Rhodium-Catalyzed Regioselective Silylation of Alkyl C-H Bonds for the Synthesis of 1,4-Diols

Article abstract of DOI:10.1021/jacs.7b11964

A rhodium-catalyzed intramolecular silylation of alkyl C-H bonds has been developed that occurs with unusual selectivity for the C-H bonds located δ to the oxygen atom of an alcohol-derived silyl ether over typically more reactive C-H bonds more proximal to the same oxygen atom. (Hydrido)silyl ethers, generated in situ by dehydrogenative coupling of tertiary alcohols with diethylsilane, undergo regioselective silylation at a primary C-H bond δ to the hydroxyl group in the presence of [(Xantphos)Rh(Cl)] as catalyst. Oxidation of the resulting 6-membered oxasilolanes generates 1,4-diols. This silylation and oxidation sequence provides an efficient method to synthesize 1,4-diols by a hydroxyl-directed, aliphatic C-H bond functionalization reaction and is distinct from the synthesis of 1,3-diols from alcohols catalyzed by iridium. Mechanistic studies show that the rhodium-catalyzed silylation of alkyl C-H bonds occurs with a resting state and relative rates for elementary steps that are significantly different from those for the rhodium-catalyzed silylation of aryl C-H bonds. The resting state of the catalyst is a (Xantphos)Rh(I)(SiR₃)(norbornene) complex, and an analogue was synthesized and characterized crystallographically. The rate-limiting step of the process is oxidative addition of the δ C-H bond to Rh. Computational studies elucidated the origin of high selectivity for silylation of the δ C-H bond when Xantphos-ligated rhodium is the catalyst. A high barrier for reductive elimination from the six-membered metalacyclic, secondary alkyl intermediate formed by cleavage of the γ C-H bond and low barrier for reductive elimination from the seven-membered metalacyclic, primary alkyl intermediate formed by cleavage of the δ C-H accounts for the selective functionalization of the δ C-H bond.

Full text of DOI:10.1021/jacs.7b11964

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Article
Rhodium-Catalyzed Regioselective Silylation of
Alkyl C-H Bonds for the Synthesis of 1,4-Diols
Caleb Karmel, Bi-Jie Li, and John F. Hartwig
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b11964 • Publication Date (Web): 02 Jan 2018
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Rhodium-Catalyzed Regioselective Silylation of Alkyl C-H
Bonds for the Synthesis of 1,4-Diols
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†
Caleb Karmel, Bijie Li , and John F. Hartwig*
Department of Chemistry, University of California, Berkeley, California, 94720, United States
Supporting Information Placeholder
ABSTRACT: A rhodium-catalyzed intramolecular silylation of alkyl C-H bonds has been developed that occurs with unusual selectivity
for the C-H bonds located δ to a silyl ether over typically more reactive C-H bonds more proximal to the hydroxyl group. (Hydrido)silyl
ethers, generated in situ by dehydrogenative coupling of tertiary alcohols with diethylsilane, undergo regioselective silylation at a primary
C-H bond δ to the hydroxyl group in the presence of [(Xantphos)Rh(Cl)] as catalyst. Oxidation of the resulting 6-membered oxasilolanes
generates 1,4-diols. This silylation and oxidation sequence provides an efficient method to synthesize 1,4-diols by a hydroxyl-directed,
aliphatic C-H bond functionalization reaction, and is distinct from the synthesis of 1,3-diols from alcohols catalyzed by iridium. Mechanis-
tic studies show that the rhodium-catalyzed silylation of alkyl C-H bonds occurs with a resting state and relative rates for elementary steps
that are significantly different from those for the rhodium-catalyzed silylation of aryl C-H bonds. The resting state of the catalyst is a
(Xantphos)Rh(I)(SiR3)(norbornene) complex, and an analogue was synthesized and characterized crystallographically. The rate-limiting
step of the process is oxidative addition of the δ C-H bond to Rh. Computational studies elucidated the origin of high selectivity for silyla-
tion of the δ C-H bond when Xantphos-ligated rhodium is the catalyst. A high barrier for reductive elimination from the six-membered
metalacyclic, secondary alkyl intermediate formed by cleavage of the γ C-H bond and low barrier for reductive elimination from the seven-
membered metalacyclic, primary alkyl intermediate formed by cleavage of the δ C-H accounts for the selective functionalization of the δ
C-H
bond.
known, but in most cases a cyclic ether is formed.11a A ni-
trate ester has been installed in certain cases at the δ posi-
tion when the Barton reaction was conducted in the pres-
ence of oxygen,11b,c but this process is a stoichiometric,
photochemical reaction.
INTRODUCTION
Catalytic functionalization of C-H bonds with main group
reagents, such as boranes and silanes, has become a practi-
cal synthetic methodology because it occurs with high re-
gioselectivity and generates intermediates that can be
transformed into a variety of products.1,2 Catalytic silyla-
tions of C-H bonds occurs both intramolecularly and in-
termolecularly, but catalytic intramolecular silylation oc-
curs with high regioselectivity, due to the formation of
cyclic silane products.3-7 We first reported the iridium-
catalyzed intramolecular silylation of primary C-H bonds of
silyl ethers, that had been generated from silanes and ei-
ther alcohols or ketones, to form 5-membered ox-
asilolanes.8 We and others have expanded the scope of this
process and applied it to the derivatization of carbohy-
drates and additional terpene natural products.8,9 Oxida-
tion of the oxasilolanes in one pot generates 1,3-diols
(Scheme 1a).
Scheme 1. Intramolecular C-H Silylation Forming Cyclic
Silyl Ethers and Subsequent Oxidation to Diols
• Previous work Exclusive γ C-H silylation
Et2
Si
HEt2Si
O
R
H
O
R
OH OH
Ir/Me4Phen
Ox.
R
norbornene
THF, 80-120 °C
R
R
R
R
R
R
Simmons & Hartwig 2012; Li, Driess, & Hartwig 2014:
• This work: δ C−H silylation
Et2
Si
HEt2Si
H
OH
O
R
Rh/Xantphos
O
R
Ox.
OH
R
norbornene
THF, 100 °C
R
R
R
Silylation of δ C-H bond in the prescence of accesible γC-H bond
C-H silylation to form a 6-membered cyclic product is al-
so desirable because it would generate 1,4-functionalized
products, instead of 1,3-functionalized products. However,
formation of a 6-membered cyclic silane is less favorable
because it requires the generation of a medium-sized, 7-
membered metalacyclic intermediate. The few examples of
C-H silylation to generate 6-membered cyclic silanes are
limited to the functionalization of activated benzylic C-H
bonds.10 Catalytic silylation of unactivated C-H bonds di-
rected by a common functional group to form a 6-
membered cyclic silane is unknown. Radical methods for
the oxygenation of alkyl C-H bonds δ to an oxygen are
The mechanism of rhodium-catalyzed silylations of C-H
bonds has been investigated previously by our group.12
The resting state of the catalyst in the intermolecular si-
lylation of arenes catalyzed by the combination of Rh and
Segphos with cyclohexene as hydrogen acceptor was
(Segphos)Rh(III)(SiR3)(H)2, and the rate-limiting step was
found to be the reductive elimination of cyclohexane. The
resting state of the catalyst in a subsequent enantioselec-
tive intramolecular silylation of aryl C-H bonds revealed a
similar Rh(III) resting state, as well as a complex with the
hydrogen acceptor, and the rate-determining step was a
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related reductive elimination of the reduced hydrogen ac- [Ir(OMe)(COD)]2 as the source of iridium and BINAP as the
ceptor.12b It is unclear whether the same type of resting
state would be present in the reactions with catalysts that
form larger metalacyclic intermediates, whether the rate-
determining step would be the same, and, most significant
for the current study, how the identity and reactivity of
these intermediates would influence the regioselectivity.
ligand, the silylation of C-H bonds was not observed (Entry
2). In contrast, the reactions conducted with a rhodium
precursor and BINAP, Segphos or DTBM-segphos as ligand
occurred to form the products of silylation of an alkyl C-H
bond (Entries 3-5), albeit in low to moderate yields. As
observed for silylation catalyzed by the complex generated
from iridium and Me4Phen, the silylation of the secondary
C-H bond at the position γ to oxygen was favored over si-
lylation of the primary C-H bond at the position δ to oxy-
gen. However, the silylation reaction catalyzed by the
combination of [RhCl(COD)]2 and Xantphos occurred at the
C-H bond located δ to oxygen to give the six-membered
oxasilolane exclusively (Entry 6). The yield of the reaction
was a high 96% when conducted with the preformed com-
plex RhCl(Xantphos) as catalyst (Entry 11).15
1
2
3
4
5
6
7
8
We report highly selective, silylations of unactivated,
primary C-H bonds located δ to hydroxyl groups (Scheme
1b) catalyzed by
a
rhodium complex of Xantphos
9
(Xantphos,
4,5-bis(diphenylphosphino)-9,9-
10
11
12
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dimethylxanthene). Oxidation of the resulting oxasilolanes
generates 1,4-diols. The catalyst for this process is unusual
for C-H bond functionalization; complexes of Xantphos
have not been shown to catalyze the silylation of alkyl C-H
bonds, and ligands like Xantphos with a wide bite-angle
have rarely been used for any type of metal-catalyzed func-
tionalization of alkyl C-H bonds.13,14 Mechanistic studies
show that the rhodium-catalyzed silylation of alkyl C-H
bonds occurs with a resting state and relative rates of ele-
mentary steps that are significantly different from those
for the rhodium-catalyzed silylation of aryl C-H bonds and
that the unusual regioselectivity results from a high barrier
to reductive elimination of secondary alkyl groups from
rhodium complexes ligated by Xantphos.
Reactions with a series of Xantphos derivatives showed
that the electronic and steric properties of the ligand had a
strong influence on the yield of the silylation process. Ar-
omatic Xantphos derivatives generate the most active cata-
lysts. The yields of reactions catalyzed by rhodium com-
plexes of methoxy-substituted or trifluoromethyl-
substituted Xantphos were lower than those of reactions
conducted with the unsubstituted Xantphos (Entries 7-8).
The reactions catalyzed by the combination of
[RhCl(COD)]2 and amino-Xantphos analog L7 or the hin-
dered t-butyl-Xantphos analog L8 did not give any prod-
ucts from silylation of C-H bonds (Entries 9-10).
RESULTS AND DISCUSSION
Reaction Development. To evaluate potential silyla-
tions of alkyl C-H bonds located δ to an alcohol, we studied
the reaction of silyl ether 2a in Table 1. Ether 2a is derived
from the corresponding tertiary alcohol 1a by a dehydro-
genative coupling with diethylsilane catalyzed by 0.1 mol %
[Ir(OMe)(COD)]2. Ether 2a contains primary, secondary,
and tertiary C-H bonds that could undergo silylation. Pri-
mary C-H bonds are typically more reactive than second-
ary and tertiary C-H bonds toward iridium-catalyzed si-
lylation. However, the primary C-H bond in 2a is located at
the position δ to the oxygen atom of the ether, rather than
the position γ to oxygen that has undergone silylation in
previous work.8a Secondary C-H bonds located γ to oxygen
have been shown recently to undergo silylation;8b there-
fore, it was unclear whether the reaction would occur at
the secondary C-H bond located γ to the oxygen atom or
the primary C-H bond located δ to the oxygen atom.
Table 1. Catalytic Silylation of Primary C-H Bond
Et
Et
Et Et
Et
Si H
Si
catalyst (4 mol%)
nbe, THF, 100 oC
Et
O
O
O
Si
+
nBu
nBu
nBu
3a
nBu
nBu
2a
3b
entry
catalyst
3a 3b
Yield% (
:
)
1
[Ir(OMe)(COD)]2/Me4Phen
L1
)
94 (0.18 : 1)
<5 (ND)
2
[Ir(OMe)(COD)]2/BINAP (
L1
)
3
[RhCl(COD)]2/BINAP (
10 (0.48 : 1)
15 (0.50 : 1)
48 (0.50 : 1)
80 (> 20 : 1)
68 (> 20 : 1)
71 (> 20 : 1)
<5 (ND)
L2
4
[RhCl(COD)]2/Segphos (
)
L3
)
5
[RhCl(COD)]2/DTBM-Segphos (
L4
6
[RhCl(COD)]2/Xantphos (
)
L5
7
[RhCl(COD)]2/MeO-Xantphos (
)
L6
8
[RhCl(COD)]2/CF3-Xantphos (
)
L7
)
The combination of an iridium pre-catalyst and 3,4,7,8-
tetramethyl-1,10-phenanthroline (Me4Phen) as ligand cat-
alyzed the reaction of 2a to form products from C-H bond
silylation in high yield. However, the reaction occurred at
both secondary and primary C-H bonds to give a mixture of
the five-membered and six-membered oxasilolanes (Entry
1, Table 1). The reaction favored silylation at the second-
ary C-H bond by a factor of about 5, indicating that the ring
size, rather than the degree of substitution at the C-H bond
controlled the site selectivity. Silylation at the tertiary C-H
bond was not observed.
9
[RhCl(COD)]2/Xantphos-NEt2 (
)
L8
10
11
[RhCl(COD)]2/Xantphos-tBu (
<5 (ND)
RhCl(Xantphos)
96 (>20 : 1)
O
O
O
PAr2
PAr2
O
PR2
, R = C6H5
PR2
L7
L8
, R = NEt2
O
L4
L2
. R = tBu
, Ar = C6H5
L5
L6
, R = 4-MeOC6H4
, R = 4-CF3C6H4
L3
, Ar = 3,5-(tBu)2-4-OMe-C6H2
To identify a catalyst that reacted with distinct selectivity
to form the six-membered oxasilolane product selectively,
we explored the combination of iridium and rhodium cata-
lyst precursors with a range of bisphosphine ligands in
place of bipyridine-type ligands. In the presence of
a
2a
Conditions:
(1.0 equiv.), catalyst (4 mol% monomer), nbe (1.2
equiv.), THF, 100 °C, 16 h. Yields were determined by GC using n-
dodecane as an internal standard. ND, not determined.
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Scope of Rh-Catalyzed Silylation of C-H Bonds. Exam-
Aryl halides, an aryl trifluoromethyl group, and a tri-
substituted alkene were compatible with the reaction con-
ditions (4j-4m). A phenol and an alcohol protected as me-
thyl, benzyl and TBS ethers were also tolerated (4n-4p).
The TBS group in the silylation product cleaved during
oxidation, producing a triol (4p).
1
2
3
4
5
6
7
8
ples of the Rh-catalyzed silylation of primary C-H bonds
located δ to the oxygen of tertiary alcohols are summarized
in Table 2. The yields shown correspond to the 1,4-diols
formed by oxidation of the six-membered oxasilolanes. The
reactions occurred in good yields with a variety of tertiary
alcohols bearing primary C-H bonds δ to oxygen. Branch-
ing at the alkyl chain was important for the silylation to
occur; reactions of tertiary alcohols containing an iso-butyl
group occurred selectively to give the products of silyla-
tion at the primary C-H bond (4a, 4b). In the presence of
primary C-H bonds at carbons located γ and δ to oxygen in
the same substrate, the silylation process occurs at the γ C-
H over the δ C-H bond.
Table 3. Functional Group Tolerance of C-H Silylationa
9
1) H2SiEt2, [Ir], Et2O, then
OH
RhCl(Xantphos) (4 mol%)
nbe, THF, 100 oC
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
OH
Pr
OH
Pr
Ar
Ar
2
2
2) KH, TBHP, TBAF, NMP
1
4
Ar =
In addition to acyclic alcohols, cyclic tertiary alcohols
underwent silylation at a primary C-H bond δ to the hy-
droxyl group (4c, 4d). The reaction occurred at this prima-
ry C-H bond over the secondary C-H bond of the ring and at
a primary C-H bond δ to the OH group when a primary C-H
bond was present at both the δ and ε positions (e.g. to
form 4a or 4e). The catalyst is not highly sensitive to steric
hindrance α to the reacting C-H bond; hydroxylation oc-
curred in 66-72% yield at the hindered methyl C-H bonds
in the neopentyl groups of 4f and 4g. In addition to ter-
tiary alcohols with branching γ to the hydroxyl group, al-
cohols with branching β to the hydroxyl group underwent
silylation selectively at the primary C-H bond (4h). The
reaction did not occur to give substantial amounts of prod-
uct when the alkyl chain lacked branching altogether, as
shown by the low yield of the reaction to form product 4i.
F
Cl
F3C
4j
, 74%
4k
, 84%
4l
, 61%
HO
O
MeO
4n
BnO
b
4m
, 52%
4o
, 87%
, 84%
4p
, 62%
a
1
Conditions: (1.0 equiv.), Et2SiH2 (1.5 equiv.), [Ir(cod)OMe]2 (0.2 mol
%), Et2O, room temperature (rt); removal of volatiles, then RhCl(Xantphos)
(4 mol%), nbe (1.2 equiv.), THF, 100 °C. Isolated yields are reported.
b
Starting from a tert-butyldimethylsilyl ether.
The compatibility of the reaction conditions with car-
bonyl groups was further investigated. In the presence of
RuCl2(PPh3)3 as a catalyst, the reactions of diethylsilane
with tertiary alcohols containing ester and carbamate
groups cleanly formed the diethyl(hydrido)silyl ether pre-
cursor to the C-H bond functionalization process. The Rh-
catalyzed silylation of C-H bonds then formed the six-
membered oxasilolanes, demonstrating compatibility of
the catalytic chemistry with the carbonyl groups in these
silyl ethers. However, this functionality in products 3q-3s
(eq 1) was not tolerated by the highly basic conditions
required for the oxidation of the resulting oxasilolanes
under Fleming-Tamao conditions. Thus, reactions at the
ester and carbamate must be conducted prior to the Flem-
ing-Tamao oxidation. Perhaps most striking, the silylation
of an alkyl C-H bond under these conditions is more toler-
ant of functional groups than common oxidation of a C-Si
bond.
Table 2. Scope of Rh-Catalyzed C-H Silylationa
1) H2SiEt2, [Ir], Et2O, then
OH
OH
RhCl(Xantphos) (4 mol%)
nbe, THF, 100 oC
OH
R1
R1
R2
R2
2) KH, TBHP, TBAF, NMP
1
4
OH
OH
OH
OH
OH
OH
OH
MeO
2
2
MeO
4a, 77%
4b, 72%
4c, 75%
OH
OH
OH
OH
OH
Me
OH
OH
Ph
Ph
tBu
4d
4e
4f
, 66%
, 76%
OH
, 86%
Et2
Si
H2SiEt2, [Ru], PhH, then
OH
OH
O
OH
(1)
OH
RhCl(Xantphos) (4 mol%)
nbe, THF, 100 oC
Ar
2
Ph
Ar
Pr
2
Ph
Pr
nBu
4g
1
3q
Ar = 4-EtOC(O)C6H4, , 92%
4h
4i
, <10%
, 72%
, 74%
t
3r
Ar = 4- BuCO2C6H4, , 90%
a
1
Conditions: (1.0 equiv.), Et2SiH2 (1.5 equiv.), [Ir(cod)OMe]2 (0.10-0.20
3s
Ar = 4-Me2NC(O)C6H4, , 94%
mol %), Et2O, room temperature (rt); removal of volatiles, then
RhCl(Xantphos) (4 mol%), nbe (1.2 equiv.), THF, 100 °C. Isolated yields are
reported.
This silylation of an unactivated C-H bond also enables
the functionalization of two primary C-H bonds in an iso-
butyl group sequentially. Starting from alcohol 1d shown
in Scheme 2, the first C-H silylation and oxidation occurred
in good yield to give the hydroxylation product 4d. After
The functional group tolerance of the process leading to
hydroxylation of the C-H bond located δ to the existing
hydroxyl group is illustrated by the examples in Table 3.
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bonds γ to alcohols should allow functionalization of a
protection of the primary alcohol as a silyl ether (5d), a
1
2
3
4
5
6
7
8
second C-H bond was silylated. Oxidation of the resulting
oxasilolane and in-situ deprotection of the silyl ether under
the conditions of Fleming-Tamao oxidation provided the
triol product 6d.
range of terpenoids.
Scheme 3. Rh-Catalyzed Silylation of Oxysterol
HO Me
H
HO Me
TBSCl
H
Scheme 2. Rh-Catalyzed Sequential C-H Silylation
H
H
H
NEt3
95%
H
H
Et2
H
Si
TBSO
OH
HO
[Rh]
O
[Ox]
1u'
1u
S
, 20( )-hydroxycholesterol
Ph
Ph
9
Ph
HO Me
H
HO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1d
1st C-H Silylation
1. Rh-catalyzed silylation
H
H
2. Fleming-Tamao Oxidation
OH
OTBS
[Rh]
OH
H
OH
TBSCl
93%
HO
4u
, 44%
Ph
4d
, 76%
5d
Experimental Mechanistic Studies. To understand the
origin of the regioselectivity of this silylation reaction and
the origin of the effect of the ligand on this selectivity, we
conducted detailed studies of the mechanism by a combi-
nation of experiment and computation. To determine the
rate limiting step of this reaction, the resting state of the
catalyst was characterized, the reaction orders for each
reagent were determined, and the rate of silylation of C-H
and C-D bonds was measured. In addition, several rhodium
complexes were synthesized that elucidate the path by
which the pre-catalyst enters the catalytic cycle. Finally, to
gain information on the energetics that control selectivity,
computations were conducted on the Segphos-ligated cata-
lyst, which generates products from silylation of secondary
C-H bonds γ to the original hydroxyl group, and on the
Xantphos ligated catalyst, which generates products from
silylation of primary C-H bonds δ to the original hydroxyl
group.
Et2
Si
OH
OH
OH
O
[Ox]
OTBS
Ph
Ph
6d
, 72%
2nd C-H Silylation
Because the Rh-catalyzed silylation is highly selective
and tolerant of functional groups, this process could be
applied to the direct functionalization of natural products
and their derivatives bearing tertiary alcohols. In an initial
example, the reaction of the silyl ether derived from 1-
methylneomenthol, synthesized from menthone and
MeMgBr, led to the site-selective functionalization of the
primary C-H bond to give the corresponding 1,4-diol 4t.
This silylation produced a single diastereomer with the
relative configuration confirmed by X-ray crystallography.
1) Rh-catalyzed silylation
Cl
(2)
OH
2a
H
O
O
P
P
2) KH, TBHP, TBAF, rt
OH
(Xantphos)RhCl
2a
=
Rh
Si
Et Et
OH
THF, RT, 1 h
nBu
nBu
[Si]
H
1t
4t
, 82%
7
(3)
Many more complex, naturally-occurring compounds
contain multiple hydroxyl groups. To determine the feasi-
bility of conducting site-selective silylation directed by one
of the hydroxyl groups in more complex structures, we
studied the alcohol-directed oxygenation of 20(S)-
hydroxycholesterol, a naturally occurring oxysterol. Oxys-
terols function as signaling molecules that modulate a
range of physiological phenomena including transporta-
tion of lipids and control over cellular states.16 Oxidation of
the C-H bonds in these molecules changes their physical
properties.17
O
O
P
P
=
[Si] =
Si
nBu
nBu
O
Et Et
PPh2
PPh2
Mechanism for the Generation of the Active Catalyst and
Identification of the Resting State. To elucidate the pathway
by which the pre-catalyst enters the catalytic reaction and
the structure of the resting state of the catalyst, the reac-
tion of (Xantphos)Rh(Cl) with silyl ether 2a and nor-
bornene was conducted. Although (Xantphos)Rh(Cl) is
insoluble, the reaction occurred quickly (< 10 m) at room
temperature to form a clear homogeneous solution con-
taining complex 7 shown in eq 3. The 31P NMR spectrum of
the solution consisted of a doublet (due to coupling to
103Rh) at 36.6 ppm, indicating two equivalent phosphines,
and the 1H NMR spectrum contained a doublet of triplets at
-14.1 ppm, indicating that the Rh complex contains a metal
hydride coupled to rhodium and two equivalent phospho-
rus atoms. The same species formed from (Xantphos)Rh(Cl)
and the silyl ether 2a in the absence of norbornene, but it
To enable functionalization directed by the tertiary alco-
hol in 20(S)-hydroxycholesterol, the secondary alcohol
was selectively protected to form the corresponding silyl
ether. Under the conditions we developed for alcohol-
directed, site-selective silylation of C-H bonds δ to alcohols,
the mono-protected diol 1u’ was functionalized at the C18
position. Subsequent Fleming-Tamao oxidation with con-
comitant deprotection provided triol 4u. These results
show that the oxygenation of C-H bonds δ to alcohols, in
addition to the previously reported oxygenation of C-H
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Journal of the American Chemical Society
1
was not formed from (Xantphos)Rh(Cl) and norbornene in
and, shown by H NMR spectroscopy to be present, would
1
the absence of the silyl ether.
be located at the site trans to the chloride.
2
3
4
5
6
7
8
9
Heating of the catalytic silylation reaction at 100 °C for 1
h led to a loss of the 31P NMR signal at 36.6. The major res-
onance observed in the 31P NMR spectrum after heating
was a doublet at 22.6 ppm with a 31P-103Rh coupling con-
Figure 2. Synthesis and Solid-State Structure of
(Xantphos)2Rh(H) (9)
2v
P
Rh
P
1 equiv. Xantphos
P
H
1
(Xantphos)RhCl
stant of 142 Hz. No signal in the hydride region of the H
P
THF, RT, 1 h
NMR spectra was observed. Based on these data, we hy-
pothesized that the resting state of the Rh catalyst is a
Xantphos-ligated Rh(I) silyl complex.
9
, 73%
P
=
We were unable to isolate complex 7 formed from
(Xantphos)Rh(Cl) and the silyl ether 2a in pure form, due
to its high solubility in organic solvents, but we isolated an
analogous complex containing the 1-adamantyl silyl ether
2v.18 The reaction of 2v with (Xantphos)Rh(Cl) formed
silyl hydride complex 8 (Figure 1). The solution-phase
NMR spectral data of complex 8 were analogous to those of
the rhodium complex formed in the catalytic system before
heating. A single doublet was observed in the 31P NMR
spectrum at 35.7 ppm, and a similar doublet of triplets at -
14.0 ppm for a hydride ligand was observed in the 1H NMR
spectrum. These data are consistent with the formula
(Xantphos)Rh(Cl)(H)(SiEt2OAd), resulting from oxidative
addition of the Si-H bond of the silane to (Xantphos)Rh(Cl).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
P
O
PPh2
PPh2
Figure 1. Synthesis and Solid-State Structure of
(Xantphos)Rh(H)(Cl)(SiEt2OAd) (8)
Cl
2v
H
O
O
P
P
(Xantphos)RhCl
Rh
H
Si
THF, RT, 1 h
[Si]
Et Et
2v
8,
44%
O
O
P
P
=
=
[Si]
Si
O
Et Et
PPh2
PPh2
Selected bond lengths (Å) and angles (deg): Rh−P1, 2.35;
Rh−P2, 2.34; P1-Rh−P2 (same ligand), 106.4; P1-Rh−P2 (be-
tween ligands), 109.8; P1-Rh−P1, 105.9; P2-Rh−P2, 118.0
The reaction of (Xantphos)Rh(Cl) with silane in the
presence of additional Xantphos produced a complex that
was different from that formed by the reaction of
(Xantphos)Rh(Cl) with silane in the absence of added
Xanphos. The resulting complex (9) is not soluble in com-
mon laboratory solvents, but was analyzed in the solid
state by single-crystal x-ray crystallography. The structure,
shown in Figure 2, is a rhodium(I) hydride complex con-
taining two Xantphos ligands with phosphorus atoms in a
nearly tetrahedral array. The P-Rh-P bite angle for each
ligand is 106°. The hydride was not located by X-ray dif-
fraction, but the infrared spectrum contains a stretching
frequency at 2156 cm-1, which is consistent with the pres-
ence of a rhodium hydride. The mild conditions under
which the complex forms imply that the barrier to reduc-
tive elimination of the silyl chloride from complex 8 is low.
We propose that complex 8 forms initially in the catalytic
reaction, and that it undergoes reductive elimination of the
silyl chloride, producing a Rh(I) hydride complex, which
enters the catalytic cycle. In the presence of excess
Xantphos, this hydride complex forms the crystalline, in-
soluble 9.
The identity of Rh complex 8 was confirmed by single-
crystal x-ray diffraction. The solid-state molecular struc-
ture of Rh silyl hydride 8 consists of an octahedral Rh(III)
center containing a meridional, tridentate Xantphos ligand.
The silyl group is oriented trans to the Xantphos oxygen,
and the chloride occupies a position axial to the plane of
the Xantphos ligand and the silyl group. The hydride lig-
The catalytic competencies of complexes 8 and 9 were
determined. The rate of the reaction conducted with iso-
5
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Journal of the American Chemical Society
Page 6 of 13
lated 8 as catalyst was the same as that for the reaction
31P NMR spectra contains a resonance at 32.6 ppm with a
strong 103Rh coupling of 193 Hz, indicating that Xantphos
remained bound to the metal. Resonances corresponding
to the adamantyl group were also observed, showing that
the silyl group is still connected to rhodium. NMR spec-
troscopy does not reveal whether the oxygen of Xantphos
is bound to Rh in complex 10. Silyl complex 10 formed in
this manner decomposed during attempts to isolate the
complex in pure form.
1
2
3
4
5
6
7
8
initiated with (Xantphos)Rh(Cl) as catalyst (see SI for de-
tails). Thus, complex 8 is catalytically competent to be an
intermediate in the silylation of C-H bonds located δ to a
silyl ether. In contrast, no product was observed when the
reaction was conducted with complex 9 as catalyst. Thus,
complex 9 is not competent to be part of the catalytic cycle,
likely due to the insolubility of this species in THF at 100
°C.
However, a norbornene adduct of Rh(I) silyl complex 10
was isolated and fully characterized. The deprotonation of
Rh-silyl complex 8 containing hydride and chloride ligands
in the presence of norbornene formed the isolable nor-
bornene silyl Rh(I) species 11 (Figure 3b). The 31P NMR
spectrum of this complex contains a single resonance,
which is a doublet at 21.4 PPM with a 31P-103Rh coupling of
140 Hz. The 1H NMR spectrum of isolated 11 contains alkyl
resonances for the silyl unit and a resonance at 2.6 ppm for
the coordinated alkene unit.
Figure 3. Synthesis and Solid-State Structure of
(Xantphos)Rh(H)(nbe)(SiEt2OAd) (10)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cl
LiHMDS
O
P
P
O
P
P
Rh
Rh
C6D6, rt, 1 h
[Si]
[Si]
H
8
10
Cl
[Si]
Rh
LiHMDS
P
P
O
P
P
Rh
H
C6D6, rt, 1 h
The composition of complex 11, deduced in solution, was
confirmed by x-ray crystallography (Figure 3). The struc-
ture consists of a Rh(III) center in which the two phospho-
rus atoms, but not the oxygen atom, of Xantphos are bound
to rhodium, along with one silyl group, one hydride, and
one alkene unit. The geometry at rhodium is trigonal py-
ramidal or square pyramidal, depending on how one con-
siders the bonding of the alkene. The C-C double bond
bound to rhodium is significantly longer (1.45 Å) than that
of the free alkene 1.34 Å, suggesting that the alkene is
bound in a metallacyclopropane structure and the overall
geometry is a square pyramid. The two norbornene car-
bons bonded to rhodium, the two phosphorus atoms, and
the rhodium center lie in a plane; the axial position of the
square pyramidal structure is occupied by the silyl group.
This 16-electron complex could undergo oxidative addition
of a C-H bond. However, the large size of the bound nor-
bornene would hinder the approach of a C-H bond to the
metal center.
[Si]
8
11
, 24 %
P
P
O
=
=
[Si]
Si
O
Et Et
PPh2
PPh2
The full characterization of 11 allows clear assignment of
the resting state of the rhodium in the catalytic reaction. As
noted earlier in this paper, the 31P NMR signal for the rest-
ing state is a doublet at 22.6 ppm with a coupling constant
of 142 Hz. Likewise, the 31P NMR signal for complex 11 is a
doublet at 21.4 ppm with a coupling constant of 140 Hz.
For comparison, the 31P NMR signal for complex 10 lacking
norbornene is a doublet at 32.6 ppm with a coupling con-
stant of 193 Hz. Therefore, the resting state of the catalyst
is a Rh complex ligated by one Xantphos, one norbornene
and one alkoxy diethylsilyl ligand.
We also sought to identify the resting state of the Rh
complex in the catalytic silylation of C-H bonds. We hy-
pothesized that this species was a Xantphos-ligated Rh(I)
silyl complex because no signal was observed in the hy-
Kinetic Analysis of the Catalytic Process. The dependence
of reaction rate on the concentration of each reagent was
measured to reveal the rate-determining step of the cata-
lytic process. The reaction orders in silane, catalyst, and
hydrogen acceptor were determined by measuring initial
rates of the silylation at 100-120° C with varied concentra-
tions of each reagent. The reactions were conducted with
chloride complex 7 as the pre-catalyst. Reactions with con-
centrations of catalyst ranging from 2 mM to 16 mM
showed that the reaction is first order in catalyst. Reac-
tions with concentrations of silane varying from 0.04 M to
0.3 M showed that the reaction is zero order in silane. Fi-
1
dride region of the H NMR spectra of the reaction ob-
tained after heating. To test this hypothesis, we inde-
pendently prepared Rh(I) silyl complex 10 (Figure 3) from
the reaction of Rh hydride complex 8 with LiHMDS (Figure
3a).19 The Rh(I) silyl complex [Rh(Xantphos)(SiEt2OAd)]
(10) was characterized by 1H, and 31P NMR spectroscopy of
the crude reaction mixture. The 1H and 31P NMR spectra of
the complex are consistent with a Rh(I) silyl complex; The
6
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Journal of the American Chemical Society
nally, reactions conducted with concentrations of nor-
taining deuterium at the position δ to the alcohol were
1
2
3
4
5
6
7
8
bornene varying from 0.4 M to 3 M showed that the reac-
tion is inverse first order in norbornene. With the resting
state shown to be a silyl norbornene complex, the zero-
order behavior in silane indicates that the silane bound to
the resting state undergoes C-H bond functionalization,
and the inverse reaction order in norbornene indicates
that norbornene dissociates reversibly from this resting
state to form a 14-electron compound prior to the func-
tionalization process.
measured separately. A kinetic isotope effect of 4.6 was
obtained from these rates (5.7 and 1.2 x 10-5 M/s), indicat-
ing that C-H bond cleavage is irreversible and rate limiting.
This result is consistent with the reaction orders and the
observed resting state and also implies that the reversible
dissociation of norbornene occurs before irreversible
cleavage of the C-H bond.
Based on the orders in substrate, hydrogen acceptor and
catalyst, kinetic isotope effect, and isolated model of the
resting state, we conclude that the reaction occurs by the
catalytic cycle in Scheme 5. The active catalyst is generated
by oxidative addition of a silyl hydride to the RhCl precata-
lyst to form complex A. Complex A forms the Rh(I)hydride
compound B, which lies on the catalytic cycle. Norbornene
undergoes migratory insertion into the Rh-H bond to form
norbornyl complex C, which undergoes oxidative addition
of a silyl hydride and reductive elimination of norbornane
to produce the 14-electron Rh(I)silyl complex D. Complex
D binds norbornene reversibly to form the resting-state E,
which lies off the catalytic cycle. Intramolecular oxidative
addition of the δ C-H bond to the rhodium center in D
forms the seven-membered rhodacycle F. Reductive elimi-
nation from F to form the C-Si bond produces a six-
membered cyclic silyl ether and regenerates Rh(I)hydride
9
Scheme 4. Kinetic Isotope Effect
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Et2
Si
1.2 equiv nbe
5% (Xantphos)Rh(Cl)
HEt2Si
O
O
THF, 100 °C
nBu
nBu
nBu
nBu
2a
nBu
3a
Et2
D
D
1.2 equiv nbe
5% (Xantphos)Rh(Cl)
HEt2Si
Si
O
CD3
O
THF, 100 °C
nBu
CD3
CD3
nBu D
2a-d7
nBu D
3a-d6
Independent rates:
kH/kD = 4.6
The kinetic isotope effect on the catalytic process was
measured to determine the potential reversibility of the C-
H bond cleavage process. The rates of the reaction of the
protio substrate (2a) and deuterio substrate (2a-d7) con-
complex
B.
Scheme 5. Proposed Catalytic Cycle for the Silylation of the C-H Bond γ to a Silyl Ether.
SiHEt2
O
R
R
SiClEt2
SiHEt2
RhLn
Resting
State
O
R
O
R
H
C
R
R
R
R
R
R
R
R
+
-
O
SiEt2
H
O
O
Rh(Cl)Ln
LnRh H
LnRh
LnRh SiEt2
LnRh SiEt2
Cl
B
R
O
D
R
Rate
Determining
Step
A
R
R
E
O
LnRh SiEt2
SiEt2
H
F
Computational Study and Origin of Selectivity. DFT
computations were performed to gain insight into the
origin of the selectivity of the Xantphos catalyst for for-
mation of the six-membered oxasilolane product. To do so,
we computed the energies and geometries of Rh(I) silyl
complexes that are potential catalytic intermediates, tran-
sition states for intramolecular cleavage of C-H bonds in
those complexes, rhodacycles that result from C-H cleav-
age, and transition states for reductive eliminations to
form C-Si bonds. Geometry optimizations were conducted
with the Gaussian 09 software package, B3LYP functional
(with gd3 dispersion correction), and LANL2DZ basis set
for Rh and 6-31g(d,p) basis set for all other atoms. Single-
point energy calculations were conducted with the M06
functional and LANL2TZ basis set for Rh and the 6-
31++g** basis set for all other atoms, along with the SMD
THF solvent correction. Thermal corrections were applied
to the optimized geometries to provide Gibbs free ener-
gies. Each Rh(I) hydride complex, Rh(I) silyl complex, tran-
sition state, and Rh(III) metallacycle was computed with
Segphos (experimental selectivity for silylation of C-H
bonds located γ to a silyl ether) and Xantphos (experi-
mental selectivity for silylation of C-H bonds located δ to a
silyl ether) as the ligand to reveal the origin of selectivity.
To reduce the computational requirements, the calcula-
tions were conducted on a model substrate containing me-
thyl groups, instead of ethyl groups, on silicon.
The minimization of the energy of octahedral Rh-
Xantphos complexes that result from oxidative addition of
a C-H bond showed that many reasonable isomeric prod-
ucts can form. Xantphos can coordinate in a facial or meri-
donal manner. Any of the three X-type ligands could be
trans to the weakly coordinating oxygen of the Xantphos
ligand in either coordination mode. The length of the alkyl
7
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Journal of the American Chemical Society
Page 8 of 13
chain of the substrate is too short to form a complex with tion was also computed. The isomer with the silyl group in
1
2
3
4
the alkyl ligand and the silyl ligand trans to each other. The
five 6-coordinate isomers in which the alkyl and silyl lig-
ands are cis to each other were modeled. The square py-
ramidal complex lacking coordination by the oxygen atom
in Xantphos and containing the silyl group in the axial posi-
this position was computed because the two methyl sub-
stituents on silicon in this isomer lie over the backbone of
Xantphos, whereas these two methyl substituents clash
with the phenyl substituents on phosphorus in the isomer
containing the silyl group in an equatorial position.
5
6
7
Figure 4. Modeling of Rhodacycles in Various Geometries and Coordination Modes
8
9
O
P
P
=
P
Si
O
Rh
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
P
H
P
P
O
H
O
H
O
H
=
H
H
Si
Si
Rh
O
P
P
P
P
P
Si
O
P
P
O
P
P
Rh
Rh
O
Rh
Si
O
O
Rh
P
Si
O
O
ΔG°
(kcal/mol)
PPh2
PPh2
0
3
9
16
32
Although the energy of six-coordinate, 18-electron struc-
tures in which the oxygen atom in Xantphos binds to rho-
dium might be expected to be lower than that of square
pyramidal 16-electron complexes lacking coordination of
the oxygen atom, our calculations showed that the energy
of the square pyramidal complex in which this oxygen does
not interact with rhodium is lower than that of the com-
plexes in which this oxygen does interact with rhodium.
The isolated resting state, complex 11, also lacked a bond-
ing interaction between the oxygen atom of Xantphos and
the rhodium center in the solid-state structure. These two
results suggest that the ability of Xantphos to bind as a
tridentate ligand does not account for the difference in
selectivity between the catalysts containing Xantphos and
Segphos
as
ligand.
Figure 5. Computed Energies for Silylation of C-H Bonds δ to a Silyl Ether (red) and γ to a Silyl Ether (Blue). Silyla-
tion with the Rh-Xantphos Catalyst (Left). Silylation with the Rh-Segphos Catalyst (Right).
O
PPh2
PPh2
O
O
O
P
P
PPh2
PPh2
=
= Segphos
P
P
= δ-silylation
= γ-silylation
=
= Xantphos
C–H Oxidative
Addition
C–Si Reductive
Elimination
O
C–H Oxidative
Addition
C–Si Reductive
Elimination
TS-OxAdd-
δ
TS-RedElim-
?
G° (kcal/mol)
G° (kcal/mol)
O
TS-RedElim-
γ
TS-OxAdd-
δ
Si
O
P
Si
Rh
O
O
Si
Si
P
P
H
Rh
+24.1
P
P
Rh
P
H
Rh
+25.8
P
H
P
H
Rhodacycle-
γ
+20.4
+21.7
+19.7
O
Rhodacycle-
δ
Si
+19.5
O
P
P
Si
Rh
O
+17.2
O
P
P
Rh
Si
O
Rh
O
P
H
P
P
H
Si
+12.1
Rh
H
TS-OxAdd-
H
+14.8
O
P
Rh
P
P
Si
O
Rh
Si
P
H
Si
γ
P
Si
P
H
P
P
Rh
+10.9
+9.1
O
Rh
P
P
P
TS-OxAdd-
P
H
γ
H
Rh
+2.6
+2.3
Rh
(-H2)
P
H
TS-RedElim-
H
δ
Si
+2.6
TS-RedElim-
δ
(-H2)
+6.9
P
Rh
H
H
Si
O
+2.3
P
Si
Si
O
O
P
H
H
or
H
H
P
P
Si
Si
O
Si
O
Rh
or
O
Rhodacycle-
δ
Si
O
H
P
Rh
Rh
P
H
H
P
H
H
Rhodacycle-
γ
H
ligated by both Xantphos (21.7 kcal/mol, shown in red in
the left energy diagram) and Segphos (24.1 kcal/mol,
shown in red in the right energy diagram) is that for oxida-
tive addition of the C-H bond. The highest calculated tran-
sition-state energy for functionalization of the γ C-H bond
by complexes of both ligands, shown in blue in both dia-
grams, is that for reductive elimination to form the C-Si
Computation of the pathways for silylation of C-H bonds δ
and γ to a hydroxyl group. The computed rate-determining
step of the Rh-catalyzed silylation of primary C-H bonds δ
to a silyl ether unit is different from the that for the com-
peting silylation of secondary C-H bonds γ to a silyl ether.
The highest calculated transition-state energy for func-
tionalization of the δ C-H bond by the rhodium complexes
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Journal of the American Chemical Society
bond. The barrier to reductive elimination from the sec- lecular processes. Further, these calculations do not reveal
1
2
3
4
5
6
7
8
the extent to which formation of a five-membered cyclic
silyl ether by reductive elimination from a secondary alkyl
intermediate is slow because of the size of the ring that is
formed or to what extent it is slow because reductive elim-
ination from a secondary alkyl complex to form an Si-C
bond is slower than reductive elimination to form a Si-C
bond from a primary alkyl complex.
ondary alkylrhodium complex to functionalize the γ C-H
bond with the Xantphos-ligated system is almost 19
kcal/mol, and the transition-state free energy is 25.8
kcal/mol higher than that of the catalyst and reactants,
whereas the analogous barrier for the complex ligated by
Segphos is only 8.3 kcal/mol and the transition state free
energy is 20.4 kcal/mol higher than that of the catalyst and
reactants.
To address these questions, we computed the reaction
coordinate for the silylation of a primary C-H bond γ to a
silyl ether by the two catalysts and compared the energies
in these reaction coordinates to those discussed in the pri-
or section on the silylation of the substrate containing
primary C-H bonds δ to a silyl ether and the substrate con-
taining secondary C-H bonds γ to a silyl ether.
9
Figure 6. Computed Energies for Oxidative Addition
of C-H Bonds δ to a Silyl Ether (red) and Reductive
Elimination of C-Si bond γ to a Silyl Ether (Blue). Silyla-
tion with Rh/Segphos as Catalyst (Top). Silylation with
Rh/Xantphos as Catalyst (Bottom).
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The reaction coordinates for silylations of primary C-H
bonds γ to a silyl ether in the model compound catalyzed
by the two rhodium-ligand combinations are shown in
green color in Figure 7, along with the reaction coordinate
(in blue color) presented earlier for the silylation of a sec-
ondary C-H bond γ to a silyl ether catalyzed by the same
two systems. The left side shows the computed reaction
coordinates for the silylation of primary and secondary C-
H bonds γ to a silyl ether catalyzed by Xantphos-ligated
system and the right side shows the computed reaction
coordinate for the silylation of the same silyl ethers cata-
lyzed by the Segphos-ligated system. For silylation of a
primary C-H bond γ to the oxygen catalyzed by complexes
of either ligand, the rate-determining step was computed
to be oxidative addition of the C-H bond because reductive
elimination from the primary alkyl intermediate has a low
barrier. In contrast, for silylation of the secondary C-H
bond γ to the silyl ether catalyzed by complexes of either
ligand, the rate-determining step was computed to be re-
ductive elimination to form the C-Si bond (vide supra).
Thus, the rate-determining step for reaction at the primary
C-H bond is computed to be different from that for reaction
at a secondary C-H bond located the same distance from
the ether oxygen as the primary C-H bond.
= δ⎢ 1⎢
⎢
= γ-silylation
C–H Oxidative
Addition
C–Si Reductive
Elimination
G° (kcal/mol)
O
O
Si
P
Rh
O
O
O
P
P
PPh2
PPh2
Si
P
H
=
+24.1
P
Rh
P
H
+20.4
O
O
Si
PPh2
PPh2
P
O
Rh
O
Si
P
P
P
H
+25.8
=
P
Rh
H
P
+21.7
These calculations show that the unusual selectivity for
formation of the six-membered oxasilolane with the Rh-
Xantphos catalyst results from a high barrier for reductive
elimination from a 6-membered metallacycle containing a
secondary alkyl and a transition-state energy that is higher
than that for oxidative addition of a δ C-H bond to the same
Rh-Xantphos catalyst to form a seven-membered metal-
lacycle. The selectivity for formation of the more common
5-membered oxasilolane with the Rh-Segphos catalysts
results from a transition-state energy for oxidative addi-
tion of the δ C-H bond to form the seven-membered metal-
lacycle that is higher than that for reductive elimination
from a 6-membered metallacycle containing a secondary
alkyl.
Conclusion on the Origin of Selectivity for Five vs Six-
Membered Cyclic Silyl Ethers with Segphos and Xantphos as
ligand. Insight into the origin of the selectivity for the for-
mation of the various-sized cyclic silyl ethers can be gained
by comparing the transition-state energies for the oxida-
tive addition of the primary C-H bond γ to a silyl ether to
that for oxidative addition of the primary C-H bond δ to a
silyl ether. The comparison of the computed transition-
state energies for oxidative addition to form six-membered
rhodacycles with primary alkyl groups to that to form the
seven-membered rhodacycles with primary alkyls ligated
by Xantphos or Segphos shows that oxidative additions
that form seven-membered metallacycles are slower than
those forming six-membered metallacycles for complexes
of both ligands. The difference in computed free energies
between the two transition states for reaction of the
Xantphos-ligated catalyst is smaller (2.6 kcal/mol) than
that for reaction of the Segphos-ligated catalyst (8
kcal/mol). However, this comparison of the transition-
state energies for oxidative addition of primary C-H bonds
to form six or seven-membered rhodacycles shows that
formation of the six-membered rhodacycle is faster for
Computational Model of the silylation of primary C-H
bonds γ to the silyl ether. The calculations just discussed
show that the rate-determining steps for functionalization
of C-H bonds δ to a silyl ether by both catalysts is different
from that for functionalization of C-H bonds γ to a silyl
ether, but they do not reveal why the oxidative addition of
a primary C-H bond δ to the silyl ether is slower than the
oxidative addition of a secondary C-H bond γ to the silyl
ether for complexes of both ligands. Oxidative addition of a
primary C-H bond is usually faster than oxidative addition
of a secondary C-H bond. Thus, the relative rates for reac-
tions of primary and secondary C-H bonds are, most likely,
influenced by the size of the ring formed in the intramo-
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complexes of both ligands. These data show quantitatively
the extent to which formation of seven-membered metal-
lacycles is slower than formation of six-membered metal-
lacycles.
Page 10 of 13
1
2
3
4
5
6
7
Figure 7. Computational Model of Silylation of a Primary and Secondary C-H bonds γ to a Silyl Ether with
Rh/Segphos and Rh/Xantphos
8
9
PPh2
PPh2
O
O
P
P
O
O
=
= Xantphos
PPh2
PPh2
P
P
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
=
= Segphos
= 1° C-H silylation
= 2° C-H silylation
C–Si Reductive
Elimination
C–H Oxidative
Addition
C–Si Reductive
Elimination
O
C–H Oxidative
Addition
TS-RedElim-γ-2°
TS-RedElim-γ-2°
G° (kcal/mol)
G° (kcal/mol)
O
TS-OxAdd-?-2°
Si
O
TS-OxAdd-γ-2°
Si
P
Rh
O
P
Si
P
H
O
Rh
Rhodacycle-γ-2°
Si
+25.8
P
P
H
Rh
P
+20.4
Rh
P
H
O
+19.7
Si
P
H
+19.5
P
Rh
Rhodacycle-γ-2°
P
P
P
H
Rh
+16.1
H
+12.1
P
P
+19.1
+14.5
O
Rh
O
+15.3
Si
H
O
O
O
Si
O
Si
Si
P
Si
Rh
O
P
P
P
P
P
Si
Rh
Si
Rh
H
P
H
P
P
Rh
H
TS-OxAdd-γ-1°
+2.6
+2.0
Rh
H
H
+4.7
P
P
+6.9
Rh
(-H2)
P
TS-OxAdd-γ-1°
Rh
P
H
O
+2.6
+2.0
TS-RedElim-γ-1°
P
P
H
+6.1
O
Si
TS-RedElim-γ-1°
Rh
H
H
(-H2)
O
P
H
Si
O
P
P
Si
Si
or
Rh
Si
H
H
O
H
O
Si
O
Si
O
Si
or
P
Rhodacycle-γ-1°
Rh
H
H
P
H
P
P
Rh
Rhodacycle-γ-1°
H
H
H
The comparison of the computed barriers to reductive
elimination that form five-membered cyclic silyl ethers
from primary alkyl complexes to those that form the same
size ring from secondary alkyl complexes ligated by
Xantphos or Segphos shows that reductive eliminations to
form C-Si bonds involving secondary alkyl groups are
much slower than those involving primary alkyl groups for
complexes of both ligands. However, the difference be-
tween the transition-state energies of reductive elimina-
tion from the primary and secondary alkyl groups to form
the C-Si bond in 5-membered rings is much greater for the
catalyst containing the Xantphos ligand (10.5 kcal/mol)
than it is for the catalyst containing the Segphos ligand (4.9
kcal/mol), and it is the difference in rates for reductive
elimination from primary and secondary alkyl groups that
lead to the unusual selectivity observed for the silylation of
alkyl C-H bonds located γ to the silyl ether over C-H bonds
located δ to the silyl ether.
This effect of the two ligands on these relative rates can
be ascribed to the greater steric demand of Xantphos lig-
and. During the reductive elimination of secondary alkyl
groups, the substituents on that carbon bound to rhodium
tilt away from the silicon, causing these substituents to be
closer to the phenyl groups of the ligand in the transition
state than in the ground state. The catalyst formed from
the Segphos ligand is more able to accommodate this in-
creased steric demand than that formed from the Xantphos
ligand possessing a wider bite angle. Thus, the difference
in rates of reductive elimination from the primary or sec-
ondary alkyl complex containing Segphos as ligand is
smaller than the differences in rates of reductive elimina-
tion from the analogous complexes containing Xantphos as
ligand.
CONCLUSION
In summary, we have developed a rhodium-catalyzed
site-selective silylation of primary C-H bonds to form six-
membered
oxasilolanes
in
the
presence
of
[Rh(Xantphos)Cl] and conducted studies that reveal the
origin of the new regioselectivity. After oxidation of the
silylation products, 1,4-diols are obtained. This C-H oxida-
tion tolerates many functional groups and has the potential
for applications in the synthesis and functionalization of
complex molecules.
The mechanism of this process is distinct from that for
silylation of arenes. In contrast to the rate-determining
reductive elimination to form the C-H bond of the reduced
hydrogen acceptor that occurs during the silylation of
arenes, the rate-limiting step of the rhodium-catalyzed
silylation of alkyl C-H bonds δ to a silyl ether is cleavage of
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(3) selected early examples of C-H silylation (a) Gustavson, W. A.; Ep-
the C-H bond undergoing functionalization. The resting
stein, P. S.; Curtis, M. D. Organometallics 1982, 1, 884. (b) Sakakura, T.;
Tokunaga, Y.; Sodeyama, T.; Tanaka, M. Chem. Lett. 1987, 2375.
(4) selected examples of intramolecular silylation: (a) Tsukada, N.;
Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 5022. (b) Furukawa, S.; Ko-
bayashi, J.; Kawashima, T. J. Am. Chem. Soc. 2009, 131, 14192. (c)
Ureshino, T.; Yoshida, T.; Kuninobu, Y.; Takai, K. J. Am. Chem. Soc.
2010, 132, 14324. (d) Simmons, E. M.; Hartwig, J. F. J. Am. Chem. Soc.
2010, 132, 17092. (e) Kuznetsov, A.; Gevorgyan, V. Org. Lett. 2012, 14,
914. (f) Kuznetsov, A.; Onishi, Y.; Inamoto, Y.; Gevorgyan, V. Org. Lett.
2013, 15, 2498. (g) Kuninobu, Y.; Yamauchi, K.; Tamura, N.; Seiki, T.;
Takai, K. Angew. Chem., Int. Ed. 2013, 52, 1520. (h) Zhang, Q.-W.; An,
K.; Liu, L.-C.; Yue, Y.; He, W. Angew. Chem., Int. Ed. 2015, 54, 6918. (i)
Murai, M.; Matsumoto, K.; Takeuchi, Y. Takai, K. Org. Lett. 2015, 17,
3102. (j) Lee, T.; Wilson, T. W.; Berg, R.; Ryberg, P.; Hartwig, J. F. J.
Am. Chem. Soc. 2015, 137, 6742. (k) Murai, M.; Takeshima, H.; Morita, H.;
Kuninobu, Y.; Takai, K. J. Org. Chem. 2015, 80, 5407. (l) Ghavtadze, N.;
Melkonyan, F. S.; Gulevich, A. V.; Huang, C.; Gevorgyan, V. Nat. Chem.
2014, 6, 122.
1
2
3
4
5
6
7
8
state of the catalyst for this process catalyzed by Xantphos-
ligated rhodium is (Xantphos)Rh(SiEt2OR)(nbe). Con-
sistent with this structure, the reaction is zero-order in
substrate and inverse first-order in norbornene because
norbornene dissociates prior to rate-determining intramo-
lecular cleavage of the alkyl C-H bond. The resting states of
prior Rh-catalyzed C-H silylation reactions underwent re-
ductive elimination of dihydrogen or reduction of the hy-
drogen acceptor before C-H bond cleavage.
9
Computational studies have revealed the origins of the
so-far unique selectivity for silylation of a δ C-H bond over
a γ C-H bond with the Rh-Xantphos catalyst. This selectivity
results from a higher barrier to reductive elimination from
the secondary alkyl intermediate with Xantphos as ligand
than with Segphos (and presumably related phosphines)
as ligand. This high barrier results from increased steric
repulsion between the ligand and the substrate during
reductive elimination to form a secondary C-Si bond. These
mechanistic insights lay the groundwork for the develop-
ment of new regioselective C-H silylation methodologies
and provide a framework to predict the site of C-H silyla-
tion in complex molecules with multiple accessible C-H
bonds.
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14
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16
17
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(5) selected examples of intermolecular sp2 C-H silylation (a) Ishikawa,
M.; Okazaki, S.; Naka, A.; Sakamoto, H. Organometallics 1992, 11, 4135.
(b) Uchimaru, Y.; El Sayed, A. M. M.; Tanaka, M. Organometallics 1993,
12, 2065. (c) Ishikawa, M.; Naka, A.; Ohshita, J. Organometallics 1993,
12, 4987. (d) Ezbiansky, K.; Djurovich, P. I.; LaForest, M.; Sinning, D. J.;
Zayes, R.; Berry, D. H. Organometallics 1998, 17, 1455. (e) Ishiyama, T.;
Sato, K.; Nishio, Y.; Miyaura, N. Angew. Chem., Int. Ed. 2003, 42, 5346.
(f) Ishiyama, T.; Sato, K.; Nishio, Y.; Saiki, T.; Miyaura, N. Chem. Com-
mun. 2005, 5065. (g) Sadow, A. D.; Tilley, T. D. J. Am. Chem. Soc. 2005,
127, 643. (h) Saiki, T.; Nishio, Y.; Ishiyama, T.; Miyaura, N. Organome-
tallics 2006, 25, 6068. (i) Fukuyama, N.; Wada, J.-i.; Watanabe, S.; Ma-
suda, Y.; Murata, M. Chem. Lett. 2007, 36, 910. (j) Lu, B.; Falck, J. R.
Angew. Chem., Int. Ed. 2008, 47, 7508. (k) Klare, H. F.; Oestreich, M.;
Ito, J.-i.; Nishiyama, H.; Ohki, Y.; Tatsumi, K. J. Am. Chem. Soc. 2011,
133, 3312.
ASSOCIATED CONTENT
Supporting Information
(6) Selected examples of directed sp2 C-H silylation: (a) Williams, N.
A.; Uchimaru, Y.; Tanaka, M. J. Am. Chem. Soc., Chem. Commun. 1995,
1129. (b) Kakiuchi, F.; Matsumoto, M.; Sonoda, M.; Fukuyama, T.;
Chatani, N.; Murai, S.; Furukawa, N.; Seki, Y. Chem. Lett. 2000, 750. (c)
Kakiuchi, F.; Igi, K.; Matsumoto, M.; Chatani, N.; Murai, S. Chem. Lett.
2001, 422. (d) Kakiuchi, F.; Igi, K.; Matsumoto, M.; Hayamizu, T.; Cha-
tani, N.; Murai, S. Chem. Lett. 2002, 396. (e) Kakiuchi, F.; Matsumoto,
M.; Tsuchiya, K.; Igi, K.; Hayamizu, T.; Chatani, N.; Murai, S. J. Orga-
nomet. Chem. 2003, 686, 134. (f) Tobisu, M.; Ano, Y.; Chatani, N. Chem.-
Asian J. 2008, 3, 1585. (g) Ihara, H.; Suginome, M. J. Am. Chem. Soc.
2009, 131, 7502. (h) Oyamada, J.; Nishiura, M.; Hou, Z. Angew. Chem.,
Int. Ed. 2011, 50, 10720. (i) Sakurai, T.; Matsuoka, Y.; Hanataka, T.;
Fukuyama, N.; Namikoshi, T.; Watanabe, S.; Murata, M. Chem. Lett.
2012, 41, 374. (j) Chen, C.; Guan, M.; Zhang, J.; Wen, Z.; Zhao, Y. Org.
Lett. 2015, 17, 3646.
Experimental procedures, characterization of new com-
pounds, crystallographic data (CIF) and spectroscopic data are
provided in the Supporting Information. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
jhartwig@berkeley.edu
Notes
The authors declare no competing financial interests.
†Present address: Center of Basic Molecular Science (CBMS),
Department of Chemistry, Tsinghua University.
(7) Selected examples of directed sp3 C-H silylation: (a) Kakiuchi, F.;
Tsuchiya, K.; Matsumoto, M.; Mizushima, E.; Chatani, N. J. Am. Chem.
Soc. 2004, 126, 12792. (b) Mita, T.; Michigami, K.; Sato, Y. Org. Lett.
2012, 14, 3462. (c) Mita, T.; Michigami, K.; Sato, Y. Chem. Asian J.
2013, 8, 2970. (d) Ihara, H.; Ueda, A.; Suginome, M. Chem. Lett. 2011,
40, 916.
(8) (a) Simmons, E. M.; Hartwig, J. F. Nature 2012, 483, 70. (b) Li, B.;
Driess, M.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 6586.
(9) (a) Frihed, T. G.; Heuckendorff, M.; Pedersen, C. M.; Bols, M. An-
gew. Chem., Int. Ed. 2012, 51, 12285. (b) Frihed, T. G.; Pedersen, C. M.;
Bols,M. Angew. Chem. Int. Ed. 2014, 53, 13889.
(10) Hua, Y.; Jung, S.; Roh, J.; Jeon, J. J. Org. Chem. 2015, 80, 4661.
(11) (a) Čeković, Z. Tetrahedron 2003, 59, 8073. (b) Allen, J.; Boar, R.
B.; McGhie, J. F.; Barton, D. H. R. J. Chem. Soc., Perkin Trans. 1 1973,
2402. (c) Boar, R. B.; Copsey, D. B. J. Chem. Soc., Perkin Trans. 1 1979,
563
ACKNOWLEDGMENT
We gratefully acknowledged financial support by the Ein-
stein Foundation Berlin (J.F.H.) and the Cluster of Excellence
UniCat (financed by the DFG and administered by the TU Ber-
lin to M.D.) for initial data and the NIH (GM5R01-GM115812)
(J.F.H.) for support. We thank Dr. Antonio DiPasquale for as-
sistance with crystallographic data. We thank Dr. Kathleen
Durkin, of the Molecular Graphics and Computation Facility
(supported by NIH grant S10OD023532), for assistance with
DFT calculations. B. L. thanks Dr. Qian Li and Dr. Qingwei
Zhang for assistance with some experiments. C. K. thanks Dr.
Ala Bunescu for helpful discussions.
(12) (a) Cheng, C.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 12064.
(b) Lee, T.; Hartwig, J. F. J. Am. Chem. Soc. 2017, 139, 4879.
(13) Catalysts bound by ligands with wide bite angles have been used
for specific types of hydroacylation reactions: (a) Moxham, G. L.; Ran-
dell-Sly, H. E.; Brayshaw, S. K.; Woodward, R. L.; Weller, A. S.; Willis,
M. C. Angew. Chem. 2006, 118, 7780. (b) Chaplin, A. B.; Hooper, J. F.;
Weller, A. S.; Willis, M. C. J. Am. Chem. Soc. 2012, 134, 4885.
(14) (a) Mita, T.; Hanagata, S.; Michigami, K.; Sato, Y. Organic
Letters 2017, 19, 5876; (b) Michigami, K.; Mita, T.; Sato, Y. Journal of
the American Chemical Society 2017, 139, 6094; (c) Cabrera-Pardo, J. R.;
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through two phosphorus and one oxygen atom.
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(19) Prepared in a manner similar to that used to prepare (Xantphos-
iPr)Rh(H): Haibach, M. C.; Wang, D. Y.; Emge, T. J.; Krogh-Jespersen,
K.; Goldman, A. S. Chem. Sci. 2013, 4, 3683–3692.
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Insert Table of Contents artwork here
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via:
1) H2SiEt2, catalyst
2) cat. RhCl(Xantphos)
+ norbornene
OH
OH CH3
OH
R2
R
R
R1
R1
3) [Ox]
7
R
R
R2
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