Direct catalytic aldol-type reactions using RCH2CN

Article abstract of DOI:10.1021/ol035206u

(Matrix presented) A copper fluoride-catalyzed cyanomethylation that can be applied to a wide range of ketones and aldehydes was developed using TMSCH₂CN as a nucleophile. The reaction was extended to a conceptually more advanced copper alkoxid

Full text of DOI:10.1021/ol035206u

ORGANIC
LETTERS
2003
Vol. 5, No. 17
3147-3150
Direct Catalytic Aldol-Type Reactions
Using RCH CN
2
Yutaka Suto,† Naoya Kumagai,† Shigeki Matsunaga,† Motomu Kanai,*,†,‡ and
,†
Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan, and PRESTO, Japan Science and Technology
Corporation
mshibasa@mol.f.u-tokyo.ac.jp
Received June 28, 2003
ABSTRACT
A copper fluoride-catalyzed cyanomethylation that can be applied to a wide range of ketones and aldehydes was developed using TMSCH CN
2
as a nucleophile. The reaction was extended to a conceptually more advanced copper alkoxide-catalyzed direct addition of alkylnitriles to
aldehydes, which can act as a surrogate direct catalytic aldol reaction of esters. These reactions can be applied to the first catalytic
enantioselective cyanomethylation of ketones and direct catalytic enantioselective cyanomethylation of aldehydes.
Because of the versatility of the nitrile group, cyanomethy-
lation of carbonyl compounds is a surrogate ester enolate
aldol reaction. The product, â-hydroxy nitriles, can be easily
converted to useful building blocks, such as â-hydroxycar-
boxylic acid derivatives and γ-amino alcohols.1 During our
development of a direct catalytic enantioselective aldol
reaction (catalytic on metal),2,3 we focused on the use of
alkylnitriles as donors (Scheme 1). Alkylnitriles contain an
R-proton with a pKa value close to that of an acetylenic
proton (∼25),4 which should be more easily deprotonated
via an interaction of the nitrile with a soft Lewis acid. A
strong interaction between a nitrile and a soft metal would
be advantageous for chemoselective deprotonation in the
presence of aliphatic aldehydes. We report here the CuOt-
Bu-catalyzed direct aldol-type addition of alkylnitriles to
aldehydes. This reaction was developed on the basis of the
CuF-catalyzed cyanomethylation of ketones and aldehydes
using TMSCH2CN as a nucleophile. These two reactions can,
in principle, be extended to catalytic enantioselective aldol-
type reactions.
Examples of the catalytic cyanomethylation reactions are
significantly more scarce than those of catalytic aldol
reactions: Palomo et al. reported a TASF- or alkaline metal
alkoxide-catalyzed cyanomethylation using TMSCH2CN as
a nucleophile.5 More recently, Verkade et al. reported a direct
† The University of Tokyo.
Scheme 1. Direct Catalytic Enantioselective Addition of
‡ PRESTO.
Nitriles
(1) For examples of cyanomethylation in natural product synthesis, see:
(a) Corey, E. J.; Wu, Y.-J. J. Am. Chem. Soc. 1993, 115, 8871. (b) Fukuda,
Y.; Okamoto, Y. Tetrahedron 2002, 58, 2513.
(2) (a) Yamada, Y. M. A.; Yoshikawa, N.; Sasai, H.; Shibasaki, M.
Angew. Chem., Int. Ed. Engl. 1997, 36, 1871. (b) Yoshikawa, N.; Yamada,
Y. M. A.; Das, J.; Sasai, H.; Shibasaki, M. J. Am. Chem. Soc. 1999, 121,
4168.
(3) For a review on direct catalytic enantioselective aldol reactions, see:
List, B. Tetrahedron 2002, 58, 5573.
(4) For a direct catalytic enantioselective alkynylation, see: Anand, N.
K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687.
10.1021/ol035206u CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/29/2003

addition of acetonitrile to aldehydes and ketones using
proazaphosphatranes as a Bro¨nsted base catalyst in the
presence of magnesium sulfate.6 In these precedent examples,
however, the substrate generality is not necessarily high,
especially for ketones. There is only one catalytic enantio-
selective cyanomethylation of an aldehyde reported so far,
using cyanomethylzinc bromide as a nucleophile.7
Table 1. CuF-Catalyzed Cyanomethylation by TMSCH2CN
We first planned to develop a general catalytic cyano-
methylation method using TMSCH2CN, on the basis of our
recent findings of the CuF-catalyzed aldol reaction for
ketones using ketene trimethylsilyl acetal as a nucleophile.8
In this reaction, a stoichiometric addition of (EtO)3SiF was
the key for generating the active catalyst, [(EtO)3SiF2]-‚
[Cu(PPh3)3]+ (1), as well as the catalyst turnover. The
fluoride transfer from 1 to trimethylsilyl enolate initiates the
catalytic cycle, which induces active copper enolate forma-
tion through a dynamic ligand exchange between silicon and
copper atoms. The highly robust feature of the reaction
prompted us to investigate the catalytic cyanomethylation
of ketones using TMSCH2CN as a nucleophile. A possible
difficulty was the higher stability of TMSCH2CN against
fluoride activation (C-Si activation) compared to that of
trimethylsilyl enolates (O-Si activation).9
When we applied the optimized aldol reaction conditions
to cyanomethylation of p-methoxyacetophenone (2d) [2.5
mol % CuF‚3PPh3‚2EtOH,10 120 mol % (EtO)3SiF, THF as
a solvent at room temperature for 24 h], the reaction did not
go to completion and product 3d was obtained in only 40%
yield after deprotection.11 Kinetic studies of the aldol reaction
indicated that a silyl enolate is an inhibitor of the reaction.8
The initial reaction rate possesses an order of -0.8 with
regard to the silyl enolate concentration. On the basis of the
analogy of the cyanomethylation to the aldol reaction, we
expected that a slow addition of TMSCH2CN, keeping the
silicon concentration sufficiently low, would improve reac-
tivity. As expected, the yield of 3d improved to 75% when
TMSCH2CN was added slowly (4.5 h)12 to a solution of the
catalyst, (EtO)3SiF, and 2d (Table 1, entry 4).
a Isolated yield. b TMSCH2CN was added slowly over 4.5 h. c TMSCH2CN
was added slowly over 1 h.
can be applied to an ethyl-substituted aromatic ketone 2e,
an enone 2f, and an easily enolizable linear aldehyde 2k.14
Thus, this is the first example of a general catalytic
cyanomethylation of carbonyl compounds.
The conversion of the cyanomethylation products to
â-hydroxycarboxylic acids was straightforward through hy-
drolysis under basic conditions.15 The results indicate the
equivalency of the cyanomethylation products to aldol
products (Scheme 2).
Under the optimized reaction conditions, the present
catalytic cyanomethylation was generally applicable to a wide
range of ketones and aldehydes (Table 1).13 For reactive
substrates such as 2a and 2b (entries 1 and 2) or aldehydes
(entries 8-12), high yields were obtained even under a one
portion addition of TMSCH2CN. Specifically, the reaction
Scheme 2. Hydrolysis of the Cyanomethylation Productsa
a Conditions: (a) 3 M NaOH (aq)/30% H2O2 (aq), rt, 1 h; 35-
45 °C, 15 h. (b) 3 M NaOH (aq)/30% H2O2 (aq), rt, 14 h.
(5) Palomo, C.; Aizpurua, J. M.; Lo´pez, M. C.; Lecea, B. J. Chem. Soc.,
Perkin Trans. 1 1989, 1692.
(6) Kisanga, P.; McLeod, D.; D’Sa, B.; Verkade, J. J. Org. Chem. 1999,
64, 3090.
(7) Soai, K.; Hirose, Y.; Sakata, S. Tetrahedron: Asymmetry 1992, 3,
677. The product with 78% ee was obtained in 45% yield, using 30 mol %
catalyst (only one example from benzaldehyde).
Although investigations to clarify the reaction mechanism
are currently ongoing, we propose the working hypothesis
(8) Oisaki, K.; Suto, Y.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2003, 125, 5644.
(9) Allyltrimethylsilane is not reactive under conditions reported in ref
8; however, allyltrimethoxysilane can react with carbonyl compounds:
Yamasaki, S.; Fujii, K.; Wada, R.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2002, 124, 6536. The degree of C-Si polarization should be larger in
TMSCH2CN than in allyltrimethylsilane.
(10) Gulliver, D. J.; Levason, W.; Webster, M. Inorg. Chim. Acta 1981,
52, 153.
(11) Initial product was the corresponding triethoxysilyl ether.
(12) Slow addition time is important for high chemical yield. See
Supporting Information (SI) for details.
(13) General Procedure for Copper Fluoride-Catalyzed Cyano-
methylation by TMSCH2CN (Table 1, Entry 6). To a solution of CuF‚
3PPh3‚2EtOH (9.6 mg, 0.01 mmol) in THF (0.4 mL) were added 2f (58.5
mg, 0.40 mmol) and (EtO)3SiF (89 µL, 0.48 mmol) in an ice bath. To the
mixed solution was added TMSCH2CN (66 µL, 0.48 mmol) slowly over 1
h with a syringe pump. After 6 h, 3HF‚NEt3 (0.3 mL) was added for
desilylation (ca. 1 h).
(14) There are no previous examples of catalytic cyanomethylation of
linear aldehydes, propiophenone, or enones.
(15) Davis, F. A.; Reddy, G. V.; Chen, B.-C.; Kumar, A.; Haque, M. S.
J. Org. Chem. 1995, 60, 6148.
3148
Org. Lett., Vol. 5, No. 17, 2003

Scheme 3. Working Hypothesis of TMSCH2CN Activation by
Fluorosilicate 1 (C-Si Activation) and Its Analogy to
Deprotonation
Table 2. Optimization of Direct Catalytic Cyanomethylation of
Benzaldehyde
entry
phosphine (mol %)
solvent
time
yielda
1
2
3
4
5
6
7
8
9
Ph3P (30)
Bu3P (30)
THF
THF
THF
THF
DMF
tBuOH
CH2Cl2
DMF
DMSO
48
48
48
48
3
3
24
6
27
34
34
17
68
54
3
cHex3P (30)
tBu3P (30)
cHex3P (30)
cHex3P (30)
cHex3P (30)
dppe (15)
95
95
dppe (15)
2
shown in Scheme 3, on the basis of the mechanism
underlying the aldol reaction with ketones.8 The first step
should be ligand redistribution between silicate 1 and
TMSCH2CN to give TMSF and silicate 4.16 The stable
carbon-silicon bond is cleaved in this step. This is possible
only by polarization of the carbon-silicon bond through
coordination of the nitrile to the copper (6). The importance
of the nitrile-copper interaction was suggested by the fact
that the aldol reaction between tert-butyl R-C-trimethylsilyl
acetate and acetophenone did not proceed under the present
reaction conditions. Silicate 4 would exist under equilibrium
with N-copper ketenimide 5, which would be the actual
nucleophile.
a Isolated yield.
a bidentate phosphine ligand (dppe) in DMSO solvent (entry
9), and the product was obtained in 95% yield in 2 h. This
high reactivity should, in part, be due to the unique
combination of the soft metal and hard alkoxide, because
hard metal-containing bases (that generate hard metal al-
dolates during the reaction) such as KOtBu, KHMDS,
NaHMDS, LiHMDS, and La(OiPr)3 (10 mol %) could not
efficiently promote the reaction (0-39% yield).
Substrate generality was investigated under the optimized
reaction conditions (Table 3). High to excellent chemical
The unique carbon-silicon bond activation step requires
a focused discussion (Scheme 3, 6). The high catalyst activity
of 1 stems partly from the combination of a hard nucleophile
(fluorosilicate) and a soft Lewis acid (Cu+). The soft Lewis
acid interacts with the soft nitrile of TMSCH2CN to polarize
the R-carbon-silicon bond. Concomitant nucleophilic attack
of the hard fluorosilicate onto the hard silicon atom of
TMSCH2CN then leads to the facile activation of the
intrinsically stable carbon-silicon bond. If another hard
nucleophile (or Bro¨nsted base)-soft Lewis acid combination
(i.e., CuOtBu17) is used, it might be possible to activate (i.e.,
deprotonate) simple alkylnitriles (Scheme 3, 7). The soft
interaction between copper and the nitrile should polarize
the R-carbon-hydrogen bond of alkylnitriles and thus acidify
the R-proton, while the hard alkoxide should attack the hard
R-proton. This led us to investigate the conceptually more
advanced direct catalytic addition of alkylnitriles.
Table 3. Direct Catalytic Addition of Alkylnitriles
a Isolated yield. b Performed using 5 mol % CuOtBu, 7.5 mol % dppe,
and 5 equiv CH3CN. c Diastereomer ratio is 1.5:1 (syn major).21 d Dia-
stereomer ratio is 1.6:1 (syn major).22
Reaction conditions of the direct catalytic cyanomethyla-
tion were optimized for the acetonitrile (20 equiv) addition
to benzaldehyde at room temperature in the presence of 10
mol % CuOtBu and various phosphine ligands (Table 2).18
The yield was improved using electron-rich phosphine
ligands in polar solvents. The best results were obtained using
yields were obtained from aromatic aldehydes, R,â-unsatur-
ated aldehyde, and aliphatic aldehydes.19 The applicability
to the addition of other alkylnitriles such as propionitrile and
butyronitrile is noteworthy, although the diastereoselectivity
(1.5:1-1.6:1) remains to be optimized.20
(16) Generation of TMSF in this step was confirmed by 1H and 19F NMR.
(17) Alkaline metal free CuOtBu was prepared by adding 1 equiv of
tBuOH to mesitylcopper generated by Saegusa’s method: Tsuda, T.;
Watanabe, K.; Miyata, K.; Yamamoto, H.; Saegusa, T. Inorg. Chem. 1981,
20, 2728. CuOtBu can be stored as a THF solution (0.5 M) at -30 °C in
a freezer under an argon atmosphere for at least two months without any
activity loss.
(18) In the previous study of ketone aldol reaction (ref 8), we noticed
the importance of the phosphine ligand in the catalyst turnover step, in
which a copper aldolate traps the silicon to form the silyl aldolate. This
step might mimic the alkylnitrile deprotonation by the copper aldolate in
the direct catalytic addition.
Org. Lett., Vol. 5, No. 17, 2003
3149

The described reactions could, in principle, be extended
to catalytic enantioselective reactions using chiral diphos-
phines as ligands (Scheme 4). Using the CuF-(S)-tol-BINAP
of aldehydes, and the products were obtained with up to 53%
ee. Although the enantioselectivity is not in a satisfactory
range, these reactions are the first examples of catalytic
enantioselective cyanomethylation of ketones and direct
catalytic enantioselective cyanomethylation of aldehydes.
Specifically, considering the equivalency of the cyano-
methylation products to the aldol products, the latter reaction
would be considered as a direct catalytic enantioselective
aldol reaction using a donor containing the carboxylic acid
oxidation state.24 The donor (acetonitrile), the substrate
(aldehyde), and a catalytic amount of the chiral metal
complex are required, and the overall reaction is a simple
proton transfer from the donor to the acceptor.
Scheme 4. Application to Direct Catalytic Enantioselective
Cyanomethylation of Aldehydes and Catalytic Enantioselective
Cyanomethylation of Ketones
In summary, we have developed a new catalytic cyano-
methylation method that can be applied to a wide range of
ketones and aldehydes using TMSCH2CN as a nucleophile
and CuF‚3PPh3‚2EtOH as a catalyst in the presence of
(EtO)3SiF. Moreover, we achieved an efficient direct catalytic
addition of alkylnitriles to aldehydes using CuOtBu-dppe
complex as a catalyst. These reactions could be extended to
the first catalytic enantioselective cyanomethylation of
ketones and the direct catalytic enantioselective cyano-
methylation of aldehydes. Improvement of enantioselectivity,
detailed studies on the reaction mechanism, and application
to other donor substrates are currently ongoing.
Acknowledgment. This work was supported by RFTF
of Japan Society for the Promotion of Science and PRESTO
of Japan Science and Technology Corporation (JST). We
thank Dr. Takao Saito at Takasago International Corporation
for kindly supplying several chiral phosphine ligands. We
also thank Reiko Wada and Kounosuke Oisaki for helpful
discussions.
complex (2.5 mol %) led to the addition of TMSCH2CN to
2a at -30 °C in THF, and 3a was obtained in 49% ee. Using
the CuOtBu-(R)-DTBM-SEGPHOS23 complex (10 mol %)
led to the direct catalytic enantioselective cyanomethylation
(19) General Procedure for CuOtBu-Catalyzed Direct Cyanomethy-
lation of Aldehyde (Table 3, Entry 6). CuOtBu (0.03 mmol, 60µL in THF)
and dppe (18 mg, 0.045 mmol) were mixed and dried under vacuum for 1
h. To the residue were added DMSO (0.3 mL), propionitrile (0.3 mL), and
2h (30 µL, 0.3 mmol) to start the reaction.
Supporting Information Available: Experimental details
and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(20) Catalytic addition of alkylnitriles other than acetonitrile is novel.
The reaction with ketones has not yet been achieved.
OL035206U
(21) Canceill, J.; Jacques, J. Bull. Soc. Chim. Fr. 1970, 2180.
(22) Gotor, V.; Dehli, J. R.; Rebolledo, F. J. Chem. Soc., Perkin Trans.
1 2000, 307.
(23) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura,
T.; Kumobayashi, H. AdV. Synth. Catal. 2001, 343, 264.
(24) For recent advances, see: (a) Evans, D. A.; Tedrow, J. S.; Shaw, J.
T.; Downey, C. W. J. Am. Chem. Soc. 2001, 124, 392. (b) Evans, D. A.;
Downey, C. W.; Shaw, J. T.; Tedrow, J. S. Org. Lett. 2002, 4, 1127. (c)
Evans, D. A.; Downey, C. W.; Hubbs, J. L. J. Am. Chem. Soc. 2003, 125,
8706.
3150
Org. Lett., Vol. 5, No. 17, 2003