Amines from carboxamides

Fig. 6 Ellipsometric analysis of films containing various mixtures of amines and carboxylic acids 3-PAA/lN (ca. 55% -CO2H) 3-PAA/3N (ca. 17% -CO2H) and 3-PAA/6N (no - CO2H groups could be distinguished from carboxamide carbonyl peak in the FTIR-ERS spectrum). The IN, 3N and 6N refers to the number of times the amidation in Eq. 3 was repeated using NH2CH2CH2N(CH3) as the amidating reagent...

When ammonia or primary amines are used, the product amines may participate in further aminomethylation, resulting in the formation of a mixture of amines. Other byproducts (aldehydes, alcohols, carboxamides) may also be formed. The reaction to produce tertiary amines from secondary amines, however, is fairly selective. Aminomethylation of ethylene with piperidine was reported to form /V-propyl-piperidine with 75% yield when the reaction was carried out in the presence of [Fe(CO)5] and water without an external source of CO (170°C, 14 h).207... 

There are nitrogen anions that are useful in alkylation reactions, but they are derived from carboxamides and sulfonamides rather than amines. Two examples are given here to illustrate the synthesis of a primary and a secondary amine (also see Section 18-IOC) ... 

Electronically excited carbonyl chromophores in ketones, aldehydes, amides, imides, or electron-deficient aromatic compounds may act as electron acceptors (A) versus alkenes, amines, carboxylates, carboxamides, and thioethers (D, donors). In addition, PET processes can also occur from aromatic rings with electron-donating groups to chloroacetamides. These reactions can be versatile procedures for the synthesis of nitrogen-containing heterocyclic compounds with six-membered (or larger) rings [2],... 

Some bridgehead amines such as 4-iodo-l-cubylamine (58%) and 1-adamantyl-amine (85%) were also obtained in this way [47]. The direct formation of alkylammonium tosylates is advantageous because of the instability of some amines of this type. No special precautions, as with BTI, were needed with HTI which, however, did not work with some cyclic carboxamides also, malonamide did not undergo degradation but tosyloxylation, affording a-tosyloxymalonamide (81%) [48]. The reaction involved the intermediacy of TV-phenyliodonium salts (RCONHI + Ph TsO-), which were actually isolated from carboxamides and [methoxy(tosyloxy)iodo]benzene [49]. 

An efficient method for the synthesis of 1,3-disubstituted ureas and carbamates from carboxamides by using iodosylbenzene as the oxidant in the presence of amines or alcohols has been described [505]. For example, carbamates 408 have been prepared by this procedure in high yields (Scheme 3.164). Various symmetric and asymmetric ureas and ureidopeptides can also be prepared in good yields by this method [505]. 

Nitriles, which are important intermediates in the manufacture of a wide variety of organic compounds such as amines, aldehydes, amidines, and heterocycles, are manufactured either from alkali cyanides or from carboxamides. The cyanides route is obviously highly toxic, whereas the carboxamide consumes the reagent in stoichiometric quantities. Solid superacids offer a clear alternative to the traditional catalysts. Thus the use of sulfated zirconia enables the dehydration to be accomplished under much milder conditions in the liquid state (Joshi and Rajadhyaksha, 1986 Rajadhyaksha and Joshi, 1991). 

Then as shown in Scheme 13.67 (a reproduction of Scheme 12.96), 5-aminoimidazole ribose 5-phosphate is carboxylated (either with CO2 or with bicarbonate) to 5-carboxyamino-l-(5 -phosphoribosyl)imidazole, which rearranges to 5-aminoimidazole ribotide-4-carboxylate, and the latter undergoes amination from aspartate (Asp, D) to yield 5-amino-l-(5-phosphoribosyl)imidazole-4-carboxamide after the loss of fumarate. Finally (Scheme 13.8), A-formylation is effected with lO-CHO-H, folate to yield the A-formyl derivative (5-formamido-l-(5 -phosphoribosyl)imidaz-ole-4-carboxyamide) and cyclization yields inosine 5 -phosphate (IMP). 

The isolation of tertiary amines from alkylation reactions is normally straightforward except in special cases , unwanted primary and secondary amines can usually be removed from the basic fraction by conversion to non-basic carboxamides (cf. ref. 46a) or sulphonamides... 

However, the use of phenyl )V-phenylphosphoramidochloridate as a condensing agent for carboxylic acids and amines yields carboxamides in a one-step method (eq 7). The amide (12) is prepared from the carboxylic acid, 2 equiv of triethylamine, 1 equiv of amine, and 1 equiv of reagent (1) and isolated by filtration or evaporation of solvent and washing with water. Once again, a mixed anhydride intermediate (13) is presumed, which results from nucleophilic attack by the carboxylate anion on the phosphorus atom with elimination of a chloride ion a further nucleophilic attack by the amine on the carbonyl group of (13) and breakdown of the complex yields the amide (12) and phenyl Af-phenylphosphoramidate (14) which can be recycled to (1) by reaction with phosphorus pentachloride. 

Pyridazinecarboxamides are prepared from the corresponding esters or acid chlorides with ammonia or amines or by partial hydrolysis of cyanopyridazines. Pyridazinecarboxamides with a variety of substituents are easily dehydrated to nitriles with phosphorus oxychloride and are converted into the corresponding acids by acid or alkaline hydrolysis. They undergo Hofmann degradation to give the corresponding amines, while in the case of two ortho carboxamide groups pyrimidopyridazines are formed. 

The aminolysis of esters of pyrimidine occurs normally to yield amides. The reagent is commonly alcoholic ammonia or alcoholic amine, usually at room temperature for 20-24 hours, but occasionally under refiux aqueous amine or even undiluted amine are used sometimes. The process is exemplified in the conversion of methyl pyrimidine-5-carboxylate (193 R = Me) or its 4-isomer by methanolic ammonia at 25 °C into the amide (196) or pyrimidine-4-carboxamide, respectively (60MI21300), and in the butylaminolysis of butyl ttracil-6-carboxylate (butyl orotate) by ethanolic butylamine to give A-butyluracil-5-carboxamide (187) (60JOC1950). Hydrazides are made similarly from esters with ethanolic hydrazine hydrate. 

The A-substituted derivatives of 4-oxo-4//-pyrido[l,2-n]pyrimidine-3-carboxamides and -3-acetamides and l,6-dimethyl-4-oxo-1,6,7,8-tetrahy-dro-4//-pyrido[l,2-n]pyrimidine-3-carboxamide were prepared by treatment of the appropriate 3-carboxylic acids and acetic acid, first with an alkyl chloroformate in the presence ofNEt3 in CHCI3 below — 10°C, then with an amine (98ACH515). A-Phenethyl and A-[2-(3,4-dimethoxyphenyl)ethyl] derivatives of 6-methyl-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetamide were obtained in the reaction of 6-methyl-6,7,8,9-tetrahydro-4//-pyrido[l,2-n]pyrimidine-3-acetic acid and phenethylamines in boiling xylene under a H2O separator. Hydrazides of 4-oxo-4//- and 4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetic acid were prepared from the appropriate ester with H2NNH2 H2O in EtOH. Heating 4-oxo-4//- and 6-methyl-4-oxo-6,7,8,9-tetrahydro-4//-pyrido[l, 2-n]pyrimidine-3-acetic hydrazides in EtOH in the presence of excess Raney Ni afforded fhe appropriafe 4-oxo-6,7,8,9-fefrahydro-4//-pyrido[l,2-n]pyrimidine-3-acefa-mide. In the case of the 4-oxo-4// derivative, in addition to N-N bond... 

A-Substituted 11-oxo-l l//-pyrido[2,l-6]quinazoline-6-carboxamides were prepared from 11-oxo-l l//-pyrido[2,l-6]quinazoline-6-carboxylic acids and amines in the presence of (/-Pr)2EtN and benzotriazol-l-yloxytris(dimethy-lamino)phosphonium hexafluorophosphate in CH2CI2 (98MIP1, 98MIP2, 99USP5908840, 99USP5914327). 

A side chain carboxyl group in perhydropyrido[l,2-a]pyrazines was obtained from an ester group by acidic or alkalic hydrolysis. A side chain carboxyl group was converted into a carboxamide group by the treatment with an amine in the presence of 1-hydroxybenzotriazole (OOJAP(K)OO/ 86659). 

Patent applications from Pfizer disclosed 1,5-diaryl-pyrazoles bearing bioisosteric replacements for the 3-carboxamide moiety. One application showed that the amide could be replaced by a-aminoketones as exemplified by compound (416) [284]. The corresponding alcohols and their ethers were also described, including compounds that allowed the amine substituent and ether to form a ring system, such as a morpholine unit. This application also allowed for the replacement of the 1,5-diaryl-pyrazole by a 1,2-diaryl-imidazole bearing a 3-carbonyl substituent, as exemplified by compound (417). A further patent application from Pfizer claims compounds in which imidazoles replace the 3-carboxamide moiety in the 1,5-diaryl-pyrazole... 

The addition of Grignard reagents to aldehydes, ketones, and esters is the basis for the synthesis of a wide variety of alcohols, and several examples are given in Scheme 7.3. Primary alcohols can be made from formaldehyde (Entry 1) or, with addition of two carbons, from ethylene oxide (Entry 2). Secondary alcohols are obtained from aldehydes (Entries 3 to 6) or formate esters (Entry 7). Tertiary alcohols can be made from esters (Entries 8 and 9) or ketones (Entry 10). Lactones give diols (Entry 11). Aldehydes can be prepared from trialkyl orthoformate esters (Entries 12 and 13). Ketones can be made from nitriles (Entries 14 and 15), pyridine-2-thiol esters (Entry 16), N-methoxy-A-methyl carboxamides (Entries 17 and 18), or anhydrides (Entry 19). Carboxylic acids are available by reaction with C02 (Entries 20 to 22). Amines can be prepared from imines (Entry 23). Two-step procedures that involve formation and dehydration of alcohols provide routes to certain alkenes (Entries 24 and 25). 

Secondary amines, such as pyrrolidine, must be alkylated with care too polar a solvent leads to participation of a second nearby polymer-bound alkylant in the formation of a quaternary ammonium salt, along with the desired immobilized trialkyl amine. The exception, as seen above, is diisopropylamine, which refuses to displace tosylate even in the refluxing pure amine, or in hot dimethyl-formamide or other polar solvent, while metal diisopropylamide is notorious as a powerful non-nucleophilic base. However, carboxamide is not difficult to form from (carboxymethyl)polystyrene, again using toluenesulfonyl chloride as condensing agent this can then be reduced to (diisopropyl-ethylaminoethyl)polystyrene, which is of interest as a polymer-bound non-nucleophilic base. ... 

When JV /V -carbonyldiimidazole (CDI) is reacted with a primary amine in a 1 1 molar ratio, the product is an imidazole-A-carboxamide. However, these compounds dissociate in solution into isocyanates and imidazole even at room temperature,[1] forming a rapidly equilibrating system. Because of this equilibrium, primary imidazole-A-carboxamides can also be prepared from isocyanates and imidazole. 

Tetramethylpiperidine, dibromomethane (99%) and 1,1,1,3,3,3-hexamethyldisilazane (98%) were purchased from Aldrich Chemical Company, Inc., and used without further purification. Use of less hindered secondary amines (such as diisopropylamine) in place of tetramethylpiperidine results in lower yields because of the formation of carboxamide by-products. 

Ketcha and Wilson reported the solid-phase version of the classic Nenitzescu indole synthesis in a process involving initial acetoacetylation of ArgoPore-NH2 resin with diketene to afford a polymer bound acetoacetamide <00TL6253>. Formation of the corresponding enaminone 102 via condensation with primary amines in the presence of trimethylorthoformate followed by addition of 1,4-benzoquinones 103 leads to formation of polymer bound 5-hydroxyindole-3-carboxamides 104 which could be cleaved from the resin using TFA yielding the indoles 105. 

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