Quinazolines. VIII. Synthesis of 1,3-diaminobenzo[f]quinazolines

Twenty-one 1,3-diaminobenzo[f]quinazolines ( 2 , R = H, alkyl, halogen, methoxy) were synthesized as planar tricyclic analogs of the antimalarial agent pyrimethamine ( 1 ). The synthetic methods included i) condensation of 1-cyano-2-naphthylamines with cyanamide in the presence of pyridine hydrochloride, ii) cyclization of N¹,N⁵-bis(2-naphthyl)biguanide hydrochlorides in diphenyl ether at 250°, iii) reaction of 2-naphthylamine hydrochlorides with excess sodium dicyanamide in boiling 1-octanol, and iv) selenium dioxide dehydrogenation of 1,3-diamino-5,6-dihydrobenzo[f]quinazolines. A number of new 2-naphthols and 2-naphthylamines were synthesized as intermediates. Substituent effects on the ultraviolet absorption spectra of 1,3-diamino-benzo[f]quinazolines were investigated and found to be additive. These compounds are of interest as inhibitors of dihydrofolate reductase and as potential antimalarial and antitumor agents.     

Quino[1,2-c]quinazolines. II. Synthesis of 12,13-dihydro-11bH-quino-[1,2-c]quinazolines via the versatile intermediates 2-(2-amino-4,5-dimethoxyphenyl)-6,7-disubstituted-1,2,3,4-tetrahydroquinolines

The versatile intermediates 2-(2-amino-4,5-dimethoxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroquinoline ( 2a ) and 6-(2-amino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]quinoline ( 2b ) were used in the preparation of a wide variety of 12,13-dihydro-11bH-quino[1,2-c]quinazolines by reaction with triethyl orthoformate, cyanogen bromide, urea and carbon disulfide in pyridine. Reaction of the thio and keto products with methyl iodide and phosphorus oxychloride, respectively, gave the requisite methylthio and chloro derivatives. Novel Reissert type reactions occurred when the intermediates 2a,b were reacted with acetic anhydride or benzoyl chloride. The attempted dehydrogenation of 12,13-dihydro-2,3,9,10-tetramethoxy-11bH-quino[1,2-c]quinazoline ( 3a ) is also reported.     

Pyrimidines

3-Arylbenzo[f]quinazolines were obtained by reaction in acetic or propionic acid of -naphthylamine, ammonia, and aromatic aldehydes containing an NR₂ or OH group. A mechanism is proposed for the formation of monoarylbenzo[f]quinazolines from the corresponding intermediate 1,3-diaryldihydrobenzo [f] quinazolines by acid cleavage of the C-aryl bond in the 1 position. This mechanism was confirmed experimentally by establishment of the fact of cleavage of 1,3-bis (p-methoxyphenyl)-1,2-dihydrobenzo[f] quinazoline when the acidity of the medium is increased; 3-(p-methoxyphenyl) benzo [f] quinazoline and anisole were obtained in the reaction products. Condensation in the presence of formic acid gave -arylidene-N-formyl--naphthylamines rather than arylbenzo [f] quinazolines.See [1] for communication LXIV.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1265–1271, September, 1978.     

Synthesis of 3,4-benzo-7-hydroxy-2,9-diazabicyclo[3.3.1]non-7-enes by cyclization of 1,3-bis(silyl enol ethers) with quinazolines

A variety of functionalized 3,4-benzo-7-hydroxy-2,9-diazabicyclo[3.3.1]non-7-enes were prepared by one-pot cyclizations of 1,3-bis(silyl enol ethers) with quinazolines. The mechanism of the cyclization was studied by B3LYP/6-31G(d) density functional theory computations. The products could be functionalized by Suzuki cross-coupling reactions. The reaction of 1,3-bis(silyl enol ethers) with phthalazine afforded open-chain rather than cyclization products.     

The reaction of tetralones with nitriles: a simple approach to the synthesis of new substituted benzo[h]quinazolines, benzo[f]quinazolines and dibenzo[a,i]phenanthridines

The one-pot reaction of 1-tetralone with nitriles in the presence of triflic anhydride affords in good yields 2,4-disubstituted 5,6-dihydrobenzo[h]quinazolines, which oxidation with DDQ leads to the corresponding benzo[h]quinazolines. 2-Tetralone undergoes identical process forming 1,3-disubstituted 5,6-dihydrobenzo[f]quinazolines. However, when the reaction of 2-tetralone is carried out with methylthiocyanate as nitrile, 5-methylthiotetrahydrodibenzo[a,i]phenanthridines are isolated in good yields. Easy transformations of the methylthio group offer possible access to a variety of substituted dibenzo[a,i]phenanthridines.     

Preparation and reactions of 1,3-diphosphacyclobutane-2,4-diyls that feature an amino substituent and/or a carbonyl group

The preparation and properties of a 1-amino-1,3-diphosphacyclobutane-2,4-diyl and a 1-benzoyl-1,3-diphosphacyclobutane-2,4-diyl, which can be regarded as functionalized cyclic biradical derivatives, were investigated. Hydrolysis of 1-diisopropylamino-3-methyl-2,4-bis(2,4,6-tri-tert-butylphenyl)-1,3-diphosphacyclobutane-2,4-diyl (7), which is formed by reaction of Mes*C[triple chemical bond]P (4; Mes*=2,4,6-tBu(3)C(6)H(2)) with lithium diisopropylamide and iodomethane, resulted in ring-opening of the 1,3-diphosphacyclobutane-2,4-diyl skeleton, as well as de-aromatization of one of the Mes* rings. 3-Oxo-1,3-diphosphapropene 8 and 7-phosphabicyclo[4.2.0]octa-1(8),2,4-triene 9 were the resultant products, and these were subsequently characterized. Isomerization and oxidation of 7 occurred in the presence of TEMPO (2,2,6,6-tetramethyl-1-piperidinoxy) to give the first example of a cyclic dimethylenephosphorane derivative, namely 3-oxo-1,3-diphospha-1,4-diene 10. 1-Benzoyl-3-tert-butyl-2,4-bis(2,4,6-tri-tert-butylphenyl)-1,3-diphosphacyclobutane-2,4-diyl (12) was isolated and characterized from the reaction of 4 with tert-butyllithium and benzoyl chloride. Compound 12 was subsequently heated and underwent rearrangement of the benzoyl group and ring-expansion to afford 1-oxo-1H-[1,3]diphosphole 13. Reaction of 4 with lithium diisopropylamide and benzoyl chloride afforded the 2H-[1,2,4]oxadiphosphinine 15, which was probably formed through the 1,3-diphosphacyclobutane-2,4-diyl intermediate 14. Thermolysis of 15 afforded 1-oxo-1H-[1,3]diphosphole 16 in an Arbuzov-type rearrangement.     

Investigation on radical polymerization of 2-methylene-1,3-dioxolanes and 2-methylene-1,3-oxazolidines

The reaction of 2-methylene-1,3-dioxolanes and 2-methylene-1,3-oxazolidines with benzoyl peroxide (acceptor radical) and with N-ethylmaleimide (acceptor) was investigated. It was shown that benzoyl peroxide adds to monomers 1a and 1b , giving the corresponding linear diester amides 1a and 1b respectively. The oxazolidine 1c adds benzoyl peroxide, without ring opening, by addition to the exomethylene group. Together with N-ethylmaleimide the oxazolidines 1a or 1b produce deep-colored charge transfer complexes, resulting in high molecular poly-N-ethylmaleimides probably via a radical mechanism. The 1,3-dioxolanes 2a and 2b were radically polymerized to produce polyacetals by vinyl polymerization. 2c was polymerized to produce randomly containing acetal units and ester units. The mechanism of polymerization of 2e is complex, affording polymers of nonuniform character. 2-Methylene-4-phenyl-1,3-dioxolane polymerization leads to polyester as the main structure, and to a lesser degree polyacetal structures. The chemical structures of the polymers were confirmed by NMR spectra and elemental analysis. © 1996 John Wiley & Sons, Inc.     

Synthesis of 1,3-diazapyrenes from benzo[<Emphasis Type="Italic">f</Emphasis>]quinazolines

Methods have been developed for the synthesis of 1,3-diazapyrenes based on the reactions of 1-methylbenzo[f]quinazolines with DMF dimethyl acetal or with 1,3,5-triazine in PPA. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii. No. 2, pp. 260–262, February, 2009.     

Oxoketene-oxoketene, imidoylketene-imidoylketene and oxoketenimine-imidoylketene rearrangements. 1,3-Shifts of phenyl groups

Dibenzoylketene 5 undergoes degenerate 1,3-shifts of the phenyl group between acyl and ketene carbon atoms, thus interconverting it with 6 and 7. This 1,3-shift takes place in the gas phase under flash vacuum thermolysis (FVT) conditions, but not in solution at 110-145 degrees C. Imidoyl(benzoyl)ketene 13 undergoes degenerate 1,3-shift of the phenyl group on FVT, thus interconverting it with 14, but the ketenimine isomer 15 is not formed, and none of these shifts take place in the solid state at 250 degrees C. Imidoyl(p-toluoyl)ketene 21 undergoes a 1,3-p-tolyl shift, interconverting it with ketene 22 but not with ketenimine 23. The imidoyl(p-toluoyl)ketene rotamer 25 cyclizes to 4-toluoyloxyquinoline 28 and 4-quinolone 29. The cyclization of imidoyl(benzoyl)ketene 13 to 4-benzoyloxyquinoline 18, and of 25 to 28 involves 1,3-C-to-O shifts of benzoyl (toluoyl) groups. Calculations of the transition states for the transformations at the B3LYP/6-31G** level of theory are in agreement with the observed reaction preferences.     

Efficient Synthesis of 2‐(2‐Aminophenyl)‐2,3‐dihydropyridin‐4(1H)‐ones Based on a Cyclization/Ring Cleavage Procedure

(Benzyloxycarbonyl)‐protected 3,4‐benzo‐7‐hydroxy‐2,9‐diazabicyclo[3.3.1]non‐7‐enes were prepared by one‐pot cyclizations of 1,3‐bis(silyl enol ethers) with quinazolines. Subsequent hydrogenation resulted in one‐pot deprotection and rearrangement to give 2‐(2‐aminophenyl)‐2,3‐dihydropyridin‐4(1H)‐ones.     

On the reactivity of 6-acetyl-7-(2-dimethylaminovinyl)pyrazolo[1,5-a]pyrimidines with 1,3- and 1,4-bisnucleophiles

Reaction of 6-acetyl-7-(2-dimethylaminovinyl)pyrazolo[1,5-a]pyrimidine 1 with 1,3- and 1,4-bisnucleophiles has been investigated; obtainment of new polycyclic heterocyclic derivatives is reported. A convenient procedure leading to new pyrazolo[1,5-a]quinazolines is described; a modest bioactivity of these compounds against two human tumor cell lines was also ascertained.     

Reissert compound studies. XXXVII. Attempts to form reissert compounds from quinazoline and cinnoline

Reaction of quinazoline with trimethylsilyl cyanide and benzoyl chloride gave 2,4-dicyano-1,3-dibenzoyl-1,2,3,4-tetrahydroquinazoline as the major product. This compound undergoes monoalkylation with methyl iodide in the presence of sodium hydride. Reaction of cinnoline with trimethylsilyl cyanide and benzoyl chloride gave 1,2-dibenzoyl-4-cyano-1,2-dihydrocinnoline.     

Quinazolines. VII. Synthesis of 1,3-Diamino-5,6-dihydrobenzo[f]quinazolines

Eighteen new 1,3-diamino-5,6-dihydrobenzo[f] quinazolines ( 6 , R. = alkyl, Cl, MeO) were synthesized via the condensation of appropriate 2-tetralones with cyanoguanidine under fusion conditions. Methods were developed for the preparation of a number of heretofore undescribed 2-tetralones as precursors. The final products can be viewed as conformationally rigid analogs of pyrimethamine ( 2 ), and are of interest as inhibitors of dihydrofolate reductase and as potential antimalarial and antitumor agents.     

Synthesis of 1,3-diamino-7,8,9,10-tetrahydropyrido[3,2-f]-quinazolines. Inhibitors of Candida albicans dihydrofolate reductase as potential antifungal agents

A series of novel 1,3-diamino-7,8,9,10-tetrahydropyrido[3,2-f]quinazolines were synthesized starting from 6-amino-5-cyanoquinoline (4). These compounds inhibited Candida albicans dihydrofolate reductase with K_i values of ≤0.60 aM. One analogue exhibited moderate in vivo efficacy in a C. albicans-infected mouse model.     

Reduction of 12-acetylaminoindolo[1,2-c]quinazolines. Preparation of derivatives of the new heterocyclic system indolo[3,2-d][1,3]benzodiazepine

Reduction of derivatives of 12-acetylaminoindolo[1,2-c]quinazoline yielded the corresponding 12-acetylamino-5,6-dihydroindolo[1,2-c]quinazolines, recyclization of which under the influence of dilute hydrochloric acid led to the formation of derivatives of the hitherto unknown system indolo[3,2-d][1,3]benzodiazepine.Deceased.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 668–673, May, 1988.     

1,3-噻唑烷衍生物的合成、结构及生物活性

为了寻找新的含噻唑杂环的先导化合物, 利用2-取代-1,3-噻唑烷1与氯甲酸取代苯基酯2及取代苯基甲酰氯4在三乙胺存在下发生缩合反应, 合成了6个2-取代-1,3-噻唑烷-3-甲酸酯类化合物3和5个N-苯甲酰基-2-取代-1,3-噻唑烷类化合物5, 并利用¹H NMR, IR, MS, 元素分析对其结构进行了表征. 用X-ray单晶衍射测定了2-硫代-1,3-噻唑烷-3-甲酸苯酯(3d)和N-苯甲酰基-2-氧代-1,3-噻唑烷(5a)的晶体结构, 证实了氯甲酸酯与2-硫代-1,3-噻唑烷的反应产物为硫酮式结构, 而非硫酯式结构. 初步生物活性试验结果表明, 在试验浓度下部分目标化合物3和5具有一定的杀菌和杀虫活性.     

金属离子对苯甲酰丙酮选择性还原的影响

以NaBH4为还原剂,研究了金属离子对苯甲酰丙酮选择性还原的影响。结果发现,添加Cd^2＋主要得到3-羰基被还原的产物,而单独使用硼氢化钠还原时却得到两个羰基同时被还原的产物。     

A novel manganese(III) acetate mediated reaction between 2-benzoyl-1,4-naphthoquinones and 1,3-dicarbonyl compounds

A manganese(III)-mediated reaction between 2-benzoyl-1,4-naphthoquinones and 1,3-dicarbonyl compounds is described. This reaction provides an effective method for the synthesis of naphtho[2,3-c]furan-4,9-diones and naphthacene-5,12-diones, and it shows fair to high chemoselectivity depending on the electronic effect of the benzoyl group substituent on the reactants. With ethyl benzoylacetate and 1,3-diketones, the novel naphtho[2,3-c]furan-4,9-diones were produced effectively with high selectivity.     

The reactivities of diarylbutadienes towards the benzoyloxy radical: the cases of 1-(1′-naphthyl)-4-phenylbuta-l,3-diene and 1,4-Di (1′-Naphthyl)buta-1,3-Diene

A study has been made of end-groups in poly(methyl methacrylate) prepared using benzoyl peroxide as initiator and either 1-(1′-naphthyl)4-phenylbuta-1,3-diene or 1,4-di(1′-naphthyl)buta-1,3-diene as additive. At 60°C, these dienes are 500–600 times as effective as methyl methacrylate in capturing benzoyloxy radicals and more than twice as effective as 1,4-diphenylbuta-1,3-diene.     

Polymerization studies on 1-ferrocenyl-1,3-butadiene

The polymerization behavior of 1-ferrocenyl-1,3-butadiene has been investigated by using both free-radical and anionic initiation techniques. Polymerization occurred readily under the promoting action of butyllithium; however, no polymerization occurred when azobisisobutyronitrile (AIBN) or benzoyl peroxide was employed as initiator. Copolymerizations were carried out with methyl methacrylate and styrene. The behavior of 1-ferrocenyl-1,3-butadiene in the copolymerizations was followed by dilatometric rate measurements, solution viscosity determinations, and elemental analysis. The major effect observed was a severe reduction in the intrinsic viscosities of the copolymers. An explanation for the observed behavior of 1-ferrocenyl-1,3-butadiene in these reactions is advanced.