Synthesis of (4Z)‐4‐(Arylmethylidene)‐5‐ethoxy‐1,3‐oxazolidine‐2‐thiones by the Reaction of Ethyl (2Z)‐3‐Aryl‐2‐isothiocyanatoprop‐2‐enoates with Organolithium Compounds

A convenient one‐pot method for the preparation of (4Z)‐4‐(arylmethylidene)‐5‐ethoxy‐1,3‐oxazolidine‐2‐thiones 2 and 3 from ethyl (2Z)‐3‐aryl‐2‐isothiocyanatoprop‐2‐enoates 1 , which can be easily prepared from ethyl 2‐azidoacetate and aromatic aldehydes, has been developed. Thus, these α‐isothiocyanato α,β‐unsaturated esters were treated with organolithium compounds, including lithium enolates of acetates, to provide 5‐substituted (4Z)‐4‐(arylmethylidene)‐5‐ethoxy‐1,3‐oxazolidine‐2‐thiones, 2 , and 2‐[(4Z)‐(4‐arylmethylidene)‐5‐ethoxy‐2‐thioxo‐1,3‐oxazolidin‐5‐yl]acetates, 3 .     

Efficient Synthesis of (3E)‐3‐[Amino(aryl)methylidene]chromane‐2,4‐diones (=(3E)‐3‐[Amino(aryl)methylene]‐2H‐1‐benzopyran‐2,4(3H)‐diones) via a Three‐Component Reaction

The Michael‐type addition of a 4‐hydroxycoumarin (=4‐hydroxy‐2H‐1‐benzopyran‐2‐one) 1 to a β‐nitrostyrene (=(2‐nitroethenyl)benzene) 2 in the presence of AcONH₄ leads to substituted (3E)‐3‐[amino(aryl)methylidene]chroman‐2,4‐diones (=(3E)‐3‐[amino(aryl)methylene]‐2H‐1‐benzopyran‐2,4(3H)‐diones) 4 (Table 1). High yields, short reaction time, and easy workup are advantages of this novel one‐pot three‐component reaction.     

Reactions of Methyl Diazoacetate with (E)‐ and (Z)‐1,2‐Bis(trifluoromethyl)ethene‐1,2‐dicarbonitrile: Novel and Unanticipated Pathways

The cycloadditions of methyl diazoacetate to 2,3‐bis(trifluoromethyl)fumaronitrile ((E)‐ BTE ) and 2,3‐bis(trifluoromethyl)maleonitrile ((Z)‐ BTE ) furnish the 4,5‐dihydro‐1H‐pyrazoles 13 . The retention of dipolarophile configuration proceeds for (E)‐ BTE with > 99.93% and for (Z)‐ BTE with > 99.8% (CDCl₃, 25°), suggesting concertedness. Base catalysis (1,4‐diazabicyclo[2.2.2]octane (DABCO), proton sponge) converts the cycloadducts, trans‐ 13 and cis‐ 13 , to a 94 : 6 equilibrium mixture (CDCl₃, r.t.); the first step is N‐deprotonation, since reaction with methyl fluorosulfonate affords the 4,5‐dihydro‐1‐methyl‐1H‐pyrazoles. Competing with the cis/trans isomerization of 13 is the formation of a bis(dehydrofluoro) dimer (two diastereoisomers), the structure of which was elucidated by IR, ¹⁹F‐NMR, and ¹³C‐NMR spectroscopy. The reaction slows when DABCO is bound by HF, but F^? as base keeps the conversion to 22 going and binds HF. The diazo group in 22 suggests a common intermediate for cis/trans isomerization of 13 and conversion to 22 : reversible ring opening of N‐deprotonated 13 provides 18 , a derivative of methyl diazoacetate with a carbanionic substituent. Mechanistic comparison with the reaction of diazomethane and dimethyl 2,3‐dicyanofumarate, a related tetra‐acceptor‐ethylene, brings to light unanticipated divergencies.     

Synthesis of 4‐Arylisocoumarins (=4‐Aryl‐1H‐2‐benzopyran‐1‐ones) through Acidic Hydrolysis of (Z)‐2‐(1‐Aryl‐2‐methoxyethenyl)benzaldehydes,Followed by Oxidation

4‐Arylisocoumarins (=4‐aryl‐1H‐2‐benzopyran‐1‐ones) 6 were prepared from 2‐(1‐aryl‐2‐methoxyethenyl)‐1‐bromobenzenes 1 . Successive treatment of these bromo styrenes with BuLi and 1‐formylpiperidine gave a mixture of (E)‐ and (Z)‐2‐(1‐aryl‐2‐methoxyethenyl)benzaldehydes 2 . Hydrolysis of (Z)‐isomers with conc. HBr, followed by pyridinium chlorochromate (PCC) oxidation of the resulting 1H‐2‐benzopyran‐1‐ol derivatives 4 (and 5 ), afforded the desired products.     

Synthesis of 3‐Aryl‐2‐methoxyinden‐1‐one (Z)‐Phenylhydrazones via Hydrobromic Acid‐Mediated Cyclization of 2‐(1‐Aryl‐2‐methoxyethenyl)benzaldehyde Phenylhydrazones

2‐(1‐Aryl‐2‐methoxyethenyl)benzaldehydes 2 , obtained by successive treatment of 1‐(1‐aryl‐2‐methoxyethenyl)‐2‐bromobenzenes 1 with BuLi and 1‐formylpiperidine, were transformed to the corresponding phenylhydrazones 3 on treatment with PhNHNH₂. When these hydrazones were allowed to react with conc. HBr, cyclization, followed by dehydrogenation with air occurred, furnished 3‐aryl‐2‐methoxyinden‐1‐one (Z)‐phenylhydrazones 4 .     

One‐Pot Synthesis of N,N‐Disubstituted (Z)‐4‐(Halomethylidene)‐4H‐3,1‐benzothiazin‐2‐amines from 2‐(2,2‐Dihaloethenyl)phenyl Isothiocyanates and Secondary Amines

We have developed a one‐pot procedure for the preparation of N,N‐disubstituted (Z)‐4‐(halomethylidene)‐4H‐3,1‐benzothiazin‐2‐amines 3 from 2‐(2,2‐dihaloethenyl)phenyl isothiocyanates 1 , easily accessible from known 2‐(2,2‐dihaloethenyl)benzenamines by a three‐step sequence, and secondary amines. Thus, the isothiocyanates 1 react with secondary amines to afford the corresponding thiourea derivatives, of which the treatment with NaH provides the desired products.     

Two‐Step Synthesis of 1,3‐Disubstituted 3,4‐Dihydro‐4‐thioxoquinazolin‐2(1H)‐ones from 1‐Bromo‐2‐fluorobenzenes

An efficient synthesis of 3‐alkyl‐3,4‐dihydro‐4‐thioxobenzoquinazolin‐2(1H)‐ones 3 has been accomplished in two steps and in satisfactory yields from 1‐bromo‐2‐fluorobenzenes 1 . Thus, the reaction of 1‐fluoro‐2‐lithiobenzenes, generated by the Br/Li exchange between 1 and BuLi, with alkyl isothiocyanates, gives N‐alkyl‐2‐fluorobenzothioamides 2 , which, in turn, react with a series of isocyanates in the presence of NaH to give the desired products 3 .     

Hydriodic Acid‐Mediated Cyclization of α‐Substituted Secondary 2‐Ethenylbenzamides: Synthesis of 2‐Substituted 2,3‐Dihydro‐3,3‐dimethyl‐1H‐isoindol‐1‐ones and 3,3‐Disubstituted (E)‐1‐(Arylimino)‐1,3‐dihydroisobenzofurans

A new and facile method for the preparation of 2‐substituted 2,3‐dihydro‐3,3‐dimethyl‐1H‐isoindol‐1‐ones 3 and 3,3‐disubstituted (E)‐1‐(arylimino)‐1,3‐dihydroisobenzofurans 6 has been developed. Thus, treatment of N‐alkyl(or aryl)‐2‐(1‐methylethen‐1‐yl)benzamides 2 with concentrated hydriodic acid (HI) in MeCN at room temperature afforded 3 . Similar treatment of N‐aryl‐2‐(1‐phenylethen‐1‐yl)benzamide 5 with concentrated HI at 0° afforded 6 .     

EPR Spectroscopy of 4, 4′‐Bis(tert‐butyl)‐2, 2′‐bipyridine‐1, 2‐dithiolatocuprates(II) in Host Lattices with Different Coordination Geometries

A series of new heteroleptic MN₂S₂ transition metal complexes with M = Cu²⁺ for EPR measurements and as diamagnetic hosts Ni²⁺, Zn²⁺, and Pd²⁺ were synthesized and characterized. The ligands are N₂ = 4, 4′‐bis(tert‐butyl)‐2, 2′‐bipyridine (tBu₂bpy) and S₂ =1, 2‐dithiooxalate, (dto), 1, 2‐dithiosquarate, (dtsq), maleonitrile‐1, 2‐dithiolate, or 1, 2‐dicyanoethene‐1, 2‐dithiolate, (mnt). The Cu^II complexes were studied by EPR in solution and as powders, diamagnetically diluted in the isostructural planar [Ni^II(tBu₂bpy)(S₂)] or[Pd^II(tBu₂bpy)(S₂)] as well as in tetrahedrally coordinated[Zn^II(tBu₂bpy)(S₂)] host structures to put steric stress on the coordination geometry of the central CuN₂S₂ unit. The spin density contributions for different geometries calculated from experimental parameters are compared with the electronic situation in the frontier orbital, namely in the semi‐occupied molecular orbital (SOMO) of the copper complex, derived from quantum chemical calculations on different levels (EHT and DFT). One of the hosts, [Ni^II(tBu₂bpy)(mnt)], is characterized by X‐ray structure analysis to prove the coordination geometry. The complex crystallizes in a square‐planar coordination mode in the monoclinic space group P2₁/a with Z = 4 and the unit cell parameters a = 10.4508(10) Å, b = 18.266(2) Å, c = 12.6566(12) Å, β = 112.095(7)°. Oxidation and reductions potentials of one of the host complexes, [Ni(tBu₂bpy)(mnt)], were obtained by cyclovoltammetric measurements.     

Regioselective Synthesis of 6‐[Chloro(difluoro)methyl]salicylates by [3+3] Cyclocondensations of 1,3‐Bis(trimethylsilyloxy)buta‐1,3‐dienes with 1‐Chloro‐1,1‐difluoro‐4‐(trimethylsilyloxy)pent‐3‐en‐2‐one

The TiCl₄‐mediated [3+3] cyclocondensation of various 1,3‐bis(trimethylsilyloxy)buta‐1,3‐dienes with 1‐chloro‐1,1‐difluoro‐4‐(trimethylsilyloxy)pent‐3‐en‐2‐one provides a regioselective access to novel 6‐(chlorodifluoromethyl)salicylates (=6‐(chlorodifluoromethyl)‐2‐hydroxybenzoates) with very good regioselectivity. For selected products, it was demonstrated that the CF₂Cl group can be transformed to CF₂H and CF₂(Allyl) by free‐radical reactions.     

Synthesis of 10‐Aryl‐ and 10‐(Arylmethyl)acridin‐9(10H)‐ones via the Reaction of (2‐Fluorophenyl)(2‐halophenyl)methanones with Benzenamines and Arylmethanamines

The reaction of 1‐fluoro‐2‐lithiobenzenes, generated from 1‐bromo‐2‐fluorobenzenes 1 and BuLi, with 2‐halobenzaldehydes and subsequent oxidation of the resulting alcohols 2 afforded (2‐fluorophenyl)(2‐halophenyl)methanones 3 , which, on treatment with benzenamines or arylmethanamines, followed by NaH, gave rise efficiently to 10‐aryl‐ or 10‐(arylmethyl)acridin‐9(10H)‐ones ( 5 or 7 ), respectively.     

A One‐Pot Biginelli Synthesis of 6‐Unsubstituted 5‐Aroylpyrimidin‐2(1H)‐ones and 6‐Acetyl‐1,2,4‐triazin‐3(2H)‐ones

The three‐component Biginelli‐like cyclocondensation reaction of enamines 1 , urea, and aldehydes in dioxane/acetic acid efficiently afforded the corresponding 6‐unsubstituted 3,4‐dihydropyrimidin‐2(1H)‐ones 2 in good yields (Scheme 1, Table). The corresponding reaction of azaenamine (=hydrazone) 7 with benzaldehyde and urea afforded 6‐acetyl‐1,2,4‐triazin‐3(2H)‐ones in good yields (Scheme 3).     

Ring Opening of 2‐(Benzylamino)‐2H‐1,4‐benzoxazin‐3(4H)‐ones and 2‐Bromo‐2H‐1,4‐benzoxazin‐3(4H)‐ones

Substituted 2‐(benzylamino)‐2H‐1,4‐benzoxazin‐3(4H)‐ones are unstable under alkaline and acidic conditions, undergoing opening of the benzoxazinone ring. 2‐Bromo‐2H‐1,4‐benzoxazin‐3(4H)‐ones show similar degradation under alkaline conditions, while replacement of Br at C(2) to give 2‐hydroxy‐2H‐1,4‐benzoxazin‐3(4H)‐ones was observed only under mild alkaline conditions. Mechanisms of ring opening and degradation to 2‐aminophenol derivatives are proposed.     

Synthesis of 1,3‐Selenazol‐2(3H)‐imines

The reaction of N,N′‐diarylselenoureas 16 with phenacyl bromide in EtOH under reflux, followed by treatment with NH₃, gave N,3‐diaryl‐4‐phenyl‐1,3‐selenazol‐2(3H)‐imines 13 in high yields (Scheme 2). A reaction mechanism via formation of the corresponding Se‐(benzoylmethyl)isoselenoureas 18 and subsequent cyclocondensation is proposed (Scheme 3). The N,N′‐diarylselenoureas 16 were conveniently prepared by the reaction of aryl isoselenocyanates 15 with 4‐substituted anilines. The structures of 13a and 13c were established by X‐ray crystallography.     

Enantiospecific Synthesis of (R)‐3‐Amino‐4‐(2,4,5‐trifluorophenyl)butanoic Acid Using (S)‐Serine as a Chiral Pool

Starting from (S)‐serine, a new method was developed for the synthesis of the β‐amino acid part of sitagliptin in ten steps and with an overall yield of 30%. The crucial step of the synthesis was the ring opening of N‐ and O‐protected (R)‐aziridin‐2‐methanol with (2,4,5‐trifluorophenyl)magnesium bromide to give N‐ and O‐protected (R)‐2‐amino‐3‐(2,4,5‐trifluorophenyl)propan‐1‐ol.     

A Simple Synthesis of 2‐{(Arylmethylidene)hydrazinylidene]‐3‐hydroxy‐4H‐furo[3,2‐c]pyran‐4(3H)‐ones

A simple synthesis of 2‐hydrazinylidene‐3‐hydroxy‐4H‐furo[3,2‐c]pyran‐4‐ones is described. A mixture of (isocyanoimino)(triphenyl)phosphorane, an aromatic aldehyde, and dehydroacetic acid (=3‐acetyl‐2‐hydroxy‐6‐methyl‐4H‐pyran‐4‐one) undergo a 1 : 1 : 1 addition reaction under mild conditions to afford the title compounds in excellent yields.     

Synthesis of 3‐(ω‐Hydroxyalkoxy)isobenzofuran‐1(3H)‐ones by Trifluoroacetic Acid‐Mediated Lactonization of tert‐Butyl 2‐(1,3‐Dioxol‐2‐yl)‐ or 2‐(1,3‐Dioxan‐2‐yl)benzoates

An efficient two‐step method for the preparation of 3‐(2‐hydroxyethoxy)‐ or 3‐(3‐hydroxypropoxy)isobenzofuran‐1(3H)‐ones 3 has been developed. Thus, the reaction of 1‐(1,3‐dioxol‐2‐yl)‐ or 1‐(1,3‐dioxan‐2‐yl)‐2‐lithiobenzenes, generated in situ by the treatment of 1‐bromo‐2‐(1,3‐dioxol‐2‐yl)‐ or 1‐bromo‐2‐(1,3‐dioxan‐2‐yl)benzenes 1 with BuLi in THF at ?78°, with (Boc)₂O afforded tert‐butyl 2‐(1,3‐dioxol‐2‐yl)‐ or 2‐(1,3‐dioxan‐2‐yl)benzoates 2 , which can subsequently undergo facile lactonization on treatment with CF₃COOH (TFA) in CH₂Cl₂ at 0° to give the desired products in reasonable yields.     

Transformations of Methyl 2‐[(E)‐2‐(Dimethylamino)‐1‐(methoxycarbonyl)ethenyl]‐1‐methyl‐1H‐indole‐3‐carboxylate

A simple and efficient synthesis of novel 2‐heteroaryl‐substituted 1H‐indole‐2‐carboxylates and γ‐carbolines, compounds 1 – 3 , from methyl 2‐(2‐methoxy‐2‐oxoethyl)‐1‐methyl‐1H‐indole‐3‐carboxylate ( 4 ) by the enaminone methodology is presented.