Highly stereoselective synthesis of functionalized β,β-di- and trisubstituted vinylic sulfoxides by cu-catalyzed conjugate addition of organozinc reagents

Article abstract of DOI:10.1021/jo048747l

β,β-Disubstituted chiral vinylic sulfoxides bearing functionalities have been synthesized via Cu-catalyzed conjugate addition of organozinc reagents to chiral 1-alkynyl sulfoxides. Due to the availability of functionalized organozinc reagents and high syn

Full text of DOI:10.1021/jo048747l

Highly Stereoselective Synthesis of Functionalized â,â-Di- and
Trisubstituted Vinylic Sulfoxides by Cu-Catalyzed Conjugate
Addition of Organozinc Reagents
Naoyoshi Maezaki, Hiroaki Sawamoto, Tomoko Suzuki, Ryoko Yoshigami, and
Tetsuaki Tanaka*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita,
Osaka 565-0871, Japan
t-tanaka@phs.osaka-u.ac.jp
Received July 22, 2004
â,â-Disubstituted chiral vinylic sulfoxides bearing functionalities have been synthesized via
Cu-catalyzed conjugate addition of organozinc reagents to chiral 1-alkynyl sulfoxides. Due to the
availability of functionalized organozinc reagents and high syn-selectivity of the reaction, both
geometric â,â-disubstituted vinylic sulfoxides were selectively synthesized. Furthermore, 1-alkynyl
sulfoxides were derivatized into trisubstituted vinylic sulfoxides by trapping the resulting R-sulfinyl
vinylic carbanion with electrophiles. Highly diastereoselective THF and THP ring formations were
accomplished by means of this methodology followed by an intramolecular Michael addition.
Introduction
gate addition of an organocopper reagent to 1-alkynyl
sulfoxides.4 However, application of this method has been
limited to introduction of relatively simple alkyl groups.
One reason is that organocopper reagents are regularly
prepared from reactive organolithium or Grignard re-
agents. To solve this problem, we have developed a novel
synthesis of â,â-disubstituted vinylic sulfoxides by
Cu-catalyzed carbozincation of the chiral 1-alkynyl sul-
foxides with organozinc reagents, which can be prepared
straightforwardly from alkyl halides by a halogen-zinc
exchange reaction and many functionalities are compat-
ible due to its mild reactivity, and the results have been
reported in a communication.5 Herein, we report full
details of a highly syn-selective Cu-catalyzed conjugate
addition of an organozinc reagent with 1-alkynyl sulfox-
ide including a geometrically selective synthesis of func-
tionalized trisubstituted vinylic sulfoxides by trap of
the resulting R-sulfinylzinc species with electrophiles. In
addition, we accomplished a synthesis of chiral R,R-
disubstituted THF and THP compounds with very high
diastereoselectivity, and the results are also described.
Vinylic sulfoxides are a well-known chiral building
block and have been applied to various asymmetric
reactions, in which high diastereoselectivity was often
realized. In addition, the sulfinyl group can be converted
into various functional groups by reduction, oxidation,
thermolysis, Pummerer reaction, R-deprotonation, and so
on.1 Therefore, the synthetic procedures have been
extensively studied. Although some useful methods to
synthesize (E)- and (Z)-â-monosubstituted vinylic sul-
foxides are available,2 there are few methods for the
synthesis of acyclic â,â-disubstituted vinylic sulfoxides.3
One widely used methodology is the syn-selective conju-
(1) For reviews of sulfoxides, see: (a) Ferna´ndez, I.; Khiar, N. Chem.
Rev. 2003, 103, 3651-3705. (b) Procter, D. J. J. Chem. Soc., Perkin
Trans. 1 2001, 335-354. (c) Procter, D. J. J. Chem. Soc., Perkin Trans.
1 2000, 835-871. (d) Carretero, J. C.; Arraya´s, R. G.; Buezo, N. D.;
Garrido, J. L.; Alonso, I.; Adrio, J. Phosphrous, Sulfur Silicon Relat.
Elem. 1999, 153-154, 259-273. (e) Aversa, M. C.; Barattucci, A.;
Bonaccorsi, P.; Giannetto, P. Tetrahedron: Asymmetry 1997, 8, 1339-
1367. (f) Carren˜o, M. C. Chem. Rev. 1995, 95, 1717-1760. (g) Marino,
J. P. Pure Appl. Chem. 1993, 65, 667-674. (h) Walker, A. J. Tetrahe-
dron: Asymmetry 1992, 3, 961-998. (i) Koizumi, T. Phosphrous, Sulfur
Silicon Relat. Elem. 1991, 58, 111-127.
(2) For geometric selective synthesis of â-monosubstituted vinylic
sulfoxides, see: (a) van Steenis, J. H.; van Es, J. J. G. S.; van der Gen,
A. Eur. J. Org. Chem. 2000, 65, 2787-2793. (b) Segorbe, M. M.; Adrio,
J.; Carretero, J. C. Tetrahedron Lett. 2000, 41, 1983-1986. (c)
Mikolajczyk, M.; Perlikowska, W.; Omelan˜czuk, J.; Cristau, H.-J.;
Perraud-Darcy, A. J. Org. Chem. 1998, 63, 9716-9722. (d) Kosugi, H.;
Kitaoka, M.; Tagami, K.; Takahashi, A.; Uda, H. J. Org. Chem. 1987,
52, 1078-1082. (e) Kosugi, H.; Kitaoka, M.; Tagami, K.; Uda, H. Chem.
Lett. 1985, 805-808. (f) Posner, G. H.; Tang, P.-W. J. Org. Chem. 1978,
43, 4131-4136. (g) Abbott, D. J.; Colonna, S.; Stirling, J. M. J. Chem.
Soc. D 1971, 471.
Result and Discussion
Cu-Catalyzed Carbozincation of 1-Alkynyl Sul-
foxides. First, we examined the Cu- or Ni-catalyzed
conjugate addition of Et2Zn to a chiral 1-alkynyl sulfoxide
(4) (a) Paley, R. S.; de Dios, A.; Estroff, L. A.; Lafontaine, J. A.;
Montero, C.; McCulley, D. J.; Rubio, M. B.; Ventura, M. P.; Weers, H.
L.; de la Pradilla, R. F.; Castro, S.; Dorado, R.; Morente, M. J. Org.
Chem. 1997, 62, 6326-6343. (b) Paley, R. S.; Weers, H. L.; Ferna´ndez,
P.; de la Pradilla, R. F.; Castro, S. Tetrahedron Lett. 1995, 36, 3605-
3608. (c) Kosugi, H.; Miura, Y.; Kanna, H.; Uda, H. Tetrahedron:
Asymmetry 1993, 4, 1409-1412. (d) Truce, W. E.; Lusch, M. J. J. Org.
Chem. 1978, 43, 2252-2258. (e) Vermeer, P.; Meijer, J.; Eylander, M.
C. Recl. Trav. Chim. Pays-Bas 1974, 93, 240-241 and ref 2d.
(5) Maezaki, N.; Sawamoto, H.; Yoshigami, R.; Suzuki, T.; Tanaka,
T. Org. Lett. 2003, 5, 1345-1347.
(3) For geometric selective synthesis of â,â-disubstituted vinylic
sulfoxides, see: (a) Alonso, I.; Carretero, J. C. J. Org. Chem. 2001, 66,
4453-4456. (b) Ruano, J. L. G.; de Diego, S. A. A.; Blanco, D.; Castro,
A. M. M.; Martin, M. R.; Ramos, J. H. R. Org. Lett. 2001, 3, 3173-
3176. (c) Ruano, J. L. G.; Gamboa, A. E.; Castro, A. M. M.; Rodr´ıguez,
J. H.; Lo´pez-Solera, M. I. J. Org. Chem. 1998, 63, 3324-3332 and ref
2d.
10.1021/jo048747l CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/04/2004
J. Org. Chem. 2004, 69, 8387-8393
8387

Maezaki et al.
TABLE 1. Synthesis of â,â-Disubstituted Vinylic
TABLE 2. Synthesis of â,â-Disubstituted Vinylic
Sulfoxides with Et2Zna
Sulfoxides with R2′Zna
Et2Znb
product
catalyst
(mol %)
(mol per 1
concn
(M)
yield
(%)
entry substrate
R
R′ Cu-catalyst (yield, %)
entry
mol of 1a)
1
2
3
4
5
6
7
8
9
1b
1c
1d
1d
1d
1d
1e
1f
TBSO(CH2)2 Et
CuI
2b (78)
2c (84)
2d (71)
2d (79)
2d (86)
2d (83)
2e (24)b
2f (21)c
2g (81)d
1
2
CuI (2)
1
2
4
2
2
2
2
2
2
2
0.1
0.1
0.1
0.1
0.1
1
1
1
0.1
1
15
72
57
35
46
97
86
69
46
34
AcO(CH2)2
I(CH2)4
I(CH2)4
I(CH2)4
I(CH2)4
H
Et
Et
Et
Et
Et
Et
Et
Me
CuI
CuI (2)
CuI
3
CuI (2)
CuI, )))
CuCN
Cu(OTf)2
CuI
4
CuI (0.5)
5
CuI (10)
6
CuI (2)
7
CuCN (2)
Cu(OTf)2 (2)
Ni(acac)2 (20)c
Ni(acac)2 (20)c
t-Bu
n-Bu
CuI
8
1a
CuI
9
a All reactions were carried out in THF using Et2Zn (hexane
solution, 2 mol per 1 mol of 1) at -78 °C to rt unless otherwise
stated. b (Z)-Isomer was produced in 21% yield. c (E)-Isomer.
d Reaction was carried out at -78 to 0 °C.
10
a All reactions were carried out in THF at -78 °C to rt for 2 h.
b Hexane solution. c Reactions were carried out in THF at -20 °C
to rt.
TABLE 3. Synthesis of â,â-Disubstituted Vinylic
1a as shown in Table 1. Upon treatment of 1a with
Et2Zn (1 mol per 1 mol of 1a) in the presence of 2 mol %
of CuI, the â,â-disubstituted vinylic sulfoxide (Z)-2a was
obtained as the sole geometric isomer,6 but in only 15%
yield (entry 1). However, the yield could be improved to
72% by using Et2Zn (2 mol per 1 mol of 1a) (entry 2).
Use of Et2Zn (4 mol per 1 mol of 1a) rather diminished
the yield, giving 57% of (Z)-2a (entry 3). The amount of
CuI is important to obtain high yield, and 2 mol % of
CuI afforded the best results. We found that the reaction
proceeds almost quantitatively at the higher concentra-
tion (entry 6). In all cases, the reaction always shows
excellent stereoselectivity, giving syn-adducts exclusively.
The Cu-salts such as CuCN or Cu(OTf)2 also provided
the adduct in moderate to good yields, but the yield was
not higher than that using CuI (entries 7 and 8).
Although Ni(acac)2 catalyzes the carbometalation of
organozinc reagents to alkynes,7 the catalyst was less
effective than Cu salts (entries 9 and 10).
Sulfoxides with RZnXa
Next, the procedure was applied to a synthesis of â,â-
disubstituted vinylic sulfoxides using 1-alkynyl sulfoxides
1a-f (Table 2). Functional groups such as TBSO, AcO,
and I are compatible under these reaction conditions
(entries 1-3). It should be noted that a nucleophile-
sensitive acetoxy group was not affected under the
conditions and no Cu-catalyzed iodine-zinc exchange
reaction8 was observed. In the case of the substrate 1d
[R ) (CH2)4I], the yield was improved by sonication (entry
4) and the use of CuCN or Cu(OTf)2 was also effective
(entries 5 and 6). The alkynyl sulfoxide bearing a proton
or a hindered t-Bu group at the â-position showed
considerably low yields (entries 7 and 8). syn-Selective
methylation of 1a was also accomplished using Me2Zn
in the presence of CuI catalyst to give 2g2d in 81% yield
(entry 9).
a All reactions were carried out in THF using RZnX in the
presence of Cu salt at -78 °C to rt. b Organozinc reagents were
prepared from RX and Zn (powder) using TMSCl and dibromo-
ethane as initiators unless otherwise cited. c Prepared from
TMSCH2MgCl and ZnBr2.
A wide range of multi-functionalized organozinc ha-
lides can be prepared by the halogen-zinc exchange
reaction.9 Consequently, reaction of these species with
1-alkynyl sulfoxides affords a versatile method to prepare
functionalized â,â-disubstituted vinylic sulfoxides. The
results of Cu-catalyzed conjugate addition with RZnX are
summarized in Table 3. Allylzinc bromide prepared by
reaction of allyl bromide with Zn dust activated with
TMSCl and 1,2-dibromoethane underwent carbozincation
to 1a in the presence of 2 mol % of CuI, leading (E)-vinylic
sulfoxide 3a in 72% yield as a single product (entry 1).
(6) The assignment of the olefin geometry was conducted by NOE
experiment between the olefinic proton and the cis-substituent. High
optical purity of 4a was confirmed by chiral HPLC (Daisel Chiralcel
OB) in comparison with the racemic sample.
(7) Houpis, I. N.; Lee, J. Tetrahedron 2000, 56, 817-846.
(8) (a) Stadtmu¨ller, H.; Vaupel, A.; Tucker, C. E.; Stu¨demann, T.;
Knochel, P. Chem.-Eur. J. 1996, 2, 1204-1220. (b) Rozema, M. J.;
Eisenberg, C.; Lutjens, H.; Ostwald, R.; Belyk, K.; Knochel, P.
Tetrahedron Lett. 1993, 34, 3115-3118.
(9) (a) Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P. Angew.
Chem., Int. Ed. 2000, 39, 4414-4435. (b) Nakamura, M.; Nakamura,
E. J. Synth. Org. Chem. Jpn. 1998, 56, 632-644 and references
therein.
8388 J. Org. Chem., Vol. 69, No. 24, 2004

Di- and Trisubstituted Vinylic Sulfoxides
TABLE 4. Synthesis of Trisubstituted Vinylic
Sulfoxides with R2Zna
SCHEME 1
SCHEME 2
yield (%)
entry
R
Cu salt (equiv)
R′ ) allyl
R′ ) H
1
2
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
CuCN‚2LiCl (1)b
CuCN‚2LiCl (1)
CuI (1)
4a (40)
4a (88)
4a (74)
4a (68)
4a (6)
4a (64)
4a (66)
4a (53)
4a (53)
4b (77)
4b (68)
(Z)-2a (22)
(Z)-2a (3)
(Z)-2a (13)
(Z)-2a (15)
(Z)-2a (53)
(Z)-2a (17)
(Z)-2a (10)
(Z)-2a (16)
(Z)-2a (22)
2g (9)
3
4
CuCN (1)
5
Cu(OTf)2 (1)
CuCN‚2LiCl (0.02)
CuI (0.02)
CuCN (0.02)
Cu(OTf)2 (0.02)
CuCN‚2LiCl (1)
CuI (0.02)
6
In this case, Cu(OTf)2 was the most efficient among the
Cu salts we tested to give 3a in 81% yield (entries 1-3).
Although a small excess of allylzinc bromide provided 3a
in 67% yield, the yield was lower than that in entry 3
(entry 4). An increase of Cu-catalyst did not improve the
yield (entry 5). Using the optimized reaction conditions,
various functionalized organozinc halides were reacted
with the 1-alkynyl sulfoxide 1a (entries 6-11). The
substituents bearing a variety of nucleophile-sensitive
functional groups were introduced stereospecifically in
moderate to good yields. In sharp contrast to the result
that TMSCH2ZnX (TMSCH2MgCl + ZnBr2) afforded syn-
adduct exclusively in the presence of Cu-catalyst (entry
11), the Cu-catalyzed addition with TMSCH2MgCl af-
forded an E/Z-mixture of 3g in 39% combined yield with
poor selectivity (E/Z ) 3/5) (Scheme 1). The results
indicate an advantage of organozinc reagents over the
Grignard reagent.10
7
8
9
10
11
2g (7)
a All reactions were carried out in THF using R2Zn (1.5 mol per
1 mol of 1a) in the presence of Cu salt at -78 °C to rt, and then
allyl bromide (5 equiv) was added to the mixture. b Carbozincation
was conducted using 2 mol % of CuCN, and then CuCN‚2LiCl was
added before the addition of allyl bromide.
tuted vinylic sulfoxide 4a was obtained in 40% yield after
quenching the intermediate with 5 equiv of allyl bromide
(entry 1). The yield was improved to 88% yield when 1
equiv of CuCN‚2LiCl was used for both carbozincation
and transmetalation (entry 2). This procedure is more
convenient than that of entry 1. CuI and CuCN also
afforded 4a in acceptable yields, while Cu(OTf)2 furnished
(Z)-2a mainly rather than 4a (entries 3-5).
Using the method, the (E)-isomer of the vinylic sul-
foxide 2a was synthesized in 74% yield by the reaction
of 1-alkynyl sulfoxide 1g and n-butylzinc iodide in the
presence of Cu(OTf)2. Because the corresponding (Z)-
isomer was also synthesized as shown in Table 1, this
method affords a powerful tool for stereoselective syn-
thesis of both geometric isomers of the â,â-disubstituted
vinylic sulfoxides by changing the combination of 1-alky-
nyl sulfoxide and the organozinc reagent (Scheme 2).
There are few methods for a geometrically selective
synthesis of trisubstituted vinylic sulfoxides.11 Next, we
examined the stereoselective synthesis of trisubstituted
vinylic sulfoxides by trapping the vinylzinc intermediate
generated by carbozincation with allyl bromide (Table 4).
One equivalent of CuCN‚2LiCl was added for trans-
metalation of the R-sulfinyl vinylzinc intermediate gener-
ated by CuCN-catalyzed carbozincation.12 The trisubsti-
Reducing the Cu salt is important from the viewpoint
of green chemistry. Therefore, we examined the reaction
using a catalytic amount of the Cu salt (entries 6-9). The
adduct 4a was obtained in moderate yield by using only
2 mol % of Cu salt. Interestingly, catalytic Cu(OTf)2
showed greater yield than that with stoichiometric
Cu(OTf)2 (entries 5 and 9). â-Methylated product 4b
was also synthesized with Me2Zn in the presence of
CuCN‚2LiCl or catalytic CuI in 77% and 68% yields,
respectively (entries 10 and 11).
Table 5 shows results of a synthesis of trisubstituted
vinylic sulfoxides by carbometalation of 1a with RZnX
(X ) Br or I) followed by allylation of the resulting
R-sulfinyl vinylic carbanion. Functionalized trisubstituted
vinylic sulfoxides 5a-c were synthesized in moderate to
good yields in the presence of stoichiometric or catalytic
Cu-salt. The addition is stereospecific, giving syn-adducts
as a single isomer.
Application to Diastereoselective Synthesis of
Cyclic Ethers. Previously, we have reported a diaste-
reoselective intramolecular conjugate addition of alkoxide
to chiral vinylic sulfoxides. The methodology was applied
successfully to asymmetric synthesis of dioxaspiro natu-
ral products. In the reactions, cyclic vinylic sulfoxides
were used as an acceptor and the intramolecular conju-
gate addition of an alkoxide proceeded with high dia-
stereoselectivity. It is of interest if high diastereoselec-
tivity can be achieved by using acyclic â,â-disubstituted
vinylic sulfoxides bearing an alcohol anti- or syn-sub-
(10) Posner and Okamura independently reported that R-sulfinyl
vinyllithium generated by R-deprotonation of (Z)-vinylic sulfoxide
immediately isomerizes to thermodynamically stable (E)-isomer (Pos-
ner, G. H.; Tang, P.-W.; Mallamo, J. P. Tetrahedron Lett. 1978, 3995-
3998. Okamura, H.; Mitsuhira, Y.; Miura, M.; Takei, H. Chem. Lett.
1978, 517-520). In sharp contrast, no E/Z-isomerization was observed
in R-sulfinyl vinylic carbanion generated by conjugate addition of
organocopper reagents to 1-alkynyl sulfoxides (ref 4). The difference
presumably arises from the ionic nature of the carbon-lithium bond
as compared with the carbon-copper bond. With these facts in mind,
we speculate that the organomagnesium intermediate in the reaction
of Scheme 1 is geometrically more unstable due to its ionic nature than
the corresponding organozinc intermediate in carbozincation, thereby
suffering from E/Z-isomerization.
(11) (a) Xu, Q.; Huang, X. Tetrahedron Lett. 2004, 45, 5657-5660.
(b) Satoh, T.; Yoshida, M.; Takahashi, Y.; Ota, H. Tetrahedron:
Asymmetry 2002, 14, 281-288. (c) Arroyo, Y.; Carren˜o, M. C.; Ruano,
J. L. G.; Amo, J. F. R.; Santos, M.; Tejedor, M. A. S. Tetrahedron:
Asymmetry 2000, 11, 1183-1191 and ref 4a,b.
(12) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390-2392.
J. Org. Chem, Vol. 69, No. 24, 2004 8389

Maezaki et al.
TABLE 5. Synthesis of Trisubstituted Vinylic
Sulfoxides with RZnXa
SCHEME 4
SCHEME 5
a All reactions were carried out in THF using RZnX (2 equiv)
in the presence of Cu salt at -78 °C to rt, and then R′X (5 equiv)
was added to the mixture. b Organozinc reagents were prepared
from RX and Zn (powder) using TMSCl and dibromoethane as
initiators.
SCHEME 3
TABLE 6. Diastereoselective Synthesis of Cyclic Ethers
9a-da
entry
substrate
R
n
product
yield (%)
drb
stituent on the vinylic sulfoxide. The reaction affords
cyclic ethers with a stereogenic center neighboring to the
ether oxygen, whose structure is included in natural
products such as ionomycin and malyngolide. As an
extension of our method, we investigated the synthesis
of chiral cyclic ethers.13
An attempt to introduce 3-acetoxy- and 3-benzoyl-
oxybutylzinc iodide afforded the (E)-vinylic sulfoxide 6a
and 6b in poor yields (Scheme 3). We found that an
organozinc reagent bearing a pivaloyl protection fur-
nished the adduct 6c in 88% yield. The pivaloyl group
was deprotected with DIBAL-H at -78 °C without
affecting the vinylic sulfoxide to give 85% of (E)-7a as a
single isomer.
Substrates 7b-e (E-isomers except for 7d) with dif-
ferent substituents were also synthesized in good yield
by the same procedure (Scheme 4).
On the other hand, the corresponding geometric iso-
mers of 7a-d were prepared by carbozincation of 1j and
1k (Scheme 5).
1
2
3
4
5
(E)-7a
(E)-7b
(E)-7c
(Z)-7d
(E)-7e
n-Bu
n-Bu
Me
Ph
n-Bu
4
3
3
3
5
9a
9b
9c
9d
9e
86
90
93
83
NR
>98:2
>98:2
96:4
>98:2
a All reactions were carried out at 0.03 M of the substrate in
THF using NaH (5 equiv) at 0 °C. b Determined by 1H NMR
spectroscopic data.
high (>98:2) except that 9c (R ) Me) afforded slightly
reduced diastereoselectivity (dr ) 96:4). High diastereo-
selectivity was observed even in the THP ring formation
(entry 1). However, in vinylic sulfoxide (E)-7e giving a
seven-membered ring ether, no cyclized product 9e was
obtained, and, instead, deconjugation of the vinylic
sulfoxide proceeded, giving â,γ-unsaturated sulfoxide 9f14
in 80% yield (entry 5).
(13) (a) Iwata, C.; Maezaki, N.; Hattori, K.; Fujita, M.; Moritani,
Y.; Takemoto, Y.; Tanaka, T.; Imanishi, T. Chem. Pharm. Bull. 1993,
41, 339-345. (b) Iwata, C.; Fujita, M.; Kuroki, T.; Hattori, K.; Uchida,
S.; Imanishi, T. Chem. Pharm. Bull. 1988, 36, 3257-3263. (c) Iwata,
C.; Hattori, K.; Kuroki, T.; Uchida, S.; Imanishi, T. Chem. Pharm. Bull.
1988, 36, 2909-2917. (d) Iwata, C.; Moritani, Y.; Sugiyama, K.; Fujita,
M.; Imanishi, T. Tetrahedron Lett. 1987, 28, 2255-2258. (e) Iwata,
C.; Fujita, M.; Hattori, K.; Uchida, S.; Imanishi, T. Tetrahedron Lett.
1985, 26, 2221-2224. (f) Iwata, C.; Hattori, K.; Uchida, S.; Imanishi,
T. Tetrahedron Lett. 1984, 25, 2995-2998.
With the substrates in hand, we next examined the
intramolecular conjugate addition. Upon treatment of the
substrates 7b-d (E-isomers except for 7d) with NaH in
THF at 0 °C, the intramolecular conjugate addition took
place to give the THF compounds 9b-d in 83-93% yields
(Table 6, entries 2-4). The diastereoselectivity was very
8390 J. Org. Chem., Vol. 69, No. 24, 2004

Di- and Trisubstituted Vinylic Sulfoxides
TABLE 7. Diastereoselective Synthesis of Cyclic Ethers
10a-da
drb
FIGURE 1. Plausible reaction mechanism.
entry
substrate
R
n
product
yield (%)
1
2
3
4
(Z)-7a
(Z)-7b
(Z)-7c
(E)-7d
n-Bu
n-Bu
Me
4
3
3
3
10a
10b
10c
10d
87
79
89
74
>98:2
>98:2
>98:2
>98:2
Cu-catalyzed addition of organozinc reagent to 1-alkynyl
sulfoxides. A variety of functionalized vinylic sulfoxides
can be synthesized due to the mild reactivity of the
organozinc reagents. The high syn-selectivity of the
carbozincation enables the stereoselective synthesis of
both geometric isomers. The method was applied to a
stereoselective synthesis of two isomers of cyclic ethers.
Ph
a All reactions were carried out at 0.03 M of the substrate in
THF using NaH (5 equiv) at 0 °C. b Determined by 1H NMR
spectroscopic data.
SCHEME 6
Experimental Section
Melting points are uncorrected. NMR spectra were recorded
in CDCl3 solution at 500 MHz (1H) and 125, 75, or 67.8 MHz
(13C). IR absorption spectra (FT: diffuse reflectance spectros-
copy) were recorded with KBr powder, and only noteworthy
absorptions (cm-1) are listed. Column chromatography was
carried out using Merck silica gel 60 (70-230 mesh). All air-
or moisture-sensitive reactions were carried out in flame-dried
glassware under an atmosphere of N2 or Ar. All solvents were
dried and distilled according to standard procedures. All or-
ganic extracts were dried over anhydrous MgSO4, filtered, and
concentrated with a rotary evaporator under reduced pressure.
Allylzinc bromide, n-BuZnI, and 3-oxo-1-cyclohexen-1-ylzinc
iodide were prepared in situ according to the literature12
[organozinc halide (reaction temperature, reaction time): al-
lylzinc bromide (0 °C, 4 h), BnZnBr (0 °C, 2 h), 3-oxo-1-cyclo-
hexen-1-ylzinc iodide (25 °C, 2 h)], and the concentration was
determined by GC analysis of a hydrolyzed reaction aliquot
using n-decane as an internal standard.16 CuCN‚2LiCl was
prepared according to the literature.16 1-Alkynylsulfoxides
1a,17 1b-d,18 1e,3e,4b 1f,4b 1g,19 1h,i,20 and 1j,k21 were synthe-
sized according to the procedure described in the literature.
Characterization data and 1H and 13C NMR spectra of (Z)-2a,
(E)-2a, and 3a were reported in the Supporting Information
of ref 5.
General Procedure for Cu-Catalyzed Conjugate Ad-
dition of R2Zn to 1-Alkynyl Sulfoxide: (R)-[(Z)-4-(tert-
Butyldimethylsilyloxy)-2-ethyl-1-butenyl] p-Tolyl Sul-
foxide (2b). Et2Zn (0.99 M in hexane) (1.11 mL, 1.11 mmol)
was slowly added to a mixture of 1b (179 mg, 0.553 mmol)
and CuI (2.10 mg, 0.011 mmol) in THF (0.55 mL) with stirring
at -78 °C. The stirring was continued for 15 min at -78 °C
and at rt for 3.5 h. The reaction was quenched with 28%
NH4OH, and the mixture was extracted with Et2O. The extract
was washed with water and brine prior to drying and solvent
evaporation. The residue was chromatographed on silica gel
with hexanes-EtOAc (2:1) to give 2b (156 mg, 78%) as a yellow
oil. [R]24D -146 (c 1.02, CHCl3). 1H NMR: δ 0.08 (s, 6H), 0.90
(s, 9H), 1.04 (t, J ) 7.3 Hz, 3H), 2.24 (ddd, J ) 14.7, 7.3, 1.3
On the other hand, the vinylic sulfoxides (Z)-7a-c and
(E)-7d were also cyclized on treatment with NaH in THF
with very high diastereoselectivities (Table 7). In all
cases, the products were epimers of the cyclic ether
compounds synthesized from the corresponding geometric
isomers.
Stereochemistry of the products was determined by
conversion of 9d and 10d into the known compound 11
(Scheme 6).15 Conversion of 9d into 11 was carried out
by a sequential reaction: (1) Pummerer reaction with
(CF3CO)2O; (2) hydrolysis of O,S-acetal with aqueous
K2CO3; and (3) reduction of the resulting aldehyde with
NaBH4. The THF compound 11 derived from 9d shows
the same sign of specific rotation as that of (S)-11, while
the sign of the specific rotation of compound 11 derived
from 10d exhibited minus value. As a result, we con-
cluded that 9d and 10d were (Rs,2S)- and (Rs,2R)-
isomers, respectively.
The stereochemical outcome can be explained by the
previously proposed reaction mechanism.13e,f Confor-
mation of the sulfinyl group was situated to minimize
A(1,3)-strain. The metal cation of alkoxide would coordi-
nate to the sulfinyl oxygen, thereby directing the ap-
proach of the alkoxide. In the vinylic sulfoxide (E)-7c
bearing a small methyl group syn to the sulfinyl group,
the A(1,3)-strain would be slightly decreased, thereby
lowering the diastereoselectivity.
(15) Akiyama, T.; Yasusa, T.; Ishikawa, K.; Ozaki, S. Tetrahedron
Lett. 1994, 35, 8401-8404.
(16) Knochel, P.; Rozema, M. J.; Tucker, C. E. In Organocopper
Reagents: A Practical Approach; Taylor, R. J. K., Ed.; Harwood, L.
M., Moody, C. J., Series Eds.; Oxford University Press: Oxford, 1994;
Chapter 4, pp 85-104.
(17) Cinquini, M.; Colonna, S.; Cozzi, F.; Stirling, C. J. M. J. Chem.
Soc., Perkin Trans. 1 1976, 2061-2067.
Conclusion
(18) Maezaki, N.; Yoshigami, R.; Maeda, J.; Tanaka, T. Org. Lett.
2001, 3, 3627-3629.
(19) Macours, P.; Braekman, J. C.; Daloze, D. Tetrahedron 1995,
51, 1415-1428.
We have developed geometrically selective syntheses
of â,â-di- and trisubstituted vinylic sulfoxides via the
(20) Louis, C.; Mill, S.; Mancuso, V.; Hootele, C. Can. J. Chem. 1994,
72, 1347-1350.
(14) The product 9f was a 1.8:1 mixture of two isomers, but the
structures were not determined.
(21) Maezaki, N.; Izumi, M.; Yuyama, S.; Sawamoto, H.; Iwata, C.;
Tanaka, T. Tetrahedron 2000, 56, 7927-7945.
J. Org. Chem, Vol. 69, No. 24, 2004 8391

Maezaki et al.
Hz, 2H), 2.40 (s, 3H), 2.70 (dt, J ) 13.2, 6.6 Hz, 1H), 2.95 (dt,
J ) 13.2, 6.6 Hz, 1H), 3.82 (t, J ) 6.6 Hz, 2H), 6.01 (s, 1H),
7.29 (d, J ) 8.3 Hz, 2H), 7.51 (d, J ) 8.3 Hz, 2H). 13C NMR:
δ -5.4 (2C), 11.4, 18.2, 21.2, 25.8 (3C), 29.9, 35.7, 62.0, 124.2
(2C), 129.7 (2C), 132.2, 140.6, 141.8, 154.8. IR: 2927 (CH),
1493 (CdC), 1043 (SdO). MS (FAB) m/z 353 (MH+). HRMS
(FAB) calcd for C19H33O2SSi (MH+), 353.1971; found, 353.1974.
4.9 Hz, 1H), 2.72 (ddd, J ) 13.4, 10.4, 6.1 Hz, 1H), 2.83 (dd, J
) 16.5, 6.1 Hz, 1H), 2.96 (d, J ) 6.1 Hz, 2H), 3.06 (dd, J )
16.5, 6.1 Hz, 1H), 4.76 (dd, J ) 10.4, 1.2 Hz, 1H), 4.79 (dd, J
) 17.1, 1.2 Hz, 1H), 5.08 (dd, J ) 17.1, 1.2 Hz, 1H), 5.08 (dd,
J ) 10.4, 1.2 Hz, 1H), 5.24 (ddt, J ) 17.1, 10.4, 6.1 Hz, 1H),
5.70 (ddt, J ) 17.1, 10.4, 6.1 Hz, 1H), 7.27 (d, J ) 7.9 Hz, 2H),
7.43 (d, J ) 7.9 Hz, 2H). 13C NMR: δ 13.9, 21.3, 22.8, 27.6,
31.4, 31.9, 36.9, 115.3, 117.3, 124.4 (2C), 129.6 (2C), 133.8,
135.9, 138.1, 139.8, 140.4, 149.8. IR: 2956 (CH), 1493 (CdC),
1043 (SdO). MS (FAB) m/z 303 (MH+). HRMS (FAB) calcd
for C19H27OS (MH+), 303.1783; found, 303.1795.
3-[(E)-4-[(R)-(p-Tolyl)sulfinyl]-1,4-nonadien-5-yl]-2-cy-
clohexenone (5b, Table 5, Entry 5). 3-Oxo-1-cyclohexen-1-
ylzinc iodide (0.67 M in THF) (0.67 mL, 0.448 mmol) was
slowly added to a mixture of 1a (49.4 mg, 0.224 mmol) and
CuI (0.9 mg, 4.48 µmol) with stirring at -78 °C. The stirring
was continued for 15 min at -78 °C and at rt for 2 h. Allyl
bromide (0.10 mL, 1.12 mmol) was added to the mixture at
-78 °C. The whole was stirred at rt for 12 h. The reaction
was quenched with saturated NH4Cl, and the mixture was
extracted with EtOAc. The extract was washed with water and
brine prior to drying and solvent evaporation. The residue was
chromatographed on silica gel with hexanes-EtOAc (2:1) to
give 5b (57.8 mg, 72%) as a yellow oil along with 3e (10.1 mg,
14%). [R]25D -90.0 (c 0.98, CHCl3). 1H NMR: δ 0.95 (t, J ) 7.3
Hz, 3H), 1.39-1.53 (m, 4H), 2.02-2.07 (m, 2H), 2.29-2.44 (m,
4H), 2.41 (s, 3H), 2.73-2.85 (m, 3H), 3.01 (dd, J ) 15.9, 6.7
Hz, 1H), 4.72 (dd, J ) 17.1, 1.2 Hz, 1H), 4.75 (dd, J ) 10.4,
1.2 Hz, 1H), 5.20 (ddt, J ) 17.1, 10.4, 6.7 Hz, 1H), 5.82 (s,
1H), 7.30 (d, J ) 7.9 Hz, 2H), 7.43 (d, J ) 7.9 Hz, 2H). 13C
NMR: δ 13.8, 21.3, 22.6, 22.7, 28.5, 28.5, 30.7, 31.4, 37.2, 116.1,
124.3 (2C), 127.9, 129.9 (2C), 135.9, 139.3 (2C), 140.9, 149.9,
160.5, 198.6. IR: 2956 (CH), 1676 (CdO), 1491 (CdC), 1045
(SdO). MS (FAB) m/z 357 (MH+). HRMS (FAB) calcd for
C22H29O2S (MH+), 357.1888; found, 357.1884.
General Procedure for Cu-Catalyzed Conjugate Ad-
dition of RZnX to 1-Alkynyl Sulfoxide: (R)-[(E)-2-Benzyl-
1-hexenyl] p-Tolyl Sulfoxide (3b). Benzylzinc bromide (0.88
M in THF) (0.57 mL, 0.505 mmol) was slowly added to a
mixture of 1a (55.6 mg, 0.252 mmol) and Cu(OTf)2 (1.82 mg,
5.05 µmol) in THF (0.25 mL) with stirring at -78 °C. The
stirring was continued for 15 min at -78 °C and at rt for 2 h.
The reaction was quenched with saturated NH4Cl, and the
mixture was extracted with Et2O. The extract was washed
with water and brine prior to drying and solvent evaporation.
The residue was chromatographed on silica gel with hexanes-
EtOAc (5:1) to give 3b (63.5 mg, 81%) as a yellow oil. [R]25
D
-154 (c 0.80, CHCl3). 1H NMR: δ 0.94 (t, J ) 7.3 Hz, 3H),
1.39 (qt, J ) 7.3, 7.3 Hz, 2H), 1.45-1.52 (m, 1H), 1.55-1.64
(m, 1H), 2.40 (s, 3H), 2.48 (ddd, J ) 13.4, 9.8, 6.1 Hz, 1H),
2.55 (ddd, J ) 13.4, 9.8, 5.5 Hz, 1H), 3.45 (s, 2H), 6.02 (s, 1H),
7.11 (d, J ) 7.3 Hz, 2H), 7.21 (t, J ) 7.3 Hz, 1H), 7.26 (t, J )
7.3 Hz, 2H), 7.30 (d, J ) 7.9 Hz, 2H), 7.47 (d, J ) 7.9 Hz, 2H).
13C NMR: δ 13.8, 21.3, 22.5, 30.8, 31.4, 42.7, 124.1 (2C), 126.7,
128.5 (2C), 129.0 (2C), 129.8 (2C), 133.5, 136.9, 140.8, 141.6,
154.9. IR: 2954 (CH), 1493 (CdC), 1039 (SdO). MS (FAB) m/z
313 (MH+). HRMS (FAB) calcd for C20H25OS (MH+), 313.1626;
found, 313.1637.
General Procedure for Cu-Catalyzed Conjugate Ad-
dition Followed by Alkylation: (R)-[(Z)-5-Ethyl-1,4-
nonadien-4-yl] p-Tolyl Sulfoxide (4a, Table 4, Entry 2).
Et2Zn (1.01 M in hexane) (0.35 mL, 0.350 mmol) was slowly
added to a mixture of 1a (51.4 mg, 0.233 mmol) and CuCN‚
2LiCl (1.00 M in THF) (0.23 mL, 0.233 mmol) with stirring at
-78 °C. The stirring was continued for 15 min at -78 °C and
at rt for 2 h. Allyl bromide (0.10 mL, 1.17 mmol) was added to
the mixture, and the whole was stirred at rt for 3 h. The
reaction was quenched with saturated NH4Cl, and the mixture
was extracted with EtOAc. The extract was washed with water
and brine prior to drying and solvent evaporation. The residue
was chromatographed on silica gel with hexanes-EtOAc
Methyl (E)-5-Butyl-2-methylene-4-[(R)-(p-tolyl)sulfinyl]-
4,7-octadienoate (5c, Table 5, Entry 6). Allylzinc bromide
(1.00 M in THF) (0.38 mL, 0.376 mmol) was slowly added to a
mixture of 1a (41.4 mg, 0.188 mmol) and CuCN‚2LiCl (1.00
M in THF) (0.19 mL, 0.188 mmol) with stirring at -78 °C.
The stirring was continued for 15 min at -78 °C and at 0 °C
for 2 h. Methyl 2-(bromomethyl)acrylate (0.07 mL, 0.564 mmol)
was added to the mixture at -78 °C. The whole was stirred at
rt for 11 h. The reaction was quenched with saturated
NH4Cl, and the mixture was extracted with EtOAc. The
extract was washed with water and brine prior to drying and
solvent evaporation. The residue was chromatographed on
silica gel with hexanes-EtOAc (5:1) to give 5c (58.1 mg, 86%)
as a yellow oil along with 3a (1.9 mg, 4%). [R]26D -185 (c 1.11,
(5:1) to give 4a (56.9 mg, 88%) as a yellow oil along with
1
(Z)-2a (1.6 mg, 3%). [R]24 -250 (c 0.80, CHCl3). H NMR: δ
D
0.97 (t, J ) 7.3 Hz, 3H), 1.04 (t, J ) 7.3 Hz, 3H), 1.42-1.55
(m, 3H), 1.58-1.66 (m, 1H), 2.20 (q, J ) 7.3 Hz, 2H), 2.39 (s,
3H), 2.61 (ddd, J ) 13.4, 9.8, 5.5 Hz, 1H), 2.71 (ddd, J ) 13.4,
9.8, 6.1 Hz, 1H), 2.80 (dd, J ) 16.5, 6.1 Hz, 1H), 3.05 (dd, J )
16.5, 6.1 Hz, 1H), 4.74 (dd, J ) 10.4, 1.8 Hz, 1H), 4.78 (dd, J
) 17.1, 1.8 Hz, 1H), 5.24 (ddt, J ) 17.1, 10.4, 6.1 Hz, 1H),
7.26 (d, J ) 7.9 Hz, 2H), 7.42 (d, J ) 7.9 Hz, 2H). 13C NMR:
δ 12.1, 13.9, 21.3, 22.9, 25.5, 27.5, 31.3, 31.7, 115.0, 124.5 (2C),
129.5 (2C), 136.1, 136.3, 139.9, 140.2, 154.2. IR: 2964 (CH),
1493 (CdC), 1043 (SdO). MS (FAB) m/z 291 (MH+). HRMS
(FAB) calcd for C18H27OS (MH+), 291.1783; found, 291.1780.
1
CHCl3). H NMR: δ 0.99 (t, J ) 7.3 Hz, 3H), 1.42-1.58 (m,
3H), 1.60-1.69 (m, 1H), 2.38 (s, 3H), 2.60 (ddd, J ) 13.4, 10.4,
4.9 Hz, 1H), 2.80 (ddd, J ) 13.4, 10.4, 6.1 Hz, 1H), 2.82 (d, J
) 6.7 Hz, 2H), 3.00 (d, J ) 18.3 Hz, 1H), 3.33 (d, J ) 18.3 Hz,
1H), 3.70 (s, 3H), 5.05 (dd, J ) 16.8, 1.8 Hz, 1H), 5.07 (dd, J
) 10.4, 1.8 Hz, 1H), 5.30 (s, 1H), 5.67 (ddt, J ) 16.8, 10.4, 6.7
Hz, 1H), 6.01 (s, 1H), 7.24 (d, J ) 7.9 Hz, 2H), 7.40 (d, J ) 7.9
Hz, 2H). 13C NMR: δ 13.9, 21.3, 22.8, 25.0, 31.4, 31.8, 37.6,
51.8, 117.6, 124.3 (2C), 125.2, 129.7 (2C), 133.4, 137.0, 137.6,
139.8, 140.6, 150.6, 167.0. IR: 2954 (CH), 1720 (CdO), 1493
(CdC), 1043 (SdO). MS (FAB) m/z 361 (MH+). HRMS (FAB)
calcd for C21H29O2S (MH+), 361.1837; found, 361.1829.
(R)-[(E)-5-Butyl-1,4,7-octatrien-4-yl] p-Tolyl Sulfoxide
(5a, Table 5, Entry 1). Allylzinc bromide (1.00 M in THF)
(0.45 mL, 0.454 mmol) was slowly added to a mixture of 1a
(50.0 mg, 0.227 mmol) and CuCN‚2LiCl (1.00 M in THF) (0.23
mL, 0.23 mmol) with stirring at -78 °C. The stirring was
continued for 15 min at -78 °C and at 0 °C for 2 h. Allyl
bromide (0.10 mL, 1.13 mmol) was added to the mixture at
-78 °C. The whole was stirred at the temperature for 30 min
and at 0 °C for 12 h. The reaction was quenched with saturated
NH4Cl, and the mixture was extracted with EtOAc. The
extract was washed with water and brine prior to drying and
solvent evaporation. The residue was chromatographed on
silica gel with hexanes-EtOAc (5:1) to give 5a (56.6 mg, 82%)
as a yellow oil along with 3a (6.5 mg, 11%). [R]25D -276 (c 1.29,
(E)-5-Butyl-6-[(R)-(p-tolyl)sulfinyl]-5-hexen-1-ol [(E)-
7a]. DIBAL-H (1.01 M in toluene, 0.16 mL, 0.16 mmol) was
added to a solution of 6c (29.9 mg, 0.0790 mmol) in CH2Cl2 (1
mL) with stirring at -78 °C, and additional DIBAL-H (0.23
mL, 0.23 mmol) was added to the mixture after 1 h. After the
stirring was continued for 10 min, saturated Rochelle salt was
gradually added to the mixture. The whole was stirred at rt
for 30 min. The mixture was extracted with EtOAc, and the
extract was washed with water and brine prior to drying and
solvent evaporation. The residue was chromatographed on
silica gel with EtOAc to give (E)-7a (19.8 mg, 85%) as a
1
CHCl3). H NMR: δ 0.97 (t, J ) 7.3 Hz, 3H), 1.40-1.55 (m,
3H), 1.58-1.66 (m, 1H), 2.39 (s, 3H), 2.59 (ddd, J ) 13.4, 10.4,
8392 J. Org. Chem., Vol. 69, No. 24, 2004

Di- and Trisubstituted Vinylic Sulfoxides
1
colorless oil. [R]25 -149 (c 0.94, CHCl3). H NMR: δ 0.96 (t,
(m, 4H), 1.60 (t, J ) 6.7 Hz, 2H), 1.88 (dt, J ) 12.2, 6.1 Hz,
1H), 1.96-2.04 (m, 1H), 2.08-2.16 (m, 1H), 2.36 (dt, J ) 12.2,
6.1 Hz, 1H), 2.41 (s, 3H), 2.89 (d, J ) 13.4 Hz, 1H), 3.05 (d, J
) 13.4 Hz, 1H), 3.91 (q, J ) 7.3 Hz, 1H), 4.04 (q, J ) 7.3 Hz,
1H), 7.31 (d, J ) 7.9 Hz, 2H), 7.55 (d, J ) 7.9 Hz, 2H). 13C
NMR: δ 14.0, 21.3, 23.0, 26.3 (2C), 34.2, 40.7, 68.5, 68.9, 83.2,
123.9 (2C), 129.9 (2C), 141.1, 142.2. IR: 2954 (CH), 1495
(CdC), 1041 (SdO). MS (FAB) m/z 281 (MH+). HRMS (FAB)
calcd for C16H25O2S (MH+), 281.1575; found, 281.1595.
D
J ) 7.3 Hz, 3H), 1.37-1.62 (m, 8H), 1.82 (br s, 1H), 2.18 (br t,
J ) 6.7 Hz, 2H), 2.40 (s, 3H), 2.53 (ddd, J ) 13.4, 9.8, 6.1 Hz,
1H), 2.62 (ddd, J ) 13.4, 9.8, 5.5 Hz, 1H), 3.61 (br t, J ) 5.5
Hz, 2H), 6.02 (s, 1H), 7.30 (d, J ) 7.9 Hz, 2H), 7.48 (d, J ) 7.9
Hz, 2H). 13C NMR: δ 14.0, 21.4, 22.8, 23.6, 31.0, 32.2, 32.2,
36.1, 62.4, 124.1 (2C), 129.8 (2C), 131.7, 140.7, 141.7, 156.1.
IR: 3024 (OH), 2931 (CH), 1493 (CdC), 1024 (SdO). MS (FAB)
m/z 295 (MH+). HRMS (FAB) calcd for C17H27O2S (MH+),
295.1732; found, 295.1721.
(S)-(2-Phenyltetrahydrofuran-2-yl)methanol [(S)-11].
Trifluoroacetic anhydride (0.02 mL, 0.170 mmol) was added
to a solution of 9d (25.6 mg, 0.0852 mmol) and 2,4,6-collidine
(0.02 mL, 0.170 mmol) in MeCN (0.61 mL) with stirring at 0
°C. After being stirred at this temperature for 10 min, the
reaction was quenched with water (0.03 mL). The mixture was
neutralized with K2CO3, and the whole was stirred at rt for 2
h. NaBH4 (9.7 mg, 0.256 mmol) was added to the mixture, and
the stirring was continued at rt for 15 min. The reaction was
quenched with saturated NH4Cl, and the mixture was ex-
tracted with EtOAc. The organic phase was washed with 5%
HCl and saturated NaHCO3 prior to drying and solvent
evaporation. The residue was chromatographed on silica gel
with hexanes-EtOAc (3:1) to give (S)-11 (13.8 mg, 91%) as a
colorless oil. [R]25 +6.9 (c 0.42, CHCl3) (lit.13 [R]22 +3.6 (c
(Z)-4-Butyl-5-[(R)-(p-tolyl)sulfinyl]-4-penten-1-ol [(Z)-
7b]. TBAF (1.0 M in THF, 0.18 mL, 0.178 mmol) was added
to a stirred solution of 8b (70.2 mg, 0.178 mmol) in THF (28
mL) at 0 °C. After the mixture was stirred at rt for 1.5 h,
saturated NH4Cl was added, and the mixture was extracted
with EtOAc. The organic phase was washed with water and
brine prior to drying and solvent evaporation. The residue was
chromatographed on silica gel with EtOAc to give (Z)-7b (53.0
mg, quant) as a yellow oil. [R]23 -81.7 (c 0.96, CHCl3). 1H
D
NMR: δ 0.88 (t, J ) 7.3 Hz, 3H), 1.25-1.35 (m, 2H), 1.38-
1.47 (m, 2H), 1.77-1.87 (m, 2H), 2.15-2.18 (m, 2H), 2.41 (s,
3H), 2.53 (ddd, J ) 13.4, 7.9, 6.1 Hz, 1H), 2.92 (br s, 1H), 2.94
(ddd, J ) 13.4, 6.7, 6.7 Hz, 1H), 3.69 (br t, J ) 7.9 Hz, 2H),
6.10 (s, 1H), 7.31 (d, J ) 7.9 Hz, 2H), 7.50 (d, J ) 7.9 Hz, 2H).
13C NMR: δ 13.7, 21.3, 22.2, 28.4, 29.2, 31.0, 35.8, 60.9, 124.1
(2C), 129.9 (2C), 131.8, 140.9, 141.1, 157.2. IR: 3388 (OH),
2929 (CH), 1493 (CdC), 1038 (SdO). MS (FAB) m/z 281 (MH+).
HRMS (FAB) calcd for C16H25O2S (MH+), 281.1575; found,
281.1575.
D
D
0.8, CHCl3)). 1H NMR: δ 1.80-1.89 (m, 1H), 1.94-2.02 (m,
1H), 2.07 (br s, 1H), 2.11 (ddd, J ) 12.2, 7.9, 4.9 Hz, 1H), 2.35
(dt, J ) 12.2, 7.9 Hz, 1H), 3.66 (s, 2H), 3.94 (q, J ) 7.3 Hz,
1H), 4.03 (q, J ) 7.3 Hz, 1H), 7.25 (t, J ) 7.3 Hz, 1H), 7.34
(dd, J ) 7.9, 7.3 Hz, 2H), 7.38 (d, J ) 7.9 Hz, 2H). 13C NMR:
δ 26.1, 34.0, 68.4, 69.0, 87.3, 125.3 (2C), 127.0, 128.3 (2C),
144.2. IR: 3439 (OH), 2872 (CH), 1446 (CdC), 1065 (CH2OC).
MS (FAB) m/z 201 (MNa+). HRMS (FAB) calcd for C11H14NaO2
(MNa+), 201.0891; found, 201.0890.
General Procedure for Intramolecular Michael Addi-
tion to Vinylic Sulfoxides: (2R)-2-Butyl-2-[(R)-(p-tolyl)-
sulfinylmethyl]tetrahydrofuran (9b). NaH (60% in oil)
(66.8 mg, 1.67 mmol) was washed with n-hexane under Ar and
suspended in THF (6 mL). A solution of (E)-7b (93.7 mg, 0.334
mmol) in THF (4 mL) was added to the suspension with
stirring at 0 °C. The stirring was continued for 30 min. The
reaction was quenched with saturated NH4Cl, and the mixture
was extracted with EtOAc. The extract was washed with water
and brine prior to drying and solvent evaporation. The residue
was chromatographed on silica gel with hexanes-EtOAc
(2:1) to give 9b (84.6 mg, 90%) as a colorless oil. [R]25D +131 (c
Supporting Information Available: Characterization
data of 2c-f, 3c-g, 4b, 6a-g, (E)-7b-e, (Z)-7a, (Z)-7c,d,
8a-d, 9a, 9c, 9d, 9f, 10a-d, (R)-11. 1H and 13C NMR spectra
of 4a, 5a, (E)-7a, (Z)-7a, 9a, and 10a. This material is available
free of charge via the Internet at http://pubs.acs.org.
1
1.12, CHCl3). H NMR: δ 0.88 (t, J ) 6.7 Hz, 3H), 1.28-1.29
JO048747L
J. Org. Chem, Vol. 69, No. 24, 2004 8393