Amines 1- ethyl isocyanate

The nitrogen of aHphatic and aromatic amines is alkylated rapidly by alkyl sulfates yielding the usual mixtures. Most tertiary amines and nitrogen heterocycles are converted to quaternary ammonium salts, unless the nitrogen is of very low basicity, eg, ia tn phenylamine. The position of dimethyl sulfate-produced methylation of several heterocycles with more than one heteroatom has been examined (22). Acyl cyanamides can be methylated (23). Metal cyanates are converted to methyl isocyanate or ethyl isocyanate ia high yields by heating the mixtures (24,25). 

A series of reactions was developed to transfer amines to ureido- and thioureido-derivatives for separation. The reaction of ureido-derivatives is widely used by the reaction with 1-phenylethyl isocyanate (PEIC) [8] or the naphthyl-analogue 1-(1-naphthyl)ethyl isocyanate (NEIC) [9]. Both reactions can be used not only for chiral amines but also for alcohols and thiols. 

A. l-Ethyl-3-(3-dimethylamino)propylcarbodiimide. A solution of 100 g. (1.41 moles) of ethyl isocyanate (Note 1) in 750 ml. of methylene chloride is prepared in a 5-1. three-necked flask equipped with a mechanical stirrer, an immersion thermometer, and a 500-ml., pressure-equalizing, addition funnel (Note 2). The flask and its contents are cooled to 5° in an ice bath, and a solution of 144 g. (1.41 moles) of N,N-dimethyl-l,3-propanedi-amine in 250 ml. of methylene chloride is added through the addition funnel at a rate such that the reaction temperature does not exceed 10° (Note 3). On completion of this addition 500 ml. of triethylamine is added to the flask, and a solution of 300 g. (1.6 moles) of -toluenesulfony 1 chloride in 300 ml. of methylene chloride is placed in the addition funnel and added to the reaction... 

N-Methylethylamine has been prepared by heating ethyl-amine with methyl iodide in alcohol at 100° 3 by the hydrolysis of N-methyl-N-ethylarenesulfonamides,4-5 -nitroso-N-methyl-N-ethylaniline,6 or methylethylbenzhydrylidene ammonium iodide 7 by catalytic hydrogenation of ethyl isocyanate or ethyl isocyanide 8 and by the reduction of ethyl isocyanate by lithium aluminum hydride,9 of N-methylacetisoaldoxime by sodium amalgam and acetic acid,10 or of a nitromethane/ethylmagnesium bromide adduct by zinc and hydrochloric acid.11... 

How an unsymmetrical urea can be prepared from a primary amine with a (diethyl-amino )propyl substituent (A) and ethyl isocyanate is illustrated using the example of compound C. This urea is the starting material for preparing a carbodiimide (see Figure 8.9), which activates carboxylic acids towards heteroatom nucleophiles. 

Resolution of sec-amines. Reaction of sec-amines with (+)- or (- )-l results in two diasteriomeric ureas, R2NCONH(CH3)C6H5, which can usually be resolved by either chromatography or crystallization. The resolved sec-amine is obtained by alcoholysis of the optically pure urea. The method is particularly valuable where both optical isomers of the amine are desired see also (R)-( - )-(l-naphthyl)ethyl isocyanate (6, 416) for a similar reagent. 

Analysis of the enantiomeric ratios of several p-blocking drugs (l-aryloxy-3-isopropylamino-2-propanol derivatives) is carried out by HPLC with UV or fluorescence detection after derivatization with (R)-NEI or (i )-(+)-l-(l-phenyl)ethyl isocyanate (in a reversed-phase system), or (S)-NEI (on silica gel) only the amine function of the drugs reacts with the NEI the hydroxy group does not. Similar schemes for HPLC determination of enantiomeric purity of tetrahydrofolate derivatives and of fluoxetine are also reported. 

Resolution of alcohols (c/., l-(naphthyl)ethyl isocyanate, 8, 356-357). A practical synthesis of the methyl ester of (S)-5-HETE (1) from arachidonic acid involves chromatographic separation of the diastereomeric urethanes prepared" from the isocyanate derived from dehydroabietylamine (hydrogen chloride and phosgene).1 Urethanes from other chiral amines are less useful. The urethanes are cleaved with triethylamine and trichlorosilane to give the corresponding pure enantiomeric esters, which can be hydrolyzed by base. 

There has been continued interest in the synthesis of oxazoles from a-diazo carbonyl compounds and nitriles catalyzed by Lewis acids. The BFa-catalyzed reaction of a-diazoacetophenones or methyl p-nitrophenyldiazoacetate with chloroacetonitrile affords 5-aryl-2-chloromethyloxazoles or 2-chloromethyl-5-methoxy-4-(p-nitrophenyl)oxazole, respectively (Equation (19)) <89BCJ618>. The former products react with primary, secondary, and tertiary amines by nucleophilic displacement of the chloride group. Methyl or ethyl isocyanate may be used as the nitrile component to prepare... 

ACIDO SALICILICO (Spanish) (69-72-7) Combustible solid (flash point 315°F/157°C). Dust or powder forms explosive mixture in air. Reacts with strong oxidizers, ethyl nitrite, iodine, iron salts, lead diacetate. Incompatible with sulfuric acid, alkalis, ammonia, aliphatic amines, alkanolamines, isocyanates, alkylene oxides, epichlorohydrin. Flow or agitation of substance may generate electrostatic charges due to low conductivity. 

ETHYL SILICON TRICHLORIDE (115-21-9) Forms explosive mixture with air (flash point 64°F/18°C oc). Violent reaction with water, steam, alcohols, forming hydrogen chloride. Violent reaction with strong oxidizers, ammonia. Incompatible with alkalis, strong acids, aliphatic amines, alkanolamines, isocyanates, alkylene oxides, epichlorohydrin, halogenated compounds, nitrogen oxides. Corrodes common metals in the presence of moisture and produces flammable hydrogen. 

The reaction is of interest as the first amine discovered was obtained in this way from ethyl isocyanate by Wurtz in 1848. 

A significant advance in the resolution of asymmetric alcohols has been the formation of carbamates from the reaction with a chiral isocyanate. Isocyanates are highly reactive and are widely used for the derivatization of hydroxyl and amine functional groups. Alcohols react relatively slowly and require heating for several hours, whereas phenols react rapidly, even at room temperature. Reagents used have included (R(-P)/S(—) phenylethyl isocyanate (15) and R(-p)/S( —)- -( -naphthyl)ethyl isocyanate (16) the diastereomeric carbamates are stable and no evidence for racemization has been recorded. The individual enantiomers can be recovered by refluxing the dias-tereomeric carbamates... 

Various Side-chain Reactions.—2-(2-Thienyl)ethyl isocyanate has been prepared from the corresponding primary amine, carbonyi suiphide, and. S-ethyl chloro-thioformate. Cyclization of 2-(2-thienyl)ethyl isothiocyanate with methyl fluorosulphonate or triethyloxonium tetrafluoroborate gave (178a) and (178b), respectively. The 3-thienyl isomer reacted in the same way. Monoesters of aliphatic dicarboxylic acids and 2-(2-thienyl)ethanol have been prepared in con-... 

Curtius transformation An alternative to the Hofmann transformation for obtaining an amine from an ester via the hydrazide, azide and isocyanate. Thus ethyl ethanoate is converted into melhylamine by the following series of reactions ... 

The use of polar solvents, such as /V, /V- dim ethyl fo rm am i de [68-12-2] is noted to result in extensive trimer formation. However, if the isocyanate is trapped using compounds such as alcohols, carboxyUc acids, and amines which contain active hydrogen, high yields are obtained (93). 

Open times of two-component urethanes can vary widely, depending on the level of catalyst. Reaction times can vary from 90 s to over 8 h. Dibutyltin dilaurate is the most common catalyst employed to catalyze the urethane reaction. This is normally added to the polyol side. A tertiary amine may also be added in small amounts. Tin catalysts do not catalyze the amine/isocyanate reaction very well. Acids, such as 2-ethyl hexanoic acid, may be employed to catalyze the amine/isocyanate reaction where needed. 

New heterocyclic ketene aminals have been obtained in yields ranging from 60 to 94% [89] starting from ethyl lff-perimidine-2-acetate or acetonitrile and isocyanates (Scheme 8.63). 

Several approaches to the 1,2,3-triazole core have been published in 2000. Iodobenzene diacetate-mediated oxidation of hydrazones 152 led to fused 1,2,3-triazoloheterocycles 153 <00SC417>. Treatment of oxazolone 154 with iso-pentyl nitrite in the presence of acetic acid gave 1,2,3-triazole 155, a precursor to 3-(W-l,2,3-triazolyl)-substituted a,P-unsaturated a amino acid derivatives <00SC2863>. Aroyl-substituted ketene aminals 156 reacted with aryl azides to provide polysubstituted 1,23-triazoles 157 <00HC387>. 2-Aryl-2T/,4/f-imidazo[43-d][l,2,3]triazoles 159 were prepared from the reaction of triethyl AM-ethyl-2-methyl-4-nitro-l//-imidazol-5-yl phosphoramidate (158) with aryl isocyanates <00TL9889>. 

The first reported synthesis of hydroxyurea (24) consists of the condensation of hy-droxylamine with potassium cyanate (Scheme 7.14) [87]. Condensation of hydroxy-lamine with ethyl carbamate also gives pure hydroxyurea in good yield after recrystallization (Scheme 7.14) [88]. Nitrogen-15 labeled hydroxyurea provides a useful tool for studying the NO-producing reactions of hydroxyurea and can be prepared by the condensation of N-15 labeled hydroxylamine with either potassium cyanate or trimethylsilyl isocyanate followed by silyl group removal (Scheme 7.14) [89, 90]. Addition of hydroxylamine to alkyl or aryl isocyanates yields alkyl or aryl N-hydroxyureas (Scheme 7.14) [91, 92]. The condensation of amines with aromatic N-hydroxy carbamates also produces N-substituted N-hydroxyureas (Scheme 7.14) [93]. 

Cyclocondensation of ethyl 2-aminonicotinate in presence of HC(OEt)3 and various primary amines gave 22 3-substituted pyrido[2,3-,7]pyrimidin-4(377)-ones 371 <1995PHA719>. Fourteen 3,5,7-triarylpyrido[2,3-r7]pyrimi-dine-2,4(l/7,37/)-diones 372 have been prepared from the reaction of either 2-amino-3-cyano-4,6-diarylpyridines or the 3-carboxamido products of alcoholic KOH hydrolysis, with aryl isocyanates better yields were obtained from the amides <1995IJB740>. 4-Aminopyrido[2,3- pyrimidin-5(8//)-one 158 was synthesized by treatment of 2-amino-3-cyano-4-methoxypyridine with trimethylsilyl iodide to give the corresponding pyridin-4(177)-one, which was refluxed with formamidine acetate in ethoxyethanol to effect the cyclization <2000JME3704>. 

The relative reaction rates of several amines with phenyl isocyanate in ether at 0°C have been determined. Aniline is about half as reactive as ethyl-, n-propyl-, n-butylamine, and n-amylamine is between eight and ten times as reactive as ammonia [28]. 

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