A Convenient Palladium-Catalyzed Reductive Carbonylation of Aryl Iodides with Dual Role of Formic Acid

Article abstract of DOI:10.1002/chem.201600387

Palladium-catalyzed reductive carbonylation of aryl halides represents a straightforward pathway for the synthesis of aromatic aldehydes. The known reductive carbonylation procedures either require CO gas or complexed compounds as CO sources. In this communication, we developed a palladium-catalyzed reductive carbonylation of aryl iodides with formic acid as the formyl source. As a convenient, practical, and environmental friendly methodology, no additional silane or H₂ was required. A variety of aromatic aldehydes were isolated in moderate to excellent yields under mild reaction conditions. Notably, this is the first procedure on using formic acid as the formyl source. Say no to CO gas! A convenient, practical, and environmental friendly palladium-catalyzed reductive carbonylation of aryl iodides with formic acid as the formyl source has been developed (see scheme). No additional silane or H₂ was required here. A variety of aromatic aldehydes were isolated in moderate to excellent yields under mild reaction conditions.

Full text of DOI:10.1002/chem.201600387

DOI: 10.1002/chem.201600387
Communication
&
Carbonylation |Hot Paper|
A Convenient Palladium-Catalyzed Reductive Carbonylation of
Aryl Iodides with Dual Role of Formic Acid
Xinxin Qi,[a] Chong-Liang Li,[a] and Xiao-Feng Wu*[a, b]
ing compounds, such as carboxylic acid derivatives, aldehydes,
Abstract: Palladium-catalyzed reductive carbonylation of
ketones, and so forth.[10] Among all the carbonylative transfor-
aryl halides represents a straightforward pathway for the
mations, reductive carbonylation is unique and straightforward
synthesis of aromatic aldehydes. The known reductive car-
for the preparation of aromatic and vinyl aldehydes.[11] One
bonylation procedures either require CO gas or com-
representative example is from Beller’s group (Scheme 1a).[12]
plexed compounds as CO sources. In this communication,
we developed a palladium-catalyzed reductive carbonyla-
tion of aryl iodides with formic acid as the formyl source.
As a convenient, practical, and environmental friendly
methodology, no additional silane or H2 was required. A
variety of aromatic aldehydes were isolated in moderate
to excellent yields under mild reaction conditions. Notably,
this is the first procedure on using formic acid as the
formyl source.
Aromatic aldehydes are a class of valuable compounds with
Scheme 1. Palladium-catalyzed reductive carbonylation of aryl halides.
numerous applications in various areas, including pharmaceuti-
cals, dyes, pesticides, spices and so forth.[1] Additionally, aro-
matic aldehydes are also potent intermediates in fine chemi-
cals synthesis.[2] Hence, their preparations have been the core
interest of synthetic chemists for a long time.[3] Traditional syn-
thetic methods are mainly based on acylation of aromatic
compounds with two types of strategies. One strategy is the
CÀC bond formation followed by oxidation, such as Duff reac-
tion[4] and Casiraghi reaction.[5] The other one is the direct in-
troduction of a formyl group into the aromatic compounds, in-
cluding Gattermann–Koch reaction, Reimer–Tiemann reaction
and so forth.[6] Recently, aromatic aldehydes have been also
prepared by the oxidation of benzylic alcohols[7] and methylar-
enes.[8] However, disadvantages, such as harsh reaction condi-
tions and low yields, limits the utility of such methods. There-
fore, procedures that are efficient, environmental friendly, and
proceed under milder conditions for aromatic aldehydes syn-
theses are still under request.
They developed a general and effective palladium-catalyzed re-
ductive carbonylation of aryl and heteroaryl bromides in the
presence of syngas. Although CO gas as one of the cheapest
C1 source holds irreplaceable position in industrial scale appli-
cations, the high toxicity, flammability, and special equipment
requirement for handling, limits CO gas-based carbonylations
in laboratories. Therefore, many efforts have been put in devel-
oping new CO-free carbonylations. Manabe and co-workers
prepared and applied N-formylsaccharin as CO source for palla-
dium-catalyzed reductive carbonylation of aryl bromides with
silane as the reductant (Scheme 1b).[13] Good yields of aromatic
aldehydes can be produced by this procedure. Additionally, al-
ternative CO surrogates, including 9-methylfluorene-9-carbonyl
chloride,[14] CO2,[15] paraformaldehyde,[16] and acetic formic an-
hydride[17] have been explored in reductive carbonylation by
different groups as well. However, silanes or metal hydrides are
needed as the reducing reagent in all the cases. Under these
backgrounds, we developed a new palladium-catalyzed reduc-
tive carbonylation procedure for the synthesis of aromatic al-
dehydes from aryl iodides. In this procedure, formic acid has
been applied as the formyl source. No special equipment or
other reducing reagent is needed here. Notably, this is the first
example on using formic acid as both the CO and hydride
source.
Since the pioneer work of Heck and co-workers in 1974,[9]
palladium-catalyzed carbonylation reactions with CO gas have
become a powerful method for constructing carbonyl-contain-
[a] Dr. X. Qi, C.-L. Li, Prof. Dr. X.-F. Wu
Department of Chemistry, Zhejiang Sci-Tech University
Xiasha Campus, Hangzhou 310018 (People’s Republic of China)
E-mail: xiao-feng.wu@catalysis.de
[b] Prof. Dr. X.-F. Wu
Initially, iodobenzene was chosen as the model substrate
with formic acid as the formyl source and acetic anhydride as
the additive in the presence of Pd(OAc)2, PPh3, and various sol-
vents with Et3N as the base at 808C (Table 1, entries 1–5). To
Leibniz-Institut für Katalyse e.V. an der Universität Rostock
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
Supporting information for this article can be found under http://
dx.doi.org/10.1002/chem.201600387.
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tained with nitrile- or trifluoro-substituted iodobenzenes (en-
tries 7–8). Aryl iodides with chloro and bromo substitutions
were also tolerated well and provided the target products in
moderate to excellent yields (entries 9–12). These halogen sub-
stituents allow the products for further modifications by palla-
dium-catalyzed cross-coupling reactions. In detail, chloro
groups located at the meta- and para-position worked better
than the ortho-substitution, which might be due to the steric
hindrance (entries 10–12 versus. 9). It is worth noting that the
heteroaryl groups, including 3-iodothiophene, 3-iodopyridine,
and 6-iodoquinoline, worked well to afford the corresponding
products in good to excellent yields (entries 13–15). Further-
more, high yields were obtained when biphenyl or naphtha-
lene substrates were utilized (entries 16–18).
Table 1. Pd-catalyzed reductive carbonylation: Screening of reaction con-
ditions.[a]
Entry
Ligand
Base
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PCy3
XPhos
DPPPE
DPPE
DPPF
DPPB
Et3N
Et3N
Et3N
Et3N
toluene
CH3CN
THF
30
39
12
47
25
0
35
37
16
40
67
7
DMF
DCM
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Et3N
Na2CO3
TMEDA
DABCO
DMAP
DIPEA
Et3N
Et3N
Et3N
Et3N
Et3N
9
10
11
12
13[c]
14[c]
15[c]
16[c]
In order to have some information on the reaction mecha-
nism of this novel carbonylation process, labelling experiments
were conducted with 4-iodo-1,1’-biphenyl as the substrate
(Scheme 2). A 13C-carbonyl-labelled aldehyde was generated in
23
33
9
Et3N
30
[a] Reaction conditions: Iodobenzene (1.0 mmol), HCOOH (4.5 mmol),
acetic anhydride (2.0 mmol), Pd(OAc)2 (3 mol%), ligand (6 mol%), base
(5 equiv), solvent (2 mL), 6 h. [b] Yields were determined by GC using do-
decane as an internal standard. [c] Ligand (3 mol%). DPPE=1,2-bis(diphe-
nylphosphino)ethane;
DPPPE=1,5-bis(diphenylphosphino)pentane;
DPPB=1,4-bis(diphenylphosphino)butane;
DPPF=1,1’-bis(diphenyl-
phosphino)ferrocene; XPhos=2-dicyclohexylphosphino-2’,4’,6’ triisopro-
pylbiphenyl; Cy=cyclohexyl; TMEDA=N,N,N’,N’-tetramethyl-ethane-1,2-
diamine; DABCO=1,4-diazabicyclo[2.2.2]octane; DMAP=4-dimethylami-
nopyridine; DIPEA=N,N-diisopropylethylamine; THF=tetrahydrofuran;
DCM=dichloromethane; DMF=N,N-dimethylformamide.
our delight, 30% yield of benzaldehyde was obtained in tolu-
ene (entry 1). Among all the tested solvents, DMF proved to
be the best solvent (entry 4). Then various bases were
screened, but no product was observed when Na2CO3 was ap-
plied as the base (entry 6). Other bases, including TMEDA,
DABCO, DMAP, and DIPEA provided the desired product in
lower yield (entries 7–10). Afterwards, various phosphine li-
gands were investigated. For monodentate ligands, PCy3 pro-
vided the desired benzaldehyde in 67% yield (entry 11), where-
as only 7% yield was reached with XPhos (entry 12). Bidentate
ligands, such as DPPPE, DPPE, DPPF, and DPPB provided lower
yields compared with PCy3 (entries 13–16). Finally, reaction
temperatures, palladium loadings, and the loading of other re-
agents were optimized as well, but no better yields could be
obtained. During the optimization process, full conversion of
the iodobenzene was observed in all the cases, and the main
byproduct was the dehalogenation product.
Scheme 2. Carbonylation of 4-iodo-1,1’-biphenyl with labelled compounds.
93% yield using 13C-labelled formic acid, and a 3:2 ratio of the
deuterated aldehyde and the normal aldehyde was obtained
employing DCO2H as the reagent. These results confirm the
role of formic acid as the formyl source. The aldehyde protons
in the products came from the carbonyl proton of formic acid.
The formation of non-deuterated aldehyde is due to the ex-
change of the palladium hydride with formic acid before re-
ductive elimination. Remarkably, the carbonylation reaction
could be performed on 5 mmol scale without any hindrance
(Scheme 2c).
Based on the above results, a possible reaction mechanism
is proposed in Scheme 3. The reaction starts with the oxidative
addition of Pd0Ln with aryl iodide to give the corresponding ar-
ylpalladium complex. Next, the benzoylpalladium complex is
obtained after the coordination and insertion of CO, which is
generated in situ from the reaction of formic acid with acetic
anhydride as the activator. Afterwards, the ligand exchange of
the iodide with formic acid affords the acylpalladium formic
acid complex. A benzoylpalladium hydride complex will be
formed after decarboxylation of the acylpalladium formic acid
complex that will finally give the desired aromatic aldehyde
after reductive elimination. The elimination of carbon dioxide
With the optimized reaction conditions in hand, we next
went on to the generality testing of this methodology. A varie-
ty of aryl iodides were tested and shown in Table 2. In general,
moderate to excellent yields of the desired aldehydes could be
isolated under the same conditions. Substrates with electron-
donating groups resulted in the desired products in high to
excellent yields (entries 2–4). Electron-withdrawing groups,
such as ketone or ester, gave the corresponding products in
good yields (entries 5–6), whereas moderate yields were ob-
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Table 2. Pd-Catalyzed reductive carbonylation of aryl iodides.[a]
Entry
1
Aryl iodides
Aldehydes
Yield [%][b]
66
Entry
10
Aryl iodides
Aldehydes
Yield [%][b]
98
2
3
4
85
93
62
11
12
13
95
61
65
5
6
7
61
79
40
14
15
16
83
85
94
8
9
35
41
17
18
66
88
[a] Reaction conditions: Aryl iodides (1.0 mmol), HCOOH (4.5 mmol), acetic anhydride (2.0 mmol), Pd(OAc)2 (3 mol%), PCy3 (6 mol%), Et3N (5 equiv), DMF
(2 mL), 6 h. [b] Yield of isolated product.
were tolerated under our conditions. Compared with the
known procedures, no gas manipulations are required here
and the use of silane or metal hydride as the reducing agent
could be avoided. Notably, this is the first procedure on using
formic acid as the formyl source in organic synthesis.
Experimental Section
Pd(OAc)2 (3 mol%) and PCy3 (6 mol%) were transferred into an
oven-dried tube, which was filled with nitrogen, and DMF (2.0 mL),
Scheme 3. Proposed reaction mechanism.
formic acid (2.5 mmol), and aryl iodides (1.0 mmol) were then
added. A mixture of formic acid (2.0 mmol) and acetic anhydride
was confirmed by the formation of white precipitate after bub-
(2.0 mmol) that was stirred for 1 h at 308C was introduced into the
bling the gas phase into clear Ca(OH)2 solution that led to the
reaction tube. After Et3N (5.0 mmol) was added, the tube was
reaction completion.
sealed and the mixture was stirred at 808C for 6 h. After the reac-
tion was completed, the reaction mixture was filtered, concentrat-
In summary, a novel palladium-catalyzed reductive carbony-
lation of aryl iodides with formic acid as the formyl precursor
has been developed. With formic acid as both the CO and hy-
drogen source, moderate to excellent yields of the desired al-
dehydes could be obtained. A wide range of functional groups
ed, and passed through column chromatography on silica gel (pe-
troleum ether/ethyl acetate 10:1) to give the pure product.
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Acknowledgements
The authors thank the financial supports from NSFC
(21472174) and Zhejiang Natural Science Fund for Distinguish-
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Keywords: aromatic aldehydes · CO source · formic acid ·
palladium · synthetic methods
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Received: January 27, 2016
Published online on March 2, 2016
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