N-Heterocyclic carbene-catalyzed [4 + 2] annulation of α,β-unsaturated carboxylic acids: enantioselective synthesis of dihydropyridinones and spirocyclic oxindolodihydropyridinones

Abstract

The N-heterocyclic carbene-catalyzed generation of dienoate from α,β-unsaturated carboxylic acid via the in situ formed mixed anhydride, and the following [4 + 2] annulation with hydrazones and isatin-derived imines was developed, affording the corresponding dihydropyridinones and spirocyclic oxindolodihydropyridinones, respectively, in moderate to good yields with good to excellent enantioselectivities.

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Introduction

Dihydropyridinones and their derivatives are privileged motifs in numerous natural products¹ and pharmacologically active compounds.² Over the last few decades, many approaches for the preparation of enantioenriched dihydropyridinones have been developed via aza-Diels–Alder reactions by employing various chiral catalysts, such as Lewis acids,³ Brønsted acids,⁴ proline derivatives⁵ and isothiourea derivatives.⁶ Even so, the development of new methodologies for dihydropyridinones, especially those using stable and readily available starting materials, is still highly desired.

Over the past few decades, N-heterocyclic carbenes (NHCs) have emerged as remarkable organocatalysts for various reactions.⁷ The NHC-catalyzed synthesis of dihydropyridinones has been developed by the [2 + 4] annulation of aldehydes,⁸ enals,⁹ chloroaldehydes,¹⁰ ketenes¹¹ and esters¹² with azadienes, by the [3 + 3] annulation of enals,¹³ bromoenals,¹⁴ and α,β-unsaturated esters¹⁵ with enamines, and by the [4 + 2] annulation of α,β-unsaturated esters,¹⁶ cyclobutenones¹⁷ and γ-aryloxylenals¹⁸ with hydrazones or imines. In seeking stable and readily available starting materials for NHC catalysis, we developed the NHC-catalyzed generation of α,β-unsaturated acyl azolium from α,β-unsaturated carboxylic acids and its following [3 + 2] and [3 + 3] annulation with aminoketones and enamines (Scheme 1, reaction (a)).¹⁹ The NHC-catalyzed generation of enolate²⁰ and homoenolate²¹ from carboxylic acids has also been established recently (reactions (b) and (c)). In this paper, we report the NHC-catalyzed generation of dienolates from α,β-unsaturated carboxylic acids, and their following [4 + 2] annulation with the C=N bond to give dihydropyridinones (reaction (d)).

Scheme 1 NHC-catalyzed generation of α,β-unsaturated acyl azolium, enolate, homoenolate and dienolate from carboxylic acids.

Results and discussion

Initially, α,β-unsaturated carboxylic acid 1a was treated with pivaloyl chloride to generate the mixed anhydride, which then reacted with hydrazone 2a under NHC catalysis (Table 1). We were encouraged to find that the desired dihydropyridinone 3a was obtained in 33% yield with 95% ee for the reaction catalyzed by 20 mol% of aminoindanol-derived preNHC A1 (entry 1). The preNHC B1 could also catalyze the reaction but resulted in very low yield albeit with high enantioselectivity (entry 2). Interestingly, the aminoindanol-derived preNHC A2 with the N-mesityl group led to a dramatic improvement of the yield (73%) with 97% ee (entry 3). Unexpectedly, the reaction using preNHC A3 with the N-pentafluorophenyl group gave only a trace of the desired product (entry 4). Several bases, such as DBU, TBD, DIPEA and Cs₂CO₃, were then screened but showed inferior performance than K₂CO₃ in terms of yield (entries 4–8). The reaction in THF gave better yield but with some loss of enantioselectivity (entry 9). Decreasing the loading of the NHC catalyst to 10 mol% or 5 mol% resulted in the loss of the yield but with high enantioselectivity maintained (entries 10 and 11).

Table 1 Condition optimization of the reaction with hydrazone 2a

Entry	NHC	Base	Solvent	T	Yield^a/%	ee^b/%
a Isolated yield. b Determined by HPLC on chiral columns. c Using 10 mol% A2 as the catalyst. d Using 5 mol% A2 as the catalyst. PivCl = pivaloyl chloride. TBD: 1,5,7-triazabicyclo[4.4.0]dec-5-ene. DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene.
1	A1	K2CO3	DCM	Reflux	33	95
2	B1	K2CO3	DCM	Reflux	15	−91
3	A2	K2CO3	DCM	Reflux	73	97
4	A3	K2CO3	DCM	Reflux	Trace	—
5	A2	DBU	DCM	Reflux	57	96
6	A2	TBD	DCM	Reflux	34	97
7	A2	DIPEA	DCM	Reflux	39	97
8	A2	Cs2CO3	DCM	Reflux	37	87
9	A2	K2CO3	THF	45 °C	88	95
10^c	A2	K2CO3	DCM	Reflux	50	95
11^d	A2	K2CO3	DCM	Reflux	35	95

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With the optimized reaction conditions in hand, the substrate scope was briefly investigated (Table 2). It was found that both β-aryl-α,β-unsaturated acids with electron-donating (R = 4-MeC₆H₄ and 4-MeOC₆H₄) and electron-withdrawing groups (R = 4-ClC₆H₄ and 4-BrC₆H₄) worked well to give the desired products (3b–3e) in good to high yields with excellent enantioselectivities. Both bulky aryl groups (R = 2-ClC₆H₄, 2-naphthyl) and heteroaryl groups (R = 2-furyl, 2-thienyl) were also tolerated, affording dihydropyridinones 3f–3i in good yields with high enantioselectivities. The reaction of β-alkyl-α,β-unsaturated acids (R = methyl) also worked but in very low yield (23%) with 53% ee (3j). Replacement of the methyl group with the ethyl group of the unsaturated acid gave the dihydropyridinone 3k in 46% yield with 96% ee. The reaction with N-arylcarbonyl (Ar′ = 4-MeC₆H₄, 4-ClC₆H₄) or N-2-furylcarbonyl hydrazones also proceeded well, giving the corresponding dihydropyridinones 3l–3n in good yields with high enantioselectivities.

Table 2 NHC-catalyzed synthesis of dihydropyridinones

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After establishing the reaction with hydrazones, we are interested in developing the reaction with oxindole-derived imines to give spirocyclic oxindoles, which are the key structural motifs found in many natural products and clinical pharmaceuticals.²² The model reaction of α,β-unsaturated carboxylic acid 1a with isatin-derived ketimine 4a was investigated under NHC catalysis (Table 3). Unfortunately, the desired spirocyclic oxindolodihydropyridinone 5a was isolated in low yield with only 7% ee when the previous conditions for hydrazone 2 were applied (entry 1). Considering the possible cooperative effort of the Lewis acid for the reaction,²³ several additives were then investigated for the reaction. We were happy to find that the yield and enantioselectivity were dramatically improved when Sc(OTf)₃ was added to the reaction (entry 2). A slightly better enantioselectivity was observed when the N-isopropylphenyl NHC precursor A4 was used instead of N-mesityl one A2 (entry 3). The L-pyroglutamic acid-derived NHC precursors B2 and B3 could also catalyze the reaction but with opposite enantioselectivities (entries 4 and 5). Further improvement of enantioselectivity was observed when Sn(OTf)₂ or La(OTf)₃ was used instead of Sc(OTf)₃ (entries 6 and 7). The reaction performed worse in DCM or toluene than in THF (entries 7 vs. 8 and 9). Lowering the reaction temperature to room temperature or 0 °C resulted in a slight increase of enantioselectivity (entries 10 and 11).

Table 3 Condition optimization of the reaction with isatin-derived imines

Entry	Cat.	Lewis acid	Solvent	T	Yield^a/%	ee^b/%
a Isolated yield. b Determined by HPLC on chiral columns.
1	A2	—	THF	40 °C	29	7
2	A2	Sc(OTf)3	THF	40 °C	78	71
3	A4	Sc(OTf)3	THF	40 °C	76	75
4	B2	Sc(OTf)3	THF	40 °C	76	−55
5	B3	Sc(OTf)3	THF	40 °C	75	−73
6	A4	Sn(OTf)2	THF	40 °C	68	84
7	A4	La(OTf)3	THF	40 °C	73	85
8	A4	La(OTf)3	DCM	40 °C	34	54
9	A4	La(OTf)3	Toluene	40 °C	45	65
10	A4	La(OTf)3	THF	rt	72	87
11	A4	La(OTf)3	THF	0	70	92

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With optimized reaction conditions in hand, various α,β-unsaturated carboxylic acids and isatin-derived imines were then evaluated (Table 4). It was found that the α,β-unsaturated carboxylic acid with electron-donating substituents (R = 4-MeC₆H₄, 3-MeC₆H₄) worked better than that with electron-withdrawing substituents (R = 4-BrC₆H₄, 3-ClC₆H₄) (5bvs.5c, and 5dvs.5e). The α,β-unsaturated carboxylic acid with a sterically hindered 1-naphthyl group also worked for the reaction, giving the corresponding product 5f in 58% yield with 83% ee. The reaction of β,β-dialkyl-α,β-unsaturated carboxylic acid (R = Me) gave the desired product 5g in very low yield and enantioselectivity. The isatin-derived ketimines with 5-chloro or N-Me instead of N-benzyl gave the corresponding products in moderate to good yields and enantioselectivities (5h–5i).

Table 4 Synthesis of spiro[oxindole-3,2′-dihydropyridinones]

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A plausible catalytic cycle for the reaction is depicted in Fig. 1. The addition of NHC to the mixed anhydride 1′, generated in situ from the carboxylic acid, gives the α,β-unsaturated acyl azolium intermediate I. The deprotonation of the γ-C–H of the α,β-unsaturated acyl azolium intermediate I affords the dienolate intermediate II, which reacts with hydrazones 2 or imines 4 in a possible [4 + 2] cycloaddition manner to give adduct III. The fragmentation of adduct III furnishes the final dihydropyridinones 3 or 5 and regenerates the NHC catalyst.

Fig. 1 Plausible catalytic cycle.

The plausible stereochemical modes are depicted in Fig. 2. The bulky aryl group in triazolium may help to establish the configuration of the dienolate. The [4 + 2] cycloaddition of the electron-deficient C=N bond in hydrazones (TS A) or isatin imines (TS B) with the dienes from the less sterically hindered face results in the observed enantioselectivity.

Fig. 2 Stereochemical modes.

Conclusions

In summary, the N-heterocyclic carbene-catalyzed [4 + 2] annulation of α,β-unsaturated carboxylic acid was developed. The dienolate intermediate, which is generated from α,β-unsaturated carboxylic acids via in situ formed mixed anhydrides in the presence of N-heterocyclic carbene, reacted with hydrazones and imines to afford the dihydropyridinones and spirocylic oxindolodihydropyridinones, respectively, in moderate to good yields with good to excellent enantioselectivities. Further development of the NHC-catalyzed reactions of α,β-unsaturated carboxylic acids is underway in our laboratory.

Acknowledgements

Financial support from the National Science Foundation of China (no. 21425207 and 21272237), and the Chinese Academy of Sciences is greatly acknowledged.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available: Experimental details, and ¹H and ¹³C NMR spectra. See DOI: 10.1039/c5qo00301f

‡ These authors contributed equally to this work.

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