Zinc-Catalyzed Esterification of N-β-Hydroxyethylamides: Removal of Directing Groups under Mild Conditions

Article abstract of DOI:10.1002/ejoc.201700748

Amide transformations involving C–N bond cleavage are recognized as difficult reactions owing to the inert nature of amides resulting from resonance. Accordingly, a strong inductive effect and geometrical distortion reasonably decrease the resonance stabilization to attenuate the C–N linkage. Although the conversion of such activated amides has been studied intensively, reaction systems for “unactivated” amides are underdeveloped. We herein report that a zinc(II) trifluoromethanesulfonate [Zn(OTf)₂] catalyst achieves the esterification of a wide range of unactivated tertiary amides with the assistance of intramolecular acyl rearrangement. The reaction was applied to the one-pot removal of various amide-based directing groups under mild reaction conditions to afford the corresponding esters in high yields.

Full text of DOI:10.1002/ejoc.201700748

A Journal of
Accepted Article
Title: Zinc-catalyzed Esterification of N-β-Hydroxyethylamides;
Removal of Directing Groups under Mild Conditions
Authors: Yuji Nishii, Takahiro Hirai, Sarah Fernandez, Paul Knochel,
and Kazushi Mashima
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700748
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10.1002/ejoc.201700748
European Journal of Organic Chemistry
COMMUNICATION
Zinc-catalyzed Esterification of N--Hydroxyethylamides;
Removal of Directing Groups under Mild Conditions
Yuji Nishii,[b] Takahiro Hirai,[a] Sarah Fernandez,[c] Paul Knochel,[c] and Kazushi Mashima*[a]
Abstract: Amide transformation involving their C–N bond cleavage
have been recognized as difficult reaction due to their inert nature
resulting from the amide resonance. Accordingly, a strong inductive
effect and geometrical distortion reasonably decrease the resonance
stabilization to attenuate the C–N linkage. Although the conversion of
such activated amides has been studied intensively, reaction systems
for “unactivated” amides are underdeveloped. We herein report that
a Zn(OTf)2 catalyst achieves the esterification of a wide range of
unactivated tertiary amides with the assistance of intramolecular acyl
rearrangement. The reaction can be applied to a one-pot removal of
various amide-based directing groups under mild reaction conditions,
affording the corresponding esters in high yields.
as the amide alcoholysis under mild reaction conditions (Scheme
1A). Upon applying this strategy, a catalytic and selective
esterification of secondary N-β-hydroxyethylamides, including
serine-containing dipeptides, was achieved. As part of our
continuing investigation, we found that kinetically stable tertiary
N,N-dialkyl amides bearing a β-hydroxyethyl entity were able to
be transesterificated using zinc catalysts (Scheme 1B), though
such cleavage of the N,N-dialkyl amides has not been realized in
any other catalytic system. It is noteworthy that the recent
achievement of amide-directed C–H functionalization protocols[9]
emphasize an increasing demand for amide transformation with
significant generality. We additionally developed a procedure for
installation of the N-β-hydroxyethyl scaffold onto the amide
nitrogen via ring-opening reaction of epoxides, and this sequential
manipulation was applied for the removal of several amide
directing groups.
Amides are ubiquitous, abundant in natural products and
synthetic compounds such as proteins, fibers, resins, and
pharmaceuticals. Cleavage of the C–N linkage of amides is
considered difficult due to their high stability resulting from the
amide resonance.[1] In practice, strong acid/base mediated
hydrolysis at relatively high temperature has been adopted to
actuate such transformations, furnishing poor functional group
compatibility. Moreover, isolation of the products, carboxylic
acids or their salts, is usually cumbersome. Alternatively, catalytic
amide alcoholysis has attracted considerable attention because
the produced esters are easy to handle, and can be readily
converted into other functionalities. Lewis acid catalysts such as
TiCl4[2] and Sc(OTf)3[3] as well as a heterogeneous CeO2[4] catalyst
have successfully been applied to facilitate the alcoholysis, and,
recently Garg et al. reported a new type of catalytic esterification
systems in which the amide C–N linkage was cleaved through
oxidative addition onto a Ni(0) catalyst.[5] All these reactions can
be applied to substrates with limited substituents on the nitrogen
atom such as primary, N-aryl, and N-Boc amides.
We previously reported amide esterification reactions catalyzed
by zinc[6] or manganese[7] facilitate the intrinsic behavior of N-β-
hydroxyethylamides, which underwent intramolecular N,O-acyl
rearrangement in the presence of appropriate metal complexes[8]
and the resulting β-aminoester intermediates were subjected to
subsequent transesterification to furnish the corresponding esters
Scheme 1. Catalytic alcoholysis of N--hydroxyethylamides
As a representative reaction, alcoholysis of amide 1a with 1-
propanol was examined in the presence of various metal catalysts
and diethyl carbonate as an aminoalcohol scavenger (Table 1).
Among the tested zinc salts, Zn(OTf)2 afforded the corresponding
ester 2a in the highest yield (entries 1–5). We previously reported
that Mn(acac)2/2,2’-bipyridine systems catalyzed the alcoholysis
of 1a at a higher reaction temperature;[7] however, only trace
amount of the product was obtained in the present conditions
(entry 6). The combined system of Sc(OTf)3 and a boronic ester,
which was an effective catalyst for alcoholysis of primary
amides,[3a] was totally inactive (entry 7). Trifluoromethanesulfonic
acid (TfOH), which was considered a possible derivative of
Zn(OTf)2 under catalytic conditions, showed no catalytic activity
[a]
[b]
[c]
Prof. Dr. K. Mashima, Mr. T. Hirai
Department of Chemistry, Graduate School of Engineering Science,
Osaka University, Toyonaka, Osaka 560-8531 (Japan)
E-mail: mashima@chem.es.osaka-u.ac.jp
Dr. Y. Nishii
Frontier Research Base for Global Young Researchers, Graduate
School of Engineering, Osaka University, Suita, Osaka 565-0871
(Japan)
Prof. Dr. P. Knochel, Dr. S. Fernandez
Ludwig Maximilians-Universität München, Department Chemie,
Butenandtstrasse 5–13, Haus F, 81377 München (Germany)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201700748
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(entry 8). Exclusion of the catalyst led to a minimal product yield
(entry 9). Other metal complexes of Co, Cu, Ni, Fe, Al, Mg, and
La were also examined and found to be ineffective.[10]
for the substrate bearing an amino group (entries 5 and 6). An
ortho-fluorinated amide 1n reacted smoothly to give a high yield
Table 2. Substrate scope for amide alcoholysis[a]
Table 1. Catalyst screening for alcoholysis of 1a[a]
entry
1
amide
yield[b]
92%
entry
1
catalyst
time
6 h
yield[b]
26%
60%
80%
96%
53%
trace
n.d.
1b
1c
Zn(OAc)2
Zn(OCOCF3)2
Zn(OTf)2
2
6 h
2
93%
3
6 h
Zn(OTf)2
4
18 h
18 h
18 h
18 h
18 h
18 h
Zn(NTf2)2
Mn(acac)2
Sc(OTf)3
5
3
4
1d
1e
92%
6[c]
7[d]
8
37% (24 h)
(93%[c]
)
TfOH (10 mol%)
none
trace
trace
9
5
6
1f
88%
[a] Reaction conditions: amide 1 (0.5 mmol), Zn(OTf)2 (5.0 mol%), and
diethyl carbonate (1.0 mmol) in 1-propanol (0.5 mL, b.p. 97 °C).
[b] Determined by 1H NMR analysis.
[c] 2,2’-Bipyridine (5.0 mol%) was added.
1g
92%
[d] 2-(3,5-Bis(trifluoromethyl)phenyl)-5,5-dimethyl-1,3,2-dioxaborinane (10
mol%) was added.
n.d. = Not detected.
[a] Reaction conditions: amide 1 (0.5 mmol), Zn(OTf)2 (5.0 mol%), and
diethyl carbonate (1.0 mmol) in 1-propanol (0.5 mL, b.p. 97 °C).
[b] Determined by 1H NMR analysis.
We evaluated the substrate scope with respect to the substituent
on the amide nitrogen atom under the optimal reaction conditions
(Table 2). An amide 1b bearing a relatively bulky isopropyl group
on the nitrogen atom was successfully converted into the ester in
92% yield (entry 1). N-Benzyl amide 1c and N-phenyl amide 1d
were both applicable to the present system to give high yields
(entries 2 and 3). On the other hand, N-benzoyl-L-prolinol (1e)
reacted sluggishly and a higher reaction temperature was
required to reach an adequate yield (entry 4). This result can be
rationalized by the less flexible behavior of the pyrrolidine moiety
which retarded the intramolecular acyl rearrangement process.
Use of heterocyclic substituents, pyridyl (1f) and furyl (1g) groups,
did not significantly affect the reaction efficiency (entries 5 and 6).
Notably, amide 1a was readily synthesized by zinc/DMAP-
catalyzed transacylation[11] of methyl benzoate with 2-
(methylamino)ethanol (eqn. 1).
[c] 1-Butanol was used as solvent, and the yield of butyl benzoate is shown.
(entry 7). The reaction was sensitive toward the steric bulkiness
of the acyl group, so that the ortho-substituted benzamides 1o
and 1p produced the esters in moderate yields at higher
temperature (entries 8–9). A heteroaromatic amide 1q and an
aliphatic amide 1r were transformed into the corresponding esters
in 89% and 70% yields, respectively (entries 10 and 11).
Next we investigated the generality of acyl groups for the present
reaction (Table 3). Benzamides with an electron-withdrawing
group at the para-position underwent the reaction smoothly,
affording the corresponding esters in high yield (entries 1–4). A
trace amount of dipropyl terephthalate was detected in the
reaction of 1j, indicating that the cyano group was esterified under
the conditions (Pinner-type reaction).[12] Electron-donating
groups were tolerated as well; however, the yield was moderate
The developed amide esterification protocol was further applied
to the removal of an 8-aminoquinolyl group, which is one of the
most frequently-used bidentate directing groups for transition
[13,14]
metal catalyzed C–H functionalization.
To remove this
directing group, hydrolysis under harsh conditions (strongly acidic
or basic, high temperature, long reaction time) were adopted, and
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10.1002/ejoc.201700748
European Journal of Organic Chemistry
COMMUNICATION
be conducted in sub-gram scale for the reaction of 3b albeit the
yield was moderate.
Table 3. Substrate scope for the amide alcoholysis[a]
entry
amide
yield[b]
86%
1
2
3
4
5
6
7
8
9
10
R = Br (1h)
R = CF3 (1i)
R = CN (1j)
R = NO2 (1k)
R = OMe (1l)
R = NH2 (1m)
R = F (1n)
R = Me (1o)
R = OMe (1p)
1q
89%
Scheme 2. Removal of 8-aminoquinolyl group via sequential
epoxide treatment and esterification
82%
91%
Additionally, a simple N-alkyl secondary amide 3g was applicable
to the consecutive esterification system, albeit higher reaction
temperature was required (entry 3). Amides bearing ortho-
substituents (3b–3d) were converted into the corresponding
esters in moderate yields (entries 4 and 5). It should be noted
that these substituent patterns were occasionally observed in
catalytic C–H bond functionalization with the assistance of an 8-
aminoquinolyl directing group.[19,20]
80%
68%
79%
30% (52%[c]
27% (45%[c]
89%
)
)
Table 4. One-pot esterification of secondary amides [a]
11
1r
70%
[a] Reaction conditions: amide 1 (0.5 mmol), Zn(OTf)2 (5.0 mol%), and
diethyl carbonate (1.0 mmol) in 1-propanol (0.5 mL, b.p. 97 °C).
[b] Determined by 1H NMR analysis.
entry
1
amide
yield[b]
[c] 1-Butanol was used as solvent, and the yield of the corresponding butyl
ester is shown.
3b
3c
3d
79%
37%[c]
2
3
41%
thus the process had little functional group compatibility in
practical applications. An 8-amino-5-methoxyquinolyl group was
recently used as a removable directing group, but strong oxidants
were required to cleave the amide linkage.[15]
34%[d]
We envisaged that the N--hydroxyethyl group, a key functional
group for zinc-catalyzed amide alcoholysis, could be installed
onto the amide nitrogen by nucleophilic ring opening of epoxide.
Accordingly, an amide 3a was deprotonated with NaH and treated
with propylene oxide in the presence of a catalytic amount of
Zn(OTf)2 to produce the corresponding N--hydroxyethyl amide 4,
which was subsequently reacted with MeOH to afford the ester 5a
in 47% (18 h) and 70% (45 h) yields (Scheme 2A). Although the
structure of intermediate 4 was not fully characterized, its
intermediacy was confirmed by isolation of the corresponding
aminoalcohol: 8-(2-hydroxypropyl)aminoquinoline.[16] In sharp
contrast, esterification of amide 3a was unsuccessful without
anion-epoxide treatment (Scheme 2B). These results prompted
us to apply the one-pot esterification protocol for the
transformation of various secondary amides (Table 4). Other
directing groups such as triazole-amine (TAM, 3b)[17] and
pyridine-isopropyl groups (PIP, 3c)[18] were targeted successfully
for transesterification (entries 1 and 2). The protocol was able to
4
5
R = Me (3e)
R = Ph (3f)
46%[d]
49%[d]
[a] Reaction conditions: amide 1 (0.5 mmol), NaH (0.6 mmol), DMF (1.2 mL),
Zn(OTf)2 (5.0 mol%), propylene oxide (5.0 mmol), and diethyl carbonate (1.0
mmol) in MeOH (0.5 mL, b.p. 65 °C).
[b] Determined by 1H NMR analysis.
[c] Isolated yield (2.5 mmol scale).
[d] 1-Propanol was used instead of MeOH in the last step, and yield of the
corresponding propyl ester is shown.
In conclusion, we demonstrated that the Zn(OTf)2-catalyzed
esterification system was applicable to various tertiary amides
through the instrumentality of the acyl rearrangement process.
The N--hydroxyethyl group, a key functional group for the
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Baker, S. M. Anthony, J.-N. Desrosiers, C. Senanayake, N. K. Garg
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esterification system, was readily installed to secondary amides
by treatment with epoxide; accordingly, one-pot removal of the
amide-based directing groups was realized under mild reaction
conditions.
[6]
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2016, 531, 220–224; b) J. He, H. Jiang, R. Takise, R.-Y. Zhu, G. Chen,
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General Procedure of Amide Esterification (Table 2 and 3): A mixture of
Zn(OTf)2 (9.1 mg, 5.0 mol%), diethyl carbonate (121 L, 1.0 mmol), and
amide (0.50 mmol) in 1-propanol (0.5 mL) was refluxed for periodic time.
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phenanthrene as an internal standard.
[10] See the Supporting Information for detail of the optimization study.
[11] a) K. Agura, Y. Hayashi, M. Wada, D. Nakatake, K. Mashima, T.
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General procedure of one-pot esterification of amides (Table 4): A mixture
of amide (0.50 mmol), NaH (14.4 mg, 0.60 mmol), and DMF (1.2 mL) was
stirred for 3 hours at 0 °C. To the resulting mixture, Zn(OTf)2 (9.1 mg, 5.0
mol%) and propylene oxide (360 L, 5.0 mmol) were added, which was
stirred for 15 hours at 80 °C. After removal of the solvent in vacuo, diethyl
carbonate (122.5 mL, 1.0 mmol) and methanol (0.50 mL) were added. The
mixture was refluxed for 18 hours. The yield was determined by 1H NMR
analysis with mesitylene as an internal standard.
[12] R. Roger, D. Neilson Chem. Rev. 1961, 61, 179.
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Acknowledgements
This work was supported by JSPS KAKENHI Grant Number
JP15H05808 in a Grant-in-Aid for Scientific Research on
Innovative Areas, Precisely Designed Catalysts with Customized
Scaffolding, and JSPS KAKENHI Grant Number JP26248028, a
Grant-in-Aid for Scientific Research(A) of The Ministry of
Education, Culture, Sports, Science, and Technology, Japan.
The authors thank Dr. Yusuke Kita (Laboratory for Materials and
Structures, Tokyo Institute of Technology) for valuable discussion.
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[16] See the Supporting Information for detail.
[17] a) Q. Gu, H. H. Al Mamari, K. Graczyk, E. Diers, L. Ackermann Angew.
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Keywords: amides • zinc • homogeneous catalyst • solvolysis •
directing groups
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Yuji Nishii, Takahiro Hirai, Sarah
Fernandez, Paul Knochel, Kazushi
Mashima*
Page No. – Page No.
Zinc-catalyzed Esterification of N--
Hydroxyethylamides; Removal of
Directing Groups under Mild
Conditions
Amide bond cleavage: zinc-catalyzed esterification of unactivated tertiary amides is
achieved with the assistance of intramolecular acyl rearrangement. This reaction can
be applied to a one-pot removal of various amide-based directing groups under mild
reaction conditions using epoxide as an external source of N--hydroxyl group.
This article is protected by copyright. All rights reserved.