Tandem Base-Promoted Ring Opening/ Brook Rearrangement/Allylic Alkylation of O-Silyl Cyanohydrins of β-Silyl-α,β-epoxyaldehydes

Article abstract of DOI:10.1021/ol025738v

(matrix presented) Metalated O-silyl cyanohydrins of β-silyl-α,β-epoxyaldehyde have been found to serve as functionalized homoenolate equivalents by a tandem sequence involving a base-promoted ring opening of the epoxide, Brook rearrangement, and alkylati

Full text of DOI:10.1021/ol025738v

ORGANIC
LETTERS
2
002
Vol. 4, No. 9
511-1514
Tandem Base-Promoted Ring Opening/
Brook Rearrangement/Allylic Alkylation
of O-Silyl Cyanohydrins of
1
â-Silyl-r,â-epoxyaldehydes
,†,‡
†
†
‡
Kei Takeda,* Eiji Kawanishi, Michiko Sasaki, Yuji Takahashi, and
§
Kentaro Yamaguchi
Institute of Pharmaceutical Sciences, Faculty of Medicine, Hiroshima UniVersity,
1-2-3 Kasumi, Minami-Ku, Hiroshima 734-8551, Japan, Toyama Medical and
Pharmaceutical UniVersity, 2640 Sugitani, Toyama 930-0194, Japan, and Chemical
Analysis Center, Chiba UniVersity, 1-33 Yayoi, Inage-Ku, Chiba 263-8522, Japan
takedak@hiroshima-u.ac.jp
Received February 18, 2002
ABSTRACT
Metalated O-silyl cyanohydrins of â-silyl-r,â-epoxyaldehyde have been found to serve as functionalized homoenolate equivalents by a tandem
sequence involving a base-promoted ring opening of the epoxide, Brook rearrangement, and alkylation of the resulting allylic anion.
Our continuing interest in the development of new synthetic
process that involves a base-promoted isomerization of the
epoxide (2 f 3), Brook rearrangement (3 f 4), and a
reaction of the resulting allylic anion with an electrophile
(4 f 5 f 6) proceeds well, the epoxysilane 1 would function
1
reactions featuring a tandem bond formation triggered by
2
Brook rearrangement led us to examine the reaction of
epoxysilanes 1 bearing an anion-stabilizing electron-
withdrawing group at the R-position with an amide base in
the presence of an electrophile (Scheme 1). If the tandem
3
as a homoenolate equivalent equipped with a synthetically
useful functionality. The internal quench conditions by
alkylating agents were selected on the basis of the results of
†
Hiroshima University.
Toyama Medical and Pharmaceutical University.
Chiba University.
1
e
‡
our previous study showing that R-cyano carbanions
§
generated by Brook rearrangement in the reaction of acryl-
(1) (a) Takeda, K.; Sawada, Y.; Sumi, K. Org. Lett. 2002, 4, 1031-
1033. (b) Takeda, K.; Yamawaki, K.; Hatakeyama, N. J. Org. Chem. 2002,
67, 1786-1794. (c) Takeda, K.; Nakane, D.; Takeda, T. Org. Lett. 2000,
2, 1903-1905. (d) Takeda, T.; Sumi, K.; Hagisawa, S. J. Organomet. Chem.
2000, 611, 449-454. (e) Takeda, K.; Ohnishi, Y. Tetrahedron Lett. 2000,
41, 4169-4172. (f) Takeda, K.; Nakajima, A.; Takeda, M.; Yoshii, E.;
Scheme 1
Zhang, J.; Boeckman, R. K., Jr. Org. Synth. 1999, 76, 199-213. (g) Takeda,
K.; Ohtani, Y. Org. Lett. 1999, 1, 677-679. (h) Takeda, K.; Tanaka, T.
Synlett 1999, 705-708. (i) Takeda, K.; Nakajima, A.; Takeda, M.; Okamoto,
Y.; Sato, T.; Yoshii, E.; Koizumi, T.; Shiro, M. J. Am. Chem. Soc. 1998,
120, 4947-4959. (j) Takeda, K.; Ohtani, Y.; Ando, E.; Fujimoto, K.; Yoshii,
E.; Koizumi, T. Chem. Lett. 1998, 1157-1158. (k) Takeda, K.; Kitagawa,
K.; Nakayama, I.; Yoshii, E. Synlett 1997, 251-252. (l) Takeda, K.;
Nakajima, A.; Yoshii, E. Synlett 1996, 753-754. (m) Takeda, K.; Takeda,
M.; Nakajima, A.; Yoshii, E. J. Am. Chem. Soc. 1995, 117, 6400-6401.
(
n) Takeda, K.; Nakatani, J.; Nakamura, H.; Sako, K.; Yoshii, E.; Yama-
guchi, K. Synlett 1993, 841-843. (o) Takeda, K.; Fujisawa, M.; Makino,
T.; Yoshii, E.; Yamaguchi, K. J. Am. Chem. Soc. 1993, 115, 9351-9352.
1
0.1021/ol025738v CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/03/2002

-
oylsilane with CN /18-crown-6 in the presence of MeI can
min, R-methylated cyanohydrins 13, products formed via the
tandem sequence (9 f 10 f 11 f 12), were obtained in
82% and 84%, respectively (Table 1).
undergo γ-alkylation without O-methylation and with the
intention of ultimately extending the reaction to an asym-
metric reaction by using homochiral epoxides.
Although base-promoted isomerization of epoxides to
allylic alcohols has been well documented,4 the only
examples, to the best of our knowledge, of a tandem sequence
involving a ring opening of expoxide followed by Brook
rearrangement are two examples by Gonz a´ lez-Nogai and co-
Table 1
5
workers, who succeeded in the generation of enol silyl ethers
via cleavage of R,â-epoxysilanes with heteroatom nucleo-
philes. In this letter, we wish to report the results of our
preliminary experiments on the tandem process.
We focused on O-silyl cyanohydrins of R,â-epoxyalde-
6
hydes 8 bearing a nitrile group as the electron-withdrawing
1
3, yield (%) (E/Z)
7
group, because 8 can be readily obtained from the corre-
RX
from 8a
from 8b
sponding aldehyde 7 and can provide functionalities useful
for further synthetic elaboration. Epoxysilanes 8a and 8b
were obtained as a diastereomeric mixture by the reaction
of TBSCN with epoxyaldehyde 7, which was derived from
-(1-ethoxyethoxy)propyne via the sequence shown in
Scheme 2. The relative stereochemistry in 8a and 8b was
determined on the basis of X-ray analysis of 8b.
Mel
Etl
i-Prl
82 (2.5)
76 (2.9)
58 (2.8)a
86 (2.7)
83 (3.4)
84 (22.0)
74 (28.0)
74 (31.0)
98 (47.0)
87 (40.0)
PhCH2Br
CH2dCHCH2Br
1f
3
8
a
1
2% yield of 13 (R ) H) was obtained.
Methylation products of intermediates 9 or 10 were not
detected. Similar results were obtained for other alkylating
agents (Table 1). Although almost the same yields were
obtained from 8a and 8b, the E/Z ratios of the two isomers
were markedly different, suggesting that the reactions from
Scheme 2
8a and 8b do not share common intermediates in their major
reaction pathways. Also, the addition of an alkylating agent
after treatment with a base did not markedly affect the yield
or E/Z ratio.
Next, we examined the effectiveness of other amide bases
to improve the E/Z-selectivity. While the use of lithium
hexamethyldisilazide (LHMDS, 1.0 M in THF) resulted in
lower yields but improvement in E/Z ratios with 8a,
comparable yields of 13 were obtained with potassium
hexamethyldisilazide (KHMDS, 0.5 M in toluene). It is
notable that the increased formation of the Z-derivative with
When 8a and 8b were treated with LDA (1.05 equiv) in
THF at -80 °C in the presence of MeI (1.2 equiv) for 5
8
a was observed in the case of the latter base. The best
(
2) For reviews on the 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
results, in terms of yield and E/Z-selectivity, were obtained
with sodium hexamethyldisilazide (NHMDS, THF solution),
allowing the formation of (E)-13 in excellent yields. It is
particularly noteworthy that the alkylation proceeds rapidly
under much milder conditions than those for O-trimethylsilyl
&
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.
1
974, 7, 77-84. For the use of the Brook rearrangement in tandem bond
formation strategies, see: (d) Moser, W. H. Tetrahedron 2001, 57, 2065-
2
6
1
084. Also see: (e) Ricci, A.; Degl’Innocenti, A. Synthesis 1989, 647-
60. (f) Bulman Page, P. C.; Klair, S. S.; Rosenthal, S. Chem. Soc. ReV.
990, 19, 147-195. (g) Qi, H.; Curran, D. P. In ComprehensiVe Organic
9
cyanohydrins of R,â-unsaturated aldehydes.
Functional Group Transformations; Katritzky, A. R., Meth-Cohn, O., Rees,
C. W., Moody, C. J., Eds.; Pergamon: Oxford, 1995; pp 409-431. (h)
Cirillo, P. F.; Panek, J. S. Org. Prep. Proced. Int. 1992, 24, 553-582. (i)
Patrocinio, A. F.; Moran, P. J. S. J. Braz. Chem. Soc. 2001, 12, 7-31.
(5) (a) Cuadrado, P.; Gonz a´ lez-Nogai, A. M. Tetrahedron Lett. 2000,
41, 1111-1114. (b) Cuadrado, P.; Gonz a´ lez-Nogai, A. M. Tetrahedron Lett.
1997, 38, 8117-8120.
(6) For alkylation of O-silyl cyanohydrins, see: (a) Arseniyadis, S.; Kyler,
K. S.; Watt, D. S. Org. React. 1984, 31, 1-364. (b) Albright, J. D.
Tetrahedron 1983, 39, 3207-3233.
(7) For a base-promoted ring opening of functionlized epoxides, see:
(epoxy nitriles) (a) Fleming, F. F.; Wang, Q.; Steward, O. W. J. Org. Chem.
2001, 66, 2171-2174. (epoxy amides) (b) Brooks, P. B. Marson, C. M.
Tetrahedron 1998, 54, 9613-9622. (epoxy esters) (c) Mohr, P.; R o¨ sslein,
L.; Tamm, C. Tetrahedron Lett. 1989, 30, 2513-2516. (d) Cory, R. M.
Ritchie, B. M.; Shrier, A. M. Tetrahedron Lett. 1990, 31, 6789-6792.
(8) For preparation of trimethylsilyl derivatives of 7 (R ) Me), see:
Urabe, H.; Matsuka, T.; Sato F. Tetrahedron Lett. 1992, 33, 4179-4182.
(3) For reviews on the homoenolates equivalents, see: (a) Ahlbracht,
H.; Beyer, U. Synthesis 1999, 365-390. (b) Kuwajima, I.; Nakamura, E.
Top. Curr. Chem. 1990, 155, 1. (c) Hoppe, D. Angew. Chem., Int. Ed. Engl.
984, 23, 932-948. (d) Werstiuk, N. H. Tetrahedron 1983, 39, 205-268.
e) Werstiuk, N. H. In Umpoled Synthons; Hase, T. A., Ed.; John Wiley &
1
(
Sons: New York, 1987; p 173. Also see: (f) Debal, A.; Cuvigny, T.;
Larchev eˆ que, M. Tetrahedron Lett. 1977, 3187-3190.
(4) For reviews on base-promoted isomerization of epoxides, see: (a)
Crandall, J. K.; Apparu, M. Org. React. 1983, 29, 345-443. (b) Satoh, T.
Chem. ReV. 1996, 96, 3303-3325.
1512
Org. Lett., Vol. 4, No. 9, 2002

Table 2
1
3, yield (%) (E/Z)
from 8a
from 8b
RX
LHMDSa
KHMDSb
NHMDSa
LHMDSa
KHMDSb
NHMDSa
Mel
Etl
i-Prl
PhCH2Br
CH2dCHCH2Br
44 (23.0)
24 (16.0)
15 (14.0)
56 (30.0)
45 (31.0)
84 (0.9)
76 (0.7)
42 (2.1)
83 (0.8)
80 (1.1)
96 (40.0)
90 (42.0)
80 (62.0)
98 (65.0)
91 (39.0)
83 (31.0)
64 (28.0)
44 (37.0)
75 (82.0)
80 (89.0)
87 (9.7)
98 (E)
81 (16.0)
73 (83.0)
88 (13.0)
83 (14.0)
89 (42.0)
89 (75.0)
99 (67.0)
92 (41.0)
a
.0 M solution in THF was used. b 0.5 M solution in toluene was used (THF/toluene ) ca. 2:3).
1
The varying yields and E/Z ratios depending on the bases
used prompted us to investigate the reaction pathway. First,
we examined several solvent systems, considering the
possibility that the increased formation of the (Z)-isomer in
the case of KHMDS may be due to the lower polarity of
toluene than that of THF. The results are summarized in
Table 3. The use of less-polar solvents resulted in a
oxygen atom of the epoxide, on the basis of the slow ring
opening of a substrate in which intramolecular chelation is
7
a
geometrically precluded. We decided to compare the
relative rates of ring opening of the diastereomers 8a and
8b. When a mixture of 8a (1 equiv) and 8b (1equiv) in THF
was treated with LDA (1 equiv) in the presence of MeI (1
equiv) at -80 °C for 5 min, a 1.0:0.7 mixture of 8a and 8b
was obtained in 40% yield together with 35% of 13 (R )
Me) (E/Z ) 6.6), indicating that 8b is more reactive than is
8
a. The difference in reactivities can be rationalized by
Table 3
invoking a concerted anti-deprotonation and ring opening,
in which the transition state from 8b is more favorable than
that from 8a in terms of less repulsive interactions between
H-4 and the O-silyl cyanohydrin moiety (A-value11 for
3
OSiMe , 0.74; for CN, 0.2) (Figure 1).
yield (%), (E/Z)
base
LDA
KHMDS hexane-tolene (1:1) CH3I
solvent
RX
13
14
hexane-tolene (1:1) CH3I
27 (0.1) 21 (0.06)
24 (1.1) 43 (0.19)
NHMDS hexane-THF (8.2:1) PhCH2Br 93 (1.5)
NHMDS toulene-THF (82:1) PhCH2Br 86 (1.0)
NHMDS Et2O-THF (82:1)
PhCH2Br 84 (1.9)
substantial enhancement of the Z-selectivity, suggesting that
the nature of the solvent, not the countercation, plays an
important role in determination of E/Z selectivity in the
reaction.10
We were also interested in the difference between the E/Z
ratios of the diastereomers 8a and 8b in the reaction with
LDA and KHMDS. Fleming and co-workers reported that
the lithium amide base-promoted ring opening of â,γ-
epoxynitrile proceeds by syn-elimination via a six-membered
transition state in which the lithium ion coordinates the
Figure 1.
This is in sharp contrast to the widely accepted chelation-
assisted syn-elimination mechanism for a base-promoted ring
(
(
9) Hertenstein, U.; H u¨ nig, S. O¨ ller, M. Synthesis 1976, 416-417.
10) (a) Stork, G.; Boeckman, R. K., Jr. J. Am. Chem. Soc. 1973, 95,
(11) Eliel, E.; Wilen, S. H. In Stereochemistry of Organic Compounds;
2016-2017. (b) Fleming, F. F.; Shook, B. C. Tetrahedron 2002, 58, 1-23.
John Wiley & Sons: New York, 1994; p 696.
Org. Lett., Vol. 4, No. 9, 2002
1513

opening,4,7 in which the pathway from 8a is sterically
preferable to that from 8b owing to the repulsive interaction
shown in Figure 1. Furthermore, the concerted anti-depro-
tonation and ring opening process was supported by the fact
that the reactivities of 8a and 8b were not affected by the
addition of HMPA, which can disrupt the chelated structure
by solvating the lithium cation.
In conclusion, we have found that O-silyl cyanohydrins
of â-silyl-R,â-epoxyaldehyde can function as a highly
functionalized homoenolate equivalent via the tandem se-
quence involving base-promoted ring opening, Brook re-
arrangement, allylic rearrangement, and alkylation. Although
a full understanding of the actual mechanism of the entire
process, including the stereochemistries of the Brook re-
arrangement and subsequent allylic rearrangement and alkyl-
ation, must await further detailed mechanistic experimenta-
tion, a number of mechanistically interesting issues seems
to be embedded in the synthetically useful reactions. More
detailed mechanistic investigation and attempts at extension
of the process to an asymmetric reaction using homochiral
epoxides will be reported in a forthcoming paper.
Acknowledgment. Acknowledgment is made to the
Uehara Memorial Foundation (K.T.) for partial support of
this research.
Supporting Information Available: Full experimental
details and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL025738V
1514
Org. Lett., Vol. 4, No. 9, 2002