Synthesis of Methyl Derivatives of 4H‐Furo[2,3‐h]quinolin‐4‐one and 5H‐Furo[3,2‐g]quinolin‐5‐one

Abstract

Synthesis of the linear and angular furoquinolin-4-one derivatives 6 and 12 was performed, using nitrobenzofurans 3 and 9 as key intermediates. These compounds were reduced to the corresponding aminobenzofurans 4 and 10, which were condensed in two steps to yield, the linear furoquinolin-4-ones 6a,b and the angular ones 12a,b.The antiproliferative activity of psoralens, which is due to their ability to photobind to DNAUll, is today well known and exploited in PUVA therapy for various skin diseased2] and in photopheresi~[~I. In order to eliminate adverse effects attributed to the capacity to form crosslink~ [~], a number of furocoumarin isosters have been preparedI51, including h e a d 6 ] and angular17] furoquinolin-2-ones. The angular isosters show not only remarkable photoinduced antiproliferative activity but, unexpectedly, they also block macromolecular synthesis in the dark, probably through topoisomerase I1 inhibition ['].With the aim of increasing activity in the dark and possibly also eliminating or reducing photoreactivity, we planned the synthesis of two different series of derivatives with structural modifications at one or other of the two reactive sites of the molecule, i.e. the double bond of the lactamic ring, or the double bond of the furan ring. In this connection, we now describe the synthesis of new linear and angular furoquinolin-4-one derivatives, in which the lactamic moiety is modified with respect to previously reported furoquinolin-2-ones.In essence, the synthetic method involves building the benzofuran nucleus as a first step, followed by condensing the y-lactamic ring on it. The alternative pathway, i.e. preparation of the quinolin-4-one moiety and cyclization of the furan ring on it, was not feasible. Attempts to cyclize the furan ring by etherification of 7-hydroxyquinolin-4-one with the appropriate alkyl chloride, resulted in simultaneous reaction at both the 0 and N atoms, owing to the great reactivity of the lactamic moiety of the quinolinone nucleus. We therefore planned our synthetic route according to Schemes I and 2, with different strategies for 4'-and 5'-methyl derivatives. The commercially available nitrocresols 1 and 7 were condensed with propargyl chloride to give the corresponding 0-propargyl ethers 2a and 8a which, submitted to Claisen rearrangement in the presence of CsFU' ], furnished 2,7-dimethyl-6-nitrobenzofuran (3a) and 2,7-dimethyl-4-nitrobenzofuran (9a). respectively.For the synthesis of our second series of derivatives, the nitrocresols 1 and 7 were condensed with chloroacetone to give ethers 2b and 8b, which were cyclized in acidic medium to yield 3,7-dimethyl-6-nitrobenzofuran (3b) and 3,7-dimethyl-4-nitrobenzofuran (9b), respectively.The use of these cresols, i.e. methyl derivatives of m-nitrophenol, in the Claisen rearrangement and the acid-induced cyclization, ensured that ring closure of the furan ring occurred regiospecifically at the free ortho position.Reduction of the nitrobenzofuran intermediates 3 and 9 by catalytic hydrogenation gave the correspondi...

Isomerization of 4-Aminobenzofurans to 4-Hydroxyindoles

“…Intermediates 5, 7, 10, 12 were prepared according to literature methods, 1 preparation of the other starting materials is not described in the literature.…”

“…In the last few years we have been interested in synthesizing some derivatives of 4H-furo [2,3-h]quinolin-4-one, 1 to find out whether they would show antiproliferative activity, similar to 2H-furo [2,3-h]quinolin-2-ones. 2 During these studies, we often used 4-aminobenzofurans as key intermediates for the synthesis of furoquinolin-4-ones.…”

“…Various methylated nitrobenzofurans were reacted under the same conditions in order to define the role of methyl substitution on the furan ring. Thus, nitrobenzofurans carrying a methyl group either in the 2 or 3 position or two methyl groups in both the 2 and 3 positions were prepared, according to Scheme 1, starting from 2-hydroxy-4-nitrotoluene (1), 2-ethoxycarbonylamino-5-nitrophenol (3), and 2-methoxy-5-nitrophenol (4), which were condensed with the appropriate a-halo ketone or propargyl chloride 1 to give ethers 5-9. These compounds were then cyclized under appropriate conditions to 7-methyl-or 7-ethoxycarbonylamino-or 7-methoxy-4-nitrobenzofurans 10-14.…”