Synthese von 4,4-disubstituierten 1,3-Thiazol-5(4H)-thionen

Synthesis of 4,4-Disubstituted 1,3-Thiazol-5(4H)-thiones An easy synthesis for the 1,3-thiazol-5(4H)-thiones 5 , a class of heterocycles which have hitherto only been available with difficulty, is described. Reaction of 3-amino-2H-azirines 25 with thiocarboxylic acids at 0° yields monothiodiamides of type 20 (Scheme 6) which, on treatment with Lawesson reagent at 100°, undergo thiation and cyclization to give 5 in good yield.     

Umsetzung von Diazoessigsäure-ethylester mit 1,3-Thiazol-5(4H)-thionen

Reaction of Ethyl Diazoacetate with 1,3-Thiazole-5(4H)-thiones Reaction of ethyl diazoacetate ( 2a ) and 1,3-thiazole-5(4H)-thiones 1a,b in Et₂O at room temperature leads to a complex mixture of the products 5–9 (Scheme 2). Without solvent, 1a and 2a react to give 10a in addition to 5a–9a . In Et₂O in the presence of aniline, reaction of 1a,b with 2a affords the ethyl 1,3,4-thiadiazole-2-carboxylate 10a and 10b , respectively, as major products. The structures of the unexpected products 6a, 7a , and 10a have been established by X-ray crystallography. Ethyl 4H-1,3-thiazine-carboxylate 8b was transformed into ethyl 7H-thieno[2,3-e][1,3]thiazine-carboxylate 11 (Scheme 3) by treatment with aqueous NaOH or during chromatography. The structure of the latter has also been established by X-ray crystallography. In the presence of thiols and alcohols, the reaction of 1a and 2a yields mainly adducts of type 12 (Scheme 4), compounds 5a,7a , and 9a being by-products (Table 1). Reaction mechanisms for the formation of the isolated products are delineated in Schemes 4–7: the primary cycloadduct 3 of the diazo compound and the C?S bond of 1 undergoes a base-catalyzed ring opening of the 1,3-thiazole-ring to give 10 . In the absence of a base, elimination of N₂ yields the thiocarbonyl ylide A ′, which is trapped by nucleophiles to give 12 . Trapping of A ′, by H₂O yields 1,3-thiazole-5(4H)-one 9 and ethyl mercaptoacetate, which is also a trapping agent for A ′, yielding the diester 7 . The formation of products 6 and 8 can be explained again via trapping of thiocarbonyl ylide A ′, either by thiirane C (Scheme 6) or by 2a (Scheme 7). The latter adduct F yields 8 via a Demjanoff-Tiffeneau-type ring expansion of a 1,3-thiazole to give the 1,3-thiazine.     

N-(1,3-Thiazol-5(4H)-yliden)amine aus 1,3-dipolaren Cycloadditionen von Aziden mit 1,3-Thiazol-5(4H)-thionen

N-(1,3-Thiazol-5(4H)-ylidene)amines via 1,3-Dipolar Cycloaddition of Azides and 1,3-Thiazol-5(4H)-thiones Organic azides 5 and 4,4-dimethyl-2-phenyl-1,3-thiazol-5(4H)-thione ( 2 ) in toluene at 90° react to give the corresponding N-(1,3-thiazol-5(4H)-ylidene)amines (= 1,3-thiazol-5(4H)-imines) 6 in good yield (Table). A reaction mechanism for the formation of these scarcely investigated thiazole derivatives is formulated in Scheme 3: 1,3-Dipolar azide cycloaddition onto the C?S group of 2 leads to the 1:1 adduct C . Successive elimination of N₂ and S yields 6 , probably via an intermediate thiaziridine E .     

Hetero-Diels-Alder-Reaktion mit 1,3-Thiazol-5(4H)-thionen

Hetro-Diels-Alder Reaction with 1,3-Thiazol-5(4H)-thiones On heating in toluene to 180° and on treatment with BF₃·Et₂O in CH₂Cl₂ room temperature, 1,3-dienes react with the C?S group of 1,3-thiazol-5(4H)-thiones 1 in a reversible Diels-Alder reaction to give spiro[4.5]-heterocycles of type 6. A 1:1 mixture of two regioisomeric cycloadducts is formed in the thermal reaction with 2-methylbuta-1,3-diene (isoprene, 5b ). In contrast, the formation of one regioisomer is strongly preferred in the BF₃-catalyzed reaction. Frontier-orbital control as well as steric factors seem to be responsible for the observed regioselectivity. BF₃-Catalyzed, cyclic 1,3-dienes and 1 also undergo a smooth Diels-Alder reaction. Whereas cyclohexa-1,3-diene ( 5c ) reacts with 1a and 1b to give a single isomer (presumably the ‘exo’-adduct), cyclopenta-1,3-diene ( 5d ) leads to a ca. 3:1 mixture of ‘exo’-and ‘endo’-isomer.     

Carbophile Additionen von Organocupraten mit 1,3-Thiazol-5(4H)-thionen

Carbophilic Additions of Organocuprates and 1,3-Thiazole-5(4H)-thiones Organocuprates and 1,3-thiazole-5(4H)-thiones 1 react in THF at 0° via carbophilic addition onto the C? S bond to give 4,5-dihydro-1,3-thiazole-5-thiols 3 (Scheme 3). This observation is in marked contrast to the previously described reaction of organolithium compounds and 1 , which undergo a thiophilic addition onto the exocyclic S-atom. As an exception, treatment of the 1,3-thiazole-5(4H)-thione 1a with tert-butyl cuprate leads to 7a (Scheme 3).     

Regioselektive 1,3-dipolare Cycloadditionen von Thiocarbonyl-yliden mit 1,3-Thiazol-5(4H)-thionen

Regioselective 1,3-Dipolar Cycloadditions of Thiocarbonyl Ylides with 1,3-Thiazole-5(4H)-thiones The thiocarbonyl ylides 13 and 1,3-thiazol-5(4H)-thiones 1 undergo a smooth reaction to yield spirocyclic 1,3-dithiolanes 14 – 16 (Schemes 4–6). The 1,3-dipolar cycloadditions occur in a regioselective manner, but the orientation of the thiobcnzophenone-S-methylide ( 13b ) differs from that of the cycloalkane thione-S-methylides 13a and 13c . Whereas the 1,3-cycloadduct with 13b is formed in accordance with frontier-orbital considerations, the inverse orientation in the reactions with 13a and 13c most likely is the result of steric hindrance in the transition state. The thiocarbonyl ylides have been prepared in situ from the corresponding 2,5-dihydro-1,3,4-thiadiazoles 12 . The more stable aliphatic precursors 12a and 12c undergo decomposition at 50°, the unstable 12b at ?30°.     

1,3-Dipolare Cycloadditionen eines Carbonyl-ylids mit 1,3-Thiazol-5(4H)-thionen und Thioketonen

1,3-Dipolar Cycloadditions of a Carhonyl-ylide with 1,3-Thiazole-5(4H)-thiones and Thioketones Inp-xylene at 150°, 3-phenyloxirane-2,2-dicarbonitrile ( 4b ) and 2-phenyl-3-thia-1-azaspiro[4.4]non-1-ene-4-thione ( 1a ) gave the three 1:1 adduets trans- 3a , cis- 3a , and 13a in 61, 21, and 3% yield, respectively (Scheme 3). The stereoisomers trans- 3a and cis- 3a are the products of a regioselective 1,3-dipolar cycloaddition of carbonylylide 2b , generated thermally by an electrocyclic ring opening of 4b (Scheme 6), and the C?S group of 1a . Surprisingly, 13a proved not to be a regioisomeric cycloadduct of 1a and 2b , but an isomer formed via cleavage of the O? C(3) bond of the oxirane 4b . A reaction mechanism rationalizing the formation of 13a is proposed in Scheme 6. Analogous results were obtained from the reaction of 4b and 4,4-dimethyl-2-phenyl-1,3-thiazole-5 (4H)-thione ( 1b , Scheme 3). The thermolysis of 4b in p-xylene at 130° in the presence of adamantine–thione ( 10 ) led to two isomeric 1:1 adducts 15 and 16 in a ratio of ca. 2:1, however, in low yield (Scheme 4). Most likely the products are again formed viathe two competing reaction mechanisms depicted in Scheme 6. The analogous reactions of 4b with 2,2,4,4-tetramethylcyclobutane-1,3-thione ( 11 ) and 9H-xanthene-9-thione ( 12 ) yielded a single 1:1 adduct in each case (Schemes). In the former case, spirocyclic 1,3-oxathiolane 17 , the product of the 1,3-dipolar cycloaddition with 2a corresponding to 3a , was isolated in only 11 % yield. It is remarkable that no 2:1 adduct was formed even in the presence of an excess of 4b. In contrast, 4b and 12 reacted smoothly to give 18 in 81 % yield; no cycloadduct of the carbonylylide 2a could be detected. The structures of cis- 3a , 13a , 15 , and 18 , as well as the structure of 14 , which is a derivative of trans- 3a , have been established by X-ray crystallography (Figs. 1–3, Table).     

Umsetzung von Di(tert-butyl)- und Diphenyldiazomethan mit 1,3-Thiazol-5(4H)-thionen: Isolierung und Kristallstruktur des primären Cycloadduktes

Reaction of Di(tert-butyl)- and Diphenyldiazomethane and 1,3-Thiazole-5(4H)-thiones: Isolation and Crystal Structure of the Primary Cycloadduct Reactions of diazo compounds with C?S bonds proceed via the formation of thiocarbonyl ylides, which, under the reaction conditions, undergo either 1,3-dipolar cycloadditions or electrocyclic ring closer to thiiranes (Scheme 1). With the sterically hindered di(tert-butyl)diazomethane ( 2c ), 1,3-thiazole-5(4H)-thiones 1 react to give spirocyclic 2,5-dihydro-1,3,4-thiadiazoles 3 (Scheme 2). These adducts are stable in solution at ?20°, and they could be isolated in crystalline form. The structure of 3c was established by X-ray crystallography. In CDCl₃ solution at room temperature, a cycloreversion occurs, and the adducts of type 3 are in an equilibrium with 1 and 2c . In contrast, the reaction of 1 with diphenyldiazomethane ( 2d ) gave spirocyclic thiiranes 4 as the only product in high yield (Scheme 3). The crystal structure of 4b was also determined by X-ray analysis. The desulfurization of compounds 4 to 4,5-dihydro-5-(diphenylmethylidene)-1,3-thiazoles 5 was achieved by treating 4 with triphenylphosphine in boiling THF. The crystal structure of 5f is shown.     

Umsetzungen von 1,3-Thiazol-5(4H)-thionen mit Grignard- und Organolithium-Verbindungen: Carbophile und Thiophile Additionen

Reactions of 1,3-Thiazole-5(4H)-thiones with Grignard- and Organolithium Compounds: Carbophilic and Thiophilic Additions Organolithium compounds and 1,3-thiazole-5(4H)-thiones 9 reacted via thiophilic addition on the exocyclic S-atom. The intermediate anion E has been trapped by protonation to give 12 and by alkylation to yield 16 , respectively (Schemes 5 and 6). In competition with protonation of E , a fragmentation to benzonitrile and a dithioester 14 was observed (Scheme 5). In some cases, the alkylation of E led to the formation of dithioacetals 17 instead of 16 (Scheme 6). Methyl, ethyl, and isopropyl Grignard reagents and 9 in THF underwent again a thiophilic addition yielding 4,5-dihydro-1,3-thiazoles of type 12 (Scheme 3). In contrast to this result, MeMgI reacted with 9a in Et₂O via carbophilic addition to 11 . Again a carbophilic attack at C(5) of 9 was observed with allylmagnesium and 2-propynylmagnesium bromide, respectively, in Et₂O.     

Additionsreaktion von 1,3-Thiazol-5(4H)-thionen und inaminen; Bildung von Thioamiden und Thioketonen

Addition Reaction of 1,3-Thiazole-5(4H)-thiones and Ynamines; Formation of Thioamides and Thioketones Ynamines and 1,3-thiazole-5(4H)-thiones of type 1 undergo an addition reaction on heating in toluene yielding mainly α,β-unsaturated 2-(4,5-dihydro-1,3-thiazol-5-yliden)thioamides of type 7 (Scheme 2 and Table). In some cases, 1-diethylamino-1-(4,5-dihydro-1,3-thiazol-5-yliden)-2-alkanethiones 8 have been isolated as minor products. In analogy to other reactions of ynamines with C?O and C?S bonds, a [2 + 2] cycloaddition to thiete intermediates, followed by an electrocyclic ring opening is suggested as reaction mechanism.     

Reaktion von Phenyldiazomethan mit 1,3-Thiazol-5(4H)-thionen: Basenkatalysierte Ring-Öffnung des Primäradduktes

Reaction of Phenyldiazomethane with 1,3-Thiazole-5(4H)-thiones: Base-Catalyzed Ring Opening of the Primary Adduct Reaction of 1,3-thiazole-5(4H)-thiones 1 and phenyldiazomethane ( 2a ) in toluene at room temperature yields the thiiranes trans- and cis-1,4-dithia-6-azaspiro[2.4]hept-5-enes (trans- and cis- 4 ; Scheme 2). With Ph₃P in THF at 70°, these thiiranes are transformed stereospecifically into (E)- and (Z)-5-benzylidene-4,5-dihydro-1,3-thiazoles 5 , respectively. In the presence of DBU, 1 and 2a react to give 1,3,4-thiadiazole derivatives 6 or 7 via base-catalyzed ring opening of the primary cycloadduct (Scheme 3). In the case of 2-(alkylthio)-substituted 1,3-thiazole-5(4H)-thiones 1c and 1d , this ring opening proceeds by elimination of the corresponding alkylthiolate, yielding isothiocyanate 7 . The structures of (Z)- 5c and 6b have been established by X-ray crystallography.     

Bortrifluorid-katalysierte Umsetzung von 3-Amino-2H-azirinen mit Amiden: Bildung von 4,4-disubstituierten 4H-Imidazolen

Boron Trifluoride Catalyzed Reaction of 3-Amino-2H-azirines and Amides: Formation of 4,4-Disubstituted 4H-Imidazoles Reaction of trifluoroacetamide and 3-amino-2H-azirines 1 in refluxing MeCN affords 4-amino-2-(trifluoromethyl)-4H-imidazoles 5 in fair yields (Scheme 3). Less acidic amides do not react with 1 under similar conditions. Therefore, a procedure involving BF₃-catalysis has been elaborated: the aminoazirine 1 in CH₂Cl₂ at ?78° is treated with BF₃ · Et₂O and then with a solution of the sodium salt of an amide in THF, prepared by addition of sodium hexamethyldisilazane at ?78°. The 4H-imidazoles of type 5 are formed in ca. 50% yield (Scheme 4). Reaction mechanisms for this ring enlargement of 1 are proposed in Schemes 5 and 6.     

4,4-Disubstituierte Imidazol-Derivate aus der Umsetzung von 3-Amino-2H-azirinen mit Salicylamid

4,4-Disubstituted Imidazole Derivatives from the Reaction of 3-Amino-2H-azirines with Salicylamide Reaction of 3-amino-2H-azirines 1a–c with salicylamide ( 7 ) in MeCN leads to imidazoles 10 and 11 in different rates, depending on the conditions. In the case of 1a and 1b, 11a and 11b , respectively, have been obtained as the main product at 50°; in reactions at 80°, 10a and 10b are the favored products (Tables 1 and 2). 2,2-Dimethyl-3-(N-methyl-N-phenylamino)-2H-azirine ( 1c ) reacts with 7 in MeCN mainly to 2-(2-hydroxyphenyl)-5,5-dimethyl-3,5-dihydroimidazol-4-one ( 10a ); in boiling toluene, 11c is formed with low preference (Table 3). The structure of the products has been established by spectroscopic means, and in the case of 10b and 11c , by X-ray crystallography. Two different reaction mechanisms for the formation of the products are discussed (Scheme 2).     

Fluoreszenz von 4,4′-disubstituierten 1,3-Diphenyl-2pyrazolinen mit Donator-Akzeptor-Substituen

Ohne Zusammenfassung     

Über den sterischen Verlauf der Umsetzung von Enaminen aus offenkettigen Aldehyden und Ketonen mit Nitroolefinen zu 2,3-disubstituierten 4-Nitroketonen

On the Steric Course of the Reaction of Enamines Derived from Open-Chain Aldehydes and Ketones with Nitro-olefins Yielding 2,3-Disubstituted 4-Nitroketones The relative configuration of the nitro-ketone 12 obtained by the title reaction has been proved by a Baeyer-Villiger degradation and subsequent reduction to the amino-alcohol (±)-(u)- 20 , the relative configuration of which is identical with a sample prepared from 2-methyl-3-hydroxybutyrate of known configuration (Scheme 1). The stereochemical course of the title reaction is thus as predicted by our topological rule. It is assumed that the other nitro-ketones 13–18 described here are also formed by (lk)-combination of the trigonal centers of the educts (diastereoselectivity > 90%, see Formulae and Fig. 1). It is not possible to reverse this relative topicity by employing (Z)- instead of (E)-components of the starting materials, due to the reversibility of the primary step of these Michael additions (Schemes 2 and 3, and Fig. 2).     

Bildung von 5,6-Dihydro-1,3(4H)-thiazin-4-carbonsäure-estern aus 4-Allyl-1,3-thiazol-5(4H)-onen

Formation of Methyl 5,6-Dihydro-l, 3(4H)-thiazine-4-carboxyiates from 4-Allyl-l, 3-thiazol-5(4H)-ones . The reaction of N-[1-(N, N-dimethylthiocarbamoyl)-1-methyl-3-butenyl]benzamid ( 1 ) with HCl or TsOH in MeCN or toluene yields a mixture of 4-allyl-4-methyl-2-phenyl-1,3-thiazol-5(4H)-one ( 5a ) and allyl 4-methyl-2-phenyl-1,3-thiazol-2-yl sulfide ( 11 ; Scheme 3). Most probably, the corresponding 1,3-oxazol-5(4H)-thiones B are intermediates in this reaction. With HCl in MeOH, 1 is transformed into methyl 5,6-dihydro-4,6-dimethyl-2-phenyl-1,3(4H)-thiazine-4-carboxylate ( 12a ). The same product 12a is formed on treatment of the 1,3-thiazol-5(4H)-one 5a with HCl in MeOH (Scheme 4). It is shown that the latter reaction type is common for 4-allyl-substituted 1,3-thiazol-5(4H)-ones.     

Thiocarbonyl-imide aus der Umsetzung von 2,2,4,4-Tetramethyl-3-thioxocyclobutanon mit Aryl-aziden

Thiocarbonyl Imides from the Reaction of 2,2,4,4-Tetramethyl-3-thioxocylobutanone and Aryl Azides Reaction of 2,2,4,4-tetramethyl-3-thioxocylobutanone ( 6 ) and 4-methoxyphenyl, phenyl, and 4-nitrophenyl azide ( 7a–c , respectively), at 80°, leads to the 11-aryl-5,10-dithia-11-azadispiro[3.1.3.2]undecane-2,8-diones 8a–c (Scheme 3), respectively, in 67–83% yield. The structure of 8b has been established by X-ray crystallography. The formation of the products may be explained via an intermediate thiocarbonyl imide of type D (Scheme 4), generated by the 1,3-dipolar cycloaddition of the aryl azide with the C? S bond of 6 and elimination of N₂.     

Synthese von 4(5)-acyl-5(4)-alkylimidazolen aus symmetrischen 1,3-dicarbonylverbindungen

Synthesis of 4(5)-Acyl-5(4)-alkylimidazoles from Symmetrical 1,3-Diones A new synthesis of 4(5)-acyl-5(4)-alkylimidazoles 1 is described. The symmetrical 1,3-diones 5a and 5b were reacted with N₂O₄ to give the nitro compounds 7a and 7b , respectively; 5c was treated with NaNO₂ to give the nitroso compound 7c (Scheme 2). Hydrogenation of 7a , 7b and 7c over Pd/C in acetic acid/acetic formic anhydride yielded the formamides 9a , 9b and 9c , whose cyclization in formamide/formic acid afforded the 4(5)-acyl-5(4)-alkylimidazoles 1a, 1b and 1c , respectively. Oxazoles 11a and 11b were obtained from the corresponding formamides 9a and 9b with methanesulfonic acid/P₂O₅.