Nucleophilic substitution of oxazino-/oxazolino-/benzoxazin [3,2- b ]indazoles: An effective route to 1 H-indazolones

Article abstract of DOI:10.1021/ol100751n

A variety of nucleophiles, thiolates, alkoxides, amines, iodide, and cyanide, react with oxazino-, oxazolino-, and benzoxazin[3,2-b]indazoles under microwave conditions to yield a diverse set of 2-substituted 1H-indazolones. The synthetic utility of these

Full text of DOI:10.1021/ol100751n

ORGANIC
LETTERS
2010
Vol. 12, No. 11
2524-2527
Nucleophilic Substitution of Oxazino-/
Oxazolino-/Benzoxazin [3,2-b]indazoles:
An Effective Route to 1H-Indazolones
Michael B. Donald,† Wayne E. Conrad,† James S. Oakdale,† Jeffrey D. Butler,†
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
haddadin@aub.edu.lb; mjkurth@ucdaVis.edu
Received March 31, 2010
ABSTRACT
A variety of nucleophiles, thiolates, alkoxides, amines, iodide, and cyanide, react with oxazino-, oxazolino-, and benzoxazin[3,2-b]indazoles
under microwave conditions to yield a diverse set of 2-substituted 1H-indazolones. The synthetic utility of these indazoles is further demonstrated
by ANRORC (addition of the nucleophile, ring-opening, and ring closure) reactions to yield isomeric pyrazoloindazolones by a process wherein
iodide acts first as a nucleophile and subsequently as a leaving group.
The indazole ring and its derivatives have been reported to
exhibit analgesic,1 antitumor,2 anticancer,3 anti-inflamma-
tory,4 and antifertility activity.5 Of the two indazole isomers,
2H-indazoles are much less explored than 1H-indazoles.6 As
a continuation of our interest in the chemistry of 2H-
indazoles and the related 1H-indazolones,7 we set out to
synthesize a series of 1H-indazolone derivatives as part of
our commitment to the National Institute of General Medical
Sciences (NIGMS) for the creation of pilot-scale libraries.
We recently reported that treatment of 2-(2-nitrobenzy-
lamino)propan-1-ol (1b) with KOH in 10% aqueous i-PrOH
results in a one-pot bis-heterocyclization to oxazolino[3,2-
b]indazole 2b.8 In contrast, treatment of 2-(2-nitrobenzy-
lamino)ethanol (1a) with KOH in 70% aqueous MeOH
produces 2-(2-methoxyethyl)-1H-indazol-3(2H)-one (3a). We
subsequently discovered that treating indazole 2b with
MeOH/KOH causes it to undergo “dealkylative” ring-
opening to give 2-(1-methoxypropan-2-yl)-1H-indazol-3(2H)-
one (3b), suggesting that 1a delivered 3a via the intermediacy
of indazole 2a (Scheme 1).
† University of California.
‡ American University of Beirut.
(1) Fletcher, S. R.; Mclver, E.; Lewis, S.; Burkamp, F.; Leech, C.;
Mason, G.; Boyce, S.; Morrison, D.; Richards, G.; Sutton, K.; Jones, A. B.
Bioorg. Med. Chem. Lett. 2006, 16, 2872.
(2) Wang, H.; Han, H.; Von Hoff, D. D. Cancer Res. 2006, 66, 9722.
(3) Kawanishi, N.; Sugimoto, T.; Shibata, J.; Nakamura, K.; Masutani,
K.; Ikuta, M.; Hirai, H. Bioorg. Med. Chem. Lett. 2006, 16, 5122.
(4) Abouzid, K. A. M.; El-Abhar, H. S. Arch. Pharmacal Res. 2003,
26, 1.
(5) (a) Silvestrini, B.; Cheng, C. Y. US Patent Appl. 99-304042, 1999.
(b) Cerecetto, H.; Gerpe, A.; Gonzalez, M.; Aran, V. J.; de Ocariz, C. O.
Mini-ReV. Med. Chem. 2005, 5, 869.
Herein, we report a study of indazole-based nucleophilic
ring-opening reactions on substrates 2c, 5, and 6. Indazole
(6) (a) Halland, N.; Nazare´, M.; R’kyek, O.; Alonso, J.; Urmann, M.;
Lindenschmidt, A. Angew. Chem., Int. Ed. 2009, 48, 6879. (b) Vin˜a, D.;
del Olmo, E.; Lopez-Pe´rez, J. L.; San Feliciano, A. Org. Lett. 2007, 9,
525. (c) Stadlbauer, W.; Camp, N. In Science of Synthesis: Houben-Weyl
Methods of Molecular Transformations; Bellus, D., Ley, S. V., Noyori, R.,
Regitz, M., Schaumann, E., Shinkai, E., Thomas, E. J., Trost, B. M., Reider,
P. J., Eds.; Thieme: Stuggart, 2002; Vol. 12, p 227.
(7) (a) Dou, G.; Shi, D. J. Comb. Chem. 2009, 11, 1073. (b) Tanimori,
S.; Ozaki, Y.; Iesaki, Y.; Kirihata, M. Synlett 2008, 19, 1973.
(8) Oakdale, J. S.; Solano, D. M.; Fettinger, J. C.; Haddadin, M. J.;
Kurth, M. J. Org. Lett. 2009, 11, 2760.
10.1021/ol100751n  2010 American Chemical Society
Published on Web 05/03/2010

Scheme 1
.
Nucleophilic Opening of Oxazolo[3,2-b]indazoles
Table 1. Nucleophilic Ring-Opening of Indazole 6
entry
nucleophile
indazolone
yield (%)
1
2
3
4
5
6
7a
8
CH3CH2SNa
C6H5SNa
HO(CH2)2SNa
CH3(CH2)7ONa
c-C5H9ONa
iPrNH2
8
9
77
99
74
52
35
10
11
12
13
14
15
NRb
C6H5NH2
KI
58
see Scheme 5
a 140 °C for 30 min. b NR ) no reaction.
alkoxides, amines, and iodide. The yields of these reactions
varied between fair to nearly quantitative, and several
reactivity trends were observed. In addition, solvent opti-
mization was conducted. Variable and generally moderate
reactivity were observed in MeOH, THF, or MeCN. How-
ever, DMF gave the best and most consistent results under
microwave conditions. Comparable results were generally
obtained using DMSO as solvent.
derivatives 2c, 5, and 69 were prepared by a one-pot
alkylation/bis-heterocyclization process starting from 1-(bro-
momethyl)-2-nitrobenzene, whereas indazole 4 was pre-
pared by an analogous, but stepwise, process (Scheme 2).
This nucleophile study began with indazolobenzoxazine
6. Thiolate, alkoxy, and primary amine nucleophiles pro-
duced 1H-indazolones 8-14 in fair to good yield. Despite
the benzylic nature of the breaking C-O-bond, 6 proved
unreactive toward several other nucleophiles (diisopropyl
amine, isocyanate, isothiocyanate, azide, and methyl Grig-
nard).
Scheme 2. Dealkylative Indazole f Indazolone Conversion
An interesting result came from the reaction of indazole
6 with KI. As depicted in Scheme 3, iodide opens the
Scheme 3. Potassium Iodide Mediated ANRORC Reaction of 6
Treating indazole 4 with sodium ethanethiolate under
microwave conditions (155 °C, 10 min) delivered the
anticipated dealkylated indazolone 7 in 62% unoptimized
yield and presumably ethyl(methyl) sulfide.10 With this
initial result in hand, we began a detailed study of the
indazole-based nucleophilic ring-opening reaction of in-
dazoles 2c, 5, and 6.
benzoxazine heterocycle as anticipated to presumably give
potassium 2-(2-(iodomethyl)phenyl)-3-oxo-2,3-dihydroinda-
zol-1-ide which, by a subsequent intramolecular N-alkylation,
cyclizes to indazolo[2,1-a]indazol-6(12H)-one (15′). This 6
f 15′ conversion proceeds by an ANRORC (addition of the
nucleophile, ring-opening, and ring closure) reaction.11
As illustrated in Table 1, a variety of nucleophiles were
investigated in the reaction with 6, including thiolates,
(9) A detailed description of the preparation of indazole 6 has been
submitted to Organic Syntheses.
(10) Caution: Although no safety issues arose with the combination of
NaH/DMF in this work, large batches have resulted in uncontrollable
exotherms. See: (a) Urben, P. G., Ed. Bretherick’s Handbook of ReactiVe
Chemical Hazards, 7th ed.; Elsevier: San Francisco, 2007; Vol. 1, p 1672.
(b) Buckley, J.; Webb, R. L.; Laird, T.; Ward, R. J. Chem. Eng. News 1982,
60, 5. (c) De Wall, G. Chem. Eng. News 1982, 60, 5–43.
With these ecouraging results in hand, we turned to a study
of the nucleophile-initiated chemistry of 5H-indazolo[3,2-
b]benzo[d]-1,3-oxazine (2c); the results are outlined in Table
2. Indazole 2c was found to be more reactive toward
Org. Lett., Vol. 12, No. 11, 2010
2525

Table 2. Nucleophilic Ring-Opening of Indazole 2c
Table 3. Nucleophilic Ring-Opening of Indazole 5
entry
nucleophile
indazolone yield (%) yield w/KI (%)
entry
nucleophile
indazolone
yield (%)
1
2
3
4
CH3CH2SNa
C6H5SNa
HO(CH2)2SNa
KCN
CH3(CH2)7ONa
c-C5H9ONa
iPrNH2
KI
OdCdNK
NaN3
16
17
18
19
20
21
22
23
24
25
26
85
99
95
38
88
80
59
1
2
3
4
CH3CH2SNa
C6H5SNa
HO(CH2)2SNa
KCN
CH3(CH2)7ONa
c-C5H9ONa
iPrNH2
KI
OdCdNK
NaN3
27
28
29
30
31
32
33
34
35
36
37
53
67
47
NRb
58
5
5
see Scheme 5
see Scheme 5
38%
see Scheme 5
NR
6
6
7a
8
61
7a
8
see Scheme 4
9
10
11
NRb
NR
NR
44
48
9
10
11
NR
NR
H3CMgBr
H3CMgBr
a 170 °C for 120 min. b NR ) no reaction.
a 170 °C for 120 min. b NR ) no reaction.
nucleophilic attack and, in most cases, delivered the ring-
opened product in higher yield compared to 6.
outlined in Table 3. Indazole 5 displayed reactivity between
that of 2c and 6. Like 6, indazole 5 reacts with potassium
iodide to give an N-alkylated final product (34′; Scheme 5)
We observed no apparent reaction upon treatment of
indazole 2c with KI, although the results with indazole 6
would suggest that, most probably, 2c does open to inter-
mediate 23′. However, confronted with an N-alkylative
cyclization to a four-membered ring, we postulate that 23′
instead cyclizes back to 2c via an O-alkylation reaction
(Scheme 4).
Scheme 5
.
ANRORC and Elimination Reactions with Indazole
5
Scheme 4. Potassium Iodide Reaction with Indazole 2c
Based on the assumption that 2c and 23′ are in equilibrium
in the presence of KI under thermal conditions, we speculated
that 2c could be effectively opened with less reactive
nucleophiles via the intermediacy of 23′. To test this,
stochiometric KI was added to the reaction mixture to form
transient intermediate 23′, which was subsequently inter-
cepted by the secondary nucleophile to give the ring-opened
1H-indazolone (rather than cyclizing back to indazole 2c).
This modified Finkelstein method12 enabled the production
of indazolones 24 and 25 in fair yields (Table 2, entries 9
and 10).
by an ANRORC process. Likewise, when potassium iodide
was added to the reaction in attempt to synthesize indazo-
lones 30, 35, and 36, the ANRORC process was favored
yielding 34′ rather than the targeted indazolones.
Another interesting result was observed in the reaction of
indazole 5 with alkoxides (Table 3, entries 5 and 6). Whereas
2c and 6 gave the targeted ether-containing indazolone, 5
gave elimination products 38 and 39 (see Scheme 5). In this
transformation, alkoxides, even primary alkoxides, react with
We next investigated nucleophilic addition to 3,4-dihydro-
2H-[1,3]oxazino[3,2-b]indazole (5), the results of which are
(11) (a) Van der Plas, H. C. AdV. Heterocycl. Chem. 1999, 74, 1. (b)
Van der Plas, H. C. Acc. Chem. Res. 1978, 11, 462.
(12) (a) Cronan, J. M.; Lee, A.; Liang, J.; Clardy, J.; Cardellina, J. H.,
II. J. Nat. Prod. 2010, 73, 346–351. (b) Finkelstein, H. Chem. Ber. 1910,
43, 1528–1532.
2526
Org. Lett., Vol. 12, No. 11, 2010

In light of this 5 f 38/39 result, we also investigated the
alkoxide-mediated chemistry of oxazolino[3,2-b]indazoles 2b
and 2d (see Scheme 6). Indazole 2b, like 2c, very cleanly
gives oxazolino opening and produces indazolone ether 40
in excellent yield. In contrast, indazole 2d gives no addition
product, producing only enamides 38 and 39 in a 9:1
thermodynamic ratio, respectively, in 99% combined yield.
In summary, we have demonstrated that nucleophilic ring-
opening of oxazolo- and oxazino[3,2-b]indazoles can lead
to novel 2-substituted 1H-indazolones that via other methods
are difficult to access. A simple route to a variety of
2-substituted 1H-indazolones is reported. In addition, an
unexpected example of the ANRORC reaction was realized.
Further investigation as to the scope and application of this
ANRORC reaction will be the focus of future reports.
Scheme 6. Alkoxide-Mediated Chemistry of Indazoles 2b and
2d
Acknowledgment. We thank the National Science Foun-
dation (CHE-0910870) and the National Institutes of Health
(GM089153) for generous financial support.
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.
5 as a base presumably to give sodium 2-allyl-2H-indazol-
3-olate. Under these basic conditions, a subsequent isomer-
ization from allyl to vinyl amide13 delivers an (E)-38/(Z)-
39 mixture in 57% combined yield (3:2 nonthermodynamic
ratio, respectively).
OL100751N
(13) Krompiec, S.; Pigulla, M.; Krompiec, M.; Baj, S.; Mrowiec-Bialon,
J.; Kasperczyk, J. Tetrahedron Lett. 2004, 45, 5257–5261.
Org. Lett., Vol. 12, No. 11, 2010
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