Palladium-catalyzed reactions of acetoxyenynes with triorganoindium reagents

The reaction of 1-acetoxy-2,7- and 2,8-enynes with triorganoindium reagents in the presence of 5 mol % palladium catalyst provides cyclic and/or acyclic substitution products depending upon substrate structure. Enynes bearing secondary acetates, quaternary centers, or heteroatoms furnish high yields of carbocyclic or heterocyclic substitution products. NMR studies show that a single trisubstituted alkene stereoisomer is formed in the reaction. A more atom-efficient procedure for the cyclization-substitution process utilizing heteroleptic indium reagents is presented.     

1-bromo-1-lithioethene: a practical reagent for the efficient preparation of 2-bromo-1-alken-3-ols

A reliable preparative-scale synthesis of 1-bromo-1-lithioethene is reported. This reagent undergoes clean 1,2-addition with a range of aldehydes and ketones at -105 degrees C to afford the corresponding 2-bromo-1-alken-3-ols in moderate to excellent yield. Efficient diastereoselective addition to alpha-siloxy and alpha-methylcyclohexanones, as well as protected 3-keto furanose sugars, is achieved in the presence of 10 mol % CeBr(3). The resulting bromoallylic alcohol adducts have considerable potential as synthetic building blocks. [reaction: see text]     

Highly stereoselective synthesis of (E)- and (Z)-alpha-fluoro-alpha,beta-unsaturated esters and (E)- and (Z)-alpha-fluoro-alpha,beta-unsaturated amides from 1-bromo-1-fluoroalkenes via palladium-catalyzed carbonylation reactions

The highly stereoselective synthesis of (E)- and (Z)-alpha-fluoro-alpha,beta-unsaturated esters and (E)- and (Z)-alpha-fluoro-alpha,beta-unsaturated amides is described. 1-Bromo-1-fluoroalkenes (E/Z approximately 1:1), which are readily available starting materials, have been found to isomerize to high E/Z ratios after storage at -20 degrees C for 1 week or by photolysis at 254 nm. Since the (E)-isomers have been found to react faster than the corresponding (Z)-isomers at room temperature in Pd(0)-catalyzed reactions, the palladium-catalyzed carboalkoxylation of high E/Z 1-bromo-1-fluoroalkenes lead to a high Z/E (Z/E >/= 98:2) ratio of the alpha-fluoro-alpha,beta-unsaturated esters. When 1-bromo-1-fluoroalkenes (E/Z approximately 1:1) were reacted with HCOOH/NBu(3)/Pd(II)/DMF, the (E)-isomer was selectively reduced, and the remaining (Z)-1-bromo-1-fluoroalkenes were recovered in essentially pure isomeric form. The resulting mixture of (Z)-1-bromo-1-fluoroalkenes and the reduced products underwent similar palladium-catalyzed carboalkoxylation reactions at 70 degrees C, and the (E)-alpha-fluoro-alpha,beta-unsaturated esters were stereospecifically obtained. This methodology was also successfully applied for the stereospecific synthesis of (Z)- and (E)-alpha-fluoro-alpha,beta-unsaturated amides: the palladium-catalyzed carboamidation reaction of high E/Z and (Z)-1-bromo-1-fluoroalkenes lead to pure (Z)- and (E)-alpha-fluoro-alpha,beta-unsaturated amides, respectively.     

Reaction of (Z)-1-aryl-3-hexen-1,5-diynes with sodium azide: synthesis of 1-aryl-1H-benzotriazoles

[reaction: see text] A novel tandem cascade reaction involving 1,3-dipolar cycloaddition reaction, anionic cyclization, and sigmatropic rearrangement for the synthesis of 1-aryl-1H-benzotriazoles 2 and 3 was accomplished by treatment of the (Z)-1-aryl-3-henen-1,5-diynes (1) with sodium azide in DMF or DMSO at 80 degrees C for 12 h and gives 65-91% yields.     

Mild and efficient molybdenum-mediated Pauson-Khand-type reaction

[reaction: see text] The molybdenum-mediated Pauson-Khand reaction promoted by Mo(CO)3(DMF)3 takes place under very mild conditions in the absence of any promoter. High yields in Pauson-Khand adducts are obtained in the cyclization of a wide variety of functionalized 1,6- and 1,7-enynes. Enynes bearing electron withdrawing groups at the alkene terminus are particularly good substrates.     

Baker's yeast reduction of prochiral γ-nitroketones. II. straightforward enantioselective synthesis of 2,7-dimethyl-1,6-dioxaspiro[4.4]nonanes

The baker's yeast reduction of 5-nitro-2,8-nonanedione 2 afforded the corresponding (2S,8S)-5-nitro-2,8-nonanediol3 with complete diastereoselectivity and high enantioselectivity. The conversion of 3 into the thermodynamic (E,E)/(Z,Z) (3:1) mixture of optically active (95% e.e.) 2,7-dimethyl-1,6-dioxaspiro[4.4]nonanes 5 was then achieved by spontaneous cyclization under the acidic conditions of the Nef reaction.     

Acetal-vinyl sulfide cyclization on sugar substrates: effect of structure and substituent

A range of 2-deoxyfuranoside and -pyranoside derivatives were fashioned into derivatives that carry a vinyl or propenyl side chain. Extension of the alkene by a Suzuki cross-coupling reaction with 1-bromo-1-(phenylthio)ethene gave thioenol ethers as the cyclization substrates. The treatment of these substrates with BF(3).Et(2)O in tert-butylmethyl ether below 0 degrees C induced cyclization to optically active bicyclic ethers. If the cyclizations are carried out in toluene as the solvent, the isomerization of the terminal thioenol ether to the inner thioenol ether can take place prior to the cyclization. The cyclization reactions can be impeded by steric and electronic factors. The opening of the bicyclic ethers could be illustrated with the base-induced conversion of the ketone 53 to the cyclooctenone 54.     

An efficient synthesis of optically active five- and six-membered cyclic compounds with selectable stereo-controls by a Ti(II)-mediated cyclization of chiral secondary 2,7- and 2,8-enyn-1-ol derivatives

Ti(II)-mediated cyclization of readily accessible optically active secondary 2,7- and 2,8-enyn-1-ol derivatives enables the selective preparation of any one of the four possible stereoisomers of the cyclized product with high optical purity.     

Divergent synthesis and chemical reactivity of bicyclic lactone fragments of complex rearranged spongian diterpenes

The synthesis and direct comparison of the chemical reactivity of the two highly oxidized bicyclic lactone fragments found in rearranged spongian diterpenes (8-substituted 6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one and 6-substituted 7-acetoxy-2,8-dioxabicyclo[3.3.0]octan-3-one) are reported. Details of the first synthesis of the 6-acetoxy-2,7-dioxabicyclo[3.2.1]octan-3-one ring system, including an examination of several possibilities for the key bridging cyclization reaction, are described. In addition, the first synthesis of 7-acetoxy-2,8-dioxabicyclo[3.3.0]octanones containing quaternary carbon substituents at C6 is disclosed. Aspects of the chemical reactivity and Golgi-modifying properties of these bicyclic lactone analogs of rearranged spongian diterpenes are also reported. Under both acidic and basic conditions, 8-substituted 2,7-dioxabicyclo[3.2.1]octanones are converted to 6-substituted-2,8-dioxabicyclo[3.3.0]octanones. Moreover, these dioxabicyclic lactones react with primary amines and lysine side chains of lysozyme to form substituted pyrroles, a conjugation that could be responsible for the unique biological properties of these compounds. These studies demonstrate that acetoxylation adjacent to the lactone carbonyl group, in either the bridged or fused series, is required to produce fragmented Golgi membranes in the pericentriolar region that is characteristic of macfarlandin E.     

CuI-catalyzed domino process to 2,3-disubstituted benzofurans from 1-bromo-2-iodobenzenes and beta-keto esters

CuI-catalyzed coupling of 1-bromo-2-iodobenzenes with beta-keto esters in THF at 100 degrees C leads to 2,3-disubstituted benzofurans. This domino transformation involves an intermolecular C-C bond formation and a subsequent intramolecular C-O bond formation process. Benzofurans with different substituents at the 5- and 6-position are accessible by employing the corresponding 1-bromo-2-iodobenzenes.     

Cu(I) catalyst in DMF: an efficient catalytic system for the synthesis of furans from 2-(1-alkynyl)-2-alken-1-ones

The cyclization of 2-(1-alkynyl)-2-alken-1-ones 1 proceeded very smoothly in the presence of alcohols 2 with a catalytic amount of Cu(I)Br in DMF at 80 degrees C, leading to the formation of highly substituted furans 3. The catalytic system reported herein is easy to handle, compared to the previously known system wherein the reaction between 1 and 2 needed to use moisture sensitive gold(III) chloride.     

Radical Cyclization of 1,n-Enynes and 1,n-Dienes for the Synthesis of 2-Pyrrolidone

2-Pyrrolidones have aroused enormous interest as a useful structural moiety in drug discovery; however, not only does their syntheses suffer from low selectivity and yield, but also it requires high catalyst loadings. The radical cyclization of 1,n-enynes and 1,n-dienes has demonstrated to be an attractive method for the synthesis of 2-pyrrolidones due to its mild reaction conditions, fewer steps, higher atom economy, excellent functional group compatibility, and high regioselectivity. Furthermore, radical receptors with unsaturated bonds (i. e. 1,n-enynes and 1,n-dienes) play a crucial role in realizing radical cyclization because of the ability to selectively introduce one or more radical sources. In this review, we discuss representative examples of methods involving the radical cyclization of 1,n-enynes and 1,n-dienes published in the last five years and discuss each prominent reaction design and mechanism, providing favorable tools for the synthesis of valuable 2-pyrrolidone for a variety of applications.     

Regio- and stereo-specific preparation of (E)-1-aryl-3,3,3-trifluoro-1-iodo-propenes and their palladium-catalyzed reaction with terminal alkynes

A new type of iodo-containing trifluoromethylated building blocks were synthesized. The reaction of 1-aryl-3,3,3-trifluoropropynes 1 with lithium iodide in acetic acid at 75 °C gave (E)-1-aryl-3,3,3-trifluoro-1-iodo-propenes 2 in high yield, which undergo the palladium-catalyzed Sonogashira reaction with terminal alkynes afforded trifluoromethyl-containing 1,3-enynes in high yield.     

(S)-(4-溴-2-甲苯)(3-甲基吗啉)甲酮的合成

以(S)-2-氨基丙醇和氯乙酰氯为起始原料,经酰化和环合反应制得(S)-5-甲基吗啉-3-酮（4）; 4经还原制得(S)-3-甲基吗啉(5); 5与4-溴-2-甲基苯甲酸酰化缩合合成了(S)-(4-溴2-甲基苯基)(3-甲基吗啉)-甲酮,总收率57%,其结构经¹H NMR 和 ¹³C NMR确证。     

An efficient synthesis of 5-bromo-2-methoxy-6-methylaminopyridine-3carboxylic acid

An efficient synthesis of 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxylic acid (1), a carboxylic acid moiety of a potent dopamine D2 and D3 and serotonin-3 (5-HT3) receptors antagonist, (R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1 ,4-diazepin-6-yl)-2-methoxy-6-methylaminopyridine-3-carboxamide, is described. Reaction of methyl 2,6-difluoropyridine-3-carboxylate (12) with methylamine in EtOH at -25 degrees C gave a mixture of methyl 2-fluoro-6-methylaminopyridine-3-carboxylate (13) and the regioisomer 14 in a ratio of 57 : 43. On the other hand, reaction of 12 and methyl 2,6-dichloropyridine-3-carboxylate (16) with sodium methoxide in tetrahydrofuran (THF) and CH2Cl2 provided the 2-methoxypyridine-3-carboxylic esters 20 and 23, respectively, as main products. Similar reaction of 16 in N,N-dimethylformamide (DMF) and MeOH proved to be highly regioselective for the 6-position. A much greater regioselectivity for substitution at the 6-position (>97%) was observed when 16 was treated with 4-methylbenzenethiolate anion in DMF (quantitative yield). After methoxylation of methyl 2-chloro-6-(4-methylbenzenethio)pyridine-3-carboxylate (25b) and successive oxidation of the 6-benzenethio moiety, nucleophilic substitution of the sulfoxide derivative 28 with methylamine gave the 6-methylamino derivative 8. Finally, bromination of 8 and alkaline hydrolysis produced the desired product 1 in an overall yield of 67%.     

6-溴-3-[2-(6-溴-2-甲氧基喹啉-3-基)-1,2-二苯乙基]-2-甲氧基喹啉的合成

以6-溴-3-(氯苯基甲基)-2-甲氧基喹啉(2)为起始原料,经过偶合对接反应合成了新型喹啉类抗结核药物TMC-207的衍生物6-溴-3-[2-(6-溴-2-甲氧基喹啉-3-基)-1,2-二苯乙基]-2-甲氧基喹啉,其结构经1H NMR和HR-MS确证.最佳反应条件:2 10 mmol,Et_3N 5 mL,KI 0.17 g,乙腈150 mL,于80 ℃反应6 h,收率73%.     

Dynamics of intramolecular electron transfer in dinitrodibenzodioxin radical anions

The activation energy for intramolecular electron transfer in radical anions of 2,7-dinitrodibenzodioxin and 2,8-dinitrodibenzodioxin, obtained by simulation of their temperature-dependent EPR spectra, are well predicted by the values calculated by the two-state Marcus-Hush model from the optical charge-transfer bands using quartic-adjusted energy surfaces. The electronic coupling is higher in the 2,8-dinitrodibenzodioxin (H(ab) = 485 cm(-1)) than in the 2,7-dinitrodibenzodioxin radical anion (H(ab) = 250 cm(-1)), but for each solvent the reorganization energy, taken as the maximum of the optical band, is only slightly higher in the latter. These values are consistent with the fact that the reaction is faster in the 2,8-dinitrodibenzodioxin radical anion isomer, as determined by EPR spectroscopy. The pre-exponential factors obtained combining the EPR-derived rate constants and the activation energies calculated from the optical bands fit well the theoretical (modified) nonadiabatic values in the less viscous solvents. However, for the more viscous solvents, the trend of the pre-exponential values with solvent can only be explained if dynamical solvent effects increasingly influence their value. The influence of solvent dynamics in the 2,8-dinitrodibenzodioxin radical anion starts in the less viscous solvents DMF and DMSO, but in the 2,7-dinitrodibenzodioxin isomer this is only fully evident for the more viscous PhCN and HMPA. The influence of solvent dynamics is higher in the radical with the lowest activation barrier.     

Novel synthetic approach toward (+/-)-beta-cuparenone via palladium-catalyzed tandem Heck cyclization of 1-bromo-5-methyl-1-aryl-hexa-1,5-dien-3-ol derivatives

A novel and convenient synthetic route toward (+/-)-beta-cuparenone and many other sesquiterpene natural product precursors has been developed via palladium-catalyzed tandem Heck cyclization of 1-bromo-5-methyl-1-aryl-hexa-1,5-dien-3-ols. [reaction: see text].     

Versatile synthesis of quinoline-3-carboxylic esters and indol-2-acetic esters by palladium-catalyzed carbonylation of 1-(2-aminoaryl)-2-yn-1-ols

1-(2-Aminoaryl)-2-yn-1-ols, easily obtained by the Grignard reaction between 1-(2-aminoaryl)ketones and alkynylmagnesium bromides, were subjected to carbonylative conditions in the presence of the PdI2-KI catalytic system, in the presence and in the absence of an external oxidant. Under oxidative conditions (80 atm of a 4:1 mixture of CO-air, in MeOH as the solvent at 100 degrees C and in the presence of 2 mol % of PdI2 and 20 mol % of KI), 1-(2-aminoaryl)-2-yn-1-ols bearing a primary amino group were selectively converted into quinoline-3-carboxylic esters in fair to good yields [45-70%, based on starting 1-(2-aminoaryl)ketones], ensuing from 6-endo-dig cyclization followed by dehydration and oxidative methoxycarbonylation. On the other hand, indol-2-acetic esters, deriving from 5-exo-dig cyclization followed by dehydrating methoxycarbonylation, were selectively obtained in moderate to good yields [42-88%, based on starting 1-(2-aminoaryl)ketones] under nonoxidative conditions (90 atm of CO, in MeOH as the solvent at 100 degrees C and in the presence of 2 mol % of PdI2 and 20 mol % of KI), in the case of 1-(2-aminoaryl)-2-yn-1-ols bearing either a primary or secondary amino group and substituted with a bulky group on the triple bond.     

Copper(II)‐Catalyzed Tandem Synthesis of Substituted 3‐Methyleneisoindolin‐1‐ones

An efficient strategy for the synthesis of a variety of 3‐methyleneisoindolin‐1‐ones has been developed. The reaction proceeded from coupling of 2‐iodobenzamides (or 2‐bromobenzamides) and terminal alkynes via Cu(OAc)₂·H₂O/2,2′‐biimidazole catalyzed in DMF at 60°C and subsequent additive cyclization produced substituted 3‐methyleneisoindolin‐1‐ones in good to excellent yields.