Angewandte
Communications
Chemie
Table 1: Optimization of the reductive carbonylation.
this problem by evaluating different ligands, per-
forming the reaction with slow addition of the tin
hydride, or testing different silanes were not very
successful.[3,4,6]
Aside from the vital role of non-deuterated aryl
aldehydes in synthesis, aldehydes incorporating
deuterium at the formyl position are often needed
for mechanistic investigations and metabolic stud-
ies.[8] Selectively labeled aldehydes of this sort are
traditionally produced from the reduction of either
the corresponding ester using LiAlD4 followed by
oxidation[9] or from the corresponding amide with
deuterated Schwartzꢀs reagent (obtained from
LiAlD4).[10] More recently, alternatives have been
proposed to overcome the cost and drawbacks
associated with LiAlD4 through H/D exchange of
the presynthesized aldehyde using D2 gas and Ir
catalysis[11] or D2O and Ru catalysis (Scheme 1e–
g).[12]
Despite the ability of water to serve as a hydride
source under CO atmosphere through the water–gas
shift reaction (WGSR),[13] it has not been used to
affect the reductive carbonylation of aryl halides.
This approach remains more challenging than the
Reppe modification of the Rh-catalyzed olefin
hydroformylation (which utilizes water as a hydride
source)[14] for the following reasons: 1) the poor
catalytic reactivity of palladium in the WGSR,
2) the intervention of the undesired reactions
known to occur in an aqueous environment, includ-
ing protodehalogenation and hydroxy carbonylation
to benzoic acids,[15] and 3) overreduction of the
aldehyde to the corresponding alcohol.
Entry
Co-catalyst
(mol%)
Ligand
Consumed
1a
Yield
1b
1c
[%][a]
[%][a]
[%][a]
1
2
3
4
5
6
7
8
9
10
11
12
13
14[c]
15[d]
16[e]
17[f]
18
–
4,4’-diMeObpy
4,4’-diMeObpy
4,4’-diMeObpy
4,4’-diMeObpy
4,4’-diMeObpy
4,4’-diMeObpy
4,4’-di-t-Bubpy
4,4’-diMebpy
bpy
4,4’-dicarboxybpy
6,6’-diMebpy
1,10-phenanthroline
PPh3
4
8
5
3
5
4
0
2
0
Ru3(CO)12 (3)
Co2(CO)8 (3)
Fe2(CO)9 (3)
74[b]
97
98
96
97
79
75
62
14
5
36
93
87
79
74
63
58
32
5
12
2
[Rh(CO)2Cl]2 (1.5)
[Rh(COD)Cl]2 (1.0)
[Rh(COD)Cl]2 (1.0)
[Rh(COD)Cl]2 (1.0)
[Rh(COD)Cl]2 (1.0)
[Rh(COD)Cl]2 (1.0)
[Rh(COD)Cl]2 (1.0)
[Rh(COD)Cl]2 (1.0)
[Rh(COD)Cl]2 (1.0)
[Rh(COD)Cl]2 (1.0)
[Rh(COD)Cl]2 (1.0)
[Rh(COD)Cl]2 (1.0)
[Rh(COD)Cl]2 (1.0)
[Rh(COD)Cl]2 (1.0)
4
5
17
9
14
24
7
2
2
4
4,4’-diMeObpy
4,4’-diMeObpy
4,4’-diMeObpy
4,4’-diMeObpy
–
81
72
19
4
76
59
13
0
10
5
0
70
12
42
[a] Determined by GC analysis with an internal standard. [b] Benzylic alcohol also
detected. [c] In acetonitrile. [d] In DMSO. [e] In 1,4-dioxane. [f] In toluene. 4,4’-
diMeObpy=4,4’-dimethoxy-2,2’-bipyridine, COD=1,5-cyclooctadiene.
Herein, we show that the dual-metallic Pd/Rh catalytic
system ligated with 4,4’-dimethoxy-2,2’-bipyridine works
cooperatively to drive the reductive carbonylation of aryl
halides, using water as the hydride source and carbon
monoxide as the carbonyl source and the terminal reductant
(Scheme 1h). This method efficiently produces 2,6-disubsti-
tuted aldehydes and their deuterated analogues with high
deuterium incorporation. The D-labeled aldehydes obtained
by this method can be engaged in subsequent WGSR-driven
reductive transformations to incorporate more deuterium
atoms in alkylated and aminated products using D2O.
selectivity for the desired aldehyde 1b compared to the
undesired deiodination to 1c and overreduction to the alcohol
(entry 4). Gratifyingly, a high yield of 1b was obtained when
[RhCO2Cl]2 was used, with only 2% 1c observed at complete
conversion of 1a (entry 5). Replacing the costly and less
stable [Rh(CO)2Cl]2 complex with [Rh(COD)2Cl]2 also led to
complete conversion of 1a (entry 6). Replacing 4,4’-
diMeObpy with other 2,2’-bipyridine ligands resulted in
a decrease in reactivity and selectivity, with the following
order of selectivity: 4,4’-diMeO > 4,4’di-t-Bu > 4,4’-diMe >
4,4’-diH > 4,4-dicarboxy (entries 7–10). A significant drop in
the yield of 1b was observed with the more sterically hindered
6,6’-dimethyl-2,2’-bipyridine (entry 11) and the rigid 1,10-
phenanthroline ligands (entry 12). Triphenylphosphine
severely inhibited the system, indicating that phosphine
ligands are not compatible with the WGSR-driven reductive
carbonylation (entry 13).
The reaction was found to proceed with higher efficiency
in polar solvents, for example, acetonitrile and dimethyl
sulfoxide, than in the less polar ones, that is, 1,4-dioxane and
toluene (entries 14–17). Attempting the reaction in dimethyl-
formamide in the absence of a ligand led to a drastic decrease
in the yield of 1b (entry 18). No enhancement in yield was
observed when the RhI dimers tested in Table 1 were replaced
by other Rh co-catalysts, including Rh0, RhII, and RhIII
precursors (see the Supporting Information, Table S2). Addi-
From initial screening, orienting experiments employed
2,6-dimethyliodobenzene (1a) together with PdCl2 as the
catalyst under CO pressure in the presence of 2 equivalents of
water,
2 equivalents
of
tetramethylethylenediamine
(TMEDA), and 0.1 equivalents of 4,4’-dimethoxy-2,2’-bipyr-
idine (4,4’-diMeObpy) as the ligand in dimethylformamide
(DMF) at 858C (Table 1).
No reaction occurred in the absence of a co-catalyst,
confirming the inability of the palladium complexes to
generate the reducing species from water (entry 1), and
therefore, other transition-metal catalysts known to affect the
WGSR were added as co-catalysts. Ruthenium and cobalt
carbonyl complexes were not suitable for this reaction as
indicated by the low conversion of 1a (entries 2 and 3). High
conversion was obtained using Fe2(CO)9, albeit with low
2
ꢀ 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2018, 57, 1 – 7
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