6478
B. Avila et al. / Tetrahedron Letters 53 (2012) 6475–6478
flask equipped with a stir bar was added acetic acid (26
l
L). The reaction
theoretically (DFT calculations) and several unique 2-amino-2H-
indazoles were synthesized. All evidence supports the reaction
proceeding through an o-nitrosobenzylidine imine intermediate,
which can undergo a concerted N,N-bond forming heterocycliza-
tion reaction. Indeed, the mechanistic insights reported here may
provide the basis for developing other substrates for the Davis–Bei-
rut reaction.
mixture was allowed to stir until TLC indicated the disappearance of o-
nitrosobenzaldehyde. The reaction was complete after 1 min., after which
saturated bicarbonate was added and extracted with ethyl acetate (3 Â 10 mL).
The combined organic extracts were washed with brine, dried over sodium
sulfate, filtered, and concentrated. The crude material was purified by flash
chromatography yielding 2, a white solid (85 mg, 85% yield). Spectral data is in
accord with literature values.3d,e (b) Method B. Synthesis of 5H-
benzo[4,5][1,3]oxazino[3,2-b]indazole (3). o-Nitrobenzyl alcohol (0.74 mmol)
was dissolved in MeOH (100 mL) in a glass beaker and was placed under a
500 W halogen lamp for 14 h. After photolysis, the solution was placed in
round-bottom flask equipped with a stir bar, after which, 14 (0.74 mmol) and
Acknowledgments
acetic acid (24 lL) was added to the solution. The reaction mixture was
allowed to stir until TLC indicated the disappearance of o-nitrosobenzaldehyde.
The resulting mixture was then diluted with saturated bicarbonate was added
and extracted with ethyl acetate (3 Â 5 mL). The combined organic extracts
were washed with brine, dried over sodium sulfate, filtered, and concentrated.
The crude material was purified by flash chromatography yielding 3, a white
solid (82 mg, 50% yield). Spectral data is in accord with literature values.3d,e (c)
Financial support was provided by the National Science Foun-
dation (CHE-0910870) and the National Institutes of Health
(GM089153). We also acknowledge the National Science Founda-
tion’s Partnership for Advanced Computational Infrastructure
(Pittsburgh Supercomputer Center). J.G.H. thanks the United States
Department of Education for a GAANN Fellowship and B.A. thanks
the Bristol–Myers Squibb Graduate Chemist Fellowship and Alfred
P. Sloan Minority Ph.D. Program for fellowship support.
Method C. Synthesis of 5H-Benzo[4,5][1,3]oxazino[3,2-b]indazole (3). To
solution of o-nitrobenzyl alcohol (0.74 mmol) and 14 in MeOH (100 mL) in a
glass beaker was added acetic acid (24 L) and was placed under a 500 W
a
l
halogen lamp for 14 h. The resulting mixture was then diluted with saturated
bicarbonate was added and extracted with ethyl acetate (3 Â 10 mL). The
combined organic extracts were washed with brine, dried over sodium sulfate,
filtered, and concentrated. The crude material was purified by flash
chromatography yielding 3, a white solid (16 mg, 10% yield). Spectral data is
in accord with literature values.3d,e
Supplementary data
Supplementary data (additional computational details) associ-
ated with this article can be found, in the online version, at
7. All calculations were performed using GAUSSIAN09. Structures were fully
optimized at the M06-2X/6-31+G(d,p) level with an implicit solvent
continuum model (CPCM) in methanol. Full references and coordinates can
be found in the Supplementary data.
8. As the reaction proceeds, there are several equivalents of water lost. To
compensate for this in the calculations, the energy of isolated water molecules
were calculated and their energy added to those of the various intermediates as
indicated; this allows all structures to be compared on the same energy scale.
9. See Supplementary data for intrinsic reaction coordinate and brief discussion.
Leading references on concerted but highly asynchronous reactions: (a)
Tantillo, D. J. J. Phys. Org. Chem. 2008, 21, 561–570; (b) Williams, A. Concerted
Organic and Bio-Organic Mechanisms; CRC Press: USA, 2000; (c) Dewar, M. J. S. J.
Am. Chem. Soc. 1984, 106, 209–219.
References and notes
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10. See Supplementary data for further discussion.
11. (a) Preparation of 18a–c. Equimolar amounts of o-nitrobenzaldehyde
derivatives 16a [or b or c] and 2-amino-6-methoxybenzothiazole (17) were
mixed thoroughly and heated at 110 °C. The Schiff base, initially a viscous red
liquid, solidified upon cooling and was dissolved in the minimal volume of
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nitobenzylamine derivatives 18a [b or c] precipitated as yellow a solid, which
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1. From 18a/b. Equimolar amounts of o-nitrobenzylamine derivative 18a [or b]
and 2-amino-6-mehoxybenzothiazole (17) were dissolved in dry THF in a
round bottom flask wrapped with aluminum foil. Five drops of DBU were
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were dissolved in dry THF in a round bottom flask wrapped with aluminum
foil. Five drops of DBU were added to the reaction mixture, which was then
stirred for 3 h at room temperature (reaction monitored by TLC). When all of
the o-nitrosobenzaldehyde had been consumed, THF was evaporated at room
temperature. The resulting dark brown mixture was purified by column
chromatography using 9:1 DCM:n-hexane as eluent. The green fluorescing
fraction was collected by evaporation of the solvent using a rotary evaporator
set at 35 °C. The yellow solid was collected and placed in a vacuum oven over
night. The structures of 19a/b prepared by Methods 1 and 2 were verified by IR,
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6. (a) Method A. o-Nitrobenzyl alcohol (2.61 mmol) was dissolved in MeOH
(400 mL) and was placed under a 500 W halogen lamp for 14 h. The solution
was concentrated by rotary evaporation at a temperature below 30 °C, and
purified by flash chromatography (100% DCM) to afford o-nitrosobenzaldehyde
13 as a white solid (168 mg, 48% yield). Spectral data is in accord with
literature values.9 5H-benzo[4,5][1,3]oxazino[3,2-b]indazole (2). To a solution
of 13 (0.44 mmol) and 14 (0.44 mmol) in MeOH (4.4 mL) in a round-bottom