Diastereoselective synthesis of chroman bearing spirobenzofuranone scaffolds via oxa-Michael/1,6-conjugated addition of para-quinone methides with benzofuranone-type olefins

Abstract

A simple and convenient cyclization of ortho-hydroxyphenyl-substituted para-quinone methides with benzofuran-2-one type active olefins via oxa-Michael/1,6-conjugated addition has been developed, which afforded an easy access to enriched functionalized chroman-spirobenzofuran-2-one scaffolds with good to excellent yields (up to 90%) and diastereoselectivities (up to >19 : 1 dr). This reaction provided an efficient method for constructing desired spirocyclic compounds combining both well-known heterocyclic pharmacophores chroman and benzofuran-2-one.

Highly diastereoselective synthesis of spirocyclic compounds combining both well-known heterocyclic pharmacophores chroman and benzofuran-2-one.

The chroman framework represents a privileged heterocyclic core commonly found within a wide variety of biologically active natural products¹ and synthetic compounds of medicinal interest (Fig. 1).² Owing to the wide application of these heterocyclic molecules, over the past few decades, numerous efforts have been devoted to the efficient synthesis of chroman nucleus motifs.^3,4 In particular, incorporating chroman into spiro-bridged and spiro-fused heterocyclic systems is appealing due to its fascinating molecular architecture and proven biological activity.⁵ Among the existing methods, the [4 + m] cycloaddition of para-quinone methides (p-QMs) is found to be an efficient pathway to access these valuable spirocyclic skeletons.⁶ For instance, the Enders group synthesized functionalized chromans with an oxindole motif by the asymmetric organocatalytic domino oxa-Michael/1,6-addition reaction.⁷ After that, the Hao,^8a Peng,^8b Shi,^8c,d Zhou,^8e Liang^8f and Wang^8g groups developed convenient methods to construct chromans bearing spirocyclic skeletons from p-QMs, respectively. Despite all these shining achievements, however, it is still very challenging to simply and conveniently construct chromans bearing quaternary carbon spirals for organic chemical or drug discovery among these [4 + m] cycloaddition reactions.

Fig. 1. Representative chroman compounds.

Benzofuran-2-(3H)-ones as one of the important oxygen-containing heterocycles that exist in a broad array of natural products⁹ and potential medicines.¹⁰ The streamlined synthesis of benzofuran-2-ones pose considerable challenge due to their quaternary carbon centers at the C-3 position,¹¹ especially those featuring relatively congested spirocyclic motifs represent challenging synthetic targets.^12,13 In our continuous interests in developing efficient method for the synthesis of spirocyclic compounds based on cyclization reaction,¹⁴ we wish to report a cycloaddition of para-quinone methides with benzofuranone derived olefins, affording the spiro-cycloadducts in good to excellent yields and diastereoselectivities. This cyclization features the simultaneous formation of chroman and spirobenzofuran-2-one skeletons in a single step (Scheme 1), which may be potentially applied as pharmaceutical agents.

Scheme 1. Strategy for the synthesis of chroman-spirobenzofuran-2-one.

We initiated our investigations with the readily available ortho-hydroxyphenyl-substituted para-quinone methides 1a and 3-benzylidenebenzofuran-2-one 2a in toluene at room temperature in the presence of base. Unfortunately, no desired chroman derivatives bearing spirobenzofuranone scaffolds 3a was isolated in the presence of 2 eq. Na₂CO₃ after stirring at room temperature for 48 h (entry 1, Table 1). A base survey showed that K₂CO₃ and CsF led to desired cycloaddcuts 3a even if with a disappointing yield (entries 2–4, Table 1). Gratifyingly, Cs₂CO₃ furnished the desired product in 70% yield and with a generally acceptable 6 : 1 dr value (entry 5, Table 1). A solvent screening indicated that the yield and diastereoselectivity are both dependent on the solvent (Table 1). Thus, the oxygenated solvents such as THF, diethyl ether and 1,4-dioxane gave comparably high yields and diastereoselectivities than polar solvents as exemplified by CH₃CN or DMF (entries 5–10). To our delight, performing the reaction in THF led to desired chroman-spirobenzofuranone 3a with an excellent diastereoselectivity, albeit with a very subtle erosion of the yield (entry 6). Further optimization of the reaction conditions by varying the temperature was also investigated. When higher temperature was used, no improvement in the final yield was observed (entry 11). Performing the reaction at lower 10 °C resulted in a increase of the yield accompanied with no erosion in diastereoselectivity (entry 12). However, the yield decreased to 64% when the reaction performed at lower 0 °C (entry 13).

Optimization of conditions^a.

Entry	Base	Solvent	Yieldb (%)	Drc
1	Na2CO3	Toluene	—	—
2	DMAP	Toluene	—	—
3	K2CO3	Toluene	25	3 : 1
4	CsF	Toluene	52	5 : 1
5	Cs2CO3	Toluene	70	6 : 1
6	Cs2CO3	THF	68	>19 : 1
7	Cs2CO3	Et2O	60	8 : 1
8	Cs2CO3	Dioxane	53	7 : 1
9	Cs2CO3	CH3CN	50	>19 : 1
10	Cs2CO3	DMF	31	15 : 1
11d	Cs2CO3	THF	65	>19 : 1
12e	Cs2CO3	THF	75	>19 : 1
13f	Cs2CO3	THF	64	>19 : 1

^aReaction conditions: p-QMs 1a (0.1 mmol), benzofuranones 2a (0.12 mmol) and base (0.2 mmol) in 2 mL of solvent for 6–48 h.

^bIsolated yields.

^cDetermined by crude ¹H NMR analysis.

^dPerformed at 30 °C.

^ePerformed at 10 °C.

^fPerformed at 0 °C.

With the optimized reaction conditions in hand, we explored the substrate scope of this cyclization reaction with a selection of benzofuranones. The results are shown in Table 2. To our pleasure, a wide range of benzofuran-2-ones derived olefins were compatible affording the corresponding chromans-spirobenzofuranone scaffolds 3 in good results. In detail, the steric hindrance of substituents had a significant impact on the cyclization reaction. The substrates with substituents on para- or meta-position on phenyl ring were tolerable affording the desired cycloadducts in good yields regardless of the electronic nature of substituents (entries 5–14). However, good diastereoselectivities were also observed in ortho-substituted substrates (entries 2–4). Furthermore, 2-naphthyl derived substrate gave also good yield and sole diastereoselectivity (entry 15). Multi-substituted substrate was also able to participate in this cyclization, for example, 3,4,5-trimethoxylphenyl substituted benzofuranone delivered cycloadduct 3p in 88% yield and with 12 : 1 dr value (entry 16). Interestingly, the extension of the reaction conditions to heteroaromatic substrates including 3-pyridyl and 3-thiophenyl benzofuranones were proceeded smoothly, giving rise to cyclization products 3q and 3r in 79% and 80% yield, respectively (entries 17–18).

Substrate scope of diastereoselective synthesis of chroman-spirobenzofuran-2-one^a.

Entry	R	3	Yieldb (%)	Drc
1	C6H5	3a	75	>19 : 1
2	2-ClC6H4	3b	69	>19 : 1
3	2-BrC6H4	3c	67	15 : 1
4	2-CH3C6H4	3d	64	>19 : 1
5	3-CH3C6H4	3e	75	>19 : 1
6	3-MeOC6H4	3f	72	>19 : 1
7	3-NO2C6H4	3g	71	>19 : 1
8	3-BrC6H4	3h	75	>19 : 1
9	4-CH3C6H4	3i	73	10 : 1
10	4-MeOC6H4	3j	86	>19 : 1
11	4-CF3C6H4	3k	82	12 : 1
12	4-NO2C6H4	3l	85	12 : 1
13	4-ClC6H4	3m	83	>19 : 1
14	4-BrC6H4	3n	81	12 : 1
15	2-Naphthyl	3o	74	>19 : 1
16	3,4,5-(OMe)3C6H2	3p	88	12 : 1
17	3-Pyridinyl	3q	79	>19 : 1
18	3-Thiophenyl	3r	80	>19 : 1

^aReaction conditions: p-QMs 1a (0.1 mmol), benzofuranones 2 (0.12 mmol) and Cs₂CO₃ (0.2 mmol) in 2 mL of THF.

^bIsolated yields for 4–48 h.

^cDetermined by crude ¹H NMR analysis.

Subsequently, the generality of this cyclization reaction was further evaluated through varying p-QMs 1. As shown in Table 3. It turned out that various p-QMs 1 can be employed to the reaction, which delivered functionalized chroman-spiro-benzofuran-2-ones scaffolds 4 in high yields (up to 90%) and with good diastereoselectivities. It seems that the position of the substituents had some delicate influence on the reaction. The C5-methoxyl- or methyl-substituted substrates p-QMs 1 generated the products with a higher yield than those of the C4- substituted counterparts (entries 3–6). Moreover, the C5-chloro- and bromo-substituted p-QMs 1 afforded the products 4a and 4b in moderate yield (entries 1–2).

Substrate scope of p-QMs^a.

Entry	R	4	Yieldb (%)	Drc
1	5-Cl	4a	73	>19 : 1
2	5-Br	4b	65	>19 : 1
3	5-CH3	4c	90	>19 : 1
4	5-OCH3	4d	80	10 : 1
5	4-CH3	4e	72	>19 : 1
6	4-OCH3	4f	66	10 : 1

^aReaction conditions: p-QMs 1 (0.1 mmol), benzofuranones 2a (0.12 mmol) and Cs₂CO₃ (0.2 mmol) in 2 mL of THF for 6–48 h.

^bIsolated yields.

^cDetermined by crude ¹H NMR analysis.

The structure and relative configuration of 3a were determined by HRMS, NMR spectroscopy and single-crystal X-ray analysis.¹⁵ The relative configuration of other cycloadducts were tentatively assigned by analogy (Fig. 2 and see ESI†).

Fig. 2. X-ray crystal structure of 3a.

Conclusions

In conclusion, we described a cyclization reaction of ortho-hydroxyphenyl-substituted para-quinone methides with benzofuran-2-one derived olefins via oxa-Michael/1,6-conjugated addition, which efficiently constructed enriched functionalized spirocyclic compounds combining both well-known heterocyclic pharmacophores chroman and benzofuran-2-one in good to excellent yields (up to 90%) and diastereoselectivities (up to 19 : 1 dr).

Conflicts of interest

There are no conflicts to declare.