Hydroxylamines 3,3 -sigmatropic rearrangements

Sigmatropic rearrangement of tertiary amine A -oxides to hydroxylamines ... 

The most frequent rearrangement of substituted hydroxylamines is the thermal [3,3]-sigmatropic rearrangement, the 3-aza-4-oxa-Cope rearrangement also called 3-aza-4-oxy-Cope rearrangement, that proceeds by a cyclic six-membered transition state (equation 1). Albeit the difficulty to prepare hydroxylamine derivatives, this rearrangement proceeds in mild conditions and is useful in the synthesis of several heterocyclic compounds. 

During the synthesis of the natural and biologically active natural products, Stemo-furan A (139), Eupomatenoid b (140) and Coumestan (141), the [3,3]-sigmatropic rearrangements of a hydroxylamine were used. 

Enehydroxylamine 0-derivatives 149 and 151, prepared from the reactions of A-alkyl-3-(hydroxyamino)cyclohex-2-enone (148, R = H) and iV-alkyl-3-(hydroxyamino)-5,5-dimethylcyclohex-2-enone (148, R = Me) with MsCl (equation 41) and Mc2NC(S)Cl (equation 42), respectively, in the presence of base rearrange spontaneously providing the corresponding [3,3]-sigmatropic rearranged products 150 and 152 in moderate to excellent yield . However, the diethyl phosphate 153 (equation 43) and the O-benzoyl hydroxylamine 154 rearrange under reflux in toluene (equation 44). 

Previously, Ayyangar and colleagues reported the synthesis of 2-chloroanilide and aniline derivatives by a [3,3]-sigmatropic rearrangement of the adduct obtained by the treatment of hydroxamic acid and hydroxylamine derivatives with thionyl chloride. 

The new metabolite from Red Sea marine invertebrates, Asmarine B (169), presents a hydroxylamine functional group (equation 50). When treated with acetic anhydride at room temperature the Asmarine B (169) underwent an unexpected [3,3]-sigmatropic rearrangement to give 170. After 1,6-addition of methanol and concomitant loss of acetic acid 170 produced the pyrimidine 171. ... 

Diastereoselective [2,3]-sigmatropic rearrangement of lithium O-allyl-A-benzylhy-droxylamides (195) bearing a stereogenic center adjacent to the migration terminus was reported 3" 3 (equation 57). When the (E) and (Z)-iV-benzyl-0-(4-methoxy-4-phenylbut-2-enyl)hydroxylamines (194) rearrange, a chelation by the lithium ion occurs and the (Z)-(lR5, 2R5 )-l-phenyl-l-methoxy-3-iV-benzylaminobut-3-ene (196) is the major product... 

The intramolecular nitrone-alkene cycloaddition reaction of monocyclic 2-azetidinone-tethered alkenyl(alkynyl) aldehydes 211, 214, and 216 with Ar-aIkylhydroxylamincs has been developed as an efficient route to prepare carbacepham derivatives 212, 215, and 217, respectively (Scheme 40). Bridged cycloadducts 212 were further transformed into l-amino-3-hydroxy carbacephams 213 by treatment with Zn in aqueous acetic acid at 75 °C. The aziridine carbaldehyde 217 may arise from thermal sigmatropic rearrangement. However, formation of compound 215 should be explained as the result of a formal reverse-Cope elimination reaction of the intermediate ct-hydroxy-hydroxylamine C1999TL5391, 2000TL1647, 2005EJ01680>. 

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). 

A-Allylamine oxides represent the pattern for [2,3]-sigmatropic rearrangement where X = N and Y = 0 . The rearrangement provides 0-allyl hydroxylamine derivatives. 

N-Allylhydroxylamines can be prepared from nitrone hydrochlorides, which are produced by the reaction of nitroso compounds with alkenes, in an ene-type mechanism (Scheme 188). Analogues of potent dopaminomimetic ergot derivatives have been prepared, in which of a (5R,8S,10R)-6-allylergoline N -oxide was converted into a substituted hydroxylamine function. The key step is a Meisenheimer [3,2] sigmatropic rearrangement of the N6-oxide (Scheme 189). 413... 

In 1919, Meisenheimer reported a detailed account of an unusual transformation of methyl-allyl-aniline 3 in the presence of benzoic peracid 4, which yielded the N,N,0-trisubstituted hydroxylamine product 6 through amine iV-oxide 5 tScheme IS.21. Although the mechanism of the process was not fully appreciated at the time, this discovery was one of the earliest examples of a [2,3]-sigmatropic rearrangement, and it served as the foundation for the discovery and development of many [2,3]-rearrangements of reactive zwitterionic substrates. 

Formation of O, N, A -trisubstituted hydroxylamines from tertiary amine oxides via [1,2]-R group migration, or [2,3]-sigmatropic rearrangement when R = allyl ... 

Sigmatropic rearrangement of allyl amine oxides is known as the Meisenheimer rearrangement. This rearrangement provides O-aUyl hydroxylamine derivatives. Some examples are [137, 138] as follows ... 

O-Propargyhc hydroxylamines 16 are converted to the isomeric 3,5-disubstituted isoxazohnes on treatment with K2CO3 [328]. The mechanism of this transformation is not yet elucidated. A possible explanation involves (2,3)-sigmatropic rearrangement of 16 to a N-aUenic hydroxylamine 17, which may further rearrange to a a,P-unsaturated oxime 18 in analogy to (1), cyclization gives rise to the isoxazoline system ... 

When formation of N-O-dvinyl hydroxylamine is favored, its [3,3]-rearrange-ment leads to 2,3,4-trisubstituted pyrroles while 1,3-prototropic shift to the O-l-propenyl oximes is hindered, [l,3]-sigmatropic rearrangement occurs to give 2,3,5-trisubstituted pyrrole (after cyclization of intermediate amino aldehyde) Scheme 1.143. 

The thermal isomerization of arylamine A-oxides 189 into substituted hydroxylamines 190 is known as the Meisenheimer rearrangement (see review in Reference 278, and Reference 279) (equation 74). In this case279 the Meisenheimer rearrangement (i.e. the [2,3]-sigmatropic shift 189 —> 190) is followed by [1,3] oxygen shift to carbon (190 — 191) on further heating. 

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