Hydroxy nitriles, formation

The formation of a-amino nitrile 2 is likely to proceed via a cyanohydrin 4 (an a-hydroxy nitrile) as intermediate, which is formed by the addition of hydrogen cyanide to the aldehyde 1 ... 

Nitrile oxides are usually prepared via halogenation and dehydrohalogenation of aldoximes [11] or via dehydration of primary nitro alkanes (Scheme 1) [12]. However, it is important to note that nitrile oxides are relatively unstable and are prone to dimerization or polymerization, especially upon heating. 1,3-Dipolar cycioaddition of a nitrile oxide with a suitable olefin generates an isoxazoline ring which is a versatile synthetic intermediate in that it provides easy access to y-amino alcohols, )5-hydroxy ketones, -hydroxy nitriles, unsaturated oximes, and a host of other multifunctional molecules (Scheme 1) [5a]. Particularly for the formation of )5-hydroxy ketones, nitrile oxide-olefin cycioaddition serve as an alternative to the Aldol reaction. 

The addition of hydrogen cyanide to a carbonyl group results in the formation of an a-hydroxy nitrile, a so-called cyanohydrin (A, Scheme 6.1) [1]. Compounds of this type have in many instances served as intermediates in the synthesis of, e.g., a-hydroxy acids B, a-hydroxy aldehydes C, fS-amino alcohols D, or a-hydroxy ketones E (Scheme 6.1) [1], In all these secondary transformations of the cyanohydrins A, the stereocenter originally introduced by HCN addition is preserved. Consequently, the catalytic asymmetric addition of HCN to aldehydes and ketones is a synthetically very valuable transformation. Besides addition of HCN, this chapter also covers the addition of trimethylsilyl cyanide and cyanoformate to car-... 

It is not known whether the cyclization of hexose derivatives takes place with the C4- or the C5-hydroxyl group work on model compounds suggests that both the furanoid and the pyranoid rings are possible. Imino-lactone formation is theoretically possible for any 4- or 5-hydroxy nitrile,... 

Actually the reaction formulated in equation (I) involves formation of lithium N,N-dimethylamide, which is a very strong base in HMPT. Electrophiles other than H can be used. Alkylating reagents can be used to form substituted nitriles (equation IV). 3-Hydroxy nitriles are obtained by addition of aldehydes... 

Several heterocyclic rings may be opened with the formation of a nitrile. In a search for compounds which block ACTH-induced responses, the isoxazole (57) was treated at 0° with sodium methoxide in THF and gave a high yield of the hydroxy nitrile [142]. 

Cyanohydrin formation Aldehyde or ketone 2-Hydroxy nitrile Synthesis of 2-hydroxy nitriles Oxynitrilase (Hydroxynitrile lyase)... 

The addition of cyanide to a carbonyl group results in the formation of a a-hydroxy nitrile (a cyanohydrin) which can act as intermediate in the synthesis of... 

Nitrile groups m cyanohydrins are hydrolyzed under conditions similar to those of alkyl cyanides Cyanohydrin formation followed by hydrolysis provides a route to the preparation of a hydroxy carboxylic acids... 

It is worth noting that the 2-pyridone 42 (99MI1) and thione 43 (88H(27)733), which could react in either of the two ways as shown, with an isocyanate or isothiocyanate and with a nitrile respectively, actually give a one-carbon insertion. There is a case of formation of 2,3 and 3,4 bonds in the preparation of 8-hydroxy-triazolopyridine 44 (83MI1). 

Aldoximes are normally dehydrated by reaction with dichlorocarbene, produced under soliddiquid two-phase conditions, to yield nitriles in high yield [41, 42], whereas a-hydroxy ketoximes are cleaved with the simultaneous formation of a nitrile and either an aldehyde or ketone (Scheme 7.33). Yields are generally >70% and, in the case of cyclic hydroxy ketoximes, the products are acyclic oxo nitriles [43],... 

Keto nitriles, such as 138, function admirably as substrates in reductive cycliza-tions [56, 57], Two product types are obtained, one the simple ketone 140, the other 139, incorporating the a-hydroxy ketone (ketol) functionality that is present in many natural products (note Eq. 42). Both controlled potential and constant current conditions have been utilized. Of the electrodes examined (Ag, Cd, Pb, Zn, C-fiber, and Sn), tin generally proved most effective. Using tin, the controlled potential reduction of 138 in i-PrOH at —2.8 V vs SCE (divided cell, ceramic diaphragm) afforded a 76% yield of ketol 139 accompanied by 2% of ketone 140. As illustrated in Table 7, the preference for ketol formation drops when the transformation is carried out at constant current or without using a diaphragm. 

The Reformatsky reaction can also be performed electrochemically either directly or using a mediator. Ni-catalysis has proven to be an efficient way to prepare j3-hydroxy ester or nitrile from the corresponding a-chlorocompounds (Table 14) [94]. Here again the first step is the oxidative addition of the cathodically generated Ni°bpy to the halocompound. The nature of the sacrificial anode also plays a crucial role in this reaction, though the formation of an organozinc intermediate has not been fully demonstrated. 

The syntheses were most successful when a nonpolar protic solvent was used. In this work, a synthesis for the formation of alkyl nitriles with a hydroxy group at the a-position is presented. 

---