Control of extremely fast competitive consecutive reactions using micromixing. Selective Friedel-Crafts aminoalkylation

Friedel-Crafts reactions of aromatic and heteroaromatic compounds with an N-acyliminium ion pool were studied. The reaction of 1,3,5-trimethylbenzene in a batch reactor gave rise to the selective formation of a monoalkylation product (69%). Presumably, the second alkylation is slower than the first alkylation because of the protonation of the monoalkylation product that decreases its reactivity. The reaction of 1,3,5-trimethoxybenzene, however, gave rise to the formation of both monoalkylation (37%) and dialkylation (32%) products. Disguised chemical selectivity due to faster reaction than mixing seems to be responsible for the lack of selectivity. The use of micromixing was found to be quite effective to solve this problem to increase the selectivity. The monoalkylation product was obtained in 92% yield together with a small amount of the dialkylation product (4%). The reaction with various aromatic and heteroaromatic compounds revealed that the low mono/dialkylation selectivity was observed only for highly reactive aromatics. In such cases, the use of micromixing was quite effective to improve the selectivity. On the basis of micromixing, the selective sequential dialkylation using two different N-acyliminium ions was achieved. CFD simulations using a laminar flow and finite-rate model are consistent with the experimental observations and clearly indicate the importance of mixing.     

Action des homocuprates sur les cetones α,α′-dibromees. Une nouvelle methode de synthese de cetones encombrees

The reaction between alkyllithium homocuprates and α,α′-dibromoketones permits the monoalkylation of ketones after hydrolysis of the reaction intermediate; the latter reacts with an excess of alkyl halide and gives the dialkylated product. Four alkylation reactions (methylation, ethylation, isopropylation and t-butylation) of α,α′-dibromoketones have been studied. While monoalkylation leads to secondary/primary and tertiary/secondary ketones from bis-primary and bis-secondary structures, dialkylation permits the synthesis of bis-secondary and bis-tertiary ketones. The introduction of two tertiary groups in the same structure is nevertheless impossible.     

N- and O-Alkylation of 3-indolylcyclopropylacetic acid derivatives

2,2-Dimethyl-3-(2-methyl-3-indolyl)cyclopropylacetic acid, its amide and esters, and the corresponding alcohol, viz., the product of ester reduction by LiAlH₄, were synthesized. The chemoselectivity of N- and O-alkylation of these compounds was studied. Selective monoalkylation at the nitrogen atom of the heterocycle, O-alkylation to the side chain, or dialkylation at both nucleophilic sites can be carried out under conditions of phase-transfer catalysis. The N-acylation at the indole fragment of nitrile of this acid occurs only under the Vilsmeier—Haak formylation conditions.     

低聚苯醚链系列化合物的醚化

在相转移催化剂PEG-600存在下,利用2-((2-甲氧基)乙氧基)氯乙烷和低聚苯醚链反应,合成双醚化的产物;与此相对应,利用2-(氯乙氧基)乙醇和低聚苯醚链反应,只生成单醚化的产物。所有的产物都经过1H-NMR,MS及元素分析表征。     

Polymerization of aromatic nuclei. XXVI. Poly(p-phenylene): Friedel–crafts alkylation,molecular weight,and propagation mechanism

Poly(p-phenylene) was alkylated with n-propyl bromide, n-propyl chloride, and isopropyl bromide in the presence of aluminum chloride. Apparently, the reactions involve dialkylation with n-propyl halides and alternating mono- and dialkylation with isopropyl bromide. Alkylation with ethyl or n-butyl bromide was unsuccessful. The dialkylated polymer was sufficiently soluble to allow molecular weight determination. Mechanistic aspects of alkylation and propagation are treated.     

Selective Iridium‐Catalyzed Alkylation of (Hetero)Aromatic Amines and Diamines with Alcohols under Mild Reaction Conditions

Selective amine alkylation : A P,N‐ligand‐stabilized iridium complex has been used as an efficient catalyst for the alkylation of (hetero)aromatic amines with alcohols at mild reaction temperatures and catalyst loadings as low as 0.1 mol % Ir (see scheme). The excellent selectivity of the catalyst for monoalkylation of the amine function has also been exploited for the N,N′‐dialkylation of diamines in both symmetric and nonsymmetric fashions.

     

Alkylation-Terminated Catellani Reactions Using Alkyl Carbagermatranes

The Catellani reaction has received substantial attention because it enables rapid multiple derivatization on aromatics. While using alkyl electrophiles to achieve ortho-alkylation was one of the earliest applications of the Catellani reaction, ipso-alkylation-terminated reactions with β-H-containing reactants has not been realized to date. Herein, we report alkylation-terminated Catellani reaction using alkyl carbagermatranes (abbreviated as alkyl- Ge ) as nucleophiles. The reactivity of alkyl- Ge and alkyl-B(OH)₂ in this reaction is discussed. This approach enables efficient dialkylation with β-H-containing reactants, which was previously inaccessible by Catellani reactions.     

3-Indolizin-2-ylquinoxalines and the derived monopodands

The reactions of 3-acetylquinoxalin-2-one with methyl-and benzylpyridines in the presence of iodine produce the corresponding 3-(2-alkylpyridinioacetyl)quinoxalin-2(1H)-one iodides. Treatment of the latter with triethylamine affords the corresponding 3-indolizin-2-ylquinoxalin-2-ones. Due to the presence of the endocyclic carbamoyl group, the reactions of these compounds with bisalkylating reagents give quinoxaline-containing monopodands and monoalkylation products containing spacers with different lengths and of different nature. Dedicated to Professor Ya. A. Levin on the occasion of his 70th birthday. Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2534–2542, November, 2005.     

Electrocyclic ring-opening reactions may cause failure of enolate alkylation of 1,4-oxazin-2-one based chiral glycine equivalents

Attempted monoalkylation of 6-methyl-5,6-diphenyl-1,4-oxazin-2-one that had been designed as a chiral glycine equivalent gave even under optimized conditions only minute amounts of the desired monoalkylation product whereas an acyclic ketone was obtained repeatedly as the major product. This result indicates that the enolate of the chiral glycine equivalent is prone to an electrocyclic ring-opening reaction. This hypothesis could be further supported by additional experiments. Based on these results, it is reasonable to assume that electrocyclic ring-opening reactions are also the cause for the failure of alkylation reactions of structurally related glycine equivalents reported in the literature.     

Synthetic Applications of π-Electron-Deficient Sulfones

Abstract

The use of π-electron-deficient aryl sulfones, especially 3,5-bis(trifluoromethyl) phenyl alkyl sulfones (BTFP-sulfones) as soft nucleophiles, as caboxylic acid protecting group and in Julia–Kocienski olefination reactions is described. In the case of α-(arylsulfonyl)acetates dialkylation, reactions are performed under phase-transfer analysis (PTC) conditions using K ₂ CO ₃ as base. Esters derived from 2-(arylsulfonyl)ethanol can be deprotected using aqueous NaHCO ₃ . Alkyl BTFP sulfones are coupled with carbonyl compounds using KOH or P4-t-Bu as bases to give the corresponding alkenes after Smiles rearrangement.     

ROOM-TEMPERATURE REDUCTIVE DIALKYLATION OF DIETHYL NAPHTHALENEDICARBOXYLATE

ABSTRACT

The reductive dialkylation of diethyl 1,4-naphthalenedicarboxylate is achieved in high yield and moderate diastereoselectivity. In liquid ammonia at ?78°C, a 5.6 : 1 ratio of trans- to cis-1,4-dimethyl-1,4-naphthalenedicarboxylates is obtained. The reductive dialkylation can also be carried out under more convenient conditions in THF at room temperature with no loss in yield, but a two-fold loss in diastereoselectivity. The alternate method is also used to synthesize 1,4-dialkylated products from ethyl bromide and allyl bromide.     

Efficient synthesis of serically constrained smmetrically alpha,alpha-disubstituted alpha-amino acids under operationally convenient conditions

Homologation of the nucleophilic glycine equivalent Ni-Gly-PABP [Ni(II) complex of glycine Schiff base with 2-[N-(alpha-picolyl)amino]benzophenone (PABP)] 2 via alkyl halide alkylations and Michael addition reactions was systematically studied as a general method for preparing symmetrically alpha,alpha-disubstituted alpha-amino acids (sym-alpha,alpha-AA). The dialkylation reactions are conducted under operationally convenient conditions without recourse to inert atmosphere, dried solvents, and low temperatures, thus enjoying key advantages of the experimental simplicity and attractive cost structure. The method has been shown to be particularly successful for the dialkylation of complex 2 with activated and nonactivated alkyl halides, including propargyl derivatives, affording a generalized and practical access to the corresponding sym-alpha,alpha-AA. This study has also shown some limitation of the method, as it cannot be extended to alpha- or beta-branched alkyl halides or Michael acceptors to be used for the dialkylation of glycine equivalent 2. High chemical yields of the dialkylated products, combined with the simplicity of the experimental procedure, render this method worth immediate use for multigram scale preparation of the sym-alpha,alpha-AA.     

Imidazolium salts as phase transfer catalysts for the dialkylation and cycloalkylation of active methylene compounds

The dialkylation and cycloalkylation reactions of active methylene compounds in the presence of readily available imidazolium salts (ionic liquids) as phase transfer catalysts were performed to afford the respective dialkylated or cycloalkylated products. This method is very efficient for the synthesis of 1,1-disubstituted derivatives and cyclopropane and cyclopentane ring systems in a facile manner.     

UNIVERSAL APPROACH TO THE SYNTHESIS OF JUVENOID HYDROPRENE AND METHOPRENE FROM 4-METHYLTETRAHYDROPYRAN

A universal approach to the synthesis of juvenoid hydroprene and methoprene was developed on the basis of monoalkylation of acetoacetate by 1-acetoxy-5-bromo-3-methylpentane, the product of acidic decyclization of 4-methyltetrahydropyran.     

N-polyazolylmethanes. 1. Synthesis and nmr study of N,N′-diazolylmethanes

Thirteen N,N-diazolylmethanes, including derivatives of pyrazole, imidazole, 1,2,4-triazole, benzimidazole and indazole were prepared by reaction of azoles with methylene chloride under phase transfer catalysis conditions. The relative amounts of isomeric mixtures obtained with ‘asymmetric’ azoles or with equimolar mixtures of azoles are compared with literature results on monoalkylation of azoles. Proton and carbon-13 nmr spectra of the N,N'-diazolylmethanes are discussed.     

Experimental and theoretical study of the reaction between bicyclo[2.2.1]hept-5-en-endo-2-ylmethylamine and 2-[(2-allylphenoxy)methyl]oxirane

In reactions of bicyclo[2.2.1]hept-5-en-endo-2-ylmethylamine with 2-[(2-allylphenoxy)methyl]oxirane alongside the product of amine monoalkylation a compound was obtained and isolated by chromatography on silica gel resulting from the reaction of the monoalkylated substance with the initial epoxide. The structure of new aminoalcohols and the regiochemistry of the oxirane opening were examined using IR, 1H NMR, and mass spectra. The features of the reaction mechanism were considered applying quantum-chemical calculations in the level of theory PCM/B3LYP/6-3aG(d).     

Synthesis and Reactivity of π‐Electron‐Deficient (Arylsulfonyl)acetates

Different π‐electron‐deficient (arylsulfonyl)acetates 9 were synthesized (Scheme 1, Table 1), and their behavior as soft nucleophiles in the dialkylation reaction under phase‐transfer catalysis conditions was studied (Schemes 2 and 3, Tables 2 and 3). The [3,5‐bis(trifluoromethyl)phenyl]sulfonyl group was shown to be the best substituent for the stereoselective synthesis of (E)‐aconitates 18 via an alkylation hydro‐sulfonyl‐elimination integrated process under very mild phase‐transfer‐catalysis conditions (Scheme 5, Table 4). Sulfonylacetates 9h , i also underwent smooth Diels‐Alder reactions with acyclic and cyclic dienes via in situ formation of the appropriate dienophile through a Knoevenagel condensation with paraformaldehyde (Scheme 6). Reductive desulfonylation with Zn and NH₄Cl in THF was shown to be an efficient method for removal of the synthetically useful sulfonyl moiety (Scheme 7).     

Synthesis of the Honey-Bee Attractant 13-Hydroxy-2-oxotridecane

13-Hydroxy-2-oxotridecane, which is isolated from extract ofEvodia hupehensisDode honey-bee eggs and actively attracts honey bees, is synthesized via ozonolysis of 1-methylcyclododecene and tetradec-13-en-2-one, the product from monoalkylation of the acetoacetic ester with 1-bromo-10-undecene followed bydecarbethoxylation, with further reduction of the intermediate peroxides using NaBH(OAc) ₃     

Insights into the Activation Mode of α-Carbonyl Sulfoxonium Ylides in Rhodium-Catalyzed C−H Activation: A Theoretical Study

A computational study has been performed to investigate the mechanism of Rh^III-catalyzed C−H bond activation using sulfoxonium ylides as a carbene precursor. The stepwise and concerted activation modes for sulfoxonium ylides were investigated. Detailed theoretical results showed that the favored stepwise pathway involves C−H bond activation, carbonization, carbene insertion, and protonation. The free energy profiles for dialkylation of 2-phenylpyridine were also calculated to account for the low yield of this reaction. Furthermore, the substituent effect was elucidated by comparing the energy barriers for the protonation of meta- and para-substituted sulfoxonium ylides calculated by density functional theory.     

Studies on steroidal plant growth regulator——27.Stereoselective construction of the side chain of brassinosteroid by employing a separated dialkylation and a tandem dialkylation of the pyranone moiety

A stereocontrolled construction of the side chain of brassinosteroid was developedvia the separated dialkylation and the tandem dialkylation of the pyranone moiety as the keystep.