α-Regioselective [3 + 2] annulations with Morita–Baylis–Hillman carbonates of isatins and 2-nitro-1,3-enynes

Abstract

An α-regioselective asymmetric [3 + 2] annulation reaction with Morita–Baylis–Hillman carbonates of isatins and (E)-2-nitro-1,3-enynes catalysed by cinchona-derived amines has been developed, providing spirooxindoles with contiguous chiral centres including adjacent quaternary ones in moderate to good yields with high enantioselectivity and excellent diastereoselectivity.

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Nitroolefins are versatile electrophiles which widely serve as Michael acceptors, or as dienophiles, 1,3-dipoles, and heterodienes in a diversity of cycloaddition reactions.¹ β-Monosubstituted nitroolefins are usually applied in asymmetric catalytic reactions owing to their ready availability and high reactivity. On the other hand, recent attention has also been paid to the application of more challenging α,β-disubstituted or even α,β,β-trisubstituted nitroolefins, to construct chiral quaternary stereogenic centres. Nevertheless, successful examples with high stereocontrol are still relatively limited.²

Over the past decade, the in situ generated zwitterionic allylic ylides between Morita–Baylis–Hillman (MBH) derivatives and a tertiary amine or phosphine have been utilised as 1,3-dipoles in an array of [3 + n] annulation reactions, furnishing variously structured carbo- or heterocycles efficiently.³ We successfully used β-monosubstituted nitroolefins in γ-regioselective [3 + 2] annulations with MBH carbonates of isatins under the catalysis of a chiral tertiary amine, providing chiral spirooxindoles incorporating a cyclopentadiene motif due to the easy elimination of a molecule of HNO₂.⁴ Recently, we were able to switch the preferable γ-regioselective [3 + 2] annulations to α-regioselective versions by using activated olefins bearing bulky electron-withdrawing groups.⁵ Thus, we were interested in the application of the multifunctional α,β-disubstituted nitroolefins, (E)-2-nitro-1,3-enynes, which are readily available⁶ and have not been explored in asymmetric catalysis.⁷ Owing to the unique activation effect of the α-ethynyl group,⁸ their successful assembly with MBH carbonates of isatins might not only switch the previous γ-regioselectivity, but also possibly construct complex spirooxindoles possessing adjacent quaternary chiral centres,⁹ as outlined in Scheme 1.

Scheme 1 Switchable regioselective [3 + 2] annulations by applying differently substituted nitroolefins.

The initial investigation with commonly used MBH carbonates of isatin and methyl acrylate⁴ furnished a sluggish and relatively complicated reaction; fortunately, the reaction of MBH carbonate 1a from isatin and acrylonitrile with α,β-disubstituted nitroolefin 2a proceeded very rapidly in CHCl₃ at 0 °C catalysed by DABCO C1, giving the desired α-regioselective [3 + 2] annulation product 3a in a moderate yield after only 5 minutes (Table 1, entry 1). Extending the reaction time would diminish the yield due to the generation of a few side products. Nevertheless, DMAP C2 produced a mixture of products (entry 2). To our gratification, a chiral tertiary amine β-isocupreidine¹⁰ (β-ICD) C3 efficiently catalysed the reaction, affording 3a in a modest yield with excellent diastereoselectivity and moderate enantioselectivity (entry 3). The enantioselectivity was significantly reduced by using amine C4 without an OH group (entry 4). In addition, α-isocupreine¹¹ (α-IC) C5 delivered product 3a having an opposite configuration with a slightly higher ee value (entry 5). Subsequently, a few solvents were screened under the catalysis of amine C5, while inferior results were generally obtained (entries 6–10).

Table 1 Screening studies of [3 + 2] annulations of MBH carbonates 1 and nitroolefin 2a^a

Entry	Cat.	1	Solvent	t (min)	Yield^b (%)	ee^c (%)
a Unless otherwise noted, reactions were performed with MBH carbonate 1 (0.1 mmol), nitroolefin 2 (0.11 mmol), and amine C (10 mol%) in solvent (1 mL) at 0 °C. b Isolated yield. c Determined by chiral HPLC analysis; dr >19 : 1 by ^1H NMR analysis. d At −20 °C. e With 5 mol% of C5.
1	C1	1a	CHCl3	5	3a, 68	—
2	C2	1a	CHCl3	30	—	—
3	C3	1a	CHCl3	25	3a, 72	−72
4	C4	1a	CHCl3	25	3a, 80	−30
5	C5	1a	CHCl3	30	3a, 74	80
6	C5	1a	DCM	26	3a, 74	66
7	C5	1a	DCE	540	3a, 82	80
8	C5	1a	Toluene	24	3a, 73	68
9	C5	1a	THF	40	3a, 67	60
10	C5	1a	EtOAc	90	3a, 65	63
11^d	C5	1a	CHCl3	60	3a, 80	78
12	C5	1b	CHCl3	18	3b, 71	80
13	C5	1c	CHCl 3	25	3c , 88	87
14	C3	1c	CHCl 3	26	3c , 71	−92
15^e	C5	1c	CHCl3	75	3c, 65	86

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Furthermore, the enantioselectivity could not be improved by conducting the reaction in CHCl₃ at lower temperature (entry 11). The same enantioselectivity was attained for product 3b by employing an N-MOM protected MBH carbonate 1b (entry 12); pleasingly, a better ee value was gained for product 3c bearing an N-benzyl group (entry 13), while β-ICD C3 produced 3c even in higher enantioselectivity, albeit in a lower yield (entry 14). Finally, reducing the catalyst loadings (5 mol%) resulted in a lower yield, while the enantioselectivity remained unchanged (entry 15).

Consequently, the scope of MBH carbonates 1 derived from isatins and (E)-2-nitro-1,3-enynes 2 was investigated under the catalysis of α-IC C5 in CHCl₃ at 0 °C. In general, the tested reactions exhibited high reactivity, and the results are summarised in Table 2. At first, an array of MBH carbonates 1 bearing either electron-withdrawing or -donating substituents on different positions of the oxindole skeleton were investigated with nitroolefin 2a, generally affording the corresponding α-regioselective spirooxindole products 3d–3i in good yields with high to excellent enantioselectivity (Table 2, entries 2–7). On the other hand, a spectrum of (E)-2-nitro-1,3-enynes 2 with diverse 3-aryl groups were tested in reactions with MBH carbonate 1a as well. Higher ee values were observed for the more electron-rich substrates (entries 8–10). In contrast, moderate enantioselectivity was obtained for nitroolefins with electron-withdrawing substituents (entries 11–14), while the meta-substituted one seemed to have a beneficial effect on the enantiocontrol (entry 12). A high ee value was obtained for the 2-naphthyl-substituted nitroolefin (entry 15); however, very low reactivity was observed for the 2-thienyl-substituted substrate, and no desired product was isolated (entry 16). Moreover, the (E)-2-nitro-1,3-enyne by replacing BnOCH₂– with a phenyl group showed lower reactivity, while good data were attained after 2 hours (entry 17). Unfortunately, the 4-alkyl-substituted substrate failed to give the desired product (entry 18).¹² Finally, it was found that β-ICD C3 could promote the similar [3 + 2] annulation of a MBH carbonate from isatin and methyl acrylate with nitroolefin 2a in excellent enantioselectivity, though a modest yield was obtained after 48 hours (entry 19). Moreover, a few substrates were investigated catalysed by β-ICD C3, and the desired annulation products with an opposite configuration were obtained in moderate yields but with similar good enantioselectivity to those of α-IC C5 (data in the parentheses).

Table 2 Substrate scope of [3 + 2] annulations of MBH carbonates 1 and nitroolefins 2^a

Entry	R	Ar	t (min)	Yield^b (%)	ee^c (%)
a Unless otherwise noted, reactions were performed with MBH carbonate 1 (0.1 mmol), nitroolefin 2 (0.11 mmol), and amine C5 (10 mol%) in CHCl3 (1 mL) at 0 °C; R^1 = Bn, EWG = CN, R^2 = BnOCH2–. b Isolated yield. c Based on chiral HPLC analysis; dr >19 : 1 by ^1H NMR analysis. d R^2 = Ph. e R^2 = nPr. f R^1 = Me, EWG = COOMe, with β-ICD C3 for 48 h.
1	H	Ph	25	3c, 88 (71)	87 (−92)
2	5-Me	Ph	25	3d, 83	86
3	5-MeO	Ph	22	3e, 88	95
4	5-F	Ph	9	3f, 72	86
5	5-Cl	Ph	7	3g, 81	84
6	6-Br	Ph	38	3h, 86	82
7	7-Cl	Ph	6	3i, 81 (63)	86 (−84)
8	H	4-MeC6H4	6	3j, 85	86
9	H	2-MeOC6H4	5	3k, 91 (70)	93 (−94)
10	H	4-MeOC6H4	13	3l, 81	85
11	H	4-FC6H4	45	3m, 79	72
12	H	3-ClC6H4	13	3n, 78	87
13	H	4-ClC6H4	11	3o, 85	74
14	H	3-CF3C6H4	36	3p, 71	79
15	H	2-Naphthyl	26	3q, 85 (65)	90 (−90)
16	H	2-Thienyl	30	—	—
17^d	H	Ph	120	3r, 84	88
18^e	H	Ph	120	—	—
19^f	H	Ph	48	3s, 54	−98

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On the other hand, single crystals suitable for X-ray diffraction analysis were obtained from chiral product 3s catalysed by β-ICD C3, which unambiguously determined the α-regioselective annulation pattern and its absolute configuration, as illustrated in Scheme 2. Thus, the absolute configuration of other products catalysed by α-IC C5, which possesses an opposite configuration, could be assigned accordingly.

Scheme 2 X-ray structure of enantiopure 3s. Thermal ellipsoids are shown at 30% probability.

A spirocyclic oxindole 4 incorporating a cyclopentadiene motif was synthesised smoothly from product 3r through the DBU-promoted elimination of HNO₂. The attempt to reduce the nitro group of 3r with Zn dust in AcOH generated an NHOH intermediate, from which an intramolecular O-Michael addition occurred to give a bridged heterocycle 5 in a poor diastereomeric ratio (Scheme 3).¹³

Scheme 3 Synthetic transformations of 3r.

In conclusion, we have developed a highly efficient [3 + 2] annulation reaction of MBH carbonates derived from isatins with (E)-2-nitro-1,3-enynes catalysed by bifunctional tertiary amines from cinchona alkaloids. The reaction exhibited exclusive α-regioselectivity and usually completed in half an hour, constructing densely functionalised spirooxindoles possessing contiguous chiral centres including adjacent quaternary ones in moderate to excellent enantioselectivity. More results in regard to the application of MBH derivatives will be reported in due course.

We are grateful for the financial support from the National Natural Science Foundation of China (21125206, 21572135 and 21321061).

Notes and references

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13. For more details, see the ESI.†.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, structural proof, and CIF file of 3s. CCDC 1470348. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6qo00118a

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