New synthesis of 1-substituted-1 H-indazoles via 1,3-dipolar cycloaddition of in situ generated nitrile imines and benzyne

Article abstract of DOI:10.1021/ol101150t

(Equation Presented). A new synthesis of 1-substitued-1H-indazoles via 1,3-dipolar cycloaddition of nitrile imines to benzyne is described. The reaction is completed within 5 min, affording the corresponding N(1)-C(3) disubstituted indazoles in moderate to excellent yields.

Full text of DOI:10.1021/ol101150t

ORGANIC
LETTERS
2010
Vol. 12, No. 15
3368-3371
New Synthesis of
1-Substituted-1H-indazoles via
1,3-Dipolar Cycloaddition of in situ
Generated Nitrile Imines and Benzyne
Christian Spiteri,†,‡ Steve Keeling,‡ and John E. Moses*,†
School of Chemistry, UniVersity of Nottingham, Nottingham,
NG7 2RD, United Kingdom, and GlaxoSmithKline, Research Medicines Centre,
SteVenage, SG1 2NY, United Kingdom
John.Moses@nottingham.ac.uk
Received May 21, 2010
ABSTRACT
A new synthesis of 1-substitued-1H-indazoles via 1,3-dipolar cycloaddition of nitrile imines to benzyne is described. The reaction is completed
within 5 min, affording the corresponding N(1)-C(3) disubstituted indazoles in moderate to excellent yields.
1H-Indazoles are a pharmaceutically important class of
nitrogen-containing heterocycles that show a broad range of
pharmacological activity including anti-HIV,1 Rho-kinase
inhibition,2 anti-inflammatory,3 antitumor,4 cardiovascular,5
and antinociceptive activity,6 among others. Their desirable
properites render them attractive targets for drug discovery,7
and as such, numerous syntheses of the indazole core have
been described.8 One general route involves the diazotisation
of o-methyl substituted anilines follwed by base promoted
cyclization.9 Other intramolecular cyclizations are also
possible.10-17 For instance, 1-aryl-1H-indazoles can be
† University of Nottingham.
‡ GlaxoSmithKline.
(1) Sun, J.-H.; Teleha, C. A.; Yan, J.-S.; Rodgers, J. D.; Nugiel, D. A.
J. Org. Chem. 1997, 62, 5627–5629.
(6) Moore, P. K.; Babbedge, R. C.; Wallace, P.; Gaffen, Z. A.; Hart,
S. L. Br. J. Pharmacol. 1993, 108, 296–297.
(2) Goodman, K. B.; Cui, H.; Dowdell, S. E.; Gaitanopoulos, D. E.;
Ivy, R. L.; Sehon, C. A.; Stavenger, R. A.; Wang, G. Z.; Viet, A. Q.; Xu,
W.; Ye, G.; Semus, S. F.; Evans, C.; Fries, H. E.; Jolivette, L. J.; Kirkpatrick,
R. B.; Dul, E.; Khandekar, S. S.; Yi, T.; Jung, D. K.; Wright, L. L.; Smith,
G. K.; Behm, D. J.; Bentley, R.; Doe, C. P.; Hu, E.; Lee, D. J. Med. Chem.
2007, 50, 6–9.
(7) Jennings, A.; Tennant, M. J. Chem. Inf. Model. 2007, 47, 1829–
1838.
(8) For a comprehensive review, see: Schmidt, A.; Beutler, A.; Snovy-
dovych, B. Eur. J. Org. Chem. 2008, 4073–4095.
(9) (a) Huisgen, R.; Bast, K. Org. Synth. 1962, 42, 69. (b) Huisgen, R.;
Bast, K. Org. Synth. Coll. 1973, 5, 650.
(3) Guglielmotti, A.; De Joannon, A. C.; Cazzolla, N.; Marchetti, M.;
Soldo, L.; Cavallo, G.; Pinza, M. Pharmacol. Res. 1995, 32, 369–373.
(4) (a) Hartmann, M.; Sommer, M. E.; Keppler, B. K.; Kratz, F.;
Einha¨user, Th. J. J. Inorg. Biochem. 1995, 59, 214. (b) Clarke, M. J.
Coordin. Chem. ReV. 2003, 236, 209–233.
(10) Song, J. J.; Yee, N. K. Tetrahedron Lett. 2001, 42, 2937–2940
.
(11) (a) Cho, C. S.; Lim, D. K.; Heo, N. H.; Kim, T.-J.; Shim, S. C.
Chem. Commun. 2004, 104–105. (b) Lebedev, A. Y.; Khartulyari, A. S.;
Voskoboynikov, A. Z. J. Org. Chem. 2005, 70, 596–602
.
(5) Shiraki, Y.; Chihara, S.; Haruta, K.; Sakai, K. Arch. Int. Pharma-
codyn. Ther. 1985, 273, 155.
(12) Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya, K. Org.
Lett. 2007, 9, 2931–2934
.
10.1021/ol101150t  2010 American Chemical Society
Published on Web 07/07/2010

synthesized via Pd catalyzed ring closure of N-aryl-N′-(o-
bromobenzyl)hydrazines, [N-aryl-N′-(o-bromobenzyl)-hy-
drazinato-N′]-triphenylphosphonium bromides,10 substituted
o-bromobenzaldehyde arylhydrazones,11 substituted o-bro-
moacetophenone arylhydrazones11b and hydrazones.12 An
alternative route involves condensation of hydrazine to
o-halo13 or o-alkoxy arylhydrazone,14 and more recently,
copper15,16 catalysis has been used for the intramolecular
amination of o-haloarylcarbonylic compounds. There are
however disadvantages of using such protocols such as
limitation of substrate choice, elevated temperatures, and the
requirement for metal mediated catalysis. An improved
intramolecular cyclization was recently reported by Stambuli
et al.,17 where mild conditions for the cyclization of
o-aminobenzoximes were developed, for selective oxime
activation, affording both 1H-indazoles and substitued-1H-
indazoles in good yield.
Scheme 2
.
Schematic Hypothesis: 1,3-Dipolar Cycloaddition of
Benzyne (1) and Nitrile Imines (2)
describe our studies on the development of a new route to
1-substituted-1H-indazoles using nitrile imines (2) as 1,3-
dipoles (Scheme 2).
Nitrile imines have been used extensively as 1,3-dipoles
in [3 + 2] cycloaddition reactions with alkynes yet, to the
best of our knowledge, have not been reported with benzyne
(1). The absence of literature precedence may be attributed
to the difficulty associated in forcing two highly unstable
intermediates to react preferentially with one another. In any
event, it presented a unique opportunity for us to exploit this
untapped transformation. Benzyne is well-known to undergo
self-dimerization to give biphenylene,23 whereas nitrile
imines can undergo [3 + 3] self-cycloaddition,24 fragmenta-
tion into nitriles,25 rearrangement into carbodiimides or
azirnes,26 and intramolecular cyclizations.27
Scheme 1. Synthesis of 1H-Indazoles via [3 + 2] Cycloaddition
Nitrile imines (2) are usually generated in situ by a base-
induced dehydrodechlorination of hydrozonyl chlorides,24,28
whereas arynes are easily accessible in situ, from o-
(trimethylsilyl)aryl triflates under very mild conditions.29 In
our work on 1,2-benzisoxazole chemistry, we demonstrated
that TBAF could mediate the in situ generation of both
benzyne (1) and nitrile oxides simultaneously21a and were
keen to determine if 1 and 2 could be obtained under
analogous conditions. Our studies began using o-(trimeth-
ylsilyl)phenyl triflate (3) as the benzyne precursor and
phenylbenzenecarbohydrazonoyl chloride (4) as a source of
nitrile imine (Table 1).
A variety of conditions were screened, varying fluoride
source, molar ratios, substrate concentrations, temperature,
and polar media (Table 1). Gratifyingly, all tested conditions
gave the target disubstituded-1H-indazole, 1,3-diphenyl-1H-
indazole (5) in varying yields. Using the strongly nucleophilc
fluoride source TBAF, the target indazole could only be
obtained in moderate yield (entries 1-4, Table 1). In each
case, a competing self-dimerization of the nitrile imine into
1,3-Dipolar cycloadditions of diazomethane derivatives
with benzyne offer an alternative route to 1H-indazoles
(Scheme 1). The first example was reported by Huisgen and
Knorr in 1961,18 and recent developments have been
described by the groups of Yamamoto (2007)19 and Larock
(2008).20 The latter methods gave 1H-indazoles in good
yields under very mild conditions. Even so, these protocols
were restricted to substrates bearing an ester group at the
3-position, limiting the diversity of the corresponding 1H-
indazole product. Consequently, we felt it desirable to
develop a protocol to access highly decorated N(1)-C(3)
disubstituted indazoles.
Recently, we have had considerable success employing
benzyne (1) in 1,3-dipolar cycloaddition reactions in the
syntheses of 1,2-benzisoxazoles21 and benzotriazoles.22 We
were keen to build upon our expertise in this area, and herein
(13) Lukin, K.; Hsu, M. C.; Fernando, D.; Leanna, M. R. J. Org. Chem.
2006, 71, 8166–8172
.
(14) Zhenqi, Z.; Tongsheng, X.; Xiaonai, C.; Yuzhu, Q.; Zheng, Z.;
Hongwen, H. J. Chem. Soc., Perkin Trans. 1 1993, 1279–1280.
(15) Liu, R.; Zhu, Y.; Qin, L.; Ji, S. Synth. Commun. 2008, 38, 249–
254.
(23) Logullo, F. M.; Seitz, A. H.; Friedman, L. Org. Synth. 1968, 48,
12.
(16) Vin˜a, D.; Del Olmo, E.; Lo´pez-Pe´rez, J. L.; San Feliciano, A. Org.
Lett. 2007, 9, 525–528.
(17) Counceller, C. M.; Eichman, C. C.; Wray, B. C.; Stambuli, J. P.
Org. Lett. 2008, 10, 1021–1023.
(24) Huisgen, R.; Seidel, M.; Wallbillich, G.; Knupfer, H. Tetrahedron
1962, 17, 3–29.
(25) Toubro, N. H.; Holm, A. J. Am. Chem. Soc. 1980, 102, 2093–
2094.
(18) Huisgen, R.; Knorr, R. Naturwissenschaften 1961, 48, 716.
(19) Jin, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2007, 119, 3387–
3389.
(26) Fischer, S.; Wentrup, C. J. Chem. Soc., Chem. Commun. 1980, 502–
503.
(27) (a) Garanti, L.; Vigevani, A.; Zecchi, G. Tetrahedron Lett. 1976,
17, 1527–1528. (b) Wentrup, C.; Damerius, A.; Reichen, W. J. Org. Chem.
1978, 43, 2037–2041.
(20) Liu, Z.; Shi, F.; Martinez, P. D. G.; Raminelli, C.; Larock, R. C. J.
Org. Chem. 2008, 73, 219–226.
(21) (a) Spiteri, C.; Sharma, P.; Zhang, F.; Macdonald, S. J. F.; Keeling,
S.; Moses, J. E. Chem. Commun. 2010, 1272–1274. (b) Spiteri, C.; Mason,
C.; Zhang, F.; Ritson, D. J.; Sharma, P.; Keeling, S.; Moses, J. E. Org.
Biomol. Chem. 2010, 8, 2537–2542.
(28) (a) Oida, T.; Shimizu, T.; Hayashi, Y.; Teramura, K. Bull. Chem.
Soc. Jpn. 1981, 54, 1429–1433. (b) Tewari, R. S.; Dixit, P. D.; Parihar,
M. P. J. Heterocycl. Chem. 1982, 19, 1573–1575
(29) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211–
1214.
.
(22) Zhang, F.; Moses, J. E. Org. Lett. 2009, 11, 1587–1590.
Org. Lett., Vol. 12, No. 15, 2010
3369

Table 1. Preliminary Screening and Optimizaton
Table 2. Scope of the Reaction
“F-”
entrya source/base equiv solvent [°C]
temp
yield
[%]c
timeb
5 min
1d
2d
3e
4e
5e
6e
7e
8e
9e
10e
TBAF
TBAF
TBAF
TBAF
CsF
2.5
2.5
2.5
2.5
2.5
THF
THF
THF
MeCN rt
MeCN rt
rt
0
rt
58
10 min 67
5 min
5 min
24 h
5 min
5 min
5 min
63
38
trace
72
79
KF/18-C-6
2.5:2.7 MeCN rt
CsF/18-C-6 2.5:2.7 MeCN rt
CsF/18-C-6 2.5:2.7 THF rt
CsF/18-C-6 3.5:4.5 MeCN rt
CsF/18-C-6 3.5:4.5 THF rt
62
5 min 99
5 min 81
a Reaction performed on 0.433 mmol of 4 (100 mg) using 1.5 equiv of
3 (0.158 mL, 0.65 mmol). b Reaction monitored by LCMS until 4 was
consumed. c Isolated yield. d Reaction performed in 0.46 mL of solvent.
e Performed in 1.5 mL of solvent.
the corresponding dihydrotetrazine derivative, 1,3,4,6-tet-
raphenyl-1,4-dihydro-(1,2,4,5)tetrazine (6) was apparent.
Several modifications of the reaction conditions were at-
tempted to solve this issue. Addition of TBAF to a solution
of 3 and 4 in THF at room temperature gave 5 in 58% (entry
1, Table 1), whereas addition under ice-cold conditions gave
an increased yield of 67% (entry 2, Table 1). It was evident
that the rate of formation of 1 was not equal to that of 2,
resulting in undesirable side reactions predominating over
the formation of 1,3-diphenyl-1H-indazole (5). Diluting the
reaction mixture by 3-fold did not offer any beneficial effect
(entry 3, Table 1), whereas shifting to a more polar solvent,
MeCN, gave significantly reduced yield (38%, entry 4, Table
1).
Switching the fluoride source to CsF furnished 5 in trace
amount (entry 5, Table 1). Interestingly, and in agreement
with a recent report by Ferringa et al.,3 when KF or CsF
were used in conjunciton with 18-crown-6 (18-C-6), better
results were achieved (72-99%, entries, 6-10, Table 1). It
was found that both molar ratio of CsF/18-crown-6 and
solvent polarity had a significant effect on product formation
(entries 7-10, Table 1). The use of 18-crown-6 drastically
increased the rate of formation of both benzyne (1) and nitrile
imine (2), and it was possible to equilibrate their generation
by changing the equivalence of 18-crown-6. Optimal results
were obtained using CsF/18-crown-6 [3.5:4.5 equiv] in
MeCN at room temperature with a reaction time of 5 min
(entry 9, Table 1).30
a Reaction performed on 0.433 mmol of hydrazonoyl chlorides. b Isolated
yield.
was found to tolerate a range of functionalities, including
aryl and heterocyclic substituted hydrozonyl chlorides (entries
1-8, Table 2). Hydrozonyl chlorides bearing heterocycles,
such as thiophene and isoxazole were also well tolerated
(entries 7 and 8, Table 2), giving 13 and 14 in 66% and
60% respectively. The electronic properties of the nitrile
imine substituents affected the efficiency of the reaction, with
electron poor fluoride substrates leading to reduced yields.
Nitrile imines generated from aryl hydrozonyl chlorides
bearing electron-donating groups, or electron-withdrawing
groups, were found to self-dimerize preferentially, thus
leading to lower yields (entries 3, 4 and 6, Table 2). Although
electronics are clearly important, sterics may also play a key
With these optimized conditions in hand, we were keen
to investigate the substrate scope (Table 2). The protocol
(30) Verduyn, L. C.-; Elsinga, P. H.; Mirfeizi, L.; Dierckx, R. A.;
Feringa, B. L. Org. Biomol. Chem. 2008, 6, 3461–3463.
3370
Org. Lett., Vol. 12, No. 15, 2010

role in determening which pathway the nitrile imine follows.
Generally, sterically hindered nitrile imines21 are longer lived
speices in solution and dimerize at a slower rate. On the
other hand, this stabilizing steric effect may also slow down
or encumber the reactivity of the 1,3-dipole with benzyne,
thus allowing the reactive aryne to undergo alternative
reaction pathways. Thus, it is clear that several factors are
crucial when finetuning the reactivity, highlighting the
problems associated with generating two highly reactive
intermediates simultaneously.
Scheme 3
.
Synthesis of Substituted 1H-Indazoles via [3 + 2]
Cycloaddition
To gain insight into the regiochemical effects that sub-
stituents on benzyne may have, studies were performed with
the benzyne precursors, 3-(methoxy)-2-(trimethylsilyl)phenyl
triflate (15) and 2-methyl-6-(trimethylsilyl)phenyl triflate
(16), in conjunction with substrate 4 under the optimized
conditions. The results are illutrsated in Scheme 3. Interest-
ingly, the reaction carried out using 15 afforded a single
regioisomer 18 in 77%, whereas 16 gave a mixture of 19:20
in a ratio of 3.0:0.8 [1H NMR] (56 and 15% yield,
respectively, Scheme 3). The difference in regio-control
observed for 15 and 16 was attributed to a more pronounced
electronic effect exerted by the methoxy group on 15 as
compared to the methyl substituent.31
yields. This unprecedented reaction complements existing
methodologies to 1H-indazoles, offering a convergent and
rapid access to this important motif. We believe this modular
protocol will find wide use in drug discovery applications
and in the synthesis of chemical arrays.
In summary, we have demonstrated for the first time that
1-substituted-1H-indazoles can be prepared by a [3 + 2]
cycloaddition between in situ generated nitrile imines and
arynes using CsF/18-crown-6. The reaction is complete
within 5 min, affording the disubstituted compounds in good
Acknowledgment. J.E.M. thanks EPSRC, GSK, and The
University of Nottingham for financial support.
Supporting Information Available: Full characterization
1
data and copies of H and 13C NMR spectra for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(31) (a) Shi, F.; Waldo, J. P.; Chen, Y.; Larock, R. C. Org. Lett. 2008,
10, 2409–2412. (b) Cheong, P. H.-Y.; Paton, R. S.; Bronner, S. M.; Im,
G-Y. J.; Garg, N. K.; Houk, K. N. J. Am. Chem. Soc. 2010, 132, 1267–
1269.
OL101150T
Org. Lett., Vol. 12, No. 15, 2010
3371