2- Amino-477-chromenes

Chen L, Huang XJ, Li YQ, Zhou MY, Zheng WJ (2009) A one-pot multicomponent reaction for the synthesis of 2-amino-2-chromenes promoted by N, N-dimethylamino-functionalized basic ionic liquid catalysis under solvent-free condition. Monatsh fUr Chem 140 45 7... 

Ren, Y.M., Cai, C. 2008. Convenient and efficient method for synthesis of substituted 2-amino-2-chromenes using catalytic amount of iodine and K(2)CO(3) in aqueous medium. Catalysis Communications 9(6) 1017-1020. 

Zhang, A.Q., Zhang, M., Chen, H.H., Chen, J., Chen, H.Y. 2007. Convenient method for s)mthe-sis of substituted 2-amino-2-chromenes. Synthetic Communications 37(l-3) 231-235. 

The reaction of aldehyde, malononitrile and a-naphthol was carried out under microwave irradiation in the presence of the water-polyethylene glycol system and nanosized MgO as the catalyst. The product 2-amino-2 chromene was obtained in high yield. The reaction is given in Scheme 11.51 [109]. 

SCHEME 2 Cetyltrimethylammonium chloride (CTACl)-catalyzed synthesis of 2-amino-2-chromenes 7 [78]. 

R. Ballini, G. Bosica, M.L. Conforti, R. Maggi, A. Mazzacani, P. Righi, G. Sartori, Three-component process for the synthesis of 2-amino-2-chromenes in aqueous media. Tetrahedron 57 (2001) 1395-1398. 

R. Maggi, R. Ballini, G. Sartori, R. Sartorio, Basic alumina catalysed synthesis of substituted 2-amino-2-chromenes via three-component reaction, Tetrahedron Lett. 45 (2004) 2297-2298. 

The Michael addition of malononitrile and/or ethyl cyanoacetate (386) to nitrostyrenes has been reported to proceed in water at 80 C over 3h. In the presence of an orthohydroxy group, as in (385), the reaction is complete within 12 h at 40 C and gives rise to 2-amino-2-chromene derivatives (387) as a result of the subsequent cyclization. ... 

Mondal et al. reported the synthesis of a new robust, non-air-sensitive, metal-free triazine-functionalized mesoporous organocatalyst TFMO-1 (Figure 1.5) and successfully used this material as an excellent catalyst in the one-pot three-component condensation reactions for the syntheses of 2-amino-chromene derivatives under solvent-free conditions (Mondal et al., 2012). TFMO-1 is an easily separable heterogeneous organocatalyst devoid of metal ions and thus is highly desirable to address industrial and environmental concerns. 

A few heterogeneous catalysts, such as nanosized magnesium oxide, Mg/Al hydrotalcite, and nanostructured diphosphate (Na2CaP207), have been developed for the synthesis of 2-amino-chromene (Solhy et al., 2010a,b). 

Among different active methylene compounds (malononitrile, ethyl cyanoacetate, and diethyl malonate), only malononitrile showed a high product yield, suggesting that it was the best-suited active methylene compound for the synthesis of 2-amino-chromene derivatives over TFMO-1. 

Solhy, A., Ehnakssoudi, A., Tahir, R., Karkouri, M., Larzek, M., Bousmina, M., Zahouily, M. 2010a. Clean chemical synthesis of 2-amino-chromenes in water catalyzed by nano-structured diphosphate Na2CaP207. Green Chemistry 12 2261-2267. 

Amino-chromenes represent an important class of compounds being the main components of many naturally occurring products. They can be utilized as cosmetics, pigments widely [91], and potential biodegradable agrochemicals [92]. These compounds have been of interest to the medicinal chemist for many years. Hj pSlaPjWjQO, J was used successfully as an efficient catalyst in the reaction of aldehydes, malononitrile, and a- and P-naphthol for the synthesis of 4 and 5 (Scheme 3.33). 

Hydroxymethyl-4,8-dimethylfuro[2,3-/z]chromen-2-one was realized in an efficient manner via a Claisen rearrangement of 4-(hydroxybut-2-ynyloxy)-4-methylchromen-2-one as depicted in the following scheme. Other examples with substitution of hydroxyl and with other substituents, such as chloro, amino, acetoxy were also reported <06JHC763>. A new approach for the synthesis of oxygenated benzo[fe]furans was developed via epoxidation and cyclization of 2 -hydroxystilbene <06T4214>. 

Recently, 2-amino-4H-chromenes revealed a high antitumor activity in vitro (04JME6299). Subsequently, extensive SAR prompted the synthesis of various types of condensed aminochromenes (including representatives of new classes of fused heterocycles) (05BML4745,07JME2858,08BML603, 08JME417) (Scheme 55). 

Somewhat different type 2-amino-4H-chromene synthesis is represented by the interaction of CH-acidic nitriles 27 with salicylic aldehyde 157 where the phenolic OH and aldehyde groups are present in the same molecule. A conventional mechanistic scheme is represented (Scheme 58), where in the presence of a base nitrile 27 condenses with the aldehyde to give Knoevenagel intermediate 158. Then nucleophilic addition of the OH group leads to iminochromene 159, which then adds a nucleophile (as a rule, the second equivalent of nitrile 27) at position 4 to form 2-amino-4H-chromene 160. 

Addition of indoles 171 to a mixture of salycylic aldehyde 157 and malononitrile 27a affords 4-(3-indolyl)-substituted 2-amino-4H-chromenes 172 (07TL6785), probably the result of an addition of indole to intermediate iminochromene 159 (Scheme 63). 

Among the fused aminopyrans, 2-amino-4H-chromenes draw especial attention due to their broad biological potential. Benzochromenes 143 in vitro inhibit the synthesis of metalloproteases that destroy cartilage tissues in rheumatoidal arthritis and osteoarthritis. Moreover, 143 inhibit proliferation of mice spleen cells (95BML2783). 

Table 1. The key compounds in the structure optimization of 2-amino-4H-chromenes... 

The mechanism of biological action of 281 has been thoroughly investigated (04MI4, 04MI5). These 2-aminochromenes reveal anticancer activity as the result of caspase activation, and, consequently, starting the apoptosis mechanism. However, somewhat different 2-amino-4H-chromenes 161 show antitumor activity by another mechanism, which involves inactivation of antiapoptotic proteins of the Bcl-2 series. 

Amino acid-modified furocoumarins were prepared by condensation of the T-hydroxysuccinimide ester of 3-(2,3,5-trimethyl-7-oxofuro[3,2-g]chromen-6-yl)propanoic acid 51 with amino acids <2003JPH177>. Ethyl 3-(7-hydroxy-4-methyl-2-oxo-2/7-3-chromenyl)propanoate 49, prepared in 56% yield by Pechmann condensation of resorcinol and diethyl 2-acetylglutarate in the presence of HCl, was condensed with 3-chlorobutan-2-one in the presence of base to give propanoate 50 (Scheme 4). The MacLeod method was then used to fuse a furan ring to the benzopyran-2-one system. Heating 50 with NaOH solution (1 M) readily cyclized it into the corresponding psoralen furocoumarin 51 with simultaneous hydrolysis of the ester. 

Reaction of 4-amino-l,2,3,4-tetrahydroquinoline-8-carboxamide and 2H-chromene-3-carbaldehydes in MeOH in the presence of pTsOH H20 at room temperature for 20 min then heating for 2 h afforded racemic... 

A three-component reaction of aromatic aldehydes, malononitrile and phenols leads to 4-aryl-2-amino-3-cyano-4//-chromenes this reaction can be carried out in aqueous media with improvements in yield and obvious environmental advantages (Scheme 35). The aromatic aldehyde undergoes a Knoevenagel condensation with malononitrile, followed by ortho-alkylation of the phenol and cyclization to form the iminopyran intermediate 114, which isomerizes to the 4//-chrorncncs (Scheme 36) <2003SL2001>. High yields for this three-component reaction can also be achieved in aqueous media when mediated by 7-alumina <2004TL2297> or cetyltrimethylammonium chloride <2001T1395>. 

Alkylisocyanates react with dimethyl acetylenedicarboxylate to form the reactive intermediate 122, which can be trapped by phenols to afford dimethyl 2-amino-4//-chromene-3,4-dicarboxylates in high yield (Scheme 40) <2003T9409>. Likewise, alkylisocyanates react with dibenzoyl acetylene and naphthols to yield the corresponding 2-amino-3,4-dibenzoyl-4//-chromenes <2003T1289>. 

The compound 3-(2-Bromoacetyl)-4-hydroxychromen-2-one (18) reacts with thiourea to afford 3-(2-amino-thiazol-4-yl)-4-hydroxychromen-2-one hydrobromide (19a). This reaction was carried out in boiling ethanol for 30 min. Compound 19a also gave positive coloration with iron(III) chloride solution (Scheme 7). In the reaction of compound 18 with 1-methylthiourea under identical experimental conditions as above, 4-hydroxy-3-(2-methyl-aminothiazol-4-yl)chromen-2-one (19b) in 67% yield was obtained. In a similar manner, 18 reacted with three arylthiourea derivatives affording the corresponding 3-(2-arylthiazol-4-yl)chromen-2-ones (19c-e) in different yields (70, 63 and 74%, respectively). The derivatives formed in these reactions were identified as 4-hydroxy-3-(2-phenylaminothiazol-4-yl)chromen-2-one(19c), 4-hydroxy-3-(2-p-tolylaminothiazol-4-yl)chromen-2-one (19d) and 4-hydroxy-3-2-(4-methoxyphenylamino)thiazol-4-yl)chromen-2-one (19e). The identities of these compounds were established by spectral data and elemental analysis. 

Another approach to ring closure reaction is the o-arylation of substituted phenoxide ions by o-bromobenzonitrile followed by Si02-catalysed lacto-nization. The phenoxide ions of the amino acid (S)-tyrosine, protected as A, O-diacetyl methyl ester, does not racemize under the standard SRN1 conditions and can be used to obtain the optically active benzo[c]chromen-6-one (the O-acetyl is hydrolyzed in the reaction media to furnish the phenoxide ion) (Sch. 43). Racemic dibenzopyranones are obtained by the reaction of the anion from the TV-acetyl methyl ester of (R)-hydroxyphe-nylglycine with o-bromobenzonitrile 2-cyano-4,5-dimethoxybromobenzene (65 and 79% respectively) [110]. 

Intramolecular reaction with nucleophilic groups can also lead to heterocycles. For example, good yields of 3-acylbenzofurans result from cyclization caused by intramolecular substitution of the tertiary amino group by a phenol formed by cleavage of a phenol ether by boron tribromide251 (equation 182). 0-Hydroxy benzyl alcohols were used to obtain 4//-chromenes by their reaction with 4-morpholino-3-buten-2-one in acetic acid-acetic anhydride187. 

Allyl-7-amino-4-oxo-4H-chromene-2-carboxylic acid ethyl ester (32 mmol) dissolved in 400 ml of CH2C12 was treated first with A.IV-diisopropylethylamine (50 mmol), then trifluoroacetic anhydride (50 mmol) while cooling the mixture in an ice bath. The mixture was stirred 1 hour at ambient temperature, then washed with 200 ml apiece 2M HC1, saturated NaHC03 solution, and brine, dried with Na2S04, and filtered. The material was concentrated and 12.2 g product isolated as a pale yellow solid, mp = 136-137°C. 

The preparation of the Step 1 co-reagent, 8-allyl-7-amino-4-oxo-4H-chromene-2-carboxylic acid ethyl ester, (I), was provided by the author and illustrated in Eq. 2. 

Zhou and co-workers [62] have reported a series of 2-amino-6-(2-oxo-2//-chromen-3-yl)-4-pyridine-3-carbonitriles 11 by a one-pot, MCR of 3-acetyl-coumarin, an aromatic aldehyde, malononitrile, and ammonium acetate in acetic acid using a domestic microwave oven. Aromatic aldehydes bearing electron-withdrawing groups gave rather low yields of 11 (Scheme 11). 

Kumar D, Reddy VB, Sharad S et al (2009) A facile one-pot green synthesis and antibacterial activity of 2-amino-4H-pyrans and 2-amino-5-oxo-5, 6, 7, 8-tetrahydro-4H-chromenes. Eur J Med Chem 44 3805-3809... 

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