Rhodium-Catalyzed Enantioselective Silylation of Cyclopropyl C?H Bonds

Article abstract of DOI:10.1002/anie.201603153

Hydrosilyl ethers, generated in situ by the dehydrogenative silylation of cyclopropylmethanols with diethylsilane, undergo asymmetric, intramolecular silylation of cyclopropyl C?H bonds in high yields and with high enantiomeric excesses in the presence of

Full text of DOI:10.1002/anie.201603153

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International Edition: DOI: 10.1002/anie.201603153
German Edition: DOI: 10.1002/ange.201603153
À
Asymmetric C H Activation
À
Rhodium-Catalyzed Enantioselective Silylation of Cyclopropyl C H
Bonds
Taegyo Lee and John F. Hartwig*
Abstract: Hydrosilyl ethers, generated in situ by the dehydro-
genative silylation of cyclopropylmethanols with diethylsilane,
undergo asymmetric, intramolecular silylation of cyclopropyl
À
C H bonds in high yields and with high enantiomeric excesses
in the presence of a rhodium catalyst derived from a rhodium
precursor and the bisphosphine (S)-DTBM-SEGPHOS. The
resulting enantioenriched oxasilolanes are suitable substrates
for the Tamao–Fleming oxidation to form cyclopropanols with
À
conservation of the ee value from the C H silylation.
À
Preliminary mechanistic data suggest that C H cleavage is
likely to be the turnover-limiting and enantioselectivity-deter-
mining step.
À
T
he functionalization of C H bonds with boranes and silanes
has been studied intensively, due to the high regioselectivity
À
of these processes for sterically accessible C H bonds and the
widespread utility of the products.[1,2] However, the develop-
ment of enantioselective variants of these reactions,[3–5]
À
particularly enantioselective functionalization of alkyl C H
bonds, has been limited (Scheme 1). The group of Kuninobu,
À
Murai, and Takai reported the asymmetric silylation of a C H
bond to generate a stereogenic silicon center with up to 88%
enantiomeric excess (ee) (Scheme 1A),[6,7] and the groups of
Shibata, He, Murai, and Takai independently reported the
synthesis of planar-chiral compounds with moderate to high
À
Scheme 1. Enantioselective C H silylation.
reagents.[14,15] In addition, Cramer and co-workers reported
Pd-catalyzed intramolecular arylations and alkylations of
cyclopropyl C H bonds to form tetrahydroquinolines, dihy-
À
enantioselectivities by asymmetric C H silylation of ferro-
cenes.[8–10] Recently, we reported an enantioselective silylation
À
of aryl C H bonds to form enantioenriched benzoxasilole
droquinolones, dihydroisoquinolones, and g-lactams.[16–18]
However, enantioselective functionalization to form products
containing a new carbon–heteroatom bond has not been
reported. Enantioselective silylation would generate a prod-
uct containing a new carbon–oxygen bond after oxidation of
À
products with up to 99% ee.[11] Although these reactions can
occur with high enantioselectivity, they are limited to the
À
functionalization of aryl C H bonds. The only published set
À
of enantioselective silylations of alkyl C H bonds occurs with
[19]
À
low ee values (37–40% ee) and with limited scope (Sche-
the C Si bond in the silylation product.
Although two
me 1B).[12]
silylations of cyclopropyl C H bonds have been reported,
no enantioselective variant of this reaction has been pub-
lished.
[20,21]
À
À
To create the first silylations of alkyl C H bonds that
occur with high enantioselectivity, we investigated reactions
À
of cyclopropanes. C H bonds of cyclopropanes are more
We report a rhodium-catalyzed, enantioselective silyla-
tion of cyclopropanes directed by a hydrosilyl group (Sche-
me 1C). The reaction is initiated by formation of silyl ether 2
from cyclopropylmethanol 1 and leads to the silylation of
À
reactive than Csp3 H bonds of unstrained rings or alkyl
chains,[13] and the rigid conformation of a cyclopropane could
allow for high stereoselectivity. Yu and co-workers reported
enantioselective, Pd-catalyzed arylation and alkylation reac-
tions of cyclopropanes containing N-aryl or triflyl amides as
À
a cyclopropyl C H bond to form the silylcyclopropane
product 3 in high yield and with high enantioselectivity. This
À
a
directing group with organoborane or iodoarene
process is a rare example of the silylation of secondary C H
bonds,[20–24] and the product undergoes oxidation with full
conservation of the enantiomeric excess of the silylation
product to form a diol containing a secondary carbinol
stereocenter that would be difficult to set by more classical
hydrogenation of the corresponding ketone.[25]
[*] T. Lee, Prof. Dr. J. F. Hartwig
Department of Chemistry, University of California
Berkeley, CA 94720 (USA)
E-mail: jhartwig@berkeley.edu
We began our investigation of the enantioselective
silylation of cyclopropanes by examining the reactions of (1-
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201603153.
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Table 1: Evaluation of reaction conditions.
phenylcyclopropyl)methanol (1a). The dehydrogenative cou-
pling of 1a with diethylsilane catalyzed by [{Ir(cod)Cl}2] or
[{Ir(cod)OMe}2] under conditions we reported previously for
the dehydrogenative silylation of alcohols and amines[24,26–28]
led to a mixture of hydrosilyl ether 2a and dialkoxysilane 4
[Eq. (1)]. In contrast, the same reaction catalyzed by
0.2 mol% [Ru(PPh3)3Cl2] at 508C delivered 2a exclusively.
Entry
Ligand
Hydrogen acceptor
Yield [%][a]
ee [%][b]
1
L1
L2
L3
L4
L5
L6
L7
L1
L1
L1
cyclohexene
cyclohexene
cyclohexene
cyclohexene
cyclohexene
cyclohexene
cyclohexene
norbornene
none
93
9
83
nd
nd
À11
À39
À45
À36
84
2[c]
3[c]
4[c]
5[c]
6
25
35
55
60
48
81
54
90
7
8
The ruthenium complex did not catalyze the silylation of
alcohol 1a with the silyl ether 2a.[27,29] Silyl ether 2a formed
by the Ru-catalyzed process was used without further
9[c]
10[d]
70
87
cyclohexene
À
purification for the silylation of a cyclopropyl C H bond
[a] Determined by GC analysis with dodecane as the internal standard.
[b] Determined by SFC analysis on a chiral stationary phase. A negative
ee value indicates ent-3a was formed as the major enantiomer. nd=not
determined. [c] 12 h. [d] 508C, 24 h.
after removal of the solvent and remaining diethylsilane.
Having identified a simple synthesis of 2a, we sought
conditions for this asymmetric, intramolecular silylation
(Table 1). Based on previous reports of Rh-catalyzed silyla-
tions of C H bonds,[9–12] we examined the Rh catalyst derived
À
from [{Rh(cod)Cl}2] and (S)-DTBM-SEGPHOS (L1) with
cyclohexene as a hydrogen acceptor[30] at 808C (entry 1). The
À
functionalization of the cyclopropyl C H bond occurred in
2 hours under these conditions, yielding the cyclized product
3a in 93% yield and 83% ee. Other SEGPHOS derivatives,
such as (S)-SEGPHOS (L2), (R)-DM-SEGPHOS (L3), and
(R)-DMM-SEGPHOS (L4), formed catalysts with lower
reactivity and enantioselectivity toward the silylation than
did (S)-DTBM-SEGPHOS (L1) (entries 2–4). These results
suggest that bulky substituents on the ligand are important for
achieving both high reactivity and high selectivity. Complexes
generated from related bisphosphine ligands, such as (R)-
DTBM-BINAP (L5), (R)-DTBM-MeOBIPHEP (L6), and
(R)-DTBM-GARPHOS (L7) (entries 5–7), were less selec-
tive catalysts.
The presence of a hydrogen acceptor in the reaction and
the proper identity of this acceptor were critical to achieve
high yield and good enantioselectivity, and the temperature
substantially affected the enantioselectivity. In the absence of
a hydrogen acceptor, competing processes occurred, including
the disproportionation of 2a to form 4 (entry 9), and low yield
and ee of the silylcyclopropane were observed. The reaction
with norbornene instead of cyclohexene as hydrogen acceptor
also occurred in lower yield, due to the hydrosilylation and
dehydrogenative silylation of norbornene (entry 8). Reac-
tions run at 508C occurred with higher enantioselectivity than
those run at 808C, and high conversion was maintained
(entry 10).
Having established conditions for the enantioselective
silylation of cyclopropane 2a, we investigated the scope of the
reaction. Table 2 shows yields of isolated products and
representative yields determined by gas chromatography
1
(GC) or H NMR spectroscopy.[34] In general, the enantiose-
lectivity of the reaction correlated with the steric properties of
the aryl ring in the substrate. The enantioselectivities for
reactions of substrates containing meta (1b,c) or ortho (1d)
substituents on the aryl rings were higher than the enantio-
selectivities for substrates lacking any substituents (1a) or
those of substrates containing only para (1g) substituents on
the aryl ring. A similar correlation between enantioselectivity
and steric properties was observed for the reactions of
cyclopropylmethanols substituted with naphthyl groups. For
example, the enantioselectivity of the reaction of (1-naph-
thylcyclopropyl)methanol (1 f) was higher than that of the
reaction of the less sterically demanding (2-naphthylcyclo-
propyl)methanol (1e).
With cyclohexene as hydrogen acceptor, L1 as ligand, and
508C as the reaction temperature (entry 10), the competing
processes were suppressed. For example, products from the
À
silylation of aryl C H bonds were not observed, although the
conditions we developed are similar to those used for the
Further reactions probed the functional-group tolerance
of the silylation process. Aryl halides (1g,h) and a trifluoro-
methylarene (1i) were both compatible with the reaction
conditions. Oxygen-based functional groups, such as methoxy
(1j), benzyloxy (1k), siloxy (1l), and alkoxycarbonyl (1m)
[11]
À
silylation of aryl C H bonds. In addition, ring opening of
the cyclopropane by the hydrosilyl group was not observed.
Opening of a cyclopropane ring by a hydrosilane in the
presence of Rh catalysts has been reported previously.[31–33]
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[a]
À
Table 2: Scope of the enantioselective C H silylation.
reaction of a cyclopropane bearing a primary alkyl substituent
was almost identical to that of the reaction of a cyclopropane
bearing a secondary alkyl substituent. The high enantioselec-
tivity for arylcyclopropanes could result from an interaction
between the aryl rings of the catalyst and the aryl substituents
of the substrate.
In addition to controlling the enantioselectivity, the chiral
catalyst could control the diastereoselectivity of the silylation
of an enantioenriched cyclopropane, such as substrate 5 in
Table 3. To determine the inherent diastereoselectivity con-
trolled by the substrate, we conducted a silylation reaction of
5 with the achiral catalyst generated from [{Ir(cod)OMe}2]
À
Table 3: Diastereoselective C H silylation on a chiral substrate.
Entry Conditions
Yield [%][a]
6a/6b[b]
1
2
3
[{Ir(cod)OMe}2]/Me4phen (2 mol%) 78
10:1
norbornene, 808C, 6 h
[Rh]/ent-L1 (4 mol%)
cyclohexene, 508C, 24 h
[Rh]/L1 (4 mol%)
66
>20:1
1:1.6
>99% ee[c]
57[d]
cyclohexene, 508C, 24 h
[a] Yields of isolated products for reactions conducted on a 0.25 mmol
scale following purification by silica gel chromatography. [b] Determined
by GC analysis. [c] The ee value corresponds to the major isomer 6a and
was determined by chiral HPLC analysis. The absolute configuration was
assigned by analogy. [d] The isolated product contained about 5% of
inseparable impurities.
and 3,4,7,8-tetramethyl-1,10-phenanthroline (Me4phen) at
808C (entry 1). This reaction yielded a mixture of 6a and
6b in 10:1 ratio. This result suggests that there is a strong
preference to form 6a over 6b, presumably to avoid the
unfavorable steric interaction between the phenyl and methyl
groups. In the matched combination of catalyst and substrate,
[a] Yields of isolated products for reactions conducted on a 0.25–
1.0 mmol scale following purification by bulb-to-bulb distillation or silica
gel chromatography. The ee values were determined by chiral SFC or
HPLC analysis. The absolute configuration was assigned by analogy.
[b] Reactions were conducted on a 0.1 mmol scale to determine yields by
GC analysis with dodecane as the internal standard. [c] Reactions were
conducted on a 0.1 mmol scale to determine yields by 1H NMR analysis
with 1,1,2,2-tetrabromoethane as an internal standard added after the
reaction.
the reaction of
5 catalyzed by the combination of
[{Rh(cod)Cl}2] and ent-L1 yielded a mixture of 6a and 6b in
a ratio over 20:1 (entry 2) and with enantiomeric excess for 6a
exceeding 99%. Thus, this silylation protocol forms an
enantiopure compound possessing three consecutive stereo-
genic centers from a readily accessible enantioenriched
secondary alcohol.[35,36] The reaction of 5 conducted with the
combination of [{Rh(cod)Cl}2] and L1 as the catalyst formed
a mixture of 6a and 6b in a 1:1.6 ratio with 6b as the major
diastereomer (entry 3). Although the diastereoselectivity was
low, the catalyst did override the substrate bias and formed
the isomer that was strongly disfavored with an achiral
catalyst as the major product.
To gain insight into the mechanism of this reaction, we
determined the kinetic isotope effect (KIE) by measuring the
initial rates of the silylation of non-deuterated and deuterated
substrates 2a and [D2]-2a in separate vessels. The KIE from
this set of experiments was 2.1 (Scheme 2). This value is
similar to that we observed for the Ir-catalyzed silylation of
groups, were also compatible with the silylation process.
Whereas nitro groups were not tolerated under the reaction
conditions, carbamates (1n) and tertiary amino groups (1o)
were.
The enantioselectivity for reactions of cyclopropanes
substituted with alkyl groups (3p,q) was lower than that for
reactions of cyclopropanes substituted with aryl groups. This
trend does not correlate with the steric environment imposed
by the alkyl groups because the enantioselectivity of the
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Keywords: asymmetric catalysis · C H activation ·
cyclopropanes · rhodium · silylation
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À
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In summary, we have developed an enantioselective
silylation of cyclopropanes, which constitutes the first highly
À
enantioselective silylation of an alkyl C H bond and the first
À
catalytic, enantioselective functionalization of the C H bond
À
deprotonation of cyclopropyl C H bonds with a stoichiometric
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NIH (S10-RR027172) for support of the X-ray facility, Dr. A.
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a generous gift of (S)-DTBM-SEGPHOS. T.L. thanks the
Samsung Scholarship for a graduate fellowship and Mat-
thew A. Larsen and Dr. Sarah Y. Lee for insightful discus-
sions.
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Received: March 30, 2016
Published online: && &&, &&&&
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Communications
À
Asymmetric C H Activation
T. Lee, J. F. Hartwig*
&&&& — &&&&
Rhodium-Catalyzed Enantioselective
À
Silylation of Cyclopropyl C H Bonds
Enantioenriched cyclopropanes: Hydro-
silyl ethers, generated in situ by the
dehydrogenative silylation of cyclopro-
pylmethanols, undergo asymmetric,
intramolecular silylation of cyclopropyl
enantiomeric excesses in the presence of
a rhodium catalyst. The silylation prod-
ucts are suitable substrates for Tamao–
Fleming oxidation to form cyclopropanols
with conservation of the ee value from the
À
À
C H bonds in high yields and with high
C H silylation.
6
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