Copper/palladium-catalyzed 1,4 reduction and asymmetric allylic alkylation of α,β-unsaturated ketones: Enantioselective dual catalysis

Article abstract of DOI:10.1002/anie.201208612

Cooperative efforts: The catalytic coupling of the two organometallic intermediates is possible through a Cu/Pd-based dual catalysis (see scheme; LG=leaving group), in which the Cu^I catalytic cycle generates catalytically the starting material

Full text of DOI:10.1002/anie.201208612

.
Angewandte
Communications
DOI: 10.1002/anie.201208612
Dual Catalysis
Copper/Palladium-Catalyzed 1,4 Reduction and Asymmetric Allylic
Alkylation of a,b-Unsaturated Ketones: Enantioselective Dual
Catalysis**
Fady Nahra, Yohan Macꢀ, Dominique Lambin, and Olivier Riant*
The development of new catalytic methods has been an area
of intense research in recent years. It is becoming more and
more vital to develop new concepts in catalysis that enable
easy and reproducible access to products that are difficult to
obtain otherwise. One of the ideas that have emerged most
recently is the combination of two or more different catalysts
in a single vessel to promote domino reactions.[1]
In most domino reactions, a single catalyst is used to
promote two or more reactions in a specific order.[2] The
significant drawback of this approach is the limited number of
reaction types that a particular catalyst can promote. By
combining two catalysts, the range of transformations that
could be achieved is thus expanded.[3] Different types of dual
catalysis have been reported recently, such as organocatalysis/
metallocatalysis,[4] biocatalysis/metallocatalysis,[5] and metal-
locatalysis/metallocatalysis.[6] In the majority of examples in
which two metal-based catalysts are used, the first metal
generates the active species, which then undergoes the
reaction and affords the desired product, whereas the
second metal is present either to regenerate the active species
of the first metal or for transmetalation, as is the case in the
palladium(0) and copper(I) is well documented, and the
compatibility and selectivity of these two metals have been
repeatedly proven in two famous examples: the Wacker–
Tsuji[8] process and the Sonagashira coupling.[9]
Our group has a long history of developing copper(I)
complexes and using them in domino reactions.[10] Our goal
was to combine our experience in copper(I) catalysis and
domino reactions with the palladium(0)-catalyzed asymmet-
ric allylic alkylation.[11] To this end, we chose the copper(I)-
catalyzed 1,4 reduction of a,b-unsaturated ketones and
a robust and easy-to-handle copper(I) catalyst with an N-
heterocyclic carbene (NHC) ligand.[10 g] Several processes
have been developed to access a-allylated ketones,[11a,12] this
study however offers a new approach starting from easily
available a,b-unsaturated ketones (Scheme 1).
À
majority of C C couplings.
The most interesting type of metal/metal catalysis is the
cooperative dual catalysis.[6g,7] In this approach, the two
catalysts separately and selectively activate two different
substrates, thus catalytically generating two active intermedi-
ates that can subsequently react with each other to form the
desired product. The formation of the final product is
generally combined with the simultaneous regeneration of
the catalysts. This type of dual catalysis is still underdevel-
oped, and only a few examples have been reported.[7] Another
contributing factor is the possible reaction of intermediates
with reagents that are present in stoichiometric amounts, thus
resulting in side reactions and undesired products, and
rendering the reaction very difficult to control.
Scheme 1. Different routes to access a-allylated ketones.[11a,12]
Herein, we report a cooperative dual catalysis based on
a palladium(0)/copper(I) system. Cooperative catalysis of
We chose commercially available d-(+)-carvone as
a model substrate for our initial optimization reactions, thus
allowing the formation of products that contain a quaternary
center. Stereoselective access to these centers remains an
important challenge in organic synthesis.[13] At first, the two
reactions were conducted separately in order to determine
the most compatible conditions. The first reaction is a 1,4
reduction of carvone by a preformed copper(I) hydride[14] to
generate the silyl enolate in situ. This intermediate was then
engaged, without further purification, in the palladium(0)-
catalyzed asymmetric allylic alkylation reaction. Preliminary
reactions were successful and allowed us to determine two
compatible systems (Scheme 2).
[*] F. Nahra, Dr. Y. Macꢀ, Dr. D. Lambin, Prof. O. Riant
Institute of Condensed Matter and Nanosciences, Molecules, Solids
and Reactivity (IMCN/MOST)—Universitꢀ Catholique de Louvain
Place Louis Pasteur 1, bte L4.01.03, 1348 Louvain-la-Neuve
(Belgium)
E-mail: olivier.riant@uclouvain.be
[**] Financial support from the Universitꢀ Catholique de Louvain, FNRS,
and Rꢀgion Bruxelloise is gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201208612.
3208
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 3208 –3212

Angewandte
Chemie
Optimization of the reaction with regard
to the solvent showed that both toluene and
THF resulted in complete conversion of the
starting material (Table 2, entries 1 and 2).
However, the formation of 3 could be
almost completely suppressed when THF
was used, and it was thus chosen as the
optimal solvent. When the reaction was
carried out at room temperature, formation
of the O-alkylation product (2) was favored
(80% yield), however, when the reaction
was carried out at a higher temperature, the
desired C-alkylation product (1) became the
only alkylated product (79% yield; Table 2,
entry 7). In this latter case, no O-alkylation
was observed. It should be noted that when
the same experiment was stopped after
three hours, a mixture of 1/2 in a ratio of
Scheme 2. Preliminary results. TBAT=tetrabutylammonium difluorotriphenylsilicate.
With these two systems at hand, the dual catalysis was
investigated. Initial investigations allowed the observation of
three products, the desired C-alkylation product 1, the O-
alkylation product 2, and the reduction product 3 (Table 1).
Different palladium sources led to significant variations of the
ratio of the three products. The combination of Pd(OAc)2 and
38:43 was obtained (Table 2, entry 8), indicating that under
these conditions, 2 is formed initially and then transformed
into 1 by a Claisen rearrangement, which is probably also
catalyzed by palladium.[15a]
Furthermore, substitution of dppe with (S)-Ph-PHOX,
a chiral P–N type ligand that is widely used in the Pd0-
catalyzed asymmetric allylic alkyla-
tion reaction,[16] increased the dia-
stereoselectivity of 1 up to 90% de
Table 1: Preliminary optimization of the dual catalysis.
along with a slight increase in the
overall yield (82%; Scheme 3).[15b]
After these satisfying results, we
concentrated our efforts on devel-
oping an enantioselective version of
Entry
“Pd complex”
[Pd(PPh3)4] (5 mol%)
1[a] [%]
d.r.[b]
2[a] [%]
3[a] [%]
this reaction, starting with the pro-
chiral substrate 4a (Scheme 4).
Some modifications of the previous
conditions were necessary to obtain
5a with a high yield and high
enantioselectivity. In this case, tol-
uene was the better solvent. We also
found it crucial to use KOtBu as an
additive in order to increase the
enantioselectivity.[17] Under these
conditions, an interesting side prod-
uct was observed; the DBM ligand
1
2
3
4
29
44
31
20
0
69/31
69/31
73/27
67/33
–
0
70
17
21
29
33
44
16
[Pd(PPh3)4] (1 mol%)
[Pd2(dba)3] (0.5 mol%)
Pd(OAc)2 (1 mol%)
Pd(OAc)2 (5 mol%)
Pd(OAc)2 (2 mol%)
Pd(OAc)2 (5 mol%)
12
30
51
0
47
0
dppe (2.5 mol%)
dppe (2.5 mol%)
dppe (12.5 mol%)
dppe (5 mol%)
5
6
9
0
56/44
–
7[c]
dppe (12.5 mol%)
1
1
[a] Yields determined by H NMR spectroscopy. [b] Diastereomeric ratio determined by H NMR
spectroscopy. [c] 1 mol% of [(IMes)Cu(DBM)] was used.
dppe acted as the best catalyst in terms of overall conversion
and yield of combined alkylated products 1 and 2 (Table 1,
entry 4). Although [Pd(PPh3)4] gives the best yield of C-
alkylated product 1, a lower overall conversion was observed
(Table 1, entry 2). Nevertheless, a higher palladium loading
results in lower yields of 1, thus suggesting that tuning the Cu/
Pd ratio could be essential to the minimization of secondary
reactions (compare entries 1 and 2). No significant changes in
diastereoselectivity of 1 were observed.
of the copper complex reacted with the p-allyl–Pd species to
form the diallylated DBM.[18] To avoid this reaction,
[(IMes)Cu(DBM)] was substituted by [(IMes)CuCl]. Final
optimization of the phosphine ligand showed that (S)-tBu-
PHOX significantly increases the enantioselectivity of the
reaction, giving 5a in 83% yield and with 87% ee.
As predicted, the Cu/Pd ratio had a significant effect on
the yield of alkylated products. A 5:1:2.5 ratio of Cu/Pd/dppe
is necessary to obtain a maximum combined yield of 1 and 2
(Table 1, entry 4). We suspect that higher Pd loadings
accelerate the consumption of the allylcarbonate in secondary
reactions.
Scheme 3. Optimized conditions for 1.
Angew. Chem. Int. Ed. 2013, 52, 3208 –3212
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 3209

.
Angewandte
Communications
Table 2: Variation of the solvent and temperature.
Table 3: Preliminary scope of the dual catalysis.
Entry
Solvent
T [8C]
1[a] [%]
d.r.[b]
2[a] [%]
3[a] [%]
Entry
1
Product[a]
Yield[b] [%]
83 (58[d])
ee[c] [%]
1
2
3
4
5
6
toluene
THF
CH2Cl2
CH3CN
THF
THF
THF
THF
RT
RT
RT
RT
0
10
45
45
20
12
trace
–
3
8
67/33
61/39
51
80
–
–
6
23
0
43
29
8
12
11
91
69
21
19
5a
5b
5c
5d
87
n.d.
61/39
67/33
60/30
2
3
4
79 (63[d])
84
86
72
7
79
38
8[c]
[a] Yields determined by 1H NMR spectroscopy. [b] Diastereomeric ratios
determined by 1H NMR spectroscopy. [c] Reaction ran for 3 h. n.d.=not
determined.
78
72
5
6
5e
5 f
40
54
77
75
7
8
5g
5h
64
43
23
75[d]
[a] Starting material prepared according to reported procedures (see the
Supporting Information). [b] Yields determined by GC analysis and
1H NMR spectroscopy. [c] Determined by GC or HPLC analysis on
a chiral stationary phase. [d] Isolated yields.
and that the active species formed in the first cycle reacts with
the one formed in the second cycle (Scheme 5). CuI hydride,
which is preformed in situ, reacts with A to form the copper
enolate species B, which is in equilibrium with the silyl
enolate C.[10g] At the same time, the Pd0 complex adds to the
methyl allylcarbonate to form the p-allyl–Pd species.
Although silyl enolates are well-known nucleophiles for the
allylic alkylation reaction,[12m,n] this particular silyl enolate
does not react with the p-allyl–Pd moiety, under these
conditions, in the absence of the copper catalyst.[19] Hydrolysis
of C leads to the reduction product E. These observations led
us to believe that copper enolate B is in fact the active species.
It reacts with the p-allyl–Pd complex to form the desired
product D and the O-alkylation product F and regenerate the
two active metal species. This last step seems to be energy
dependent (Table 2), thus giving rise to a possible independ-
ent third catalytic cycle at higher temperatures. In this third
catalytic cycle, F is transformed into D through Claisen
rearrangement.[15b] A full investigation of the reaction mech-
anism is still ongoing, and a detailed analysis will be reported
in due course.
Scheme 4. Effect of the ligand on the enantiomeric excess of 5a.
[a] [(IMes)CuCl] was used instead of [(IMes)Cu(DBM)] and 2.0 equiv
of methyl allyl carbonate.
The optimal conditions thus obtained were then applied to
other cyclic enones (Table 3). The reaction showed a tolerance
toward alkyl and benzyl groups, and the corresponding
products were obtained with comparable yields and enantio-
selectivities (Table 3, entries 1–7). The phenyl group is also
tolerated under these conditions, and 5h was obtained in
a good yield, but unfortunately with low enantioselectivity
(Table 3, entry 8). Furthermore, Michael acceptors with 6-
membered rings (Table 3, entries 1–4, 7 and 8) as well as 5-
membered rings (entries 5 and 6) undergo the reaction using
our optimized conditions.
The optimization reactions described above gave us
valuable information on the mechanism of the reaction. It
appears that the two catalytic cycles are intrinsically linked,
3210
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 3208 –3212

Angewandte
Chemie
[4] a) Y. J. Park, J.-W. Park, C.-H. Jun, Acc. Chem. Res. 2008, 41,
222 – 234; b) Z. Shao, H. Zhang, Chem. Soc. Rev. 2009, 38, 2745 –
2755; c) M. Rueping, R. M. Koenigs, I. Atodiresei, Chem. Eur. J.
2010, 16, 9350 – 9365; d) D. DiRocco, T. Rovis, J. Am. Chem. Soc.
2012, 134, 8094 – 8097; e) Z. Chai, T. Rainey, J. Am. Chem. Soc.
2012, 134, 3615 – 3618; f) Y. Ye, M. Sanford, J. Am. Chem. Soc.
2012, 134, 9034 – 9037.
[5] a) O. Pꢁmies, J.-E. Baeckvall, Chem. Rev. 2003, 103, 3247 – 3261;
b) C. Zhong, X. Shi, Eur. J. Org. Chem. 2010, 2999 – 3025; c) J. H.
Lee, K. Han, M.-J. Kim, J. Park, Eur. J. Org. Chem. 2010, 999 –
1015; d) B. L. Conley, M. K. Pennington-Boggio, E. Boz, T. J.
Williams, Chem. Rev. 2010, 110, 2294 – 2312; e) A. C. Marr, S.
Liu, Trends Biotechnol. 2011, 29, 199 – 204.
[6] a) J. Cossy, F. Bargiggia, S. BouzBouz, Org. Lett. 2003, 5, 459 –
462; b) Y. Nishibayashi, M. Yoshikawa, Y. Inada, M. Hidai, S.
Uemura, J. Am. Chem. Soc. 2004, 126, 16066 – 16072; c) A. S.
Goldman, A. H. Roy, Z. Huang, R. Ahuja, W. Schinski, M.
Brookhart, Science 2006, 312, 257 – 261; d) T. A. Cernak, T. H.
Lambert, J. Am. Chem. Soc. 2009, 131, 3124 – 3125; e) K.
Takahashi, M. Yamashita, T. Ichihara, K. Nakano, K. Nozaki,
Angew. Chem. 2010, 122, 4590 – 4592; Angew. Chem. Int. Ed.
2010, 49, 4488 – 4490; f) M. Kuriyama, T. Takeichi, M. Ito, N.
Yamasaki, R. Yamamura, Y. Demizu, O. Onomura, Chem. Eur.
J. 2012, 18, 2477 – 2480; g) K. Motoyama, M. Ikeda, Y. Miyake,
Y. Nishibayashi, Organometallics 2012, 31, 3426 – 3430; h) E.
Skucas, D. Macmillan, J. Am. Chem. Soc. 2012, 134, 9090 – 9093;
i) J. Park, S. Hong, Chem. Soc. Rev. 2012, 41, 6931 – 6943.
[7] a) M. Sawamura, M. Sudoh, Y. Ito, J. Am. Chem. Soc. 1996, 118,
3309 – 3310; b) B. Trost, X. Luan, J. Am. Chem. Soc. 2011, 133,
1706 – 1709; c) B. Trost, X. Luan, Y. Miller, J. Am. Chem. Soc.
2011, 133, 12824 – 12833; d) J. Panteleev, L. Zhang, M. Lautens,
Angew. Chem. 2011, 123, 9255 – 9258; Angew. Chem. Int. Ed.
2011, 50, 9089 – 9092; e) E. Shirakawa, D. Ikeda, S. Masui, M.
Yoshida, T. Hayashi, J. Am. Chem. Soc. 2012, 134, 272 – 279; f) Z.
Gu, A. T. Herrmann, A. Zakarian, Angew. Chem. 2011, 123,
7274 – 7277; Angew. Chem. Int. Ed. 2011, 50, 7136 – 7139.
[8] J. Keith, P. Henry, Angew. Chem. 2009, 121, 9200 – 9212; Angew.
Chem. Int. Ed. 2009, 48, 9038 – 9049, and references there.
[9] a) K. Sonogashira in Metal-Catalyzed Reactions (Eds.: F. Die-
derich, P. J. Stang), Wiley-VCH, New York, 1998, pp. 203 – 229;
b) K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem. 2005,
117, 4516 – 4563; Angew. Chem. Int. Ed. 2005, 44, 4442 – 4489;
c) R. Chinchilla, C. Nꢂjera, Chem. Rev. 2007, 107, 874 – 922;
d) H. Doucet, J.-C. Hierso, Angew. Chem. 2007, 119, 850 – 888;
Angew. Chem. Int. Ed. 2007, 46, 834 – 871.
[10] a) J. Deschamp, T. Hermant, O. Riant, Tetrahedron 2012, 68,
3457 – 3467; b) A. Welle, V. Cirriez, O. Riant, Tetrahedron 2012,
68, 3435 – 3443; c) A. Welle, J. Petrignet, B. Tinant, J. Wouters, O.
Riant, Chem. Eur. J. 2010, 16, 10980 – 10983; d) J. Deschamp, O.
Riant, Org. Lett. 2009, 11, 1217 – 1220; e) J. Deschamp, O.
Chuzel, J. Hannedouche, O. Riant, Angew. Chem. 2006, 118,
1314 – 1319; Angew. Chem. Int. Ed. 2006, 45, 1292 – 1297; f) O.
Chuzel, J. Deschamp, C. Chausteur, O. Riant, Org. Lett. 2006, 8,
5943 – 5946; g) A. Welle, S. Diez-Gonzalez, B. Tinant, S. P.
Nolan, O. Riant, Org. Lett. 2006, 8, 6059 – 6062.
[11] a) B. Trost, G. Schroeder, Chem. Eur. J. 2005, 11, 174 – 184;
b) B. M. Trost, Chem. Pharm. Bull. 2002, 50, 1 – 14; c) B. M.
Trost, D. L. Van Vranken, Chem. Rev. 1996, 96, 395 – 422;
d) B. M. Trost, Acc. Chem. Res. 1996, 29, 355 – 364; e) D. C.
Behenna, Y. Liu, T. Yurino, J. Kim, D. E. White, S. C. Virgil,
B. M. Stoltz, Nat. Chem. 2012, 4, 130 – 133.
Scheme 5. Proposed mechanism of the dual catalysis.
Cooperative dual catalysis in domino processes is emerg-
ing as an important approach for the development of more
time-efficient and less wasteful synthetic pathways.[7] In
conclusion, we herein report a Cu/Pd dual catalysis reaction
based on the catalytic coupling of the two organometallic
intermediates. Thus, the CuI catalytic cycle generates the
starting material for the Pd0 catalytic cycle. Although the
reagents are present in stoichiometric amounts in the reaction
mixture and are in principal able to trap both active species
(four different possible pathways), the reaction proceeds as
desired.
Received: October 26, 2012
Revised: December 19, 2012
Published online: February 4, 2013
Keywords: asymmetric allylic alkylation · copper · dual catalysis ·
.
Michael acceptors · palladium
[1] a) For a review on cooperative multicatalyst systems for one-pot
organic transformations, see: J. M. Lee, Y. Na, H. Han, S. Chang,
Chem. Soc. Rev. 2004, 33, 302 – 312; b) for a review on current
tandem catalysis, see: J.-C. Wasilke, S. J. Obrey, R. T. Baker,
G. C. Bazan, Chem. Rev. 2005, 105, 1001 – 1020.
[2] a) A. Bruggink, R. Schoevaart, T. Kieboom, Org. Process Res.
Dev. 2003, 7, 622 – 640; b) L. M. Ambrosini, T. H. Lambert,
ChemCatChem 2010, 2, 1373 – 1380; c) D. B. Ramachary, S. Jain,
Org. Biomol. Chem. 2011, 9, 1277 – 1300.
[3] a) S. Kamijo, Y. Yamamoto in Multimetallic Catalysis in Organic
Synthesis (Eds.: M. Shibasaki, Y. Yamamoto), Wiley-VCH,
Weinheim, 2004, pp. 1 – 52; b) M. H. Pꢀrez-Temprano, J.
Casares, P. Espinet, Chem. Eur. J. 2012, 18, 1864 – 1884; c) J. J.
Hirner, Y. Shi, S. A. Blum, Acc. Chem. Res. 2011, 44, 603 – 613.
[12] a) X. Zhao, D. Liu, H. Guo, Y. Liu, W. Zhang, J. Am. Chem. Soc.
2011, 133, 19354 – 19357; b) J. Weaver, A. Recio, A. Grenning, J.
Tunge, Chem. Rev. 2011, 111, 1846 – 1913; c) B. Trost, J. Xu, T.
Schmidt, J. Am. Chem. Soc. 2009, 131, 18343 – 18357; d) B. Trost,
B. Schꢃffner, M. Osipov, D. A. Wilton, Angew. Chem. 2011, 123,
3610 – 3613; Angew. Chem. Int. Ed. 2011, 50, 3548 – 3551; e) A.
Angew. Chem. Int. Ed. 2013, 52, 3208 –3212
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3211

.
Angewandte
Communications
Doyle, E. Jacobsen, J. Am. Chem. Soc. 2005, 127, 62 – 63; f) E.
Bꢀlanger, K. Cantin, O. Messe, M. Tremblay, J.-F. Paquin, J. Am.
Chem. Soc. 2007, 129, 1034 – 1035; g) D. C. Behenna, B. M.
Stoltz, J. Am. Chem. Soc. 2004, 126, 15044 – 15045; h) D. C.
Behenna, B. M. Stoltz, J. T. Mohr, A. M. Harned, US Patent,
0,084,820, 2006; i) A. Y. Hong, M. R. Krout, T. Jensen, N. B.
Bennett, A. M. Harned, B. M. Stoltz, Angew. Chem. 2011, 123,
2808 – 2812; Angew. Chem. Int. Ed. 2011, 50, 2756 – 2760; j) H.
Mukherjee, N. T. McDougal, S. C. Virgil, B. M. Stoltz, Org. Lett.
2011, 13, 825 – 827; k) N. B. Bennett, A. Y. Hong, A. M. Harned,
B. M. Stoltz, Org. Biomol. Chem. 2012, 10, 56 – 59; l) B. Stoltz,
et al., Chem. Eur. J. 2011, 17, 14199 – 14223; m) J. Tsuji, I.
Minami, I. Shimizu, Chem. Lett. 1983, 1325 – 1326; n) J. Tsuji, I.
Minami, I. Shimizu, H. Kataoka, Chem. Lett. 1984, 1133 – 1136.
[13] a) M. Shimizu, Angew. Chem. 2011, 123, 6122 – 6124; Angew.
Chem. Int. Ed. 2011, 50, 5998 – 6000; b) B. M. Wang, Y. Q. Tu,
Acc. Chem. Res. 2011, 44, 1207 – 1222; c) J. Christoffers, A. Baro,
Quaternary Stereocenters-Challenges and Solutions for Organic
Synthesis, Wiley-VCH, Weinheim, 2005.
[14] N. P. Mankad, D. S. Laitar, J. P. Sadighi, Organometallics 2004,
23, 3369 – 3371.
[15] a) J. L. van der Baan, F. Bieckehaupt, Tetrahedron 1986, 27,
6267 – 6270; b) No transformation from 2 to 3 was observed with
the (S)-Ph-PHOX ligand (see the Supporting Information for
details).
[16] a) P. von Matt, A. Pfaltz, Angew. Chem. 1993, 105, 614 – 615;
Angew. Chem. Int. Ed. Engl. 1993, 32, 566 – 568; b) K. Tani, D. C.
Behenna, R. M. McFadden, B. M. Stoltz, Org. Lett. 2007, 9,
2529 – 2531.
[17] Investigations into the role of KOtBu are ongoing.
[18] See the Supporting Information (page S-12).
[19] See the Supporting Information (page S-13).
3212
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 3208 –3212