Copper-Catalyzed Asymmetric Conjugate Addition of Dimethylzinc to Acyl-N-methylimidazole Michael Acceptors: A Powerful Synthetic Platform

Article abstract of DOI:10.1002/anie.201506189

An efficient copper-catalyzed enantioselective conjugate addition of dimethylzinc to α,β- and α,β,γ,δ-unsaturated 2-acyl-N-methylimidazoles has been achieved using a chiral bidentate hydroxyalkyl-NHC ligand. The reactions proceeded with both excellent regio- and enantioselectivity (14 examples, 87-95 % ee) to afford the desired 1,4-adducts, which were easily transformed to the corresponding aldehydes, esters, and ketones. Subsequently, this powerful methodology was therefore successfully applied in the synthesis of natural products. Furthermore, an iterative process was also disclosed leading to highly desirable 1,3-desoxypropionate skeletons (up to 94 % d.e.). The enantioselective conjugate addition of dimethylzinc to (poly)unsaturated 2-acyl-N-methylimidazoles proceeds under Cu catalysis with excellent regio- and enantioselectivities (up to 95 % ee). The resulting 1,4-adducts can be easily transformed to the corresponding aldehydes, esters, ketones, and amines. This methodology was successfully applied in the synthesis of 1,3-desoxypropionate subunits and natural products.

Full text of DOI:10.1002/anie.201506189

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International Edition: DOI: 10.1002/anie.201506189
German Edition: DOI: 10.1002/ange.201506189
Asymmetric Catalysis
Copper-Catalyzed Asymmetric Conjugate Addition of Dimethylzinc to
Acyl-N-methylimidazole Michael Acceptors: a Powerful Synthetic
Platform
Sammy Drissi-Amraoui, Marie S. T. Morin, Christophe CrØvisy, Olivier BaslØ,
Renata Marcia de Figueiredo, Marc Mauduit,* and Jean-Marc Campagne*
Abstract: An efficient copper-catalyzed enantioselective con-
jugate addition of dimethylzinc to a,b- and a,b,g,d-unsaturated
2-acyl-N-methylimidazoles has been achieved using a chiral
bidentate hydroxyalkyl-NHC ligand. The reactions proceeded
with both excellent regio- and enantioselectivity (14 examples,
87–95% ee) to afford the desired 1,4-adducts, which were
easily transformed to the corresponding aldehydes, esters, and
ketones. Subsequently, this powerful methodology was there-
fore successfully applied in the synthesis of natural products.
Furthermore, an iterative process was also disclosed leading to
highly desirable 1,3-desoxypropionate skeletons (up to 94%
d.e.).
the methyl-Grignard nucleophile, allowing notably iterative
ECA processes to form 1,3-desoxypropionate subunits.[7] In
this context, the acylimidazole function, which has the
advantage to be easily transformed into various functional
groups such as aldehydes, ketones, and esters[8] should be
considered as a promising EWG. Nevertheless, despite
numerous successful uses in additions of stabilized nucleo-
philes,[9] to the best of our knowledge the ECA of unstabilized
organometallics with unsaturated 2-acyl-N-methylimidazoles
has been confined to alkylboron compounds.[10] Herein, we
report the first efficient copper-catalyzed enantioselective
conjugate addition of a dialkylzinc reagent to either a,b- or
a,b,g,d-unsaturated 2-acyl-N-methylimidazoles and its appli-
cations in the synthesis of natural molecules or towards
iterative processes leading to 1,3-desoxypropionate units
(Scheme 1).
We started our study by screening various classes of chiral
nonracemic ligands in the conjugate addition of dimethylzinc
to the a,b-unsaturated 2-acyl-N-methylimidazole 1a as model
reaction (for a complete survey, see the Supporting Informa-
tion, SI). Binap-type atropoisomeric ligands were first
evaluated. Initial experiments with Binap[11] highlighted the
potential of Me2Zn in these reactions to achieve good
conversions and 1,4-regioselectivity at room temperature,
albeit with only modest enantioselectivities up to 26%.
Control experiments showed that both ligand and metal are
essential: no conversion could be observed in the absence of
I
n the last two decades, transition-metal-catalyzed enantio-
selective conjugate additions (ECA) of organometallic
reagents to electron-deficient unsaturated systems have
emerged as a versatile and efficient methodology for the
asymmetric formation of C C bonds.[1] Among the myriad of
À
transition metals studied, tremendous attention has been
given to copper catalysis, which resulted in significant break-
throughs,[2] such as perfect regiocontrol in 1,6- or 1,4-addition
with extended Michael acceptors[3] as well as the subsequent
sequential 1,6/1,4 processes.[4] These recent achievements
with a large variety of Michael acceptors and organometallic
reagents allowed for the efficient preparation of numerous
valuable enantioenriched building blocks[1] with remarkable
applications in total synthesis.[5] Nevertheless, the enantiose-
lective transfer of a methyl group to form all-carbon methyl-
substituted chiral scaffolds, which are present in numerous
natural products,[5] remains a challenge.[6] On the other hand,
the electron-withdrawing group (EWG) of Michael acceptors
has to be considered not only as a platform for postfunction-
alization but should also be compatible with the methylated
organometallic reagents and allow its enantioselective addi-
tion. To this end, thioesters have been successfully used with
[*] S. Drissi-Amraoui, Dr. R. Marcia de Figueiredo,
Prof. Dr. J.-M. Campagne
Institut Charles Gerhardt Montpellier, UMR 5253 CNRS-UM-ENSCM
Ecole Nationale SupØrieure de Chimie
8 Rue de l’Ecole Normale, 34296 Montpellier Cedex 5 (France)
E-mail: jean-marc.campagne@enscm.fr
Dr. M. S. T. Morin, Dr. C. CrØvisy, Dr. O. BaslØ, Dr. M. Mauduit
Ecole Nationale SupØrieure de Chimie de Rennes, UMR CNRS 6226
11 AllØe de Beaulieu, CS 50837, 35708 Rennes Cedex 7 (France)
E-mail: marc.mauduit@ensc-rennes.fr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201506189.
Scheme 1. Copper-catalyzed enantioselective conjugate addition of
alkyl-metal hard nucleophiles to (extended) Michael acceptors.
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copper. The use of more reactive organometallic reagents
such as Me3Al or MeMgBr[12] led only to racemic 1,4-product
2a or a mixture of 1,2/1,4 adducts, respectively (see SI). When
other atropoisomeric classical ligands such as tol-binap,[11]
Segphos,[13] difluorphos,[14] and phosphoramidites[15] were
used, unsatisfying enantioselectivities were observed that
did not exceed 70%. Higher selectivity was observed with
Josiphos L1a[16] (87% ee) whereas less than 5% ee was
observed with the structural isomer L1b (Scheme 2; Table 1,
entries 1–3). We next evaluated our home-made hydroxy-
alkyl-NHC ligands L2 and L3[17–19] and the best results were
observed with the last generation L3b (Table 1, entry 6).[2e]
The copper-NHC catalyst prepared in situ by deprotonation
of L3b with n-butyllithium in the presence of copper(II)
triflate (2 mol%) promoted the methyl 1,4-addition effi-
ciently, allowing the formation of 2a with complete regiose-
lectivity, good yield (85%), and excellent 95% ee.
With these optimized reaction conditions in hands, the
reaction with alternative organometallic species was re-
investigated (Table 1, entries 7–10). In the presence of
Scheme 3. Substrate scope for the copper-catalyzed ECA of dimethyl-
zinc with b-substituted a,b-unsaturated 2-acyl-N-methylimidazoles
1 catalyzed by L3b/Cu(OTf)2. [a] The conversion was determined by
1H NMR spectroscopy. [b] Yield of isolated product. [c] Enantiomeric
excesses were determined by HPLC on a chiral stationary phase.
[d] Reaction performed with with Cu(OTf)2 (8 mol%), with the same
ratio of Cu/L3b/nBuLi. [e] Reaction performed with Cu(OTf)2
(4 mol%), with the same ratio of Cu/L3b/nBuLi.
Scheme 2. Selected chiral nonracemic ligands involved in the copper-
catalyzed 1,4-addition of dimethylzinc to a,b-unsaturated 2-acyl-N-
methylimidazoles.
AlMe3 or MeMgBr, low selectivities were observed
(Table 1, entries 7 and 8). Not surprisingly, with diethylzinc
and diphenylzinc reagents (Table 1, entries 9 and 10), despite
a good control of the chemical reactivity and the 1,4-
regioselectivity, low enantioselectivity was observed, further
demonstrating the important role of the ligand in the enantio-
discriminating step.
Table 1: Screening of chiral ligands L1–L3 for copper-catalyzed ECA of
organometallic nucleophiles to a,b-unsaturated 2-acyl-N-methyl-
imidazole 1a.
The scope of the reaction was next investigated on
a collection of differently substituted a,b-unsaturated 2-
acyl-N-methylimidazole derivatives (Scheme 3). Either ali-
phatic or aromatic substituents are well tolerated, though
lower catalytic loadings are usually required for reactions
involving aliphatic substituents (2 and 4 mol% Cu(OTf)2,
respectively). As illustrated with compounds 2b and 2c, the
enantiodiscrimination remains excellent (94% ee) with less
bulky substituents. On the other hand, the use of more bulky
branched alkyl substituents is also efficient as illustrated in
the selective access to compounds 2d and 2e (94% and 91%
ee, respectively).
Entry
L
R-Metal Method T [8C] Conv [%][a] Yield [%][b] ee[c]
1
2
3
4
5
6
7
8
9
10
L1a Me2Zn
L1a Me2Zn
L1b Me2Zn
A
B
B
C
C
C
C
C
C
C
0
99
44
74
64
80
79
85
78
25
84
94
87
85
2
75
85
95
0
4
19
18
rt 99
rt 87
rt 99
rt 99
rt 99
À78 99
À78 99[d]
rt 99
L2
Me2Zn
L3a Me2Zn
L3b Me2Zn
L3b Me3Al
L3b MeMgBr
L3b Et2Zn
L3b Ph2Zn
rt 99
Method A: CuTC (5 mol%), ligand L1(5 mol%), R-M (3 equiv), THF,
À788C, À10, 08C or room temperature, 16 h. Method B: Method A with
Cu(OTf)2 as copper source. Method C: Cu(OTf)2 (2 mol%), ligand L
(3 mol%), nBuLi (8 mol%), R-M (3 equiv), 08C to room temperature,
16 h. [a] Determined by 1H NMR spectroscopy. [b] Yield of isolated
product. [c] Enantiomeric excesses were determined by HPLC on a chiral
stationary phase. [d] A mixture of 32/68 1,4/1,2-adducts was obtained.
CuTC=copper(I)-thiophene-2-carboxylate.
Remarkably, the addition of dimethylzinc to the more
sterically demanding substrate 1 f bearing a tert-butyl group
was also successful affording the 1,4-adduct 2 f with up to
91% ee; however, the yield remained moderate (34%)
despite the use of 8 mol% of the copper catalyst. To the
best of our knowledge this is the first time that a methyl group
is enantioselectively transferred to a b-substituted tert-butyl
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Michael acceptor.[20] This could lead to valuable highly
hindered aliphatic substrates, which are present in many
natural products.[21] It should also be emphasized that these
reactions are carried out under non-cryogenic conditions
(08C to rt) at low catalyst loadings.
derivatives such as aldehyde 4, methyl ester 5, and methyl
ketone 6 with high yielding procedures. It is also noteworthy
that the unprecedented transformation of acylimidazole 2a
into amine 7 could be successfully accomplished in very good
yield (87%).
Differently substituted aromatic derivatives afforded
conjugate addition products with good yields in the presence
of 4 mol% of copper to reach full conversion with high levels
of enantioselectivity (87–91% ee). Using a furan-substituted
substrate did neither affect the yield nor the enantiomeric
excess. Regioselectivity (i.e., 1,6- versus 1,4-addition) on
extended unsaturated systems was next investigated. Gratify-
ingly, highly regioselective (> 96:4) 1,4-addition was observed
on model compound 1k, giving 2k in good yield and with an
enantioselectivity of up to 95%. This 1,4-selectivity is in sharp
contrast to the selectivities usually obtained with extended
conjugated systems.[4b, 12] This highlights the crucial role of the
Having a direct and efficient access to aldehyde 4, the
iterative introduction of a second methyl group was thus
explored (Scheme 5). Indeed unsaturated acyl imidazole 9
was obtained in high yield and E/Z selectivity in two steps
from 4.
As previously observed with citronellal derivatives (see 2l
and 2m, Scheme 3), the iterative introduction of a second
methyl group proved efficient leading to 10 in 69% yield and
94% d.e.
The synthetic potential of this methodology has been
highlighted in two applications (Scheme 6). Firstly, starting
from 1n (obtained in three steps from cyclocitral), the
addition of dimethylzinc enabled the selective formation of
À
N Me imidazole moiety in the addition mechanism. DFT
studies are currently in progress to unveil the role of the
imidazole moiety in the catalytic cycle. Finally, when starting
from the two enantiomers of the unsaturated acyl-imidazole
derived from enantiomerically pure citronellal (see SI for
details), the corresponding 1,3-desoxypropionate units 2l and
2m have been obtained in good yields and excellent
diastereoselectivities.
This diastereoselectivity outcome highlights the promi-
nent role of the catalyst in the double stereodifferentiation
and paves the way for future work on iterative 1,4-addition.
This iterative 1,4-addition will thus require ready access to
a newly created unsaturated acyl-imidazole. The transforma-
tion of acylimidazole 2a was thus explored (Scheme 4). As
previously stated,[8] the acyl-imidazole moiety can be easily
transformed into a wide range of carbonyl and carboxyl
Scheme 5. Enantioselective iterative process for the synthesis of 1,3-
desoxyproprionate units.
Scheme 4. Post-transformation of the acyl-N-methylimidazole 1,4-
adduct 2a into the corresponding enantioenriched aldehyde 4, ester 5,
ketone 6, and amine 7. Reaction conditions: a) 1) NaBH4, MeOH, 2 h,
rt; 2) MeI, EtOAc, 16 h, 608C; 3) NaOH 2 m, glycine, toluene, 5 h,
808C. b) 1) NaBH4, MeOH, 2 h, rt; 2) MeI, EtOAc, 16 h, 608C;
3) NaOH 2 m, BnNH2, toluene, 5 h, 808C; 4) NaBH4, MeOH, 16 h, rt.
c) 1) MeOTf, CH2Cl2, 2 h, rt; 2) DBU, MeOH. d) 1) MeMgCl, THF, 2 h,
rt; 2) MeI, EtOAc, 16 h, 608C; 3) DBU, toluene, 16 h, 808C. DBU=1,8-
Diazabicyclo[5.4.0]undec-7-ene.
Scheme 6. Application in the asymmetric synthesis of ionone deriva-
tive 12 and ar-turmerone 13.
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tog, K. Geurts, A. J. Minnaard, B. L. Feringa, Chem. Rev. 2008,
108, 2824.
2n in good yield, excellent 1,4-selectivity and high enantio-
selectivity (93% ee). A two-step regeneration of the aldehyde
functionality finally furnished 12 (with no erosion of the
enantioselectivity), which is a novel ionone derivative with
a pleasant fruity/floral smell. In a second synthetic applica-
tion, ar-turmerone 13[22] was efficiently synthesized from p-
tolualdehyde in a few steps. The addition of the methyl group
to unsaturated 1o (obtained in two steps from p-tolualde-
hyde) led to 2o in high selectivity and finally the imidazole
moiety was successfully transformed, thus affording (+)-ar-
turmerone 13.[23]
In conclusion, a catalytic system through the combination
of copper/chiral-NHC complex was proposed to mediate
enantioselective conjugate addition of dimethylzinc to unsa-
turated acyl-N-methylimidazole systems, a still underex-
plored class of Michael acceptors to date. The advantages of
using such flexible substrates could be underscored with
1) the synthesis of several 1,4-adducts in high regio- and
enantioselectivities (up to 95% ee), 2) the derivatization into
versatile building blocks such as aldehydes, esters, ketones,
and amines, and 3) the use as key intermediates during the
asymmetric syntheses of both ionone derivative and ar-
turmerone. Besides, the powerful catalytic system proposed
herein, in which the high levels of selectivity might be
correlated with the chirality of the chelating side arm (e.g.,
the amino alcohol side chain) of the NHC ligand used, could
pave the way to an enantioselective iterative process as
illustrated with the synthesis of a 1,3-desoxyproprionate unit.
Currently, further applications of this expedient methodology
on asymmetric transformations are under investigation, and
the results will be reported in due course. DFT studies are
currently underway to determine the role of the N-methyl-
imidazole and ligand moieties in the observed selectivities.
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Acknowledgements
This work was supported by the Agence Nationale de la
Recherche (project SCATE, number ANR-12-B507-0009-01
granted to M.S.T.M. and S.D.A.). R.M.F., M.M., and O.B. also
thank the CNRS. We thank Takasago for a generous gift of
citronellal and V. Vidal for a loan of DIFLUORPHOS.
Keywords: acyl-N-methylimidazoles · asymmetric catalysis ·
N-heterocyclic carbenes · conjugate addition ·
iterative processes
[8] For examples of the transformation of the 2-acylimidazole
moiety to other functional groups such as esters, amides, ketone
derivatives, carboxylic acids, see: a) S. Otha, S. Hayakawa, K.
Nishimura, M. Okamoto, Chem. Pharm. Bull. 1987, 35, 1058;
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[9] a,b-Unsaturated 2-acyl-N-methylimidazoles have been success-
fully used in metal-catalyzed ECA (i.e., Friedel–Crafts alkyla-
tion) involving non-organometallic nucleophiles. With indoles:
a) D. A. Evans, K. R. Fandrick, H.-J. Song, J. Am. Chem. Soc.
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Benedetti, L. Bethge, S. Vonhoff, S. Klussmann, J.-J. Vasseur, J.
Cossy, M. Smietana, S. Arseniyadis, Angew. Chem. Int. Ed. 2013,
[1] For recent books and review in asymmetric conjugate addition,
see: a) M. Mauduit, O. BaslØ, H. Clavier, C. CrØvisy, A.
Denicourt-Nowicki in Comprehensive Organic Synthesis II,
Vol. 4 (Eds.: P. Knochel, G. A. Molander), Elsevier, Amsterdam,
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A. Alexakis, N. Krause, S. Woodward), Wiley, Hoboken, 2014;
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52, 11546; Angew. Chem. 2013, 125, 11760; With malonitriles:
f) C. Wang, L.-A. Chen, H. Huo, X. Shen, K. Harms, L. Gong, E.
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[19] For the NHC precursor 8, see: a) H. Clavier, L. Coutable, J.-C.
Guillemin, M. Mauduit, Tetrahedron: Asymmetry 2005, 16, 921;
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Labat, L. Toupet, C. CrØvisy, M. Mauduit, Eur. J. Inorg. Chem.
2009, 1989; For L3a,b, see ref. [2e].
[20] The copper-catalyzed addition of diethylzinc has been reported
on the b-substituted tert-butyl a-phenylenone with 74% ee and
5% yield, see: Y. Takahashi, Y. Yamamoto, K. Katagari, H.
Danjo, K. Yamaguchi, T. Imamoto, J. Org. Chem. 2005, 70, 9009.
[21] The conjugate addition of Me2CuLi to the bridgehead-norcam-
phor b-substituted enone 14 was used as key step in the total
racemic synthesis of sesquiterperne (Æ)-zizaene, see: R. M.
Coates, R. L. Sowerby, J. Am. Chem. Soc. 1972, 94, 5386.
[10] M. Yoshida, H. Ohmiya, M. Sawamura, J. Am. Chem. Soc. 2012,
134, 11896.
[11] For previous use of BINAP and tol-BINAP in Cu-ECA, see for
instance: a) T. den Hartog, A. Rudolph, B. Macia, A. J. Min-
naard, B. L. Feringa, J. Am. Chem. Soc. 2010, 132, 14349; b) L.
Grimaud, A. Alexakis, Angew. Chem. Int. Ed. 2012, 51, 794;
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BaslØ, C. CrØvisy, V. Ratovelomanana-Vidal, M. Mauduit,
Synthesis, 2015, DOI: 10.1055/s-0034-1378813.
[12] During a seminal study dealing with the Cu-ECA of Grignard
reagents to extended Michael acceptors, the acyl-N-methylimid-
azole function has been considered with BnCH2MgBr leading to
the 1,4-adduct in low yield (34%) and negligible enantioselec-
tivity (2%): T. den Hartog, Y. Huang, M. Fananas-Mastral, A.
Meuwese, A. Rudolph, M. Perez, A. J. Minnaard, B. L. Feringa,
ACS Catal. 2015, 5, 560.
[13] For previous use of SEGPHOS in ECA, see for instance: G.
Chen, N. Tokunaga, T. Hayashi, Org. Lett. 2005, 7, 2285.
[14] For previous use of DIFLUORPHOS in Cu-ECA, see
Ref. [11c].
[15] For phosphoramidite-type ligands in Cu-ECA, see: J. F. Teichert,
B. L. Feringa, Angew. Chem. Int. Ed. 2010, 49, 2486; Angew.
Chem. 2010, 122, 2538.
[22] a) C. Fuganti, S. Serra, A. Dulio, J. Chem. Soc. Perkin Trans.
1
1999, 279. The (S)-(+)-ar-turmerone has been recently
synthetized through the ECA of trimethylaluminum to N-
[16] For ferrocenyl-type ligands in Cu-ECA, see for instance: B. L.
Feringa, R. Badorrey, D. Pena, S. R. Harutyunyan, A. J.
Minnaard, Proc. Natl. Acad. Sci. USA 2004, 101, 5834.
[17] For a recent review and book on NHC-TM and applications in
catalysis, see: a) S. Díez-Gonzµlez, N-Heterocyclic Carbenes,
RSC Catalysis series, RSC Publishing, Cambridge, 2011; b) S.
Díez-Gonzµlez, N. Marion, S. P. Nolan, Chem. Rev. 2009, 109,
3612.
acylpyrrole derivatives: Ref. [6b].
[23] The enantiomeric excess of (+)-ar-turmerone has been deter-
20
D
mined by chiral HPLC and rotation (½aŠ ¼ + 52.4) is in good
20
D
agreement with previously reported data ½aŠ ¼ + 50.6
(Ref.[6b]).
[18] For a review dealing with chiral hydroxyalkyl-NHCs in Cu-ECA,
see: J. Wencel, H. HØnon, S. Kehrli, M. Mauduit, A. Alexakis,
Aldrichimica Acta 2009, 42, 43.
Received: July 6, 2015
Published online: August 18, 2015
11834 www.angewandte.org
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Angew. Chem. Int. Ed. 2015, 54, 11830 –11834