.
Angewandte
Communications
Table 2: Scope of the substituent on the aminoalcohol moiety.[a]
(3 h). Although we previously demonstrated that amines and
N-heteroaromatic compounds increased the catalytic activity
of the zinc cluster for transesterification,[9] such positive
effects of amines were not observed in this transformation of
an amide into an ester (see the Supporting Information).
The chemical yield of the desired butyl ester 2a was
limited to a maximum yield of approximately 20% when
using any zinc complex, thus suggesting that this catalytic
reaction is reversible. In fact, the reversibility of this trans-
formation was confirmed by the following control experi-
ments: 1) amidation of the butyl ester 2a using aminoalcohol
to give 1a, a reverse reaction, proceeded under the same
reaction conditions, and 2) addition of aminoalcohol to the
reaction mixture of the amide cleavage/esterification reaction
suppressed the yield of the butyl ester 2a (20–9%). Thus, it is
reasonable to anticipate that any aminoalcohol-capture
reagent efficiently shifts the equilibrium of the reversible
reaction to afford the esters in high yield. At the outset,
carbonyl compounds, such as benzaldehyde (3a), acetophe-
none (3b), and benzophenone (3c), were added as amino-
alcohol-capture reagents, because aminoalcohol can react
with these carbonyl compounds to afford the corresponding
imines. As expected, the yield of the ester increased up to
52% (entries 8–10). Finally, diethylcarbonate (3d) was found
to be the best trapping reagent of aminoalcohol, thus
accelerating the amide cleavage/esterification of 1a to give
2a in 61% yield (entry 11) together with a trace amount of
the corresponding ethyl ester as the product of the trans-
esterification of the ester with ethanol derived from diethyl-
carbonate. The increase in the amount of carbonate (2 equiv-
alents to amide) improved the yield of the ester 2a from 61 to
70% (entry 12), and increasing the reaction time (45 h) led to
an increase in the yield of 2a to 85% (entry 13). Other
alcohols were then examined under these optimized reaction
conditions. As a result, 1-butanol and 1-pentanol indicated
high reactivity, probably because of its suitable refluxing
temperature (see the Supporting Information).
With the optimized reaction conditions in hand, the scope
of the present amide cleavage/esterification reaction was
investigated with respect to the aminoalcohol moiety
(Table 2). Substrates having methyl, benzyl, and dimethyl
groups adjacent to the nitrogen atom participated in this
catalytic reaction to form the ester 2a in high yield (entries 1–
3), and the methyl substituent next to the oxygen atom was
also applicable to this catalytic system (entry 4). Amide 8,
having a three-carbon chain, was transformed into the
corresponding ester 2a in a relatively lower yield (entry 5),
and the O-protected hydroxyamide 9 elicited almost no
reaction under the same reaction conditions, thus suggesting
a plausible mechanism involving N,O-acyl rearrangement[10]
(see below).
We then examined the generality of amides with a b-
hydroxyethyl group (Table 3). The amide cleavage/esterifica-
tion of a series of benzamide derivatives (1b–1k) afforded the
corresponding butyl esters 2b–2k (entries 1–10). The results
obtained using the substituted benzamides indicated that an
electronic effect influenced this catalytic transformation. The
use of benzamide with an electron-donating group at the
para position retarded the reaction (entries 2 and 3), whereas
Entry
Amide
Yield
[%][b]
1
2
4
5
85
86
3
4
5
6
6
7
8
9
87
84
36
trace
[a] Reaction conditions: A mixture of amide (1.0 mmol), Zn(OTf)2
(0.050 mmol), and diethylcarbonate (2.0 mmol) in 1-butanol (1.0 mL)
was refluxed for 45 h. [b] Determined by GC analysis based on the
produced butyl ester.
benzamide with an electron-withdrawing group at the para
position successfully underwent the reaction (entries 4 and 5).
The reaction was also sensitive to the steric environment of
the amide moiety, and thus sterically congested substrates
afforded moderate yield (entries 7, 8, and 12). A rate-
accelerating effect resulting from the electron-withdrawing
group could compensate for this unfavorable steric effect
(entry 9). Aliphatic amides 1l and 1m were also applicable to
this catalytic system (entries 11 and 12). Notably, the amide
1n, bearing both a hexylcarbamoyl group and a hydroxy-
ethylcarbamoyl group, afforded only butyl 4-(hexylcarba-
moyl)benzoate, in which the hydroxyamide moiety was
selectively converted into a butyl ester and the hexyl amide
moiety remained intact (entry 13), thus demonstrating that
hydroxyamide could be selectively converted under this
catalytic system.
Consequently, as shown in Scheme 1, an initial intra-
molecular attack of the hydroxy group on the carbonyl carbon
atom at the amide bond affords an ester intermediate (N,O-
acyl rearrangement). Subsequent transesterification with 1-
butanol gives the butyl ester. Thus, a two-step reaction
achieves the amide–ester exchange. The dissociated ethanol-
amines react with diethylcarbonate (3d) to afford the
corresponding carbamate, which was isolated in the reaction
of amide 5. The coordination of the amide to the zinc complex
increased the electrophilicity enough to facilitate the intra-
molecular attack of the hydroxy group.[11] On the basis of the
previous report on metal-assisted transesterification,[7,12] we
assume that the zinc catalyst spontaneously mediated the
transesterification of a nascent b-aminoethanolate. In addi-
2
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
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