- Dichloromeldrum's acid (DiCMA): A practical and green amine dichloroacetylation reagent
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Dichloromeldrum's acid is introduced as a bench-stable, nonvolatile reagent for the dichloroacetylation of anilines and alkyl amines to produce α,α-dichloroacetamides, which are important motifs for medicinal chemistry. Products are formed in good to excellent yields with reagent grade solvents, and, as the only byproducts are acetone and CO2, no column chromatography is required. Thus, this reagent is practical, efficient, and green for the dichloroacetylation of primary amines.
- Heard, David M.,Lennox, Alastair J.J.
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supporting information
p. 3368 - 3372
(2021/05/06)
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- Photo-on-Demand Synthesis of Vilsmeier Reagents with Chloroform and Their Applications to One-Pot Organic Syntheses
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The Vilsmeier reagent (VR), first reported a century ago, is a versatile reagent in a variety of organic reactions. It is used extensively in formylation reactions. However, the synthesis of VR generally requires highly toxic and corrosive reagents such as POCl3, SOCl2, or COCl2. In this study, we found that VR is readily obtained from a CHCl3 solution containing N,N-dimethylformamide or N,N-dimethylacetamide upon photo-irradiation under O2 bubbling. The corresponding Vilsmeier reagents were obtained in high yields with the generation of gaseous HCl and CO2 as byproducts to allow their isolations as crystalline solid products amenable to analysis by X-ray crystallography. With the advantage of using CHCl3, which bifunctionally serves as a reactant and a solvent, this photo-on-demand VR synthesis is available for one-pot syntheses of aldehydes, acid chlorides, formates, ketones, esters, and amides.
- Liang, Fengying,Eda, Kazuo,Okazoe, Takashi,Wada, Akihiro,Mori, Nobuaki,Konishi, Katsuhiko,Tsuda, Akihiko
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p. 6504 - 6517
(2021/05/06)
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- Unexpected Formation of 2,2-Dichloro-N-(chloromethyl)acetamides during Attempted Staudinger 2,2-Dichloro-β-lactam Synthesis
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In the quest for 3,3-dichloro-β-lactam building blocks, the serendipitous formation of 2,2-dichloro-N-(chloromethyl)acetamides was observed. This peculiar reactivity was investigated in detail, both experimentally and computationally by means of Density Functional Theory (DFT) calculations. 2,2-Dichloro-N-(chloromethyl)acetamides were thus shown to be formed experimentally through reaction of 2,2-dichloroacetyl chloride with glyceraldehyde-derived imines, i. e. (2,2-dimethyl-1,3-dioxolan-4-yl)methanimines, bearing aromatic N-substituents, in the presence as well as in the absence of a base. Deployment of aliphatic imines, however, resulted in complex reaction mixtures, pointing to the importance of a stabilizing aromatic substituent at nitrogen. The DFT results indicate that the substituents can alter the governing equilibria on the one hand and intrinsic barrier heights for the different routes on the other hand, showing that these are controlling the reaction outcome. Furthermore, the 2,2-dichloro-N-(chloromethyl)acetamides proved to be rather unstable in solution and thus difficult to isolate. Nonetheless, their molecular structure was confirmed by means of NMR analysis of several purified analogs and X-ray study of a 4-methoxyphenyl derivative.
- Deketelaere, Sari,Van Den Broeck, Elias,Cools, Lore,Deturck, Daan,Naeyaert, Hannes,Van Hecke, Kristof,Stevens, Christian V.,Van Speybroeck, Veronique,D'hooghe, Matthias
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supporting information
p. 5823 - 5830
(2021/11/17)
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- Zwitterion-Catalyzed Deacylative Dihalogenation of β-Oxo Amides
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α,α-Dihalo-N-arylacetamides are commonly used as intermediates in various organic reactions. In the study described here, a catalytic synthesis of α,α-dihalo-N-arylacetamides from β-oxo amides was developed using zwitterionic catalysts and N-halosuccinimi
- Chan, Kin-San,Ke, Zhihai,Lam, Ying-Pong,Yeung, Ying-Yeung
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supporting information
p. 7353 - 7357
(2020/10/02)
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- An unsymmetrical covalent organic polymer for catalytic amide synthesis
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Herein, we present the first report on the Covalent Organic Polymer (COP) directed non-classical synthesis of an amide bond. An economical route has been chosen for the synthesis of APC-COP using p-aminophenol and cyanuric chloride. APC-COP acts as a smart, valuable and sustainable catalyst for efficient access to the amide bond under mild conditions at room temperature in 30 min. APC-COP exhibits selectivity towards carboxylic acids over esters. The key features of this protocol involve the variety of parameters, viz. wider substrate scope, no use of additive and recyclability, which makes this approach highly desirable in gramscale synthesis. Moreover, we have shown the practical utility of the present method in the catalytic synthesis of paracetamol.
- Yadav, Deepika,Awasthi, Satish Kumar
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supporting information
p. 179 - 186
(2019/12/28)
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- Dichloroacetophenones targeting at pyruvate dehydrogenase kinase 1 with improved selectivity and antiproliferative activity: Synthesis and structure-activity relationships
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Dichloroacetophenone is a pyruvate dehydrogenase kinase 1 (PDK1) inhibitor with suboptimal kinase selectivity. Herein, we report the synthesis and biological evaluation of a series of novel dichloroacetophenones. Structure-activity relationship analyses (SARs) enabled us to identify three potent compounds, namely 54, 55, and 64, which inhibited PDK1 function, activated pyruvate dehydrogenase complex, and reduced the proliferation of NCI-H1975 cells. Mitochondrial bioenergetics assay suggested that 54, 55, and 64 enhanced the oxidative phosphorylation in cancer cells, which might contribute to the observed anti-proliferation effects. Collectively, these results suggested that 54, 55, and 64 could be promising compounds for the development of potent PDK1 inhibitors.
- Zhang, Shao-Lin,Yang, Zheng,Hu, Xiaohui,Tam, Kin Yip
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supporting information
p. 3441 - 3445
(2018/09/29)
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- One-pot dichlorinative deamidation of primary β-ketoamides
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An approach to the dichlorinative deamidation of primary β-ketoamides through ketonic cleavage is described, and a series of α,α-dichloroketones were furnished mostly in the presence of TEMPO. Based on control experiments, a mechanism involving tandem dichlorination and deamidation is proposed to interpret the observed reactivity.
- Zheng, Congke,Zhang, Xiaohui,Ijaz Hussain, Muhammad,Huang, Mingming,Liu, Qing,Xiong, Yan,Zhu, Xiangming
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p. 574 - 577
(2017/01/16)
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- Synthesis technique of medical chemical intermediate N-phenyl dichloroacetamide
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The invention discloses a synthesis technique of a medical chemical intermediate N-phenyl dichloroacetamide. The technique comprises the following steps: carrying out reflux condensation on tetrahydrofuran, dichloroacetyl chloride, aniline, a self-made la
- -
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Paragraph 0024; 0034; 0035; 0036; 0037-0060
(2017/08/29)
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- CFBSA: a novel and practical chlorinating reagent
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A structurally simple, highly reactive chlorinating reagent, N-chloro-N-fluorobenzenesulfonylamine (CFBSA), was conveniently prepared from inexpensive Chloramine B in high yield. A wide range of substrates were chlorinated with it to obtain products in good to high yields and appropriate selectivity.
- Lu, Zehai,Li, Qingwei,Tang, Minghua,Jiang, Panpan,Zheng, Hao,Yang, Xianjin
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supporting information
p. 14852 - 14855
(2015/10/06)
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- Efficient partial hydrogenation of trichloromethyl to gem-dichloromethyl groups in platinum on carbon-catalyzed system
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While gem-dichloromethyl groups can be directly synthesized by the mono-dechlorination of the corresponding trichloromethyl groups, the suppression control of the over-reduction to form chloromethyl or methyl functionalities is quite difficult. We have established the efficient and widely applicable mono-dechlorination method of the trichloromethyl groups to form the corresponding gem-dichloromethyl groups using platinum on carbon in dimethylacetamide as a specific solvent at 25 °C under a hydrogen atmosphere. The mono-dechlorination of the α,α,α- trichloromethylcarbonyl groups smoothly proceeded by the use of platinum on carbon as a catalyst in a highly chemoselective manner, while the efficient mono-dechlorination of the alkyl- and aryl-trichloromethyl groups required the combined use of Bu3SnH.
- Sawama, Yoshinari,Imanishi, Takahiro,Nakatani, Ryosuke,Fujiwara, Yuta,Monguchi, Yasunari,Sajiki, Hironao
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p. 4540 - 4546
(2014/06/10)
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- Homologation of isocyanates with lithium carbenoids: A straightforward access to α-halomethyl- and α,α-dihalomethylamides
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Treatment of widely available isocyanates with monohalolithium and dihalolithium carbenoids provides a valuable protocol for the one-pot preparation of α-halo- and α,α-dihaloacetamide derivatives. While monohalolithium carbenoids can be prepared by a smoo
- Pace, Vittorio,Castoldi, Laura,Mamuye, Ashenafi Damtew,Holzer, Wolfgang
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p. 2897 - 2909
(2015/01/16)
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- Divergent synthesis of α,α-dihaloamides through α,α-dihalogenation of β-oxo amides by using N-halosuccinimides
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An efficient and divergent one-pot synthesis of α,α- dihaloamides from readily available β-oxo amides based on the selection of reaction conditions is reported. α,α-Dihalo-β-oxo amides were produced by treating β-oxo amides with N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS) in water at room temperature, whereas α,α-dihaloacetamides were synthesized by subjecting β-oxo amides to NCS or NBS in ethanol under reflux. A divergent synthesis of α,α-dihalo-β-oxo amides and α,α-dihaloacetamides has been developed from readily available β-oxo amides. Upon treatment with N-halosuccinimides in water at room temperature, α,α-dihalo-β- oxo amides were produced, whereas dihaloacetamides were synthesized by treatment of β-oxo amides with N-halosuccinimides in ethanol under reflux. Copyright
- Wang, Jia,Li, Hongtao,Zhang, Dingyuan,Huang, Peng,Wang, Zikun,Zhang, Rui,Liang, Yongjiu,Dong, Dewen
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p. 5376 - 5380
(2013/09/02)
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- Palladium(II)-catalyzed sequential c-cl bond formation: A novel and efficient method for direct α,α-dichlorination of β-dicarbonyl compounds
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A simple and concise procedure for the synthesis of 2,2-dichloro-3-oxo-N- phenylbutanamides, via palladium-catalyzed C(sp3)-H dichlorination of 3-oxo-N-phenylbutanamides, is described. The protocol provides a direct route to α,α-dichlorinated products starting from β-dicarbonyl compounds. A plausible mechanism for this transformation involving two consecutive chlorination steps is described.
- Liu, Weibing,Tan, Liquan,Zhou, Peng,Chen, Cui,Zhang, Qing
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p. 2600 - 2604
(2013/09/24)
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- Approach for the direct synthesis of β-dichlorosubstituted acetanilides using iodine trichloride (ICl3) as the oxidant and catalyst
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A reliable method for direct synthesis of β-dichlorosubstituted acetanilides is reported. The key transformation involves the oxidative and catalytic cleavage of a carbon-carbon bond in the presence of iodine trichloride (ICl3). In this protoco
- Zhang, Qing,Liu, Weibing,Chen, Cui,Tan, Liquan
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supporting information
p. 453 - 455
(2013/08/25)
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- Platinum on carbon-catalyzed precise reduction control of trichloromethyl to Geminal-dichloromethyl groups
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Geminal-dichloromethyl derivatives could be efficiently synthesized by the highly chemoselective platinum on carbon-catalyzed mono-dechlorination of trichloromethyl substrates in dimethylacetamide (DMA) as a specific solvent at 25 °C under a hydrogen atmosphere. Copyright
- Imanishi, Takahiro,Fujiwara, Yuta,Sawama, Yoshinari,Monguchi, Yasunari,Sajiki, Hironao
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p. 771 - 776
(2012/06/30)
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- Organic synthesis using (diacetoxyiodo)benzene (DIB): Unexpected and novel oxidation of 3-oxobutanamides to 2,2-dihalo-N-phenylacetamides
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A novel and reliable method for the direct preparation of 2,2-dihalo-N-phenylacetamides is reported. The key transformation involves the cleavage of a carbon-carbon bond in the presence of DIB and a Lewis acid as the halogen source, and thus this method s
- Liu, Wei-Bing,Chen, Cui,Zhang, Qing,Zhu, Zhi-Bo
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supporting information; experimental part
p. 344 - 348
(2012/05/04)
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- Novel N-phenyl dichloroacetamide derivatives as anticancer reagents: Design, synthesis and biological evaluation
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A current study shows that sodium dichloroacetate (DCA) can induce cancer cell apoptosis and inhibit tumor growth, but its cytotoxic activity is low (IC50 > 1000 μM for A549). In this paper, a variety of DCA derivatives were synthesized, and their cytotoxic activities were evaluated. The result showed that the N-phenyl-2,2-dichloroacetamide analogues had satisfactory potencies. Among them, N-(3-iodophenyl)-2,2-dichloroacetamide (3e), an optimized lead compound, has an IC50 against A549 as low as 4.76 μM. Furthermore, it can induce cancer cell apoptosis and has a low toxicity in mice (LD50 = 1117 mg/kg). N-phenyl-2,2-dichloroacetamide analogues has higher cytotoxic activity and N-(3-iodophenyl)-2,2-dichloroacetamide (3e) is an optimized lead compound.
- Yang, Yongchong,Shang, Peihua,Cheng, Changmei,Wang, Dongchun,Yang, Ping,Zhang, Feng,Li, Tianwen,Lu, Aijun,Zhao, Yufen
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experimental part
p. 4300 - 4306
(2010/10/02)
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- Synthesis and characterization of N-acylaniline derivatives as potential chemical hybridizing agents (CHAs) for wheat (Triticum aestivum L.)
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Induction of male sterility by deployment of chemical hybridizing agents (CHAs) are important in heterosis breeding of self-pollinated crops like wheat, wherein the male and female organs are in the same flower. Taking a lead from the earlier work on rice, a total of 25 N-acylanilines comprising of malonanilates, acetoacetanilides, and acetanilides (including halogenated acetanilides) were synthesized and screened as CHAs on three genotypes of wheat, viz., PBW 343, HD 2046, and HD 2733 at 1500 ppm in the winter of 2001-2002. The N-acylanilines containing variations at the acyl and aromatic domain were synthesized by condensation of substituted anilines with appropriate diesters, acid chlorides, or monoesters. The test compounds with highly electronegative groups such as F/Br at the para position of the aryl ring were identified as the most potent CHAs, causing higher induction of male sterility. A variation of N-substitution at the side chain generally furnished analogues like 4′-fluoroacetoacetanilide (7) and ethyl 4′-fluoromalonanilate (1), which induced 89.12 and 84.66% male sterility, respectively, in PBW 343. Among halogenated acetanilides, the increasing number of chlorine atoms in the side chain led to an increase in the activity of 4′-fluoro (23) and 4′-bromo (24) derivatives of trichoroacetanilides, which induced >87% male sterility. Quantitative structure-activity relationship (QSAR) models indicated the positive contributions of the field effect exemplified by the Swain-Lupton constant (Fp) and negative contributions of the Swain-Lupton resonance constant (R) for the aromatic substitution. The positive influences of parachor (P) for the acyl domain have been underlined. These leads will be significant in explaining the CHA fit in the macromolecular receptor site. The CHAs appeared to act by causing an imbalance in the acid-base equilibrium in pollen mother cells resulting in dissolution of the callose wall by premature callase secretion.
- Chakraborty, Kajal,Devakumar
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p. 6800 - 6808
(2007/10/03)
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- Synthesis, Fourier transform infrared and Raman spectra, assignments and analysis of N-(phenyl)- and N-(chloro substituted phenyl)-2,2-dichloroacetamides
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N-(phenyl)-2,2-dichloroacetamide (NPA) and N-(chloro substituted phenyl)-2,2-dichloroacetamides of the configuration XyC 6H5-y-NHCO-CHCl2 (where, X = Cl and y = 1, 2 and 3) were synthesised and the Fourier trans
- Arjunan,Mohan,Subramanian,Thimme Gowda
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p. 1141 - 1159
(2007/10/03)
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- Substituent effect on the infrared and Raman spectra of N-(substituted-phenyl)-2,2-dichloroacetamides, XyC6H 5-yNHCOCHCl2 (X = o/m/p-CH3 or Cl; y = 1, 2 or 3)
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Several substituted N-(phenyl)-2,2-dichloroacetamides of the configuration XyC6H5-yNHCOCHCl2 (where, X = H, CH3 or Cl and y = 1, 2 or 3) have been synthesized and their infrared and Raman spectra measured in the solid state with the objective of correlating CO and NH frequencies of these substituted phenyldichloroacetamides with those of substituted phenylchloroacetamides and trichloroacetamides. The study reveals that there is no systematic variation in the frequencies with the substitution. The effect of substitution in the phenyl ring in terms of electron-donating and electron-withdrawing groups could not be generalized. The same trend is observed even with disubstituted phenyl-2,2-dichloroacetamides, which may be due to the varying crystalline states of the amides as the spectra are measured in the solid state. The infrared and Raman frequencies of the amides of the configuration XyC6H5-yNHCOR (where, X = H, CH3 or Cl and y = 1, 2 or 3 and R = CH2Cl, CHCl2, CCl3) have also been examined for comparison purpose. The entire data indicate that neither the infrared CO or NH absorption frequencies nor the Raman scattered CO or NH frequencies show regular trends in all these compounds for the stated above.
- Kumar, B.H. Arun,Gowda, B. Thimme
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p. 231 - 235
(2007/10/03)
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- "RS+" as a coupling reagent for phosphorylation and carboxylic acid activation
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Phenylsulfenyl chloride, a sulfenium ion transfer reagent, promotes the formation of pyrophosphate from tetrabutylammonium phosphate, under controlled "pH" conditions, in yields of up to 85%. Dichloroacetic and succinic acids, in the presence of phenylsulfenyl chloride and a tertiary amine, form the corresponding anhydrides in very good yields. The treatment of dichloroacetic acid or p-nitrobenzoic acid with phenylsulfenyl chloride in the presence of a tertiary amine, followed by the addition of aniline, affords the corresponding anilides in yields of up to 42%.
- Pasquato, Lucia,Santoni, Gabriella,Modena, Giorgio
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p. 3457 - 3460
(2007/10/03)
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- Ozone-mediated Reaction of Anilides and Phenyl Esters with Nitrogen Dioxide: Enhanced Ortho-reactivity and Mechanistic Implications
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In the presence of ozone, anilides 1 can be nitrated rapidly with nitrogen dioxide in chloroform at 0 deg C to give a high proportion of ortho-nitro derivatives (ortho:para = 1.2-4.4) in good yields.The phenyl esters 15 can be similarly nitrated on the aromatic ring without significant cleavage of the ester bond, giving a mixture of isomeric nitro derivatives in which the ortho-isomer predominantes (ortho:para = 1.1-1.5).The oridin of the enhanced ortho reactivity is discussed in terms of an electron-transfer process involving the nitrogen trioxide as initial electrophile.
- Suzuki, Hitomi,Tatsumi, Atsuo,Ishibashi, Taro,Mori, Tadashi
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p. 339 - 344
(2007/10/02)
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- Synthesis of 2-methylindole analogues and skatole dimers under Friedel-Crafts reaction conditions
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A one pot synthesis of 2-methylindole analogues and skatole dimers of biological interest using excess amounts of the substrates and the catalyst and higher temperature under Friedel-Crafts acylation conditions is reported. The products were defined by spectroscopic and single crystal X-ray analysis. Rationalization for the formation of the products has also been attempted.
- Mahato, Shashi B.,Mandal, Nirup B.,Chattopadhyay, Sukanya,Luger, Peter,Weber, Manuela
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p. 12667 - 12676
(2007/10/02)
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- DICHLOROKETENE IMINES AND DICHLOROKETENEIMINIUM DICHLOROMETHANIDES IN THE REACTION OF DICHLOROCARBENE WITH PRIMARY AMINES. SYNTHESIS OF N-ALKYL-N-(2,2-DICHLOROVINYL)CARBAMOYL CHLORIDES
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Isocyanides, dichloroketene imines, and dichloroketeneiminium dichloromethanides are formed successively in the reaction of primary amines with the dichlorocarbene produced by the reaction of potassium hydroxide with chloroform in the presence of benzyltr
- Khlebnikov, A. F.,Novikov, M. S.,Kostikov, R. R.
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p. 1642 - 1645
(2007/10/02)
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- HYDRODEHALOGENATION OF TRICHLOROACETAMIDES DURING THERMOCATALYTIC DECOMPOSITION OF SODIUM TRICHLOROACETATE
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N-Substituted trichloroacetamides are reduced to the corresponding dichloroacetamides during the thermal decomposition of sodium trichloroacetate in chloroform in the presence of benzyltriethylammonium chloride as phase-transfer catalyst.The relative reac
- Khlebnikov, A. F.,Kostik, E. I.,Novikov, M. S.,Kostikov, R. R.
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p. 1468 - 1471
(2007/10/02)
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- Reaction of Azobenzene with Dichlorocarbene in Phase-transfer-catalyzed System
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Azobenzene (2) reacted with dichlorocarbene at 40 deg C in the presence of several phase-transfer catalysts in a binary solvent (CHCl3-aqueous KOH), giving 2,2,3,3-tetrachloro-1-phenylaziridine (3), 1-phenyl-1,3-dihydro-2H-benzimidazol-2-one (4b), dichloroacetanilide (6), N,N'-diphenylurea (7), and trace amounts of 2-chloro-1-phenylbenzimidazole (8).
- Fujiu, Tomohisa,Izumi, Kazuo,Sekiguchi, Shizen
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p. 1055 - 1056
(2007/10/02)
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- Studies on Ketene and Its Derivatives. CXIII. Reaction of Dichloroketene with Aromatic Amine N-Oxides
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Reaction of dichloroketene with pyridine 1-oxide (1) gave four products, namely, 2-dichloromethylpyridine (2), 4-dichloromethylpyridine (3), 3,3,7-trichloro-6-dichloroacetyl-2-oxo-2,3,3a,6,7,7a-hexahydrofuropyridine (4), and 3,3-dichloro-6-dichloroacetyl-7-hydroxy-2-oxo-2,3,3a,6,7,7a-hexahydrofuropyridine (5).Reaction of dichloroketene with 1, followed by treatment with abs. methanol gave 3, methyl 2,2-dichloro-2-(2-pyridyl)acetate (6), and methyl 2,2-dichloro-2-(4-pyridyl)acetate (7).Similar reaction of dichloroketene with methylpyridine 1-oxides gave the corresponding 2-dichloro and 4-dichloro methylpyridines.On the other hand, reaction of dichloroketene with 2,6-dimethylpyridine 1-oxide (18), followed by treatment with abs. methanol gave 4-dichloromethyl-2,6-dimethylpyridine (19) and bis(2,6-dimethyl-4-pyridyl)dichloromethane (21).Dichloroketene also reacted with quinoline 1-oxide (24) and isoquinoline 2-oxide (29) to give the corresponding dichloromethyl derivatives (25 and 26, and 30, respectively).Keywords --- aromatic amine N-oxide; dichloroketene; dichloromethylpyridine; dichloromethylquinoline; dichloromethylisoquinoline
- Katagiri, Nobuya,Niwa, Ryuji,Furuya, Yoichi,Kato, Tetsuzo
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p. 1833 - 1841
(2007/10/02)
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