Pd(ii)-catalyzed oxidative alkoxycarbonylation of 2-phenoxypyridine derivatives with CO and alcohols

Article abstract of DOI:10.1039/c4ob00084f

A Pd(ii)-catalyzed oxidative alkoxycarbonylation of phenol derivatives with atmospheric pressure of CO-O₂ and alcohols has been achieved. The reaction provides an efficient strategy for the synthesis of carboxylic esters and can be applied to the late-stage modification of complex molecules. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00084f

Organic &
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Pd(II)-catalyzed oxidative alkoxycarbonylation of
2-phenoxypyridine derivatives with CO and
alcohols†
Cite this: Org. Biomol. Chem., 2014,
12, 2538
Received 12th January 2014,
Accepted 21st February 2014
Bin Liu,a Huai-Zhi Jianga and Bing-Feng Shi*a,b
DOI: 10.1039/c4ob00084f
www.rsc.org/obc
A Pd(II)-catalyzed oxidative alkoxycarbonylation of phenol deriva- directed by hydroxyl auxiliary using amino acid ligands to
tives with atmospheric pressure of CO–O2 and alcohols has been promote the reaction.7l Recently, Huang and co-workers
achieved. The reaction provides an efficient strategy for the syn- reported an efficient method for the synthesis of phenylacetic
thesis of carboxylic esters and can be applied to the late-stage acid esters from simple toluenes through Pd-catalyzed non-
modification of complex molecules.
directed benzylic C–H bond activation in the presence of CO.6
Beller and co-workers reported a ruthenium catalyzed carbony-
lative C–C bond formation by directed C–H functionalization.8f
In these reports, however, nucleophiles are mainly restricted to
heteroatoms in the directing groups with active protons
(Fig. 1A), such as amines7a–k,8a–c or alcohol,7l,m,9 or carbon
nucleophiles (Fig. 1B), such as alkenes8d,e or arenes.7o,8f
Aromatic and heteroaromatic carbonyl compounds are vital
intermediates in the manufacture of agrochemicals, dyes,
pharmaceuticals, and other industrial products. Palladium-
catalyzed coupling reactions have become a powerful tool in
organic synthesis. Today, there are numerous applications of
palladium-catalyzed carbonylation in the preparation of phar-
maceuticals, agrochemicals, and advanced materials both on
the laboratory and industrial scales. However, Pd(II)-catalyzed
intermolecular alkoxycarbonylation of arenes with CO and
alcohols remains a great challenge.10 Shi reported a Pd(II)-cata-
lyzed carbonylation of N,N-dimethylbenzylamines with the
assistance of LiCl.10b Very recently, our group reported an
Since the pioneering work of Heck and co-workers in the
1970s on palladium catalyzed carbonylation reactions, the
application of CO as a cost-efficient C1 building block to access
carboxylic acid derivatives has attracted tremendous interest in
the past 40 years.1–3 However, this method necessitates the use
of prefunctionalized starting materials, which require
additional synthetic operation, and thus reduces the overall
efficiency of this transformation. For this reason, transition-
metal catalyzed direct carbonylation of relatively unactivated
C–H bonds has emerged as an increasingly viable alternative
to the traditional method.4 Since the seminal work of Fujiwara
in 1980,5 direct oxidative carbonylation of C–H bonds with CO
in the presence of various nucleophiles using palladium,
ruthenium, and rhodium catalysts has undergone rapid
development.6–10 Amine derivatives have long been used as
directing groups for the oxidative carbonylation. In 2004, Orito
developed a Pd(II)-catalyzed direct aromatic carbonylation that
affords benzolactams from secondary ω-phenylalkyl amines.7a
In 2011, Zhu developed an efficient synthesis of quinazolin-
4(3H)-ones from N-aryl amidines through palladium catalyzed
intramolecular C(sp2)–H carboxamidation.7e Later, Zhu and
Zhang developed an unprecedented C–H aminocarbonylation
reaction using unprotected aniline NH2 as a directing group,7j,k
and various free (NH) phenanthridinone derivatives were
efficiently synthesized. Yu and coworkers developed the first
palladium catalyzed carbonylation of aromatic C–H bonds
aDepartment of Chemistry, Zhejiang University, Hangzhou, 310027, China.
E-mail: bfshi@zju.edu.cn
bState Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032,
China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4ob00084f
Fig. 1 Transition-metal-catalyzed C–H carbonylation.
2538 | Org. Biomol. Chem., 2014, 12, 2538–2542
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efficient protocol for the preparation of aryl carboxylic esters
With the optimized conditions in hand, we examined the
via palladium(II)-catalyzed alkoxycarbonylation of arenes and scope and limitations of the alkoxycarbonylation process
heteroarenes with atmospheric pressure of CO and alcohols.10c (Table 2). We were pleased to find that a variety of phenol
In our continuous studies of the synthesis of bioactive mole- derivatives were compatible with the optimal conditions and
cules via C–H functionalization, we are particularly interested could be converted to the desired carboxylic esters in modest
in C–H functionalization directed by removable directing to good yields (up to 92%). An o-methylphenol derivative gave
groups.11 Herein, we report an efficient protocol for the syn- a reduced yield (2b, 30%) due to the steric hindrance between
thesis of carboxylic esters via Pd-catalyzed alkoxycarbonylation the directing group and the methyl group in the ortho-position.
of 2-phenoxypyridines under atmospheric pressure of CO and Other methyl-substituted phenols gave reasonable yields as
O2 (Fig. 1C).12
shown. Surprisingly, 3,5-dimethylphenol derivative 1e reacted
We commenced our studies by probing a variety of oxidants smoothly to give the desired product in 67% yield, regardless
for the alkoxycarbonylation of 1a with pentanol (15 equiv.) in of the steric congestion in the ortho-position. Phenol deriva-
the presence of a balloon pressure of CO/O2 (4 : 1, v/v, Table 1). tives containing electron-donating groups were generally more
The use of CuBr2 as an oxidant gave only unsatisfactory results reactive and afforded higher yields (2f–2h). Fluoride is also
(entries 1–4); unfortunately a number of solvents, such as compatible with the process, albeit affording the product in
DCE, DMF and toluene, were tested in the presence of CuBr2: lower yield (2i, 37%). Primary alcohols, such as MeOH and
they were ineffective for the reaction (entries 2–4). To improve EtOH, gave moderate yields (2k and 2l, 64% and 67%, respect-
the reaction further, we evaluated the influence of other reac- ively). Notably, secondary alcohols, such as isopropanol, were
tion parameters. As shown in Table 1, a more promising result also compatible with this protocol (2m, 71%). When
was obtained using CuSO4 as an oxidant and 1,4-dioxane as a CF3CH2OH and phenol were used, the ortho-alkoxycarbony-
solvent (entry 5, 55% yield). A variety of other oxidants, such lated products were hydrolyzed to phenols under the standard
as CuCl, AgBF4, AgOTf, AgOAc and AgTFA, were then tested, reaction conditions (3n, 50%, and 3o, 48%). The same thing
and the desired product was obtained in 75% yield when happened to m-methoxylphenol and 1-naphthol derivatives
AgTFA was used as the oxidant (entries 6–10). A reduced yield (3g, 73%, and 3j, 84%). It is interesting to note that mono-
was obtained in the absence of O2, since oxygen might be a co- carbonylation products were obtained in all cases from the
oxidant in this reaction (entry 11, 41%). Among the reaction corresponding substrates.
temperatures examined, it turned out that the yield decreased
We were delighted to find that the palladium-catalyzed
when the temperature was lower than 100 °C or higher than alkoxycarbonylation reaction was compatible with a natural-
100 °C (entries 12 and 13); at last it was revealed that the trans- product-derived substrate, such as estrone, as shown in
formation was best conducted at 100 °C (entries 10 and Scheme 2. The pyridyl auxiliary can be installed via a copper-
12–14).
catalyzed C–O bond formation of estrone (4).13 Subsequently,
the alkoxycarbonylation can be achieved selectively at the
less sterically hindered C–H bond under our optimal reaction
conditions (5a, 53% yield with phenol; 5b, 52% yield with
pentanol). This process highlights the potential utility of
this reaction in the late-stage modification of complex
molecules (Scheme 1). It is worth noting that the pyridine
auxiliary can be removed as demonstrated by Ackermann
and Wu.12a–c
Table 1 Optimization of the reaction conditionsa
To check the reversibility of the C–H activation step, a reac-
tion using substrate 1h was carried out in CD3OD in the
absence of CO (Scheme 2). No deuterium incorporation was
detected even after 24 h. When the same reaction was con-
ducted in the presence of CO and was stopped after 24 h, no
deuterium incorporation was observed in the starting material
1h or in the product. These deuterium experiments suggested
that the C–H activation step was irreversible.
Although the details of the mechanism of this reaction
remain to be elucidated, a plausible mechanism can be pro-
posed on the basis of the above results and previous studies
(Fig. 2).12c First, as reported previously, coordination of Pd(II)
with 2-phenoxypyridine (1) triggers cyclopalladation to form
the dimeric palladacycle A, which has been characterized by
X-ray crystallographic analysis.12c Intermediate B is then
formed via ligand exchange. Subsequently, 1,1-migratory inser-
tion of CO into the Pd–C bond to a seven-membered cyclic
Entry
Oxidant
T (°C)
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
CuBr2
CuBr2
CuBr2
CuBr2
CuSO4
CuCl
AgBF4
AgOTf
AgOAc
AgTFA
AgTFA
AgTFA
AgTFA
AgTFA
100
100
100
100
100
100
100
100
100
100
100
80
1,4-Dioxane
CH2Cl2
Toluene
10
0
0
ClCH2CH2Cl
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
0
55
31
37
Trace
0
75
41
47
66
70
9
10
11c
12
13
14
90
110
a Reaction conditions: 1a (0.4 mmol), Pd(OAc)2 (10 mol%) and oxidant
(0.4 mmol) in 2 mL solvent for 24 h. b Yields are given for isolated
products after chromatography. c 1 atm CO only.
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Table 2 The scope of olefins
Entry
1
Substrate
Product
Yielda [%]
75
Entry
9
Substrate
Product
Yielda [%]
37
2
30
10
15
3
4
50
50
84b
64
11
12
13
1h
1h
1h
5
6
7
67
44
24c
67
71
14
15
1h
1h
50
48
73b,c
8
92
a Isolated yield. b Py was removed. c CuSO4 was used as an oxidant.
intermediate C takes place, followed by C–O bond reductive would finish the catalytic cycle. However, an alternative route
elimination to afford the desired product (2a) and Pd(0). that involves the insertion of CO into the Pd–OR bond cannot
Finally, Pd(0) is oxidized by Ag(I)/O2 to regenerate Pd(II), which be ruled out at this stage (Fig. 2).10b,14
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the utility of this protocol in the derivatization of a natural
product, which showcases that this reaction could be applied
in late stage total synthesis.
Acknowledgements
Financial support from the National Science Foundation of
China (21002087, 21142002, and 21272206), the Fundamental
Research Funds for the Central Universities (2014QNA3008),
Zhejiang Provincial NSFC (Z12B02000), the Qianjiang Project
(2013R10033) and the Specialized Research Fund for the Doc-
toral Program of Higher Education (20110101110005) is grate-
fully acknowledged.
Scheme 1 Derivatization of estrone.
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In conclusion, we have achieved a Pd(II)-catalyzed oxidative
alkoxycarbonylation of phenol derivatives with atmospheric
pressure of CO–O2 and alcohols. This protocol obviates the
need for pre-functionalization to generate aryl halide and
utilize carbon monoxide, providing an efficient strategy for the
synthesis of carboxylic esters. Furthermore, we demonstrate
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