Regio- and diastereoselective construction of 1′,2′-(dihydrospiro[indoline-3,3′-pyrrol]-2′-yl)acrylates through phosphine-catalyzed [4 + 1] annulation of Morita–Baylis–Hillman carbonates with oxindole-derived α,β-unsaturated imines

Abstract

Phosphine-catalyzed [4 + 1] annulation of Morita–Baylis–Hillman (MBH) carbonates with oxindole-derived α,β-unsaturated imines has been developed, giving the corresponding 1′,2′-(dihydrospiro[indoline-3,3′-pyrrol]-2′-yl)acrylates in moderate to good yields and diastereoselectivities under mild conditions.

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Spirooxindole backbones have drawn tremendous interest in the area of synthetic organic chemistry and medicinal chemistry since they are the core structures in a variety of pharmacological agents and natural alkaloids¹ and have various types of biological activities.² For example, the 1′,2′-dihydrospiro[indoline-3,3′-pyrrol]-2-one featuring the molecular structures of spirotryprostatin B is a mammalian cell cycle inhibitor.^1d Moreover, the spiro[indoline-3,3′-pyrrolidin]-2-one skeleton as a structural characteristic has been found in alkaloid rhynchophylline (Fig. 1).^1b Therefore, they have recently become one of the most attractive synthetic targets for organic chemists. Subsequently, many kinds of elegant synthetic approaches have been thus far developed for their syntheses.³

Fig. 1 Selected examples of natural products with spirooxindole motifs.

Over the past decade, nucleophilic phosphine catalysis has made significant progress⁴ and phosphine-mediated/catalyzed annulations have emerged as a powerful tool for the synthesis of a variety of unique carbo- and heterocyclic frameworks.⁵ In this arena, Lu and coworkers first reported a series of intra- and intermolecular [3 + n] annulations (n = 2, 4, 6) using Morita–Baylis–Hillman (MBH) carbonates as 1,3-dipoles with various electron-deficient olefins catalyzed by tertiary phosphine, affording the corresponding cycloadducts in good yield and high regioselectivities under mild conditions.⁶ Furthermore, [3 + 2] annulations of allenoates/alkynes or MBH acetate/carbonates with electron-deficient alkenes or imines have been widely explored and established as an effective method for constructing a wide range of highly functionalized five-membered ring systems.⁷ Apart from phosphine-catalyzed [3 + 2] annulations, phosphine-catalyzed [4 + 1] annulations are also efficient methodologies to construct functionalized five-membered carbo- and heterocycles. Recently, Zhang,⁸ Huang,⁹ He,¹⁰ Shi,¹¹ Lu¹² and Fu¹³ as well as their co-workers have developed many [4 + 1] annulations utilizing MBH carbonates, maleimides¹⁴ or others as 1,1-dipoles with various electron-deficient alkenes to obtain the desired heterocyclic products in high yields under mild conditions, respectively also along with their asymmetric versions. Another type of [4 + 1] annulation was disclosed by Tong¹⁵ in 2010, using 2,3-butadienoate as a C₄ synthon under phosphine catalysis to construct cyclopentene containing products.

α,β-unsaturated imines as synthetically useful C₂ or C₄ synthons have been widely utilized to construct multifunctional five- and six-membered heterocycles.^10a,16,17 Our group has reported an efficient method to construct spiro-fused six-membered heterocycles through [4 + 2] annulations of vinyl ketones with oxindole-derived α,β-unsaturated imines in the presence of phosphine.^17c However, to the best of our knowledge, there has been no report on phosphine-catalyzed synthesis of isatin-based spiro-fused five-membered heterocycles through [4 + 1] annulation by oxindole-derived α,β-unsaturated imines.¹⁷ Herein, we wish to disclose a phosphine-catalyzed regio- and diastereoselective [4 + 1] annulation of MBH carbonates with oxindole-derived α,β-unsaturated imines to produce 1′,2′-(dihydrospiro[indoline-3,3′-pyrrol]-2′-yl)acrylates in moderate to good yields and moderate to good diastereoselectivities under mild conditions (Scheme 1).

Scheme 1 Phosphine-catalyzed annulations of oxindole-derived α,β-unsaturated imines to construct six- or five-membered spiro heterocyclic compounds.

Initially, we examined the reaction outcome of oxindole-derived α,β-unsaturated imine 1a (0.1 mmol) with MBH carbonate 2a (0.12 mmol, 1.2 equiv.) catalyzed by PPh₃ in toluene (1.0 mL) at room temperature. The desired [4 + 1] cycloadduct 3a was obtained in 90% total yield along with 1.2 : 1 dr value within 24 h (Table 1, entry 1). To improve the dr value, other phosphines such as P(p-MeOC₆H₄)₃, P(p-FC₆H₄)₃, PPh₂Me, PPhMe₂, PBu₃, and dppb were further tested in this reaction and the results of these experiments are summarized in Table 1. It was found that PPh₂Me is the best catalyst, affording 3a in 90% total yield along with 5.5 : 1 dr value (Table 1, entries 1–7). We next examined the solvent effects of this reaction in CH₂Cl₂, THF, MeCN or Et₂O. It was found that toluene is the best solvent in this reaction (Table 1, entries 8–11). Reducing the reaction temperature to 0 °C gave the corresponding annulation product 3a in 88% total yield along with 8 : 1 dr (Table 1, entry 12). Therefore, the best reaction conditions have been determined as that using PPh₂Me (20 mol%) as the catalyst and carrying out the reaction in toluene at 0 °C within 24 hours.

Table 1 Optimization of reaction conditions for the [4 + 1] annulation

Entry	Catalyst	Solvent	Time (h)	Yield^a (%)	dr^b (%)
a Yield was determined by ^1H NMR spectroscopic data of crude products using 1,3,5-trimethoxybenzene as a calibrated internal standard.b Determined ^1H NMR spectroscopic data of crude products.c The reaction mixtures were stirred at 0 °C.
1	PPh3	Toluene	24	90	1.2 : 1
2	P(p-MeOC6H4)3	Toluene	24	78	4 : 1
3	P(p-FC6H4)3	Toluene	48	82	1.6 : 1
4	PPh2Me	Toluene	24	90	5.5 : 1
5	PPhMe2	Toluene	12	89	1.2 : 1
6	PBu3	Toluene	12	55	1.1 : 1
7	dppb	Toluene	24	60	4 : 1
8	PPh2Me	CH2Cl2	24	69	2 : 1
9	PPh2Me	THF	24	66	3 : 1
10	PPh2Me	MeCN	24	65	3 : 1
11	PPh2Me	Et2O	24	81	3 : 1
12^c	PPh2Me	Toluene	24	88	8 : 1

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With the optimized reaction conditions in hand, we next turned our attention to the scope and limitations of this reaction using a variety of oxindole-derived α,β-unsaturated imines 1 with MBH carbonates 2 and the results are summarized in Table 2. Using MBH carbonate 2a as substrate, we examined its reaction with various substituted oxindole-derived α,β-unsaturated imines 1b–1t and found that these [4 + 1] annulation proceeded smoothly to give the desired products in moderate to good yields. Substrates with electron-rich or electron-withdrawing substituents on the Ar group gave the corresponding products 3b–3g in good yields (up to 95% yield) and good dr values (up to 9 : 1 dr), respectively (Table 2, entries 1–6). We next examined oxindole-derived α,β-unsaturated imines 1h–1o bearing different substituents on their benzene rings of oxindole or having different N-protecting groups, and it was found that all of the reactions proceeded very well to produce the corresponding products 3h–3o in moderate to good yields along with good dr values (Table 2, entries 7–14). It should be pointed out that when electron-withdrawing substituents were introduced on their benzene rings, the reactions afforded the desired products in slightly lower yields, but with better diastereoselectivities perhaps due to the electronic effect (Table 2, entries 9–14). When R² was a heteroaromatic group (R² = 2-thienyl), the reactions also proceeded efficiently to produce the corresponding products 3p–3r in good yields and good dr values, respectively (Table 2, entries 15–17). When R² was a sterically more bulky 2,4,6-triisopropylphenyl moiety, the desired spirooxindole products 3s and 3t could also be obtained in good yields, but in lower diastereoselectivities (Table 2, entries 18 and 19). The relative configuration of the major diastereoisomer of 3t was assigned by X-ray diffraction (see the ESI†).¹⁸ Ethyl 2-(((tert-butoxycarbonyl)oxy)methyl)acrylate 2b was also used to react with 1a, affording the corresponding product 3u in 85% yield and moderate dr value (dr = 5 : 1) (Table 2, entry 20) and the configuration of the major diastereoisomer of 3u was also assigned by X-ray diffraction. Its ORTEP drawing is shown in Fig. 2 and the corresponding CIF data are presented in the ESI.†¹⁸

Table 2 Substrate scope of the [4 + 1] annulation of 1 with 2

Entry^a	Ar	R^1	R^2	R^3	R^4	Yield^b (%)	dr^c
a 1 (0.2 mmol), 2 (0.3 mmol) and PPh2Me (0.04 mmol) were stirred in 1.0 mL of toluene at 0 °C within 24 h.b Isolated yield.c Determined by ^1H NMR spectroscopic data of crude products.
1	4-FC6H4	H	4-Methylphenyl	Me	^tBu	3b, 72	8 : 1
2	4-ClC6H4	H	4-Methylphenyl	Me	^tBu	3c, 84	8 : 1
3	4-BrC6H4	H	4-Methylphenyl	Me	^tBu	3d, 78	7 : 1
4	4-MeOC6H4	H	4-Methylphenyl	Me	^tBu	3e, 95	9 : 1
5	4-MeC6H4	H	4-Methylphenyl	Me	^tBu	3f, 86	7 : 1
6	4-(CH3)3CC6H4	H	4-Methylphenyl	Me	^tBu	3g, 88	7 : 1
7	4-MeOC6H4	5-Me	4-Methylphenyl	Me	^tBu	3h, 88	9 : 1
8	4-MeOC6H4	6-MeO	4-Methylphenyl	Me	^tBu	3i, 84	5 : 1
9	4-MeOC6H4	5 F	4-Methylphenyl	Me	^tBu	3j, 63	20 : 1
10	4-MeOC6H4	5-Cl	4-Methylphenyl	Me	^tBu	3k, 65	20 : 1
11	4-MeOC6H4	6-Cl	4-Methylphenyl	Me	^tBu	3l, 54	20 : 1
12	4-MeOC6H4	5-Br	4-Methylphenyl	Me	^tBu	3m, 68	20 : 1
13	C6H5	5-Cl	4-Methylphenyl	Bn	^tBu	3n, 62	12 : 1
14	C6H5	5-Cl	4-Methylphenyl	Allyl	^tBu	3o, 68	10 : 1
15	C6H5	H	2-Thienyl	Me	^tBu	3p, 84	9 : 1
16	4-MeOC6H4	H	2-Thienyl	Me	^tBu	3q, 80	8 : 1
17	4-MeC6H4	H	2-Thienyl	Me	^tBu	3r, 76	7 : 1
18	4-ClC6H4	H	2,4,6-Triisopropylphenyl	Me	^tBu	3s, 83	4 : 1
19	4-BrC6H4	H	2,4,6-Triisopropylphenyl	Me	^tBu	3t, 82	4 : 1
20	C6H5	H	4-Methylphenyl	Me	Et	3u, 85	5 : 1

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Fig. 2 X-ray crystal structure of the major diastereomeric product 3u.

Next, we examined the asymmetric [4 + 1] annulation of 1a with MBH carbonate 2a using natural amino acid derived chiral phosphine catalyst CP,^18,19 giving the corresponding cycloadduct 3a in 78% isolated yield along with 7 : 1 dr and 61% ee value for the major diastereomeric isomer in toluene at room temperature (Scheme 2).

Scheme 2 Asymmetric [4 + 1] annulation catalyzed by chiral phosphine catalyst CP.

On the basis of above experimental results and closely related reports,^6d,8,9,10,11 a plausible reaction mechanism has been outlined in Scheme 3. PPh₂Me attacks from the β-position of MBH carbonate 2 to take off carbon dioxide and t-BuOH, affording phosphorus ylide I, which undergoes the nucleophilic attack with α,β-unsaturated imine 1a to give the corresponding intermediate II. Subsequent hydrogen transfer produces intermediate III, which is followed by a Michael addition and elimination of PPh₂Me to produce 3.

Scheme 3 A plausible reaction mechanism.

In summary, we have developed an interesting phosphine-catalyzed regio- and diastereoselective [4 + 1] annulation of MBH carbonates with oxindole-derived α,β-unsaturated imines, affording the corresponding functionalized 1′,2′-(dihydrospiro[indoline-3,3′-pyrrol]-2′-yl)acrylates in moderate to good yields and dr values under mild conditions. A plausible reaction mechanism has also been proposed on the basis of previous literature. Further efforts in our laboratory will focus on exploring the more effective asymmetric version and possible application of this annulation in organic synthesis.

Acknowledgements

We are grateful for the financial support from the National Basic Research Program of China (973)-2015CB856603, and the National Natural Science Foundation of China (20472096, 21372241, 21361140350, 20672127, 21421091, 21372250, 21121062, 21302203 and 20732008).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterization data of new compounds. CCDC 1024783 and 1019412. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra09147k

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