SYNTHESIS OF NOVEL BITHIOPHENE-SUBSTITUTED HETEROCYCLES BEARING CARBONITRILE GROUPS

Symmetrical and unsymmetrical bithiophene-substituted heterocycles bearing carbonitriles including imidazo[1,2-a]pyridine, benzimidazole, and pyridine derivatives have been synthesized via different synthetic protocols. The bithiophene bis-imidazo[1,2-a]pyridine derivatives 3a,b were achieved in three steps starting from 2-acetyl-5-bromothiophene. Suzuki coupling reaction of 2a with 5-formylthiophen-2-ylboronic acid forms the formyl derivative 5, which by condensation with 3,4-diaminobenzonitrile in the presence of sodium bisulfite furnishes the unsymmetrical bithiophene derivative 6. The bis-benzimidazole derivative 8 was obtained via hexabutylditin-mediated homocoupling of 5-bromothiophene-2-carboxaldehyde, while the benzimidazole derivatives 12a,b were prepared via the formyl derivatives 11a,b, a product of Velsmier formylation reaction of 10a,b. Two synthetic protocols for the aryl/hetaryl-2,2'-bithiophene derivative 14 have also been presented. In addition, the guanyl hydrazones of bithiophenes, 16 and 17, were prepared from bis(tri-n-butylstannyl)-2,2'-bithiophene through a Stille coupling reaction followed by a condensation step.     

Synthesis of naphthalenes through three-component coupling of alkynes, Fischer carbene complexes, and benzaldehyde hydrazones via isoindole intermediates

The synthesis of naphthalene derivatives through three-component coupling of 2-alkynylbenzaldehyde hydrazones with carbene complexes and electron-deficient alkynes has been examined. The reaction involves formation of an isoindole derivative, followed by intramolecular Diels-Alder reaction, followed by nitrene extrusion. The reaction was highly regioselective using unsymmetrical alkynes.     

Synthesis and mass spectral fragmentations of new spiro heterocycles

The reaction of dichlorodiphenoxymethane (2) with ortho-functionlized benzoic acids 1a-c yielded the spiro derivatives of bezodioxinone 4a, benzoxazinone 4b and benzodioxepinone 4c. The same reaction with 1,8-diaminonaphthalene afforded the spiro perimidine 6, while with 1,1'-binaphthy1-2,2'-diol gave the semi-cyclized derivative 2,2-diphenoxydinaphthodioxepine 8.     

Facile Synthesis of Unsymmetrical N-Aryl-2, 2-di(1H-indol-3-yl) Acetamide Derivatives

A facile and highly efficient method has been developed for the synthesis of unsymmetrical N-aryl-2,2-di(1H-indol-3-yl)acetamide derivatives by regioselective Friedel-Crafts alkylation of the N-aryl-2-hydroxy-2-(1H-indol-3-yl) acetamide derivatives with various indoles catalyzed by 2 mol/L H₂SO₄ at room temperature in a short reaction time, the yield was up to 94%.     

Oxime-based salen-type tetradentate ligands with high stability against imine metathesis reaction

Although salen and its analogues are versatile chelate ligands in inorganic and organometallic chemistry, synthesis of unsymmetrical salen derivatives consisting of two different salicylideneimine moieties is difficult because of the C=N bond recombination. To develop stable analogues of salen-type ligands, we synthesized a series of new ligands salamo (=1,2-bis(salicylideneaminooxy)ethane) on the basis of O-alkyl oxime instead of the imine moiety. Eight salamo ligands 1a-h were prepared in 64-88% yields as colorless crystals from the corresponding salicylaldehydes 2a-h. The crystal structure of 1a-c suggests that the oxime-OH form is more predominant than the keto-NH form. The reaction of 2a-e with excess 1,2-bis(aminooxy)ethane gave monooximes 3a-e in 59-86%, which further reacted with a different salicylaldehyde to afford unsymmetrical salamo ligands 4-8 as stable crystals in 51-70%. No reaction took place when a mixture of salamo derivatives 1a and 1b was treated at 40 degrees C in H2O/MeCN (5:95). However, the metathesis reaction of salen derivatives 9a and 9b completed in 2 h to give a statistical mixture. Monooxime 3b was much more stable than monoimine 11 which is difficult to be isolated. These results indicate the extremely high stability of the salamo derivatives 1 and precursors 3.     

Highly enantioselective Diels-Alder reactions of Danishefsky type dienes with electron-deficient alkenes catalyzed by Yb(III)-BINAMIDE complexes

1-Methoxy-3-trimethylsiloxy-1,3-butadiene (Danishefsky's diene) is recognized as a synthetically useful diene due to its high reactivity in the Diels-Alder reaction with electron-deficient alkenes to give oxygen-functionalyzed cyclohexenes and substituted cyclohexenones, which are important building blocks for the total synthesis of natural products. However, the development of catalytic enantioselective versions of Diels-Alder reactions using Danishefsky type dienes with electron-deficient alkenes has been difficult because of the instability of the dienes under Lewis acidic conditions. Only highly reactive CO and CN double bonds are employed in a hetero-Diels-Alder reaction which proceeds under catalysis of chiral Lewis acids. We have developed a new chiral ligand, BINAMIDE, which is easily prepared from 1,1'-binaphtyl-2,2'-diamine by acylation. The highly diastereo- and enantioselective Diels-Alder reaction of Danishefsky type dienes with electron-deficient alkenes in the presence of an Yb(III)-BINAMIDE complex has been developed. The reaction proceeded in an exoselective mode and gave chiral highly functionalized cyclohexene derivatives in good yields.     

Carbene-carbene rearrangements as a route to 1,5-dihydropentalene

1,5-Dihydropentalene (4) is formed as the main product on treatment of trans-1,2-bis(2,2-dibromocyclo-propyl)ethene 3 with methyllithium at −40°. In addition the reaction affords 1- and 2-propadienylcyclopentadienes (5a) and (5b), and trans-1,2,4,6,7-octapentaene (6), new C₈H₈ isomers. Diels-Alder adducts of 4, 5a and 5b were obt in the reaction with perfluorobut-2-yne. The formation of 1,5-dihydropentalene 4 is explained by a double ring expansion sequence involving consecutive carbene-carbene rearrangements with 1,3-carbon and subsequent 1,2-hydrogen shifts, supported by the reaction of double labelled (¹³C-depleted) 3. From readily available 3 at low temperatures formation and fusion of two 5-membered rings are achieved in one step.     

Generation of ortho-quinone methides upon thermal extrusion of sulfur dioxide from benzosultones

3H-1,2-Benzoxathiole 2,2-dioxides (benzosultones) undergo thermal extrusion of sulfur dioxide to form ortho-quinone methides that enter Diels-Alder reaction with maleimides to form chroman 2,3-dicarboxylic acid derivatives.     

Enantioselective and structure-selective Diels-Alder reactions of unsymmetrical quinones catalyzed by a chiral oxazaborolidinium cation. Predictive selection rules

The chiral oxazaborolidinium cation 1 promotes Diels-Alder reactions between 2-triisopropylsilyloxy-1,3-butadiene and a number of unsymmetrical 1,4-benzoquinones in a highly enantioselective and structurally selective manner. The basis for the enantioselectivity is explained rationally in terms of a preferred type of transition-state assembly. Selection rules have been developed that allow the prediction of the principal reaction product of Diels-Alder reaction between unsymmetrical diene and quinone components.     

Synthesis of Novel Bithiophene-Substituted Heterocycles Bearing Carbonitrile Groups

Symmetrical and unsymmetrical bithiophene-substituted heterocycles bearing carbonitriles including imidazo[1,2-a]pyridine, benzimidazole, and pyridine derivatives have been synthesized via different synthetic protocols. The bithiophene bis-imidazo[1,2-a]pyridine derivatives 3a,b were achieved in three steps starting from 2-acetyl-5-bromothiophene. Suzuki coupling reaction of 2a with 5-formylthiophen-2-ylboronic acid forms the formyl derivative 5, which by condensation with 3,4-diaminobenzonitrile in the presence of sodium bisulfite furnishes the unsymmetrical bithiophene derivative6. The bis-benzimidazole derivative 8 was obtained via hexabutylditin-mediated homocoupling of 5-bromothiophene-2-carboxaldehyde, while the benzimidazole derivatives 12a,b were prepared via the formyl derivatives 11a,b, a product of Velsmier formylation reaction of 10a,b. Two synthetic protocols for the aryl/hetaryl-2,2′-bithiophene derivative 14 have also been presented. In addition, the guanyl hydrazones of bithiophenes, 16 and 17, were prepared from bis(tri-n-butylstannyl)-2,2′-bithiophene through a Stille coupling reaction followed by a condensation step.     

Domino 6pi-electrocyclization/Diels-Alder reactions on 1,6-disubstituted (E,Z,E)-1,3,5-hexatrienes: versatile access to highly substituted tri- and tetracyclic systems

The (E,Z,E)-1,3,5-hexatrienes 1a, 2a,b and 3b undergo 6pi-electrocyclization within 15-30 min upon heating to 200-215 degrees C. While the cyclohexene-annelated products 8a,b were stable, the analogous cyclopentene- and cycloheptene-annelated derivatives 7a and 9b easily underwent dehydrogenation to the corresponding aromatic compounds 10a and 12b during the work-up. The cyclohexadiene derivatives 8a,b were employed in thermal Diels-Alder reactions with 4-phenyl-3H-1,2,4-triazoline-3,5-dione (PTAD) and tetracyanoethylene (TCNE) to give the expected [4+2] cycloadducts 13a and 14a in good yields (60 and 78%). The initially formed cycloadduct of 8a and dimethyl acetylenedicarboxylate (DMAD) underwent a subsequent retro-Diels-Alder reaction to give the tetrahydronaphthalene 11b (47%). Under high pressure (10 kbar), the cycloadduct 15a was formed at room temperature and could be isolated in 44% yield. TCNE and N-phenylmaleimide with 8a under high pressure also led to the [4+2] cycloadducts 14a and 16a in good yields (60 and 77%). The 6pi-electrocyclization and subsequent Diels-Alder reaction, when performed as a one-pot domino process, provided direct access to Diels-Alder products of intermediately formed 6pi-electrocyclization products, for example from the 1,3,5-hexatrienes 1a,b, 2a,b, 3b and TCNE to the corresponding tricyclic products 17a,b, 14a,b, 18b in moderate to good yields (27-80%) depending on the nature of the alkoxycarbonyl group. Such sequential reactions with N-phenylmaleimide, maleic anhydride, dimethyl maleate and fumarodinitrile, the latter two under high pressure (10 kbar), worked as well to yield 16b (70%), 19a,b (19, 32%) and 20b (39%) and 21b (76%), respectively. With PTAD, however, the hexatrienes 2a,b reacted at ambient temperature without 6pi-electrocyclization to give the formal [4+2] cycloadducts 27a,b (48 and 46%), most probably via zwitterionic intermediates 23a,b and 25a,b.     

Concise preparation of 2,2-difluorohomopropargyl carbonyl derivatives. Application to the synthesis of 4,4-difluoroisoquinolinone congeners

A scalable synthesis of 2,2-difluorohomopropargyl esters was achieved using a magnesium-promoted Barbier reaction of substituted difluoropropargyl bromides with alkyl chloroformates. These 2,2-difluorohomopropargyl esters were effective precursors in the synthesis of homopropargylic amides-by aminolysis using AlMe3, as well as of ketones-through the reaction of the corresponding Weinreb amides with Grignard reagents. Ring closing metathesis using difluorinated 1,7-enyne carbonyl compounds furnished six-membered diene products, which were used as susbstrates in a Diels-Alder reaction to afford 4,4-difluoroisoquinolin-3-ones. The [2 + 2 + 2] cycloaddition of alkynes with fluorinated 1,7-diyne amides gave 4,4-difluoro-1,4-dihydro-3(2H)-isoquinolinone derivatives regioselectively.     

Highly regio- and chemoselective [2 + 2 + 2] cycloaddition of electron-deficient diynes with allenes catalyzed by nickel complexes: a novel entry to polysubstituted benzene derivatives

Diynes 1a-c [X(CH(2)Ctbd1;CCO(2)Me)(2): X = (CH(2))(2), 1a, X = CH(2), 1b and X = O, 1c] undergo [2 + 2 + 2] ene-diyne cycloaddition reactions with a variety of allenes (n-butylallene 2a, phenylallene 2b, (4-chlorophenyl)allene 2c, (4-bromophenyl)allene 2d, (3-methoxyphenyl)allene 2e, 1-naphthylallene 2f, cyclohexylallene 2g and cyclopentylallene 2h) in the presence of Ni(dppe)Br(2) and Zn powder in CH(3)CN at 80 degrees C for 8 h to give the corresponding polysubstituted benzene derivatives 4a-l in good to excellent yields. Under similar reaction conditions, unsymmetrical diynes 5a-c (HCtbd1;CCH(2)XCH(2)Ctbd1;CCO(2)Me) react with allenes 2 to afford exclusively the corresponding meta-isomers 6a-g in 73-86% yields. The catalytic reaction is highly regioselective and completely chemoselective. This synthetic method is compatible with many functional groups such as Cl, Br, and OMe on the phenyl group of the allene moiety and an ether linkage in a diyne moiety. In this catalytic reaction, allenes are synthetically equivalent to terminal alkynes. Interestingly, unsymmetrical diyne 7 (MeCtbd1;C(CH(2))(4)Ctbd1;CCO(2)Me) undergoes 2:1 cocyclotrimerization with allenes 2a and 2g to afford the corresponding polysubstituted benzene derivatives 9a,b in 87% and 82% yields, respectively. A plausible mechanism involving a nickelacycloheptadiene intermediate is proposed to account for this nickel-catalyzed reaction.     

Synthesis of unsymmetrical 2,2'-biindolyl derivatives by a Cu-catalyzed N-arylation/Pd-catalyzed direct arylation sequential process

A one-pot synthesis of unsymmetrical 2,2'-biindolyl derivatives through a Cu-catalyzed N-arylation/Pd-catalyzed direct arylation sequence was described. The reaction involved easily prepared o-gem-dibromovinyl substrates, and the desired biindolyls were obtained in moderate to good yields.     

Development of efficient Lewis acid catalysts for intramolecular cycloaddition reactions of ester-tethered substrates

We have developed novel bidentate Lewis acids that efficiently promote the intramolecular cycloaddition reactions of ester-tethered substrates. Bis-aluminated triflic amide derivatives [TfN(AlR(1)R(2))2], which are generated by simply mixing triflic amide and 2 equiv of methyl aluminum or aluminum hydride, catalyzed intramolecular Diels-Alder (DA) reactions of ester-tethered 1,7,9-trienes and intermolecular DA reactions of alpha,beta-unsaturated lactones. We also found that bimetallic Lewis acid derived from 1,1'-biphenyl-2,2'-di(triflyl)amide and dimethylaluminum chloride promoted the intramolecular [3 + 2] cycloaddition reaction of acrylate derivatives having an allylsilane part.     

Synthesis of 6-amino-3,4-dihydroisoquinolinium derivatives by ring-opening reactions of acridizinium ions

The reaction of the 9-fluoroacridizinium (9-fluorobenzo[b]quinolizinium) or the 9-aminoacridizinium (9-aminobenzo[b]quinolizinium) ion with primary alkyl amines gives with high diastereoselectivity 6-amino-3,4-dihydroisoquinolinium derivatives as main products, which exhibit pronounced absorption and fluorescence properties. It is proposed that the reaction proceeds via a nucleophilic ring-opening followed by an aza Diels-Alder reaction.     

Generation and cyclization of thiocarbonyl S‐ylides by reaction of diazocompounds with C‐sulfonyldithioformates

The unexpected 1,3‐benzodithiine derivatives 5b,c were obtained from the reactions of trimethylsilyldiazomethane 2 with C‐sulfonyldithioformates, bearing pentachlorophenylthio group, 1b,c via unprecedented cyclization of the transient thiocarbonyl ylides 4b,c . While the corresponding reaction with C‐sulfonyldithioformates, bearing phenylthio group, afforded 5a via [2 + 3]‐cycloadditive dimerization of a transient thiocarbonyl ylides 4a . Under the same reaction condition, C‐sulfonyldithioformates 1d–f react with diazomethane and/or phenyldiazomethane to afford the unsymmetrical 1,3‐dithiolane 7d,e and thiirane 8e,f derivatives, respectively. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:28–33, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20246     

Synthesis of cavity extended cyclotriveratrylenes

Aromatic nucleophilic substitution reaction of cyclotriguaiacylene 1 with fluorobenzene derivatives bearing electron-withdrawing groups X (CHO, COCH(3), CN, NO(2)) in the para position gives a series of cyclotriveratrylene derivatives (3a-d), where the X substituents can be transformed to hydrogen-bond donor groups to afford new CTV-based heteroditopic receptors. The substituents of compounds 3a-d favor the facile demethylation reaction of the CTV derivatives. Attempts to perform alkylation reactions on derivatives (8c,d) evidenced the formation of a stereoisomeric mixture of symmetrical and unsymmetrical compounds.     

9-Allyl-1,7-dicarbadodecaborane as a dienophile in aza Diels-Alder reactions of 1,2,4-triazines: synthesis of pyridines bearing a carborane cage

The synthesis of pyridine and bipyridine derivatives of m-carborane via aza Diels-Alder reaction of 1,2,4-triazines with 9-allyl m-carborane and their structural characterization and photophysical properties are described. The products 3- and 4-(m-carborane-9-ylmethyl)-2,2′-bipyridines form Zn(II) complexes on reaction with ZnCl₂, which increases significantly their fluorescence intensity.     

Intramolecular ionic Diels-Alder reactions of alpha-acetylenic acetals

The intramolecular ionic Diels-Alder reaction of alpha-acetylenic acetals as a precursor of the propargyl cation has been investigated in the presence of Lewis acids and in protic acids. The reaction of diene-tethered alpha-acetylenic acetals (1-2) with formic acid yielded the regioselective intramolecular ionic Diels-Alder reaction products, bicyclodienal (9) and bicyclodienone (11) derivatives, in good yields.