Synthesis of 3-substituted indazoles from arynes and N-tosylhydrazones

Article abstract of DOI:10.1021/ol201086g

Readily available, stable, and inexpensive N-tosylhydrazones react with arynes under mild reaction conditions to afford 3-substituted indazoles in moderate to good yields. The reaction appears to involve a dipolar cycloaddition of in situ generated diazo

Full text of DOI:10.1021/ol201086g

ORGANIC
LETTERS
2011
Vol. 13, No. 13
3340–3343
Synthesis of 3-Substituted Indazoles from
Arynes and N-Tosylhydrazones
Pan Li,† Jingjing Zhao,† Chunrui Wu,† Richard C. Larock,‡ and Feng Shi*,†
Key Laboratory of Natural Medicine and Immuno-Engineering of Henan Province,
Henan University, Jinming Campus, Kaifeng, 475004, PR China, and
Department of Chemistry, Iowa State University, Ames, Iowa 50010, United States
fshi@henu.edu.cn
Received April 25, 2011
ABSTRACT
Readily available, stable, and inexpensive N-tosylhydrazones react with arynes under mild reaction conditions to afford 3-substituted indazoles in
moderate to good yields. The reaction appears to involve a dipolar cycloaddition of in situ generated diazo compounds and arynes.
The indazole unit constitutes a key structural moiety in
pharmaceutically relevant structures that exhibits a broad
range of bioactivities.1,2 Synthesis of the indazole system
Scheme 1. Aryne Approaches to Indazoles
has therefore attracted much attention from the synthetic
organic chemistry community.1b,3 Recently, new and ef-
fective routes for the synthesis of indazoles utilizing aryne
[3 þ 2] dipolar cycloaddition reactions have been devel-
oped. We2,4 and Yamamoto5 reported the dipolar cycload-
dition of arynes with diazo compounds to be an effective
route to indazoles, and Moses disclosed the [3 þ 2] dipolar
cycloaddition of arynes with in situ generated nitrile imides
(Scheme 1).6
Despite the success of these synthetic approaches, both
methods have their drawbacks. Moses’ method is limited
to N-aryl nitrile imides and therefore can only be used to
prepare 1,3-diarylindazoles. Yamamoto’s and our pre-
vious methods are limited to stable and isolable diazo
compounds, which typically contain electron-withdrawing
† Henan University.
groups. Since simple monosubstituted diazo compounds
‡ Iowa State University.
are unstable and difficult to handle, the simplest 3-sub-
stituted indazoles remain ironically largely inaccessible
through aryne cycloaddition chemistry. Thus, the aryne
approach to indazoles needs further refinement. Herein,
we wish to report a formal aryne [3 þ 2] annulation
route to simple 3-substituted indazoles using stable,
readily available, and inexpensive N-tosylhydrazones
as starting materials.
N-Tosylhydrazones have been recognized as precursors
to diazo compounds under basic conditions in many
transformations,7ꢀ9 including [3 þ 2] dipolar cycloaddi-
tion reactions.10 Although strong bases, such as LiOtBu11
(1) For excellent reviews of the bioactivity and synthesis of indazoles,
ꢀ
ꢀ
ꢀ
see: (a) Cerecetto, H.; Gerpe, A.; Gonzalez, M.; Aran, V. J.; de Ocariz,
C. O. Mini-Rev. Med. Chem. 2005, 5, 869. (b) Stadlbauer, W. Science of
Synthesis, Vol. 12; Georg Thieme: Stuttgart, 2002; pp 227ꢀ324.
(2) Liu, Z.; Shi, F.; Martinez, P. D. G.; Raminelli, C.; Larock, R. C.
J. Org. Chem. 2008, 73, 219 and references therein.
(3) (a) Counceller, C. M.; Eichman, C. C.; Wray, B. C.; Stambuli, J. P.
Org. Lett. 2008, 10, 1021. (b) Huang, L.-J.; Shih, M.-L.; Chen, H.-S.;
Pan, S.-L.; Teng, C.-M.; Lee, F.-Y.; Kuo, S.-C. Bioorg. Med. Chem. 2006,
14, 528. (c) Bartsch, R. A.; Yang, I. W. J. Heterocycl. Chem. 1984, 21, 1063.
(d) Kovach, E. G.; Barnes, D. E. J. Am. Chem. Soc. 1954, 76, 1176.
(e) Inamoto, K.; Katsuno, M.; Takashi, Y.; Arai, Y.; Hiroya, K.; Sakamoto,
T. Tetrahedron 2007, 63, 2695.
(4) Wu, C.; Fang, Y.; Larock, R. C.; Shi, F. Org. Lett. 2010, 12, 2234.
(5) Jin, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2007, 46, 3323.
(6) Spiteri, C.; Keeling, S.; Moses, J. E. Org. Lett. 2010, 12, 3368.
r
10.1021/ol201086g
Published on Web 06/01/2011
2011 American Chemical Society

Table 1. Reaction Optimizationa
Scheme 2. Reaction of N-Tosylhydrazones with Arynes: Dif-
ferent Mechanisms Leading to the Same Indazoles
TEBAC
t
time
(h)
yield
(%)b
entry
Fꢀ
(mol %)
solvent
(°C)
1
CsF
CsF
TBAF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
CsF
0
0
MeCN
MeCN
THF
50
80
rt
16
6
45
51
0
38c
37
0
2
3
0
24
24
10
10
24
6
4
0
THF
70
85
105
90
80
70
90
70
70
5
0
DME
dioxane
THF
6
0
7
0
38
50
61
58
77
87
8
10
10
10
10
25
MeCN
THF
and Cs2CO3,12 are often used, the fluoride used for the in situ
generation of arynes from o-(trimethylsilyl)aryl triflates
should be sufficiently basic to generate diazo compounds
from N-tosylhydrazones in situ (Scheme 2, path A).13
From a mechanistic point of view, even if this in situ
generation of diazo compounds does not occur for what-
ever reasons, the formal [3 þ 2] annulation of arynes
through the conjugate bases of the N-tosylhydrazones
(Scheme 2, path B) looks equally promising.
Thus, we examinedthe reactionof anisaldehydeN-tosyl-
hydrazone (2a) with the benzyne precursor 1a under
various reaction conditions (Table 1). Three equivalents
of fluoride were employed in this reaction to provide suffi-
cient base for generation of the tosylhydrazone anion.
Upon initial screening (entries 1ꢀ4), we found that CsF
was the best fluoride source, and THF and acetonitrile
were both suitable solvents. However, we noticed that the
reaction quickly formed large amounts of a precipitate,
likely the Cs salt of the conjugate base of 2a, that inhibited
efficient stirring of the reaction. Although heating the
reaction mixture to increase the solubility led to a higher
yield in acetonitrile (compare entries 1 and 2), it failed to
improve the yield in ethereal solvents (entries 4ꢀ7). Under
these reaction conditions, the reaction afforded a complex
9
24
24
24
24
10
11d
12d
THF
THF
THF
a All reactions were carried out on 0.4 mmol of 2a in 5 mL of solvent.
TEBAC = [Et3NBn]Cl. b Isolated yield. c Incomplete conversion; 59%
of 2a recovered. d 10 mL of solvent were used.
mixture containing the desired product 3a, the product of
N-arylation of the hydrazone (the “side product” shown in
Scheme2), and phenylp-toluenesulfinatefrom the reaction
of Tsꢀ with benzyne. We next examined the effect of
adding a phase transfer catalyst14 to help dissolve the con-
jugate base of2a. Indeed, although the addition of 10 mol %
of TEBAC ([Et3NBn]þClꢀ) failed to improve the yield in
acetonitrile, itsignificantly increased the yield of3ainTHF
(compare entries 4 and 9, and 7 and 10). Further dilution
brought the yield up to 77% (entry 11), and increasing the
TEBAC to 25 mol % resulted in an 87% yield of 3a.15 To
our pleasant surprise, further N-arylation of 3a was minimal
under these reaction conditions, as opposed to the previous
diazo route.2
Having the optimal conditions in hand, we examined the
scopeand limitationsof thismethod. Different arynes were
tested first (Table 2, entries 1 and 2). The symmetrical
(7) Creary, X. Org. Synth. 1986, 64, 207.
(8) For a comprehensive review of processes generating diazo com-
pounds from N-tosylhydrazones, see: Fulton, J. R.; Aggarwal, V. K.; de
Vicente, J. Eur. J. Org. Chem. 2005, 1479.
(9) For the related BamfordꢀStevensꢀShapiro reaction, see: (a)
Nickon, A.; Zurer, P. S. J. J. Org. Chem. 1981, 46, 4685. (b) Casanova,
J.; Waegell, B. Bull. Soc. Chim. Fr. 1975, 922. (c) Nickon, A.;
Bronfenbrenner, J. K. J. Am. Chem. Soc. 1982, 104, 2022.
(10) (a) Taber, D. F.; Guo, P. J. Org. Chem. 2008, 73, 9479. (b) Wu,
L.; Shi, M. J. Org. Chem. 2010, 75, 2296.
(14) In situ generation of diazo compounds from N-tosylhydrazones
is often performed in the presence of phase transfer catalysts; see: (a)
Aggarwal, V. K.; de Vicente, J.; Bonnert, R. V. J. Org. Chem. 2003, 68,
5381. (b) Aggarwal, V. K.; Fulton, J. R.; Sheldon, C. G.; de Vicente, J.
J. Am. Chem. Soc. 2003, 125, 6034. (c) Aggarwal, V. K.; Patel, M.;
Studley, J. Chem. Commun. 2002, 1514. (d) Aggarwal, V. K.; Alonso, E.;
Bae, I.; Hynd, G.; Lydon, K. M.; Palmer, M. J.; Patel, M.; Porcelloni,
M.; Richardson, J.; Stenson, R. A.; Studley, J. R.; Vasse, J. L.; Winn,
C. L. J. Am. Chem. Soc. 2003, 125, 10926. (e) Zhang, Z.; Liu, Y.; Ling, L.;
Li, Y.; Dong, Y.; Gong, M.; Zhao, X.; Zhang, Y.; Wang, J. J. Am. Chem.
Soc. 2011, 133, 4330.
(15) Typical procedure (entry 12, Table 1): to an oven-dried 25 mL
round-bottom flask equipped with a stir bar were added 122 mg of 2a
(0.4 mmol), followed by 143 mg of 1a (0.48 mmol). THF (10 mL) was
added, followed by 23 mg of TEBAC (0.1 mmol) and 182 mg of CsF (1.2
mmol). The reaction mixture was stirred at 70 °C for 24 h, cooled to
room temperature, poured into brine, and extracted with EtOAc. The
combined extracts were dried over MgSO4, filtered, and evaporated. The
residue was purified by column chromatography (petroleum ether/
EtOAc = 2:1) to afford 78 mg of 3a (87%) as a white solid.
(11) (a) Zhou, L.; Ye, F.; Zhang, Y.; Wang, J. J. Am. Chem. Soc.
2010, 132, 13590. (b) Xiao, Q.; Ma, J.; Yang, Y.; Zhang, Y.; Wang, J.
ꢀ
Org. Lett. 2009, 11, 4732. (c) Barluenga, J.; Moriel, P.; Valdes, C.; Aznar,
F. Angew. Chem., Int. Ed. 2007, 46, 5587. (d) Zhao, X.; Lu, K.; Zhang,
Y.; Wang, J. Chem. Commun. 2010, 46, 1724. (e) Zhao, X.; Wu, G.;
Zhang, Y.; Wang, J. J. Am. Chem. Soc. 2011, 133, 3296.
(12) (a) Xiao, Q.; Xia, Y.; Li, H.; Zhang, Y.; Wang, J. Angew. Chem.,
Int. Ed. 2011, 50, 1114. (b) Zhou, L.; Shi, Y.; Xiao, Q.; Liu, Y.; Ye, F.;
Zhang, Y.; Wang, J. Org. Lett. 2011, 13, 968.
ꢀ
ꢀ
(13) Barluenga, J.; Tomas-Gamasa, M.; Aznar, F.; Valdes, C. Nat.
Chem. 2009, 1, 494.
Org. Lett., Vol. 13, No. 13, 2011
3341

Table 2. Reaction Scopea
a All reactions were carried out on approximately 0.4 mmol of hydrazonein 10 mL of solvent. b Isolated yield. c 4.8:1 Regioselectivity, combined yield.
The major isomer was assigned by an NOESY experiment (see the Supporting Information).
dimethoxybenzyne afforded the desired indazole in a
moderate 56% yield (entry 1). The unsymmetrical mono-
methoxybenzyne gave a 4.8:1 mixture of regioisomers in a
60% combined yield (entry 2). The latter example is
particularly worth mentioning, as it provides valuable
information on the reaction mechanism. It is already
known16 that reactions involving 3-methoxybenzyne can
be highly regioselective with nucleophilic attack at the
meta-position (with respect to OMe) being more favorable
for both electronic and steric reasons. Therefore, if the
reaction goes through the diazo intermediate (path A in
Scheme 2), one would expect formation of the 7-methoxy
regioisomer (Scheme 3), as was reported in our previous
publication.2 On the contrary, if the reaction proceeds
through the conjugate base of the N-tosylhydrazone
(path B in Scheme 2), one might expect formation of the
4-methoxy regioisomer (Scheme 3).17 As a matter of fact,
the reaction shown in entry 2, Table 2, afforded the
7-methoxy isomer as the major product18 in an ∼4.8:1
ratio. This appears to be strong evidence for possible
involvement of the diazo intermediate, although the other
route cannot be ruled out.
(16) (a) Dubrovskiy, A. V.; Larock, R. C. Org. Lett. 2010, 12, 1180.
(b) Tadross, P. M.; Gilmore, C. D.; Bugga, P.; Virgil, S. C.; Stoltz, B. M.
Org. Lett. 2010, 12, 1224.
3342
Org. Lett., Vol. 13, No. 13, 2011

the stability of the diazo intermediate. It is also worth
noting that hydrazone 2k derived from cinnamaldehyde
did not react with benzyne under the reaction conditions
but simply cyclized to form 5-phenyl-1H-pyrazole.19 Hy-
drazone 2l with an ester group was also tested (Scheme 4).
This substrate should initially afford the adduct 3m, which
is already known2 to undergo an acyl migration to form a
more stable isomer 5. Indeed, this rearrangement pro-
ceeded smoothly and the desired product 5 could be
isolated in a 63% yield. It should be pointed out that this
ketone-derived hydrazone might be the only one that
worked in our reaction, as N-tosylhydrazones derived
from other ketones, either aromatic or aliphatic, cyclic or
open chain, failed to give the desired indazoles. Thus, the
current protocol is largely limited to N-tosylhydrazones
derived from aromatic aldehydes.
Scheme 3. Possible Reaction Mechanisms of an Unsymmetrical
Benzyne
With regard to the scope of the N-tosylhydrazones,
those derived from aromatic aldehydes give the best yields
(entries 3ꢀ8). The scope includes electron-poor (entries
4ꢀ7), electron-rich (entries 1, 2, and 8), and sterically
hindered (entries 6 and 7) aryl N-tosylhydrazones. Those
derived from heteroaromatic aldehydes, such as pyridine-
3-carbaldehyde (2h) and thiophene-2-carbaldehyde (2i),
also afforded the expected indazole products (entries 9
and 10). However, the 36% yield for the latter reaction was
less than satisfactory (entry 10). Unfortunately, N-tosyl-
hydrazones derived from aliphatic aldehydes were not
suitable substrates. Only pivalaldehyde N-tosylhydrazone
(2j) gave a 33% yield of the desired product 3l (entry 11).
All other aliphatic substrates tested failed to provide the
anticipated indazoles. Observed side products included
simple N-arylation of the hydrazone and phenyl p-tolue-
nesulfinate. Notably, compared with N-tosylhydrazones
derived from other aliphatic aldehydes, 2j has the greatest
steric bulk adjacent to the imine carbon and, therefore,
should in theory disfavor path B (Scheme 2). Therefore, its
success might provide additional support for the postu-
lated involvement of the diazo intermediate at least for this
particular substrate, as the steric bulk may be beneficial to
Scheme 4. An Indazole from Additional Acyl Migration
In summary, we have developed a method for the pre-
paration of 3-arylindazoles starting from arynes and readily
available, bench stable, inexpensive N-tosylhydrazones.
The reaction appears to involve in situ formation of a
diazo compound and eliminates the problem of preparing
and isolating such unstable and hazardous intermediates.
Thus, it extends our previous aryne-diazo cycloaddition
route to indazoles.
Acknowledgment. This project was financially sup-
ported by the National Natural Science Foundation of
China (No. 21002021) and the Key Project of the Chinese
Ministry of Education (No. 210127). We thank Mr. Lei
Liu, Prof. Shrong-Shi Lin, Dr. Jiang Zhou (all Peking
University), Mr. Huaiqiu Wang, and Prof. Zheng Duan
(both Zhengzhou University) for their help in spectro-
scopic analysis and the State Key Laboratory for Physical
Chemistry of the Solid Surfaces (Xiamen University) for
providing computational resources.
(17) From Hammond’s postulate and a softꢀhard acidꢀbase argu-
ment, we consider the other resonance structure of the conjugate base,
where the negative charge resides on the imine carbon, as a less
important structure to participate in the reaction. A brief computational
study of benzaldehyde N-mesylhydrazone as a simplified system on a
B3LYP/6-31G(d) level reveals that the nitrogen carries a much more
negative charge (ꢀ0.494 vs ꢀ0.065 for the carbon), and therefore the
reaction with a highly reactive agent, such as benzyne, should occur
more favorably at the nitrogen, rather than at the carbon.
Supporting Information Available. Experimental de-
tails and characterization of the final products, including
full 1H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
(18) See the Supporting Information for the NOESY spectrum.
(19) Similiar reactions have been reported in the literature; see:
Doyle, M. P.; Yan, M. J. Org. Chem. 2002, 67, 602. See also ref 12d.
Org. Lett., Vol. 13, No. 13, 2011
3343