1,7-palladium migration via C-H activation, followed by intramolecular amination: Regioselective synthesis of benzotriazoles

Article abstract of DOI:10.1021/ja2007438

A novel 1,7-palladiummigration-cyclization-dealkylation sequence for the regioselective synthesis of benzotriazoles has been developed. These reactions proceed in excellent yields with high regioselectivities. The mechanism of the reaction has also been investigated.

Full text of DOI:10.1021/ja2007438

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1,7-Palladium Migration via CꢀH Activation, Followed by
Intramolecular Amination: Regioselective Synthesis of Benzotriazoles
Jun Zhou, Jianjun He, Binjie Wang, Weijun Yang, and Hongjun Ren*
Department of Chemistry, Zhejiang University, 38 Zheda Road, Hangzhou 310027, P. R. China
S Supporting Information
b
Scheme 1. The Structure of Benzotriazole 1, an Inhibitor of
c-Kit Protooncogene, and its Three Isomers
ABSTRACT: A novel 1,7-palladium migrationꢀcyclizationꢀ
dealkylation sequence for the regioselective synthesis of ben-
zotriazoles has been developed. These reactions proceed in
excellent yields with high regioselectivities. The mechanism of
the reaction has also been investigated.
ecause of their interesting structures, high reactivity, and
anticancer properties, N-substituted benzotriazoles are
B
widely used in synthetic organic chemistry,1 materials science,2
and pharmaceutical science.3 For example, benzotriazole 1 is an
inhibitor of c-Kit protooncogene4 and exists as either the N1-,
N2-, or N3-substituted isomer (Scheme 1). N-Substituted ben-
zotriazoles can be prepared by copper-catalyzed Buchwaldꢀ
Hartwig-type reactions,5 a transition-metal-free procedure using
aryne chemistry for N-arylation,6 the [3 þ 2] cycloaddition
reaction between aryne and organic azides,7 and the reaction of
(Z)-1-aryl-3-hexen-1,5-diynes with sodium azide.8 However, the
products are formed as a mixture of N1-, N2-, and N3-arylation
isomers in all cases except the synthesis involving Buch-
waldꢀHartwig-type reactions.
Scheme 2. Regioselective Synthesis of Benzotriazoles
Larock9 and Gallagher10 recently reported the 1,4-palladium
migration for the synthesis of fused polycycles. This process
involves a Pd-catalyzed CꢀH activation proceeding via a key five-
membered-ring palladacycle intermediate.11 Aryltriazenes are
unique compounds that have been used in medicinal chemistry,12
combinatorial chemistry,13 organic synthesis,14 and molecular
architectures synthesis15 and as precursors to heterocycles.16
Herein we report a regioselective synthesis of benzotriazoles from
aryltriazenes via a novel 1,7-palladium migration and intramolecular
aminationꢀdealkylation sequence.
3a was obtained in a trace amount with Cs2CO3 as the base and
dppp as the ligand in toluene or DMF (Table 1, entries 1 and 7).
After the base was changed from Cs2CO3 to K2CO3, 3a was
formed in 64% yield (entry 2). Both bidentate ligands such as
dppb, dppe, dppp, and dppf (entries 3ꢀ5 and 9) and a monopho-
sphorus ligand (PPh3, entry 6) led to the formation of compound
3a in 31ꢀ75% yield using toluene as solvent. The best result was
obtained with dppp as the ligand in the presence of KOAc as the
base and DMF as the solvent (entry 8).
When R = H, the cis/trans isomerization of 1,3-diphenyltria-
zene occurs under basic conditions,17 and the intramolecular
amination is possible (Scheme 2).5b,c Thus, heating triazene 2aa
in the presence of Pd(OAc)2 gave the direct amination product
4a in 96% yield. We envisioned that if the H were to be replaced
by an alkyl group, the reaction of triazene 2a (with R = Me)
would give benzotriazole 3a via a 1,7-palladium migrationꢀ
cyclizationꢀdealkylation sequence involving a CꢀH activation
(Scheme 2).
To explore the reaction scope, a number of 3-methyl-1,
3-diphenyltriazenes 2bꢀ2p were examined under the optimal
reaction conditions. The substituents on the two aromatic groups
had different effects on the yields (3bꢀ3g in Table 2). Electron-
donating groups on the bromo-substituted aromatic ring (shown
in red) decreased the yield (3l, 3o, and 3p; the yield could be
improved by running the reaction at high temperature), while on
the other aromatic system (shown in blue), the yields increased
to up to 98% (3n) under the optimal reaction conditions. The
To probe the viability of this envisioned intramolecular 1,
7-palladium migration and the subsequent amination reaction,
palladium complexes derived from various ligands and bases
were screened in toluene or N,N-dimethylformamide (DMF).
The results are summarized in Table 1. The desired benzotriazole
Received: January 25, 2011
Published: April 15, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/ja2007438 J. Am. Chem. Soc. 2011, 133, 6868–6870
|

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Table 1. Screen of 1,7-Palladium Migration Reaction
Variablesa
Scheme 3. Reaction of Substrates with Groups Other Than
Me on the Triazene
entry
base
solvent
ligand
yield (%)b
1
2
3
4
5
6
7
8
9
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KOAc
toluene
toluene
toluene
toluene
toluene
toluene
DMF
dppp
dppp
dppb
dppe
dppf
trace
64
Scheme 4. Reaction of Substrates 5a and 2a and Deuterium
Substrate 6a
32
56
40
PPh3
dppp
dppp
dppp
31
Cs2CO3
KOAc
trace
75
DMF
KOAc
toluene
55
a All of the reactions were carried out with 2a (1.0 mmol), Pd(OAc)2
(0.05 mmol), ligand (0.1 mmol), and base (1.2 mmol) in 4 mL of solvent
at 110 °C for 12 h. b Yield of isolated product after chromatography.
Table 2. Substrate Scope of the 1,7-Palladium Migration
Reactiona,b
structure of 3h was determined by X-ray analysis (see the
Supporting Information). Lower yields were obtained when
steric hindrance was introduced near the reaction site (3k and
3m), and higher temperatures gave better yields. Gratifyingly,
1-(4-methoxyphenyl)-1H-benzotriazole-5-carboxylic acid ethyl
ester (3o), the important intermediate leading to benzo-
triazole 1, was obtained in 80% yield after treatment with
Pd(OAc)2 and dppp at 150 °C.
Furthermore, we also used substrates with groups other than
Me on the triazene motif. All of the substrates with alkyl groups such
as Et, n-Bu, i-Pr, and Bn gave the desired product 3a in good yields
from 43 to 76% (Scheme 3). Even with a very bulky group like t-Bu,
the desired product was obtained in 59% yield. However, N-phenyl-
triazene (2v) did not produce the desired product 3a.
To probe the reaction mechanism, substrate 5a was subjected
to the standard reaction conditions, and N-substituted benzo-
triazole 3a was formed in 97% yield. This result strongly indicates
that the same intermediate is formed when the substrates 2a and
5a are treated with Pd(OAc)2 in the presence of base and ligand.
When we changed the base to potassium laurate, the byproduct
methyl laurate was observed along with 3a using GCꢀMS
analysis. Furthermore, d5-triazene 6a was synthesized and
subjected to the standard reaction conditions (using toluene as
the solvent), and 83% deuterium incorporation at the ortho
1
position of 7a was observed using H NMR and GCꢀMS
a All of the reactions were carried out with substrate (1.0 mmol), Pd-
(OAc)2 (0.05 mmol), dppp (0.1 mmol), and KOAc (1.2 mmol) in DMF
(4 mL) at 110 °C for 12 h. b Yields of isolated products after chromatog-
raphy are shown. c The reaction was carried out at 150 °C for 12 h.
analysis (Scheme 4).
On the basis of these results, a plausible reaction mechanism
for this fascinating process is depicted in Scheme 5. Presumably,
Pd(0) would first undergo oxidative addition to bromotriazene
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Scheme 5. Plausible Mechanism for the 1,7-Palladium
MigrationꢀCyclizationꢀDealkylation Sequence (The
Coordinated Ligand Has Been Omitted for Clarity)
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’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures, characterization data, copies of 1H and 13C NMR spectra
for all products, complete ref 3d, and crystallographic data for
compound 3h (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
renhj@zju.edu.cn
’ ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China
(J20091112) as well as the Fundamental Research Funds for the
Central Universities (2010QNA3011) for financial support.
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