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DOI: 10.1039/D4OB01611D (Communication) Org. Biomol. Chem., 2025, 23, 90-93

Palladium-catalyzed [3 + 2] cycloaddition of 4-vinyl-4-butyrolactones with sulfamate-derived cyclic imines: construction of sulfamate-fused pyrrolidines†

Honghao Sun ab, Siyuan Ding a, Bo Wang *b, Jiaxing Huang *a and Hongchao Guo *a
aDepartment of Chemistry and Innovation Center of Pesticide Research, China Agricultural University, Beijing 100193, P. R. China. E-mail: hchguo@cau.edu.cn; 05084@cau.edu.cn
bInstitute of Food Science and Technology, Chinese Academy of Agricultural Sciences, Beijing, 100193, China. E-mail: 362395987@qq.com

Received 5th October 2024 , Accepted 5th November 2024

First published on 6th November 2024

Abstract

The palladium-catalyzed [3 + 2] decarboxylative cycloaddition of 4-vinyl-4-butyrolactones with sulfamate-derived cyclic imines has been developed, providing the sulfamate-fused pyrrolidine derivatives in high yields with good diastereoselectivities. The scale-up reaction and further derivation of the product worked well, demonstrating the potential application of the current reaction in organic synthesis. A plausible reaction mechanism was also proposed.

The sulfamate moiety1 is often found in the skeletons of natural products and pharmaceutical compounds having biological activities such as anticancer, antibiotic and antiviral properties. Pyrrolidine2 is the commonly used five-membered heterocyclic structure in organic synthesis and pharmaceutical chemistry. The structures of more than 50 drugs include pyrrolidine fragments. Due to the important value of the sulfamate moiety and pyrrolidine framework, it is very meaningful to develop a synthetic method for sulfamate-fused pyrrolidine derivatives.

Palladium-catalyzed decarboxylative cycloaddition reactions have been intensively studied in the past decades and have been proven to be one of the effective methods for the synthesis of valuable cyclic compounds.3 In recent years, a variety of novel palladium-catalyzed decarboxylative cycloaddition reactions have been discovered.4–7 Because the sulfamate moiety is a core structural part of some bioactive molecules, sulfamate-derived cyclic imines were often used as electron-deficient reaction partners in palladium-catalyzed cycloaddition reactions to produce bioactive sulfamate-fused heterocyclic compounds (Scheme 1a). In 2018, our group reported a palladium-catalyzed highly stereoselective [4 + 2] cycloaddition reaction of vinyl benzoxazinones with sulfamate-derived cyclic imines to access chiral tetrahydroquinazolines.8 In 2020, the Kim group accomplished an enantioselective [5 + 2] cycloaddition reaction of vinylethylene carbonates and cyclic imines, completing the synthesis of N-fused 1,3-oxazepines bearing one stereogenic center.9 In 2021, the Chen group developed asymmetric regiodivergent [5 + 2] and [3 + 2] annulations of vinyl indoloxazolidones under palladium catalysis, furnishing distinct azepino[4,3-b]indole and pyrrolo[3,4-b]indole frameworks.10 In 2023, the Mao group disclosed a palladium-catalyzed [4 + 2] cycloaddition of 2-methylidenetrimethylene carbonate or methylene cyclic carbamate with sulfamate-derived cyclic imines, affording pharmacologically interesting oxazine or hydropyrimidine derivatives in high yields.11 To the best of our knowledge, there are limited reports on the construction of the pyrrolidine framework through palladium-catalyzed decarboxylative cycloaddition reactions.


image file: d4ob01611d-s1.tif
Scheme 1 Palladium-catalyzed cycloaddition reactions.

In the recent five years, our group focused on developing novel precursors of π-allyl palladium zwitterionic intermediates and their applications in palladium-catalyzed cycloadditions to construct novel structural skeletons.12 We designed and synthesized 4-vinyl-4-butyrolactones (VBLs) as precursors for π-allyl palladium zwitterionic intermediates,13 and recently applied them in palladium-catalyzed [3 + 2] cycloaddition with alkenes to afford various spirocyclopentane products.14 As our continuous efforts on cycloaddition reactions,15 in order to further expand the application scope of 4-vinyl-4-butyrolactones, we herein report a palladium-catalyzed [3 + 2] decarboxylative cycloaddition of 4-vinyl-4-butyrolactones with sulfamate-derived cyclic imines, providing the biologically important sulfamate-fused pyrrolidine derivatives.

Initially, we studied the reaction between VBL 1a and sulfamate-derived cyclic imine 2a by screening a series of ligands in the presence of Pd2(dba)3·CHCl3 with dichloromethane (DCM) as the solvent (Table 1, entries 1–6). To our delight, the common phosphine ligands such as PPh3 and Xantphos were able to promote the reaction of VBL 1a and sulfamate-derived cyclic imine 2a, generating the [3 + 2] cycloaddition product 3aa (CCDC number: 2355129, detailed in the ESI†)16 in 88% yield with 8[thin space (1/6-em)]:[thin space (1/6-em)]1 dr and in 62% yield with 7[thin space (1/6-em)]:[thin space (1/6-em)]1 dr, respectively (entries 1 and 2). Other diphosphine ligands such as dppe and dppf did not promote the reaction (entries 3 and 4). The dinitrogen ligands such as 1,10-Phen and PyOX displayed high catalytic activities, providing the [3 + 2] cycloaddition product 3aa in 95% yield with 19[thin space (1/6-em)]:[thin space (1/6-em)]1 dr and in 85% yield with 17[thin space (1/6-em)]:[thin space (1/6-em)]1 dr, respectively (entries 5 and 6). Subsequently, a quick screening of solvents such as CHCl3, 1,2-dichloroethane (DCE), toluene, EtOAc, and THF (entries 7–12) revealed that a high yield and excellent diastereoselectivity were achieved in DCE (93% yield, >20[thin space (1/6-em)]:[thin space (1/6-em)]1 dr). Decreasing the loading of the ligand to 10 mol% did not deteriorate both yield and stereoselectivity (entry 13). The optimal reaction conditions were determined as the use of Pd2(dba)3·CHCl3 (5 mol%) and 1,10-Phen (10 mol%) in DCE at 25 °C.

Table 1 Optimization of reaction conditionsa

image file: d4ob01611d-u1.tif
Entry Ligand Solvent t (h) Yieldb (%) drc
a All reactions were carried out with Pd2(dba)3·CHCl3 (5 mol%), ligand (20 mol%), 1a (0.12 mmol) and 2a (0.1 mmol) in 1 mL of solvent at 25 °C. b Isolated yield; NR: no reaction. c Determined by 1H NMR analysis. d 10 mol% of ligand was used.
1 PPh3 DCM 12 88 9[thin space (1/6-em)]:[thin space (1/6-em)]1
2 Xantphos DCM 12 62 7[thin space (1/6-em)]:[thin space (1/6-em)]1
3 dppe DCM 48 NR —
4 dppf DCM 48 NR —
5 1,10-Phen DCM 12 95 19[thin space (1/6-em)]:[thin space (1/6-em)]1
6 PyOX DCM 12 85 17[thin space (1/6-em)]:[thin space (1/6-em)]1
7 1,10-Phen CHCl3 12 87 19[thin space (1/6-em)]:[thin space (1/6-em)]1
8 1,10-Phen DCE 12 93 >20[thin space (1/6-em)]:[thin space (1/6-em)]1
9 1,10-Phen Toluene 48 43 16[thin space (1/6-em)]:[thin space (1/6-em)]1
10 1,10-Phen EtOAc 12 NR —
11 1,10-Phen MeCN 12 81 >20[thin space (1/6-em)]:[thin space (1/6-em)]1
12 1,10-Phen THF 12 NR —
13d 1,10-Phen DCE 12 93 >20[thin space (1/6-em)]:[thin space (1/6-em)]1

With the optimal reaction conditions in hand, we set out to explore the generality of this catalytic system. The scope with respect to various VBLs 1 with various substituents was first examined. As shown in Scheme 2, a wide range of aryl substituted VBLs having different electronic and steric properties performed the reaction well, producing a variety of sulfamate-pyrrolidine derivatives (3ba–3ka) in 86–93% yields with >20[thin space (1/6-em)]:[thin space (1/6-em)]1 dr. There was no remarkable difference in the reactivity between electron-withdrawing and electron-donating group-substituted VBLs. All these substrates displayed high reactivities and good stereoselectivities. The introduction of a 2-naphthyl substituent into the VBL was also feasible for this reaction (3ma). It is worth noting that when R′ was ethyl, the product (3na) was still obtained in 86% yield with >20[thin space (1/6-em)]:[thin space (1/6-em)]1 dr. The 2-thiophenyl-substituted VBL displayed high reactivity, offering 84% yield of the product 3la, but low diastereoselectivity (1[thin space (1/6-em)]:[thin space (1/6-em)]1 dr). Unfortunately, when VBL 1 had only one ester group, its reactivity was very poor, giving a trace amount of the product.


image file: d4ob01611d-s2.tif
Scheme 2 Scope of 4-vinyl-4-butyrolactones 1. Reactions of 1 (0.12 mmol) and 2a (0.10 mmol) were performed in the presence of Pd2(dba)3·CHCl3 (5 mol%) and 1,10-Phen (10 mol%) in 1 mL of DCE at 25 °C for 12 h. Isolated yield, >20[thin space (1/6-em)]:[thin space (1/6-em)]1 dr unless otherwise noted, determined by 1H NMR analysis.

We next investigated the scope of sulfamate-derived cyclic imines 2 (Table 2). A series of sulfamate-derived cyclic imines with different substituents on the benzene ring were capable of undergoing [3 + 2] cycloaddition with 4-vinyl-4-butyrolactone 1a under standard reaction conditions, affording the corresponding sulfamate-fused pyrrolidine derivatives (3aa–3am) in high yields (87–95%, entries 1–13). The results showed that the introduction of different electron-withdrawing and electron-donating groups at the 6, 7 and 8 positions of sulfamate-derived cyclic imines 2 had no significant influence on the reaction (entries 1–13), and the corresponding products were obtained in high yields with excellent diastereoselectivities.

Table 2 Scope of sulfamate-derived cyclic imines 2a

image file: d4ob01611d-u2.tif
Entry R 3 Yieldb (%) drc
a Reactions of 1a (0.12 mmol) and 2 (0.10 mmol) were performed in the presence of Pd2(dba)3·CHCl3 (5 mol%) and 1,10-phen (10 mol%) in 1 mL of DCE at 25 °C for 12 h. b Isolated yield. c Determined by 1H NMR analysis.
1 H (2a) 3aa 93 >20[thin space (1/6-em)]:[thin space (1/6-em)]1
2 7-F (2b) 3ab 89 >20[thin space (1/6-em)]:[thin space (1/6-em)]1
3 6-Cl (2c) 3ac 91 >20[thin space (1/6-em)]:[thin space (1/6-em)]1
4 7-Br (2d) 3ad 95 >20[thin space (1/6-em)]:[thin space (1/6-em)]1
5 8-Br (2e) 3ae 90 >20[thin space (1/6-em)]:[thin space (1/6-em)]1
6 6-Me (2f) 3af 94 >20[thin space (1/6-em)]:[thin space (1/6-em)]1
7 7-Me (2g) 3ag 89 >20[thin space (1/6-em)]:[thin space (1/6-em)]1
8 8-Me (2h) 3ah 90 >20[thin space (1/6-em)]:[thin space (1/6-em)]1
9 6-t-Bu (2i) 3ai 92 >20[thin space (1/6-em)]:[thin space (1/6-em)]1
10 7-t-Bu (2j) 3aj 93 >20[thin space (1/6-em)]:[thin space (1/6-em)]1
11 8-t-Bu (2k) 3ak 93 >20[thin space (1/6-em)]:[thin space (1/6-em)]1
12 7-OMe (2l) 3al 87 >20[thin space (1/6-em)]:[thin space (1/6-em)]1
13 8-OEt (2m) 3am 91 >20[thin space (1/6-em)]:[thin space (1/6-em)]1

In order to investigate the practicality of the current reaction, the scale-up reaction of VBL 1a (1.2 mmol) with sulfamate-derived cyclic imine 2a (1.0 mmol) was performed under the optimal reaction conditions, resulting in the corresponding product 3aa with 91% yield and >20[thin space (1/6-em)]:[thin space (1/6-em)]1 dr. Further transformation of the product was also carried out. The product 3aa was treated with DIBAL in DCM at −78 °C for 2 h to afford the alcohol derivative 4aa in 57% yield (Scheme 3).


image file: d4ob01611d-s3.tif
Scheme 3 Scale-up reaction and further transformation of the product.

As shown in Scheme 4, a plausible reaction mechanism was proposed. Under the catalysis of palladium/1,10-Phen, VBL 1a produced the zwitterionic intermediate A through a decarboxylation ring-opening reaction. This intermediate A then underwent addition to sulfamate-derived cyclic imine 2a to generate the intermediate B. Subsequent intramolecular annulation led to the product 3aa.


image file: d4ob01611d-s4.tif
Scheme 4 A plausible reaction mechanism.

In summary, we have successfully achieved a palladium-catalyzed [3 + 2] cycloaddition of VBLs with sulfamate-derived cyclic imines, giving various sulfamate-fused pyrrolidine derivatives in high yields with excellent diastereoselectivities. The combination of two active skeletons in these novel sulfamate-fused pyrrolidine derivatives has the potential to be biologically active and to improve medicinal chemistry.

Data availability

The datasets supporting this article have been uploaded as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the Natural Science Foundation of China (No. 21871293 and 22071264).

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  16. Crystallographic data for 3aa have been respectively deposited with the Cambridge Crystallographic Data Centre as deposition number CCDC 2355129.†.

Footnote

† Electronic supplementary information (ESI) available. CCDC 2355129. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4ob01611d
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