Synthesis, photophysical and nonlinear optical properties of push-pull tetrazoles.

A 2,5-disubstituted tetrazole with p-nitrophenyl and 3-pyridyl units as acceptors (1a), and three push-pull tetrazoles with p-nitrophenyl as an acceptor and phenyl (1b), 2-(dibenzo[b,d]furan-4-yl) (1c), and 4-(N,N-diphenylamino)phenyl (1d) as donor groups, were synthesized by copper-catalyzed aerobic C-N coupling of p-nitrophenyl tetrazole with appropriately substituted aryl boronic acids. The absorption and emission spectra of 1a-c showed minimal dependence on the polarity of the solvent; however, in the case of 1d a blue shift was noted in the longest absorption band (λ 1) as the polarity increased. The fluorescence intensity of the title compounds was found to be solvent-dependent; however, no apparent correlation to solvent polarity could be established. The absorption and emission characteristics of 1a-d were also influenced by the nature of the substituent as 1d, bearing a strong electron donating 4-(N,N-diphenylamino)phenyl group, displayed a significant red shifted absorption (λ 1) as well as emission (λ em) bands compared to other compounds. Time dependent density functional calculations (CAM-B3LYP/6-311++G**) revealed that the longest wavelength band (λ 1) is associated with an intramolecular charge transfer (ICT) from HOMO/HOMO-1/HOMO-2 → LUMO/LUMO+1 in these molecules. The first hyperpolarizability values, ß HRS, of 1a-d were measured using the solution-based hyper-Rayleigh scattering technique using a femtosecond Ti:Sapphire laser and the highest NLO activity was measured for 1d with the greatest push-pull characteristics. A strong correlation was observed between the calculated hyperpolarizability (ß tot) and experimentally measured values (ß HRS).

Curtin-Hammett-Driven Intramolecular Cyclization of Heteroenyne-Allenes to Phenanthridine-Fused Quinazoliniminiums.

Intramolecular cyclization of the heteroenyne-allene 2-((biphenyl-2-ylimino)methyleneamino)benzonitrile 1 to phenanthridine-fused quinazoliniminium salt PQ in the presence of a Lewis acid at room temperature involves formation of two new bonds: a C-C bond and a C-N bond. In this article, density functional theory (B3LYP and M06-2X) was employed in conjunction with 6-311G* basis set to gain insights into the mechanism of this cyclization reaction. The solvent effects were considered using Polarizable Continuum Model with nitromethane as the solvent. Our calculations show that C-C bond formation precedes the C-N bond formation. Precisely, the mechanism involves initial protonation of 1 at Nα and Nß of the carbodiimide to form rapidly equilibrating conformers of the tautomers 2a,b and 3a,b. The Curtin-Hammett principle is invoked to determine the course of the reaction from these protonated species, which predicts that the intramolecular Friedel-Crafts type N-acylation (C-C bond formation) occurs between the protonated carbodiimide and biphenyl ring of the isomer 3b to form phenanthridinium cation 6b via transition state TS3b6b. Once 6b is formed, it converts to its most stable tautomers 8R and 9a. Once again, the Curtin-Hammett principle suggests that intramolecular nucleophilic attack is preferred from the tautomer 8R, where phenanthridine N-atom (Nß) attacks the protonated nitrile group (C-N bond formation) and results in the formation of intermediate 11 via TS8R11. 11 then tautomerizes to the most stable cation 13. The coordination of the latter with the chloride anion yields the phenanthridine-fused heterocyclic salt PQ with overall release of energy. The pathways involving protonation at the nitrile (Nγ) of 1 were found to be energetically unfavorable and thus insignificant to the mechanism of cyclization.

Mechanistic Investigation on the Formation of 2-Halo-3-aryl-4(3H)-quinazoliniminium Halides from Heteroenyne-allenes: A Computational Study.

Intramolecular cyclization of the heteroenyne-allene, 2-((phenylimino)methyleneamino)-benzonitrile (1) in the presence of HCl to produce 2-chloro-3-phenyl-4(3H)-quinazoliniminium chloride (Qz) involves the formation of two new bonds: a C-Cl bond and a C-N bond. We propose five pathways for this reaction. Four of these pathways involve chloride capture to form the C-Cl bond prior to the intramolecular nucleophilic attack to form the C-N bond, while one pathway involves ring closure to form the C-N bond prior to C-Cl bond formation. All calculations were carried out at B3LYP and MP2 levels of theory and employed the 6-311G* basis set. The solvent effects were considered using a Polarized Continuum Model with dichloromethane as the solvent. The calculations at both levels show that the mechanism involves initial protonation of 1, preferentially at Nα to give 2 which rapidly captures the chloride ion to form 5. This intermediate is protonated at the -CN group to form 8ROT, which then tautomerizes to its more stable isomer 9ROT. The latter undergoes intramolecular nucleophilic attack from Nß to the protonated -CN group to form the cyclized intermediate 12, which tautomerizes to its most stable isomer 13. The coordination of Cl(-) ion present in the solution with 13 gives the final product Qz.

One-pot cascade approach to phenanthridine-fused quinazoliniminiums from heteroenyne-allenes.

A one-pot cascade method to obtain functionalized phenanthridine-fused quinazoliniminiums from a variety of heteroenyne-allenes is described. This protocol involves formation of C-N and C-C bonds in a single step in the presence of a Lewis acid and trace water to afford pentacyclic title compounds in moderate to good yields.

Controlling molecular tautomerism through supramolecular selectivity.

We have isolated the stable as well as the metastable tautomers of 1-deazapurine in the solid state by exploiting principles of supramolecular selectivity in the context of cocrystal design.

Bioactivity of synthetic 2-halo-3-aryl-4(3H)-quinazoliniminium halides in L1210 leukemia and SK-BR-3 mammary tumor cells in vitro.

BACKGROUND: Because quinazolines and their derivatives exhibit a wide range of pharmacological profiles, there is a continuous interest among synthetic and medicinal chemists in the discovery of more potent analogs. Ten novel quinazoliniminium salts were synthesized and tested for their effectiveness against murine and human tumor cell proliferation in vitro. MATERIALS AND METHODS: Various markers of tumor cell metabolism, DNA degradation and mitotic disruption were assayed in vitro to evaluate drug cytotoxicity. RESULTS: All compounds induced concentration- and time-dependent antitumor effects in vitro but the 2-chloro-3-(4-methoxyphenyl)quinazolin-4(3H)-iminium chloride (4) was the most effective inhibitor of leukemia L1210 cell proliferation at days 2-4 (IC50: 2.1-0.9 µM), suggesting that the para-methoxyphenyl substituent on the N3 of 4 may enhance the antiproliferative properties of the quinazoliniminium scaffold. In mammary SK-BR-3 tumor cells, 4 reduced the Ki-67 marker of cell proliferation at 24 h and the metabolic activity at days 2 and 4. Moreover, a 1.5- or 3-h treatment with 4 was sufficient to inhibit the rates of DNA, RNA and protein syntheses measured in L1210 cells over 0.5- or 1-h periods of pulse-labeling with 3H-thymidine, 3H-uridine and 3H-leucine, respectively. As 4 did not reduce the fluorescence of the ethidium bromide-DNA complex, this compound was unlikely to directly bind to or destabilize double-stranded DNA. However, 4 induced DNA cleavage at 24 h in L1210 cells containing 3H-thymidine-prelabeled DNA, suggesting that this antitumor drug might trigger an apoptotic pathway of DNA fragmentation. After 12-48 h, 4 weakly increased the mitotic index of L1210 cells but stimulated the formation of many binucleated cells, multinucleated cells and micronuclei, suggesting that this antitumor compound might enhance mitotic abnormality, induce chromosomal damage or missegregation, and block cytokinesis. CONCLUSION: Although 4 may have interesting bioactivity, more compounds based on the quinazoliniminium scaffold must be synthesized to elucidate structure-activity relationships, identify more potent antitumor lead compounds, and investigate their molecular targets and mechanisms of action.

An easy entry into 2-halo-3-aryl-4(3H)-quinazoliniminium halides from heteroenyne-allenes.

An efficient three-step synthesis of 2-halo-3-aryl-4(3H)-quinazoliniminium halides from commercially available materials is described. Upon reaction with hydrogen halides, generated in situ from a Lewis acid (MX) and trace water, a variety of easily accessible heteroenyne-allenes underwent facile intramolecular cyclization to afford the title compounds in good yields. The method is highly versatile and provides a general way to construct quinazoliniminium ring systems with a variety of different substitutions.

Clean photodecomposition of 1-methyl-4-phenyl-1H-tetrazole-5(4H)-thiones to carbodiimides proceeds via a biradical.

The photochemistry of 1-methyl-4-phenyl-1H-tetrazole-5(4H)-thione (1a) and 1-(3-methoxyphenyl)-4-methyl-1H-tetrazole-5(4H)-thione (1b) was studied in acetonitrile at 254 and 300 nm, which involves expulsion of dinitrogen and sulfur to form the respective carbodiimides 5a,b as sole photoproducts. Photolysis of the title compounds in the presence of 1,4-cyclohexadiene trap led to the formation of respective thioureas, providing strong evidence for the intermediacy of a 1,3-biradical formed by the loss of dinitrogen. In contrast, a trapping experiment with cyclohexene provided no evidence to support an alternative pathway of photodecomposition involving initial desulfurization followed by loss of dinitrogen via the intermediacy of a carbene. Triplet sensitization and triplet quenching studies argue against the involvement of a triplet excited state. While the quantum yields for the formation of the carbodiimides 5a,b were modest and showed little change on going from a C(6)H(5) (1a) to mOMeC(6)H(4) (1b) substituent on the tetrazolethione ring, the highly clean photodecomposition of these compounds to a photostable end product makes them promising lead structures for industrial, agricultural, and medicinal applications.

Synthesis and antiproliferative evaluation of 5-oxo and 5-thio derivatives of 1,4-diaryl tetrazoles.

A series of 1,4-diaryl tetrazol-5-ones were synthesized by copper mediated N-arylation of 1-phenyl-1H-tetrazol-5(4H)-one with aryl boronic acids, o-R(1)C(6)H(4)B(OH)(2) where R(1)=H, OMe, Cl, CF(3), Br, CCH. The 1,4-diaryl tetrazol-5-ones substituted with OMe, Cl, CF(3), Br underwent thionation with Lawesson's reagent to yield the corresponding 5-thio derivatives. The 1-(2-bromophenyl)-4-phenyl-1H-tetrazole-5(4H)-thione so obtained was subjected to lithiation/protonation and Sonogashira coupling to produce 1,4-diphenyl-1H-tetrazole-5(4H)-thione and 1-(2-ethynylphenyl)-4-phenyl tetrazole-5-thione, respectively. The title compounds were found to be stable to strong Lewis acid conditions. Three of these novel compounds were found to inhibit L1210 leukemia cell proliferation and SK-BR-3 breast cancer cell growth over several days in culture in vitro. Shorter tetrazole derivative treatments also reduced the expression of the Ki-67 marker of cell proliferation in SK-BR-3 cells and the rate of DNA synthesis in L1210 cells.

Nitrosative cytosine deamination. An exploration of the chemistry emanating from deamination with pyrimidine ring-opening.

A discussion of nitrosative deamination of cytosine 1 is presented that argues for the formation of 6 by diazotization of 1 to cytosinediazonium ion 2 and its electrostatic complex 3, dediazoniation to 4 <--> 5, and amide-bond cleavage to 6. The reaction channels available to 6 include hydrolytic deglycation to 3-isocyanatoacrylonitrile 7, water addition to carbamic acid 9 with the possibility for re-closure to uracil 13, water addition to carbamic acid 9, and decarboxylation to 3-aminoacrylonitrile 10. With a view to the instability of the carbamic acid 9, the carbamate models ethyl (Z)-2-cyanovinylcarbamate 14 and (Z)-2-cyano-1-tert-butylvinylcarbamate 20 were studied. Acid-catalyzed hydrolysis of 14 leads to 2-amino-carbonylphenylcarbamate 15, and its cyclization yields the benzo-fused uracil quinazoline-2,4-dione 16. In contrast to the aromatic system 14, acid-catalyzed cyclization cannot compete with oligomerization in the case of 20, and 5-tert-butyluracil 22 is accessible only with base-catalysis. It is shown that 23, the parent of 10, also easily polymerizes. The experimental results provide a rationale as to why 9, 10, and 12 would have escaped detection in in vitro studies: they would have oligomerized. In contrast to the in vitro experiments, the oligomerizations of 9, 10, or 12 clearly are not relevant in vivo because of low monomer concentrations. With the exclusion of recyclization and of oligomerization in vivo, attention thus needs to focus on (Z)-3-aminoacrylonitrile 10 as the most likely deamination product of cytosine aside from uracil.

Nitrosative guanine deamination: ab initio study of deglycation of N-protonated 5-cyanoimino-4-oxomethylene-4,5-dihydroimidazoles.

5-Cyanoimino-4-oxomethylene-4,5-dihydroimidazoles (1) (R at N1) have been discussed as possible intermediates in nitrosative guanine deamination, which are formed by dediazoniation and deprotonation of guaninediazonium ion. The parent system 1 (R = H) and its N1 derivatives 2 (R = Me) and 3 (R = MOM) are considered here. Protonation of 1-3, respectively, may occur either at the cyano-N to form cations 4 (R = H), 6 (R = Me), and 8 (R = MOM) or at the imino-N to form cations 5 (R = H), 7 (R = Me), and 9 (R = MOM), respectively. This protonation is the first step in the acid-catalyzed water addition to form 5-cyanoimino-imidazole-4-carboxylic acid, which then leads to oxanosine. There also exists the option of a substitution reaction by water at the R group of 6-9, and this dealkylation forms N-[4-(oxomethylene)-imidazol-5-yl]carbodiimide (10) and N-[4-(oxomethylene)-imidazol-5-yl]cyanamide (11). In the case of DNA, the R group is a deoxyribose sugar, and attack by water leads to deglycation. To explore this reaction option, the S(N)1 and S(N)2 reactions of 6-9 with water were studied at the MP2/6-31G*//RHF/6-31G* and CCSD/6-31G*//RHF/6-31G* levels, with the inclusion of implicit solvation at the IPCM(MP2/6-31G*)//RHF/6-31G* level, and the electron density distributions of tautomers 1, 10, and 11 were analyzed. The low barriers determined for the MOM transfer show that the deglycation could occur at room temperature but that the process cannot compete with water addition.

5-Cyanoimino-4-oxomethylene-4,5-dihydroimidazole and 5-cyanoamino-4-imidazolecarboxylic acid intermediates in nitrosative guanosine deamination: evidence from 18O-labeling experiments.

The nitrosative deaminations (37 degrees C, NaNO2, NaAc buffer, pH 3.7) of guanosine 1r in (18O)water (97.6%) and of [6-18O]-1r in normal water were studied. [6-(18)O]-1r was prepared from 2-amino-6-chloropurine riboside using adenosine deaminase. The reaction products xanthosine 3r and oxanosine 4r were separated by HPLC and characterized by LC/MS analysis and 13C NMR spectroscopy. The 18O-isotopic shifts on the 13C NMR signals were measured and allowed the identification of all isotopomers formed. The results show that oxanosine is formed via 5-cyanoimino-4-oxomethylene-4,5-dihydroimidazole, 5, and its 1,4-addition product 5-cyanoamino-4-imidazolecarboxylic acid, 6. This hydration of 5 to 6 leads to aromatization and greatly dominates over water addition to the cyanoimino group of 5 to form 5-guanidinyliden-4-oxomethylene-4,5-dihydroimidazole, 7. 5-Guanidinyl-4-imidazolecarboxylic acid, 8, the product of water addition to 6, is not involved.

5-cyanoimino-4-oxomethylene-4,5-dihydroimidazole and nitrosative guanine deamination. A theoretical study of geometries, electronic structures, and N-protonation.

The 5-cyanoimino-4-oxomethylene-4,5-dihydroimidazole 1 (R = H), its N1-derivatives 2 (R = Me) and 3 (R = MOM) and their cyano-N (4, 6, 8) and imino-N protonated (5, 7, 9) derivatives were studied with RHF, B3LYP, and MP2 theory. Solvation effects were estimated with the isodensity polarized continuum model (IPCM) at the MP2 level using the dielectric constant of water. Carbodiimide 10, cyanamide 12, N-cyanomethyleneimine 13, and its protonated derivatives 14 and 15 were considered for comparison as well. Adequate theoretical treatment requires the inclusion of dispersion because of the presence of intramolecular van der Waals, charge-dipole, and dipole-dipole (including H-bonding) interactions. All conformers were considered for the MOM-substituted systems, and direct consequences on the preferred site of protonation were found. The vicinal push (oxomethylene)-pull (cyanoimino) pattern of the 5-cyanoimino-4-oxomethylene-4,5-dihydroimidazoles results in the electronic structure of aromatic imidazoles with 4-acylium and 5-cyanoamido groups. The gas-phase proton affinities of 1-3 are over 30 kcal/mol higher than that for N-cyanomethyleneimine 13, and this result provides compelling evidence in support of the zwitterionic character of 1-3. Protonation enhances the push-pull interaction; the OC charge is increased from about one-half in 1-3 to about two-thirds in the protonated systems. In the gas phase, cyano-N protonation is generally preferred but imino-N protonation can compete if the R-group contains a suitable heteroatom (hydrogen-bond acceptor, Lewis base). In polar solution, however, imino-N protonation is generally preferred. Solvation has a marked consequence on the propensity for protonation. Whereas protonation is fast and exergonic in the gas phase, it is endergonic in the polar condensed phase. It is an immediate consequence of this result that the direct observation of the cations 8 and 9 should be possible in the gas phase only.

Nitrosative adenine deamination: facile pyrimidine ring-opening in the dediazoniation of adeninediazonium ion.

[reaction: see text]. Dediazoniation of adeninediazonium ion, 1, forms the heteroaromatic cation, 2. Ab initio studies at the CCSD(fc)/6-31G**//MP2(full)/6-31G** level now reveal that the cyclic cation 2 is kinetically and thermodynamically unstable with respect to the pyrimidine ring-opened cation, 3. The results suggest that 4-cyano-5-isocyano-imidazole, 4, and 4,5-dicyanoimidazole, 5, might be formed to some extent in nitrosative deaminations of adenine.