The synthesis of novel acetolactate synthase inhibitors,N‐(asymmetrically disubstituted phosphoryl)‐N′‐(4,6‐dimethoxypyrimidin‐2‐yl) ureas

In view of the isosterism of the sulfonyl group(‐SO₂‐) and the phosphoryl group, two new types of compounds N‐(N‐aryl‐O‐alkyl phosphoryl)‐N′‐(4,6‐dimethoxypyrimidin‐2‐yl) ureas (2) and N‐(N‐aryl‐N‐alkylphosphoryl)‐N′‐(4,6‐dimethoxypyrimidin‐2‐yl) ureas (3) were designed and synthesized by treating N‐(arylaminochlorophosphoryl)‐N′‐(4,6‐dimethoxypy‐rimidinyl‐2‐) ureas (4) with alcohols or amines. Compounds 4 were obtained by treating dichloro‐phosphoryl isocyanate with 4,6‐dimethoxy‐2‐amino‐pyrimidine and then with aromatic amines. The enzyme tests in vitro indicated that compounds 2 and 3 were two novel classes of acetolactate synthase (ALS) inhibitors and also showed that phosphoryl groups[‐P(O)(OR)‐, R=alkyl] and [‐P(O)(NHR), R=alkyl] were likely to be good bioisosteres of the sulfonyl group (‐SO₂‐) in the sulfonylureas. © 1999 John Wiley & Sons, Inc. Heteroatom Chem 10:237–241, 1999     

Synthesis of novel N‐alkyl/aryl‐N′‐(4‐arylthiazol‐2‐yl)‐N″‐xylosyl guanidines

The reaction of 2,3,4‐tri‐O‐acetyl‐β‐D‐xylopyranosyl isothiocyanate ( 1 ) and 2‐amino‐4‐arylthiazoles ( 2 ) gave xylosylthioureas 3 . These thiourea derivatives reacted with alkyl/aryl amine in the presence of HgCl₂ to give a new series of N‐alkyl/aryl‐N″‐(4‐arylthiazol‐2‐yl)‐N″‐xylosyl guanidines 4 . Some of the synthesized guanidines were screened for their biological activity. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:688–694, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20379     

Pinacol Rearrangement of 3,4‐Dihydro‐3,4‐dihydroxyquinolin‐2(1H)‐ones: An Alternative Pathway to Viridicatin Alkaloids and Their Analogs

3‐Alkyl/aryl‐3‐hydroxyquinoline‐2,4‐diones were reduced with NaBH₄ to give cis‐3‐alkyl/aryl‐3,4‐dihydro‐3,4‐dihydroxyquinolin‐2(1H)‐ones. These compounds were subjected to pinacol rearrangement by treatment with concentrated H₂SO₄, resulting in 4‐alkyl/aryl‐3‐hydroxyquinolin‐2(1H)‐ones. When a benzyl (Bn) group was present in position 3 of the starting compound, its elimination occurred during the rearrangement, and the corresponding 3‐hydroxyquinolin‐2(1H)‐one was formed. The reaction mechanisms are discussed for all transformations. All compounds were characterized by IR, ¹H‐ and ¹³C‐NMR spectroscopy, as well as mass spectrometry.     

Study of direction of cyclization of 1‐azolil‐4‐aryl/alkyl‐thiosemicarbazides

On a four series of 1‐azolil‐4‐aryl/alkyl‐thiosemicabazides, a study on the influence of azole moiety on the capability for intramolecular cyclization and its direction was carried out. It was found that for 4‐aryl/alkyl‐thiosemicabazides with triazole, imidazole, or pyrrole moiety at N‐1 nitrogen atom possible products were only s‐triazoles, both in alkaline and acidic medium. Successful dehydrocyclization of 1‐azolil‐4‐aryl/alkyl‐thiosemicarbazides leading to a thiadiazole has been documented only for a series of 1‐(4‐methyl‐1,2,3‐thiadiazol‐5‐yl‐carbonyl)‐4‐aryl/alkyl‐thiosemicarbazides. It can be speculative that the determination of pK_a value of oxygen atom of 1‐azolil‐4‐aryl/alkyl‐thiosemicarbazide can be a very valuable parameter in the prediction of the possibility of dehydrocyclization to form thiadiazole. © 2010 Wiley Periodicals, Inc. Heteroatom Chem 21:521–532, 2010; View this article online at wileyonlinelibrary.com . DOI 10.1002/hc.20643     

Cycloaromatization Reaction of 4‐Alkoxy‐1,1,1‐trifluoroalk‐3‐en‐2‐ones with 2,6‐Diaminotoluene: The Unexpected Regioselective Synthesis of 2,4,7,8‐Tetrasubstituted Quinolines

This article reports a convenient and general method for the regioselective synthesis of a new series of 2‐alkyl(aryl)‐8‐methyl‐4‐trifluoromethyl‐7‐aminoquinolines in 86–93% yields, from cycloaromatization reactions of N‐(oxotrifluoroalkenyl)‐2,6‐diaminotoluenes in a strongly acidic medium polyphosphoric acid and absence of solvent. The enaminoketone intermediates were easily isolated from the reaction of 4‐alkoxy‐4‐alkyl(aryl)‐1,1,1‐trifluoroalk‐3‐en‐2‐ones [CF₃C(O)CH═C(R)OR¹, where R = H, Me, Ph, 4‐FPh, 4‐BrPh, 4‐MePh, and R¹ = Me, Et] with 2,6‐diaminotoluene (2,6‐DAT) in methanol under mild conditions, in 46–70% yields. Another synthetic route also allowed the regioselective synthesis of 2‐aryl(heteroaryl)‐4‐methyl‐4‐trifluoromethyl‐7‐aminoquinolines from direct cyclocondensation reactions of 4‐alkoxy‐4‐aryl(heteroaryl)‐1,1,1‐trifluoroalk‐3‐en‐2‐ones with 2,6‐diaminotoluene in methanol under mild conditions, in 21–36% yields.     

New Approaches to the Synthesis of 4‐(2‐Aminophenyl)‐1,3‐dihydro‐2H‐imidazol‐2‐ones and 3‐Ureidoindoles and a Study of Their Interconversion

3‐Alkyl/aryl‐3‐ureido‐1H,3H‐quinoline‐2,4‐diones ( 2 ) and 3a‐alkyl/aryl‐9b‐hydroxy‐3,3a,5,9b‐tetrahydro‐1H‐imidazo[4,5‐c]quinoline‐2,4‐diones ( 3 ) react in boiling concentrated HCl to give 5‐alkyl/aryl‐4‐(2‐aminophenyl)‐1,3‐dihydro‐2H‐imidazol‐2‐ones ( 6 ). The same compounds were prepared by the same procedure from 2‐alkyl/aryl‐3‐ureido‐1H‐indoles ( 4 ), which were obtained from the reaction of 3‐alkyl/aryl‐3‐aminoquinoline‐2,4(1H,3H)‐diones ( 1 ) with 1,3‐diphenylurea or by the transformation of 3a‐alkyl/aryl‐9b‐hydroxy‐3,3a,5,9b‐tetrahydro‐1H‐imidazo[4,5‐c]quinoline‐2,4‐diones ( 3 ) and 5‐alkyl/aryl‐4‐(2‐aminophenyl)‐1,3‐dihydro‐2H‐imidazol‐2‐ones ( 6 ) in boiling AcOH. The latter were converted into 1,3‐bis[2‐(2‐oxo‐2,3‐dihydro‐1H‐imidazol‐4‐yl)phenyl]ureas ( 5 ) by treatment with triphosgene. All compounds were characterized by ¹H‐ and ¹³C‐NMR and IR spectroscopy, as well as atmospheric pressure chemical‐ionisation mass spectra.     

An efficient and regiospecific preparation of trifluoromethyl substituted 4‐( 1H‐pyrazol‐1 ‐yl)‐7‐chloroquinolines

A new series of 4‐[3‐alkyl(aryl)(heteroaryl)‐5‐hydroxy‐5‐trifluoromethyl‐4,5‐dihydro‐1H‐pyrazol‐1‐yl]‐7‐chloroquinolines, where [alkyl = CH₃; aryl = C₆H₅, 4‐CH₃C₆H₄, 4‐FC₆H₄, 4‐ClC₆H₄, 4‐BrC₆H₄, 4‐CH₃OCgH₄, 4‐NO₂CgH₄, 4‐biphenyl, 1‐naphthyl; heteroaryl = 2‐furyl and 2‐thienyl] has been regiospecifi‐caly obtained from the reaction of 7‐chloro‐4‐hydrazinoquinoline with 4‐substituted‐l,1,1‐trifluoro‐4‐methoxybut‐3‐en‐2‐ones in 61 ‐ 96 % yield. Subsequently, dehydration reaction of 4,5‐dihydropyra‐zolylquinolines under acid conditions furnished a new series of 4‐(3‐substituted‐5‐trifluoromethyl‐1H‐pyra‐zol‐1‐yl)‐7‐chloroquinolines in 73 ‐ 96 % yield.     

Ruthenium Catalyzed C−H Acylmethylation of N‐Arylphthalazine‐1,4‐diones with α‐Carbonyl Sulfoxonium Ylides: Highway to Diversely Functionalized Phthalazino‐fused Cinnolines

A direct ortho‐Csp²‐H acylmethylation of 2‐aryl‐2,3‐dihydrophthalazine‐1,4‐diones with α‐carbonyl sulfoxonium ylides is achieved through a Ru^II‐catalyzed C?H bond activation process. The protocol featured high functional group tolerance on the two substrates, including aryl‐, heteroaryl‐, and alkyl‐substituted α‐carbonyl sulfoxonium ylides. Thereafter, 2‐(ortho‐acylmethylaryl)‐2,3‐dihydrophthalazine‐1,4‐diones were used as potential starting materials for the expeditious synthesis of 6‐arylphthalazino[2,3‐a]cinnoline‐8,13‐diones and 5‐acyl‐5,6‐dihydrophthalazino[2,3‐a]cinnoline‐8,13‐diones under Lawesson's reagent and BF₃?OEt₂ mediated conditions, respectively. Of these, the BF₃?OEt₂‐mediated cyclization proceeded in DMSO as a solvent and a methylene source via dual C?C and C?N bond formations.     

One‐Pot Stereoselective Synthesis of 2‐Acylaziridines and 2‐Acylpyrrolidines from N‐(Propargylic)hydroxylamines

The stereoselective direct transformation of N‐(propargylic)hydroxylamines into cis‐2‐acylaziridines was achieved by the combined use of AgBF₄ and CuCl. Copper salts were found to promote the transformation of the intermediary 4‐isoxazolines into 2‐acylaziridines and both 3‐aryl‐ and 3‐alkyl‐substituted 2‐acylaziridines could be prepared by using this method. Furthermore, subsequent 1,3‐dipolar cycloaddition of azomethine ylides that were generated in situ from the intermediary 2‐acylaziridines with maleimides was achieved in a stereoselective one‐pot procedure to afford the corresponding 2‐acylpyrrolidines, which consisted of an octahydropyrrolo[3,4‐c]pyrrole skeleton.     

15N NMR spectroscopy of 3‐substituted 5‐trichloromethyl‐1,2‐dimethyl‐1H‐pyrazolium chlorides

¹⁵N NMR data of a series of 3‐alkyl[aryl] substituted 5‐trichloromethyl‐1,2‐dimethyl‐1H‐pyrazolium chlorides (where the 3‐substituents are H, Me, Et, n‐Pr, n‐Bu, n‐Pe, n‐Hex, (CH₂)₅CO₂Et, CH₂Br, Ph and 4‐Br‐C₆H₄), are reported. The ¹⁵N substituent chemical shifts (SCS) parameters are determined and these data are compared with the ¹³C SCS values and data obtained by MO calculations. Copyright © 2002 John Wiley & Sons, Ltd.     

Catalytic Asymmetric Intramolecular Homologation of Ketones with α‐Diazoesters: Synthesis of Cyclic α‐Aryl/Alkyl β‐Ketoesters

A catalytic asymmetric intramolecular homologation of simple ketones with α‐diazoesters was firstly accomplished with a chiral N,N′‐dioxide–Sc(OTf)₃ complex. This method provides an efficient access to chiral cyclic α‐aryl/alkyl β‐ketoesters containing an all‐carbon quaternary stereocenter. Under mild conditions, a variety of aryl‐ and alkyl‐substituted ketone groups reacted with α‐diazoester groups smoothly through an intramolecular addition/rearrangement process, producing the β‐ketoesters in high yield and enantiomeric excess.     

Regiospecific synthesis of trichloromethyl substituted 4,5‐dihydro‐1h‐1‐tosylpyrazoles

The regiospecific synthesis of a new series of eight 3‐alkyl(aryl)‐5‐hydroxy‐5‐trichloromethyl‐4,5‐dihydro‐1H‐1‐tosylpyrazoles is reported. The 1‐p‐tosyl‐2‐pyrazolines were obtained from the cyclocondensation reaction of 4‐alkyl(aryl)‐4‐alkoxy‐1,1,1‐trichloroalk‐3‐en‐2‐ones, [where alkyl = H, Me and aryl = ‐C₆H₅, 4‐CH₃C₆H₄, 4‐OCH₃C₆H₄, 4‐FC₆H₄, 4‐ClC₆H₄, 4‐BrC₆H₄,] with p‐tosylhydrazine in 64 to 92 % yields, employing anhydrous toluene at reflux or diethyl ether at room temperature as the reaction condition.     

One‐Pot Synthesis of 2‐Substituted 4‐Aryl‐4,5‐dihydro‐3,1‐benzoxazepines from 2‐(2‐Aminophenyl)‐1‐arylethanols via Dehydration of the Corresponding Amides

An efficient method for the preparation of 2‐substituted 4‐aryl‐4,5‐dihydro‐3,1‐benzoxazepine derivatives under mild conditions has been developed. The reaction of 2‐(2‐aminophenyl)ethanols 1 with acid chlorides in the presence of excess Et₃N in THF at room temperature gave the corresponding N‐acylated intermediates 2 , which were dehydrated by treatment with POCl₃ to give 2‐substituted 4‐aryl‐4,5‐dihydro‐3,1‐benzoxazepines 3 in a one‐pot reaction.     

Perchloric Acid–Silica (HClO4⋅SiO2)‐Catalyzed Synthesis of 14‐Alkyl‐ or 14‐Aryl‐14H‐dibenzo[a,j]xanthenes and N‐[(2‐Hydroxynaphthalen‐1‐yl)methyl]amides

The synthesis of 14‐aryl‐ or 14‐alkyl‐14H‐dibenzo[a,j]xanthenes 3 involving the treatment of naphthalen‐2‐ol ( 1 ) with arenecarboxaldehydes or alkanals 2 in the presence of HClO₄?SiO₂ as a heterogeneous catalyst was achieved (Table 1), and this reaction was extended to the preparation of N‐[(2‐hydroxynaphthalen‐1‐yl)methyl]amides 5 by a three‐component reaction with urea ( 4a ) or an amide 4b – d as a third reactant (Table 2).     

Generation of Aryl(2‐lithiophenyl)methanone O‐Methyl Oximes and Their Use for the Synthesis of N‐(3‐Alkyl‐1‐aryl‐ or 1,3‐diaryl‐1H‐isoindol‐1‐yl)‐O‐methylhydroxylamines via the Reaction with Nitriles

An efficient two‐step procedure for the preparation of a new type of 1H‐isoindoles, i.e., N‐(3‐alkyl‐1‐aryl‐ or 1,3‐diaryl‐1H‐isoindol‐1‐yl)‐O‐methylhydroxylamines 5 , from readily available aryl(2‐bromophenyl)methanones 1 has been developed. Aryl(2‐bromophenyl)methanone O‐methyloximes 2 , derived from the corresponding ketones, were treated with BuLi in Et₂O at 0° to generate novel lithium compounds, aryl(2‐lithiophenyl)methanone O‐methyloximes 3 , which were allowed to react with nitriles to give the desired products 5 in moderate‐to‐fair yields.     

New Pyrazolyl‐Nicotinic Acids,Methyl Esters,and 1,3,4‐Oxadiazolyl‐pyrazolyl‐pyridine Tricyclic Scaffold Derivatives from 6‐Hydrazinylnicotinic Acid Hydrazide Hydrate

This paper describes an efficient approach for the synthesis of a new series of 6‐[3‐alkyl(aryl/heteroaryl)‐5‐trifluoromethyl‐1H‐pyrazol‐1‐yl]nicotinic acids (where alkyl = CH₃; aryl = Ph, 4‐OCH₃Ph, 4,4′‐BiPh; and heteroaryl = 2‐Furyl) from the hydrolysis reaction of alkyl(aryl/heteroaryl)substituted 2‐(5‐trifluoromethyl‐5‐hydroxy‐4,5‐dihydro‐1H‐pyrazol‐1‐yl)‐5‐(5‐trifluoromethyl‐5‐hydroxy‐4,5‐dihydro‐1H‐1‐carbonylpyrazol‐1‐yl)pyridines, under basic conditions and at 70–95% yields. In a subsequent step, the esterification reaction of pyrazolyl‐nicotinic acids done in thionyl chloride and methanol led to the isolation of a series of methyl 6‐[alkyl(aryl/heteroaryl)‐5‐trifluoromethyl‐1H‐pyrazol‐1‐yl] nicotinates as stable hydrochloride salts at 64–84% yields, which could be easily converted to hydrazides to give new oxadiazolyl‐pyrazolyl‐pyridine tricyclic scaffolds at good yields from a [4 + 1] cyclocondensation reaction with 1,1,1‐triethoxyethane and 1‐(triethoxymethyl)benzene as the reagent/solvent.     

Synthesis of N‐alkyl‐N′‐aryl or Alkenylpiperazines: A Copper‐Catalyzed C–N Cross‐Coupling in the Presence of Aryl and Alkenyl Triflates and DABCO

Unsymmetrical piperazines are key constituents of many pharmaceuticals. Given that the selective introduction of an aryl and alkyl motif onto the piperazine is not always straightforward, direct arylation and alkenylation of 1,4‐diaza‐bicyclo[2.2.2]octane would obviate the inefficiencies associated with the preparation of these target molecules. We have utilized alkyl halides, aryl or alkenyl triflates, and 1,4‐diaza‐bicyclo[2.2.2]octane for the synthesis of N‐alkyl‐N ′‐aryl or alkenylpiperazines. The optimum conditions are developed using CuCl, t‐BuOL i in NMP . Alkenyl triflates requires N ,N ′‐dimethylethylenediamine and higher temperature to afford the desired cross‐coupled product. Substrates bearing electron‐deficient and electron‐rich groups were successfully coupled under the optimum reaction conditions.     

Synthesis of Some New 2‐Oxo‐N‐[(10H‐phenothiazin‐10‐yl)alkyl] Derivatives of Azetidine‐1‐carboxamides

The synthesis of a new series of 4‐aryl‐3‐chloro‐2‐oxo‐N‐[3‐(10H‐phenothiazin‐10‐yl)propyl]azetidine‐1‐carboxamides, 4a – 4m , is described. Phenothiazine on reaction with Cl(CH₂)₃Br at room temperature gave 10‐(3‐chloropropyl)‐10H‐phenothiazine ( 1 ), and the latter reacted with urea to yield 1‐[3‐(10H‐phenothiazin‐10‐yl)propyl]urea ( 2 ). Further reaction of 2 with several substituted aromatic aldehydes led to N‐(arylmethylidene)‐N′‐[3‐(phenothiazin‐10‐yl)propyl]ureas 3a – 3m , which, on treatment with ClCH₂COCl in the presence of Et₃N, furnished the desired racemic trans‐2‐oxoazetidin‐1‐carboxamide derivatives 4a – 4m . The structures of all new compounds were confirmed by IR, and ¹H‐ and ¹³C‐NMR spectroscopy, FAB mass spectrometry, and chemical methods.     

A New Class of Organosuperbases,N‐Alkyl‐ and N‐Aryl‐1,3‐dialkyl‐4,5‐dimethylimidazol‐2‐ylidene Amines: Synthesis,Structure, pKBH+ Measurements,and Properties

A series of stable organosuperbases, N‐alkyl‐ and N‐aryl‐1,3‐dialkyl‐4,5‐dimethylimidazol‐2‐ylidene amines, were efficiently synthesized from N,N′‐dialkylthioureas and 3‐hydroxy‐2‐butanone and their basicities were measured in acetonitrile. The derivatives with tert‐alkyl groups on the imino nitrogen were found to be more basic than the tBu P₁ (pyrr) phosphazene base in acetonitrile. The origin of the high basicity of these compounds is discussed. In acetonitrile and in the gas phase, the basicity of the alkylimino derivatives depends on the size of the substituent at the imino group, which influences the degree of aromatization of the imidazole ring, as measured by ¹³C NMR chemical shifts or by the calculated ΔNICS(1) aromaticity parameters, as well as on solvation effects. If a wider range of imino‐substituents, including electron‐acceptor substituents, is treated in the analysis then the influence of aromatization is less predominant and the gas‐phase basicity becomes more dependent on the field‐inductive effect, polarizability, and resonance effects of the substituent.     

One‐Pot Syntheses of 2‐(2‐Sulfanyl‐4H‐3,1‐benzothiazin‐4‐yl)acetic Acid Derivatives via Reactions of 3‐(2‐Isothiocyanatophenyl)prop‐2‐enoic Acid Derivatives with Thiols or Sodium Sulfide

Two efficient methods for the preparation of 2‐(2‐sulfanyl‐4H‐3,1‐benzothiazin‐4‐yl)acetic acid derivatives 3 under mild conditions have been developed. The first method is based on the reaction of 3‐(2‐isothiocyanatophenyl)prop‐2‐enoates 1a – 1c with thiols in the presence of Et₃N in THF at room temperature, leading to the corresponding dithiocarbamate intermediates 2 , which underwent spontaneous cyclization at the same temperature by an attack of the S‐atom at the prop‐2‐enoyl moiety in a 1,4‐addition manner (Michael addition) to give 2‐(2‐sulfanyl‐4H‐3,1‐benzothiazin‐4‐yl)acetates in one pot. The second method involves treatment of 3‐(2‐isothiocyanatophenyl)prop‐2‐enoic acid derivatives 1b – 1d with Na₂S leading to the formation of 2‐(2‐sodiosulfanyl‐4H‐3,1‐benzothiazin‐4‐yl)acetic acid intermediates 5 by a similar addition/cyclization sequence, which are then allowed to react with alkyl or aryl halides to afford derivatives 3 . 2‐(2‐Thioxo‐4H‐3,1‐benzothiazin‐4‐yl)acetic acid derivatives 6 can be obtained by omitting the addition of halides.