Efficient Synthesis of Fluorine-Containing Dibenzo[b,h][1,6]naphthyridines and Thiochromeno[3,2-c]quinolines Using Highly Chemoselective Nucleophilic Substitution Reaction of 4-Dimethylamino-2-methoxy-3-trifluoroacetylquinoline

Selective Aromatic Nucleophilic Substitution of 4-(Dimethylamino)-2-methoxy-3-(trifluoroacetyl)quinoline with Thiols – DFT Calculation Study

“…Indeed, N-O exchange of 1 with excess phenethyl alcohol readily proceeds in refluxing mesitylene (Scheme 4). 7 The energy change E3' to form VII' 11 from 1 is estimated as 14.3 kcal/mol, which is a result quite similar to E3 for the reaction of 1 with n-butanol under alcoholysis conditions (Table 1).…”

“…Fluorine-containing heterocycles have been very fascinating synthetic targets for a variety of studies because their potentially high and unique biological activities have often drawn much attention for the various scope in life science research. [1][2][3][4] In recent years, we have succeeded in establishing the convenient synthetic methods which avail to access novel fluorine-containing 4-methoxypyrazolo[4,3-c]quinolines, 5 6-methoxy-1,4-diazepino [6,5-c]quinolines, 5 5-methoxypyrimido- [5,4-c]quinolines, 6 5-methoxybenzo[h] [1,6]naphthyridines, 6 6-methoxydibenzo [b,h] [1,6]naphthyridines, 7 and 6-methoxythiochromeno [3,2-c]quinolines. 7 The key step reaction on the above studies is a unique highly selective aromatic nucleophilic substitution of 4-dimethylamino moiety of trifluoroacetylated quinoline 1 with appropriate nucleophiles (Scheme 1).…”

“…[1][2][3][4] In recent years, we have succeeded in establishing the convenient synthetic methods which avail to access novel fluorine-containing 4-methoxypyrazolo[4,3-c]quinolines, 5 6-methoxy-1,4-diazepino [6,5-c]quinolines, 5 5-methoxypyrimido- [5,4-c]quinolines, 6 5-methoxybenzo[h] [1,6]naphthyridines, 6 6-methoxydibenzo [b,h] [1,6]naphthyridines, 7 and 6-methoxythiochromeno [3,2-c]quinolines. 7 The key step reaction on the above studies is a unique highly selective aromatic nucleophilic substitution of 4-dimethylamino moiety of trifluoroacetylated quinoline 1 with appropriate nucleophiles (Scheme 1). 7,8 It is impressive that the nucleophilic substitution of 1 with alcohols are easily performed at its 4-position exclusively by simple alcoholysis to…”

“…7 The key step reaction on the above studies is a unique highly selective aromatic nucleophilic substitution of 4-dimethylamino moiety of trifluoroacetylated quinoline 1 with appropriate nucleophiles (Scheme 1). 7,8 It is impressive that the nucleophilic substitution of 1 with alcohols are easily performed at its 4-position exclusively by simple alcoholysis to…”

“…give the N-O exchanged products solely without base or acid catalytic condition. 7 It is commonly known that alkoxy groups are better leaving group than dialkylamino groups in nucleophilic substitution reactions. Also, in the nucleophilic substitution at carbonyl center, transesterification occurs more easily than the transformation from amides to the corresponding esters.…”