Nitrile anion cyclization with epoxysilanes followed by Brook rearrangement/ring-opening of cyclopropane nitriles/alkylation

Article abstract of DOI:10.1021/jo0519413

The reaction of δ-silyl-γ,δ-epoxypentanenitrile derivatives 9-12 with a base and an alkylating agent affords (Z)-δ-siloxy-γ,δ-unsaturated pentanenitrile derivatives via a tandem process that involves the formation of a cyclopropane derivative by epoxy nit

Full text of DOI:10.1021/jo0519413

Nitrile Anion Cyclization with Epoxysilanes Followed by Brook
Rearrangement/Ring-Opening of Cyclopropane Nitriles/Alkylation
Seigo Okugawa,† Hyuma Masu,‡ Kentaro Yamaguchi,‡ and Kei Takeda*,†
Department of Synthetic Organic Chemistry, Graduate School of Medical Sciences, Hiroshima University,
1-2-3 Kasumi, Minami-Ku, Hiroshima 734-8551, Japan, and Tokushima Bunri University, Shido,
Sanuki, Kagawa 769-2193, Japan
takedak@hiroshima-u.ac.jp
Received September 16, 2005
The reaction of δ-silyl-γ,δ-epoxypentanenitrile derivatives 9-12 with a base and an alkylating agent
affords (Z)-δ-siloxy-γ,δ-unsaturated pentanenitrile derivatives via a tandem process that involves
the formation of a cyclopropane derivative by epoxy nitrile cyclization followed by Brook
rearrangement and an anion-induced cleavage of the cyclopropane ring. Exclusive formation of a
(Z)-derivative from trans-epoxides is explained by the reaction pathway that involves a backside
displacement of the epoxide by the R-nitrile carbanion and the O-Si bond formation followed by
concerted processes involving Brook rearrangement and the anti-mode of eliminative ring fission
of the cyclopropane from the rotamer 19. The fact that (E)-isomers are exclusively obtained from
cis-epoxides and R-cyclopropyl-R-silylcarbinol derivative 26 provides experimental support for the
proposed pathway.
SCHEME 1. Tandem Base-Promoted
Introduction
Ring-Opening/Brook Rearrangement/Allylic
Alkylation of γ-Silyl-â,γ-epoxybutanenitriles
Since the pioneering studies of Stork,1 there has been
great interest in epoxy nitrile cyclization,2 which was
recently further enhanced because of the ready avail-
ability of enantiomerically pure epoxides. The main
reason that nitrile anions have been used extensively in
synthesis is their high thermal stability and small steric
demand.2 We have recently found that γ-silyl-â,γ-ep-
oxybutanenitrile derivatives 1 and 2 can serve as func-
tionalized nitrile carbanion equivalents via a tandem
sequence that involves a base-promoted ring opening,
Brook rearrangement,3 and alkylation of the resulting
allylic anion (Scheme 1).4
bond, and enhanced reactivity of the allylic anion with
the â-siloxy group, prompted us to investigate similar
reactions for a substrate in which one more carbon atom
is introduced between the epoxide and the nitrile group
in 1. Reaction of epoxy nitrile derivative 3 with a base
would afford 7 via a tandem process that involves the
formation of cyclopropane derivative 5 by epoxy nitrile
cyclization followed by Brook rearrangement and an
anion-induced cleavage of the cyclopropane ring.
In this case, the nucleophilic characters of the R-nitrile
carbanions 4 and 6 might be critical factors in controlling
the reaction. In contrast to the case of 1, in which a base-
promoted ring-opening proceeds in a concerted process
The finding that the reaction is completed within 1 min
even at -80 °C, which may be attributed to the ring
strain of the epoxide, concomitant formation of an Si-O
† Hiroshima University.
‡ Tokushima Bunri University.
(1) (a) Stork, G.; Cama, L. D.; Coulson, D. R. J. Am. Chem. Soc.
1974, 96, 5268-5270. (b) Stork, G.; Cohen, J. F. J. Am. Chem. Soc.
1974, 96, 5270-5272.
(2) (a) Fleming, F. F.; Shook, B. C. Tetrahedron 2002, 58, 1-23. (b)
Arseniyadis, S.; Kyler, K. S.; Watt, D. S. Org. React. 1984, 31, 1-364.
(c) Yamamoto, M.; Yoshitake, M.; Kishikawa, K.; Kohmoto, S. J. Synth.
Org. Chem., Jpn. 1992, 50, 638-651.
10.1021/jo0519413 CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/10/2005
J. Org. Chem. 2005, 70, 10515-10523
10515

Okugawa et al.
SCHEME 3. Preparation of Epoxynitriles 9-12
SCHEME 2. Nitrile Anion Cyclization with
Epoxysilanes Followed by Brook Rearrangement/
Ring Opening of Cyclopropane Nitriles/Alkylation
TABLE 1. Base-Mediated Isomerization of trans-9
via an anti-opening of the epoxide followed by the
formation of an O-Si bond,4b the three processes, cyclo-
propane formation from 4 (4 f 5), carbanion-mediated
ring-opening of the cyclopropane (5 f 6),5 and alkylation
(6 f 7), should be affected more by the nature of the
carbanions. Thus, the ring-opening of the epoxide and
the alkylation can be facilitated by increasing the nu-
cleophilicity of the carbanions, whereas the cyclopropane
ring cleavage can be enhanced by increasing the stability
of the anion in 6. Corbel and Durst reported that reaction
of epoxy nitrile derivatives (Y ) H, Ph) lacking the silyl
group in 3 with LDA afforded the corresponding cyclo-
propane derivatives in 59% and 94% yields, respectively.6
Stirling and co-workers also reported carbanion-activated
eliminative ring fissions of cylopropanes in which the
leaving group is stabilized by a cyano group, a reaction
corresponding to the process from 5 to 6.7 With the above
consideration in mind, we chose compounds 9-12 (Scheme
3) as substrates, in which generated R-nitrile carbanions
should have different stabilities in the decreasing order
of 10, 11, 12,8 and 9. In this paper we describe in detail
the reaction communicated earlier in a preliminary form.9
base
solvent
temp (°C)
yield (%)
LDA (4 equiv)
THF
THF
-30 to 0
-30 to 0
-30 to 0
-30 to 0
-30 to 5
-30 to 5
KHMDS (4 equiv)
KHMDS (4 equiv)
KHMDS (4 equiv)
NHMDS (4 equiv)
NHMDS (2 equiv)
25
18
20
58
73
toluene
Et2O
THF
THF
derivatives10 (Scheme 3). In the case of 10, dialkylation
was a major side reaction in the alkylation step of
lithiomalononitrile.
First, exploratory experiments to find conditions al-
lowing the transformation shown in Scheme 2 to occur
were carried out by using a combination of trans-9 and
acetic acid as an electrophile with bases in several
solvents (Table 1). The best result was obtained with 2
equiv of NaN(SiMe3)2 (NaHMDS) in THF, which afforded
enol silyl ether 13 with Z-geometry (J4,5 ) 5.6 Hz) in 73%
yield. No products protonated at the stage of 4 and 5 were
detected. Use of LDA or KN(SiMe3)2 (KHMDS) resulted
in significant decomposition. Also, use of smaller amounts
of a base resulted in recovery of considerable amounts of
the starting material. The E-isomer could not be detected
even with the addition of HMPA, suggesting that an
internal chelation structure 14 is not responsible for the
formation of the (Z)-isomer.11 The stereochemistry of the
process will be discussed later.
With this result in hand, we next examined the
behavior of trans-9 toward alkylation reaction. When
trans-9 was treated with NaHMDS (2 equiv) at -30 to 5
°C followed by the addition of MeI (1.1 equiv) at -15 °C,
monomethylated product (Z)-15a was obtained in 63%
yield (Scheme 4). Although the reaction with EtI gave a
similar result, in the case of i-PrI, (Z)-13, a product of
protonation, was obtained. To obtain information about
the alkylation process (6 f 7), an alkylation reaction of
(Z)-13 was carried out with NaHMDS (Scheme 5). Reac-
Results and Discussion
δ-Silyl-γ,δ-epoxy nitriles 9-12 were prepared from
allyl alcohol 8 via allylation of the corresponding R-lithio
(3) For reviews on Brook rearrangement, see: (a) Brook, M. A.
Silicon in Organic, Organometallic, and Polymer Chemistry; John
Wiley & Sons: New York, 2000. (b) Brook, A. G.; Bassindale, A. R. In
Rearrangements in Ground and Excited States; de Mayo, P., Ed.;
Academic Press: New York, 1980; pp 149-221. (c) Brook, A. G. Acc.
Chem. Res. 1974, 7, 77-84. For the use of Brook rearrangement in
tandem bond formation strategies, see: (d) Moser, W. H. Tetrahedron
2001, 57, 2065-2084. Also, see: (e) Ricci, A.; Degl’Innocenti, A.
Synthesis 1989, 647-660. (f) Bulman Page, P. C.; Klair, S. S.;
Rosenthal, S. Chem. Soc. Rev. 1990, 19, 147-195. (g) Qi, H.; Curran,
D. P. In Comprehensive Organic Functional Group Transformations;
Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Moody, C. J., Eds.;
Pergamon: Oxford, UK, 1995; pp 409-431. (h) Cirillo, P. F.; Panek,
J. S. Org. Prep. Proc. Int. 1992, 24, 553-582. (i) Patrocinio, A. F.;
Moran, P. J. S. J. Braz. Chem. Soc. 2001, 12, 7-31.
(4) (a) Takeda, K.; Kawanishi, E.; Sasaki, M.; Takahashi, Y.;
Yamaguchi, K. Org. Lett. 2002, 4, 1511-1514. (b) Sasaki, M.; Kawan-
ishi, E.; Nakai, Y.; Matsumoto, T.; Yamaguchi, K.; Takeda, K. J. Org.
Chem. 2003, 68, 9330-9339. (c) Matsumoto, M.; Masu, H.; Yamaguchi,
K.; Takeda, K. Org. Lett. 2004, 6, 4367-4369.
(5) Recently cyclopropane ring opening by a carbanion generated
by Brook rearrangement was reported. Clayden, J.; Watson, D. W.;
Chambers, M. Tetrahedron 2005, 61, 3195-3203.
(10) (a) Urabe, H.; Matsuka, T.; Sato, F. Tetrahedron Lett. 1992,
33, 4179-4182. (b) Chen, A. P.-C.; Chen, Y.-H.; Liu, H.-P.; Li, Y.-C.;
Chen, C.-T.; Liang, P.-H. J. Am. Chem. Soc. 2002, 124, 15217-15224.
(11) This is also supported by the fact that (Z)-13 was formed
exclusively irrespective of the countercations. The difference in yield
among Li, Na, and K as countercations cannot be explained at present,
but possibly it may be due to the difference in the reactivity and
stability of the carbanion based on the ionic character of the carbon-
metal bond.
(6) Corbe1, B.; Durst, T. J. Org. Chem. 1976, 41, 3648-3650.
(7) (a) Huges, S.; Griffiths, G.; Stirling, C. J. M. J. Chem. Soc., Perkin
Trans. 2 1987, 1253-1264. (b) Stirling, C. J. M. Chem. Rev. 1978, 78,
517-567.
(8) For comparison of the R-anion stabilizing ability between phenyl
group and trimethylsilyl group, see: Takeda, K.; Ubayama, H.; Sano,
A.; Yoshii, E.; Koizumi, T. Tetrahedron Lett. 1998, 39, 5243-5246.
(9) Okugawa, S.; Takeda, K. Org. Lett. 2004, 6, 2973-2975.
10516 J. Org. Chem., Vol. 70, No. 25, 2005

(Z)-δ-Siloxy-γ,δ-unsaturated Pentanenitrile Derivatives
SCHEME 4. Alkylation of trans-9
SCHEME 6. Methylation of 12
SCHEME 7. Reaction of 11a with n-BuLi
SCHEME 5. Alkylation of (Z)-13
TABLE 2. Alkylation of 11
obtained in 69% yield together with (Z)-16 (R ) H) (8%).
On the other hand, treatment of 11a with n-BuLi at -80
°C afforded a 1:1 mixture of 11a and 11b in 87% yield,
indicating that an R-nitrile carbanion derived from
R-phenyl derivative 11 is more stable than that obtained
from R-trimethylsilyl derivative 12, which is consistent
with our previous results.8
(Z)-16a-e
RX
yield (%)
a
b
c
d
e
Mel
EtI
84
73
65
75
75
The observed Z-selectivity in all cases can be explained
by assuming the formation of silicate intermediate 1813,14
via backside displacement of the epoxide by the R-nitrile
carbanion and the O-Si bond formation followed by
concerted processes involving Brook rearrangement and
the anti-mode of eliminative ring fission of the cyclopro-
pane from the rotamer 19 (Scheme 8),15 in which the C4-
Si bond can adopt a coplanar arrangement with the C2-
C3 bond. In this case, Brook rearrangement should occur
with retention of configuration at the silyl-bearing carbon
atom, because the (E)-derivative should be obtained if
the rearrangement proceeds with inversion of configu-
ration.16 If our analysis for the stereoselectivity is correct,
the use of cis-epoxide cis-9 should provide (E)-enol silyl
ether via 20. To confirm this, we decided to examine the
reaction of cis-9, which was prepared from cis-allyl
alcohol 214b via the sequence shown in Scheme 9.
In fact, exposure of cis-9 to NaHMDS followed by
quenching with AcOH gave (E)-13 in 62% yield (Table 3,
entry 1). Alkylation also proceeded in the same way to
afford (E)-15a,b. No (Z)-enol silyl ether derivative was
detected. The observed stereospecificity is compatible
with the concerted pathway indicated in Scheme 8.
Finally, to obtain further information about the ster-
eochemistry of the ring-opening of cyclopropane, we
i-PrI
CH2dCHCH2Br
PhCH2Br
tion with MeI gave (Z)-15a in 94% yield, while reaction
with i-PrI resulted in a recovery of (Z)-13, presumably
due to competition with the elimination reaction.
When treated under the same conditions as those used
for trans-9, 10 was recovered unchanged, suggesting that
the malononitrile carbanion is too stable to attack at the
epoxide carbon atom.
Next, we carried out the same reaction using 11 in
which R-nitrile carbanion can be stabilized by the phenyl
group. Treatment of a diastereomeric mixture of R-phenyl
derivatives 11a,b under reaction conditions similar to
those used for 9 resulted in a recovery of the starting
material, but use of 4 equiv of NaHMDS and elevated
temperature (15 °C) gave (Z)-16a-e in good to excellent
yields (Table 2). The reduced reactivity observed with 11
can be attributed to the phenyl-stabilized carbanion 4 (R
) Ph), which is supported by the fact that treatment of
11a and 11b12 separately with NaHMDS at -30 °C
followed by quenching with AcOH afforded a mixture of
11a and 11b in the same ratio. This result also suggests
that the ring-opening of the epoxide is the slowest step.
In contrast to the cases of trans-9 and 11, in the case
of trimethylsilyl derivative 12 (diastereomeric mixture),
use of n-BuLi was required to achieve a complete reaction
probably because of the lower acidity8 of the R-nitrile
proton compared to that of phenyl derivative 11 and of
steric congestion around the proton as shown in Scheme
6. The use of LDA or NaHMDS resulted in removal of
the trimethylsilyl group.
(13) Although the possibility of a silicate transition state cannot be
excluded, we believe that the species is likely to be involved on the
basis of our previous work and calculations14 of the structure in the
gas phase. Tanaka, K.; Masu, H.; Yamaguchi, K.; Takeda, K. Tetra-
hedron Lett. 2005, 46, 6429-6432.
(14) (a) Antoniotti, P.; Tonachini, G. J. Org. Chem. 1993, 58, 3622-
3632. (b) Antoniotti, P.; Canepa, C.; Tonachini, G. J. Org. Chem. 1994,
59, 3952-3959. Also, see: (c) Fleming, I.; Lawrence, A. J.; Richardson,
R. D.; Surry, D. S.; West, M. C. Helv. Chim. Acta 2002, 85, 3349-
3365.
(15) Elimination reactions of R-oxidosilanes with a â-leaving group
are known to proceed in an anti manner. Hudrlik, P. F.; Hudrlik, A.
M.; Kulkarni, A. K. J. Am. Chem. Soc. 1985, 107, 4260-4264.
(16) For discussions on the stereochemistry of Brook rearrangement
of R-silyl alkoxides bearing an R,â-leaving group, see: (a) Reich, H. J.;
Holtan, R. C.; Bolm, C. J. Am. Chem. Soc. 1990, 112, 5609-5617. (b)
Also, see ref. 5.
When 11a was treated under the same conditions as
those employed for 12, a mixture of 11a and 11b was
(12) The relative stereochemistry was not determined.
J. Org. Chem, Vol. 70, No. 25, 2005 10517

Okugawa et al.
SCHEME 8. Stereochemical Processes of
Base-Mediated Isomerization of trans- and cis-9
SCHEME 10. Preparation of 26a,b
SCHEME 11. Reaction of 26a and 26b
SCHEME 9. Preparation of cis-9
TABLE 3. Alkylation of cis-9
sure to LDA followed by DIBAL reduction. Their stere-
ochemistries were assigned on the basis of results of
X-ray analysis of 26a.
Although Brook rearrangement followed by ring open-
ing in 26a occurred instantly at -80 °C by treatment
with NaHMDS to give (E)-27, methylation of the anion
required a higher reaction temperature of -20 °C. On
the other hand, methylation of phenyl derivative 26b was
completed at -80 to -70 °C to give (E)-16a (Scheme 11).
The results suggest that the ring-opening of the cyclo-
propane is a much faster process than the other steps.
The process, however, requires the presence of an anion-
stabilizing group such as a nitrile group to proceed
because the reaction of trimethylsilyl derivative 30,
prepared from â-trimethylsilylacryloysilane19 by NaBH4
reduction followed by Simmons-Smith reaction,20 with
NaHMDS did not afford the corresponding ring-opening
product to give O-methylation derivative 31 (Scheme 12).
Since the alkylation was completed at temperatures less
than -20 °C even in the case of 26a, the slowest step in
the reaction cascade of 11 and 12 would be the anion-
induced ring-opening of the epoxide. In the case of 9,
although the possibility of the slowest step of the ring
opening of cyclopropane cannot be excluded, the slowest
entry
RX
yield (%)
1
2
3
(AcOH)
MeI
EtI
62
71
54
decided to prepare R-silyl alcohol derivative 26, a precur-
sor for 5, and to examine its Brook rearrangement-
induced alkylation reaction. Although the parent sub-
strate (R ) H in 26a) could not be prepared, dinitrile
derivative 26a and phenyl derivative 26b were prepared
from acryloylsilane 2217 by the route outlined in Scheme
10. While in the case of the dinitrile derivative the
cyclopropane ring was formed directly from the reaction
of R-bromoacryloysilane 23 with malononitrile anion, in
the case of the phenyl derivative the reaction with benzyl
cyanide anion resulted in the formation of addition
product 24, which was transformed into 26b18 by expo-
(17) Reich, H. J.; Kelly, M. J.; Olson, R. E.; Holtan, R. C. Tetrahedron
1983, 39, 949-960.
(18) 25 was obtained as a single isomer and the relative configura-
tions of the nitrile-bearing carbon atom were assigned on the basis of
NOESY correlations between the dimethyl group of TBS and the
aromatic protons. The relative stereochemistry at C2 and C1′ in 26b
was assigned on the basis of literature analogy (ref 20).
(19) Takeda, K.; Nakajima, A.; Takeda, M.; Yoshii, E.; Zhang, J.;
Boeckman, R. K., Jr. Org. Synth. 1999, 76, 199-213.
(20) (a) Sakaguchi, K.; Mano, H.; Ohfune, Y. Tetrahedron Lett. 1998,
39, 4311-4312. (b) Sakaguchi, K.; Higashino, M.; Ohfune, Y. Tetra-
hedron 2003, 59, 6647-6658.
10518 J. Org. Chem., Vol. 70, No. 25, 2005

(Z)-δ-Siloxy-γ,δ-unsaturated Pentanenitrile Derivatives
gel, 60 g, elution with hexane:AcOEt ) 3:1) to give trans-9
(2.16 g, 80%). Colorless oil, Rf 0.41 (hexane:AcOEt ) 2:1). IR
(film) 2361 cm-1. 1H NMR (400 MHz) δ -0.05 and -0.02 (each
3H, s, SiMe2), 0.95 (9H, s, t-Bu), 1.76-1.88 and 1.98-2.08 (each
1H, m, H-3), 2.14 (1H, d, J ) 3.2 Hz, H-3′), 2.49 (2H, t, J )
7.2 Hz, H-2), 2.83-2.89 (1H, m, H-2′). 13C NMR (100 MHz) δ
-8.3, 14.3, 16.8, 26.6, 30.1, 50.2, 50.6, 119.2. HRMS calcd for
C7H12NOSi 154.0688 (M+ - t-Bu), found 154.0702.
SCHEME 12. Reaction of 30
(2R*,3R*)-2-((3-(tert-Butyldimethylsilyl)oxiran-2-yl)-
methyl)malononitrile (10). To a cooled (-80 °C) solution of
malononitrile (284 µL, 5.12 mmol) in THF (35 mL) was added
n-BuLi (2.25 M n-hexane, 2.28 mL, 5.12 mmol) and the
mixture was stirred at the same temperature for 10 min before
addition of a solution of (E)-(3-bromoprop-1-enyl)-tert-bu-
tyldimethylsilane (1.00 g, 4.27 mmol) in THF (5 mL). After
being warmed to room temperature, the reaction mixture was
poured into 10% aqueous NH4Cl solution (20 mL) and ex-
tracted with Et2O (10 mL × 3). Combined organic phases were
washed with saturated brine (20 mL), dried, and concentrated.
The residual oil was subjected to column chromatography
(silica gel, 30 g, elution with hexane:AcOEt ) 5:1) to give
2-((E)-3-(tert-butyldimethylsilyl)allyl)malononitrile (265 mg,
28%) and bis(3-(tert-butyldimethylsilyl)allyl)malononitrile (481
mg, 30%).
step can also be the ring opening of the epoxide step since
attempts to trap the cycropropane derivatives corre-
sponding to 26a (R ) H) were unsuccessful. Also, the
exclusive formation of (E)-isomers is consistent with the
intermediary 29, an intermediate corresponding to 20
(Scheme 8), which provides further support for our
analysis of the stereochemical outcome of the reaction.
In conclusion, we have demonstrated that the reaction
of δ-silyl-γ,δ-epoxypentanenitrile derivatives with a base
and alkylating agents affords δ-siloxy-γ,δ-unsaturated
pentanenitrile derivatives via nitrile anion cyclization
with epoxysilanes, Brook rearrangement-mediated elimi-
native ring fissions of cyclopropanes, and R-alkylation of
nitrile in a tandem fashion. We have also shown the
stereochemical course of the reaction by the synthesis of
proposed intermediates by an independent route and
examination of the reaction to the products.
The monoalkylated product was dissolved in CHCl3 (2.4 mL)
and mCPBA (70%, 228 mg, 1.32 mmol) was added. The
reaction mixture was stirred at room temperature for 12 h and
diluted with Et2O (5 mL) and saturated aqueous K2CO3
solution (10 mL). Phases were separated and the aqueous
phase was extracted with Et2O (3 × 5 mL). Combined organic
phases were washed with saturated brine (10 mL), dried, and
concentrated. The residual oil was subjected to column chro-
matography (silica gel, 10 g, elution with hexane:AcOEt ) 4:1)
to give 10 (194 mg, 64%). Colorless oil, Rf 0.28 (hexane:AcOEt
Experimental Section
(E)-(3-Bromoprop-1-enyl)-tert-butyldimethylsilane. To
a cooled (0 °C) solution of NBS (13.6 g, 76.5 mmol) in CH2Cl2
(200 mL) was added dropwise Me2S (6.70 mL, 91.8 mmol). The
solution was stirred at the same temperature for 20 min and
recooled to -15 °C before addition of a solution of 3-(tert-
butyldimethylsilanyl)prop-2-en-1-ol (8) (8.80 g, 51.0 mmol) in
CH2Cl2 (50 mL). The mixture was warmed to room temper-
arture and stirred for 3 h. The reaction mixture was poured
into hexanes-Et2O (1:1, 100 mL) and ice water (100 mL).
Phases were separated and the aqueous phase was extracted
with Et2O. Combined organic phases were washed with
saturated brine (100 mL), dried, and concentrated. The
residual oil was filtered through a short pad of silica gel to
give the title compound (6.18 g, 54%). Colorless oil, Rf 0.80
(hexane:AcOEt ) 3:1). IR (film) 1610, 833 cm-1. 1H NMR (400
MHz) δ 0.05 (6H, s, SiMe2), 0.88 (9H, s, t-Bu), 3.95 (2H, d, J
) 6.8 Hz, H-3), 5.94 (1H, d, J ) 18.4 Hz, H-1), 6.17 (1H, dt, J
) 18.4, 6.8 Hz, H-2). 13C NMR (100 MHz) δ -6.1, 16.7, 26.5,
35.2, 133.1, 142.3. MS 177 (M+ - t-Bu).
(2R*,3R*)-3-(3-(tert-Butyldimethylsilyl)oxiran-2-yl)-
propanenitrile (trans-9). To a cooled (-80 °C) solution of
MeCN (806 µL, 15.4 mmol) in THF (80 mL) was added
dropwise n-BuLi (2.25 M hexane, 6.80 mL, 15.3 mmol) and
the solution was stirred at the same temperature for 10 min.
This mixture was added to a solution of (E)-(3-bromoprop-1-
enyl)-tert-butyldimethylsilane (3.00 g, 12.8 mmol) in THF (48
mL) via cannula over a period of 30 min. The reaction mixture
was stirred at the same temperature for 5 min and diluted
with 10% aqueous NH4Cl solution (50 mL). Phases were
separated and the aqueous phase was extracted with Et2O (3
× 20 mL). Combined organic phases were washed with
saturated brine (50 mL), dried, and concentrated to give crude
(E)-4-(tert-butyldimethylsilyl)but-3-enenitrile (3.00 g).
1
) 3:1). IR (film) 2258 cm-1. H NMR (500 MHz) δ -0.02 and
-0.08 (each 3H, s, SiMe2), 0.95 (9H, s, t-Bu), 2.15 (1H, ddd, J
) 14.0, 7.1, 5.5 Hz, H-2), 2.24 (1H, d, J ) 3.5 Hz, H-3′), 2.41
(1H, ddd, J ) 14.0, 8.5, 3.5 Hz, H-2), 2.98 (1H, ddd, J ) 7.1,
3.5, 3.5 Hz, H-2′), 3.93 (1H, dd, J ) 6.8, 4.4 Hz, H-1). 13C NMR
(125 MHz) δ -8.4, -8.2, 16.7, 20.2, 26.5, 35.6, 50.9, 51.2, 112.2,
112.4. HRMS calcd for C8H11N2OSi 179.0641 (M+ - t-Bu),
found 179.0620.
(2R*,3R*)-3-(3-(tert-Butyldimethylsilyl)oxiran-2-yl)-2-
phenylpropanenitrile (11). To a cooled (-80 °C) solution of
benzyl cyanide (1.76 mL, 15.4 mmol) in THF (30 mL) was
added n-BuLi (2.25 M n-hexane, 6.80 mL, 15.4 mmol) and the
mixture was stirred at the same temperature for 10 min. This
mixture was added to a cooled (-80 °C) solution of (E)-(3-
bromoprop-1-enyl)-tert-butyldimethylsilane (3.00 g, 12.8 mmol)
in THF (55 mL) via cannula over a period of 30 min and stirred
at the same temperature for 5 min. The solution was diluted
with 10% NH4Cl solution (50 mL) and extracted with Et2O (3
× 20 mL). Combined organic phases were washed with
saturated brine (50 mL), dried, and concentrated to give crude
(E)-5-(tert-butyldimethylsilyl)-2-phenylpent-4-enenitrile.
This compound was dissolved in CHCl3 (26 mL) and mCPBA
(70%, 4.40 g, 17.8 mmol) was added. The reaction mixture was
stirred at room temperature for 12 h and diluted with Et2O
(50 mL) and saturated aqueous K2CO3 solution (50 mL).
Phases were separated and the aqueous phase was extracted
with Et2O (3 × 20 mL). Combined organic phases were washed
with saturated brine (50 mL), dried, and concentrated. The
residual oil was subjected to column chromatography (silica
gel, 60 g, elution with hexane:AcOEt ) 3:1) to give 11 (2.56 g,
70%) as a 1:1 mixture of diastereomers. This mixture was
separated by MPLC (elution with hexane:AcOEt ) 1:2) to give
11a (more polar) and 11b (less polar). 11a: Colorless oil, Rf
0.32 (hexane:AcOEt ) 5:1). IR (film) 2245, 1601 cm-1. 1H NMR
(400 MHz) δ -0.10 and -0.07 (each 3H, s, SiMe2), 0.94 (9H, s,
t-Bu), 2.08-2.13 (1H, m, H-3), 2.17 (1H, d, J ) 3.6 Hz, H-3′),
2.24-2.32 (1H, m, H-3), 2.71-2.76 (1H, m, H-2′), 3.96 (1H,
dd, J ) 7.2, 7.2 Hz, H-2), 7.25-7.42 (5H, m, Ph). 13C NMR
This compound was dissolved in CHCl3 (26 mL) and mCPBA
(70%, 4.40 g, 17.8 mmol) was added. The reaction mixture was
stirred at room temperature for 12 h, and diluted with Et2O
(50 mL) and saturated aqueous K2CO3 solution (50 mL).
Phases were separated and the aqueous phase was extracted
with Et2O (2 × 20 mL). Combined organic phases were washed
with saturated brine (50 mL), dried, and concentrated. The
residual oil was subjected to column chromatography (silica
J. Org. Chem, Vol. 70, No. 25, 2005 10519

Okugawa et al.
(100 MHz) δ -8.4, -8.2, 16.7, 26.6, 34.6, 39. 9, 50.4, 52.3,
120.5, 127.5, 128.5, 129.4, 134.9 (Ar). HRMS calcd for C13H16-
NOSi 230.1001 (M+ - t-Bu), found 230.0997. 11b: Colorless
H-5). 13C NMR (100 MHz) δ -5.2, 17.6, 20.2, 18.4, 25.7, 105.6,
120.0, 141.5. HRMS calcd for C7H12NOSi 154.0688 (M+
-
t-Bu), found 154.0678.
oil, Rf 0.32 (hexane:AcOH ) 5:1). IR (film) 2245, 1601 cm-1
.
General Procedure for Alkylation of trans-9: Reac-
tion of trans-9 with NaHMDS and MeI. To a cooled (-30
°C) solution of 9 (100 mg, 0.470 mmol) in THF (3.9 mL) was
added NaHMDS (1.0 M THF, 0.94 mL, 0.94 mmol) and the
reaction mixture was warmed to 5 °C. Then the mixture was
cooled to -10 °C, and MeI (32 µL, 1.1 mmol) was added with
stirring at the same temperature for 15 min before addition
of 10% aqueous NH4Cl solution (10 mL). The phases were
separated, and the aqueous phase was extracted with Et2O (3
× 5 mL). Combined organic phases were washed with satu-
rated brine (10 mL), dried, and concentrated. The residual oil
was subjected to column chromatography (silica gel, 5 g,
elution with hexane:AcOEt ) 10:1) to give (Z)-15a (67 mg,
63%). Colorless oil. Rf 0.54 (hexane:AcOEt ) 3:1). IR (film)
1H NMR (400 MHz) -0.03 and -0.01 (each 3H, s, SiMe2), 0.95
(9H, s, t-Bu), 1.90-2.00 (1H, m, H-3), 2.16 (1H, d, J ) 3.6 Hz,
H-3′), 2.21-2.30 (1H, m, H-3), 2.98-3.05 (1H, m, H-2′), 4.03
(1H, dd, J ) 10.4, 4.4 Hz, H-2), 7.37 (5H, m, Ar). 13C NMR
(100 MHz) δ -8.3, -8.0, 16.8, 26.7, 35.3, 41.2, 51.1, 52.9, 120.3,
127.2, 128.5, 129.4, 135.5. HRMS calcd for C13H16NOSi 230.1001
(M+ - t-Bu), found 230.1004.
3-((2R*,3R*)-3-(tert-Butyldimethylsilyl)oxiran-2-yl)-2-
(trimethylsilyl)propanenitrile (12). To a cooled (-80 °C)
solution of lithium diisopropylamide (LDA) prepared from
diisopropylamine (939 µL, 6.7 mmol) and n-BuLi (2.3 M
hexane, 2.91 mL, 6.7 mmol) in THF (23 mL) was added
dropwise a solution of trimethylsilylacetonitrile (759 mg, 6.7
mmol) in THF (9 mL) and the solution was stirred at the same
temperature for 10 min. This mixture was added to a cooled
(-80 °C) solution of (E)-(3-bromoprop-1-enyl)-tert-butyldim-
ethylsilane (1.50 g, 6.38 mmol) in THF (32 mL) via cannula
over a period of 30 min and the reaction mixture was warmed
to -60 °C. The solution was diluted with 10% NH4Cl solution
(100 mL) and extracted with hexane (2 × 50 mL). Combined
organic phases were washed with saturated brine (50 mL),
dried, and concentrated to give crude (E)-5-(tert-butyldimeth-
ylsilyl)-2-trimethylsilylpent-4-enenitrile.
1
2243, 1658 cm-1. H NMR (400 MHz) δ 0.14 (6H, s, SiMe2),
0.92 (9H, s, t-Bu), 1.29 (3H, d, J ) 7.2 Hz, 2-Me), 2.37 (2H,
dd, J ) 6.8, 6.0 Hz, H-3), 2.50-2.68 (1H, m, 1H, H-2), 4.5 (1H,
dt, J ) 6.0, 6.0 Hz, H-4), 6.35 (1H, d, J ) 6.0 Hz, H-5). 13C
NMR (100 MHz) δ -5.2, 17.6, 18.4, 25.7, 25.8, 28.3, 104.4,
123.3, 141.8. HRMS calcd for C8H14NOSi 168.0845 (M+
t-Bu), found 168.0814.
-
General Procedure for Alkylation of 11: Reaction of
11 with NaHMDS and MeI. To a cooled (-30 °C) solution of
a mixture of 11a and 11b (100 mg, 0.350 mmol) in THF (2.1
mL) was added NaHMDS (1.0 M THF, 1.40 mL, 1.40 mmol)
and the reaction mixture was warmed to 15 °C. Then the
mixture was cooled to -10 °C, and MeI (85 µL, 1.40 mmol)
was added with stirring at the same temperature for 15 min
before addition of 10% aqueous NH4Cl solution (10 mL). The
phases were separated, and the aqueous phase was extracted
with Et2O (3 × 5 mL). Combined organic phases were washed
with saturated brine (10 mL), dried, and concentrated. The
residual oil was subjected to column chromatography (silica
gel, 5 g, elution with hexane:AcOEt ) 18:1) to give (Z)-16a
(89 mg, 84%). Colorless oil. Rf 0.55 (hexane:AcOH ) 5:1). IR
This compound was dissolved in CHCl3 (13 mL) and mCPBA
(77%, 2.00 g, 8.9 mmol) was added. The reaction mixture was
stirred at room temperature for 12 h, and diluted with Et2O
(20 mL) and saturated aqueous K2CO3 solution (20 mL).
Phases were separated and the aqueous phase was extracted
with Et2O (3 × 10 mL). Combined organic phases were washed
with saturated brine (20 mL), dried, and concentrated. The
residual oil was subjected to column chromatography (silica
gel, 45 g, elution with hexane:AcOEt ) 8:1) to give 12 (1.29 g,
71%) as a 3:4 mixture of diastereomers. This mixture was
separated with MPLC (elution with hexane:AcOEt ) 15:1) to
give 12a (more polar) and 12b (less polar). 12a: Colorless
needles (EtOH-H2O), mp 64-65 °C, Rf 0.43 (hexane:AcOEt
1
(film) 2236, 1658, 1602 cm-1. H NMR (400 MHz) δ 0.12 and
0.13 (each 3H, s, SiMe2), 0.93 (9H, s, t-Bu), 1.71 (3H, s, Me),
2.66-2.80 (2H, m, H-3), 4.45 (1H, dt, J ) 6.0, 6.0 Hz, H-4),
6.32 (1H, d, J ) 6.0 Hz, H-5), 7.25-7.49 (5H, m, Ph). 13C NMR
(100 MHz) δ -5.2, -5.2, 18.3, 25.8, 26.7, 36.3, 42.5, 103.3,
123.9, 125.8, 127.8, 128.9, 140.7, 142.0. HRMS calcd for C14H18-
NOSi 244.3885 (M+ - t-Bu), found 244.3848.
1
) 5:1). IR (KBr pellet) 2217 cm-1. H NMR (500 MHz) δ 0.03
(6H, s, SiMe2), 0.18 (9H, s, SiMe3), 0.95 (9H, s, t-Bu), 1.56 (1H,
ddd, J ) 14.0, 7.1, 3.4 Hz, H-3), 1.85 (1H, ddd, J ) 14.0, 12.4,
4.4 Hz, H-3), 2.01 (1H, dd, J ) 12.4, 3.4 Hz, H-2), 2.18 (1H, d,
J ) 3.4 Hz, H-3′), 2.95 (1H, ddd, J ) 7.1, 4.4, 3.4 Hz, H-2′).
13C NMR (125 MHz) δ -8.37, -8.17, -3.31, 16.4. 16.7, 26.6,
32.1, 51.2, 54.7, 121.6. HRMS calcd for C10H20NOSi2 226.1083
(M+ - t-Bu), found 226.1084. Anal. Calcd for C10H20NOSi2: C
59.30, H 10.31, N 4.94. Found: C 59.36, H 10.05, N 4.90. 12b:
Colorless prisms (EtOH-H2O), mp 55-56 °C, Rf 0.43 (hexane:
AcOH ) 5:1). IR (KBr) 2217 cm-1. 1H NMR (500 MHz) δ -0.05
and -0.00 (each 3H, s, SiMe2), 0.20 (9H, s, SiMe3), 0.96 (9H,
s, t-Bu), 1.70 (1H, ddd, J ) 14.2, 5.5, 3.9 Hz, H-3), 1.81 (1H,
dd, J ) 10.8, 3.9 Hz, H-2), 2.02 (1H, ddd, J ) 14.2, 10.8, 4.8
Hz, H-3), 2.12 (1H, d, J ) 3.4 Hz, H-3′), 2.98 (1H, ddd, J )
5.5, 4.8, 3.4 Hz, H-2′). 13C NMR (125 MHz) δ -8.35, -8.21,
-3.16, 15.2. 16.7, 26.6, 30.9, 49.3, 54.4, 121.7. HRMS calcd
for C10H20NOSi2 226.1083 (M+ - t-Bu), found 226.1084.
Reaction of 12 with n-BuLi and MeI. To a cooled (-50
°C) solution of 12 (80 mg, 0.28 mmol) in THF (2.8 mL) was
added n-BuLi (2.3 M hexane, 130 µL, 0.3 mmol), and the
reaction mixture was warmed to 15 °C. Then the mixture was
cooled to -10 °C, and MeI (35 µL, 0.56 mmol) was added with
stirring at the same temperature for 15 min before addition
of 10% aqueous NH4Cl solution (5 mL). The phases were
separated, and the aqueous phase was extracted with hexane
(3 × 5 mL). Combined organic phases were washed with
saturated brine (5 mL), dried, and concentrated. The residual
oil was subjected to column chromatography (silica gel, 4 g,
elution with hexane:AcOEt ) 10:1) to give 17 (58 mg, 70%).
Pale yellow oil, Rf 0.45 (hexane:AcOEt ) 5:1). IR (film) 1656,
1
2215 cm-1. H NMR (500 MHz) δ 0.12 and 0.12 (each 3H, s,
Reactionoftrans-9withNaHMDSFollowedbyQuench-
ing with Acetic Acid. To a cooled (-30 °C) solution of 9 (500
mg, 2.4 mmol) in THF (19 mL) was added NaHMDS (0.94 M
THF, 5.1 mL, 4.8 mmol) and the reaction mixture was warmed
to 5 °C before addition of AcOH (1 M THF, 4.8 mL, 4.8 mmol).
The solution was diluted with 10% NH4Cl solution (30 mL)
and extracted with Et2O (2 × 15 mL). Combined organic
phases were washed with saturated brine (30 mL), dried, and
concentrated. The residual oil was subjected to column chro-
matography (silica gel, 15 g, elution with hexane:AcOEt ) 10:
1) to give (Z)-13 (367 mg, 73%). Rf 0.54 (hexane:AcOEt ) 3:1).
SiMe2), 0.17 (9H, s, SiMe3), 0.90 (9H, s, t-Bu), 1.23 (3H, s,
2-Me), 2.29 (1H, ddd, J ) 14.2, 8.2, 1.1 Hz, H-3), 2.35 (1H,
ddd, J ) 14.2, 6.6, 1.4 Hz, H-3), 4.60 (1H, ddd, J ) 8.2, 6.6,
5.7 Hz, H-4), 6.37 (1H, ddd, J ) 5.7, 1.4, 1.1 Hz, H-5). 13C NMR
(125 MHz) δ -5.32, -5.28, -4.22, 18.2, 18.3, 22.5, 25.6, 28.1,
104.4, 125.2, 141.3. HRMS calcd for C11H22NOSi2 240.1240 (M+
- t-Bu), found 240.1242.
(Z)-(3-Bromoprop-1-enyl)-tert-butyldimethylsilane. To
a cooled (0 °C) solution of DIBAL-H (31.5 mL, 177 mmol) in
Et2O was added dropwise 3-(tert-butyldimethylsilyl)-2-pro-
pyne-1-ol (10.0 g, 58.7 mmol) in Et2O (13 mL). After refluxing
for 2 h, the reaction mixture was cooled to -30 °C and a 10:1
mixture of Et2O/MeOH (100 mL), water (100 mL), and 1 N
1
IR (film) 2246, 1658 cm-1. H NMR (400 MHz) δ 0.14 (6H, s,
SiMe2), 0.92 (9H, s, t-Bu), 2.35-2.45 (4H, m, H-2 and H-3),
4.51 (1H, dt, J ) 5.6, 5.2 Hz, H-4), 6.29 (1H, d, J ) 5.6 Hz,
10520 J. Org. Chem., Vol. 70, No. 25, 2005

(Z)-δ-Siloxy-γ,δ-unsaturated Pentanenitrile Derivatives
hydrochloric acid (50 mL) were added. Phases were separated
and the aqueous phase was extracted with Et2O (3 × 100 mL).
Combined organic phases were washed with saturated brine,
dried, and concentrated to give crude (E)-3-(tert-butyldimeth-
ylsilyl)-2-propene-1-ol. The product was used in the following
step without further purification.
General Procedure for Alkylation of cis-9: Reaction
of cis-9 with NaHMDS and MeI. To a cooled (-30 °C)
solution of cis-9 (100 mg, 0.470 mmol) in THF (3.9 mL) was
added NaHMDS (0.94 M THF, 1.0 mL, 0.94 mmol) and the
reaction mixture was warmed to 5 °C. Then the mixture was
cooled to -10 °C, and MeI (32 µL, 0.52 mmol) was added with
stirring at the same temperature for 15 min before addition
of 10% aqueous NH4Cl solution (10 mL). The phases were
separated, and the aqueous phase was extracted with Et2O (3
× 5 mL). Combined organic phases were washed with satu-
rated brine (10 mL), dried, and concentrated. The residual oil
was subjected to column chromatography (silica gel, 5 g,
elution with hexane:AcOEt ) 10:1) to give (E)-15a (75 mg,
71%). Colorless oil, Rf 0.52 (hexane:AcOEt ) 3:1). IR (film)
To a cooled (0 °C) solution of NBS (16.1 g, 90.5 mmol) in
CH2Cl2 (120 mL) was added dropwise Me2S (8.4 mL, 108.5
mmol). The solution was stirred at the same temperature for
20 min and cooled to -15 °C before addition of a solution of
the above compound in CH2Cl2 (30 mL). The mixture was
warmed to room temperature and stirred for 2 h. The reaction
mixture was poured into hexanes-Et2O (1:1, 100 mL) and ice
water (200 mL). Phases were separated and the aqueous phase
was extracted with hexane (2 × 100 mL). Combined organic
phases were washed with saturated brine (100 mL), dried, and
concentrated. The residual oil was filtered through a short pad
of silica gel to give the title compound (8.24 g, 65%). Colorless
oil, Rf 0.75 (hexane:AcOEt ) 3:1). IR (film) 1601 cm-1. 1H NMR
(400 MHz) δ 0.15 (6H, s, SiMe2), 0.90 (9H, s, SiMe3), 3.99 (2H,
d, J ) 8.1 Hz, H-3), 5.71 (1H, d, J ) 13.9 Hz, H-1), 6.57 (1H,
dt, J ) 13.9, 8.1 Hz, H-2). 13C NMR (100 MHz) δ -4.15, 17.0,
26.5, 32.3, 132.4, 143.5. MS 177 (M+ - t-Bu).
3-((2R*,3S*)-3-(tert-Butyldimethylsilyl)oxiran-2-yl)pro-
panenitrile (cis-9). To a cooled (-80 °C) solution of MeCN
(537 µL, 10.2 mmol) in THF (43 mL) was added dropwise
n-BuLi (2.3 M hexane, 4.43 mL, 10.2 mmol) and the solution
was stirred at the same temperature for 10 min. This mixture
was added to a solution of (Z)-(3-bromoprop-1-enyl)-tert-
butyldimethylsilane (2.00 g, 8.5 mmol) in THF (43 mL) via
cannula over a period of 30 min. The reaction mixture was
stirred at the same temperature for 5 min and diluted with
10% aqueous NH4Cl solution (50 mL). Phases were separated
and the aqueous phase was extracted with hexane (3 × 20 mL).
Combined organic phases were washed with saturated brine
(50 mL), dried, and concentrated to give crude (Z)-4-(tert-
butyldimethylsilyl)but-3-enenitrile.
1
1664, 2240 cm-1. H NMR (500 MHz) δ 0.13 (6H, s, SiMe2),
0.90 (9H, s, t-Bu), 1.27 (3H, d, J ) 7.1 Hz, 2-Me), 2.11-2.21
(2H, m, H-3), 2.57 (1H, ddq, J ) 7.1, 7.1, 7.1 Hz, H-2), 4.97
(1H, ddd, J ) 11.7, 7.8, 7.8 Hz, H-4), 6.34 (1H, d, J ) 11.7 Hz,
H-5). 13C NMR (125 MHz) δ -5.22 (SiMe2), 17.3 (Me), 18.3
(CMe3), 25.7 (CMe3), 26.8 (C-2), 32.2 (C-3), 105.7 (C-4), 122.7
(CN), 143.7 (C-5). HRMS calcd for C8H14NOSi 168.0845 (M+
- t-Bu), found 168.0842.
2-Bromo-1-(tert-butyldimethylsilyl)prop-2-enone (23).
To a cooled (0 °C) solution of 1-(tert-butyldimethylsilyl)prop-
2-enone (3.00 g, 17.6 mmol) in CH2Cl2 (59 mL) was added
dropwise bromine (1.00 mL, 19.4 mmol) and the solution was
stirred at the same temperature for 10 min. The solution was
concentrated to give crude 2,3-dibromo-1-(tert-butyldimethyl-
silyl)propanone. The product was used in the following step
without further purification.
To a cooled (0 °C) solution of the above compound in CH2-
Cl2 (176 mL) was added Et3N (12 mL, 86.1 mmol) and the
solution was stirred for 10 min. The mixture was diluted with
1 N HCl solution (100 mL) and extracted with hexane (3 × 50
mL). Combined organic phases were successively washed with
saturated Na2CO3 solution and saturated brine, dried, and
concentrated. The residual oil was subjected to column chro-
matography (silica gel, 50 g, elution with hexane:AcOEt ) 10:
1) to give 23 (4.2 g, 96%). Orange oil, Rf 0.37 (hexane:CH2Cl2
) 2:1). IR (film) 1624 cm-1. 1H NMR (500 MHz) δ 0.31 (6H, s,
SiMe2), 0.93 (9H, s, t-Bu), 6.75 and 6.82 (each 1H, d, J ) 2.5
Hz, H-3). 13C NMR (125 MHz) δ -4.61, 17.1, 26.6, 132.0, 140.4,
224.6. MS 191 (M+ - t-Bu).
This compound was dissolved in CHCl3 (17 mL) and mCPBA
(70%, 2.9 g, 11.9 mmol) was added. The reaction mixture was
stirred at room temperature for 12 h, and diluted with Et2O
(20 mL) and saturated aqueous K2CO3 solution (20 mL).
Phases were separated and the aqueous phase was extracted
with Et2O (10 mL × 2). Combined organic phases were washed
with saturated brine (20 mL), dried, and concentrated.
The residual oil was subjected to column chromatography
(silica gel, 60 g, elution with hexane:AcOEt ) 3:1) to give cis-9
(1.19 g, 66%). Colorless oil, Rf 0.32 (hexane:AcOEt ) 3:1).
(tert-Butyldimethylsilyl)-(2,2-dicianocyclopropyl)meth-
anol (26a). To a cooled (-80 °C) solution of malononitrile (872
mg, 13.2 mmol) in THF (50 mL) was added dropwise n-BuLi
(2.3 M hexane, 5.7 mL, 13.2 mmol) and the solution was stirred
at the same temperature for 5 min before addition of a solution
of 23 (3.00 g, 12.0 mmol) in THF (10 mL). After being warmed
to -20 °C, the mixture was diluted with 10% NH4Cl solution
(100 mL) and extracted with hexane (2 × 50 mL). Combined
organic phases were washed with saturated brine, dried, and
concentrated. The residual oil was subjected to column chro-
matography (silica gel, 60 g, elution with hexane:AcOEt ) 3:1)
to give 2-(tert-butyldimethylsilanecarbonyl)cyclopropane-1,1-
dicarbonitrile (2.13 g, 76%). Yellow oil, Rf 0.37 (hexane:AcOEt
IR (film) 2248 cm-1 1H NMR (400 MHz) δ 0.03 and 0.07
.
(each 3H, s, SiMe2), 0.96 (9H, s, t-Bu), 1.57-1.66 (1H, m, H-3),
2.03-2.11 (1H, m, H-3), 2.36 (1H, d, J ) 5.1 Hz, H-3′), 2.48-
2.56 (2H, m, H-2), 3.16-3.20 (1H, m, H-2′). 13C NMR (100
MHz) δ -6.15, -5.88, 15.2, 16.9, 26.6, 28.1, 49.1, 55.4, 119.1.
HRMS calcd for C7H12NOSi 154.0688 (M+ - t-Bu), found
154.0688.
Reaction of cis-9 with NaHMDS Followed by Quench-
ing with Acetic Acid. To a cooled (-30 °C) solution of cis-9
(100 mg, 0.470 mmol) in THF (4.2 mL) was added NaHMDS
(0.94 M THF, 1.0 mL, 0.94 mmol) and the reaction mixture
was warmed to 5 °C before addition of AcOH (1 M THF, 0.94
mL, 0.94 mmol). The solution was diluted with 10% NH4Cl
solution (5 mL) and extracted with Et2O (2 × 5 mL). Combined
organic phases were washed with saturated brine (5 mL),
dried, and concentrated. The residual oil was subjected to
column chromatography (silica gel, 5 g, elution with hexane:
AcOEt ) 10:1) to give (E)-13 (R ) H) (62 mg, 62%). Colorless
1
) 5:1). IR (film) 1642, 2251 cm-1. H NMR (500 MHz) δ 0.29
and 0.30 (each 3H, s, SiMe2), 0.97 (9H, s, t-Bu), 1.92 (1H, dd,
J ) 8.5, 5.3 Hz, H-4), 2.19 (1H, dd, J ) 7.8, 5.3 Hz, H-4), 3.37
(1H, dd, J ) 8.5, 7.8 Hz, H-2). 13C NMR (125 MHz) δ -7.45,
-7.37, 7.02, 17.0, 21.3, 26.4, 36.8, 111.6, 114.5, 234.9. HRMS
calcd for C8H9N2OSi 177.0484 (M+ - t-Bu), found 177.0453.
To a cooled (0 °C) solution of the above compound (80 mg,
0.34 mmol) in MeOH/THF (1:10, 3.4 mL) was added NaBH4
(3 mg, 0.085 mmol) and the solution was stirred at the same
temperature for 15 min. The reaction mixture was diluted with
10% NH4Cl solution (10 mL) and extracted with Et2O (3 × 5
mL). Combined organic phases were washed with saturated
brine (10 mL), dried, and concentrated. The residual oil was
subjected to column chromatography (silica gel, 3 g, elution
with hexane:AcOEt ) 4:1) to give 26a (30 mg, 30%). Colorless
needles (Et2O-hexane), mp 107-109 °C, Rf 0.35 (hexane:
oil, Rf 0.48 (hexana:AcOEt ) 5:1). IR (film) 1664, 2247 cm-1
.
1H NMR (400 MHz) δ 0.15 (6H, s, SiMe2), 0.92 (9H, s, t-Bu),
2.25 (2H, dt, J ) 7.3, 6.6 Hz, H-3), 2.35 (2H, t, J ) 6.6 Hz,
H-2), 4.98 (1H, dt, J ) 11.7, 7.3 Hz, H-4), 6.38 (1H, d, J )
11.7 Hz, H-5). 13C NMR (100 MHz) δ -5.15, 18.4, 19.0, 25.1,
25.8, 107.1, 119.4, 143.2. HRMS calcd for C11H22NOSi 212.1471
(M+ + 1), found 212.1479.
J. Org. Chem, Vol. 70, No. 25, 2005 10521

Okugawa et al.
AcOEt ) 5:1). IR (KBr) 2254, 3484 cm-1. 1H NMR (500 MHz)
δ 0.045 and 0.14 (each 3H, s, SiMe2), 0.98 (9H, s, t-Bu), 1.62
(1H, dd, J ) 8.5, 6.2 Hz, H-4), 1.85 (1H, d, J ) 5.1 Hz, OH),
2.0 (1H, dd, J ) 9.2, 6.2 Hz, H-4), 2.32 (1H, ddd, J ) 11.0, 9.2,
8.5 Hz, H-2), 3.21 (1H, dd, J ) 11.0, 5.1 Hz, H-1). 13C NMR
(125 MHz) δ -8.37, -6.96, 4.23, 16.9, 23.5, 26.9, 36.9, 64.9,
(2 mL), dried, and concentrated. The residual oil was subjected
to column chromatography (silica gel, 1 g, elution with hexane:
AcOEt ) 5:1) to give (E)-27 (7.6 mg, 76%). Colorless oil, Rf
0.36 (hexane:AcOEt ) 5:1). IR (film) 1664, 2254 cm-1. 1H NMR
(500 MHz) δ 0.17 (6H, s, SiMe2), 0.92 (9H, s, t-Bu), 2.62 (2H,
ddd, J ) 8.0, 6.4, 1.2 Hz, H-3), 3.65 (1H, t, J ) 6.4 Hz, H-2),
5.00 (1H, dt, J ) 11.9, 8.0 Hz, H-4), 6.52 (1H, dt, J ) 11.9, 1.2
Hz, H-5). 13C NMR (100 MHz) δ -5.34, 24.6, 25.5, 26.7, 30.1,
101.8, 112.9, 146.6. HRMS calcd for C8H11N2OSi 179.0639 (M+
- t-Bu), found 179.0641.
Reaction of 26a with NaHMDS and MeI. To a cooled
(-80 °C) solution of 26a (50 mg, 0.21 mmol) and CH3I (14 µL,
0.23 mmol) in THF (1.9 mL) was added NaHMDS (0.94 M
THF, 0.24 mL, 0.23 mmol). After being warmed to -20 °C,
the reaction mixture was diluted with 10% NH4Cl solution (5
mL) and extracted with Et2O (3 × 5 mL). Combined organic
phases were washed with saturated brine (5 mL), dried, and
concentrated. The residual oil was subjected to column chro-
matography (silica gel, 2 g, elution with hexane:AcOEt ) 5:1)
to give (E)-28 (40 mg, 76%). Colorless oil, Rf 0.46 (hexane:
AcOEt ) 5:1). IR (film) 1663, 2251 cm-1. 1H NMR (500 MHz)
δ 0.16 (6H, s, SiMe2), 0.92 (9H, s, t-Bu), 1.73 (3H, s, 2-Me),
2.53 (2H, dd, J ) 8.0, 0.9 Hz, H-3), 5.00 (1H, dt, J ) 11.9, 8.0
Hz, H-4), 6.49 (1H, dt, J ) 11.9, 0.9 Hz, H-5). 13C NMR (125
MHz) δ -5.23, 18.4, 23.7, 25.6, 33.0, 38.0, 101.1, 116.2, 147.1.
HRMS calcd for C9H13N2OSi,193.0797 (M+ - t-Bu), found
179.0818.
114.4, 115.3. HRMS calcd for C8H11N2OSi 179.0641 (M+
-
t-Bu), found 179.0634. Anal. Calcd for C8H11N2OSi: C 60.97,
H 8.53, N 11.85. Found: C 60.92, H 8.49, N 11.74. X-ray
data: crystal system, monoclinic; space group, P2(1)/c; unit
cell dimensions, a ) 18.120(7) Å, R ) 90°, b ) 6.607(2) Å, â )
107.072(5)°, c ) 12.804(5) Å; volume, 1465.4(9) Å3; Z ) 4; R )
0.061.
2-(tert-Butyldimethylsilanecarbonyl)-1-phenylcyclo-
propanecarbonitrile (25). To a cooled (-80 °C) solution of
benzyl cyanide (515 mg, 4.40 mmol) in THF (37 mL) was added
dropwise n-BuLi (2.25 M hexane, 1.96 mL, 4.40 mmol) and
the solution was stirred at the same temperature for 15 min
before addition of a solution of 23 (1.0 g, 4.01 mmol) in THF
(3 mL). After being warmed to -60 °C, the mixture was diluted
with 10% NH4Cl solution (30 mL) and extracted with Et2O (3
× 20 mL). Combined organic phases were washed with
saturated brine (30 mL), dried, and concentrated to give 24.
This was used in the following step without further purifica-
tion.
To a cooled (-80 °C) solution of lithium diisopropylamide
(LDA) prepared from diisopropylamine (560 µL, 4.01 mmol)
and n-BuLi (2.25 M hexane, 1.78 mL, 4.01 mmol) in THF (25
mL) was added dropwise a solution of the above compound in
THF (15 mL). After being warmed to -60 °C, the reaction
mixture was diluted with 10% NH4Cl solution (30 mL) and
extracted with Et2O (3 × 20 mL). Combined organic phases
were washed with saturated brine (30 mL), dried, and con-
centrated. The residual oil was subjected to column chroma-
tography (silica gel, 30 g, elution with hexane:AcOEt ) 10:1)
and MPLC (elution with hexane:AcOEt ) 10:1) to give 25 (36
mg, 3%). Yellow oil, Rf 0.52 (hexane:AcOEt ) 3:1). IR (film)
Reaction of 26b with NaHMDS and MeI. To a cooled
(-80 °C) solution of 26b (35 mg, 0.12 mmol) and CH3I (15 µL,
0.24 mmol) in THF (1.1 mL) was added dropwise NaHMDS
(0.94 M THF, 143 µL, 0.134 mmol). After being warmed to
-70 °C, the reaction mixture was diluted with 10% NH4Cl
solution (5 mL) and extracted with Et2O (3 × 5 mL). Combined
organic phases were washed with saturated brine (5 mL),
dried, and concentrated. The residual oil was subjected to
column chromatography (silica gel, 2 g, elution with hexane:
AcOEt ) 10:1) to give (E)-16a (25 mg, 69%). Pale yellow oil,
1
1663, 2239 cm-1. H NMR (500 MHz) δ 0.24 and 0.27 (each
Rf 0.44 (hexane:AcOEt ) 8:1). IR (film) 1660, 1730, 2243 cm-1
.
3H, s, SiMe2), 0.96 (9H, s, t-Bu), 1.75 (1H, dd, J ) 7.8, 5.0 Hz,
H-4), 2.36 (1H, dd, J ) 7.1, 5.0 Hz, H-4), 3.06 (1H, dd, J )
7.8, 7.1 Hz, H-2), 7.31-7.42 (5H, m, Ph). 13C NMR (100 MHz)
δ -7.38, -7.28, 17.0, 20.9, 24.7, 26.4, 41.5, 118.2, 126.0, 128.3,
129.2, 135.0, 237.9. HRMS calcd for C17H23NOSi 285.1554
(M+), found 285.1552.
1H NMR (500 MHz) δ 0.08 (6H, s, SiMe2), 0.87 (9H, s, t-Bu),
1.69 (3H, s, 2-Me), 2.44 (1H, ddd, J ) 14.2, 8.2, 0.9 Hz, H-3),
2.49 (1H, ddd, J ) 14.2, 7.6, 1.1 Hz, H-3), 4.86 (1H, ddd, J )
11.9, 8.2, 7.6 Hz, H-4), 6.25 (1H, dt, J ) 11.9, 1.1, 0.9 Hz, H-5).
13C NMR (125 MHz) δ -5.32, 18.2, 25.6, 26.2, 40.8, 43.1, 104.3,
123.3, 125.7, 127.7, 128.8, 140.0, 144.4. HRMS calcd for C14H18-
NOSi 244.1158 (M+ - t-Bu), found 244.1133.
(tert-Butyldimethylsilyl)-(2-cyano-2-phenylcyclopro-
pyl)methanol (26b). To a cooled (-80 °C) solution of 25 (36
mg, 0.126 mmol) in THF was added dropwise DIBAL-H (0.95
M hexane, 146 µL, 0.139 mmol), and the solution was stirred
at the same temperature for 30 min before addition of MeOH
(0.3 mL) and water (0.3 mL). The mixture was diluted with
10% NH4Cl solution (5 mL) and extracted with Et2O (3 × 5
mL). Combined organic phases were washed with saturated
brine (5 mL), dried, and concentrated. The residual oil was
subjected to column chromatography (silica gel, 500 mg,
elution with hexane:AcOEt ) 5:1) to give 26b (25 mg, 69%).
Pale yellow oil, Rf 0.21 (hexane:AcOEt ) 5:1). IR (film) 1602,
(tert-Butyldimethylsilyl)-(2-trimethylsilanylcyclopro-
pyl)methanol (30). To a cooled (-15 °C) solution of 1-(tert-
butyldimethylsilyl)-3-trimethylsilylpropenone (2.00 g, 8.2 mmol)
in MeOH/THF (1:10, 82 mL) was added NaBH4 (310 mg, 8.2
mmol) and the solution was stirred at the same temperature
for 10 min. The reaction mixture was diluted with 10% NH4-
Cl solution (50 mL) and extracted with Et2O (3 × 30 mL).
Combined organic phases were washed with saturated brine
(50 mL), dried, and concentrated to give crude 1-(tert-bu-
tyldimethylsilyl)-3-trimethylsilylprop-2-en-1-ol. This was used
in the following step without further purification.
1
1635, 1722, 2236, 3483 cm-1. H NMR (500 MHz) δ 0.05 and
0.12 (each 3H, s, SiMe2), 1.00 (9H, s, t-Bu), 1.53 (1H, dd, J )
7.3, 5.7 Hz, H-4), 1.71 (1H, dd, J ) 8.7, 5.7 Hz. H-4), 1.85 (1H,
ddd, J ) 11.2, 8.7, 7.3 Hz, H-2), 1.97 (1H, br, 1-OH), 3.41 (1H,
d, J ) 11.2 Hz, H-1), 7.27-7.40 (5H, m, Ph). 13C NMR (125
MHz) δ -8.3, -6.9, 16.9, 20.6, 22.8, 27.0, 35.9, 66.8, 121.5,
126.3, 127.8, 129.0, 136.0. HRMS calcd for C13H16NOSi 230.1001
(M+ - t-Bu), found 230.0967.
To a cooled (-10 °C) solution of the above compound and
CH2I2 (3.9 mL, 48.4 mmol) in CH2Cl2 (65 mL) was added
dropwise ZnEt2 (1.0 M hexane, 48.4 mL, 48.4 mmol) and the
solution was stirred at the same temperature for 2 h. The
reaction mixture was diluted with 10% NH4Cl solution (50 mL)
and extracted with Et2O (3 × 30 mL). Combined organic
phases were washed with saturated brine (50 mL), dried, and
concentrated. The residual oil was subjected to column chro-
matography (silica gel, 60 g, elution with hexane:Et2O ) 3:1)
to give 30 (1.17 g, 55%). Pale yellow oil, Rf 0.27 (hexane:Et2O
Reaction of 26a with NaHMDS Followed by Quench-
ing with Acetic Acid. To a cooled (-80 °C) solution of 26a
(10 mg, 0.04 mmol) in THF (0.4 mL) was added NaHMDS (0.94
M THF, 48 µL, 0.044 mmol), and the solution was stirred at
the same temperature for 5 min before addition of AcOH (1.0
M THF, 44 µL, 0.044 mmol). The reaction mixture was diluted
with water (2 mL) and extracted with Et2O (3 × 2 mL).
Combined organic phases were washed with saturated brine
) 3:1). IR (film) 3462 cm-1 1H NMR (500 MHz) δ -0.43 to
.
-0.02 (1H, m, H-3), -0.05 (9H, s, SiMe3), -0.02 and 0.05 (each
3H, s, SiMe2), 0.39-0.42 (2H, m, H-4), 0.95 (9H, s, t-Bu), 0.97-
1.03 (1H, m, H-2), 2.60 (1H, d, J ) 10.1 Hz, H-1). 13C NMR
10522 J. Org. Chem., Vol. 70, No. 25, 2005

(Z)-δ-Siloxy-γ,δ-unsaturated Pentanenitrile Derivatives
(100 MHz) δ -8.56, -6.53, -2.11, 3.55, 7.78, 16.8, 20.9, 27.0,
71.6. HRMS calcd for C9H21OSi2 201.1131 (M+ - t-Bu), found
201.1128.
17.1, 27.1, 59.4, 81.2. HRMS calcd for C10H23OSi2 215.1287 (M+
- t-Bu), found 215.1291.
Acknowledgment. This research was partially sup-
ported by a Grant-in-Aid for Scientific Research (B)
15390006, and a Grant-in-Aid for Scientific Research
on Priority Areas 17035054 from the Ministry of Educa-
tion, Culture, Sports, Science and Technology (MEXT).
We thank the Research Center for Molecular Medicine,
Faculty of Medicine, Hiroshima University and N-
BARD, Hiroshima University for the use of their facili-
ties.
(tert-Butyldimethylsilyl)-(2-trimethylsilanylcyclopro-
pyl)methyl Methyl Ether (31). To a cooled (-80 °C) solution
of 30 (100 mg, 0.41 mmol) and CH3I (28 µL, 0.43 mmol) in
THF (4.1 mL) was added NaHMDS (1.0 M THF, 0.43 mL, 0.43
mmol). After being warmed to room temperature, the solution
was diluted with 10% NH4Cl solution (10 mL) and extracted
with Et2O (3 × 5 mL). Combined organic phases were washed
with saturated brine (10 mL), dried, and concentrated. The
residual oil was subjected to column chromatography (silica
gel, 6 g, elution with hexane:Et2O ) 10:1) to give 30 (20 mg,
20%) and 31 (54 mg, 48%). Colorless oil, Rf 0.74 (hexane:AcOEt
) 5:1). IR (film) 2951 cm-1. 1H NMR (500 MHz) δ -0.67-0.62
(1H, m, H-3), -0.05 and 0.03 (each 3H, s, SiMe2), -0.04 (9H,
s, SiMe3), 0.54-0.57 (2H, m, H-4), 0.76-0.81 (1H, m, H-2), 0.92
(9H, s, t-Bu), 2.25 (1H, d, J ) 9.9 Hz, H-1), 3.42 (3H, s, Me).
13C NMR (125 MHz) δ -8.05, -5.58, -1.95, -0.47, 10.8, 16.7,
Supporting Information Available: Full experimental
details and spectral data and X-ray structural data for
compound 26a (CIF file). This material is available free of
charge via the Internet at http://pubs.acs.org.
JO0519413
J. Org. Chem, Vol. 70, No. 25, 2005 10523