An improved protocol for palladium-catalyzed alkoxycarbonylations of aryl chlorides with alkyl formates

Article abstract of DOI:10.1002/adsc.201000047

The palladium-catalyzed alkoxycarbonylation of aryl and heteroaryl halides using butyl formate has been investigated. In the presence of palladium (II) acetate/n-butylbis(1-adamantyl)phosphine (L1), and l,8-diazabicyclo[5.4.0]undec- 7-ene (DBU) as base fo

Full text of DOI:10.1002/adsc.201000047

UPDATE
DOI: 10.1002/adsc.201000047
An Improved Protocol for Palladium-Catalyzed
Alkoxycarbonylations of Aryl Chlorides with Alkyl Formates
Thomas Schareina,a Alexander Zapf,a Alain Cottꢀ,b Matthias Gotta,b
and Matthias Bellera,*
a
Leibniz-Institut fꢁr Katalyse e.V. an der Universitꢂt Rostock, Albert-Einstein-Strasse 29a, 18059 Rostock, Germany
Fax : (+49)-381-1281-5000; e-mail: matthias.beller@catalysis.de
Saltigo GmbH, Katzbergstr. 1, 40764 Langenfeld, Germany
b
Received: January 20, 2010; Revised: March 24, 2010; Published online: April 28, 2010
Abstract: The palladium-catalyzed alkoxycarbony-
lation of aryl and heteroaryl halides using butyl for-
mate has been investigated. In the presence of pal-
reacted with different nucleophiles under a carbon
monoxide atmosphere in the presence of palladium
catalysts. Thereby, the halide is formally replaced by
the nucleophile with incorporation of carbon monox-
ide. Typically, the reactions take place at 60–1408C
and 5–60 bar of carbon monoxide and require a stoi-
chiometric amount of base to regenerate the catalyst.
Clearly, carbon monoxide is an inexpensive and in-
dustrially widely used feedstock; however its toxic
nature, gaseous form, and flammability render its han-
dling on a laboratory scale inconvenient. Often addi-
tional safety measurements and special waste treat-
ment are needed.
ladium(II)
phine (L1), and 1,8-diazabicycloAHCUTNGTRENNUNG
acetate/n-butylbis(1-adamantyl)phos-
[5.4.0]undec-7-ene
(DBU) as base for the first time non-activated
chloroarenes can be conveniently carbonylated in
good yields.
Keywords: alkoxycarbonylation; aryl chlorides;
carbon monoxide-free conditions; catalysis; palladi-
um
Although alkoxycarbonylations using CO at low
and ambient pressure are known,[2] there exists a sig-
nificant interest in the use of more easy to handle and
Palladium-catalyzed carbonylation reactions of aryl less toxic synthetic equivalents of carbon monoxide.[3]
halides and related compounds leading to carboxylic In this respect especially formic acid derivatives are
acid derivatives have become a versatile tool in or- promising alternatives due to their low price and
ganic synthesis.[1] Nowadays various aromatic carbox- good availability.
ylic acid derivatives, which are of interest for pharma-
Based on our previous work in palladium-catalyzed
ceuticals and agrochemicals (Figure 1), are accessible carbonylations,[4] we became interested in the use of
by this methodology. In general, aromatic halides are alkyl formates in alkoxycarbonylations of inexpensive
aryl chlorides under practical conditions.
The first successful carbonylation reactions of aryl
bromides and chromium complexes of aryl chlorides
with alkyl formates have been achieved by Carpentier
and Mortreux et al.[5] Later on, Jenner and Bentaleb
demonstrated carbonylations towards benzoic acid
salts.[6] With respect to aryl chlorides it should be
noted that aminocarbonylations have also been
achieved with Mo(CO)6 under microwave activa-
tion.[7]
Despite these studies, a more general method for
the alkoxycarbonylation of aryl chlorides without
using carbon monoxide is still desirable.
Initial studies focused on the alkoxycarbonylation
of 4-chloro-o-xylene with butyl formate in NMP,
which constitutes a challenging model reaction due to
the deactivation of the chloroarene by the methyl
Figure 1. Examples for aromatic acid derivatives as active
compounds.
Adv. Synth. Catal. 2010, 352, 1205 – 1209
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Thomas Schareina et al.
UPDATE
Figure 2. Tested ligands in the model reaction.
groups. Noteworthy, butyl formate allows for a con-
venient coupling protocol in standard glassware.
In a further series of experiments, the choice of
base was investigated in more detail (Table 2).
In previous work the addition of ruthenium co-cata- Among the various amines and inorganic salts tested,
lysts to the reaction mixture was claimed to be benefi- DBU provided the highest yield. Interestingly, a sig-
cial for the product yield, since the ruthenium com- nificantly lower yield was obtained in the case of
plex should activate the corresponding formic acid DBN, which is structurally similar to DBU.
ester.[3,6] Therefore, a mixture of 0.5 mol% Pd
N
To the best of our knowledge such a highly specific
As shown in Table 1 the choice of ligand is crucial the model reaction gave yields in a range between 30
for the success of the model reaction. The best activi- to 52% (Table 3). To our delight applying acetonitrile
ty is found for ligand L1 [n-butylbis(1-adamantyl)- as solvent provided the desired product in >80%
phosphine, cataCXiumꢄA], which gave 87% conver- yield! Other nitriles were also more effective com-
sion and 52% yield of butyl 3,4-dimethylbenzoate. It pared to standard solvents.
should be noted that this ligand induced also im-
Advantageously, in the presence of acetonitrile the
proved activities in reductive carbonylations and al- addition of ruthenium co-catalysts is also not necessa-
koxycarbonylations of aryl bromides using gaseous ry. Hence, no difference in product yield is observed
CO.[8,9] In addition, in the presence of dppf some ac- in the presence or absence of Ru. Having defined an
tivity and excellent selectivity was obtained.
optimized set of conditions, the scope of the aryl chlo-
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Adv. Synth. Catal. 2010, 352, 1205 – 1209

An Improved Protocol for Palladium-Catalyzed Alkoxycarbonylations of Aryl Chlorides
Table 1. Alkoxycarbonylation of 3,4-dimethyl-1-chloroben-
Table 3. Optimization of reaction conditions – influence of
zene – influence of ligands.[a]
solvents.[a]
Entry
Solvent
T [8C]
Conv. [%]
Yield [%]
1
2
3
4
5
6
NMP
160
160
160
160
160
140
87
66
71
60
55
88
52
42
43
39
35
81
DMAc[b]
dioxane
diglyme
toluene
acetonitrile
Entry T [8C] Ligand (mol%) Conv. [%] Yield [%]
[a]
Reaction conditions: 1 mmol 4-chloro-o-xylene, 1 mL
butyl formate, 0.5 mol% Pd(OAc)2, 0.07 mol%
Ru3(CO)12, 2 mol% L1, 1 mL solvent, 16 h, closed vessel.
GC yields.
1
2
3
4
5
6
7
8
160
160
160
160
140
160
160
160
160
160
160
160
140
140
L1 (2)
L2 (2)
L3 (2)
L4 (1)
L5 (2)
L6 (2)
L7 (2)
L8 (2)
L9 (2)
L10 (2)
L11 (2)
L12 (2)
L13 (2)
L14 (2)
87
23
2
7
18
1
1
3
1
1
52
15
1
4
18
0
0
1
0
0
AHCTUNGTRENNUNG
[b]
Abbreviations: DMAc=N,N-dimethylacetamide.
tion led to lower yields (Table 4, entry 3). As shown
by GC-MS in all cases the main side product is the
corresponding dehalogenated arene.
9
10
11
12
13
14
1
1
0
0
1
0
0
0
Compared to electron-rich arenes, for example, 4-
chloroanisole, which performed well (69%, Table 4,
entry 4), arenes with electron-withdrawing substitu-
ents gave low yields. This observation is in agreement
with other CO-free carbonylation reactions.[10a] Appa-
rently, oxidative addition of the metal complex is not
the rate-determining step, but more likely insertion of
the carbonyl compound or reductive elimination.
On further optimization, we discovered that the use
of butyl formate as both solvent and reagent consider-
ably improved the yields for electron-poor substrates
(see method C in Table 4, entries 5–8). Aryl bromides
reacted with higher yields than the corresponding
chlorides. For example, 4-bromo-o-xylene gave 91%
of the target compound (Table 4, entry 9). Notably, al-
koxycarbonylation of 5-bromo-N-methylimidazole
provided the backbone of the narcotic etomidate in
one step (Table 4, entry 10).[11]
Starting from methyl 4-chlorobenzoate, the isolated
product turned out to be dibutyl terephthalate.
During the course of the reaction 1-butanol is
formed, which reacted with the methyl group of the
ester. This supports the assumption that the mecha-
nism of this alkoxycarbonylation is similar to the one
reported previously.[10]
Finally, 1-chloro-4-vinylbenzene was used as sub-
strate in order to study chemoselectivity issues. Here,
carbonylation of the double bond is observed only to
a minor amount (Table 4, entry 13), resulting in ca.
[a]
Reaction conditions: 1 mmol 3,4-dimethyl-1-chloroben-
zene, 1 mL butyl formate, 0.5 mol% Pd(OAc)2,
0.07 mol% Ru3(CO)12, ligand as given, 120 mol% DBU
(DBU=2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]aze-
pine), 1 mL NMP (NMP=1-methylpyrrolidin-2-one),
temperature as given, 16 h, closed vessel. GC yields.
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
Table 2. Optimization of reaction conditions – base.[a]
Entry Base (mol%) Conv. Yield
[%]
[%]
1
2
3
4
5
6
DBU (120)
87
99
29
5
52
27
18
3
6
11
K3PO4 (120)
DMAP[b] (120)
DBN[b] (120)
1,1,3,3-tetramethylguanidine (120) 85
DBU (20)+K3PO4 (100) 27
[a]
Reaction conditions: 1 mmol 4-chloro-o-xylene, 1 mL
butyl formate, 0.5 mol% Pd(OAc)2, 0.07 mol%
Ru3(CO)12, 2 mol% L1, 1 mL NMP, 1608C, 16 h, closed
vessel. GC yields.
Abbreviations:
AHCTUNGTRENNUNG
[b]
DMAP=4-dimethylaminopyridine,
[1,2-a]pyrimidine.
DBN=2,3,4,6,7,8-hexahydropyrroloAHCUTNGTRENNUNG
ride coupling reaction with butyl formate was ex- 15% of the side product butyl 3-(4-chlorophenyl)acry-
plored next. Highlighted in Table 4, a number of neu- late.
tral and electron-rich chloroarenes, which are in gen-
In addition, some other formates were tested in the
eral less reactive in coupling reactions than electron- alkoxycarbonylation of 3,4-dimethylchlorobenzene
deficient chlorobenzenes, were successfully reacted to (Figure 3). Here, ethyl formate gave a reasonably
give the substituted benzoates in moderate to good good result of 56% yield. The isopropyl ester was
yields. While ortho substituents on the aryl chloride formed in lower yield presumably because of steric
were well tolerated (Table 4, entry 2), 2,6-disubstitu- reasons.
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Thomas Schareina et al.
UPDATE
Table 4. Palladium-catalyzed alkoxycarbonylations with
butyl formate – scope and limitations.[a]
Entry Substrate
1
Method Conv. [%] Yield [%]
B
B
67
82
57
51
2
3
Figure 3. Alkoxycarbonylation with different formates.
B
33
16
Advantageously compared to previous work, it has
been shown that the presented catalyst system does
not need the presence of ruthenium co-catalysts. No-
tably, the reactions can be conveniently carried out
and performed in standard equipment.
4
5
B
C
80
69
69
100
Experimental Section
6
C
100
53[b]
General Remarks
NMP (N-methylpyrrolidone) was dried over CaH2, distilled
at reduced pressure and stored under argon. Butyl formate
was fractionally distilled and stored under argon. Acetoni-
trile was distilled from phosphorus pentoxide and stored
under argon. Ligands L1–L7 and L9 are commercially avail-
able. Ligands L8,[12] L10,[13] L11–L14[14] were available as
samples from our group. All other chemicals are commer-
cially available and were used without further purification.
7
C
C
B
B
C
99
56
63
91
69
56
8
90
9
100
100
100
10
11
Standard Reaction Procedure
All solid ingredients were weighed into a pressure-proof
glass tube with a PTFE-lined cap. The tube was flushed with
argon for at least 1 min, then the liquid compounds were in-
troduced by syringe under a constant flow of argon (stock
solutions of palladium acetate in the respective solvent were
used if appropriate), with the formate ester always as the
last addition. Hexadecane was used as internal GC standard.
The tube was sealed and heated with magnetic stirring for
the time and at the temperature given in the Tables. After
cooling to room temperature ethyl acetate (5 mL) was
added and the reaction mixture was analyzed by GC. Con-
version and yield were calculated as average of 2 parallel
runs. The products can be isolated by column chromatogra-
phy (silica gel, hexane/ethyl acetate) after washing the or-
ganic phase with water, drying over sodium sulfate and dis-
tilling off the solvents.
Butyl 3,4-dimethylbenzoate (product of model reaction):
1H NMR (300 MHz, CDCl3): d=7.8 (bs, 1H), 7.77 (dd, J=
2 Hz, 8 Hz, 1H), 7.18 (d, J=8 Hz, 1H), 4.30 (t, J=6.3 Hz,
2H), 2.32 (s, 6H), 1.75 (m, 2H), 1,45 (m, 2H), 0.98 (t, J=
7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=167.0, 142.1,
136.7, 130.6, 129.6, 128.1, 127.1, 64.6, 30.9, 20.0, 19.7, 19.3,
13.8; IR (ATR, neat): n=2959 (m), 2934 (sh), 2873 (m),
1713 (s, C=O), 1289 (s), 1259 (s), 1218 (s), 1178 (s), 1124
(m), 1101 (s), 759 cmÀ1 (s); elemental analysis: calculated
12
A
B
100
100
45
51
13
[a]
Reaction conditions: 1 mmol aryl halide, 0.5 mol%
Pd(OAc)2, 2 mol% L1, 120 mol% DBU, 16 h, closed
vessel. Method A: 1 mL butyl formate, 0.07 mol%
Ru3(CO)12, 1 mL NMP, 1608C. Method B: 0.5 mL butyl
formate, 1408C, 1 mL acetonitrile. Method C: 1 mL butyl
formate, 1408C. GC yields.
ACHTUNGTRENNUNG
[b]
Product is dibutyl terephthalate.
In summary, an improved protocol for the palladi-
um-catalyzed alkoxycarbonylation of aryl and hetero-
aryl halides using alkyl formates has been developed.
For the first time non-activated chloroarenes have
been successfully carbonylated using alkyl formates. for C13H18O2: C 75.69, H 8.80; found: C 75.65, H 8.71; MS
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Adv. Synth. Catal. 2010, 352, 1205 – 1209

An Improved Protocol for Palladium-Catalyzed Alkoxycarbonylations of Aryl Chlorides
(EI, 70 eV): m/e (%)=206 (9) M+, 150 (100), 133 (99), 105
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Acknowledgements
Financial support for this work from Lanxess (Saltigo
GmbH) and by the State of Mecklenburg-Vorpommern and
the BMBF as well as the DFG (Leibniz Price) is gratefully
acknowledged.
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Adv. Synth. Catal. 2010, 352, 1205 – 1209
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