Hydroxylamine conjugate addition

The conjugate addition of activated nitrogen nucleophiles, such as hydroxylamine and hydrazine derivatives, to a,/3-unsaturated bicyclic lactam 284 gave the corresponding /3-amino product 285 in good yield and excellent diastereoselectivity. These products can be manipulated to afford enantiopure /3-aminopyrrolidinones of potential application as conformationally constrained, substituted glutamate templates (Equation 45) <2001J(P1)2997>. 

Whereas the reactions of allenephosphonates 171 (R2 = OEt) with primary aliphatic and aromatic amines 172 and the reactions of the phosphane oxides 171 (R2 = Ph) with aliphatic amines 172 afford the conjugated addition products 173 always in good yields, the addition of anilines to 171 (R2 = Ph) leads to an equilibrium of the products 173 and 174 [231]. However, treatment of both phosphane oxides and phos-phonates of type 171 with hydroxylamines 172 (R3 = OR4) yields only the oximes 174 [232, 233]. The analogous reaction of the allenes 171 with diphenylphosphinoylhy-drazine furnishes hydrazones of type 174 [R3 = NHP(0)Ph2] [234],... 

Isoniazide, the hydrazide of pyridine-4-carboxylic acid, is still, well over half a century after its discovery, one of the mainstays for the treatment of tuberculosis. Widespread use led to the serendipitous discovery of its antidepressant activity. This latter activity is retained when pyridine is replaced by isoxazole. The requisite ester (45-4) is obtained in a single step by condensation of the diketo ester (45-1), obtained by aldol condensation of acetone with diethyl oxalate, with hydroxylamine. One explanation of the outcome of the reaction assumes the hrst step to consist of conjugate addition-elimination of hydroxylamine to the enolized diketone to afford (45-2) an intermediate probably in equilibrium with the enol form (45-3). An ester-amide interchange of the product with hydrazine then affords the corresponding hydrazide (45-5) reductive alkylation with benzaldehyde completes the synthesis of isocarboxazid (45-6) [47]. 

With hydroxylamine, the pyrylium salt (86) undergoes ring opening to an intermediate 1,5-enedione oxime (87) conjugate addition of the a,(3-unsaturated ketone gives (88), which in the presence of acid forms the isoxazole (89). 

The conjugate addition of hydrazine, hydroxylamine, methoxylamine and alkylamines with various alkyl and halegenofumaric acids to give N-substituted aspartic acids can be carried out enantioselectively in the presence of the enzyme 3-methylaspartase91. 

Very recently it has been discovered that / -methylaspartase also catalyzes the conjugate addition of hydrazine, hydroxylamine, methoxylamine, methylamine, and dimethylamine to various substituted fumaric acids136. 

Blechert has developed an interesting synthesis of 2-substituted indoles which involves the conjugate addition of V-phenylhydroxylamine salts (or V-phenylnitrones) to electron-deficient allenes, followed by carbanion-accelerated hetero-Cc rearrangement of the Michael adduct. For exanple, addition of the hydroxylamine salt (46) to the allenyl sulfone (47) produces the anion (48), which undergoes rapid 3.3-sigmatropic rearrangement to afford the -keto sulfone (49). Cyclization to the indole proceeds smoothly upon exposure to formic acid (Scheme 3). 

Alcohols undergo conjugate addition only very slowly in the absence of a catalyst they are not such good nucleophiles as amines for the very reason we have just mentioned in connection with the reactivity of hydroxylamine—oxygen is more electronegative than nitrogen, and so its lone pairs are of lower energy and are therefore less reactive. Alkoxide anions are, however, much more nucleophilic. NaOMe... 

Reddy and co-workers (05HC235) (Scheme 42) treated 4-[3-(4-oxo-4//-chromen-3-yl)acryloyl]pyrazol-3-one 157 with hydroxylamine hydrochloride in pyridine under microwave irradiation, to obtain, after condensation via intermediate 158 followed by intramolecular conjugate addition, the 4-[5-(4-oxo-4f/-chromen-3-yl)isoxazol-3-yl]pyrazol-3-one 159, in 63% yield. 

It is better to differentiate the two electrophilic sites more sharply. The bromoenones 59 give some regioselectivity at different pHs. Hydroxylamine is usually added as the crystalline hydrochloride and base is needed to release the free amine. Carbonate does this and with K2C03 in EtOH, isoxazole 60 is the product. It appears that conjugate addition of the nitrogen atom 61 occurs first.5... 

With the stronger base NaOEt in the same solvent, the isomeric isoxazole 62 is the main product. Presumably the hydroxylamine anion is the nucleophile and now the oxyanion does conjugate addition 64 in the first step. Attractive and rational though this method may be, the average yields of either isomer are only 25-50%. This type of approach relies too much on delicate choices between similar groups and a better way is needed. 

The mixture of 80 and 81 reacts with hydroxylamine in another tandem conjugate addition to give a heterocycle 82 that loses water to give Sceletium-A4 72 in one step from the mixture. 

Michael reaction. Silyl ether 2A and the enantiomeric ent-2A have been employed in inducing the Michael reaction of N-Boc hydroxylamine and malonate esters, respectively, to enals, whereas 3A has been afhrmed to promote the addition of 5 -(2,2,2-trifluoroethyl) alkanethioates to enals. Furthermore, 3A and 3B hnd use in asymmetric conjugate addition of benzaldoxime ° (products are for conversion into chiral 1,3-alkanediols) and RSH, also to enals. 

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