Facile Syntheses of Novel Benzo-1,3-dioxolo-, Benzothiazolo-, Pyrido-, and Quinolino-fused 5 H -Benzo[ d ]-pyrazolo[5,1-b ][1,3]-oxazines and 1 H -Pyrazoles

Article abstract of DOI:10.1021/ol103108z

A number of novel benzo-1,3-dioxolo-, benzothiazolo-, pyrido-, and quinolino-fused 5H-benzo[d]pyrazolo[5,1-b][1,3]-oxazines and 1H-pyrazoles were synthesized utilizing an easy and effective N,N-bond forming heterocyclization reaction. In so doing, the substrate scope of this heterocyclization reaction, which starts with o-nitroheterocyclic aldehydes, was expanded to provide several unique heterocyclic compounds for biological screening. This work further demonstrates the versatility of this simple, base-mediated, one-pot heterocyclization method in the construction of novel heterocycles.(Figure Presented)

Full text of DOI:10.1021/ol103108z

ORGANIC
LETTERS
2011
Vol. 13, No. 5
1060–1063
Facile Syntheses of Novel Benzo-
1,3-dioxolo-, Benzothiazolo-, Pyrido-,
and Quinolino-fused 5H-Benzo[d]-
pyrazolo[5,1-b][1,3]-oxazines and
1H-Pyrazoles
Belem Avila,† Danielle M. Solano,†,‡ 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
mjkurth@ucdavis.edu
Received December 22, 2010
ABSTRACT
A number of novel benzo-1,3-dioxolo-, benzothiazolo-, pyrido-, and quinolino-fused 5H-benzo[d]pyrazolo[5,1-b][1,3]-oxazines and 1H-pyrazoles
were synthesized utilizing an easy and effective N,N-bond forming heterocyclization reaction. In so doing, the substrate scope of this
heterocyclization reaction, which starts with o-nitroheterocyclic aldehydes, was expanded to provide several unique heterocyclic compounds for
biological screening. This work further demonstrates the versatility of this simple, base-mediated, one-pot heterocyclization method in the
construction of novel heterocycles.
Indazoles (e.g., benzo-fused pyrazoles) have been shown
to display a wide array of biological activities, including
antiangiogenic,1 antiviral,2 and anti-inflammatory
applications.3 These biological activities have prompted
synthetic chemists to develop new methodologies to
synthesize and functionalize the indazole ring system.3 In
that regard, the literature contains examples of heterocy-
clization routes to indazole derivatives;4,5 however, of the
two indazole isomers, 2H-indazoles are considerably less
studied.6 Of special interest, pyrazolopyridines have been
shown to have improved log P and water solubilities
† University of California.
‡ Present address: Department of Chemistry, California State University,
9001 Stockdale Hwy, Bakersfield, California 93311.
§ American University of Beirut.
(1) Huang, L.-J.; Shih, M.-L.; Chen, H.-S.; Pan, S.-L.; Teng, C.-M.;
Lee, F.-Y.; Kuo, S.-C. Bioorg. Med. Chem. 2006, 14, 528.
(2) Kim, D.; Wang, L.; Caldwell, C. G.; Chen, P.; Finke, P. E.; Oates,
B.; MacCoss, M.; Mills, S. G.; Malkowitz, L.; Gould, S. L.; DeMartino,
J. A.; Springer, M. S.; Hazuda, D.; Miller, M.; Kessler, J.; Danzeisen, R.;
Carver, G.; Carella, A.; Holmes, K.; Lineberger, J.; Schleif, W. A.;
Emini, E. A. Bioorg. Med. Chem. Lett. 2001, 11, 3103.
(3) Schmidt, A.; Beutler, A.; Snovydovych, B. Eur. J. Org. Chem.
2008, 4073.
(4) Heller, S. T.; Natarajan, S. R. Org. Lett. 2007, 9, 4947.
(5) (a) Hurst, J. J. Chem. Soc. (C) 1968, 1487. (b) Foster, H.; Hurst, J.
J. Chem. Soc., Perkin Trans. I 1973, 319. (c) Chapman, D.; Hurst, J.
J. Chem. Soc., Perkin Trans. I 1980, 2398.
(6) (a) 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: Stutggart, 2002; Vol. 12, p 227. (b) Wu,
C.; Fang, Y.; Larock, R. C.; Shi, F. Org. Lett. 2010, 12, 2234.
r
10.1021/ol103108z
Published on Web 02/04/2011
2011 American Chemical Society

tion reaction by treatment with KOH and water in
alcoholic solvent.12 It was also found that 5H-indazolo-
[3,2-b]benzo[d][1,3]-oxazines can be obtained in a one-pot
reaction starting with o-nitrobenzaldehyde.12e We envi-
saged that these methods (Scheme 1a/b) could be extended
to the synthesis of a variety of novel heterocyclic analogs
by, for example, introduction of a nitrogen atom in the
benzo ring of 2H-indazoles or in any of the rings fused to
this benzo ring (Scheme 1c). Indeed, a host of unique
heterocycles can be envisioned in which the pyrazole ring
is the common denominator and we report here that a
number of benzo-1,3-dioxolo-, benzothiazolo-, pyrido-,
quinolino-fused 5H-benzo[d]-pyrazolo[5,1-b]-[1,3]-oxa-
zines and 1H-pyrazoles are accessible in moderate to high
yields (35-88%) via this N,N-bond forming heterocycliza-
tion reaction.
Figure 1. Pyrazolopyridine and 4-(pyrazol-4-yl)pyrimidines
inhibitors.
compared to indoles and indazoles exhibiting protein
kinase B/Akt inhibitory activities7,4 and, more recently,
4-(pyrazol-4-yl)pyrimidines have been shown to selectively
inhibit CDK4/6 (Figure 1).8
The benzo-1,3-oxazine ring system has also been shown
to exhibit antihypertensive affects,9 potency as antirheu-
matic agents,10 and antianginal acitivity.11 In contrast,
heterocycle-fused 5H-benzo[d]pyrazolo[5,1-b][1,3]-ox-
azines, to the best of our knowledge, are unknown. This,
together with the biological potential and intriguing struc-
tures of these compounds, prompted us to study the
synthesis of this novel class of heterocycles.
Scheme 2. Synthesis of o-Nitroarylmethylaminesa
a Method A: R1NH2 þ acetic acid in MeOH; then NaBH3CN/
MeOH. Method B: R1NH2 (excess) in refluxing MeOH.
Scheme 1. Synthetic Routes to Benzo-Fused [(a) and (b)] and
Heterocycle-Fused (c) Pyrazoles
Scheme 2 demonstrates that o-nitroheterocyclic amine 3
can be accessed from either o-nitroheterocyclic aldehydes
(1; Method A) or o-nitroheterocyclic halides (2; Method
B). In Method A, the targeted o-nitroarylmethylamine 3 is
obtained in nearly quantitative yield by utilizing an excess
of amine. Moreover, the resulting o-nitroarylmethylamine
generally does not require purification and crude 3 can be
used directly in the subsequent heterocyclization with no
significiant loss in yield or complication in product isola-
tion/purification. In Method B, the starting o-nitroheter-
ocyclic halide 2 is prepared in low yield (benzylic
bromination; 30-40%) making this a generally less effec-
tive route to o-nitroarylmethylamine 3.
All o-nitroheterocyclic aldehydes (4a-e, Scheme 3) ex-
cept for 4e, which was commercially available, were
synthesized according to literature procedures.13 Our tar-
geting of heterocycle-fused pyrazoles started with treat-
ment of the specific o-nitroheterocyclic aldehyde 4 with
2-aminobenzyl alcohol or p-bromoaniline followed by
reduction of the resulting anil with NaBH3CN to obtain
the o-nitroheterocyclic amine 3 (Scheme 3).
We have previously demonstrated that 3-alkoxy-2H-
indazoles (Scheme 1a) and 5H-indazolo[3,2-b]benzo[d]-
1,3-oxazines (Scheme 1b) can be obtained from o-nitroar-
ylmethylamines via an N,N-bond forming heterocycliza-
(7) Zhu, G.-D.; Gandhi, V. B.; Gong, J.; Thomas, S.; Woods, K. W.;
Song, X.; Li, T.; Diebold, R. B.; Luo, Y.; Liu, X.; Guan, R.; Klinghofer,
V.; Johnson, E. F.; Bouska, J.; Olson, A.; Marsh, K. C.; Stoll, V. S.;
Mamo, M.; Polakowski, J.; Campbell, T. J.; Martin, R. L.; Gintant,
G. A.; Penning, T. D.; Li, Q.; Rosenberg, S. H.; Giranda, V. L. J. Med.
Chem. 2007, 50, 2990.
(8) Cho, Y. S.; Borland, M.; Brain, C.; Chen, C. H.-T.; Cheng, H.;
Chopra, R.; Chung, K.; Groarke, J.; He, G.; Hou, Y.; Kim, S.; Kovats,
S.; Lu, Y.; O’Reilly, M.; Shen, J.; Smith, T.; Trakshel, G.; Vogtle, M.;
Xu, M.; Sung, M. J. J. Med. Chem. 2010, 53, 7938.
(9) Clark, R. D.; Caroon, J. M.; Kluge, A. F.; Repke, D. B.;
Roszkowski, A. P.; Strosberg, A. M.; Baker, S.; Bitter, S. M.; Okada,
M. D. J. Med. Chem. 1983, 26, 657.
(10) Matsuoka, H.; Ohi, N.; Mihara, M.; Suzuki, H.; Miyamoto, K.;
Maruyama, N.; Tsuji, K.; Kato, N.; Akimoto, T.; Takeda, Y.; Yano, K.;
Kuroki, T. J. Med. Chem. 1997, 40, 105.
(12) (a) Kurth, M. J.; Olmstead, M. M.; Haddadin, M. J. J. Org.
Chem. 2005, 70, 1060. (b) Mills, A. D.; Nazer, M. Z.; Haddadin, M. J.;
Kurth, M. J. J. Org. Chem. 2006, 71, 2687. (c) Mills, A. D.; Maloney, P.;
Hassanein, E.; Haddadin, M. J.; Kurth, M. J. J. Comb. Chem. 2007, 9,
171. (d) Butler, J. D.; Solano, D. M.; Robins, L. I.; Haddadin, M. J.;
Kurth, M. J. J. Org. Chem. 2008, 73, 234. (e) Solano, D. M.; Butler, J. D.;
Haddadin, M. J.; Kurth, M. J. Org. Synth. 2010, 87, 339.
(13) (a) Niu, C.; Li, J.; Doyle, T. W.; Chen, S.-H. Tetrahedron 1998,
54, 6311. (b) Vetelino, M. G.; Coe, J. W. Tetrahedron Lett. 1994, 35, 219.
(c) Yan, M.-C.; Tu, Z.; Lin, C.; Ko, S.; Hsu, J.; Yao, C.-F. J. Org. Chem.
2004, 69, 1565. (d) Godard, A.; Queguiner, G. J. Heterocycl. Chem.
1980, 17, 465. (e) Couch, G. D.; Knox, R. J.; Moody, C. J. Tetrahedron
2008, 64, 2816.
(11) Benedini, F.; Bertolini, G.; Cereda, R.; Dona, G.; Gromo, G.;
Levi, S.; Mizrahi, J.; Sala, A. J. Med. Chem. 1995, 38, 130.
Org. Lett., Vol. 13, No. 5, 2011
1061

to 60 °C was required. This relative ease of formation of
heterocycles 5a-c and 6a-c is likely due to the increased
acidity of the benzylic hydrogen 4a-c. In the synthesis of
5a-c, iPrOH was used as solvent in the N,N-bond forming
heterocylization reactions; when MeOH was used, LC/MS
of the crude reaction mixture indicated some indazolone
formation.14 However, when targeting heterocycle-fused
pyrazoles 6a-c, MeOH was used as reactant and solvent
and no indazolone was observed.
Scheme 3. Route to Heterocycle-Fused Pyrazoles
Table 2. Synthesis of Quinolino- and Benzo-1,3-dioxolo-fused
5H-Benzo[d]pyrazolo[5,1-b][1,3]-oxazines and 1H-Pyrazolesa,b
As previously mentioned, these amine intermediates
were not isolated, but were further treated with aqueous
KOH in iPrOH (for 5a-e) or in MeOH (for 6a-e) to effect
the heterocyclization leading to a series of heterocycle-
fused pyrazole derivatives. The overall yields ranged from
80 to 85% for 5a-e and 44-67% for 6a-e (Scheme 3).
Interestingly, the heterocyclization reactions which give
pyrido- and quinolino-fused 1H-pyrazoles (Table 1) were
effected at room temperature - a deviation from the
previously reported methods (Scheme 1a/b) where heating
a Products were characterized by 1H, 13C NMR, IR, and ESI MS.
b Isolated yields after purification by chromatography on silica gel.
c See 4d-e in Scheme 3.
Table 1. Synthesis of Pyrido- and Quinolino-Fused 5H-Benzo-
[d]pyrazolo[5,1-b][1,3]-oxazines and 1H-Pyrazolesa,b
Next, a study of quinolino- and benzo-1,3-dioxolo-fused
analogs of 5 and 6 were explored (Table 2). Compounds
5d,e and 6d,e were synthesized by the same methods
employed for 5a-c/6a-c (Scheme 3). It is interesting to note
thatreactionsof4ef 5eand4ef 6eproceedwell(yieldsof
44% and 88%, respectively) despite the fact that starting
material 4e is relatively electron rich.
Benzothiazolo-fused pyrazoles 11 and 12 (Scheme 4) are
additional examples of benzo-fused heterocyclic pyrazoles
attainable by this method. To synthesize these compounds,
the key synthetic intermediate, 6-bromomethyl-7-nitro-
benzothiazole (10), was synthesized in three steps (25%
overall yield) from 6-methyl-2-benzothiazolamine (7).15,16
Step one involved deamination of 7 with phosphoric acid
and sodium nitrite followed by reduction with hypopho-
sphorous acid to give 6-methylbenzothiazole (8). Subsequent
regioselective nitration delivered 6-methyl-7-nitroben-
zothiazole (9) in improved yield (95%) when purified by
flash chromatography instead of recrystallization. Nitro-
benzothiazole 9 was then reacted with stoichiometric NBS
(14) Oakdale, J. S.; Solano, D. M.; Fettinger, J. C.; Haddadin, M. J.;
Kurth, M. J. Org. Lett. 2009, 11, 2760.
(15) Matveev, M.; Ponyaev, A. I.; El’tsov, A. V. Russ. J. Gen. Chem.
a Products were characterized by 1H, 13C NMR, IR, and ESI MS.
b Isolated yields after purification by chromatography on slica gel.
c See 4a-c in Scheme 3.
2001, 71, 1286.
(16) Katritzky, A. R.; Rogovoy, B. V.; Chassaing, C.; Vvedensky, V.;
Forood, B.; Flatt, B.; Nakai, H. J. Heterocycl. Chem. 2000, 37, 1655.
1062
Org. Lett., Vol. 13, No. 5, 2011

Scheme 4. Synthesis of Benzothiazolo-Fused 5H-Benzo-[d]pyrazolo-
[5,1-b][1,3]-oxazines and 1H-Pyrazolesa,b
Scheme 5. Attempted Synthesis of a Thieno-Fused 1H-Pyrazole
a Products were characterized by 1H, 13C NMR, IR, and
ESI MS. b Isolated yields after purification by chromatogra-
phy on silica gel.
the targeted heterocycle 15. This difficulty in formation of
thieno-fused 1H-pyrazole 15 appears to derive from the
weak acidity of the sp3 hybridized proton of 160, which thus
impedes 1,4-elimination of water. However, this tentative
explanation remains to be supported by further investigation.
In summary, several unique pyrazole-based heterocycles
were synthesized by a one-pot, N,N-bond forming hetero-
cyclization of o-nitroarylmethylamines. These novel het-
erocycles have been submitted to the NIH Molecular
Libraries Small Molecule Repository (MLSMR) for
high-throughput biological screening. In view of the utility
of this N,N-bond forming heterocyclization, which has
been demonstrated in the synthesis of a wide variety of
often complex heterocycles in this work as well as in six
earlier pulications,12,14 we propose to call this method the
“Davis-Beirut” reaction in recognition of the merits of
international collaboration.
in carbon tetrachloride (AIBN catalyst), under reflux for
12 h, to give 7-bromo-methyl-6-nitrobenzothiazole (10) in
40% yield. Benzyl bromide 10 was then N-alkylated with
excess 2-aminobenzyl alcohol, or p-bromoaniline, to gen-
erate the corresponding o-nitroarylmethylamines in
MeOH which, without isolation, was treated with aqueous
i
KOH in PrOH (f 11) or in MeOH (f 12) to deliver
benzothiazolo-fused pyrazoles 11 and 12 in 43 and 35%
yields, respectively.
Finally, with these successes in preparing the unique
heterocycles delineated above through this easy and effec-
tiveN,N-bondforming heterocyclizationmethodology, we
attempted to synthesize thiophene-fused pyrazole 15
(Scheme 5). N-((2-Nitrothiophen-3-yl)methyl)aniline 14
was obtained from 2-nitrothiophene-3-carbaldehyde17
(13) and 2-fluoroaniline by reductive amination. Subject-
ing 14 to heterocyclization conditions at 0 °C (significant
decomposition ensued at room temperature), failed to
deliver the anticipated thieno-fused pyrazole 15. Rather,
the major product of this reaction proved to be 2-fluoro-
N-((2-nitrothiophen-3-yl)methylene)aniline (17).18 We
speculate that nitroso imine 16 is the initial product of this
reaction,12a,b but subsequent nitroso f nitro air oxidation19
out-competes N,N-bond formation to deliver 17 rather than
Acknowledgment. Financial support was provided by
the National Science Foundation (CHE-0910870, CHE-
0449845) and the National Institutes of Health (GM089153).
B.A. thanks the Bristol-Myers Squibb Graduate Minority
Chemist Fellowship and Alfred P. Sloan Minority Ph.D.
Program for fellowship support.
Supporting Information Available. Full experimental
details and characterization data (IR, 1H NMR, 13C NMR,
and ESI MS) of all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(17) Makosza, M.; Owczarczyk, Z. Tetrahedron Lett. 1987, 28, 3021.
(18) The structure of 17 has been independently varified through its
direct preparation by condensation of 13 with o-fluoroaniline; see
Supporting Information.
(19) We have observed nitroso f nitro air oxidation in a related
system (o-nitrosoaniline f o-nitroaniline); unpublished results.
Org. Lett., Vol. 13, No. 5, 2011
1063