Bis -Enaminones as versatile precursors for terheterocycles: synthesis and reactions

This review summarizes the results of literature reports concerning synthesis and chemical reactions of bis(enaminones) reported by us and by other research groups from 1995 to mid 2011. It outlines their utility as versatile precursors for synthesis of various terheterocycles


Introduction
The term enaminones 1 usually refers to the compounds that contain the conjugate system N-C=C-C=O.Sometimes they are referred to as ß-aminovinyl ketones, ß-aminoenones or αenaminoketones.From the structural point of view, enaminones are usually classified according to the degree of substitution on the nitrogen atom into primary (1 o ), secondary (2 o ) and tertiary (3 o ) enaminones (Chart 1).Also, enaminones are usually classified according to their carbon skeleton into acyclic 1, endocyclic 2, exocyclic 3 and heterocyclic 4 enaminones (Chart 1).Furthermore, acyclic enaminones are further classified according to the degree of substitution at αand ß-carbons into α-substituted, ß-substituted and α,ß-disubstituted enaminones A-D, respectively (Chart 2).A literature survey reveals that enaminones are very stable compounds and constitute a versatile class of useful precursors in organic synthesis, in pharmaceutical development and in heterocyclic synthesis. 1Although the chemistry of mono-enaminones 1-4 has been the subject of several reviews, [2][3][4][5][6][7][8][9][10] the chemistry of bis-enaminones of type 5 has not been covered hitherto.The intention of this review is to focus mainly on publications dealing with the synthesis and reactions of various bis(enaminones) 5 that have been reported during the period from 1995 to mid 2011 is presented.Also, the bis(enaminone) 11 was obtained by refluxing a solution of 6,6'-diacetyl-2,2'bipyridine 10 in dimethylformamide dimethylacetal in xylene under nitrogen. 16ondensation of 1,3-and 1,4-diacetylbenzenes 16a,b each with two mole equivalents of DMF-DMA in dry toluene was also reported to afford the bis(enaminones) 17. 11,18 When this reaction was repeated in a pressure tube for a few minutes in a microwave oven at 360W, it gave also the respective bis(enaminones) 17.

Reaction of mono-enaminones with diamines
The reaction of the monoenamines 24 each with  Similarly, when a mixture of the enaminone 31, 1,2-diaminoethane and formaldehyde in methanol was irradiated in a microwave oven, it afforded the respective bis(enaminones) 32a in 71% yield. 23The reaction was found to be general with other diamines to give the respective product 32 in 51-68% overall yields.Use of 1,4-phenylenediamine in lieu of aliphatic diamines, the reaction yielded the corresponding bis(naminones 33. 23

Miscellaneous methods
Recently, a new series of ten bis-enaminones 44 was isolated in satisfactory yields of 47-91%, by the reaction of enones 43 with 1,3-phenylenediamine at a molar ratio of 2:1, respectively.The reactions were reported to be carried out in ethanol, water, water/dichloromethane (1:1) or water/chloroform (1:1) at a temperature range of 25 to 80 °C.The best results were obtained when enones 43a-j were added to 1,3-phenylenediamine, in pure ethanol for 43a-d and 43f-j or in water/chloroform (1:1) solution for 43e.Buehrdel et al. 29 reported that reaction of the bis-imidoyl chloride 46 with each of tetrahydro-1-napthanone and methyl ketones in tetrahydrofuran in the presence of potassium t-butoxide at -70 o C yielded the respective bis(enaminones) 47 and 48.Recently, the polyfunctional bis(enaminones) 55 were successfully synthesized stereoselectively via reactions of a mixture of primary amines 49, aldehydes 50, propargylic acid 51, isocyanides 52, and piperazine 53 in one pot.The reaction was said to proceed via formation of an N-substituted-2-alkynamide 54 as an intermediate which contains an active triple bond suitable for further nucleophilic addition reaction.

Chemical Reactions
The chemical reactivity of enaminones is in general attributed to the fact that they combine the ambident nucleophilicity of enamines and the amibident electrophilicity of enones.For example, each enaminone can be attacked by a given nucleophile at the two sites namely the C-3 (the dialkylaminoethylene group) and C-1 (the carbonyl group) with reactivity order C-3 > C-1.Also, it can be attacked by an electrophile at C-2, oxygen and/or nitrogen sites with reactivity order C-2 > N > O. Recently, it was reported that treatment of the bis-enaminone 35 with primary amine in npropanol at 95 o yielded the respective dimethyl 4-oxo-1,4-dihydropyridine-3,5-dicarboxylate 57. 24milar reaction of 35 with 1,4-diaminobenzene under the same reaction conditions afforded the respective 1,4-bis(4-oxo-3,5-dimethoxucarbonyl -1,4-dihydropyridin-1-yl)benzene 58. 242.Reactions with heterocyclic amines 3.2.1.Reaction with 5-aminopyrazoles.Reaction of a given enaminone with 5-amino-1Hpyrazole can theoretically proceed through two possible routes to give 5-substitututed pyrazolo[1,5-a]pyrimidine A and/or 7-substitututed pyrazolo[1,5-a]pyrimidine B as shown below.However, literature reports indicate that such a reaction is site selective as it afforded in most cases 5-substituted pyrazolo[1,5-a]pyrimidine derivatives A. Also, Shawali et al. 35 reported that reaction of the bis-enaminones 15 with 3-amino-1,2,4triazole is site selective although it can theoretically lead to either the 1,2,4-triazolo[1,5-a]pyrimidine 62 and/or its [4,3-a] isomer 63.For example, reaction of 15a-c each with 3-amino-1,2,4-triazole in acetic acid under reflux yielded, in each case, only one isolable product which was identified as the respective 3,4-bis[1,2,4-triazolo-[1,5-a]pyrimidine-7-yl]pyrazole derivative 62 and not its 1,2,4-triazolo [4,3-a]pyrimidine isomers 63 on the basis of their 1 H NMR spectral data.Similar reaction of 7 with five equivalents of formamidine acetate and five equivalents of sodium ethoxide in refluxing ethanol was reported to result in the formation of a mixture of 65 and 66 in 50% and 34%, respectively.The condensation of 7 with the amidine 67 in 1:1 ratio gave 69 in 66% yield which is converted into 70 by condensation with pyridine-2-carboxamidine under standard conditions.13  Cyclocondensation of bis-enaminone 17b with various substituted hydrazines in ionic liquids in the presence of an acid catalyst was reported to give the respective 1,4-bis-[1-substitutedpyrazol-5-yl]benzenes 88 in good yields.31 The site selectivity in this reaction was found to depend on the structure of the hydrazine derivative used.Similarly, when each of the bis-enaminones 15a-c was refluxed with hydroxylamine hydrochloride in ethanol in the presence of ammonium acetate, it yielded, in each case, a single product identified as the respective 3,4-bis(isoxazol-3-yl)pyrazole 92 rather than its bis(isoxazol-5-yl)pyrazole 94. 35 The assigned structure 92 was confirmed by the alternate synthesis of 92b as a representative example of the series prepared.Thus, reaction of the bis-oxime 95b, prepared from 1-p-tolyl-3,4-diacetyl-5-methylpyrazole 96 and two equivalents of hydroxylamine hydrochloride in refluxing ethanol in the presence of potassium hydroxide, with DMF-DMA in refluxing xylene gave a product that proved identical in all respects with 92b isolated from reaction of 15b with hydroxylamine hydrochloride.However, in another report it was indicated that such a reaction of the bis-enaminone 7 with benzoylacetonitrile, when carried out in refluxing toluene, it yielded 5,5"-dibenzoyl-1,1"dihydro-2,2':6',2"-terpyridine-6,6"-dione 102 in 40% yield.3.8.3.Reaction with malononitrile.Reaction of the bis-enaminone 7 with malononitrile in refluxing ethanol in the presence of piperidine yielded 1H,1"H-6,6"-dioxo-5,5"-dicyano-2,2":6',2"-terpyridine 104.14 The latter product 104 was also obtained by refluxing the bisenaminone 7 with cyanoacetamide in dry toluene.Shawali et al. 35 also reported that reaction of malononitrile with each of the enaminones 15ac in refluxing glacial acetic acid in the presence of ammonium acetate gave rise, in each case, a single product that proved to be the respective 3,4-bis(5-cyano-6-oxo-1H-pyridin-2-yl)-1-aryl-5methylpyrazole 105.The assigned structure 105 was further evidenced by alternate synthesis of 105a as an example of the series prepared.Thus, reaction of 15a with cyanoacetamide in refluxing dry toluene afforded that proved identical in all respects with that one obtained above from reaction of 15a with malononitrile.Similar reaction of the bis-enaminone 42 with two fold excess of malononitrile in refluxing ethanol in the presence of few drops of piperidine was also reported to give N,N'-(1,4phenylene)bis-(2-cyano-4-(dimethylamino)phenylmethylene)pent-2-enediamide 108.27 The formation of the latter was considered to result via initial substitution of the dimethylamino group to give the intermediate 106 followed by cyclization to give 107, which in turn reacted with dimethylamine to give 108 as end product.Refluxing the latter in ethanolic sodium ethoxide solution resulted in the formation of N,N'- (1,4-diphenylene) The bis-enaminone 7 reacted with cyanoacetamide in refluxing toluene in the presence of piperidine as a catalyst and gave 1H,1"H-6,6"-dioxo-2,2':6,2"-terpyridine-5.5"-dicarbonitrile 110 via substitution of the dimethylamino group followed by cyclization.14 The latter product was also obtained by reaction of 7 with malononitrile.  T bis-enaminone 42 was also reported to react with cyanoacetamide in refluxing ethanol in the presence of few drops of piperidine as a catalyst to give 111a via substitution of the dimethylamino group.Refluxing the latter in ethanolic sodium ethoxide solution furnished its cyclization and afforded the product 112a identical with that one obtained by reaction of 42 with malononitrile under the same reaction conditions.27 Use of cyanothioacetamide in lieu of cyanoacetamide in this reaction gave the respective N,N'- (1,4-  35 Ethyl benzoylacetoacetate reacted similarly with each of 15a-c under the same reaction conditions and afforded the respective 3,4-bis[5-ethoxycarbonyl-6-phenyl-pyrid-2-yl]-1-aryl-5-methylpyrazoles 120a-c.35 The reaction pathway that was suggested to account for the formation of the products 119 and 120 involves initial addition of the active methylene moiety to the activated double bond of 15 to afford 115(116) as intermediates that undergo elimination of dimethylamine to afford 117(118) which in turn condenses with ammonium acetate to yield the respective 3,4bis(pyridine-6-yl)pyrazoles 119(120) as end products.The bis-enaminone 7 was also reported to react with ethyl acetoacetate in refluxing acetic acid in the presence of ammonium acetate to give 5,5"-diethoxycarbonyl-6,6"-dimethyl-2,2':6',2"-terpyridine 122.14 The formation of the latter product was considered to follow the sequence depicted in the following scheme.The reaction starts with addition of the keto ester to the double bond of the enaminone to yield the Michael adduct 121 which in turn cyclized in the presence of ammonium acetate to yield 122 as end product.

Reactions with hydrazonoyl halides
Reaction of the bis-enaminone 7 with N-aryl-2-oxopropane hydrazonoyl chloride in refluxing dry benzene in the presence of triethylamine was reported to be regioselective as it gave only the respective 125 and not 126. 14The formation of 125 was considered to result via 1,3-dipolar cycloaddition of the nitrilimine, generated from hydrazonoyl chloride, with concurrent elimination of dimethylamine. 14The isolated product 125 condensed with hydrazine hydrate to give the corresponding 2,6-bis(4-methyl-1-aryl-pyrazolo [3,4-d] The reactions of the bis-enaminones 15 with nitrilimines I, generated in situ by basecatalyzed dehydrochlorination of the respective hydrazonoyl chlorides 130A-C, were also reported by Shawali et al. 17 Reaction of each of 15a-d with hydrazonoyl chlorides 130A-C in refluxing benzene in the presence of triethylamine yielded, in each case, a single product.The isolated products were identified, on the basis of their elemental analyses and spectral (IR, 1 H NMR and Ms) data, as the respective 3,5-Bis-(1-phenyl-3-substituted-pyrazol-4-carbonyl)-5methyl-1-aryl-pyrazoles 131-133.
Although the reaction of 131-133 with hydrazine hydrate can theoretically lead to two possible pyrazolopyridazines, Shawali et al reported that it is site selective.For example, when a mixture of 131a and hydrazine hydrate was refluxed, it yielded only one product as evidenced by TLC of the crude product.On the basis of the IR and other spectral data, the isolated product was identified as 134a. 17The site-selectivity of such a reaction was further confirmed by the finding that reactions of hydrazine hydrate with both 132a and 133a afforded, in both cases, one and the same product, whose spectra (IR, 1 H NMR and Ms) and elemental analysis data proved it to have structure 135b.with diazotized aniline in ethanol in the presence of sodium acetate gave the corresponding coupling products 144a-c. 33Although the latter compounds can exist in the E-and/or Z-forms, their 1 H NMR spectra revealed that they exist only in the form Z-3 (Figure 1) as such spectra reveal, in each case, two singlet signals in the regions δ 10.35-10.37 and 12.79-12.88due to the resonances of the -CHO and hydrazone NH protons, respectively. 33ondensation of the product 144a with hydrazine hydrate yielded a single product that was identified, on the basis of its spectral and elemental analyses, as 145 rather than 146.The assigned structure 145 was confirmed by comparison of 145 with an authentic sample of 146, prepared by alternate unambiguous synthesis as depicted below. 33Thus, reaction of 3,6dimethylpyrazolo [3,4-d]

6 . 4 3. 7 .
of the bis-enaminone 17b with hydroxylamine hydrochloride in an ionic liquid was reported to give 1,4-bis(5-isoxazolyl)benzene 97.Reaction with acetylenic ketones Heating a mixture of each of the bis-enaminones 23A-C with aroyl acetylenes 98 in refluxing toluene for 12 h resulted in smooth trimerization to afford the respective 1,3,5-triaroylbenzene derivatives 99 in good yields.20Reaction with methyl ketones 2,5-Bis(2,2'-bipyridin-6-yl)pyrazine 100 was obtained when a mixture of the bis-enaminone 9 and two equivalents of acetylpyridine was stirred at room temperature in tetrahydro-furan in the presence of t-BuOK for 4 days, followed by treatment with ammonium acetate in acetic acid.15

9 .
Reaction with N-benzoylglycineWhen the bis-enaminones 45 was refluxed with N-benzoylglycine in acetic anhydride, it gave the respective 124.