A convenient reagent for the conversion of aldoximes into nitriles and isonitriles

Article abstract of DOI:10.1039/d0cc00188k

For the dehydroxylation of aldoximes with 4-nitro-1-((trifluoromethyl)sulfonyl)-imidazole (NTSI), slight modifications of reaction conditions resulted in significantly different reaction paths to provide either nitriles or isonitriles. The challenging conversion of aldoximes into isonitriles was achieved under mild conditions.

Full text of DOI:10.1039/d0cc00188k

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DOI: 10.1039/D0CC00188K
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A Convenient Reagent for the Conversion of Aldoximes into
Nitriles and Isonitriles
Wei Zhang,a Jin-Hong Lin,a Pengfei Zhang,*b and Ji-Chang Xiao*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
nitro-1-((trifluoromethyl)sulfonyl)-imidazole (NTSI) (eq 3). The
substituent migration was involved for the formation of
isonitriles under mild conditions.
For the dehydroxylation of aldoximes with 4-nitro-1-
((trifluoromethyl)sulfonyl)-imidazole
(NTSI
),
slight
modifications of reaction conditions resulted in significantly
different reactions paths to provide either nitriles or isonitriles. The
challenging conversion of aldoximes into isonitriles was
achieved under mild conditions.
Previous work:
OH
O
N
N
- H2O
(1)
(2)
R
N
N
It is well known that reaction conditions play an important role
in organic conversions and may determine reaction paths. If
slight modifications of reaction conditions could result in
completely different reaction paths to provide different useful
products, the transformations may deserve much attention.
Dehydroxylation of aldoximes has found widespread
applications in organic synthesis since it may deliver nitriles1 or
provide amides2 via the first formation of nitriles followed by a
hydrolysis3 (Scheme 1, eq 1). A migration of the substituent anti
to the hydroxyl unit from the carbon to the nitrogen atom may
be involved in the dehydroxylation of oximes, but the oximes
which can undergo this rearrangement are limited to
ketoximes.4 For the dehydroxylation of aldoximes, the direct
elimination of the proton in the CH=N moiety to afford nitriles
is preferred, and thus this rearrangement usually does not
occur.2b Although a previous example for the dehydroxylation
of aldoximes have shown that the migration process may
proceed to give isonitriles, the transformation suffers from a
tedious two-step procedure and the need for isolation of the
first-step products (eq 2).5 Interestingly, we found that slight
modifications of the reaction conditions could significantly
change the reaction paths to furnish different products, nitriles
and isonitriles, for the dehydroxylation of aldoximes with 4-
H
R
NH2
R
R
OR'
OH
BF3
R
N C
H
H
R
challenging from aldoximes to isonitriles
This work:
NOH
NTSI, K2HPO4
NTSI, Et3N
rt
(3)
R
R
N
N
C
50 o
C
R
H
NTSI:
N
NSO2CF3
O2N
X-ray structure
Scheme 1 The conversion of aldoximes into nitriles and isonitriles
The dehydroxylation reagent, NTSI, could be easily prepared
by a reaction of nitro-imidazole with trifluoromethanesulfonic
anhydride at room temperature (See supporting Information).
The side product was removed by filtration, and the pure NTSI
was obtained as a solid simply by concentration under vacuum
to remove the solvent. Compared with the similar compound
without a NO2 substituent, a reagent which has to be purified
by distillation and is usually used to convert phenols into aryl
triflates,6 NTSI may show wider application due to the
convenient operations for its isolation and its higher
electrophilic reactivity enhanced by the electron-withdrawing
NO2 group. Although both nitrile 2-1 and isonitrile 3-1 were
produced in the dehydroxylation of aldoxime 1-1 with NTSI in
most cases (Table 1), the base and the reaction solvent were
found to be crucial for the respective reaction path. The use of
CH3CN as the solvent favoured the formation of nitrile 2-1
a. Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, University of Chinese Academy of Sciences, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai, 200032, China. Email: jchxiao@sioc.ac.cn.
b. NHC Key Laboratory of Cancer Proteomics, Xiangya Hospital, Central South
University, 87 Xiangya Road, Changsha, Hunan, 410008, China. Email:
zhangpf690421@csu.edu.cn.
Electronic Supplementary Information (ESI) available: Experimental procedures,
characterization data, CCDC 1996499 (NTSI). See DOI: 10.1039/x0xx00000x
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irrespective of whether an organic or inorganic base was used carbonyl groups. The compatibility of Bpin (2-8), sViyielw(2Ar-t1icl1e)Oanlninde
DOI: 10.1039/D0CC00188K
(entries 1-6). Whereas isonitrile 3-1 was obtained in 38% yield halide (2-16, 2-23, 2-33 and 2-34) groups with these conditions
in CH3CN by using K2HPO4 as the base (entry 5). The conversion may allow for further coupling reactions of these CN-containing
into nitrile 2-1 occurred rapidly, and was finished within 10 min products.
to give a high yield (entry 7). The conditions for the generation
Since nitriles are widely present as key structural motifs in
biologically active molecules and have emerged as versatile
intermediates in synthetic chemistry,7 significant efforts have
been devoted to the development of efficient methods for the
incorporation of a nitrile group into organic molecules.8
Cyanation is apparently one of the most straightforward
strategies, and a large number of cyanation approaches have
been developed.9 But the most commonly used reagents,
including TMSCN10, KCN11 and CuCN12, are highly toxic and are
prone to hydrolysis to generate hazardous HCN gas. We have
previously shown that the combination of difluorocarbene and
ammonia could act as a CN- source for cyanation.13 The
transformation from aldoximes is also a convenient strategy
since aldoximes could be easily prepared. It has been reported
that the conversions of aldoximes into nitriles could proceed
smoothly under the catalysis of various transition metals,14 such
as palladium15 and copper16. However, a high reaction
temperature (80 oC or higher) is usually needed. Compared with
the previous methods, the protocol is attractive due to the mild
conditions and the rapid reaction rate.
of isonitrile 3-1 was further screened (entries 8-14). A brief
survey of the reaction solvents (entries 8-11) revealed that in
CH3NO2 nitrile 2-1 could be suppressed and isonitrile 3-1 was
obtained in 35% yield (entry 11). Prolonging the reaction time
and elevating the reaction temperature increased the yield of
isonitrile to 72% yield (entry 13). 13C NMR analysis could easily
distinguish the isonitrile structure from the nitrile structure.
Two unique triplet signals were observed for the isonitrile (δ =
167 ppm and δ = 124 ppm), corresponding to the N≡C carbon
and the C-(N ≡ C) carbon, respectively (See Supporting
Information and the references therein).
Table 1 Optimization of The Reaction Conditionsa
OH
NC
CN
NSO2CF3
N
N
base, solvent
r.t., 2 h
+
+
O2N
NTSI
1-1
2-1
3-1
yield (%)b
2-1
86
58
48
38
45
entry
base
Et3N
pyridine
Na2CO3
KF
K2HPO4
Na2HPO4
Et3N
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
solvent
3-1
12
20
37
30
38
1
2
3
4
5
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Acetone
EA
Et3N
N
NSO2CF3
OH
+
CN
2
R-
R
N
CH3CN, r.t., 10 min
O2N
1
NTSI
6
trace
87
trace
12
Me
7c
8
CN
CN
CN
CN
CN
CN
32
40
43
trace
7
28
20
22
35
46
72
64
MeO
iPrO
PhO
MeS
9
Me
O
Me
2-1
2-2
2-3
2-4
2-5
93%
82%
72%
92%
92%
10
11
12d
13de
14df
THF
CN
CN
CN
CN
CH3NO2
CH3NO2
CH3NO2
CH3NO2
Ac
N
N
Bpin
Ms
2-10
O
2-7
8
13
H
2-6
2-8
2-9
62%
96%
35%
CN
84%
CN
77%
CN
CN
CN
NO2
aReaction conditions: 1-1 (0.2 mmol), NTSI (1.2 equiv), base (2.0 equiv),
solvent (2.0 mL), under N2, 2 h; EA = Ethyl Acetate; THF = Tetrahydrofuran;
bThe yields were determined by 1H NMR spectroscopy by using CH2Br2 as an
O
NC
TMS
2-11
2-12
2-13
2-14
Et
2-15
97%
Br
69%
97%
CN
62%
81%
CN
c
internal standard; The reaction time was 10 min; dThe reaction time was
MeO
O
O
N
O
O
e
o
f
overnight; The reaction temperature was 50 C; The reaction temperature
was 70 oC.
CN
93%
CN
CN
OMe
2-18
CN
CN
2-16
2-17
2-19
2-20
94%
97%
94%
80%
N
CN
CN
With the optimal conditions in hand (Table 1, entry 7), we
then investigated the substrate scope of the conversion into
nitriles. As shown in Scheme 2, this process could be extended
to a wide range of aryl (2-1 ~ 2-22), heteroaryl (2-23 ~ 2-34),
alkenyl (2-35 ~ 2-37) and alkyl (2-38 ~ 2-40) aldoximes. All
reactions proceeded very fast and a reaction time of 10 min
gave moderate to high yields. Electron-rich, -neutral, and -
deficient aryl aldoximes could all be transformed smoothly,
indicating that substituent electronic effects have no obvious
impact on this transformation. This protocol could be applied to
the synthesis of various heteroaryl nitriles (2-23 ~ 2-34). A
variety of functional group could be tolerated, such as vinyl,
Bpin, amide, silyl, nitro, cyanide, Ms (CH3SO2), halide, and
CN
Br
N
MeO
N
2-21
2-22
2-23
2-24
2-25
82%
82%
86 %
79%
88%
CN
CN
N
CN
N
CN
N
N
H
O
N
H
S
CN
96%
2-26
2-31
2-27
2-28
2-29
2-30
93%
80%
73%
CN
48 %
O
CN
CN
CN
N
O
N
Me
2-34
CN
O
S
Me
S
N
Cl
Ph
2-32
O
Br
2-33
2-35
83%
79%
82 %
82 %
86 %
CN
CN
CN
CN
CN
O
O
Ph
iPr
2-36
2-37
2-38
2-39
2-40
75%
70%
64%
78%
75%
2 | J. Name., 2012, 00, 1-3
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H
O
base = Et3N
Scheme 2 The conversions of aldoximes into nitriles. Reaction conditions:
substrate 1 (0.5 mmol), NTSI (0.6 mmol), Et3N (1.0 mmol) in CH3CN (2 mL) at
room temperature for 10 min. Isolated yields are shown.
View Article Online
DOI: 10.1039/D0CC00188K
R-CN
- Et3N+H TfO-
- Et3N+H
NOH
H
N
Tf
1
H
base
O
H
H
R
R
Tf
N
N
base = K2HPO4
R = Ar
A
- KH2PO4
- KOTf
H
R'
+
We further investigated the substrate scope of the
conversion into isonitriles by using K2HPO4 as the base. As
shown in Scheme 3, moderate to good yields were obtained in
most cases. Because of its substantial sublimation, product 3-1
was isolated in a lower yield (51%) compared with its NMR yield
(72% shown in Table 1, entry 13). The electronic effect of the
substituent had a strong impact on the reactions of aryl
aldoximes. Electron-donating groups are favourable, but an
electron-withdrawing group would suppress this conversion (3-
11). Unlike the conversion into nitriles, the transformation into
isonitriles could not be extended to alkyl aldoximes.
R'
C
B
K2HPO4
N
D
H
Ar-NC
Ar
Scheme 4 The proposed mechanism
Conclusions
In summary, we have described the use of NTSI as a
dehydroxylation reagent for the conversion of aldoximes into
nitriles and isonitriles. It is interesting that slight modifications
of the reaction conditions could result in significantly different
reaction paths. We have also shown that a dehydroxylation
reagent and a base are important for the challenging
transformation of aldoximes into isonitriles. NTSI may become
an attractive dehydroxylation reagent because of its easy
availability and high reactivity.
K2HPO4 (2.0 eq.)
N
NSO2CF3
NO2
OH
R-NC
+
R
N
CH3NO2, 50 °C, overnight
1
3
NTSI
NC
Me
NC
NC
NC
O
O
NC
N
MeS
O
Br
O
Me
Me
3-1
3-2
3-3
3-4
3-5
48%
51%
71%
57%
65%
Et
NC
NC
MeO
NC
O
N
NC
We thank the National Natural Science Foundation (21421002,
21672242, 21971252, 21991122), Key Research Program of
Frontier Sciences (CAS) (QYZDJSSW-SLH049), Youth Innovation
Promotion Association CAS (2019256), the Fujian Institute of
Innovation, Chinese Academy of Sciences (FJCXY18040102) for
financial support.
NC
O
CF3
OMe
NC
a
3-6
3-11
73%
15%
3-7
3-10
65%
42%
3-8
3-9
71%
71%
Scheme 3 The conversion of aldoximes to isonitriles. Reaction conditions:
substrate 1 (0.5 mmol), NTSI (0.6 mmol), K2HPO4 (1.0 mmol) in CH3NO2 (2 mL)
at 50 C for overnight. Isolated yields are shown. The yield of product 3-11
was a 19F NMR yield by using CF3CH2OH as an internal standard.
o
a
Isonitriles are commonly found in naturally occurring
compounds,17 and have served as important intermediates due
to the dual nucleophilic and electrophilic character of the
isonitrile group.18 Many methods for the synthesis of isonitriles
have been developed, such as direct isocyanation,19
dehydration of formamides,20 and carbylamine reaction of
primary amines with a dihalocarbene21. The transformation
from aldoximes is a promising approach for the synthesis of
isonitriles, but it is a challenging task since the direct conversion
into nitriles is preferred over the substituent migration. In our
protocol, this reaction proceeds smoothly by using suitable
reagents.
Conflicts of interest
There are no conflicts to declare.
Notes and references
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