Synthesis of novel four-fused-ring chromeno-benzoxepinones from salicylaldehydes and 1-benzoxepin-5-ones via the oxa-Michael reaction/aldol condensation

In this study, the synthesis of a series of novel four-fused-ring chromeno-benzoxepinones is described. The reaction of 1-benzoxepin-5-ones with salicylaldehydes mediated by 1,4-diazabicyclo[2,2,2]octane (DABCO) involves domino reactions including an oxa-Michael reaction, an aldol condensation and dehydration in a one-pot sequence to yield the target compounds in fairly good yields.


Introduction
The oxa-Michael reaction has become a useful, concise and efficient tool for the synthesis of oxycyclic compounds, and was recently reviewed by Nising et al. 1 Furthermore, the reactions of salicylaldehydes with α,β-unsaturated cyclic carbonyl compounds catalyzed by base to undergo the domino oxa-Michael and aldol condensation to provide an easy access to a variety of chromene derivatives have also been documented in the literature.For instance, the reaction of salicylaldehydes with α,β-unsaturated cyclohexenone yielded three-fused ring compounds with 1-chromene fused to a cyclohexanone ring, providing the key intermediates for various bioactive tetrahydroxanthones, 2 the reaction of salicylaldehydes with chiral substituted α,β-unsaturated cyclohexenone via the Morita-Baylis-Hillman reaction or oxa-Michael addition generated the bioactive diversonol, 3 the reaction of salicylaldehydes with α,β-unsaturated aldehydes catalyzed by prolinol yielded chiral chromenes, 4 the reaction of 2-(2-nitrovinyl)phenol with α,βunsaturated aldehydes gave tetrahydro-6H-benzo[c]chromenes, 5 the reaction of salicylaldehyde with α,β-unsaturated aldehydes catalyzed by chiral amine/chiral acid afforded chiral chromenes, 6 as well as others. 7Although numerous syntheses based on these oxa-Michael addition/aldol condensation have been well developed, the construction of four-fused-ring systems had not been studied.Therefore, to synthesize such four-fused-ring chromene derivatives is an attractive and important topic, not only for synthetic purposes, but also in the search for bioactive compounds.In continuing our studies on benzoheterocyclic compounds, 8 herein we report the synthesis of a series of novel four-ring compounds, specifically 5a,6-dihydro-12H-chromeno-[2,3-c][1]benzoxepin-12-ones, comprising a 1-benzoxepin-5-one and chromene units.

Results and Discussion
Scheme 1. Preparation of the key intermediate benzoxepin-5-ones (1a-c) from salicylaldehydes. 9r synthetic strategy is based on the reaction of the key intermediate 1-benzoxepin-5-ones (prepared from salicylaldehydes in four synthetic steps as outlined in Scheme 1 9 ), with further salicylaldehydes, mediated by 1,4-diazabicyclo[2,2,2]octane (DABCO) (Scheme 2).Our synthetic strategy successfully provides a concise one-pot reaction to afford the target compounds in fairly good yields.As shown in Table 1, in 1,4-dioxane:H2O = 1:2 as reaction solvent, DABCO as base, and at the reflux temperature (100-102 o C), 3c was produced in the highest yield (73%, entry 7).Comparing those reaction conditions, we found the utilization of H2O as a sole reaction solvent without any organic solvent and the utilization of DABCO as a reaction base gave a lower yield (28%) (entry 1).Furthermore, other organic solvents such as 1,4-dioxane, CH3OH, and DMSO used as reaction solvent, and DABCO used as base, did not improve the yields (42-55%) (entries 2, 3 and 5).When CH2Cl2 was used as reaction solvent and DABCO as base, the yield of 3c was lower (15%) than other conditions and starting materials were recovered (entry 4).In order to improve the percentage yields, binary solvent systems were examined.In the mixed solvent system H2O/DMSO (2:1) and base DABCO, the reaction of 1a with 2b under reflux gave 3c in 60% yield (entry 6).Under the same reaction condition as entry 7 (dioxane:H2O = 1:2, DABCO, and at reflux) but DABCO was replaced by DBU as a reaction base, the yield of compound 3c was 46% (entry 8).Finally, the reaction of 1a with 2b in the mixed solvents 1,4-dioxane/H2O (1:2) and the use of DABCO base under reflux gave 3c in 73% yield (entry 7), the highest yield.Thus, the reaction trend of solvent systems we found in this reaction is H2O/1,4-dioxane > H2O/DMSO > DMSO > 1,4-dioxane > CH3OH > H2O > CH2Cl2.For the tertiary amine used in the reaction, we found that DABCO is superior to DBU in giving the final product.
In our synthetic strategy, two possible reaction pathways may occur to yield the same target products.One pathway could go initially through the oxa-Michael reaction and the other one may start with a Baylis-Hillman reaction.In order to understand which reaction pathway is more possible, 1-benzoxepin-5-one (1a) was reacted with o-benzyloxybenzaldehyde in which the phenolic OH is protected, under the conditions which gave a high yield, described above i.e., solvent, H2O/1,4-dioxane = 2:1; base, DABCO, at reflux.After 24 h, we found that no Baylis-Hillman adduct was obtained, just the recovery of both starting materials (Scheme 3).This result strongly suggests that the reaction of 1-benzoxepin-5-one (1a) with o-hydroxybenzaldehyde mediated by DABCO may predominantly be via a domino sequence of reactions involving an oxa-Michael reaction, aldol condensation, and dehydration.Therefore, the formation of 3a from the reaction of 1a and 2a, as an example, could be rationally illustrated by the mechanism shown in Scheme 4. Initially, the phenolic proton of salicylaldehyde (2a) is abstracted by DABCO to generate a phenolate anion (step 1).The anion then attacks 1-benzoxepin-5-one (1a) in a Michael addition and yields the intermediate I (step 2), which then undergoes an intramolecular crossed aldol reaction to afford the intermediate II (step 3).This then picks up a proton from protonated DABCO to generate the intermediate III and regenerate free DABCO (step 4).Finally, the intermediate III is dehydrated by initial deprotonation by DABCO and hydroxide ion elimination to yield the final product, compound 3a (step 5).

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According to the best reaction conditions we found, the reactions of 1a-c with 2a-c were carried out mediated by DABCO in 1,4-dioxane:H2O = 1:2 at reflux, to afford compounds 3a-g in 68-77% yields.The structural elucidation of compounds 3a-g is mainly based on their 1 H-NMR spectra, 13 C-NMR, EI-MS and HRMS or EA.For instance, the 1 H-NMR spectrum of 2,10-dibromo-5a,6dihydro-12H-chromeno[2,3-c][1]benzoxepin-12-one (3d) was assigned as follows.Two double doublet sp 3 -protons, one at δ 4.38 and the other at δ 4.79, indicate the signals of H-6a and H-6b which are coupled to each other and commonly coupled with H-5a, respectively.The signal at δ 5.14 with multiplet splitting (ddd), coupled with H-13, H-6a and H-6b, was assigned to H-5a.An aromatic proton with a doublet (J 8.8 Hz) signal at δ 6.86 was assigned to H-4.The proton with a doublet signal at δ 7.02, which has a typical ortho coupling constant (J 8.8 Hz), was assigned to H-8.The doublet signal at δ 7.28 that has an allylic coupling (J 1.6 Hz) with H-5a, was assigned to H-13.The proton with a doublet (J 2.4 Hz) signal at δ 7.36 was assigned to H-1, the proton with a double doublet (J 9.2, 2.4 Hz) signal at δ 7.38 was assigned to H-3, The correlation of H-1 linked with H-3, and H-3 linked with H-4 was also proved by the COSY technique.The proton with a double doublet signal at δ 7.56 which has a typical ortho and meta coupling constant J 8.8, 2.8 Hz was assigned to H-9.Similarly, the proton with a doublet signal at δ 8.24 which has a meta coupling constant J 2.8 Hz was assigned to H-11.The other spectral data of compound 3d such as 13 C-NMR, EI-MS and HRMS are all consistent with the proposed structure.
For further structural confirmation, an X-ray analysis of 2,10-dibromo-5a,6-dihydro-12Hchromeno[2,3-c][1]benzoxepin-12-one (3d) was undertaken.The resulting ORTEP, which is consistent with the structure of compound 3d, is depicted in Figure 1.All structures of these novel four-fused ring benzooxycyclic compounds 3a-g obtained from the oxa-Michael reaction/aldol condensation of 1a-c and 2a-c, were confirmed by physical and spectral data, and HRMS.Their physical and selected spectral data were compiled in Table 2.

Conclusions
In this study we have established an efficient synthesis of various substituted 5a,6-dihydro-12Hchromeno[2,3-c][1]benzoxepin-12-ones, novel four-fused-ring heterocyclic compounds, via sequential reactions including an oxa-Michael addition/aldol condensation/dehydration in one pot.This study also demonstrated that in this reaction participation of the Baylis-Hillman reaction can be excluded.All title compounds have been fully characterized by spectral data such as 1 H-NMR, 13 C-NMR and HRMS.The structure of compound 3d was further confirmed by X-ray diffraction.

Scheme 4 .
Scheme 4. The proposed mechanism of formation of 3a from the reaction of 1a and 2a.

Table 1 .
Comparison of various conditions a for the synthesis of