Convenient palladium-catalyzed aminocarbonylation of anilines to N-arylbenzamides

Article abstract of DOI:10.1016/j.tetlet.2011.04.111

The first one-pot diazotization/aminocarbonylation reaction of anilines to benzamides has been developed. In the presence of commercially available palladium acetate/P(o-Tolyl)₃ as the catalyst system without base at low temperature (50°C) a variety of amides were synthesized in moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2011.04.111

Tetrahedron Letters 52 (2011) 3702–3704
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Convenient palladium-catalyzed aminocarbonylation of anilines to
N-arylbenzamides
⇑
Xiao-Feng Wu, Johannes Schranck, Helfried Neumann, Matthias Beller
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Strasse 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The first one-pot diazotization/aminocarbonylation reaction of anilines to benzamides has been devel-
oped. In the presence of commercially available palladium acetate/P(o-Tolyl)3 as the catalyst system
without base at low temperature (50 °C) a variety of amides were synthesized in moderate to good yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 8 April 2011
Revised 27 April 2011
Accepted 27 April 2011
Available online 10 May 2011
Keywords:
Palladium
Carbonylation
Anilines
Diazotization
Amides
Palladium-catalyzed coupling reactions have become a general
tool for achieving all kinds of synthetic transformations of aryl
and heteroaryl compounds.1,2 Nowadays, palladium catalysts are
regularly applied for the synthesis of pharmaceuticals, agrochemi-
cals, as well as advanced materials both on the laboratory as well
as on the industrial scale. Among the different known palladium-
catalyzed coupling processes, carbonylation reactions allow for
the direct incorporation of CO, the most inexpensive and readily
available C1-source, into parent molecules resulting in a variety
of carboxylic acid and carbonyl derivatives.3
Compared to aryl halides, aryldiazonium salts have been so far
much less explored as substrates in palladium-catalyzed cross-
coupling reactions.4 The first carbonylation reactions of the latter
substrates were reported by Matsuda and co-workers already in
1981.5 Here, sodium acetate was used as the nucleophile to pro-
vide mixed anhydrides. More recently, improvements of this meth-
odology were realized by Siegrist et al.6 Nevertheless, until date
only few examples of alkoxycarbonylations7 and reductive car-
bonylations 8 of diazonium compounds were reported. In addition,
carbonylative coupling reactions of aryldiazonium salts with
organotin reagents to give ketones were disclosed by Kikukawa’s
group.9 Instead of organotin reagents also aryl boronic acids can
be used as shown in 2002 by Andrus et al.10 Later on, the same
group described the related coupling of aryl boronic acids, aryldi-
azonium salts, ammonia, and CO in the presence of palladium cat-
alysts to give aryl amides in high yields.11 Notably, all these
published carbonylation processes make use of pre-formed aryldi-
azonium tetrafluoroborate salts ArN2BF4 as coupling partners.5–11
With respect to the commercial availability and the hazardous
preparation of ArN2BF4, it would be interesting to develop pro-
cesses in which anilines can be in situ activated to give the respec-
tive aryldiazonium salts. Based on our continuing interest in
palladium-catalyzed carbonylations,12 and considering the impor-
tance of benzamides,13 here we wish to report for the first time a
general palladium-catalyzed one-pot diazotization/aminocarbony-
lation sequence of anilines to benzamides.14 Compared with the
more common aminocarbonylation of aryl halides,15 this method-
ology proceeds under milder conditions and allows for the use of
abundant and easily available anilines.
Initially, the carbonylation of aniline was studied as a model
reaction. Activation of aniline should proceed via well known diaz-
otization with tert-butyl nitrite in the presence of 1.3 equiv of ace-
tic acid. Subsequent formation of the aryl–palladium complex,
carbonylation, and amidation would then lead to the product.
Indeed, the desired transformation took place toward N-phenylb-
enzamide and in the first set of experiments we tested the influ-
ence of different phosphine ligands (2 or 4 mol %) in the presence
of 2 mol % of Pd(OAc)2 in DMF at 90 °C (Table 1). In general, mono-
dentate phosphines such as PPh3, PCy3, TFP, BuPAd2, and P(o-To-
lyl)3 gave better yields (Table 1, entries 1–5; 38–81%) compared
to bidentate ligands (Table 1 and 6–12; 16–61%).
Best results were obtained in the presence of inexpensive
P(o-Tolyl)3, which was used as a standard ligand for further optimi-
zation experiments.
Next, the influence of different solvents was investigated in
more detail (Table 2). Nonpolar solvents, for example, heptane
resulted in only 17% of the amide (Table 2, entry 1). Also DME,
⇑
Corresponding author. Tel.: +49 381 1281 500.
E-mail address: matthias.beller@catalysis.de (M. Beller).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.111

X.-F. Wu et al. / Tetrahedron Letters 52 (2011) 3702–3704
3703
Table 1
Table 3
Aminocarbonylation of aniline: variation of ligandsa
Palladium-catalyzed aminocarbonylation of anilinesa
O
NH2
CO
Pd(OAc)2 (2mol%)
O
NH2
N
H
P(o-Tolyl)3 (4mol%)
CO
N
H
tert-BuONO (1.3equiv)
R
R
AcOH (1.3equiv)
2.3 mmol
10 bar
DMF (
2ml), 50oC, 16h
R
Entry
Ligand (mol %)
Yieldb (%)
1
2
3
4
5
6
7
8
9
PPh3
PCy3
TFP
BuPAd2
P(o-Tolyl)3
DPPE
DPPP
DPPF
62
75
57
38
81
16
35
23
39
43
40
61
Isolated
Entry
1
Product
Yield [%]b
O
95
N
H
Xantphos
DIOP
DPPB
10
11
12
O
DPEphos
a
2
3
75
50
Pd(OAc)2 (2 mol %), ligand (4 mol % P), AcOH (1.3 mmol), DMF (2 mL), aniline
N
H
(2.3 mmol), tert-BuONO (1.3 mmol), CO (10 bar), 90 °C, 16 h.
Yield was determined by GC using hexadecane as internal standard. TFP = tris-
2-furylphosphine; P(o-Tolyl)3 = tri(o-toyl)phosphine; DPEphos = bis(2-diphenyl-
phosphinophenyl)ether;
anthene; DIOP = (+)-2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphosphino)
butane.
b
O
S
O
Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylx-
N
H
O
dioxane, and toluene gave low yields of the product (20–29%; Table
2, entries 2–4). In acetonitrile and NMP 44% and 41% of the amide
were produced, respectively (Table 2, entries 5 and 6), while DMF
gave surprisingly N-phenylbenzamide in 81% yield. The yield of the
product is further improved to 99% by decreasing the reaction tem-
perature to 50 °C (Table 2, entry 7). Obviously, the in situ generated
PhN2OAc is more stable and gives less side reactions at lower tem-
perature. However, running the model reaction under 1 bar of CO,
only 25% yield of the amide was achieved (Table 2, entry 8).
With optimized conditions in our hands (Table 2, entry 7), we
studied the scope and limitations of this novel methodology (Table
3). p-Toluidine gave 75% of the corresponding N-aryl amide (Table
3, entry 1). Electron-rich methoxy- and methylthio-substituted
anilines are more sensitive and led to decreased yields of the cor-
responding N-aryl benzamides (Table 3, entries 3–6). On the other
hand, anilines with electron-withdrawing substituents gave im-
proved yields (58–96%) of amides (Table 3, entries 7–11). Chloride-
and bromide-substituted anilines showed no additional activation
O
4
30
N
H
S
O
O
5
6
7
58
50
58
N
H
O
O
O
N
H
O
O
O
N
H
O
Cl
O
8
9
96
78
89
N
H
Table 2
Aminocarbonylation of aniline: variation of solvents and reaction parametersa
Cl
Br
Br
F
O
Pd(OAc)2 2%
O
NH2
P(o-Tolyl)3 4%
CO
N
H
N
H
tert -Butyl-Nitrite1.3equiv
AcOH 1.3equiv
Yieldb (%)
O
Entry
Solvent
10
1
2
3
4
5
6
7
8
Heptane
DME
17
20
N
H
Dioxane
Toluene
CH3CN
NMP
DMF
DMF
26
29
44
F
CF3
O
41
99c
25d
11
69
N
H
F3C
a
Pd(OAc)2 (2 mol %), P(o-Tolyl)3 (4 mol %), AcOH (1.3 mmol), DMF (2 mL), aniline
(2.3 mmol), tert-BuONO (1.3 mmol), CO (10 bar), 90 °C, 16 h.
a
Pd(OAc)2 (2 mol %), P(o-Tolyl)3 (4 mol %), AcOH (1.3 mmol), DMF (2 mL), Aniline
b
Yield was determined by GC using hexadecane as the internal standard.
50 °C.
(2.3 mmol), tert-BuONO (1.3 mmol), CO (10 bar), 50 °C, 16 h.
c
b
Yield was calculated based on 1 mmol of starting material.
d
50 °C, CO (1 bar). DME = 1, 2-dimethoxyethane.

3704
X.-F. Wu et al. / Tetrahedron Letters 52 (2011) 3702–3704
Angew. Chem., Int. Ed. 2005, 44, 4442–4489; (i) Torborg, C.; Beller, M. Adv. Synth.
PhNH2
tert-BuONO
AcOH
PhN2OAc
Catal. 2009, 351, 3027–3043; (j) Zapf, A.; Beller, M. Top. Catal. 2002, 19, 101–
109; (k) Tucker, C. E.; de Vries, J. G. Top. Catal. 2002, 19, 111–118.
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49, 9047–9050.
3. For reviews on palladium-catalyzed carbonylations see: (a) Grigg, R.; Mutton, S.
P. Tetrahedron 2010, 66, 5515–5548; (b) Brennführer, A.; Neumann, H.; Beller,
M. Angew. Chem., Int. Ed. 2009, 48, 4114–4133; (c) Brennführer, A.; Neumann,
H.; Beller, M. ChemCatChem 2009, 1, 28–41; (d) Skoda-Földes, R.; Kollár, L. Curr.
Org. Chem. 2002, 6, 1097–1119; (e) Beller, M.; Cornils, B.; Frohning, C. D.;
Kohlpaintner, C. W. J. Mol. Catal. A: Chem. 1995, 104, 17–85.
L = P(o-Tolyl)3
O
Pd0Ln
1
Ph
O
Ph
N
H
5
N2
L
Ph
L
Pd NH
L
Ph Pd OAc
Ph
4. Roglans, A.; Pla-Quintana, A.; Moreno-Manas, M. Chem. Rev. 2006, 106, 4622–
4643.
4
L
2
5. (a) Nagira, K.; Kikukawa, K.; Wada, F.; Matsuda, T. J. Org. Chem. 1980, 45, 2365–
2368; (b) Kikukawa, K.; Kono, K.; Nagira, K.; Wada, F.; Matsuda, T. J. Org. Chem.
1981, 46, 4413–4416; (c) Kikukawa, K.; Kono, K.; Nagira, K.; Wada, F.; Matsuda,
T. Tetrahedron Lett. 1980, 21, 2877–2878.
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7. Sengupta, S.; Sadhukhan, S. K.; Bhattacharyya, S.; Guha, J. J. Chem. Soc., Perkin
Trans. 1 1998, 407–410.
8. (a) Kikikawa, K.; Totoki, T.; Wada, F.; Matsuda, T. J. Organomet. Chem. 1984, 270,
283–287; (b) Herr, R. J.; Fairfax, D. J.; Meckler, H.; Wilson, J. D. Org. Process Res.
Dev. 2002, 6, 677–681.
AcOH
CO
3
L
O
Pd OAc
L
PhNH2
Ph
Scheme 1. Proposed reaction mechanism.
9. (a) Kikukawa, K.; Idemoto, T.; Katayama, A.; Kono, K.; Wada, F.; Matsuda, T. J.
Chem. Soc., Perkin Trans. 1 1987, 1511–1514; (b) Kikukawa, K.; Kono, K.; Wada,
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of the C–X bond and isolated yields of 78–96% of halo-substituted
N-aryl benzamides were achieved (Table 3, entries 8 and 9). Unfor-
tunately, applying heterocyclic anilines no amides were obtained.
Instead, only the corresponding reduced product is detected. For
example, 5-amino-benzothiazole resulted in the formation of
benzothiazole.
With respect to the mechanism (Scheme 1) we assume that the
in situ generated PhN2OAc undergoes oxidative addition to Pd0 1,
which is easily formed from Pd(OAc)2 and the phosphine ligand,
to form aryl palladium(II) species 2. Subsequent coordination and
insertion of carbon monoxide forms the acyl palladium complex
3. Exchange of acetate by aniline should give complex 4 and final
reductive elimination leads to the terminal product 5 and regener-
ates the catalyst Pd0 1.
In conclusion, we have developed the first aminocarbonylation
of anilines to N-aryl benzamides. The procedure proceeds via
in situ formation of aryldiazonium salts, from abundantly available
anilines and subsequent palladium-catalyzed carbonylation under
base-free conditions at low temperature. 11 different N-aryl benz-
amides have been isolated in 30–96% yield.
10. Andrus, M. B.; Ma, Y.; Zang, Y.; Song, C. Tetrahedron Lett. 2002, 43, 9137–9140.
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13. See for examples: N-aryl amides; The Merck Index, 11th ed., Merck, Rahway,
USA, 1989.
14. Typical reaction procedure for carbonylation reaction of aniline: Pd(OAc)2
(2 mol %) and P(o-Tolyl)3 (4 mol %) were transferred into a vial (4 mL reaction
volume) equipped with a septum, a small cannula and a stirring bar. After the
vial was purged with argon, DMF (distilled from sodium ketyl, 2 mL), aniline
(2.3 mmol), tert-butyl nitrite (1.3 mmol), and AcOH (1.3 mmol) were injected
into 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 InstrumentsÒ
under argon atmosphere. After flushing the autoclave three times with CO, a
pressure of 10 bar was adjusted and the reaction was performed for 16 h at
50 °C. After the reaction, the autoclave was cooled down to room temperature
and the pressure was released carefully. To the reaction mixture 6 mL water
were added and the solution was extracted 3–5 times with 2–3 mL of ethyl
acetate. The extracts were evaporated with adsorption on silica gel and the
crude product was purified by column chromatography using n-heptane and n-
heptane/AcOEt (4:1) as the eluent. 1H NMR (300 MHz, CDCl3): d 10.26 (s, 1H),
7.93–7.99 (m, 2H), 7.76–7.83 (m, 2H), 7.49–7.63 (m, 3H), 7.32–7.39 (m, 2H),
7.11 (t, 1H, J = 7.44 Hz). 13C NMR (75 MHz, CDCl3): d 165.5, 139.1, 134.9, 131.5,
128.6, 128.3, 127.6, 123.6, 120.3. GC–MS (EI, 70eV): m/z (%) = 197 (M+, 60), 105
(100), 77 (40).
Acknowledgments
The authors thank the state of Mecklenburg-Vorpommern, the
Bundesministerium für Bildung und Forschung (BMBF) and the
DFG (Leibniz price) for financial support. We also thank Drs. W.
Baumann, C. Fischer (LIKAT) for analytical support.
15. For selected examples on palladium-catalyzed aminocarbonylation of aryl
halides see: (a) Martinelli, J. R.; Clark, T. P.; Watson, D. A.; Munday, R. H.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2007, 46, 8460–8463; (b) Tambade, P. J.;
Patil, Y. P.; Bhanage, B. M. Appl. Organomet. Chem. 2009, 23, 235–240; (c)
Szilágyi, A.; Farkas, R.; Petz, A.; Kollár, L. Tetrahedron 2009, 65, 4484–4489; (d)
Salvadori, J.; Balducci, E.; Zaza, S.; Petricci, E.; Taddei, M. J. Org. Chem. 2010, 75,
1841–1847; (e) Martinelli, J. P.; Watson, D. A.; Freckmann, D. M. M.; Barder, T.
E.; Buchwald, S. L. J. Org. Chem. 2008, 73, 7102–7107.
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