R3Al-R′3SiOTf: Novel and powerful reagent system for stereospecific alkylation-silylation reactions of epoxides

Article abstract of DOI:10.1021/ol035075x

(Matrix presented) A novel and powerful reagent system R ₃Al-R′₃SiOTf for the one-pot alkylation-silylation reaction of epoxides was discovered, and the reactions of various epoxides with the new reagent system have been demonstrated to occur stereospecifically giving rise to the corresponding alkylation-silylation products in excellent yields.

Full text of DOI:10.1021/ol035075x

ORGANIC
LETTERS
2003
Vol. 5, No. 18
3265-3268
R Al−R′3SiOTf: Novel and Powerful
3
Reagent System for Stereospecific
Alkylation−Silylation Reactions of
Epoxides
Ponnusamy Shanmugam and Masaaki Miyashita*
DiVision of Chemistry, Graduate School of Science, Hokkaido UniVersity,
Sapporo 060-0810, Japan
miyasita@sci.hokudai.ac.jp
Received June 13, 2003
ABSTRACT
A novel and powerful reagent system R Al−R′3SiOTf for the one-pot alkylation−silylation reaction of epoxides was discovered, and the reactions
3
of various epoxides with the new reagent system have been demonstrated to occur stereospecifically giving rise to the corresponding alkylation−
silylation products in excellent yields.
Stereoselective carbon-carbon bond-forming reactions of
epoxides with carbon nucleophiles are one of the most
important transformations in organic synthesis,1 particularly
in natural product synthesis.2 Although various organoalu-
minum reagents have been used as carbon nucleophiles3 for
epoxide-opening reactions, this type of reaction is restricted
to a structurally limited number of substrates such as 2,3-
epoxy alcohols,4 γ,δ-epoxy unsaturated esters,5 epoxy sul-
fides,6 and so on and not applicable to simple epoxy alkanes
themselves.
For example, the reaction of trans-4-epoxyoctane (1) with
trimethylaluminum (Me3Al, 3 equiv) did not occur at -30
(1) (a) Yamamoto, H. In Organometallics in Synthesis; Schlosser, M.,
Ed.; Wiley: Chichester, 2002; pp 535-578. (b) For a review, see: Klunder,
J. M.; Posner, G. H. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol.3, pp 207-239. (c) Knight,
D. W. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 3, pp 241-270. (d) Garratt, P. J. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 3, pp 271-292. (e) Sasaki, M.; Tanino, K.;
Miyashita, M. Org. Lett. 2001, 3, 1765. (f) Miyazawa, M.; Ishibashi, N.;
Ohnuma, S.; Miyashita, M. Tetrahedron Lett. 1997, 38, 3419.
(2) (a) Posner, G. H. Org. React. 1975, 22, 253-400. (b) Lipshutz, B.
H.; Sengupta, S. Org. React. 1992, 41, 135-631. (c) Bonini, C.; Righi, G.
Synthesis 1994, 225. (d) Lipshutz, B. H.; Wilhelm, R. S.; Kozlowski, J.
A.; Parker, D. J. Org. Chem. 1984, 49, 3928. (e) Shiratani, T.; Kimura,
K.; Yoshihara, K.; Hatakeyama, S.; Irie, H.; Miyashita, M. J. Chem.
Soc., Chem. Commun. 1996, 21. (f) Miyashita, M.; Shiratani, T.; Kawamine,
K.; Hatakeyama, S.; Irie, H. J. Chem. Soc., Chem. Commun. 1996,
1027.
(3) (a) Mole, T.; Jeffery, E. A. In Organoaluminum Compounds;
Elsevier: Amsterdam, 1972. (b) Negishi, E. In Organometallics in Organic
Synthesis; Wiley: New York, 1980; Vol. 1, pp 286-393. (c) Eisch, J. J. In
ComprehensiVe Organometallic Chemistry; Wilkinson, G., Stone, F. G. A.,
Abel, E. W., Eds.; Pergamon: Oxford, 1982; Vol. 1, pp 555-682. (d)
Negishi, E. Acc. Chem. Res. 1987, 20, 65. (e) Maruoka, K.; Yamamoto, H.
Tetrahedron 1988, 44, 5001.
(4) (a) Suzuki, T.; Saimoto, H.; Tomioka, H.; Oshima, K.; Nozaki, H.
Tetrahedron Lett. 1982, 23, 3597. (b) Roush, W. R.; Adam, M. A.; Pesekis,
S. M. Tetrahedron Lett. 1983, 24, 1377.
(5) (a) Miyashita, M.; Hoshino, M.; Yoshikoshi, M. J. Org. Chem. 1991,
56, 6483. (b) Ishibashi, N.; Miyazawa, M.; Miyashita, M. Tetrahedron Lett.
1998, 39, 377.
(6) (a) Liu, C.; Hashimoto, Y.; Kudo, K.; Saigo, K. Bull. Chem. Soc.,
Jpn. 1996, 69, 2095. (b) Sasaki, M.; Tanino, K.; Miyashita, M. J. Org.
Chem. 2001, 66, 5388.
10.1021/ol035075x CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/09/2003

°C at all and the starting material was quantitatively
recovered unchanged. Even with the use of the more active
Me3Al-H2O system,5,7 less than 10% of the product was
formed (Scheme 1). The reaction with the Gillman reagent
(Me2CuLi, 2 equiv) furnished only 67% of the desired
product.
Table 1. Alkylation-Silylation of 1 with R3Al-R′3SiOTfa
isolated
yield
(%)
entry
conditions
product
Scheme 1. Reactions of trans-4-Epoxyoctane (1) with Me3Al.
1
2
3
4
5
6
7
A,b -50 °C,1 h
A, -50 °C, 1 h
R1 ) Me, R2 ) H
91
93
92
94
90
95
95e
R1 ) Me, R2 ) TMS
R1 ) Me, R2 ) TES
R1 ) Me, R2 ) TBS
R1 ) Et, R2 ) TMS
A,c -50 °C, 50 min
A,c -50 °C, 50 min
B,c,d -50 °C, 1 h
B,c,d -50 °C, 75 min R1 ) Et, R2 ) TES
C,f -50 °C, 1 h
R1 ) CtCTMS, R2 ) TMS
a All reactions were carried out in dichloromethane. A: Me3Al (1.5
equiv), R3SiOTf (1.5 equiv), Et3N (1.5 equiv). B: Et3Al (1.5 equiv),
R3SiOTf (1.5 equiv), Et3N (1.5 equiv). C: Me2AlC ≡ CTMS (2 equiv),
R3SiOTf (2 equiv), Et3N (1.5 equiv). b Without Et3N. c Performed with 1.3
equiv of the reagents. d Carried out with 4 mL/mmol concentration. e Isolated
along with 8% of the reduction product. f Me2AlCtC-TMS was prepared
by the treatment of Me2AlOTf with Li CtCTMS in CH2Cl2.
To overcome the synthetic limitation of organoaluminums
and to realize efficient carbon-carbon bond-forming reac-
tions of epoxides, we explored a new type of activation of
organoaluminum reagents, although a few types of activa-
tions are known in the literature.8 As a result, we discovered
that the combination of trialkylaluminum (R3Al) and tri-
alkylsilyltriflate (R′3SiOTf) serves as an excellent carbon
nucleophile for epoxide-opening reactions. We report herein
the powerful activation and enhancement in the reactivity
of organoaluminums by the combination with R′3SiOTf,
which act as efficient and potentially useful alkylating
reagents of various epoxides to afford the corresponding
silylated products in the presence of Et3N in a one-pot
operation and in remarkably high yields.
We chose trans-4-epoxyoctane (1) as a model substrate
for the present study. First, the epoxide 1 was treated with
Me3Al (1.5 equiv) and TMSOTf (1.5 equiv) in CH2Cl2 at
-50 °C to afford the anti-methylated alcohol as a single
product in 91% yield (Table 1, entry 1).9
Notably, we found that on the addition of Et3N (1.5 equiv)
to the reaction mixture after the disappearance of the starting
material (TLC; ca. 30-40 min), the corresponding TMS-
ether of the alcohol was formed in 93% yield (entry 2). We
also examined the combination of Me3Al and other triflates
(TESOTf and TBSOTf) to demonstrate the scope and
generality of the present method. Thus, the reaction of 1 with
Me3Al in the presence of TESOTf and Et3N or TBSOTf and
Et3N afforded the corresponding silyl ethers with complete
stereoselectivity in remarkably high yields (entries 3 and 4).
We found that the reactivity of the triflates was TMSOTf
>TESOTf > TBSOTf, probably due to the bulkiness of the
reagents. Hence, the reaction of 1 with TIPSOTf furnished
only the starting material even after prolonged reaction time
and conditions. To get insight into the scope of the present
method, other organoaluminum reagents such as Et3Al and
Me2AlC‚CTMS were examined. These reagents also served
as excellent carbon nucleophiles to afford the corresponding
substitution products in excellent yields (entries 5-7),
although 4 mL/mmol concentration was required to minimize
side products (e.g., ketones) in these reactions. All reactions
in Table 1 proceeded smoothly, giving rise to a single
product. It should be noted that the present method provides
a variety of the alkylation-silylation products in one-pot
operation with extremely high stereoselectivity.
(7) Abe, N.; Hanawa, H.; Maruoka, K.; Sasaki, M.; Miyashita, M.
Tetrahedron Lett. 1999, 40, 5369.
The excellent preliminary results prompted us to examine
various epoxides under the optimized conditions. Thus, cis-
4-epoxyoctane (2), cyclohexaneoxide (3), and trans- and cis-
γ,δ-epoxy unsaturated esters (4 and 5, respectively) were
examined and the results are summarized in Table 2. As
shown, all the reactions proceeded stereospecifically giving
rise to the corresponding silyl ethers of alkylation products
as single products in excellent yields (entries 1-12). The
configuration of the products was unambiguously confirmed
by agreement with that of the products obtained by the
reaction of 1 and 2 with the Gillman reagent (Me2CuLi),2a
although the later reactions gave lesser yields (40 and 67%,
respectively) of products. It is noteworthy that the reactions
of trans-γ,δ-epoxy unsaturated ester (4) having no particular
oxygen function on the side chain also occurred smoothly
(8) (a) Zhou, H.; Campbell, E. J.; Nguyen, S. T. Org. Lett. 2001, 3, 2229.
(b) Schneider, C.; Brauner, J. Tetrahedron Lett. 2000, 41, 3043. (c) Pfaltz,
A.; Mattenberger, A. Angew. Chem., Int, Ed. Engl. 1982, 21, 71. (d)
Inghardt, T.; Frejd, T. Tetrahedron, 1991, 47, 6483.
(9) Representative Procedure. To a solution of the epoxide 1 (100 mg,
0.78 mmol) in dry CH2Cl2 (2 mL) were added Me3Al (1 M solution in
hexane, 1.2 mL, 1.2 mmol) and TMSOTf (0.23 mL, 1.2 mmol) at -50 °C
under an argon atmosphere. After the mixture was stirred for 45 min at the
same temperature, Et3N (0.16 mL, 1.2 mmol) was added and the mixture
was further stirred for an additional 15 min at the same temperature. The
reaction was quenched with 0.05 M HCl (2 mL), and the mixture was
extracted with ethyl acetate (50 mL) and successively washed with water
(4 × 25 mL) and brine (25 mL), dried (anhydrous MgSO4), and concentrated
in vacuo. The crude product was immediately purified by a silica gel column
chromatography (5% hexanes-ethyl acetate) to give the pure trimethyl-
(2-methyl-1-propylpentyloxy)-silane (159 mg, 93%). It is critical to purify
the crude products immediately to obtain the corresponding products in
high yield. The reaction was quenched with 1 M HCl (without adding Et3N),
followed by the same workup procedure, to afford the pure 5-methyl-oct-
4-ol (93 mg, 91%).
3266
Org. Lett., Vol. 5, No. 18, 2003

Table 2. Alkylation-Silylation Reactions of Various Epoxides with R3Al-R′3SiOTf-Et3Na
a All reactions were carried out in dichloromethane. b A: Me3Al (1.5 equiv), R3SiOTf (1.5 equiv), Et3N (1.5 equiv). B: Et3Al (1.5 equiv), R3SiOTf
(1.5 equiv), Et3N (1.5 equiv). C: Me3Al (2 equiv), R3SiOTf (2 equiv), Et3N (1.3 equiv). c Without Et3N.
with complete regioselectivity at the γ-position to give single
γ-substitution products (entries 9-12), which were in
contrast with the very sluggish reaction of 4 with the Me3-
Al-H2O system resulting in the formation of an 80:20
mixture of γ- and δ-methylation products.5 Similarly, the
corresponding cis-analogue 5 reacted cleanly to give an
approximately 80:20 mixture of γ- and δ-substitution
products (entries 13-15), while the reaction of 5 with Me3-
Al-H2O gave a complex mixture. As was anticipated, the
reactions of terminal epoxides (6 and 7) produced the C1
substitution products regioselectively (entries 16 and 17) and
reactions of a trisubstituted epoxide (8) gave a product
bearing a quaternary carbon center predominantly (entry 18).
In conclusion, we have developed a novel and one-pot
alkylation-silylation reaction of epoxides by the combination
of R3Al, R3′SiOTf, and Et3N. The present method involves
the powerful activation of organoaluminums as carbon
nucleophiles, which affords the alkylation-silylation prod-
ucts stereospecifically in excellent yields. Therefore, the
present method should provide an extremely useful means
in organic synthesis, including natural product synthesis.
Further investigations on the new reagent system and its
application to natural product synthesis are in progress in
our laboratory.
Acknowledgment. This research was supported by
Grants-in-Aid for Scientific Research on Priority Areas (A)
“Exploitation of Multi-Element Cyclic Molecules” (No.
13029003), Scientific Research (A) (No.12304042), and
Sprout Research (No. 14654138). P.S thanks the Japan
Society for the Promotion of Science (JSPS) for the award
of a Research Fellowship (P-02132) and CSIR (New Delhi),
Org. Lett., Vol. 5, No. 18, 2003
3267

Regional Research Laboratory, Trivandrum, India, for grant-
ing deputation abroad.
Supporting Information Available: Typical experimen-
tal procedures, tabulated spectral details, and copies of
1H and 13C NMR spectra of selected compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Note Added after ASAP Posting. The heading in ref 9
and the triple bond in entry 7 of Table 1 were missing in
the version posted ASAP on August 9, 2003. The corrected
version was posted on August 20, 2003.
OL035075X
3268
Org. Lett., Vol. 5, No. 18, 2003