Reductive carbonylation of aryl and heteroaryl iodides using Pd(acac) 2/dppm as an efficient catalyst

Article abstract of DOI:10.1016/j.tetlet.2011.02.097

Palladium catalyzed simple and efficient protocol for reductive carbonylation of aryl and heteroaryl compounds has been developed. The formylation of aryl and heteroaryl iodides takes place in the presence of Pd(acac)₂/dppm catalyst at 10 bar pressure of synthetic gas to give the desired aromatic and heteroaromatic aldehydes in good to excellent yields. Easy work-up, stability of the catalyst, low catalyst loading and less reaction time are the advantages of this method.

Full text of DOI:10.1016/j.tetlet.2011.02.097

Tetrahedron Letters 52 (2011) 2383–2386
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reductive carbonylation of aryl and heteroaryl iodides using Pd(acac) /dppm
2
as an efficient catalyst
⇑
Abhilash S. Singh, Bhalchandra M. Bhanage, Jayashree M. Nagarkar
Department of Chemistry, Institute of Chemical Technology (Deemed), N. M. Parekh Marg, Matunga, Mumbai 400 019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Palladium catalyzed simple and efficient protocol for reductive carbonylation of aryl and heteroaryl com-
pounds has been developed. The formylation of aryl and heteroaryl iodides takes place in the presence of
Pd(acac) /dppm catalyst at 10 bar pressure of synthetic gas to give the desired aromatic and heteroaro-
2
matic aldehydes in good to excellent yields. Easy work-up, stability of the catalyst, low catalyst loading
and less reaction time are the advantages of this method.
Received 8 January 2011
Revised 18 February 2011
Accepted 22 February 2011
Available online 26 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Formylation
Pd(acac)
Dppm
2
Aryl(heteroaryl) iodides
Homogeneous catalysis
Aromatic and heteroaromatic aldehydes are key intermediates
in pharmaceuticals, pesticides, perfumery, and dyestuff industries.
The presence of highly active formyl group makes aldehyde an
important substrate for C–C, C–N, C–S coupling, and for other or-
ganic transformation reactions. It has a major application in the
synthesis of Schiff bases which are useful in antifungal, antimicro-
bial, antibacterial, antitubercular, and anticancer applications. In
addition it also possesses herbicidal properties. The direct method
for synthesis of aromatic aldehyde includes Gattermann–Koch,
Gattermann reaction, Reimer–Tiemann, Duff and Vilsmeier reac-
tions where as indirect method includes oxidation and reduction
hydride by PMHS poly(methylhydroxysilane) as reducing agent.5
The use of formate salt as reducing agent is also being employed
for palladium catalyzed reductive carbonylation. Hitherto the
6
use of formate salt is considered to be the most reliable method
for reductive carbonylation. But these reactions are generally
accompanied by reductive dehalogenation and require high cata-
lyst loading. The use of CO gas is replaced by acetic formic anhy-
dride as formyl source in the presence of palladium catalyst by
7
Cacchi et al. But the described formylating agent is unstable at
room temperature. The comprehensive study on formylation
3
was shown by Barnard and co-workers using Et SiH as reducing
1
8
process, which suffers from drawbacks like very low yield, poor
agent in presence of palladium catalyst and CO gas (3 bar). Bel-
ler and co-workers have developed a selective catalytic method
for the reductive carbonylation of aromatic, heteroaromatic and
selectivity and harsh reaction conditions. They also require envi-
ronmentally disagreeable reagents and generate excess amount
of waste.
vinylic bromide substrates using synthetic gas (CO/H
2
1:1)
The catalytic method involves use of carbon monoxide as a
carbonyl source which is an easily available carbonylating agent.
The palladium chemistry is well explored for coupling and other
organic synthetic reactions.2 The first palladium catalyzed syn-
thesis of aromatic, heteroaromatic and vinylic aldehydes was
effectively achieved by Heck.3 However, the method required
high pressure (80–100 bar), temperature (125–150 °C) and high
catalyst loading. The method was further simplified by Stille
and co-workers by using tin hydride as reducing agent at low
pressure of CO (1 bar).4 Pri-Bar and Buchman replaced metal
(5 bar), di-1-adamantyl-n-butylphosphine (CataCXium) as ligand
and Pd(OAc) as palladium source. This was the first industrially
2
applied, simple, and economically feasible method for the pro-
duction of aromatic aldehydes on ton scale by using synthetic
2
gas (CO/H 1:1).
Despite the potential utility of the described method by Beller
and co-workers using synthetic gas at low pressure it suffers from
the limitation of high cost of the catalyst. Herein we report a new
protocol for reductive carbonylations of aryl and hetero aryl io-
dides by using simple, low cost, and environmentally benign Pd(a-
9
2
cac) /dppm as a catalyst.
The reaction of iodobenzene with synthetic gas (CO/H
the presence of palladium source and phosphine ligand was chosen
as a model reaction.
2
1:1) in
⇑
Corresponding author. Tel.: +91 22 33611111/2222; fax: +91 22 33611020.
E-mail addresses: jm.nagarkar@ictmumbai.edu.in, jayashreenagarkar@yahoo.-
co.in (J.M. Nagarkar).
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.097

2
384
A. S. Singh et al. / Tetrahedron Letters 52 (2011) 2383–2386
Pd(TMHD)
2% and 20% yields, respectively. Further different ligands were
screened and it was observed that reaction of catalyst formed
in situ via interaction of Pd(acac) with 1,1-bis(diphenylphos-
2 2
and Pd(acac) were able to catalyze the reaction with
1
P
P
P
P
2
phino)methane dppm gave excellent result with 93% yield (Table 1,
entry 7). Monodentate phosphines like triarylphosphines (TPP) and
tributylphosphine (TBP) were less effective in promoting the
reaction towards product formation of desired aldehyde (Table 1,
entries 8 and 9). Other bidentatephosphine ligands such as 1,2-
L
1
L
2
L
3
Ph
P
P Ph
P Ph
Ph
bis(diphenylphosphino)ethane
phino)butane (dppb) failed in complete conversion of iodobenzene
Table 1, entries 10 and 11). The results obtained with 2,2-
(dppe),
1,4-bis(diphenylphos-
P
P
P
(
bis(diphenylphosphino)-1,1-binapthyl(BINAP) and bis(diphenyl-
phosphino)ferrocene (dppf) were also not encouraging (Table 1,
entries 12 and 13). We observed that the reductive dehalogenation
takes place in the reaction where benzene is formed as s by-prod-
uct of the model reaction (Fig. 1).
The influence of the different organic and inorganic bases on the
reductive carbonylation of iodobenzene was also studied. The inor-
2 3 2 3
ganic bases like Cs CO and K CO gave poor yield of the product
due to low solubility in organic solvent (Table 2, entries 1 and 2).
Among the nitrogen containing various organic bases such as
DBU (1,8-diazabicycloundec-7-ene), morpholine, triethylamine,
and tetramethylethylenediamine (TMEDA), it was found that TME-
DA is the best suited base for the model reaction (Table 2, entries
L
4
L
5
L
6
Ligands abbreviation:
= 1,1-Bis(diphenylphosphino)methane
DPPM)
= Triphenylphosphine (TPP)
= Tributylphosphine (TBP)
L
1
2
(
P
L
L
Fe
3
P
L
4
= 1,2-Bis(diphenylphosphino)ethane
(
DPPE)
= 1,4-Bis(diphenylphosphino)butane
DPPB)
= 2,2,-Bis(diphenylphosphino)-1,1-
binapthyl (BINAP)
L
5
(
L
7
L
6
3
–6). Among the different solvents studied, the complete conver-
sion of iodobenzene to benzaldehyde took place in presence of tol-
uene as a solvent (Table 2, entry 6). Other protic and aprotic
solvents such as DMF, DMSO, ACN, and THF failed to catalyze the
formylation reaction of the iodobenzene to benzaldehyde. The
reaction proceeded smoothly in 1,4-dioxane as a solvent, however,
due to easy availability and low cost of the solvent we preferred
toluene as the best suited solvent for carrying out further reactions
of the substrate under similar conditions.
L
7
= Bis(diphenylphosphino)ferrocene
(DPPF)
Figure 1. Various phosphine ligands used for model reaction.
Initially our attempt to catalyze the reaction using heteroge-
neous catalyst like Pd/C or Pd-NHC (palladium N-heterocyclic car-
bene) failed as the reaction is accompanied by reductive
dehalogenation leading to the formation of benzene (Table 1, en-
tries 1 and 2). The reaction was further studied using various
homogeneous catalysts prepared in situ from Pd-source and the li-
gand with the ratio of 1:2. It was found that Pd(acac)
result (Table 1, entries 3–7). When the reaction was carried out in
the absence of phosphine ligand it was observed that only
The influence of catalyst loading of ligand and palladium source
was studied. It was found that 1 mol % of Pd(acac) and ligand
2
loading of 2 mol % were sufficient to catalyze the reaction. Further
increase in catalyst concentration could not lead to increase the
2
gave the best
ꢀ1
product yield. In a typical reaction TON of 100 and TOF of 10 h
was observed (Table 3).
Considering these optimized reaction conditions the reaction of
iodobenzene gave high yield of the desired product (Table 4, entry
1
1
1
). The electron donating adduct such as 4-iodoanisole and 4-
iodotoluene gave remarkable conversion and selectivity (Table 4,
entries 2 and 3). As 4-iodotoluene is less active than 4-iodoanisole,
the former requires higher temperature for conversion. Though 4-
Table 1
a
Screening of different palladium source and ligands for formylation of iodobenzene
CHO
I
+
Pd/L
CO
+
H2
Solvent /Base
Table 2
Entry Palladium
source
Ligand Conversionb
(%)
Select.b
(%)
Yieldb
(%)
Influence of different bases and solvents on formation of benzaldehyde yielda
Entry Base
Solvent
Conversionb
%)
Select.b (%) Yieldb (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
Pd/C
Pd-NHC
Pd(Peg)
Pd(OAc)
––
––
100
100
10
0
0
0
0
0
0
(
2
L
L
L
L
L
L
L
L
L
L
L
1
1
1
1
1
2
3
4
5
6
7
1
2
3
4
5
6
7
8
CS
CO
DBU
Morpholine
2
CO
3
Toluene 48
Toluene 30
Toluene 10
Toluene 20
78
45
0
10
8
0
26
74
90
95
98
98
84
85
97
96
0
15
40
80
93
9
11
80
84
0
K
2
3
2
PdCl
Pd(TMHD)
2
0
0
2
100
100
12
Pd(acac)
Pd(acac)
Pd(acac)
Pd(acac)
Pd(acac)
Pd(acac)
Pd(acac)
2
2
2
2
2
2
2
Triethylamine Toluene 69
90
98
0
20
90
96
65
50
93
0
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
Toluene 100
15
86
DMF
DMSO
ACN
50
95
42
0
1
2
3
6
88
02
39
9
10
11
33
88
2
Dioxane 98
THF
89
22
9
a
a
Reaction conditions: iodobenzene, (1 mmol), Pd precursor (1 mol %), ligand
2 mol %), base (1 equiv), 50 mg N-hexadecane (internal standard), toluene 10 mL,
CO/H (1:1) 10 bar, 100 °C, 10 h.
GC yield.
Reaction conditions: iodobenzene, (1 mmol), Pd(acac)
2
(1 mol %), ligand dppm
(
(2 mol %), TMEDA (1 equiv), 50 mg N-hexadecane (internal standard), toluene
°
2
10 mL, CO/H (1:1) 10 bar, 100 C, 10 h.
2
b
b
GC yield.

A. S. Singh et al. / Tetrahedron Letters 52 (2011) 2383–2386
2385
Table 3
Pd (CO) L
n
m
n
a
Influence of amount of catalyst loading on the yield (GC)
+
L
-L
Entry
Pd(acac)
2
(mol %)
Conversionb (%)
Yieldb (%)
-
CO + CO
1
2
3
4
5
6
7
0
0
0
0.2
0.4
0.6
0.8
1.0
1.2
15
36
58
78
100
100
10
30
50
70
93
94
PdL2
+
L
-L
TMEDA.HI + ArCHO
TMEDA
PdL
ArI
a
Reaction conditions: iodobenzene, (1 mmol), TMEDA (1 equiv), 50 mg N-hexa-
decane (internal standard), toluene 10 mL, CO/H
2
(1:1) 10 bar, 100 °C, 10 h.
b
GC yield.
L
I
L
iodoaniline is highly active, it leads to slight decrease in the
selectivity of the product (Table 4, entry 4). Even sterically hin-
dered 2-iodoanisole gave complete conversion with 75% yield of
the desired product (Table 4, entry 5). With electron withdrawing
group as in 4-iodochlorobenzene, the catalyst gave low conversion
of the desired product (Table 4, entry 6). However, the catalyst
failed to activate the carbonylation of 4-iodonitrobenzene (Table 4,
entry 7). This protocol also works successfully for the formylation
of iodonapthalene (Table 4, entry 8). Since the heteroaromatic
aldehydes are biologically active compounds, their synthesis is also
beneficial. The reductive carbonylation of 5-iodoindole was done
selectively with 78% isolated yield (Table 4, entry 9). The catalyst
was not highly effective in the carbonylation of orthosubstituted
heterocycles like 2-iodothiophene. The formylation of 3-iodopyri-
dine took place effectively with 78% yield of the product (Table 4,
I
Pd
Pd
H
Ar
ArC(O)
H
L
I
H2
Pd
CO
ArC(O)
Figure 2. Proposed catalytic cycle for the Pd-catalyzed reductive carbonylation of
aryl iodides with synthesis gas.
entry 11). The catalyst was ineffective when formylation of aryl
bromide was carried out under similar conditions.
Table 4
a
Reductive carbonylation of various aryl and heteroaryl iodides
Entry
1
Substrate
Temp (°C)
Conversionb (%)
100
Select.b (%)
98
GC (isolated) yieldb (%)
93 (91)
I
100
I
2
3
4
100
120
100
100
95
99
98
80
95 (92)
88 (84)
80 (75)c
MeO
I
I
100
H N
2
I
5
6
7
100
120
120
100
65
75
89
90
75 (71)
56 (50)d
5
O
CHO
I
Cl
10
O N
2
I
8
9
100
100
100
100
77
95
77 (72)
H
N
82 (78)e
I
1
0
1
I
120
100
48
90
100
81
33 (29)
81 (78)
S
I
1
N
a
2 2
Reaction conditions: substrate (1 mmol), Pd(acac) (1 mol %), ligand (2 mol %), TMEDA (1 equiv), 50 mg n-hexadecane (internal standard), toluene 10 mL, CO/H (1:1)
1
0 bar, 10 h.
b
Isolated yield.
Melting point of 4-aminobenzaldehyde: 71 °C.
Melting point of 4-chlorobenzaldehyde: 47 °C.
c
d
e
Melting point of indole5-carboxaldehyde: 10 °C.

2
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A. S. Singh et al. / Tetrahedron Letters 52 (2011) 2383–2386
5. (a) Kikukawa, K.; Totoki, T.; Wada, T.; Matsuda, T. J. Organomet. Chem. 1984,
The rationale behind this comprehensive catalytic cycle was
10
207, 283–287; (b) Pri-Bar, I.; Buchman, O. J. Org. Chem. 1984, 49, 4009–4011.
(a) Ben-David, Y.; Portnoy, M.; Milstein, D. J. Chem. Soc. Chem. Commun. 1989,
first revealed by Beller and co-workers. The rate determining
step of this cycle is the oxidative addition of aryl iodide to palla-
dium species, which is then followed by CO insertion and finally
with the help of base, the hydrogen halide was removed there by
generating product and maintaining the concentration of active
palladium species throughout this catalytic cycle (Fig. 2).
6.
2
3, 1816–1817; (b) Pri-Bar, I.; Buchman, O. J. Org. Chem. 1988, 53, 624–626; (c)
Okano, T.; Harada, N.; Kiji, J. Bull. Chem. Soc. Jpn. 1994, 67, 2329–2332; (d) Cai,
M. Z.; Zhao, H.; Zhou, J.; Song, C. S. Synth. Commun. 2002, 32, 923–926.
Cacchi, S.; Fabrizi, G.; Goggiamani, A. J. Comb. Chem. 2004, 6, 692–694.
Ashfield, L.; Barnard, C. F. J. Org. Pro. Res. Dev. 2007, 11, 39–43.
7
8
.
.
9. (a) Klaus, S.; Neumann, H.; Zapf, A.; Strubing, D.; Hubner, S.; Almena, J.;
Riermeier, T.; Gross, P.; Sarich, M.; Krahnert, W.-R.; Rossen, K.; Beller, M.
Angew. Chem., Int. Ed. 2006, 45, 154–158; (b) Brennfuhrer, A.; Neumann, H.;
Klaus, S.; Riermeier, T.; Almena, J.; Beller, M. Tetrahedron 2007, 63, 6252–6258.
10. Sergeev, A. G.; Spannenberg, A.; Beller, M. J. Am. Chem. Soc. 2008, 130, 15549–
In conclusion, an efficient protocol for reductive carbonylation
2
of aryl and heteroaryl iodide by using Pd(acac) /dppm has been
developed. The commercially available synthesis gas is used as car-
bonylation source. The reaction was optimized under various
parameters like catalyst concentration, effect of solvent and base.
The developed method is chemo selective for the conversion of
aromatic iodide in presence of aromatic bromide.
15563.
1
1. General experimental procedure for reductive carbonylation of (hetero)aryl
iodides: The reaction was performed in high pressure autoclave of 100 mL
capacity manufactured by M/s Amar Industries. Toluene (10 mL), Pd(acac)2
(
3 mg, 1 mol %), and dppm (7.7 mg, 2 mol %) were added to the autoclave
reactor. To this solution iodobenzene (204 mg, 1.0 mmol), n-hexadecane
0
0
(
50 mg, internal GC standard), TMEDA (N,N,N ,N -tetramethylethylene-
diamine, 1 equiv) were added. The mixture was flushed twice with CO/H2
:1, then synthetic gas pressure was adjusted to 10 bar and the mixture was
References and notes
1
1
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Crawford, L. P.; Richardson, S. K. Gen. Synth. Methods 1994, 16, 37–91; (c)
Ferguson, L. N. Chem. Rev. 1946, 38, 227–254; (d) Fetter, J.; Bertha, F.;
Poszavacz, L.; Simig, G. J. Heterocycl. Chem. 2005, 42, 137–139.
Negishi, E. Organopalladium Chemistry for Organic Synthesis; Wiley-Interscience:
New York, 2002.
Schoenberg, A.; Heck, R. F. J. Am. Chem. Soc. 1974, 96, 7761–7764.
(a) Baillardgeon, V. P.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 452–461; (b)
Baillardgeon-Geon, V. P.; Stille, J. K. J. Am. Chem. Soc. 1983, 105, 7175–7176.
heated at 100 °C for 10 h. After completion of reaction, the reaction mixture
was cooled to room temperature. The light yellow colored solution was
evaporated and residue obtained was purified by column chromatography
(silica gel, mesh size 60–120) using pet ether/ethyl acetate (95:05) as eluent to
get the desired formylated product. The products were confirmed by GC–MS,
2
.
1
13
H NMR, and C NMR techniques. The purity of compounds was determined
by GC–MS analysis.
3
4
.
.