Pyrimidines-19: Ring transformation of 5-nitrouracil into nitroresorcinols

The first intermolecular right transformation of a uracil derivative into the benzene system is reported. Treatment of 1,3-dimethyl-5-nitrouracil (1) with acetone in NaOMe/MeOH afforded 6-acetonyl-5,6-dihydro-1,3-dimethyl-5-nitrouracil (6) which was converted into 4-nitroresorcinol (5) upon treatment with NaOEt/EtOH at reflux. Reaction of1 with butanone gave two major products, 3-(5,6-dihydro-1,3-dimethyl-5-nitrouracil-6-yl)butanone (7) and the 1-(uracil-6-yl)butanone isomer (8). Prolonged treatment of7 with NaOEt/EtOH afforded 4-methyl-6-nitro-resorcinol (9) whereas8 was converted into 2-methyl-4-nitro-resorcinol (10). Treatment of1 with diethyl acetonedicar?ylate in NaOEt/EtOH afforded diethyl-2-(5,6-dihydro-1,3-dimethyl-5-nitrouracil-6-yl)-acetonedicar?ylate (2). Prolonged treatment of2 with NaOEt/EtOH at reflux afforded (5,6-dihydro-1,3-dimethyl-6-nitrouracil-6-yl)-acetate (3). Apparently,2 underwent a retroClaisen reaction to give3. Reaction of1 with ethyl acetoacetate in NaOEt/EtOH gave adduct isomers4 which underwent transformation reaction to give eventually 6-nitroresorcinol (5).     

Substituent effect on the photochemistry of 4,4-dialkoxylated- and 4-hydroxylated cyclohexenones

Photochemistry of the title compounds in various solvents was studied using a broad band of light centered at 350 nm. C-4 spiroketal cyclohexenone 4 (1.0 M) afforded dimers and 12b with the predominance of the former in polar solvent and the latter in nonpolar solvent. When the concentration was reduced to, 4 underwent solvent addition in nonpolar solvent and ring-contraction in polar solvents. 4,4-Dimethoxycyclohexenones 5a–d in TFE exhibited a different photochemical behavior. The 5-vinyl-substituted enone afforded the bridged-bicyclic ketone 16. Cyclohexenone 5b with methyl moieties at C-2 and C-3 underwent aromatization whereas cyclohexenones with butyl substituent at C-5 and 5d with silylated alcohol at C-2 underwent solvent exchange. In γ-hydroxylated cyclohexenones 6a–c ring-contraction and solvent exchange were observed. Photochemistry of the title compounds from the mechanistic viewpoint is also described.     

Addition of selenium dibromide to divinyl sulfide: spontaneous rearrangement of 2,6-dibromo-1,4-thiaselenane to 5-bromo-2-bromomethyl-1,3-thiaselenolane

Synthesis of the novel selenium heterocycles 1, 2, and 3 based on the addition reaction of selenium dibromide to divinyl sulfide is described. The reaction proceeded in CCl₄ at room temperature to give the thiaselenane 1. Even at low temperature in chloroform solution, the 6-membered thiaselenane 1 underwent spontaneous rearrangement to the 5-membered thiaselenolane 2. In turn, the thiaselenolane 2 underwent spontaneous dehydrobromination to the thiaselenole 3 in chloroform.     

Synthesis of 4,6-(and 5,7-)dimethoxy-3,3-dimethyl-1-indanones

Grignard reaction of ethyl 3-(3,5-dimethoxyphenyl)-propionate (4) followed by cyclodehydration of the carbinol (5) with conc H₂SO₄ gave 4,6-dimethoxy-3,3-dimethylindane (6). Oxidation of the indane (6) with CrO₃-pyridine complex in methylene chloride gave 4,6-dimethoxy-3,3-dimethylindan-1- one (1) in high yield. Conjugate addition of methyl magnesium iodide to methyl α-cyano-β-methyl-3,5-dimethoxycinnamate (11), prepared from 3,5-dimethoxyacetophenone (10) by Knoevenagel condensation, resulted in methyl 2-cyano-3-(3,5-dimethoxyphenyl)-3,3-dimethylpropionate (12). Refluxing the ester (12) with aq DMSO containing sodium chloride gave the corresponding nitrile (15) which underwent Höesch reaction to yield 5,7-dimethoxy-3,3-dimethylindan-1-one (2).     

Enantioselective diethylzinc addition to the exocyclic CN double bond of some 4-arylideneamino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-one derivatives

4-Arylideneamino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-ones 2a–f have been evaluated as substrates in the enantioselective diethylzinc addition reaction in the presence of (1S,2R)-N-alkyl-N-benzylnorephedrines 3a–d as chiral ligands. The utility of using a dual catalytic system (amino alcohol/halosilane) for the diethylzinc addition reaction has been also examined. The addition products 4-(1-arylpropyl)amino-3-mercapto-6-methyl-4H-1,2,4-triazin-5-ones 4a–f were obtained in high yields and with enantiomeric excesses of up to 92%. The treatment of arylimines 2a–f with a diethylzinc reagent did not affect the hetero-ring opening although the CN double bond of the lateral chain did undergo an addition reaction to yield the C-ethylated products 4a–f. The reductive cleavage of the 1,2,4-triazinyl heterocyclic ring from addition products 4a–f led smoothly to the corresponding free primary amines 5a–f without a significant loss of enantiomeric purity.     

Indenone chemistry—III: Use of the 2-carboethoxymethyl-6-methoxyindenone in the synthesis of the gibbane skeleton

The 2-carboethoxymethyl-6-methoxyindenone 5 has been synthesized in good yield. The endo head-to-tail dimer 6 and the exo head-to-tail dimer 7 can be synthesized stereoselectively from the indenone 5. Diels Alder addition of 5 to 1,3-butadiene affords the 7-methoxy-9aα-carboethoxymethyl-9a, 1,4aα, 4-tetrahydrofluorenone 8. The corresponding acid 9 can be cyclised to the 2 - methoxy - 4bαH - gibba - A,5 - tetraene - 8,10 - dione 10.     

Synthesis of bicyclic dioxetanes tethering a fluororescer through an ω-carbamoyl-substituted linker and their high-performance chemiluminescence in an aqueous system

Bicyclic dioxetanes 3 and 4 tethering a fluorescein or 4-(benzothiazol-2-yl)-3-hydroxyphenyl moiety through a linker were synthesized by the use of dihydrofuran-intermediate 5 or its advanced intermediate 6. These dioxetanes underwent base-induced decomposition to effectively give light due to intramolecular energy-transfer from an excited oxidobenzoate to a tethered fluorophore. Although the chemiluminescence efficiency Φ^CL values for 3 and 4 were only ca. 2-fold greater than that for parent 2 in a TBAF/acetonitrile system, these values were 30–550-fold greater than that for 2 in a NaOH/H₂O system. Such marked increase of Φ^CL was hardly observed by the simple addition of 25 or 26 as a model of a tethered fluorescer.     

A formal insertion of dichlorocarbene into a CArS bond

Reaction of phase transfer generated dichlorocarbene with 9-thiomethylphenanthrene (4) leads to 6 rather than the expected addition product 5. 6 is formally derived from a carbene insertion into the C,S bond. ¹³C-labelling shows that the CH₃ group of 4 is lost during the reaction.     

A general strategy for the formal synthesis of (−)-trans-kumausyne and total synthesis of (5R)-Hagen’s gland lactones from diacetone-d-glucose

A general strategy for the formal synthesis of (−)-trans-kumausyne 1 via the bicyclic lactone (3aR,5R,6aR)-4 and total synthesis of (5R)-Hagen’s gland lactones 2 and 3 via bicyclic lactone (3aR,5S,6aR)-5 starting from diacetone-d-glucose 6 is described. Syntheses of 4 and 5 were achieved by Wittig olefination–lactonization–Michael addition of the corresponding lactols 16 and 17, respectively.     

Search for a simpler synthetic model system for intramolecular 1,3-dipolar cycloaddition to the 5,6-double bond of a pyrimidine nucleoside

In search for a simpler model system for the study of intramolecular thermal reactions between the base and 5'-functionalized sugar moiety in nucleosides, 1-(3-azidopropyl)uracil (2), 1-(4-azidobutyl) pyrimidines (12 and 13) and 1-(5-azidopentyl)-uracil (14) was synthesized through the corresponding ω-benzoyloxy-(6,7 and 8) and ω-hydroxyalkyl-pyrimidines (9,10 and 11). Heating 2 gave 1,N⁶-trimethylene-6-aminouracil (4), while heating 12 and 13 gave N¹-C₆ cleaved addition products. 15 and 16, respectively. 15 was regiospecifically transformed to 1,2,3-triazole derivatives, 17,18 and 19. Heating 1-(4-azidobutyl)-5-bromouracil (20) yielded 3,9-tetramethylene-8-azaxanthine (22). 9 with NBA gave 1,0⁶-tetramethylene-5-bromo-6-hydroxy-5,6-dihydrouracil (24) and the 5-brominated analog of 9 (25). The 4-functionalized butyl side chain proved to serve as a substitute for the 5'-functionalized sugar moiety in pyrimidine ribonucleosides.     

Clean synthesis of calix[4]crown-5-sulfonyl cyclothiourea derivatives at room temperature in aqueous solution

Calix[4]-crown-5-sulfonyl cyclothiourea derivatives 6 and 7 were synthesized from calix[4]-crown-5-monosulfonylethylenediamine derivatives 4 and 5 and carbon disulfide through nucleophilic addition and subsequent cyclization of intramolecule at room temperature in aqueous solution. The advantages of the novel protocol are the mild reaction condition, free organic solvent, simple final treatment, easy isolation of products and excellent yields.     

Reactivite de lithiens derives d'ethers de la cyanhydrine du benzaldehyde vis-a-vis d'α-enones cycliques

Conjugate addition of reagent 1A to 2-cyclohexenone 3 can be realized in THF-HMPT, so that one-pot conjugate addition—CH₃I enolate trapping, leading to trans 2-methyl 3-benzoylcyclohexanone 17 can be easily performed. From isophorone 4 and Δ¹⁽⁹⁾-2-octalone 5, 1, 4-addition under kinetic control is observed in THF. In the presence of HMPA, the reaction is under thermodynamic control. At low temperatures enolate 19a is in equilibrium with 1A and 4; from 4 at 0° or 5 at ?65° or at 0°, the equilibrium lies on the side of starting materials. No reaction between 1A and 6 takes place in any solvent.The reaction of 1B and isophorone 4 in THF leads to 1, 2-addition under kinetic control and to 1, 4-addition under thermodynamic control. In THF-HMPT, retro-Michael addition is observed. However, 1, 2-addition takes place in THF to 6.The different results are interpreted in terms of interplay of ion-pairing, steric decompression and steric hindrance to 1, 4-addition as well as the possibility of participation of the Li cation for 1, 2-addition.     

Site selectivity in the reaction of tetracyanoethene with tetracyclo [5.3.2.02,10. 03,6] dodeca-4,8,11-triene : A borderline case of homo-diels-alder reaction

Tetracyanoethene reacted with tetracyclo [5.3.2.0^2,10.0^3.6] dodeca-4,8,11-triene (1) according to two competitive reaction modes, both involving the sole homotropilidene moiety, to give a mixture of adducts 4 and 6. Structure 6 was established by X-ray analysis. Compounds 4 and 6 result from a thermally allowed homocycloaddition and a forbidden[Π²₅ + σ²₅+ Π²_s+Π²_s] reaction, respectively. The reaction rate and the 6:4 ratio increased on passing from benzene to nitromethane as reaction medium. The homo-Dies-Alder reaction leading to 4 was shown to be reversible. In methanol compound 4 gave rise to a zwitterion which was trapped by solvent. Reaction mechanisms are discussed. A zwitterion is proposed as intermediate on the pathway to 6 whereas experimental findings do not permit a definitive choice between an ionic two step and a concerted cycloaddition in the formation of 4. The neutral and base catalyzed addition of methanol to the tetracyanoethylene moiety of 4, 6 and related derivatives was also investigated.     

Synthesis of γ-sulfonyl δ-lactones and β-sulfonyl styrenes

A facile route to the synthesis of γ-sulfonyl lactones 5 and β-sulfonyl styrenes 6 has been developed, achieving moderate to good yields via the (1) NaH mediated Michael addition of β-ketosulfones 3 and methyl acrylate in refluxing THF and (2) NaBH₄ mediated stereoselective reduction/lactonization of δ-ketoesters 4 in boiling MeOH, or (3) boron trifluoride etherate mediated ring-opening of lactones 5 in MeOH at reflux.     

Diastereoselective synthesis of multisubstituted isoindolines via Sequential Ugi and aza-Michael addition reaction

A new efficient and diastereoselective synthesis of multisubstituted isoindolines with two stereogenic centers via sequential Ugi/aza-Michael addition reaction was developed. Ugi-3CR of aldehydes 1, amines 2 and isocyanates 3 in the presence of catalytic amount of H₃PO₄ produced intermediates 4, which were then transformed to isoindolines 5 with good 1,3-trans diastereoselectivity in the presence of K₂CO₃ by intramolecular aza-Michael addition. Sequential Ugi-azide and aza-Michael addition reaction of aldehydes 1, amines 2 and trimethylsilyl azide 6 also produced 4-tetrazolyl substituted isoindolines 8 with good 1,3-trans diastereoselectivity in the presence of potassium carbonate.     

Conjugate addition of lithiated Schöllkopf's bislactim ether to 1E,3E-butadienylphosphonates: Stereocontrolled access to 2,3-anti-4E 2-amino-6-phosphono-4-hexenoic acid derivatives

Face-selective 1,6-addition of lithiated Schöllkopf's bislactime ether 5 to 4-substituted, 1,4- or 3,4-disubstituted 1E,3E-butadienylphosphonates6a-d allows a direct and stereocontrolled access to semi-rigid AP6 analogues, the 2,3-anti-4E 2-amino-6-phosphono-4-hexenoic acid derivatives 4a-c. The relative stereochemistry was assigned from a NMR study of the cyclic derivative 12c. Ten-membered trans-fused chair-boat-like transition states are invoked to rationalize the stereochemical outcome of the addition.     

Reactivite des dienes fonctionnels—IX: Reaction du tetracyanoethylene sur les dihydroanisoles

Tetracyanoethylene reacts with 5,6-dihydroanisoles 3 to give bicyclo[2,2,2]octenes 5. With 2,5-dihydroanisoles ², which are non-conjugated, TCNE leads to compounds 5, anisoles 1 and cyclobutanes 6 obtained by addition to the enol ether: these latter compounds are not stable and give compounds 1 and 5. Products 1 and 5 may also be obtained by reaction of 1-methoxy 3-methylene cyclohexenes 4.     

METAL DEPENDENT 1,3-ASYMMETRIC INDUCTION IN THE RETRO-[1,4]-BROOK REARRANGEMENT OF A SILYLATED TIGLYL ALKALIMETAL COMPOUND

At −78°C in THF, the tiglyl phenyl sulfide 5 and lithium naphthalenide gave a tiglyl lithium species which underwent an irreversible retro-[1,4]-Brook rearrangement giving rise to a 22:78 mixture of the anti,trans and the syn,trans diastereomer of the tiglyl silane 6. The same sulfide 5 and potassium naphthalenide provided the same products anti,trans- and syn,trans- 6 as a 96:4 mixture. This time they arose from the reversible retro-[1,4]-Brook rearrangement of a tiglyl potassium intermediate. © 1997 Elsevier Science Ltd.     

Elaboration of a novel type of planar-chiral methylene bridged biphenols based on [2.2]paracyclophanes

A new class of chiral methylene bridged biphenols with planar chirality has been designed and elaborated. The synthetic approach is based on the use of 4-hydroxy-5-hydroxymethyl[2.2]paracyclophane 9 derived from either racemic or enantiomerically pure (S)-4-formyl-5-hydroxy[2.2.]paracyclophane (FHPC) by reduction with LiAlH₄. The condensation of 9 with chiral racemic 4-hydroxy[2.2]paracyclophane 4 and achiral phenols, such as 2,5-dimethylphenol 10 and 2-isopropyl-5-methylphenol 11, afforded the target bridged biphenols 6, 12 and 13, respectively. The preliminary results on the asymmetric addition of Et₂Zn to benzaldehyde promoted by (S,S)-6 are reported.     

Synthesis of (−)-(1′S,4aS,8aR)- and (+)-(1′S,4aR,8aS)-4a-ethyl-1-(1′-phenylethyl)-octahydroquinolin-7-ones

A synthesis of the enamine (−)-(1′S)-5-ethyl-1-(1′-phenylethyl)-1,2,3,4-tetrahydropyridine 4 and its application in a synthesis of (−)-(1′S,4aS,8aR)- and (+)-(1′S,4aR,8aS)-4a-ethyl-1-(1′-phenylethyl)-octahydroquinolin-7-ones 5 and 6 is described. In addition, an X-ray study of 6 is reported. Finally, the preparation of (+)-(4aS,8aR)-4a-ethyl-octahydroquinolin-7-one 7 is described.