Reactions via Aldehyde Functionality

The above synthetic methods have all shown that, while TEMPO can certainly be incorporated into 3-methyl-but-1-ene or 3-methyl-1,4-pentadiene, rearrangement around the alkene to form a more sterically favourable, and more substituted, alkene product is

63 preventing formation of the desired compounds. Ideally, the alkene group would be ‘protected’ in order to prevent rearrangement of the radical intermediate. An RSA of the target compound conducted with this in mind (Figure 29) suggests that the simplest method of implementing this would be by introducing the alkene functionality after that of the TEMPO group, therefore preventing the rearrangement process.

Figure 29: RSA for protecting the alkene prior to TEMPO addition

The addition of TEMPO into this system was attempted using hydrogen abstraction reactions again, now that there is no facility for undesired rearrangement to primary species. Once TEMPO has been incorporated, the aldehyde can be converted into an alkene via a Wittig reaction. Use of a phenyl group as part of this system will facilitate hydrogen abstraction, leading to a resonance stabilised benzylic radical. The structure of the new target precursor compound 2.05 is given in Figure 30.

Figure 30: New target molecule 2.05 2.05

64 2.5.1. Reaction Between TEMPO and 2-Phenyl propanal, Using a Cobalt Catalyst Under Oxygen.

The aldehyde 2-phenylpropanal was reacted with a Co2+ _{catalyst and oxygen, and the}

resulting radical trapped with TEMPO in order to form target precursor molecule 2.05. This is shown below in Figure 31.

Figure 31: Proposed reaction to form 2.05

However, the reaction failed to yield the target product, with starting material clearly detectable at the end of the synthesis. The failure of this reaction could be due to two reasons: steric hindrance or C-H bond strength. Regarding sterics, the trapping of TEMPO in this position is not made easier by the bulk around the carbon radical, however there are (admittedly few) examples of tertiary TEMPO functionality within the literature, so it is unlikely that sterics alone cause the failure of this reaction.139 _{The C-H bond targeted}

for abstraction may be too strong for the reaction to easily occur: an observation supported by the lack of any indication of ‘other’ hydrogen abstraction products within the reaction mixture. Indeed, at approximately 353 kJ mol-1_{, this is stronger than the C-H}

bonds targeted previously with the diene chemistry.120 _{Supporting this is the observation}

in a literature system, again based around a cobalt activating oxygen, of radical reaction with aromatic toluene being ca. a sixth of non-aromatic equivalents.140 _{Attempting to form}

2.05 through hydrogen abstraction of 2-phenylpropanal also proved unsuccessful when Fenton chemistry was applied. As such, a different approach is instead required in order to synthesise a TEMPO functionalised aldehyde.

65 2.5.2. Oxidation of a TEMPO Functionalised Alcohol

Given the lack of success towards synthesising 2.05, formation of the corresponding TEMPO functionalised alcohol 2.06, and subsequent oxidation to 2.05 would be a potentially viable route. The formation of 2.06 has been described previously within the literature by Prechter et al.141 _{This reaction, in Figure 32, proceeds in two key steps. The}

first is based on Fenton chemistry, and involves the formation of a hydroxyl radical, which will subsequently react with the double bond of α-methylstyrene to form a carbon centred radical. The second step has the carbon radical trapped out by the excess TEMPO present within the reaction mixture, giving the tertiary functionalised alkoxyamine product 2.06.

Figure 32: Formation of 2.06 via methodology from Prechter et al.141

Using this synthesis, a 24% yield of 2.06 was obtained, almost identical to that recorded by Prechter et al.141 _{The next step, conversion of an alcohol to an aldehyde, is a common}

procedure within the literature: there are a variety of oxidation methodologies that can be applied in order to form the corresponding aldehyde 2.05 from alcohol 2.06 (Figure 33).

Figure 33: Oxidation of 2.06 to form 2.05

2.05 2.06

66 The first method of oxidation trialled was reaction of 2.06 with pyridinium chlorochromate (PCC). This method, developed by Corey et al.,142 _{is known to be an effective single oxidant,}

with the chromium being reduced from Cr(VI) to Cr(IV) during this process. However, the product obtained from this reaction was not the target aldehyde, indeed NMR suggests that the major product of the reaction was instead acetophenone, with no indication of the target aldehyde at all by NMR.

Formation of acetophenone from PCC oxidations has been observed in the past from other benzylic alcohols by Fernandes et al.143 _{They suggested that the acetophenone is formed}

via a C-C bond cleavage, along with a degradative oxidation, and also provided evidence of similar reactions occurring with allylic alcohols. However in some instances the target oxidation products were also observed, although in a significantly lower yield that the product that has undergone C-C cleavage. Unfortunately there does not appear to be any of this non cleaved product in the system studied here.

Other methodologies for oxidation were also trialled, using the Dess-Martin procedure,144

and also Swern oxidation.145 _{The Dess-Martin procedure requires coordination of the}

alcohol to an iodine complex, Dess-Martin Periodinane (DMP), which will gradually decompose to release the oxidised aldehyde product.146 _{The Swern oxidation meanwhile}

is based on ‘activated’ DMSO reacting with the starting alcohol, to form an alkoxysulfonium species which can subsequently be deprotonated before fragmentation to produce the aldehyde.147 _{Both species are known to be effective single oxidants.}

Both oxidation methods do however fail to oxidise alcohol 2.06. In each case, starting material can clearly be observed, both by NMR and mass spectrometry. The failures of these reactions could be attributable to undesired interactions, for example between the oxygen of the TEMPO group with the periodinane. Also, oxidation around the nitrogen of TEMPO may be hindering formation of the desired compounds. DMP can be found within the literature to have oxidised an alkoxyamine,148 _{however in doing so the rate constant}

for C-O bond cleavage increased, giving the suggestion that any small amount of oxidised compound is lost due to ensuing C-O homolysis. Given the failure of these oxidation

67 methods, it appears that changing focus to a different method of introducing TEMPO into a molecule already functionalised with an aldehyde may be prudent.