Metal-free radical oxidative alkoxycarbonylation and imidation of alkanes

Article abstract of DOI:10.1039/c7cc03671j

A metal-free radical oxidative carbonylation of alkanes is demonstrated, yielding esters and imides by means of di-tert-butylperoxide as an oxidant. Various alkanes, alcohols and amides were compatible in this system generating the desired carbonyl products in up to 86% yields. We proposed a plausible radical cross-coupling process based on the preliminary mechanistic studies.

Full text of DOI:10.1039/c7cc03671j

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Reactivity differences of Sc
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3
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Metal-Free Radical Oxidative Alkoxycarbonylation and Imidation
of Alkanes
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
a
a
ab
Lijun Lu, Danyang Cheng, Yuanfeng Zhan, Renyi Shi, Chien-Wei Chiang, and Aiwen Lei*
DOI: 10.1039/x0xx00000x
www.rsc.org/
6
A
metal-free radical oxidative carbonylation of alkanes is challenging and sustainable approach.
demonstrated, yielding esters and imides by means of di-tert-
On the other hand, radical carbonylation could afford
butylperoxide as oxidant. Various alkanes, alcohols and amides carbonyl derivatives in the absence of transition-metal
7
were compatible in this system generating the desired carbonyl catalysts (scheme 1B). However, the great mass of reports
8
products in up to 86% yields. We proposed a plausible radical involved organic halides. It is an urgent need for developing
cross-coupling process based on the preliminary mechanistic radical oxidative carbonylation of C-H bonds.
studies.
Oxidant-induced alkane C-H bond activation producing
3
radical might be an alternative to achieve the C(sp )-H
Carboxylic acids and derivatives (e.g., esters, amides, etc.) are
the basic constituents of numerous natural products,
1
pharmaceuticals and agrochemicals. Since the pioneering
carbonylation which would avoid the usage of transition-metal
9
catalysts. Recently, radical oxidative cross-coupling have
1
0
become dominant in the research area of C-H activation.
work of Heck and his co-workers in 1974, transition-metal-
catalyzed carbonylation has become a powerful tool to
construct carbonyl compounds from organic halides, CO and
Herein, we report a novel radical oxidative carbonylation of
alkanes employing alcohols and amides as nucleophiles. A
series of esters and imides can be obtained in the absence of
any metal (scheme 1C).
2
nucleophiles. In general, organic halides and analogues were
prepared via prefunctionalization of the corresponding
hydrocarbons. During the past decade, increased attention has
been focused on transition-metal-catalyzed C-H carbonylation
which is regarded as an atom-economic and step-economic
H
[M]
M
A)
B)
C)
Difficult
3
O
O
method. For example, palladium-catalyzed C-H carbonytion is
II
X
Conditions
CO
FG
0
FG
usually proposed to proceed Pd /Pd cycle. While the strong
coordination of CO to Pd and the decomposition of Pd catalysis
3
Conditions such as AIBN/Bu SnH, hv, etc.
4
under a CO atmosphere might influence the catalytic activity.
3
In addition, oxidative carbonylation of C(sp )-H is more
O
H
[O]
[O]
CO, NuH
Nu
challenging due to the high bond dissociation energy and low
3
polarity of C(sp )-H bonds. In current reports, directing groups
5
were invited to the transformation to solve this problem. It
This work
Scheme 1. Oxidative Carbonylation of Alkanes.
remains a great challenge to directly activate simple alkanes to
Initially, we chose cyclohexane (1a) and benzyl alcohol (2a
)
form alkyl-metal species (scheme 1A). Obviously, utilizing as model substrates in the presence of 40 bar CO (Table 1).
easily available alkanes, CO with nucleophiles for the synthesis Interestingly, when 2.0 equivalent of DTBP (di-tert-
of alkyl carboxylic acid derivatives represents a very attractive, butylperoxide) was added as oxidant, 55% desired product
could be obtained (Table 1, entry 1). DCE (1,2-dichloroethane)
as co-solvent improved the yield to 83%, which was consistent
6
a
with the palladium-catalyzed system (Table 1, entry 2). Other
similar oxidants such as DCP (dicumyl peroxide) and TBHP
(
(
tert-Butyl hydroperoxide) led to the decrease of the yield
Table 1, entries 3, 4). 1.0 equivalent of oxidant could also
afford 64% desired ester (Table 1, entry 5). We screened the
influence of CO pressure and found that 40 bar is an optimal
pressure for this transformation (Table 1, entries 6, 7).
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Journal Name
O
Reducing the temperature and reaction time both decreased
the yield (Table 1, entries 8, 9).
2.0 equiv. DTBP
.0 mL DCE, 120 oC, 10 h
CO
ROH
OR
1
a
1a
2
3
Table 1 Screening of Reaction Conditions.
2
.0 mL
40 bar
0.2 mmol
O
O
O
3aa, X = H, 83% 3ae, X = I, 31%
3
3
ab, X = F, 52% 3af, X = OMe, 40%
ac, X = Cl, 70% 3ag, X = COOMe,63%
S
O
O
HO
Oxidant
O
CO
X 3ad, X = Br, 66% 3ah, X = CF , 79%
3
3ai, 66%
1
a
2a
3aa
O
O
O
O
O
O
b
Entry
Oxidant
CO pressure
Yield [%]
O
O
c
1
DTBP
DTBP
TBHP
DCP
40 bar
40 bar
40 bar
40 bar
40 bar
30 bar
50 bar
40 bar
40 bar
55
3aj, 76%
3ak, 79%
3al, 80%
O
O
2
3
4
78(83)
Trace
52
O
O
O
O
O
5
O
O
3
am, 79%a
3an, 52%
3ao, 79%
O
O
O
O
d
O
Cl
5
DTBP
DTBP
DTBP
DTBP
DTBP
64
3
ap, 73%
3aq, 50%
3ar, 68%
6
7
68
O
75
H
e
H
H
8
44
O
O
H
H
H
H
f
O
O
9
67
3
as, 53%
3at, 62%
a
Reaction conditions: 1a (2.0 mL), 2a (0.20 mmol), CO (40 bar),
Scheme 2 Substrate Scope of Alcohols. Reaction conditions: 1a (2.0
mL), 2 (0.20 mmol), CO (40 bar), DTBP (2.0 equiv. based on 2),
DCE (1.0 mL), 120 C, 10 h. Yield of isolated product. 1,6-
o
b
Oxidant (2.0 equiv. based on 2a), DCE (1.0 mL), 120 C, 10 h.
Yields were determined by GC analysis, calibrated usingc
o
a
biphenyl as the internal standard (isolated yield in parentheses).
d
e
o
o
f
Hexanediol 2m (0.10 mmol), DTBP (4.0 equiv. based on 2m).
Without DCE. 1.0 equiv. Oxidant. 100 C instead of 120 C. 6
h instead of 10 h.
After that, we investigated the substrate scope of alkanes
With the optimized reaction conditions in hand, we turned our (Scheme 3). Gaseous ethane and solid-state adamantane afforded
attention to investigate the substrate scope of alcohols (Scheme 2). the corresponding products in moderate to good yields (3ba, 3ea).
Firstly, we tested various benzyl alcohols bearing different Using cyclopentane as substrate, the desired imide was formed in
functional groups. Halide groups such as F, Cl, Br and I could be 45% (3ca). For the reaction of linear alkanes such as n-hexane, a
retained and give satisfactory yields (3ab-3ae). Electron-donating mixed product in 50% yield was obtained (3da). Notably, we
and electron-withdrawing substituents such as p-OMe, p-CF
3
, and p- evaluated the scalability of this radical oxidative carbonylation by
COOMe were compatible to afford the desired products (3af-3ah). performing the reaction on gram scale to give 1.77 g benzyl
Heteroaromatic alcohol such as 2-thiophenemethanol was also cyclohexanecarboxylate smoothly (3aa).
O
effective under the standard conditions (3ai). Primary, secondary
and tertiary alcohols all showed good reaction efficiency (3aj-3al).
Delightfully, diol could give the diester in 79% yield (3am). In
addition, a variety of functional groups such as keto, alkoxy, chloro
and alkenyl could be transformed into the corresponding esters
smoothly (3an-3aq). At last, we focused on natural products such as
L-menthol, dehydroepiandrosterone and stigmasterol, the good
compatibility might make this method possible to be applied in
total synthesis (3ar-3at).
2.0 equiv. DTBP
HO
R-H
CO
R
O
.0 mL DCE, 120 oC, 10 h
1
1
2a
3
2
.0 mL
40 bar
0.2 mmol
O
O
O
O
O
O
3ba, 30%a
3
aa, 83%
3ca, 45%
(
81%, 1.77 g)
O
O
1
1
2
2
O
O
3
3da, 50% (C1:C2:C3 = 2:3:2)
3ea, 77%b (C :C = 2:1)
1 2
Scheme 3 Substrate Scope of Alkanes. Reaction conditions: 1 (2.0
mL), 2a (0.20 mmol), CO (40 bar), DTBP (2.0 equiv. based on 2a),
o
a
DCE (1.0 mL), 120 C, 10 h. Yield of isolated product. C H (40
2
6
bar), CO (20 bar), DTBP (3.0b equiv. based on 2a),
(
(
trifluoromethyl)benzene (2.0 mL).
trifluoromethyl)benzene (2.0 mL).
Adamantane (1.5 mmol),
To demonstrate the utility of this method, several representative
amides which have low nucleophilicity compared with alcohols and
amines were chosen as substrate (Scheme 4). Simple N-methyl
2
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acetamide could afford 83% yield of desired product (5aa), and 86% generated from the homolytic cleavage of DTBP abstracts hydrogen
yield of corresponding imides could be obtained from ε- atom from the alkane to afford the alkyl radical (I). Then, CO adds
caprolactam (5ab). No matter changing methyl to phenyl or acetyl to alkyl radical to form acyl radical (II). After that, acyl radical reacts
to benzoyl, desired imides were both formed in high yields (5ac, with nucleophile by losing a proton to afford a radical anion species
5ad). N-methylformamide could be transformed into the (III). Finally, DTBP abstracts an electron from radical anion (III) to
corresponding imides efficiently, but formanilide could only afford give the desired product.
N-phenyl benzamide due to the low stability of the imides (3ae, 3af).
Remarkably, amino acid derivative such as ethyl 2-
acetamidoacetate was well tolerated in this system, which further
expanded the application value of this transformation (5ag).
Scheme 6 Proposed Reaction Mechanism.
In conclusion, we developed a metal-free radical oxidative
carbonylation of alkanes under simple reaction conditions.
Numerous alcohols and amides were compatible to afford
corresponding esters and imides in good to high yields.
Preliminary mechanistic studies indicated a radical process was
involved. This transformation might be applied in some fields
disliking metals such as pharmaceutical industry.
Scheme 4 Substrate Scope of Amides. Reaction conditions: 1a (2.0
mL), 4 (0.20 mmol), CO (60 bar), DTBP (2.0 equiv. based on 4),
DCE (1.0 mL), 120 C, 10 h. Yield of isolated product.
This work was supported by the National Natural Science
Foundation of China (21390402, 21520102003), the Ministry of
Science and Technology of China (2012YQ120060), the
o
To gain brief insights into the reaction mechanism, we conducted Fundamental Research Funds for the Central Universities and the
experiments to explore the existence of radical intermediates Program of Introducing Talents of Discipline to Universities of China
(
Scheme 5). When 2.0 equivalent of TEMPO ((2,2,6,6- (111 Program).
tetramethylpiperidin-1-yl)oxy) were added under the standard
reaction conditions, no desired product was obtained. When we
used 1,1-diphenylethylene as radical-trapping reagent, the
formation of 2-cyclohexyl-1,1-diphenylethylene (6a) and 1-
cyclohexyl-3,3-diphenylprop-2-en-1-one (6b) indicated that
cyclohexyl radical and cyclohexylformyl radical were probably
involved in this transformation.
Notes and references
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1
1
Based on our results and previous reports, a plausible reaction
mechanism is proposed (Scheme 6). Firstly, tert-butoxyl radical
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Metal-free radical oxidative carbonylation of alkanes proceeded to
give corresponding esters and imides in good to high yields.