Concentration.

Generally, concentration plays the most significant part in the outcome o f free radical reactions. Using acetonitrile as the solvent and the /V-aectoxy-N-bcnzyl pent-4-enamide (108) as substrate, the effect o f concentration was investigated. It was decided to use the concentration o f the preliminary cyclisations (0.19M) as a convenient starting point; this concentration was then halved and the process repeated a further 3 times. The results o f which are shown in table 14.

Chapter 3 : New alternative methods for generating amidvl radicals.

Table 14. Effect of concentration on the cyclisation o f (108)

Entry Solvent Cone. Yield8 _Ratiob

(106:115:116) 1 MeCN 0.19M 85% 58:15:27 2 MeCN 0.09M 96% _72:3:25 3 MeCN 0.05M 81% 62:3:35 4 MeCN 0.02M 93% 56:3:41 5 MeCN 0.01M 72% 43:0:57

a Combined yields o f all three components. b Ratio determined by 400 MHz N.M.R..

As can be seen from the results the lower the concentration the lower the amount of mono-cyclised product (106) formed with its complete exclusion when the concentration is 0.01M. The concentration o f 0.01 M proved to be the best providing the finest result, in fact the only result where the amount of tandem product (116) reached a synthetically useful yield o f 46% (determined by N.M.R.).

Concentration effects on the Cu(II)(OTf)2 mediated cyclisation of /V-acetoxy-A-benzyl pent-4-enamide (108).

Concentration (M)

Figure 19. Effect of concentration on the Cu(II)(OTf)] mediated cyclisation of jV-acetoxy-yv-benzyl pent-4-enamide (108).

Chapter 3 : New alternative methods for generating amidvl radicals.

The effect of concentration may well give an insight into the mechanism involved in forming each o f the observed products. If the mechanism described in scheme 51 was correct then one might expect that as the concentration was reduced the amount o f tandem product (116) observed would also decrease, due to the lower concentration o f the copper (II) species. This may indicate that the proposed mechanism is wrong and that the process does not involve the copper (II) oxidation to the corresponding cation but is a radical type process. The amount o f monocyclised product (115) observed remained constant with a slight decrease when the concentration was reduced. This would be consistent with the hydrogen abstraction mechanism proposed, as the variation in solvent concentration would have little effect as it was present in such a large excess. The amount of reduction product was reduced when the concentration was decreased, implicating the concentration o f the Cu(II) salt in its mechanism o f formation.

However, very recently my attention was drawn to a paper published on the Diels Alder reaction shown in scheme 52.<l9a'b) The precursor employed to investigate this type o f Diels Alder reaction was strikingly similar to that used to investigate the Cu(OTf)2

mediated cyclisation as shown in scheme 52. This indicates that two separate mechanisms may be in operation. •

• Cu(II) causing cleavage o f the N-O bond to give a radical which can undergo mono-cyclisation and reduction (section 3.2.3).

• Aza Diels Alder reaction to give the tricyclic compound (116).

Chapter 3 : New alternative methods for generating amidvl radicals.

OAc

Scheme S2

The two mechanisms are probably in direct competition. At low concentrations there is very little initiation by copper to give the radical and thus little reduction and monocyclisation are observed. Therefore, when the copper is in low concentration a high proportion o f the tricyclic compound is observed via the Diels Alder mechanism. At higher concentrations o f copper the alternative mechanism is more prevalent and proceeds via the Cu(II) mechanism to give more reduction and mono-cyclised products.

The amount o f monocyclisation is always small relative to reduction due to the competing hydrogen abstraction reaction with the vast excess o f solvent present. The aza-Diels-Alder mechanism also provides an explanation why different ratios of products are observed with different O-acyl protecting groups. Each o f the different O- acyl groups would have different abilities to undergo elimination from the precursor. The corollary o f this is that had the mechanism come to light before the end of the research, significantly better yields o f the tri-cyclic compound (116) could have been isolated.

Chapter 3 : New alternative methods for generating am idyl radicals.

In an attempt to broaden the scope o f the reaction we investigated the cyclisation o f the related /V-acetoxy-jV-methyl pent-4-enamide (113). Several different attempts however using the reaction conditions discovered for the reaction of (113) led to failure, with starting material being isolated.

This may indicate that the inclusion o f a A'-benzyl group protecting the nitrogen may be essential for the reaction to be successful indicating the mechanism may be more complicated than first thought. Indeed, it may mean that the redox potential o f the copper salt system may have to be refined for each different precursor. This would render the reaction almost synthetically useless. In order to try to generate radicals from this second precursor we screened a wide variety o f other copper reagents as the redox potential of the copper salt may be the important factor. However when the Cu(OTf).C6H6, Cu(OTf)2.DBN or Cu(OTf)2-DBU were utilised the reactions gave only

starting material. When the Cu(I) reagent Cu(CH3CN)4PF6 was utilised the starting

material underwent quantitative reduction, with no cyclised material detected.

3.2.4.4 Future work.

Future work could be carried out to determine if the Diels Alder mechanism is in fact operative in the reaction. This would only require repeating the reaction with no copper salt present at the temperature stated. Also if the mechanism is operative then future

Chapter 3 : New alternative methods for generating amidvl radicals.

work could include looking at various different precursors with suitably substituted double bonds. The stereochemistry o f such reactions may also be probed.

3.3 Tin mediated radical cyclisation of 7V-acetoxy-Ar-benzyl-pent-4-enamide (108).

The cyclisation of A'-acetoxy-A^-benzyl pent-4-enamide (108) with tin will test Zard’s hypothesis that the initial radical formed (185) must be further stabilised by delocalisation (i.e. into a phenyl ring o f a benzoyl-protecting group) (scheme 53).

R

Scheme 53. Barton-McCombie reaction.

Research carried out showed that the substitution o f the benzoyl group with an acetyl group did not cause the reaction efficiency to decrease. Comparison between the cyclisation o f the benzoyl and acetyl precursor proved favourable with comparable amount o f cyclised and reduction product being formed in each case.

The reaction would also allow us to compare the product ratios obtained from the cyclisation o f (108) with Cu(OTf) 2 with that o f tin. Also, to determine whether this

benzoyl stabilisation was truly necessary for the tin mediated generation o f amidyl radicals we reacted (108) with tributyltin hydride. Cyclisation o f (108) with BuaSnH added over 8 hours using AIBN via syringe pump was successful giving 28% (115) and

Chapter 3 : New alternative methods for generating am idyl radicals.

of mono (115) (6%) and tandem (116) (45%) cyclised products] and 17% reduced

(106). In the tributyltin hydride case no tandem product was observed presumably due to the absence of any oxidising agent.