Effects of Remote Substitution on the Photo-oxidation of Exocyclic s-cis-Butadienes Grafted onto Bicyclo [2.2.1]heptanes. Thermal and Rhodium Catalyzed Rearrangements of 3,6-Dihydro-1,2-dioxines

The rates of photo-oxidation of exocyclic S-cis-butadienes grafted onto bicyclo-[2.2.1]heptanes and 7-oxabicyclo[2.2.1]heptanes ( 1–6 ) are dependent upon remote modifications of the bicyclic skeletons. They correlate with the rates of Diels-Alder additions of these dienes to strong dienophiles. The 2,3-dimethylidenenorbornane ( 1 ), 5,6-dimethylidene-2-norbornene ( 2 ) and 2,3-dimethylidene-7-oxanorbornane ( 3 ) gave the corresponding endo-peroxides (3,6-dihydro-1,2-dioxines) 7–9 in good yield. The 2, 3, 5, 6-tetramethylidene-7-oxanorbornane ( 4 ) gave the mono-endo-pe-roxide 6 , the latter did not react with a second equivalent of oxygen. Similarly, 5, 6-dimethylidene-7-oxa-2-norbornene ( 5 ) was unreactive toward photo-oxidation. Thermal isomerization of the endo-peroxides 7 and 9 gave, the trans-diepoxides 10 and 14 , respectively, with high stereoselectivity. The endo-peroxides 6 , 7 and 9 were cleanly isomerized into the corresponding α, β-unsaturated γ-hydroxy aldehydes in the presence of catalytic amounts of Rh₂(CO)₄Cl₂.     

Furopyridines. XI. 13C NMR Spectra of 2- or 3-Substituted Furo[2,3-b]-, Furo[3,2-b]-, Furo[2,3-c]- and Furo[3,2-c]pyridine

The ¹³C nmr spectra of 2- or 3-monosubstituted furo[2,3-b]- 1a-1j , furo[3,2-b]- 2a-2j , furo[2,3-c]- 3a-3j and furo[3,2-c]pyridine derivatives 4a-4j are reported. Effects by change in annelation and substituent effects on ¹³C chemical shifts and carbon-proton coupling constants are discussed. The spectra of benzo[b]furan derivatives 5a-5j having the corresponding substituent are also reported for comparison.     

Pairwise effects of chlorine substituents on the 13C NMR chemical shifts of dichlorobicyclo[2.2.1]heptanes (norbornanes)

The ¹³C NMR spectra of nine dichlorinated bicyclo[2.2.1]heptanes (norbornanes) have been measured and assigned. The pairwise effects of chlorine substituents which cause deviations from the additivity of single-substituent effects were investigated and are discussed. The largest effect found is the high-field shift of carbons bearing vicinal cis substituents. In the case of geminal substitution deviations from additivity were found to be to low field and large in the γ, smaller in the β and negligible in the α chemical shifts. The observed deviations for 1,3-disubstituted cases vary from ?3.2 to +1.1 ppm at different carbons, allowing no simple explanation. Replacement of α-hydrogen in a diaxial 1,3-arrangement by CH₃, OH or CI causes the single substituent effect, namely the γ_a effect, to change considerably.     

Influence of substituents on carbonyl carbon chemical shifts in 4-substituted bornane-2,3-diones and the preparation of bornane-2,3-dione

¹³C Chemical shifts of the 4-substituted boniane-2,3-dione(1–6) have been assigned. The shielding of the CO carbons brought about by electron withdrawing substituents is attributed to a field effect of the substituent which serves to increase the CO bond order. For the substituent bearing carbons C(4), enhanced shielding is noted and these carbons exhibit small substituent chemical shifts. A preparative method leading to borane-2,3-dione is described and briefly discussed.     

Substituent effects on carbon-13 chemical shifts of para-substituted benzylbenzenes

Carbon-13 chemical shifts of fourteen para-substituted benzylbenzenes have been determined. The relative substituent chemical shifts (SCS) of the methylene carbons and the aromatic ring carbons (C-4, C-1′ and C-4′) correlated well with the Hammett substituent effects using the dual substituent parameter method. The transmission of substituent effects through the benzylbenzene system is briefly discussed.     

Geometrical isomerism and 13C spectra of the β-substituted Enones R1?C(1)O?C(2)HC(3)H?R2

The ¹³C chemical shifts of the unsaturated carbons were measured in 31 cis and trans pairs of β-substituted enones R₁? C(1)O? C(2)H?C(3)H? R₂. In these polarized ethylenes the chemical shifts of the olefinic carbons are simply related by the equation δ_c=δ_t+A. The steric and electronic effects introduced by the R₁ and R₂ substituents influence the chemical shifts of C-2 and C-3 in both isomers. It is shown that the sign and magnitude of the intercept A mainly reflect the π-charge electronic density changes which arise in the cis isomer and are transmitted via the π-framework. The effect of the steric interaction on the chemical shift of C-3 in the cis isomers is postulated to be related to the symmetry of the substituents. Therefore, the differential shielding of C-3 is indicative of the conformational structure of the cis molecule.     

Pyrrolo[2,3-d] pyrimidines. I. 5-hydroxypyrrolo[2,3-d] pyrimidines

5-Hydroxy-7-alkyl-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitriles (VIIb-d) and 5-hydroxy-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid, ethyl ester (VIIa) were prepared from 5-carbethoxy-4-chloro-2-phenylpyrimidine (IV) via 4-[(cyanomethyl)alkylamino[-2-phenyl-5-pyrimidinecarboxylic acid, ethyl esters (Vb-d) and 4-[(carboxymethyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid, diethyl ester (Va), respectively. The hydroxy group of the pyrrolo-[2,3-d]pyrimidines could be methylated, acetylated and tosylated. Hydrolysis of 5-methoxy-7-methyl-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carbonitrile (IX) afforded the corresponding amide (X).     

Conversion of 3-cyclopentenyl hydroperoxide into 5-substituted-2,3-dioxabicyclo[2.2.1]heptanes

3-Cyclopentenyl hydroperoxide $\text{8}$ has been prepared from cyclopentadiene via hydroboration and autoxidation. Bromination of $\text{8}$ followed by treatment with an appropriate silver salt has afforded the 5-substituted-2,3-dioxabicyclo[2.2.1] heptanes $\text{11}$ ($\text{endo}$-bromo), $\text{13}$ ($\text{exo}$-bromo), and $\text{12}$ ($\text{exo}$-trifluoroacetoxy).     

Dithioketals as precursors for [2,3] sigmatropic rearrangements. Synthesis of betweenanenes with vinylic heteroatoms.

Alkoxycarbonyl-stabilized ylides from $\text{gem}$-disulfides undergo [2,3]sigmatropic shifts and provided the first entry to betweenanenes with a heteroatom (sulfur) directly attached to the encapsulated olefinic carbon.     

Diels-Alder Regioselectivity Controlled by Remote Substituents. The Cycloadditions of 1-(Dimethoxymethyl)-2,3-dimethylidene- and -2,3,5,6-tetramethylidene-7-oxabicyclo[2.2.1]heptanes

The syntheses of 2,3-dimethylidene- and 2,3,5,6-tetramethylidene-7-oxabicyclo[2.2.1]heptanes substituted in position C(1) are reported. The 1-dimethoxymethyl group in derivatives 2 and 6 controls the regioselectivity of the Lewis-acid-catalyzed Diels-Alder additions with methyl vinyl ketone and butynone. For the EtAlCl₂-catalyzed addition of methyl vinyl ketone to 6 , the regioselectivity can be reversed by a small solvent modification. The tetraene 2 is a versatile reagent for regioselective ‘tandem’ cycloadditions.     

Pyrrolopyrimidine nucleosides. IV. The synthesis of certain 4,5-disubstituted-7-(β-d-ribofuranosyl)pyrrolo[2,3-d]pyrimidines related to the pyrrolo[2,3-d]pyrimidine nucleoside antibiotics

The treatment of 4-chloro-7-(2′,3′,5′-tri-O-acetyl-β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine ( 4 ) with N-bromoacetamide in methylene chloride has furnished the 5-bromo derivative of 4 which on subsequent deacetylation provided a good yield of 5-bromo-4-chloro-7-(β-D-ribo-furanosyl)pyrrolo[2,3-d] pyrimidine ( 6 ). Assignment of the halogen substituent to position 5 was made on the basis of pmr studies. Treatment of 6 with methanolic ammonia afforded 4-amino-5-bromo-7-(β-D-ribofuranosyl)pyrrolo[2,3-d ]pyrimidine ( 8 , 5-bromotubercidin) and a subsequent study has revealed that the 4-chloro group of 6 was replaced preferentially in a series of nucleophilic displacement reactions. The analogous synthesis of 4,5-dichloro-7-(β-D-ribo-furanosyl)pyrrolo[2,3-d]pyrimidine ( 13b ) and 4-chloro-5-iodo-7-(β-D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine ( 13a ) from 4 furnished 5-chlorotubercidin ( 15 ) and 5-iodotubercidin ( 14 ), respectively, on treatment of 13b and 13a with methanolic ammonia. The possible biochemical significance of these tubercidin derivatives is discussed.     

Derivatives of exo-5-Aminomethyl-endo-5-methylbicyclo[2.2.1]hept-2-ene and exo-5-Aminomethyl-endo-5-methyl-exo-2,3-epoxybicyclo[2.2.1]heptane

exo-5-Aminomethyl-endo-5-methylbicyclo[2.2.1]hept-2-ene and its 2,3-epoxy derivative were synthesized, and their geometric parameters and conformational properties, in particular the barriers to rotation of the aminomethyl fragment about the exocyclic C⁵ÄC bond, were studied by the molecular-mechanics method (MMX) and compared with those found for structurally related exo-5-aminomethylbicyclo[2.2.1]hept-2-ene. The title compounds were brought into reactions with electrophilic reagents: arenesulfonyl chlorides, isocyanates, and isothiocyanates.     

Pyrimidines. LII Synthesis of pyrido[2,3-d]pyrimidine-2,4-diones and pyrido[2,3-d:6,5-d']dipyrimidine-2,4,6,8-tetrones

Reactivities of 5-dimethylaminomethylene-6-imino-1,3-dimethyluracil hydrochloride ( 1 ) toward a variety of active methylene compounds 2 and 5 were investigated. Treatment of 1 with active methylene compounds such as malononitrile and ethyl cyanoacetate in the presence of triethylamine gave pyrido[2,3-d]pyrimidine-2,4-dione derivatives 3. Reaction of 1 with barbituric acids resulted in the formation of pyrido[2,3-d:6,5-d′]di-pyrimidine-2,4,6,8-tetrone derivatives 6.     

NMR studies of sulphur heterocycles. II—substituent effects in the thieno[2,3-b] [1]benzothiophene and thieno[3,2-b] [1]benzothiophene systems

Substituent chemical shifts for the title systems have been determined at infinite dilution in CDCl₃ from a study of 40 derivatives. An excellent correlation is found between the ortho effect of substituents in the thiophene ring and the corresponding effects in thiophene itself, indicating negligible perturbation by the fused rings. Long range effects of 2- and 3-substituents on the 5- and 6-protons are electronic in origin, but cannot be interpreted in terms of simple resonance theory. These long range effects correlate linearly with σ_p°. An O, S-cis conformation for the formyl group in 2-formyl-thieno[2,3-6][1]benzothiophene is adduced on the basis of chemical shifts.     

Preparation and Reactions of 2-Oxa-6-thiabicyclo[3.2.0]-heptanes and 2-Oxa-5-thiabicyclo[2.2.1]heptanes from Pentoses

Abstract:

The preparation of the two diastereoisomeric 3-methoxy-2-oxa-6-thiabicyclo-[3.2.0]heptan-4-ols 4 and 5 from D-xylose 1 via methyl 2,3-anhydro-α-D-ribofuranoside and the corresponding β-anomer is described. Oxidation of 4 and 5 yields the sulfoxides 6 and 7 and the sulfones 8. – On the other hand, the two diastereoisomeric 3-methoxybicyclo[2.2.1]heptan-7-ols 11 and 12 are obtained from methyl 5-acetylthio-5-deoxy-2-O-mesyl-D-xylofuranosides 9 and 10 via Mitsunobu reaction and intramolecular cyclization. – The stereoisomeric counterparts of 4 and 5, 13 and 14, are obtained in only four steps from L-arabinose.     

Reassignment of configurations for 5-bromo-2,3-dioxabicyclo[2.2.1]heptanes and its mechanistic implications

The configuration of the 5-bromo-2,3-dioxabicyclo[2.2.1]heptane obtained by treating 3,4-dibromocyclopentyl hydroperoxide with AgO₂CCF₃ and that of the isomer obtained using Ag₂O have been reassigned after identifying which 4-bromocyclopentane-1,3-diol is obtained from each upon catalytic hydrogenation. This implies a bromonium ion mechanism for the AgO₂CCF₃-induced dioxabicyclization in contrast to the S_N2-type displacements found for related compounds.     

The synthesis of [1]benzothieno[2,3-c]quinolines, [1]benzothieno[2,3-c][1,2,4]triazolo[4,3-a]quinoline,and [1]benzothieno[2,3-c]tetrazolo[1,5-a]quinoline

Photocyclization of 3-chloro-N-phenylbenzo[b]thiophene-2-carboxamide 10 afforded [1]benzothieno[2,3-c]-quinolin-6(5H)-one 11 which was chlorinated to 6-chloro[1]benzothieno[2,3-c]quinoline 12 followed by dechlorination to give [1]benzothieno[2,3-c]quinoline 5 . A series of 6-substituted alkoxy and thioalkoxy[1]benzothieno[2,3-c]quinoline derivatives were prepared along with the N-methyl quaternary salt 13 of 5 . 6-Chloro[1]-benzothieno[2,3-c]quinoline 12 was converted into 6-hydrazino[1]benzothieno[2,3-c]quinoline 23 which upon treatment with formic acid yielded [1]benzothieno[2,3-c][1,2,4]triazolo[4,3-a]quinoline 6 . Treatment of 23 with nitrous acid resulted in [1]benzothieno[2,3-c]tetrazolo[1,5-a]quinoline 7 . Compounds 6 and 7 are novel heterocyclic ring systems.     

Cleaner Citral Condensation - Synthesis of Pyrano [2,3-a] Carbazoles

Citral condensation¹ with phenols are characterized by the formation of multitudinous products, poor yields and unpredictable course as evidenced by conflicting reports.^2,3 They are sensitive to temperature and amount of catalyst -usually pyridine - used.⁴ In the attempts to synthesize pyrano [2,3-a] carbazole derivatives isomeric with Mahanimbine⁵ (I), a representative C-23 pyrano [3,2-a] carbazole alkaloid, the usual pyridine catalysed citral condensation was tried but the expected pyranocarbazole derivatives could not be isolated in pusstate. The reaction of l-hydroxy-6-methylcarbazole with citral in pyridine, for instance, gave a product on chromatographic purification followed by micro-distillation at 195–200° (bath)/0.01 mm. Though homogeneous on TLC, it indicated the presence of atleast two closely related pyranocarbazole derivatives when its PMR spectrum was examined. It showed two deuterium exchangeable protons at δ 7.86 and δ 8.00. The olefinic protons appeared as doublet of doublets at δ 5.52 and δ 6.52. Addition of benzoic acid (2% of thecatalyst) as recommended⁶ gave no better results.     

Synthesis of 1H-pyrazino[1,2-a]pyrido[2,3-e]pyrazine and 2H-Pyrano[2,3-b]pyrido[2,3-e]pyrazine Derivatives

With a continuing interest on heteropolycyclic structures which may show biological activities, we synthesized new tricyclic derivatives in which the pyridopyrazine skeleton is fused with pyrazine 7 and 8, B , n = 1. However, the initial design of obtaining also the cyclohomologous structure B (n = 2) produced instead a pyranopyridopyrazine derivative 11 . Thus during the attempt to prepare a pyridodiazepine intermediate, beside a very small amount of the desired product 10 , the pyridopyrazine 9 was obtained. The latter compound reacted with chloroacetyl chloride/chloroketene to give 4-carbethoxy-10-(chloroacetyl)-5,10-dihydro-5-methyl-2H-pyrano[2,3-b]pyrido[2,3-e]pyrazin-2-one ( 11 ). In studying the behavior of this derivative, compounds 12–14 were obtained. Compounds 4b,c, 5a,b, 7, 8, 9 and 14 have been submitted to preliminary pharmacological screening as CNS depressant agents.     

Furopyridines. XXIV. Nitration,chlorination, acetoxylation and cyanation of 2,3-dihydrofuro[2,3-b]-, -[3,2-b]-, -[2,3-c]- and -[3,2-c]pyridine N-Oxides

Nitration of 2,3-dihydrofuro[3,2-b]- N-oxide 3b and -[2,3-c]pyridine N-oxide 3c afforded the nitropyridine compounds 4b, 5b and 6 from 3b and 4c, 5c, 5′c and 7 from 3c , while -[2,3-b]- N-oxide 3a and -[3,2-c]pyridine N-oxide 3d did not give the nitro compound. Chlorination of 3b and 3c with phosphorus oxychloride yielded mainly the chloropyridine derivatives 15b, 15′b from 3b and 15c and 15′c from 3c , whereas 3a and 3d gave pyridine derivatives formed through fission of the 1–2 ether bond of the furo-pyridines 13a , 14 and 13d . Acetoxylation of 3b and 3c gave 3-acetoxy derivatives 18b and 18c and the parent compound 1b and 1c . Acetoxylation of 3a yielded compounds formed through fission of the 1–2 bond 16 and 17 and 3d gave furopyridones 19 and 19 ′. Cyanation of 3b and 3c yielded mainly the cyanopyridine compounds 20b, 20c and 20′c . Cyanation of 3a and 3d gave the cyanopyridine compounds 20a , 20d and 20′d accompanying formation of the pyridine derivatives 21a, 21d and 21′d .