Hydrogen-bond-assisted transition-metal-free catalytic transformation of amides to esters

Article abstract of DOI:10.1007/s11426-020-9883-3

The amide C-N cleavage has drawn a broad interest in synthetic chemistry, biological process and pharmaceutical industry. Transition-metal, luxury ligand or excess base were always vital to the transformation. Here, we developed a transition-metal-free hydrogen-bond-assisted esterification of amides with only catalytic amount of base. The proposed crucial role of hydrogen bonding for assisting esterification was supported by control experiments, density functional theory (DFT) calculations and kinetic studies. Besides broad substrate scopes and excellent functional groups tolerance, this base-catalyzed protocol complements the conventional transition-metal-catalyzed esterification of amides and provides a new pathway to catalytic cleavage of amide C-N bonds for organic synthesis and pharmaceutical industry. [Figure not available: see fulltext.]

Full text of DOI:10.1007/s11426-020-9883-3

SCIENCE CHINA
Chemistry
•ARTICLES•
https://doi.org/10.1007/s11426-020-9883-3
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Hydrogen-bond-assisted transition-metal-free catalytic
transformation of amides to esters
Changyu Huang1†, Jinpeng Li1†, Jiaquan Wang1, Qingshu Zheng1, Zhenhua Li1 & Tao Tu1,2,3*
1Shanghai Key Laboratory of Molecular Catalysis and Innovative Materials, Department of Chemistry, Fudan University,
Shanghai 200438, China;
2State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China;
3Green Catalysis Center and College of Chemistry, Zhengzhou University, Zhengzhou 450001, China
Received July 29, 2020; accepted October 29, 2020; published online November 12, 2020
The amide C-N cleavage has drawn a broad interest in synthetic chemistry, biological process and pharmaceutical industry.
Transition-metal, luxury ligand or excess base were always vital to the transformation. Here, we developed a transition-metal-
free hydrogen-bond-assisted esterification of amides with only catalytic amount of base. The proposed crucial role of hydrogen
bonding for assisting esterification was supported by control experiments, density functional theory (DFT) calculations and
kinetic studies. Besides broad substrate scopes and excellent functional groups tolerance, this base-catalyzed protocol com-
plements the conventional transition-metal-catalyzed esterification of amides and provides a new pathway to catalytic cleavage
of amide C–N bonds for organic synthesis and pharmaceutical industry.
amides, C–N bond cleavage, esterification, hydrogen bonding, transition-metal-free catalysis
Citation:
Huang C, Li J, Wang J, Zheng Q, Li Z, Tu T. Hydrogen-bond-assisted transition-metal-free catalytic transformation of amides to esters. Sci China
Chem, 2020, 63, https://doi.org/10.1007/s11426-020-9883-3
1 Introduction
[1,19–23,34,35].
Transition-metal-catalyzed reactions may represent one
of the most successful catalytic approaches for this purpose
[36,37]. For example, using a Ni0/NHC catalyst, Garg and
co-workers esterified amides [14,15], and Danoun et al.
[16] further extended it to a cobalt system. In all these
cases the C–N bond undergoes resonance destabilization
and is cleaved by oxidative addition to generate an acyl
metal intermediate (Figure 1(a)) [38]. Recently, the Szos-
tak group [29] reported the first transition-metal-free es-
terification of amides using excess K3PO4 (ca. 3 equiv.), in
which tetrahedral intermediate may be involved. During
the preparation of this manuscript, Lei and co-workers [30]
realized the transformation of activated amides to esters
with Cs2CO3. Besides these advances, the substrate scope
Amide bonds are widely existed in natural products, phar-
maceuticals and functional materials [1–6]. Unlike the con-
struction, their cleavage remains largely underdeveloped [7],
due to their weak electrophilic property and high C–N bond
energy (15−20 kcal/mol) stabilized by two resonance con-
tributors (Figure 1(a)) [8–10]. A number of strategies have
been developed for C–N bond activation to realize transa-
midation and esterification of amides [11–33]. It has to be
noted, esterification of amides is more difficult, due to in-
ferior nucleophilicity of alcohols than amines. In general,
harsh conditions and a large excess of alcohols are required
†These authors contributed equally to this work.
*Corresponding author (email: taotu@fudan.edu.cn)
© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020
chem.scichina.com link.springer.com

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Huang et al. Sci China Chem
2 Experimental
General procedure for NaOtBu-catalyzed esterification of
amides. To a dry 35 mL sealed tube with a stir bar, amide
(0.5 mmol), NaOtBu (0.1 mmol), phenol/alcohol (1.0 mmol)
and toluene (5.0 mL) were added. After sealed with a Teflon-
lined cap, the reaction mixture was stirred at 150 °C for 24 h.
Then the mixture was cooled to room temperature and
quenched with H2O (5.0 mL). The mixture was separated
and extracted with ethyl acetate (EA) (15 mL×3). The
combined organic layer was dried over anhydrous Na2SO4,
filtered and concentrated in vacuo. The residue was purified
by column chromatography with ethyl acetate/petroleum
ether to give the desired product. More experimental details
and characterizations are available in the Supporting In-
formation online.
3 Results and discussion
Figure 1 Different strategies for esterification of amides (color online).
To test our hypothesis, we performed the model reaction by
using amide 1a and phenol 2a as substrates in toluene in a
sealed tube at 150 °C (bath temp.) for 24 h. As expected, no
reaction was observed without base (Table 1, entry 1). In
order to mimic the catalytic system of serine proteases,
20 mol% catalytic amounts of organic bases like imidazole,
triethylamine and pyridine were examined. These conditions
only gave trace amounts of ester 3 (0–9%, Table S1, Sup-
porting Information online). In contrast, the use of 20 mol%
inorganic bases including K2CO3, K3PO4 and NaOH all re-
sulted in excellent yields (91%–93%, entries 2–4, Table 1). A
quantitative yield of ester 3 was achieved when NaOtBu was
applied (entry 5, Table 1), inferior yields were observed with
LiOtBu and KOtBu (48% and 95%, respectively, entries 8
and 10, Table S1). When the amount of NaOtBu was de-
creased to 10 mol%, slightly lower yield was obtained (86%,
entry 6, Table 1). Poor outcomes were found with o-xylene,
dimethyl sulfoxide (DMSO), N,N-dimethylformamide
(DMF), anisole and other selected organic solvents (10%–
26%, Table S1). Although the reaction proceeded smoothly
in toluene with trace water (entry 22, Table S1), additional
water dramatically prevented the esterification (entries 8, 9,
Table 1).
With optimal reaction conditions in hand, the scope of
phenols was investigated (Scheme 1). A broad range of
phenols with electron-donating (4, 5, 8), electron-with-
drawing (6), and sterically hindered groups (8a, 10–12) were
all well tolerated. The conversion of halo-phenols, which
were often problematic in the transition-metal-catalyzed re-
actions [42], also gave good yields (6a–6d, 73%–86%).
Sensitive functional groups including allyl (12, 80%) and
ketone (16, 81%) were well preserved. Disappointedly, no
esterification was detected with 4-nitrophenol and 4-cyano-
still restricted to imide-type amides. How to develop a new
transition-metal-free protocol also suitable for normal
amides with H/alkyl/aryl substitutes is still very challen-
ging and attractive.
Unlike the challenging situation in laboratory, nature has
many efficient methods for the esterification of amides.
Many peptidases such as proteases or amidases can readily
increase the esterification rate up to 1015 fold [39]. Upon
formation of hydrogen-bonding between the aspartate car-
boxyl group and histidine (Figure 1(b)), the nitrogen atom of
imidazole is more electronegative for bonding to the serine
OH and thereby increasing the nucleophilicity of serine [40].
Attacking the carbonyl group of an amide forms an oxyanion
tetrahedral intermediate with the concomitant hydrogen
transfer to histidine nitrogen. The basicity of the substrate
nitrogen increases significantly in the tetrahedral inter-
mediate (due to the loss of amide resonance), and the for-
mation of a hydrogen bond to the histidine NH allows rapid
collapse of the intermediate to form an ester (an acyl-enzyme
intermediate) and release amine [41].
Inspired by the plausible mechanism of serine proteases
for amide-to-ester transformation [40], we have designed a
model reaction (Figure 1(c)), in which several considerations
are pre-set down. Firstly, phenol with a small amount of base
may generate a mixture of phenol and phenolate, which can
form a hydrogen bond pair. Next, N-Boc-substituted amide
1a is initially selected because the resulting amine is a poor
nucleophile, thereby avoiding the possible reverse transfor-
mation to reform the amide. Finally, strong polar solvents,
protic solvents or other solvents containing hydrogen ac-
cepter are avoided for the possibility to disrupt the hydrogen
bonding formation.

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Huang et al. Sci China Chem
a)
Table 1 Optimization of reaction conditions
b)
Entry
Base
−
X (mol%)
Solvent
Toluene
Temperature (°C)
Yield (%)
1
2
3
4
5
6
7
8
9
−
150
150
150
150
150
150
100
150
150
0
K2CO3
K3PO4
NaOH
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
20
20
20
20
10
20
20
20
Toluene
92
91
93
Toluene
Toluene
c)
Toluene
99
c)
Toluene
86
c)
Toluene
44
Toluene/H2O (19:1)
58
Toluene/H2O (3:1)
/
a) Reaction was carried out with amide 1a (0.5 mmol), phenol 2a (1.0 mmol), base in 5.0 mL solvent and heated for 24 h; b) yields were determined by 1H
nuclear magnetic resonance (1H NMR) using 1,3,5-trimethoxybenzene as an internal standard; c) isolated yield.
boiling points, excess (5 equiv.) methanol or ethanol were
required to achieve good results for esters 18a–18b. All
tested benzylic alcohols with electron-deficient, electron-
rich, sterically hindered substituents as well as heterocyclic
substrates were readily converted to esters 21–33 in good to
excellent yields (58%–90%). Although the conversion of
highly active ferrocene-methanol (Fc-MeOH) was nearly
quantitative, the product 33 was not very stable during the
purification, thus leading to relatively low isolated yield
(58%). Pleasingly, the linear alcohols bearing alkenyl or al-
kynyl groups, were successfully converted to esters 34–37 in
good to excellent yields (70%–97%). This methodology was
readily extended to the secondary alcohols and esters 38 and
39 were obtained in good yields (77%–88%). Furthermore,
diols were well tolerated and the corresponding diesters 40a–
40c were attained in excellent yields (85%–90%). Selected
natural products featuring chiral or achiral primary or sec-
Scheme 1 Esterification of amide 1a with diverse phenols in 0.5 mmol
scale with 20 mol% NaOtBu in 5.0 mL toluene in a sealed tube at 150 °C
for 24 h. Superscript a) isolated yields; b) with 2.5 equiv. amide and
50 mol% NaOtBu at 150 °C for 36 h; c) with 4.0 equiv. amide and 80 mol%
NaOtBu at 150 °C for 48 h (color online).
ondary alcohols were well compatible and readily delivered
the desired esters 41–44. The important utility of the protocol
was demonstrated by the late-stage diversification of phar-
maceuticals. Under the optimized reaction conditions, qui-
nine (cinchona alkaloid, an antimalarial medication) and
perphenazine (for mental disorder therapy) were successfully
transferred into the esters 44 and 45 in 85% and 60% yields,
respectively.
With the broad scope of phenols and alkyl alcohols, the
applicability of the protocol towards diverse amides was then
explored (Scheme 3). The N-Boc substituted aryl amides
bearing electron-rich, electron-deficient substituents or het-
erocyclic amides were all well compatible and gave corre-
sponding esters 46–55 in good to excellent yields (68%–
92%). The protocol was readily extended to synthesis of tri-
ester 56 from the corresponding tri-amide. Aliphatic amides,
one type of challenging substrates in the transition-metal-
phenol (7), but the corresponding amide was fully converted.
The diphenols and triphenol reacted well and released the
corresponding diesters 13, 14 and triester 15 in excellent
yields (85%–95%). The protocol readily accommodates
chiral estrone and Vitamin E, generating the desired esters
16, 17 in good yields (70%–81%) with unchanged chiral
centers.
In light of lower reactivity of alkyl alcohols than phenols
[43], we subsequently examined the applicability of the
protocol towards a variety of alkyl alcohols (Scheme 2). All
tested linear primary alcohols with different chain lengths
reacted smoothly with amide 1a, affording esters 18–37 in
moderate to excellent yields (58%–97%). Due to their low

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Huang et al. Sci China Chem
Scheme 3 The scope of N-Boc-substituted amides. 0.5 mmol scale with
20 mol% NaOtBu in 5.0 mL toluene at 150 °C for 24 h. Superscript a)
isolated yields; b) with 4.0 equiv. phenol at 150 °C for 36 h; c) with 6.0
equiv. phenol at 150 °C for 72 h (color online).
Scheme 2 Esterification of amide 1a with primary and secondary alco-
hols in 0.5 mmol scale with 20 mol% NaOtBu in 5.0 mL toluene in a sealed
tube at 150 °C for 24 h. Superscript a) isolated yields; b) 5 equiv. 2 was
used; c) stirred at 35 °C for 15 h; d) after 36 h; e) with 2.5 equiv. amide and
50 mol% NaOtBu at 150 °C for 36 h (color online).
Pleasingly, beside imide-type amides, the unprotected
benzamide (R1=R2=H), an extremely inactive substrate in the
previously reported transition-metal-free catalyzed ester-
ification [29,30], was also compatible by our protocol, de-
livered the ester product 3 in 38% yield (Scheme 4). When
less-active benzyl alcohol was applied, the esterified product
could also be obtained in a slightly lower yield (26%). With
these results in hand, other inactive benzamides with diverse
alkyl, aryl or cyclic substituents as well as heterocyclic
amides were therefore examined. Pleasingly, all these se-
lected inactive amides reacted smoothly with phenol to re-
lease the corresponding esters in moderate to good yields,
even for di-esterification (40%–65%). When organometallic
alcohol Fc-MeOH was applied, amides were readily con-
verted into corresponding esters 33 in moderate yields
(40%–55%).
To explore the plausible mechanism, a series of control
experiments were carried out. Firstly, a stoichiometric
amount of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)
was used as radical inhibitor (Scheme S1, Supporting In-
formation online). Only a small decrease of yield was ob-
served (99% vs. 89%), suggesting no radical intermediate is
involved [45]. Secondly, the amount of NaOtBu strongly
affects the esterification process, with excess base usually
leading to poorer yields (Scheme S2 and Table S2). Inspired
catalyzed esterification [15], were easily converted into de-
sired esters 57–61 in good to excellent yields (74%–92%).
Remarkably, benzenepropanamide and cinnamamide were
readily esterified by (+)-menthol to give excellent yields of
esters 59 and 60. This protocol is also suitable for natural
derivative, cinnamamide was converted to its ester derivative
of testosterone 61 in a good yield (74%).
To our delight, amides with diverse (de)activating groups
were also compatible with the protocol (Scheme 3). Selected
N-Boc-benzamides and N-Ts-benzamides (Ts: p-toluene-
sulfonyl) bearing Boc, Bn, or Ph groups all resulted in good
to excellent yields (65%–96%, 3 and 36, Scheme 3), when-
ever phenol or vinyl alcohol was applied. When 1-benzoyl-
piperidine-2,6-dione was esterified, ester 3 was produced in
72% yield. However, N-Boc-benzamide containing methyl
group only generated ester 3 and 36 in 37% and 41% isolated
yields, respectively. In addition, secondary N-Boc/Bn-ben-
zamides 1f and 1g were also suitable for the esterification,
32% and 30% yields of ester 3 were obtained, respectively
(Scheme 3). The applicability of the protocol was further
demonstrated by gram-scale synthesis of butoxycaine 62
(Supporting Information online), a local anesthetic drug [44],
in 80% yield.

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Huang et al. Sci China Chem
Scheme 5 Capture and transformation of 64 (color online).
(Figures S3 and S4, Supporting Information online) is crucial
for the esterification. Although this hydrogen-bonding for-
mation may increase the solubility, computational study on
the esterification of amide 1a indicated the anion pair (spe-
cies I, Figure 2) formed by 3-nitrobenzyl alcohol had a
higher stability than pure 3-nitrobenzyloxide anion under the
basic conditions (–16.9 kcal/mol), with a hydrogen bond to
disperse the negative charge on oxygen atom, especially in
non-polar solvent like toluene. This is further confirmed by
the similar computational outcome found for phenol
(–12.3 kcal/mol).
Excess base will deprotonate all the phenols so that there is
no H-bond acceptor left. Consequently, species I will not be
generated and thus the catalytic process was hampered. After
generation, the species I can undergo nucleophilic attack at
the amide to form a very unstable intermediate II
(14.6 kcal/mol), leading to the formation of a relatively
stable tetrahedral intermediate anion III (6.1 kcal/mol), sta-
bilized by additional alcohol molecule via hydrogen-bond-
ing. The anion III could be converted to intermediate IV
(12.6 kcal/mol) through the electron transfer from oxygen
atom to nitrogen atom. The C–N bond between the carbonyl
group and nitrogen atom in intermediate IV could be cleaved
into an ester, along with the release of amine alkyloxide pair
V (–2.4 kcal/mol). Finally, protonolysis of the pair V with
another molecular alcohol could produce amine product VI
(–9.1 kcal/mol) and regenerate species I to complete the
catalytic cycle. When benzamide was applied instead of 1a
in the DFT calculations, the ∆G for all intermediates
are relatively high, especially for amine formation VI
(9.0 kcal/mol, Figure S3). This is also consistent with our
experiment results—benzamide is more challenging to be
transformed to esters, with only 38% yield obtained even
with extended reaction times (72 h, 3 in Scheme 4).
Scheme 4 The scope of N–H/alkyl/aryl substituted amides. Reaction
conditions: 0.5 mmol scale with 6.0 equiv. phenol/alcohol and 20 mol%
NaOtBu in 5.0 mL toluene at 150 °C for 72 h. Superscript a) isolated yields;
b) with2.0 equiv. alcohol and 20 mol% NaOtBu in 5.0 mL toluene at 150 °C
for 36 h (color online).
by the serine protease-catalyzed esterification [40], the ad-
duct of phenol and phenoxide anion may be responsible for
the esterification. When the ratio of phenol and sodium
phenoxide was 1:1, a 75% yield was achieved, which further
increased to 91% when the ratio was 9:1 (entries 2 and 3,
Table S2). Thirdly, the competition experiments were carried
out. The electron-deficient amide was found to be more re-
active (Scheme S3), which in accord with the relative elec-
trophilicity of the amide bond. At last, an intramolecular and
intermolecular competition reaction with 4-hydroxy-
phenethyl alcohol or the mixture containing equal amount of
phenol and benzyl alcohol were selected to react with amide
1a under the otherwise identical reaction conditions (Scheme
S4). The hydroxyl groups of phenols are inherently more
reactive than that of alkyl hydroxyl analogues, and 3:1 ratio
for phenol esters to alcohol esters were found in both cases,
which further supported the nucleophilic substitution path-
way.
To gain further insight of the reaction mechanism, attempts
of capturing and isolating the possible reaction intermediates
were made. As shown in Scheme 1, no esterification pro-
ducts 7a and 7b were detected when phenols with strong
electron-withdrawing groups (–NO2 or –CN) were applied as
substrates. Similar situation was observed with 3-nitrobenzyl
alcohol 63 as the substrate. It is worth noting that, only in this
case, a tetrahedral compound 64 was isolated (Scheme 5),
which was the possible intermediate for the esterification. No
tetrahedral intermediate was isolated when 4-nitrobenzyl
alcohol was applied, instead, ester product 23 was isolated in
10% yield (Scheme 2). Pleasingly, compound 64 was readily
converted into ester 65 after heating at 150 °C for several
hours or at ambient condition for several days. The isolation
and conversion of 64 demonstrates that a catalytic amount of
base can lead to the formation of a tetrahedral intermediate,
which is crucial for the esterification.
The calculation of apparent activation energy was carried
out (Figures S1 and S2). In light of the nucleophilic sub-
stitution reaction pathway, we assumed a quasi-second order
reaction mechanism. To simplify the calculation process, all
possible sub-reaction and concentration effects were omitted
and the reaction of amide and phenol to give the ester was
assumed to be quantitative. According to Arrhenius formula,
the apparent activation energy of benzamide to phenyl
benzoate 3 is to be 9.27 kcal/mol, which is in good agree-
ment with the DFT calculation (9.1 kcal/mol).
Computational density functional theory (DFT) calcula-
tions revealed the conjugated acid-base pair formation

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Huang et al. Sci China Chem
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bond assisted base-catalyzed esterification of diverse amides
has been realized. Good to excellent yields were obtained for
electron-rich, electron-poor and sterically hindered sub-
strates. Diverse alkyl amides, aryl amides, phenols and al-
cohols were all compatible. Control experiments and DFT
calculations revealed that hydrogen-bonding assisted nu-
cleophilic substitution was crucial for the esterification. The
base-catalyzed protocol developed complements the con-
ventional transition-metal-catalyzed esterification of amides
and provides a plausible new pathway to catalytic cleavage
of amide C–N bonds for organic synthesis and the pharma-
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Acknowledgements This work was supported by the National Key R&D
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Supporting information The supporting information is available online at
http://chem.scichina.com and http://link.springer.com/journal/11426. The
supporting materials are published as submitted, without typesetting or
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