Phosphine-catalyzed [3 + 2] annulation of β-sulfonamido-substituted enones with trans-α-cyano-α,β-unsaturated ketones for the synthesis of highly substituted pyrrolidines

To synthesize highly substituted pyrrolidines, we developed a phosphine-catalyzed [3 + 2] annulation of β-sulfonamido-substituted enones with trans-α-cyano-α,β-unsaturated ketones. We prepared a series of pyrrolidines under mild conditions with high yields and moderate-to-good diastereoselectivities. A catalytic mechanism for this reaction is suggested.

To synthesize highly substituted pyrrolidines, we developed a phosphine-catalyzed [3 + 2] annulation of β-sulfonamido-substituted enones with trans-α-cyano-α,β-unsaturated ketones.

Nucleophilic phosphine catalysis is a practical and powerful synthetic approach to obtain heterocyclic compounds using various annulation reactions, the advantages of which are it being mild and metal-free, ecologically friendly, and inexpensive.¹ Phosphine-catalyzed intermolecular [3 + 2],² [4 + 1],³ [2 + 2 + 1]⁴ and intramolecular annulations are often used to obtain pyrrole derivatives. Intermolecular [3 + 2] annulations of imines and phosphorus ylides formed in situ from allenoates, alkynes, or Morita–Baylis–Hillman carbonates under the presence of phosphine catalysts are especially the most widely used approach to synthesize pyrrolidine derivates. In these reactions, phosphorus ylides act as C–C–C synthons for the [3 + 2] annulations with a C N bond converting to a pyrrolidine ring (Scheme 1). However, literature reports on exploring new activation modes, namely, phosphorus ylides acting as C–C–N synthons for the [3 + 2] annulations, are rare.Open in a separate windowScheme 1Pyrrolidine ring formation through reaction of phosphorus ylides act as C–C–C and C–C–N synthons.β-Sulfonamido-substituted enones could be used as C–C–N synthons to form various N-based heterocycles. Catalytically activated (by amines) β-sulfonamido-substituted enones act as nucleophiles towards electron-deficient olefins or imines during [3 + 2] annulation reactions. Du''s⁵ and Pan''s groups⁶ have made outstanding contributions to this field.⁷ In 2018, Guo''s group developed a Bu₃P-catalyzed [5 + 1] annulation of γ-sulfonamido-substituted enones with N-sulfonyl-imines to obtain chiral 2,4-di-substituted imidazolidines. They also synthesized γ-sulfonamido-substituted enones attacked by phosphine catalyst and acting as C–C–C–C–N synthon (see Scheme 2).⁸ Recently, Guo et al.⁹ used β-sulfonamido-substituted enone as a phosphine acceptor as well as a C–C–N synthon for the [3 + 2] annulation with sulfamate-derived cyclic imines (see Scheme 2). Using of β-sulfonamido-substituted enone as a novel phosphine acceptor is very promising for phosphine-catalyzed reactions. Inspired by Guo''s work, we further extended the substrate scope of this reaction from sulfamate-derived cyclic imines to unsaturated ketones for the construction of pyrrolidine rings. Therefore, in this work, we report phosphine-catalyzed [3 + 2] annulation of β-sulfonamido-substituted enones and trans-α-cyano-α,β-unsaturated ketones, to synthesize highly substituted pyrrolidines (see Scheme 2), which are among the primary building blocks and the core structures of natural and bioactive compounds.¹⁰Open in a separate windowScheme 2Phosphine-catalyzed annulation of γ-sulfonamido-substituted enones and β-sulfonamido-substituted enones.We first used trans-α-cyano-α,β-unsaturated ketone 1a and β-sulfonamido-substituted enone 2a as model substrates to obtain optimum reaction conditions. Tertiary phosphine catalysts were screened with 1,2-dichloroethane (DCE) as solvent at room temperature (see † Thus, the optimum reaction conditions were determined as follows: using 20 mol% of PMe₃ as catalyst, CHCl₃ as solvent at room temperature.Optimization of reaction conditions^a

Entry	PR3	Solvent	t/h	Con./mol L−1	Yieldb (%)	drc
1	MePPh2	DCE	8	0.1	85	5 : 1
2	EtPPh2	DCE	8	0.1	74	4 : 1
3	n-PrPPh2	DCE	8	0.1	76	4 : 1
4	Me2PPh	DCE	8	0.1	82	3 : 1
5	PBu3	DCE	8	0.1	78	3 : 1
6	PMe3	DCE	8	0.1	84	6 : 1
7	PMe3	THF	8	0.1	85	7 : 1
8	PMe3	Toluene	8	0.1	75	7 : 1
9	PMe3	EtOAc	8	0.1	78	5 : 1
10	PMe3	CHCl3	8	0.1	88	8 : 1
11d	PMe3	CHCl3	8	0.1	84	8 : 1
12e	PMe3	CHCl3	8	0.1	86	8 : 1
13	PMe3	CHCl3	24	0.05	85	9.5 : 1
14	PMe3	CHCl3	48	0.033	85	11 : 1
15	PMe3	CHCl3	24	0.02	65	14 : 1
16	PMe3	CHCl3	72	0.02	86	14 : 1

Open in a separate window^aUnless otherwise indicated, all reactions were carried out at room temperature using 0.12 mmol of 1aa and 0.1 mmol of 2aa in a solvent containing 20 mol% of the catalyst.^bIsolated yield.^cDetermined by ¹H NMR.^d100 mg 3 Å molecular sieves were used.^e100 mg 4 Å molecular sieves were used.Under the optimum conditions, the performance of various trans-α-cyano-α,β-unsaturated ketone 1 with β-sulfonamido-substituted enones 2a in the cycloaddition reactions was analyzed (see 11Screening of various trans-α-cyano-α,β-unsaturated ketones as substrates^a

Entry	R1	3	Yieldb (%)	drc
1	Ph (1a)	3aa	86	14 : 1
2	2-MeC6H4 (1b)	3ba	75	10.5 : 1
3	3-MeC6H4(1c)	3ca	77	12.5 : 1
4	4-MeC6H4 (1d)	3da	78	10.5 : 1
5	4-OMeC6H4 (1e)	3ea	80	14 : 1
6	4-CF3-C6H4 (1f)	3fa	66	10.5 : 1
7	2-FC6H4 (1g)	3ga	72	9.5 : 1
8	3-FC6H4 (1h)	3ha	74	6 : 1
9	4-FC6H4 (1i)	3ia	76	5 : 1
10	2-ClC6H4 (1j)	3ja	74	8 : 1
11	3-ClC6H4(1k)	3k	76	10 : 1
12	4-ClC6H4 (1l)	3la	82	5 : 1
13	4-BrC6H4 (1m)	3ma	85	6 : 1
14	1-Naphthyl (1n)	3na	81	14 : 1
15	2-Naphthyl (1o)	3oa	80	8 : 1
16	2-thienyl (1p)	3pa	78	7 : 1
17	2-furyl (1q)	3qa	80	14 : 1

Open in a separate window^aUnless otherwise indicated, all reactions were conducted at room temperature for 3 days using 0.12 mmol of compound 1 and 0.1 mmol of compound 2 in 5 ml CHCl₃ in the presence of 20 mol% of PMe₃.^bIsolated yield.^cDetermined by ¹H NMR.We also tested various substituted enones containing different R groups under the optimal reaction conditions (see