Ab initio computational studies of conformationally restricted cope rearrangements. First examples of fully concerted allenyl cope rearrangements

Results of (8,8)CASPT2/6-31G//(8,8)CASSCF/6-31G level calculations on the potential surface for the conformationally restricted allenyl Cope rearrangements of syn-5-propadienylbicylco[2.1.0]pent-2-ene (14) and syn-6-propadienylbicyclo[2.1.1]hex-2-ene (15) are reported. Both are found to proceed through concerted pathways. Also included are the results of (6,6)CASPT2/6-31G//(6,6)CASSCF/6-31G level calculations on the Cope rearrangements of syn-5-ethenylbicyclo[2.1. 0]pent-2-ene (18), syn-6-ethenylbicyclo[2.1.1]hex-2-ene (19), and syn-7-vinylnorborene (20), which are found to involve diallylic diradical intermediates 26, 30, and 36, respectively. Previous studies have shown that the allenyl Cope rearrangement of 1,2, 6-heptatriene (1) to 3-methylene-1,5-hexadiene (2) involves a single transition structure that either proceeds to the monoallylic cyclohexane-1,4-diyl derivative 3 or bypasses 3 to form 2 directly. (4) More recently, the conformationally restricted allenyl Cope rearrangement of syn-7-allenylnorbornene (7) has also been found to involve tricyclic monoallylic cyclohexane-1,4-diyl intermediate 11. (7) The rearrangements of 14 and 15 appear to represent the first reported examples of fully concerted allenyl Cope rearrangements. Concertedness in these cases is ascribed to two parallel factors: (1) the relative instability of possible tricyclic diradical intermediates 16 and 17, compared to diradical intermediates 3 and 11 formed in the rearrangements of 1 and 7, respectively; and (2) the opportunity that exists to form sp-sp(2) sigma bonds in transition structures 21 and 23 that lead, respectively, to products 22 and 24. By contrast, only weaker sp(2)-sp(2) sigma bonds could form in unobserved concerted transition structures leading to products 28 and 32, formed in the nonconcerted rearrangements of 18 and 19.     

Re-examining the Mechanisms of Competing Pericyclic Reactions of 1,3,7-Octatriene

DFT (both B3LYP and M06-2X), CASSCF, and CASPT2 calculations were used to investigate competing [3,?3] and [3,?5] sigmatropic shifts and intramolecular [4+2] cycloaddition of 1,3,7-octatriene. In accord with previous results on 1,5-hexadiene, CASSCF calculations found both stepwise and concerted pathways for the [3,?3] rearrangement. For the competing [3,?5] sigmatropic rearrangement, CASSCF and CASPT2 calculations revealed three stepwise pathways with similar barriers. UB3LYP and UM06-2X calculations predicted a different potential energy landscape: no stepwise [3,?3] pathway, only two competing [3,?5] sigmatropic shifts, and an intramolecular Diels-Alder cycloaddition/homolytic ring-opening pathway. Significant lowering of barriers for all rearrangements was predicted for some 1,3,7-octatrienes with substituents at the 4- and 7-positions.     

Die Dienol-Benzol-Umlagerung von Allyldienolen: aromatische [1,2]-, [3,3]- und [3,4]-sigmatropische Umlagerungen

The dienol-benzene rearrangement of syn and anti-4-allyl-4-methylcyclohexa-2,5-dien-1-ol (syn and anti 15) occurs by formation of a benzonium ion intermediate in p-toluene-sulphonic acid in ether below 0° and leads to a mixture of 2-, 3- and 4-allyltoluenes in the ratio 54:10:36. By the introduction of ¹⁴C-, D- and methyl labelled dienols it is shown that only the allyl group migrates and that this rearrangement is an intramolecular, one-step process. The formation of 2-allyltoluene occurs with retention, whereas the 3- and 4-allyltoluenes are formed by inversion of the carbon skeleton of the migrating allyl group. These rearrangements can be therefore classified as suprafacial, aromatic sigmatropic reactions of the order [1,2], [3,3] and [3,4]. The transition state can be postulated as representing a positively charged complex consisting of interacting allyl and tolyl radicals. The interaction of the two parts is controlled by the symmetry of the highest occupied π-orbitals (ψ₃ for toluene and ψ₂ for the allyl group) in agreement with the Woodward-Hoffmann rules. The better “distribution” of the charge in the transition state of these reactions in comparison to the ground state is chiefly responsible for the CoPE-like [3,3] sigmatropic reaction occurring at low temperatures. In general, sigmatropic reactions in charged systems are faster. The rearrangement of syn and anti 2-allyl-2-methylcyclohexa-3,5-dien-1-ol (syn and anti 28) gives results similar to those obtained with the para-allyldienols. The thermal rearrangement of 15 and 28 gives 3-allyltoluene by a [3,3] sigmatropic Cope rearrangement followed by elimination of water.     

Die Dienol-Benzol-Umlagerung von Propargylcyclohexadienolen: aromatische [1,2]-, [3,3]- und [3,4]-sigmatropische Umlagerungen

The acid catalysed dienol-benzene rearrangement of methyl substituted o- and p-propargylcyclohexadienols ( 18–22 , 34 and 35 ) was investigated. In the first step water is eliminated to yield the corresponding methyl propargyl benzonium ions (cf. scheme 6, a ), which undergo [1s, 2s] sigmatropic rearrangements to give propargylbenzenes ( 28 , 29 , 30 , 38 ) and [3s, 4s] sigmatropic rearrangements to give allenylbenzenes ( 24–27 , 40) (cf. schemes 2, 3, 5, 6). [3s, 3s] sigmatropic rearrangements occur only to a small extend. In the rearrangement of 2-propargyl-2,4,6-trimethylcyclohexa-3,5-dien-1-ol ( 18 ) a [1s, 2s] sigmatropic methyl shift is observed (4%).     

One-step reaction leading to new pyrazolo[1,5-a]pyrimidines by condensation of 2-pyrone with 5(3)-amino-3(5)-arylpyrazoles

Condensation of 5(3)-amino-3(5)-arylpyrazoles with 4-hydroxy-6-methylpyran-2-one leads to 5,7-dimethyl-2-arylpyrazolo[1,5-a]pyrimidines, 5-alkoxycarbonylmethyl-7-methyl-2-arylpyrazolo[1,5-a]pyrimidines and their isomeric 7-alkoxycarbonylmethyl-5-methyl-2-arylpyrazolo[1,5-a]pyrimidines. These compounds result from competitive reactions and from different cyclization pathways. Structure and mechanism of formation of these new products are reported.     

Stereochemie von [3.3]- und [5.5]-sigmatropischen umlagerungen

The knowledge of the stereochemical course of Cope and Claisen rearrangements is important both for mechanistic and synthetic reasons. In the first part an analysis of the possible transition state geometries (cf Table 1) for these reactions is given and methods which allow to distinguish between the various geometries are discussed (cf Schemes 1 and 2). In the second part known examples are analyzed. Generally, in Cope and Claisen rearrangements of acyclic systems a chair-like transition state (C) is favoured above a boat-like (B). Steric effects may alter this preference.     

A new palladium(II)-catalyzed [3,3] aza-Claisen rearrangement of 3-allyloxy-5-aryl-1,2,4-oxadiazoles

A new efficient palladium(II)-catalyzed [3,3] aza-Claisen, formal sigmatropic rearrangement of 3-allyloxy-5-aryl-1,2,4-oxadiazoles was developed. The mechanism was studied by analyzing the regiochemical and stereochemical course of the reaction. The results obtained indicated the intervention of a cationic pallada-cycle similar to the one postulated for the Cope rearrangement of 1,5-dienes.     

Chirality transfer in the aza-[2,3]-Wittig sigmatropic rearrangement

The aza-[2,3]-Wittig sigmatropic rearrangements of substrates derived from enantiomerically pure alanine, valine and serine with phenyl and ester anion stabilising groups were investigated for their efficiency in chirality transfer. It was found that a methyl substituent at the stereogenic centre of the rearrangement precursors was inadequate to control the alkene stereoselectivity and enantioselectivity of the rearrangement. Ester stabilised anions of valine and serine derivatives were the most successful with up to 66% yield, 14 : 1 alkene (E)-stereoselection and 88% chirality transfer. A limitation to the steric bulk of the stereogenic centre was noted in that the substituent has to be bulky enough to dictate alkene stereoselection, but not too large to compromise the directing effect of the activating phenyldimethyl silyl substituent on the anion stabilising group. Experimental evidence suggested a possible complimentary coordinating effect of an O-MOM serine substituent, which may assist alkene stereoselectivity and enantioselectivity.     

Synthesis of 2-deoxy-2-c-alkyl glycal and glycopyranosides from 2-hydroxy glycal ester

A method to convert 2-hydroxy glycal ester to the corresponding 2-deoxy-2-C-alkyl glycal in a facile manner, through key reactions including (i) C-allylation at C-1, (ii) Wittig reaction, and (iii) Cope rearrangement of a 1,5-diene derivative, is reported. The α-anomer of the 1,5-diene derivative underwent Cope rearrangement to afford 2-deoxy-2-C-glycal derivative, whereas the β-anomer was found to be unreactive. Employing this sequence, 3,4,6-tri-O-benzyl-2-O-acetyl-1,5-anhydro-d-arabino-hex-1-enitol was transformed to 3,4,6-tri-O-benzyl-2-deoxy-2-C-alkyl-1,5-anhydro-D-arabino-hex-1-enitol. 2-Deoxy-2-C-alkyl glycal derivative is a suitable glycosyl donor to prepare 2-deoxy-2-C-alkyl glycosides, mediated through haloglycosylation and a subsequent dehalogenation. A number of 2-deoxy-2-C-alkyl glycosides, with both glycosyl and nonglycosyl moieties at the reducing end, are thus prepared from the glycal.     

Domino Reactions with 2-Fluoro-3-trifluoromethylfurans and -thiophenes [1]

Summary.  The single fluorine atom of 2-fluoro-3-trifluoromethylfurans and -thiophenes can be readily replaced by various nucleophiles. Depending on the substituent pattern, certain products obtained upon nucleophilic substitution with benzyl alcohols are susceptible to [1,3]- and [1,5]-benzyl group migrations under very mild conditions. Therefore, these rearrangements can be integrated into domino reactions. Received March 9, 2001. Accepted April 2, 2001     

Reactions with pyrrolidine-2,4-diones,I. New synthesis of pyrano[2,3-c]pyrrole and pyrrolo[3,4-b]pyridine systems

The synthesis of some substituted 4-hydroxy-2,5,6,7-tetrahydro-pyrano[2,3-c]pyrrole-2,5-diones (5) and 4-hydroxy-1,2,6,7-tetrahydro-5H-pyrrolo[3,4-b]pyridine-2,5-diones (6) by reacting 1,5-diaryl-pyrrolidine-2,4-diones (1) and 1,5-diaryl-1,5-dihydro-4-amino-2H-pyrrol-2-ones (3) with bis-2,4,6-trichlorophenyl malonates (4) is described.Dedicated to Prof. Dr. Dr. h. c.O. Kratky, Graz, on the occasion of his 80th birthday.     

Synthesis and cytotoxic activity of benzo[a]pyrano[3,2-h] and [2,3-i]xanthone analogues of psorospermine, acronycine, and benzo[a]acronycine

Condensation of 2-hydroxy-1-naphthalenecarboxylic acid with phloroglucinol afforded 9,11-dihydroxy-12H-benzo[a]xanthen-12-one (6). Construction of an additional dimethylpyran ring onto this skeleton, by alkylation with 3-chloro-3-methyl-1-butyne followed by Claisen rearrangement, gave access to 6-hydroxy-3,3-dimethyl-3H,7H-benzo[a]pyrano[3,2-h]xanthen-7-one (12) and 5-hydroxy-2,2-dimethyl-2H,6H-benzo[a]pyrano[2,3-i]xanthen-6-one (13), which were methylated into 6-methoxy-3,3-dimethyl-3H,7H-benzo[a]pyrano[3,2-h]xanthen-7-one (14) and 5-methoxy-2,2-dimethyl-2H,6H-benzo[a]pyrano[2,3-i]xanthen-6-one (15), respectively. Osmium tetroxide oxidation of 14 and 15 gave the corresponding (+/-)-cis-diols 16 and 17, which afforded the corresponding esters 18-21 upon acylation. Similarly, condensation of 2-hydroxy-1-naphthalenecarboxylic acid with 3,5-dimethoxyaniline gave 11-amino-9-methoxy-12H-benzo[a]xanthen-12-one (23) which was converted into 11-amino-9-hydroxy-12H-benzo[a]xanthen-12-one (24) upon treatment with hydrogen bromide in acetic acid. Alkylation with 3-chloro-3-methyl-1-butyne followed by Claisen rearrangement afforded 6-amino-3,3-dimethyl-3H,7H-benzo[a]pyrano[3,2-h]xanthen-7-one (25) and 5-amino-2,2-dimethyl-2H,6H-benzo[a]pyrano[2,3-i]xanthen-6-one (26). The new benzopyranoxanthone derivatives only displayed marginal antiproliferative activity when tested against L1210 and KB-3-1 cell lines. The only compounds found significantly active against L1210 cell line, 16 and 20, belong to the benzo[a]pyrano[3,2-h]xanthen-7-one series, which possess a pyran ring fused angularly onto the xanthone basic core.     

Über den Anteil sigmatroper 1, 5-Wanderung von Kohlenwasserstoffgruppen bei der thermolytischen Skelettisomerisierung 5,5-disubstituierter 1, 3-Cyclohexadiene

On the Extent of Sigmatropic 1, 5-Migration of Hydrocarbon Groups in the Thermolytic Skeletal Rearrangement of 5,5-Disubstituted 1,3-Cyclohexadienes The uncatalyzed skeletal isomerization of 5, 5-disubstituted 1, 3-cyclohexadienes was investigated with the aim to establish the extent to which sigmatropic 1,5-shifts of hydrocarbon groups are participating in these reactions. Gas phase pyrolysis of 5,5-diethyl-1,3-cyclohexadiene ( 7 ) at 460° followed by chloranil aromatization yields only 4% of 1,3-diethylbenzene resulting from 7 through a 1, 5-ethyl migration in the primary reaction step. 2, 3-Dimethylethylbenzene (56%) and 1, 4-diethylbenzene (4%) are obtained as other C₁₀-compounds. This shows that isomerization proceeds mainly through a sequence of electrocyclic and 1, 7-shift reactions. Ethylbenzene (24%) and other aromatic C₈- and C₉-hydrocarbons are formed to a considerable extent, indicating that C, C-bond cleavage is a major competing process and that the 1, 3-diethylbenzene found is the result of a radical recombination reaction and not of a concerted sigmatropic shift of the ethyl group. 5-Methyl-5-phenyl-1, 3-cyclohexadiene ( 12 ) yields 3-methylbiphenyl ( 14 ) and biphenyl upon thermolysis and aromatization. Through ¹³C-substitution of the methyl group in 12 it is shown that in solution at 300° skeletal isomerization proceeds through electrocyclic and 1, 7-H-shift reactions exclusively. In the gas phase at 500° 4% of the isomerization product is formed by a 1, 5-shift of a substitutent, presumably of the methyl group, through a dissociative mechanism. Thermolysis of 5, 5-diphenyl-1, 3-cyclohexadiene ( 22 ) at 560° in the gas phase leads to 1, 1-diphenyl-1, 3, 5-hexatriene ( 23 ) and 1-vinyl-4-phenyl-1, 2-dihydronaphthalene ( 24 ) through electrocyclic reaction steps. In addition a small amount of m-terphenyl is obtained at high conversion of 22 . This indicates that sigmatropic 1,5-phenyl migration can participate in product formation only at high temperature and in the absence of other irreversible pathways to stable products.     

Exploring the Reactivity of α‐Lithiated Aryl Benzyl Ethers: Inhibition of the [1,2]‐Wittig Rearrangement and the Mechanistic Proposal Revisited

By carefully controlling the reaction temperature, treatment of aryl benzyl ethers with tBuLi selectively leads to α‐lithiation, generating stable organolithiums that can be directly trapped with a variety of selected electrophiles, before they can undergo the expected [1,2]‐Wittig rearrangement. This rearrangement has been deeply studied, both experimentally and computationally, with aryl α‐lithiated benzyl ethers bearing different substituents at the aryl ring. The obtained results support the competence of a concerted anionic intramolecular addition/elimination sequence and a radical dissociation/recombination sequence for explaining the tendency of migration for aryl groups. The more favored rearrangements are found for substrates with electron‐poor aryl groups that favor the anionic pathway.     

Novel parallel reaction between a [1,5] sigmatropic alkylthio shift and a [1,5] sigmatropic hydrogen shift observed in a 2H-azepine ring

Although heating 2-methoxy-2H-azepine results in a [1,5] sigmatropic hydrogen shift, heating 2-propylthio-2H-azepine results in not only a [1,5] sigmatropic hydrogen shift but also a [1,5] sigmatropic propylthio shift. Kinetic measurements reveal that migratory aptitudes increase in the order of MeO < H, PrS. These [1,5] sigmatropic shifts are discussed on the basis of ab initio DFT calculations. [reaction: see text].     

Reaction of carbenes with bicyclo[2.1.0]pentane

Bicyclo[2.1.0]pentane reacts with phenylcarbene and dicarbomethoxycarbene by simple insertion at the cyclobutane methylene position. By contrast, difluorocarbene reacts by two bond cleavage to give 1,1-difluoro-1,5-hexadiene.     

Synthesis and oxidation of aromatic substituted 6,7-dihydropyrazolo[1,5-a]pyrimidines

Condensation of 5-amino-3-methylpyrazole with chalcone or dypnone gives aromatic substituted 6,7-dihydropyrazolo[1,5-a]pyrimidines which undergo air oxidation. An x-ray structure for 2-methyl-6-hydroxy-5,7-diphenyl-6,7-dihydropyrazolo[1,5-a]pyrimidine is reported.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 109–114, January, 1993.     

Re‐examining the Mechanisms of Competing Pericyclic Reactions of 1,3,7‐Octatriene

DFT (both B3LYP and M06‐2X), CASSCF, and CASPT2 calculations were used to investigate competing [3, 3] and [3, 5] sigmatropic shifts and intramolecular [4+2] cycloaddition of 1,3,7‐octatriene. In accord with previous results on 1,5‐hexadiene, CASSCF calculations found both stepwise and concerted pathways for the [3, 3] rearrangement. For the competing [3, 5] sigmatropic rearrangement, CASSCF and CASPT2 calculations revealed three stepwise pathways with similar barriers. UB3LYP and UM06‐2X calculations predicted a different potential energy landscape: no stepwise [3, 3] pathway, only two competing [3, 5] sigmatropic shifts, and an intramolecular Diels–Alder cycloaddition/homolytic ring‐opening pathway. Significant lowering of barriers for all rearrangements was predicted for some 1,3,7‐octatrienes with substituents at the 4‐ and 7‐positions.     

CASSCF and CASPT2 calculations on the cleavage and ring inversion of bicyclo[2.2.0]hexane find that these reactions involve formation of a common twist-boat diradical intermediate.

(6/6)CASSCF and CASPT2/6-31G calculations have been performed to understand the experimental finding of Goldstein and Benzon (J. Am. Chem. Soc. 1972, 94, 5119) that exo-bicyclo[2.2.0]hexane-d(4) (1b) undergoes ring inversion to form endo-bicyclo[2.2.0]hexane-d(4) (4b) faster than it undergoes cleavage to form cis,trans-1,5-hexadiene-d(4) (3b). Goldstein and Benzon also found that the latter reaction, which must occur via a chairlike transition structure (TS), is much faster than cleavage of 1b to trans,trans-1,5-hexadiene-d(4) (2b) via a boatlike TS. Our calculations reveal that all three of these reactions involve ring opening of 1, through a boat diradical TS (BDTS), to form a twist-boat diradical intermediate (TBDI). TBDI can reclose to 4 via a stereoisomeric boat diradical TS (BDTS'), or TBDI can cleave, either via a half-chair diradical TS (HCDTS) to form 3 or via a boat TS (BTS) to form 2. The calculated values of DeltaH(++) = 34.6 kcal/mol, DeltaS(++) = -1.6 eu, and DeltaH(++) = 35.2 kcal/mol, DeltaS(++) = 2.0 eu for ring inversion of 1 to 4 and cleavage of 1 to 3, respectively, are in excellent agreement with the values measured by Goldstein and Benzon. The higher value of DeltaH(++) = 37.6 kcal/mol, computed for cleavage of TBDI to 2, is consistent with the experimental finding that very little 2b is formed when 1b is pyrolyzed. The relationships between BDTS, HCDTS, and BTS and the chair and boat Cope rearrangement TSs (CCTS and BCTS) are discussed.     

Synthesis of Chiral Pyrazoles: A 1,3‐Dipolar Cycloaddition/[1,5] Sigmatropic Rearrangement with Stereoretentive Migration of a Stereogenic Group

The reactions between terminal alkynes and α‐chiral tosylhydrazones lead to the obtention of chiral pyrazoles with a stereogenic group directly attached at a nitrogen atom. The cascade reaction includes decomposition of the hydrazone into a diazocompound, 1,3‐dipolar cycloaddition of the diazo compound with the alkyne, and [1,5] sigmatropic rearrangement with migration of the stereogenic group. This strategy has been successfully applied to the synthesis of structurally diverse chiral pyrazoles through α‐chiral tosylhydrazones, obtained from α‐phenylpropionic acid, α‐amino acids, and 2‐methoxycyclohexanone. Notably, the stereoretention of the [1,5] sigmatropic rearrangements represent very rare examples of this stereospecific transformation.