A novel efficient route to 4-trifluoromethyl-substituted quinoline derivatives through the Zn(II)-mediated alkynylation-cyclization of o-trifluoroacetyl anilines is described.
Recently great efforts have been made on developing methodology for generating secondary carbinols as well as secondary propargyl alcohol and propargyl amine by enantioselective alkynylation of aldehydes and aldimines.[1] However, the asymmetric synthesis of tertiary carbinols and carbinamines by addition of carbon nucleophiles to ketones and ketimines has experienced considerable frustration. Human immunodeficiency virus (HIV) is prone to mutation, which in turn leads to drug resistance. Dihydroquinazolines DPC 961 and DPC 083 are second-generation HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs) with enhanced potency when compared to Efavirenz (Sustiva). [2] DPC 961 is currently undergoing clinical evaluation owing to its activity against wild-type HIV-1 and its increased potency toward the K103N-containing HIV as well as other NNRTIresistant mutant viruses. [3] The challenge for synthesizing this class of NNRTIs is to form a tertiary carbinamine in an asymmetric manner. The syntheses of these compounds include diastereoselective 1,4-addition of a magnesium acetylide to 2(3H)-quinazolinone containing a chiral auxiliary substituent [4] or 1,2-enantioselective addition of a lithium acetylide to a cyclic N-acyl ketimines using lithium cinochona alkaloids [5] or lithium 4b-morpholinocaran-3a-ol as a chiral moderator.[6] The asymmetric addition step, for which the enantiomeric excess is consistently around 92 % to 94 %, requires the use of 3-5 equivalents of organometallic acetylide and low temperatures (À60 8C to À75 8C). In addition, the strongly basic conditions lead to decomposition of the product. Therefore, it is highly desirable to search for a practical asymmetric synthesis of this new class of dihydroquinazolinones which can then be scaled up to satisfy clinical demands. The method involving a chiral additive appears to be the most advantageous because it avoids the step involving auxiliary attachment and removal and holds the potential for direct recovery and reuse of the unchanged chiral reagent. We have been developing a practical enantioselective preparation of chiral alchohols with CÀC bond formation by alkynylation of a carbonyl group and activation of the C À H bond in terminal alkynes by a combination of zinc salt, tertiary amine, and a readily available chiral amino alcohol as the ligand. [7] We were interested in studying the enantioselective alkynylation of the cyclic N-acyl ketimine 1 (see Scheme 1) using a chiral amino alcohol as ligand by activation of the C À H bond in terminal alkynes.To examine the possibility of alkynylation of ketimine 1 with a terminal acetylene, the reaction was carried out in the presence of zinc salts and triethylamine without a chiral amino alcohol as ligand. Treatment of 1 with one equivalent of cyclopropyl acetylene (2 a), Zn(OTf) 2 , and triethylamine gave the racemic adduct 3 a in 95 % yield at room temperature after 10 h (Scheme 1). The use of ZnCl 2 instead of Zn(OTf) 2 could not promote the reaction. This result stimulated us to investigate the asy...
We developed a procedure to synthesize a series of N-alkyl-2-methoxy-11-hydroxynoraporphines from thebaine and evaluated their binding affinities at dopamine D1 and D2 receptors in rat forebrain tissue. At D2 receptors, the most potent 10,11-catechol-aporphine was (R)-(-)-2-methoxy-N-n-propylnorapomorphine (D2, Ki = 1.3 nM; D1, Ki = 6450 nM), and the most selective and potent 11-monohydroxy aporphine was (R)-(-)-2-methoxy-11-hydroxy-N-n-propylnoraporphine (D2, Ki = 44 nM; D1, Ki = 1690 nM). In contrast, the N-methyl congeners (R)-(-)-2-methoxy-11-hydroxy-N-methyl-aporphine (D1 vs D2, Ki = 46 vs 235 nM) showed higher D1 than D2 affinity, indicating that N-alkyl substituents have major effects on D2 affinity and D2/D1 selectivity in such 2-methoxy-11-monohydroxy-substituted aporphines.
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