Asymmetric synthesis of chromene skeletons via organocatalytic domino reactions of in situ generated ortho-quinone methide with malononitrile and β-functionalized ketone

Enantioselective organocatalytic domino reactions of in situ generated ortho-quinone methides with malononitrile and b-functionalized ketones have been developed. This strategy could generate various chiral chromenes in high yields (up to 99%) and stereoselectivities (up to >99 : 1 e.r.) in the presence of 5 mol% of a bifunctional organocatalyst. Gram-scale and useful synthetic transformations of this process are also presented.

As an important structure in biologically active compounds, the chromene skeleton is a pervasive structural moiety in a plethora of pharmaceuticals. 1 In particular, 2-amino-4H-chromenes are widely found in many biologically active molecules and exhibit various biological activities. 2 Compared with racemic 2-amino-4H-chromenes, studies on the synthesis of chiral 2-amino-4Hchromenes are still rare. 3,4Wang et al. reported a chiral thiourea-catalyzed Mannich/cyclization sequence and conjugate additions of nitroalkanes to 2-iminochromenes.4a,b The Feng group developed metal complex catalyzed cascade reactions.4d Despite signicant progress in this area, a few issues, such as unsatisfactory yields, poor stereoselectivities and limited substrate scope, have not yet been resolved.Hence, the development of an efficient protocol to access purely chiral chromenes remains in high demand.
ortho-Quinone methides (o-QMs) are highly reactive intermediates and are easily obtained from various precursors. 5Due to their distinctive electrophilic properties, o-QMs have been widely explored in organic chemistry.In recent years, much attention has been made in their use in catalytic asymmetric reactions. 6For instances, Sigman and co-workers reported a palladium-catalyzed asymmetric dialkoxylation of 2-propenyl phenols through a palladium ortho-quinone methide intermediate.Although some progress have been made in the synthesis of chiral chromenes, the substrate scope is still limited.Very recently, Enders's group have developed organocatalytic domino oxa-Michael/1,6-addition reactions to synthesize functionalized chromenes (Scheme 1d). 8Inspired by this work, we envisioned that an organocatalytic 1,6-conjugate addition and subsequent cycloaddition reactions of in situ generated o-QMs with malononitrile and b-functionalized ketones might provide a novel approach for the construction of various types of chiral chromenes (Scheme 1e).
We started our preliminary investigation with the reaction between quinone methide 1a and malononitrile 2 in the presence of catalyst 4a.To our delight, 84% yield and 85 : 15 e.r. were obtained (Table 1, entry 1).With the initial experimental results in hand, we then switched our attention to other organocatalysts.The assessment of catalysts indicated that bifunctional catalyst 4e, which was pioneered by Rawal and coworkers, 9 was the most efficient catalyst to furnish the desired product 3a in 86% yield and 93 : 7 e.r.(Table 1, entry 5).Aer identifying catalyst 4e as the best catalyst, we investigated the role of solvent in this process.Further investigations revealed that solvents also played a key role in this transformation.For instances, moderate e.r. were obtained when toluene, PhCF 3 , anisole, xylenes and dichloroethane were utilized (Table 1, entries 10-14).Switching the solvent to chloroform afforded the product 3a in 89% yield and 94 : 6 e.r.(Table 1, entry 15).To further optimize the reaction conditions, we changed the concentration and reaction temperature.The results showed that e.r. would improve to 97.5 : 2.5 with 90% yield when 1.0 mL of CHCl 3 was used (Table 1, entry 16).Further increasing the volume of CHCl 3 would not improve e.r.(Table 1, entry 17).90% yield and 95 : 5 e.r. were observed when we reduced the reaction temperature to 0 C for 48 h with 1.0 mL of CHCl 3 (Table 1, entry 18).Gratifyingly, if we decreased the catalyst loading to 5 mol%, the desired product 3a could be still obtained in 97% yield with 97.5 : 2.5 e.r.(Table 1, entry 19).
With the optimized conditions in hand, we then tested the substrate scope of this cascade process.As indicated in Table 2, QMs 1, which contained various functional groups were surveyed.The substrates bearing both electron-withdrawing groups (F, Cl, Br) and electron-donating groups (Me, OMe) in para, meta and ortho positions of the phenyl ring were all tolerated in this reaction to afford the corresponding products in excellent yields and e.r.(3a-i).Furthermore, the substrate 1j, which contained naphthyl moiety, also participated in this process and gave the desired product 3j in 96% yield and 95 : 5 e.r.aer 24 h at room temperature.When we replaced the tertbutyl group of the QMs by isopropyl group, the desired product 3k was obtained in 99% yield and 93 : 7 e.r.
Inspired by the success, we shied our focus to b-functionalized ketones to access chiral chromenes with more functional groups.As shown in Table 3, we started our investigation with reaction between quinone methide 1a and b-keto amide 5a.To our delight, the desired product 6aa was obtained in 85% yield  a Reaction conditions: a mixture of 1a (0.05 mmol), 2 (0.06 mmol) and catalyst (10 mol%) in the solvent (0.3 mL) was stirred at room temperature for 24 h.b Isolated yield.c Determined by HPLC analysis.d 1.0 mL of CHCl 3 was used.e 1.5 mL of CHCl 3 was used.f The reaction was conducted at 0 C for 48 h.g 5 mol% of 4e was used for 48 h.
and 94 : 6 e.r.through a cascade reaction in the presence of bifunctional catalyst 4e and a subsequent dehydration catalyzed by p-toluenesulfonic acid (for optimal conditions, see ESI †).The substrates QMs 1, which bearing electron-withdrawing or electron-donating groups in the different position of phenyl ring, underwent this transformation to give the desired products 6aafa in excellent yields (73-99%) and e.r.(93 : 7-96 : 4).A naphthyland hydroxy-substituted QM also took part in this process and gave the desired product 6ga in 68% yield and 77 : 23 e.r.
Replacing the tert-butyl group of the QMs by isopropyl group also furnished the desired product 6ha in 69% yield and 96 : 4 e.r.Encouraged by the above results, the generality of b-functionalized ketones 5 was also evaluated.A wide range of b-keto amides (5b-h) was tolerated under the reaction conditions to provide the corresponding products 6ab-ah in 68-97% yields and 90 : 10-99 : 1 e.r.Gratifyingly, 1,3-diketones 5i and 5j, a-ester ketone 5k and b-ketonitrile 5l also participated in this transformation successfully to give the desired products 6ai-al in 53-85% yields and 90 : 10 to >99 : 1 e.r.
To test the synthetic utility of our method, 3a was prepared on a gram scale.As shown in Scheme 2, the desired product 3a was obtained in 92% yield with 97.5 : 2.5 e.r.under optimal reaction conditions.As indicated in Scheme 3, some useful synthetic transformations of this process were also presented.Treatment of 3a with another equivalent of malononitrile in the presence of triethylamine in EtOH at reux afforded benzopyranopyridine 7 in 53% yield and 90 : 10 e.r.Furthermore, the AlCl 3 -mediated de-tert-butylation of 5aa was also attempted and the desired product 8 was obtained in 92% yield and 93 : 7 e.r.(Scheme 3).
To verify the mechanism of this process, a control experiment using TBS-protected substrate 9 was performed in the presence of catalyst 4e.The experiment showed that product 10 could be obtained in 87% yield aer 72 h at room temperature (Scheme 4).Meanwhile, 50 : 50 e.r. was observed, which indicated that the hydroxy group is important in the enantioselectivity-determining step and this process proceeded  through o-QM intermediate.As shown in Scheme 5, a plausible mechanism is proposed to explain the reaction process.First of all, substrate 1d would be transformed into o-QM 1d 0 in the presence of bifunctional catalyst 4e and the 1,6-conjugated addition of o-QM 1d 0 with malononitrile 2 formed the intermediated A in the presence of catalyst 4e.Subsequently, the intramolecular oxa-nucleophilic addition took place to afford the intermediated B, which would be transformed into the nal product 3d through tautomerization process.The absolute conguration of the adduct 3d and 6da were unambiguously determined by X-ray crystallography. 10n summary, we have developed an asymmetric organocatalytic domino reactions of in situ generated ortho-quinone methides with malononitrile and b-functionalized ketones for the synthesis of chiral chromenes in high yields and enantioselectivities.This strategy provides an efficient and convenient pathway to synthesize chiral chromene skeletons.Further investigation regarding the utilization of this organocatalytic procedure in the preparation of natural products is underway.
6a Lectka et al. developed an organocatalyzed [4 + 2] cycloaddition reaction of o-QMs with silylketene acetals to afford coumarin derivatives in good enantioselectivities. 6b More recently, o-QMs have been utilized for the synthesis of chiral chromenes. 7Schneider and Rueping independently developed Brønsted acid catalyzed conjugate addition/cyclodehydration reactions of b-diketones with in situ generated o-QMs for the synthesis of 4H-chromenes.7a,b Moreover, the Han group reported quinine-catalyzed annulations of o-QMs with malononitrile to furnish chiral 2-amino-4H-chromenes in high stereoselectivities (Scheme 1a).7c Later, Zhou et al. developed a novel method for the asymmetric synthesis of 2-amino-4Hchromenes from in situ generated o-QMs and active methylene compounds (Scheme 1b).7d Bernardi's group reported a bifunctional squaramide-catalyzed reaction of o-QMs generated in situ from 2-(1-arylsulfonyl-alkyl)phenols with active methylene compounds (Scheme 1c).4e

Table 1
Optimization of the reaction conditions a

Table 2
Substrate scope