Synthesis of 2,4-diaminoquinazolines and tricyclic quinazolines by cascade reductive cyclization of methyl N-cyano-2-nitrobenzimidates

An efficient route to N(4)-substituted 2,4-diaminoquinazolines has been developed by employing tandem condensation of cyanoimidate-amine and reductive cyclization in iron-HCl system. This method is tolerant of a following intramolecular N-alkylation and produces two fused heterocycles in a one-pot procedure. This protocol is a facile two-step synthesis of tricyclic quinazolines, which is effected by potent cyanoimidation and tandem reductive cyclization from 2-nitrobenzaldehydes. Moreover, the forming process of tricyclic quinazolines has been investigated from the ring-opening/ring-closing cascade point of view. It is found that the preparation of tricyclic quinazolinones in good yields relies on the selective hydrolysis of tricyclic quinazolines in base or acid system.     

Traceless solid-phase synthesis of 2,4-diaminoquinazolines

[reaction: see text] The solid-phase synthesis of 2,4-diaminoquinazolines is presented. The chemistry involves the sequential condensation of 2-aminobenzonitriles and amines starting from an acyl isothiocyanate resin via a traceless cleavage and cyclization. The alpha-1 antagonist prazosin was synthesized, as well as several other examples, in good yields and purity.     

Synthesis of some novel halogenated 2,4-diaminoquinazolines

Three new 2,4-diaminoquinazolines, the 5,6-difluoro, 6,7-difluoro and 7,8-difluoro isomers were prepared by the reaction of the requisite trifluorobenzonitrile and guanidine carbonate. Surprisingly, 2,3,6-trifluorobenzonitriles gave 2,4-diamino-5,6-difluoroquinazoline exclusively as determined by high resolution nuclear magnetic resonance spectroscopy. On the other hand, 3-amino-2,6-difluorobenzonitrile on reaction with guanidine carbonate yielded only 5-fluoro-2,4,8-triaminoquinazoline. This compound was subsequently converted to 8-chloro-2,4-diamino-5-fluoroquinazoline using the Sandmeyer procedure. The nitration of 2,4-diamino-8-fluoroquinazoline occurred exclusively at position six yielding 2,4-diamino-8-fluoro-6-nitroquinazoline, which upon reduction with stannous chloride afforded 8-fluoro-2,4,6-triaminoquinazoline. In a similar fashion 7-fluoro-2,4-diaminoquinazoline underwent nitration at position six and was then reduced to give 7-fluoro-2,4,6-triaminoquinazoline. Finally, both of these triaminoquinazolines were converted to the 6-chloro derivatives under Sandmeyer conditions to yield 6-chloro-2,4-diamino-8-fluoroquinazoline and 6-chloro-2,4-diamino-7-fluoroquinazoline, respectively.     

Solid-phase synthesis of 6-hydroxy-2,4-diaminoquinazolines

A new method for the solid-phase synthesis of 6-hydroxy-2,4-diaminoquinazolines has been developed. The synthesis utilizes solid-phase bound 6-hydroxy-2,4-dichloroquinazoline as a key intermediate. Sequential substitution of the two chlorines furnishes the title compounds regioselectively with high purity. A library of 18×22 compounds demonstrates the general utility of this approach.     

Direct synthesis of 2,4-diaminoquinazolines from 2-fluorobenzonitriles

In a search for new methods for preparing 2,4-diaminoquinazolines having a diversity of substituents in the benzenoid ring, it was found that the reaction of 2,6-difluorobenzonitrile with guanidine carbonate gave 2,4-diamino-5-fluoroquinazoline in excellent yield. Extension of this approach to other 2-fluorobenzonitriles, some of which were elaborated for the first time, showed that this reaction possesses considerable generality. The cyclization was successful even when electron donating groups were present at position six. Only in two cases where a primary or secondary amino group was also present ortho to the cyano group was this transformation unsuccessful.     

Lewis acid promoted cyclization of enyne triesters and diesters

Reactions of enynes with three or two ester groups (1-4) in the presence of halogen-ligand Lewis acids gave cyclized products with halide incorporation (5-8) with high generality. The cyclization process was also analyzed in a theoretical study. Facile isomerization and dehydrohalogenation of five-membered products 5 and 8 by Al(2)O(3) or Et(3)N were also observed; this process introduces conjugated moieties into the products.     

Access to 1,2,3-triazole-fused isoindolines via an unexpected Lewis acid catalyzed cyclization reaction

An unexpected cyclization reaction of N-sulfonyl 1,2,3-triazoles carrying the electron-deficient alkenes with amines under the catalysis of Lewis acid has been accomplished. This strategy involves the removal of the sulfonyl group and further intramolecular 1,4-addition, providing a series of 1,2,3-triazole-fused isoindoline compounds in good yields under the mild conditions.     

Internal Lewis acid assisted hydrogen bond donor catalysis

Boronate ureas are introduced as a new class of noncovalent catalysts for conjugate addition reactions with enhanced activity. Through intramolecular coordination of the urea functionality to a strategically placed Lewis acid, rate enhancements up to 10 times that of more conventional urea catalysts are observed. The tunable nature of boronate ureas is a particularly attractive feature and enables the rational design of catalysts for optimal performance, in terms of both activity and stereocontrol, in new bond-forming processes.     

Lewis acid promoted phenylseleno group transfer tandem radical cyclization reactions

[reaction: see text] A new Lewis acid promoted phenylseleno group transfer tandem radical cyclization method was developed. In the presence of Lewis acids such as Yb(OTf)3 or Mg(ClO4)2, under photolysis condition at low temperature (-45 degrees C), various unsaturated alpha-phenylseleno beta-keto amides underwent radical cyclization reactions to give monocyclic or bicyclic products in a highly efficient, regioselective, and stereoselective manner.     

Highly efficient synthesis of fused bicyclic 2,3-diaryl-pyrimidin-4(3H)-ones via Lewis acid assisted cyclization reaction

An expedient one-pot synthesis of fused bicyclic 2,3-diaryl-pyrimidin-4(3H)-ones from three readily available components is described. The key step is a Lewis acid assisted cyclization reaction.     

Lewis acid-promoted cyclization of heteroatom-substituted enynes

Lewis acid-promoted cyclizations of heteroatom-substituted enynes have been examined. The reaction of enynes and bearing silicon substituents on an alkyne afforded the halogenated five-membered gamma-lactones and gamma-lactams as the main products. The reaction of substrates and having 2-phosphonoacrylate instead of malonate also gave halogenated five-membered cyclic compounds and as the major products. The cyclized products are highly substituted and potentially useful for further synthetic transformations.     

Lewis acid - assisted high speed living anionic polymerization by the aluminum porphyrin - Lewis acid systems

Living anionic polymerization of methacrylic esters initiated with aluminum porphyrins ( 1 ) was found to be dramatically accelerated (e.g., 46 000 times) upon addition of bulky Lewis acids such as alkylaluminum diphenolates ( 3 ). Under appropriate conditions, a narrow MWD poly(methyl methacrylate) with Mn exceeding a million could be synthesized. The key conception of this high speed living polymerization is the coexistence of nucleophile ( 2 ) and Lewis acid ( 3 ) realized by steric repulsion.     

Lewis acid assisted methyl/chlorine exchange in silylated hydrazinochlorophosphanes

Differently substituted hydrazinophosphanes of the type (Me(3)Si)(2)N-N(SiMe(3))-PR(1)R(2) (R(1) = Cl with R(2) = Me, C(6)F(5) and R(1) = Me, R(2) = C(6)H(5)) have been studied in the reaction with Lewis acids such as ECl(3) (E = Al, Ga). For (Me(3)Si)(2)N-N(SiMe(3))-P(Cl)(Me) and (Me(3)Si)(2)N-N(SiMe(3))-P(Me)(C(6)H(5)), only adduct formation was found while a chlorine/methyl exchange reaction was observed for (Me(3)Si)(2)N-N(SiMe(3))-P(Cl)R (R = C(6)H(5) and C(6)F(5)) leading to the formation of (Me(2)ClSi)(Me(3)Si)N-N(SiMe(3))-P(Me)R, which crystallize as ECl(3) adducts. The free hydrazinophosphanes can be obtained by removal of the Lewis acid with the help of a strong base such as 4-(dimethylamino)pyridine (DMAP).     

Inhibition of human dihydrofolate reductase by 2,4-diaminoquinazolines bearing simple substituents on the aromatic ring

A series of thirty eight 2,4-diaminoquinazolines having diverse substitution patterns on the aromatic ring was evaluated for inhibitory activity against dihydrofolate reductase (DHFR) obtained from a human lymphoblast cell line. Many of these compounds were also evaluated as inhibitors of rat liver DHFR under the same experimental conditions. In most instances the results obtained with each enzyme were comparable indicating that the rodent enzyme is a suitable model for the human DHFR as far as the determination of I₅₀ values is concerned. The results demonstrate that relatively simple 5-substituted- or 5,6-disubstituted-2,4-diaminoquinazolines can be potent DHFR inhibitors. The presence of a nonpolar substituent at position 7 or 8 was highly detrimental to inhibitory potency.     

Lewis acid assisted ring-closing metathesis of chiral diallylamines: an efficient approach to enantiopure pyrrolidine derivatives

Lewis acid assisted ring-closing olefin metathesis (RCM) of chiral diallylamines, using the second generation RCM ruthenium-based catalyst, leads to enantiopure pyrrolidine derivatives in 79-93% yields under very mild conditions. The scope of the olefin metathesis has been expanded. [structure: see text]     

Synthesis of 2H-indazoles via Lewis acid promoted cyclization of 2-(phenylazo)benzonitriles

Lewis-acid promoted "coarctate" cyclization of 10 2-(phenylazo)benzonitrile derivatives furnishes the isoindazole ring system in ca. 65-95% yield. A plausible mechanism for this unusual transformation is proposed.     

Regulation of stereoselectivity using Lewis acid in the cyclization of allenic aldehydes catalyzed by palladium complex

A highly diastereoselective synthesis of 3 is achieved from the reaction of 1 with hexamethylditin catalyzed by palladium complex in the presence of 20 mol % tris(pentafluorophenyl)borane as a Lewis acid additive for a reversal of diastereoselectivity, whereas 2 is formed in the absence of Lewis acid additive. The method described herein is successful with various substrates 1 in good yields and high levels of diastereoselectivity. [reaction: see text]