Conjugate addition 1.6 cyanide

Formal oxidation of pyrrolidine to the succinimide stage affords a series of compounds used as anticonvulsant agents for treatment of seizures in petit mal epilepsy. Knoevnagel condensation of benzaldehyde with ethyl cyanoacetate affords the unsaturated ester, 9. Conjugate addition of cyanide ion leads to the di-nitrile ester (10). Hydrolysis in mineral acid affords the succinic acid (11), presumably by decarboxylation of the intermediate tricarboxyllie acid. Lactamization with methylamine gives phensuximide (12). ... 

Conjugate addition, 34-5, 51-2,53, 132, 133 Conjugate hydroxymethylation, 59-60 Copper(n) bromide, 54 Copper([) chloride, 120 Copper(n) chloride, 120 Copper(i) cyanide, 7,52, 53 Copper(i) iodide, 54 Corey s internal quench, 104 Cyanohydrin trimethylsilyl ether, 137 Cycloaddition. 34,112 Cydobutane-l,2-dione, 135 Cyclohept-2-dione, 135 Cyclohex-2-enone, 52,123 Cyclohcxa-1,3-diene, 26 Cyclohexane carboxaldehyde, 22-3,69 73,78... 

Coumalic acid, 56, 51 Crotyl fluoride, 57,73 18-CROWN-6,57, 30 Curtius rearrangement, 59, 1 Cyanide ion, as catalyst for conjugate addition of aldehydes, 59, 56 p-Cyanobenzenesulfonyl cyanide, 57, 89 2-( 1 -Cyanocyclohexyljhydrazinecarboxylic acid methyl ester, 58,102 Cy a noferrocene, 56, 30 Cyanogen chloride, 57, 88... 

CYANIDE-CATALYZED CONJUGATE ADDITION OF ARYL ALDEHYDES 4-(3-PYRIDYL)-4-OXOBUTYRONITRILE... 

The mechanism of the cyanide- and thioazolium ion-catalyzed conjugate addition reactions is considered to be analogous to the Lapworth mechanism for the cyanide-catalyzed benzoin condensation. Thus the cyano-stabilized carbanion resulting from deprotonation of the cyanohydrin of the aldehyde is presumed to be the actual Michael donor. After conjugate addition to the activated olefin, cyanide is eliminated to form the product and regenerate the catalyst. 

Cyanide ion acts as a carbon nucleophile in the conjugate addition reaction. The pK of HCN is 9.3, so addition in hydroxylic solvents is feasible. An alcoholic solution of potassium or sodium cyanide is suitable for simple compounds. 

Diethylaluminum cyanide mediates conjugate addition of cyanide to a, (3-unsaturated oxazolines. With a chiral oxazoline, 30-50% diastereomeric excess can be achieved. Hydrolysis gives partially resolved a-substituted succinic acids. The rather low enantioselectivity presumably reflects the small size of the cyanide ion. 

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... 

Such dideoxynucleosides as CNT (306) and the potent anti-HIV drug ddC (307) have been obtained (280), respectively, from the butenolide 248 and from its saturated analogue. Thus, conjugate addition of cyanide to 248, followed by reduction of the lactone group, acetylation of HO-1, and coupling with silylated thymine, afforded, after deprotection, compound 306. 

These reactions mainly involve conjugate additions to carbonyl compounds by nucleophiles such as the cyanide ion, CN, and primary or secondary amines, RNH2 or R2NH. Figure 11-31 shows the conjugate addition by the cyanide ion, and Figure 11-32 shows the conjugate addition by a secondary amine. 

Triethylaluminum-hydrogen cyanide and diethylaluminum cyanide are also useful reagents for conjugate addition of cyanide. The latter is the more reactive of the two reagents. These reactions presumably involve the coordination of the aluminum reagent as a Lewis acid at the carbonyl oxygen. 

This technique also greatly improves yields of conjugate addition of cuprates to y..[>-unsaturated esters and amides.38 Trimethylsilyl cyanide also accelerates conjugate addition.39... 

Many of the synthetic routes derived for pregabalin (2) before 2003 have relied on classical chiral resolution of either an intermediate or the final racemic 3-isobutyl GABA (43). In 2003, Jacobsen and co-workers published their work on a novel enantio-selective synthesis of pregabalin (2) (Sammis and Jacobsen, 2003). The Harvard group was able to promote conjugate addition of hydrogen cyanide into the unsaturated imide... 

Phosphorous oxychloride (POCI3) can also be used without further activation. For the synthesis of the antidepressant (/ )-(—)-rolipram 24, cyclization of the (3-hydroxy amide 21 with POCI3 gave the oxazoline intermediate 22. Diastereo-selective conjugate addition of cyanide gave the cyano derivative 23, which was further transformed to (/ )-( )-rolipram (Scheme 8.11). 

Aside from the nitronates, cyanide anion and acyl anion equivalents, e.g. (219), examples of conjugate additions of a-aza-stabilized carbanions are rare. The aminomethyl synthon [ CHRNH2] is typically introduced with either nitronates or cyanide however, a-metallomethyl isocyanides (248) also show synthetic promise in conjugate additions. In addition, depending on hydrolytic conditions employed, they also serve as equivalents for the N-formamidomethyl anion ["CHRNHCHO] or the isocyanatomethyl anion ["CHRN=C ] (Scheme 84).189... 

Except for the well-documented conjugate additions of diethylaluminum cyanide,92 triethylaluminum-hydrogen cyanide and Lewis acid-tertiary alkyl isonitriles,93 examples of Lewis acid catalyzed conjugate additions of acyl anion equivalents are scant Notable examples are additions of copper aldimines (233),94, 94b prepared from (232), and silyl ketene acetals (234)940 to a,(3-enones which afford 1,4-ketoal-dehydes (235) and 2,5-diketo esters (236), respectively (Scheme 37). The acetal (234) is considered a glyoxylate ester anion equivalent. 

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