Tertiary amides reaction with

A new synthesis of isoquinolines from allylarenes (95) and nitriles has been reported 1,3 - dimethylisoquinoline (96) is obtained in 65% yield by this method. 7 Reaction of the Vilsmeier reagent from the tertiary amide (97) with methyl cyanide leads to the 3-dimethylaminoisoquinoline (98). 

Sulfation by sulfamic acid has been used ia the preparation of detergents from dodecyl, oleyl, and other higher alcohols. It is also used ia sulfating phenols and phenol—ethylene oxide condensation products. Secondary alcohols react ia the presence of an amide catalyst, eg, acetamide or urea (24). Pyridine has also been used. Tertiary alcohols do not react. Reactions with phenols yield phenyl ammonium sulfates. These reactions iaclude those of naphthols, cresol, anisole, anethole, pyrocatechol, and hydroquinone. Ammonium aryl sulfates are formed as iatermediates and sulfonates are formed by subsequent rearrangement (25,26). 

The present authors have found that the preparation of 7V-acetyl aziridine derivates provides the most secure method of differentiating aziridines from primary amines which are alternate reaction products in a number of cases. The infrared spectra of the former derivatives show only a peak at 1690 cm" for a tertiary amide peaks at ca. 3440 and 1530 cm" indicative of a secondary amide are absent. Acetylation also shifts the aziridine ring protons to a lower field in the NMR by ca. 1 ppm relative to the parent aziridine. The A"-acetyl aziridines are hydrolyzed with 3% methanolic potassium hydroxide. " Published NMR spectra of several 16j5,17j -aziridines reveal resonance patterns resembling those of the respective epoxides. " ... 

Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitution mechanisms. The halogen can be replaced by -OH to yield an acid, by —OCOR to yield an anhydride, by -OR to yield an ester, or by -NH2 to yield an amide. In addition, the reduction of an acid halide yields a primary alcohol, and reaction with a Grignard reagent yields a tertiary alcohol. Although the reactions we ll be discussing in this section are illustrated only for acid chlorides, similar processes take place with other acid halides. 

We ve already studied the two most general reactions of amines—alkylation and acylation. As we saw earlier in this chapter, primary, secondary, and tertiary amines can be alkylated by reaction with a primary alkyl halide. Alkylations of primary and secondary amines are difficult to control and often give mixtures of products, but tertiary amines are cleanly alkylated to give quaternary ammonium salts. Primary and secondary (but not tertiary) amines can also be acylated by nucleophilic acyl substitution reaction with an acid chloride or an acid anhydride to yield an amide (Sections 21.4 and 21.5). Note that overacylation of the nitrogen does not occur because the amide product is much less nucleophilic and less reactive than the starting amine. 

More recently, the same group has used a simpler and more easily prepared chiral ammonium phase-transfer catalyst 99 derived from BINOL in asymmetric Darzens reactions with a-halo amides 97 to generate glycidic tertiary amides 98 (Table 1.13). Unfortunately the selectivities were only moderate to low [48]. As mentioned in Section 1.2.3.1, tertiary amides can be converted to ketones. 

Allyl(trimethyl)silanes react efficiently with Lewis acids to give the corresponding tertiary alcohols67. Although only modest diastereofacial selectivity was observed for reaction with menthyl esters67, improved selectivity was found for chiral a-oxo imides68 and a-oxo amides derived from proline69. 

This procedure, which is based on the work of Ishii and co-workers, affords a mild and general method for converting a wide variety of esters to primary, secondary, and tertiary amides (Table 1). While the preparation of the tertiary amide, N,N-dimethylcyclohexanecarboxamide, described here is carried out in benzene, aluminum amides derived from ammonia and a variety of primary amines have been prepared by reaction with trimethylaluminum in dichloromethane and utilized for aminolysis in this solvent. Although 1 equivalent of the dimethylaluminum amides from amines was generally sufficient for high conversion within 5-48 hours, best results were obtained when 2 equivalents of the aluminum reagent from ammonia was used. Diethyl-aluminum amides can also effect aminolysis, but with considerably slower rates. 

Similar reactions have also been observed with tertiary amides and the adducts can be alkylated by tandem SN2 reactions. 

Neutral tertiary and secondary amides react with very reactive alkylating agents, such as triethyloxonium tetrafluoroborate, to give O-alkylation.63 The same reaction occurs, but more slowly, with tosylates and dimethyl sulfate. Neutralization of the resulting salt provides iminoethers. 

In this series, too, replacement of the N-methyl by a group such as cyclopropylmethyl leads to a compound with reduced abuse potential by virtue of mixed agonist-antagonist action. To accomplish this, reduction of 24 followed by reaction with tertiary butylmagnesium chloride gives the tertiary carbinol 27. The N-methyl group is then removed by the classic von Braun procedure. Thus, reaction with cyanogen bromide leads to the N-cyano derivative (28) hydrolysis affords the secondary amine 29. (One of the more efficient demethylation procedures, such as reaction with ethyl chloroformate would presumably be used today.) Acylation with cyclopropylcarbonyl chloride then leads to the amide 30. Reduction with lithium aluminum hydride (31) followed by demethylation of the phenolic ether affords buprenorphine (32).9... 

To synthesize new surfactants, having incorporated both structural elements, the known siloxanyl modified halogenated esters and ethers of dicyclopentadiene [5] were treated with different amines according to the reaction scheme. Triethylamine yielded quaternary ammonium salts directly. Alternatively, after reaction with diethylamine or morpholine, the isolated siloxanyl-modified tertiary amines were also converted to quaternary species. To obtain anionic surfactants, the halogenated precursors were initially reacted with n-propylamine. In subsequent reaction steps the secondary amines formed were converted with maleic anhydride into amides, and the remaining acid functions neutralized. Course and rate of each single reaction strongly depended on the structure of the initial ester or ether compound and the amine applied. The basicity of the latter played a less important role [6]. 

Imino- and iminiumtriflates could be generated from secondary or tertiary amides with trifluoromethanesulfonic anhydrate in the presence of pyridine at low temperatures. Subsequent treatment with hydrogen sulfide immediately gives rise to the corresponding secondary or tertiary thioamides at low temperature. This reaction affords both aliphatic as well as aromatic thioamides (Scheme 9).30... 

The applications of polyoxometalates in catalytic dehalogenation of halocar-bons have been succinctly reviewed by Hill and coworkers [188]. This reaction involves the photocatalytic transformation of organic halides coupled with the oxidation of sacrificial organic reductants (secondary alcohols or tertiary amides) (Eq. (9)) [189, 190] ... 

Alkyllanthanum triflates, RLa(OTf)2. Alkyl- or aryllithium reagents are known to cleave tertiary amides to ketones, but yields are low because of a further reaction with the ketone to form a tertiary alcohol. The amides can be cleaved to ketones in high yield by reaction with alkyl- or aryllanthanum triflates, generated in situ by reaction of RLi or ArLi with La(OTf), (equation I). 

Cyclobutanones (11, 560-561). Ketenimium salts are more reactive than ke-tenes in [2 + 2] cycloadditions with alkenes to prepare cyclobutanones. The salts are readily available by in situ reaction of tertiary amides with triflic anhydride and a base, generally 2,4,6-collidine. The cycloaddition proceeds satisfactorily with alkyl-substituted alkenes and alkynes, but not with enol ethers or enamines.1... 

The problem of the nucleophilicity of amides in glycosylation reactions is not limited to the sulfoxide method and has been shown to result in the formation of glycosyl imidates from intermolecular reaction with activated donors. It appears that this problem may be suppressed by the prior silylation of the amide [348,349]. Accordingly, it may be sufficient to operate the sulfoxide method with an excess of triflic anhydride when amides are present so as to convert all amides into O-triflyl imidates, which are then hydrolyzed on work-up. Despite these problems, several examples have been published of successful sulfoxide glycosylation reactions with acceptors carrying remote peptide bonds [344,345] and with donors coupled to resins via amide-based linkages [346,347], with no apparent problems reported. Sulfonamides and tertiary amides appear to be well tolerated by the sulfoxide method [340,350],... 

Scheme 55, Eq. 55a) [119]. A plausible mechanism is depicted in Scheme 55 and involves radical addition of the 2-tetrahydrofuryl radical to the aldehyde followed by a rapid reaction of the alkoxyl radical with Et3B. Triethylborane has a crucial role since by reacting with the alkoxyl radical it favors the formation of the condensation product relative to the -fragmentation process (back reaction). A similar reaction with tertiary amines, amides and urea is also possible (Eq. 55b) [120]. 

A tertiary homopropargylic alcohol could also be prepared by treatment of ethyl acetate with two equivalents of B-allenyl-9-BBN. However, the reaction proceeded slowly and was not general for other esters, which proved to be unreactive, as were tertiary amides and alkyl halides. However, homopropargylic amines could be prepared in high yield and with minimal allenic byproduct through allenylboration of imines with B-allenyl-9-BBN (Eq. 9.24). 

The hydrochloric acid is removed by the strong tertiary base, methyldibutylamine, which has a soluble hydrochloride. In B.P. s 631,549 and 652,981 it was shown that compound (II) could be prepared by the action of dimethylamine on P0C13 in chloroform containing an excess of methylbutylamine. The further reaction with water is very conveniently carried out in the same system by adding an excess of aqueous sodium hydroxide solution. The chloroform layer contains the tertiary amine and (I). The solvent and amine are stripped off leaving the product. Side reactions take place, and the commercial product also contains some triphosphoric pentadimethylamide (I A) and smaller amounts of other phosphoric amides. The compound (I A) is itself also a valuable systemic insecticide. 

The catalysed two-phase alkylation of carboxamides has the advantages of speed and simplicity over the traditional procedures and provides a valuable route to secondary and tertiary amines by hydrolysis or reduction of the amides, respectively. The procedure appears to be limited, however, to reactions with primary haloalkanes and dialkyl sulphates, as secondary haloalkanes are totally unreactive [6, 7]. The use of iodoalkanes should be avoided, on account of the inhibiting effect of the released iodide ion on the catalyst. Also, the A-alkylation reaction is generally susceptible to steric effects, as seen by the low yields in the A -cthylation of (V-/-butylacetamide and of A-ethylpivalamide [6]. However, the low steric demand of the formyl group permits A,A-dialkylation and it is possible to obtain, after hydrolysis in 60% ethanolic sulphuric acid, the secondary amines having one (or, in some cases, two) bulky substituent(s) [7]. 

The reluctance of tertiary amides to undergo hydrolysis, especially those produced in the Birch reduction-alkylation with a quaternary center next to the carbonyl group, has inspired the development of a variety of intramolecular transacylation reactions as illustrated by the cleavage of the SEM ether in 16... 

Mechanisms of the manifold reactions of a-dialkylamino alkyllithium intermediates R(Me2N)CLiNu, formed when tertiary amides (RCONMc2) react with PhMc2SiLi followed by a second lithium reagent NuLi, have been discussed. The formation of diverse products following 1 1 insertion of an isonitrile RNC into the Li-C bond of LiCH(SiMc3)2 has been discussed. ... 

These reactions also provide us with a convenient way of making secondary and tertiary amines. Thus, a primary amine may be converted into an amide by reaction with an acyl chloride, then LAH reduction... 

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