Conjugate Adducts Research Articles

Formation of Conjugate Adducts in the Reactions of Malonaldehyde−Acetaldehyde and Malonaldehyde−Formaldehyde with Guanosine

The reactions of guanosine with malonaldehyde in buffered aqueous solutions in the presence of acetaldehyde or formaldehyde were studied. The reaction mixtures were analyzed by RP-HPLC. Two adducts were formed in the reaction of malonaldehyde and acetaldehyde and one in the reaction of malonaldehyde and formaldehyde. The products were isolated and purified by preparative C-18 chromatography and structurally characterized by UV absorbance, 1H NMR, and 13C NMR spectroscopy and mass spectrometry. The adducts formed in the reaction of malonaldehyde and acetaldehyde were identified as 7-(2,2-diformyl-1-methylethyl)-3-(beta-D-ribofuranosyl)pyrimido[1,2-a]-purin-10(3H)-one (M2AA-Guo I) and 2-(3,5-diformyl-4-methyl-1,4-dihydro-1-pyridyl)-9-(beta-D-ribofuranosyl)-purin-6(9H)-one (M2AA-Guo II). In the reaction of malonaldehyde and formaldehyde, the major product was identified as 7-formyl-3-(beta-D-ribofuranosyl)pyrimido[1,2-a]purin-10(8H)-one (M1FA-Guo). The highest yields of M2AA-Guo I and M2AA-Guo II, 7 and 2 mol %, respectively, were obtained in the reaction performed at pH 7.4 and 37 degrees C for 6 days, while M1FA-Guo was produced at a yield of 0.3 mol % after 3 days of reaction at pH 7.4 and 37 degrees C. The products are formed by reactions of malonaldehyde-acetaldehyde and malonaldehyde-formaldehyde condensation products with guanosine and are analogous to the previously identified condensation products formed with adenosine, cytidine, and proteins.

α‐Oxoketene Dithioacetal Mediated Aromatic Annulation: Highly Efficient and Concise Synthetic Routes to Potentially Carcinogenic Polycyclic Aromatic Hydrocarbons.

AbstractFor Abstract see ChemInform Abstract in Full Text.

α‐Oxoketene Dithioacetals Mediated Heteroaromatic Annulation Protocol for Benzoheterocycles: An Efficient Regiocontrolled Synthesis of Highly Substituted and Annulated Indazoles.

AbstractFor Abstract see ChemInform Abstract in Full Text.

α-Oxoketene dithioacetals mediated heteroaromatic annulation protocol for benzoheterocycles: an efficient regiocontrolled synthesis of highly substituted and annulated indazoles

An efficient regiocontrolled synthesis of highly substituted and annulated indazoles involving base induced addition–elimination of 1,3-diphenyl-5-cyanomethylpyrazole to a variety of acyclic and cyclic α-oxoketene, followed by acid assisted cycloaromatization of the resulting conjugate adducts has been reported.

α-Oxoketene dithioacetal mediated aromatic annulation: highly efficient and concise synthetic routes to potentially carcinogenic polycyclic aromatic hydrocarbons

Highly efficient regiospecific routes to potentially carcinogenic polycyclic aromatic hydrocarbons such as substituted benzo[ c]phenanthrenes, benzo[ c]fluorenes, 16,17-dihydro-11-methyl-15[ H]cyclopenta[ a]phenanthrene, 5-methyl-7,8,9,10-tetrahydrochrysene and 1,4-dimethylphenanthrene have been developed. The overall strategy involves our aromatic annulation protocol through base induced conjugate addition–elimination on the cyclic and acyclic α-oxoketene dithioacetals with the appropriate arylacetonitriles followed by acid induced cyclodehydration of the resulting conjugate adducts. Subsequent reductive dethiomethylation (Raney Ni) and dehydrogenation (DDQ) of the cyclized products affords the methyl substituted PAHs in high yields.

Domino Carbocationic Cyclization of Functionalized Cyclopropyl Ketones: Facile One‐Pot Access to Peri‐ and Angularly Fused Polycyclic Aromatic and Heteroaromatic Frameworks.

Conjugate adducts obtained by base-induced 1,4-addition-elimination of various aryl/heteroaryl acetonitriles with 1-(2-arylcyclopropyl)-3,3-(bismethylthio)-2-propen-1-ones have been shown to undergo facile acid-induced domino carbocationic rearrangement yielding a variety of substituted tricyclic aromatic and heteroaromatic frameworks in high yields in a one-pot operation. The methodology provides efficient, high-yield routes for synthesis of novel substituted dihydrophenalenes, dihydrobenzo[d,e]anthracene, cyclopenta[a]naphthalene, and fused heteroaromatics such as substituted 4,5-dihydrobenzo[c,d]indole, dihydronaphtho[1,8-b,c]thiophene, dihydroindeno[5,4-b]- and -[4,5-b]-thiophenes, cyclopenta[a]carbazole, and dihydrocyclopenta[e]indazol-3-one derivatives. The probable mechanism of this interesting domino process appears to involve stepwise or concomitant acid-induced ring opening and intramolecular cyclocondensation of cyclopropyl ketones to give benzo-fused arene (or heteroarene) intermediates bearing a reactive benzylic carbocation that is captured intramolecularly either by a preexisting aromatic (or heteroaromatic) ring or by a newly formed benzene ring to give either peri-fused or angularly fused products, respectively. Thus, the overall domino process entails formation of two C-C bonds, a substituted benzene ring along with a peri-fused cyclohexane or angularly fused cyclopentane ring in a single operation.

Domino carbocationic cyclization of functionalized cyclopropyl ketones: facile one-pot access to peri- and angularly fused polycyclic aromatic and heteroaromatic frameworks.

Conjugate adducts obtained by base-induced 1,4-addition-elimination of various aryl/heteroaryl acetonitriles with 1-(2-arylcyclopropyl)-3,3-(bismethylthio)-2-propen-1-ones have been shown to undergo facile acid-induced domino carbocationic rearrangement yielding a variety of substituted tricyclic aromatic and heteroaromatic frameworks in high yields in a one-pot operation. The methodology provides efficient, high-yield routes for synthesis of novel substituted dihydrophenalenes, dihydrobenzo[d,e]anthracene, cyclopenta[a]naphthalene, and fused heteroaromatics such as substituted 4,5-dihydrobenzo[c,d]indole, dihydronaphtho[1,8-b,c]thiophene, dihydroindeno[5,4-b]- and -[4,5-b]-thiophenes, cyclopenta[a]carbazole, and dihydrocyclopenta[e]indazol-3-one derivatives. The probable mechanism of this interesting domino process appears to involve stepwise or concomitant acid-induced ring opening and intramolecular cyclocondensation of cyclopropyl ketones to give benzo-fused arene (or heteroarene) intermediates bearing a reactive benzylic carbocation that is captured intramolecularly either by a preexisting aromatic (or heteroaromatic) ring or by a newly formed benzene ring to give either peri-fused or angularly fused products, respectively. Thus, the overall domino process entails formation of two C-C bonds, a substituted benzene ring along with a peri-fused cyclohexane or angularly fused cyclopentane ring in a single operation.

Identification of conjugate adducts formed in the reactions of malonaldehyde-acetaldehyde and malonaldehyde-formaldehyde with cytidine.

Malonaldehyde was reacted with cytidine in buffered aqueous solutions in the presence of acetaldehyde or formaldehyde. The reaction mixtures were analyzed by HPLC, and the products were isolated by preparative C18 chromatography and structurally characterized by UV absorbance, fluorescence emission, (1)H and (13)C NMR spectroscopy, and mass spectrometry. The major adducts formed in the reaction of malonaldehyde and acetaldehyde were identified as 7-(beta-D-ribofuranosyl)-4-methyl-6-oxo-6,7-dihydro-4H-pyrimido[1,6-a]pyrimidine-3-carbaldehyde (M(1)AA-Cyd) and 1-(beta-D-ribofuranosyl)-4-(3,5-diformyl-4-methyl-1,4-dihydro-1-pyridyl)pyrimidine (M(2)AA-Cyd). In the reaction of malonaldehyde and formaldehyde, the major product was identified as 7-(beta-D-ribofuranosyl)-6-oxo-6,7-dihydro-4H-pyrimido[1,6-a]pyrimidine-3-carbaldehyde (M(1)FA-Cyd). The highest yields of M(1)AA-Cyd and M(2)AA-Cyd, 3.2 and 0.5 mol %, respectively, were obtained in the reaction performed at pH 4.6 and 37 degrees C for 8 days, while M(1)FA-Cyd was produced at a yield of 0.3 mol % after 3 days of reaction at pH 4.0 and 37 degrees C. The products consist of units derived from malonaldehyde and acetaldehyde (M(1)AA-Cyd and M(2)AA-Cyd) or from malonaldehyde and formaldehyde (M(1)FA-Cyd), and are thus further examples of nucleoside modifications containing structural elements derived from aldehyde condensation reactions. Trace amounts of the adducts may be formed at physiological conditions and may be involved in the mutagenicity of the studied aldehydes.

α-(N-Carbamoyl)alkylcuprate Chemistry in the Synthesis of Nitrogen Heterocycles

The conjugate adducts obtained via coupling of alpha-(N-carbamoyl)alkylcuprates with alpha,beta-ynoates, alpha-allenyl esters, or alpha.beta-enoates or enimides undergo N-Boc deprotection and cyclization onto the ester functionality upon treatment with PhOH/TMSCl, catecholboron bromide, or trimethylsilyl triflate. This two-pot sequence provides synthetic routes to 4-alkylidinepyrrolidine-2-ones, 4-alkylidinepyrrolizidin-2-ones, and 4-alkylidineindolizidin-2-ones via allenyl esters; pyrrolin-2-ones, tetrahydropyrrolizin-2-ones, and tetrahydroindolizin-2-ones via alpha/beta-ynoates; pyrrolidin-2-ones, pyrrolizidin-2-ones, and indolizidin-2-ones via alpha,beta-enoates or alpha.beta-enimides. The reluctance of gamma-carbamoyl-alpha,beta-enoates to undergo E/Z isomerization requires the use of (Z)-beta-iodo-alpha,beta-enoates readily prepared by the addition of HI to the alkynyl esters for the efficient preparation of pyrrolinones, tetrahydropyrrolizinones, and tetrahydroindolizinones. Utilization of omega-functionalized alpha,eta-ynoates or beta-iodo-alpha,beta-enoates allows for cyclization onto the omega-functionality providing for a synthetic route to quinolizidines.

A Novel Method for the Stereoselective Synthesis of Tetralins and Indanes

Heavily-substituted 1-aryltetralins and 1-arylindanes were prepared in a highly stereoselective manner using a two-step sequence. Addition of t-butyl benzyl sulfoxides to unsaturated carbonyl compounds gave conjugate adducts with high diastereoselectivity. Treatment of the adducts with SnCl 4 generated benzyl carbocations which reacted intramolecularly with suitably-positioned aromatic rings to give tetralins and indanes, again with high diastereoselectivity.

ChemInform Abstract: Synthetically Useful Desulfurization Reactions of Heteroaryl Sulfoxide Conjugate Adducts.

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Evidence for Gliotoxin–Glutathione conjugate adducts

The equilibrium constant for the gliotoxin/glutathione pair was found to be 1200±100 M −1 at pH 7.0 at 25 °C. Under conditions where the reaction was quenched rapidly with the addition of acid, gliotoxin–glutathione conjugate adducts were detected.

Identification of fluorescent 2'-deoxyadenosine adducts formed in reactions of conjugates of malonaldehyde and acetaldehyde, and of malonaldehyde and formaldehyde.

2'-Deoxyadenosine was reacted with malonaldehyde in the presence of formaldehyde or acetaldehyde. The reactions were carried out at 37 degrees C in aqueous solution at acidic conditions. The reaction mixtures were analyzed by HPLC. In both reactions, two major products were formed. The reaction products were isolated and purified by C18 chromatography, and their structures were characterized by UV absorbance, fluorescence emission, (1)H and (13)C NMR spectroscopy, and mass spectrometry. The reaction products isolated from the mixture containing formaldehyde, malonaldehyde, and deoxyadenosine were identified as 3-(2'-deoxy-beta-D-ribofuranosyl)-7H-8-formyl[2,1-i]pyrimidopurine (M(1)FA-dA) and 9-(2'-deoxy-beta-D-ribofuranosyl)-6-(3,5-diformyl-1, 4-dihydro-1-pyridyl)purine (M(2)FA-dA). In the reaction mixture consisting of acetaldehyde, malonaldehyde, and deoxyadenosine, the identities of the products were determined to be 3-(2'-deoxy-beta-D-ribofuranosyl)-7-methyl-8-formyl[2, 1-i]pyrimidopurine (M(1)AA-dA) and 9-(2'-deoxy-beta-D-ribofuranosyl)-6-(3,5-diformyl-4-methyl-1, 4-dihydro-1-pyridyl)purine (M(2)AA-dA). The yields of the compounds were 1.8 and 0.7% for M(1)FA-dA and M(2)FA-dA, respectively, and 6.8 and 10% for M(1)AA-dA and M(2)AA-dA, respectively. All compounds exhibited marked fluorescent properties. These findings show that in addition to direct reaction of a specific aldehyde with 2'-deoxyadenosine, aldehyde conjugates also may react with the base. Although three of the adducts (M(1)FA-dA, M(2)FA-dA, and M(1)AA-dA) could not be detected in reactions carried out under neutral conditions, the possibility that trace amounts of the adducts may be formed under physiological conditions cannot be ruled out. Therefore, conjugate adducts must be considered in work that aims at clarifying the mechanism of aldehyde genotoxicity.

ChemInform Abstract: A Facile Synthesis of Polysubstituted Pyrroles.

α-Aminoalkylcuprates prepared from CuX·2LiCl (X = Cl, CN) and 1 equiv of an α-lithiocarbamate undergo conjugate addition reactions to α,β-alkynyl ketones in moderate to good yields, affording E:Z mixtures of α,β-enones. Treatment of the conjugate adducts with PhOH/TMSCl in CH2Cl2 effected carbamate deprotection and cyclization to afford a flexible two-step synthesis of substituted pyrroles.

α-Oxoketene Dithioacetals Mediated Benzoannelation of Aromatic Heterocycles: an Efficient Regiocontrolled Synthesis of Highly Substituted and Polycyclic Benzo[ b]thiophenes

An efficient regiocontrolled synthesis of highly substituted and complex polycyclic benzo[ b]thiophenes has been developed via our benzoannelation strategy involving conjugate addition–displacement on a variety of α-oxoketene dithioacetals by carbanions derived from 2- and 3-cyanomethylthiophenes followed by acid induced cyclization of the resulting conjugate adducts.

A facile synthesis of polysubstituted pyrroles.

alpha-Aminoalkylcuprates prepared from CuX.2LiCl (X = Cl, CN) and 1 equiv of an alpha-lithiocarbamate undergo conjugate addition reactions to alpha,beta-alkynyl ketones in moderate to good yields, affording E:Z mixtures of alpha,beta-enones. Treatment of the conjugate adducts with PhOH/TMSCl in CH(2)Cl(2) effected carbamate deprotection and cyclization to afford a flexible two-step synthesis of substituted pyrroles.

Conjugate Addition Reactions of α-Aminoalkylcuprates with α,β-Enones and Enals

Deprotonation of Boc-protected amines with sec-BuLi or transmetallation of α-aminostannanes with n-BuLi affords α-aminoalkyllithium reagents which can be converted into α-aminoalkylcuprate reagents with CuCN or THF soluble CuCN·2LiCl. These reagents undergo conjugate addition reactions with α,β-enones and enals. Reagents prepared from 2 equiv. of the α-aminoalkyllithium reagent give higher yields of conjugate adducts than those prepared from RCuCNLi, particularly when insoluble CuCN is employed. When CuCN·2LiCl is used, the two cuprate reagents give comparable yields of 1,4-adducts and the RCuCNLi reagent, economical in α-aminoalkyl ligand, is preferred. The Boc protecting group can be removed with PhOH/TMSCl and the amino ketone isolated as the hydrochloride salt.

Synthetically Useful Desulfurisation Reactions of Heteroaryl Sulfoxide Conjugate Adducts

Efficient desulfurisation reactions of the conjugate addition products derived from 1-methyl-2-imidazolyl and 2-pyridyl sulfoxides have been achieved. Hydrodesulfurisation was effected either by reduction of the sulfoxides to sulfides, followed by treatment with Raney nickel, or more reliably by reaction of either the sulfides or the sulfoxides with nickel boride. Pyrolytic elimination furnished alkenes stereoselectively on heating the sulfoxides to reflux in toluene or chloroform.

Asymmetric conjugate addition of diethyl zinc to enones with chiral phosphorus ligands derived from TADDOL

The asymmetric conjugate addition of diethyl zinc to cyclohexen-2-one, chalcone and benzalacetone was studied with 0.5% copper (II) triflate and 1% chiral phosphorus ligands derived from TADDOL. Among the several ligand tested, the cyclic phosphite obtained with 1S,2R phenylcyclohexanol gave up to 96% ee of conjugate adduct to cyclohexenone.

A chemical scale for evaluating the electron transfer ability of alkylcopper reagents

AbstractIn order to evaluate the electron transfer ability of organocopper reagents, the reactions of appropriate Michael acceptors with methyl and butylcopper reagents were investigated. The ratio of the conjugate adduct and reduction product was used as a chemical scale for evaluating the electron transfer ability of the alkylcopper reagents. Consequently, the electron transfer ability of methyl and butylcopper reagents is in the following order; Me3CuLi2 > Me2CuLi >> Me2Cu(CN)Li2 > MeCu > MeCu(CN)Li; Bu2CuLi > BuCu(CN)Li ‐ Bu2Cu(CN)Li2 > BuCu.