The use of Cr (CO)6 as an alternative CO source in Pd-catalyzed C-N bond formation: Synthesis of benzamides

Article abstract of DOI:10.1002/aoc.5049

An efficient strategy for the synthesis of benzamides from acetamides and aryl iodides using 1?mol% Pd (OAc)₂ as catalyst and Cr (CO)₆ as CO-precursor is described. This new synthetic methodology displays high functional group tolerance on both substrates and avoids the need for ligands, reducing agents, or other additives. The corresponding products were obtained in good to excellent yields at atmospheric pressure under mild reaction conditions.

Full text of DOI:10.1002/aoc.5049

Received: 14 March 2019
DOI: 10.1002/aoc.5049
Revised: 6 May 2019
Accepted: 6 May 2019
C O M M U N I C A T I O N
The use of Cr (CO) as an alternative CO source in Pd‐
6
catalyzed C‐N bond formation: Synthesis of benzamides
Mozhdeh Mozaffari | Najmeh Nowrouzi
| Mohammad Abbasi
Department of Chemistry, Faculty of
An efficient strategy for the synthesis of benzamides from acetamides and aryl
Sciences, Persian Gulf University, Bushehr
5169, Iran
7
iodides using 1 mol% Pd (OAc) as catalyst and Cr (CO) as CO‐precursor is
2
6
described. This new synthetic methodology displays high functional group tol-
erance on both substrates and avoids the need for ligands, reducing agents, or
other additives. The corresponding products were obtained in good to excellent
yields at atmospheric pressure under mild reaction conditions.
Correspondence
Najmeh Nowrouzi, Department of
Chemistry, Faculty of Sciences, Persian
Gulf University. Bushehr 75169, Iran.
Email: nowrouzi@pgu.ac.ir
KEYWORDS
6
Acetamide, Benzamide, C‐N bond formation, Cr (CO) , Pd‐catalyzed
1
| INTRODUCTION
can be synthesized by aminocarbonylation of aryl halides
in the presence of direct carbon monoxide or other car-
[
14]
Amides are very important functional groups due to their
wide applications in different area such as pharmaceuti-
cal and agrochemical industries.
bon monoxide sources.
Recently the use of metal car-
bonyls as an indirect carbon monoxide sources has been
[1–3]
[15,16]
They are also valu-
developed.
Metal carbonyls are relatively stable car-
able intermediates for the synthesis of various useful
bonyl sources and are easy to handle. Therefore, they are
appropriate replacement for CO gas which is highly toxic,
flammable, and its handling and storage is difficult.
Among the methods mentioned above, synthesis of
benzamides from different acetamides has been less
studied and there is only a few examples (Scheme 1, a
[4]
organic compounds. Besides, amide bond is the main
chemical bond linkage in proteins and peptides as well
as a variety of important drugs, for example paclitaxel
[
5]
(
(
it is used to treat a number of types of cancer ), alpidem
[6]
It is used specifically for the treatment of anxiety ), and
[
17]
mosapride (It is approved for the treatment of gastritis,
gastroesophageal reflux disease and functional dyspep-
and b).
Herein, we want to introduce a new method for syn-
thesizing benzamides from acetamides and aryl iodides
[7]
sia ) (Figure 1). Amide motifs are also available in
numerous industrial materials including polymers, lubri-
using Cr (CO) as a solid carbonyl source and readily
6
[8]
cants and detergents.
available palladium salt as catalyst, without using any
ligands (Scheme 1, c).
The first approaches to synthesize amides are conden-
sation reactions between carboxylic acids or its deriva-
[9]
tives and amines. Due to the great importance of this
group of compounds, researchers paid a lot of attention
to provide new synthetic methods for preparation of these
structures.
2 | RESULTS AND DISCUSSION
The first study was performed using iodobenzene and
acetamide in toluene in the presence of 5 mol% of Pd
(OAc) and 1.5 equivalent of Cr (CO) at 100 °C for
Different synthetic methodologies such as the rear-
[
10]
rangement of ketoximes,
amides,
oxidation of aldimines to
2
6
[11]
[12]
hydroaminocarbonylation of olefines,
24 hr. The yield of transformation was surprisingly high
(Table 1, entry 1). The reaction conditions were further
optimized by varying different parameters such as sol-
vent, base and the amount of Pd (OAc) and Cr (CO) .
transamidation, hydroamination of alkynes and oxidation
of benzyl amines and benzaldehydes with amines have
[13]
been widely studied.
Alternatively, aromatic amides
2
6
Appl Organometal Chem. 2019;e5049.
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https://doi.org/10.1002/aoc.5049

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MOZAFFARI ET AL.
TABLE 1 Effect of reaction parameters on transformation of
a
acetamide to benzamide
Pd (OAc)
(mol%)
2
Cr (CO)
(equiv) Yield(%)
6
o
b
Entry Solvent/ C Base
1
2
3
4
PhCH
3
/100
K
2
K
2
K
2
K
2
CO
CO
CO
CO
3
3
3
3
5
5
5
5
1.5
1.5
1.5
1.5
90
DMF/100
N.R
N.R
57
DMSO/100
3
CH CN/
reflux
5
6
7
THF/reflux
K
2
K
2
K
2
CO
CO
CO
3
3
3
5
5
5
1.5
1.5
1.5
42
67
27
FIGURE 1 Examples of biologically active molecules containing
amide bond
H
2
O/100
PEG‐200/
00
1
8
9
1
1
1
PhCH
PhCH
PhCH
PhCH
3
3
3
3
/100 Na
2
CO
3
5
5
3
2
1
1.5
1.5
1.5
1.5
1.5
74
62
88
87
87
/100 Bu
3
N
0
1
2
/100
/100
K
2
2
CO
3
3
K
CO
PhCH
00
3
/
2 3
K CO
1
1
1
1
1
1
3
4
5
6
7
PhCH
PhCH
PhCH
PhCH
PhCH
3
3
3
3
3
/100
/100
/100
/100
/100
K
2
K
2
K
2
K
2
K
2
CO
CO
CO
CO
CO
3
0.5
1
1.5
1.0
1.2
1.7
1.5
70
52
69
90
72
3
3
3
3
1
1
c
SCHEME 1 Transformation of acetamides to benzamides
1
a
The reactions were performed by using 1.0 mmol of iodobenzene and
1
.5 mmol of acetamide, in 1.5 ml of solvent for 24 hr.
The results are shown in Table 1. In order to study the
effect of solvent in this reaction, a series of solvents were
screened. In DMF and DMSO actually no reaction was
occurred between the starting materials (Table 1, entries
b
Yields are of pure isolated products.
c
1
.0 mmol of acetamide was used.
2
and 3). The product was formed when CH CN, THF,
amount of Cr (CO) causes an obvious reduction in the
3
6
H O or PEG‐200 was used as the solvent, but the effi-
reaction efficiency (Table 1, entries 14 and 15). The best
result was obtained when 1.5 mmol of acetamide was
used in the reaction mixture (Table 1, entry 17).
2
ciency of transformation was lower than toluene under
similar conditions (Table 1, entries 4–7). Therefore, tolu-
ene was selected as the best solvent for this reaction. No
further yield improvement was achieved by changing
the base (Table 1, entries 8 and 9) and K CO was the best
After identifying the best reaction conditions, the sub-
strate scope of this transformation was investigated. As
summarized in Scheme 2, a variety of aryl iodides and
diverse aryl acetamides carrynig both electron‐donating
and electron‐withdrawing substituents have been toler-
ated this procedure to give the corresponding products
up to 92% yield under the selected conditions (Scheme 2,
2
3
choice to promote the desired reaction. Decreasing the
amount of Pd (OAc) from 5 mol% to 1 mol% have no
2
effect on the yield of benzamide (Table 1, entries 10–
1
2), but further lowering to 0.5 mol% reduced the effi-
[
17–22]
ciency (Table 1, entry 13). It was found that the optimum
amount of catalyst loading is 1 mol%. Another important
parameter that should be checked was the carbonyl con-
tent. As can be seen in Table 1, although increasing the
amount of solid carbonyl source has no significant effect
in product formation (Table 1, entry 16), reducing the
3h).
Not only aryl acetamides but also heteroaryl
acetamides are suitable substrates for this transformation
(Scheme 2, 3m). The process was also successfully applied
to alkyl acetamides such as N‐cyclohexylacetamide and N‐
butylacetamide accomplishing high transformation as
well as aryl acetamides (Scheme 2, 3n and 3o). N‐

MOZAFFARI ET AL.
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SCHEME
3
Proposed
mechanism
for
Pd‐catalyzed
transformation of acetamide to benzamide
of chromium hexacarbonyl. In order to confirm the role
of Cr (CO) in reducing of Pd (II), the ultraviolet (UV)
6
spectrum was investigated. The UV spectrum of Pd
(
OAc) solution is shown in Figure 2 (graph a). The peak
2
at around 520 nm shows the presence of Pd (II). Graph b
is related to the mixture of Pd (OAc) and Cr (CO) in the
2
6
selected reaction condition. The disappearance of the
peak around 520 nm confirms that Pd (II) has been
reduced to the Pd(0) species in the presence of Cr (CO)6
(
Figure 2). In fact, heating the solution of Cr (CO) in tol-
6
uene results in replacement of three CO ligands, which
[18]
plays the role of reducing agent in these reactions.
Oxidative addition of Pd(0) to carbon‐iodide bond of aryl
iodide leads in the formation of Pd (II) species (I), which
SCHEME 2 Scope and versatility of the reaction
benzylacetamide was also examined and was found to
afford the related benzamide in a satisfying yield
(Scheme 2, 3p). Unfortunately, the bromo‐ and chloroben-
zenes were failed to give the desired product under opti-
mized conditions.
Based on the product formation, a probable mecha-
nism is summarized in Scheme 3 and exemplified by
the formation of 3a. It was proposed that the process is
started by conversion of Pd (II) to Pd(0) in the presence
FIGURE 2 UV spectra of the palladium catalyst. (Graph a is
related to Pd (OAc) and graph b is related to Pd (OAc) + Cr
2
2
6
(CO) )

4
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MOZAFFARI ET AL.
then undergoes the carbon monoxide insertion to afford
the intermediate (II). In continue, acylation of acetamide
and deacylation of the formed product (III) via hydroly-
sis, yields the corresponding product. The selective hydro-
lysis of COCH3 over COPh may be referred to their
[2] I. E. Valverde, S. Vomstein, C. A. Fischer, A. Mascarin, T. L.
Mindt, J. Med. Chem. 2015, 58, 7475.
[3] J. A. D. Good, J. Silver, C. Núñez‐Otero, W. Bahnan, K. S.
Krishnan, O. Salin, P. Engström, R. Svensson, P. Artursson, S.
Bergström, F. Almqvist, J. Med. Chem. 2016, 59, 2094.
17b
[4] a)J. M. Humphrey, A. R. Chamberlin, Chem. Rev. 1997, 97,
relative stabilities.
2243. b)T. Cupido, J. Tulla‐Puche, J. Spengler, F. Albericio,
Curr. Opin. Drug Discovery Dev. 2007, 10, 768. c)H. Lundberg,
F. Tinnis, N. Selander, H. Adolfsson, Chem. Soc. Rev. 2014,
3
| CONCLUSIONS
43, 2714. d)C. L. Allen, J. M. J. Williams, Chem. Soc. Rev.
2011, 40, 3405.
In conclusion, a synthetic methodology to obtain
benzamides has been developed. Using Cr (CO) as CO‐
[5] W. P. McGuire, W. D. Hoskins, M. F. Brady, P. R. Kugera, E. E.
Partridge, K. Y. Look, D. L. Clarke‐Pearson, M. Davidson, N.
Engl. J. Med. 1996, 334, 1.
6
source, is convenient way to perform sequential acylation
and deacylation of acetamides in lab scale without the
need of special equipment such as autoclaves when using
CO gas. The current strategy displays high functional
group tolerance on both substrates and avoids the need
for ligands, reducing agent, or other additives.
[6] B. Zivkovic, E. Morel, D. Joly, G. Perrault, D. J. Sanger, K. G.
Lloyd, Pharmacopsychiatry 1990, 23, 108.
[7] M. P. Curran, D. M. Robinson, Drugs 2008, 68, 981.
[8] a)T. Cupido, J. Tulla‐Puche, J. Spengler, F. Albericio, Curr.
Opin. Drug Discovery Dev. 2007, 10, 768. b)J. W. Bode, Curr.
Opin. Drug Discovery Dev. 2006, 9, 765.
4
4
| EXPERIMENTAL SECTION
.1 | Typical procedure for the
[
9] a)L. J. Goossen, D. M. Ohlmann, P. P. Lange, Synthesis 2009, 1,
160. b)S. Ghosh, A. Bhaumik, J. Mondal, A. Mallik, S.
Sengupta, C. Mukhopadhyay, Green Chem. 2012, 14, 3220. c)
D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey,
J. L. Leazer Jr, R. J. Linderman, K. Lorenz, J. Manley, B. A.
Pearlman, A. Wells, A. Zaks, T. Y. Zhang, Green Chem. 2007,
preparation of N‐Phenylbenzamide (3a)
Iodobenzene (1.0 mmol), acetamide (1.5 mmol), K CO3
2
9, 411. d)A. El‐Faham, F. Albericio, Chem. Rev. 2011, 111, 6557.
(2.0 mmol), Pd (OAc) (0.01 mmol), Cr (CO) (1.5 mmol)
2 6
and toluene (1.5 ml) were added to a vial. The reaction mix-
ture was stirred at 100 °C for 24 hr. After that time, the
reaction mixture was cooled and extracted with EtOAc.
The organic layer was separated and removed. The crude
product was purified by chromatography over silica gel
using n‐hexane/ethyl acetate as eluent to afford the pure
[10] B. Karimi, H. Behzadnia, Synlett 2010, 13, 2019.
[11] S. Gao, Y. Ma, W. Chen, J. Luo, Synlett 2018, 29, 2191.
[12] S. Liu, H. Wang, X. Dai, F. Shi, Green Chem. 2018, 20, 3457.
[
13] a)R. V. Kolakowski, N. Shangguan, R. R. Sauers, L. J. Wil-
liams, J. Am. Chem. Soc. 2006, 128, 5695. b)N. Samuel, K.
L. Hull, Org. Lett. 2015, 17, 3236. c)J. D. Moore, R. J. Byrne,
P. Vedantham, D. L. Flynn, P. R. Hanson, Org. Lett. 2003, 5,
4241. d)S. D. Sarkar, S. Grimme, A. Studer, J. Am. Chem.
Soc. 2010, 132, 1190. e)L. J. Gooben, L. Huang, M. Arndt,
K. Gooben, H. Heydt, Chem. Rev. 2015, 115, 2596. f)Y. Wang,
D. P. Zhu, L. Tang, S. J. Wang, Z. Y. Wang, Angew. Chem.,
Int. Ed. 2011, 50, 8917. g)K. R. Reddy, C. U. Maheswari, M.
Venkateshwar, M. L. Kantam, Eur. J. Org. Chem. 2008,
2008, 3619. h)S. Kegnaes, J. Mielby, U. V. Mentzel, T. Jensen,
P. Fristrup, A. Riisager, Chem. Commun. 2012, 48, 2427.
1
N‐phenylbenzamide (3a) as a white solid (yield 87%). H
NMR (400 MHz, DMSO‐d ): δ = 10.27 (s, 1 H), 7.98 (d,
6
J = 7.2 Hz, 2 H), 7.81 (d, J = 8.0 Hz, 2 H), 7.61–7.53 (m, 3
H), 7.37 (t, J = 7.0 Hz, 2 H), 7.12 (t, J = 7.0 Hz, 1 H) ppm.
13
C NMR (100 MHz, DMSO‐d ): δ = 166.0, 139.6, 135.4,
6
1
32.0, 129.0, 128.8, 128.1, 124.1, 120.8 ppm. IR (KBr):
−
1
νmax = 3446, 1662 cm (Supporting information).
[
14] a)M. V. Khedkar, T. Sasaki, B. M. Bhanage, ACS Catal. 2013, 3,
ACKNOWLEDGEMENTS
287. b)J. Salvadori, E. Balducci, S. Zaza, E. Petricci, M. Taddei,
We thank the Persian Gulf University Research Council
for support of this study.
J. Org. Chem. 2010, 75, 1841. c)J. Tambade, Y. P. Patil, M. J.
Bhanushali, B. M. Bhanage, Synthesis 2008, 15, 2347. d)B.
Urbán, M. Papp, D. Srankó, R. Skoda‐Földes, J. Mol. Catal. A:
Chem. 2015, 397, 150. e)W. Han, F. Jin, Q. Zhou, Synthesis
2015, 47, 1861. f)S. D. Friis, T. Skrydstrup, S. L. Buchwald,
Org. Lett. 2014, 16, 4296. g)T. Xu, H. Alper, J. Am. Chem. Soc.
ORCID
Najmeh Nowrouzi https://orcid.org/0000-0002-9734-981X
2014, 136, 16970. h)R. S. Mane, T. Sasaki, B. M. Bhanage,
RSC Adv. 2015, 5, 94776. i)N. Sharma, G. Sekar, Adv. Synth.
Catal. 2016, 358, 314.
REFERENCES
[
15] a)J. Wannberg, M. Larhed, J. Org. Chem. 2003, 68, 5750. b)P.
Caldirola, R. Chowdhury, A. M. Johansson, U. Hacksell,
Organometallics 1995, 14, 3897.
[
1] T. Ganesh, J. X. Jiang, M. S. Yang, R. Dingledine, J. Med. Chem.
014, 57, 4173.
2

MOZAFFARI ET AL.
5 of 5
[
16] a)L. Åkerbladh, L. R. Odell, M. Larhed, Synlett 2019, 30, 141. b)
E. Etemadi‐Davan, N. Iranpoor, P. Arshad, Asian J. Org. Chem.
[22] T. Wang, L. Yuan, Z. Zhao, A. Shao, M. Gao, Y. Huang, F.
Xiong, H. Zhang, J. Zhao, Green Chem. 2015, 17, 2741.
2
2
018, 7, 683. c)E. Etemadi‐Davan, N. Iranpoor, ChemistrySelect
016, 1, 4300. d)N. Iranpoor, H. Firouzabadi, E. Etemadi‐
SUPPORTING INFORMATION
Davan, A. Nematollahi, H. R. Firouzi, New J. Chem. 2015, 39,
445.
17] a)C. Chen, W. Liu, P. Zhou, Beilstein J. Org. Chem. 2016, 12,
250. b)S. Kumar, R. Vanjari, T. Guntreddi, K. Nand Singh,
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.
6
[
2
RSC Adv. 2015, 5, 9920.
[
[
[
18] M. Kaushik, A. Singh, M. Kumar, Eur. J. Chem. 2012, 3, 367.
How to cite this article: Mozaffari M, Nowrouzi
19] B. Y.‐H. Tan, Y.‐C. Teo, Org. Biomol. Chem. 2014, 12, 7478.
N, Abbasi M. The use of Cr (CO) as an alternative
20] S.‐K. Xiang, J.‐M. Li, H. Huang, C. Feng, H.‐L. Ni, X.‐Z. Chen,
B.‐Q. Wang, K.‐Q. Zhao, P. Hu, C. Redshaw, Adv. Synth. Catal.
6
CO source in Pd‐catalyzed C‐N bond formation:
Synthesis of benzamides. Appl Organometal Chem.
2019;e5049. https://doi.org/10.1002/aoc.5049
2
015, 357, 3435.
[
21] A. Nain‐Perez, L. C. A. Barbosa, C. R. A. Maltha, G. Forlani,
J. Nat. Prod. 2017, 80, 813.