Synthesis of 4-Amino-3-pyridinyl and 4-Amino-5-pyrimidinyl Aryl Ketones and Related Compoundsviaanortho-Lithiation Reaction

Synthesis of Substituted Quinazolin-4(3H)-ones and Quinazolines via Directed Lithiation

“…49 Lithiation took place at C-8 to produce compound (10) and at C-2 to produce compound (11). Lithiation of 4,6-disbstituted quinazolines (12)(13)(14)(15) by LTMP (2.2 equivalents) in THF at -78 °C for 30 min, followed by reaction of the lithio reagents thus obtained with some electrophiles (acetaldehyde, benzaldehyde, iodine, trimethylsilane) afforded the corresponding 8-substituted quinazolines (16)(17)(18)(19)(20)(21)(22)(23) (Scheme 6) in moderate yields (Table 1). In the case of 4,6-dimethoxyquinazoline (12), lithiation took place at C-8, peri to the ring N-1 nitrogen atom to give the corresponding lithio reagent which, on reaction with acetaldehyde afforded 8-substituted derivative (16) in 54% yield and at C-7, ortho to the methoxy group to give 7-substituted quinazoline derivative in 39% yield.…”

“…In the case of 4,6-dimethoxyquinazoline (12), lithiation took place at C-8, peri to the ring N-1 nitrogen atom to give the corresponding lithio reagent which, on reaction with acetaldehyde afforded 8-substituted derivative (16) in 54% yield and at C-7, ortho to the methoxy group to give 7-substituted quinazoline derivative in 39% yield. 49 Regioselective lithiation of 6-chloro-4-substituted quinazolines (13)(14)(15) occurred at C-8.…”

“…8 The rapid expansion of the list of functionalities capable of directing lithiation 9 had made this reaction a very important strategy for the synthesis of regiospecifically substituted benzenes and pyrimidines. [10][11][12][13][14][15][16][17][18][19][20] The addition of organolithium compounds to the C=N bond of pyridine and related nitrogen heterocycles is a well-established reaction. [21][22][23][24] In particular, organolithium reagents undergo 1,2-addition to pyridine and quinoline.…”

Cyclocondensation of ethyl 3,3-diaminoacrylate with aromatic ketones and nitriles containing a labile halogen atom in the ortho position

“…In the present work, we studied the feasibility of using ketones and nitriles in this reaction and investigated the cyclocondensation of ethyl 3,3-diaminoacrylate (1) with 2-fluoro-5-nitroacetophenone (2) [4], three 5-acyl-4,6-dichloropyrimidines (3a-c) [5][6][7], and two pyrimidinecarbonitriles (4a,b) [8,9]. Acetophenone 2 reacts with diaminoacrylate 1 to give only 3-aminoisoquinoline 5.…”

Convenient Synthesis of More Complex 2-Substituted 4(3H)-Quinazolinones via Lithiation of 2-Alkyl-4(3H)-quinazolinones

“…The rapid expansion of the list of functionalities capable of directing metalation 1 has made this an important strategy for the synthesis of regiospecifically substituted benzenes and heterocycles, but there are relatively few reports concerning the metalation of pyrimidine compounds [2][3][4][5][6][7][8][9][10][11][12][13] . In a continuation of our own interests in heterocyclic chemistry 14 , particularly in the use of directed lithiation for heterocyclic synthesis 15 , we have recently shown the lithiation of 3-acylamino-, 3-amino-and 3-methylamino-2-alkyl-4(3H)-quinazolinones [16][17][18] .…”