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[reaction: see text] Effective nickel-catalyzed cocycloaddition of nonconjugated diynes with conjugated diynes yields polysubstituted arylalkynes in good to excellent yields with high regio- and chemoselectivity.
Treatment of 'GaI' with a 1,3-diyne, Me3SiC[triple bond]CC[triple bond]CSiMe3, leads to C-C coupling reactions and the isolation of the novel organogallium species, [Ga4I8[C8(SiMe3)4]], as two isomeric forms; their X-ray crystal structures show them to contain the first structurally authenticated gem-organodigallium fragments and to exhibit rare examples of Ga-alkyne pi-interactions.
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The (Z)-hex-1,5-diyne-3-ene reactive core common to the enediyne antitumor antibiotics undergoes a Bergman cyclization after proper activation to afford reactive diradical intermediates that are responsible for initiating DNA cleavage. Direct modification of the enediyne core has been proposed as a method to permit cancer cell-specific triggering of the diradical-generating cyclization. For example, 3-aza-3-ene-1,5-diynes undergo an aza-Bergman cyclization to afford the fleeting 2,5-didehydropyridine diradicals. While protonation of these aza-enediynes can afford products of diradical trapping, the hydrolytic instability of the 3-aza-3-ene-1,5-diyne moiety prevents its use in pH-triggered DNA cleaving anticancer agents. Recently, more hydrolytically stable systems incorporating the 4-aza-3-ene-1,6-diyne moiety were developed. We report here studies of the 4-aza-3-ene-1,6-diyne-containing benzimidazolium salt AZB002 [1-methyl-2-(phenylethynyl)-3-(3-phenylprop-2-ynyl)-3H-benzimidazolium tetrafluoroborate] and two structurally related heterocycles that lack the aza-enediyne functionality, AZB016 [1,3-dimethyl-2-(phenylethynyl)-3H-benzimidazolium triflate] and AZB004 [3-methyl-2-(phenylethynyl)benzothiazolium triflate]. The interaction of these compounds with supercoiled DNA, a double-stranded DNA fragment, and a short DNA duplex oligonucleotide was investigated. There are three distinct DNA interactions exhibited by AZB002: a frank strand scission leading to the relaxation of supercoiled DNA and formation of at least two different DNA adducts, one of which leads to cytosine-specific cleavage after piperidine/heat treatment. In contrast, analogues lacking the aza-enediyne functionality either fail to interact with DNA (AZB016) or cleave DNA at guanine residues, presumably through alkylation of the N-7 position (AZB004). We also investigated the cytotoxicity of AZB002 and the related heterocyclic compounds AZB004 and AZB016 and find that only the DNA interactive compounds AZB002 and AZB004 display significant cytotoxicity. In particular, AZB002 is cytotoxic against a wide range of cancer cell lines.
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.
Alkyl-, alkoxy-, and aryloxy-substituted conjugated enynes 1 in the presence of Pd(PPh(3))(4) catalyst smoothly underwent the regiospecific [4 + 2] cycloaddition reaction with conjugated alkyl- and alkoxy-substituted symmetric diynes 2 to give multisubstituted aryl ethers 3 in good to high yields. Benzannulation of enynes 1d-g with unsymmetric diyne 6, possessing alkyl and alkoxy groups at acetylenic terminii, in most cases produced an aromatic product 8 with an alkoxy group of diyne attached to the ethynyl moiety of the aromatic product. Remarkably, alkoxy-substituted diynes 2c and 6 underwent the benzannulation reaction with 1 at an unusually low temperature of 0 degrees C! One-pot consecutive benzannulation of alkyl-substituted enynes 1d,e and alkoxy-substituted enynes 1f,g with alkoxy-substituted diynes 2c and 6 followed by protonolysis with TsOH afforded coumaranones 9a-c and 10 in reasonable to high overall yields.
A series of silyl-terminated diynes of varying lengths and substitution patterns have been prepared. These diynes undergo zirconocene coupling with selective formation of trimeric macrocycles from linear alkynes, while nonlinear diynes give cyclodimeric products. The length of the linear diynes can be increased for the preparation of macrocycles with large nanoscale cavities. Reaction of the zirconium-containing macrocycles with acid results in the synthesis of metal-free cyclophanes. All of these macrocycles were prepared in multigram quantities, in the absence of high-dilution conditions, to give products in > 75% yield that are easily purified as crystalline solids.
The cycloisomerization of diyne-ols catalyzed by [CpRu(CH3CN)3]PF6 to 2-vinyl-1-acylcycloalkenes proceeds via a ruthenacyclopentadiene involving initial ionization of the tertiary or secondary alcohol, followed by readdition. In the case of primary alcohols, a competing pathway wherein water first adds would appear to occur. The feasibility of this proposed minor pathway was tested in the reaction of diynes in the presence of water. Quite excitingly, cyclization comcommittant with addition of water to form 1-acylcycloalkenes occurs. This proves to be general process to form five- and six-membered rings. Interestingly, hydrative cyclization of Z-5-decen-2,8-diyne to 1-acetyl-2-ethyl-cyclohexa-1,4-diene occurs without isomerization of the double bonds. Furthermore, the epoxide of the same substrate cyclizes without opening of the strained epoxide. Unsymmetrically substituted diynes cyclize with remarkable chemoselectivity wherein water attacks the less hindered alkynes. beta-branching of any kind gives only a single product. Remarkably, even competing methyl versus ethyl still effects a 2.5:1 selectivity in favoring water addition to the methyl-bearing alkyne. Alcohols can replace water and provide enol ethers. Strong mechanistic evidence suggests two reaction manifolds indeed operate, depending upon the presence of propargyl alcohols and the degree of substitution on the hydroxyl-bearing carbon.
A 1:1 mixture of the platinum dimethyl diimine complex [PhN[double bond]C(Me)C(Me)[double bond]NPh]PtMe(2) (4a) and B(C(6)F(5))(3) catalyzed the cyclization/hydrosilylation of dimethyl dipropargylmalonate (1) and HSiEt(3) to form 1,1-dicarbomethoxy-3-methylene-4-(triethylsilylmethylene)cyclopentane (3) in 82% isolated yield with 26:1 Z:E selectivity. Platinum-catalyzed diyne cyclization/hydrosilylation tolerated a range of functional groups including esters, sulfones, acetals, silyl ethers, amides, and hindered ketones. Diynes that possessed propargylic substitution underwent facile cyclization/hydrosilylation to form silylated 1,2-dialkylidene cyclopentanes as mixtures of regioisomers. Diynes that possessed an electron-deficient internal alkyne underwent cyclization/hydrosilylation in moderate yield to form products resulting from silyl transfer to the less substituted alkyne. The silylated 1,2-dialkylidenecyclopentanes formed via diyne cyclization/hydrosilylation underwent a range of transformations including protodesilylation, Z/E isomerization, and [4 + 2] cycloaddition with dieneophiles.
[reaction: see text] Catalytic hydrogenation of ethyl glyoxalate in the presence of 1,3-diynes 4a-9a using chirally modified rhodium catalysts enables formation of alpha-hydroxy esters 4c-9c in highly optically enriched form. Notably, for such trialkylsilyl-substituted 1,3-diynes, C-C coupling occurs exclusively at the carbon atom bearing silicon. Pi-back-bonding from low valent rhodium as described by the Dewar-Chatt-Duncanson model appears to direct the regiochemistry of C-C coupling, as corroborated by calculations of the diyne LUMO coefficients.
The compound [Ru3(mu-H)(mu3-eta2-ampy)(CO)9] (1; Hampy =2-amino-6-methylpyridine) reacts with diynes RC4R in THF at reflux temperature to give the ynenyl derivatives [Ru3(mu3-eta2-ampy)(mu-eta3-RC...CC-CHR)(mu-CO)2-(CO)6] (2: R=CH2OPh; 3: R=Ph). These products contain a 1,4-disubstituted butynen-3-yl ligand attached to two ruthenium atoms. The compound [Ru3(mu-eta2-ampy)[mu3-eta6-PhCC5(C...CPh)-HPh2](CO)7] (4), which contains an eta5-cyclopentadienyl ring and a bridging carbene fragment, has also been obtained from the reaction of 1 with diphenylbutadiyne. This compound arises from a remarkable [3+2] cycloaddition reaction of a preformed 1,4-diphenylbutynen-4-yl ligand with a triple bond of a second diphenylbutadiyne molecule. The reactivity of the ynenyl derivatives 2 and 3 with diynes and alkynes has been studied. In all cases, compounds of the general formula [Ru3(mu-eta2-ampy)[mu3-eta5-C(=CHR)C=CRCR1=CR2](CO)7] (5-17) have been obtained. They all contain a ruthenacyclopentadienyl fragment formed by coupling of the coordinated ynenyl ligand of 2 (R = CH2OPh) or 3 (R = Ph) with a triple bond of the new reagent (the CR1=CR2 fragment results from the incoming diyne or alkyne reagent). While most of the products derived from 2 have the alkenyl C=CHR fragment with a Z configuration (R cis to Ru), all the compounds obtained from 3 have this fragment with an E configuration. Except 2 and 3, all the cluster complexes described in this article have a five-electron donor ampy ligand attached to only two metal atoms, a coordination mode unprecedented in cluster chemistry.
In the presence of 2.5 mol % of [Pd(2)(dba)(3)] (dba=dibenzylideneacetone) and 5 mol % of PPh(3), nearly equimolar amounts of dimethyl nona-2,7-diyne-1,9-dioate derivatives (diyne diesters) and dialkyl acetylenedicarboxylates were allowed to react in toluene at 110 degrees C to afford [2+2+2] cycloadducts in moderate-to-good yields. Similarly, dimethyl trideca-2,7,12-triyne-1,13-dioate derivatives (triyne diesters) were catalytically transformed into phthalic acid ester analogues in excellent yields. To gain insight into the mechanism of these intramolecular alkyne cyclotrimerizations, stoichiometric reactions of [Pd(2)(dba)(3)] with a diyne diester and a triyne diester bearing ether tethers were conducted in acetone at room temperature to furnish an oligomeric bicyclopalladacyclopentadiene and a Pd(0) triyne complex, respectively. The structures of these novel complexes were unequivocally determined by Xray structure analysis. The isolated triyne complex was heated at 50 degrees C or treated with PPh(3) in acetone at room temperature to afford the arene product. Furthermore, the same complex catalyzed the triyne cyclization with or without PPh(3).
A family of dicationic diyne salts of the general formula [(Co2(CO)6)2-mu,eta2,eta2-(Nu-CH2C(triple bond)C-C(triple bond)CCH2-Nu)][BF4]2 [Nu = SMe2 (3); Nu = NC6H7, 3-picoline, (5); Nu = NC9H7, quinoline (7)] were prepared and fully characterized. Three X-ray molecular structures of 3, 5, and the neutral starting material 2,4-hexadiyne-1,6-diol complex [(Co2(CO)6)2-mu,eta2,eta2-(HO-CH2C(triple bond)C-C(triple bond)CCH2-OH)] (1) are presented. Complex 1 crystallizes in the triclinic space group P1 with a = 14.722(2) A, b = 14.571(3) A, c = 14.722(2) A, alpha = 105.17(1) degrees, beta = 113.30(1) degrees, gamma = 99.20(1) degrees, and Z = 4. Complex 3 crystallizes in the monoclinic space group P2(1)/n with a = 12.758(3) A, b = 13.360(3) A, c = 20.494(3) A, beta = 91.44(1) degrees, and Z = 4, and compound 5 also crystallizes in the monoclinic space group P2(1)/n with a = 9.426(2) A, b = 21.739(5) A, c = 18.704(3) A, beta = 94.86(1) degrees, and Z = 4. The X-ray structures provide us with valuable information on the arrangement of the Co2-alkyne units, which have a cis geometry and are in sharp contrast to that observed generally for diyne-tetracobalt compounds. Complex [(Co2(CO)6)2-mu,eta2,eta2-(Me2S-CH2C(triple bond)C-C(triple bond)CCH2-SMe2)][BF4]2 (3) reacts with N-, S-, and P-centered nucleophiles and affords the related substituted complexes in high yields. The stability and reactivity of the disulfonium diyne complex 3 toward nucleophiles are compared to those of the analogous disulfonium-yne complex [(Co2(CO)6)2-mu,eta2,eta2-(Me2S-CH2-C(triple bond)C-CH2-SMe2)][BF4]2 (4).
Catalytic hydrogenation of carbon-, nitrogen- and oxygen-tethered 1,6-diynes 1a-9a and 1,6-enynes 10a-18a using cationic Rh(I) precatalysts at ambient temperature and pressure enables reductive carbocyclization to afford 1,2-dialkylidene cyclopentanes 1b-9b and monoalkylidene cyclopentanes 10b-18b, respectively, in good to excellent yields and as single alkene stereoisomers. Notably, the 1,3-diene and alkene containing cyclization products 1b-9b and 10b-18b are not subject to over-reduction under the conditions of catalytic hydrogenation in which they are formed. Reductive cyclization 1,6-diyne 1a and 1,6-enyne 10a performed under an atmosphere of D(2) provides the carbocyclization products deuterio-1b and deuterio-10b, respectively, which incorporate two deuterium atoms. The collective data are consistent with a catalytic mechanism involving heterolytic activation of elemental hydrogen (H(2) + Rh(+)X(-) --> Rh-H + HX) followed by Rh(I)-mediated oxidative cyclization of the 1,6-diyne or 1,6-enyne substrates to afford (hydrido)Rh(III)-based metallocyclopentadiene and metallocyclopentene intermediates, respectively. These transformations represent the first examples of metal-catalyzed reductive carbocyclization mediated by hydrogen.
Reaction of alkynyl halides with in situ prepared zirconacyclopentanes, -pentenes, and -pentadienes in the presence of CuCl under mild reaction conditions afforded alkynes or diynes. Control of the reaction conditions selectively afforded monoalkynylation products of zirconacycles. Reaction of zirconacycles with 2 equiv of alkynyl halides resulted in the formation of diynes. Selective monoalkynylation of zirconacycle with an alkynyl halide, followed by reaction with a different alkynyl halide, afforded unsymmetrical diynes. Bisalkynylation product of zirconacyclopentadiene was gradually converted into a tricyclic compound.
The factors that affect the kinetics of the aza-Bergman cyclization of aza-enediynes (C,N-dialkynyl imines) have not previously been elucidated. Here we report our kinetic studies of the aza-Bergman reactions of a series of 6-triisopropylsilyl and 6-unsubstituted 1-phenyl-4-aryl-3-aza-3-ene-1,4-diynes in which the aryl group is phenyl, o-(methoxy)phenyl, or p-(methoxy)phenyl. These aza-enediynes are prepared as single isomers in modest yield from the corresponding 1-aryl-3-(triisopropylsilyl)propynone oximes. These aza-enediynes undergo aza-Bergman reaction followed by a rapid retro-aza-Bergman cyclization to afford beta-alkynyl acrylonitrile products. In no case are products corresponding to trapping the intermediate 2,5-didehydropyridine diradical isolated. While the rate of aza-Bergman cyclization is not greatly affected by the nature of the 4-aryl substituent, the rate is very dependent on the nature of the 6-substituent. 1-Phenyl-4-aryl-3-aza-3-ene-1,5-diynes that lack a 6-substituent undergo aza-Bergman cyclization spontaneously at 20 degrees C with first-order half-lives of 36-78 min. The effect of solvent on the kinetics of aza-Bergman cyclization of 1,4-diphenyl-3-aza-3-ene-1,5-diyne was investigated. The rate of this cyclization is solvent dependent, proceeding more rapidly in less polar solvents.
The [2 + 2 + 2] cycloaddition of diynes and enones occurred in the presence of both nickel and zinc together. This binary metal-mediated reaction had two interesting features: (1) a terminally unsubstituted diyne reacted with an enone to give an aromatic compound with the concomitant incorporation of two hydrogen atoms abstracted from an expected 1,3-diene product into another molecule of the starting enone and (2) a trimethylsilyl-substituted diyne reacted with an equimolar amount of enone to regioselectively afford a 1,3-diene, in which the trimethylsilyl group is adjacent to the carbonyl group.
A strictly "pair"-selective synthesis of conjugated diynes via Pd-catalyzed cross coupling of 1,3-diynylzincs is described. This method, like the Cadiot-Chodkiewicz reaction, requires three steps for the synthesis of R(1)Ctbd1;CCtbd1;CR(2) from R(1)Ctbd1;CH, R(2)X, and HCtbd1;CH. However, the high "pair"-selectivity permitting high-yield production of the desired conjugated diynes without separation of symmetrical diynes promises to make the present protocol superior to the Cadiot-Chodkiewicz reaction in many cases.