Transition-metal clusters as catalysts for chemoselective transesterification of alcohols in the presence of amines

Chemoselective acylation of alcohols in the presence of amines

Pre-protonation of alkyl amino groups by highly acidic reagents such as hydrochloric acid and trifluoroacetic acid is a straightforward route for the esterification of aliphatic amino alcohols (eq. 1). A unique example was reported by Takata and Kihara et al. who used rotaxane compounds for a O-selective acylation followed by N-acylation to lock the rotaxane structure (Scheme 1) [3]. Copper ions were coordinated in a chelating fashion to amino acid functionalities so that the hydroxyl group was esterified, and then removed by hydrogen sulfide [4] or 8-hydroxyquinoline (Scheme 2) [5].

Scheme 1

O-selective acylation of rotaxane compounds.

Scheme 2

O-selective acylation of Cu-chelated amino acid derivatives.

Enhancement of the nucleophilicity of the hydroxy group is another strategy used for the chemoselective acylation of aromatic substrates. Selective O-acylation of phenols in the presence of aromatic amino groups is accomplished by acylating reagents bearing a specific leaving group, such as N-methyl-N-nitroso [6] and 2-bipyridinyl groups [7] in which a proton of the hydroxy group is accepted via a concerted proton transfer, as schematically depicted in Fig. 3.

Fig. 3

Possible transition state in acylation of phenol with specific acyl donor. (a) N-methyl-N-nitroso group; (b) 2-bipyridinyl group.

Studer et al. developed N-heterocyclic carbene (NHC), which mediates the chemoselective acylation of alcohols in the presence of amines (eq. 2) [8]. The DFT calculations on NHC–H₂NMe and NHC–HOMe indicate that the stronger hydrogen bonding energy for NHC–HOMe than that for NHC–H₂NMe elongates the O–H bond.

The 1,2- and 1,3-amino alcohols are unique in that they act in intramolecular hydrogen bonding of the hydroxy group with the amino group in nonpolar solvent, and as non-hydrogen-bonded molecules in polar solvent (Fig. 4a). Such hydrogen bonding enhances the nucleophilicity of the oxygen atom, while attenuating the nucleophilicity of the nitrogen, which results in an inversion of reactivity toward the acylation. Maeng and Funk demonstrated chemoselective O-esterification for the synthesis of cytotoxin fasicularin (Fig. 4b) [9]. Using the same synthetic strategy, Piarulli and Gennari et al. conducted O-selective acylation of (R)-N-benzylserine methyl ester using HATU to afford the corresponding ester compound (Fig. 4c) [10].

Fig. 4

Intramolecular hydrogen bonding of the hydroxy group with the amino group in 1,2-amino alcohols. (a) The lone pair of electrons on the nitrogen atom is used to form the intramolecular hydrogen bond with the hydrogen atom on the hydroxy group; (b) and (c) examples of chemoselective O-acylations of 1,2-amino alcohols under basic conditions.

Some enzymes act to fix the transition state conformation in favor of O-acylation. Lipase catalyzes the selective O-acylation of the serine moiety of a dipeptide, (S)-Phe-(S)-Ser(OH)-NH-β-Naph, even in the presence of highly nucleophilic α-NH₂ group of Phe, to give the O-acetylated product, (S)-Phe-(S)-Ser(OAc)-NH-β-Naph, in 98 % yield[11]. Molecular modeling studies suggest that such O-selectivity is caused by interference with the hydrogen transfer in the transition state [12].

Yttrium catalysts

Lin and RajanBabu reported yttrium-catalyzed selective O-acylation over N-amidation using Y₅(OⁱPr)₁₃O as a catalyst to promote the selective O-acetylation of amino alcohols without the formation of the amide by activated acylation reagents such as vinyl or isopropenyl acetate [13]. When a stoichiometric mixture of 1-phenylethanol and 1-phenylethanamine is treated with the yttrium catalyst and isopropenyl acetate, the alcohol quantitatively converts to O-acetate and only a trace amount of the N-acetyl derivative is detected (eq. 3). Recently, Ishihara et al. also reported that a La(OⁱPr)₃–2-(2-methoxyethoxy)ethanol catalyst system catalyzes the chemoselective transesterification of methyl esters in the presence of amines (eq. 4) [14].

Zinc catalysts

We reported that the zinc cluster Zn₄(OCOCF₃)₆O (1) [15] effectively catalyzes the hydroxy group-selective acylation with unactivated methyl esters in the presence of primary and secondary aliphatic amino groups (eq. 5) [15b]. The present method provides a new protocol to directly convert amino alcohols to the corresponding amino esters without the use of protecting groups, outlined in Fig. 2a. Representative examples are the transesterification of methyl benzoate with amino alcohols such as trans-4-aminohexan-1-ol and 4-piperidinemethanol to give the corresponding amino esters without any amides (eqs. 6 and 7), while ethanolamine and cis-4-aminohexane-1-ol predominantly produce the corresponding amides via intramolecular O,N-rearrangement of the initially generated amino esters. In addition, under refluxing conditions in excess amounts of EtOAc, the alcohols are acetylated in high yield while hydroxyl group selectivity is maintained [15d].

Amine additive effects

The addition of catalytic amounts of amines and N-heteroaromatics to zinc catalyst 1 has drastic additive effects on the transesterification of alcohols to increase the catalytic activity compared with the original reactivity of 1. A typical example is shown in eq. 8: in the presence of cyclohexylamine, transesterification proceeds smoothly to reach 94 % yield while maintaining the O-selectivity [15h]. DMAP works better than primary amines, facilitating the transesterification of sterically demanding esters and alcohols (Scheme 3). In fact, in the presence of a catalytic amount (20 mol%) of DMAP, transesterification of methyl adamantine-1-carboxylate and 1-butanol under toluene refluxing conditions for 90 h affords 94 % yield, which is greatly improved compared with only a trace amount obtained with no additive and 29 % yield by the addition of cyclohexylamine. We propose that the addition of DMAP stabilizes the clusters with lower nuclearities and enhances catalytic activity for transesterification.

Scheme 3

Additive effects of the zinc cluster-catalyzed transesterification.

Cobalt catalysts

Because zinc and yttrium cluster complexes show high hydroxyl group selectivity and the additive of amines and N-heteroaromatic compounds to zinc cluster catalyst 1 improved catalytic activity, we tested the catalytic performance of various metal carboxylates for chemoselective acylation of alcohols over amines [15i]. Scheme 4 shows the results of the test reaction of methyl 3-phenylpropanoate with a 1:1 mixture of n-hexanol (1.2 equiv) and n-hexylamine (1.2 equiv) in the presence of various metal acetates, M_n(OCOCH₃)_m (5 mol% metal). Acetate complexes of middle and late first-row transition metals in an oxidation state of two show moderate catalytic activity and maintain sufficient chemoselectivity, producing O-acylated product (blue bar) over N-acylated product (red bar). Without the addition of n-hexylamine, the catalytic activity of transesterification is suppressed to almost no reaction or low yield, and the addition of n-hexylamine interacts with carboxylate compounds of Mn(II), Fe(II), Co(II), Cu(II), Cu(I), and Zn(II) to give catalytically active species that catalyze O-selective acylation.

Scheme 4

Catalytic activity and chemoselectivity of various metal acetates for acylation of n-hexanol and n-hexylamine with methyl 3-phenylpropionate.