Identification of a valuable kinetic process in copper-catalyzed asymmetric allylic alkylation

Article abstract of DOI:10.1002/anie.201005373

Copper bottomed: The application of a previously described process of dynamic kinetic asymmetric transformation to acyclic substrates allowed the identification of a relevant kinetic process in the title reaction (see scheme; CuTC= copper(I) thiophencarboxylate, Naphth= naphthyl). The optimization of the reaction conditions and generality of the method, as well as mechanistic considerations are disclosed.

Full text of DOI:10.1002/anie.201005373

DOI: 10.1002/anie.201005373
Asymmetric Catalysis
Identification of a Valuable Kinetic Process in Copper-Catalyzed
Asymmetric Allylic Alkylation**
Jean-Baptiste Langlois and Alexandre Alexakis*
Since the past decade, copper-catalyzed asymmetric allylic
alkylation has attracted the interest of many research groups,
and such groups have succeeded in considerably extending
the range of applications as well as the efficiency of this
reaction.[1] Prochiral substrates are generally used, thus
providing versatile chiral synthons stemming from a selective
SN2’ displacement of the leaving group.[2] Because of this
particular feature, chemists rarely studied racemic substrates
as an anti SN2’ process would lead to racemic products.
However, the few investigations on the reactivity of this class
of substrates gave rise to the development of outstanding
Scheme 1. Evaluation of acyclic allylic halides as candidates for a
processes that significantly contributed to the understanding
dynamic kinetic asymmetric transformation.
of the reaction.[3] In 1998, Pineschi, Feringa, and co-workers
achieved pioneering work in this field with the kinetic
resolution of cycloalkadiene monoepoxide in the presence
of chiral phosphoramidite ligands.[4] A few years later, the
same groups established that the enantiomers of the racemic
allylic epoxide might have different reactivity under the
reaction conditions and that they could be selectively trans-
formed into two distinct regioisomers (regiodivergent kinetic
resolution).[5] Recently, our group reported on the develop-
substrates led us to unveil a new and valuable process for
copper-catalyzed asymmetric allylic alkylation.
Our investigations started with the reaction of (E)-4-
bromopent-2-ene (1)[7] with phenethylmagnesium bromide in
dichloromethane at À788C. In using the reaction conditions
previously described for the DYKAT,[6a,b] a combination of
CuTC (copper (I) thiophenecarboxylate) and the phosphor-
amidite ligand L1 was chosen as the catalyst. This attempt
quantitatively afforded the alkylation product 3 albeit as an
inseparable mixture of E and Z stereoisomers (Table 1,
entry 1). Interestingly, we noticed that both isomers of 3 were
isolated in promising enantiomeric excesses of 72 and 66%,
respectively. The use of ligands L2 and L3 failed to improve
this result even though a slight preference for the Z isomer
was observed (entries 2 and 3). Better enantioselectivities and
an E/Z ratio of 45:55 were obtained when the sterically
hindered ligand L4 was used (entry 4). Performing the
reaction with (E)-4-chloropent-2-ene (2) led to a significant
increase of the ee values to 84 and 81% (entry 5).[8] Further-
more, improvement of the enantioselectivity was achieved
when the Grignard reagent was added over a period of
30 minutes (entry 6).[9] Thus, the alkylation product 3 was
obtained as an equimolar mixture of the E and Z isomers in
90 and 88% ee, respectively.
ment of
a dynamic kinetic asymmetric transformation
(DYKAT).[6] Such a process used the difference in reactivity
of the enantiomers of a racemic substrate to quantitatively
form a unique enantioenriched product (up to 99% ee;
Scheme 1a). From a synthetic point of view, this reaction
constitutes a significant achievement considering the com-
plete conversion of the starting material as well as the
formation of a unique isomer of the alkylation product.
Notwithstanding, the reaction proved to be effective only on
3-bromocyclohexene derivatives and this lack of generality
limited its application in organic synthesis. To address this
problem, the reactivity of acyclic racemic substrates should be
studied (Scheme 1b). Herein, we present our findings on the
difficulty of performing a DYKAT process on acyclic
substrates and how the conformational flexibility of these
Goering and co-workers have demonstrated that a
significant amount of the Z adduct could be formed in the
alkylation of various E-allylic substrates by using an organo-
copper reagent, but never as an equimolar mixture with the
E adduct.[10] This specific feature strongly compromised the
development of a DYKAT, wherein the alkylation product
should be recovered as a single isomer.[6c,d] However, the high
level of enantioinduction observed for each isomer prompted
us to get more insight into the reaction mechanism.
[*] J.-B. Langlois, Prof. Dr. A. Alexakis
Department of Organic Chemistry, University of Geneva
Quai Ernest Ansermet 30, 1211 Geneva (Switzerland)
Fax: (+41)22-379-32-15
E-mail: alexandre.alexakis@unige.ch
[**] This work was supported by the Swiss National Research Founda-
tion (grant no. 200020-126663) and COSTaction D40 (SER contract
no. C07.0097). We warmly thank Dr. Jiri Mareda and Daniel Emery
for their availability and advice about computational chemistry as
well as Andre Pinto for NMR measurements. We also thank BASF
for the generous gift of chiral amines.
The product mixture obtained from the reaction listed in
entry 6 of Table 1 was submitted to ozonolysis and subsequent
reduction using NaBH4 (Scheme 2). (R)-2-methyl-4-phenyl-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201005373.
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Table 1: Optimization of the methodology.[a]
starting material. In the present case, the calculated value of
ee2initial was found to be inferior to 3%, which was consistent
with the use of a racemic substrate.[14] Based on these results
and observations, we postulated a reaction mechanism
(Scheme 3).
Entry
Substrate
Ligand
Conv. [%][b]
E/Z[c]
ee [%][d]
(E)-3
(Z)-3
1
2
3
4
1
1
1
1
2
2
L1
L2
L3
L4
L4
L4
>99
>99
>99
>99
>99
>99
44:56
37:63
35:65
45:55
47:53
48:52
72
72
66
76
84
90
66
54
42
74
81
88
5
6[e]
[a] Reaction conditions: The racemic substrate (0.25 mmol) was added
to a solution of CuTC (10 mol%) and ligand (11 mol%) in dry CH2Cl2 at
À788C. The Grignard reagent (1m in Et2O, 1.2 equiv) was added
dropwise and the reaction mixture was stirred for 1 h. The sterochemical
descriptors Ra and Sa used for ligands L1–L4 refer to the axial chirality.
[b] Conversion relative to the formation of product 3, determined by GC–
MS analysis. [c] Determined by 1H NMR analysis. [d] Determined by GC
analysis using a chiral stationary phase. [e] The Grignard reagent was
added over 30 min. Naphth=naphthyl.
Scheme 3. Plausible reaction mechanism.
Some prerequisites are needed to better understand the
reaction pathway: 1) the reactivity of each enantiomer of the
allylic chloride 2 has to be distinguished, 2) as mentioned, the
reactivity of the organocopper species implies an anti-SN2’
displacement of the leaving group,[2] and 3) the chiral catalyst
induces a selective attack on one enantiotopic face of the
disubstituted olefin, that is, the Si face given the observed
absolute configuration of the alkylation products. The facial
selectivity might be ascribed to steric interactions between the
chiral ligand and the vinylic methyl group but the difficulty in
obtaining a crystal structure of the catalyst prevented us from
asserting exactly which interactions governed the facial
selectivity. Thus, (S)-2 is perfectly disposed to undergo an
oxidative addition from its pro-E conformer, leading to the
(E)-s-allyl intermediate As. Subsequent reductive elimina-
tion, either directly or through the p-allyl complex Ap, will
selectively afford the E isomer of the alkylation product 5. In
sharp contrast, an anti attack on the pro-E conformer of (R)-2
would involve the approach of the chiral catalyst on the Re
face of the olefin. This possibility would be considerably
disfavored but the conformational flexibility offered by an
acyclic system allowed a rotation around the C3–C4 bond,
leading to the pro-Z conformer of the substrate. The latter
could be attacked on the Si enantiotopic face providing (Z)-s-
allyl intermediate Bs, then a possible p-allyl complex Bp, and
finally (Z)-5 after reductive elimination. Interestingly, when
the reaction was stopped at 72% conversion, a 43:57 mixture
of the E/Z isomers of 3 was recovered, indicating a slight
kinetic preference for the formation of the Z isomer
(Scheme 4). This observation means that the rotation
Scheme 2. Identification of the process.
butanol (4) was isolated in 91% yield and 88% ee indicating
that both isomers of 3 possess the same absolute configu-
ration. This observation strongly suggested that the adducts
arise from an attack on the same enantiotopic face of the
starting material given that such a product distribution could
be hardly attained by equilibrium between the s- and p-allyl
species. In addition, the small difference in energy between
the conformers of 2 (DE2 = 1.14 kcalmolÀ1) certainly facili-
tated their equilibration allowing the organocopper reagent
to attack either the pro-E or the pro-Z conformers.[11]
Obtaining two distinct enantioenriched isomers of the
alkylation product encouraged us to consider the possibility
of a parallel kinetic resolution process (PKR).[12] In 1967,
Guettꢀ and Horeau developed a simple equation based on the
respective proportions and optical purities of each adduct
obtained in a PKR reaction [Eq. (1)].[13] Thus, at full
conversion the relationship between the isomers of 3 should
be equal to the value of the initial enantiomeric excess of the
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Scheme 4. Control experiment.
required for the formation of this stereoisomer did not slow
down the reactivity of (R)-2 and that the system could easily
make up for this expense of energy if the approach of the
chiral catalyst is facilitated. This mechanism represents the
first example of stereodivergent kinetic resolution (SKR) in
copper-catalyzed asymmetric allylic alkylation.[15]
Having established a plausible reaction pathway, a specific
aspect remains intriguing: the formation of a p-allyl inter-
mediate is neither stereo- nor enantiodetermining in the
proposed mechanism.[16] In contrast to cyclic systems, it could
be assumed that the flexibility of acyclic substrates may allow
preorganization of the system before the key oxidative
addition step. Thus, in the present case and in opposition to
the DYKAT process, the enantio-, stereo- and regioselections
are determined before the possible formation of a p-allyl
moiety, thereby rendering its involvement only formal.
This particular feature might be exemplified by the
application of the process to unsymmetrical substrates.
Unfortunately, the preparation of the regioisomerically pure
unsymmetrical secondary allylic chlorides remains a difficult
challenge in organic synthesis.[17] (E)-(3-chlorobut-1-en-1-
yl)benzene (6) was a rare exception and has been synthesized
as a unique isomer.[18] To our delight, the alkylation reaction
gave the SN2’ adduct 7 as the major product (7/8 92:8) and as a
mixture of E and Z stereoisomers in 84 and 92% ee,
respectively (Scheme 5a). Importantly, a different chiral
ligand, L5, was needed owing to the significant structural
modification of the substrate.[19] Interestingly, when substrate
9 was submitted to the reaction conditions, (E)-10 was
obtained as the sole SN2’ stereoisomer albeit in a racemic
form (Scheme 5b). This result could be explained by a strong
1,3-allylic strain destabilizing the pro-Z conformer of 9
(Me–Me interaction, DE9 = 5.10 kcalmolÀ1) and leading
exclusively to the formation of the racemic E-adduct 10.[20]
The larger proportion of the SN2 adduct 11 formed in this
reaction could be ascribed to the propensity of the system to
release the strain induced by the formation of a quaternary
center.
Scheme 5. Use of unsymmetrical substrates. n.d.=not determined
Table 2: Generality of the reaction.[a]
Entry Substr. R2
Prod. Yield E/Z[c] ee [%][d]
[%][b]
eeE eeZ
1
2
3
4
5
6
7
2
2
2
2
2
2
12
PhCH2CH2
3
85
92
97
91
87
85
95
48:52 90 88
48:52 90 88
44:56 89 91
49:51 74 88
48:52 80 76
=
(CH3)2C CHCH2CH2 13
C12H25
tBuO(CH2)4
Cy
14
15
16
17
18
Ph
93:7
0
0
–
PhCH2CH2
48:52 88[f]
[a] Reaction conditions: The racemic substrate (0.25 mmol) was added
to a solution of CuTC (10 mol%) and L4 (11 mol%) in dry CH2Cl2 at
À788C. The Grignard reagent (1m in Et2O, 1.2 equiv) was added over
30 min and the reaction mixture was stirred for 1 h. [b] Yield of isolated
mixture of E and Z products. [c] Determined by 1H NMR analysis.
[d] Determined by GC analysis using a chiral stationary phase. [e] Deter-
mined by supercritical fluid chromatography (SFC) analysis using a
chiral stationary phase. Material used was obtained from the reaction
sequence described in Scheme 2a. Cy=cyclohexyl.
The generality of the reaction was finally explored using
the readily accessible model substrate 2 and various Grignard
reagents (Table 2). The introduction of homoprenyl group
was achieved with rigorously the same efficiency than the
model phenethyl group, affording the product 13 in 92% yield
(isolated) and ee values of 90 and 88% (entries 1 and 2,
Table 2). The addition of dodecylmagnesium bromide pro-
vided 14 in high yield and in about 90% ee (entry 3). (R,E)-
and (R,Z)-8-(tert-butoxy)-4-methyloct-2-ene (15) were
obtained in good yield and as an equimolar mixture. Surpris-
ingly, the E isomer was isolated with lower asymmetric
induction than the Z isomer (74 and 88% ee, respectively;
entry 4). Cyclohexylmagnesium bromide proved to react in
the same manner as the primary alkyl Grignard reagents
albeit in lower enantioselectivity (entry 5). In stark contrast,
phenylmagnesium bromide displayed a totally different
reactivity, leading to racemic (E)-pent-3-en-2-ylbenzene
(17) in good stereoselectivity (entry 6).[21] Finally, (E)-7-
chloroundec-5-ene (12) showed a similar reactivity and
adducts 18 were recovered in 95% yield and 88% ee
(entry 7).[22]
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Communications
In addition to mechanistic interest, the process reported
[1] For reviews, see: a) H. Yorimitsu, K. Oshima, Angew. Chem.
2005, 117, 4509; Angew. Chem. Int. Ed. 2005, 44, 4435; b) A.
Alexakis, C. Malan, L. Lea, K. Tissot-Croset, D. Polet, C.
Falciola, Chimia 2006, 60, 124; c) S. R. Harutyunyan, T. den
Hartog, K. Geurts, A. J. Minnaard, B. L. Feringa, Chem. Rev.
2008, 108, 2824; d) Z. Lu, S. M. Ma, Angew. Chem. 2008, 120,
264; Angew. Chem. Int. Ed. 2008, 47, 258; e) A. Alexakis, J. E.
Bꢂckvall, N. Krause, O. Pamies, M. Dieguez, Chem. Rev. 2008,
108, 2796; f) C. A. Falciola, A. Alexakis, Eur. J. Org. Chem. 2008,
3765.
herein could be a valuable tool for organic synthesis. Simple
transformations such as ozonolysis, hydrogenation, or cross-
metathesis might erase the dichotomy between the stereoiso-
mers of the alkylation product and quantitatively afford a
single enantioenriched compound. For instance, (E)- and
(Z)-3 were prepared on a synthetically useful scale (2 mmol)
using the SKR process and subsequently reacted with methyl
acrylate in the presence of the second-generation Hoveyda–
Grubbs catalyst (Scheme 6).[23] (E)-a,b-unsaturated ester (19)
[2] a) H. L. Goering, V. D. Singleton, J. Am. Chem. Soc. 1976, 98,
7854; b) H. L. Goering, S. S. Kantner, J. Org. Chem. 1984, 49,
422; c) C. C. Tseng, S. J. Yen, H. L. Goering, J. Org. Chem. 1986,
51, 2892.
[3] For a review, see: M. Pineschi, New J. Chem. 2004, 28, 657.
[4] a) F. Badalassi, P. Crotti, F. Macchia, M. Pineschi, A. Arnold,
B. L. Feringa, Tetrahedron Lett. 1998, 39, 7795; For addition
referenced on the reaction, see: b) R. Millet, A. Alexakis, Synlett
2007, 435; c) R. Millet, A. Alexakis, Synlett 2008, 1797; For
vinylic aziridines, see: d) F. Gini, F. Del Moro, F. Macchia, M.
Pineschi, Tetrahedron Lett. 2003, 44, 8559.
[5] a) F. Bertozzi, P. Crotti, F. Macchia, M. Pineschi, B. L. Feringa,
Angew. Chem. 2001, 113, 956; Angew. Chem. Int. Ed. 2001, 40,
930; b) M. Pineschi, F. Del Moro, P. Crotti, V. Di Bussolo, F.
Macchia, J. Org. Chem. 2004, 69, 2099; c) M. Pineschi, F.
Del Moro, P. Crotti, V. Di Bussolo, F. Macchia, Synthesis 2005,
334.
[6] a) J. B. Langlois, A. Alexakis, Chem. Commun. 2009, 3868;
b) J. B. Langlois, A. Alexakis, Adv. Synth. Catal. 2010, 352, 447;
For information about DYKAT, see: c) K. Faber, Chem. Eur. J.
2001, 7, 5004; d) J. Steinreiber, K. Faber, H. Griengl, Chem. Eur.
J. 2008, 14, 8060.
[7] Substrate 1 was formed in situ by treatment of (E)-pent-3-en-2-
yl acetate with trimethylsilylbromide (1.4 equiv) at room
temperature for 4 h. Control experiments proved that generated
TMSOAc was inert under the reaction conditions.
Scheme 6. Scale-up preparation and derivatization of adducts 3.
HG II=Hoveyda–Grubbs second-generation catalyst.
was isolated as the sole stereoisomer in 82% yield and
88% ee.[24]
In conclusion, acyclic allylic systems have shown a
fundamentally different reactivity profile compared to cyclic
substrates, which precluded the development of a DYKAT.
However, the conformational flexibility of this class of
substrates allowed us to identify a highly enantioselective
stereodivergent kinetic resolution (up to 91% ee). Such a
process is rare in transition-metal catalysis and unprece-
dented in copper chemistry. Studies are currently ongoing in
our laboratory to extend our comprehension of the system
and particularly to understand the striking difference between
DYKATand SKR processes towards the influence of a p-allyl
intermediate on the reaction outcome.
[8] (E)-4-chloropent-2-ene (2) has been successfully used in nickel-
catalyzed enantioselective dynamic resolution process: S. Son,
G. C. Fu, J. Am. Chem. Soc. 2008, 130, 2756.
[9] Slow addition of the Grignard reagent is known to favor the
formation of the organocopper reagent instead of the organo-
cuprate. See Ref. [1e].
[10] For alkylation of allylic alcohols by the Murahashi method, see:
a) H. L. Goering, S. S. Kantner, J. Org. Chem. 1981, 46, 2144;
b) H. L. Goering, C. C. Tseng, J. Org. Chem. 1985, 50, 1597; For
alkylation of allylic carbamates, see: c) H. L. Goering, S. S.
Kantner, C. C. Tseng, J. Org. Chem. 1983, 48, 715; For alkylation
of allylic carboxylates, see: d) H. L. Goering, S. S. Kantner, J.
Org. Chem. 1983, 48, 721; e) H. L. Goering, C. C. Tseng, J. Org.
Chem. 1983, 48, 3986; f) See Ref. [2c]; g) T. L. Underiner, S. D.
Paisley, J. Schmitter, L. Lesheski, H. L. Goering, J. Org. Chem.
1989, 54, 2369; however, no formation of the Z isomer was
detected in the alkylation of allylic phosphonates: h) J. L.
Belelie, J. M. Chong, J. Org. Chem. 2001, 66, 5552.
Experimental Section
In a flame-dried Schlenk tube an under nitrogen atmosphere, CuTC
(4.8 mg, 0.025 mmol, 0.1 equiv) and L4 (17.6 mg, 0.028 mmol,
0.11 equiv) were dissolved in dry CH2Cl2 (2 mL) and the solution
was stirred for 10 min at room temperature. The reaction mixture was
then cooled to À788C and the freshly prepared substrate (0.25 mmol)
was added. After 10 min at this temperature, the Grignard reagent
(1m in Et2O, 0.3 mL, 0.3 mmol, 1.2 equiv) was added over 30 min and
the reaction mixture was stirred for 1 h. The reaction was quenched
with HCl 1m (5 mL) and extracted with diethyl ether (3 ꢁ 5 mL). The
organic layer was dried over Na2SO4, filtered, and concentrated under
vacuum. The crude reaction mixture was purified by chromatography
on silica gel (n-pentane) and the desired product (up to 97%) was
recovered as a colorless liquid. For additional details, see the
Supporting Information.
[11] DE2 represents the difference in energy between the conformers
of substrate 2. The value has been calculated with Gaussian 03
using MP2/6-311G**//PBE1PBE/6-311G** methods. See the
Supporting Information for experimental details.
Received: August 27, 2010
Revised: November 9, 2010
Published online: January 21, 2011
[12] For reviews on PKR, see: a) E. Vedejs, X. Chen, J. Am. Chem.
Soc. 1997, 119, 2584; b) J. R. Dehli, V. Gotor, Chem. Soc. Rev.
Keywords: alkylation · allylic compounds · asymmetric catalysis ·
copper · Grignard reagents
.
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2002, 31, 365; c) E. Vedejs, M. Jure, Angew. Chem. 2005, 117,
4040; Angew. Chem. Int. Ed. 2005, 44, 3974.
[13] J. P. Guettꢀ, A. Horeau, Bull. Soc. Chim. Fr. 1967, 1747.
[14] 3% ee is negligible given that the 1H NMR methods used to
determine the proportion of each isomer have an error of about
3%.
[15] For the unique previous example of transition-metal-catalyzed
SKR, see: L. C. Miller, J. M. Ndungu, R. Sarpong, Angew. Chem.
2009, 121, 2434; Angew. Chem. Int. Ed. 2009, 48, 2398.
[16] For relevant computational studies on the involvement of p-
allyl/CuIII intermediate in the reaction mechanism, see: a) M.
Yamanaka, S. Kato, E. Nakamura, J. Am. Chem. Soc. 2004, 126,
6287; b) N. Yoshikai, S. L. Zhang, E. Nakamura, J. Am. Chem.
Soc. 2008, 130, 12862.
Paisley, H. L. Goering, J. Org. Chem. 1986, 51, 2884; b) See
Ref. [10g]; c) T. L. Underiner, H. L. Goering, J. Org. Chem.
1991, 56, 2563; d) J. E. Bꢂckvall, E. S. M. Persson, A. Bombrun,
J. Org. Chem. 1994, 59, 4126.
[22] (E)-5-chloro-2,6-dimethylhept-3-ene and (E)-5-chloro-2,2,6,6-
tetramethylhept-3-ene have been evaluated in the reaction
conditions. Unfortunately, an undesired elimination reaction
leading to the formation of a diene and a lack of reactivity were
respectively observed.
[23] For previous examples of copper-catalyzed asymmetric allylic
alkylation/cross-metathesis sequences involving an acrylate as a
coupling partner, see: a) A. Alexakis, K. Croset, Org. Lett. 2002,
4, 4147; b) M. A. Kacprzynski, T. L. May, S. A. Kazane, A. H.
Hoveyda, Angew. Chem. 2007, 119, 4638; Angew. Chem. Int. Ed.
2007, 46, 4554; c) A. W. van Zijl, W. Szymanski, F. Lopez, A. J.
Minnaard, B. L. Feringa, J. Org. Chem. 2008, 73, 6994.
[24] This SKR/cross-metathesis sequence could be particularly
interesting since the copper-catalyzed asymmetric allylic alkyla-
tion of crotyl chloride remained a preeminent challenge in this
field, affording after extensive optimizations only 80% ee for the
g-alkylated product.
[17] The regioselectivity of the chlorination step is often problematic
leading to a mixture of SN2 and SN2’ adducts.
[18] This exceptional regioselectivity is certainly the result of a
stabilizing conjugation of the double bond with the phenyl
moiety. For energy difference between the conformers of
substrate 6, DE6 = 1.14 kcalmolÀ1
.
[19] Ligand L5 is known to be efficient for the alkylation of cinnamyl
chloride: K. Tissot-Croset, D. Polet, A. Alexakis, Angew. Chem.
2004, 116, 2480; Angew. Chem. Int. Ed. 2004, 43, 2426.
[20] R. W. Hoffmann, Chem. Rev. 1989, 89, 1841.
[21] For reports on the special reactivity of aryl Grignard reagents in
copper-catalyzed allylic substitution, see: a) C. C. Tseng, S. D.
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