Reaction of lithioalkoxyallenes with isothio-cyanates: Synthesis of pyrroles and 5,6-dihydropyridines

We have found a novel synthesis route for 2,3-disubstituted pyrroles and 5,6-dihydropyridines, starting from lithiated alkoxyallenes, and organic isothiocyanates.Irkutsk Institute of Organic Chemistry, Siberian Branch, Russian Academy of Sciences, Irkutsk 664033. Preparative Organic Chemistry Group, Utrecht University, The Netherlands. Translated from Khimya Geterotsiklicheskikh Soedinenii, Vol. 32, No. 7, pp. 917–918, July, 1996. Original article submitted April 17, 1996.     

Simultaneous synthesis of 4,5-dihydro-3H-azepines and 3H-azepines, bearing alkoxy and alkylsulfanyl substituents, through metallation of 2-aza-1,3,5-trienes by t-BuOK

A new range of alkoxy- and alkylsulfanyl-substituted 4,5-dihydro-3H-azepines and 3H-azepines have simultaneously been obtained from conjugated 2-aza-1,3,5-trienes by treatment with t-BuOK under mild reaction conditions (THF/DMSO, ∼−30 °C, 30 min). One-pot synthesis of 1-aza-1,3,4-trienes from α-lithiated alkoxyallenes, isopropyl isothiocyanate and alkyl iodides, followed by the thermally induced sigmatropic [1,5]-H shift, easily leads to starting 2-aza-1,3,5-trienes. The reaction proceeds via generation and [1,7]-electrocyclization of azatrienyl anions and represents a novel simple approach to both azacycloheptadienes and azacycloheptatrienes.     

Heterocumulenes reactions with organometallic reagents: XX. Quantum-chemical study of concurrent processes of structural reorganization of N-Methyl-2-methoxy- and 2-(methylsulfanyl)buta-2,3-dienimidothioates into pyrroles and/or 2,3-dihydropyridines

Utilizing the MP2/6-31G(d,p) method a quantum-chemical investigation was performed of thermally induced formation of pyrrole and/or 2,3-dihydropyridine structures from methyl N-methyl-2-methoxy- and 2-(methylsulfanyl)buta-2,3-dienimidothioates (1-aza-1,3,4-trienes). According to calculations the pyrrole and dihydropyridine cyclization of a methoxy-substituted 1-aza-1,3,4-triene is both kinetically and thermodynamically virtually equally probable with a little prevalence of the first pathway. The main direction of the structural reorganization of methylsulfanyl-substituted 1-aza-1,3,4-triene is the kinetically controlled formation of the dihydropyridine ring.     

Reactions of Heterocumulenes with Organometallic Reagents: XXV. Quantum Chemical Study of the Substituent Effects in Alkyl [(Buta-2,3-dienimidoyl)sulfanyl]acetates on Their Cyclization to Thiophene Derivatives

Russian Journal of Organic Chemistry - Base-catalyzed low-temperature transformation of alkyl [(buta-2,3-dienimidoyl)sulfanyl]acetates [1-aza-1,3,4-trienes generated from lithiated alkoxy(or...     

Structural reorganization of (allyl-, benzyl-, and propargylsulfanyl)-substituted 2-aza-1,3,5-trienes in t-BuOK/THF/DMSO: access to rare functionalized 2-thiazolines

Treatment of (allyl-, benzyl-, and propargylsulfanyl)-substituted 2-aza-1,3,5-trienes, which are readily accessible from lithiated methoxyallene, isopropyl isothiocyanate, and allyl, benzyl, or propargyl bromide, respectively, with t-BuOK in THF/DMSO resulted in the unexpected formation of 2-thiazoline derivatives along with seven-membered azaheterocycles [in the case of (allyl- and benzylsulfanyl)-substituted 2-aza-1,3,5-trienes]. An unprecedented structural reorganization of the azatrienes into 2-thiazolines presumably occurs via α-deprotonation of the substituents at the sulfur atom followed by intramolecular [1,5]-cyclization. Deprotonation of the ketimine fragment of the same molecule followed by [1,7]-electrocyclization resulted in azepine ring formation.     

Reactions of heterocumulenes with organometallic reagents: XXIV. Quantum-chemical study of the effect of the substituent nature at sulfur atom in buta-2,3-dienimidothioates on the direction of their structural transformations

Applying B3LYP/6-31G(d,p) method we have performed a quantum-chemical study of structural transformations of propargyl and acetyl 2-methoxy-N-methylbuta-2,3-dienimidothioates (1-aza-1,3,4-trienes) into pyrroles and thiophenes. Heterocyclization mechanisms have been analyzed, thermodynamic and kinetic characteristics were obtained for the gradient channels of aza- and thiaheterocycles formation.     

Reactions of heterocumulenes with organometallic reagents: XIV. Quantum-chemical study on the mechanism of unusual thermally induced transformation of methyl <Emphasis Type="Italic">N</Emphasis>-Methylbuta-2,3-dienimidothioates into iminocyclobutenes with migration of the methylsulfanyl group

The mechanism of formation of cyclobutene ring from methyl 2-methoxy-and 2-phenyl-N-methylbuta-2,3-dienimidothioates (H₂C=C=C(R)-C(SMe)=NMe, 1-aza-1,3,4-trienes) was studied by quantum-chemical methods. The limiting stage in the [1,3]-sigmatropic migration of the methylsulfanyl group was found to follow a reaction path involving a “collapsed” state of the azatriene with linear configuration of the C=N-Me fragment, which is characterized by reduced activation barrier. The results of calculations substantiate preferential formation of pyrrole and dihydropyridine heterorings in the thermolysis of methyl 2-methoxy-N-methylbuta-2,3-dienimidothioate and of dihydropyridine and cyclobutene structures in the thermolysis of methyl N-methyl-2-phenylbuta-2,3-dienimidothioate.     

Heterocumulenes reactions with organometallic reagents: XXI. Quantum-chemical study of structural transformations of 2-methoxy- and 2-(methylsulfanyl)-N-methylbuta-2,3-dienimidothioates in the Presence of cubr: Pyrrole or methyl-3-(methylsulfanyl)but-2-enimidothioate?

Utilizing the MP2/6-31G(d,p) method a quantum-chemical investigation was performed of processes catalyzed by CuBr leading to the formation of pyrrole structures from methyl-2 methoxy- and methyl 2-(methylsulfanyl)-N-methylbuta-2,3-dienimidothioates (1-aza-1,3,4-trienes). According to calculations 1-aza-1,3,4-trienes may form highly stable adducts with CuBr owing to the coordination bonding of the copper atom with the π-system (C=C=C) and/or heteroatoms (N, S, O). The main channel of the structural reorganization of the CuBr adduct with methoxy-substituted 1-aza-1,3,4-triene is the thermodynamically controlled formation of the pyrrole ring. In the 3-(methylsulfanyl)-1-aza-1,3,4-triene CuBr initiates the cleavage of the C-S bond in the imidothioate fragment (MeS-C=N-Me) and the kinetically controlled formation of methyl N-methyl-2,3-bis(methylsulfanyl) but-2-enimidothioate.     

A stereoselective and short total synthesis of the polyhydroxylated gamma-amino acid (-)-detoxinine,based on stereoselective preparation of dihydropyrrole derivatives from lithiated alkoxyallenes

Based on our earlier results employing lithiated methoxyallene 2 as C(3) building block and imines 3 for the synthesis of dihydropyrrole derivatives 5, we have investigated chiral imines 6, 10, and 15 as electrophilic components. Combined with lithiated alkoxyallenes, these imines provide the corresponding primary adducts and finally the dihydropyrrole derivatives 8, 12, 17, 20, and 22 in good yields and with high to excellent syn selectivities. This stereochemical outcome is interpreted as a result of alpha-chelate control. Treatment with hydrochloric acid converted syn-8 and syn-12 into bicyclic compounds 9 and 13, whereas under more mildly acidic conditions adduct syn-17 was transformed into diol syn-18. The total synthesis of the uncommon gamma-amino acid (-)-detoxinine could be achieved by starting from (S)-malic acid, which was converted into imine 15 in four steps. Lithiated benzyloxyallene added to imine 15 and efficiently furnished the crucial dihydropyrrole derivative syn-22. The hydrogenolysis of this compound did not directly provide the protected triol 29 as anticipated, but a stepwise protocol made the triol available in a fairly satisfactory manner. A second crucial step of the synthesis was the selective oxidation of 29, which could be achieved by employing platinum dioxide and oxygen. The resulting bicyclic lactone 30 was smoothly transformed into enantiopure (-)-detoxinine. Thus, a fairly short synthesis of this natural product based on a lithiated alkoxyallene could be performed, demonstrating the potential of these intermediates for syntheses of interesting functionalized heterocyclic compounds.     

Reactions of heterocumulenes with organometallic reagents: XVI. Quantum-chemical study on the mechanisms of formation of homo- and heteroannular azacycloheptadienes in reactions of 2-aza-1,3,5-trienes with potassium <Emphasis Type="Italic">tert</Emphasis>-butoxide

Mechanisms of intramolecular transformations of carbanions generated from 2-aza-1,3,5-trienes by the action of potassium tert-butoxide, which could lead to homo- or heteroannular azacycloheptadienes, were studied by quantum-chemical methods in terms of the density functional theory. The corresponding gradient channels were localized for model 1-methylsulfanyl-1-(cyclopentylideneamino)- and 1-methylsulfanyl-1-(cyclohexylideneamino)buta-1,3-dien-2-ols. Analysis of the kinetic and thermodynamic parameters showed that carbanion generated from N-cyclopentylidenebuta-1,3-dien-1-amine undergoes rearrangement mainly into homoannular azacycloheptadiene and that analogous N-cyclohexylidene derivative gives rise to heteroannular isomer. The results of calculations were consistent with the experimental data.     

Cycloaddition reactions of 1-lithio-1,3-dienes with aromatic nitriles affording multiply substituted pyridines, pyrroles, and linear butadienylimines

Fully or partially substituted 1-iodo- or 1-bromo-1,3-dienes could be readily lithiated using t-BuLi or n-BuLi to afford their corresponding 1-lithio-1,3-diene derivatives in quantitative yields. When these in situ generated lithium reagents were treated with organonitriles, depending on the substitution patterns of the butadienyl skeletons, substituted pyridines, pyrroles, and/or linear butadienyl imines were formed in good to excellent yields via N-lithioketimine intermediates. In the cases of 1,2,3,4-tetrasubstituted and 2,3-disubstituted 1-lithio-1,3-dienes, pyridine derivatives or linear butadienyl imines were generally formed depending on the reaction temperatures. When 1,2,3,4-tetrasubstituted 4-halo-1-lithio-1,3-dienes and 1,2-disubstituted 1-lithio-1,3-dienes were treated with organonitriles, pyrrole derivatives or linear butadienyl imines were obtained. Competition between 5-exo and 6-endo cyclization was found to be responsible for the formation of either pyrroles or pyridines. Selective elimination of RLi from the lithiated cyclic N-containing intermediates was observed. The order of elimination was found to be LiCl > Me3SiLi > LiH.     

Application of Organolithium and Related Reagents in Synthesis. Part 111. Metallation of 2-Methyl- and 4-Methylnicotinic Acids. A Useful Method for Preparation of AZA-Isocoumarins

The metallation (LDA/THF) of 2-methyl- and 4-methylnicotinic acids (1) and (2), and the subsequent reaction of the lithiated species (3) and (4) with carbonyl electrophiles as a synthetic route of 5-aza- and 7-aza-isocoumarins (7), (8), (9) and (10), is described. The isocoumarins (9) and (10) appeared to be readily transformable into the corresponding naphthyridines (11) and (12).     

Stereoselectivity in intramolecular diels alder reactions I : synthesis of hydroisoindoles

The effects of solvent, steric bulk and the nature of the electron demand (normal or inverse) on the ratio of cis vs trans isomers during intramolecular DIELS-ALDER cyclization of 4-aza-1,6,8-trienes were studied.     

Synthesis,Structure, and In Vitro Anti-HIV Activity of New Pyrazole, 1,2,4-Thiadiazole,and 1,2,4-Triazole Derivatives

α,α′-Dichloroazo compounds 6 react with Lewis acid to furnish 1-(chloroalkyl)-1-aza-2-azoniaallene salts 4. The cations 4 react with acetylenes, isothiocyanates, isocyanates, and carbodiimides under [3+2]-cycloaddition. The cycloadducts undergo consecutive reactions, e.g., [1,2]-shifts of alkyl groups. The newly synthesized products were evaluated for their anti-HIV-1 and anti-HIV-2 activity in MT-4 cells.     

Reactions of heterocumulenes with organometallic reagents: XIX. Quantum-chemical study on S-alkylation and intramolecular cyclization of lithiated methoxyallene adducts with methyl, phenyl, and 3-(methylsulfanyl)phenyl isothiocyanates. Concurrent formation of pyrrole and/or thiophene rings

Concurrent reaction paths leading to the formation of thiophene and/or pyrrole rings from adducts of lithiated methoxyallene with methyl, phenyl, and 3-(methylsulfanyl)phenyl isothiocyanates were simulated by quantum-chemical methods. According to the calculations, pyrrole ring closure is kinetically more favorable for the adduct of 1-lithio-1-methoxyallene with methyl isothiocyanate, both reaction channels are equally probable for the adduct with phenyl isothiocyanate, and thiophene ring closure is the main reaction path for the adduct with 3-(methylsulfanyl)phenyl isothiocyanate.     

Reaction of chromone-3-carbaldehyde with α-amino acids—syntheses of 3- and 4-(2-hydroxybenzoyl)pyrroles

Azomethine ylides generated from the reaction of chromone-3-carbaldehyde with α-amino acids undergo 1,5-electrocyclization reactions to afford 3- and 4-(2-hydroxybenzoyl)pyrroles. These ylides can be trapped with dipolarophiles in 1,3-dipolar cycloaddition reactions to yield chromonyl pyrrolidines. The reaction of chromone-3-carbaldehyde with methyl glycinate gives a mixture of pyrrole, pyridine, and 3-aza-9-xanthenone derivatives.     

Regio- and diastereoselective preparation of tetrahydrobenzo[c]-1-aza-2lambda(5)-phospholes through dearomatization cyclization of lithiated N-benzyl-N-alkyl(diphenyl)phosphinamides. Synthesis of gamma-(N-alkylamino)phosphinic acids

A study of the protonation of the cycloadducts derived from the dearomatization reaction of lithiated N-alkyl-N-benzyldiphenylphosphinamides has been carried out. The regio- and stereoselectivity of the process has been analyzed in terms of the size of the N-alkyl substituent, the acidity and size of the protonating reagent, and the cosolvent used. The optimization of these variables allowed the preparation of tetrahydrobenzo[c]-1-aza-2lambda(5)-phospholes containing a 1,3-cyclohexadiene or 1,4-cyclohexadiene system with moderate to excellent regio- and stereocontrol. The heterocycles were readily hydrolyzed, affording gamma-(N-alkylamino)diphenylphosphinic acids with the functionalities linked to a cyclohexadiene substructure.     

Acylethynylpyrroles as a platform for the one-pot access to 2-(pyrrol-2-yl)-3-acylpyridines via the dihydrogenative annelation with propargylamine

Acylethynylpyrroles, available via the transition metal-free coupling of pyrroles with acylhaloacetylenes are readily annelated with propargylamine in a one-pot step-wise procedure: catalyst-free heating (60–65?°C, 6–16?h) in DMSO and then keeping for 2.5?h with CuI at the same temperature. The products are pyrrolyl-pyridines isolated in good to excellent yields (56–94%). It is experimentally shown that dehydrogenation of intermediate dihydropyridine moiety is not resulted from the oxidation with DMSO (Me₂S was not detected) or air (argon blanket) and is likely associated with the CuI catalysis.     

XVI. (2,5-C4Bu2RHN)MCl3 (M = Ti, Zr, Hf; R = H, SiMe3)—Azacyclopentadienyl-Komplexe der Gruppe 4-Metalle

The azacyclopentadienyl compounds (2,5-C₄^tBu₂RHN)MCl₃ (M = Ti, Zr, Hf; R = H, SiMe₃) have been prepared as stable solids from the lithiated pyrroles and MCl₄. The π-coordination of the azacyclopentadienyl ligands, as suggested from ¹³ C NMR data, has been confirmed for (2,5-C₄^tBu₂H₂N)TiCl₃ by an X-ray diffraction study.     

Rh<Subscript>2</Subscript>(OAc)<Subscript>4</Subscript>-catalyzed reaction of 2-(2-carbonylvinyl)-3-phenyl-2<Emphasis Type="Italic">H</Emphasis>-azirines with diazo esters

Rh₂(OAc)₄-catalyzed reaction of 2-(2-carbonylvinyl)-3-phenyl-2H-azirines with diazo esters proceeds through an intermediate generation of azirinium ylide suffering a nonstereoselective ring opening to form (3Z)- and (3E)-2-azahexa-1,3,5-trienes. The former depending on configuration of the C ⁵ =C ⁶ bond may undergo cyclization either in derivative of 2,3-dihydropyridine, or in pyrrolium ylide that isomerizes into a derivative of 1H-pyrrole. According to DFT calculation, the preferred formation of pyrroles at increasing volume of Z-substituent at the atom C ⁶ and of substituents at the atom C ¹ of 2-azahexatriene occurs due to the destabilization of more sterically loaded transition states of 1,6-cyclization.