II. JURISPRUDENCIA RELEVANTE
2.4. PERÚ
Having determined an enhanced reactivity profile of triazolium-derived NHCs in the achiral series, the asymmetric Steglich rearrangement using chiral triazolium-derived NHCs was next
investigated, beginning with the 5:5-fused bicyclic triazolium salts 56, 134, 399 and 164
(Figure 113, Table 19).
Figure 113: 5:5-Fused bicyclic triazolium-derived NHCs in the asymmetric Steglich rearrangement
Triazolium salt Solvent Conversion (R)-266:254 (%) a ee of (R)-266 (%) 56 THF ~70:30 <5 56 toluene ~55:45 <5 134 THF >98:<2 20 (ent) 134 toluene 95:5 20 (ent) 399 THF >98:<2 <5 399 toluene >98:<2 34 164 THF >98:<2 16 164 toluene 88:12 31
a Determined by 1H NMR spectroscopic analysis of the crude reaction product
Table 19: 5:5-Fused bicyclic triazolium-derived NHCs in the asymmetric Steglich rearrangement
Using the standard conditions in THF, these triazolium-derived NHC catalysts proved effective in promoting efficient rearrangement, generally obtaining the desired C-carboxyazlactone 266 in
>98% conversion within 1 h. The least effective precatalyst was the pyrrolidinone-derived triazolium salt 56, affording a ~70:30 mixture of desired product 266 to the decarboxylated
product, azlactone 254.i The levels of enantioenrichment, however, were modest (≤20% ee). By repeating the reactions using toluene as the solvent, the competing formation of azlactone 254
was more pronounced, though the phenylalanine-derived precatalyst 399 suffered no such loss in
product formation. The change of solvent to toluene also generally resulted in an increase in the enantioselectivity of the process, with the phenylalanine-derived precatalyst 399 proving optimal
also in terms of enantioselectivity (34% ee).
The range of morpholinone-derived NHC-precatalystsii was evaluated under similar conditions (Figure 114, Table 20). Similar trends of reactivity and enantioselectivity were obtained with
these morpholinone-derived triazolium salts, in comparison with 5:5-fused bicyclic triazolium salts. All of these triazolium-derived NHCs proved highly effective catalysts in THF, obtaining exclusively the desired C-carboxyazlactone product 266, though as effectively racemic products
in all cases. By changing the solvent to toluene, competing decarboxylation was observed in most cases, though this was minimal (<10%). The only catalyst which gave a significant, though small, increase in enantioselectivity was that derived from triazolium salt 416 (<5% → 20% ee).
Figure 114: Morpholinone-derived NHCs as catalysts for the asymmetric Steglich rearrangement
Triazolium salt Solvent Conversion (R)-266:254 (%) a ee of (R)-266 (%) 137 THF >98:<2 <5 137 toluene >98<:2 <5 ent-170 THF >98:<2 <5 (ent) ent-170 toluene >95:<5 <5 (ent) 416 THF >98:<2 <5 (ent) 416 toluene 95:5 20 (ent) 403 THF >98:<2 <5 403 toluene 88:12 <5 407 THF >98:<2 <5 407 toluene 90:10 6
a Determined by 1H NMR spectroscopic analysis of the crude reaction product
Table 20: 6:5-Fused bicyclic triazolium-derived NHCs in the asymmetric Steglich rearrangement
Having obtained relatively low levels of enantioselectivity with all NHC catalysts, other variables were next investigated to try to improve the enantioselectivity. Since the aminoindanol-derived catalysts, both known to effect excellent levels of enantioselectivity in Stetter reactions, proved ineffective at promoting asymmetry in the rearrangement reaction under the conditions evaluated, these triazolium salts were chosen for initial optimisation (Figure 115, Table 21). Variation of the base which generated the NHC appeared to have little effect on the ee
of the product, returning essentially racemic products, so the catalyst loading, solvent and reaction temperature were varied. Under a wide variety of conditions, with only some selected as an illustration, the aminoindanol-derived NHCs suffered from at least one of several drawbacks: at temperatures of ≥0 ºC, complete rearrangement was observed within 1 h but the products were
essentially racemic; lowering of the reaction temperature did improve the enantioselectivity, but this was modest (≤20% ee), and at the detriment of requiring extended reaction times (up to 16 h) to effect complete rearrangement. Furthermore, at low temperature, significant proportions of the decarboxylated azlactone precursor 254 were returned (up to 20%), even with strict
exclusion of air and moisture from the reaction manifold, presumably as a result of competing decarboxylation. Variation of the N-aryl moiety from phenyl to the more hindered mesityl substituent also appeared detrimental to the reaction in terms of both reactivity and enantioselectivity, however, the role of the different counterion cannot be excluded.
Figure 115: Optimisation studies using aminoindanol-derived triazolium salts
Precatalyst
Precatalyst loading
(mol%)
Base (mol%) Solvent Temp (ºC)
Conversion (R)-266:254 (%) a ee (%) 10 KHMDS (9) THF 0 >98:<2 <5 10 KHMDS (9) -78 to rt ~90:10 12 5 KHMDS (4.5) -78 to rt ~90:10 12 1 KHMDS (0.9) -78 to rt ~85:15 13 10 n-BuLi (9) -78 to rt ~90:10 9 10 LiHMDS (9) -78 to rt ~90:10 10 10 Et3N (9) rt ~90:10 11 5 KHMDS (4.5) toluene rt >98:<2 <5 5 KHMDS (4.5) -78 to rt ~85:15 20 50 KHMDS (45) -78 to rt ~95:5 <5 10 KHMDS (9) THF -78 to rt ~85:15 8 (ent) 10 Et3N (9) THF rt ~85:15 5 (ent) 5 KHMDS (4.5) toluene -78 to rt ~80:20 11 (ent) a Determined by 1H NMR spectroscopic analysis of the crude reaction product
Table 21: Optimisation studies using aminoindanol-derived triazolium salts
also be differences in electronic properties between these systems. Nolan and co-workers have obtained X-ray crystal structures of NHC-Pt complexes and examined the tilt angles θ between
different N-aryl ring substituents and the central azolium core (Figure 116).150 From the X-ray crystallographic data, a significant tilt angle is observed the N-phenyl substituted NHC of 419,
with an average of 50.9º observed, presumably as a balance between the steric repulsion in the complex and with the orbital overlap of the aromatic substituents with the central azolium core. In the N-mesityl substituted NHCs of complexes 417 and 418, the steric encumbrance introduced
by the N-substituents enforces the aromatic rings significantly out of conjugation with the triazolium ring, to nearly an orthogonal orientation (θ >74º). This loss of orbital overlap could
have a significant impact on the electronic properties of the NHC. Whilst these observations have been made in the solid state and with related NHCs, these data may provide an explanation for the significant differences in behaviour between the differentially substituted NHCs observed in the Steglich rearrangement and also other NHC-catalysed processes.
Pt S Cl Cl O Me Me N N Mes Mes Pt S Cl Cl O Me Me N N Mes Mes Pt S Cl Cl O Me Me N N N Ph Ph Ph 417 418 419 average tilt angle 74.4º 78.0º 50.9º
Figure 116: Tilt angles between different N-aryl substituents