A facile synthesis of 2-aminobenzoxazoles and 2-aminobenzimidazoles using N -cyano- N -phenyl- P -toluenesulfonamide (NCTS) as an efficient electrophilic cyanating agent

Article abstract of DOI:10.1055/s-0034-1380166

A facile synthesis of 2-aminobenzoxazole and 2-aminobenzimidazole derivatives employing a nonhazardous electrophilic cyanating agent: N-cyano-N-phenyl-p-toluenesulfonamide (NCTS) with various substituted 2-aminophenols and benzene-1,2-diamine derivatives in the presence of lithium hexamethyldisilazide (LiHMDS) is described. This novel protocol boasts operational simplicity, shorter reaction time, and simple workup.

Full text of DOI:10.1055/s-0034-1380166

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 897–900
letter
897
M. Kasthuri et al.
Letter
Synlett
A Facile Synthesis of 2-Aminobenzoxazoles and 2-Aminobenzim-
idazoles Using N-Cyano-N-phenyl-p-toluenesulfonamide (NCTS)
as an Efficient Electrophilic Cyanating Agent
Mahesh Kasthuri*
N
C
NH2
H. Sharath Babu
K. Shiva Kumar
Ch. Sudhakar
N
N
S
LiHMDS
R1
R1
NH2
+
O
THF, 5 °C to r.t.
X
XH
O
14 examples
up to 96% yield
P. V. Nagendra Kumar
X = O, NH, NR2
Department of Chemistry, GITAM University, Hyderabad Campus,
Rudraram Village, Patancheru Mandal, Medak Dist., Telangana State,
502 329, India
mahesh.kasthuri@gmail.com
mahesh.kasthuri@gitam.in
Received: 17.11.2014
Accepted after revision: 22.01.2015
Published online: 19.02.2015
of multiple reagents and tedious experimental procedures.
Thus, the development of novel, versatile, safe and nonhaz-
ardous synthetic protocols for their synthesis still remains
as a challenge to modern organic chemists.
DOI: 10.1055/s-0034-1380166; Art ID: st-2014-b0948-l
Abstract A facile synthesis of 2-aminobenzoxazole and 2-aminobenz-
imidazole derivatives employing a nonhazardous electrophilic cyanating
agent: N-cyano-N-phenyl-p-toluenesulfonamide (NCTS) with various
substituted 2-aminophenols and benzene-1,2-diamine derivatives in
the presence of lithium hexamethyldisilazide (LiHMDS) is described.
This novel protocol boasts operational simplicity, shorter reaction time,
and simple workup.
In general, these heterocycles are often accessed from
the corresponding 2-aminophenol and benzene-1,2-di-
amine derivatives via coupling reactions with cyanogen
bromide, which typically require reflux temperature and
extended reaction times.8 Moreover, cyanogen bromide is
highly toxic and its toxicity resembles that of hydrocyanic
acid.14 Therefore, there is a need for an alternative less toxic,
eco-friendly electrophilic cyanating agent for the safe and
efficient synthesis of these biologically important com-
pounds. After an extensive survey on the source of nonme-
tallic, less toxic electrophilic cyanating agents, we were
Key words 2-aminobenzoxazoles, 2-aminobenzimidazoles, electro-
philic cynating agent, nonhazardous, N-cyano-N-phenyl-p-toluenesul-
fonamide
2-Aminobenzoxazoles and 2-aminobenzimidazoles are
important core scaffolds in many biologically active com-
pounds. These structural derivatives are crucial pharmaco-
phores in drug discovery.1 They are identified as potential
antibacterial agents,2 anti-Alzheimer’s agents,3 aurora ki-
nase inhibitors,4 antihistamine drugs such as astemizole5
and norastemizole.6 However, due to remarkable side ef-
fects and multidrug resistance7 to existing potential benz-
oxazoles and benzimidazole, there is a pressing need for
novel drug discovery collectively by synthetic chemists and
biologists.
Several methods have been reported in the literature for
their synthesis such as reaction between bisnucleophiles
and toxic cyanogen bromide,8 coupling of bisnucleophiles
to carbon disulfide9 or isothiocyanates10 followed by intra-
molecular condensation, transition-metal-catalyzed ami-
nation with N-chloroamines,11a amines11b and imides,11c
metal-free methods for the oxidative C–H bond activation
of benzoxazoles.12 Recently, isocyanide insertion reactions
have also been developed.13 However, most of the existing
protocols seriously suffered from environmental concern,
toxic issues, use of expensive metal catalyst or ligands, use
attracted
to
N-cyano-N-phenyl-p-toluenesulfonamide
(NCTS), which was first synthesized by Kurzer in 1949 (Fig-
ure 1).15 It is an air-stable, less toxic, crystalline compound,
and it can be easily synthesized from inexpensive phenyl
urea by dehydrative tosylation in pyridine without the use
of toxic cyanogen halides in an environmentally benign
fashion. Very recently, its potential electrophilic cyanating
utility was reported by Beller and coworkers via rhodium-
catalyzed cyanation of arylboronic acids.16 Furthermore,
the same group has also developed an electrophilic cyana-
tion through the reaction of NCTS with aromatic Grignard
N
C
N
O
S
O
Figure 1 Structure of nonhazardous electrophilic cyanating agent:
N-cyano-N-phenyl-p-toluenesulfonamide (NCTS)
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 897–900

898
M. Kasthuri et al.
Letter
Synlett
reagents.17 Similarly, BF3·OEt2-catalyzed direct cyanation of
indoles and pyrroles using NCTS was reported by Wang and
coworkers.18
derivatives, we found the maximum yield with 4-amino-
[1,1′-biphenyl]-3-ol as a bisnucleophile (Table 2, entry 6).21
Without any further alteration of the optimized reaction
conditions, we have also successfully synthesized 2-amino-
benzimidazoles from substituted N1-alkylbenzene-1,2-di-
amine derivatives with almost similar reactivity in good to
moderate yields (Table 2, entries 8–14).22 The substrate
scope of the various substituted aminophenols and ben-
zene-1,2-diamines possessing electron-donating and elec-
tron-withdrawing groups were studied, as shown in Table
2. This result reveals that irrespective of the electronic na-
ture of the substrate, all the reactions ran smoothly under
the standard conditions to provide the desired compounds
in moderate to good yields.
To the best of our knowledge there are no literature re-
ports available for the construction of 2-aminobenzoxazole
and 2-aminobenzimidazoles by using NCTS. Therefore,
herein we report for the first time the synthesis of these bi-
ologically important heterocycles by using NCTS as poten-
tial electrophilic cyanating agent. As an initial screen, we
have carried out a reaction between 2-aminophenol and
NCTS in the presence of 3.0 equivalents of LiHMDS at 5 °C
to room temperature for one hour, which resulted in the
formation of desired 2-aminobenzoxazole in 75% yield (Ta-
ble 1, entry 1).
In addition, we attempted to evaluate the effect of other
alternative HMDS bases such as KHMDS and NaHMDS,
wherein we observed 8% and 12% of the desired compound
formation, respectively (Table 1, entries 2 and 3). Next, we
wish to optimize the stoichiometry of LiHMDS. Surprising-
ly, we observed excellent yields with 1.0 equivalent of
LiHMDS for this conversion (Table 1, entry 4). Further, ex-
ploration for suitable base was examined with LDA. It was
observed that reaction with LDA was found to be sluggish;
as a result lower yield was obtained (Table 1, entry 5). Addi-
tionally, we began to investigate the use of bases with dif-
ferent counteranion such as NaOt-Bu, NaOAc, and KOAc to
find a simple alternative to LiHMDS. We found that these
bases were ineffective to form the desired 2-aminobenzox-
azole (Table 1, entries 6–8).
Table 2 Synthesis of 2-Aminobenzoxazoles and 2-Aminobenzimidaz-
oles Using NCTS and LiHMDS Combination
NH2
N
NCTS (I)
R
R
NH2
LiHMDS
THF, 5 °C to r.t., 1 h
X
XH
1a–n
X = O, NH, NR
Entry Substrate
Product
Yield
(%)a
N
O
NH2
OH
NH2
1
90
1a
N
NH2
NH2
2
92
78
O
Table 1 Development of Reaction Conditions for Electrophilic Cyana-
tion and Cyclization
OH
1b
N
O
NH2
OH
NH2
NH2
N
O
Ph
CN
reagent
3
N
+
NH2
O2N
1c
O2N
THF, temp
Ts
OH
Base
N
Yield (%)a
NH2
Entry
Molar ratio (equiv) Temp
NH2
4
94
86
O
1
2
3
4
5
6
7
8
LiHMDS
KHMDS
NaHMDS
LiHMDS
LDA
3.0
3.0
3.0
1.0
1.0
3.0
3.0
3.0
5 °C to r.t.
75
8
Br
1d
Br
OH
5 °C to r.t.
5 °C to r.t.
5 °C to r.t.
5 °C to r.t.
r.t.
N
O
NH2
12
90
38
–
NH2
5
Cl
1e
Cl
OH
NaOt-Bu
NaOAc
KOAc
r.t.
–
N
NH2
OH
6
96
93
r.t.
–
NH2
O
a Isolated yields after silica gel column purification.
1f
N
O
NH2
Based on the above observations, it was found that
LiHMDS could be the most effective base for the desired
transformation. With the optimized reaction conditions in
hand,19 we have successfully synthesized various substitut-
ed 2-aminobenzoxazole derivatives in good yields (Table 2,
entries 1–7).20 Among the various substituted aminophenol
NH2
7
MeO
1g
MeO
OH
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 897–900

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M. Kasthuri et al.
Letter
Synlett
Table 2 (continued)
Entry Substrate
evidence for our mechanistic proposal we have isolated the
eliminated compound III and confirmed by mass m/z =
248.4 [M + H]+.
Product
Yield
(%)a
N
NH2
NH2
NH2
Ts
LiHMDS
NH2
+
8
9
56
62
N
Ph
N
H
XH
X
NH2
1h
N
–
N
L+i
I
Ts
N
X = O, NH, NR
N
NH2
II
NH2
Ph
N
H
NH2
Ts
1i
NH
Ph
III
Br
N
Br
NH2
NH2
H
N
10
11
12
60
52
66
NH2
X
N
X
N
H
NH2
N
NH2
NH
1j
X
O2N
N
O2N
NH2
IV
VI
V
NH2
N
H
Scheme 1 Proposed plausible reaction pathway
NH2
1k
In summary, for the first time we have successfully de-
veloped a facile and eco-friendly synthesis of 2-aminoben-
zoxazoles and 2-aminobenzimidazoles using air-stable,
eco-friendly electrophilic cyanating agent: N-cyano-N-phe-
nyl-p-toluenesulfonamide (NCTS) in combination with
LiHMDS. Wide range of substrate scope involving various
substituted 2-aminophenols and benzene-1,2-diamine de-
rivatives were studied. We expect that this novel method is
highly applicable in the field of combinatorial chemistry, li-
brary synthesis and development of various new classes of
2-aminobenzoxazoles and 2-aminobenzimidazoles for the
novel drug discovery. Prominent features of this novel syn-
thetic protocol are operational simplicity and eco-friendly
approach.
MeO
N
MeO
Cl
NH2
NH2
NH2
N
H
1l
Cl
NH2
N
N
NH2
13
14
86
79
NH
Me
Me
1m
O2N
N
N
O2N
NH2
NH2
NH
Me
Me
1n
a Isolated yields after column chromatography purification.
Acknowledgment
However, yields were lower in case of substituted ben-
zene-1,2-diamine derivatives (Table 2, entries 8–11). Next,
the scalability of the developed reaction conditions at a
scale of 10 g of 2-aminophenol for the synthesis of 2-ami-
nobenzoxazole was examined. An excellent yield (88%) was
achieved with 1.0 equivalent of LiHMDS and a reaction time
of one hour.
Based on the above observations, we postulated the fol-
lowing reaction mechanism for our synthetic route. Initial
reaction between bisnucleophile and NCTS in the presence
of an equimolar ratio of LiHMDS leads to the formation of II,
which will then undergo elimination of III and leading to
the formation of intermediate IV (Scheme 1). The in situ
formed intermediate IV subsequently undergoes cycliza-
tion to form intermediate V. Finally, during the workup in-
termediate V is converted into the desired product VI. As an
We thank to Department of Chemistry, GITAM University, Hyderabad
Campus for providing financial and instrumental support.
References and Notes
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Mp 136–138 °C; Rf = 0.28 (40% EtOAc–cyclohexane). 1H NMR
(400 MHz, DMSO-d6): δ = 6.96 (d, J = 7.65 Hz, 1 H), 7.09 (s, 1 H),
7.12 (m, 2 H), 7.19 (d, J = 7.28 Hz, 1 H), 7.30 (m, 2 H), 7.32 (m, 1
H), 7.36 (s, 2 H, NH2). 13C NMR (100 MHz, DMSO-d6): δ = 118.2,
121.1, 124.6, 126.5, 128.2, 132.4, 138.2, 142.8, 144.6, 152.1, 168.
ESI-MS: m/z = 211.19 [M + H]+.
Spectral Data for 1g (Table 2, Entry 7)
Mp 168–170 °C; Rf = 0.32 (40% EtOAc–cyclohexane). 1H NMR
(400 MHz, DMSO-d6): δ = 7.22 (d, J = 8.4 Hz, 1 H), 6.90 (d, J = 2.4
Hz, 1 H), 6.76 (s, 1 H), 5.24 (br s, 2 H, NH2), 3.82 (s, 3 H). 13C NMR
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166.2. ESI-MS: m/z = 165.2 [M + H]+.
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