use of inorganic bases was found to be superior to the use
of Et3N for the N-arylation process. The use of K3PO4·3H2O
in the transformation of the tetrazole resulted in higher con-
versions and enhanced selectivity in favor of the 2-azido de-
rivative 1a compared to the use of Cs2CO3, K2CO3, and
KOH (Table 1, entries 1–4). Among the ligands screened
(L1–L5), L5 was found to be the most effective (Table 1, en-
tries 5–8). Copper(I) and copper(II) sources (CuBr, Cu2O,
5 mol% CuACTHGNUTERN(NUG OAc)2·H2O in DMF at 908C for 1 h, it under-
went reduction[10] to give 2a with 100% conversion and se-
lectivity.
Alternatively, the tetrazole derivative can also be convert-
ed into 2a via 1a by using 5 mol% CuACHTUNRTGENUNG(OAc)2·H2O and
2 equivalents of K3PO4·3H2O in DMF at 908C for 2 h in the
absence of ligand (Scheme 3). The reactions of 4-Me, 4-
OMe and 2,4-dimethylphenylisothiocyanate with 4-Me- and
4,5-dimethyl-2-bromoaniline were investigated. The reac-
tions gave the target compounds 2a–f in 62–72% yield. The
structure of 2e was confirmed by single-crystal X-ray analy-
sis (see the Supporting Information).
Finally, a click reaction of 2-azido-[1H]-benzo[d]imidazole
and aryl alkynes to give substituted 2-(1H-1,2,3-triazo-1-yl)-
1H-benzo[d]imidazoles was investigated (Scheme 4). Opti-
mization studies revealed that the required products could
be obtained when using reaction conditions developed by
the research group of Sharpless (5 mol% CuI and 2 equiva-
lents of Et3N at room temperature).[11a] The click reactions
of 2-azido-[1H]-benzo[d]imidazole (1a, 1m, 1v and 1w)
gave 2-(1H-1,2-3-triazo-1-yl)-1-aryl-1H-benzo[d]imidazoles
3a—d, respectively, in high yields. Recrystallization of 3c in
MeOH gave crystals, which were used to confirm the struc-
ture of 3c by single-crystal X-ray analysis (see the Support-
ing Information).
CuI, CuSO4·5H2O, and CuACHTNUTRGNE(UNG OAc)2·H2O) exhibited similar
levels of activity and selectivity (Table 1, entries 1 and 9–
12). For the N-arylation/tautomerization reaction, either
lowering the amount of base (1.5 equivalents), lowering the
amount of the copper source (2.5 mol%), or conducting the
reaction in the absence of ligand gave lower conversions;
for these reactions, 1a and 2a were obtained in less than
85% conversion (Table 1, entries 13–15). In a control reac-
tion in which a copper source was absent, 1a and 2a were
not formed (Table 1, entry 16).
2-Iodoaniline could also be used as a substrate and the re-
action gave the target products 1a and 2a in a shorter reac-
tion time [Eq. (1)]. In contrast, in the case of 2-chloroani-
line, the N-arylation/tautomerization reaction did not occur
and only the tetrazole derivative could be isolated (see the
Supporting Information).
A proposed catalytic cycle is shown in Scheme 5. Toward
determining the reaction pathway, a 1:1 mixture of 4-
methyl-2-bromoaniline and phenylisothiocyanate was stirred
in DMF at room temperature for 14 hours to afford the cor-
responding thiourea.[5k] When the thiourea derivative was
added to a mixture of 3 equivalents of sodium azide,
3 equivalents of Et3N, and 50 mol% CuACHTNUGTRNEUNG(OAc)2·H2O, the cor-
responding tetrazole derivative was obtained with 100%
conversion [Eq. (2)]. Recrystallization of the tetrazole deriv-
ative in MeOH gave single crystals, which were used to de-
termine the structure of the tetrazole by single-crystal X-ray
analysis (see the Supporting Information). The tetrazole de-
rivative underwent N-arylation followed by tautomeriza-
With optimized conditions established, the scope of the
protocol was next explored (Scheme 2). The process was
found to be generally applicable; various isothiocyanates
and 2-bromoaniline derivatives in the presence of sodium
azide gave the corresponding 2-azido-1-substituted-1H-ben-
zo[d]imidazoles 1b–y in moderate to good yield. Aryl iso-
thiocyanates bearing electron-donating substituents on the
aryl ring (4-Me, 4-OMe, 4-Et, 4-iPr, 2,4-dimethyl, 3,4-di-
methyl, 2,5-dimethyl, and 3,5-dimethyl groups) were more
reactive than those bearing electron-withdrawing substitu-
ents on the aryl ring (4-Cl, 4-F and, 4-CF3 groups). In addi-
tion, aryl isothiocyanates were more reactive than alkyl iso-
thiocyanates. Regarding the scope of the 2-bromoaniline
component, the use of both 2-bromoaniline (nonsubstituted)
and the 4-Me, 4-iPr, 4-Cl, 4-OMe, 2,4-dimethyl, and 3,4-di-
methylbromoaniline derivatives gave good yields of the cor-
responding products. The structure of compound 1c was
confirmed by single-crystal X-ray analysis (see the Support-
ing information).
tion[6] when treated with
Cu(OAc)2·H2O, 10 mol % L5, and 2 equivalents of
a
mixture of 5 mol%
AHCTUNGTRENNUNG
K3PO4·3H2O at room temperature; the reaction gave a 19:1
mixture of 1a and 2a in 100% conversion [Eq. (3)]. Further-
more, 1a could be reduced to give 2a in 100% conversion
when the substrate was treated with 5 mol% Cu
in DMF at 908C for 1 h [Eq. (4)]. In addition, when the tet-
razole derivative was treated with 5 mol% Cu(OAc)2·H2O
ACHTUNGTERN(NUNG OAc)2·H2O
AHCTUNGTRENNUNG
and 2 equivalents of K3PO4·3H2O in DMF at 908C for 2 h it
underwent sequential N-arylation, tautomerization, and re-
duction to afford 2a directly in good yield [Eq. (5)].
These results clearly show that the reaction of 2-bromo-
AHCTUNGTREGaNNNU niline and isothiocyanate gives a thiourea, which in the
presence of a copper source and Et3N gives intermediate a.
Nucleophilic substitution of a with sodium azide gives b
with CuS and a sulfide as byproducts (see the Supporting In-
formation). Electrocyclization of b could give tetrazole de-
rivative c,[12] which could react with a copper(I) species
(could be derived from a copper(II) species)[13] through oxi-
The above reactions gave 2-amino-1H-benzo[d]imidazoles
as byproducts (5–10%). Because these compounds have a
structure that is found as a motif in many medicinal com-
pounds,[8] the selective transformation of 1a into 2a was
next investigated (Scheme 3). When 1a was treated with
&
2
&
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!
Ramana, Tamminana
