Note

Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX pubs.acs.org/joc

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 100048, China
*
S Supporting Information

ABSTRACT: The preparation of nitriles from primary amides or

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aldoximes was achieved by using oxalyl chloride with a catalytic amount

of dimethyl sulfoxide in the presence of Et3N. The reactions were complete
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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.

N itriles 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 as carboxyl derivatives, amines,
ketones, and various heterocycles.1 Many cyanated compounds
display attractive applications as pharmaceuticals, agrochem-
icals, or fragrances.2 A plethora of 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 cyanating reagents3 and the
other involving creation of a cyano group by chemical
transformation of other functional groups.4
The dehydration of amides or aldoximes is the most
commonly used approach for the creation of a cyano group by
far. A wide variety of reagents have been described for the
transformation of primary amides or aldoximes to nitriles.5
However, many of these existing methods suffer from
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 could be achieved via catalysis under mild
conditions.6 It is worth highlighting that a highly efficient
catalytic Appel-type dehydration of amides to nitriles has been
developed by Malkov and Rubtsov using oxalyl chloride and
triethylamine along with triphenylphosphine oxide as a
catalyst.6b
The combination of DMSO and oxalyl chloride has been
used widely in the oxidation of primary and secondary alcohols
since Swern first reported this method in 1978.7 In addition, it
was also very efficient for other transformations, such as
methylthiomethyl esterification of carboxylic acids8 and
dehydration of primary amides.9 In our recent work, novel
application of the combined reagents of R2SO (R = Me or Ph)
and (COX)2 (X = Cl or Br) has been developed, such as
sulfenllactonization10 and chlorolactonization of alkenoic
acids,11 bromination of alkenes, alkynes, and ketones,12 and
preparation of α,β-unsaturated γ-lactones.13 We noticed that
primary amides could be dehydrated to afford nitriles under
Swern oxidation conditions; however, DMSO and (COCl)2
were used in stoichiometric amounts and the reactions needed
to be carried out at −78 °C.9 Obviously, it is very inconvenient
to run reactions at such a low temperature. The work of
Malkov and Rubtsov6b inspired us to investigate if the
dehydration of amides or aldoximes may be achieved under
conditions of a catalytic Swern oxidation at room temperature.
Herein, we report 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 Et3N at room
temperature (Scheme 1).
Scheme 1. Dehydration of Amides or Aldoximes to Nitriles
by a Catalytic Swern Oxidation
The investigation began by employing benzamide (1a) as a
model substrate (Table 1). First, the experiment was carried
out under conditions mimicking those in the protocol from
amides to nitriles developed by Malkov and Rubtsov,6b in
which 2 equiv of oxalyl chloride in anhydrous MeCN was
added dropwise to the solution of 1a, 1 mol % of DMSO, and
Received: August 24, 2018
Published: September 21, 2018

© XXXX American Chemical Society A DOI: 10.1021/acs.joc.8b02190

J. Org. Chem. XXXX, XXX, XXX−XXX
The Journal of Organic Chemistry Note

Table 1. Optimization of the Reaction Conditions of Table 2. Dehydration of Amides to Nitriles under the
Dehydration of Amides Conditions of a Catalytic Swern Oxidation

DMSO (COCl)2 yield

entry (equiv) (equiv) base (equiv) time (%)
1 0.01 2.0 Et3N (3.0) 10 min 92a
2 0.01 2.0 0 24 h 1b
3 0.01 2.0 Et3N (3.0) 24 h 1b,c
4 0.01 1.2 Et3N (2.5) 40 min 90a
5 0 1.2 Et3N (2.5) 24 h 0b
6 0.01 1.2 DBU (2.5) 24 h 0b
7 0.01 1.2 NMM (2.5) 24 h 58b
a
Isolation yield after chromatographic purification. bDetermined by
GCMS. cThe only difference against the conditions of entry 1 was
that Et3N was added last.

3 equiv of Et3N in 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 Et3N, in which only a trace of benzonitrile (2a) was
detected by GCMS even after 24 h of stirring at rt (entry 2).
Another experiment was performed under conditions similar to
those in entry 1 except that 3 equiv of Et3N was added to the
reaction mixture at last (entry 3). The conversion of
benzonitrile (2a) was only 1% after 24 h of stirring 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 oxidation
at rt, in which Et3N was needed to be added to the reaction
mixture in advance. One more experiment was carried out to
optimize the amounts of (COCl)2 and Et3N, in which they
were reduced to 1.2 and 2.5 equiv, respectively (entry 4). It
was observed that the reaction proceeded slightly slower than
that in entry 1 but produced the desired nitrile 2a in a very
close yield. The reaction was also attempted 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 reported by Nakajima and Ubukata.9 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, Et3N is the most effective base for this
conversion.
The dehydration of more amides was explored under the
same conditions as those in entry 4 of Table 1. The results are
shown in Table 2. Three benzamides with substituted groups
on the phenyl ring (1b−d) were converted to the
corresponding benzonitriles (2b−d) in good to excellent
yields, regardless of whether they bore electron-withdrawing
group (2b, 2d) or electron-donating group (2c). Among the
aromatic amides, 1d with two electron-withdrawing nitro
groups on the phenyl ring afforded the nitrile in the lowest
yield of 80%. Two heterocyclic amides 1e and 1f were then
investigated. 2-Cyanothiophene 2e and 3-cyanopyridine 2f
were obtained in 89% and 90% yields, respectively. The
dehydration of 2-naphthamide 1h gave 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.
B DOI: 10.1021/acs.joc.8b02190
In addition, aliphatic linear (1i, 1j, 1k), cyclic (1l), and
branched (1m, 1n) amides were dehydrated to produce the
corresponding nitriles 2i−n in 80−87% yields, which were
slightly lower than those from the above unsaturated amides.
Phenyl-protected α-hydroxy amide 1k was also a compatible
substrate, which gave the desired nitrile 2k in 80% yield. The
same protocol also was applied to the two α-amino amides 1o
and 1p with Boc and Cbz protective groups, respectively, and
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 of Malkov and Rubtsov.6b For these
substrates, the yields obtained in our work are comparable with
those obtained via a catalytic Appel reaction. In addition, an
acid-sensitive Boc-protected substrate 1o was converted to the
corresponding nitrile in a good yield in our work, whereas it
was mentioned that Boc-protected amino acids could not be
converted to the desired nitriles under the conditions of a
catalytic Appel reaction.6b
Among the substrates mentioned above, some were also
examined by Nakajima and Ubukata9 under Swern oxidation
conditions with stoichiometric use of DMSO, including 1c, 1d,
1g, 1h, 1l, and 1p. Except for p-methoxybenzamide 1c with a
similar yield and 3,5-dinitrobenzamide 1d with a lower yield,
the other amides were converted to the corresponding nitriles
in higher yields in our work. In the work of Nakajima and
Ubukata,9 all of the reactions were carried out at −78 or −78
°C to rt with the combination of stoichiometric amounts of
(COCl)2, DMSO, and Et3N, in which the addition of Et3N
could be done either with (COCl)2 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
J. Org. Chem. XXXX, XXX, XXX−XXX
The Journal of Organic Chemistry Note

it was necessary to add Et3N to the reaction mixture in advance Table 3. Optimization of the Reaction Conditions of
of our protocol, which indicatd that Et3N acted as base to Dehydration of Aldoximes
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)

Scheme 2. Possible Mechanistic Pathway for the

DMSO (COCl)2 yield
Dehydration of Amides under Catalytic Swern Oxidation entry (equiv) (equiv) base (equiv) time (%)
Conditions 1 0 1.5 0 24 h 0a
2 0.01 1.2 0 30 min 2a
3 0.05 1.5 0 24 h 100a
4 0.05 1.5 TEA (3.0) 20 min 100a
5 0.01 1.2 TEA (2.5) 1h 93b
6 0.01 1.2 DBU (2.5) 24 h 0a
7 0.01 1.2 NMM (2.5) 2h 100a
a b
Determined by HNMR. Isolation yield after chromatographic
purification.

and 1.5 equiv of (COCl)2 in the absence of base (entry 3). The
addition of Et3N (3.0 equiv) reduced the reaction time from
24 h to 20 min (entry 4). The amounts of reagents were
optimized further. The reaction was complete in 1 h an
reacted with (COCl)2 to produce the intermediate chlor- produced 2a in 93% isolated yield in the presence of 0.01 equiv
odimethylsulfonium chloride (B), which was attacked by the of DMSO, 1.2 equiv of (COCl)2, and 2.5 equiv of Et3N (entry
oxygen of an amide through a nucleophilic substitution in the 5). DBU and NMM were also used in attempts to replace Et3N
presence of Et3N to give the intermediate C. It was then to promote the dehydration of 3a. No nitrile was obtained in
deprotonated by Et3N to generate the intermediate D, which the presence of DBU (entry 6). In contrast, the nitrile was
underwent elimination to afford the corresponding nitrile and obtained in the presence of NMM in a yield comparable to
release DMSO (A) to enter the next cycle. No product was that with Et3N but over a longer reaction time of 2 h (entry 7).
obtained when Et3N was replaced by DBU, which might be These results were similar to those obtained from the
due to the reaction between DBU and (COCl)2.14 In contrast, dehydration of amides.
NMM gave the desired product in a lower yield for a longer Five other aldoximes underwent dehydration under the
reaction time than Et3N, which indicated that the elimination above optimized conditions: o-bromobenzaldehyde oxime 3b,
of the intermediate C to the nitrile is the rate-limiting step thiophene-2-carbaldehyde oxime 3e, trans-cinnamaldehyde
influenced by the basicity of the amine. oxime 3g, cyclohexanecarboxaldehyde oxime 3l, and 3-
There is an alternative possible pathway for the trans- phenylpropanal oxime 3q. The results are shown in Table 4.
formation of the intermediate C to nitrile; i.e., the All of these substrates were converted to the corresponding
deprotonation may occur on the methyl group to give the nitriles in high yields, and the reactions were complete in 1 h.
intermediate E, which undergoes a retro-heteroene reaction to Yadav et al. reported that bromodimethylsulfonium bromide
generate nitrile. In order to clarify the mechanism, DMSO-d6 was used to convert aldoximes and primary amides to nitriles,5a
was used for the dehydration of benzamide (1a), and the in which it was claimed that the presence of a base slowed the
reaction mixture was analyzed by GC−EIMS after the reaction
was complete. Compared with the mass spectrum of DMSO- Table 4. Dehydration of Aldoximes to Nitriles under the
d6, the major fragment ion peaks in the spectrum of DMSO in Conditions of a Catalytic Swern Oxidation
the reaction mixture are similar to those of the standard
DMSO-d6. 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 small amount of DMSO-d6 was converted into DMSO-
d5 after the reaction. These results indicate that the
transformation of the intermediate C to nitrile occurs mainly
by an E2 mechanism but do not exclude a retro-heteroene
mechanism to some extent.
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)2 only if without
DMSO (entry 1). Compound 3a was converted into 2a
thoroughly after 24 h by treatment with 0.05 equiv of DMSO
C DOI: 10.1021/acs.joc.8b02190
J. Org. Chem. XXXX, XXX, XXX−XXX
The Journal of Organic Chemistry
dehydration of aldoximes. In contrast, it was observed that the
reactions of all the aldoximes in our work were very slow in the
absence of Et3N and completed in 5−48 h. The possible
mechanistic pathway for the dehydration of aldoximes is shown
in Scheme 3, which is similar to the catalytic cycle above for
Scheme 3. Possible Mechanistic Pathway for the
Dehydration of Aldoximes under Catalytic Swern Oxidation
Conditions
the dehydration of amides. The presence of Et3N is crucial for
the regeneration of DMSO, which is necessary for the next
reaction cycle.
In work of Denton et al. about the dehydration of oximes
using oxalyl chloride in combination with 5 mol % of Ph3PO, a
catalytic cycle was proposed involving the activated mono
oxime ester generated from the reaction of oxime and oxalyl
chloride as intermediate, which was then converted to nitrile
by Ph3PO or chlorophosphonium salt. In order to explore the
possibility 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 activated mono
oxime ester (G) was possible (Scheme 4). However, in the
case of amides, the mechanism shown in Scheme 2 is more
reasonable.
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
Scheme 4. Possible Mechanistic Pathway for the
Dehydration of Aldoximes through the Activated Mono
Oxime Ester
D DOI: 10.1021/acs.joc.8b02190
Note
with a catalytic amount of DMSO. This approach has several
advantages, such as simple operation, mild conditions, high
yields, and 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 laboratory.
■ EXPERIMENTAL SECTION
General Information. NMR spectra were obtained on a Bruker
AV 300 spectrometer (1H NMR at 300 MHz, 13C NMR at 75 MHz)
in CDCl3 using TMS as an internal standard. Chemical shifts (δ) are
given in ppm and coupling constants (J) in hertz. GC−MS data were
obtained on an Agilent 7890B-5977A under the following conditions:
capillary column HP-5MS 5% Phenyl Methyl Silox (30 m × 0.25 mm
× 0.25 um); oven temperature programmed from 50 to 150 °C at a
rate of 15 °C/min, then 10 to 280 °C at a rate of 10 °C/min; carrier
gas, helium; flow rate, 1.2 mL/min; electron ionization, 70 eV; ion
source temperature, 230 °C. TLC was performed with precoated TLC
plates, silica gel 60F-254, layer thickness 0.25 mm. Flash
chromatography separations were performed on 200−300 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 laboratory.
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
Et3N (1.04 mL, 7.5 mmol, 2.5 equiv). Oxalyl chloride (0.31 mL, 3.6
mmol, 1.2 equiv) in anhydrous 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 vacuo. Distilled water (15 mL) was added, the
mixture was extracted with EtOAc (3 × 10 mL), and combined
extracts were washed with brine (2 × 20 mL), dried over anhydrous
Na2SO4, filtered, and concentrated in vacuo. 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 × 30
mL). The combined extracts were washed with brine (50 mL), dried
over anhydrous Na2SO4, filtered, and concentrated in vacuum to give
the corresponding aldoxime 3.
Analytical Data. Benzonitrile (2a).6b Colorless oil, 285 mg, 92%
yield. 1H NMR (300 MHz, CDCl3): δ 7.68−7.64 (m, 2H, H-o-
phenyl), 7.64−7.58 (m, 1H, H-p-phenyl), 7.50−7.44 (m, 2H, H-m-
phenyl). 13C NMR (75 MHz, CDCl3): δ 132.9 (C-p-phenyl), 132.3
(C-o-phenyl), 129.2 (C-m-phenyl), 119.0 (C−CN), 112.6 (C1-
phenyl).
2-Bromobenzonitrile (2b).15 White solid, 516 mg, 95% yield. 1H
NMR (300 MHz, CDCl3): δ 7.70−7.64 (m, 2H, H−C3-phenyl and
H−C6-phenyl), 7.49−7.39 (m, 2H, H−C4-phenyl and H−C5-
phenyl). 13C NMR (75 MHz, CDCl3): δ 134.4 (C6-phenyl), 134.0
(C4-phenyl), 133.3 (C3-phenyl), 127.8 (C5-phenyl), 125.4 (C2-
phenyl), 117.2 (C−CN), 116.0 (C1-phenyl). The NMR peak
assignments were confirmed by the HMQC and HMBC spectra.
4-Methoxybenzonitrile (2c).6b White solid, 380 mg, 95% yield. 1H
NMR (300 MHz, CDCl3): δ 7.61−7.56 (m, 2H, H-o-phenyl), 6.97−
6.93 (d, 2H, H-m-phenyl), 3.86 (s, 3H, H−OCH3). 13C NMR (75
MHz, CDCl3): δ 163.0 (C-p-phenyl), 134.1 (C-o-phenyl), 119.4 (C−
CN), 114.9 (C-m-phenyl), 104.2 (C1-phenyl), 55.7 (C-OCH3).
3,5-Dinitrobenzonitrile (2d). White solid, 463 mg, 80% yield. 1H
NMR (300 MHz, CDCl3): δ 9.27 (t, J = 2.1 Hz, 1H, H-p-phenyl),
8.85 (d, J = 2.1 Hz, 2H, H-o-phenyl). 13C NMR (75 MHz, CDCl3): δ
J. Org. Chem. XXXX, XXX, XXX−XXX
The Journal of Organic Chemistry
149.0 (C-m-phenyl), 132.1 (C-o-phenyl), 122.8 (C-p-phenyl), 116.0
(C−CN), 114.7 (C1-phenyl).
Thiophene-2-carbonitrile (2e).6b Colorless oil, 292 mg, 89% yield.
1
H NMR (300 MHz, CDCl3): δ 7.65−7.63 (m, 1H, H−C-3), 7.61
(dd, J = 5.1, 1.2 Hz, 1H, H−C-5), 7.14 (dd, J = 5.1, 3.6 Hz, 1H, H−
C-4). 13C NMR (75 MHz, CDCl3): δ 137.5 (C-3), 132.7 (C-5), 127.7
(C-4), 114.3 (C−CN), 110.0 (C-2). The NMR peak assignments
were confirmed by the HMQC and HMBC spectra.
Nicotinonitrile (2f).6b White solid, 281 mg, 90% yield. 1H NMR
(300 MHz, CDCl3): δ 8.89 (d, J = 1.2 Hz, 1H, H−C-2), 8.82 (dd, J =
4.8, 1.8 Hz, 1H, H−C-6), 7.96 (dt, J = 7.8, 1.8 Hz, 1H, H−C-4), 7.44
(ddd, J = 7.8, 4.8, 0.9 Hz, 1H, H−C-5). 13C NMR (75 MHz, CDCl3):
δ 153.1 (C-6), 152.6 (C-2), 139.3 (C-4), 123.7 (C-5), 116.6 (C−
CN), 110.3 (C-3). The NMR peak assignments were confirmed by
the HMQC spectrum.
Cinnamonitrile (2g).6b Colorless oil, 357 mg, 92% yield. 1H NMR
(300 MHz, CDCl3): δ 7.48−7.37 (m, 6H, H-phenyl and H−CHPh),
5.88 (d, J = 16.8 Hz, 1H, H−CHCN). 13C NMR (75 MHz, CDCl3):
δ 150.7 (C-CHPh), 133.6 (C1-phenyl), 131.3 (C-p-phenyl), 129.2
(C-m-phenyl), 127.4 (C-o-phenyl), 118.2 (C−CN), 96.4 (C-CHCN).
2-Naphthonitrile (2h).15 White solid, 441 mg, 96% yield. 1H NMR
(300 MHz, CDCl3): δ 8.24 (s, 1H, H−C-1), 7.94−7.88 (m, 3H, H−
C-4, H−C-5 and H−C-8), 7.69−7.57 (m, 3H, H−C-3, H−C-6 and
H−C-7). 13C NMR (75 MHz, CDCl3): δ 134.8 (C-4a), 134.3 (C-1),
132.4 (C-8a), 129.3, 129.2, 128.6, 128.2, 127.8, 126.5 (C-3, C-4, C-5,
C-6, C-7 and C-8), 119.4 (C−CN), 109.6 (C-2).
Hexanenitrile (2i).16 Colorless oil, 233 mg, 80% yield. 1H NMR
(300 MHz, CDCl3): δ 2.33 (t, J = 7.2 Hz, 2H, H−C-2), 1.71−1.62
(m, 2H, H−C-3), 1.49−1.32 (m, 4H, H−C-4 and H−C-5), 0.92 (t, J
= 7.2 Hz, 3H, H−C-6). 13C NMR (75 MHz, CDCl3): δ 120.0 (C−
CN), 30.9 (C-4), 25.2 (C-3), 22.0 (C-5), 17.2 (C-2), 13.8 (C-6). The
NMR peak assignments were confirmed by the HMQC spectrum.
2-Phenylacetonitrile (2j).6b Light yellow oil, 291 mg, 83% yield.
1
H NMR (300 MHz, CDCl3): δ 7.42−7.31 (m, 5H, H-phenyl), 3.75
(s, 2H, H−CH2). 13C NMR (75 MHz, CDCl3): δ 130.0 (C1-phenyl),
129.3 (C-o-phenyl), 128.2 (C-p-phenyl), 128.0 (C-m-phenyl), 118.0
(C−CN), 23.7 (C−CH2).
2-Phenoxyacetonitrile (2k).6b Colorless oil, 320 mg, 80% yield. 1H
NMR (300 MHz, CDCl3): δ 7.40−7.33 (m, 2H, H-m-phenyl), 7.13−
7.07 (m, 1H, H-p-phenyl), 7.02−6.97 (m, 2H, H-o-phenyl), 4.77 (s,
2H, H−CH2). 13C NMR (75 MHz, CDCl3): δ 156.7 (C1-phenyl),
130.0 (C-m-phenyl), 123.3 (C-p-phenyl), 115.1 (C-o-phenyl and C−
CN), 53.7 (C−CH2).
Cyclohexanecarbonitrile (2l).17 Colorless oil, 285 mg, 87% yield.
1
H NMR (300 MHz, CDCl3): δ 2.61 (tt, J = 8.1, 3.9 Hz, 1H, H−C-
1), 1.89−1.80 (m, 2H, H−C-2 and H−C-6), 1.77−1.63 (m, 4H, H′−
C-2 and H′−C-6, H−C-3 and H−C-5), 1.51−1.36 (m, 4H, H′−C-3
and H′−C-5, H−C-4). 13C NMR (75 MHz, CDCl3): δ 122.7 (C−
CN), 29.6 (C-2 and C-6), 28.1 (C-1), 25.3 (C-4), 24.2 (C-3 and C-
5). The NMR peak assignments were confirmed by the HMQC
spectrum.
2-Phenylbutanenitrile (2m).6b Yellow oil, 379 mg, 87% yield. 1H
NMR (300 MHz, CDCl3): δ 7.42−7.29 (m, 5H, H-phenyl), 3.74 (t, J
= 7.2 Hz, 1H, H−CHCN), 2.00−1.90 (m, 2H, H−CH2), 1.08 (t, J =
7.5 Hz, 3H, H−CH3). 13C NMR (75 MHz, CDCl3): δ 135.9 (C1-
phenyl), 129.1 (C-m-phenyl), 128.1 (C-p-phenyl), 127.4 (C-o-
phenyl), 120.9 (C−CN), 39.0 (H-CHCN), 29.3 (C−CH2), 11.6
(C−CH3). The NMR peak assignments were confirmed by the
HMBC spectrum.
Adamantane-1-carbonitrile (2n).15 White solid, 396 mg, 82%
yield. 1H NMR (300 MHz, CDCl3): δ 2.04 (br, 9H, H−CH2−β-CN
and H−CH-γ-CN), 1.77−1.68 (m, 6H, H−CH2−δ-CN). 13C NMR
(75 MHz, CDCl3): δ 125.4 (C−CN), 40.0 (C-β-CN), 35.9 (C-δ-
CN), 30.3 (C-α-CN), 27.2 (C-γ-CN). The NMR peak assignments
were confirmed by the dept135 and HMQC spectra.
(S)-tert-Butyl 1-Cyano-2-methylpropylcarbamate (2o).18 White
solid, 493 mg, 83% yield. 1H NMR (300 MHz, CDCl3, 40 °C) δ 4.93
(br d, J = 8.7 Hz, 1H, H-NH), 4.42 (br s, 1H, H−CHCN), 2.01
(octet, J = 6.6 Hz, 1H, H−CH(CH3)2), 1.46 (s, 9H, H−OC(CH3)3),
1.08 (d, J = 6.6 Hz, 3H, H−CH(CH3)2), 1.06 (d, J = 6.3 Hz, 3H, H−
E DOI: 10.1021/acs.joc.8b02190
Note
CH(CH3)2). 13C NMR (75 MHz, CDCl3) δ 154.7 (CO), 118.1
(CN), 80.7 (C−OC(CH3)3), 48.4 (C-CHCN), 31.7 (C-CH(CH3)2),
28.1 (C-OC(CH3)3), 18.4 (C−CH(CH3)2), 17.9 (C−CH(CH3)2).
The NMR peak assignments were confirmed by the HMQC
spectrum. [α]23D = −66.3 (c 1.41, MeOH).
(S)-Benzyl 1-Cyano-2-methylpropylcarbamate (2p).19 White
solid, 530 mg, 76% yield. 1H NMR (300 MHz, CDCl3, 40 °C): δ
7.41−7.28 (m, 5H, H-phenyl), 5.29 (br d, J = 8.4 Hz, 1H, H-NH),
5.15 (s, 2H, H−CH2Ph), 4.49 (br s, 1H, H−CHCN), 2.11−1.96 (m,
1H, H−CH(CH3)2), 1.08 (d, J = 6.6 Hz, 3H, H−CH(CH3)2), 1.06
(d, J = 6.9 Hz, 3H, H−CH(CH3)2).13C NMR (75 MHz, CDCl3): δ
155.4 (CO), 135.7 (C1-phenyl), 128.7, 128.6, 128.3 (C2−C6-
phenyl), 117.8 (CN), 67.8 (C-CH2Ph), 49.1 (C-CHCN), 31.8 (C-
CH(CH3)2), 18.6 (C−CH(CH3)2), 18.0 (C−CH(CH3)2). The NMR
peak assignments were confirmed by the HMQC spectrum. [α]23D =
−53.8 (c 1.05, CH2Cl2).
3-Phenylpropanenitrile (2q).20 Colorless oil, 355 mg, 90% yield.
1
H NMR (300 MHz, CDCl3): δ 7.37−7.20 (m, 5H, H-phenyl), 2.94
(t, J = 7.5 Hz, 2H, H−C-3), 2.60 (t, J = 7.5 Hz, 2H, H−C-2). 13C
NMR (75 MHz, CDCl3): δ 138.1 (C1-phenyl), 128.9 (C-m-phenyl),
128.3 (C-o-phenyl), 127.3 (C-p-phenyl), 119.2 (C−CN), 31.6 (C-3),
19.4 (C-2). The NMR peak assignments were confirmed by the
HMQC and HMBC spectra.
Cyclohexanecarbaldehyde Oxime (3l).21 Colorless oil, 1.05 g,
83% yield. 1H NMR (300 MHz, CDCl3): δ 8.94 (br s, 1H, H−OH,
major and minor), 7.32 (d, J = 6.0 Hz, 1H, H−CHN, major), 6.53
(d, J = 7.2 Hz, 1H, H−CHN, minor), 3.02−2.90 (m, 1H, H−C1-
cyclohexane, minor), 3.26−2.15 (m, 1H, H−C1-cyclohexane, major),
1.85−1.09 (m, 10H, H-5CH2, major and minor). 13C NMR (75 MHz,
CDCl3): δ 156.6 (C−CHN, minor), 156.1 (C−CHN, major),
38.6 (C1-cyclohexane, major), 33.9 (C1-cyclohexane, minor), 30.3
(C2- and C6-cyclohexane, major), 29.5 (C2- and C6-cyclohexane,
minor), 26.01 (C4-cyclohexane, minor), 25.96 (C4-cyclohexane,
major), 25.5 (C3- and C5-cyclohexane, major), 25.3 (C3- and C5-
cyclohexane, minor). The NMR peak assignments were confirmed by
the HMQC spectrum.
3-Phenylpropanal Oxime (3q).21 White solid, 1.19 g, 80% yield.
1
H NMR (300 MHz, CDCl3) δ 8.80 (br s, 1H, H−OH, major and
minor), 7.38 (t, J = 6.0 Hz, 1H, H−CHN, minor), 7.24−7.09 (m,
5H, H-phenyl, major and minor), 6.67 (t, J = 5.1 Hz, 1H, H−CH
N, major), 2.77−2.71 (m, 2H, H−C-3, major and minor), 2.67−2.59
(m, 2H, H−C-2, major), 2.48−2.41 (m, 2H, H−C-2, minor). 13C
NMR (75 MHz, CDCl3) δ 151.8 (C−CHN, major), 151.5 (C−
CHN, minor), 140.7 (C1-phenyl), 140.6 (C1-phenyl), 128.6,
128.5, 128.4, 126.4 (C2−C6-phenyl), 32.9 (C-3, minor), 32.0 (C-3,
major), 31.3 (C-2, minor), 26.5 (C-2, major). The NMR peak
assignments were confirmed by the HMQC spectrum.
■
ASSOCIATED CONTENT
*
S Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b02190.
1
H and 13C NMR spectra of all the synthesized
compounds (PDF)
■
AUTHOR INFORMATION
Corresponding Authors
*Tel and Fax: +8610 68984545. E-mail: tianhy@btbu.edu.cn.
*Tel and Fax: +8610 68984545. E-mail: sunbg@btbu.edu.cn.
ORCID
Hongyu Tian: 0000-0002-7117-6420
Baoguo Sun: 0000-0003-4326-8237
Notes
The authors declare no competing financial interest.
J. Org. Chem. XXXX, XXX, XXX−XXX
The Journal of Organic Chemistry
■ ACKNOWLEDGMENTS
Financial support from the National Key Research and
Development Program (2016YFD0400801), the Beijing
Postdoctoral Research Foundation (2017-22-011), and the
Importation and Development of High-Caliber Talents Project
of Beijing Municipal Institutions (CIT&TCD20140306) is
gratefully acknowledged.
■
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