Substituted quinazolines synthesis

The synthesis of substituted quinazolin-4(. 7/)-ones and quinazolines via directed lithiation has been reviewed <2000H(53)1839>, and the topic has also been briefly discussed in a more general review on the synthesis of quinazolinones and quinazolines <2005T10153>. For example, the lithiation of 4-methoxyquinazoline 312 with LiTMP followed by reaction with acetaldehyde gave only a minor amount of the 2-substituted product 313, with the major product 314 being the result of lithiation at the 8-position in the benzene ring <1997T2871>. 

The procedure has also been extended to the synthesis of 2-dialkylamino-4-substituted quinazolines, as shown by the synthesis of 4-cyclohexyl-2-morpholinoquinazoline 868 <2006JA14254>. 

Synthesis of pyrido[ 1,2-bJquinazolines through formation of the azole ring from properly substituted quinazoline precursors is also known (61AP556). Thus, the cyclodehydrobromination of the 2-(4-bromo-butyl)quinazolin-4-one (445) with alkali was claimed to give only the linearly annulated 1,2,3,4-tetrahydropyrido[ 1,2-6]quinazolin-4-ones (446) (61AP556). Oxidation of the 3-amino-2-(butyn-l-yl)quinazolin-4-ones (447) with lead tetraacetate led to intramolecular addition of the produced /V-nitrene intermediate to the triple bond to give 449 [86JC S(P 1) 1215]. 

A similar rapid microwave one-pot synthesis of substituted quinazolin-4-ones was also reported, which involved cyclocondensation af anthranilic acid, formic acid (or an orthoester) and an amine under solvent-free conditions (Scheme 3.37)61. A complimentary approach was adopted to synthesise 4-aminoquinazolines in very good yields, involving the reaction of aromatic nitrile compounds with 2-aminobenzonitrile in the presence of a catalytic amount ofbase (Scheme 3.38)62. The reactions were performed in a domestic microwave oven and required only a very short heating time. A microwave-assisted synthesis of a variety of new 3-substituted-2-alkyl-4-(3H)-quinazolinones using isatoic anhydride, 2-aminobenzimidazole and orthoesters has also been described (Scheme 3.38)63. 

Rad-Moghadam, K. and Khajavi, M.S., One-pot synthesis of substituted quinazolin-4(3H)-ones under microwave irradiation,/. Chem. Res., 1998, 702-703. 

A very recent synthesis of 2,4-diamino-5-substituted quinazolines (261) has been described. Elaboration of these compounds into precursors for the preparation of isoFA and isoAP analogues is in progress [146]. 

Scheme 21 Microwave-assisted domino reaction protocol for the synthesis of 2,3-di-substituted-quinazolin-4-ones...

The reductive cyclization of 2-nitrobenzyl-A, A -bis(formamide) with zinc in acetic acid to quinazoline was first described by RiedelT ° The reaction is used successfully for the synthesis of larger quantities of quinazoline and its benzene-ring-substituted derivatives 12 from 2-ni-trobenzyl-A, A -bis(formamides) 11. The method is suitable only for the preparation of 4-un-substituted quinazolines, because 2-nitro-substituted phenones do not condense with aliphatic amides to yield bis(amide) derivatives. Zinc in acetic acid is the reducing agent of choice, but iron in hydrochloric acid or Raney nickel can also be used. " Applications of compounds other than bis(formamides) [e.g., bis(acetamides) ] and preparation of 2-substituted quinazolines by Riedel s synthesis are scarce. 

A -Aryl-A -(ethoxyearbonyl)iinidamides and 2-alkyl-l-aryl-3-(ethoxycarbonyl)isothioureas 12 cyclize thermally to yield 2-substituted quinazolin-4(3//)-ones 13. When an A-aryl-A -(ethoxy-carbonyl)imidamide is boiled briefly in quinoline, ethanol is evolved and the corresponding 2-arylquinazolin-4(3//)-one is formed in 49-88% yield. Presumably elimination of ethanol yields an imidoyl isocyanate which undergoes cyclization to form the 2-arylquinazolin-4(3//)-one. These cyclizations are most likely simple thermal processes, since they proceed equally well when diphenyl ether is used instead of quinoline or when the imidamide is heated at 50-70 C above its melting point in the absence of a solvent.This reaction is also suitable for the synthesis of benzo-fused quinazolin-4(3//)-ones. °... 

Reaction of carboxamides with isatoic anhydrides 7 in place of anthranilic acid as a source of the anthraniloyl group is an attractive extension of the Niementowski synthesis (cf. p 30). The reaction of isatoic anhydrides 7 with formamide or 2-hydroxybenzamides at elevated temperatures in a melt or in tbe presence of suitable solvents gives high yields of tbe respective quinazolin-4(3//)-oncs 8/ whereas with alkyl-, aralkyl-, or arylcarboxamides the yields of the corresponding 2-substituted quinazolin-4(3//)-oncs arc low Guanidine and ami-... 

Substituted quinazolin-4-amines 12 are prepared in a one-step synthesis by heating quin-azolin-4(3/f)-one in a mixture of phosphorus pentoxide, A,A-dimethylcyclohexylamine (DMCA), and an appropriate amine or amine hydrochloride. Dimethylamine and primary arylamines are used as hydrochlorides, whereas with secondary amines, heterocyclic amines, benzyl- and furfurylamines it is necessary to use the free amine rather than the amine hydrochloride. 

Scheme 3.22 Fluorous synthesis of a library of substituted quinazoline-2,4-diones (46) [22]. The key to this approach is a fluorous benzyloxycarbonyl group on which the target molecules are stepwise constructed and which keeps the different synthetic intermediates bound to fluorous reversed-phase silica gel (FRPSG) during the purification cycles. The structural diversity of the target compound library (46) is introduced by the different anthranilic acid derivatives and primary amines in boxes) (TBTU = 0-(benzotriazol-1-yl)-N,/ /,N, N -tetramethyluronium tetrafluoroborate).

Synthesis of substituted quinazolin-4(3//)-ones and quinazolines via directed lithiation 00H(53)1839. 

A general synthesis of quinazoline 1,3-dioxides and their 1,2-dihydro derivatives was devised by Taylor and Bartulin. In this synthesis o-hydroxyl-aminobenzaldehyde oxime condensed with aldehydes and ketones to yield 2,2-disubstituted 1,2-dihydro-l-hydroxyquinazoline 3-oxides (63). When the dihydro compounds (63 R1 = H) derived from aldehydes or from formaldehyde were oxidized with chloranil, benzoquinone, or mercuric oxide, 2-substituted quinazoline 1,3-dioxides (64) and the parent quinazoline 1,3-dioxide (63 R = H) were produced.173... 

Denny and co-workers used a two-step sequence to prepzire 4-thiomethyl substituted quinazolines as versatile intermediates for the synthesis diversely substituted quinazolines. Treatment of 6-methyl-6//-pyrrolo[2,3-g]-quinazoline with Lawesson s reagent, followed by methylation using methyl iodide under basic conditions, gave the corresponding quinazoline in 32% yield over two steps. 

The Bischler synthesis is still practical today for the synthesis of 2-substituted quinazolines and quinazolinones. However, it has been largely replaced by the Neimentowksi reaction, which can be conducted under milder conditions and is therefore more practical for synthesis highly functionalized quinazolines and quinazolinones. 

The striking improvement in the Niementowski quinazoline synthesis [156, 157] has been fulfilled using microwave irradiation by Besson et al. [158,159] (Scheme 7). Using microwave irradiation and/or Appel s salt, new efficient routes to various substituted and fused quinazolines have been developed by Besson et al. [158,159] and also by others [ 160,161]. 

After Rossi s synthesis of quinazolines via 6 7T-electrocyclization (see Scheme 2), a few but unique quinazoline synthesis by electrocyclization were reported [202,203]. On the other hand, rapid analogue synthetic methods of substituted l,2,3-triazolo[l,5-a]quinazolines based on cycloaddition/conden-sation of 2-azidobenzoic acid or related compounds were developed by... 

A number of procedures for the preparation of 2-substituted quinazo-lines were reported in 2013. Wu and coworkers prepared 2-substituted quinazolines via a copper-catalyzed cascade synthesis by treating (2-ami-nophenyl) methanols 68 with aromatic aldehydes in the presence of copper(I) chloride, cerium nitrate hexahydrate, ammonium chloride, and potassium hydroxide in acetonitrile in moderate-to-high yields (Scheme 31) (13JOC11342). Electron-withdrawing substituents on either the (2-aminophenyl)methanol or the aromatic aldehyde resulted in a decrease in yield. 

Zhou and collaborators devised a procedure for the synthesis of 2-substituted quinazolines via an iridium-catalyzed hydrogen transfer (Scheme 32) (13RSCA334). Treatment of 2-aminobenzylamines 69 with aryl and alkyl aldehydes and styrene as the hydrogen acceptor in the presence of (pentamethylcyclopentadienyl)iridium (III) chloride dimer in xylene under refluxing conditions afforded the desired products in moderate yields. A base, for example, potassium hydroxide, had to be added when employing benzyl alcohol instead of benzaldehyde to furnish 2-phenylquin-azoline (70) in 61% yield (Scheme 32). 

Chen and collaborators developed an efficient, regioselective, Cu(II)-catalyzed one-pot synthesis of substituted quinazolines via a [2 + 2 + 2] cascade annulation of diaryliodonium salts with two nitriles. The authors proposed the following mechanism (Scheme 34) (13CC6752). The first nitrile reacts with the diaryliodonium salt to form A/-arylnitrilium intermediate 72, which is treated with the second nitrile to give an intermediate 73. Subsequent electrophilic aromatic substitution yielded the desired multi-substituted quinazolines 74 in moderate-to-good yields. 

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