Rhodium-Catalyzed Relay Carbenoid Functionalization of Aromatic C-H Bonds toward Fused Heteroarenes

Article abstract of DOI:10.1021/acs.orglett.8b00119

A rhodium-catalyzed annulation between ethyl benzimidates and α- aroyl sulfur ylides was developed, affording a series of pyrano[4,3,2-ij]isoquinoline derivatives in moderate to good yields with good functional group compatibility. The procedure featured

Full text of DOI:10.1021/acs.orglett.8b00119

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Rhodium-Catalyzed Relay Carbenoid Functionalization of Aromatic
C−H Bonds toward Fused Heteroarenes
Xiaopeng Wu, Hao Xiong, Song Sun, and Jiang Cheng*
School of Petrochemical Engineering, and Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, Changzhou
University, Changzhou 213164, P. R. China
S
* Supporting Information
ABSTRACT: A rhodium-catalyzed annulation between ethyl
benzimidates and α- aroyl sulfur ylides was developed,
affording a series of pyrano[4,3,2-ij]isoquinoline derivatives
in moderate to good yields with good functional group
compatibility. The procedure featured dual ortho-C−H
functionalization and dual cyclization in one pot. The
optoelectronic properties of those fused heteroarenes were tested by UV/vis and fluorescence spectrometers.
he directing group assisted functionalization of arene C−
achieve this, the selection of a proper substrate possessing dual
coordination sites to ensure the secondary directing group
assisted C−H functionalization is the key factor.
T
H bonds represents one of the hottest topics in organic
synthetic chemistry.1−3 However, further removal of those
directing groups was required in most cases. To circumvent
this, procedures employing either traceless4 or transient
directing groups5 were developed (Scheme 1, eq 1).
Ethyl benzimidates are potential substrates since both N and
O atoms may coordinate with the transition-metal catalyst in
directing-group-assisted functionalization of arene C−H
bonds.8 Meanwhile, sulfur ylides9 function as surrogates of
diazo compounds in metal-catalyzed reactions due to the
relatively higher security and stability of sulfur ylides.10,11 In
view of the well-developed Rh-catalyzed C−C and C−X bonds
Scheme 1. Constructed Frameworks after Ortho-C−H
Functionalization
formation reactions via C−H activation,12,13 Aιs
̈ sa and co-
workers pioneered a rhodium-catalyzed coupling of aromatic
C(sp2)−H with α-aroyl sulfur ylides.14 Afterward, Li applied
this strategy in the synthesis of a variety of carbocycles and N-
heterocycles.15
We initially chose ethyl benzimidate (1a) and α-benzoyl
sulfur ylide (2a) as model substrates to explore the dual ortho-
C−H fuctionalization/cyclization reaction. In the presence of a
catalytic amount of [Cp*RhCl2]2/AgSbF6 (5 mol %), and
NaOAc (2.0 equiv) as the base, the reaction took place at 80 °C
in DCM to generate the desired pyrano[4,3,2-ij]isoquinoline
(3aa), albeit in a low yield (13%, Table 1, entry 5). The
reaction did not run in many solvents, such as THF, DMF,
MeCN, and EtOH, even at 120 °C (Table 1, entries 1−4). To
our delight, the yield increased to 55% in DCE (Table 1, entry
6). The sliver salts improved the reaction efficiency, and
Cp*Rh(OAc)2 was superior to [Cp*IrCl2]2 and CoCp*(CO)I2
(Table 1, entry 7). The fused aromatic compound 3aa was
isolated in 81% yield in the presence of 0.2 equiv of Cu(OAc)2
(Table 1, entry 8). Among the bases tested, sodium acetate was
the best one (Table 1, entries 8−12). The yield decreased in
the absence of any base (53%, Table 1, entry 13). The
practicability of this method was investigated in a 1 mmol scale,
and 3aa was isolated in an acceptable 66% yield.
Alternatively, the in situ conversion of directing group into
the skeleton of the final product is a better idea that allows
rapid access to the target molecule with chemical complexity
and diversity. As a result, the sequential directing group assisted
C−H functionalization and annulation between the introduced
functional group and the directing group provides a facile
pathway toward benzo products (Scheme 1, eq 2).6
Accordingly, fused aromatic frameworks could be constructed
facilely through sequential dual C−H functionalization7 and
annulation with the directing group (Scheme 1, eq 3).7 To
Received: January 17, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00119
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Selected Results for Screening the Optimized
a
Reaction Conditions
b
entry
base
additive (equiv) solvent
yield (%)
1
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
KOAc
THF
DMF
MeCN
EtOH
DCM
DCE
nr
nr
2
3
trace
trace
4
i
5
13
6
55
e
c
d
f
g
7
DCE
18 , 34 , 77 , trace , trace
h
i
8
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
Cu(OAc)2 (0.2)
DCE
DCE
DCE
DCE
DCE
DCE
DCE
81, 49 , 32
9
63
19
10
11
12
13
14
KHCO3
K2HPO4 Cu(OAc)2 (0.2)
21
K2CO3
Cu(OAc)2 (0.2)
Cu(OAc)2 (1.0)
Cu(OAc)2 (1.0)
<10
53
c
20
a
Reaction conditions: ethyl benzimidate 1a (0.1 mmol), dimethylox-
osulfonium benzoylmethylide 2a (0.22 mmol), catalyst: [Cp*RhCl2]2
(5 mol %), Cp* = 1,2,3,4,5-pentamethylcyclopenta-1,3-diene, AgSbF6
(20 mol %), base (0.2 mmol), additive, solvent (2.0 mL), under N2, at
120 °C for 12 h, in a sealed Schlenk tube, unless otherwise noted.
b
c
d
Isolated yield. Without AgSbF6. [Cp*Rh(MeCN)3)](SbF6)2 (5
e
f
mol %), without Ag salt. Cp*Rh(OAc)2 (5 mol %). [Cp*IrCl2]2 (5
mol %). CoCp*(CO)I2. 100 °C. 80 °C.
g
h
i
Figure 1. Scope of substituted ethyl benzimides. (a) Reaction
conditions: substituted ethyl benzimidate 1 (0.1 mmol), dimethylox-
osulfonium benzoylmethylide 2a (0.22 mmol), catalyst: [Cp*RhCl2]2
(5 mol %), AgSbF6 (20 mol %), Cu(OAc)2 (20 mol %), NaOAc (0.2
mmol), DCE (2.0 mL), under N2, at 120 °C for 12 h, in a sealed
Schlenk tube, unless otherwise noted. (b) Isolated yield. (c) It is
difficult to isolate the corresponding cross-coupling mixture (3ba and
With the optimized reaction conditions in hand, the scope
and limitation of ethyl benzimidate derivatives were studied as
shown in Figure 1. Generally, the reaction efficiency was not
sensitive to the electron nature of the substituents on the aryl as
substrates bearing both electron-donating (3ba−ga and 3ka,
49−83%) and electron-withdrawing groups (3ha−ja, 65−90%)
all worked well to deliver the desired products in good to
excellent yields. Specially, substrates with a meta substituent in
phenyl resulted in a mixture of two regioselective isomers
(3ba/3ca, 49%, 1.3/1), and ethyl 2-methylbenzimidate failed to
work. Notably, halo groups survived well under the procedure,
which provided handles for potential further functionalizations.
In addition, the structure of 3ha was further confirmed by X-ray
crystallography (for details, see the Supporting Information).
Next, the scope of sulfur ylides was investigated as shown in
Figure 2. Generally, α- aroyl sulfur ylides bearing both electron-
donating (3ab−af, 66−87%) or withdrawing groups (3ag−ai,
79−86%) all worked well to deliver the desired products in
moderate to good yields. In addition, this procedure was
applicable to sulfur ylides with 2-thiophene-yl (2j) and
cyclohexyl (2k) attached in the carbonyl.
The reactivities of different alkyl benzimidates were also
tested as shown in Scheme 2. As expected, the alkyl groups
have little effect on the yield of 3aa except the methyl substrate
(1l).
The UV/vis and fluorescence emission properties of 3aa, 3aj,
3ae, 3ai, 3ia, and 3ga were studied as shown in Figure 3 and
Table 2. All products showed similar optoelectronic properties:
one absorption maxima around 340 nm and one fluorescence
maximum around 465 nm. The optical properties were
significantly changed by substituents. The fluorescence maxima
are red-shifted (Figure 3) when the alkyl (3aa, 464 nm; 3ae,
1
3ca); their ratio data was determined by H NMR spectrum.
Figure 2. Substrate scope of α-aroyl sulfur ylides. (a) Reaction
conditions: ethyl benzimidate 1a (0.1 mmol), α-aroyl sulfur ylide 2
(0.22 mmol), catalyst: [Cp*RhCl2]2 (5 mol %), AgSbF6 (20 mol %),
Cu(OAc)2 (20 mol %), NaOAc (0.2 mmol), DCE (2.0 mL), under N2,
at 120 °C for 12 h, in a sealed Schlenk tube, unless otherwise noted.
(b) Isolated yield.
468 nm) or halogen (3ai, 462 nm) group is replaced by an aryl
group (3ga, 471 nm). To our delight, the Stokes shift of 3aj is
as large as 141 nm (Table 2).
In the control experiment (Scheme 3), 1-ethoxy-3-phenyl-
isoquinoline (4) was detected at 40 °C, indicating the high
reactivity of the imide group in ortho-C−H activation and
cyclization.15c Intriguingly, 1-ethoxyisoquinoline (5) failed to
deliver product 6 under the standard procedure. This result
B
DOI: 10.1021/acs.orglett.8b00119
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Reaction of Alkyl Benzimidate and Sulfur Ylide
Scheme 4. Proposed Mechanism
Figure 3. UV−vis (left) and fluorescence (right) spectra.
a
Table 2. Absorption and Emission Data
3aa
3aj
3ae
3ai
3ia
3ga
λabs (nm)
341
344
344
342
343
353
ε342 nm
7726
8048
7817
6870
7959
7744
(L mol−1cm−1
)
λem (nm)
Stokes shift (cm−1
464
485
468
462
465
471
)
7773
8451
7702
7595
7649
7097
a
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00119.
Solvent of all samples was DCM.
■
S
Scheme 3. Control Experiments
Experimental procedures along with copies of spectra
(PDF)
Accession Codes
CCDC 1823329 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
indicated that before the cyclization of imide it was the nitrogen
atom rather than the oxygen atom which chelated with rhodium
to facilitate the secondary cleavage of C−H bond.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jiangcheng@cczu.edu.cn.
ORCID
On the basis of the control experiments and previous
reports,7,14,15 a catalytic cycle for the dual ortho-C−H
functionalization and cyclization is proposed (Scheme 4).
Initially, de-dimerization of [Cp*RhCl2]2 and C−H activation
of ethyl benzimide produce a rhodacyclic intermediate A. Then
coordination of 2a with A leads to a Rh(III) intermediate B,
which transforms to a carbene species C by α-elimination of
DMSO. Afterward, the migratory insertion and protonolysis
afford the acylmethylated intermediate E. Finally, after the
secondary catalytic cycle, E furnishes 3aa by release of Rh(III)
catalyst and a dehydrating process.
Song Sun: 0000-0002-9974-6456
Jiang Cheng: 0000-0003-2580-1616
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(nos. 21572025, and 21602019), “Innovation & Entrepreneur-
ship Talents” Introduction Plan of Jiangsu Province, Natural
Science Foundation of Jiangsu Province (BK20171193), the
Key University Science Research Project of Jiangsu Province
(15KJA150001), Jiangsu Key Laboratory of Advanced Catalytic
Materials & Technology (BM2012110), and Advanced
Catalysis and Green Manufacturing Collaborative Innovation
In conclusion, we have developed a rhodium-catalyzed dual
ortho- C−H functionalization and annulation between ethyl
benzimidates and α-aroyl sulfur ylides toward a series of
functionalized isoquinazolones in good to moderate yields. The
compounds are fluorescent with emission maxima around 465
nm and Stokes shifts up to 141 nm.
C
DOI: 10.1021/acs.orglett.8b00119
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(10) Lu, L.-Q.; Li, T.-R.; Wang, Q.; Xiao, W.-J. Chem. Soc. Rev. 2017,
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Center for financial supports. S.S. thanks the Young Natural
Science Foundation of Jiangsu Province (BK20150263) for
financial support.
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DOI: 10.1021/acs.orglett.8b00119
Org. Lett. XXXX, XXX, XXX−XXX