Synthesis of CF3-containing isoindolinone derivatives through rhodium-catalyzed oxidative coupling of benzamides with 2-trifluoromethylacrylate

Article abstract of DOI:10.1246/CL.200609

The oxidative coupling of benzamides with methyl 2- trifluoromethylacrylate proceeds smoothly under rhodium(III) catalysis to produce trifluoromethyl-substituted isoindolinone derivatives. The catalyst system [CpERhCl2]2/AgSbF6 is effective for the oxidat

Full text of DOI:10.1246/CL.200609

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Synthesis of CF3-Containing Isoindolinone Derivatives through Rhodium-Catalyzed
Oxidative Coupling of Benzamides with 2-Trifluoromethylacrylate
Risa Yoshimoto, Hideaki Morisaka, Yoshinosuke Usuki, Yu Shibata,
Ken Tanaka, and Tetsuya Satoh*
Advance Publication on the web September 19, 2020
doi:10.1246/cl.200609
© 2020 The Chemical Society of Japan
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1
Synthesis of CF3-Containing Isoindolinone Derivatives through Rhodium-Catalyzed
Oxidative Coupling of Benzamides with 2-Trifluoromethylacrylate
Risa Yoshimoto,1 Hideaki Morisaka,1 Yoshinosuke Usuki,1 Yu Shibata,2 Ken Tanaka,2 and Tetsuya Satoh*1
1Department of Chemistry, Graduate School of Science, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585
2Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology, Ookayama, Meguro-ku,
Tokyo 152-8550
(Received <Month> <Date>, <Year>; CL-<No>; E-mail: <insert corresponding e-mail address>)
The oxidative coupling of benzamides with methyl 2-
trifluoromethylacrylate proceeds smoothly under rhodium(III)
catalysis to produce trifluoromethyl-substituted isoindolinone
derivatives. The catalyst system [CpERhCl2]2/AgSbF6 is
pentamethylcyclopentadienyl, 0.02 mmol), AgSbF6 (0.2
mmol), and AcOH (1 mmol) under argon in tBuOH (3 mL) at
60 C for 24 h. As a result, the desired isoindolinone, methyl
o
3,3,3-trifluoro-2-(2-methyl-3-oxoisoindolin-1-yl)propanoate
(3a), was formed as an oxidative coupling product in a low
yield (7%, entry 1 in Table 1). Instead, a redox-neutral
coupling product, methyl 3,3,3-trifluoro-2-(2-
(methylcarbamoyl)benzyl)propanoate (4a), was obtained
predominantly (60%) as in our previous report.8a Neither 3a
nor 4a was formed when [RhCl(cod)]2 was employed in place
of [Cp*RhCl2]2 (entry 2). Interestingly, the use of [CpERhCl2]2
effective
for
the
oxidative
coupling,
while
[Cp*RhCl2]2/AgSbF6 leads to their redox-neutral coupling
predominantly. The oxidative coupling reactions with related
acrylates have also been examined. Keywords: rhodium
catalyst; oxidative coupling; isoindolinone; organofluorine
compound
Nitrogen-containing fused heterocyclic frameworks can
be seen in naturally occurring and synthetic bioactive
molecules.1 Among them, variously substituted isoindolinone
derivatives have been recognized as nonbenzodiazepine
sedative and anti-anxiety agents.2 Especially, isoindolinones
possessing a trifluoromethyl group, which is known to affect
their lipophilicity as well as metabolic robustness, have
attracted much attention and their synthetic methods have
been developed.3 Recently, Wang’s group reported a copper-
catalyzed intramolecular aminotrifluoromethylation of o-
vinylbenzamides using Togni’s reagent for preparing CF3-
containing isoindolinones.3b Zhang’s group also disclosed a
similar cyclization using CF3SO2Na as a CF3 source.3a
However, less accessible disubstituted aromatic substrates
were usually required to be employed in these procedures to
impose synthetic limitation.
( C p E
= 1 , 3 - b i s ( e t h o x y c a r b o n y l ) - 2 , 4 , 5 -
trimethylcyclopentadienyl), which was developed by
Tanaka’s group,9 as a catalyst altered the product distribution
dramatically. Thus, 3a was produced in 54% yield,10 no 4a
being detected (entry 3). In the case without AcOH, the yield
of 3a decreased (entry 4). As expected, the addition of
Ag2CO3 (1 mmol) as an oxidant significantly enhanced the 3a
yield to 81% (entry 5). Increasing the reaction temperature to
o
80 C somewhat decreased the reaction efficiency (entry 6).
To our delight, 3a was obtained in a good yield (97%), when
o
the reaction temperature was reduced to 40 C (entry 7). The
NMR spectra of 3a indicated that it consists of two
diastereoisomers (see the Supporting Information). It was
confirmed that the addition of AcOH is essential for
Table 1. Reaction of N-Methylbenzamide (1a) with
Methyl 2-Trifluoromethylacrylate (2)a
Meanwhile,
transition-metal-catalyzed
C-H
functionalization has been developed and widely utilized in
O
O
organic synthesis.4 The direct coupling of aromatic substrates
O
Rh-cat.
Me
N
H
CF3
CO2Me
AgSbF6
Me
N
Me
bearing
a heteroatom-containing directing group with
N
+
+
H
unsaturated compounds is one of the most powerful tools for
constructing fused heterocyclic compounds from readily
available monosubstituted aromatic substrates.5 During our
continuous studies on rhodium(III)-catalyzed direct annulative
coupling reactions,6 we found that simple benzamides7
undergo direct coupling with methyl 2-trifluoromethylacrylate
under rhodium(III) catalysis to produce CF3-containing
isoindolinones (Scheme 1).8 The new findings are described
herein.
additive
tBuOH
H
CF3
MeO2C
3a
MeO2C
CF3
1a
2
4a
yield (%)b
entry
Rh-cat.
additive(s)
temp. (oC)
3a
4a
[Cp*RhCl2]2
AcOH
AcOH
60
60
60
60
60
80
40
40
40
1
2
3
4
5
6
7
8
9
7
0
60
0
[RhCl(cod)]2
[CpERhCl2]2
[CpERhCl2]2
[CpERhCl2]2
[CpERhCl2]2
[CpERhCl2]2
[CpERhCl2]2
[Cp*RhCl2]2
AcOH
54
0
-
23
0
AcOH / Ag2CO3
AcOH / Ag2CO3
AcOH / Ag2CO3
Ag2CO3
81
0
60
97 (97)c
0
0
26
0
AcOH / Ag2CO3
8
40
a Reaction conditions: 1a (0.5 mmol), 2 (0.5 mmol), Rh-cat. (0.01 mmol), AgSbF6
(0.2 mmol), additive (1 mmol) in tBuOH (3 mL) under Ar for 24 h. b GC yield based
on the amount of 1a used. Value in parentheses indicates yield after purification. c
3a was obtained as a mixture of diastereoisomers (64 : 36).
Scheme 1.
In an initial attempt, N-methylbenzamide (1a) (0.5
mmol) was treated with methyl 2-trifluoromethylacrylate (2)
(0.5 mmol) in the presence of [Cp*RhCl2]2 (Cp* = 1,2,3,4,5-

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2
conducting the reaction efficiently. Without it, the yield of 3a
considerably decreased (entry 8). Even in the presence of
AcOH and Ag2CO3, 4a was obtained as a major product again
in the case using [Cp*RhCl2]2 as a catalyst (entry 9).
dihydro-3H-benzo[4,5]thieno[2,3-c]pyrrol-3-one
selectively.
(3k)
In addition to secondary and primary amides, a tertiary
benzamide, N,N-dimethylbenzamide (5), also underwent the
oxidative coupling with 2. As expected, an acyclic ortho-
alkenylated product 6 was formed as a mixture of geometric
isomers, albeit with a low yield (Scheme 2).
Under the optimized conditions (entry 7 in Table 1), we
next examined the reactions using various benzamides 1 with
2 (Table 2). Both N-n- and N-i-propylbenzamides underwent
the reaction smoothly to produce 3b and 3c, respectively, as
diastereoisomer mixtures. In addition to these secondary
amides, a primary amide, N-unsubstituted 4-t-butylbenzamide
could also be employed for the present reaction to give N-H
isoindolinone 3d. The reactions of relatively electron-rich N-
n-propylbenzamides possessing methyl, methoxy, and phenyl
groups proceeded efficiently to afford 3e-g in 77-87% yields.
In contrast, the reactions of 4-bromo- and 4-
O
[CpERhCl2]2 (0.01 mmol)
O
H
Me
N
CF3
CO2Me
AgSbF6 (0.2 mmol)
Me
N
+
Me
Ag2CO3 (1 mmol)
AcOH (1 mmol)
tBuOH (3 mL)
Me
MeO2C
CF3
80 oC, Ar, 24 h
5 (0.5 mmol)
2 (0.5 mmol)
6 (29%, E/Z = 84:16)
Scheme 2.
o
methoxycarbonylbenzamides were sluggish even at 80 C to
give 3h and 3i in moderate yields. 2-Methyl substituted N-n-
propylbenzamide coupled with 2 effectively to produce 3j.
Besides these benzamides, N-n-propylbenzo[b]thiophene-2-
carboxamide also underwent the reaction at 60 oC to give 1,2-
A plausible mechanism for the reaction of benzamides 1
and 5 with methyl 2-trifluoromethylacrylate (2) is illustrated
in Scheme 3. As proposed in our previous paper for the redox-
neutral coupling of 1 with 2-trifluoromethylacrylic acid,8a
a
seven-membered intermediate C seems to be formed through
coordination of the amide directing group to a cationic
CpERh+ species,11 cyclorhodation at the ortho-position of A,
and the insertion of 2 into the C-Rh bond of B. Subsequently,
b-hydrogen elimination to liberate an ortho-alkenylated
benzamide 3’ or 6 and reductive elimination may take place to
form a CpERh(I) species, which is then oxidized by a silver
salt to regenerate an active CpERh+ species. Finally, 3’ may
undergo intramolecular nucleophilic addition to form
isoindolinone 3.
Table 2. Reaction of Benzamides 1 with Methyl 2-
Trifluoromethylacrylate (2)a
O
O
Ar
N
R
[CpERhCl2]2 / AgSbF6
CF3
CO2Me
R
N
+
Ar
H
Ag2CO3 / AcOH
tBuOH
CF3
H
MeO2C
1
2
3
product yield (%)b
O
O
O
O
N
nPr
CF3
N
iPr
N
H
tBu
NRR'
NRR'
O
NR
CF3
CF3
CF3
MeO2C
MeO2C
MeO2C
1 or 5 (R, R' = alkyl or H)
O
CpERh+X
Ag
Rh+ CpE
3b 91%, dr = 70:30
3c 83%, dr = 72:28
3d 40%, dr = 56:44
X
A
MeO2C
O
O
O
3
AgX
CpERh
N
nPr
CF3
N
nPr
CF3
N
nPr
R' = H
–HX
β-H elimination/
reductive elimination
Me
MeO
Ph
–H+
O
CF3
CO2Me
CF3
MeO2C
MeO2C
3f 77%, dr = 70:30
MeO2C
R'RN
NRR'
NRR'
3e 80%, dr = 68:32
O
3g 87%, dr = 83:17
2
Rh+ CpE
CO2Me
O
Rh+
O
O
MeO2C
CF3
CpE
CF3
3’ or 6
nPr
N
nPr
N
C
B
Br
MeO2C
CF3
CF3
Scheme 3.
MeO2C
MeO2C
3h 37%,c dr = 63:37
3i 55%,c dr = 65:35
It was found that a strongly electron-withdrawing CF3
group on the alkene moiety of 3’ is essential for inducing the
intramolecular nucleophilic addition step. Thus, treatment of
1a with methyl 2-fluoroacrylate (7) in place of 2 under
standard conditions gave an acyclic ortho-alkenylated product
8 in 55% yield (Scheme 4a). No isoindolinone derivative was
detected at all. In addition, the reaction of 1a with methyl
methacrylate (9) was sluggish to form only a small amount of
ortho-alkenylbenzamide 10 as a geometric mixture (Scheme
4b).
Me
O
O
S
nPr
N
nPr
N
CF3
CF3
MeO2C
MeO2C
3k 48%,d dr = 59:41
3j 69%, dr = 68:32
a Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), [CpERhCl2]2 (0.01 mmol),
AgSbF6 (0.2 mmol), Ag2CO3 (1 mmol), AcOH (1 mmol) in tBuOH (3 mL) under Ar
at 40 oC for 24 h, unless otherwise noted. b dr (diastereomer ratio) was
determined by 1H NMR. Isolated yield includes both diastereomers. c Reaction
was conducted at 80 oC. d Reaction was conducted at 60 oC.

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3
a)
K. M. Engle, J.-Q. Yu, Synthesis 2012, 44, 1778-1791. d) P.
Thansandote, M. Lautens, Chem. Eur. J. 2009, 15, 5874-5883.
For example: a) T. Okada, A. Sakai, T. Hinoue, T. Satoh, Y.
Hayashi, S. Kawauchi, K. Chandrababunaidu, M. Miura
J. Org. Chem. 2018, 83, 5639-5649. b) R. Morioka, K. Nobushige,
T. Satoh, K. Hirano, M. Miura, Org. Lett. 2015, 17, 3130-3133. c)
Y. Yokoyama, Y. Unoh, R. A. Bohmann, T. Satoh, K. Hirano, C.
Bolm, M. Miura, Chem. Lett. 2015, 44, 1104-1106. d) T. Iitsuka, K.
Hirano, T. Satoh, M. Miura, J. Org. Chem. 2015, 80, 2804-2814. e)
M. Fukui, Y. Hoshino, T. Satoh, M. Miura, K. Tanaka, Adv. Synth.
Catal. 2014, 356, 1638-1644. See also reviews: f) T. Satoh, M.
Miura, Chem. Eur. J. 2010, 16, 11212-11222. g) T. Satoh, M.
Miura, Synthesis, 2010, 3395-3409.
For Rh(III)-catalyzed oxidative coupling of benzamides with
alkenes, see: a) Y. Qiu, W.-J. Kong, J. Struwe, N. Sauermann, T.
Rogge, A. Scheremetjew, L. Ackermann, Angew. Chem., Int.
Ed. 2018, 57, 5828-5832. b) D. Wang, X.Yu, X. Xu, B. Ge, X.
Wang, Y. Zhang, Chem. Eur. J. 2016, 22, 8663-8668. c) S. Rakshit,
C. Grohmann, T. Besset, F. Glorius, J. Am. Chem. Soc. 2011, 133,
2350-2353. d) F. Patureau, T. Besset, F. Glorius, Angew. Chem.,
Int. Ed. 2011, 50, 1064-1067. e) F. Wang, G. Song, X. Li, Org. Lett.
2010, 12, 5430-5433.
O
[CpERhCl2]2 (0.01 mmol)
O
H
Me
N
F
AgSbF6 (0.2 mmol)
6
Me
H
N
+
H
CO2Me
Ag2CO3 (1 mmol)
AcOH (1 mmol)
tBuOH (3 mL)
F
CO2Me
40 oC, Ar, 24 h
1a (0.5 mmol)
7 (0.5 mmol)
8 (55%)
b)
O
[CpERhCl2]2 (0.01 mmol)
AgSbF6 (0.2 mmol)
O
H
Me
N
H
Me
Me
N
+
H
CO2Me
Ag2CO3 (1 mmol)
AcOH (1 mmol)
tBuOH (3 mL)
7
Me
CO2Me
40 oC, Ar, 24 h
1a (0.5 mmol)
9 (0.5 mmol)
10 (<10%)
Scheme 4.
In summary, we have demonstrated that isoindolinone
derivatives possessing trifluoromethyl group can be
a
constructed from readily available benzamides and methyl 2-
trifluoromethylacrylate. The oxidative coupling reaction of
these substrates proceeds efficiently under rhodium catalysis
through ortho C–H bond cleavage of benzamides. The choice
of ligand for the rhodium(III) catalyst has been found to be
important to promote the oxidative coupling. However, the
exact role of ligand is obscure at the present stage. Work is
underway for further understanding the effect of ligand.
This work was partly supported by JSPS KAKENHI
Grant Numbers 20H02745 and 18K19083 to T.S. and JSPS
KAKENHI Grant Number JP18H04627 to Y.U.
8
For non-annulative, redox-neutral coupling of benzamides with 2-
trifluoromethylacrylic acid, see: a) R. Yoshimoto, Y. Usuki, T.
Satoh, Chem. Asian J. 2020, 15, 802-806. For b-selective arylation
and alkenylation of 2-trifluoromethylacrylic acid, see: b) R.
Yoshimoto, Y. Usuki, T. Satoh, Chem. Lett. 2019, 48, 461-464.
Y. Shibata, K. Tanaka, Angew. Chem. Int. Ed. 2011, 50, 10917-
10921.
In this case, a higher amount of oxidative coupling product 3a was
formed than that of AgSbF6, which can act as an oxidant. Therefore,
it is possible that, at least in part, alkene 2 acted as a hydrogen
accepter in cooperation with AcOH. Previously, we proposed a
9
10
similar reoxidation process through oxidative addition of
a
carboxylic acid toward a low valent metal species, insertion of
unsaturated compound into a hydride-metal bond, and protonation:
K. Hirosawa, Y. Usuki, T. Satoh, Adv. Synth. Catal. 2019, 361,
5253-5257.
Supporting Information is available electronically on J-
STAGE.
11
Another pathway via a nitrogen coordination mode, especially in
cases using secondary amides 1 cannot be excluded: T. K. Hyster,
T. Rovis, J. Am. Chem. Soc. 2010, 132, 10565-10569.
References and Notes
1
R. D. Taylor, M. MacCoss, A. D. G. Lawson, J. Med. Chem. 2014,
57, 5845-5859.
2
a) N. Kanamitsu, T. Osaki, Y. Itsuji, M. Yoshimura, H. Tsujimoto,
M. Soga, Chem. Pharm. Bull. 2007, 55, 1682-1688. b) R. Brenk, E.
A. Meyer, K. Reuter, M. T. Stubbs, G. A. Garcia, F. Diederich, G.
Klebe, J. Mol. Biol. 2004, 338, 55-75. c) J. Wrobel, A. Dietrich, S.
A. Woolson, J. Millen, M. McCaleb, M. C. Harrison, T. C.
Hohman, J. Sredy, D. Sullivan, J. Med. Chem. 1992, 35, 4613-4627.
d) T. Wada, R. Nakajima, E. Kurihara, S. Narumi, Y. Masuoka, G.
Goto, Y. Saji, N. Fukuda, Japan. J. Pharmacol. 1989, 49, 337-349.
a) H.-Y. Zhang, W. Huo, C. Ge, J. Zhao, Y. Zhang, Synlett 2017,
28, 962-965. b) K. Shen, Q. Wang, Org. Chem. Front. 2016, 3,
222-226.
For selected reviews for C–H functionalization, see: a) C.
Sambiagio, D. David Schöbauer, R. Blieck, T. Dao-Huy, G.
Pototschnig, P. Schaaf, T. Wiesinger, M. F. Zia, J. Wencel-Delord,
T. Besset, B. U. W. Maes, M. Schnürch, Chem. Soc. Rev. 2018, 47,
6603-6743. b) M. Gulías, J. L. Mascareñas, Angew. Chem., Int. Ed.
2016, 55, 11000-11019. c) Z. Chen, B. Wang, J. Zhang, W. Yu, Z.
Liu, Y. Zhang, Org. Chem. Front. 2015, 2, 1107-1295. d) G. Song,
X. Li, Acc. Chem. Res. 2015, 48, 1007-1020. e) J. Ye, M. Lautens,
Nature Chem. 2015, 7, 863-870. f) M. Miura, T. Satoh, K. Hirano,
Bull. Chem. Soc. Jpn. 2014, 87, 751-764. g) S. De Sarkar, W. Liu,
S. I. Kozhushkov, L. Ackermann, Adv. Synth. Catal. 2014, 356,
1461-1479. h) J. Wencel-Delord, F. Glorius, Nat. Chem. 2013, 5,
369-375. i) D. A. Colby, A. S. Tsai, R. G. Bergman, J. A. Ellman,
Acc. Chem. Res. 2012, 45, 814-825. j) K. M. Engle, T.-S. Mei, M.
Wasa, J.-Q. Yu, Acc. Chem. Res. 2012, 45, 788-802. k) S. H. Cho,
SJ. Y. Kim, J. Kwak, S. Chang, Chem. Soc. Rev. 2011, 40, 5068-
5083. l) R. Giri, B.-F. Shi, K. M. Engle, N. Maugel, J.-Q. Yu,
Chem. Soc. Rev. 2009, 38, 3242-3272.
3
4
5
For selected reviews, see: a) M. Gulías, J. L. Mascareñas, Amgew.
Chem., Int. Ed. 2016, 55, 11000-11019. b) N. Yoshikai, Y. Wei,
Asian J. Org. Chem. 2013, 2, 466-478. c) T.-S. Mei, L. Kou, S. Ma,