Rh(III)-Catalyzed and Solvent-Controlled Chemoselective Synthesis of Chalcone and Benzofuran Frameworks via Synergistic Dual Directing Groups Enabled Regioselective C-H Functionalization: A Combined Experimental and Computational Study

Article abstract of DOI:10.1021/acscatal.8b02402

By virtue of a synergistically dual-directing-group (the O-NHAc part and the hydroxyl group)-assisted strategy, the efficient and practical Rh(III)-catalyzed regioselective redox-neutral C-H functionalization of diverse N-phenoxyacetamides with propargyl alcohols has been realized, which led to the divergent synthesis of privileged benzofuran and chalcone frameworks in a solvent-controlled chemoselective manner. Experimental and computational studies reveal that the formation of the hydrogen bonding between dual directing groups and the subsequent coordination interaction between the hydroxyl group and the Rh(III) catalyst play a decisive role in promoting the regioselective migratory insertion of the alkyne moiety. Thereafter, two solvent-controlled switchable reaction pathways, which respectively involve tandem β-H elimination/hydrogen transfer/oxidative addition/C-O bond reductive elimination/oxidation (for low-polar solvents: path I-I_a via a Rh^III-Rh^I-Rh^III pathway) and oxidative addition/β-H elimination/hydrogen transfer/protonolysis (for high-polar solvents: path II-II_b via a Rh^III-Rh^V-Rh^III pathway), are followed to deliver the corresponding products with excellent chemoselectivity. Taken together, our results presented here not only give an expansion in the area of O-NHAc-directed C-H activations but also provide a rational basis for future development of synergistic dual DGs-enabled C-H functionalization reactions.

Full text of DOI:10.1021/acscatal.8b02402

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Article
Rh(III)-Catalyzed and Solvent-Controlled Chemoselective
Synthesis of Chalcone and Benzofuran Frameworks via
Synergistic Dual Directing Groups Enabled Regioselective C–H
Functionalization: a Combined Experimental and Computational Study
Wei Yi, Weijie Chen, Fu-Xiaomin Liu, Yuting Zhong, Dan Wu, zhi Zhou, and Hui Gao
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b02402 • Publication Date (Web): 05 Sep 2018
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ACS Catalysis
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Rh(III)-Catalyzed and Solvent-Controlled Chemoselective Syn-
thesis of Chalcone and Benzofuran Frameworks via Synergistic
Dual Directing Groups Enabled Regioselective C–H Function-
alization: a Combined Experimental and Computational Study
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Wei Yi,†,* Weijie Chen,† Fu-Xiaomin Liu,† Yuting Zhong,† Dan Wu,† Zhi Zhou,†,* and Hui Gao†,‡,*
Dedicated to Professor Xiyan Lu on the occasion of his 90th birthday
†Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences & the Fifth Affili-
ated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China
‡ School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
Supporting Information Placeholder
ABSTRACT: By virtue of a synergistically dual directing groups (the O–NHAc part and the hydroxyl group)-assisted strat-
egy, the efficient and practical Rh(III)-catalyzed regioselective redox-neutral C–H functionalization of diverse N-
phenoxyacetamides with propargyl alcohols has been realized, which led to the divergent synthesis of privileged
benzofuran and chalcone frameworks in a solvent-controlled chemoselective manner. Experimental and computational
studies reveal that the formation of the hydrogen bonding between dual directing groups and the subsequent coordina-
tion interaction between the hydroxyl group and the Rh(III) catalyst play a decisive role in promoting the regioselective
migratory insertion of the alkyne moiety. Thereafter, two solvent-controlled switchable reaction pathways which respec-
tively involve tandem β–H elimination/hydrogen transfer/oxidative addition/C–O bond reductive elimination/oxidation
(for low-polar solvents: path I-Ia via a RhIII-RhI-RhIII pathway) and oxidative addition/β–H elimination/hydrogen trans-
fer/protonolysis (for high-polar solvents: path II-IIb via a RhIII-RhV-RhIII pathway), are followed to deliver the correspond-
ing products with excellent chemoselectivity. Taken together, our results presented here not only give a remarkable
and meaningful expansion in the area of O–NHAc-directed C–H activations but also provide a rational basis for future
development of synergistic dual DGs-enabled C–H functionalization reactions.
KEYWORDS: Rh(III) catalyst, N-phenoxyacetamides, propargyl alcohols, benzofurans, chalcones, experimental and com-
putational studies
INTRODUCTION
motifs. In this regard, recently developed bidentate che-
lating auxiliaries4-7 have emerged as one of the most at-
tractive strategies to realize some elegant and important
transformations with the controllable regioselectivity, in
which the conventional monodentate DG remains un-
solved. Indeed, such strategy can confer to the new prop-
erty of the metallacycle complex, thus leading to the dis-
covery of novel and regioselective C–H activation mode
(Scheme 1a). Unfortunately, the bidentate chelating auxil-
iaries reported in TM-catalyzed C–H functionalization are
limited to N,N-,4d,5 N,O-6 or N,S-based7 skeletons and of-
ten need strict spatial dimension for achieving the coor-
dination with the TM, which lead inevitably to relatively
poor product diversity in comparison with monodentate
DGs.
The directing group (DG)-assisted and transition metal
(TM)-catalyzed C–H functionalization has become a pow-
erful, straightforward and regioselective approach that
relies on simple and readily available starting inputs for
the construction of a variety of organic building blocks
via the cleavage of inert C–H bond and the final formation
of new C–C or C–X bonds.1 In direct C–H bond functional-
ization, the chelation-assisted ortho-metalation is typical-
ly involved to yield a nucleophilic metallacycle complex as
the active intermediate, which adds across with a valuable
coupling partner (CP) to generate an ideal and functional-
ized product. Up to date, a large number of versatile DGs
as well as CPs have been developed for the diverse C–H
bond transformations.2-3 Despite the remarkable advances
in this field, further exploration of novel chelation-
assisted strategy for achieving the effective and character-
istic C–H functionalization is still highly desirable, espe-
cially for the direct construction of privileged structural
To address these drawbacks, very recently a synergetic
dual DGs-directed strategy containing both a convention-
al monodentate DG and a traceless DG attached in the
CPs has been developed by Glorius group8 to furnish the
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expected bidentate coordination (Scheme 1b). In principle,
the hydroxyl group in propargyl alcohols and the origin of
the conventional monodentate DG enables chelation-
assisted C–H activation, and the introduction of the se-
cond traceless DG at the CP moiety plays a crucial role in
controlling the regioselectivity and/or improving the reac-
tivity. However, to the best of our knowledge, very few
TM-catalyzed examples8,9 that only used Mn(I) or Ir(III)
as the catalyst have been reported so far. To a certain ex-
tent, it might be due to the lack of a clear and basic mech-
anism for understanding such synergetic strategy-based
C–H activation mode and action.
the chemoselectivity were clarified. Besides, the distinc-
tive catalytic modes for the divergent synthesis of the re-
lated products by following two novel and differ-
ent reaction pathways (respectively named path I-Ia (via a
RhIII-RhI-RhIII pathway) and path II-IIb (via a RhIII-RhV-
RhIII pathway) were also deduced rationally.
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RESULTS AND DISCUSSION
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Scheme 2. Rh(III)-Catalyzed Divergent C–H Func-
tionalization of N-Phenoxyacetamides with Tunable
Selectivity
Solvent-Controlled Divergent C–H functionaliza-
tion of N-Phenoxyacetamides with Propargyl Alco-
hols. Method Development. The O–NHAc part repre-
sents one of the versatile oxidizing directing groups
(ODGs) for the redox-neutral coupling with various rea-
gents including alkynes,12 alkenes,13 diazo compounds,14
and other CPs.15 Precedent literatures have well-addressed
Scheme 1. Chelation-Assisted TM-Catalyzed C-H Acti-
vation
the
divergent
C–H
functionalization
of
N-
phenoxyacetamides with proper CPs via selective C–N or
C–O bond reductive elimination.12-15 Based on these and
inspired by the emerging synergistically dual DGs-
directed strategy, we herein employ readily available
propargyl alcohols as the chelating partners to react with
N-phenoxyacetamides bearing a monodentate –ONHAc
ODG, expecting to develop the novel reaction mode and
obtain the interesting product structure. At the outset of
our investigation, N-phenoxyacetamide (1a) and 1-
phenylbut-2-yn-1-ol (2a) were chosen as the model sub-
strates and the reaction was carried out under the Rh(III)
catalysis (see Tables S1 and S2 in the Supporting Infor-
mation for details). To our delight, with methanol being
the solvent, the reaction proceeded smoothly under the
initial conditions to deliver a free hydroxyl-substituted
chalcone 3a in the presence of [Cp*RhCl2]2 and CsOAc.
Very interestingly, further screening of various experi-
mental parameters indicated that the solvent exerted a
crucial influence on the reaction outcome. With the high-
polar solvents being the reaction medium such as metha-
nol and CH3CN, the chalcone derivative 3a was obtained
as the main product via the ortho-alkenylation, while an
alternative [3+2] annulation process was achieved by
simply switching the solvents to low-polar DCE or DCM,
leading to the efficient synthesis of benzofuran derivative
4a (Scheme 2). Noteworthily, further examination indi-
cated that 3a could not be converted to 4a under the reac-
tion conditions, revealing that two different mechanisms
In a search for appropriate CPs equipped with chelating
auxiliaries, we turned our attention to propargyl alcohols,
which are easily accessible and have been precedently
proven to be good reactants for TM-catalyzed C–H func-
tionalization.10 Moreover, because of the binding affinity
potential of the hydroxyl group with the TM catalyst, they
can be viewed as promising chelating CPs. In our previous
work, we have revealed the switchable [3+2] and [4+2]
annulations of oximes with using tertiary propargyl alco-
hols as the CPs, in which the hydroxyl group provided
distinctive interactions with different TM catalysts to af-
fect the regio- and chemoselectivity of the reaction.9a Fur-
ther expansion of the versatile CPs to the N-
phenoxyacetamide substrates has also been achieved un-
der the Ir(III) catalysis.9b
On the basis of the above information and in continua-
tion of our interest in Rh(III)-catalyzed C–H functionali-
zation, herein, we aim to report the first Rh(III)-catalyzed,
solvent-controlled, redox-neutral, regioselective C–H
functionalization of N-phenoxyacetamides with new type
of chelating propargyl alcohols (readily available primary
or secondary propargyl alcohols) using a synergetic dual
DGs-enabled regioselective strategy for the divergent and
chemoselective synthesis of benzofurans and chalcones,
two privileged core structural motifs widely found in nat-
ural products, organic materials and biologically active
compounds.11 Through a series of experimental investiga-
tions together with detailed theoretical studies, the role of
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might be involved in the solvent-controlled divergent C–
ciency and indispensability of [Cp*RhCl2]2 for these trans-
formations.
2
H functionalization reactions.
3
Scope of the C–H Alkenylation Reaction for the Syn-
thesis of Chalcone Derivatives. With the optimal reac-
tion conditions established, we started to investigate the
scope and generality of this methodology for the efficient
synthesis of chalcones by screening a series of substrates
bearing kinds of functional groups with different steric
and electrical properties. Firstly, a variety of substituted
N-phenoxyacetamides were assessed for this transfor-
mation by using CH3CN as the solvent (Scheme 3). Grati-
fyingly, the developed Rh(III)-catalyzed system proved to
be broadly applicable, and various commonly encoun-
tered functional groups including alkyl- (3b-c, 3j, 3l-m),
halogens- (3d-g, 3k), cyano- (3h) and ester-substituted N-
phenoxyacetamides (3i) were well tolerated to deliver the
corresponding products in moderate to good yields.
Summarizing all these substrates, a significant electronic
effect could be deduced qualitatively since N-
phenoxyacetamides bearing the electron-withdrawing
group gave relatively low yields compared with those
bearing the electron-donating group. Of note, when meta-
substituted N-phenoxyacetamides were employed, the
reaction proceeded smoothly and provided the desired
products in good yields with exclusive regioselectivities
toward the less-hindered site (3j-l), while ortho-methyl-
substituted N-phenoxyacetamide 1m led to a low yield of
the corresponding chalcone derivative, demonstrating
that the position of substituent on the phenyl ring had a
clear influence on the reactivity. Moreover, naphthalene
substrate was compatible to the reaction conditions, fur-
nishing the desired product 3n in 61% yield.
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Table 1. Examinations of the Solvent Effecta
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Yieldb (%)
Entry Catalyst (x mol %)
Solvent
3a
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30
51
27
53
55
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10
81
/
4a
/
/
1
[Cp*RhCl2]2 (5)
[Cp*RhCl2]2 (5)
[Cp*RhCl2]2 (5)
[Cp*RhCl2]2 (5)
[Cp*RhCl2]2 (5)
[Cp*RhCl2]2 (5)
[Cp*RhCl2]2 (5)
[Cp*RhCl2]2 (5)
[Cp*RhCl2]2 (5)
[Cp*RhCl2]2 (5)
[Cp*RhCl2]2 (5)
[Cp*RhCl2]2 (5)
[Cp*RhCl2]2 (5)
[Cp*IrCl2]2 (5)
Cp*Co(CO)I2 (10)
[CyRuCl2]2 (5)
Mn(CO)5Br (10)
MeOH
EtOH
iPrOH
dioxane
DMA
2
3
4
5
6
7
8
9
<5
<5
/
<5
<5
<5
36
47
53
/
THF
acetone
CH3CN
toluene
DCE
DCM
CH3CN
10
11
12c
13d,e
14
15
16
17
DCM
84
CH3CN/DCM
CH3CN/DCM
CH3CN/DCM
CH3CN/DCM
NR
NR
NR
NR
aReaction conditions: 1a (0.2 mmol), 2a (0.2 mmol),
[Cp*RhCl2]2 (5 mol %) and CsOAc (1 equiv) in solvent (0.1 M)
at room temperature for 24 h under air. bIsolated yield. 2
c
d
equiv of 2a was used. 1.5 equiv of 2a was used, the reaction
was conducted at 50 oC. eNaOAc (1 equiv) was used instead of
CsOAc.
Enlightened by the tunable selectivity and the synthetic
utility potential for the efficient construction of chalcones
and benzofurans, we next screened the experimental pa-
rameters systemically to figure out the optimal reaction
conditions as well as the effect of the solvent.16 As shown
in Table 1, a series of organic solvents including alcohols,
ethers and halohydrocarbons were tested, showing that
chalcone derivative 3a was obtained as the dominant
product in most of the high-polar solvents, among which
CH3CN resulted in the highest yield up to 57% (entry 8).
However, when the low-polar solvents such as toluene,
DCE and DCM was respectively subjected to the reaction
conditions with the same substrates, a mixture of 3a and
cyclized benzofuran product 4a was obtained, among
which DCM gave the best chemoselectivity, affording 4a
in 53% yield (entry 11). Further screening of additives, re-
action temperature as well as the proportion of substrates
resulted in the optimal conditions for both products, thus
providing an efficient solvent-controlled strategy for the
divergent synthesis of chalcone and benzofuran deriva-
tives (entries 12 and 13). As a comparison, other TM cata-
lysts which showed good reaction activities and diversities
in precedent literatures17 including Ir(III), Ru(II), Co(III)
and Mn(I) species were also screened and seemed to be
totally ineffective (entries 14-17), reflecting the high effi-
Scheme 3. Scope of Substrates for the Synthesis of
Chalcones. Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol),
[Cp*RhCl2]2 (5 mol %) and CsOAc (1 equiv) in CH3CN (0.1 M)
at room temperature for 24 h under air; isolated yields were
reported. bDCM was used as the solvent instead of CH3CN.
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Subsequently, the scope of propargyl alcohols for the
= H) were not tolerated under our conditions for the syn-
thesis of either chalcones or benzofurans.
synthesis of chalcones was explored. The results demon-
strated that aryl (3o), thienyl (3p) and alkyl groups (3q
and 3r) could be all well tolerated for this transformation,
affording the corresponding chalcone derivatives in mod-
erate yields. Interestingly, 3-phenylprop-2-yn-1-ol also
reacted smoothly, leading to the desired ortho-
hydroxylphenyl-substituted phenylacrylaldehyde product
3s. Considering the mild reaction conditions, excellent
regioselectivity and good functional group tolerance, we
were next intrigued to apply the present method for the
late-stage C-H modification of complex bioactive com-
pounds. Pleasantly, the derivatives of dopamine and L-
tyrosine underwent the coupling with 2a smoothly to
yield the desired chalcone products 3t and 3u in moderate
yields, which illustrated profound potentials for the rapid
synthesis of drug derivatives and the construction of
complex structures.
Scope of the Alternative [3+2] Annulation for the
Synthesis of Benzofurans. Having established the effi-
cient and practical approach for the synthesis of chalcone
derivatives via Rh(III)-catalyzed C–H alkenylation, we
next examined the substrate scope for the construction of
benzofuran skeleton. As shown in Scheme 4a, various N-
phenoxyacetamides bearing different substituents at ei-
ther para-, meta- or ortho-position were fully tolerated,
delivering the desired benzofurans in moderate to good
yields (4a-p). Notably, trifluoromethyl- and ester-
substituted N-phenoxyacetamides seemed to be less reac-
tive, affording the desired benzofurans in relatively low
yields (4i and 4j). The result implied that the electrical
property of the substituent might be crucial for determin-
ing the reaction outcome. No obvious difference on the
yield was observed in terms of the substituted position on
phenyl ring, which fully testified that this transformation
had a broad substrate scope. Remarkably, the reaction
also showed good compatibility with several natural
products or drug derivatives such as dopamine, L-tyrosine
and estrone skeletons, providing the corresponding
benzofurans as new analogs of such structures (4q-s).
To better probe the versatility of this protocol for the
chemoselective synthesis of benzofurans, a diverse array
of propargyl alcohols were then examined under the
standard conditions (Scheme 4b). In general, the reaction
was compatible with various 1-arylpropargyl alcohols re-
gardless of the electrical property of the substituent on
the phenyl ring (5a-c). Notably, thienyl- and furyl-
substituted propargyl alcohols were also good reactants
for this transformation, giving the corresponding products
5d and 5e in good yields. Moreover, we were pleased to
find that long-chain alkyl- and cycloalkyl-substituted
propargyl alcohols readily participated in the [3+2] annu-
lation, furnishing the desired benzofuran procducts 5f and
5g in 74% and 65% yields, respectively. Besides the 1-aryl
substituted propargyl alcohols, 4-phenylbut-3-yn-2-ol was
also found to be a productive substrate for this transfor-
mation, thus delivering the desired 5h in a moderate yield.
It is necessary to note that terminal propargyl alcohols (R2
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Scheme 4. Scope of Substrates for the Synthesis of
Benzofurans. Reaction conditions: 1 (0.2 mmol), 2 (0.3
mmol), [Cp*RhCl2]2 (5 mol %) and NaOAc (1 equiv) in DCM
o
(0.1 M) at 50 C for 24 h under air; isolated yields were re-
ported.
Mechanistic Studies. Given the novel and distinctive
reaction modes enabled by the synergetic dual DGs-
directed strategy and the tunable selectivity controlled by
the solvent, we were next intrigued to design a set of
mechanistic experiments including the experimental in-
vestigations as well as the density functional theory (DFT)
studies to figure out the reaction mechanism, in particular,
to clarify the role of the hydroxyl group and the origin of
the chemoselectivity uniquely controlled by the solvent.
Experimental investigations to probe the reaction
mechanism. To gain a better mechanistic understanding,
a series of experimental investigations were first carried
out (Scheme 5). Control experiments between 1a and but-
1-yn-1-ylbenzene 2k resulted in the ortho-hydroxylphenyl-
substituted enamide 6 and benzofuran 7 with the contrary
regioselectivities compared with propargyl alcohols
(Scheme 5a). These results revealed that the hydroxyl
group in propargyl alcohol was indispensable for tuning
the site- and regioselectivity of these approaches, and its
introduction probably led to the totally reversal of the
regioselectivity and different pathways to form unprece-
dented novel skeletons.18 In addition, compound 8 was
prepared and subjected to the Rh(III)-catalyzed [3+2] an-
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nulation conditions (Scheme 5b). The result displayed
be not involved in the rate-determining step (Scheme 6b).
2
that 85% of 8 was recovered and only trace product 4a was
observed, thus ruling out the presumption that the
benzofuran product 4a was derived from the alcohol pre-
cursor. Another coupling reaction of 1a with 2a under N2
atmosphere resulted in the formation of (3-methyl-2,3-
dihydrobenzofuran-2-yl)(phenyl)methanone intermediate,
which could be easily converted into the final benzofuran
product 4a in 78% yield, verifying that 4a was generated
by further oxidation of the dihydrobenzofuran precursor.
Further control experiments showed that the addition of
methanol could switch the selectivity from [3+2] annula-
tion to ortho-alkenylation gradually; to the end, the cy-
clization pathway could be totally prevented in the pres-
ence of 30% of methanol (Scheme 5c). The results exposed
an obvious solvent effect that existed in these parallel ex-
periments, and also suggested that the introduction of
methanol was detrimental to the formation of the cycliza-
tion product, probably due to the protonation effect.
Finally, the effort to capture the potent intermediate was
achieved by treating 1a with stoichiometric amount of
[Cp*RhCl2]2 to give the desired five-membered
rhodacycle complex A (Scheme 6c). The following cou-
pling of rhodacycle A with 2a facilely conversed into the
final chalcone and benzofuran products, which provided
adequate evidence to support the two C–H activation pro-
cesses involving the formation of the five-membered
rhodacycle A as the active intermediate.
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Scheme 6. Experimental Investigations
Computational studies to further uncover the reac-
tion mechanism. To elucidate our experimental results
and further cast light on details of the mechanism, com-
putational studies were performed with density functional
theory (DFT) calculations. Briefly, all the structures were
optimized at the M06 level20 in experimental solvents
(DCM and methanol, respectively) to further reveal: 1) the
origin of the chemoselectivity; 2) why the introduction of
the hydroxyl group into the alkyne has a unique property
for controlling the regioselectivity? 3) how the solvent
uniquely switches the reaction outcome for the tunable
synthesis of benzofurans and chalcones, respectively?
Scheme 5. Control Experiments
Deuterium-labeling experiments were next conducted
to define the reversibility of the C–H activation process.
As shown in Scheme 6a, no deuterium incorporation was
observed in the recovered starting material 1a under both
conditions. Moreover, both chalcone product 3a and
benzofuran derivative 4a could be obtained smoothly in
the presence of deuterated methanol and showed no ob-
vious deuterium incorporation at the ortho-position of the
DG. These results indicated that the C–H metalation step
was irreversible.19 Besides, approximately 38% deuteration
at the alkenyl moiety of 3a was detected, suggesting that
an active hydrogen transfer might be involved in the or-
tho-alkenylaition. Furthermore, the primary KIE values of
the two divergent transformations were determined to be
1.73 and 1.34 from the independent, side-by-side experi-
ments by measuring the initial rates of different reactions
using 1a and [D]5-1a as the substrates under standard
conditions, implying that the C–H cleavage process might
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Figure 1. Computed Gibbs free energy changes of the reaction pathways for N–H deprotonation, C–H activation, and
migratory insertion of propargyl alcohols in DCM (in methanol).
To address these issues, the proposed mechanism was
divided into 4 key steps: N–H deprotonation, C–H activa-
tion, migratory insertion of propargyl alcohols, and the
tunable formation for the products including the solvent
effect for controlling such chemoselectivity. To the end,
our results revealed two novel favorable mechanisms that
was significantly different from that of the reported com-
putational investigations,21 in which the O–NHAc part was
employed as the ODG. Therefore, the present DFT results
provide insights into the mechanistic understandings for
future development of synergistic dual DGs-directed C–H
functionalization reactions.
N–H deprotonation, C–H activation, and migratory
insertion of propargyl alcohols. Figure 1 shows the
computational results for the formation of a seven-
membered rhodacycle in both DCM and methanol solvent
model. The complex Cp*Rh(OAc)2 (Cat.) was selected as
the starting point. With DCM being the solvent, it is
found that both of the N–H and C–H activation occur via
a concerted metalation-deprotonation (CMD) mecha-
nism,22 through transition states TS-1 (G≠ = 14.7 kcal/mol)
and TS-2 (G≠ = 18.4 kcal/mol), respectively. Thereafter,
the regioselective insertion of the alkyne part proceeds via
TS-3 (G≠ = 17.2 kcal/mol), leading to the seven-membered
rhodacycle intermediate INT-7 with a free energy of -8.7
kcal/mol. A similar reaction pathway proceeds with a
higher energy profile (values in the brackets) in methanol
than that in DCM, which is consistent with the previous
reported similar Rh(III)-catalyzed system.21a,23
netic barrier is required for the regioselective insertion
through the formation of the hydrogen bonding between
dual directing groups (17.2 kcal/mol for TS-3 vs 21.1
kcal/mol for TS-3'), and then, b) a stable seven-membered
rhodacycle intermediate (INT-7) is yielded with a low free
energy of -8.7 kcal/mol compared with the INT-7' (-2.9
kcal/mol), which should be ascribed to both the extra
coordination interaction between the hydroxyl group and
the catalyst metal together with the preceding formation
of the hydrogen bonding. Taken together with the exper-
imental observations, these results give a clear evidence
for clarifying the remarkable role of the hydroxyl group in
controlling the regioselectivity.
Chemoselective product formation pathways in
DCM (via a RhIII-RhI-RhIII pathway). We first computed
the feasibility of –H elimination from the complex INT-7
in DCM (Figure 2). The –H elimination and subsequent
hydrogen transfer occur via the transition state TS-4 (G≠
= 10.0 kcal/mol), leading to a hydride intermediate INT-8.
It should be emphasized that, the hydrogen transfer tunes
the coordination mode of C–Rh–N moiety and converts
the N–Rh covalent bond into coordination bond. Thereaf-
ter, the Rh–H bond is cleaved and the hydride is trans-
ferred to the carbon atom (via TS-5) with a low energy
barrier, which leads to the stable intermediate INT-9 with
a free energy of -13.3 kcal/mol. Then, further hydrogen
transfer proceeds via TS-6 with a free energy barrier of
28.4 kcal/mol, yielding the Rh(I) species INT-10.
From INT-10, two possible pathways have been pro-
posed to elaborate the chemoselectivity. In path Ia, the
By analyzing the data from Figure 1, the regioselectivity
in migratory insertion of propargyl alcohols is worth not-
ing. Our calculations showed that: a) a relatively low ki-
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Figure 2. Computed Gibbs free energy changes of the reaction pathway in DCM.
migration of NAc from O to Rh occurs at first via a N–O
cleavage transition state (TS-7) with a free energy of 7.6
kcal/mol, giving the Rh(III) intermediate INT-11 in an
irreversible manner. Thereafter, the species INT-11 under-
goes a reductive elimination via TS-8, leading to INT-12.
Finally, the product PC1 is generated along with the re-
lease of the active Rh(III) catalyst through the ligand ex-
change with HOAc. As an alternative catalytic cycle (path
Ib), the hydrogen transfer via a H-bonding transition state
TS-9 with a free energy of 2.8 kcal/mol is occurred to give
the intermediate INT-13. Then, another hydrogen transfer
via the transition state TS-10 with a free energy of 16.6
kcal/mol is conducted to provide the intermediate INT-14.
Thereafter, INT-14 undergoes an intramolecular hydrogen
bond dissociation via TS-11 to generate the intermediate
INT-15. Obviously, the highest free energy barrier of path
Ia is 11.8 kcal/mol (from INT-10 to TS-7) that is far lower
than that of path Ib (18.7 kcal/mol, from INT-13 to TS-10),
suggesting that the path Ia is more favorable, which is
agreement well with the experimental observation that
the benzofuran product (PC1) is delivered as the major
product when DCM is used as the solvent.
KIE value is detected.
Chemoselective product formation pathways in
methanol (via a RhIII-RhV-RhIII pathway). Instead of the
–H elimination, firstly, we computed the oxidative addi-
tion to the O−N bond from complex INT-7 in methanol
(Figure 3). Initially, the migration of NAc from O to Rh
occurs via the N–O cleavage transition state (TS-12) with a
free energy of 27.1 kcal/mol, providing the intermediate
INT-16. It can further form a more stable Rh(V) nitrenoid
intermediate INT-17 via TS-13 with a free energy of 25.9
kcal/mol.
Following INT-17, two possible pathways have been
proposed to elaborate the chemoselectivity. In path IIa,
INT-17 undergoes the reductive elimination via TS-14 with
a free energy of 19.4 kcal/mol, leading to INT-18. Subse-
quently, hydrogen transfer occurs via TS-15 and TS-16,
respectively. Finally, the ligand exchange with HOAc gen-
erates the product and regenerates the Rh(III) catalyst.
On the other hand, In path IIb, the first hydrogen transfer
of INT-17 delivers an intermediate INT-20 via the transi-
tion state TS-17 with a free energy of 16.7 kcal/mol, fol-
lowed by the second hydrogen transfer via the transition
state TS-18 with a low free energy of -47.9 kcal/mol to give
an intermediate INT-21, which further approves our deu-
Besides, the highest free energy barrier (28.4 kcal/mol,
from INT-9 to TS-6) in the whole favorable catalytic cycle
is far higher than that of the C–H activation step (18.4
kcal/mol, from Cat. to TS-2), indicating that the C-H acti-
vation is not the turn-over limiting step. The result is also
in line with our kinetic isotope experiments that a small
terium-labeling
result
that
obvious
deuterium
incorportion is observed at the alkenyl moiety of product
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Figure 3. Computed Gibbs free energy changes of the reaction pathway in methanol.
3a. Subsequently, INT-21 affords the intermediate INT-22
with the addition of HOAc. Further intramolecular hy-
drogen transfer in INT-22 via the transition state TS-19
with a free energy of -58.2 kcal/mol offers the intermedi-
ate INT-23. Finally, the ligand exchange with HOAc gen-
erates the product with extrusion of the Rh(III) catalyst.
Obviously, the free energy barrier for formation of INT-18
in path IIa is 17.1 kcal/mol (from INT-17 to TS-14) that is
higher than that of path IIb (14.4 kcal/mol, from INT-17 to
TS-17), suggesting that the path IIb is more favorable,
which is agreement well with the experimental observa-
tion that the chalcone derivative (PC2) presents as the
preferential product with methanol being the solvent.
Moreover, our computational results show that, even if
the INT-18 is formed, it is still difficult to yield the PC1 via
TS-16 due to the existence of a higher barrier (more than
30.0 kcal/mol, from INT-19 to TS-16), which further vali-
dates our experimental observation that compound 8
cannot be transformed into the corresponding
benzofuran product under the current Rh(III)-catalyzed
reaction conditions.
observed small experimental KIE value in the preceding
C–H cleavage process.
Tunable chemoselectivity controlled by the solvent.
To better expose the solvent effect in determining the
chemoselectivity, an overall comparison for the changes
of the free energy in different solvents was investigated by
using the representative DCM and methanol as the media
model.24
Figure 4. An overall comparison for the changes of the free
energy in different solvents in determining the reactivity and
chemoselectivity.
Moreover, the highest free energy barrier (27.4 kcal/mol,
from INT-7 to TS-12) in the whole favorable catalytic cy-
cle pathway is higher than that of the C–H activation step
(23.0 kcal/mol, from Cat. to TS-2), revealing that the N–O
cleavage process rather than the C–H activation step is
the rate-determining step, which is consistent with the
As summarized in Figure 4, our calculated results show
that: a) the favorable pathway is path I in DCM, in which
the rate-determining step barrier of 28.4 kcal/mol is sig-
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nificantly lower than that of 33.5 kcal/mol in path II, b) in turnover-limiting oxidative addition process (27.4
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8
contrast, in methanol the favorable pathway is path II
since the rate-determining step barrier of 27.4 kcal/mol is
lower than that of 29.5 kcal/mol in path I, c) from path I,
the path Ia is adopted preferentially over the path Ib, due
to the involvement of lower free energy barrier (11.8
kcal/mol vs 20.8 kcal/mol), and however, d) following
path II, the path IIb is prior to the path IIa since a lower
free energy barrier of 14.4 kcal/mol (17.4 kcal/mol for path
IIa) was involved in path IIb.
kcal/mol, from INT-7 to TS-12) in the high-polar solvents
(e.g. methanol and CH3CN) to give the Rh(V) species C
(INT-17). Further β–H elimination of C and then hydro-
gen transfer yield an intermediate D (INT-21), followed
by the protonolysis of D with the aid of HOAc to deliver
the chalcone derivative 3a and regenerate the active
Rh(III) catalyst.
9
We further calculated the electrostatic potential surfac-
es of the transition states (TS-12) for the determining step
(N-O bond cleavage step) in path II as well as their pre-
intermediate (INT-7) in both solvents (DCM and MeOH,
respectively, see Figure S3 in the Supporting Information
for details). In INT-7, the electron densities of the N-O
bond are almost the same in both solvents, however,
higher charge dispersion in TS-12 is observed in MeOH
than that in DCM. The obvious charge dispersion change
indicates that the high-polar solvent decrease the barrier
of TS-12, thus making the path II become a more favora-
ble pathway in MeOH (different from that of path I in
DCM), which leads to the chemoselective products.
Based on these, we can conclude that the low-polar sol-
vents such as DCM favors the β–H elimination/hydrogen
transfer/oxidative addition/C–O bond reductive elimina-
tion pathway (path I-Ia, via a RhIII-RhI-RhIII pathway),
leading to the chemoselective synthesis of benzofuran
product via a [3 + 2] annulation. However, the high-polar
solvents such as methanol prefers to follow the oxidative
addition/β–H elimination/hydrogen transfer/protonolysis
pathway (path II-IIb, via a RhIII-RhV-RhIII pathway), re-
sulting in the chemoselective construction of chalcone
product via the ortho-alkenylation, which goes well with
the experimental observations.
Mechanistic proposal. On the basis of these computa-
tional and experimental studies, a plausible mechanism
involving the synergistic O–NHAc part and hydroxyl
group-directed regioselective C–H activation process is
proposed (Scheme 7). Initially, the active Cp*Rh(OAc)2 is
generated through anion exchange, followed by facile
irreversible ortho-rhodation via a CMD mechanism to
deliver the five-membered rhodacycle intermediate A
(INT-5). Subsequent regioselective migratory insertion of
the alkyne moiety of 2a into the Rh–C bond of A forms
the seven-membered intermediate B (INT-7), which is
stabilized by the Rh–O coordination and the hydrogen
bonding interaction. Thereafter, there are two distinct
reaction pathways depending on the polarity of the sol-
vent. For the low-polar solvents (e.g. DCM and DCE), a
plausible β–H elimination and subsequent hydrogen
transfer are involved to afford the intermediate E (INT-9).
Further intramolecular hydrogen transfer occurs that is
used as the rate-determining step with a free energy bar-
rier of 28.4 kcal/mol (from INT-9 to TS-10) to generate
the Rh(I) intermediate F (INT-10), which then undergoes
sequential oxidative addition/C–O bond reductive elimi-
nation to provide the cyclized dihydrobenzofuran skele-
ton H (PC1) along with the release of the active Rh(III)
catalyst. Further oxidation of H under air25 provides the
final benzofuran product 4a. Alternatively, B undergoes a
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Scheme 7. Summary of the Proposed Mechanism
CONCLUSION
In summary, by employing the synergetic dual DGs-
directed strategy, we have developed for the first time the
mild rhodium(III)-catalyzed and solvent-controlled re-
dox-neutral
C–H
functionalization
of
N-
phenoxyacetamides with new type of primary or second-
ary chelating propargyl alcohols for the divergent synthe-
sis of chalcone and benzofuran derivatives with exclusive
regioselectivity, tunable chemoselectivity, and good sub-
strate/functional group compatibility. The role of the hy-
droxyl group, the distinct catalytic mode, the rate-
determining step, the origin of the chemoselectivity, as
well as two solvent-controlled chemoselective reaction
pathways are rationally clarified by a combined experi-
mental and DFT study. Taken together, our present re-
sults not only give a remarkable and meaningful expan-
sion in the area of TM-catalyzed and O–NHAc-assisted
C–H activations but also provide a rational basis for fu-
ture development of synergistic dual DGs-directed C–H
functionalization reactions. Furthermore, recognizing the
great importance of the obtained product skeletons in
organic synthesis, medicinal chemistry and materials sci-
ence, we believe that the two versatile transformations
should have attractive prospects for the synthetic utility.
Further expansion of this synergetic dual DGs-directed
strategy to develop the more diverse transformations is in
progress.
ASSOCIATED CONTENT
Supporting Information. Experimental procedures, char-
acterization of products, computational details and copies
1
of H and 13C spectra are provided. This material is availa-
ble free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
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Page 10 of 13
ing Group for C-H Functionalizations. Angew. Chem., Int.
Corresponding Author
Ed. 2016, 55, 10578-10599. (m) Mishra, N. K.; Sharma, S.;
Park, J.; Han, S.; Kim, I. S. Recent Advances in Catalytic
C(sp2)–H Allylation Reactions. ACS Catal. 2017, 7, 2821-
2847. (n) Ackermann, L. Carboxylate-Assisted Transition-
Metal-Catalyzed C-H Bond Functionalizations: Mechanism
and Scope. Chem. Rev. 2011, 111, 1315-1345. (o) Gensch, T.;
Hopkinson, M. N.; Glorius, F.; Wencel-Delord, J. Mild
Metal-Catalyzed C-H Activation: Examples and Concepts.
Chem. Soc. Rev. 2016, 45, 2900-2936. (p) Huang, H.; Ji, X.;
Wu, W.; Jiang, H. Transition Metal-Catalyzed C-H Func-
tionalization of N-Oxyenamine Internal Oxidants. Chem.
Soc. Rev. 2015, 44, 1155-1171. (q) Ping, L.; Chung, D. S.;
Bouffard, J.; Lee, S.-G. Transition Metal-Catalyzed Site- and
Regio-Divergent C-H Bond Functionalization. Chem. Soc.
Rev. 2017, 46, 4299-4328. (r) Kim, D.-S.; Park, W.-J.; Jun,
C.-H. Metal-Organic Cooperative Catalysis in C-H and C-C
Bond Activation. Chem. Rev. 2017, 117, 8977-9015.
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*zhouzhi@gzhmu.edu.cn
*gaoh9@gzhmu.edu.cn
*yiwei@gzhmu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
9
We thank NSFC (81502909 and 21877020), Guangdong
Natural Science Funds for Distinguished Young Scholar
(2017A030306031), Natural Science Foundation Research
Team of Guangdong Province (2018B030312001) and Nat-
ural Science Foundation of Guangdong Province
(2017A030313058) for financial support on this study.
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(3) For the latest selected examples, see: (a) Mei,
R.; Sauermann, N.; Oliveira, J. C. A.; Ackermann, L.
Electroremovable Traceless Hydrazides for Cobalt-
Catalyzed Electro-Oxidative C-H/N-H Activation with In-
ternal Alkynes. J. Am. Chem. Soc. 2018, 140, 7913-7921. (b)
Font, M.; Cendón, B.; Seoane, A.; Mascareñas, J. L.; Gulías,
M. Rhodium(III)-Catalyzed Annulation of 2-Alkenyl
Anilides with Alkynes through C-H Activation: Direct Ac-
cess to 2-Substituted Indolines. Angew. Chem., Int. Ed. 2018,
57, 8255-8259. (c) Lu, Q.; Mondal, S.; Cembellín, S.; Glorius,
F. Mn(I)/Ag(I) Relay Catalysis: Traceless Diazo-Assisted
C(sp2)-H/C(sp3)-H Coupling to beta-(Hetero)Aryl/Alkenyl
Ketones. Angew. Chem., Int. Ed. 2018, 57, 10732-10736. (d)
Zhou, X.; Xia, J.; Zheng, G.; Kong, L.; Li, X. Divergent Cou-
pling of Anilines and Enones by Integration of C-H Activa-
tion and Transfer Hydrogenation. Angew. Chem., Int. Ed.
2018, 57, 6681-6685. (e) Qiu, Y.; Tian, C.; Massignan, L.;
Rogge, T.; Ackermann, L. Electrooxidative Ruthenium-
Catalyzed C-H/O-H Annulation by Weak O-Coordination.
Angew. Chem., Int. Ed. 2018, 57, 5818-5822. (f) Li, M.;
Kwong, F. Y. Cobalt-Catalyzed Tandem C-H Activation/C-
C Cleavage/C-H Cyclization of Aromatic Amides with
Alkylidenecyclopropanes. Angew. Chem., Int. Ed.
2018, 57, 6512-6516. (g) Hong, S. Y.; Park, Y.; Hwang, Y.;
Kim, Y. B.; Baik, M.-H.; Chang, S. Selective Formation of γ-
Lactams via C-H Amidation Enabled by Tailored Iridium
Catalysts. Science 2018, 359, 1016-1021. (h) Shin, K.; Park, Y.;
Baik, M.-H.; Chang, S. Iridium-Catalysed Arylation of C-H
Bonds Enabled by Oxidatively Induced Reductive Elimina-
tion. Nat. Chem., 2018, 10, 218-224. (i) Halskov, K. S.; Witten,
M. R.; Hoang, G. L.; Mercado, B. Q.; Ellman, J. A. Rhodi-
um(III)-Catalyzed Imidoyl C-H Activation for Annulations to
Azolopyrimidines. Org. Lett. 2018, 20, 2464-2467. (j) Su, B.;
Hartwig, J. F. Ir-Catalyzed, Silyl-Directed, peri-Borylation
of C-H Bonds in Fused Polycyclic Arenes and Heteroarenes.
Angew. Chem., Int. Ed. 2018, 57, 10163-10167. (k) Lu, H.; Fan,
Z.; Xiong, C.; Zhang, A. Highly Stereoselective Assembly of
Polycyclic Molecules from 1,6-Enynes Triggered by Rhodi-
um(III)-Catalyzed C-H Activation. Org. Lett. 2018, 20,
3065-3069. (l) Yu, X.; Chen, K.; Wang, Q.; Zhang, W.; Zhu,
J. Synthesis of 2,5-Disubstituted Oxazoles via Cobalt(III)-
Catalyzed Cross-Coupling of N-Pivaloyloxyamides and Al-
kynes. Chem. Commun. 2018, 54, 1197-1200.
REFERENCES
(1) For recent selected reviews, see: (a) Baudoin, O. Ring Con-
struction by Palladium(0)-Catalyzed C(sp3)-H Activation.
Acc. Chem. Res. 2017, 50, 1114-1123. (b) Wei, Y.; Hu, P.;
Zhang, M.; Su, W. Metal-Catalyzed Decarboxylative C-H
Functionalization. Chem. Rev. 2017, 117, 8864-8907. (c) He,
J.; Wasa, M.; Chan, K. S. L.; Shao, Q.; Yu, J.-Q. Palladium-
Catalyzed Transformations of Alkyl C-H Bonds. Chem. Rev.
2017, 117, 8754-8786. (d) Park, Y.; Kim, Y.; Chang, S. Transi-
tion Metal-Catalyzed C-H Amination: Scope, Mechanism,
and Applications. Chem. Rev. 2017, 117, 9247-9301. (e)
Gandeepan, P.; Ackermann, L. Transient Directing Groups
for Transformative C–H Activation by Synergistic Metal
Catalysis. Chem 2018, 4, 199-222.
(2) For representative reviews, see: (a) Lewis, J. C.; Bergman, R.
G.; Ellman, J. A. Direct Functionalization of Nitrogen
Heterocycles via Rh-Catalyzed C-H Bond Activation. Acc.
Chem. Res. 2008, 41, 1013-1025. (b) Chen, X.; Engle, K. M.;
Wang, D. H.; Yu, J.-Q. Palladium(II)-Catalyzed C-H Activa-
tion/C-C Cross-Coupling Reactions: Versatility and Practi-
cality. Angew. Chem., Int. Ed. 2009, 48, 5094-5115. (c) Colby,
D. A.; Bergman, R. G.; Ellman, J. A. Rhodium-Catalyzed C-
C Bond Formation via Heteroatom-Directed C-H Bond Ac-
tivation. Chem. Rev. 2010, 110, 624-655. (d) Cho, S. H.; Kim,
J. Y.; Kwak, J.; Chang, S. Recent Advances in the Transition
Metal-Catalyzed Twofold Oxidative C-H Bond Activation
Strategy for C-C and C-N Bond Formation. Chem. Soc. Rev.
2011, 40, 5068-5083. (e) Song, G.; Wang, F.; Li, X. C-C, C-O
and C-N Bond Formation via Rhodium(III)-Catalyzed Oxi-
dative C-H Activation. Chem. Soc. Rev. 2012, 41, 3651-3678.
(f) Li, B.-J.; Shi, Z.-J. From C(sp2)-H to C(sp3)-H: Systematic
Studies on Transition Metal-Catalyzed Oxidative C-C For-
mation. Chem. Soc. Rev. 2012, 41, 5588-5598. (g) Hartwig, J.
F. Borylation and Silylation of C-H Bonds: a Platform for
Diverse C-H Bond Functionalizations. Acc. Chem. Res. 2012,
45, 864-873. (h) Wencel-Delord, J.; Glorius, F. C-H Bond
Activation Enables the Rapid Construction and Late-Stage
Diversification of Functional Molecules. Nat. Chem. 2013, 5,
369-375. (i) Ackermann, L. Carboxylate-Assisted Rutheni-
um-Catalyzed Alkyne Annulations by C-H/Het-H Bond
Functionalizations. Acc. Chem. Res. 2014, 47, 281-295. (j)
Kuhl, N.; Schröder, N.; Glorius, F. Formal SN-Type Reac-
tions in Rhodium(III)-Catalyzed C-H Bond Activation. Adv.
Synth. Catal. 2014, 356, 1443-1460. (k) Shin, K.; Kim, H.;
Chang, S. Transition-Metal-Catalyzed C-N Bond Forming
Reactions Using Organic Azides as the Nitrogen Source: a
Journey for the Mild and Versatile C-H Amination. Acc.
Chem. Res. 2015, 48, 1040-1052. (l) Zhu, R. Y.; Farmer, M. E.;
Chen, Y. Q.; Yu, J. Q. A Simple and Versatile Amide Direct-
(4) For recent selected reviews on C-H functionalization using
bidentate chelating auxiliaries, see: (a) Rouquet, G.;
Chatani, N. Catalytic Functionalization of C(sp2)-H and
C(sp3)-H Bonds by Using Bidentate Directing Groups.
Angew. Chem., Int. Ed. 2013, 52, 11726-11743. (b) Liu, J.;
Chen, G.; Tan, Z. Copper-Catalyzed or -Mediated C-H
Bond Functionalizations Assisted by Bidentate Directing
10
ACS Paragon Plus Environment

Page 11 of 13
ACS Catalysis
Groups. Adv. Synth. Catal. 2016, 358, 1174-1194. (c) Yang, X.;
thesis of Divergent Heterocycles Bearing a Quaternary
Carbon. J. Org. Chem. 2018, 83, 4650-4656.
Shan, G.; Wang, L.; Rao, Y. Recent advances in transition
metal (Pd, Ni)-catalyzed C(sp3)H bond activation with
bidentate directing groups. Tetrahedron Lett. 2016, 57, 819-
836. (d) Kommagalla, Y.; Chatani, N. Cobalt(II)-Catalyzed
C-H Functionalization Using an N,N'-Bidentate Directing
Group. Coord. Chem. Rev. 2017, 350, 117-135.
1
2
3
4
5
6
7
(11) (a) Sahu, N. K.; Balbhadra, S. S.; Choudhary, J.; Kohli, D. V.
Exploring Pharmacological Significance of Chalcone Scaf-
fold: a Review. Curr. Med. Chem. 2012, 19, 209-225. (b)
Nevagi, R. J.; Dighe, S. N.; Dighe, S. N. Biological and Me-
dicinal Significance of Benzofuran. Eur. J. Med. Chem. 2015,
97, 561-581. (c) Zhuang, C.; Zhang, W.; Sheng, C.; Zhang,
W.; Xing, C.; Miao, Z. Chalcone: A Privileged Structure in
Medicinal Chemistry. Chem. Rev. 2017, 117, 7762-7810.
(5) For selected reviews, see: (a) Daugulis, O.; Roane, J.; Tran,
L. D. Bidentate, Monoanionic Auxiliary-Directed Func-
tionalization of Carbon-Hydrogen Bonds. Acc. Chem. Res.
2015, 48, 1053-1064. (b) Misal Castro, L. C.; Chatani, N.
Nickel Catalysts/N,N'-Bidentate Directing Groups: An Ex-
cellent Partnership in Directed C-H Activation Reactions.
Chem. Lett. 2015, 44, 410-421.
(6) For selected examples, see: (a) Hao, X.-Q.; Chen, L.-J.; Ren,
B.; Li, L.-Y.; Yang, X.-Y.; Gong, J.-F.; Niu, J.-L.; Song, M.-P.
Copper-Mediated Direct Aryloxylation of Benzamides As-
sisted by an N,O-Bidentate Directing Group. Org. Lett.
2014, 16, 1104-1107. (b) Guan, M.; Pang, Y.; Zhang, J.; Zhao, Y.
Pd-Catalyzed Sequential β-C(sp3)-H Arylation and
Intramolecular Amination of δ-C(sp2)-H Bonds for Synthe-
sis of Quinolinones via an N,O-Bidentate Directing Group.
Chem. Commun., 2016, 52, 7043-7046. (c) Li, G.; Liu, P.;
Zhang, J.; Shi, D.-Q.; Zhao, Y. Palladium-Catalyzed Direct
Ortho-Alkynylation of Arylalkylacid Derivatives at γ and δ
Positions via an N,O-Bidentate Directing Group. Org.
Chem. Front., 2017, 4, 1931-1934.
(7) (a) Gutekunst, W. R.; Baran, P. S. Total Synthesis and
Structural Revision of the Piperarborenines via Sequential
Cyclobutane C-H Arylation. J. Am. Chem. Soc., 2011, 133,
19076-19079. (b) Tran, L. D.; Daugulis, O. Nonnatural
Amino Acid Synthesis by Using Carbon-Hydrogen Bond
Functionalization Methodology. Angew. Chem., Int. Ed.
2012, 51, 5188-5191. (c) Parella, R.; Gopalakrishnan, B.; Babu,
S. A. Auxiliary-Enabled Pd-Catalyzed Direct Arylation of
Methylene C(sp3)-H Bond of Cyclopropanes: Highly
Diastereoselective Assembling of Di- and Trisubstituted
Cyclopropanecarboxamides. Org. Lett. 2013, 15, 3238-3241.
(8) Lu, Q.; Greβies, S.; Cembellín, S.; Klauck, F. J. R; Daniliuc,
C. G.; Glorius, F. Redox-Neutral Manganese(I)-Catalyzed
C-H Activation: Traceless Directing Group Enabled
Regioselective Annulation. Angew. Chem., Int. Ed. 2017, 56,
12778-12782.
(9) (a) Gong, W.; Zhou, Z.; Shi, J.; Wu, B.; Huang, B.; Yi, W.
Catalyst-Controlled [3 + 2] and [4 + 2] Annulations of
Oximes with Propargyl Alcohols: Divergent Access to
Indenamines and Isoquinolines. Org. Lett. 2018, 20, 182-185.
(b) Chen, W.; Liu, F.-X.; Gong, W.; Zhou, Z.; Gao, H.; Shi, J.;
Wu, B.; Yi, W. Hydroxyl Group-Prompted and Iridium(III)-
Catalyzed Regioselective C–H Annulation of N-
phenoxyacetamides with Propargyl Alcohols. Adv. Synth.
Catal. 2018, 360, 2470-2475.
8
9
(12) The selected examples for TM-catalyzed and O–NHAc-
directed C-H functionalizations with alkynes, see: (a) Liu,
G.; Shen, Y.; Zhou, Z.; Lu, X. Rhodium(III)-Catalyzed Re-
dox-Neutral Coupling of N-Phenoxyacetamides and Al-
kynes with Tunable Selectivity. Angew. Chem., Int. Ed. 2013,
52, 6033-6037. (b) Zhou, Z.; Liu, G.; Chen, Y.; Lu, X. Cas-
cade Synthesis of 3-Alkylidene Dihydrobenzofuran Deriva-
tives via Rhodium(III)-Catalyzed Redox-Neutral C-H Func-
tionalization/Cyclization. Org. Lett. 2015, 17, 5874-5877. (c)
Zhou, Z.; Liu, G.; Shen, Y.; Lu, X. Synthesis of Benzofurans via
Ruthenium-Catalyzed Redox-Neutral C–H Functionaliza-
tion and Reaction with Alkynes under Mild Conditions.
Org. Chem. Front. 2014, 1, 1161-1165. (d) Chen, Y.; Wang, D.;
Duan, P.; Ben, R.; Dai, L.; Shao, X.; Hong, M.; Zhao, J.;
Huang, Y. A Multitasking Functional Group Leads to
Structural Diversity Using Designer C-H Activation Reac-
tion Cascades. Nat. Commun. 2014, 5, 4610. (e) Xie, Y. Ac-
ylation of Csp2-H Bond with Acyl Sources Derived from Al-
kynes: Rh-Cu Bimetallic Catalyzed C[triple bond, length as
m-dash]C Bond Cleavage. Chem. Commun. 2016, 52, 12372-
12375. (f) Hu, S.; Lu, L.; Zhu, T.; Wu, Q.; Chen, Y.; Li, J. J.;
Zhao, J. Rh(III)-Catalyzed ortho-C-H Alkynylation of N-
Phenoxyacetamides with Hypervalent Iodine-Alkyne Rea-
gents at Room Temperature. Org. Biomol. Chem. 2018, 16,
43-47. (g) Zhou, J.; Shi, J.; Qi, Z.; Li, X.; Xu, H. E.; Yi, W.
Mild and Efficient Ir(III)-Catalyzed Direct C-H
Alkynylation of N-Phenoxyacetamides with Terminal Al-
kyne. ACS Catal. 2015, 5, 6999.
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16
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21
22
23
24
25
26
27
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35
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49
50
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52
53
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55
56
57
58
59
60
(13) The selected examples for TM-catalyzed and O–NHAc-
directed C-H functionalizations with alkenes, see: (a) Shen,
Y.; Liu, G.; Zhou Z.; Lu, X. Rhodium(III)-Catalyzed C-H
Olefination for the Synthesis of ortho-Alkenyl Phenols Us-
ing an Oxidizing Directing Group. Org. Lett. 2013, 15, 3366-
3369. (b) Wang, X.; Lerchen, A.; Daniliuc, C. G.; Glorius, F.
Efficient Synthesis of Arylated Furans by a Sequential Rh-
Catalyzed
Arylation
and
Cycloisomerization
of
Cyclopropenes. Angew. Chem., Int. Ed. 2018, 57, 1712-
1716. (c) Wang, X.; Lerchen, A.; Gensch, T.; Knecht, T.;
Daniliuc, C. G.; Glorius, F. Combination of Cp*RhIII-
Catalyzed C-H Activation and a Wagner-Meerwein-Type
Rearrangement. Angew. Chem., Int. Ed. 2017, 56, 1381-1384.
(d) Lerchen, A.; Knecht, T.; Daniliuc, C. G.; Glorius, F. Un-
natural Amino Acid Synthesis Enabled by the
(10) For selected recent examples on TM-catalyzed C-H func-
tionalization with propargyl alcohols, see: (a) Wu, X.;
Wang, B.; Zhou, Y.; Liu, H. Propargyl Alcohols as One-
Carbon Synthons: Redox-Neutral Rhodium(III)-Catalyzed
C-H Bond Activation for the Synthesis of Isoindolinones
Bearing a Quaternary Carbon. Org. Lett. 2017, 19, 1294-1297.
(b) Sen, M.; Dahiya, P.; Premkumar, J. R.; Sundararaju, B.
Dehydrative Cp*Co(III)-Catalyzed C-H Bond Allenylation.
Org. Lett. 2017, 19, 3699-3602. (c) Wu, X.; Wang, B.; Zhou,
S.; Zhou, Y.; Liu, H. Ruthenium-Catalyzed Redox-Neutral
[4+1] Annulation of Benzamides and Propargyl Alcohols via
C–H Bond Activation. ACS Catal. 2017, 7, 2494-2499. (d)
Wu, S.; Wu, X.; Fu, C.; Ma, S. Rhodium(III)-Catalyzed C-H
Functionalization in Water for Isoindolin-1-one Synthesis.
Org. Lett. 2018, 20, 2831-2834. (e) Wu, X.; Ji, H. Rhodium-
Catalyzed [4+1] Cyclization via C-H Activation for the Syn-
Regioselective
Cobalt(III)-Catalyzed
Intermolecular
Carboamination of Alkenes. Angew. Chem., Int. Ed. 2016,
55, 15166-15170. (e) Zhang, H.; Wang, K.; Wang, B.; Yi, H.;
Hu, F.; Li, C.; Zhang, Y.; Wang, J. Rhodium(III)-Catalyzed
Transannulation
of
Cyclopropenes
with
N-
Phenoxyacetamides through C-H Activation. Angew.
Chem., Int. Ed. 2014, 53, 13234-13238. (f) Hu, Z.; Tong, X.;
Liu, G. Rhodium(III) Catalyzed Carboamination of Alkenes
Triggered by C-H Activation of N-Phenoxyacetamides un-
der Redox-Neutral Conditions. Org. Lett. 2016, 18, 1702-
1705. (g) Piou, T.; Rovis, T. Rhodium-Vatalysed syn-
Carboamination of Alkenes via a Transient Directing
Group. Nature 2015, 527, 86-90. (h) Prakash, S.;
Muralirajan, K.; Cheng, C.-H. Rh-Catalyzed Oxidizing
Group-Directed ortho C-H Vinylation of Arenes by
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Vinylstannanes. Chem. Commun. 2015, 51, 13362-13364. (i)
Li, Y.; Tang, Y.; He, X.; Shi, D.; Wu, J.; Xu, S. Rhodium(III)-
Catalyzed Annulative Carbooxygenation of 1,1-
Disubstituted Alkenes Triggered by C-H Activation. Chem.
-Eur. J. 2017, 23, 7453-7457.
(17) (a) Hummel, J. R.; Boerth, J. A.; Ellman, J. A. Transition-
Metal-Catalyzed C-H Bond Addition to Carbonyls, Imines,
and Related Polarized π Bonds. Chem. Rev. 2017, 117, 9163-
9227. (b) Xia, Y.; Qiu, D.; Wang, J. Transition-Metal-
Catalyzed Cross-Couplings through Carbene Migratory In-
sertion. Chem Rev. 2017, 117, 13810-13889. (c) Kim, H.; Chang,
S. The Use of Ammonia as an Ultimate Amino Source in
the Transition Metal-Catalyzed C-H Amination. Acc. Chem.
Res., 2017, 50, 482-486. (d) Moselage, M.; Li, J.; Ackermann,
L. Cobalt-Catalyzed C–H Activation. ACS Catal. 2016, 6,
498-525.
1
2
3
4
5
6
7
8
(14) The selected examples for TM-catalyzed and O–NHAc-
directed C-H functionalizations with diazo compounds,
see: (a) Hu, F.; Xia, Y.;Ye, F.; Liu, Z.; Ma, C.; Zhang Y.;
Wang, J. Rhodium(III)-catalyzed ortho alkenylation of N-
phenoxyacetamides with N-tosylhydrazones or diazoesters
through C-H activation. Angew. Chem., Int. Ed. 2014, 53,
1364-1367. (b) Hu, Z.; Liu, G. Rhodium(III)‐Catalyzed Cas-
cade Redox‐Neutral C–H Functionalization and Aroma-
tization: Synthesis of Unsymmetrical ortho‐Biphenols.
Adv. Synth. Catal. 2017, 359, 1643-1648. (c) Wu, Y.; Chen, Z.;
Yang, Y.; Zhu, W.; Zhou, B. Rh(III)-Catalyzed Redox-
Neutral Unsymmetrical C-H Alkylation and Amidation Re-
actions of N-Phenoxyacetamides. J. Am. Chem. Soc. 2018,
140, 42-45. (d) Zhou, J.; Shi, J.; Liu, X.; Jia, J.; Song, H.; Xu,
H. E.; Yi, W. Rh(III)-Catalyzed and Alcohol-Involved
Carbenoid C-H Insertion into N-Phenoxyacetamides Using
α-Diazomalonates. Chem. Commun. 2015, 51, 5868-5871.
(15) For representative examples, see: (a) Wang, X.; Gensch,
9
(18) Other control experiments with 1-phenyl-2-butyne sub-
strate were conducted and resulted in the formation of a
mixture of benzofurans containing two regio isomers. For
details, see the Supporting Information.
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44
45
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50
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53
54
55
56
57
58
59
60
(19) (a) Ferrer Flegeau, E.; Bruneau, C.; Dixneuf, P. H.; Anny
Jutand, A. Autocatalysis for C–H Bond Activation by Ru-
thenium(II) Complexes in Catalytic Arylation of Functional
Arenes. J. Am. Chem. Soc. 2011, 133, 10161–10170. (b) Acker-
mann, L.; Wang, L.; Wolfram, R.; Lygin, A. V. Ruthenium-
Catalyzed Oxidative C-H Alkenylations of Anilides and
Benzamides in Water. Org Lett. 2012, 14, 728-731. (c)
Hyster, T. K.; Rovis, T. Rhodium-Catalyzed Oxidative
Cycloaddition of Benzamides and Alkynes via C-H/N-H
Activation J. Am. Chem. Soc. 2010, 132, 10565-10569. (d)
Guimond, N.; Gorelsky, S. I.; Fagnou, K. Rhodium(III)-
Catalyzed Heterocycle Synthesis Using an Internal Oxidant:
Improved Reactivity and Mechanistic Studies. J. Am. Chem.
Soc. 2011, 133, 6449-6457.
T.; Lerchen,
A.;
Daniliuc,
C.
G.; Glorius,
F.
Cp*Rh(III)/Bicyclic Olefin Cocatalyzed C-H Bond
Amidation by Intramolecular Amide Transfer. J. Am. Chem.
Soc. 2017, 139, 6506-6512. (b) Li, B.; Zhou, L.; Cheng,
H.; Huang, Q.; Lan, J.; Zhou, L.; You, J. Dual-Emissive 2-
(2'-Hydroxyphenyl)oxazoles for High Performance Organic
Electroluminescent Devices: Discovery of a New Equilibri-
um of Excited State Intramolecular Proton Transfer with a
Reverse Intersystem Crossing Process. Chem. Sci. 2018, 9,
1213-1220. (c) Li, B.; Tang, G.; Zhou, L.; Wu, D.; Lan,
J.; Zhou, L.; Lu, Z.; You, J. Unexpected Sole Enol-Form
Emission of 2‐(2'-Hydroxyphenyl)oxazoles for Highly Ef-
ficient Deep-Blue-Emitting Organic Electroluminescent
Devices. Adv. Funct. Mater. 2017, 27, 1605245. (d) Li, B.; Lan,
J.; Wu, D.; You, J. Rhodium(III)-Catalyzed ortho-
Heteroarylation of Phenols through Internal Oxidative C-
H Activation: Rapid Screening of Single-Molecular White-
Light-Emitting Materials. Angew. Chem., Int. Ed. 2015, 54,
14008-14012. (e) Wu, Q.; Chen, Y.; Yan, D.; Zhang, M.; Lu,
Y.; Sun, W.-Y.; Zhao, J. Unified Synthesis of mono/bis-
Arylated Phenols via RhIII-Catalyzed Dehydrogenative
Coupling. Chem. Sci. 2017, 8, 169-173. (f) Wu, Q.; Yan, D.;
Chen, Y.; Wang, T.; Xiong, F.; Wei, W.; Lu, Y.; Sun, W.-Y.;
Li, J. J.; Zhao, J. A Redox-Neutral Catechol Synthesis. Nat.
Commun. 2017, 8, 14227. (g) Duan, P.; Lan, X.; Chen, Y.;
Qian, S.-S.; Li, J. J.; Lu, L.; Lu, Y.; Chen, B.; Hong, M.; Zhao,
J. Rhodium(III)-Catalyzed C-H Activation/[4+3] Annula-
tion of N-Phenoxyacetamides and α,β-Unsaturated Alde-
hydes: an Efficient Route to 1,2-Oxazepines at Room Tem-
perature. Chem. Commun. 2014, 50, 12135-12138. (h) Duan,
P.; Yang, Y.; Ben, R.; Yan, Y.; Dai, L.; Hong, M.; Wu, Y.-D.;
Wang, D.; Zhang X.; Zhao, J. Palladium-Catalyzed
Benzo[d]isoxazole Synthesis by C–H Activation/[4 + 1] An-
nulation. Chem. Sci. 2014, 5, 1574-1578. (i) Wang, H.; Wang,
B.; Li, B. Synthesis of 3-Arylbenzofuran-2-ylphosphines via
Rhodium-Catalyzed Redox-Neutral C-H Activation and
Their Applications in Palladium-Catalyzed Cross-Coupling
of Aryl Chlorides. J. Org. Chem. 2017, 82, 9560-9569. (j)
Zhang, Y.; He, Y.; Li, L.; Ji, M.; Li, X-Z.; Zhu, G. Synthesis of
Polyaryl-Substituted Olefins via a Rh(III)-Catalyzed One-
Pot Reaction Using N-Phenoxyacetamides, Ketones, and
Hydrazines. J. Org. Chem. 2018, 83, 2898-2903.
(20) For details, see the Supporting Information.
(21) (a) Yang, Y.-F.; Houk, K. N.; Wu, Y.-D. Computational
Exploration of Rh(III)/Rh(V) and Rh(III)/Rh(I) Catalysis in
Rhodium(III)-Catalyzed C-H Activation Reactions of N-
Phenoxyacetamides with Alkynes. J. Am. Chem. Soc. 2016,
138, 6861-6868. (b) Li, J.; Qiu, Z. DFT Studies on the Mech-
anism of the Rhodium(III)-Catalyzed C-H Activation of N-
Phenoxyacetamide. J. Org. Chem. 2015, 80, 10686-10693. (c)
Chen, J.; Guo, W.; Xia, Y. Computational Revisit to the β-
Carbon Elimination Step in Rh(III)-Catalyzed C-H Activa-
tion/Cycloaddition Reactions of N-Phenoxyacetamide and
Cyclopropenes. J. Org. Chem. 2016, 81, 2635-2638. (d)
Vásquez-Céspedes, S.; Wang, X.; Glorius, F. Plausible Rh(V)
Intermediates in Catalytic C−H Activation Reactions. ACS
Catal. 2018, 8, 242-257.
(22) (a) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. Analysis of the
Concerted Metalation-Deprotonation Mechanism in Palla-
dium-Catalyzed Direct Arylation Across a Broad Range of
Aromatic Substrates. J. Am. Chem. Soc. 2008, 130, 10848-
10849. (b) Lapointe, D.; Fagnou, K. Overview of the Mech-
anistic Work on the Concerted Metallation–Deprotonation
Pathway. Chem. Lett. 2010, 39, 1118-1126. (c) Wu, J.-Q.;
Zhang, S.-S.; Gao, H.; Qi, Z.; Zhou, C.-J.; Ji, W.-W.; Liu, Y.;
Chen, Y.; Li, Q.; Li, X.; Wang, H. Experimental and Theo-
retical Studies on Rhodium-Catalyzed Coupling of
Benzamides with 2,2-Difluorovinyl Tosylate: Diverse Syn-
thesis of Fluorinated Heterocycles. J. Am. Chem. Soc.
2017, 139, 3537-3545.
(23) Yu, J.-L.; Zhang, S.-Q.; Hong, X. Mechanisms and Origins
of Chemo- and Regioselectivities of Ru(II)-Catalyzed
Decarboxylative C−H Alkenylation of Aryl Carboxylic Acids
with Alkynes:
A Computational Study. J. Am. Chem.
Soc. 2017, 139, 7224-7243.
(24) For the detailed DFT results of paths I, Ia and Ib in DCM
and paths II, IIa, and IIb in methanol, please see figures 2-
3; for the detailed free energy profiles of both disfavored
path II (in DCM) and the disfavored path I (in methanol)
that select as the rate-determining steps, please see the
(16) For detailed optimization studies, see Table S1 and S2 in
the Supporting Information.
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Supporting Information. For the summary results, please
see figure 4.
(25) (a) Huo, C.; Xu, X.; An, J.; Jia, X.; Wang, X.; Wang, C. Ap-
proach to Construct Polysubstituted 1,2-
Dihydronaphtho[2,1-b]furans and Their Aerobic Oxidative
Aromatization. J. Org. Chem. 2012, 77, 8310-8316. (b) Shen,
H.; Fu, J.; Yuan, H.; Gong, J.; Yang, Z. Synthesis of 2,3-
Disubstituted Indoles and Benzofurans by the Tandem Re-
action of Rhodium(II)-Catalyzed Intramolecular C-H In-
sertion and Oxygen-Mediated Oxidation. J. Org. Chem.
2016, 81, 10180-10192.
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