A simple, mild, catalytic, enantioselective addition of terminal acetylenes to aldehydes [8]

Full text of DOI:10.1021/ja016378u

J. Am. Chem. Soc. 2001, 123, 9687-9688
9687
organometal (RM, M ) Zn, Ti, Mg, Li) or organometalloid (Si,
B, Sn) nucleophile.3,7 Importantly, those processes which are noted
as catalytic, are catalytic in metal only with respect to the active,
chiral complex that serves to activate the nucleophilic or elec-
trophilic reaction partners.8 With the exception of methods
proceeding via enolates reported by Shibasaki and Trost,9 to the
best of our knowledge, a method to enantioselectively add in situ
generated carbanions to aldehydes which is truly catalytic in metal
is unprecedented.
We recently documented the enantioselective addition of Zn-
alkynilides to aldehydes using stoichiometric quantities of com-
mercially available Zn(OTf)2, (+)- or (-)-N-methylephedrine and
Et3N.1c-g In analogy to the additions of R2Zn in the presence of
chiral catalysts,3f the products were obtained in high enantiose-
lectivities, however, by contrast, the addition reactions of in situ
generated Zn-alkynilides were not catalytic. Even after numerous
investigations involving the use of additives and various ligands,
as well as variation of solvent, the reaction proved recalcitrant to
catalysis. We speculated that the lack of turnover was a conse-
quence of a kinetic barrier inhibiting protonation of the first-
formed Zn-alkoxide.
We subsequently determined that catalysis could be attained
by conducting the reaction at 60 °C (Table 1).10 The catalytic
process displays wide substrate scope and is compatible with
functionality on both the alkyne and the aldehyde. At the current
level of development the addition works ideally with R-substituted
aldehydes,11 while unbranched unsubstituted aliphatic aldehydes
deliver products in high enantioselectivites and useful yields
(entries 5 and 16).12 With R,R-disubstituted aldehydes, the reaction
worked most efficiently when a 20 mol %:10 mol % ratio of
Zn(OTf)2:(+)-N-methylephedrine was employed (entries 6 and
7).13 In general, although the use of 20 mol % Zn(OTf)2 14 reliably
affords adducts in the selectivities and yields noted,15 we found
that the ligand could be reduced to as little as 5 mol % with
retention of high enantioselectivity.16 The robust nature of the
process is underscored when it is noted that, even when the
reaction was conducted at 100 °C, propargyl alcohol adduct was
produced in high % ee (entries 12 and 14). We have also observed
that the catalytic addition reaction is tolerant of moisture and air.
For example, when 4-phenyl-1-butyne was added to cyclohexane
carboxaldehyde under an atmosphere of air using freshly opened
bottle of ACS reagent-grade toluene (103 ppm H2O content by
Karl Fischer titration) the chiral propargyl alcohol was formed
A Simple, Mild, Catalytic, Enantioselective Addition
of Terminal Acetylenes to Aldehydes
Neel K. Anand and Erick M. Carreira*
Laboratorium fu¨r Organische Chemie
ETH-Zu¨rich, UniVersita¨tstrasse 16
CH-8092 Zu¨rich, Switzerland
ReceiVed June 10, 2001
The enantioselective addition of terminal acetylenes to alde-
hydes1 or ketones2 affords direct access to optically active
propargyl alcohols which are useful, versatile building blocks that
enjoy wide application in chemical synthesis. The existing
methods for carrying out these enantioselective addition reactions
require the use of stoichiometric quantities of metalated acetyl-
enes, which have taken the form of boryl acetylides or, more
recently, in situ generated Zn(II) alkynilides.1-3 In our continuing
interest in the development of mild, practical methods for
asymmetric C-C bond-formation,1e we have investigated the in
situ C-H activation of terminal acetylenes to give nucleophilic
carbanions that participate in catalytic, enantioselective additions
to aldehydes. Herein, we report the enantioselective addition of
terminal acetylenes to aldehydes, which is catalytic in both metal
and chiral ligand. This is the first time that Zn-carbanions have
been added enantioselectively to aldehydes using truly catalytic
amounts of metal; previously, stoichiometric R2Zn has always
been employed.3 The propargylic adducts are isolated in useful
yields and excellent selectivities. Additionally, we document the
first example of an alkynilide addition to an aldehyde that can
be conducted solvent-free with 1.0 equiv of aldehyde and 1.05
equiv of alkyne.4 As such, this volumetrically efficient5 process
exemplifies ideal atom economy,6 not only because the two
reactants comprise the product but also since it obviates the use
of solvent.
(7) (a) Noyori, R.; Kitamura, M. Angew. Chem., Int. Ed. Engl. 1991, 30,
49. (b) Gauthier, D. R., Jr.; Carreira, E. M. Angew. Chem., Int. Ed. Engl.
1996, 35, 2363.
(8) The Alder ene reaction of olefins and aldehydes, if considered to proceed
via an ionic rather than pericyclic mechanism, may constitute one exception,
see: (a) Hao, J.; Hatano, M.; Mikami, K. Org. Lett. 2000, 2, 4059. (b) Johnson,
J. S.; Evans, D. A. Acc. Chem. Res. 2000, 33, 325.
(9) (a) Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki,
M. J. Am. Chem. Soc. 1999, 121, 4168. (b) Yoshikawa, N.; Kumagai, N.;
Matsunaga, S.; Moll, G.; Ohshima, T.; Suzuki, T.; Shibasaki, M. J. Am. Chem.
Soc. 2001, 123, 2466. (c) Trost, B. M.; Ito, H.; Silcoff, E. R. J. Am. Chem.
Soc. 2001, 123, 3367. (d) Ito, Y.; Sawamura, M.; Hayashi, T. J. Am. Chem.
Soc. 1986, 108, 6405.
(10) Racemic addition could also be achieved at this temperature using
catalytic quantities of Zn(OTf)2 in the absence of the chiral ligand by
conducting the reaction in acetonitrile.
(11) We have investigated a variety of conditions to add alkynes to aromatic
aldehydes and have found that the yields are considerably reduced due to
Canizzaro reaction.
(12) The remaining aldehyde was consumed in aldol self-condensation.
(13) Reactivity dependence on the relative stoichiometry of aldehyde, zinc
species, and ligand in related systems has been reported: Kitamura, M.; Suga,
S.; Kawai, K.; Noyori, R. J. Am. Chem. Soc. 1986, 108, 6071.
(14) With certain substrates 10 mol % Zn(OTf)2 suffices.
(15) We have also conducted the addition reaction on 50 mmol scale to
give the adduct of entry 2 in 94% yield and 96% ee.
To date, the processes that have been reported for the
enantioselective additions of a wide range of nonstabilized
carbanions to carbonyls prescribe stoichiometric amounts of an
(1) (a) Mukaiyama, T.; Suzuki, K.; Soai, K.; Sato, T. Chem. Lett. 1979,
447. (b) Tombo, G. M. R.; Didier, E.; Loubinoux, B. Synlett 1990, 547. (c)
Frantz, D. E.; Fa¨ssler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122, 1806.
(d) Boyall, D.; Lo´pez, F.; Sasaki, H.; Frantz, D.; Carreira, E. M. Org. Lett.
2000, 2, 4233. (e) Frantz, D. E.; Fa¨ssler, R.; Tomooka, C. S.; Carreira, E. M.
Acc. Chem. Res. 2000, 33, 373. (f) Sasaki, H.; Boyall, D.; Carreira, E. M.
HelV. Chim. Acta 2001, 84, 964. (g) Bode, J. W.; Carreira, E. M. J. Am. Chem.
Soc. 2001, 123, 3611.
(2) (a) Tan, L.; Chen, C.-Y.; Tillyer, R. D.; Grabowski, E. J. J.; Reider, P.
J. Angew. Chem., Int. Ed. 1999, 38, 711.
(3) For enantioselective procedures which are catalytic with respect to the
chiral ligand, see: (a) Niwa, S.; Soai, K. J. Chem. Soc., Perkin Trans. 1 1990,
937. (b) Chelucci, G.; Conti, S.; Falorni, M.; Giacomelli, G. Tetrahedron 1991,
47, 8251. (c) Corey, E. J.; Cimprich, K. A. J. Am. Chem. Soc. 1994, 116,
3151. (d) Ishizaki, M.; Hoshino, O. Tetrahedron: Asymmetry 1994, 5, 1901.
(e) Li, Z.; Upadhyay, V.; DeCamp, A. E.; DiMichelle, L.; Reider, P. J.
Synthesis 1999, 1453. (f) For an excellent recent review, see: (a) Pu, L.; Yu,
H.-B. Chem. ReV. 2001, 101, 757.
(4) Very recently, a system for the enantioselective alkylation of aldehydes
using 3.4-10 mol % of chiral ligand and 2.2-5 equiv of Et2Zn without
additional solvent has been reported: Sato, I.; Saito, T.; Soai, K. J. Chem.
Soc., Chem. Commun. 2000, 2471
(5) Jacobsen, E. N.; Finney, N. S. Chem. Biol. 1994, 1, 85.
(6) Trost, B. M. Science 1991, 254, 1471.
(16) When 4-phenyl-1-butyne was added to cyclohexane-carboxaldehyde
using 20 mol % of Zn(OTf)2 and 5 mol % of ligand, the chiral propargyl
alcohol was formed in 79% yield and 91% ee (cf. Table 1, entry 2).
10.1021/ja016378u CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/07/2001

9688 J. Am. Chem. Soc., Vol. 123, No. 39, 2001
Communications to the Editor
Table 1. Catalytic, Enantioselective Addition of Alkynes to
Scheme 1
Aldehydesa
are worth noting: first, unlike the reaction in toluene, the solvent-
free reaction did not require the prescribed 2 h mixing period
(Zn, ligand, and amine) to form the active complex, therefore
reducing the overall time required for the reaction, and second,
aqueous workup could be obviated, as direct transfer of the
contents of the reaction vessel onto a column of silica yielded,
after the chromatographic purification, analytically pure chiral
propargyl alcohol adduct.
Finally, using the catalytic addition reaction it is possible to
access optically active dialkynyl methanols (eq 2). Thus, in
preliminary results the addition of alkyne 2 to alkynal 1 furnished
alcohol 3 in 89% ee. Such alcohols in which the ends of the
alkynes are differentiated provide ideal building blocks that can
be extensively synthetically elaborated, not only for use in
traditional total synthesis but also for materials application.17
In conclusion, we have described the first process in which
terminal alkynes undergo addition to aldehydes in up to 99% ee
using truly catalytic quantities of metal and ligand. The procedure
is practical, facile, and utilizes reactants that require no prior
preparation; moreover, the Zn(II) salt and both enantiomers of
the chiral ligand are commercially available. The conditions
tolerate air and moisture and are very versatile; thus, while the
general procedure described works well for a variety of substrates,
the range of reaction conditions that can be employed is
sufficiently broad to allow the relative amounts of Zn(II) and
ligand to be varied. The flexibility of the method is especially
highlighted by the fact that the addition can be conducted at
temperatures as high as 100 °C to afford products in excellent
yields and %ee. We have also demonstrated the first example of
a solvent-free alkynilide addition reaction that furnishes chiral
propargyl alcohols as useful building blocks with excellent
enantioselectivity. As such the process epitomizes the concept
of atom economy. Further studies are underway and will be
reported in due course.
a 20 mol % Zn(OTf)2, 22 mol % (+)-N-methylephedrine, 50 mol %
Et3N, 1.2 equiv alkyne, and 1.0 equiv (0.5 mmol) aldehyde in toluene
(1 M) at 60 °C. b For entries 4, 7-11, 13, and 15 the adducts were
converted to their 3,5-dinitrobenzoate esters and then analyzed by HPLC
using Chiralcel column; for all other entries the ee was determined
directly by Chiralcel HPLC analysis. c Absolute configuration of the
products was established by correlation with known compounds or by
analogy. d Stirred at 23 °C. e Stirred at 50 °C. f Stirred at 100 °C.
g Aldehyde was added dropwise to the reaction mixture over 2.5 h.
h 10 mol % (+)-N-methylephedrine was used. i Yield and ee shown
for the desilylated product.
in 79% yield and 92% ee (cf. Table 1, entry 2). All of these results
demonstrate that the system is highly versatile and amenable to
fine-tuning of conditions for optimization of selectivity for a given
substrate.
To maximize the practicality and efficiency of the catalytic
reaction, we subsequently embarked on a study aimed at examin-
ing whether alkyne addition could be conducted in the absence
of solvent. In this respect, excellent yields and enantioselectivities
were achieved in a reaction mixture consisting of 1.0 equiv of
aldehyde and 1.05 equiv of alkyne along with catalytic quantities
of Zn(II), amine, and ligand (Scheme 1). A number of observa-
tions which attest to the advantages of the solvent-free system
Acknowledgment. We thank the ETH for their generous support.
Supporting Information Available: Experimental details and char-
acterization for all new compounds (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
JA016378U
(17) Modern Acetylene Chemistry; Stang, P. J., Diederich, F., Eds.; VCH:
Weinheim, 1995.