α-Arylation of Silyl Enol Ethers via Rhodium(III)-Catalyzed C-H Functionalization

Article abstract of DOI:10.1021/acscatal.9b05622

Carbon-hydrogen (C-H) bond functionalization streamlines synthesis by increasing step-and atom-economies. This approach, catalyzed by Rh(III), is combined with the α-arylation of ketone-derived silyl enol ethers to achieve a direct cross-coupling event. T

Full text of DOI:10.1021/acscatal.9b05622

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Article
#-Arylation of Silyl Enol Ethers via
Rhodium(III)-Catalyzed C–H Functionalization
Xuezhen Kou, and Kevin G. M. Kou
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b05622 • Publication Date (Web): 04 Feb 2020
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Page 1 of 8
ACS Catalysis
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α-Arylation of Silyl Enol Ethers via Rhodium(III)-Catalyzed C–H
Functionalization
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Xuezhen Kou and Kevin G. M. Kou*
Department of Chemistry, University of California, Riverside, California, 92507, United States
ABSTRACT: Carbon–hydrogen (C–H) bond functionalization streamlines synthesis by increasing step- and atom-economies.
This approach, catalyzed by Rh(III), is combined with the α-arylation of ketone-derived silyl enol ethers to achieve a direct
cross-coupling event. The advancement of electron-rich alkenes as substrates is enabled through the use of a silver additive
and complements existing C–H activation methods that transform enol ester derivatives and electron-deficient alkenes. A
Rh(III)/(V)/(III) catalytic cycle is proposed to rationalize mechanistic observations.
KEYWORDS: C–H functionalization, α-arylation, C–H activation, acylalkylation, silyl enol ethers, rhodium, benzamides
Metal-catalyzed α-arylations of carbonyl compounds,
including the palladium-catalyzed cross-coupling of ketone
enolates and aryl halides to produce α-aryl ketones, are
powerful carbon–carbon bond-forming reactions useful for
the assembly of functional molecules that impact
agriculture, materials, and medicine.1 Molecules containing
the α-aryl ketone motif can serve as precursors for
heterocycle synthesis.2–5 Their preparations typically
involve the use of alkali metal enolates6 or silyl enol ethers
1,7 the latter of which react under milder reaction
conditions and offer enhanced functional group
compatibility. Since Kuwajima and Urabe’s initial
discovery to cross-couple silyl enol ethers 1 with aryl
halides using a palladium catalyst and tributyltin fluoride
(Scheme 1A),8 significant advances have been made to
improve reactivity, selectivity, and scope.9–19 More
attenuate electron-density at the alkene and facilitate the
migra-
A) Traditional cross-coupling approach
[Pd(II)] (cat.)
OTMS
O
+
Bu3SnF,
C6H6, 
R
1
X
R
X = Br, I
B) C H functionalization approach using enol ester derivatives

O
O
OAc
H
[Rh(III)] (cat.)
OPiv
OPiv
N
H
NH
+
CsOAc,
MeOH, 45 °C
H
H
2a
3
4
O
O
OTs
[Rh(III)] (cat.)
NH
H
F
N
H
H
+
+
OMe
CsOPiv,
MeOH, 35 °C
F
H
F
F
recently, the Hartwig group disclosed
a traceless
2a
5
6
protecting strategy to α-arylate carboxylic acids and
amides with aryl halides via silylated intermediates
generated in situ,20 which further underscores the
practicality of enol silanes for α-arylation.
O
O
O
NR2
O
[Rh(III)] (cat.)
O
NR2
O
neat, 80 °C
R'
H
R'
R'
7
R'
The ability to transform inert C–H bonds can impart
step-21 and atom-economy22 advantages to a synthesis
plan. This in turn has spurred the development of cross-
coupling methodologies that incorporate C–H activation.23
However, C–H functionalization in the context of carbonyl
α-arylation reactions is underexplored and unknown with
silyl enol ethers 1. Some success has been reported with
derivatives of enol esters (Scheme 1B). Marsden and
coworkers demonstrated α-arylation of vinyl acetate (3)
with pivaloyl hydroxamate (2a) to produce isoquinolone 4
using a rhodium(III) catalyst.24 Similarly, Li and Wang
merged 2,2-difluorovinyl tosylate (5) with benzamide 2a,
yielding fluorinated dihydroisoquinolone 6.25 The Kakiuchi
group reported a method involving C–H functionalization
of arenes with cyclic alkenyl carbonates (7).26 In most
cases, the oxygens of the enol ester derivatives are masked
with electron-withdrawing groups, presumably to
C) C H functionalization of electron-rich enol ethers

O
O
[Rh(III)] (cat.)
On-Bu
NH
+
NR2
CsOAc, MeOH
45 °C
H
8
On-Bu
This work  complementary regioselectivity with enol silanes
O
O
[Rh(III)] (cat.)
OMe
OTMS
OMe
N
N
H
R
R
+
AgOAc,
THF, 50 °C
OH
R'
R'
1
H
2
9
Scheme 1. The Development of α-Arylation Reactions
with Enolate Derivatives
tory insertion step. Alternative strategies to acylalkylate
aromatic C–H bonds employ α-sulfonyloxy- or α-chloro-
ketones,27 and carbene precursors derived from carbonyl
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Page 2 of 8
compounds.28–32 C–H functionalization with electron-rich
alkenes are rare, with the only examples documented by
favoring activation of silyl enol ether 1a, C–C bond
formation, and catalyst turnover. Good reactivity is
retained when the precatalyst loading is reduced to 1
mol% of the rhodium dimer (entry 7). Both 1 and 2
equivalents of Ag2CO3 in place of AgOAc support
1
2
3
4
5
6
7
8
OH
O
OH
OH O
NH OH
O
NH
C5H11
Table 1. Surveying Reaction Conditions for Cross-
Coupling Benzamide 2b with Silyl Enol Ether 1a via C–
H Activationa
HO
O
O
MeO
WJ35
O
rupreschstyril
H2N
OH
O
H
N
HO
N
N
OH
[Cp*RhCl2]2 (x mol%)
additive (y equiv)
O
O
9
O
OH
OMe
OH
MeO
CO2H
OH
OTMS
Ph
OMe
+
N
10
11
12
13
14
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N
H
O
OMe
Ph
hyalachelin B
solvent, 40 °C
18 h
H
tamynine
Ph
2b
1a
9ba
OMe
NH
O
O
FIGURE
1.
Natural
products
containing
the
dihydroisoquinolone/isoquinolone core structure.
the Fagnou33 and Marsden labs.24 In the case of vinyl ether
8, the regiochemical outcome alters to favor migratory
insertion at the internal carbon (Scheme 1C). This
reactivity is not precedented with electron-rich silyl enol
ethers 1, which are readily accessible and perhaps the
most synthetically versatile of the enolate derivatives. We
thus posit 1 would be ideal precursors that, if successful,
could significantly broaden the scope of ketones
participating in C–H functionalization and α-arylation. The
challenge lies in forming the new C–C bond at the electron-
rich terminal site of the silyl enol ethers. The resulting
dihydroisoquinolones 9 constitute core structures of many
naturally occurring compounds (Figure 1),34–37 including
bioactive isoquinoline alkaloids.38 Additionally, this
structural motif has been integrated into drug leads that
act as antagonists of 5-HT3 receptors,39 modulators of
retinoic acid receptors,40 as well as inhibitors of
thymidylate synthase41 and human tumor necrosis factor
α.42
Ph
10
Entry
x
Additive
NaOAc
CsOAc
y
Solvent
THF
Yieldb
1
2
2.5
2.5
2.0
2.0
0
0
THF
AgOAc
0.10
1.2
3
4
2.5
2.5
THF
THF
0
Bu3SnF
AgOAc
CsF
0.10
1.2
0
5
6
2.5
2.5
1.0
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
AgF
AgOAc
AgOAc
Ag2CO3
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
Cu(OAc)2
2.2
2.2
2.2
1.0
2.2
2.2
2.2
2.2
2.2
2.2
2.0
THF
THF
THF
THF
35
90 (94)c
7
83
70 (74)d
83
8
9
1,4-dioxane
Et2O
10
11
12
13
14
15
86
The use of electron-rich silyl enol ethers to functionalize
C–H bonds necessitates a mechanistic manifold distinctive
from those proposed for enol ester derivatives (c.f. Scheme
1). This is supported by the lack of reactivity observed
when catalyst systems reported for these α-arylations
were investigated for the Rh(III)-catalyzed cross-coupling
of N-methoxybenzamide (2b) and trimethylsilyl enol ether
1a (Table 1). For example, combining [Cp*RhCl2]2 with
acetate additives to facilitate C–H activation of 2b by
concerted-metalation-deprotonation failed to produce any
of the coupling product (entries 1 and 2). The Kuwajima,6,7
Hartwig,11,12 and Rawal13 groups have demonstrated that
fluoride sources activate silyl enol ethers for palladium-
catalyzed α-arylation. In our studies, stoichiometric
additions of Bu3SnF (entry 3) or CsF (entry 4) with
catalytic Rh(III) and AgOAc were unproductive. However,
addition of 2.2 equivalents of AgF effects α-arylation to
generate 10, which spontaneously cyclizes to its
hemiamidal form (9ba) with the N-methoxy group intact,
in 35% yield (entry 5). Of note, C–C bond formation
occurred at the electron-rich position 1a, amounting to the
first α-arylation through C–H activation. We found that the
catalyst system originating from the combination of 2.5
mol% [Cp*RhCl2] dimer and AgOAc in THF delivers the
product in 90–94% yields (entry 6). This outcome suggests
silver (rather than fluoride) to be the key component
PhMe
58
1,2-DCE
MeOH
HFIP
48
48
0
THF
0
aReaction conditions: benzamide 2b (0.2 mmol), silyl enol
b
ether 1a (0.24 mmol), 0.2 M with respect to 2b. Isolated
yields. c50 °C, 15 h. d2 equiv Ag2CO3.
Rh(III) catalyzed C–H functionalization, but with
diminished yields between 70–74% (entry 8). Other
ethereal solvents, such as 1,4-dioxane and diethyl ether,
are effective in promoting C–H functionalization, albeit in
slightly lower yields of 83% and 86%, respectively (entries
9 and 10). More weakly coordinating solvents are less
effective. Dihydroisoquinolone 9ba is formed in 58% yield
in toluene (entry 11) and 48% yield in 1,2-DCE (entry 12).
The reaction is operative in MeOH (48%, entry 13), but not
in hexafluoroisopropanol (HFIP, entry 14). Product
formation does not occur in polar aprotic solvents such as
MeCN, DMF, and DMSO (not listed). Attempts to replace
the AgOAc oxidant with Cu(OAc)2 failed to give product
(entry
methoxyamide as
functionalization/α-arylation.43,44 In contrast to the
15). This transformation leverages the N-
a
directing group for C–H
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ACS Catalysis
reactions with enol ester derivatives (Scheme 1B), which
C–H functionalize pivaloyl hydroxamate 2a, the N-
pivaloxyamide group is ineffective in directing reactivity.
N-Methyl and N-phenyl benzamides are acylalkylated
under the reaction conditions, albeit in lower yields (See
the SI). Of note, the current reaction system is resistant to
air and moisture (see the SI).
1
2
3
4
5
6
7
Table 2. Scope of the of C–H Activation/α-Arylationa
8
9
O
OMe
NH
O
O
O
9
OTMS
R'
OMe
OMe
OH
[Cp*RhCl2]2 (2.5 mol %)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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N
H
N
R
+
R
R
AgOAc (2.2 equiv),
THF, 50 °C, 15 h
H
R'
R'
2
1
10
Varying benzamides 2 (with silyl enol ether 1a)
ortho-substituted
para-substituted
meta-substituted
9ba, R = H,
9ca, R = Me,
9da, R = Ph,
9ea, R = Cl,
9fa, R = Br,
9ga, R = I,
9ha, R = OMe,
9ia, R = OAc,
9ja, R = F,
9ka, R = CF3,
9la, R = CN,
9ma, R = NO2,
94%
96%
95%
73%
81%
86%
90%
97%
81%
84%
40%
51%
O
R
O
O
O
Cl
Cl
OMe
OH
9pa, R = Cl,
9qa, R = Br,
9ra, R = CF3,
86%
90%
74%
66%
OMe
OH
Ph
53%
0%b
N
N
OMe
OH
R
OMe
OH
N
N
Ph
R
9sa, R = NO ,
2
Ph
Ph
9va,
62%
9ta, R = Me,
9ua, R = I,
O
O
OMe
O
O
O
O
N
OMe
N
N
OMe
OH
OMe
N
OMe
OMe
OH
S
OH
Ph
N
N
R
R
Ph
OH
Ph
OH
Ph
N
N
9na/oa
11na/qo
Ph
Ph
Boc
R = CO2Me,
R = OH,
9na/11nac
82%, 1:1.4
98%, 1:1.7
9wa,
9xa,
9ya,
9za,
9oa/11oac
96%
85%
20%
47%
Varying silyl enol ethers 1 (with benzamide 2b)
para-substituted aryl
meta-substituted aryl
ortho-substituted aryl
O
O
O
9bj, R = Me, 95%
9bk, R = F,
9bl, R = Cl,
9bm, R = Br, 91%
9bn, R = NO2, 94%
OMe
N
OMe
N
OMe
OH
N
9bb, R = Me,
9bf, R = I,
9bg, R = OMe,
9bh, R = CO Me,
9bi, R = NO2,
96%
94%
9bo, R = Me,
9bp, R = F,
9bq, R = Br,
9br, R = OMe,
97%
95%
91%
93%
92%
96%
90%
93%
96%
94%
92%
95%
OH
OH
9bc, R = F,
9bd, R = Cl,
9be, R = Br,
2
R
R
R
O
O
O
O
O
O
O
OMe
N
OMe
OMe
OMe
OH
OMe
N
OMe
N
OMe
N
N
N
N
OH
OH
OH
OH
OH
OH
O
R
S
N
Me
Me
Boc
O
O
9bw, R = H,
9bw', R = Me,
87%
86%
9by,
86%
9bs,
9bt,
9bu,
9bv,
9bx,
O
94%
95%
94%
85%
88%
alkyl-, alkenyl-, and acyl-substituted
O
OMe
O
O
O
O
N
O
OMe
NH
O
OMe
OMe
OMe
OMe
OH
N
OMe
OH
N
N
N
N
OH
OH
OH
Me
Me Me
R
9bzc
10bzc
9bzd
11bzd
Me
(dr = 1.2:1)
9bzb, R = H,
9bzb', R = Me,
90%
95%
56%, 3.2:1
9bzd/11bzdc
9bzc/10bzc
O
79%, 2.7:1
9bz,
O
9bza,
83%
53%
O
O
O
O
O
OMe
OMe
OH
OMe
OMe
OMe
OMe
OH
OMe
OH
N
N
N
N
N
N
N
OH
OH
OEt
OH
Me
Me
9bzi
11bzi
O
Ph
9bzh
, 94%
(dr = 1.2:1)
Ph
N
Boc
O
9bzi/11bzic
9bzj,
51%
9bze,
9bzf,
9bzg,
96%
91%, 1:2.1
69%
92%
aReaction conditions: benzamide 2 (0.2 mmol), silyl enol ether 1 (0.24 mmol), 0.2 M with respect to 2. bComplete
deiodination observed (76% 9ba isolated). Treatment with HCl (1 equiv) in MeOH leads to 11 in quantitative yield
c
A comprehensive examination of the substrate scope with
respect to C–H functionalization/α-arylation is presented
(Table 2). This transformation is accommodating to
varying substitution patterns about the benzamide com-
ponent. Benzamide derivatives 2 bearing electron-neutral
(R = H, Me, Ph), electron-rich (R = OMe, OAc), and halogen
(R = Cl, Br, I) substituents at the para-position undergo C–
H functionalization in high yields (73–97%, 9ba–9ia).
Inductively electron-withdrawing para-fluoro- and
trifluoromethyl-substituted benzamides couple to silyl
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Page 4 of 8
enol ether 1a in 81% (9ja) and 84% (9ka) yields,
approach, albeit in lower yields of 20% and 47%.
Excepting benzamides substituted with para-hydroxy and
1
2
3
4
5
6
7
8
respectively. With para-cyano- and nitro- substituted
benzamides, only modest conversions to the
corresponding dihydroisoquinolones 9la (40% yield) and
9ma (51% yield) were observed, possibly due to their
propensities to coordinate rhodium and suppress catalysis.
This is consistent with the trend noted in meta-substituted
benzamides: chloro-, bromo-, and trifluoromethyl-
substituted benzamides were converted in high yields (74–
90%, 9pa–9ra), whereas the more coordinating nitro-
substituted analog resulted in only 66% yield of product
9sa. Benzamides substituted at the ortho-position are less
reactive. The ortho-methylbenzamide is transformed into
dihydroisoquinolone 9ta in 53% yield. We postulate the
added steric en-
ester functionalities
dihydroisoquinolone
that
9na/9oa
furnish
and
mixtures
isoquinolones
of
11na/11oa, all other reactions form 9 as the major
product.
A wide spectrum of silyl enol ethers 1 are available for
cross-coupling due to the ease of their synthesis. The α-
arylation of those derived from acetophenone derivatives
provides 3-aryl dihydroisoquinolones 9bb–9bu in high
isolated yields (90–97%), irrespective of the decoration on
the aromatic component. Dihydroisoquinolones containing
additional heteroaromatic groups, including benzodioxole
(9bv), furan (9bw and 9bw’), thiophene (9bx), and indole
(8by), are synthesized in 85–88% yields. Apart from
aromatic groups, various alkyl substituted silyl enol ethers
1
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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Scheme 2. Application to drug derivatization
A) pregnenolone acetate
O
Scheme 3. Mechanistic experiments
a. TMSCl, NaI
Et3N (93%)
O
Me
N
H
OMe
Me
Me
2b
b. [Rh] (cat.),
A) deuterium labeling experiment
O
[Cp*RhCl2]2
(2.5 mol%)
Me
H
AgOAc, 50 °C, 15 h;
then HCl, MeOH
(76%)
O
OTMS
Ph
OMe
OH
Me
H
H
N
OMe
D
H
H
N
H
+
AgOAc,
THF, 50 °C,
15 h
H
D
OAc
Ph
D
D
OAc
12
13
glucocorticoid; anti-aging
2b
1a-d2, 95% D
9ba-d2, 86%, 85% D
B) aspirin
B) kinetic isotope effect experiments
i. measurement from intermolecular competition experimentsa
AcO
O
N
amidation
d.
AcO
O
OMe
1a
e. [Rh] (cat.),
O
O
OH
kH
OMe
OH
AgOAc, 50 °C, 15 h
(62%)
OMe
N
N
H
HO
OTMS
Ph
14
NSAID
15
Ph
kH
kD
1a
9ba
O
2b
= 2.9
C) probenecid and transformations of the dihydroisoquinilone motif
[Rh2] (2.5 mol%),
AgOAc (2.2 equiv),
THF, 50 °C
D
D
O
D
D
O
O
amidation
f.
g. [Rh] (cat.),
OH
D
D
OMe
D
D
OMe
OH
kD
OMe
N
H
N
1a
Pr
N
N
Pr
N
same vessel
D
AgOAc, 50 °C, 20 h
(81%)
Ph
Pr
S
O
Pr
S
O
HO
17,
2.11 g
O
O
2b-d5
9ba-d4
16
gram-scale
ii. measurement from two parallel reactions using method of initial ratesb
uricoduric drug; antigout
j. CsOAc,
PivOH, 100 °C
O
O
as
above
h.
HCl, MeOH, 5 min (95%)
OTMS
Ph
OMe
OH
kH
OMe
N
(92%)
O
O
N
H
+
OMe
Pr
N
N
Pr
N
O
Ph
kH
1a
9ba
2b
= 1.0
Pr
S
Pr
S
kD
O
O
O O
18
20
D
D
O
D
D
O
as
above
D
D
OMe
+
D
D
OMe
OH
kD
NaH,
DMF
i.
120 °C, 1 h
(90%)
k. KOH,
EtOH
80 °C, 4 h
(84%)
OTMS
Ph
N
H
N
D
O
O
Ph
OH
O
2b-d5
1a
9ba-d4
Pr
Pr
N
NH
aAverage of 3 runs. bInitial rates used to determine kH and kD were derived
from the average of 3 runs.
N
Pr
S
Pr
S
O
O
O
O
19
21
C) Probing silver
O
cumbrance imposed by the ortho-substituent plays a role
in hindering the substrate–rhodium complex from
adopting geometries conducive to C–H activation.
Unexpectedly, the ortho-iodobenzamide did not convert to
the corres-ponding product 9ua. Instead, complete
deiodination occurred to yield 9ba (76%). In addition, to
[Cp*RhCl2]2
(10 mol%)
O
OTMS
Ph
OMe
OH
OMe
N
N
H
+
AgOAc
Ph
(38 mol%),
THF, 50 °C
1a
9ba
trace product
2b
combine with benzamide 2b to give butyl (9bz), tert-butyl
(9bza), cyclopropyl (9bzb, 9bzb’), adamantyl (9bzc),
norbornenyl (9bzd, 11bzd), piperidinyl (9bze), and
tetrahydropyranyl (9bzf) substituted products in 53–95%
yields. Even alkenyl and carbonyl groups are added in
mono-substituted
dihydroisoquinolones,
6,7-
dichlorodihydro-isoquinolone 9va, benzoisoquinolone
9wa, and pyrroloisoquinolone 9xa are synthesized in high
yields. Benzonaphthyridinone and benzothienopyridinone
analogs 9ya and 9za, respectively, can be prepared via this
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ACS Catalysis
synthetically useful yields (9bzg–9bzj). In cases where
both 3-hydroxydihydroisoquinolone 9 and isoquinolone
11 are formed, treatment with acid quantitatively converts
the mixtures to 11.
small amount of deuterium loss is attributed to H/D
exchange following product formation, possibly via keto-
enol tautomerization of intermediate 10. Any scrambling
of the deuterium atoms to the aromatic ring was
unmeasurable by NMR analysis. Kinetic isotope effect
(KIE) studies were subsequently pursued to explore the
nature of the C–H activation step (Scheme 3B). When 1:1
mixtures of 2b and pentadeuterobenzamide 2b-d5 were
examined together in competition experiments, an average
KIE = 2.9 was measured at low conversions (between 16–
22%). However, the KIE was measured to be 1.0 when
examining the initial rates for two reactions performed in
parallel. Together, the results suggest C–H activation to be
irreversible but not turnover-limiting.45
1
2
3
4
5
6
7
8
9
To further probe synthetic utility and amenability to
transform the dihydroisoquinolone moiety, derivatizations
of medicinal agents were targeted. The steroid
prenenolone acetate (12) is converted to the
corresponding silyl enol ether, which is then subjected to
α-arylation with benzamide 2b (Scheme 2A). Ensuing
treatment with HCl in MeOH furnishes isoquinolone-
modified prenenolone acetate 13 in 76% yield. Amidation
of aspirin (14) followed by Rh(III)-catalyzed C–H
functionalization with silyl enol ether 1a affords 15 in 62%
yield (Scheme 2B). The scalability of this reaction is
demonstrated with probenecid (16, Scheme 2C). The
coupling of silyl enol ether 1a with the N-
methoxybenzamide derivative of 16 occurs in 81% yield to
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
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60
In the commonly proposed Rh(III)/(I)/(III) cycle for the
C–H functionalization of N-methoxybenzamides 2, a
stoichiometric oxidant turns over the catalyst by
reoxidizing Rh(I) to Rh(III).44 In the present reaction, the
N-methoxyamide moiety is not consumed in the reaction
and the AgOAc additive ostensibly regenerates the active
catalyst. We surmised that limiting the silver loading to
only permit formation of [Cp*RhIII(OAc)2] from
[Cp*RhIIICl2]2 would suppress catalyst turnover but still
promote product formation. To test this hypothesis, the
reactivity was examined by increasing the precatalyst
loading to 10 mol% rhodium dimer and decreasing AgOAc
to 38 mol% to permit chloride abstraction (Scheme 3C). In
the absence of surplus oxidant, the 20 mol% Rh(III)
should, in theory, deliver 20% C–H functionalization
product 9ba. The lack of reactivity observed suggests
Rh(III) species are incapable of promoting the α-arylation
of silyl enol ether 1a with benzamide 2b. Taken together
with the complementary regio-outcome when compared
with enol ethers,24,33 we believe a different mechanism is
operative, one in which AgOAc enables a Rh(III)/(V)/(III)
pathway46,47 that facilitates an otherwise difficult C(sp2)–
C(sp3) bond-forming process. AgOAc-mediated oxidations
of some Ir(III) and Rh(III) complexes to higher valent
species, which have been achieved in the Rohde
laboratory,48 and recent investigations of oxidatively-
induced reductive eliminations by the Chang laboratory
provide support for this proposal.49
Scheme 4. Proposed mechanism
[Cp*RhIIICl2]
O
OMe
NH
O
2 AgOAc
2 AgCl
9
turnover-limiting
2b substrate binding
R
10
[Cp*RhIII](OAc)2
HOAc
O
A
OMe
O
C(sp2)C(sp3)
reductive
HN
OMe
N
OAc
[RhIII
]
Cp*
elimination
O
[RhV] Cp*
O
B
Me
OAc
R
O
F
CH activation
2 Ag0
HOAc
O
OMe
HN
2 AgOAc
silyl enol ether
activation
OMe
N
O
[RhIII
] Cp*
O
[RhIII
]
Cp*
OMe
C
N
R
E
OTMS
[RhIII
OTMS
] Cp*
O
R
1
TMSOAc
HOAc
D
R
On the basis of our mechanistic observations, we favor a
catalytic cycle where the binding of benzamide 2b to
Rh(III) species A is turnover-limiting (Scheme 4). The
resulting amide-bound intermediate (B) subsequently
undergoes C–H activation to give rhodacycle C, to which
silyl enol ether 1 coordinates. Departing from the
traditional migratory insertion of the alkene into the
rhodium–carbon bond, which favors addition to the
electron-deficient carbon, we propose α-metalation of
electron-rich 1, potentially via activation by acetic acid.
The resulting acylalkyl Rh(III) intermediate (E) could be
oxidized by AgOAc to afford Rh(V) complex F, which
reductively eliminates to liberate ketone 10 and the active
catalyst. Rhodium oxidation can also occur at earlier steps
of the cycle. This proposed mechanism addresses
challenges associated with migratory insertion of electron-
rich olefins and C(sp2)–C(sp3) reductive elimination. At this
time, we cannot rule out the possibilities of any Rh(IV)
species being catalytically-active.
give over 2 g of the desired hemiamidal (17), which can
serve as an intermediate for diversification. Brief exposure
to HCl affords isoquinolone 18 in 95% yield and ensuing
cleavage of the N–O bond proceeds in 90% yield by heating
with NaH in DMF at reflux. Upon treating
dihydroisoquinolone 17 with CsOAc, isocoumarin 20 is
isolated in 92% yield. Subsequent basic hydrolysis results
in the formation of acylalkylated probenecid 21 in 84%
yield.
The current cross-coupling of benzamides with enol
silanes requires a silver additive that is not necessary in
related transformations with enol acetate, enol sulfonates,
and carbene precursors. Of note is the apparent
regiodivergent behavior between silyl enol ethers and
vinyl ethers (Scheme 1C).24,33 Several experiments were
thus conducted to probe the mechanism. The reaction of
benza-mide 2b with deuterated silyl enol ether 1a-d2
provided product 9ba-d2, which retains the majority of the
deuterium label at the benzylic position (Scheme 3A). The
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Hartwig, J. F. Simple, Highly Active Palladium Catalysts for Ketone
In summary, we advanced the first α-arylation of silyl
enol ethers through C–H activation using a Rh(III) catalyst.
In contrast to conventional electron-deficient alkene and
alkyne substrates, electron-rich silyl enol ethers present
unique mechanistic demands, which are addressed by
employing a silver salt additive. The use of ketone-derived
and Malonate Arylation: Dissecting the Importance of Chelation
and Steric Hindrance. J. Am. Chem. Soc. 1999, 121, 1473–1478. (d)
Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. Highly Active and
Selective Catalysts for the Formation of α-Aryl Ketones. J. Am.
Chem. Soc. 2000, 122, 1360–1370. (e) Solé, D.; Vallverdú, L.; Solans,
X.; Font-Bardía, M.; Bonjoch, J. Intramolecular Pd-Mediated
Processes of Amino-Tethered Aryl Halides and Ketones: Insight
into the Ketone α-Arylation and Carbonyl-Addition Dichotomy. A
new Class of Four-Membered Azapalladacycles. J. Am. Chem. Soc.
2003, 125, 1587–1594. (f) Marelli, E.; Renault, Y.; Sharma, S. V.;
Nolan, S. P.; Goss, R. J. M. Mild, Aqueous α-Arylation of Ketones:
Towards New Diversification Tools for Halogenated Metabolites
and Drug Molecules. Chem. Eur. J. 2017, 23, 3832–3836.
(7) Kuwajima, I.; Nakamura, E. Reactive Enolates from Enol
Silyl Ethers. Acc. Chem. Res. 1985, 18, 181–187.
(8) Kuwajima, I.; Urabe, H. Regioselective Arylation of Silyl
Enol Ethers of Methyl Ketones with Aryl Bromides. J. Am. Chem.
Soc. 1982, 104, 6831–6833.
(9) Chae, J.; Yun, J.; Buchwald, S. L. One-Pot Sequential Cu-
Catalyzed Reduction and Pd-Catalyzed Arylation of Silyl Enol
Ethers. Org. Lett. 2004, 6, 4809–4812.
1
2
3
4
5
6
7
8
enol
silanes
gives
rise
to
3-substituted
dihydroisoquinolones and complements existing methods
with enol esters. A variety of N-methoxybenzamide and
enol silane derivatives cross-couple in moderate to high
yields. Silyl enol ethers are readily available and thus
enhance accessibility to a range of products. Current
efforts in our laboratory are directed toward devising
strategies to α-arylate substituted silyl enol ethers and
facilitate natural product synthesis.
9
10
11
12
13
14
15
16
17
18
19
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21
22
23
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
(10) Hama, T.; Liu, X.; Culkin, D. A.; Hartwig, J. F. Palladium-
Catalyzed α-Arylation of Esters and Amides under More Neutral
Conditions. J. Am. Chem. Soc. 2003, 125, 11176–11177.
(11) Liu, X.; Hartwig, J. F. Palladium-Catalyzed Arylation of
Trimethylsilyl Enolates of Esters and Imides. High Functional
Group Tolerance and Stereoselective Synthesis of α-Aryl
Carboxylic Acid Derivatives. J. Am. Chem. Soc. 2004, 126, 5182–
5191.
Procedures, characterization data, NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
*kevin.kou@ucr.edu
(12) Su, W.; Raders, S.; Verkade, J. G.; Liao, X.; Hartwig, J. F. Pd-
Catalyzed α-Arylation of Trimethylsilyl Enol Ethers with Aryl
Bromides and Chlorides: A Synergistic Effect of Two Metal
Fluorides as Additives. Angew. Chem. Int. Ed. 2006, 45, 5852–
5855.
ACKNOWLEDGMENT
UCR is gratefully acknowledged for startup funds. The Agilent
6545 Q-TOF LC/MS instrument is funded by NSF grant CHE-
0541848. We thank Dr. Yan Xu for helpful discussions.
(13) Iwama,
T.;
Rawal,
V.
H.
Palladium-Catalyzed
Regiocontrolled α-Arylation of Trimethylsilyl Enol Ethers with Aryl
Halides. Org. Lett. 2006, 8, 5725–5728.
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