Tandem pseudopericyclic reactions: [1,5]-X sigmatropic shift/6pi-electrocyclic ring closure converting N-(2-X-carbonyl)phenyl ketenimines into 2-X-quinolin-4(3H)-ones

N-(2-X-Carbonyl)phenyl ketenimines undergo, under mild thermal conditions, [1,5]-migration of the X group from the carbonyl carbon to the electron-deficient central carbon atom of the ketenimine fragment, followed by a 6pi-electrocyclic ring closure of the resulting ketene to provide 2-X-substituted quinolin-4(3H)-ones in a sequential one-pot manner. The X groups tested are electron-donor groups, such as alkylthio, arylthio, arylseleno, aryloxy, and amino. When involving alkylthio, arylthio, and arylseleno groups, the complete transformation takes place in refluxing toluene, whereas for aryloxy and amino groups the starting ketenimines must be heated at 230 degrees C in a sealed tube in the absence of solvent. The mechanism for the conversion of these ketenimines into quinolin-4(3H)-ones has been studied by ab initio and DFT calculations, using as model compounds N-(2-X-carbonyl)vinyl ketenimines bearing different X groups (X = F, Cl, OH, SH, NH(2), and PH(2)) converting into 4(3H)-pyridones. This computational study afforded two general reaction pathways for the first step of the sequence, the [1,5]-X shift, depending on the nature of X. When X is F, Cl, OH, or SH, the migration occurs in a concerted mode, whereas when X is NH(2) or PH(2), it involves a two-step sequence. The order of migratory aptitudes of the X substituents at the acyl group is predicted to be PH(2) > Cl > SH > NH(2) > F> OH. The second step of the full transformation, the 6pi-electrocyclic ring closure, is calculated to be concerted and with low energy barriers in all the cases. We have included in the calculations an alternative mode of cyclization of the N-(2-X-carbonyl)vinyl ketenimines, the 6pi-electrocyclic ring closure leading to 1,3-oxazines that involves its 1-oxo-5-aza-1,3,5-hexatrienic system. Additionally, the pseudopericyclic topology of the transition states for some of the [1,5]-X migrations (X = F, Cl, OH, SH), for the 6pi-electrocyclization of the ketene intermediates to the 4(3H)-pyridones, and for the 6pi-electrocyclization of the starting ketenimines into 1,3-oxazines could be established on the basis of their geometries, natural bond orbital analyses, and magnetic properties. The calculations predict that the 4(3H)-pyridones are the thermodynamically controlled products and that the 1,3-oxazines should be the kinetically controlled ones.     

From thiourea to bicyclic structures: an original route to imidazo[2,1-b]thiazoles, 5H-thiazolo[3,2-a]pyrimidines, 7H-imidazo[2,1-b][1,3]thiazines,and 2H,6H-pyrimido[2,1-b][1,3]thiazines

We report an example of an efficient regioselective synthesis of biheterocyclic compounds using thiourea as starting material. In fact, N,N'-bis(dimethylaminomethylene)thiourea (1), easily prepared by double condensation of N,N-dimethylformamide dimethyl acetal with thiourea, can be reacted with haloketones or acrylic dienophiles to give thiazolic (2) and thiazinic (3) diazadienes, respectively, themselves undergoing cyclization reactions to yield imidazo[2,1-b]thiazoles, 5H-thiazolo[3,2-a]pyrimidines, 7H-imidazo[2,1-b][1,3]thiazines, and 2H,6H-pyrimido[2,1-b][1,3]thiazines without any regioisomeric ambiguity. This straightforward route represents an original and unambiguously regioselective pathway to these valuable heterocycles.     

Quantum mechanical inspection of the Diels-Alder approach to biaryls mechanism

The Diels-Alder reaction of substituted cyclohexadienes with substituted phenylacetylenes offers an attractive alternative for the synthesis of biaryl compounds via a two-step cycloaddition/cycloelimination pathway. Quantum mechanical calculations using B3LYP and M06-2X density functional methods for the reaction of 2-chloro-6-nitrophenylacetylene with 1-carbomethoxy-cyclohexadiene show the reaction proceeds by a stepwise diradical [4+2] cycloaddition followed by concerted [2+4] cycloelimination of ethylene. [2+2] cycloadducts are also the result of stepwise addition. [2+2] cycloadducts isomerize to [4+2] cycloadducts via diradical pathways, which involve the same diradical intermediate in cycloaddition. There is also a competitive conrotatory ring opening followed by trans-cis double bond isomerization pathway of the [4.2.0] bicycle (the [2+2] cycloadduct) to give the cis,cis,cis-1,3,5-cyclooctatriene.     

Exploring two-state reaction pathways in the photodimerization of cyclohexadiene.

The ground- (S0) and lowest triplet-state (T1) pathways associated with dimerization of cyclohexadiene to give [2+2] and [4+2] cycloadducts have been theoretically studied at the UBLYP and UB3LYP levels of theory with the 6-31G* basis set. The DFT energies were validated by CCSD(T) single-point energy calculations. These cycloaddition reactions follow stepwise mechanisms with formation of bis-allylic biradical (BB) intermediates. In the S0 ground state, the interaction between two cyclohexadiene molecules with formation of BB intermediate IN(S0) has a large activation enthalpy of 32.0 kcal mol(-1). On the other hand, C-C bond-formation in the lowest triplet state (T1) leading to BB intermediate IN(T1) has a low activation enthalpy of 5.0 kcal mol(-1), but the subsequent ring closure involves a very large activation enthalpy of 43.4 kcal mol(-1). Triplet-to-singlet intersystem crossing from IN(T1) to IN(S0) favors cyclization to give the corresponding [2+2] and [4+2] cycloadducts.     

Features of the reaction of unsymmetrical 2-mercapto-imidazoles with aromatic and aliphatic ketones

The cyclization of unsymmetrical 2-mercaptoimidazoles with aliphatic and aromatic ketones has been studied. Using ¹H NMR and X-ray analysis it has been shown that 4-R¹-1H-2-mercaptoimidazoles undergo selective oxidative cyclization to the corresponding 3-R³-2-R²-6-R¹-imidazo[2,1-b][1,3]thiazoles while 6-R⁴-1H-2-mercaptobenzo[d]imidazoles give a mixture of 6-R⁴-3-R²-2-R³-benzo[4,5]imidazo[2,1-b][1,3]thiazole and 7-R⁴-3-R²-2-R₃-benzo[4,5]imidazo[2,1-b][1,3]thiazole in the ratio 1: 1. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 115–122, January, 2007.     

Unprecedented intramolecular [3 + 2] cycloadditions of azido-ketenimines and azido-carbodiimides. Synthesis of indolo[1,2-a]quinazolines and tetrazolo[5,1-b]quinazolines

N-(2-azidomethyl)phenyl ketenimines and N-(2-azidomethyl)phenyl-N'-alkyl(aryl) carbodiimides undergo, under mild thermal conditions, intramolecular [3 + 2] cycloaddition reactions between the azido group and either the C=C or the distal C=N double bonds of the ketenimine and carbodiimide functions respectively. The reaction products are indolo[1,2-a]quinazolines and/or indolo[2,1-b]quinazolines in the case of azido-ketenimines, and tetrazolo[5,1-b]quinazolines in the case of azido-carbodiimides. The formation of the two classes of indoloquinazolines implies the ulterior dinitrogen extrusion from the non-isolated, putative [3 + 2] cycloadducts between the azide and ketenimine functions, whereas in the case of azido-carbodiimides the initial cycloadducts, tetrazoloquinazolines, were cleanly isolated and further converted into 2-aminoquinazolines by thermally induced dinitrogen extrusion.     

Tetracyclic Systems: An Efficient and Rapid Synthesis of New Pyrrolothieno[1,3]Thiazocines

The Pyrrolo[2,1-b]thieno[2,3-e][1,3]thiazocinediones (6a,b) resulting from a few known eight membered ring cyclization were successfully described via the Friedel-Crafts cyclodehydration of the appropriates 1-(thien-2′-ylmethyl)-2-pyrrolidinone-5-thioglycolic acids (5a,b).     

Novel [4 + 2]-cycloaddition of 1-phenyl-1-benzothiophenium salts with dienes. Experimental evidence for a lack of aromaticity in the thiophene ring

The [4 + 2]-cycloaddition reaction of 1-phenyl-1-benzothiophenium triflates has been conducted for the first time. [4 + 2]-Cycloaddition with dienes such as cyclopentadiene and 1,3-diphenylisobenzofuran occurs successfully to give cycloadducts. This result indicates that the C=C bond of the thiophene ring acts as a 2pi electron component in the cycloaddition reaction. Cycloadducts were formed in high yields with high stereoselectivity. However, the cycloaddition with other less reactive dienes such as 2,3-dimethyl-1,3-butadiene did not take place. The structure and stereochemistry of cycloadduct 2a were analyzed by NMR techniques. Furthermore, reaction of the cycloadducts with sodium methoxide in methanol gave the ring-opened products in high yields.     

On the [2+2] cycloaddition of 2-aminothiazoles and dimethyl acetylenedicarboxylate. Experimental and computational evidence of a thermal disrotatory ring opening of fused cyclobutenes

The reaction of 2-(phenylamino)- and 2-(dimethylamino)thiazoles with dimethyl acetylenedicarboxylate led unexpectedly to dimethyl 6-(phenylamino)- and 6-(dimethylamino)-3,4-pyridinedicarboxylates. Those compounds reasonably result from a sequence of reactions initiated by a [2 + 2] cycloaddition of the alkyne to the formal C=C of the thiazole ring. These pyridines were obtained in nearly all the cases assayed as the exclusive reaction products under rather mild conditions and in fair to good yields. In contrast, the regioisomeric 2-amino-3,4-pyridinedicarboxylates, which would result from a [4 + 2] cycloaddition followed by sulfur extrusion, were only obtained in one particular case. The two reaction paths leading alternatively to both regioisomers were investigated computationally. The respective [2 + 2] and [4 + 2] cycloadducts were found to be formed stepwise from a common dipolar intermediate. Notably, the step following the [2 + 2] cycloaddition (i.e., the ring opening of the fused cyclobutene intermediate to give an all-cis 1,3-thiazepine) was found to take place in a disrotatory mode. Although geometric constraints and electronic factors may reduce the energy for the disrotation, the implication of the fused five-membered ring in the electronic reorganization leading to the 1,3-thiazepine is determinant. In this sense, this step could be regarded also as a thermally allowed six-electron five-center disrotatory electrocyclic ring opening. The proposed mechanism was experimentally supported by the isolation of several intermediates and other experimental facts.     

1,3‐cycloadditions of pyridinium N‐arylimides

The title compounds (5a: Ar = C₆H5, 5b: Ar = 2‐pyridyl) are 1,3‐dipoles of the azomethine imine type; their 1,3‐cycloadditions are accompanied by the loss of the pyridinium resonance energy. As a consequence, the interaction with electron‐deficient ethylenes gives rise to cycloaddition/cycloreversion equilibria, in contrast to the cycloadditions of isoquinolinium N‐arylimides; enamines do not react with 5. The cycloadducts of 5a to dimethyl maleate, fumaronitrile, and acrylonitrile are N^β‐dienyl‐phenylhydrazines, which undergo a hydrazo rearrangement affording aminals derived from a tetracyclic system. Like enamines, the dienehydrazine system of the cycloadducts reacts with dimethyl acetylenedicarboxylate by [2 + 2] cycloaddition and electrocyclic ring opening furnishing tetrahydropyrrolo[3,2‐a]azocine derivatives. © 1999 John Wiley & Sons, Inc. Heteroatom Chem 10: 79–88, 1999     

Synthesis of Some Prospective Bioactive Azeto[2,1-d][1,5]benzothiazepinones

Ten azeto[2,1-d][1,5]benzothiazepinone derivatives 6a–j were synthesized starting from 4-acetyl-2-phenyl-1,2,3-triazole 1. First, condensation of 1 with various aldehydes 2a–e afforded α,β-unsaturated carbonyl compounds 3a–e, which subsequently underwent cyclization with o-aminothiophenol to yield the corresponding 2,4-disubstituted-1,5-benzothiazepines 4a–e. Treatment of 4a–e with chloroacetyl chloride 5a or phenoxyacetyl chloride 5b by [2+2] cycloaddition reaction gave the title compounds 6a–j. The assignment of the structures of 6a–j was made by ¹H NMR, MS, and elemental analyses.     

Synthesis, molecular structure and reactivity of 5-methylidene-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolines

Synthesis of novel 5-methylidene-1,2,3,5-tetrahydro[2,1-b]-quinazoline derivatives 2-4 with potential biological activities mediated by alpha-adrenergic and/or imidazoline receptors was performed by reacting 2-chloro-4,5-dihydroimidazole (1) with the corresponding 2-aminoacetophenones. Compound 2, which incorporates an enamine moiety, underwent a 1,3-dipolar cycloaddition reaction with the appropriate nitrones 5-9 to give 1,2,3,5-tetrahydro-imidazo[2,1-b]quinazolin-5,5'-spiro-2',3'-diphenylisoxazol-idines 10-14. Reactions of the title compounds 2 and 4 with dimethyl acetylene-dicarboxylate (DMAD) afforded dimethyl 2-(2,3-dihydroimidazo[2,1-b]quinazolin-5(1H)-ylidenemethyl)but-2-enedioates 15, 16. Imidazo[2,1-b]quinazoline 2 was further treated with acetyl chloride, benzoyl chloride and mesyl chloride to give the 1-substituted derivatives 17, 18 and 19, respectively. The structures of all new compounds obtained were confirmed by elemental analysis and spectral data (IR, (1)H- and (13)C-NMR) as well asX-ray crystallographic analysis of 3 and 18.     

Synthesis and study of 5a,6-dihydro-12H-indolo[2,1-b][1,3]-benzoxazines

Reaction of 2,3,3-trimethyl-, 2,3,3,5- and 2,3,3,7-tetramethyl-3H-indoles with 4-nitro-2-chloromethylphenol has given the 5a,6-dihydro-12H-indolo-[2,1-b][1,3]-benzoxazines, which have been examined for ring-chain interconversion by NMR spectroscopy. Treatment of 5a,6-dihydro-12H-indolo[2,1-b][1,3]benzoxazines with either perchloric acid or potassium hydroxide results in opening of the dihydrooxazine ring with the formation of indole derivatives.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 672–676, May, 1989.     

Total syntheses of (+/-)-beta-erythroidine and (+/-)-8-oxo-beta-erythroidine by an intramolecular Diels-Alder cycloaddition of a 2-amidoacrolein

[reaction: see text] The total syntheses of (+/-)-beta-erythroidine and (+/-)-8-oxo-beta-erythroidine are described. The tetracyclic ring system of the natural products was quickly assembled by a strategy that features a retrocycloaddition/cycloaddition reaction of an amidodioxin, an intramolecular Heck reaction, and a 6pi-electrocyclic ring closure of a dienoic acid.     

A cornucopia of cycloadducts: theoretical predictions of the mechanisms and products of the reactions of cyclopentadiene with cycloheptatriene

The potential cycloaddition reactions between cyclopentadiene and cycloheptatriene have been explored theoretically. B3LYP/6-31G was used to locate the transition states, intermediates, and products for concerted pathways and stepwise pathways passing through diradical intermediates. Interconversions of various cycloadducts through sigmatropic shifts were also explored. CASPT2/6-31G single point calculations were employed to obtain independent activation energy estimates. MM3 was also used to compute reaction energetics. Several bispericyclic cycloadditions in which two cycloadducts are linked by a sigmatropic shift have been identified. B3LYP predicts, in line with frontier molecular orbital predictions, that the [6+4] cycloaddition is the favored concerted pathway, but an alternative [4+2] pathway is very close in energy. By contrast, CASPT2 predicts that a [4+2] cycloaddition is the preferred pathway. B3LYP predicts that the lowest energy path to many of the cycloadducts will involve diradical intermediates, whereas CASPT2 predicts that each of the products of orbital symmetry allowed reactions will be reached most readily by closed shell processes-concerted cycloadditions and sigmatropic shift rearrangements of cycloadducts.     

1,3-Dioxopyrrolo[3,4-b]porphyrins: synthesis and chemistry

A novel 1,3-dioxopyrrolo[3,4-b]porphyrin (2) has been synthesized in 70% yield following a [4 + 2] cycloaddition reaction of pyrrolo[3,4-b]porphyrin 1 with (1)O(2). The new imide was used as a template to other 1,3-dioxopyrrolo[3,4-b]porphyrins and to the corresponding open counterparts. The UV/vis absorption spectra of the new compounds show significant red-shifts when compared with those of the nonsubstituted analogues. The structure of an imide derivative was confirmed by single-crystal X-ray diffraction.     

区域和立体选择性合成新型螺羟吲哚类化合物

2-芳亚甲基苯并[4,5]咪唑并[2,1-b]噻唑-3-酮与甲亚胺叶立德(经靛红与肌氨酸反应在线生成)进行l,3-偶极环加成反应, 合成了8个新的螺羟吲哚类化合物. 采用元素分析, NMR, IR, 质谱以及X射线单晶衍射等多种谱学技术对产物进行详细表征, 而产物的晶体结构表明了此类反应具有高度的立体选择性和区域选择性.     

Aryne [3 + 2] cycloaddition with N-sulfonylpyridinium imides and in situ generated N-sulfonylisoquinolinium imides: a potential route to pyrido[1,2-b]indazoles and indazolo[3,2-a]isoquinolines

The aryne [3 + 2] cycloaddition process with pyridinium imides breaks the aromaticity of the pyridine ring. By equipping the imide nitrogen with a sulfonyl group, the intermediate readily eliminates a sulfinate anion to restore the aromaticity, leading to the formation of pyrido[1,2-b]indazoles. The scope and limitation of this reaction are discussed. As an extension of this chemistry, N-tosylisoquinolinium imides, generated in situ from N'-(2-alkynylbenzylidene)-tosylhydrazides via an AgOTf-catalyzed 6-endo-dig electrophilic cyclization, readily undergo aryne [3 + 2] cycloaddition to afford indazolo[3,2-a]-isoquinolines in the same pot, offering a highly efficient route to these potential anticancer agents.     

Specific synthesis of 1,2- and 1,3-dialkylidenecycloheptanes by [3+2+2] cyclization of alkenyl Fischer carbene complexes and allenes

The 1,2- and 1,3-dialkylidenecycloheptane rings are specifically assembled from chromium alkenyl Fischer carbene complexes and allenes via [3+2+2] cyclization reactions. The former cycloadducts are obtained when the cyclization is performed in the presence of 1 equiv of [Ni(cod)2], while the [Rh(cod)Cl]2-catalyzed cyclization leads to the latter cycloadducts.     

Mannich bases and methiodides of 6-(2-furyl)imidazo[2,1-b]thiazole and its substituted derivatives

The Mannich reaction in a number of 6-(2-furyl)-substituted imidazo[2,1-b]thiazoles is realized initially in the 5 position of the imidazothiazole system, whereas it is also realized in the 5 position of the furan ring in the presence of excess reagents if the latter position is not substituted. Iodomethylation occurs at the N₇ atom of imidazothiazole. The Mannich bases of 6-(5-nitro-2-furyl)imidazo[2,1-b]thiazole are iodomethylated only at the aminomethyl group. The pK_a values of the series of compounds were measured.