A Case of Abnormal Bishler-Napieralski Cyclization Reaction,Leading to Form Benzyl Oxazole Derivatives

1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid is a type of naturally occurring bio-active alkaloid1. Moreover, it can be used as building block for the synthesis of other natural products containing the 1,2,3,4-tetrahydroisoquinoline moiety2. Compound 2 was an intermediate in our attempt to the total synthesis of Ecteinascidin analogs. We employed the Bishler-Napieralski reaction to prepare this product and refluxed the N-acetyl phenylalanine compound 1 in POCl3/benzene. However, we fail…     

Lewis acid catalyzed cascade reactions of diarylvinylidenecyclopropanes and 1,1,3-triarylprop-2-yn-1-ols or their methyl ethers

The reactions of vinylidenecyclopropanes 1 with 1,1,3-triarylprop-2-yn-1-ols or their methyl ethers 2 in the presence of a Lewis acid selectively produce 4-dihydro-1H-cyclopenta[b]naphthalene derivatives 3 or 1,2,3,8-tetrahydrocyclopenta[a]indene derivatives 4 depending on the substituents on the cyclopropane. Good to high yields are obtained under mild conditions. A plausible cascade Meyer-Schuster rearrangement and Friedel-Crafts reaction mechanism has been proposed. Moreover, novel functionalized methylenecyclobutene derivatives 5 could also be obtained in moderate to good yields under similar conditions when strongly electron-donating methoxy groups were introduced into the benzene rings of 2.     

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.     

Direct carbonylation at a C-H bond in the benzene ring of 2-phenyloxazolines catalyzed by Ru(3)(CO)(12). Scope, limitations, and mechanistic aspects

The ruthenium-catalyzed carbonylation at a C-H bond in the benzene ring of a 2-phenyloxazoline is described. The reaction of 2-phenyloxazolines with CO and ethylene in toluene in the presence of a catalytic amount of Ru(3)(CO)(12) resulted in propionylation at an ortho C-H bond in the benzene ring. The presence of the oxazoline ring on the benzene ring is essential for the carbonylation to proceed. Other heterocycles, such as oxazine, oxazole, and thiazoline rings, also served as acceptable directing groups as did the oxazoline ring. A wide functional group compatibility was observed. The site selectivity of the carbonylation was examined using meta-substituted phenyloxazolines. It was found that the carbonylation took place exclusively at the less-hindered C-H bond, irrespective of the nature of substituents, indicating that the site selectivity was determined by steric factors. The reaction was also applicable, not only to a benzene ring, but also to naphthyl and thiophenyl rings. Olefins such as propene and trimethylvinylsilane in place of ethylene could also be used in the carbonylation reaction, while other olefins, such as 1-hexene, tert-butylethylene, vinylcyclohexane, isoprene, 1,5-hexadiene, cyclohexene, 1, 5-cyclooctadiene, styrene, methyl acrylate, vinyl acetate, allyltrimethylsilane, and triethoxyvinylsilane did not afford the coupling products. An equilibrium between 2-phenyloxazolines, carbon monoxide, and olefins exists on one hand and the corresponding ketones on the other hand, and product composition is governed by the equilibrium thermodynamics of the system. The results of deuterium labeling experiments suggest that the catalysis involves a reversible C-H bond cleavage and that the rate-determining step is not the cleavage of a C-H bond. The results of kinetic study of the effects of CO pressure show that the reaction rate accelerates with decreasing CO pressure.     

Addition–elimination versus Tishchenko reaction in the gas phase

Gas phase reactions of the substituted phenide ions with methyl formate have been studied. It was found that the results of these reactions depend mainly on the basicity of the phenide ion, which is related to the presence of the electron‐accepting or electron‐donating substituents in the benzene ring. It was shown that the phenide ions substituted with electron‐withdrawing groups react with methyl formate in the gas phase in a two‐step reaction. The first step that proceeds according to the typical addition–elimination mechanism results in the formation of the anion of the respective benzaldehyde derivative with the negative charge located either in the aldehyde group (acyl anion) or in the benzene ring (phenide anion) in position ortho to an aldehyde moiety. In the second step, the preliminary‐formed anion reacts with the second molecule of methyl formate yielding formally product of the second addition–elimination reaction. Theoretical calculations as well as collision induced dissociation spectra of the model compounds suggest that this reaction proceeds according to the Tishchenko reaction mechanism yielding the respective phthalide anion. According to our knowledge, this is the first example of the Tishchenko‐type reaction in the gas phase. Copyright © 2014 John Wiley & Sons, Ltd.     

Brønsted acid TfOH-mediated [3 + 2] cycloaddition reactions of diarylvinylidenecyclopropanes with nitriles

Diarylvinylidenecyclopropanes undergo a [3 + 2] cycloaddition reaction with MeCN in the presence of Br?nsted acid TfOH to give the corresponding 3,4-dihydro-2 H-pyrrole derivatives 2 in moderate to excellent yields under reflux within a short time. As for the diarylvinylidenecyclopropane substrate containing a strongly electron-donating methoxy group on the benzene ring, the reaction leads to the formation of a different type of 3,4-dihydro-2 H-pyrrole derivatives 4 under the same conditions.     

Reactions of chlorobenzene and bromobenzene with methyl acrylate using a conventional supported palladium catalyst

Reactions of bromobenzene and chlorobenzene with methyl acrylate were carried out in N-methylpyrrolidone (NMP) over a conventional Pd/C catalyst under Heck coupling conditions indicating both heterogeneous and homogeneous character. Benzene and biphenyl are produced in addition to the Heck coupling product of methyl cinnamate. It is proposed that the formation of methyl cinnamate and biphenyl proceed homogeneously with dissolved palladium species, while the formation of benzene takes place heterogeneously on the surface of supported palladium particles or free colloidal particles formed during the reaction. This revised version was published online in August 2006 with corrections to the Cover Date.     

Approaches to the Synthesis of Dicarboxylic Derivatives of Bis(pyrazol-1-yl)alkanes

Carboxylation of bis(pyrazol-1-yl)alkanes by oxalyl chloride was studied. It was found that 4,4′-dicarboxylic derivatives of substrates with electron-donating methyl groups and short linkers (from one to three methylene groups) can be prepared using this method. Longer linkers lead to significantly lower product yields, which is probably due to instability of the intermediate acid chlorides that are initially formed in the reaction with oxalyl chloride. Thus, bis(pyrazol-1-yl)methane gave only monocarboxylic derivative even with a large excess of oxalyl chloride and prolonged reaction duration. An alternative approach involves the reaction of ethyl 4-pyrazolecarboxylates with dibromoalkanes in a superbasic medium (potassium hydroxide–dimethyl sulfoxide) and is suitable for the preparation of bis(4-carboxypyrazol-1-yl)alkanes with both short and long linkers independent of substitution in positions 3 and 5 of pyrazole rings. The obtained dicarboxylic acids are interesting as potential building blocks for metal-organic frameworks.     

The photoconversion R-CH3 → R-CHO in indazole derivatives

The UV irradiation of 1-(p-nitrophenyl)-3-methyl-indazole leads to the formation of the corresponding 3-formyl derivative as product of the photooxidation R-CH₃ → R-CHO. This method was applied to a series of substituted indazoles and the same reaction was observed with methyl groups attached to the pyrazole and to the benzene ring of the indazole.     

Total synthesis of phorboxazole A via de novo oxazole formation: convergent total synthesis

The phorboxazoles are mixed non-ribosomal peptide synthase/polyketide synthase biosynthetic products that embody polyketide domains joined via two serine-derived oxazole moieties. Total syntheses of phorboxazole A and analogues have been developed that rely upon the convergent coupling of three fragments via biomimetically inspired de novo oxazole formation. First, the macrolide-containing domain of phorboxazole A was assembled from C3-C17 and C18-C30 building blocks via formation of the C16-C18 oxazole, followed by macrolide ring closure involving an intramolecular Still-Genarri olefination at C2-C3. Alternatively, a ring-closing metathesis process was optimized to deliver the natural product's (2Z)-acrylate with remarkable geometrical selectivity. The C31-C46 side-chain domain was then appended to the macrolide by a second serine amide-derived oxazole assembly. Minimal deprotection then afforded phorboxazole A. This generally effective strategy was then dramatically abbreviated by employing a total synthesis approach wherein both of the natural product's oxazole moieties were installed simultaneously. A key bis-amide precursor to the bis-oxazole was formed in a chemoselective one-pot, bis-amidation sequence without the use of amino or carboxyl protecting groups. Thereafter, both oxazoles were formed from the key C18 and C31 bis-N-(1-hydroxyalkan-2-yl)amide in a simultaneous fashion, involving oxidation-cyclodehydrations. This synthetic strategy provides a total synthesis of phorboxazole A in 18% yield over nine steps from C3-C17 and C18-C30 synthetic fragments. It illustrates the utility of a synthetic design to form a mixed non-ribosomal peptide synthase/polyketide synthase biosynthetic product based upon biomimetic oxazole formation initiated by amide bond formation to join synthetic building blocks.     

A computational study on the substituent effects and product stereoselectivity of the intermolecular formal aza-[3+3] cycloaddition reaction between vinylogous amides and α,β-unsaturated imine cations

The substituent effects and product stereoselectivity of the title reaction has been studied using density functional theory (DFT) calculations at the B3LYP/6-31G(d,p) level of theory. It was found that the substituents do not perturb the mechanism of intermolecular formal aza-[3+3] cycloaddition. Our calculations also show that methyl or benzyl groups on the N atom of vinylogous amide favor the addition step, but alkyl substituents on the either N atom or terminal C atom of α,β-unsaturated imine cation have opposite effects. Alkyl substituents on the N atom of α,β-unsaturated imine cation may lower the activation barriers for elimination of amide. The steric interaction between two substituents leads to the formation of major product both thermodynamically and kinetically.     

Unexpected one-step synthesis of 3-benzoyl-2-phenylbenzofurans under Wittig conditions

The reaction of 2-hydroxybenzyltriphenylphosphonium bromide with substituted benzoyl chlorides under Wittig conditions, led to 2-phenylbenzofuran derivatives 4a–p and the unexpected formation of 3-benzoyl-2-phenylbenzofuran derivatives 5a–p. Benzoyl chlorides possessing electron-withdrawing groups afforded 3-benzoyl-2-phenylbenzofuran derivatives in higher yields than those with electron-donating groups. This reaction represents a simple and regioselective, one-pot route towards the preparation of deactivated 3-benzoyl-2-phenylbenzofuran compounds which are difficult to obtain by the direct acylation of 2-phenylbenzofurans.     

Zn粉作为催化剂前体催化对甲苯磺酰胺/二溴海因与烯烃的区域选择性和立体选择性氨溴加成反应

Zn粉作为催化剂前体, 在反应中可被原位氧化成高效Zn(Ⅱ)-催化剂. 在该催化剂催化下, 以对甲苯磺酰胺和1,3-二溴-5,5-二甲基乙内酰脲(二溴海因)为氮源/卤素源, 二氯甲烷作溶剂, 建立了烯键上的高度区域选择和立体选择性氨溴加成反应新体系. 该方法在室温下可高产率地制得邻位氨基溴的加成产物, 最高收率可达99%. 实验结果表明, 当与双键直接相连的苯环对位有强给电子基团(CH₃O)时, 反应收率高, 并可得到唯一的氨溴加成产物(α-溴-β-氨基); 当与双键直接相连的苯环对位有强拉电子基团(NO₂)或弱拉电子基团(如Br和F)时, 该反应的产率相对较低, 但也能制得另一个唯一的氨溴加成产物异构体(α-氨基-β-溴型). 本文考察了20种不同结构底物的氨溴加成反应情况, 产物结构经过¹H NMR、¹³C NMR和元素分析确证, 并探讨了该反应的机理.     

Theoretical study of main-group metal-borazine sandwich complexes

Using density functional theory within the generalized gradient approximation, we have theoretically studied the formation of neutral metal-aromatic complexes R1-M and R1-M-R2, where M is either neutral lithium, calcium, or gallium and R1 or R2 is benzene or borazine. We first find that calcium atom is an effective mediator for cooperative formation of a sandwich complex with borazine, while others are not. When benzene and borazine are mixed in the presence of calcium, a 1:2:1 mixture of benzene-calcium-benzene, borazine-calcium-benzene, and borazine-calcium-borazine is expected. An "A"-shaped structure is predicted for homo- and heterocomplexes of borazine with partial B-B and B-C bonds, while two rings are planar in the case of homocomplexes of benzene. Our analysis of the electron density distributions in HOMO-1 to LUMO in terms of orbital symmetry in conjunction with analysis of l,m-projected electronic local density of states shows that this correlates with the charge transfer and the interaction of pi states of the rings mediated by empty d-states of Ca, which is ultimately related to the polarity of the B-N bond. We find that there is a large accumulation of electron density on particular atoms upon complex formation, predicting characteristic behavior in electron-transfer reaction and nucleophilic reaction different from those for pure benzene or borazine molecule. The hetero-sandwich complex is of particular interest due to its asymmetrical distribution of excess electrons.     

Formation of Oxazoles from Elusive Gold(I) α‐Oxocarbenes: A Mechanistic Study

The gold(I) catalyzed reaction between phenylacetylene, pyridine N‐oxide and acetonitrile leading, via a putative gold‐α‐oxocarbene intermediate, towards an oxazole product has been investigated. A novel mass spectrometric method called “delayed reactant labeling” is used to track consecutive and parallel reactions. It clearly shows that the intramolecular formation of a pyridine adduct of gold‐α‐oxocarbene is in competition with the formation of the oxazole product. The reaction mechanism most probably corresponds to competition between acetonitrile and pyridine in an almost barrierless reaction with putative gold‐α‐oxocarbene within the solvent cage. The detected ionic species have been characterized by helium tagging infrared photodissociation spectroscopy.     

Mechanism of photocleavage of (coumarin-4-yl)methyl esters

(Coumarin-4-yl)methyl esters (CM-A) are caged compounds that, upon excitation, release the masked biologically active acid HA and the highly fluorescent (coumarin-4-yl)methyl alcohol CM-OH very rapidly and in part with high efficiency. The results of photostationary and time-resolved investigations of 25 CM-A esters and corresponding CM-OH alcohols with varying substitution on the (coumarin-4-yl)methyl moiety and a wide variation in the structure of the acidic part have been analyzed. The initial step of the photoreaction is heterolytic ester cleavage leading to the singlet ion pair 1[CM+ A-] with rate constant k1. 1[CM+ A-] hydrolyzes to CM-OH and HA with rate constant k2 or recombines to ground-state CM-A with rate constant krec. 1[CM+ A-] is the key intermediate of the reaction. Stabilization of both CM+ by using electron-donating substituents and A- by increasing the acid strength leads to a strong enhancement of k1 and simultaneously to a diminution of krec. Therefore, stabilization of the ion pair has a two-fold positive effect on the photocleavage of (coumarin-4-yl)methyl esters: increasing the rate of the initial reaction step, which might require less than 30 ps, and increasing the efficiency of product formation.     

Quinone imine dye formation via photocycloaddition between isocyanates and chloranil

Photochemical [2+2]cycloaddition between electron-donating aryl isocyanates and chloranil was observed in acetonitrile or benzene, and the following elimination of carbon dioxide resulted in the formation of the corresponding quinone imine dyes. This new route for synthesis of quinone imine was investigated by product analyses, laser flash photolyses, and molecular orbital calculation.     

Ruthenium-catalyzed transfer hydrogenation of imines by propan-2-ol in benzene

Transfer hydrogenation of a variety of different imines to the corresponding amines by propan-2-ol in benzene catalyzed by [Ru2(CO)4(mu-H)(C4Ph4COHOCC4Ph4)] (1) has been studied. The reaction is highly efficient with turnover frequencies of over 800 per hour, and the product amines were obtained in excellent yields. A remarkable concentration dependence of propan-2-ol was observed when the reaction was run in benzene as cosolvent. An optimum was obtained at 24 equivalents of propan-2-ol to imine, and further increase of the propan-2-ol led to a dramatic decrease in rate. Also the use of polar cosolvents with 24 equivalents of propan-2-ol gave a low rate. It was found that ketimines react faster than aldimines and that electron-donating substituents on the imine increase the rate of the catalytic transfer hydrogenation. Electron-withdrawing substituents decreased the rate. An isomerization was observed with imines having an alpha-hydrogen at the N-alkyl substituent, which is in accordance with a mechanism involving a ruthenium-amine intermediate. It was demonstrated that the ruthenium-amine complex from alpha-methylbenzylamine, corresponding to the postulated intermediate, can replace 1 as catalyst in the transfer hydrogenation of imines. A primary deuterium isotope effect of kCH/CD = 2.7 +/- 0.25 was observed when 2-deuterio-propan-2-ol was used in place of propan-2-ol in the transfer hydrogenation of N-phenyl-(1-phenylethylidene)amine.     

几种4-取代-L-脯氨酸衍生物的合成

以Boc-(4R)-羟基-(2S)-脯氨酸为原料,在NaH作用下与苄位溴代试剂发生醚化反应,合成了几种4-取代-L-脯氨酸类手性催化剂,即在(4R)-羟基-(2S)-脯氨酸的4-位上引入不同的苄氧基以期提高其催化活性和脂溶性,并通过1 H NMR、13 C NMR和HRMS对合成产物的结构进行表征,确定其为目标产物.实验结果还表明,当苯环上连有强的吸电子基团时反应很难进行,而当连有给电子基团时反应相对较容易进行且反应条件较温和.     

Combined computational and experimental studies of the mechanism and scope of the retro-Nazarov reaction

Density functional theory calculations (B3LYP/6-31+G) demonstrate that conjugating and electron-donating substituents at carbons three and four of a cyclopentenyl oxyallylic cation should have a rate-accelerating effect on the retro-Nazarov reactions of these species. The retro-Nazarov reaction of these intermediates is predicted to exhibit significant torquoselectivity when carbon three is substituted with a methoxy and a methyl group. Experimental studies show that oxyallylic cations can undergo effective retro-Nazarov reactions when two alkyl and one aryl/vinyl groups are on carbons three and four. An equal number of alkyl substituents or a single aryl substituent is not effective in promoting the reaction. Interestingly, a single alkoxy substituent at carbon three is sufficient for the retro-Nazarov reaction to occur. The methodology developed was used in a total synthesis of the natural product turmerone.