N,N-bond-forming heterocyclization: Synthesis of 3-alkoxy-2H-indazoles

Article abstract of DOI:10.1021/jo0524831

A one-step heterocyclization of o-nitrobenzylamines to 3-alkoxy-2H- indazoles is reported. The electronic nature of the nitrophenyl group, the steric and electronic nature of the R¹-functionalized benzylic amine, and the nature of the alcoholic solvent affect the efficiency of this heterocyclization reaction (～40-90%).

Full text of DOI:10.1021/jo0524831

N,N-Bond-Forming Heterocyclization: Synthesis of
3-Alkoxy-2H-indazoles
Aaron D. Mills,† Musa Z. Nazer,‡ Makhluf J. Haddadin,§ and Mark J. Kurth*,†
Department of Chemistry, UniVersity of California, One Shields AVenue, DaVis, California 95616,
Chemistry Department, Faculty of Science, UniVersity of Jordan, Amman, Jordan, and Department of
Chemistry, American UniVersity of Beirut, Beirut, Lebanon
mjkurth@ucdaVis.edu
ReceiVed December 1, 2005
A one-step heterocyclization of o-nitrobenzylamines to 3-alkoxy-2H-indazoles is reported. The electronic
nature of the nitrophenyl group, the steric and electronic nature of the R1-functionalized benzylic amine,
and the nature of the alcoholic solvent affect the efficiency of this heterocyclization reaction (∼40-
90%).
SCHEME 1. Routes to 2H-Indazoles
Introduction
Seven of the top 10 selling drugs are nitrogen-containing
heterocycles,1 and these structural motifs are also found in many
natural products.2 Motivated by these synthetic challenges,
chemists have developed an array of methods for the construc-
tion of these important heterocycles.3 The indazole ring, the
subject of our work, is an intriguing heterocycle with biological,
agricultural, and industrial applications.4 Within the indazole
arena, the chemistry of 2H-indazoles has not been as well-
explored as the chemistry of 1H-indazoles.5 As outlined in
Scheme 1, routes to 2H-indazoles include palladium-catalyzed
cyclization6 of substituted hydrazines and aryl bromides (Scheme
1A), metal reductions of o-nitrobenzylamines mediated by Sn,
Zn, or Fe (generally giving low yields of the 2H-indazole as
side products),7 and N-alkylation or N-arylation of preformed
1H-indazoles at N2 (typically with limited regioselectivity) using
CuI (Scheme 1B).8 In addition, in a recent reinvestigation of a
purported route to 2,1-benzisoxazoles,9 we discovered a new
route to 3-alkoxy-2H-indazoles from o-nitrobenzylamines (Scheme
1C).
This new method, while not fully explored in our original
report, offered the advantage of requiring no expensive or toxic
metals to mediate heterocycle formation and proceeded under
mild base treatment at a relatively low temperature in an
alcoholic solvent.10 In addition to our route (Scheme 1C), we
* Corresponding author. Phone: (530)752-8192.
† University of California.
‡ University of Jordan.
§ American University of Beirut.
(1) Butler, M. S. J. Nat. Prod. 2004, 67, 2141.
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Cartrin, A. M.; Quentin, J. Aust. J. Chem. 1995, 48, 2023.
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10.1021/jo0524831 CCC: $33.50 © 2006 American Chemical Society
Published on Web 03/02/2006
J. Org. Chem. 2006, 71, 2687-2689
2687

Mills et al.
TABLE 1. N,N-Bond-Forming Heterocyclizationa,b
a Products were characterized by 1H and 13C NMR and IR. b Isolated yields after purification by chromatography on silica gel. c See 3-13 in Scheme 2.
SCHEME 2. Synthesis of o-Nitrobenzylaminesa
are aware of only one other strategy for the synthesis of
3-alkoxy-substituted 2H-indazoles. This approach involves N,N-
bond-forming heterocyclization from o-azidobenzamides by
treatment with thionyl chloride to give 3-chloro-2H-indazole.
Upon subsequent alkoxide treatment, the 3-chloro-2H-indazole
delivers the 3-alkoxyalkyl-2H-indazole.11 However, the use of
halogenating agents restricts the types of functional groups that
can be incorporated. There are three other methods in addition
to ours for the N,N-bond-forming heterocyclization to 2H-
indazoles.11,12
Since the scope of our o-nitrobenzylamine f 2H-indazole
cyclization reaction as well as the electronic requirements of
a Method A: R1NH2 (excess; used to prepare all amines except 5 and
the reactants were not explored in our first report, we set out to
study this heterocyclization reaction in greater detail. Herein,
we report the details of a study which culminates in the
preparation of a small collection of unique 3-alkoxy-2H-
indazoles (see Table 1).
6). Method B: R1NH2, neat, 150 °C, then NaBH4/MeOH.
quantitative yields. However, arylamine derivatives were not
reactive enough for Method A and, consequently, substrates 5
and 6 were prepared by way of the corresponding imine of 2
via Method B. This protocol worked well for both electron-
rich (e.g., 4-methoxyanaline) and electron-poor (e.g., 6-chloro-
2-aminopyridine) systems (98 and 73% yield, respectively).14
Results and Discussion
As outlined in Scheme 2, the starting o-nitrobenzylamines
were readily prepared from either benzyl halide 1 (Method A)
or benzyladehyde 2 (Method B). Method A was used to
synthesize amines 3, 4, and 7-13. By employing an excess of
the amine,13 the targeted benzylamines were obtained in nearly
(12) (a) Frontana-Uribe, B. A.; Moinet, C. Acta Chem. Scand. 1999, 53,
814. (b) Frontana-Uribe, B. A.; Moinet, C. Tetrahedron 1998, 54, 3197.
(c) Johnston, D.; Smith, D. M.; Shepherd, T.; Thompson, D. J. Chem. Soc.,
Perkin Trans. 1 1987, 3, 495. (d) Boyer, J. H.; Pagoria, P. F.; Pillai, T. P.;
Pace, M. D.; Stec, D. J. Chem. Res., Synop. 1986, 11, 416.
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42, 8405.
(11) (a) Ardakani, M. A.; Smalley, R. K.; Smith, R. H. J. Chem. Soc.,
Perkin Trans. 1 1983, 10, 2501. (b) Manouchehr, A. A.; Smalley, R. K.;
Smith, R. H. Synthesis 1979, 4, 308.
(14) Johnston, D.; Smith, D. M.; Shepherd, T.; Thompson, D. J. Chem.
Soc., Perkin Trans. 1 1987, 3, 495.
2688 J. Org. Chem., Vol. 71, No. 7, 2006

N,N-Bond-Forming Heterocyclization
SCHEME 3. Aryl Amine Derivatives
in the starting o-nitrobenzylamine. In contrast, when X is an
electron-withdrawing group, such as a carboxylate, the indazole
yield increased (13 f 28; 96%).
The alcohols found to be acceptable in this reaction (Scheme
1C) were methanol, ethanol, ethylene glycol, and ethylene glycol
monomethyl ether. Reactions run in propargyl alcohol, etha-
nolamine, furfuryl alcohol, and allyl alcohol did not produce
indazole products (o-nitrobenzylamine decomposition was
observed). Results with n-propanol were marginal (cf., 10 f
25; 11%). Collectively, these results suggest that subtle changes
in solvent properties (chemical reactivity, dielectric constant,
dipole moment, eluotropic value, miscibility, polarity index,
viscosity, etc.) rather strikingly mediated the effectiveness of
this heterocyclization reaction.
In summary, the one-step heterocyclization of o-nitrobenzyl-
amines to 3-alkoxy-2H-indazoles is reported in generally fair
yields (∼40-90%).
Experimental Section
General Procedures for the Synthesis of 2H-Indazoles. A
solution of nitrobenzyl bromide (1.2 mmol) in tetrahydrofuran (2
mL) was added dropwise to a solution of the amine (12.0 mmol)
in tetrahydrofuran (2 mL). The reaction was allowed to stir for 4
h and then concentrated. The resulting crude reaction mixture was
diluted with EtOAc, washed consecutively with aq sodium bicar-
bonate and brine, dried over sodium sulfate, and concentrated. 1H
NMR spectra indicated that most amines were pure enough to be
used directly in the cyclization reaction (the remainder were purified
by flash chromatography). Benzyl(2-nitrobenzyl)amine, 4-meth-
oxybenzyl(2-nitrobenzyl)amine, and 4-methoxyphenyl(2-nitroben-
zyl)amine were synthesized by the respective literature meth-
ods.10,15,16
Next, these 2-nitrobenzylamines were added to solutions of 5%
KOH in the appropriate alcoholic solvent (5 mL). Each reaction
was allowed to stir for 6 h at 60 °C and then concentrated. The
crude reaction mixture was taken up with EtOAc (100 mL), washed
consecutively with water (100 mL), sodium bicarbonate (100 mL),
and brine (100 mL) and then dried over sodium sulfate, concen-
trated, and purified by flash chromatography to afford the 2H-
indazole.
2-Benzyl-3-methoxy-2H-indazole (14). Benzyl(2-nitrobenzyl)-
amine (3) was prepared according to literature methods.9 Crude
amine 3 (0.300 g, 1.239 mmol) gave 14 (Rf ) 0.37 (2:5, hexane/
ethyl acetate) as a light yellow oil (61%): 1H NMR (400 MHz,
CDCl3) δ 7.67 (dd, J ) 8.7 Hz, 1.2, 1H), 7.57 (dd, J ) 8.1 Hz, 0.9
Hz, 1H), 7.32-7.18 (m, 6H), 6.92 (dt, J ) 6.6 Hz, 0.9 Hz, 1H),
5.44 (s, 2H), 4.21 (s, 3H); 13C NMR δ 147.3, 146.6, 136.3, 128.6,
127.7, 127.5, 126.1, 119.6, 119.4, 117.7, 106.8, 60.4, 52.0; IR (neat)
1624, 1526, 1510, 1406, 1385, 1113, 737, 701 cm-1; HPLC purity
) 97%; HREIMS calcd for C15H14N2O (M+), 238.1106; found,
238.1104.
With a variety of o-nitrobenzylamines in hand (3-13), we
turned to study the N,N-bond-forming heterocyclization reaction.
Our results are outlined in the table with variables including:
(1) the electronic nature of the nitrophenyl group, (2) the steric
and electronic nature of the benzylic amine R1 group, and (3)
the nature of the alcoholic solvent.
As illustrated with 2H-indazoles 14, 22, 25, 27, and 28, the
reaction is quite tolerant of electronic variation in the nitrophenyl
group. Benzoic acid derivative 13 was particularly effective in
this transformation, either as a consequence of the electron-
withdrawing nature of the carboxyl group or as a result of the
improved solubility of the intermediates in the formation of 28.
This heterocyclization reaction tolerates a variety of R1 groups
in 3-13 with the exception that arylamine derivatives give
variable results. Specifically, as depicted in Scheme 3, the N-4-
methoxyphenyl-2-nitrobenzylamine analogue 5 cyclized to
indazole 18 in poor yield (23%), while N-(6-chloropyridin-2-
yl)2-nitrobenzylamine 6 failed to undergo heterocyclization to
indazole 19. We believe the electron-withdrawing chloropyridyl
moiety favors hemiaminal retrocondensation to the nitroso
aldehyde rather than dehydration to the imine. Presumably, this
dehydration does occur in the reaction of 5 (albeit to a lesser
extent than with nonarylamines 3-4 and 7-13), and the
resulting nitroso imine undergoes heterocyclization to 2H-
indazole 18. Indeed, 6-chloropyridin-2-ylamine was isolated in
60% yield, together with 2-nitrosobenzaldehyde, when 6 was
treated with ethanolic KOH.
Acknowledgment. We thank the National Science Founda-
tion (CHE-0313888) for support of this work. The 400- and
300-MHz NMR spectrometers used in this study were funded
in part by a grant from NSF (CHE-9808183).
When X and Y in the o-nitrobenzylamine are electron-
donating groups (e.g., methoxy in 10 and 11), the yield of
indazole decreased. We believe this drop in reaction productivity
is a consequence of decreased acidity at the benzylic position
Supporting Information Available: Experimental details,
characterization data, and 1H and 13C NMR spectra of compounds
14-18, 20, 22-23, and 25-28 are available free of charge via the
Internet at http://pubs.acs.org.
(15) Kienzle, F.; Kaiser, A.; Chodnekar, M. S. Eur. J. Med. Chem. 1982,
17, 547.
(16) Frontana-Uribe, B. A.; Moinet, C. Tetrahedron 1998, 54, 3197.
JO0524831
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