Asymmetric Remote C-H Functionalization: Use of Internal Olefins in Tandem Hydrometallation-Isomerization-Asymmetric Conjugate Addition Sequences

Article abstract of DOI:10.1071/CH14556

We describe catalytic asymmetric C-C formation using terminal alkyl-metal nucleophiles generated from internal olefins through a 'chain-walking' isomerization mechanism. Hydrometallation of internal olefins with the Schwartz reagent gives the least hindered alkyl-zirconocene after thermal (60°C in THF) isomerization. After switching the solvent from THF to dichloromethane, the alkyl-zirconocenes can be used in copper-catalyzed asymmetric conjugate additions. Addition to a variety of cyclic α,β-unsaturated species were achieved in modest (22-50%) yield with high (84-92% ee) enantioselectivity. This work demonstrates that remote C-H functionalization coupled with asymmetric C-C bond formation is possible, but the present procedures are limited in terms of yield and olefin scope.

Full text of DOI:10.1071/CH14556

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2015, 68, 401–403
Communication
http://dx.doi.org/10.1071/CH14556
Asymmetric Remote C–H Functionalization: Use of Internal
Olefins in Tandem Hydrometallation–Isomerization–
Asymmetric Conjugate Addition Sequences*
A
A
A B
,
Laura Mola, Mireia Sidera, and Stephen P. Fletcher
A
Department of Chemistry, Chemistry Research Laboratory, University of Oxford,
12 Mansfield Road, Oxford, OX1 3TA, UK.
B
Corresponding author. Email: stephen.fletcher@chem.ox.ac.uk
We describe catalytic asymmetric C–C formation using terminal alkyl-metal nucleophiles generated from internal olefins
through a ‘chain-walking’ isomerization mechanism. Hydrometallation of internal olefins with the Schwartz reagent gives
the least hindered alkyl-zirconocene after thermal (608C in THF) isomerization. After switching the solvent from THF to
dichloromethane, the alkyl-zirconocenes can be used in copper-catalyzed asymmetric conjugate additions. Addition to a
variety of cyclic a,b-unsaturated species were achieved in modest (22–50 %) yield with high (84–92 % ee) enantio-
selectivity. This work demonstrates that remote C–H functionalization coupled with asymmetric C–C bond formation is
possible, but the present procedures are limited in terms of yield and olefin scope.
Manuscript received: 11 September 2014.
Manuscript accepted: 15 October 2014.
Published online: 21 November 2014.
C–H Bond functionalization has been under development for
over 50 years,[1] with the activation of remote C–H bonds
typically relying on metal-mediated strategies.[2–6] The
design of redox-efficient olefin isomerization reactions[7–9] is
one approach to remote C–H activation. Here a position far
from the original double bond is functionalized through a
‘chain-walking’ mechanism. Recent reports of Pd[10,11] or
Ru[12]-catalyzed migration/C–C bond forming processes hint
towards the tremendous potential of this strategy in remote
C–H functionalization.[6]
A well-established method for olefin isomerization reactions
involves hydrometallation of an internal olefin with the
Schwartz reagent.[13–15] After initial hydrozirconation, internal
olefins typically isomerize to the least sterically hindered
primary alkyl-zirconocene product via b-hydride elimination
and re-addition sequences.[16,17] These methods allow the
C–H functionalization of otherwise inert terminal methyl
groups,[15,18] and several synthetic applications have been
reported.[19,20] Zirconocene mediated ‘chain-walking’ was also
recently reported to initiate C–C bond activation,[21] demon-
strating that there is tremendous breadth of reactivity still
remaining to be found in zirconocene initiated isomerization
processes. We note that despite the extensive previous work,
processes which couple olefin migration with asymmetric C–C
bond formation at sites remote from the initial olefin unit have
not been reported. This is remarkable because such transforma-
tions represent a straightforward approach to remote asymmet-
ric C–H functionalization, a major goal of contemporary
synthetic chemistry.
Alkylzirconium reagents, generated in situ by hydrometalla-
tion of terminal alkenes, can be used in asymmetric conjugate
addition (ACA) reactions[22–25] to cyclic Michael acceptors
to form tertiary centres,[26–28] quaternary centres,[29,30] and
lactones.[31] Here we report that the combination of Schwartz
reagent and internal alkenes can convert remote C–H bonds into
terminal alkylzirconium reagents that can be used in ACA
reactions.
Our studies began by examining the sequential hydro-
metallation–isomerization–ACA (HM-I-ACA) of trans-4-
octene to 4,4-dimethylcyclohexen-2-one (Table 1). For simplic-
ity we varied only the conditions for hydrometallation, keeping
the reaction conditions previously reported for asymmetric
addition to unsubstituted cyclic enones constant.[26] In the case
of terminal alkenes we use CH2Cl2 as solvent for hydrozircona-
tion, which is generally complete within 30 min at room tem-
perature as judged by the appearance of a clear yellow solution.
The hydrozirconation of internal alkenes is more energetically
demanding than monosubstituted alkenes, and stirring trans-4-
octene in CH2Cl2 at room temperature for more than 6 h
provided no hydrozirconated product, and so we examined
solvents with higher boiling points (Table 1). HM-I-ACA using
chloroform at 608C, for the hydrozirconation, provided no ACA
product. However, when using THF at the same temperature,
1 was obtained in moderate yield and low (50 %) enantiomeric
excess (entry 2). We then performed the hydrometallation in
THF at 608C, and once judged finished by the appearance of a
clear solution, the THF was removed under reduced pressure
and CH2Cl2 was added before adding the isomerization product
*Dedicated to the late Professor Richard Langler.
Journal compilation Ó CSIRO 2015
www.publish.csiro.au/journals/ajc

402
L. Mola, M. Sidera, and S. P. Fletcher
O
Table 1. Optimization of the conditions for hydrometallation–
isomerization
O
R3 R3
CuCl (10 mol-%),
L1 (10 mol-%)
O
Cp2ZrHCl
CuCl (10 mol-%),
O
AgOTf (11 mol-%)
Alkene
L1 (10 mol-%)
THF, 60°C
then CH2Cl2
TMSCl (5.0 equiv.), Et2O
R
Cp2ZrHCl
AgOTf (11 mol-%)
R3 R3
Solvent
60°C
TMSCl (5.0 equiv.), Et2O
6
R
3 ϭ H, Me
Ph
Ph
O
1
Alkenes ϭ
P
N
O
O
O
O
Ph
L1
Ph
Entry
Solvent
Yield [%]
ee [%]
1
2
35 %, 84 % ee
50 %, 90 % ee
1
CHCl3
0
53
46
50
NA
50
2
THF
O
3
4A
THF then CH2Cl2
THF then CH2Cl2
58
90
ATHF was removed under reduced pressure after the addition of CH2Cl2.
4
3
22 %, 89 % ee
39 %, 87 % ee
Scheme 1. Asymmetric conjugate addition to cyclohexenones using
to the copper-ligand solution (entry 3). This procedure increased
the ee of the ACA product to 58 %. The ee was dramatically
increased (from 58 to 90 % ee) by using a procedure where the
THF was co-evaporated with CH2Cl2 before adding additional
CH2Cl2, and we suspect that this procedure gives higher
enantioselectivity because it removes most of the THF from
the reaction.
internal alkenes.
O
CuCl (10 mol-%),
L2 (10 mol-%)
O
With optimized hydrozirconation–isomerization conditions
in hand we explored the generality of the HM-I-ACA to cyclic
enones to form tertiary centres (Scheme 1).
Cp2ZrHCl
AgNTf2 (11 mol-%)
Alkene
tBuOMe
THF, 60°C
R
The method affords 3-substituted cyclohexenones with
high enantioselectivity and moderate yields. The use of methyl
styrene provided 2 in moderate yield (35 %) and enantioselec-
tivity (84 % ee). The NMR spectrum of the crude reaction
mixture suggested the presence of branched side products which
we were unable to isolate in pure form. Such products could
arise from incomplete chain-walking migration or migration
towards the aromatic ring. Regiomerichydrometallationproducts
have previously been observed[20] and likely contribute to the
lower yield observed with 2. The use of trans-5-decene afforded
3 in 39 % yield and 87 % ee. When using 2-cyclohexenone
instead of 4,4-dimethyl-2-cyclohexenone, 4 was obtained with
comparable enantioselectivity (89 % ee), but the yield was
diminished (to 22 %). We note that ACAs of alkylzirconiums
to cyclohexenone typically give lower yields than to substituted
cyclohexenones because some of the enolate produced during
1,4-addition to cyclohexenone undergoes further reaction with
unreacted starting material.[26]
then CH2Cl2
Ph
N
Alkenes ϭ
Ph
Ph
O
P
O
L2
O
O
5
6
30 %, 90 % ee
43 %, 87 % ee
O
Ph
7
30 %, 92 % ee
We next explored the formation of quaternary centres. In this
case, ligand L2 developed in our group, and copper triflimide
(rather than copper triflate) in tert-butyl methyl ether generally
provides the highest enantioselectivity.[29] The use of HM-I-
ACA also worked in this case (Scheme 2) to provide 5, 6, and 7
with excellent enantioselectivities despite low yields.
Scheme 2. Formation of quaternary centres via ACA using internal
alkenes.
isomerization in THF followed by solvent exchange 8 was
obtained in 40 % yield and 84 % ee.
When performing HM-I-ACA with an a,b-unsaturated lac-
tone (Scheme 3) we used our previously developed conditions
(complex A in Et2O with 5 equivalents of TMSCl).[31] After
In conclusion, we report preliminary studies into a copper-
catalyzed hydrometallation–isomerization asymmetric conjugate
addition reaction that serves as an asymmetric remote C–H

Asymmetric Remote C–H Functionalization
403
O
O
O
Cp2ZrHCl
Complex A (10 mol-%)
O
3
3
THF, 60°C
then CH2Cl2
Et2O, TMSCl (5.0 equiv.)
7
Ϫ
8
OTf
Ph
40 %, 84 % ee
ϩ
Cu
Ph
O
P
N
O
Complex A
Scheme 3. ACA of trans-5-decene to 6,7-dihydrooxepin-2(5H)-one.
activation sequence. Tertiary and all-carbon quaternary centres
are formed with high levels of enantioselectivity by coupling
unactivated methyl groups to cyclic Michael acceptors. The
current system is limited to linear alkenes and yields are generally
low. Conceptually, this work allows internal alkenes to act as the
equivalents of premade terminal organometallic nucleophiles in
catalytic asymmetric reactions for the first time.
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Supplementary Material
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Acknowledgements
The authors thank the EPSRC for generous support of this research in the
form of a Career Acceleration Fellowship to S.F. (EP/H003711/1).
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