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J. Am. Chem. Soc. 2001, 123, 1256-1257
Table 1. One-Pot Synthesis of 2b from Cyclohexene 1ba
Novel Multiaction of Zr Catalyst: One-Pot Synthesis
of â-Cyanohydrins from Olefins
Shingo Yamasaki, Motomu Kanai, and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences
The UniVersity of Tokyo, Hongo, Bunkyo-ku
Tokyo 113-0033, Japan
ReceiVed NoVember 16, 2000
Improving the efficiency of organic syntheses, including
minimizing the energy cost and chemical waste, is a major goal
in synthetic chemistry. To this regard, performing multistep bond-
formation and/or bond-cleavage in one pot is an attractive
strategy.1 Therefore, we are interested in developing catalytic
tandem reactions, in which one catalyst promotes each step of
sequential reactions.2 Significant contribution has been achieved
by using late transition metal catalysts.3 On the other hand, we
have recently reported the one-pot process to synthesize trans-
â-acetoxy alcohols from olefins in the presence of bis(trimeth-
ylsilyl) peroxide (BTSP) and TMSOAc, promoted by a catalytic
amount of Zr(Oi Pr)4.4 In this reaction, the Zr catalyst promotes
the epoxidation step5 and the epoxide-opening step. We planned
to extend this chemistry to a more valuable carbon-carbon bond-
forming reaction, using TMSCN as the nucleophile. In this work,
the first one-pot trans-â-cyanohydrin synthesis with broad
substrate scope is reported. From mechanistic studies, it seems
that the Zr catalyst plays a multiple role being an oxidant, a Lewis
acid, and a nucleophile, in a tandem reaction process.
a The reaction was performed with 2 equiv of BTSP and TMSCN
in dichloroethane as solvent at 50 °C unless otherwise noted. b For the
preparation method of 3-6, see ref 13. c The reaction was quenched
when 1b disappeared on NMR. d Isolated yield. e The reaction was
conducted at room temperature.
nucleophilicity of the zirconium cyanide. Among the additives
screened,7 it was found that the reaction became much faster and
cleaner in the presence of 20 mol % of Ph3PO and the product
was obtained in 94% yield in 1.5 h (entry 5).8 Surprisingly, in
the presence of 40 mol % of Ph3PO, the reaction did not proceed
at all, indicating that the Lewis acidity of Zr would also play an
important part. The ring size of the diol ligand is not important
for the activity of the catalyst and only the steric factor seemed
to have a dominant role (entry 7-9). Finally, we have found that
even in the presence of 5 mol % of catalyst 3, 2b was obtained
in 95% yield at room temperature for 12 h (entry 6).
We first found extremely sluggish â-cyanohydrin formation,
when the best reaction conditions of acetoxy alcohol synthesis
were applied, using TMSCN instead of TMSOAc. From cyclo-
hexene 1b, the corresponding cyanohydrin 2b was obtained in
33% yield at room temperature for 30 days (CH2Cl2 as solvent)
in the presence of Zr(Oi Pr)4 (10 mol %), BTSP (2 mol equiv),
and TMSCN (2 mol equiv). Preliminary optimization of the
reaction conditions such as solvent, concentration, and reaction
temperature resulted in a synthetically acceptable reaction time
and chemical yield, using 20 mol % of Zr(Oi Pr)4 (Table 1, entry
2). Systematical survey of the Zr source6 revealed an intriguing
relationship between the steric bulkiness of the ligand of Zr and
the reaction rate (Table 1, entry 1-4). The catalyst containing
the bulkiest tertiary alkoxide ligand (3) showed the shortest
reaction time for the complete consumption of the starting material
(entry 4). We assumed that this tendency should stem from the
more facile ligand exchange (for example, from OtBu to CN) in
the case of Zr catalyst with bulkier alkoxide ligand. Efficient
ligand exchange should be the key for promoting the two
completely different steps (epoxidation and epoxide-opening).
Therefore, we attempted to observe the effect of additives which
should coordinate to Zr and facilitate the ligand exchange.
Moreover, we expected that the Lewis base should enhance the
Next we investigated the generality of this one-pot â-cyano-
hydrin synthesis. As shown in Table 2, cyanohydrin 2d could be
obtained in good yield even from much less reactive cyclooctene
1d (entry 4).9 The ester group is also tolerated and the product
was obtained in completely stereoselective manner (entry 5). It
is noteworthy that the reaction of 1e catalyzed by Zr(OtBu)4 in
the absence of Ph3PO resulted in the formation of many side
products. The reaction was successfully applied to 1f which could
be prone to aromatize due to the oxidative conditions (entry 6).
The regioselectivity of 1j and 1k was perfect (entry 10, 11),
although in the case of 1k, trans isomer was contaminated with
cis isomer.10 The regioselectivity of sterically unsymmetrical
olefins was moderate only in one case (entry 12), but perfect in
other cases (entry 13-15).11 In all these cases, the major isomer
was derived from the attack of cyanide at the less hindered carbon
center.12 Thus, this one-pot â-cyanohydrin synthesis is general
to a wide variety of olefins with synthetically useful selectivities.13
To get preliminary insight into the reaction mechanism, several
(7) Other additives: Bu3PO, 57% (6.5 h); HMPA, 75% (3.5 h); DMSO,
62% (6.5 h); pyridine oxide, 82% (15 h).
(8) For an example of ligand-accelerated catalysis, see: Jacobsen, E. N.;
Marko´, I.; Mungall, W. S.; Schro¨der, G.; Sharpless, K. B. J. Am. Chem. Soc.
1988, 110, 1968-1970.
(1) (a) Tietze, L. F.; Haunert, F. In Stimulating Concepts in Chemistry;
Vo¨gtle, F., Stoddart, J. F., Shibasaki, M., Eds.; Wiley-VCH: Weinheim, 2000;
p 39. (b) Hall, N. Science 1994, 266, 32-34.
(9) Even the epoxide opening reaction by cyanide from cyclooctene oxide
is unprecedented.
(10) The trans/cis selectivity was higher with use of Ph3AsO than with
use of Ph3PO (trans/cis ) 2.6/1) as additive in the case of 1k.
(11) In other cases than entry 14, no advantage was observed with Hf
catalyst.
(2) Another interesting tandem system composed of multi (two) artificial
catalysts in one pot was reported recently: Jeong, N.; Seo, S. D.; Shin, J. Y.
J. Am. Chem. Soc. 2000, 122, 10220-10221.
(3) For example, see: de Meijere, A.; Bra¨se, S. In PerspectiVes in Organo-
palladium Chemistry for the XXI Century; Tsuji, J., Ed.; Elsevier: 1999; p 88.
(4) Sakurada, I.; Yamasaki, S.; Go¨ttlich, R.; Iida, T.; Kanai, M.; Shibasaki,
M. J. Am. Chem. Soc. 2000, 122, 1245-1246.
(12) In the absence of Ph3PO, 1o gave the primary alcohol derived from
the internal attack of the cyanide as the major product.
(13) Representative procedure (Table 2, entry 2): To a mixture of the diol
(0.025 mmol) and Ph3PO (0.025 mmol) in dichloroethane (0.43 mL) was added
Zr(OtBu)4 (0.025 mmol) at 0 °C and the whole mixture was stirred for 10
min. To the resulting clear solution were added BTSP (213 µL, 1 mmol),
TMSCN (133 µL, 1 mmol), and 1b (0.5 mmol) to start the reaction.
(5) (a) Irie, R.; Hosoya, N.; Katsuki, T. Synlett 1994, 255-256. (b) Yudin,
A. K.; Sharpless, K. B. J. Am. Chem. Soc. 1997, 119, 11536-11537.
(6) Other metals such as Ti or Sn were completely ineffective.
10.1021/ja005794w CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/19/2001