Enzyme-like chemoselective acylation of alcohols in the presence of amines catalyzed by a tetranuclear zinc cluster

Article abstract of DOI:10.1021/ja711349r

Acylation of alcohols and amines is one of the most fundamental reactions. Due to the greater nucleophilicity of the amino group compared to the hydroxyl group, complete N-acylation occurs. Only an enzymatic reaction can promote a highly selective O-acyla

Full text of DOI:10.1021/ja711349r

Published on Web 02/13/2008
Enzyme-Like Chemoselective Acylation of Alcohols in the Presence of
Amines Catalyzed by a Tetranuclear Zinc Cluster
Takashi Ohshima,* Takanori Iwasaki, Yusuke Maegawa, Asako Yoshiyama, and Kazushi Mashima*
Department of Chemistry, Graduate School of Engineering Science, Osaka UniVersity,
Toyonaka, Osaka 560-8531, Japan
Received December 21, 2007; E-mail: ohshima@chem.es.osaka-u.ac.jp; mashima@chem.es.osaka-u.ac.jp
Scheme 1. Acylation of Aminoalcohol 1
Esters and amides are ubiquitous functional groups in natural
and synthetic organic compounds, thus esterification and amidation
are among the most fundamental and important reactions in organic
synthesis.1 They are commonly synthesized by acylation of the cor-
responding alcohol and amine, respectively, with a carboxylic acid,
an acid chloride, or an acid anhydride. As the nucleophilicity of
the amino group is much greater than that of the hydroxyl group,
the amine can be selectively acylated to give the corresponding
amide, even in the presence of excess alcohols and/or water.2 This
chemoselectivity has been well utilized for several highly efficient
amidation reactions such as the Schotten-Baumann reactions
(Scheme 1, path a, 1 f 2).3 On the other hand, selective O-acylation
(path c, 1 f 5) is quite difficult to perform in ordinary organic
reactions, even though lipase catalyzes highly selective O-acylation
in the presence of primary alkyl amines.4 When an aminoester 5 is
targeted, the only feasible route is an indirect protection-depro-
tection process2 including in situ protection with acid5 (path b).
The requirement for such a multistep transformation decreases the
atom economy of this process. Moreover, some notable exception6
aside, any acylation, including esterification and amidation, using
a carboxylic acid, an acid chloride, or an acid anhydride requires
a stoichiometric amount of the condensing reagent or base, resulting
in the formation of more than a stoichiometric amount of unwanted
chemical waste. To comply with the demand for an environmentally
benign process,7 reversing the normal chemoselectivity of path a
and minimizing waste are very important. The ideal method leading
to the development of a new transformation without using protecting
groups8 is a direct catalytic conversion of aminoalcohol 1 to
aminoester 5 in a highly chemoselective manner (path c); however,
to our knowledge, there are no examples of such a reaction using
an artificial catalyst.9
Recently, we reported that the newly developed µ-oxo-tetra-
nuclear zinc cluster Zn4(OCOCF3)6O (6) effectively catalyzes the
direct conversion of esters, lactones, and carboxylic acids to
oxazolines in high yield with broad substrate generality.10 Because
this catalysis proceeds through acylation and cyclodehydration
reactions, which utilize a cooperative mechanism of zinc ions similar
to that of aminopeptidase11 and efficient multimetallic catalysts,12
the zinc cluster 6 is expected to efficiently catalyze the acylation
of alcohols in a manner similar to that of lipase.4 Here we report
that the Zn cluster 6 catalyzes selective acylation of hydroxyl groups
in the presence of primary and secondary amino groups in a highly
chemoselective manner, demonstrating that assembled zinc ions
acquire highly enhanced oxophilicity.
focused on transesterification13 using the tetranuclear Zn cluster 6
as a catalyst because this process produces the desired ester without
generating stoichiometric amounts of waste. The Zn cluster 6
efficiently catalyzed the transesterification of alcohols without using
any additional promoters or a large excess of either alcohols or
acyl donors. Surprisingly, under the optimized condition (diiso-
propyl ether-refluxed conditions),14 the acylation of amine was quite
slow, suggesting that the Zn cluster 6 has high oxophilicity in spite
of the general tendency for Zn ions to have an azaphilic nature.
Although so-called monomeric Zn complexes Zn(OCOR)2 showed
only moderate reactivity,14 when the Zn cluster 6 was used for this
chemoselective acylation reaction, alcohol 8a was selectively
acylated to afford ester 10aa in 96% yield, along with only 1% of
amide 11aa (Table 1, entry 1). In contrast to our catalysis, the
reaction with Al(O-i-Pr)3, reported to catalyze the transesterification
of aminoesters with low to moderate selectivity,15 afforded a mixture
of ester 10aa (12%) and amide 11aa (46%). We next performed
the selective O-acylation using various combinations of alcohols
and amines, and the results are summarized in Table 1 (entries
2-12). Although the reactions using the linear alkyl amine 9b gave
a small amount of amide 11ab, the chemoselectivity of this catalysis
was still high (10ab/11ab ) >11:1) and ester 10ab was obtained
in 92% yield (entries 2 and 3). All of the reactions we evaluated
with primary amines proceeded in a highly chemoselective manner
(entries 5-9). When the reaction was performed in the presence
of secondary amines, we observed some amide due to the higher
nucleophilicity of the secondary amines (entries 10-12). The fact
that the desired ester 10aa was obtained in reasonably high yield
(82-86%) even in the presence of such good amine nucleophiles,
however, clearly indicates the extremely high oxophilicity of this
Zn catalysis.14 We next examined the scope of this method using
various methyl esters 7 as the acylation reagent. Under the optimized
conditions, aromatic esters with electron-donating and electron-
withdrawing substituents (entries 13-20), an R,â-unsaturated ester
(entry 21), and aliphatic esters (entries 22-24) were selectively
converted to the corresponding cyclohexyl esters 10 in high yields
(94-99%) accompanied by only trace amounts of amides 11.
Moreover, the highly acid-sensitive tetrahydropyranyl ether of
phenol remained intact (entry 18), demonstrating the high tolerance
of sensitive functionalities in this transformation. In the transition
state, both esters and alcohols may be simultaneously activated by
the two adjacent Zn ions in the cluster, leading to a highly selective
O-acylation rather than the usual nucleophilicity-dependent
We first investigated selective O-acylation using a 1:1 mixture
of cyclohexanol (8a) and cyclohexylamine (9a). When PhCOCl or
(PhCO)2O was used as an acylation reagent with triethylamine, the
acylation of amine 9a proceeded exclusively to give the corre-
sponding N-cyclohexylbenzamide (11aa) in >99% yield and
cyclohexyl benzoate (10aa) was not detected, consistent with normal
chemoselectivity. To tackle the issue of chemoselectivity, we
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C O M M U N I C A T I O N S
instability of the resulting aminoester 5aa.9,14,17 When aminoalcohols
1b-d tethered by long alkyl chains were treated, we obtained
aminoesters 5 in good yields (82-90%) (entries 2-4). Furthermore,
the reaction of trans-4-aminocyclohexanol (1e) provided aminoester
5ae exclusively (99%), presumably due to trans-stereochemistry
preventing the intramolecular O f N acyl transfer reaction. Even
when aminoalcohols 1f and 1g with highly nucleophilic secondary
amino groups (piperidine unit) were used, the reactions proceeded
in an O-acylation selective manner to give the corresponding
aminoesters 5 in high yields (88% and 92%).
Table 1. Chemoselective Acylation of Alcohols
In summary, using a Zn cluster-catalyzed transesterification
reaction, we succeeded in developing a highly O-selective acylation
in the presence of primary and secondary alkyl amines, in a manner
similar to that of lipase.4 This catalytic system will be useful as an
environmentally ideal acylation and provides an option for develop-
ing a new transformation without the use of protecting groups.8
The results reported here also suggest that the strategy of assembling
metal ions as the core structure of an artificial enzyme has a high
potential to enhance reactivity as well as to change the azaphilic
nature of late transition metals, leading to further enzyme-like
chemoselective reactions.
Acknowledgment. This work was supported by Encouragement
of Young Scientists from JSPS, a Grant-in-Aid for Science Research
in a Priority Area “Chemistry of Concerto Catalysis” from MEXT,
Uehara Memorial Foundation, Sumitomo Foundation, and Hoh-
ansha Foundation. T.I. expresses his special thanks for The Global
COE Program of Osaka University.
Supporting Information Available: Experimental procedures and
characterization of the products (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
b
c
d
a Isolated yield. GC yield. Not detected. Reaction time was 24 h.
Table 2. Chemoselective Acylation of Aminoalcohols 1
References
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a Isolated yield after Boc protection. bIsolated yield. cNot detected.
dSolvent was toluene.
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reaction.1-3 Such cooperation between the two Zn ions11,12 may be
closely related to the efficient transesterification catalyzed by alkali-
metal alkoxide clusters16a and transamidation catalyzed by a
trisamidoaluminum(III) dimer.16b To the best of our knowledge,
this is the first example of a highly chemoselective acylation of
alcohols, which is far superior to that of primary and secondary
alkyl amines using an artificial catalyst.
To demonstrate the usefulness and effectiveness of this Zn
catalysis in organic synthesis, we performed selective O-acylation
of aminoalcohols 1 (Table 2). When â-aminoalcohol 1a was used
as a substrate, hydroxyamide 2aa was obtained in 77% yield along
with diacylation products 12aa in 23% yield (entry 1). The product
2aa is produced through O-acylation (1a f 5aa) and the following
complete O f N acyl transfer reaction (5aa f 2aa) due to the
(13) (a) Otera, J. Chem. ReV. 1993, 93, 1449. (b) Hoydonckx, H. E.; De Vos,
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(17) This result suggests that the Zn cluster-catalyzed oxazoline formation10
also proceeds through transesterification and the following complete O
f N acyl transfer reaction.
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