Copper(i)-catalysed asymmetric allylic reductions with hydrosilanes

Article abstract of DOI:10.1039/c7cc07008j

A copper(i)-catalysed asymmetric allylic reduction enables a regio- and stereoselective transfer of a hydride nucleophile in an S_N2′-fashion onto allylic bromides. This transformation represents a conceptually orthogonal approach to allylic substitution reactions with carbon nucleophiles. A copper(i) complex based upon a chiral N-heterocyclic carbene (NHC) ligand allows for stereoselectivity reaching 99% ee. The catalyst enables a stereoconvergent reaction irrespective of the double bond configuration of the starting materials.

Full text of DOI:10.1039/c7cc07008j

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Copper(I)-catalysed asymmetric allylic reductions
with hydrosilanes†
Cite this:DOI: 10.1039/c7cc07008j
T. N. Thanh Nguyen, Niklas O. Thiel and Johannes F. Teichert
*
Received 6th September 2017,
Accepted 5th October 2017
DOI: 10.1039/c7cc07008j
rsc.li/chemcomm
A copper(I)-catalysed asymmetric allylic reduction enables a regio- and
stereoselective transfer of a hydride nucleophile in an SN20-fashion onto
allylic bromides. This transformation represents a conceptually ortho-
gonal approach to allylic substitution reactions with carbon nucleo-
philes. A copper(I) complex based upon a chiral N-heterocyclic carbene
(NHC) ligand allows for stereoselectivity reaching 99% ee. The catalyst
enables a stereoconvergent reaction irrespective of the double bond
configuration of the starting materials.
The catalytic asymmetric allylic substitution reaction is a hallmark
of transition metal catalysis, which enables the generation of
terminal alkenes bearing a stereogenic center in the allylic
position.1 Especially for carbon-based nucleophiles, chiral copper(I)
complexes are well-established catalysts for asymmetric allylic sub-
stitution reactions.2 However, no generally applicable catalyst is
Scheme 1 Alternative approaches to chiral a-olefins: copper(I)-catalysed
asymmetric allylic substitutions with carbon or hydride nucleophiles
(LG = leaving group).
available, and for every nucleophile class to be transferred (bearing an isolated, catalyst-controlled process.12,13 We report herein
either an aryl or alkyl group, from e.g. Zn, Mg, B or Al-based reagents) the development of a copper-catalysed enantioselective hydride
a specialised protocol is required (Scheme 1, top).3–8 An ortho- transfer in an SN20-fashion.14 This asymmetric allylic reduction
gonal alternative approach would be the stereoselective transfer of relies on hydrosilanes as stoichiometric hydride donors.
a hydride nucleophile to a higher substituted starting material.
Following the precedence of the racemic variant, in orienting
This approach would ideally be applicable to a wide variety of experiments we have identified chiral copper(I)/NHC complexes
allylic acceptors, independent of the nature of the substituents R (NHC = N-heterocyclic carbene) as potent catalysts to induce stereo-
and R0 (Scheme 1, bottom). However, two possible challenges selectivity for the envisaged catalytic transformation. Employing
might hamper the development of a successful catalytic protocol: 2-naphthophenone-derived trisubstituted allylic bromide 1 as a
(i) the higher substituted starting materials might be sterically non-volatile model substrate with a catalyst derived from the ligand
too demanding for effective catalysis and (ii) stereoinduction precursor (S,S)-415 and heptamethyltrisiloxane as a hydride source,
might be difficult for a relatively small hydride nucleophile.
the corresponding terminal alkene 2 was obtained from E-1 in good
Even though copper(I) hydride complexes have been success- yield and with an excellent 97% ee (Scheme 2).16 It was found that
fully employed as hydride nucleophiles in a wide variety of also Z-1 gave (S)-2 with a similar ee value (95%), indicating a
asymmetric transformations,9 their use in asymmetric allylic stereoconvergent process.17 In both reactions the regioselectivity
substitution reactions has not been described to the best of our was high (o5% a-substitution product 3). This stereoconvergence
knowledge. Such a copper-catalysed allylic hydride transfer – an obviates the need for a stereoselective preparation of the allylic
allylic reduction – has been postulated as a part of a multi-step bromide and therefore, E/Z mixtures of the corresponding allylic
catalytic transformation,10,11 but has never been realised as bromides can directly be employed without the need for separation
of isomers. This feat simplifies the overall process, as the stereo-
selective synthesis of allylic bromides can be tedious.
¨
¨
Institut fur Chemie, Technische Universitat Berlin, Strasse des 17. Juni 115,
With optimised conditions in hand, we sought to explore
10623 Berlin, Germany. E-mail: johannes.teichert@chem.tu-berlin.de
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c7cc07008j the substrate scope and limitations of the asymmetric allylic
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Scheme 2 Optimised conditions for the copper-catalysed allylic reduction
and stereoconvergence (Np = 2-naphthyl).
Scheme 4 Cu-Catalysed allylic reduction and generation of stereocenters
bearing alkyl substituents. (Yield is given as combined yield of 9 and 10. The
9/10 ratio was determined by GC analysis. Determination of ee values by GC
or HPLC analysis employing chiral stationary phases. a The Z/E ratio of the
starting material 8. b Determined via NMR analysis of the Mosher ester
derivative (obtained from hydroboration/oxidation and transformation to
the Mosher ester); see the ESI† for details. c Product is volatile.)
reduction protocol. Generally, the isolated yields and regio-
selectivity (6/7) were good to excellent (Schemes 3 and 4).
Furthermore, in most cases E/Z-mixtures of the allylic bromides
5 or 8 were employed. First, we investigated a variety of methyl-
substituted allylic bromides 5, to probe whether the present
method could be used to install stereogenic centers bearing a
methyl group (Scheme 3). We found that for the successful
transfer of the relatively small hydride nucleophile with the
optimised catalyst, small electronic and steric variations have a
large impact on the stereoselectivity of the overall reaction:
while moving from the 2-naphthyl-substituent in 1 (Scheme 2)
to the phenyl group in 5a, a significant drop in stereoselectivity
was observed (34% ee). In contrast, the electron-rich anisole-
derived terminal alkene 6b could be isolated with excellent
99% ee. ortho-Substituents on the aromatic ring seem to interfere
with the catalyst, as can be seen from the diminished regio- and
stereoselectivity in the generation of terminal alkene 6c with 40% ee
and an SN20 to SN2 ratio of 50 : 50. While the sterically demand-
ing adamantyl-derived allylic bromide 5d was converted with
acceptable 80% ee, the present method finds limitations with
undecenyl-derived compound 6e (12% ee). This last example, how-
ever, represents a particularly challenging substrate, as (i) a relatively
small hydride nucleophile has to be transferred and (ii) the catalyst
has to differentiate between a primary (methyl-) and a secondary
alkyl carbon atom (n-octyl) for stereodiscrimination. Allylic bromides
bearing electron-withdrawing groups such as 5f gave full conversion
(g/a = 90 : 10), but rapidly decomposed during workup.
We investigated allylic bromides substituted by other alkyl
groups in the g-position next. Compared to the results of terminal
alkene 6a in terms of stereoselectivity (Scheme 3), the corres-
ponding longer alkyl chains give rise to significantly higher ee
values (Scheme 4): terminal alkenes 9a–9c bearing ethyl, n-propyl
Scheme 3 Cu-Catalysed allylic reduction and generation of stereocenters and n-pentyl chains can be isolated with 68%, 93% and 72%
bearing a methyl group. (Yield is given as combined yield of 6 and 7. The 6/7
ratio was determined by GC analysis. Determination of ee values by GC or
HPLC analysis employing chiral stationary phases. a The Z/E ratio of the
starting material 5. b Determined via NMR analysis of the Mosher ester
derivative (obtained from hydroboration/oxidation and transformation to
the Mosher ester); see the ESI† for details.)
enantiomeric excesses, respectively. A branched substituent such
as in the iso-butyl-derivative 9d seemed to interfere with the
stereoinduction (35% ee). We found that the present asymmetric
allylic reduction protocol is especially suited for allylic bromides
bearing small rings in the g position: the cyclopropyl- to
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cyclopentyl-substituted terminal alkenes 9e–9g can be furnished
with high enantiomeric excesses (78–99% ee). It should be noted
that there is no general approach to this substrate class in the
literature.18 The cyclohexyl derivative 9h gave only negligible
values of enantioselectivity (6% ee) which serves as an indication
for the mode of stereodiscrimination (see below).
To explain the stereoselectivity and -convergence found for the
allylic reduction protocol, we resort to a previously developed
model for similar allylic borylations.15 Following this precedent,
we hypothesise that the stereoselectivity of the present allylic
reduction is governed solely by the two substituents in the
g-position of the allylic bromide when approaching the copper(I)
hydride NHC complex (hydride attack from the Re face). This leads
to a stereoconvergent process independent of the double bond
configuration (Fig. 1). Indeed, comparing the absolute configu-
ration obtained in the present asymmetric allylic reduction with
the literature precedents of borylations15 and silylations19 shows
that all the nucleophiles are delivered from the same face to the
corresponding allylic acceptors when employing (S,S)-4.20 Follow-
ing this model, the difference in size of the two g-substituents is
essential for high stereoinduction, which explains the low ee value
found for the cyclohexyl-derivative 9h (Scheme 4). Here, the steric
demands of the cyclohexyl and phenyl groups seem to be relatively
similar, leading to little enantioinduction.
Scheme 5 Plausible catalytic cycle.
With regards to the catalytic cycle, the fact that for most of the
allylic reduction experiments a small amount (generally o5%) of
the corresponding a-substituted internal alkenes 7 or 10 is detected
serves as an indication that during the catalytic cycle a p-allyl-
copper complex should be accessible. This is also backed up by our
findings from the racemic variant, where minute changes of the
electronic properties of the NHC ligand led to a drastic reversal of
the regioselectivity of the reaction.14 Therefore, a plausible mecha-
nism is presented in Scheme 5: after initial salt metathesis to yield
the active copper(I)-tert-butoxide complex A, the copper(I) hydride
complex B is formed through s bond metathesis.21 Subsequent
oxidative addition leads to a s-allyl complex which most likely is in
equilibrium with the corresponding p-allyl complex C.22 Reductive
elimination then leads to the allylic reduction product and
copper(I) bromide complex D, which can re-enter the catalytic cycle
via the reaction with another equivalent of NaOtBu.
allylic reduction delivers the corresponding terminal alkenes
bearing a stereocenter with high regioselectivity and up to
excellent ee values, and therefore represents a conceptually
orthogonal approach to the well-established asymmetric allylic
substitutions with carbon-based nucleophiles. Particularly,
substrates bearing small rings previously unavailable through
other asymmetric syntheses deliver very good results in terms of
stereoselectivity. These ee values are remarkable considering the
size of the hydride nucleophile being transferred. The present
catalyst allows for the application of both double bond isomers of
the starting materials through a stereoconvergent catalytic pro-
cess, which circumvents the need for a laborious stereoselective
preparation of the allylic bromides.
This research was supported by the Fonds der Chemischen
Industrie (Liebig-Stipendium for J. F. T. and T. N. T. N.). We kindly
thank Prof. Dr Martin Oestreich (TU Berlin) for generous support.
In conclusion, we have developed a hitherto unknown copper(I)-
catalysed asymmetric transfer of a hydride nucleophile stemming
from a hydrosilane to allylic bromides. The resulting asymmetric
Conflicts of interest
There are no conflicts to declare.
Notes and references
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