Ketonic Strecker reactions

This MCR chemistry began in 1850 when the Strecker reaction S-3CR of ammonia, aldehydes, and hydrogen cyanide was introduced. Since 1912 the Mannich reaction M-3CR of secondary amines, formaldehyde, and (3-protonated ketones is used. 

The potential substrates for the Strecker reaction fall into two categories ald-imines (derived from aldehydes, for which cyanide addition results in formation of a tertiary stereocenter) and ketoimines (derived from ketones, for which addition results in a quaternary stereocenter). As in the case of carbonyl cyanation, significant differences are observed between the substrate subclasses. To date, while a few catalyst systems have been found to display broad substrate scope with respect to aldimine substrates, successful Strecker reactions of ketoimines have been reported in only two cases. As is the case for all asymmetric catalytic methodologies, the breadth of the substrate scope constitutes a crucial criterion for the application of the Strecker reaction to a previously unexplored substrate. 

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). 

The synthesis of enantiopure amino-functionalized compounds such as a- and (3-amino acids or nonfunctionalized amines can be envisaged by the use of aldehydes, ketones, a- or (3-keto acids, or derivatives thereof as substrates for imine formation followed by, for example, diastereoselective Strecker reactions, reductions, or organometallic addition reactions. In the literature, diastereoselective syntheses based on a large variety of chiral auxiliaries, such as a-arylethylamines,4... 

Few examples of crystallization-induced asymmetric transformations in Strecker reactions based on arylalkyl-methyl ketones have been reported a) Weinges, K., Gries, K., Stemmle, B., Schrank, W. Chem. Ber. 1977, 110, 2098 b) Weinges, K., Klotz, K-P., Droste, H. Chem. Ber. 1980, 113, 710. 

Since HCN and aldehydes were produced directly from the electric discharge in the Miller s experiment [33], the Strecker reaction was very early proposed as a likely pathway for the prebiotic synthesis of amino acids. This reaction discovered in 1850 [34] is the most anciently known abiotic synthesis of a-amino acids, it originally consisted in the formation of an a-aminonitrile 1 from a carbonyl compound (either aldehyde or ketone), ammonia and hydrogen cyanide in moderately alkaline aqueous solution followed by aminonitrile hydrolysis in strong acid. 

Bousquet, C., Tadros, Z., Tonnel, J., Mion, L., Taillades, J. Auxiliary chiral ketones in the asymmetric synthesis of a-amino acids by Strecker reaction. Bull. Soc. Chim. Fr. 1993, 130, 513-520. 

Therefore, it is possible to obtain compounds with four different substituents at the 2- and 5-positions of the 4-oxoimidazoli-dine ring by reacting the appropriate carbonyl compound with an alpha aminonitrile formed in a Strecker reaction from a selected ketone. The oxidation of these imidazolidines by hydrogen peroxide in the presence of catalytic amounts of sodium tungstate in acetic acid gave new stable nitroxyl radicals (12) shown in Chart 4. 

The basis of the process leading to the enantiomerically pure acid is essentially the same as that for a-H-a-amino acids. However, in this case, a ketone is used as the starting material which undergoes a Strecker reaction, followed by hydrolysis of the resulting aminonitrile to form the racemic a-alkyl-a-amino acid amide. Enzymatic hydrolysis results in the formation of the L-a-alkyl-a-amino acid (Fig. 12.2-2). 

The ketone 59 was converted into the aldehyde 60 which was submitted to a Strecker reaction with -<-butyl 3-methyl-4-aminobutyrate and potassium cyanide to give, after benzoylation, the cyano ester 61 as a mixture of stereoisomers. This mixture was cyclized and saponified to afford the enamino ester 62 which was transformed into the ketone... 

The use of cyclodextrins14 has provided the ability to conduct the Strecker reaction with TMSCN in water via supramolecular catalysis involving reversible guest-host interactions. Activation of imine 16 by complexation with the hydroxyl groups present in cyclodextrins was found to work best with p-cyclodextrin. This chemically green reaction could be applied to ketones as well as aldehydes. 

A series of cyclobutane derivatives that possess neurokinin-1 (NK1) receptor antagonist activity has been reported.4S These compounds could not be prepared utilizing the classical Strecker reaction conditions, as the intermediate a-aminonitrile 105 could not be hydrolyzed. Thus, ketone 104 was exposed to the Bucherer-Bergs reaction conditions to produce the corresponding hydantoins 106 and 107. The related a-amino acids, 108 and 109, respectively, could be generated by hydrolysis. 

Undoubtedly, the products of these primary biochemical events, i.e., fatty and other acids, peptides, and amino adds, contribute to cheese flavor, perhaps very significantly in many varieties and proteolysis certainly has a major influence on the various rheological properties of cheese, e.g., texture, meltability, and stretchability. However, the finer points of cheese flavor are almost certainly due to further modification of the products of the primary reactions. The most clear-cut example of this is the oxidation of fatty acids to methyl ketones in blue cheeses. Catabolism of amino acids leads to the production of numerous sapid compounds, including amines, carbonyls, acids, thiols, and alcohols. Many of these compounds may interact chemically with each other and the compounds of other reactions via the Maillard and Strecker reactions. At present, relatively little is known concerning the enzymology of amino acid catabolism in most cheeses and even less is known about the chemical reactions. It is very likely that research attention will focus on these secondary and tertiary reactions in the short-term future. 

Recently, a general aminocatalytic synthesis of aldimines catalysed by pyrrolidine has been described. DABCO was the catalyst of choice for isomerisation of 5-hydro yl-2,3-dienoate. ° The Strecker synthesis of a-amino acids is one of the simplest and most atom economical reactions. Tri-methylsilyl cyanide has been widely used for this purpose. Recently, Feng and coworkers have used a catal) c amount of tetramethylguanidine (TMG) to carry out the Strecker reaction of aldehydes and ketones under solvent-free conditions. ... 

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. 

The Strecker Reaction The Strecker reaction [66] is one of the most general methods for synthesis of a-aminonitriles 71 (Scheme 5.51), which are intermediates of amino acids and pharmacologically valuable compounds. This procedure implies MCR of aldehydes or ketones, amines, and a cyanide source. However, the majority of the studies are restricted to aldehydes, mainly due to the harsh reaction conditions and difficult manipulations required when ketones are used [67]. Recently, both Pd and NHC systems shown in Scheme 5.51 have been found to be active catalysts in one-pot Strecker... 

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. 

Although the Strecker reaction has been extensively studied with aldehydes using various kinds of catalysts and types of catalysis, the MC version nsing ketones has been less explored, maybe due to the less reactivity shown by these substrates, and only in 2007 it was reported the first efficient and extensively developed strategy using gallium triflate as catalyst (Scheme 10.25) [62]. 

Various fluorinated and nonfluorinated ketones were successfully employed in this MC Strecker reaction, and interestingly, the proper choice of the reaction conditions (catalyst and solvent) was crucial for the achievement of the process with very good results. Later, this research group developed a similar procedure using TMSOTf [63] or Nafion -H [64] as efficient catalysts of this reaction. 

SCHEME 10.25 Ga(OTf)3-catalyzed Strecker reaction using ketones. 

As mentioned in Section 10.2.3, the application of Ga(OTf)3 as an effective and reusable catalyst for the Strecker reaction has been demonstrated [62]. This is a simple and alternative route to the stepwise methodologies for the Strecker reaction of ketones. Moreover, the use of fluorinated ketones is a significant aspect of this procedure due to the increase interest in organofluorated compounds. 

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. 

Prakash, Olah, and coworkers developed an efficient strategy using Nafion -H (perfluoroalkanesutfonic acid polymer) and Nafion" SAC-13 (10-20% Nafion -H polymer on amorphous silica, porous nanocomposite) as heterogeneous catalysts for one-pot Strecker reaction using aldehydes, ketones, and fluorinated ketones, affording final a-aminonitriles in high yields [64]. 

G. K. S. Prakash, T. Mathew, C. Panja, S. Alconcel, H. Vaghoo, C. Do, G. A. Olah, Proc. Natl. Acad Sci. U. S. A. 2007, 104, 3703-3706. Gallium (III) triflate catalyzed efficient Strecker reaction of ketones and their fluorinated analogs. 

N. H. Khan, S. Agrawal, R. I. Kureshy, S. H. R. Abdi, S. Singh, E. Suresh, R. V. Jasra, Tetrahedron Lett. 2008,49,640-644. FefCpjjPF catalyzed efficient Strecker reactions of ketones and aldehydes under solvent-free conditions. 

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... 

G.-W. Zhang, D.-H. Zheng, J. Nie, T. Wang, J.-A. Ma, Org. Biomol. Chem. 2010, 8, 1399-1405. Brpnsted acid-catalyzed efficient Strecker reaction of ketones, amines and trimethyl-silyl cyanide. 

The Strecker reaction has been widely studied for the synthesis of a-amino acids. Matsumoto and coworkers reported the multicomponent nncatalyzed Strecker reaction under high pressure in 2005 for the synthesis of quaternary a-amino acids 170 [86]. The reaction of ketones 168, aniline 9a, and TMSCN (169) at 0.6 GPa pressure and SO C afforded the corresponding a-aminonitriles 170 in very good to excellent yields (81-99%) (Scheme 11.36). 

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