Ir-Catalyzed Enantioselective, Intramolecular Silylation of Methyl C-H Bonds

Article abstract of DOI:10.1021/jacs.7b06679

We report highly enantioselective intramolecular, silylations of unactivated, primary C(sp³)-H bonds. The reactions form dihydrobenzosiloles in high yields with excellent enantioselectivities by functionalization of enantiotopic methyl groups u

Full text of DOI:10.1021/jacs.7b06679

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Communication
Iridium-Catalyzed Enantioselective Silylation of Unactivated C(sp3)-H Bonds
Bo Su, and John F. Hartwig
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b06679 • Publication Date (Web): 18 Aug 2017
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Ir-Catalyzed Enantioselective, Intramolecular Silylation of Methyl
C-H Bonds
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Bo Su and John F. Hartwig*
Department of Chemistry, University of California, Berkeley California, 94720, CA
Supporting Information Placeholder
In 2013, Takai, Kuninubu, and coworkers published the
ABSTRACT: We report highly enantioselective silylations
first enantioselective silylation of aromatic C-H bonds.10
The reaction was catalyzed by a rhodium complex ligated
by a chiral diphosphine (Scheme 1a, left), forming chiral
spirosilabifluorenes in up to 90.5:9.5 er. In 2015, Shibata,
He, and Takai independently reported enantioselective si-
lylations of aromatic C-H bonds that form chiral ferrocenes
(Scheme 1a, middle) catalyzed by rhodium complexes of
chiral bisphosphine or diene ligands.11 He and coworkers
reported Rh-catalyzed tandem desymmetrizations of silacy-
clobutanes and silylations of C-H bonds to construct chiral
tetraorganosilanes.12 Our group reported rhodium-catalyzed
enantioselective silylations of aromatic C-H bonds in dia-
rylmethanols (Scheme 1a, right) 13 and silylations of cyclo-
propyl C-H bonds (Scheme 1b, left).14 The only enantiose-
lective silylations of unactivated C(sp3)-H bonds were re-
ported by Takai and Murai, and these reactions occur with
enantioselectivities below 70:30 er (Scheme 1b, right).11b
of unactivated, primary C(sp3)-H bonds. The reactions form
dihydrobenzosiloles in high yields with excellent enanti-
oselectivities by functionalization of enantiotopic methyl
groups under mild conditions. The reaction is catalyzed by
an iridium complex generated from [Ir(COD)OMe]2 and
chiral dinitrogen ligands that were recently developed by
our group. The C-Si bonds in the enantioenriched dihydro-
benzosiloles were further transformed to C-Cl, C-Br, C-I
and C-O bonds in final products. The potential of this reac-
tion was illustrated by sequential C(sp3)-H and C(sp2)-H
silylations and functionalizations, as well as diastereoselec-
tive C-H silylations of a chiral, natural-product derivative
containing multiple types of C-H bonds. Preliminary mech-
anistic studies suggest that C-H cleavage is likely the rate-
determining step.
Reactions that form carbon-silicon bonds are valuable
because carbon-silicon bonds can be transformed to a va-
riety of carbon-carbon and carbon-heteroatom bonds1 and
because organosilicon compounds, themselves, have appli-
cations in material science2, agroscience,3 and medicinal
chemistry4 (Figure 1). Among the reactions that form C-Si
bonds,1b, 1c, 5 transition metal-catalyzed direct silylations of
inert C-H bonds have been pursued because of the potential
of this reaction to generate organosilanes under mild, neu-
Scheme 1. Transition Metal-Catalyzed Enantiose-
lective Silylations of C-H Bonds
tral conditions from readily available starting materials.6
Me
CO2Et
NH3Cl
N
N
I
Si
Ph
Si
Me Me
Si
spirocyclic s-receptor
ligand
sila-analogue of
tetrahydroisoquinoline
NMe2
HO
Si
O
N
Cl
Si
F
Me Me
sila-haloperidol
sila-dimetracrine
Figure 1. Representative Biologically Active Silicon-
Containing Molecules
Although progress on the silylation of both aromatic and
aliphatic C-H bonds has been made over the past two dec-
ades,7,8 the development of enantioselective variants of
these reactions, particularly enantioselective silylation of
unactivated C(sp3)-H bonds, has been limited (Scheme 1).9
All of these prior enantioselective silylations of C-H
bonds were catalyzed by rhodium complexes ligated by
chiral phosphine or diene ligands. Iridium complexes con-
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taining chelating, N,N-donor ligands, which have shown (eq 1). The alkene serving as a hydrogen acceptor affected
1
2
3
4
5
6
7
8
the most favorable combination of reactivity and functional
group-compatibility in our studies in the C-H silylations,7f,
had not been applied to the enantioselective silylation
of C-H bonds until our recent work on iridium-catalyzed
the yield without changing the enantioselectivity (Table 1,
entries 6-10). Among the hydrogen acceptors tested, the
reaction with norbornene occurred in the highest yield
(73%). The solvent had a small effect on enantioselectivity,
but reactions in ethers occurred with higher enantioselectiv-
ities than those in more polar and potentially coordinating
solvents (eq 1). Among ethers, reactions conducted in di-
ethyl ether occurred with the highest enantioselectivity
(96:4 er), but only 60% yield. Fortunately, the yield in-
creased to 88% when the reaction time was prolonged from
12 h to 24 h (Table 1, entry 20). The absolute configuration
of compound 2a was determined after oxidation under
Tamao oxidation conditions to form the corresponding diol
for which the absolute configuration had been determined
previously (see SI for details).17
7h, 7i
silylation
of
aromatic
C-H
bonds
to
form
diarylmethanols.15
Here, we report highly enantioselective silylations of un-
activated C(sp3)-H bonds. These reactions occur at one of
two prochiral methyl groups with an iridium complex ligat-
ed by a chiral pyridyl oxazoline ligand (Scheme 1c). This
process represents a rare example of the desymmetrization
of isopropyl group by a transition metal-catalyzed C-H
bond functionalization. In contrast to recently reported
desymmetrizations of isopropyl groups to form C-C
bonds,16 the process we report forms carbon-silicon bonds
that can be transformed to carbon-halogen and carbon-
oxygen bonds.
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[Ir(cod)OMe]2, L4
*
Si
(1)
norbornene, solvent
SiH
Table 1. Effect of Reaction Parameters on the Enantiose-
lective Silylation of C(sp3)-H bonds.a
1a
2a
THF
14%
80%
65%
60%
68%
69%
95:5
cyclohexane 59%
toluene 51%
ethyl acetate 68%
95:5
95:5
95:5
88:12
96:4
TBME
95:5
94:6
96:4
93:7
95:5
dioxane
Et2O
MeCN
Et2O
22%
88% (84%)a
[Ir(cod)OMe]2, ligand
*
Si
DCE
norbornene, solvent
SiH
heptane
1a
2a
Yieldb
Reaction conditions: 1a (0.20 mmol), [Ir(cod)OMe]2 (2.0 mol %), ligand (4.5 mol %),
norbornene (1.0 equiv), solvent (1.0 mL), 12 h under N2.The yield was determined by GC
using dodecane as internal standard.aThe reaction was conducted for 24 h, and the yield
in parentheses refers to isolated yield.
Entry
Ligand
H2 Acceptor
Temperture
erc
1
L1
L2
L3
L4
L3
L4
L4
L4
L4
L4
norbornene
norbornene
norbornene
norbornene
norbornene
norbornene
cyclohexene
1-hexene
80 o
80 o
80 o
80 o
50 o
50 o
50 o
50 o
50 o
50 o
C
C
C
C
C
C
C
C
C
C
80%
20%
93%
94%
68%
73%
17%
70%
51%
14%
74:26
74:26
91:9
92:8
93:7
95:5
95:5
95:5
95:5
95:5
2
Table 2. Scope of the Enantioselective Silylation of C(sp3)-
H bonds.a
3
4
5
6
7
8
9
3,3-dimethylbutene
none
10
O
O
N
O
O
N
N
N
N
N
N
N
L1
L2
L3
L4
aThe reaction was conducted with 1a (0.20 mmol), [Ir(cod)OMe]2 (2.0 mol %), ligand (4.5
mol %), and norbornene (1.0 equiv) in THF (1.0 mL) for 12 h under N2. bThe yield was
determined by GC using dodecane as internal standard. cThe er value was determined by
chiral GC.
To identify conditions for the iridium-catalyzed enantio-
selective silylation of unactivated C(sp3)-H bonds, we
tested iridium complexes derived from [Ir(cod)OMe]2 and
chiral N,N-donor ligands L1-L4 for the intramolecular
o
silylation of dimethylarylsilane 1a in THF at 80 C (Table
1, entries 1-4). Reactions with indane-fused oxazoline L3
and L4 formed product 2a in higher yields (93% and 94%)
and enantioselectivity (91:9 er and 92:8 er) than those with
oxazoline-containing L1 (80%, 74:26 er) and L2 (20%,
74:26 er). The reaction with tetrahydroquinoline-based L4
occurred with slightly higher enantioselectivity than that
with quinoline-based L3 (Table 1, entries 5-6), and the
selectivity of the reactions catalyzed by complexes of L3
and L4 were further increased by running the reaction at 50
oC, instead of 80 oC. Changes to the hydrogen acceptor and
solvent further increased the yield and enantioselectivity
Having identified conditions for the enantioselective si-
lylation of compound 1a, the scope of the reaction was
assessed (Table 2). Reactions of dimethylarylsilanes con-
taining a range of functional groups afforded the products
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Journal of the American Chemical Society
of C-H silylation in high yields (up to 97%) and with excel-
the C(sp2)-Si bond to C-O, C-Cl, C-Br and C-I bonds, giv-
ing products 3-6 in 81-98% yields.1b, 1c, 7d, 7e
1
2
3
4
5
6
7
8
lent enantioselectivity (up to 98:2 er). Unsubstituted 1a and
alkyl or aryl substituted 1b and 1c gave the products 2a-2c
in good yields with excellent enantiomeric ratios (er). Vari-
ous oxygen-containing functional groups, such as alkoxy
ethers (2d and 2e), silylether (2f), methylsulfonate ester
(2g), pivalate ester (2h), carbonates (2i and 2j) and carba-
mate (2k) were shown to be tolerated by the reaction. Reac-
tions of substrates containing aryl chlorides (1o), alkyl
chlorides (1p) and ketals (1q) also occurred to afford prod-
ucts 2o-2q in good yield with high enantiomeric ratios.
Substrates containing varied steric and electronic proper-
ties of the arenes were also tested. Varying the electronic
properties of the arene did not significantly affect the yield
or er of the reaction (2l-2n). Moreover, meta- and ortho-
substituted 1r and 1s underwent silylation to form products
2r and 2s with excellent yields and er values. However, no
reaction occurred when the very bulky 2,4,6-triisopropyl-
substituted 1t was subjected to the reaction conditions.
To determine if the reaction can be applied to the enanti-
oseletive formation of products containing quaternary car-
bon centers with high enantioselectivity, we subjected
compound 1u to the silylation conditions. Compound 2u
was obtained in 90% yield, and modest 86:14 er due to the
small difference in steric hindrance between –Me and–
CH2OMOM groups. Replacement of the –CH2OMOM
group with a bulkier ethylene glycol-protected aldehyde
afforded product 2v in 97% yield and 95:5 er.
Compounds 3-6 obtained from 2v can be transformed to
further functionalized molecules. Compound 6 was oxi-
dized to alcohol 7, which contains a chiral quaternary car-
bon center at the β position of the hydroxyl group inacces-
sible by classic asymmetric hydrogenation. Under acidic
conditions, compound 7 was deprotected to afford aldehyde
8 in 71% yield. Under Mitsunobu conditions, compound 3
was transformed to enantioenriched 3,3-disubstituted-2,3-
dihydrobenzofuran 9 in 88% yield. To underscore the abil-
ity of a silicon tether to enable the introduction of a series
of functional groups, we conducted sequential silylations of
C(sp3)-H and C(sp2)-H bonds, followed by functionaliza-
tions (Scheme 3). The enantioselective C(sp3)-H silylation
of 1a was conducted on a 6.0 mmol scale, affording silole
2a in 95% yield and 95:5 er. After chlorination of the
C(sp2)-Si bond of 2a to form trialkylfluorosilane 10, com-
pound 10 was transformed to silole 12 in 59% yield over
two steps by reduction of the Si-F bond in 10 and silylation
of the C(sp2)-H bond in compound 11. The newly formed
C-Si bond in compound 12 was converted to a C-I bond to
form trialkylfluorosilane 13. Compound 13 was then oxi-
dized to alcohol 14 under Tamao oxidation conditions. By
this series of sequential silylation reactions, a simple start-
ing material (1a) was transformed to a product (14) con-
taining one chiral tertiary carbon center and three new
functionalities (C-Cl, C-I and C-O bonds).
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10
11
12
13
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60
Scheme 2. Transformations of the Enantioenriched Dihy-
drobenzosilolesa
Scheme 3. Sequential Silylations of C-H Bonds
O
O
O
O
O
O
OH
Si
F
h
O
OH
I
9, 88%
3, 92%
4, 81%
O
O
c
b
O
O
O
O
Si
F
d
a
Br
5, 94%
SiH
Si
e
1v (4.3 mmol, 1.1 g)
2v, 91%
Scheme 4. Diastereoselective Silylation of C(sp3)-H Bond
of Dehydroabietic Acid Derivative
O
O
O
O
OHC
OH
Si
OH
g
Br
SiH
Si
f
F
Cl
6, 98%
Cl
8, 71%
Cl
H3C
H3C
H3C
a
b
7, 74%
aConditions: a) [Ir(cod)OMe]2 (0.50 mol %), L4, (1.1 mol %), nbe, Et2O, 50 oC; b) t-
BuOOH, t-BuOK, TBAF; c) NIS, AgF, MeCN; d) NBS, AgF, MeCN; e) NCS, AgF, MeCN; f) t-
MeO
MeO
MeO
H
CH3
H
CH3
H
CH3
17, 78%,
15
16, 76%
BuOOH, KH, TBAF; g) HCl, THF/H2O; h) DEAD, PPh3, THF.
O
O
O
94:6 dr
To demonstrate the potential applications of this reac-
tion, the enantioselective silylation was conducted on a
gram scale, and the resulting silole was converted to prod-
ucts containing a series of functional groups. The silylation
of compound 1v was conducted on a 4.0 mmol scale (1.1 g)
with 0.50 mol % [Ir(cod)OMe]2 and 1.1 mol % ligand. Un-
der these conditions product 2v was isolated in 92% yield
with the same enantioselectivity (95:5 er) as that of the
reaction conducted on a 0.20 mmol scale (Scheme 2).
Product 2v was then subjected to conditions that convert
a) Mg, THF, Me2SiHCl; b) [Ir(cod)OMe]2/L4, nbe, Et2O
The silylation with a chiral iridium catalyst was also ap-
plied to the functionalization of a biologically active natu-
ral product, dehydroabietic acid (Scheme 4). Aryldime-
thrylsilane 16 was prepared from known bromide 1518 in
76% yield by a one-pot metallation and in situ nucleophilic
substitution with dimethylchlorosilane. Under the C-H si-
lylation conditions described above, compound 17 was
obtained in 78% yield and 94:6 dr, and this value is close to
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40, 4902-4911; (c) Gutekunst, W. R.; Baran, P. S., Chem. Soc. Rev.
that of the enantioselective reaction of related isopropy-
larylsilanes. This application demonstrates the potential to
use the silylation to control diastereoselectivity for the di-
versification of analogues of biologically active compounds
by late-stage, C-H bond functionalization.
To gain insight into the mechanism of the reaction, we
determined the kinetic isotopic effect (KIE) of separate
reactions of protiated (1a) and deuterated (1a-d6) substrates
(eq 2). A KIE of 1.9 ± 0.1 was obtained from this set of
experiments. This value is similar to that observed in our
previous Ir-catalyzed silylation of secondary C(sp3)-H
bonds (2.0 ± 0.1)7h and Rh-catalyzed silylation of cyclo-
propyl C-H bonds (2.1 ± 0.1)14 and implies that C-H cleav-
age is likely the rate-determining step of the reaction.19
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CD3
[Ir(cod)OMe]2 (6 mol %)
CD3
L4 (13 mol %)
CD3
D
or
(2)
or
SiH
nbe (1.2 equiv)
C6D6
kH/kD = 1.9 ± 0.1
D
Si
Si
SiH
1a
1a-d6
2a-d5
2a
In summary, we have developed a system for highly
enantioselective silylations of unactivated C(sp3)-H bonds.
The silylation reaction is catalyzed by a combination of
[Ir(cod)OMe]2 and chiral pyridyl oxazoline ligands and
occurs in high yields and excellent enantioselectivity with
substrates containing a wide range of functional groups.
The C-Si bond in the enantioenriched dihydrobenzosiloles
can be transformed to various functionalities, such as a
hydroxyl group, or a chloride, bromide or iodide. Sequen-
tial silylations of C(sp3)-H and C(sp2)-H bonds and func-
tionalizations, as well as diastereoselective silylations show
the potential of this process for diverse synthetic applica-
tions. Preliminary mechanistic studies suggest that C-H
activation is likely the rate-determining step. Further stud-
ies of the scope and mechanism of the enantioselective
silylation of C-H bonds are underway in our lab.
ASSOCIATED CONTENT
Experimental procedures, spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
10. Kuninobu, Y.; Yamauchi, K.; Tamura, N.; Seiki, T.; Takai,
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AUTHOR INFORMATION
Corresponding Author
jhartwig@berkeley.edu
Acknowledgement
We thank the NIH (GM-115812) for support.
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