The “Off‐Shore” Construction of Optionally Substituted 4‐Trifluoromethyl‐2‐quinolinones

Abstract

Treatment of ortho-lithiated tert-butyl N-arylcarbamates (i.e., BOC-protected anilines) with N-(trifluoroacetyl)piperidine provides 2-(N-BOC-amino)aryl trifluoromethyl ketones which, upon consecutive reaction with an α-alkoxycarbonylsubstituted phosphorus ylide and acid (or base) yields 4-tri-The common access to the pharmaceutically attractive 4-trifluoromethyl-2-quinolinones [1,2] consists of two reaction steps which have to be controlled carefully (Scheme 1). The preparation of the prerequisite N- (4,4,4-trifluoroacetoacetyl)anilides poses the first problem. In particular anilines carrying electron-withdrawing substituents tend to produce concomitantly or exclusively the isomeric "anils" [3] (or β-anilinocrotonate tautomers thereof), the precursors to 2-trifluoromethyl-4-quinolinones.[4] Even if this stumbling block can be circumvented by applying the "watering protocol" [2] or another suitable regiodiscriminating method, [5] one has to be aware of another pitfall. The cyclization of the acetoacetanilide may go astray providing still 2-trifluoromethyl-4-quinolinones rather than the targeted 2-quinolinone isomers if the reaction is not carried out in a most effective manner using hot concentrated sulfuric acid.[2] Scheme 1. Known condensation of anilines with ethyl 4,4,4-trifluoroacetoacetate giving 4-trifluoromethyl-2-quinolinones.[ Such uncertainties encouraged us to develop a new method that would open a regiochemically unbiased, though structurally flexible entry to 4-trifluoromethyl-2-quinolinones. We opted for an "off-shore" [6] cyclization approach, that is the construction of the heterocyclic part without the active participation of the aromatic ring. In this way, electronegative substituents would not compromise the electrophilic attachment of a heterofunctional side chain, the crucial feature of any "on-shore" process. This design concretized in an ortho-trifluoroacetylation of the aniline starting material bearing an N-tert-butoxycarbonyl ("BOC") protective group at the nitrogen atom, a C 2 chain extension by a suitable condensation reaction and an ultimate closure of the lactam unit (affording products 1, 2 and 3, respectively) (Scheme 2).Scheme 2. Projected new reaction sequence leading to 4-trifluoromethyl-2-quinolinones: ortho-lithiation, trifluoroacetylation, reaction with an α-(alkoxycarbonyl)-bearing phosphorus ylide and ring closure.The ortho-acylation of ortho-lithiated [7][8][9] BOC-protected anilines was accomplished with N-(trifluoroacetyl)piperidine as the reagent. Trifluoroacetic anhydride, previously successfully employed in the reaction with N, 3-dilithiated N-pivaloyl-3,4-dimethoxyaniline [10] gave only poor results. The oxacarbamates 1a (71 %), 1b (68 %), and 1c (51 %) thus obtained were transformed into the cinnamic ester derivatives 2a (79 %), 2b (76 %), and 2c (74 %) by simple Wittig reaction using 1-methoxy-2-(triphenylphosphonio)ethene

Synthesis of fluoromethyl-containing analogs of antitumor alkaloid luotonin A

“…15 This includes ortho trifluoroacetylation of aniline bearing an appropriate N protecting group, introduction of a C 2 fragment by coupling at the keto group, and, finally, the lactam ring closure. In the case of the synthesis of 4 trifluoromethyl 2 quinolones, this scheme is advantageous as compared to the classic Knorr synthesis of 2 quinolones.…”

“…In the case of the synthesis of 4 trifluoromethyl 2 quinolones, this scheme is advantageous as compared to the classic Knorr synthesis of 2 quinolones. In the frame work of the method developed, 15 3 methyl 4 trifluoro methyl 2 quinolone 4a (Х = F, R´ = H, see Scheme 2) was synthesized starting from N Вoc aniline using pyro phoric Bu t Li as a lithiating agent.…”

“…In the synthesis of quinolines 3 based on the Schlosser approach, 15 we modified the stage of ortho fluoroacetyla tion of anilines. We chose a pivaloyl group (Pg = COCMe 3 , R = H) and a propionyl group (Pg = COCH 2 Me, R = Br, see Scheme 2) as protecting and ortho directing groups.…”

Efficient synthetic access to novel N-(Pyrimidinyl)-N-(1H-benzo[d]imidazolyl)amines in an aqueous medium

“…The presence of the trifluoromethyl group also increases the lipophilicity of the molecules, causing greater cellular permeability [16,17], and many heterocycles containing fluorine atoms present biological activity with potential applications in medicine and agriculture [18][19][20][21][22].…”

Synthesis of Some 2-(3-Alkyl/aryl-5-trifluoromethylpyrazol-1-yl)-4-(coumarin-3-yl)thiazoles as Novel Antibacterial Agents

“…anti-inflammatory, antimicrobial, antihypertensive etc. [15][16][17][18][19][20] The search for a simple and efficient access to such compounds with a CF 3 group at a specific position is one of the important goals in this area. However, there are a limited number of regioselective syntheses of trifluoromethyl containing heteroaromatic compounds in good yield.…”