3.3.3. Mechanistic Studies

Several practical and theoretical studies have been carried out to investigate the mechanism of the HKR of terminal epoxides by Co(III)salen complexes. Even though the cooperative mechanism has been supported by many studies [28,29], a few features about this reaction required further investigation. One of them was the influence of di fferent counterions on the reactivity of the catalyst.

In most of the early papers regarding the HKR of epoxides using Co(III)salen catalysts, the acetate anion was employed as the counterion. However, later studies showed that the reaction could be promoted or demoted by changing the counterion [110,150]. Jacobsen and coworkers [151] performed extensive mechanistic studies in an e ffort to understand and explain this e ffect, and to identify more active catalysts for the HKR of terminal epoxides. As illustrated in Scheme 45, two possible reaction pathways that compete with each other are proposed. When the counterion (X) is completely non-nucleophilic (e.g., hexafluoroantimonate), the reaction undergoes a less selective monometallic pathway, where the epoxide is activated by the Co(III)salen(X) and attacked by water (Scheme 45, top). When the counterion is nucleophilic (e.g., chloride or acetate), a bimetallic cooperative pathway takes place (Scheme 45, bottom). In the latter pathway, the active nucleophile Co(III)salen(OH) is formed irreversibly from an initial hydrolysis of Co(III)salen(X). The bimetallic pathway being the major pathway is supported by kinetic studies by Kleij and Jacobsen [114,139] and DFT calculations by Li [152]. In the bimetallic pathway, the key to obtaining high rates in the HKR reaction is to have an equal ratio of Co(III)salen(X) (which could activate the epoxide) and Co(III)salen(OH) (which could act as nucleophile). Kinetic studies of a number Co–salen complexes with di fferent counterions showed that Co(III)salen(OTs) achieved full conversion fastest in the HKR of 1,2-epoxyhexane. This was attributed to its slower coordination to the epoxide, thus maintaining a more favorable Co-X/Co-OH ratio throughout the reaction [151]. The experimentally observed trends of reaction rates between di fferent counterions (OTs > OAc > Cl) were also supported by DFT calculations performed by Sherrill and coworkers [153].

**Scheme 45.** Proposed reaction pathways for the HKR of terminal epoxides catalyzed by Co(III)salen complexes [151]. (top) A monometallic pathway with one Co–salen catalyst activating the epoxide and H2O acting as a nucleophile. (bottom) A bimetallic cooperative pathway with initial formation of Co(III)salen(OH) from the reaction between Co(III)salen(X), H2O, and epoxide, followed by a reaction between the so-formed activated nucleophile Co(III)salen(OH) and an epoxide activated by another Co(III)salen(X) catalyst.

Another mechanistic mystery concerned the deactivation of the catalyst. In the original paper where Co–salen **63** (Scheme 40) was first employed in the HKR of epoxides, the catalyst needed to be regenerated by treatment with acetic acid in air before it could be reused [109]. One of the possible

explanations was that Co(III) was reduced to Co(II) through a one-electron transfer oxidation during the reaction. Although many of the later Co–salen catalysts did not require reactivation, the reason for the occasionally observed deactivation remained unclear. In a mechanistic study, Davis and coworkers ruled out the reduction hypothesis by UV-Vis and XANES (X-ray absorption near edge structure) spectroscopic studies of the catalyst before and after the HKR reaction [154]. Another suspected reason of deactivation, the formation of a catalyst dimer, was investigated by ESI-MS studies. While dimer formation was detected over time for Co–salen complex **64** (Figure 26) in dichloromethane, no di fference in reactivity or enantioselectivity in the HKR reaction was observed between the dimeric material and fresh catalyst. Instead, it was proposed that the deactivation was mainly due to the formation of the less active Co(III)salen(OH) species [155]. In the proposed mechanism (Scheme 45), the Co(III)salen(OH) species is formed irreversibly and the more selective bimetallic pathway is dependent on the presence of both Co(III)salen(OH) and Co(III)salen(X), where the Co(III)salen(X) complex is good at activating the epoxide. This hypothesis was further supported by experiments where a Co(III)salen(Cl) complex was recycled in the HKR of epichlorohydrin. Without reactivation, Co(III)salen(Cl) showed a significant loss of catalytic activity after one reaction cycle, because of the rapid formation of Co(III)salen(OH). By adding a non-cooperative complex Co(III)salen(SbF6), the catalytic activity was completely restored.

There has also been some theoretical studies focused on the mechanistic origin of the high selectivity and broad scope of the HKR of epoxides catalyzed by Co(III)salen complexes. Jacobsen and coworkers published a comprehensive study on this issue, resulting in several important findings [156]. First, effective catalysis could be induced only when the two salen moieties in the cooperative pathway had the same absolute configuration. The specific stereochemistry of the salen was not important, only the *matched* stereochemistry (i.e., the two interacting Co-complexes should either both be (*S*,*S*) or both (*R*,*R*)). Secondly, the stereochemical communication was primarily due to the stepped conformation of the entire metal–salen complex (Figure 50), and not due to the shape of the diamine backbone. The stepped conformation is the tilt of the salicylaldimine aryl rings relative to the equatorial plane of the complex. This conformation is not dependent on the presence of an enantiomerically pure diamine backbone that enforces the conformation, such as *trans*-1,2-diaminocyclohexyl. Rather, it was found that salen complexes derived from achiral diamines such as 1,2-ethylenediamine were also capable of adopting this stepped conformation. This finding was further supported by X-ray crystal structures and computational studies. Finally, the binding geometry of the terminal epoxides to the Co(III)salen complexes was independent of the substituent of the epoxides which could explain the broad scope of HKR reactions catalyzed by Co(III)salen catalysts.

**Figure 50.** The stepped conformation of a metal–salen complex.

## 3.3.4. Other Studies

Berkessel and Ertuerk [157] reported an interesting catalyst for the HKR of terminal epoxides. They designed and synthesized DIANANE (*endo*,*endo*-2,5-diaminonorbornane)-based Cr(III) complexes **127** and **128** (Scheme 46), which exhibited high reactivity and enantioselectivity in the HKR of terminal epoxides under low catalyst loading (Scheme 46). Both catalysts were more enantioselective than the parent Cr–salen complex **1** (Scheme 4). Complex **127** with Cl– counterion was less active than complex **128** with OTs– counterion, which is in line with the counterion e ffect previously described.

**Scheme 46.** The hydrolytic kinetic resolution of terminal epoxides catalyzed by Cr-DIANANE-salen complex **128**. DIANANE = *endo*,*endo*-2,5-diaminonorbornane.

Schulz and coworkers [67] implemented a heterobimetallic dual-catalyst system for the HKR of terminal epoxides. A 1:1 mixture of complex **129** and **130** (Figure 51) was employed in the HKR of phenyl glycidyl ether, allyl glycidyl ether, and styrene oxide in THF. The reactions with mixed catalysts afforded both products with excellent conversions (up to 57%) and enantioselectivities (up to 94% *ee* for 1,2-diols, up to 99% *ee* for the unreacted epoxides), while reactions employing only catalyst **129** were less reactive and enantioselective. Kinetic studies revealed a first order dependence on the concentration of the Co–salen complex **129**, which supported a heterobimetallic cooperative pathway similar to the cooperative mechanism in Scheme 45, where Co–salen complex **129** would be responsible for the generation of the nucleophilic Co(III)salen(OH) and Mn–salen complex **130** would be responsible for the activation of the epoxides. The study also included an investigation of different combinations of the absolute configuration of the two complexes. Higher enantioselectivity was achieved when the two complexes had the same absolute configuration which was in agreemen<sup>t</sup> with Jacobsen's [156] findings for a similar system.

**130**0 0Q

**Figure 51.** Salen complexes **130** and **131**.

There are also examples of research that focus on more general reaction conditions. For example, Kim and coworkers [158] described the advantage of ultrasonication over mechanical stirring in the Co(III)salen-catalyzed HKR of terminal epoxides, both for homogeneous and heterogeneous catalysts. With ultrasonication, a shortening of the reaction time was observed in all cases.

#### *3.4. With Alcohols, Phenols, and Carboxylic Acids*

In addition to water (HKR), other oxygen-containing nucleophiles such as phenols, alcohols and carboxylic acids have also been employed in the KR of terminal epoxides. The ring-opened products are monoprotected enantioenriched 1,2-diols, which are versatile building blocks in the pharmaceutical industry and natural product synthesis [159]. Many of the catalysts mentioned above that are effective in the HKR of terminal epoxides are also found to work well for the KR of epoxides with phenols and alcohols as nucleophiles.

Jacobsen and coworkers [160] investigated several of their Co–salen complexes as catalysts in the KR of epoxides with phenols and alcohols as nucleophiles. In an early example, they employed catalyst **131** (Scheme 47) in the phenolic kinetic resolution of a number of different terminal epoxides. The ring-opened products where obtained in high yields and with high enantioselectivity (Scheme 47). The protocol could also be extended to different *para*- and *meta*-substituted phenols as nucleophiles, with consistently high yields and *ee* values for the ring-opened products.

**Scheme 47.** The phenolic kinetic resolution catalyzed by Co–salen complex **131**.

The polystyrene resin-supported Co–salen catalyst **108** (Figure 41) was employed in the phenolic KR of terminal epoxides in the first examples of an enantioselective catalytic synthesis of parallel libraries [161]. Following this protocol, a wide range of terminal epoxides and phenol nucleophiles were employed in parallel syntheses, resulting in 110 different 1-aryloxy-2-alcohols which were obtained in high yields (80–99%) and *ee* values (up to 99% *ee*). The reactions were performed using the epoxide as a solvent. As such, an excess of epoxides was used and therefore all yields were calculated based on the nucleophile [139,161].

The oligomeric macrocyclic Co–salen catalyst **35** (Scheme 10) was proven to also be efficient in the KR of epoxides with phenols and alcohols as nucleophiles [58]. Using complex **35** as catalyst, a broad range of phenols (with electron withdrawing and -donating substituents in the *ortho*-, *meta*and *para*-position) and primary alcohols (including benzylic and allylic) could be used as nucleophiles in the HKR of a number of different terminal epoxides. The ring-opened products were isolated in high yields (36–45%) and with excellent enantioselectivities (97–99% *ee*). All reactions were performed in acetonitrile with catalyst loadings of 0.0075–0.5 mol% Co, with more sterically hindered nucleophiles requiring the higher catalyst loadings.

Weck and coworkers applied their oligomeric Co–salen complex **77** (Figure 31) in the KR of epichlorohydrin and 1,2-epoxyhexane with a limited number of phenols and aliphatic alcohols. The reactions performed in TBME or acetonitrile and with a low catalyst loading (0.02 mol% Co) afforded the ring-opened products in 38–45% yield and 95–99% *ee* [162].

Kim and coworkers published a number of studies where different Co(III)salen catalysts were employed in the phenolic KR of terminal epoxides. Most of these studies focused on dimeric Co–salen complexes linked by group 13 elements (catalyst **54–56** in Scheme 34) [163,164] and the immobilization of these catalysts on microporous materials such as zeolite [165,166], mesoporous materials such as SBA-15 and SBA-16 [146,148], and different macroporous materials [167,168]. In all cases the catalysts exhibited good enantioselectivities, but the substrate scopes were usually limited.

Kim's group also made efforts to apply Co–salen catalysts in the KR of terminal epoxides with carboxylic acids as nucleophiles. Dimeric Co–salen complexes bridged by the Lewis acids GaCl3 and Al(NO3)3 (complex **55** in Scheme 34 and complex **132** in Figure 52) were investigated in the KR of terminal epoxides with a number of different carboxylic acids in TBME [128,169]. The reactions afforded 2-hydroxy monoesters in good yields (35–43%) and with moderate to good enantioselectivities (53–86% *ee*), but most of the products needed further recrystallization or other treatment to provide practically applicable enantioenriched compounds. One of the applications of this reaction was the synthesis of highly enantioenriched (*S*)-glycidyl butyrate (Scheme 48). Hence, catalyst **55** was employed in the KR of epichlorohydrin with butyric acid. The so formed chlorohydrin (76% *ee*) was then subjected to a ring closing reaction under basic conditions, again promoted by catalyst **55**, affording (*S*)-glycidyl butyrate in 98% *ee*.

**132** ; 12

**Figure 52.** Dimeric Co–salen complex **132**.

**Scheme 48.** The synthesis of (*S*)-glycidyl butyrate by kinetic resolution of epochlorohydrin employing catalyst **55** (Scheme 34).

The dimeric Co–salen catalyst **54** bridged by AlCl3 (Scheme 34) exhibited good catalytic activity in the KR of terminal epoxides with different sulfonic acids (Scheme 49) [170]. The reactions were performed in TBME and it was discovered that the addition of tetrabutylammonium chloride (TBACl) increased the yields and *ee* values significantly (from 32% to 47% yield and from 68% to 99% *ee* for the reaction of phenyl glycidyl ether and *p*-toluenesulfonic acid). No explanation for this enhancement of the catalytic activity was given.

**Scheme 49.** The kinetic resolution of terminal epoxides with substituted sulfonic acid catalyzed by dimeric Co–salen catalyst **54** (Scheme 34). TBACl = tetrabutylammonium chloride.
