HFIP-Empowered One-Pot Synthesis of C4-Aryl-Substituted Tetrahydroquinolines with Propargylic Chlorides and Anilines

Abstract

Transition-metal-free, practical one-pot synthesis of C4-aryl-substituted tetrahydroquinolines from simple anilines and readily accessible propargylic chlorides has been developed. Activation of the C−Cl bond by 1,1,1,3,3,3-hexafluoroisopropanol turned out to be the key interaction, which allowed C−N bond formation under an acidic medium. Propargylated aniline is formed as an intermediate via propargylation, and subsequential cyclization and reduction gave 4arylated tetrahydroquinolines. To demonstrate the synthetic utility, total syntheses of aflaquinolone F and I have been accomplished.

HFIP Mediated Synthesis of C4‐Aryl‐2‐quinolones through Serial Oxidation

“…A plausible mechanism is suggested in Scheme 5 ,A based on these experimental findings along with the preceding studies [15,19] . The nucleophilic attack of the nitrogen to propargylic carbon with the HFIP‐activated C−Cl bond constructs the C−N bond ( step A ).…”

“…Surprisingly, an improved yield of 54 % was obtained for the nitro‐substituted propargylic chloride 2g ( 4ag ). In the preceding studies, nitro‐substituted propargylic chloride gave poor yield of tetrahydroquinoline in spite of its electron‐withdrawing nature [15] . From this unexpected result, we supposed that the HFIP did not disturb the nitro group solely, but in presence with a strong Brønsted acid (in this case triflic acid) it could suppress the reaction [18] .…”

“…This modification not only provides a better option for the propargyl chlorides, but also for the electron‐poor anilines as well. Trifluoromethylated‐aniline derived substrate 5du afforded 2‐quinolone 4du in 20 % yield, in contrast to no reaction with bis(4‐(trifluoromethyl)phenyl)amine under the standard condition [15] …”

“…Unfortunately, the standard conditions failed to give meaningful yields for the substrates with electron rich substituents (Me, OMe), due to the rapid decomposition of the corresponding propargylic chlorides at elevated temperatures in acidic HFIP condition [15] . To expand the boundary of the scope, propargylated anilines were put forward to exclude the decomposition of starting materials, which were prepared by alkylation of the aniline in basic condition (see Supporting Information for details).…”

1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) Promoted N-Alkylation of Quinazolinones through Nucleophilic Substitution of Benzyl Alcohols

“…Although no metal was used in this protocol, stoichiometric byproduct triphenylphosphine oxide was produced, making this protocol less attractive. On the other hand, 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) has been widely applied in organic synthesis for its unique ability to stabilize ionic species. − In continuation of our interest in the synthesis of quinazolinone derivatives, we tried to find whether HFIP could promote the alkylation reaction of quinazolinones and alcohols in the absence of any metal catalysts.…”