Lithium phosphonate umpolung catalysts: Do fluoro substituents increase the catalytic activity?

Fluorinated and nonfluorinated phosphonates are employed as precatalysts in lithium phosphonate catalyzed cross benzoin couplings. Surprisingly, a decreased catalytic activity for the fluorinated precatalysts compared to the nonfluorinated systems is observed. Furthermore, the ring size of six, seven and nine membered ring catalysts appears not to be crucial for their catalytic activity.

Recently, we introduced fenchol based phosphonates as precatalysts, which are similarly accessible as fencholate metal catalysts [21][22][23][24][25], in the benzoin coupling (Scheme 2) [26]. A strong increase of the catalytic activity was observed for a benzylic fencholate, when the benzylic positions were occupied by CF 3groups (92% versus 19% yield, Scheme 2) [26]. This increased reactivity is thought to arise from a favored formation of the carbanionic d 1 -synthon intermediate, due to the electron withdrawing effect of the CF 3 groups. A comparison of fluorinated and nonfluorinated TADDOL phosphonates (which were used Scheme 1: Proposed catalytic cycle of the lithium phosphonate catalyzed cross benzoin coupling [18].
by Johnson's group) as precatalysts in benzoin coupling does not show any difference in reactivity (Scheme 2). In contrast the enantioselectivity is clearly higher with the fluorinated TADDOL precatalyst (Scheme 2).
Here, we analyze the effect of fluoro substituents on the catalytic activity by using different fluorinated and nonfluorinated phosphonates as precatalysts in the benzoin coupling.
Biphenyl-based fluorinated and nonfluorinated systems (6 [28][29][30], 7 and 8, Scheme 3) were chosen as precursors for the synthesis of nine ring phosphonates. The synthesis of these diols was realized by a double ortho lithiation of biphenyl and subsequent addition to the corresponding carbonyl compound. By this procedure, two asymmetric carbon centres and a chiral axis, which is fixed by intramolecular hydrogen bonds (6: Intramolecular O1-O2 distance 2.83 Å, 7: Intramolecular O1-O2 distance 2.81 Å, Figure 1 and Figure a Direction of hydrogen bond; b B3LYP 6-31G*. mate); t R1 = 9.1 min). A dimer associated by a hydrogen bond is apparent for the enantiomeric pair (6: intermolecular O1-O2 distance 2.81 Å, 7: intermolecular O1-O2 distance 2.80 Å, Figure 1 and Figure 2, respectively). The favored formed enantiomeric pair has the same configuration (R,R or S,S) for both benzylic carbon centres, which defines the conformation of the biphenyl axis (M(inus) for S,S and P(lus) for R,R).
The conformational stability of the biphenyl axis can be demonstrated by the energy difference of the optimized structures (B3LYP 6-31G*) ( Table 1) (Table 1). For these diastereomers two possible  phonates (Table 2). In general, 1 J(P-H) coupling constants increase with the electronegativity of the substituents [33]. The influence of electronegativity results from the change in s-character, given that the Fermi-contact is the dominant coupling mechanism [33]. According to Bent's rule [34] electron withdrawing substituents require more p-character in the bonding orbitals, which leads to an increased s-character in the bonding P-H orbital. The smallest influence on the coupling constant is apparent for phosphonate 11, in which the fluoro substituents are not in close proximity to the phosphorous atom (five bonds  The lithium phosphonate catalyzed benzoin reaction (Scheme 5) with phosphonates 9-15 as precatalysts led to the benzoin product in low to moderate yields (5-44%) ( Figure 5). The supposed increase in catalytic activity, which was observed for fencholbased phosphonate (Scheme 2) [21] with fluoro-substituted phosphonates as precatalysts, could not be confirmed. The highest yield was achieved with phosphonate 14 as precatalyst (44%). Contrary to expectations this yield is twice as high as the yield achieved with phosphonate 15. The reduction of the nucleophilic character of the phosphorus nucleophile in the first step of the catalytic cycle, and of the d 1 -synthon in the third step of the catalytic cycle (Scheme 1), could explain these results. The increased 1 J(P-H) coupling constants for the CF 3 substituted phosphonates (10, 13, 15, Table 2) suggest an increase in s-character at the phosphorus atom, which confirms a reduction in nucleophilic character. In contrast to the fenchol- based phosphonates [26] the best result was achieved by a nine membered ring phosphonate instead of a seven membered ring phosphonate. It can be concluded that the ring size is not of basic importance to the catalytic activity.

Conclusion
Three types of cyclic fluorinated and nonfluorinated phosphonates were synthesized and used as precatalysts in cross benzoin couplings with yields ranging from 5 to 44%. The inductive effect of CF 3 substituents in benzylic position of phosphonates 10, 13 and 15 gives rise to increased 1 J(P-H) couplings in P-H precatalysts and hence points to increased s-character at the phosphorus lone pair in the active anionic catalysts [33]. A rise of catalytic activity due to the inductive effect of CF 3 substituents, as was observed before for a fenchol-based phosphonate (Scheme 2) [26], was not realized with the phosphonates employed herein. Instead a reduction of catalytic activity was apparent with fluorinated phosphonates compared to the nonfluorinated phosphonates. This can be explained by a weaker nucleophilic character of the phosphorus nucleophile, as a consequence of the increased s-character. Comparisons of phosphonates with different ring sizes show that the nine ring phosphonates result in higher yields than do the six and seven ring phosphonates.

Supporting Information File 1
Experimental procedure and characterization data.