Co2(CO)8 as a convenient in situ CO source for the direct synthesis of benzamides from aryl halides (Br/I) via aminocarbonylation

Article abstract of DOI:10.1016/j.tetlet.2013.12.062

A fast, mild, and functional group tolerant method for the direct synthesis of benzamides from aryl halides (Br, I) via aminocarbonylation, using solid Co₂(CO)₈ as a convenient CO source, has been demonstrated. The developed method is applicable to a wide variety of 1° and cyclic and acyclic 2°amines. Nitro substituted (o, m and p) aryl halides have easily been converted to the corresponding benzamides, without the reduction of the nitro group, in high yields using this in situ carbonylation methodology under microwave irradiation.

Full text of DOI:10.1016/j.tetlet.2013.12.062

Tetrahedron Letters 55 (2014) 1006–1010
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Tetrahedron Letters
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Co2(CO)8 as a convenient in situ CO source for the direct synthesis
of benzamides from aryl halides (Br/I) via aminocarbonylation
⇑
Poongavanam Baburajan, Kuppanagounder P. Elango
Department of Chemistry, Gandhigram Rural Institute (Deemed University), Gandhigram 624302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A fast, mild, and functional group tolerant method for the direct synthesis of benzamides from aryl
halides (Br, I) via aminocarbonylation, using solid Co2(CO)8 as a convenient CO source, has been demon-
strated. The developed method is applicable to a wide variety of 1° and cyclic and acyclic 2° amines. Nitro
substituted (o, m and p) aryl halides have easily been converted to the corresponding benzamides,
without the reduction of the nitro group, in high yields using this in situ carbonylation methodology
under microwave irradiation.
Received 29 October 2013
Revised 13 December 2013
Accepted 17 December 2013
Available online 21 December 2013
Keywords:
Ó 2013 Elsevier Ltd. All rights reserved.
Benzamide
Aryl halide
Carbonylation
Microwave
The aromatic carbonyl derivatives namely esters and amides
are important building blocks in the synthesis of valuable organic
compounds including pharmaceuticals and agrochemicals.1 In car-
bonyl derivatives, the benzamide derivatives possess important
biological activities. Several methods have been published for the
synthesis of benzamides.2 Also, a variety of carbonyl derivatives
have been synthesized by atom economy and functional group tol-
erant methods using easily available starting materials based on
the palladium catalyzed carbonylation developed by Heck3 in
1970s through the three-component coupling reaction using
CO(g), aryl halides and a nucleophile (OÀ, NÀ, CÀ). Such carbonyl-
ation methods, using CO gas, is based on the excellent ability of
CO to act as pi-acid ligand toward transition metals.4 However,
CO is a highly toxic and flammable gas. Also, these reactions re-
quire special pressure reaction setups, and these methods are
inconvenient in laboratory (small scale) and library (analogous)
syntheses. To overcome this inconvenience to some extent, in
2002 Mats and coworkers have developed an in situ carbonylation
method using non-gaseous CO precursors (transition metal
carbonyls) employing a fast and furious microwave instrument.
Subsequently, many reports have been published based on this
methodology.5 Although, they are able to overcome the inconve-
nience to some extent, using this methodology, higher tempera-
tures (>120 °C) and/or higher equivalence of CO source are
required to get good yields. Recently, a new ex situ method of gen-
eration of CO from Mo(CO)6 using a bridged two-vial system has
Table 1
Condition optimization of aminocarbonylation
HN
2
O
O
Br
Pd(OAc)2/Xantphos
base, Co2(CO)8, 90°C,
M/W, 20 min
N
O
3
1
Entry Carbonyl
source
Base
Solventa Temp
(°C)
Time
(min)
Yieldb
(%)
c
c
c
c
c
c
c
c
1
2
3
4
5
6
7
8
9
Co2(CO)8
Co2(CO)8
Co2(CO)8
Co2(CO)8
Co2(CO)8
Co2(CO)8
Co2(CO)8
Co2(CO)8
DMAP Toluene 90
30
30
30
30
30
30
20
15
30
30
30
30
81
70
77
69
64
91
92
88
72
35
30
69
DMAP DMSO
DMAP DMF
DMAP DME
DMAP THF
DMAP Dioxane 90
DMAP Dioxane 90
DMAP Dioxane 90
DMAP Dioxane 90
DMAP Dioxane 90
DMAP Dioxane 90
DMAP Dioxane 90
90
90
90
90
d
Mo(CO)6
d
10
11
12
Cr(CO)6
d
W(CO)6
e
Co2(CO)8
All the reactions were executed with 0.5 mmol of 4-bromotoluene, 5 mol % of
Pd(OAc)2, 5 mol % of ligand (4,5-bis(diphenylphosphanyl)-9,9-dimethylxanthene),
1 mmol of morpholine and 0.25 mmol of Co2(CO)8 at microwave irradiation.
a
All the solvents were freshly distilled and used.
Yield of the isolated product by column chromatography.
0.25 equiv of Co2(CO)8 were used.
0.5 equiv of metal carbonyls (Mo, Cr, W) were used.
b
c
d
e
The reaction was performed with oil bath heating at 90 °C for 1 h.
⇑
Corresponding author. Tel.: +91 451 2452371; fax: +91 451 2454466.
E-mail address: drkpelango@rediffmail.com (K.P. Elango).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.12.062

P. Baburajan, K. P. Elango / Tetrahedron Letters 55 (2014) 1006–1010
1007
Table 2
Synthesis of morpholine amides of aryl halides
HN
O
O
2
Br, I
Pd(OAc)2, Xantphos
N
O
DMAP, Co2(CO)8, dioxane
90 °C MW, 20 min
R
R
3a-3k
1a-1k
Arylhalide
(1a-k)
Entry
Product
(3a-k)
Yields
(%)a
Co2(CO)8
(eqv.)
O
O
O
X
N
N
N
X=Br, 91
X=I, 88
1
0.25
0.25
O
O
O
X
X=Br, 89
X=I, 93
2
3
X
X=Br, 95
X=I, 83
0.25
0.30
0.25
O
O
O
O
Br
N
N
82
O
O
4
5
X
X=Br, 92
X=I, 84
Cl
Cl
O
O
Br
N
93
6
0.25
0.25
O
O
O
X
N
X=Br, 90
X=I, 86
7
8
O
EtOOC
O
EtOOC
O
O
O
O
Br
N
N
N
0.30
0.25
82
O
O
O
Ph
Ph
Br
Br
X=Br, 87
X=I, 91
9
Ph
Ph
75
80
10
11
0.30
0.30
N
N
O
Br
N
O
O
O
S
S
O
O
a
Yield of isolated product.
been reported for the carbonylation of nitro substituted aryl
halides.6 The major advantage of this method (i.e., carbonylation
of nitro substituted aryl halides without affecting the nitro group)
is based on the fact that the reduction of nitro group to aniline by
Mo(CO)6 is known in the literature.7 Recently, we have described
the synthesis of esters directly from aryl halides by using Co2(CO)8
as a simple and successful in situ CO source.8 In continuation of
this work, herein we report a simple and convenient protocol for
the synthesis of benzamides in excellent yields through
aminocarbonylation of different aryl halides including nitro substi-
tuted ones at low temperatures and at lower equivalents of CO
source.
chosen as model substrates using microwave irradiation. As in
the previous case, Pd(OAc)2/xantphos in the presence of DMAP
base was found to be the effective catalytic system in the present
reaction also. The effect of various reaction conditions such as sol-
vent, transition metal carbonyl, reaction time and equivalence of
metal carbonyl on the isolated yield of the product is shown in
Table 1.
The results given in Table 1 indicate that, among the various
solvents investigated, 1,4-dioxane (Entry 4) was found to be the
best solvent. Further, based on the reaction time variation studies
(Entries 6–8), 20 min was fixed as the optimum time as the
reaction gets completed within this period with excellent yields
(Entry 7). With these stabilized reaction conditions (Entry 7),
we have carried out the CO source variation study (Entries
9–11). The results showed that molybdenum hexacarbonyl (Entry
9) gave good yields (72%) and the rest of the metal carbonyls
As part of our on-going work on carbonylation reactions using
Co2(CO)8 as CO source, in this Letter we report a convenient meth-
od of amino carbonylation of aryl halides. With an aim to optimize
the reaction conditions, 4-bromotoluene and morpholine were

1008
P. Baburajan, K. P. Elango / Tetrahedron Letters 55 (2014) 1006–1010
Table 3
Aminocarbonylation of nitro substituted aryl halides
HN
O
O
Br, I
Pd(OAc)2, Xantphos
N
O
DMAP, Co2(CO)8, dioxane
O2N
O2N
90 °C MW, 20 min
Arylhalides
Co2(CO)8
(eqv.)
Product
(3l-o)
Yields
(%)a
Entry
(1l-o)
O
X
X
N
X=Br, 8
X=I, 90
0 25
0 25
1
O
O2N
O2N
O2N
O2N
O
N
X=Br, 81
X=I, 87
2
3
O
NO2
NO2
O
O
Br
N
N
76
71
0.30
0 25
O
O
O
O
N
N
Br
4
O2N
O N
All the reactions were executed with 0.5 mmol of aryl halide, 1 mmol of morpholine, 5 mol % of
Pd(OAc)2, 5 mol % of xantphos (4,5-bis(diphenylphosphanyl)-9,9-dimethylxanthene) at microwave
irradiation at 90 °C for 20 min.
a
Yield of isolated product.
result poor yields (<35%). Thus, Co2(CO)8 was found to be the rel-
atively best in situ CO source for the aminocarbonylation of aryl
halides at lower temperatures in microwave irradiation. The reac-
tion was also carried out with the traditional heating method (oil
bath heating) at 90 °C (Entry 12) and the isolated yield is slightly
lower than the microwave heating condition. In general,
0.25 equiv of Co2(CO)8 was used in the reaction. However,
0.3 equiv of it was also employed, as and when required, for com-
pletion of the reaction. With the defined protocol (Entry 7) in
hand, the substrate scope with a wide variety of aryl halides (I,
Br) was explored. As can be seen from Table 2, good to excellent
yields of the morpholine amides were obtained from aryl halides
possessing variety of substituents with the substituents remain
unaffected. The hetero arylhalide (Entry 10) also gave good yields
of the corresponding amide.
More importantly, in the case of nitro substituted aryl ha-
lides (Table 3), the carbonylation occurred successfully in good
yields without reducing the nitro group to amine. This is be-
cause, as mentioned earlier, Mo(CO)6 has been reported as a re-
agent in the reduction of nitro group to amine.7 Also, it is
known that the S–O bond in sulfones can be reductively
cleaved by Mo(CO)6.9 In the present study, sulfone substituted
aryl halide (Table 2, Entry 11) has also been converted to cor-
responding amide without affecting the sulfone moiety. Hence,
using the present protocol, the nitro and sulfone substituted
aryl halides can easily be aminocarbonylated to the correspond-
ing benzamides.
excellent with these chosen nucleophiles. In the case of 4-
methoxy benzamide (4a) (Entry 1), among the three different
amine sources used, 0.5 M ammonia in dioxane gave excellent
yields.
The pressure of the reaction container at varying initial concen-
trations of the aryl halides (1, 2.5, and 5 mmol) and Co2(CO)8 (in
1:0.25 equiv ratio) in 30 ml MW vial was monitored. The observed
pressure values are given in Figure 1. When the reaction was per-
formed with 1 mmol of aryl halide, no pressure was observed. In
the case of 2.5 mmol of aryl halide, the pressure was increased
up to 1.5 bar and found to decrease slowly (ꢀ1 bar) during the
course of the reaction (Fig. 1, P1). Whereas in the case of 5 mmol
of aryl halide, the pressure increased up to 2.5 bar and then gets
decreased slowly to ꢀ1.5 bar (Fig. 1, P2). As there is not much in-
crease in pressure observed during the course of the reaction, it is
safe to carry out the reaction in MW under the proposed
conditions.
To conclude, we have demonstrated a simple and convenient
one pot method of making benzamides directly from aryl ha-
lides using Co2(CO)8 as an in situ carbonyl source at low tem-
peratures. This protocol is mainly useful in laboratory scale
reactions and Library synthesis (automated platform) in medic-
inal chemistry field. One of the significances of the proposed
protocol is that nitro substituted aryl halides can also be con-
verted into corresponding benzamides without affecting the ni-
tro group.
In addition to the synthesis of morpholine amides discussed
above, the proposed protocol was found to work extremely well
to produce other amides by using a variety of amine nucleo-
philes (1° and 2° Cyclic/acyclic amines). The yields thus
obtained are shown in Table 4. The results indicated that the
yields of the corresponding amides were found to be good to
Supplementary data
Supplementary data (The experimental section and 1H & 13C
NMR spectra of the compounds are provided) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2013.12.062.

P. Baburajan, K. P. Elango / Tetrahedron Letters 55 (2014) 1006–1010
1009
Table 4
Synthesis of amides by using different amines
O
R1R2NH,
Pd(OAc)2, Xantphos
R1
Br, I
N
R2
MeO
MeO
DMAP, Co2(CO)8, Dioxane
90 °C, MW, 20 min
4a-j
Yield
(%)b
Co2(CO)8
(eqv.)
R1R2NHa
Product
(4a-j)
Entry
O
O
62c/70d/86e
NH2
NH3
NH2
1
2
0.25
MeO
N
H
90
0.25
0.25
MeO
MeO
MeO
O
O
N
H
3
94
79
NH2
N
H
0.25
NH2
4
5
O
N
H
92
NH2
0.25
0.25
MeO
O
O
O
O
O
N
H
81
70
82
NH2
6
7
8
MeO
MeO
MeO
MeO
MeO
N
H
NH2
0.30
0.25
0.30
N
H
NH2
H
N
N
90
91
N
9
HN
10
0.25
All the reactions were executed with 1 mmol of aryl halide, 5 mol % of Pd(OAc)2, 5 mol % of xantphos (4,5-
bis(diphenylphosphino)-9,9-dimethylxanthene) and 0.25 mmol of Co2CO8 at microwave irradiation at
90 °C for 20 min.
a
2 equiv of amines was used.
Yield of isolated products.
b
c
Isolated yield when ammonia hydroxide solution (ꢀ25% in water) used as amine source.
d
Isolated yield when ammonia solution (2.0 M in ethanol) used as amine source.
e
Isolated yield when ammonia solution (0.5 M in dioxane) used as amine source.
References and notes
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