Initial exploration of in situ oxidative cyclisation

Initial attempts to put this design into practice using various Michael acceptors like cinnamates, crotonates and chalcones together with homoallylic Grignard reagents and alkyllithiums

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failed, either due to problems with enforcing complete conversion during the conjugate addition, or due to unselective oxidation.

Several oxidant systems, that were previously studies by the Jahn group,155-157,160,161 were explored. These were 1) 52 in combination with TEMPO, 2) 109 (scheme 33), 3) 109 with catalytic amount of 52. In most cases, after oxidation of the enolate, cyclisation was pre-empted either by rapid trapping of the α-carbonyl radical by TEMPO or by halogenation. The problem is illustrated on the example of Cu catalysed conjugate addition to cyclohex-2-en-1-one (scheme 33), followed by oxidation by methods 1)-3). The complex product mixtures contained predominantly TEMPO-adduct 110a and halogenated 110b, arising presumably from fast atom transfer halogenation of the α- carbonyl radical by Cu(II) bromide species.

Scheme 33. Conjugate addition to cyclohex-2-en-1-one followed attempted by in situ oxidative cyclisation.

This problem was ultimately solved by Kapras ¹⁵⁷ during the total synthesis of ent- progesterone, who avoided the formation of 110b by excluding Br atoms and found conditions for persistent-radical-effect-mediated thermal cyclisation of 110a. This method however doesn’t lend itself to the desired one-pot annulation. Attempts at using alkyl nitrites with or without BF3 as the terminal oxidant were unsuccessful. Conjugate addition followed by oxidation with alkyl nitrite (scheme 34) resulted in no cyclisation. To our surprise, the product mixture largely consisted of acyclic aldoxime 111 and aldehyde 112, likely originating from oxidant-assisted hydrolysis of 111.¹⁶⁴

Scheme 34. Conjugate addition coupled with in situ enolate oxidation by i-AmONO leading to fragmentation.

This unexpected reactivity can be attributed to a direct 2-electron nitrosation of the enolate by the nitrite, followed by nucleophilic addition of alkoxide to the ketone triggering retro-aza-Claisen fragmentation. Further experiments showed that this is a general reaction pathway of nitrite-mediated oxidation of ketone enolates in THF and led to the discovery of synthetically useful C-C cleavage reaction, discussed in detail in chapter 4.5. On the other hand, it excluded the use of alkyl nitrites as terminal oxidants for the radical cyclisation.

Due to the undesired fast quenching of α-carbonyl radicals by TEMPO and the interference of CuBrn salts (scheme 33), we switched our focus to ylidenemalonates as Michael acceptors. Their increased electrophilicity was expected to improve the efficiency of the conjugate addition step. At the same time, oxidation of their enolates produces more stabilised and more electrophilic 2-malonyl radicals, which should be less easily quenched by TEMPO trapping or halogen transfer. Additionally, the products of such premature quenching may undergo homolysis, therefore group-transfer

41 cyclisation may still occur from that stage. To find a suitable solvent and Cu source for the conjugate addition, model benzylidene malonate 113 was arylated using in situ generated PhLi in THF in the presence of 0.2 equiv. CuBr∙DMS (scheme 35). Fast and fully regioselective addition proceeded at – 40 °C, therefore these conditions were selected as the basis for the planned one-pot sequence.

Scheme 35. β-arylation of benzylidene malonate 113.

The first system to successfully implement the conjugate addition/in-situ oxidation concept was addition of bromostyrene 115 to malonate 113, followed by oxidation by excess 52 (table 3).

First, smooth formation of the Michael adduct 116 was verified by quenching the enolate and isolating 116 in 90% yield. Oxidation of the enolate by 52 in the presence of TEMPO gave a mixture of cyclic products, including inseparable isomeric alkenes 117a (24%) and 117b (7%), tertiary alcohol 117c (13%) and a trace of lactone 117d. None of the products contained the TEMPO moiety, suggesting that a secondary oxidation of the cyclic benzylic radical took place. Alternatively, 117a and 117b may have been formed by TEMPOH elimination, due to the known instability of tertiary TMP-oxy ethers.¹⁶⁵ Oxidation by 2.2 equiv. of 52 (entries 2, 3) in the absence of TEMPO resulted in a very similar product distribution. Interestingly, introduction of O2 to otherwise identical experiment (entry 4) still led to the formation of alkenes 117a, 117b, however, instead of alcohol 117c, lactone 117d was obtained in 22% yield.

Table 3. One-pot conjugate addition/in-situ oxidative cyclisation.

Entry Solvent Oxidant (equiv.) T °C 117a (%) 117b (%) 117c (%) 117d (%) 1 THF FeCp2+ PF6- (1.2),

TEMPO (1.2)

–40 24 7 13 1

2 ^a) THF FeCp2+ PF6- (2.2) 0 30 8 15 2

3 ^a) THF FeCp2+ PF6- (2.2) 0 27 3 17 0

4 DME FeCp2+ PF6- (2.2), O2 0 30 12 0 22

a) Duplicate experiments.

Despite not being immediately useful for the synthesis of natural products, these results proved, that the concept of conjugate addition/in-situ oxidation is valid in principle. Compounds 117a- d all result from a regioselective conjugate addition, followed by 6-endo-selective cyclisation, and are all likely descended from cationic intermediate 118. The benzylic stabilisation increases the lifetime of the radical and therefore allows the second SET oxidation. Similar double oxidation by 52 in the

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context of 5-exo-trig cyclisation was in fact described earlier.¹⁶⁶ The exclusive 6-endo-trig cyclisation mode is fully controlled by the position of the methyl group in α-styrene.

In order to reverse the cyclisation mode to 5-exo-trig, lithiated β-methylstyrene 119 was subjected to Cu-catalysed conjugate addition to 113, followed by oxidation of the enolate by the 52/TEMPO system (scheme 36). As predicted, exclusive 5-exo-trig cyclisation took place followed by TEMPO trapping of the cyclised radical, giving a partially separable mixture of all four possible diastereomers of 120 in 55% yield.

Scheme 36. One-pot conjugate addition/in-situ oxidative cyclisation of styrene 119.

Unlike in the case of α-methylstyrene 115, the non-stabilised nature of the proximate cyclisation product (the cyclic secondary radical intermediate) makes the use of persistent radical TEMPO mandatory in this cyclisation. Such radicals are not oxidized efficiently by FF due to short lifetime and the high energy of resulting secondary carbenium ion. Non-stabilised secondary alkyl radicals are however known to undergo very fast (near diffusion controlled) trapping by TEMPO.¹⁶⁵

Considered together, the results of annulation of α- and β-styrene guided the next step on the way to the methodology required for the synthesis of FISs, that is annulation of stilbenes, which will be discussed in the following chapters. The fact that CuX2 salts were tolerated during the oxidation and perhaps even aid in the SET process prompted us to invest more effort into the optimization of the Cu-catalysed conjugate addition using bromostilbenes.