Passerini reaction acid components

Like the Strecker synthesis, the Ugi reaction also involves a nucleophilic addition to an imine as the crucial step in which the stereogenic center of an a-amino acid derivative is formed4. The Ugi reaction, also denoted as a four-component condensation (A), is related to the older Passerini reaction5 (B) in an analogous fashion as the Strecker synthesis is to cyanohydrin formation. In both the Ugi and the Passerini reaction, an isocyanide takes the role of cyanide. 

The first MCR involving isocyanides (IMCR) was reported in 1921 with the Passerini reaction (P-3CR) [8], and over the years these reactions have become increasingly important and have been highlighted in several publications (for discussions, see below). Another older MCR which leads to (non-natural) a-amino acids is the Bucherer-Bergs reaction (BB-4CR), which was first reported in 1929 [9]. This type of transformation is closely related to the Strecker reaction, with C02 employed as a fourth component. 

Four-component condensation (4CC) of carboxylic acids, C-isocyanides, amines, and carbonyl compounds to afford diamides. Cf. Passerini reaction. 

The amide (typically a tertiary one) or the ester derived from the carboxylic acid component in classical Ugi and Passerini reactions can undergo nucleophilic S Ac by various nucleophiles [54], These post-condensation reactions, however, do not... 

Because of the retained isocyano functionality, the dihydropyridone MCR product 85 can be used in various follow-up (multicomponent) reactions. For example, the Passerini reaction between 85, a carboxylic acid, and an aldehyde or ketone produces a series of dihydropyridone-based conformationally constrained depsipeptides 86 [171]. The subsequent Passerini reaction could also be performed in the same pot, resulting in a novel 6CR toward these complex products containing up to seven points of variation. Reaction of 85 with an aldehyde or ketone and amine component resulted in the isolation of dihydrooxazolopyridines (DHOPs, 87) [172] via a similar approach as the 2,4,5-trisubstituted oxazole variant toward 42 reported by Tron and Zhu (Fig. 15) [155]. The corresponding DHOPs (87), which... 

Finally a fourth way to achieve asymmetric induction in the Passerini reaction is by way of a chiral catalyst, such as a Lewis acid. This approach is not trivial since in most cases the Lewis acid replaces the carboxylic acid as third component, leading to a-hydroxyamides or to other kinds of products instead of the classical adducts 7 (vide infra). After a thorough screening of combinations of Lewis acids/ chiral ligands, it was possible to select the couple 13 (Scheme 1.6), which affords clean reaction and a moderate ee with a model set of substrates [17]. Although improvements are needed in order to gain higher ees and to use efficiently sub-stoichiometric quantities of the chiral inducer, this represents the first example of an asymmetric classical Passerini reaction between three achiral components. 

When a mineral or Lewis acid replaces the carboxylic component in the Passerini reaction, the final products are usually a-hydroxyamides. Also in this case, when chiral carbonyl compounds or isocyanides are employed, the asymmetric induction is, with very few exceptions, scarce [18, 19]. For example, the pyridinium trifluoroacetate-mediated reaction of racemic cyclic ketone 14 with t-butyl isocyanide is reported to afford a single isomer [19] (Scheme 1.7). This example, together with those reported in Schemes 1.3 and 1.4, suggests that high induction may be obtained only by using rigid cyclic or polycyclic substrates. 

Tandem Passerini/Knoevenagel reactions were also performed by employing 2-nitrophenylacetic acid as the acid component to give the butenolides 65 that were reduced to the intermediate amines 66, which immediately cyclized to give indoles 67 in very high yields via a ring-switching process (Scheme 2.24) [52],... 

Davidson s synthesis consists of the cydization of a-acyloxyketones with ammonia or ammonium acetate to give 2,4,5-trisubstituted oxazoles. The Passerini reaction between arylglyoxals, carboxylic acids, and isocyanides afforded N-substituted 2-acyloxy-3-aryl-3-oxopropionamides 83 in high yields. Upon heating with an excess of ammonium acetate in acetic acid, compounds 83 were cydized to N,2,4-trisubstituted oxazole-5-carboxamides 84 in fair yields [59]. A large number of a-acyloxy-jS-ketoamides can be prepared by changing the reaction components, so the method provides straightforward access to a variety of oxazole-5-carboxamides (Scheme 2.30). 

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... 

L. Banfi and co-workers utilized the Passerini three component reaction to prepare a 9600 member hit generation library of nor-statines. " ° These compounds are potential transition state mimetics for the inhibitors of aspartyl proteases. The authors produced the library by starting out from eight A/-Boc-a-aminoaldehydes, twenty isocyanides and sixty carboxylic acids. The key Passerini reaction occurred under mild conditions. This transformation was followed by removal of the Boc protecting group and acyl transfer. Three representative examples of the library are shown. 

Ugi reaction Also called the Ugi four-component condensation (4CC) in which an isonitrile is treated with a carboxylic acid and an aldehyde or a ketone in the presence of ammonia or an amine to give a bis-amide. Related to the Passerini reaction. 

Application of the Davidson oxazole synthesis to products of the Passerini reaction has expanded the usefulness of this well-known route <91LAll07>. The a-acyloxy ketones or a-acyloxy -keto esters employed in the Davidson synthesis are not readily available. However, the use of arylglyoxals as the carbonyl component of the Passerini reaction, along with cyclohexyl isocyanide and carboxylic acids, gives a wide variety of iV-cyclohexyl-2-acyloxy-3-aryl-3-oxopropionamides (151). Reaction of these intermediates with ammonium formate in acetic acid affords A -cyclohexyl-2,4-diaryl-5-oxazolecarboxamides (152) in fair yields (Scheme 69). 

We have developed a (salen)AlCl (141 (-catalyzed enantioselective three-component Passerini reaction (Scheme 5.44) [87]. In order to overcome the catalyst turnover dilemma, using a chiral catalyst with only one coordination site available was the working hypothesis of our research, and this turned out to be rewarding. A variety of non-chelating aldehydes, including a-branched compounds, carboxylic acids, and isocyanides participated in this catalytic enantioselective process to afford Passerini adducts in good to excellent ee. Unfortunately, aromatic aldehydes were not acceptable as substrates under these catalytic conditions. The similar catalyst (salen)AlMe... 

In 1921 Passerini reported the synthesis of the a-acyloxycarboxamides (6a-e) according to the scheme below. The formation of a-acyloxycarboxamides by a three-component reaction of carboxylic acids (3), carbonyl compounds (4) and isocyanides (5) is the proper Passerini reaction. The reactions described in Sections 4.6.2.2-4.6.2.4 are closely related to the Passerini reaction we call them reactions of the Passerini type. ... 

The Passerini reaction and the formation of a-hydroxycarboxamides (24) may compete with the Ugi reaction. When carboxylic acids (3) and carbonyl compounds (4) with electron-withdrawing groups are subjected to 4CC in nonpolar solvents such as dichloromethane, the Passerini reaction may compete strongly. Also, with bulky components the Passerini reaction becomes a serious side reaction of the Ugi reaction. ... 

A truncated Passerini reaction between various aldehydes or ketones and a-alkyl-a-isocyanoacetamides in toluene at 70 °C in the presence of LiBr afforded 2,4,5-trisubstituted oxazoles in satisfactory yields (38-98%). For instance, stereoselective nucleophilic addition of 110 to A,A-dibenzylphenylalanal 111 led predominantly to the awfi-adduct 112 (dr = 9 1) which was smoothly converted after acidic hydrolysis of the oxazole ring into the dipeptide 113, containing an a-hydroxy-P-amino acid (norstatine) component <04T4879>. 

Marcaccini and co-workers used the Passerini reaction to prepare N-substituted oc-acyloxy (B-ketoamides 382, valuable intermediates for their synthesis of 2,4-diaryl-5-oxazolecarboxamides 383 (Scheme 1.105). In their work, the authors used an arylglyoxal as the carbonyl component, whereby only the aldehyde was reactive. For example, condensation of phenylglyoxal (R = H), 2-chloroben-zoic acid (Rj = 2-Cl) and cyclohexylisocyanide produced 382 in excellent yield. 

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]. 

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. 

Fourthly, no intermediates have been isolated from Passerini reactions that used conventional substrates. However, the reaction of 1-isocyanocyclohexane carboxylic acid (15) and acetone resulted in the isolation of oxazolin-5-one 16. Due to geometrical constraints 16 cannot easily undergo the 0— 0 acyl migration" supporting the likelihood of an iso-imide intermediate for the three-component Passerini reaction. 

The mechanism of Passerini reactions promoted by a Lewis acid has not been as extensively studied as the mechanism of the classic reaction. However, two precepts in regard to the component substitution should be noted. First, metal and metalloid-based Lewis acids are typically much more powerful acids than common carboxylic acids and second, as a consequence, nucleophiles (i.e., Lewis bases) will be both lower in strength and concentration under these conditions. Most of the differences in mechanism are inferred from indirect evidence, relying upon insight about the origins of observed products and side reactions, all of which logically proceed from a nitrilium intermediate. 

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. 

Alternatively, cyclic enol ethers can serve as the electrophile in Passerini-type reactions as they undergo protonation by strong Bronsted acids to produce oxocarbeniums as the reactive partner. More recently, acyl cyanides have been demonstrated to participate as the carbonyl component in Passerini reactions, giving a-acyloxy-a-cyano amides in good yields. ... 

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