CAPÍTULO III: MATERIALES Y MÉTODOS
3.4 METODOLOGÍA DEL REACTOR RAFA
Section 2.1: Preparation of model oxazolyl carbonate substrates
To further extend the scope of the Steglich rearrangement and to gain a greater understanding of the reactivity of the substrates and catalysts, a wide range of oxazolyl carbonate substrates were prepared. The principal substrates chosen for investigation were derivatives of phenylalanine, with differing electronic and steric characteristics, with particular focus on the effect of changing the electronic properties of the carbonate function.110 The p-anisyl aromatic C(2)-substituent was chosen as this was shown to provide highly regioselective α-carboxylation, good levels of
stability to the final C-carboxyazlactone products, and was also shown to provide the greatest levels of enantioselectivity in the asymmetric rearrangement protocols adopted by Vedejs and Fu. The key intermediate azlactone 254, the precursor to the carbonate substrates, was ultimately
derived from DL-phenylalanine 250 via a facile four step procedure in excellent yield (Scheme 1).106 To investigate the differing effects of the carbonate function, a range of carbonates 255–259 was prepared with the respective chloroformate and Et3N in reproducibly
good to excellent yield. Under the reaction conditions, exclusive O-carboxylation was observed, with no direct C-carboxylation detected spectroscopically.
Scheme 1: Conversion of DL-phenylalanine to oxazolyl carbonates
Section 2.2: Synthesis of azolium salt precatalysts
To reaffirm the suitability of NHCs to promote the Steglich rearrangement, triazolium salt 128
was prepared according to literature precedent,110 via a three step protocol from lactam 260
(Scheme 2). This standard protocol, originally described by Rovis and co-workers, began from a key amide substrate: γ-butyrolactam 260 was treated with Meerwein’s salt to obtain the
phenylhydrazine, to afford the hydrazone hydrotetrafluoroborate salt 262. Final cyclisation with
triethyl orthoformate in methanol at reflux afforded the desired triazolium salt 128 in excellent
yield over the three steps.
Scheme 2: Synthesis of the triazolium salt precatalyst
To determine if other NHCs could promote the rearrangement, a selection of azolium salts from a range of precatalyst classes, namely, thiazolium, imidazolium and imidazolinium salts, were prepared and investigated. A simple thiazolium salt 203 was prepared from the commercially
available 4,5-dimethylthiazole 263 and benzyl chloride in good yield (Figure 59).
Figure 59: Synthesis of related thiazolium salt 203
The imidazolium and imidazolinium salts IMes HCl 79 and SIMes HCl 245 are commercially
available, but to determine the effect that the counterion of the azolium salt has upon the Steglich rearrangement, the related imidazolium tetrafluoroborate 265 (IMes HBF4) was prepared. This
was prepared from mesitidine 264,glyoxal, paraformaldehyde and aqueous tetrafluoroboric acid
in a one-pot procedure (Figure 60).
Figure 60: Preparation of IMes HBF4
Section 2.3: Examination of NHC catalyst classes
With the required substrates and catalysts in hand, a full investigation of the rearrangement protocol was undertaken, with the aim to better understand the behaviours of the catalysts and substrates. It was envisaged that the results of the study would prove useful in identifying the requirements for successful rearrangement, and thus give an insight into understanding the reaction.
Phenylalanine-derived phenyl carbonate 256 was chosen as the model substrate and was
investigated, using KHMDS as the base, in order to determine a reactivity profile (Figure 61, Table 1). The triazolium-derived NHC 247 successfully promoted complete rearrangement of the
phenylalanine-derived phenyl carbonate 256 to its C-carboxyazlactone product 266. Thiazolium
salts 203 and the commercially available 267 were ineffective at promoting rearrangement, but
that imidazolium salts 79 and 245 were more effective. It appeared that the nature of the
counterion may also play a role, with IMes HBF4 265 giving significantly less product
conversion than with the related chloride salt 79. Although these imidazolium-derived NHCs
promoted the rearrangement, the reaction mixture was generally contaminated with several side-products, of which the decarboxylated product, azlactone 254, was identified. These results
are in contrast with those described in the original publication (see Figure 57, page 32), in which only the triazolium-derived NHC 247 proved effective in promoting full rearrangement of the
alanine-derived methyl carbonate 244. Imidazolium-derived NHCs promoted only high levels of
rearrangement of the (phenylalanine-derived) phenyl carbonate 256.
Figure 61: Rearrangement screen with the different azolium salt classes
Precatalyst Conversion (%) a Isolated yield (%) b 128 >98 80 203 11 - 267 <5 - 79 >90 68 265 ~40 - 245 >90 -
a Determined by 1H NMR spectroscopic analysis of the crude reaction product b Isolated yield of homogeneous product following chromatographic purification Table 1: Evaluation of NHC catalyst classes
In order to investigate if this difference was due to the nature of the carbonate, the related phenylalanine-derived methyl carbonate 255 was evaluated using a range of azolium-derived
NHCs (Figure 62, Table 2). Consistent with the results obtained in the original publication and those with the phenyl carbonate, the triazolium-derived NHC 247 proved highly effective in
promoting rearrangement of the methyl carbonate 255. The imidazolium and imidazolinium salts 79 and 245 also proved much less effective, with only IMes promoting appreciable
rearrangement. Intuitively, this striking difference in chemoselectivity between the phenyl and methyl carbonates could be attributed primarily to the difference in electrophilicity of the carbonyls, as the phenyl carbonate would be expected to be more electrophilic than the methyl carbonate. The reactivity difference between different carbonates will be addressed in subsequent discussions throughout the thesis.
Figure 62: Screening of the methyl carbonate 255
Precatalyst (mol%)
KHMDS
(mol%) Time (min)
Conversion (%) a 128 (10) 9 90 >98 (76) b 128 (5) 4.5 90 >98 128 (1) 0.9 90 >98 128 (1) 0.9 5 >98 79 (10) 9 90 ~75 (68) b 245 (10) 9 90 <5
a Determined by 1H NMR spectroscopic analysis of the crude reaction product b Isolated yield of homogeneous product following chromatographic purification Table 2: Screening of methyl carbonate 255 with NHCs