Oxidative Alkane C?H Alkoxycarbonylation

Article abstract of DOI:10.1002/chem.201602791

Directly utilizing a chemical feedstock to construct valuable compounds is an attractive prospect in organic synthesis. In particular, the combination of C(sp³)?H activation and oxidative carbonylation involving alkanes and CO gas is a promising and efficient method to synthesize carbonyl derivatives. However, due to the high C?H bond dissociation energy and low polarity of unactivated alkanes, the carbonylation of unactivated C(sp³)?H bonds still remains a great challenge. In this work, we introduce a palladium-catalyzed radical oxidative alkoxycarbonylation of alkanes to prepare numerous alkyl carboxylates. Various alkanes and alcohols were compatible, generating the desired products in up to 94 % yield. Remarkably, ethane, a constituent of natural gas, could be employed as a substrate under the standard reaction conditions. Preliminary mechanistic studies revealed a probable palladium-catalyzed radical process.

Full text of DOI:10.1002/chem.201602791

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Title: Oxidative Alkane C-H Alkoxycarbonylation
Authors: Lijun Lu; Renyi Shi; Luyao Liu; Jingwen Yan; Fangling Lu; Aiwen Lei
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COMMUNICATION
Oxidative Alkane C-H Alkoxycarbonylation
Lijun Lu, [a] Renyi Shi, [a] Luyao Liu, [a] Jingwen Yan, [a] Fangling Lu, [b] and Aiwen Lei*[a, b]
Abstract: Directly utilizing chemical feedstock to construct valuable
compounds is an attractive prospect in organic synthesis.
Significantly, the combination of C(sp3)-H activation and oxidative
carbonylation involving alkanes and CO gas is a promising and
efficient method to synthesize carbonyl derivatives. However, due to
the high C-H bond dissociation energy and low polarity of
unactivated alkanes, the carbonylation of unactivated C(sp3)-H
bonds still remains a great challenge. In this work, we introduce a
palladium-catalyzed radical oxidative alkoxycarbonylation of alkanes
to prepare numerous alkyl carboxylates. Various alkanes and
alcohols were compatible, generating the desired products in up to
94% yields. Remarkably, ethane, a constituent of natural gas, could
be employed as a substrate under standard reaction conditions.
Preliminary mechanistic studies revealed a probable palladium-
catalyzed radical process.
typical Pd-catalyzed C-H bond activation process until with the
assistance of directing groups.
Alternatively, radical process has shown its potential in C-H
bond functionalization, especially for C(sp3)-H bonds in the past
several decades. Numerous examples have been reported that
the hydrogen atom from alkanes could be abstracted under
simple and mild reaction conditions, among which Ryu and
others have done pioneering works in radical carbonylation of
alkanes.[11] Meanwhile, Pd catalysis has shown its power in the
carbonylation transformations. Hence, oxidative C(sp3)-H
carbonylation might be achieved by combining Pd catalysis with
radical process (Scheme 1). Herein we reported a novel
palladium-catalyzed radical oxidative carbonylation of alkanes
with alcohols to afford a series of alkyl carboxylates in one step.
Abundant, readily available from petroleum and natural gas,
alkanes are main energy substances as well as important
feedstock for the chemical industry. During the last decades,
continuous efforts have been devoted to the conversion of
alkanes.[1] On the other hand, as an important C1 source, CO
has been widely applied in industry and academic research.[2]
For example, Fischer-Tropsch synthesis and hydroformylation
are mature in industry, and palladium-catalyzed carbonylation
reaction represents one of the most powerful synthetic methods
to obtain multifariously useful carbonyl derivatives such as acids,
esters, amides, ketones, heterocycles, etc.[3] Hence, it is
attractive to directly utilize easily available alkanes and CO to
construct valuable compounds.
Scheme 1. Combination of Pd Catalysis and Radical Process.
Table 1. Optimization of Reaction Conditions for the Palladium-catalyzed
Radical Oxidative Carbonylation of Cyclohexane with Benzyl Alcohol.[a]
Entry
1
Variations from the standard conditions
Without PdCl2
Yield [%][b]
In recent years, C(sp3)-H activation and functionalization has
become a hot topic within the chemistry community.[4] For
selected examples, Yu’s ligand-controlled C(sp3)-H arylation and
olefination, Hartwig’s borylation of alkanes and MacMillan’s H-
atom transfer process of C-H bonds are significant
advancements in this area.[5] Meanwhile, oxidative carbonylation
between C-H and X-H bonds has attracted more attention, which
meets the principles of green chemistry and sustainable
17
2
-
84 (79)
54
3
1 mol% PdCl2 instead of 5 mol% PdCl2
Pd(OAc)2 instead of PdCl2
1.0 equiv. DTBP instead of 1.8 equiv. DTBP
TBHP instead of DTBP
Without DCE
4
67
5
54
chemistry.[6]
Therefore,
C(sp3)-H
activation/oxidative
6
4
carbonylation is a promising and efficient method to convert
simple alkanes into their functionalized forms,[7] such as alkyl
carboxylates and their derivatives.[8] These commodity
chemicals are important building blocks of numerous natural
products, pharmaceuticals and agrochemicals.[9]
7
41
8
MeCN instead of DCE
Without PPh3
68
9
24
However, it is still a great challenge to achieve C(sp3)-H
functionalization. In general, the pKa value of alkanes are more
than 40 which is too high to undergo deprotonation with the aid
of base, and C(sp3)-H bonds of alkanes also have a high bond
dissociation energy and a very low polarity.[10] It is difficult to
achieve the C(sp3)-H oxidative carbonylation of alkanes by the
10
11
1 atm CO instead of 5 atm CO
90 oC instead of 110 oC
75
76
[a] Reaction conditions: 1a (1.5 mL), 2a (0.20 mmol), CO (5 atm), PdCl2 (5
mol% based on 2a), PPh3 (11 mol% based on 2a), DTBP (1.8 equiv. based
on 2a), DCE (0.5 mL), 110 oC, 24 h. [b] Yields were determined by GC
analysis, calibrated using biphenyl as the internal standard (isolated yield in
parentheses).
[a]
L. Lu, R. Shi, L. Liu, J. Yan, Prof. A. Lei
College of Chemistry and Molecular Sciences, the Institute for
Advanced Studies, Wuhan University
Wuhan 430072, People’s Republic of China
E-mail: aiwenlei@whu.edu.cn
F. Lu , Prof. A. Lei
National Research Center for Carbohydrate Synthesis, Jiangxi Normal
University, Nanchang 330022,
Nanchang 330022, People’s Republic of China
Initially, we explored the process with cyclohexane (1a) and
benzyl alcohol (2a) as substrates (Table 1). With the
combination of 5 mol% PdCl2 as catalyst, 11 mol% PPh3 as
ligand and DTBP (di-tert-butyl peroxide) as oxidant, 84% yield of
[b]

Chemistry - A European Journal
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COMMUNICATION
the desired product could be obtained in DCE (entry 2). To our
surprise, 17% yield of 3aa was obtained without Pd catalyst
(entry 1). With Pd(OAc)2 the yield was slightly decreased (entry
4). When decreasing the Pd catalyst loading to 1 mol%, there
was an obvious drop in yield (entry 3). DTBP plays an important
role in this reaction. We observed a drop in yield when we used
less equivalent of DTBP or used TBHP instead of DTBP as
oxidant (entries 5, 6). Under neat condition or using MeCN as
solvent resulted in less yields (entries 7, 8), and the reaction
could not proceed well without PPh3 (entry 9). The pressure of
CO and the temperature seemed to have less influence for this
transformation, for 75% yield of 3aa could be obtained even
when using non-pressurized CO (entries 10, 11).
excellent yields (5aa-5ae). In addition, a variety of functional
groups such as alkoxy, chloro and alkenyl were tolerated in this
transformation (5af-5aj). To further explore the applicability of
alcohols, various secondary alcohols were also investigated.
Reactions of isopropanol, 2-octyl alcohol and cyclohexanol
proceeded well to afford the desired esters in excellent yields
(5ak-5am). However, tertiary alcohols such as 2-methyl-2-
hexanol and 1-adamantanol could only give moderate yields
(5an, 5ao). In comparison to 1,4-benzenedimethanol, diols such
as ethanediol, 1,4-butanediol, neopentyl glycol and 1,6-
hexanediol showed better reaction efficiency (5ap-5as).
Surprisingly, trimethylolethane was also compatible (5at).
Importantly, natural products such as L-menthol and
dehydroepiandrosterone (DHEA), widely exist in plants and
animals, can be reacted smoothly with 1a to provide the
oxidative carbonylation products (5au, 5av).
Encouraged by the results in Table 1, we next explored the
substrate scope of this palladium-catalyzed radical oxidative
alkoxycarbonylation reaction. Firstly, various benzyl alcohols
were tested (Scheme 2). Ortho, meta and para-position methyl
benzyl alcohols all afforded high yields (3ab-3ad). Benzyl
alcohol with electron-donating groups such as methoxyl group
was effective under the standard conditions (3ae). Electron-
withdrawing substituents, such as p-CF3, and p-COOMe also
gave the desired products in satisfactory yields (3ai, 3ak).
Delightfully, 1,4-benzenedimethanol could give the diester in
58% yield (3al). Halide groups such as F, Cl and Br were well
tolerated (3af-3ah). Furthermore, 4-biphenylmethanol, 1-
naphthalenemethanol and 2-naphthalenemethanol could be
transformed into the corresponding esters smoothly (3aj, 3am,
3an). Not only primary alcohols, but also secondary alcohols
were suitable substrates for this reaction (3ao-3aq). Moreover,
chiral alcohols underwent this reaction with full retention. Other
aromatic alcohols such as 2-phenylethanol and furfuryl alcohol
gave the esters in 82% and 58% yields, respectively (3ar, 3as).
Scheme 3. Substrate Scope of Aliphatic Alcohols. Reaction conditions: 1a (1.5
mL), 4x (0.20 mmol), CO (5 atm), PdCl2 (5 mol% based on 4x), PPh3 (11
mol% based on 4x), DTBP (1.8 equiv. based on 4x), DCE (0.5 mL), 110 oC, 24
h. Yield of isolated product. [a] 4x (0.10 mmol), PdCl2 (10 mol% based on 4x),
PPh3 (22 mol% based on 4x), DTBP (3.6 equiv. based on 4x). [b] 4t (0.06
mmol), PdCl2 (15 mol% based on 4t), PPh3 (33 mol% based on 4t), DTBP (5.4
equiv. based on 4t).
Furthermore, numerous alkanes were tested (Scheme 4). In
the case of cycloalkanes, such as cyclopentane, cyclohexane,
cycloheptane, cyclooctane and cyclododecane, becase all the
reacting sites are equivalent, the reaction proceeded smoothly to
afford single products (3aa-3ea). Other alkanes with
nonequivalent reacting sites offered mixed products (See
Supporting Information). Above all, linear alkanes from C5 to
C16 were compatible (3fa-3ka). In addition, branched alkane, 2,
2-dimethylbutane gave the mixed products in 42% yield (3la).
Cyclohexane with alkyl substituent such as methylcyclohexane,
Scheme 2. Substrate Scope of Aromatic Alcohols. Reaction conditions: 1a
(1.5 mL), 2x (0.20 mmol), CO (5 atm), PdCl2 (5 mol% based on 2x), PPh3 (11
mol% based on 2x), DTBP (1.8 equiv. based on 2x), DCE (0.5 mL), 110 oC, 24
h. Yield of isolated product. [a] 2l (0.10 mmol), PdCl2 (10 mol% based on 2l),
PPh3 (22 mol% based on 2l), DTBP (3.6 equiv. based on 2l). [b] Enantiomeric
excess = 100%.
1,
4-dimethylcyclohexane,
bi(cyclohexane)
and
Moving on to aliphatic alcohols (Scheme 3), we were pleased
to find that, ethanol, isobutanol, 1-butanol, 1-hexanol and 1-
dodecanol all afforded the corresponding products in good to
decahydronaphthalene could be transformed into the
corresponding products in moderate to high mixed yields (3ma-

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COMMUNICATION
3pa). Additionally, solid adamantane gave a good mixed yield
(3qa).
d12 were also monitored (Scheme 5, see Supporting Information).
A significant kinetic isotopic effect (kH/kD = 5.0) can be observed,
which indicated that C-H bond activation might be involved in the
rate-determining step.
On the other hand, radical-trapping experiments were
conducted. When TEMPO was used as the radical-trapping
reagent, no desired product 3aa could be detected (Eq. (2)).
With the treatment of 1,1-diphenylethene, the desired product
3aa was obtained in only 31% yield while the coupling products
of
1,1-diphenylethene
with
cyclohexane
(6a)
and
cyclohexanecarboxaldehyde (6b) were obtained in 35% and
13% yield, respectively (Eq. (3)). 6a and 6b were also detected
in the absence of Pd catalyst (Eq. (4)). These results indicated
that cyclohexyl radical and cyclohexylformyl radical are probably
involved in this transformation.
Scheme 4. Substrate Scope of Alkanes. Reaction conditions: 1x (1.5 mL), 2a
(0.20 mmol), CO (5 atm), PdCl2 (5 mol% based on 2a), PPh3 (11 mol% based
on 2a), DTBP (1.8 equiv. based on 2a), DCE (0.5 mL), 110 oC, 24 h. Yield of
isolated product. [a] 5 mol% Xantphos instead of 11 mol% PPh3, 6.0 equiv.
DTBP instead of 1.8 equiv. DTBP. [b] 10 mol% PdCl2 instead of 5 mol% PdCl2,
10 mol% Xantphos instead of 11 mol% PPh3, 6.0 equiv. DTBP instead of 1.8
equiv. DTBP. [c] 10 mol% PdCl2 instead of 5 mol% PdCl2, 22 mol% PPh3
instead of 11 mol% PPh3, 4.0 equiv. DTBP instead of 1.8 equiv. DTBP. [d] 1q
(1.00 mmol), 2a (0.20 mmol), CO (5 atm), PdCl2 (10 mol% based on 2a), PPh3
(22 mol% based on 2a), DTBP (4.0 equiv. based on 2a),
(Trifluoromethyl)benzene (0.5 mL), DCE (1.5 mL), 110 oC, 24 h.
Although the mechanistic details of this transformation remain
unclear at the moment, we proposed a plausible mechanism on
the basis of the results obtained (Scheme 6). Firstly, DTBP
abstracts hydrogen atom from the alkane to afford the alkyl
radical. Then, CO coordinated with metal could be attacked by
the alkyl radical to form acyl metal species which can be
transformed into acyl radical. At last, acyl metal species can be
reacted with DTBP and benzyl alcohol to generate the desired
product.
It is especially noteworthy that gaseous ethane could be used
as alkane source in this reaction, affording 61% yield of benzyl
propionate under 5 atm of CO (Eq. (1) 3ra).
In order to gain brief insights into the mechanism of the
reaction, several experiments were conducted under the
standard reaction conditions. The competition experiment of the
mixture of cyclohexane and cyclohexane-d12 was performed
affording the desired products in a 4.6:1.0 ratio. The reaction
progress of the carbonylation of cyclohexane and cyclohexane-
Scheme 6. Proposed Reaction Mechanism.
Notably, this reaction could be performed on gram scale (Eq.
(5)). Treatment 1.08 g of 2a in 50.0 mL of 1a furnished 1.77 g of
3aa in 81% yield.
Scheme 5. Kinetic Isotope Effect Experiments.

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In conclusion, the present study provides a promising and
efficient method to construct alkyl carboxylates by directly
utilizing the commonly available alkanes and CO. This process
has an excellent substrate suitability, which can demonstrates
potential applications in the area of agricultures and
pharmaceutical chemistry. Ongoing work seeks to gain a
detailed mechanistic understanding of this reaction, and
applications of this process in other reactions are currently in
progress.
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Experimental Section
General procedure for palladium-catalyzed
radical oxidative
alkoxycarbonylation of cyclohexane: In an oven-dried teflon tube
equipped with a stir-bar, PdCl2 (1.8 mg, 5 mol% based on benzyl alcohol),
PPh3 (5.8 mg, 11 mol% based on benzyl alcohol) were combined. Then
cyclohexane (1.5 mL) and DCE (0.5 mL) were added to the teflon tube
via a syringe. After that, benzyl alcohol (0.2 mmol), DTBP (65 µL, 0.36
mmol) were added to the teflon tube. At last, place the teflon tube in an
autoclave, then the autoclave was purged for three times and charged
with CO at 5 atm. The reaction mixture was stirred at 110 oC for 24 hours
and then cooled to room temperature. Next CO was carefully released.
The corresponding reaction mixture was purified by flash column
chromatography on a silica gel to give the desired product using hexane
and ethyl acetate (12:1).
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Acknowledgements
This work was supported by the 973 Program (2012CB725302),
the National Natural Science Foundation of China (21390400,
21520102003, 21272180, 21302148), the Hubei Province
Natural Science Foundation of China (2013CFA081), the
Research Fund for the Doctoral Program of Higher Education of
China (20120141130002), and the Ministry of Science and
Technology of China (2012YQ120060). The Program of
Introducing Talents of Discipline to Universities of China (111
Program) is also appreciated.
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Keywords: C-H activation • palladium-catalyzed • radical •
carbonylation • alkane
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COMMUNICATION
Lijun Lu, Renyi Shi, Luyao Liu, Jingwen
Yan, Fangling Lu, and Aiwen Lei*
Page No. 1– Page No. 4
Oxidative Alkane C-H
Alkoxycarbonylation
A novel palladium-catalyzed radical oxidative alkoxycarbonylation of alkanes has
been developed. Various alkanes and alcohols were compatible, generating the
desired products in up to 94% yields. In this transformation, Pd catalysis and radical
process were combined smoothly, which solves the problems of high-pressure CO
and activation of C(sp3)-H bonds.