Rhodium(III)-catalyzed chemodivergent annulations between: N-methoxybenzamides and sulfoxonium ylides via C-H activation

Article abstract of DOI:10.1039/c7cc07753j

Chemodivergent and redox-neutral annulations between N-methoxybenzamides and sulfoxonium ylides have been realized via Rh(iii)-catalyzed C-H activation. The sulfoxonium ylide acts as a carbene precursor, and coupling occurs under acid-controlled condition

Full text of DOI:10.1039/c7cc07753j

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Rhodium(III)-catalyzed chemodivergent
annulations between N-methoxybenzamides and
Cite this:DOI: 10.1039/c7cc07753j
sulfoxonium ylides via C–H activation†
Received 6th October 2017,
Accepted 15th December 2017
Youwei Xu,ab Guangfan Zheng,a Xifa Yangab and Xingwei Li
*
a
DOI: 10.1039/c7cc07753j
rsc.li/chemcomm
Chemodivergent and redox-neutral annulations between N-methoxy-
benzamides and sulfoxonium ylides have been realized via Rh(III)-
catalyzed C–H activation. The sulfoxonium ylide acts as a carbene
precursor, and coupling occurs under acid-controlled conditions,
where Zn(OTf)2 and PivOH promote chemodivergent cyclizations.
In the past decade, transition metal-catalyzed C–H activation of
arenes has dramatically improved the efficiency and step-economy
of organic syntheses.1 Among the transition metals, Cp*Rh(III)
catalysts have significantly contributed to the arsenal of new hetero-
cycle synthesis.2 Isoquinolones and isocoumarins are two important
classes of heterocycles that are ubiquitously encountered in
pharmaceuticals and organics.3,4 Consequently, the development
of efficient approaches to access these heterocycles is of great
interest.5,6 Miura and coworkers pioneered in Rh(III)-catalyzed
oxidative coupling of carboxylic acids and internal alkynes for
isocoumarin synthesis.7 We and others achieved isoquinolone via
coupling of benzamides with alkynes.8,9 To develop intrinsically
unique coupling partners, Glorius and coworkers accomplished the
Scheme 1 Synthesis of isoquinolones and isocoumarins via annulative
C–H activation.
C–H activation of amide for the synthesis of isoquinolones using using sulfoxonium ylides as a carbene source (Scheme 1c).13a,b
a-MsO/TsO/Cl ketones as oxidized alkyne equivalents (Scheme 1a),10 However, only one example of cyclization has been reported13b and
where the amide functions as a nucleophilic directing group (DG). this reagent has been applied in the synthesis of pyrroles via a
Alternatively, the synthesis of isocoumarins has been accomplished different mechanism.13c Given the ambiphilicity of the methylene
via an alkylation–nucleophilic cyclization sequence (Scheme 1b), ketone moiety in the product, we proposed chemodivergent annula-
where the carbonyl of benzamide is attacked by an OH group tions with N-methoxybenzamides, which calls for steerable activa-
(Scheme 1b).11
tion of methylene carbonyl and the amide carbonyl groups toward
As versatile DGs, N-methoxy amides have found wide utility cyclization possibly by Lewis or Brønsted acids.14 However, chal-
in Cp*Rh(III)-catalyzed C–H activation and heterocycle synthesis.12 lenges remain. First, the homo-coupling of a sulfoxonium ylide
Although the N-methoxy amide group contains both nucleophilic may occur because it may act as both an arene and a coupling
and electrophilic sites, it is challenging to achieve chemodivergent partner.15 Second, it is challenging to distinguish between these
cyclizations by taking advantage of both sites starting from exactly two functional groups for selective activation. Third, the leaving
the same substrates. We and others recently reported the Cp*Rh(III)- groups may pose an inhibitory effect. We now report acid-
catalyzed C–H activation and versatile acylmethylation of arenes controlled divergent annulations between sulfoxonium ylides
and N-methoxybenzamide for the synthesis of isoquinolones
and isocoumarins (Scheme 1d).
a State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics,
We commenced our investigation with the screening of
reaction parameters for the coupling of N-methoxybenzamide
(1a) and sulfoxonium ylide (2a). To our delight, the desired
Chinese Academy of Sciences, Dalian 116023, P. R. China. E-mail: xwli@dicp.ac.cn
b University of Chinese Academy of Sciences, Beijing 100049, China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c7cc07753j
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Table 1 Optimization of reaction conditionsa
Yieldb (%)
Entry
Additive (equiv.)
Solvent
3a
4a
1d
CsOAc (0.3)/HOPiv (2)
CsOAc (0.3)
CsOAc (0.3)
CsOAc (0.3)
AgOAc (0.2)
Zn(OTf)2 (0.5)
HOPiv (2)
CsOAc (0.3)
Zn(OTf)2 (0.5)
Zn(OAc)2 (0.5)
Zn(NTf)2 (0.5)
AgOTf (0.5)
DCE
DCE
tBuOH
HFIP
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
495 (90)c
22
15
o5
51
40
2d
3d
4d
o5
20
5d
44
o5
6d
10
38
52
63
7e
27
34
8e
9e
o5
495 (95)c
45
10e
11e
12e
13e
14f
41
Scheme 2 Scope of isocoumarin synthesis. a See the ESI† for detailed
conditions A. b Isolated yield.
o5
22
28
50
19
18
76
AgOAc (0.5)
Zn(OTf)2 (0.5)
19
We then investigated the generality of the synthesis of
isoquinolones (conditions B, Scheme 3). A variety of isoquinolones
were synthesized in moderate to excellent yields. Electron-donating
and -withdrawing groups at different positions of the N-methoxy-
benzamide had a marginal influence on the coupling with a
sulfoxonium ylide, and the desired isoquinolones were isolated in
consistently high yields (4a–4i). In addition, N-ethoxybenzamides (4j)
also coupled to afford the desired product in a good yield. The
arenes can also be extended to a thiophene amide (4k) in a moderate
yield. Sulfoxonium ylides bearing a methoxy (4l), alkyl (4m, 4q, 4r),
halogen (4n and 4o), and CF3 (4p) group at different positions
all coupled smoothly with N-methoxybenzamide, and the
corresponding products were isolated in 65–88% yield. Besides,
an alkyl-substituted sulfoxonium ylide also showed great reac-
tivity (4s–4v). To our surprise, no isocoumarin was generated
when alkyl-substituted sulfoxonium ylides were employed under
conditions A. Instead, isoquinolones were isolated in good yields
a
Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), catalyst, and additives
were stirred in the solvent (2 mL) at 100 1C for 16 h. b NMR yield of the crude
product using 1,3,5-trimethoxybenzene as an internal standard. Iso-
lated yield on a 0.2 mmol scale of 1a. [RhCp*Cl2]2 (4 mol%) was used
c
d
e
as a catalyst. [RhCp*(MeCN)3](SbF6)2 (5 mol%) was used as a catalyst.
f
RhCp*(OAc)2 (8 mol%) was used as a catalyst.
isocoumarin (3a) was isolated in 90% yield in the presence of
[RhCp*Cl2]2, CsOAc, and PivOH (Table 1, entry 1). The PivOH
additive proved necessary to ensure high selectivity for isocoumarin.
In the absence of PivOH, both isocoumarin 3a and isoquinolone 4a
were produced (entry 2). Thus, PivOH serves to activate the amide
carbonyl group toward oxygen attack. Further screening of the
solvent revealed that alcoholic solvents such as tBuOH and HFIP
both gave inferior results (entries 3 and 4). Significantly, changing
the additive to Lewis acid Zn(OTf)2 increased the NMR yield of 4a
(entry 6), and the isolated yield of 4a was increased to 95% when a
cationic catalyst [RhCp*(MeCN)3](SbF6)2 was used (entry 9). After
extensive screening of the Lewis acid, Zn(OTf)2 was identified as the
optimal one (entries 10–13). However, using RhCp*(OAc)2 (8 mol%)
as a catalyst gave a diminished yield of 4a.13b Thus, the conditions in
entries 1 (conditions A) and 9 (conditions B) were adopted for
subsequent studies.
With the optimal conditions in hand, we first investigated
the scope of isocoumarin synthesis (conditions A, Scheme 2).
Introduction of electron-donating and -withdrawing groups into the
para position of the benzene ring was fully tolerated (3a–3g). The
reaction was also extended to o-substituted N-methoxybenzamides
(3h, 3i), indicating tolerance of steric hindrance. In addition, a
meta-Me substituted benzamide also reacted smoothly, and the
coupling occurred at the less hindered ortho site (3j). Besides, a
thiophene ring also coupled to afforded product 3k in a moderate
yield. The functional group compatibility with respect to the
sulfoxonium ylide was also briefly explored, and introduction of
electron-donating and -withdrawing groups into the benzene ring
was all well tolerated (3l–3p, 85–90%). The sulfoxonium ylide was
not limited to aryl substitution, and alkyl substituted ylides (3q–3s)
also coupled in high efficiency.
Scheme 3 Scope of isoquinolone synthesis. a See the ESI† for detailed
conditions B. b Isolated yield. c Under conditions A. d Determined by GC-MS
analysis.
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(4s–4v). In contrast, the sulfoxonium ylide with a sterically
hindered group failed to undergo any reaction under conditions
B (4w).
To demonstrate the synthetic utility of the catalytic systems,
larger-scale reactions have been performed (Scheme 4). The
synthesis of both isocoumarin 3a and isoquinolone 4a at a
2 mmol-scale has been realized (Scheme 4a and b). The synthetic
utility of the coupled products has been demonstrated in several
derivatization reactions. Treatment of 3a with a phenyl Grignard
reagent afforded the corresponding benzophenone 5 in 72%
yield (Scheme 4c).5b Moreover, N-methoxy isoquinolone 4a was
readily reduced to the corresponding NH isoquinolone (6) in
91% yield (Scheme 4d).16
A series of experiments have been conducted to probe the
reaction mechanism. Coupling of 1a with 2q under conditions
A in CD3OD provided 3q-dn together with the recovery of 1a-dn.
These data suggest that the C–H activation is reversible. The
observed deuterium incorporation at the olefinic position of
3q-dn may suggest enolization of the acylmethylated intermediate
due to enhanced acidity of the methylene protons. Coupling of 1a
with 2s under standard conditions B in CD3OD led to analogous
results in terms of H/D exchange. In both coupling systems,
coindicant values of KIE = 1.1 were obtained from parallel experi-
ments using 1a and 1a-d5 in the coupling with 2q or 2s under
standard conditions A or B, respectively. These insignificant values
suggest that C–H activation is not involved in the turnover-limiting
step. When the reaction of 1a and 2a was conducted under
conditions A at 40 1C, intermediate 7 was isolated in 30% yield
along with 3a.10 Notably, 7 was fully and selectively converted to 3a
or 4a in the presence of CsOAc/PivOH or Zn(OTf)2, respectively.
This also indicated that the coupling systems likely proceeded via
initial acylmethylation (Scheme 5).
Scheme 5 Mechanistic studies.
Scheme 6 Proposed catalytic cycle.
On the basis of literature precedents and our preliminary
mechanistic results, a plausible mechanism of coupling of 1a
with 2a is proposed in Scheme 6. Cyclometalation of N-methoxy- Rh–N and Rh–C bonds releases the acylmethylated intermediate
benzamide gives a rhodacyclic intermediate I. Coordination of V together with the regeneration of the active catalyst. The
sulfoxonium ylide generates a Rh(III) alkyl species II, and the ketone carbonyl is then nucleophilically attacked by the NH
subsequent a-elimination of DMSO from II affords a reactive group to reversibly give intermediate 7.
rhodium a-oxo carbene species III, which is then proposed
Following the formation of V and 7, two pathways may be
to undergo migratory insertion of the Rh–C bond to give a possible. In path a, relatively soft acid PivOH or the neutral
six-membered rhodacyclic intermediate IV. Protonolysis of the Rh(III) catalyst activates the amide group toward nucleophilic
attack by the enol oxygen (VI), leading to lactonization with the
elimination of NH2OMe in the protonated form. In fact, a
related Cp*Rh(III)–HOAc catalytic system has been previously
reported by us to promote C–H activation–lactonization.14a It is
possible that the PivOH also serves to stabilize the NH2OMe
coproduct through protonation. In contrast, a hard Lewis acid
Zn(OTf)2 additive together with the more Lewis acidic cationic
Rh(III) catalyst selectively activates the ketone carbonyl so that
the nucleophilic attack of the amide nitrogen affords the
lactamization product upon dehydration.11
In summary, we have developed rhodium-catalyzed and acid-
controlled chemodivergent annulations between N-methoxybenz-
amides and sulfoxonium ylides, which provide two classes of
heterocycles from the same starting materials. This annulation
Scheme 4 Larger-scale synthesis and synthetic applications.
system proceeded in high efficiency and regio- and chemoselectivity.
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Other novel transformations of suloxonium ylides in the context of
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We thank the National Natural Science Foundation of China
(21472186 and 21525208) for financial support.
Conflicts of interest
There are no conflicts to declare.
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