- Flow synthesis of 2-methylpyridines via α-methylation
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A series of simple 2-methylpyridines were synthesized in an expedited and convenient manner using a simplified bench-top continuous flow setup. The reactions proceeded with a high degree of selectivity, producing α-methylated pyridines in a much greener fashion than is possible using conventional batch reaction protocols. Eight 2-methylated pyridines were produced by progressing starting material through a column packed with Raney nickel using a low boiling point alcohol (1-propanol) at high temperature. Simple collection and removal of the solvent gave products in very good yields that were suitable for further use without additional work-up or purification. Overall, this continuous flow method represents a synthetically useful protocol that is superior to batch processes in terms of shorter reaction times, increased safety, avoidance of work-up procedures, and reduced waste. A brief discussion of the possible mechanism(s) of the reaction is also presented which involves heterogeneous catalysis and/or a Ladenberg rearrangement, with the proposed methyl source as C1 of the primary alcohol.
- Manansala, Camille,Tranmer, Geoffrey K.
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- Bimetallic C-C Bond-Forming Reductive Elimination from Nickel
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Ni-catalyzed cross-coupling reactions have found important applications in organic synthesis. The fundamental characterization of the key steps in cross-coupling reactions, including C-C bond-forming reductive elimination, represents a significant challenge. Bimolecular pathways were invoked in early proposals, but the experimental evidence was limited. We present the preparation of well-defined (pyridine-pyrrolyl)Ni monomethyl and monophenyl complexes that allow the direct observation of bimolecular reductive elimination to generate ethane and biphenyl, respectively. The sp3-sp3 and sp2-sp2 couplings proceed via two distinct pathways. Oxidants promote the fast formation of Ni(III) from (pyridine-pyrrolyl)Ni-methyl, which dimerizes to afford a bimetallic Ni(III) intermediate. Our data are most consistent with the subsequent methyl coupling from the bimetallic Ni(III) to generate ethane as the rate-determining step. In contrast, the formation of biphenyl is facilitated by the coordination of a bidentate donor ligand.
- Xu, Hongwei,Diccianni, Justin B.,Katigbak, Joseph,Hu, Chunhua,Zhang, Yingkai,Diao, Tianning
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- Transformations of pyridine bases on a nickel-aluminum catalyst
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The electronic structures of some pyridine bases are analyzed by means of 1H and 13C NMR spectroscopic data for substituted pyridines and the calculated bond orders in the pyridine ring. The differences in the chemical bonds in the pyridine ring of isomeric methylpyridines and the carbon-carbon bonds between the ring and the methyl groups in these compounds are in agreement with the experimental data on the thermal stability of the simplest pyridine bases and the gas-phase transformation of the isomeric methylpyridines on an industrial nickel-aluminum catalyst. The possibility of obtaining mono- or dialkylpyridines under these conditions, depending on the structure of the starting pyridine bases, is demonstrated.
- Antonova,Ovchinnikova,Bespalov,Serova,Promonenkov,Ustavshchikov
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- Palladium-Catalyzed Methylation of Aryl, Heteroaryl, and Vinyl Boronate Esters
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A method for the direct methylation of aryl, heteroaryl, and vinyl boronate esters is reported, involving the reaction of iodomethane with aryl-, heteroaryl-, and vinylboronate esters catalyzed by palladium and PtBu2Me. This transformation occurs with a remarkably broad scope and is suitable for late-stage derivatization of biologically active compounds via the boronate esters. The unique capabilities of this method are demonstrated by combining carbon-boron bond-forming reactions with palladium-catalyzed methylation in a tandem transformation.
- Haydl, Alexander M.,Hartwig, John F.
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supporting information
p. 1337 - 1341
(2019/02/26)
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- A mild and efficient H2O2 oxygenation of N-heteroaromatic compounds to the amine N-oxides and KI deoxygenation back to the tertiary amine with hexaphenyloxodiphosphonium triflate
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A mild and efficient method for the oxidation of N-heteroaromatic compounds to the corresponding N-oxides using H2O2 in the presence of hexaphenyloxodiphosphnium triflate (Hendrickson reagent) in EtOH at room temperature was reported. This methodology presented relatively fast and selective reactions to afford the N-oxides in good yields. The reverse reactions, deoxygenation reactions, were also carried out under the same reaction conditions by KI to produce the tertiary amines.
- Khodaei, Mohammad Mehdi,Alizadeh, Abdolhamid,Hezarkhani, Hadis Afshar
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p. 1843 - 1849
(2018/07/06)
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- Convenient procedure for the α-methylation of simple pyridines
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A convenient and straightforward laboratory procedure is presented for a highly selective mono-α-methylation of pyridines without reactive functional groups. The methylating agent is probably carbon monoxide/dihydrogen generated in situ from a high-boiling alcohol on a metal surface. The reaction is catalyzed by a Raney nickel catalyst at ambient pressure, which renders the protocol practicable in standard organic laboratories. The intrinsically high reaction temperature and long reaction times restrict the application to pyridine derivatives with less reactive substituents. The outcome of the reaction can be rationalized by the assumption of a simple heterogeneous mechanism. Copyright Taylor & Francis Group, LLC.
- Broering, Martin,Kleeberg, Christian
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scheme or table
p. 3672 - 3682
(2009/04/03)
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- Azabicyclic-substituted fused-heteroaryl compounds for the treatment of disease
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The invention provides compounds of Formula I: wherein Azabicyclo is These compounds may be in the form of pharmaceutical salts or compositions, racemic mixtures, or pure enantiomers thereof. The compounds of Formula I are useful in pharmaceuticals in which α7 is known to be involved.
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- Quinuclidines-substituted-multi-cyclic-heteroaryls for the treatment of disease
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The invention provides compounds of Formula I: 1where in W is 2These compounds may be in the form of pharmaceutical salts or compositions, racemic mixtures, or pure enantiomers thereof. The compounds of Formula I are useful to treat diseases or conditions in which α7 is known to be involved.
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- Substituted 7-aza[2.2.1]bicycloheptanes for the treatment of disease
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The invention provides compounds of Formula I: which may be in the form of pharmaceutical acceptable salts or compositions, are useful in treating diseases or conditions in which α7 nicotinic acetylcholine receptors (nAChRs) are known to be involved.
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- Inhibitors of cell proliferation, angiogenesis, fertility, and muscle contraction
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The invention concerns inhibitors of cell proliferation, angiogenesis, fertility, and muscle contraction, characterized by formula I wherein, X, Y and Z independently represent C or N; ------ is an optional double bond; n is 0 or 1; R1, R2, and R4 independently represent hydrogen, a chemical bond, C1-10 alkyl; C2-10 alkenyl; C2-10 alkinyl; aryl; aryl-C1-10 alkyl; C3-10 heterocyclyl; C5-10 heteroaryl; halo, CF3; NO2; NHC(O)R*, OR, said alkyl, alkenyl, alkinyl, aryl, arylalkyl, heterocyclyl, or heteroaryl being optionally substituted; R3, R5, and R6 independently represent hydrogen, C1-10alkyl; C2-10 alkenyl; C2-10 alkinyl; aryl; aryl-C1-10alkyl; C3-10 heterocyclyl; C5-10 heteroaryl; halo, CF3; NO2; NHC(O)R*, OR, said alkyl, alkenyl, alkinyl, aryl, heterocyclyl, or heteroaryl being optionally substituted; or R5 and R6 together form a 5- or 6-member aryl, heterocyclyl or heteroaryl group; R is hydrogen or C1-6 alkyl; R* is hydrogen, or C1-6 alkyl, or OH, wherein the optional substituents are preferably selected from the group of one to three OH, C1-6 alkyl, halo, NO2, C1-6 alkoxy, and CF3, or a pharmaceutically acceptable salt thereof.
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- A method for producing pyridine bases
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A method for producing pyridine bases which comprises reacting in a gas-phase an aliphatic aldehyde, aliphatic ketone or mixture thereof with ammonia in the presence of a zeolite comprising titanium and/or cobalt and silicon as zeolite constituent elements in which the atomic ratio of silicon to titanium and/or cobalt is about 5 to 1000 gives improved yield.
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- Electron and Hydrogen Transfer Reductions of Some 2,4-Disubstituted Pyridines
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New synthesis of 2,4-diacetylpyridine 1 was undertaken by Claisen condensation of 2,4-diethoxycarbonylpyridine 2a with ethyl acetate, followed by hydrolysis of the intermediate 3. Reduction of 1 with zinc or its salt in hydrochloric, formic or acetic acids afforded mixtures of the ketocarbinol 4 dicarbinol 5 or diethyl 6 pyridine derivatives. Formation of 6 as the complete reduction product was chemically proved to proceed via 4 and 5. Electrochemical reduction of 2a leads to 2,4-dimethylpyridine 7, and that of 1 gave rise to a mixture of 5 and 6 along with 2,4-diethyl-1,2,5,6-tetrahydropyridine 8 and 2,4-diethylpiperidine 9. Finally, metal hydride reduction of 1 gave 5, and that of diesters 2 or diacid chloride 10 derivatives afforded 2,4-dihydroxymethylpyridine 11.
- Attia, A.,El-Salam, O. I. Abd,Youssef, T. E.
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p. 351 - 362
(2007/10/03)
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- Hydroxymethylation and carbamoylation of di- and tetramethylpyridines using radical substitution (minisci) reactions
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Reaction of hydroxymethyl radicals with N-methoxy 2,4- and 2,6- dimethylpyridinium salts gave 2,4,6-substituted hydroxymethylpyridines. Similar reactions with 2,3,5,6-tetramethylpyridine and derivatives failed, however 4-substitution could be achieved using a carbamoyl radical.
- Amrollahi Biyouki, Mohammad A.,Smith, Robin A. J.,Bedford, Jennifer J.,Leader, John P.
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p. 3817 - 3825
(2007/10/03)
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- Zeolite-Catalyzed Isomerization of Aromatic Amines to Methyl-Aza-Aromatics
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The scope and mechanism of the isomerization of arylamines to methyl-substituted aromatic heterocycles have been studied.Aniline, toluidines, naphthylamines and m-phenylenediamine all reacted to the corresponding ortho-methyl-substituted aza-aromatiics when exposed to high NH3 pressure and elevated temperature in the presence of acid catalysts.Zeolites with a three-dimensional pore structure, especially H-ZSM-5, showed the best performance.Optimum reaction conditions are around 600 K and 10 MPa.Two mechanisms which had been proposed earlier for this apparent N-ortho C exchange reaction proved untenable.Neither incorporation of the N atom into the aromatic ring nor a mechanism based on an intramolecular Ritter reaction could explain the required high NH3 pressure or the product distribution.Two new mechanisms are proposed which can explain all observations.In both mechanisms, reaction starts with addition of NH3 to the arylamine, followed by ring opening.In one mechanism an alkyno-imine intermediate is formed; in the other mechanism an enamino-imine intermediate is formed through a reverse aldol reaction.In both cases ring closure and NH3 elimination lead to the required aromatic heterocycles.The high NH3 pressure is explained by the need to add NH3 to the aromatic ring, and the high temperature by the need to desorb NH3 from the acid sites.
- Stamm, T.,Kouwenhoven, H. W.,Seebach, D.,Prins, R.
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p. 268 - 282
(2007/10/02)
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- SYNTHESIS OF SIX-MEMBERED NITROGEN-CONTAINING HETEROCYCLES AND ACETONITRILE BY REACTION BETWEEN ACETYLACETONE, ACETYLENE, AND AMMONIA UNDER CONDITIONS OF HETEROGENEOUS CATALYSIS
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The use of phosphogypsum, which is a waste product of the phosphorus fertilizer industry, as a heterogeneous catalyst in condensation of acetylacetone, acetylene, and ammonia is considered.
- Nurmanov, S. E.,Ikramov, A.,Sirlibaev, T. S.,Turdiev, Sh. A.,Kutbitdinov, Kh. K.
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p. 1732 - 1734
(2007/10/02)
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- HETEROGENEOUS-CATALYTIC SYNTHESIS OF PYRIDINE BASES FROM DIMETHYLETHYNYLCARBINOL, ACETALDEHYDE, AND MONOETHANOLAMINE
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The heterogeneous-catalytic synthesis of pyridine bases from dimethylethynylcarbinol and ammonia in the presence of acetaldehyde and also of monoethanolamine was investigated.The employed zinc-chromium-aluminum catalyst was prepared from the respective compounds by the suspension method.The effect of temperature and of the initial reagents on the formation of alkylpyridines was studied.Possible hypothetical reactions were investigated, and their schemes were demonstrated by alternative synthesis.
- Ikramov, A.,Sirlibaev, T. S.,Faizullaeva, M. F.
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p. 392 - 395
(2007/10/02)
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- POTENTIOMETRIC STUDIES ON THE REACTION OF PICRIC ACID WITH SOME AROMATIC AMINES IN METHYL ISOBUTYL KETONE
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The reaction between picric acid and some aniline and pyridine derivatives has been investigated in methyl isobutyl ketone by the potentiometric method.Overall picrate formation constants KBHA, ammonium cationic acid dissociation constants KBH+ and apparent ion-pair formation Ki* and dissociation Kd* constants have been determined.
- Smagowski, Henryk,Bartnicka, Halina
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p. 201 - 209
(2007/10/02)
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- Catalysts for alkoxylation reactions
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Catalysts producing a sharply peaked alkoxylation distribution during the alkoxylation of organic materials comprise mixtures of BF3 and metal alkyls or metal alkoxides, SiF4 and metal alkyls or metal alkoxides, or mixtures of these catalysts.
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- Methods of alkoxylation
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Catalysts comprising mixtures of HF and metal alkoxides and mixed metal alkoxides produce a sharply peaked alkoxylation distribution during the alkoxylation of organic materials.
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- An Improved Liquid-Phase Synthesis of Simle Alkylpyridines
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The synthesis of pyridines from mixtures of aldehydes or ketones and NH3 in the liquid phase has been reinvestigated, using continuous dosage of the carbonyl components to the reaction mixture.The main product from the reaction of acetaldehyde and formaldehyde is 3-methylpyridine (6), which is also the main product from the reaction of acrolein or a mixture of crotonaldehyde and formaldehyde under the same conditions.The reaction of other aldehydes with formaldehyde give 3,5-dialkylpyridines, e.g. 10, 16.Acetone reacts with either formaldehyde or acetaldehyde to give polysubstituted alkylpyridines.A mechanistic pathway is proposed which accounts for the formation of the observed products.
- Grayson, J. Ian,Dinkel, Rolf
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p. 2100 - 2110
(2007/10/02)
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- Catalytic Reactions of Pyridines. V. Alkylation of α-, β-, and γ-Picolines with Alcohols catalyzed by Ammonium Halides
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A new method was found for the homogeneous liquid-phase alkylation of α-, β-, and γ-picolines with either methanol or ethanol.Addition of a catalytic amount of an ammonium halide to a mixture of a picoline and an alcohol resulted in a great increase in the yields of both side-chain and α-alkylated derivatives of the starting picoline when the reaction was carried out at 320-335 deg C in an atmosphere of nitrogen.The higher the reaction temperature, the greater the yields of side-chain alkylated derivatives became.In practice, this alkylation gave 2-ethylpyridine, and 2,6-lutidine from α-picoline with methanol, 3-ethylpyridine and 2,5-lutidine from β-picoline from methanol, 4-ethylpyridine and 2,4-lutidine from γ-picoline with methanol, 2-propylpyridine and 2-ethyl-6-methylpyridine from α-picoline with ethanol, 2-ethyl-5-methylpyridine from β-picoline with ethanol, and 4-propylpyridine and 2-ethyl-4-methylpyridine from γ-picoline with ethanol.Keywords-alkylation; catalyst; ammonium halide; α-picoline; β-picoline; γ-picoline; ethylpyridine; propylpyridine; methanol; ethanol
- Kashiwagi, Hiroshi,Enomoto, Saburo
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p. 2213 - 2218
(2007/10/02)
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- Catalytic Reactions of Pyridines. IV. Heterogeneous Vapor-phase Side-chain Alkylation of Pyridines with Alcohols over Na+, K+, Rb+, and Cs+ Exchanged Zeolites
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The heterogeneous vapor-phase alkylation of pyridine with methanol over Na+, K+, Rb+, or Cs+ exchanged X- or Y-type zeolite in an atmophere of nitrogen resulted in the formation of 2- and 4-ethylpyridines and 2- and 4-vinylpyridines together with picolines and lutidines.Next, the alkylation of α-, β-, and γ-picolines with methanol was studied over alkali cation exchanged zeolites and was found to produce mainly the side-chain methylated derivatives: ethylpyridines and vinylpyridines.However, considerable amounts of ring-alkylated derivatives (lutidines) were formed simultaneously.In general, the catalytic activity became observable under reaction conditions involving both a high temperature and a small flow rate of carrier gas (N2).The yields of ethylpyridines were highest when the CsY catalyst was used at 450 deg C, whereas the yields of vinylpyridines were highest when the CsX catalyst was used at 425 deg C.This catalytic side-chain alkylation over alkali cation exchanged zeolites was successfully applied to a variety of picolines, lutidines, and ethylpyridines with either methanol or ethanol.
- Kashiwagi, Hiroshi,Enomoto, Saburo
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p. 404 - 411
(2007/10/02)
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- Catalytic Reactions of Pyridines. III. γ-Ray-Induced α-Methylation of Pyridine and γ-Picoline with Methanol catalyzed by Nickel Nitrate
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γ-Ray irradiation of a binary solution consisting of pyridine and methanol caused almost no reaction of pyridine.However, the addition of a catalytic amount of nickel nitrate to this binary solution induced the α-methylation of pyridine in good yield upon γ-ray irradiation at room temperature either in air or in vacuo.This α-methylation gave α-picoline as a major product.The yield of α-picoline increased with increase in the irradiation time at the initial stage of the reaction, reached a maximum (27.8percent) at an irradiation duration of between 8 and 10h, and then decreased progressively at greater irradiation times.In addition, the yield of α-picoline at a given irradiation time showed a tendency to increase with increasing amount of the nickel nitrate catalyst or with increasing fraction of methanol in the starting solution. γ-Ray irradiation in the presence of nickel nitrate was also found to induce the catalytic α-methylation of γ-picoline with methanol at room temperature either in air or in vacuo, giving 2,4-lutidine as a major product in a maximum yield of 8.3percent.Further, the demethylation reaction of α-picoline to pyridine and that of 2,4-lutidine to γ-picoline were also promoted greatly upon γ-ray irradiation at room temperature in air in the presence of both methanol and nickel nitrate.
- Kashiwagi, Hiroshi,Enomoto, Saburo
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- Preparation of dithiophosphoric acid diester-halides
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A process for the preparation of a dithiophosphoric acid diester-halide of the formula STR1 IN WHICH R1 is alkyl with 1 to 10 carbon atoms, aralkyl with 1 to 6 carbon atoms in the alkyl radical, or alkoxyalkyl or alkylthioalkyl with 1 to 5 carbon atoms in each alkyl radical, R2 is alkyl with 1 to 8 carbon atoms, and Hal is halogen, Which comprises reacting an S-alkyl or S-aralkyl ester of a dithiophosphoric acid dihalide of the formula STR2 WITH ABOUT A 5 TO 300% MOLAR EXCESS OF AN ALCOHOL OF THE FORMULA in the presence of about a 5 to 300% molar excess of a tertiary pyridine base or tertiary aralkyl-alkylamine at a temperature between about -10° and +60° C. Advantageously the tertiary base is pyridine, 2-, 3- or 4-methyl-pyridine, 4-ethyl-pyridine, 5-ethyl-2-methyl-pyridine, 2,4- or 2,6-dimethyl-pyridine, 2,4,6-trimethyl-pyridine, quinoline, isoquinoline, 2-, 4- or 6-methyl-quinoline, 6-chloro-2-methyl-quinoline, 2-chloro-4-methyl-quinoline, 8-chloro-2-methyl-quinoline or dimethylbenzylamine, the reaction is carried out at about 0° to 30° C., the alcohol is ethanol employed in about a 15 to 30% molar excess, about a 20 to 210% molar excess of the tertiary base is employed, R1 is alkyl with 1 to 8 carbon atoms, aralkyl with 1 to 3 carbon atoms in the alkyl radical, or alkoxyalkyl or alkylthioalkyl with 1 to 3 carbon atoms in each alkyl radical and Hal is chlorine.
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