Synthesis of Isoindolinones through Intramolecular Amidation of ortho-Vinyl Benzamides

Article abstract of DOI:10.1002/adsc.202000260

A synthetic approach of isoindolinones through intramolecular amidation of ortho-vinyl benzamides was reported. A variety of N-aryl isoindolinone derivatives were prepared in moderate to excellent yields using perfluorobutyl iodide as oxidant. (Figure pre

Full text of DOI:10.1002/adsc.202000260

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DOI: 10.1002/adsc.202000260
Synthesis of Isoindolinones through Intramolecular Amidation of
ortho-Vinyl Benzamides
Wen-tao Wei,+a Zhen-yu Chen,+b Yong-lu Lin,+a, c Ri-xing Chen,c Qi Wang,a
Qing-guang Wu,c Si-jun Liu,c,* Ming Yan,b and Xue-jing Zhangb,*
a
Institute of Clinical Pharmacology, Science and Technology Innovation Center, Guangzhou University of Chinese Medicine,
Guangzhou 510405, People’s Republic of China
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou
b
510006, People’s Republic of China
E-mail: zhangxj33@mail.sysu.edu.cn
School of Pharmaceutical Science, Guangzhou University of Chinese Medicine, Guangzhou 510006, People’s Republic of China
c
E-mail: liusijun@gzucm.edu.cn
+
Authors contributed equally to this work.
Manuscript received: February 25, 2020; Revised manuscript received: March 19, 2020;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202000260
stoichiometric or catalytic amount of oxidants or the
use of an acidic solvent is required to achieve the
Abstract: A synthetic approach of isoindolinones
through intramolecular amidation of ortho-vinyl
benzamides was reported. A variety of N-aryl
catalytic alkenylation of aromatic CÀ H bonds. Thus,
an efficient method for rapid construction of isoindoli-
isoindolinone derivatives were prepared in moderate
nones with readily available and easily modified
to excellent yields using perfluorobutyl iodide as
starting materials in mild condition should be devel-
oxidant.
oped.
Recently, we developed a new CÀ O dehydrogen-
Keywords: intramolecular amidation; isoindoli-
nones; ortho-vinyl benzamides; perfluorobutyl iodide
ative coupling reaction of oximes with acetonitrile
(bond energy: 95~97 kcal/mol), ketones and esters in
the presence of cesium carbonate and perfluorobutyl
iodide (Scheme 1a).[9] The formation of the EDA
The isoindolinone structural motif found in many complex between oxime anion and perfluorobutyl
natural products and medicinal intermediates exhibits iodide was proposed to enable the single electron
various important pharmaceutical and biological activ- transfer process which initiate the formation of radical
ities,
such
as
anxiolytic,[1]
antiretroviral,[2] intermediates and subsequent radical coupling reaction.
antimicrobial,[3] and antitumor properties.[4] Over the In 2017,[10] our group reported the intramolecular
past few years, studies have been performed to hydroamidation of ortho-vinyl benzamides promoted
construct this intriguing scaffold.[5] The transition- by potassium tert-butoxide and N,N-dimeth-
metal-catalyzed intermolecular oxidative coupling re- ylformamide (Scheme 1b) . The amidyl radical gen-
action of aromatic amides and alkyne or olefin is one erated from amides in the presence of t-BuOK/dimeth-
of the most practical methods for preparing isoindoli- ylformamide (DMF) and subsequently added to olefins
nones because of the easy-availability of starting produced valuable hydroamidation products. We won-
substrates and the good step economy.[6] Kondo[7] der whether the amidyl radical could be formed in the
developed an approach for the synthesis of N- presence of cesium carbonate and perfluorobutyl
arylisoindolinones through the copper-catalyzed sp3 iodide via an EDA complex and thus trigger the
CÀ H cyclic amination of 2-alkyl-N-arylbenzamides. intramolecular amidation of ortho-vinyl benzamides
Zhu[8] described one-pot multicomponent isoindolinone (bond energy: ~97 kcal/mol). Herein, a perfluorobutyl
synthesis through the relay catalysis of Rh, starting iodide promoted isoindolinones synthesis through
from commercially available aldehydes, 2-pyridin- intramolecular amidation of ortho-vinyl benzamides
amine, and olefins. Although these tandem catalytic was reported. A variety of N-aryl isoindolinone
systems offer many advantages, the addition of
Adv. Synth. Catal. 2020, 362, 1–6
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Table 1. Optimization of reaction conditions.[a]
Entry Base (equiv.) Additive (equiv.) Solvent Yield (%)[b]
1
2
3
4
5
6
7
8
Cs2CO3 (2.0) C4F9I (2.0)
K2CO3 (2.0) C4F9I (2.0)
Na2CO3 (2.0) C4F9I (2.0)
K3PO4 (2.0) C4F9I (2.0)
t-BuOK (2.0) C4F9I (2.0)
Cs2CO3 (2.0) NIS (2.0)
Cs2CO3 (2.0) TBAI (2.0)
Cs2CO3 (2.0) I2 (2.0)
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
97
trace
N.D.
trace
trace
10
N.D.
N.D.
9
Cs2CO3 (2.0) C4F9I (2.0)
Cs2CO3 (2.0) C4F9I (2.0)
Cs2CO3 (2.0) C4F9I (2.0)
Cs2CO3 (2.0) C4F9I (2.0)
Cs2CO3 (2.0) C4F9I (2.0)
MeOH N.D.
DCE N.D.
Toluene N.D.
DMSO 94
10
11
12
13
14
15
16
17
Scheme 1. Base-promoted radical reactions.
DMA
DMF
DMF
DMF
DMF
DMF
DMF
DMF
95
–
C4F9I (2.0)
–
N.D.
N.D.
80
75
75
Cs2CO3 (2.0)
derivatives were prepared in moderate to excellent
yields (Scheme 1c).
Cs2CO3 (1.6) C4F9I (2.0)
Cs2CO3 (2.0) C4F9I (1.6)
With ortho-vinyl benzamide as the starting material,
the intramolecular amidation product was obtained
with excellent yield. However, product 2a was proved
to be 5-exo-trig product. Then the reaction conditions
were optimized and results were summarized in
Table 1. Other bases, such as K2CO3, Na2CO3, K3PO4,
and t-BuOK, were also tested, no substantial amounts
of 2a was obtained (Table 1, entries 2–5). When C4F9I
was replaced by other iodine reagents, such as TBAI,
and I2, the product was not obtained. Other perfluoro
iodides such as perfluoroiodohexane was also tried,
however, the best result was obtained by using C4F9I
18[c] Cs2CO3 (2.0) C4F9I (2.0)
19[d] Cs2CO3 (2.0) C4F9I (2.0)
20[e] Cs2CO3 (2.0) C4F9I (2.0)
90
N.D.
[a] Reaction conditions: 1a (0.1 mmol), base, and solvent (1 mL)
at room temperature under an air atmosphere.
[b] Isolated yield.
[c] Reaction was carried out in the dark.
[d] TEMPO (0.15 mmol) was added.
[e] DPPH (0.15 mmol) was added.
as oxidant. The reaction solvent was also investigated. galvinoxyl were added, notable inhibitory effects were
N,N-Dimethylacetamide (DMA) and dimethyl observed. The single electron scavenger 7,7’,8,8’-
sulfoxide (DMSO) were applicable, and the products tetracyanoquinodimethane (TCNQ) was also added to
were isolated with yields of 94% and 95%, respec- the mixture, the reaction was completely inhibited
tively (Table 1, entries 12 and 13). Other solvents, such which indicates that the single electron transfer process
as MeOH, DCE, and toluene were incompatible and no happened and radical intermediate existed under the
2a could be obtained. The effects of Cs2CO3 and C4F9I reaction conditions (see SI for details).
loading were also examined, the best result was
With the optimized reaction condition in hand, a
achieved when Cs2CO3 and C4F9I were added in variety of N-phenyl-2-vinylbenzamide derivatives 1a–
2.0 equiv. (Table 1, entry 1). A decrease in either 1ag were examined, and the results are summarized in
Cs2CO3 or C4F9I loading would lead to a significant Scheme 2. The amidation reaction displayed good
loss of the yield (Table 1, entries 14–17). In addition, functional group tolerance. The electron-withdrawing
reaction could be carried out in the dark (Table 1, groups of NO2, COOMe, CN, and CF3 in the para
entry 18). TEMPO (2,2,6,6-tetramethylpiperidin-1- position of the N-phenyl ring generated the expected
oxyl) was added as a free radical inhibitor and the products in excellent yields. Other functional groups,
expected product was obtained in 90% yield (Table 1, such as p-OMe, p-Me, p-tBu, p-Br, and p-Cl, were also
entry 19). As we know, TEMPO is not only a radical well tolerated. In general, electron-deficient substrates
scavenger but also a radical initiator. It can also trigger were more reactive than electron-rich ones in terms of
the formation of new radical. While, DPPH (1,1- yields. The N-aryl moiety could also be substituted by
diphenyl-2-picrylhydrazyl) could inhibit the reaction N-pyridyl and N-naphthyl rings. 2k and 2l were
completely (Table 1, entry 20). Other radical scav- obtained in yields of 45% and 63%, respectively. No
engers such as BHT (butylated hydroxytoluene) and significant change was observed when the substituents
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Scheme 2. Intramolecular amidation of 1a–1ag. [a]Reaction conditions: 1a–1ag (0.2 mmol), Cs2CO3 (0.40 mmol), C4F9I
(0.40 mmol), and DMF (2.0 mL) at room temperature under an air atmosphere for 12 h. [b]Isolated yields.
were located at the ortho position of the N-phenyl ring. using 1t as substrate, indicating that deiodination
Isoindolinone derivatives of 2m, 2n, and 2o were occurred before 3-methylene-2-phenylisoindolinone
acquired in moderate to good yields. In addition, the was formed. Furthermore, the substrates were extended
substitution on the phenyl ring of benzamide with 5- to different kinds of alkylamine derivatives. When the
Cl, 5-Me, and 5-OMe was tolerated well, and antici- N-substitutents were hydrogen, methoxyl, t-butyl, and
pated products 2p–2r were acquired in good yields.
benzyl, the consequences were inferior, and no
The substrates were further extended to aryl alkene isoindolinone products were obtained.
derivatives. The terminal hydrogen of alkene is vital
The transformation of 2o was achieved for the
for the amidation. No anticipated product could be reaction application, tetracyclic isoindolinone could be
acquired when the hydrogen was substituted by meth- smoothly constructed with the aid of Pd catalysis
yl. A different consequence was observed in the (Scheme 3a). In addition, a gram-scale reaction of 1a
reaction when the methyl group was introduced to the was performed to produce isoindolinone 2a with an
β position of styrene. Iodo-isoindolinone 2s was 83% yield (Scheme 3b).
acquired in 95% yield. A similar result was observed
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anionic intermediate A to C4F9I, N-radical intermediate
B, perfluobutyl radical, and iodide ion are generated.
We tried to capture the intermediate B by adding
styrene, however no aimed product was obtained
maybe because of the high reactivity of intramolecular
reaction. Subsequently, N-radical intermediate B is
oxidized by C4F9I to give intermediate C. Meanwhile,
the perfluorobutyl radical may abstract one hydrogen
from the starting material 1a to give the intermediate
B and release the perfluorobutane as gas. Then, the
C=C bond of styrene may be activated by the
iodonium ion to form the iodonium intermediate D,
and the subsequent intramolecular nucleophilic addi-
tion with a nitrogen anion generates the iodo-isoindoli-
none intermediate E which then released one HI to
yield product 2a.[12]
Scheme 3. Reaction applications: a. Pd-catalyzed Heck annula-
tion for the synthesis of tetracyclic isoindolinone derivative. b.
A gram-scale reaction.
In summary, a simple and concise method was
developed to synthesize isoindolinones through the
intramolecular amidation of ortho-vinyl benzamides. A
variety of N-aryl isoindolinone derivatives with good
The UV-vis spectroscopic measurement on various yields were acquired through this approach. Perfluor-
combinations of 1a, C4F9I and Cs2CO3 in DMF was obutyl iodide was proved to be necessary and used as
offered. We observed a red shift of absorption when the unique oxidant.
substrate 1a, C4F9I and Cs2CO3 were combined in
DMF, which indicates the formation of EDA complex
(see SI for details).
Experimental Section
On the basis of our experimental results and a General Procedure of Intramolecular Amidation
previous reported work,[9,11] we proposed a tentative
A
solution of N-phenyl-2-vinylbenzamide 1a (44.7 mg,
reaction mechanism of the intramolecular amidation of
ortho-vinyl benzamides (Scheme 4). Under a base
condition, the deprotonation of substrate 1a firstly
produces the anionic intermediate A. Then an EDA
complex could form between N-anionic intermediate A
0.2 mmol), Cs2CO3 (130 mg, 0.4 mmol), and C4F9I (69 μL,
0.4 mmol) in DMF (1 mL) was stirred at room temperature for
12 h. After the completion of the reaction, the mixture was
diluted with EtOAc (15 mL) and water (15 mL). The organic
layer was separated, and the aqueous layer was extracted with
and C4F9I. Through the single electron transfer from N- EtOAc (15 mL×3). The combined organic layers were dried
over Na2SO4, filtered, and concentrated in vacuo. Then, the
crude product was purified through flash chromatography to
produce 3-methylene-2-phenylisoindolin-1-one 2a as a pale-
yellow solid (43 mg, 97% yield). M. p. 175.0–176.5 C. 1H
°
NMR (400 MHz, CDCl3) δ 7.83 (d, J=7.5 Hz, 1H), 7.66 (d,
J=7.7 Hz, 1H), 7.54 (t, J=7.5 Hz, 1H), 7.49–7.39 (m, 3H),
7.34–7.26 (m, 3H), 5.13 (d, J=2.0 Hz, 1H), 4.71 (d, J=2.0 Hz,
1H). 13C NMR (100 MHz, CDCl3) δ 166.69, 143.13, 136.28,
134.62, 132.35, 129.79, 129.38, 128.95, 128.15, 128.07, 123.58,
120.11, 90.50. HRMS (ESI) calculated for C15H11NONa (M+
Na)+: 244.0733, found: 244.0737.
Acknowledgements
This work was supported by the National Science Foundation of
China (21702236, 21772240), the Doctor Initiated Project of
Guangdong Natural Science Foundation (2016A030310459),
and Guangzhou Science Technology and Innovation Commis-
sion Technology Research Projects (201805010005).
Scheme 4. Proposed mechanism
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Terajima, K. Tsutsui, T. Shishido, J. Org. Chem. 2017,
References
82, 1231–1239; d) X. W. Wu, B. Wang, Y. Zhou, H. Liu,
Org. Lett. 2017, 19, 1294–1297; e) S. Z. Wu, X. Y. Wu,
C. L. Fu, S. M. Ma, Org. Lett. 2018, 20, 2831–2834;
f) G. Q. Yang, W. B. Zhang, Org. Lett. 2012, 14, 268–
271.
[1] T. Kondo, K. Yoshida, Y. Yoshimura, S. Tanayama,
Biopharm. Drug Dispos. 1995, 16, 755–773.
[2] A. Mertens, H. Zilch, B. Konig, W. Schafer, T. Poll, W.
Kampe, H. Seidel, U. Leser, H. Leinert, J. Med. Chem.
1993, 6, 2526–2535.
[3] D. Augner, O. Krut, N. Slavov, D. C. Gerbino, H. G.
Sahl, J. Benting, C. F. Nising, S. Hillebrand, M. Kronke,
H. G. Schmalz, J. Nat. Prod. 2013, 76, 1519–1522.
[4] Y. L. Choi, J. K. Kim, S. U. Choi, Y. K. Min, M. A. Bae,
B. T. Kim, J. N. Heo, Bioorg. Med. Chem. Lett. 2009, 19,
3036–3040.
[7] K. Nozawa-Kumada, J. Kadokawa, T. Kameyama, Y.
Kondo, Org. Lett. 2015, 17, 4479–4481.
[8] Y. Zhang, H. Q. Zhu, Y. T. Huang, Q. Hu, Y. He, Y. H.
Wen, G. G. Zhu, Org. Lett. 2019, 21, 1273–1277.
[9] Z. Y. Chen, H. J. Liang, R. X. Chen, L. Chen, X. Z.
Tang, M. Yan, X. J. Zhang, Adv. Synth. Catal. 2019, 361,
3324–3330.
[10] Z. Y. Chen, L. Y. Wu, H. S. Fang, T. Zhang, Z. F. Mao,
Y. Zou, X. J. Zhang, M. Yan, Adv. Synth. Catal. 2017,
359, 3894–3899.
[5] a) E. M. Marigorta, J. M. Santos, A. M. Retana, J.
Vicario, F. Palacios, Beilstein J. Org. Chem. 2019, 15,
1065–1085; b) A. D. Mola, L. Palombi, A. Massa, Curr.
Org. Chem. 2012, 16, 2302–2320; c) W. Gao, M. W.
Chen, Q. P. Ding, Y. Y. Peng, Chem. Asian J. 2019, 14,
1306–1322; d) A. E. Harairy, Y. L. Qi, B. B. Lai, L. G.
Vaccaro, M. H. Li, Y. L. Gu, Adv. Synth. Catal. 2019,
3342–3350; e) R. B. Bedford, J. G. Bowen, C. Méndez-
Gálvez, J. Org. Chem. 2017, 82, 1719–1725; f) J. Han,
N. Wang, Z. B. Huang, Y. S. Zhao, D. Q. Shi, J. Org.
Chem. 2017, 82, 6831–6839; g) J. T. Zhang, H. Chen, C.
Lin, Z. X. Liu, C. Wang, Y. H. Zhang, J. Am. Chem. Soc.
2015, 137, 12990–12996; h) L. Li, M. Wang, X. J.
Zhang, Y. W. Wang, D. W. Ma, Org. Lett. 2009, 11,
1309–1312; i) S. Serna, I. Tellitu, E. Domínguez, I.
Moreno, R. SanMartín, Tetrahedron Lett. 2003, 44,
3483–3486.
[11] a) J. Barluenga, M. Trincado, E. Rubio, J. M. González,
J. Am. Chem. Soc. 2004, 126, 3416–3417; b) D. Fischer,
H. Tomeba, N. K. Pahadi, N. T. Patil, Z. B. Huo, Y.
Yamamoto, J. Am. Chem. Soc. 2008, 130, 15720–15725;
c) W. H. Zhong, S. Liu, J. Yang, X. B. Meng, Z. J. Li,
Org. Lett. 2012, 14, 3336–3339; d) B. Godoi, R. F.
Schumacher, G. Zeni, Chem. Rev. 2011, 111, 2937–2980;
e) J. M. Yu, C. Cai, Eur. J. Org. Chem. 2017, 6008–
6012; f) A. Sreenithya, C. M. Hadad, R. B. Sunoj, Chem.
Sci., 2019, 10, 7082–7090.
[12] We could not exclude the 5-exo-trig radical cyclization of
intermediate B, which could happen to give the product
directly and abstract one I radical from C4F9I to give 2s
and 2t, the 6-endo-trig radical cyclization reaction maybe
also happen (or more inclined to happen) from intermedi-
ate B to generate six-membered product (see ref. 10).
However, no six-membered product was detected and
that’s why we prefer the mechanism we proposed.
[6] a) X. X. Zheng, C. Du, X. M. Zhao, X. J. Zhu, J. F. Suo,
X. Q. Hao, J. L. Niu, M. P. Song, J. Org. Chem. 2016,
81, 4002–4011; b) C. K. Xia, A. J. P. White, K. K. M.
Hii, J. Org. Chem. 2016, 81, 7931–7938; c) H. Miura, S.
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Synthesis of Isoindolinones through Intramolecular
Amidation of ortho-Vinyl Benzamides
Adv. Synth. Catal. 2020, 362, 1–6
W.-t. Wei, Z.-y. Chen, Y.-l. Lin, R.-x. Chen, Q. Wang, Q.-g.
Wu, S.-j. Liu*, M. Yan, X.-j. Zhang*