Chameleon-like Behavior of the Directing Group in the Rh(III)-Catalyzed Regioselective C-H Amidation of Indole: An Experimental and Computational Study

Article abstract of DOI:10.1021/acscatal.9b02512

The Rh(III)-catalyzed regioselective C-H amidation of N-methoxy-1H-indole-1-carboxamides by 1,4,2-dioxazol-5-ones was studied. N-Methoxy amide, the directing group (DG) of interest, undergoes four different transformations through DG-retained, -coupled, -eliminated, or -migrated processes under moderately varied reaction conditions. Solvents, additives, and temperature play important roles in these selective transformations; a trace addition of water favors the functional group (FG)-assisted DG elimination; extra addition of KHSO₄ greatly enhances the formation of the DG-coupled product; high-temperature and proper FG together can shift the position of DG through intermolecular Friedel-Crafts-like acylation. The catalytic mechanisms underlying these reactions were further investigated through density functional theory calculations and experimental studies including the characterization of amido-inserted rhodacycle. An overall catalytic pathway was proposed to illustrate the reactions involved in the regioselective amidation of N-methoxy-1H-indole-1-carboxamide.

Full text of DOI:10.1021/acscatal.9b02512

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Article
Chameleon-Like Behavior of the Directing Group in
the Rh(III)-Catalyzed Regioselective C-H Amidation
of Indole: An Experimental and Computational Study
Jinquan Zhang, Hujun Xie, Hua-jian Zhu, Shuaizhong Zhang, Madhava Reddy Lonka, and Hong-Bin Zou
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b02512 • Publication Date (Web): 01 Oct 2019
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Chameleon-Like Behavior of the Directing Group in
the Rh(III)-Catalyzed Regioselective C−H
Amidation of Indole: An Experimental and
Computational Study
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Jinquan Zhang,†,⊥Hujun Xie,§,⊥ Huajian Zhu,†‡,⊥ Shuaizhong Zhang, † Madhava Reddy Lonka†
and Hongbin Zou*,†
† College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, P. R. China
§ Department of Applied Chemistry, Zhejiang Gongshang University, Hangzhou 310018, P. R.
China
‡ Zhejiang University City College, Hangzhou, 310015, P. R. China
ABSTRACT: The Rh(III)-catalyzed regioselective C−H amidation of N-methoxy-1H-indole-1-
carboxamides by 1,4,2-dioxazol-5-ones was studied. N-methoxy amide, the directing group (DG)
of interest, undergoes four different transformations through DG-retained, -coupled, -eliminated,
or -migrated processes under moderately varied reaction conditions. Solvents, additives and
temperature play important roles in these selective transformations: A trace addition of water
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favors the functional group (FG)-assisted DG elimination; Extra addition of K2S2O8 greatly
enhances the formation of DG-coupled product; High temperature and proper FG together can
shift the position of DG through intermolecular Friedel-Crafts-like acylation. The catalytic
mechanisms underlying these reactions were further investigated through DFT calculations and
experimental studies including the characterization of amido-inserted rhodacycle. An overall
catalytic pathway was proposed to illustrate the reactions involved in the regioselective
amidation of N-methoxy-1H-indole-1-carboxamide.
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KEYWORDS: C−H activation, directing group, regioselective amidation, Friedel-Crafts-like
acylation, DFT
INTRODUCTION
In the past few decades, transition-metal-catalyzed C−H bond activation, often incorporated in
the organic manipulation of N-heterocyles,1 has attracted wide attention from organic chemists,
for being a highly efficient, atom-economical and environmentally benign synthetic tool.2
Among the many forms of this methodology, directed C−H functionalization, first discovered in
1963, has recently reemerged as a reliable approach for achieving a diverse collection of carbon–
carbon (C−C) and carbon–heteroatom (C−X) functionalization reactions.3 This strategy
introduces a directing group (DG) into a hydrocarbon substrate, and activates C−H bond through
organometallic intermediates which ultimately convert the C−H bond to a functional group (FG).
Various novel coordinating DGs have been designed and successfully installed onto the
substrates of interest, where they promote the subsequent one-pot catalytic selective C−H
functionalization through one of the three main pathways (Scheme 1a): (i) the majority of
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installed DGs remain intact at the incorporated position;4 (ii) some DGs further react with the
inserted FG to form a cyclized product immediately following C−H activation;5 and (iii) the rest
DGs are readily eliminated in situ to produce desired products, which usually requires multiple
chemical transformations and is not always achievable.6 Taken together, these schemes infer
unlimited synthetic capacity of DGs in catalytic site-selective preparation of structurally
diversified products.
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However, identifying DG and FG that are compatible with a target substrate is always
challenging, as is determining the reaction conditions to robustly control the regioselectivity of
C−H functionalization. In 2008, Yu’s team reported the highly selective construction of C−C and
C−N bonds through the directed activation of C−H bond using N-methoxy amides.7 N-methoxy
amide is a carbonyl-related DG consisting of a chelating amide and a methoxy group as nitrogen-
protecting motif used in regioselective C−H functionalization.8 This agent is particularly useful
as a synthon, since N-methoxy amide can be readily converted to a number of synthetically
versatile groups, including esters, amides and alkanes. Over the past ten years, N-methoxy amide
has shown increasingly high success in forming C−C and C−X bonds via processes catalyzed by
various transition-metals, such as rhodium, copper, palladium and ruthenium.9‒11 Different
products with attractive structural features have been achieved through highly efficient one-pot
regioselective reactions. In most cases, N-methoxy amide either remains on the products9 or is
further coupled with an adjacent FG to afford extra heterocycle.10 A partial cleavage of the
methoxy protecting group was also observed in some experiments.11 However, complete
detachment of N-methoxy amide from substrate following C−H functionalization has not yet
been reported.
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Inspired by the feasibility of using N-methoxy amide as an intramolecular DG, we investigated
the directed regioselective amidation of N-methoxy amide-substituted indole 1 by the amidating
reagent 1,4,2-dioxazol-5-one 212 (Scheme 1b). This model study showed the versatile
transformations of N-methoxy amide group under varied reaction conditions, including
temperature, solvent and additive, whereby structurally attractive and diverse functionalized
indoles 3, 4, 5 and 6 were achieved through Rh(III)-catalyzed C−H bond activation. In addition
to incorporating FG at C2 to yield 3, N-methoxy amide DG also acted as a coupling partner to
give product 4 in tetrahydrofuran (THF) solvent at low temperature. Notably, the presence of a
small amount of water led to the formation of DG-free product 5, which demonstrates the first
example of in situ elimination of N-methoxy amide. Moreover, product 6 was obtained after DG
was shifted from N1 to C3 at high reaction temperature. Further experimental and computational
studies were carried out to elucidate the underlying reaction mechanisms and reveal the cause of
product diversity.
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Scheme 1. Versatile DG Behavior in Transition-Metal Catalyzed C-H Bond Activation
(a) Directing group strategy in transition-metal catalyzed C-H functionalization
DG
(ii) DG further cyclisation
FG
DG
FG
DG
H
(i) non-removable DG
+
FG
(iii) removable DG
FG
(b) This work: N-Methoxy amide as versatile directing group in Rh(III)-catalyzed C-H amidation
O
R1
R1
R2
r.t.
60 oC
THF
N
N
N
N
H
THF
O
NH
R1
cat. [Rh]
Base
O
O
O
R2
O
cat. [Rh]
Base
O
N
3
4
O
N
+
O
O
R2
O
O
N
N
H
O
R1
130 oC
DCE
2
60 oC
R1
H
1
N
H
N
R2
N
H
NH
R2
THF+H2O
H
O
5
6
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RESULTS AND DISCUSSION
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Reaction Conditions Optimization. N-methoxy-1H-indole-1-carboxamide (1a) and 1,4,2-
dioxazol-5-one (2a) were selected as starting materials to model the metal-mediated indole
amidation. We began our optimization study by screening a wide range of reaction parameters,
including catalysts, ligands, salt additives, solvents and temperatures (see Table S1‒S4 in
Supporting Information for detailed reaction condition screening). The simple mixture of
commercially available complexes [Cp*RhCl2]2 and Zn(OTf)2 was used as the catalytic system,
and solvent 1,2-dichloroethane (DCE) was applied initially. The reaction at room temperature
formed a new C−N bond to give products 3a, 4a, 5a and 6a, in the yields of 52%, 9%, 17% and
7%, respectively (Table 1, entry 1). Replacing DCE with untreated THF (≤ 0.05% water) slightly
improved the yield of 3a and 5a (Table 1, entry 2). And substituting CsOAc with NaOAc
elevated the yield of 3a to 88% (Table 1, entry 3), presumably due to the alkalinity difference
between the two bases. Notably, raising the reaction temperature to 60 °C drastically decreased
the yield of 3a to less than 5% whereas the turnover of product 5a was dramatically increased,
and the yield of 4a was also slightly improved (Table 1, entry 4). We next attempted the chemo-
selective study of 4a and 5a. As shown in Table 1 (entries 5‒7), a more balanced mixture of
products 4a and 5a was obtained when anhydrous THF was employed as solvent, and replacing
additive CsOAc with NaOAc/K2S2O8 boosted the yield of 4a from 24% to 78%, suggesting
K2S2O8 could promote the cyclization reaction. Since KHSO4 has also been reported to assist
similar cyclizations,13 we attempted the reaction once more using NaOAc/KHSO4 as the additive,
and found the yield of 4a was further increased to 81% (entry 8). Also of note, using untreated
THF as solvent yielded slightly more 5a than using anhydrous THF (Table 1, entries 4 and 5),
indicating that the presence of water favors the production of 5a. This result prompted us to add
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10% water (v/v) into THF and as expected, the new solvent mixture gave distinct product 5a in
an excellent yield of 85% (Table 1, entry 9). However, same additional water into THF in entry 3
(Table 1) resulted in the slightly decreased yield of 3a (Table S1, entry 10). To further explore
the effect of temperature, we steadily raised it while keeping the rest conditions intact.
Interestingly, the yield of product 6a continuously increased until reaching 62% at 130 °C,
whereas 3a, 4a and 5a gradually diminished (Table 1, entries 10‒12). The experimental
outcomes also showed that the presence of CsOAc or NaOAc as an additive is crucial for the
success of these transformations wherein Cp*Rh(OAc)2, rather than [Cp*RhCl2]2, most likely
acts as the active catalyst, as evidenced by the density functional theory (DFT) calculations
(Figure S9, S10). Meanwhile, Zn(OTf)2 was found to slightly increase the yield of 3a, 5a and 6a
(Table S1, S3 and S4) which might be ascribed to its promotion of the transformation
[Cp*RhCl2]2 to Cp*Rh(OAc)2 in the presence of CsOAc or NaOAc. We also screened the
efficiency of various complexes containing the basic amide moiety (see Supporting Information
for details). The results showed that N-methoxy amide outcompeted the rest of candidates in
directing Rh(III)-catalyzed C−H amidation and promoting the subsequent transformations.
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Table 1. Optimization of Reaction Conditions
O
[Cp*RhCl2]2/Zn(OTf)2
O
+
O
N
N
Additive/Solvent/T(oC)/12 h
-CO2
Ph
2a
O
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O
N
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1a
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O
N
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N
N
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Ph
+
Ph
+
+
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N
N
N
H
N
N
H
NH
Ph
NH
O
H
O
O
Ph
O
4a
6a
5a
3a
yield (%)a
3a 4a 5a 6a
52 17
entry
solvent
DCE
additive T (°C)
1
2
3
4
5
6
CsOAc
CsOAc
r.t.
r.t.
r.t.
60
60
60
9
7
untreated THF
68 <5 21 <5
88 <5 <5 <5
<5 10 75 <5
<5 24 49 <5
<5 34 44 <5
untreated THF NaOAc
untreated THF
anhydrous THF
anhydrous THF
CsOAc
CsOAc
NaOAc
NaOAc
K2S2O8
7 b
8 b
anhydrous THF
60
<5 78 <5 <5
NaOAc
KHSO4
anhydrous THF
60
<5 81 <5 <5
9
THF/H2O (10:1) CsOAc
60
60
<5 <5 85 <5
<5 12 51 24
<5 <5 25 48
<5 <5 <5 62
10
11
12
DCE
DCE
DCE
CsOAc
CsOAc
CsOAc
95
130
The reaction was conducted with 1a (0.2 mmol), 2a (0.24 mmol), [Cp*RhCl2]2 (5 mol%), Zn(OTf)2 (30 mol%), additive (0.2
mmol), solvent (2 mL), yield of isolated products.a Isolated yield; b Zn(OTf)2 was not used.
Substrate Scope. With the optimized reaction conditions in hand, we sought to evaluate the
substrate scope of these processes, starting with the formation of DG-retained product 3 using
the same catalytic system as shown in Table 1 (entry 3). The results showed that the mono-
substituted 3-phenyl dioxazolones were well tolerated in the reaction with 1a, affording 3a3g,
3j and 3k in good to excellent isolated yields ranging from 72% to 92% (Scheme 2). The
dioxazolones containing electron-withdrawing group at para-position of the phenyl ring, such as
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fluorine, chlorine and trifluoromethyl group, gave higher yield of products (3d, 3e and 3g) than
those with electron-donating group. This trend was further verified by the high yield of 3m
(83%) derived from dioxazolones containing 3, 4-chloro group on the phenyl ring. However,
para-methyl ester or cyano substituents on phenyl ring prevented dioxazolones from producing
desired product (3h and 3i). Meanwhile, more sterically hindered diphenyl-substituted
dioxazolone resulted in much lower yield (3l, 56%). In addition, we found alkyl-substituted
dioxazolone also compatible to react with 1a to afford 3n in moderate yield. Similarly tolerated
was the dioxazolone bearing styryl substituent as a conjugated side chain (3o). Moreover,
dioxazolones with thiophene substituent reacted with 1a smoothly, giving 3p in good yield.
Subsequently, we investigated the scope of N-methoxy amide-substituted indoles. As a result, a
variety of electron-donating and -withdrawing substituents on phenyl ring of indole were well
tolerated in the reaction, affording the corresponding desired products (3q‒3t and 3x‒3ab) in
moderate to good yields ranging from 57% to 86%, with the exception of the compounds with
strong electrophilic methyl ester, nitro or cyano substituents (3u‒3w).
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Scheme 2. Synthesis of Products 3 with DG Retained
5
6
7
8
O
R1
O
R1
O
[Cp*RhCl2]2 (5 mol%)
Zn(OTf)2 (30 mol%)
N
N
R2
N
O
H
R2
N
O
NH
OMe
O
NH
OMe
NaOAc (1.0 equiv.)
THF, r.t., 12 h
2
1
3
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O
O
O
R
N
N
H
N
N
N
N
H
H
O
NH
OMe
3a
R
O
NH
OMe
O
NH
OMe
R=CH3 3j
, 79%
R=H
CH3
OCH3 3c
, 92%
3l
, 56%
OCH3 3k
3b
, 72%
, 76%
, 75%
, 89%
, 86%
, 82%
O
O
Cl
Cl
F
3d
3e
N
N
N
N
H
NH
OMe
, 67%
Cl
Br
CF3
H
O
NH
OMe
3m
O
3f
3g
CO Me 3h
, 87%
, 0%
, 83%
3n
2
CH3
CN
3i
, 0%
O
O
O
N
N
N
N
N
N
H
NH
OMe
, 81%
H
H
S
O
NH
OMe
3o
O
NH
OMe
, 85%
O
3p
3q
, 63%
R
O
O
O
N
N
R
N
N
N
N
H
H
H
Br
O
NH
OMe
3ab
O
NH
OMe
3x
, 63%
3y
, 72%
3z
3aa
O
NH
OMe
3r
R=CH3
F
Cl
Br
, 57%
R=CH3
Cl
Br
, 75%
, 82%
, 86%
, 0%
, 0%
3s
3t
, 77%
, 79%
CO2Me 3u
CN
NO2
3v
3w
, 0%
The reaction was conducted with 1 (0.2 mmol), 2 (0.24 mmol), [Cp*RhCl2]2 (5 mol%), Zn(OTf)2 (30
mol%), NaOAc (0.2 mmol), THF (2 mL), room temperature, yield of isolated products.
Next, we surveyed the substrate scope for the synthesis of DG-coupled products, 4H-
[1,3,5]oxadiazino[3,4-a]indol-4-ones (4, Scheme 3). A broad range of indoles and aryl-
dioxazolones were investigated for their reaction compatibility. Dioxazolones, whether bearing
neutral hydrogen or phenyl, electron-donating methyl or methoxy, or electron-withdrawing
fluoro or chloro on the phenyl ring, all successfully reacted with 1a to give corresponding
products in moderate to good isolated yields (4a‒4h), among which 4d, derived from phenyl-
substituted phenyl-dioxazolone, was achieved in the highest yield of 91%. Employing
naphthalene, benzyl or styryl-substituted dioxazolones as substrates resulted in moderate yields
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of the desired products (4i‒4k). Similar yields were obtained by replacing the substituents of
dioxazolone with heterocycles, such as furan and thiophene (4l and 4m). Indoles bearing
different groups were also found compatible in the coupling assembly of the corresponding
cyclized heterocycles (4n‒4z), albeit in slightly lower yields.
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Scheme 3. Synthesis of Product 4 with DG Coupled
R1
O
R1
[Cp*RhCl2]2 (5 mol%)
KHSO4 (1.0 equiv.)
NaOAc (1.0 equiv.)
THF, 60 oC, 12 h
N
O
N
N
O
R2
N
O
NH
OMe
O
O
R2
2
1
4
N
N
N
N
N
O
N
N
R
O
O
O
O
O
R
R=H
4a
, 81%
, 75%
, 72%
, 91%
, 43%
, 47%
R=CH3 4g
, 75%
Cl
4i
, 62%
CH3 4b
OCH3 4c
Ph
F
4h
, 45%
N
4d
4e
4f
N
N
O
R
O
O
O
O
Cl
4j
, 49%
4k
, 59%
CH3
N
N
X
N
N
O
N
N
O
O
O
O
X=CH3 4o
Br 4p
, 69%
, 37%
X=O 4l
S
, 45%
4m
, 41%
4n
, 61%
R
N
N
R
N
N
N
N
O
O
O
O
Me
O
O
R=CH3 4q
, 62%
R=CH3 4v
, 77%
4z
, 53%
OCH3 4r
F
4w
, 60%
, 51%
F
Cl
Br
4s
Cl
Br
4x
4y
, 38%
4t
, 45%
, 55%
, 52%
4u
, 46%
The reaction was conducted with 1 (0.2 mmol), 2 (0.24 mmol), [Cp*RhCl2]2 (5 mol%), NaOAc (0.2
mmol), KHSO4 (0.2 mmol), THF (2 mL), 60 oC, yield of isolated products.
Notably, a unique reaction occurred when we replaced DCE with aqueous THF as the reaction
solvent: An elimination of the DG took place in situ following the successful insertion of the
substituted amide unit to C2 position of the indole ring of 1, leading to the formation of DG-free
product 5 (Scheme 4). The substrate scope and reaction limitatio.ns were accordingly examined.
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The results indicated that the electron-donating substituents on the phenyl ring of dioxazolones
resulted in higher isolated yields of products (5b, 5c and 5g) than those obtained with electron-
withdrawing substituents (5d‒5f and 5h). When using naphthalene, benzyl and styryl-substituted
dioxazolone as substrates, the desired products were yielded in moderate to good amount
(5i‒5k). We then extended the phenyl substituents of dioxazolones to alkyls and heterocycles,
and found that isobutyl and furan-dioxazolone were also viable in forming desired products (5l
and 5m), albeit in slightly lower yields. In addition, substrates with N-carboxamides substituted
on various positions of indole ring efficiently generated N-(indol-2-yl)amides in moderate to
good yields (5n‒5x).
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Scheme 4. Synthesis of Product 5 with DG Eliminated
[Cp*RhCl2]2 (5 mol%)
Zn(OTf)2 (30 mol%)
R1
O
O
R1
O
N
O
N
H
N
R2
CsOAc (1.0 equiv.)
THF:H2O (10:1)
60 oC, 12 h
R2
N
O
NH
OMe
H
2
1
5
O
O
O
R
N
H
N
N
H
N
N
H
N
H
H
H
R
R=H
CH3 5b
OCH3 5c
F
Cl
5a
, 82%
, 85%
, 75%
, 69%
, 66%
, 48%
R=CH3 5g
Cl
, 88%
, 78%
5i
, 77%
5h
O
O
5d
5e
N
H
N
N
H
N
H
H
NO2 5f
5j
5k, 53%
, 35%
R
O
O
O
O
N
H
N
H
N
H
5l
N
N
H
N
H
H
5m
, 34%
R=CH3 5n
, 82%
, 29%
Br
5o
R
, 70%
O
O
O
N
H
N
H
R
N
H
N
H
N
H
N
H
CH3
R=CH3
F
Cl
Br
5t
5u
5v
, 79%
, 45%
, 58%
R=CH3
OCH3 5q
Cl
Br
5p
, 76%
5x
, 75%
, 85%
, 69%
5r
5s
5w
, 67%
, 62%
The reaction was conducted with 1 (0.2 mmol), 2 (0.24 mmol), [Cp*RhCl2]2 (5 mol%), Zn(OTf)2 (30
mol%), CsOAc (0.2 mmol), THF (2 mL), H2O (0.2 mL), 60 oC, yield of isolated products.
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As shown in Scheme 5, N-methoxy-1H-indole-1-carboxamide (1a) reacted smoothly with
various aromatic dioxazolones to introduce the FG to C2 position of the indole ring while
transferring the DG from N-1 to C-3, which then generated desired products (6a−6g) in moderate
to good isolated yields. Using 1a derivatives bearing electron-donating methyl or methoxy
groups on aromatic ring also afforded the desired products 6h and 6i in good yields. However, no
observable target product was generated from 1a or 2a containing an electron-withdrawing
substituent such as chloro or bromo group.
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Scheme 5. Synthesis of Product 6 with DG Migrated
O
O
O
R1
N
R1
H
O
[Cp*RhCl2]2 (5 mol%)
Zn(OTf)2 (30 mol%)
CsOAc (1.0 equiv.)
DCE, 130 oC, 12 h
N
O
R2
N
H
NH
R2
N
O
NH
OMe
O
2
1
6
O
O
O
O
O
O
N
N
N
H
H
H
N
H
NH
N
H
NH
N
H
NH
R
O
O
O
R
6a
, 62%
6b
, 59%
6d
, 65%
R = CH3
R = CH3
6c
6e
OCH3 , 57%
OCH3 , 53%
O
O
O
O
O
O
N
H
N
H
R
N
H
N
H
NH
N
H
NH
N
H
NH
O
O
O
6h
, 67%
6i
OCH3 , 72%
R = CH3
6f
, 38%
6g
, 45%
The reaction was conducted with 1 (0.2 mmol), 2 (0.24 mmol), [Cp*RhCl2]2 (5 mol%), Zn(OTf)2 (30
mol%), CsOAc (0.2 mmol), DCE (2 mL), 130 oC, yield of isolated products.
Mechanistic Studies. The versatile N-methoxy amide DG has exhibited great synthetic capacity
by successfully furnishing four different series of indole amidation products through Rh(III)-
catalyzed C−H activation. To gain insight into the pathways underlying the reaction and its
diversity, we conducted mechanistic investigations using a combined experimental and
computational methodology to address specifically: (1) What is the key intermediate in the
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synthesis of products 3a, 4a, 5a or 6a? (2) What cascade steps it takes for these four
transformations to take place? (3) Why does the C−H amidation prefer the site of C2 instead of
C7 in similar proximity? (4) How do DG elimination and DG migration occur in the synthesis of
5 and 6, respectively?
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Scheme 6. Intermediate Study for the Amidation
(a) Formation of amido-inserted rhodacycle IN5 and IN8
[RhCpCl2]2, NaOAc
THF, 70 oC, 48h
N
N
Rh
NH
O
N
O
OMe
OMe
IN5
, 96%
O
Ph
Ph
O
O
O
N
N
O
N
N
O
H
N
Ph
H
O
N
IN5
Rh
+
O
NH
H
O
N
O
NaOAc, THF
r.t., 48h
Cp*
Ph
H
O
3a
, 90%
IN8
, 6%
(b) IN5 leading to products 3a, 4a, 5a and 6a
KHSO4, NaOAc
NaOAc
3a
, 92%
4a
, 83%
THF, 60 o
C
O
THF, r.t.
N
O
Rh
Cp*
O
N
+
Ph
N
O
OMe
2a
CsOAc
CsOAc
5a
, 87%
6a
, 56%
DCE, 130 o
C
THF/H2O, 60 o
C
IN5
(c) 3a leading to products 4a, 5a and 6a
KHSO4, NaOAc
4a
, 84%
THF, 60 o
C
O
N
N
Ph
CsOAc
DCE, 130 o
H
6a
, 65%
C
O
NH
O
3a
CsOAc
THF/H2O, 60 o
5a
, 89%
C
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Figure 1. Molecular structure and atom numbering scheme for IN5 and IN8.
In order to investigate all the possible intermediates, we first obtained a stable five-membered
rhodacycle IN5 by treating substrate 1a with [Cp*RhCl2]2 at 70 oC as shown in Scheme 6a. The
subsequent reaction between IN5 and 2a successfully afforded product 3a in excellent yield as
well as a small amount of di-amidated Rh complex IN8. Both intermediates IN5 and IN8 were
confirmed by X-ray crystallography (Figure 1). Next, we achieved products 3a, 4a, 5a and 6a in
92%, 83%, 87% and 56% yield respectively, by coupling IN5 with 2a under different conditions
(entries 3, 7, 8 and 11, Table 1) without employing additional [Cp*RhCl2]2 (Scheme 6b). This
finding suggests that IN5 very likely acts as an intermediate in C−H activation to afford desired
products. In order to verify the role of 3a in the formation of the rest products, we subjected it to
the standard conditions without adding [Cp*RhCl2]2. As a result, products 4a, 5a and 6a were
isolated in yields of 84%, 89% and 65% respectively (Scheme 6c), suggesting that 3a is most
likely the central intermediate to form the three other products.
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Cp*
O
AcO
Rh
AcO
O
Cp*
O
H
C
N
N
N
Rh
O
C
C
Rh
N
N
O
O
N
O
H
H
O
O
Cp*
O
Cp*
Rh
OMe
OMe
O
OMe
O
N
N
TS1
IN1
TSa
N
O
Ph
N
18.9
TSa
N
O
6
Ph
Rh Cp*
18.7
IN1
OMe
N
14.9
TS2
O
(AcOH)
Cp*
14.4
TS1
OMe
7
8
9
N
13.0
TS3
Rh
O
N
10.9
IN2
CO2
O
OMe
IN4
Ph
AcO
Rh
N
AcOH
Cp*
N
O
C
O
N
5.2
H
O
4.6
N
AcOH
Ph
O
IN6
IN4
(AcOH)
O
N
H
O
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N
N
Rh
1.5
OMe
IN2
0.8
0.0
Cp*
-0.6
IN7
MeO
O
O
Rh
N
IN3
C
O
H
O
IN5
Ph
H
Cp*
[Cp*Rh(OAc)2
+
]
N
O
C
O
O
OMe
INX2
Cp*
Rh
O
N
O
C
OAc
Rh Cp*
N
Ph
Rh Cp*
O
N
O
-21.2
TS5
N
Rh
N
O
N
O
N
N
O
AcOH
N
Rh Cp*
N
N
Ph
N
Ph
OMe
N
OMe
Cp*
-35.5
INX1
-33.8
TS4
O
N
H
OMe
IN6
O
N
-34.5
O
-34.6
O
O
O
NH
NH
OMe
INX2
-37.3
OMe
IN5
INX3
O
IN7
AcOH
-49.6
OMe
OMe
1a
O
IN3
INX4
3a
Ph
Ph
H
O
N
O
Ph
O
C
N
N
H
O
Rh
INX
N
-56.0
3a
N
H
C
Rh
N
O
N
O
O
N
C
O
O
+
N
N
Ph
Cp*
OMe
N
O
Cp*
Rh
MeO
H
O
Cp*Rh(OAc)2
H
TS4
Rh
Cp*
MeO
O
N
Cp*
C
O
C
O
OMe
INX
O
INX3
INX4
Figure 2. Free energy profiles (kcal mol−1) for the generation of 3a from 1a and 2a.
Figure 3. Optimized structures (Å) for selected transition states as shown in Figure 2.
In order to further study the mechanism to form 3a, we conducted a series of density functional
theory (DFT) calculations at the level of M0614 using the Gaussian 09 suite of computational
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programs15. (see Supporting Information for computational details). The Rh and Cl atoms were
described by the Lanl2dz basis set and effective core potential.16 The 6-31G(d,p) basis set17 was
applied for the C, H, O and N atoms. In addition, polarization functions of Rh(ζf) = 1.350 and
Cl(ζd) = 0.514 were added.18 Frequencies were calculated at the same level of theory to obtain
the thermodynamic corrections and to confirm whether the structures were minima (no
imaginary frequency) or transition states (only one imaginary frequency). Intrinsic reaction
coordinate (IRC) calculations19 were conducted to confirm all transition-state structures that
connected the proposed reactants and products. The most plausible pathway from 1a to 3a was
then identified among several proposed routes (see Supporting Information). As shown in Figure
2, starting material 1a is initially coordinated to the catalyst to form a complex that undergoes
subsequent deprotonation by OAc− twice and transforms to the intermediate IN5, confirmed by
X-ray crystallography. A kinetic isotope effect (KIE) study (kH/kD = 1.31, see Supporting
Information) suggested that the C−H bond cleavage at the ortho-position of the indole is not the
rate determining step, a finding consistent with the KIE result of TS1 (kH/kD = 1.46) from the
DFT calculation (Figure 2). Next, the other starting material 2a is coordinated to Rh(III) complex
IN5 to give IN6 with an endergonicity of 4.4 kcal/mol, which is followed by the CO2 release
through TS2 (Figure 3) with a barrier of 16.6 kcal/mol. IN7 further carries out a C−N bond
coupling, which has a barrier of 13.6 kcal/mol, to transiently form TS3 wherein the C-Rh(III)
bond was cleaved to deliver intermediate INX. However, the six-membered rhodacycle INX was
not detected throughout our experiment, presumably because INX is so reactive that it converts
to 3a immediately after formation. Subsequently, the coupling of INX to acetic acid leads to TS4
via INX1and the following protonation of TS4 gives rise to INX2. Further coordination of
additional acetic acid to Rh(III) on INX2 and the N-Rh(III) bond cleavage together generate TS5
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via INX3, which ultimately results in the formation of the final product 3a through INX4 and the
5
6
regeneration of catalyst Cp*Rh(OAc)2.
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9
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Scheme 7. Selective C−H Activation of C2 Over C7
(a) Diamidated product using IN8 as starting material
Ph
2
Ph
N
N
O
H
7
O
NaOAc
N
H
N
O
N
Rh
H
H
N
O
O
O
O
NH
Ph
THF/H2O, 60 o
C
Cp*
Ph
H
IN8
8
, 18%
(b) Regioselective amidation on C7 of indole 1aa
O
[Cp*RhCl2]2
N
CH3
N
CH3
NH
O
+
O
NaOAc, THF
12h, 60 o
O
NH
H
O
NH
O
N
Ph
O
C
Ph
O
2a
9
1aa
, 72%
(c) Relative Gibbs free energies (kcal/mol) for C-H activation on C2 and C7
O
C
H
16.2
O
AcO
Rh
H
N
Rh
N
N
TSC7
14.4
O
N
O
Cp*
Cp*
Rh
N
C
O
N
O
OMe
O
Cp*
OMe
TSC2
OMe
1.5
TSC2
TSC7
IN3
It is noteworthy that during the treatment of IN5 with 2a (Scheme 6a), a small amount of IN8,
exhibiting C−H activation potential at C7, was alternatively obtained in place of INX. We thus
continued investigation using this di-amidated intermediate as a starting material under various
standard conditions excluding the addition of [Cp*RhCl2]2. As a result, none of the products 3a,
4a, 5a or 6a was detected. Instead, compound 8 with amidation on both C2 and C7 of indole was
obtained (Scheme 7a). The C−H activation on C7 was further confirmed by reaction between
C2-methylated 1aa and 2a, which led to product 9 in good yield (Scheme 7b). However, no C7-
amidated product was observed in the reaction between 1a and 2a, suggesting that the C−H
activation at C2 was favored in this catalytic system.
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To understand the cause of this distinct selectivity, we computationally analyzed the relative
Gibbs free energies of C−H activation for both sites C2 and C7. Scheme 7c shows that C2
exhibits relatively lower energy barrier (12.9 kcal/mol) than C7 (14.7 kcal/mol), hence being the
preferred activating site. This finding accords with our experimental results shown in Scheme 2,
7a and 7b, and explains the regioselectivity observed with N-methoxy-1H-indole-1-carboxamide
(1a).
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Also of note, the carbonyl group on the cyclized product 4 has several possible sources: starting
material 1 or 2, or their spontaneous decomposition product CO2. Through stable-isotope
13
labeling experiments with C, we were able to clarify that the carbonyl group comes straight
from 1, a finding that is consistent with Scheme 6c (see Supporting Information for more details).
To our surprise, product 5a and 6a were also formed through intermediate 3a, indicating that DG
elimination and translocation took place during the process (Scheme 6c). This very unusual
observation prompted us to investigate the underlying mechanisms. As shown in Scheme 8a,
compound 1a did not afford DG-free indole under the same elimination condition of 3a (Scheme
8a), suggesting that the amidation of 3a contributes to the DG removal, presumably by
increasing the electron density of the adjacent nitrogen to which DG was attached. This effect of
FG on the translocation of DG was also detected in the transformation of 3a under the standard
condition to form 6a (Scheme 8b), in contrast to the reaction of 1a or 1aa wherein no DG
migration was observed. As shown in Scheme 8b, instead of giving any DG-shifted product,
moderate electron-donating 2-methyl-substituted 1aa delivered mainly DG-free product 10 in 45%
isolated yield, along with remaining 1aa. However, when 5a reacted with 1aa in a 1:1 ratio, the
DG-shifted product 6a was obtained in 53% isolated yield and compound 10 was produced in 75%
yield, leaving no traceable unreacted 1aa. Taken together, these outcomes indicate that the
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migration of DG from N1 to C3 might also be attributed to the electron-donating effect of the
amide FG in proximity which activates the amidation of C3 by enhancing its electronegativity
and hence accelerating the translocation of DG.
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Scheme 8. FG Effect on DG Elimination and Migration
(a) Effect of FG on DG elimination
CsOAc
N
R1
O
N
H
R1
THF/H2O, 60 o
C
O
N
H
R1=H, N.D.
1a
3a
: R1= H
: R1= NHCOPh
5a
: R1= NHCOPh, 82%
(b) Effect of FG on DG migration
O
O
N
CsOAc
H
N
R2
O
N
R2
O
+
+
DCE, 130 o
C
N
R2
N
H
R2
O
N
H
N
O
H
H
1a
3a
: R2= H
: R2= NHCOPh
R2=H, N.D.
6a
1a
3a
R2=H, N.D.
, 80%
, N.D.
: R2= NHCOPh, 65%
R2= NHCOPh, <5%
O
O
N
CsOAc
DCE, 130 o
H
N
O
C
N
H
1aa
+
+
N
H
O
N
H
1aa
10
, 45%
N.D.
30%
O
O
O
CsOAc
DCE, 130 o
O
N
N
H
C
H
1aa
+
+
+
N
NH
N
H
N
H
H
O
Ph
N
NH
Ph
H
N.D.
10
, 75%
<5%
6a
, 53%
5a
O
On the basis of the experimental and computational results, we propose four plausible
mechanisms underlying the C-H bond functionalization as shown in Scheme 9. In the presence
of CsOAc, dimeric compound [Cp*RhCl2]2 transforms to Cp*Rh(OAc)2, which is then captured
by 1a to afford rhodacycle IN5 through N-metalation and turnover-limiting C−H activation. The
transmetalation of IN5 by 2a at room temperature leads to product 3a as well as a small amount
of IN8, which presumably gives the proposed intermediate INX during the reaction. The fact that
no INX was detected could be ascribed to its high instability. Next, ortho-amidated product 3a
serves as a key intermediate to form 4a, 5a and 6a. In the presence of NaOAc, the
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tautomerization of 3a takes place to give A which then undergoes lactonization to ultimately
furnish DG-coupled product 4a via [4+2] cyclization. On a parallel pathway, the DG of 3a is
removed by base CsOAc to obtain B followed by protonation in the presence of water, which
eventually leads to the formation of DG-free product 5a. Meanwhile, at high temperature, the
electron rich C3 of the same intermediate B could also attack the carbonyl group in DG of 3a
through the intermolecular Friedel-Crafts-like acylation to form product 6a, and regenerate
molecule of B to continuously drive the reaction cycle.
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Scheme 9. Proposed Reaction Pathways
0.5[Cp*RhCl2]2
N
2CsOAc
H2N
O
O
Ph
O
N
H
2CsCl
Cp*Rh(OAc)2
N
N
1a
N
N
OH
O
O
O
Ph
NH
O
4a
NaOAc
A
Ph
O
Cp*
N
O
Rh
N
H+
O
N
N
CsOAc
N
N
Ph
H
O
O
H
H
O
N
N
Ph
NH
O
IN5
H
5a
3a
O
Ph
B
O
N
O
Ph
2a
O
N
N
O
Ph
H
O
CsOAc
N
O
NH
O
H
INX
N
N
O
H
O
O
3a
Ph
N
Rh
N
H
NH
H
O
O
N
O
Cp*
Ph
N
N
H
Ph
N
N
O
H
O
Ph
Rh
O
N
Cp*
B
IN8
6a
O
CONCLUSION
In summary, we developed rhodium-catalyzed regioselective C−H amidation of indoles and
obtained four different products under moderately varied reaction conditions. The four ways of
C-H functionalization were achieved by fully utilizing the reacting potential of N-methoxy amide
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as intramolecular DG of N-methoxy-1H-indole-1-carboxamides when interacting with 1,4,2-
dioxazol-5-ones. The traditional mechanism of C−H activation, assisted by N-methoxy amide
DG, successfully introduces amide FG to the indole moiety to produce compound 3. A slight
modification of reaction conditions overrides the conventional mechanism and renders the
chelating carbonyl group of DG so much more reactive that it forms a further coupled product 4.
Notably, the addition of a small amount of water results in an in situ elimination of DG to give
product 5, the first time N-methoxy amide acts as a completely removable DG. Furthermore,
unprecedented DG migration gives rise to unexpected product 6, a process accelerated by high
reaction temperature and facilitated by ortho-amidated intermediate 3. To our best knowledge,
this is the first case of DG migration occurring in directed transition-metal-catalyzed C−H
functionalization wherein the newly installed FG plays a crucial role in the intermolecular
Friedel-Crafts-like acylation. Mechanistic studies involving both experimental and theoretical
methodologies were carried out. Two Cp*Rh(III) complexes were isolated and characterized.
The DFT calculations revealed the possible pathway to obtain 3a and explained preferred C−H
activation site of C2 over C7 on N-methoxy-1H-indole-1-carboxamide (1a). This rhodium-
catalyzed reaction provides a facile approach to indole amidation with high regioselectivity,
tolerates a broad range of substrates and efficiently produces a variety of indoles through one-pot
DG-coupled, -eliminated or -migrated reactions. The enabling manipulations significantly
expand the synthetic utility of N-methoxy amide, be it an easily accessible directing agent, a C-H
functional building block, a removable group or a potentially transferable moiety. Such versatile
strategy and its extension may encourage researchers to discover more promising DGs for
transition-metal-catalyzed C−H bond activation, making available new targets and materials that
would have been previously out of range.
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ASSOCIATED CONTENT
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Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website at DOI:
1H and 13C NMR spectra of all newly synthesized compounds (PDF)
AUTHOR INFORMATION
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Corresponding Author
* zouhb@zju.edu.cn
ORCID
Hong-Bin Zou: 0000-0001-6784-2737
Author Contributions
⊥J.-Q.Z., H.-J.X., and H.-J.Z. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the National Natural Science Foundation of China (No. 21472170),
the Zhejiang Provincial Fund for Distinguished Young Scholars (LR15B020001). We thank
Prof. Yongping Yu and Prof. Sunliang Cui (Zhejiang University, China) for useful discussions,
Dr. Supakarn Chamni (Chulalongkorn University, Thailand) for thoughtful suggestion toward
manuscript preparation.
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