POCl3-mediated reaction of 1-Acyl-1-carbamoyl Oximes: A new entry to cyanoformamides

Article abstract of DOI:10.1021/ol503643p

A facile and efficient one-pot synthesis of cyanoformamides was developed from readily available 1-acyl-1-carbamoyl oximes mediated by phosphoryltrichloride (POCl₃) under mild conditions in good to high yields.

Full text of DOI:10.1021/ol503643p

Letter
pubs.acs.org/OrgLett
POCl3‑Mediated Reaction of 1‑Acyl-1-carbamoyl Oximes: A New
Entry to Cyanoformamides
Jiming Yang,† Dexuan Xiang,† Rui Zhang,†,‡ Ning Zhang,*,† Yongjiu Liang,† and Dewen Dong*,†,‡
†Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China
‡Changzhou Institute of Energy Storage Materials & Devices, Changzhou, 213000, P. R. China
S
* Supporting Information
ABSTRACT: A facile and efficient one-pot synthesis of cyanoformamides was
developed from readily available 1-acyl-1-carbamoyl oximes mediated by
phosphoryltrichloride (POCl3) under mild conditions in good to high yields.
yanoformamides have been used as key building blocks1
in the synthesis of symmetrical/unsymmetrical substi-
Scheme 1. Synthesis of Cyanoformamides from Amines
C
tuted ureas,2 acrylonitriles,3 and some aza-heterocycles, such as
tetrazoles4 and lactams.5 They also act as stable sources of
isocyanates and hydrogen cyanide in reactions requiring neutral
or thermal conditions.6 In addition, N,N-dimethyl cyano-
formamide has been isolated from several vegetables and fruits,
such as tomatoes, oranges, and apples, as a degradation
metabolite of a pesticide.7 The first natural product with this
functionality in its structure, ceratinamine (Figure 1), was
previous work, we also achieved a one-pot synthesis of fully
substituted 1H-pyrazoles from the oximes of 1-acyl-1-
carbamoyl cyclopropanes under Vilsmeier conditions (POCl3/
DMF).14 When DMF was replaced with CH2Cl2, the same
substrates, cyclopropyloximes, afforded fully substituted iso-
xazoles in high yields (Scheme 2). The result suggested that
POCl3, being a reagent,15 showed different reaction behavior
from the Vilsmeier reagent, POCl3/DMF.
Inspired by these findings and in continuation of our
research interests in β-oxo amide derivatives, we became
interested in examining the reaction behavior of the readily
available 1-acyl-1-carbamoyl oximes toward POCl3 under
different conditions. As a result, we have provided a facile
and efficient one-pot synthesis of cyanoformamides under mild
conditions. Herein, we report our preliminary results.
The substrates, 1-acyl-1-carbamoyl oximes 1, were prepared
from commercially available β-oxo amides and sodium nitrite in
the presence of acetic acid in water in good yields.16 With
substrates 1 in hand, we then selected 2-(hydroxyimino)-3-oxo-
N-phenyl butanamide 1a as the model compound to examine
its behavior with POCl3. Thus, the reaction of 1a with a
Vilsmeier reagent (POCl3/DMF, 1.2 equiv) was first attempted
at room temperature, but a complex mixture was formed as
indicated by TLC (Table 1, entry 1). When 1a was heated with
Figure 1. Chemical structure of ceratinamine.
isolated in 1996 from the marine sponge Pseudoceratinapurpur-
ea8 and was synthesized later;9 it has cytotoxic and potent
antifouling activity. Its analogue, 7-hydroxyceratinamine, was
isolated three years later from the marine sponge Aplysinel-
lasp.10
In past decades, there have been only a few reports
concerning the preparation of cyanoformamides. These involve
the reactions of amines with reagents such as carbonyl cyanide,
4-chloro-5H-1,2,3-dithiazol-5-one, isonitroso Meldrum’s acid,
or its tosyl derivatives.1,5b,6a,11 The toxicity and complexity of
these reagents and the high reactivity of the system limit the
́
utility of these approaches. Later on, Garcia-Egido and co-
workers developed a synthetic route to cyanoformamides from
primary amines and carbon dioxide under mild conditions, in
which guanidine and cyanophosphonate were employed
(Scheme 1).12
During the course of our studies on β-oxo amides, we
developed an efficient synthesis of substituted pyridin-2(1H)-
ones, pyrimidin-2(1H)-ones, and 1H-pyrazoles via the
Vilsmeier−Haack reaction of a variety of β-oxo amide
derivatives including cyclopropanes and enaminones.13 In our
Received: December 17, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ol503643p
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Under the conditions reported for 2a in Table 1 (entry 8), a
series of reactions of 1-acyl-1-carbamoyl oximes 1 and POCl3
were carried out, and some of the results are listed in Table 2. It
Scheme 2. Reaction of Cyclopropyl Oximes with POCl3 in
Different Solvents
Table 2. Synthesis of Cyanoformamides 2 from 1-Acyl-1-
a
carbamoyl Oximes 1
b
entry
1
R1
R2
2
yield (%)
1
1a
1b
1c
1d
1e
1f
C6H5
H
H
H
H
H
H
H
H
H
H
H
Me
Et
2a
2b
2c
2d
2e
2f
83
91
94
88
67
95
84
89
86
92
89
83
85
72
2
4-MeOC6H4
4-ClC6H4
4-MeC6H4
4-CF3C6H4
2-MeOC6H4
2-ClC6H4
2,4-Me2C6H3
5-Cl-2-MeOC6H3
4-Cl-2,5-(MeO)2C6H2
Bn
3
4
5
6
a
Table 1. Reaction of 1a with POCl3 in Different Conditions
7
1g
1h
1i
2g
2h
2i
8
9
10
11
12
13
14
1j
2j
1k
1l
2k
2l
C6H5
b
entry POCl3 (equiv)
solvent
temp (°C) time (h) yield (%)
1m
1n
Et
2m
2n
(CH2)5
1
2
3
4
5
6
7
8
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.5
DMF
rt
12
2
mixture
21
a
DMF
80
Reagents and conditions: 1 (1.0 mmol), POCl3 (1.5 mmol), DCE
b
CH2Cl2
CH2Cl2
CH3CN
toluene
DCE
rt
12
12
2
0
(5.0 mL), 80 °C, 1−2.5 h. Isolated yield.
reflux
reflux
80
24
was observed that the reactions of oximes 1b−k bearing varied
aryl and alkyl primary amide groups proceeded efficiently to
afford the corresponding cyanoformamides 2b−k in good-to-
high yields (entries 2−11). The versatility of this protocol for
cyanoformamide synthesis was further evaluated by reacting
1l−n bearing secondary amide groups with the POCl3 in DCE
(entries 12−15). The results shown above demonstrate the
efficiency and synthetic value of the reaction for the synthesis of
cyanoformamides 2 with respect to substrates 1 bearing variable
amide groups R1 and R2.
47
2
59
reflux
reflux
2
72
DCE
2
83
b
a
Reagents and conditions: 1 (1.0 mmol), solvent (5.0 mL). Isolated
yield.
POCl3 (1.2 equiv) in DMF at 80 °C for 2 h, the reaction
proceeded smoothly and furnished a colorless solid after
workup and purification by silica gel column chromatography
of the resulting reaction mixture, which was characterized as
phenylcarbamoyl cyanide 2a on the basis of its NMR spectral
and analytical data (Table 1, entry 2). Moreover, the presence
of the absorption band at 2234 cm−1 in its IR spectra is
assigned to the CN stretching mode, which further confirms
the formation of the cyano group (see Supporting Informa-
tion).
On the basis of the obtained results and our previously
reported work,14,15,17 a plausible mechanism for the synthesis of
cyanoformamides 2 is presented in Scheme 3. The reaction
Scheme 3. Plausible Mechanism for the Reaction of 1 with
POCl3 in DCE
Our optimization of the reaction conditions, including
solvent, reaction temperature, and the ratio of POCl3 to 1a
were then investigated as shown in Table 1. No reaction was
observed when 1a was treated with POCl3 (1.2 equiv) in
CH2Cl2 at rt (Table 1, entry 3). Increasing the reaction
temperature to reflux furnished 2a in 24% yield along with the
recovery of 1a in 53% yield (Table 1, entry 4). Similarly, the
yield of 2a was still not satisfactory when the reaction of 1a
with POCl3 (1.2 equiv) was performed in acetonitrile under
reflux or in toluene at 80 °C (Table 1, entries 5 and 6). By
subjecting 1a and POCl3 (1.2 equiv) to 1,2-dichloroethane
(DCE) under reflux, the reaction proceeded smoothly and
afforded the corresponding 2a in 72% yield (Table 1, entry 7).
The optimal conditions entailed reacting 1a with POCl3 (1.5
equiv) in DCE at 80 °C for 2 h, whereby the yield of 2a
reached 83% (Table 1, entry 8).
commences from the phosphorylation between oxime 1 and
POCl3 to generate phosphorate intermediate A and a chloride
anion.15,18 The attack of the chloride anion on the carbonyl
group of A along with elimination of acyl chloride and the
phosphorodichloride anion gives rise to cyanoformamide 2.19
In summary, a facile and efficient one-pot synthesis of
cyanoformamides 2 has been developed from readily available
1-acyl-1-carbamoyl oximes 1 in the presence of POCl3 in DCE.
This protocol is associated with readily available starting
materials, mild conditions, good-to-high yields, a broad
substrate scope, and potential utility of the products. Expanding
B
DOI: 10.1021/ol503643p
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(15) For POCl3-mediated heteroannulations, see: (a) Venkatesh, C.;
Singh, B.; Mahata, P. K.; Ila, H.; Junjappa, H. Org. Lett. 2005, 7, 2169.
(b) Gammon, D. W.; Hunter, R.; Wilson, S. A. Tetrahedron 2005, 61,
10683. (c) Sharma, S. D.; Anand, R. D.; Kaur, G. Synth. Commun.
2004, 34, 1855. (d) Sharma, S. D.; Kanwar, S. Indian J. Chem. Sect. B:
Org. Chem. Incl. Med. Chem. 1998, 37, 965.
(16) Huggins, M.; Barber, P.; Florian, D.; Howton, W. Synth.
Commun. 2008, 38, 4226.
(17) Xiang, D.; Huang, P.; Wang, K.; Zhou, G.; Liang, Y.; Dong, D.
Chem. Commum. 2008, 6236.
the scope of the methodology and utilization of the products
are currently under investigation in our laboratory.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Experimental details, spectral and analytical data, copies of H
NMR and 13C NMR spectra for new compounds 2. These
materials are available free of charge via the Internet at http://
pubs.acs.org.
(18) Katagiri, N.; Ishikura, M.; Morishita, Y.; Yamaguchi, M.
Heterocycles 2000, 52, 283.
(19) Bachman, G.; Welton, D. J. Org. Chem. 1947, 12, 221.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: ning.zhang@ciac.ac.cn.
*E-mail: dwdong@ciac.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support of this research by the National Natural
Science Foundation of China (21172211, 21304086, and
51373170) is greatly acknowledged.
REFERENCES
■
(1) (a) Beketoff, N. Chem. Ber. 1870, 3, 872. (b) Welcher, R.;
Castellion, M.; Wystrach, V. J. Am. Chem. Soc. 1959, 81, 2541.
(2) (a) Chang, Y.; Lee, H.; Kim, K. Tetrahedron Lett. 2001, 42, 8197.
(b) Paz, J.; Per
2010, 75, 8039.
́
ez-Balado, C.; Iglesias, B.; Munoz, L. J. Org. Chem.
̃
(3) Hirata, Y.; Yada, A.; Morita, E.; Nakao, Y.; Hiyama, T.; Ohashi,
M.; Ogoshi, S. J. Am. Chem. Soc. 2010, 132, 10070.
(4) Ford, R.; Knowles, P.; Lunt, E.; Marshall, S.; Penrose, A.;
Ramsden, C.; Summers, A.; Walker, J.; Wright, D. J. Med. Chem. 1986,
29, 538.
(5) (a) Kobayashi, Y.; Kamisaki, H.; Yanada, R.; Takemoto, Y. Org.
Lett. 2006, 8, 2711. (b) Kobayashi, Y.; Kamisaki, H.; Takeda, H.; Yasui,
Y.; Yanada, R.; Takemoto, Y. Tetrahedron 2007, 63, 2978. (c) Yasui,
Y.; Kamisaki, H.; Takemoto, Y. Org. Lett. 2008, 10, 3303.
(6) (a) Tsukamoto, S.; Kato, H.; Hirota, H.; Fusetani, N. J. Org.
Chem. 1996, 61, 2936. (b) Schoenfeld, R.; Ganem, B. Tetrahedron Lett.
1998, 39, 4147.
(7) Harvey, J., Jr.; Han, J. C.-Y.; Reiser, R. W. J. Agric. Food Chem.
1978, 26, 529.
(8) Tsukamoto, S.; Kato, H.; Hirota, H.; Fusetani, N. J. Org. Chem.
1996, 61, 2936.
(9) Schoenfeld, R. C.; Ganem, B. Tetrahedron Lett. 1998, 39, 4147.
(10) Fu, X.; Schmitz, F. J. Nat. Prod. 1999, 62, 1072.
(11) (a) Oku, A.; Shono, M.; Oda, R. Makromol. Chem. 1964, 78,
186. (b) Linn, W.; Webster, O.; Benson, R. J. Am. Chem. Soc. 1965, 87,
3651. (c) Martin, E. Org. Synth. 1988, Coll. Vol. 6, 268. (d) Katagiri,
N.; Morishita, Y.; Kaneko, C. Heterocycles 1997, 46, 503. (e) Katagiri,
N.; Ishikura, M.; Morishita, Y.; Yamaguchi, M. Heterocycles 2000, 52,
283.
(12) García-Egido, E.; Paz, J.; Iglesias, B.; Munoz, L. Org. Biomol.
̃
Chem. 2009, 7, 3991.
(13) (a) Pan, W.; Dong, D.; Wang, K.; Zhang, J.; Wu, R.; Xiang, D.;
Liu, Q. Org. Lett. 2007, 9, 2421. (b) Xiang, D.; Yang, Y.; Zhang, R.;
Liang, Y.; Pan, W.; Huang, J.; Dong, D. J. Org. Chem. 2007, 72, 8593.
(c) Xiang, D.; Wang, K.; Liang, Y.; Zhou, G.; Dong, D. Org. Lett. 2008,
10, 345. (d) Zhang, R.; Liang, Y.; Zhou, G.; Wang, K.; Dong, D. J. Org.
Chem. 2008, 73, 8089. (e) Zhang, R.; Zhang, D.; Liang, Y.; Zhou, G.;
Dong, D. J. Org. Chem. 2011, 76, 2880. (f) Huang, P.; Zhang, N.;
Zhang, R.; Dong, D. Org. Lett. 2012, 14, 370.
(14) Wang, K.; Xiang, D.; Liu, J.; Pan, W.; Dong, D. Org. Lett. 2008,
10, 1691.
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DOI: 10.1021/ol503643p
Org. Lett. XXXX, XXX, XXX−XXX