DABCO catalyzed unusual formal [4 + 2] cycloaddition of 3-acyl(or alkoxycarbonyl)-1,4-enediones with 2,3-butadienoates: effective access to highly functionalized pyrans

Abstract

A convenient and efficient DABCO-catalyzed formal [4 + 2] cycloaddition of 3-acyl(or alkoxycarbonyl)-1,4-enediones with 2,3-butadienoates is presented. This transformation takes advantage of mild conditions, wide substrate scope and significant functional group tolerance as well as excellent regioselectivity, which makes this method powerful for one-pot synthesis of highly functionalized pyrans in moderate to excellent yields.

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Multi-substituted pyran rings are important frameworks which can be found in biologically active compounds and natural products.¹ Despite many strategies being developed to synthesize substituted pyrans,² the development of novel methodologies for the convenient and effective synthesis of high functionalized pyrans remains highly desirable.

In the past few decades, Lewis base catalyzed reactions of allenoates have attracted much attention for constructing molecular diversity and complexity.³ Since 1995, Lu et al. first published phosphine-catalyzed [3 + 2] cycloaddition reaction of allenoates with alkene;⁴ in 2003, Kwon et al. reported a novel [4 + 2] annulation of α-alkylallenoates with imines;⁵ In addition, several other reactions, such as Kwon's [3 + 3] annulations with aziridines⁶ and Tong's [4 + n], [3 + n] annulations were well established.⁷ Compared to phosphines, the corresponding amine analogues usually display markedly different reaction modes in these types of transformations. However, the cycloaddition of allenoates catalyzed by amine is relatively rare⁸ and only a few [4 + 2] cycloadditions have been developed (Fig. 1).⁹ As shown in Fig. 1, in most cases, when amine was used as the catalyst, allenoate acted as a surrogate of a “1,2-dipole” and underwent β,γ-addition, exocyclic double bond adducts were formed.^9a–e However, when H-bond bifunctional organocatalyst derived from Cinchona alkaloid was used, the mixture of two regioisomers was yielded, the major isomer was the α,β-adduct.^9f

Fig. 1 Amine-catalyzed [4 + 2] cycloaddition of allenoates.

On the other hand, the 1,4-enedione is an important structural motif that is not only widely presented in natural products and medicinal molecules,¹⁰ but also served as versatile building blocks in a variety of transformations, such as Diels–Alder cyclization and Michael addition¹¹ as well as precursors for the preparation of many heterocyclic compounds such as furans, thiophenes, pyrroles etc.¹²

Recently, we reported the Ph₃P and 1,4-diazabicyclo[2.2.2]octane (DABCO) catalyzed cycloaddition of 2,3-butadienoates with 3-acyl-2H-chromen-ones for the convenient synthesis of dihydropyran-fused and cyclopenten-fused chromen-2-ones with high regio- and stereo-selectivities.¹³ As part of our continuing interest in cycloaddition involving 2,3-butadienoate and investigating its regioselectivity, herein, we report a DABCO-catalyzed unusual formal [4 + 2] cycloaddition of 2,3-butadienoates with 3-acyl(or alkoxycarbonyl)-1,4-enediones, the unexpected α,β-adduct regioisomer – highly functionalized pyrans 3 were generated (Scheme 1).

Scheme 1 DABCO-catalyzed unusual formal [4 + 2] cycloaddition of 2,3-butadienoates with 3-acyl(or alkoxycarbonyl)-1,4-enediones.

Initially, the cycloaddition of 3-benzoyl-1,4-biphenyl-1,4-enedione (1a) with ethyl 2,3-butadienoate (2b) was used as the model substrate to screen for experimental conditions. When 1,4-enedione 1a was treated with 1.5 equiv. of ethyl 2,3-butadienoate 2a in the presence of 20 mol% of DABCO in toluene (4.0 mL) at room temperature, the reaction afforded the desired multi-substituted pyran 3a in 57% yield (Table 1, entry 1). Encouraged by this result, different amine catalysts such as DMAP, DBU, TMEDA and Et₃N were examined (Table 1, entries 1–5), DABCO gave the highest yield (Table 1, entry 1). However, a variety of phosphines (Ph₃P, n-Bu₃P and Me₃P) cannot trigger the reactions (Table 1, entries 6–8). The effect of solvents was investigated, and EtOH was shown to be the optimal solvent for this reaction (Table 1, entries 9–14).

Table 1 Reaction conditions screening^a

Entry	Catalyst (mol%)	Solvent	Temp (°C)	Time (h)	Yield^b (%)
a Reaction conditions: 1a (0.50 mmol), 2a (0.75 mmol), catalyst in solvent (4.0 mL), under N2 atmosphere.b Isolated yield.
1	DABCO (20)	Toluene	Room temp.	24	57
2	DMAP (20)	Toluene	Room temp.	24	Trace
3	DBU (20)	Toluene	Room temp.	24	Trace
4	TMEDA (20)	Toluene	Room temp.	24	40
5	Et3N (20)	Toluene	Room temp.	24	35
6	Ph3P (20)	Toluene	Room temp.	36	Trace
7	n-Bu3P (20)	Toluene	Room temp.	24	Trace
8	Me3P (20)	Toluene	Room temp.	24	Trace
9	DABCO (20)	CH2Cl2	Room temp.	24	50
10	DABCO (20)	CH3CN	Room temp.	24	73
11	DABCO (20)	THF	Room temp.	24	60
12	DABCO (20)	C2H5OH	Room temp.	12	87
13	DABCO (20)	DMF	Room temp.	24	63
14	DABCO (20)	DMSO	Room temp.	24	71
15	DABCO (20)	C2H5OH	−5	40	75
16	DABCO (20)	C2H5OH	0	36	85
17	DABCO (20)	C2H5OH	40	12	79
18	DABCO (20)	C2H5OH	50	12	81
19	DABCO (30)	C2H5OH	Room temp.	10	90

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Subsequently, the effect of reaction temperature was also explored (Table 1, entries 15–18). Increasing or decreasing the temperature did not affect the reaction yield remarkably. The amount of catalyst was also evaluated, and the results showed that a loading of 30 mol% DABCO gave the best result, led to the desired product 3a in 90% yield (Table 1, entry 19).

With the optimized conditions in hand, initially, a variety of 3-acyl(or alkoxycarbonyl)-1,4-enediones 1 were subjected to the above mentioned optimal conditions to examine the generality of this methodology (Table 2). The 1-substituted phenyl(or heteroaryl) substituted 1,4-enediones bearing electron-donating (CH₃, OCH₃) or electron-withdrawing groups (F, Cl, NO₂) or different substituted pattern on the phenyl ring were found to be suitable substrates for this reaction, gave the desired products 3a–3j in a range of 78–91% yields. More importantly, 1-furyl or thienyl substituted 1,4-enediones 1k and 1l also proceeded smoothly to give the desired products 3k–3l with satisfactory results (75% and 71% yield, respectively). It was noted that 3-ethoxycarbonyl substituted 1,4-enediones can be also employed in this transformation and provide the desired products 3m and 3n in 85% and 68% yield, respectively, and it was found that the 3-substituents has no significant influence on the reaction (3a, 3m–3n). However, when trans-1,4-diphenyl-2-butene-1,4-dione was used as the substrate, the formal [3 + 2] product 3r was obtained as a light yellow crystal in 76% yield (please see the ESI†), which displayed different reaction mode from the 3-acyl(or alkoxycarbonyl)-1,4-enedione substrates.

Table 2 Substrate Scope^a,b

a Unless otherwise noted, reactions were carried out with 1 (0.50 mmol), 2 (0.75 mmol), DABCO (0.15 mmol) in EtOH (4.0 mL) at room temperature under N₂ atmosphere.b Isolated yield.

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Then, we evaluated the scope of 2,3-butadienoates 2. Methyl or benzyl 2,3-butadienoates (2b, 2c) are also suitable candidates for this transformation, affording the desired products 3o–3q in excellent yields (86–96% yield). Unfortunately, when α- or γ-alkyl substituted allenoates (for example, α-methyl or benzyl substituted or γ-methyl substituted 2,3-butadienoates) were used as the substrates, no reaction occurred under these above conditions (the results are not listed).

The structures and configurations of the formal [4 + 2] cycloadducts 3 were assigned via ¹H-NMR, ¹³C-NMR, MS, elemental analysis (see the ESI†). Moreover, the structure of 3q was unambiguously determined by X-ray crystallographic analysis (Fig. 2, CCDC: 1483768†).

Fig. 2 X-ray crystal structure of compound 3q.

Based on our investigations and the reported literature,^9a,9b,9f a possible mechanism is suggested as shown in Scheme 2. First of all, DABCO attacks the β-carbon of ethyl 2,3-butadienoate 2a to give intermediate A, which can isomerize to the more stable intermediate B, because both the ammonium ion and ester group can stabilize the β-carbanion of B. Subsequently, compound B undergoes 1,4-addition with 1,4-enedione 1a to generate intermediate C, which follows by the enolization and 1,3-proton transfer and converts to intermediate E. Finally, the formal [4 + 2] cycloadduct 3a is formed by the intramolecular nucleophilic attacking and then the release of DABCO.

Scheme 2 Possible mechanism proposed for the formal [4 + 2] cycloadditions of 3-acyl(or alkoxycarbonyl)-1,4-enediones with 2,3-butadienoates catalyzed by DABCO.

Conclusions

In conclusion, we developed a convenient and efficient DABCO-catalyzed formal [4 + 2] cycloaddition of 3-acyl(or alkoxycarbonyl)-1,4-enediones with 2,3-butadienoates. This methodology possesses mild condition, wide substrate scope and significant functional group tolerance as well as excellent regioselectivity, which provides a convenient and effective pathway for the preparation of highly functionalized pyrans. Further investigation of the chiral amine-catalyzed formal [4 + 2] annulation of 3-acyl(or alkoxycarbonyl)-1,4-enediones with 2,3-butadienoates is currently underway and will be reported in due course.

Acknowledgements

We are grateful to the National Natural Science Foundation of China (No. 21342004 and 51573066), and the Syngenta Ph.D. (postgraduate) program for support of this work.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, copies of ¹H and ¹³C NMR spectra. CCDC 1483768. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra15117e

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