3-(Dichloroacetyl)chromone; A New Building Block for the Synthesis of Formylated Purine Isosteres: Design and Synthesis of Fused α-(Formyl)pyridines

Abstract

The first synthesis of 3-(dichloroacetyl)chromone from 3-(dimethylamino)-1-(2-hydroxyphenyl)propen-1-one and dichloroacetyl chloride is described. The reaction of electron-rich aminoheterocycles with 3-(dichloroacetyl)chromone provides a set of diverse fused pyridines bearing the CHCl 2 -substituent at the a-position of the pyridine core. Subsequent hydrolysis leads to the formation of annulated a-(formyl)pyridines.Purine isosteres and purine-like scaffolds are of considerable interest as major privileged scaffolds 1 often used in medicinal chemistry and drug design. In the past decade, functionalized derivatives of purine isosteres have proved to be of high pharmacological importance as lead structures and synthetic building blocks in medicinal and agricultural chemistry. [2][3][4][5][6][7][8] At the same time, purine-like scaffolds, bearing a carbonyl function 9 at the 2-position of the purine core, are considered as a promising heterocyclic platform for the design of inosine 5¢-monophosphate dehydrogenase (IMPDH) inhibitors. IMPDH is considered as an important target enzyme for drug design. 9,10 In our present study we have developed a preparative approach to purine isosteres bearing a formyl function located at the 2-position of the purine/pseudo-purine core.Retrosynthetically, structures of this type can be assembled by annulation of the a-formyl-substituted pyridine ring with an aminoheterocyclic moiety. As 1,3-C,N-dinucleophiles, which are suitable for this purpose, we envisaged electron-rich hetarylamines 1-10 ( Figure 1) and 1,1-dichloro-4-ethoxybut-3-en-2-one (11) 11 as a 1,3-C,C-dielectrophile. With this concept in hand, we began to investigate the reaction of amines 1-10 with building block 11.Unfortunately, many reactions of 11 with aminoheterocycles did not give satisfactory results as, in most cases, complex product mixtures were formed which could not be separated by preparative column chromatography. Only amines 1a and 5 reacted smoothly with 11 leading to pyridine ring annulation. In these cases, the reactions gave 6-(dichloromethyl)-2-phenyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (12) and 5-(dichloromethyl)-1-methyl-3-phenyl-1,3-dihydro-2H-imidazo[4,5-b]pyridine-2-thione (13) bearing a CHCl 2 substituent located at the aposition of the annulated pyridine ring. Figure 1 Structures of the 1,3-C,N-dinucleophiles usedN N NH 2 O R 1 N NH 2 R NC N S NH 2 Alk 2 N NH 2 MeO N N NH 2 Ph N N O R 1 R 2 O NH 2 N N NH 2 Ph S Me 1 a R 1 = Ph, R 2 = H 1 b R 1 = Me, R 2 = H 1 c R 1 = H, R 2 = Me 3 a Alk 2 N = piperidino 3 b Alk 2 N = morpholino 3 c Alk 2 N = NMe 2 2 a R = 4-MeOC 6 H 4 CH 2 2 b R = c-Hex 2 c R = t-Bu 6 a R 1 = H, R 2 = H 6 b R 1 = Me, R 2 = Me 6 c R 1 = H, R 2 = Me NH 2 Me 2 N 9 OMe NH 2 MeO 8 OMe MeO 4 5 1 0 NH 2 MeO MeO 7 R 2 Downloaded by: University of Liverpool. Copyrighted material.

Domino Reactions of Chromone‐3‐carboxylic Acids with Aminoheterocycles: Synthesis of Heteroannulated Pyrido[2,3‐c]coumarins and their Optical and Biological Activity

“…Our starting point was the development of suitable conditions for the synthesis of pyrido[3,2‐ c ]coumarin 3a by reaction of chromone‐3‐carboxylic acid 1a with aminopyrazole 2a (Scheme ). The aminopyrazole 2a and related aminoheterocycles used in this study were prepared as previously reported in our work related to the synthesis of heteroannulated pyridines, spirocyclic 1,4‐dihydropyridine compounds, and 3,4‐fused coumarins . The best yield of 3a (up to 90 %) was obtained under the conditions reported in entry 5 of Table using acetic acid as solvent (14 h, 60 °C).…”

Reactions of 3‐Acylchromones with Heterocyclic Ketene Aminals: One‐Pot Synthesis and Phosphatase Inhibitory Activity of Fused Pyridine Derivatives

“…We prepared a series of 3‐methoxalylchromones 1a – d , 3‐aroylchromones 2a – h , and 3‐cinnamoylchromone 3 starting from readily accessible 3‐(dimethylamino)‐1‐(2‐hydroxyaryl)prop‐2‐en‐1‐ones by using a one‐pot acylation procedure (Table ) , , . Almost all the chromones used in this study were reported and described in our previous work , …”

Domino Reactions of Chromones with Heterocyclic Enamines

“…The reaction of 2-amino-cyanopyrrols 10a-c with 50 afforded pyrrolo [2,3-b]pyridines 53a-c in very good yield and with very good regioselectivity (Scheme 25). 40 The products are formed by the same mechanism as discussed for the formation of product 52 (Scheme 23). Reflux of a methanolic solution of 53b in the presence of KOH resulted in hydrolysis of the dichloromethyl group and formation of aldehyde 54 (Scheme 26).…”

“…Reflux of a methanolic solution of 53b in the presence of KOH resulted in hydrolysis of the dichloromethyl group and formation of aldehyde 54 (Scheme 26). 40 Scheme 26 Synthesis of 54. Reagents and conditions: i, 1) MeOH, KOH, reflux, 2 h; 2) concd HCl.…”