Reaction of indium ate complexes with allylic compounds. Controlling SN2/SN2′ selectivity by solvents

Vinyl and methylindium ate complexes (indates) were prepared and both the tendency of immigration and regioselectivity toward cinnamyl bromide were investigated. The vinyl group was more preferably transferred than the Me group, giving a regioisomeric mixture of S_N2 and S_N2′ products. The ratio of S_N2/S_N2′ selectivity can be controlled by solvents; in the presence of polar solvents, such as N-butylpyrrolidone (NBP) and THF, the S_N2′ product was mainly obtained, whereas the S_N2 product was selectively prepared in solutions containing hexane. The vinylindium compound, generated by the reaction of allylic-type diindium reagents with imine, was also converted to the corresponding vinyl indate, which was allowed to react with allyl chloride to give a three-component coupling product.     

Regioselective arylation of 3-bromopyridine

The addition of aryl Grignard reagents to the 1-phenoxycarbonyl salt of 3-bromopyridine affords 2-aryl-5-bromo-1-phenoxycarbonyl-1,2-dihydropyridines and 4-aryl-3-bromo-1-phenoxycarbonyl-1,4-dihydropyridines. The crude dihydropyridines were aromatized with o-chloranil in refluxing toluene to give 4- and 6-aryl-3-bromopyridines. The regioselectivity of this two-step process, 6- vs. 4-substitution, was examined and found to be dependent upon the structure of the Grignard reagent. Unhindered aryl Grignard reagents, e.g., phenyl and 2-naphthyl, gave mainly 6-aryl-3-bromopyridines (49-52%) along with 9% of the 4-substituted isomer and less than 4% of the 2-aryl-3-bromopyridine. Hindered aryl Grignard reagents, e.g., o-tolyl and 1-naphthyl, are less regioselective. When a catalytic amount of cuprous iodide is present during the Grignard reaction, nearly exclusive 1,4-addition results. The crude 4-aryl-3-bromo-1,4-dihydropyridines were aromatized with p-chloranil to provide 4-aryl-3-bromopyridines in good yield and high isomeric purity. The sequential use of the cuprous iodide-catalyzed Grignard reaction and the “normal” Grignard reaction provided a regiospeci-fic synthesis of 3-bromo-6-(p-methoxyphenyl)-4-phenylpyridine from 3-bromopyridine.     

Reactions of 3-isopropenyltropolones with bromine and N-bromosuccinimide: Formation of 8H-cyclohepta[b]furan-8-one derivatives

3-Isopropenyltropolones 1a-c were treated with bromine in carbon tetrachloride to give 3-methyl-8H-cyclohepta[b]furan-8-ones 2a-c and their corresponding 7-bromo-substituted compounds 3a-c , while reactions in acetic acid gave the bromo-substituted compounds 3a-c . On the other hand, bromination of 1a-c with N-bromosuccinimide afforded 7-bromo-3-(2-bromo-1-methylethenyl)tropolones 5a-c . The compound 2a was treated with bromine to give 2-bromo-3-methyl-8H-cyclohepta[b]furan-8-one ( 4 ). The tropolones 5a-c were heated in the presence of potassium carbonate to give the cyclized compounds 3a-c .     

Stereoselective synthesis of chiral 3-aryl-1-alkynes from bromoallenes and heterocuprates

The synthesis of chiral 3-aryl-1-alkynes 3 via cross-coupling of 3-alkyl- and 3,3-dialkyl-1-bromo-1,2-dienes 1 and arylbromocuprates (RCuBr)MgBr.LiBr 2 was examined. With phenylcopper reagents and its para-substituted derivatives, as well as with 2-naphthyl cuprates, the reaction gave compounds 3 with high regioselectivity and good yields on the chemically pure product. On the contrary, when ortho-substituted phenyl reagents and 1-naphthyl cuprates were used, the regioselectivity of the process was very dependent upon the steric requirements of the alkyl substituents on the bromoallenic substrate. When the steric bulk was increased, remarkable quantities of isomeric arylallenes 4 were also observed in the reaction mixtures. The high 1,3-anti stereoselectivity of the coupling process allowed us to obtain enantiomerically enriched 3-aryl-1-alkynes from optically active allenic substrates, thus indicating a simple pathway toward the synthesis of quaternary stereogenic centers characterized by an aryl group. A possible cross-coupling mechanism was also suggested to explain the regio- and stereochemical data. For the preparation of omega-functionalized 3-phenyl-1-alkynes, the reaction of 1-bromo-3-phenylpropadiene with Knochel reagents RCu(CN)ZnCl.2LiCl was also studied; this reaction led to the acetylenic compounds in high yields mainly when the R group (also omega-functionalized) on the copper reagent was primary.     

Lithiation of 3-(Acylamino)-2-unsubstituted-, 3-(Acylamino)-2-ethyl-, and 3-(Acylamino)-2-propyl-4(3H)-quinazolinones: Convenient Syntheses of More Complex Quinazolinones(1)

3-(Pivaloylamino)- and 3-(acetylamino)-4(3H)-quinazolinones react with alkyllithium reagents to give 1,2-addition products in very good yields. Lithiation takes place with LDA and is regioselective at position 2. The lithium reagents thus obtained react with a variety of electrophiles to give the corresponding substituted derivatives in very good yields. Reactions of the lithium reagents with iodine give oxidatively dimerized cyclic structures. 3-(Pivaloylamino)- and 3-(acetylamino)-2-ethyl-4(3H)-quinazolinones and 3-(pivaloylamino)- and 3-(acetylamino)-2-propyl-4(3H)-quinazolinones are lithiated at the benzylic position with LDA. The lithium reagents so produced also react with a variety of electrophiles to give the corresponding 2-substituted-4(3H)-quinazolinone derivatives in very good yields. However, lithiation of 3-(acylamino)-2-(1-methylethyl)-4(3H)-quinazolinones was unsuccessful, as were lithiations of compounds having a diacetylamino group at position 3. The amide groups have been cleaved in good yield under basic or acidic conditions from some of the products to provide access to the free amino compounds.     

Radical reactions initiated by the photochemical cleavage of carbon-indium bonds of organoindium compounds

Intra- and intermolecular reactions of carbon-centered radicals generated by photolysis of organoindium compounds were examined. The photolysis of vinylindium compounds and indium acetylides provided vinyl and alkynyl radicals, respectively, which were trapped with ethyl iodoacetate giving the corresponding β,γ-unsaturated esters. Allylic indium compounds, prepared from 8-bromo- or 8-iodooct-1,6-dienes and powdered indium metal, underwent an intramolecular radical cyclization to afford the 5-exo-trig product.     

σ-Complexes of transition metals in organic synthesis. 9. Reactions of allyl organomanganese compounds with γ-bromine derivatives of esters of α, Β-unsaturated carboxylic acids

The allyl Mn(II) organic compounds R¹CH=C(R²)CH₂MnCl (R¹=H, Me; R²=H, Me, Bu), obtained in situ from Grignard reagents and Li₂MnCl₄, react with esters of 4-bromocrotonic, (2-bromobutylidene)-, (4-bromo-2-butenylidene)-, (2-bromoisobutylidene) malonic, and (2-bromoheptylidene)cyanoacetic acids in THF at –78 to +20C to give derivatives of substituted cyclopropanecarboxylic or cyclopropane-1, 1-dicarboxylic acids. These derivatives contain a fragment of the allyl type. When ethers of 2-(bromomethyl)acrylic, 4-bromo-2-methyl-, and 4-bromo-3-methyl-2-butenoic acids are used, cross-combination products result.For previous communication, see [1].Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 3, pp. 656–663, March, 1991.     

Pyridine-substituted hydroxythiophenes. IV. Preparation of 3- and 4-(2-, 3- and 4-pyridyl)-2-hydroxythiophenes

3-(2-, 3- and 4-Pyridyl)-2-methoxythiophenes have been prepared in good yields through the Pd(0)-cat-alyzed coupling of the three isomeric bromopyridines with 3-trimethylstannyl-2-methoxythiophene. This compound was prepared through halogen-metal exchange of 3-bromo-2-methoxythiophene followed by stannylation. 3-Bromo-2-methoxythiophene was prepared by dibromination and α-debromination of 2-methoxythiophen. Most attempts to demethylate 2-methoxy-3-pyridylthiophenes using a large variety of reagents failed, probably due to the instability and high reactivity of the desired 3-pyridyl-2-hydroxythiophene systems. Only 2-methoxy-3-(3-pyridyl)thiophene reacted with boron tribromide to give 3-(3-pyridyl)-3-thiolene-2-one, which only was stable in ether solution at ?20°. The attempted demethylation of 2-methoxy-3-(2-pyridyl)thiophene with trimethylsilane chloride/sodium iodide in refluxing acetonitrile led to a dimer. Demethylation of the 2-methoxy-3-pyridylthiophenes with dibenzyl diselenide and sodium borohydride gave 3-pyridylthiophan-2-ones. A number of other routes to prepare 3-pyridyl-2-hydroxythiophenes were also explored, but none of them gave the desired compounds. On the other hand, the 4-(2-, 3-, and 4-pyridyl)-2-hydroxythiophene systems could easily be prepared by hydrogen peroxide oxidation of the corresponding 4-pyridyl-2-thiopheneboronic esters, which were obtained from 2-bromo-4-pyridylthiophenes by halogen-metal exchange followed by reaction with ethyl borate. The 2-bromo-4-pyridylthiophenes were prepared by dibromination of the known 3-pyridylthiophenes to the 2,5-dibromo derivatives, and removal of the 2-bromine by halogen-metal exchange at ?100°, followed by hydrolysis. The ¹H nmr and ir spectroscopic investigations show that these quite stable 2-hydroxythiophene systems exist exclusively in the 4-pyridyl-3-thiolen-2-one forms.     

Studies on tellurium-containing heterocycles. Part 20. Reactions of 2-benzoselenopyrylium salts and 2-benzotelluropyrylium salts with nucleophiles: formation of 1-functionalized 1H-isoselenochromenes and 1H-isotellurochromenes

The reactions of the 2-benzoselenopyrylium (1A) and 2-benzotelluropyrylium cations (1B) with a variety of nucleophiles have been investigated. LiAlH(4), sodium alkoxide (NaOMe, NaOi-Pr and NaOt-Bu), diethylamine, n-butylamine and acetone reacted with 1 to give the 1H-isochromenes (2) and the corresponding 1-substituted products (4-9) under mild conditions in almost good to high yields. The 1-alkyl(phenyl)isoselenochromenes (10-13) and 1-benzylisochromenes (18A, 18B), which were produced by the reaction of the salts 1 with Grignard reagents, were converted to the corresponding 1,3-disubstituted 2-benzopyrylium salts (14-17, 19) by treatment with triphenylcarbenium tetrafluoroborate (Ph(3)C(+) BF(4)(-)), respectively. The 1-benzylselenopyrylium salts (19A) and 1-benzyltelluropyrylium salts (19B) exist in the solvent as an equilibrium mixture of the salts (19) and the corresponding (Z)-benzylidene compounds (20).     

Reactions of 1-aryl-2-bromo-3,4,4-trichlorobut-3-en-1-ones with some nucleophilic reagents

Reactions of 2-bromo-1-phenyl- and 2-bromo-1-(4-methylphenyl)-3,4,4-trichlorobut-3-en-1-ones with morpholine and diethylamine are accompanied by prototropic allylic rearrangement, leading to 3-amino-1-aryl-2-bromo-4,4-dichlorobut-2-en-1-ones as mixtures of E and Z isomers. The title compounds react with hydrazine, hydroxylamine, and thiourea to give the corresponding 5-aroyl-4-methoxypyrazoles, 3-aryl-5-hydroxyiminomethyl-4-methoxyisoxazoles, and 2-amino-4-aryl-5-trichlorovinylthiazoles.     

Synthesis of Tetrahydropyridinyltriazolothiadiazines as Possible Muscarinic Agonists

4-Amino-5-(pyridin-3-yl)-4H-l,2,4-triazole-3-thiol 1 were condensed with 2-bromo-l-(substituted phenyl)ethanone to give pyridinyltriazolothiadiazines 2a-c, which were quaternarized with methyl iodide and oxidized with 30 % hydrogen peroxide to afford the corresponding methyl pyridinium salts 3a-c and pyridine- 1 -oxides 4a-c, respectively. The redtiction of compounds 3 and 4 with NaBH4 in methanol produced the target compounds 1-methyl- 1.2.5.6-tetrahydropyridin-3-yl)-6-aryl-s-triazolothiadiazines 5a-c and 3-( l-hydroxyl- 1, 2, 5, 6-tetrahydropyridin -3-yl)-6-aryl-s-triazolothiadiazines 6a-c, respectively. The endothelium vascular relaxing activity of the target compounds was screened.     

Cross-coupling reactions of indium organometallics with 2,5-dihalopyrimidines: synthesis of hyrtinadine A

The palladium-catalyzed cross-coupling reaction of triorganoindium reagents (R3In) with 5-bromo-2-chloropyrimidine proceeds chemoselectively, in good yields, to give 5-substituted-2-chloropyrimidines or 2,5-disubstituted pyrimidines using 40 or 100 mol % of R3In, respectively. Sequential cross-couplings are also performed, in one pot, using two different R3In. This method was used to achieve the first synthesis of the alkaloid hyrtinadine A. The key step was a two-fold cross-coupling reaction between a tri(3-indolyl)indium reagent and 5-bromo-2-chloropyrimidine.     

Easy access to CF2-containing molecules based on the reaction of 2,2,3,3-tetrafluorooxetane with various nucleophiles

2,2,3,3-Tetrafluorooxetane reacted easily with organolithium reagents to give 1,1,3-trisubstituted 2,2-difluoropropan-1-ols in good to excellent yields. On the other hand, the reaction with Grignard reagent led to 3-bromo-1,1-disubstituted 2,2-difluoropropan-1-ols in good yields. On treating with lithium enolates, generated from enol silyl ethers and MeLi/LiBr, the corresponding 1-bromo-2,2-difluoro-3,5-dicarbonyl compounds were obtained in fair to good yields. 3-Iodo-2,2-difluoropropanoate, prepared readily from 2,2,3,3-tetrafluorooxetane and NaI, reacted successfully with various silyl enol ethers in the presence of a radical initiator to provide the corresponding coupling products in good yields.     

Synthetic and structural studies on C-ethynyl- and C-bromo-carboranes

A high-yield preparation of the C-monoethynyl para-carborane, 1-Me(3)SiC[triple bond]C-1,12-C2B10H11, from C-monocopper para-carborane and 1-bromo-2-(trimethylsilyl)ethyne, BrC[triple bond]CSiMe(3) is reported. The low-yield preparation of 1,12-(Me3SiC[triple bond]C)2-1,12-C2B10H10 from the C,C'-dicopper para-carborane derivative with 1-bromo-2-(trimethylsilyl)ethyne, BrC[triple bond]CSiMe3, has been re-investigated and other products were identified including the C-monoethynyl-carborane 1-Me3SiC[triple bond]C-1,12-C2B10H11 and two-cage assemblies generated from cage-cage couplings. The contrast in the yields of the monoethynyl and diethynyl products is due to the highly unfavourable coupling process between 1-RC[triple bond]C-12-Cu-1,12-C2B10H10 and the bromoalkyne. The ethynyl group at the cage carbon C(1) strongly influences the chemical reactivity of the cage carbon at C(12)-the first example of the "antipodal effect" affecting the syntheses of para-carborane derivatives. New two-step preparations of 1-ethynyl- and 1,12-bis(ethynyl)-para-carboranes have been developed using a more readily prepared bromoethyne, 1-bromo-3-methyl-1-butyn-3-ol, BrC[triple bond]CCMe2OH. The molecular structures of the two C-monoethynyl-carboranes, 1-RC[triple bond]C-1,12-C2B10H11 (R = H and Me3Si), were experimentally determined using gas-phase electron diffraction (GED). For R = H (R(G) = 0.053) a model with C(5v) symmetry refined to give a C[triple bond]C bond distance of 1.233(5) A. For R = Me3Si (R(G) = 0.048) a model with C(s) symmetry refined to give a C[triple bond]C bond distance of 1.227(5) A. Molecular structures of 1,12-Br2-1,12-C2B10H10, 1-HC[triple bond]C-12-Br-1,12-C2B10H10 and 1,12-(Me(3)SiC[triple bond]C)2-1,12-C2B10H10 were determined by X-ray crystallography. Substituents at the cage carbon atoms on the C2B10 cage skeleton in 1-X-12-Y-1,12-C2B10H10 derivatives invariably lengthen the cage C-B bonds. However, the subtle substituent effects on the tropical B-B bond lengths in these compounds are more complex. The molecular structures of the ethynyl-ortho-carborane, 1-HC[triple bond]C-1,2-C2B10H11 and the ethene, trans-Me3SiBrC=CSiMe3Br are also reported.     

气相色谱-质谱法研究多卤代产物的组成和结构

在制备取代的１,４－己二烯过程中,在钯（Ⅱ）催化下烯丙基溴对１,４－二氯－２－丁炔的加成反应生成了一系列未曾预料的复杂产物,运用气相色谱－质谱法（ＧＣ－ＭＳ）对产物进行了逐个分析。分析结果显示：（１）８个化合物中除两个为预期产物外,其余均为氯和溴交换反应的副产物,并且８个化合物中的每两个为一对几何异构体;（２）４对几何异构体中Ｚ／Ｅ的比例随着分子量的增加而逐渐下降。     

Some reactions of 3-halogenocinnolines catalysed by palladium compounds

3-Bromo- or 3-iodo-cinnoline (and 4-substituted analogues) are condensed with terminal alkynes in the presence of Pd and Cu compounds as catalysts to give the 3-alkynyl-derivatives. When 4-chloro- or 4-phenoxy-compounds are used, the products react with amines, in the presence of copper(I) iodide, to form pyrrolo[3,2-c]cinnolines and with hydrazines to give either the same ring system or a pyrazolo[4,3-c]cinnoline. Hydrolysis of 3-alkynyl-4-phenoxycinnoline to 3-alkynyl-4(1H)-cinnoline, followed by cyclisation, yields the furo[3,2-c]cinnoline. Attempts to condense 3-halogenocinnolines with alkenes gave variable results: 3-phenyl ethenyl- and 3(2-pyridylethenyl)-4-(1H)-cinnolinones were obtained but 3-bromocinnoline gave the 3,3′-bicinnolinyl. Action of palladium acetate in the presence of ethyl acrylate converted 3-bromo-4-phenoxycinnoline into benzofuro[3,2-c]cinnoline and 3-bromo-4-phenylaminocinnoline into indolo[3,2-c]cinnoline.     

Reaction of 5-(1-bromo-2-aryl-vinyl)-3-methyl-4-nitro-isoxazoles and 1,3-dicarbonyl compounds

The preparation of E-5-(1-bromo-2-aryl-vinyl)-3-methyl-4-nitro-isoxazoles and their reaction with 1,3-dicarbonyl compounds to give cyclopropanes or dihydrofurans is described.     

Reactions of zinc enolates derived from 1-aryl-2-bromo-2-phenylethanone and 2-bromoindan-1-one with alkyl 2-oxochromene-and 6-bromo-2-oxochromene-3-carboxylates

Zinc enolates derived from 1-aryl-2-bromo-2-phenylethanone react with alkyl 2-oxochromene-3-carboxylates and methyl 6-bromo-2-oxochromene-3-carboxylate to give, respectively, alkyl 4-(2-aryl-2-oxo-1-phenylethyl)-2-oxochroman-3-carboxylates and methyl 6-bromo-4-(2-aryl-2-oxo-1-phenylethyl)-2-oxochroman-3-carboxylate as a single stereoisomer. Zinc enolates derived from 2-bromoindan-1-one react with alkyl 2-oxochromene-3-carboxylates to give alkyl 2-oxo-4-(1-oxoindan-2-yl)chroman-3-carboxylates as a single stereoisomer.     

Two new bromotyrosine-derived metabolites from the sponge Psammaplysilla purpurea

Two new bromotyrosine-derived metabolites (1, 2) have been isolated along with the known compounds 3,5-dibromo-4-methoxyphenylacetonitrile, 3-bromo-4-methoxyphenylacetonitrile, 3-bromo-4-hydroxyphenylacetonitrile, 1-hydroxyuracil, 1-methoxyhemibastadin 2, purpuramine H and a steroid 5alpha,8alpha-epidioxycholest-6-en-3beta-ol from the sponge Psammaplysilla purpurea. Compounds 1 and 2 were characterized by interpretation of their spectral data. The antibacterial activity of these compounds is summarized.     

Synthesis of new synthons for organofluorine compounds from halothane containing sulfur functional groups

To develop new synthons for the syntheses of organofluorine compounds, the treatment of Halothane, 2-bromo-2-chloro-1,1,1-trifluoroethane, (1) with 4-methylbenzenethiol (2) in the presence of sodium hydride gave 1-chloro-2,2,2-trifluoroethyl 4-methylphenyl sulfide (3), which was oxidized with m-chloroperbenzoic acid (m-CPBA) to the corresponding sulfoxide (4) and sulfone (5). Reaction of 3 and 5 with allyltributyltin in the presence of 2,2'-azobis(isobutyronitrile) (AIBN) gave 1-(trifluoromethyl)-3-butenyl compounds (9, 11). Sulfoxide 4 was decomposed in this condition. The treatment of 3 with allyltrimethylsilane in the presence of Lewis acids gave 1-(trifluoromethyl)-3-butenyl compounds (9) in good yield. This result suggests that 4-methylphenylthio substituent stabilizes the alpha-carbocation effectively, though the trifluoromethyl group destabilizes it strongly. Aromatic compounds similarly reacted with 3 in the presence of titanium(IV) chloride to give 2-aryl-1,1,1-trifluoro-2-(4-methylphenylthio)ethanes. Thus, sulfur compounds derived from Halothane were found to be useful new synthons for organofluorine compounds.