Size‐Induced Inversion of Selectivity in the Acylation of 1,2‐Diols

Abstract

Relative rates for the Lewis base-catalyzed acylation of aryl-substituted 1,2-diols with anhydrides differing in size have been determined by turnover-limited competition experiments and absolute kinetics measurements. Depending on the structure of the anhydride reagent, the secondary hydroxyl group of the 1,2-diol reacts faster than the primary one. This preference towards the secondary hydroxyl group is boosted in the second acylation step from the monoesters to the diester through size and additional steric effects. In absolute terms the first acylation step is found to be up to 35 times faster than the second one for the primary alcohols due to neighboring group effects.

Annelated Pyridine Bases for the Selective Acylation of 1,2‐Diols

“…Exploiting π ‐ π ‐interactions between secondary alcohol G and the planar TCAP motif as well as size effects of the anhydride reagents, it was indeed possible to steer intermolecular competition reactions towards preferred acylation of the secondary alcohol G (Figure 1, left side). The same factors were subsequently also found to impact the intramolecular competition between primary and secondary OH groups in 1,2‐diols of general structure I (Figure 1, right side) [22] . In absolute terms the regioselectivity of the TCAP‐mediated process was found to be quite moderate in the first acylation step and then to increase in acylations of the initially formed monoesters.…”

“… [21,25] The relative rate constant k rel reflecting the selectivities of the formation of the products 12 and 13 is here defined as the ratio between the effective rate constant k 2 for acylation of primary alcohol 11 and the effective rate constant k 1 for acylation of secondary alcohol 10 . As acylation reagent 2‐methyl‐6‐nitrobenzoic anhydride 14 was selected due to its comparatively high reactivity and preference for secondary alcohols identified in earlier studies [21–22] . Turnover‐limited competition experiments were performed with a 1 : 1 mixture of 10 and 11 adding 14 as the limiting acylation reagent to allow conversions of 20–70 %, an excess of auxiliary base Et 3 N ( 15 ), and 10 mol% of the corresponding Lewis‐base catalysts 1 – 6,8 b in CDCl 3 at +23 °C.…”

“…Based on their performance in the 1 : 1 competition studies described above, seven catalysts were selected for further studies in the acylation of 1‐(naphth‐2‐yl)ethane‐1,2‐diol 16 testing their ability to differentiate vicinal primary and secondary hydroxyl groups. Following earlier work on 16 [22] the initial formation of monoesters 17 and 18 and the subsequent second acylation to yield diester 19 were followed using absolute kinetics measurements (Scheme 3). Analysis of these results yields selectivity value k rel,a defined as the ratio between the effective acylation rate of primary hydroxyl group ( k 3 ) and the secondary hydroxyl group of 16 ( k 4 ).…”

“…The ratio between the effective acylation rate of primary alcohol 18 ( k 6 ) over the secondary alcohol 17 ( k 5 ) is reflected in selectivity value k rel,b for the second acylation of the monoesters 17/18 to the diester 19 . The migration from 18 to 17 is neglected in this study [22] . With these definitions both selectivity values k rel,a and k rel,b reflect the acylation selectivities for primary over secondary hydroxyl groups.…”

“…The same factors were subsequently also found to impact the intramolecular competition between primary and secondary OH groups in 1,2-diols of general structure I (Figure 1, right side). [22] In absolute terms the regioselectivity of the TCAPmediated process was found to be quite moderate in the first acylation step and then to increase in acylations of the initially formed monoesters. In kinetic resolution experiments it was already demonstrated earlier that size effects can have a strong influence on the enantioselectivity.…”