Synthesis of fully functionalised spiropyran pyrazolone skeletons via a formal [4 + 2] cascade process using β-nitro-styrene-derived MBH-alcohols

Abstract

An efficient protocol was established to construct spiro pyrazolone tetrahydropyran scaffolds at ambient temperature under metal-free conditions. The reaction proceeded via formal [4 + 2] cyclisation of trans-β-nitro-styrene-derived Morita–Baylis–Hillman (MBH) alcohol with α-arylidene pyrazolone. The reaction followed an oxa-Michael/Michael cascade pathway, resulting in the formation of new C–C and C–O bonds. Organocatalytic synthesis of spiropyrazolones using quinine-derived catalyst resulted in 94% enantiomeric excess (ee) and excellent (>20 : 1) diastereoselectivity.

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The nitrogen-containing pyrazolone compounds are highly efficient and amenable to their activity as antimicrobials, antitumor agents, and type 4 inhibitors of phosphodiesterase, and thereby play a crucial role in pharmaceutical and medicinal chemistry (Fig. 1).¹ The synthesis of skeletons possessing spirocyclohexane pyrazolones,² spiropyrazolone tetrahydroquinolines,³ spirobenzofuran pyrazoloedione,⁴ spiropyroloidinepyrazolones,⁵ spiro tetrahydrofuran pyrazolones,⁶ spiropyrazolone epoxide,^7a spiro oxindole-fused spiropyrazolones,^7b spirooxindole pyrrolidine pyrazolone,⁸ spiropyrazolonecyclohexene carbaldehydes,⁹ spiropyarazolonecyclohexanone,¹⁰ and fused pyrazolones such as dihydropyranopyrazoles¹¹ and tetrahydropyranopyrazoles¹² has received considerable interest in recent years. Arylidene pyrazolone has attracted considerable attention due to its unique 1,2-ambiphilic nature for the construction of elegant building blocks such as spirocycles,¹³ dispirocycles¹⁴ and fused heterocycles.^15a–c Spiropyrazolones have been synthesized from the reaction of α-arylidene pyrazolone with various substrates, but the reaction using MBH adducts are scarce.^15d To the best of our knowledge, there has been to date only one report on the synthesis of spiropyrazolone tetrahydropyran derivatives using alkylidene trimethylene carbonate,¹⁶ and no report on the synthesis of functionalized spiropyrazolones using MBH-alcohol with 5 contiguous stereocenters. Of the MBH adducts, β-nitro-styrene-derived MBH adducts were previously used by various research groups for the construction of spiropyrazolone skeletons (Scheme 1).

Fig. 1 Biologically active spiropyrazolone skeletons.

Scheme 1 Annulation reactions using β-nitro-styrene-derived adducts.

Enders and his team carried out a sequential organo- and silver catalysis for the synthesis of spiropyrazolones using alkyne-tethered nitroalkenes¹⁷ (eqn (a), Scheme 1). Miao et al. reported the synthesis of spirochromane 3,3 pyrazoles using 2-nitro vinyl phenols¹⁸ (eqn (b), Scheme 1). Chen and co-workers constructed spiranopyrazoles¹⁹ using 5-nito-6-phenyl-hex-5-en-2-one (eqn (c), Scheme 1). On the other hand, the utility of nitro-styrene-derived MBH alcohols as 1,4-bis-ambiphiles (α-C, δ-O) has been less extensively investigated.²⁰ In continuation of our efforts towards the synthesis of various spirocyclic systems,²¹ herein we report the synthesis of spiropyrazolone tetrahydropyran scaffolds using β-nitro-styrene-derived MBH alcohols, resulting in the formation of the desired products with 4 to 5 contiguous chiral centers through [4 + 2] annulation (eqn (d), Scheme 1).

Initially, we carried out an optimization of conditions for the construction of spiro pyrazolone tetrahydropyran scaffolds using various types of solvents and bases at room temperature. Treatment of unsaturated arylidene pyrazolone and nitro-styrene-derived primary MBH alcohol using DABCO in the presence of acetonitrile (CH₃CN) furnished the desired product in 16% yield (entry 1, Table 1). Performing the reaction instead in a polar solvent, e.g., THF, did not improve the yield (entry 2, Table 1). And performing the reaction instead in a chlorinated solvent, e.g., CHCl₃ or DCM, also did not considerably enhance the yield of product 3a (entries 3 and 4, Table 1). An increase in yield was observed by shifting to an inorganic base, i.e., Cs₂CO₃, which together with using CH₂Cl₂ as the solvent gave the product 3a in 60% yield (entry 5, Table 1); and here, use of the polar aprotic solvent CH₃CN instead of CH₂Cl₂ increased the yield to 66% (entry 6, Table 1). The best reaction conditions were obtained when using K₂CO₃ as an inorganic base in CH₃CN to obtain product 3a in 93% yield (entry 7, Table 1). A decrease in the yield for product formation was observed when heating the reaction mixture at 60 °C (entry 8, Table 1).

Table 1 Optimization of reaction conditions for the synthesis of spiropyran pyrazolone using β-nitro-styrene-derived 1° MBH alcohol^a

Entry	Base	Solvent	Time (h)	Yield (%)	dr^b
a Unless otherwise noted, reactions were carried out with (0.19 mmol of) 1 with (0.28 mmol of) 2 using 0.47 mmol of base in 1.5 ml of CH3CN solvent.b Determined from a ^1H-NMR analysis of a crude reaction mixture.c Reaction carried out at 60 °C.
1	DABCO	CH3CN	8	16	n.d
2	DABCO	THF	7	22	n.d
3	DABCO	CHCl3	7	27	>20 : 1
4	DABCO	DCM	7	25	n.d
5	Cs2CO3	CH2Cl2	1	60	> 20 : 1
6	Cs2CO3	CH3CN	1	66	>20 : 1
7	K2CO3	CH3CN	1	93	>20 : 1
8^c	K2CO3	CH3CN	1	76	>20 : 1

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Based on the best optimized conditions, we studied the scope of different substituents at the aryl ring of pyrazolone 1 as well as primary MBH alcohol 2. The 2,4-dichloro-substituted arylidene pyrazolone 1b gave the desired product 3b in 71% yield (Table 2). Use of the electron-donating group –CH₃ at the para position of the MBH alcohol furnished the corresponding product 3c in 57% yield. Electron-rich donating groups –OMe and –OBn gave 3d–e in 61 and 57% yields, respectively. An electron-withdrawing group at the para position also gave a good yield for product 3f. We examined the yield and functional group tolerance by changing the substituents at arylidene pyrazolones and MBH alcohols; here, products 3g–j were obtained in moderate to good yields.

Table 2 Substrate scope for the synthesis of spiropyran pyrazolone

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We next focused on building fully substituted spiro pyrazolone tetrahydropyrans scaffolds 5a–c using β-nitro-styrene-derived secondary (2°)-MBH alcohols with arylidene pyrazolones. With the best optimized set of conditions obtained previously, we carried out the construction of fully substituted spiropyran pyrazolone using K₂CO₃ in CH₃CN to give 5a in 67% yield (entry 1, Table 3). The chlorinated solvents CH₂Cl₂, CHCl₃, and CCl₄ gave 5a in only 41–56% yields (entries 2–4, Table 3). And a further decline in yield was observed when using instead THF as solvent (entry 5, Table 3). We found that Cs₂CO₃ in the presence of CHCl₃ was the best base–solvent combination for the formation of product 5a, with a 78% yield and good diastereoselectivity (entry 6, Table 3).

Table 3 Optimization for the synthesis of fully substituted spiropyran pyrazolones using β-nitro-styrene-derived 2° MBH alcohol^a

Entry	Base	Solvent	Time (h)	Yield	dr^b
a Unless otherwise noted, reactions were carried out with (0.19 mmol of) 1 with (0.28 mmol of) 4 using 0.47 mmol% of base in 1.5 ml of CHCl3 solvent.b Diastereomeric ratio was determined from ^1H-NMR analysis of a crude reaction mixture.
1	K2CO3	CH3CN	1	67	>20 : 1
2	K2CO3	CH2Cl2	1	56	n.d
3	K2CO3	CHCl3	1	47	>20 : 1
4	K2CO3	CCl4	1	41	>10 : 1
5	K2CO3	THF	1	36	n.d
6	Cs2CO3	CHCl3	1	78	>20 : 1

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Use of the electron-donating groups methyl and methoxy at the para position of the MBH alcohol resulted in 56–60% yields of product, i.e., of 5c and 5b (Table 4). Furthermore, all the compounds 3a–j and 5a–c were confirmed from the results of IR, ¹H, ¹³C NMR, HRMS, and NOESY analyses. The compound 3h was further confirmed using single-crystal XRD (Table 2).²²

Table 4 Substrate scope for the synthesis of fully substituted spiropyran pyrazolones

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We further pursued our studies towards asymmetric synthesis of spiropyrazolones 3a using various chiral catalysts (I–IV). We observed a poor enantiomeric excess for the product formation in the presence of cinchona catalyst I (entry 1, Table 5). Using NOBIN-based catalysts II and III resulted each in a 10% enantiomeric excess (entries 3–4, Table 5). Interestingly, we obtained an excellent enantiomeric excess (94% ee) with high diastereoselectivity (>20 : 1) when using the thiourea-based hydrogen bonding catalyst IV (entry 4, Table 5; see ESI† for information on the transition state).

Table 5 Asymmetric version of spiro pyrazolone tetrahydropyran 3a^a

Entry	Catalyst	Time (h)	Yield (%)	ee^b (%)	dr^c
a All the reactions were carried out with (0.19 mmol of) 1, (0.11 mmol of) 2 and 10 mol% of catalyst in 1 ml of CH3CN solvent.b Enantiomeric excess determined from HPLC analysis.c Diastereomeric ratio was determined from ^1H-NMR analysis of a crude reaction mixture.
1	I	1	35	50	>20 : 1
2	II	1	>10	17	>20 : 1
3	III	1	>15	11	>20 : 1
4	IV	1	61	94	>20 : 1

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To further demonstrate the practical and scalable utility of our protocol, we carried out gram scale preparation of spiro pyrazolone tetrahydropyrans 3a and 5a, and achieved yields of 81% and 66% (Scheme 2).

Scheme 2 Gram scale synthesis of spiro pyrazolone tetrahydropyrans 3a and 5a.

We investigated the feasibility of carrying out a triple-cascade reaction for the construction of spiro pyrazolone tetrahydropyrans 3a and 5a via the Knoevenagel/oxa-Michael/Michael process. To our delight, the reaction was amenable to a one-pot [1 + 1 + 4] formal cyclization to give the products 3a and 5a in 58% and 62% yields (Scheme 3).

Scheme 3 Approaching a triple cascade for the construction of spiro pyrazolone tetrahydropyran in a three-component manner.

Most of the annulation reactions using MBH adducts involve the use of inorganic bases for proton abstraction, in line with a previous literature report,²³ and in the current work a plausible mechanism for the construction of spiropyrazolone tetrahydropyran scaffolds was derived. According to this proposed mechanism, the initial reaction of the alkali carbonate serving as a base (i.e., K₂CO₃/Cs₂CO₃) with MBH alcohol generated the nucleophilic oxygen intermediate A. Attack by intermediate A from the “rear” position onto the benzylic carbon of α-arylidine pyrazolone via an oxa-Michael reaction generated a new O–C bond. And finally according to the proposed mechanism, further rearrangement of the resulting enol to a ketone and subsequent attack on the electrophilic olefinic site of MBH alcohol via formal [4 + 2] annulation resulted in the formation of a new C–C bond through a Michael reaction (Scheme 4). In situ Raman studies carried out for the reaction mixture shows the presence of keto group (i.e. 1495 cm⁻¹) of α-arylidene pyrazolone at the beginning of the reaction. This corresponding peak of 1495 cm⁻¹ gradually disappeared after the initial oxa-Michael addition to form intermediate B. The intermediate B on reaction with benzyl bromide resulted in the disappearance of corresponding keto group peak, before completion of the final cyclisation via Michael Addition (S5 page of ESI†).

Scheme 4 Plausible reaction mechanism for the synthesis of spiro pyrazolone tetrahydropyrans.

Conclusions

In conclusion, the 1,4 ambiphilicity of β-nitro-styrene-derived MBH alcohols was investigated for achieving an efficient synthesis of tetrahydrospiropyrazolones via formal [4 + 2] cyclization at room temperature within 1 h. β-Nitro-styrene-derived 1° MBH alcohol gave tetrasubstituted spiropyrazolones when using K₂CO₃ whereas 2° MBH alcohol gave fully substituted spiropyrazolones when using Cs₂CO₃. The reaction tolerated various electron-withdrawing and electron-donating groups on the aryl ring of the arylidene pyrazolone as well as β-nitro-styrene-derived MBH alcohols to result in the desired products in high yields. Organocatalytic synthesis using quinine-derived thiourea catalyst resulted in desired spiropyrazolones with >94% enantiomeric excess and >20 : 1 dr. Interestingly, a triple-cascade three-component reaction produced the same spiropyrazolone tetrahydropyrans via the Knoevenagel/oxa-Michael/Michael process.

Author contribution

All authors contributed to the conception and design of the study. Material preparation, data collection, and analysis were performed by Yeruva Pavankumar Reddy. Shaik Anwar contributed additional analysis required to address the comments and issues from the reviewers. All authors read and approved the final manuscript.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

SA thanks DST-SERB for providing the financial support under a Fast Track scheme (SB/FT/CS/079-2014). We are indebted to Vignan’s Foundation for Science, Technology and Research for providing research facilities at CoExAMMPC.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2215596. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d2ra06076k

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