A Novel Palladium-Mediated Cascade Reaction Triggered by Strain Release of the Cyclobutane System. A New General Route to Benzo- and Naphthohydrindans

Article abstract of DOI:10.1021/jo971377z

A novel palladium-mediated cascade reaction was reported.By this procedure, the olefinic cyclobutanols 17, 24, and 31; 41; 37; and 45 afforded the benzo- and naphthohydrindans (46-49, 50-53, 54-57, and 58-61) respectively in one operation in the ratios depending on the mediators and solvents employed.This provides a novel and efficient synthesis of biologically important A-nor and C11-alkylated steroids.

Full text of DOI:10.1021/jo971377z

7850
J . Org. Chem. 1997, 62, 7850-7857
A Novel P a lla d iu m -Med ia ted Ca sca d e Rea ction Tr igger ed by
Str a in Relea se of th e Cyclobu ta n e System . A New Gen er a l Rou te
to Ben zo- a n d Na p h th oh yd r in d a n s
Hideo Nemoto,* J unji Miyata, Masahiro Yoshida, Naomi Raku, and Keiichiro Fukumoto
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-77, J apan
Received J uly 25, 1997X
A novel palladium-mediated cascade reaction was reported. By this procedure, the olefinic
cyclobutanols 17, 24, and 31; 41; 37; and 45 afforded the benzo- and naphthohydrindans (46-49,
50-53, 54-57, and 58-61) respectively in one operation in the ratios depending on the mediators
and solvents employed. This provides a novel and efficient synthesis of biologically important A-nor
and C11-alkylated steroids.
In tr od u ction
of both simple and complex compounds. Of these, cyclic
cascade carbopalladations4,5 have gained wide acceptance
and have now become a rapidly growing area in synthetic
organic chemistry, because of their increasing synthetic
efficiency. In this context, we have developed a novel
palladium-mediated cascade reaction providing a new
general route to benzo- and naphthohydrindans (A-nor
steroid 9 and equilenin type steroid 10, respectively). The
compounds 9 and 10 thus obtained could also be potential
intermediates6 for the synthesis of A-nor steroids 1-37
and C11 â-substituted estradiols 4-68 which have at-
tracted growing attention owing to their neurosteroid
analogues (1-3) and high-affinity ligands for the estrogen
receptor (4-6), respectively (Figure 1). Here, we report
the results.
In recent years, palladium-mediated cyclization1-3 of
substrates containing various unsaturated systems has
provided general and versatile methods for the synthesis
X Abstract published in Advance ACS Abstracts, October 1, 1997.
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Masters, J . J .; J ung, D. K.; Bornmann, W. G.; Danishefsky, S. J .
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Reactions; Wiley: New York; 1992. (c) Waldmann, H. Nachr. Chem.
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51, 13103-13159. (h) Denmark, S. E.; Thorarensen, A. Chem. Rev.
1996, 96, 137-165. (i) Winkler, J . D. Chem. Rev. 1996, 96, 167-176.
(j) Ryu, I.; Sonoda, N.; Curran, D. P. Chem. Rev. 1996, 96, 177-194.
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Chem. Rev. 1996, 96, 339-363.
plexation (7a and 8a ) of palladium followed by ring
(5) For cyclic cascade carbopalladations, see: (a) Abelman, M. M.;
Overman, L. E. J . Am. Chem. Soc. 1988, 110, 2328-2329. (b)
Carpenter, N. E.; Kucera, D. J .; Overman, L. E. J . Org. Chem. 1989,
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1343-1346. (e) Meyer, F. E.; de Meijere, A. Synlett 1991, 777-778. (f)
Meyer, F. E.; Parsons, P. J .; de Meijere, A. J . Org. Chem. 1991, 56,
6487-6488. (g) Negishi, E.; Harring, L. S.; Owczarczyk, Z.; Mohamud,
M. M.; Ay, M. Tetrahedron Lett. 1992, 33, 3253-3256. (h) Negishi, E.;
Ay, M.; Sugihara, T. Tetrahedron 1993, 49, 5471-5482. (i) Sugihara,
T.; Cope´ret, C.; Owczarczyk, Z.; Harring, L. S.; Negishi, E. J . Am.
Chem. Soc. 1994, 116, 7923-7924.
(6) For recent studies on the synthesis of benzohydrindans and their
transformation into various types of biologically important steroids,
see: (a) Nemoto, H.; Ando, M.; Fukumoto, K. Tetrahedron Lett. 1990,
31, 6205-6208. (b) Nemoto, H.; Matsuhashi, N.; Imaizumi, M.; Nagai,
M.; Fukumoto, K. J . Org. Chem. 1990, 55, 5625-5631. (c) Nemoto,
H.; Satoh, A.; Ando, M.; Fukumoto, K. J . Chem. Soc., Chem. Commun.
1990, 1001-1002; J . Chem. Soc., Perkin Trans. 1 1991, 1309-1314.
(d) Nemoto, H.; Matsuhashi, N.; Satoh, A.; Fukumoto, K. J . Chem. Soc.,
Perkin Trans. 1 1992, 495-498. (e) Nemoto, H.; Satoh, A.; Fukumoto,
K. J . Chem. Soc., Perkin Trans. 1 1993, 2237-2238. (f) Nemoto, H.;
Satoh, A.; Fukumoto, K. J . Chem. Soc., Perkin Trans. 1 1994, 943-
946. (g) Nemoto, H.; Satoh, A.; Fukui, H.; Fujimori, S.; Fukumoto, K.
Chem. Pharm. Bull. 1994, 42, 1963-1965. (h) Nemoto, H.; Satoh, A.;
Fukumoto, K.; Kabuto, C. J . Org. Chem. 1995, 60, 594-600. (i) Nemoto,
H.; Satoh, A.; Fukumoto, K. Tetrahedron 1995, 51, 10159-10174. (j)
Nemoto, H.; Satoh, A.; Fukumoto, K. Synlett 1995, 199-200.
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Katzenellenbogen, J . A. J . Steroid Biochem. 1989, 33, 859-865. (c)
Pomper, M. G.; Van Brocklin, H.; Thieme, A. M.; Thomas, R. D.;
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1995, 60, 5316-5318.
S0022-3263(97)01377-7 CCC: $14.00 © 1997 American Chemical Society

A Novel Palladium-Mediated Cascade Reaction
J . Org. Chem., Vol. 62, No. 22, 1997 7851
stannane to give the styrene 13 (90%), which upon the
Wittig reaction with cyclopropylidenetriphenylphos-
phorane under modified McMurry conditions11 afforded
the cyclopropylidene derivative 14 (97%). Successive
treatment of 14 with m-chloroperbenzoic acid (mCPBA)
and then fluoroboric acid gave, via the epoxide 15, the
cyclobutanone 16 (83%) which was then converted to 17
(95%) stereoselectively by the Grignard reaction with
isopropenylmagnesium bromide in the presence of cerium
trichloride. By following the same procedure, 24, 31, and
37 were prepared in 36%, 30%, and 20% overall yields
starting from 18, 25, and 3212 via 19-23, 26-30, and
33-36 respectively.13
The diastereoisomer 41 was also prepared in 39%
overall yield by successive chlorination of 31, substitution
of the chloride 38 with thiophenoxide, oxidation of the
sulfide 39, and stereoselective [2,3]sigmatropic rear-
rangement of the resulting sulfoxide 40. By following
the same procedure, the diastereoisomer 45 was prepared
in 42% overall yield starting from 37 via 42-44 (Scheme
3).14
F igu r e 1.
Ch a r t 1
Ca sca d e Rin g Exp a n sion a n d In ser tion Rea ction .
As a preliminary experiment, the cascade reaction of 17
was examined using various types of mediators and
solvents (Table 1). The reaction proceeded in moderate
yield (up to 55%, entry 2) to give the four possible isomers
46-49 depending upon the reaction conditions. Although
no stereoselectivity was observed in entries 1, 2, 3, 8, 11,
and 17 (48:49/50:50), a moderate (48:49/40:60 in entry
10, 25:75 in entry 12, and 20:80 in entry 7, and 46:47/
17:83 in entries 9 and 13) to high cis stereoselectivity
(48:49/9:91 in entry 16 and 46:47/4:96 in entry 14) was
recognized. In contrast to these, a moderate trans
stereoselectivity (48:49/75:25) was found in entries 4-6.
These characteristic features were found in the same
reaction of the substrates 24, 31, and 41 examined under
the conditions corresponding to entries 2, 6, and 15 in
Table 1, although somewhat greater tendencies toward
cis preference were observed in the case of 31 and 41
(entries 2, 3, 5, 6, and 8 in Table 2). In contrast to the
greater cis preference for 41 (entries 3 and 6) than that
for 31 (entries 2 and 5), the remarkable reverse tendency
of 41 favoring trans (entry 9) comparing with the
complete cis selectivity (entry 8) of 31 was noteworthy.
Thus, the general features of this reaction were con-
firmed.
expansion (a) of the cyclobutanol ring to a cyclopentanone
palladium complex (f7b and 8b), insertion (b) of olefins
(f7c and 8c), and elimination (c) of palladium to give 9
and 10 as shown in Chart 1.9
On the basis of the findings described above, our
attention was turned to the development of the cascade
method to C11 alkylated equilenin-type steroid 10.
The cascade reaction of 37 and 45 was examined under
the same conditions as outlined in Table 2 (Table 3). In
entry 3, trans selectivity which was observed in entries
5 and 6 in Table 1 and entries 4 and 5 in Table 2 was
reduced to almost a 50:50 mixture of cis and trans. A
high degree of cis selectivity was found in entry 8,
Resu lts a n d Discu ssion
Syn t h esis of t h e Su b st r a t es for t h e Ca sca d e
Rea ction . The synthesis of the olefinic cyclobutanols 17,
24, 31, and 37 substrates for the cascade reaction was
straightforward (Schemes 1 and 2). The triflate 12,
prepared (96%) from 4-methoxysalicylaldehyde (11), was
subjected to the Stille reaction10 with tri-n-butylvinyl-
(9) For some previous works on the palladium catalysed ring
expansion of cyclobutanes, see: (a) Boontanonda, P.; Grigg, R. J . Chem.
Soc., Chem. Commun. 1977, 583-584. (b) Clark, G. R.; Thiensathit,
S. Tetrahedron Lett. 1985, 26, 2503-2506. (c) Liebeskind, L. S.;
Mitchell, D.; Foster, B. S. J . Am. Chem. Soc. 1987, 109, 7908-7910.
(d) Demuth, M.; Pandey, B.; Wietfeld, B.; Said, H.; Viader, J . Helv.
Chim. Acta 1988, 71, 1392-1398. (e) de Almeida Barbosa, L.-C.; Mann,
J . J . Chem. Soc., Perkin Trans. 1 1990, 177-178. (f) Mitchell, D.;
Liebeskind, L. S. J . Am. Chem. Soc. 1990, 112, 291-296. (g) Nemoto,
H.; Nagamochi, M.; Fukumoto, K. J . Chem. Soc., Perkin Trans. 1 1993,
2329-2332. (h) Nemoto, H.; Nagamochi, M.; Ishibashi, H.; Fukumoto,
K. J . Org. Chem. 1994, 59, 74-79. (i) Nemoto, H.; Shiraki, M.;
Fukumoto, K. Synlett 1994, 599-600. (j) Nemoto, H.; Miyata, J .;
Fukumoto, K. Tetrahedron 1996, 52, 10363-10374. For review, see:
(k) Liebeskind, L. S.; Chidambaram, R.; Mitchell, D.; Foster, B. S. Pure
Appl. Chem. 1988, 60, 27-34.
(10) Scott, W. J .; Stille, J . K. J . Am. Chem. Soc. 1986, 108, 3033-
3040.
(11) Stafford, J . A.; McMurry, J . E. Tetrahedron Lett. 1988, 29,
2531-2534.
(12) Narasimhan, N. S.; Mali, R. S.; Barve, M. V. Synthesis 1979,
906-909.
(13) The stereochemistry of 17, 24, 31, and 37 was confirmed by
the observation of the definite NOE between methyl protons of
isopropenyl group and adjacent methine proton in these NMR spectra,
which were observed at 1.83 and 3.95 ppm for 17, 1.85 and 4.17 ppm
for 24, 1.84 and 4.12-4.19 ppm for 31, and 1.84 and 4.30 ppm for 37,
respectively.
(14) Brown, W. L.; Fallis, A. G. Tetrahedron Lett. 1985, 26, 607-
610. The direct formation of the sulfoxides 40 and 44 by treatment of
31 and 37 with phenylsulfenyl chloride under basic condition was
failed.

7852 J . Org. Chem., Vol. 62, No. 22, 1997
Nemoto et al.
Sch em e 1
Sch em e 2
catalytic amount of palladium(II) catalyst with some
reoxidants (Table 4).
From these results, it became clear that this cascade
reaction could be done catalytically with palladium(II)
in rather higher yield compared to that with an equimo-
lar amount of palladium(II) under comparable conditions,
beside the additives (entry 8 in Table 2), making this
process efficient, although the catalytic reaction pro-
ceeded slowly. Thus, we could disclose a novel palladium-
mediated cascade reaction providing a general route to
the stereoselective synthesis of benzo- and naphthohy-
drindans.
Exp er im en ta l Section
Gen er a l P r oced u r e. All nonaqueous reactions were car-
ried out under a positive atmosphere of argon in rigorously
dried glassware unless indicated otherwise. Materials were
obtained from commercial suppliers and used without further
purification except when otherwise noted. Solvents were
distilled prior to use: THF, Et2O, hexane, and DME were
freshly distilled from sodium benzophenone; CH2Cl2, ClCH2-
CH2Cl, DMF, and triethylamine were distilled from CaH2 and
stored over 4 Å molecular sieves. The phrase “residue upon
workup” refers to the residue obtained when the organic layer
was separated and dried over anhydrous MgSO4 and the
solvent was evaporated under reduced pressure. Chromatog-
raphy was carried out by using Merck 60 (230-400 mesh) or
Cica 60 (spherical/40-100 µm) silica gel. Reactions and
chromatography fractions were analyzed by employing pre-
coated silica gel 60F254 plates (Merck).
Gen er a l Exp er im en ta l P r oced u r es for Sch em es 1 a n d
2. Exp er im en ta l Deta ils for th e Syn th esis of 17 via 12,
13, 14, a n d 16. 2-[[(Tr iflu or om et h yl)su lfon yl]oxy]-4-
m eth oxyben za ld eh yd e (12). To a stirred solution of 4-meth-
oxysalicylaldehyde (11) (10.0 g, 65.7 mmol) and a catalytic
amount of 4-(dimethylamino)pyridine (DMAP) in pyridine (130
mL) was added trifluoromethanesulfonic anhydride (Tf2O)
(12.2 mL, 72.3 mmol) at 0 °C and stirring was continued for 1
h at room temperature. The resulting solution was diluted
with water and extracted with CH2Cl2. The combined extracts
were washed sequentially with 10% HCl, saturated aqueous
NaHCO3, and NaCl. The residue upon workup was chromato-
graphed on silica gel with hexane-AcOEt (9:1 v/v) as eluant
to give the triflate 12 (17.8 g, 96%) as a colorless oil.
although the high cis selectivity was observed in the case
of benzohydrindans (entries 14 and 15 in Table 1 and
entries 7 and 8 in Table 2). In the case of the isomeric
substrate 45, the moderate cis (entry 4) and trans (entry
8) selectivities were observed.
From these results, it could be emphasized that the
stereoselectivity in these cascade reactions markedly
changes from the substrates 17 (Table 1), 24, and 31
(Table 2) to 37 (Table 3), favoring cis stereochemistry
under the same conditions, and the reverse stereoselec-
tivities were observed in the isomeric substrates 41 and
45 compared with 31 and 37, respectively.15
Finally, we have examined the catalytic process for this
cascade reaction of 31 as a typical example using a
(15) The stereochemistry of these product in Tables 1-3 was
confirmed by the observation of the definite NOE between methyl and
methine protons at angular positions in these NMR spectra, which
were observed at 1.07 and 3.05 ppm for 47, 1.04 and 3.01 ppm for 49,
1.01 and 3.12 ppm for 51, 1.01 and 2.96 ppm for 53, 1.14 and 3.13-
3.22 ppm for 55i, 1.03 and 2.92-3.01 ppm for 57i, 1.19 and 3.32 ppm
for 59, and 1.15 and 3.07 ppm for 61, respectively. In addition to these
data, the general tendencies that the angular methyl group of this type
of trans-benzohydrindan resonates at higher field than that of corre-
sponding cis isomer in its NMR spectrum because of the shielding effect
of aromatic ring have been recognized (see ref 6).
(16) Larock, R. C.; Hightower, T. R.; Kraus, G. A.; Hahn, P.; Zheng,
D. Tetrahedron Lett. 1995, 36, 2423-2426. Under this condition, the
enone 62 was produced in 22% yield beside the cascade products 54-
57. The structure of 62 was characterized as its deprotected derivative
62I.
4-Meth oxy-2-vin ylben za ld eh yd e (13). To a slurry of LiCl
(1.44 g, 33.9 mmol) and Pd(PPh3)4 (159 mg, 0.226 mmol) in
THF (110 mL) was added a solution of the triflate 12 (3.22 g,
11.3 mmol) and vinyltributyltin (4.0 mL, 13.6 mmol). The
mixture was refluxed for 1 h with stirring, cooled to room
temperature, and diluted with Et2O (100 mL). The resulting

A Novel Palladium-Mediated Cascade Reaction
J . Org. Chem., Vol. 62, No. 22, 1997 7853
Sch em e 3
Ta ble 1. Ca sca d e Rin g Exp a n sion a n d In ser tion Rea ction of 17a
product
ratio (46:47:48:49)b
entry
mediator
solvent
DME
DME
CH3CN
THF
DMF
DMF
ClCH2CH2Cl
DME
CH3CN
THF
DMF
ClCH2CH2Cl
DME
ClCH2CH2Cl
ClCH2CH2Cl
CH3CN
CH3CN
time (h)
yield (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
Pd(OAc)2(PPh3)2
Pd(OAc)2(PPh3)2
Pd(OAc)2(PPh3)2
Pd(OAc)2(PPh3)2
Pd(OAc)2(PPh3)2
Pd(OAc)2(AsPh3)2
Pd(OAc)2(AsPh3)2
Pd(OAc)2(AsPh3)2
Pd(OAc)2
14
10
10
14
12
0:0:50:50
0:0:50:50
0:0:50:50
0:0:75:25
0:0:75:25
0:0:75:25
0:0:20:80
0:0:50:50
17:83:0:0
0:0:40:60
0:0:50:50
0:0:25:75
17:83:0:0
4:96:0:0
53
55 (65)
22
50 (55)
53
46 (51)
33 (42)
21 (22)
40 (44)
16 (36)
30 (36)
35 (65)
30 (40)
45
10
14
144
16
144
144
32
24
12
10
21
5:95:0:0
0:0:9:91
0:0:50:50
53
15
17 (69)
PdCl2(PPh3)2
20
a
b
The reaction was carried out under argon at room temperature by using an equimolar amount of mediator. The isomer (46, 47, 48,
and 49) ratio was determined by 1H NMR integration of angular methyl signals (δ 0.68 for 46, δ 1.07 for 47, δ 0.70 for 48, and δ 1.04 for
49). c All yields were isolated one. The yields in parentheses were based on recovered 17.
solution was washed sequentially with water, 10% NH4OH,
water, and saturated aqueous NaCl. The residue upon workup
was chromatographed on silica gel with hexane-AcOEt (9:1
v/v) as eluant to give the vinylbenzaldehyde 13 (1.89 g, 90%)
as a colorless oil.
diluted with water and extracted with Et2O. The combined
extracts were washed with saturated aqueous NaCl. The
residue upon workup was chromatographed on silica gel with
hexane-AcOEt (9:1 v/v) as eluant to give the cyclopropylidene
derivative 14 (222 mg, 97%) as a colorless oil.
4-(Cyclop r op ylid en em eth yl)-3-vin yla n isole (14). To a
stirred suspension of NaH (98.4 mg, of 60% oil suspension,
2.46 mmol) in THF (7 mL) was added cyclopropyltri-
phenylphosphonium bromide (0.945 g, 2.46 mmol) at room
temperature. After the mixture had been stirred for 10 h at
62 °C, a solution of the aldehyde 13 (200 mg, 1.23 mmol) in
THF (3 mL) was added in 30 min, and stirring was continued
for 1.5 h at the same temperature. The reaction mixture was
2-(4-Meth oxy-2-vin ylp h en yl)cyclobu ta n on e (16). To a
stirred solution of the cyclopropylidene derivative 14 (49.3 mg,
0.265 mmol) in CH2Cl2 (2 mL) was added m-chloroperbenzoic
acid (mCPBA) (51.9 mg, of 80% purity, 0.265 mmol) at 0 °C,
and stirring was continued for 2 h at 0 °C. The reaction
mixture was washed with saturated aqueous NaHCO2 and
NaCl. To a stirred solution of the residue upon workup in
CH2Cl2 (2 mL) was added 10% HBF4 (0.5 mL). The mixture

7854 J . Org. Chem., Vol. 62, No. 22, 1997
Ta ble 2. Ca sca d e Rin g Exp a n sion a n d In ser tion Rea ction of 24, 31, a n d 41a
Nemoto et al.
product
entry
substrate
mediator
solvent
DME
DME
DME
DMF
DMF
DMF
time (h)
ratiob
yield (%)c
1
2
3
4
5
6
7
8
9
24
31
41
24
31
41
24
31
41
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
Pd(OAc)2(AsPh3)2
Pd(OAc)2(AsPh3)2
Pd(OAc)2(AsPh3)2
10
10
10
10
10
10
10
10
10
0:0:62:38
0:0:60:40
0:0:35:65
0:0:78:22
0:0:61:39
2:9:16:73
0:100:0:0
0:100:0:0
93:4:3:0
71
81
90
68
62
84
34
21 (68)
35 (95)
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
a
b
The reaction was carried out under argon at room temperature by using an equimolar amount of mediator. The product ratios for
entries 1, 4, and 7 corresponded to 50:51:52:53 and were determined by 1H-NMR integration of angular methyl signals (δ 0.61 for 50, δ
1.01 for 51, δ 0.67 for 52, and δ 1.01 for 53). For entries 2, 3, 5, 6, 8, and 9, the initial products were subjected to deprotection and
analyzed. So, these product ratios corresponded to 54i (R ) OH), 55i (R ) OH), 56i (R ) OH), and 57i (R ) OH) and were determined
by 1H-NMR integration of angular methyl signals (δ 0.61 for 54i, δ 1.14 for 55i, δ 0.69 for 56i, and δ 1.03 for 57i). c All yields were
isolated one. The yields in parentheses were based on recovered 31 and 41.
Ta ble 3. Ca sca d e Rin g Exp a n sion a n d In ser tion Rea ction of 37 a n d 45a
product
entry
substrate
mediator
solvent
DME
DME
DMF
time (h)
ratiob
yield (%)c
1
2
3
4
37
45
37
45
37
45
37
45
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
Pd(OAc)2(AsPh3)2
Pd(OAc)2(AsPh3)2
Pd(OAc)2
10
10
10
10
23:23:14:40
22:26:20:32
4:15:48:33
2:9:16:73
81
63
56
79
DMF
5d
6d
7
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
ClCH2CH2Cl
10
10
0:83:0:17
50:20:26:4
69
46
8
Pd(OAc)2
a
b
The reaction was carried out under argon at room temperature by using an equimolar amount of mediator. The isomer ratio was
determined by 1H-NMR integration of angular methyl signals (δ 0.55 for 58, δ 1.19 for 59, δ 0.67 for 60, δ 1.15 for 61, respectively). c All
yields were isolated one. Unidentified complex mixture was formed.
d
was stirred for 0.5 h at room temperature and washed with
saturated aqueous NaHCO3 and NaCl. The residue upon
workup was chromatographed on silica gel with hexane-
AcOEt (95:5 v/v) as eluant to give the cyclobutanone 16 (44.7
mg, 83%) as a colorless oil.
6.87 (1H, d, J ) 2.2 Hz), 7.03 (1H, dd, J ) 2.2 and 8.8 Hz),
7.95 (1H, d, J ) 8.8 Hz), 10.13 (1H, s); 13C-NMR (75 MHz,
CDCl3) δ 56.2, 108.3, 114.2, 116.5, 121.8, 132.5, 151.3, 165.5,
185.6; MS m/ z 283 (M+); HRMS calcd for C9H7 F3O5S 283.9966
(M+), found 283.9966.
(1S*,2S*)-1-Isop r op en yl-2-(4-m et h oxy-2-vin ylp h en yl-
)cyclobu ta n ol (17). To a stirred suspension of CeCl3 (3.80
g, 15.4 mmol) in THF (45 mL) was added a 1.0 M solution of
isopropenylmagnesium bromide in THF (15.4 mL, 15.4 mmol)
at -78 °C. After stirring had been continued for 1 h, a solution
of the cyclobutanone 16 (1.04 g, 5.14 mmol) in THF (15 mL)
was added dropwise to this reaction mixture at the same
temperature and the temperature was then increased to room
temperature in 2 h. The reaction mixture was treated with
saturated aqueous NH4Cl and extracted with Et2O. The
combined extracts were washed with saturated aqueous NaCl.
The residue upon workup was chromatographed on silica gel
with hexane-AcOEt (98:2 v/v) as eluant to give the cyclobu-
tanol 17 (1.20 mg, 95%) as a colorless oil.
13: IR (neat) 1690 cm-1; 1H-NMR (300 MHz, CDCl3) δ 3.91
(3H, s), 5.50 (1H, dd, J ) 1.5 and 11.0 Hz), 5.70 (1H, dd, J )
1.5 and 17.0 Hz), 6.93 (1H, dd, J ) 2.6 and 8.4 Hz), 7.02 (1H,
d, J ) 2.6 Hz), 7.56 (1H, dd, J ) 11.0 and 17.0 Hz), 7.79 (1H,
d, J ) 8.4 Hz), 10.15 (1H, s); 13C-NMR (75 MHz, CDCl3) δ 54.9,
111.7, 112.9, 118.5, 126.1, 133.0, 133.6, 142.2, 190.3; MS m/ z
162 (M+); HRMS calcd for C10H10O2 162.0680 (M+), found
162.0681.
14: IR (neat) 1620 cm-1; 1H-NMR (300 MHz, CDCl3) δ 1.14-
1.19 (2H, m), 1.34-1.39 (2H, m), 3.83 (3H, s), 5.33 (1H, dd, J
) 1.5 and 11.0 Hz), 5.63 (1H, dd, J ) 1.5 and 21.0 Hz), 6.83
(1H, dd, J ) 2.6 and 8.4 Hz), 6.97 (1H, d, J ) 2.6 Hz), 6.98
(1H, br s), 7.10 (1H, dd, J ) 11.0 and 21.0 Hz), 7.67 (1H, d, J
) 8.4 Hz); 13C-NMR (75 MHz, CDCl3) δ 1.0, 4.0, 55.2, 110.8,
114.1, 114.8, 116.2, 123.9, 127.9, 129.0, 135.0, 136.9, 158.7;
Ch a r a cter iza tion Da ta for Sch em es 1 a n d 2. 12: IR
1
(neat) 1700 cm-1; H-NMR (300 MHz, CDCl3) δ 3.93 (3H, s),

A Novel Palladium-Mediated Cascade Reaction
J . Org. Chem., Vol. 62, No. 22, 1997 7855
Ta ble 4. Ca ta lytic P r ocess for Ca sca d e Rin g Exp a n sion
a n d In ser tion Rea ction of 31a
br s), 5.01 (1H, br s), 5.44 (1H, dd, J ) 2.2 and 17.0 Hz), 5.50
(1H, dd, J ) 2.2 and 11.0 Hz), 6.65 (1H, dd, J ) 11.0 and 17.0
Hz), 6.83 (1H, dd, J ) 1.0 and 7.5 Hz), 7.22 (1H, dd, J ) 1.0
and 7.5 Hz), 7.30 (1H, t, J ) 7.5 Hz); 13C-NMR (75 MHz,
CDCl3) δ 18.9, 21.7, 31.8, 44.5, 55.7, 80.6, 109.4, 110.1, 120.6,
120.8, 128.0, 128.2, 131.6, 138.1, 148.6, 157.7; MS m/ z 244
(M+). Anal. Calcd for C16H20O2: C, 78.72; H, 8.26. Found:
C, 78.72; H, 8.06.
31 f 54 + 55 + 56 + 57
product
time
ratio
yield
entry
additive
solvent
(day) (54:55:56:57)b (%)c
26: yield 98%; oil; IR (neat) 1705 cm-1; 1H-NMR (300 MHz,
CDCl3) δ 0.31 (6H, s), 1.01 (9H, s), 7.26 (1H, dd, J ) 1.5 and
7.8 Hz), 7.37 (1H, t, J ) 7.8 Hz), 7.53 (1H, dd, J ) 1.5 and 7.8
Hz), 10.21 (1H, s); 13C-NMR (75 MHz, CDCl3) δ -4.7, 18.4,
25.5, 116.5, 120.5, 122.1, 126.5, 128.8, 129.8, 148.8, 186.8; MS
m/ z 327 (M+ -57). Anal. Calcd for C14H18F3O5SSi: C, 46.04;
H, 5.31; S, 9.45. Found: C, 46.24; H, 5.41; S, 9.36.
1
Cu(OAc)2
Cu(OAc)2
ClCH2CH2Cl 37
ClCH2CH2Cl 33
8:92:0:0
12:86:1:1
2:98:0:0
77
66
77
44
29a
39b,d benzoquinone ClCH2CH2Cl 36
416
DMSO
25
34:64:0:2
a
The reaction was carried out under an argon (entries 1 and
3) or oxygen (entries 2 and 4) atmosphere at room temperature
by using 0.1 equimolar amount of Pd(OAc)2(AsPh3)2 as catalyst
27: yield 50%; oil; IR (neat) 1700 cm-1; 1H-NMR (300 MHz,
CDCl3) δ 0.20 (6H, s), 1.00 (9H, s), 5.28 (1H, dd, J ) 1.1 and
16.0 Hz), 5.72 (1H, dd, J ) 1.1 and 11.0 Hz), 6.99 (1H, dd, J
) 11.0 and 16.0 Hz), 7.02 (1H, dd, J ) 1.2 and 7.8 Hz), 7.26
(1H, t, J ) 7.8 Hz), 7.53 (1H, dd, J ) 1.2 and 7.8 Hz), 10.19
(1H, s); 13C-NMR (75 MHz, CDCl3) δ -4.2, 18.2, 26.0, 121.3,
123.9, 124.1, 128.2, 129.7, 134.2, 136.0, 154.0, 192.8; MS m/ z
262 (M+). Anal. Calcd for C15H22O2Si: C, 74.04; H, 6.23.
Found: C, 74.38; H, 6.04.
b
and 2 equimolar amounts of additives (entries 1-3). The product
ratios corresponded to 54i:55i:56i:57i. c The yields were isolated
one.
MS m/ z 186 (M+); HRMS calcd for C13H14O 186.1044 (M+),
found 186.1045.
16: IR (neat) 1780 cm-1; 1H-NMR (300 MHz, CDCl3) δ 2.05-
2.19 (1H, m), 2.45-2.58 (1H, m), 2.95-3.09 (1H, m), 3.13-
3.27 (1H, m), 3.81 (3H, s), 4.66-4.73 (1H, m), 5.33 (1H, dd, J
) 1.1 and 11.0 Hz), 5.63 (1H, dd, J ) 1.1 and 17.0 Hz), 6.80
(1H, dd, J ) 2.8 and 8.5 Hz), 6.88 (1H, dd, J ) 11.0 and 17.0
Hz), 7.03 (1H, d, J ) 2.8 Hz), 7.22 (1H, d, J ) 8.5 Hz); 13C-
NMR (75 MHz, CDCl3) δ 18.7, 44.4, 55.2, 61.6, 111.7, 113.4,
116.7, 126.8, 127.8, 134.6, 137.9, 158.8, 208.8; MS m/ z 186
(M+); HRMS calcd for C13H14O 186.1044 (M+), found 186.1044.
17: IR (neat) 3500, 1620 cm-1; 1H-NMR (300 MHz, CDCl3)
δ 1.51 (1H, s), 1.83 (3H, s), 1.83-1.91 (1H, m), 2.04-2.41 (1H,
m), 2.37-2.47 (2H, m), 3.83 (3H, s), 3.95 (1H, t, J ) 8.5 Hz),
4.84 (1H, br s), 5.00 (1H, br s), 5.25 (1H, dd, J ) 1.0 and 7.3
Hz), 5.55 (1H, dd, J ) 1.0 and 16.0 Hz), 6.89 (1H, dd, J ) 2.9
and 9.0 Hz), 6.91 (1H, dd, J ) 7.3 and 16.0 Hz), 7.00 (1H, d,
J ) 2.9 Hz), 7.42 (1H, d, J ) 9.0 Hz); 13C-NMR (75 MHz,
CDCl3) δ 18.7, 20.8, 31.0, 43.9, 55.1, 80.6, 110.1, 111.9, 113.2,
116.4, 128.0, 129.5, 135.4, 139.4, 148.6, 158.5; MS m/ z 244
(M+); HRMS calcd for C16H20O2 244.1462 (M+), found 244.1463.
19: yield 100%; mp 50 °C (from Et2O); IR (CHCl3) 1700
cm-1; 1H-NMR (300 MHz, CDCl3) δ 3.97 (3H, s), 7.31 (1H, dd,
J ) 1.0 and 7.8 Hz), 7.47 (1H, t, J ) 7.8 Hz), 7.54 (1H, dd, J
) 1.0 and 7.8 Hz), 10.26 (1H, s); 13C-NMR (75 MHz, CDCl3) δ
56.54, 116.7, 118.7, 120.9, 121.3, 129.7, 151.9, 186.8; MS m/ z
151 (M+ -133). Anal. Calcd for C9H7F3O5S: C, 38.04; H, 2.48;
S, 11.28. Found: C, 38.27; H, 2.52; S, 11.40.
28: yield 84%; oil: IR (neat) 1620 cm-1; 1H-NMR (300 MHz,
CDCl3) δ 0.22 (6H, s), 1.00 (9H, s), 1.13-1.20 (2H, m), 1.37-
1.45 (2H, m), 5.45 (1H, dd, J ) 2.3 and 17.9 Hz), 5.58 (1H, dd,
J ) 2.3 and 11.6 Hz), 6.71 (1H, d, J ) 8.1 Hz), 6.84 (1H, dd,
J ) 11.6 and 17.9 Hz), 7.09 (1H, br s), 7.10 (1H, t, J ) 8.1
Hz), 7.44 (1H, d, J ) 8.1 Hz); 13C-NMR (75 MHz, CDCl3) δ
-4.1, 0.8, 4.0, 18.3, 25.8, 117.2, 117.4, 119.9, 120.8, 124.6,
127.4, 128.9, 132.0, 137.7, 153.7; MS m/ z 286 (M+). Anal
Calcd for C18H26OSi: C, 75.46; H, 9.15. Found: C, 75.22; H,
8.89.
30: yield 86%; oil; IR (neat) 1790, 1630 cm-1; 1H-NMR (300
MHz, CDCl3) δ 0.19 (6H, s), 0.99 (9H, s), 2.08-2.22 (1H, m),
2.40-2.54 (1H, m), 2.96-3.09 (1H, m), 3.11-3.25 (1H, m),
4.79-4.88 (1H, m), 5.43 (1H, dd, J ) 2.1 and 18.0 Hz), 5.50
(1H, dd, J ) 2.1 and 11.4 Hz), 6.70 (1H, dd, J ) 11.4 and 18.0
Hz), 6.72 (1H, d, J ) 7.8 Hz), 6.90 (1H, d, J ) 7.8 Hz), 7.10
(1H, t, J ) 7.8 Hz); 13C-NMR (75 MHz, CDCl3) δ -4.1, 18.2,
19.9, 25.8, 44.7, 63.0, 118.0, 120.0, 120.3, 128.0, 130.0, 132.4,
136.3, 153.7, 209.3; MS m/ z 302 (M+); HRMS calcd for
C18H26O2Si 302.1701 (M+), found 302.1729.
31: yield 74%; oil; IR (neat) 3500, 1640 cm-1; 1H-NMR (300
MHz, CDCl3) δ 0.17 (3H, s), 0.18 (3H, s), 0.97 (9H, s), 1.65
(1H, br s), 1.84 (3H, br s), 1.92-2.16 (2H, m), 2.29-2.44 (2H,
m), 4.12-4.19 (1H, m), 4.81-4.84 (1H, m), 5.00 (1H, br s), 5.34
(1H, dd, J ) 2.1 and 17.9 Hz), 5.47 (1H, dd, J ) 2.1 and 11.4
Hz), 6.60 (1H, dd, J ) 11.4 and 17.9 Hz), 6.75 (1H, dd, J ) 2.6
and 6.9 Hz), 7.17 (1H, t, J ) 6.9 Hz), 7.19 (1H, dd, J ) 2.6
and 6.9 Hz); 13C-NMR (75 MHz, CDCl3) δ -4.2, -4.1, 18.2,
18.9, 21.7, 25.8, 31.8, 44.7, 80.6, 110.0, 118.0, 120.7, 121.2,
127.6, 131.3, 132.5, 138.2, 148.6, 153.6; MS m/ z 344 (M+).
Anal. Calcd for C21H32O2Si: C, 73.20; H, 9.36. Found: C,
72.82; H, 9.12.
20: yield 91%; mp 59 °C (from Et2O); IR (CHCl3) 1690 cm-1
;
1H-NMR (300 MHz, CDCl3) δ 3.90 (3H, s), 5.35 (1H, dd, J )
1.6 and 18.0 Hz), 5.77 (1H, dd, J ) 1.6 and 11.0 Hz), 7.05 (1H,
dd, J ) 11.0 and 18.0 Hz), 7.09 (1H, dd, J ) 1.0 and 8.6 Hz),
7.37 (1H, t, J ) 8.6 Hz), 7.54 (1H, dd, J ) 1.0 and 8.6 Hz);
13C-NMR (75 MHz, CDCl3) δ 55.37, 114.6, 119.8, 123.6, 128.4,
131.3, 135.2, 157.3, 192.0; MS m/ z 162 (M+). Anal. Calcd for
C10H10O2: C, 74.06; H, 6.21. Found: C, 74.01; H, 6.29.
21: yield 86%; oil; IR (neat) 1580 cm-1; 1H-NMR (300 MHz,
CDCl3) δ 1.13-1.18 (2H, m), 1.36-1.42 (2H, m), 3.82 (3H, s),
5.51 (1H, dd, J ) 2.0 and 17.0 Hz), 5.59 (1H, dd, J ) 2.0 and
11.0 Hz), 6.75 (1H, br s), 6.85 (1H, dd, J ) 11.0 and 17.0 Hz),
7.09 (1H, dd, J ) 1.1 and 7.0 Hz), 7.18 (1H, t, J ) 7.0 Hz),
7.42 (1H, dd, J ) 1.1 and 7.0 Hz); 13C-NMR (75 MHz, CDCl3)
δ 0.9, 4.0, 55.6, 108.6, 116.8, 119.4, 120.8, 125.2, 127.7, 131.1,
34: yield 58% (from 32); mp 74 °C (from MeOH); IR (CHCl3)
1680 cm-1; 1H-NMR (300 MHz, CDCl3) δ 5.49 (1H, dd, J ) 2.1
and 18.2 Hz), 6.01 (1H, dd, J ) 2.1 and 11.8 Hz), 7.37 (1H,
dd, J ) 11.8 and 18.2 Hz), 7.54-7.66 (2H, m), 7.83 (1H, d, J
) 8.6 Hz), 7.87 (1H, d, J ) 8.6 Hz), 7.99 (1H, d, J ) 8.6 Hz),
8.18 (1H, d, J ) 8.6 Hz), 10.44 (1H, s); 13C-NMR (75 MHz,
CDCl3) δ 122.9, 125.9, 126.1, 127.0, 128.1, 128.5, 128.9, 130.6,
131.4, 131.6, 135.8, 143.4, 192.8; MS m/ z 182 (M+). Anal.
Calcd for C13H10O: C, 85.69; H, 5.53. Found: C, 85.84; H, 5.81.
35: yield 86%; oil; IR (neat) 1620 cm-1; 1H-NMR (300 MHz,
CDCl3) δ 1.14-1.23 (2H, m), 1.46-1.55 (2H, m), 5.45 (1H, dd,
J ) 2.1 and 18.0 Hz), 5.82 (1H, dd, J ) 2.1 and 11.8 Hz), 7.13
(1H, dd, J ) 11.8 and 18.0 Hz), 7.25 (1H, s), 7.38-7.49 (2H,
m), 7.71 (1H, d, J ) 8.6 Hz), 7.77 (1H, d, J ) 8.6 Hz), 8.03
(1H, d, J ) 8.6 Hz), 8.10 (1H, d, J ) 8.6 Hz); 13C-NMR (75
MHz, CDCl3) δ 0.7, 4.4, 117.2, 122.4, 124.4, 125.4, 125.5, 125.7,
125.8, 126.1, 127.3, 128.2, 132.2, 132.7, 132.9, 133.8; MS m/ z
206 (M+); HRMS calcd for C16H14 206.1095 (M+), found
206.1098.
133.1, 137.4, 157.6; MS m/ z 186 (M+); HRMS calcd for C13H14
O
186.1044 (M+), found 186.1050.
23: yield 55%; oil; IR (neat) 1780, 1580 cm-1; 1H-NMR (300
MHz, CDCl3) δ 2.12-2.19 (1H, m), 2.47-2.49 (1H, m), 3.04-
3.20 (2H, m), 3.82 (3H, s), 4.86 (1H, t, J ) 9.4 Hz), 5.53 (1H,
dd, J ) 1.5 and 18.0 Hz), 5.54 (1H, dd, J ) 1.5 and 11.0 Hz),
6.73 (1H, dd, J ) 11.0 and 18.0 Hz), 6.80 (1H, d, J ) 7.5 Hz),
6.92 (1H, d, J ) 7.5 Hz), 7.22 (1H, t, J ) 7.5 Hz); 13C-NMR
(75 MHz, CDCl3) δ 19.6, 44.5, 55.4, 62.5, 109.2, 119.3, 120.1,
126.7, 128.2, 131.2, 135.9, 157.6, 208.7; MS m/ z 202 (M+).
Anal. Calcd for C13H14O: C, 77.13; H, 6.99. Found: C, 77.11;
H, 7.08.
24: yield 83%; oil; IR (neat) 3400 cm-1; 1H-NMR (300 MHz,
CDCl3) δ 1.85 (3H, br s), 1.88-2.19 (2H, m), 2.31-2.48 (2H,
m), 3.82 (3H, s), 4.17 (1H, dd, J ) 4.8 and 16.0 Hz), 4.83 (1H,
36: yield 80%; oil; IR (neat) 1780 cm-1; 1H-NMR (300 MHz,
CDCl3) δ 2.17-2.29 (1H, m), 2.46-2.61 (1H, m), 3.02-3.14 (1H,

7856 J . Org. Chem., Vol. 62, No. 22, 1997
Nemoto et al.
m), 3.17-3.32 (1H, m), 4.98-5.08 (1H, m), 5.45 (1H, dd, J )
2.1 and 18.2 Hz), 5.78 (1H, dd, J ) 2.1 and 11.8 Hz), 7.18 (1H,
dd, J ) 11.8 and 18.2 Hz), 7.39 (1H, d, J ) 8.6 Hz), 7.40-7.51
(2H, m), 7.72-7.82 (2H, m), 8.01-8.09 (1H, m); 13C-NMR (75
MHz, CDCl3) δ 19.6, 45.0, 63.4, 122.3, 124.7, 125.8, 125.9,
126.3, 128.0, 128.2, 131.5, 132.0, 132.6, 134.0, 135.6, 209.2;
MS m/ z 222 (M+). Anal. Calcd for C16H14O: C, 86.45; H, 6.35.
Found: C, 86.17; H, 6.31.
37: yield 82%; oil; IR (neat) 3400 cm-1; 1H-NMR (300 MHz,
CDCl3) δ 1.52 (1H, s), 1.84 (3H, s), 2.01-2.11 (1H, m), 2.12-
2.21 (1H, m), 2.40-2.59 (2H, m), 4.30 (1H, t, J ) 8.7 Hz), 4.81
(1H, s), 4.97 (1H, s), 5.32 (1H, dd, J ) 2.3 and 17.6 Hz), 5.74
(1H, dd, J ) 2.3 and 11.2 Hz), 6.99 (1H, dd, J ) 11.2 and 17.6
Hz), 7.12-7.27 (1H, m), 7.40-7.47 (2H, m), 7.76-7.83 (3H,
m), 8.05-8.12 (1H, m); 13C-NMR (75 MHz, CDCl3) δ 18.9, 21.7,
37.5, 44.8, 81.4, 110.0, 122.1, 125.5, 126.0, 126.2, 126.3, 127.2,
128.1, 131.9, 132.6, 133.5, 134.5, 136.7, 148.7; MS m/ z 264
(M+). Anal. Calcd for C19H20O: C, 86.32; H, 7.63. Found: C,
85.95; H, 7.74.
Gen er a l Exp er im en ta l P r oced u r es for Sch em e 3. Ex-
p er im en t a l Det a ils for t h e Syn t h esis of 41 via 38-40.
1-[3-(ter t-Bu tyld im eth ylsiloxy)-2-vin ylp h en yl]-2-(1-m eth -
yl-2-th iop h en yleth ylid en e)cyclobu ta n e (39). To a stirred
solution of the cyclobutanol 31 (1.11 g, 3.22 mmol) and pyridine
(0.52 mL, 6.4 mmol) in THF (30 mL) was added thionyl
chloride (0.31 mL, 4.2 mmol) at 0 °C and stirring was
continued for 1 h at room temperature. The reaction mixture
was diluted with water and extracted with Et2O. The com-
bined extracts were washed with saturated aqueous NaCl. The
residue upon workup was dissolved in DMF (5 mL). To a
stirred suspension of NaH (0.26 g, of 60% oil suspension, 6.5
mmol) was added thiophenol (0.83 mL, 8.1 mmol) at 0 °C and
stirring was continued. After 10 min, to the reaction mixture
was added a solution of the residue at 0 °C and stirring was
continued for 6 h at room temperature. The resulting solution
was diluted with water and extracted with Et2O. The com-
bined extracts were washed with 10% aqueous NaOH and
saturated aqueous NaCl. The residue upon workup was
chromatographed on silica gel with hexane-AcOEt (99:1 v/v)
as eluant to give the phenyl sulfide 39 (822 mg, 58%) as a
colorless oil.
1-[3-(ter t-Bu t yld im e t h ylsiloxy)-2-vin ylp h e n yl]-2-[1-
m eth yl-2-(p h en ylsu lfin yl)eth ylid en e]cyclobu ta n e (40).
To a stirred solution of the sulfide 39 (57.9 mg, 0.133 mmol)
in CH2Cl2 (3 mL) were added NaHCO3 (22.3 mg, 0.266 mmol)
and m-chloroperbenzoic acid (m-CPBA) (28.6 mg, 80%, 0.133
mmol) at -78 °C and stirring was continued for 1 h at the
same temperature. The temperature was increased to 0 °C
in 1 h. The reaction mixture was diluted water and extracted
with Et2O. The combined extracts were washed with satu-
rated aqueous NaCl. The residue upon workup was chromato-
graphed on silica gel with hexane-AcOEt (92:8 v/v) to give
the sulfoxide (54.6 mg, 91%) as a colorless oil.
Hz), 3.14 (0.1H, br d, J ) 12.0 Hz), 3.17 (0.1H, br d, J ) 12.0
Hz), 3.30 (0.1H, br d, J ) 12.0 Hz), 3.39 (0.4H, br d, J ) 12.0
Hz), 3.47 (0.4H, br d, J ) 12.0 Hz), 3.63 (0.8H, br d, J ) 11.1
Hz), 4.27-4.43 (1H, m), 5.19 (0.1H, dd, J ) 18.0 and 2.4 Hz),
5.30-5.41 (1H, m), 5.43-5.52 (0.9H, m), 6.48 (0.1H, dd, J )
18.0 and 11.4 Hz), 6.61-6.78 (2.5H, m), 6.82-6.91 (0.4H, m),
6.97-7.13 (1H, m), 7.26-7.75 (5H, m); MS m/ z 327 (M+
-
57); HRMS calcd for C21H31OSi (M+ - 57) 327.2144, found
327.2136.
41: IR (neat) 1620, 3480 cm-1; 1H-NMR (300 MHz, CDCl3)
δ 0.15 (6H, s), 0.97 (9H, s), 1.27 (3H, br s), 1.89-2.00 (2H, m),
2.02-2.14 (1H, m), 2.21 (1H, br s), 2.38-2.48 (1H, m), 3.97
(1H, t, J ) 9.6 Hz), 4.87 (1H, br s), 4.99 (1H, br s), 5.59 (1H,
dd, J ) 2.4 and 11.4 Hz), 5.62 (1H, dd, J ) 2.4 and 17.9 Hz),
6.71 (1H, br d, J ) 7.8 Hz), 6.79 (1H, br d, J ) 7.8 Hz), 6.87
(1H, dd, J ) 11.4 and 17.9 Hz), 7.05 (1H, t, J ) 7.8 Hz); 13C-
NMR (75 MHz, CDCl3) δ -4.1, -4.0, 17.7, 18.2, 18.4, 25.9, 31.7,
50.3, 82.8, 111.5, 118.0, 120.4, 121.0, 127.3, 130.0, 133.2, 139.7,
145.1, 153.0; MS m/z 344 (M+). Anal. Calcd for C21H30OSi:
C, 73.20; H, 9.36. Found: C, 73.13; H, 9.23.
43 (E:Z/69:31): yield 60% (from 37); oil; IR (neat) 1630 cm-1
;
1H-NMR (300 MHz, CDCl3) δ 1.34 (2.07H, s), 1.73 (0.93H, s),
1.75-1.83 (1H, m), 2.26-2.40 (1H, m), 2.44-2.86 (2H, m), 2.95
(0.31H, d, J ) 14.0 Hz), 3.28 (0.31H, d, J ) 14.0 Hz), 3.37
(0.69H, d, J ) 13.0 Hz), 3.64 (0.69H, d, J ) 13.0 Hz), 4.35
(0.31H, m), 4.54 (0.69H, m), 5.25-5.38 (1H, m), 5.67-5.77 (1H,
m), 6.91-7.09 (1H, m), 7.10-7.54 (8H, m), 7.61-7.75 (1H, m),
7.76-7.82 (1H, m), 8.03-8.10 (1H, m); MS m/ z 356 (M+);
HRMS calcd for C25H24S (M+) 356.1599, found 356.1587.
44 (E:Z/69:31): yield 98%; oil; IR (neat) 1630 cm-1; 1H-NMR
(300 MHz, CDCl3) δ 1.28 (1.38H, s), 1.30 (0.69H, s), 1.61-2.18
(1.93H, m), 2.18-2.46 (1H, m), 2.51-2.91 (2H, m), 2.91-3.24
(0.62H, m), 3.34-3.49 (0.69H, m), 3.56-3.66 (0.69H, m), 3.85-
4.25 (0.31H, m), 4.50-4.66 (0.69H, m), 5.17-5.38 (1H, m),
5.63-5.80 (1H, m), 6.79-7.85 (11H, m), 7.86-8.14 (1H, m);
MS m/ z 355 (M+ - 17); HRMS calcd for C25H23S (M+ -17)
355.1521, found 355.1499.
45: yield 71%; oil; IR (neat) 3000 cm-1; 1H-NMR (300 MHz,
CDCl3) δ 1.19 (3H, s), 2.00-2.24 (4H, m), 2.48-2.57 (1H, m),
4.15 (1H, t, J ) 9.0 Hz), 4.90 (1H, s), 5.08 (1H, s), 5.52 (1H,
dd, J ) 2.6 and 18.1 Hz), 5.87 (1H, dd, J ) 2.6 and 11.5 Hz),
7.25 (1H, dd, J ) 11.5 and 18.1 Hz), 7.37-7.50 (3H, m), 7.71
(1H, d, J ) 9.1 Hz), 7.76-7.85 (1H, m), 8.10-8.18 (1H, m);
13C-NMR (75 MHz, CDCl3) δ 17.9, 18.5, 32.0, 50.8, 82.9, 111.8,
122.2, 125.1, 125.3, 125.9, 126.1, 127.0, 128.1, 131.6, 132.5,
134.9, 135.4, 145.1; MS m/ z 264 (M+) HRMS calcd for C19H20
O
264.1514 (M+), found 264.1553.
Gen er a l P r oced u r e for Ca sca d e Rin g Exp a n sion a n d
In ser tion Rea ction . P r oced u r e for th e Rea ction of 17
(en tr y 1 in Ta ble 1). A slurry of the cyclobutanol 17 (10.3
mg, 0.042 mmol) and PdCl2(CH3CN)2 (10.9 mg, 0.042 mmol)
in DME (0.5 mL) was stirred for 14 h at room temperature.
After evaporation of the solvent, the residue was passed
through a short pad of silica gel with Et2O as eluant to give a
mixture of the benzohydrindans 48 and 49 (5.5 mg, 53%) as a
colorless oil.
Ch a r a cter iza tion Da ta for P r od u cts in Ta bles 1-3.
Samples for analysis were prepared by careful column chro-
matography of all products in the tables on silica gel using
each solvent systems.
46 + 47 (ratio of 6:94, entry 9 in Table 1, AcOEt-hexane
1:99 v/v): oil; IR (neat) 1740 cm-1; 1H-NMR (300 MHz, CDCl3)
δ 0.68 (0.18H, s), 1.07 (2.82H, s), 1.78-1.91 (1.06H, m), 2.08
(0.94H, d, J ) 14.0 Hz), 2.28-2.75 (4H, m), 2.93-3.07 (1H,
m), 3.83 (3H, s), 5.06 (0.94H, s), 5.12 (0.06H, s), 5.52 (0.94H,
s), 5.75 (0.06H, s), 6.82-6.89 (1H, m), 7.04-7.16 (1.94H, m),
7.21-7.24 (0.06H, m); MS m/ z 242 (M+); HRMS calcd for
C16H18O2 242.1306 (M+), found 242.1297.
(1R*,2S*)-2-[3-(ter t-Bu tyldim eth ylsiloxy)-2-vin ylph en yl]-
1-isop r op en ylcyclobu ta n -1-ol (41). A solution of the sul-
foxide 40 (775 mg, 1.71 mmol) and trimethyl phosphite (2.2
mL, 19 mmol) in methanol (60 mL) was refluxed for 9 h. The
solvent was evaporated and the residue was chromatographed
on silica gel with hexane-AcOEt (98.5:1.5 v/v) to give the
cyclobutanol 41 (440 mg, 75%) as a colorless oil.
Ch a r a cter iza tion Da ta for Sch em e 3. 39 (E:Z/19:81):
1
IR (neat) 1630 cm-1; H-NMR (300 MHz, CDCl3) δ 0.17 (3H,
s), 0.19 (3H, s), 0.98 (9H, s), 1.38-1.42 (2.43H, m), 1.62-1.83
(1.57H, m), 2.19-2.36 (1H, m), 2.37-2.63 (1.81H, m), 2.63-
2.72 (0.19H, m), 3.02 (0.19H, br d, J ) 12.6 Hz), 3.31-3.41
(1H, m), 3.63 (0.81H, br d, J ) 12.6 Hz), 4.03-4.13 (0.19H,
m), 4.26-4.34 (0.81H, m), 5.32 (0.19H, dd, J ) 2.1 and 18.3Hz),
5.37 (0.81H, dd, J ) 2.1 and 17.3 Hz), 5.43 (0.19H, dd, J ) 2.1
and 11.7 Hz), 5.45 (0.81H, dd, J ) 2.1 and 11.9 Hz), 6.56-
6.71 (2.81H, m), 6.92-6.98 (1H, m), 7.06 (0.19H, t, J ) 7.8
Hz), 7.15-7.36 (3.38H, m), 7.41-7.47 (1.62H, m); MS m/ z 436
(M+): HRMS calcd for C27H36OSSi 436.2254 (M+), found
436.2258.
47 (entry 15 in Table 1, AcOEt-hexane 1:99 v/v): oil; IR
1
(neat) 1740 cm-1; H-NMR (300 MHz, CDCl3) δ 1.07 (3H, s),
1.79-1.93 (1H, m), 2.08 (1H, d, J ) 14.0 Hz), 2.28-2.48 (3H,
m), 2.54 (1H, d, J ) 14.0 Hz), 3.05 (1H, dd, J ) 6.0 and 10.0
Hz), 3.83 (3H, s), 5.06 (1H, s), 5.52 (1H, s), 6.88 (1H, dd, J )
2.2 and 8.0 Hz), 7.10 (1H, d, J ) 2.2 Hz), 7.15 (1H, d, J ) 8.0
Hz); 13C-NMR (75 MHz, CDCl3) δ 20.4, 29.4, 36.3, 37.5, 47.0,
48.3, 55.4, 108.7, 111.9, 115.3, 129.9, 130.2, 134.7, 139.8, 158.2,
40 (E:Z/20:80): IR (neat) 1630 cm-1 1H-NMR (300 MHz,
;
CDCl3) δ 0.25-0.35 (6H, m), 0.95-1.06 (9H, m), 1.34-1.43
(2.4H, m), 1.64-1.79 (1.6H, m), 1.79-2.07 (0.4H, m), 2.08-
2.42 (1.6H, m), 2.42-2.73 (1H, m), 3.03 (0.1H, br d, J ) 12.0

A Novel Palladium-Mediated Cascade Reaction
J . Org. Chem., Vol. 62, No. 22, 1997 7857
221.4; MS m/z 242 (M+); HRMS calcd for C16H18O2 242.1306
(M+), found 242.1321.
7.5 Hz), 7.15 (1H, t, J ) 7.5 Hz); 13C-NMR (75 MHz, CDCl3) δ
21.8, 29.7, 37.7, 39.9, 47.8, 48.6, 114.1, 114.6, 121.1, 121.5,
129.1, 138.9, 140.7, 153.0, 222.2; MS m/ z 228 (M+); HRMS
calcd for C15H16O2 228.1149 (M+), found 228.1182. Anal.
Calcd for C15H16O2: C, 78.92; H, 7.06. Found: C, 78.54; H,
6.84.
48 (entry 1 in Table 1, AcOEt-hexane 1:99 v/v): oil; IR
1
(neat) 1740 cm-1; H-NMR (300 MHz, CDCl3) δ 0.70 (3H, s),
1.95-2.09 (1H, m), 2.06 (3H, s), 2.25-2.39 (1H, m), 2.44 (1H,
dd, J ) 8.5 and 18.0 Hz), 2.67 (1H, dd, J ) 8.5 and 18.0 Hz),
3.09 (1H, dd, J ) 5.0 and 12.0 Hz), 3.84 (3H, s), 6.25 (1H, s),
6.81 (1H, dd, J ) 2.2 and 8.2 Hz), 6.90 (1H, d, J ) 2.2 Hz),
7.09 (1H, d, J ) 8.2 Hz); 13C-NMR (75 MHz, CDCl3) δ 13.8,
19.6, 19.8, 37.0, 46.2, 49.3, 55.5, 111.2, 111.3, 125.1, 129.1,
130.0, 133.0, 137.8, 158.6, 216.0; MS m/ z 242 (M+); HRMS
calcd for C16H18O2 242.1306 (M+), found 242.1299.
56i (entry 2 in Table 2, AcOEt-hexane 0.8:99.2 v/v): mp
94 °C (from hexane-AcOEt); IR (CHCl3) 3600, 1740 cm-1; 1H-
NMR (300 MHz, CDCl3) δ 0.69 (3H, s), 1.92-2.08 (1H, m), 2.28
(3H, s), 2.28-2.51 (2H, m), 2.61-2.74 (1H, m), 2.99-3.08 (1H,
m), 5.10 (1H, s), 6.19 (1H, s), 6.69 (1H, d, J ) 7.8 Hz), 6.76
(1H, d, J ) 7.8 Hz), 7.13 (1H, t, J ) 7.8 Hz); 13C-NMR (75
MHz, CDCl3) δ 13.2, 20.0, 22.9, 37.0, 47.3, 48.6, 116.1, 117.5,
123.1, 128.4, 130.3, 132.9, 139.7, 153.1, 216.9; MS m/ z 228
(M+); HRMS calcd for C15H16O2 228.1149 (M+), found 228.1152.
57i (entry 2 in Table 2, AcOEt-hexane 0.5:99.5 v/v): mp
49 (entry 1 in Table 1, AcOEt-hexane 1:99 v/v): oil; IR
1
(neat) 1740 cm-1; H-NMR (300 MHz, CDCl3) δ 1.04 (3H, s),
1.60-1.77 (1H, m), 2.07 (3H, s), 2.09-2.20 (1H, m), 2.23-2.33
(2H, m), 3.01 (1H, dd, J ) 6.5 and 11.0 Hz), 3.84 (3H, s), 5.25
(1H, s), 6.81 (1H, dd, J ) 2.2 and 7.9 Hz), 6.92 (1H, d, J ) 2.2
Hz), 7.16 (1H, d, J ) 7.9 Hz); 13C-NMR (75 MHz, CDCl3) δ
19.5, 21.4, 29.0, 36.6, 47.4, 52.5, 55.4, 110.4, 112.3, 125.2, 128.8,
129.0, 132.1, 133.4, 158.8, 221.4; MS m/ z 242 (M+); HRMS
calcd for C16H18O2 242.1306 (M+), found 242.1304.
164 °C (from hexane-AcOEt); IR (CHCl3) 3640, 1740 cm-1
;
1H-NMR (300 MHz, CDCl3) δ 1.03 (3H, s), 1.71-1.86 (1H, m),
2.04-2.19 (1H, m), 2.21-2.30 (1H, m), 2.30 (3H, s), 2.30-2.42
(1H, m), 2.92-3.01 (1H, m), 5.01 (1H, s), 5.08 (1H, s), 6.64 (1H,
br d, J ) 7.8 Hz), 6.82 (1H, br d, J ) 7.8 Hz), 7.09 (1H, t, J )
7.8 Hz); 13C-NMR (75 MHz, CDCl3) δ 21.5, 25.2, 29.6, 37.6,
50.2, 52.9, 117.5, 120.9, 122.2, 125.5, 130.4, 135.3, 141.6, 157.1,
221.5; MS m/ z 228 (M+). Anal. Calcd for C15H16O2: C, 78.92;
H, 7.06. Found: C, 78.83; H, 6.98.
50 + 51 (ratio of 20:80, entry 7 in Table 2, AcOEt-hexane
1:99 v/v): oil; IR (neat) 1740 cm-1; 1H-NMR (300 MHz, CDCl3)
δ 0.61 (0.6H, s), 1.01 (2.4H, s), 1.75-2.72 (6H, m), 3.08-3.14
(1H, m), 3.86 (3H, s), 5.34 (0.8H, s), 5.41 (0.2H, s), 5.96 (0.8H,
s), 6.09 (0.2H, s), 6.77-6.93 (2H, m), 7.10-7.24 (1H, m); MS
m/ z 242 (M+); HRMS calcd for C16H18O2 242.1306 (M+), found
242.1305.
58 + 60 (ratio of 48:52, entry 1 in Table 3, AcOEt-hexane
1:99 v/v): oil; IR (neat) 1740 cm-1; 1H-NMR (300 MHz, CDCl3)
δ 0.55 (1.44H, s), 0.67 (1.56H, s), 2.00-2.39 (2H, m), 2.39-
2.54 (1H, m), 2.43 (1.56 H, s), 2.57-2.75 (1H, m), 2.67 (0.48H,
d, J ) 13.6 Hz), 2.94 (0.48H, d, J ) 13.6 Hz), 3.00 (0.48H, dd,
J ) 6.3 and 12.0 Hz), 3.23 (0.52H, dd, J ) 6.3 and 12.0 Hz),
5.48 (0.48H, s), 5.55 (0.48H, s), 6.51 (0.52H, s), 7.30-7.49 (3H,
m), 7.74-7.88 (2H, m), 8.26 (0.52H, d, J ) 8.4 Hz), 8.41 (0.48H,
d, J ) 9.3 Hz); HRMS calcd for C19H18O 262.1357 (M+), found
262.1355.
51 (entry 7 in Table 2, AcOEt-hexane 1:99 v/v): oil; IR
1
(neat) 1740 cm-1; H-NMR (300 MHz, CDCl3) δ 1.01 (3H, s),
1.76-1.94 (1H, m), 2.01 (1H, d, J ) 11.0 Hz), 2.26-2.48 (3H,
m), 2.52 (1H, d, J ) 11.0 Hz), 3.12 (1H, dd, J ) 5.4 and 9.5
Hz), 3.86 (3H, s), 5.34 (1H, s), 5.96 (1H, s), 6.80 (1H, d, J )
7.4 Hz), 6.86 (1H, d, J ) 7.4 Hz), 7.21 (1H, t, J ) 7.4 Hz);
13C-NMR (75 MHz, CDCl3) δ 20.8, 29.7, 37.6, 39.5, 47.8, 48.1,
55.5, 108.9, 118.0, 121.5, 123.1, 128.2, 135.4, 140.4, 157.4,
220.0; MS m/ z 242 (M+); HRMS calcd for C16H18O2 242.1306
(M+), found 242.1320.
59 (entry 7 in Table 3, AcOEt-hexane 1:99 v/v): oil; IR
1
(neat) 1740 cm-1; H-NMR (300 MHz, CDCl3) δ 1.19 (3H, s),
1.82-1.95 (1H, m), 2.21 (1H, d, J ) 12.9 Hz), 2.33-2.54 (3H,
m), 2.71 (1H, d, J ) 12.9 Hz), 3.32 (1H, t, J ) 7.5 Hz), 5.46-
5.56 (2H, m), 7.31 (1H, d, J ) 9.4 Hz), 7.43-7.53 (2H, m), 7.74
(1H, d, J ) 9.4 Hz), 7.82 (1H, d, J ) 8.6 Hz), 8.49 (1H, d, J )
8.6 Hz); 13C-NMR (75 MHz, CDCl3) δ 22.6, 29.6, 38.0, 40.6,
48.8, 49.2, 117.9, 125.5, 125.9, 126.4, 126.9, 128.2, 128.5, 130.1,
132.4, 133.2, 136.6, 138.9, 222.5; MS m/ z 262 (M+); HRMS
calcd for C19H18O 262.1357 (M+), found 262.1379.
52 (entry 1 in Table 2, AcOEt-hexane 1:99 v/v): oil; IR
1
(neat) 1740 cm-1; H-NMR (300 MHz, CDCl3) δ 0.67 (3H, s),
1.91-2.07 (1H, m), 2.22 (3H, s), 2.24-2.38 (1H, m), 2.44 (1H,
dd, J ) 8.5 and 16.0 Hz), 2.66 (1H, dd, J ) 8.5 and 16.0 Hz),
3.01 (1H, dd, J ) 5.5 and 12.0 Hz), 3.82 (3H, s), 6.17 (1H, s),
6.80 (1H, d, J ) 7.3 Hz), 6.87 (1H, d, J ) 7.3 Hz), 7.24 (1H, t,
J ) 7.3 Hz); 13C-NMR (75 MHz, CDCl3) δ 13.2, 20.2, 23.3, 37.2,
47.5, 48.5, 55.6, 111.0, 117.4, 125.1, 128.3, 130.1, 133.5, 139.2,
157.0, 216.3; MS m/ z 242 (M+); HRMS calcd for C16H18O2
242.1306 (M+), found 242.1296.
60 + 61 (ratio of 62:38, entry 4 in Table 3, AcOEt-hexane
1:99 v/v): oil; IR (neat) 1740 cm-1; 1H-NMR (300 MHz, CDCl3)
δ 0.67 (1.86H, s), 1.15 (1.14H, s), 1.82-1.99 (0.38H, m), 2.00-
2.12 (0.62H, m), 2.23-2.39 (1H, m), 2.39-2.56 (1H, m), 2.43
(1.86H, s), 2.48 (1.14H, s), 2.64-2.75 (1H, m), 3.07 (0.38H, dd,
J ) 6.3 and 12.0 Hz), 3.23 (0.62H, dd, J ) 6.3 and 12.0 Hz),
5.36 (0.38H, s), 6.51 (0.62 H, s), 7.33-7.49 (3H, m), 7.74-7.88
(2H, m), 8.26 (0.62H, d, J ) 8.4 Hz), 8.38 (0.38H, d, J ) 8.7
Hz); MS m/ z 262 (M+); HRMS calcd for C19H18O 262.1357
(M+), found 262.1354.
53 (entry 1 in Table 2, AcOEt-hexane 1:99 v/v): oil; IR
1
(neat) 1740 cm-1; H-NMR (300 MHz, CDCl3) δ 1.01 (3H, s),
1.71-1.86 (1H, m), 2.07-2.40 (3H, m), 2.24 (3H, s), 2.96 (1H,
dd, J ) 6.9 and 12.0 Hz), 3.81 (3H, s), 5.07 (1H, s), 6.84 (1H,
d, J ) 7.1 Hz), 6.86 (1H, d, J ) 7.1 Hz), 7.20 (1H, t, J ) 7.1
Hz); 13C-NMR (75 MHz, CDCl3) δ 20.2, 24.3, 27.8, 36.7, 48.9,
51.8, 55.6, 111.1, 121.4, 124.5, 128.5, 130.2, 133.3, 139.3, 157.6,
221.7; MS m/ z 242 (M+); HRMS calcd for C16H20O2 242.1306
(M+), found 242.1298.
6-(3-H yd r oxy-2-vin ylp h en yl)-2-m et h yl-1-h exen -3-on e
(62i): oil; IR (neat) 3400, 1660 cm-1 1H-NMR (300 MHz,
;
54i (entry 9 in Table 2, AcOEt-hexane 0.8:99.2 v/v): mp
CDCl3) δ 1.82-1.94 (5H, m), 2.60 (2H, t, J ) 7.8 Hz), 2.70 (2H,
t, J ) 7.2 Hz), 5.58 (1H, dd, J ) 1.8 and 18.3 Hz), 5.62 (1H, br
s), 5.72 (1H, dd, J ) 1.8 and 11.4 Hz), 5.75 (1H, br s), 5.90
(1H, br s), 6.74 (1H, d, J ) 7.8 Hz), 6.80 (1H, d, J ) 7.8 Hz),
7.10 (1H, t, J ) 7.8 Hz); MS m/ z 230 (M+); HRMS calcd for
C15H18O2 230.1307 (M+), found 230.1307.
158-159 °C (from hexane-AcOEt); IR (CHCl3) 3500, 1730
cm-1 1H-NMR (300 MHz, CDCl3) δ 0.61 (3H, s), 1.98-2.16
;
(1H, m), 2.31-2.44 (2H, m), 2.52-2.70 (2H, m), 2.72-2.91 (2H,
m), 5.43 (1H, br s), 5.68 (1H, br s), 5.84 (1H, s), 6.74 (1H, d, J
) 8.1 Hz), 6.88 (1H, d, J ) 8.1 Hz), 7.18 (1H, t, J ) 8.1 Hz);
13C-NMR (75 MHz, CDCl3) δ 16.8, 20.9, 36.5, 39.2, 46.5, 48.6,
115.0, 116.0, 117.0, 122.2, 128.8, 139.5, 139.7, 153.1, 220.1;
MS m/ z 228 (M+); HRMS calcd for C15H16O2 228.1149 (M+),
found 228.1147.
Su p p or tin g In for m a tion Ava ila ble: 1H-NMR spectra of
compounds 12-14, 16, 17, 21, 30, 35, 39, 40, 43-45, 46+47,
47-49, 51-53, 54i, 56i, 58 + 59, 59, 60 + 61, and 62 (26
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
55i (entry 8 in Table 2, AcOEt-hexane 0.8:99.2 v/v): mp
133-134 °C (from hexane-AcOEt); IR (CHCl3) 3530, 1730
cm-1 1H-NMR (300 MHz, CDCl3) δ 1.14 (3H, s), 1.75-1.93
;
(1H, m), 2.08 (1H, d, J ) 12.6 Hz), 2.30-2.48 (3H, m), 2.56
(1H, d, J ) 12.6 Hz), 3.13-3.22 (1H, m), 5.36 (1H, s), 5.59
(1H, s), 5.79 (1H, s), 6.80 (1H, d, J ) 7.5 Hz), 6.82 (1H, d, J )
J O971377Z