The First ZnII-Catalyzed Oxidative Amidation of Benzyl Alcohols with Amines under Solvent-Free Conditions

Article abstract of DOI:10.1002/ejoc.201300367

The first zinc-catalyzed oxidative amidation of benzyl alcohols has been developed. Both aliphatic and aromatic amines can be tolerated and applied in this reaction. Various amides were prepared in good yields under solvent-free and mild conditions. Copyright

Full text of DOI:10.1002/ejoc.201300367

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300367
The First ZnII-Catalyzed Oxidative Amidation of Benzyl Alcohols with Amines
under Solvent-Free Conditions
Xiao-Feng Wu,*[a,b] Muhammad Sharif,[b,c] Anahit Pews-Davtyan,[b] Peter Langer,[b,d]
Khurshid Ayub,[d] and Matthias Beller*[b]
Dedicated to Professor Christophe Darcel
Keywords: Zinc / Amidation / Benzyl alcohols / Amines / Oxidation
The first zinc-catalyzed oxidative amidation of benzyl
alcohols has been developed. Both aliphatic and aromatic
amines can be tolerated and applied in this reaction. Various
amides were prepared in good yields under solvent-free and
mild conditions.
Wolff[9] reactions lead to the same inference. In the last few
years significant reports, adapting sophisticated methods to
afford new access for amide syntheses have been appeared
in the literature.[10] Moreover, the direct oxidative amidation
was reported as well.[11] These methods need the use of ex-
pensive metals as catalyst, such as ruthenium or rhodium,
or heterogeneous catalysts, such as alumina-supported sil-
ver clusters, Au/TiO2 systems, Au/HT systems, and Au/
DNA nanohybrids.
Introduction
The development of simple and convenient methodolo-
gies for the construction of an amide bond has become
highly desirable in synthetic chemistry.[1] The amide bond
is pervasive in nature, and this motif plays a significant role
in biological systems and is also very important in the phar-
maceutical industry, as nitrogen-containing compounds
play an essential role in medicine for the treatment of vari-
ous kinds of bacterial and fungal diseases caused by dif-
ferent pathogenic bacterial and fungal strains.[2] Further-
more, it has been assessed that about 25% of all synthetic
pharmaceutical drugs contain an amide unit.
Conventionally, amides are synthesized by the reactions
of carboxylic acids, their activated acid derivatives, active
esters and amines, or by coupling reactions of alkyl/aryl
halides with amides.[3] Alternatively, the transition-metal-
catalyzed aminocarbonylation with amines offers an inter-
esting and convenient procedure for their preparation.[4]
Additionally, name reactions like the acid-promoted
Schmidt reaction,[5] Ritter,[6] Beckmann,[7] Ugi,[8] and
In view of the copious advantages of zinc catalysis[12] and
our incessant research interests in developing zinc-catalyzed
oxidation reactions,[13] we became interested in exploring a
zinc catalyst for the direct oxidative amidation of benzyl
alcohols. Herein, for the first time we present an interesting
zinc-catalyzed oxidative amidation of benzyl alcohols with
aryl/alkylamines under solvent-free conditions.
Results and Discussion
Initial trials were carried out by the reaction of benzyl
alcohol with n-butylamine under different conditions. The
results are tabulated in Table 1.
[a] Department of Chemistry, Zhejiang Sci-Tech University,
Xiasha Campus, Hangzhou, Zhejiang Province 310018, People’s
Republic of China
Based on our previous investigations in the zinc-cata-
lyzed oxidative amidation/esterification of aromatic alde-
hydes and some other oxidation reactions, we initiated our
studies by employing the standard reaction conditions [cat-
alyst: 10 mol-% of ZnBr2, ZnCl2, ZnI2, ZnF2, Zn(OAc)2 or
Zn(CN)2; temperature: 80 °C; reaction time: 16 h; oxidant:
3 equiv. of tert-butyl hydroperoxide (TBHP)] in the synthe-
sis of N-butylbenzamide from benzyl alcohol and bu-
tylamine. Thereby the N-butylbenzamide was formed from
benzyl alcohol (1 mmol) and butylamine (1 mmol) with
conversions ranging from 60 to 77% and GC yields from 11
E-mail: xiao-feng.wu@catalysis.de
Homepage: www.catalysis.de
[b] Leibniz-Institut für Katalyse an der Universität Rostock e.V.
Albert-Einstein-Str. 29a, 18059 Rostock, Germany
E-mail: matthias.beller@catalysis.de
Homepage: www.catalysis.de
[c] Department of Chemistry, COMSATS Institute of Information
Technology,
Abbottabad, Pakistan
[d] Institut für Chemie, Universität Rostock,
Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300367.
Eur. J. Org. Chem. 2013, 2783–2787
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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X.-F. Wu, M. Beller et al.
SHORT COMMUNICATION
Table 1. Zn-catalyzed oxidation of benzyl alcohol to benzamide (Table 1, Entry 11). The results are shown in Table 2. In ge-
(model reaction).[a]
neral, the halogeno-substituted benzyl alcohols showed a
lower reactivity giving moderate yields (Table 2, Entries 5
and 6). Good yields were produced again in the case of
isobutylamine and hexylamine (Table 2, Entries 11–13). The
reaction between thiophen-2-ylmethanol and butylamine or
pentanamine was not straightforward, and the desired
amides were produced in lower quantities (23 and 30%;
Table 2, Entries 7 and 8). Remarkably, even methylthio sub-
stitution can be tolerated under our conditions and gives
the desired amide in 60% yield (Table 2, Entry 4). Besides
aliphatic amines and anilines, even benzylamine succeeded
to be applied as coupling partner without further optimiza-
tion (Table 2, Entries 19–21).
Entry
1
Catalyst
ZnBr2
Oxidant Solvent Conversion[b] Yield[b]
TBHP
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
acetone
75%
77%
60%
66%
67%
73%
66%
69%
77%
70%
100%
100%
0%
20%
26%
47%
16%
11%
18%
55%
60%
49%
Ͻ 1%
70%
69%
0%
(10 mol-%) (3 equiv.)
ZnCl2 TBHP
(10 mol-%) (3 equiv.)
ZnI2 TBHP
(10 mol-%) (3 equiv.)
ZnF2 TBHP
(10 mol-%) (3 equiv.)
Zn(OAc)2 TBHP
(10 mol-%) (3 equiv.)
Zn(CN)2 TBHP
(10 mol-%) (3 equiv.)
ZnI2 TBHP
(5 mol-%) (3 equiv.)
ZnI2 TBHP
(5 mol-%) (3 equiv.)
ZnI2 TBHP
(2 mol-%) (3 equiv.)
2
3
4
5
6
Conclusions
7
We have developed for the first time a general procedure
for the zinc-catalyzed oxidative amidation reaction of
benzyl alcohols and amines. This methodology allows for
the straightforward synthesis of amides. All the reactions
were performed in air under solvent-free conditions. Vari-
ous benzamides were prepared in good to excellent yields.
In addition, some heterocycles and secondary amides were
also synthesized from the corresponding alcohols and
amines.
8[c]
9[c]
10[c]
11[d]
12[d]
13[d]
14[d]
15[d]
16[d]
17[d]
18[d]
–
TBHP
(3 equiv.)
TBHP
ZnI2
(5 mol-%) (4 equiv.)
ZnI2 TBHP
(5 mol-%) (5 equiv.)
ZnI2 TBHP
(5 mol-%) (4 equiv.) (1 mL)
ZnI2 TBHP MeCN
(5 mol-%) (4 equiv.) (1 mL)
ZnI2 TBHP THF
(5 mol-%) (4 equiv.) (1 mL)
ZnI2 TBHP dioxane
(5 mol-%) (4 equiv.) (1 mL)
ZnI2 TBHP EtOH
(5 mol-%) (4 equiv.) (1 mL)
ZnI2 TBHP H2O
(5 mol-%) (4 equiv.) (1 mL)
74%
30%
67%
35%
100%
43%
0%
Experimental Section
General Comments: All reactions were carried out in air. Reactions
were monitored by TLC analysis (pre-coated silica gel plates with
fluorescent indicator UV254, 0.2 mm) and visualized with 254 nm
UV light or iodine. Chemicals were purchased from Aldrich, Alfa
Asar and – unless otherwise noted – were used without further
32%
0%
68%
1
purification. All compounds were characterized by H NMR, 13C
NMR, and IR spectroscopy as well as by GC–MS, HRMS. 1H
NMR spectra were recorded with Bruker AV 300 and AV 400 spec-
trometers. 13C NMR spectra were recorded at 282 MHz. IR spectra
were recorded with an FT-IR Alpha (Bruker) instrument with
platinum ATR (Bruker). EI (70 eV) mass spectra were recorded
with a MAT 95XP (Thermo Electron Corporation) instrument. GC
was performed with an Agilent 6890 chromatograph with a 30 m
HP5 column. HRMS was performed with MAT 95XP (EI) and
Agilent 6210 Time-of-Flight LC/MS (ESI) instruments. GC–MS
was performed with an Agilent 5973 chromatograph and mass-se-
lective detector. All yields reported refer to isolated yields.
[a] Benzyl alcohol (1 mmol), butylamine (1 mmol), oxidant, cata-
lyst, 80 °C, 16 h. [b] Yields were determined by GC based on benzyl
alcohol using hexadecane as internal standard. [c] 60 °C. [d] 40 °C.
to 47% under solvent-free conditions (Table 1, Entries 1–6).
While a decrease of the catalyst loading to 5 mol-% led to
an increase of the yield of the desired product to 55%, it
can be further improved to 70% by a decrease of the reac-
tion temperature to 40 °C (Table 1, Entries 7 and 11). No
amide was detected in the absence of a zinc catalyst, and a
higher loading of TBHP cannot improve the result (Table 1,
Entries 10 and 12). Attempts to use solvents did not further
increase the yield of the amide (Table 1, Entries 13–18).
To explore the generality, the scope and the limitations
of the reaction, the zinc-catalyzed oxidative amidation reac-
tion was carried out with various benzyl alcohols and
General Procedure for the Oxidative Amidation of Benzyl Alcohols:
ZnI2 (5 mol-%) and a stirring bar were added to a 50 mL pressure
tube. Then, benzyl alcohol (1 mmol) and amine (1 mmol) were
added by using a syringe. Finally, TBHP (4 equiv.) was added, and
the resulting solution was kept at 40 °C for 16 h. The mixture was
cooled to room temperature and diluted with ethyl acetate. The
organic layer was washed with water. After removal of the solvent
in vacuo, the product were isolated by column chromatography
with hexane/ethyl acetate (4:1).
Supporting Information (see footnote on the first page of this arti-
amines under the best optimized conditions in hand cle): Analysis data and NMR spectra.
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ZnII-Catalyzed Oxidative Amidation of Benzyl Alcohols
Table 2. Zn-catalyzed oxidation of benzyl alcohols to amides.[a]
Eur. J. Org. Chem. 2013, 2783–2787
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X.-F. Wu, M. Beller et al.
SHORT COMMUNICATION
Table 2. (Continued)
[a] All the reactions were carried out with benzyl alcohols (1 mmol), amines (1 mmol) and ZnI2 (0.05 mmol) with TBHP (4 equiv.) at
40 °C for 16 h. [b] Isolated yields.
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Received: March 11, 2013
Published Online: April 15, 2013
Eur. J. Org. Chem. 2013, 2783–2787
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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