Reaction of ketenes with N,N-Disubstituted 2-Aminomethylenecycloalkanones III. Synthesis of N,N-Disubstituted 3,3-Diehloro-4-amino-5,6-polymethylene-3,4-dihydro-α-pyrones

The reaction of dichloroketene with N,N-Disubstituted 2-aminomethylenecyclopentanones, cyclohexanones, cycloheptanones and cyclooctanones gave the 1,4-cycloadducts, namely N,N-Disubstituted 3,3-dichloro-4-amino-5,6-polymethylene-3,4-dihydro-α-pyrones. The structures of these products were determined by uv, ir and nmr spectral data, as well as by dehydrochlorination of the adduct, 3,3-dichloro-4-diphenylamino-5,6-tetramethylene-3,4-dihydro-α-pyrone, which led to 3-chloro-4-diphenylamino-5,6-tetramethylene-α-pyrone. The by-product of the cycloaddition reaction was the N,N-Disubstituted dichloroacetamide, the formation of which varies according to the substituents on the nitrogen atom.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. XX. Synthesis of 2H-pyrano[2,3-f]quinazoline derivatives

The polar 1,4-cycloaddition of dichloroketene to N,N-disubstituted (E)-6-aminomethylene-7,8-dihydro-(2-methyl)(2-phenyl)quinazolin-5(6H)-ones III , prepared in good yields from 7,8-dihydro-(2-methyl)-(2-phenyl)quinazolin-5(6H)-ones via their 6-hydroxymethylene derivatives I and II , gave in satisfactory to excellent yields N-N-disubstituted 4-amino-3,3-dichloro-3,4,5,6-tetrahydro-(8-methyl)(8-phenyl)-2H-pyrano- [2,3,-f]quinazolin-2-ones IV , which are derivatives of the new heterocyclic system pyrano[2,3-f]quinazoline. This cycloaddition occurred both in the case of aliphatic and aromatic N-substitution only with 2-phenyl-enaminones III , whereas with 2-methyl derivatives III the reaction took place only in the case of aromatic N-monosubstitution. Dehydrochlorination of IV with DBN afforded, generally in excellent yields, N,N-disubstituted 4-amino-3-chloro-5,6-dihydro-(8-methyl)(8-phenyl)-2H-pyrano[2,3-y]quinazolin-2-ones, which were dehydrogenated with DDQ to give N,N-disubstituted 4-amino-3-chloro-(8-methyl)(8-phenyl)-2H-pyrano[2,3-f]quinazolin-2-ones in excellent yields.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. XVI. Synthesis of N,N-disubstituted 4-amino-5,6-tetramethylene-3-phenyl-2-pyranones

1,4-Cycloaddition of phenylchloroketene (prepared in situ from α-chlorophenylacetyl chloride and triethyl-amine) to a number of N,N-disubstituted (E)-2-aminomethylenecyclohexanones gave the corresponding adducts, namely N,N-disubstituted 4-amino-3-chloro-3,4,5,6,7,8-hexahydro-2H-1-benzopyran-2-ones III in the case of aliphatic N,N-disubstitution or aromatic N-monosubstitution. Purification of III was possible only in the case of IIIh (NR₂ = NMePh), therefore they were dehydrochlorinated in situ with DBN to give the title compounds in moderate overall yields.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones VIII. Synthesis of N,N-disubstituted 4-amino-3-chloro-6-phenyl-2H-pyran-2-ones

The dipolar 1,4-cycloaddition of dichloroketene to N,N-disubstituted 3-amino-1-phenyl-2-propene-1-onesled directly to N,N-disubstituted 4-amino-3-chloro-6-phenyl-2H-pyran-2-ones only in the case of an usual aliphatic N,N-disubstitution. In the case of partial or full aromatic N-substitution, N,N-disubstituted 4-amino-3,3-dichloro-3,4-dihydro-6-phenyl-2H-pyran-2-ones were instead obtained, which were dehydrochlorinated with DBN to the corresponding 4-amino-3-chloro-6-phenyl-2H-pyran-2-ones.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. XVIII. Synthesis of N,N-disubstituted 4-amino-3-phenyl-2H-naphtho[1,2-b]pyran-2-ones

1,4-Cycloaddition of phenylchloroketene to N,N-disubstituted 2-aminomethylene-3,4-dihydro-1(2H)naphthalenones gave the corresponding adducts, namely N,N-disubstituted 4-amino-3-chloro-3,4,5,6-tetrahydro-3-phenyl-2H-naphtho[1,2-b]pyran-2-ones II, in the case of aliphatic N,N-disubstitution or aromatic N-monosubstitution. Apart from IIf (NR₂ = NMePh), adducts II were unstable and were dehydrochlorinated in situ with DBN to give N,N-disubstituted 4-amino-5,6-dihydro-3-phenyl-2H-naphtho[1,2-b]pyran-2-ones III in fair overall yields. Compounds III were dehydrogenated with Pd/C in boiling p-cymene to afford the title compounds generally in high yields.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. XI. Synthesis of 2H-pyrano[3,2-g]benzothiazole derivatives

Cycloaddition of dichloroketene to N,N-disubstituted 6-aminomethylene-5,6-dihydro-2-phenylbenzothiazol-7-(4H)ones gave in good yield N,N-disubstituted 4-amino-3,3-dichloro-3,4,5,6-tetrahydro-8-phenyl-2H-pyrano[3,2-g]benzothiazol-2-ones II, which are derivatives of the new heterocyclic system 2H-pyrano[3,2-g]benzothiazole. Dehydrochlorination with triethylamine of II afforded N,N-disubstituted 4-amino-3-chloro-5,6-dihydro-8-phenyl-2H-pyrano[3,2-g]benzothiazol-2-ones III in good to moderate yield. The dimethylamino adduct was dehydrochlorinated in high yield by refluxing in toluene, whereas the diisopropylamino adduct gave in low yield 6-(2,2-dichloroethylidene)-5,6-dihydro-2-phenylbenzothiazol-7-(4H)one with the triethylamine treatment. The dehydrochlorinated product IIId (NR₂ = pyrrolidino) was obtained directly in low yield by cycloaddition of dichloroketene to the corresponding enaminone. Full aromatisation of IIIa,g [NR₂ = N(CH₃)₂ and N(CH₃)C₆H₅, respectively] to the corresponding N,N-disubstituted 4-amino-3-chloro-8-phenyl-2H-pyrano-[3,2-g]benzothiazol-2-ones was accomplished with DDQ in refluxing benzene.     

Synthesis of 1,2′,3,3′,5′,6′-hexahydro-3-phenylspiro[isobenzofuran-1,4′-thiopyrans] and 1,2′,3,3′,5′,6′-hexahydro-3-phenylspiro-[isobenzofuran-1,4′-pyrans]

The 1,2′,3,3′,5′,6′-hexahydro-3-phenylspiro[isobenzofuran-1,4′-thiopyran] ring system ( 2a ) has been prepared from o-bromobenzoic acid. The 1,2′,3,3′,5′,6′-hexahydro-3-phenylspiro[isobenzofuran-1,4′-pyran] ring system ( 3a ) has been prepared from 2-bromobenzhydrol methyl ether. Several 3-(dimethylaminoalkyl) derivatives of both 2a and 3a were prepared by lithiation followed by alkylation.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. XIX. Synthesis of N,N-disubstituted 4-amino-3-phenyl-2H-furo[2,3-h]-1-benzopyran-2-ones (4-amino-3-phenylangelicins). Crystal and molecular structure of 3-Phenylangelicin

1,4-Cycloaddition of phenylchloroketene to N,N-disubstituted 5-aminomethylene-6,7-dihydrobenzo[b]- furan-4(5H)-ones gave the corresponding adducts, namely N,N-disubstituted 4-amino-3-chloro-3,4,5,6-tetra- hydro-3-phenyl-2H-furo[2,3-h]-l-benzopyran-2-ones II , which were dehydrochlorinated with DBN to N,N-disubstituted 4-amino-5,6-dihydro-3-phenyl-2H-furo[2,3-h]-1-benzopyran-2-ones III . Compounds III afforded the title compounds IV by dehydrogenation with DDQ. In the cycloaddition step, 3-phenylangelicin V , whose structure was confirmed by ¹H-nmr shift reagents data and by X-ray crystal structure determination, was almost always formed, probably starting from II by dehydrochlorination, dehydrogenation and hydrogenolysis of the disubstituted amino group. Separation of V was achieved by alumina chromatography either in the cycloaddition step or, in most cases, in the dehydrochlorination step. 3-Phenylangelicin crystallizes in the trigonal system, space group R3, with cell parameters (hexagonal axes) a = b = 41.021(10), c = 3.888(2) Å. The angelicin moiety forms a dihedral angle of 42.1(1)° with the phenyl substituent. Disordered solvent molecules of ethyl acetate are clathrated in channels in the direction of the crystallographic axis c.     

1,2-Epoxycarotinoide. 6. Mitteilung. Isolierung von 1′,2′-Epoxy-1′,2′-dihydro-ε,ψ-carotin aus der ‘Delta-Mutanten’-Tomate

1,2-Epoxycarotenoids Isolation of 1′,2′-Epoxy-1′,2′-dihydro-ε,ψ-carotene from a ‘Delta Mutant’ Tomato From ‘Delta Mutant’ tomatoes, optically active 1′,2′-epoxy-1′,2′-dihydro-ε,ψ-carotene ( 7 ) was isolated. According to the CD data, the configuration is 6R and presumably 2′S.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. XIII. Synthesis of 2H-pyrano[3,2-d]-1-benzoxepin derivatives

Cycloaddition of dichloroketone to N,N-disubstituted (E)-4-aminomethylene-3,4-dihydro-1-benzoxepin-5(2H)-ones gave N,N-disubstituted 4-amino-3,3-dichloro-3,4,5,6-tetrahydro-2H-pyrano[3,2-d]-1-benzoxepin-2-ones II, which are derivatives of the new heterocyclic system 2H-pyrano[3,2-d]-1-benzoxepin. Dehydrochlorination with triethylamine of II afforded N,N-disubstituted 4-amino-3-chloro-5,6-dihydro-2H-pyrano-[3,2-d]-1-benzoxepin-2-ones III in good to moderate yields. In the triethylamine treatment of IIh (NR₂ = diphenylamino), 3-chloro-5,6-dihydro-2H-pyrano[3,2-d]-1-benzoxepin-2-one was isolated in low yield near to IIIh, whereas IIc (NR² = diisopropylamino) gave in low yield 4-diisopropylamino-5,6-dihydro-2H-pyrano(3,2-d)-1-benzoxepin-2-one.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. X. Synthesis of N,N-disubstituted 6-alkyl-4-amino-3,3-dichloro-3,4-dihydro-2H-pyran-2-ones and of 6-alkyl-4-amino-3-chloro-2H-pyran-2-ones

Cycloaddition of dichloroketene to N,N-disubstituted 1-amino-4-methyl-1-penten-3-ones and 1-amino-4,4-dimethyl-1-penten-3-ones occurred in moderate to fair yield only in the case of aromatic N-substitution to give N,N-disubstituted 6-alkyl-4-amino-3,3-dichloro-3,4-dihydro-2H-pyran-2-ones, which were dehydrochlorinated with DBN to afford in good yield N,N-disubstituted 6-alkyl-4-amino-3-chloro-2H-pyran-2-ones. In the case of aliphatic N,N-disubstitution, cyclo-addition led directly to 6-alkyl-4-dialkylamino-3-chloro-2H-pyran-2-ones only for N,N-disubstituted 1-amino-4,4-dimethyl-1-penten-3-ones. The reaction between 1-dimethylamino-4-methyl-1-penten-3-one and dichloroketene gave 3-chloro-4-dimethylamino-3,6-dihydro-6-isopropylidene-2H-pyran-2-one in low yield.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. XII. Synthesis of N,N-disubstituted 4-amino-3-chloro-6-(2-methyl-l-propenyl) (2-phenylethenyl)-2H-pyran-2-ones

Cycloaddition of dichloroketene to N,N-disubstituted (E)-amino-5-methyl-1,4-hexadien-3-ones IV and (E,E)-1-amino-5-phenyl-1,4-pentadien-3-ones V occurred in moderate to good yield only in the case of aromatic N-substitution to give N,N-disubstituted 4-amino-3,3-dichloro-3,4-dihydro-6-(2-methyl-l-propenyl) (2-phenylethenyl)-2H-pyran-2-ones, which were dehydrochlorinated with DBN to afford in good yield N,N-disubstituted 4-amino-3-chloro-6-(2-methyl-propenyl)(2-phenylethenyl)-2H-pyran-2-ones. In the case of aliphatic N,N-disubstitution (dimethylamino group) of enaminones IV and V, the Cycloaddition led directly in low yield to 3-chloro-4-dimethylamino-6-(2-methyl-l-propenyl)(2-phenylethenyl)-2H-pyran-2-ones.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. XVII. Synthesis of 2H-[1]benzothiepino[5,4-b]pyran derivatives

1,4-Cycloaddition of dichloroketene to a number of N,N-disubstituted (E)-4-amino methylene-3,4-dihydro-[1]benzothiepin-5(2H)-ones gave in excellent yield N,N-disubstituted 4-amino-3,3-dichloro-3,4,5,6-tetrahydro-2H-[1]benzothiepino[5,4-b]pyran-2-ones III, which are derivatives of the 2H-[1]benzothiepino[5,4-b]pyran system. Dehydrochlorination of III with DBN afforded N,N-disubstituted 4-amino-3-chloro-5,6-dihydro-2H-[1]-benzothiepino[5,4-b]pyran-2-ones, generally in excellent yield.     

Synthese und Chiralität von (5R, 6R)-5,6-Dihydro-β, ψ-carotin-5,6-diol, (5R, 6R, 6′R)-5,6-Dihydro-β, ε-carotin-5,6-diol, (5S, 6R)-5,6-Epoxy-5,6-dihydro-β, ψ-carotin und (5S, 6R, 6′R)-5,6-Epoxy-5,6-dihydro-β,ε-carotin

Synthesis and Chirality of (5R, 6R)-5,6-Dihydro-β, ψ-carotene-5,6-diol, (5R, 6R, 6′R)-5,6-Dihydro-β, ε-carotene-5,6-diol, (5S, 6R)-5,6-Epoxy-5,6-dihydro-β,ψ-carotene and (5S, 6R, 6′R)-5,6-Epoxy-5,6-dihydro-β,ε-carotene Wittig-condensation of optically active azafrinal ( 1 ) with the phosphoranes 3 and 6 derived from all-(E)-ψ-ionol ( 2 ) and (+)-(R)-α-ionol ( 5 ) leads to the crystalline and optically active carotenoid diols 4 and 7 , respectively. The latter behave much more like carotene hydrocarbons despite the presence of two hydroxylfunctions. Conversion to the optically active epoxides 8 and 9 , respectively, is smoothly achieved by reaction with the sulfurane reagent of Martin [3]. These syntheses establish the absolute configurations of the title compounds since that of azafrin is known [2].     

Optisch aktive 4,5-Epoxy-4,5-dihydro-α-ionone und Synthese der stereoisomeren 4,5:4′,5′-Diepoxy-4,5,4′,5′-tetrahydro-ϵ,ϵ-carotine und der sterische Verlauf ihrer Hydrolyse

Optically Active 4,5-Epoxy-4,5-dihydro-α-ionones; Synthesis of the Stereoisomeric 4,5:4′,5′-Diepoxy-4,5,4′,5′-tetrahydro-?,?-carotenes and the Steric Course of their Hydrolysis We prove that epoxidation with peracid of α-ionone, contrary to a recently published statement, predominantly leads to the cis-epoxide. Acid hydrolysis affords a single 4,5-glycol whose structure, established by an X-ray analysis, shows that oxirane opening occurred with inversion at the least substituted position (C(4)). Stable cis-and trans-epoxides are prepared by epoxidation of the C₁₅-phosphonates derived from α-ionone. Both the racemic and optically active form are used for the synthesis of the 4,5:4′,5′-diepoxy-4,5,4′,5′-tetrahydro-?,?-carotenes having the following configuration in the end groups: meso-cis/cis, meso-trans/trans, rac-cis/trans, rac- and (6R, 6′ R)-cis/cis, rac- and (6R, 6′R)-trans/trans, rac- and (6R, 6′R)-cis/trans, and (6R, 6′ R)-cis/?. Acid hydrolysis of the cis/cis-epoxycarotenoids under relatively strong conditions occurs again with inversion at C(4)/C(4′) in case of the cis/cis-epoxycarotenoids, but at C(5)/C(5′) in case of the trans/trans-epoxycarotenoids. An independent synthesis of this 4,5,4′,5′-tetrahydro-?,?-carotene-4,5,4′,5′-tetrol is presented. The irregular results of the oxirane hydrolysis are explained by assumption of neighbouring effects of the lateral chain. 400-Mz-¹H-NMR data are given for each of the stereoisomeric sets. In the visible range of the CD spectra, the (6R, 6R′)-epoxycarotenoids compared with (6R, 6R′)-?,?-carotene exhibit an inversion of the Cotton effects.     

Carotinoide mit 7-Oxabicyclo[2.2.1]heptyl-Endgruppen. Teil I. Versuch einer Synthese von Cycloviolaxanthin (= (3S,5R,6R,3′S,5′R,6′R)-3,6:3′,6′-Diepoxy-5,6,5′,6′-tetrahydro-β,β-carotin-5,5′-diol)

Carotenoids with 7-Oxabicyclo[2,2.1]heptyl End Groups. Attempted Synthesis of Cycloviolaxanthin ( = (3S,5R,6S,3′S,5′R,6′R)-3,6:3′,6′- Diepoxy-5,6,5′,6′-tetrahydro-β,β-carotin-5,5′-diol) Starting from our recently described synthon (+)- 24 , the enantiomerically pure 3,6:4,5:3′,6′:4′,5′-tetraepoxy-4,5,4′,5′-tetrahydro-ε,ε-carotene ( 34 ) and its 15,15′-didehydro analogue 32 were synthesized in eleven and nine steps, respectively (Scheme 4). Chiroptical data show, in contrast to the parent ε,ε-carotene, a very weak interaction between the chiral centers at C(5), C(5′), C(6), C(6′), and the polyene system. Diisobutylaluminium hydride reduction of 32 lead rather than to the expected 15,15′-didehydro analogue 35 of Cycloviolaxanthin ( 8 ), to the polyenyne 36 (Scheme 5). We explain this reaction by an oxirane rearrangement leading to a cyclopropyl ether followed by a fragmentation to an aldehyd on the one side and an enol ether on the other (Scheme 6). This complex rearrangement includes a shift of the whole polyenyne chain from C(6), C(6′) to C(5), C(5′) of the original molecule.     

Synthesis of 7,8,9,10-tetrahydropyrido[3′,4′:4,5]pyrrolo[2,3-c]quinolines

A series of structurally novel 7,8,9,10-tetrahydropyrido[3′,4′:4,5]pyrrolo[2,3-c,]quinolines, 4a-c , were synthesized via a facile Fischer indole cyclization from the appropriately substituted hydrazinoquinolines 2a-c . Acetamides 4a,c were hydrolyzed to 5a,b and further converted to tertiary amines 6a-c . Potent antihypertensive activity has been observed with a number of the title compounds as well as the intermediate 3a .     

Photochemical Reactions. 126th Communication. Photochemistry of an α, β: δ, ε-unsaturated ketone: 4-(2′, 7′, 7′-Trimethylbicyclo [3.2.0]hept-2′-en-1′-yl)-3-buten-2-one

On ¹n,π*-excitation, the title compound 2 undergoes a photoinduced intramolecular [4 + 2]-cycloaddition affording the tetracyclic enol ether 3 as the only product in 79% yield. The assigned structure of 3 was confirmed by its conversion to the p-nitrobenzoate 6 whose structure was determined by X-ray analysis.     

Reaction of sulfene with heterocyclic N,N-disubstituted α-aminomethyleneketones. X. Synthesis of thieno[2,3-h]-1,2-benzoxathiin derivatives

The polar 1,4-cycloaddition of sulfene to N,N-disubstituted (E)5-aminomethylene-6,7-dihydrobenzo[b]-thiophen-4(5H)ones II gave in excellent yield and only in the case of aliphatic N-substitution, N,N-disubstituted 4-amino-3,4,5,6-tetrahydrothieno[2,3-h]-1,2-benzoxathiin 2,2-dioxides III, which are derivatives of the new heterocyclic system thieno[2,3-h]-1,2-benzoxathiin. Dehydrogenation with DDQ of cycloadducts IIIa-d was successful only in the case of IIIa (NR₂ = dimethylamino) to give in low yield 4-dimethylamino-3,4-dihydrothieno[2,3-h]-1,2-benzoxathiin 2,2-dioxide.