A general palladium-catalyzed aminocarbonylation of phenols to primary benzamides via in situ generation of aryl nonaflates

Article abstract of DOI:10.1002/chem.201102683

Amides in mind! A novel palladium-catalyzed amino-carbonylation of in situ formed aryl nonaflates to give primary amides in moderate to excellent yields has been developed (see scheme). Copyright

Full text of DOI:10.1002/chem.201102683

COMMUNICATION
DOI: 10.1002/chem.201102683
A General Palladium-Catalyzed Aminocarbonylation of Phenols to Primary
Benzamides via In Situ Generation of Aryl Nonaflates
[
a, b]
[b]
[b]
Xiao-Feng Wu,
Helfried Neumann, and Matthias Beller*
[
8]
[9]
Primary amides are an important class of carboxylic acid
derivatives in organic synthesis. They are widely applied as
intermediates for the synthesis of pharmaceuticals and in
amides and hydroxylamine. Interestingly, Mori and co-
[10]
workers
utilized a titanium–nitrogen complex as the
origin of ammonia, which delivered primary amides in
modest yields. In 2010, our research group developed an im-
proved palladium catalysts based on BuPAd or DPPF as li-
gands for the synthesis of primary amides. Notably, am-
monia acts both as reagent and base in these reactions.
In addition to aryl halides, phenols are aromatic scaffolds
frequently found in important pharmaceuticals, agrochemi-
[1]
material chemistry. Numerous methodologies have been
developed for the further modification of primary amides.
Hence, primary amines, nitriles, heterocycles, and even
amino-acid derivatives can be easily produced from the cor-
2
11]
[
[2]
responding primary amides. Because of their importance,
there exists continuing interest to develop new and selective
methodologies for their synthesis.
[12]
cals, polymers, and biologically active natural compounds.
In general, aromatic primary amides are synthesized by
reacting benzoic acid derivatives with ammonia (Scheme 1,
It is well known that phenols can be easily transformed into
the corresponding aryl sulfonates. Owing to the highly reac-
tive leaving group, the latter compounds are often used as
versatile intermediates in modern organic synthesis, in par-
ticular in the preparation of biologically active compounds.
Comparing the different aryl sulfonates, aryl nonaflates are
more stable and inexpensive than the corresponding triflates
and they are more reactive than similar mesylates and tosy-
[3]
pathway a). In recent years, also palladium-catalyzed car-
bonylation reactions of aryl halides have been used for the
[4]
production of primary amides (Scheme 1, pathway b).
[13]
lates. Moreover, C F SO F, which is used as reagent for
4
9
2
aryl nonaflate synthesis, is stable under air, not sensitive to
moisture, and can be stored conveniently at room tempera-
ture.
Scheme 1. Strategies for the synthesis of primary amides.
Based on our continuing interest in palladium-catalyzed
[14]
carbonylations of aryl halides and related substrates, and
the importance of primary benzamides, herein, we wish to
report a novel procedure for the catalytic aminocarbonyla-
tion of phenols via in situ formation of aryl nonaflates to
give primary amides in the presence of CO and ammonia
under mild conditions.
The first set of reactions was carried out to test the influ-
ence of different ligands on the aminocarbonylation of the
in situ generated phenyl nonaflate. Applying [Pd-
However, only few of these protocols use economically and
[5]
ecologically favorable ammonia as reagent for the synthe-
sis of primary amides. In general, more sophisticated ammo-
nia synthons are employed as nucleophilic partner in the
carbonylation reaction. More specifically, hexamethyldisila-
zane (HMDS) has been used in the aminocarbonylation of
[6]
aryl iodides and triflates leading to primary amides. Indo-
[7a]
lese and some of us, as well as Alterman, Larhed and co-
[7b]
workers
succeeded in using formamide to give primary
ACHTUNGTNERNU(GN cinnamyl)Cl] (1 mol%) and the respective ligand (2 or
2
amides in moderate to good yields by palladium-catalyzed
aminocarbonylation of aryl bromides. Other ammonia sour-
ces which have been applied more recently to convert aryl
iodides and bromides to primary amides are N-tert-butyl-
4 mol%), an equimolar amount of C F SO F (1 mmol) was
4 9 2
reacted with phenol in the presence of NEt (two equiva-
3
lents, 2 mmol) under pressure of CO and NH3 at 1008C
(Table 1). The standard ligand PPh gave 17% of the desired
3
benzamide (Table 1, entry 1), while other tested monophos-
phines and bidentate ligands with small bite angles gave no
product at all (Table 1, entries 2–5). However, other chelat-
ing ligands gave benzamide in 37–46% yield (Table 1, en-
tries 6–11). Considering the price of the ligands, we decided
[
a] Dr. X.-F. Wu
Department of Chemistry, Zhejiang Sci-Tech University
Xiasha Campus, Hangzhou
Zhejiang Province, 310018 (P.R. China)
[
b] Dr. X.-F. Wu, Dr. H. Neumann, Prof. Dr. M. Beller
Leibniz-Institut fꢀr Katalyse e.V. an der Universitꢁt Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
Fax : (+49)381-1281-5000
[15]
to choose DPEphose for the further optimization.
In the presence of this ligand, we investigated the influ-
ence of solvents and bases in more detail (Table 2). In tolu-
ene, 31% of benzamide was obtained (Table 2, entry 1),
E-mail: matthias.beller@catalysis.de
Chem. Eur. J. 2012, 18, 419 – 422
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
419

Table 1. Palladium-catalyzed aminocabonylation of in situ formed phenyl
nonaflate: influence of the ligands.
When the reaction was performed at 808C instead of
008C a similar yield of benzamide was obtained (Table 2,
[a]
1
entry 7). However, a further decrease of the temperature to
08C led to lower conversion of phenyl nonaflate (Table 2,
entry 8).
As shown in Table 2, the influence of base is also impor-
tant for the transformation of phenol to amide (Table 2, en-
tries 9–15). The best result was obtained in the presence of
DBU (78%; Table 2, entry 14). In the absence of additional
base, no benzamide was formed, instead only sulfonamide
was detected (Table 2, entry 15).
Having suitable conditions in our hand (Table 2,
entry 14), next, reactions of various phenols were per-
formed. Phenols with electron-donating substituents (alkyl
and methoxy groups) gave excellent yields under these con-
ditions (Table 3, entries 2–6). Furthermore, 4-methylthiophe-
nol gave 52% of the corresponding amide (Table 3, entry 7).
Notably, 97% of 2-naphthamide was produced from 2-naph-
thol, while only a moderate yield was obtained in the case
of the sterically more hindered 1-naphthol (Table 3, entries 8
and 9).
Functionalized phenols with electron-withdrawing groups
were successfully transformed into primary benzamides in
moderate to excellent yields (Table 3, entries 10–13). For ex-
ample, 4-trifluoromethoxyphenol gave the respective benza-
mide in 97% yield. Furthermore, nicotinamide was pro-
duced in 85% yield from the parent heterocyclic phenol
6
[
b]
Entry
Ligand
PPh (4%)
BuPAd (4%)
PCy (4%)
DPPE (2%)
DPPP (2%)
DPPB (2%)
DPPPe (2%)
Xantphos (2%)
DPEphos (2%)
BINAP (2%)
DIOP (2%)
Yield [%]
1
2
3
4
5
6
7
8
9
3
17
0
0
0
0
44
46
46
45
45
37
2
3
1
1
0
1
[
a] [Pd
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(cinnamyl)Cl]
2
(1 mol%), ligand, phenol (1 mmol),
C
4
F
9
SO
(2 bar),
008C, 16 h. [b] Yield was determined by GC using hexadecane as inter-
=n-butyldiadamantylphosphine,
2
F
(
1 mmol), NEt (2 mmol), dioxane (2 mL), CO (2 bar), NH
3
3
1
nal standard based on phenol. BuPAd
2
DPPPe=1,5-bis(diphenylphosphino)pentane, Xantphos=4,5-bis(diphe-
nylphosphino)-9,9-dimethylxanthene, DPEphos=oxydi-2,1-phenylene)-
bis(diphenylphosphine, BINAP=(R)-(+)-(1,1’-binaphthalene-2,2’-diyl)-
bis(diphenylphosphine), DIOP=(+)-2,3-O-isopropylidene-2,3-dihydroxy-
1
,4-bis(diphenylphosphino)butane.
Table 2. Palladium-catalyzed aminocabonylation of in situ formed phenyl
[
a]
nonaflate: Influence of solvents.
(
Table 3, entry 14). Unfortunately, 4-hydroxypyridine as well
as nitro- and aldehyde-functionalized phenols resulted only
in small amounts of the corresponding amides (Table 3, en-
tries 15–17).
[
b]
[c]
Entry
Solvent
Base
Temp [8C]
Yield [%]
In Scheme 2, the general reaction mechanism for the se-
quential activation and palladium-catalyzed carbonylation of
1
2
3
4
5
6
7
8
9
toluene
DMF
DME
NEt
NEt
NEt
NEt
NEt
NEt
NEt
NEt
3
3
3
3
3
3
3
3
(2 mmol)
(2 mmol)
(2 mmol)
(2 mmol)
(2 mmol)
(2 mmol)
(2 mmol)
(2 mmol)
(2 mmol)
100
100
100
100
100
100
80
60
80
80
80
31
27
52
69
64
67
69
53
61
51
51
43
36
78
0
[16]
phenol is shown. In agreement with previous studies, the
in situ generated phenyl nonaflate undergoes oxidative addi-
DMSO
0
CH
3
CN
tion to the active Pd phosphine species to form the corre-
NMP
sponding arylpalladium(II) complex. After coordination and
insertion of CO followed by the nucleophilic attack of am-
monia the primary benzamide is formed. Finally, under the
CH
CH
CH
CH
CH
CH
CH
CH
CH
3
3
3
3
3
3
3
3
3
CN
CN
CN
CN
CN
CN
CN
CN
CN
NBu
3
0
10
11
12
13
14
15
DiPEA (2 mmol)
pyridine (2 mmol)
TMEDA (1 mmol)
DABCO (1 mmol)
DBU (1 mmol)
–
assistance of base, the active Pd species is regenerated.
In conclusion, the first catalytic carbonylations of easily
available phenols via in situ generated nonaflates have been
developed. In the presence of commercially accessible palla-
dium catalysts a variety of phenols were efficiently trans-
formed to synthetically important primary benzamides. Ad-
vantageously, in the present procedure no intermediates
have to be isolated and the corresponding amides are ob-
tained in a one-pot procedure under mild reaction condi-
tions.
80
80
80
80
[
(
[
a] [Pd
1 mmol), base, solvent (2 mL), CO (2 bar), NH
c] Yield was determined by GC using hexadecane as internal standard
based on phenol. DME=1,2-dimethoxyethane, DIPEA=N,N-diisopro-
pylethylamine, TMEDA=N,N,N’,N’-tetramethylethylenediamine,
DABCO=1,4-diazabicyclo[2.2.2]octane, DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene.
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(cinnamyl)Cl]
2
(1%), DPEphos (2%), Phenol (1 mmol), C
4 9 2
F SO F
(2 bar), 16 h. [b] 2 mL.
3
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
Experimental Section
while a yield of 52% was achieved in DME (Table 2,
entry 3). To our delight DMSO, CH CN, and NMP gave im-
proved yields up to 69% (Table 2, entries 4–6). Considering
3
Typical reaction procedure for the aminocarbonylation of in situ formed
phenyl nonaflate: [Pd ACHTUGNTRNEUGN( cinnamyl)Cl] (1 mol%, 0.01 mmol), DPEphos
2
(2 mol%) and phenol (1 mmol) were transferred into a vial (4 mL reac-
tion volume) equipped with a septum, a small cannula, and a stirring bar.
the properties of solvents, CH CN was chosen for our fur-
3
ther studies as the reaction solvent.
420
www.chemeurj.org
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 419 – 422

Palladium-Catalyzed Aminocarbonylation of Phenols to Primary Benzamides
Table 3. Palladium-catalyzed aminocabonylation of in situ formed aryl
COMMUNICATION
[
a]
nonaflates: Scope and limitations.
[
b]
Entry
1
Phenols
Amides
Yield [%]
78
2
3
4
5
6
7
92
93
95
95
83
52
Scheme 2. Proposed reaction mechanism.
After the vial was purged with argon, CH
3
CN (distilled from sodium
ketyl, 2 mL), C SO F (1 mmol), and DBU (1 mmol) were injected into
4
F
9
2
the vial by syringe. Then, the vial was placed in an alloy plate, which was
transferred into a 300 mL autoclave of the 4560 series from Parr Instru-
ments under argon atmosphere. After flushing the autoclave three times
3 3
with NH , a pressure of 2 bar of NH and 2 bar of CO was adjusted and
the reaction was performed for 16 h at 808C. After the reaction, the auto-
clave was cooled down to room temperature and the pressure was re-
leased carefully. To the reaction mixture hexadecane (0.1 mmol) was
added, and a part of the mixture was used for GC and GC-MS analysis
after proper mixing. Product identification was performed by GC-MS
analysis and comparison with authentic samples. All products are com-
mercially available.
8
9
61
Acknowledgements
97
63
89
We thank the state of Mecklenburg-Vorpommern and the Bundesminis-
terium fꢀr Bildung und Forschung (BMBF) for financial support.
1
1
1
0
1
2
Keywords: amides · aminocarbonylation reactions · aryl
nonaflate · palladium · phenols
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Chem. Eur. J. 2012, 18, 419 – 422