Multicomponent reaction (MCR) for constructing bis-spirocyclohexane skeletons using β-nitrostyrene derived MBH acetates, 1,3-indanedione and aldehydes via [1 + 1 + 1 + 3] annulation

Abstract

An AB₂C type four-component quadruple cascade reaction has been established between nitroallylic MBH acetate, 1,3-indanedione and aldehyde for generating bis-spirocyclohexanes. This reaction progressed in an unusual [1 + 1 + 1 + 3] annulation manner via a Knoevenagel/Michael/Michael/Michael sequence, resulting in the generation of three/four chiral centres, and two all-carbon quaternary centres through the formation of 3 new C–C bonds.

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Introduction

The development of novel synthetic strategies for constructing new chiral spirocyclic compounds with varied medicinal potentials is a great challenge in organic and pharmaceutical chemistry.¹ In this regard, Multicomponent Reactions (MCRs)² are preferred for the synthesis of chiral spirocyclic compounds³ by virtue of their advantages, i.e., one-pot synthesis, avoiding isolation of intermediates and atom economy.

In recent times, the β-nitrostyrene derived Morita–Baylis–Hillman (MBH)⁴ adducts have been explored extensively towards the construction of various MCRs.⁵ The β-nitrostyrene derived MBH adducts^6–8 are one of the essential classes of molecules in medicinal chemistry, due to their utility as building blocks for constructing complex and biologically sound molecules.⁹

Among the various β-nitrostyrene derived MBH adducts, nitroallylic MBH acetates have been explored extensively to give various spirocycles,¹⁰ heterocycles,¹¹ carbocycles,¹² bicyclic skeletons,¹³ and arenes.¹⁴ But to date there are no available reports for the construction of bis-spirocyclohexanes utilizing nitrostyrene derived MBH acetate with 1,3-indanedione¹⁵ or arylidene indanedione.^16,17

In 2015, He et al. successfully utilized acrylate derived MBH adducts along with 2-arylidene-1,3-indanediones to demonstrate a [2 + 2 + 2] annulation protocol for producing substituted bis-spirocyclohexanes (eqn (a), Scheme 1).¹⁸

Scheme 1 Construction of substituted bis-spirocyclohexanes using MBH acetates.

Hereby, we propose an MCR strategy to explore the utility of nitroallylic MBH acetate for generating fully substituted bis-spirocyclohexanes in a unique [1 + 1 + 1 + 3] annulation fashion (eqn (b), Scheme 1).

In continuation of our perpetual study on heterocycles and spirocycles,¹⁹ we have demonstrated an AB₂C type four-component reaction²⁰ between 1,3-indanedione, aryl aldehydes, and β-nitrostyrene derived MBH acetates via [1 + 1 + 1 + 3] cyclization strategy (Scheme 2).

Scheme 2 AB₂C type four component quadruple cascade reaction.

Results and discussion

Optimization studies of quadruple cascade reactions were carried out and the obtained results were tabulated (Table 1). The reaction initially carried out with potassium carbonate (1.5 equiv.) in acetonitrile at ambient temperature, gave the desired compound 8a in 24% yield (entry 1, Table 1). Increasing the amount of indanedione to 2 equiv. gave a marginal increase in the yield i.e., 25% for the product formation 8a (entry 2, Table 1). The use of chlorinated solvents, i.e., chloroform, didn't alter the yield even after 24 h (entry 3, Table 1). The yield for product 8a improved to 35% with the use of potassium carbonate in 3 equiv. amounts (entry 4, Table 1). There is no improvement was observed with the change in reaction time as well as temperature (entries 5 and 6, Table 1). The use of methanol as solvent decreased the diastereomeric excess and yield due to the poor solubility of in situ-formed KC product (entry 7, Table 1). Utilisation of organic bases such as DABCO, urea and thiourea couldn't improve the yield for the product formation 8a (entries 8–15, Table 1). We also examined the effect of other inorganic bases such as Cs₂CO₃ but, there is no appreciable improvement was observed for the formation of desired product 8a (entries 16 and 17, Table 1). It was observed that, there is no improvement in the yield with the higher concentrations of aldehyde (entries 18–20, Table 1). As the base concentration increases, the yield of 8a gets decreases due to the high amount of side products formation (entries 21 and 22 Table 1). The use of mixture of solvents did not improve the yield and delivered the compound 8a in 25% of yield (entry 23, Table 1). This is due to the less solubility of in situ formed KC side product for further cascade process.

Table 1 Optimization studies for quadruple cascade reaction^a

S. no	6 (equiv.)	Base (equiv.)	Solvent	Temp (°C)/time (h)	Yield (%)^b	dr^c
a Compound 4a (110.5 mg, 0.5 mmol), 6 (0.5 or 1.0 mmol), 7a (92.5 mg, 0.5 mmol) and base (0.75 or 1.5 mmol) were dissolved in 5 mL of solvent.b Isolated yields.c Determined by ^1H NMR.d 1.5 equiv. of aldehyde was used.e 2.0 equiv. of aldehyde was used.f 3.0 equiv. of aldehyde was used.g ACN and H2O (1 : 1) used; nd = not determined.
1	1	K2CO3 (1.5)	ACN	30 (4)	24	>20 : 1
2	2	K2CO3 (1.5)	ACN	30 (4)	25	>20 : 1
3	2	K2CO3 (1.5)	CHCl3	30 (24)	20	>20 : 1
4	2	K2CO3 (3)	ACN	30 (4)	35	>20 : 1
5	2	K2CO3 (3)	ACN	30 (12)	20	>20 : 1
6	2	K2CO3 (3)	ACN	60 (4)	20	>20 : 1
7	1	K2CO3 (3)	MeOH	30 (4)	18	19 : 1
8	1	DABCO (3)	MeOH	30 (4)	15	16 : 1
9	1	Thiourea (3)	MeOH	30 (4)	22	10 : 1
10	2	Thiourea (3)	MeOH	30 (4)	20	10 : 1
11	2	Urea (3)	MeOH	30 (4)	20	nd
12	1	Thiourea (3)	ACN	30 (4)	24	nd
13	2	Thiourea (3)	ACN	30 (4)	25	nd
14	1	Urea (3)	ACN	30 (4)	23	nd
15	2	Urea (3)	ACN	30 (4)	25	nd
16	1	Cs2CO3 (1.5)	ACN	30 (4)	21	nd
17	2	Cs2CO3 (1.5)	ACN	30 (4)	27	nd
18^d	2	K2CO3 (3)	ACN	30 (4)	25	nd
19^e	2	K2CO3 (3)	ACN	30 (4)	23	nd
20^f	2	K2CO3 (3)	ACN	30 (4)	20	nd
21	2	K2CO3 (4)	ACN	30 (4)	26	nd
22	2	K2CO3 (5)	ACN	30 (4)	20	nd
23^g	2	K2CO3 (3)	ACN	30 (4)	25	nd

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The lower yield for 8a is due to the formation of side product 11 (i.e., double Michael reaction of MBH acetate 4a with 1,3-indanedione 6) and 10a (Knoevenagel condensation between aldehyde 7a and 1,3-indanedione 6). It was also observed that, recovery of aldehyde for the most of the reactions was predominant. In conclusion of the optimization studies, the use of potassium carbonate (3 equiv.) in acetonitrile solvent gave the maximum yield. The final product 8a obtained with highly diastereoselectivity was fully characterized by ¹H NMR, ¹³C NMR, DEPT-135 and the structure was further confirmed by single crystal X-ray analysis.²¹

The studies for the formation of bis-spirocyclohexane were further explored into substrate scope study with various MBH acetates 4/5 and aldehydes 7a–i possessing electron withdrawing and donating substituents (Table 2). This reaction when employed with p-nitrobenzaldehyde resulted in 34% yield for product 8b. When the reaction was carried out with p-cyanobenzaldehyde, the corresponding bis-spirocyclohexane 8c was obtained in a 39% yield. Compound 8d was obtained in 31% of yield with the use of unsubstituted benzaldehyde. m-bromobenzaldehyde on reacting with indanedione 6 and MBH aetate 4 retained high diastereoselectivity for product 8e in 24% of yield. It was observed that the substitution of an electron-withdrawing group i.e., m-cyano, gave 8f with a yield of 31%. The ortho-nitro substituted benzaldehyde delivered the corresponding bis-spirocyclohexane 8g in 35% yield.

Table 2 Substrate scope for construction of bis-spiroyclohexanes^a,b,c

a Compound 4/5 (0.5 mmol), 6 (1.0 mmol), aldehyde 7 (0.5 mmol) and K₂CO₃ (1.5 mmol) were dissolved in 5 mL of ACN and stirred at 30 °C.b Isolated yields.c dr was determined by ¹H NMR.

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A good yield of 42% for the formation of compound 8h was observed when o,p-dichlorobenzaldehyde was employed in the reaction. Heteroaromatic aldehydes also tolerated the reaction conditions towards the formation of bis-spirocyclohexanes. The quadruple cascade reaction with 2-thiophenyl aldehyde produced compound 8i in a good yield of 40%. An impressive yield of 59% was observed for compound 8j, by the reaction of p-methoxy MBH acetate 4b, 1,3-indanedione and o,p-dichloro benzaldehyde. We further explored the utility of secondary nitroallylic MBH acetate 5 to develop fully substituted bis-spirocyclohexanes 9a–d. The reaction involving unsubstituted benzaldehyde, gave the desired compound 9a in 19% yield. The substitution of electron-withdrawing groups like –NO₂, –CN at the para position of the benzaldehyde resulted in compounds 9b and 9c in 28% and 35%, respectively. Whereas, the p-bromo benzaldehyde delivered the compound 9d in 31% of the yield. Attempts using aliphatic aldehydes led to trace amounts of corresponding bis-spirocyclohexanes. This may be presumably due to poor reactivity of 2-alkylidene indanediones.

We further examined the scalability of our protocol by gram scale preparation of bis-spirocyclohexane 8a (Scheme 3). To our delight the reaction retained with high diastereoselectivity for product 8a formation.

Scheme 3 Gram scale synthesis of bis-spirocyclohexane 8a.

A possible mechanistic pathway for the formation of bis-spirocyclohexane products 8/9 is explained in Scheme 4. Base assisted MBH acetate 4a on reaction with 1,3-indanedione via S_N2 manner generates intermediate A as a Michael adduct. Intermediate A undergoes another Michael addition with in situ generated KC product arylideneindanedione 10a to form intermediate B which further undergoes 6-endo-trig cyclization via Michael addition to produce 8a. The overall reaction follows a Knoevenagel/Michael/Michael/Michael quadruple cascade reaction sequence via [1 + 1 + 1 + 3] annulation. This plausible mechanism is further supported by the isolation of side product 11. The formation of side product 11 is due to a parallel reaction of intermediate A with MBH acetate 4a in a Michael addition manner via double S_N2 fashion.

Scheme 4 Plausible reaction mechanism for the quadruple cascade sequence.

Conclusions

A multicomponent reaction was demonstrated for developing fully substituted bis-spirocyclohexanes derived from β-nitrostyrene derived MBH acetates. This AB₂C type four-component cascade protocol between nitroallylic MBH acetate, 1,3-indanedione, and aldehyde resulted in synthesis of bis-spirocyclohexanes in high diastereoselectivity.

Conflicts of interest

There are no conflicts of interest.

Acknowledgements

SA greatly acknowledges DST-SERB for providing financial support under TARE (TAR/2022/000207). GVB thanks CSIR-New Delhi for Senior Research Fellowship (09/1253(0003)/2020-EMR-I). We are thankful to VFSTR for providing Central Instrumentation facilities at CoExAMMPC.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2149813 2149825 2175054. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d3ra04996e

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