Mechanistic considerations and conclusions

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intermediate.²³⁷ Desilylation of 295b by MeLi followed by oxidative cleavage afforded a very high 87% yield of hydroxyiminoester 296b as a single diastereomer (table 29, entry 3). Direct one-step cleavage of 296b in the presence of the Cu catalyst was also attempted, because the presence of the methyl group at C-2 in carvone prevents deprotonation of the α-nitrosoketone intermediate during oxidation, therefore tautomerization to α-hydroxyiminoketone cannot compete with the alkoxide addition that triggers fragmentation. During the course of optimization, we found that the initially low yield of 296b (entry 4) is at least partially caused by interaction of copper salts with the oxime during quench or aqueous workup. Using metal-binding EDTA for workup, a synthetically useful yield of 42% was achieved after optimization (entries 5, 6), it however compared unfavourably with the two- step method.

Table 29. Conjugate addition to enones 294a,b followed by nitrosative cleavage.

Entr y

294 R¹ R² Method T¹ (°C) T² (°C) 296 (%)

1 a H H C –78 +23 a 24

2 a H H D –40 –78 a 73

3 b propen-2-yl Me D –40 –30 b 87

4 b propen-2-yl Me C 0 +23 b 32

5 b propen-2-yl Me C ^a) 0 +23 b 38

6 b propen-2-yl Me C ^a) –30 +23 b 42

a) EDTA used for work-up.

To find out whether the poor yield of the one-pot protocol was due to the presence of Cu or due to the nature of enolate counterion, the magnesium enolate of 3,5-dimethylcyclohexanone (273a) was generated by direct deprotonation using i-Pr2MgCl in THF or THF/HMPA mixture.²³⁸ Oxidation by i-AmONO afforded only up to 31% (by ¹H NMR) of 274a. It can be therefore concluded, that the lower yield of one-pot conjugate addition/cleavage protocol is likely due to lower reactivity of magnesium enolates, and only to a minor degree due to the presence of copper salts.

103 Moreover, the expected α-hydroxyiminoketone is not the major product for most ketones.

Instead, a very fast alkoxide attack on the carbonyl group results in a retro-aza-Claisen fragmentation cleaving the C-C bond between the carbonyl and the α-carbon atom. The results suggest that the products distribution is purely under kinetic control - decided at the stage of the first intermediate 298, which can either undergo nucleophilic attack at the carbonyl group (pathway I) or be deprotonated by the alkoxide to give anion 300 (scheme 86, pathway II). The fragmentation (pathway I) presumably occurs via the cyclic Zimmerman-Traxler transition state 299 to give an ester and an oxime salt as products and is the dominant pathway for most unhindered ketones, especially when Na or K enolates are used. For ketones that are too sterically hindered to undergo nucleophilic attack on 298 or too conformationally rigid to adopt the transition state 299, deprotonation to give the stable salt 300 predominates and the reaction defaults to the more common α-hydroxyimination. The formation of salt 300 is likely irreversible under the conditions, as attempts to cleave 300 or its neutral parent hydroxyiminoketone form 301 by alkoxide did not lead to cleavage. Which pathway dominates can be influenced by the choice of reaction conditions. In general, Na, K and Li enolates favour pathway I, Mg enolates favour pathway II. THF as solvent was found to promote the cleavage reaction as opposed to protic solvents, which favour α-hydroxyimination.

Scheme 86. Competing reaction channels during base mediated nitrosation of ketones. I) Nucleophilic addition of alkoxide, followed by retro-aza-Claisen fragmentation via Zimmerman- Traxler TS 299. II) Deprotonation to give salt 300 as observed in hindered ketones.

We found that excess base (especially KHMDS) and oxidant can lead to secondary cleavage of esters and Beckmann fragmentation of aldoximines. By carefully controlling the loading of base and oxidant, the reaction can be stopped at the hydroxyamino ester product(s), making nitrosative cleavage a potentially useful method for the scission of the α-C-C bond in ketones. In particular, it allows anti-Beckmann cleavage of aryl ketones to benzoic esters, which is complementary to the standard methods like the BR and BVO. Simple and substituted cyclic ketones can be cleaved to ω- hydroxyiminoesters. Most importantly, regioisomeric enolates and TMS enol ethers can be cleaved with a high degree of regio-specificity. Methyl ketones are also amenable to the cleavage, although with lower efficiency (table 27). Unsaturated ketones can serve as substrates either directly via deprotonation (table 28, entries 2, 3) or the cleavage reaction can be coupled with prior conjugate addition (table 29). Both steric hindrance in the vicinity of the carbonyl group and conformational rigidity of certain cyclic substrates may hamper cleavage (scheme 85). However, some hindered substrates like O-methyl estrone (286b) and 273b were cleaved very smoothly (table 28, entry 5; table 25), while the non-hindered bicyclo[4.1.0]heptan-2-one (278d) (table 26, entry 9) resisted cleavage, we should therefore conclude that conformational flexibility might be the key factor.

The products of the cleavage reaction may be of synthetic interest. The oxime functional group itself is a very versatile synthetic handle that can be converted to a primary amine, hydroxylamine,ketone or can undergo oxidative cycloadditions with alkynes and alkenes.^240,241 It contains the energy-loaded N-O bond that allows generation of high energy iminyl radicals or can be used to power transition metal catalysis.²⁴² Cyclic ketones may serve via oxidative cleavage as

104

precursors for ω-aminoacids. In this vein, we envisioned a potential use for this methodology in the preparation of valuable cyclic non-natural amino acids, used for the construction of foldamers.^243,244 Attempted Mannich-type cyclisation of oxime ether 272 (table 23, entry 13) under the conditions of soft enolization using TiCl4 or TiCl3(Oi-Pr) and Et3N indeed led to cyclic products, however the desired product 302 (scheme 87) proved too unstable under the conditions, undergoing a secondary enolization and aziridine formation to yield the isolable product 303, along with varying amounts of rearranged vinylogous amide 304. Extensive optimization of this reaction unfortunately did not lead to synthetically useful yields of 302.

Scheme 87. Mannich cyclisation of 272 under the conditions of soft enolization.

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