An Alternative Route to Protected Aldols: Cobalt-Catalyzed Hydroformyl­ation of Epoxides and in situ Protection of β-Hydroxyaldehydes by HC(OMe)₃

Abstract

A wide range of epoxides were efficiently converted to protected aldols by hydroformylation-acetalization using Co 2 (CO) 8 as a catalyst in trimethyl orthoformate. The formylation of terminal epoxides was regioselective for the terminal position, and (S)-1-benzyloxy-2,3-epoxypropane was transformed into (R)-1-benzyloxy-4,4-dimethoxybutan-2-ol with retention of the configuration.The aldol addition is one of the most useful C-C bond forming reaction for the synthesis of b-hydroxy carbonyl compounds, and the extensive work on this subject has been devoted to develop the stereoselective and catalytic variants. 1 In general, a control of the reaction between the different aliphatic aldehydes has been understood to be difficult because of some accompanying problems: (1) each aldehyde possibly reacts as an electrophilic acceptor and a nucleophilic donor to give a mixture of aldol products (b-hydroxyaldehydes), (2) the reaction of an aldol product with an aldehyde monomer or with itself gives the aldehyde trimer or aldol product dimer, respectively, and (3) dehydration of an aldol product yields a,b-unsaturated aldehyde which allows Michael-type reaction. 2 Recent advances have overcome these undesired reactions and demonstrated the catalytic and selective condensation between different aliphatic aldehydes. 3 Transition-metal catalyzed hydroformylation of epoxides is also an effective method to give b-hydroxyaldehydes. 4,5 Similar to the aldol reaction above mentioned, the reactive aldehyde function potentially causes some unwanted side reactions such as dimerization of products or reduction of carbonyl function under the hydroformylation condition (Scheme 1). Accordingly, in order to establish the synthetic utility of epoxide hydroformylation, it is required to protect the functional groups (hydroxy and/or formyl group) in situ. A successful example for protection of hydroxyl group is the rhodium-catalyzed silylformylation of epoxides reported by Murai et al. where HSiR 3 is used instead of H 2 . 6 On the other hand, for the protection of formyl group, Orchin et al. attempted the cobalt-catalyzed hydroformylation of cyclohexene oxide in the presence of ethylene glycol which would have trapped the hydroformylation product as an acetal. 7 However, in fact, ethylene glycol coordinated to the cobalt center to retard the reaction. For the purpose of efficient hydroformylation followed by a transformation into acetal, we focused on transacetalization reaction. The use of orthoformate [HC(OEt) 3 ] or acetal [H 2 C(OMe) 2 ] in combination with acid catalyst such as SnCl 2 or PPTS (pyridinium p-toluenesulfonate) was shown to be effective for the in situ acetalization of a formyl group in the rhodium-catalyzed hydroformylation of olefins. 8 Here, we report the cobaltcatalyzed hydroformylation-acetalization of epoxides by using HC(OMe) 3 . Dimethyl acetals of b-hydroxyaldehydes were obtained as a stable protected monomer form.In this system, acidic HCo(CO) 4 , derived from Co 2 (CO) 8 under the reaction condition, operated not on...

Cobalt-catalysed hydroformylation of epoxides in the presence of phosphine oxides

“…Nozaki and co-workers described the synthesis of β-hydroxy dimethyl acetals from epoxides by Co 2 (CO) 8 -catalysed tandem hydroformylation/acetalization performed in the presence of an excess of trimethyl orthoformate. 53…”

“…Nozaki and co-workers described the synthesis of β-hydroxy dimethyl acetals from epoxides by Co 2 (CO) 8 -catalysed tandem hydroformylation/acetalization performed in the presence of an excess of trimethyl orthoformate. 53 As mentioned in the introduction, an alternative to obtain stable and useful products from epoxides under the hydroformylation conditions is the consecutive hydrogenation of β-hydroxyaldehydes into 1,3-diols. However, such cobalt-catalysed hydrogenations proceed only under harsh conditions of temperature and pressure.…”