Strecker three-component

Rhizopus delemar lipase ribonucleotide reductase ring-opening metathesis Strecker three-component reaction... 

Three basic types of MCRs can take place.MCRs of type I are equilibria that form mixtures of reactants, intermediate products, and final products, whereas the reactants and intermediate products of MCRs of type II equilibrate, but their final products are in practice formed preferentially and irreversibly. MCRs of type III are sequences of irreversible subreactions from the reactants toward their final products. Usually, only rather low yields of products are formed by MCRs of type I. In 1850, StreckerP introduced the formation of a-amino-substituted alkyl cyanides 3 from ammonia, hydrogen cyanide, and the corresponding carbonyl compound 1, via the cationic intermediate 2 (Scheme 1). The introduction of the Strecker three-component reaction (S-3CR), an MCR of type I, heralded the beginning of MCR chemistry. 

Officially, the history of MCRs dates back to the year 1850, with the introduction of the Strecker reaction (S-3CR) describing the formation of a-aminocyanides from ammonia, carbonyl compounds, and hydrogen cyanide [4]. In 1882, the reaction progressed to the Hantzsch synthesis (H-4CR) of 1,4-dihydropyridines by the reaction of amines, aldehydes, and 1,3-dicarbonyl compounds [5], Some 25 years later, in 1917, Robinson achieved the total synthesis of the alkaloid tropinone by using a three-component strategy based on Mannich-type reactions (M-3CR) [6]. In fact, this was the earliest application of MCRs in natural product synthesis [7]. 

Scheme 6.15 Representative N-acetyl-Strecker products resulting from the 9-catalyzed three-component acylcyanation reaction.

The Strecker reaction is a three-component reaction of an aldehyde (or ketone), ammonia (86, or another amine) and hydrogen cyanide (87, or equivalents) to give a-amino nitriles and, after hydrolysis, a-amino acids (Scheme 9.16). 

Scheme 9. Three-component Strecker synthesis with chiral zirconium binuclear catalyst 22 (Kobayashi and co-workers).

Alder, cyanation, allylation, Michael reaction, and Friedel-Crafts acylation). The same catalyst was also effective in three-component reactions such as Mannich-type reactions, Strecker, and quinoline-forming reactions. The polymer catalyst was recovered and reused many times without loss of activity (Eq. 31). 

Another application of high pressure in combinatorial chemistry has been reported by Matsumoto and Jenner. For the first time, uncatalysed, high-pressure (0.6 GPa) three-component Strecker synthesis of a-amino nitriles 202 was carried out in high yields by reacting aniline (200) with various ketones 201... 

This three-component coupling reaction, with its greater than 150 year history, continues to enjoy great utility. It is the most efficient synthesis of non-natural amino acids due to its generality, simplicity, and low cost. These attributes are particularly attractive to process chemists where the cost of goods is a key driver for the scale up and development of chemical matter. Initial studies around this reaction gave rise to racemic versions of the product. However, more recent examples of the Strecker reaction have focused on asymmetric variations to provide optically active a-aminonitriles or a-amino acids. 

The mechanism of the Strecker reaction has received considerable attention over its lifespan.4 The conversion of a carbonyl compound into an a-amino acid, by this method, requires a two-step process. The first step consists of the three-component condensation of cyanide and ammonia with the carbonyl compound 1 to produce an intermediate, a-aminonitrile 3. The second step involves the hydrolysis of the nitrile functional group to reveal the latent carboxylic acid 4. Whereas the second step is fairly straightforward and can be done under basic or acid conditions, the first step is more involved than one may expect. The widely accepted sequence for the first step is the nucleophilic addition of ammonia to the carbonyl carbon to produce the corresponding imine derivative 2. Once formed, this initial species is captured by the cyanide anion to generate the requisite a-aminonitrile 3. 

The present Strecker-type reactions were successfully applied to asymmetric reactions. In the presence of 10mol% Yb(OTf)3 and 100mol% 2,6-di-f-butyl-4-methyl-pyridine (DTMP), the three-component reaction of benzaldehyde, (i5,2/ )-(+)-2-amino-1,2-diphenylethanol, and TMSCN proceeded smoothly at -45°C, to afford the corresponding a-amino nitrile in an excellent diastereoselectivity. In the reaction using cyclohexanecarboxaldehyde, the selectivity decreased slightly ... 

Thus, Strecker-type reactions of aldehydes, amines, and Bu3SnCN were successfully performed using Sc(OTf)3 as a catalyst. The reactions proceeded smoothly in both organic and aqueous solutions to afford a-amino nitriles in high yields. It is noted that the experimental procedure is very simple just mixing the three components and Sc(OTf)3 in an appropriate solvent at room temperature. Moreover, complete recovery of the tin materials in these reactions has been achieved. While many useful tin reagents have been... 

A one-pot three-component synthesis of a-iminonitriles 866 via an IBX/tetrabutylammonium bromide-mediated oxidative Strecker reaction has been developed (Scheme 3.346) [1183]. This methodology was employed in a two-step synthesis of indolizidines via a microwave-assisted intramolecular cycloaddition of a-iminonitriles. 

The first multicomponent reaction was the Strecker reaction reported in 1850 by Adolf Strecker [241aj. It is a three-component coupling between carbonyl derivatives, amines, and cyanide source, such as hydrogen cyanide, to provide a-aminonitriles which constitute potent starting materials to achieve important a-amino acids by simple hydrolysis. The mechanism of the Strecker reaction involves the initial formation of an imine from condensation of the amine component to the carbonyl component, after which addition of the cyanide component to this imine intermediate follows. Although the first enantioselective, metal-catalyzed Strecker... 

Scheme 10.37 Three-component acyl-Strecker reaction catalyzed by thiourea.

A few drug discovery synthesis routes were used to diversify the thiohydantoin structures. The first route exploited a convergent concept where a three-component Strecker reaction of an amine, a ketone and trimethylsilyl cyanide was used to generate (he cyanoamine analog 24 (Scheme 1). Isothiocyanate prepared from the amine with thiophosgene was added to the cyanoamine to give thiohydantoin -imine 25 which was hydrolyzed to afford the desired thiohydantoins 26. 

Hao and colleagues disclosed a rapid total synthesis of ( )-tr onoliimine A via a Strecker/Houben-Hoesch sequence.The three-component Strecker-type reaction of 169, 170, and TMSCN was found to be effectively promoted by TMSOTf to furnish intermediate 171 this intermediate was unstable in basic or neutral environments and thus was treated directly with triflic acid at room temperature to effect the Houben-Hoesch cyclization and give ketone 172. Finally, the addition of hydrazine triggered deprotection of the amine and subsequent cyclization to furnish 173 (130L528). 

J. Jarusiewiez, Y. Choc, K. S. Yoo, C. P. Park, K. W. Jung, J. Org. Chem. 2009, 74, 2873-2876. Efficient three-component Strecker reaction of aldehydes/ketones via NHC-amidate palladium(II) complex catalysis. 

J. Choi, H. Y. Yang, H. J. Kim, S. U. Son, Angew. Chem. Int. Ed. 2010, 49, 7718-7722. Organometallic hollow spheres bearing bis(N-heterocyclic carbenej-palladium species catalytic application in three-component Strecker reactions. 

The Strecker reaction [48], discovered in 1850 [1], is the most practical and efficient tool for the preparation of a-amino acids [49] via the formation of a-aminonitriles (Scheme 10.15) [50]. This three-component coupling between an amine or its equivalent, a carbonyl compound (generally an aldehyde), and hydrogen cyanide or its alkaline metal cyanides can be also made enantioselectively through the use of both metal-based catalysts and chiral organocatalysts. 

This method is a simple and practical method for the synthesis of racemic a-aminonitriles through a one-pot, three-component Strecker reaction under mild reaction conditions. Reactions proceeded very efficiently at room... 

In this field, Najera and coworkers developed more recently a three-component Strecker reaction with TMSCN in the absence of solvent and catalyst, which could potentially be applied at an industrial level (Scheme 10.31) [91]. 

The first organocatalytic asymmetric three-component Strecker reaction was reported by List and Pan using Jacobsen s thiourea catalyst 75. Diverse a-aminonitriles 76 and 77 were formed in excellent yields and enantioselectivities from aliphatic and aromatic aldehydes, different amines, and acyl cyanides by using 5mol% of catalyst 75 (Scheme 10.33) [97]. 

Contemporaneously, an alternative organocatalytic asymmetric three-component Strecker reaction was described using a C2-symmetric chiral bisformamide 78 as efficient catalyst, furnishing a-aminonitriles 79 in excellent yields and good enantioselectivities (Scheme 10.34) [98]. However, some final adducts were obtained optically pure (>99% ee)... 

More recently, Ma and coworkers have developed an alternative route for the one-pot three-component Strecker reaction of ketones using Brpnsted acids as organocatalysts (Scheme 10.35). Although the methodology was extended to... 

SCHEME 10 J5 Chiral phosphoric acid-catalyzed three-component Strecker reaction of ketones. 

P. Fontaine, A. Chiaroni, G. Masson, J. Zhu, Org. Lett. 2008, 10, 1509-1512. One-pot three-component synthesis of a-iminonitriles by IBX/TBAB-mediated oxidative Strecker reaction. 

J.-B. Gualtierotti, X. Schumacher, P. Fontaine, G. Masson, Q. Wang, J. Zhu, Chem. Eur. J. 2012, 18, 14812-14819. Amidation of aldehydes and alcohols through a-iminonitriles and a sequential oxidative three-component Strecker reaction/ thio-Michael addition/alumina-promoted hydrolysis process to access P-mercaptoamides iiom aldehydes, amines, and thiols. 

F. Cruz-Acosta, A. Santos-Expdsito, P. de Armas, F. Garcia-Tellado, Chem. Commun. 2009, 6839-6841. Lewis base-catalyzed three-component Strecker reaction on water. An efficient manifold for the direct a-cyanoamination of ketones and... 

K. Iwanami, H. Seo, J.-C. Choi, T. Sakakura, H. Yasuda, Tetrahedron 2010, 66, 1898-1901. Al-MCM-41 catalyzed three-component Strecker-type synthesis of a-aminonitriles. 

For previous use of acetone cyanohydrin in a one-pot Strecker reaction, see A. S. Paraskar, A. Sudalai, Tetrahedron Lett. 2006, 47, 5759-5762. Cu(OTf)j or EtjN-catalyzed three-component condensation of aldehydes, amines and cyanides a high yielding synthesis of a-aminonitriles. 

For other recent work performed in water, see S. Ramesh, K. Sivakumar, C. Panja, P. N. Amnachalam, A. Lahtha, Synth. Commun. 2010, 40, 3544—3551. Water-mediated Strecker reaction. An efficient and environmentally friendly approach for the synthesis of a-aminonitriles via a three-component condensation. 

X.-L. Zhang, Q.-P. Wu, Q.-S. Zhang, J. Chem. Res. 2013, 37, 690-693. Efficient three-component Strecker reaction of acetals and aromatic amines catalyzed by hafninm tetrachloride at room temperature. 

S. C. Pan, B. List, Synlett 2007, 318-320. Catalytic one-pot, three-component acyl-Strecker reaction, (d) A. Heydari, A. Arefi, S. Khaksar, R. K. Shiroodi, J. Mol. Catal. A Chem. 

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