On the Formation of 2‐Sulfonylbenzo[a]heptalene‐1,3‐diols as Precursors for the Synthesis of Colchicinoids

The benzo[a]heptalene formation from 4‐[(R‐sulfonyl)acetyl]heptalene‐5‐carboxylates 15 and 5‐[(R‐sulfonyl)acetyl]heptalene‐4‐carboxylates 16 (R=Ph or morpholino) in the presence of R′SO₂CH₂Li and BuLi has been investigated (Scheme 6). Only the sulfonyl moiety linked to the C?O group at C(4) of the heptalene skeleton is found at C(3) of the formed benzo[a]heptalene‐2,4‐diols 3 in accordance with the general mechanism of their formation (Scheme 3). Intermediates that might rearrange to corresponding 2‐sulfonylbenzo[a]heptalene‐1,3‐diols lose HO^? under the reaction conditions to yield the corresponding cyclopenta[d]heptalenones of type 11 (Schemes 6 and 7). However, the presence of an additional Me group at C(α) of the lithioalkyl sulfones suppresses the loss of HO^?, and 4‐methyl‐2‐sulfonylbenzo[a]heptalene‐1,3‐diols of type 4c have been isolated and characterized for the first time (Schemes 8 and 10). A number of X‐ray crystal‐structure analyses of starting materials and of the new benzo[a]heptalenes have been performed. Finally, benzo[a]heptalene 4c has been transformed into its 1,2,3‐trimethoxy derivative 23 , a benzo[a]heptalene with the colchicinoid substitution pattern at ring A (Scheme 11).     

New Anellation Methods for the Synthesis of 8H-Heptaleno[1,10-bc]furans,-pyrroles,and -thiophenes

Heptaleno[1,2-c]furan-6-carbaldehydes such as 8 or their thiocarbaldehyde or iminomethyl derivatives easily undergo thermal cyclization, followed by a [1,5]- H shift, to give the corresponding heptalenodifurans, thienoheptalenofurans, as well as furoheptalenopyrroles (cf. Schemes 2 and 3). Generation of the 6-acetyl derivative of 8 from the corresponding secondary alcohol 15 with 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide (IBX) at 0° (cf. Scheme 4) leads directly to the formation of the cyclization product 16 which, upon standing at room temperature, undergoes the [1,5]-sigmatropic H-shift to the final difuran 17 . 1-Formylheptalene-4,5-dicarboxylates such as 9 can also be cyclized thermally, followed by the [1,5]-H shift, to the corresponding 8H-heptaleno[1,10-bc]furan-5,6-dicarboxylate 11 . On thiation with Lawesson′s reagent, 9 yields directly the corresponding heptalenothiophene 13 (cf. Scheme 3).     

Thermal and Photochemical Reactions of 1,2-Annelated Barrelenes and Hydrobarrelenes in the presence of transition-metal carbonyls

The [Co₂(CO)₈]-mediated retro-Diels-Alder reaction of the annelated barrelenes 1 afforded the 1H-indol-2(3H)-one derivatives 3 (Scheme 1), while the hydrobarrelene 4a , under the same conditions, was converted to the anilide 6 (Scheme 2); 4b remained unaffected. The direct irradiation of 1 led to the annelated cyclooctatetraenes 7 (Scheme 3). On irradiation in the presence of excess of [Fe(CO)₅], 1a , 1b , and 4a gave the tricarbonyliron complexes 8 , 9 , and 11 , respectively (Schemes 3 and 4); under these conditions, 4b was inert.     

Formation of Heptaleno[1,2-c]furans and Heptaleno[1,2-c]furanones

The dehydrogenation reaction of the heptalene-4,5-dimethanols 4a and 4d , which do not undergo the double-bond-shift (DBS) process at ambient temperature, with basic MnO₂ in CH₂Cl₂ at room temperature, leads to the formation of the corresponding heptaleno[1,2-c]furans 6a and 6d , respectively, as well as to the corresponding heptaleno[1,2-c]furan-3-ones 7a and 7d , respectively (cf. Scheme 2 and 8). The formation of both product types necessarily involves a DBS process (cf. Scheme 7). The dehydrogenation reaction of the DBS isomer of 4a , i.e., 5a , with MnO₂ in CH₂Cl₂ at room temperature results, in addition to 6a and 7a , in the formation of the heptaleno[1,2-c]-furan-1-one 8a and, in small amounts, of the heptalene-4,5-dicarbaldehyde 9a (cf. Scheme 3). The benzo[a]heptalene-6,7-dimethanol 4c with a fixed position of the C?C bonds of the heptalene skeleton, on dehydrogenation with MnO₂ in CH₂Cl₂, gives only the corresponding furanone 11b (Scheme 4). By [²H₂]-labelling of the methanol function at C(7), it could be shown that the furanone formation takes place at the stage of the corresponding lactol [3-²H₂]- 15b (cf. Scheme 6). Heptalene-1,2-dimethanols 4c and 4e , which are, at room temperature, in thermal equilibrium with their corresponding DBS forms 5c and 5e , respectively, are dehydrogenated by MnO₂ in CH₂Cl₂ to give the corresponding heptaleno[1,2-c]furans 6c and 6e as well as the heptaleno[1,2-c]furan-3-ones 7c and 7e and, again, in small amounts, the heptaleno[1,2-c]furan-1-ones 8c and 8e , respectively (cf. Scheme 8). Therefore, it seems that the heptalene-1,2-dimethanols are responsible for the formation of the furan-1-ones (cf. Scheme 7). The methylenation of the furan-3-ones 7a and 7e with Tebbe's reagent leads to the formation of the 3-methyl-substituted heptaleno[1,2-c]furans 23a and 23e , respectively (cf. Scheme 9). The heptaleno[1,2-c]furans 6a, 6d , and 23a can be resolved into their antipodes on a Chiralcel OD column. The (P)-configuration is assigned to the heptaleno[1,2-c]furans showing a negative Cotton effect at ca. 320 nm in the CD spectrum in hexane (cf. Figs. 3–5 as well as Table 7). The (P)-configuration of (–)- 6a is correlated with the established (P)-configuration of the dimethanol (–)- 5a via dehydrogenation with MnO₂. The degree of twisting of the heptalene skeleton of 6 and 23 is determined by the Me-substitution pattern (cf. Table 9). The larger the heptalene gauche torsion angles are, the more hypsochromically shifted is the heptalene absorption band above 300 nm (cf. Table 7 and 8, as well as Figs. 6–9).     

Chemistry of the Benzotropone Endoperoxides and Their Conversion into Tropolone Derivatives: Unusual Endoperoxide Rearrangements

The chemistry of two bicyclic endoperoxides, obtained by photooxygenation of 2,3‐benzotropone (=5H‐benzocyclohepten‐5‐one; 5 ) and of its ethyl carboxylate derivative 15 , was investigated with the aim of synthesizing the respective benzotropolone derivatives. The reaction of the endoperoxide 10 derived from 5 with thiourea gave the desired benzotropolone, i.e., 6‐hydroxy‐5H‐benzocyclohepten‐5‐one ( 11 ), in high yield (Scheme 1). On the other hand, the endoperoxide 16 derived from the ethyl carboxylate derivative 15 underwent an unprecedented transformation yielding mainly the ring‐contracted lactones 28 and 29 besides the expected substituted benzotropolone derivative 27 (Scheme 5). However, the thermolysis reaction of the same endoperoxide 16 resulted in the formation of four rearranged compounds with different skeletons (Scheme 3). The formation mechanism of all products is discussed (Schemes 4 and 6).     

Benzo[a]heptalenes from Heptaleno[1,2‐c]furans. Part I

It is shown that heptaleno[1,2‐c]furans 1 , which are available in two steps from heptalene‐4,5‐dicarboxylates by reduction and oxidative dehydrogenation of the corresponding vicinal dimethanols 2 with MnO₂ or IBX (Scheme 4), react thermally in a Diels–Alder‐type [4+2] cycloaddition at the furan ring with a number of electron‐deficient dipolarophiles to yield the corresponding 1,4‐epoxybenzo[d]heptalenes (cf. Schemes 6, 15, 17, and 19). The thermal reaction between dimethyl acetylenedicarboxylate (ADM) and 1 leads, kinetically controlled, via a sterically less‐congested transition state (Fig. 4) to the formation of the (M*)‐configured 1,4‐dihydro‐1,4‐epoxybenzo[a]heptalenes, which undergo a cyclic double‐bond shift to the energetically more‐relaxed benzo[d]heptalenes 4 (Schemes 6 and 7). Most of the latter ones exhibit under thermal conditions epimerization at the axis of chirality, so that the (M*)‐ and (P*)‐stereoisomers are found in reaction mixtures. The (P*)‐configured forms of 4 are favored in thermal equilibration experiments, in agreement with AM1 calculations (Table 1). The relative (P*,1S*,4R*)‐ and (M*,1S*,4R*)‐configuration of the crystalline main stereoisomers of the benzo[d]heptalene‐2,3‐dicarboxylates 4a and 4f , respectively, was unequivocally established by an X‐ray crystal‐structure determination (Figs. 1 and 2). Acid‐induced rearrangement of 4 led to the formation of the corresponding 4‐hydroxybenzo[a]heptalene‐2,3‐dicarboxylates 5 in moderate‐to‐good yields (Schemes 8, 13, and 14). When the aromatization reaction is performed in the presence of trifluoroacetic acid (TFA), trifluoroacetates of type 6 and 13 (Schemes 8, 12, and 13) are also formed via deprotonation of the intermediate tropylium ions of type 7 (Scheme 11). Thermal reaction of 1 with dimethyl maleate gave the 2,3‐exo‐ and 2,3‐endo‐configured dicarboxylates 14 as mixtures of their (P*)‐ and (M*)‐epimers (Scheme 15). Treatment of these forms with lithium di(isopropyl)amide (LDA) at ?70° gave the expected benzo[a]heptalene‐2,3‐dicarboxylates 15 in good yields (Scheme 16). Fumaronitrile reacted thermally also with 1 to the corresponding 2‐exo,3‐endo‐ and 2‐endo,3‐exo‐configured adducts 17 , again as mixtures of their (P*)‐ and (M*)‐epimers (Scheme 17), which smoothly rearranged on heating in dimethoxyethane (DME) in the presence of Cs₂CO₃ to the benzo[a]heptalene‐2,3‐dicarbonitriles 18 (Scheme 18). Some cursory experiments demonstrated that hex‐3‐yne‐2,5‐dione and (E)/(Z)‐hexa‐3‐ene‐2,5‐dione undergo also the Diels–Alder‐type cycloaddition reaction with 1 (Scheme 19). The mixtures of the stereoisomers of the 2,3‐diacetyl‐1,4‐epoxytetrahydrobenzo[d]heptalenes 22 gave, on treatment with Cs₂CO₃ in DME at 80°, only mixtures of the regioisomeric inner aldol products 24 and 25 of the intermediately formed benzo[a]heptalenes 23 (Scheme 20).     

Thermal Reactions of Guaiazulene and Its 3-Methyl Derivative with Dimethyl Acetylenedicarboxylate

The thermal reaction of 7-isopropyl-1,3,4-trimethylazulene (3-methylguaiazulene; 2 ) with excess dimethyl acetylenedicarboxylate (ADM) in decalin at 200° leads to the formation of the corresponding heptalene- ( 5a/5b and 6a/6b ; cf. Scheme 3) and azulene-1,2-dicarboxylates ( 7 and 8 , respectively). Together with small amounts of a corresponding tetracyclic compound (‘anti’- 13 ) these compounds are obtained via rearrangement (→ 5a/5b and 6a/6b ), retro-Diels-Alder reaction (→ 7 and 8 ), and Diels-Alder reaction with ADM (→ ‘anti’- 13 ) from the two primary tricyclic intermediates ( 14 and 15 ; cf. Scheme 5) which are formed by site-selective addition of ADM to the five-membered ring of 2 . In a competing Diels-Alder reaction, ADM is also added to the seven-membered ring of 2 , leading to the formation of the tricyclic compounds 9 and 10 and of the Diels-Alder adducts ‘anti’- 11 and ‘anti’- 12 , respectively of 9 and of a third tricyclic intermediate 16 which is at 200° in thermal equilibrium with 9 and 10 (cf. Scheme 6). The heptalenedicarboxylates 5a and 5b as well as 6a and 6b are interconverting slowly already at ambient temperature (Scheme 4). The thermal reaction of guaiazulene ( 1 ) with excess ADM in decalin at 190° leads alongside with the known heptalene- ( 3a ) and azulene-1,2-dicarboxylates ( 4 ; cf. Schemes 2 and 7) to the formation of six tetracyclic compounds ‘anti’- 17 to ‘anti’- 21 as well as ‘syn’- 19 and small amounts of a 4:1 mixture of the tricyclic tetracarboxylates 22 and 23 . The structure of the tetracyclic compounds can be traced back by a retro-Diels-Alder reaction to the corresponding structures of tricyclic compounds ( 24--29 ; cf. Scheme 8) which are thermally interconverting by [1,5]-C shifts at 190°. The tricyclic tetracarboxylates 22 and 23 , which are slowly equilibrating already at ambient temperature, are formed by thermal addition of ADM to the seven-membered ring of dimethyl 5-isopropyl-3,8-dimethylazulene-1,2-dicarboxylate ( 7 ; cf. Scheme 10). Azulene 7 which is electronically deactivated by the two MeOCO groups at C(1) and C(2) shows no more thermal reactivity in the presence of ADM at the five-membered ring (cf. Scheme 11). The tricyclic tetracarboxylates 22 and 23 react with excess ADM at 200° in a slow Diels-Alder reaction to form the tetracyclic hexacarboxylates 32 , ‘anti’- 33 , and ‘anti’- 34 (cf. Schemes 10–12 as well as Scheme 13). A structural correlation of the tri- and tetracyclic compounds is only feasible if thermal equilibration via [1,5]-C shifts between all six possible tricyclic tetracarboxylates ( 22, 23 , and 35–38 ; cf. Scheme 13) is assumed. The tetracyclic hexacarboxylates 32 , ‘anti’- 33 , and ‘anti’- 34 seem to arise from the most strained tricyclic intermediates ( 36–38 ) by the Diels-Alder reaction with ADM.     

Some Unusual Products from the Thermal Reaction of Azulenes with Dimethyl Acetylenedicarboxylate

The thermal reaction of azulene-1-carbaldehydes 5 and 6 with excess dimethyl acetylenedicarboxylate (ADM) in decalin leads mainly to the formation of (1 + 1) and (1 + 2) adducts arising from the addition of ADM at the seven-membered ring of the azulenes (cf. Schemes 2 and 4). The (1 + 2) adducts are formed in a homo-Diels-Alder reaction of ADM and isomeric tricyclic carbaldehydes which are derived from the primary tricyclic carbaldehydes by reversible [1s5s]-C shifts (cf. Schemes 3 and 5). The thus formed pentacyclic carbaldehydes seem to undergo deep-seated skeletal rearrangements (cf. Scheme 7) which result finally in the formation of the formyl-tetrahydrocyclopenta[bc]acenaphthylene-tetraesters 12 and 19 , respectively. In other cases, e.g., azulene-1-carbaldehydes 7 and 8 (cf. Scheme 8), the thermal reaction with excess ADM furnishes only the already known tetracycfic (1 + 2) adducts of type anti- 26 to ‘anti’- 29 . The thermal reaction of 1,3,4,8-tetramethylazulene ( 9 ) with excess ADM in decalin resulted in the formation of two (1 + 2) and one (1 + 3) adduct in low yields (cf. Scheme 9). The latter turned out to be the 2,6-bridged barrelene derivative 32 . There are structural evidences that 32 is formed by similar pathways as the formyl-tetrahydrocyclopenta[bc]acenaphthylene-tetraesters (cf. Schemes 7 and 11). [²H₃]Me-Labelling experiments are in agreement with the proposed mechanisms (cf. Scheme 13).     

Ring transformation of 6H-cyclopropa[e]pyrazolo[1,5-a]pyrimidine. IV (1). Reduction and reaction of 5a-acetyl-6a-ethoxycarbonyl-5a,6a-dihydro-6H-cyclopropa[e]pyrazolo[1,5-a]pyrimidine-3-carbonitriles with primary amines

The reaction of 5a-acetyl-6-ethoxycarbonyl-5a,6a-dihydro-6H-cyclopropa[e]pyrazolo[1,5-a]pyrimidine-3-carbonitrile ( 1a ) with benzylamine gave ethyl l-benzyl-5-cyano-8a,9-dihydro-2-methyl-1H-pyrrolo[3,4-e]-pyrazolo[1,5-a]pyrimidine-8a-carboxylate ( 2a ), in addition to 5-acetyl-3-benzylamino-1-(4-cyanopyrazol-3-yl)- 2-pyridone ( 3 ). Reaction of 1a with aniline gave ethyl 6-acetyl-8-anilino-3-cyano-7,8-dihydro-4H-pyrazolo-[1,5-a][1,3]diazepine-8-carboxylate ( 4 ), in addition to ethyl 3-cyano-7-methyl-6-pyrazolo[1,5-a]pyrimidine-acrylate ( 5 ). On the other hand, the same reactions of 1b with benzylamine or aniline gave 2b or 8b , respectively. Though catalytic hydrogenation of 1a over 5% palladium-carbon proceeded by ring fission of cyclopropane ring to give 9 , 1a (or 1b ) afforded 4,5-dihydro derivatives ( 13 or 15 ) by catalytic hydrogenation over platinum oxide. The reactivity of 5-methoxy-4,5,5a,6a-tetrahydro-6H-cyclopropa[e]pyrazolo[1,5-a]pyrimidine ( 16 ), which are related analogs of 1a,b , is also described.     

New heterocyclic syntheses from hydrazidoyl halides. Convenient syntheses of fused pyrimidines,pyridazines, and quinazolines

Aminocyanopyrazole derivatives and pyrazolo[2,3-a]quinazolones were obtained in good yields from hydrazidoyl halides and malononitrile. Pyrazolo[3,4-d]pyridazine and pyridazo[4′,5′: 1,2]pyrazolo[1,5-a]quinazoline derivatives were synthesized in quantitative yields by reaction of hydrazine hydrate with 2 and 16 , respectively. A novel ring system, a 3-substituted tetrahydro derivative of 7-oxo-6H,8H-pyridazo[3′,4′,5′-c'd']-pyrazolo[3,4-d]pyrimidine was prepared by reaction of 6 with dimethyl carbonate. Pyrazolo[3,4-d]pyrimidine-4,6-dithiones were obtained in good yields by reaction of 2 with carbon disulfide. The structures of the products were assigned and confirmed on the basis of their elemental analyses, spectral data, and alternate synthesis wherever possible. The structures of the parent fused heterocyclic systems discussed in this work are summarized in Scheme 1 .     

A New Approach to the Synthesis of Long-Chain Polypropionates Based on the Diels-Alder Monoadditions of 2,2′-Ethylidenebis[3,5-dimethylfuran]

Acidic condensation of 2,4-dimethylfuran with acetaldehyde provided 2,2′-ethylidenebis[3,5-dimethylfuran] ( 7 ) which added 1 equiv. of methyl bromopropynoate to give a major adduct 8 . Regio- and stereoselective hydroboration of the latter 7-oxanorbornadiene derivative followed by alcohol protection and methanolysis of its β-bromoacrylate moiety gave (1RS,2RS,4RS,5SR,6SR,1′RS)-methyl 4-[1′-(3″,5″-dimethylfuran-2″-yl)ethyl]-3,3-dimethoxy-6-exo-[(2-methoxy)ethoxy]-1,5-endo-dimethyl-7-oxabicyclo[2.2.1]heptane-2-endo-carboxylate ( 24 ) (Schemes 2 and 3). Reduction of 24 with LiAlH₄, followed by H₂O and MeOH elimination gave the 3-methyl-idene-7-oxanorbornan-2-one derivative 26 which underwent 7-oxa ring opening through a S_N2′ type of reaction with Me₂CuLi (Scheme 4). Stereoselective hydrogenation and ketone reduction provided (1RS, 2SR,3RS,4RS,5RS,6RS,1′SR)-1- [1″-(3 ″,5″-dimethylfuran-2″-yl)]-c-3-ethyl-c-5-[(2-methoxyethoxy)m e-c-ethyl-c-c-5-(2-methoxyethoxy)methoxy]-t-4,t-6-dimethyl-cyclohexane-r-1,c-2-diol ( 32 ), the oxidative cleavage of which with Pb(OAc)₄ generated a 6-oxo-aldehyde 33 (Schemes 4 and 5). Chemoselective protection of 33 and chemo- and stereoselective reductions generated (2RS,3RS,4SR,5SR,6SR,7RS)-7-(3′,5″-dimethylfuran-2′-yl)-2-ethyl-6-hydroxy-4-[(2-methoxyethoxy)methoxy]-3,5-dimethyloct-1-yl pivaloate ( 36 ) and its 4-hydroxy 6-epimer 40 (12 and 13 steps, resp., from adduct 8 ; Scheme 5). Oxidation of the furan ring of 36 led to a (2RS,3SR,4RS,5SR,6RS,7RS)-7-ethyl-3,5,8-trihydroxy-2,4,6-trimethyl-octanoic acid derivative 44 , a polypropionate fragment with six contiguous stereogenic centres (Scheme 6).     

Investigations Concerning an Unexpected Reaction between the Dimsyl Anion ( = (Methylsulfinyl)methanide) and a γ,δ-Epoxy-ketone

The reaction of 2,2-dimethyl-5-(1,2-epoxypropyl)cyclohexanone ( 7 ) with t-BuOK in DMSO furnished a small amount of 5-(1-hydroxyprop-2-enyl)-2,2-dimethylcyclohexanone ( 12 ) and the 4 unexpected products 13–16 which contain one to three additional C-atoms (Scheme 2). The relative configuration of the major product 1-(4′,4′-dimethyl-2′,3′-dimethylidenecyclohexyl)propane-1,2-diol ( 15 ) was shown to be 1RS, 2RS,1′SR via NOE measurements performed on a derivative thereof. A crossover experiment in DMSO/[¹³C₂]DMSO 1:1 as solvent showed that the two additional C-atoms of this product originate from a single molecule of DMSO (Scheme 5). A tentative mechanistic scheme, consistent with all experimental observations, is proposed which involves a [2,3]-sigmatropic rearrangement of an (allylsulfinyl)methanide to a sulfenic acid as one of the key steps ( V → 24 , Scheme 8). We corroborated part of this hypothetic scheme by taking recourse to a model compound (7-(methylsulfinyl)-p-mentha-1,8-diene ( 32/33 ), readily prepared in two steps from perilla alcohol ( 30 )), which reacted as predicted by the proposed mechanism (Schemes 9 and 10).     

Synthesis of Functionalized Bicyclo[3.1.0]hexanes from Aucubin: An Access to Fused Aminocyclopentitols

Treatment of iodolactone 8a , having a cyclopentano[c]pyran skeleton and deriving from aucubin ( 1 ) (Scheme 1), with sodium trimethylsilanolate permitted a straightforward rearrangement to bicyclo[3.1.0]hexenes 10a and 10b (Schemes 3 and 4). Introduction of an N‐atom via a modified Curtius reaction provided an easy entry to fused aminocyclopentitols (Schemes 4 and 5). Target 4 is a conformationally restricted cyclopropane‐fused analogue of the glycosidase inhibitors mannostatins A ( 2 ) and B ( 3 ).     

A ‘One-Pot’ Anellation Method for the Transformation of Heptalene-4,5-dicarboxylates into Benzo[a]heptalenes

It has been found that dimethyl heptalene-4,5-dicarboxylates, when treated with 4 mol-equiv. of lithiated N,N-dialkylamino methyl sulfones or methyl phenyl sulfone, followed by 4 mol-equiv. of BuLi in THF in the temperature range of ?78 to 20°, give rise to the formation of 3-[(N,N-dialkylamino)sulfonyl]- or 3-(phenylsul-fonyl)benzo[a]heptalene-2,4-diols of. (cf. Scheme 4, and Tables 2 and 3). Accompanying products are 2,4-bis{[(N,N-dialkylamino)sulfonyl]methyl}- or 2,4-bis[(phenylsulfonyl)methyl]-4,10a-dihydro-3H-heptaleno[1,10-bc]furan-3-carboxylates as mixtures of diastereoisomers of. cf. Scheme 4, and (Tables 2 and 3) which are the result of a Michael addition reaction of the lithiated methyl sulfones at C(3) of the heptalene-4,5-dicarboxylates, followed by (sulfonyl)methylation of the methoxycarbonyl group at C(5) and cyclization of. (cf. Scheme 5). It is assumed that the benzo[a]heptalene formation is due to (sulfonyl)methylation of both methoxycarbonyl groups of the heptalene-4,5-dicarboxylates of. (cf. Schemes 6 and 8). The resulting bis-enolates 35 are deprotonated further. The thus formed tris-anions 36 can then cyclize to corresponding tris-anions 37 of cyclopenta[d]heptalenes which, after loss of N,N-dialkylamido sulfite or phenyl sulfinate, undergo a ring-enlargement reaction by 1,2-C migration finally leading to the observed benzo[a]heptalenes of. (cf. Schemes 8 and 9). The structures of the new product types have been finally established by X-ray crystal-structure analyses (cf. Figs. 1 and 2 as well as Exper. Part).     

New Synthetic Approach to Naphtho[1,2‐b]furan and 4′‐Oxo‐Substituted Spiro[cyclopropane‐1,1′(4′H)‐naphthalene] Derivatives

A one‐step synthesis of ethyl 2,3‐dihydronaphtho[1,2‐b]furan‐2‐carboxylate and/or ethyl 4′‐oxospiro[cyclopropane‐1,1′(4′H)‐naphthalene]‐2′‐carboxylate derivatives 2 and 3 , respectively, from substituted naphthalen‐1‐ols and ethyl 2,3‐dibromopropanoate is described (Scheme 1). Compounds 2 were easily aromatized (Scheme 2). In the same way, 3,4‐dibromobutan‐2‐one afforded the corresponding 1‐(2,3‐dihydronaphtho[1,2‐b]furan‐2‐yl)ethanone and/or spiro derivatives 8 and 9 , respectively (Scheme 6). A mechanism for the formation of the dihydronaphtho[1,2‐b]furan ring and of the spiro compounds 3 is proposed (Schemes 3 and 4). The structures of spiro compounds 3a and 3f were established by X‐ray structural analysis. The reactivity of compound 3a was also briefly examined (Scheme 9).     

Thermische Umlagerung von Propargyloxy-cycloheptatrien-Derivaten

The thermal rearrangement of 7 -propargyloxy-cycloheptatriene in decane solution at 180°C gave bicyclo[3.3.2]deca-3,7,9-trien-2-one ( 13 ) and the unstable 2,7-dihydro-cyclohepta[ b ]-pyran ( 12 ) (Scheme 2). The structures of these compounds were determined mainly by NMR. spectroscopy. Derivatives of 13 were also identified by comparison with known compounds (Scheme 3). Possible mechanisms for the formation of 13 and 12 are outlined in Schemes 5 and 6 respectively. The thermal rearrangement of 2-propargyloxy-cycloheptatrienone ( 21 ) gave, in high yield, 2-methyl-8H-cyclohepta[b]furan-8-one ( 22 ) (Scheme 7).     

2,4-Disubstituted Pyrrolo[2,3-d]pyrimidine α-D- and β-D-Ribofuranosides Related to 7-Deazaguanosine

Nucleobase-anion glycosylation (KOH, tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1), MeCN) of the pyrrolo[2,3-d]pyrimidines 4a – d with 5-O-[(1,1-dimethylethyl)dimethylsilyl]-2,3-O-(1-methylethylidene)-α-D -ribo-furanosyl chloride ( 5 ) gave the protected β-D -nucleosides 6a – d stereoselectively (Scheme 1). Contrary, the β-D -halogenose 8 yielded the corresponding α-D -nucleosides ( 9a and 9b ) apart from minor amounts of the β-D -anomers. The deprotected nucleosides 10a and 11a were converted into 4-substituted 2-aminopyrrolo[2,3-d]-pyrimidine β-D -ribofuranosides 1 . 10c , 12 , 14 , and 16 and into their α-D -anomers, respectively (Scheme 2). From the reaction of 4b with 5 , the glycosylation product 7 was isolated, containing two nucleobase moieties.     

The Synthesis of 4b, 5, 12, 12a-Tetrahydro-5, 12-ethano-13H-indeno[2,3-b]anthracenes, 4b, 5, 10, 10a - tetrahydro-5,10-ethano-11H-indeno[2,3-b]naphtalenes and 1,2,3,4,4a, 9a-Hexahydro-1,4-(peri-naphthaleno)-fluorenes

The synthesis of endo- and exo-13-oxo-4b, 5, 12, 12a-tetrahydro-5, 12-ethanoindeno[2,3-b]anthracene ( 23 ; Schemes 1 and 2), exo- and endo-11-oxo-4b, 5, 10, 10a-tetrahydro-5, 10-ethano-indeno[2,3-b]naphthalene ( 31 ; Scheme 3), 1,2,3,4,4a,9a-hexahydro?1,4-(peri-naphthaleno)-fluoren-9-one (36; Scheme 4), and the corresponding hydrocarbons of the stereoisomeric ketone pairs 23 and 36 , is described.     

Benzo[a]heptalenes from Heptaleno[1,2‐c]furans. Part 2

It is shown in this ‘Part 2’ that heptaleno[1,2‐c]furans 1 react thermally in a Diels–Alder‐type [4+2] cycloaddition at the furan ring with vinylene carbonate (VC), phenylsulfonylallene (PSA), α‐(acetyloxy)acrylonitrile (AAN), and (1Z)‐1,2‐bis(phenylsulfonyl)ethene (ZSE) to yield the corresponding 1,4‐epoxybenzo[d]heptalenes (cf. Schemes 1, 5, 6, and 8). The thermal reaction of 1a and 1b with VC at 130° and 150°, respectively, leads mainly to the 2,3‐endo‐cyclocarbonates 2,3‐endo‐ 2a and ‐ 2b and in minor amounts to the 2,3‐exo‐cyclocarbonates 2,3‐exo‐ 2a and ‐ 2b . In some cases, the (P*)‐ and (M*)‐configured epimers were isolated and characterized (Scheme 1). Base‐catalyzed cleavage of 2,3‐endo‐ 2 gave the corresponding 2,3‐diols 3 , which were further transformed via reductive cleavage of their dimesylates 4 into the benzo[a]heptalenes 5a and 5b , respectively (Scheme 2). In another reaction sequence, the 2,3‐diols 3 were converted into their cyclic carbonothioates 6 , which on treatment with (EtO)₃P gave the deoxygenated 1,4‐dihydro‐1,4‐epoxybenzo[d]heptalenes 7 . These were rearranged by acid catalysis into the benzo[a]heptalen‐4‐ols 8a and 8b , respectively (Scheme 2). Cyclocarbonate 2,3‐endo‐ 2b reacted with lithium diisopropylamide (LDA) at ?70° under regioselective ring opening to the 3‐hydroxy‐substituted benzo[d]heptalen‐2‐yl carbamate 2,3‐endo‐ 9b (Scheme 3). The latter was O‐methylated to 2,3‐endo‐(P*)‐ 10b . The further way, to get finally the benzo[a]heptalene 13b with MeO groups in 1,2,3‐position, could not be realized due to the fact that we found no way to cleave the carbamate group of 2,3‐endo‐(P*)‐ 10b without touching its 1,4‐epoxy bridge (Scheme 3). The reaction of 1a with PSA in toluene at 120° was successful, in a way that we found regioisomeric as well as epimeric cycloadducts (Scheme 5). Unfortunately, the attempts to rearrange the products under strong‐base catalysis as it had been shown successfully with other furan–PSA adducts were unsuccessful (Scheme 4). The thermal cycloaddition reaction of 1a and 1b with AAN yielded again regioisomeric and epimeric adducts, which could easily be transformed into the corresponding 2‐ and 3‐oxo products (Scheme 6). Only the latter ones could be rearranged with Ac₂O/H₂SO₄ into the corresponding benzo[a]heptalene‐3,4‐diol diacetates 20a and 20b , respectively, or with trimethylsilyl trifluoromethanesulfonate (TfOSiMe₃/Et₃N), followed by treatment with NH₄Cl/H₂O, into the corresponding benzo[a]heptalen‐3,4‐diols 21a and 21b (Scheme 7). The thermal cycloaddition reaction of 1 with ZSE in toluene gave the cycloadducts 2,3‐exo‐ 22a and ‐ 22b as well as 2‐exo,3‐endo‐ 22c in high yields (Scheme 8). All three adducts eliminated, by treatment with base, benzenesulfinic acid and yielded the corresponding 3‐(phenylsulfonyl)‐1,4‐epoxybenzo[d]heptalenes 25 . The latter turned out to be excellent Michael acceptors for H₂O₂ in basic media (Scheme 9). The Michael adducts lost H₂O on treatment with Ac₂O in pyridine and gave the 3‐(phenylsulfonyl)benzo[d]heptalen‐2‐ones 28a and 3‐exo‐ 28b , respectively. Rearrangement of these compounds in the presence of Ac₂O/AcONa lead to the formation of the corresponding 3‐(phenylsulfonyl)benzo[a]heptalene‐1,2‐diol diacetates 30a and 30b , which on treatment with MeONa/MeI gave the corresponding MeO‐substituted compounds 31a and 31b . The reductive elimination of the PhSO₂ group led finally to the 1,2‐dimethoxybenzo[a]heptalenes 32a and 32b . Deprotonation experiments of 32a with t‐BuLi/N,N,N′,N′‐tetramethylethane‐1,2‐diamine (tmeda) and quenching with D₂O showed that the most acid C? H bond is H? C(3) (Scheme 9). Some of the new structures were established by X‐ray crystal‐diffraction analyses (cf. Figs. 1, 3, 4, and 5). Moreover, nine of the new benzo[a]heptalenes were resolved on an anal. Chiralcel OD‐H column, and their CD spectra were measured (cf. Figs. 8 and 9). As a result, the 1,2‐dimethoxybenzo[a]heptalenes 32a and 32b showed unexpectedly new Cotton‐effect bands just below 300 nm, which were assigned to chiral exciton coupling between the heptalene and benzo part of the structurally highly twisted compounds. The PhSO₂‐substituted benzo[a]heptalenes 30b and 31b showed, in addition, a further pair of Cotton‐effect bands in the range of 275–245 nm, due to chiral exciton coupling of the benzo[a]heptalene chromophore and the phenylsulfonyl chromophore (cf. Fig. 10).     

[(1,3-Dioxolan-2-yliden)methyl]phosphonate und -phosphinate als (einfache) Synthone in der Heterocyclensynthese

[(1,3-Dioxolan-2-ylidene)methyl]phosphonates and -phosphinates as [simple] Synthons in Heterocyclic Synthesis The readily available [(1,3-dioxolane-2-ylidene)methyl]phosphonates and -phosphinates 2a–f (Scheme 1) can be transformed with amines to aliphatic ketene N,O-and N,N-acetales (see Scheme 2, 2a → 3–7 ). Alkanediamines yield with 2a–f the imidazolidines 8a–f and the hexahydropyrimidines 9a–d (Scheme 3). the oxazolidine derivatives 10a–e and the thiazolidine 11 are accessible under special reaction conditions starting from 2a, b (Scheme 4). Hydrazines react with the CN-group-containing ketene O,O-acetals 2a–c to the pyrazoles 12a–g , whereof 12a, d, e can be cyclized to pyrazolo[1,5-a]pyrimidines 13a–d (Scheme 5). Amidines as starting materials transform 2a–c in an analogous way to the pyrimidine derivatives 14a–c (Scheme 6).