Domino reactions of chromones with activated carbonyl compounds

Domino reactions of chromones with activated carbonyl compounds, such as dimethyl acetone-1,3-dicarboxylate and 1,3-diphenylacetone, and with 1,3-bis(silyloxy)-1,3-butadienes, electroneutral equivalents of 1,3-dicarbonyl dianions, allow for a convenient synthesis of a great variety of products. The regioselectivity and course of the reaction depends of the substituent located at carbon C3 of the chromone moiety and also on the type of nucleophile employed.


Introduction
Domino reactions (also called cascade or tandem reactions) allow for the synthesis of complex products with formation of several bonds in only one step [1][2][3][4][5].In contrast to non-activated acetone (1a), methylene-active compounds, such as 1,3dicarbonyl compounds, are of considerable relevance as building blocks in domino reactions (Scheme 1).For example, methyl acetoacetate (2a) possesses one CH-acidic methylene carbon which can be deprotonated in equilibrium by weak organic bases, such as triethylamine, piperidine or DBU, under thermodynamic conditions.Dimethyl acetone-1,3-dicarboxylate (3a) contains even two reactive methylene groups which can undergo cyclization reactions under mild conditions.In case of 1,3-diphenylacetone (4a) some activation of the methylene group is observed as well, because of benzylic stabilization.

1,3-Bis(silyloxy)-1,3-butadienes
The reaction of chromones 9a-j with 1,3-bis(silyloxy)-1,3-butadienes 6a-h, carried out in the presence of Me 3 SiOTf, and subsequent treatment with triethylamine in methanol afforded benzocoumarines 18a-ac (Scheme 4) [33,34].The formation of the product, which was obtained in a two-step one-pot reaction, can be explained by a mechanism similar to the one discussed for the formation of 17. 1,4-Addition gave intermediate D which was isolated, but used in crude form for the next step.Treatment of the latter with triethylamine in methanol resulted in ring-cleavage to give intermediate E. Subsequent base-mediated Knoevenagel reaction with extrusion of water gave intermediate F which underwent lactonization and resulted in the formation of the final product.The reaction proved to be rather general and various dienes and chromones were successfully employed to give the corresponding benzozocoumarines in good yields.The yields were in most of the cases in the range of 42 to 65% (over two steps) and did not depend much on the substituents attached to the chromone and at carbon C-4 of the diene.However, in case of a benzyl and a benzyloxy group located at carbon C-4 of the diene, the overall yields were rather low (20%).This might be explained by steric effects.One of the best yields was obtained for the reaction of diene 6a with unsubstituted chromone 9a and for the diene containing a methoxy group (R 4 = OMe).The products proved to be interesting, due to their blue fluorescence.

3-Formylchromones
Dimethyl acetone-1,3-dicarboxylate The reaction of 3 with 3-formylchromones 10a-d afforded benzophenones 19a-d in moderate to good yields (Scheme 5) [32].The formation of the products can be explained by Michael reaction (1,4-addition) of 3 to the chromone and ring cleavage to give intermediate G. Subsequent Knoevenagel reaction by attack of the methylene carbon to the aldehyde resulted in the formation of the final products.The regioselective cyclization can be explained by the higher electrophilicity of the aldehyde as compared to the ketone.The yields were in general quite good (51-65%).Relatively low yields (51-52%) were obtained for chromones containing methyl substituents, presumably due to the lower electrophilicity of the chromone based on the electron-donating effect of the methyl groups.Good yields were obtained for parent 3-formylchromone (10a) and for chlorine-substituted chromones, because of the higher electrophilicity of the chromone based on the electron-withdrawing effect of the methyl groups.

1,3-Bis(silyloxy)-1,3-butadienes
The reaction of 3-formyl-and 3-acetylchromones 10a-i with 1,3-bis(silyloxy)-1,3-butadienes 6a-h, catalysed by Me 3 SiOTf, afforded hydroxylated benzophenones 20a-ag (Scheme 6) [35,36].The products are formed by a mechanism related to the one discussed for the formation of products 19a-d.The same type of product is formed in the reaction of 3-formylchromones with (2,4-dioxobutylidene)phosphoranes [37].The yields were in a range of 33 to 82%.No clear trend was observed for the yields depending on the structure of the diene and the chromone.Similar to unsubstituted diene 6a, dienes containing a substituent R 5 located at carbon C-4 gave good yields, except for methoxy and benzyloxy which did not work at all.Dienes derived from 1,3-diketones (R 6 = Me, Ph) gave similar yields to those obtained from dienes derived form β-ketoesters, although yields were slightly lower in case of R 6 = Me.The best yield was obtained for the cyclization of unsubstituted diene 6a with a chlorine-substituted chromone, presumably because of the electron-withdrawing character of the chlorine atoms and, thus, higher electrophilicity of the chromone.

3-(Methoxalyl)chromones
Dimethyl acetone-1,3-dicarboxylate The reaction of dimethyl acetone-1,3-dicarboxylate (3) with 3-(methoxalyl)chromones 11a-g, a new type of chromone developed in our group, afforded benzophenones 21a-g in moderate to very good yields (Scheme 7) [38].The formation of the products can be explained by Michael reaction (1,4-addition) of 3 to the chromone and ring cleavage to give intermediate I. Subsequent Knoevenagel reaction by attack of the methylene carbon to the carbonyl group adjacent to the ester group resulted in the formation of the final products.The regioselective cyclization can be explained by the higher electrophilicity of the carbonyl group adjacent to the ester, due to the electron-withdrawing effect of the latter.The yields were generally good to very good and no trend was observed depending on the structure of the chromones.

1,3-Bis(silyloxy)-1,3-butadienes
The reaction of 11a-c with 1,3-bis(silyloxy)-1,3-butadienes 6a-h, catalyzed by Me 3 SiOTf, afforded products 23a-j with excellent diastereoselectivity (Scheme 9) [39].The formation of the products can be explained by 1,4-addition of the terminal carbon of the diene to the chromone to give intermediate J and subsequent attack of the central carbon atom of the 1,3-dicarbonyl unit (aldol reaction).No aromatization and extrusion of the hydroxy group was observed under these conditions, because the electron-withdrawing character of the additional ester group which destabilizes formation of a cation at the neighboring position.The yields were in most cases moderate (42-54%).Two products were obtained in higher yields (71 and 80%).However, no clear trend was observed for the yields depending on the substitution pattern.Instead, the individual purity and quality of the dienes played an important role.Reflux of an EtOH solution of 23a in the presence of PTSA (para-toluenesulfonic acid) afforded benzophenone 24a in 50% yield.The reaction of 6a-r with 13a-c, following the conditions discussed above for the synthesis of 23a-j, and subse-Scheme 11: Synthesis of 25a-f.Conditions: i, DBU (1.3 equiv), dioxane, 20 °C, 12 h.quent treatment with PTSA afforded benzophenones 24a-w in a two-step on-pot procedure (Scheme 10) [39].The formation of the products can be explained by 1,4-addition and subsequent aldol reaction to give products 24 and subsequent acid-catalyzed ring-cleavage and Knoevenagel reaction, similar to the formation of products 21 and 22.The products were formed in 54-84% yields.Again, no systematic trend was observed for the yields.Good yields were observed for dienes containing various substituents located at carbon C-4 and for chromones containing a hydrogen, methyl or bromide at carbon C-6 of the chromone.

3-(Benzoyl)chromones Dimethyl acetone-1,3-dicarboxylate
The reaction of dimethyl acetone-1,3-dicarboxylate (3) with 3-aroylchromones 12a-f afforded benzophenones 25a-f (Scheme 11) [38].A variety of aryl groups were tolerated, including 3-and 4-nitrophenyl and 3,5-dinitrophenyl.The formation of the product proceeds analogously to the reaction leading to benzophenones 19 and 21.The yields were in most cases moderate to good.A poor yield (7%) was obtained from the chromone substituted by a 2-thienyl group which might be explained by the electron-rich nature of the thiophene and, thus, a reduced electrophilicity of the neighboring carbonyl group.Likewise, a poor yield (23%) was observed for a 2-fluorophenyl group, presumably due to steric hindrance because of the ortho-substituent.Excellent yields (70 and 83%) were obtained for a 3-nitro-and a 3,5-dinitrophenyl group, presumably due to the electron-withdrawing character of the nitro groups and an enhanced electrophilicity.A moderate yield (49%) was obtained for the phenyl derivative.

3-(2-Nitrobenzoyl)chromones
Dimethyl acetone-1,3-dicarboxylate A completely different result was obtained when chromones containing a 2-nitrobenzoyl group were employed.The reaction of dimethyl acetone-1,3-dicarboxylate (3) with 3-(2nitrobenzoyl)chromones 13a-c afforded benzocoumarines 27a-c in good yields (Scheme 13) [38].The formation of the products can be explained by 1,4-addition of 3 to the chromone and ring cleavage to give intermediate K. Subsequent Knoevenagel reaction by attack of the methylene carbon to the carbonyl group adjacent to the phenol moiety resulted in formation of intermediate L and lactonization gave the final products.The regioselectivity of the cyclization can be explained by steric hindrance of the carbonyl group adjacent to the 2-nitrophenyl moiety containing an ortho-substituent.Interestingly, in case of a 2-fluorophenyl group, the regioselectivity was different and product 26 was obtained (see Scheme 12).The yields were, in general, very good.The best yield (84%) was obtained for the reaction of 6-methyl-substituted 3-(2-nitrobenzoyl)chromone 13b, presumably due to a better solubility of the product.However, the yields were in a similar range (72-84%).

3-(Perfluoroalkanoyl)chromones Dimethyl acetone-1,3-dicarboxylate
The reaction of dimethyl acetone-1,3-dicarboxylate (3) with 3-trifluoroacetyl-and 3-(perfluoroalkanoyl)chromones 14a-n afforded hemiacetals 29a-n in moderate to good yields (Scheme 15) [38].The first step is again a 1,4-addition with subsequent ring cleavage of the chromone (intermediate M).Similar to the formation of products 27, the cyclization proceeded by attack of the methylene carbon to the carbonyl group adjacent to the phenol moiety (intermediate N).This might be explained by the fact that the carbonyl adjacent to the perfluoroalkyl group exists as a hydrate which reduces significantly its electrophilicity.The products are finally generated by intramolecular formation of a semi-acetal.The yields were generally good (56-78%).The yields for pentafluoroethyl-and heptafluoropropyl-substituted derivatives were slightly better than the yields of trifluoromethyl-substituted derivatives which might be explained by a better solubility.For the other substituents of the chromone, no clear trend was observed.Product 29c underwent cleavage of the perfluoroalkyl group upon treatment with potassium hydroxide in methanol to give benzocoumarine 30.

1,3-Bis(silyloxy)-1,3-butadienes
The reaction of 3-(trifluoroacetyl)chromone (14a) with 1,3bis(silyloxy)-1,3-butadienes proved not to be successful in our hands.However, reaction of 3-(trifluoroacetyl)thiochromone (31) with 1,3-bis(silyloxy)-1,3-butadienes 6a,b, in the presence of Me 3 SiOTf, afforded products 32a,b with excellent diastereoselectivity (Scheme 16) [40].The formation of the products can be explained by 1,4-addition of the terminal carbon of the diene to the chromone to give intermediate O and subsequent attack of the central carbon atom of the 1,3-dicarbonyl unit (aldol reaction).No aromatization and extrusion of the hydroxy group was observed, because the electron-withdrawing character of the CF 3 group which destabilizes the formation of a cation at the neighboring position.In addition, the carbon-sulfur bond was not cleaved, due to the lower leaving group ability of sulfur as compared to oxygen.The yields of the two products were moderate.

3-Ketoamides
The reaction of 3-ketoamides 34a-f with 3-halochromones 15a-g afforded 2-(salicyloyl)furans 35a-x in mostly good to excellent yields (Scheme 18) [41].The reaction proceeds by 1,4-addition of the methylene carbon of 34 to the chromone to give intermediate T, cyclization by regioselective intramolecular nucleophilic attack of the oxygen to the halide to give intermediate U and subsequent ring-cleavage.The reaction of 3-ketoamide 34a (R 3 = Me, R 4 = Ph) with 3-chloro-, 3-bromo-, and 3-iodochromone showed that the yields strongly depend on the type of halogen atom located at position 3 of the chromone.During the optimization of the conditions, the best yields were in many cases obtained when chloride was employed as the leaving group.However, for some other products the yields were slightly better in case of employment of 3-bromochromone.Most of the yields were higher than 70%, in several cases excellent (higher than 90%).Only in a few cases, the yields were moderate (46-53%).However, no clear trend was observed for the yields depending on the substituents.The reaction of 7-methoxy-substituted 3-halochromones were in most cases lower as compared to unsubstituted or chloro-substituted chromones, presumably due to the electron-donating character of the methoxy group and the lower electrophilicity of the chromone.But this trend was also not general.Similar yields were obtained for ketones (R 3 = Me, Ph) or esters (R 3 = OMe).
Treatment of 2-(salicyloyl)furan 35a with iodine in the presence of DBU afforded furo [3,2-b]chromen-9-one 36a in 32% yield.Based on this observation, the two-step one-pot reaction of ketoamides 34a-f with 3-halochromones 15a-c was studied which afforded furo[3,2-b]chromen-9-ones 36a-f, albeit, in only low to moderate yields (Scheme 19) [41].The formation of these products can be explained by initial formation of the corresponding 2-(salicyloyl)furans V. Iodination of the latter afforded iodonium salt W which underwent cyclization by attack of the salicylate hydroxy group to give intermediate X.
Extrusion of hydrogen iodide afforded the final product.Similarly to products 35, relatively low yields were observed for reactions of methoxy-substituted 3-halochromones.The two-step one-pot reaction of N-unsubstituted ketoamide 33a with 3-halochromones 29a and 31a afforded spirocycles 36a,b, albeit, in only moderate yields (Scheme 20) [41].The formation of these products can be explained, similarly to the formation of 35a-f, by generation of intermediate Y which afforded iodonium salt Z upon addition of iodine.Cyclization by attack of the salicylate hydroxy group to carbon C5 gave intermediate AB.Hydrolysis of the iodide upon aqueous workup to give an alcohol and oxidation of the latter resulted in formation of the final product.The reason for the change of the regioselectivity of cyclization, as compared to the formation of products 36, remains unclear at present.The reaction of 3-halochromones with 3H-indole-2-thiones (thiooxindoles) 38a-c afforded 2-salicyloyl-8H-thieno[2,3b]indoles 39a-i in mostly moderate to good yields (Scheme 21) [41].The formation of these products can be explained, similarly to the formation of products 35, by 1,4-addition of the carbon atom of 38 to the chromone to give intermediate AB, cyclization by nucleophilic attack of the sulfur to the bromide (intermediate AC) and subsequent ring-cleavage.In most reactions, DBU was employed as the base.In case of products derived N-unsubstititued 3H-indole-2-thiones (R 3 = H), employment potassium carbonate proved to be advantageous.Similarly to the formation of products 35, the use of 3-chloro-chromones gave the best yields.Likewise, the presence of a methoxy group located at the chromone moiety, resulted in a decrease of the yield, due to the electron-donating effect of the methoxy group.
The reaction proved to be rather general and a variety of substituted 3-cyanochromones were successfully employed.

1,3-Bis(silyloxy)-1,3-butadienes
The two-step reaction of 3-cyanochromones 16a-h with 1,3bis(silyloxy)-1,3-butadienes 6a-z afforded azaxanthones 41a-am (Scheme 23) [45,46].The formation of the products can be explained by the mechanism discussed for formation of 40 that involves intermediates AF and AG.For most the yields were in the range of 30 to 66%.Employment of dienes derived from 1,3-diketones (R 3 = Me, Ph) proved to be unsuccessful, presumably due to the lower nucleophilicity of these dienes as compared to those derived from β-ketoesters (R 3 = Oalkyl).Substituents located at carbon C-4 of the diene (R 1 ) were generally tolerated as well.In fact, the best yield (66%) was obtained for the product derived from unsubstituted 3-cyanochromone (16a) and a diene containing a phenoxy group located at carbon C-4 (R 1 = OPh).But in other cases, the yields were less.In fact, in some cases, cyano-substituted benzocoumarines, similar to products 18, were formed as byproducts.Substituents located at carbon C-2 of the diene (R 2 ) were tolerated, but the yields were lower, presumably due to the instability of these dienes [13].In summary, no clear trend was observed for the influence of the substituents on the yields.
The reaction of 3-cyanochromones 16a-h with 2-fluoro-1,3bis(silyloxy)-1,3-butadienes 42a-z afforded separable mixtures of azaxanthones 43a-aa and biphenyls 44a-ac (Scheme 24) [47].In case of 4-unsubstituted 2-fluoro-1,3-bis(silyloxy)-1,3butadienes, azaxanthones 43 were exclusively formed in 33-56% yields.A similar result was obtained for the corresponding 2-chloro-1,3-bis(silyloxy)-1,3-butadiene [48].In case of 4-alkyl-2-fluoro-1,3-bis(silyloxy)-1,3-butadienes, biphenyls 44 were formed as the major products in 63-79% yields.In some cases, these products were exclusively formed.In other cases, azaxanthones 43 were isolated as minor products as well (7-20% yields).The formation of biphenyls 44 can be explained by 1,4-addition and ring-cleavage to give intermediate AH, aldol reaction (intermediate AI), migration of the ester group from the quaternary carbon to the phenolic oxygen atom (intermediate AJ) and aromatization.The steric influence of the fluorine atom and of the substituent R 1 might have an influence on the conformation which facilitates the intramolecular aldol reaction at the expense of the nitrile addition.In the case of formation of biphenyls 44, these products were generally obtained in good yields (63-79%).While the presence of a substituent located at carbon C-4 was mandatory, the exact type of substituent was not decisive for the yield.The substituents located at the chromone moiety also did not have a great impact on the yield.

Conclusion
The present review highlighted reactions of chromones with 1,3-dicarbonyl compounds and 1,3-bis(silyloxy)-1,3-butadienes which can be regarded as electroneutral equivalents of dianions of 1,3-dicarbonyl compounds.The regioselectivity of these reactions depends mainly on the type of chromone.2,3-Unsubstituted chromones undergo initial 1,4-addition and subsequent Knoevenagel condensation via the carbonyl group.In contrast, in case of 3-formylchromones the cyclization proceeds via the formyl group, due to its higher electrophilicity.The same regioselectivity was observed for 3-(methoxalyl)-and 3-benzoylchromones.In contrast, a cyclization via the carbonyl group of the chromone moiety was observed for 3-(2-nitrobenzoyl)chromone, presumably due to steric hindrance.The same selectivity was observed also for 3-trifluorochromone and 3-perfluoroalkanoylchromones which might be explained by the fact that the carbonyl adjacent to the perfluoroalkyl group exists as a hydrate which reduces significantly its electrophilicity.In case of 3-halochromones, the halide acts as a leaving group during the reaction.For 3-cyanochromones, a nucleophilic attack of chromone-derived hydroxy group to the nitrile was observed in most cases.However, a different reaction was observed for long chained 2-fluoro-1,3-bis(silyloxy)-1,3butadienes.In conclusion, the interaction of activated carbonyl compounds with chromones offer a great variety of different reaction pathways leading to various types of products with potential applications in materials science and medicinal chemistry.
The domino reactions presented, which involve mostly the combination of 1,4-additions of the carbonyl compounds to the chromone moiety with ring cleavage reactions, allow for the synthesis of products which are not readily available by other methods.The benefit for the employment of chromones as building blocks is their dense functionalization in combination with their (commercial) availability.On the other hand, highly substituted or functionalized chromones have to be prepared in multi-step syntheses.In general, the substitution pattern of the chromone does not seem to have a great influence on the yields which is beneficial for studies related to the scope and the synthesis of compound libraries.The use of dimethyl acetone-1,3dicarboxylate as a starting material has the advantage that it is commercially available, stable and easy to handle.The use of 1,3-bis(silyloxy)-1,3-butadienes is, on the other hand, significantly more difficult and usually requires the use of the Schlenck technique to avoid hydrolysis of the moisture sensitive compounds.The handling of these reagents, which have to be stored at low temperature, requires some experience.In fact, the synthesis of the dienes has to proceed with full conversion and in high yield as the they cannot be purified by chromatography.Distillation is also problematic, as dienes containing substituents located at carbon atom C-2 readily undergo isomerization reactions.The reactions of 1,3-bis(silyloxy)-1,3-butadienes with chromones requires the action of trimethylsilyl trifluoromethanesulfonate (TMSOTf) which is a relatively expensive reagent.
In future studies, especially the chemistry of 3-methoxalyl-and 3-nitrochromones should be further explored.In case of the methoxalyl derivatives, so far not many synthetic applications have been developed.In the future, it will be interesting also to study reactions of 3-nitrochromone with carbonyl compounds.In this context, biological properties of the products will be interesting, as the nitro group can be transformed to the biologically important amino group.

Scheme 2 :Scheme 3 :
Scheme 2: Structures of chromones with different substituents located at carbon C-3 and atom numbering scheme exemplified for 9a.
1,4-addition of 3 to the chromone to give intermediate A and ring cleavage to give intermediate B. Subsequent Knoevenagel reaction by attack of the methylene carbon to the carbonyl group gave intermediate C which underwent lactonization to give the final product.