Palladium-Catalyzed Carbonylative Esterification of Primary Alcohols with Aryl Chlorides through Dehydroxymethylative C-C Bond Cleavage

Article abstract of DOI:10.1021/cs501778q

Aryl chlorides in the presence of Pd/C catalyst and NaF react with primary alcohols to form esters, arenes, and alkanes. In this reaction, aryl chlorides act as both oxidants and coupling partners, whereas alcohols serve as both carbonyl sources and alkoxy components of the ester products. (Formula Presented).

Full text of DOI:10.1021/cs501778q

Letter
pubs.acs.org/acscatalysis
Palladium-Catalyzed Carbonylative Esterification of Primary Alcohols
with Aryl Chlorides through Dehydroxymethylative C−C Bond
Cleavage
Hyo-Soon Park, Dong-Su Kim, and Chul-Ho Jun*
Department of Chemistry, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-749, Korea
S
* Supporting Information
ABSTRACT: Aryl chlorides in the presence of Pd/C catalyst and
NaF react with primary alcohols to form esters, arenes, and
alkanes. In this reaction, aryl chlorides act as both oxidants and
coupling partners, whereas alcohols serve as both carbonyl
sources and alkoxy components of the ester products
KEYWORDS: C−C activation, carbonylative esterification, catalysis, decarbonylation, palladium
arbonylative coupling reactions are of current interest in
generated in these reactions through a carbonylative
Cthe chemical industry because they produce many esterification process. Specifically, the primary alcohol and
carbonyl compounds such as esters, amides, and ketones.1
aryl chloride participate in a Pd promoted dehydroxymethyla-
tive C−C bond cleavage reaction that produces Pd(0)CO,
which is trapped sequentially by the aryl chloride and alcohol.
This is a rare example of a process in which the reactants play
dual roles with the aryl chloride serving as an oxidant and
coupling partner and the alcohol as a source of the carbonyl
and alkoxy group of the ester.
In initial experiments, we observed that reaction of
chlorobenzene (1a) with 2-(naphth-1-yl)ethanol (2a) in the
presence of Pd/C (3a, 5 mol %) and NaF (4a, 2 equiv) at 150
°C for 9 h leads to formation of benzene (6a) and ester 7a in
respective 57% and 37% yields based on 1a (eq 1). Another
interesting product, 1-methylnaphthalene (5a), is generated in
a 45% yield based on 1a, presuming that 1 equiv of 1a
dehydroxymethylates 1 equiv of 2a to give 5a.
Especially important are processes that produce esters, which
serve as components of many industrial processes. One
common method for synthesis of esters involves transition
metal-catalyzed, carbonylative coupling reactions of aryl halides
with alcohols using CO gas.2 Owing to the toxic nature and
pressure control problems associated with CO gas, other
nontoxic and nongaseous carbonyl surrogates like alkyl
formates,3 chloroform,4 and formic anhydrides5 have been
developed for use in carbonylative coupling reactions.
In the course of recent studies of palladium-catalyzed
oxidations of primary alcohols, we observed that addition of
aryl chlorides to the reaction mixture causes production of
alkanes along with a mixture of arenes and of cross-coupled
esters. We speculated that the carbonyl group of the ester
product is derived from the alcohol through an oxidation and
decarbonylation sequence (Scheme 1).
Herein, we describe the results of an investigation, which has
confirmed this proposal by demonstrating that esters are
Scheme 1. Concept of Carbonylative Esterification through
Dehydroxymethylation
Received: November 10, 2014
Revised: December 8, 2014
© XXXX American Chemical Society
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Letter
The nature and relative amounts of the products suggest that
5a and 6a arise from 2a and 1a, respectively, and that ester 7a is
derived from 1a and 2a (Scheme 2). In the initial step of the
Scheme 2. Mechanistic Overview of Carbonylative
Esterification of 1a and 2a
Figure 1. 13C NMR analysis of 7b*.
Scheme 4. Catalytic Cycle for the Carbonylative
Esterification Reaction
pathway for this process, alcohol 2a undergoes chlorobenzene
(1a) and Pd(0) promoted dehydroxymethylation by C−C
bond cleavage to produce 6a and 5a. Pd(0)(CO), also
generated in the initial step, then participates in carbonylative
esterification with 1a and the 2a to form the ester 7a. Using this
pathway, the theoretical yields of 5a, 6a, and 7a produced in the
process based on 1a are 50%, 50%, and 50%, respectively.
To demonstrate the validity of this mechanistic proposal and,
specifically, that the carbonyl group in the ester product and
methylnaphthalene both arise via oxidative cleavage of 2-
(naphth-1-yl)ethanol followed by decarbonylation of resulting
aldehyde, reaction using the 1,1-d2 derivative 2a-d2 was
explored (Scheme 3).6 In accord with the proposed mechanism
Scheme 3. Carbonylative Esterification with 1,1-d2-Labeled
2-(Naphth-1-yl)ethanol
is neutralized by NaF (4a). Aldehyde 9 is then readily
decarbonylated to generate alkane 5 and Pd(0)CO 10, which
undergoes oxidative addition with aryl chloride 1 followed by
migratory insertion to form acyl-Pd(II)chloride 11. Reaction of
11 with the alcohol produces the ester product 7 along with
regenerated Pd(0) and HCl.
In order to uncover the optimal conditions for the ester-
forming reaction, various transition metal catalysts were tested
(Table 1). The results show that palladium catalysts such as 3a
and 3b promote the process (entries 1, 2). However, in the
reaction using 3b, ligand decomposition (e.g., P−C bond
cleavage) was observed to take place.7 Other transition metals
do not catalyze the ester-forming reaction (entries 3−4). As a
result, Pd/C (3a) is the optimal catalyst for the esterification
reaction. In this process, a base is required to neutralize HCl
generated from the aryl chloride in both steps in which it
participates. Among various bases tested (entries 1, 5−11),
greater than 2 equiv of NaF (4a) displayed the best activity
without causing the production of side products (entries 1, 5−
6).8 It is important to note that bases such as Na2CO3,
NaHCO3, and NaOH, which are commonly used in cross-
coupling processes, promote reactions that generate only a low
yield of ester 7a and large amounts of side products such as
biphenyl (8a) (entries 7−11).
involving the intermediacy of d1-aldehyde 9a, reaction of 2a-d2
leads to formation of 5a-d1, which contains 95% of deuterium
in its methyl group.
To unambiguously identify the source of the ester carbonyl
group, 1-13C-2-phenylethanol (2b*) was utilized as the starting
material in the reaction. The results of 13C NMR analysis of the
products show that phenethyl ester 7b*, bearing the 13C-
labeled carbonyl group, is generated in this process (Figure 1).
This observation demonstrates that the carbonyl group in 7b*
comes from hydroxymethyl group of 2b* (eq 2).
The experimental results suggest that mechanism displayed
in Scheme 4 is operating in the ester-forming reaction.
Specifically, the aryl chloride along with Pd(0) oxidizes the
primary alcohol 2 to form aldehyde 9, arene 6 and HCl, which
The aryl chloride substrate scope of the process was explored
next (Table 2). The results of this effort show that steric
hindrance of the aryl group affects the ester-forming reaction as
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Letter
a
Table 1. Optimization of Carbonylative Esterification
b
yield (%)
entry
catalyst
ligand
base (x equiv)
NaF (4a, 2)
5a
6a + 7a (6a, 7a)
8a
1
2
3
4
5
6
7
8
3a
45
40
5
94 (57, 37)
95 (65, 30)
7 (7, 0)
0
0
Pd(PPh3)4 (3b)
4a (2)
4a (2)
RhCl(PPh3)3 (3c)
PPh3 (9a)
PPh3 (9a)
0
[Ir(COE)2Cl2]2 (3d)
4a (2)
12
33
43
22
34
28
13
36
4 (4, 0)
0
3a
3a
3a
3a
3a
3a
3a
4a (1)
68 (39, 29)
96 (61, 35)
65 (45, 20)
64 (63, 1)
64 (49, 15)
66 (53, 13)
86 (85, 1)
0
4a (3)
0
KF (4b, 2)
CsF(4c, 2)
Na2CO3 (4d, 2)
NaHCO3 (4e, 2)
NaOH (4f, 2)
32
19
36
34
8
c
9
d
10
11
Reaction conditions: 1a (0.4 mmol), 2a (0.56 mmol), 3 (0.02 mmol), 4 and 9a (0.02 mmol) at 150 °C for 9 h and with yields calculated based on 1a
a
b
Small amounts (<5%) of dehydroxylated product and Tishchenko type ester were formed. 7a is isolated yield. Yields of 5a and 6a were
c
d
1
determined by GC-MS and H NMR. 14% of Tishchenko type ester formed. 11% of Tishchenko product formed.
a
4-bromochlorobenzene was also applied in this reaction, any
Table 2. Substrate Scope of Aryl Halide
ester product was not obtained, implying that aryl bromide
destroys the catalytic activity of Pd/C (entry 11).
The use of various alcohols for this transformation was also
probed (Table 3). As expected based on the proposed
a
Table 3. Substrate Scope of Alcohol
Reaction conditions: 1 (0.4 mmol), 2a (0.56 mmol), 3a (0.02 mmol)
a
and 4a (0.8 mmol) at 150 °C for 9 h and yields are based on 1. Small
Reaction conditions: 1a (0.4 mmol), 2 (0.56 mmol), 3a (0.02 mmol)
and 4a (0.8 mmol) at 150 °C for 9 h and yields calculated based on 1a.
amounts (<5%) of dehydroxylated compounds and Tishchenko type
b
esters are generated. 7 is isolated yield. Yields of 5a and 6 were
a
c
determined by GC-MS and 1H NMR. 14% of dehydroxylated
Small amounts (<5%) of dehydroxylated compounds and Tishchen-
b
d
ko type esters were produced. 7 is isolated yield. Yields of 5 and 6a
compound was produced. 3% of 1a and 10% of 8a were obtained.
c
1
were determined by GC-MS and H NMR. 42% of dehydroxylated
d
compound was produced. 18% of dehydroxylated compound and
23% of Tishchenko type ester were produced. 1,4-dioxane(50 μL)
e
exemplified by the fact that ortho-methylchlorobenzene (1d) is
much less reactive than is its para-substituted analogue 1b
(entries 2−4). In addition, aryl chlorides with electron-donating
substituents (e.g., 1e) are more reactive than their electron-
withdrawing substituted counterparts (e.g., 1f and 1g) (entries
5−7). It is interesting to note that only chloroarenes participate
in this reaction, while other haloarenes such as fuloro (1h),
bromo (1i), and iodobenzene (1j) do not (entries 8−10). A
likely reason for this selectivity is that chloroarenes oxidize
primary alcohols more readily than do other haloarenes.9 When
was used as solvent.
mechanism, only primary alcohols serve as substrates for the
process owing to their capability to form key aldehyde
intermediates that undergo decarbonylation to generate
Pd(0)CO.10 This type of dehydroxymethylation process is an
interesting example of a C−C bond cleavage reactions.11
Primary alcohols containing aryl groups display higher
reactivity than do their aliphatic alcohol analogues. In contrast
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Letter
to other primary alcohols, including benzyl alcohol (2c), 3-
phenyl propanol (2d), 4-phenyl butanol (2e), the ω-phenyl
alkanol 2-phenylethanol (2b) participates in the highest
yielding reactions to form ester 7b (entries 1−4). We believe
that phenylacetaldehyde formed from 2-phenylethanol (2b) is
more readily dehydroxymethylated because it gives the more
stable benzyl palladium complex. It should be noted that
examples exist in which stable benzyl transition metal
complexes are formed by C−C bond activation of benzyl
ketones.12 Among the 2-phenylethanols probed, electron-
donating substituted members like the p-methoxy-derivative
2f react more efficiently than do their electron-withdrawing
group substituted analogues p-fluoro-derivative 2g (entries 5,
6).
Methanol is a good carbonyl source owing to the fact that
C−C bond cleavage is not required to form the Pd−CO
complex. Reaction of chlorobenzene with methanol, carried out
in the presence of Pd/C (3a) and NaF (4a) at 150 °C for 24 h,
was observed to form benzene (6a) and methyl benzoate (7q)
in 89% total yield (52/37 ratio) along with 10% of the
homocoupling product 8a (entry 1 in Table 4). Other aryl
Compound characterization data, 1H and 13C NMR
spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: junch@yonsei.ac.kr. Fax: (+82)-2-3147-2644.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by a grant from the National
Research Foundation of Korea (NRF) (2011-0016830).
■
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ASSOCIATED CONTENT
* Supporting Information
The following file is available free of charge on the ACS
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