A facile synthesis of an unsymmetric benzopyranobenzopyran ring system

Article abstract of DOI:10.1016/j.tetlet.2004.06.008

A facile route to the synthesis of an unsymmetric benzopyranobenzopyran ring system is described. A key feature of this synthesis incorporates a tandem deprotection-cyclization strategy to construct the C-ring of the tetracyclic system.

Full text of DOI:10.1016/j.tetlet.2004.06.008

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5837–5839
A facile synthesis of an unsymmetric benzopyranobenzopyran
ring system
Ramesh M. Kanojia, Nareshkumar Jain, Jiayi Xu and Zhihua Sui*
Johnson & Johnson Pharmaceutical Research and Development, LLC, 1000 Route 202, Raritan, NJ 08869, USA
Received 13 May 2004; revised 28 May 2004; accepted 2 June 2004
Abstract—A facile route to the synthesis of an unsymmetric benzopyranobenzopyran ring system is described. A key feature of this
synthesis incorporates a tandem deprotection–cyclization strategy to construct the C-ring of the tetracyclic system.
ꢀ 2004 Elsevier Ltd. All rights reserved.
In conjunction with our medicinal chemistry efforts to
discover novel selective estrogen receptor modulators
(SERMs), we chose to access the steroid-mimetic scaf-
fold, unsymmetric bisbenzopyran II through the lactone
precursor I. To facilitate our SAR studies, we looked
for a synthetic method that would allow us to introduce
a variety of functional groups into the A-, B-, and
D-rings.
Pechmann condensation of a and b (path A), following
the Baran-Marszak conditions,1a gave only a trace
amounts of Ia. Although we were able to effect isomer-
ization of isoxindigo c to the symmetric bislactone d
utilizing literature procedures (path B),1b–d the poor
solubility of compound d posed a significant challenge
for its desymmetrization to the desired product I (path
B). Intramolecular Claisen type cyclization of f via the
Box protocol1e (path C) also failed to deliver the desired
product.
O
C
O
D
R2
R2
Having explored these literature approaches, we decided
to access our key intermediate through coumarin IV
(Scheme 2). The lynchpin of this strategy is the incor-
poration of a two-step cascade reaction sequence initi-
ated by the deprotection of an oxygen moiety and its
subsequent intramolecular nucleophilic capture of a
proximally positioned electrophile to construct the
C-ring. Although less likely, it is worth noting that
structure I could be formed through electrocyclization
of vinylogous o-quinone methide generated from IV
upon deprotection.1f
R1
A
B
O
R1
R
O
O
II
I
O
O
R2
R1
O
O
III
A brief survey of the literature revealed that although
the synthesis of symmetrical bislactones like III was
documented, the synthesis of an unsymmetrical system
like I had not been well studied.1 Using dimethoxy
analog (Ia) as an example, we explored three literature
approaches to access this key intermediate (Scheme 1).
Details of this cascade reaction sequence including the
preparation of the precursor are outlined in Scheme 3.
Modified Perkin reaction2a–c of a mixture of 2-hy-
droxyacetophenones 1 and 2,4-dimethoxyphenylacetic
acid 2 in the presence of triethylamine in refluxing acetic
anhydride delivered coumarin 3 in moderate to good
yield. Global demethylation and deacetylation of 3a
with pyridine hydrochloride at 200 ꢁC, per-acetylation
of the tris-phenol 4a and radical bromination of the
triacetate 4b with N-bromosuccinimide afforded the allyl
bromide 5 in modest yield.
Keyword: Benzopyran.
* Corresponding author. Tel.: +1-908-704-5778; fax: +1-908-526-6469;
e-mail: zsui@prdus.jnj.com
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.008

5838
R. M. Kanojia et al. / Tetrahedron Letters 45 (2004) 5837–5839
O
OMe
H+
+
A:
B:
( Pechmann )
O
MeO
OH
O
EtO
a
b
O
OCH3
O
O
OMe
OMe
O
O
O
H3CO
O
O
MeO
O
O
O
MeO
Ia (R1 = R2= OMe )
c
d
OMe
Br
O
Br
O
Diethylaniline
Br
C:
MeO
∆
O
MeO
O
f
O
e
Scheme 1.
Y
O
lactone 7 in multi-gram quantities. Bromination of 3b
was conveniently carried out using lithium hexameth-
yldisilazine (LiHMDS) as a base in THF at )32 ꢁC to
generate the carbanion, which was added dropwise to a
solution of NBS in THF at )78 ꢁC to provide 6.
Demethylation of 6 was conveniently accomplished with
BBr3 in dichloromethane at room temperature. In situ
treatment of the corresponding tris-phenol with aqueous
NaOH solution directly resulted in the formation of 7,
which was isolated from the alkaline aqueous solution
by acid precipitation.
X
O
C
R2
R2
R1
R1
O
O
O
O
IV
I
Scheme 2.
Treatment of a colorless solution of bromotriacetate 5
with K2CO3 in an acetone/methanol mixture at room
temperature resulted in an immediate color change,
indicating the rapid formation of the tetracyclic struc-
tures 7 via deacetylation of the phenyl acetate 5 followed
by instantaneous displacement of the allylic bromide by
the newly generated adjacent phenoxide anion to form
the pyran ring C. Compound 7 was isolated by acid
precipitation in high yield.4
In conclusion, we have developed a novel, convenient,
and practical method to synthesize the tetracyclic benzo-
pyranobenzopyran lactones I. In addition to the com-
pounds exemplified in this paper, related analogs with
various A/D ring substitution patterns including both
electron-donating and electron-withdrawing groups
were synthesized, and employed as pivotal intermediates
in our synthesis of novel nonsteroidal SERMs.3 The
biological properties of these novel structures will be
reported in future communications.
We also explored the anionic bromination of 3b, a
modification that allowed us to synthesize the target
R'
OMe
OMe
Me
O
Me
Me
O
a
b
O
OH
+
HO
R"
OMe
30-60%
OMe
~80%
R
O
R
O
R
O
1a, R = OH
4a, R = R' = R'' = OH
4b, R = R' = R" = OAc
2
3a, R = OAc
3b, R = OMe
c
1b, R = OMe
~40%
d
f
30-60%
Br
OMe
Br
OAc
O
OH
g
OMe
OAc
MeO
O
O
AcO
O
O
HO
O
O
6
7
5
70-90%
e
Scheme 3. Reagents and conditions: (a) Et3N, Ac2O/reflux; (b) pyridine, HCl/200 ꢁC; (c) Ac2O/pyridine; (d) NBS/benzoyl peroxide, CCl4/hm;
(e) K2CO3/MeOH/acetone; (f) LiHMDS/THF/)32 ꢁCfiNBS/THF/)78 ꢁC; (g) BBr3/DCMfiNaOH/Hþ.

R. M. Kanojia et al. / Tetrahedron Letters 45 (2004) 5837–5839
5839
5.12. Found: C, 67.75; H, 4.99. Compound 4a: mp 282–
1
Acknowledgements
283 ꢁC; H NMR (300 MHz, DMSO-d6) d 10.41 (1H, br s),
9.34 (2H, s), 7.62 (1H, d, J ¼ 8:8 Hz), 6.81 (2H, dd, J ¼ 2:5,
8.3 Hz), 6.72 (1H, d, J ¼ 2:2 Hz), 6.35 (1H, d, J ¼ 2:1 Hz),
6.27 (1H, dd, J ¼ 2:1 Hz), 2.13 (3H, s); IR (KBr) 3454,
3264, 1673, 16160, 1562, 1509 cmꢀ1; MS (CI) 285 (MHþ),
283 (M)H). Anal. Calcd for C16H12O5/0.25H2O: C, 66.55;
H, 4.36. Found: C, 66.63; H, 4.53. Compound 4b: mp 145–
146 ꢁC; 1H NMR (300 MHz, CDCl3) d 7.70 (1H, d,
J ¼ 8:7 Hz), 7.26 (1H, J ¼ 2:3 Hz), 7.16–7.10 (4H, m),
2.36 (3H, s), 2.32 (3H, s) 2.28 (3H, s), 2.22 (3H, s); IR (KBr)
1763, 1726, 1611, 1573, 1501 cmꢀ1; MS (CI) 411 (MHþ),
232 (M+Na). Anal. Calcd for C22H18O8: C, 64.39; H, 4.23.
Found: C, 64.16; H, 4.23. Compound 5: mp 171–172 ꢁC; 1H
NMR (300 MHz, CDCl3) d 7.81 (1H, d, J ¼ 8:7 Hz), 7.49
(1H, d, J ¼ 8:3 Hz), 7.19–7.13 (4H, m), 4.40 (1H, d,
J ¼ 10 Hz), 4.27 (1H, d, J ¼ 10 Hz), 2.38 (3H, s), 2.33
(3H, s), 2.11 (3H, s); IR (KBr) 1766, 1725, 1613, 1571, 1499,
1426, 1369, 1194 cmꢀ1; MS (CI) 488 (MHþ), 512 (M+Na).
Anal. Calcd for C22H17BrO8: C, 54.01; H, 3.50. Found: C,
54.03; H, 3.42. Compound 7: mp >350 ꢁC; 1H NMR
(300 MHz, DMSO-d6) d 10.65 (1H, br s), 9.85 (1H, br s),
8.19 (1H, d, J ¼ 8:0 Hz), 7.62 (1H, d, J ¼ 8:1 Hz), 6.82 (1H,
d, J ¼ 8:2 Hz), 6.76 (1H, s), 6.47 (1H, d, J ¼ )7.75 Hz), 6.38
(1H, s), 5.33 (2H, s); IR (KBr) 3373, 1699, 1620, 1597, 1508,
1464, 1299, 1264, 1166 cmꢀ1; MS (CI) 283 (MHþ), 305
(M+Na), 321 (M+K), 281 (M)H). Anal. Calcd for
C16H10O5/0.2H2O: C, 67.23; H, 3.67. Found: C, 67.31; H,
3.55.
We acknowledge the valuable technical support in scale-
up preparations by Dr. Ronald Russell and Richard
Adams.
References and notes
1. (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(1), 35–44; (c) Nesvadba, P.;
Jandke, J. WO 9952909, 1999; (d) Becker, H. D.; Lingnert,
H. J. Org. Chem. 1982, 47(6), 1095–1101; (e) Box, V. G. S.;
Humes, C. G. Heterocycles 1980, 14(11), 1775–1777; (f)
Van De Water, R. W.; Pettus, T. R. R. Tetrahedron 2002,
58, 5367–5405.
2. (a) Perkin, W. H. J. Chem. Soc. 1868, 21, 53:; (b) Perkin, W.
H. J. Chem. Soc. 1868, 31, 388; (c) Bargellini, G.; Atti, R.
Accad. Lincei 1925, 2, 261.
3. Kanojia, R. M.; Jain, N.; Ng, R.; Sui, Z.; Xu, J. WO
2003053977, 2003.
4. Analytical data for all the new compounds. Compound 3a:
mp 149–150 ꢁC; 1H NMR (300 MHz, CDCl3) d 7.67 (1H, d,
J ¼ 8:7 Hz), 7.13–7.06 (3H, m), 6.58 (1H, d, J ¼ 12:13 Hz),
6.56 (1H, s), 3.85 (3H, s), 3.76 (3H, s), 2.36 (3H, s), 2.24
(3H, s); IR (KBr) 1762, 1731, 1610, 1574, 1506 cmꢀ1; MS
(CI) 355 (MHþ). Anal. Calcd for C20H18O6: C, 67.79; H,