One-pot synthesis of 1-alkyl-1H-indazoles from 1,1-dialkylhydrazones via aryne annulation

Article abstract of DOI:10.1039/c2ob07117g

The reaction of readily accessible 1,1-dialkylhydrazones with commercially available o-(trimethylsilyl)aryl triflates provides a direct one-step route to pharmaceutically important 1-alkylindazoles. The products are obtained in high yields by one-pot NCS-

Full text of DOI:10.1039/c2ob07117g

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PAPER
One-pot synthesis of 1-alkyl-1H-indazoles from 1,1-dialkylhydrazones via
aryne annulation†
Nataliya A. Markina, Anton V. Dubrovskiy and Richard C. Larock
Received 16th December 2011, Accepted 16th January 2012
DOI: 10.1039/c2ob07117g
The reaction of readily accessible 1,1-dialkylhydrazones with commercially available o-(trimethylsilyl)
aryl triflates provides a direct one-step route to pharmaceutically important 1-alkylindazoles. The products
are obtained in high yields by one-pot NCS-chlorination/aryne annulation or Ac2O-acylation/
deprotection/aromatization protocols.
Introduction
Results and discussion
1H-Indazoles represent an important class of heterocyclic com-
pounds that exhibit a wide range of biological and pharma-
ceutical activities,1 including anti-inflammatory,2 antitumor,3 and
anti-HIV4 activity among others. Selected examples of 1-alkyl-
1H-indazoles with notable pharmacological activities include
granisetron, a serotonin 5-HT3 receptor antagonist used to treat
nausea and vomiting after chemotherapy;5 lonidamine, used for
the treatment of brain tumors;6 and CL-958, an antitumor agent,
which is currently in clinical evaluation (Fig. 1).7
Various methods for the synthesis of the 1H-indazole core
have been developed.8 However, most of them employ harsh
reaction conditions, thus have limited the scope and applicability.
Recently, several methodologies have been reported that involve
aryne intermediates in [3 + 2] cycloaddition reactions with diazo
compounds,9 N-tosylhydrazones,10,11 and in situ generated
nitrile imines.12 These methods afford 1H-indazoles, 1-acyl-1H-
indazoles or 1-aryl-1H-indazoles under mild reaction conditions.
However, no aryne-annulation approach to 1-alkyl-1H-indazoles
has yet been reported.
In our previous work, we have shown that the reaction of a
variety of N,N-dialkylhydrazones with arynes seemingly pro-
ceeds through a cyclic intermediate 3 that subsequently under-
goes ring opening to form the corresponding o-(dialkylamino)
aryl imines 4 (Scheme 1).13
An unexpected result was obtained in the case of the mesityl-
substituted substrate, where the corresponding indazole 5 was
formed, albeit in only a 33% yield. In order to improve the
scope and efficiency of this process, we envisioned that one can
retain the cyclic nature of the intermediate 9 in two complemen-
tary ways (Scheme 2), namely by having a nearby leaving group
(path a) or trapping the amide 9 with a trapping agent (path b).
To our delight, we found that the reaction of N,N-dimethyl-
hydrazone chloride 7 (R1 = Ph, R2 = Me) with benzyne 2, gener-
ated in situ from o-(trimethylsilyl)aryl triflate14 8 in presence of
fluoride source, proceeds smoothly to afford indazole 11 in an
81% yield (Scheme 2, path a).
However, it did not prove to be efficient to purify and isolate
the labile starting materials 7. We promptly investigated the
possibility of a one-pot procedure wherein the chlorine-contain-
ing hydrazones are not isolated, but generated in situ from 1,1-
dialkylhydrazones 6 and NCS and further reacted with the o-(tri-
methylsilyl)aryl triflate 8 in the presence of a fluoride source.15
Fig. 1 Biologically active 1-alkyl-1H-indazoles.
Department of Chemistry, Iowa State University, Ames, IA, 50011, USA.
E-mail: larock@iastate.edu; Fax: +1 515 294-6342; Tel: +1 515 294-
0105
†Electronic supplementary information (ESI) available: Experimental
details for the preparation and characterization of starting materials and
products; copies of 1H and 13C NMR spectra; copies of NOE spectra for
the compound 15l. See DOI: 10.1039/c2ob07117g
Scheme 1
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Scheme 3
Scheme 2
Chart 2
the desired indazoles, seemingly due to complications during the
NCS chlorination step.
Other aryne precursors were also tested. Symmetrical naphtha-
lyne and dimethoxybenzyne precursors afforded the desired
indazoles 15j and 15k in good 63 and 62% yields, respectively.
The unsymmetrical 3-methoxybenzyne precursor provided
exclusively the 4-OMe regioisomer 15l in a 64% yield.
The structure of the product 15l is consistent with the pro-
posed mechanism (Scheme 2, path a).16
When cyclic hydrazones derived from N-aminopiperidine and
N-aminomorpholine were employed in this one-pot process, the
interesting products 15m and 15n were obtained, both in a 60%
yield (Scheme 3). In these cases, the initially formed indazolium
salt 16 undergoes ring-opening by the succinimide moiety
present in the reaction media from the chlorination step.17
In order to overcome some limitations of the methodology
using NCS, we also studied the reaction between the hydrazone
6a (R1 = Ph) and the benzyne precursor 8 in the presence of
acetic anhydride (Scheme 2, path b). We were pleased to observe
formation of the corresponding trapped product 17a (R1 = Ph) in
an 83% yield, which could also be subsequently deacetylated
and aromatized in situ to produce the indazole 15a (overall yield
for the 2 steps of 63%). After some optimization studies, we
were able to obtain the latter in an 83% overall yield without iso-
lating the intermediate product 17a. The scope of this process is
summarized in Chart 2.
Chart 1
To our delight, the desired indazole 11 was obtained in a 78%
yield. The optimal reaction conditions were found to be 1.1
equiv. of NCS per 1 equiv. of the hydrazone 6, and a slight
excess of the substrate 6 (1.2 equiv.) per 1 equiv. of the aryne
precursor 8. Both steps conveniently proceed in acetonitrile at
65 °C.
With the optimal conditions in hand, we next examined the
scope and limitations of this method (Chart 1). A range of hydra-
zones was studied first. Aryl, alkenyl and heteroaryl hydrazones
afforded the corresponding indazoles 15a–i in 32–78% yields.
Electron-poor aryl hydrazones afforded the corresponding inda-
zoles 15d and 15e in lower yields (59 and 45%, respectively).
The presence of a cyano group, terminal alkyne moiety, and an
ortho-bromo substituent was tolerated under these reaction con-
ditions. Unfortunately, hydrazones with R1 = 4-nitrophenyl, 2-
furyl, 2,3,5-trimethoxyphenyl and alkyl groups did not afford
Gratifyingly, a variety of substituents in the R1 position of the
hydrazone are well tolerated. For example, the product 15o is
obtained in an 80% yield. The electron-rich hydrazones, that
failed to react efficiently under our NCS-mediated protocol, have
afforded the corresponding indazoles 15p and 15q in excellent
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All melting points were obtained using an EZ-Melt automated
melting point apparatus and are uncorrected. High resolution
mass spectra (HRMS) were obtained using an Agilent QTOF
6540 mass spectrometer (ESI at a voltage of 70 eV). All mass
spectra (MS) were obtained using a GCT-Agilent 6890 gas chro-
matograph/mass spectrometer (EI at a voltage of 70 eV). All IR
spectra were obtained using a Nicolet 380 FT-IR apparatus.
Scheme 4
General procedure for the preparation of indazoles 15 by a
one-pot NCS procedure [1-methyl-3-phenyl-1H-indazole18 (15a)
as an example]
To a solution of benzaldehyde dimethylhydrazone 6a (46 mg,
0.31 mmol, 1.25 equiv.) in 1 mL of acetonitrile under an inert
atmosphere N-chlorosuccinimide (46 mg, 0.34 mmol, 1.38
equiv.) was added and the reaction mixture was stirred for 1 h at
65 °C. Then an additional 4 mL of acetonitrile, together with
CsF (114 mg, 0.75 mmol, 3 equiv.) and o-(trimethylsilyl)phenyl
triflate (61 μL, 0.25 mmol, 1.0 equiv.) were added and the reac-
tion mixture was stirred at 65 °C for an additional 10 h (moni-
tored by TLC). After cooling to room temperature, the reaction
mixture was filtered through a short column of Celite and con-
centrated under vacuum. The crude reaction mixture was sub-
jected to column chromatography using ethyl acetate–hexanes
(1 : 10) as eluent and afforded 40.6 mg (78%) of product 15a,
Scheme 5
yields (91 and 76%), despite their steric encumbrance. On the
other hand, electron-deficient hydrazones, such as 2-thiophenyl
and 3-pyridyl hydrazones, provide the corresponding products
15i and 15r in only 39 and 29% yields, respectively. In the case
of a stronger electron-withdrawing CO2Et group, N-acyl imine
20 was isolated in a 54% yield, instead of the desired indazole
(Scheme 4). This result can be rationalized by considering the
proposed intermediate 18, in which the acidic C-3 hydrogen can
be easily transferred to the negatively charged nitrogen atom.
Subsequent ring-opening results in formation of the product 20.
Alternatively, Boc2O has been tested as a trapping source
(with subsequent deprotection with aqueous HCl), but in most
cases similar or lower yields of the indazoles have been
obtained, except for the 2-thiophenyl product 15i, for which the
yield improved from 39 to 56%.
Surprisingly, N,N-dibenzyl-substituted hydrazone 6t provided
the corresponding indazole 15t with neither a trapping agent nor
NCS employed (Scheme 5). The product was isolated in a
higher (51%) yield when a two fold-excess of the benzyne pre-
cursor 8 was used. All attempts to obtain this indazole through
the optimized NCS or Ac2O routes have so far proved to be
inferior to the one described above.
1
gray solid: M.P. 81–83 °C; H NMR (400 MHz, CDCl3) δ 4.13
(s, 3H), 7.21 (s, 1H), 7.42 (t, J = 4.3 Hz, 3H), 7.52 (t, J = 7.6
Hz, 2H), 7.99 (d, J = 8.3 Hz, 2H), 8.04 (d, J = 8.2 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 35.72, 109.38, 121.09, 121.53,
121.81, 126.45, 127.57, 127.99, 128.98, 133.89, 141.63, 143.91;
MS (EI) m/z (%) 208 (M+, 100%), 77 (10%); HRMS (EI) calcd
for [M + H]+ C14H13N2 209.1073, found 209.1075; IR (CH2Cl2,
cm−1) 2939 (m), 1617 (s), 1495 (s), 1351 (s).
General procedure for the one-pot synthesis of indazoles 15
Method
A
(Ac2O–N2H4) [1-methyl-3-phenyl-1H-indazole
(15a) as an example]. To a mixture of benzaldehyde dimethylhy-
drazone 6a (37 mg, 0.25 mmol), CsF (114 mg, 0.75 mmol, 3
equiv.), acetic anhydride (47 μL, 0.50 mmol, 2 equiv.) and 5 mL
of acetonitrile in a 10 mL vial, o-(trimethylsilyl)phenyl triflate
(84 mg, 0.28 mmol, 1.1 equiv.) was added. The vial was capped
and the reaction mixture was allowed to stir for 10 h at 65 °C.
Then the solvent was evaporated under reduced pressure, 3 mL
of N2H4·H2O (85% solution, w/w) was added and the mixture
was heated at 100 °C for an additional 10 h. After cooling to
room temperature, 25 mL of dichloromethane was added to the
residue, and the reaction mixture was poured into 50 mL of
water in a separatory funnel. After shaking the layers, the
organic fraction was separated and the aqueous layer was
extracted with dichloromethane (2 × 15 mL). All organic frac-
tions were combined and concentrated under reduced pressure.
The residue was purified by flash chromatography on silica gel
using hexanes–EtOAc as the eluent to afford the desired indazole
15a in an 83% yield.
Conclusion
In summary, 1-alkyl-1H-indazoles can be prepared from arynes
and hydrazones in high yields by one-pot NCS-chlorination/
aryne annulation or Ac2O-acylation/deprotection protocols. This
chemistry provides a convenient route to 1-alkyl-1H-indazoles
from readily available N,N-dimethylhydrazones and presents a
valuable extension of the known synthetic routes to indazoles.
Experimental
The 1H and 13C NMR spectra were recorded at 300 and
75.5 MHz or 400 and 100 MHz, respectively. Chemical shifts
are reported in δ units (ppm) by assigning the TMS resonance in
1
the H NMR spectrum as 0.00 ppm and the CDCl3 resonance in
the 13C NMR spectrum as 77.23 ppm. All coupling constants (J)
are reported in Hertz (Hz). All commercial reagents were used
directly as obtained. Thin layer chromatography was performed
using commercially prepared 60-mesh silica gel plates, and visu-
alization was effected with short wavelength UV light (254 nm).
Method B (Boc2O–HCl) [1-methyl-3-phenethyl-1H-indazole
(15o) as an example]. To a mixture of dihydrocinnamaldehyde
dimethylhydrazone 6o (44 mg, 0.25 mmol), CsF (114 mg,
This journal is © The Royal Society of Chemistry 2012
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2 A. Guglielmotti, A. C. De Joannon, N. Cazzolla, M. Marchetti, L. Soldo,
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A. Fabi and F. Cognetti, Drugs Today, 2003, 39, 157.
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Eur. J. Org. Chem., 2008, 4073.
9 T. Jin and Y. Yamamoto, Angew. Chem., Int. Ed., 2007, 46, 3323; Z. Liu,
F. Shi, P. D. G. Martinez, C. Raminelli and R. C. Larock, J. Org. Chem.,
2008, 73, 219.
10 P. Li, J. Zhao, C. Wu, R. C. Larock and F. Shi, Org. Lett., 2011, 13,
3340.
0.75 mmol, 3 equiv.), di-tert-butyl dicarbonate (344 μL,
1.50 mmol, 6 equiv.) and 5 mL of acetonitrile in a 10 mL vial,
o-(trimethylsilyl)phenyl triflate (84 mg, 0.28 mmol, 1.1 equiv.)
was added. The vial was capped and the reaction mixture was
allowed to stir for 10 h at 65 °C. Then 3 mL of 1 M HCl was
added and the mixture was heated at 75 °C for an additional 3 h.
After cooling to room temperature, 25 mL of dichloromethane
was added to the residue, and the reaction mixture was poured
into 25 mL of water in a separatory funnel. After shaking the
layers, the organic fraction was separated and the aqueous layer
was extracted with dichloromethane (2 × 10 mL). All organic
fractions were combined and concentrated under reduced
pressure. The residue was purified by flash chromatography on
silica gel using hexanes–EtOAc as the eluent to afford the
desired indazole 15o as a colorless amorphous solid in an 81%
1
(method A: 80%): H NMR (400 MHz, CDCl3) δ 3.15 (dd, J =
11 N-Tosylhydrazones have been alternatively employed as starting materials
for the benzyne Fischer-indole reaction: D. McAusland, S. Seo,
D. G. Pintori, J. Finlayson and M. F. Greaney, Org. Lett., 2011, 13, 3667.
12 C. Spiretti, S. Keeling and J. E. Moses, Org. Lett., 2010, 12, 3368.
13 A. V. Dubrovskiy and R. C. Larock, Org. Lett., 2011, 13, 4136.
14 Y. Himeshima, T. Sonoda and H. Kobayashi, Chem. Lett., 1983, 1211.
15 During our optimization studies, we have investigated the first NCS-
chlorination step by conducting the reaction in CD3CN and monitoring
the completeness of the reaction by 1H NMR spectroscopy. We have
found that the hydrazone 6a was fully converted to the chlorohydrazone
7a in about 30 minutes. We have also found that upon addition of CsF to
the resulting reaction mixture, the chlorohydrazone 7a is instantly con-
verted to its fluoro analogue 7a′ (supported by HRMS).
16 For an explanation of the reactivity of the unsymmetrical monomethoxy
benzyne, see: Z. Liu and R. C. Larock, J. Org. Chem., 2006, 71, 3198;
R. Sanz, Org. Prep. Proced. Int., 2008, 40, 215; P. H.-Y. Cheong, R.
S. Paton, S. M. Bronner, G.-Y. J. Im, N. K. Garg and K. N. Houk, J. Am.
Chem. Soc., 2010, 132, 1267.
17 Supporting the mechanism outlined in Scheme 2, GC/MS analysis of the
crude reaction mixture for the preparation of 15a showed a peak (m/z =
113.1) corresponding to N-methylsuccinimide. Additionally, the absence
of a peak (m/z = 264.32) corresponding to the dimerization product of
compound 6a suggests that this reaction does not proceed through a
[3 + 2] cycloaddition of an azomethyneimine and an aryne.
18 D. Vina, E. del Olmo, J. L. López-Pérez and A. San Feliciano, Org. Lett.,
2007, 9, 525.
10.2, 6.2 Hz, 2H), 3.30 (dd, J = 10.1, 6.1 Hz, 2H), 4.04 (s, 3H),
7.12 (t, J = 7.6 Hz, 1H), 7.20–7.26 (m, 1H), 7.28–7.50 (m, 6H),
7.63 (d, J = 8.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 29.47,
35.36, 35.96, 109.04, 117.54, 119.81, 120.47, 122.81, 126.18,
126.35, 128.59, 140.98, 142.00, 144.80; MS (EI) m/z (%) 236
(M+, 58%), 145 (100%), 91 (21%); HRMS (EI) calcd for
[M + H]+ C16H17N2 237.1386, found 237.1393; IR (CH2Cl2,
cm−1) 2928 (s), 2859 (m), 1616 (s), 1505 (s).
Acknowledgements
We thank the National Science Foundation and the National
Institutes of Health Kansas University Center of Excellence in
Chemical Methodology and Library Development (P50
GM069663) for their generous financial support.
Notes and references
1 For a review, see: S. Brase, C. Gil and K. Knepper, Bioorg. Med. Chem.,
2002, 10, 2415.
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This journal is © The Royal Society of Chemistry 2012