A practical and sustainable protocol for direct amidation of unactivated esters under transition-metal-free and solvent-free conditions

Article abstract of DOI:10.1039/d1gc00720c

In this paper, a NaOtBu-mediated synthesis approach was developed for direct amidation of unactivated esters with amines under transition-metal-free and solvent-free conditions, affording a series of amides in good to excellent yields at room temperature. In particular, an environmentally friendly and practical workup procedure, which circumvents the use of organic solvents and chromatography in most cases, was disclosed. Moreover, the gram-scale production of representative products3a,3wand3auwas efficiently realized by applying operationally simple, sustainable and practical procedures. Furthermore, this approach was also applicable to the synthesis of valuable molecules such as moclobemide (a powerful antidepressant), benodanil and fenfuram (two commercial agricultural fungicides). These results demonstrate that this protocol has the potential to streamline amide synthesis in industry. Meanwhile, quantitative green metrics of all the target products were evaluated, implying that the present protocol is advantageous over the reported ones in terms of environmental friendliness and sustainability. Finally, additional experiments and computational calculations were carried out to elucidate the mechanistic insight of this transformation, and one plausible mechanism was provided on the basis of these results and the related literature reports.

Full text of DOI:10.1039/d1gc00720c

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A practical and sustainable protocol for direct
amidation of unactivated esters under transition-
Cite this: DOI: 10.1039/d1gc00720c
metal-free and solvent-free conditions†
Rui Zhang, a Wei-Zhong Yao,a Liang Qian,a Wei Sang,b Ye Yuan,b Min-Chen Du,b
Hua Cheng,*a Cheng Chen *b and Xin Qin*c
In this paper, a NaOtBu-mediated synthesis approach was developed for direct amidation of unactivated
esters with amines under transition-metal-free and solvent-free conditions, affording a series of amides
in good to excellent yields at room temperature. In particular, an environmentally friendly and practical
workup procedure, which circumvents the use of organic solvents and chromatography in most cases,
was disclosed. Moreover, the gram-scale production of representative products 3a, 3w and 3au was
efficiently realized by applying operationally simple, sustainable and practical procedures. Furthermore,
this approach was also applicable to the synthesis of valuable molecules such as moclobemide (a power-
ful antidepressant), benodanil and fenfuram (two commercial agricultural fungicides). These results
demonstrate that this protocol has the potential to streamline amide synthesis in industry. Meanwhile,
quantitative green metrics of all the target products were evaluated, implying that the present protocol is
advantageous over the reported ones in terms of environmental friendliness and sustainability. Finally,
additional experiments and computational calculations were carried out to elucidate the mechanistic
insight of this transformation, and one plausible mechanism was provided on the basis of these results
and the related literature reports.
Received 24th February 2021,
Accepted 21st April 2021
DOI: 10.1039/d1gc00720c
rsc.li/greenchem
thesis approaches using diverse substrates have been devel-
oped,7 and the majority of them proceeded by the reaction of
Introduction
The amide bond, one of the most fundamental functional amines with activated carboxylic acids or their derivatives.8
groups in chemistry and living cells, has been widely rep- However, these methods highlighted several drawbacks includ-
resented in natural products,1 pharmaceuticals,2 agrochem- ing poor atom economy and generation of harmful or toxic
icals3 and functional materials.4 Due to its great importance, wastes. In contrast, direct amide synthesis from amines and
amide bond formation has been recognized as one of the most unactivated esters (especially alkyl esters) was seldomly exe-
frequently utilized transformations in academic research for cuted for a long time since alkyl esters possess much higher
the synthesis of active pharmaceutical ingredients,5 and it has nO ! πC* vO isomerization than the aryl counterparts.9 Indeed,
also been labeled as a high-priority research field in the these unactivated esters possess intrinsic advantages as acylat-
pharmaceutical industry.6 As a consequence, expedient syn- ing reagents due to their good stability and ready availability.
Accordingly, amide synthesis directly from alkyl esters
(especially methyl esters) is an appealing alternative to tra-
aDepartment of Chemical Engineering and Food Science, Hubei University of Arts
and Science, 296 Longzhong Road, Xiangyang 441053, P. R. China.
E-mail: cch510@126.com
bState Key Laboratory of Advanced Technology for Materials Synthesis and
Processing, Wuhan University of Technology, 122 Luoshi Road, Wuhan 430070,
P. R. China. E-mail: chengchen@whut.edu.cn; Fax: (+86)-27-87879468;
Tel: (+86)-27-88016035
cSchool of Basic Medicine, Hubei University of Arts and Science, 296 Longzhong
Road, Xiangyang 441053, China. E-mail: 543755712@qq.com
†Electronic supplementary information (ESI) available: Comparison of this work
with the literature reports, detailed calculated green metrics, supplementary
results, characterization data and original spectra of all the target compounds.
See DOI: 10.1039/d1gc00720c
ditional methods, with improved atom/step economy in many
cases and alcohol (only methanol for a methyl ester) as the
sole byproduct, which is in accordance with the principles of
green chemistry and sustainability.10
Recently, utilization of alkyl esters for the construction of
the amide bond under various conditions has been developed
using versatile reagents or catalysts, including transition-
metal-based homogeneous catalysts,11 organocatalysts,12
N-heterocyclic carbenes (NHCs),13 ionic liquids,14 hetero-
geneous catalysts,15 enzymes16 and metal salts or bases.17
However, most of them suffer from at least one of the follow-
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Table 1 Optimizations of reaction conditionsa
Yieldb (%)
Entry
x
y
Base (z equiv.)
t (h)
3a
Unreacted 1a
1
2
3
4
5
6
7
8
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
3.0
2.0
1.5
1.2
1.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
NaOtBu (1.5)
NaOtBu (1.5)
NaOtBu (1.5)
NaOtBu (1.5)
NaOtBu (1.5)
NaOtBu (1.5)
NaOtBu (0.5)
NaOtBu (1.0)
NaOtBu (2.0)
LiOtBu (1.5)
KOtBu (1.5)
NaOH (1.5)
KOH (1.5)
Na2CO3 (1.5)
K2CO3 (1.5)
Cs2CO3 (1.5)
KOAc (1.5)
DIPEA (1.5)
DBU (1.5)
0.5
0.5
0.5
0.5
0.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
88
90
85
73
66
96
51
65
96
20
60
10
5
12
25
30
—
46
32
—
73
36
99
97
95
96
98
96
97
96
Fig. 1 Selected approaches for direct amidation of unactivated esters.
(a) Newman’s work, (b) Szostak’s work, (c) Park & Yoon’s work, (d) this
work.
9
10
11
12
13
14
15
16
17
18
19
ing drawbacks: limited substrate scope,12h time-consump-
c
—
—
—
—
—
—
—
—
tion,11e
unfavorable
reaction
conditions
(high
c
c
c
c
c
c
c
temperature11o,12a or use of toxic catalysts17d), and utilization
of transition-metal catalysts11b,c,i,j,l–p or rare-metal catalysts,11e
thus limiting their potential application in industry and/or
introducing hazardous substances into the environment. On
the other hand, most of the reported approaches involve
organic solvents during reaction set-up and product purifi-
cation (Fig. 1a–c as representative examples), which does not
meet the criteria of green and sustainable chemistry.10 Since
non-benign organic solvents are major wastes generated in
organic synthesis, it is highly desirable to develop environmen-
tally benign synthesis methods. Inspired by the ability of
NaOtBu in promoting the solventless transamidation of ter-
tiary amides with amines in our previous work,18 we were intri-
gued to incorporate this base-promoted solventless strategy into
the direct amidation of alkyl esters with amines. To our delight,
a practical and sustainable strategy was developed for this trans-
formation at room temperature, in the absence of transition
metals and solvents (Fig. 1d). This protocol features a broad
substrate scope, solventless reaction conditions, easy operation
(a benchtop setup instead of a glovebox setup) and practical
work-up procedures (without utilizing organic solvents and
chromatography techniques for most products). More signifi-
cantly, this methodology is scalable and can be applied to the
synthesis of commercial drugs/pesticides. Furthermore, green
metrics of this work and representative references were calcu-
lated and compared, which demonstrates the advantages of our
synthesis method in terms of greenness and sustainability. A
comparison of the present protocol with the reported ones is
given in Table S1.† Finally, a plausible reaction mechanism was
proposed based on a few additional experiments, computational
calculations and several related publications.
a Conditions: a mixture of 1a (x equiv.), 2a (y equiv.) and base (z equiv.)
was stirred at room temperature under argon for an assigned period.
b Isolated yields on a 2.15 mmol scale. c 3a was not detected.
to optimize the reaction conditions (as listed in Table 1). An
initial hit stemmed from the optimized reaction conditions in
our previous work.18 With NaOtBu (1.5 equiv.) as a base, the
reaction of 1a (1.0 equiv.) and 2a (3.0 equiv.) was carried out at
room temperature under a solventless condition for 0.5 h,
leading to 88% of N-phenylbenzamide (3a) and 10% of
unreacted 1a (entry 1). This result inspired us to continue the
optimization. From a perspective of green and sustainable
chemistry, the ratio of each reagent should be as close to equal
molar as possible. Therefore, the ratio of 2a/1a was systemati-
cally assessed (entries 1–5). Decreasing the ratio from 3.0/1.0
to 2.0/1.0 or 1.5/1.0 gave rise to the comparable yield of 3a
(entries 2 and 3 vs. entry 1), while an even smaller ratio (1.2/
1.0 or 1.0/1.0) led to poor results from the viewpoint of reac-
tion efficiency (entries 4 and 5 vs. entry 3). To further increase
the yield of 3a, the reaction times for the reactions listed in
entries 3–5 were extended (as detailed in Fig. S1†). Under all
circumstances, the yield of 3a was gradually increased until a
plateau was reached, and the best result was obtained at a
ratio of 1.5/1.0 after 1.0 h, which resulted in a 96% yield of 3a
and 0% of unreacted 1a (entry 6). Subsequently, the amounts
of NaOtBu were screened (entries 6–9). If the equivalents
(equiv.) of NaOtBu were reduced from 1.5 to 0.5–1.0, only a
moderate yield of 3a was observed, with substantial amounts
of 1a remaining (entries 7 and 8). On the other hand, an
Results and discussion
With the above consideration in mind, the reaction of aniline increased amount of NaOtBu (2.0 equiv.) resulted in a constant
(1a) and methyl benzoate (2a) was selected as a model reaction yield of 3a (entry 9 vs. entry 6). Therefore, 1.5 equiv. of NaOtBu
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was identified as the most suitable amount. Afterwards, the substrate scope and limitations of this method. Firstly, the
different bases were screened to evaluate their effects on this compatibility of the current protocol in the reactions of methyl
transformation. Among various metal salts, LiOtBu (entry 10) benzoate (2a) with various amines was studied (as shown in
and KOtBu (entry 11) delivered 3a in low to moderate yields Scheme 1). Various amides (3a–3ah) were efficiently obtained
(20–60%). Besides, other bases including hydroxides (entries from primary amines (aromatic and aliphatic, 1a–1ac) or sec-
12 and 13), carbonates (entries 14–16), potassium acetate ondary amines (1ad–1ah) in good to excellent yields. In detail,
(KOAc, entry 17) and organic bases (entries 18 and 19) were anilines with either electron-donating (1b–1d) or electron-with-
also attempted. Unfortunately, the above bases were entirely drawing (1e–1j) groups reacted well with 2a to furnish the
ineffective (entries 12–19). These results illustrate that efficient corresponding amides (3b–3j) in 81–99% yields, which indi-
formation of 3a with an excellent yield is accomplished under cates that the electronic properties of aniline substituents have
transition-metal-free and solvent-free conditions, with the opti- no obvious impact on this process. It appears that the substitu-
mized reaction conditions discovered as follows: 1a (1.0 ent positions marginally affect the yield of the desired pro-
equiv.), 2a (1.5 equiv.), NaOtBu (1.5 equiv.), and room tempera- ducts, with amides 3b, 3k and 3l being prepared in similar
ture for 1 h (entry 6).
yields, ranging from 88% to 97%. Apart from mono-substituted
Apart from methyl benzoate (2a), a few derivatives of 2a anilines, di-substituted substrates 1m and 1n were also tested,
bearing varied R groups [ethyl benzoate (2a-Et), isopropyl ben- delivering amides 3m and 3n in 99% and 96% yields, respect-
zoate (2a-iPr), tert-butyl benzoate (2a-tBu), benzyl benzoate (2a- ively. Moreover, amines comprising unique bioactive substruc-
Bn), phenyl benzoate (2a-Ph) and benzoic acid (2a-H)] were tures,20 such as [1,1′-biphenyl]-2-amine (1o), 4-phenoxyaniline
attempted to react with aniline (1a) under the optimized con- (1p), and N1-phenylbenzene-1,4-diamine (1q), were screened to
ditions (as listed in Table 2). It was found that the steric hin- further expand the scope of this methodology. To our delight,
drance of R had a significant influence on this reaction, and these three substrates could be efficiently transformed into the
the yield of 3a gradually decreased as the steric bulk increased corresponding amides (3o–3q) in 81–98% yields. Particularly,
(entries 1–4). It has been well documented that a benzyl ester (R only mono-benzoylated product 3q was isolated in 90% yield,
= Bn) is prone to the C(sp3)–O cleavage,17u so this reactive ester which implies that secondary aromatic amines are probably
delivered 3a in a 95% yield (entry 5). Generally, the relative reac- incompatible for this transformation. Meanwhile, amidation
tivity of these esters followed the order of 2a ≈ 2a-Bn > 2a-Et > of 2a with heteroaromatic amines 1r–1u proceeded smoothly
2a-iPr > 2a-tBu (entries 1–5). As for 2a-Ph, 3a was isolated in a to yield the corresponding amides (3r–3u) in 75–85% yields.
51% yield and 40% of 1a remained, which is probably attributed Furthermore, the primary aliphatic amines such as benzyla-
to the high viscosity of the reaction mixture causing the inter- mine (1v), 2-phenylethan-1-amine (1w), furan-2-ylmethana-
ference in the interaction of the two reactants (entry 6). As mine (1x) and hexane-1-amine (1y) exhibited remarkable reac-
expected, benzoic acid (2a-H) cannot go through direct amida- tivity, generating the desired products 3v–3y in good to excel-
tion with aniline (1a) under the standard conditions (entry 7), lent yields (80–98%). Interestingly, t-butyloxy carbonyl (Boc)-
probably due to the high activation energy between a carboxylic protected amines 1z and 1aa were also tolerated, albeit only
acid and an amine, consistent with the result in the literature.19 70–76% of amides 3z and 3aa were obtained. It is worthwhile
From the aspects of both reactivity and atom economy, methyl to mention that these two amides could permit further
esters were selected for further investigations.
functionalization to synthesize potentially useful chemicals.21
After achieving the optimal reaction conditions and select- Furthermore, anilines bearing base-sensitive groups such as
ing methyl esters as the preferred substrates, we then explored methyl 4-aminobenzoate (1ab) and 4′-aminoacetophenone
(1ac) were also tolerated, affording the desired amide products
(3ab and 3ac) in 44–73% yields. In addition to primary ali-
phatic amines, secondary counterparts were also suitable sub-
strates. Cyclic secondary amines (1ad and 1ae) and
N-benzylmethylamine (1af) gave rise to amides 3ad–3af in
82–94% yields, while N-methylaniline (1ag) and N,4-dimethyl-
aniline (1ah) provided amides 3ag–3ah in 25–55% yields.
Unfortunately, diphenylamine (1ai) was not a suitable sub-
strate for our protocol, and amide 3ai could not be obtained.
To further enhance the utility of this protocol, the reactions
of aniline (1a) with different methyl esters were examined (as
shown in Scheme 2). Initially, an array of aromatic methyl
esters was tested. It appears that this protocol is not very sensi-
tive to the electronic and steric environment around the aryl
substitutions of esters. Substrates containing either electron-
rich (2aj and 2ak) or electron-deficient (2al and 2am) groups
performed well to yield the corresponding amides in satisfac-
tory yield. In addition, compared with methyl 4-methyl-
Table 2 Reactivity of 2a and its derivativesa
Entry
R
Yield of 3a b (%)
1
2
3
4
5
6
7
Me
Et
iPr
tBu
Bn
Ph
H
96
72
55
30
95
51
0
a Conditions: aniline (1a, 1.0 equiv.), an ester (1.5 equiv.), NaOtBu (1.5
equiv.), room temperature for 1.0 h. b Isolated yields on a 2.15 mmol
scale.
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Scheme 1 NaOtBu-promoted direct amidation of methyl esters with amines: scope of amines.
Scheme 2 NaOtBu-promoted direct amidation of methyl esters with amines: scope of methyl esters.
benzoate (2aj), methyl 3-methylbenzoate (2an) selectively gen- 3ao in a slightly lower yield. Importantly, heterocycle-contain-
erated the respective product (3an) in comparable yield, while ing esters 2ap–2ar also coupled with 1a to efficiently give
methyl 2-methylbenzoate (2ao) exclusively provided product amides bearing pyridine (3ap), pyrazine (3aq) and furan (3ar)
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moieties in excellent yields (90–98%). Notably, a few aliphatic
methyl esters including cyclic (2as and 2at) and acyclic (2au and
2av) ones were also attempted, and the corresponding amides
(3au–3av) were obtained in good to excellent yields (73–96%).
From the perspective of potential application in industry,
an environmentally friendly and practical workup procedure is
of great significance. In practice, the workup procedure is
equally important for the reaction setup. Therefore, we endea-
vored to optimize the workup procedure in an eco-friendly and
practical fashion. As for a standard reaction, slightly excess
amounts of NaOtBu and a methyl ester were used, and ice
water was added dropwise to quench the reaction. In the pres-
ence of water, NaOtBu would be converted into water-soluble
substances (NaOH and tBuOH). Besides, the excess methyl
ester could easily undergo hydrolysis under basic aqueous
solutions, affording the corresponding carboxylates. Therefore,
all the above-mentioned by-products could be dissolved in
water, which inspired us to develop a workup process
mediated only with water. Moreover, most of the amides are
solid products, which could be collected by vacuum filtration
and washed several times with pure water. In this way, pro-
ducts with enough purity were obtained in most cases. It is
crucial to note that this protocol features not only the solvent-
and transition-metal-free conditions for reaction setup, but
also an eco-friendly and practical process for product separ-
ation and purification. On the other hand, the scalability of a
protocol is also a pivotal factor for industrial application.
Therefore, production of representative products 3a, 3w and
3au were conducted on a larger scale (20 mmol, as shown in
Scheme 3). N-Phenylbenzamide (3a, 3.70 g, 18.8 mmol) was
efficiently prepared in a 94% yield at room temperature for
1.5 h via the reaction of aniline (1a, 1.82 mL, 20 mmol),
methyl benzoate (2a, 3.76 mL, 30 mmol) and NaOtBu (2.88 g,
30 mmol) (Scheme 3a). Similarly, N-phenethylbenzamide (3w,
4.19 g, 18.6 mmol) and N-phenylacetamide (3au, 2.43 g,
18.0 mmol) were prepared in 93% and 90% yields, respectively
(Scheme 3b and c). Notably, the above water-mediated workup
procedure is also applicable to these larger-scale reactions.
Furthermore, the diversity of this methodology is illustrated by
the synthesis of amide-containing pharmaceuticals and fungi-
Scheme 4 Application of this protocol in medicinal and pesticide
chemistry: synthesis of (a) moclobemide (3aw, an antidepressant drug),
(b) benodanil (3ax, an agricultural fungicide) and (c) fenfuram (3ay, an
agricultural fungicide).
cides (as depicted in Scheme 4). Moclobemide (3aw,
Scheme 4a), benodanil (3ax, Scheme 4b), and fenfuram (3ay,
Scheme 4c) were successfully prepared from the corresponding
methyl esters and amines in good to excellent yield. On the
whole, all the above results demonstrate the great potential of
this protocol in industrial applications.
To verify the greenness and sustainability of the present
protocol, quantitative green metrics, including atom economy
(AE), E-factor, carbon efficiency (CE), reaction mass efficiency
(RME), mass intensity (MI) and mass productivity (MP), were
evaluated.10a,d The above-mentioned green metrics of this
work (Fig. 2b, d and f) and representative references (Fig. 2a, c
and e)11o,17q,u were calculated and compared based on the
reported methods (as detailed in Table S2†).10a,d AE is a theore-
tical value that only takes the starting materials and products
into account. Since all the methods are applied to the same
type of reactions, the AE values for the same products are iden-
tical (except the reference in Fig. 2a, which used ethyl esters
instead of methyl esters). Meanwhile, the E-factor, a parameter
that considers the generated wastes from all the consumed
reagents, was examined. To our delight, the E-factor values
obtained in this work (0.9–7.6) are much lower than those of
the representative references (22.6–63.4), indicating that the
current process is more beneficial to the environment. This
result is evidently attributed to the solvent- and transition-
metal-free conditions of this protocol. Subsequently, the calcu-
lation of CE and RME values illustrates good efficiency of our
protocol, even though these values are comparable or margin-
ally lower than those in the literature approaches. For the
mass-related green metrics including MI and MP, the present
work also exhibits considerably better results in comparison
with the selected references. Based on these findings, we envi-
sage that this NaOtBu-promoted amidation process is relatively
greener and more sustainable than the reported ones.
Subsequently, additional experiments were carried out to
give further insight into the reaction mechanism (as listed in
Table 3). Interestingly, the reaction could proceed smoothly
under dry air, with a comparable yield than that under argon
Scheme 3 Preparation of representative amide products (3a, 3w and
3au) on a 20 mmol scale.
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Fig. 2 Comparison of green metrics between representative references and this work: (a) KOtBu-promoted amidation of ethyl esters.17q (c) Ni-cata-
lyzed amidation of methyl esters.11o (e) LiHMDS-promoted amidation of methyl esters.17u (b), (d) and (f) This work.
(92% vs. 96%, entry 2 vs. entry 1). In order to further confirm which possibly involves a radical process reported by Yoon and
whether a radical process was involved in this transformation, co-workers.17q This KOtBu-promoted amidation could only
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO, entry 3) and 1,1- proceed smoothly in air with a water-containing solvent, but
diphenylethylene (entry 4) were added into the reaction neither in argon nor in an anhydrous solvent. As reported,
mixture. It is worth noting that the addition of these radical KOtBu is a good electron transfer reagent and has been widely
scavengers has no significant effect on the yield of 3a (90% studied in transition-metal-free cross-coupling reactions22 and
and 91% vs. 96%, entries 3 and 4 vs. entry 1). Therefore, the transamidation of amides23 via a radical process. In contrast,
radical-mediated process is excluded for this transformation, NaOtBu has been rarely involved in
a radical process.
unlike the KOtBu-promoted amidation of esters with amines Accordingly, we believe that our NaOtBu-mediated process
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Table 3 Additional experimentsa
Yield of 3a b
Atmosphere (%)
Entry Radical scavenger
1
None
None
Argon
Dry air
Argon
96
92
90
91
2c
3
Tempo (1.0 equiv.)
1,1-Diphenylethylene (1.0 equiv.) Argon
4
a Conditions: a mixture of 1a (200 mg, 2.15 mmol), 2a (439 mg, 1.5
equiv.), NaOtBu (309.9 mg, 1.5 equiv.) and radical scavenger (0 or 1.0
equiv.) was stirred at room temperature for 1.0 h. b Isolated yields.
c Equipped with a CaCl2-containing drying tube.
undergoes a different reaction pathway from the reported
KOtBu-promoted amidation.17q
On the basis of the above results and previously related
publications, we proposed a plausible mechanism comprising
1,3-chelation of an ester with NaOtBu24 and subsequent
nucleophilic addition by the activated amine18 (as shown in
Scheme 5). As reported, Na+ can form strong interactions with
the oxygen atoms of the methyl ester, and such interaction can
lead to the activation of a carbonyl group.24 In our previous
report, NaOtBu could activate amine 1 via coordination to
generate intermediate 4.18 Meanwhile, ester 2 was transformed
into intermediate 2′ via a 1,3-chelation step,24 followed by
nucleophilic addition of 4 into 2′ to deliver an unstable tetra-
hedral intermediate (5).14a,17n Ultimately, elimination of
MeOH from 5 results in the formation of the desired amide
3.14a,25 Furthermore, the stability of key intermediates 2′ and 4
was evaluated via the computational calculation. The
vibrational frequencies and changes in Gibbs free energy (ΔG)
at 298 K were both calculated. No imaginary frequency appears
Fig. 3 Optimized structures of key intermediates 2’ and 4 via compu-
tational calculations.
(data of the vibrational frequency are shown in the ESI†),
which indicates that 2′ and 4 are stable intermediates instead
of transition states. The optimized structures of 2′ and 4 are
shown in Fig. 3. Meanwhile, changes in ΔG for the transform-
ations of 1 to 4 and 2 to 2′ were calculated as −0.096 eV and
0.193 eV, respectively (as listed in Table S3†), which implies
that the formation of both intermediates is favored at 298 K.
Therefore, we can conclude that intermediates 2′ and 4 are
stable on the basis of the computational calculation.
Experimental
General considerations
All the reactions were carried out using standard Schlenk tech-
niques unless otherwise mentioned. 1H-NMR and 13C-NMR
spectra were recorded on a Bruker Avance 500 spectrometer in
CDCl3 or DMSO-d6, with tetramethylsilane (TMS) as an
internal reference. Multiplicities were shown using the follow-
ing abbreviations: s = singlet, d = doublet, t = triplet, m = mul-
tiplet, dd = doublet of doublets, and dq = doublet of quartets.
Melting points of products in solid states were taken on a
Buchi M-560 melting point apparatus without calibration.
High resolution mass spectrometry (HRMS) analyses were
carried out with a Thermo Fisher Q Exactive™ UHMR
Orbitrap™ instrument. NaOtBu was obtained from Adamas
Beta® (99% purity), and used directly without any pre-treat-
ment. Besides, all the common reagents, including amines
(1a–1ai, 1aw), methyl benzoate (2a) and its derivatives (2a-Et,
Scheme 5 A plausible mechanism.
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2a-iPr, 2a-tBu, 2a-Bn, 2a-Ph, 2a-H), and other methyl esters graphy techniques in most cases. Moreover, the gram-scale
(2aj–2ay), were purchased from commerical suppliers and synthesis of representative target compounds (3a, 3w and 3au),
used directly without further purification.
as well as preparation of an antidepressant drug (moclobe-
mide) and agricultural fungicides (benodanil and fenfuram)
were accomplished, which provides evidence for the practical
importance of the present protocol in industrial applications.
In view of the quantitative green metrics, this NaOtBu-pro-
moted amidation displays relatively better performance than
the reported processes in terms of greenness and sustainabil-
ity. On the basis of additional experiments, computational cal-
culations and related papers, one plausible reaction mecha-
nism involving 1,3-chelation of an ester and subsequent
nucleophilic addition was proposed.
General procedure for direct amidation of alkyl esters with
amines
To an oven-dried 25 mL Schlenk flask was added an amine (1,
2.15 mmol), an alkyl ester (2, 3.22 mmol) and NaOtBu
(309.9 mg, 3.22 mmol). The flask was subjected to three cycles
of evacuation-backfilling with argon, and then stirred at room
temperature for 1.0 h under argon. Subsequently, water
(20 mL) was added dropwise to quench the reaction, and the
resulting mixture was stirred for another 1.0 h. The solid was
then collected by vacuum filtration, washed with water (3 ×
5 mL), dried in an oven to afford the desired products (3).
Note: compounds 3s, 3t, 3u and 3ac–3ah were purified by
column chromatography on silica gel using hexane/EtOAc (6/
1–3/1) as eluents.
Author contributions
Rui Zhang: conceptualization, funding acquisition, investi-
gation, project administration, resources, methodology, super-
vision, writing – original draft, writing–review & editing; Wei-
Zhong Yao: investigation, methodology, data curation, soft-
ware, visualization; Liang Qian: investigation, methodology;
Wei Sang: data curation, formal analysis, software; Ye Yuan:
formal analysis, software; Min-Chen Du: formal analysis, soft-
ware; Hua Cheng: formal analysis, data curation, resources,
software, funding acquisition, writing – review & editing.
Cheng Chen: conceptualization, funding acquisition, formal
analysis, project administration, resources, supervision,
writing – original draft, writing – review & editing; Xin Qin:
funding acquisition, formal analysis, resources, writing –
review & editing. All authors approve the current version of the
manuscript.
For the gram-scale synthesis of 3a, methyl benzoate (2a,
3.76 mL, 30 mmol) was added dropwise into a mixture of
NaOtBu (2.88 g, 30.0 mmol) and aniline (1a, 1.82 mL,
20.0 mmol). The resulting mixture was then stirred at room
temperature under argon for 1.5 h. A similar workup pro-
cedure with the standard one was used to afford compound 3a
(3.70 g, 94% yield) as a white solid. For the gram-scale syn-
thesis of N-phenethylbenzamide (3w) and N-phenylacetamide
(3au), similar procedures as used for 3a were exploited.
Calculation of green metrics
The green metrics of the selected references and this work was
calculated based on the literature methods.10a,d
Computational methods
All calculations were done using Gaussian 16.26 The geometry
optimization calculation for 1, 2, 2′, 4 and NaOtBu was per-
formed by using the B3LYP DFT method.27 The basis set used
for C, H, O and N atoms was 6-31G(d), and the LANL2DZ pseu-
dopotential basis set was employed for the Na atom. The
vibrational frequency was computed at the same level of theory
to check whether each optimized structure was an energy
minimum or a transition state, and to evaluate its zero-point
energy (ZPE) and the thermal corrections at 298 K (all ΔG
values were based on these calculations).
Conflicts of interest
There are no conflicts of interest to declare.
Acknowledgements
This research was supported by the Innovation Team
Cultivation Fund of Hubei University of Arts and Sciences (No.
2020kypyt004), National Undergraduate Innovation and
Entrepreneurship Training Program (201910519006), the
Conclusions
In summary, a NaOtBu-promoted, green, practical and user- Foundation of Hubei University of Arts and Science (Grant No.
friendly protocol was developed for the facile construction of 2059057), Scientific Research Program Guiding Project of
the amide bond, which efficiently converted various alkyl Hubei Provincial Department of Education (B2019135), the
esters (mainly abundant methyl esters) and amines into the fund of the Key Laboratory of Catalysis and Energy Materials
desired amides in good to excellent yields at ambient tempera- Chemistry of Ministry of Education and Hubei Key Laboratory
tures. Gratifyingly, the protocol was realized under solvent- of Catalysis and Materials Science (No. CHCL19002). The
and transition-metal-free conditions. It is also worth empha- project was also supported by State Key Laboratory of
sizing that an eco-friendly and practical workup procedure was Advanced Technology for Materials Synthesis and Processing
obtained without the use of organic solvents and chromato- (Wuhan University of Technology, No. 2021-KF-19).
Green Chem.
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