Z-selective copper-catalyzed asymmetric allylic alkylation with grignard reagents

Article abstract of DOI:10.1021/ja300743t

Allylic gem-dichlorides undergo regio- and enanantioselective (er up to 99:1) copper-catalyzed allylic alkylation with Grignard reagents affording chiral Z-vinyl chlorides. This highly versatile class of synthons can be subjected to Suzuki cross coupling affording optically active Z-alkenes and 1,3-cis,trans dienes.

Full text of DOI:10.1021/ja300743t

Communication
pubs.acs.org/JACS
Z-Selective Copper-Catalyzed Asymmetric Allylic Alkylation with
Grignard Reagents
Massimo Giannerini, Martín Fananas-Mastral, and Ben L. Feringa*
́
̃
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands.
S
* Supporting Information
Scheme 1. State of the Art on Asymmetric Z-Selective γ-
Allylic Alkylation
ABSTRACT: Allylic gem-dichlorides undergo regio- and
enanantioselective (er up to 99:1) copper-catalyzed allylic
alkylation with Grignard reagents affording chiral Z-vinyl
chlorides. This highly versatile class of synthons can be
subjected to Suzuki cross coupling affording optically
active Z-alkenes and 1,3-cis,trans dienes.
he alkene moiety is one of the most widespread functional
T
groups in chemistry and the chemo- and the stereo-
selective formation and conversion of a carbon−carbon double
bond is key to numerous synthetic transformations.1,2 So far
catalytic methodologies for the exclusive preparation of the
higher-energy Z-stereoisomer are scarce.3,4 Despite significant
recent progress3,4 new procedures capable to ensure the
formation of a Z-olefin, in particular bearing functionality
enabling stereoselective cross-coupling reactions, will provide
precious tools for synthetic chemistry. As the presence of
multiple stereochemical elements is a recurrent feature in
biological active molecules, it is worthwhile to note that
frequently a Z-olefin (or diene) is accompanied by a
stereocenter in the allylic position.5 Therefore, a highly
desirable and attractive approach toward these structures is
an enantioselective catalytic process capable of both generating
the α-stereocenter and the Z-olefin in a single step;
methodology we present here.
the Z-selective γ-allylic alkylation of optically active allylcarba-
mates with Grignard reagents in the presence of copper
(Scheme 1, eq 1) was introduced by Woerpel and co-workers.11
Cu-catalyzed asymmetric allylic alkylation (AAA)12 has been
extensively applied to the synthesis of chiral nonracemic
terminal olefins. However, the possibility of obtaining enantio-
enriched internal olefins with the Z-geometry via this procedure
has been scarcely explored. Recently our group reported how in
situ generated α-chloroacetates undergo AAA to afford enol
acetates with Z-selectivity (Scheme 1, eq 2).13 These products
can be subsequently hydrolyzed to α,β-unsaturated aldehydes.
In contrast, a Cu-catalyzed AAA protocol applied to racemic 1-
methyl-substituted allylchlorides showed good enantioselectiv-
ity but gave rise to the corresponding alkenes as 1:1 E/Z
mixtures.14
Allylic substitution6 represents a powerful method for C−C
bond formation, in particular when simultaneously a stereo-
center is introduced in the allylic position of the resulting
alkene product. However, the control of the geometry of the
double bond still remains a major issue. Goering et al. showed
that the SN2′ substitution of 1,1-disubstituted allylic substrates
with alkyl cuprates leads predominantly to the formation of the
E-isomer.7 Few nonenantioselective examples have been
reported in which the allylic substitution promoted the
formation of the Z-isomer. The Cu-catalyzed addition of
Grignard reagents to 1-alkynyl-2-propenyl acetates results in
the formation of Z-enynes as described by Piccardi and co-
workers.8 Hoveyda et al. showed that, by placing a directing
phosphine group in the substrate, a nickel-catalyzed γ-allylic
alkylation gives rise to a predominance in the formation of the
Z-isomer, depending on the nature of the substrate and the
position of the phosphine group.9 Trost and co-workers
reported how the use of a chiral racemic ligand in a Pd-
catalyzed α-allylic substitution with substrates with a pre-
existing E double bond could lead to a Z-olefin in the
product.10 A chiral substrate-based stoichiometric protocol for
Inspired by our results achieved with α-chloroacetates13 and
realizing that the presence of two chlorides in a substrate might
allow a dual role as leaving group and stereocontrol element,
we envisioned that a new AAA method based on gem-
dichlorides15 might result in high stereoselectivity giving access,
in a single step, to chiral Z-vinyl chorides16 (Scheme 1, eq 3).
Furthermore these products are highly valuable building blocks
for cross-coupling17 reactions giving access to, e.g., 1,3-cis,trans-
diene moieties bearing a stereocenter in the α position (vide
infra).5
Received: January 23, 2012
Published: February 21, 2012
© 2012 American Chemical Society
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Table 1. Screening of Ligands and Conditions
a
b
b
,
c
d
entry
1
L
X
add. time (h)
1
conv. (%)
100
2a/(3 + 4)
Z/E
er (%)
L1
5.5
91:9
73:27
75:25
75:25
95:5
Z:81:19
E:91:9
Z:95:5
E:99:1
Z:97:3
E:99:1
Z:93:7
2
3
4
5
6
L1
L1
L2
L3
L4
5.5
10
6
6
6
6
6
100
100
50
96:4
>98:2
>98:2
>98:2
>98:2
5.5
5.5
5.5
e
E: n.a.
68
93:7
Z:80:20
e
E: n.a.
100
99:1
Z:99:1
e
E: n.a.
a
Reactions were run on a 0.3 mmol scale using 1.5 equiv of EtMgBr (3.0 M in Et2O) diluted with CH2Cl2 (final conc. 0.5 M) and added via syringe
b
c
d
e
1
pump. Reaction mixture stirred for 16 h at −78 °C. Determined by H NMR. Determined by GC. Determined by chiral HPLC. n.a. = not
applicable.
Table 2. Scope of the Reaction
a
b
c
entry
1
R2
Z/E
2, yield (%)
er (%)
1
2
1a
1a
1a
1a
1a
1b
1c
1d
1d
1e
Et
99:1
96:4
96:4
96:4
95:5
95:5
91:9
95:5
93:7
99:1
2a, 74
2b, 77
99:1
97:3
95:5
98:2
90:10
95:5
98:2
97:3
97:3
98:2
n-hex
Me
d
3
2c, 56
4
6-heptenyl
iBu
2d, 72
2e, 74
2f, 75
2g, 78
2h, 71
2i, 76
2j, 67
5
6
Et
7
Et
8
Et
9
n-hex
10
Et
a
Reactions were run on a 0.3 mmol scale using 1.5 equiv of R2MgBr (sol. in Et2O) diluted with CH2Cl2 and added over 6 h using a syringe pump.
b
c
No SN2 products were observed by 1H NMR analysis of the crude mixture unless otherwise indicated. Determined by GC. Determined by chiral
HPLC or GC. SN2′/SN2 88:12, 90% conv.
d
We started our studies with the reaction between cinnamyl-
derivate 1a (see Supporting Information for details on the
synthesis of dichlorides 1) and ethylmagnesium bromide
(addition time 1 h) using copper(I)-thiophene-2-carboxylate
(CuTC)18 in combination with phosphoramidite L119 (Table
1, entry 1). In this initial experiment the chemo-, regio-, and
enantioselectivity of the reaction was already very high, but the
most important observation was the formation of the Z-isomer
of 2a as the predominant product. The addition rate is often a
crucial parameter in this C−C bond-forming reaction involving
Grignard reagents.13 Although a slow addition over 6 h of the
organometallic reagent enhanced both the regio- and the
enantioselectivity, the Z:E ratio was not affected (entry 2). The
use of a 2:1 ligand/Cu ratio (entry 3) gave rise to similar
results; for this reason a 1:1 ratio was employed throughout.
The most effective approach to increase selectivity was found
to be through ligand screening. The use of ligand L2 gave
excellent regio- and Z-selectivity, but full conversion could not
be achieved (entry 4). Poor conversion and lower er were also
observed using ligand L3 (entry 5). O-Methoxy-substituted
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Communication
Scheme 2. Synthetic Application of Z-Vinyl Chlorides
Scheme 3. Proposed Rationale for the Z-Selectivity
Observed
Major efforts dedicated in recent years to expand the scope
of the Suzuki cross-coupling17 resulted in the development of
efficient protocols involving vinyl chlorides.23,24 We chose the
Suzuki cross-coupling to illustrate the versatility of the optically
active Z-vinyl chlorides 2 in the transformation into more
elaborate olefinic compounds preserving the geometry of the
double bond and without any deterioration of the chiral
information (Scheme 2). For instance, by using 2a and in situ
prepared alkylborane, with Pd(OAc)2/DavePhos as catalyst in
the presence of CsF/dioxane as the base/solvent system, the
chiral Z-dialkyl-substituted olefin 5 was formed exclusively
(>99% Z, er 98:2). Employing Pd2(dba)3/XPhos and the
appropriate alkenyl- or aryl-boronic acid, the 1,3-cis,trans-diene
6 and aryl-substituted Z-olefin 7 were obtained again with
excellent selectivities. Applying this catalytic procedure starting
with alkenylchloride 2h afforded the synthetically versatile
ester-substituted 1,3-cis,trans-diene 8 without any racemization.
It is worthy to comment on the robust Z-selectivity observed
during this study. In analogy with the proposed mechanism by
Goering and co-workers7e a catalytic cycle25 depicted in
Scheme 3 can be proposed in order to rationalize the results.
Coordination between the copper complex26 and a chloride in
the π-Cu(I) intermediate would impose a conformation
favoring the Z-geometry after oxidative addition to form a
Cu(III) σ-allyl complex. Reductive elimination would than
preserve this configuration, leading exclusively to the Z-vinyl
chloride product.
In conclusion we have developed a new copper-catalyzed
AAA methodology using Grignard reagents capable of
generating in a single step Z-alkenyl chlorides with an allylic
stereogenic center showing excellent regio- and enantioselec-
tivity. The use of a new class of substrates for the
enantioselective allylic alkylation, i.e. gem-dichlorides, provides
chiral building blocks that turn out to be highly versatile
substrates for subsequent Suzuki cross-coupling reactions. This
two-stage catalytic process, comprising the formation of both
the α-stereocenter and the Z-olefin followed by a selective
cross-coupling, allows a rapid entry into optically active Z-alkyl-
and aryl-substituted alkenes and Z−E dienes. Studies toward
the elucidation of the mechanism of this copper-catalyzed AAA
and in particular the origin of the high Z-selectivity will be
reported in due course.
phosphoramidite L4 instead turned out to be the ligand of
choice capable of imparting excellent selectivity not only for the
formation of the desired branched product 2a but also
providing near perfect asymmetric induction (99:1 er).
Moreover full control of the olefin geometry was obtained
with exclusive formation of the Z-isomer (99:1 Z:E ratio, entry
6).
Once the optimized conditions were established, we studied
the scope of the reaction using different dichlorides 1 and
Grignard reagents. The high selectivity toward the Z-olefin and
excellent enantioselectivity are a characteristic feature of this
reaction irrespective of the nature of the substrate or the
organometallic reagent (see Table 2). This includes Grignard
reagents bearing a longer alkyl chain (entry 2) and MeMgBr20
both showing high Z-selectivity. In the latter case the lower
reactivity of MeMgBr and higher volatility of the product
resulted in a decreased yield (56%) (entry 3). Also a sterically
hindered Grignard such as iBuMgBr could be used without
alteration of the selectivity of the reaction and with satisfactory
enantioselectivity (entry 5). To our delight a functionalized
Grignard reagent, which provides important opportunities for
subsequent elaboration of the product,21 participated in the
reaction with high selectivity (entry 4). Both electron-
withdrawing and donating groups are tolerated in the
cinnamyl-derived substrates like 1b and 1c (Table 2, entries
6 and 7). An important result was obtained using ester-
substituted dichlorides 1d and 1e. Albeit at least two
competitive reactions are possible22 (1,2- or 1,4-addition to
the carbonyl moiety) the catalytic transformation still proceeds
without formation of any traces of the 1,2- or 1,4-adduct nor of
the α-alkylation product. The selectivity toward the Z double
bond geometry as well as the enantioselectivity in the formation
of chiral ester-functionalized vinylchlorides 2h−2j remained
excellent (Table 2, entries 8−10). This is a particular valuable
transformation not only facing the complexity of discerning
between four possible reaction pathways but also for providing
easy access to optically active multifunctional optically active
synthons in view of the presence of both the vinylchloride and
ester moieties.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and spectroscopic data for the
reaction products. This material is available free of charge via
the Internet at http://pubs.acs.org.
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Journal of the American Chemical Society
Communication
advance in the field see: (f) Per
Rudolph, A.; Harutyunyan, S. R.; Feringa, B. L. Nature Chem. 2011, 3,
359.
́
ez, M.; Fananas
́
-Mastral, M.; Bos, P. H.;
̃
AUTHOR INFORMATION
Corresponding Author
B.L.Feringa@rug.nl
■
́
(13) Fananas-Mastral, M.; Feringa, B. L. J. Am. Chem. Soc. 2010, 38,
̃
13153.
Notes
(14) Langlois, J.-B.; Alexakis, A. Angew. Chem., Int. Ed. 2011, 50,
1877.
The authors declare no competing financial interest.
(15) (a) Newman, M. S.; Sujeeth, P. K. J. Org. Chem. 1978, 43, 4367.
(b) Courtheyn, D.; Verhe, R.; de Kimpe, N.; de Buyck, L.; Schamp, N.
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J. Org. Chem. 1981, 46, 3226.
(16) For a synthetic approach to Z-vinyl chlorides with an allylic
stereocenter using a chiral auxiliary see: Hoffmann, R. W.; Dresly, S.;
Lanz, W. Chem. Ber. 1988, 121, 1501.
ACKNOWLEDGMENTS
■
We thank The Netherlands Organization for Scientific
Research (NWO-CW) and the National Research School
Catalysis (NRSC-C) for financial support.
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2002, 4, 4147. (b) Tissot-Croset, K.; Polet, D.; Alexakis, A. Angew.
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