Asymmetric [4 + 2] cycloaddition synthesis of 4H-chromene derivatives facilitated by group-assisted-purification (GAP) chemistry

In this work, we present a strategy for the preparation of functionalized 4H-chromene derivatives via a Cs2CO3-catalyzed [4 + 2] cycloaddition of enantiopure chiral salicyl N-phosphonyl imines with allenoates. Fifteen examples were achieved in excellent yields and diastereoselectivity. The products were purified simply by washing the crude mixture with hexanes following the Group-Assisted Purification (GAP) chemistry/technology to bypass traditional separation methods. The absolute configuration was unambiguously determined by X-ray structure analysis.


Introduction
4H-Chromenes represent an important class of bicyclic oxygenated heterocyclic compounds which are prevalent in a variety of natural products. [1][2][3][4] Molecules exhibiting these motifs demonstrate biological activities such as anticonvulsant, 5 anti-HIV 6,7 and antimicrobial 8,9 and numerous other biological activities (Fig. 1). In addition, chromenes possess anti-cancer properties as they induce apoptosis via interaction with tubulin at the binding sites of colchicine which results in the death of cancer cells. [10][11][12][13] In recent years, the chemistry of allenes has attracted signicant attention and they are considered reactive substrates with synthetic utility as starting materials from which to prepare complex molecules via cycloaddition reactions. [14][15][16][17][18][19][20] The presence of electron withdrawing or electron donating groups on the allene moiety can induce electronic effects and drive allenes to react as either electrophiles or nucleophiles. [21][22][23][24] The reactivity of allenes is contingent upon their ability to form zwitterionic intermediates in the presence of nitrogenous/ phosphorous-based or nucleophilic Lewis base catalysts. [25][26][27][28][29][30][31][32][33] In addition, it has been reported that allenes can react with nucleophilic compounds in the presence of carbonate catalysis (Scheme 1). [34][35][36] Shi and co-workers utilized allene esters and ketones to establish the rst synthesis of chromenes via [4 + 2] cycloaddition assisted by nitrogen-based catalysts such as DABCO and DBU (Scheme 2a). [37][38][39] In 2015, Tong and co-workers reported the synthesis of 4H-chromenes from d-acetoxy allenoates with salicylaldehyde derivatives in an amine-catalyzed reaction (Scheme 2b). 25 Although in both of the aforementioned methods 4H-chromenes were prepared in excellent yields, the enantioselectivity of these methods still need to be improved. In recent years, carbonate catalyzed reactions of allenes with nucleophiles have been recognized as an appropriate method for the synthesis of chromenes. In 2018, our group synthesized 4H-chromenes from the reaction of hydroxychalcones and allenoates in the presence of cesium carbonate in high yield and chemo-selectivity (Scheme 2c). 34 Over the past decade, our group has developed Group-Assisted Purication (GAP) chemistry. [40][41][42][43][44] In essence, highly functionalized chiral N-phosphonyl/N-phosphinyl imines were a Mannich-type reaction, 45 aza-MBH reaction, 46 Strecker reaction, 43 Umpolung reaction, 47 and the synthesis of peptides 48 among others. Recently, our group discovered a novel form of chirality, multi-layer 3D chirality, via GAP chemistry in which restriction of the free rotation of intramolecular layers generates chirality. [49][50][51][52] To the best of our knowledge, although several routes have been reported for the synthesis of 4H-chromenes through applying auxiliary group, a practical method for the diastereoselective synthesis of these valuable synthons has yet to be devised. The broad spectrum of pharmaceutical properties of this class of heterocyclic compounds and their abundance in natural products with low toxicity inspired us to develop a novel method of preparing them with high chemo and diastereoselectivity. Herein, continuing our investigations into the construction of heterocyclic compounds enabled by GAP technology, we report a facile and efficient [4 + 2] cycloaddition reaction to synthesize 4H-chromenes. Salicyl N-phosphonyl imines react with allenoates in the presence of cesium carbonate and THF at À30 degrees to yield 4H-chromenes in good yield (up to 72%) and high chemo and diastereoselectivity (up to 99%) (Scheme 2d).

Results and discussion
At the outset of our investigation, salicyl N-phosphonyl imine 1a was subjected to benzyl buta-2,3-dienoate 2a (2.00 equiv.) in the presence of various combinations of solvents and bases (2.00 equiv.) at room temperature. The progress of the reactions was monitored by thin layer chromatography and 31 P NMR. The results are summarized in Table 1. In the presence of lithium hydroxide monohydrate in dry THF, 4H-chromene was obtained in 45% yield and 80 : 20 diastereoselectivity (Table 1, entry 1). Then, other solvent systems in the presence of LiOH$H 2 O were examined. Dimethylsulfoxide (DMSO), toluene and acetonitrile resulted in lower yield and dr while no product was isolated in dichloromethane and chloroform ( Table 1, entries 2-6). As result, we recognized THF as the optimal solvent. Next, we tried other inorganic and organic bases. The combination of potassium carbonate and dry THF furnished 58% of the desired product with good diastereoselectivity (  1, entry 18). However, the reaction did not proceed to completion at À40 C and most of the salicyl N-phosphonyl imine was not consumed ( Table 1, entry 19).
With optimized reaction conditions in hand, a wide range of annulation reactions implementing various substitution patterns on the salicyl N-phosphonyl imine and allenoate were evaluated with regard to the synthesis of 4H-chromenes. A wide range of enantiomerically pure salicyl N-phosphonyl auxiliary imines were isolated in the presence of TiCl 4 and N,N-diisopropylethylamine in dry dichloromethane and under argon gas. Enantiopure salicyl N-phosphonyl imines with both electronwithdrawing electron-donating groups on various positions of the aromatic ring were synthesized in good yields and excellent diastereoselectivity (Scheme 2). In addition, various allenoates were prepared according to a previously reported method (Scheme 3). 53 Next, various salicyl N-phosphonyl imines were subjected to allenoates (3.0 equiv.) in the presence of cesium carbonate (3.0 equiv.) and dry THF at À30 C. A broad scope of functionalized 4H-chromenes were synthesized in good yield (up to 78%) and excellent diastereoselectivity (up to 99 : 1). A variety of substituents on the phenolic moiety of the salicyl Nphosphonyl group, including MeO, Me, Cl, F and Br, were successfully implemented in these transformations under the above conditions. With an electron-donating group on the aromatic ring of the salicyl N-phosphonyl imine, the 4Hchromene was obtained smoothly in high yield and excellent diastereoselectivity. However, when the salicyl N-phosphonyl imine possessed an electron-withdrawing group at the meta or para position on the aromatic ring, the result was that less desired product was observed as it is hypothesized that they reduced the nucleophilicity of the oxygen atom, present on the imine. The presence of an electron decient group at the ortho position reduced the rate of reaction signicantly and just a trace amount of desired product was observed aer 48 hours. Generally, the substrates with electron-donating groups resulted in slightly better diastereoselectivity compared to electron withdrawing groups. One explanation for lower diastereoselectivity of substrates with halogens as electron withdrawing groups could be the steric hindrance Scheme 3 Substrate scope for the synthesis of salicyl N-phosphonylimines. Scheme 4 Substrate scope of [4 + 2] annulation for the synthesis of functionalized chromenes. a a Reactions were performed with salicyl Nphosphonyl imine (1 mmol), cesium carbonate (3 mmol) and allenoate (3 mmol) in dry THF at À35 C for 48 h. b Isolated yields after GAP washing. c The dr is determined from 31 P NMR of the crude mixture. effect of halogen groups. Next, we decided to modify the ester group of the allenoate to expand the synthetic scope. The reaction proceeded smoothly with ethyl 2,3-butadienoate and 80% of product with 95 : 5 diastereoselectivity was isolated. Subsequently, other nonterminal allenoates including 4-OMeC 6 H 4 , 4-MeC 6 H 4, 4-ClC 6 H 4, 4-BrC 6 H 4 and 2-MeC 6 H 4 were subjected to N-salicyl phosphonyl imine. In all cases, 4Hchromenes were obtained in high yield and dr, demonstrating the efficiency of the reaction. It was observed that the substituent on the allenoate did not affect the reaction yield and diastereoselectivity noticeably (Scheme 4). The structures of the products were unambiguously determined by X-ray crystallographic analysis of compound 3a (Fig. 2).
Based on our investigation and previous reports, 12,34,36,54 especially the recent review regarding stepwise [4 + 2] cycloaddition reactions, 55 a plausible mechanism for the reaction is represented in Scheme 5. The sequence is initiated by deprotonation of salicyl N-phosphonyl imine 1 by cesium carbonate as a non-nucleophilic base to form intermediate A.

Conclusions
In summary, a new and facile asymmetric [4 + 2] cycloaddition of salicyl N-phosphonyl imines with allenoates has been developed under convenient condition. The reaction provides an easy access to highly functionalized 4H-chromenes 4Hchromenes in good yield (up to 80%) and excellent diastereoselectivity (up to 99%). The products were conveniently separated from the crude mixtures by simple washing with hexanes to bypass traditional purication methods. This method complements other methods to access functionalized 4H-chromene derivatives for potential applications in biological activity screening. Our further studies will be focused on new asymmetric GAP reactions of salicyl N-phosphonyl imines for synthesis of a series of new 2,3-dihydrobeznofuran derivatives.

Conflicts of interest
There are no conicts to declare.