Synthesis of benzo-fused medium ring cyclic ethers via a Michael addition-ring closing metathesis strategy involving nitroaliphatic compounds

Article abstract of DOI:10.1016/j.tet.2007.09.009

Nitroalkenes derived from O-protected salicylaldehyde undergo facile Michael-type addition of nucleophiles possessing unsaturated tether. Ring closing metathesis of the Michael adducts provides benzo-fused medium ring cyclic ethers possessing a nitroalkyl

Full text of DOI:10.1016/j.tet.2007.09.009

Tetrahedron 63 (2007) 11991–11997
Synthesis of benzo-fused medium ring cyclic ethers
via a Michael addition–ring closing metathesis
strategy involving nitroaliphatic compounds
*
Indubhusan Deb, Sumod John and Irishi N. N. Namboothiri
Department of Chemistry, Indian Institute of Technology, Powai, Mumbai 400 076, India
Received 17 June 2007; revised 19 August 2007; accepted 6 September 2007
Available online 11 September 2007
Abstract—Nitroalkenes derived from O-protected salicylaldehyde undergo facile Michael-type addition of nucleophiles possessing un-
saturated tether. Ring closing metathesis of the Michael adducts provides benzo-fused medium ring cyclic ethers possessing a nitroalkyl
functionality.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
HO
A large number of bioactive natural products possess func-
OH
O
tionalized medium-sized rings.1 Medium-sized oxacycles,2
in particular, constitute a common skeleton in many macro-
cycles,3 marine toxins,4 allelopathic agents,5 anticancer
compounds6 and other bioactive natural products.7 Although
various coupling,8 ring expansion/fragmentation,9 rear-
rangement10 and other miscellaneous methods11 are avail-
able in the literature, ring closing metathesis (RCM)12 is
obviously the method of choice to access medium-sized
oxacycles.13 However, synthesis of RCM precursors often
involves cumbersome multi-step reaction sequences.
O
Helianane
Heliannuol A
OH
HO
HO
O
O
O
Heliannuol H
Heliannuol K
Figure 1.
Benzo-fused medium ring oxacycles, in particular, are seen
in allelopathic natural products such as helianane,14 helian-
nuol A,15 heliannuol H, heliannuol K, etc. (Fig. 1).5 We re-
port here a facile and efficient synthesis of such oxacycles
based on the excellent Michael acceptor ability of conju-
gated nitroalkenes. In fact, Michael addition to nitroal-
kenes16 has emerged as a very useful and convenient
initiating step for the synthesis of more complex molecules
via enolate trapping and other inter- and intramolecular reac-
tions of the Michael adducts often involving the nitroalkyl
moiety.17–21 Our strategy relies on the ring closing metathe-
sis (RCM) of the Michael adducts arising from addition of
carbon and heteroatom centred nucleophiles possessing an
addition–RCM strategy has not been employed for the syn-
thesis of medium-sized rings until recently.22 Furthermore,
although Grubbs catalysts are well-known for their func-
tional group tolerance,23 there is only one report, to our
knowledge, which describes RCM of a substrate possessing
a nitroaliphatic moiety.22
2. Results and discussion
It was envisioned that cyclic ethers of type 1 possessing a ni-
troalkyl moiety would arise via ring closing metathesis of
a,u-diene 2 (Scheme 1). Diene 2, the key RCM precursor,
would be accessible via Michael-type addition of various
nucleophiles of type 3 possessing an unsaturated tether to
O-protected nitroarene 4. Aldehyde 5 would be a suitable
precursor to nitroarene 4 as the former can be subjected to
condensation with nitromethane (Henry reaction).17,24
unsaturated tether to nitroalkenes. Such
a Michael
Keywords: Medium ring ethers; Michael addition; Ring closing metathesis;
Nitro compounds.
* Corresponding author. E-mail: irishi@iitb.ac.in
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.09.009

11992
I. Deb et al. / Tetrahedron 63 (2007) 11991–11997
Table 1. Preparation of nitroalkenes 8 from O-protected salicylaldehydes
N
Cl
Cl
N
PCy3
Ru
PCy3
Mes
Mes
Ph
Cl
Cl
1. CH3NO2, Aq. NaOH
O-Protected salicylaldehyde
7
Nitroalkene
8
Ru
PCy3
Ph
2. 4N HCl
Nitroalkene 8, yielda (%)
G1
G2
Entry O-Protected salicylaldehyde 7
CHO
NO2
1
2
3
7a
7b
7c
8a
8b
8c
77
78
84
O
O
Our attempts to construct a 10-membered ring via RCM
of Michael adduct 10e using Grubbs catalyst G1 or G2
provided only traces of the desired product 11e (Table
2, entry 5). The RCM of vinyl ether 10f was also not fac-
ile under a variety of conditions using G1 and G2 (Table
2, entry 6).25
Br
CHO
O
Br
NO2
O
CHO
O
NO2
O
O
The benzo-fused medium ring cyclic ethers could be con-
structed via enyne metathesis as well. For instance, the prop-
argyl ethers 10g and 10h underwent RCM in the presence of
10 mol % of G1 to afford the dienes 11g and 11h, respec-
tively, in moderate yield (Table 2, entries 7 and 8).
CHO
NO2
4
7d
8d
82
O
a
Isolated yield after purification by silica gel column chromatography.
Having constructed eight- and nine-membered benzo-fused
cyclic ethers 11 via RCM of Michael adducts 10 arising
from addition of Grignard reagents 9 to nitroalkenes 8, we
turned our attention to generate novel functionalized me-
dium rings, including those possessing additional hetero-
atoms, via a similar strategy. The key RCM precursors,
e.g. 13, in this scheme could be prepared via conjugate addi-
tion of other nucleophiles possessing an unsaturated tether,
e.g. 12, to nitroalkenes 8 (Table 3). For instance, conjugate
addition of allyl malonate 12a to nitroalkene 8a provided
the adduct 13a in 70% yield (Table 3, entry 1). The Michael
adduct 13a underwent smooth RCM in the presence of
7 mol % of G1 providing the nine-membered cyclic ether
14a in 62% yield.
Thus, the nitroalkenes 8a–d were prepared in high yields
from their corresponding O-protected salicylaldehydes
7a–d via Henry reaction with nitromethane (Table 1, see
also Section 4).
NO2
NO2
YX
( )n
3
X
R
R
( )
( )
RCM
n
n
X
( )
O
2
m
O
( )m
NO2
1
R
R
R
CHO
OH
CHO
( )
O-protect
CH3NO2
base
Our Michael addition–RCM strategy has been employed to
construct benzo-fused medium ring ethers possessing an
additional heteroatom in the ring besides the nitroalkyl
side chain. Thus, conjugate addition of allyl alcohol 12b
and allyl mercaptan 12c provided the Michael adducts
13b–e in high yield (68–78%, Table 3, entries 2–5). Even
though Michael adduct 10f, derived from nitroalkene 8c
(Table 2, entry 6), was unreactive, we generated RCM pre-
cursors 13c and 13e from 8c (Table 3, entries 3 and 5) to
examine whether additional heteroatom in the chain would
facilitate ring closure. However, attempted RCM of Mi-
chael adducts 13c and 13e did not proceed (Table 3, entries
3 and 5).25 On the other hand, while Michael adduct 13b
provided only complex mixture (Table 3, entry 2), 13d
could be successfully cyclized to the nine-membered ring
containing both oxygen and sulfur 14d in 40% yield (Table
3, entry 4).
( )
m
m
O
O
4
5
6
Scheme 1.
Our initial experiment using o-allyloxynitrostyrene 8a with
allyl magnesium bromide 9a provided Michael adduct 10a
in 78% yield (Table 2, entry 1). Subsequently, a dilute solu-
tion of 10a (w0.002 M) was heated in toluene at 80 ꢀC in the
presence of 5 mol % of Grubbs catalyst G1 in anticipation of
obtaining the cyclic ether 11a. Indeed, we were pleased to
isolate the benzo-fused eight-membered cyclic ether 11a
possessing a nitromethyl moiety in good yield (60%) after
8 h. These results encouraged us to subject all the nitrostyr-
enes 8a–d to the Michael addition of various Grignard
reagents 9a–c possessing an unsaturated tether. These exper-
iments provided adducts 10b–h in high yield (63–75%,
Table 2, entries 2–8). The diverse Michael adducts 10b–h
possessing a unique a,u-unsaturation were then subjected
to RCM as in the case of 10a. As expected, 10b provided
the desired eight-membered ether 11b in high yield (70%,
Table 2, entry 2). Formation of nine-membered cyclic ether
was also facile as the RCM products 11c and 11d
were isolated in 65 and 69% yields, respectively (Table 2,
entries 3 and 4).
Application of the above Michael–RCM sequence for the
synthesis of allelopathic natural products such as helianane,
heliannuol A, etc., which possess a benzo-fused medium
ring (eight-membered) cyclic ether skeleton will be reported
in due course. The nitroalkyl moiety is expected to be the la-
tent functionality for the benzylic methyl group in these nat-
ural products. Expanding the scope of the above strategy by
employing other Michael acceptors such as a,b-unsaturated
ketones, esters, etc. is also an attractive prospect.

I. Deb et al. / Tetrahedron 63 (2007) 11991–11997
11993
Table 2. Michael addition of Grignard reagents 9 to nitrostyrenes 8 and subsequent ring closing metathesis of the Michael adducts 10 to medium ring ethers 11
Grubbs catalyst
GI or G2
Toluene, 80 °C
Nitroalkene + RMgBr
Michael adduct
10
RCM product
11
-78 °C, 5 h
8
9
Entry
1
Nitroalkene 8
NO2
RMgBr 9 R¼
Michael adduct 10
Yielda (%) RCM cat and conditions
RCM product 11
Yielda (%)
O2N
O2N
8a
8b
8a
8b
8a
8c
8d
9a Allyl
10a
78
73
75
75
69
63
68
G1,b 8 h
G1,b 8 h
G1,b 8 h
G1,b 8 h
G1 or G2c
G1 or G2c
G1,e 15 h
11a
60
O
O
O
O2N
O2N
Br
NO2
Br
Br
2
3
4
5
6
7
9a Allyl
10b
11b
11c
11d
11e
11f
70
O
O
O
O2N
O2N
NO2
9b Homo-allyl 10c
9b Homo-allyl 10d
9c n-Pentenyl 10e
9b Homo-allyl 10f
65
O
O
O
O2N
O2N
Br
NO2
Br
Br
69
O
O
O
O2N
NO2
NO2
<5d
O
O
O
O
O
O2N
O2N
NO2
NO2
—
O
O
O2N
O2N
9a Allyl
10g
11g
20
O
O
O
O2N
O2N
NO2
8
8d
9b Homo-allyl 10h
70
G1,e 12 h
11h
43
O
O
a
Isolated yield after purification by silica gel column chromatography.
5 mol %.
Variety of conditions.
Considerable amounts of dimers were isolated in these cases.
10 mol %.
b
c
d
e
3. Conclusions
4. Experimental section
b-Nitrostyrenes possessing o-allyloxy, o-vinyloxy and
o-propargyloxy groups undergo facile Michael addition of
a variety of carbon and heteroatom centred nucleophiles
containing an unsaturated tether to afford novel substrates
suitable for ring closing metathesis. The RCM of majority
of these substrates, except those containing the vinyl ether
moiety, to eight- and nine-membered rings takes place satis-
factorily. The novel benzo-fused medium ring cyclic ethers
possess nitroalkyl and olefinic/dienic moieties, which can
be easily transformed to other functionalities.
4.1. General
Melting points are uncorrected. IR spectra were recorded on
a Perkin Elmer Spectrum One FT spectrometer. NMR spec-
tra (1H and 13C) were recorded on an AMX-400 or VXR-
300S spectrometer. H–1H COSY spectra were recorded
1
on an AMX-400 spectrometer using gDQCOSY pulse se-
quence. Coupling constants (J values) are given in hertz.
High resolution mass spectra were recorded at 60–70 eV
on a Waters Micromass Q-TOF spectrometer (ESI, Ar) or

11994
I. Deb et al. / Tetrahedron 63 (2007) 11991–11997
Table 3. Michael addition of C and heteroatom centred nucleophiles 12 to nitrostyrenes 8 and subsequent ring closing metathesis of the Michael adducts 13 to
medium ring ethers 14
Grubbs catalyst
GI or G2
YX
Nitroalkene +
Michael adduct
RCM product
Toluene, 80 °C
8
12
13
14
Entry
8
12 XY¼
Reagents and conditions
Michael adduct 13
Yielda RCM cat
RCM product 14
Yielda
(%)
(%)
and conditions
E
O2N
O2N
E
NO2
NO2
1
8a
8a
12a CH-E2 BuOK, THF, ꢁ20 ꢀC
13a
70
G1,c 20 h
14a
14b
62
b
t
E
E
O
O
O
O
O
O2N
O2N
O
tBuOK, THF, ꢁ60 ꢀC,
d
2
12b OH
13b
78
G1 or G2
—
O
20 min
O
O2N
O2N
O2N
NO2
NO2
tBuOK, THF, ꢁ60 ꢀC,
O
e
3
4
8c
8a
12b OH
13c
13d
70
68
G1 or G2
14c
14d
—
O
S
20 min
O
O
O
O
O
O2N
S
12c SH
Et3N, THF, rt, 12 h
G1,c 10 h
40
O
O2N
O2N
NO2
S
e
—
5
8c
12c SH
Et3N, THF, rt, 12 h
13e
70
G1 or G2
14e
S
O
O
O
a
Isolated yield after purification by silica gel column chromatography.
E¼CO2Et.
b
c
d
e
7 mol %.
Complex mixture.
Vinyl ethers 13c and 13e remained unreactive under a variety of conditions using G1 and G2, see Ref. 25.
on a JEOL MSRoute spectrometer (EI). O-Protected salicyl-
aldehydes 7a–d26 and nitroalkenes 8a27 and 8d28 are known
compounds.
(m); 1H NMR (400 MHz, CDCl3) d 4.65 (dd, J¼6.0, 2.0 Hz,
1H), 4.94 (dd, J¼13.5, 2.0 Hz, 1H), 6.64 (dd, J¼13.5,
6.0 Hz, 1H), 7.06–7.18 (m, 2H), 7.44–7.54 (m, 2H), 7.80
(d, J¼14.0 Hz, 1H) and 8.16 (d, J¼14.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3) d 98.0, 116.5, 120.2, 123.5,
131.4, 133.2, 134.3, 138.6, 146.7 and 156.3; MS (ESI) m/z
(rel intensity) 192 (M+, 20%), 144 (100) and 121 (50);
HRMS calcd for C10H10NO3 (M+) 192.0661, found
192.0659.
4.2. General procedure for the preparation
of nitrostyrenes 8
To an ice-cold mixture of O-protected salicylaldehyde 7
(0.05 mol), nitromethane (3.4 mL, 0.05 mol) in methanol
(10 mL) was added dropwise. Cold aqueous NaOH (42%,
10 mL) was then added over 10 min, maintaining the tem-
perature at 5 ꢀC and the reaction mixture was stirred for
15 min at the same temperature. The reaction mixture con-
taining a white precipitate was diluted with ice-cold water
(20 mL) and the resulting solution was added dropwise to
cold aqueous 4 N HCl (25 mL). The yellow precipitate
was filtered under suction, washed thoroughly with water
and recrystallized from hot ethanol.
4.3. General procedure for the addition of Grignard
reagents 9 to nitroalkenes 8
To activated Mg turnings (38 mg, 1.6 mmol) in dry ether
(2 mL), at room temperature, was added alkyl halide
(0.5 mmol) under N2. After the reaction had begun, the re-
maining alkyl halide (1.0 mmol) in ether (2 mL) was added
dropwise. Stirring was continued at room temperature for
2 h. The reagent 9 was diluted with dry THF (2 mL) and
the resulting mixture was cooled to ꢁ78 ꢀC. A solution of ni-
troalkene 8 (1.0 mmol) in dry THF (1.5 mL) was then added
dropwise to the reaction mixture and the reaction mixture
4.2.1. Representative data: 1-(2-nitrovinyl)-2-(vinyloxy)-
benzene (8c). Yield 84%; bright yellow solid; mp 71 ꢀC; IR
(film) cmꢁ1 1634 (s), 1508 (m), 1348 (m), 1241 (s) and 1147

I. Deb et al. / Tetrahedron 63 (2007) 11991–11997
11995
was stirred for 2 h at ꢁ78 ꢀC. The reaction mixture was then
4.5. General procedure for the addition of allyl alcohol
12b to nitroalkenes 8
brought to room temperature and stirring continued for
another 8 h. The reaction mixture was then poured into
saturated aqueous ammonium chloride (5 mL) and was
extracted with ether (3ꢂ20 mL). The combined organic
layers were washed with brine (10 mL), dried (anhyd
Na2SO4) and concentrated in vacuo to afford a yellowish
oil. Purification of this residue by silica gel column chroma-
tography using ethyl acetate/petroleum ether (1:9) as eluent
provided pure Michael adducts 10.
A solution of allyl alcohol 12b (1.74 g, 30 mmol) in THF
t
(25 mL) was stirred at ꢁ20 to ꢁ60 ꢀC, while BuOK
(3.38 g, 30 mmol) was added in small portions. After the en-
tire base had dissolved, a solution of nitroalkene 8 (8 mmol)
in THF (15 mL) was added dropwise over 15 min. After con-
tinued stirring for another 15 min, the reaction mixture was
cooled to 0 ꢀC and AcOH (2.5 mL) was added, followed by
water (20 mL). The reaction mixture was extracted with
EtOAc (2ꢂ40 mL) and the combined organic layers were
washed with water (25 mL), dried (anhyd Na2SO4) and con-
centrated in vacuo. The crude residue was purified by silica
gel column chromatography using EtOAc/n-hexane (1:9) as
eluent to afford pure Michael adducts 13b–c.
4.3.1. Representative data: 1-(allyloxy)-2-(1-nitropent-4-
en-2-yl)benzene (10a). Yield 78%; pale yellow liquid; IR
(film) cmꢁ1 3080 (w), 2919 (w), 2866 (w), 1552 (s), 1493
(m), 1453 (m), 1379 (m), 1240 (m), 1132 (m), 1020 (m),
997 (m), 922 (s) and 754 (m); 1H NMR (400 MHz,
CDCl3) d 2.47–2.66 (m, 2H), 3.89 (quintet, J¼7.3 Hz,
1H), 4.56 (dt, J¼5.1, 1.4 Hz, 2H), 4.68 (ABqd, J¼12.4,
7.2 Hz, 2H), 5.00–5.11 (m, 2H), 5.31 (dABq, J¼10.5,
1.5 Hz, 1H), 5.45 (dABq, J¼17.1, 1.5 Hz, 1H), 5.61–5.70
(m, 1H), 6.10 (m, 1H), 6.90 (dd, J¼17.0, 7.6 Hz, 2H), 7.06
(dd, J¼7.6, 1.6 Hz, 1H) and 7.20 (dt, J¼6.5, 1.7 Hz, 1H);
13C NMR (100 MHz, CDCl3) d 35.8, 39.3, 68.8, 78.4,
112.1, 117.4, 117.5, 120.9, 127.2, 128.5, 128.9, 133.0,
134.9 and 156.2; MS (ESI) m/z (rel intensity) 270 (MNa+,
20%), 201 (28), 187 (90), 147 (100) and 99 (90); HRMS
calcd for C14H17NO3Na (MNa+) 270.1106, found 270.1110.
4.5.1. Representative data: 1-(allyloxy)-2-(1-(allyloxy)-2-
nitroethyl)benzene (13b). Yield 78%; pale yellow liquid;
IR (film) cmꢁ1 3081 (w), 2923 (w), 2862 (w), 1556 (s),
1489 (m), 1454 (m), 1380 (m), 1239 (m), 1103 (m), 929
(m) and 758 (m); 1H NMR (400 MHz, CDCl3) d 3.89 (ddt,
J¼12.6, 5.9, 1.3 Hz, 1H), 4.05 (ddt, J¼12.6, 5.3, 1.4 Hz,
1H), 4.45 (dd, J¼12.8, 9.9 Hz, 1H), 4.57 (dd, J¼12.7,
2.9 Hz, 3H), 5.18 (tABq, J¼10.6, 1.2 Hz, 1H), 5.28 (tABq,
J¼15.9, 1.6 Hz, 2H), 5.45 (dABq, J¼17.2, 1.4 Hz, 1H),
5.58 (dd, J¼9.9, 2.7 Hz, 1H), 5.81–5.92 (m, 1H), 6.00–
6.11 (m, 1H), 6.90 (d, J¼7.7 Hz, 1H), 7.02 (td, J¼7.7,
0.8 Hz, 1H), 7.30 (td, J¼7.7, 1.6 Hz, 1H) and 7.44 (dd,
J¼7.4, 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 68.6,
70.5, 72.6, 78.9, 111.7, 117.3 (ꢂ2), 121.1, 124.6, 126.9,
129.6, 132.6, 133.8 and 155.5; MS (ESI) m/z (rel intensity)
286 (MNa+, 28%), 203 (57), 145 (53), 119 (38) and 99
(100); HRMS calcd for C14H17NO4Na (MNa+) 286.1055,
found 286.1055.
4.4. Procedure for the addition of malonate 12a
to nitroalkene 8a
To a solution of allyl diethylmalonate 12a (0.307 g,
1.5 mmol) in THF (3 mL), cooled to ꢁ20 ꢀC under N2,
t
was added BuOK (0.168 g, 1.5 mmol) in portions over
10 min and the reaction mixture was stirred at room temper-
ature for 30 min. The reaction mixture was then cooled to
ꢁ20 ꢀC and a solution of nitroalkene 8a (0.205 g,
1.0 mmol) in THF (3 mL) was added dropwise at ꢁ20 ꢀC
during 5 min. The reaction mixture was stirred at 0 ꢀC for
30 min, quenched with saturated aqueous NH4Cl (2 mL)
and extracted with ether (3ꢂ10 mL). The combined organic
layers were washed with water (3 mL) and brine (10 mL),
dried (anhyd Na2SO4) and concentrated in vacuo. The crude
product was purified by silica gel column chromatography
using EtOAc/n-hexane (1:4) as eluent to afford pure Michael
adduct 13a.
4.6. General procedure for the addition of allyl
mercaptan 12c to nitroalkenes 8
To a stirred solution of allyl mercaptan 12c (0.16 g, 2.2 mmol)
and Et3N (0.06 mL, 0.2 equiv) in THF (2.5 mL) at 0 ꢀC was
added a solution of nitroalkene 8 (2 mmol) in THF (1.5 mL)
over 15 min and the reaction mixture was stirred at room tem-
perature overnight (12 h). The reaction mixture was then
diluted with water (5 mL) and extracted with EtOAc
(2ꢂ10 mL). The combined organic layers were washed with
water (10 mL) and brine (10 mL), dried (anhyd Na2SO4)
and concentrated in vacuo. The crude residue was purified
by silica gel column chromatography using EtOAc/n-hexane
(1:9) as eluent to afford pure Michael adducts 13d–e.
4.4.1. Diethyl 2-allyl-2-(1-(2-(allyloxy)phenyl)-2-nitro-
ethyl)malonate (13a). Yield 70%; white solid; mp 38 ꢀC;
IR (film) cmꢁ1 2985 (w), 1729 (s), 1552 (m), 1399 (s),
1384 (m), 1305 (m), 1216 (m), 1008 (m), 934 (m) and 759
1
(m); H NMR (400 MHz, CDCl3) d 1.25–1.31 (m, 7H),
4.6.1. Representative data: allyl(1-(2-(allyloxy)phenyl)-
2-nitroethyl)sulfane (13d). Yield 68%; pale yellow liquid;
IR (film) cmꢁ1 3020 (s), 2920 (w), 1600 (m), 1555 (s),
1492 (m), 1425 (m), 1376 (m), 1216 (m), 926 (m) and 759
(s); 1H NMR (400 MHz, CDCl3) d 3.15–3.21 (m, 2H),
4.60 (d, J¼4.8 Hz, 2H), 4.75 (dd, J¼10.9, 6.1 Hz, 1H),
4.85 (dd, J¼12.8, 7.3 Hz, 1H), 4.90 (dd, J¼10.9, 7.3 Hz,
1H), 5.17 (td, J¼9.1, 1.1 Hz, 2H), 5.32 (dt, J¼9.7, 0.6 Hz,
1H), 5.47 (dt, J¼17.1, 1.5 Hz, 1H), 5.74–5.82 (m, 1H),
6.02–6.12 (m, 1H), 6.88 (d, J¼8.2 Hz, 1H), 6.94 (t,
J¼7.5 Hz, 1H), 7.25 (td, J¼7.5, 1.2 Hz, 1H) and 7.31 (dd,
J¼7.6, 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) d 35.4,
2.25–2.40 (m, 1H), 2.45–2.55 (m, 1H), 4.16–4.32 (m, 4H),
4.56 (dt, J¼5.1, 1.6 Hz, 2H), 4.87–5.10 (m, 4H), 5.29 (dd,
J¼10.5, 1.2 Hz, 1H), 5.43 (d, J¼1.2 Hz, 1H), 5.85 (m,
1H), 6.06–6.08 (m, 1H), 6.87 (dd, J¼15.7, 7.4 Hz, 2H),
7.04 (d, J¼7.4 Hz, 1H) and 7.22 (dd, J¼15.7, 1.6 Hz, 1H);
13C NMR (100 MHz, CDCl3) d 13.9, 14.0, 38.5, 60.9,
61.6, 61.7, 69.2, 78.1, 112.7, 117.4, 118.7, 120.9, 123.8,
129.4, 133.0, 157.1, 169.6 and 169.9; MS (ESI) m/z (rel in-
tensity) 428 (MNa+, 55%), 360 (20), 233 (100), 159 (55) and
99 (40); HRMS calcd for C21H27NO7Na (MNa+) 428.1685,
found 428.1686.

11996
I. Deb et al. / Tetrahedron 63 (2007) 11991–11997
2. Reviews on medium ring cyclic ethers: (a) Elliott, M. C.
Contemp. Org. Synth. 1994, 1, 457; (b) Moody, C. J.; Davies,
M.J.StudiesinNaturalProductsChemistry; 1992; Vol. 10, p 201.
3. (a) Surry, D. S.; Su, X.; Fox, D. J.; Franckevicius, V.;
Macdonald, S. J. F.; Spring, D. R. Angew. Chem., Int. Ed.
2005, 44, 1870; (b) Delgado, M.; Martin, J. D. J. Org. Chem.
1999, 64, 4798; (c) Spring, D. R.; Krishnan, S.; Schreiber,
S. L. J. Am. Chem. Soc. 2000, 122, 5656.
41.2, 69.0, 78.5, 112.4, 117.5, 117.9, 121.0, 125.9, 128.8,
129.3, 132.8, 133.7 and 155.9; MS (ESI) m/z (rel intensity)
302 (MNa+, 40%), 206 (100) and 160 (90); HRMS calcd
for C14H17NO3NaS (MNa+) 302.0827, found 302.0824.
4.7. General procedure for ring closing metathesis
(RCM)
4. (a) Nicolaou, K. C.; Snyder, A. Classics in Total Synthesis II:
Targets, Strategies, Methods; John Wiley & Sons: Chichester,
UK, 2003; (b) Takemura, A.; Fujiwara, K.; Shimawaki, K.;
Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron 2005, 61,
7392; (c) Nakata, T. Chem. Rev. 2005, 105, 4314; (d) Clark,
J. S.; Grainger, D. M.; Ehkirch, A. A.-C.; Blake, A. J.;
Wilson, C. Org. Lett. 2007, 9, 1033; (e) Kadota, I.; Abe, T.;
Ishitsuka, Y.; Touchy, A. S.; Nagata, R.; Yamamoto, Y.
Tetrahedron Lett. 2007, 48, 219; (f) Crawford, C.; Nelson,
A.; Patel, I. Org. Lett. 2006, 8, 4231.
To a solution of Michael adduct 10 or 13 (0.25 mmol) in de-
gassed toluene (60 mL) was added dropwise a solution of
bis(tricyclohexylphosphine)-benzylideneruthenium dichlor-
ide (Grubbs catalyst G1, 5–10 mol %) in degassed toluene
(100 mL). The resulting solution was allowed to stir at
80 ꢀC for several hours. Toluene was removed in vacuo
and the residue was purified by silica gel column chromato-
graphy using EtOAc/n-hexane (1:9) as eluent to afford the
cyclized product 11 or 14.
5. (a) Venkateswaran, R. V.; Sabui, S. K. Tetrahedron Lett. 2004,
45, 9653; (b) Sen, P. K.; Biswas, B.; Venkateswaran, R. V.
Tetrahedron Lett. 2005, 46, 8741; (c) Ghosh, S.; Tuhina, K.;
Bhowmik, D. R.; Venkateswaran, R. V. Tetrahedron 2007, 63,
644; (d) Nguyen, V. T. H.; Bellur, E.; Langer, P. Tetrahedron
Lett. 2006, 47, 113; (e) Macias, F. A.; Varela, R. M.; Torres,
A.; Molinillo, J. M. G.; Fronzek, F. R. J. Nat. Prod. 1999, 62,
1636.
6. (a) Shiina, I.; Hashizume, M.; Yamai, Y.; Oshiumi, H.;
Shimazaki, T.; Takasuna, Y.; Ibuka, R. Chem.—Eur. J. 2005,
11, 6601; (b) Kaliappan, K. P.; Kumar, N. Tetrahedron 2005,
61, 7461.
7. For recent articles: (a) Clark, J. S.; Freeman, R. P.; Cacho, M.;
Thomas, A. W.; Swallow, S.; Wilson, C. Tetrahedron Lett.
2004, 45, 8639; (b) Crimmins, M. T.; Emmitte, K. A.; Choy,
A. L. Tetrahedron 2002, 58, 1817; (c) Buon, C.; Chacun-
Lefevre, L.; Rabot, R.; Bouyssou, P.; Coudert, G.
Tetrahedron 2000, 56, 605.
4.7.1. Representative data: 5,6-dihydro-6-(nitromethyl)-
2H-benzo[b]oxocine (11a). Yield 60%; pale yellow liquid;
IR (film) cmꢁ1 3079 (w), 2926 (w), 1551 (s), 1493 (m),
1452 (m), 1423 (m), 1379 (m), 1241 (m), 1019 (m), 997
1
(m), 917 (m) and 755 (m); H NMR (400 MHz, CDCl3)
d 2.35–2.39 (m, 1H), 3.12 (ABq, J¼11.6 Hz, 1H), 3.65–
3.75 (m, 1H), 4.39 (dd, J¼15.4, 5.0 Hz, 1H), 4.41–4.51
(m, 2H), 4.92 (dt, J¼15.4, 2.9 Hz, 1H), 5.41 (ddABq,
J¼10.6, 4.9, 1.4 Hz, 1H), 5.73–5.83 (m, 1H), 7.03–7.11
(m, 3H) and 7.28 (dd, J¼3.4, 1.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3) d 30.5, 43.8, 72.8, 81.4, 123.3, 125.0,
127.7, 129.4, 130.0, 130.6, 132.2 and 157.0; MS (ESI) m/z
(rel intensity) 242 (MNa+, 100%), 159 (80); HRMS calcd
for C12H13NO3Na (MNa+) 242.0793, found 242.0798.
Acknowledgements
8. (a) Metay, E.; Leonel, E.; Condon, S.; Nedelec, J.-Y.
Tetrahedron 2006, 62, 8515; (b) Sasaki, M.; Fuwa, H.;
Ishikawa, M.; Tachibana, K. Org. Lett. 1999, 1, 1075; (c)
Hoffmann, H. M. R.; Pohlmann, J. Tetrahedron Lett. 1998,
39, 7085; (d) Nicolaou, K. C.; Shi, G.-Q.; Gunzner, J. L.;
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Watanabe, M.; Nishiyama, M.; Koie, Y. Tetrahedron Lett.
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J. Chem. Soc., Perkin Trans. 1 1998, 3623; (b) Harusawa, S.;
Moriyama, H.; Kase, N.; Ohishi, H.; Yoneda, R.; Kurihara, T.
Tetrahedron 1995, 51, 6475; (c) Kulinkovich, O. G.; Meijere,
A. D. Chem. Rev. 2000, 100, 2789; (d) Ollivier, J.; Lecornue,
F. Org. Biomol. Chem. 2003, 1, 3600.
The authors thank DST, India, for financial assistance, SAIF,
IIT Bombay, for selected NMR data and Dr. P. J. Biju for his
support. I.D. thanks CSIR, India, for a research fellowship
and Abhijit Dev Roy for selected Mass spectral data. S.J.
thanks MG University, Kerala, for granting leave.
Supplementary data
Complete characterization data for all the new compounds
and known compounds for which data are not available in
the literature as well as copies of 1H, 13C NMR and relevant
1H–1H COSY spectra are provided as Supplementary data.
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.09.009.
10. (a) Fujiwara, K.; Goto, A.; Sato, D.; Kawai, H.; Suzuki, T.
Tetrahedron Lett. 2005, 46, 3465; (b) Giner, J.-L. J. Org.
Chem. 2005, 70, 721.
References and notes
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22. Since we presented our preliminary work at the ACS-CSIR
Joint International Conference on Organic Chemistry and
Chemical Biology, Jan 6–9, 2006, in Pune, India, the follow-
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