Solvent-free synthesis of δ-carbolines/carbazoles from 3-nitro-2-phenylpyridines/2-nitrobiphenyl derivatives using DPPE as a reducing agent

A green and efficient preparation of functionalized δ-carbolines/carbazoles via reductive ring closure by 1,2-bis(dipenylphosphino)ethane under solvent-free conditions is described. The starting materials 3-nitro-2-phenylpyridines/2-nitrobiphenyl derivatives are readily prepared through Suzuki-Miyaura cross-coupling reaction from commercially available compounds. And the polar by-product ethane-1,2-diylbis(diphenylphosphine oxide) is easily removed from the relatively polar reaction mixture. Various substituted δ-carbolines/carbazoles are obtained in acceptable yields. It is particularly worth mentioning that substrates with electron-withdrawing groups (EWG) also give the desired products in good yield.     

Temperature-controlled regioselectivity in the reductive cleavage of p-methoxybenzylidene acetals

The regioselective ring opening of pyranosidic 4,6-p-methoxybenzylidene acetals with BH(3)/Bu(2)BOTf in THF can be tuned by adjusting the reaction temperature and reagent concentrations. Reductive cleavage at 0 degrees C resulted in the exclusive formation of 4-O-p-methoxybenzyl (PMB) ethers, whereas reaction at -78 degrees C produced 6-O-PMB ethers in high yields. The latter condition was observed to be compatible with a variety of acid-sensitive functional groups, including allyl and enol ethers. The presence of water does not interfere with reductive ring opening and may contribute toward in situ generation of H(+) as a catalyst for 6-O-PMB ether formation. Reductive cleavage under rigorously aprotic conditions is greatly decelerated, and yields only the 4-O-PMB ether. The temperature-dependent reductive cleavage of the 4,6-acetal can be described in terms of kinetic versus thermodynamic control: Lewis-acid coordination of the more accessible O-6 is favored at higher temperatures, whereas protonation of the more basic but sterically encumbered O-4 predominates at low temperatures.     

DFT study on the reaction mechanism and regioselectivity for the [1,2]-anionic rearrangement of 2-benzyloxypyridine derivatives

The reaction mechanism of the [1,2]-anionic rearrangement of 2-benzyloxypyridines has been investigated using DFT calculations. Calculated results indicate that: the deprotonation step is relatively fast and the rearrangement step is the rate-determining step; electron-donating group on the benzene ring decreases the activation energy of the rearrangement, which correlates with an increase in reaction yield, while electron-withdrawing groups show the opposite effect. The rearrangement is calculated to proceed by way of an oxirane-like transition state that had previously been postulated as a transient intermediate. Furthermore, the mechanism for the rearrangement of 2-(benzyloxy)nicotinonitrile was discussed. The quick formation of the five membered ring intermediate leads to the predominant formation of 2-phenylfuro[2,3-b]pyridin-3-amine. The calculation results indicate the possibilities of derivatizing the starting pyridyl ether as well as facilitating the rearrangement reaction by adding an appropriate electron-donating group on the benzene ring or electron-withdrawing group on the pyridine ring for future studies.     

Ru(3)(CO)(12) in Acidic Media. Intermediates of the Acid-Cocatalyzed Water-Gas Shift Reaction (WGSR)

The elucidation of the WGSR promoted by ruthenium carbonyls in acidic media started with the detection of the Ru(0), Ru(I), and Ru(II) intermediate complexes, namely Ru(3)(CO)(12), Ru(2)[&mgr;-eta(2)-OC(CF(3))O](2)(CO)(6), and fac-[Ru(CF(3)COO)(3)(CO)(3)](-), which accumulate when CF(3)COOH is employed as an acid cocatalyst. Under catalytic conditions, the three were found to interconvert through elementary steps which produce CO(2) and H(2). In fact, Ru(0) is oxidized by H(+) to Ru(I) and half the hydrogen of the catalytic cycle is supplied by this reaction. On the other hand, Ru(I) disproportionates to Ru(0) and Ru(II), and this latter species undergoes nucleophilic attack by H(2)O. The decomposition of the metallacarboxylic acid intermediate gives back Ru(I), while H(2) and CO(2) are produced in a 1/2 molar ratio. The two alternating pathways for dihydrogen formation, namely Ru(0) oxidation by H(+) and the decomposition of a metallacarboxylic acid intermediate, involve H(2) reductive elimination from the same RuHCF(3)COO(CO)(2)L(2) intermediate (L = H(2)O, ethers). These findings define an acid-cocatalyzed WGSR whose distinctive features are (i) the intervention of a disproportionation reaction to generate a Ru(II) electron poor complex, whose CO ligands can undergo nucleophilic attack by water, (ii) the generation of the hydrido intermediate for dihydrogen production through two distinct reaction patways, and (iii) the reductive elimination of H(2) from the hydrido intermediate without involving H(+) from the medium.     

Pd-catalyzed ring opening of oxa- and azabicyclic alkenes with aryl and vinyl halides: efficient entry to 2-substituted 1,2-dihydro-1-naphthols and 2-substituted 1-naphthols

An efficient syntheses of 2-substituted 1,2-dihydro-1-naphthols and 2-substituted 1-naphthols has been developed that involves the sequential palladium-catalyzed ring opening of oxabicyclic alkenes with aryl and vinyl halides followed by oxidation of with IBX. In the first step of the sequence, a combination of Pd(OAc)2, PPh3, Zn, and PMP in dry DMF was employed to catalyze the ring opening of 7-oxabenzonorbornadienes with aryl and vinyl halides to afford the corresponding cis-2-substituted 1,2-dihydronaphthols in good to excellent yields. These reactions occurred under very mild conditions with a variety of aryl halides bearing electron-withdrawing or -donating groups. Similarly, a 7-azabenzonorbornadiene substituted with an electron-withdrawing group on the nitrogen atom underwent facile ring-opening reaction with aryl halides to provide cis-2-substituted (1,2-dihydro-1-naphthyl)carbamates in excellent yields. Oxidation of the intermediate 1,2-dihydro-1-naphthols using IBX yielded the corresponding 2-substituted 1-naphthols in good to excellent yields.     

TiCl3-Mediated Synthesis of 2,3,3-Trisubstituted Indolenines: Total Synthesis of (+)-1,2-Dehydroaspidospermidine, (+)-Condyfoline,and (−)-Tubifoline

2,3,3-Trisubstituted indolenine constitutes an integral part of many biologically important monoterpene indole alkaloids. We report herein an unprecedented access to this skeleton by a TiCl₃-mediated reductive cyclization of tetrasubstituted alkenes bearing a 2-nitrophenyl substituent. The proof of concept is demonstrated firstly by accomplishing a concise total synthesis of (+)-1,2-dehydroaspidospermidine featuring a late-stage application of this key transformation. A sequence of reduction of nitroarene to nitrosoarene followed by 6π-electron-5-atom electrocyclization and a 1,2-alkyl shift of the resulting nitrone intermediate was proposed to account for the reaction outcome. A subsequent total synthesis of (+)-condyfoline not only illustrates the generality of the reaction, but also provides a mechanistic insight into the nature of the 1,2-alkyl shift. The exclusive formation of (+)-condyfoline indicates that the 1,2-alkyl migration follows a concerted Wagner–Meerwein pathway, rather than a stepwise retro-Mannich/Mannich reaction sequence. Conditions for almost quantitative conversion of (+)-condyfoline to (−)-tubifoline by way of a retro-Mannich/1,3-prototropy/transannular cyclization cascade are also documented.     

ENDOR/HYSCORE studies of the common intermediate trapped during nitrogenase reduction of N2H2, CH3N2H, and N2H4 support an alternating reaction pathway for N2 reduction

Enzymatic N(2) reduction proceeds along a reaction pathway composed of a sequence of intermediate states generated as a dinitrogen bound to the active-site iron-molybdenum cofactor (FeMo-co) of the nitrogenase MoFe protein undergoes six steps of hydrogenation (e(-)/H(+) delivery). There are two competing proposals for the reaction pathway, and they invoke different intermediates. In the 'Distal' (D) pathway, a single N of N(2) is hydrogenated in three steps until the first NH(3) is liberated, and then the remaining nitrido-N is hydrogenated three more times to yield the second NH(3). In the 'Alternating' (A) pathway, the two N's instead are hydrogenated alternately, with a hydrazine-bound intermediate formed after four steps of hydrogenation and the first NH(3) liberated only during the fifth step. A recent combination of X/Q-band EPR and (15)N, (1,2)H ENDOR measurements suggested that states trapped during turnover of the α-70(Ala)/α-195(Gln) MoFe protein with diazene or hydrazine as substrate correspond to a common intermediate (here denoted I) in which FeMo-co binds a substrate-derived [N(x)H(y)] moiety, and measurements reported here show that turnover with methyldiazene generates the same intermediate. In the present report we describe X/Q-band EPR and (14/15)N, (1,2)H ENDOR/HYSCORE/ESEEM measurements that characterize the N-atom(s) and proton(s) associated with this moiety. The experiments establish that turnover with N(2)H(2), CH(3)N(2)H, and N(2)H(4) in fact generates a common intermediate, I, and show that the N-N bond of substrate has been cleaved in I. Analysis of this finding leads us to conclude that nitrogenase reduces N(2)H(2), CH(3)N(2)H, and N(2)H(4) via a common A reaction pathway, and that the same is true for N(2) itself, with Fe ion(s) providing the site of reaction.     

Theoretical study on intramolecular allene-diene cycloadditions catalyzed by PtCl2 and Au(I) complexes

The intramolecular [4C+3C] cycloaddition reaction of allenedienes catalysed by PtCl(2) and several Au(I) complexes has been studied by means of DFT calculations. Overall, the reaction mechanism comprises three main steps: (i) the formation of a metal allyl cation intermediate, (ii) a [4C(4π)+3C(2π)] cycloaddition that produces a seven-membered ring and (iii) a 1,2-hydrogen migration process on these intermediates. The reaction proceeds with complete diastereochemical control resulting from a favoured exo-like cycloaddition. Allene substituents have a critical influence in the reaction outcome and mechanism. The experimental observation of [4C+2C] cycloadducts in the reaction of substrates lacking substituents at the allene terminus can be explained through a mechanism involving Pt(IV)-metallacycles. With gold catalysts it is also possible to obtain [4C+2C] cycloaddition products, but only with substrates featuring terminally disubstituted allenes, and employing π-acceptor ligands at gold. However the mechanism for the formation of these adducts is completely different to that proposed with PtCl(2), and consists of the formation of a metal allyl cation, subsequent [4C+3C] cycloaddition and a 1,2-alkyl shift (ring contraction). Electronic analysis indicates that the divergent pathways are mainly controlled by the electronic properties of the gold heptacyclic species (L-Au-C(2)), in particular, the backdonation capacity of the metal center to the unoccupied C(2) (pπ-orbital) of the intermediate resulting from the [4C+3C] cycloaddition. The less backdonation, (i.e. using P(OR)(3)Au(+) complexes), the more favoured is the 1,2-alkyl shift.     

Enantioselective total synthesis of (+)-lysergic acid, (+)-lysergol, and (+)-isolysergol by palladium-catalyzed domino cyclization of allenes bearing amino and bromoindolyl groups

Enantioselective total synthesis of the biologically important indole alkaloids (+)-lysergol, (+)-isolysergol, and (+)-lysergic acid is described. Key features of these total synthesis include (1) a facile synthesis of a chiral 1,3-amino alcohol via the Pd(0)- and In(I)-mediated reductive coupling reaction between L-serine-derived 2-ethynylaziridine and formaldehyde; (2) the Cr(II)/Ni(0)-mediated Nozaki-Hiyama-Kishi (NHK) reaction of an indole-3-acetaldehyde with iodoalkyne; and (3) Pd(0)-catalyzed domino cyclization of an allene bearing amino and bromoindolyl groups. This domino cyclization enabled direct construction of the C/D ring system of the ergot alkaloids skeleton, as well as the creation of the C5 stereogenic center with transfer of the allenic axial chirality to the central chirality.     

Palladium-catalyzed tetrakis(dimethylamino)ethylene-promoted reductive coupling of aryl halides

Tetrakis(dimethylamino)ethylene (TDAE)/cat. PdCl(2)(PhCN)(2)-promoted reductive coupling of aryl bromides having either electron-donating or electron-withdrawing groups on their para- and/or meta-position proceeded smoothly to afford the corresponding biaryls in good to excellent yields. Notably, TDAE is such a mild reductant that easily reducible groups, such as carbonyl and nitro groups, are tolerate. A similar reductive coupling of ortho-substituted aryl bromides did not occur at all. The proper choice of palladium catalysts is essential for the reductive coupling; thus, PdCl(2)(PhCN)(2), PdCl(2)(MeCN)(2), Pd(hfacac)(2), Pd(2)(dba)(3), PdCl(2), and Pd(OAc)(2) were used successively for this reaction, but phosphine-ligated palladium catalysts such as Pd(PPh(3))(4), PdCl(2)(PPh(3))(2), and Pd(dppp) did not promote the reaction. The reductive coupling did not occur with nickel catalysts such as NiBr(2), NiCl(2)(bpy), and Ni(acac)(2). The TDAE/cat. palladium-promoted reductive coupling of aryl halides having electron-withdrawing groups took place more efficiently than that of aryl halides substituted with electron-donating groups. A plausible mechanism of TDAE/cat. palladium-promoted reaction is discussed.     

Substituted 3-and 5-formylpyridin-2-ones in the synthesis of 1-aryl-1, 6-naphthyridinone derivatives

New 1-aryl-6-[2-(dimethylamino)vinyl]4-oxo-1,4-dihydropyrimidine-5-carbonitriles and 4-arylamino-2-oxo-1,2-dihydropyridine-3-carbonitriles containing electron-withdrawing substituents in the benzene ring were synthesized from enamino amides and dimethylformamide dialkylacetals. The influence of various dimethylformamide acetals on the yield of 3-(4-chloro-anilino)-2-cyano-5-(dimethylamino)penta-2,4-dienoic acid N-(dimethylamino)methyl-ideneamide was investigated in the reaction of these acetals with 3-(4-chloroanilino)-2-cyanocrotonamide. New 4-arylamino-5-formyl-2-oxo-1,2-dihydropyridine-3-carbonitriles and 4-arylamino-2-oxo-1,2-dihydropyridine-3-carbaldehydes containing electron-withdrawing substituents in the benzene ring were synthesized. The latter compounds were converted into new substituted l,6-naphthyridinones by the action of various CH acids. A new approach to the synthesis of 4-(4-fluoroanilino)-5-formyl-2-oxo-1,2-dihydropyridine-3-carbonitrile using dimethylformamide diisopropylacetal under mild conditions was developed. The comparative reactivity of the formyl group in the reactions of 4-arylamino-5-formyl-2-oxo-1,2-dihydropyridine-3-carbonitriles and in 4-arylamino-2-oxo-1,2-dihydropyridine-3-carb-aldehydes with malononitrile was determined using HPLC.     

Convergent, enantioselective syntheses of guanacastepenes A and E featuring a selective cyclobutane fragmentation

The evolution of a convergent strategy that led to efficient, enantioselective syntheses of both natural (+)- and unnatural (-)-guanacastepene E and formal total syntheses of (+)- and (-)-guanacastepene A is described. A union of five- and six-membered ring intermediates by an efficient pi-allyl Stille cross-coupling reaction was followed by an intramolecular enone-olefin [2 + 2] photocycloaddition and a stereoelectronically controlled, reductive fragmentation of the resulting cyclobutyl ketone. The latter two transformations enabled controlled formation of the C-11 quaternary stereocenter and the central seven-membered ring of the guanacastepenes. An enantiospecific synthesis of the functionalized five-membered ring vinyl stannane from the monoterpene R-(-)-carvone featuring a carbon-carbon bond forming ring contraction was also developed.     

Cyclopentene Synthesis from 1,3-Dienes via Base-Induced Ring Contraction of 3,6-Dihydro-2H-thiopyrans: Studies on Diastereoselection and Mechanism

An investigation of the scope and mechanism of a new synthesis of cyclopentenes from 3,6-dihydro-2H-thiopyrans is described. Alkyl halides substituted with an electron-withdrawing group in the alpha-position were reacted with sodium thiosulfate, yielding the corresponding Bunte salts, which could be transformed to reactive thiocarbonyl compounds by elimination of the elements of bisulfite with mild base treatment. In situ trapping by 1,3-dienes afforded in good yields a variety of 3,6-dihydro-2H-thiopyrans substituted with electron-withdrawing groups at the 2-position. Exposure of these cycloadducts to strong base at low temperature effected a novel ring contraction, affording 2-(methylthio)-3-cyclopentenes after quenching with methyl iodide. The level of diastereoselectivity exhibited during the generation of these cyclopentenes was found to be dependent on the nature of the electron-withdrawing group at the 2-position of the dihydrothiopyran as well as the substitution pattern originally present in the diene component. In some cases, reducing the temperature during the ring contraction resulted in the isolation of good yields of vinyl cyclopropanes of high isomeric purity. With one substrate, highly diastereoselective rearrangement of a vinyl cyclopropane to a cyclopentene was unambiguously demonstrated, suggesting that this might be a key feature of the overall ring contraction mechanism.     

Theoretical studies on the mechanism of α-hydroxy-acid gas-phase elimination process and its substituent effect

The α-hydroxy-acid gas-phase elimination process has been studied theoretically by HF/3-21G.The calculated results can be summed up as follows:(1) The elimination process is a stepwise reaction.In the first step,a 3-membered ring intermediate is formed via a 5-membered ring transition state;while the product is formed in the second step via a 3-membered ring transition state.(2) The obtained results of the substituent effect show that the increase of electronic donation of the alkyl groups is favorable for the reaction.Other substituents which show the electron-withdrawing inductive effect (e.g.-Cl,-CN,-CF3) are unfavorable for this process.     

Synthesis of amino-1,2,4-triazoles by reductive ANRORC rearrangements of 1,2,4-oxadiazoles

The reaction of various 1,2,4-oxadiazoles with an excess of hydrazine in DMF has been investigated. 3-Amino-1,2,4-triazoles are produced through a reductive ANRORC pathway consisting of the addition of hydrazine to the 1,2,4-oxadiazole followed by ring-opening, ring-closure, and final reduction of the 3-hydroxylamino-1,2,4-triazole intermediate. The general applicability of 1,2,4-oxadiazoles ANRORC reactivity is demonstrated also in the absence of C(5)-linked electron-withdrawing groups.     

Divergent and solvent dependent reactions of 4-ethoxycarbonyl-3-methyl-1-tert-butoxycarbonyl-1,2-diaza-1,3-diene with enamines

Starting from 1-tert-butyloxycarbonyl-3-methyl-4-ethoxycarbonyl-1,2-diaza-1,3-diene and β,β,β and α,β-substituted enamines a careful choice of solvents and temperatures allows the divergent synthesis of 5,6-dihydro-4H-pyridazines, 2-(1-N-boc-hydrazono-ethyl)-4-pyrrolidin-1-yl-but-3-enoic acid ethyl ester, and 1-amino-pyrroles. Moreover, some interesting conclusions about the mechanism(s) of the reaction have been drawn by careful analysis of products' structure and distribution. Thus, the reaction may proceed through a stereospecific [4+2] cycloaddition mechanism giving rise to 5,6-dihydro-4H-pyridazines or by simple addition or domino addition/cyclization pathways affording, respectively, 2-(1-N-boc-hydrazono-ethyl)-4-pyrrolidin-1-yl-but-3-enoic acid ethyl ester and 1-amino-pyrroles (formally the [3+2] cycloaddition product).     

Fluorination with xenon difluoride. Reaction with halogenated hydrocarbons

Filler and coworkers [1-5] have demonstrated the utility of xenon difluoride as a selective fluorinating agent for aromatic hydrocarbons in the liquid phase, while Mackenzie and coworker [6] have fluorinated aromatic compounds in the vapour phase. We have developed a fluorination reaction of phenyl substituted olefins resulting in high yields of vicinal difluorides [7,8] and trifluoroacetates, depending on the catalyst. In our continued interest in the use of xenon difluoride as a mild fluorinating agent for fluorination of organic compounds, we have tries to fluorinate some heterocyclic ring systems, e.g. imidazo-(1,2-b)-pyridazine, under conditions similar of those used for fluorination of phenyl substituted olefins [7,8,9] (room temperature, methylene chloride as solvent, hydrogen fluoride as catalyst). It is well known that heteroaromatic compounds are less reactive toward electrophilic substitution reactions then aromatic hydrocarbon systems. However, it has been shown that bromination of imidazo-(1,2-b) -pyridazine results in 3-bromo products [10], while in chlorination with phosphorus pentachloride [11], the entering order of chlorine atoms is at position 3 > 2, 7 > 8 > 6 (Radical reactions).     

Palladium- and Ruthenium-Catalyzed Intramolecular Carbene CAr−H Functionalization of γ-Amino-α-diazoesters for the Synthesis of Tetrahydroquinolines

A synthetic method to prepare tetrahydroquinoline-4-carboxylic acid esters has been developed through the transition-metal-catalyzed intramolecular aromatic C−H functionalization of α-diazoesters. Both [{Pd(IMes)(NQ)}₂] (IMes=1,3-dimesitylimidazol-2-ylidene, NQ=1,4-naphthoquinone) and the first-generation Grubbs catalyst proved effective for this purpose. The ruthenium catalyst was found to be the most versatile, although in a few cases the palladium complex afforded better yields or selectivities. According to DFT calculations, Pd⁰- and Ru^II-catalyzed sp²-C_Ar−H functionalization proceeds through different reaction mechanisms. Thus, the Pd⁰-catalyzed reaction involves a Pd-mediated 1,6-H migration from the sp²-C_Ar−H bond to the carbene carbon atom, followed by a reductive elimination process. In contrast, electrophilic addition of the ruthenacarbene intermediate to the aromatic ring and subsequent 1,2-proton migration are operative in the Grubbs catalyst promoted reaction.     

TiCl3‐Mediated Synthesis of 2,3,3‐Trisubstituted Indolenines: Total Synthesis of (+)‐1,2‐Dehydroaspidospermidine, (+)‐Condyfoline,and (−)‐Tubifoline

2,3,3‐Trisubstituted indolenine constitutes an integral part of many biologically important monoterpene indole alkaloids. We report herein an unprecedented access to this skeleton by a TiCl₃‐mediated reductive cyclization of tetrasubstituted alkenes bearing a 2‐nitrophenyl substituent. The proof of concept is demonstrated firstly by accomplishing a concise total synthesis of (+)‐1,2‐dehydroaspidospermidine featuring a late‐stage application of this key transformation. A sequence of reduction of nitroarene to nitrosoarene followed by 6π‐electron‐5‐atom electrocyclization and a 1,2‐alkyl shift of the resulting nitrone intermediate was proposed to account for the reaction outcome. A subsequent total synthesis of (+)‐condyfoline not only illustrates the generality of the reaction, but also provides a mechanistic insight into the nature of the 1,2‐alkyl shift. The exclusive formation of (+)‐condyfoline indicates that the 1,2‐alkyl migration follows a concerted Wagner–Meerwein pathway, rather than a stepwise retro‐Mannich/Mannich reaction sequence. Conditions for almost quantitative conversion of (+)‐condyfoline to (?)‐tubifoline by way of a retro‐Mannich/1,3‐prototropy/transannular cyclization cascade are also documented.     

N,N'-二(2-羟苄基)取代咪唑烷的合成、表征及抑菌活性

利用生物活性叠加原理,将"邻羟苯基"和"咪唑烷"分子片断有机结合,以水杨醛和乙二胺为起始原料,经缩合、NaBH4还原制得N,N'-二邻羟苄基乙二胺(2),进而与芳醛类化合物缩合关环,合成了8种N,N'-二(2-羟苄基)取代咪唑烷类化合物(3a～3h). 化合物的结构经1H NMR、IR、MS和元素分析等测试技术进行了表征. 结果表明,水杨醛与乙二胺的缩合反应,可专一性地生成对称双缩席夫碱化合物(1);芳醛上的取代基对缩合关环反应有显著影响,邻、对位吸电基可使芳醛的羰基活化,有利于缩合关环反应的进行,邻、对位供电基可使芳醛的羰基钝化,不利于缩合关环反应进行. 抑菌测试结果表明,质量分数为0.1%时,N,N'-二(2-羟苄基)取代咪唑烷化合物对不同菌株的抑菌活性具有明显的特异性,对白色念珠菌、大肠杆菌的抑菌率达100%.