[4 + 2] Cycloaromatization of 4-bis(methylthio)-3-buten-2-one with active methylene ketones: A simple and facile phenol annulation

Article abstract of DOI:10.1021/jo020219r

A new method for β-phenol annulation involving base-induced [4C + 2C] cycloaromatization of readily available 4-bis(methylthio)-3-buten-2-one with a variety of cyclic and acyclic active methylene ketones has been reported. Appropriate choice of ketones allows synthesis of diverse frameworks such as dihydroindan, tetrahydronaphthalenes, their higher homologues, dihydro/octahydrophenanthrenes, anthracene, and heteroannulated analogue in high yields with regiocontrol of phenolic functionality.

Full text of DOI:10.1021/jo020219r

[
4 + 2] Cycloa r om a tiza tion of
materials. Particularly noteworthy aromatic annulation
reactions leading to substituted phenols developed re-
cently include methods based on Diels-Alder reaction
4
-Bis(m eth ylth io)-3-bu ten -2-on e w ith Active
Meth ylen e Keton es: A Sim p le a n d F a cile
P h en ol An n u la tion
6
of suitably functionalized dienes and dienophiles, Rob-
7
inson annulation, Dotz reaction of Fischer carbene
Okram Barun, Sukumar Nandi, Kausik Panda,
Hiriyakkanavar Ila,* and Hiriyakkanavar J unjappa*
8a,b
8c
complexes, transition-metal-catalyzed [2 + 2 + 2] and
8d
[
4 + 2] cycloaddition, thermal and photochemical elec-
trocyclization of dienylketene intermediates, carbonyl
9
Department of Chemistry, Indian Institute of Technology,
Kanpur 208 016, U. P. India
10
11
condensations, and other related reactions. Our con-
tinued interest in the development of new aromatic annu-
lation strategies relies upon utilization of R-oxoketene
dithioacetals as three carbon 1,3-bielectrophilic compo-
nents in a [3C + 3C] cyclocondensation with various 1,3-
binucleophilic species yielding a variety of regiospecifi-
hila@iitk.ac.in
Received April 1, 2002
Abstr a ct: A new method for â-phenol annulation involving
base-induced [4C + 2C] cycloaromatization of readily avail-
able 4-bis(methylthio)-3-buten-2-one with a variety of cyclic
and acyclic active methylene ketones has been reported.
Appropriate choice of ketones allows synthesis of diverse
frameworks such as dihydroindan, tetrahydronaphthalenes,
their higher homologues, dihydro/octahydrophenanthrenes,
anthracene, and heteroannulated analogue in high yields
with regiocontrol of phenolic functionality.
cally substituted and fused aromatic and heteroaromatic
12,13
structural frameworks.
These studies prompted us to
investigate new methods for construction of substituted
phenolic ring utilizing these precursors, and we now re-
port a versatile phenol annulation capable of broad appli-
cation, which unlike our earlier [3C + 3C] cycloaroma-
tization process is based upon [4C + 2C] Robinson aro-
matic annulation of readily accessible 4-bis(methylthio)-
Substituted and fused phenols constitute structural
subunit of several important natural products such as
3
-buten-2-one (2) with various active methylene ketones.
The utility of Robinson annulation7 for regiospecific
-hydroxycalamenene,1a,b ferruginol, hinokiol, 9,10-
1c
1d
7
2
dihydrophenanthrenes such as juncusol, and effusol
displaying interesting microbial and cytotoxic properties.3
Classical approaches to these complex subunits invari-
ably exploit readily available phenolic precursors as an
aromatic template on which the remaining molecular
framework or substituents are introduced in the subse-
quent steps, which rely heavily on the conventional
phenol annulation has been recognized in a few instances.
14
Thus, Boger’s method employs 2-(phenylsulfinyl)cyclo-
(6) (a) Oppolzer, W. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming. I., Eds.; Pergamon: Oxford, 1991; Vol. 5, pp 315-399.
(b) Danishefsky, S.; Kitahara, T.; Yan, C. F.; Morris, J . J . Am. Chem.
Soc. 1979, 101, 6996. (c) Danishefsky, S.; Etheredge, S. J . J . Org. Chem.
1979, 44, 4716. (d) Danishefsky, S.; Harayama, T.; Singh, R. K. J . Am.
Chem. Soc. 1979, 101, 7008. (e) Andersen, N. G.; Maddaford, S. P.;
Keay, B. A. J . Org. Chem. 1996, 61, 2885. (f) Boger, D. L.; Mullican,
M. D. Tetrahedron Lett. 1982, 23, 4551.
(7) (a) J ung, M. E. Tetrahedron 1976, 32, 3. (b) Gawley, R. E.
Synthesis 1976, 777. (c) Abad, A.; Agullo, C.; Arno, M.; Cunat, A. C.;
Teresa Garcia, M.; Zaragoza, R. J . J . Org. Chem. 1996, 61, 5916. (d)
Banwell, M. G.; Lambert, J . N.; Corbett, M.; Greenwood, R. J .; Gulbes,
J . M.; Macky, M. F. J . Chem. Soc., Perkin. Trans. 1 1992, 1415.
(8) (a) Dotz, K. H. Angew. Chem., Int. Ed. Engl. 1984, 23, 587. (b)
Dotz, K. H.; Tomuschat, P. Chem. Soc. Rev. 1999, 28, 187. (c) Vollhardt,
K. P. C. Angew. Chem., Int. Ed. Engl. 1984, 23, 539. (d) Saito, S.;
Yamamoto, Y. Chem. Rev. 2000, 100, 2901.
4
a-e
electrophilic, nucleophilic substitutions
or metala-
tion-functionalization reactions.4 However, these meth-
ods suffer from serious regiochemical ambiguities and
require long multistep reactions resulting in lower yields
of the target compounds. Important modern methods for
f,g
regiospecific elaboration of substituted phenols involve
highly convergent annulation reactions5 in which the
aromatic system is assembled from acyclic precursors and
the substitution pattern of the product phenols is dictated
by the structures and functionalities of the starting
(
9) (a) Loebach, J . L.; Bennet, D. M.; Danheiser, R. L. J . Org. Chem.
1
998, 63, 8380. (b) Danheiser, R. L.; Brisbois, R. G.; Kowalczyk, J . J .;
Miller, R. F. J . Am. Chem. Soc. 1990, 112, 3093. (c) Turnbull, P.; Moore,
H. W. J . Org. Chem 1995, 60, 644. (d) Moore, H. W.; Decker, O. H. W.
Chem. Rev. 1986, 86, 821. (e) Bellus, D.; Ernst, B. Angew. Chem., Int.
Ed. Engl. 1988, 27, 797. (f) Liebeskind, L. S. Tetrahedron 1989, 45,
3053.
(10) (a) Takeuchi, N.; Ochi, K.; Murase, M.; Tobinaga, S. J . Chem.,
Soc. Chem. Commun. 1980, 593. (b) Hirota, K.; Kitade, Y.; Senda, S.
J . Org. Chem. 1981, 46, 3949. (c) Milart, P.; Sepiol, J . Tetrahedron
Lett. 1990, 31, 2735 (d) Robi, J . A. Tetrahedron Lett. 1990, 31, 3421.
(e) Barton, D. H. R.; Dressaire, G.; Wills, B. J .; Barrett, A. G. M.;
Pfeffer, M. J . Chem. Soc. 1982, 665. (f) Serra, S.; Fuganti, C.; Moro,
A. J . Org. Chem. 2001, 66, 7883 and references therein.
(11) (a) Tius, M. A. Tetrahedron Lett. 1981, 22, 3335. (b) Tius, M.
A.; Ali, S. J . Org. Chem. 1982, 47, 3163. (c) Tius, M. A.; Thurukauf,
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Thurukauf, A. J . Org. Chem. 1983, 48, 3839. (e) Chan, T.-H.; Brown-
bridge, P. J . Am. Chem. Soc. 1980, 102, 3534. (f) Chan, T. H.;
Brownbridge, P. Tetrahedron 1981, 37, 387. (g) Chan T. H.; Prasad,
C. V. C. J . Org. Chem, 1986, 51, 3012. (h) J akobi, P. A.; Kravitz, J . I.;
Zheng, W. J . Org, Chem. 1995, 60, 376.
(12) Review: (a) J unjappa, H.; Ila, H.; Asokan, C. V. Tetrahedron
1990, 46, 5423. (b) J unjappa, H.; Ila, H. Phosphorous, Sulfur Silicon
1994, 95, 35. (c) Ila, H.; J unjappa, H.; Barun, O. J . Organomet. Chem.
2001, 64, 34. (d) Ila, H.; J unjappa, H.; Mohanta, P. K. In Progress in
Heterocyclic Chemistry; Gribble, G. H., Gilchrist, L. T., Eds.; Pergamon
Press: Oxford, 2001; Vol. 13, Chapter 1, pp 1-24.
*
To whom correspondence should be addressed. Fax: 91-0512-
97436, 91-0512-590260.
1) (a) Rowe, J . W.; Toda, J . K. Chem. Ind. (London) 1969, 922. (b)
5
(
Lindgren, O. B.; Svahn, C. M. Phytochemistry 1968, 7, 1407; Chem.
Abstr. 1968, 69, 65131. (c) Ohashi, M.; Maruishi, T.; Kakisama, H.
Tetrahedron Lett. 1968, 719. (d) Matsumoto, T.; Usui, S.; Kamashima,
H. Mitsuki. Bull. Chem. Soc. J pn. 1981, 54, 581.
(2) (a) Miles, D. H.; Bhattacharya, J .; Mody, N. V.; Atwood, J . L.;
Black, S.; Hedin, P. A. J . Am. Chem. Soc. 1977, 99, 618. (b) McDonald,
E.; Martin, R. T. Tetrahedron Lett. 1978, 4723. (c) Kende, A. S.; Curran,
D. P. J . Am. Chem. Soc. 1979, 101, 1857. (d) Leed, A. R.; Boettger, S.
D.; Ganem, B. J . Org. Chem. 1980, 45, 1098. (e) J acobi, P. A.; Kravitz,
J . I.; Zheng, W. J . Org. Chem. 1995, 60, 376.
(3) (a) Cava, M. P.; Buck, K. T.; Noguchi, I.; Srinivasan, M.; Rao,
M. G.; daRocha, A. I. Tetrahedron 1975, 31, 1667. (b) Cava, M. P.; Buck,
K. T.; daRocha, A.I. J . Am. Chem. Soc. 1972, 94, 5931.
(4) (a) Olah, G. A. Acc. Chem. Res. 1971, 4, 240. (b) Hartshorn, S.
R. Chem. Soc. Rev. 1974, 3, 167. (c) Bunnett, J . F. Acc. Chem. Res.
978, 11, 413. (d) Bohlmann, F.; Mailahn, W. Chem. Ber. 1981, 114,
091. (e) Alexander J .; Rao, G. S. K. Tetrahedron 1971, 27, 645. (f)
1
1
Chander, B.; Green, L.; Snieckus, V. Pure Appl. Chem. 1999, 71, 1521.
g) Beak, P.; Snieckus, V. Acc. Chem. Res. 1982, 15, 306.
5) Reviews: (a) Katritzky, A. R.; Li, J .; Xie, L. Tetrahedron Report
(
(
No. 496. Tetrahedron 1999, 55, 8263. (b) Bamfield, P.; Gordon, P. F.
Chem. Soc. Rev. 1984, 13, 441.
1
0.1021/jo020219r CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/26/2002
5
398
J . Org. Chem. 2002, 67, 5398-5401

hexanone with an R-eliminating group that on cyclocon-
densation with a few substituted buten-3-ones (Michael
acceptors) under basic conditions directly affords the
phenol-annulated cyclohexanones in moderate yields. On
the other hand, Takaki has utilized 3-(phenylthio)-3-
buten-2-one with an R-eliminating group as a Michael
acceptor in Robinson annulation with few cycloal-
kanones.15 The initially formed Michael adducts or the
ketols were transformed into the corresponding phenols
either by oxidative elimination or under acidic/basic
conditions. The 3-(phenylthio)-3-buten-2-one is, however,
shown to undergo dimerization under alkaline conditions
requiring milder conditions and care for successful Rob-
inson annulation. Recently, 1-acetoxy-3-buten-2- one and
the corresponding 1,4-diacetoxy-2-butanone are shown to
undergo Robinson-type annulation with pyrrolidine enam-
ines yielding pyrrolidino-substituted benzene derivatives
in moderate yields.16
TABLE 1. â-P h en ol An n u la tion of Va r iou s Keton es
We became interested in examining 4-bis(methylthio)-
3
-buten-2-one (2), a stable readily available analogue of
methylvinyl ketone with two leaving groups at the
â-position, as a potential 4-carbon Michael acceptor
component in Robinson-type phenol annulation. We first
investigated annulation of 2 with aliphatic cyclic ketones
(Table 1). When equimolar quantities of cyclohexanone
and 2 in the presence of sodium hydride were stirred in
DMF at room temperature for 6 h (method A), workup,
and column chromatography of the reaction mixture
furnished a white solid (78%), which was characterized
as 7-hydroxy-5-methylthio-1,2,3,4-tetrahydronaphthalene
(4a ) on the basis of its spectral and analytical data. Thus,
the entire reaction sequence, i.e., formation of conjugate
addition-elimination adduct 3 followed by intramolecu-
lar Aldol condensation and cycloaromatization proceeds
under surprisingly mild conditions affording the annu-
lated phenol 4a directly without isolation of the adduct
(Scheme 1). This novel phenol annulation was found to
be equally facile with other cyclic aliphatic ketones such
as 4-methyl-, 2-methyl-, and 4-tert-butylcyclohexanones,
cyclopentanone, cycloheptanone, cyclooctanone, and cy-
clododecanone (Table 1, entries 2-8), yielding 3-meth-
ylthio-4,5-annulated phenols 4b-h in 68-89% overall
yields (Table 1). Similarly, when the corresponding 1- and
2
-trans-decalones 1i and 1j were subjected to phenol
annulation under the identical conditions, the corre-
sponding 3-hydroxyoctahydrophenanthrene (4i) and 2-hy-
droxyoctahydroanthracene (4j) were obtained in 77% and
8
7% yields respectively (Table 1, entries 9 and 10). A few
of the annulated phenols (4d -f,h ) were desulfurized with
Raney Ni (W2) to give the corresponding dethiomethy-
lated products 5d -f,h in high yields. Alternatively, the
(13) Recent references: (a) Suresh, J . R.; Syam Kumar, U. K.; Ila,
H.; J unjappa, H. Tetrahedron 2001, 57, 781. (b) Mohanta, P. K.;
Peruncheralathan, S.; Ila, H.; J unjappa, H. J . Org. Chem. 2001, 66,
1
2
503. (c) Suresh, J . R.; Barun, O.; Ila, H.; J unjappa, H. Tetrahedron
000, 56, 8153. (d) Mehta, B. K. Nandi, S.; Ila, H.; J unjappa, H.
Tetrahedron 1999, 55, 12853 (e) Basveswara Rao, M. V.; Syam Kumar,
U. K.; Ila, H.; J unjappa, H. Tetrahedron 1999, 55, 11563. (f) Patra, P.
K.; Suresh, J . R.; Ila, H.; J unjappa, H. Tetrahedron 1998, 54, 10169.
(
g) Syam Kumar, U. K.; Patra, P. K. Ila, H.; J unjappa, H. Tetrahedron
Lett. 1998, 39, 2029.
(
(
14) Boger, D. L.; Mullican, M. D. J . Org. Chem. 1980, 45, 5002.
15) (a) Takaki, K.; Okada, M.; Yamada, M.; Negoro, K. J . Chem.
Soc., Chem. Commun. 1980, 1183. (b) Takaki, K.; Okada, M.; Yamada,
M.; Negoro, K. J . Org. Chem. 1982, 47, 1200.
a
Yields of Raney Ni desulfurization. b Yields by cycloannulation
(16) Wang, C.; Kohn, H. Org. Lett. 2000, 2, 1773.
with 6 (method A).
J . Org. Chem, Vol. 67, No. 15, 2002 5399

SCHEME 1
on glass plates coated with silica gel containing 13% calcium
sulfate as binder, and visualization was effected with short-
wavelength UV light (254 nm) or acidic KMnO
reagents were used directly as obtained commercially unless
4
solution. All
otherwise noted. DMF was distilled over CaH
molecular sieves.
2
and stored over
All the chemically pure solvents, i.e., DMF and ethanol, were
purchased from standard firms and further dried whenever
needed by standard procedures. Cyclopentanone, cyclohexanone,
2
-methylcyclohexanone, 4-methylcyclohexanone, 4-tert-butylcy-
clohexanone, cycloheptanone, cyclooctanone, cyclododecanone,
-tetralone, 6-methoxytetralone, acetophenone, and 4-methoxy-
acetophenone were purchased from a commercial supplier and
1
1
8
used as such. 4-Bis(methylthio)-3-buten-2-one and 3,4-dihydro-
1
-benzothiepin-5(2H)-one19 were prepared according to the
reported procedures.
Gen er a l P r oced u r e for th e Cycloa r om a tiza tion of 4-Bis-
m eth ylth io)-3-bu ten -2-on e (2) w ith Cyclic Alip h a tic Ke-
synthesis of sulfur-free annulated phenols 5d ,f,h could
also be accomplished in good yields by cycloannulation
of the respective ketones with â-methylthiomethylene-
acetone 6 prepared by our earlier reported procedure
(
ton es: Syn th esis of 4a -j (Meth od A). A solution of ketone (6
mmol) and 4-bis(methylthio)-3-buten-2-one (1.0 g, 6 mmol) in
DMF (20 mL) was added dropwise to a stirring suspension of
sodium hydride (0.75 g, 12.5 mmol, 40%) in DMF (15 mL) at 0
°C over a period of 45 min. The reaction mixture was brought
to room temperature, and the stirring was further continued for
through partial reductive dethiomethylation of 2 with
nickel boride.17
The phenol annulation studies were further extended
to benzocyclic ketones such as 1-tetralone (1k ), which
gave a mixture of conjugate adduct and 3-hydroxy-1-
5
-8 h (monitored by TLC). It was then poured into an aqueous
saturated solution of ammonium chloride (50 mL) and extracted
with benzene (2 × 50 mL). The combined benzene extracts were
washed with water (2 × 25 mL), dried (Na SO ), and evaporated
(methylthio)-9,10-dihydrophenanthrene (4k ) in a ratio of
2
4
2
:1 when exposed to 2 in the presence of sodium hydride/
to give the crude products that were purified by column
chromatography using hexanes-ethyl acetate (25:4) as eluent.
Gen er a l P r oced u r e for Tw o-Step Rea ction of 4-Bis-
DMF at room temperature (method a). Treatment of the
reaction mixture with p-toluenesulfonic acid in refluxing
benzene (5 h) furnished 4k in a total yield of 64% (method
B). The corresponding 6-methoxytetralone 1l and the
benzothiepinone 1m also underwent smooth two steps
addition-cycloaromatization protocol (method B) with 2
to afford the respective annulated phenols 4l and 4m in
good yields (Table 1). Versatility of the methodology was
further demonstrated when the substituted acetophe-
nones 1n -o are employed as acyclic annulation partners
affording 3-hydroxybiphenyls 4n -o in reasonably good
yields (Table 1, entries 14 and 15).
(
4
m eth ylth io)-3-bu ten -2-on e w ith Keton es: Syn th esis of
k -o (Meth od B). A solution of crude residue obtained after
workup (method A) and dry PTSA (0.95 g, 5.0 mmol) in dry
benzene (30 mL) was refluxed with stirring for 3 h (monitored
by TLC). The reaction mixture was then cooled to room tem-
parature and poured into water (50 mL), and the organic layer
was separated, washed with water (4 × 50 mL), dried (Na
2 4
SO ),
and evaporated to give a crude product that was purified by
column chromatography over silica gel using hexanes-ethyl
acetate (24:1) as eluent.
7-H yd r oxy-5-(m et h ylt h io)-1,2,3,4-t et r a h yd r on a p h t h a -
len e (4a ): yield 78% (0.90 g); white solid (chloroform-hexane);
mp 68-69 °C; R
928, 1590, 1449 cm ; H NMR (400 MHz, CDCl
m, 2H, CH ), 1.77-1.83 (m, 2H, CH ), 2.40 (s, 3H, SCH
t, J ) 6.0 Hz, 2H, CH ), 2.68 (t, J ) 6.0 Hz, 2H, CH
brs, 1H, OH), 6.33 (d, J ) 1.9 Hz, 1H, ArH), 6.48 (d, J ) 1.9
f
0.20 (9:1 hexanes-EtOAc); IR (KBr) 3356,
-
1 1
2
3
) δ 1.69-1.75
), 2.57
), 5.09
Con clu sion
(
(
(
2
2
3
2
2
In summary, the work described in this paper provides
a simple and efficient method for â-phenol annulation of
both cyclic and acyclic ketones by making use of readily
available 4-bis(methylthio)-3-buten-2-one (2) as 4-carbon
component. Appropriate choice of ketones allows synthe-
sis of diverse frameworks such as dihydroindane, tet-
rahydronaphthalenes, their higher homologues, dihydro/
octahydrophenanthranenes, anthracene, and heteroan-
nulated analogue in good yields with regiocontrol of
phenolic functionality. The simplicity of the sequence and
mild reaction conditions indicate that this process could
be capable of broad application for elaboration of more
complex and highly functionalized carbon ring systems,
which is now underway in our laboratory.
13
Hz, ArH); C NMR (100 MHz, CDCl
3
) δ 14.9, 22.7, 23.2, 25.9,
+
3
0.1, 108.7, 111.8, 126.4, 138.7, 139.3, 153.4; MS (m/z) 194 (M ,
96.5), 176 (100). Anal. Calcd for C11
H, 7.26. Found: C, 68.11; H, 7.34.
H
14OS (194.30): C, 67.99;
7
-H yd r oxy-3-m et h yl-5-(m et h ylt h io)-1,2,3,4-t et r a h yd r o-
n a p h th a len e (4b): yield 85% (1.0 g); white solid (chloroform-
hexane); mp 76 °C; R 0.20 (9:1 hexanes-EtOAc); IR (KBr) 3370,
f
-1
1
2
)
916, 1581, 1451 cm ; H NMR (400 MHz, CDCl
6.3 Hz, 3H, CH ), 1.26-1.36 (m, 1H, CH ), 1.76-1.82 (m, 2H,
CH ), 2.00-2.07 (m, 1H, CH ), 2.39 (S, 3H, SCH ), 2.68-2.80
(m, 3H, CH ), 5.22 (brs, 1H, OH), 6.34 (d, J ) 1.96 Hz, 1H, ArH),
.48 (d, J ) 2.2 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl
) δ
4.9, 22.2, 29.4, 30.0, 30.9, 34.5, 108.7, 111.6, 126.4, 138.3, 139.1,
3
) δ 1.07 (d, J
3
2
2
2
3
2
6
1
1
3
+
53.4; MS (m/z) 208 (M , 100), 193 (97). Anal. Calcd for C12
16
H -
OS (208.33): C, 69.18; H, 7.74. Found: C, 69.48; H, 7.92.
-Hyd r oxy-5-(m eth ylth io)-3-(ter t-bu tyl)-1,2,3,4-tetr a h y-
d r on a p h th a len e (4d ): yield 73% (1.0 g); white solid (chloro-
7
Exp er im en ta l Section
form-hexane); mp 145-146 °C; R
f
0.24 (9:1 hexanes-EtOAc);
Gen er a l Meth od s. H NMR (400 MHz) and 13C NMR (100
MHz) spectra were recorded in CDCl3, and TMS was used as
internal reference. Melting points are uncorrected. Chromato-
graphic purification was done by column chromatography using
1
1
1
IR (KBr) 3285, 2956, 1580, 1457 cm ; H NMR (400 MHz, CDCl
3
)
δ 0.95 (s, 9H, CH
CH), 1.90-1.95 (m, 1H, CH), 2.13-2.20 (m, 2H, CH
3H, SCH ), 5.23 (s, 1H, OH), 6.34 (d, J
3
), 1.08-1.30 (m, 1H, CH), 1.38-1.46 (m, 1H,
2
), 2.39 (s,
3
), 2.65-2.76 (m, 2H, CH
2
1
3
6
0-120 mesh silica gel. All reactions were monitored by TLC
) 1.9 Hz, 1H, ArH), 6.48 (d, J ) 1.9 Hz, 1H, ArH); C NMR
(
17) Myrboh, B.; Singh, L. W.; Ila, H.; J unjappa, H. Synthesis 1982,
(18) Thuillier, A.; Vialle, J . Bull. Soc. Chim. Fr. 1962, 2182.
(19) Traynelis, V. J .; Love, R. F. J . Org. Chem. 1961, 26, 2728.
3
07.
5
400 J . Org. Chem., Vol. 67, No. 15, 2002

(
3
100 MHz, CDCl
3
) δ 14.8, 24.0, 27.2, 27.55, 27.56, 27.57, 31.2,
10-H yd r oxy-8-(m et h ylt h io)-6,7-d ih yd r od ib en z[b,d ]t h i-
ep in (4m ): yield 62% (1.02 g); red viscous liquid; R 0.26 (9:1
hexanes-EtOAc); IR (CCl ) 3357, 2928, 1593, 1428 cm
NMR (400 MHz, CDCl ) δ 2.45 (s, 3H, SCH ), 2.84 (s, 4H, CH
2.5, 45.0, 108.6, 111.3, 126.7, 138.6, 139.5, 153.4; MS (m/z) 250
f
+
-1
1
(
M , 100), 236 (7.8). Anal. Calcd for C15
H, 8.85. Found: C, 72.16; H, 8.98.
-Hyd r oxy-4-(m eth ylth io)In d a n e (4e): yield 78% (0.84 g);
white solid (chloroform-hexane); mp 64-65 °C; R 0.21 (9:1
hexanes-EtOAc); IR (KBr) 3270, 2493, 1710, 1580 cm
NMR (400 MHz, CDCl ) δ 2.02-2.09 (m, 2H, CH ), 2.38 (s, 3H,
SCH ), 2.74 (t, J ) 7.5 Hz, 2H, CH ), 2.83 (t, J ) 7.5 Hz, 2H,
CH ), 5.22 (brs, 1H, OH), 6.46 (s, 1H, ArH), 6.47 (s, 1H, ArH);
C NMR (100 MHz, CDCl ) δ 14.7, 25.0, 30.7, 33.2, 108.0, 109.0,
33.8, 135.0, 145.8, 154.9; MS (m/z) 180 (M , 52.7), 165 (100).
H
22OS (250.41): C, 71.95;
4
; H
3
3
2
),
6
5.38 (brs, 1H, OH), 6.68 (d, J ) 2.4 Hz, 1H, ArH), 7.05 (d, J )
f
2.4 Hz, 1H, ArH), 7.22-7.29 (m, 3H, ArH), 7.62 (d, J ) 7.3 Hz,
-
1
1
13
;
H
3
1H, ArH); C NMR (100 MHz, CDCl ) δ 15.7, 24.3, 28.8, 107.8,
3
2
111.5, 124.1, 126.9, 127.4, 127.7, 127.9, 134.0, 136.0, 137.4, 138.2,
+
3
2
154.6; MS (m/z) 274 (M , 0.5), 242 (95), 227 (75). Anal. Calcd
2
for C15
5.36.
2
H14OS (274.41): C, 65.64; H, 5.14. Found: C, 65.79; H,
1
3
3
+
1
5-Hyd r oxy-3-(m eth ylth io)bip h en yl (4n ): yield 64% (0.83
g); red viscous liquid; R 0.24 (9:1 hexanes-EtOAc); IR (CCl )
Anal. Calcd for C10
C, 66.86; H, 6.89.
H12OS (180.27): C, 66.63; H, 6.71. Found:
f
4
-
1 1
3340, 3055, 2926, 1672, 1587 cm , H NMR (400 MHz, CDCl )
3
3
-Hyd r oxy-1-(m eth ylth io)-6,7,8,9-tetr a h yd r o-5H-ben zo-
cycloh ep ten e (4f): yield 88% (1.0 g); white solid (chloroform-
hexane); mp 95-96 °C; R 0.23 (9:1 hexanes-EtOAc); IR (KBr)
307, 2917, 1595, 1449 cm-1; 1H NMR (400 MHz, CDCl
) δ 1.53-
.62 (m, 4H, CH ), 1.76-1.80 (m, 2H, CH ), 2.34 (s, 3H, SCH ),
.68 (t, J ) 5.3 Hz, 2H, CH ), 2.88 (t, J ) 5.3 Hz, 2H, CH ), 5.36
δ 2.49 (s, 3H, SCH ), 5.75 (brs, 1H, OH), 6.74 (t, J ) 1.2 Hz, 1H,
3
ArH), 6.83 (t, J ) 2 Hz, 1H, ArH), 7.01 (t, J ) 1.2 Hz, 1H, ArH),
7.31-7.42 (m, 3H, ArH), 7.51-7.53 (m, 2H, ArH); 13C NMR (100
f
3
1
2
3
MHz, CDCl ) δ 15.7, 111.2, 113.0, 117.6, 127.1, 127.6, 128.4,
3
+
2
2
3
140.4, 143.2, 155.4; MS (m/z) 216 (M , 100), 201 (5). Anal. Calcd
2
2
for C13H12OS (216.30): C, 72.18; H, 5.58. Found: C, 72.24; H,
5.68.
(
brs, 1H, OH), 6.41 (d, J ) 2.2 Hz, 1H, ArH), 6.54 (d, J ) 2.2
13
Hz, 1H, ArH); C NMR (100 MHz, CDCl
3
) δ 16.4, 27.3, 28.0,
Gen er a l P r oced u r e for th e Ra n ey-Ni Desu lfu r iza tion of
P h en ols: Syn th esis of 5d -f,h . To a solution of the appropriate
thiomethylphenol (5 mmol) in absolute ethanol (10 mL) was
added Raney-Ni (W2) (∼3 g), and the reaction mixture was
refluxed with stirring for 6-7 h (monitored by TLC). It was then
filtered through a sintered glass funnel and washed with hot
ethanol and the filtrate concentrated to afford crude phenol,
which was purified by column chromatography over silica gel
using hexanes-ethyl acetate (24:1) as eluent.
Gen er a l P r oced u r e for Cycloa r om a tiza tion of 4-(Meth -
ylth io)-3-bu ten -2-on e (6) w ith Keton es 1d ,f,h : Syn th esis
of P h en ols 5d ,f,h . The previous procedure (method A) was
followed using ketone (6 mmol), NaH (0.75 g, 12.5 mmol, 40%),
and 6 (0.69 g, 6 mmol) in 20 mL of DMF. Workup and column
chromatography (method A) yielded pure phenols 5d , 5f, and
2
9.9, 32.4, 36.5, 110.4, 113.5, 133.6, 137.4, 145.7, 153.3; MS (m/
+
z) 208 (M , 100), 193 (50.9). Anal. Calcd for C12H16OS (208.33):
C, 69.18; H, 7.74. Found: C, 69.30; H, 7.92.
3
-Hydr oxy-1-(m eth ylth io)-5,6,7,8,9,10,11,12,13,14-decah y-
d r oben zod od ecen e (4h ): Yield 89% (1.48 g); white solid
chloroform-hexane); mp 133-134 °C; R 0.25 (9:1 hexanes-
EtOAc); IR (KBr) 3477, 3377, 1573, 1439 cm ; H NMR (400
MHz, CDCl ),
), 2.56 (t, J ) 8.5 Hz,
), 4.85 (brs, 1H, OH), 6.48
(
f
-
1
1
3
) δ 1.40-1.45 (m, 6H, CH
.67-1.71 (m, 4H, CH ), 2.40 (s, 3H, SCH
H, CH ), 2.74 (t, J ) 7.8 Hz, 2H, CH
2
), 1.47-1.57 (m, 6H, CH
2
1
2
2
3
2
2
1
3
(
d, J ) 2.4 Hz, 1H, ArH), 6.53 (d, J ) 2.5 Hz, 1H, ArH);
C
3
NMR (100 MHz, CDCl ) δ 15.9, 22.2, 23.0, 25.7, 26.7, 26.8, 27.0,
2
7.5, 27.6, 29.5, 30.6, 109.9, 113.0, 130.7, 139.6, 143.1, 153.5;
+
MS (m/z) 278 (M , 100), 263 (18.8). Anal. Calcd for C17
278.47): C, 73.33; H, 9.41. Found: C, 73.12; H, 9.60.
-H yd r oxy-1-(m et h ylt h io)-4a ,5,6,7,8,8a ,9,10-oct a h yd r o-
ph en an th r en e (4i): yield 77% (1.14 g); white solid (chloroform-
H26OS
(
5
h .
3
6
-H yd r oxy-2-(t er t -b u t yl)-1,2,3,4-t e t r a h yd r on a p h t h a -
len e (5d ): yield 88% (0.89 g, with Raney Ni), 63% (0.77 g, from
); white solid (chloroform-hexane); mp 92-93 °C; R 0.30 (9:1
hexanes-EtOAc); IR (KBr) 2957, 1501, 1451, 1364 cm
NMR (400 MHz, CDCl ) δ 0.84 (s, 9H, CH ), 1.16-1.24 (m, 1H,
hexane); mp 158-159 °C; R
f
0.22 (9:1 hexanes-EtOAc); IR (KBr)
360, 1581, 1450, 1280 cm-1; 1H NMR (400 MHz, CDCl
) δ 0.83-
.89 (m, 1H, CH), 1.35-1.93 (m, 6H, CH ), 1.94-2.07 (m, 2H,
), 2.48-2.78 (m, 5H, CH ), 4.64 (brs, 1H,
OH), 6.33 (d, J ) 2.2 Hz, 1H, ArH), 6.48 (d, J ) 2.2 Hz, 1H,
6
f
3
0
3
-1
1
;
H
2
3
3
CH), 2.42 (s, 3H, SCH
3
2
CH), 1.27-1.34 (m, 1H, CH), 1.82-1.87 (m, 1H, CH), 2.31-2.38
(
m, 1H, CH), 2.59-2.67 (m, 3H, CH), 4.98 (brs, 1H, OH), 6.45
1
3
ArH); C NMR (100 MHz, CDCl
2
3
) δ 14.9, 22.7, 23.9, 28.3, 28.6,
(d, J ) 2.4 Hz, 1H, ArH), 6.50 (dd, J ) 2.4, 8.0 Hz, 1H, ArH),
9.4, 33.3, 33.4, 33.8, 108.5, 111.8, 125.0, 137.1, 139.3, 153.4;
13
6
2
1
3
.83 (d, J ) 8.0 Hz, 1H, ArH); C NMR (100 MHz, CDCl ) δ
+
MS (m/z) 248 (M , 100), 233 (50). Anal. Calcd for C15
248.40): C, 72.53; H, 8.11. Found: C, 72.78; H, 8.34.
-Hydr oxy-1-(m eth ylth io)-5,6,7,8,8a,9,10,10a-octah ydr oan -
th r a cen e (4j): white solid (chloroform-hexane); mp 162-163
C; yield 87% (1.29 g); R
H20OS
4.4, 27.2, 30.1, 30.6, 32.4, 45.0, 112.9, 114.8, 129.7, 130.3, 138.4,
(
+
+
52.9; MS (m/z) 205 (M + 1, 18), 204 (M , 86). Anal. Calcd for
20O (204.31): C, 82.30; H, 9.86. Found: C, 82.52; H, 9.93.
-Hyd r oxy-2,3-d ih yd r o-1H-in d en e (5e): yield 74% (0.49 g,
with Raney Ni); red viscous liquid; R 0.31 (9:1 hexanes-EtOAc);
IR (CCl ) 3356, 2915, 1489, 1263 cm
CDCl ) δ 1.95-1.98 (m, 2H, CH ), 2.69-2.74 (m, 4H, CH
brs, 1H, OH), 6.52 (d, J ) 8.0 Hz, 1H, ArH), 6.62 (s, 1H, ArH),
3
14
C H
5
°
3
1
f
0.23 (9:1 hexanes-EtOAc); IR (KBr)
365, 2920, 1563, 1444 cm-1; 1H NMR (400 MHz, CDCl
) δ 1.08-
.17 (m, 2H, CH ), 1.21-1.32 (m, 1H, CH), 1.36-1.46 (m, 3H,
), 2.40 (s,
), 2.45-2.58 (m, 1H, CH), 2.72-2.77 (m, 1H, CH), 3.58
brs, 1H, OH), 6.51 (d, J ) 2.2 Hz, 1H, ArH), 6.59 (d, J ) 1.75
f
3
-1
1
4
;
H NMR (400 MHz,
), 5.83
2
3
2
2
CH), 1.75-1.90 (m, 4H, CH), 2.20-2.34 (m, 2H, CH
3
(
2
(
6
2
H, SCH
3
13
.94 (d, J ) 8.0 Hz, 1H, ArH); C NMR (100 MHz, CDCl
3
) δ
5.7, 31.9, 32.9, 111.4, 113.0, 124.8, 136.2, 145.9, 154.0; MS (m/
1
3
Hz, 1H, ArH); C NMR (100 MHz, CDCl
3
) δ 14.0, 26.1, 26.6,
+
z) 133 (M - 1, 2), 115 (3). Anal. Calcd for C
8
9
H10O (134.18): C,
2
1
6.9, 30.6, 31.2, 34.2, 39.8, 44.0, 108.5, 108.8, 126.4, 139.1, 142.4,
53.7; MS (m/z) 248 (M , 100), 233 (41.3). Anal. Calcd for C15
0.56; H, 7.51. Found: C, 80.77; H, 7.68.
+
20
H -
OS (248.40): C, 72.53; H, 8.11. Found: C, 72.64; H, 8.28.
-H yd r oxy-1-(m et h ylt h io)-9,10-d ih yd r op h en a n t h r en e
4k ): red viscous liquid; yield 64% (0.93 g); R 0.24 (9:1 hexanes-
EtOAc); IR (CCl ) 3017, 2926, 1597, 1428 cm ; H NMR (400
MHz, CDCl ) δ 2.45 (s, 3H, SCH ), 2.85 (s, 4H, CH ), 5.14 (brs,
H, OH), 6.68 (d, J ) 2.2 Hz, 1H, ArH), 7.05 (d, J ) 2.2 Hz, 1H,
ArH), 7.23-7.29 (m, 3H, ArH), 7.63 (d, J ) 7.3 Hz, 1H, ArH);
Ack n ow led gm en t. O.B., S.K.N., and K.P. thank
3
CSIR New Delhi for Senior Research Fellowships.
Financial assistance under CSIR scheme is also ac-
knowledged.
(
f
-
1
1
4
3
3
2
1
Su p p or tin g In for m a tion Ava ila ble: Characterization
data for products 4c, 4g, 4l, 4o, 5f, and 5h . This material is
available free of charge via the Internet at http://pubs.acs.org.
1
3
C NMR (100 MHz, CDCl
3
) δ 15.7, 24.4, 28.8, 107.8, 111.6,
1
24.1, 126.9, 127.5, 127.7, 127.9, 134.0, 136.0, 137.4, 138.2, 154.6;
+
MS (m/z) 242 (M , 100), 227 (78). Anal. Calcd for C15
242.35): C, 74.34; H, 5.82. Found: C, 74.58; H, 5.95.
H14OS
(
J O020219R
J . Org. Chem, Vol. 67, No. 15, 2002 5401