Organic Letters
Letter
Scheme 3. Preparation of N1-Substituted Cyanamides (4)
from Amidoximes (2)
approach for the preparation of a wide variety of cyanamide
derivatives (4).
a,b
The reactions of p-toluamidoxime (2b) with TsCl under
various conditions were investigated to optimize the rearrange-
ment reaction (Table 1). The optimum conditions were to
Table 1. Optimization for the Formation of N-
Toluylcyanamide (2b)
a
entry
base
Et3N
solvent (0.1 M)
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
3
3
3
3
3
3
3
3
1
64
87
64
82
47
83
45
80
95
DIPEA
DBU
DABCO
Cs2CO3
DIPEA
DIPEA
Cs2CO3
THF
MeCN
pyridine (1 M)
a
Isolated yield.
a
b
Isolated yield from amidoxime 2; Conditions A: TsCl (1.05 equiv),
DIPEA (1.05 equiv), CH2Cl2 (0.1 M), 0 °C to rt, 3 h. Conditions B: o-
NsCl (equiv), DIPEA, CH2Cl2 (0.1 M), reflux, 1 h. Conditions C:
ArSO2Cl (1.05 equiv), pyridine (1 M), 0 °C to rt, 0.5−12 h
carry out the reaction with 1.05 equiv of TsCl and 1.05 equiv of
DIPEA in CH2Cl2 from 0 °C to room temperature in 3 h
(entry 2 in Table 1, as conditions A). Alternatively, we also
found that the yield could be substantially improved when the
reaction was carried out in pyridine at ambient temperature
(entry 9 in Table 1, as conditions C).
c
d
e
(monitored by TLC). 24 h. 2.1 equiv of TsCl and DIPEA. 1.05
equiv of TsCl and DIPEA.
With the optimized conditions established, various amidox-
imes 2a−u, prepared from carbonitriles 1a−u with hydroxyl-
amine, were subjected to the reaction with TsCl under
conditions A in order to explore the scope and generality of
the reaction. Most of the π-electron-rich aryl amidoximes (2a−
c,h,i,k), except m-methoxybenzamidoxime (2g), can undergo
the rearrangement to afford the corresponding cyanamides
(4a−c,h,i,k) in good yields. The reactions of p-nitro- and p-
trifluoromethylbenzamidoximes (2e,f), 2-chloropyridine-3-ami-
doxime (2l) as well as butyramidoxime (2m) resulted in the
corresponding O-tosyl amidoximes (3e,f,l,m) as their only
products, whereas the rest of the amidoximes (2d,g) gave
complicated results (Scheme 3).
We postulated that the heterolytic N−O bond cleavage of
the amidoximes is the driving force for the rearrangement.
Thus, o-nitrobenzenesulfonyl chloride (o-NsCl) was employed
instead of TsCl to provide a better leaving group, and the
reaction temperature was slightly raised to the reflux temper-
ature of CH2Cl2 to facilitate the rearrangement. The improved
conditions allowed the rearrangement to proceed, and the
corresponding cyanamides (4) were obtained in good yields
(conditions B in Scheme 3). The reaction of the amidoximes
(2) with TsCl or o-NsCl in pyridine produced the same results
with even better yields (conditions C in Scheme 3). It is
notable that the reaction of p-aminobenzamidoxime (2p) under
conditions A gave only 33% of the isolated product, which was
identified as N1-tosylated N1-phenylcyanamide (4p). Upon
increasing both TsCl and DIPEA to 2.1 equiv, 4p was obtained
in 77% yield. N1-Tosyl-N1-phenylethenylcyanamide (4q) was
obtained from cinnamidoxime (2q) under the same circum-
stances (Scheme 3).
Since nitrene has been proposed as the reactive intermediate
in the Tiemann rearrangement, the reactions of benzamidox-
imes possessing ortho-nucleophilic substituents were inves-
tigated, with the intent to trap the putative nitrene intermediate
with the ortho-nucleophiles prior to the rearrangement. We
anticipated that 3-amino-benzo-1,2-heteroazoles (5′) would be
obtained if the nitrene intermediate was formed and
immediately trapped by the adjacent heteroatom nucleophiles.
In contrast, 2-aminobenzo-1,3-heteroazoles (5) would be
obtained if the Tiemann rearrangement took place prior to
the intramolecular nucleophilic ring closure.
When 2-hydroxybenzamidoxime (2r) was treated with TsCl
under conditions A, 2-aminobenzoxazole (5r) was obtained as
the sole product in 67% yield, and its structure was confirmed
by comparing the NMR spectra with the same compound
previously reported in the literature.17 Similarly, when 2-
aminobenzamidoxime (2s) was reacted with 1.05 equiv of TsCl
under conditions A, 1-tosyl-2-aminobenzimidazole (5s) was
obtained as the only product in 35% yield, and its structure was
confirmed by X-ray crystallography. The yield was increased to
75% when 2.1 equiv of TsCl and DIPEA were used. To further
clarify the sequence of the tosylation and cyclization in the
reaction, both 5-chloro- and 5-nitro-2-aminobenzamidoximes
(2t,u) were subjected to the same conditions. The correspond-
ing 6-substituted 1-tosyl-2-aminobenzimidazoles (5t,u) were
obtained as the only products, and their structures were
confirmed by X-ray crystallography. It is noticeable that the N-
tosylation took place exclusively at the ring-nitrogen instead of
the exocyclic amino group. The regiospecific tosylation was
concatenated with the reaction sequence in which the
B
dx.doi.org/10.1021/ol403645y | Org. Lett. XXXX, XXX, XXX−XXX