Copper-catalyzed enantioselective allylic substitution with alkylboranes

Article abstract of DOI:10.1021/ja3093955

The first catalytic enantioselective allylic substitution reaction with alkylboron compounds has been achieved. The reaction between alkyl-9-BBN reagents and primary allylic chlorides proceeded with excellent γ-selectivities and high enantioselectivities under catalysis of a Cu(I)-DTBM-SEGPHOS system. The protocol produces terminal alkenes with an allylic stereogenic center branched with functionalized sp³-alkyl groups. The reaction with a γ-silicon-substituted allyl chloride affords an efficient strategy for the enantioselective synthesis of functionalized α-stereogenic chiral allylsilanes.

Full text of DOI:10.1021/ja3093955

Communication
pubs.acs.org/JACS
Copper-Catalyzed Enantioselective Allylic Substitution with
Alkylboranes
Yoshinori Shido, Mika Yoshida, Masahito Tanabe, Hirohisa Ohmiya,* and Masaya Sawamura*
Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
S
* Supporting Information
the branched γ-substitution product (S)-4aa (γ/α > 98:2) with
77% ee in 83% yield (Scheme 1).15,16 The enantioselection could
ABSTRACT: The first catalytic enantioselective allylic
substitution reaction with alkylboron compounds has been
achieved. The reaction between alkyl-9-BBN reagents and
primary allylic chlorides proceeded with excellent γ-
selectivities and high enantioselectivities under catalysis
of a Cu(I)−DTBM-SEGPHOS system. The protocol
produces terminal alkenes with an allylic stereogenic
center branched with functionalized sp3-alkyl groups. The
reaction with a γ-silicon-substituted allyl chloride affords
an efficient strategy for the enantioselective synthesis of
functionalized α-stereogenic chiral allylsilanes.
Scheme 1. Cu-Catalyzed Enantioselective Allylic
Substitutions of 2a and 3a
rganoboron compounds are useful reagents for C−C bond
Oformations because of their broad availability and excellent
functional group compatibility.1 Recently, enantioselective
methods for C−C bond formation using organoboron
compounds under the influence of chiral transition metal
catalysts have made impressive progress.2 Nevertheless, catalytic
enantioselective allylic substitutions with organoboron com-
pounds have not been well exploited.3−7 Specifically, sp3-
alkylboron reagents have not yet been used successfully.
Herein, we report the first catalytic enantioselective allylic
substitution reaction with alkylboron compounds.8−10 The
reaction between alkyl-9-BBN reagents and primary allylic
chlorides proceeded with excellent γ-selectivities and high
enantioselectivities under catalysis of a Cu(I)−DTBM-SEG-
PHOS system.11 This protocol produces enantioenriched
terminal alkenes with an allylic stereogenic center branched
with functionalized sp3-alkyl groups. The reaction with (Z)-1-
dimethylphenylsilyl-3-chloro-1-pentene as an allylic substrate
also proceeded selectively to afford enantioenriched α-stereo-
genic allylsilanes.9b,c,12−14
Earlier, we reported that the allyl−alkyl coupling between
enantioenriched chiral secondary (Z)-allylic phosphates and
alkyl-9-BBN reagents proceeded with excellent γ-selectivity and
stereospecificity under the influence of a catalytic amount of a
Cu(I) salt and a stoichiometric potassium alkoxide base.9a−c On
the basis of this knowledge, we initiated a program to develop an
unprecedented catalytic enantioselective allylic alkylation with
alkylboranes. The initial screening with a substrate combination
of alkylborane 2a (0.25 mmol), which was prepared from
dimethoxyallylbenzene (1a), and (Z)-allylic chloride 3a (0.2
mmol) identified optimal reaction conditions using
(CuOTf)2·toluene (5 mol %), (R)-DTBM-SEGPHOS11 (10
mol %), and MeOK (0.22 mmol) in 1,4-dioxane/dichloro-
methane (DCM) (1:3, 0.8 mL) at 10 °C for 48 h, which afforded
be improved to 80% ee by reducing the reaction temperature to 5
°C at the expense of the yield (55%). The reaction of allylic
chloride 3a with E-configuration under otherwise identical
conditions provided the product with the same absolute
configuration with 64% ee (Scheme 1, vide infra for discussion
on the effect of the alkene geometries).17
The screening of chiral ligands revealed that introducing 3,5-
di-tert-butyl-4-methoxyphenyl (DTBM) substituents on the
phosphorus atoms of chiral bisphosphines was essential not
only for the enantiocontrol but also for the catalytic activity with
bisphosphine-based chiral Cu catalysts. Among various DTBM-
substituted chiral bisphosphine ligands, (R)-DTBM-SEGPHOS
was optimal (see Supporting Information (SI) for ligand effects).
The introduction of the DTBM substituents may have induced
the deaggregation of alkylcopper(I) species to form a catalytically
active monomeric Cu complex.18
Effects of leaving groups and reaction conditions are
summarized in Table 1.16 In the earlier stage of the investigation,
we used CuCl (5 mol %) as a Cu source for the reaction between
2a and (Z)-3a. The reaction with (R)-DTBM-SEGPHOS (5 mol
%) and MeOK in 1,4-dioxane at 35 °C proceeded with moderate
yield and enantioselectivity (48% and 61% ee) (entry 1).
Changing the leaving group to a bromide or phosphate caused
drastic reductions of the product yield and enantioselectivity
(entries 2 and 3).
Received: September 22, 2012
Published: October 29, 2012
© 2012 American Chemical Society
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Communication
Table 1. Cu-Catalyzed Enantioselective Allylic Substitutions
between 2a and 3a under Various Conditions
Table 2. Scope of Enantioselective Allylic Substitution with
Alkylboranes
a
a
a
The reaction was carried out with 3a (0.2 mmol), 2a (0.25 mmol),
Cu salt, ligand, and MeOK (0.21 mmol; entries 1−6 and 9−12, 0.22
mmol; entries 7 and 8) in solvent (0.8 mL) for 12 h (entries 1−6 and
9−12) or 48 h (entries 7 and 8). Alkylborane 2 was prepared in
advance by hydroboration of 1 with the 9-BBN dimer at 60 °C (1 h)
b
and used without purification. The yield was determined by 1H
c
1
NMR. Constitutional isomer ratio γ/α > 20:1 (determined by H
d
NMR analysis of the crude product). The enantiomeric excess was
determined by HPLC analysis.
Solvents also showed marked influences on both yield and
enantioselection. The use of THF or toluene as a solvent instead
of 1,4-dioxane resulted in poor yields (11% and 7%) and lower
enantioselectivities (40% and 41% ees) (Table 1, entries 4 and
5). Dichloromethane (DCM) as solvent inhibited the reaction
almost completely (entry 6). The enantioselection was improved
to 74% ee by carrying out the reaction at 10 °C with a 10 mol %
catalyst loading in 1,4-dioxane, but with a serious reduction of the
yield (23%, entry 7). Finally, we found that the reaction
proceeded much more efficiently in a mixed solvent system, 1,4-
dioxane/DCM (1:3). The reaction with a 10 mol % catalyst
loading at 10 °C afforded (S)-4aa with 77% ee in 81% yield
(entry 8). The slightly higher yield (83%) was obtained by
changing CuCl to (CuOTf)2·toluene with the enantioselectivity
unchanged (Scheme 1).
The nature of the base also had a strong impact on the yield
and enantioselection. Changing the alkoxide base from MeOK to
the bulkier t-BuOK caused a decrease in the yield (39%) and
enantioselectivity (57% ee) (Table 1, entry 9). No reaction
occurred with the weaker base PhOK (entry 10). The use of Li or
Na methoxides also resulted in virtually no reaction (entries 11
and 12).
The inefficiency of the Li or Na methoxides may reflect higher
solubilities of Li or Na salts, which may cause inhibitory effects in
the hydrophobic solution phase of the reaction mixture. This
assumption also explains the increase in the reaction efficiency
when DCM was used as a cosolvent with 1,4-dioxane (Table 1,
entry 8).
Various terminal alkenes and Z-allylic chlorides were subjected
to the one-pot protocol involving the 9-BBN-hydroboration of
terminal alkenes (1) and the subsequent enantioselective allylic
substitution with the (CuOTf)2·toluene/(R)-DTBM-SEG-
PHOS catalyst system (Table 2).16,19 The reactions proceeded
with excellent γ-selectivities (γ/α > 98:2) and high enantiose-
lectivities (72−90% ee). Terminal alkenes having functional
groups such as silyl ether, ester, acetal, and phthalimide moieties
a
The reaction was carried out with 3 (0.2 mmol), 2 (0.25 mmol),
(CuOTf)2·toluene (5 mol %), (R)-DTBM-SEGPHOS (10 mol %),
and MeOK (0.22 mmol) in 1,4-dioxane/DCM (1:3, 0.8 mL) at 10 °C
(entry 3) or 15 °C (entries 1, 2 and 4−9) for 48 h (entries 2, 3, 7, and
9) or 72 h (entries 1, 4−6, and 8). Alkylborane 2 was prepared in
advance by hydroboration of 1 with the 9-BBN dimer at 60 °C (1 h)
b
and used without purification. The yield of the isolated product.
c
1
Constitutional isomer ratio γ/α > 98:2 (determined by H NMR
d
analysis of the crude product). The enantiomeric excess was
determined by HPLC analysis. Reaction in 1.0 mmol scale.
e
at the terminal of the aliphatic chain were compatible with the
hydroboration−enantioselective substitution protocol (entries
1−8). Functional groups such as silyl ether and chloro moieties
in the allylic substrates were also tolerated (entries 2, 7, and 8).
The tolerance of this reaction toward smaller or sterically more
demanding γ-substituents is demonstrated in the successful
conversion of the γ-methyl or γ-cyclohexyl-substituted allyl
chlorides (3d, e), although reductions in yield and enantiose-
lection were observed (4dd, 62%, 72% ee; 4de, 53%, 76% ee,
Table 2, entries 4 and 5). Unfortunately, the attempt to use the
alkylborane (2g) derived from styrene (1g) failed (entry 9).
The Cu-catalyzed protocol is applicable to the reaction
between a γ-silylated allyl chloride (3g) and alkylboranes, which
affords enantioenriched α-stereogenic chiral allylsilanes (Table
3).16 For instance, the reaction between alkylborane 2h, which
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Communication
a
CuX(DTBM-SEGPHOS) [A, X = OMe or Cl] and a
trialkyl(alkoxo)borate B, may play a role in activating the
chloride leaving group through its Lewis acidic character.9c The
addition of alkylcopper(I) species C would occur with anti
stereochemistry with respect to the leaving group, being followed
by anti-β-elimination.
Table 3. Synthesis of Chiral Allylsilanes
Earlier, we reported that the stereochemical courses of the Cu-
catalyzed allyl−alkyl coupling between enantioenriched chiral
allylic phosphates and alkylboranes were switchable between 1,3-
anti and 1,3-syn selectivities by the choice of achiral alkoxide
bases with different steric demands: t-BuOK and MeOK showed
1,3-anti and 1,3-syn stereochemistry, respectively.9c For the
reaction with the sterically less hindered MeOK base, it was
proposed that in situ generated 9-BBN-OMe bridges the leaving
group and the Cu atom through Lewis acid/base bifunctional
participation. Nevertheless, in the present enantioselective
catalysis with the chiral bisphosphine ligand, the coordination
of 9-BBN-OMe to the Cu center is ruled out because the Cu
center bearing the alkyl group and the chiral bisphosphine ligand
is coordinatively saturated upon alkene coordination.
The enantioselection likely occurs at transition states of the
R1−Cu addition across the C−C double bond. Enantioselection
models for the reaction of (Z)-3 are given in Figure 2 (E-TS-1
a
The reaction was carried out with 3g (0.2 mmol), 2 (0.25 mmol),
(CuOTf)2·toluene (5 mol %), (R)-DTBM-SEGPHOS (10 mol %),
and MeOK (0.22 mmol) in 1,4-dioxane/DCM (1:3, 0.8 mL) at 15 °C
for 48 h (entries 1, 2, 4 and 5) or 72 h (entry 3). Alkylborane 2 was
prepared in advance by hydroboration of 1 with the 9-BBN dimer at
b
60 °C (1 h) and used without purification. The yield of the isolated
c
product. Linear isomer was not detected: γ/α > 99:1 (1H NMR).
d
The enantiomeric excess was determined by HPLC analysis.
e
Reaction in 1.0 mmol scale.
was derived from terminal alkene 1h, and 3g under the
conditions optimized for the reaction of (Z)-3a (Scheme 1)
proceeded with complete γ-selectivity and afforded chiral
allylsilane 4hg with 91% ee in 77% yield (Table 3, entry 1).20
The terminal alkenes (1c,e,f,i) bearing acetal, ester, phthalimide,
or chloro moieties were also compatible with the protocol with
comparable enantioselectivities (entries 2−5).
A possible catalytic cycle for the present Cu catalysis can be
postulated as illustrated in Figure 1. It would involve addition−β-
elimination of a neutral organocopper(I) species C as proposed
for the Cu-catalyzed allyl−alkyl coupling between secondary
allylic phosphates and alkylboranes.9a−c During this addition−
elimination pathway [D → E-TS → F → 4], methoxyborane (9-
BBN-OMe), which is derived from the transmetalation between
Figure 2. Models for enantiodiscrimination.
and E-TS-2). In this model, the Cu adopts tetrahedral
coordination geometry, the axis of the C−C double bond is
coplanar with the Cu−R1 bond, and Ar1 and Ar3 are equatorial
and Ar2 and Ar4 are axial. Importantly, Ar1 points toward the allyl
chloride substrate more significantly than the other equatorial
aryl group (Ar3). The axial aryl groups (Ar2 and Ar4) are much
more distal to the substrate. According to these assumptions, E-
TS-1 has less steric strain than E-TS-2, because Ar1 is close to
both the R2 and ClCH2 substituents in E-TS-2, while E-TS-1
encounters the corresponding steric repulsions only between Ar3
and the R2 substituent, which should be relatively small due to
the distal location of Ar3.
In the case of the reaction with (E)-3, Ar1 causes steric
repulsions toward either the ClCH2 (E-TS-3) or R2 substituents
(E-TS-4). Consequently, the energy difference between E-TS-3
and E-TS-4 is smaller than that between E-TS-1 and E-TS-2.
These considerations explain the more efficient enantioselection
in the reaction with the allylic substrate with Z-configuration
(Scheme 1). The observed stereoconvergency from the Z and E
Figure 1. Possible catalytic cycle.
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Journal of the American Chemical Society
Communication
enantioselective allylic substitution of allylic ethers with arylboronic
acids, see: (e) Kiuchi, H.; Takahashi, D.; Funaki, K.; Sato, T.; Oi, S. Org.
Lett. 2012, 14, 4502.
(8) For reviews on Cu-catalyzed enantioselective allylic substitutions
with organomagnesium, organozinc, or organoaluminum reagents, see:
(a) Hoveyda, A. H.; Hird, A. W.; Kacprzynski, M. A. Chem. Commun.
2004, 1779. (b) Yorimitsu, H.; Oshima, K. Angew. Chem., Int. Ed. 2005,
44, 4435. (c) Falciola, C. A.; Alexakis, A. Eur. J. Org. Chem. 2008, 3765.
allylic substrates affording the product with the identical absolute
configuration suggests Ar1 has greater steric interaction with the
R2 substituent (E-TS-4) than with the ClCH2 substituent (E-TS-
3).
In summary, we demonstrated the enantioselective reaction
between alkylboron compounds (alkyl-9-BBN) and allylic
chlorides under catalysis of the Cu(I)−DTBM-SEGPHOS
system that proceeds with excellent γ-selectivities and high
enantioselectivities. Introducing the DTBM substituents to the
chiral ligand is crucial for promotion of the reaction. To our
knowledge, this is the first catalytic enantioselective allylic
substitution reaction of alkylboron derivatives. The protocol
produces enantioenriched chiral terminal alkenes with an allylic
stereogenic center branched with functionalized sp3-alkyl groups
and affords an efficient strategy for the enantioselective synthesis
of α-stereogenic chiral allylsilanes.
̀ ́
(d) Alexakis, A.; Backvall, J. E.; Krause, N.; Pamies, O.; Dieguez, M.
̈
Chem. Rev. 2008, 108, 2796. (e) Harutyunyan, S. R.; den Hartog, T.;
Geurts, K.; Minnaard, A. J.; Feringa, B. L. Chem. Rev. 2008, 108, 2824.
(9) For Cu-catalyzed γ-selective allylic substitutions with alkyl-9-BBN
(nonenantioselective system), see: (a) Ohmiya, H.; Yokobori, U.;
Makida, Y.; Sawamura, M. J. Am. Chem. Soc. 2010, 132, 2895. (b) Nagao,
K.; Ohmiya, H.; Sawamura, M. Synthesis 2012, 44, 1535. (c) Nagao, K.;
Yokobori, U.; Makida, Y.; Ohmiya, H.; Sawamura, M. J. Am. Chem. Soc.
2012, 134, 8982. (d) Whittaker, A. M.; Rucker, R. P.; Lalic, G. Org. Lett.
2010, 12, 3216. See also: (e) Ohmiya, H.; Yokobori, U.; Makida, Y.;
Sawamura, M. Org. Lett. 2011, 13, 6312.
ASSOCIATED CONTENT
* Supporting Information
(10) For Cu-catalyzed enantioselective conjugate addition with alkyl-
9-BBN reagents, see: (a) Yoshida, M.; Ohmiya, H.; Sawamura, M. J. Am.
Chem. Soc. 2012, 134, 11896. See also: (b) Ohmiya, H.; Yoshida, M.;
Sawamura, M. Org. Lett. 2011, 13, 482. (c) Ohmiya, H.; Shido, Y.;
Yoshida, M.; Sawamura, M. Chem. Lett. 2011, 40, 928.
(11) Saito, T.; Yokozawa, T.; Ishizaki, T.; Moroi, T.; Sayo, N.; Miura,
T.; Kumobayashi, H. Adv. Synth. Catal. 2001, 343, 264.
(12) For reviews on the synthesis of allylsilanes, see: (a) Masse, C. E.;
Panek, J. S. Chem. Rev. 1995, 95, 1293. (b) Fleming, I.; Barbero, A.;
Walter, D. Chem. Rev. 1997, 97, 2063. (c) Chabaund, L.; James, P.;
Landais, Y. Eur. J. Org. Chem. 2004, 3173.
■
S
Experimental details and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
ohmiya@sci.hokudai.ac.jp; sawamura@sci.hokudai.ac.jp
■
Notes
(13) For the synthesis of enantioenriched allylsilanes through Cu-
catalyzed enantioselective allylic substitutions of prochiral γ-silylated
primary allylic alcohol derivatives with organozinc or organoaluminum
reagents, see: (a) Kacprzynski, M. A.; May, T. L.; Kazane, S. A.;
Hoveyda, A. H. Angew. Chem., Int. Ed. 2007, 46, 4554. (b) Gao, F.;
McGrath, K. P.; Lee, Y.; Hoveyda, A. H. J. Am. Chem. Soc. 2010, 132,
14315. For the synthesis of allylsilanes through Cu-catalyzed allylic
substitutions with silylating reagents, see: (c) Vyas, D. J.; Oestreich, M.
Chem. Commun. 2010, 568. (d) Vyas, D. J.; Oestreich, M. Angew. Chem.,
Int. Ed. 2010, 49, 8513.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Grants-in-Aid for Young Scientists
(A), JSPS and the Uehara Memorial Foundation to H.O. and by
CREST, JST to M.S.
REFERENCES
■
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1
(15) The yields of 4aa in Scheme 1 were determined by H NMR
analysis of the crude products.
(16) For Scheme 1 and Tables 1−3, unreacted allylic chloride (3) was
detected in the crude materials after removal of the catalyst.
(17) For stereoconvergent synthesis of α-stereogenic chiral
allylboronates from an E/Z mixture of allylic aryl ethers using a
NHC−Cu catalyst, see: Park, J. K.; Lackey, H. H.; Ondrusek, B. A.;
McQuade, D. T. J. Am. Chem. Soc. 2011, 133, 2410.
(18) For discussion on the effect of the DTBM groups in the
enantioselective Cu-catalyzed hydrosilylation of aryl ketones, see:
Lipshutz, B. H.; Noson, K.; Chrisman, W.; Lower, A. J. Am. Chem. Soc.
2003, 125, 8779.
(19) The absolute configuration of 4bb was determined by
transforming it to a known compound. See SI for details. Absolute
configurations of 4aa and the other products listed in Table 2 were
assigned by consideration of the stereochemical pathway.
(20) The absolute configuration of allylsilane 4hg was determined by
transforming it to a chiral secondary alcohol by alkene reduction,
followed by Fleming−Tamao oxidation with retention of configuration.
See SI for details. Absolute configurations of the other allylsilanes were
assigned by consideration of the stereochemical pathway.
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