Zirconium-catalyzed direct amide bond formation between carboxylic esters and amines

Article abstract of DOI:10.1016/j.tet.2015.06.066

Development of catalytic amide bond formation reactions from readily available starting materials remains a challenging task for modern organic chemistry. Herein, we report that unactivated carboxylic esters and amines react in the presence of 10 mol % of zirconocene dichloride (Cp₂ZrCl₂) in toluene at 110 °C to afford amides in very good to excellent conversions. The Zr-catalyzed reaction is amenable for the amidation of aliphatic and aromatic carboxylic esters with primary and secondary amines. The reaction proceeds with almost complete retention of configuration for chiral esters and chiral amines.

Full text of DOI:10.1016/j.tet.2015.06.066

Accepted Manuscript
Zirconium-catalyzed direct amide bond formation between carboxylic esters and
amines
Danny C. Lenstra, D.Thao Nguyen, Jasmin Mecinović
PII:
S0040-4020(15)00963-1
10.1016/j.tet.2015.06.066
TET 26902
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 April 2015
Revised Date: 3 June 2015
Accepted Date: 16 June 2015
Please cite this article as: Lenstra DC, Nguyen DT, Mecinović J, Zirconium-catalyzed direct amide bond
formation between carboxylic esters and amines, Tetrahedron (2015), doi: 10.1016/j.tet.2015.06.066.
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Zirconium-catalyzed direct amide bond
formation between carboxylic esters and
amines
Leave this area blank for abstract info.
Danny C. Lenstra, D. Thao Nguyen, and Jasmin Mecinović
Institute for Molecules and Materials, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands

1
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Tetrahedron
journal homepage: www.elsevier.com
Zirconium-catalyzed direct amide bond formation between carboxylic esters and
amines
a
a
a
Danny C. Lenstra , D. Thao Nguyen , and Jasmin Mecinović*
a
Institute for Molecules and Materials, Radboud University Nijmegen, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
E-mail: j.mecinovic@science.ru.nl
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Development of catalytic amide bond formation reactions from readily available starting
materials remains a challenging task for modern organic chemistry. Herein, we report that
unactivated carboxylic esters and amines react in the presence of 10 mol% of zirconocene
2 2
dichloride (Cp ZrCl ) in toluene at 110 °C to afford amides in very good to excellent
Available online
conversions. The Zr-catalyzed reaction is amenable for the amidation of aliphatic and
aromatic carboxylic esters with primary and secondary amines. The reaction proceeds with
almost complete retention of configuration for chiral esters and chiral amines.
Keywords:
Amide bond
Amine
2
009 Elsevier Ltd. All rights reserved.
Carboxylic ester
Catalysis
Zirconium
organic molecules raises the necessity of developed catalytic
methods for their conversion into other important functionalities
such as the amides. Despite the fact that the catalytic conversion
of carboxylic acids into amides has an advantage in atom
economy (releases only one water molecule), acids have a
potential to undergo decarboxylation at elevated temperature, are
difficult to purify by chromatography, and undergo deprotonation
reactions with various reagents. On the other hand, due to
enhanced thermodynamic stability of amides, catalytic
transamidation of primary carboxamides is typically carried out
at harsh experimental conditions (110–140 °C). In this context,
using carboxylic esters as starting material may circumvent some
of these drawbacks of related carboxylic acids and amides.
Recent studies have demonstrated that carboxylic esters react
with stoichiometric amounts of aminoalcohols in the presence of
1
. Introduction
The amide bond is one of the central bonds in nature. It
provides a covalent linkage between adjacent amino acids for the
formation of diverse classes of biologically functional proteins.
Amide bonds are also present in other naturally occuring
molecules, including nucleobases of DNA, and cofactors, such as
coenzyme
mononucleotide, and glutathione.
A recent study by the consortium of leading pharma
companies has ranked the development of novel catalytic amide
bond formation reactions as number one among the
contemporary synthetic challenges for the medicinal chemistry
research. Current synthetic methods for the formation of amide
bonds are limited to the use of stoichiometric amounts of
activating agents, which makes the existing methods nonoptimal
from the perspective of atom economy and green chemistry. Due
to its relevance in chemical sciences, development of catalytic
amide bond formation has become one of the emerging areas of
modern organic chemistry. Several catalytic methods for the
formation of amide bonds using readily accessible carboxylic
acids and amines have been reported. In addition, catalytic
transamidation reactions have also been developed in the past
decade.
A,
NADH,
te1trahydrofolic
acid,
flavin
2
various organocatalysts via
a mechanism in which the
3
nucleophilic attack of alcohol gives the ester intermediate which
subsequently undergoes the O-N acyl transfer reaction to afford
7
the final amide bond. A metal-catalyzed direct amidation of
4
carboxylic esters has been achieved in the presence of Ru-pincer
8
9
complexes, lanthanum(III) triflate, zirconium(IV) alkoxide in
1
0
5
the presence of 1-hydroxy-7-azabenzotriazole additive, and
iridium(III) complexes under solvent-free conditions. Amides
can also be prepared from carboxylic esters and amines in the
11
6
1
2
presence of stoichiometric amounts of CaCl or Mg(OCH ) .
2
3 2
In comparison with carboxylic acids and amides, there has
been limited success in developing catalytic variations of direct
amidation of carboxylic esters. The common occurrence of
carboxylic esters as intermediates in the multistep syntheses of
Recently, an elegant conversion of carboxylic esters into the
corresponding amides in the presence of catalytic amounts of
1
3
simple sodium methoxide in toluene has also been reported.

2
Tetrahedron
Similarly, a two-fold excess of potassium tert-butoxide
substitutents (as in Cp*ZrCl ) resulted in significantly lower
ACCEPTED MANUSCRIPT
2
mediates a direct amidation of carboxylic esters under mild
reaction conditions.
conversion (44%), highlighting the importance of the size and
14
electronics of the Cp-like substitutent. Similarly, replacement of
two Cp ligands by bulkier indenyl counterparts led to 60%
conversion, again demonstrating that the size of Cp-type ligand
affects the catalytic properties for direct amidation. Interestingly,
catalytic amidation of methyl benzoate in the presence of 10
mol% of Cp Zr(OTf) only afforded N-benzylbenzoate in 55%
We have envisaged that the widely used carboxylic esters
could undergo direct amide bond formation with amines in the
presence of transition metal ions as catalysts. We hypothesized
that, if successful, the proposed catalytic reaction would be based
on the activation of esters by the complexation of their C=O
oxygen by the transition metal that acts as a Lewis acid and is not
directly consumed in the reaction. Herein, we report that
2
2
conversion.
Cp ZrCl2 catalyzes direct amide bond formation between
structurally diverse carboxylic esters and amines in very good to
excellent yields.
Table 1. Screening of catalysts for amide bond formation between
carboxylic esters and amines
2
a
2
. Results and Discussion
Initially, we have screened a series of common transition
metals and simple organocatalysts as potential catalysts for the
reaction between methyl benzoate (1.0 equiv.) and benzylamine
b
Entry
Catalyst
Conversion (%)
(
1
1.3 equiv.) in anhydrous toluene at 110 °C for 20 hours (Table
). Tested catalysts in the series also included those that have
been previously proven to catalyze direct amide bond formation
1
2
3
4
5
6
7
8
9
Cp
Cp
2
2
ZrCl
2
85
45
34
78
33
4
TiCl
2
5-6
TiCl
4
between amines and carboxylic acids or amides. Pleasingly, we
have found that direct amide bond formation proceeds in 85%
conversion in the presence of 10 mol% of Cp ZrCl (Table 1,
entry 1). Other reagents from group IV, including Cp TiCl , and
TiCl , were found to possess poor catalytic properties for the
conversion of methyl benzoate into N-benzylbenzamide (Table 1,
entries 2–3). Cp HfCl was found to be almost as effective (78%
conversion) as Cp ZrCl , but its increased cost relative to the
zirconium-based catalyst makes it less attractive for further use as
a catalyst for direct amidation of esters (Table 1, entry 4).
The first row transition metal salts were observed to catalyze
the amide bond formation in poor conversions (2–57%) (Table 1,
entries 5–12). CoCl and MnI were the only two transition metal
salts evaluated that gave reasonable amounts of the amide
product, whereas most of copper-, zinc-, nickel-, and iron-based
Cp HfCl
2
2
2
2
Cu(OTf)
2
2
2
CuCl
4
ZnCl
2
20
11
31
57
56
2
2
2
FeCl3
2
2
Fe(OTf)
2
1
0
MnI
CoCl
NiCl
AlCl
InBr
2
11
2
1
1
2
3
2
2
2
3
7
14
15
3
42
19
21
9
salts afforded <30% of N-benzylbenzamide. AlCl and InBr ,
3
3
HONH ·HCl
2
L-proline
Urea
both possessing Lewis acid properties, were found to have little
catalytic activity for the formation of the amide bond (Table 2,
entries 13–14).
1
6
17
We next evaluated potential small molecule organocatalysts
that have the ability to activate other carbonyl-containing
compounds towards the nucleophilic attack. In the presence of 10
mol% of hydroxylamine hydrochloride, L-proline, urea, thiourea,
and imidazole, respectively, less than 25% of amide was formed
for our standard reaction, demonstrating that these compounds do
not exhibit catalytic properties for the conversion of the ester into
the amide (Table 1, entries 15–19). The model reaction was only
poorly catalyzed by HCl yielding 30% amide; this result implies
that high catalytic activity of Cp ZrCl does not derive from its
1
1
2
8
9
0
Thiourea
Imidazole
HCl
23
16
30
9
21
a
-
Methyl benzoate (5 mmol), benzylamine (6.5 mmol), catalyst (10
b
mol%), anhydrous toluene (1.2 mL), 110 °C, 20 h. Conversion determined
by GC.
Cl
2
2
potential decomposition into HCl (Table 1, entry 20). The control
reaction in the absence of any catalyst showed that methyl
benzoate and benzylamine produced only very small amounts
Cl Zr Cl
Cl Zr Cl
Cl
Cl Zr Cl
Cl
85%
71%
24%
(9%) of corresponding N-benzylbenzamide under standard
conditions (Table 1, entry 21).
In order to gain some deeper insight into why Cp ZrCl
2
2
exhibits superior catalytic activity for amidation of methyl
benzoate relative to other Lewis acids, we evaluated its simple
analogues as catalysts for the model reaction (Fig. 1).
Cl Zr Cl
Cl Zr Cl
TfO Zr OTf
Substitutions on Cp ZrCl2 were introduced with the aim of
2
probing the chemical character of ligands that chelate the Zr(IV)
cation. Decreasing the number of Cp ligands had a substantial
effect on the catalytic properties of the catalyst; in the presence of
4
4%
60%
55%
Fig. 1. Cp ZrCl and its analogues as catalysts for direct amidation of
methyl benzoate with benzylamine.
2
2
1
0 mol% of CpZrCl3 and ZrCl , 71% and 24% of N-
4
benzylbenzamide was formed. The presence of two sterically
larger and more electron-rich pentamethylcyclopentadienyl

3
Examinations of the effect of the solvent, temperature, catalyst
loading, molarity of the solution, and time for the reaction
between methyl benzoate and benzylamine in the presence of
Cp ZrCl provided us with the most optimal reaction conditions
Having shown that Cp ZrCl catalyzes the amide bond
2 2
ACCEPTED MANUSCRIPT
formation between methyl benzoate and benzylamine, we then
investigated the scope of the reaction by examining various esters
and amines under standard reactions conditions (Tables 3 and 4).
Methyl benzoates bearing electron-withdrawing substituents at
the para position of the aromatic ring reacted with benzylamine
to afford corresponding amides in 70–91% conversions (Table
3). In contrast, the electron-donating para-OMe analogue yielded
only 52% of amide, demonstrating that the perturbation of the
electrophilic character of the C=O group of the ester has a
substantial effect on the overall progress of the catalytic reaction.
In this regard, it is not surprising that the same trend has been
observed for the background reactions; para-NO2 gave the
highest conversion (26%), whereas para-OMe the lowest
conversion (1%) (see Supporting Information).
2
2
for the catalytic amide bond formation (see Supporting
Information). Overall, these results demonstrate that the
conversion of methyl benzoate into N-benzylbenzamide occurs
efficiently when heated at 110 °C for 20 hours in toluene (2 M)
in the presence of 10 mol% Cp ZrCl . The reaction between N-
2
2
benzylbenzamide and 1.3 equiv. of methanol in the presence of
0 mol% Cp ZrCl under standard conditions did not afford any
1
2
2
observable amounts of methyl benzoate, indicating that the our
catalytic amide bond formation is not reversible.
The effect of the side chain of benzoate esters on the
Cp ZrCl -catalyzed direct amide bond formation with
2
2
benzylamine under standard reaction conditions was then
investigated (Table 2). Reactions with longer linear alkylated
benzoates proceeded with only 37–58% conversions (30–52%
yields). Iso-propyl benzoate and sec-butyl benzoate reacted with
benzylamine under catalytic conditions to afford the
corresponding amides in 22% and 26% conversions, respectively.
Notably, sterically hindered tert-butyl benzoate only reacted
poorly under standard catalytic conditions affording 9% of N-
benzylbenzamide. Reactions with benzyl benzoate and allyl
benzoate proceeded efficiently with 65–70% conversions (58–
The more-favorable electronics and sterics of aliphatic esters
caused a significant decrease in the reaction time for direct
amidation of aliphatic esters when compared to amidation of
aromatic esters. The reactions between methyl butyrate and
methyl phenylacetate with benzylamine proceeded at 110 °C for
4 hours to give 81% and 73% conversions, respectively. Cyclic γ-
butyrolactone underwent uncatalyzed ring opening in the
presence of benzylamine to yield the corresponding amide
quantitatively under standard reaction conditions (the reaction
also proceeded in excellent yield (98%) at 50 °C for 20 hours).
The background reaction, however, only led to 21% amide when
carried out at 50 °C for 1 hour, whereas the Cp ZrCl -catalyzed
5
9% isolated yields). Direct amidations of vinyl benzoate and
phenyl benzoate were observed to give quantitative conversions,
but these have also been found with the control reactions in the
2
2
reaction gave 85% of the amide under the same conditions. In
absence of Cp ZrCl2 catalyst (Table 2, entries 10–11). All
addition, amidation of sterically hindered tert-BuCOOCH only
2
3
background reactions using alkylated benzoate esters in the
absence of catalyst afforded only traces (<9%) of N-
benzylbenzamide product (Table 2, entries 1–9). These results
indicate that the Zr-promoted amide bond formation takes place
with several aromatic esters, but most efficiently with sterically
accessible esters.
afforded 38% of the corresponding amide; this result is in
agreement with low transamidation conversion of tert-BuCONH
2
6
d
with benzylamine in the presence of 10 mol% of Cp ZrCl .
2
2
Methyl and ethyl esters of protected amino acids underwent
Cp ZrCl -catalyzed amidations with benzylamine in only 4 hours
2
2
at 110 °C. We were pleased that acid-sensitive N-protecting
groups of amino acids remained unaffected by the employed
reaction conditions. Ethyl hippurate gave excellent conversions
(97%) for the catalytic reaction, and only 4% amide for the
uncatalyzed reaction. Similarly, Boc-protected methyl glycinate
was also converted into the corresponding amide in 99%
conversion, whereas the background reaction in the absence of
the catalyst only afforded the amide in 15% conversion. Cbz-
protected methyl glycinate underwent Cp ZrCl -catalyzed
Table 2. The effect of the side-chain of the ester on zirconium-
a
b
catalyzed and uncatalyzed amidation of carboxylic esters and
amines
2
2
amidation in 1 hour at 110 °C affording 86% of the
corresponding amide. The reaction under our conditions (and
also at 50 °C) was not applicable for amidation of base-sensitive
esters, such as Fmoc-protected methyl glycinate, due to
deprotection of the Fmoc group in the presence of equimolar
amounts of amine.
Entry
R
Catalytic
Conversion (%)
Uncatalytic
Conversion (%)
c
d
1
2
3
4
5
6
7
8
9
Me
85 (78)
9
Et
58 (52)
40 (32)
22 (15)
37 (30)
26 (23)
9 (4)
2
Pr
3
Notably, reactions of enantiopure Boc-protected methyl esters
of alanines proceeded with virtually complete (>99%) retention
of the chiral configuration under our catalytic conditions (see
Supporting Information). Similarly, sterically hindered Boc-L-
Phe-OMe and Boc-D-Phe-OMe underwent Cp ZrCl -catalyzed
iso-Pr
Bu
6
1
sec-Bu
tert-Bu
Bn
2
2
2
1
reaction with benzylamine with almost complete retention
(>98.5%) of configuration.
70 (59)
65 (58)
100
4
Allyl
Vinyl
Ph
7
1
1
0
1
96
100
100
a
Alkyl benzoate (5 mmol), benzylamine (6.5 mmol), Cp
2
ZrCl
2
(10 mol%),
b
anhydrous toluene (1.2 mL), 110 °C, 20 h. Conditions as in catalysis, but in
c
d
2 2
the absence of Cp ZrCl . Conversion determined by GC. Isolated yield.

4
Tetrahedron
a
Table 3. Amidation of various esters with benzylamine
nucleophilic 4-methoxyaniline proceeded to 96% conversion at
ACCEPTED MANUSCRIPT
1
40 °C under catalytic conditions, whereas background reaction
only afforded 3% of the amide. The utility of our catalytic
method was further demonstrated by the amidation of methyl
benzoate with a representative secondary amine piperidine that
also proceeded well with 78% conversion. Background reactions
for all amines afforded <20% amides, indicating that catalytic
amounts of Cp ZrCl2 are required for the efficient direct
2
amidation reaction (see Supporting Information).
5
6
4
7% (70)
1% (74)
4% (52)
63% (72)
77% (91)
70% (81)
Zirconium-catalyzed reaction between methyl benzoate and
racemic and enantiomerically pure (S)-1-phenylethylamine
yielded the corresponding amides in 55% conversion (Table 4).
We attribute the decreased conversion to increased sterics of this
amine relative to primary benzylamine. It is noteworthy that
Cp ZrCl -catalyzed amidation reaction occurs with the complete
2
2
retention of configuration, without noticeable recamization (see
Supporting Information).
a
Table 4. Expanded substrate scope for amidation reaction
c
8
1% (85)
6
3
6% (73)
1% (38)
O
N
H
d
Cl
8
9% (97)
5
1% (65)
55% (73)
e
8
5
3% (99)
0% (70)
71% (86)
7
5
4% (90)
2% (66)
57% (75)
85% (98)
48% (66)
b
b
6
7% (71)
65% (70)
a
Reaction conditions: ester (5.0 mmol), benzyl amine (6.5 mmol), Cp
2
ZrCl
2
b
6
6% (74)
7
5% (85)
(10 mol%). 4 h for aliphatic esters, 20 h for aromatic esters. Isolated yield
b
c
d
(Conversion). Reaction time 8 h. 1 h at 50 °C. Ethyl ester of hippuric acid
e
was used. 1 h at 110 °C.
b
8
3% (96)
44% (78)
48% (55)
A diverse set of amines was then evaluated for the catalytic
and uncatalytic direct amidation of methyl benzoate under
standard conditions (Table 4). Primary amines, including para-
chlorobenzylamine,
2-(aminomethyl)thiophene,
and
phenethylamine all reacted very well affording corresponding
amides in 65%, 73%, and 90% conversions, respectively.
Tetrahydrofurfurylamine, allylamine, and octylamine also
efficiently reacted with methyl benzoate to produce amides in
44% (55)
a
Reaction conditions: ester (5.0 mmol), amine (6.5 mmol), Cp
2
ZrCl
2
(10
b
mol%). Isolated yield (Conversion). Reaction was performed in o-xylene at
1
40 °C for 20 h.
7
5%, 66%, and 98% conversions under catalytic conditions.
Notably, 4-aminobenzylamine that contains two different types
of primary amines (i.e. a less nucleophilic aromatic NH and a
3. Conclusions
2
more nucleophilic aliphatic NH ) exclusively reacted through its
2
In conclusion, we have developed the Cp ZrCl -catalyzed
2
2
aliphatic amine to afford the amide in excellent 85% conversion.
In this regard, it is not surprising that aniline did not react with
methyl benzoate at 110 °C for 20 hours (we observed only 1%
conversion). At harsher conditions at 140 °C, however, aniline
reacted with methyl benzoate in the presence of 10 mol% of
Cp ZrCl to yield 74% of amide, whereas background reaction
direct amidation of structurally diverse carboxylic esters. This
redox-free condensation reaction is applicable for amidation of
unactivated aliphatic and aromatic esters with primary and
secondary amines, and proceeds with almost complete retention
of configuration. Development of related catalytic amide bond
formations is currently ongoing in our laboratory.
2
2
only produced traces (1%) of the amide. The amidation of more

5
4
. Experimental Section
N-Benzyl-4-methoxybenzamide
ACCEPTED MANUSCRIPT
1
H NMR (300 MHz, CDCl ): δ 7.79 (d, J = 9 Hz, 2H), 7.38–7.29
m, 5H), 6.92 (d, J = 9 Hz, 2H), 6.50 (bs, 1H), 4.63 (d, J = 3 Hz,
H), δ 3.85 (s, 3H); C NMR (75 MHz, CDCl ): δ 167.2, 162.6,
38.8, 129.2, 129.1, 128.2, 127.9, 127.0, 114.1, 55.8, 44.4; MS
3
General procedure:
Carboxylic ester (5.0 mmol), amine (6.5 mmol), and Cp ZrCl
(
2
1
13
2
2
3
(146.7 mg, 0.5 mmol) were suspended in 1.2 mL of anhydrous
toluene. The reaction was stirred at 110 °C for 4–20 hours. The
solvent was then removed under reduced pressure. The crude
product was purified on a Biotage Isolera One using a Biotage
+
+
(
2
ESI): m/z 242.1 (M + H ); HRMS (ESI): (M + H ), found
+
42.1190. [C H NO ] requires 242.1181.
TM
15 16 2
SNAP Ultra cartridge (12 g or 25 g, 10–60% EtOAc in n-
heptane) to isolate the desired amide.
4
-Benzoylpiperidine
1
H NMR (300 MHz, CDCl ): δ 7.39 (s, 5H), 3.68 (bs, 2H), 3.34
3
13
(bs, 2H), 1.68 (bs, 4H), 1.52 (bs, 2H); C NMR (75 MHz,
N-Benzylbenzamide
CDCl ): δ 170.6, 136.9, 128.7, 127.1, 49.1, 43.5, 26.9, 26.0, 24.9;
MS (ESI): m/z 190.2 (M + H ); HRMS (ESI): (M + H ), found
1
1
3
H NMR (300 MHz, CDCl ): δ 7.82 (d, J = 9 Hz, 2H), 7.52–7.29
m, 8H), 6.60 (bs, 1H), 4.65 (d, J = 6 Hz, 2H); C NMR (75
+
+
3
13
(
+
90.1231. [C H NO] requires 190.1232.
12 16
MHz, CDCl ): δ 167.7, 138.6, 134.7, 131.9, 129.1, 128.9, 128.3,
3
+
1
(
27.9, 127.3, 44.5; MS (ESI): m/z 212.1 (M + H ); HRMS (ESI):
N-Allylbenzamide
+
+
M + H ), found 212.1091. [C H NO] requires 212.1075.
1
14
14
H NMR (300 MHz, CDCl ): δ 7.82 (dd, J = 8.4 Hz, 2.4 Hz, 2H),
3
7
=
.53–7.36 (m, 3H), 6.50 (bs, 1H), 6.00–5.87 (m, 1H), 5.23 (dd, J
10.2 Hz, 1.5 Hz, 2H), 4.08 (t, J = 10.2 Hz, 2H); C NMR (75
N-Benzyl-4-nitrobenzamide
13
1
H NMR (300 MHz, CDCl ): δ 8.26 (d, J = 9 Hz, 2H), 7.96 (d, J
3
MHz, CDCl ): δ 167.8, 134.9, 131.8, 130.3, 128.9, 127.3, 116.9,
4
found 162.0928. [C H NO] requires 162.0919.
3
=
9 Hz, 2H), 6.75 (bs, 1H), 7.41–7.30 (m, 5H), 4.65 (d, J = 3 Hz,
+
+
2.8; MS (ESI): m/z 162.1 (M + H ); HRMS (ESI): (M + H ),
13
2
1
H); C NMR (75 MHz, CDCl ): δ 165.7, 150.0, 140.3, 137.8,
29.3, 128.6, 128.3, 124.2, 44.8; MS (ESI): m/z 257.1 (M + H );
+
3
+
10 12
+
+
MS (ESI): m/z 257.0941 (M + H ); HRMS (ESI): (M + H ),
N-Benzyl-4-hydroxybutanamide
+
found 257.0941. [C H NO] requires 212.0926.
1
14
14
H NMR (400 MHz, CDCl ): δ 7.34–7.21 (m, 4H), 6.51 (s, 1H),
3
4
2
.37 (d, J = 5.7 Hz, 2H), 3.62 (t, J = 5.8 Hz, 2H), 3.53 (s, 1H),
.37–2.30 (m, 2H), 1.89–1.79 (m, 2H); C NMR (101 MHz,
N-(Thiophen-2-ylmethyl)benzamide
13
1
H NMR (300 MHz, CDCl ): δ 7.80 (d, J = 6 Hz, 2H), 7.54–7.40
3
CDCl ): δ 173.5, 138.1, 128.6, 127.7, 127.4, 77.4, 77.0, 76.7,
6
3
(m, 3H), 7.25 (d, J = 5.1 Hz, 1H), 7.05 (d, J = 3.6 Hz, 1H), 6.98
+
2.0, 43.6, 33.7, 28.1; MS (ESI): m/z 194.1 (M + H ); HRMS
(
dd, J = 5.1, 3.6 Hz, 1H), 6.67 (bs, 1H), 4.81 (d, J = 3 Hz, 2H);
+
+
(ESI): (M + H ), found 194.1178. [C H NO ] requires
1
3
11 16 2
C NMR (75 MHz, CDCl ): 167.5, 141.2, 134.5, 132.0, 128.9,
3
1
94.1181.
+
1
27.4, 127.3, 126.6, 125.7, 39.2; MS (ESI): m/z 217.9 (M + H );
+
+
HRMS (ESI): (M + Na ), found 240.0481. [C H NOSNa]
12
11
N-Benzylpivalamide
requires 240.0459.
1
H NMR (400 MHz, CDCl ): δ 7.47–6.91 (m, 5H), 5.96 (s, 1 H),
3
13
4
.43 (d, J = 5.6 Hz, 2H), 1.23 (s, 9H); C NMR (101 MHz,
N-Benzyl-4-fluorobenzamide
CDCl ): δ 178.3, 138.6, 128.7, 127.6, 127.4, 77.3, 77.0, 76.7,
4
1
3
H NMR (300 MHz, CDCl ): δ 7.81 (dd, J = 6 Hz, J = 9 Hz, 2H),
+
3
3.5, 38.7, 27.6; MS (ESI): m/z 192.1 (M + H ); HRMS (ESI):
+ +
7
.38–7.29 (m, 5H), 7.11 (t, J = 9 Hz, 2H), 6.50 (bs, 1H), 4.64 (d,
(M + H ), found 192.1397. [C H NO] requires 192.1388.
13
12 18
J = 6 Hz, 2H); C NMR (75 MHz, CDCl ): δ 166.7, 163.4,
3
1
38.4, 129.7, 129.2, 128.3, 128.1, 116.1, 115.8, 44.6; MS (ESI):
Benzyl (2-(benzylamino)-2-oxoethyl)carbamate
1
+
+
m/z 230.0 (M + H ); HRMS (ESI): (M + H ), found 230.1000.
H NMR (400 MHz, CDCl ): δ 7.44–7.08 (m, 10H), 6.35 (s, 1H),
+
3
[
C H NOF] requires 230.0981.
14 13
5
.43 (s, 1H), 5.09 (s, 2H), 4.44 (d, J = 5.7 Hz, 2H), 3.89 (d, J =
13
5
1
6
.7 Hz, 3H); C NMR (101 MHz, CDCl ): δ 168.3, 156.1, 137.2,
3
N-Benzyl-4-bromobenzamide
35.5, 128.3, 127.8, 127.6, 127.3, 127.2, 105.7, 77.0, 76.5, 76.1,
1
H NMR (300 MHz, CDCl ): δ 7.68 (d, J = 9 Hz, 2H), 7.57 (d, J
+
3
6.8, 44.2, 43.7; MS (ESI): m/z 298.9 (M + H ); HRMS (ESI):
=
2
9 Hz, 2H), 7.41–7.29 (m, 5H), 6.54 (bs, 1H), 4.63 (d, J = 6 Hz,
+
+
(
M + Na ), found 321.1227. [C H N O Na] requires 321.1215.
13
17 18 2 3
H); C NMR (75 MHz, CDCl ): δ 166.8, 138.3, 133.6, 132.2,
3
1
+
39.2, 129.0, 128.3, 128.1, 126.6, 44.6; MS (ESI): m/z 290.0 (M
(
R,S)-N-(1-Phenylethyl)benzamide
+
+
+
H ); HRMS (ESI): (M + H ), found 290.0203. [C H NOBr]
1
14
13
H NMR (300 MHz, CDCl ): δ 7.80 (d, J = 9 Hz, 2H), 7.53–7.29
3
requires 290.0181.
(m, 8H), 6.41 (bs, 1H), 5.37 (quin., J = 6 Hz, 1H), 1.63 (d, J = 6
13
Hz, 3H); C NMR (75 MHz, CDCl ): δ 166.9, 143.5, 135.0,
1
m/z 226.0 (M + H ); ; HRMS (ESI): (M + H ), found 226.1249.
[
3
N-Benzyl-4-iodobenzamide
31.8, 129.1, 128.9, 127.8, 127.3, 126.6, 49.6, 22.1; MS (ESI):
1
H NMR (300 MHz, CDCl ): δ 7.79 (d, J = 9 Hz, 2H), 7.53 (d, J
+
+
3
=
2
1
9 Hz, 2H), 7.41–7.29 (m, 5H), 6.51 (bs, 1H), 4.63 (d, J = 6 Hz,
+
21
C H NO] requires 226.1232; [α] 0.0 (c 0.73, MeOH).
13
15 16 D
H); C NMR (75 MHz, CDCl ): δ 166.9, 138.4, 138.2, 134.1,
3
29.2, 129.0, 128.3, 128.1, 98.9, 44.6; MS (ESI): m/z 338.1 (M +
(
S)-N-(1-Phenylethyl)benzamide
+
+
+
H ); HRMS (ESI): (M + H ), found 338.0057. [C H NOI]
requires 338.0042.
1
14
13
H NMR (300 MHz, CDCl ): δ 7.78 (d, J = 9 Hz, 2H), 7.53–7.30
3
(m, 8H), 6.46 (bs, 1H), 5.36 (quin., J = 6 Hz, 1H), 1.62 (d, J = 6
13
Hz, 3H); C NMR (75 MHz, CDCl ): δ 166.9, 143.5, 135.0,
1
m/z 226.0 (M + H ); HRMS (ESI): (M + H ), found 226.1244.
[
3
N-(4-Chlorobenzyl)benzamide
31.8, 129.1, 128.9, 127.8, 127.3, 126.6, 49.6, 22.1; MS (ESI):
1
H NMR (300 MHz, CDCl ): δ 7.80 (d, J = 6 Hz, 2H), 7.55–7.50
+
+
3
(m, 1 H), 7.46–7.40 (m, 2H), 7.34–7.28 (m, 4H), 6.67 (bs, 1H), δ
+
21
C H NO] requires 226.1232. [α] 4.9 (c 1.00, MeOH).
13
15 16 D
4
1
.60 (d, J = 6 Hz, 2H); C NMR (75 MHz, CDCl ): δ 167.8,
3
37.2, 134.5, 133.7, 132.0, 129.5, 129.2, 130.0, 127.3, 43.7; MS
tert-Butyl (2-(benzylamino)-2-oxophenyl)carbamate
1
H NMR (300 MHz, CDCl ): δ 7.34 (bs, 1H), 7.23–7.11 (m, 5H),
5
+
(ESI): m/z 246.1 (M + H; HRMS (ESI): (M + H ), found
+
3
2
46.0711. [C H NOCl] requires 246.0686.
14 13
.87 (bs, 1H), 4.26 (d, J = 6 Hz, 2H), 3.86 (d, J = 6 Hz, 2H), 1.32

6
Tetrahedron
1
3
(
s, 9H); C NMR (75 MHz, CDCl ): δ 169.8, 156.5, 138.3,
3
ACCEPTED MANUSCRIPT
1
29.1, 128.0, 127.9, 80.7, 44.9, 43.8, 28.6; MS (ESI): m/z 287.0
N-(4-Aminobenzyl)benzamide
+
+
1
(M + Na ); HRMS (ESI): (M + Na ), found 287.1374.
H NMR (300 MHz, (CD ) SO)): δ 8.84 (t, J = 6 Hz, 1H), 7.88
3
2
+
[
C H N O Na] requires 287.1372.
(d, J = 6 Hz, 2H), 7.55–7.42 (m, 3H), 6.99 (d, J = 9 Hz, 2H), 6.52
14
20
2
3
13
(d, J = 9 Hz, 2H), 4.94 (s, 2H), 4.31 (d, J = 6 Hz, 2H); C NMR
(
S)-tert-Butyl (1-(benzylamino)-1-oxopropan-2-yl)carbamate
(75 MHz, (CD ) SO): δ 165.9, 147.5, 134.6, 131.0, 128.2, 127.2,
3
2
1
+
H NMR (300 MHz, CDCl ): δ 7.36–7.24 (m, 5H), 6.59 (bs, 1H),
126.6, 113.7, 112.1, 42.3; MS (ESI): m/z 226.9 (M + H ); HRMS
+ +
3
5
1
1
.03 (bs, 1H), 4.46 (d, J = 3 Hz, 2H), 4.20 (bs, 1H), 1.43 (s, 9H),
(ESI): (M + Na ), found 249.1014. [C H N ONa] requires
14 14 2
13
.39 (d, J = 9 Hz, 3H); C NMR (75 MHz, CDCl ): δ 172.9,
249.1004.
3
55.9, 138.4, 129.1, 128.0, 127.8, 50.6, 43.8, 28.7, 18.7; MS
+
+
(ESI): m/z 278.8 (M + H ); HRMS (ESI): (M + Na ), found
N-(2-Benzylamino)-2-oxoethyl)benzamide
+
21
1
3
0
01.1534. [C H N O Na] requires 301.1528; [α]
–24.7 (c
H NMR (300 MHz, (CD ) SO): δ 8.79 (t, J = 6 Hz, 1H), 8.44 (t,
15
22
2
3
D
3 2
.82, MeOH).
J = 6 Hz, 1H), 7.91 (d, J = 9 Hz, 2H), 7.59–7.44 (m, 3H), 7.36–
1
3
7
.20 (m, 5H), 4.31 (d, J = 6Hz, 2H), 3.94 (d, J = 6 Hz, 2H);
C
(
R)-tert-Butyl (1-(benzylamino)-1-oxopropan-2-yl)carbamate
NMR (75 MHz, (CD ) SO)): δ 169.0, 166.5, 139.4, 134.0, 131.3,
3
2
1
H NMR (300 MHz, CDCl ): δ 7.36–7.25 (m, 5H), 6.60 (bs, 1H),
128.2, 127.4, 127.1, 126.7, 42.7, 42.0; MS (ESI): m/z 291.1 (M +
3
+
+
5
1
1
.03 (bs, 1H), 4.46 (d, J = 3 Hz, 2H), 4.20 (bs, 1H), 1.43 (s, 9H),
Na ); HRMS + (ESI): (M
+
Na ), found 291.1113.
13
.38 (d, J = 9 Hz, 3H); C NMR (75 MHz, CDCl ): δ 172.9,
[C H N O Na] requires 291.1110.
16 16 2 2
3
55.9, 138.4, 129.0, 128.0, 127.8, 50.6, 43.8, 28.7, 18.7; MS
+
+
(ESI): m/z 278.9 (M + H ); HRMS (ESI): (M + Na ), found
N-Phenethylbenzamide
1
+
21
3
0
01.1531. [C H N O Na] requires 301.1528; [α]
21.8 (c
H NMR (300 MHz, CDCl ): δ 7.72 (d, J = 6 Hz, 2H), 7.52–7.27
15
22
2
3
D
3
.84, MeOH).
(m, 8H), 6.27 (bs, 1H), 3.72 (q, J = 12 Hz, 6 Hz, 2H), 2.96 (t, J =
13
6
Hz, 2H); C NMR (75 MHz, CDCl ): δ 167.8, 139.3, 135.0,
3
(
S)-tert-Butyl
(1-(benzylamino)-1-oxo-3-phenylpropan-2-
131.7, 129.2, 129.1, 128.9, 127.2, 127.0, 41.5, 36.1; MS (ESI):
+
+
yl)carbamate
m/z 226.1 (M + H ); HRMS (ESI): (M + H ), found 226.1245.
1
+
H NMR (300 MHz, CDCl ): δ 7.32–7.09 (m, 10H), 6.17 (bs,
[C H NO] requires 226.1232.
3
15 16
1
H), 5.10 (bs, 1H), 4.41–4.36 (m, 3H), 3.12–3.08 (m, 2H), 1.41
13
(s, 9H); C NMR (75 MHz, CDCl ): δ 171.4, 155.7, 138.1,
N-Phenylbutyramide
3
1
1
4
37.4, 129.7, 129.0, 128.0, 127.8, 127.3, 118.5, 80.6, 56.4, 43.8,
H NMR (300 MHz, CDCl ): δ 7.54 (d, J = 6 hz, 2H), 7.46 (bs,
3
+
0.0, 28.6; MS (ESI): m/z 354.9 (M + H ); HRMS (ESI): (M +
1H), 7.32 (t, J = 6 Hz, 2H), 7.11 (t, J = 6 Hz, 1H), 2.35 (t, J = 6
Hz, 2H), 1.77 (m, 2H), 1.01 (t, J = 6 Hz) ); C NMR (75 MHz,
+
+
21
13
Na ), found 377.1846. [C H N O Na] requires 377.1841; [α]
21
26
2
3
D
–
2.3 (c 0.22, MeOH).
CDCl ): δ 171.8, 138.4, 129.3, 124.5, 120.2, 40.0, 19.4, 14.1; MS
3
+
+
(
ESI): m/z 164.1 (M + H ); HRMS (ESI): (M + H ), found
+
(R)-tert-Butyl
(1-(benzylamino)-1-oxo-3-phenylpropan-2-
164.1075. [C H NO] requires 164.1075.
10 14
yl)carbamate
1
H NMR (400 MHz, CDCl ): δ 7.29–7.09 (m, 10H), 6.16 (s, 1H),
.09 (s, 1H), 4.35 (d, J = 5.6 Hz, 3H), 3.08 (m, 2H), 1.38 (s, 9H);
N-(p-Methoxy)phenylbutyramide
3
1
5
H NMR (400 MHz, CDCl ): δ 7.48 (bs, 1H), 7.40 (d, J = 6 Hz,
3
13
C NMR (101 MHz, CDCl ): δ 171.0, 168.0, 137.6, 136.6,
2H), 6.82 (d, J = 6 Hz, 2H), 3.77 (s, 3H), 2.30 (t, J = 6 Hz, 2H),
1.73 (m, 2H), 0.98 (t, J = 6 Hz, 3H); C NMR (101 MHz,
3
13
1
5
(
29.3, 128.7, 128.6, 127.6, 127.4, 126.9, 77.3, 77.0, 76.7, 68.3,
+
6.0, 43.4, 38.6, 28.2; MS (ESI): m/z 354.9 (M + H ); HRMS
CDCl ): δ 171.3, 156.3, 131.1, 121.8, 114.0, 55.4, 39.4, 19.1,
3
+
+
+
+
ESI): (M + Na ), found 377.1843. [C H N O Na] requires
13.7; MS (ESI): m/z 194.1 (M + H ); HRMS (ESI): (M + H ),
21
26
2
3
21
+
3
77.1841; [α] 2.3 (c 0.44, MeOH).
found 194.1184. [C H NO ] requires 194.1181.
D
11 16
2
N-Benzylbutyramide
H NMR (300 MHz, CDCl ): δ 7.38–7.26 (m, 5H), 5.94 (bs, 1H),
N-Octylbenzamide
1
1
H NMR (400 MHz, CDCl ): δ 7.78 – 7.75 (m, 2H), 7.50 – 7.39
3
3
5
.44 (d, J = 6 Hz, 2H), 2.20 (t, J = 9 Hz, 2H), 1.70 (sext., J = 9
(m, 3H), 6.23 (bs, 1H), 3.47–3.42 (m, 2H),1.64–1.57 (m, 2H),
1.41–1.21 (m, 10H), 0.88 (t, J = 6 Hz, 3H); C NMR (101 MHz,
13
13
Hz, 2H), 0.97 (t, J = 9 Hz, 3H); C NMR (75 MHz, CDCl ): δ
3
1
73.2, 138.8, 129.0, 128.1, 127.8, 43.9, 39.0, 19.5, 14.1; MS
CDCl ): δ 167.9, 135.2, 131.6, 128.9, 127.2, 40.5, 32.2, 30.0,
3
+
+
+
(ESI): m/z 178.1 (M + H ); HRMS (ESI): (M + Na ), found
29.7, 29.6, 27.4, 23.0, 15.4; MS (ESI): m/z 234.3 (M + H );
+
+
+
2
00.1055. [C H NONa] requires 200.1051.
HRMS (ESI): (M + H ), found 234.1868. [C H NO] requires
11
15
15 24
2
34.1858.
N-((Tetrahydrofuran-2-yl)methyl)benzamide
1
5. References and notes
H NMR (300 MHz, CDCl ): δ 7.79 (d, J = 6 Hz, 2H), 7.53–7.40
3
(
m, 3H), 6.60 (bs, 1H), 4.12–4.04 (m, 1H), (dd, J = 9 Hz, 6 Hz,
1
.
G. Arthur, The amide linkage: Selected structural aspects in chemistry,
biochemistry, and material science, Wiley-Interscience 2000.
1
1
1
2
H) , 7.38–7.74 (m, 2H), 3.40–3.31 (m, 1H), 2.09–1.88 (m, 3H),
13
.68–1.57 (m, 1H); C NMR (75 MHz, CDCl ): δ 167.9, 134.9,
2. D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey, J. J. L.
Leazer, R. J. Linderman, K. Lorenz, J. Manley, B. A. Pearlman, A.
Wells, A. Zaks, T. Y. Zhang, Green Chem. 2007, 9, 411-420.
3. a) E. Valeur, M. Bradley, Chem. Soc. Rev. 2009, 38, 606-631; b) J. S.
Carey, D. Laffan, C. Thomson, M. T. Williams, Org. Biomol. Chem.
3
31.8, 128.9, 127.3, 78.2, 68.5, 44.0, 29.0, 26.3; MS (ESI): m/z
+
+
06.1 (M + H ); HRMS (ESI): (M + H ), found 206.1189.
+
[
C H NO ] requires 206.1181.
12 16 2
2
006, 4, 2337-2347; c) C. A. G. N. Montalbetti, V. Falque, Tetrahedron
N-Benzyl-2-phenylacetamide
2005, 61, 10827-10852; d) A. El-Faham, F. Albericio, Chem. Rev. 2011,
111, 6557-6602.
1
H NMR (300 MHz, CDCl ): δ 7.41–7.17 (m, 10H), 5.83 (bs,
3
13
4. a) C. L. Allen, J. M. J. Williams, Chem. Soc. Rev. 2011, 40, 3405-3415;
b) H. Lundberg, F. Tinnis, N. Selander, H. Adolfsson, Chem. Soc. Rev.
1
H), 4.41 (d, J = 6 Hz, 2H), 3.64 (s, 2H); C NMR (75 MHz,
CDCl ): δ 171.2, 138.5, 135.2, 129.8, 129.4, 129.0, 127.8, 127.8,
3
2
4
014, 43, 2714-2742; c) V. R. Pattabiraman, J. W. Bode, Nature 2011,
80, 471-479; d) R. M. Lanigan, T. D. Sheppard, Eur. J. Org. Chem.
+
1
27.7, 44.2, 43.9; MS (ESI): m/z 226.1 (M + H ); HRMS (ESI):
+ +
(M + H ), found 226.1247 [C H NO] requires 226.1232.
15 16

7
2
2
013, 2013, 7453-7465; e) J. W. Bode, Curr. Opin. Drug Discov. Devel.
006, 9, 765-775.
ACCEPTED MANUSCRIPT
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a) R. M. Al-Zoubi, O. Marion, D. G. Hall, Angew. Chem. Int. Ed. 2008,
7, 2876-2879; b) C. L. Allen, A. R. Chhatwal, J. M. J. Williams, Chem.
4
Commun. 2012, 48, 666-668; c) H. Lundberg, F. Tinnis, H. Adolfsson,
Chem. Eur. J. 2012, 18, 3822-3826; d) F. Tinnis, H. Lundberg, H.
Adolfsson, Adv. Synth. Catal. 2012, 354, 2531-2536; e) D. C. Lenstra, F.
P. J. T. Rutjes, J. Mecinovic, Chem. Commun. 2014, 50, 5763-5766.
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5
1, 1383-1386; d) B. N. Atkinson, A. R. Chhatwal, H. V. Lomax, J. W.
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1
2
5

ACCEPTED MANUSCRIPT
Supporting Information
Zirconium-catalyzed direct amide bond
formation between carboxylic esters
and amines
Danny C. Lenstra, D. Thao Nguyen, and Jasmin Mecinović*
Institute for Molecules and Materials, Radboud University Nijmegen, Heyendaalseweg 135,
Nijmegen 6525 AJ, Netherlands
*
E-mail: j.mecinovic@science.ru.nl; Tel. +31 24 3652381
S1

ACCEPTED MANUSCRIPT
Contents
1
2
3
4
5
6
7
8
9
1
1
. Materials and methods
. General procedures
. Uncatalyzed reaction conversions
. Solvent effect
. Molarity effect
. Catalyst load
. Time course
. Characterization of products
. Chiral HPLC data
1
13
0. H and C NMR spectra of products
1. References
S2

ACCEPTED MANUSCRIPT
1
. Materials and methods
Solvents were dried by purging over activated alumina columns in a MBraun MB SPS800 and stored
under nitrogen. Chemicals were purchased from commercial sources and were used without further
purification. Reactions were carried out under an inert atmosphere of dry nitrogen or argon. Standard
syringe techniques were applied for the transfer of dry solvents and air- or moisture-sensitive reagents.
NMR spectra were recorded on a Bruker DMX 300 (300 MHz), and a Varian 400 (400 MHz)
1
spectrometer in CDCl solutions. H NMR chemical shifts are given in ppm with respect to
3
1
3
tetramethylsilane (TMS, δ 0.00 ppm) as internal standard, C NMR shift are given in ppm with
respect to CHCl (δ 77.4 ppm) or (CD ) SO (δ 39.5 ppm). Coupling constants are reported as J-values
3
3 2
in Hz.
Gas chromatography (GC) was performed on a Shimadzu GC2010+, containing an Agilent DB-1
column (30 m, 0.32 mm ID, 0.25 Am DF) using FID detection. The chiral HPLC measurements were
performed on a Shimadzu LC2010C Analytical HPLC system equipped with a 250 x 4.6 ID mm
Diacel Chiralpak AD-H column with Heptane/Isopropanol (90:10 v/v). Mass spectra were recorded on
a Thermo Finnigan LCQ Advantage Max electrospray-ion trap mass spectrometer.
2
. General procedures
Amine (6.5 mmol) and ester (5.0 mmol) were suspended in 1.2 mL of anhydrous toluene. While
stirring, zirconocene dichloride (146.7 mg, 0,5 mmol), was added. The reaction was stirred at 110 °C
for 4 - 20 hours. The solvent was then removed under reduced pressure. The crude product was
TM
purified on a Biotage Isolera One using a Biotage SNAP Ultra cartridge (12g or 25g, 10-60%
EtOAc in n-heptane) to isolate the desired amide.
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ACCEPTED MANUSCRIPT
3
. Uncatalyzed reaction conversions
[
a]
Scheme S1. Uncatalyzed conversions
O
N
H
Br
7
%
4%
O
N
H
O2N
2
3%
26%
1%
1
%
2
0%
21%
[c]
1
%
4%
1
7%
25%
3%
2
%
[b]
[b]
1
0%
8%
[
a]
Reaction conditions: ester (5.0 mmol), benzyl amine (6.5 mmol). 4 h for
[b]
[c]
aliphatic esters, 20 h for aromatic esters. Reaction time 8 h. Ethyl ester
of hippuric acid was used.
S4

ACCEPTED MANUSCRIPT
[
a]
Scheme S2. Uncatalyzed conversions
5
%
3%
1
8%
16%
20%
1
%
[b]
2
0%
1%
[
b]
3
%
9%
1%
3
%
[
a]
Reaction conditions: ester (5.0 mmol), benzyl amine (6.5 mmol). 4 h for
[b]
aliphatic esters, 20 h for aromatic esters. Reaction was performed in o-xylene
at 140 °C for 20 hours.
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4
. Solvent effect
Table S1. Effect of solvent
Entry
Solvent
Temperature (°C)
Conversion (%)
1
2
3
4
5
toluene
dioxane
n-heptane
cyclohexane
THF
110
100
100
81
85
63
78
41
49
66
5
. Molarity effect
Table S2. Effect of molarity
Entry
Molarity (M)
Cat. conversion (%)
Uncat.conversion (%)
1
2
3
4
0.5
1
2
25
57
85
93
1
2
9
neat
31
6
. Catalyst load
Table S3. Catalyst load
Entry
Catalyst load (%)
Conversion (%)
1
2
3
4
1
2
5
26
38
54
85
10
7
. Time course
Table S4. Effect of time
Entry
Time (hours)
Conversion (%)
1
2
3
4
5
6
7
8
0
0.5
1
2
4
6
8
20
0
40
45
48
54
59
67
85
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ACCEPTED MANUSCRIPT
8
. Characterization of products
1
N-benzylbenzamide
1
H NMR (300 MHz, CDCl ): δ 7.82 (d, J = 9 Hz, 2H), 7.52–7.29 (m, 8H), 6.60 (bs, 1H), 4.65 (d, J = 6
3
1
3
Hz, 2H); C NMR (75 MHz, CDCl ): δ 167.7, 138.6, 134.7, 131.9, 129.1, 128.9, 128.3, 127.9, 127.3,
4
3
+
4.5; MS (EI): m/z 212.1 (M + H ).
2
N-benzyl-4-nitrobenzamide
1
H NMR (300 MHz, CDCl ): δ 8.26 (d, J = 9 Hz, 2H), 7.96 (d, J = 9 Hz, 2H), 6.75 (bs, 1H), 7.41-7.30
3
1
3
(
1
m, 5H), 4.65 (d, J = 3 Hz, 2H); C NMR (75 MHz, CDCl ): δ 165.7, 150.0, 140.3, 137.8, 129.3,
3
+
28.6, 128.3, 124.2, 44.8; MS (EI): m/z 257.1 (M + H ).
3
N-(thiophen-2-ylmethyl)benzamide
1
H NMR (300 MHz, CDCl ): δ 7.80 (d, J = 6 Hz, 2H), 7.54-7.40 (m, 3H), 7.25 (d, J = 5.1 Hz, 1H),
.05 (d, J = 3.6 Hz, 1H), 6.98 (dd, J = 5.1, 3.6 Hz, 1H), 6.67 (bs, 1H), 4.81 (d, J = 3 Hz, 2H); C NMR
3
1
3
7
(
2
75 MHz, CDCl ): 167.5, 141.2, 134.5, 132.0, 128.9, 127.4, 127.3, 126.6, 125.7, 39.2; MS (EI): m/z
17.9 (M + H ).
3
+
4
N-benzyl-4-fluorobenzamide
1
H NMR (300 MHz, CDCl ): δ 7.81 (dd, J = 6 Hz, J = 9 Hz, 2H), 7.38-7.29 (m, 5H), 7.11 (t, J = 9 Hz,
3
1
3
2
1
H), 6.50 (bs, 1H), 4.64 (d, J = 6 Hz, 2H); C NMR (75 MHz, CDCl ): δ 166.7, 163.4, 138.4, 129.7,
3
+
29.2, 128.3, 128.1, 116.1, 115.8, 44.6; MS (EI): m/z 230.0 (M + H ).
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5
N-benzyl-4-bromobenzamide
1
H NMR (300 MHz, CDCl ): δ 7.68 (d, J = 9 Hz, 2H), 7.57 (d, J = 9 Hz, 2H), 7.41-7.29 (m, 5H), 6.54
3
1
3
(
1
bs, 1H), 4.63 (d, J = 6 Hz, 2H); C NMR (75 MHz, CDCl ): δ 166.8, 138.3, 133.6, 132.2, 139.2,
3
+
29.0, 128.3, 128.1, 126.6, 44.6; MS (EI): m/z 292.0 (M + H ).
6
N-benzyl-4-iodobenzamide
1
H NMR (300 MHz, CDCl ): δ 7.79 (d, J = 9 Hz, 2H), 7.53 (d, J = 9 Hz, 2H), 7.41-7.29 (m, 5H), 6.51
3
1
3
(
1
bs, 1H), 4.63 (d, J = 6 Hz, 2H); C NMR (75 MHz, CDCl ): δ 166.9, 138.4, 138.2, 134.1, 129.2,
3
+
29.0, 128.3, 128.1, 98.9, 44.6; MS (EI): m/z 338.1 (M + H ).
7
N-(4-chlorobenzyl)benzamide
1
H NMR (300 MHz, CDCl ): δ 7.80 (d, J = 6 Hz, 2H), 7.55-7.50 (m, 1 H), 7.46-7.40 (m, 2H), 7.34-
3
13
7
1
.28 (m, 4H), 6.67 (bs, 1H), δ 4.60 (d, J = 6 Hz, 2H); C NMR (75 MHz, CDCl ): δ 167.8, 137.2,
3
+
34.5, 133.7, 132.0, 129.5, 129.2, 130.0, 127.3, 43.7; MS (EI): m/z 246.1 (M + H ).
2
N-benzyl-4-methoxybenzamide
1
H NMR (300 MHz, CDCl ): δ 7.79 (d, J = 9 Hz, 2H), 7.38-7.29 (m, 5H), 6.92 (d, J = 9 Hz, 2H), 6.50
3
1
3
(
1
bs, 1H), 4.63 (d, J = 3 Hz, 2H), δ 3.85 (s, 3H); C NMR (75 MHz, CDCl ): δ 167.2, 162.6, 138.8,
3
+
29.2, 129.1, 128.2, 127.9, 127.0, 114.1, 55.8, 44.4; MS (EI): m/z 242.1 (M + H ).
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8
4
-benzoylpiperidine
1
H NMR (300 MHz, CDCl ): δ 7.39 (s, 5H), 3.68 (bs, 2H), 3.34 (bs, 2H), 1.68 (bs, 4H), 1.52 (bs, 2H);
3
1
3
C NMR (75 MHz, CDCl ): δ 170.6, 136.9, 128.7, 127.1, 49.1, 43.5, 26.9, 26.0, 24.9; MS (EI): m/z
3
+
1
90.2 (M + H ).
9
N-allylbenzamide
1
H NMR (300 MHz, CDCl ): δ 7.82 (dd, J = 8.4 Hz, 2.4 Hz, 2H), 7.53-7.36 (m, 3H), 6.50 (bs, 1H),
3
1
3
6
.00-5.87 (m, 1H), 5.23 (dd, J = 10.2 Hz, 1.5 Hz, 2H), 4.08 (t, J = 10.2 Hz, 2H); C NMR (75 MHz,
+
CDCl ): δ 167.8, 134.9, 131.8, 130.3, 128.9, 127.3, 116.9, 42.8; MS (EI): m/z 162.1 (M + H ).
3
2
(
R,S)-N-(1-phenylethyl)benzamide
1
H NMR (300 MHz, CDCl ): δ 7.80 (d, J = 9 Hz, 2H), 7.53-7.29 (m, 8H), 6.41 (bs, 1H), 5.37 (quin., J
3
1
3
=
1
6 Hz, 1H), 1.63 (d, J = 6 Hz, 3H); C NMR (75 MHz, CDCl ): δ 166.9, 143.5, 135.0, 131.8, 129.1,
3
+
21
28.9, 127.8, 127.3, 126.6, 49.6, 22.1; MS (EI): m/z 226.0 (M + H ); [α] 0.0 (c 0.73, MeOH).
D
2
(
S)-N-(1-phenylethyl)benzamide
1
H NMR (300 MHz, CDCl ): δ 7.78 (d, J = 9 Hz, 2H), 7.53-7.30 (m, 8H), 6.46 (bs, 1H), 5.36 (quin., J
3
1
3
=
1
6 Hz, 1H), 1.62 (d, J = 6 Hz, 3H); C NMR (75 MHz, CDCl ): δ 166.9, 143.5, 135.0, 131.8, 129.1,
3
+
21
28.9, 127.8, 127.3, 126.6, 49.6, 22.1; MS (EI): m/z 226.0 (M + H ); [α] 4.9 (c 1.00, MeOH).
D
S9

ACCEPTED MANUSCRIPT
1
0
tert-butyl (2-(benzylamino)-2-oxoethyl)carbamate
1
H NMR (300 MHz, CDCl ): δ 7.34 (bs, 1H), 7.23-7.11 (m, 5H), 5.87 (bs, 1H), 4.26 (d, J = 6 Hz, 2H),
3
1
3
3
1
.86 (d, J = 6 Hz, 2H), 1.32 (s, 9H); C NMR (75 MHz, CDCl ): δ 169.8, 156.5, 138.3, 129.1, 128.0,
3
+
27.9, 80.7, 44.9, 43.8, 28.6; MS (EI): m/z 287.0 (M + Na ).
11
(
S)-tert-Butyl (1-(benzylamino)-1-oxo-3-phenylpropan-2-yl)carbamate
1
H NMR (300 MHz, CDCl ): δ 7.32-7.09 (m, 10H), 6.17 (bs, 1H), 5.10 (bs, 1H), 4.41-4.36 (m, 3H),
3
1
3
3
1
2
.12-3.08 (m, 2H), 1.41 (s, 9H); C NMR (75 MHz, CDCl ): δ 171.4, 155.7, 138.1, 137.4, 129.7,
3
+
21
29.0, 128.0, 127.8, 127.3, 118.5, 80.6, 56.4, 43.8, 40.0, 28.6; MS (EI): m/z 354.9 (M + H ); [α]
-
D
.3 (c 0.22, MeOH).
1
1
(
R)-tert-Butyl (1-(benzylamino)-1-oxo-3-phenylpropan-2-yl)carbamate
1
H NMR (400 MHz, CDCl ): δ 7.29 - 7.09 (m, 10H), 6.16 (s, 1H), 5.09 (s, 1H), 4.35 (d, J = 5.6 Hz,
3
1
3
3
1
+
H), 3.08 (m, 2H), 1.38 (s, 9H); C NMR (101 MHz, CDCl ): δ 171.0, 168.0, 137.6, 136.6, 129.3,
3
28.7, 128.6, 127.6, 127.4, 126.9, 77.3, 77.0, 76.7, 68.3, 56.0, 43.4, 38.6, 28.2; MS (EI): m/z 354.9 (M
+
21
H ); [α] 2.3 (c 0.44, MeOH).
D
1
2
N-benzylbutyramide
O
N
H
1
H NMR (300 MHz, CDCl ): δ 7.38-7.26 (m, 5H), 5.94 (bs, 1H), 5.44 (d, J = 6 Hz, 2H), 2.20 (t, J = 9
3
13
Hz, 2H), 1.70 (sext., J = 9 Hz, 2H), 0.97 (t, J = 9 Hz, 3H); C NMR (75 MHz, CDCl ): δ 173.2, 138.8,
1
3
+
29.0, 128.1, 127.8, 43.9, 39.0, 19.5, 14.1; MS (EI): m/z 178.1 (M + H ).
1
3
N-((tetrahydrofuran-2-yl)methyl)benzamide
O
O
N
H
S10

ACCEPTED MANUSCRIPT
1
H NMR (300 MHz, CDCl ): δ 7.79 (d, J = 6 Hz, 2H), 7.53-7.40 (m, 3H), 6.60 (bs, 1H), 4.12-4.04 (m,
3
1
1
H), (dd, J = 9 Hz, 6 Hz, 1H) , 7.38-7.74 (m, 2H), 3.40-3.31 (m, 1H), 2.09-1.88 (m, 3H), 1.68-1.57 (m,
1
3
H); C NMR (75 MHz, CDCl ): δ 167.9, 134.9, 131.8, 128.9, 127.3, 78.2, 68.5, 44.0, 29.0, 26.3; MS
3
+
(
EI): m/z 206.1 (M + H ).
1
4
N-benzyl-4-hydroxybutanamide
1
H NMR (400 MHz, CDCl ): δ 7.34 - 7.21 (m, 4H), 6.51 (s, 1H), 4.37 (d, J = 5.7 Hz, 2H), 3.62 (t, J =
3
1
3
5
1
1
.8 Hz, 2H), 3.53 (s, 1H), 2.37 - 2.30 (m, 2H), 1.89 - 1.79 (m, 2H); C NMR (101 MHz, CDCl ): δ
3
73.52, 138.10, 128.64, 127.68, 127.44, 77.35, 77.04, 76.72, 62.02, 43.60, 33.67, 28.14; MS (EI): m/z
+
94.1 (M + H ).
1
5
benzyl (2-(benzylamino)-2-oxoethyl)carbamate
1
H NMR (400 MHz, CDCl ): δ 7.44 - 7.08 (m, 10H), 6.35 (s, 1H), 5.43 (s, 1H), 5.09 (s, 2H), 4.44 (d, J
5.7 Hz, 2H), 3.89 (d, J = 5.7 Hz, 3H); C NMR (101 MHz, CDCl ): δ 168.26, 156.13, 137.22,
3
3
1
3
=
1
35.53, 128.27, 127.81, 127.62, 127.26, 127.15, 105.66, 76.95, 76.53, 76.11, 66.78, 44.20, 43.66; MS
+
(
EI): m/z 298.9 (M + H )
1
6
N-benzylpivalamide
1
H NMR (400 MHz, CDCl ): δ 7.47 - 6.91 (m, 5H), 5.96 (s, 1 H), 4.43 (d, J = 5.6 Hz, 2H), 1.23 (s,
3
13
9
4
H); C NMR (101 MHz, CDCl ): δ 178.25, 138.61, 128.67, 127.60, 127.38, 77.34, 77.02, 76.70,
3
+
3.54, 38.69, 27.59; MS (EI): m/z 191.1 (M + H ).
1
7
N-benzyl-2-phenylacetamide
1
H NMR (300 MHz, CDCl ): δ 7.41-7.17 (m, 10H), 5.83 (bs, 1H), 4.41 (d, J = 6 Hz, 2H), 3.64 (s, 2H);
3
1
3
C NMR (75 MHz, CDCl ): δ 171.2, 138.5, 135.2, 129.8, 129.4, 129.0, 127.8, 127.8, 127.7, 44.2,
3
+
4
3.9; MS (EI): m/z 226.1 (M + H ).
S11

ACCEPTED MANUSCRIPT
1
8
N-(4-aminobenzyl)benzamide
1
H NMR (300 MHz, (CD ) SO)): δ 8.84 (t, J = 6 Hz, 1H), 7.88 (d, J = 6 Hz, 2H), 7.55-7.42 (m, 3H),
.99 (d, J = 9 Hz, 2H), 6.52 (d, J = 9 Hz, 2H), 4.94 (s, 2H), 4.31 (d, J = 6 Hz, 2H); C NMR (75 MHz,
3
2
1
3
6
(
(
CD ) SO): δ 165.9, 147.5, 134.6, 131.0, 128.2, 127.2, 126.6, 113.7, 112.1, 42.3; MS (EI): m/z 226.9
M + H ).
3
2
+
1
9
N-(2-benzylamino)-2-oxoethyl)benzamide
1
H NMR (300 MHz, (CD ) SO): δ 8.79 (t, J = 6 Hz, 1H), 8.44 (t, J = 6 Hz, 1H), 7.91 (d, J = 9 Hz, 2H),
.59-7.44 (m, 3H), 7.36-7.20 (m, 5H), 4.31 (d, J = 6Hz, 2H), 3.94 (d, J = 6 Hz, 2H); C NMR (75
3
2
1
3
7
MHz, (CD ) SO)): δ 169.0, 166.5, 139.4, 134.0, 131.3, 128.2, 127.4, 127.1, 126.7, 42.7, 42.0; MS
3
2
+
(
EI): m/z 291.1 (M + Na ).
2
N-phenethylbenzamide
1
H NMR (300 MHz, CDCl ): δ 7.72 (d, J = 6 Hz, 2H), 7.52-7.27 (m, 8H), 6.27 (bs, 1H), 3.72 (q, J =
3
1
3
1
1
2 Hz, 6 Hz, 2H), 2.96 (t, J = 6 Hz, 2H); C NMR (75 MHz, CDCl ): δ 167.8, 139.3, 135.0, 131.7,
3
+
29.2, 129.1, 128.9, 127.2, 127.0, 41.5, 36.1; MS (EI): m/z 226.1 (M + H ).
2
0
N-phenylbutyramide
1
H NMR (300 MHz, CDCl ): δ 7.54 (d, J = 6 hz, 2H), 7.46 (bs, 1H), 7.32 (t, J = 6 Hz, 2H), 7.11 (t, J =
3
1
3
6
1
Hz, 1H), 2.35 (t, J = 6 Hz, 2H), 1.77 (m, 2H), 1.01 (t, J = 6 Hz) ); C NMR (75 MHz, CDCl ): δ
3
+
71.8, 138.4, 129.3, 124.5, 120.2, 40.0, 19.4, 14.1; MS (EI): m/z 164.1 (M + H ).
S12

ACCEPTED MANUSCRIPT
2
1
N-(p-methoxy)phenylbutyramide
1
H NMR (400 MHz, CDCl ): δ 7.48 (bs, 1H), 7.40 (d, J = 6 Hz, 2H), 6.82 (d, J = 6 Hz, 2H), 3.77 (s,
3
1
3
3
1
H), 2.30 (t, J = 6 Hz, 2H), 1.73 (m, 2H), 0.98 (t, J = 6 Hz, 3H) ; C NMR (100 MHz, CDCl ): δ
3
+
71.3, 156.3, 131.1, 121.8, 114.0, 55.4, 39.4, 19.1, 13.7; MS (EI): m/z 194.1 (M + H ).
2
2
N-octylbenzamide
1
H NMR (400 MHz, CDCl ): δ 7.78 – 7.75 (m, 2H), 7.50 – 7.39 (m, 3H), 6.23 (bs, 1H), 3.47 – 3.42
m, 2H),1.64 – 1.57 (m, 2H), 1.41 – 1.21 (m, 10H), 0.88 (t, J = 6 Hz, 3H) ; C NMR (100 MHz,
3
1
3
(
CDCl ): δ 167.9, 135.2, 131.6, 128.9, 127.2, 40.5, 32.2, 30.0, 29.7, 29.6, 27.4, 23.0, 15.4; MS (EI): m/z
3
+
2
43.3 (M + H ).
2
3
(
S)-tert-Butyl (1-(benzylamino)-1-oxopropan-2-yl)carbamate
1
H NMR (300 MHz, CDCl ): δ 7.36 – 7.24 (m, 5H), 6.59 (bs, 1H), 5.03 (bs, 1H), 4.46 (d, J = 3 Hz,
3
1
3
2
1
H), 4.20 (bs, 1H), 1.43 (s, 9H), 1.39 (d, J = 9 Hz, 3H); C NMR (75 MHz, CDCl ): δ 172.9, 155.9,
3
+
21
38.4, 129.1, 128.0, 127.8, 50.6, 43.8, 28.7, 18.7; MS (EI): m/z 278.8 (M + H ); [α] -24.7 (c 0.82,
D
MeOH).
2
3
(
R)-tert-Butyl (1-(benzylamino)-1-oxopropan-2-yl)carbamate
1
H NMR (300 MHz, CDCl ): δ 7.36 – 7.25 (m, 5H), 6.60 (bs, 1H), 5.03 (bs, 1H), 4.46 (d, J = 3 Hz,
3
1
3
2
1
H), 4.20 (bs, 1H), 1.43 (s, 9H), 1.38 (d, J = 9 Hz, 3H); C NMR (75 MHz, CDCl ): δ 172.9, 155.9,
3
+
21
38.4, 129.0, 128.0, 127.8, 50.6, 43.8, 28.7, 18.7; MS (EI): m/z 278.9 (M + H ); ; [α] 21.8 (c 0.84,
D
MeOH).
S13

ACCEPTED MANUSCRIPT
9
. Chiral HPLC data
(
S)-N-(1-phenylethyl)benzamide
(
R,S)-N-(1-phenylethyl)benzamide
S14

ACCEPTED MANUSCRIPT
(
S)-tert-Butyl (1-(benzylamino)-1-oxopropan-2-yl)carbamate
(
R)-tert-Butyl (1-(benzylamino)-1-oxopropan-2-yl)carbamate
O
BocHN
N
H
S15

ACCEPTED MANUSCRIPT
(
S)-tert-Butyl (1-(benzylamino)-1-oxo-3-phenylpropan-2-yl)carbamate
O
N
H
NHBoc
(
R)-tert-Butyl (1-(benzylamino)-1-oxo-3-phenylpropan-2-yl)carbamate
S16

ACCEPTED MANUSCRIPT
1
13
1
0. H and C NMR spectra of products
N-benzylbenzamide
230
220
210
200
190
180
170
160
150
140
130
120
110 100
f1 (ppm)
90
80
70
60
50
40
30
20
10
0
-10
S17

ACCEPTED MANUSCRIPT
N-benzyl-4-nitrobenzamide
2
30
220
210
200
190
180
170
160
150
140
130
120
110 100
f1 (ppm)
90
80
70
60
50
40
30
20
10
0
-10
S18

ACCEPTED MANUSCRIPT
N-(thiophen-2-ylmethyl)benzamide
2
30
220
210
200
190
180
170
160
150
140
130
120
110 100
f1 (ppm)
90
80
70
60
50
40
30
20
10
0
-10
S19

ACCEPTED MANUSCRIPT
N-benzyl-4-fluorobenzamide
2
30
220
210
200
190
180
170
160
150
140
130
120
110 100
f1 (ppm)
90
80
70
60
50
40
30
20
10
0
-10
S20

ACCEPTED MANUSCRIPT
N-benzyl-4-bromobenzamide
2
30
220
210
200
190
180
170
160
150
140
130
120
110 100
f1 (ppm)
90
80
70
60
50
40
30
20
10
0
-10
S21