Interception of benzyne with thioethers: a facile access to sulfur ylides under mild conditions

Abstract

Reactive benzyne generated from o-(trimethylsilyl)phenyl triflate under the action of CsF has been trapped in situ by thioethers to give sulfonium ylides, which in turn have been intercepted by isatins to give rise to corresponding spiroepoxy oxindoles in moderate to high yields. This reaction provides a facile and efficient synthesis of spiroepoxy oxindoles.

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Since being discovered in 1930,¹ sulfonium ylides have been involved in various transformations, such as epoxidation of aldehydes/ketones,² aziridination of imines,³ cyclopropanation of conjugated enones/enoates and their congeners,^2c,4 as well as 2,3-Wittig rearrangement of allylic/propargyl sulfonium ylides,⁵ providing invaluable synthetic methods. Recently, Aggarwal group has made great advances in sulfonium ylide mediated catalytic asymmetric epoxidation.⁶ The Tang laboratory has also achieved a series of excellent asymmetric Michael addition/cyclization cascades triggered by sulfonium ylides;^4c,7 moreover Xiao and colleagues have disclosed several efficient heterocyclic synthesis featuring formal [4 + 1] cycloaddition on sulfonium ylides.⁸ Although there exist a handful of methods for sulfonium ylide formation,⁹ deprotonation of corresponding sulfonium salts constitutes the major avenue to the ylide formation due to their inherent benefits (Method A, Fig. 1).¹⁰ Reaction of thioethers with carbenes/metal carbenoids constitutes a second consequential approach which has found broad applications (Method B, Fig. 1).^10a,11 Another elegant yet undeveloped strategy for sulfonium ylide formation, namely, nucleophilic attack of alkyl thioether on benzyne followed by an intramolecular 1,4-proton shift (Method C, Fig. 1)¹² has been almost totally neglected since its debut, wherein the o-fluorophenylmagnesium bromide was employed as the benzyne precursor, as few further investigations have followed.¹³ The poor compatibility of these protocols with some common functional groups seriously limited their applications.

Fig. 1 Three strategies to generate sulfonium ylide.

Recent flourishing advances in the area of aryne chemistry have brought new reactivities and applications to these highly reactive intermediates.¹⁴ This resurgence in aryne chemistry is attributed largely to the introduction of o-(trimethylsilyl)aryl triflates, by Kobayashi et al., as convenient and efficient aryne precursors that require only very mild conditions (weakly basic fluoride anion source and ambient temperature) to promote the in situ formation of corresponding arynes.¹⁵ We therefore decided to use o-(trimethylsilyl)aryl triflate to revisit the thioether/benzyne strategy of sulfonium ylide formation, hoping to develop new synthetic processes. Here we report a convenient one-pot synthesis of epoxyoxindoles¹⁶ via this thioether/benzyne strategy.

We chose cinnamyl p-tolyl sulfide (2a) and N-methyl isatin (3a) as benzyne interceptor and sulfonium ylide interceptor respectively to test this strategy.¹⁷ Thus a mixture of 1, 2a, and 3a with cesium fluoride (1/2a/3a/CsF : 1.2/1.5/1.0/3.0) in anhydrous acetonitrile was vigorously stirred overnight at room temperature. A pair of diastereoisomers (cis-4a and trans-4a) was isolated in 25% yield, and the by-product phenyl tolyl thioether 5a was also collected and identified. These observations confirmed our proposal. Brief screening of solvents quickly distinguished acetonitrile as a better reaction medium than other solvents such as tetrahydrofuran, ethyl acetate, N,N-dimethylformamide and dichloromethane. Further optimization was carried out in acetonitrile and the results were shown in Table 1. When the reaction mixture was stirred overnight at 40 °C, the epoxide isomers 4aa was obtained in 87% yield (entry 2), much higher than both at 25 °C (entry 3, 68%) and at 80 °C (entry 4, 41%). With the isatin 3a as limiting reagent, the reaction gave diastereomers 4aa in 68% yield at 40 °C (entry 5). Interestingly, the modest Dr value obtained at room temperature improved toward the trans-product evidently as the reaction temperature increased (entries 1–4).

Table 1 Optimization of reaction conditions^a

Entry	1/2a/3a/CsF	T (°C)	Yield^b (%)	Dr^c (cis/trans)
a All reactions were performed on 0.25 mmol of N-methyl isatin 3a with o-(trimethylsilyl)aryl triflate 1, thioether 2a, and CsF in anhydrous acetonitrile.b Sum of isolated yields of cis-4aa and trans-4aa after column chromatography, based on the isatin.c Determined by the isolated yields of two isomers.d Yield based on 1.
1	1.2/1.5/1.0/3.0	25	68	56/44
2	1.2/1.5/1.0/3.0	40	87	44/56
3	1.2/1.5/1.0/3.0	60	65	35/65
4	1.2/1.5/1.0/3.0	80	41	21/79
5	1.0/1.0/1.6/3.0	40	68^d	27/73

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At this stage, the optimal conditions in Table 1 were set as standards (conditions for entry 2 Table 1) for further studies. A number of substituted isatins 3b–k were subjected to the standard conditions to test the substitution effects on isatin aromatic ring (Table 2). These data demonstrated that the electronic property undoubtedly exerts profound effects on the reactions, notably manifested by the yields of the corresponding 5-subtituted spiroepoxy oxindoles 4, which roughly parallel with the donating/withdrawing abilities of their 5-subtituents (entries 1–7). Strong electron donating 5-methoxyl group gave 4ac in a yield as low as 32%, while strong electron withdrawing 5-NO₂ and 5-F groups delivered 4ag and 4af in 84% and 93% yields respectively; isatins 3b, 3d and 3e bearing relatively weaker electron donating groups on 5-position resulted in moderate yields. 7-Cl isatin 3k under standard conditions achieved better yield (entry 11) than its 5- and 6-congeners (entries 5 and 9); and 4-Br isatin 3h showed a less negative impact on the yield in comparison to its 5-epimer (entry 8 vs. 4), yet still less than the parent isatin 3a (entry 1). The impressive electronic and positional effects, though lacking concrete rationale at this time, may indicate that the epoxidation of isatin proceeded stepwise with the first step, namely, the nucleophilic attack of ylide on the isatin carbonyl group, as the rate limiting step. Overall, this tandem reaction is fairly non-diastereoselective, even though the steric effect at 4-position favours the cis-isomer more than the anti-isomer as exhibited by the highest cis/trans ratio of 76/24 presented in Table 2 entry 8 probably due to steric effect.

Table 2 Substituent effects on isatin aromatic ring^a

Entry	Istatin 3, R	Product 4 yield^b %	Dr^c (cis : trans)
a All reactions were performed on 0.25 mmol of isatins 3 with o-(trimethylsilyl)aryl triflates 1 (1.2 equiv.), thioether 2a (1.5 equiv.), and CsF (3.0 equiv.) in anhydrous acetonitrile at 40 °C overnight.b Sum of isolated yields of cis-4 and trans-4 after column chromatography, based on the isatin.c Determined by the isolated yields of two isomers.
1	3a, H	4aa, 87	44 : 56
2	3b, 5-CH3	4ab, 50	54 : 46
3	3c, 5-OMe	4ac, 32	59 : 41
4	3d, 5-Br	4ad, 36	53 : 47
5	3e, 5-Cl	4ae, 58	43 : 57
6	3f, 5-F	4af, 93	33 : 67
7	3g, 5-NO2	4ag, 84	45 : 55
8	3h, 4-Br	4ah, 64	76 : 24
9	3i, 6-Cl	4ai, 42	45 : 55
10	3j, 6-F	4aj, 31	43 : 57
11	3k, 7-Cl	4ak, 70	49 : 51

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With isatin 3f as epoxidation acceptor, a series of thioethers 2 were examined under standard conditions, the results are charted in Table 3 allylic, benzylic and simple alkyl aryl thioethers all give good to excellent yields. As previously observed, the diastereoselectivities are normally low and steric bulkiness seems be an important factor which favours cis-isomers over their trans-counterparts. More sterically demanding benzylic thioethers 2c–f reversed the cis/trans ratio with an exception of 2-NO₂ benzylic sulfide 4bf whose strong dipolar nature may be involved to some extent in the transition state.

Table 3 The substrate scope of thioethers^a

Entry	Sulfide 2, Ar, R	Product 4 yield^b (%)	Dr^c (cis : trans)
a All reactions were performed on 0.25 mmol of isatins 3a with o-(trimethylsilyl)aryl triflates 1 (1.2 equiv.), thioether 2 (1.5 equiv.), and CsF (3.0 equiv.) in anhydrous acetonitrile at 40 °C overnight.b Sum of isolated yields of cis-4 and trans-4 after column chromatography, based on the isatin.c Estimated on the isolated yield.d Determined via the ^1H NMR of the crude product. Z-PV = Z-phenylvinyl.
1	2a, p-MePh, Z-PV	4af, 93	33 : 67
2	2b, p-MePh, 2-NO2Ph	4bf, 99	31 : 69^d
3	2c, p-MePh, 2-ClPh	4cf, 74	57 : 43^d
4	2d, p-MePh, 3-FPh	4df, 89	74 : 26
5	2e, p-MePh, 3-ClPh	4ef, 83	81 : 19
6	2f, p-MePh, 4-ClPh	4ff, 92	70 : 30
7	2g, p-MePh, CHCH2	4gf, 73	46 : 56
8	2h, Ph, Ph	4hf, 83	61 : 39
9	2i, Ph, Me	4if, 85	47 : 53

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The structure of these spiroepoxides has been established by NMR spectra and high resolution mass spectra. Specifically, four pairs of representative diastereoisomers of 4af, 4ag, 4ff and 4gf were each submitted to acquire 2D ¹H–¹H NOESY spectrum. The presence of cross-peaks at the 4-H next to the fluoride atom and the epoxide H set a key diagnosis interactions which distinguished the cis-configuration from its anti-counterpart without doubt (refer to the NOESY spectra in ESI†). The relative stereochemistry of the others was assigned by analogy to those four pairs.

A possible mechanism for this process has been outline in Fig. 2. O-(trimethylsilyl)aryl triflate 1 is converted to the reactive benzyne 6, which is attacked by thioether 2 delivering intermediate zwitterion 7. Immediate intramolecular 1,3-proton shift from the alkyl carbon onto the aromatic carbon produces sulfonium ylide 8. Reaction of 8 with isatin 3 gives the spiroepoxide 4 via intermediate 9.

Fig. 2 Proposed mechanism for the cascade of benzyne formation, sulfonium ylide formation and epoxidation.

Conclusions

In summary, we have established a one pot process to spiro epoxyoxindoles. This method features two successive in situ capturing steps of reactive intermediates in very mild conditions. The use of o-(trimethylsilyl)aryl triflate as benzyne source upon a fluoride activation is the base for this improved protocol.

Acknowledgements

We thank the Natural Science Foundation of China (21002032 and 21272077), Shanghai Pujiang Program (11PJ1403100), Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), and the Natural Science Foundation of Jiangsu Province (SBK201321632) for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: General experimental information, detailed procedures, characterize data of compounds, copies of ¹H and ¹³C NMR spectra for selected compounds. See DOI: 10.1039/c3ra47206j

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