Synthesis of 5,8‐dimethoxy‐2(1H)‐quinolinones by intramolecular Wittig reaction

Abstract

The title compounds 12, which are key intermediates for antitumoral diazaquinomycin A analogues, are obtained by intramolecular Wittig reaction of 1-[3',6'-dimethoxy-2'-(1~-2(1H)-quinolinones 12 and 17 is examined. oxoacylamino)phenyl]alkyltriphenylphosphonium salts 11, which are prepared via lithiation of 2',5'-dimethoxy-N-pivaloylaniline 6. The applicability of this route to polysubstituted Diazaquinomycin A['], a novel Streptomyces sp. OM-704 metabolite, exhibits promising activity as an antitumor agent but failed to enter human trials because of its insolubility. Nevertheless, diazaquinomycin A is regarded as a novel "lead" compound to design diazaquinomycin congeners, which have currently been synthesized in our group by hetero Diels-Alder cyclizations12] of activated 1 -azadienes 1 with 2,5,8( 1H)-quinolinetriones 2. The dienophiles 2 are readily available by oxidative demethylatiod31 of 5,8-dimethoxy-2( 1H)-quinolinones, which are obtainable by means of several strategied41. The search of preparative routes for 3,4-disubstituted 5,8-dimethoxy-2( 1 H)-quinolinones 12 led us to the utilization of Capuano's 2( 1H)-quinolinone synthesis involving intramolecular Wittig reaction of 2-(a-oxoacylamino)benzyltriphenylphosphonium salts 3 as the key step, where three successful examples were already This reaction is chemoselective in spite of the possible competition between the keto and amide groups, affording 3-substituted 2-quinolinones 4 and 2-acylindoles 5 in a 1O:l ratio. The methods reported for the preparation of 2-amino-3,6-dimethoxybenzaldehyde as the potential starting material for the intramolecular Wittig reaction giving 5,8-dimethoxy-2-quinolinones are tedious and suffered from poor to modest overall yieldsc61. Therefore, we now describe a versatile and efficient method of preparing derivatives 7 and 8 by ortho functionalization of 2,5-dimethoxyaniline. Thus, lithiation of 2',5'-dimethoxy-N-pivaloylaniline 6 (nBuLi, THF, O'C), followed by addition of DMF or the corresponding aldehyde and subsequent reduction of 7, afforded 2'-(1-hydroxyalkyl)-3',6'-dimethoxy-N-pivaloylanilines 8 in good yields. The pivaloyl protecting group was hydrolytically removed by treatment with 10% hydrochloric acid and the free bases 9 were condensed with triphenylphosphonium bromide to afford the phosphonium salts 10, which were acylated with the adequate a-oxoacyl chloride to 11. Since the use of potassium tert-butoxide in the following cyclization step as described by Capuano et al.[5' gave poor results, triethylamine was employed instead. The outcome of the reaction depended on the nature of R1 in 11. The benzyltriphenylphosphonium salts lla-c (R' = H) mainly afforded, 2-quinolinones 12a-c in acceptable yields (25-39%), together with small amounts of 2-acylindoles 13a-c. When derivatives with R' C H were employed, only traces of 12d and 13d (R' = CH3) were detected. In the case of l l e (R' = Ph), 2-acetyl-5,8-dimethoxy-4-phenyl-4H-3,l-benzoxazine 14 was obtained as the only isolable product in 49% yield.Since the method to ...

Palladium‐Catalyzed Regioselective Cross‐Coupling Reactions of 3‐Bromo‐4‐tosyloxyquinolin‐2(1H)‐one with Arylboronic Acids. A Facile and Convenient Route to 3,4‐Disubstituted Quinolin‐2(1H)‐ones

“…On the other hand, recently we found that the 4-tosyloxy group attached to the electron-withdrawing a,bunsaturated double bond increased its capability for oxidative addition to transition metals [5] although arenesulfonates are relatively unreactive compared to the corresponding halides and triflates. [19] Based on the results in which oxidative addition of the CA C H T U N G T R E N N U N G (sp 2 ) À Br bond to the transition metal is easier than that of the CA C H T U N G T R E N N U N G (sp 2 ) À OTs bond in cross-coupling reactions, we conceived that the regioselective cross-coupling of 3-bromo-4-tosyloxyquinolin-2(1H)-one may be fulfilled under suitable conditions. Due to their easy handling and long shelf life, arylboronic acid derivatives would be the starting materials of choice.…”

“…Members of this family have wide applications in medicinal chemistry, being used as anticancer, [2] antiviral, [3] and antihypertensive agents.…”

Efficient, Simple Synthesis of Stable Phosphorus Ylides Derived from 4-Aryl Urazoles

“…8 Phosphorus ylides are reactive intermediates that take part in many valuable reactions in organic synthesis. [9][10][11][12][13][14][15][16][17][18][19][20][21][22] Several methods have been developed for the preparation of phosphorus ylides. These ylides are usually prepared by treatment of a phosphonium salt with a base, and phosphonium salts are usually prepared from the phosphine and an alkyl halide.…”

“…basis of the well established chemistry of trivalent phosphorus nucleophiles,[9][10][11][12][13][14][15][16][17][18][19][20][21][22] it is reasonable to assume that phosphorus ylide 3 results from the initial addition of triphenylphosphine to the acetylenic ester and subsequent protonation of the zwitterionic intermediate 4 by the NH-acid 2. Then the positively charged ion 5 is attacked by the conjugate base of the NH-acid 6 to form phosphorane 3 (Scheme 2).…”

An Efficient and Novel Protocol for the Synthesis of Pyrazolo[5,1-a]isoindole Derivatives

“…[17][18][19][20] Thus, the pyrazoloisoindole derivatives 5b,c (Scheme 2) can be considered as products of an intramolecular Wittig reaction that occurs upon heating compounds 4b,c in boiling dioxane (Scheme2).…”