Reactions of Thioketones Possessing a Conjugated CC Bond with Diazo Compounds

The reactions of several thioketones containing a conjugated C?C bond with diazo compounds were investigated. All of the selected compounds reacted via a 1,3‐dipolar cycloaddition with the C?S group and subsequent N₂ elimination to yield thiocarbonyl ylides as intermediates, which underwent a 1,3‐dipolar electrocyclization to give the corresponding thiirane 25 , or, by a subsequent desulfurization, to give the olefins 33a and 33b . None of the intermediate thiocarbonyl ylides reacted via 1,5‐dipolar electrocyclization. If the α,β‐unsaturated thiocarbonyl compound bears an amino group in the β‐position, the reactions with diazo compounds led to the 2,5‐dihydrothiophenes 40a – 40d . In these cases, the proposed mechanism of the reactions led once more to the thiocarbonyl ylides 36 and thiiranes 38 , respectively. The thiiranes reacted via an S_Ni′‐like mechanism to give the corresponding thiolate/ammonium zwitterion 39 , which underwent a ring closure to yield the 2,5‐dihydrothiophenes 40 . Also in these cases, no 1,5‐dipolar electrocyclization could be observed. The structures of several key products were established by X‐ray crystallography.     

Selenophen‐2‐yl‐Substituted Thiocarbonyl Ylides – at the Borderline of Dipolar and Biradical Reactivity

The reactions of aryl (selenophen‐2‐yl) thioketones with CH₂N₂ occur with spontaneous elimination of N₂, even at low temperature (?65°), to give regioselectively sterically crowded 4,4,5,5‐tetrasubstituted 1,3‐dithiolanes and/or a novel type of twelve‐membered dithia‐diselena heterocycles as dimers of the transient thiocarbonyl S‐methanides. The ratio of these products depends on the type of substituent located at C(4) of the phenyl ring. Whereas the formation of the 1,3‐dithiolanes corresponds to a [3+2] cycloaddition of an intermediate thiocarbonyl ylide with the starting thioketone, the twelve‐memberd ring has to be formed via dimerization of the ‘thiocarbonyl ylide’ with an extended biradical structure.     

5‐Morpholino‐1,2,3,4‐thiatriazole as a Sulfur‐Transfer Reagent in the Reactions with Thioketones

The thermal decomposition of 5‐morpholino‐1,2,3,4‐thiatriazole ( 7 ), which leads to the extrusion of an active form of sulfur, in the presence of different thioketones is described. The interception of the S‐atom by the C?S bond leads to in situ formation of an elusive thiocarbonyl S‐sulfide of type 5 . This intermediate is a prone 1,3‐dipole, which undergoes effectively [2+3] cycloadditions with thioketones to yield 1,2,4‐trithiolane derivatives in a regioselective manner. Unexpectedly, 3,3‐dichloro‐2,2,4,4‐tetramethyl‐3‐thioxocyclobutanone ( 1c ) does not lead to the expected symmetrical 1,2,4‐trithiolane. This result can be explained by the reduced stability of the corresponding thiosulfine 5c . Three‐component reactions, which were carried out in the presence of equimolar amounts of two different thioketones, result in the formation of ‘mixed’ 1,2,4‐trithiolanes of type 8 .     

1,5‐Dipolar Electrocyclizations of Thiocarbonyl Ylides Bearing CN Groups: Reactions of N‐[(Dimethylamino)methylene]thiobenzamide and 2‐(Dimethylhydrazono)‐1‐phenylethane‐1‐thione with Diazo Compounds

The reactions of thiobenzamide 8 with diazo compounds proceeded via reactive thiocarbonyl ylides as intermediates, which underwent either a 1,5‐dipolar electrocyclization to give the corresponding five membered heterocycles, i.e., 4‐amino‐4,5‐dihydro‐1,3‐thiazole derivatives (i.e., 10a, 10b, 10c , cis‐ 10d , and trans‐ 10d ) or a 1,3‐dipolar electrocyclization to give the corresponding thiiranes as intermediates, which underwent a S_Ni′‐like ring opening and subsequent 5‐exo‐trig cyclization to yield the isomeric 2‐amino‐2,5‐dihydro‐1,3‐thiazole derivatives (i.e., 11a, 11b, 11c , cis‐ 11d , and trans‐ 11d ). In general, isomer 10 was formed in higher yield than isomer 11 . In the case of the reaction of 8 with diazo(phenyl)methane ( 3d ), a mixture of two pairs of diastereoisomers was formed, of which two, namely cis‐ 10d and trans‐ 10d , could be isolated as pure compounds. The isomers cis‐ 11d and trans‐ 11d remained as a mixture. In the reactions of the thioxohydrazone 9 with diazo compounds 3b and 3d , the main products were the alkenes 18 and 23 , respectively. Their formation was rationalized by a 1,3‐dipolar electrocyclization of the corresponding thiocarbonyl ylide and subsequent desulfurization of the intermediate thiiran. As minor products, 2,5‐dihydro‐1,3‐thiazol‐5‐amines 21 and 24 were obtained, which have been formed by 1,5‐dipolar electrocyclization of the thiocarbonyl ylide, followed by a 1,3‐shift of the dimethylamino group.     

1,3‐Dipolar Cycloadditions of α‐Diazo Ketones Derived from N‐Protected (S)‐Proline with Aromatic and Cycloaliphatic Thioketones

Enantiomerically pure α‐oxo diazo compounds derived from (S)‐proline were used for 1,3‐dipolar cycloaddition with aryl and hetaryl thioketones, as well as with cycloalkanethiones. Whereas the reactions with hetaryl thioketones in boiling THF yield α,β‐unsaturated ketones via a cascade of cycloaddition, 1,3‐dipolar electrocyclization, and desulfurization, the analogous reactions with thiobenzophenone and cycloalkanethiones result in the formation of 1,3‐oxathiole derivatives. In the latter case, the 1,5‐dipolar electrocyclization of the intermediate thiocarbonyl ylide is the key step of the reaction sequence. In all cases, the isolated products are optically active, i.e., the multistep processes occur with retention of the stereogenic center incorporated via the use of (S)‐proline as the precursor of the diazo compounds.     

Thermal [2+3]‐Cycloadditions of trans‐1‐Methyl‐2,3‐diphenylaziridine with CS and CC Dipolarophiles: An Unexpected Course with Dimethyl Dicyanofumarate

The thermal reaction of trans‐1‐methyl‐2,3‐diphenylaziridine (trans‐ 1a ) with aromatic and cycloaliphatic thioketones 2 in boiling toluene yielded the corresponding cis‐2,4‐diphenyl‐1,3‐thiazolidines cis‐ 4 via conrotatory ring opening of trans‐ 1a and a concerted [2+3]‐cycloaddition of the intermediate (E,E)‐configured azomethine ylide 3a (Scheme 1). The analogous reaction of cis‐ 1a with dimethyl acetylenedicarboxylate ( 5 ) gave dimethyl trans‐2,5‐dihydro‐1‐methyl‐2,5‐diphenylpyrrole‐3,4‐dicarboxylate (trans‐ 6 ) in accord with orbital‐symmetry‐controlled reactions (Scheme 2). On the other hand, the reactions of cis‐ 1a and trans‐ 1a with dimethyl dicyanofumarate ( 7a ), as well as that of cis‐ 1a and dimethyl dicyanomaleate ( 7b ), led to mixtures of the same two stereoisomeric dimethyl 3,4‐dicyano‐1‐methyl‐2,5‐diphenylpyrrolidine‐3,4‐dicarboxylates 8a and 8b (Scheme 3). This result has to be explained via a stepwise reaction mechanism, in which the intermediate zwitterions 11a and 11b equilibrate (Scheme 6). In contrast, cis‐1,2,3‐triphenylaziridine (cis‐ 1b ) and 7a gave only one stereoisomeric pyrrolidine‐3,4‐dicarboxylate 10 , with the configuration expected on the basis of orbital‐symmetry control, i.e., via concerted reaction steps (Scheme 10). The configuration of 8a and 10 , as well as that of a derivative of 8b , were established by X‐ray crystallography.     

Chemoselectivity of the Reactions of Diazomethanes with 5‐Benzylidene‐3‐phenylrhodanine

The reactions of 5‐benzylidene‐3‐phenylrhodanine ( 2 ; rhodanine=2‐thioxo‐1,3‐thiazolidin‐4‐one) with diazomethane ( 7a ) and phenyldiazomethane ( 7b ) occurred chemoselectively at the exocyclic C?C bond to give the spirocyclopropane derivatives 9 and, in the case of 7a , also the C‐methylated products 8 (Scheme 1). In contrast, diphenyldiazomethane ( 7c ) reacted exclusively with the C?S group leading to the 2‐(diphenylmethylidene)‐1,3‐thiazolidine 11 via [2+3] cycloaddition and a ‘two‐fold extrusion reaction’. Treatment of 8 or 9b with an excess of 7a in refluxing CH₂Cl₂ and in THF at room temperature in the presence of [Rh₂(OAc)₄], respectively, led to the 1,3‐thiazolidine‐2,4‐diones 15 and 20 , respectively, i.e., the products of the hydrolysis of the intermediate thiocarbonyl ylide. On the other hand, the reactions with 7b and 7c in boiling toluene yielded the corresponding 2‐methylidene derivatives 16, 21a , and 21b . Finally, the reaction of 11 with 7a occurred exclusively at the electron‐poor C?C bond, which is conjugated with the C?O group. In addition to the spirocyclopropane 23 , the C‐methylated 22 was formed as a minor product. The structures of the products (Z)‐ 8, 9a, 9b, 11 , and 23 were established by X‐ray crystallography.     

Tri‐ and Tetrasubstituted N‐Phthalimidoaziridines in 1,3‐Dipolar Cycloaddition Reactions

The thermal reactions of the 2,2,3‐trisubstituted N‐phthalimidoaziridine 1a with dimethyl acetylenedicarboxylate (DMAD), thioketones 4a – 4d , and dimethyl azodicarboxylate ( 5 ) proceed even at room temperature leading to the five‐membered cycloadducts 2a, 6 – 8 , and 12 , respectively, with retention of the spatial arrangement of the aziridine substituents, in contrast to the expectation based on the conservation of orbital symmetry in concerted reactions. The analogous reactions of the tetrasubstituted phthalimidoaziridine 1b with thioketones at 40° lead to the 1,3‐thiazolidine derivatives 10 and 11 as mixtures of diastereoisomers. These unexpected results may be explained by either the isomerization of the intermediate azomethine ylides or a non‐concerted stepwise cycloaddition reaction of these ylides with the dipolarophiles. The structures of some adducts have been determined by X‐ray crystallography.     

Concerted vs. Non‐Concerted 1,3‐Dipolar Cycloadditions of Azomethine Ylides to Electron‐Deficient Dialkyl 2,3‐Dicyanobut‐2‐enedioates

The quantum‐chemical calculations of the thermal ring opening of 1‐methyl‐2,3‐diphenyl‐ and 1,2,3‐triphenylaziridine with formation of the corresponding azomethine ylides of S‐, U‐, and W‐type as well as their cycloaddition to dimethyl acetylenedicarboxylate (DMAD) and dimethyl 2,3‐dicyanobut‐2‐enedioate, were performed at the DFT B3LYP/6‐31G(d) level of theory with the PCM solvation model. The calculations are in complete accordance with experimental results and explain the switch from the concerted to the non‐concerted pathway depending on substituents in the dipolarophile and the ylide. It was found that strong electron‐withdrawing substituents in dipolarophiles, such as in dialkyl dicyanobutenedioates, significantly reduce the barrier for the formation of zwitterionic intermediates in the reaction of azomethine ylides with such dipoles. This can render the stepwise cycloaddition competitive with the concerted one. However, the concertedness of the cycloaddition even to dipolarophiles with several electron‐withdrawing substituents is governed by a fine balance of electronic and steric effects in both ylide and dipolarophile counterparts. The hypothesis that introduction of substituents in the azomethine ylide that destabilize the positive charge in a corresponding zwitterion will favor the concerted cycloaddition even with dialkyl dicyanobutenedioates was tested theoretically and experimentally.     

Phosphonylated thiocarbonyl ylides from the reaction of aromatic thioketones with diethyl diazomethylphosphonates

The reaction of diazomethylphosphonates with aromatic thioketones at −65 °C to room temperature yields 2,5-dihydro-1,3,4-thiadiazole-2-phosphonates, which eliminates N₂ to give phosphonylated thiocarbonyl ylides as reactive intermediates. These sulfur-centered 1,3-dipoles undergo typical reactions of thiocarbonyl ylides, i.e., 1,3-dipolar cycloadditions, cyclodimerization, and electrocyclic ring closure, depending on the involved thioketone and, therefore, on the reaction conditions. In the case of the most reactive thiofluorenone, the phsophonylated thiocarbonyl methanide can be intercepted with thiobenzophenone, a phosphonodithioformate, and tetracyanoethylene. In the absence of such reactive dipolarophiles, cyclodimerization occurs to give the corresponding 1,4-dithiane.     

Reduction of Thiocarbonyl Compounds with Lithium Diisopropylamide

Treatment of 4,4‐disubstituted 2‐phenyl‐1,3‐thiazole‐5(4H)‐thiones with lithium diisopropylamide (LDA; LiNⁱPr₂) in THF at ?78° yielded the corresponding 1,3‐thiazole‐5(4H)‐thioles in moderate yields. Sequential treatment with LDA and MeI under the same conditions led to the 5‐methylsulfanyl derivatives. Similarly, reaction of some cycloalkanethiones as well as diaryl thioketones with LDA and MeI gave cycloalkyl methyl sulfides and diarylmethyl methyl sulfides, respectively. A reaction mechanism via H transfer from LDA to the thiocarbonyl C‐atom via a six‐membered transition state is proposed for this unprecedented reduction of the C?S bond.     

Regio‐ and Stereoselectivity in the Lewis Acid‐ and NaH‐Induced Reactions of Thiocamphor with (R)‐2‐Vinyloxirane

The reaction of the enolizable thioketone (1R,4R)‐thiocamphor (= (1R,4R)‐1,7,7‐trimethylbicyclo[2.2.1]heptane‐2‐thione; 1 ) with (R)‐2‐vinyloxirane ( 2 ) in the presence of a Lewis acid such as SnCl₄ or SiO₂ in anhydrous CH₂Cl₂ gave the spirocyclic 1,3‐oxathiolane 3 with the vinyl group at C(4′), as well as the isomeric enesulfanyl alcohol 4 . In the case of SnCl₄, an allylic alcohol 5 was obtained in low yield in addition to 3 and 4 (Scheme 2). Repetition of the reaction in the presence of ZnCl₂ yielded two diastereoisomeric 4‐vinyl‐1,3‐oxathiolanes 3 and 7 together with an alcohol 4 , and a ‘1 : 2 adduct’ 8 (Scheme 3). The reaction of 1 and 2 in the presence of NaH afforded regioselectively two enesulfanyl alcohols 4 and 9 , which, in CDCl₃, cyclized smoothly to give the corresponding spirocyclic 1,3‐oxathiolanes 3, 10 , and 11 , respectively (Scheme 4). In the presence of HCl, epimerization of 3 and 10 occurred to yield the corresponding epimers 7 and 11 , respectively (Scheme 5). The thio‐Claisen rearrangement of 4 in boiling mesitylene led to the allylic alcohol 12 , and the analogous [3,3]‐sigmatropic rearrangement of the intermediate xanthate 13 , which was formed by treatment of the allylic alcohol 9 with CS₂ and MeI under basic conditions, occurred already at room temperature to give the dithiocarbonate 14 (Schemes 6 and 7). The presented results show that the Lewis acid‐catalyzed as well as the NaH‐induced addition of (R)‐vinyloxirane ( 2 ) to the enolizable thiocamphor ( 1 ) proceeds stereoselectively via an S_N2‐type mechanism, but with different regioselectivity.     

Thermolysis of Imidates: A New Method for the Generation of Carbonyl Ylides

Thermolysis of dimethyl 2‐[(3‐oxo‐3H‐isoindol‐1‐yl)oxy]malonate ( 8 ) promotes a [1,4]‐H shift in the imidic ? N?C? O? CH? fragment of the starting molecule, which leads to a reactive carbonyl ylide. This carbonyl ylide can be trapped by the C?N bond of imidates and imines, as well as the C?O bond of benzaldehyde. The corresponding cycloadducts 11, 14 , and 16 are formed regioselectively in good yields (60–95%) and with high stereoselectivity. In the case of 11 , the minor cycloadduct in solution undergoes an isomerization to give the more stable stereoisomer. The structures of two cycloadducts, i.e., 11a and 14a , have been established by X‐ray crystallography.     

Total Synthesis of the Alkaloid (±)‐Aspidophytine Based on Carbonyl Ylide Cycloaddition Chemistry

The Rh^II‐catalyzed cycloaddition cascade of an indolyl‐substituted α‐diazo imide was used for the total synthesis of the complex pentacyclic alkaloid (±)‐aspidophytine. Treatment of the resulting dipolar cycloadduct with BF₃?OEt₂ induces a domino fragmentation cascade. The reaction proceeds by an initial cleavage of the oxabicyclic ring and formation of a transient N‐acyl iminium ion which reacts further with the adjacent tert‐butyl ester and sets the required lactone ring present in aspidophytine. A three‐step sequence was then used to remove both the ester and OH groups. Subsequent functional group manipulations allowed for the high‐yielding conversion to (±)‐aspidophytine.     

One‐Pot Synthesis of Dispiro[oxindole‐3,3′‐pyrrolidines] by Three‐Component [3+2] Cycloadditions of in situ‐Generated Azomethine Ylides with 3‐Benzylidene‐2,3‐dihydro‐1H‐indol‐2‐ones

An efficient one‐pot, three‐component synthesis of novel dispiro[oxindole‐3,3′‐pyrrolidines] by 1,3‐dipolar cycloaddition of azomethine ylides, in situ generated by reaction of 1,2‐diones with sarcosine and subsequent decarboxylation, with a series of (E)‐3‐benzylidene‐2,3‐dihydro‐1H‐indol‐2‐ones is reported. Molecular complexity is generated in only one synthetic step. All reactions proceed with excellent regioselectivity and in good‐to‐excellent yields. The workup is easy, the reaction times are short, and no catalyst is required.     

氟烷基叠氮化合物和缺电子烯烃反应的研究

本论文研究了氟烷基叠氮化合物和缺电子烯烃的1,3-偶极反应, 合成了一系列含氟烷基三唑啉和氟烷基吡唑啉类化合物, 并提出了一个通过开环和以重氮化合物为中间体的反应机理.     

A Facile Synthesis of 2‐Imino‐4‐methylene‐1,3‐dithiolanes

A one‐pot synthesis of 2‐imino‐4‐methylidene‐1,3‐dithiolanes via a three‐component reaction of propargyl bromide (=3‐bromoprop‐1‐yne), primary amines, and carbon disulfide (CS₂) is described.     

Synthesis and characterization of second‐generation S,S‐dialkyl‐S‐(dimethylhydroxyphenyl)sulfonium salt photoinitiators

A new, simplified method has been developed for the synthesis of S,S‐dialkyl‐S‐(dimethylhydroxyphenyl)sulfonium salt cationic photoinitiators. This novel method has successfully been used for the preparation of S,S‐dialkyl‐S‐(3,5‐dimethyl‐4‐hydroxyphenyl)sulfonium and S,S‐dialkyl‐S‐(3,5‐dimethyl‐2‐hydroxyphenyl)sulfonium salts showing a wide variation in the length and structure of the alkyl chains on the positively charged sulfur atom. These photoinitiators can also be prepared with a wide variety of different anions. The manipulation of the lengths of the alkyl chains permits the design of compatible photoinitiators for highly nonpolar monomers and oligomers such as epoxy‐functional silicones, epoxidized polybutadiene, and epoxidized vegetable oils. This article describes the synthesis and characterization of these photoinitiators. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 2556–2569, 2003     

Reactions of Acid Chlorides/Ketenes with 2‐Substituted 4,5‐Dihydro‐4,4‐dimethyl‐1,3‐thiazoles: Formation of Penam Derivatives

Addition reactions of acid chlorides with various 2‐substituted 4,5‐dihydro‐4,4‐dimethyl‐5‐(methylsulfanyl)‐1,3‐thiazoles under basic conditions were studied. Two kinds of products were obtained from these additions, β‐lactams and non‐β‐lactam adducts. When the reaction was carried out with 4,5‐dihydro‐1,3‐thiazoles with a Ph substituent at C(2), the reaction proceeded via formal [2+2] cycloaddition and led to the correspoding β‐lactam. On the other hand, acid chlorides and 4,5‐dihydro‐1,3‐thiazoles bearing an α‐H‐atom at the C(2)‐substituent underwent C(α)‐ and/or N‐addition reactions and furnished non‐β‐lactam adducts, i.e., C(α)‐ and/or N‐acylated 1,3‐thiazolidines. The attempted transformations of sulfonyl esters of exo‐6‐hydroxy penams to endo‐6‐azido penams failed, although they were successful with mono‐β‐lactams under the same conditions.