Ag-catalyzed diastereoselective [6 + 3] cycloaddition of tropone with homoserine lactone-derived azomethine ylides: synthesis of tricyclic spiropiperidines

Abstract

Ag-catalyzed [6 + 3] cycloaddition of tropone with homoserine lactone derived azomethine ylides has been developed. The reaction works efficiently under mild conditions to give tricyclic spiropiperidines in moderate to excellent yields with excellent diastereoselectivities.

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The 1,3-dipolar cycloaddition reaction provides a reliable tool for synthesis of diverse heterocyclic compounds from simple starting materials.¹ In the past three decades, lots of 1,3-dipolar cycloaddition reactions of a wide range of 1,3-dipoles such as azomethine ylides, azomethine imines, nitrones, carbonyl ylides and azides etc. have successfully been developed. Among these cycloadditions, the 1,3-diploar cycloaddition reactions with the use of azomethine ylide as one of the reaction partners have become an active research area,² since Zhang³ and Jørgensen⁴ reported the first example of the catalytic asymmetric 1,3-dipolar [3 + 2] cycloaddition of azomethine ylides derived from iminoesters with activated alkenes. A variety of cycloaddition reactions involving azomethine ylides such as [3 + 2],^2,5 [3 + 3]⁶ and [6 + 3]⁷ cycloadditions have been reported. Especially, the catalytic asymmetric 1,3-dipolar [3 + 2] cycloaddition of azomethine ylides with electron-deficient alkenes is the most studied reaction in these reactions and has emerged as an extremely useful tool for the enantioselective preparation of structurally diverse pyrrolidines.^2,5 Besides well-established [3 + 2] cycloaddition reactions,^2,5 other types of cycloaddition reactions of azomethine ylides have also attracted increasing attention in recent five years.^6,7 Particularly, since the higher-order cycloaddition provides a rapid and facile excess to medium-sized carbo- and heterocycles from a wide range of simpler precursors, the research on higher-order cycloaddition of azomethine ylides is very significant. However, in contrast to the substantial amount of work on [3 + 2] cycloaddition reactions of azomethine ylides, the research on these higher-order cycloaddition reactions is not very fruitful and only very limited successful examples have been disclosed. In 2003, [6 + 3] cycloaddition of azomethine ylides with fulvenes was first achieved to give piperidine derivatives with high stereoselectivity.^7a Nearly ten years later, through using chiral copper catalyst, catalytic asymmetric [6 + 3] cycloaddition of azomethine ylides with fulvenes was also developed, providing chiral piperidine derivatives with four stereocenters in high yields with high regio- and enantioselectivities.^7b–d In 2014, metal-catalyzed [6 + 3] cycloaddition of azomethine ylides with tropone was accomplished to afford piperidine-fused bicyclic heterocycles in moderate to excellent yields with excellent enantioselectivities and moderate to excellent diastereoselectivies.^7e,f Most recently, metal-catalyzed asymmetric [6 + 3] cycloaddition of azomethine ylides with acyl cycloheptatrienes was disclosed to produce piperidine derivatives in moderate to high yields with good to excellent diastereo- and enantioselectivies.^7g,h On the basis of our previous work on [6 + 3] cycloaddition of azomethine ylides with tropone,^7e we hope to continue to expand the scope of azomethine ylides to homoserine lactone-derived azomethine ylides, which provide a good scaffold for synthesis of spirocyclic heterocyclic compounds. The homoserine lactone-derived azomethine ylides could be conveniently prepared from homoserine lactone and aldehydes, and have been used in couples of cycloaddition reactions for synthesis of spirocyclic heterocyclic compounds.^6b,8 As the other reaction partner, tropone is commercially available and a very useful substrate for higher-order cycloaddition reaction. With the use of tropone as the component, a range of cycloaddition reactions including [6 + 3],⁹ [6 + 4],¹⁰ [8 + 2],¹¹ or [8 + 3]¹² cycloadditions had been achieved for synthesis of bioactive molecules and natural products.¹³ As our continuous efforts on 1,3-dipoles-based cycloaddition reactions,¹⁴ we herein present Ag-catalyzed [6 + 3] cycloaddition of tropone with homoserine lactone derived azomethine ylides to synthesize biologically important tricyclic spiropiperidine derivatives (Scheme 1).

Scheme 1 Ag-catalyzed [6 + 3] cycloaddition of tropone with homoserine lactone derived azomethine ylides.

Our studies began with the identification of the optimized reaction conditions using tropone 1a and homoserine lactone 2a as model substrate (Table 1). In our previous work,^7e we have observed that Ag(I)/Ph₃P catalytic system was very efficient for [6 + 3] cycloaddition of tropone with azomethine ylides. On the basis of these observations, we first screened a series of Ag(I) salts in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) with the use of methanol as the solvent at room temperature (entries 1–5). As showed in the Table 1, several commercially available Ag salts such as AgBF₄, AgSO₃CF₃, AgSO₃CH₃ and AgCO₂CF₃ could promote the reaction, but only produced the tricyclic spiropiperidine derivative 3a as major diastereomer in moderate yields with excellent enantioselectivity (>20 : 1 dr). In contrast, AgOAc displayed very excellent catalytic activity, leading to the cycloadduct 3a in 92% yield (entry 5). Further attempts to improve the yield through variation of amount of DBU were not successful. Decreasing the amount of DBU to 10 mol% led to a dramatic drop of yield to 30% (entry 6). But increasing the amount of DBU to 30 mol% had no influence on the yield (entry 7). In order to further increase the yield, several Lewis bases such as triethylamine (Et₃N), 1,4-diazabicyclo[2.2.2]octane (DABCO) and 4-dimethylaminopyridine (DMAP) were also investigated. Unfortunately, all these bases resulted in lower yields than DBU did (entries 8–10). With the use of AgOAc/PPh₃ (10 mol%) as the catalyst and DBU (20 mol%) as the base, we next screened a series of solvents (entries 11–13). The results showed that in dichloromethane, THF or CH₃CN, only poor to moderate yields were obtained. Finally, we tried increasing the reaction temperature to further improve the reaction yield, but a slight lower yield was observed, in comparison with the yield at room temperature (entry 14 vs. 5). The relative configuration of the cycloadduct 3a was determined by X-ray crystallographic analysis (Fig. 1).¹⁵

Table 1 Screening of the reaction conditions^a

Entry	Metal salts	Base (mol%)	Solvent	Yield^b (%)
a Unless otherwise noted, reactions of 1 (0.3 mmol) and 2a (0.45 mmol) were carried out in the presence of metal salt (10 mol%) and PPh3 (20 mol%) and base at room temperature in 3 mL of methanol.b Isolated yield. >20 : 1 dr, determined by ^1H NMR analysis of the crude product.c The reaction was performed at 50 °C.
1	AgBF4	DBU (20)	MeOH	41
2	AgSO3CF3	DBU (20)	MeOH	77
3	AgSO3CH3	DBU (20)	MeOH	75
4	AgCO2CF3	DBU (20)	MeOH	36
5	AgOAc	DBU (20)	MeOH	92
6	AgOAc	DBU (10)	MeOH	31
7	AgOAc	DBU (30)	MeOH	90
8	AgOAc	Et3N (20)	MeOH	65
9	AgOAc	DABCO (20)	MeOH	85
10	AgOAc	DMAP (20)	MeOH	34
11	AgOAc	DBU (20)	CH2Cl2	52
12	AgOAc	DBU (20)	THF	27
13	AgOAc	DBU (20)	CH3CN	41
14^c	AgOAc	DBU (20)	MeOH	88

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Fig. 1 The X-ray crystallographic structure of the product 3a.

Under the optimized reaction conditions, a range of homoserine lactone derived azomethine ylides were investigated. As shown in Table 2, with the use of AgOAc/PPh₃ as the catalyst and in the presence of DBU, various azomethine ylides prepared from homoserine lactone and aromatic aldehydes bearing both electron-donating and electron-withdrawing substituents underwent [6 + 3] cycloaddition with tropone at room temperature to afford tricyclic spiropiperidine heterocyclic compounds (3b–3k) in moderate to good yields with excellent diastereoselectivities (>20 : 1 dr). The position of substituent on the benzene ring in the azomethine ylides seemed to have no remarkable influence on the yield and diastereoselectivity. Particularly, the azomethine ylides prepared from 2-CH₃, 4-OCH₃ and 2-F substituted benzaldehydes were not very reactive and carried out the reaction to provide the corresponding tricyclic spiropiperidine derivative in moderate yields. Notably, 1-naphthyl substituted-azomethine ylide underwent [6 + 3] cycloaddition under the standard reaction conditions to give the cycloadduct 3k in 67% yield with excellent diastereoselectivity.

Table 2 Substrate scope of Ag-catalyzed [6 + 3] cycloaddition of tropone with azomethine ylides^a,b,c

a Unless otherwise noted, reactions of 1 (0.3 mmol) and 2 (0.45 mmol) were carried out in the presence of AgOAc (10 mol%) and PPh₃ (20 mol%) and DBU (20 mol%) at room temperature in 3 mL of methanol.b Isolated yield.c dr > 20 : 1, determined by ¹H NMR analysis of the crude product.d 30 mol% of DBU was used.

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Experimental

Unless otherwise stated, all reagents were purchased from commercial suppliers and used without further purification. Organic solutions were concentrated under reduced pressure using a rotary evaporator or oil pump. Reactions were monitored through thin-layer chromatography (TLC). Chromatograms were visualized by fluorescence quenching under UV light at 254 nm. Flash column chromatography was performed using Qingdao Haiyang flash silica gel (200–300 mesh). Infrared spectra were recorded using a Bruker Optics TENSOR 27 instrument. ¹H and ¹³C NMR spectra were recorded using a Bruker-300 spectrometer. Accurate mass measurements were performed using an Agilent instrument with the ESI-MS technique.

General procedure for the [6 + 3] cycloaddition between tropone and azomethine ylides by AgOAc/PPh₃: under nitrogen atmosphere, AgOAc (5.0 mg, 0.03 mmol) and triphenylphosphine (15.8 mg, 0.06 mmol) were dissolved in 1 mL of methanol. The resulting mixture was stirred at room temperature for about 1 hour, followed by addition of tropone 1 (0.3 mmol, 30 μL), α-iminoesters 2 (0.45 mmol), DBU (9.1 mg, 0.06 mmol) and methanol (2 mL). Upon completion of the reaction as monitored by TLC (about 10 hours), the mixture was concentrated in vacuo. The residue was purified through flash column chromatography (EtOAc/petroleum ether) to afford the corresponding product.

Conclusions

In conclusion, we have successfully accomplished a diastereoselective [6 + 3] cycloaddition of tropone with homoserine lactone derived azomethine ylides with the use of AgOAc/PPh₃ as the catalyst in the presence of DBU. The reaction worked well under mild conditions to produce a range of tricyclic spiropiperidine in moderate to excellent yields with excellent diastereoselectivities.

Acknowledgements

We are greatly thankful for the financial support from the National Natural Science Foundation of China (No. 21372256 and 21572264), the National S&T Pillar Program of China (2015BAK45B01) and Special Research Fund for the Doctoral Program of Higher Education (No. 20120008110038).

Notes and references

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15. ESI†.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1473250. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra14018a

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