Ball-milling enables highly selective solvent-free N-tert-butoxycarbonylation for activation of amides

Article abstract of DOI:10.1016/j.tetlet.2020.152140

A ball-milling enabled chemoselective activation of amides via N-tert-butoxycarbonylation catalyzed by 4-dimethylaminopyridine is described under solvent-free conditions. High chemoselectivity with respect to NH acidity of amides has been observed. A one-pot two-step procedure for selective esterification of amides has been demonstrated in model reaction of benzamides with p-cresol and benzyl alcohol.

Full text of DOI:10.1016/j.tetlet.2020.152140

Journal Pre-proofs
Ball-milling enables highly selective solvent-free N-tert-butoxycarbonylation
for activation of amides
Weijia Shi, Guoping Sun, Gang Zou
PII:
S0040-4039(20)30599-2
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152140
TETL 152140
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Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
7 May 2020
1 June 2020
8 June 2020
Please cite this article as: Shi, W., Sun, G., Zou, G., Ball-milling enables highly selective solvent-free N-tert-
butoxycarbonylation for activation of amides, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.
2020.152140
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Ball-milling enables highly selective solvent-
free N-tert-butoxycarbonylation for
activation of amides
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Weijia Shi, Guoping Sun and Gang Zou*
1.2-2.5equiv. Boc2O
O
O
5-30mol% DMAP
R''
R'
R
N
R
N
, 30Hz, 2-4h
up to 98% yield
H
Boc
R'' = Boc, alkyl, Ar
R' = H, alkyl, Ar
Solvent-free condition
High chemoselectivity

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Ball-milling enables highly selective solvent-free N-tert-butoxycarbonylation for
activation of amides
Weijia Shia, Guoping Sunb and Gang Zoua, 
a
School of Chemistry & Molecular Engineering, East China University of Science & Technology, 130 Meilong Rd, Shanghai, China.
bJiangsu Danxia New Material Co. Ltd., Jingsi Road, Ecological Chemical Technology Industrial Park, Suqian, Jiangsu Province, China
———
ARTICLE INFO
ABSTRACT
 Corresponding author. Tel.: +86-21-64253881; e-mail: zougang@ecust.edu.cn
Article history:
Received
A ball-milling enabled chemoselective activation of amides via N-tert-butoxycarbonylation
catalyzed by 4-dimethylaminopyridine is described under solvent-free conditions. High
Received in revised form
Accepted
Available online
chemoselectivity with respect to NH acidity of amides has been observed. A one-pot two-step
procedure for selective esterification of amides has been demonstrated in model reaction of
benzamides with p-cresol and benzyl alcohol.
2009 Elsevier Ltd. All rights reserved.
Keywords:
Mechanochemistry
Amide activation
Solvent-free synthesis
N-tert-Butoxycarbonylation
Introduction
recognized that, after conversion into imides, both primary and
secondary amides could become a versatile acetyl source [24-32].
With increasing concerns over environment and sustainable
development, solvent-free synthetic technology as a green
alternative to the conventional processes in organic solvents has
been attracting interests [1-3]. In fact, solvent-free synthesis has
proven not only environmentally benign but also economically
feasible, profiting from the shorter reaction time and smaller
batch-size because of the high reactant concentrations in the
absence of solvents. The most common difficulty encountered in
solvent-free organic synthesis lies in low mixing efficiency at
molecular level, in particular, in the cases involving solid
materials. Ball-milling, the simplest form of mechanochemistry,
has a privilege of mixing solid materials under solvent-free
conditions. Indeed, mechanochemical synthesis via ball-milling
has recently attracted increasing attentions as an emerging
synthetic methodology [4-13], showing not only environmental
advantages but also capabilities to alter selectivities and / or
reaction pathways [14] benefiting from the extremely short and
localized yet high temperature and pressure spots generated by
the unique mechanical impacts and/or the simple increase in
mixing rates and thermal energy [15-17].
N-Sulfonylation and N-tert-butoxycarbonylation (Boc) of
amides have proven to be the most feasible way to convert
primary and secondary amides into bias imides to activate the
target C(O)-N bond. Compared with N-sulfonylation, N-tert-
butoxycarbonylation of amides by Boc2O catalyzed by 4-
dimethylaminopyridine (DMAP) is operationally simple yet
powerful, capable of reaction with both primary and secondary
amides affording the corresponding imides under open-flask
conditions [33]. Conventionally, N-tert-butoxycarbonylation of
amides requires use of environmentally hazardous solvents, e.g.
CH3CN and CH2Cl2 etc., in the presence of a tertiary amine as
base or, at least, catalyst. With the rapid increase in applications
of N-Boc-amides, it is important to develop an environmentally
benign synthetic procedure. We report herein ball-milling
enabled
highly
chemoselective
solvent-free
N-tert-
butoxycarbonylation for amide activation and demonstration of
its potential in sequential telescope transformations by selective
esterification of p-cresol and benzyl alcohol.
Results and Discussion
Amides generally represent the least reactive carboxylic acid
derivatives because of the conjugation of electron pair on
nitrogen with carbonyl group. Therefore, although they are
abundant in natural and artificial sources, ranging from discrete
small molecules to polymeric macromolecules [18], amides have
been rarely used as acetyl reagents [19, 20]. Since the seminal
reports on the nickel or palladium catalyzed cross-coupling of
activated amides by Houk and Garg [21], Szostak [22], and
ourselves [23], independently, in 2015, it has come to be
Initially, when a mixture of benzamide (1a) with 1.2 equiv.
Boc2O was milled at 30 Hz for 2h in the presence of 10 mol%
DMAP as catalyst to produce mono-Boc amide, N, N-di-Boc-
benzamide (2a) was found to be the sole isolable product with
about half amount of benzamide recovered (Table 1, entry 1).
Under
various
ball-milling
conditions,
mono-
butoxycarbonylation product, PhCONH(Boc), could not be
isolated although it was reported that ArCONH(Boc) could be
obtained in various yields via a similar procedure in common

2
Tetrahedron Letters
solvents, such as CH2Cl2 [34], and THF [35]. Neither mono- nor
di-butoxycarbonylation occurred without DMAP catalyst. These
results indicated that the second N-tert-butoxycarbonylation
should take place much faster than the first one under ball-
milling conditions, due to the higher NH acidity in the
intermediate imide PhCONH(Boc) than that in amide PhCONH2.
In fact, N, N-di-Boc-benzamide could be obtained in excellent
isolated yields (95-96%) with 2.5 equiv. Boc2O using 5-10 mol%
DMAP (Table 1, entries 3 and 4). Control experiments indicated
that the reaction was cleaner and faster under the solvent-free
ball-milling conditions than in conventional CH3CN solution
(Figure 1). The former completed in 2h while the later gave 2a in
84% yield after 8h.
Figure 1. TLC of the control experiment in CH3CN solution (2)
vs solvent-free ball-milling (3) under otherwise identical
conditions at 2h when the ball-milling reaction almost completed.
Table 1. DMAP catalyzed di-N-tert-butoxycarbonylation of primary amides under solvent-free ball-milling conditions[a]
O
O
cat. DMAP
, 30Hz
Boc
+
(Boc)2O
R
N
R
NH2
Boc
Yield(%)[b]
47
1
Amide ( )
Boc2O(equiv.) DMAP(mol%)
2
Entry
1
Imide ( )
Time(h)
O
O
Boc
2a
(
)
1.2
10
2
1a
(
)
Ph
N
Ph
NH2
Boc
2a
1a
1a
1a
2
3
4
2.2
2.5
2.5
10
10
5
2
2
2
81
96
95
2a
2a
2a
1a
5
2.5
1
4
87
O
O
Boc
1b
6
2.5
5
2
94
(
)
N
2b
)
NH2
(
Boc
F
F
O
O
28
Boc
(
1c
7
2.5
5
4
(
)
N
NH2
2c
)
Boc
Boc
MeO
MeO
2c
1c
1c
8
9
2.5
4.0
10
5
4
4
78
97
2c
O
O
2d
(
)
1d
1e
2.5
5
4
70
(
(
)
10
N
NH2
Boc
N
N
O
O
Boc
11
12
2.5
4.0
10
10
4
4
61
91
)
2e
(
)
Ph
N
Ph
NH2
Boc
1e
2e
O
O
Boc
31
81
2f
(
)
1f
13
14
(
)
2.5
4.0
5
4
4
N
NH2
Boc
1f
2f
10
[a] Reaction run in 1 mmole scale in a planetary ball mill with 60 min on, 10 min off cycle to take sample for TLC analysis.
[b] Isolated yields

3
The NH acidity of amides appeared to play a crucial role in the
solvent-free mechanochemical N-tert-butoxycarbonylation via
ball-milling. For example, 4-fluorobenzamide (1b) reacted
similarly to 1a while 4-methoxybenzamide (1c) gave a low yield
(28%) even after double reaction time. No remarkable conversion
was observed after 4h, indicating a competitive decomposition of
Boc2O under ball-milling conditions. The reaction of less reactive
1c could complete with high loading of Boc2O (4.0 equiv.) to
give 2c in 97% yield (Table 1, entries 7-9). The relatively low
yield (70%) with nicotinamide may be attributed to the
competition of the pyridine moiety with the catalyst. Aliphatic
amides, e.g. 3-phenylpropanamide (1e) and acrylamide (1f),
reacted slower and gave lower yields than aromatic ones,
requiring high loadings of both Boc2O (4.0 equiv.) and catalyst
DMAP (10 mol%) to achieve good yields (Table 1, entries 11-
14).
much more slowly than primary benzamide 1a to give the
corresponding Boc derivative 4a in only 50% yield. High
loadings of both DMAP catalyst (30 mol%) and Boc2O (2.0
equiv.) had to be used to obtain good yields (Table 2, entries 1-
4). However, benzamides bearing an electron-withdrawing
substituent on nitrogen, e.g. N-(2,2,2-trifluoroethyl) (3b) and N-
phenyl (3f) benzamides as well as methyl benzoylglycinate (3d)
showed remarkably high reactivities, giving the corresponding N-
Boc amides in good to excellent yields (94-99%) with 10 mol%
DMAP and 1.2 equiv. Boc2O (Table 2, entries 5, 7 and 9). The
low reactivity of methyl benzoylleucinate (3e) reflected the steric
influence of N-substituent of benzamides (Table 2, entry 8),
indicating that small steric hindrance could be negligible while
large one could not be overcome by simply increasing the
loadings of DMAP and Boc2O. Caprolactam 3g reacted readily,
consistent with the high reactivity of lactams in acylation.
A large electronic effect of the N-substituent in secondary
amides has been observed. N-methyl benzamide (3a) reacted
Table 2. Reactivities of secondary amides under solvent-free ball-milling conditions[a]
O
O
cat. DMAP
, 30Hz
Boc
R'
+
(Boc)2O
R
N
R
N
H
4
3
R'
Entry
1
Boc2O(equiv.)
3
DMAP(mol%)
4
Amide ( )
Imide ( )
Time(h)
Yield(%)[b]
O
O
Me
4a
(
)
1.2
1.2
10
30
4
4
50
74
Me
3a
(
)
Ph
N
Ph
N
H
Boc
3a
2
4a
3a
3a
3
4
2.0
2.0
10
30
4
4
72
90
4a
4a
O
O
O
O
4b
5
6
7
1.2
2.0
10
10
10
4
4
4
(
)
98
3b
(
)
Ph
N
CF3
Ph
Ph
Ph
Ph
N
CF3
Ph
H
Boc
O
4c
(
)
81
94
3c
(
)
Ph
N
N
H
Boc
O
4d
)
3d
(
(
)
1.2
2.0
Ph
Ph
N
CO2Me
N
H
CO2Me
Boc
O
O
O
8
4e
(
)
30
4
35
3e
(
)
N
CO2Me
Ph
Ph
N
H
CO2Me
Boc
O
4f
(
)
9
Ph
Ph
O
1.2
1.2
10
10
4
4
99
95
3f
(
)
Ph
N
N
H
Boc
O
3g
(
)
4g
10
(
)
N
NH
Boc
[a] Reaction run in 1 mmole scale in a planetary ball mill with 60min on, 10min off cycle to take sample for TLC analysis.
[b] Isolated yields
Given the strong influence of the NH acidity, it is envisaged
that chemoselective N-tert-butoxycarbonylation could be feasible
among electronically varied amides. Therefore, intermolecular
competition of 3 pairs of amides was investigated, including
primary / secondary benzamides, primary aromatic / aliphatic
amides and secondary benzamides bearing N-electronically
different substituents (Scheme 1). When a 1:1 (mole ratio)
mixture of primary (1a) and secondary (3a) benzamides was
milled with 1.3 equiv. Boc2O in total (2.6 equiv. with respect to
1a) and 5 mol% DMAP for 2h, N, N-di-Boc-benzamide (2a) was
isolated in 98% yield while only trace 4a could be detected by
TLC, showing an excellent selectivity between primary and

4
Tetrahedron
Conclusions
secondary benzamides. Modest (6/1) to good (9/1) selectivities
between primary aromatic (1a) and aliphatic (1e) amides as well
as secondary benzamides 3a and 3d could be achieved,
respectively.
In summary, we have demonstrated that mechanochemistry
via ball-milling could not only enable an environmentally benign
N-tert-butoxycarbonylation of amides under solvent-free
conditions but also make the amide activation more
chemoselective with respect to the NH acidity. Primary amides
reacted to directly give di-Boc imides without isolable mono-Boc
intermediates. Secondary amides reacted much more slowly than
primary ones unless bearing an electron-donating group on NH
moiety. Indeed, a high chemoselectivity could be effected not
only between the primary and secondary amides, but also among
secondary ones with NH substituted by electronically various
substituents. Selective esterification of amides via one-pot two-
step procedure has been demonstrated to be feasible in the model
reaction of benzamides with p-cresol and benzyl alcohol under
solvent-free ball-milling conditions.
O
1.3equiv. (Boc)2O
5mol% DMAP
O
R
R'
Ph
N
Ph
N
A:
H
, 30Hz, 2h
Boc
1a
R = H (
)
2a
4a
R' = Boc ( ), 98%
R' = Me ( ), trace
1a 3a
/
= 1/1
3a
R = Me (
)
O
O
1.3equiv. (Boc)2O
5mol% DMAP
Boc
R
N
R
NH2
B:
C:
, 30Hz, 2h
Boc
, 95%
, 16%
2a
2e
1a 1e
/
= 1/1
1a
R = Ph (
R = PhCH2CH2(
)
1e
)
O
R
0.6equiv. (Boc)2O
10mol% DMAP
O
Acknowledgments
R
Ph
N
Ph
N
H
, 30Hz, 2h
Boc
, 10%
, 94%
We are grateful for financial support provided by the National
Natural Science Foundation of China (21472041).
4a
4d
3a
R = Me (
R = CH2CO2Me (
)
3a 3d
/
= 1/1
3d
)
Scheme 1. Competition of amides
References and notes
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Ph
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OBn
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2-4h
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1.0equiv.
n-C6H13OH
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OnC6H13
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2.0equiv.Cs2CO3
3a
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, 30Hz, 2h
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Supplementary Material
Experimental procedures, compound characterization and
copies of NMR and HRMS (4b) spectra of products.
Highlights
Mechanochemical solvent-free N-tert-butoxycarbonylation of
amides.
High chemoselectivity with respect to NH acidity.
Capable of one-pot two-step sequential transformations.
Highlights
Mechanochemical solvent-free N-tert-butoxycarbonylation of
amides.
High chemoselectivity with respect to NH acidity.
Capable of one-pot two-step sequential transformations.