A three-component tandem reductive aldol reaction catalyzed by N-heterocyclic carbene-copper complexes

Article abstract of DOI:10.1021/ol062495o

(Chemical Equation Presented) An efficient catalytic system for the three-component coupling of electrophilic alkenes, aldehydes, and silane was optimized with a new family of copper N-heterocyclic carbene complexes. These catalysts do not require activat

Full text of DOI:10.1021/ol062495o

ORGANIC
LETTERS
2006
Vol. 8, No. 26
6059-6062
A Three-Component Tandem Reductive
Aldol Reaction Catalyzed by
N-Heterocyclic Carbene−Copper
Complexes
Alexandre Welle,† Silvia D´ıez-Gonza´lez,‡ Bernard Tinant,§ Steven P. Nolan,*,‡ and
Olivier Riant*,†
Unite´ de Chimie Organique et Me´dicinale and Unite´ de Chimie Structurale et des
Me´canismes Re´actionnels, Place Louis Pasteur 1, UniVersite´ catholique de LouVain,
1348 LouVain la NeuVe, Belgium, and Institute of Chemical Research of Catalonia
(ICIQ), AV. Pa¨ısos Catalans 16, 43007 Tarragona, Spain
riant@chim.ucl.ac.be; snolan@iciq.es
Received October 10, 2006
ABSTRACT
An efficient catalytic system for the three-component coupling of electrophilic alkenes, aldehydes, and silane was optimized with a new family
-
of copper N-heterocyclic carbene complexes. These catalysts do not require activation and show high activity (TOF > 15 000 h 1) as well as
some anti diastereoselectivity.
Since the first example of an N-heterocyclic carbene (NHC)
copper(I) complex was reported less than 15 years ago by
Arduengo,1 the use of these complexes in catalysis has been
developed thanks to their easy synthesis and stability. They
have exhibited excellent reactivity in a wide range of
transformations.2 Notably, (NHC)copper-halogen complexes
have been shown to be effective precursors of copper hydride
species3 which can be used in useful reduction processes such
as in the hydrosilylation of carbonyl compounds4 and
electrophilic double bonds,5 Copper(I) hydride complexes
have been recently used in intramolecular tandem reduction-
aldol cyclization with Stryker’s reagent [(PPh3)CuH]6 as the
copper hydride source.6 Riant and Shibasaki reported the first
examples of enantioselective copper hydride-catalyzed domino
reduction-aldol reaction of methyl acrylate with aldehydes
and ketones.7 In these catalytic systems, copper hydride
complexes bearing various chiral diphosphine ligands are
generated and react with the acrylate to generate copper
enolate nucleophiles. After the subsequent reaction of the
(2) Selected examples in catalysis: Allylic alkylation: (a) Tominaga,
S.; Oi, Y.; Kato, T.; Keun, An D.; Okamoto, S. Tetrahedron Lett. 2004,
45, 5585-5588. (b) Larsen, A. O.; Leu, W. L.; Oberhuber, C. N.; Campbell,
J. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 11130-11131.
Asymmetric conjugated addition of organometallics to enones: (c) Guillen,
F.; Winn, C. L.; Alexakis, A. Tetrahedron: Asymmetry 2001, 12, 2083-
2086. (d) Pytkowics, J.; Roland, S.; Mangeney, P. Tetrahedron: Asymmetry
2001, 12, 2087-2089. (e) Alexakis, A.; Winn, C. L.; Guillen, F.; Pytkowicz,
J.; Roland, S.; Mangeney, P. AdV. Synth. Catal. 2003, 345, 345-348. (f)
Lee, K.-S.; Brown, M. K.; Hird, A. W.; Hoveyda, A. H. J. Am. Chem. Soc.
2006, 128, 7182-7183. (g) Martin, D.; Kehrli, S.; d’Augustin, M.; Clavier,
H.; Mauduit, M.; Alexakis, A. J. Am. Chem. Soc. 2006, 128, 8416-8417.
Carbene transfer: (h) Fructos, M. R.; Belderrain, T. R.; Nicasio, M. C.;
Nolan, S. P.; Kaur, H.; Diaz-Requejo, M. M.; Pe´rez, P. J. J. Am. Chem.
Soc. 2004, 126, 10846-10847. Boration of alkenes and aldehydes (i) Laitar,
D. S.; Tsui, E. Y.; Sadighi, J. P. Organometallics 2006, 25, 2405-2408.
(j) Laitar, D. S.; Tsui, E. Y.; Sadighi, J. P. J. Am. Chem. Soc. 2006, 128,
11036-11038.
† Unite´ de Chimie Organique et Me´dicinale, Universite´ catholique de
Louvain.
‡ Institute of Chemical Research of Catalonia.
§ Unite´ de Chimie Structurale et des Me´canismes Re´actionnels, Universite´
catholique de Louvain.
(1) Arduengo, A. J., III; Rasika Dias, H. V.; Calabrese, J. C.; Davidson,
F. Organometallics 1993, 12, 3405-3409.
(3) Mankad, N. P.; Laitar, D. S.; Sadighi, J. P. Organometallics 2004,
23, 3369-3371.
10.1021/ol062495o CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/24/2006

enolate with the electrophile, the copper hydride catalysts
are regenerated by reaction of the copper aldolates with a
hydrosilane. High reactivities could be reached with the
proper choice of diphosphine ligand and we were interested
to investigate the performance of NHC ligands in such
catalytic reactions.
Scheme 1. Synthesis of (NHC)Copper Complexes 1 and 2
As for the (NHC)CuX complexes, their main drawback
is the mandatory use of an activator such as NaO-t-Bu (1-6
equiv per copper atom).4,5 This permits a halide-alkoxide
exchange on the copper atom which in turn can react with
the hydrosilane to generate the copper hydride active species.
To avoid the use of an activator, variation of the co-ligand
on the metal center was envisaged to design a “ready to use”
copper hydride precursor. The choice of the co-ligand was
made on the assumption that a weak Cu-O bond on the
co-ligand should allow direct activation of the complex to
generate the desired copper hydride catalyst. After several
experiments, we found that dibenzoylmethanoate was an
acceptable ligand (DBM) (Scheme 1). Complexes 1 and 2
could be prepared in high yield by simply reacting the
corresponding (NHC)CuX complex with the potassium salt
of DBMH. Alternatively, a two step “one-pot” procedure
was devised by mixing the imidazolium salt, copper(I)
chloride, DBMH, and 2 equiv of KO-t-Bu in dry THF. The
corresponding DBM complexes were isolated as stable
orange crystalline solids after simple filtration crystallization.
All complexes can be prepared on a multigram scale as air
stable solids except the ones bearing unhindered alkyl- or
benzyl-substituted NHC ligands such as 1c and 2b. In the
latter case, rapid decomposition was observed when the
complex was handled in aerobic conditions both in the solid
state and in solution, and therefore, they were kept in a
glovebox. The structure of (IMes)Cu(DBM) complex 1a was
also confirmed by X-ray crystallography (Figure 1).
corresponding Cu-H resonance. Although the resonance for
the corresponding dimer was reported at 2.67 ppm by Sadighi
et al.,3 the presence of the silylated DBM ligand on copper
is presumably responsible for this chemical shift.
Preliminary optimization experiments were carried out on
the reaction of methyl acrylate with cyclohexane carbox-
aldehyde (Table 1) which gave the correponding aldol
adducts after deprotection of the silyl aldolates (NH4F,
MeOH) along with the alcohol 6 arising from the competitive
direct reduction of the aldehyde 3. Various reaction param-
eters were examined such as solvent, temperature, silane,
and the catalyst structure. In all cases, excellent reactivity
was achieved, and we examined the influence of those
parameters on the chemoselectivity and diastereoselectivity
of this reaction. The reaction can be carried out in various
solvents (Et2O, DCM, CH3CN, THF, PhMe) but we found
We were pleased to find that direct activation of the
complex 1b by a hydrosilane afforded the copper hydride
species. This was confirmed by 1H NMR spectra of degassed
solutions of (IPr)Cu(DBM) in anhydrous C6D6 in the
presence of various silanes. In all cases, a sharp singlet
located at 4.46 ppm was observed that was attributed to the
(4) (a) Kaur, H.; Zinn, F. K.; Stevens, E. D.; Nolan, S. P. Organometallics
2004, 23, 1157-1160. (b) D´ıez-Gonza´lez, S.; Kaur, H.; Zinn, F. K.; Stevens,
E. D.; Nolan, S. P. J. Org. Chem. 2005, 70, 4784-4796. (c) Bantu, B.;
Wang, D.; Wurst, K.; Buchmeiser, M. R. Tetrahedron 2005, 61, 12145-
12152. (d) D´ıez-Gonza´lez, S.; Scott, N. M.; Nolan, S. P. Organometallics
2006, 25, 2355-2358.
(5) (a) Jurkauskas, V.; Sadighi, J. P.; Buchwald, S. L. Org. Lett. 2003,
5, 2417-2420. (b) Yun, J.; Kim, D.; Yun, H. J. Chem. Soc., Chem. Commun.
2005, 5181-5183.
(6) For intramolecular reductive aldol reaction with a stoichiometric
amount of Stryker’s reagent, see: (a) Chiu, P.; Chen, B.; Cheng, K. F.
Tetrahedron Lett. 1998, 39, 9229-9232. (b) Chiu, P.; Szeto, C.-P.; Geng,
Z.; Cheng, K.-F. Org. Lett. 2001, 3, 1901-1903. (c) Chiu, P.; Szeto, C. P.;
Geng, Z.; Cheng, K. F. Tetrahedron Lett. 2001, 42, 4091-4093. For
intramolecular reductive aldol reaction with a catalytic amount of Stryker’s
reagent, see: (d) Chiu, P.; Leung, S. K. Chem. Commun. 2004, 2308-
2309. (e) Chiu, P. Synthesis 2004, 2210-2215. For intramolecular reductive
aldol reactions catalyzed by Cu(OAc)2‚H2O, see : (f) Lam, H. W.; Joensuu,
P. M. Org. Lett. 2005, 7, 4225-4228. (g) Lam, H. W.; Murray, G. J.; Firth,
J. D. Org. Lett. 2005, 7, 5743-5746.
Figure 1. Ball-and-stick drawing of 1a. Hydrogen atoms were
omitted for clarity. Selected bond lengths and angles: Cu-C(1),
1.861 Å; Cu-O(1), 1.974 Å; Cu-O(2), 1.986 Å; C(1)-Cu-O(1),
136.0°; C(1)-Cu-O(2), 132.5°; O(1)-Cu-O(2), 91.3°.
(7) (a) Deschamp, J.; Chuzel, O.; Hannedouche, J.; Riant, O. Angew.
Chem., Int. Ed. 2006, 45, 1292-1297. (b) Zhao, D. B.; Oisaki, K.; Kanai,
M.; Shibasaki, M. Tetrahedron Lett. 2006, 47, 1403-1407. (c) Chuzel, O.;
Deschamp, J.; Chausteur, C.; Riant, O. Submitted for publication.
6060
Org. Lett., Vol. 8, No. 26, 2006

Table 1. Optimization Studies on the Reductive Aldol Reactiona
entry
complex
T (°C)
silane
PhSiH3
PhSiH3
PhSiH3
cat. loading (mol %)
chemoselectivityb,c
anti/synb
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
2a
2b
25
25
-20
-50
25
25
25
25
25
25
25
25
25
1
0.1
1
1
1
1
1
1
1
1
1
1
1
82
93
90
88
67
n.r.
93
75
91
90
96
77
84
68/32
69/31
74/26
72/28
73/27
PhSiH3
Ph2SiH2
Me2(EtO)SiH
Me(EtO)2SiH
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
PhSiH3
66/34
73/27
70/30
65/35
73/27
69/31
68/32
a All reactions were carried out at 25 °C under an oxygen-free argon atmosphere containing 3 (1 equiv), 4 (1.1 equiv), the copper catalysts (1 mol %),
and PhSiH3 (1.2 equiv) unless otherwise stated. b Determined by GC analysis after deprotection (NH4F, MeOH) of the silyl ether. c Chemoselectivity )
(5/(5 + 6)100).
that toluene afforded the highest reaction rates. We were very
pleased to see that very high reactivity was indeed reached
with complex 1a, as the reaction was completed in less than
4 min when 0.1 mol % of the catalyst was used, reaching
thus a TOF > 15 000 h-1 (entry 2). It should also be noted
that reaction of (NHC)CuCl in the absence of an activator
does not lead to any activity while the addition of KO-t-Bu
restores the catalytic activity of the carbene complex.
Under these reaction conditions, very little competitive
reduction of the aldehyde occurred and the anti aldol adduct
was always observed as the major isomer. Fast reactions also
occurred at lower temperature (1 h at -50 °C), although
little influence on the anti/syn ratio was observed (entries 3
and 4). The influence of the steric bulk around the copper
atom was also studied with the NHC complexes 1a-e
(entries 1 and 9-11). This catalytic system is quite insensi-
tive as little modification in the anti/syn ratio was observed
when the NHC steric hindrance was modified. Saturated
ligands SIMes and SIBn also gave similar diastereoselec-
tivities, albeit with a slightly reduced chemoselectivity
(entries 12 and 13). The lack of influence of the structure of
the ligand on the diastereoselectivity suggests that the aldol
reaction goes through an open transition state in which the
aldehyde is not coordinated to the copper enolate. This
hypothesis is also supported by the low Lewis acidity of
copper(I) coordinated to a strong σ-donor ligand and by the
important steric congestion around the metal center, although
the hypothesis of a closed chairlike Zimmerman-Traxler
transition state with low E/Z selectivity cannot be completely
excluded.
observed for silanes such as tetramethyldisiloxane (TMDS),
heptamethyltrisiloxane (HMTS), and Me2(EtO)SiH, excellent
reactivity was obtained when more reactive silanes such as
Ph2SiH2 and Me(EtO)2SiH were used (entries 5 and 7).
Methyldiethoxysilane was finally selected for further opti-
mization as it is one of the less expensive silane reagent
available.8 Furthermore, the corresponding aldol adducts are
fairly stable to hydrolysis, which allow the isolation of fully
protected adducts bearing a methyldiethoxysilyl protecting
group on the alkoxy moiety. This optimized procedure using
(IMes)Cu(DMB) 1a (1 mol %) complex as a precatalyst was
then used to analyze the scope of the tandem reaction (Table
2).9 Good yields were obtained with various aliphatic and
aromatic aldehydes, the anti isomer being always the major
product. We were also pleased to see that the catalytic system
was not restricted to the use of aldehydes and acrylate as
Michael acceptors. Indeed, good reactivity was also observed
with methyl crotonate as the enolate precursor, albeit with
reduced chemoselectivity (entry 2). This problem could be
easily overcome by the use of an excess (2 equiv) of the
Michael acceptor. Promising results were also obtained with
ketones as the adduct of methyl acrylate, and acetophenone
10 was obtained in a 78% yield with our catalysts (erythro/
threo 57:43).
We also tested variation of the electron withdrawing
groups on the Michael acceptor and preliminary tests with
(8) Cost: Me(EtO)2SiH, 265 euros/mol; Et3SiH, 180 euros/mol.
(9) Typical Procedure for Tandem Hydrosilylation-Aldolization. A
flame-dried flask under argon was loaded with the (NHC)copper complex
(0.01 mmol, 0.01 equiv) under argon. A 5 mL portion of freshly distilled
toluene was introduced, followed by sequential addition of the electrophilic
olefin (1.1 mmol, 1.1 equiv), the electrophile (1 mmol, 1 equiv), and the
silane (1.2 mmol, 1.2 equiv). After being stirred for 1 h, the solution was
stirred for an additional 1 h under air. The volatile compounds were removed
under reduced pressure, and the residue was purified by chromatography
on triethylamine-pacified silica gel.
All optimization experiments were carried out with a
strongly reactive, albeit expensive silane (PhSiH3). To
develop a practical experimental protocol, we searched for
more economical alternatives. While little or no activity was
Org. Lett., Vol. 8, No. 26, 2006
6061

Table 2. (NHC)Copper-Catalyzed Reductive Aldol Reactiona
entry
electrophile
R′
product
chemoselectivityb,c
anti/synb
yieldd (%)
1
2
3
4
5
6
7
8
9
CyCHO
CyCHO
EtCHO
i-PrCHO
t-BuCHO
PhCHO
2-PyrCHO
2-ThCHO
PhCOCH3
H
9a
9b
9c
9d
9e
9f
9g
9h
10
95
77
93
95
90
97
93
98
>95
70/30
71/29
57/43
67/33
68/32
71/29
73/27
69/31
57/43e
70
75
75
78
80
72
72
72
78
Me
H
H
H
H
H
H
H
a All reactions were carried out in toluene at 25 °C under an oxygen-free argon atmosphere containing 3 (1 equiv), 4 (1.1 equiv), the copper catalysts (1
mol %), and Me(EtO)2SiH (1.2 equiv) unless otherwise stated. b Determined by GC analysis. c Chemoselectivity ) (9/(9 + alcohol)100). d Isolated yield.
e Erythro/threo.
unsaturated ketones, and nitriles also gave the corresponding
adducts with cyclohexane carboxaldehydes in good yields
and promising diastereoselectivities (Scheme 2).
These equivalents of aldols adducts should be particularly
interesting for the preparation of new building blocks such
as γ-amino alcohols.
In conclusion, we have shown that a new family of (NHC)-
copper(I) complexes could efficiently catalyze the three
component reaction of electrophilic double bonds and
aldehydes with dimethylethoxysilane without the need of an
activating agent. We are currently studying the scope of this
catalytic system in view of developing efficient enantio-
selective versions for the construction of useful enantiomeri-
cally enriched building blocks.
Scheme 2. Reductive Aldol Reaction with Various
Electrophilic Alkenes
Acknowledgment. Universite´ catholique de Louvain and
FNRS are gratefully acknowledged for financial support of
this work. Shimadzu Benelux is also gratefully acknowledged
for financial support for the acquisition of a FTIR-8400S
spectrometer. S.P.N. acknowledges the ICIQ Foundation and
ICREA for a Research Professorship. Eli Lilly (assistance
with materials) and Boehringer Ingelheim (unrestricted grant)
are gratefully acknowledged for support of this work.
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The selectivities in favor of the anti adduct were especially
high in the case of crotononitrile with a 92:8 anti/syn ratio.
OL062495O
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Org. Lett., Vol. 8, No. 26, 2006