because they serve as versatile building blocks for hetero-
cyclic compounds in the fields of organic synthetic chemistry,
medicinal chemistry, and materials science. Although cy-
anoimidates are important chemical reagents, there is a
paucity of reliable synthetic methods for producing them.2
The yields for synthesis of aryl-substituted N-cyanoimidates
are also unsatisfactory. We report an efficient and convenient
synthetic route (Scheme 1) for synthesizing N-cyanoimidates
via a one-pot reaction of aldehyde derivatives in a t-BuONa/
NBS system to give aromatic cyanoimidates in good to
excellent yields. The results are summarized in Tables 1 and
2.
Scheme 2
.
Tentative Mechanism for Selective Cyanoimidation
and Oxidative Esterification of Aldehyde
With an interest in synthesizing potentially bioactive
nitrogenous compounds, we focused on the application and
prolongation of active nitrogen sources and development of
the catalyzed amidation. We found that the saturated C-H
bonds of cyclic ethers and tertiary amines could be activated
by transition metals.3 We also attended to a series of studies
on metal-catalyzed amidation of aldehydes and amidation
of aldehydes under metal-free conditions.4 Although the
methodologies mentioned above were well suited for some
amides, such as carboxamide and sulfonamide, and could
effectively form carbon-nitrogen bonds, the use of cyana-
mide as a nitrogen source has never been reported in the
literature. As part of our continuing interest in catalyzed
amidation, we would like to establish an effective reaction
system for the oxidative amidation of aldehydes and ketones
Table 1. Optimization of Selective Reaction Conditionsa
% yield (conversion)b
of 3b/4b
entry
base
oxidant
SeO2
Scheme 1. Cyanoimidation of Aldehydes
1
2
3
4
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
K2CO3
trace/-
12/-
trace/-
24/-
32/25
64/16
35/37 (86)
41/12
58/15
78/8 (91)
83/trace (94)
85/trace (97)
-/85 (87)
PhI(OAc)2
c
CuCl2
NCS
I2
5
6
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
7d
8
using cyanamide as a nitrogen source. In our first attempt to
obtain amide derivatives, we chose PhI (OAc)2 as the oxidant
and either Al2O3 or K2CO3 as the base. Unfortunately,
products of amidation were not obtained; only the starting
material was recovered. However, using t-BuOK/NBS with
CH3OH as solvent led to the formation of the nonamidated
product N-cyanoimidate 3 (Scheme 1).
A possible mechanism for the selective N-cyanoimidation-
esterification of aldehydes is proposed in Scheme 2. According
to route 1, condensation of compound A, which was determined
9
KOH
10e
11f
12g
13
t-BuONa
t-BuONa
t-BuONa
a Unless otherwise noted, all reactions were carried out with molar ratio
1b/H2NCN/base ) 1:1.2:1.5 at rt for 30 min, and then oxidant (1.5 equiv
of 1) was added at 50 °C for 12 h. b Isolated yields. c 20 mol % catalytic
amounts CuCl2 of 1b were used. d The addition of each reagent had no
interval. e The molar ratio was 1b/H2NCN/t-BuONa/NBS ) 1:2:2:2. f The
molar ratio was 1b/H2NCN/t-BuONa/NBS ) 1:3:3:3. g The molar ratio was
1b/H2NCN/t-BuONa/NBS ) 1:4:4:4.
1
by H NMR and HRMS, occurred at first. The subsequent
Michael addition of CH3OH to N-(benzo[d][1,3]dioxol-5-
ylmethylene) cyanamide generated intermediate B.5 Subse-
quently, the active hydrogen of intermediate B was captured
by bromine to produce haloamine C in the presence of NBS,
finally haloamine C which in the presence of an alkali converted
to 3A with the elimindation of HBr.6 Similar oxidation and
elimination steps were performed via hemiacetal intermediate
D and its halide E to generate carboxylic ester 4A using NBS
as an oxidant7 via route 2.
(3) (a) He, L.; Yu, J.; Zhang, J.; Yu, X. -Q. Org. Lett. 2007, 9, 2277.
(b) Liu, N.; Tang, B. Y.; Chen, Y.; He, L. Eur. J. Org. Chem. 2009, 26,
2059.
(4) (a) Yoo, W. J.; Li, C. J. J. Am. Chem. Soc. 2006, 128, 13064. (b)
Chan, J.; Baucom, K. D.; Murry, J. A. J. Am. Chem. Soc. 2007, 129, 14106.
(c) Chang, J. W. W.; Chan, P. W. H. Angew. Chem., Int. Ed. 2008, 47,
1138. (d) Seo, S.; Marks, T. J. Org. Lett. 2008, 10, 317. (e) Suto, Y.;
Yamagiwa, N.; Torisawa, Y. Tetrahedron Lett. 2008, 49, 5732. (f) Wang,
L.; Fu, H.; Jiang, Y. Y.; Zhao, Y. F. Chem.sEur. J. 2008, 14, 10722. (g)
Ekoue-Kovi, K.; Wolf, C. Org. Lett. 2007, 9, 3429. (h) Gao, J.; Wang,
G. W. J. Org. Chem. 2008, 73, 2955.
(5) (a) Ishihara, M.; Togo, H. Tetrahedron. 2007, 63, 1474. (b) Li, G. L.;
Fronczek, F. R.; Antilla, J. C. J. Am. Chem. Soc. 2008, 130, 12216.
Org. Lett., Vol. 11, No. 23, 2009
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