Iron/caffeine as a catalytic system for microwave-promoted benzamide formation

Article abstract of DOI:10.1002/ejoc.201403173

The amide bond is an essential unit in many drugs and polymers. The catalyzed oxidation of alcohols and amines is an effective method to form amides with limited undesired waste. Herein, we demonstrate the beneficial effect of microwave activation for this reaction. The benzamides were directly formed from alcohols and amine hydrochloride salts in short reaction times with yields up to 84% and TOFs (turnover frequencies) up to 33.6 h^-1. Among the examined transition metals, only nontoxic and inexpensive FeCl₂?·4H₂O together with caffeine as a stabilizing ligand provided a uniquely efficient catalytic system for the transformation. Natural sources of caffeine were also evaluated under the amidation conditions.

Full text of DOI:10.1002/ejoc.201403173

Job/Unit: O43173
/KAP1
Date: 27-11-14 12:25:43
Pages: 7
FULL PAPER
DOI: 10.1002/ejoc.201403173
Iron/Caffeine as a Catalytic System for Microwave-Promoted Benzamide
Formation
Xavier Bantreil,*[a] Pauline Navals,[a] Jean Martinez,[a] and Frédéric Lamaty*[a]
Dedicated to Professor Max Malacria on the occasion of his 65th birthday
Keywords: Homogeneous catalysis / Oxidation / Microwave chemistry / Amides / Iron
The amide bond is an essential unit in many drugs and poly-
mers. The catalyzed oxidation of alcohols and amines is an
effective method to form amides with limited undesired
waste. Herein, we demonstrate the beneficial effect of micro-
wave activation for this reaction. The benzamides were di-
rectly formed from alcohols and amine hydrochloride salts in
short reaction times with yields up to 84% and TOFs (turn-
over frequencies) up to 33.6 h–1. Among the examined transi-
tion metals, only nontoxic and inexpensive FeCl2·4H2O to-
gether with caffeine as a stabilizing ligand provided a
uniquely efficient catalytic system for the transformation.
Natural sources of caffeine were also evaluated under the
amidation conditions.
Introduction
The amide functional group is present in numerous
highly valuable compounds.[1] Because of its distinct planar
structure and polarity, the amide group participates in in-
teractions (e.g., hydrogen bonding or electrostatic interac-
tions) that are closely related to the activity of a compound.
Many natural products, peptides, and proteins, as well as
non-natural drugs and polymers contain an amide group.
Several structures of pharmaceutical compounds that have
an amide moiety are depicted in Figure 1. In most cases,
the amide functionality in those molecules was introduced
by a carboxylic acid that was activated by using a stoichio-
metric amount of an acylating or coupling agent. Although
a wide variety of coupling agents have been developed,[2]
most methods generate an excess amount of undesired
waste.
Figure 1. Structure of pharmaceutical compounds that feature an
amide bond.
To develop new methods to efficiently form amide bonds amines into the corresponding amides has been widely
and reduce the impact on the environment, chemists have studied. Much effort has been devoted to finding conditions
turned their attention to catalysis.[3] Among the most recent that employ less expensive and less toxic transition metals
techniques, boronic acid catalyzed couplings[4] and metal- than Ru and Rh. In this context, we recently demonstrated
catalyzed reactions[5] have attracted much attention. In par- that amides could be directly obtained from benzylic
ticular, since the pioneering works on ruthenium[6] and rho- alcohols and amines in the presence of tert-butyl hydroper-
dium chemistry,[7] the oxidative coupling of alcohols and oxide (TBHP) as the oxidant and by using copper as an
inexpensive and nontoxic catalyst.[8] Since then, copper
nanoparticles,[9] zinc,[10] and iron[11] have been proven to
[a] Institut des Biomolécules Max Mousseron (IBMM), UMR
5247 CNRS-Universités Montpellier 1 et 2-ENSCM, Bâtiment
Chimie (17), Université Montpellier 2,
catalyze this domino reaction efficiently. One major im-
provement of these procedures would be to combine the
efficiency of the catalytic system with an activation method
such as microwaves. Indeed, although microwave activation
has been widely studied and efficiently used in organic syn-
thesis as well as organometallic chemistry,[12] its beneficial
Place Eugène Bataillon, 34095 Montpellier cedex 5, France
E-mail: frederic.lamaty@univ-montp2.fr
xavier.bantreil@univ-montp2.fr
www.greenchem.univ-montp2.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403173.
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X. Bantreil, P. Navals, J. Martinez, F. Lamaty
FULL PAPER
effects in the oxidation of alcohols into amides have never vated reaction (see Table 1, Entries 1–4). Among them, only
been witnessed.[13] Herein, among the transition metals de- iron was able to give a satisfactory 71% isolated yield. Sev-
scribed above, we demonstrated that only iron in combina- eral iron(II) and iron(III) salts were then evaluated, which
tion with a suitable caffeine ligand was able to promote the confirmed that FeCl2·4H2O was the best candidate (see
efficient formation of benzamide upon microwave acti- Table 1, Entries 4–7). Lowering or increasing the catalyst
vation.
loading did not improve the 71% yield (see Table 1, En-
tries 8 and 9). Gratifyingly, 3aa could be isolated in 84%
yield by using 2 equiv. of 1a (see Table 1, Entry 10). As ex-
plained earlier, caffeine was introduced as a very weak base
to allow for the slow deprotonation of 2a. However, when
a catalytic amount of caffeine was used (10 mol-%, see
Table 1, Entry 11), 3aa was isolated in 81% yield, which
demonstrates that caffeine might not act as a base but as a
possible stabilizing ligand of iron. Such an interaction is
well accepted under physiological conditions, as caffeine
from drinking tea or coffee is strongly suspected to prevent
iron absorption in the human body.[18] The beneficial effect
of caffeine was confirmed when the amount was reduced to
5 and 0 mol-%, which resulted in a decrease of yield (see
Table 1, Entries 12 and 13). Replacing caffeine with the
structurally simplified analogue N-methylimidazole
(10 mol-%) resulted in a decreased yield of 45%. This con-
firmed the necessity of the complete bicyclic structure of
caffeine for an optimum yield. Such behavior tends to sup-
port a simplified mechanism in which the hydrochloride salt
of amine A slowly releases free amine AЈ and hydrochloric
acid into the reaction media. In the meantime, alcohol B is
oxidized into the corresponding aldehyde C, which con-
sumes the available free amine in the mixture to form hemi-
aminal D. Upon oxidation, D converts into benzamide E
(see Scheme 1). Finally, the best reagents and amounts (see
Table 1, Entry 11) were employed, but the reaction was car-
ried out by using traditional heating at 80 °C for 4 h instead
(see Table 1, Entry 14). In this case, amide 3aa was isolated
in only 18% yield, which attests to the remarkable syner-
gistic effect of microwave activation with the iron/caffeine
catalytic system.
Results and Discussion
We began our study of microwave activation by directly
adapting the conditions from our last report about benz-
amide formation.[11c] However, under those reaction condi-
tions, the use of CaCO3 as the base provoked a fast release
of CO2, which resulted in a sudden and dangerous rise of
pressure in the sealed microwave reactor. Such behavior
prompted us to turn our attention toward others bases that
would be able to mimic the reactivity of calcium carbonate
and slowly liberate the free amine in the reaction mix-
ture.[14] To modulate the equilibrium for the deprotonation
of the (α)-methylbenzylamine hydrochloride salt (pKa
=
9.83[15]), a screening of organic bases with different pKa val-
ues was performed (see Figure 2). The use of pyridine (pKa
= 5.14)[16] afforded the formation of amide 3aa in 55% iso-
lated yield. By lowering the pKa value of the base to be-
tween 2.84 (3-chloropyridine) and 0.61 (caffeine), thereby
reducing the formation of the free amine in the reaction
mixture, we observed an increase in the yield to 71%. How-
ever, urea and 2-fluoropyridine, with very low pKa values,
proved inefficient. Among the three optimal bases, caffeine,
which is less toxic and less expensive, was selected for fur-
ther studies.
Table 1. Variation of the conditions for microwave-assisted forma-
tion of 3aa.[a]
Entry Catalyst [mol-%]
Caffeine [mol-%]
Yield [%][b]
1
2
3
4
5
6
7
8
CuSO4 (5%)
MnO2 (5%)
ZnI2 (5%)
100
100
100
100
100
100
100
100
100
100
10
34
35
n.d.[c]
71
FeCl2·4H2O (5%)
FeCl3·6H2O (5%)
FeSO4·7H2O (5%)
Fe(NO3)3·9H2O (5%)
FeCl2·4H2O (1%)
FeCl2·4H2O (10%)
FeCl2·4H2O (5%)
FeCl2·4H2O (5%)
FeCl2·4H2O (5%)
FeCl2·4H2O (5%)
FeCl2·4H2O (5%)
43
56
59
48
9
70
10
11
12
13
14
84[d]
81[d]
71[d]
66[d]
18[d,e]
Figure 2. Variation of the base for microwave-assisted formation of
3aa (MW = microwave).
5
0
10
Copper,[8] manganese,[17] zinc,[10] and iron,[11a,11c] which
were reported to efficiently participate in the formation of
benzamides under traditional activation conditions in the
[a] Reagents and conditions: 2a (0.5 mmol), 1a (0.75 mmol), caf-
feine, TBHP (70% in H2O, 3.0 mmol), catalyst, CH3CN (1 mL),
130 °C, MW, 30 min. [b] Isolated yield. [c] Not determined. [d] 1a
presence of TBHP, were subjected to the microwave-acti- (2 equiv.) was used. [e] Under traditional heating for 4 h at 80 °C.
2
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Iron/Caffeine for Microwave-Promoted Benzamide Formation
highly hygroscopic and difficult to handle hydrochloride
salts. Alkylamines that contained the butyl, cyclohexyl, or
tert-butyl group (i.e., 2f, 2g, and 2h) gave the corresponding
amides in 71, 73, and 77% yield, respectively. The beneficial
effect of the use of a microwave is highlighted by this last
result, as the corresponding yield of 3ah under traditional
conditions was only 59%.[11c] Benzoylated morpholine 3ai,
dibenzylamine 3aj, and sarcosine methyl ester 3ak were iso-
lated in 64–69% yield. Finally, the aromatic moiety of
hydroxy partner 1 was varied and submitted to a reaction
with 2a. A chloro substituent did not have an impact on
the reaction (e.g., 3ba, 73% yield; 3da, 71% yield), whereas
a nitro and methoxy group strongly decreased the yield
(e.g., 3ca, 3ea, and 3fa, 52–59% yield). Finally, 2-chlo-
robenzyl alcohol 1g, which is more hindered than 1b and
1d, underwent the reaction to yield amide 3ga in 49% yield.
It is important to stress that the TOF values[19] that were
obtained as a result of microwave activation (TOF 14.7–
33.6 h–1) are significantly higher than those of other reports
(TOF Ͻ11 h–1).[11c]
Finally, we envisioned that this reaction was possible by
using directly natural sources of caffeine, coffee beans, or
tea leaves. Indeed, it has already been shown that the forma-
tion of Ag, Pd, and Fe nanoparticles with caffeine/pol-
yphenols is possible by using coffee or tea extract.[20] Thus,
Arabica and Robusta coffee beans were evaluated in vary-
ing quantities along with water or chloroform as an additive
to ensure good extraction of the caffeine (see Table 2, En-
tries 1–6). However, the yield of 3aa could not exceed 58%.
Using crushed beans did not improve the reaction results
(see Table 2, Entry 4). Similar results were obtained with
tea leaves (see Table 2, Entry 7). As shown previously (see
Table 1, Entry 13), the reaction in the absence of caffeine
afforded a 66% yield of 3aa. These data demonstrate that,
apart from caffeine, other organic compounds that are con-
tained in the beans might be extracted during the reaction
process, and those undesired compounds might react and,
hence, consume the reagents or poison the catalyst in the
reaction media.
Scheme 1. Proposed mechanism for microwave-promoted amide
formation.
An exemplification of this method was then performed
by using the iron/caffeine/microwave activation combina-
tion (see Scheme 2). Benzamides 3aa, 3ab, 3ac, 3ad, and
3ae, which feature oxidizable benzylic positions, were iso-
lated in 48–81% yield. Remarkably, the hydroxy group of
phenyl glycinol 2c remained unchanged during the reaction,
which proved the selectivity of the conditions towards the
benzylic alcohols.
In addition, no epimerization at the stereogenic centers
was observed by using the microwave-promoted conditions.
Amide 3aa was also obtained in 84% yield by using (α)-
methylbenzylamine and concentrated HCl to preform 2a in
situ, which proves that this procedure could be applied to
Table 2. Reactions in the presence of coffee beans or tea leaves.[a]
Entry Caffeine source
Solvent
Yield [%]
1
2
3
4
5
6
7
Arabica coffee bean (104 mg)
CH3CN
CH3CN
CH3CN[b]
52
53
58
46
10
Robusta coffee bean (97 mg)
Robusta coffee beans (480 mg)
crushed Robusta beans (480 mg) CH3CN[b]
Scheme 2. Scope and limitations for microwave-assisted formation
of benzamides. Reagents and conditions: 2a–2k (0.5 mmol), 1a–1g
(1.0 mmol), TBHP (70% in H2O, 3.0 mmol), FeCl2·4H2O
(0.025 mmol), caffeine (0.05 mmol), CH3CN (1 mL), 130 °C, MW,
30–45 min. Isolated yields are reported. The TOF (turnover fre-
quency) is reported in h–1 within the brackets (Cy = cyclohexyl).
[a] Amine (0.5 mmol) and HCl (12 n, 0.5 mmol) were used.
Robusta coffee beans (490 mg)
Robusta coffee beans (560 mg)
tea leaves (420 mg)
CH3CN/H2O (2:1)[b]
CH3CN/CHCl3 (2:1)[b] 30
CH3CN[b]
53
[a] Reagents and conditions: 2a (0.5 mmol), 1a (1.0 mmol), TBHP
(3.0 mmol), FeCl2·4H2O (0.025 mmol), CH3CN (1 mL), 130 °C.
[b] The volume of the solvent was 1.5 mL.
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X. Bantreil, P. Navals, J. Martinez, F. Lamaty
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(1 mL) and then HCl (37% solution, 42 μL, 0.5 mmol, 1 equiv.)
were added at 0 °C until a white precipitate [(α)-methylbenzyl-
amine·HCl] appeared. FeCl2·4H2O (5.0 mg, 0.025 mmol, 5 mol-%),
Conclusions
In summary, we demonstrated that the unique catalytic
system that involves iron(II) and caffeine as a stabilizing caffeine (9.7 mg, 0.05 mmol, 10 mol-%), benzyl alcohol (104 μL,
1.0 mmol, 2 equiv.), and tert-butyl hydroperoxide (70% in H2O,
140 μL, 2 equiv.) were then added. After stirring at 130 °C for
10 min under microwave irradiation, additional tert-butyl hydro-
peroxide (70% in H2O, 2 equiv.) was added, and the mixture was
stirred at 130 °C for 10 min. Once again, tert-butyl hydroperoxide
(70% in H2O, 2 equiv.) was added, and the mixture was stirred at
130 °C for 10 min. After cooling to room temp., HCl 1 n solution,
5 mL) and AcOEt (5 mL) were added, and the mixture was ex-
tracted with AcOEt (2ϫ 5 mL). The combined organic phases were
washed with saturated aqueous NaHCO3 solution (10 mL) and
ligand was compatible with microwave activation to ef-
ficiently perform a domino benzamide formation with
TOFs up to 33.6 h–1. In only 30 to 45 min, a variety of
benzamides were formed directly from alcohols and amine
hydrochlorides in yields up to 84%. The importance of
microwave irradiation was confirmed when a low yield was
obtained by traditional heating. In addition, it was shown
that amine hydrochlorides could be formed in situ directly
from the corresponding amine and concentrated HCl, thus
allowing the use of a wide range of amines, the hydrochlor- brine (10 mL), dried with magnesium sulfate, and concentrated un-
der reduced pressure. The crude mixture was purified by
chromatography on a silica gel column (cyclohexane/ethyl acetate).
ide salts of which would be hygroscopic and difficult to han-
dle.
Characterization of Compounds
(؎)-N-(α-Methylbenzyl)benzamide (3aa):[21] 1H NMR (200 MHz,
CDCl3): δ = 7.90–7.67 (m, 2 H), 7.55–7.18 (m, 8 H), 6.60 (d, J =
6.9 Hz, 1 H), 5.33 (p, J = 7.0 Hz, 1 H), 1.59 (d, J = 6.9 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.7, 143.3, 134.6,
131.4, 128.7, 128.5, 127.3, 127.1, 126.3, 49.2, 21.8 ppm.
Experimental Section
General Methods: All reagents were purchased from chemical sup-
pliers and used without further purification. The 1H and 13C NMR
spectroscopic data were recorded with Bruker Avance DPX
200 MHz and Bruker Avance AM 300 MHz spectrometers. The
chemical shifts were calibrated by using the solvent signals as in-
N-Benzylbenzamide (3ab):[22] 1H NMR (200 MHz, CDCl3): δ =
7.89–7.70 (m, 2 H), 7.57–7.27 (m, 8 H), 6.67 (s, 1 H), 4.62 (d, J =
5.7 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.5, 138.3,
134.5, 131.6, 128.9, 128.7, 128.0, 127.7, 127.1, 44.2 ppm.
1
ternal references (CHCl3, δ = 7.26 ppm for H NMR and CDCl3,
δ = 77.16 ppm for 13C NMR; [D6]DMSO, δ = 2.50 ppm for 1H
NMR and [D6]DMSO, δ = 39.52 ppm for 13C NMR). Analytical
high performance liquid chromatography was performed on a
Waters Millenium 717 that was equipped with an autosampler and
had a variable wavelength diode detector. A Chromolith RP18 col-
umn (50ϫ4.6 mm) was employed, and a flow rate of 5 mLmin–1
was used with a linear gradient of CH3CN in water of 0–100%
(0.1% TFA) over 4.5 min. Flash chromatography was performed
by using prepacked silica columns on a Biotage® IsoleraTM Four
system. Reactions were performed in a Biotage® Initiator+ micro-
wave synthesizer. The temperature was measured with an IR sensor
on the outer surface of the reaction vial. The general procedures
below for the iron-catalyzed synthesis of the amides under micro-
wave activation involve the reaction of (α)-methylbenzylamine·HCl
(2a) and benzyl alcohol (1a).
(S)-N-Benzoylphenylglycinol (3ac):[23] 1H NMR (300 MHz, [D6]-
DMSO): δ = 8.70 (d, J = 8.0 Hz, 1 H), 7.91 (d, J = 6.8 Hz, 2 H),
7.62–7.43 (m, 3 H), 7.40 (d, J = 7.2 Hz, 2 H), 7.32 (t, J = 7.4 Hz,
2 H), 7.23 (t, J = 7.1 Hz, 1 H), 5.09 (dd, J = 13.6, 7.9 Hz, 1 H),
4.94 (s, 1 H), 3.83–3.57 (m, 2 H) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 166.2, 141.4, 134.7, 131.2, 128.2, 128.1, 127.4, 127.0,
126.8, 64.6, 56.0 ppm.
(S)-N-Benzoylphenylalanine (3ad):[11c] 1H NMR (200 MHz,
CDCl3): δ = 7.72 (d, J = 6.8 Hz, 2 H), 7.63–7.11 (m, 7 H), 6.94 (s,
1 H), 6.02 (s, 1 H), 5.56 (s, 1 H), 4.91 (dd, J = 13.9, 7.1 Hz, 1 H),
3.21 (qd, J = 13.6, 6.8 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 173.1, 167.4, 136.7, 133.8, 132.1, 129.5, 129.0, 128.8, 127.4,
127.2, 54.6, 38.5 ppm.
(S)-N-Benzoylphenylalanine tert-Butyl Ester (3ae):[24] 1H NMR
(200 MHz, CDCl3): δ = 7.70–7.61 (m, 2 H), 7.48–7.06 (m, 8 H),
6.60 (d, J = 7.2 Hz, 1 H), 4.88 (dt, J = 7.4, 5.8 Hz, 1 H), 3.15 (d,
J = 5.8 Hz, 2 H), 1.35 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 170.8, 166.8, 136.3, 134.2, 131.7, 129.7, 128.6, 128.5, 127.1,
82.6, 54.0, 38.1, 28.1 ppm.
Procedure for Amide Formation by Using a Preformed Amine
Hydrochloride: In a microwave reactor (0.5–2.0 mL) were added
FeCl2·4H2O (5.0 mg, 0.025 mmol, 5 mol-%), caffeine (9.7 mg,
0.05 mmol, 10 mol-%), and (α)-methylbenzylamine·HCl (78.8 mg,
0.5 mmol, 1 equiv.). CH3CN (1 mL), benzyl alcohol (104 μL,
1.0 mmol, 2 equiv.), and tert-butyl hydroperoxide (70% in H2O,
140 μL, 2 equiv.) were then added. After stirring at 130 °C for
10 min under microwave irradiation, additional tert-butyl hydro-
peroxide (70% in H2O, 2 equiv.) was added, and the mixture was
stirred at 130 °C for 10 min. Once again, tert-butyl hydroperoxide
(70% in H2O, 2 equiv.) was added, and the mixture was stirred at
130 °C for 10 min. After cooling to room temp., HCl (1 n solution,
5 mL) and AcOEt (5 mL) were added, and the mixture was ex-
tracted with AcOEt (2ϫ 5 mL). The combined organic phases were
washed with a saturated aqueous solution of NaHCO3 (10 mL)
and brine (10 mL), dried with magnesium sulfate, and concentrated
under reduced pressure. The crude mixture was purified by
chromatography on a silica gel column (cyclohexane/ethyl acetate).
N-n-Butylbenzamide (3af):[25] 1H NMR (200 MHz, CDCl3): δ =
7.81–7.68 (m, 2 H), 7.52–7.29 (m, 3 H), 6.45 (s, 1 H), 3.51–3.32 (m,
2 H), 1.68–1.46 (m, 2 H), 1.47–1.27 (m, 2 H), 0.92 (t, J = 7.2 Hz,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.7, 134.9, 131.3,
128.5, 127.0, 39.9, 31.8, 20.2, 13.8 ppm.
N-Cyclohexylbenzamide (3ag):[26] 1H NMR (200 MHz, CDCl3): δ
= 7.87–7.61 (m, 2 H), 7.55–7.29 (m, 3 H), 6.17 (s, 1 H), 4.12–3.78
(m, 1 H), 2.02–1.74 (m, 2 H), 1.68–1.60 (m, 3 H), 1.52–1.05 (m, 5
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.8, 135.2, 131.3,
128.5, 127.0, 48.8, 33.3, 25.6, 25.0 ppm.
N-tert-Butylbenzamide (3ah):[27] 1H NMR (200 MHz, CDCl3): δ =
Procedure for Amide Formation by Using an in-situ-Generated
7.87–7.58 (m, 2 H), 7.58–7.28 (m, 3 H), 5.97 (s, 1 H), 1.46 (s, 9
Amine Hydrochloride: In a microwave reactor (0.5–2.0 mL) was H) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.0, 136.0, 131.1,
added (α)-methylbenzylamine (64 μL, 0.5 mmol, 1 equiv.). CH3CN
128.5, 126.8, 51.6, 28.9 ppm.
4
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Iron/Caffeine for Microwave-Promoted Benzamide Formation
N-Benzoylmorpholine (3ai):[28] 1H NMR (200 MHz, CDCl3): δ =
7.39 (s, 5 H), 4.18–3.09 (m, 8 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 170.5, 135.3, 129.9, 128.6, 127.1, 66.9 ppm.
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N,N-Dibenzylbenzamide (3aj):[24] 1H NMR (200 MHz, CDCl3): δ =
7.58–7.44 (m, 2 H), 7.44–7.28 (m, 11 H), 7.17 (s, 2 H), 4.71 (s, 2
H), 4.42 (s, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 172.3,
137.0, 136.5, 136.2, 129.7, 128.9, 128.6, 128.5, 127.7, 127.1, 126.8,
51.6, 46.9 ppm.
[4]
[5]
[6]
N-Benzoylsarcosine Methyl Ester (3ak):[29] 1H NMR [200 MHz,
CDCl3; rotamers, 65:35]: δ = 7.55–7.29 (m, 5 H), 4.25 (s, 2 H, 65%),
3.97 (s, 2 H, 35%), 3.75 (s, 3 H), 3.08 (s, 3 H, 35%), 3.01 (s, 3 H,
65%) ppm. 13C NMR (75 MHz, CDCl3): δ = 172.1, 169.6, 135.5,
129.9, 128.7, 128.4, 127.2, 126.6, 53.2, 52.4, 52.2, 49.1, 38.7,
34.4 ppm.
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(؎)-N-(p-Chlorobenzoyl)-α-methylbenzylamine (3ba):[30] 1H NMR
(200 MHz, CDCl3): δ = 7.77–7.58 (m, 2 H), 7.45–7.27 (m, 7 H),
6.74 (d, J = 7.4 Hz, 1 H), 5.28 (p, J = 7.0 Hz, 1 H), 1.57 (d, J =
6.9 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.7, 143.1,
137.7, 133.0, 128.8, 128.8, 128.6, 127.6, 126.3, 49.5, 21.8 ppm.
[8]
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(؎)-N-(p-Nitrobenzoyl)-α-methylbenzylamine (3ca):[31] 1H NMR
(200 MHz, CDCl3): δ = 8.27–8.12 (m, 2 H), 7.94–7.83 (m, 2 H),
7.41–7.27 (m, 5 H), 6.77 (d, J = 7.4 Hz, 1 H), 5.30 (p, J = 7.0 Hz,
1 H), 1.61 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 164.8, 149.5, 142.7, 140.2, 128.9, 128.3, 127.8, 126.3, 123.7,
49.8, 21.7 ppm.
[10]
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(؎)-N-(m-Chlorobenzoyl)-α-methylbenzylamine (3da):[32] 1H NMR
(200 MHz, CDCl3): δ = 7.74 (d, J = 1.6 Hz, 1 H), 7.62 (d, J =
7.6 Hz, 1 H), 7.49–7.17 (m, 7 H), 6.72 (s, 1 H), 5.29 (p, J = 7.0 Hz,
1 H), 1.58 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 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 ppm.
[12]
(؎)-N-(m-Methoxybenzoyl)-α-methylbenzylamine (3ea):[8] 1H NMR
(200 MHz, CDCl3): δ = 7.50–7.15 (m, 8 H), 7.15–6.76 (m, 1 H),
6.57 (d, J = 7.4 Hz, 1 H), 5.31 (p, J = 7.0 Hz, 1 H), 3.80 (s, 3 H),
1.59 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
166.6, 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 ppm.
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As in previous reports, the protection of the nitrogen atom as
an ammonium salt was necessary for this reaction. Its con-
trolled deprotonation was essential to avoid side reactions be-
tween the amine and TBHP, which would lead to a decrease in
the yield. Indeed, the direct use of (α)-methylbenzylamine, in-
stead of corresponding ammonium salt, did not allow for any
conversion into amide 3aa.
E. B. Leffler, H. M. Spencer, A. Burger, J. Am. Chem. Soc.
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The pKa value of pyridine (5.14) corresponds to the pKa of
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mainder of the publication, the same analogy could be applied,
that is, the pKa value of a base corresponds to the pKa of the
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(؎)-N-(m-Nitrobenzoyl)-α-methylbenzylamine (3fa):[33] 1H NMR
(200 MHz, CDCl3): δ = 8.57 (t, J = 1.9 Hz, 1 H), 8.29 (ddd, J =
8.2, 2.2, 1.1 Hz, 1 H), 8.22–8.05 (m, 1 H), 7.57 (t, J = 8.0 Hz, 1
H), 7.43–7.23 (m, 5 H), 7.02 (d, J = 7.6 Hz, 1 H), 5.31 (p, J =
7.0 Hz, 1 H), 1.61 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 164.4, 148.2, 142.7, 136.2, 133.5, 129.9, 128.9, 127.7,
126.4, 126.1, 121.9, 49.9, 21.7 ppm.
[15]
[16]
(؎)-N-(o-Chlorobenzoyl)-α-methylbenzylamine (3ga):[34] 1H NMR
(200 MHz, CDCl3): δ = 7.76–7.55 (m, 1 H), 7.55–7.27 (m, 8 H),
6.51 (d, J = 5.2 Hz, 1 H), 5.34 (p, J = 7.0 Hz, 1 H), 1.61 (d, J =
6.9 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.7, 142.9,
135.2, 131.4, 130.7, 130.4, 130.3, 128.8, 127.6, 127.2, 126.4, 49.7,
21.9 ppm.
[17]
[18]
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectra of all compounds and chiral HPLC
analysis.
[19]
[20]
Acknowledgments
This work was realized thanks to the funding from the Centre
National de la Recherche Scientifique (CNRS) and the Université
Montpellier 2.
[21]
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X. Bantreil, P. Navals, J. Martinez, F. Lamaty
FULL PAPER
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Received: September 5, 2014
Published Online: ᭿
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Job/Unit: O43173
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Date: 27-11-14 12:25:43
Pages: 7
Iron/Caffeine for Microwave-Promoted Benzamide Formation
Amide Formation
X. Bantreil,* P. Navals, J. Martinez,
F. Lamaty* ....................................... 1–7
Iron/Caffeine as a Catalytic System for Mi-
crowave-Promoted Benzamide Formation
Keywords: Homogeneous catalysis / Oxi-
dation / Microwave chemistry / Amides /
Iron
Upon microwave activation, benzamides
were formed directly from alcohols and
amines in yields up to 84% and TOFs
(turnover frequencies) up to 33.6 h–1.
Among the examined transition metals,
only nontoxic and inexpensive FeCl2·4H2O
along with caffeine as a stabilizing ligand
provided the uniquely efficient catalytic sy-
stem for the benzamide formation.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7