Tributyltin hydride-mediated straightforward synthesis of a new isoxazolo-benzazulene ring system

Article abstract of DOI:10.1016/j.tetlet.2006.07.106

Tributyltin hydride-mediated straightforward synthesis of a new isoxazolo-benzazulene system from the derivatives afforded by the Baylis-Hillman reaction of 3-(2-bromophenyl)-4-isoxazolecarbaldehydes is described.

Full text of DOI:10.1016/j.tetlet.2006.07.106

Tetrahedron Letters 47 (2006) 7043–7045
Tributyltin hydride-mediated straightforward synthesis of a new
isoxazolo-benzazulene ring systemI
Vijay Singh and Sanjay Batra*
Medicinal Chemistry Division, Central Drug Research Institute, PO Box 173, Lucknow 226 001, India
Received 23 May 2006; revised 10 July 2006; accepted 21 July 2006
Available online 14 August 2006
Abstract—Tributyltin hydride-mediated straightforward synthesis of a new isoxazolo-benzazulene system from the derivatives
afforded by the Baylis–Hillman reaction of 3-(2-bromophenyl)-4-isoxazolecarbaldehydes is described.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Isoxazole is a privileged aromatic heterocycle, since
its derivatives have been used as key intermediates in
organic synthesis1 and are known to be associated with
a wide spectrum of biological activities.2 These reasons
have maintained the development of the chemistry of
isoxazole derivatives.3 Our interest in isoxazoles relates
to the Baylis–Hillman reaction of different isoxazolecar-
baldehydes and exploration of the chemistry and biolog-
ical activity of the resulting derivatives.4
chain cyclization6a while Shanmugam and Rajasingh
described the construction of tetrahydrofurans6b and
tetrahydropyrans6c through intramolecular vinyl radi-
cal-cyclization. However, the intramolecular cyclization
involving a halide on the phenyl ring and the methylene
group of the Baylis–Hillman adduct in the presence of
tributyltin hydide has not been reported. Therefore, to
examine this possibility we carried out the reactions of
the Baylis–Hillman adducts of 3-(2-bromophenyl)-5-
methyl-4-isoxazolecarbaldehyde and its corresponding
derivatives with tributyltin hydride. This successfully
led to the straightforward formation of the expected
isoxazole-annulated ring system in fair yields. Details
of the results of our preliminary investigation are dis-
closed in this letter.
Recently, we reported the synthesis of a new isoxazole-
benzazepinone ring system from the acetyl derivative
of the Baylis–Hillman adducts of 4-isoxazolecarbaldehy-
des.5 In continuation of our work on the synthesis of
isoxazole-annulated architectures, we envisaged the syn-
thesis of a novel isoxazolo-benzazulene system from the
derivatives of the Baylis–Hillman adducts of 3-(2-bromo-
phenyl)-4-isoxazolecarbaldehyde. In principle, radical-
promoted intramolecular cyclization involving the
2-bromo group of the phenyl ring present at the 3-posi-
tion of the isoxazole and the double bond of the carbon
chain at C-4 using tributyltin hydride should furnish the
desired ring system. A literature survey revealed that
tributyltin hydride-promoted intramolecular cycliza-
tions of derivatives of Baylis–Hillman adducts have
been carried out earlier.6 Corey and co-workers accom-
plished the synthesis of salinsporamide A via radical-
The preparation of the starting Baylis–Hillman adducts
1,3a–c and 2a,c, was accomplished following the re-
ported procedure.4e Initially, treatment of compound
1a with tributyltin hydride in the presence of AIBN in
toluene at reflux yielded a mixture of products. Purifica-
tion of this mixture led to the isolation of two products.
Spectral analysis confirmed the structure of the major
product as the expected isoxazole-annulated benzazu-
lene 4a as mixture of diastereoisomers (1:1 based on
NMR), while the minor product was found to be
dehalogenated 5a (Scheme 1).7 The isolation of 5a was
intriguing, as it was expected that tributyltin hydride
might abstract the halide from the phenyl ring and could
simultaneously add a hydride to the methylene group. In
order to ascertain unambiguously the structure of 5a, an
authentic sample of this compound was prepared from
3-phenyl-5-methyl-4-isoxazolecarbaldehyde.4a The gen-
erality of the reaction was confirmed by carrying out
Keywords: 5,6-Dihydro-4H-2-oxa-1-aza-benzo[e]azulene; Tributyltin
hydride; Baylis–Hillman; 4-Isoxazolecarbaldehyde.
q CDRI Communication No. 7020.
*
Corresponding author. Tel.: +91 522 2262411 18x4368; fax: +91 522
2623405/2623938; e-mail: batra_san@yahoo.co.uk
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.106

7044
V. Singh, S. Batra / Tetrahedron Letters 47 (2006) 7043–7045
Scheme 1.
´
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Bioorg. Med. Chem. 2005, 13, 5391–5398; (e) Kang, Y. K.;
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Med. Chem. 2002, 37, 635–648; (i) Diana, G. D.; McKinlay,
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similar reactions on compounds 1b–c to afford the
corresponding products 4b, c and 5b and c. However,
replacing the bromine with chlorine led to failure of
the reaction in these substrates and recovery of the start-
ing materials.
In view of these results, we decided to investigate the
derivatives of the Baylis–Hillman adducts of 3-(2-bro-
mo)-4-isoxazolecarbaldehyde for the analogous reac-
tion. Therefore, the acetyl derivatives 2a,c were treated
with tributyltin hydride in a similar fashion. This reac-
tion also led to a mixture of two products, which were
separated via column chromatography to afford com-
pounds 6a,c and 7a,c. The isolation of compounds
7a,c indicated that here too a highly chemoselective
side-reaction occurs wherein the halogen on the phenyl
ring is substituted with hydride. With a view to further
enhance the scope of this strategy; compounds 3a–c, ob-
tained from the reduction of the acetate derivatives of
the Baylis–Hillman adducts with sodium borohydride
were reacted with tributyltin hydride. As expected, these
substrates also furnished the isoxazolo-benzazulenes
8a–c in moderate yields along with debrominated prod-
ucts 9a–c in minor yields.
3. (a) Yavari, I.; Moradi, L. Tetrahedron Lett. 2006, 47, 1627–
1629; (b) Becht, J. M.; Marin, S. D. L.; Maruani, M.;
Wagner, A.; Mioskowski, C. Tetrahedron 2006, 62, 4430–
4434; (c) Coutouli-Argyropoulou, E.; Lianis, P.; Mitakou,
M.; Giannoulis, A.; Nowak, J. Tetrahedron 2006, 62, 1494–
1501; (d) Ruano, J. L. G.; Fajardo, C.; Martin, M. R.
Tetrahedron 2005, 61, 4363–4371; (e) Itoh, K.-i.; Horiuchi,
C. A. Tetrahedron 2004, 60, 1671–1681.
In summary, we have demonstrated a simple and
convenient strategy for the synthesis of a novel
isoxazolo-benzazulene system from the Baylis–
Hillman derivatives of 3-(2-bromophenyl)-5-methyl-4-
isoxazolecarbaldehyde.
4. (a) Batra, S.; Rastogi, S. K.; Kundu, B.; Patra, A.; Bhaduri,
A. P. Tetrahedron Lett. 2000, 41, 5971–5974; (b) Patra, A.;
Batra, S.; Kundu, B.; Joshi, B. S.; Roy, R.; Bhaduri, A. P.
Synthesis 2001, 276–281; (c) Patra, A.; Batra, S.; Joshi, B.
S.; Roy, R.; Kundu, B.; Bhaduri, A. P. J. Org. Chem. 2002,
67, 5783–5788; (d) Patra, A.; Roy, A. K.; Batra, S.; Joshi,
B. S.; Roy, R.; Batra, S.; Bhaduri, A. P. Tetrahedron 2003,
59, 633–670; (e) Roy, A. K.; Batra, S. Synthesis 2003, 1347–
1356; (f) Roy, A. K.; Batra, S. Synthesis 2003, 2325–2330;
(g) Patra, A.; Batra, S.; Bhaduri, A. P.; Khanna, A. K.;
Chander, R.; Dikshit, M. Bioorg. Med. Chem. 2003, 11,
2269–2276; (h) Roy, A. K.; Batra, S. Synthesis 2003, 2325–
2330; (i) Batra, S.; Roy, A. K.; Patra, A.; Bhaduri, A. P.;
Surin, W. S.; Raghvan, S. A. V.; Sharma, P.; Kapoor, K.;
Dikshit, M. Bioorg. Med. Chem. 2004, 12, 2059–2077; (j)
Saxena, R.; Singh, V.; Batra, S. Tetrahedron 2004, 60,
10311–10320; (k) Singh, V.; Saxena, R.; Batra, S. J. Org.
Chem. 2005, 70, 353–356; (l) Pathak, R.; Roy, A. K.; Batra,
S. Synlett 2005, 848–850; (m) Pathak, R.; Roy, A. K.;
Kanojiya, S.; Batra, S. Tetrahedron Lett. 2005, 46, 5289–
5292; (n) Singh, V.; Batra, S. Synthesis 2006, 63–72.
Acknowledgements
One of the authors (V.S.) acknowledges the financial
support from DST in the form of a fellowship. This
work was supported by the financial Grant under DST
Project No. SR/SI/OC-04/2003.
References and notes
1. (a) Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini, G. P.;
Simoni, D. Synthesis 1987, 857–869; (b) Pinho e Melo, T.
M. V. D. Curr. Org. Chem. 2005, 9, 925–958.
2. (a) Balbi, A.; Anzaldi, M.; Mazzei, M.; Miele, M.;
Bertolotto, M.; Ottonello, L.; Dallegri, F. Bioorg. Med.
5. Batra, S.; Roy, A. K. Synthesis 2004, 2550–2554.

V. Singh, S. Batra / Tetrahedron Letters 47 (2006) 7043–7045
7045
6. (a) Reddy, L. R.; Saravanan, P.; Corey, E. J. J. Am.
Chem. Soc. 2004, 126, 6230–6231; (b) Shanmugum, P.;
Rajasingh, P. Tetrahedron 2004, 60, 9283–9295; (c) Shan-
mugum, P.; Rajasingh, P. Synlett 2005, 939–942; For
tributyltin hydride-mediated intermolecular processes
involving Baylis–Hillman derivatives refer to: (d) Sibi,
M. P.; Patil, K. Tetrahedron: Asymmetry 2006, 17, 516–
519; (e) Nagano, H.; Yokota, M.; Iwazaki, Y. Tetrahedron
Lett. 2004, 45, 3035–3037; (f) Hirasawa, S.; Nagano, H.;
Kameda, Y. Tetrahedron Lett. 2004, 45, 2207–2209; (g)
Piber, M.; Leahy, J. W. Tetrahedron Lett. 1998, 39, 2043–
2046; (h) Jenn, T.; Heissler, D. Tetrahedron 1998, 54, 97–
106.
CDCl3) d = 2.54 (s, 3H, CH3), 2.58 (s, 3H, CH3), 3.01–3.09
(m, 2H, CH2), 3.24–3.32 (m, 2H, CH2) 3.43–3.55 (m, 2H,
2 · CHCN), 5.03 (br s, 2H, 2 · OH), 5.75–5.78 (m, 2H,
2 · CHOH), 7.31–7.42 (m, 6H, 2 · 3ArH), 7.99–8.11 (m, 2H,
2 · 1ArH); 13C NMR (50.32 MHz, CDCl3) d = 17.0, 37.6,
37.8, 42.8, 43.5, 68.7, 71.0, 107.8, 112.1, 118.4, 125.3, 132.9,
133.2, 133.5, 135.3, 135.4, 135.6, 135.7, 141.3, 142.3, 163.8,
163.9, 174.9, 175.4; mass (ES+) m/z 241.2 (M++1). Anal.
Calcd. for C14H12N2O2: C, 69.99; H, 5.03; N, 11.66. Found:
C, 70.23; H, 5.26; N, 11.47. 4-Acetoxy-3-methyl-5,6-dihydro-
4H-2-oxa-1-aza-benzo[e]azulene-5-carboxylic acid methyl
ester 6a—yellow oil; mmax (neat) 1725 (CO2Me and OCOMe)
;
cmÀ1 1H NMR (200 MHz, CDCl3) d = 1.96 (s, 3H,
7. The NMR data for all the compounds described herein is for
diastereoisomers. General procedure for the tributyltin
hydride-mediated reaction—A mixture of appropriate
bromo-derivative 1–3, 2 equiv of tributyltin hydride and a
catalytic amount of AIBN in anhydrous toluene was heated
at reflux under nitrogen. The reaction was maintained at
reflux until complete disappearance of the starting material
(15 h, preferably overnight). The solvent was removed and
the crude product was purified via silica gel column
chromatography using hexane–EtOAc (80:20 v/v for 4 and
90:10 v/v for 6 and 8) to afford pure products. 4-Hydroxy-3-
methyl-5,6-dihydro-4H-2-oxa-1-aza-benzo[e]azulene-
5-carboxylic acid methyl ester 4a—yellow oil; mmax (neat)
OCOCH3), 2.48 (s, 3H, CH3), 3.11–3.17 (m, 2H, CH2),
3.39–3.52 (m, 1H, CHCO2CH3), 3.72 (s, 3H, CO2CH3), 6.43
(d, 1H, J = 3.2 Hz, CHOCOCH3), 7.31–7.43 (m, 3H, ArH),
8.06–8.10 (m, 1H, ArH); mass (ES+) m/z 316.1 (M++1).
Anal. Calcd for C17H17NO5: C, 64.75; H, 5.43; N, 4.44.
Found: C, 65.03; H, 5.52; N, 4.56. Acetic acid 5-cyano-3-
methyl-5,6-dihydro-4H-2-oxa-1-aza-benzo[e]azulen-4-yl ester
6c—yellow oil; mmax (neat) 1749 (OCOMe), 2221 (CN) cmÀ1
;
1H NMR (200 MHz, CDCl3) d = 2.11 (s, 3H, OCOCH3),
2.52 (s, 3H, CH3), 3.19–3.29 (m, 2H, CH2), 3.43–3.48 (m,
1H, CHCN), 6.14 (d, 1H, J = 5.2 Hz, CHOCOCH3), 7.29–
7.35 (m, 1H, ArH), 7.41–7.45 (m, 2H, ArH), 7.97–8.01 (m,
1H, ArH); mass (ES+) m/z 283.2 (M++1). Anal. Calcd
for C16H14N2O3: C, 68.07; H, 5.00; N, 9.92. Found: C,
68.23; H, 5.12; N, 9.88. 3-Methyl-5,6-dihydro-4H-2-oxa-1-
aza-benzo[e]azulene-5-carboxylic acid methyl ester 8a—
1731 (CO2Me), 3396 (OH) cmÀ1 1H NMR (200 MHz,
;
CDCl3) d = 2.56 (s, 3H, CH3), 2.57 (s, 3H, CH3), 2.97–3.11
(m, 4H, 2 · CH2), 3.38–3.60 (m, 2H, 2 · CHCO2CH3), 3.76
(s, 3H, CO2CH3), 3.77 (s, 3H, CO2CH3), 5.14–5.24 (m, 2H,
2 · CHOH), 7.29–7.37 (m, 6H, 2 · 3ArH), 7.90–8.13 (m,
1H, ArH), 8.15–8.17 (m, 1H, ArH); mass (ES+) m/z 274.2
(M++1). Anal. Calcd for C15H15NO4: C, 65.92; H, 5.53; N,
5.13. Found: C, 65.76; H, 5.59; N, 5.28. 2-[Hydroxy-(5-
methyl-3-phenyl-isoxazol-4-yl)-methyl]-acrylic acid methyl
ester 5a-colourless oil; mmax (neat) 1719 (CO2Me), 3407 (OH)
yellow oil; mmax (neat) 1731 (CO2Me) cmÀ1 1H NMR
;
(200 MHz, CDCl3)d = 2.44 (s, 3H, CH3), 2.62–2.81 (m, 2H,
CH2), 2.89–2.99 (m, 2H, CH2), 3.12–3.15 (m, 1H,
CHCO2Me), 3.73 (s, 3H, CO2CH3), 7.35–7.37 (m, 3H,
ArH), 7.78–7.80 (m, 1H, ArH); mass (ES+) m/z 258.2
(M++1). Anal. Calcd for C15H15NO3: C, 70.02; H, 5.88; N,
5.44. Found: C, 70.23; H, 6.02; N, 5.56. 3-Methyl-5,6-
dihydro-4H-2-oxa-1-aza-benzo[e]azulene-5-carboxylic acid
1
cmÀ1; H NMR (CDCl3, 200 MHz) d = 2.48 (s, 3H, CH3),
2.96 (br s, 1H, OH), 3.73 (s, 3H, CO2CH3), 5.62 (s 1H,
CHOH), 5.74 (s, 1H, @CH), 6.32 (s, 1H, @CH), 7.41–7.47
(m, 3H, ArH), 7.56–7.61 (m, 2H, ArH); mass (FAB+) m/z
274 (M++1). Anal. Calcd for C15H15NO4: C, 65.92; H, 5.53;
N, 5.13%. Found: C, 65.89; H, 5.50; N, 5.22%. 4-Hydroxy-3-
methyl-5,6-dihydro-4H-2-oxa-1-aza-benzo[e]azulene-5-car-
boxylic acid ethyl ester 4b-yellow oil; mmax (neat) 1715
ethyl ester 8b—yellow oil; mmax (neat) 1741 (CO2Et) cmÀ1
;
1H NMR (200 MHz, CDCl3) d = 1.26 (t, 3H, J = 7.1 Hz,
CH3CH2), 2.52 (s, 3H, CH3), 2.60–2.85 (m, 2H, CH2), 2.85–
3.05 (m, 2H, CH2), 3.20–3.32 (m, 1H, CHCO2Et), 4.21 (q,
2H, J = 7.2 Hz, CH2CH3), 7.28–7.41 (m, 3H, ArH), 7.66–
7.81 (m, 1H, ArH); mass (ES+) m/z 272.0 (M++1). Anal.
Calcd for C16H17NO3: C, 70.83; H, 6.32; N, 5.16. Found: C,
70.49; H, 6.02; N, 5.23%. 3-Methyl-5,6-dihydro-4H-2-oxa-1-
aza-benzo[e]azulene-5-carbonitrile 8c—white solid, mp
(CO2Et), 3377 (OH) cmÀ1 1H NMR (200 MHz, CDCl3)
;
d = 1.14–1.42 (m, 6H, 2 · CH3CH2), 2.57 (two s merged,
6H, 2 · CH3), 3.02–3.09 (m, 4H, 2 · CH2), 3.31–3.44 (m,
2H, 2 · CHCO2Et), 4.18–4.27 (m, 4H, 2 · CH2CH3), 5.15–
5.22 (m, 2H, 2 · CHOH), 7.34–7.46 (m, 6H, 2 · 3ArH),
7.91–7.95 (m, 1H, ArH), 8.14–8.18 (m, 1H, ArH); mass
(ES+) m/z 288.1 (M++1). Anal. Calcd. for C16H17NO4: C,
66.89; H, 5.96; N, 4.88. Found: C, 67.08; H, 6.05; N, 4.96. 4-
Hydroxy-3-methyl-5,6-dihydro-4H-2-oxa-1-aza-benzo[e]azu-
lene-5-car- bonitrile 4c—white solid, mp 170–172 ꢁC; mmax
120–122 ꢁC; mmax (KBr) 2235 (CN) cmÀ1
;
1H NMR
(200 MHz, CDCl3) d = 2.46 (s, 3H, CH3), 2.75–2.83 (m,
2H, CH2), 2.97–3.04 (m, 2H, CH2), 3.29–3.35 (m, 1H,
CHCN), 7.33–7.45 (m, 3H, ArH), 7.77–7.81 (m, 1H, ArH);
13C NMR (50.32 MHz, CDCl3) d = 10.4, 23.3, 30.2, 34.6,
108.4, 120.9, 127.4, 127.8, 128.8, 129.7, 130.0, 134.5, 161.6,
165.2; mass (ES+) m/z 225.2 (M++1). Anal. Calcd for
C14H12N2O: C, 74.98; H, 5.39; N, 12.49. Found: C, 75.23;
H, 5.48; N, 12.54.
(KBr) 2244 (CN), 3336 (OH) cmÀ1 1H NMR (200 MHz,
;