3
4
5
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7
8
9
0
2
ꢀcyanonaphthalene 2h in a high yield of 96%. Likewise, the unsaturated cinnamamide 1g was
also converted smoothly to the nitrile 2g in 92% yield. In addition, aliphatic linear (1i, 1j, 1k),
cyclic (1l) and branched (1m, 1n) amides were dehydrated to produce the corresponding nitriles
2
iꢀn in 80ꢀ87% yields, which were slightly lower than those from the above unsaturated amides.
Phenylꢀprotected αꢀhydroxy amide 1k was also compatible substrate, which gave the desired
nitrile 2k in 80% yield. The same protocol also was tried to apply to the two αꢀamino amides 1o
and 1p with Boc and Cbz protective groups respectively, the corresponding nitriles 2o and 2p
were obtained in 83% and 76% yields respectively with the protective groups intact. Moreover,
the specific rotation values of the products indicated that no racemization occurred during the
dehydration process. Most of the substrates included in Table 2 were also investigated in the work
6
b
of Malkov and Rubtsov. For these substrates, the yields obtained in our work are comparable
with those by the method of a catalytic Appel reaction. In addition, an acidꢀsensitive
Bocꢀprotected substrate 1o was converted to the corresponding nitrile in a good yield in our work,
whereas it was mentioned that Bocꢀprotected amino acids could not be converted to the desired
6
b
nitriles under the conditions of a catalytic Appel reaction.
Table 2. The Dehydration of Amides to Nitriles under the Conditions of a Catalytic Swern
Oxidation
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(COCl)2 (1.2 equiv)
3
Et N (2.5 equiv)
O
DMSO (1 mol %)
R
N
R
NH
N
2
MeCN, rt, 40 min
1
2
N
N
R
0
1
2
3
4
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0
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S
e, 89%
N
2
2f, 90%
R = H,
R = o-Br,
2a, 92%
2b, 95%
2c, 95%
N
N
R = p-OMe,
R = 3,5-dinitro, 2d, 80%
2g, 92%
2l, 87%
2h, 96%
N
N
N
N
R
R = nC
Ph
4
H
9
, 2i, 80%
2j, 83%
R = PhO, 2k, 80%
R = Ph,
2m, 87%
N
N
NHBoc
NHCbz
2p, 76%
2
n, 82%
2o, 83%
Among these substrates mentioned above, some of them were also examined by Nakajima
9
and Ubukata under Swern oxidation conditions with stoichiometric use of DMSO, including 1c,
1
d, 1g, 1h, 1l, and 1p. Except pꢀmethoxybenzamide 1c with a similar yield and
3
,5ꢀdinitrobenzamide 1d with a lower yield, the other amides were converted to the corresponding
9
nitriles in higher yields in our work. In the work of Nakajima and Ubukata, all the reactions were
o
o
2
carried out at ꢀ78 C or ꢀ78 C to rt with the combination of stoichiometric amounts of (COCl) ,
3 3 2
DMSO and Et N, in which the addition of Et N could be done either with (COCl) at the same
time or at last without any effect on yields. In contrast, the reactions were able to be performed at
rt mildly due to the usage of catalytic amount of DMSO in our present work. It was noteworthy
that it was necessary that Et N was added to the reaction mixture in advance in our protocol,
3
3
which was supposed that Et N acted as base to eliminate the intermediates to release DMSO
required for the next reaction cycle. The possible mechanistic pathway for the dehydration of
amides under catalytic Swern oxidation conditions was proposed as follows (Scheme 2). DMSO
(
A) reacted with (COCl)
2
to produce the intermediate chlorodimethylsulfonium chloride (B),
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which was attacked by the oxygen of an amide through a nucleophilic substitution in the presence
3 3
of Et N to give the intermediate C. It was then deprotonated by Et N to generate the intermediate
D, which underwent elimination to afford the corresponding nitrile and release DMSO (A) to enter
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
the next cycle. No product was obtained when Et N was replaced by DBU, which might be due to
14
the reaction between DBU and (COCl)
2
.
In contrast, NMM gave the desired product in a lower
yield for longer reaction time than Et N, which indicated that the elimination of the intermediate C
3
to the nitrile is the rateꢀlimiting step influenced by the basicity of the amine.
There is alternative possible pathway for the transformation of the intermediate C to nitrile,
i.e. the deprotonation may occur on the methyl group to give the intermediate E, which undergoes
a retroꢀheteroꢀene reaction to generate nitrile. In order to clarify the mechanism, DMSOꢀd6 was
used for the dehydration of benzamide (1a) and the reaction mixture was analyzed by GCꢀEIMS
after the reaction completed. Compared with the mass spectrum of DMSOꢀd6, the major fragment
ion peaks in the spectrum of DMSO in the reaction mixture are similar to those of the standard
DMSOꢀd6. However, two additional minor peaks at m/z 83 and 63 both with an intensity of 2.6%
appear in the mass spectrum of DMSO in the reaction mixture, which indicates that a little amount
of DMSOꢀd6 was converted into DMSOꢀd5 after the reaction. These results indicate that the
transformation of the intermediate C to nitrile occurs mainly by an E2 mechanism, but doesn’t
exclude a retroꢀheteroꢀene mechanism to some extent.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
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3
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R
N
(COCl)
2
O
S
Me
Me
A
CO
2
+ CO
CH
S
3
Me
Me
CH
2
S
O
or
Me
E
O
S
Cl
Cl
B
D
Me
-
R
N
H
R
N
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
.
3
+ Et N
Et
3
N HCl
Me
S
R
NH
2
Me
O
.
Et
3
N
R
NH
Cl-
3
Et N HCl
C
Scheme 2. Possible Mechanistic Pathway for the Dehydration of Amides under Catalytic Swern
Oxidation Conditions
The application scope of the present method was further explored by transforming aldoximes
to the nitriles. The dehydration of benzaldehyde oxime (3a) was investigated under different
conditions in order to optimize reaction conditions (Table 3). The reaction failed to produce
benzonitrile (2a) in the presence of (COCl) only if without DMSO (entry 1). 3a was able to be
2
converted into 2a thoroughly after 24 h by treatment with 0.05 equiv of DMSO and 1.5 equiv of
2 3
(COCl) in the absence of base (entry 3). The addition of Et N (3.0 equiv) reduced the reaction
time from 24 h to 20 min (entry 4). The amounts of reagents were optimized further. The reaction
completed in 1 h to produce 2a in 93% isolated yield in the presence of 0.01 equiv of DMSO, 1.2
equiv of (COCl) and 2.5 equiv of Et N (entry 5). DBU and NMM were also tried to replace Et N
2
3
3
to promote the dehydration of 3a. No nitrile was obtained in the presence of DBU (entry 6). In
contrast, the nitrile was obtained in the presence of NMM in a yield comparable with Et N but in a
3
little longer reaction time of 2 h (entry 7). These results were similar to those obtained from the
dehydration of amides.
Table 3. Optimization of the Reaction Conditions of Dehydration of Aldoximes
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OH
N
N
H
3a
2a
Entry
DMSO
(COCl)
2
base (equiv)
Time
Yield
(%)
(
equiv)
0
(equiv)
1.5
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
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3
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4
4
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4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
1
2
3
4
5
6
7
0
24 h
30 min
24 h
0%
a
0.01
0.05
0.05
0.01
0.01
0.01
1.2
0
2%
a
1.5
0
100%
100%
a
1.5
TEA (3.0)
TEA (2.5)
DBU (2.5)
NMM (2.5)
20 min
1 h
b
1.2
93%
a
1.2
24 h
0%
a
1.2
2 h
100%
a
b
Determined by HNMR. Isolation yield after chromatographic
purification.
The other five aldoximes underwent dehydration under the above optimized conditions,
including oꢀbromobenzaldehyde oxime 3b, thiopheneꢀ2ꢀcarbaldehyde oxime 3c,
transꢀcinnamaldehyde oxime 3g, cyclohexanecarboxaldehyde oxime 3l and 3ꢀphenylpropanal
oxime 3q. The results are shown in Table 4. All these substrates were converted to the
corresponding nitriles in high yields and the reactions were complete in 1 h. Yadav et al. reported
that bromodimethylsulfonium bromide was used to convert aldoximes and primary amides to
5
a
nitriles, in which it was claimed that the presence of a base slowed the dehydration of aldoximes.
In contrast, it was observed that the reactions of all the aldoximes in our work were very slow in
3
the absence of Et N and completed in 5ꢀ48 h. The possible mechanistic pathway for the
dehydration of aldoximes is shown in Scheme 3, which is similar to the catalytic cycle above for
the dehydration of amides. The presence of Et N is crucial for the regeneration of DMSO, which
3
is necessary for the next reaction cycle.
Table 4. The Dehydration of Aldoximes to Nitriles under the Conditions of a Catalytic Swern
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2
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2
2
2
2
2
2
2
3
3
3
3
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3
3
3
3
4
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5
5
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5
5
5
5
6
Oxidation
(
2
COCl) (1.2 equiv)
Et N (2.5 equiv)
3
OH
H
N
DMSO (1 mol %)
R
N
R
MeCN, rt, 1 h
3
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
N
N
N
S
Br
2
a, 93%
2b, 93%
2e, 95%
N
N
N
N
2
g, 95%
2l, 89%
2q, 95%
R
O
S
(
COCl)
2
Me
Me
A
CO2 + CO
Me
Me
Me
N
Me
S
Cl
B
S
Cl-
O
Cl-
Et
3
N
+
R
H
OH
F
N
.
+
Et N
3
Et
3
N HCl
R
H
Scheme 3. Possible Mechanistic Pathway for the Dehydration of Aldoximes under Catalytic
Swern Oxidation Conditions
In the Denton et al.’s work about the dehydration of oximes using oxalyl chloride in
combination 5 mol % of Ph
oxime ester generated from the reaction of oxime and oxalyl chloride as intermediate, which was
then converted to nitrile by Ph PO or chlorophosphonium salt. In order to explore the possibility
3
PO, a catalytic cycle was proposed involving the activated mono
3
of the similar pathway, two more experiments were carried out, in which benzamide 1a or
benzaldehyde oxime 3a reacted with 1.5 equiv of oxalyl chloride first for 5 h at room temperature
and then 0.05 equiv of DMSO was added. In the case of benzamide 1a, no product was detected
after 24 h. In contrast, benzaldehyde oxime 3a was converted to the desired nitrile in 90% yield
after stirring for 6 h. These results indicated that for oximes, a catalytic cycle involving the
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activated mono oxime ester (G) was possible (Scheme 4). However, in the case of amides, the
mechanism shown in Scheme 2 is more reasonable.
Me
S
O
S
O
Me
A
O
N
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Me
Me
O
A
O
H
Cl
-
Cl
2
CO + CO + HCl
O
N
O
R
R
N
O
H
Cl
Me
O
R
S
O
Cl
B
Me
Me
G
Me
O
H
Cl-
S
Cl
Cl-
N
2
CO + CO + HCl
B
R
Scheme 4. Possible Mechanistic Pathway for the Dehydration of Aldoximes through the Activated
Mono Oxime Ester
In conclusion, a highly efficient preparation method of nitriles from primary amides or
aldoximes has been developed using the combination of oxalyl chloride and triethylamine with a
catalytic amount of DMSO. This approach has several advantages, such as simple operation, mild
conditions, high yields, short reaction time. It offers a practical alternative for the preparation of
nitriles by the dehydration of primary amides or aldoximes. The investigation about the generality
of this method is still ongoing in our lab.
EXPERIMENTAL SECTION
1
General Information. NMR spectra were obtained on a Bruker AV 300 spectrometer ( H
13
NMR at 300 MHz, C NMR at 75 MHz) in CDCl using TMS as an internal standard. Chemical
3
shifts (δ) were given in ppm and coupling constants (J) in Hz. GCꢀMS data were obtained on an
Agilent 7890B‐5977A under the following conditions: capillary column HPꢀ5MS 5% Phenyl
Methyl Silox (30 m × 0.25 mm × 0.25 um); the oven temperature was programmed from 50 °C to
150 °C at a rate of 15 °C/min, then 10 °C to 280°C at a rate of 10 °C/min; carrier gas, helium;
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
flow rate, 1.2 mL/min; electron ionization, 70 eV; ion source temperature, 230 °C. TLC was
performed with precoated TLC plates, silica gel 60Fꢀ254, layer thickness 0.25 mm. Flash
chromatography separations were performed on 200ꢀ300 mesh silica gel. Reagents and solvents
are commercial grade and were used as supplied. Amides (1a-p), and aldoximes (3a, 3b, 3e and 3g)
are commercially available and were purchased from Innochem; the other aldoximes (3l and 3q)
were synthesized in our lab.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
General Procedure for Dehydration of Primary Amides or Aldoximes to Nitriles
Amide 1 (3 mmol, 1.0 equiv) or aldoxime 3 (3 mmol, 1.0 equiv) was dissolved in 10 mL of
anhydrous acetonitrile, followed by addition of DMSO (2.5 mg, 0.03 mmol, 0.01 equiv) and Et
3
N
(1.04 mL, 7.5 mmol, 2.5 equiv). Oxalyl chloride (0.31 mL, 3.6 mmol, 1.2 equiv) in anhydrous
o
acetonitrile (5 mL) was added dropwise at 20 C and stirred at room temperature. After completion
of reaction as indicated by TLC or GCMS, the mixture was filtered and concentrated in vacuum.
Distilled water (15 mL) was added and the mixture was extracted with EtOAc (3 x 10 mL) and
2 4
combined extracts were washed with brine (2 x 20 mL), dried over anhydrous Na SO , filtered,
and concentrated in vacuum. Purification by flash chromatography (silica gel, petroleum
ether/ethyl acetate = 9:1) afforded the corresponding nitrile 2.
General Procedure for Synthesis of Aldoximes from Aldehydes
To a mixture of an aldehyde (10 mmol, 1.0 equiv) and hydroxylamine hydrochloride (1.38 g,
20 mmol, 2.0 equiv) in anhydrous dichloromethane (30 mL) was added pyridine (3.22 mL, 40
mmol, 4.0 equiv). The mixture was stirred for 24 h at room temperature. HCl (aq. 2.0 M, 30 mL)
was added to the reaction mixture and the solution was extracted with dichloromethane (3 x 30
2 4
mL). The combined extracts were washed with brine (50 mL), dried over anhydrous Na SO ,
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filtered, and concentrated in vacuum to give the corresponding aldoxime 3.
Analytical Data
6b
1
Benzonitrile (2a) Colorless oil, 285 mg, 92% yield. H NMR (300 MHz, CDCl ) δ 7.68 –
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
7
.64 (m, 2H, Hꢀoꢀphenyl), 7.64 – 7.58 (m, 1H, Hꢀpꢀphenyl), 7.50 – 7.44 (m, 2H, Hꢀmꢀphenyl).
NMR (75 MHz, CDCl ) δ 132.9 (Cꢀpꢀphenyl), 132.3 (Cꢀoꢀphenyl), 129.2 (Cꢀmꢀphenyl), 119.0
(CꢀCN), 112.6 (C1ꢀphenyl).
3
-Bromobenzonitrile (2b) White solid, 516 mg, 95% yield. H NMR (300 MHz, CDCl ) δ
C
3
15
1
2
7.70 – 7.64 (m, 2H, HꢀC3ꢀphenyl and HꢀC6ꢀphenyl), 7.49 – 7.39 (m, 2H, HꢀC4ꢀphenyl and
13
HꢀC5ꢀphenyl). C NMR (75 MHz, CDCl
3
) δ 134.4 (C6ꢀphenyl), 134.0 (C4ꢀphenyl), 133.3
(
C3ꢀphenyl), 127.8 (C5ꢀphenyl), 125.4 (C2ꢀphenyl), 117.2 (CꢀCN), 116.0 (C1ꢀphenyl). The NMR
peak assignments were confirmed by the HMQC and HMBC spectra.
6
b
1
4
3
-Methoxybenzonitrile (2c) White solid, 380 mg, 95% yield. H NMR (300 MHz, CDCl )
1
3
δ 7.61 – 7.56 (m, 2H, Hꢀoꢀphenyl), 6.97 – 6.93 (d, 2H, Hꢀmꢀphenyl), 3.86 (s, 3H, HꢀOCH3).
C
3
NMR (75 MHz, CDCl ) δ 163.0 (Cꢀpꢀphenyl), 134.1 (Cꢀoꢀphenyl), 119.4 (CꢀCN), 114.9
3
(Cꢀmꢀphenyl), 104.2 (C1ꢀphenyl), 55.7 (CꢀOCH ).
1
3
3
,5-Dinitrobenzonitrile (2d) White solid, 463 mg, 80% yield. H NMR (300 MHz, CDCl ) δ
13
9.27 (t, J = 2.1 Hz, 1H, Hꢀpꢀphenyl), 8.85 (d, J = 2.1 Hz, 2H, Hꢀoꢀphenyl). C NMR (75 MHz,
CDCl ) δ 149.0 (Cꢀmꢀphenyl), 132.1 (Cꢀoꢀphenyl), 122.8 (Cꢀpꢀphenyl), 116.0 (CꢀCN), 114.7
3
(
C1ꢀphenyl).
Thiophene-2-carbonitrile (2e) Colorless oil, 292 mg, 89% yield. H NMR (300 MHz,
CDCl ) δ 7.65 – 7.63 (m, 1H, HꢀCꢀ3), 7.61 (dd, J = 5.1, 1.2 Hz, 1H, HꢀCꢀ5), 7.14 (dd, J = 5.1, 3.6
6b
1
3
13
3
Hz, 1H, HꢀCꢀ4). C NMR (75 MHz, CDCl ) δ 137.5 (Cꢀ3), 132.7 (Cꢀ5), 127.7 (Cꢀ4), 114.3
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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5
6
(
CꢀCN), 110.0 (Cꢀ2). The NMR peak assignments were confirmed by the HMQC and HMBC
spectra.
Nicotinonitrile (2f) White solid, 281 mg, 90% yield. H NMR (300 MHz, CDCl
6b
1
3
) δ 8.89 (d,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
J = 1.2 Hz, 1H, HꢀCꢀ2), 8.82 (dd, J = 4.8, 1.8 Hz, 1H, HꢀCꢀ6), 7.96 (dt, J = 7.8, 1.8 Hz, 1H,
13
HꢀCꢀ4), 7.44 (ddd, J = 7.8, 4.8, 0.9 Hz, 1H, HꢀCꢀ5). C NMR (75 MHz, CDCl
3
) δ 153.1 (Cꢀ6),
1
52.6 (Cꢀ2), 139.3 (Cꢀ4), 123.7 (Cꢀ5), 116.6 (CꢀCN), 110.3 (Cꢀ3). The NMR peak assignments
were confirmed by the HMQC spectrum.
6b
1
Cinnamonitrile (2g) Colorless oil, 357 mg, 92% yield. H NMR (300 MHz, CDCl
3
) δ 7.48
7.37 (m, 6H, Hꢀphenyl and HꢀCHPh), 5.88 (d, J = 16.8 Hz, 1H, HꢀCHCN). C NMR (75 MHz,
CDCl ) δ 150.7 (CꢀCHPh), 133.6 (C1ꢀphenyl), 131.3 (Cꢀpꢀphenyl), 129.2 (Cꢀmꢀphenyl), 127.4
13
–
3
(Cꢀoꢀphenyl), 118.2 (CꢀCN), 96.4 (CꢀCHCN).
15
1
2
-Naphthonitrile (2h) White solid, 441 mg, 96% yield. H NMR (300 MHz, CDCl
3
) δ 8.24
(s, 1H, HꢀCꢀ1), 7.94 – 7.88 (m, 3H, HꢀCꢀ4, HꢀCꢀ5 and HꢀCꢀ8), 7.69 – 7.57 (m, 3H, HꢀCꢀ3, HꢀCꢀ6
13
and HꢀCꢀ7). C NMR (75 MHz, CDCl
3
) δ 134.8 (Cꢀ4a), 134.3 (Cꢀ1), 132.4 (Cꢀ8a), 129.3, 129.2,
1
28.6, 128.2, 127.8, 126.5 (Cꢀ3, Cꢀ4, Cꢀ5, Cꢀ6, Cꢀ7 and Cꢀ8), 119.4 (CꢀCN), 109.6 (Cꢀ2).
1
6
1
Hexanenitrile (2i) Colorless oil, 233 mg, 80% yield. H NMR (300 MHz, CDCl ) δ 2.33 (t,
3
J = 7.2 Hz, 2H, HꢀCꢀ2), 1.71 – 1.62 (m, 2H, HꢀCꢀ3), 1.49 – 1.32 (m, 4H, HꢀCꢀ4 and HꢀCꢀ5), 0.92
13
(
t, J = 7.2 Hz, 3H, HꢀCꢀ6). C NMR (75 MHz, CDCl
3
) δ 120.0 (CꢀCN), 30.9 (Cꢀ4), 25.2 (Cꢀ3),
2
2.0 (Cꢀ5), 17.2 (Cꢀ2), 13.8 (Cꢀ6). The NMR peak assignments were confirmed by the HMQC
spectrum.
6b
1
2
-Phenylacetonitrile (2j) Light yellow oil, 291 mg, 83% yield. H NMR (300 MHz, CDCl )
3
13
2 3
δ 7.42 – 7.31 (m, 5H, Hꢀphenyl), 3.75 (s, 2H, HꢀCH ). C NMR (75 MHz, CDCl ) δ 130.0
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(
C1ꢀphenyl), 129.3 (Cꢀoꢀphenyl), 128.2 (Cꢀpꢀphenyl), 128.0 (Cꢀmꢀphenyl), 118.0 (CꢀCN), 23.7
2
(CꢀCH ).
6b
1
2
3
-Phenoxyacetonitrile (2k) Colorless oil, 320 mg, 80% yield. H NMR (300 MHz, CDCl )
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
δ 7.40 – 7.33 (m, 2H, Hꢀmꢀphenyl), 7.13 – 7.07 (m, 1H, Hꢀpꢀphenyl), 7.02 – 6.97 (m, 2H,
13
Hꢀoꢀphenyl), 4.77 (s, 2H, HꢀCH
2
). C NMR (75 MHz, CDCl
3
) δ 156.7 (C1ꢀphenyl), 130.0
(
Cꢀmꢀphenyl), 123.3 (Cꢀpꢀphenyl), 115.1 (Cꢀoꢀphenyl and CꢀCN), 53.7 (CꢀCH2).
1
7
1
Cyclohexanecarbonitrile (2l) Colorless oil, 285 mg, 87% yield. H NMR (300 MHz,
CDCl ) δ 2.61 (tt, J = 8.1, 3.9 Hz, 1H, HꢀCꢀ1), 1.89 – 1.80 (m, 2H, HꢀCꢀ2 and HꢀCꢀ6), 1.77 – 1.63
m, 4H, H′ꢀCꢀ2 and H′ꢀCꢀ6, HꢀCꢀ3 and HꢀCꢀ5), 1.51 – 1.36 (m, 4H, H′ꢀCꢀ3 and H′ꢀCꢀ5, HꢀCꢀ4).
3
(
13
3
C NMR (75 MHz, CDCl ) δ 122.7 (CꢀCN), 29.6 (Cꢀ2 and Cꢀ6), 28.1 (Cꢀ1), 25.3 (Cꢀ4), 24.2 (Cꢀ3
and Cꢀ5). The NMR peak assignments were confirmed by the HMQC spectrum.
6b
1
2
3
-Phenylbutanenitrile (2m) Yellow oil, 379 mg, 87% yield. H NMR (300 MHz, CDCl )
2
δ 7.42 – 7.29 (m, 5H, Hꢀphenyl), 3.74 (t, J = 7.2 Hz, 1H, HꢀCHCN), 2.00 – 1.90 (m, 2H, HꢀCH ),
13
1
.08 (t, J = 7.5 Hz, 3H, HꢀCH
3
). C NMR (75 MHz, CDCl
3
) δ 135.9 (C1ꢀphenyl), 129.1
(
(
Cꢀmꢀphenyl), 128.1 (Cꢀpꢀphenyl), 127.4 (Cꢀoꢀphenyl), 120.9 (CꢀCN), 39.0 (HꢀCHCN), 29.3
CꢀCH ), 11.6 (CꢀCH ). The NMR peak assignments were confirmed by the HMBC spectrum.
2
3
1
5
1
Adamantane-1-carbonitrile (2n) White solid, 396 mg, 82% yield. H NMR (300 MHz,
1
3
CDCl
3
) δ 2.04 (br, 9H, HꢀCH
2
ꢀβꢀCN and HꢀCHꢀγꢀCN), 1.77 – 1.68 (m, 6H, HꢀCH
2
ꢀδꢀCN).
C
3
NMR (75 MHz, CDCl ) δ 125.4 (CꢀCN), 40.0 (CꢀβꢀCN), 35.9 (CꢀδꢀCN), 30.3 (CꢀαꢀCN), 27.2
(CꢀγꢀCN). The NMR peak assignments were confirmed by the dept135 and HMQC spectra.
18
(
S)-tert-butyl 1-cyano-2-methylpropylcarbamate (2o) White solid, 493 mg, 83% yield.
1
o
H NMR (300 MHz, CDCl
3
, 40 C) δ 4.93 (br d, J = 8.7 Hz, 1H, HꢀNH), 4.42 (br s, 1H, HꢀCHCN),
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6
2
.01 (octet, J = 6.6 Hz, 1H, HꢀCH(CH ) ), 1.46 (s, 9H, HꢀOC(CH ) ), 1.08 (d, J = 6.6 Hz, 3H,
3
2
3 3
1
3
3 2 3 2 3
HꢀCH(CH ) ), 1.06 (d, J = 6.3 Hz, 3H, HꢀCH(CH ) ). C NMR (75 MHz, CDCl ) δ 154.7 (C=O),
118.1 (CN), 80.7 (CꢀOC(CH
3
)
3
), 48.4 (CꢀCHCN), 31.7 (CꢀCH(CH
3
)
2
), 28.1 (CꢀOC(CH
3 3
) ), 18.4
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3 2 3 2
(CꢀCH(CH ) ), 17.9 (CꢀCH(CH ) ). The NMR peak assignments were confirmed by the HMQC
23
D
spectrum. [α]
= ꢀ66.3 (c 1.41, MeOH).
19
1
(
S)-benzyl 1-cyano-2-methylpropylcarbamate (2p) White solid, 530 mg, 76% yield. H
o
NMR (300 MHz, CDCl
3
, 40 C) δ 7.41 – 7.28 (m, 5H, Hꢀphenyl), 5.29 ( br d, J = 8.4 Hz, 1H,
2 3 2
HꢀNH), 5.15 (s, 2H, HꢀCH Ph), 4.49 ( br s, 1H, HꢀCHCN), 2.11 – 1.96 (m, 1H, HꢀCH(CH ) ),
13
1
3 2 3 2
.08 (d, J = 6.6 Hz, 3H, HꢀCH(CH ) ), 1.06 (d, J = 6.9 Hz, 3H, HꢀCH(CH ) ). C NMR (75 MHz,
3
CDCl ) δ 155.4 (C=O), 135.7 (C1ꢀphenyl), 128.7, 128.6, 128.3 (C2–C6ꢀphenyl), 117.8 (CN), 67.8
(CꢀCH Ph), 49.1 (CꢀCHCN), 31.8 (CꢀCH(CH ) ), 18.6 (CꢀCH(CH ) ), 18.0 (CꢀCH(CH ) ). The
2
3 2
3 2
3 2
23
D
NMR peak assignments were confirmed by the HMQC spectrum. [α]
2 2
= ꢀ53.8 (c 1.05, CH Cl ).
20
1
3-Phenylpropanenitrile (2q) Colorless oil, 355 mg, 90% yield. H NMR (300 MHz,
CDCl ) δ 7.37 – 7.20 (m, 5H, Hꢀphenyl), 2.94 (t, J = 7.5 Hz, 2H, HꢀCꢀ3), 2.60 (t, J = 7.5 Hz, 2H,
3
13
HꢀCꢀ2). C NMR (75 MHz, CDCl
Cꢀoꢀphenyl), 127.3 (Cꢀpꢀphenyl), 119.2 (CꢀCN), 31.6 (Cꢀ3), 19.4 (Cꢀ2). The NMR peak
assignments were confirmed by the HMQC and HMBC spectra.
3
) δ 138.1 (C1ꢀphenyl), 128.9 (Cꢀmꢀphenyl), 128.3
(
21
1
Cyclohexanecarbaldehyde oxime (3l) Colorless oil, 1.05 g, 83% yield. H NMR (300
MHz, CDCl ) δ 8.94 (br s, 1H, HꢀOH, major and minor), 7.32 (d, J = 6.0 Hz, 1H, HꢀCH=N,
major), 6.53 (d, J = 7.2 Hz, 1H, HꢀCH=N, minor), 3.02 – 2.90 (m, 1H, HꢀC1ꢀcyclohexane, minor),
.26 – 2.15 (m, 1H, HꢀC1ꢀcyclohexane, major), 1.85 – 1.09 (m, 10H, Hꢀ5CH , major and minor).
3
3
2
13
3
C NMR (75 MHz, CDCl ) δ 156.6 (CꢀCH=N, minor), 156.1 (CꢀCH=N, major), 38.6
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(
C1ꢀcyclohexane, major), 33.9 (C1ꢀcyclohexane, minor), 30.3 (C2ꢀ and C6ꢀcyclohexane, major),
29.5 (C2ꢀ and C6ꢀcyclohexane, minor), 26.01 (C4ꢀcyclohexane, minor), 25.96 (C4ꢀcyclohexane,
major), 25.5 (C3ꢀ and C5ꢀcyclohexane, major), 25.3 (C3ꢀ and C5ꢀcyclohexane, minor). The NMR
peak assignments were confirmed by the HMQC spectrum.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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2
3
4
5
6
7
8
9
0
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1
3
-Phenylpropanal oxime (3q) White solid, 1.19 g, 80% yield. H NMR (300 MHz, CDCl
δ 8.80 (br s, 1H, HꢀOH, major and minor), 7.38 (t, J = 6.0 Hz, 1H, HꢀCH=N, minor), 7.24 – 7.09
m, 5H, Hꢀphenyl, major and minor), 6.67 (t, J = 5.1 Hz, 1H, HꢀCH=N, major), 2.77 – 2.71 (m,
H, HꢀCꢀ3, major and minor), 2.67 – 2.59 (m, 2H, HꢀCꢀ2, major), 2.48 – 2.41 (m, 2H, HꢀCꢀ2,
3
)
(
2
13
minor). C NMR (75 MHz, CDCl
3
) δ 151.8 (CꢀCH=N, major), 151.5 (CꢀCH=N, minor), 140.7
(
C1ꢀphenyl), 140.6 (C1ꢀphenyl), 128.6, 128.5, 128.4, 126.4 (C2–C6ꢀphenyl), 32.9 (Cꢀ3, minor),
32.0 (Cꢀ3, major), 31.3 (Cꢀ2, minor), 26.5 (Cꢀ2, major). The NMR peak assignments were
confirmed by the HMQC spectrum.
ASSOCIATED CONTENT
Supporting Information
1
13
H and C NMR spectra of all the synthesized compounds.
AUTHOR INFORMATION
Corresponding Author
*
tianhy@btbu.edu.cn and sunbg@btbu.edu.cn
ORCID
Hongyu Tian: 0000ꢀ0002ꢀ7117ꢀ6420
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support from the National key research and development program (2016YFD0400801),
Beijing Postdoctoral Research Foundation (2017ꢀ22ꢀ011) and the Importation and Development of
HighꢀCaliber Talents Project of Beijing Municipal Institutions (CIT&TCD20140306) is gratefully
acknowledged.
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