Titanocene(III) mediated radical cyclizations of epoxides for the synthesis of medium-sized cyclic ethers

Article abstract of DOI:10.1016/j.tet.2007.08.072

Titanocene(III) chloride (Cp₂TiCl) mediated 7-exo and 8-endo radical cyclizations of epoxides towards the synthesis of 7- and 8-membered cyclic ethers have been described. Titanocene(III) chloride was prepared in situ from commercially available titanocene dichloride (Cp₂TiCl₂) and activated zinc dust in THF.

Full text of DOI:10.1016/j.tet.2007.08.072

Tetrahedron 63 (2007) 11341–11348
Titanocene(III) mediated radical cyclizations of epoxides
for the synthesis of medium-sized cyclic ethers
*
Samir Kumar Mandal and Subhas Chandra Roy
Department of Organic Chemistry, Indian Association for the Cultivation of Science, 2A and 2B, Raja S. C. Mullick Road,
Jadavpur, Kolkata 700 032, West Bengal, India
Received 8 May 2007; revised 24 August 2007; accepted 24 August 2007
Available online 30 August 2007
Abstract—Titanocene(III) chloride (Cp2TiCl) mediated 7-exo and 8-endo radical cyclizations of epoxides towards the synthesis of 7- and
8-membered cyclic ethers have been described. Titanocene(III) chloride was prepared in situ from commercially available titanocene dichloride
(Cp2TiCl2) and activated zinc dust in THF.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
detail7 towards the synthesis of medium-sized cyclic ethers
by 7-exo and 8-endo radical cyclization reactions.
The synthesis of medium and large-sized ring ethers espe-
cially those annulated with aromatic moieties such as ben-
zo[b]oxocines and benzo[b]oxepines is of much current
interest due to their presence in a number of bioactive nat-
ural products, e.g., helianane, heliannuols, radulanin-E,
etc.1 Although several methodologies including ring-clos-
ing metathesis have been developed for constructing me-
dium-sized rings,2 general methods for the synthesis of
these systems selectively, atom economically and under
mild reaction conditions are still scarce. The use of radical
chemistry in organic synthesis witnessed a renaissance in
recent years due to the approached mildness, high func-
tional group tolerance and predictable behaviour in many
organic transformations.3 Although tin hydride mediated
radical reactions have been used for the synthesis of
medium-sized oxacyclic ring systems on several occa-
sions,2 its limitations in the substrate control on the course
of the reaction and other reasons have led to an alternative
method based on reagent control cyclization using titanoce-
ne(III) chloride (Cp2TiCl) being established by Rajanbabu
and Nugent.4 Epoxides are an attractive class of radical
precursors in organic synthesis due to their ready availabil-
ity and predictable stereochemistry. Reductive opening of
epoxides at room temperature with high regioselectivity
mediated by titanocene(III) chloride as radical initiator
have been employed in carbon–carbon bond formation
reactions.4,5 As a part of our activities6 in titanocene(III)
chloride mediated radical reactions, we report here in
HO
OH
Heliannuol A
OH
O
O
Helianane
HO
OH
O
O
COOH
Heliannuol C
Radulanin E
2. Results and discussion
The synthesis of 8-membered cyclic ether 4a has been
accomplished through 8-endo-dig cyclization mediated by
titanocene(III) chloride using 2-allyl phenol 1a as the start-
ing material (Scheme 1). 2-Allyl phenol 1a on treatment
with propargyl bromide and K2CO3 in acetone afforded
the propargyl ether 2a, which on epoxidation with
m-CPBA in dichloromethane furnished 3a in excellent yield.
The epoxy ether 3a treated with Cp2TiCl in THF under argon
afforded the 8-membered cyclic ether 4a in moderate yield
along with the reduced product 5a (12%) and another
unidentified product (18%, w/w). Similarly, the cyclic ethers
4b–d were synthesized in moderate yield from the allyl
phenols 1b—d, respectively, following the same sequence
along with the reduced product 5b–d (9–10%) and another
unidentified product (18–20%, w/w). It is noteworthy that
* Corresponding author. Tel.: +91 33 2473 4971; fax: +91 33 2473 2805;
e-mail: ocscr@iacs.res.in
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.072

11342
S. K. Mandal, S. C. Roy / Tetrahedron 63 (2007) 11341–11348
radical cyclization of the epoxide 11 yielded the cyclized
O
Br
acetone, reflux, 4 h
OH
K2CO3,
product 12 along with a trace amount of reduced product,
but pure cyclized compound 12 could easily be isolated in
63% yield by column chromatography over silica gel.
R
R
2a, R = H (93%)
2b, R = Me (90%)
2c, R = OMe (91%)
2d, R = Cl (94%)
1a, R = H
1b, R = Me
1c, R = OMe
1d, R = Cl
After successful synthesis of 8-membered cyclic ethers the
radical methodology was applied to the preparation of
7-membered cyclic ethers. Since 8-endo cyclization was
much favoured compared to 7-exo as we observed earlier,
a radical stabilizing group,8,9 namely, carbethoxy moiety
was incorporated at the terminus of the acetylene moiety
in 2a forcing the cyclization to follow the 7-exo mode.
Thus, compound 13a was prepared from 2a using ethyl
chloroformate and n-BuLi. The epoxide 14a was prepared
from 13a by epoxidation with m-CPBA (Scheme 4). Treat-
ment of the epoxide 14a in the presence of Cp2TiCl in
THF afforded a mixture of three compounds in a ratio of
1.7:1.5:1. The lactone 15a was separated by preparative
TLC in 25% yield but the other two compounds could not
be separated by usual chromatographic methods. But from
Cp2TiCl,
THF, rt
O
m-CPBA
O
CH2Cl2, rt, overnight
R
3a, R = H (93%)
3b, R = Me (90%)
3c, R = OMe (88%)
3d, R = Cl (83%)
O
O
another unidentified
product
+
+
R
OH
R
OH
5a, R = H (12%)
4a, R = H (52%)
5b, R = Me (9%)
5c, R = OMe (9%)
5d, R = Cl (10%)
4b, R = Me (58%)
4c, R = OMe (57%)
4d, R = Cl (54%)
Scheme 1.
1
the H NMR of the crude mixture left after preparative
TLC, we could determine that it was a mixture of trans-ester
16a and the reduced product 17a. Similarly, 13c was pre-
pared from 2c, which on epoxidation with m-CPBA afforded
the epoxide 14c. Radical cyclization of 14c by Cp2TiCl
afforded a mixture of three compounds in a ratio of
2:1.8:1. The lactone 15c was separated by preparative TLC
in 27% yield. The other two compounds (a mixture of 16c
and 17c) could not be separated by usual chromatographic
methods.
no 7-membered cyclic ethers were formed in any case by
7-endo-dig radical cyclizations. In another investigation,
2-allyl phenol 1a was transformed into the epoxide 6 in
a single-step using epichlorohydrin (Scheme 2). Reductive
opening of the epoxide 6 using Cp2TiCl in THF under argon
afforded the 8-membered ether 7 (44%) along with the
reduced product 8 (11%) and two other unidentified products
(25%).
The 8-endo radical cyclization was further extended for the
synthesis of naphthyl annulated cyclic ether 12 starting from
the 1-allyl-2-naphthol 9 in a similar manner (Scheme 3). The
On the other hand, the epoxide 19a, prepared from the ester
18a, on radical cyclization reaction with Cp2TiCl in THF
afforded a mixture of lactones 20a and 21a in a ratio of
2:3 (Scheme 5). The lactones were formed by 7-exo-trig
radical cyclization10 followed by in situ lactonization. The
lactones 20a and 21a were separated by preparative TLC
in 26% and 39% yields, respectively, as crystalline solids.
O
Cp2TiCl,
THF
Cl
O
OH
O
O
NaOEt, EtOH
0° C - rt, 1 h
72%
rt, 6 h
Similarly, lactones 20c and 21c were also synthesized by
radical cyclization of the epoxide 19c following the same
reaction sequences in 31% and 38% yield, respectively,
(Scheme 5). The absolute stereochemistry of the lactone
21a was finally confirmed by single crystal X-ray analysis
(Fig. 1, CCDC No. 646191).
1a
6
OH
O
OH
two other
unidentified
products
+
+
8 (11%)
7 (44%)
The lactone 15a under catalytic hydrogenation over Pd on
C afforded the mixture of 20a and 21a in a ratio of 1:1. To
prove the E stereochemistry of the ethyl ester around the
double bond in 16c or in 16a, the inseparable probable
mixture of 16c and 17c was subjected to catalytic hydro-
genation over Pd on C and the crude product was column
chromatographed over silica gel to afford the lactones 20c
and 21c in 24% yield in a ratio of 1:9. All the new products
were characterized thoroughly by IR, NMR and HRMS
studies.
Scheme 2.
K2CO3,
Br
m-CPBA
O
OH
CH2Cl2, rt
overnight
55%
acetone,
reflux, 4 h
88%
10
9
HO
O
O
Cp2TiCl,
THF, rt
63%
In summary, a detail study has been performed for the
synthesis of 7- and 8-membered cyclic ethers by radical
cyclizations of epoxides using titanocene(III) chloride as
the radical source. The aromatic annulated medium-sized
oxacyclic rings are important core structures of many natu-
rally occurring bioactive compounds.
O
11
12
Scheme 3.

S. K. Mandal, S. C. Roy / Tetrahedron 63 (2007) 11341–11348
11343
CO2Et
O
O
ClCO2Et, nBuLi
THF, -40° C
m-CPBA, DCM
Overnight
R
R
R
2a, R = H
2c, R = OMe
13a, R = H (94%)
13c, R = OMe (91%)
CO2Et
O
O
CO2Et
O
Cp2TiCl
THF, rt
+
O
O
R
R
OH
O
16a, R = H
16c, R = OMe
15a, R = H (25%)
14a, R = H (85%)
14c, R = OMe (83%)
15c, R = OMe (27%)
CO2Et
O
+
OH
R
1.7:1.5:1.0
2.0:1.8:1.0
17a, R = H
17c, R = OMe
Scheme 4.
K2CO3,
O
CO2Me
OH
the internal standard. IR spectra were recorded on Shimadzu
FTIR-8300. Column chromatography was performed on
silica gel (60–120 mesh) and preparative TLC was per-
formed using pre-coated silica 60 F 254 plates (0.2 mm).
High-resolution mass spectra were obtained using a Qtof
Micro YA263 instrument. Diethyl ether and tetrahydrofuran
were freshly distilled from sodium. Methylene chloride was
freshly distilled over calcium hydride. Light petroleum of
boiling range 60–80 ꢀC was used for chromatography.
Methyl 4-bromocrotonate
acetone, reflux, 4 h
R
R
18a, R = H (82%)
18c, R = OMe (84%)
1a, R = H
1c, R = OMe
O
CO2Me
m-CPBA
O
Cp2TiCl,
THF, rt
CH2Cl2, rt, overnight
R
19a, R = H (78%)
19c, R = OMe (76%)
O
O
H
H
3.1.1. 1-Allyl-2-prop-2-ynyloxy-benzene (2a). A mixture
of 2-allyl phenol 1a (670 mg, 5 mmol), K2CO3 (1.38 g,
10 mmol) and propargyl bromide (655 mg, 5.5 mmol) in
dry acetone (30 mL) was heated to reflux under nitrogen
for 4 h. After completion of the reaction (monitored by
TLC), the mixture was cooled to room temperature. Most
of the acetone was removed under reduced pressure and
water (20 mL) was added to the residue. It was extracted
with diethyl ether (3ꢁ100 mL). The combined organic ex-
tract was successively washed with water (1ꢁ10 mL), brine
(1ꢁ10 mL) and finally dried (Na2SO4). After removal of the
solvent under reduced pressure the residue obtained was
purified by column chromatography over silica (5% ethyl
acetate in light petroleum) to furnish 2a (800 mg, 93%) as
a viscous yellowish oil. Rf¼0.60; IR (neat): 3294, 3076,
+
O
O
R
R
O
O
H
H
20a, R = H (26%)
20c, R = OMe (31%)
21a, R = H (39%)
21c, R = OMe (38%)
Scheme 5.
2912, 2117, 1490, 1220, 1028, 752 cmꢂ1
;
1H NMR
(CDCl3, 300 MHz): d 2.46 (t, J¼2.3 Hz, 1H), 3.39 (d, J¼
6.5 Hz, 2H), 4.67 (d, J¼2.3 Hz, 2H), 5.02–5.08 (m, 2H),
5.91–6.05 (m, 1H), 6.89–6.96 (m, 2H), 7.14–7.21 (m, 2H);
13C NMR (CDCl3, 75 MHz): d 34.1, 55.9, 75.1, 78.8,
111.9, 115.4, 121.4, 127.1, 129.1, 129.9, 136.7, 155.2;
HRMS calcd for C12H13O 173.0966 [M+H]+, found
173.0969.
Figure 1. ORTEP diagram of 21a.
3.1.2. 2-Allyl-4-methyl-1-prop-2-ynyloxy-benzene (2b).
Compound 2b was prepared from 1b (740 mg, 5 mmol) as
a colourless oil (837 mg, 90%) following the same proce-
dure described for 2a. Rf¼0.58 (5% ethyl acetate in light
petroleum); IR (neat) 3300, 3008, 2920, 2117, 1500, 1217,
3. Experimental section
3.1. General
1
The compounds described are all racemates. Melting points
were determined in open capillary tubes and are uncorrected.
1H NMR and 13C NMR spectra were recorded in CDCl3 with
Bruker DPX 300 spectrometer using tetramethyl silane as
1031, 758 cmꢂ1; H NMR (CDCl3, 300 MHz): d 2.26 (s,
3H), 2.45 (t, J¼2.3 Hz, 1H), 3.36 (d, J¼6.6 Hz, 2H), 4.64
(d, J¼2.3 Hz, 2H), 5.01–5.08 (m, 2H), 5.91–6.04 (m, 1H),
6.84 (d, J¼8.5 Hz, 1H), 6.93–6.96 (m, 2H); 13C NMR

11344
S. K. Mandal, S. C. Roy / Tetrahedron 63 (2007) 11341–11348
(CDCl3, 75 MHz): d 20.4, 34.1, 56.1, 74.9, 79.0, 112.2,
115.3, 127.3, 129.0, 130.6, 130.7, 136.9, 153.1; HRMS calcd
for C13H15O 187.1123 [M+H]+, found 187.1125.
the same procedure described for 2a. Colourless oil (yield:
84%). Rf¼0.57 (5% ethyl acetate in light petroleum); IR
(neat) 2950, 1726, 1498, 1224, 1041 cmꢂ1 1H NMR
;
(CDCl3, 300 MHz): d 3.50 (d, J¼6.5 Hz, 2H), 3.85 (s,
3H), 3.86 (s, 3H), 4.74 (dd, J¼2.0, 3.7 Hz, 2H), 5.15–5.21
(m, 2H), 6.01–6.13 (m, 1H), 6.31 (td, J¼2.0, 15.7 Hz, 1H),
6.76–6.85 (m, 3H), 7.19 (td, J¼3.7, 15.7 Hz, 1H); 13C
NMR (CDCl3, 75 MHz): d 34.6, 51.8, 55.7, 67.5, 111.5,
112.9, 116.0, 116.4, 121.2, 130.5, 136.6, 143.4, 150.0,
154.2, 166.8; HRMS calcd for C15H18O4Na 285.1103
[M+Na]+, found 285.1101.
3.1.3. 2-Allyl-4-methoxy-1-prop-2-ynyloxy-benzene (2c).
Compound 2c was prepared from 1c (820 mg, 5 mmol) as
a viscous oil (919 mg, 91%) following the same procedure
described for 2a. Rf¼0.60 (5% ethyl acetate in light petro-
leum); IR (neat) 3290, 2937, 2833, 2117, 1496, 1213,
1045 cmꢂ1
;
1H NMR (CDCl3, 300 MHz): d 2.50 (t,
J¼2.4 Hz, 1H), 3.41 (d, J¼6.6 Hz, 2H), 3.77 (s, 3H), 4.66
(d, J¼2.4 Hz, 2H), 5.06–5.13 (m, 2H), 5.93–6.06 (m, 1H),
6.71–6.77 (m, 2H), 6.93 (d, J¼8.7 Hz, 1H); 13C NMR
(CDCl3, 75 MHz): d 34.3, 55.5, 57.0, 75.0, 79.1, 111.3,
113.9, 115.7, 116.0, 130.8, 136.5, 149.5, 154.3; HRMS calcd
for C13H15O2 203.1067 [M+H]+, found 203.1059.
3.1.8. 4-(2-Allyl-phenoxy)-but-2-ynoic acid ethyl ester
(13a). To a magnetically stirred solution of aryl propargyl
ether 2a (860 mg, 5 mmol) in THF (30 mL) a solution of
n-BuLi (1.1 M in hexane) was added dropwise at ꢂ40 ꢀC
over a period of 30 min under argon. The reaction mixture
was allowed to stir for another 30 min and then ethyl chlor-
oformate (650 mg, 6 mmol) was added dropwise to it. After
stirring for 1 h the reaction mixture was quenched with few
drops of water. The solvent was removed under reduced
pressure and the residue obtained was extracted with diethyl
ether (3ꢁ100 mL). The combined organic layer was succes-
sively washed with water (1ꢁ10 mL), brine (1ꢁ10 mL) and
finally dried (Na2SO4). After removal of the solvent under
reduced pressure the crude mass was purified by column
chromatography over silica (7% ethyl acetate in light petro-
leum) to furnish 13a (1.15 g, 94%) as a colourless oil.
Rf¼0.68; IR (neat) 2981, 2908, 1716, 1490, 1253, 1024,
3.1.4. 2-Allyl-4-chloro-1-prop-2-ynyloxy-benzene (2d).
Compound 2d was prepared from 1d (900 mg, 5.34 mmol)
as a viscous oil (1.04 g, 94%) following the same procedure
described for 2a. Rf¼0.62 (5% ethyl acetate in light petro-
leum); IR (neat) 3298, 3078, 2914, 2117, 1488, 1224,
1028 cmꢂ1
;
1H NMR (CDCl3, 300 MHz): d 2.51 (t,
J¼2.4 Hz, 1H), 3.37 (d, J¼6.6 Hz, 2H), 4.69 (d, J¼2.4 Hz,
2H), 5.05–5.12 (m, 2H), 5.89–6.02 (m, 1H), 6.89 (d, J¼
7.4 Hz, 1H), 7.14–7.17 (m, 2H); 13C NMR (CDCl3,
75 MHz): d 33.9, 56.3, 75.6, 78.4, 113.2, 116.3, 126.4, 126.8,
129.8, 131.2, 135.8, 153.8; HRMS calcd for C12H11ClONa
229.0395 [M+Na]+, found 229.0393.
750 cmꢂ1
;
1H NMR (CDCl3, 300 MHz): d 1.18 (t, J¼
3.1.5. 1-Allyl-2-prop-2-ynyloxy-naphthalene (10). Com-
pound 10 was prepared from 9 (920 mg, 5 mmol) as a viscous
oil (977 mg, 88%) following the same procedure described
for 2a. Rf¼0.55 (5% ethyl acetate in light petroleum); IR
7.1 Hz, 3H), 3.30 (d, J¼6.6 Hz, 2H), 4.11 (q, J¼7.1 Hz,
2H), 4.69 (s, 2H), 4.93–4.99 (m, 2H), 5.81–5.92 (m, 1H),
6.79–6.89 (m, 2H), 7.05–7.13 (m, 2H); 13C NMR (CDCl3,
75 MHz): d 13.8, 34.0, 55.6, 62.1, 78.3, 81.9, 111.8, 115.5,
121.8, 127.2, 129.2, 130.0, 136.5, 152.8, 154.9; HRMS calcd
for C15H17O3 245.1172 [M+H]+, found 245.1171.
(neat) 3292, 3066, 2117, 1595, 1218 cmꢂ1 1H NMR
;
(CDCl3, 300 MHz): d 2.48 (t, J¼2.4 Hz, 1H), 3.88 (d, J¼
5.7 Hz, 2H), 4.81 (d, J¼2.11 Hz, 2H), 4.96–5.03 (m, 2H),
6.00–6.11 (m, 1H), 7.31–7.38 (m, 2H), 7.48 (dt, J¼6.9,
1.2 Hz, 1H), 7.73–7.81 (m, 2H), 7.95 (d, J¼8.4 Hz, 1H);
13C NMR (CDCl3, 75 MHz): d 29.3, 57.5, 75.4, 79.1,
115.2, 115.4, 122.6, 123.8 (2C), 126.4, 128.0, 128.5,
129.9, 133.2, 136.7, 152.6; HRMS calcd for C16H15O
223.1123 [M+H]+, found 223.1121.
3.1.9. 4-(2-Allyl-4-methoxy-phenoxy)-but-2-ynoic acid
ethyl ester (13c). Compound 13c was prepared from 2c
(1.01 g, 5 mmol) as a colourless oil (1.25 g, 91%) following
the same procedure described in 13a. Rf¼0.63 (7% ethyl
acetate in light petroleum); IR (neat): 2981, 1716, 1498,
1253, 1024, 750 cmꢂ1 1H NMR (CDCl3, 300 MHz):
;
d 1.30 (t, J¼7.1 Hz, 3H), 3.38 (d, J¼6.6 Hz, 2H), 3.75
(s, 3H), 4.23 (q, J¼7.1 Hz, 2H), 4.75 (s, 2H), 5.04–5.10
(m, 2H), 5.90–6.03 (m, 1H), 6.69–6.75 (m, 2H), 6.88 (d,
J¼8.7 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d 13.9, 34.2,
55.5, 56.9, 62.1, 78.3, 82.3, 111.4, 114.0, 115.8, 116.1,
130.9, 136.4, 149.3, 152.9, 154.6; HRMS calcd for
C16H19O4 275.1283 [M+H]+, found 275.1281.
3.1.6. 4-(2-Allyl-phenoxy)-but-2-enoic acid methyl ester
(18a). Compound 18a was prepared from 1a (670 mg,
5 mmol) and methyl 4-bromo-crotonate (85%) (1.05 g,
5 mmol) as a viscous oil (951 mg, 82%) following the
same procedure described for 2a. Rf¼0.58 (5% ethyl acetate
in light petroleum); IR (neat) 3074, 1726, 1492, 1307,
1242 cmꢂ1 1H NMR (CDCl3, 300 MHz): d 3.47 (d,
;
J¼6.6 Hz, 2H), 3.79 (s, 3H), 4.70 (dd, J¼2.1, 3.8 Hz, 2H),
5.07–5.13 (m, 2H), 5.97–6.12 (m, 1H), 6.26 (dt, J¼2.1,
15.7 Hz, 1H), 6.81 (d, J¼7.9 Hz, 1H), 6.96 (td, J¼0.8,
7.5 Hz, 1H), 7.10–7.22 (m, 3H); 13C NMR (CDCl3,
75 MHz): d 34.3, 51.6, 66.4, 111.4, 115.5, 121.1, 121.2,
127.3, 128.9, 130.1, 136.7, 143.1, 155.6, 166.6; HRMS calcd
for C14H16O3Na 255.0997 [M+Na]+, found 255.0989.
3.1.10. 2-(2-Prop-2-ynyloxy-benzyl)-oxirane (3a). A mix-
ture of ether 2a (688 mg, 4 mmol) and m-CPBA (1.5 g,
4.8 mmol, 55% dispersion) in dichloromethane (20 mL)
was stirred overnight at room temperature. Aqueous satu-
rated Na2SO3 solution (10 mL) was added to it and was
further stirred for half an hour. The organic layer was sepa-
rated and was washed successively with saturated NaHCO3
solution (10 mL), water (10 mL), brine (10 mL) and finally
dried (Na2SO4). After removal of the solvent under reduced
pressure the residue obtained was purified by column chro-
matography over silica gel (10% ethyl acetate in light
petroleum) to provide epoxy ether 3a (700 mg, 93%) as
3.1.7. 4-(2-Allyl-4-methoxy-phenoxy)-but-2-enoic acid
methyl ester (18c). Compound 18c was prepared from 1c
(820 mg, 5 mmol) and methyl 4-bromo-crotonate (85%)
(1.05 g, 5 mmol) as a viscous oil (1.1 g, 84%) following

S. K. Mandal, S. C. Roy / Tetrahedron 63 (2007) 11341–11348
11345
a yellowish oil. Rf¼0.63; IR (neat): 3290, 3043, 2920, 2117,
1492, 1222, 1026, 754 cmꢂ1; 1H NMR (CDCl3, 300 MHz):
d 2.49 (t, J¼2.3 Hz, 1H), 2.57 (dd, J¼2.7, 4.9 Hz, 1H), 2.77
(tapp, J¼4.9 Hz, 1H), 2.82 (dd, J¼5.8, 14.2 Hz, 1H), 2.97
(dd, J¼5.2, 14.2 Hz, 1H), 3.17–3.22 (m, 1H), 4.72 (d,
J¼2.3 Hz, 2H) 6.94–6.99 (m, 2H), 7.21–7.26 (m, 2H); 13C
NMR (CDCl3, 75 MHz): d 33.2, 47.1, 51.5, 55.7, 75.3,
78.5, 111.7, 121.4, 126.1, 127.7, 130.7, 155.4; HRMS calcd
for C12H13O2 189.0915 [M+H]+, found 189.0920.
1H); 13C NMR (CDCl3, 75 MHz): d 27.9, 47.4, 51.8, 57.2,
75.5, 78.9, 114.6, 119.8, 123.5, 123.9, 126.7, 128.5 (2C),
129.7, 133.5, 153.1; HRMS calcd for C16H14O2Na
261.0891 [M+Na]+, found 261.0901.
3.1.15. 4-(2-Oxiranylmethyl-phenoxy)-but-2-ynoic acid
ethyl ester (14a). Compound 14a was prepared from 13a
(975 mg, 4 mmol) as a viscous oil (885 mg, 85%) following
the same procedure described for 3a after purification by
column chromatography over silica gel using 10% ethyl
acetate in light petroleum. Rf¼0.53; IR (neat): 2985, 1714,
3.1.11. 2-(4-Methyl-2-prop-2-ynyloxy-benzyl)-oxirane
(3b). Compound 3b was prepared from 2b (745 mg,
4 mmol) as a viscous oil (727 mg, 90%) following the
same procedure described for 3a. Rf¼0.60 (10% ethyl ace-
tate in light petroleum); IR (neat): 3286, 2920, 2117, 1500,
1492, 1253, 1022, 750 cmꢂ1
;
1H NMR (CDCl3,
300 MHz): d 1.29 (t, J¼7.1 Hz, 3H), 2.54 (dd, J¼2.6,
4.8 Hz, 1H), 2.76 (dd, J¼4.0, 4.8 Hz, 1H), 2.83 (dd,
J¼5.7, 14.3 Hz, 1H), 2.94 (dd, J¼5.4, 14.3 Hz, 1H), 3.16–
3.20 (m, 1H), 4.22 (q, J¼7.1 Hz, 2H), 4.83 (s, 2H), 6.91–
6.99 (m, 2H), 7.21–7.26 (m, 2H); 13C NMR (CDCl3,
75 MHz): d 13.7, 33.0, 47.0, 51.4, 55.5, 62.1, 78.4, 81.5,
111.6, 121.8, 126.2, 127.8, 130.8, 152.7, 155.1; HRMS calcd
for C15H17O4 261.1127 [M+H]+, found 261.1131.
1217, 1029, 806 cmꢂ1 1H NMR (CDCl3, 300 MHz):
;
d 2.27 (s, 3H), 2.47 (t, J¼2.3 Hz, 1H), 2.56 (dd, J¼2.6,
5.0 Hz, 1H), 2.74–2.82 (m, 2H), 2.91 (dd, J¼5.3, 14.2 Hz,
1H), 3.16–3.20 (m, 1H), 4.67 (d, J¼2.3 Hz, 2H), 6.85 (d,
J¼8.8 Hz, 1H), 7.00–7.03 (m, 2H); 13C NMR (CDCl3,
75 MHz): d 20.3, 33.2, 47.1, 51.6, 55.9, 75.1, 78.7, 111.8,
125.9, 127.9, 130.7, 131.4, 153.3; HRMS calcd for
C13H15O2 203.1072 [M+H]+, found 203.1075.
3.1.16. 4-(4-Methoxy-2-oxiranylmethyl-phenoxy)-but-2-
ynoic acid ethyl ester (14c). Compound 14c was prepared
from 13c (1.1 g, 4.01 mmol) as a viscous oil (966 mg,
83%) following the same procedure described for 3a.
Rf¼0.50 (10% ethyl acetate in light petroleum); IR (neat):
3.1.12. 2-(5-Methoxy-2-prop-2-ynyloxy-benzyl)-oxirane
(3c). Compound 3c was prepared from 2c (810 mg,
4 mmol) as a viscous oil (767 mg, 88%) following the
same procedure described for 3a. Rf¼0.58 (10% ethyl ace-
tate in light petroleum); IR (neat): 3284, 2918, 2117, 1498,
2987, 1714, 1498, 1255, 1039 cmꢂ1 1H NMR (CDCl3,
;
300 MHz): d 1.31 (t, J¼7.1 Hz, 3H), 2.56 (dd, J¼2.6,
4.8 Hz, 1H), 2.78 (tapp, J¼4.8 Hz, 1H), 2.83 (dd, J¼5.6,
14.4 Hz, 1H), 2.91 (dd, J¼5.4, 14.4 Hz, 1H), 3.17–3.20
(m, 1H), 3.77 (s, 3H), 4.23 (q, J¼7.1 Hz, 2H), 4.78 (s,
2H), 6.75 (dd, J¼2.9, 8.8 Hz, 1H), 6.82 (d, J¼2.9 Hz, 1H),
6.88 (d, J¼8.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz):
d 13.9, 33.3, 47.1, 51.6, 55.6, 56.7, 62.2, 78.4, 82.0, 112.1,
113.6, 116.9, 127.9, 149.5, 152.9, 154.5; HRMS calcd for
C16H18O5Na [M+Na]+ 313.1052, found 313.1042.
1
1215, 1041 cmꢂ1; H NMR (CDCl3, 300 MHz): d 2.48 (t,
J¼2.4 Hz, 1H), 2.57 (dd, J¼2.7, 5.1 Hz, 1H), 2.75–2.85
(m, 2H), 2.93 (dd, J¼5.4, 14.4 Hz, 1H), 3.16–3.22 (m,
1H), 3.76 (s, 3H), 4.66 (d, J¼2.4 Hz, 2H), 6.74 (dd, J¼3.0,
9.0 Hz, 1H), 6.81 (d, J¼3.0 Hz, 1H), 6.92 (d, J¼9.0 Hz,
1H); 13C NMR (CDCl3, 75 MHz): d 33.4, 47.2, 51.6, 55.6,
56.8, 75.2, 78.9, 112.0, 113.5, 116.8, 127.7, 149.7, 154.2;
HRMS calcd for C13H14O3Na 241.0841 [M+Na]+, found
241.0842.
3.1.17. 4-(2-Oxiranylmethyl-phenoxy)-but-2-enoic acid
methyl ester (19a). Compound 19a was prepared from
18a (930 mg, 4 mmol) as a viscous oil (775 mg, 78%) fol-
lowing the same procedure described for 3a. Rf¼0.52
(10% ethyl acetate in light petroleum); IR (neat): 2950,
3.1.13. 2-(5-Chloro-2-prop-2-ynyloxy-benzyl)-oxirane
(3d). Compound 3d was prepared from 2d (825 mg,
4 mmol) as a viscous oil (737 mg, 83%) following the
same procedure described for 3a. Rf¼0.60 (10% ethyl
acetate in light petroleum); IR (neat): 3292, 2995, 2117,
1724, 1494, 1242 cmꢂ1 1H NMR (CDCl3, 300 MHz):
;
d 2.54 (dd, J¼2.7, 4.9 Hz, 1H), 2.76 (t, J¼4.9 Hz, 1H),
2.88 (dd, J¼5.4, 14.3 Hz, 1H), 2.96 (dd, J¼5.4, 14.3 Hz,
1H), 3.17–3.22 (m, 1H), 3.75 (s, 3H), 4.70 (dd, J¼1.8,
3.9 Hz, 1H), 6.19 (dd, J¼1.8, 15.7 Hz, 1H), 6.80 (d,
J¼8.2 Hz, 1H), 6.93 (t, J¼7.4 Hz, 1H), 7.10 (td, J¼3.9,
15.7 Hz, 1H), 7.17–7.23 (m, 2H); 13C NMR (CDCl3,
75 MHz): d 33.1, 47.0, 51.5 (2C), 66.3, 111.2, 121.1,
121.2, 125.8, 127.8, 130.7, 142.7, 155.7, 166.3; HRMS calcd
for C14H16O4Na 271.0946 [M+Na]+, found 271.0937.
1488, 1226, 1026 cmꢂ1 1H NMR (CDCl3, 300 MHz):
;
d 2.50–2.55 (m, 2H), 2.76 (tapp, J¼4.5 Hz, 1H), 2.84 (tapp
,
J¼3.8 Hz, 2H), 3.14–3.19 (m, 1H), 4.69 (d, J¼1.9 Hz,
2H), 6.89 (d, J¼8.4 Hz, 1H), 7.16–7.20 (m, 2H); 13C
NMR (CDCl3, 75 MHz): d 33.1, 47.1, 51.2, 56.2, 75.8,
78.2, 113.1, 126.3, 127.5, 128.2, 130.6, 154.0; HRMS calcd
for C12H11ClO2Na 245.0345 [M+Na]+, found 245.0353.
3.1.14. 2-(2-Prop-2-ynyloxy-naphthalen-1-ylmethyl)-
oxirane (11). Compound 11 was prepared from 10
(890 mg, 4 mmol) as a viscous oil (523 mg, 55%) following
the same procedure described for 3a. Rf¼0.58 (10% ethyl
acetate in light petroleum); IR (neat): 3288, 3053, 2117,
3.1.18. 4-(4-Methoxy-2-oxiranylmethyl-phenoxy)-but-2-
enoic acid methyl ester (19c). Compound 19c was prepared
from 18c (1.05 g, 4 mmol) as a viscous oil (845 mg, 76%)
following the same procedure described for 3a. Rf¼0.49
(10% ethyl acetate in light petroleum); IR (neat) 2950,
1
1595, 1220 cmꢂ1; H NMR (CDCl3, 300 MHz): d 2.49 (t,
J¼2.4 Hz, 1H), 2.65 (dd, J¼2.6, 5.0 Hz, 1H), 2.71 (tapp
,
1724, 1500, 1305, 1224, 1039 cmꢂ1 1H NMR (CDCl3,
;
J¼5.0 Hz, 1H), 3.22–3.26 (m, 1H), 3.33 (dd, J¼5.9,
13.9 Hz, 1H), 3.50 (dd, J¼4.5, 13.9 Hz, 1H), 4.83 (d,
J¼2.4 Hz, 2H), 7.33–7.40 (m, 2H), 7.51 (dt, J¼1.2,
8.1 Hz, 1H), 7.78 (tapp, J¼6.7 Hz, 2H), 8.02 (d, J¼8.6 Hz,
300 MHz): d 2.46 (dd, J¼2.6, 5.0 Hz, 1H), 269 (tapp
,
J¼4.2 Hz, 1H), 2.75 (dd, J¼5.5, 14.4 Hz, 1H), 2.84 (dd,
J¼5.4, 14.4 Hz, 1H), 3.08–3.12 (m, 1H), 3.67 (s, 6H), 4.57
(dd, J¼2.0, 3.7 Hz, 2H), 6.10 (td, J¼1.6, 15.8 Hz, 1H),

11346
S. K. Mandal, S. C. Roy / Tetrahedron 63 (2007) 11341–11348
6.63–6.72 (m, 3H), 7.00 (td, J¼4.0, 15.8 Hz, 1H); 13C NMR
(CDCl3, 75 MHz): d 33.5, 47.2, 51.7, 51.8, 55.7, 67.4, 112.1,
112.7, 117.1, 121.3, 127.4, 143.2, 150.2, 154.1, 166.6;
HRMS calcd for C15H18O5Na 301.1052 [M+Na]+, found
301.1053.
(202 mg, 1 mmol) as a viscous oil (118 mg, 58%) following
the same procedure described for 4a. Rf¼0.20 (10% ethyl
acetate in light petroleum); IR (neat): 3398, 3012, 2920,
1498, 1203, 1014, 756 cmꢂ1; 1H NMR (CDCl3, 300 MHz):
d 2.27 (s, 3H), 2.50 (dd, J¼11.4, 15.9 Hz, 1H), 3.19 (dd,
J¼5.4, 15.9 Hz, 1H), 3.63–3.80 (m, 3H), 4.40 (dd, J¼4.8,
15.6 Hz, 1H), 4.91 (td, J¼2.1, 15.6 Hz, 1H), 5.43–5.49
(m, 1H), 5.54–5.61 (m, 1H), 6.87–6.99 (m, 3H); 13C
NMR (CDCl3, 75 MHz): d 20.6, 35.6, 40.5, 67.2, 72.8,
122.4, 126.7, 128.0, 131.2, 132.7, 133.3, 133.4, 154.6;
HRMS calcd for C13H16O2Na 227.1048 [M+Na]+, found
227.1053.
3.1.19. 2-(2-Allyl-phenoxymethyl)-oxirane (6). Compound
1a (670 mg, 5 mmol) in ethanol (10 mL) was added slowly to
a solution of sodium ethoxide (340 mg, 5 mmol) in ethanol
(10 mL) at 0 ꢀC over 20 min. After complete generation of
phenoxide ion (about 1 h), epichlorohydrin (573 mg,
6.2 mmol) was added slowly at 0 ꢀC and was stirred for an
additional 1 h at room temperature. The reaction mixture
was then quenched by slow addition of water (5 mL). Most
of the ethanol was removed under reduced pressure and the
residue was extracted with diethyl ether (3ꢁ100 mL). Com-
bined organic layer was washed successively with water
(10 mL), brine (10 mL) and finally dried (Na2SO4). The res-
idue obtained after removal of the solvent was purified by
column chromatography over silica gel (5% ethyl acetate
in light petroleum) to afford epoxy aryl ether 6 (685 mg,
72%) as colourless oil. Rf¼0.40; IR (neat): 3062, 2923,
1492, 1242, 1031, 752 cmꢂ1; 1H NMR (CDCl3, 300 MHz):
d 2.74 (dd, J¼2.6, 4.5 Hz, 1H), 2.86 (t, J¼4.5 Hz, 1H),
3.30–3.35 (m, 1H), 3.40 (d, J¼6.6 Hz, 2H), 3.95 (dd,
J¼5.4, 11.0 Hz, 1H), 4.20 (dd, J¼3.0, 11.0 Hz, 1H), 5.02–
5.09 (m, 2H), 5.92–6.05 (m, 1H), 6.81 (d, J¼8.0 Hz, 1H),
6.90 (tapp, J¼7.3 Hz, 1H), 7.13–7.18 (m, 2H); 13C NMR
(CDCl3, 75 MHz): d 34.2, 44.4, 50.1, 68.6, 111.5, 115.3,
121.0, 127.2, 128.8, 129.8, 136.7, 156.0; HRMS calcd for
C12H15O2 191.1072 [M+H]+, found 191.1075.
3.1.22. (8-Methoxy-5,6-dihydro-2H-benzo[b]oxocin-5-
yl)-methanol (4c). Compound 4c was prepared from 3c
(218 mg, 1 mmol) as a viscous oil (125 mg, 57%) following
the same procedure described for 4a. Rf¼0.15 (10% ethyl
acetate in light petroleum); IR (neat): 3396, 2918, 1496,
1202, 1012 cmꢂ1 1H NMR (CDCl3, 300 MHz): d 2.51
;
(dd, J¼11.7, 15.0 Hz, 1H), 3.22 (dd, J¼6.0, 15.0 Hz, 1H),
3.68–3.79 (m, 6H), 4.37 (dd, J¼4.5, 15.0 Hz, 1H), 4.91 (br
d, J¼15 Hz, 1H), 5.43–5.48 (m, 1H), 5.55–5.62 (m, 1H),
6.59 (d, J¼3.0 Hz, 1H), 6.72 (dd, J¼3.0, 9.0 Hz, 1H), 6.95
(d, J¼9.0 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d 36.5,
40.8, 55.8, 67.8, 73.7, 113.2, 115.8, 123.9, 127.5, 133.5,
134.6, 151.0, 156.3; HRMS calcd for C13H16O3Na
243.0997 [M+Na]+, found 243.0987.
3.1.23. (8-Chloro-5,6-dihydro-2H-benzo[b]oxocin-5-yl)-
methanol (4d). Compound 4d was prepared from 3d
(222.5 mg, 1 mmol) as a viscous oil (121 mg, 54%) follow-
ing the same procedure described for 4a. Rf¼0.15 (10%
ethyl acetate in light petroleum); IR (neat): 3367, 2931,
3.1.20. (5,6-Dihydro-2H-benzo[b]oxocin-5-yl)-methanol
solution of titanocene dichloride (548 mg,
(4a).
A
1485, 1176, 1010 cmꢂ1 1H NMR (CDCl3, 300 MHz):
;
2.2 mmol) in dry THF (25 mL) was stirred with activated
zinc dust (393 mg, 6 mmol) for 1 h under argon. The result-
ing green solution was then transferred through a cannula to
a dropping funnel and was added dropwise to a magnetically
stirred solution of epoxy propargylic ether 3a (188 mg,
1 mmol) in dry THF (35 mL) at room temperature under ar-
gon over 8 h. The reaction mixture was stirred for an addi-
tional 6 h and then quenched with a saturated aqueous
solution of NaH2PO4 (30 mL). The volatiles were removed
under reduced pressure and the residue obtained was ex-
tracted with diethyl ether (3ꢁ50 mL). The combined ether
layer was washed with brine (20 mL) and dried (Na2SO4).
Removal of the solvent under reduced pressure afforded
the product, which was chromatographed over silica gel
(10% ethyl acetate in light petroleum) to yield 4a (52%,
Rf¼0.23) as a colourless viscous oil along with the reduced
product 5a (12%) and another unidentified product. Spectral
data for 4a: IR (neat): 3398, 2920, 1490, 1207, 1006, 777; 1H
NMR (CDCl3, 300 MHz): d 2.58 (dd, J¼11.1, 15.9 Hz, 1H),
3.22 (dd, J¼4.9, 15.9 Hz, 1H), 3.65–3.79 (m, 3H), 4.46 (dd,
J¼4.8, 15.5 Hz, 1H), 4.94 (td, J¼2.4, 15.5 Hz, 1H), 5.44–
5.50 (m, 1H), 5.56–5.63 (m, 1H), 7.00–7.08 (m, 3H),
7.15–7.21 (m, 1H); 13C NMR (CDCl3, 75 MHz): d 35.6,
40.8, 67.3, 72.8, 122.7, 124.1, 126.7, 127.5, 130.7, 133.5,
133.4, 156.9; HRMS calcd for C12H14O2Na 213.0892
[M+Na]+, found 213.0890.
d 2.54 (dd, J¼11.1, 16.2 Hz, 1H), 3.19 (dd, J¼4.5, 16.2 Hz,
1H), 3.65–3.76 (m, 3H), 4.42 (dd, J¼4.9, 15.3 Hz, 1H),
4.93 (td, J¼2.4, 15.3 Hz, 1H), 5.43–5.49 (m, 1H), 5.55–
5.62 (m, 1H), 6.94 (d, J¼8.4 Hz, 1H), 7.05 (d, J¼2.4 Hz,
1H), 7.13 (dd, J¼2.4, 8.4 Hz, 1H); 13C NMR (CDCl3,
75 MHz): d 33.5, 40.5, 67.0, 73.0, 124.1, 126.6, 127.6,
128.9, 130.5, 133.5, 135.1, 155.6; HRMS calcd for
C12H14O2Cl 225.0682 [M]+, found 225.0674.
3.1.24. (3,4,5,6-Tetrahydro-2H-benzo[b]oxocin-3-yl)-
methanol (7). Compound 7 was prepared from the epoxide
6 (190 mg, 1 mmol) as a viscous oil (85 mg, 44%) following
the same procedure described for 4a. Rf¼0.18 (10% ethyl
acetate in light petroleum); IR (neat): 3398, 2922, 2873,
1
1488, 1218, 1008, 744 cmꢂ1; H NMR (CDCl3, 300 MHz):
d 1.43–1.57 (m, 2H), 1.62–1.78 (m, 2H), 1.96–2.04 (m, 1H),
2.65–2.73 (m, 1H), 2.78–2.88 (m, 1H), 3.41 (d, J¼6.3 Hz,
2H), 3.85 (tapp, J¼11.3 Hz, 1H), 4.24 (dd, J¼4.3, 11.3 Hz,
1H), 7.01–7.21 (m, 4H); 13C NMR (CDCl3, 75 MHz):
d 30.2, 30.4, 30.9, 40.5, 65.0, 78.0, 121.2, 124.2, 127.5,
129.7, 136.7, 157.0; HRMS calcd for C12H16O2Na 215.1047
[M+Na]+, found 215.1049.
3.1.25. (11,12-Dihydro-8H-7-oxa-cycloocta[a]naphtha-
len-11-yl)-methanol (12). Compound 12 was prepared
from the epoxide 11 (238 mg, 1 mmol) as a viscous oil
(151 mg, 63%) following the same procedure described for
4a. Rf¼0.15 (10% ethyl acetate in light petroleum); IR
3.1.21. (8-Methyl-5,6-dihydro-2H-benzo[b]oxocin-5-yl)-
methanol (4b). Compound 4b was prepared from 3b
(neat): 3398, 2875, 1467, 1203, 1066 cmꢂ1 1H NMR
;

S. K. Mandal, S. C. Roy / Tetrahedron 63 (2007) 11341–11348
11347
(CDCl3, 300 MHz): d 3.18 (dd, J¼11.7, 16.2 Hz, 1H), 3.32
(dd, J¼4.5, 16.2 Hz, 1H), 3.77 (d, J¼6.3 Hz, 2H), 3.91–
3.99 (m, 1H), 4.58 (dd, J¼4.2, 15.9 Hz, 1H), 4.94 (d,
J¼15.9 Hz, 1H), 5.36–5.42 (m, 1H), 5.49–5.64 (m, 1H),
7.19 (d, J¼8.7 Hz, 1H), 7.38 (tapp, J¼7.8 Hz, 1H), 7.46
(tapp, J¼8.4 Hz, 1H), 7.68 (d, J¼8.7 Hz, 1H), 7.77 (d,
J¼7.8 Hz, 1H), 7.98 (d, J¼8.4 Hz, 1H); 13C NMR (CDCl3,
75 MHz): d 31.4, 40.7, 67.8, 73.1, 122.8, 123.3, 124.6,
126.2, 126.4, 126.5, 128.5, 128.6, 131.1, 132.9, 133.3,
154.1; HRMS calcd for C16H16O2Na 263.1048 [M+Na]+,
found 263.1039.
a mixture of products 20a and 21a in a ratio of 2:3. Com-
pounds 20a (57 mg, 26%) and 21a (85 mg, 39%) were sep-
arated by preparative TLC (25% ethyl acetate in light
petroleum) as crystalline solids. 20a: mp 142–144 ꢀC;
Rf¼0.28; IR (KBr): 2945, 1732, 1490, 1226, 1035 cmꢂ1
;
1H NMR (CDCl3, 300 MHz): d 1.75–1.88 (m, 1H), 1.98
(dd, J¼12.7, 17.9 Hz, 1H), 2.27–2.42 (m, 1H), 2.47 (d,
J¼14.2 Hz, 1H), 2.63 (dd, J¼5.3, 17.9 Hz, 1H), 2.82 (dd,
J¼11.4, 13.7 Hz, 1H), 3.32 (dd, J¼10.4, 12.2 Hz, 1H),
4.08 (tapp, J¼11.2 Hz, 1H), 4.24 (dd, J¼3.6, 12.2 Hz, 1H),
4.47 (dd, J¼4.7, 11.2 Hz, 1H), 7.01–7.06 (m, 2H), 7.13–
7.21 (m, 2H); 13C NMR (CDCl3, 75 MHz): d 31.6, 34.4,
37.6, 40.8, 73.7, 75.1, 121.3, 124.3, 128.3, 130.4, 131.8,
159.9, 168.9; HRMS calcd for C13H15O3 219.1016
[M+H]+, found 219.1024. 21a: mp 158–160 ꢀC; Rf¼0.26;
3.1.26. 4a,5-Dihydro-4H,11H-3,10-dioxa-dibenzo [a,d]-
cyclohepten-2-one (15a). The epoxide 14a (260 mg,
1 mmol) was subjected to radical cyclization reaction using
Cp2TiCl following the same procedure described for 4a to
furnish a mixture of products in a ratio of 1.7:1.5:1. Com-
pound 15a was separated (54 mg) in pure form in 25% yield
by preparative TLC (25% ethyl acetate in light petroleum) as
a crystalline solid, mp 110–112 ꢀC. Rf¼0.26; IR (neat):
1
IR (KBr): 2933, 1732, 1487, 1226, 1087 cmꢂ1; H NMR
(CDCl3, 300 MHz): d 2.35–2.41 (m, 1H), 2.48–2.59 (m,
1H), 2.68 (dd, J¼6.9, 17.8 Hz, 1H), 2.84–2.99 (m, 2H),
3.13 (dd, J¼9.8, 15.1 Hz, 1H), 4.05–4.07 (m, 2H), 4.23
(dd, J¼6.1, 11.5 Hz, 1H), 4.36 (dd, J¼3.9, 11.5 Hz, 1H),
6.94–7.00 (m, 2H), 7.09 (d, J¼6.1 Hz, 1H), 7.16 (dt,
J¼1.8, 7.7 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d 30.0,
32.8, 34.4, 36.0, 72.5, 72.8, 120.7, 123.5, 128.2, 129.4,
131.1, 159.0, 170.8; HRMS calcd for C13H15O3 219.1016
[M+H]+, found 219.1018.
2918, 1732, 1488, 1228, 1051 cmꢂ1 1H NMR (CDCl3,
;
300 MHz): d 2.72 (dd, J¼3.8, 10.9 Hz, 1H), 2.87 (dd,
J¼10.9, 14.5 Hz, 1H), 2.99–3.07 (m, 1H), 4.11 (tapp, J¼
11.0 Hz, 1H), 4.45 (dd, J¼5.4, 11.0 Hz, 1H), 4.53 (br d,
J¼14.5 Hz, 1H), 4.75 (d, J¼14.5 Hz, 1H), 5.85 (s, 1H),
6.95–7.15 (m, 4H); 13C NMR (CDCl3, 75 MHz): d 32.2,
34.9, 70.1, 73.6, 116.7, 120.8, 124.1, 128.4, 129.1, 130.5,
158.3, 158.8, 163.6; HRMS calcd for C13H13O3 217.0859
[M+H]+, found 217.0853.
3.1.29. 7-Methoxy-4aR,5,11,11aS-tetrahydro-1H,4H-
3,10-dioxa-dibenzo[a,d]cyclohepten-2-one (20c) and
7-methoxy-4aR,5,11,11aR-tetrahydro-1H,4H-3,10-di-
oxa-dibenzo[a,d]cyclohepten-2-one (21c). The epoxide
19c (278 mg, 1 mmol) was subjected to radical cyclization
reaction using Cp2TiCl following the same procedure de-
scribed for 4a to furnish a mixture of products 20c and 21c
in a ratio of 5:6. Compounds 20c (77 mg, 31%) and 21c
(94 mg, 38%) were separated by preparative TLC (25% eth-
yl acetate in light petroleum) as crystalline solids. 20c: mp
166–168 ꢀC; Rf¼0.26; IR (KBr) 2920, 1732, 1487, 1224,
The remaining portion was probably a mixture of 16a and
17a, which could not be separated by usual chromatographic
methods.
3.1.27. 7-Methoxy-4a,5-dihydro-4H,11H-3,10-dioxa-di-
benzo[a,d]cyclohepten-2-one (15c). The epoxide 14c
(290 mg, 1 mmol) was subjected to radical cyclization reac-
tion using Cp2TiCl following the same procedure described
for 4a to furnish a mixture of products in a ratio of 2:1.8:1.
Compound 15c was separated (66 mg) in pure form in 27%
yield by preparative TLC (25% ethyl acetate in light petro-
leum) as a crystalline solid, mp 122–124 ꢀC. Rf¼0.24; IR
1
1087 cmꢂ1; H NMR (CDCl3, 300 MHz): d 1.75–1.88 (m,
1H), 1.97 (dd, J¼12.7, 18.0 Hz, 1H), 2.26–2.43 (m, 2H),
2.62 (dd, J¼5.3, 18.0 Hz, 1H), 2.83 (dd, J¼11.5, 13.6 Hz,
1H), 3.27 (dd, J¼10.7, 12.2 Hz, 1H), 3.78 (s, 3H), 4.08 (t,
J¼11.5 Hz, 1H), 4.22 (dd, J¼3.8, 12.2 Hz, 1H), 4.47 (dd, J¼
4.7, 11.4 Hz, 1H), 6.69–6.72 (m, 2H), 6.96 (d, J¼8.8 Hz,
1H); 13C NMR (CDCl3, 75 MHz): d 31.7, 34.7, 37.8, 41.0,
55.7, 73.8, 76.6, 112.6, 116.0, 122.1, 133.0, 153.9, 156.1,
169.2; HRMS calcd for C14H16O4Na 271.0946 [M+Na]+,
found 271.0952. 21c: mp 132–134 ꢀC; Rf¼0.24; IR (KBr)
(neat): 2920, 1732, 1498, 1209, 1049 cmꢂ1 1H NMR
;
(CDCl3, 300 MHz): d 2.76 (dd, J¼4.2, 14.3 Hz, 1H), 2.90
(dd, J¼10.5, 14.3 Hz, 1H), 3.01–3.08 (m, 1H), 3.77 (s,
3H), 4.19 (tapp, J¼10.4 Hz, 1H), 4.49–4.56 (m, 2H), 4.75
(d, J¼14.8 Hz, 1H), 5.89 (s, 1H), 6.67 (d, J¼3.0 Hz, 1H),
6.73 (dd, J¼3.0, 8.6 Hz, 1H), 6.97 (d, J¼8.6 Hz, 1H); 13C
NMR (CDCl3, 75 MHz): d 32.6, 35.0, 55.6, 70.3, 74.4,
113.1, 115.7, 116.9, 121.8, 131.0, 152.2, 156.1, 159.1,
163.7; HRMS calcd for C14H14O4Na 269.0790 [M+Na]+,
found 269.0784.
2929, 1728, 1496, 1207, 1072 cmꢂ1 1H NMR (CDCl3,
;
300 MHz): d 2.29–2.37 (m, 1H), 2.45–2.55 (m, 1H), 2.65–
2.80 (m, 2H), 2.98 (dd, J¼9.8, 18.2 Hz, 1H), 3.14 (dd,
J¼10.2, 14.9 Hz, 1H), 3.77 (s, 3H), 3.97–3.99 (m, 2H),
4.27 (dd, J¼5.5, 11.5 Hz, 1H), 4.38 (dd, J¼3.8, 11.5 Hz,
1H), 6.64–6.70 (m, 2H), 6.91 (d, J¼8.5 Hz, 1H); 13C
NMR (CDCl3, 75 MHz): d 30.2, 33.2, 34.4, 36.5, 55.7,
73.1, 73.4, 112.7, 116.3, 121.7, 131.6, 153.4, 155.8, 170.7;
HRMS calcd for C14H16O4Na 271.0946 [M+Na]+, found
271.0956.
The remaining portion was probably a mixture of 16c and
17c, which could not be separated by usual chromatographic
methods.
3.1.28. 4aR,5,11,11aS-Tetrahydro-1H,4H-3,10-dioxa-di-
benzo[a,d]cyclohepten-2-one (20a) and 4aR,5,11,11aR-
tetrahydro-1H,4H-3,10-dioxa-dibenzo[a,d]cyclohepten-
2-one (21a). The epoxide 19a (248 mg, 1 mmol) was
subjected to radical cyclization reaction using Cp2TiCl
following the same procedure described for 4a to furnish
Acknowledgements
We thank DST, New Delhi for financial support. S.K.M.
thanks CSIR for awarding the Fellowship.

11348
S. K. Mandal, S. C. Roy / Tetrahedron 63 (2007) 11341–11348
J. Org. Chem. 2002, 67, 6034; (p) Crimmins, M. T.;
Supplementary data
McDougall, P. J.; Emmitte, K. A. Org. Lett. 2005, 7, 4033;
(q) Basu, S.; Waldmann, H. J. Org. Chem. 2006, 71, 3977; (r)
Majumdar, K. C.; Rahaman, H.; Muhuri, S.; Roy, B. Synlett
2006, 466.
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.08.072.
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