Amines Experimental Procedure

The next seven references are cited not because of the experimental procedures described but because they indicate diversification in the types of enamines prepared and studied. Both Paquette (25) and Kasper 26) have condensed 2,5-methylene-l,2,5,6-tetrahydrobenzaldehyde (5-nor-bornene-2-carboxyaldehyde) (2) with several cyclic and open-chain aliphatic secondary amines. Kasper studied the ratio of endo to exo aldehyde formed upon hydrolysis of these enamines and the dihydro enamines. Paquette investigated the addition of sulfene to the enamines. -Fluoro-... 

Interestingly, photolysis of phenyl azide in liquid ammonia yields 3//-azepin-2-amine (39)35 (see experimental procedure in Houben-Weyl, Vol.4/5b, pi268). 

Primary aromatic amines (aniline, 3-toluidine, 4-anisidine and 3-chloroanilinc) react with 4 to give 2-[2-(arylamino)-l-cyanoviny]]benzimidazoles9 (see Houben-Weyl, Vol.E8c, p 314 with an experimental procedure).289... 

Other examples of esterification with trialkyloxonium salts have been reported.7,8 The present procedure offers the advantages that the reactive carboxylate ion is generated in sitv and that a low-boiling, nonaqueous solvent is employed, whereby the experimental procedure is considerably simplified. A related method has been reported which utilizes a hindered amine wdth dimethyl sulfate [Sulfuric acid, dimethyl csterj as the alkylating agent.9 The present procedure is carried out under somewhat milder conditions and avoids the use of highly toxic reagents. 

Miriyala and Williamson have described the synthesis of /i-kctocarboxam idcs from primary and secondary amines and 2,2-dimethyl-2H,4H-l,3-dioxin-4-ones as reactive a-oxoketene precursors (Scheme 6.158) [304], The experimental procedure involved heating a mixture of the dioxinone with 2-3 equivalents of the amine at ca. 180 °C for 1-3 min under solvent-free conditions in a sealed vessel by microwave irradiation. A small collection of 18 /3-ketocarboxamides was prepared in very high yields using this protocol. 

Photolysis or thermolysis of heteroatom-substituted chromium carbene complexes can lead to the formation of ketene-like intermediates (cf. Sections 2.2.3 and 2.2.5). The reaction of these intermediates with tertiary amines can yield ammonium ylides, which can undergo Stevens rearrangement [294,365,366] (see also Entry 6, Table 2.14 and Experimental Procedure 2.2.1). This reaction sequence has been used to prepare pyrrolidones and other nitrogen-containing heterocycles. Examples of such reactions are given in Figure 2.31 and Table 2.21. 

Indeed, there were those who described the azide coupling method as racemization-free. [15l However, this viewpoint proved to be overly optimistic. In 1970, Sieber reported that during a synthesis of calcitonin M by the azide method, significant epimerization occurred during two of the segment condensation steps in one of these reactions 40% of the epimerized product was observed. 16 There is a crucial detail in the experimental procedure here. The workers used tert-butyl nitrite to convert a peptide hydrazide into a peptide azide, but did not isolate the azide as was typical for research at that time. Instead, they neutralized the active intermediate in situ with DIPEA and added the amino segment for acylation. This demonstrates another important theme in the control of epimerization, the presence of a tertiary amine in the reaction mixture, even if only as a neutralization equivalent, can result in the formation of epimerized products. Indeed, most observations of racemization during... 

Non-activated aryl bromides (but not fluorides) can be used as substrates for palla-dium(0)-catalyzed aromatic nucleophilic substitutions with aliphatic or aromatic amines. These reactions require sodium alcoholates or cesium carbonate as a base, and sterically demanding phosphines as ligands. Moreover, high reaction temperatures are often necessary to achieve complete conversion (Entries 7 and 8, Table 10.4 Experimental Procedure 10.1). Unfortunately, the choice of substituents on the amine... 

As in the case of Boc protection, the Fmoc group is not usually introduced on solid phase, but rather in solution, by the use of an activated Fmoc derivative (e.g. the chloroformate Fmoc-Cl or O-Fmoc-.V-hydroxysuccinimide, Fmoc-OSu) and aqueous base (Experimental Procedure 10.3)., V-/ lkylamino acids bound to cross-linked polystyrene have been Fmoc-protected by treatment with Fmoc-Cl (4 equiv.) and DIPEA (6 equiv.) in DCM for 2 h [132,259], Primary amines on insoluble supports can also be converted into Fmoc derivatives under these conditions [260]. 

Isothiocyanates can be prepared from support-bound primary amines by treatment with thiophosgene [14] or synthetic analogs thereof (Entry 5, Table 14.2). In an alternative two-step procedure, the amine is first treated with CS2 and a tertiary amine to yield an ammonium dithiocarbamate, which is subsequently desulfurized with TsCl or a chloroformate (Entry 6, Table 14.2 Experimental Procedure 14.1). Highly reactive acyl isothiocyanates have been prepared from support-bound acyl chlorides and tetra-butylammonium thiocyanate (Entry 7, Table 14.2). These acyl isothiocyanates react with amines to give the corresponding 7V-acylthiourcas, which can be used to prepare guanidines on insoluble supports (Entry 6, Table 14.3). 

Experimental Procedure 14.1 Conversion of polystyrene-bound primary aliphatic amines into isothiocyanates [26]... 

Wang resin bound 4-nitrophenyl carbonate is a convenient intermediate for the attachment of amines to polystyrene as carbamates (see Experimental Procedure 14.2). Aliphatic amines [82-87], ammonia [88], and amino acids [89] react exothermically with this support, whereas anilines generally require catalysis and/or long reaction times (Entry 3, Table 14.7). For the immobilization of anilines as carbamates, Wang resin derived chloroformate [90-92] generally leads to better results than resin-bound 4-nitrophenyl carbonates. Amidines also react with polystyrene-bound 4-nitrophenyl carbonates to yield /V-alkoxycarbonyl amidines (Section 3.9 [93-95]). Support-bound alkoxycarbonyl hydrazines can be prepared by treating polystyrene-bound phenyl carbonates with hydrazine [96-98]. 

The p-sulfanyl amides 28 are synthesized from N-protected amino acids 24 via amino alcohols 25, which are converted into (5-acetylsulfanyl amides 26 by a Mitsunobu reaction. The (5-amine disulfide 27 is subsequently coupled with a variety of carboxylic acids, followed by reduction with tributylphosphine in aqueous THF in the presence of pyridine to produce the free thiol 28 (Scheme 5).1211 Detailed experimental procedures for these compounds have not been reported. 

The phenolic group is activating and ortho-para directing. The electrophilic substitution reactions in the nucleus in (a) nitrosation and nitration (b) halogenation and (c) acylation and alkylation, are therefore particularly facile, and various experimental procedures need to be adopted to control the extent of substitution (cf. substitution reactions of aromatic amines and their acylated derivatives, Sections 6.6.1 and 6.6.2, pp. 906 and 916 respectively). 

Experimental Procedure. The resin is washed with appropriate solvents and a small portion (ca. 1-5 mg) is transferred to a small glass tube. To this tube are added three drops of each of the reagent solutions A and B. The tube is then heated at 100° for 3 min. A negative test, indicating the absence of free primary amines, is communicated by a yellow or orange-pink solution and naturally colored beads. A positive test is indicated by a dark blue or purple solution and beads. Variations in the darkness of the solution reflect variations in amine concentration while variations in... 

Experimental Procedure. The resin is washed with MeOH and a small portion (1-3 mg) is transferred to an Eppendorf tube and suspended in DMF. To this tube is added 1 drop of each of the above solutions. The solution is left for 5 min at room temperature. The resin is washed extensively with DMF. The presence of free amines is indicated by orange or red beads. 

The proline-catalyzed direct asymmetric a-amination of aldehydes was reported in 2002 by both List [46] and j0rgensen [47]. As shown in Scheme 4.27 a variety of azodicarboxylates 58 can be added to aldehydes, affording the a-aminated products 59 in very good yields and with excellent ee. The experimental procedures are, furthermore, very convenient. The primary addition products 59 are configuration-ally unstable and are usually either reduced to the corresponding alcohols 60 (e.g. 

General Experimental Procedure. A mixture of the amine, 0.1 mole in 250 cc. of absolute alcohol, with 10 g. of sulfuric acid and 28 g. of arseni-ous chloride, cooled to 0°, is diazotized with a saturated aqueous solution of the calculated amount of sodium nitrite (starch-iodide end point). Then, and not before, 1 g. of cuprous bromide is added the mixture is thoroughly stirred, warmed to 60° until no more nitrogen is evolved, and then distilled with steam. The separated arsonic add is recrystallized. 

Groups R studied were various alkyl groups, phenyl, trimethylsilyl and phenylthio groups. The yields depend strongly upon the method by which 98 is generated and on the reaction conditions in general. Only one detailed experimental procedure (151) is available and certain yields were assayed by the NMR or by hydrolysis 170). It can be concluded that this approach is a valuable extension of electrophilic amination but thus far it is of only limited value for the preparation of ynamines. 

Enamines can be reduced to the corresponding saturated amines by treatment with formic acid. A very simple experimental procedure can be used in which formic acid is added to the neat enamine at such a rate that foaming due to evolution of carbon dioxide can be kept under control. The reduction of the morpholine enamine from camphor was studied in a two-level factorial design in order to determine whether or not an excess of formic acid should be used and at which temperature the reaction should be run. 

Examples of off-bead yield estimation that do not require cleavage include reactions where new species are stoichiometrically formed in solution, and their quantification provides an indirect, but accurate, yield estimation of the SPS step. The classical Fmoc deprotection of amines in peptide synthesis is a widely used example. In a typical experimental procedure, the beads are treated with a 20% DMF solution of piperidine at rt for 20 min and the solution is recovered together with the resin washings. The solution is brought to a constant volume (typically 10 mL) by addition of DMF, and the quantitation is carried out by reading the UV absorbance of the piperidine-... 

Synthesized from the corresponding pyrylium fluoride or tetrafluoroborate and the primary amine, RNHj (see experimental procedures in text). 

---