Unprotected primary amines

After a substantial exploratory chemistry involving other oxidants, such as Swern, Ac20/DMS0, NaOCl, Al(Or-Bu)3/acetone, 5% TPAP/NMO and P205/DMS0, it was found that an Omura-Sharma-Swern oxidation was unique providing a 88% yield of the desired ketone, with no interference from the unprotected primary amine. 

The best substrates for an//-selective reduction appear to be the unprotected primary amine hydrochlorides, followed by their rV-monoalkylated derivatives (e.g., d.r. >95 <5 for... 

Unprotected primary amines serve as efficient directing groups in the cationic ruthenium(II)-catalyzed oxidative coupling of various benzy-lamines or heteroarylmethylamines with internal alkynes (Eq. (7.40)) [49]. A variety of isoquinolines, benzoisoquinolines, and fused heteroaryl[2,3-c] pyridines were generated from this catalytic C-H functionalization process. In some cases, products with insertion of two alkynes were also isolated. 

In order to explore the generality of this new domino reaction the conversion of various primary amines with 2-341 and the cyclohexane analogue was investigated (Scheme 2.81). For example, the reaction proceeds with high yields when benzyl- or (2-phenylethyl)amine are used (entries 1 and 2). In comparison, sterically more hindered amines such as 2-butylamine produced much lower yield (entry 4) Furthermore, the reaction tolerates other functional groups, such as an unprotected hydroxyl group (entry 5), and variation of the enone ring size is possible (entries 6 and 7). More recent results have revealed that the addition of Sn(OTf)2 or In(OTf)2 makes the transformation more reliable. 

Isopropenyl esters of N-protected amino acids. In the presence of the Ru(II) catalyst, Cbo- or Boc-amino acids add to propyne at 100° to provide isopropenyl esters in 55-85% yield with no racemization. Unprotected amino acids do not add to the alkyne. These esters react with primary amines at room temperature in ethyl acetate to afford amides in 75-90% yield. 

Under the conditions used in peptide synthesis, unprotected aliphatic hydroxy groups can undergo two types of side reactions they can be acylated or dehydrated, the latter leading to dehydroamino acids. The hydroxy group of serine is a primary alcoholic function and therefore exhibits the highest reactivity. The secondary alcoholic functions of threonine, hydroxyproline, (3-phenylserine, hydroxynorvaline, and hydroxynorleucine, as well as of other noncoded amino acids, are less reactive and thus more suited for use in the unprotected form. The aromatic hydroxy group of tyrosine is more acidic than the ahphatic hydroxy groups nevertheless, it can be acylated to form esters. These are active esters which in turn can react with primary amines to form amide bonds. 

The formal total synthesis of roseophilin was accomplished by B.M. Trost et al. who used the Paal-Knorr pyrrole synthesis to install the trisubstituted pyrrole moiety.The 1,4-diketone substrate was reacted with various primary amines to obtain A/-substituted pyrroles. The best yield was obtained when benzylamine was used as the amine component, but the A/-deprotection of the product proved to be problematic. This forced the researchers to prepare the otherwise unstable A/-unprotected pyrrole under carefully controlled conditions and protect it immediately with SEM-chloride. 

Heating a primary amine with dibenzylformamide-dimethyl acetal in CH3CN gives the formamidine in 49-99% yield. A, A -Dibenzyl chloromethylene iminium chloride is a more reactive reagent that can be used at lower temperatures with excellent yields for amines not bearing unprotected alcohols. It is cleaved by hydrogenolysis (Pd(OH)2, MeOH, H2O, Hj, 52-99% yield). ... 

A similar approach was reported by Wang et al. [60] a year later, consisting of a double Michael reaction of simple oxindoles with dienones. The reaction was simply catalyzed by a cinchona-based primary amine catalyst (XIII). The reaction afforded the final spirocyclic oxindoles in good yields and excellent enantioselectivities when diaryldienones were used. The only limitation of the reaction was the need to use carbamate-protected oxindoles thus, the use of unprotected or benzylated oxindoles is ineffective for this transformation. In 2010, the same research group proposed a similar approach [61]. They performed a reaction with an oxindole derivative decorated with a ketone in position 3 of the oxindole and acyclic enones. This reaction was catalyzed by chiral primary amines, affording the final spirooxindoles in good yields and enantioselectivities. 

Because of the inherently low reactivity of most components, a very large number of other functional groups are tolerated in the reaction. Functionalities that are not compatible within the Passerini reaction include those that are reactive toward activated or unhindered aldehydes or ketones under the mildly acidic conditions, lest such reactivity be competitive with the slow Passerini reaction. As a direct consequence, unprotected primary or secondary amines are not compatible because of the facility by which they form imines and iminiums by acid-catalyzed condensation. Iminiums, themselves are susceptible to nucleophilic attack by isonitriles and the formation of a-acylamino amides by this process is called the Ugi reaction (see chapter 3.6). In reactions where the Ugi and Passerini reactions are possible competitive processes the Ugi products are generally favored to the detriment of any Passerini products. ... 

Thus, in a model reaction, valine methyl ester hydrochloride 732 was reacted with triphosgene in the presence of diisopropylethylamine (DIEA) in dichloromethane at room temperature for 30 min to give the intermediate 733. Serine benzyl ester hydrochloride 734 and DIEA in dichloromethane were then added over a period of 10 min. Product 735 was obtained in 89% yield as a result of a typical sequential, three-component reaction. The reaction can be successfully applied to various other amines bearing multiple functionalities, and exhibits high selectivity for N-nudeophiles amines (primary and/or secondary) bearing an unprotected primary or secondary hydroxy group can be used directly (85-88% yield). 

Reductive Amination Methodology for Synthesis of Primary Amines from Unprotected Synthons... 

Some imidoyl halides have been used to effect amide-bond formation between acids and primary amines. Owing to the highly selective nature of the reagents, peptides can be obtained from unprotected a-amino-acids although, if possible, it is best to protect the amino group of the first amino-acid. The sulphuryl halide SO2CIF can also be used to directly couple acids and amines, under mild conditions. ... 

Table 3 summarizes the scope and limitation of substrates for this hydrogenation. Complex 5 acts as a highly effective catalyst for functionalized olefins with unprotected amines (the order of activity tertiary > secondary primary), ethers, esters, fluorinated aryl groups, and others [27, 30]. However, in contrast to the reduction of a,p-unsaturated esters decomposition of 5 was observed when a,p-unsaturated ketones (e.g., trans-chalcone, trans-4-hexen-3-one, tra s-4-phenyl-3-buten-2-one, 2-cyclohexanone, carvone) were used (Fig. 3) [30],... 

A convenient one-step transformation of primary and secondary amines into the corresponding unprotected guanidines using 4-bcnzy 1-3,5-dimcthyl-IH-pyrazole-l-... 

The other commercial stabilizer (UV-3), a hindered-amine type, is presumed to afford photochemical protection by functioning primarily as a free radical and/or oxygen scavenger (13). Thus protection should only occur in the primary substrate, the cellulose acetate film, and not in a secondary substrate such as the blue wool fabric. The results shown in Table II verified this assumption the AE values obtained, irrespective of the concentration of UV-3 used in the film, were within experimental error of those observed with the unprotected fabric. 

A convenient one-step transformation of primary and secondary amines into the corresponding unprotected guanidines using 4-benzyl-3,5-dimethyl-l/f-pyrazole-l-carboxamidine 90 and its polymer-bound variant were described <06S461>. 1,3-Dipolar cycloaddition of polymer-bound alkynes to azomethine imines generated in situ from N-aminopyridine iodides followed by aromatization of the cycloadducts gave polymer-bound pyrazolopyridines that were released from the resin as carboxylic acids with trifluoroacetic acid or as methyl esters with sodium methoxide <06JCO344>. 

Herbert and McNeil have shown that the appropriate 2-iodoindole can be carbonylated in the presence of primary and secondary amines to afford the corresponding 2-indole-carboxamides in 33-97% yield. Further application of this protocol leads to amide 344, which is a CCK-A antagonist (Lintitript) [400]. Carbonylation of unprotected 4-, 5-, 6-, and 7-bromoindoles with nucleophiles affords the corresponding amides, esters, and carboxylic acids [401]. 

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