Stereoselective synthesis of isoxazolinobenzoxepanes via intramolecular nitrile oxide cycloaddition

Article abstract of DOI:10.1055/s-0030-1260201

Concise routes to the synthesis of indole-tethered nitrile oxides have been developed, and their intramolecular nitrile oxide cycloadditions were studied. Heterocyclic scaffolds involving isoxazolinobenzoxepane frameworks have been achieved via intramolecular nitrile oxide cycloaddition of 3-[1-(2- allyloxyphenyl)-2-nitroethyl]-1H-indole derivatives using (Boc)₂O and DMAP. This protocol affords products with excellent trans-selectivity. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260201

PAPER
3277
Stereoselective Synthesis of Isoxazolinobenzoxepanes via Intramolecular
Nitrile Oxide Cycloaddition
Stereoselective
Sy
.
nthesis of Iso
R
xazolinobenzoxe
a
panes machandiran, K. Karthikeyan, T. Nandhakumar, D. Muralidharan, P. T. Perumal*
Organic Chemistry Division, Central Leather Research Institute (CSIR), Adyar, Chennai 600020, Tamilnadu, India
Fax +91(44)24911589; E-mail: ptperumal@gmail.com
Received 21 June 2011; revised 21 July 2011
The nitrile oxide cycloaddition is a useful method to pre-
pare heterocyclic compounds.11,12 Isoxazoline, the cy-
cloadduct of nitrile oxide, is regarded as a versatile
synthetic precursor for g-amino alcohols and b-hydroxy
Abstract: Concise routes to the synthesis of indole-tethered nitrile
oxides have been developed, and their intramolecular nitrile oxide
cycloadditions were studied. Heterocyclic scaffolds involving isox-
azolinobenzoxepane frameworks have been achieved via intramo-
lecular nitrile oxide cycloaddition of 3-[1-(2-allyloxyphenyl)-2- ketones. There have been many examples applying the
nitroethyl]-1H-indole derivatives using (Boc)2O and DMAP. This
present methodology for the preparation of five- or six-
membered carbo- and heterocyclic compounds13 as well
protocol affords products with excellent trans-selectivity.
Key words: intramolecular nitrile oxide cycloaddition, Michael ad-
dition, isoxazolinobenzoxepanes, trans-selectivity
as the preparation of medium- or large-sized cyclic com-
pounds.14,15 Intramolecular nitrile oxide cycloaddition
(INOC) reaction offers a powerful strategy to construct
carbo- or heterocyclic compounds and many reports on
The structural diversity and biological importance of ni- the stereoselective INOC reaction have been published in
trogen and oxygen containing heterocycles have made recent years.16
them attractive synthetic targets over many years. Seven-
membered oxacycles (oxepanes) are an important struc-
The conjugate addition of nucleophilic species to a,b-un-
saturated systems is a fundamental concept in organic
tural unit found in a variety of biologically active sub-
chemistry and is considered as one of the most versatile
stances and natural products (Figure 1).1 Natural products
methods in organic synthesis. Among the manifold of car-
produced by marine organisms include compounds such
bon–carbon bond forming reactions, the Michael addi-
as the brevetoxins, ciguatoxin, and maitotoxin that are
tion, also termed 1,4-addition, is especially valuable for
based on oxepanes.2 An increasing number of natural
selectively creating a new bond at the b-position of acti-
products of marine and terrestrial origin with an oxepane
vated olefins.17 Conjugate addition to nitroalkene and sub-
or an oxocane framework are being reported in the litera-
sequent generation of nitrile oxide is frequently applied to
ture.1a,3,4 A variety of natural products and compounds
achieve successful INOC reaction.18,19
carrying isoxazoline and isoxazole nucleus moiety exhibit
Recently, we have described an efficient synthesis of
isoxazolobenzoxepane derivatives from the correspond-
ing nitroalkane aryl propargyl ethers using (Boc)2O and
DMAP.20 Herein we wish to report the results of our in-
vestigations on the INOC of nitroalkane aryl allyl ether to
novel isoxazolinobenzoxepane derivatives. Furthermore,
to the best of our knowledge, there is no report on the syn-
thesis of these heterocyclic compounds.
antibacterial,5 anti-HIV,6 anticoagulants,7 anti-inflamma-
tory,8 antituberculosis,9and antithrombotic10 activities.
Due to their abundance and significant biological activity,
efficient methods for their synthesis assume importance.
O
HO
HO
HO
HO
OH
Various isoxazolinobenzoxepanes were synthesized from
the corresponding INOC precursors. The preparation of
INOC precursors 6 were carried out by the Michael addi-
tion of indoles with nitroalkenes21 4 (Scheme 1) in the
presence of KHSO4 in water (Scheme 2).22 The Michael
addition reaction went into completion within 3–5 hours
at room temperature and the corresponding adducts 6
were isolated by column chromatography. For example,
treatment of 1-(allyloxy)-2-[(E)-2-nitrovinyl]benzenes
(4a) with N-methylindole (5a) in KHSO4/H2O medium
resulted in the formation of adduct 6a in 82% yield. The
Michael addition progressed smoothly resulting in the
corresponding products 6 in excellent yields when the in-
dole moiety had a methyl or ethyl substituent at the R3 po-
sition (Table 1, entries 1, 3, 6–8, and 10), while a
substitution of benzyl group on the R3 position resulted in
O
O
O
OH
OH
O
O
HO
HO
O
O
O
OH
OH
OH
Figure 1 Natural products (heliannuols) containing oxepane
SYNTHESIS 2011, No. 20, pp 3277–3286
x
x.
x
x
.
2
0
1
1
Advanced online publication: 05.09.2011
DOI: 10.1055/s-0030-1260201; Art ID: Z62111SS
© Georg Thieme Verlag Stuttgart · New York

3278
K. Ramachandiran et al.
PAPER
NO2
Br
O
O
O
R2
R2
R2
MeNO2, NH4OAc
AcOH, 80–100 °C
2
H
H
K2CO3, DMSO
r.t., 10 min
OH
O
R1
R1
R1
3a R1 = H, R2 = H
3b R1 = OEt, R2 = H
3c R1 = H, R2 = Br
1
4a–c
Scheme 1 Synthesis of 1-(allyloxy)-2-[(E)-2-nitrovinyl]benzenes 4a–c
Me
Me
Me
N
R4
R3
N
N
N
N
NO2
different
methods
R3
5a–d
R4
+
N
O
N
R2
H
H
O
NO2
R2
NO2
KHSO4, H2O
r.t., 3–5 h
O
H
H
O
O
O
cis-8a
R1
O
6a
trans-7a
4a–c
R1
6a–j
Scheme 3 Generation of nitrile oxide and sequential INOC for syn-
thesis of 7a and 8a by different methods
Scheme 2 Michael addition of indoles to 1-(allyloxy)-2-[(E)-2-ni-
trovinyl]benzenes 4a–c
Table 2 Different Methods To Generate Nitrile Oxide and Sequen-
tial INOC for Synthesis of 7a and 8a
Table 1 Synthesis of Michael Adduct 6
Entry Conditions
Solvent
Temp Time Yield
(°C)
60
40
90
90
40
90
60
40
40
90
(h)
12
24
24
12
12
24
8
(%)a
Entry Nitroalkene Indole
Michael Time Yield
4
R3
Me
H
R4
H
5
adduct 6
(%)
82
88
90
62
85
91
85
82
90
84
1
2
PhNCO, Et3N
MeCN
CH2Cl2
toluene
20
1
2
4a
4a
4a
4a
4b
4b
4b
4c
4c
4c
5a
5b
5c
5d
5b
5c
5a
5a
5b
5c
6a
3.0
3.5
3.0
5.0
4.0
3.0
3.5
4.5
5.0
4.5
15
Me
H
6b
3
25
3
Et
6c
4
EtOCOCl, Et3N, DMAP MeCN
38
4
Bn
H
H
6d
5
CH2Cl2
toluene
trace
20
5
Me
H
6e
6
6
Et
6f
7
(Boc)2O, DMAP
MeCN
CH2Cl2
toluene
toluene
40
7
Me
Me
H
H
6g
8
12
8
25
8
H
6h
9
35
10b
2
85
9
Me
H
6i
a Yield of a mixture of both isomers.
10
Et
6j
b Typical cycloaddition condition: (Boc)2O (2.5 equiv) in toluene was
added to the nitroalkane and DMAP (10 mol%) in toluene.
products with poor yields. The Michael addition product
6a was confirmed through NMR and mass spectral stud-
ies.
mol%) in toluene at 90 °C was found to be the optimum
condition to obtain the highest yield in the cycloaddition.
The most commonly used method (Scheme 3) for con-
verting nitroalkanes to the corresponding nitrile oxides is
the Mukaiyama aromatic isocyanate method.23 Thus,
treatment of indole-tethered nitro compound 6a with phe-
nyl isocyanate and Et3N in toluene, MeCN, and CH2Cl2
provided the cycloadducts 7a and 8a in 25, 20, and 15%
yield, respectively (Table 2, entries 1–3). Two other
methods were employed to generate the corresponding ni-
trile oxide in situ from 6a, including the Shimizu ethyl
chloroformate method (Table 2, entries 4–6)24 and the
Hassner (Boc)2O–DMAP method (Table 2, entries 7–
10).25 The use of (Boc)2O (2.5 equiv) and DMAP (10
To achieve maximum yield of the cycloaddition, the ef-
fects of various solvents and different reaction tempera-
tures on the cycloaddition 6a, using (Boc)2O and DMAP
method, were studied. Among the various solvents
screened, toluene was found to be the best choice, giving
the highest yield in the cycloaddition (Table 2, entry 10).
An increase in temperature from 40 to 90 °C led to an in-
crease in yield (Table 2, entries 9 and 10), but further in-
crease in temperature to 110 °C resulted in a lower yield,
probably due to the decomposition of the cycloadduct 7a
and 8a.
Synthesis 2011, No. 20, 3277–3286 © Thieme Stuttgart · New York

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Stereoselective Synthesis of Isoxazolinobenzoxepanes
3279
R3
R3
R3
N
N
N
R4
N
R4
N
R4
NO2
(Boc)2O, DMAP
Ha
Ha
+
O
R2
R2
R2
O
toluene, 90 °C
2–6 h
Hb
Hb
O
O
O
R1
R1
R1
6a–j
trans-7a–j
cis-8a–j
Scheme 4 Synthesis of isoxazolinobenzoxepanes 7a–j and 8a–j
Generation of nitrile oxides were carried out through op- sults are summarized in Table 3. The yield of isoxazoli-
timized conditions by treating Michael adducts 6 with nobenzoxepanes 7 and 8 were in the range of 74–88%
(Boc)2O (2.5 equiv) and DMAP (10 mol%) in toluene at (Table 3). For example, Michael adduct 6e underwent the
90 °C and subsequent INOC resulted in a diastereomeric INOC reaction to give isoxazolinobenzoxepanes 7e and
mixture of isoxazolinobenzoxepanes 7 (major isomer) 8e in 87% yield with diastereoisomeric ratio as 90:10.
and 8 (minor isomer) in good yield (Scheme 4). The re-
Table 3 Synthesis of Isoxazolinobenzoxepanes 7a–j and 8a–j
Entry
Michael adduct Cycloadduct
Time (h)
Yield (%)
dr
trans
cis
Me
Me
N
N
H
N
H
N
1
6a
2.0
85
90:10
O
O
H
H
O
O
7a
8a
O
N
t-Bu
O
N
t-Bu
O
O
2
6b
3.0
78
89:11
H
N
H
N
O
O
H
H
O
O
7b
7c
7d
8b
8c
8d
N
N
H
N
H
N
3
6c
2.0
82
92:08
O
O
H
H
O
O
Bn
Bn
N
N
H
N
H
N
4
6d
4.5
74
87:13
O
O
H
H
O
O
Synthesis 2011, No. 20, 3277–3286 © Thieme Stuttgart · New York

3280
K. Ramachandiran et al.
PAPER
Table 3 Synthesis of Isoxazolinobenzoxepanes 7a–j and 8a–j (continued)
Entry
Michael adduct Cycloadduct
Time (h)
Yield (%)
dr
trans
cis
t-Bu
t-Bu
O
N
O
O
O
N
5
6e
2
87
90:10
H
H
N
N
O
O
H
H
O
N
O
N
OEt
OEt
7e
8e
H
N
H
N
6
6f
2.5
81
88:12
O
O
H
H
O
O
OEt
OEt
8f
7f
Me
Me
N
N
H
H
N
N
7
8
9
6g
6h
6i
2.0
4.5
6.0
88
76
75
89:11
85:15
84:16
O
O
H
H
O
O
OEt
OEt
7g
8g
Me
Me
N
N
H
H
N
N
O
O
Br
Br
H
H
O
O
8h
7h
t-Bu
t-Bu
O
O
O
O
N
N
H
H
N
N
O
O
Br
Br
H
H
O
N
O
N
7i
8i
H
H
N
N
10
6j
5.5
80
88:12
O
O
Br
Br
H
H
O
O
7j
8j
Synthesis 2011, No. 20, 3277–3286 © Thieme Stuttgart · New York

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Stereoselective Synthesis of Isoxazolinobenzoxepanes
3281
the fraction boiling in the range 60–80 °C. IR measurements were
carried out using PerkinElmer Spectrum RXI FT-IR spectropho-
tometer. The 1H and 13C NMR spectra were recorded in CDCl3 and
DMSO-d6 using TMS as internal standard on Jeol ECA-500 MHz
and Bruker 400 and 500 MHz high resolution NMR spectrometers.
Standard abbreviations were used to denote the multiplicities in
NMR spectra. The mass spectra were recorded using a Electrospray
Ionization Method with Thermo Finnigan mass spectrometer. Melt-
ing points were determined in capillary tubes and are uncorrected.
Analytical TLC was performed on precoated plastic sheets of silica
gel G/UV-254 of 0.2 mm thickness (Macherey-Nagel, Germany).
Elemental analysis data were recorded using Thermo Finnigan
FLASH EA 1112 CHN instrument.
The structures were confirmed by NMR and mass spectral
studies. The 1H NMR spectrum of the major diastereoiso-
mer 7e showed two doublet of doublets at d = 4.36 ppm
(J = 9.9, 8.4 Hz) and 4.48 ppm (J = 10.7, 6.1 Hz), which
were assigned to hydrogens at C-5. The multiplet at d =
3.72–3.76 ppm and singlet at d = 5.76 ppm were attributed
to Hb and Ha protons, respectively. In the 1H NMR spec-
trum of the minor diastereoisomer 8e, the triplet at d =
4.46 ppm (J = 9.9 Hz) and doublet of doublet at d = 4.55
ppm (J = 11.5, 6.9 Hz) were attributed to hydrogens at
C-5. The multiplet at d = 3.90–3.95 ppm and the singlet at
d = 5.44 ppm were assigned to Hb and Ha protons respec-
tively. In both diastereoisomers, the mass spectra revealed
the molecular ion peak [M + H]+ at m/z 463.
3-[1-(2-Allyloxyphenyl)-2-nitroethyl]-1-methyl-1H-indole (6a);
Typical Procedure (6a)
To the nitroalkene 4a (357 mg, 1.74 mmol) in H2O (10 mL) was
added KHSO4 (71.1 mg, 30 mol%) and the mixture was stirred for
5 min. 2-Methylindole (5a; 228.2 mg, 1.74 mmol) was added to the
mixture and the stirring was continued at r.t. following the progress
of the reaction by TLC (eluent: PE–EtOAc, 8:2). After completion
of the reaction, the mixture was extracted with EtOAc (3 × 10 mL).
The combined organic layers were dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue was column chro-
matographed over silica gel using EtOAc–PE (1.5:8.5) as eluent to
afford pure 6a; yield: 479.9 mg (82%); viscous liquid; Rf = 0.32
(20% EtOAc–PE) (Table 1).
The stereochemistry of compound 7e has been unambigu-
ously determined as trans-configured by X-ray crystal-
lography (Figure 2).26 This is due to the Ha and Hb protons
in 7e being trans to each other. The stereochemistry of the
minor isomer 8e was cis-configured.
IR (film): 1123, 1242, 1377, 1488, 1550, 1697, 2361, 2917, 3060
cm–1.
1H NMR (500 MHz, CDCl3): d = 3.75 (s, 3 H), 4.62–4.66 (m, 2 H),
4.98 (dd, J = 13, 3.8 Hz, 1 H), 5.05 (dd, J = 12.2, 6.8 Hz, 1 H), 5.32
(d, J = 9.2 Hz, 1 H), 5.44 (d, J = 17.5 Hz, 1 H), 5.63 (t, J = 9.2 Hz,
1 H), 6.10 (m, 1 H), 6.84 (t, J = 6.8 Hz, 1 H), 6.90 (d, J = 8.4 Hz, 1
H), 7.00 (s, 1 H), 7.06 (t, J = 7.6 Hz, 1 H), 7.13 (d, J = 7.6 Hz, 1 H),
7.20 (m, 2 H), 7.28 (d, J = 8.4 Hz, 1 H), 7.47 (d, J = 7.6 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 32.9, 35.8, 69.0, 78.3, 109.4,
112.1, 112.2, 117.5, 119.3, 121.1, 122.1, 126.8, 127.1, 127.7, 128.6,
129.2, 133.1, 137.3, 155.9.
ESI-MS (LCQ): m/z = 337 [M + 1].
Anal. Calcd for C20H20N2O3 (336.15): C, 71.41; H, 5.99; N, 8.33.
Found: C, 71.52; H, 5.95; N, 8.27.
Figure 2 ORTEP diagram of compound 7e
3-[1-(2-Allyloxyphenyl)-2-nitroethyl]-2-methyl-1H-indole (6b)
Yield: 88%; viscous liquid; Rf = 0.24 (20% EtOAc–PE).
Furthermore, the advantage of this method is the utiliza-
tion of di-tert-butyl dicarbonate, which allows the reac-
tion to be carried out with substrates containing NH IR (film): 1124, 1248, 1382, 1468, 1557, 1689, 2364, 2917, 3059
cm–1.
groups without requiring protecting groups, thus leading
1H NMR (500 MHz, CDCl3): d = 2.38 (s, 3 H), 4.59–4.61 (m, 2 H),
5.11–5.15 (m, 1 H), 5.23–5.27 (m, 1 H), 5.30 (d, J = 10.7 Hz, 1 H),
5.51 (dd, J = 9.9, 5.3 Hz, 1 H), 5.54 (d, J = 16 Hz, 1 H), 6.04–6.10
(m, 1 H), 6.88 (d, J = 7.6 Hz, 2 H), 7.06 (t, J = 7.6 Hz, 1 H), 7.11
(t, J = 7.6 Hz, 1 H), 7.20–7.25 (m, 2 H), 7.35 (d, J = 8.4 Hz, 1 H),
7.55 (d, J = 7.6 Hz, 1 H), 7.87 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 12.2, 35.8, 69.0, 77.7, 108.0,
110.8, 111.9, 117.7, 119.0, 119.7, 120.8, 121.1, 127.5, 127.6, 128.5,
128.7, 133.1, 133.4, 135.5, 155.9.
the INOC reaction to N-Boc products (Table 3, entries 2,
5, and 9).
In summary, we have demonstrated the first stereoselec-
tive synthesis of isoxazolinobenzoxepanes through in-
tramolecular nitrile oxide-alkene cycloaddition (INOC) of
nitroalkenes derived from Michael addition of indoles to
b-nitrostyrenes possessing O-allyloxy groups by utilizing
(Boc)2O and DMAP. High trans-diastereoselectivity (up
to 92%) was observed in the formation of isoxazolino-
benzoxepanes. A study on the further investigation of this
method to synthesize novel heterocyclic compounds by
using different nucleophiles is underway.
ESI-MS (LCQ): m/z = 337 [M + 1].
Anal. Calcd for C20H20N2O3 (336.15): C, 71.41; H, 5.99; N, 8.33.
Found: C, 71.52; H, 5.95; N, 8.42.
3-[1-(2-Allyloxyphenyl)-2-nitroethyl]-1-ethyl-1H-indole (6c)
Yield: 90%; light yellow solid; mp 58–60 °C; Rf = 0.21 (20%
EtOAc–PE).
IR (KBr): 1008, 1235, 1462, 1550, 2926, 3055 cm–1.
All the substituted salicylaldehydes, allyl bromide, propargyl bro-
mide, DMAP, (Boc)2O, indoles, CDCl3, and DMSO-d6 were pur-
chased from Aldrich Chemicals. Petroleum ether (PE) used refers to
Synthesis 2011, No. 20, 3277–3286 © Thieme Stuttgart · New York

3282
K. Ramachandiran et al.
PAPER
1H NMR (500 MHz, CDCl3): d = 1.45 (t, J = 6.9 Hz, 3 H), 4.14 (q,
J = 6.8 Hz, 2 H), 4.62–4.46 (m, 2 H), 4.99 (dd, J = 12.2, 9.2 Hz, 1
H), 5.09 (dd, J = 12.2, 6.8 Hz, 1 H), 5.32 (d, J = 10.7 Hz, 1 H), 5.01
(dd, J = 16.05, 1.5 Hz, 1 H), 5.63 (t, J = 8.4 Hz, 1 H), 6.07–6.13 (m,
1 H), 6.85 (t, J = 7.6 Hz, 1 H), 6.91 (d, J = 8.4 Hz, 1 H), 7.05 (t,
J = 7.6 Hz, 1 H), 7.08 (s, 1 H), 7.13–7.15 (m, 1 H), 7.19–7.23 (m, 2
H), 7.32 (d, J = 8.4 Hz, 1 H), 7.48 (d, J = 8.4 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 15.6, 36.1, 41.1, 68.9, 78.3, 109.5,
112.1, 112.2, 117.5, 119.2, 119.4, 121.1, 121.9, 125.1, 127.2, 127.7,
128.6, 129.3, 133.1, 136.3, 155.9.
Anal. Calcd for C23H26N2O4 (354.19): C, 70.03; H, 6.64; N, 7.10.
Found: C, 70.16; H, 6.69; N, 7.21.
3-[1-(2-Allyloxy-3-methoxymethylphenyl)-2-nitroethyl]-
1-methyl-1H-indole (6g)
Yield: 85%; viscous liquid; Rf = 0.23 (20% EtOAc–PE).
IR (film): 1199, 1275, 1469, 1551, 2355, 2927, 2989, 3055 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.46 (t, J = 6.9 Hz, 3 H), 3.73 (s,
3 H), 4.06 (q, J = 7.0 Hz, 2 H), 4.53–4.62 (m, 2 H), 5.0 (d, J = 7.6
Hz, 2 H), 5.25 (d, J = 9.2 Hz, 1 H) 5.40 (dd, J = 16.8, 1.5 Hz, 1 H),
5.62 (t, J = 7.6 Hz, 1 H), 6.13–8.18 (m, 1 H), 6.78–6.82 (m, 2 H),
6.91–6.96 (m, 2 H), 7.06 (t, J = 6.9 Hz, 1 H), 7.21 (t, J = 7.6 Hz, 1
H), 7.26 (t, J = 6.8 Hz, 1 H), 7.51 (d, J = 7.6 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 15.1, 32.9, 35.7, 64.2, 74.0, 78.6,
109.4, 112.6, 117.8, 119.3, 120.1, 122.1, 124.1, 126.6, 126.9, 133.2,
134.4, 137.3, 145.8, 152.3.
ESI-MS (LCQ): m/z = 351 [M + 1].
Anal. Calcd for C21H22N2O3 (350.16): C, 71.98; H, 6.33; N, 7.99.
Found: C, 72.07; H, 6.37; N, 7.87.
3-[1-(2-(Allyloxyphenyl)-2-nitroethyl]-1-benzyl-1H-indole (6d)
Yield: 62%; viscous liquid; Rf = 0.21 (20% EtOAc–PE).
1H NMR (500 MHz, CDCl3): d = 4.64 (m, 2 H), 5.01 (dd, J = 12.2,
9.1 Hz, 1 H), 5.12 (dd, J = 13.0, 6.9 Hz, 1 H), 5.30 (s, 2 H), 5.32 (dd,
J = 10.7, 1.5 Hz, 1 H), 5.50 (dd, J = 17.6, 1.5 Hz, 1 H), 5.67 (dd,
J = 9.2, 6.9 Hz, 1 H), 6.08 (m, 1 H), 6.88 (t, J = 7.6 Hz, 1 H), 6.93
(d, J = 8.4 Hz, 1 H), 7.07–7.12 (m, 4 H), 7.17–7.20 (m, 2 H), 7.22–
7.34 (m, 5 H), 7.53 (d, J = 7.6 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 36.1, 50.2, 69.0, 78.3, 110.1,
112.2, 113.0, 117.5, 119.5, 119.7, 121.1, 122.4, 126.3, 126.8, 127.8,
128.7, 128.9, 129.3, 133.1, 136.8, 137.5, 156.0.
ESI-MS (LCQ): m/z = 381 [M + 1].
Anal. Calcd for C22H24N2O4 (380.17): C, 69.46; H, 6.36; N, 7.36.
Found: C, 69.57; H, 6.38; N, 7.44.
3-[1-(2-Allyloxy-5-bromophenyl)-2-nitroethyl]-1-methyl-1H-
indole (6h)
Yield: 82%; colorless solid; mp 148–150 °C; Rf = 0.17 (20%
EtOAc–PE)
IR (KBr): 1018, 1203, 1283, 1385, 1385, 1418, 1645, 2907, 3048
cm–1.
3-[1-(2-Allyloxy-3-methoxymethylphenyl)-2-nitroethyl]-
2-methyl-1H-indole (6e)
Yield: 85%; colorless solid; mp 125–127 °C; Rf = 0.18 (20%
EtOAc–PE).
1H NMR (500 MHz, CDCl3): d = 2.41 (s, 3 H), 4.53–4.57 (m, 2 H),
5.08 (dd, J = 9.9 Hz, 1 H), 5.17 (dd, J = 13.0 Hz, 1 H), 5.30 (d,
J = 10.7 Hz, 1 H), 5.4 (dd, J = 16.8, 1.5 Hz, 1 H), 5.42–5.47 (m, 1
H), 5.99–6.04 (m, 1 H), 6.73 (d, J = 8.4 Hz, 1 H), 7.06–7.13 (m, 2
H), 7.26–7.30 (m, 2 H), 7.41 (d, J = 2.3 Hz, 1 H), 7.49 (d, J = 7.6
Hz, 1 H), 7.89 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 12.4, 35.6, 69.3, 107.4, 110.8,
113.2, 113.6, 118.1, 118.7, 119.9, 121.4, 127.2, 129.9, 131.2, 131.5,
132.6, 133.4, 135.4, 154.9.
IR (KBr): 1148, 1236, 1339, 1421, 1692, 2847, 2913, 3055 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.43 (t, J = 6.8 Hz, 3 H), 2.39 (s,
3 H), 4.04 (q, J = 7.6 Hz, 2 H), 4.38 (dd, J = 11.4, 5.3 Hz, 1 H), 4.62
(dd, J = 6.1, 12.2 Hz, 1 H), 5.05–5.09 (m, 1 H), 5.19–5.25 (m, 2 H),
5.35 (dd, J = 15.2, 1.5 Hz, 1 H), 5.49 (dd, J = 6.8, 9.9 Hz, 1 H),
6.10–6.15 (m, 1 H), 6.81–6.82 (m, 1 H), 6.93–6.99 (m, 2 H), 7.03 (t,
J = 6.9 Hz, 1 H), 7.07 (t, J = 6.9 Hz, 1 H), 7.24 (t, J = 7.6 Hz, 1 H),
7.53 (d, J = 7.6 Hz, 1 H), 7.85 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 12.3, 15.1, 35.6, 64.2, 73.9, 77.9,
108.3, 110.7, 112.6, 118.1, 119.6, 119.9, 121.1, 123.8, 127.3, 133.2,
134.4, 135.4, 145.8, 152.1, 163.1.
ESI-MS (LCQ): m/z = 415 [M + 1].
Anal. Calcd for C20H19BrN2O3 (414.06): C, 57.84; H, 4.61; N, 6.75.
Found: C, 57.93; H, 4.65; N, 6.82.
3-[1-(2-Allyloxy-5-bromophenyl)-2-nitroethyl]-2-methyl-1H-
indole (6i)
Yield: 90%; viscous liquid; Rf = 0.36 (20% EtOAc–PE).
ESI-MS (LCQ): m/z = 381 [M + 1].
Anal. Calcd for C22H24N2O4 (380.17): C, 69.46; H, 6.36; N, 7.36.
Found: C, 69.53; H, 6.39; N, 7.43.
IR (film): 1021, 1208, 1291, 1386, 1413, 1645, 2907 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.77 (s, 3 H), 4.61–4.63 (m, 2 H),
4.93–5.01 (m, 2 H), 5.33 (d, J = 10.7 Hz, 1 H), 5.48 (dd, J = 17.6,
1.5 Hz, 1 H), 5.60 (t, J = 6.8 Hz, 1 H), 6.05–6.08 (m, 1 H), 6.78 (d,
J = 8.4 Hz, 1 H), 7.00 (s, 1 H), 7.07 (t, J = 7.6 Hz, 1 H), 7.20–7.24
(m, 2 H), 7.28–7.30 (m, 2 H), 7.44 (d, J = 8.4 Hz, 1 H).
3-[1-(2-Allyloxy-3-ethoxyphenyl)-2-nitroethyl]-1-ethyl-1H-in-
dole (6f)
Yield: 91%; colorless solid; mp 97–99 °C; Rf = 0.23 (20% EtOAc–
PE).
13C NMR (125 MHz, CDCl3): d = 33.0, 35.3, 69.3, 78.0, 109.6,
111.5, 113.4, 113.9, 117.9, 119.1, 119.5, 122.3, 126.6, 126.9, 130.2,
131.4, 131.9, 132.6, 137.3, 154.9.
IR (KBr): 1091, 1273, 1376, 1468, 1551, 2360, 2929, 2978 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.41–1.48 (m, 6 H), 4.06 (q,
J = 7.6 Hz, 2 H), 4.12 (q, J = 7.6 Hz, 2 H), 4.53–4.61 (m, 2 H), 5.0
(d, J = 7.6 Hz, 2 H), 5.25 (d, J = 9.2 Hz, 1 H), 5.39 (d, J = 15.3 Hz,
1 H), 5.62 (t, J = 8.4 Hz, 1 H), 6.12–6.17 (m, 1 H), 6.78–6.82 (m, 2
H), 6.95 (t, J = 8.4 Hz, 1 H), 6.98 (s, 1 H), 7.05 (t, J = 7.6 Hz, 1 H),
7.19 (t, J = 8.4 Hz, 1 H), 7.30 (d, J = 8.4 Hz, 1 H), 7.5 (d, J = 7.6
Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 15.1, 15.6, 35.8, 41.1, 64.2, 73.9,
78.6, 109.5, 112.5, 112.7, 117.7, 119.3, 119.4, 120.2, 121.9, 124.1,
124.9, 127.1, 133.2, 134.4, 136.3, 145.8, 152.3.
ESI-MS (LCQ): m/z = 415 [M + 1].
Anal. Calcd for C20H19BrN2O3 (414.06): C, 57.84; H, 4.61; N, 6.75.
Found: C, 57.93; H, 4.65; N, 6.83.
3-[1-(2-Allyloxy-5-bromophenyl)-2-nitroethyl]-1-ethyl-1H-in-
dole (6j)
Yield: 84%; viscous liquid; Rf = 0.23 (20% EtOAc–PE).
IR (film): 1010, 1124, 1244, 1376, 1481, 1547, 2926, 2974 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.46 (t, J = 6.9 Hz, 3 H), 4.15 (q,
J = 7.6 Hz, 2 H), 4.58–4.64 (m, 2 H), 4.95 (dd, J = 14.2, 9.2 Hz, 1
ESI-MS (LCQ): m/z = 395 [M + 1].
Synthesis 2011, No. 20, 3277–3286 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of Isoxazolinobenzoxepanes
3283
H), 5.02 (dd, J = 13.0, 6.8 Hz, 1 H), 5.33 (d, J = 10.7 Hz, 1 H), 5.47
(d, J = 18.3 Hz, 1 H), 5.59 (t, J = 7.6 Hz, 1 H), 6.04–6.12 (m, 1 H),
6.77 (dd, J = 9.15 Hz, 1 H), 7.06–7.09 (m, 2 H), 7.20–7.23 (m, 2 H),
7.28–7.34 (m, 2 H), 7.46 (d, J = 7.6 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 15.5, 35.6, 41.2, 69.3, 78.1, 109.7,
111.5, 113.4, 113.9, 117.9, 119.1, 119.4, 122.1, 124.9, 127.1, 130.2,
131.4, 131.9, 132.6, 136.3, 155.1.
(m, 2 H), 5.60 (s, 1 H), 6.55 (s, 1 H), 7.11–7.14 (m, 3 H), 7.23 (t,
J = 8.4 Hz, 1 H), 7.28–7.35 (m, 3 H), 7.72 (d, J = 7.6 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 15.5, 41.1, 41.5, 50.3, 70.5, 73.3,
109.5, 112.2, 119.4, 119.6, 121.9, 122.8, 125.0, 126.8, 126.9, 129.1,
131.5, 136.3, 159.1, 159.7.
ESI-MS (LCQ): m/z = 333 [M + 1].
Anal. Calcd for C21H20N2O2 (323.4): C, 75.88; H, 6.06; N, 8.43.
Found: C, 75.96; H, 6.09; N, 8.35.
ESI-MS (LCQ): m/z = 429 [M + 1].
Anal. Calcd for C21H21BrN2O3 (428.107): C, 58.75; H, 4.93; N,
6.53. Found: C, 58.85; H, 4.96; N, 6.62.
trans-4-(1-Benzyl-1H-indol-3-yl)-10,10a-dihydro-1H,4H-2,9-di-
oxa-3-azabenzo[f]azulene (trans-7d)
trans-4-(1-Methyl-1H-indol-3-yl)-10,10a-dihydro-1H,4H-2,9-
dioxa-3-azabenzo[f]azulene (trans-7a) and cis-4-(1-Methyl-1H-
indol-3-yl)-10,10a-dihydro-1H,4H-2,9-dioxa-3-azabenzo[f]azu-
lene (cis-8a); Typical Procedure
The nitroalkane 6a (336 mg, 1.0 mmol) and DMAP (24 mg, 0.2
mmol) were dissolved in toluene (5 mL). Di-tert-butyl dicarbonate
(545 mg, 2.5 mmol) in toluene (5 mL) was added in portions over a
period of 0.5 h at 90 °C to the nitroalkane solution and the reaction
was allowed to proceed for a further 2 h. The mixture was evaporat-
ed and the products 7a and 8a were purified by column chromatog-
raphy using EtOAc–PE (2:8) as eluent; yield of diastereomeric
mixture: 270 mg (85%) (Table 3).
Viscous liquid; Rf = 0.23 (20% EtOAc–PE).
IR (film): 1016, 1237, 1478, 1613, 1715, 2879, 2931, 3056 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.71–3.76 (m, 2 H), 3.94–3.97 (m,
1 H), 4.37–4.41 (m, 2 H), 5.21 (s, 2 H), 5.62 (s, 1 H), 6.99 (d, J = 6.8
Hz, 2 H), 7.09–7.14 (m, 3 H), 7.17–7.19 (m, 1 H), 7.21–7.23 (m, 1
H), 7.25–7.27 (m, 5 H), 7.35 (t, J = 6.9 Hz, 1 H), 7.73 (d, J = 7.6
Hz, 1 H).
ESI-MS (LCQ): m/z = 395 [M + 1].
Anal. Calcd for C26H22N2O2 (394.17): C, 79.16; H, 5.62; N, 10.0.
Found: C, 79.25; H, 5.67; N, 10.11.
trans-3-(8-Ethoxy-10,10a-dihydro-1H,4H-2,9-dioxa-3-azaben-
zo[f]azulen-4-yl)-2-methylindole-1-carboxylic Acid tert-Butyl
Ester (trans-7e)
trans-7a
Yellow solid; mp 118 °C; Rf = 0.21 (20% EtOAc–PE).
IR (KBr): 1014, 1241, 1417, 1732, 1928, 2956, 3055 cm–1.
Colorless solid; mp 158 °C; Rf = 0.12 (20% EtOAc–PE).
1H NMR (500 MHz, CDCl3): d = 3.67 (s, 3 H), 3.73–3.76 (m, 2 H),
3.93–3.96 (m, 1 H), 4.36–4.39 (m, 2 H), 5.60 (s, 1 H), 6.50 (s, 1 H),
7.12–7.16 (m, 3 H), 7.26 (t, J = 6.1 Hz, 1 H), 7.28–7.31 (m, 2 H),
7.34–7.36 (m, 1 H), 7.73 (d, J = 8.4 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 32.9, 41.5, 50.3, 70.5, 73.4, 109.4,
112.2, 119.2, 119.6, 122.1, 122.9, 125.0, 126.8, 128.4, 129.1, 131.0,
131.5, 137.4, 159.1, 159.7.
IR (KBr): 1072, 1162, 1354, 1469, 1580, 1730, 2934, 2979, 3050
cm–1.
1H NMR (500 MHz, CDCl3): d = 1.46 (t, J = 6.9 Hz, 3 H), 1.68 (s,
9 H), 2.52 (s, 3 H), 3.72–3.76 (m, 1 H), 4.06–4.17 (m, 4 H), 4.36
(dd, J = 9.9, 8.4 Hz, 1 H), 4.48 (dd, J = 10.7, 6.1 Hz, 1 H), 5.76 (s,
1 H), 6.60 (d, J = 6.9 Hz, 1 H), 6.88 (d, J = 6.9 Hz, 1 H), 6.93 (t,
J = 8.4 Hz, 1 H), 7.05–7.12 (m, 2 H), 7.20 (t, J = 7.6 Hz, 1 H), 8.14
(d, J = 8.4 Hz, 1 H).
ESI-MS (LCQ): m/z = 319 [M + 1].
13C NMR (125 MHz, CDCl3): d = 14.4, 15.0, 28.4, 38.6, 50.1, 64.7,
71.5, 71.9, 84.1, 113.1, 115.1, 115.5, 119.1, 121.7, 122.6, 123.5,
124.8, 128.8, 132.2, 135.5, 136.1, 146.5, 150.6, 151.9, 160.2.
Anal. Calcd for C20H18N2O2 (318.14): C, 75.45; H, 5.70; N, 8.80.
Found: C, 75.54; H, 5.79; N, 8.92.
trans-3-(10,10a-Dihydro-1H,4H-2,9-dioxa-3-azabenzo[f]azu-
len-4-yl)-2-methylindole-1-carboxylic Acid tert-Butyl Ester
(trans-7b)
ESI-MS (LCQ): m/z = 463 [M + 1].
Anal. Calcd for C27H30N2O5 (462.22): C, 70.11; H, 6.54; N, 6.06.
Found: C, 70.13; H, 6.52; N, 6.15.
Viscous liquid; Rf = 0.27 (20% EtOAc–PE).
IR (film): 1109, 1352, 1487, 1711, 2212, 1878, 2929, 3057 cm–1.
trans-8-Ethoxy-4-(1-ethyl-1H-indol-3-yl)-10,10a-dihydro-
1H,4H-2,9-dioxa-3-azabenzo[f]azulene (trans-7f)
Viscous liquid; Rf = 0.23 (20% EtOAc–PE).
1H NMR (500 MHz, CDCl3): d = 1.68 (s, 9 H), 2.51 (s, 3 H), 3.66–
3.73 (m, 1 H), 4.03 (dd, J = 11.4, 7.6 Hz, 1 H), 4.14 (t, J = 8.4 Hz,
1 H), 4.39–4.44 (m, 2 H), 5.75 (s, 1 H), 7.02–7.05 (m, 3 H), 7.11 (d,
J = 8.4 Hz, 2 H), 7.18–7.21 (m, 1 H), 7.25–7.28 (m, 1 H), 8.12 (d,
J = 8.4 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 14.3, 28.4, 39.3, 50.1, 71.6, 72.1,
84.2, 114.8, 115.4, 119.1, 122.6, 122.7, 123.5, 124, 129.1, 129.8,
131.1, 135.6, 135.9, 150.6, 157.8, 159.9.
IR (film): 1196, 1266, 1469, 1581, 1735, 2249, 2879, 2931, 2976
cm–1.
1H NMR (500 MHz, CDCl3): d = 1.44–1.50 (m, 6 H), 3.67 (t,
J = 10.7 Hz, 1 H), 3.75 (t, J = 10.7 Hz, 1 H), 3.91–4.15 (m, 13 H),
4.16–4.21 (m, 4 H), 4.31–4.40 (m, 2 H), 4.41 (dd, J = 11.5, 5.3 Hz,
1 H), 4.63–4.67 (m, 2 H), 5.58 (s, 1 H), 5.66 (s, 1 H), 6.49 (d, J = 7.6
Hz, 1 H), 6.71 (s, 1 H), 6.79–6.87 (m, 2 H), 6.92 (t, J = 8.4 Hz, 1
H), 7.01–7.05 (m, 2 H), 7.15 (t, J = 7.6 Hz, 1 H), 7.17–7.25 (m, 3
H), 7.31 (d, J = 7.6 Hz, 1 H), 7.35 (d, J = 8.4 Hz, 1 H), 7.40 (d,
J = 7.6 Hz, 1 H), 7.64 (s, 1 H), 7.74 (d, J = 7.6 Hz, 1 H).
ESI-MS (LCQ): m/z = 419 [M + 1].
Anal. Calcd for C25H26N2O4 (418.19): C, 71.75; H, 6.26; N, 6.69.
Found: C, 71.83; H, 6.29; N, 6.61.
13C NMR (125 MHz, CDCl3): d = 15.0, 15.6, 15.7, 37.7, 41.1, 41.5,
50.2, 53.2, 64.5, 64.6, 69.9, 70.3, 73.7, 74.0, 109.4, 109.5, 110.1,
112.5, 112.8, 119.1, 119.3, 119.4, 109.5, 110.1, 112.5, 112.8, 119.1,
119.4, 119.6, 120.1, 121.5, 121.7, 122.6, 125.0, 125.1, 127.0, 127.2,
127.8, 128.4, 134.8, 135.8, 136.2, 139.5, 147.0, 148.5, 151.2, 151.4,
159.3, 159.7.
trans-4-(1-Ethyl-1H-indol-3-yl)-10,10a-dihydro-1H,4H-2,9-di-
oxa-3-azabenzo[f]azulene (trans-7c)
Viscous liquid; Rf = 0.23 (20% EtOAc–PE).
IR (film): 1014, 1210, 1470, 1613, 1713, 2876, 2931, 3056 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.36 (t, J = 6.9 Hz, 3 H), 3.72–
3.78 (m, 2 H), 3.93–3.96 (m, 1 H), 4.03–4.08 (m, 2 H), 4.35–4.38
ESI-MS (LCQ): m/z = 377 [M + 1].
Synthesis 2011, No. 20, 3277–3286 © Thieme Stuttgart · New York

3284
K. Ramachandiran et al.
PAPER
Anal. Calcd for C23H24N2O3 (323.4): C, 73.38; H, 6.43; N, 7.44.
Found: C, 73.45; H, 6.47; N, 7.35.
7.22 (t, J = 6.8 Hz, 1 H), 7.29 (dd, J = 8.4, 2.3 Hz, 1 H), 7.37 (t,
J = 7.6 Hz, 2 H), 7.65 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 15.6, 41.2, 50.1, 70.6, 73.4, 109.6,
111.5, 117.3, 119.2, 119.7, 122.1, 124.7, 126.6, 126.8, 131.9, 133.1,
134.1, 136.3, 158.2, 159.1.
trans-8-Ethoxy-4-(1-methyl-1H-indol-3-yl)-10,10a-dihydro-
1H,4H-2,9-dioxa-3-azabenzo[f]azulene (trans-7g)
Colorless solid; mp 101 °C; Rf = 0.14 (20% EtOAc–PE).
IR (KBr): 1012, 1269, 1584, 1476, 1725, 1288, 3054 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.48 (t, J = 6.8 Hz, 3 H), 3.80 (s,
3 H), 3.96–3.97 (m, 2 H), 4.09–4.15 (m, 3 H), 4.34–4.37 (m, 1 H),
4.64 (dd, J = 11.4, 6.1 Hz, 1 H), 5.65 (s, 1 H), 6.55 (d, J = 7.6 Hz,
1 H), 6.82 (d, J = 6.9 Hz, 1 H), 6.87 (t, J = 8.4 Hz, 1 H), 6.94 (t,
J = 8.4 Hz, 1 H), 7.05–7.08 (m, 1 H), 7.33 (d, J = 8.4 Hz, 1 H), 7.46
(d, J = 8.4 Hz, 1 H), 7.57 (s, 1 H).
13C NMR (125 MHz, CDCl3): d = 15.1, 32.9, 37.8, 52.9, 64.5, 70.1,
107.6, 109.4, 110.3, 112.6, 119.2, 120.2, 121.7, 125.0, 127.6, 128.8,
129.9, 134.8, 136.8, 146.9, 151.6, 159.5.
ESI-MS (LCQ): m/z = 411 [M + 1].
Anal. Calcd for C21H19BrN2O2 (410.06): C, 61.32; H, 4.66; N, 6.81.
Found: C, 61.43; H, 4.64; N, 6.92.
cis-4-(1-Methyl-1H-indol-3-yl)-10,10a-dihydro-1H,4H-2,9-di-
oxa-3-azabenzo[f]azulene (cis-8a)
Colorless solid; mp 120–122 °C; Rf = 0.16 (20% EtOAc–PE).
1H NMR (500 MHz, CDCl3): d = 3.73 (s, 3 H), 3.76–3.79 (m, 2 H),
3.91–3.95 (m, 1 H), 4.39–4.42 (m, 2 H), 5.93 (s, 1 H), 6.54 (d,
J = 7.6 Hz, 1 H), 7.14–7.18 (m, 3 H), 7.28 (t, J = 6.2 Hz, 1 H), 7.24–
7.27 (m, 2 H), 7.36–7.39 (m, 1 H), 7.79 (d, J = 8.4 Hz, 1 H).
ESI-MS (LCQ): m/z = 363 [M + 1].
13C NMR (125 MHz, CDCl3): d = 32.8, 41.9, 50.9, 70.7, 73.2, 109.7,
112.2, 119.3, 119.3, 119.7, 122.1, 122.8, 125.1, 126.8, 128.6, 129.2,
131.1, 131.6, 137.4, 159.2, 159.8.
Anal. Calcd for C22H22N2O3 (362.16): C, 72.91; H, 6.12; N, 7.73.
Found: C, 72.98; H, 6.15; N, 7.82.
ESI-MS (LCQ): m/z = 319 [M + 1].
trans-6-Bromo-4-(1-methyl-1H-indol-3-yl)-10,10a-dihydro-
1H,4H-2,9-dioxa-3-azabenzo[f]azulene (trans-7h)
Light yellow solid; mp 148 °C; Rf = 0.17 (20% EtOAc–PE).
Anal. Calcd for C20H18N2O2 (318.14): C, 75.45; H, 5.70; N, 8.80.
Found: C, 75.49; H, 5.72; N, 8.87.
IR (KBr): 1094, 1232, 1417, 1732, 2946, 3055 cm–1.
cis-3-(10,10a-Dihydro-1H,4H-2,9-dioxa-3-azabenzo[f]azulen-4-
yl)-2-methylindole-1-carboxylic Acid tert-Butyl Ester (cis-8b)
Viscous liquid; Rf = 0.17 (20% EtOAc–PE).
IR (film): 1362, 1481, 1712, 2212, 1878, 2923, 3061 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.68 (s, 9 H), 2.59 (s, 3 H), 3.91–
3.98 (m, 1 H), 4.06–4.13 (m, 2 H), 4.49–4.55 (m, 2 H), 5.45 (s, 1 H),
6.93 (t, J = 7.6 Hz, 1 H), 7.03 (d, J = 7.6 Hz, 1 H), 7.07–7.12 (m, 2
H), 7.16–7.21 (m, 2 H), 7.36 (d, J = 8.4 Hz, 1 H), 8.11 (d, J = 8.4
Hz, 1 H).
1H NMR (500 MHz, CDCl3): d = 3.69 (s, 3 H), 3.70–3.72 (m, 2 H),
3.94–3.97 (m, 1 H), 4.36–4.39 (m, 2 H), 5.55 (s, 1 H), 6.52 (s, 1 H),
7.10 (d, J = 8.4 Hz, 1 H), 7.15 (t, J = 6.85 Hz, 1 H), 7.24–7.31 (m,
2 H), 7.38 (dd, J = 8.4, 2.3 Hz, 1 H), 7.48 (d, J = 2.3 Hz, 1 H), 7.70
(d, J = 8.4 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 32.9, 41.1, 50.1, 70.6, 73.4, 109.5,
111.5, 117.3, 119.1, 119.7, 122.2, 124.8, 126.6, 128.3, 131.9, 133.1,
134.0, 137.4, 158.2, 159.1.
ESI-MS (LCQ): m/z = 397 [M + 1].
13C NMR (125 MHz, CDCl3): d = 15.3, 28.4, 38.1, 52.5, 71.8, 72.7,
83.8, 115.4, 116.1, 120.4, 122.4, 123.5, 124.6, 128.7, 129.1, 130.1,
130.4, 135.2, 135.8, 150.8, 158.3, 158.6.
Anal. Calcd for C20H17BrN2O2 (396.05): C, 60.47; H, 4.31; N, 7.05.
Found: C, 60.45; H, 4.39; N, 7.11.
ESI-MS (LCQ): m/z = 419 [M + 1].
trans-3-(6-Bromo-10,10a-dihydro-1H,4H-2,9-dioxa-3-azaben-
zo[f]azulen-4-yl)-2-methylindole-1-carboxylic Acid tert-Butyl
Ester (trans-7i)
Anal. Calcd for C25H36N2O4 (418.19): C, 71.75; H, 6.26; N, 6.69.
Found: C, 71.83; H, 6.29; N, 6.61.
Yellow solid; mp 94 °C; Rf = 0.32 (20% EtOAc–PE).
IR (KBr): 1104, 1341, 1490, 1703, 2207, 2852, 2922, 3087 cm–1.
cis-4-(1-Ethyl-1H-indol-3-yl)-10,10a-dihydro-1H,4H-2,9-dioxa-
3-azabenzo[f]azulene (cis-8c)
Viscous liquid; Rf = 0.18 (20% EtOAc–PE).
1H NMR (500 MHz, CDCl3): d = 1.66 (s, 9 H), 2.53 (s, 3 H), 3.66–
3.71 (m, 1 H), 4.02 (dd, J = 11.4, 7.6 Hz, 1 H), 4.13 (t, J = 7.6 Hz,
1 H), 4.38–4.42 (m, 2 H), 5.70 (s, 1 H), 6.98–7.00 (d, J = 6.1 Hz, 1
H), 7.07–7.09 (m, 2 H), 7.19–7.23 (m, 2 H), 7.36 (dd, J = 8.4, 2.3
Hz, 1 H), 8.12 (d, J = 8.4 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 14.4, 28.4, 39.1, 49.8, 71.7, 72.2,
84.3, 114.1, 115.5, 117.4, 118.8, 122.8, 123.7, 124.4, 128.2, 131.9,
132.1, 133.6, 135.8, 135.9, 157.0, 159.2.
1H NMR (500 MHz, CDCl3): d = 1.39 (t, J = 6.9 Hz, 3 H), 3.76–3.79
(m, 2 H), 3.98–4.01 (m, 1 H), 4.03–4.08 (m, 2 H), 4.33–4.36 (m, 2
H), 5.91 (s, 1 H), 6.59 (s, 1 H), 7.18–7.21 (m, 3 H), 7.25–7.33 (m, 4
H), 7.73 (d, J = 7.6 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 15.7, 41.2, 41.5, 50.3, 70.5, 73.4,
109.9, 112.5, 119.5, 119.6, 121.9, 122.8, 125.1, 126.9, 126.9, 129.2,
131.4, 136.3, 159.2, 159.8.
ESI-MS (LCQ): m/z = 497 [M + 1].
ESI-MS (LCQ): m/z = 333 [M + 1].
Anal. Calcd for C25H25BrN2O4 (496.10): C, 60.37; H, 5.07; N, 5.63.
Found: C, 60.45; H, 5.09; N, 5.74.
Anal. Calcd for C21H20N2O2 (332.15): C, 75.88; H, 6.06; N, 8.43.
Found: C, 75.92; H, 6.09; N, 8.55.
trans-6-Bromo-4-(1-ethyl-1H-indol-3-yl)-10,10a-dihydro-
1H,4H-2,9-dioxa-3-azabenzo[f]azulene (trans-7j)
Colorless solid; mp 87–89 °C; Rf = 0.23 (20% EtOAc–PE).
IR (KBr): 1010, 2164, 1367, 1461, 1714, 2322, 2925 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.50 (t, J = 7.6 Hz, 3 H), 3.72–
3.76 (m, 1 H), 3.94–4.16 (m, 2 H), 4.20–4.25 (m, 2 H), 4.36–4.42
(m, 1 H), 4.57 (dd, J = 11.45, 6.1 Hz, 1 H), 5.61 (s, 1 H), 6.96 (d,
J = 8.4 Hz, 1 H), 7.01 (d, J = 2,3 Hz, 1 H), 7.05 (t, J = 8.4 Hz, 1 H),
cis-4-(1-Benzyl-1H-indol-3-yl)-10,10a-dihydro-1H,4H-2,9-di-
oxa-3-azabenzo[f]azulene (cis-8d)
Viscous liquid; Rf = 0.14 (20% EtOAc–PE).
1H NMR (500 MHz, CDCl3): d = 3.76–3.79 (m, 2 H), 3.97–4.03 (m,
1 H), 4.34–4.39 (m, 2 H), 5.32 (s, 2 H), 5.91 (s, 1 H), 6.55 (s, 1 H),
6.95 (d, J = 6.8 Hz, 2 H), 7.11–7.15 (m, 2 H), 7.17–7.22 (m, 2 H),
7.25–7.28 (m, 1 H), 7.27–7.30 (m, 5 H), 7.39 (t, J = 6.9 Hz, 1 H),
7.81 (d, J = 7.6 Hz, 1 H).
Synthesis 2011, No. 20, 3277–3286 © Thieme Stuttgart · New York

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Stereoselective Synthesis of Isoxazolinobenzoxepanes
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ESI-MS (LCQ): m/z = 395 [M + 1].
1H NMR (500 MHz, CDCl3): d = 1.68 (s, 9 H), 2.58 (s, 3 H), 3.87–
3.94 (m, 1 H), 4.05–4.13 (m, 2 H), 4.46–4.52 (m, 2 H), 5.38 (s, 1 H),
6.95 (d, J = 8.4 Hz, 1 H), 7.11–7.16 (m, 2 H), 7.19–7.23 (m, 2 H),
7.33 (d, J = 7.6 Hz, 1 H), 8.11 (d, J = 8.4 Hz, 1 H).
Anal. Calcd for C26H22N2O2 (394.17): C, 79.16; H, 5.62; N, 7.10.
Found: C, 79.09; H, 5.69; N, 7.15.
cis-3-(8-Ethoxy-10,10a-dihydro-1H,4H-2,9-dioxa-3-azaben-
zo[f]azulen-4-yl)-2-methylindole-1-carboxylic Acid tert-Butyl
Ester (cis-8e)
13C NMR (125 MHz, CDCl3): d = 15.4, 28.4, 38.1, 52.1, 72.1, 72.9,
84.1, 115.4, 115.5, 117.5, 119.8, 122.5, 123.6, 124.3, 128.6, 131.8,
132.5, 133.1, 135.4, 135.8, 157.3, 163.1.
Colorless solid; mp 176 °C; Rf = 0.1 (20% EtOAc–PE).
ESI-MS (LCQ): m/z = 497 [M + 1].
IR (KBr): 1071, 1168, 1357, 1472, 1585, 1732, 2936, 2969, 3055
cm–1.
Anal. Calcd for C25H25BrN2O4 (496.10): C, 60.37; H, 5.07; N, 5.63.
Found: C, 60.45; H, 5.09; N, 5.74.
1H NMR (500 MHz, CDCl3): d = 1.46 (t, J = 6.9 Hz, 3 H), 1.67 (s,
9 H), 2.61 (s, 3 H), 3.90–3.95 (m, 1 H), 4.06–4.15 (m, 4 H), 4.46 (t,
J = 9.9 Hz, 1 H), 4.55 (dd, J = 11.5, 6.9 Hz, 1 H), 5.44 (s, 1 H), 6.63
(d, J = 8.4 Hz, 1 H), 6.79 (d, J = 6.9 Hz, 1 H), 6.86 (t, J = 8.4 Hz,
1 H), 7.11 (t, J = 6.9 Hz, 1 H), 7.18 (t, J = 6.9 Hz, 1 H), 7.48 (d,
J = 7.6 Hz, 1 H ), 8.09 (d, J = 8.4 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 14.9, 15.3, 28.4, 38.3, 52.1, 64.6,
71.9, 72.9, 83.8, 112.4, 115.4, 116.3, 120.5, 121.7, 122.4, 123.4,
124.6, 128.9, 132.3, 134.9, 135.8, 147.2, 150.8, 151.8, 158.8.
cis-6-Bromo-4-(1-ethyl-1H-indol-3-yl)-10,10a-dihydro-1H,4H-
2,9-dioxa-3-azabenzo[f]azulene (cis-8j)
Colorless solid; mp 96 °C; Rf = 0.17 (20% EtOAc–PE).
IR (KBr): 1010, 2164, 1367, 1461, 1714, 2322, 2925 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.38, (t, J = 7.6 Hz, 3 H), 3.69–
3.74 (m, 2 H), 3.93–3.97 (m, 1 H), 4.04–4.09 (m, 2 H), 4.38–4.39
(m, 2 H), 5.54 (s, 1 H), 6.56 (s, 1 H), 7.01 (d, J = 8.4 Hz, 1 H), 7.13
(t, J = 6.8 Hz, 1 H), 7.24 (t, J = 7.6 Hz, 1 H), 7.32 (d, J = 8.4 Hz, 1
H), 7.37–7.39 (m, 1 H), 7.48 (d, J = 2.3 Hz, 1 H), 7.69 (d, J = 7.6
Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 15.6, 29.8, 41.2, 50.1, 70.5, 73.4,
109.6, 115.6, 117.4, 119.2, 119.7, 122.1, 124.7, 126.6, 126.8, 131.9,
133.1, 134.1, 136.3, 158.2, 159.1.
ESI-MS (LCQ): m/z = 463 [M + H]+.
Anal. Calcd for C27H30N2O5 (462.22): C, 72.46; H, 6.53; N, 3.13.
Found: C, 72.52; H, 6.58; N, 3.21.
cis-8-Ethoxy-4-(1-methyl-1H-indol-3-yl)-10,10a-dihydro-
1H,4H-2,9-dioxa-3-azabenzo[f]azulene (cis-8g)
Colorless solid; mp 108–110 °C; Rf = 0.11 (20% EtOAc–PE).
1H NMR (500 MHz, CDCl3): d = 1.42 (t, J = 6.8 Hz, 3 H), 3.79 (s,
3 H), 3.93–3.96 (m, 2 H), 4.08–4.15 (m, 2 H), 4.32–4.35 (m, 1 H),
4.45–4.48 (m, 2 H), 5.95 (s, 1 H), 6.59 (d, J = 7.6 Hz, 1 H), 6.85–
6.89 (m, 2 H), 6.95 (t, J = 8.4 Hz, 1 H), 7.08–7.11 (m, 1 H), 7.31 (d,
J = 8.4 Hz, 1 H), 7.40 (d, J = 8.4 Hz, 1 H), 7.59 (s, 1 H).
ESI-MS (LCQ): m/z = 411 [M + 1].
Anal. Calcd for C21H19BrN2O2 (410.29): C, 61.32; H, 4.66; N, 6.81.
Found: C, 61.45; H, 4.70; N, 6.92.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
13C NMR (125 MHz, CDCl3): d = 15.2, 32.8, 37.9, 52.9, 64.5, 70.1,
109.5, 110.3, 112.6, 119.3, 120.3, 121.8, 125.2, 127.9, 128.8, 129.8,
134.8, 136.7, 146.9, 151.5, 159.6.
Acknowledgment
The authors thank the Council of Scientific and Industrial Research
(CSIR), New Delhi, India, for research fellowships.
ESI-MS (LCQ): m/z = 363 [M + 1].
Anal. Calcd for C22H22N2O3 (362.16): C, 72.91; H, 6.12; N, 7.73.
Found: C, 72.83; H, 6.19; N, 7.85.
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IR (KBr): 1221, 1425, 1732, 2959, 3043 cm–1.
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K. Ramachandiran et al.
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Synthesis 2011, No. 20, 3277–3286 © Thieme Stuttgart · New York