Rhodium(III)-Catalyzed Annulation between N-Sulfinyl Ketoimines and Activated Olefins: C-H Activation Assisted by an Oxidizing N-S Bond

Article abstract of DOI:10.1021/acscatal.5b02297

C-H activation under redox-neutral conditions, especially by Rh(III) catalysis, has offered attractive synthetic strategies. Previous work in redox-neutral C-H activation relied heavily on the cleavage of oxidizing N-O and N-N directing groups, and cleavable N-S bonds have been rarely used, although they may offer complementary coupling patterns. In this work, N-sulfinyl ketoimines were designed as a novel substrate for the redox-neutral coupling with different activated olefins via a Rh-catalyzed C-H activation pathway. The coupling with acrylate esters afforded 1H-isoindoles with the formation of three chemical bonds around a quaternary carbon. Furthermore, the coupling with maleimides furnished pyrrolidone-fused isoquinolines. A broad scope of substrates has been established. The mechanism of the coupling with acrylates has been studied in detail by a combination of experimental and computational methods. This coupling proceeds via imine-assisted C-H activation of the arene followed by ortho C-H olefination to afford a Rh(III) olefin hydride intermediate which, upon deprotonation, may exist in equilibrium with a Rh(I) olefin species. Cleavage of the N-S bond occurs only after C-H olefination to generate a Rh(III) imide species. DFT studies indicated that the imide group can undergo migratory insertion to produce a Rh(III) secondary alkyl which isomerizes under the assistance of acetic acid to a Rh(III) tertiary alkyl that is prone to insertion of the second acrylate.

Full text of DOI:10.1021/acscatal.5b02297

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Article
Rhodium(III)-Catalyzed Annulation between N-Sulfinyl Ketoimines and
Activated Olefins: C-H Activation Assisted by an Oxidizing N-S Bond
Qiang Wang, Yingzi Li, Zisong Qi, Fang Xie, Yu Lan, and Xingwei Li
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.5b02297 • Publication Date (Web): 09 Feb 2016
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ACS Catalysis
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Rhodium(III)-Catalyzed Annulation between N-Sulfinyl Ketoimines
and Activated Olefins: C-H Activation Assisted by an Oxidizing N-S
Bond
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Qiang Wang,a Yingzi Li,b Zisong Qi,a Fang Xie,a Yu Lan,*,b Xingwei Li*,a
a Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
b School of Chemistry and Chemical Engineering, Chongqing University, Chongqing 400030, China
ABSTRACT: C-H activation under redox-neutral conditions, especially by Rh(III) catalysis, has offered attractive synthetic strate-
gies. Previous work in redox-neutral C-H activation relied heavily on the cleavage of oxidizing N-O and N-N directing groups, and
cleavable N-S bonds have been rarely used although they may offer complementary coupling patterns. In this work, N-sulfinyl ke-
toimines were designed as a novel substrate for the redox-neutral coupling with different activated olefins via a Rh-catalyzed C-H
activation pathway. The coupling with acrylate esters afforded 1H-isoindoles with the formation of three chemical bonds around a
quaternary carbon. Furthermore, the coupling with maleimides furnished pyrrolidone-fused isoquinolines. A broad scope of sub-
strates has been established. The mechanism of the coupling with acrylates has been studied in details by a combination of experi-
mental and computational methods. This coupling proceeds via imine-assisted C-H activation of the arene followed by ortho C-H
olefination to afford a Rh(III) olefin hydride intermediate which, upon deprotonation, may exist in equilibrium with a Rh(I) olefin
species. Cleavage of the N-S bond occurs only after C-H olefination to generate a Rh(III) imide species. DFT studies indicated that
the imide group can undergo migratory insertion to produce a Rh(III) secondary alkyl which isomerizes under the assistance of
acetic acid to a Rh(III) tertiary alkyl that is prone to insertion of the 2nd acrylate.
KEYWORDS: C-H bond activation, Rh(III) catalyst, N-S bonds cleavage, N-sulfinyl imine, olefin, isoindole
Introduction
While the concept of oxidizing DG is appealing, it is
important to note that the substrate should be readily available
and C-H activation reactions using external oxidants or using
alternative substrates are poorly accessible. We reasoned that
readily accessible N-sulfinylimines may serve this purpose
because the coordinating properties and polarity of the S=O
bond may facilitate both C-H activation and N-S bond
cleavage. Previously, C-H activation assisted by N-sulfonyl
imine or other N-S functionalities have been extensively
explored.14 However, only in one case was N-S cleavage
involved (Scheme 1).13 On the other hand, although the N-O
bond in oxime ethers/esters may well act as an internal
oxidizing DG, their couplings with olefins only afforded six-
membered rings (Scheme 1).15 We now report complementary
reactivity of N-sulfinylimines in C-H activation and coupling
with different olefins, leading to efficient construction of 5-
and 6-membered heterocycles that are hardly accessible.
In the past several years, Rh(III)-catalyzed C-H activation
of arenes has been increasingly explored, which allowed the
development of a large number of important synthetic methods
with high reactivity, selectivity, functional group tolerance,
and broad applicability.1 Building on the extensively studied
Rh(III)-catalyzed C-H activation and coupling with various
unsaturated partners under oxidative conditions using external
oxidants,2 there has been increasing interest in taking ad-
vantage of an internal oxidant or an oxidizing directing group.
Pioneering work by Fagnou3 and Glorius4 utilized oxidizing
N-O and N-N bonds as directing groups, and these C-H activa-
tion reactions proceeded with redox-economy and high selec-
tivity under relatively mild conditions.5 Inspired by these sem-
inal works, the N-N, N-O, and even C-N bonds in oximes,6
hydrazines,7
N-phenoxyamides,8
N-oxides,9
N-
nitrosoanilines,10 N-hydroxyaniline11 and α-ammonium aceto-
phenones12 have been designed and applied as viable oxidizing
directing groups. Despite the progress, cleavage of a N-S di-
recting group is highly rare.13 This is likely due to the lower
oxidizing potential of a N-S bond. Thus development of cou-
pling systems for arenes bearing a cleavable N-S bond is of
significant interest and may complement existing internal oxi-
dizing systems.
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entry
additive (equiv) solvent
yield (%)b
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9
1
2
3
4
5
-
DCE
< 10
39
HOAc (1.2)
PivOH (1.2)
TFA (1.5)
HOAc (1.2)
HOAc (1.2)
-
DCE
DCE
25
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DCE
<10
30
PhCl
Scheme 1. C-H Activation of Imines Bearing an Oxidizing
DG
6
DCM
35
Results and Discussions
7
DCE/HOAc (20:1)
DCE/HOAc (30:1)
DCE/HOAc (50:1)
DCE/HOAc (30:1)
DCE/HOAc (30:1)
DCE/HOAc (30:1)
DCE/HOAc (30:1)
DCE/HOAc (30:1)
DCE/HOAc (30:1)
DCE/HOAc (30:1)
73
Optimization Studies. We initiated our studies with the
exploration of the reactions parameters of the coupling
between benzophenone-derived N-tert-butylsulfinyl ketoimine
8
-
81
9
-
56
((R)-1a) and
ethyl acrylate (2a) catalyzed
by
[RhCp*Cl2]2/AgSbF6 in DCE at 100 oC (Table 1). The
coupling proceeded with poor efficiency when no additive was
employed (entry 1). Introduction of HOAc (1.2 equiv) as an
additive improved the GC yield to 39% (entry 2), and the
coupled product 3aa was fully characterized as a racemic 1H-
isoindole, and the identity of one of its analogues has been
unambiguously confirmed by X-ray crystallography (3ed, see
Scheme 2).16 Thus, three bonds were constructed around a
quaternary carbon in a single step.17 Other acid additives (TFA
and PivOH) proved to be less efficient (entries 3, 4). Further
improvement was realized when HOAc was used as a co-
solvent, and the optimal volumetric ratio of DCE:HOAc was
found to be 30:1, which corresponds to 8 equiv of AcOH
(entries 7-9), under which conditions the product was isolated
in 81% yield. In contrast to in situ activation of the rhodium
catalyst via chlroide abstraction, coupling using a pre-formed
cationic complex [RhCp*(MeCN)3](SbF6)2 only gave inferior
results (entry 10). To our delight, high GC yield (92%) of 3aa
was secured when Zn(OTf)2 (0.1 equiv) was further introduced
as a co-additive (entry 11).9b Notably, the N-tert-butylsulfinyl
group played an important role because switching this group
to a N-tert-butylsulfonyl (1a’) or to a N-para-tolylsulfinyl
10
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12
13
14
15
-
69c
92(93)
79
Zn(OTf)2 (0.1)
Zn(OTf)2 (0.3)
Zn(OTf)2 (0.1)
Zn(OTf)2 (0.1)
AgOTf (0.1)
Cu(OTf)2 (0.1)
N.D.d
30e
75
16
50
a
Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol),
[RhCp*Cl2]2 (4 mol%), AgSbF6 (16 mol%), and additive in a
solvent (3 mL) at 100 oC, sealed tube under N2 for 12 h. GC
b
yield using mesitylene as an internal standard (isolated yield in
parenthesis). c [RhCp*(MeCN)3](SbF6)2 (8 mol%) was used as
a catalyst. Substrate 1a, was used as the imine source.
d
e
Substrate 1a,, was used as the imine source.
Substrate Scope. Having established the optimal
conditions, we next explored the scope and limitations of this
coupling system (Scheme 2). Imines derived from symmetric
benzophenones bearing a para substituent coupled with ethyl
acrylate in consistently high efficiency.
(1a’’) group all gave poor or no reaction (entries 13, 14).
We also found that the reaction efficiency was soemwhat
lower when AgOTf or Cu(OTf)2 was used as an additive
(entries 15, 16).
Table 1. Optimization Studiesa
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Scheme 2. Scope of Synthesis of 1H-Isoindoles.a,b aReaction conditions: imine (0.2 mmol), acrylate ester (0.6 mmol),
[RhCp*Cl2]2 (4 mol %), AgSbF6 (16 mol %), Zn(OTf)2 (0.1 equiv) in DCE/AcOH (3 mL, 30:1) at 100 oC for 12 h, sealed tube un-
der N2. bIsolated yield after column chromatography.
(3ba-3fa), and both electron-donating and withdrawing para
substituents are tolerated. Introduction of a meta-Me group
into both the benzene rings caused the reaction to occur at the
less hindered ortho site (3ga). 1- and 2-naphthylphenone-
derived sulfinylimines are also viable substrates, and the
isolation of 3ia in good yield indicates tolerance of steric
hindrance associated with a 1-naphthyl group. A variety of
unsymmetrically substituted imines also coupled in high
selectivity, and the selectivity can be well dictated by the
steric effect. Thus, with the introduction of a sterically more
hindered, ortho- or meta-substituent into one phenyl ring, C-H
activation occurred at the more sterically accessible ring in
high yield and high site selectivity (3ja-3oa). To examine the
electronic preference of this coupling reaction, an
electronically biased diaryl imine was allowed to couple with
extended to those of acetophenones, and such imines can be
smoothly converted to the isoindole product in relatively lower
yields (3pa-3ra), where the decrease of the reaction yield is
ascribable to the higher tendency of hydrolysis (reduced steric
protection). The acrylate coupling partner has also been
extended to methyl, n-butyl, and benzyl acrylates, and
couplings with these acrylates also tolerated various
substituents in the imine substrate (3ab-3hc). In all cases,
good to excellent yields were obtained.
Coupling with an Enone. To better define the scope of the
olefin, ethyl vinyl ketone was applied as a direct anlogue.
While enones may seem more reactive, the coupling afforded
an indene in good yield under mild conditions.18 This reaction
likely proceeded via hydroarylation of the olefin to afford an
alkylated intermediate followed by hydrolysis of the imine
moiety; subsequent intramolecular aldol condensation
furnished the final product.18a
1
ethyl acrylate. H, 19F, and 13C NMR analyses of the product
mixture (3pa and 3pa,) revealed that the C-H activation
occurred preferentially at the more electron-rich ring. Indeed,
this observation is consistent with the fact that essentially no
desired reaction occurred for the imine derived from bis(para-
trifluoromethylphenyl)m- ethanone. The imine can be
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Experimental Mechanistic Studies: H/D exchange and
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Kinetic Isotope Effect. A series of mechanistic studies have
been performed to probe the reaction mechanism (Scheme 4).
To explore the C-H activation process, H/D exchange was
performed for 1a in DCE-CD3COOD in the absence of any
1
olefin (Scheme 4a). H NMR analysis revealed 15% deuter-
Coupling with Maleimides. To further define the scope of
the olefin, we applied N-methyl maleimide as an activated
olefin.19 We reasoned that migratory insertion of an aryl group
into this cyclic olefin should lead to an alkyl species that can-
ation at the ortho positions of the para-substituted benzene
ring, suggestive of reversible C-H activation in the absence of
1
any olefin. Moreover, H NMR analysis of the coupled prod-
uct obtained from 1a-d10 and ethyl acrylate (DCE-AcOH) re-
vealed essentially no H/D exchange in any alkyl group and
only 3aa-d9 was obtained. On the other hand, when the cou-
pling of 1a with 2a was performed in DCE-CD3COOD, no
deuterium was incorporated into any phenyl ring, which col-
lectively points to irreversible C-H activation in the presence
of an olefin substrate. Importantly, H/D exchange was ob-
served at both α-methylene positions (Scheme 4a). In one of
the methylene groups, both protons are deuterated to the same
extent (72% D). However, in the other α-methylene, only one
of the protons was partially deuterated (20% D). Control ex-
periments confirmed that the deuteration did not originate
from post-coupling H/D exchange. These data also cast light
on details of the mechanism (vide infra). To further probe the
C-H activation process, KIE experiment has been measured.
1H NMR analyses of the product mixture obtained from an
intramolecular competition using imine 1a-d5 revealed that the
C6H5 group reacts preferentially with a kH/kD of 3.0 (Scheme
4b). In addition, KIE measurement using an equimolar mixture
of 1a and 1a-d10 gave kH/kD = 2.3. These data consistently
suggest that C-H activation is likely involved in the turnover-
limiting step.
not undergo
β-H elimination due to requirement of syn-
9
coplanar orientation of the H-C-C-Rh moiety. Therefore, dif-
ferent reactivity should be expectable. Indeed, the coupling of
1a with N-methyl maleimide afforded a pyrrolidone-fused
isoquinoline, and a similar scope and regioselectivity of the
imine substrate have been observed (Scheme 3). Notably, ace-
tophenone-derived N-sulfinylimines reacted with equally high
efficiency (5i-5q). In nearly all cases, good to high yields have
been obtained. It is noteworthy that while maleimides have
been used as a coupling partners in C-H activation reactions,
in all cases they either acted as a C1 source or a simple π-
bond,19 and coupling with loss of an oxygen atom has not been
reported.
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The Intermediacy of an Olefinated Imine. To probe
whether the reaction proceeded via initial C-H olefination,
olefinated imine 7 was prepared as a Z/E mixture and was
subjected to the standard conditions. However, it failed to
undergo any conversion (Scheme 4c). We reasoned that it
remains a possible intermediate because imine 7, generated via
β-H elimination, is accompanied with a Rh(III) hydride
species which could exist in equilibrium with a Rh(I) species
upon deprotonation, and it is the Rh(I) olefin or the Rh(III)
hydride species that gave activity. Thus, we reasoned that by
borrowing the transient Rh(I) or Rh(III) species generated in
situ from the coupling of 1a with ethyl acrylate, intermediate 7
could be converted. Indeed, reaction of a mixture of 7, 1a, and
ethyl acrylate afforded 3aa that exceeded 100% yield if based
the amount of 1a (together with some benzophenone
byproduct, Scheme 4d). Direct evidence was obtained using a
Rh(I) catalyst. The coupling of 7 with ethyl acrylate catalyzed
by [RhCp*(C6Me6)] afforded product 3aa in 60% yield
(Scheme 4e). In contrast, no coupling occurred when 1a and
2a were allowed to react using this Rh(I) catalyst.
Furthermore, reaction of n-butyl acrylate with a mixture of 7
and 1a afforded a mixed-ester product 8 together with a homo-
Scheme 3. Scope of the Coupling with Maleimides.a,b a Re-
action conditions: imine (0.2 mmol), maleimide (0.3 mmol),
[RhCp*Cl2]2 (4 mol%), AgSbF6 (16 mol%), Zn(OTf)2 (0.3
o
equiv), AcOH (0.24 mmol), DCE/AcOH (3 mL) at 100 C for
b
12 h, sealed tube under N2. Isolated yield after column chro-
matography.
Derivatization of
a Coupled Product. To briefly
demonstrate the synthetic usefulness of the fused isoquinoline
product, heterocycle 5h was derivatized. Simple treatment of
5h with NaBH4 in the presence of ZnCl2 afforded a pyrrole-
fused isoquinoline (6) in 78% yield (eq 2). This extended
aromatic system may exhibit valuable biological activities.20
ester
3ac
in
2:1
ratio
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ACS Catalysis
(Scheme 4f, GC-MS analyses). To gain further mechanistic details, we relied on DFT studies.
1
2
3
4
5
O
S
S(O)tBu
H/D
CO2Et
O
S
[RhCp*Cl2]2 (4 mol%)
AgSbF6 (16 mol%)
N
H/D
N
ethyl acrylate
N
standard conditions
15% D
(c)
(d)
traces of 3aa
(a)
DCE/CD3COOD (30:1)
100 oC, 12 h
H/D H/D
1a
6
7
1a-dn
CO2Et
O
S
7
8
ethyl acrylate
[RhCp*Cl2]2 (4 mol%)
AgSbF6 (16 mol%)
O
S
H
CO2Et
N
N
O
ethyl acrylate (1 mmol)
20% D
H/D
+
1a
3aa
+
9
Ph
Ph
Ph
Zn(OTf)2 (0.1 equv)
standard conditions
CO2Et
N
DCE/CD3COOD (30:1)
H/DH/D
7
72% D
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100 o
C
1a
0.2 mmol
0.12 mmol
0.2 mmol
0.23 mmol
3aa-
dn
ethyl acrylate
[RhCp*Cl2]2 (4 mol%)
AgSbF6 (16 mol%)
CO2Et
O
D4
O
S
S
EtO2C
EtO2C
EtO2C
[Cp*Rh(C6Me6)] (4 mol%)
N
7
OEt
+
N
(e)
+
3aa
O
(b)
standard conditions
60%
Zn(OTf)2 (0.1 equv)
Ph
C6D5 EtO2C
N
Ph
C6D5
1a-d5
N
DCE/AcOH (10:1), 60 o
C
2a
3aa-
d5
3aa-
d4
3:1
CO2Et
O
S
ethyl acrylate
[RhCp*Cl2]2 (4 mol%)
AgSbF6 (16 mol%)
butyl acrylate (3 equiv)
[Cp*Rh(C6Me6)] (4 mol%)
O
S
BuO2C
EtO2C
O
N
7
S
3ac
(f)
+
1a
+
N
+
N
3aa-
3aa
d9
+
standard conditions
Ph
Zn(OTf)2 (0.1 equv)
DCE/AcOH (30:1)
60 oC, 5 h
N
C6D5
C6D5
Ph
Ph
2.3:1
8
2 : 1
1a
1a-
d10
Scheme 4. Mechanistic Studies.
Scheme 5. Possible mechanistic pathways for the coupling of imine 1a with olefin acrylate 2a (in the circle) and a likely
mechanism for the coupling with a maleimide (outside the circle).
General Remarks on DFT Studies. All the DFT calcula-
tions were carried out using the GAUSSIAN 0921 series of
programs. Density functional B3-LYP22 with a standard 6-
31g* basis set (LANL08(f) basis set for Rh) was used for ge-
ometry optimizations. The M11-L23 functional, proposed by
Truhlar et al., was used with a 6-311+g* basis set (LANL08(f)
basis set for Rh) to calculate the single-point energies because
it was envisaged that this strategy would provide greater accu-
racy with regard to the energetic information.9b,24 The solvent
effects were considered by single-point calculations on the
gas-phase stationary points with SMD25 solvation model. The
energies presented in this paper are the M11-L calculated
Gibbs free energies in 1,2-dichloroethane solvent with B3-
LYP calculated thermodynamic corrections.
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Figure 1. Free energy profiles for the N-sulfinylketoimine-directed acetate-assisted C-H activation of N-sulfinylketoimines. Values are
given in kcal/mol and represent the relative free energies calculated by the M11-L method in DCE solvent. The values given in parentheses
are the relative free energies calculated using the B3-LYP method in the gas phase. The values for the bond lengths given in the geometry
information have been reported in units of angstrom.
Possible Mechanistic Pathways. As shown in Scheme 5,
on the basis of these experimental data, several possible path-
ways have been taken into account for the coupling between
1a and 2a as a model for theoretical studies at the DFT level.
These four pathways begin with Rh(III) acetic acid complex
A, which is followed by cyclometalation of imine 1a to gener-
ate a rhodacyclic intermediate B. In Pathway a (blue pathway),
the Rh-C(aryl) bond of the common intermediate B is pro-
posed to undergo migratory insertion into ethyl acrylate 2a to
generate a Rh(III) alkyl intermediate C, which is expected to
catalyst A. Although our experimental studies suggested the
intermediacy of olefinated imine 7 and suggested that the C-H
olefination occurs prior to the cleavage of the N-S bond,
Pathway b (red line) was still examined for comparisons. In
this pathway, N-S oxidative addition of the intermediate B
occurs prior to C-H olefination to afford a putative Rh(V) im-
ide species F, the Rh-C(aryl) bond of which might then under-
go migratory insertion into ethyl acrylate to form a Rh(V)
intermediate G. Followed by intramolecular (or intermolecu-
lar) deprotonation, a common intermediate E could also be
reached. Alternatively in Pathway d (purple line), the N-S
oxidative addition of might occur at the stage of intermediate
C to produce the intermediate G.
undergo
β-H elimination to afford a Rh(III) hydride D. As
discussed above, hydride species D may exist in equilibrium
with the corresponding Rh(I) olefin intermediate D’. An
intramolecular deprotonation of the Rh-H in D by the sulfinyl
oxygen may take place with concomitant N–S bond cleavage
Plausible Mechanism of the Coupling with Maleimides.
In line with the coupling with acrylates, the coupling with
maleimides (Scheme 5, outside the circle) likely involves a
Rh(III) alkyl species M that undergoes protonolysis to furnish
intermediate N. Subsequent dissociate of the imine ligand
released the active Rh(III) catalyst A. The resulting hydroary-
lated intermediate is proposed to undergo 6π-
electrocyclization in its enol form (O) to provide a dearoma-
tized intermediated P. Elimination of t-butylsulfinic acid fur-
nished product 5a. In this coupling reaction, the Zn(OTf)2
additive likely facilitated the ketone-enol tautomerization.
t
to give intermediate E by releasing one molecule of BuSOH.
As discussed above, hydride species D also may exist in equi-
librium with the corresponding Rh(I) olefin intermediate I
(pathway e). The followed intermolecular oxidative addition
with N-S bond in complex I would generate Rh(III) interme-
diate J. Protonolysis of intermediate J would release one mol-
t
ecule of BuSOH and generate the same intermediate E. The
transformation of intermediate C to intermediate E might also
occur in a concerted fashion via a proposed transition state H
(Pathway c, green). Subsequently, migratory insertion of the
imide group in Rh(III) imide intermediate E generates a
Rh(III) alkyl intermediate K’ which further isomerizes to a
Rh(III) alkyl intermediate K via a formal rhodium shift. Inser-
tion of the 2nd molecule of ethyl acrylate then takes place to
give intermediate L, which is protonolyzed by acetic acid to
release the final product 3a with the regeneration of the active
The C-H Activation Process. To better understand the
mechanism of the coupling with acrylates, all these four possi-
ble pathways have been evaluated by using DFT calculations.
The free energy profiles for the C-H activation step of the
rhodium-catalyzed annulation between N-sulfinylketoimines
and olefins are given in Figure 1. The energy of solvento com-
plex Cp*RhIII(OAc)(AcOH)+ (CP1)
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Figure 2. Free energy profiles for the first olefin insertion and the N–S bond cleavage in rhodium-catalyzed annulation between N-
sulfinylketoimines and olefins. Values are given in kcal/mol and represent the relative free energies calculated by the M11-L method in
DCE solvent. The values given in parentheses are the relative free energies calculated by using the B3-LYP method in the gas phase. The
values for the bond lengths given in the geometry information have been reported in units of angstrom.
was set to a relative zero value in the whole free energy pro-
files, and this complex could be readily generated from the
[Cp*RhCl2]2 and AgSbF6 via chloride abstraction and coordi-
nation of AcOH.26 The dissociative ligand substitution be-
tween CP1 and substrate 1a forms an imine complex CP3
with 4.1 kcal/mol exothermicity. The subsequent imine-
directed, acetate-assisted C-H activation takes place via the
transition state TS3-4 (CMD mechanism) with an overall acti-
vation free energy of 27.7 kcal/mol, leading to formation of
rhodacycle CP4 and an acetic acid. The reversibility estab-
lished by DFT is in line with our observation of an imine sub-
strate in the absence any coupling partner (Scheme 4a).
The 1st Olefin Insertion and Cleavage of the N-S bond.
Starting from intermediate CP4, the free energy profiles of the
1st olefin insertion and the N–S bond cleavage for all the
plausible pathways are given in Figure 2. In Pathway a (blue
pathway), the coordination of 2a forms olefin complex CP5
with 7.2 kcal/mol endothermicity, aand the subsequent olefin
insertion occurs via transitionstate TS5-6 with an activation
free energy of 20.0 kcal/mol to reversibly produce a seven-
membered rhodacycle CP6. Subsequent
β-H elimination of
CP6 has been established via transition state TS6-7, and the
barrier of this step is found to be 19.9 kcal/mol, which could
be attributed to the strain and rigidity of the metalacycle in
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CP6. The subsequent intramolecular proton abstraction with
concomitant N–S bond cleavage takes place via transition
state TS7-8 with a barrier of as low as 2.7 kcal/mol, and the
imide complex CP8 is formed irreversibly with the release of
one molecule of tert-BuSOH. We also considered the deproto-
nation of CP7 (Path e). As shown in Figure 2 (orange lines),
when acetic acid is chosen as proton acceptor, the proton
transfer from CP7 to acetic acid is exothermic. However, this
barrier of this course is as high as 16.3 kcal/mol via transition
state TS7-11. The relative free energy of TS7-8 is 13.6
kcal/mol lower than that of TS7-11, therefore, Path e is kinet-
ically unfavorable.
of 22.7 kcal/mol. Thus, further intramolecular deprotonation
1
2
3
4
5
6
7
8
of the methine CH in intermediate CP15 occurs readily and
reversibly via transition state TS15-16 to form isoindolyl rho-
dium intermediate CP16, which is 3.5 kcal/mol more stable
than intermediate CP13 likely owing to the formation of a
stable five-membered rhodacycle. Therefore, the acetic acid-
promoted rhodium-shift is both kinetically and thermodynami-
cally favorable. This mechanistic profile is also consistent
with our experimental H/D exchange studies using CD3COOD
(Scheme 4b). The reversibility of this proton abstraction can
readily give rise to deuteration of the two methylene protons
α- to the ester group. The coordination of the 2nd ethyl acrylate
to CP16 is 17.1 kcal/mol uphill in free energy, which can be
largely attributed to the excess coordination in intermediate
CP18. The overall activation free energy for olefin insertion
via transition state TS18-19 is 24.7 kcal/mol. The intermediate
CP19 undergoes protonolysis by acetic acid to produce an N-
bound isoindole complex CP20. Ligand substitution by an
acetic acid released the active catalyst CP1 together with the
final product 3aa. Notably, our theoretical data are in line with
the fact that the coupling reaction will stop at the stage of the
mono-insertion of the olefin because comparisons between the
energy profiles in Figure 3 and those in Figure 2 indicate that
the kinetic barriers of the imide migratory insertion, rhodium
migration, and the 2nd olefin insertion are all lower than those
in preceding processes.
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We also managed to locate the transition state TS6-8,
through which direct deprotonation of the alkyl C-H of CP6
occurs to give CP8. However, the relative free energy of tran-
sition state TS6-8 is 20.8 kcal/mol higher than that of the tran-
sition state TS6-7. Therefore, the proposed Pathway c is un-
likely. In the calculated energy profiles of Pathway b, as
shown in Figure 2 (red lines), the activation free energy for the
N-S oxidative addition of CP4 via transition state TS4-9 was
found to be 33.3 kcal/mol, leading to formation of a Rh(V)
sulfinyl intermediate CP9 with 10.3 kcal/mol endothermicity.
Furthermore, the activation free energy for the olefin insertion
into the Rh-C bond in CP9 via transition state TS9-10 is also
much higher than those for the olefin insertion, β-H elimina-
tion, and N–S bond cleavage in Pathway a. Therefore, Path-
way b should also be explicitly ruled out due to unfavorable
activation barriers. Analogously, the direct intramolecular N-S
oxidative addition of CP6 to generate CP10 (Pathway d)
could not occur because the relative free energy of transition
stateTS6-10 is 26.2 kcal/mol higher than that of transition
state TS6-7 in Pathway a. Based on our theoretical calcula-
tions, we conclude that the N–S bond cleavage only occurs
on the rhodium olefin hydride species, and the redox neutrality
is maintained by the release of a t-BuSOH molecule.
Summary of DFT Studies. The rhodium-catalyzed annula-
tion between N-sulfinyl ketoimines and acrylate has been ex-
amined in detail by DFT method, and the most likely mecha-
nism for this reaction has been outlined in Pathway a that in-
volves four Rh(III) alkyl species. In this lowest energy path-
way, the reaction proceeds with initial N-sulfinyl ketoimine-
directed, acetate-assisted C-H activation as a turnover-limiting
step, followed by insertion of an olefin to afford the 1st alkyl
species.
β-H elimination generates a Rh(III) olefin hydride
which is likely in equilibrium with a Rh(I) olefin intermediate.
N–S bond cleavage occurs upon intramolecular abstraction of
the Rh-H proton by the sulfinyl oxygen to afford an imide
intermediate, which undergoes migratory insertion to give the
2nd alkyl species. Isomerization of this secondary alkyl to the
3rd, tertiary alkyl species has been examined in detail and it is
likely assisted by reversible protonolysis of the Rh-C(enolate)
bond by AcOH. The 4th alkyl is generated from the insertion of
the 2nd molecule of olefin, and it is eventually protonolyzed by
AcOH to afford the coupled product. Thus, the DFT data are
in line with the experimental results in terms of intermediacy
of an olefinated imine, KIE studies, H/D exchange experi-
ments, and the observed 1:2 coupling with olefins. The DFT
studies are also consistent with the absence of any diasterose-
lectivity because the chiral sulfinyl group was already elimi-
nated prior to the stereo–determining step.
Imide Migratory Insertion, Rhodium Migration, and the
2nd Olefin Insertion. As shown in Figure 3, with the for-
mation of intermediate CP8, the intramolecular imide migrato-
ry insertion readily takes place via transition state TS8-13 with
a barrier of only 13.5 kcal/mol to irreversibly form intermedi-
ate CP13. The direct rhodium-shift via transition state TS13-
16 to form intermediate CP16 was found to be kinetically
inaccessible because this bears a barrier as high as 39.5
kcal/mol. We also considered the
re-insertion mechanism (green lines), however, the activation
free energy for -H elimination of complex CP13 is also as
β-H elimination and olefin
β
high as 32.5 kcal/mol. Therefore, we deduce that acetic acid
may promote this formal rhodium-shift. As shown in Figure 3,
the coordination of a molecule of acetic acid forms intermedi-
ate CP14, and the proton-transfer from acetic acid to the eno-
late carbon moiety (protonolysis) takes place reversibly via
transition state TS14-15 with an overall activation free energy
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Figure 3. Free energy profiles for imide migratory insertion, formal rhodium shift, and protonolysis steps of the rhodium-catalyzed annula-
tion between N-sulfinylketoimines and acrylates. Values are given in kcal/mol and represent the relative free energies calculated by the
M11-L method in DCE solvent. The values given in parentheses are the relative free energies calculated by using the B3-LYP method in
the gas phase. The values for the bond lengths given in the geometry information have been reported in units of angstrom.
Conclusions
alkyl which isomerizes under the assistance of acetic acid to a
Rh(III) tertiary alkyl that is prone to insertion of the 2nd acry-
late. These coupling systems extended the scope of arenes in
Rh-catalyzed C-H activation, especially under redox-neutral
conditions. Future studies are directed to asymmetric C-H
activation/coupling reactions using this type of sulfinyl
directing group.
We have designed N-tert-butylsulfinylimines as a novel
arene substrate for the coupling with activated olefins with a
N-S bond being an internal oxidant. The coupling with
acrylates afforded substituted 1H-isoindoles as a result of C-H
activation and 1:2 coupling, in which process four chemical
bonds have been constructed around a quaternary center. The
coupling with maleimides proceeded under similar conditions
to afford pyrrolidone-fused isoquinolines. The mechanism of
the coupling of N-tert-butylsulfinylimines with acrylates have
been elaborated using a combination of experimental and
theoretical methods. Our mechanistic studies revealed that the
reaction proceeds via chelation-assisted C-H activation fol-
lowed by ortho-C-H olefination to afford a Rh(III) olefin hy-
dride intermediate that may exist in equilibrium with a Rh(I)
olefin species upon deprotonation, and cleavage of the N-S
bond occurs only after C-H olefination to generate a Rh(III)
imide species. DFT studies also indicated that this imide group
undergoes migratory insertion to produce a Rh(III) secondary
ASSOCIATED CONTENT
1
Experimental procedures, characterization data, copies of H and
13C NMR spectra, crystallographic data for 3ed (CIF), and com-
putational details (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Email: xwli@dicp.ac.cn, phone: +86-411-84379089 (X.L.)
Email: lanyu@cqu.edu.cn, phone: +86-23-88288267 (Y.L.)
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H. Synthesis 2009, 8, 1400-1402. (h) Parthasarathy, K.; Jeganmohan,
M.; Cheng, C-H. Org. Lett., 2008, 10, 325-328.
Notes
1
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The authors declare no competing financial interest
(7) (a) Chuang, S.-C.; Gandeepan, P.; Cheng, C.-H. Org. Lett.
2013, 15, 5750-5753. (b) Zheng, L.; Hua, R. Chem. Eur. J. 2014, 20,
2352-2356. (c) Han, W. J.; Zhang, G. Y.; Li, G. X.; Huang, H. M.
Org. Lett. 2014, 16, 3532-3535. (d) Muralirajan, K.; Cheng, C.-H.
Adv. Synth. Catal. 2014, 356, 1571-1576. (e) Huang, X.-C.; Yang, X.-
H.; Song, R.-J.; Li, J.-H. J. Org. Chem. 2014, 79, 1025-1031. (f) Su,
B.; Wei, J.-b.; Wu, W.-l.; Shi, Z.-j. ChemCatChem 2015, 7, 2986-
2990.
(8) (a) Shen, Y.; Liu, G.; Zhou, Z.; Lu, X. Org. Lett. 2013, 15,
3366-3369. (b) Liu, G.; Shen, Y.; Zhou, Z.; Lu, X. Angew. Chem. Int.
Ed. 2013, 52, 6033-6037. (c) Zhang, H.; Wang, K.; Wang, B.; Yi, H.;
Hu, F.; Li, C.; Zhang, Y.; Wang, J. Angew. Chem. Int. Ed. 2014, 53,
13234-13238. (d) Chen, Y.; Wang, D.; Duan, P.; Ben, R.; Dai, L.;
Shao, X.; Hong, M.; Zhao, J.; Huang, Y. Nat Commun 2014, 5, 4610.
(e) Hu, F.; Xia, Y.; Ye, F.; Liu, Z.; Ma, C.; Zhang, Y.; Wang, J. An-
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Angew. Chem. Int. Ed. 2013, 52, 12970-12974. (b) Zhang, X.; Qi, Z.;
Li, X. Angew. Chem. Int. Ed. 2014, 53, 10794-10798. (c) Sharma, U.;
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R. B.; Chang, S. J. Am. Chem. Soc. 2015, 137, 4908-4911. (e) Kong,
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ACKNOWLEDGMENT
Financial support from the NSFC (Nos. 21272231, 21402190, and
21525208) and the Chinese Academy of Sciences are gratefully
acknowledged.
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