Cyanide, addition conjugated ketones

There are many addition reactions of a,(3-unsaturated aldehydes, ketones, and related compounds that are the same as the carbonyl addition reactions described previously. Others are quite different and result in addition to the alkene double bond. Organometallic compounds are examples of nucleophilic reagents that can add to either the alkene or the carbonyl bonds of conjugated ketones (see Section 14-12D). Hydrogen cyanide behaves likewise and adds to the carbon-carbon double bond of 3-butene-2-one, but to the carbonyl group of 2-butenal ... 

Regiosp>ecific synthesis of enol silyl ethers can also be achieved from enones either by reductive silylation or by 1,4-addition of the conjugated system. Thus, Li/NH reduction of the decalone (27) and silylation give the enol silyl ether (28). Similarly, addition of lithium dimethylcuprate to cyclohexenone followed by silylation gives the enol silyl ether (29). Trimethylsilyl cyanide (30) normally adds 1,2 to conjugated ketones (e.g. carvone, 31). However, in the presence of trialkylaluminum, 1,4-addition bdces place to give the enol silyl ether (32 Scheme 9). The same overall transformation can be accomplished by diethylaluminum cyanide and trimethylchlorosilane. ... 

As part of a projected synthesis of corrins, a simple synthesis of y-substi-tuted y-butyrolactams via the conjugate addition of hydrogen cyanide to unsaturated ketones is described contrary to a much earlier report, the )S-cyanohydrin (101) is not produced, but a mixture of the two butyro-lactams (102) and (103) is isolated, (103) being convertible into (102) by reaction with basic cyanide solution. Reaction of one of those, (102), with potassium t-butoxide in t-butyl alcohol gave, inter alia, the semi-corrinoid (104), These transformations are outlined in Scheme 35. 

The medicinal chemists subsequently discovered an improved route to racemic acid 9 that started with 2-bromo-2-cyclopente-l-one 11 (Scheme 7.2) [5]. Suzuki-Miyaura cross-coupling of 11 with 4-fluorophenyl boronic acid 12 provided 13 in 67% yield. Conjugate addition of cyanide furnished ketone 14 in 71% yield. Reduction of 14 with NaB H4 gave a 2.8 1 mixture of desired 15 and undesired 16 which were separated by silica gel chromatography. The observed diastereoselec-tivity with the cyano group was similar to ester 6. Hydrolysis of 15 with 5 M NaOH in MeOH gave racemic acid 9 in 91% yield, which was resolved as outlined in Scheme 7.1. 

The conjugate addition of hydrogen cyanide, generated in situ from KCN and acetic acid to (i-mesityl ketones, gives high yields of the corresponding oxo nitriles in aqueous ethanol (Eq. 10.19).41... 

We ll consider the low-temperature reaction first. As you know from Chapter 6, it is quite normal for cyanide to react with a ketone under these conditions to form a cyanohydrin. Direct addition to the carbonyl group turns out to be faster than conjugate addition, so we end up with the cyanohydrin. 

So far, most of the reactions presented in the book that are useful in synthesis have made C-O, C-N, or C-halogen bonds and only a few (Wittig, Friedel-Crafts, and reactions of cyanides and alkynes) make C-C bonds. This limitation has severely restricted the syntheses that we can discuss in this chapter. This is by design as we wanted to establish the idea of synthesis before coming to more complicated chemistry. The next four chapters introduce the main C-C bond-forming reactions in the chemistry of enols and enolates. You met these valuable intermediates in Chapter 21 but now you are about to see how they can be alkylated and acylated and how they add directly to aldehydes and ketones and how they do conjugate addition to unsaturated carbonyl compounds. Then in Chapter 30 we return to a more general discussion of synthesis and develop a new approach in the style of the last synthesis in this chapter. 

In recent years, Ireland and his colleagues have made a major contribution to the total synthesis of tetra- and penta-cyclic triterpenoids. The details of some of this work have been published in a series of papers.55-58 The tetracyclic ketone (75) was conceived as a key intermediate in the synthesis of shionone (76). Three routes to (75) were undertaken.55 The most efficient involved a triethylaluminium-catalysed conjugate addition of cyanide to the enone (77) (see Vol. 5, p. 135). The second... 

The 1,4 conjugate addition of HCN to a, d-unsaturated ketones has received partictUar attention, because of its selectivity in the steroid field [2S). Alkyl aluminum cyanides are used as catalysts in these reactions. Two methods have been developed which allow either thermodynamic (Equation (39 or kinetic control (Equation (40)) of the addition stereochemistry (Nagata reaction). 

Mercaptans add to olefins according to Markownikoff s rule in the presence of sulfur or sulfuric acid. The mode of addition is reversed by peroxides. The yields of sulfides are generally in the range of 60-90%. Somewhat lower yields (50-60%) are obtained by the addition of mercaptans to vinyl chloride and allyl alcohol. Conjugated olefinic aldehydes, ketones, esters, and cyanides add mercaptans and thiophenols in excellent yield. In certain cases the unsaturated compound may be converted directly to a symmetrical sulfide by addition of hydrogen sulfide (cf. method 388). 

Androst-is-en-iy-ones (9) readily add methanol, hydrogen cyanide, etc., with stereospecific i5j8-attachment (10) of the nucleophile [265]. The stereochemistry of conjugate addition to both Ai -20-ketones and A S-i -ketones follows the same pattern as for electrophilic attack upon the A - and A -enolic derivatives respectively of 17-0x0- and 16-0x0 steroids (p. 167). AU these reactions probably depend upon a combina-... 

The Michael-type addition, a nucleophilic addition of an anion to the carbon-carbon double bond of an a,(3-unsaturated ketone, aldehyde, nitrile, nitro, sulphonyl, or carboxylic acid derivative, provides a powerful tool for carbon-carbon bond formation. The reaction is most successful with relatively nonbasic ( soft ) nucleophiles such as thiols, cyanide, primary and secondary amines, and P-dicarbonyl compounds. There is often a competition between direct attack on the carbonyl carbon (1,2-addition) and conjugate addition (1,4-addition) when the substrate is an a,(3-unsaturated carbonyl compound. 

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