A facile synthesis of new 5H-indazolo[3,2-b]benzo[d]-1,3-oxazines via one-pot intramolecular bis-heterocyclizations

Article abstract of DOI:10.1021/jo702067z

(Chemical Equation Presented) The parent 5H-indazolo[3,2-b]benzo[d]-1,3- oxazine heterocycle as well as a series of novel analogues have been synthesized utilizing two subsequent intramolecular heterocyclizations in one pot. A variety of diversity groups were added to explore the scope of this reaction and to provide a number of new compounds for biological screening.

Full text of DOI:10.1021/jo702067z

A Facile Synthesis of New 5H-Indazolo[3,2-b]benzo[d]-1,3-oxazines
via One-Pot Intramolecular Bis-heterocyclizations
Jeffrey D. Butler,†,§ Danielle M. Solano,†,§ Lori I. Robins,† 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 September 20, 2007
The parent 5H-indazolo[3,2-b]benzo[d]-1,3-oxazine heterocycle as well as a series of novel analogues
have been synthesized utilizing two subsequent intramolecular heterocyclizations in one pot. A variety
of diversity groups were added to explore the scope of this reaction and to provide a number of new
compounds for biological screening.
Introduction
The indazolobenzoxazine ring system 1 (Figure 1) is a rare
heterocycle comprised of benzo-1,3-oxazine (2) and 2H-indazole
(3) substructures. Indazoles,1 which encompass both 1H- and
2H-renditions, are known to display a wide range of biological
activities including anti-angiogenic activity,2 antiviral activity,3
and strong antihypertensive effects.4 Of special interest, an
indazole derivative has recently been reported to exhibit potential
as a male contraceptive.5 Benzo-1,3-oxazines are also known
to be biologically active, demonstrating antianginal activity,6
FIGURE 1. Heterocycles of interest: 5H-indazolo[3,2-b]benzo[d]-
1,3-oxazine (1), 2,4-dihydro-1H-benzo[d]-1,3-oxazine (2), and 3-alkoxy-
2H-indazole (3).
antihypertensive affects,7 and potency as antirheumatic agents.8
Thus, it is envisioned that indazolobenzoxazines, which contain
both the indazole and benzoxazine moieties, may afford unique
biological activities.
While 1H- and 2H-indazoles and 1H-benzo[d]-1,3-oxazines9
are well represented, 5H-indazolo[3,2-b]benzo-[d]-1,3-oxazines
are rare in the chemical literature. The related indazolobenzox-
azinones have been employed in the synthesis of indazoloin-
dazolediones,10 and derivatives of indazolobenzoxazines have
been used to dope electroluminescent devices.11 To the best of
our knowledge, the parent system (1) and substituted inda-
zolobenzoxazines are unknown, which provided the impetus to
synthesize these novel compounds.
* To whom correspondence should be addressed. Fax: (530)752-8995.
Phone: (530)752-8192.
† University of California.
§ Co-first authors.
‡ American University of Beirut.
(1) Stadlbauer, W. Sci. Synth. 2002, 12, 227-324.
(2) 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, 528-536.
(3) Kim, D.; Wang, L.; Caldwell, C. G.; Chen, P.; Finke, P. E.; Oates,
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A.; Springer, M. S.; Hazuda, D.; Miller, M.; Kessler, J.; Danzeisen, R.;
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E. A. Bioorg. Med. Chem. Lett. 2001, 11, 3103-3106.
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Ye, G.; Semus, S. F.; Evans, C.; Fries, H. E.; Jolivette, L. J.; Kirkpatrick,
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2007, 50, 6-9.
Previously, it has been demonstrated that 3-alkoxy-2H-
indazoles (3, Figure 1) can be obtained from o-nitrobenzy-
lamines via an N,N-bond-forming heterocyclization reaction
(5) (a) Cheng, C. Y.; Mruk, D.; Silvestrini, B.; Bonanomi, M.; Wong,
C.-H.; Siu, M. K. Y.; Lee, N. P. Y.; Lui, W.-Y.; Mo, M-Y. Contraception
2005, 72, 251-261. (b) Mruk, D. D.; Wong, C.-H.; Silvestrini, B.; Cheng,
C. Y. Nature Med. 2006, 12, 1323-1328.
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10.1021/jo702067z CCC: $40.75 © 2008 American Chemical Society
Published on Web 12/04/2007
234
J. Org. Chem. 2008, 73, 234-240

Synthesis of 5H-Indazolo[3,2-b]benzo[d]-1,3-oxazines
TABLE 1. Diversification of Indazolobenzoxazine Carboxamides
8-10
SCHEME 1. Route to Indazolobenzoxazine 1
SCHEME 2. Route to Indazolobenzoxazine Carboxamides
8-10
indazolo[3,2-b]benzo[d]-1,3-oxazine (1) system, which culmi-
nated in the preparation of a novel library focused on this
heterocycle.
mediated by potassium hydroxide in alcoholic solvent; methanol,
ethanol, and 1-propanol all work well.12 On this basis, it was
surmised that an intramolecular variant of this reaction would
provide an effective entry into indazolobenzoxazines and would
further demonstrate the generality of this intriguing heterocy-
clization. This work reports the synthesis of the parent 5H-
Results and Discussion
Indazolobenzoxazine 1, the parent heterocycle, was prepared
by first performing the reductive amination13 of 2-nitrobenzal-
dehyde with 2-aminobenzyl alcohol to yield 4 (Scheme 1). Bis-
heterocyclization of 4 to 1, presumably via a nitroso imine
intermediate, was achieved under basic conditions, using
aqueous KOH in 2-propanol or methanol. It is interesting to
note that intramolecular cyclization 4 f 1 is preferred over the
potentially competing intermolecular possibility (e.g., 4 f
3).12,14 The two-step overall yield of 1 was 61%, demonstrating
this as a viable approach to the synthesis of 5H-indazolo[3,2-
b]benzo[d]-1,3-oxazines.
A demonstration of the scope of this intramolecular bis-
heterocyclization reaction was undertaken as outlined in Scheme
2. The diversification potential of this study focused on the
indazolo ring of 1 by placing a manipulatable carboxylic acid
functional group at C9. Thus, 2-aminobenzyl alcohols 5a-c
(9) (a) Hoback, J. H.; Crum, J. D.; Carroll, D. W. W. V. UniV. Bull.,
Ser. 1955, 56, 40-43. (b) Wagner, G. Arch. Pharm. 1957, 290, 520-527.
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Heydenreich, M.; Koch, A.; Klod, S.; Szatmari, I.; Fueloep, F.; Kleinpeter,
E. Tetrahedron 2006, 62, 11081-11089. (f) Ando, Y.; Ando, K.; Yamagu-
chi, M.; Kunitomo, J.; Koida, M.; Fukuyama, R.; Nakamuta, H.; Yamashita,
M.; Ohta, S.; Ohishi, Y. Bioorg. Med. Chem. Lett. 2006, 16, 5849-5854.
(g) Li, J.-R.; Ma, S.-L.; Sun, Y.-J.; Wei, X.-J.; Zhou, Z.-M. J. Heterocycl.
Chem. 2006, 43, 745-748. (h) Basheer, A.; Rappoport, Z. J. Org. Chem.
2006, 71, 9743-9750. (i) Yadav, L. D. S.; Rai, V. K. Synlett 2007, 1227-
1230. (j) Kiskan, B.; Yagci, Y. J. Polym. Sci., Part A: Polym. Chem. 2007,
45, 1670-1676. (k) Spagnol, G.; Rajca, A.; Rajca, S. J. Org. Chem. 2007,
72, 1867-1869. (l) Anwar, H. F.; Skattebøl, L.; Hansen, T. V. Tetrahedron
2007, 63, 9997-10002.
(10) Alkhader, M. A.; Smalley, R. K.; Mohajerani, B. Synthesis 1980,
381-383.
(11) Sato, Y.; Murata, J. (Mitsubishi Chemical Industries Co., Ltd.,
Japan). Jpn. Kokai Tokkyo Koho 05311162, 1993.
(12) Mills, A. D.; Nazer, M. Z.; Haddadin, M. J.; Kurth, M. J. J. Org.
Chem. 2006, 71, 2687-2689.
(13) Koshio, H.; Hirayama, F.; Ishihara, T.; Shiraki, R.; Shigenaga, T.;
Taniuchi, Y.; Sato, K.; Moritani, Y.; Iwatsuki, Y.; Kaku, S.; Katayama,
N.; Kawasaki, T.; Matsumoto, Y.; Sakamoto, S.; Tsukamoto, S. Bioorg.
Med. Chem. 2005, 13, 1305-1323.
(14) Mills, A. D.; Maloney, P.; Hassanein, E.; Haddadin, M. J.; Kurth,
M. J. J. Comb. Chem. 2007, 9, 171-177.
J. Org. Chem, Vol. 73, No. 1, 2008 235

Butler et al.
SCHEME 3. Route to Alkynyl Indazolobenzoxazines 14
SCHEME 4. Route to (5-Isoxazolyl)indazolobenzoxazines 17
indazole (e.g., 3) byproduct was observed]. Diversification at
the benzoxazine subunit was then accomplished by Sonogashira
coupling.16 In the event, coupling of 11 with various terminal
alkynes delivered alkynyl indazolobenzoxazines 14a-e in good
to excellent yields as summarized in Scheme 3. Indeed, the four-
step yield of 14a from methyl 5-iodoanthranilate is 73% overall.
A third diversification protocol is delineated in Scheme 4;
the strategy here was to again vary the benzoxazino aryl rings
this time with a 5-isoxazoloyl moiety. Sonogashira coupling of
13 with trimethylsilyl acetylene worked beautifully, affording
15 in 86% yield. Subsequent application of the base-mediated
bis-heterocyclization was accompanied by concurrent protode-
silylation to give 16 in 76% yield. Nitrile oxide (formed in situ
from the corresponding nitroalkanes employing 1,4-phenylene
diisocyanate)17 1,3-dipolarcycloaddition with various nitroal-
kanes delivered (5-isoxazolyl)indazolobenzoxazines 17a-c in
good yields (56-88%). This transformation was most effective
when excess base (3 equiv of triethylamine) was employed and
the nitroalkane was added dropwise over 6-8 h while heating
at 50 °C. These results are summarized in Scheme 4.
a Reaction run at 50 °C.
were efficiently N-alkylated with 4-bromomethyl-3-nitrobenzoic
acid to generate N-(2-nitrobenzyl)anilines 6a-c. Bis-heterocy-
clizations of these isolated intermediates to indazolobenzox-
azines 7a-c were accomplished with aqueous KOH in 2-pro-
panol (or methanol). The resulting indazolocarboxylic acids were
purified by aqueous base f aqueous acid precipitation of 7a-c
and subsequent filtration. This crucial transformation was
performed in good to excellent yields (60-88%). Amidation
of the C9 carboxylic acid with primary and secondary amines
yielded 8a-i, 9a-i, and 10a-i. These results are delineated in
Table 1.
A second indazolobenzoxazine diversification strategy that
is focused on the benzoxazine half of 1 is detailed in Scheme
3. The key synthetic intermediate for this protocol, iodoinda-
zolobenzoxazine 11, was prepared in three steps (75% overall
yield) from methyl 5-iodoanthranilate. Applying Stefaniak’s
procedure,15 the first step consisted of benzoate ester reduction
with DIBALH to benzyl alcohol 12 where diluting the reaction
with THF before quenching afforded improved yields. This was
followed by step 2, reductive amination of 2-nitrobenzaldehyde
with 12, to give benzylaniline 13.13 Bis-heterocyclization of 13,
the third step enroute to 11, was affected by aqueous potassium
hydroxide in 2-propanol. However, it was determined that
iodoindazolobenzoxazine 11 was also obtained in methanol and
in better yield [92%; none of the anticipated 3-alkoxy-2H-
Conclusions
In summary, the rare 5H-indazolo-[3,2-b]benzo[d]-1,3-ox-
azine system has been synthesized utilizing a one-pot, intramo-
lecular bis-heterocyclization reaction. Furthermore, the scope
of this reaction was explored with different substrates and the
reactivity of its heterocyclic products was investigated via further
diversification. The resultant library of novel heterocycles has
been submitted to the NIH Molecular Libraries Small Molecule
Repository (MLSMR) for high-throughput biological screening.
(16) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed.
2005, 44, 4442-4489.
(17) Kantorowski, E. J.; Brown, S. P.; Kurth, M. J. J. Org. Chem. 1998,
63, 5272-5274.
(15) Alabaster, C. T.; Bell, A. S.; Campbell, S. F.; Ellis, P.; Henderson,
C. G.; Roberts, D. A.; Ruddock, K. S.; Samuels, G. M. R.; Stefaniak, M.
H. J. Med. Chem. 1988, 31, 2048-2056.
236 J. Org. Chem., Vol. 73, No. 1, 2008

Synthesis of 5H-Indazolo[3,2-b]benzo[d]-1,3-oxazines
ethyl acetate (150 mL). The ethyl acetate solution was washed
consecutively with 1 N HCl (100 mL), water (100 mL), and brine
(100 mL), dried over sodium sulfate, and concentrated yielding
orange crystals (1.15 g, 83%): mp 133-135 °C; IR (neat) νmax
Experimental Section
General Procedures. All chemicals were purchased from
commercial suppliers and used without further purification. Analyti-
cal thin layer chromatography was carried out on pre-coated plates
(silica gel 60F254, 250 µm thickness) and visualized with UV light.
Flash chromatography was performed with 60 Å, 32-63 µm silica
gel (Scientific Adsorbents). Concentration refers to rotary evapora-
tion under reduced pressure. 1H NMR spectra were recorded at 300,
400, or 600 MHz at ambient temperature with DMSO-d6 or CDCl3
as solvents. 13C NMR spectra were recorded at 75, 100, or 150
MHz at ambient temperature with DMSO-d6 or CDCl3 as solvents.
Chemical shifts are reported in parts per million relative to DMSO-
d6 (1H, δ 2.50; 13C, δ 39.52) or CDCl3 (1H, δ 7.26; 13C, δ 77.16).
Infrared spectra were recorded on a FTIR spectrophotometer
(Mattson Genesis II). The specifications of the LC/MS are as
follows: electrospray (+) ionization, mass range 150-1500 Da,
20 V cone voltage, and Xterra MS C18 column (2.1 mm × 50 mm
× 3.5 µm). HOBt refers to 1-hydroxybenzotriazole and EDC refers
to N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride.
(2-(2-Nitrobenzylamino)phenyl)methanol (4). 2-Nitrobenzal-
dehyde (1.0 g, 6.6 mmol) and 2-aminobenzyl alcohol (0.80 g, 6.6
mmol) were added to a dry round-bottomed flask together with
1,2-dichloroethane (33 mL) and the solution was allowed to stir
while adding acetic acid (1.5 mL, 26.4 mmol). This solution was
allowed to stir under a nitrogen atmosphere at room temperature
for 5 h. Sodium cyanoborohydride (2.0 g, 33.1 mmol) was added
and the solution was allowed to react for an additional 8 h under
a nitrogen atmosphere at room temperature. The solution was
concentrated and then diluted with ethyl acetate. The organic layer
was washed with aqueous sodium bicarbonate (100 mL), 1 N HCl
(100 mL), water (100 mL), and brine (100 mL). The resulting
solution was dried over sodium sulfate and concentrated. The crude
material was purified via flash chromatography (1:3 ethyl acetate/
hexanes) yielding 4 (1.2 g, 68%). Orange oil: IR (neat) νmax 3403,
3021, 2871, 1613, 1525, 744 cm-1; 1H NMR (600 MHz, CDCl3) δ
8.04 (d, J ) 8.4 Hz, 1H), 7.63 (d, J ) 7.8 Hz, 1H), 7.52 (t, J ) 6.6
Hz, 1H), 7.39 (t, J ) 7.8 Hz, 1H), 7.10 (t, J ) 7.8 Hz, 1H), 7.64
(d, J ) 6.6 Hz, 1H), 6.66 (t, J ) 7.2 Hz, 1H), 6.43 (d, J ) 7.8 Hz,
1H), 4.73 (s, 2H), 4.66 (s, 2H); 13C NMR (150 MHz, CDCl3) δ
148.5, 146.9, 135.9, 133.9, 129.8, 129.5, 128.2, 125.5, 124.8, 117.4,
111.1, 64.7, 45.3; ESI MS m/z 241 (-H2O, M + H)+. Purity was
determined to be 84% by HPLC analysis on the basis of absorption
at 214 nm.
1
3435, 2845, 2607, 2234, 1939, 1696, 1525, 744 cm-1; H NMR
(300 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.50 (s, 1H), 8.15 (d, J )
8.0 Hz, 1H), 7.73 (d, J ) 8.0 Hz, 1H), 7.13 (d, J ) 6.8 Hz, 1H),
6.96 (t, J ) 7.9 Hz, 1H), 6.57 (t, J ) 6.8 Hz, 1H), 6.33 (d, J ) 7.9
Hz, 1H), 5.91 (br s, 1H), 5.18 (br s, 1H), 4.78 (d, J ) 4.0 Hz, 2H),
4.52 (s, 2H); 13C NMR (75 MHz, DMSO-d6) δ 166.2, 148.8, 146.0,
141.4, 134.3, 131.4, 130.4, 128.7, 128.4, 126.8, 126.2, 116.9, 110.5,
62.1, 44.7; ESI MS m/z 285 (-H2O, M + H)+. Purity was
determined to be 85% by HPLC analysis on the basis of absorption
at 214 nm.
4-((4-Methyl-2-(hydroxymethyl)phenylamino)methyl)-3-ni-
trobenzoic Acid (6b). By using the general procedure for synthesis
of o-nitro-p-methylphenylamino alcohols, the target was synthesized
yielding orange crystals (1.195 g, 82%): mp 141-142 °C; IR (neat)
νmax 3445, 2927, 2617, 2229, 1955, 1696, 1525, 1251, 744 cm-1
;
1H NMR (400 MHz, DMSO-d6) δ 13.60 (s, 1H), 8.49 (s, 1H), 8.14
(d, J ) 7.8, 1.5 Hz, 1H), 7.67 (d, J ) 8.4 Hz, 1H), 7.19 (d, J ) 8.4
Hz, 1H), 6.95 (dd, J ) 8.7, 2.7 Hz, 1H), 6.33 (d, J ) 8.7 Hz, 1H),
6.02 (br s, 1H), 4.77 (s, 2H), 4.51 (s, 2H); 13C NMR (100 MHz,
DMSO-d6) δ 166.2, 148.7, 144.4, 140.9, 134.4, 131.4, 130.2, 129.0,
127.8, 127.5, 126.3, 120.5, 112.0, 61.0, 44.7; ESI MS m/z 299
(-H2O, M + H)+. Purity was determined to be 86% by HPLC
analysis on the basis of absorption at 214 nm.
4-((4-Chloro-2-(hydroxymethyl)phenylamino)methyl)-3-ni-
trobenzoic Acid (6c). By using the general procedure for the
synthesis of o-nitro-p-methylphenylamino alcohols, the target was
synthesized yielding orange crystals (1.38 g, 89%): mp 150-
151 °C; IR (neat) νmax 3083, 2648, 2519, 1701, 1515, 1272, 816,
1
744 cm-1; H NMR (300 MHz, DMSO-d6) δ 12.80 (s, 1H), 8.50
(d, J ) 1.5 Hz, 1H), 8.15 (dd, J ) 8.0 Hz, 1H), 7.73 (d, J ) 8.0
Hz, 1H), 7.13 (d, J ) 6.8 Hz, 1H), 6.96 (t, J ) 7.9 Hz, 1H), 6.57
(t, J ) 6.8 Hz, 1H), 6.33 (d, J ) 7.9 Hz, 1H), 5.91 (br s, 1H), 5.18
(br s, 1H), 4.78 (d, J ) 4.0 Hz, 2H), 4.52 (s, 2H); 13C NMR (75
MHz, DMSO-d6) δ 166.2, 148.8, 146.0, 141.4, 134.3, 131.4, 130.4,
128.7, 128.4, 126.8, 126.2, 116.9, 110.5, 62.1, 44.7; ESI MS m/z
318 (-H2O, M + H)+. Purity was determined to be 82% by HPLC
analysis on the basis of absorption at 214 nm.
General Procedure for the Synthesis of Indazolobenzoxazine
Carboxylic Acids: 5H-Indazolo[3,2-b]benzo[d]-1,3-oxazine-9-
carboxylic Acid (7a). Compound 6a (1.0 g, 3.3 mmol, 1 equiv)
was dissolved in 50 mL of a 10% by volume water in 2-propanol
solution under a nitrogen atmosphere. Subsequently, KOH (2.5 g,
42 mmol) was added and the solution was allowed to stir for 12 h
at room temperature. The solution was diluted with ethyl acetate
(150 mL) and washed with 1 N HCl (100 mL), water (100 mL),
and brine (100 mL). The solution was dried over sodium sulfate
and concentrated. This cyclized product was purified via acid-
base precipitation yielding 7a (780 mg, 88%). Tan crystals: mp
286-287 °C; IR (neat) νmax 2292, 2601, 1696, 1530, 1463, 1204,
5H-Indazolo[3,2-b]benzo[d]-1,3-oxazine (1). Compound 4 (250
mg, 0.9 mmol) was dissolved in 5.0 mL of a 10% by volume water
in 2-propanol solution under a nitrogen atmosphere. Subsequently,
KOH (1.2 g, 19.4 mmol) was added and the solution was allowed
to stir for 12 h at room temperature. The solution was diluted with
ethyl acetate (150 mL) and washed with 1 N HCl (100 mL), water
(100 mL), and brine (100 mL). The solution was dried over sodium
sulfate and concentrated. The resulting solid was purified via flash
chromatography (1:5 ethyl acetate/hexanes) yielding a brown solid
(183 mg, 90%): mp 96-97 °C; IR (neat) νmax 3052, 2922, 2850,
1
739 cm-1; H NMR (300 MHz, DMSO-d6) δ 13.06 (s, 1H), 8.12
1634, 1530, 1504, 1463, 1096, 739 cm-1; H NMR (300 MHz,
1
(s, 1H), 7.89 (d, J ) 7.8 Hz, 1H), 7.61 (d, J ) 9.3 Hz, 1H), 7.53
(t, J ) 7.4 Hz, 1H), 7.46 (m, 3H), 5.64 (s, 2H); 13C NMR (75
MHz, DMSO-d6) δ 168.2, 147.8, 144.4, 133.2, 131.0, 130.4, 128.4,
126.3, 122.8, 120.8, 120.8, 120.3, 121.1, 116.2, 108.3, 68.8; ESI
MS m/z 267 (M + H)+. Purity was determined to be 89% by HPLC
analysis on the basis of absorption at 214 nm.
CDCl3) δ 7.91 (d, J ) 8.1 Hz, 1H), 7.49-7.37 (m, 3H), 7.23-
7.13 (m, 3H), 6.85 (dd, J ) 8.7, 6.6 Hz, 1H), 5.34 (s, 2H); 13C
NMR (75 MHz, CDCl3) δ 149.3, 133.8, 130.0, 128.5, 127.0, 125.0,
121.5, 120.6, 119.5, 117.4, 116.2, 106.9; ESI MS m/z 223 (M +
H)+. Purity was determined to be 98% by HPLC analysis on the
basis of absorption at 214 nm.
General Procedure for the Synthesis of o-Nitro-p-methylphe-
nylamino Alcohols: 4-((2-(Hydroxymethyl)phenylamino)methyl)-
3-nitrobenzoic Acid (6a). 4-Bromomethyl-3-nitrobenzoic acid
(1.0 g, 4.6 mmol) and 2-aminobenzyl alcohol (2.3 g, 18.5 mmol,
4.0) were dissolved in methanol (20 mL) and added to a dry round-
bottomed flask containing Hu¨nig’s base (1.8 mL, 18.5 mmol). The
solution was allowed to stir for 12 h at room temperature under a
nitrogen atmosphere, concentrated, and subsequently taken up in
3-Methyl-5H-indazolo[3,2-b]benzo[d]-1,3-oxazine-9-carboxy-
lic Acid (7b). By using the general procedure for the synthesis of
indazolobenzoxazine carboxylic acids, the target was synthesized
yielding tan crystals (669 mg, 75%): mp 293 °C; IR (neat) νmax
2917, 2632, 2539, 1675, 1515, 1235, 816, 744 cm-1; 1H NMR (300
MHz, DMSO-d6) δ 13.01 (s, 1H), 8.11 (s, 1H), 7.78 (d, J ) 8.1
Hz, 1H), 7.61 (d, J ) 8.1 Hz, 1H), 7.39 (d, J ) 8.7 Hz, 1H), 7.33
(d, J ) 8.4 Hz, 1H), 7.25 (s, 1H), 5.59 (s, 2H), 2.34 (s, 3H); 13C
NMR (75 MHz, DMSO-d6) δ 168.2, 147.6, 144.1, 138.1, 131.0,
J. Org. Chem, Vol. 73, No. 1, 2008 237

Butler et al.
130.8, 130.7, 126.6, 122.8, 120.7, 120.2, 120.0, 116.1, 108.4, 68.8,
21.4; ESI MS m/z 281 (M + H)+. Purity was determined to be
83% by HPLC analysis on the basis of absorption at 214 nm.
3-Chloro-5H-indazolo[3,2-b]benzo[d]-1,3-oxazine-9-carboxy-
lic Acid (7c). By using the general procedure for the synthesis of
indazolobenzoxazine carboxylic acids, the target was synthesized
yielding tan crystals (539 mg, 60%): mp 298-300 °C; IR (neat)
(d, J ) 8.8 Hz, 1H), 7.25 (d, J ) 8.8 Hz, 1H), 7.17 (d, J ) 8.4 Hz,
1H), 6.66 (t, J ) 5.6 Hz, 1H), 5.89 (m, 1H), 5.31 (s, 2H), 5.22 (d,
J ) 17.2 Hz, 1H), 5.12 (d, J ) 10.4 Hz, 1H), 4.05 (t, J ) 5.6 Hz,
2H), 2.31 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.1, 147.9,
143.6, 137.6, 134.5, 134.4, 131.1, 130.4, 125.4, 121.4, 119.9, 118.7,
116.9, 116.6, 116.1, 108.0, 68.6, 42.7, 21.4; ESI MS m/z 320 (M
+ H)+. Purity was determined to be 98% by HPLC analysis on the
basis of absorption at 214 nm.
ν
max 2839, 2632, 2539, 1686, 1520, 1500, 820, 745 cm-1; 1H NMR
(300 MHz, DMSO-d6) δ 13.06 (s, 1H), 8.09 (s, 1H), 7.86 (d, J )
9.3 Hz, 1H), 7.61-7.55 (m, 3H), 7.38 (d, J ) 8.7 Hz, 1H), 5.62 (s,
2H); 13C NMR (75 MHz, DMSO-d6) δ 168.1, 147.9, 144.3, 132.3,
132.1, 131.2, 130.3, 126.3, 124.8, 120.7, 120.3, 120.2, 117.9, 108.3,
68.8; ESI MS m/z 300 (M + H)+. Purity was determined to be
93% by HPLC analysis on the basis of absorption at 214 nm.
General Procedure for the Synthesis of Indazolobenzoxazine
Carboxamides: Isopropyl-5H-indazolo[3,2-b]benzo[d]-1,3-ox-
azine-9-carboxamide (8a). Carboxylic acid 7a (100 mg, 0.3 mmol,
1 equiv), HOBt (40 mg, 0.36 mmol, 1.2 equiv), and EDC (69 mg,
0.36 mmol, 1.2 equiv) were dissolved in a 1:4 DMF/CH2Cl2 solution
(50 mL) and combined at 0 °C in a dry round-bottomed flask and
allowed to stir for 30 min. Isopropylamine was added (0.03 mL,
0.3 mmol, 1 equiv). The solution was allowed to stir under a
nitrogen atmosphere for 24 h while warming to 30 °C. The resulting
solution was concentrated and taken up in ethyl acetate (50 mL).
The solution was then extracted with sodium bicarbonate (100 mL),
1 N HCl (100 mL), water (100 mL), and brine (100 mL). The
organic layer was dried over sodium sulfate, concentrated, and
purified via flash chromatography (1:1 ethyl acetate/hexanes)
resulting in white crystals (70 mg, 76%): mp 219-220 °C; IR (neat)
N-(2-Methoxyethyl)-3-methyl-5H-indazolo[3,2-b]benzo[d]-1,3-
oxazine-9-carboxamide (9c). By using the general procedure for
the synthesis of indazolobenzoxazine carboxamides, the target was
synthesized yielding yellow crystals (64 mg, 63%): mp 187-
188 °C; IR (neat) νmax 3336, 2922, 2876, 1639, 1515, 1266, 1106,
1
749 cm-1; H NMR (600 MHz, CDCl3) δ 7.93 (s, 1H), 7.01 (d, J
) 7.8 Hz, 1H), 7.52 (d, J ) 9.0 Hz, 1H), 7.29 (d, J ) 8.4 Hz, 1H),
7.24 (d, J ) 8.4 Hz, 1H), 6.99 (s, 1H), 6.69 (s, 1H), 5.37 (s, 2H),
3.65 (m, 2H), 3.56 (m, 2H), 3.38 (s, 3H), 2.35 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 168.1, 148.0, 143.7, 137.7, 134.6, 131.2,
130.5, 125.5, 121.5, 119.9, 118.8, 116.9, 116.1, 108.0, 71.4, 68.7,
59.1, 39.9, 21.4; ESI MS m/z 338 (M + H)+. Purity was determined
to be 98% by HPLC analysis on the basis of absorption at 214 nm.
Piperidinyl-3-methyl-5H-indazolo[3,2-b]benzo[d]-1,3-oxazine-
9-carboxamide (9e). By using the general procedure for the
synthesis of indazolobenzoxazine carboxamides, the target was
synthesized yielding white crystals (59 mg, 57%): mp 188-
189 °C; IR (neat) νmax 2927, 2855, 1618, 1520, 1427, 1375, 827
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.81 (d, J ) 8.4 Hz, 1H),
7.53-7.51 (m, 2H), 7.23 (d, J ) 8.4 Hz, 1H), 6.99 (s, 1H), 6.91
(d, J ) 8.8 Hz, 1H), 5.36 (s, 2H), 3.69-3.38 (m, 4H), 2.34 (s,
3H), 1.64-1.52 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 170.6,
148.0, 143.8, 137.5, 136.2, 131.2, 130.4, 125.5, 121.4, 120.1, 119.4,
116.0, 115.7, 107.0, 68.6, 46.2, 26.4, 24.8, 21.4; ESI MS m/z 348
(M + H)+. Purity was determined to be 96% by HPLC analysis on
the basis of absorption at 214 nm.
νmax 3279, 2974, 1629, 1520, 759 cm-1 1H NMR (300 MHz,
;
DMSO-d6) δ 7.92 (d, J ) 7.9 Hz, 1H), 7.84 (s, 1H), 7.50 (d, J )
9.0 Hz, 1H), 7.43 (t, J ) 7.7 Hz, 1H), 7.16-7.28 (m, 3H), 5.92
(br s, 1H), 5.40 (s, 2H), 4.24 (m, 1H), 1.21 (d, J ) 7.5 Hz, 6H);
13C NMR (75 MHz, CDCl3) δ 167.2, 148.3, 135.2, 133.5, 130.1,
127.4, 124.9, 121.5, 120.0, 118.9, 116.6, 116.3, 107.8, 68.6, 42.1,
29.9, 23.0; ESI MS m/z 308 (M + H)+. Purity was determined to
be 94% by HPLC analysis on the basis of absorption at 214 nm.
N-(2-Methoxyethyl)-5H-indazolo[3,2-b]benzo[d]-1,3-oxazine-
9-carboxamide (8c). By using the general procedure for the
synthesis of indazolobenzoxazine carboxamides, the target was
synthesized yielding tan crystals (69 mg, 68%): mp 159-161 °C;
IR (neat) νmax 3352, 2927, 2855, 1629, 1536, 1096, 765 cm-1; 1H
NMR (600 MHz, DMSO-d6) δ 8.61 (t, J ) 5.4 Hz, 1H), 8.02 (s,
1H), 7.88 (m, 2H), 7.60 (m, 3H), 7.57 (d, J ) 9.6, 1H), 5.64 (s,
2H), 3.46-3.43 (m, 4H), 3.26 (s, 3H); 13C NMR (150 MHz, CDCl3)
δ 168.1, 148.3, 144.1, 134.8, 133.6, 130.1, 127.5, 125.0, 121.6,
120.1, 118.9, 116.9, 116.3, 107.9, 71.4, 68.6, 59.1, 39.9; ESI MS
m/z 324 (M + H)+. Purity was determined to be 97% by HPLC
analysis on the basis of absorption at 214 nm.
N-(Cyclopropylmethyl)-5H-indazolo[3,2-b]benzo[d]-1,3-oxazine-
9-carboxamide (8i). By using the general procedure for the
synthesis of indazolobenzoxazine carboxamides, the target was
synthesized yielding white crystals (78 mg, 82%): mp 186-
187 °C; IR (neat) νmax 3300, 3067, 2912, 1639, 1520, 1266, 754
cm-1; 1H NMR (600 MHz, CDCl3) δ 7.67-7.65 (m, 2H), 7.24 (d,
J ) 9.0 Hz, 1H), 7.18 (t, J ) 6.0 Hz, 1H), 7.04-6.99 (m, 2H),
6.94 (d, J ) 7.2 Hz, 1H), 6.33 (s, 1H), 5.14 (s, 2H), 3.50 (t, J )
6.0 Hz, 2H), 0.81 (m, 1H), 0.27 (d, J ) 7.8 Hz, 2H), 0.00 (d, J )
4.8 Hz, 2H); 13C NMR (150 MHz, CDCl3) δ 168.1, 148.3, 143.9,
134.9, 134.5, 129.9, 127.4, 124.9, 121.5, 119.9, 118.9, 116.8, 116.2,
107.8, 68.6, 45.2, 10.9, 3.7; ESI MS m/z 320 (M + H)+. Purity
was determined to be 90% by HPLC analysis on the basis of
absorption at 214 nm.
Morpholino-3-methyl-5H-indazolo[3,2-b]benzo[d]-1,3-oxazine-
9-carboxamide (9f). By using the general procedure for the
synthesis of indazolobenzoxazine carboxamides, the target was
synthesized yielding cream-colored crystals (54 mg, 52%): mp
212-214 °C; IR (neat) νmax 2974, 2922, 2855, 1629, 1520, 1427,
1
1246, 1116, 816 cm-1; H NMR (400 MHz, CDCl3) δ 7.83 (d, J
) 8.0 Hz, 1H), 7.57 (s, 1H), 7.55 (d, J ) 8.0 Hz, 1H), 7.26 (d, J
) 6.8 Hz, 1H), 7.02 (s, 1H), 6.93 (d, J ) 8.0 Hz, 1H), 5.39 (s,
2H), 3.69 (m, 8H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
170.8, 147.8, 143.9, 137.6, 134.9, 131.2, 130.6, 125.5, 121.4, 120.4,
119.3, 116.3, 116.0, 107.2, 68.7, 67.1, 45.6, 21.4; ESI MS m/z 350
(M + H)+. Purity was determined to be 94% by HPLC analysis on
the basis of absorption at 214 nm.
N-((S)-1-Hydroxy-3-methylbutan-2-yl)-3-methyl-5H-indazolo-
[3,2-b]benzo[d]-1,3-oxazine-9-carboxamide (9h). By using the
general procedure for the synthesis of indazolobenzoxazine car-
boxamides, the target was synthesized yielding tan crystals (82 mg,
75%): mp 202-203 °C; IR (neat) νmax 3435, 3290, 2964, 2876,
1608, 1515, 1360, 1075, 821 cm-1; 1H NMR (400 MHz, CDCl3) δ
7.85 (s, 1H), 7.76 (d, J ) 8.4 Hz, 1H), 7.43 (d, J ) 8.8 Hz, 1H),
7.25-7.21 (m, 2H), 6.98 (s, 1H), 6.72 (d, J ) 8.8 Hz, 1H), 5.35
(s, 2H), 3.95 (m, 1H), 3.80 (m, 2H), 2.36 (s, 3H), 2.02 (m, 1H),
1.01 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 169.2, 147.9, 143.7,
137.6, 134.7, 131.1, 130.5, 125.4, 121.5, 119.9, 118.9, 116.6, 116.1,
108.0, 68.6, 63.9, 57.9, 29.5, 21.4, 19.5; ESI MS m/z 366 (M +
H)+. Purity was determined to be 93% by HPLC analysis on the
basis of absorption at 214 nm.
Isopropyl-3-chloro-5H-indazolo[3,2-b]benzo[d]-1,3-oxazine-
9-carboxamide (10a). By using the general procedure for the
synthesis of indazolobenzoxazine carboxamides, the target was
synthesized yielding white crystals (71 mg, 70%): mp 209-
210 °C; IR (neat) νmax 3269, 3062, 2974, 2922, 2860, 1639, 1510,
739 cm-1; 1H NMR (600 MHz, CDCl3) δ 7.91-7.88 (m, 2H), 7.55
(d, J ) 9.0 Hz, 1H), 7.47 (dd, J ) 8.4, 1.8 Hz, 1H), 7.30 (dd, J )
7.8, 1.2 Hz, 1H), 7.25 (m, 1H), 6.09 (d, J ) 7.8 Hz, 1H), 5.43 (s,
N-Allyl-3-methyl-5H-indazolo[3,2-b]benzo[d]-1,3-oxazine-9-
carboxamide (9b). By using the general procedure for the synthesis
of indazolobenzoxazine carboxamides, the target was synthesized
yielding tan crystals (72 mg, 75%): mp 186-187 °C; IR (neat)
ν
max 2839, 2632, 2539, 1686, 1520, 1500, 820, 745 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.89 (s, 1H), 7.73 (d, J ) 8.0 Hz, 1H), 7.44
238 J. Org. Chem., Vol. 73, No. 1, 2008

Synthesis of 5H-Indazolo[3,2-b]benzo[d]-1,3-oxazines
2H), 4.30 (m, 1H), 1.28 (d, J ) 6.6 Hz, 6H); 13C NMR (150 MHz,
CDCl3) δ 167.3, 148.2, 143.9, 135.5, 133.1, 131.9, 130.2, 125.2,
122.9, 120.0, 119.2, 117.7, 116.5, 107.8, 68.1, 42.3, 22.9; ESI MS
m/z 342 (M + H)+. Purity was determined to be 88% by HPLC
analysis on the basis of absorption at 214 nm.
with sodium sulfate, filtered, and then concentrated. The crude
product was purified via flash chromatography (1:3 ethyl acetate/
hexanes) to afford 4.48 g of 11 (12.7 mmol, 92% yield). Pale yellow
solid: mp 193-194 °C; IR (neat) νmax 1633, 1500, 1370, 1303,
1
818, 740 cm-1; H NMR (300 MHz, DMSO-d6) δ 7.90-7.86 (m,
2H), 7.65 (d, J ) 8.1 Hz, 1H), 7.54 (d, J ) 8.4 Hz, 1H), 7.47 (d,
J ) 9.3 Hz, 1H), 7.26 (apparent t, J ) 7.7 Hz, 1H), 6.93 (dd, J )
8.6, 6.5 Hz, 1H), 5.59 (s, 2H); 13C NMR (150 MHz, DMSO-d6) δ
148.3, 143.5, 138.2, 134.0, 132.5, 128.3, 124.1, 120.3, 119.3, 117.2,
117.0, 106.0, 91.8, 67.0; ESI MS m/z 349 (M + H)+. Purity was
determined to be 90% by HPLC analysis on the basis of absorption
at 214 nm.
Morpholino-3-chloro-5H-indazolo[3,2-b]benzo[d]-1,3-oxazine-
9-carboxamide (10f). By using the general procedure for the
synthesis of indazolobenzoxazine carboxamides, the target was
synthesized yielding yellow crystals (68 mg, 61%): mp 195-
196 °C; IR (neat) νmax 2979, 2922, 2855, 1779, 1623, 1504, 1427,
1117, 832, 811 cm-1; 1H NMR (600 MHz, CDCl3) δ 7.88 (d, J )
8.4 Hz, 1H), 7.59-7.57 (m, 2H), 7.46 (m, 1H), 7.25 (s, 1H), 6.96
(d, J ) 6.6 Hz, 1H), 6.57 (br s, 1H), 5.43 (s, 2H), 3.8-3.5 (m,
8H); 13C NMR (150 MHz, CDCl3) δ 170.9, 147.9, 144.3, 135.1,
133.3, 131.7, 130.4, 125.4, 122.9, 120.7, 119.7, 117.7, 116.3, 107.3,
68.2, 67.1, 46.5; ESI MS m/z 369 (M + H)+. Purity was determined
to be 88% by HPLC analysis on the basis of absorption at 214 nm.
2-Amino-5-iodobenzyl Alcohol (12). Methyl 5-iodoanthranilate
(10.0 g, 36.1 mmol) was dissolved in dry THF (25 mL) under an
atmosphere of nitrogen. The solution was cooled to -30 °C, and
DIBALH (99 mL of a 1.2 M solution in toluene, 120 mmol) was
slowly added. After remaining at -30 °C for 1 h, the reaction was
allowed to warm to room temperature overnight. Upon completion
of the reaction it was diluted with THF (100 mL), cooled to 0 °C,
and then quenched by slow addition of methanol (250 mL).
Aluminum salts were removed via vacuum filtration and washed
several times with ethyl acetate and methanol. The filtrate was
concentrated and then purified via flash chromatography (1:49
methanol/chloroform) to afford 8.19 g of 12 (32.9 mmol, 91%
yield). Cream-colored solid: mp 120-122 °C (lit.13 mp 125 °C);
IR (neat) νmax 3359, 3191 (br), 2881, 1473, 1392, 1269, 1003, 824
cm-1; 1H NMR (600 MHz, DMSO-d6) δ 7.35 (d, J ) 1.8 Hz, 1H),
7.22 (dd, J ) 8.4, 2.4 Hz, 1H), 6.46 (d, J ) 8.4 Hz, 1H), 5.11-
5.08 (m, 3H), 4.32 (d, J ) 5.4 Hz, 2H); 13C NMR (150 MHz,
DMSO-d6) δ 145.8, 135.6, 135.1, 128.4, 117.0, 76.5, 60.0; ESI
MS m/z 232 (-H2O, M + H)+, 250 (M + H)+. Purity was
determined to be 98% by HPLC analysis on the basis of absorption
at 214 nm.
General Procedure for the Synthesis of Alkynyl Indazoloben-
zoxazines: 3-(1-Hexynyl)-5H-indazolo[3,2-b]benzo[d]-1,3-ox-
azine (14a). 1-Hexyne (76 µL, 0.66 mmol) was added under a
nitrogen atmosphere to 11 (209 mg, 0.60 mmol) in dry acetonitrile
(8 mL). To this was added PdCl2(PPh3)2 (21 mg, 0.03 mmol),
copper(I) iodide (12 mg, 0.06 mmol), and finally triethylamine
(417 µL, 3.0 mmol). The reaction mixture was stirred overnight at
room temperature, quenched with saturated aqueous NH4Cl (∼4
mL), and then diluted with water (∼10 mL). The product was
extracted three times with dichloromethane. The combined organic
layers were washed with brine, dried with sodium sulfate, filtered,
and then concentrated. The crude product was purified via flash
chromatography (1:9 ethyl acetate/hexanes) to afford 178 mg of
14a (0.59 mmol, 98% yield). White solid: mp 107-108 °C; IR
(neat) νmax 2957, 2935, 2858, 1634, 1508, 1377, 822, 745 cm-1
;
1H NMR (600 MHz, DMSO-d6) δ 7.81 (d, J ) 8.4 Hz, 1H), 7.51-
7.46 (m, 4H), 7.25 (ddd, J ) 8.4, 6.6, 1.2 Hz, 1H), 6.92 (dd, J )
8.4, 6.6 Hz, 1H), 5.59 (s, 2H), 2.44 (t, J ) 7.2 Hz, 2H), 1.56-1.51
(m, 2H), 1.48-1.43 (m, 2H), 0.92 (t, J ) 7.5 Hz, 3H); 13C NMR
(150 MHz, DMSO-d6) δ 148.4, 143.5, 132.5, 132.0, 128.3, 128.2,
122.2, 121.8, 120.3, 119.2, 117.0, 115.4, 106.0, 92.0, 79.8, 67.6,
30.2, 21.4, 18.3, 13.5; ESI MS m/z 303 (M + H)+. Purity was
determined to be 95% by HPLC analysis on the basis of absorption
at 214 nm.
3-(1-Octynyl)-5H-indazolo[3,2-b]benzo[d]-1,3-oxazine (14b).
The general procedure for the synthesis of alkynyl indazoloben-
zoxazines was employed with use of 1-octyne to afford 122 mg of
14b (0.37 mmol, 62%). Pale yellow solid: mp 96-97 °C; IR (neat)
νmax 3054, 2943, 2847, 1644, 1540, 1520, 1501, 1389, 839, 732
cm-1; 1H NMR (600 MHz, DMSO-d6) δ 7.81 (d, J ) 8.4 Hz, 1H),
7.55-7.47 (m, 4H), 7.26 (apparent t, J ) 7.8 Hz, 1H), 6.93
(apparent t, J ) 7.5 Hz, 1H), 5.60 (s, 2H), 2.45 (t, J ) 7.2 Hz,
2H), 1.57-1.52 (m, 2H), 1.45-1.41 (m, 2H), 1.33-1.29 (m, 4H),
0.88 (t, J ) 6.9 Hz, 3H); 13C NMR (150 MHz, DMSO-d6) δ 148.4,
143.6, 132.5, 132.0, 128.3, 128.2, 122.3, 121.8, 120.3, 119.3, 117.0,
115.4, 106.0, 92.0, 79.8, 67.6, 30.8, 28.1, 28.0, 22.0, 18.7, 14.0;
ESI MS m/z 331 (M + H)+. Purity was determined to be 93% by
HPLC analysis on the basis of absorption at 214 nm.
3-(2-Cyclopentylethynyl)-5H-indazolo[3,2-b]benzo[d]-1,3-ox-
azine (14c). The general procedure for the synthesis of alkynyl
indazolobenzoxazines was employed with use of cyclopentyl
acetylene to afford 139 mg of 14c (0.44 mmol, 74%). Pale yellow
solid: mp 143-144 °C; IR (neat) νmax 2941, 2868, 1630, 1525,
1376, 975, 825, 746 cm-1; 1H NMR (600 MHz, DMSO-d6) δ 7.80
(d, J ) 8.4 Hz, 1H), 7.54-7.46 (m, 4H), 7.25 (apparent t, J ) 7.5
Hz, 1H), 6.92 (dd, J ) 8.4, 6.6 Hz, 1H), 5.59 (s, 2H), 2.91-2.86
(m, 1H), 2.01-1.97 (m, 2H), 1.73-1.69 (m, 2H), 1.65-1.57 (m,
4H); 13C NMR (150 MHz, DMSO-d6) δ 148.4, 143.5, 132.5, 132.0,
128.3, 128.2, 122.2, 121.8, 120.3, 119.3, 117.0, 115.4, 106.0, 96.0,
79.3, 67.6, 33.4, 30.0, 24.6; ESI MS m/z 315 (M + H)+. Purity
was determined to be 97% by HPLC analysis on the basis of
absorption at 214 nm.
(2-(2-Nitrobenzylamino)-5-iodophenyl)methanol (13). 2-Ni-
trobenzaldehyde (2.55 g, 16.9 mmol) and 12 (4.20 g, 16.9 mmol)
were dissolved in 1,2-dichloroethane (90 mL) under an atmosphere
of nitrogen. Glacial acetic acid (4.8 mL, 85 mmol) was added, and
the reaction was stirred at room temperature for 5 h. Sodium
cyanoborohydride (4.25 g, 67.6 mmol) was added to the reaction
mixture, and the reaction was stirred an additional 12 h at room
temperature. The reaction was quenched by adding 10% aqueous
K2CO3 (∼150 mL) and then diluted with dichloromethane (∼300
mL). The organic layer was washed twice with 10% aqueous K2-
CO3 and once with brine, then dried with sodium sulfate, filtered,
and concentrated. The crude product was purified via flash
chromatography (1:2 ethyl acetate/hexanes) to afford 5.58 g of 13
(14.5 mmol, 89% yield). Orange solid: mp 104-106 °C; IR (neat)
ν
max 3508, 3361, 1575, 1511, 1335, 1273, 998, 802, 723 cm-1; 1H
NMR (400 MHz, DMSO-d6) δ 8.06 (d, J ) 12 Hz, 1H), 7.66
(apparent t, J ) 11.4 Hz, 1H), 7.52 (m, 2H), 7.42 (d, J ) 2.4 Hz,
1H), 7.23 (dd, J ) 12.9, 2.7 Hz, 1H), 6.19 (d, J ) 12.6 Hz, 1H),
5.98 (t, J ) 8.4 Hz, 1H), 5.28 (t, J ) 7.5 Hz, 1H), 4.67 (d, J ) 9
Hz, 2H), 4.46 (d, J ) 6.6 Hz, 2H); 13C NMR (150 MHz, DMSO-
d6) δ 148.2, 144.9, 135.9, 135.2, 135.1, 133.7, 129.1, 129.0, 128.1,
124.9, 112.5, 77.3, 60.2, 43.5; ESI MS m/z 367 (-H2O, M + H)+,
385 (M + H)+. Purity was determined to be 80% by HPLC analysis
on the basis of absorption at 214 nm.
3-Iodo-5H-indazolo[3,2-b]benzo[d]-1,3-oxazine (11). Potassium
hydroxide was dissolved (10.2 g, 182 mmol) in water (20 mL).
This solution was added to 13 (5.17 g, 14.0 mmol) in methanol
(180 mL). The reaction mixture was heated at 50 °C overnight,
quenched with 1 M aqueous HCl (∼150 mL), and then diluted with
water (∼200 mL). The product was extracted three times with ethyl
acetate. The combined organic layers were washed with brine, dried
3-(2-Cyclohexylethynyl)-5H-indazolo[3,2-b]benzo[d]-1,3-ox-
azine (14d). The general procedure for the synthesis of alkynyl
indazolobenzoxazines was employed with use of cyclohexyl
acetylene to afford 146 mg of 14d (0.44 mmol, 74%). Pale yellow
solid: mp 159-160 °C; IR (neat) νmax 2929, 2851, 1631, 1526,
J. Org. Chem, Vol. 73, No. 1, 2008 239

Butler et al.
1
1375, 838, 744 cm-1; H NMR (600 MHz, DMSO-d6) δ 7.81 (d,
General Procedure for the Synthesis of (5-Isoxazolyl)inda-
zolobenzoxazines: 3-(3-Methylisoxazol-5-yl)-5H-indazolo[3,2-
b]benzo[d]-1,3-oxazine (17a). 1,4-Phenylene diisocyanate (144 mg,
0.90 mmol) was added to 16 (74 mg, 0.30 mmol) in dry
tetrahydrofuran (4 mL). Triethylamine (125 µL, 0.90 mmol) was
added to the reaction mixture and this was heated to 50 °C.
Nitroethane (65 µL, 0.90 mmol) was added in portions over a period
of 6-8 h, and then the reaction was heated an additional 2 h. The
reaction was quenched with water (2 mL) and allowed to stir at
room temperature for 1 h. 1,4-Phenylene diisocyanate was removed
by filtration over celite (washing several times with ethyl acetate),
and the filtrate was then concentrated and subjected to flash
chromatography (2:3 ethyl acetate/hexanes) to afford 57 mg of 17a
(0.19 mmol, 63% yield). White solid: mp 217-218 °C; IR (neat)
J ) 7.8 Hz, 1H), 7.54-7.47 (m, 4H), 7.25 (apparent t, J ) 7.5 Hz,
1H), 6.93 (dd, J ) 7.8, 6.6 Hz, 1H), 5.59 (s, 2H), 2.68-2.66 (m,
1H), 1.84-1.82 (m, 2H), 1.71-1.68 (m, 2H), 1.51-1.46 (m, 3H),
1.38-1.34 (m, 3H); 13C NMR (150 MHz, DMSO-d6) δ 149.0,
144.2, 133.2, 132.7, 129.0, 128.9, 122.9, 122.4, 121.0, 119.9, 117.6,
116.1, 106.6, 96.3, 80.5, 68.3, 32.8, 29.4, 26.0, 24.9; ESI MS m/z
329 (M + H)+. Purity was determined to be 92% by HPLC analysis
on the basis of absorption at 214 nm.
3-(2-Phenylethynyl)-5H-indazolo[3,2-b]benzo[d]-1,3-oxazine
(14e). The general procedure for the synthesis of alkynyl inda-
zolobenzoxazines was employed with use of phenyl acetylene (while
heating at 50 °C) to afford 145 mg of 14e (0.45 mmol, 78%). Peach-
colored solid: mp 154-156 °C; IR (neat) νmax 2918, 1621, 1519,
1494, 1388, 833, 747, 721, 702 cm-1; 1H NMR (600 MHz, DMSO-
d6) δ 7.90 (d, J ) 8.2 Hz, 1H), 7.72 (dd, J ) 8.2, 1.5 Hz, 1H),
7.68 (s, 1H), 7.59-7.55 (m, 3H), 7.49 (d, J ) 8.9 Hz, 1H), 7.47-
7.45 (m, 3H), 7.28-7.26 (m, 1H), 6.94 (dd, J ) 8.3, 6.6 Hz, 1H),
5.65 (s, 2H); 13C NMR (150 MHz, DMSO-d6) δ 148.5, 143.7, 132.8,
132.7, 131.4, 129.1, 128.9, 128.5, 128.4, 122.4, 122.0, 120.7, 120.4,
119.3, 119.2, 117.0, 116.9, 115.6, 106.0, 90.4, 88.5, 67.6; ESI MS
m/z 323 (M + H)+. Purity was determined to be 91% by HPLC
analysis on the basis of absorption at 214 nm.
ν
max 1636, 1620, 1531, 1513, 1426, 1381, 828, 803, 732 cm-1; 1H
NMR (600 MHz, DMSO-d6) δ 7.99-7.95 (m, 3H), 7.56 (d, J )
8.4 Hz, 1H), 7.49 (d, J ) 9.0 Hz, 1H), 7.27 (apparent t, J ) 5.4
Hz, 1H), 6.95-6.92 (m, 2H), 5.70 (s, 2H), 2.30 (s, 3H); 13C NMR
(150 MHz, DMSO-d6) δ 167.6, 160.6, 148.6, 143.8, 133.8, 128.5,
127.0, 125.4, 122.8, 122.7, 120.4, 119.3, 117.0, 115.9, 106.0, 101.5,
67.8, 11.13; ESI MS m/z 304 (M + H)+. Purity was determined to
be 97% by HPLC analysis on the basis of absorption at 214 nm.
3-(3-Ethylisoxazol-5-yl)-5H-indazolo[3,2-b]benzo[d]-1,3-ox-
azine (17b). The general procedure for the synthesis of (5-
isoxazolyl)indazolobenzoxazines was employed to afford 87 mg
of 17b (0.17 mmol, 56% yield). White solid: mp 164-165 °C; IR
(neat) νmax 2973, 1637, 1619, 1530, 1511, 1433, 1377, 803, 730
cm-1; 1H NMR (600 MHz, DMSO-d6) δ 8.00-7.95 (m, 3H), 7.55
(d, J ) 8.5 Hz, 1H), 7.49 (d, J ) 8.9 Hz, 1H), 7.28-7.25 (m, 1H),
6.99 (s, 1H), 6.94 (dd, J ) 8.2, 6.7 Hz, 1H), 5.69 (s, 2H), 2.69 (q,
J ) 7.6 Hz, 2H), 1.25 (t, J ) 7.6 Hz, 3H); 13C NMR (150 MHz,
DMSO-d6) δ 167.6, 165.8, 148.5, 143.8, 133.8, 128.4, 127.0, 125.5,
122.8, 122.7, 120.4, 119.3, 117.0, 115.9, 106.0, 100.3, 67.8, 19.0,
12.5; ESI MS m/z 318 (M + H)+. Purity was determined to be
90% by HPLC analysis on the basis of absorption at 214 nm.
3-(3-Propylisoxazol-5-yl)-5H-indazolo[3,2-b]benzo[d]-1,3-ox-
azine (17c). The general procedure for the synthesis of (5-
isoxazolyl)indazolobenzoxazines was employed to afford 87 mg
of 17c (0.26 mmol, 88% yield). White solid: mp 149-150 °C; IR
(neat) νmax 2954, 1634, 1614, 1529, 1512, 1419, 1375, 983, 818,
734 cm-1; 1H NMR (600 MHz, DMSO-d6) δ 8.00-7.95 (m, 3H),
7.55 (d, J ) 8.4 Hz, 1H), 7.49 (d, J ) 8.9 Hz, 1H), 7.27 (apparent
t, J ) 7.6 Hz, 1H), 6.97 (s, 1H), 6.94 (apparent t, J ) 7.5 Hz, 1H),
5.69 (s, 2H), 2.64 (t, J ) 7.4 Hz, 2H), 1.68 (m, 2H), 0.95 (t, J )
7.2 Hz, 3H); 13C NMR (150 MHz, DMSO-d6) δ 167.6, 164.5, 148.6,
143.8, 133.8, 128.5, 127.0, 125.5, 122.8, 122.7, 120.4, 119.3, 117.0,
115.9, 106.0, 100.5, 67.8, 27.3, 21.0, 13.6; ESI MS m/z 332 (M +
H)+. Purity was determined to be 96% by HPLC analysis on the
basis of absorption at 214 nm.
(2-(2-Nitrobenzylamino)-5-(2-(trimethylsilyl)ethynyl)phenyl)-
methanol (15). Trimethylsilylacetylene (169 µL, 1.20 mmol) was
added under nitrogen to 13 (404 mg, 1.09 mmol) in dry acetonitrile
(15 mL). To this was added PdCl2(PPh3)2 (38 mg, 0.055 mmol),
copper(I) iodide (21 mg, 0.11 mmol), and finally triethylamine
(757 µL, 5.45 mmol). The reaction mixture was stirred overnight
at room temperature, quenched with saturated aqueous NH4Cl (∼10
mL), and then diluted with water (∼20 mL). The product was
extracted three times with dichloromethane. The combined organic
layers were washed with brine, dried with sodium sulfate, filtered,
and then concentrated. The crude product was purified via flash
chromatography (1:3 ethyl acetate/hexanes) to afford 333 mg of
15 (0.94 mmol, 86% yield). Orange-brown oil: IR (neat) νmax 3398,
2957, 2142, 1608, 1513, 1247, 838 cm-1; H NMR (400 MHz,
1
DMSO-d6) δ 8.07 (d, J ) 8.4 Hz, 1H), 7.66 (apparent t, J ) 7.2
Hz, 1H), 7.54-7.50 (m, 2H), 7.24 (d, J ) 1.6 Hz, 1H), 7.05 (dd,
J ) 8.4, 2.0 Hz, 1H), 6.31 (d, J ) 8.4 Hz, 1H), 6.22 (t, J ) 6.0
Hz, 1H), 5.24 (t, J ) 5.6 Hz, 1H), 4.72 (d, J ) 6.0 Hz, 2H), 4.48
(d, J ) 5.6 Hz, 2H), 0.17 (s, 9H); 13C NMR (150 MHz, DMSO-
d6) δ 148.1, 145.9, 135.0, 133.7, 131.6, 131.0, 129.0, 128.2, 126.1,
125.0, 109.7, 108.9, 107.1, 90.6, 60.6, 43.5, 0.2; ESI MS m/z 265
(-H2O, -TMS, M + H)+, 283 (-TMS, M + H)+, 337 (-H2O, M
+ H)+, 355 (M + H)+. Purity was determined to be 84% by HPLC
analysis on the basis of absorption at 214 nm.
3-Ethynyl-5H-indazolo[3,2-b]benzo[d]-1,3-oxazine (16). Potas-
sium hydroxide was dissolved (675 mg, 12.0 mmol) in water (15
mL). This was added to 15 (328 mg, 0.925 mmol) in 13.5 mL of
methanol. The reaction mixture was heated at 50 °C overnight,
quenched with 1 M aqueous HCl (∼10 mL), and then filtered. The
precipitate was dissolved in ethyl acetate, dried with sodium sulfate,
filtered, and then concentrated. The crude product was purified via
flash chromatography (1:9 ethyl acetate/hexanes) to afford 174 mg
of 16 (0.71 mmol, 76% yield). White solid: mp 177-178 °C; IR
(neat) νmax 3250, 1633, 1504, 824, 750 cm-1; 1H NMR (400 MHz,
DMSO-d6) δ 7.85 (d, J ) 8.0 Hz, 1H), 7.64 (d, J ) 8.0 Hz, 1H),
7.60 (s, 1H), 7.55 (d, J ) 7.6 Hz, 1H), 7.48 (d, J ) 8.8 Hz, 1H),
7.26 (apparent t, J ) 7.8 Hz, 1H), 6.93 (dd, J ) 8.4, 6.4 Hz, 1H),
5.62 (s, 2H), 4.34 (s, 1H); 13C NMR (150 MHz, DMSO-d6) δ 149.2,
144.4, 133.8, 133.5, 129.5, 129.0, 123.0, 121.0, 120.8, 120.0, 117.6,
116.1, 106.6, 83.3, 82.6, 68.2; ESI MS m/z 247 (M + H)+. Purity
was determined to be 96% by HPLC analysis on the basis of
absorption at 214 nm.
Acknowledgment. The authors thank the National Science
Foundation (CHE-0614756) and the National Institues of Health
(GM076151) for their financial support of this work. NMR
spectrometers used were partially funded by the National
Science Foundation (CHE-0443516 and CHE-9808183). We
also thank Dr. Aaron Mills for helpful discussions and Mr.
Michael Donald for providing synthetic assistance.
Supporting Information Available: 1H NMR and 13C NMR
spectra of intermediates and selected library members as well as a
summary of LC/MS data for all other library members. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO702067Z
240 J. Org. Chem., Vol. 73, No. 1, 2008