Isonitriles, Passerini reaction

Besides numerous applications of a-acidic isocyanides in classical IMCRs, such as the Ugi and Passerini reaction, the presence of an a-acidic proton enables other reaction paths and, subsequently, the development of novel MCRs. Here we focus on novel MCRs involving a-acidic isonitriles that have been described in literature since 1998. 

A related reaction is the addition of isonitriles 75 to aldehydes 1 (the Passerini reaction). Denmark has demonstrated that SiCU, upon activation by a chiral Lewis base, which increased the Lewis acidity of the silicon (vide supra Scheme 7.14), can mediate this reaction to produce a-hydroxy amides 77 after aqueous work-up (Scheme 7.16). Phosphoramide 60 was employed as the chiral Lewis-basic catalyst [74]. Modification of the procedure for hydrolysis of 76 gives rise to the corresponding methyl ester (rather than the amide 77) [74]. (For experimental details see Chapter 14.5.5). 

Table 4.5 Ugi and Passerini reactions with glycosyl isonitriles...

The reaction of -halo carbonyl compounds with primary amides is appropriate for oxazoles containing one or more aryl groups . Ureas form 2-aminooxazoles. Formamide can be used resulting in a free 2-position in the oxazole. A convenient synthesis of 5-substituted-4-cyanooxazoles 223 is based on the condensation of -hydroxy—cyanoenamines 222 with trimethyl orthoformate (Scheme 109). The cyanoenamine intermediates 222 are derived from Lewis acid-catalyzed Passerini reactions between /-butyl isonitrile and aldehydes <2002S1969>. 

A few years later Passerini, developed a new 3CR towards a-acyloxy amides 9 which are formed by reacting an aldehyde or ketone 6, a carboxylic acid 8 and an isocyanide 7 (Scheme 2) ([25] and see for review [26]). Since the first synthesis of isocyanides (formerly known as isonitriles [27]) in 1858, the Passerini 3-component reaction (P-3CR) was the first MCR involving these reactive species. It has become one of the renowned examples of an important subclass of MCRs, the isocyanide-based MCRs (IMCRs). Especially important for the Passerini reaction, but also for a lot of other IMCRs, is the ability of isocyanides to form a-adducts, by reacting with nucleophiles and electrophiles (at the carbon atom). The nucleophilic... 

Marquarding, D., Gokel, G., Hoffmann, P., Ugi, I. Passerini reaction and related reactions. Isonitrile Chem. 1971,133-143. 

Passerini reaction The formation of an a-acyloxyamide when an isonitrile is treated with a carboxylic acid and an aldehyde or ketone. Related to the Ugi reaction. 

Isonitriles can be used for a few useful synthetic transformations. The Passerini reaction is a convenient route to amide esters. When propionic acid was heated with acetone and fcrt-butylisonitrile, for example, the product was a-propanoyloxy amide 9. A useful modification of the Passerini reaction used trifluoroacetic acid rather than a normal aliphatic carboxylic acid. When a-phenoxyacetaldehyde (10) reacted with fcrf-butylisonitrile and trifluoroacetic acid (TFA), 11 was formed. Hydrolysis of this trifluoroacetyl ester with aqueous sodium carbonate led to isolation of the a-hydroxyamide (12) in 69% yield. This modification has the advantage that hydrolysis conditions for trifluoroacetate esters are milder than for normal esters. 

The condensation of a carbonyl compound with an isonitrile usually takes place in the presence of a carboxylic acid to give carboxamides (Passerini reaction) and plays a central role in combinatorial chemistry. Activation of the carbonyl group can be achieved by TMSOTf (eq 58), although higher yields can be obtained with the system Zn(OTf)2/TMSCl. ... 

The IBX-mediated oxidative Ugi-type multicomponent reaction of tetrahydroisoquinoUne with isocyanides and carboxylic acids affords the nitrogen- and carbon-functionalized tetrahydroisoquinolines 867 in good to excellent yields [1184]. Likewise, the three-component Passerini reaction of an alcohol, carboxylic acid and an isonitrile in the presence of IBX affords the corresponding a-acyloxy carboxamides 868 in generally high yields (Scheme 3.347) [1185]. 

This reaction was first reported by Hofmann in 1868. It is the synthesis of isonitriles (also known as isocyanides) from primary amines and chloroform in the presence of alkali and is known as the Hofmann isonitrile synthesis, Hofmann carbylamine reaction, or Hofmann carbylamine synthesis. This reaction has been used to test the presence of primary amines from the order of isocyanides. Alternatively, the isonitriles can be prepared by means of the treatment of formamide of primary amines with toluenesulfonyl chloride" or phosphorus oxychloride (POCls)." Currently, the isonitriles have gained much attention in organic synthesis because of their application as versatile building blocks for heterocycles and in multicomponent reactions to generate combinatorial libraries, such as that in the Passerini reaction and Ugi reaction ... 

The novel mode of Lewis-hase activation of Lewis acid was also applied hy Denmark to the Passerini reaction, the addition of isonitriles 21.119 to aldehydes 21.4 (Scheme 21.17). This reaction produced a-hydro g amides 21.121 after aqueous workup. Phosphoramide 21.104 was employed as the chiral Lewis-hasic catalyst.Modification of the procedure for hydrolysis of 21.120 gives rise to the corresponding methyl ester (rather than amide 21.121). ... 

The Passerini reaction describes the coupling of three components, an aldehyde or ketone 1, an isonitrile 2, and a carboxylic acid 3, to form an a-acyloxyamide 4. The reaction is typically performed at high concentration, in organic solvents of low polarity (as permitted by the solubilities of the starting materials) at or below room temperature. In many cases, the a-acyloxyamides precipitate from solution as the reactions proceed and a simple filtration of the crude reaction provides the desired product. 

In the second communication, Passerini also determined that the addition of hydrogen peroxide was unnecessary and, to an extent, deleterious as it mediated the decomposition of /7-isonitrileazobenzene. The formation of a-acyloxyamides from isonitriles, carboxylic acids and ketones or aldehydes subsequently became known as the Passerini reaction or the Passerini multicomponent reaction. The process is sometimes denoted as P-3CR according to Ugi s classification of multicomponent reactions (MCR). ... 

For a brief period of time it was thought that the TiCU-promoted Passerini reaction occurred via a mechanism where a nitrilium adduct did not play any significant role. This thinking was based on some initial evidence that isonitriles inserted into Ti-Cl bonds and formed titanium imidochlorides and that these species were incorporated into the mechanism as intermediates. However, subsequent FT-IR and X-ray crystal structure data strongly suggested that isonitriles do not insert into... 

The Passerini reaction is normally a sluggish reaction, often performed over several days. Therefore, an important consideration is the relatively low reactivity of the component substrates. Electronic or steric elements that might further retard the reaction rate will predictably give lower yields and substantially more side products. Conversely, more reactive carbonyl compounds such as chloral can be attacked by isonitriles and form a-hydroxyamides even in the absence of an acid component. 

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. ... 

With regard to the carbonyl component, the low nucleophilicity of isonitriles means that only the more active carbonyl substrates give Passerini products in good yields. Formaldehyde, aldehydes, and unhindered or activated ketones all have participated in successful Passerini reactions. On the contrary, a,P unsaturated aldehydes and ketones fail to give good yields of Passerini products under classical conditions, but the more strongly acidic mineral acid-based or Lewis acid-based protocols can result in good yields of the desired products. 

The synthesis of hydrastine (61) by Falck and Manna demonstrate that the amide product of the Passerini reaction could be used in a subsequent Bischler-Napieralski reaction as a method to produce isoquinolines. In their report, carboxybenzaldehyde derivative 62 was condensed with isonitrile 63 in 71% yield to provide amide 64. Cyclization (POCI3/CH3CN), reduction of the dihydroisoquinoline (Adam s catalyst/H2), and reductive alkylation with formaldehyde gave a diastereomeric mixture of a- and p-hydrastines in 58% overall yield from Passerini product 64. 

The Passerini and Ugi reactions are closely related. As shown in Scheme 10.45 (for the Passerini reaction), when an isonitrile (isocyanide) is allowed to react with... 

If in Chapter 7 different aspects about Ugi reaction have been discussed, in this chapter, we are going to disclose to the reader a vision about the new contributions regarding other crucial isonitrile-based multicomponent reaction (MCR) the Passerini reaction (P-3CR) discovered in 1921 [1], The traditional multicomponent Passerini reaction [2] is another isonitrile-based MCR that provides easy access to a-acyloxycarboxamides 4 in a one-pot synthesis involving an aldehyde 1, a carboxylic acid 2, and an isonitrile 3 (Scheme 8.1), which has been subject of intensive studies in the last decade [3], The importance of using isocyanides lays in its dual role as nucleophile and electrophile, and moreover, if R R, a new stereocenter could be created under asymmetric conditions. 

P. R. Krishna, G. Dayaker, P. V. N. Reddy, Tetrahedron Lett. 2006, 47, 5977-5980. Diastereoselective Passerini reactions using /)-toluenesulfonyhnethyl isocyanide (TosMlC) as the isonitrile component. 

T. Ngouansavanh, J. Zhu, Angew. ChettL Int. Ed. 2006, 45, 3495-3497. Alcohols in isonitrile-based multicomponent reaction Passerini reaction of alcohols in the presence of O-iodoxybenzoic acid. 

One could argue that this synthesis actually employs protective groups in the Passerini reaction by use of the formamide in 123. However, the formamide also allows dehydration to the desired isonitrile 126. This dual role offers considerable advantages in terms of both atom and step economy. The observed yields and selec-tivities of the MCR sequence were more than satisfactory and therefore allowed industrial application. 

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