One pot direct synthesis of β-ketoesters via carbonylation of aryl halides using cobalt carbonyl

Article abstract of DOI:10.1016/j.tetlet.2014.04.087

A direct method for the synthesis of β-ketoesters from aryl halides (iodide, bromide) has been described by using cobalt carbonyl as carbon monoxide source in microwave irradiation. Using this protocol, a wide variety of substituted aryl halides has been successfully converted to corresponding β-ketoesters.

Full text of DOI:10.1016/j.tetlet.2014.04.087

Accepted Manuscript
One pot direct synthesis of β-ketoesters via carbonylation of aryl halides using
cobalt carbonyl
Poongavanam Baburajan, Kuppanagounder P. Elango
PII:
S0040-4039(14)00712-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.087
TETL 44549
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 January 2014
23 April 2014
23 April 2014
Please cite this article as: Baburajan, P., Elango, K.P., One pot direct synthesis of β-ketoesters via carbonylation of
aryl halides using cobalt carbonyl, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.04.087
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1
One pot direct synthesis of β-ketoesters via carbonylation of aryl halides
using cobalt carbonyl
Poongavanam Baburajan and Kuppanagounder P. Elango*
Department of Chemistry, Gandhigram Rural Institute (Deemed University),
Gandhigram 624302, India
E-mail: drkpelango@rediffmail.com
Abstract
A direct method for the synthesis of β-ketoesters from aryl halides (iodide, bromide) has been
described by using cobalt carbonyl as carbon monoxide source in microwave irradiation. Using this protocol, a
wide variety of substituted aryl halides has been successfully converted to corresponding β-ketoesters.
Key words: Aryl halides, Carbonylation, β-ketoesters, Imidazole, Co2(CO)8
Over the years, transition metal catalyzed cross-coupling reactions have emerged as a valuable method
for making carbon-carbon bonds. In these reactions, palladium mediated carbonylative cross coupling of aryl
halides with a variety of nucleophiles offered compounds which are important building blocks in the field of
pharmaceutical and natural products. Ever since, Heck reported the first successful carbonylative method in
1974, many synthetic protocols using carbon monoxide gas in such reactions are known in literature.1 Later,
metal carbonyls have also been reported as an alternate source for CO(g).2 During the past decade, apart from
esters and amides, a variety of carbon nucleophiles have also been employed in carbonylative cross-coupling
reactions of aryl halides such as Heck,3 Sonagashira,4 C-H activation,5 Suzuki,6 Stille7 and Negishi8 type coupling
reactions.
In organic synthesis, reagents containing variety of functionalities play very important role as they can
be used as versatile and effective source for the preparation of complex structures from relatively simple starting
materials. In particular, β-ketoesters are used as significant building blocks in natural product chemistry for
making a variety of complex structures and biologically active heterocyclic molecules. To synthesize β-
ketoesters, a number of approaches have been documented, through the formation of either one of the following
different bonds in Figure 1.

2
O1
C1
O2
C3
R3
R1
C2
R2
O3
Figure 1. General formula of β-ketoesters
Frequently, they were synthesized by the formation of C1-C2 and C2-C3 bonds by using aliphatic
/aromatic acid derivatives and unsymmetrical ketones, respectively.9 Methods involving C-alkylation at C2 have
also been reported.10 A three-component alkoxycarbonylation (C2-C3-O3) of α-halo ketones with CO(g) and
alcohol nucleophiles have been found to afford β-ketoesters.11 However, synthesis of β-ketoesters by making R1-
C1bond is relatively difficult and less studied.
Review of literature revealed that in 1986 Tanaka and Kobayashi have documented for the synthesis of
β-ketoesters directly from aryl iodides by intermolecular carbonylative arylation method in the presence of large
excess of carbon monoxide gas (20 atm).12 However, the yields of the reactions are not stabilized and it covered
only four substrates. Torii and co-workers have reported the preparation of cyclic β-ketoesters through
intramolecular carbonylative Heck coupling using large excess of CO gas.13 Very recently, Korsager et al. have
developed a method for the synthesis of β-ketoesters from aryl halides using ex situ CO(g) and acids (acetic acid
or formic acid).14 However, special reaction set-ups and a palladium source are required to generate CO gas for
the reaction. All these reported methodologies involve the use of external CO source. Herein, we report an
effective method for the synthesis of β-ketoesters by using cobalt carbonyl as an in situ CO source in microwave
irradiation.
In the present work, we have demonstrated an effective reaction protocol for the synthesis of β-
ketoesters directly from aryl halides (bromides and iodides) using Co2(CO)8 as the carbonyl source under
microwave irradiation. To the best of our knowledge this is the first systematic attempt to synthesize β-
ketoesters directly from aryl halides in good yields in the absence of external CO gas. The carbonylation of aryl
halides-, to yield β-ketoesters-, has been carried out using potassium monoethylmalonate as carbon nucleophile
in the presence of Pd(OAc)2/xantphos and Co2(CO)8 (0.3 eqv.) under microwave irradiation. To optimize the
reaction conditions, carbonylation of 4-bromotoluene has been carried out in the presence of different bases and
solvents, Pd(OAc)2/Xantphos, and the chosen cobalt carbonyl. Of all the bases tried, MgCl2 (2 eqv.)/TEA
system showed the formation of the desired product (Entry 1, Table 1). The reaction performed with different

3
solvents (Entry 2-5) showed that THF was the best solvent for the reaction. Further change in any of the other
parameters gave no improvement in yields.
Table 1. Screening reaction conditions
KO
O
O
O
O
O
O
2
Br
Pd(OAc)2, Xantphos
O
R
Base, Additive,
Co2(CO)8, M/W
1a
R- additive
3a
1
Entry
Solvent
Base
Additive
Yield (%)a
R
-
1a
3
1
2
DMF
DMSO
Toluene
Dioxane
THF
MgCl2/TEA
MgCl2/TEA
MgCl2/TEA
MgCl2/TEA
MgCl2/TEA
MgCl2/TEA
MgCl2/TEA
MgCl2/TEA
MgCl2/TEA
MgCl2/TEA
-
-
10
-
-
-
-
-
3
-
4
-
-
-
5
-
-
31
5
6
THF
PhONa
W. amine
Map amine
Imidazole
Bt
88
74
69
-
7
THF
-
8
THF
-
9
THF
68
38
-
10
11
12b
13
THF
8
THF
Imidazole
Imidazole
Imidazole
-
THF
MgCl2/TEA
MgCl2/TEA
-
-
THF
-
89
All the reaction were executed with 0.5 mmol of 4-bromotoluene,
5 mol% of Pd(OAc)2, 5 mol% of xantphos (4,5-
bis(diphenylphosphanyl)-9,9-dimethylxanthene) and 0.15 mmol Co2(CO)8 90 °C under microwave irradiation for 30 min. Bt
;
=
a
Benzotriazole, W. amine = N,O-Dimethylhydroxylaminehydrochloride, Map amine = Methyl-pyridin-2-yl-amine. Isolated yields;
b
Reaction performed without the addition of cobalt carbonyl.
Recently, Buchwald et al. have established that the less reactive aryl chlorides can effectively be converted to
corresponding amides through aminocarbonylation by adding sodium phenoxide as an additive.15 In line with
the above in the present study the carbonylation has also been carried out in the presence of different additives
(Entry 6-10). The results indicated that addition of sodium phenoxide, Weinreb amine and Map amine yielded
corresponding acyl derivatives (1a) as major product. To our delight, in the presence of imidazole (Entry 9,
Table 1), a moderate yield of the desired β-ketoester was obtained. Also, the results indicated that in the absence
of either MgCl2/TEA or Co2(CO)8 there is no product formation (Entry 11-12). After fine tuning the reaction
conditions, we observed that an excellent yield of the desired product was obtained in the presence of 2
equivalents of imidazole (Entry 13). Hence, this has been employed as the optimum condition for further study.

4
Table 2. Screening of different palladium catalytic systems
KO
O
O
O
O
O
2
Br
Pd/L, MgCl2, Et3N
O
Imidazole, Co2CO8
90 °C, 30 min, M/W
3b
1b
Entry Pd (5 mol %)
Ligand
Yield
(5 mol %) (%)a
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Xantphos 85
2
-
-
3
dppf
dppp
PPh3
17
-
4
5
6
6
Xantphos 28
Xantphos 22
7
Pd(ACN)2Cl2
Pd(PPh3)4
Pd(PPh3)2Cl2
Pd(dppf)2Cl2
Pd(PPh3)4
8
Xantphos
-
9
Xantphos 36
Xantphos 10
10
11
Xantphos
-
All the reaction were executed with 0.5 mmol of bromobenzene, 0.75 mmol of MgCl2, 1.5 mmol of Et3N, 0.22 mmol of Co2(CO)8, 1
mmol of imidazole in THF at 90 °C under microwave irradiation for 30 min. a Isolated yields.
The optimization of the catalytic system employed in the study has been carried out with different Pd
sources and ligands and the results obtained are shown in Table 2. The results indicated that the
Pd(OAc)2/xantphos catalytic system was found to be the most successful system in the conversion of bromo
benzene to the corresponding β-ketoester (Table 2, Entry 1). Once the optimized reaction conditions were
identified, the title reaction has been carried out with different aryl halides (bromides and iodides). The products
obtained with isolated yields are shown in Scheme 1. The results indicated that both aryl bromides and aryl
iodides gave good to excellent yields (55-92%) of the products (3a-3w). When compared to the substrates with
electron withdrawing substituents, those with electron releasing substituents gave relatively better yields.
Chemo selectivity was observed in the case of substrates with fluoro (1d), fluoro/chloro (1k). In the case of 4-
chloro-1-iodobenzene (3e), the chloro was also coupled to monoethyl potassium malonate to some extent. Hetro
aryl halides (3s-w) also gave good yields.

5
Scheme 1. The synthesis of β-ketoesters from different substituted aryl and heteroaryl halides (I, Br).
KO
OEt
2
O
O
O
O
Pd(OAc)2, Xantphos
Ar
1(a - w)
X
Ar
OEt
Imidazole, MgCl2/Et3N
Co2(CO)8, M/W, 90 °C,
30 min
3(a - w)
X = Br, I
Ar = aryl, heteroaryl
Yield (%)a
Entry
Ar
X
3 (3a - w)
1
4-MeC6H4
Br/I
Br/I
Br/I
Br/I
Br
89/77
85/82
92/89
70/62
74
2
C6H5
3
4-OMeC6H4
4-FC6H4
4
5
4-ClC6H4
6
Br/I
Br
90/87
84
4-tBuC6H4
7
4-CF3C6H4
8
Br/I
Br/I
Br/I
Br
70/82
90/88
66/73
81
3-OMeC6H4
4-PhC6H4
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
3-MeC6H4
3-Cl-5-FC6H3
3,5-di-OMeC6H3
3,5-di-FC6H3
3-CNC6H4
Br
56
Br
68
Br
60
Br
77
3,5-di-MeC6H3
3-COPhC6H4
4-COOEtC6H4
3,5-di-CF3C6H3
Pyridine-3-yl
Thiophen-3-yl
6-F-Pyridin-3-yl
2-dibenzothiophene
2-dibenzofuran
Br
70
Br/I
Br
55/74
89
Br
71
Br
86
Br
66
Br
75
Br
69
a Isolated yield(s) of product from corresponding Br/I aryl and heteroaryl halides.

6
With an aim to examine the CO source used in the carbonylation of aryl halides the reaction has been
carried out by varying the available metal carbonyl compounds. The results obtained are collected in Table 3
(Entry 1-6). It is evident from the results that Co2(CO)8 was observed to be the effective carbonyl source in the
reaction with an observed yield of 85% of the desired β-ketoester (Table 3, Entry 1). The 57% yield was
observed, when the reaction is carried out with external CO(g) at 1 atm pressure in autoclave reactor (Table 3,
Entry 5). Also, the reaction was found to yield significant amount of the desired product when carried out under
traditional thermal heating condition (Table 3, Entry 6).
Table 3. Experiments on other CO sources
KO
O
O
O
2
O
O
Pd(OAc)2/Xantphos,
Imidazole, MgCl2, Et3
Br
N
O
CO source,
90 °C, 30 min, M/W
O
O
1c
3c
Entry
Carbonyl
source
Temp
(°C)
90
Yield(%)a
b
1
2
Co2(CO)8
85
20
44
-
c
Cr(CO)6
90
c
3
Mo(CO)6
90
90
80
90
c
4
W(CO)6
d
5
COg
57
64
6e
Co2(CO)8
b
a Isolated yield, b 0.3 eqv. of cobalt carbonyl per eqv. of aryl halide, c 0.5 eqv. of Cr, Mo, W- metal carbonyls per eqv. of aryl
halide, d The reaction was executed in autoclave equipment at 1 atm pressure for 14 h. e Reaction executed in traditional thermal heating
condition.
Based on the foregoing results and discussion the following mechanism has been tentatively proposed for the
carbonylation of aryl halides (Figure 2). The transformation of I to IV is well established and documented in
literature.16 The conversion of IV to V is supported by the observation that the added imidazole significantly
increased the yield of the product. This is further supported by the fact that, the reaction of VII with V to yield
the corresponding β-ketoester is known in literature.17

7
ArX
O
Ac
O
Ar
PdII
X
VIII
OEt
L
Pd0
I
II
L
Co2(CO)8
CO2
CO
NEt3.HX
Imidazole
Ar
PdII
L
CO
Mg
III
O
X
Ar
O
O
N
V
OEt
O
N
O
L
PdII
C
VII
O
X
Ar
Imidazole, NEt3N
IV
MgCl2/TEA
EtOOCCH2COOK
VI
Figure 2. Plausible reaction mechanism
In summary, we have demonstrated the synthesis of β-ketoesters directly from aryl and heteroaryl
halides using cobalt carbonyl as an in situ carbon monoxide source.18 This reaction is mainly useful for
laboratory scale synthesis of β-ketoesters as we did not observe high pressure (<1 bar observed) formation
during the course of microwave irradiation, hence safe. Further, the proposed methodology was found to work
well with both arylbromide and aryl iodides possessing electron releasing and withdrawing substituents without
the use of external CO gas.
Supporting Information Supplementary data (synthesized compounds) associated with this article can be
found, in the online version, at http://
References and notes
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8
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18. General procedure for the synthesis of β-ketoesters of aryl halides (I, Br). To a stirred mixture of aryl or
heteroaryl halide (Br, I) (0.5 mmol), potassium mono ethyl malonate (0.75 mmol) in THF (10 mL) taken in a 30
mL microwave vial, was added Pd(OAc)2 (5 mol%), xantphos (5 mol %), MgCl2 (0.75), Et3N ( 0.75 mmol),
imidazole (1 mmol) followed by Co2(CO)8 (0.15 mmol). The vial was sealed immediately and microwave
irradiated at 90 °C for 30 min. The reaction mixture was concentrated and diluted with ethyl acetate and water.
The ethyl acetate layer was separated, dried over sodium sulphate and concentrated. The crude product obtained
was purified by column chromatography (60-120 mesh silica gel; 0-25% v/v ethyl acetate in hexane) to get the
pure compound.
All the compounds (3a-w) in Scheme 1 were prepared by adopting the same procedure using the
corresponding aryl halides (Br, I). The products were characterized using 1H and 13C NMR spectral techniques
1
(see supporting information) and LCMS or UPLC mass spectrometry. The spectra results of H NMR & 13C
NMR studies indicated the existence of most of the products in keto-enol tatuomeric form wherein keto form is
present in excess.

10
Highlights
* Direct one pot synthesis of β-ketoesters from wide variety of aryl halides.
* Cobalt carbonyl as an in situ CO source in microwave irradiation without CO gas.
* This is one of very few methods of making β-ketoesters in good yields.

11
Graphical Abstract
----------------------------------------------------------------------------------------------------------------
-----
One pot direct synthesis of β-ketoesters via carbonylation of aryl halides using Cobalt
carbonyl
Poongavanam Baburajan and Kuppanagounder P. Elango*
KO
OEt
2
O
O
O
O
X
OEt
Pd(OAc)2, Xantphos
R
R
Imidazole, MgCl2/Et3N
Co2(CO)8, M/W, 90 °C,
30 min
1(a - r)
3(a - w)
X= Br, I
----------------------------------------------------------------------------------------------------------------
-----