Synthesis of isoxazolobenzoxepanes via Michael addition of indoles to nitroalkenes and sequential intramolecular nitrile oxide cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2010.04.001

Nitroalkenes derived from O-propargyl salicylaldehyde undergo facile Michael addition with indoles leading to indole-derived Michael adducts. Intramolecular nitrile oxide cycloaddition (INOC) of the Michael adducts results in isoxazolobenzoxepanes in good

Full text of DOI:10.1016/j.tetlet.2010.04.001

Tetrahedron Letters 51 (2010) 3006–3009
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Tetrahedron Letters
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Synthesis of isoxazolobenzoxepanes via Michael addition of indoles to
nitroalkenes and sequential intramolecular nitrile oxide cycloaddition
*
K. Ramachandiran, K. Karthikeyan, D. Muralidharan, P. T. Perumal
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Nitroalkenes derived from O-propargyl salicylaldehyde undergo facile Michael addition with indoles
leading to indole-derived Michael adducts. Intramolecular nitrile oxide cycloaddition (INOC) of the
Michael adducts results in isoxazolobenzoxepanes in good to excellent yields.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 12 February 2010
Revised 29 March 2010
Accepted 1 April 2010
Available online 4 April 2010
Keywords:
Intramolecular nitrile oxide cycloaddition
Michael addition
Isoxazoles
Benzoxepanes
Nitrogen and oxygen containing heterocycles are ubiquitous
substructures in a myriad of biologically active natural products
and small-molecule pharmaceuticals.1,2 The nitrile oxide cycload-
dition is a useful method to prepare heterocyclic compounds.3,4
Isoxazole, the cycloadduct of nitrile oxide, is regarded as a versatile
chromatography. For example, the treatment of the 1-ethoxy-3-
(2-nitrovinyl)-2-(prop-2-ynyloxy)benzene (4b) with N-ethylindole
(5c) in KHSO4/H2O medium resulted in the formation of adduct 6h
in 89% yield. The Michael addition product 6h was confirmed
through NMR and mass spectral studies.16
synthetic precursor for
c
-amino alcohols and b-hydroxy ketones.
Initial studies of INOC were carried out using Michael adduct 6h
as a model substrate with phenyl isocyanate and Et3N in CH3CN at
60 °C (Scheme 3). The reaction yielded a single product 7h, which
was isolated by column chromatography (Table 1, entry 1). The
There have been many examples applying the present methodol-
ogy to the preparation of five- or six-membered carbo- and hetero-
cyclic compounds5 as well as the preparation of medium- or large-
sized cyclic compounds.6,7
Nitrile oxides are readily generated through various methods
such as dehydration of primary nitro compounds8 or oxidative
treatment of oximes.9 Intramolecular nitrile oxide cycloaddition
(INOC) offers a powerful strategy to construct carbo- or heterocy-
clic compounds and many reports on the stereoselective INOC
reaction have been published in recent years.10 Nitroalkenes have
been known as a good Michael acceptor and widely used in organic
synthesis.11 Conjugate addition to a nitroalkene and subsequent
generation of a nitrile oxide is frequently applied to achieve a suc-
cessful INOC reaction.12
Br
R2
CHO
O
R2
CHO
OH
R3
2a,b
K2CO3, DMSO
R1
R1
R3
rt,10 min
3a-d
1a-c
AcOH, 80-100 ºC,
3h
CH3NO2, AcONH4
In continuation of our work with 1,3-dipolar cycloadditions,13
we herein report the facile synthesis of isoxazolobenzoxepanes
by INOC. The preparation of INOC precursors 6 was carried out
by the Michael addition of indoles with nitroalkenes14 (Scheme
1) in the presence of KHSO4 in water15 (Scheme 2). The Michael
addition reaction was completed within 3–5 h at room tempera-
ture and the corresponding adducts 6 were isolated by column
R1 R2 R3
NO2
4a
H
H
H
H
H
R2
4b OEt
4c
4d
H
Br
H
H
O
R1
R3
Et
OEt
4a-d
* Corresponding author. Tel.: +91 44 24911329; fax: +91 44 24911539.
E-mail address: ptperumal@gmail.com (P.T. Perumal).
Scheme 1. Preparation of nitroalkenes 4.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.001

K. Ramachandiran et al. / Tetrahedron Letters 51 (2010) 3006–3009
3007
R4
N
NO2
R5
R2
R2
NO2
KHSO4 / H2O,
R5
+
N
O
rt, 3-5 h
R4
O
R1
R3
R1
R3
4a-d
5a-e
6a-n
Scheme 2. Michael addition of indoles to nitroalkenes.
R4
N
R4
N
Et
Et
N
N
R5
N
R5
(Boc)2O,
DMAP
Ha
N
Methods
NO2
R2
NO2
R2
O
O
Hb
Toluene,
90 ºC,2-6 h
R3
O
O
O
O
OEt
6h
R1
R1
R3
OEt
7h
7a-n
6a-n
Scheme 3. Synthesis of isoxazolobenzoxepane (7h) by different methods.
Scheme 4. Synthesis of isoxazolobenzoxepanes (7a–n).
Table 1
Methods to generate nitrile oxide and sequential INOC (7h)
d 4.94 (J = 14.5, 1.9 Hz) and 5.24 (J = 14.5, 1.5 Hz) ppm were as-
signed to –OCH2 protons. The two singlets at
d 5.82 and
Entry Methods
Solvent
Temp (°C) Time (h) Yielda (%)
8.08 ppm were attributed to Ha and Hb protons, respectively. The
mass spectrum revealed the molecular ion peak [M+H]+ at m/z
375. The structure was further confirmed by X-ray crystallographic
analysis of the compound 7h (Fig. 1).18
1
2
PhNCO, Et3N
CH3CN
CH2Cl2
THF
60
40
60
12
24
24
24
12
12
12
24
8
20
35
Trace
42
38
Trace
10
52
40
48
3
4
Toluene 90
5
EtOCOCl, Et3N, DMAP CH3CN
90
40
60
Having obtained the isoxazolobenzoxepane product, we next
varied the reaction conditions in order to increase the yield of
the products from its initial low yield of 20%. Change of solvent
from CH3CN to CH2Cl2, THF and toluene moderately increased
the yield up to 42% (Table 1, entries 2–4). Then we changed the
reaction conditions from phenyl isocyanate/Et3N to ethyl chloro-
formate/Et3N and DMAP and (Boc)2O/DMAP, the yield increased
moderately (Table 1, entries 5–12). When toluene was used as a
solvent at 90 °C in (Boc)2O/DMAP method the yield was maximum
(up to 92%) (Table 1, entry 13).
6
7
8
CH2Cl2
THF
Toluene 90
CH3CN
CH2Cl2
THF
Toluene 60
Toluene 90
9
(Boc)2O, DMAP
60
40
60
10
11
12
13
12
12
4
26
74
2
92
a
Isolated yield after column chromatography.
Under the above optimized condition the reaction of various
substituted Michael adducts 6a–n was examined and the corre-
sponding isoxazolobenzoxepane derivatives 7a–n were obtained
in good yields (Scheme 4, Table 2). After these encouraging results,
we modified the O-propargyl group with an internal alkyne instead
of a terminal alkyne moiety to examine the feasibility and yield of
the reaction, but only a small variation was observed.
The additional advantage of this method is the use of di-tert-bu-
tyl dicarbonate which allows the reaction to be carried out with
substrates that contain –NH groups without requiring protecting
groups, thus the cycloaddition leads to N-Boc products. For exam-
ple, cycloaddition of 2-methyl-3-{2-nitro-1-[2-(prop-2-ynyl-
oxy)phenyl]ethyl}-1H-indole (6b) with (Boc)2O and DMAP affords
the N-Boc protected indolyl substituted isoxazolobenzoxepane 7b
in 85% yield (Table 2, entry 2).
In summary, we have reported the Michael addition of indoles
to b-nitrostyrenes possessing O-propargyloxy groups to generate
nitroalkanes and the use of (Boc)2O, in combination with DMAP
to convert the nitroalkanes into nitrile oxide to undergo intramo-
lecular nitrile oxide-alkyne cycloaddition (INOC) to form iso-
xazolobenzoxepane. A study on the application of this method to
synthesize novel heterocyclic compound by using different nucle-
ophiles is underway.
Figure 1. ORTEP diagram of compound 7h.
structure was confirmed by NMR and mass spectral studies.17 In 1H
NMR spectrum of the compound 7h, the two doublet of doublets at

3008
K. Ramachandiran et al. / Tetrahedron Letters 51 (2010) 3006–3009
Table 2
Synthesis of isoxazolobenzoxepanes (7a–n)
Entry
Nitro alkenes 4
Indoles 5
Michael adducts 6
Yielda (%)
Cycloadducts 7
Time (h)
Yielda (%)
R4
R5
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4a
4a
4a
4a
4a
4b
4b
4b
4b
4b
4d
4c
4c
4c
Me
H
Et
H
Me
H
H
H
H
Me
H
H
H
5a
5b
5c
5d
5e
5a
5b
5c
5d
5e
5a
5a
5b
5c
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
90
85
92
60
55
91
88
89
64
59
92
90
84
86
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
2.0
2.0
2.5
5.0
6.0
3.5
3.0
2.5
5.5
6.0
3.0
2.5
3.5
3.0
96
85
92
83
75
92
90
92
80
72
86
85
91
87
Bn
p-Br–Bn
Me
H
Et
Bn
p-Br–Bn
Me
Me
H
H
H
Me
H
Et
a
Isolated yield after column chromatography.
7. (a) Paek, S.-M.; Seo, S.-Y.; Kim, S.-H.; Jung, J.-Q.; Lee, Y.-S.; Jung, J.-K.; Suh, Y.-G.
Org. Lett. 2005, 7, 3159; (b) Sengupta, J.; Mukhopadhyay, R.; Bhattacharya, A.;
Bhadbhade, M. M.; Bhosekar, G. V. J. Org. Chem. 2005, 70, 8579.
Acknowledgement
The authors, K.R. and K.K., thank the Council of Scientific and
Industrial Research, New Delhi, India, for the research fellowship.
8. Mukaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82, 5339.
9. Liu, K.-C.; Shelton, B. R.; Howe, R. K. J. Org. Chem. 1980, 45, 3916.
10. Some examples for INOC reactions: (a) Ishikawa, T.; Kudo, T.; Saito, S. J. Synth.
Org. Chem. Jpn. 2003, 61, 1186; (b) Falb, E.; Nudelman, A.; Gottlieb, H. E.;
Hassner, A. Eur. J. Org. Chem. 2000, 645; (c) Enders, D.; Haertwig, A.; Runsink, J.
Eur. J. Org. Chem. 1998, 1793; (d) Hassner, A.; Murthy, K. S. K.; Padwa, A.;
Chiacchio, U.; Dean, D. C.; Schoffstall, A. M. J. Org. Chem. 1989, 54, 5277; (e)
Chiacchio, U.; Corsaro, A.; Librando, V.; Rescifina, A.; Romeo, R.; Romeo, G.
Tetrahedron 1996, 52, 14323; (f) Uddin, Md. J.; Kikuchi, M.; Takedatsu, K.; Arai,
K.-I.; Fujimoto, T.; Motoyoshiya, J.; Kakehi, A.; Irie, R.; Shirai, H.; Yamamoto, I.
Synthesis 2000, 365; (g) Irie, O.; Fujiwara, Y.; Nemoto, H.; Shishido, K.
Tetrahedron Lett. 1996, 37, 9229.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.04.001.
References and notes
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16. Representative experimental procedure for the synthesis of nitroalkane (6h): To
the nitroalkene 4b (1.74 mmol) in water (10 mL) was added KHSO4 (30 mol %)
and the mixture was stirred for 5 min. N-Ethylindole 5c (1.74 mmol) was
added to the mixture and the stirring was continued following the progress of
the reaction by TLC. After completion of the reaction, the reaction mixture was
extracted with ethyl acetate (3 Â 10 mL), dried over anhydrous sodium sulfate,
filtered, concentrated under reduced pressure and the residue was column
chromatographed over silica gel using EtOAc/Petroleum ether (1.5:8.5) as
eluent to get the pure product (6h).
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Grund, H.; Buß, V.; Schwab, W.; Müller, I. Bull. Chem. Soc. Belg. 1983, 92, 1039;
(c) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410; (d) Jäger, V.; Grund, H.;
Franz, R.; Ehrler, R. Lect. Heterocycl. Chem. 1985, 8, 79; (e) Torssell, K. B. G. In
Nitrile Oxides, Nitrones, and Nitronates, Organic Synthesis; VCH
Verlaggesellschaft mbH: Weinheim, 1988; (f) Curran, D. P.. In Advances in
Cycloaddition Chemistry; Curran, D. P., Ed.; JAI: Greenwich, Conneticut, 1988;
Vol. 1, p 129.
4. (a) Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247; (b) Pellissier, H. Tetrahedron
2007, 63, 3235; (c) Namboothiri, I. N. N.; Hassner, A. Top. Curr. Chem. 2001, 216,
1; (d) Desimoni, G.; Faita, G.; Jorgensen, K. A. Chem. Rev. 2006, 106, 3561; (e)
Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765; (f) Najera, C.; Sansano, J. M.
Angew. Chem., Int. Ed. 2005, 44, 6272; (g) Kanemasa, S. Synlett 2002, 1371; (h)
Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863.
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2007, 9, 753; (b) Scott, J. P.; Oliver, S. F.; Brands, K. M. J.; Brewer, S. E.; Davies, A.
J.; Gibb, A. D.; Hands, D.; Keen, S. P.; Sheen, F. J.; Reamer, R. A.; Wilson, R. D.;
Dolling, U.-H. J. Org. Chem. 2006, 71, 3086; (c) Kalita, P. K.; Baruah, B.; Bhuyan,
P. J. Tetrahedron Lett. 2006, 47, 7779; (d) Fernandez-Mateos, A.; Coca, G. P.;
Gonzalez, R. R. Tetrahedron 2005, 61, 8699; (e) Alcaide, B.; Almendros, P.; Saez,
E. ARKIVOC 2004, 137; (f) Park, K.-H.; Marshall, W. J. Tetrahedron Lett. 2004, 45,
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Tetrahedron Lett. 1999, 40, 8979.
3-{1-[3-Ethoxy-2-(prop-2-ynyloxy)phenyl]-2-nitroethyl}-1-ethyl-1H-indole (6h):
Colourless solid; mp 95–97 °C; Rf = 0.28 (20% ethylacetate/petroleum ether); IR
(cmÀ1): 1551, 1376, 1461, 2162, 3282, 2976; 1H NMR (500 MHz, CDCl3): d
1.43–1.48 (m, 6H), 2.49 (t, 1H, J = 2.3 Hz), 4.06 (q, 2H, J = 6.9 Hz) 4.13 (q, 2H,
J = 6.8 Hz), 4.72 (dd, 1H, J = 15.3, 2.3 Hz), 4.84 (dd, 1H, J = 15.3, 2.3 Hz), 5.02–
5.10 (m, 2H), 5.69 (dd, 1H, J = 9.2, 6.9 Hz), 6.79–6.82 (m, 2H), 6.96 (t, 1H,
J = 7.6 Hz), 7.03–7.06 (m, 2H), 7.19 (t, 1H, J = 8.4 Hz), 7.30 (d, 1H, J = 8.4 Hz),
7.55 (d, 1H, J = 7.6 Hz); 13C NMR (125 MHz, CDCl3): d 15.0, 15.6, 36.1, 41.1, 59.9,
64.3, 75.6, 78.5, 79.7, 109.5, 112.5, 112.6, 119.2, 119.7, 120.5, 121.9, 124.6,
124.8, 127.2, 133.6, 136.2, 144.7, 152.1; ESI-MS (LCQ) m/z = 393 [M+H]+; Anal.
Calcd for C23H24N2O4 (392.17): C, 70.39; H, 6.16; N, 7.14. Found: C, 70.45; H,
6.14; N, 7.17.
17. Representative experimental procedure for the synthesis of isoxazolobenzoxepane
(7h): The nitroalkanes (1.0 mmol) 6h and DMAP (0.2 mmol) were dissolved in
toluene (5 mL). Di-tert-butyl dicarbonate (2.5 mmol) in toluene (5 mL) was
added in portions over a period of 0.5 h at 90 °C to the nitroalkanes solution

K. Ramachandiran et al. / Tetrahedron Letters 51 (2010) 3006–3009
3009
and the reaction was allowed to proceed for a further 2 h. The mixture was
evaporated and the product was purified by column chromatography using
EtOAc/Petroleum ether (2:8) as eluent.
8-Ethoxy-4-(1-ethyl-1H-indol-3-yl)-4H,10H-2,9-dioxa-3-azabenzo[f]azulene (7h):
Colourless solid; mp 158–160 °C; Rf = 0.24 (20% ethylacetate/petroleum ether);
IR (cmÀ1): 1265, 1472, 1594, 2978, 3220; 1H NMR (500 MHz, CDCl3): d 1.38 (t,
3H, J = 6.8 Hz), 1.48 (t, 3H, J = 6.8 Hz), 4.05–4.16 (m, 4H), 4.94 (dd, 1H, J = 14.5,
1.9 Hz), 5.24 (dd, 1H, J = 14.5, 1.5 Hz), 5.82 (s, 1H), 6.91 (d, 1H, J = 7.6 Hz), 6.96–
6.97 (m, 1H), 7.04–7.09 (m, 2H), 7.04–7.09 (m, 1H), 7.17 (t, 1H, J = 6.9 Hz), 7.27
(t, 1H, J = 8.4 Hz), 7.77 (d, 1H, J = 7.6 Hz), 8.08 (s, 1H); 13C NMR (125 MHz,
CDCl3): d 15.1, 15.6, 38.9, 41.1, 64.3, 64.4, 109.3, 112.8, 112.9, 116.3, 119.1,
119.7, 121.4, 121.6, 125.4, 126.6, 127.2, 135.9, 136.5, 145.9, 152.4 152.8, 161.5;
ESI-MS (LCQ) m/z = 375 [M+H]+; Anal. Calcd for C23H22N2O3 (374.16): C, 73.78;
H, 5.92; N, 7.48. Found: C, 73.87; H, 5.96; N, 7.37.
18. Crystallographic data of compound 7h in this Letter have been deposited with
the Cambridge Crystallographic Data centre as supplemental publication No.
CCDC-764294. Copies of the data can be obtained, free of charge on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44 01223 336033 or
email: deposit@ccdc.cam.ac.uk).