Computational assessment of the electronic structures of cyclohexa-1,2,4-triene, 1-oxacyclohexa-2,3,5-triene (3delta(2)-pyran), their benzo derivatives, and cyclohexa-1,2-diene. An experimental approach to 3delta(2)-pyran.

The six-membered cyclic allenes given in the title have been studied theoretically by means of an MR-CI approach. For all compounds, the allene structures were found to be the ground states in the gas phase. In the cases of cyclohexa-1,2-diene (1), the isobenzene 2, and the isonaphthalene 7, the most stable structures having a planar allene moiety are the diradicals 1b, 2b, and 7b, representing the transition states for the racemization of 1a, 2a, and 7a and being less stable than the latter by 14.1, 8.9, and 11.2 kcal/mol, respectively. At variance with this order, the 3delta(2)-pyran 4 and the chromene 5 have the zwitterions 4c and 5c as the most stable planar structures, which lie only 1.0 and 5.4 kcal/mol above 4a and 5a, respectively. According to the simulation of the solvent effect, 4c even becomes the ground state of 4 in THF solution. The frontier orbitals of the respective states of 2 and 4 suggest different rates and sites for the reaction with nucleophiles. For the first time, the pyran 4 has been generated and trapped. As a precursor for 4, 3-bromo-4H-pyran (9) was chosen, the synthesis of which was achieved on two routes from 4H-pyran. The treatment of 9 with potassium tert-butoxide (KOt-Bu)/18-crown-6 gave 4-tert-butoxy-4H-pyran as the only discernible product, whether styrene or furan was present, indicating the interception of 4 by KOt-Bu. Finally, the disagreement between the experiment and the theory concerning the heat of formation and the electronic nature of the isobenzene 2 is resolved by demonstrating that the experimental data can provide only an upper limit of the DeltaH(f) degrees value.     

Silyl stabilization of unsymmetrical bisketenes: 3-(Trimethylsilyl) and 3-(triisopropylsilyl)-2-substituted-1,3-butadiene-1,4-diones

The bisketenes 2-phenyl and 2-methyl-3-(trimethylsilyl)-1,3-butadiene-1,4-dione ( 8 and 10 ) are calculated on the basis of additivity of substituent effects to be less stable than the 3-phenyl and 3-methyl-4-(trimethylsilyl)cyclobut-3-ene-1,2-diones ( 7 and 9 ) by 1.9 and 2.6 kcal/mol, respectively. In agreement with this prediction, 8 and 10 are formed by photolysis of 7 and 9 , respectively, and undergo thermal reversion to their precursors at similar rates. The concentration of 8 in thermal equilibrium with 7 in CDCl₃, as measured by ¹H NMR spectroscopy, varied from 2.8% (161°C) to 0.5% (100.5°C), whereas the amount of 10 present at equilibrium with 9 was distinctly less. These measurements allowed the calculation of values of Δ G° (25°C) = 4.4 kcal/mol, Δ H° = 6.9±(1.3) kcal/mol, and Δ S° = 8.5 (±3.2) cal/deg mol for the conversion of 7 to 8 , and the equilibrium concentration of 8 at 25°C was estimated to be 0.06%. The triisopropylsilyl analog 12 of 8 was prepared and at 66°C was 2.6 times more reactive in ring closure to the corresponding cyclobutenone compared to 8 . Reactions of 8 and 10 with MeOH in CDCl₃ give the isolable monoketenes 3-phenyl and 3-methyl-2-(trimethylsilyl)-3-carbomethoxy-1-ene-1-one ( 20 , 21 ). Reaction of 20 with excess MeOH or H₂O gave the diastereomeric dimethyl 2-(trimethylsilyl)-3-phenylsuccinates ( 22 ) or ester-acids 24 , respectively. Reaction of 8 with excess N-methylaniline gave the diamide 25 .     

Strain estimates for small-ring cyclic allenes and butatrienes

Isodesmic and homodesmic equations at the B3LYP/6-311+G(d,p)+ZPVE level of theory have been used to estimate strain for the homologous series of cyclic allenes and cyclic butatrienes. A simple fragment deformation approach also has been applied and appears to work better for the larger rings. For the cyclic allene series, estimates for allene functional group strain (kcal/mol) include: 1,2-cyclobutadiene, 65; 1,2-cyclopentadiene, 51; 1,2-cyclohexadiene, 32; 1,2-cycloheptadiene, 14; 1,2-cyclooctadiene, 5; 1,2-cyclononadiene, 2; 1,2,4-cyclohexatriene, 34; and bicyclo[3.2.1]octa-2,3-diene, 39. For cyclic butatrienes, functional group strain estimates include: 1,2,3-cyclobutatriene, >100; 1,2,3-cyclopentatriene, 80; 1,2,3-cyclohexatriene, 50; 1,2,3-cycloheptatriene, 26; 1,2,3-cyclooctatriene, 17; and 1,2,3-cyclononatriene, 4. Barriers to interconversion of enantiomers in cyclic allenes are reduced with increasing strain. Newly predicted values include: 1,2-cyclopentadiene <1 kcal/mol and bicyclo[3.2.1]octa-2,3-diene, 7.4 kcal/mol. Estimated levels of strain parallel the known reactivity of these substances.     

Structural assignment of regioisomeric 3-[2- or 5-anilino-2-(alkylamino)phenyl]propanoic acids, 2H-1,4-benzothiazin-3(4H)-ones and 2,3-dihydro-1,5-benzothiazepin-4(5H)-ones by 1D NOE and gHMBC NMR techniques

The 1H and 13C NMR spectra of compounds 1-11 and 16-22 in CDCl3 and DMSO-d6 solutions allowed structural assignment to regioisomers 1/5 and 2/6 and their regioselective cyclization products 16-18 utilizing one- and two-dimensional NMR techniques (APT, DEPT, NOE difference, COSY, NOESY, HETCOR and gHMQC, gHMBC). Temperature-dependent 1H NMR spectra of 8-anilino-5-(4-methyl-2-pentyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (18) indicated a free energy of activation (deltaG++) of ca 17 kcal mol(-1) for interconversion between rotamers. The 1H and 13C NMR spectra of 20 and 22 containing two chiral centers exhibit duplication of several signals, indicating the existence of two diastereomeric forms. The structure of 4 was unambiguously confirmed by x-ray crystallography.     

Syntheses of pyrrolo- and indoloisoquinolinones by intramolecular cyclizations of 1-(2-arylethyl)-5-benzotriazolylpyrrolidin-2-ones and 3-benzotriazolyl-2-(2-arylethyl)-1-isoindolinones.

1,5,6,10b-Tetrahydropyrrolo[2,1-alpha]isoquinolin-3(2H)-ones 17a,b, 17d,e, and 5,12b-dihydroisoindolo[1,2-alpha]isoquinolin-8(6H)-ones 22a-e were prepared by intramolecular cyclizations of 1-(2-arylethyl)-5-benzotriazolyl-pyrrolidin-2-ones 15a,b, 15d,e, and 3-benzotriazolyl-2-(2-arylethyl)-1-isoindolinones 20a-e, respectively, in the presence of titanium chloride. Products from chiral amines were obtained with stereoselectivities of > or = 94%.     

Carboranes and baskets from reaction of B4H10 with allene

The reaction of the boron hydride B4H10 with allene was studied at the CCSD(T)/6-311+G(d)//MP2/6-31G(d) level. The mechanism is surprisingly complex with 44 transition states and several branching points located. The four carboranes and one basket that have been observed experimentally are all connected by pathways that have very similar free energies of activation. In addition, two new structures, a basket (2,4-(CH2CH2CH2)B4H8, 5a) and a "classical" structure (1,4-(Me2C)bisdiborane, 7), which might be obtained from the B4H10 + C3H4 reaction under the right conditions (hot/cold, quenched, etc.) have been identified. The first branch point in the reaction is the competition between H2 elimination from B4H10 (DeltaG(298 K) = 32.2 kcal/mol) and the hydroboration of allene by B4H10 (DeltaG(298 K) = 31.3 kcal/mol). The next branch point in the hydroboration mechanism controls the formation of 2,4-(MeCHCH2)B4H8 (1) (DeltaG(298 K) = 31.5 kcal/mol) and arachno-1,2/arachno-1,3-Me2-1-CB4H7 (8 and 8a) (DeltaG(298 K) = 34.3 kcal/mol). Another branch point in the H2-elimination mechanism controls the formation of 1-Me-2,5-micro-CH2-1-CB4H7 (29) (DeltaG(298 K) = 0.1 kcal/mol) and 2,5-micro-CHMe-1-CB4H7 (25/26) (DeltaG(298 K) = 7.3 kcal/mol). Formation of 2-Me-2,3-C2B4H7, a carborane observed in the reaction of methylacetylene with B4H10, is calculated to be blocked by a high barrier for H2 elimination. All free energies are relative to B4H10 + allene. An interesting reaction step discovered is the "reverse hydroboration step" in which a hydrogen atom is transferred from carbon back to boron, which allows a CH hydrogen to shuttle between the terminal and central carbon of allene.     

{H(3-(t)Bupz)B(3-(t)Bupz)(2)-eta(2)}AlEt(2) and {H(3-(t)Bupz)B(3-(t)Bupz)(5-(t)Bupz)-eta(2)}AlEt(2). Structure, Dynamic Solution Behavior, and the 1,2-Borotropic Shift

HB(3-(t)Bupz)(3)Tl and AlEt(3) in benzene yield {H(3-(t)Bupz)B(3-(t)Bupz)(2)-eta(2)}AlEt(2), 1, as a hydrocarbon-soluble crystalline solid. Compound 1 is also obtained in a related reaction involving ClAlEt(2) via a preferential metathesis of the Al-Cl bond. Crystal data for 1 at -101 degrees C: a = 11.770(3) ?, b = 11.054(3) ?, c = 21.973(6) ?, beta = 95.57(1) degrees, Z = 4, space group P2(1)/a. In 1 the Al center is four-coordinate with Al-C = 1.97(1) ? and Al-N = 1.99(1) ? and with C-Al-C = 127 degrees and N-Al-N = 101 degrees being the largest and smallest angles, respectively. The average N-B-N angle is 109(1) degrees. In toluene-d(8) and tetrahydrofuran-d(8), 1 shows two types of 3-(t)Bupz groups in the integral ratio 2:1 and two distinct ethyl ligands. At low temperature there is a broadening of the 3-(t)Bupz singlet that is assigned to the eta(2)-(t)Bupz ligands. Up to +60 degrees C, compound 1 is nonfluxional on the NMR time scale but does isomerize to {H(3-(t)Bupz)B(3-(t)Bupz)(5-(t)Bupz)-eta(2)}AlEt(2), 2. Crystal data for 2 at -172 degrees C: a = 29.235(5) ?, b = 11.298(1) ?, c = 22.033(3) ?, beta = 129.66(1) degrees, Z = 8, space group = C2/c. In 2 there is a pseudotetrahedral Al center with Al-C = 1.97(1) ? (average) and Al-N = 1.95(1) ? (average) and with C-Al-C = 119 degrees and N-Al-N = 98 degrees as the largest and smallest angles, respectively. The average N-B-N angle is 108(1) degrees. In 2 the eta(2)-tris(alkylpyrazolyl)borate ligand isomerizes by a 1,2-borotropic shift to give one 5-(t)Bupz fragment that is part of the eta(2)-N,N' aluminum-bonded ligand. Variable-temperature (1)H NMR spectra of 2 in toluene-d(8) and THF-d(8) reveal temperature-dependent exchange involving the 3-(t)Bupz moieties, with more rapid site exchange in toluene-d(8) than in THF-d(8). At low temperature there are two ethyl signals, one of which indicates diastereotopic methylene protons, as well as three (t)Bu signals in the ratio 1:1:1. The dynamic behavior of 2 is consistent with an eta(2) right harpoon over left harpoon eta(3) exchange process as opposed to an eta(2) right harpoon over left harpoon eta(1) exchange wherein the Al center is transiently three-coordinate. The isomerization of 1 to 2 has been studied in benzene-d(6) (DeltaH() = 21.0(2) kcal/mol, DeltaS() = -15(1) eu) and THF-d(8) (DeltaH() = 18.3(4) kcal/mol, DeltaS() = -15(1) eu) and compared to a related isomerization involving {H(2)B(3-(t)Bupz)(2)-eta(2)}AlMe(2) reported by Parkin and Looney [Polyhedron 1990, 9, 265] in benzene-d(6) (DeltaH() = 34.5(8) kcal/mol, DeltaS() = 6(2) eu). It is proposed that the rate-determining 1,2-borotropic shift in the 1 --> 2 reaction occurs in a noncoordinating (t)Bupz group and that this is followed by a rapid associative interchange of pz groups wherein the sterically less demanding 5-(t)Bupz moiety remains bound to the metal.     

Criteria for pericyclic and pseudopericyclic character of electrocyclization of (Z)-1,2,4,6-heptatetraene and (2Z)-2,4,5-hexatriene-1-imine

The electrocyclic reaction mechanisms of (Z)-1,2,4,6-heptatetraene and (2Z)-2,4,5-hexatriene-1-imine were studied by ab initio MO methods. The activation energy barrier height of the electrocyclic reaction of (Z)-1,2,4,6-heptatetraene is extremely a low energy barrier of 8.58 kcal/mol by a MRMP method. The activation energy barrier height of the electrocyclic ring closure of the trans-type of (2Z)-2,4,5-hexatriene-1-imine is lower by 3.18 kcal/mol than that of (Z)-1,2,4,6-heptatetraene. These low energy barriers come from some orbital interactions relating to allene group. For the reaction of (Z)-1,2,4,6-heptatetraene, the interactions of the vertical and side π orbitals of the allene group with another terminal π orbital are important at the transition state. The interaction of the vertical π orbital of allene group with a lone pair orbital of N atom is dominant at the transition state of the reaction of the trans-type of (2Z)-2,4,5- hexatriene-1-imine. The electrocyclic mechanism of the cis-type of (2Z)-2,4,5-hexatriene-1-imine was also discussed. Contribution of the Mark S. Gordon 65th Birthday Festschrift issue.     

Dissociation channels of the 1-buten-2-yl radical and its photolytic precursor 2-bromo-1-butene

The work presented here is the first in a series of studies that use a molecular beam scattering technique to investigate the unimolecular reaction dynamics of C(4)H(7) radical isomers. Photodissociation of the halogenated precursor 2-bromo-1-butene at 193 nm under collisionless conditions produced 1-buten-2-yl radicals with a range of internal energies spanning the predicted barriers to the unimolecular reaction channels of the radical. Resolving the velocities of the stable C(4)H(7) radicals, as well as those of the products, allows for the identification of the energetic onset of each dissociation channel. The data show that radicals with at least 30.7 +/- 2 kcal/mol of internal energy underwent C-C fission to form allene + methyl, and radicals with at least 36.7 +/- 4 kcal/mol of internal energy underwent C-H fission to form H + 1-butyne and H + 1,2-butadiene; both of these observed barriers agree well with the G3//B3LYP calculations of Miller. HBr elimination from the parent molecule was observed, producing vibrationally excited 1-butyne and 1,2-butadiene. In the subsequent dissociation of these C(4)H(6) isomers, the major channel was C-C fission to form propargyl + methyl, and there is also evidence of at least one of the possible H + C(4)H(5) channels. A minor C-Br fission channel produces 1-buten-2-yl radicals in an excited electronic state and with low kinetic energy; these radicals exhibit markedly different dissociation dynamics than do the radicals produced in their ground electronic state.     

Photolysis of (3-methyl-2H-azirin-2-yl)-phenylmethanone: direct detection of a triplet vinylnitrene intermediate

The photoreactivity of (3-methyl-2H-azirin-2-yl)-phenylmethanone, 1, is wavelength-dependent (Singh et al. J. Am. Chem. Soc. 1972, 94, 1199-1206). Irradiation at short wavelengths yields 2P, whereas longer wavelengths produce 3P. Laser flash photolysis of 1 in acetonitrile using a 355 nm laser forms its triplet ketone (T(1K), broad absorption with λ(max) ~ 390-410 nm, τ ~ 90 ns), which cleaves and yields triplet vinylnitrene 3 (broad absorption with λ(max) ~ 380-400 nm, τ = 2 μs). Calculations (B3LYP/6-31+G(d)) reveal that T(1K) of 1 is located 67 kcal/mol above its ground state (S(0)) and has a long C-N bond (1.58 ?), and the calculated transition state to form 3 is only 1 kcal/mol higher in energy than T(1K) of 1. The calculations show that 3 has significant 1,3-carbon iminyl biradical character, which explains why 3 reacts efficiently with oxygen and decays by intersystem crossing to the singlet surface. Photolysis of 1 in argon matrixes at 14 K produced ketene imine 7, which presumably is formed from 3 intersystem crossing to 7. In comparison, photolysis of 1 in methanol with a 266 nm laser produces mainly ylide 2 (λ(max) ~ 380 nm, τ ~ 6 μs, acetonitrile), which decays to form 2P. Ylide 2 is formed via singlet reactivity of 1, and calculations show that the first singlet excited state of the azirine chromophore (S(1A)) is located 113 kcal/mol above its S(0) and that the singlet excited state of the ketone (S(1K)) is 85 kcal/mol. Furthermore, the transition state for cleaving the C-C bond in 1 to form 2 is located 49 kcal/mol above the S(0) of 1. Thus, we theorize that internal conversion of S(1A) to a vibrationally hot S(0) of 1 forms 2, whereas intersystem crossing from S(1K) to T(1K) results in 3.     

Synthesis of 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide

The reaction of methyl 2-bromo-6-(trifluoromethyl)-3-pyridinecarboxylate ( 1 ) with methanesulfonamide gave methyl 2-[(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridine-carboxylate ( 2 ). Alkylation of compound 2 with methyl iodide followed by cyclization of the resulting methyl 2-[methyl(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridinecarboxylate ( 3 ) yielded 1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 4 ). The reaction of compound 4 with α,2,4-trichlorotoluene, methyl bromopropionate, methyl iodide, 3-trifluoromethylphenyl isocyanate, phenyl isocyanate and 2,4-dichloro-5-(2-propynyloxy)phenyl isothiocyanate gave, respectively, 4-[(2,4-dichlorophenyl)methoxy]-1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazine 2,2-dioxide ( 5 ), methyl 2-[[1-methyl-2,2-dioxido-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4-yl]oxy]propanoate ( 6 ), 1,3,3-trimethyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2]thiazin-4(3H)-one 2,2-dioxide ( 7 ), 4-hydroxy-1-methyl-7-(trifluoromethyl)-N-[3-(trifluoromethyl)phenyl]-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ( 8 ), 4-hydroxy-1-methyl-7-(trifluoromethyl)-N-phenyl-1H-pyrido[2,3-c][1,2]thiazine-3-carboxamide 2,2-dioxide ( 9 ) and N-[2,4-dichloro-5-(2-propynyloxy)phenyl]-4-hydroxy-1-methyl-7-(trifluoromethyl)-1H-pyrido[2,3-c][1,2] thiazine-3-carboxamide 2,2-dioxide ( 10 ).     

Reaction mechanism of naphthyl radicals with molecular oxygen. 1. Theoretical study of the potential energy surface

Potential energy surfaces (PESs) of the reactions of 1- and 2-naphthyl radicals with molecular oxygen have been investigated at the G3(MP2,CC)//B3LYP/6-311G** level of theory. Both reactions are shown to be initiated by barrierless addition of O(2) to the respective radical sites of C(10)H(7). The end-on O(2) addition leading to 1- and 2-naphthylperoxy radicals exothermic by 45-46 kcal/mol is found to be more preferable thermodynamically than the side-on addition. At the subsequent reaction step, the chemically activated 1- and 2-C(10)H(7)OO adducts can eliminate an oxygen atom leading to the formation of 1- and 2-naphthoxy radical products, respectively, which in turn can undergo unimolecular decomposition producing indenyl radical + CO via the barriers of 57.8 and 48.3 kcal/mol and with total reaction endothermicities of 14.5 and 10.2 kcal/mol, respectively. Alternatively, the initial reaction adducts can feature an oxygen atom insertion into the attacked C(6) ring leading to bicyclic intermediates a10 and a10' (from 1-naphthyl + O(2)) or b10 and b10' (from 2-naphthyl + O(2)) composed from two fused six-member C(6) and seven-member C(6)O rings. Next, a10 and a10' are predicted to decompose to C(9)H(7) (indenyl) + CO(2), 1,2-C(10)H(6)O(2) (1,2-naphthoquinone) + H, and 1-C(9)H(7)O (1-benzopyranyl) + CO, whereas b10 and b10' would dissociate to C(9)H(7) (indenyl) + CO(2), 2-C(9)H(7)O (2-benzopyranyl) + CO, and 1,2-C(10)H(6)O(2) (1,2-naphthoquinone) + H. On the basis of this, the 1-naphthyl + O(2) reaction is concluded to form the following products (with the overall reaction energies given in parentheses): 1-naphthoxy + O (-15.5 kcal/mol), indenyl + CO(2) (-123.9 kcal/mol), 1-benzopyranyl + CO (-97.2 kcal/mol), and 1,2-naphthoquinone + H (-63.5 kcal/mol). The 2-naphthyl + O(2) reaction is predicted to produce 2-naphthoxy + O (-10.9 kcal/mol), indenyl + CO(2) (-123.7 kcal/mol), 2-benzopyranyl + CO (-90.7 kcal/mol), and 1,2-naphthoquinone + H (-63.2 kcal/mol). Simplified kinetic calculations using transition-state theory computed rate constants at the high-pressure limit indicate that the C(10)H(7)O + O product channels are favored at high temperatures, while the irreversible oxygen atom insertion first leading to the a10 and a10' or b10 and b10' intermediates and then to their various decomposition products is preferable at lower temperatures. Among the decomposition products, indenyl + CO(2) are always most favorable at lower temperatures, but the others, 1,2-C(10)H(6)O(2) (1,2-naphthoquinone) + H (from a10 and b10'), 1-C(9)H(7)O (1-benzopyranyl) + CO (from a10'), and 2-C(10)H(7)O (2-benzopyranyl) + O (from b10 and minor from b10'), may notably contribute or even become major products at higher temperatures.     

Synthesis of 8-(1-aminoethyl)quinoline

8-(1-Aminoethyl)quinoline, which has antimonoaminooxidase activity, was synthesized by the Leuckart reaction. Reduction of 8-acetylquinoline oxime with lithium aluminum hydride gives 8-(1-aminoethyl)-1,2-dihydroquinoline.     

Reactions of C(6)F(5)Li with tetracyclone and 3-ferrocenyl-2,4, 5-triphenylcyclopentadienone: An (19)F NMR and X-ray crystallographic study of hindered pentafluorophenyl rotations

Tetracyclone, 2a, reacts with C(6)F(5)Li to yield 2-pentafluorophenyl-2,3,4,5-tetraphenylcyclopent-3-en-1-one, 7, and 5-hydroxy-5-pentafluorophenyl-1,2,3,4-tetraphenylcyclopentadiene, 8, as the result of 1,6 and 1,2 additions, respectively. In contrast, treatment of 3-ferrocenyl-2,4,5-triphenylcyclopentadienone, 2b, with lithiopentafluorobenzene leads to 4-ferrocenyl-4-pentafluorophenyl-2, 3,5-triphenylcyclopent-2-en-1-one, 9, and 5-hydroxy-5-pentafluorophenyl-2-ferrocenyl-1,3, 4-triphenylcyclopentadiene, 10, the products of 1,4 and 1,2 addition, respectively. The structures of 7-9 have been established by X-ray crystallography, and the barriers to rotation (19-21 kcal mol(-)(1)) of the pentafluorophenyl groups in 8-10 have been studied by variable-temperature (19)F NMR. Nucleophilic attack at the ferrocenyl-bearing carbon in 2b is rationalized in terms of a zwitterionic structure in which the positive charge of the "cyclopentadienyl cation" is delocalized onto the iron atom in the organometallic substituent.     

Preparation of 2-, 3-, 4- and 7-(2-alkylcarbamoyl-1-alkylvinyl)benzo[b]furans and their BLT1 and/or BLT2 inhibitory activities

Several 2-alkylcarbamoyl-1-alkylvinylbenzo[b]furans were designed to find a selective leukotriene B4 (LTB4) receptor antagonist. 2-(2-Alkylcarbamoyl-1-alkylvinyl)benzo[b]furans having a substituent group at the 3-position, 4-(2-alkylcarbamoyl-1-methylvinyl)benzo[b]furans having a substituent group at the 3-position, and 7-(2-alkylcarbamoyl-1-methylvinyl)benzo[b]furans and 3-(2-alkylcarbamoyl-1-alkylvinyl)benzo[b]furans were prepared and evaluated for LTB4 receptor (BLT1 and BLT2) inhibitory activities. (E)-3-Amino-4-[2-[2-(3,4-dimethoxyphenyl)ethylcarbamoyl]-1-methylvinyl]benzo[b]furan ((E)-17c) showed potent and selective inhibitory activity for BLT2. On the other hand, (E)-7-(2-diethylcarbamoyl-1-methylvinyl)benzo[b]furan ((E)-27a) showed potent inhibitory activity for both BLT1 and BLT2.     

Synthesis of 1-[6-Fluoro-(2S)-3H,4H-dihydro-2H-2-chromenyl]-(1R)-1,2- ethanediol and 1-[6-Fluoro-(2R)-3H,4H-dihydro-2H-2-chromenyl]- (1R)-1,2-ethanediol

Benzopyran compounds possess diverse pharmacological properties such as β-blockade, anticonvulsant and antimicrobial.[1,2] Our interest has been focused on the synthesis of 1-[6-Fluoro-2S]-3H,4H-dihydro-2H-2-chromenyl]-(1R)-1,2-ethanediol (6) and 1-[6-fluoro-(2R)-3H,4H-dihydro-2H-2-chromenyl]-(1R)-1,2-ethanediol (7) which are particularly convenient precursor to (S,R,R,R)-NE (8). 8 containing four asymmetrical carbon atoms was reported to be the most active isomer.[3] Chandrasekhar[4] has reported on the synthesis of 8. The key step to synthesize this compound is to obtain the chiral chromanone 6 and 7. 6 was accomplished in 8 steps by the Clasien rearrangement and a one-pot Sharpless asymmetric epoxidation, but the compound 7 was accomplished in 10 steps. Johannes[5] used Zr-catalytic kinetic resolution of allylic ethers and Mo-catalyzed chromene formation to synthesize 8 in 14 steps. However both of the methods request many synthetic steps and expensive reagents.     

Reversal of stability on metalation of pentagonal-bipyramidal (1-MB6H7(2-) 1-M-2-CB5H7(1-) and 1-M-2,4-C2B4H7) and Icosahedral (1-MB11H12(2-) 1-M-2-CB10H12(1-) and 1-M-2,4-C2B9H12) boranes (M = Al, Ga, In, and Tl): energetics of condensation and relationship to binuclear metallocenes

The usual assumption of the extra stability of icosahedral boranes (2) over pentagonal-bipyramidal boranes (1) is reversed by substitution of a vertex by a group 13 metal. This preference is a result of the geometrical requirements for optimum overlap between the five-membered face of the ligand and the metal fragment. Isodesmic equations calculated at the B3LYP/LANL2DZ level indicate that the extra stability of 1-M-2,4-C(2)B(4)H(7) varies from 14.44 kcal/mol (M = Al) to 15.30 kcal/mol (M = Tl). Similarly, M(2,4-C(2)B(4)H(6))(2)(1-) is more stable than M(2,4-C(2)B(9)H(11))(2)(1-) by 9.26 kcal/mol (M = Al) and by 6.75 kcal/mol (M = Tl). The preference for (MC(2)B(4)H(6))(2) over (MC(2)B(9)H(11))(2) at the same level is 30.54 kcal/mol (M = Al), 33.16 kcal/ mol (M = Ga) and 37.77 kcal/mol (M = In). The metal-metal bonding here is comparable to those in CpZn-ZnCp and H(2)M-MH(2) (M= Al, Ga, and In).     

Reaction of 2-(5-aminopyrazol-1-yl)quinoxaline 4-oxides with dimethyl acetylenedicarboxylate

The reaction of 6-chloro-2-hydrazinoquinoxaline 4-oxide 6 with ethyl 2-(ethoxymethylene)-2-cyanoacetate or (1-ethoxyethylidene)malononitrile gave 2-(5-amino-4-ethoxycarbonylpyrazol-1-yl)-6-chloroquinoxaline 4-oxide 7a or 2-(5-amino-4-cyano-3-methylpyrazol-1-yl)-6-chloroquinoxaline 4-oxide 7b , respectively. The reaction of compound 7a or 7b with dimethyl acetylenedicarboxylate resulted in the 1,3-dipolar cycloaddition reaction and then ring transformation to afford 4-(5-amino-4-ethoxycarbonylpyrazol-1-yl)-8-chloro-1,2,3-trismethoxycarbonylpyrrolo[1,2-α]quinoxaline 8a or 4-(5-amino-4-cyano-3-methylpyrazol-1-yl)-8-chloro-1,2,3-trismethoxycarbonylpyrrolo[1,2-α]quinoxaline 8b , respectively.     

Synthesis and conversions of 3-(4-amino-5-methyl-4H-1,2,4-triazol-3-ylmethylene)-2-oxo-1,2,3,4-tetrahydroquinoxaline

The reaction of the hydrazone 3a with hydrazine hydrate in DBU/ethanol conveniently gave 3-(4-amino-5-methyl-4H-1,2,4-triazol-3-ylmethylene)-2-oxo-1,2,3,4-tetrahydroquinoxaline 6 . The reactions of 6 with an equimolar and 2-fold molar amount of nitrous acid afforded 3-(α-hydroxyimino-4-amino-5-methyl-4H-1,2,4-triazol-3-ylmethyl)-2-oxo-1,2-dihydroquinoxaline 9 and 3-(α-hydroxyimino-5-methyl-2H-1,2,4-triazol-3-ylmethyl)-2-oxo-1,2-dihydroquinoxaline 10 , respectively, which were converted into the 3-heteroarylisoxazolo[4,5-b]quin-oxalines 13a,b and 11 , respectively. Compound 9 was also cyclized into the 8-quinoxalinyl-1,2,4-triazolo-[3,4-f][1,2,4]triazines 14a,b .     

Synthesis of pyridazino[4,5-b]indole derivatives from 2-(3-carboxy-1-methylindole)acetic acid anhydride

2-(3-Carboxy-1-methylindole)acetic acid anhydride ( 1 ) reacts with aryldiazonium salts to give 85–95% of the corresponding α-hydrazono anhydrides 2 . Treating 2 with boiling hydrazine hydrate in xylene, the respective 2-aryl-4-carbohydrazido-5-methyl-1-oxo-1,2-dihydro-5H/-pyridazino[4,5-b]indoles 3 were obtained (47–67%), and these compounds characterized as the respective benzylidene derivatives 4 . Compounds 2 react with amines (aniline, morpholine, piperidine) to give the respective 2-(3-carboxy-1-methylindole)aceta-mide 5 or the respective 2-aryl-4-carboxamido-5-methyl-5H-pyridazino[4,5-b]indole 6 , the product obtained depending on the structure of the aryl substituent. Boiling 2b (aryl = 4-chlorophenyl) with 5% sodium hydroxide gave (80%) 2-(3-carboxy-1-methylindole)acetic acid ( 7 ). Hydrolysis of 2b gave a mixture of 7 and 2-(3-carboxy-1-methylindolyl)-2-(4-chlorophenylhydrazono)acetic acid ( 8 ).