Facile synthesis of 1,3,4-benzotriazepines and 1-arylamide-1H-indazoles via palladium-catalyzed cyclization of aryl isocyanates and aryl hydrazones under microwave irradiation

Article abstract of DOI:10.1039/c0ob00021c

A strategy involving palladium-catalyzed cyclization of halo-phenyl hydrazones and aryl isocyanates provides a convenient approach to the synthesis of 1,3,4-benzotriazepines (4) or 1-arylamide-1H-indazoles (5) in good isolated yields. Microwave irradiation was found to afford high reaction efficiency, while the choice of halophenyl hydrazone had an effect on the pathway of the reaction.

Full text of DOI:10.1039/c0ob00021c

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Facile synthesis of 1,3,4-benzotriazepines and 1-arylamide-1H-indazoles via
palladium-catalyzed cyclization of aryl isocyanates and aryl hydrazones under
microwave irradiation†
Chune Dong,* Lingli Xie, Xiaohong Mou, Yashan Zhong and Wei Su
Received 20th April 2010, Accepted 19th August 2010
DOI: 10.1039/c0ob00021c
A strategy involving palladium-catalyzed cyclization of halo-
phenyl hydrazones and aryl isocyanates provides a conve-
nient approach to the synthesis of 1,3,4-benzotriazepines
(4) or 1-arylamide-1H-indazoles (5) in good isolated yields.
Microwave irradiation was found to afford high reaction
efficiency, while the choice of halophenyl hydrazone had an
effect on the pathway of the reaction.
synthesis.6 The Cho group recently described a one-pot synthesis
of indazoles from 2-bromobenzaldehydes and aryl hydrazines.7
More recently, Voskoboynikov and coworkers reported that inda-
zoles can also be obtained by the cyclization of aryl hydrazones.8
Obviously, these newer methods provide improved results over
the classical indazole syntheses. However, the poor availability
of certain phosphine ligands as well as the generally drastic
reaction conditions (e.g., high temperature, long reaction time)
required for these transformations are limitations that preclude
the straightforward approach to indazole synthesis. Therefore,
the development of efficient methods for the preparation of such
compounds from easily available precursors is highly desirable.
To our knowledge, however, there are no reports of the facile
synthesis of 1-arylamide-1H-indazoles under mild conditions by
a Pd-catalyzed cyclization reaction approach.
Transition metal-catalyzed cyclization reactions are very at-
tractive methods for organic synthesis that often provide very
convenient and effective one-step procedures for ring homolo-
gation and give rise to heterocyclic derivatives that are either un-
available or poorly accessible through conventional approaches.9
Palladium-catalyzed cyclization, in particular, is one of the
most powerful methods for forming carbon–carbon and carbon–
heteroatom bonds.10 For the past several years, we have success-
fully developed some efficient metal catalyst systems for use in
cyclocarbonylation11 and cycloaddition12 reactions to form five-
and six-membered ring heterocycles. In a continuation of our inter-
est in developing new methodology for synthesis of N-heterocycles
that are of potential in the pharmaceutical sector, we envisioned
that we would be able to direct the metal-catalyzed cyclization
reaction pathways so as to form either 1,3,4-benzotriazepines (4)
or 1-arylamide-1H-indazoles (5) (Scheme 2). Our hypothesis was
that the higher reactivity of C–I bonds compared to C–Br bonds
in terms of the rate of Pd(0) oxidative addition, with aryl iodides
usually being the most reactive aryl halides in this regard,13 could
be used to effect a divergence of the pathway of cyclization of
halophenyl hydrazones (1 or 2) with aryl isocyanates 3.
The chemistry of functionalized N-heterocycles, in particular
1,3,4-benzotriazepines and indazoles, continues to be of interest
because of the industrial use and biological importance of these
classes of compounds.1 They are known to exhibit a wide
range of biological and pharmaceutical properties, including
antitumor, anti-inflammatory, and anti-HIV activities; they also
act as parathyroid hormone-1 related protein receptor ligands
(PTH1R), phosphodiesterase 4 (PDE4) inhibitors and estrogen
receptor ligands etc (Scheme 1).2 Thus, functionalized 1,3,4-
benzotriazepines have been used as key building blocks for the
preparation of a variety of novel bioactive agents.3 However,
the synthesis of these compounds in a modular fashion is not
straightforward. For example, 1,3,4-benzotriazepines are generally
prepared by routes involving multiple steps; the products are
usually obtained in quite low yields, and toxic reagents are also
used,4 all of which limits the full potential use of these heterocycles
in drug discovery. Thus far, in particular, there are no practical and
efficient methods for the preparation of 1,3,4-benzotriazepines in
one step.
Scheme 1 Pharmaceutically important benzotriazepine and indazoles.
Numerous approaches have been reported for the construction
of the indazole skeleton, many of which employ transition metal
catalysts and those of palladium in particular.5 For example,
Pd-catalyzed amination reactions have been utilized for indazole
College of Pharmacy, State Key Laboratory of Virology, Wuhan Univer-
sity, Wuhan, 430071, China. E-mail: cdong@whu.edu.cn; Fax: +86-27-
68759850; Tel: +86-27-68759586
† Electronic supplementary information (ESI) available: Experimental
details. CCDC reference number 773012. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c0ob00021c
Scheme 2 One-step synthesis of two different sets of N-heterocycles.
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Table 1 Cyclization reaction of hydrazones with isocyanates catalyzed by
A divergent synthesis of these two heterocycles from aryl
hydrazones and aryl isocyanates was indeed achieved, and we
also observed that the structure of the halophenyl hydrazone
controlled the reaction manifold. Thus, heating 2-bromophenyl
hydrazones (1) and isocyanates (3) in MeCN at 80 ◦C under
microwave irradiation in the presence of Pd(OAc)2 (0.05 equiv)
and PPh3 (0.2 equiv), using K2CO3 as the base, afforded 1,3,4-
benzotriazepines (4) in moderate to good isolated yields. By
contrast, when 2-iodophenyl hydrazones (2) were used under oth-
erwise identical reaction conditions, 1-arylamide-1H-indazoles (5)
were obtained smoothly and in good yields.
palladium under microwave irradiationa
Entry
1
3
Conv. (%)b
% Yield of 4
Synthesis of 1,3,4-benzotriazepines
1
2
3
4
5
6
7
8
1a
3a
3b
3c
3d
3e
3a
3b
3c
3c
3d
3e
3a
3b
3c
3d
3e
48
58
50
93
66
78
75
83
80
95
82
82
88
89
> 98
93
14 (4a)c
20 (4b)d
24 (4c)e
51 (4d)f
30 (4e)g
35 (4f)
43 (4g)
56 (4h)
56 (4h)
80 (4i)
1a
Our studies were initiated by the reaction of 1-(2-
bromophenyl)ethanone hydrazone14 1a and p-chlorophenyl iso-
cyanate 3d. After a brief survey of reaction conditions, we found
that the solvent, the catalyst and the ligand are critical determi-
nants of the reaction efficiency (see Supporting Information, Table
S1†). Ultimately, we found that CH3CN was the solvent of choice,
and Pd(OAc)2 and PPh3 was the preferred catalyst system for
achieving good yields and higher regioselectivity in the reaction
of 1a (1 equiv.) and 3d (1.2 equiv.) (Table S1, entry 3), and gave
the cyclized product 4d and ring-opened product 6d in a ratio of
1/1.3 and in 51% overall yield.
1a
1a
1a
1b
1b
1b (trans)
9
1b (cis)
1b
10
11
12
13
14
15
16
1b
68 (4j)
1c
43 (4k)
37 (4l)
70 (4m)
82 (4n)
75 (4o)
1c
1c
1c
1c
Microwave-enhanced organic synthesis has established itself as
being superior in many instances when compared to reactions
carried out using conventional heating. The use of microwave
irradiation often helps to reduce reaction time, increase yields,
and improve selectivity.15 Thus, we next carried out the reaction of
halophenyl hydrazones with aryl isocyanates 3 under microwave
irradiation. We were pleased to find that under microwave irra-
diation, for example, the reaction of 1-(2-bromophenyl)ethanone
hydrazone 1a and p-chlorophenyl isocyanate 3d proceeded in a
much shorter time (20 min) and with improved yield (93% overall
yield) and selectivity (1/1.1 ratio of 4d/6d) when compared to that
obtained under the optimized conventional reaction conditions
above (Table S1, entry 17 vs. entry 3†). As in the majority of cases
where microwave irradiation has been found to enhance reactivity
and improve yields and selectivity, the improvement we observed
in our work may also be attributed to a heating effect, especially
when using acetonitrile as solvent, presumably because the heating
process in this solvent with a large tan d value is very fast.
With optimized reaction conditions in hand, we investigated the
scope and limitation of this reaction using various aryl hydrazones
and aryl isocyanates; representative results are shown in Table 1.
In all the reactions investigated, hydrazones 1 with different
substituents at R1 position exhibited different reactivity toward
aryl isocyanates 3. For example, when less bulky hydrazone 1a was
used, ring-opened side-products were isolated in addition to the
desired products, (Table 1, entries 1–5). For example, reaction of 1a
with 3d gave 4d in 51% isolated yield, with the side product being
obtained in 42% yield (Table 1, entry 4). When n-pentyl substituted
hydrazone 1b was reacted with isocyanate 3, the products were
obtained in 35–80% isolated yields along with only trace amounts
of ring-opened products (Table 1, entries 6–11). When using
hydrazone 1b with phenyl isocyanate 3a, the desired product 4f
was obtained in 35% yield together with an unknown compound
isolated in ca. 28% yield. Unfortunately, we failed in all of our
a Reaction conditions: 1 mmol of 1, 1.2 mmol of 3, 0.05 mmol of Pd(OAc)2,
0.2 mmol of PPh3, 1.5 mmol of K2CO3, in CH3CN, MW(500 W, 80 ◦C),
20 min. The temperature in the MW experiments was measured by an
internal IR sensor. b Conversion was calculated based on the crude 1H
NMR. c The ring-opened product was isolated in 12%, d 18%, e 20%, f 42%,
g 29% yields, respectively.
attempts to identify this product (entry 6). In most cases, higher
conversions were observed in the reactions of 3 with hydrazone
1c, which has a bulky phenyl group. The desired products 4 were
obtained as the major components, and no ring-opened products
were observed (Table 1, entries 12–16).
It should be noted that the substituent on the aryl isocyanates
significantly affects the nature of the product. Aryl isocyanates
with an electron-donating group or without an aryl substituent
gave lower yields. When aryl isocyanates containing electron-
withdrawing substituents on the aromatic ring (i.e. 3c–e) were
used, the reactions proceeded smoothly in most cases, resulting
in the formation of seven-membered ring products 4 in good to
excellent conversions and high yields. For example, reaction of 1b
with phenyl isocyanate 3a formed 4f in only 35% yield (Table 1,
entry 6). Significantly, under the same reaction conditions,
p-chlorophenyl isocyanate 3d and m-chlorophenyl isocyanate 3e
afforded the products 4i and 4j in 80% and 68% isolated yields,
respectively (Table 1, entries 10 and 11). In both reactions of
1c with 3a and 3b, good conversions were obtained, but the
desired product was isolated in lower yield due to the formation
of unknown side products (Table 1, entries 12 and 13). While
when 1c was used for the reaction with aryl isocyanates 3c–3e,
the reactions proceeded smoothly, resulting in the formation of
4m–4o in excellent conversions (93–100%) and good isolated yields
(70–82%) (Table 1, entries 14–16).
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Table 2 One-step synthesis of 1-arylamide-1H-indazolesa
the case of 3d and 3e, 5i and 5j were formed in 89% and 75% yields,
respectively (entries 9 and 10). However, when phenyl substituted
hydrazone 2c was reacted with 3, we were surprised to find that
the desired products were isolated in quite low yields, along with
1,3,4-benzotriazepines 4. For example, the reaction of 2c with 3a
gave the expected product 5k in 25%, along with 4k (48%) (entry
11). When 3c was employed in the reaction, 5m was isolated in 12%
yield, due to the formation of 4m (60%) (entry 13). These results
strongly suggest that the reaction is inherently sensitive to the steric
hindrance of the hydrazone and the presence of the substituent
at the R1 position is critical for enforcing this selectivity. The
structure of 1-arylamide-1H-indazoles was confirmed by the
X-ray crystallography of 5d (Fig. 1).
Entry
2
3
Conv. (%)b
% Yield of 5
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
2c
2c
2c
2c
2c
3a
3b
3c
3d
3e
3a
3b
3c
3d
3e
3a
3b
3c
3d
3e
83
61
51
61
58
88
90
98
> 98
96
78
42
82
52
68 (5a)
46 (5b)
35 (5c)
50 (5d)
43 (5e)
68 (5f)
72 (5g)
84 (5h)
89 (5i)
75 (5j)
25 (5k)c
20 (5l)d
12 (5m)e
9 (5n)f
9
10
11
12
13
14
15
74
15 (5o)g
a Reaction conditions: 1 mmol of 2, 1.2 mmol of 3, 0.05 mmol of Pd(OAc)2,
0.2 mmol of PPh3, 1.5 mmol of K2CO3, in CH3CN, MW (500 W, 80 ◦C),
20 min. b Conversion was calculated based on the crude 1H NMR. c 4k was
isolated in 48%. d 4l (22%). e 4m (60%). f 4n (33%). g 4o (59%).
Fig. 1 X-Ray crystal structure of 5d.
Mechanistic hypothesis
Interestingly, the pure trans and cis isomers of hydrazone 1b
reacted with 3c, giving the same amount of cyclized product
4h (Table 1, entries 8 and 9), implying that the hydrazone is
undergoing geometric isomerization during the reaction.
While a precise description of the reaction pathways of the present
Pd-catalyzed cyclization reaction still requires comprehensive
mechanistic study, we offer a proposal that is presented in
Scheme 3. The reaction is initiated by addition of the hydrazone
to the isocyanate to afford intermediate A, which is observed in
all cases. Subsequently, coordination of A with the palladium(0)
complex leads to the formation of intermediate B. Alternatively,
intramolecular palladation of B generates C or D. Then reductive
elimination affords the desired products 4 or 5. It is assumed
that complex C was formed when 1 was used as starting material,
while complex D was formed when 2 was used in the reaction. This
can be explained based on the fact that with sterically hindered
Synthesis of the 1-arylamide-1H-indazoles
We next attempted to apply the conditions developed for the 2-
bromohydrazones to other more reactive 2-iodophenyl hydrazones
2. We expected that the 1H-indazole derivatives would likely be
formed from the competitive palladium-catalyzed cyclization of
2 with aryl isocyanates 3 under microwave irradiation. Further
experiments revealed the optimal conditions developed above
were also generally applicable to the synthesis of the 1-arylamide
substituted 1H-indazoles 5 (Table 2). It should be noted that
the substituent on the aryl hydrazones and aryl isocyanates also
has significant effects on the reaction selectivity. Compared to
the formation of seven-membered ring products, however, the
less bulky hydrazones showed higher reactivity in terms of five-
membered ring product formation. When 2a–b was employed
in the reaction, the desired products 5 were obtained in higher
conversions and good yields. For example, when the hydrazone 2a
was mixed with aryl isocyanates 3a and 3d, the reaction generated
5a and 5d in moderate yields (entries 1 and 4), respectively. In
the reaction of 2a with 3e, 5e was isolated in 43% yield (entry
5). Almost full conversion and high selectivity were obtained by
employing the arylhydrazone 2b in the above conditions, affording
the indazoles in good yields. The reaction of 2b with 3b gave the
corresponding indazole 5g in 72% yield (entry 7). Similarly, 2b
reacted smoothly with 3c, producing 5h in 84% yield (entry 8). In
Scheme 3 Mechanistic hypothesis.
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In conclusion, we have developed a facile, efficient route to 1,3,4-
benzotriazepine and 1H-indazole derivatives by the palladium-
catalyzed cyclization reaction of readily available aryl hydrazones
and aryl isocyanates under microwave irradiation. These condi-
tions are applicable to the cyclization of a wide variety of aryl
hydrazones and aryl isocyanates, and enable the rapid construction
of diverse arrays of 1,3,4-benzotriazepines and 1-arylamide-1H-
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core synthons for many pharmaceutical products. Efforts to study
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Acknowledgements
This work is supported by National Nature Science Foundation
of China (20972121, 20872116), the Science Foundation of
Ministry of Education for the New Teacher at the University
of China (20090141120058), the Important National Science &
Technology Specific Projects (No. 2009ZX09301-14), and the
startup fund from Wuhan University (Grant 306276315). Prof.
John A. Katzenellenbogen is thanked for critical reading of this
manuscript. Professor Haibing Zhou is acknowledged for helpful
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