A phosphine-free Pd catalyst for the selective double carbonylation of aryl iodides

Article abstract of DOI:10.1039/c2cc17124d

The first phosphine-free Pd-catalysed double carbonylation of aryl iodides is reported as a general and practical method, giving excellent conversions and selectivities for a wide range of aryl iodides and amine nucleophiles under atmospheric CO pressure. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc17124d

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COMMUNICATION
A phosphine-free Pd catalyst for the selective double carbonylation of
aryl iodidesw
a
a
b
a
´
Veronica de la Fuente, Cyril Godard, Ennio Zangrando, Carmen Claver* and
Sergio Castillon*
c
´
Received 16th November 2011, Accepted 2nd December 2011
DOI: 10.1039/c2cc17124d
The first phosphine-free Pd-catalysed double carbonylation of
aryl iodides is reported as a general and practical method, giving
excellent conversions and selectivities for a wide range of aryl
iodides and amine nucleophiles under atmospheric CO pressure.
iodides and amine nucleophiles under atmospheric pressure of
carbon monoxide.
Aiming at developing a catalytic system without phosphine,
and since a base is required in the catalytic process, we
investigated the use of coordinating nitrogen donors that can
behave as ligand and base. Initially, DMAP was tested using
Pd2(dba)3 as precursor at 60 1C in toluene for 14 h, but low
conversion was achieved (Table 1, entry 1). Interestingly, the
use of DABCO increased the conversion but mainly the
monocarbonylation product was obtained (entry 2).
However, when DBU was used (entry 3), moderate
conversion was obtained but with excellent selectivity to the
double carbonylation product 3a. It is noteworthy that in the
absence of ligand and base, although the conversion was
very low, the selectivity to 3a remained at ca. 50% (entry 4).
When [Pd(Z3-C3H5)(m-Cl)]2 was tested the selectivity to 3a
remained excellent, while the conversion increased up to 83%
(entry 5).
The Pd-catalysed double carbonylation of aryl halides
(Scheme 1) is a direct and valuable method for the production
of a-ketoamides,1 a function present in many biologically active
compounds2–4 and also in suitable starting materials for the
synthesis of several families of heterocycles.5 However, there are
only a few reports describing efficient catalytic systems for this
reaction and most of them involve the use of high CO pressures.
The reported catalysts for this process all contain phosphine
ligands such as PPh3,6 PPh2Me,7 PCy3,7 or PtBu3,8 which limit
their application due to their propensity to undergo oxidation.
The most efficient catalytic system to date was reported by
Uozumi and co-workers using a Pd/PPh3 catalyst in the presence
of DABCO as a base that provides excellent selectivities to the
a-ketoamide products under atmospheric CO pressure.6 More
recently, Kondo and co-workers reported the use of an efficient
Pd/PtBu3 system using DBU as base, producing a-ketoamides
with excellent chemoselectivity.8 However, the use of such a basic
phosphine ligand is often an issue when it is to be applied to a
large scale process.
Table 1 Phosphine-free Pd-catalysed double carbonylation of
1-iodo-p-methoxybenzene with n-butylamine: optimization of reaction
conditionsa
Here, we report the first phosphine-free Pd-catalyst in the
selective double carbonylation of aryl iodides using a nitrogen
donor ligand. This catalytic system provided total selectivity to
the double carbonylation products for a wide range of aryl
Ligand/base Conv.b
Sel.b (3a)
[%]
Entry Pd prec.
T/1C (mmol)
[%]
1
2
3
4
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
60
60
60
60
DMAP (1) 19
DABCO (1) 92
11
3
>95
46
Scheme 1 Pd-catalysed double carbonylation of aryl iodides.
DBU (1)
—
56
8
a
´
´
`
Departament de Quımica Fısica i Inorganica, Universitat Rovira i
Virgili, C/Marcel.li Domingo s/n, 43007 Tarragona, Spain.
E-mail: carmen.claver@urv.cat
5
6
7
[Pd(Z3-C3H5)Cl]2 60
Pd(DBU)2Cl2 (5) 60
[Pd(Z3-C3H5)Cl]2 80
[Pd(Z3-C3H5)Cl]2 80
[Pd(Z3-C3H5)Cl]2 80
Pd(DBU)2Cl2 (5) 80
DBU (1)
DBU (1)
DBU (1)
DBU (1)
DBU (1)
KOtBu (1)
83
56
>95
91
99
91
>95
92
>95
>95
47
b Dipartimento di Scienze Chimiche e Farmaceutiche, via Licio
8c
9c,d
10e
Giorgieri, 1, 34127 Trieste, Italy
c
´
´
`
Departament de Quımica Analıtica i Organica, Universitat Rovira i
Virgili, C/Marcel.li Domingo s/n, 43007 Tarragona, Spain.
E-mail: sergio.castillon@urv.cat
90
a
[Pd] (0.005 mmol), 1-iodo-p-methoxybenzene (0.5 mmol), base (1 mmol),
b
butylamine (1.2 mmol), toluene (5 mL), CO (1 bar), 14 h. Determined
w Electronic supplementary information (ESI) available: Experimental
section, X-ray structure, analytical and NMR data of the prepared
compounds. See DOI: 10.1039/c2cc17124d
by 1H-NMR and GC-MS. 1 h. +0.01 mmol PPh3. +5 equiv. DBU.
c
d
e
c
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Chem. Commun., 2012, 48, 1695–1697 1695

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Table 2 Phosphine-free Pd-catalysed double carbonylation of different
aryl iodies with butylaminea
selectivity to the double carbonylation product was somewhat
intermediate (65%) (entry 3). However, in this case the selectivity
was improved to 98% lowering the temperature to 60 1C. Using
the ortho, para-OMe disubstituted phenyl iodide as substrate (1d)
(entry 4), the conversion was similar to those obtained with the
monosubstituted substrates (95%) and the very low selectivity
to the double carbonylation product was comparable to that
of the ortho-iodo anisole (1b). However, when ortho-tolyl-
iodide was used as substrate, the selectivity to the double
carbonylation product was excellent (entry 7). The low selec-
tivity obtained with the ortho-iodoanisole (entry 2) can thus
not be only explained by the steric hindrance induced by the
OMe substituent. When phenyl iodide (1e) was used as sub-
strate (entry 5), excellent conversion (98%) and high selectivity
to 3e (76%) were obtained at 60 1C. Using alkyl-substituted
phenyl iodides as substrates (1f–j) (entries 6–10), high conver-
sions (94–99%) and selectivities to 3f–j (84–98%) were
obtained in all cases. The presence of electron withdrawing
groups directs the reaction towards the amide 4k,l (entries 11
and 12). Bromobenzene derivatives were not active.
T/1C
(time/h) [%]
Conver.b Product (3a–l)
Entry Aryl iodide
selec.b [%]
1
2
3
4
5
6
7
8
1a (R = p-OMe)c
1b (R = o-OMe)
1c (R = m-OMe)
1d (R,R = o,p-OMe) 80 (1)
1e (R = p-H)
1f (R = p-Me)
1g (R = o-Me)
1h (R,R = m-Me)
1i (R = p-Et)
1j (R = p-tBu)
1k (R = p-CN)
1l (R = p-NO2)
80 (1)
80 (1)
80 (1)
99
93
95
95
98
99
99
97
94
98
99
99
3a [98,87d]
3b [2]
3c [65]e
3d [8]
60 (14)
60 (14)
60 (14)
60 (14)
60 (14)
60 (14)
60 (14)
60 (14)
3e [76]
3f [90]
3g [84]
3h [91]
3i [98]
3j [97]
3k [1]f
3l [1]f
9
10
11
12
a
[Pd(Z3-C3H5)(m-Cl)]2 (0.005 mmol), aryl iodide (0.5 mmol), DBU
(1 mmol), butylamine (1.2 mmol), toluene (5 mL), CO (1 bar). b Determined
by 1H-NMR and GC-MS. c The bromobenzene derivative was not active.
d Isolated yield. e 98% at 60 1C. f Amides 4k and 4l were obtained.
Next, the scope of the nucleophile was studied with primary
and secondary amines. The results are listed in Table 3. When
primary amines were used as nucleophiles (entries 1–4), excellent
conversions (>99%) and selectivities (>99%) to the products
3m–p were obtained. In the case of methylbenzylamine (entry 4),
the selectivity was improved when the reaction was performed at
60 1C. Using secondary amines (entries 5–8), similar results were
obtained with excellent selectivity to 3q–t at 60 1C. Using diethyl-
amine (entry 5) and cyclic amines (entries 6–8) as nucleophiles,
high conversions (>80%) and selectivities (>90%) to the double
carbonylation product were achieved in all cases. This shows that
this catalytic system is efficient for a range of amine nucleophiles.
In order to shed some light onto the mechanism involved in
this novel catalytic system, the reactivity of the complex 5 in the
presence of the reagents involved in the catalytic process was
investigated. First, a sample of 5 was dissolved in d8-toluene and
placed into a 5 mm NMR tube. At that point, 10 equivalents of
To ensure the coordination of DBU, the complex
[PdCl2(DBU)2] (5) was synthesised and isolated as a yellow
powder in 71% yield (see ESIw).
When 5 was used as precursor in the double carbonylation of
1-iodo p-methoxybenzene in the presence of additional DBU
(entry 6), 56% conversion was achieved with excellent selectivity
to 3a. These results indicated that Pd species containing coordi-
nated DBU are active in this catalytic process. At 80 1C using
[Pd(Z3-C3H5)(m-Cl)]2 precursor and DBU (entry 7) total conver-
sion and selectivity to 3a were achieved. When the reaction was
stopped after 1 h under the same conditions (entry 8), the
conversion was found to only slightly decrease to 91%.
The effect of additional phosphine was then investigated
and when the experiment was repeated in the presence of
2 equivalents of PPh3 per Pd (entry 9), the selectivity decreased
dramatically to 47%. This result clearly indicates that the
presence of PPh3 strongly affects the selectivity of this process
towards the production of the monocarbonylation product 4a. In
contrast, when the reaction was performed with a 5-fold excess of
DBU with respect to the Pd precursor 5 and KOtBu as a base
(entry 10), the conversion and the selectivity to 3a were excellent.
This demonstrated that Pd/DBU is the real catalytic system in
this process where DBU acts as a ligand and that other bases such
as KOtBu can be successfully used in this phosphine free process.
To enlarge the scope of the reaction, various aryl iodides were
used as substrates with n-butylamine as nucleophile using the
previously optimised conditions under which DBU was used as
ligand and base. The results are summarized in Table 2.
Using para-, ortho- and meta-iodo anisoles (1a–c) as substrates
(entries 1–3), high conversions were achieved in all cases (93–99%).
However, clear differences in selectivity were observed. When
the p-iodo anisole (1a) was used, excellent selectivity to the
double carbonylation product was achieved (98%). However,
in the case of the ortho-substituted substrate (1b), the selectivity
was practically total to the monocarbonylation product (98%)
(entry 2) while with the meta-substituted substrate (1c), the
Table
3 Phosphine-free Pd-catalysed double carbonylation of
1-iodo-p-methoxybenzene with different nucleophilesa
Product (3m–t)
selec.b/yieldc (%)
Entry
Nu
T/1C (time/h)
Conv.b [%]
1
2
3
4
5
6
7
8
2b
2c
2d
2e
2f
2g
2h
2i
80 (1)
80 (1)
80 (1)
60 (14)
60 (14)
60 (14)
60 (14)
60 (14)
90
93
99
99
82
93
96
87
3m (98/83)
3n (94/84)
3o (99)
3p (99/88)
3q (96/75)
3r (91)
3s (92)
3t (95)
a
[Pd(Z3-C3H5)(m-Cl)]2 (0.005 mmol), 1-iodo-p-methoxybenzene
(0.5 mmol), DBU (1 mmol), nucleophile (1.2 mmol), toluene (5 mL),
b
CO (1 bar). Determined by H-NMR and GC-MS. Isolated yield.
1
c
c
1696 Chem. Commun., 2012, 48, 1695–1697
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induced by the bicyclic structure of DBU which hampers the
attack at the Pd-acyl. Such a behaviour was described by
Buchwald and coworkers in the aminocarbonylation of aryl
chlorides.9 They established through a kinetic study that the
base used in the reaction, namely sodium phenoxide, had a
dual role and also acted as an acyl transfer agent. The results
described in this work indicate that DBU acts in an analogous
manner thus producing a nucleophilic attack at the terminal
CO of the Pd(CO)(acyl) intermediate (9).
Scheme 2 Species detected by NMR in the presence of all reagents
used in catalysis except the amine nucleophile.
In summary, we report here the first phosphine-free
Pd-catalysed double carbonylation of aryl iodide as a general
and practical method. Using Pd/DBU as a catalytic system
excellent conversions and selectivities were achieved for a wide
range of aryl iodides and amine nucleophiles under atmo-
spheric CO pressure. The role of DBU is key since in this
process this species acts as a ligand, a nucleophile (or acyl
transfer agent) and a base.
Scheme 3 Proposed last steps of the catalytic cycle leading to 3.
phenyl iodide were added to the sample which was subsequently
heated to 80 1C and the reaction monitored by NMR spectro-
scopy. During this experiment, small crystals suitable for X-ray
crystallography were obtained for the reaction mixture and
revealed that the iodide analogue of 5, namely the species trans-
PdI2(DBU)2 6, was formed during the reaction. Phenyl chloride
was also detected by GC as a reaction product. Full structural
data for species 6 can be found in the ESI.w
When the reaction was repeated in the presence of
all reagents used in the catalysis, no Pd species could be
characterised due to the high reaction rates on the NMR
timescale. However, when the reaction was performed in the
absence of amine nucleophile, 3 new products 7, 8a and 8b
were identified by NMR and MS (Scheme 2). These products are
the a-ketoamide 7 that contains a charged DBU unit, and the cis
and trans isomers of the Pd-acyl complex [Pd(DBU)2(CO-aryl)I] 8.
This experiment clearly demonstrated that DBU acts as a
nucleophile under these conditions.
We thank the Spanish Ministerio de Educacion y Ciencia
´
(Fellowship to VdlF, Ramon y Cajal to CG) CTQ2008-01569-
BQU, CTQ2010-15835, Consolider Ingenio CSD2006-0003,
for financial support.
Notes and references
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Based on these results, the following mechanism is proposed:
the Pd precursor 5 is reduced to Pd(0) under carbonylation
conditions, and reacts with an aryl iodide to form the oxidative
addition product. After coordination and migratory insertion of
CO, a Pd-acyl is formed. This intermediate can either react with
the amine nucleophile to form the monocarbonylation product 4
or react with a second molecule of CO to form a cationic species 9
containing a terminal CO and an acyl moiety with the iodide as
counter-ion. At this stage, the nucleophilic attack at the terminal
CO could occur from the amine nucleophile to directly form a
Pd-acyl-amide species (10, Nu = RNH2) or from the DBU
(Nu = DBU), forming a Pd-species that reacts with the amine
to form the same Pd-acyl-amide species. This step is thus crucial in
order to achieve high selectivity to the double carbonylation
product. Reductive elimination from the latter complex forms the
a-ketoamide 3 and regenerates the initial Pd(0) species (Scheme 3).
The results described in this communication suggest that the
strong nucleophilic character of DBU enables the selective
attack at a terminal CO coordinated to Pd. This selectivity of
the nucleophilic attack at the terminal CO rather than at the
Pd-acyl moiety can be explained by the steric hindrance
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 1695–1697 1697