Phthalimidesulfenyl Chloride. 11. Generation, General Reactivity, and Synthetic Applications of o-Thioquinones

Full text of DOI:10.1021/jo962014m

J . Org. Chem. 1997, 62, 2611-2615
2611
Notes
P h th a lim id esu lfen yl Ch lor id e.1 11.
Sch em e 1
Gen er a tion , Gen er a l Rea ctivity, a n d
Syn th etic Ap p lica tion s of o-Th ioqu in on es†
G. Capozzi,* C. Falciani, S. Menichetti,* and C. Nativi
Centro C.N.R. “Chimica dei Composti Eterociclici”,
Dipartimento di Chimica Organica,
Universita’ di Firenze, Via G. Capponi 9,
I-50121, Firenze, Italy
Received October 28, 1996
In tr od u ction
Hetero Diels-Alder reactions represent one of the
main topics of contemporary organic chemistry.2 Among
the diverse heterodienes, o-quinones3 and o-quinome-
thides4 have been found several applications which have
also been used for the construction of biologically active
compounds. Less attention has been devoted to the
corresponding sulfur-substituted species5 despite the
interest in the building of thio-substituted rings fused
to aromatic systems.
We have recently reported a new method to prepare
R,R′-dioxothiones, a new class of electron poor hetero-
dienes, on the basis of the reactivity of phthalimidesulfe-
nyl chloride.6,7 In preliminary reports8-10 we have shown
that following a similar approach, it is possible to obtain
o-thioquinones, a hitherto unknown class of electron poor
dienes, which are possible intermediates for the synthesis
of various benzo-condensed thio-substituted heterocycles
and which has been used for stereoselective preparation
of O-aryl-2-deoxy glycosides.9 In this paper we report our
studies on the generation and trapping of o-thioquinones,
o-thionaphthoquinones, and o-thiophenanthroquinones,
as well as a selected synthetic application toward a new
synthesis of isovanillin sweeteners.
Resu lts a n d Discu ssion
The reaction of phthalimidesulfenyl chloride 1 with
activated hydroxyl arenes 2a -g in chloroform at room
temperature forms the key intermediates for the genera-
tion of o-thioquinones (Scheme 1). o-Hydroxythiophthal-
imides 3a -g are generally obtained in good yields, with
complete regioselectivity and without polysubstitution
byproducts even when using an excess of 1 with highly
activated phenols.1 Derivatives 3a -g are solids which
can be purified by flash chromatography and/or recrys-
tallization and stored at room temperature for prolonged
times without decomposition.
The reaction of phthalimides 3a -g with 2 equiv of
pyridine and 2 equiv of ethyl vinyl ether 4 in chloroform
at 60 °C gave 1,4-benzooxathiin cycloadducts 5a -g
(Scheme 2). A reasonable mechanism involves pyridine
deprotonation of the hydroxyl group to give phenates
6a -g which undergo phthalimide anion elimination with
the formation of o-thioquinones 7a -g. These reactive
electron poor dienes are then trapped11 by the electron
rich alkene 4 to give 5 via an inverse electron demand
Diels-Alder reaction (Scheme 2).
† Dedicated to Prof. Richard W. Franck on the occasion of his 60th
birthday.
(1) For part 10 of this series see: Capozzi, G.; Falciani, C.; Men-
ichetti, S.; Nativi, C. Gazz. Chim. Ital. 1996, 126, 227.
(2) (a) Desimoni, G.; Tacconi, G. Chem. Rev. 1975, 75, 651. (b) Boger,
D. L.; Weinreb, S. M. Hetero Diels-Alder Methodology in Organic
Synthesis; Academic Press: San Diego, 1987.
In all the examples reported in Scheme 2 we observed
the formation of a single regioisomeric 1,4-benzooxathiin
where the oxygen of the o-thioquinone is linked to the
hetero-substituted carbon of vinyl ether 4. Quantum
mechanic calculations12 carried out on o-thioquinone 7e
and ethyl vinyl ether 4 indicated that HOMO-LUMO
orbital energies are in agreement with an inverse electron
demand Diels-Alder reaction. Moreover the orbital
coefficients show that the favorite interaction involves
the oxygen of 7e and the hetero-substituted carbon of 4.
The reaction of o-thioquinones with enol ethers can be
carried out also using cyclic systems like 2,3-dihydrofu-
ran, 5,6-dihydro-2H-pyran, and 6-ethoxy-5,6-dihydro-2H-
pyran which react with derivatives 3e-g, in the previous
reported conditions, to give cycloadducts 8-12.
(3) (a) Finley, K. T. In The Chemistry of Quinoid Compounds; Patai,
S., Rappoport, Z., Eds.; Wiley: New York, 1984; p 537, and references
cited therein. (b) Nair, V.; Kumar, S. J . Chem. Soc., Chem. Commun.
1994, 1341.
(4) (a) Talley, J . J . J . Org. Chem. 1985, 50, 1695. (b) Inoue, T.; Inoue,
S.; Sato, K. Chem. Lett. 1989, 653. (c) Karabelas, K.; Moore, H. W. J .
Am. Chem. Soc. 1990, 112, 5372. (d) Murphy, W. S.; Tuladhar, S. M.;
Duffy, B. J . Chem. Soc., Perkin Trans. 1 1992, 605. (e) Appendino, G.;
Cravotto, G.; Toma, L.; Annunziata, R.; Palmisano, G. J . Org. Chem.
1994, 59, 5556.
(5) (a) Mayer, A.; Meier, H. Tetrahedron Lett. 1994, 35, 2161. (b)
Mayer, A.; Meier, H. Synthesis 1996, 327. (c) Naghipur, A.; Reszka,
K.; Sapse, A.-M.; Lown, W. J . J . Am. Chem. Soc. 1989, 111, 258. (d)
Schulz, R.; Schweig, A. Angew. Chem. 1981, 93, 603.
(6) Capozzi, G.; Franck, R. W.; Mattioli, M.; Menichetti, S.; Nativi,
C.; Valle, G. J . Org. Chem. 1995, 60, 6416.
(7) Capozzi, G.; Dios, A.; Franck, R. W.; Geer, A.; Marzabaldi, C.;
Menichetti, S.; Nativi, C.; Tamarez, M. Angew. Chem., Int. Ed. Engl.
1996, 35, 777.
(8) Capozzi, G.; Menichetti, S.; Nativi, C.; Simonti, M. C. Tetrahe-
dron Lett. 1994, 35, 9451.
(9) Capozzi, G.; Falciani, C.; Menichetti, S.; Nativi, C.; Franck, R.
W. Tetrahedron Lett. 1995, 36, 6755.
(10) Capozzi, G.; Fratini, P; Menichetti, S.; Nativi, C. Tetrahedron
1996, 52, 12247.
1H NMR coupling constants of benzooxathiins 8-11
indicate a cis fusion of the two heterocyclic rings with
the oxygen and the sulfur of the oxathiin in pseudoaxial
and pseudoequatorial positions, respectively.
S0022-3263(96)02014-2 CCC: $14.00 © 1997 American Chemical Society

2612 J . Org. Chem., Vol. 62, No. 8, 1997
Notes
Ta ble 1. Rea ction of o-Th ioqu in on e 7e w ith Dien op h iles
13-16
Sch em e 2
Sch em e 3
Indeed 7e reacts with silyl enol ether 13, phenyl vinyl
sulfide (14), vinylpyrrolidone (15), and p-methoxystyrene
(16) to give the expected cycloadducts 17-20 as single
regioisomers (Table 1).
Derivative 12 was isolated as a 80/20 mixture of
diastereoisomers. Also in this case, the analysis of the
1H NMR chemical shifts and coupling constants support
the same structure of the oxathiin ring for both isomers,
and show that the ethoxy group in the major isomer lies
in a pseudoequatorial position.
The versatility of o-thioquinones as efficient electron
poor dienes has been verified in the reaction of 7e with
ethoxyethyne 21 giving bis-adduct 22 which was isolated
in 72% yield after 10 h at room temperature (see
Experimental Section). As in the case of R,R′-di-
oxothiones,6 this result can easily be explained, assuming
the reaction of 7e with 21 gives monoadduct 23 and is
followed by a second, faster, cycloadditon of 7e with the
intermediate 23 giving the final product (Scheme 3).
In a preliminary communication7 we have shown that
the carbon-sulfur double bond of o-thioquinones can also
behave as a dienophile. In fact, generating 7e in the
(11) Attempts to detect the transient o-thioquinines by 1H NMR, in
the absence of trapping agents, were unsuccessful as well as the
possibility to trap the thioquinones as a metal legands.
(12) Ab initio calculations were obtained minimizing using a 3-21G*
basis set with a geometric optimization implemented via a Spartan
program running on an IBM-RISC 6000 workstation. Calculated
energies (eV): 7e HOMO -8.977; LUMO -0.261. 4:6 HOMO, -9.088;
LUMO, 5.578.
We showed that it was possible to use electron rich
alkenes other than vinyl ethers in this Diels-Alder
reaction by using o-thioquinone 7e as a model substrate.

Notes
J . Org. Chem., Vol. 62, No. 8, 1997 2613
Sch em e 4
The versatility of this new approach to potentially
sweet compounds has been verified in the total synthesis
of isovanillin-containing derivative 34 which has been
reported to be 500 times as sweet as sucrose.14 As
described in Scheme 5, the synthesis was carried out
starting from p-hydroquinone. Thus, monoprotection of
one of the hydroxyl groups of hydroquinone with tert-
butyldimethylsilyl chloride, followed by the regiospecific
sulfenylation with 1, affords the thiophthalimide 35
which, under the standard conditions, generates the
corresponding o-thioquinone 36. Cycloaddition of 36 to
the styrene 29 affords the silyl-derivative 37 which can
be desilylated with cesium fluoride in methanol to give
the expected non-glycoside sweetener 34 (Scheme 5).
presence of 2,3-dimethyl-1,3-butadiene leads to a very
slow cycloaddition reaction to give the spiro derivative
24, isolated in 46% yield after 10 days at 60 °C.
Two conclusions can be drawn from this result. First
of all, o-thioquinones seem to be the real intermediates
formed by basic treatment of sulfenamides 3, since only
the presence of a carbon-sulfur double bond can ratio-
nalize the formation of 24. Secondly, the very low cyclo-
addition rate observed indicates that the carbon-sulfur
double bond in o-thioquinone 7e is a low-efficiency
dienophile.
Con clu sion
In conclusion, we have shown that o-hydroxythio-
phthalimides, simply obtained from hydroxyl arenes and
phthalimidesulfenyl chloride, are the precursors of o-
thioquionones, which represent an interesting class of
electron poor dienes. These reactive intermediates can
be trapped by a number of different electron-rich alkenes
and alkynes with complete regiochemical control to give
1,4-benzooxathiin systems.
Using activated styrenes as dienophiles, the cycload-
dition of o-thioquinones affords derivatives with potential
biological activity in a single step. Following this ap-
proach, the total synthesis of a non-glycoside sweetener
was achieved in four steps starting from hydroquinone.
Further aspects of the reactivity of o-thioquinones, as
well as the 1,4-benzooxathiins, are under investigation
in this laboratory.
We verify this hypothesis by reacting 7e with 2,3-
dimethoxy-1,3-butadiene (25) which, in principle, can act
both as an electron rich diene or as a dienophile. Under
the usual reaction conditions equimolar amounts of 3e
and 25 gave oxathiin 26 and bis-adduct 2713 in 2:1 ratio
and an 88% overall yield (Scheme 4). Compound 26
derives from the reaction of 7e with one of the activated
double bonds of 25. The formation of 27 can be explained,
assuming the reaction of the dienophilic thiocarbonyl
residue of 7e with the diene 25 to gives the spiro
derivative 28, which in turn is a very reactive dienophile
for further reaction with 1 equiv of o-thioquinone.
In a similar experiment R,R′-dioxothiones gave, as the
sole isolated product, the compound deriving from the
reaction of the thione acting as dienophile.6 This result
indicates that, in contrast with the aliphatic species, for
o-thioquinones the reactivity as dienes is higher than the
reactivity as dienophiles. The reconstruction of the
aromaticity in the final cycloadduct could play a role in
this behavior.
Exp er im en ta l Section
1H and 13C NMR spectra were recorded (when not specified)
in CDCl3 at 200 and 50 MHz, respectively, using the residual
CHCl3 peak at 7.26 ppm for 1H and the central peak of CDCl3
at 77 ppm for 13C as reference lines. Mass spectra and GC-MS
analyses were obtained using a gas chromatograph, equipped
with an OV101 30 m capillary column, interfaced to a mass
spectrometer. Melting points are uncorrected. CHCl3 and
CH2Cl2 were dried following standard procedures. All com-
mercial reagents were used without further purification as
obtained from freshly opened containers. Monoprotection of
The sweetening activity of a number of isovanillin-
containing heterocyclic systems has been reported.14 The
structure of these compounds is strictly related to that
of derivative 20 (see Table 1).
In this light we prepared a number of 5-aryl-1,4-
benzooxathiins using o-thioquinones 7c or 7e as dienes
and â-trans-methyl-4-methoxystyrene (anethole), â-trans-
methyl-4-hydroxy-3-methoxystyrene (trans-isoeugenole),
or 4-methoxy-3-hydroxystyrene (29) as electron-rich di-
enophiles. Cycloadducts 30-32 were obtained in good
yield with control of the regiochemistry and with reten-
tion of the alkene geometry.
(13) In the crude reaction mixture, bis-adduct 27 was actually
present as a 95:5 mixture of regioisomers. The structure reported for
the major isomer, isolated by flash chromatography, was tentatively
assigned in analogy with the parallel result obtained in the case of
R,R′-dioxothiones.6
(14) (a) Arnoldi, A.; Bassoli, A.; Merlini, L.; Ragg, E. J . Chem. Soc.,
Perkin Trans. 2 1991, 1399. (b) Arnoldi, A.; Bassoli, A.; Merlini, L.;
Ragg, E. J . Chem. Soc., Perkin Trans. 1 1993, 1359. (c) Arnoldi, A.;
Bassoli, A.; Caputo, R.; Merlini, L.; Palumbo, G.; Pedatella, S. J . Chem.
Soc., Perkin Trans. 1 1994, 1241.

2614 J . Org. Chem., Vol. 62, No. 8, 1997
Notes
1.94-2.14 (m, 1H), 2.18-2.32 (m, 1H), 3.69-3.80 (m, 1H), 3.93-
4.05 (m, 1H), 4.12-4.22 (m, 1H), 5.81 (d, J ) 4.4 Hz, 1H), 7.22
(d, J ) 9.0 Hz, 1H), 7.40-7.54 (m, 3H), 7.70-7.80 (m, 1H), 8.21-
8.27 (m, 1H); 13C NMR δ 30.8 (t), 41.7 (d), 68.4 (t), 101.3 (d),
112.6 (s), 120.9, 122.0, 125.3, 125.8, 126.2, 127.5 (d), 126.3, 132.7,
148.8 (s); MS m/ z (rel int) 244 (M+•, 100), 211 (64), 183 (55),
Sch em e 5
146 (95). Anal. Calcd for
Found: C, 68.90; H, 5.07.
C14H12O2S: C, 68.84; H, 4.96.
5a ,5,6,6,7,7a -H e xa h yd r o-7,9-d ioxa -10-t h ia b e n z[a ]a n -
th r a cen e (5a r,7a r) (9):17 81% yield; pale yellow solid; mp 96-
99 °C; 1H NMR δ 1.77-2.04 (m, 4H), 3.27-3.34 (m, 1H), 3.78-
3.86 (m, 1H), 4.08-4.24 (m, 1H), 5.77 (d, J ) 2.6 Hz, 1H), 7.12
(d, J ) 8.8 Hz, 1H), 7.36-7.54 (m, 3H), 7.69-7.79 (m, 1H), 8.20-
8.29 (m, 1H). Anal. Calcd for C15H14O2S: C, 69.75; H, 5.47.
Found: C, 69.68; H, 5.20.
6-Eth oxy-5a ,5,6,6,7,7a -h exa h yd r o-5,9-d ioxa -10-th ia ben z-
[a ]a n th r a cen e (5a r,7a r) (12).17 Analysis of the crude reaction
mixture showed the presence of two isomers in a 80/20 ratio
isolated in 90% overall yield. Pure samples of both compounds
were obtained by further flash chromatography (petroleum
ether:ethyl acetate ) 5:1). Major isomer: oil; 1H NMR δ 1.29
(X3 part of an ABX3 system, J AX ) J BX ) 7.0 Hz, 3H), 1.68-1.80
(m, 2H), 1.95-2.35 (m, 2H), 3.48-3.56 (m, 1H), 3.56-3.70 (m,
1H), 3.94-4.09 (m, 1H), 5.13 (dd, J ) 2.8, 6.4 Hz, 1H), 5.78 (d,
J ) 2.2, 1H), 7.12 (d, J ) 8.8 Hz, 1H), 7.38-7.57 (m, 3H), 7.28-
7.89 (m, 2H); 13C NMR δ 15.2 (q), 24.1, 28.2 (t), 35.9 (d), 64.1
(t), 92.1 (d), 97.6 (d), 109.0 (s), 119.3, 122.6, 124.3, 126.0, 126.4,
128.3 (d), 129.6, 130.9, 147.0 (s); MS m/ z (rel int) 302 (M+•, 100),
256 (15). Anal. Calcd for
Found: C, 67.24; H, 6.34
C17H18O3S: C, 67.52; H, 6.00.
hydroquinone was done following standard procedures.15
Phthalimidesulfenyl chloride (1),16 thiophthalimides 3a -g,1 and
cyclodducts 5c-e,g, 10, and 1110 were prepared as reported
elsewhere. Thiophthalimide 35 and cyclodducts 5a ,b,f, 8, 12,
17-20, 24, 26, 27, 30-33, and 37 have been similarly prepared;
physical and spectroscopic data are as follows.
Minor isomer: yellowish oil; 1H NMR δ 1.29 (X3 part of an
ABX3 system, J AX ) J BX ) 7.0 Hz, 3H), 1.68-1.80 (m, 2H), 1.95-
2.35 (m, 2H), 3.40-3.52 (m, 1H), 3.50-3.64 (m, 1H), 3.94-4.08
(m, 1H), 4.87 (bt, J ) 4.0 Hz, 1H), 5.65 (d, J ) 2.2 Hz, 1H), 7.07
(d, J ) 8.8 Hz, 1H), 7.34-7.58 (m, 3H), 7.73-7.82 (m, 2H).
(5a )-[(Tr im eth ylsilyl)oxy]-5a ,5,6,7,8,8a -h exa h yd r o-5-oxa -
10-th ia ben z[a ]a n th r a cen e (17): 89% yield; white solid; mp 88
°C; 1H NMR δ 0.03 (s, 9H), 1.28-1.80 (m, 5H), 1.82-1.97 (m,
2H), 2.30-2.44 (m, 1H), 3.06 (dd, J ) 4.0, 10.0 Hz, 1H), 7.02 (d,
J ) 8.0 Hz, 1H), 7.32-7.53 (m, 3H), 7.73-7.80 (m, 1H), 7.91-
7.98 (m, 1H); 13C NMR δ 1.5 (q), 23.4 (t), 25.3, 31.7 (t), 39.9 (d),
44.6 (t), 95.2 (s), 109.9 (s), 119.8, 122.8, 123.9, 125.3, 126.0, 128.6
(d), 129.42, 131.2, 146.2 (s); MS m/ z (rel int) 344 (M+•, 77), 271
(1), 73 (100). Anal. Calcd for C19H24O2SSi: C, 66.24; H, 7.02.
Found: C, 66.10; H, 6.90.
N-[[(2-Hyd r oxy-5-[(ter t-bu tyld im eth ylsilyl)oxy]p h en yl]-
th io]p h th a lim id e (35): 60% yield; white solid; mp 154-156 °C;
1H NMR δ 0.17 (s, 6H), 0.94 (s, 9H), 6.88-6.89 (m, 2 H), 7.33
(bs, 1H), 7.76-7.91 (m, 4H), 7.94 (s, 1H). Anal. Calcd for
C
20H23NO4SSi: C, 59.82; H, 5.77; N, 3.49. Found: C, 59.50; H,
5.81; N, 3.50.
2-Eth oxy-2,3-d ih yd r o-7-m eth oxy-1,4-ben zoxa th iin (5a ):
58% yield; glassy solid; 1H NMR δ 1.25 (X3 part of an ABX3
system, J AX ) J BX ) 7.1 Hz, 3H), 3.04 (AB part of an ABX
system, J AB ) 13.0 Hz, 2H), 3.65-4.15 (m, 5H), 5.37 (X part of
an ABX system, J ) 4.8, 2.2 Hz, 1H), 6.44-6.55 (m, 2H), 6.95
(d, J ) 8.4 Hz, 1H); 13C NMR δ 15.1 (q), 29.2 (t), 55.4, 64.4 (q),
95.0 (d), 101.7 (s), 104.2, 108.8, 127.7 (d), 150.53, 158.3 (s); MS
m/ z (rel int) 226 (M+•, 81), 197 (11), 181 (21), 165 (100). Anal.
Calcd for C11H14O3S: C, 58.39; H, 6.24. Found: C, 58.17; H,
6.37.
7-(P h en ylt h io)-6,7-d ih yd r o-5-t h ia -8-oxa p h en a n t h r en e
1
(18): 70% yield; yellow oil; H NMR δ 3.50 (AB part of an ABX
system, J AB ) 12.8 Hz, 2H), 5.95 (X part of an ABX system, J )
3.0, 4.6 Hz, 1H), 7.10 (d, J ) 8.0 Hz, 1H), 7.31-7.65 (m, 8H),
7.73-7.98 (m, 2H); 13C NMR δ 30.1 (t), 81.6 (d), 110.7 (s), 120.1,
122.5, 124.4, 126.2, 126.4, 127.9, 128.3, 129.0 (d), 129.64, 131.0,
132.6, 133.2, 146.8 (s); MS m/ z (rel int) 310 (M+•, 50), 201 (69),
135 (100). Anal. Calcd for C18H14OS2: C, 69.65; H, 4.55.
Found: C, 69.58; H, 4.71.
2-Eth oxy-2,3-dih ydr o-1,4-ben zoxath iin -7-ol (5b): 81% yield;
glassy solid;1H NMR δ 1.24 (X3 part of an ABX3 system, J AX
)
J BX ) 7.0 Hz, 3H), 3.03 (AB part of an ABX system, J AB ) 13.0
Hz, 2H), 3.65-4.04 (m, 2H), 5.63 (s, 1H), 5.36 (X part of an ABX
system, J ) 4.6, 2.2 Hz, 1H), 6.40-6.50 (m, 2H), 6.89 (d, J )
9.2 Hz, 1H); 13C NMR δ 15.0 (q), 29.1, 64.4 (t), 94.8, 105.8 (d),
108.5 (s), 109.7, 127.9 (d), 150.4, 154.1 (s); MS m/ z (rel int) 212
(M+•, 100), 183 (13), 167 (14). Anal. Calcd for C10H12O3S: C,
56.58; H, 5.70. Found: C, 56.27; H, 5.67.
7-(2′-Oxo-2′,3′,4′,5′-tetr a h yd r op yr r olid in o)-6,7-d ih yd r o-
5-th ia -8-oxa p h en a n th r en e (19): 70% yield; white solid; mp
168-170 °C; IR 1692 cm-1; 1H NMR δ 2.00-2.20 (m, 2H), 2.46-
2.54 (m, 2H), 3.07 (A part of an ABX system, J AB ) 12.8 Hz,
1H), 3.31 (B part of an ABX J AB ) 12.8 Hz, 1H), 3.41-3.58 (m,
1H), 3.60-3.72 (m, 1H), 6.21 (X part of an ABX system, J ) 2.2,
8.8 Hz, 1H), 7.03 (d, J ) 8.0 Hz, 1H), 7.34-7.56 (m, 3H), 7.72-
7.88 (m, 2H); 13C NMR δ 18.1, 29.6, 31.2, 42.5 (t), 77.3 (d), 109.7
(s), 119.4, 122.7, 124.3, 126.4, 126.5, 128.2 (d), 129.3, 130.9,
149.4, 175.4 (s); MS m/ z (rel int) 285 (M+•, 31), 200 (75), 110
(100). Anal. Calcd for C16H15NO2S: C, 67.34; H, 5.30, N, 4.91.
Found: C, 67.42; H, 5.54, N, 4.74.
7-(4′-Met h oxyp h en yl)-6,7-d ih yd r o-5-t h ia -8-oxa p h en a n -
th r en e (20): 62% yield; white solid; mp 100 °C; 1H NMR δ 3.30
(AB part of an ABX system, J AB ) 13.2 Hz, 2H), 3.85 (s, 3H),
5.25 (X part of an ABX system, J ) 8.8, 2.6 Hz, 1H), 6.94-7.01
(m, 2H), 7.14 (d, J ) 8.8 Hz, 1H), 7.36-7.57 (m, 5H), 7.76-7.94
(m, 2H); 13C NMR δ 31.3 (t), 55.3 (q), 76.2 (d), 110.2 (s), 114.1,
120.0, 122.6, 124.1, 125.7, 126.3 (d), 127.3 (d, 2C), 128.9, 131.1,
132.4, 150.1, 159.7 (s); MS m/ z (rel int) 308 (M+•, 63), 149 (100).
Anal. Calcd for C19H16O2S: C, 74.00; H, 5.23. Found: C, 73.61;
H, 5.48.
6-Eth oxy-6,7-dih ydr o-5-oxa-8-th iaph en an th r en e (5f): 87%
1
yield; glassy solid; H NMR δ 1.26 (X3 part of an ABX3 system,
J AX ) J BX ) 7.1 Hz, 3H), 3.20 (AB part of an ABX system, J AB
) 12.8 Hz, 2H), 3.75-4.11 (AB part of an ABX3, J AB ) 16.8 Hz,
2H), 5.59 (X part of an ABX system, J ) 4.6, 2.2 Hz, 1H), 7.12
(d, J ) 8.8 Hz, 1H), 7.30-7.55 (m, 3H), 7.37-7.73 (m, 1H), 8.01-
8.19 (m, 1H); 13C NMR δ 15.1 (q), 29.3, 64.54 (t), 94.6 (d), 111.7
(s), 120.3, 121.1, 125.1, 125.3, 125.9 (d), 126.1 (s), 127.7 (d), 132.3,
143.8 (s); MS m/ z (rel int) 246 (M+•, 100), 217 (4), 201 (7), 144
(15). Anal. Calcd for C14H14O2S: C, 68.26; H, 5.73. Found: C,
68.49; H, 6.08.
Tet r a h yd r ofu r a n o[6a ,7a -b]-5-oxa -8-t h ia p h en a n t h r en e
(6a r,7a r) (8): 73% yield; white solid; mp 90-93 °C; 1H NMR δ
(15) Kendall, P. M.; J ohnson, J . V.; Cook, C. E. J . Org. Chem. 1979,
44, 1421.
(16) Bombala, M. U.; Ley, S. V. J . Chem. Soc., Perkin Trans. 1 1979,
3013.
(17) Nonsystematic numbering system.

Notes
Bis-Ad d u ct (22). Due to the high volatility of ethoxyethyne
J . Org. Chem., Vol. 62, No. 8, 1997 2615
(E)-6-Meth yl-7-(3′-h yd r oxy-4′-m eth oxyp h en yl)-6,7-d ih y-
d r o-5-th ia -8-oxa p h en a n th r en e (31): 69% yield; white solid;
mp 130-133 °C; 1H NMR δ 1.22 (d, X3 part of an AMX3 system,
J ) 8.0 Hz, 3H), 3.53 (dq, M part of an AMX3 system, J ) 6.0,
8.0 Hz, 1H), 3.93 (s, 3H), 4 .78 (d, A part of an AMX3 system, J
) 8.0 Hz, 1H), 5.77 (bs, 1H, OH), 6.89-7.02 (m, 3H), 7.14 (d, J
) 10.0 Hz, 1H), 7.39-7.57 (m, 3H), 7.77-7.95 (m, 2H); 13C NMR
δ 18.2 (q), 38.4 (d), 56.5 (q), 83.45 (d), 109.7 (d), 112.4 (s), 114.9,
120.2, 121.3, 123.1, 124.6, 126.0, 126.8, 128.8 (d), 129.9, 131.0,
131.3, 146.6, 147.5, 150.5 (s); MS m/ z (rel int) 338 (M+•, 54),
164 (100). Anal. Calcd for C20H18O3S: C, 70.98; H, 5.36.
Found: C, 71.21; H, 5.29.
21, the reaction was carried out at room temperature adding 4
mol equiv of the acetylene in small aliquots during 10 h. The
usual workup and column chromatography gave 22, 72% yield
as n yellow oil; 1H NMR δ 1.23 (t, J ) 7.0 Hz, 3H), 4.17 (q, J )
7.0, Hz, 2H), 5.00 (s, 1H), 7.13 (d, J ) 8.8 Hz, 2H), 7.37-7.83
(m, 10 H); MS m/ z (rel int) 418 (M+•, 9); 244 (100). Anal. Calcd
for C24H18O3S2: C, 68.88; H, 4.33. Found: C, 68.67; H, 4.58.
Sp ir o d er iva tive 24: 46% yield; glassy solid; 1H NMR δ
1.78-1.88 (m, 6H), 2.58-2.88 (m, 3H), 3.20 (A part of an AB
system, J ) 16.8 Hz, 1H), 6.21 (d, J ) 9.8 Hz, 1H), 7.24-7.60
(m, 5H); 13C NMR δ 19.7, 20.3 (q), 30.5, 36.6 (t), 51.3 (s), 122.9,
124.4, 127.1 (d), 127.7 (s), 127.9 (d), 129.4, 129.8, 129.9 (2s +
1d), 141.8 (s) 142.5 (d), 195.1 (s); MS m/ z (rel int) 256 (M+•, 14),
254 (100), 209 (17). Anal. Calcd for C16H16OS: C, 74.96; H, 6.29.
Found: C, 75.12; H, 6.19.
7-(1′-Meth oxyeth yn yl)-7-m eth oxy-5-th ia -8-oxa -7,8-d ih y-
d r op h en a n th r en e (26): 44% yield; white solid; mp 95-97 °C;
1H NMR δ 3.28 (AB system, J AB ) 13.2 Hz, 2H), 3.34 (s, 3H),
3.70 (s, 3H), 4.42 (d, J ) 2.5 Hz, 1H), 4.79 (d, J ) 2.5 Hz, 1H),
7.16 (d, J ) 8.8 Hz, 1H), 7.26-7.51 (m, 2H), 7.58 (d, J ) 8.8 Hz,
1H), 7.77 (dd, J ) 8.6, 1.4 Hz, 1H), 7.94 (dd, J ) 8.6, 0.6 Hz,
1H); 13C NMR δ 31.7 (t), 50.8, 55.5 (q), 85.7 (t), 95.0, 111.6 (s),
119.7, 122.8, 124.3, 125.9, 126.3, 128.1 (d), 129.4, 130.9, 146.7,
157.9 (s); MS m/ z (rel int) 288 (M+•, 10); 256 (25); 43 (100). Anal.
Calcd for C16H16O3S: C, 66.64; H, 5.59. Found: C, 66.72; H,
5.77.
Bis-a d d u ct (27): 44% yield; yellow solid; mp 179-182 °C;
1H NMR δ 2.94 (AB system, J AB ) 14.0 Hz, 2H), 3.28 (A part of
an AY system, J AY ) 13.9 Hz, 1H), 3.38 (s, 3H), 3.53 (s, 3H),
4.16 (Y part of an AY system, J AM ) 13.9 Hz, 1H), 6.28 (d, J )
10.0 Hz, 1H), 6.99 (d, J ) 9.2 Hz, 1H), 7.21-7.58 (m, 8H), 7.65-
8.01 (m, 2H); 13C NMR δ 33.7, 47.9 (t), 50.89, 52.1 (q), 59.6, 86.9,
99.3, 109.3, 112.8 (s), 119.4 (d), 124.1 (s), 124.7 (d), 125.2 (s),
126.9, 127.1, 128.0, 128.6, 128.8, 129.8, 134.8 (d), 130.1, 131.8,
133.1 (s), 142.4 (d), 148.1 (s), 200.4 (s); MS m/ z (rel int) 461 ((M
- 1)+•, 1), 288 (22), 256 (100). Anal. Calcd for C26H22O4S2: C,
67.52; H, 4.80. Found: C, 67.07; H, 4.99.
(E)-2-(3-Meth oxy-4-h ydr oxyph en yl)-3-m eth yl-2,3-dih ydr o-
6-m eth oxy-1,4-ben zoxa th iin (32): 85% yield; pale yellow
1
solid; mp 148-150 °C; H NMR δ 1.06 (d, X3 part of an AMX3
system, J ) 6.6 Hz, 3H), 3.47 (dq, M part of an AMX3 system, J
) 6.6, 8.8 Hz, 1H), 3.76 (s, 3H), 3.92 (s, 3H), 4.57 (d, A part of
an AMX3 system, J ) 8.8 Hz, 1H), 5.69 (s, 1H, OH), 6.58-6.63
(m, 2H), 6.80-6.93 (m, 4H); 13C NMR δ 17.5 (q), 38.5 (d), 55.7,
55.9 (q), 82.9, 109.0, 110.4, 111.8, 114.3, 119.0 (d), 119.8 (s), 120.7
(d), 130.5, 145.9, 146.5, 146.8, 154.1 (s); MS m/ z (rel int) 318
(M+•, 33), 181 (20), 164 (100). Anal. Calcd for C17H18O4S: C,
64.13; H, 5.70. Found: C, 64.02; H, 5.77.
2-(3-Hyd r oxy-4-m eth oxyp h en yl)-2,3-d ih yd r o-6-m eth oxy-
1,4-ben zoxa th iin (33): 51% yield; oil; 1H NMR δ 3.14 (AB part
of an ABX system, J AB ) 13.0 Hz, 2H), 3.75 (s, 3H), 3.91 (s, 3H),
5.02 (X part of an ABX system, J ) 1.8, 9.5 Hz, 1H), 5.67 (s, 1H,
-OH), 6.56-6.89 (m, 6H); 13C NMR δ 31.8 (t), 55.7, 56.0 (q), 76.1,
110.6 (d), 111.3 (s), 112.1, 112.4 (d), 117.7 (s), 117.8, 119.3, 133.6
(d), 145.8, 146.5, 146.6, 154.0 (s); MS m/ z (rel int) 304 (M+•
,
36), 150 (100). Anal. Calcd for C16H16O4S: C, 63.14; H, 5.30.
Found: C, 63.13; H, 5.52.
2-(3-Hyd r oxy-4-m eth oxyp h en yl)-2,3-d ih yd r o-6-[(ter t-bu -
tyld im eth ylsilyl)oxy]-1,4-ben zoxa th iin (37): 47% yield; oil;
1H NMR δ 0.17 (s, 6H), 0.97 (s, 9H), 3.01 (A part of an ABX
system, J AB ) 12.9 Hz, 1H), 3.25 (B part of an ABX system, J AB
) 12.9 Hz, 1H), 3.91 (s, 3H), 5.01 (X part of an ABX system, J
) 9.8, 2.0 Hz, 1H), 6.20 (s, 1H, OH), 6.46-6.99 (m, 6H). Anal.
Calcd for C21H28O4SSi: C, 62.34; H, 6.98. Found: C, 62.23; H,
6.72.
2-(3-Hyd r oxy-4-m eth oxyp h en yl)-2,3-d ih yd r o-1,4-ben zox-
a th iin -6-ol (34). A solution of 37 (32 mg, 0.08 mmol) and
cesium fluoride (16 mg, 0.12 mmol) in 2 mL of methanol was
maintained under stirring at room temperature for 3 h. The
mixture was then diluted with diethyl ether (30 mL), washed
twice with saturated NH4Cl, and dried over anhydrous Na2SO4.
Flash chromatography (petroleum ether:ethyl acetate ) 3:1)
afforded 12 mg (52% yield) of 34 which was identified by
comparison with literature data:14 1H NMR δ 2.98-3.31 (AB
part of an ABX system, J AB ) 13.2 Hz, 2 H), 3.91 (s, 3 H), 4.51
(bs, 1H, OH), 5.01 (X part of an ABX system, J ) 9.4, 2 Hz, 1
H), 5.66 (bs, 1H, OH), 6.47-6.98 (m, 6 H).
3-Hyd r oxy-4-m eth oxystyr en e (29). To a solution of 1.08
g (2.6 mmol) of instant ylide in 50 mL of dry THF kept at -78
°C was added 3-hydroxy-4-methoxybenzaldehyde (isovanillin)
200 mg (1.3 mmol) in THF (2 mL) dropwise. The reaction
mixture was allowed to reach room temperature and stirred 10
h. The crude mixture was then diluted with petroleum ether
and washed with saturated NH4Cl (20 mL) and with water (2
× 20 mL). Flash chromatography (petroleum ether/ethyl acetate
3:1) afforded 66 mg (87% yield) of 29 which was used without
further purification: 1H NMR δ 3.89 (s, 3H), 5.15 (dd, J ) 11.0,
1.0 Hz, 1H), 5.61 (dd, J ) 17.6, 1.0 Hz, 1H), 5.78 (s, 1H, OH),
6.63 (dd, J ) 17.6, 11.0 Hz, 1H), 6.78-7.08 (m, 3H).
(E)-6-Meth yl-7-(4′-m eth oxyp h en yl)-6,7-d ih yd r o-5-th ia -8-
oxa p h en a n th r en e (30): 74% yield; white solid; mp 123-125
1
°C; H NMR δ 1.22 (d, X3 part of an AMX3 system, J ) 7.0 Hz,
3H), 3.54 (dq, M part of an AMX3 system, J ) 7.0, 8.4 Hz, 1H),
3.86 (s, 3H), 4.83 (d, A part of an AMX3 system, J ) 8.4 Hz,
1H), 6.93-7.03 (m, 2H), 7.13 (d, J ) 8.8 Hz, 1H), 7.31-7.56 (m,
5H) 7.77-7.82 (m, 1H), 7.89-7.93 (m, 1H); 13C NMR δ 18.2 (q),
38.4 (d), 55.8 (q), 83.1 (d), 112.3 (s), 114.6, 120.2, 123.1, 124.6,
126.0, 126.8, 128.8, 129.0, 129.2 (d, 11C), 131.3, 131.4, 150.5,
160.4 (s); MS m/ z (rel int) 322 (M+•, 1), 147 (100). Anal. Calcd
for C20H18O2S: C, 74.50; H, 5.63. Found: C, 74.30; H, 5.68.
Ack n ow led gm en t. Acknowledgements for support
of this work are due to the Minestero della Universita’
e della Ricerca Scientifica e Tecnologica (MURST), Italy,
and to Progetto Strategico Tecnologie Chimiche Innova-
tive CNR, Rome, Italy.
J O962014M