Covalently bound benzyl ligand promotes selective palladium-catalyzed oxidative esterification of aldehydes with alcohols

Article abstract of DOI:10.1002/anie.201201960

It's a benzyl kind of magic: In the title reaction proceeding with benzyl chloride as the oxidant, the benzyl group serves as a carbon ligand, thus having an ³-coordination effect on palladium (see scheme). A variety of aldehydes and alcohols were selectively converted into the corresponding esters in good to excellent yields. Copyright

Full text of DOI:10.1002/anie.201201960

Angewandte
Chemie
DOI: 10.1002/anie.201201960
Synthetic Methods
Covalently Bound Benzyl Ligand Promotes Selective Palladium-
Catalyzed Oxidative Esterification of Aldehydes with Alcohols**
Chao Liu, Shan Tang, Liwei Zheng, Dong Liu, Heng Zhang, and Aiwen Lei*
Esterification is a fundamental transformation in chemistry.
The essential feature of esterification that particularly
distinguishes it from other reactions lies in its broad
utilization in industry. Up to now, esterification only largely
occurs between carboxylic acid derivatives and alcohols.[1]
Aldehydes are also readily available and are bulk scale raw
chemicals in industry. Theoretically, esterification of alde-
hydes with alcohols is an attractive alternative. However,
current methods to esterify an aldehyde with an alcohol
require oxidation to the acid in advance. As a result, multiple
steps are involved with production of toxic irremovable by-
products, and is incongruent with the current demand of
environmentally benign processes. Therefore, successful
efforts during the past ten years have been focused on
direct esterification of aldehydes with alcohols in the presence
of an oxidant and catalyst.[2] However, challenges still remain.
The key issue is the selectivity between esterification
(aldehyde oxidation) and alcohol oxidation.
catalyzed oxidation of an alcohol into an aldehyde occurs
before esterification of an aldehyde with an alcohol. There-
fore, to find the factors that control the selectivity is essential
for both selective palladium-catalyzed aldehyde formation
and oxidative esterification (Path b, Scheme 1).
We assume that the palladium-catalyzed oxidative
esterification and alcohol oxidation to an aldehyde proceed
through the catalytic cycles shown in Scheme 2. First, the
The oxidation of an alcohol to an aldehyde in the presence
of palladium catalysts has been a fundamental research area
in the chemical synthesis community.[3] In such transforma-
tions, the aldehyde is produced and remains unreacted, thus
resulting in selective aldehyde formation (Path a, Scheme 1).
These facts suggest that in most cases selective palladium-
Scheme 2. Proposed catalytic cycles for alcohol oxidation (Path a) and
oxidative esterification (Path b).
0
À
oxidative addition of oxidant A B to Pd generates the
intermediate A-PdII-B (I1). The following alcoholysis step
À
selectively occurs at the Pd B bond of I1 with an alcohol to
Scheme 1. Alcohol oxidation (Path a) and oxidative esterification
(Path b).
generate the alkoxy palladium intermediate I2 with the aid of
a base. Two pathways are available for intermediate I2. Path a
describes a direct b-hydride elimination to afford the
aldehyde and the palladium hydride intermediate I4 which
undergoes reductive elimination to regenerate Pd0 species.[3c]
This cylcle is the acknowledged pathway for oxidation of an
alcohol into an aldehyde. Path b describes an oxidative
esterification. Before the b-hydride elimination of I2, the
aldehyde insertion occurs to result in the hemiacetal palla-
dium intermediate I3. The b-hydride elimination of I3
releases the ester and the palladium hydride intermediate I4.
Upon examination of the catalytic cycles, it becomes clear
that a key challenge in developing a highly selective
esterification is to control the rate of alcohol oxidation
relative to formation of the hemiacetal palladium species
[*] C. Liu, S. Tang, L. Zheng, D. Liu, Prof. H. Zhang, Prof. A. Lei
College of Chemistry and Molecular Sciences, Wuhan University
Wuhan 430072 (P. R. China)
E-mail: aiwenlei@whu.edu.cn
Homepage: http://www.chem.whu.edu.cn/GCI_WebSite/
main.htm
Prof. A. Lei
State Key Laboratory for Oxo Synthesis and Selective Oxidation,
Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, Lanzhou 730000 (P.R. China)
[**] This work was supported by the National Natural Science
Foundation of China (21025206, 20832003, and 20972118) and the
973 Program (2012CB725302).
À
(Path a versus Path b). In intermediates I1, I2, and I3, the A
Pd bond is preserved, and A will serve as a covalent ligand.
Especially for I2, we believe that the structural and electronic
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201960.
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properties of A will strongly affect the selectivity between
paths a and b.
excellent yield in the presence of 5 mol% [PdCl2(PPh3)2] and
1 equivalent K2CO3 in THF at 608C. However, when 2-
chloroacetophenone was applied as the oxidant, 1b was
selectively converted into its corresponding 4-methylbenzal-
dehyde (2b) in a good yield without any observation of ester
3a. The starting 2a remained intact. Similarly, 4-bromoto-
luene also selectively afforded aldehyde 2b in 72% with just
a trace amount of 3a observed.[5]
N-ligands and P-ligands are normally considered for
palladium-catalyzed alcohol oxidation processes. Actually,
0
À
the oxidative addition of an organohalide (C X) to Pd
À
generates a complex which contains a covalent C Pd bond.
Alcoholysis first occurs at the Pd X bond, and the remaining
À
organo group serves as a covalent ligand through a bond to
a carbon atom (Scheme 2, A = R).[3c] The effect of this
covalently bound carbon ligand in both alcohol oxidation
and esterification has never been taken into account. Herein,
we describe a novel report on a covalently bound benzyl
ligand which promotes palladium-catalyzed oxidative esterifi-
cation of aldehydes with alcohols in a selective manner
[Eq. (1)].
It has been shown that the alcoholysis of I1 selectively
À
À
À
occurred at the Pd Cl bond (A B = Bn Cl, Bn = benzyl)
[Eq. (2)],[6] whereas it selectively occurred at the Pd–enolate
bond of I1’ (generated from the oxidative addition of 2-
0
À
À
chloroacetophenone with Pd , A B = Cl enolate) in the 2-
À
chloroacetophenone system [Eq. (3)], and at the Pd Br bond
of I1’’ (generated from the oxidative addition of 4-bromoto-
0
À
À
luene with Pd , A B = p-tol Br) in the aryl bromide system
[Eq. (4)].[7] As a result, the benzyl group is preserved in the
selective oxidative esterification system [Eq. (2)] (we further
confirmed it by an isotopic labeling experiment; see
Scheme S2 in the Supporting Information), whereas the
chloride and aryl groups are preserved in the selective alcohol
oxidation systems [Eqs. (3) and (4)]. These results show that
the benzyl group is the key for the selective esterification of
aldehydes with alcohols.
Recently, Beller and co-workers as well as our group
simultaneously investigated the palladium-catalyzed oxida-
tive esterification of benzylic alcohols with aliphatic alco-
hols.[4] Ligands were found to be essential for the success of
both transformations. However, little was known about the
ligand effect for the achievement of palladium-catalyzed
oxidative esterification. Based on the above hypothesis, some
organohalides were tested in the oxidative esterification of
aldehydes with alcohols to get some information about ligand
effects on palladium-catalyzed oxidative esterification
(Scheme 3). Interestingly, by using benzyl chloride as the
oxidant, benzaldehyde (2a) was selectively esterified with p-
tolylmethanol (1b; with a 1:1 ratio) to afford 3a in an
To further confirm the benzyl ligand effect, stoichiometric
experiments were carried out by direct utilization of Bn-
[PdCl(PPh3)2] and [PdCl2(PPh3)2] as the oxidant in this
oxidative esterification. In the presence of 1 equivalent of
Bn-[PdCl(PPh3)2], 4-methylbenzaldehyde and benzyl alcohol
were converted into the corresponding ester 3d in 59% yield
without any observation of alcohol oxidation product
[Eq. (5)], whereas use of 1 equivalent of [PdCl2(PPh3)2] led
only to the conversion of benzyl alcohol into benzaldehyde
with a yield of 65%; 4-methylbenzaldehyde was recovered
and ester 3d was not observed [Eq. (6)]. These stoichiometric
experiments obviously show that the covalently bound benzyl
group can control the selectivity and promote the ester
formation.
Here, the covalently bound benzyl group is displayed as
À
Scheme 3. Three oxidants tested in palladium-catalyzed oxidative
esterification. [a] The yield was determined by GC analysis. [b] Yield of
isolated product.
a
carbon ligand (C Pd), which can easily form
h3 coordination to palladium [Eq. (2)]. The h3-coordination
2
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Table 1: Palladium-catalyzed oxidative esterification of aldehyde with
alcohol.[a]
Entry
1
R’-CHO
HO-R
3
Yield
[%][b]
3b
85
2
3
4
3c
3d
3e
96
84
98
effect on palladium might lead to facile dissociation of PPh3,[8]
and will favor of the coordination of the aldehyde to the
palladium center. To prove this h3-coordination effect, a rigid
bidentate ligand, 1,1’-bis(diphenylphosphino)ferrocene)
(dppf), was tested in the oxidative esterification of 2a with
1b. Low yield (33%) of the ester was obtained with trace
amounts of alcohol oxidation were observed (see Scheme S1
in the Supporting Information). This result may be due to the
bidentate ligands having stronger binding to palladium and
thus preventing the h3 coordination, which indicates the
importance of the phosphine ligand dissociation for the
selective esterification.
As the precursor of the covalently bound benzyl ligand,
benzyl chloride is a fundamental industrial chemical, which is
cheap and easily obtained. The side product of this protocol is
toluene which is a widely applied as a solvent and is easy to
separate and recover [Eq. (1)]. This makes the oxidative
esterification more applicable and practical. The reported
oxidants, such as H2O2,[2f,g] PhI(OAc)2,[2d] oxone,[2e] MnO2,[9]
TBHP,[2b] and O2,[2h] for oxidative esterification of aldehydes
with alcohols are usually too strong to control the selectivity
between esterification and alcohol oxidation, therefore,
excess alcohol, especially methanol, is usually applied as
solvent to achieve full conversion of aldehydes. In contrast,
benzyl chloride is a mild oxidant and allows the oxidative
esterification in a 1:1 ratio.
5
6
3 f
91
74
3g
7
8
3h
3i
96
>99
9
3j
98
90
10
3k
11
3l
90
12
3m
3n
>99
13[c]
76
14
15
3o
3p
85
95
16
3q
84
17
18
3r
74
72
We further tested the substrate scope and the data are
listed in Table 1. Various aldehydes and alcohols could be
used to give good to excellent product yields (72–100%).
Aromatic aldehydes were well tolerated (entries 1–7, and 18).
Both strong electron-withdrawing (p-CF3) and strong elec-
tron-donating (p-OMe) groups could be used (entries 5, 6,
3s
[a] Reaction conditions: 2 (0.5 mmol), 1 (0.5 mmol), [PdCl2(PPh3)2]
(5 mol%), K2CO3 (0.5 mmol), BnCl (0.5 mmol) in THF (2 mL) at 608C
for 20 h. [b] Yield of isolated product. [c] 15% of olefin reduction product
was observed.
À
and 18), and aromatic C Cl bonds were well tolerated in this
transformation (entry 7). Aliphatic aldehydes typically
cannot survive strong oxidants, such as H2O2, TBHP, but
they were oxidatively esterified in excellent yields with
various alcohols by using the mild oxidant benzyl chloride
(entries 8–12, 14–17). Aldehydes bearing a secondary ali-
phatic substituent also afforded the esterification product in
excellent yields (entries 11, 12, and 15–17). As we know,
aliphatic aldehydes easily undergo aldol condensations in the
presence of a base, however, no such by-products were
detected in these reaction systems. a,b-Unsaturated alde-
hydes, such as cinnamyl aldehyde, was also successfully
employed in this oxidative esterification.[10] It was oxidatively
esterified with pentan-1-ol to afford the desired ester in 76%
yield (entry 13). In this system, the olefin reduction product of
3n was observed in the yield of 15%. Aliphatic alcohols all
afforded the corresponding esters in excellent yields
(entries 2, 4, 7, 10, 13, and 18). In addition, benzylic alcohols
are known to be readily oxidized into the corresponding
aldehydes, however, both electron-rich and electron-poor
benzylic alcohols were suitable for this transformation. No
alcohol oxidation products were observed, which demon-
strates an excellent selectivity towards esterification
(entries 1, 3, 5, 6, 8, 9, 11, 12, and 16). Allylic alcohol was
also successfully employed in this oxidative esterification.[10]
Cinnamyl alcohol was selectively converted into the corre-
sponding esters with decanal and cyclohexanecarbaldehyde in
excellent yields (entries 14 and 15). No olefin reduction
products were observed in these cases. It is worth noting that
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nonconjugated alkenyl groups could also be tolerated in this
oxidative cross-esterification (entry 16). Importantly, secon-
dary alcohols, both benzylic and aliphatic types, were also
suitable substrates to react with aldehydes to afford the
tion for the further design of ligands in achieving selective
palladium-catalyzed oxidative esterification.
corresponding esters in good yields (entries 17 and 18). To the Experimental Section
General procedure (3a): [PdCl2(PPh3)2] (17.5 mg, 0.025 mmol) and
best of knowledge, this is the most general and selective
oxidative esterification of aldehyde with alcohol in a 1:1 ratio.
To our delight, this esterification could also proceed in the
absence of the THF solvent (Table 2). We scaled up the
amount of alcohol and aldehyde, yet lowered the catalyst
K2CO3 (69.5 mg, 0.5 mmol) were placed in a oven-dried Shlenck tube,
which was filled with nitrogen by using standard Schlenk techniques.
THF (2.0 mL), aldehyde 2a (0.50 mmol), and alcohol 1b (0.50 mmol)
were then added to the reaction tube. The reaction mixture was
stirred at 608C for 20 h and the resulting mixture was quenched with
water. The suspension was then extracted by ethyl acetate (3 ꢀ 5 mL),
the organic layers were combined, and dried over sodium sulfate. The
pure product was obtained by flash column chromatography on silica
gel (petroleum ether/ethyl acetate = 50:1). The yield of the siolated
product was 96%. 1H NMR (300 MHz, CDCl3): d = 7.98 (d, J =
7.2 Hz, 2H), 7.44 (t, J = 7.5 Hz, 1H), 7.32 (t, J = 7.5 Hz, 2H), 7.25
(d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.1 Hz, 2H), 5.23 (s, 2H), 2.26 ppm (s,
3H). 13C NMR (75 MHz, CDCl3): d = 166.4, 138.0, 132.8, 130.0, 129.5,
129.1, 128.2, 66.5, 21.0 ppm.
Table 2: Palladium-catalyzed oxidative esterification of aldehydes with
alcohols under solvent-free conditions.[a]
Entry
R’-CHO
HO-R
3
Yield
[%][b]
1
2
3
3d
3k
3e
97
>99
99
Received: March 12, 2012
Published online: && &&, &&&&
Keywords: aldehydes · esterification · ligand design · oxidation ·
palladium
.
4
5
6
3t
3g
3r
72
83
62
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loading at 1108C. Various aldehydes and alcohols were
esterified under these solvent-free conditions. Several typical
examples are listed in Table 2 for a 5 mmol scale reaction of
aldehydes and alcohols in the presence of 0.25 mol% of
[PdCl2(PPh3)2]. Good to excellent yields of the desired esters
were obtained and contained various functional groups, such
as p-OMe and p-CF3 (entries 4 and 5). Aliphatic aldehydes
and alcohols afforded excellent yields of the corresponding
esters (entries 2 and 3). A secondary alcohol was also
esterified in good yield (entry 6). To our knowledge, very
few reported procedures could achieve such a low catalyst
loading for oxidative esterifications.[11]
In conclusion, we have demonstrated that a covalently
bound benzyl ligand promotes the selective palladium-
catalyzed oxidative esterification of aldehydes with alcohols
by using benzyl chloride as the oxidant. The covalently bound
benzyl group is a carbon ligand which provides an h3-
coordination effect on palladium. The study of the substrate
scope showed that various aldehydes and alcohols were
selectively converted into the corresponding esters in high
selectivity and good to excellent yields by using benzyl
chloride as the oxidant. Moreover, the ratio of the aldehyde
and alcohol is 1:1. Neither of the substrates needs to be excess.
Under solvent-free reaction conditions large-scale reactions
were carried out in the presence of a low catalyst loading.
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Communications
Synthetic Methods
C. Liu, S. Tang, L. Zheng, D. Liu,
H. Zhang, A. Lei*
&&&& — &&&&
Covalently Bound Benzyl Ligand
Promotes Selective Palladium-Catalyzed
Oxidative Esterification of Aldehydes with
Alcohols
It’s a benzyl kind of magic: In the title
reaction proceeding with benzyl chloride
as the oxidant the benzyl group serves as
a carbon ligand, thus having an h3-
coordination effect on palladium (see
scheme). A variety of aldehydes and
alcohols were selectively converted into
the corresponding esters in good to
excellent yields.
6
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Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!