Dehydrative reduction: a highly diastereoselective synthesis of syn-bisaryl(or heteroaryl) dihydrobenzoxathiins and benzodioxane.

Article abstract of DOI:10.1021/ol0274763

TFA/Et(3)SiH-mediated cyclization of thioketones 5 derived from the reaction of functionalized thiophenols (catechols) with bromo ketones gave syn 2,3-bisaryl(or heteroaryl) dihydrobenzoxathiins and benzodioxane 1 with total diastereoselectivity (>99:1),

Full text of DOI:10.1021/ol0274763

ORGANIC
LETTERS
2003
Vol. 5, No. 5
685-688
Dehydrative Reduction: A Highly
Diastereoselective Synthesis of
syn-Bisaryl(or Heteroaryl)
Dihydrobenzoxathiins and Benzodioxane
Seongkon Kim,* Jane Y. Wu, Helen Y. Chen, and Frank DiNinno
Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 2000,
Rahway, New Jersey 07065
seongkon_kim@merck.com
Received December 16, 2002
ABSTRACT
TFA/Et3SiH-mediated cyclization of thioketones 5 derived from the reaction of functionalized thiophenols (catechols) with bromo ketones gave
syn 2,3-bisaryl(or heteroaryl) dihydrobenzoxathiins and benzodioxane 1 with total diastereoselectivity (>99:1), in excellent yields.
Many benzodioxane and dihydrobenzoxathiin derivatives are
of interest in several pharmaceutical areas,1 since they exhibit
a variety of biological properties1a such as antihypertensive,
antidepressant, anxiolytic, and serenic activities as a conse-
quence of their specific, observed affinities.1b-g Silybin1f and
Americanol A,1g naturally occurring benzodioxane deriva-
tives,1h-i were also found to have antihepatotoxic and
neurotropic activities, respectively. In conjunction with a
medicinal chemistry program targeting selective estrogen
receptor modulators (SERMs), a method to synthesize syn-
2,3-bisaryl-substituted dihydrobenzoxathiins and benzodiox-
anes 1 was needed. Although several methods were known
to afford the anti isomer,2 only a limited number of
precedents were available in the literature prior to our study,
which lead to the syn isomer.3 Perhaps, this might be, in
part, attributable to the difficulties associated with the
diastereocontrolled chemistry necessary for the formation of
the heterocyclic systems. Herein, we wish to report a novel
diastereoselective synthesis of these substances by a dehy-
drative reduction of thioketones 5 under the conditions of
the Kursanov-Parnes reaction4 (TFA/Et3SiH).
The cyclic oxocarbonium ion generated from the acid-
promoted reaction of a ketal or a hemiketal has been
(2) (a) Capozzi, G.; Falciani, C.; Menichetti, S.; Nativi, C. J. Org. Chem.
1997, 62, 2611. (b) Tanaka, H.; Shibata, M.; Ohira, K.; Ito, K. Chem. Pharm.
Bull. 1985, 33, 1419. (c) Procopiou, P. A.; Brodie, A. C.; Deal, M. J.;
Hayman, D. F. Tetrahedron Lett. 1993, 34, 7483. (d) Guz, N. R.; Stermitz,
F. R.; Johnson, J. B.; Belson, T. D.; Willen, S.; Hsiang, J. Lewis, K. J.
Med. Chem. 2001 44, 261. (e) Li, L.; Hang, T. Org. Lett. 2001, 3, 739. (f)
Ganesh, T.; Davidkrupadanam, G. L. Synth. Commum. 1998, 28, 3121. (g)
She, X.; Jing, X.; Pan, X.; Chan, A. S. C.; Yang, T. K. Tetrahedron Lett.
1999, 40, 4567. (h) Matsumoto, K.; Takahashi, H.; Miyake, Y.; Fukuyama,
Y. Tetrahedron Lett. 1999, 40, 3185. (i) Gu, W.; Jing, X.; Pan, X.; Chan,
A. S. C.; Yang, T. K. Tetrahedron Lett. 2000, 41, 6079. (j) Arnoldi, A.;
Bassoli, A.; Caputo, R.; Merlini, L.; Palumbo, G.; Pedatella, S. J. Chem.
Soc., Perkin Trans. 1 1994, 1241. (k) Tegeler, J.; Org, H. H.; Profih, J. A.
J. Heterocycl. Chem. 1983, 20, 867.
(1) (a) Boulton, A. J. Compr. Heterocycl. Chem. II 448. (b) Maria, W.
Q.; Sayeed, K. T.; Alersandro, P.; Maria, O. G.; Gabriella, M.; Carlo, M.
J. Med. Chem. 1993, 35, 1520. (c) Gaster, L. M.; Jenning, A. J. et al. J.
Med. Chem. 1993, 36, 4121. (d) Quaglia, W.; Pigini, M.; Giannella, M. J.
Med. Chem. 1990, 33, 2946. (e) Melchiorre, C.; Brasili, L.; Giardina, D.;
Pigini, M. J. Med. Chem. 1984, 27, 1536. (f) Tanaka, H.; Shibata, M.; Ohira,
K.; Ito, K. Chem. Pharm. Bull. 1985, 33, 1419. (g) Fukuyama, Y.;
Hasegawa, T.; Toda, M.; Kodama, M.; Okazaki, H. Chem. Pharm. Bull.
1992, 40, 252. (h) Soukri, M.; Lazar, S.; Akssira, M.; Guillaumet, G. Org.
Lett. 2000, 2, 1557. (i) Labrosse, J. R.; Lhoste, P.; Sinou, D. Org. lett.
2000, 2, 527. (j) Sweetner; Arnoldi, A.; Bassoli, A.; Merlini, L.; Ragg, E.
J. Chem. Soc., Perkin Trans 1. 1993, 1359.
(3) (a) Nair, V.; Mathew, B. Tetrahedron lett. 2000, 41, 6919. (b)
Corsano, S.; Proietti, G.; Castagnino, E.; Strappaghetti, G. Farmaco Ed.
Sci. 1982, 38, 265. (c) Schonberg, A.; Awad, W. I.; Mousa, G. A. J. Am.
Chem. Soc. 1955, 77, 3850.
(4) Kursanov, D. N.; Parnes, Z. N.; Lolm, N. M. Synthesis 1974, 633.
10.1021/ol0274763 CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/01/2003

considered to be an important intermediate in organic
synthesis, particularly in the most common nucleophilic
capture strategies for C-C bond formation5 (e.g., silicon-
containing nucleophiles such as silylenol ethers, silylketene
acetals, allylsilanes, etc.). Also, there have been many recent
reports concerning the diastereoselective outcome of the
incoming nucleophile to the oxocarbonium ion, which
appears to be governed by both steric and stereoelectronic
factors.6 We, therefore, postulated that the most stable
configuration of the oxocarbonium ion 2 would be 2-II
wherein placement of one of the aryl groups in the pseudo-
axial position would alleviate the severe steric interaction
of the two aryl groups found in 2-I. Consequently, the phenyl
group at the C-3 position of intermediate 2-II would then
differentiate the approach of the nucleophile to the prochiral
oxocarbonium ion, such that hydride delivery away from it,7
at the more stereoelectronically favorable R face, was
anticipated to afford the requisite syn product 1 (Scheme
1).
resonated at δ 5.6 ppm as a doublet (J ) 2.2 Hz) and H-3
at 4.46 ppm as a doublet (J ) 2.2 Hz). Based on the
magnitude of the coupling constant,10 the aryl groups at C-2,3
were believed to be cis.
Further proof of the cis configuration was provided by an
alternative synthesis of 1b11 and the corresponding trans
1
isomer 7, as depicted in Scheme 3.12 The H NMR of 1b
Scheme 3a
a Reaction conditions: (a) NaBH4, EtOH, quantitative; (b) PPh3,
DIAD, THF, rt, >80%; (c) SOCl2, 40°C, 35%; (d) 10% Pd, H2,
EtOAc, 100%.
Scheme 1
was quite distinguishable from that of the trans compound
7, as 1b exhibited a singlet at δ 5.48 vs 4.5 ppm for 7.
Encouraged by this result, we were prompted to further
explore the synthetic potential of this process. As illustrated
in Table 1, the dehydrative reduction was found to be quite
Initially, we prepared the simple compounds 5a/5b,8
according to a reported method,9 which were reacted with
TFA in CH2Cl2 containing Et3SiH at room temperature to
give indeed the syn compounds 1a/1b (>99% diastereose-
lectivity), as no anti isomer was detected, which is described
in Scheme 2. BF3 etherate could also be used, but the former
Table 1. Cyclization of Representative Phenylthioketones
entry
X
R1
R2
R3
R4 temp (°C) time (h) yieldb (%)
Scheme 2
a
b
c
d
e
f
g
h
i
S
S
S
S
S
S
S
S
S
S
S
H
F
H
Et
H
BnO
H
F
H
H
H
H
H
H
H
H
BnO
BnO
BnO
BnO
BnO
BnO
BnO Me
BnO
BnO Et
BnO
H
H
H
H
rt
rt
rt
rt
rt
rt
0
10
10
6
30c
34d
55
65
75
50
85e
73
85
91
80
H
5
5
H
4
H
2
H
0
0
0
0
10
3
2
H
H
Cl
Me
H
j
k
Br
BnO Br
20
a Reaction conditions: 10 equiv of TFA and 3-4 equiv of Et3SiH in
CH2Cl2 (ca. 0.05 M). b All cases showed total diastereoselectivity (>99:1)
with JH-H ) 2.2 Hz. c Low yield may be due to the formation of over-
reduced products such as 10. d Mostly starting material was recovered.
e Trans isomer synthesized by an independent route showed a large coupling
constant (JH-H ) 9.0 Hz).
seemed to give better yields. The structural assignment of
1a was based on its H NMR spectral data, in which H-2
1
(5) (a) Romero, J. A. C.; Tabacco, S. A.; Woerpel, K. A. J. Am. Chem.
Soc. 2000, 122, 168. (b) Alexakis, A.; Mangeney, P. Tetrahedron:
Asymmetry 1990, 1, 447. (c) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841.
(d) Mukaiyama, T.; Murakami, M. Synthesis 1987, 1043.
general (>99% diastereoselectivity) and to proceed in good
to excellent yield13 for most of the thioketones. Significant
686
Org. Lett., Vol. 5, No. 5, 2003

electronic effects, however, were observed depending upon
the substituents. For example, meta-benzyloxy-substituted
phenolic thioketones (entries a-f) gave typically lower yields
and required longer reaction times, due perhaps to the
inductive effect of the substituent, which resulted in reduced
nucleophilicity of the phenol. Similar inductive effects were
also observed for the reaction of fluoro-substituted thioke-
tones (entries b and h14). On the other hand, para-benzyloxy-
substituted phenolic thioketones exhibited dramatic differ-
ences in yield and rate (entries g-k), presumably due to the
electron donation to the phenol, thus enhancing the rate of
cyclization in the first step. Interestingly, the yield of this
process could also be greatly improved by the addition of
alkyl groups (entries c-e and j), which inferred that the
reaction could be influenced by steric factors as well as
electronic factors. In those cases examined, wherein the rate
of cyclization was slow, the major byproduct was identified
as 10.15
Table 2. Cyclization of Representative Thioketones
Having succeeded in our original goal, we then focused
on the extension of the optimal cyclization process to other
thioketones in which both heteroaromatic and various alkyl
groups would be located at the eventual pendant position of
the benzoxathiin. As shown in Table 2, the cyclization was
a See Table 1 or as indicated. b With 20% over-reduction product (ORP).
(6) 1,3-Stereoselectivity: (a) Colobert, F.; Mazery, R. D.; Solladie, G.;
Carreno, M. C. Org. Lett. 2002, 4, 1723. (b) Ghosh, A.; Wang, Y. J. Am.
Chem. Soc. 2000, 122, 11027. (c) Paquette, L. A.; Barriault, L.; Pissarnitski,
D. J. Am. Chem. Soc. 1999, 121, 4542. (d) Larsen, C. H.; Ridgway, B. H.;
Shaw, J. T.; Woerpel, K. A. J. Am. Chem. Soc. 1999, 121, 12208. (e) Jaouen,
V.; Jegou, A.; Lemee, L.; Veyrieres, A. Tetrahedron 1999, 55, 9245. (f)
Jaouen, V.; Jegou, A.; Lemee, L.; Veyrieres, A. Tetrahedron 1999, 55, 9245.
(g) Mukaiyama, T.; Shimpuku, T.; Takashima, T.; Kobayashi, S. Chem.
Lett. 1989, 145. (h) Deslongchamps, P. Stereoelectronic Effects in Organic
Chemistry; Pergamon: New York, 1983, 209. (i) Lewis, M. D.; Cha, J. K.;
Kishi, Y. J. Am. Chem. Soc. 1982, 104, 4976. (j) Stevens, R. V.; Lee, A.
W. M. J. Am. Chem. Soc. 1979, 101, 7032.
(7) Kraus observed that axial delivery of hydride (Et3SiH) to a cyclic
oxoniumion was favored to avoid A1,2 strain; see: (a) Kraus, G. A.; Molina,
M. T.; Walling, J. A. J. Chem. Soc., Chem. Commum. 1986, 1568. (b) Kraus,
G. A.; Molina, M. T.; Walling, J. A. J. Org. Chem. 1987, 52, 1273.
(8) For 5a, the major tautomeric form would be 5a-II; γ(CO and OH)
1675, 3391 cm-1 (see: Shtsuka, Y.; Oishi, T. Chem. Pharm. Bull. 1983,
31, 443). For 5b, the major tautomeric form would be 5b-I (see: Dzvinchuk,
I. B.; Lozinskii, M. O. Zh. Org. Khim. 1991, 27, 560).
(9) (a) Ganesh, T.; Kumar, H.; Krupadanam, G. L. Synth. Commum. 1999,
29, 2069 and references therein. The functionalized thiophenols 3 were
prepared by the known procedure with minor modifications. (b) Werner,
G.; Biebrich, W. U.S. Patent 2,276,553; 2,332,418. (c) Hanzlik, R. P.;
Weller, P. E.; Desai, J.; Zheng, J.; Hall, L. R.; Slaughter, D. E. J. Org.
Chem. 1990, 55, 2736.
(10) The coupling constant for the trans isomers in related compounds
is in the range of 7-9 Hz, while the cis isomers exhibit couplings of 2-3
Hz (see refs 1g, 2b, and: Pfundt, G.; Farid, S. Tetrahedron 1966, 22, 2237).
The trans isomer that was independently synthesized (see ref 2j) exhibited
a large coupling constant (J ) 9.0 Hz) for H2,3.
(11) In contrast, hydrogenation of the analogous benzoxathiin returned
only starting material (>90%), even at high pressures, presumably due to
catalyst poisoning by the sulfur atom.
c With 12% ORP. d With 17% ORP. e Cis:trans ) 20:1. f Cis:trans ) 11:1.
effective for electron-rich heteroaromatics (entries 1 and 2)
and also proceeded with high diastereoselectivity. However,
the reaction with pyridine-substituted thioketones (entries 3
and 4) required extended times and gave relatively poor
yields, suggesting a possible enolization of the ketone,
assisted by the electron-deficient pyridinium substituent,
thereby hampering nucleophilic addition of the phenol to the
carbonyl group.
(13) Typical procedure is exemplified for the synthesis of 9g: To a flask
charged with thioketone 5g (1.35 g, 2.2 mmol) in dichloromethane (ca.
0.04 M) at 0 °C under an atmosphere of nitrogen was added slowly TFA
(1.8 mL, 10 equiv). Then, neat Et3SiH (1.3 mL, 4 equiv) was slowly added
and the reaction mixture was stirred until starting material was consumed
as monitored by TLC. The reaction mixture was poured into saturated
NaHCO3-ice water, stirred for 10 min, and extracted with dichloromethane.
The organic extract was washed with brine (2 × 100 mL), dried over Na2-
SO4, and concentrated in vacuo to afford a light yellow oil. Purification
via flash chromatography (1:5 EtOAc-hexanes) provided 1.15 g (85%) of
9g as an oil: 1H NMR (500 MHz, CDCl3) δ (ppm) 7.5-7.3 (m, 5H), 6.94
(d, 1H), 6.85 (d, 2H), 6.84 (d, 1H), 6.80 (d, 2H), 6.74 (dd, 1H), 6.65 (d,
2H), 6.64 (d, 2H), 5.43 (d, J ) 2.1 Hz, 1H), 5.05 (s, 2H), 4.30 (d, J ) 2.1
Hz, 1H), 1.23 (m, 3H), 1.10 (d, 18H).; 13C NMR (100 MHz, CDCl3) δ
(ppm) 155.7, 155.4, 153.9, 146.9, 137.3, 131.3, 131.0, 130.4, 128.8, 128.3,
128.2, 127.8, 119.7, 119.5, 114.9, 112.9, 112.1, 79.4, 70.9, 47.9, 18.2, 12.9;
MS m/z 599.1 (M+), 359.
(14) For the preparation of the fluoro-substituted thiophenol 3h, see:
Watanabe, M.; Date, M.; Tsukazake, M.; Furukawa, S. Chem. Pharm. Bull.
1989, 37, 36.
(12) (a) Adam, W. et al. J. Org. Chem. 1984, 49, 3920. (b) Procopiou,
P. A. et al. Tetrahedron Lett. 1993, 34, 7483.
Org. Lett., Vol. 5, No. 5, 2003
687

Although the cyclization reaction effected excellent control
of diastereoselectivity for the majority of the substrates, the
reaction occasionally gave some trans product (5-10%)
[entries 10 and 15], which in entry 10 was shown to be
temperature dependent, since raising the temperature to 0-10
°C increased the amount of the trans isomer to 33%. The
success of the reaction was also dependent on the acid
stability of the phenolic covering groups, wherein triisopro-
pylsilyl and benzyl ethers, as well as acetate, were compatible
with the standard reaction conditions, whereas, MOM and
MEM groups suffered hydrolysis during the course of
reaction.
In summary, the method described herein provides a high-
yielding, mechanism-based synthesis of dihydrobenzoxathiins
and benzodioxanes, and, in most instances, with total
diastereoselective control. The application of this method for
the synthesis of more complex, biologically active derivatives
with an affinity for estrogen receptors will be reported in
due course.
(15) We have shown that this product does not arise from the starting
material 5. For example, exposure of the silylated ketone, corresponding
to entry 8 in Table 2, to the reaction conditions or at higher temperatures
ranging from zero degrees to room temperature failed to yield any
appreciable quantity of the analogous reduction product. Related experiments
have also eliminated the product as the source and suggest the involvement
of an intermediate leading to the oxonium species as the potential source.
Acknowledgment. We gratefully acknowledge Professor
Barry M. Trost for helpful discussions during his scientific
consultations.
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Org. Lett., Vol. 5, No. 5, 2003