An oxazolo[3,2-b]indazole route to 1H-lndazolones

Article abstract of DOI:10.1021/ol900891s

The novel heterocycle 2,3-dlhydrooxazolo[3,2-b]lndazole has been synthesized and utilized to provide easy access to 1 H-lndazolones, particularly the previously unreported 2-(2-alkoxyethyl)-1 H-lndazol-3(2H)-ones. Mechanistic as well as optimization and r

Full text of DOI:10.1021/ol900891s

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2760-2763
An Oxazolo[3,2-b]indazole Route to
1H-Indazolones†
James S. Oakdale,‡ Danielle M. Solano,‡ James C. Fettinger,‡
Makhluf J. Haddadin,§ and Mark J. Kurth*,‡
Department of Chemistry, UniVersity of California, One Shields AVenue, DaVis, California 95616, and
Department of Chemistry, American UniVersity of Beirut, Beirut, Lebanon
mjkurth@ucdaVis.edu
Received April 24, 2009
ABSTRACT
The novel heterocycle 2,3-dihydrooxazolo[3,2-b]indazole has been synthesized and utilized to provide easy access to 1H-indazolones, particularly
the previously unreported 2-(2-alkoxyethyl)-1H-indazol-3(2H)-ones. Mechanistic as well as optimization and reaction scope studies are reported.
1H-Indazol-3(2H)-ones (1, Scheme 1 inset) are known to
exhibit a wide range of biologically and pharmaceutically
Scheme 1
.
Formation of 1H-Indazolone 3a along with
2H-Indazole 4a
relevant properties and are reported to exhibit analgesic,1
antitumor,2 anticancer,3 and anti-inflammatory activities.4
Due in part to these wide ranging biological implications, a
number of techniques for synthesizing indazolones have been
reported.5 These include such strategies as base-mediated
ring opening of pyrazoles,4 base-mediated intramolecular ipso
substitution of 2-fluorobenzohydrazides,3 PIFA-mediated
intramolecular N-acylnitrenium trapping,6 acid-induced rear-
rangement of azobenzenes,7 o-azidobenzanilide treatment
with thionyl chloride followed by base-mediated hydrolysis,1
† Dedicated to the memory of Professor Aaron Mills (University of
Idaho), deceased May 2009.
‡ University of California.
§ American University of Beirut.
(1) Fletcher, S. R.; McIver, E.; Lewis, S.; Burkamp, F.; Leech, C.;
Mason, G.; Boyce, S.; Morrison, D.; Richards, G.; Sutton, K.; Jones, A. B.
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(2) Wang, H.; Han, H.; Von Hoff, D. D. Cancer Res. 2006, 66, 9722–
9730.
zinc/sodium hydroxide reductive cyclization of 2-nitroben-
zamides,8 copper-mediated C-N bond-forming heterocy-
clization of 2-halohydrazides,9 protection of the N-2 position
followed by alkylation/deprotection,8b CuO-catalyzed cou-
(3) Kawanishi, N.; Sugimoto, T.; Shibata, J.; Nakamura, K.; Masutani,
K.; Ikuta, M.; Hirai, H. Bioorg. Med. Chem. Lett. 2006, 16, 5122–5126.
(4) Abouzid, K. A. M.; El-Abhar, H. S. Arch. Pharmacal Res. 2003,
26, 1–8.
(5) For a review, see: Baiocchi, L.; Corsi, G.; Palazzo, G. Synthesis
1978, 633–648.
(8) (a) Bird, C. W.; Chng, J. C. W.; Rama, N. H.; Saeed, A. Synth.
Commun. 1991, 21, 545–548. (b) Bruneau, P.; Delvare, C.; Edwards, M. P.;
McMillan, R. M. J. Med. Chem. 1991, 34, 1028–1036.
(9) Tanimori, S.; Ozaki, Y.; Iesaki, Y.; Kirihata, M. Synlett 2008, 1973–
1976.
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10.1021/ol900891s CCC: $40.75
Published on Web 06/08/2009
 2009 American Chemical Society

pling of 2-haloarylcarboxylic acids with methylhydrazine,10
and other methods reported from this laboratory.11
(i.e., 3,4-dihydro-2H-[1,3]oxazino[3,2-b]indazoles).13 How-
ever, other mechanistic routes were also considered. For
example, in Path B/B′, formation of the 2H-indazole 4a
would occur first and subsequent intramolecular SN2 (Path
B) or SN2′ (Path B′) reaction would afford the 1H-indazolone
(3a).
In support of Path A, attempts were made to synthesize
5a from 2a under a variety of conditions, but the isolation
of 5a proved to be unsuccessful. Consequently, tactics were
changed and evidence was sought to eliminate Path B/B′ as
possible reaction mechanisms. The reaction of o-nitroben-
zylamine 2a in ethanol with no added water (Figure 2)
En route to the 3-allyloxy-2H-indazole 4a (Scheme 1) via
our previously reported one-step heterocyclization of
o-nitrobenzylamines (e.g., 2a),12 it was surprising to observe
that 4a was only a minor reaction product. As indazolones
have been observed in reactions that form indazoles,11 it was
suspected that the unidentified major product could be a 1H-
indazolone. Indeed, spectral data corroborated this suspicion,
and subsequent X-ray crystallography (Figure 1) identified
Figure 1. X-ray crystal structure of 1H-indazolone 3a.
the major reaction product as 2-(2-(allyloxy)ethyl)-1H-
indazol-3(2H)-one (3a).
This intriguing result (2a f 3a) called into question the
possible reaction mechanism for the formation of indazolone
3a and led to the consideration of two options (Scheme 2).
Scheme 2
.
Mechanistic Options for the Formation of
1H-Indazolone 3a
Figure 2
formation.
. Effect of the concentration of water on 1H-indazolone
resulted in formation of indazolone 3b as a product (80%)
along with the corresponding 2H-indazole 4b (15%); these
observations eliminated Path B′ as a viable option. Isolated
and purified indazole 4b was then resubjected to the reaction
conditions for an extended period of time in varying
concentrations of water (Figure 2). No conversion of 4b to
indazolone 3b was observed, thus effectively eliminating Path
B as a possible mechanism for indazolone formation.
Earlier observations demonstrated that 2H-indazole forma-
tion is highly dependent on the percentage of water present
in the reaction;14 this insight led us to analyze the effects of
water concentration on indazolone formation. As summarized
in Figure 2, a series of reactions were performed in which
only the percentage of water in alcohol was varied. The clear
trend was observed in which increasing the percentage of
water results in a decreased yield of indazole 4b with a
corresponding increase in the yield of indazolone 3b. These
Path A involves the formation of a 2,3-dihydrooxazolo[3,2-b]-
indazole (5a) by intramolecular alkoxide addition with
subsequent intermolecular allyloxide attack at C2 to open
the C-ring and form indazolone 3a. Path A appeared quite
feasible given our recent report that “intramolecular C-ring”
2H-indazole formation can occur to give six-membered rings
(10) Vin˜a, D.; del Olmo, E.; Lo´pez-Pe´rez, J. L.; San Feliciano, A. Org.
Lett. 2007, 9, 525–528.
(11) Kurth, M. J.; Olmstead, M. M.; Haddadin, M. J. J. Org. Chem.
2005, 70, 1060–1062.
(12) Mills, A. D.; Nazer, M. Z.; Haddadin, M. J.; Kurth, M. J. J. Org.
Chem. 2006, 71, 2687–2689.
(13) Butler, J. D.; Solano, D. M.; Robins, L. I.; Haddadin, M. J.; Kurth,
M. J. J. Org. Chem. 2008, 73, 234–240.
(14) Mills, A. D.; Maloney, P.; Hassanein, E.; Haddadin, M. J.; Kurth,
M. J. J. Comb. Chem. 2007, 9, 171–177.
Org. Lett., Vol. 11, No. 13, 2009
2761

results are consistent with Path A in that as the percentage
of alcohol present in the reaction mixture decreases, oxazo-
loindazole 5a (presumed precursor of 3b) would be formed
over the competing reaction to form indazole 4b. Optimal
conditions for indazolone formation (e.g., 3b) appear to be
70% water in alcohol. Furthermore, at particularly high
concentrations of water, formation of 2-(2-hydroxyethyl)-
1H-indazol-3(2H)-one (3c) becomes the dominant path: 3c
could arise by either hydroxide attack at C2 of 5a or by direct
addition of water during the initial heterocyclization reaction
(giving 3c instead of indazole 4b).
attempt to mitigate the reactivity of presumed intermediate
5a. Indeed, we were gratified to find that modification led
to 2,3-dihydrooxazolo[3,2-b]indazoles 5b-e as the major
reaction products under a variety of reaction conditions (see
Table 1). These confirming results led to intensified efforts
to isolate the novel parent system 5a. Ultimately, we found
that interrupting the reaction of 2a (entry 1) prior to complete
consumption of starting material resulted in the isolation of
5a in an overall yield of 24% (53% recovery of 2a); complete
consumption of starting material 2a resulted in only evidence
of trace amounts of 5a (LC/MS data; see Table 1, entry 1
vs entry 2).
In an attempt to further support Path A, 3,4-dihydro-2H-
[1,3]oxazino[3,2-b]indazole (7) was synthesized from
o-nitrobenzylamine 6 (Scheme 3). Indazolone 8 was not
When thus isolated 2,3-dihydrooxazolo[3,2-b]indazole 5a
was subjected to base-mediated methanolysis, indazolone 3d
was obtained in 97% yield (Table 2, entry 1). Similar
Scheme 3. Synthesis of
3,4-Dihydro-2H-[1,3]oxazino[3,2-b]indazole (7)
Table 2. Oxazoloindazoles React To Give Indazolones
entry
R1
R2
time (h)
Reaction
yield (%)a
1
2
3
4
H
H
Me
Bn
H
Me
H
8
144
14
5a f 3d
5b f 3e
5c f 3f
5d f 3g
97
40
92
72
H
18
observed en route to 7, nor was it observed when isolated and
purified 7 was resubjected to the reaction conditions. Thus,
although the ready formation and isolation of 7 lends credence
to the formation of 5a, its lack of reactivity vis-a`-vis formation
of 8 left the intermediacy of 5a still in question.
a Isolated yield after silica gel chromatography.
treatment of indazoles 5c and 5d also proceeded smoothly
to give the corresponding indazolones 3f and 3g. However,
the steric hindrance of 5b significantly reduced the reactivity
of this indazole leading to a decreased yield of indazolone
3e. Taken together, these results clearly support Path A as
the most probable mechanistic explanation of 2a f 3a.
Having this support of Path A as the operative process,
attention was next turned to evaluating the scope of this
Table 1. Formation of 2,3-Dihydrooxazolo[3,2-b]indazoles
ROH/H2O time temp
yield
(%)
Table 3. Formation of 1H-Indazolones Utilizing Different
Alcohols
entry
R1
R2
(%)
(h)
(°C)
reaction
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
i-PrOH/10
i-PrOH/10
4
24
32
12
32
18
18
18
18
60
60
70
70
70
60
70
60
60
2a f 5a
2a f 5a
2b f 5b
2b f 5b
2b f 5b
2c f 5c
2d f 5d
2d f 5d
2e f 5e
24b
5c
Me MeOH/70
Me EtOH/30
Me i-PrOH/10
H
H
H
H
30c
65a
67a
84a
10c
88a
80a
H
Me
Bn
Bn
i-Pr
i-PrOH/10
i-PrOH/0
i-PrOH/10
i-PrOH/10
product
entry
ROH
Ra
reaction
ratiob
1
2
3
4
5
6
allyl alcohol
ethanol
methanol
isopropyl alcohol CH(CH3)2
tert-butyl alcohol C(CH3)3
CH2CHdCH2 2a f 3a + 3c 56:22
a Isolated yield after silica gel chromatography. b Reaction was
prematurely evaluated. Isolated yield after silica gel chromatography; starting
material was recovered in 53% yield. c Yield as determined by crude LC/
MS trace.
CH2CH3
CH3
2a f 3b + 3c 67:18
2a f 3d + 3c 80:-
2a f 3h + 3c 38:46
2a f 3i + 3c
2a f 3j + 3c
-:85
77:-
ethylene glycol
CH2CH2OH
a 3c; R ) H. b Yield determined by crude LC/MS trace.
At this point, the addition of R groups to the ethanolamine
moiety of 2a (see 2a in Table 1) was investigated in an
2762
Org. Lett., Vol. 11, No. 13, 2009

It was further demonstrated that a variety of o-nitroben-
zylamines can successfully undergo indazolone formation
(Table 4). From o-nitrobenzylbromide, several new ethanol-
amine-substituted o-nitrobenzylamines were prepared from
amino acid derived aminoalcohols. Each of these 2-(2-
nitrobenzylamino)alkan-1-ols underwent heterocyclization/
alcoholysis to give indazolones 3f, 3g, 3k, and 3l using
methanol as a solvent.
Table 4. Formation of 1H-Indazolones Utilizing Different
o-Nitrobenzylamines
In summary, a new method for the formation of indazo-
lones has been demonstrated. This unique process works with
a variety of alcohols and o-nitrobenzylamines. Evidence
suggests that these reactions proceed via the intermediacy
of a 2,3-dihydrooxazolo[3,2-b]indazole. A study of related
indazoles and their reactivity with various nucleophiles is
currently underway and will be reported in due course.
entry stereochemistry
R
reaction yield (%)a
1
2
3
4
S
R
S
R
CH3
2b f 3f
2c f 3g
2d f 3k
89a
48a
60b
59b
CH2Ph
CH(CH3)2
CH2CH(CH3)2 5e f 3l
a Yield determined by crude LC/MS trace. b Isolated yield after silica
gel chromotography.
Acknowledgment. The authors thank the National Science
Foundation (CHE-0614756) for their financial support of this
work. DMS thanks the Alfred P. Sloan Minority Ph.D.
Program and the UC Davis Alliance for Graduate Education
and the Professoriate (AGEP) Advantage Program. JSO
thanks the Chevron Summer Undergraduate Research Fel-
lowship for partial financial support. We also thank Mr.
Jeffrey Butler (UC Davis) and Professor Aaron Mills†
(University of Idaho) for helpful discussions.
transformation under one-pot reaction conditions. As detailed
in Table 3, o-nitrobenzylamine 2a was subjected to hetero-
cyclization/alcoholysis with a variety of alcohols employing
the optimal conditions for indazolone formation (70% water
in alcohol). Primary alcohols performed well, delivering
indazolones 3a, 3b, 3d, and 3j in good yield, while isopropyl
alcohol (Table 3, entry 4) delivered 3h in decreased yield.
tert-Butyl alcohol (Table 3, entry 5) gave only trace amounts
of alkoxide-incorporated indazolone, instead favoring forma-
tion of 2-(2-hydroxyethyl)-1H-indazol-3(2H)-one (3c). With
these non-nucleophilic alcohols indazolone 3c most probably
occurs via a mechanism similar to Path A, but indazole 5a
is opened by hydroxide rather than alkoxide.
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL900891S
Org. Lett., Vol. 11, No. 13, 2009
2763