Iron-catalyzed benzamide formation. Application to the synthesis of moclobemide

Article abstract of DOI:10.1016/j.tet.2014.06.001

A convenient and user-friendly method to yield benzamides from primary and secondary amines and various benzylic alcohols in the presence of a cheap iron salt (FeCl₂·4H₂O) and tert-butylhydroperoxide (70% in water) as a stoichiometric oxidant is described. Control experiments indicated that this reaction might involve radical species. This method proved to be general, generating a family of 30 benzamides and was applied to the preparative synthesis of anti-anxiety drug moclobemide.

Full text of DOI:10.1016/j.tet.2014.06.001

Accepted Manuscript
Iron-catalyzed benzamide formation. Application to the synthesis of moclobemide
Xavier Bantreil , Nasreddine Kanfar , Nicolas Gehin , Ethan Golliard , Pauline
Ohlmann , Jean Martinez , Frédéric Lamaty
PII:
S0040-4020(14)00847-3
10.1016/j.tet.2014.06.001
TET 25666
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 30 April 2014
Revised Date: 30 May 2014
Accepted Date: 1 June 2014
Please cite this article as: Bantreil X, Kanfar N, Gehin N, Golliard E, Ohlmann P, Martinez J, Lamaty F,
Iron-catalyzed benzamide formation. Application to the synthesis of moclobemide, Tetrahedron (2014),
doi: 10.1016/j.tet.2014.06.001.
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Iron-catalyzed benzamide formation.
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Application to the synthesis of moclobemide
Xavier Bantreil, Nasreddine Kanfar, Nicolas Gehin, Ethan Golliard, Pauline Ohlmann, Jean Martinez and
Frédéric Lamaty
Institut des Biomolécules Max Mousseron, Place E. Bataillon, 34095 Montpellier Cedex 5, France.
FeCl2•4H2O cat.
O
O
O
R1
R2
TBHP
CaCO3
OH
R1
+
N
Cl
H2N
Ar
N
R2
N
H
Ar
CH3CN, 80°C, 4h
up to 89%
moclobemide
30 examples
Cl

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Iron-catalyzed benzamide formation. Application to the synthesis of
moclobemide
Xavier Bantreil,a Nasreddine Kanfara, Nicolas Gehina, Ethan Golliarda, Pauline Ohlmanna, Jean Martineza
and Frédéric Lamatya
a Institut des Biomolécules Max Mousseron, UMR 5247 CNRS─UM I─UM II, Université Montpellier II, Place E. Bataillon, 34095 Montpellier Cedex 5, France.
ARTICLE INFO
ABSTRACT
Article history:
Received
A convenient and user-friendly method to yield benzamides from primary and secondary amines
and various benzylic alcohols in the presence of a cheap iron salt (FeCl2 4H2O) and tert-
.
Received in revised form
Accepted
Available online
butylhydroperoxide (70% in water) as a stoichiometric oxidant is described. Control experiments
indicated that this reaction might involve radical species. This method proved to be general,
generating a family of 30 benzamides and was applied to the preparative synthesis of anti-
anxiety drug moclobemide.
Keywords:
Iron
2009 Elsevier Ltd. All rights reserved
.
Homogeneous catalysis
Amides
Oxidation
Green Chemistry
R2 R3
1. Introduction
R2 R3
N
N
H
[O]
R1 OH
R1
R1 OH
Amides are highly important functional groups due to their
preponderance in many natural products such as peptides and
proteins, pharmaceutical agents or man-made polymers, such as
Nylon 6,6.1 In most cases, common techniques to generate an
amide bond involve the use of toxic coupling agents and toxic
solvents. On industrial scale, these drawbacks directly impact
environment and economics. To circumvent such issues,
organometallic methodologies to form amides directly from
alcohols and amines have recently emerged.2 The general
mechanism for this type of reaction involves the oxidation of an
alcohol to the corresponding aldehyde, which will react with the
amine to form an hemiaminal intermediate that is converted to
the amide upon oxidation. It is important to note that in a
competitive pathway, the aldehyde could be oxidised to the
carboxylic acid, an undesired side-product (Scheme 1).
O
[O]
[O]
R2 R3
N
OH
R1
O
R1
O
Scheme 1. General mechanism for amide formation
Efficient approaches have been reported using transition
metals such as ruthenium3 and rhodium,4 and heterogeneous
catalysts,5 such Au/TiO2 systems,6 Au/DNA nanohybrids,7 and
alumina-supported silver clusters.8 Such approaches are highly
attractive as catalysis, step and atom economy are part of the 12
principles of green chemistry developed by Anastas and Warner.9
———
Corresponding author. Tel: +33 (0) 467143967; Fax: +33 (0) 467144866; E-mail: xavier.bantreil@univ-montp2.fr; frederic.lamaty@univ-
mont2.fr.
Corresponding author. Tel: +33 (0) 467143967; Fax: +33 (0) 467144866; E-mail: xavier.bantreil@univ-montp2.fr; frederic.lamaty@univ-
mont2.fr.

2
Tetrahedron
ACCEPTED MANUSCRIPT
R1
OH
Entry [Fe] (mol%)
[Ox] (equiv.) Conversion (%)b
+
.
H
N
R2
1
2
3
4
5
6
7
8
FeSO4 7H2O (5)
TBHP (4)
TBHP (4)
84
87
53
78
84
87
45
<5
Ar
(5 equiv.)
.
FeCl2 4H2O (5)
.
K4Fe(CN)6 3H2O (5) TBHP (4)
1) NCS
Fe(acac)3 (5)
TBHP (4)
(5) TBHP (4)
TBHP (4)
.
2) [Fe] / TBHP
Fe(NO3)3 9
FeCl3 (5)
OH
+
TBHP (4)c
.
[Fe]
FeCl2 4H2O (5)
[Cu] or [Zn]
TBHP
O
.
Ar
OH
FeCl2 4H2O (5)
H2O2 (4)
1) TEMPO
R1
N
a
Reaction conditions: benzyl alcohol (0.5 mmol), cyclohexylamine
Ar
Ar
one-pot
2) TBHP
R2
hydrochloride (0.75 mmol), CaCO3 (0.75 mmol), TBHP (70% in H2O, 270
µL, 4 equiv.), CH3CN (1 mL), 80°C, 4h.
R1
H2N
R2
R1R2NH2Cl
Cl
b Conversion was determined by HPLC, based on 1a.
[Fe] / TBHP
one-pot
c tert-butylhydroperoxide, 5.5M in nonane
.
this work
Screening of iron salts was realized. Apart from
K4Fe(CN)6 3H2O that gave only 53% conversion, all sources of
R1
OH
.
+
Cl
H2N
R2
Ar
iron tested gave around 80-85% conversion independently of the
oxidation state of the metal (Table 1, entries 1-6). The best
Scheme 2. Benzamide formation from alcohols in the
.
litterature
results were obtained using FeCl2 4H2O and FeCl3, giving 87%
.
conversion of amide 3aa. As FeCl2 4H2O is less corrosive than
FeCl3, the optimisation was continued with this salt. Replacement
of TBHP (70% in H2O) by TBHP (5.5M in nonane) or hydrogen
peroxide induced a decrease to respectively 45% and 5%
conversion (entries 7-8).
To compete with those techniques involving expensive metals,
studies on copper- or iron-catalyzed formation of amides from
aldehydes have been reported.10 As a part of our general interest
in amide bonds,11 we recently reported the copper-catalyzed
amidation directly from benzylic alcohols and amines, which
allowed to go one step further and realise a one-pot double
oxidation.12 Similar approach using zinc was developed (Scheme
2, left).13 In 2013, Porcheddu et al. reported the iron-catalyzed
amidation of N-chloramines, generated from toxic and non atom-
economic N-chlorosuccinimide, which required the use of 5
equivalents of alcohols to obtain good yields (Scheme 2, top).14
More recently, Ghosh et al. reported a stepwise iron-catalyzed
synthesis of benzamides, requiring a first step of oxidation of
alcohol into aldehyde prior to addition of the amine and TBHP
(tert-butylhydroperoxide) as final oxidant (Scheme 2, right).15 In
here, we want to report a one-pot two steps convenient and
practical method using a cheap iron salt as catalyst and readily
available hydrochloric salt of amines (TON < 9, TOF < 0.9 h-1).
Table 2. Optimization of the reaction conditions with a
reverse stoichiometry.a
Entry [Fe] (mol%)
[Ox] (equiv.) Ratio 2a/1a
Yield (%)b
.
1
2
3
4
5
FeCl2 4H2O (5)
TBHP (5)
TBHP (5)
TBHP (4)
TBHP (4)
TBHP (4)
1:1.3
1:1.3
1:1.3
1:1.3
1:1.3
72
89
89
82
27
.
FeCl2 4H2O (10)
.
FeCl2 4H2O (10)
.
FeCl2 4H2O (10)c
-
a
Reaction conditions: benzyl alcohol (0.65 mmol), cyclohexylamine
hydrochloride (0.5 mmol), CaCO3 (0.5 mmol), TBHP (70% in H2O, 270 µL,
4 equiv.), CH3CN (1 mL), 80°C, 4h.
b Isolated yield, based on 2a.
.
c FeCl2 4H2O 99.99% and CaCO3 99.995% pure were used.
As explained above (Scheme 1), the main side-product formed
during the amidation is carboxylic acid. During our previous
study on copper-catalyzed amidation, we realized that alcohols
featuring electron-donating groups were prone to convert quickly
to corresponding benzoic acids. Thus, in view to develop the
most general conditions and increase the isolated yield of this
reaction, a reverse of the amine/alcohol stoichiometry was
envisioned (Table 2). While the use of 1.3 equivalents of alcohols
in the presence of 5 equivalents of TBHP and 5 mol% of
2. Results/discussion
Optimisation of the reaction conditions was started using
benzylic alcohol and cyclohexamine hydrochloric salt (1.5
equiv.) in the presence of TBHP (70% in H2O) as oxidant and an
iron salt in refluxing acetonitrile. It is worth noting that initial
attempts to perform the amidation directly from free amines
failed, proving that masking of the nitrogen as its ammonium salt
was compulsory to the reaction. As already stated for copper
catalysis,12 calcium carbonate gave the best results. Its weak
basicity and poor solubility induce a slow and controlled release
of free amine within the reaction media. In the meantime, the
alcohol would be oxidized to aldehyde that could react with free
amine to yield corresponding amide after a second oxidation.
This choice of base proved to be the key point for the feasibility
of a one-pot two-steps reaction.
.
FeCl2 4H2O gave a 72% yield (entry 1), increasing the quantity of
iron salt to 10 mol% induced a satisfactory 89% yield (entry 2).
Decreasing the excess of TBHP to 4 equivalents did not affect
the isolated yield (89%, entry 3). As commercially available iron
salts are often contaminated with other metals, the reaction was
performed using extra pure iron source and base. Resulting amide
was isolated in 82% (entry 4), indicating that traces of metals
were not responsible for the amidation reaction. Finally, a control
experiment in the absence of iron salt indicated that the transition
Table 1. Optimization of reaction conditions.a
.
metal was necessary to the reaction (27% without FeCl2 4H2O,
entry 5).
[Fe]
[Ox]
O
CaCO3
Table 3. Variation of primary and secondary amines in the
amidation conditions.
Cy
Cl
H3N Cy
Ph
OH
Ph
N
H
CH3CN, T
1a
(1 equiv.)
2a
3aa
(1.5 equiv.)

3
Table 4. Variation of benzylic alcohols in the amidation
conditions.
ACCEPTED MANUSCRIPT
Reaction conditions: benzyl alcohol 1b-m (0.65 mmol), amine hydrochloride 2g (0.5
.
mmol), FeCl2
(0.05 mmol), CaCO3 (0.5 mmol), T-Hydro (270 µL, 4 equiv.),
CH3CN (1 mL), 80°C, 4h. a 2 equiv. of p-methoxybenzylalcohol were used.
The diversification was continued using various benzylic
alcohols in the presence of ( )-methylbenzyl amine 2g (Table 4).
Electron-donating substituents in para position gave a slight
decrease in yield with 58% and 69% for respectively 3bg and
3cg. p-Chlorobenzyl alcohol was efficiently converted to amide
3dg (85%). Introducing electron-withdrawing groups led to
respectively 82% and 58% yield for p-CO2Me and p-CF3 groups.
Surprisingly, p-NO2 substitution, which accounted for the best
yield in copper-catalyzed amidation, gave a poor 47% of
corresponding amide 3gg. When meta-substituted benzylic
alcohols were used, yields from 65% to 89% were obtained, with
methoxy (3hg), chloro (3ig) and nitro (3jg) substituents. Finally,
ortho substitution, which combined steric and electronic
influence, gave lower yields of amides 3kg and 3lg, bearing
respectively methoxy (45%) and chloro groups (41%). Ortho-
nitrobenzyl alcohol did not react as expected and amide 3mg was
not observed.
Reaction conditions: benzyl alcohol (0.65 mmol), amine hydrochloride 2a-
q (0.5 mmol), FeCl2 (0.05 mmol), CaCO3 (0.5 mmol), TBHP (70% in
H2O, 270 µL, 4 equiv.), CH3CN (1 mL), 80°C, 4h.
The scope of the reaction was then examined. First, variation
of the amine was investigated (Table 3). For convenience, even if
not specified, the amine hydrochloride salts were used
throughout this study. Methyl andbutyl amine reacted efficiently
yielding 3ab and 3ac in 70% and 76% respectively. Increasing
the bulkiness with iso-propyl and cyclohexyl amine did not affect
the amidation reaction (3ad, 72%; 3aa, 89%). Even bulkier tert-
butyl amine gave 3ae in 59% yield. Benzyl amine, which was
shown to yield easily benzamide in the presence of iron and
TBHP,16 was found to produce amide 3af in 63% yield.
Substituted benzylamines 2g-i furnished corresponding amides in
yields spanning from 52% to 86%. Phenethyl and p-
methoxyphenethyl amines 2j and 2k gave corresponding amides
in moderate yields (≈60%). Phenylalanine tert-butyl ester gave
77% of corresponding benzoylated aminoacid 3al. To our
delight, the use of unprotected phenylalanine hydrochloric salt
allowed the coupling in 70% yield (3am), indicating the
tolerance of the conditions toward the carboxylic acid
functionality. To the best of our knowledge, such reaction with
substrate featuring a free acid had never been accomplished in
previous reports. The iron-catalyzed amidation was also
performed in the presence of more nucleophilic but also more
hindered secondary amines. Although bearing two benzylic
oxidable positions, dibenzylamine gave a good 81% yield of 3an.
Cyclic amines reacted correctly, HCl-Pro-tBu (2o), piperidine
(2p) and morpholine (2q) yielding the corresponding amides in
respectively 55% (3ao), 65% (3ap) and 64% (3aq).
Table 5. Comparison of TON and TOF with literature.a
TON
< 8.9
< 44
< 17
< 16.2
< 7
TOF (h-1)
< 2.2
< 11
< 1.1
.
FeCl2 4H2O/TBHP
CuO/TBHP (Lamaty)12
ZnI2/TBHP (Beller)13
Fe(NO3)3 9H2O/TEMPO/TBHP (Chen)15
< 0.9
.
FeCl3 6H2O/NCS/TBHP (De Luca)14
n.d.b
.
a TON=(mmol of product)/(mmol of catalyst). TOF=TON/(reaction time).
TON and TOF were calculated using literature data.
b Reaction time was not specified in the publication.
In order to compare this catalytic reaction with literature,
TON (turnover number) and TOF (turnover frequency) were
calculated using the best results reported in previous works and
herein (Table 5). The copper catalyzed reaction12 was by far the
most efficient regarding TON (up to 44) and TOF (up to 11 h-1),
as only 2 mol% of CuO and 4h of reaction were necessary to
obtain good yields. Apart from copper, considering TOF, the use
.
of FeCl2 4H2O as catalyst (TOF up to 2.2 h-1) gave better results
than other catalytic systems involving zinc or iron (TOF up to 1.1
h-1), therefore attesting that these reaction conditions represent a
good alternative to reported procedures.

4
Tetrahedron
ACCEPTED MANUSCRIPT
O
5a. Thus, p-chlorobenzyl alcohol 1d was reacted with
(1)
(2)
(3)
commercially available 2-chloroethylamine hydrochloride. The
isolated yield of amide 5a being only 35%, the synthesis of
synthetic intermediates 5b and 5c was intended. While reacting
1d with ethanolamine hydrochloride gave also a poor yield (5b,
30%), the use of glycine methylester yielded amide 5c in 79%
yield on a 0.5 mmol scale. On a 10-fold scale (5 mmol) under the
exact same conditions, amide 5c could be isolated with a slight
depletion of the yield (57%). The final steps of the synthesis were
achieved according to literature procedures. Reacting NaBH4 in a
mixture THF/MeOH18 allowed the reduction of 5c to alcohol 5b
in 89% yield. Quantitative substitution of the hydroxyl group by
a chlorine atom and reaction with morpholine directly yielded
moclobemide, with a 42% yield over 2 steps. This modest yield
was consistent with the reported one (33%),19 and moclobemide
could be obtained from easily available substrates and in a more
sustainable manner to generate the amide functionality.
.
H3N Cy
Cl
Ph
(1.3 equiv.)
or
OH
FeCl2 4H2O (10 mol%)
TBHP (4 equiv.)
O
CaCO3 (1 equiv.)
Cy
Ph
N
H
CH3CN, 80°C, 4h
H
0 %
Cy
Ph
N
4
.
FeCl2 4H2O (10 mol%)
TBHP (4 equiv.)
CaCO3 (1 equiv.)
O
H3N Cy
Cl
Ph
OH
Cy
Ph
N
H
CH3CN, 80°C, 4h
TEMPO or
hydroquinone (4 equiv.)
(1.3 equiv.)
0 %
Scheme 3. Control experiments for amidation reaction
Control experiments were then run to assess if the iron-
catalyzed amidation was indeed going through the general
mechanism depicted in Scheme 1. First, when benzoic acid was
used instead of benzylic alcohol in the presence of
cyclohexylamine and under the exact optimized conditions used
above, no reaction occurred, proving that no direct thermal
condensation between acid and amine happened as described
elsewhere (Scheme 3, eq. 1).17 In addition, when aldimine 4 was
reacted under the amidation conditions, no expected amide was
observed, proving that formation of amide bond might result
from oxidation of the hemiaminal rather than from corresponding
aldimine (Scheme 3, eq. 2). Finally, reaction between benzylic
alcohol and cyclohexylamine was performed in the presence of
TEMPO or hydroquinone as radical scavengers (Scheme 3, eq.
3). Expected amide 3aa could not be observed under those
conditions, indicating that the iron-catalyzed amidation might
certainly involve the formation of radical species during the
oxidation process. However, no trapping intermediate could be
isolated.
3. Conclusions
In conclusion, we described a new protocol of iron-catalyzed
direct formation of benzamides from alcohols and amines. This
system required the use of a cheap iron salt and TBHP as a non-
toxic stoichiometric oxidant, which decomposes only to form
tert-butanol and water. Ammonium salts of amines, which are
easily accessible, user-friendly and stable, were used in this
study. Primary, secondary aliphatic and benzylic amines were
well tolerated, as well as benzylic alcohols featuring electron-
withdrawing and -donating groups. To validate the usefulness of
this methodology, the synthesis of the anti-anxiety drug
moclobemide was performed starting from easily available
substrates.
4. Experimental section
4.1. General
.
OH
In a sealed tube were added FeCl2 4H2O (9.9 mg, 0.05 mmol,
10 mol%), cyclohexylamine.HCl (67.8 mg, 0.5 mmol, 1 equiv.)
and CaCO3 (50.1 mg, 0.5 mmol, 1 equiv.). 1 mL of CH3CN,
benzyl alcohol (67 µL, 0.65 mmol, 1.3 equiv) and tert-
butylhydroperoxide (70% in H2O, 140 µL, 2 equiv.) were then
added. After 2h of stirring at 80°C, another 2 equiv. of tert-
butylhydroperoxide (70% in H2O) were added, and the mixture
was further stirred for 2h. After cooling to rt, HCl 1N (5 mL) and
AcOEt (5 mL) were added. The mixture was extracted with
AcOEt (2 x 5 mL), and the combined organic phases were
washed with saturated aqueous NaHCO3 solution (10 mL), brine
(10 mL), dried over magnesium sulfate and concentrated under
reduced pressure. The crude mixture was purified by
chromatography on silica gel using mixtures of cyclohexane and
ethyl acetate as eluant.
1d
Cl
FeCl2·4H2O
TBHP, CaCO3
CH3CN, 80°C, 4h
O
X
Cl
H3N
Cl
H3N
OMe
0.5 mmol, 79%
5 mmol, 57%
O
O
OMe
O
X
Ar
N
H
Ar
N
H
X = Cl, 35% (5a)
X = OH, 30% (5b)
5c
NaBH4
THF/MeOH
89%
N-cyclohexylbenzamide 3aa:20 89% yield (90.2 mg) as a
1) MsCl, NaCl,
DMAP, NEt3
DCM, rt
1
white solid. H NMR (CDCl3, 200 MHz): δ (ppm) = 7.85-7.64
O
O
O
(m, 2H), 7.53-7.30 (m, 3H), 6.17 (d, 1H, J = 6.6 Hz), 3.95 (ttd,
1H, J = 11.9, 8.0, 3.8 Hz), 2.09-1.91 (m, 2H), 1.84-1.55 (m, 3H),
1.50-1.10 (m, 5H). 13C NMR (CDCl3, 75 MHz): δ (ppm) = 166.8,
135.2, 134.3, 128.6, 127.0, 48.8, 33.3, 25.7, 25.0.
OH
N
Ar
N
H
N
H
2) morpholine
100°C
Cl
5b
Moclobemide
42%
Scheme 4. Synthesis of moclobemide using iron-catalyzed
amidation.
N-methylbenzamide 3ab: 70% yield (48.7 mg) as a white
solid. 1H NMR (CDCl3, 200 MHz): δ (ppm) = 7.84-7.67 (m, 2H),
7.52-7.30 (m, 3H), 6.71 (s, 1H), 2.96 (d, J = 4.8 Hz, 3H). 13C
NMR (CDCl3, 75 MHz): δ (ppm) = 168.5, 134.7, 131.4, 128.6,
127.0, 26.9.
N-n-butylbenzamide 3ac:21 76% yield (67.4 mg) as a white
solid. 1H NMR (CDCl3, 200 MHz): δ (ppm) = 7.78-7.73 (m, 2H),
7.46-7.34 (m, 3H), 6.42 (br s, 1H), 3.42 (q, 2H, J = 6.5 Hz), 1.65-
To prove that this methodology could be efficiently applied to
the synthesis of compounds of interest, the synthesis of
moclobemide was envisioned using an iron-catalyzed amidation
as a first synthetic step (Scheme 4). Moclobemide, an Hoffmann-
La Roche drug used against depression and social anxiety, could
be readily obtained from 4-chloro-N-(2-chloroethyl)benzamide

5
1.47 (m, 2H), 1.43-1.24 (m, 2H), 0.93 (t, 3H, J = 7.2 Hz). 13C
NMR (CDCl3, 75 MHz): δ (ppm) = 167.7, 134.9, 131.3, 128.6,
127.0, 39.9, 31.8, 20.2, 13.9.
1H, CO2H), 5.41 (s, 1H, ½ H2O), 4.90 (s, 1H), 3.40-3.01 (m,
ACCEPTED MANUSCRIPT
2H). 13C NMR (CD3OD, 75 MHz): δ (ppm) = 176.3, 170.1,
138.7, 135.3, 132.8, 130.3, 129.5, 129.4, 128.4, 127.8, 56.3, 38.9.
N-isopropylbenzamide 3ad:22 72% yield (58.6 mg) as a
white solid. H NMR (CDCl3, 200 MHz): δ (ppm) = 7.84-7.68
(m, 1H), 7.53-7.30 (m, 2H), 6.18 (s, 1H), 4.40-4.11 (m, 1H), 1.23
(d, J = 6.6 Hz, 3H). 13C NMR (CDCl3, 75 MHz): δ (ppm) =
166.8, 135.1, 131.3, 128.5, 126.9, 41.9, 22.9.
N,N-dibenzylbenzamide 3an:29 69% yield (104.0 mg) as a
1
1
white solid. H NMR (CDCl3, 200 MHz): δ (ppm) = 7.65-7.29
(m, 7H), 7.18 (s, 1H), 4.73 (s, 1H), 4.42 (s, 1H). 13C NMR
(CDCl3, 75 MHz): δ (ppm) = 172.3, 137.0, 136.5, 136.2, 129.7,
128.9, 128.6, 128.5, 127.6, 127.1, 126.8, 51.6, 46.9.
N-tert-butylbenzamide 3ae:10d 59% yield (52.0 mg) as a
N-benzoyl proline tert-butyl ester 3ao: 55% yield (76.4 mg)
as a white solid. H NMR (CDCl3, 200 MHz): δ (ppm) = 7.56-
7.51 (m, 2H), 7.42-7.29 (m, 3H), 4.52 (dd, J = 8.0, 5.5 Hz, 1H,
1
1
white solid. H NMR (CDCl3, 200 MHz): δ (ppm) = 7.93-7.60
(m, 2H), 7.42 (m, 3H), 5.99 (s, 1H), 1.46 (s, 9H). 13C NMR
(CDCl3, 75 MHz): δ (ppm) = 167.0, 136.0, 131.2, 128.6, 126.8,
51.7, 20.0.
70%), 4.26-4.13 (m, 1H, 30%), 3.79-3.41 (m, 2H), 2.34-2.14 (m,
1H), 2.01-1.79 (m, 3H), 1.47 (s, 9H, 70%), 1.29 (s, 9H, 30%). 13
C
NMR (CDCl3, 100 MHz): δ (ppm) = 171.5, 169.6, 136.6, 130.1,
128.3, 127.3, 126.8, 81.3, 60.0, 50.0, 29.5, 28.1, 27.8, 25.4
(major rotamer). δ (ppm) = 171.5, 170.5, 137.2, 129.7, 81.8, 62.1,
46.7, 31.6, 29.8, 22.7. (minor rotamer).
N-benzylbenzamide 3af:23 63% yield (66.6 mg) as a white
solid. 1H NMR (CDCl3, 200 MHz): δ (ppm) = 7.75-7.70 (m, 2H),
7.47-7.17 (m, 8H), 6.62 (br s, 1H), 4.55 (d, 2H, J = 5.7 Hz). 13C
NMR (CDCl3, 75 MHz): δ (ppm) = 167.6, 138.4, 134.4, 131.5,
128.8, 128.6, 127.9, 127.5, 127.1, 44.1.
N-benzoyl piperidine 3ap:7 66% yield (62.2 mg) as a
1
translucid oil. H NMR (CDCl3, 200 MHz): δ (ppm) = 7.36 (s,
N-(α-methylbenzyl)benzamide 3ag:24 77% yield (86.2 mg)
5H), 3.68 (s, 2H), 3.31 (s, 2H), 1.64-1.51 (m, 6H). 13C NMR
(CDCl3, 75 MHz): δ (ppm) = 170.3, 136.6, 129.4, 128.4, 126.8,
48.8, 43.1, 26.6, 25.7, 24.6.
1
as a white solid. H NMR (CDCl3, 200 MHz): δ (ppm) = 7.89-
7.65 (m, 2H), 7.59-7.20 (m, 8H), 6.56 (d, J = 7.1 Hz, 1H), 5.33
(p, J = 7.0 Hz, 1H), 1.59 (d, J = 6.9 Hz, 3H). 13C NMR (CDCl3,
75 MHz): δ (ppm) = 166.7, 143.3, 134.7, 131.5, 128.8, 128.6,
127.5, 127.1, 126.3, 49.3, 21.8.
N-benzoyl-phenylglycinol 3ah:25 71% yield (85.9 mg) as a
white solid. 1H NMR (DMSO-d6, 200 MHz): δ (ppm) = 8.70 (d, J
= 8.1 Hz, 1H), 7.90 (d, J = 6.3 Hz, 2H), 7.64-7.11 (m, 8H), 5.07
(dd, J = 13.8, 8.1 Hz, 1H), 4.94 (t, J = 5.8 Hz, 1H), 3.80-3.55 (m,
2H). 13C NMR (DMSO-d6, 75 MHz): δ (ppm) = 166.3, 141.4,
134.7, 131.2, 128.3, 128.2, 127.4, 127.0, 126.9, 64.6, 56.1.
N-benzoyl morpholine 3aq:10c 64% yield (61.2 mg) as a
1
white oil. H NMR (CDCl3, 200 MHz): δ (ppm) = 7.39 (s, 5H),
3.69 (br s, 6H), 3.45 (br s, 2H). 13C NMR (CDCl3, 75 MHz): δ
(ppm) = 170.5, 135.4, 129.9, 128.6, 127.1, 67.0.
N-(p-methoxybenzoyl)-α-methylbenzyl amine 3bg:30 58%
1
yield (74.4 mg) as a white solid. H NMR (CDCl3, 200 MHz): δ
(ppm) = 7.71 (d, 2H, J = 8.9 Hz), 7.47-7.08 (m, 6H), 6.95-6.79
(m, 2H), 6.45 (d, 1H, J = 7.5 Hz), 5.28 (p, 1H, J = 7.0 Hz), 3.78
(s, 3H), 1.54 (d, 3H, J = 6.9 Hz). 13C NMR (CDCl3, 75 MHz): δ
(ppm) = 166.3, 162.2, 143.5, 128.9, 128.8, 127.4, 126.9, 126.3,
113.8, 55.5, 49.2, 21.9.
N-(1,2-diphenylethyl)benzamide 3ai:26 52% yield (78.4 mg)
1
as a white solid. H NMR (CDCl3, 200 MHz): δ (ppm) = 7.75-
7.55 (m, 2H), 7.51-7.13 (m, 11H), 7.08 (d, J = 5.9 Hz, 2H), 6.56
(d, J = 7.4 Hz, 1H), 5.45 (q, J = 7.2 Hz, 1H), 3.19 (d, J = 7.0 Hz,
2H). 13C NMR (CDCl3, 75 MHz): δ (ppm) = 166.9, 141.6,
137.35, 134.7, 131.55, 129.5, 128.7, 128.6, 128.5, 127.6, 127.0,
126.8, 54.9, 42.7.
N-(p-methylbenzoyl)-α-methylbenzyl amine 3cg:31 69%
1
yield (83.8 mg) as a white solid. H NMR (CDCl3, 200 MHz): δ
(ppm) = 7.65 (d, 2H, J = 8.2 Hz), 7.44-7.11 (m, 7H), 6.37 (d, 1H,
J = 7.0 Hz), 5.31 (p, 1H, J = 7.0 Hz), 2.36 (s, 3H), 1.57 (d, 3H, J
= 6.9 Hz). 13C NMR (CDCl3, 75 MHz): δ (ppm) = 166.7, 143.4,
142.0, 131.8, 129.3, 128.8, 127.5, 127.1, 126.4, 49.2, 21.9, 21.5.
N-(p-chlorobenzoyl)-α-methylbenzyl amine 3dg:32 85%
yield (111.4 mg) as a white solid. 1H NMR (CDCl3, 200 MHz): δ
(ppm) = 7.61 (dd, 2H, J = 8.2, 1.2 Hz), 7.34-7.13 (m, 7H), 6.59
(d, 1H, J = 7.2 Hz), 5.21 (p, 1H, J = 7.0 Hz), 1.50 (dd, 3H, J =
6.9, 1.0 Hz). 13C NMR (CDCl3, 75 MHz): δ (ppm) = 165.7,
143.1, 137.7, 133.0, 128.8, 128.8, 128.6, 127.6, 126.3, 49.5, 21.8.
N-phenethylbenzamide 3aj:10a, 27 61% yield (69.0 mg) as a
1
white solid. H NMR (CDCl3, 200 MHz): δ (ppm) = 7.77-7.60
(m, 2H), 7.54-7.16 (m, 8H), 6.23 (s, 1H), 3.72 (q, 2H, J = 6.9
Hz), 2.94 (t, 2H, J = 6.9 Hz). 13C NMR (CDCl3, 75 MHz): δ
(ppm) = 167.6, 139.0, 134.7, 131.5, 128.9, 128.8, 128.6, 126.9,
126.7, 41.3, 35.8.
N-p-methoxyphenethylbenzamide 3ak:28 58% yield (73.8
1
mg) as a white solid. H NMR (CDCl3, 200 MHz): δ (ppm) =
7.72-7.68 (m, 2H), 7.51-7.34 (m, 3H), 7.16-7.12 (m, 2H), 6.87-
6.83 (m, 2H), 6.36 (br s, 1H), 3.78 (s, 3H), 3.66 (q, 2H, J = 7.0
Hz), 2.86 (t, 2H, J = 7.0 Hz). 13C NMR (CDCl3, 75 MHz): δ
(ppm) = 167.6, 158.4, 134.8, 131.4, 131.0, 129.8, 128.6, 127.9,
126.9, 114.2, 55.3, 41.4, 34.9.
N-(p-(methoxycarbonyl)benzoyl)-α-methylbenzyl
amine
1
3eg:31 82% yield (115.5 mg) as a white solid. H NMR (CDCl3,
200 MHz): δ (ppm) = 8.09 (d, J = 8.6 Hz, 2H), 7.82 (d, J = 8.6
Hz, 2H), 7.45-7.28 (m, 5H), 6.34 (d, J = 6.7 Hz, 1H), 5.35 (p, J =
6.8 Hz, 1H), 1.63 (d, J = 6.9 Hz, 3H). 13C NMR (CDCl3, 75
MHz): δ (ppm) = 166.4, 165.9, 143.0, 138.6, 132.6, 129.8, 128.8,
127.6, 127.2, 126.3, 52.4, 49.5, 21.7.
N-benzoylphenylalanine tert-butyl ester 3al:29 77% yield
1
(124.8 mg) as a white solid. H NMR (CDCl3, 200 MHz): δ
(ppm) = 7.72-7.55 (m, 2H), 7.46-7.23 (m, 3H), 7.23-7.05 (m,
5H), 6.67 (d, 1H, J = 7.3 Hz), 4.88 (dt, 1H, J = 7.4, 5.8 Hz), 3.14
(d, 2H, J = 5.7 Hz), 1.34 (s, 9H). 13C NMR (CDCl3, 75 MHz): δ
(ppm) = 170.8, 166.8, 136.3, 134.1, 131.7, 129.6, 128.6, 128.4,
127.0, 82.6, 54.0, 38.1, 28.0.
N-(p-trifluorobenzoyl)-α-methylbenzyl amine 3fg: 58%
yield (85.2 mg) as a white solid. H NMR (CDCl3, 200 MHz): δ
1
(ppm) = 7.83 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 8.3 Hz, 2H), 7.42-
7.26 (m, 5H), 6.85 (d, J = 7.6 Hz, 1H), 5.30 (p, J = 7.0 Hz, 1H),
1.59 (d, J = 6.9 Hz, 3H). 13C NMR (CDCl3, 75 MHz): δ (ppm) =
165.6, 142.9, 138.0, 133.2 (q, J = 32.5 Hz), 128.9, 127.7, 127.6,
126.3, 125.7, 125.6, 123.8 (q, J = 271 Hz), 49.6, 21.7. 19F NMR
(CDCl3, 282 MHz): δ (ppm) = -62.9. HRMS(ESI+) m/z
calculated for (MH+): 294.1106. Found: 294.1107.
N-benzoylphenylalanine.½H2O 3am: 70% yield (97.6 mg)
as a white solid. 1H NMR (CDCl3, 200 MHz): δ (ppm) = 7.73 (d,
J = 6.8 Hz, 2H), 7.64-7.28 (m, 8H), 6.87 (s, 1H, NH), 5.81 (s,

6
Tetrahedron
ACCEPTED MANUSCRIPT
N-(p-trifluorobenzoyl)-α-methylbenzyl amine 3gg:33 53%
in CH2Cl2 (9.9 mL) and methanesulfonyl chloride (460 µL, 5.93
1
yield (71.8 mg) as a white solid. H NMR (CDCl3, 200 MHz): δ
(ppm) = 8.31-8.12 (m, 2H), 7.98-7.83 (m, 2H), 7.44-7.27 (m,
5H), 6.70 (d, 1H, J = 7.3 Hz), 5.30 (p, 1H, J = 7.0 Hz), 1.61 (d,
3H, J = 6.9 Hz). 13C NMR (CDCl3, 75 MHz): δ (ppm) = 164.8,
149.5, 142.7, 140.2, 128.9, 128.3, 127.8, 126.3, 123.7, 49.8, 21.7.
N-(m-methoxybenzoyl)-α-methylbenzyl amine 3hg:12 89%
yield (114.5 mg) as a white solid. 1H NMR (CDCl3, 200 MHz): δ
(ppm) = 7.43-7.34 (m, 8H), 7.21-6.92 (m, 1H), 6.65 (d, J = 6.6
Hz, 1H), 5.56-5.23 (p, 1H, J = 7.0 Hz), 3.86 (s, 3H), 1.64 (d, 3H,
J = 6.9 Hz). 13C NMR (CDCl3, 75 MHz): δ (ppm) = 166.5, 159.9,
143.3, 136.1, 129.6, 128.8, 127.5, 126.3, 118.8, 117.7, 112.5,
55.5, 49.4, 21.8.
mmol) was added dropwise. The mixture was stirred overnight
and completion of the reaction was assessed by HPLC. Reaction
was quenched using a saturated solution of NH4Cl and extracted
with CH2Cl2. The combined organic layers were washed with a
saturated solution of NaHCO3, brine, dried over MgSO4 filtered
and concentrated under reduced pressure. The crude chloride was
filtered through a pad of silica using CH2Cl2 as eluant. Filtered
compound (white solid, 450 mg) was found pure enough for
1
further reaction. H NMR (CDCl3, 200 MHz): δ (ppm) = 7.81-
7.62 (m, 2H), 7.47-7.33 (m, 2H), 6.69 (s, 1H), 3.87-3.64 (m, 4H).
13C NMR (CDCl3, 75 MHz): δ (ppm) = 166.7, 138.2, 132.6,
129.1, 128.6, 44.2, 41.9. A mixture of compound 5a (109.0 mg,
0.5 mmol) and morpholine (348 µL, 4 mmol) was then stirred at
100°C for 2h. After cooling to room temperature, 5 mL of H2O
and then a 10% ammonia solution were added. The solution was
extracted with CH2Cl2. The organic layers were combined, dried
over MgSO4, filtered and evaporated under reduced pressure.
Purification on silica gel using a mixture CH2Cl2/MeOH 95:5
afforded 56.6 mg of moclobemide as a white solid (42 % yield).
1H NMR (CDCl3, 200 MHz): δ (ppm) = 7.72 (dd, J = 8.9, 2.2 Hz,
2H), 7.41 (dd, J = 8.9, 2.2 Hz, 2H), 6.78 (s, 1H), 3.78-3.69 (m,
4H), 3.54 (dd, J = 11.4, 5.4 Hz, 2H), 2.67-2.56 (m, 2H), 2.56-
2.46 (m, 4H). 13C NMR (CDCl3, 75 MHz): δ (ppm) = 166.4,
137.6, 133.0, 128.8, 128.4, 66.9, 56.9, 53.4, 36.2.
N-(m-chloro)-α-methylbenzyl amine 3ig:34 77% yield (100.2
1
mg) as a white solid. H NMR (CDCl3, 200 MHz): δ (ppm) =
7.72 (t, J = 1.8 Hz, 1H), 7.64-7.54 (m, 1H), 7.45-7.17 (m, 7H),
6.74 (d, J = 7.5 Hz, 1H), 5.26 (p, J = 7.0 Hz, 1H), 1.54 (d, J = 6.9
Hz, 3H). 13C NMR (CDCl3, 75 MHz): δ (ppm) = 165.5, 143.0,
136.5, 134.7, 131.5, 129.9, 128.8, 127.6, 127.4, 126.3, 125.2,
49.5, 21.7.
N-(m-nitro)-α-methylbenzyl amine 3jg:35 65% yield (88.0
1
mg) as a white solid. H NMR (CDCl3, 200 MHz): δ (ppm) =
8.55 (s, 1H), 8.25 (d, J = 8.1 Hz, 1H), 8.10 (d, J = 7.7 Hz, 1H),
7.52 (t, J = 8.0 Hz, 1H), 7.35-7.21 (m, 4H), 7.12 (d, J = 7.1 Hz,
1H), 5.28 (p, J = 6.9 Hz, 1H), 1.58 (d, J = 6.9 Hz, 3H). 13C NMR
(CDCl3, 75 MHz): δ (ppm) = 164.4, 148.1, 142.8, 136.2, 133.5,
129.8, 128.8, 127.6, 126.3, 126.0, 122.0, 49.9, 21.7.
References and notes
1.
a) Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997,
N-(o-methoxybenzoyl)-α-methylbenzyl amine 3kg:12 45%
yield (57.4 mg) as a slurry. 1H NMR (CDCl3, 200 MHz): δ (ppm)
= 8.27 (d, 1H, J = 6.7 Hz), 8.20 (dd, 1H, J = 7.8, 1.8 Hz), 7.55-
7.18 (m, 6H), 7.08 (dt, 1H, J = 7.5, 0.8 Hz), 6.97 (d, 1H, J = 8.3
Hz), 5.35 (p, 1H, J = 6.9 Hz), 3.94 (s, 3H), 1.59 (d, J = 6.9 Hz,
3H). 13C NMR (CDCl3, 75 MHz): δ (ppm) = 164.7, 157.6, 143.8,
133.0, 132.4, 128.8, 127.3, 126.2, 121.5, 111.5, 56.1, 49.3, 22.6.
97, 2243-2266; b) Carey, J. S.; Laffan, D.; Thomson, C.; Williams,
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a) Allen, C. L.; Williams, J. M. J. Chem. Soc. Rev. 2011,
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3.
a) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science
N-(o-chlorobenzoyl)-α-methylbenzyl amine 3lg:36 41%
yield (53.4 mg) as a white solid. 1H NMR (CDCl3, 200 MHz): δ
(ppm) = 7.65 (dd, J = 6.0, 3.1 Hz, 1H), 7.45-7.26 (m, 8H), 6.46
(s, 1H), 5.34 (p, J = 7.0 Hz, 1H), 1.62 (d, J = 6.9 Hz, 3H). 13C
NMR (CDCl3, 75 MHz): δ (ppm) = 165.6, 142.9, 135.2, 131.4,
130.8, 130.4, 130.3, 128.9, 127.6, 127.2, 126.4, 49.8, 21.9.
N-(p-chlorobenzoyl)-glycine methyl ester 5c:10e 79% yield
(90.2 mg) as a white solid. 1H NMR (CDCl3, 200 MHz): δ (ppm)
= 7.82-7.68 (m, 2H), 7.48-7.36 (m, 2H), 6.64 (s, 1H), 4.24 (d, J
= 5.0 Hz, 2H), 3.81 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ (ppm)
= 170.6, 166.5, 138.3, 132.2, 129.1, 128.7, 52.7, 41.9.
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N-(p-chlorobenzoyl)-glycinol 5b:37 Following a literature
procedure,18 ester 5c (488.2 mg, 2.15 mmol), NaBH4 (408.8 mg,
10.75 mmol) and THF (1.8 mL) were stirred at 65°C for 15 min.
Then MeOH (1.2 mL) was added and the resulting mixture was
stirred for another 15 min at 65°C. The mixture was then cooled
to room temperature, quenched with HCl 1M and extracted with
CH2Cl2. The combined organic layers were dried over MgSO4,
filtered and concentrated under reduced pressure to afford the
expected alcohol 5b as a white solide in 89% yield (384.4 mg).
The crude compound was found pure enough for further
reactions.1H NMR (CDCl3, 200 MHz): δ (ppm) = 7.73-7.60 (m,
2H), 7.39-7.27 (m, 2H), 7.01 (s, 1H), 3.84-3.71 (m, 2H), 3.55
(dd, J = 10.2, 5.2 Hz, 2H), 3.46 (s, 1H). 13C NMR (CDCl3, 75
MHz): δ (ppm) = 167.7, 138.1, 132.6, 128.9, 128.6, 62.0, 42.9.
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mmol), and sodium chloride (346.6 mg, 5.93 mmol) were stirred

7
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ACCEPTED MANUSCRIPT
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Commun. 2012, 48, 6833-6835.

ACCEPTED MANUSCRIPT
Iron-catalyzed benzamide formation. Application to
the synthesis of moclobemide
Xavier Bantreil,* Nasreddine Kanfar, Nicolas Gehin, Ethan Golliard, Pauline Ohlmann, Jean Martinez
and Frédéric Lamaty*
Institut des Biomolécules Max Mousseron, UMR 5247 CNRS─UM I─UM II, Université Montpellier II, Place E.
Bataillon, 34095 Montpellier Cedex 5, France.
Fax: +33 (0) 467144866;
Tel: +33 (0) 467143967;
E-mail: xavier.bantreil@univ-montp2.fr; frederic.lamaty@univ-montp2.fr
Table of Content
1. NMR Spectra of Synthesized Compounds
2
1

ACCEPTED MANUSCRIPT
1. NMR Spectra of Synthesized Compounds
1H NMR (200 MHz, CDCl3) of N-cyclohexylbenzamide 3aa
O
Ph
N
H
3aa
13C NMR (75 MHz, CDCl3) of N-cyclohexylbenzamide 3aa
O
Ph
N
H
3aa
2

ACCEPTED MANUSCRIPT
1H NMR (200 MHz, CDCl3) of N-methylbenzamide 3ab
O
CH3
Ph
N
H
3ab
13C NMR (75 MHz, CDCl3) of N-methylbenzamide 3ab
O
CH3
Ph
N
H
3ab
3

ACCEPTED MANUSCRIPT
1H NMR (200 MHz, CDCl3) of N-butylbenzamide 3ac
O
Ph
N
H
3ac
13C NMR (75 MHz, CDCl3) of N-butylbenzamide 3ac
O
Ph
N
H
3ac
4

ACCEPTED MANUSCRIPT
1H NMR (200 MHz, CDCl3) of N-isopropylbenzamide 3ad
O
Ph
N
H
3ad
13C NMR (75 MHz, CDCl3) of N-isopropylbenzamide 3ad
O
Ph
N
H
3ad
5

ACCEPTED MANUSCRIPT
1H NMR (200 MHz, CDCl3) of N-tertbutylbenzamide 3ae
O
Ph
N
H
3ae
13C NMR (75 MHz, CDCl3) of N-tertbutylbenzamide 3ae
O
Ph
N
H
3ae
6

ACCEPTED MANUSCRIPT
1H NMR (200 MHz, CDCl3) of N-benzylbenzamide 3af
O
Ph
N
H
Ph
3af
13C NMR (75 MHz, CDCl3) of N-benzylbenzamide 3af
O
Ph
N
H
Ph
3af
7

ACCEPTED MANUSCRIPT
1H NMR (200 MHz, CDCl3) of N-[(±)-1-phenylethyl]benzamide 3ag
O
CH3
Ph
N
H
Ph
3ag
13C NMR (75 MHz, CDCl3) of N-[(±)-1-phenylethyl]benzamide 3ag
O
CH3
Ph
N
H
Ph
3ag
8

ACCEPTED MANUSCRIPT
1H NMR (200 MHz, DMSO-d6) of N-benzoylphenylglycinol 3ah
OH
Ph
O
Ph
N
H
3ah
13C NMR (75 MHz, DMSO-d6) of N-benzoylphenylglycinol 3ah
OH
O
Ph
N
H
Ph
3ah
9

ACCEPTED MANUSCRIPT
1H NMR (200 MHz, CDCl3) of N-[(±)-1-(phenyl)phenethyl]benzamide 3ai
O
Ph
Ph
Ph
N
H
3ai
13C NMR (75 MHz, CDCl3) of N-[(±)-1-(phenyl)phenethyl]benzamide 3ai
O
Ph
Ph
Ph
N
H
3ai
10

ACCEPTED MANUSCRIPT
1H NMR (200 MHz, CDCl3) of N-[2-phenethyl]benzamide 3aj
O
N
H
3aj
13C NMR (75 MHz, CDCl3) of N-[2-phenethyl]benzamide 3aj
O
N
H
3aj
11

ACCEPTED MANUSCRIPT
1H NMR (200 MHz, CDCl3) of N-[2-(4-methoxyphenyl)ethyl]benzamide 3ak
OMe
O
N
H
3ak
13C NMR (75 MHz, CDCl3) of N-[2-(4-methoxyphenyl)ethyl]benzamide 3ak
OMe
O
N
H
3ak
12

ACCEPTED MANUSCRIPT
1H NMR (200 MHz, CDCl3) of tert-butyl-(2S)-(benzoylamino)-3-phenylpropanoate 3al
Ph
O
Ph
N
H
CO2tBu
3al
13C NMR (75 MHz, CDCl3) of tert-butyl-(2S)-(benzoylamino)-3-phenylpropanoate 3al
Ph
O
Ph
N
H
CO2tBu
3al
13

ACCEPTED MANUSCRIPT
1H NMR (200 MHz, CDCl3) of N-benzoylphenylalanine 3am
Ph
O
Ph
N
H
CO2H
3am
13C NMR (75 MHz, CD3OD) of N-benzoylphenylalanine 3am
Ph
O
Ph
N
H
CO2H
3am
14

ACCEPTED MANUSCRIPT
1H NMR (200 MHz, CDCl3) of N,N-dibenzylbenzamide 3an
O
Ph
3an
N
Ph
Ph
13C NMR (75 MHz, CDCl3) of N,N-dibenzylbenzamide 3an
O
Ph
3an
N
Ph
Ph
15

ACCEPTED MANUSCRIPT
1H NMR (200 MHz, CDCl3) of tert-butyl-(2S)-1-benzoyl-2-pyrrolidinecarboxylate 3ao
t
O
CO2 Bu
Ph
3ao
N
13C NMR (75 MHz, CDCl3) of tert-butyl-(2S)-1-benzoyl-2-pyrrolidinecarboxylate 3ao
t
O
CO2 Bu
Ph
3ao
N
16

ACCEPTED MANUSCRIPT
1H NMR (200 MHz, CDCl3) of N-benzoylpiperidine 3ap
O
Ph
3ap
N
13C NMR (75 MHz, CDCl3) of N-benzoylpiperidine 3ap
O
Ph
3ap
N
17

ACCEPTED MANUSCRIPT
1H NMR (200 MHz, CDCl3) of N-benzoylmorpholine 3aq
O
Ph
3aq
N
O
13C NMR (75 MHz, CDCl3) of N-benzoylmorpholine 3aq
O
Ph
N
O
3aq
18

ACCEPTED MANUSCRIPT
1H NMR (200 MHz, CDCl3) of 4-methoxy-N-(1-phenylethyl)benzamide 3bg
O
CH3
N
H
Ph
3bg
MeO
13C NMR (75 MHz, CDCl3) of 4-methoxy-N-(1-phenylethyl)benzamide 3bg
O
CH3
N
H
Ph
3bg
MeO
19

ACCEPTED MANUSCRIPT
1H NMR (200 MHz, CDCl3) of 4-methyl-N-(1-phenylethyl)benzamide 3cg
O
CH3
N
H
Ph
3cg
Me
13C NMR (75 MHz, CDCl3) of 4-methyl-N-(1-phenylethyl)benzamide 3cg
O
CH3
N
H
Ph
3cg
Me
20

ACCEPTED MANUSCRIPT
1H NMR (200 MHz, CDCl3) of 4-chloro-N-(1-phenylethyl)benzamide 3dg
O
CH3
N
H
Ph
3dg
Cl
13C NMR (75 MHz, CDCl3) of 4-chloro-N-(1-phenylethyl)benzamide 3dg
O
CH3
N
H
Ph
3dg
Cl
21