The preparation and some chemistry of 2,2-dimethyl-1,2-dihydroquinolines

The cyclisation of N-(1,1-dimethylpropargyl) anilines, using cuprous chloride in refluxing toluene, yields 6-substituted-2,2-dimethyl-1,2-dihydroquinolines. The reactivity of the double bond in the heterocyclic ring of these products is exemplified by chlorination, to yield 6-substituted-3,4-cis-dichloro-2,2-dimethyl-1,2,3,4-tetrahydroquinolines which can be selectively dechlorinated to provide 6-substituted-3-chloro-2,2-dimethyl-1,2,3,4-tetrahydroquinolines; epoxidation to yield an epoxide, which can be hydrogenolysed to the corresponding 3-hydroxy product and in turn oxidised to the 3-keto derivative; and oxymercuration to provide a 4-hydroxy product and hence a 4-keto derivative. Dehydrochlorination of a 3,4-dichloro product provides a 3-chloro-1,2-dihydroquinoline which can be hydrolysed to a 3-keto system. The formation of cis 3,4-dichloro products from the chlorination, as well as the formation of a cis chlorohydrin from the chlorination of N-acetyl-2,2,6-trimethyl-1,2-dihydroquinoline in partially aqueous solution, suggests that N-acetyl, or N-trifluoroacetyl groups, participate in the addition process.     

Formation of 2-halomethylene-4-cyclopentene-1,3-diones and/or 2-halo-1,4-benzoquinones via ring-expansion of 4-ethynyl-4-hydroxy-2,3-substituted-2-cyclobuten-1-ones. Total synthesis of methyl linderone

An in-depth study of the reactions of 4-(ethynyl)-4-hydroxy-2,3-substituted-2-cyclobuten-1-ones with N-bromo- or N-iodosuccinimide, affording in most cases 2-halomethylene-4-cyclopentene-1,3-dione, is described. This reaction was used in a short total synthesis of methyl linderone.     

N-Arylation of 4-fluoro-5-trimethylsilyl-1H-pyrazole

The 1,3-dipolar cycloaddition reaction of fluoro(trimethylsilyl)acetylene prepared in situ with an excess of diazomethane smoothly proceeded to give the corresponding 4-fluoro-5-trimethylsilyl-1H-pyrazole in 84% yield. The copper iodide-catalyzed N-arylation of the fluorinated pyrazole with a variety of aryl iodides afforded N-aryl-4-fluoropyrazoles as desilylation products in good to excellent yields.     

Synthesis of 3-substituted-4-hydroxyquinoline N-oxides from the Baylis-Hillman adducts of o-nitrobenzaldehydes

The reaction of the Baylis-Hillman adducts 1b-f derived from o-nitrobenzaldehydes in trifluoroacetic acid in the presence of triflic acid (0.2 equiv.) afforded 3-substituted-4-hydroxyquinoline N-oxides 2b-e and 2a in good to moderate yields. The reaction mechanism was evidenced by the experiment with 1f, the Baylis-Hillman adduct of 2-nitrobenzaldehyde N-tosylimine, as the one involving N-hydroxyisoxazoline as the key intermediate.     

6-Substituted-5H-pyrrolo[2,3-b]pyrazines via palladium-catalyzed heteroannulation from N-(3-chloropyrazin-2-yl)-methanesulfonamide and alkynes

We herein report the efficient and convenient synthesis of 6-substituted-5H-pyrrolo[2,3-b]pyrazines. The reaction is a palladium-catalyzed heteroannulation process followed by deprotection to yield the desired pyrrolo[2,3-b]pyrazine substrates. The reaction starts with readily accessible N-(3-chloropyrazin-2-yl)-methanesulfonamide and commercially available terminal alkynes and works with aryl- and alkylalkynes.     

A convenient and efficient method for the synthesis of mono- and N,N-disubstituted thioureas

A convenient method for the synthesis of mono- and N,N-disubstituted thioureas by the debenzoylation of N-substituted- and N,N-disubstituted-N′-benzoylthioureas with hydrazine hydrate under solvent-free conditions has been developed. N-Substituted-N′-benzoylthioureas and hydrazine hydrate were mixed, and stirred at room temperature without a solvent to give the corresponding N-substituted thioureas in high yields.     

Ruthenium-catalyzed reduction of N-alkoxy- and N-hydroxyamides

A ruthenium-catalyzed reduction of N-alkoxy- and N-hydroxyamides was found to afford corresponding amides in good to high yields. A simple RuCl₃/Zn-Cu/alcohol system, without the addition of any other ligands, exhibited a high catalytic activity, and therefore the present reaction does not require a stoichiometric amount of metals or metal complexes as reductants. When β-substituted-α,β-unsaturated N-methoxyamides were employed as substrates, concurrent hydrogenation of the olefin moiety proceeded slowly with deprotection of the methoxy group. In the reduction of N-hydroxyamides, the alcoholic solvent was found to function as a hydrogen donor.     

Experimental and theoretical study of the structure of N,N-dimethyl-4-nitroaniline derivatives as model compounds for non-linear optical organic materials

Molecular and crystal structure of a series of derivatives of N,N-dimethyl-4-nitroaniline has been studied by both X-ray diffraction method and high-level ab initio calculations. According to these data, the dimethylamino groups were found to have a trigonal-pyramidal configuration and are considerably turned with respect to the ring plane in all molecules having a substituent in the ortho-position; on the contrary, this group is planar in the meta-substituted molecules. Topological analysis of the electron density function for all molecules studied within the framework of Bader's ‘atoms in molecules’ (AIM) theory revealed that introduction of a substituent into the ortho- or meta-position of the ring results in increasing of the contribution of the resonance forms different from the quinoid one. Contribution of the latter form is predominant for the structure of N,N-dimethyl-4-nitroaniline (1). Topological analysis of the electron density distribution was used to explain a decreasing of the molecular hyperpolarisabilites of the ortho- and meta-substituted compounds as compared with those for 1.     

Synthesis and hybridization affinity of oligodeoxyribonucleotides incorporating 4-N-(N-arylcarbamoyl)deoxycytidine derivatives

Modified oligodeoxynucleotides incorporating 4-N-(N-arylcarbamoyl)-dC derivatives 1a-c were synthesized. The ¹H NMR spectra of 1a-c suggest that the carbamoyl group forms an intramolecular hydrogen bond with the cytosine ring nitrogen atom so that formation of a Watson-Crick base pair with the complementary guanine base is inhibited. The hybridization properties of oligodeoxynucleotides containing 1a-c were investigated by use of T_m analysis. The hybridization properties of 4-N-(N-phenylcarbamoyl)-dC (1a) were similar to those of 4-N-(N-alkylcarbamoyl)-dC derivatives reported previously. In sharp contrast to 1a, it turned out that 4-N-(N-napht-1-yl) and (N-quionol-5-yl)-dC (1b,c) have a unique property as a universal base.     

A novel and facile synthesis of mesoionic 1,2,4-triazolium-3-thiolate derivatives

Mesoionic 1,2,4-triazolium-3-thiolate derivatives were synthesized from the reaction of N-substituted-2-phenylhydrazinocarbothioamides with tetracyanoethylene (TCNE) to give tricyanovinyl intermediates, followed by heterocyclization to afford 5-(1-amino-2,2-dicyano-vinyl)-4-substituted-1-phenyl-4H-1,2,4-triazol-1-ium-3-thiolates in 67–76% yields. The structures of the products have been confirmed unambiguously by single crystal X-ray structure analyses. A rationale for the formation of the products is presented.     

Isoquinolin-1(2H)-ones and 1,6-naphthyridin-5(6H)-ones by an N-acylation-SNAr sequence

A new synthesis of 2,3-dialkyl-4-carbomethoxyisoquinolin-1(2H)-ones and 6,7-dialkyl-8-carbomethoxy-1,6-naphthyridin-5(6H)-ones is reported. The process involves treatment of a β-enaminoester with 2-fluoro-5-nitrobenzoyl chloride, 2-fluorobenzoyl chloride or 2-chloronicotinoyl chloride followed by heating in the presence of base. The conversion, which proceeds by an N-acylation-S_NAr reaction sequence, affords 50–86% yields when R¹ is n-alkyl but ≤30% yields when R¹ is α-branched.     

Synthesis of the new ring system pyrrolizino[2,3-b]indol-4(5H)-one

Derivatives of the new ring system pyrrolizino[2,3-b]indol-4(5H)-one were prepared in four steps starting from substituted benzonitriles bearing a functionalized amino group in the adjacent position. The unsubstituted- and the dimethoxy-pyrrolizinoindolones 5a and 5b exhibited modest activity against the HL-60(TB) human leukemia cell line, whereas the N-methylated dimethoxy-pyrrolizinoindolone 6b showed to be selective against MOLT-4 leukemia, A549/ATCC, HOP-92, and NCI-H460 non-small cell lung cancer, and CAKI-1 renal cancer cell lines.     

Spin trapping of alkoxyl radicals generated from 5-methyl and 5-aryl-3-alkoxy-4-methylthiazole-2(3H)-thiones in photochemically induced and microwave-initiated reactions

Methoxyl and isopropoxyl radicals were generated from N-alkoxy-4,5-dimethylthiazole-2(3H)-thiones (λ_max∼320 nm) and 5-aryl derivatives (aryl=p-XC₆H₄; X=MeO, H, AcNH, Cl) (λ_max∼335 nm) in photochemically and microwave-induced reactions. Alkoxyl radicals were trapped with dimethylpyrrolidine N-oxide and characterized as spin adducts via EPR. Cumyloxyl radicals were liberated in a similar manner from N-cumyloxy-5-(4-methoxyphenyl)-4-methylthiazole-2(3H)-thione. A noteworthy bathochromic shift was found for the lowest energy transition of N-(hydroxy)indeno[2,1-d]thiazole-2(3H)-thione (λ_max=376 nm), if compared to the UV-vis absorption of N-hydroxy-4-methyl-5-phenylthiazole-2(3H)-thione (λ_max=338 nm). Syntheses of alkoxyl radical precursors and procedures for conducting N,O-homolysis are described in a full account.     

‘Push-Pull’ and spirobicyclic structures by reacting N-methyl cyclic ketene-N,X (X=S, O)-acetals with isocyanates and isothiocyanates

Nucleophilic N-methyl cyclic ketene-N,X (X=S, O)-acetals can react with electrophilic aryl isocyanates and aryl isothiocyanates to form ‘push-pull’ mono-adducts, di-adducts and spirobicyclic 6/5 ring compounds.     

A simple and efficient biphasic method for the preparation of 4-nitrophenyl N-methyl- and N-alkylcarbamates

Treatment of 4-nitrophenyl chloroformate with alkylammonium hydrochloride salts and solid anhydrous Na₂CO₃ in either CH₂Cl₂ or CH₃CN gave 4-nitrophenyl N-methylcarbamate and other N-alkylcarbamate analogues in excellent yields. Of particular interest is the observation that 4-nitrophenyl N-methylcarbamate, a safer alternative to the highly toxic methyl isocyanate, is obtained in quantitative yield (?95% pure as determined by ¹H NMR) after simple filtration and solvent evaporation.     

Facile access to (Z)-alkene-containing diketopiperazine mimetics utilizing organocopper-mediated anti-SN2′ reactions

Regio- and stereoselective anti-S_N2′ alkylation of γ-phosphoryloxy-α,β-unsaturated-δ-lactams with organocopper reagents allowing the preparation of N-alkylated-α,δ-substituted-β,γ-unsaturated-δ-lactams as highly functionalized diketopiperazine mimetics is presented.     

Diastereoselective reduction of enantiopure N-p-toluenesulfinyl ketimines derived from pyridyl ketones

DIBAL reduction of enantiopure N-p-toluenesulfinyl ketimines derived from 2-pyridyl ketones bearing an additional substituent on the 6-position of the pyridine ring afforded the related N-p-toluenesulfinyl amines with high yields and diastereoselectivities. The results of a number experiments exploring the conversion of a optically active 1-substituted N-toluenesulfinyl 1-(6-bromopyridin-2-yl)methylamine in a number of more complex pyridine derivatives with maintenance of the toluenesulfinyl group N-protecting group is also reported.     

A straightforward synthesis of pyrimido[4,5-b]quinoline derivatives assisted by microwave irradiation

Several pyrimido[4,5-b]quinolines, flavin analogues, have been prepared by assisted microwave intramolecular cyclization of N⁴-substituted-2,4-diamino-6-chloropyrimidine-5-carbaldehydes. The reaction takes place with hydrolysis of amino-group and chlorine. Particularly valuable features of this method included the broader substrate scope and operational simplicity as well as increased safety for small-scale high-speed synthesis.     

The effect of spiroadamantane substitution on the conformational preferences of N-Me pyrrolidine and N-Me piperidine: a description based on dynamic NMR spectroscopy and ab initio correlated calculations

Dynamic NMR spectroscopy and ab initio correlated calculations revealed that the attachment of a spiroadamantane entity at the C-2 position of N-methylpyrrolidine or N-methylpiperidine induces a severe steric crowding around nitrogen, which changes the conformational space of the heterocycle resulting in: (a) the complete destabilization of the N-Me(eq) conformer in spiranic structures; in contrast the N-Me(eq) conformer corresponds to the global minimum in N-methylpyrrolidine or N-methylpiperidine. The spiroadamantane structure raises the energy of the equatorial conformer because of the severe van der Waals repulsion between the N-Me(eq) group and adamantane C-H bonds. (b) The interconversion between the only populated enantiomeric N-Me(ax) conformers ax→[eq]→ax′; the interconversion eq→ax between N-Me(eq) and N-Me(ax) conformers, which are both populated, is observed in N-methylpyrrolidine or N-methylpiperidine. (c) The raising of ring and nitrogen inversion barriers ax→ts by ∼4-6 kcal mol⁻¹. The dynamic NMR study provides evidence that the most important process required for the enantiomerization between the axial N-Me conformers in spiropiperidine 4 and spiropyrrolidine 5 are different, i.e., a nitrogen inversion in 5 (9.10 kcal mol⁻¹) and a ring inversion in 4 (15.2 kcal mol⁻¹). While an enantiomerization interconverts N-Me axial conformers in spiropiperidine 5 and spiropyrrolidine 4, substitution of the pyrrolidine ring of 5 with a C-Me group effects a diastereomerization between two N-Me axial conformers and reduces effectively the nitrogen inversion barrier according to the protonation experiments and the calculations. In general, all the calculations levels used, i.e., the MM3, B3LYP/6-31+G^∗∗ and MP2/6-311++G^∗∗//B3LYP/6-31+G^∗∗, predict correctly the different stability of the local minima; however only MP2/6-311++G^∗∗//B3LYP/6-31+G^∗∗ was found to be reliable for the calculation of the nitrogen inversion barriers.     

C-(β-d-Glucopyranosyl)formamidrazones,formic acid hydrazides and their transformations into 3-(β-d-glucopyranosyl)-5-substituted-1,2,4-triazoles: a synthetic and computational study

Synthesis of O-perbenzoylated 3-(β-d-glucopyranosyl)-5-substituted-1,2,4-triazoles, precursors of potent inhibitors of glycogen phosphorylase, was studied by ring closures of N¹-acyl-carboxamidrazone type intermediates. Reactions of C-(β-d-glucopyranosyl)formimidate or C-(β-d-glucopyranosyl)formamidine with acid hydrazides as well as acylation of C-(β-d-glucopyranosyl)formamidrazone by acid chlorides unexpectedly gave the corresponding 1,3,4-oxadiazoles instead of 1,2,4-triazoles. The desired triazoles were obtained in reactions of C-(β-d-glucopyranosyl)formamidine or C-(β-d-glucopyranosyl)formyl chloride with arenecarboxamidrazones, and also in acylations of N¹-tosyl-C-(β-d-glucopyranosyl)formamidrazone with acid chlorides. Theoretical calculations (B3LYP and M06-2X DFT with the standard 6-31G(d,p) basis set) on simple model compounds with methyl and phenyl substituents to understand the bifurcation of the ring closure of N¹-acyl-carboxamidrazones indicated that in general the reaction led to 1,2,4-triazoles. However, the probability of the 1,3,4-oxadiazole forming pathway was shown to be significantly higher with N¹-benzoyl-acetamidrazones, which were closest analogues of the intermediates resulting in C-glucosyl-1,3,4-oxadiazoles. It was thereby demonstrated that the substitution pattern of the N¹-acyl-carboxamidrazones played a fundamental role in determining the direction of the ring closing reaction.