Diethyl N,N-dimethylaminomethylenemalonate in the synthesis of fused heterocyclic systems

The reactions of diethyl N,N-dimethylaminomethylenemalonate ( 3 ) with N- and C- nucleophiles were studied. In the reaction of 3 with heterocyclic amines 4 , with the amino group attached at α-position in respect to the ring nitrogen atom, substitution of the dimethylamino group in 3 with the heterocyclic amino took place to give diethyl heteroarylaminomethylenemalonates 5 , which can cyclize into fused azino- 6 or azolopyrimidinones 7 . In the reaction of 3 with the compound with an active methylene group attached at α-position in regard to the ring nitrogen atom, such as pyridinylacetonitrile ( 8 ), ethyl pyridinyl- ( 9 ), and quinolinylacetate ( 10 ), fused quinolizines 11 and 12 , and benzo[c]quinolizine 13 were formed, respectively. Heterocyclic systems with an active or potentially active methylene group incorporated in the ring system, such as pyrazole 14 , pyrimidine 15 , and pyridine derivative 18 , gave with 3 fused pyranones 16, 17 , and 19 , and dihydroxynaphthalenes 22 and 23 naphtho[2,1-b]pyranones 24 and 25 .     

Regiochemistry of nucleophilic substitution of 4-phenylsulfonyl tetrafluoropyridine with unequal bidentate nucleophiles

The regiochemistry of nucleophilic substitution of 4-phenylsulfonyl tetrafluoropyridine with unequal bidentate nucleophiles was investigated. The first nucleophilic substitution occurs at the 2-position of the pyridine ring by nitrogen nucleophile site (secondary or primary amine) followed by intermolecular ring closure at the geometrically accessible 3-position of the pyridine ring (by S, O and N nucleophiles). From this investigation, difluorinated tetrahydropyrido[3,4-b][1,4]oxazine, thiazine and pyrazine scaffolds were synthesized very readily by a one-pot annelation reaction of 4-phenylsulfonyl tetrafluoropyridine with appropriate unequal bidentate nucleophiles.     

The synthesis and chemical reactions of certain pyrazolo[1,5-a]-1,3,5-triazines

3-Aminopyrazole was utilized as a starting material for the preparation of certain pyrazolo-[1,5-a]-1,3,5-triazines. 4-Chloro-2-methylthiopyrazolo[1,5-a]-1,3,5-triazine was prepared and used for studies of nucleophilic displacement reactions, and it has been found that both the chloro and methylthio groups may be displaced by nucleophiles. By modifications of these procedures we have prepared the adenine, hypoxanthine, and xanthine analogs of the pyrazolo-[1,5-a]-1,3,5-triazine ring system. Electrophilic substitution occurs in the 8-position of this ring system. The methyl group was introduced into the 4-position by a novel ring opening and ring closing of the 1,3,5-triazine ring.     

Reaction of 1,3,4-thiadiazolo and 1,3,4-triazolo[3,2-c]quinazoline derivatives with active methylene compounds

Fused quinazoline derivatives 1 and 4 react with active methylene compounds and depending on the annelated five-membered ring, two types of transformations have been observed. The 1,3,4-thiadiazolo[3,2-c]quinazoline 1 , underwent the five-membered ring opening reaction to afford the 3,4-dihydroquinazolines 2 in good yields, whereas the 1,3,4-triazolo[3,2-c]quinazoline 4 underwent nucleophilic attack at 2-position of the quinazoline ring to yield the corresponding 1,2,4-triazoles 5 .     

Synthetic utility of 4-bromo-2,3,5,6-tetrafluoropyridine

The regiochemistry of nucleophilic substitution of 4-bromo-2,3,5,6-tetrafluoropyridine has been investigated. Efficient, regioselective reactions occur with alkylamine, benzylamine and alkoxide nucleophiles, yielding products where substitution occurs ortho to the ring nitrogen. The resulting 2-substituted-4-bromo-3,5,6-trifluoropyridines can be functionalised further, either by a second regioselective nucleophilic displacement or palladium catalysed elaboration at the 4-position. Reactions with aromatic N-nucleophiles yield mixtures of ortho- and para-substituted products.     

Quantum Chemical Study of Mechanisms of Organic Reactions: VII. Reaction of Ethane-1,2-dithiol with 1,3-Dichloropropene in the System Hydrazine Hydrate–KOH

A mechanism has been proposed for the reaction of 1,3-dichloropropene with ethane-1,2-dithiol in the system hydrazine hydrate–potassium hydroxide on the basis of DFT quantum chemical calculations [B3LYP/6-311++G(d,p)]. The proposed mechanism involves several consecutive steps, in particular nucleophilic substitution of chlorine at the sp³-hybridized carbon atom by sulfur, prototropic allylic rearrangement of the monosubstitution product with double bond migration toward the sulfur atom, dithiolane ring closure via nucleophilic attack of the second thiolate group on the carbon atom in the γ-position with respect to the second chlorine atom, and prototropic allylic rearrangement of 2-vinyl-1,3-dithiolane to more stable 2-ethylidene-1,3-dithiolane.     

Selective synthesis of β-alkylpyrroles

β-Alkylpyrroles are key structural motifs found in many natural products and biologically active compounds as well as functional organic materials. For this reason, synthetic chemists continue to be interested in construction of the framework of β-alkylpyrroles. Due to sufficient aromaticity and π-excessive nature of pyrroles, a straightforward approach to β-alkylpyrroles should be electrophilic aromatic substitution (S(E)Ar) toward the pyrrole ring. However, since a primary nucleophilic site of pyrroles is an α-position, some "trick" is required to direct incoming alkyl electrophiles toward a β-position. This Concept article focuses on presenting previous efforts that have been devoted to the synthesis of β-alkylpyrroles, mainly through the S(E)Ar route.     

Synthesis of 1,2,4-triazole dendrimers

A convergent synthetic strategy towards novel 1,2,4-triazole dendrimers, in which 3,5-dichloro-4-(4-methoxyphenyl)-4H-1,2,4-triazole was used as the heterocyclic building block, was successfully explored. Nucleophilic aromatic substitution at this novel AB₂-monomer was used as the key step in the propagation of the heterocyclic dendrons and these dendrons were attached to both a 1,3,5-triazine and a methylene core. The peripheral 1,2,4-triazole could be varied not only by nucleophilic aromatic substitution but also by Suzuki cross-coupling. The presented dendrimers are promising candidates to be used in applications where the large number of heteroatoms can be exploited or a better resistance to the applied conditions is required.     

Synthesis of 2-guanyl-4-(3-substituted-phenyl)thiazoles with potent histamine H2-antagonism activity

The syntheses of novel 2-guanyl-4-(3-substituted-phenyl)thiazoles showing potent histamine H ₂-antagonism activity is reported. The most potent compound is 17 where the substitution at the 3-position of the phenyl ring is an N-methylamidino function.     

7-substituted 2-azabicyclo[2.2.1]heptanes as key intermediates for the synthesis of novel epibatidine analogues; synthesis of syn-and anti-isoepiboxidine

Neighboring group participation by the 2-nitrogen in anti-7-bromo-2-benzyl-2-azabicyclo[2.2.1]heptane allows ready nucleophilic substitution at the 7-position by C, N, O, and halogen nucleophiles and opens the way to a range of novel 7-substituted 2-azabicyclo[2.2.1]heptanes. Conversion of an anti-7-ethoxycarbonyl group into a methylisoxazole ring provides anti-isoepiboxidine, a conversion that is possible even without protection of the secondary bicyclic nitrogen. Successful base-induced epimerization alpha to the carbonyl of the anti-7-ethoxycarbonyl derivative gives the syn-stereoisomer and hence syn-isoepiboxidine.     

Synthesis of 3-functionalized 3-methylazetidines

1-t-Butyl- and 1-(4-methylbenzyl)-3-bromo-3-methylazetidines were prepared from the corresponding N-(2,3-dibromo-2-methylpropylidene)alkylamines and their propensity to undergo nucleophilic substitution at the 3-position by different nucleophiles was assessed, providing a convenient access to novel 3-alkoxy-, 3-aryloxy-, 3-hydroxy-, 3-cyano-, 3-carboxy-, 3-(aminomethyl)- and 3-(hydroxymethyl)azetidines.     

Nucleophilic β-amination of pyridine nuclei

3-Bromo-4-nitropyridine N-oxide behaves as a useful substrate for causing nucleophilic substitution at the β-position (3-position) with amines to afford 3-aminopyridine derivatives.     

Synthesis of novel,azasugar-modified anthraquinone derivatives and their cytotoxicity

A series of novel, azasugar-modified 2-monosubstituted, 2,6- and 2,7-bissubstituted anthraquinone derivatives have been synthesized by the nucleophilic substitution of N-alkylamino azasugar with mono-, bis（2-chloroacetamido）anthraquinones. Their cytotoxic activities against HeLa and MCF-7 ceils were preliminarily evaluated and compound 9a with mono-azasugar pendant at 2-position showed similar activity to the control drug （Cisplatin）.     

氨基硝基吡啶及其氮氧化物的亲核取代胺化反应

以盐酸羟胺、1,1,1-三甲基肼碘化物(TMHI)和4-氨基-1,2,4-三唑(ATA)为胺化剂,研究了2-氨基-3,5-二硝基吡啶(1)和2-氨基-3,5-二硝基吡啶-1-氧化物(3)的亲核取代（VNS）胺化反应。 结合VNS胺化反应机理讨论了胺化剂活性、胺化剂和胺化底物的立体、电子效应对产物的组成和收率的影响。 以羟胺为胺化剂时,氨基可被引入到底物的6-位和4-位,胺化产物的收率在64%~89%之间;以TMHI和ATA为胺化剂时,氨基只能被引入到底物的6-位,胺化产物的收率在90%以上;在相同条件下,胺化产物的收率随胺化剂活性的提高而提高;受N+→O-的影响,化合物3的胺化产物收率稍高于化合物1的胺化产物收率。     

Synthesis and biological activity of N-(aminoiminomethyl)-1H-indole carboxamide derivatives as Na+/H+ exchanger inhibitors

A series of N-(aminoiminomethyl)-1H-indole carboxamide derivatives were synthesized and their inhibitory potencies against the Na+/H+ exchanger were measured. Variation of the carbonylguanidine group at the 2- to 7-position of the indole ring system showed that a substitution at the 2-position improved the Na+/H+ exchanger inhibitory activity the most in vitro. This led to the synthesis and evaluation of an extensive series of N-(aminoiminomethyl)-1H-indole-2-carboxamide derivatives. Derivatives having an alkyl or substituted alkyl group at the 1-position of the indole ring system showed higher levels of in vitro activities. N-(aminoiminomethyl)- 1-(2-phenylethyl)-1H-indole-2-carboxamide (49) had the strongest activity.     

Nucleophilic substitution in the furazan series. Reactions of nitrofurazans with ammonia

The reactions of 3-nitro-4-R-furazans with ammonia were studied. The effect of the substituent R on the specific features of the nucleophilic substitution reaction observed was considered. The nitro group attached to the furazan ring can act as both the leaving group and the activating group facilitating the displacement of the second substituent (for example, OR" or N(NO₂)R").     

Synthesis and In Vitro Evaluation of Bis‐intercalators with Varied Linkers between Aminochloropyrimidine Rings

The synthesis of two groups of aminochloropyrimidine bis‐intercalators with different lipophilicity or limited flexibility of linkers as potential DNA intercalators is described. The lipophilic linkers in the synthesized bis‐intercalators are represented by alternating methylene groups and oxygen atoms in a chain, with a pyrimidine ring containing an amino group and a chloro group at each end ( 10 , 11 , 12 , 13 ). The bis‐intercalators with limited flexibility contain chains with two benzene rings ( 15 , 16 , 17 , 18 , 19 ). All these compounds were obtained by nucleophilic substitution of 2‐amino‐4,6‐dichloropyrimidine ( 1 ). The spectral data and other physical properties of the new compounds are presented. The anticancer activity of these newly synthesized compounds is also reported. Compounds 7 and 8 described in one of our previous publications display good anticancer activity against murine lymphoma.     

The loss of carbon dioxide from activated perbenzoate anions in the gas phase: unimolecular rearrangement via epoxidation of the benzene ring

The unimolecular reactivities of a range of perbenzoate anions (X-C6H5CO3-), including the perbenzoate anion itself (X = H), nitroperbenzoates (X = para-, meta-, ortho-NO2), and methoxyperbenzoates (X = para-, meta-OCH3) were investigated in the gas phase by electrospray ionization tandem mass spectrometry. The collision-induced dissociation mass spectra of these compounds reveal product ions consistent with a major loss of carbon dioxide requiring unimolecular rearrangement of the perbenzoate anion prior to fragmentation. Isotopic labeling of the perbenzoate anion supports rearrangement via an initial nucleophilic aromatic substitution at the ortho carbon of the benzene ring, while data from substituted perbenzoates indicate that nucleophilic attack at the ipso carbon can be induced in the presence of electron-withdrawing moieties at the ortho and para positions. Electronic structure calculations carried out at the B3LYP/6-311++G(d,p) level of theory reveal two competing reaction pathways for decarboxylation of perbenzoate anions via initial nucleophilic substitution at the ortho and ipso positions, respectively. Somewhat surprisingly, however, the computational data indicate that the reaction proceeds in both instances via epoxidation of the benzene ring with decarboxylation resulting--at least initially--in the formation of oxepin or benzene oxide anions rather than the energetically favored phenoxide anion. As such, this novel rearrangement of perbenzoate anions provides an intriguing new pathway for epoxidation of the usually inert benzene ring.     

Stereoselective synthesis of both enantiomers of N-aryl indoles with axially chiral N-C bonds

N-Aryl indoles with axially chiral N-C bonds were synthesized by stereoselective nucleophilic aromatic substitution reactions of planar chiral tricarbonyl(2,6-disubstituted-1-fluorobenzene)chromium complexes. The stereochemistry of the products is highly dependent on the position of the substituent in the indole. When indoles devoid of a substituent at the 2-position were used, N-aryl indole chromium complexes having anti orientation with respect to the tricarbonylchromium fragment were obtained diastereoselectively. In contrast, 2-substituted indoles gave the N-aryl indoles with syn orientation between the tricarbonylchromium fragment and the benzene ring of the indole. These results demonstrate that we have succeeded in synthesizing both enantiomers of N-aryl indoles utilizing an identical planar chiral arene chromium complex.     

Synthesis of enantiopure substituted piperidines via an aziridinium ring expansion

Herein we report a novel methodology for the asymmetric synthesis of 3-substituted piperidines from readily available chiral building blocks. This method, which features a novel irreversible dihydropyrole-tetrahydropyridine ring expansion, allows the introduction of a large variety of substituents at the 3-position and permits substitution at the 2- and 6-position giving mono-, di-, or trisubstituted piperidines with high diastereocontrol.