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Synlett 2023; 34(12): 1457-1461
DOI: 10.1055/a-2043-4862
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Special Issue Honoring Masahiro Murakami’s Contributions to Science

Facile Synthesis of Isoindolinones via Radical-Mediated Intramolecular Coupling of Two C–H Bonds

Shuxiong Han
a   Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, P. R. of China
,
Shuo He
a   Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, P. R. of China
,
Zhibin Huang
a   Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, P. R. of China
,
Yingsheng Zhao∗
a   Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, P. R. of China
,
Gong Chen∗
b   State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin, 300071, P. R. of China
› Author Affiliations

This work was supported by National Natural Science Foundation of China (No. 22171197), the Major Basic Research Project of the Natural Science Foundation of Jiangsu Higher Education Institutions (21KJA150002), National Local Joint Engineering Laboratory to Functional Adsorption Material Technology for the Environmental Protection (SDGC2121) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) project. The project was also supported by the Open Research Fund of the School of Chemistry and Chemical Engineering, Henan Normal University.
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Abstract

A metal-free method for the construction of 3,3-dimethyl isoindolinones via radical-mediated intramolecular coupling of two C–H bonds of N,N-diisopropyl benzamides was developed. The reactions can proceed in moderate to high yield and with excellent chemoselectivity. A reaction sequence of the formation of an alkyl radical via oxidative cleavage of alkyl C–H bond and the formation of lactam ring via intramolecular homolytic aromatic substitution was proposed.


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Key words

C–H activation - isoindolinone - homolytic aromatic substitution - alkyl radical - benzamide

Isoindolin-1-ones, sometimes referred to as isoindolones, are an important class of nitrogen-containing heterocycles and are widely found in natural products and small-molecule drugs.[1] Considerable efforts have been devoted to the methodological studies of isoindolinone synthesis.[2] In recent years, C–H activation has emerged as an attractive strategy for streamlining the synthesis of isoindolinones using more readily accessible starting materials (Scheme [1]A).[3] [4] For example, benzamides can undergo ortho-directed C–H activation with proper coupling partners and concomitant cyclization with the carboxamide nitrogen to incorporate the C3 unit under various metal catalysis.[5] Benzylamines and derivatives can also undergo ortho C–H activation with CO to incorporate the carbonyl unit.[6] In these metal-catalyzed ortho-directed aryl C–H activation reactions, five-membered metallocycle intermediates are usually involved. Alkyl C–H activation strategies, such as intramolecular amination of the benzylic C–H bond of ortho-alkyl-substituted benzamides[7] and intramolecular arylation of α C–H bond of benzoyl alkylamines,[8] [9] have also been successfully employed for isoindolinone synthesis with or without the use of metal catalysts. Notably, most of these alkyl C–H activation reactions proceed through radical-mediated intermediates. For example, Kalyani discovered that 2-bromo-N,N-diisopropyl benzamides can undergo intramolecular coupling between the aryl halides and the alkyl C–H bond adjacent to nitrogen using substoichiometric Ni(COD)2 or 1,10-phenanthroline and NaOt-Bu as base at 145 °C (Scheme [1]B).[8a] Later, Xu reported that analogous iodo-substituted benzamides can undergo intramolecular alkyl C–H arylation at room temperature under visible-light irradiation in the presence of a photoredox catalyst.[8c] In both systems, it was proposed that an aryl radical intermediate was first generated from aryl halides and then underwent 1,5-hydrogen atom transfer (HAT) to form an alkyl radical, which subsequently reacted with the aryl group to form the 5-membered lactam ring.

Zoom Image
Scheme 1 Isoindolinone synthesis via C–H activation

A further advance along the above-mentioned intramolecular C–H arylation strategy would be an intramolecular coupling of two C–H bonds of benzamides without reactive ortho handle.[10] [11] Previously, Clayden reported an interesting three-step synthesis of isoindolinones from N-benzyl-N-alkyl benzamides. Deprotonation of the relatively acidic benzylic C–H bond with LDA led to the formation of a stable extended enolate intermediate via dearomatic cyclization; air oxidation and aromatization by the treatment of mesyl chloride (MsCl) gave the isoindolinone product (Scheme [1]C).[12] Notably, less acidic α alkyl C–H bonds of benzamides were unaffected. Herein, we report a new protocol for isoindolinone synthesis via radical-mediated intramolecular couplings of an alkyl C–H and an aryl C–H bond of N-isopropyl-N-alkyl benzamides using ammonium persulfate (NH4)2S2O8 as oxidant (Scheme [1]D).[13]

Methods for metal-catalyzed ortho-directed C–H activation of benzamides have been well developed.[14] Inspired by the seminal works of Gevorgyan,[8e] we initially questioned whether the combination of ortho-directed C–H cleavage by a metal catalyst and a proper single-electron oxidant could form an ortho aryl radical intermediate, which can undergo intramolecular arylation of α alkyl C–H bonds of benzamides. As shown in Table [1], the reactions of N,N-diisopropylbenzamide (1a) with 2 equiv of K2S2O8 in the 1:1 mixed solvents of AcOH and MeCN at 120 °C for 12 h in the presence of Ni catalyst such as Ni(dppf)Cl2 gave the desired product 2a in moderate yield (entry 1). The use of catalysts such as Pd(OAc)2, [Cp*IrCl2]2, or [Cp*RhCl2]2 gave little 2a (entries 2–4). Interestingly, the reaction of 1a with K2S2O8 alone also gave 2a in a similar yield as in the presence of Ni catalyst (entry 5). (NH4)2S2O8 provided a better oxidant (entry 6). In contrast to the persulfates, oxidants including di-tert-butyl peroxide (DTBP), mCPBA, benzoyl peroxide (BPO), Oxone, and TEMPO gave little 2a (entries 7–11). The yield of 2a was further improved to 68% when the reaction was conducted in MeCN solvent along with a small amount of AcOH additive (3.0 equiv, entry 12). Notably, the reaction is very clean, generating little other side products except a small amount (15%) of unreacted 1a. The same reaction at a 10.0 mmol scale gave product 2a in 50% isolated yield. Either lowering or increasing the amount of (NH4)2S2O8 led to diminished yield of 2a (entries 13–15). Addition of 2 equiv of TEMPO completely halted the reaction (entry 16).

Table 1 Model Reactions of Compound 1a

Entry

Catalyst (10 mol%)

Oxidant (equiv)

Solvent, additive (equiv)

Yield of 2a (%)a

 1

Ni(dppf)Cl2

K2S2O8 (2)

MeCN/AcOH (1:1)

38

 2

Pd(OAc)2

K2S2O8 (2)

MeCN/AcOH (1:1)

 0

 3

[Cp*IrCl2]2

K2S2O8 (2)

MeCN/AcOH (1:1)

 0

 4

[Cp*RhCl2]2

K2S2O8 (2)

MeCN/AcOH (1:1)

 0

 5

–

K2S2O8 (2)

MeCN/AcOH (1:1)

43

 6

–

(NH4)2S2O8 (2)

MeCN/AcOH (1:1)

63

 7

–

DTBP (2)

MeCN/AcOH (1:1)

 0

 8

–

mCPBA (2)

MeCN/AcOH (1:1)

 0

 9

–

BPO (2)

MeCN/AcOH (1:1)

 0

10

–

Oxone (2)

MeCN/AcOH (1:1)

 0

11

–

TEMPO (2)

MeCN/AcOH (1:1)

 0

12

–

(NH4)2S2O8 (2)

MeCN, AcOH (3)

68 (50b)

13

–

(NH4)2S2O8 (1)

MeCN, AcOH (3)

40

14

–

(NH4)2S2O8 (3)

MeCN, AcOH (3)

64

15

–

(NH4)2S2O8 (4)

MeCN, AcOH (3)

46

16

–

(NH4)2S2O8 (4)

MeCN, AcOH (3), TEMPO (2)

 0

a Isolated yield on a 0.2 mmol scale.

b 10 mmol scale.

With the optimal reaction conditions in hand, a series of analogues of N,N-diisopropylbenzamide were examined (Scheme [2]).[15] In general, benzamides bearing various alkyl, alkoxyl, and halogen groups at the para position worked well, providing the corresponding products in moderate to good yields (2b–o). The reactions of ortho-substituted benzamides typically proceeded in lower yields (2p–s,x,y). We suspected that the ortho substituent might hinder the radical cyclization step. Notably, the ortho-iodo group of 2s was not affected. The reaction of meta-methyl benzamide gave a mixture of regioisomers 2w-1 and 2w-2. Interestingly, the cyclization reactions of meta-halogen-substituted benzamides selectively took place at the more hindered positions with good yields (2t–v). The reaction of N,N-dicyclohexylbenzamide gave 2z in 40% yield. The reactions of N-ethyl-N-isopropylbenzamide (3), N,N-diethylbenzamide (4), N-isopropyl-N-benzylbenzamide (5), N-methyl-N-isopropylbenzamide (6), and N-isopropyl-N-phenylbenzamide (7) did not give any corresponding isoindolinones products. Both 3 and 4 underwent de-ethylation. Compound 5 underwent debenzylation. Compounds 6 and 7 showed little reactivity.

Zoom Image
Scheme 2 The substrate scope of benzamides. Isolated yields on a 0.2 mmol scale.
Zoom Image
Scheme 3 Mechanistic considerations

As shown in Scheme [3]A, the parallel kinetic isotope experiments of 1a and 1a-D gave a KIE value of 1.23, indicating that the cleavage of aryl C–H bond is not the rate-limiting step. Based on this data and previous reports,[16] a plausible reaction mechanism for 1a is proposed in Scheme [3]B. Upon heating, sulfate radical anion is generated from persulfate and then undergoes hydrogen atom transfer (HAT) with 1a to form alkyl radical intermediate I. Intermediate I then reacts intramolecularly with the arene moiety to form II. Single-electron transfer (SET) oxidation of II by sulfate radical anion and the following deprotonation gives the final product 2a. HAT of II with sulfate radical anion could also directly give 2a. Intermediate I could potentially be oxidized to generate IV,[14] which can be hydrolyzed to give an N-dealkylation side product. The chemoselectivities of the reactions of 1a and its analogues are not fully understood at the moment. We suspect that the HAT of compound 1a might be reversible. In the case of 1a, the cyclization of alkyl radical intermediate I is probably much faster than its SET oxidation and the reverse HAT. A bulky bystanding N-isopropyl group appears to play an important role in facilitating the radical cyclization of the other N-isopropyl group through steric effect. The secondary α C–H bonds of compounds 3 and 5 can also be cleaved by HAT to generate the corresponding secondary alkyl radical intermediates. For unclear reasons, SET oxidation of the alkyl radical derived from 3 is much more favored than the radical cyclization, leading to the de-ethylation product. HAT of compound 6 might selectively take place at the tertiary α C–H bond; however, the following radical cyclization is unfavored, probably due to the lack of a bulky bystanding substituent on the N atom. The reverse HAT would regenerate the starting material.

In summary, we have developed a new method for isoindolinone synthesis via radical-mediated intramolecular couplings of an alkyl C–H and an aryl C–H bond of N,N-dialkyl benzamides using ammonium persulfate as oxidant. The reactions likely follow the sequence of oxidative cleavage of an alkyl C–H bond for the formation of an alkyl radical and the intramolecular homolytic aromatic substitution. The reactions can proceed with excellent chemoselectivity. The scope of the N-alkyl groups of benzamides remains limited. We hope that new strategies for the oxidative cleavage of the alkyl C–H bonds could expand the scope of this transformation in future studies.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2043-4862.
  • Supporting Information

Corresponding Authors

Yingsheng Zhao
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University
Suzhou 215123
P. R. of China   

Gong Chen
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University
Tianjin, 300071
P. R. of China   

Publication History

Received: 15 January 2023

Accepted after revision: 27 February 2023

Accepted Manuscript online:
27 February 2023

Article published online:
17 March 2023

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Zoom Image
Scheme 1 Isoindolinone synthesis via C–H activation
Zoom Image
Scheme 2 The substrate scope of benzamides. Isolated yields on a 0.2 mmol scale.
Zoom Image
Scheme 3 Mechanistic considerations