The Davis-Beirut reaction: N 1, N 2-disubstituted-1 H-indazolones via 1,6-electrophilic addition to 3-alkoxy-2 H-indazoles

Article abstract of DOI:10.1021/ol2010424

A variety of electrophiles (anhydrides, acid chlorides, carbonochloridates, sulfonyl chlorides, and alkyl bromides) react with 3-methoxy-2H-indazole (1a), benzoxazin[3,2-b]indazole (1d), and oxazolino[3,2-b]indazole (1e) - substrates available by the Davi

Full text of DOI:10.1021/ol2010424

ORGANIC
LETTERS
The DavisꢀBeirut Reaction: N1,
N2-Disubstituted-1H-Indazolones via
1,6-Electrophilic Addition to
3-Alkoxy-2H-Indazoles
2011
Vol. 13, No. 12
3138–3141
Wayne E. Conrad,† Ryo Fukazawa,† Makhluf J. Haddadin,*,‡ and Mark J. Kurth*,†
Department of Chemistry, University of California, One Shields Avenue, Davis,
California 95616, United States, and Department of Chemistry,
American University of Beirut, Beirut, Lebanon
haddadin@UAB.edu.lb; mjkurth@ucdavis.edu
Received April 19, 2011
ABSTRACT
A variety of electrophiles (anhydrides, acid chlorides, carbonochloridates, sulfonyl chlorides, and alkyl bromides) react with 3-methoxy-2H-
indazole (1a), benzoxazin[3,2-b]indazole (1d), and oxazolino[3,2-b]indazole (1e) ; substrates available by the DavisꢀBeirut reaction ; to yield a
diverse set of N1,N2-disubstituted-1H-indazolones. With certain electrophiles, an AERORC (Addition of the Electrophile, Ring Opening, and Ring
Closure) process on indazole 1d results in indazoloindazolone formation. An intriguing aspect of these N1,N2-disubstituted-1H-indazolones is that
they are poised for diversification through, for example, azideꢀalkyne cycloaddition chemistry reported here.
The indazole and indazolone ring systems are privileged
heterocycles1 known to exhibit analgesic, antitumor, antic-
ancer, antiangiogenic, antiviral, and anti-inflammatory
activities. Of the two isomers, 2H-indazoles are less explored
than 1H-indazoles.2 In previous reports,3 our laboratory
has demonstrated the utility of the DavisꢀBeirut reaction ;
an effective N,N-bond forming heterocyclization reaction ;
to deliver 3-alkoxy-2H-indazoles, benzoxazin[3,2-b]-inda-
zole, oxazolino[3,2-b]indazole, and a variety of other inda-
zolo-fused heterocycles from 2-nitrobenzaldehyde or
1-(bromomethyl)-2-nitrobenzene.
We showed more recently that 3-alkoxy-2H-indazoles
can be converted into N2-substituted-1H-indazolones by
treatment with various nucleophiles.4 For example, reaction
of indazole 1a with sodium ethanethiolate under micro-
wave conditions (155 °C, 10 min) delivers, by demethyla-
tion, indazolone 2 in 62% yield (Scheme 1). This led to an
† University of California.
‡ American University of Beirut.
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2008, 4073. (b) Fletcher, S. R.; McIver, E.; Lewis, S.; Burkamp, F.;
Leech, C.; Mason, G.; Boyce, S.; Morrison, D.; Richards, G.; Sutton,
K.; Jones, A. B. Biorg. Med. Chem. Lett. 2006, 16, 2872. (c) Kawanishi,
N.; Sugimoto, T.; Shibata, J.; Nakamura, K.; Masutani, K.; Ikuta, M.;
Hirai, H. Biorg. Med. Chem. Lett. 2006, 16, 5122. (d) Huang, L.-J.; Shih,
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Aran, V. J.; Ochoa de Ocariz, C. Mini-Rev. Med. Chem. 2005, 5, 869.
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Lett. 2011, 13, 1060. (b) Solano, D. M.; Butler, J. D.; Haddadin, M. J.;
Kurth, M, J. Org. Synth. 2010, 87, 339. (c) Butler, J. D.; Solano, D. M.;
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r
10.1021/ol2010424
Published on Web 05/25/2011
2011 American Chemical Society

investigation of the scope of nucleophilic ring opening of
indazoles 1bꢀd and established that a variety of nucleo-
philes can be employed to produce a diverse set of
N2-substituted-1H-indazolones.
Scheme 3. 1,6-Electrophilic Addition to 3-Methoxy-2H-inda-
zole 1a
Scheme 1. Nucleophilic Ring Opening of 3-Alkoxy-2H-inda-
zoles
With these results as a backdrop, we speculated that
3-alkoxy-2H-indazoles, available by the DavisꢀBeirut
reaction, might also react with an electrophile to give a
positively charged N1 which would, in turn, drive a coun-
teranion to attack giving net 1,6-electrophilic addition
across the 2H-indazole. In fact, treating indazole 1a with
refluxing HOAc affords indazolone 2 (Scheme 2), while
heatingwithsodium acetateinDMFforthe sameperiod of
time (118 °C, 17 h) gives no reaction.
Scheme 4, indazole 1e reacts with all nine electrophiles
(E1ꢀE9) to produce a diverse set of N1,N2-disubstituted-
1H-indazolones in excellent yield. It was also noted that
electrophilic addition to 1e was generally much faster
and higher yielding than addition to indazole 1a, most
likely due to relief of strain in the five-membered ox-
azolino ring.
Scheme 2. DavisꢀBeirut Reaction f 1a f 2
An interesting turn of events occurred when we
investigated the electrophilic addition to indazole 1d.
While treatment of 1d with benzoyl chloride in acet-
ronitrile at 60 °C delivered the anticipated indazolone
20 in 99% yield, treating it with 2-bromo-1-morpholi-
noethanone in acetonitrile at 82 °C gave indazolo-
[2,1-a]indazol-6(12H)-one 22 as the sole product
(Scheme 5). LCMS monitoring of the reaction indi-
cated that the originally anticipated indazolone 21 was
indeed formed as a transient intermediate, but under
the conditions of the reaction, it quickly converted to
indazoloindazolone 22. Based on the fact that 22 is not
formed when N1 of the indazole is acylated (1d f 20),
we speculate that indazoloindazolone formation oc-
curs via an AERORC (Addition of the Electrophile,
Ring Opening, and Ring Closure)6 process that we
speculate transposes through the intermediacy of
Building on this simple but encouraging result, we
launched an investigation of the effectiveness of 1,6-elec-
trophilic addition to indazole 1a using the diverse set of
electrophiles shown in Scheme 3 (E1ꢀE9). This study
revealed that indazole 1a reacts with each of these various
electrophiles to produce a diverse set of N1,N2-disubsti-
tuted-1H-indazolones. Reaction optimization established
that thermal heating, although requiring a longer reaction
time than microwave irradiation, results in higher yields.
Additionally, for all electrophiles except E1 and E2 where
reactionswereperformedinHOAcandAc2O(respectively),
solvent optimization showed that CH3CN led to higher
yields than either DMF or DMSO.
(6) (a) While the ANRORC6bꢀd process is well documented, this is a
rare example of a heterocyclic AERORC process. (b) Van der Plas, H. C.
Acc. Chem. Res. 1978, 11, 462. (c) Van der Plas, H. C. Adv. Heterocycl.
Chem. 1999, 74, 1. (d) See ref 8.
We next investigated the 1,6-electrophilic addition re-
activity of oxazolino[3,2-b]indazole 1e. As presented in
Org. Lett., Vol. 13, No. 12, 2011
3139

Scheme 4. 1,6-Electrophilic Addition to Oxazolino[3,2-b]-inda-
zole 1e
Scheme 6. CuAAC Reactions on Indazolone 7
indazoloindazolium 210. Indeed, this AERORC pro-
cess (1d f 22) is competitive in rate with the alkylation/
ring opening reaction (1d f 21) and the only way to obtain
appreciable amounts of 21 (28%) is to stop the reaction
early (∼57% conversion of 1d). It was also found that
treating 1d with catalytic (10 mol %) 2-bromo-1-morpho-
linoethanone delivers 22 in high yield (82 °C, 7 d, 79%
yield; μw, 150 °C, 5 h, 92% yield).
An intriguing aspect of many of the indazolones pre-
sented in Schemes 3 and 4 is that they are poised for further
diversification through, for example, azideꢀalkyne cy-
cloaddition chemistry.7 Capitalizing on this opportunity,
we next set out to synthesize a small library of 20 triazolyl-
indazolones (23ꢀ32, Scheme 6; and 33ꢀ42, Scheme 7) as a
part of our commitment to the NIH Molecular Libraries
Small Molecule Repositoryfor high-throughput biological
screening. Asillustrated inScheme6, indazolone7 (entry 6,
Scheme 3), containing a propynyl moiety, was used for
part one of this click diversification study. In situ generated
azides ; prepared from amines A1ꢀA10 by treatment
with 1H-imidazole-1-sulfonyl azide8 and CuSO4 ; were
employed in these copper(I)-catalyzed cycloadditions to
give indazolones 23ꢀ32 in high yields.
Scheme 5. 1,6-Electrophilic Addition (f 20) vs AERORC
(f 22)
For part two of this click diversification study, we
decided to prepare a collection of 10 triazolyl-indazolones
based on indazole 19 (entry 9, Scheme 4). We envisioned a
one-pot reaction9 for this process wherein indazolone 19
was heated first with sodium azide, followed by the addi-
tion of copper(I) and the alkyne. To test the reliability of
the first step (RꢀBr f RꢀN3), indazolone 19 was treated
(7) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, B. K.
Angew. Chem., Int. Ed. 2002, 41, 2596. (b) Tornoe, C. W.; Christensen,
C.; Meldal, M. J. Org. Chem. 2002, 67, 3057. For reveiews of click
chemistry, see:(c) Meldal, M.; Tornøe, W. Chem. Rev. 2008, 108, 2952.
(d) Hein, J. E.; Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1302.
(8) Goddard-Borger, E. D.; Stick, R. V. Org. Lett. 2007, 9, 3797.
(9) Feldman, A. K.; Colasson, B.; Fokin, V. V. Org. Lett. 2004, 6,
3897.
3140
Org. Lett., Vol. 13, No. 12, 2011

with sodium azide at 60 °C in DMF and the corresponding
primary azide was cleanly obtained within a 3 h reaction
time. We next sought to trap the azide with an alkyne in a
one-pot, two-step reaction to give the corresponding triazole
product. The results of 10 such reactions are summarized
in Scheme 7 and show that a variety of alkynes react to give
1,4-triazoles in good to excellent yields.
Scheme 7. CuAAC Reactions on Indazolone 19
In summary, we have demonstrated that electrophilic
addition to 3-methoxy-2H-indazole (1a), benzoxazin-
[3,2-b]indazole (1d), and oxazolino[3,2-b]indazole (1e)
substrates can lead to novel N1,N2-disubstituted-1H-
indazolones that are difficult to access by other methods.
A rare example of a heterolytic AERORC reaction
has been demonstrated with the rearrangement of
benzoxazin-[2,3-b]indazole 1d to indazolonoindazole 22
via the intermediacy of indazolone 21. Finally, further
diversification of two N1,N2-disubstituted-1H-indazolone
products through azideꢀalkyne cycloaddition chemistry
was demonstrated yielding a small library of novel
triazoles.
Acknowledgment. We thank the National Science
Foundation (CHE-0910870) and the National Institutes
of Health (GM089153) for generous financial support.
W.E.C. acknowledges the United States Department of
Education for a GAANN Fellowship.
Supporting Information Available. Full experimental
details and characterization data (1H NMR, 13C NMR,
IR, and LC/MS) for all new compounds. This material
is available free of charge via the Internet at http://pubs.
acs.org.
Org. Lett., Vol. 13, No. 12, 2011
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