A novel approach to the synthesis of 11,11-dimethyl-bisbenzopyran-5-ones

Article abstract of DOI:10.1016/j.tetlet.2005.10.150

A facile route for the synthesis of 11,11-dimethyl-bisbenzopyran-5-ones ring system is described. The key step, the late stage oxidation of the allylic methylene group was achieved by benzyl(triethyl)ammonium permanganate in CH ₂Cl₂.

Full text of DOI:10.1016/j.tetlet.2005.10.150

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 225–228
A novel approach to the synthesis of
11,11-dimethyl-bisbenzopyran-5-ones
Nareshkumar Jain,* Jiayi Xu, Ningyi Chen and Zhihua Sui
Johnson and Johnson Pharmaceutical Research and Development, LLC 1000 Route 202, PO Box 300, Raritan, NJ 08869, USA
Received 29 September 2005; revised 27 October 2005; accepted 27 October 2005
Available online 18 November 2005
Abstract—A facile route for the synthesis of 11,11-dimethyl-bisbenzopyran-5-ones ring system is described. The key step, the late
stage oxidation of the allylic methylene group was achieved by benzyl(triethyl)ammonium permanganate in CH2Cl2.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Recently, we have disclosed a series of potent selective
estrogen receptor modulators (SERMs) with bisbenzo-
pyran system (A) mimicking steroid scaffold.1 This novel
class of compounds has demonstrated excellent in vitro
and in vivo biological profiles for potential treatment
of postmenopausal syndrome and hormone-dependent
tumors such as breast and endometrial cancers. During
development of this series of compounds, we observed
that bisbenzopyran system (A) was found to be unstable
in the air. At room temperature, these compounds turn
into complex unidentifiable mixtures after a few days.
We discovered that after staying in methanol for
extended time, the methylene group in bisbenzopyran
A was substituted with a methoxy group to yield C. We
reasoned that the formation of oxonium B is the major
mechanism for the instability of bisbenzopyran A, and
decided to introduce gem-dimethyls to the methylene
group to block the oxidation process (Scheme 1). Herein,
we wish to report the chemistry we developed for the syn-
thesis of the key intermediate, gem-dimethyl lactones 1.
Analogous to our earlier synthesis of lactones 2,2a we
first attempted the sequence illustrated in Scheme 2.
Although the Perkin reaction of 2,4-dihydroxyphenyl-
isoproanone 3a and 2,4-dimethoxyphenylacetic acid
delivered coumarin 4a in moderate yield and the conver-
sion of 4a to 4b proceeded in reasonable yield,3 all
attempts to introduce halogens using our previously
reported anionic method (Br or Cl) to the allylic methine
were unsuccessful.2a,c
Since lactones 2 can be prepared in large scale, we
decided to explore possible ways to directly introduce
gem-dimethyl groups to methylene in 2. Scheme 3
describes our first successful synthesis of lactone 1. We
discovered that bisbenzopyran lactone 2b gave mixture
of bromination products 5b and 5c in the 2:3 ratio when
treated with LiHMDS, followed by reaction with
NBS. When the mixture was stirred for extended time
(>8 h) in saturated solution of NaHCO3, hemiacetal
6b was obtained as the major product in 55% yield over
two steps. This indicates that both 5b and 5c were con-
verted to 6b during hydrolysis. We reasoned that this
conversion proceeds through the oxonium intermediate
B so that the overall yield of 6b is higher than that from
full conversion of 5b. To our delight, 6b reacts with
MeMgBr efficiently and gave secondary alcohol 7 in
high yield, which was converted to tertiary alcohol 9
in two steps by oxidation with Dess–Martin periodine
to yield compound 8, followed by addition of MeMgBr.
The cyclization and global deprotection was achieved in
one pot using 1 N HCl in 1:1 THF/ACN as solvent
Me
Me
O
11
O
OR
OR
RO
O
O
RO
O
O
1
2
*
Corresponding author. Tel.: +1 908 704 5749; fax: +1 908 526
6469; e-mail: njain@prdus.jnj.com
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.150

226
N. Jain et al. / Tetrahedron Letters 47 (2006) 225–228
O
MeO
O
OH
Air
OH
O
OH
MeOH
HO
HO
O
O
HO
O
R
R
R
A
C
B
Scheme 1. Proposed mechanisms of the instability of bisbenzopyran A.
OMe
O
a
54%
OMe
PO
O
O
HO
OH
4a, P=Ac
4b, P=Me
b,c
3a
0%
d
O
OH
Br
OMe
OMe
HO
O
O
MeO
O
O
1a
5b
Scheme 2. Reagents and conditions: (a) Et3N, Ac2O/reflux, 2,4-dimethoxyphenylacetic acid, 36 h; (b) K2CO3, MeOH, rt, 7 h; (c) MeI, K2CO3,
acetone, reflux, 12 h; (d) LiHMDS, THF, ꢁ30 °C, NBS, ꢁ30 °C to rt, 12 h.
O
OSEM
O
OSEM
+
O
OSEM
Br
a
Br
O
SEMO
O
O
SEMO
HO
O
SEMO
O
O
2b
5b
5c
HO
Me
OSEM
O
OSEM
55%
O
OSEM
b
77%
SEMO
H2O
OH
SEMO
O
O
O
O
SEMO
O
O
7
6b
B
c
53%
OH
Me
Me
O
Me
OSEM
Me
Me
OSEM
e
O
OH
d
44%
OH
OH
88%
SEMO
O
O
SEMO
O
O
HO
O
O
8
9
1a
Scheme 3. Reagents and conditions: (a) LiHMDS/THF/ꢁ32 °C!NBS/THF/ꢁ78 °C, 30 min-workup by satd aq NaHCO3; (b) MeMgBr/THF/0 °C,
30 min; (c) Dess–Martin periodine (1.5 equiv)/CH2Cl2, 1 h; (d) MeMgBr (4 equiv)/THF/ꢁ10 °C, 12 h; (e) TFA/CH3CN/THF (1:1:1), 0 °C, 3 h.
system to yield the final product 11,11-dimethylbenzo-
pyran lactone 1a.
for large scale synthesis and the overall yield is moderate
(ꢀ16%). To develop a second-generation synthesis for
these critical intermediates, we took advantage of the
symmetric nature of bisbenzopyran core in lactones 2
to introduce the gem-dimethyl groups first, followed
Although the above conversion provided us with a rea-
sonable access to gem-dimethyl lactones 1, it is lengthy

N. Jain et al. / Tetrahedron Letters 47 (2006) 225–228
227
O
OTBS
Me
Me
O
OTBS
b
O
OTBS
OH
a
88%
77%
TBSO
TBSO
O
O
TBSO
Me
OH
O
Me
2c
10
11
Me
Me
c (54%)
O
OTBS
e
1a
93%
or
d (77%)
TBSO
O
O
1c
Scheme 4. Reagents and conditions: (a) MeMgBr (excess)/THF/ꢁ10 °C, 7 h; (b) TFA/toluene/0 °C, 30 min; (c) PCC (5 equiv), CrO3 (5 equiv), 3,4-
dimethylpyrazole (10 equiv), CH2Cl2, ꢁ20 °C; 6 h; (d) benzyl(triethyl)ammonium permanganate (9 equiv), CH2Cl2, 0 °C, 3 h.
by the oxidation of the methylene to re-introduce the
lactone function group. Thus, the key intermediate 11
was prepared by addition of MeMgBr (10 equiv) to 2c
to yield tertiary alcohol 10, followed by cyclization
under acidic conditions. We screened many allylic oxi-
dation conditions to re-introduce the lactone group.4
Jones reagent, MnO2, and RuO4 failed to produce any
desired compound. Oxidation via selenium dioxide,
PCC, and KO2 also proved unsuccessful. A protocol
originally developed by Paquette using a mixture of
PCC (5 equiv), chromium trioxide (5 equiv), and 3,5-
dimethylpyrazole (10 equiv) proved to be successful
and yielded 11,11-dimethylbisbenzopyran lactone 1c in
moderate yield. To our delight, when we carried out
the reaction with benzyl(triethyl)ammonium permanga-
nate as oxidant, the yield was improved to 77%. Finally,
the deprotection of TBS group was achieved by tetra-
butylammonium fluoride in high yield.4 The overall
yield to 1a is 48% (Scheme 4). This synthetic sequence
was employed in the synthesis of several lactones 1 with
various protecting groups of the phenol hydroxyl
groups, including in multi gram scale.
gel using 20% ethyl acetate in hexane as gradient solvent
to yield 10 (2.3 g, 4.3 mmol, 88%). H NMR (CDCl3,
400 MHz) d (ppm): 7.41 (d, J = 9 Hz, 1H), 6.25 (d,
J = 9 Hz, 1H), 6.21 (m, 4H), 4.15 (Abq, J = 14 Hz,
2H), 1.28 (s, 3H), 1.21 (s, 3H), 0.8 (s, 18H), 0.02 (s,
6H), 0.01 (s, 6H). m/z: 543 (M+1).
1
3.2. Synthesis of bisbenzopyran 11
To the solution of 10 (2.3 g, 4.3 mmol) in toluene
(100 mL) at 0 °C was added 0.4 mL of TFA and was
stirred for 30 min. The reaction mixture was diluted with
ethyl acetate (250 mL) and 5% aqueous solution of
sodium bicarbonate (350 mL). After stirring vigorously
for 1 h, the organic layer was separated. The aqueous
layer was extracted with ethyl acetate (150 mL). The
combined organic layers were dried over anhydrous
Na2SO4. After filtration, the organic layer was concen-
trated in vacuum to yield crude 11 as a dark viscous
oil. This crude oil was purified by flash column chroma-
tography using 20% ethyl acetate in hexane as mobile
phase to yield 11 (1.73 g, 3.3 mmol, 77%). 1H NMR
(CDCl3, 400 MHz) d (ppm) 7.1 (d, J = 9 Hz, 1H), 6.8
(d, J = 9 Hz, 1H), 6.4 (m, 4H), 4.9 (s, 2H), 1.7 (s,
6H), 0.97 (s, 18H), 0.2 (s, 6H), 0.18 (s, 6H). m/z: 525
(M+1).
In conclusion, we have developed a novel, convenient,
and practical method for the synthesis of 11,11-dimethyl-
bisbenzopyran system (1). This procedure has been
successfully used for the synthesis of SERM analogs.
3.3. Synthesis of 11,11-dimethylbisbenzopyran 1c using
PCC
3. Experimental procedures for Scheme 4
3.1. Synthesis of tertiary alcohol 10
˚
In a 50 mL round bottom flask, 4 A molecular sieve
(125 mg) was flame-dried under high vacuum and cooled
to rt under nitrogen. The flask was charged with pyrid-
ium chlorochromate (216 mg, 1.0 mmol), chromium tri-
oxide (100 mg, 1.0 mmol), 3,5-dimethylpyrazole
(192.3 mg, 2.0 mmol), and dichloromethane (2 mL).
The reaction mixture was cooled to ꢁ20 °C and stirred
for 30 min. Bisbenzopyran 11 (105 mg, 0.2 mmol) in
1 mL of dichloromethane was added slowly to the above
reaction mixture at ꢁ20 °C. After stirring for 6 h at
ꢁ20 °C, the reaction mixture was diluted with 100 mL
of CH2Cl2 and filtered through a pad of silica gel
(10 g). The silica gel was washed by 50 mL of dichloro-
methane and ethyl acetate (1:1). The combined organic
layer was evaporated and purified by flash column chro-
To a solution of 2c (2.55 g, 5 mmol) in 50 mL THF at
ꢁ20 °C was added methyl magnesium bromide in ethyl
ether (3.0 M, 5 mL). The reaction mixture was warmed
to ꢁ10 °C and was stirred for 7 h at ꢁ10 °C. The reac-
tion mixture was then quenched with aqueous saturated
solution of ammonium chloride (200 mL) and extracted
with ethyl acetate (300 mL). The organic layer was sepa-
rated and the aqueous layer was extracted again with
100 mL of ethyl acetate. The combined organic layers
were filtered through a pad of MgSO4 (anhydrous)
and concentrated at reduced pressure. The crude residue
was purified by flash column chromatography on silica

228
N. Jain et al. / Tetrahedron Letters 47 (2006) 225–228
matography using 20% ethyl acetate in hexane as mobile
phase to yield 1c as a yellow oil (59 mg, 0.109 mmol,
54%). 1H NMR (CDCl3, 400 MHz) d (ppm): 8.1 (d,
J = 9 Hz, 1H), 7.4 (d, J = 9 Hz, 1H), 6.6 (d, J = 1 Hz,
1H), 6.56 (dd, J = 1, 9 Hz, 1H), 6.33 (dd, J = 1, 9 Hz,
1H), 6.28 (d, J = 1 Hz, 1H) 1.65 (s, 6H), 0.77 (s, 18H),
0.25 (s, 6H), 0.2 (s, 6H). m/z: 539 (M+1).
filtration, the organic layer was concentrated in vacuum
to yield crude 1a as a dark yellow solid. This crude oil
was purified by short flash column chromatography
using 50% ethyl acetate in hexane as mobile phase to
1
yield 1a as yellow solid (63 mg, 0.20 mmol, 93%). H
NMR (DMSO-d6, 400 MHz) d (ppm): 10.6 (s, 1H), 9.8
(s, 1H), 8.23 (d, J = 9 Hz, 1H), 7.6 (d, J = 9 Hz, 1H),
6.85 (dd, J = 9 Hz), 6.75 (d, J = 1 Hz, 1H), 6.5 (dd,
J = 1, 9 Hz, 1H), 6.38 (d, J = 1 Hz, 1H) 1.55 (s, 6H);
m/z: 311 (M+H), 333 (M+Na).
3.4. Synthesis of 11,11-dimethylbisbenzopyran 1c using
benzyl(triethyl) ammonium permanganate
To a solution of 11 (330 mg, 0.62 mmol) in 10 mL of
dichloromethane at 0 °C was added 11.2 mL of freshly
prepared stock solution of benzyl(triethyl)ammonium
permanganate (0.5 M in CH2Cl2, 5.6 mmol). After stir-
ring for 3 h, the reaction mixture was diluted with
50 mL of CH2Cl2 and filtered through a pad of silica
gel (10 g). The silica gel was washed with 50 mL of
dichloromethane and ethyl acetate (1:1). The combined
organic layers were dried with MgSO4 and the solvents
were evaporated. Flash column chromatography using
20% ethyl acetate in hexane as mobile phase yielded 1c
References and notes
1. (a) Kanojia, R. M.; Jain, N. F.; Ng, R.; Sui, Z.; Xu, J. WO
2003053977, 2003; (b) Kanojia, R. M.; Jain, N. F.; Ng, R.;
Sui, Z.; Xu, J. U.S. Patent 71,997,520,031,121, 2004.
2. (a) Kanojia, R. M.; Jain, N.; Xu, J.; Sui, Z. Tetrahedron
Lett. 2004, 45, 5837–5839; (b) Perkin, W. H. J. Chem. Soc.
1868, 21, 53; (c) Perkin, W. H. J. Chem. Soc. 1868, 31, 388;
(d) Bargellini, G.; Atti, R. Accad. Lincei. 1925, 2, 261.
3. (a) Baran-Marszak, M.; Massicot, J.; Molho, D. Bull. Soc.
Chim. Fr. 1971, 1, 191–198; (b) Chatterjea, J. N.; Prasad, N.
J. Indian Chem. Soc. 1968, 45, 35–44; (c) Nesvadba, P.;
Jandke, J. WO 9952909, 1999; (d) Becker, H. D.; Lingnert,
H. J. Org. Chem. 1982, 47, 1095–1101; (e) Box, V. G. S.;
Humes, C. G. Heterocycles 1980, 14, 1775–1777; (f) Van De
Water, R. W.; Pettus, T. R. R. Tetrahedron 2002, 58, 5367–
5405.
1
as a yellow oil (257 mg, 0.477 mmol, 77%). H NMR
and MS are identical to the product described in the last
section.
3.5. Synthesis of 11,11-dimethylbisbenzopyran 1a
A solution of 1c (118 mg, 0.21 mmol) in anhydrous THF
was cooled to 0 °C. To this solution, TBAF (1 M in
THF, 0.8 mL, 0.8 mmol) was added. After stirring for
3 h at 0 °C, the reaction mixture was diluted with
50 mL of aqueous saturated solution of NH4Cl and
50 mL of ethyl acetate. After stirring vigorously for
1 h, the organic layer was separated. The aqueous layer
was extracted with ethyl acetate (50 mL). The combined
organic layers were dried over anhydrous Na2SO4. After
4. (a) Bal, B. S.; Kochhar, K. S.; Pinnick, H. W. J. Org. Chem.
1981, 46, 1492–1493; (b) Schuda, P. F.; Cichowicz, M. B.;
Heimann, M. R. Tetrahedron Lett. 1983, 24, 3829–3830; (c)
Abelman, M. M.; Overman, L. E.; Tran, D. V. J. Am.
Chem. Soc. 1990, 112, 6959–6964; (d) Paquette, L. A.;
Owen, R. D.; Bibart, R. T.; Seekamp, C. K.; Kahane, A. L.;
Lanter, J. C.; Corral, M. A. J. Org. Chem. 2001, 66, 2828–
2834; (e) Schmidt, H.; Schafer, H. J. Angew. Chem., Int. Ed.
Engl. 1979, 18, 69–71.