Peroxide promoted tunable decarboxylative alkylation of cinnamic acids to form alkenes or ketones under metal-free conditions

Article abstract of DOI:10.1039/c5cc01762a

A tunable decarboxylative alkylation of cinnamic acids with alkanes was developed to form alkenes or ketones under transition metal-free conditions. In the presence of DTBP or DTBP/TBHP, the reaction gave alkenes and ketones respectively via a radical mechanism in moderate to good yields. This journal is

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Peroxide promoted tunable decarboxylative alkylation
of cinnamic acids to form alkenes or ketones under
metal-free conditions
Cite this: DOI: 10.1039/x0xx00000x
Received 00th February 2015,
Accepted 00th February 2015
Jing Ji, Ping Liu and Peipei Sun*
DOI: 10.1039/x0xx00000x
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and the ketones or alkenes were obtained simply in the presence of
peroxide.
A tunable decarboxylative alkylation of cinnamic acids with
alkanes was developed to form alkenes or ketones under
transition metal-free conditions. In the presence of DTBP or
DTBP/TBHP, the reaction gave alkenes and ketones
respectively via a radical mechanism in moderate to good
yields.
Initially, we performed the reaction of cinnamic acid 1a with
cyclohexane 2a in the presence of CuCl and diꢀtertꢀbutyl peroxide
(DTBP, 2.0 equiv.) at 120 °C under N2 for 24 h, and the
decarboxylative alkylation product (E)ꢀ(2ꢀcyclohexylvinyl)benzene
(4aa) was obtained in 74% yield (Table 1, entry 1). Other Cu salts,
such as CuI or Cu(OTf)2, showed no obvious difference (entries 2
and 3). To our delight, the 75% yield was obtained even without any
metal catalyst (entry 4). Then we decided to carry out the reaction
under transition metalꢀfree conditions. Some other representative
peroxides, such as tertꢀButyl peroxybenzoate (TBPB), dicumyl
peroxide (DCP) or tertꢀbutyl hydroperoxide (TBHP) were also
screened, and the reaction did not work well under the same
conditions (entries 5ꢀ7). To our surprise, the product 4aa was
obtained in only a very low yield, accompanied with a 13% yield of
The use of simple alkane as the coupling partner has been aroused
great attention in view of green and sustainable chemistry, as well as
in economic terms.1 This approach opened the conspicuous field for
development of lowꢀcost hydrocarbons direct into complex organic
compounds without prefunctionalization. A series of C–C bond, as
well as C–heteroatom bond formation methods were established by
the direct C(sp3)−H bond activation of alkanes recently under
transitionꢀmetal catalysis or metalꢀfree conditions.2 To look for the
further synthetic application of alkanes is continuously a challenging
task for organic chemists.
On the other hand, carboxylic acids served as versatile
connection points via extrusion of CO2, which gave access to various
valuable product classes in the last decade.3 These reactions mainly
focused on arylation, vinylation, conjugate additions and carbon–
heteroatom bond forming reactions. Generally, to loss of CO2 from
most carboxylic acids requires harsh conditions and the addition of a
transition metal mediator, e.g., Cu,4 Ag,5 Pd,6 Rh7, Au,8 etc.
Specially, the decarboxylative cross coupling of cinnamic acids
catalyzed by Cu,9 Fe,10 Pd,11 Ir,12 Ru,13 etc provided styryl group,
which was used for the synthesis of various olefin derivatives.
Niꢀcatalyzed decarboxylative crossꢀcouplings of cinnamic acids with
ether or amide to give aryl ketones were also reproted.14 It is
noteworthy that the coupling reaction under metalꢀfree conditions
provided a new opportunity for organic synthesis, especially in
pharmaceutical synthesis.15 A range of encouraging works using this
strategy were developed in recent years, and brought out great
vitality for the synthesis of many useful compounds. Several
decarboxylative cross couplings of monocarboxylic acids in the
absence of metal were reported recently to construct C−C, C−O and
C−N bonds.16 As the continuous study of our group on C−H bond
functionalization, especially the oxidative coupling in the absence of
metal,2f,17 herein we want to disclose a decarboxylative cross
coupling of cinnamic acids with alkanes under metalꢀfree conditions,
decarboxylative
carbonylation
coupling
product
2ꢀcyclohexylꢀ1ꢀphenylethanꢀ1ꢀone (3aa) when 2.0 equiv. DTBP
combined with 1.0 equiv. TBHP were used (entry 8). The addition of
4A molecular sieves was helpful to the formation of ketone product
and improved the yield to 36% (entry 9). Increasing the amount of
TBHP promoted the transformation, and the product 3aa was
achieved in 65% yield in the presence of 2.0 equiv. DTBP and 4.0
equiv. TBHP (entries 10 and 11); further increasing the amount of
TBHP had no enhancement (entry 12). Increasing DTBP to 4.0
equiv. brought a slight increase of 4aa and decrease of 3aa (entry
13), however, decreasing DTBP to 1.0 equiv. improved the yield of
3aa to 68%, and only trace 4aa was detected (entry 14). Performing
the reaction under air or at 130 oC did not give better results (entries
15 and 16); yet a very low yield of 3aa was obtained when lowered
the temperature to 100 oC (entry 17). Thus, the general reaction
conditions were established for the generation of 3aa and 4aa
respectively.
Table 1 Optimization of reaction conditionsa
O
COOH
catalyst, peroxide
+
+
1a
2a
3aa
4aa
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Entry
Catalyst
Peroxide
(equiv.)
T (oC)
Yield (%)b
3aa
4aa
1
2
CuCl
CuI
Cu(OTf)2
-
ꢀ
ꢀ
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
DTBP (2.0)
TBPB (2.0)
DCP (2.0)
120
120
0
0
0
74
71
76
75
trace
30
3aa 68%
3ea 63%
3ca 50%
3ga 70%
3da 46%
3ba 61%
3fa 65%
3
4
5
6
7
8
120
120
120
120
120
120
trace
0
0
<10
13
3ha 60%
TBHP (2.0)
DTBP (2.0)
/TBHP (1.0)
DTBP (2.0)
/TBHP (1.0)
DTBP (2.0)
/TBHP (2.0)
DTBP (2.0)
/TBHP (4.0)
DTBP (2.0)
/TBHP (6.0)
DTBP (4.0)
/TBHP (4.0)
DTBP (1.0)
/TBHP (4.0)
DTBP (1.0)
/TBHP (4.0)
DTBP (1.0)
/TBHP (4.0)
DTBP (1.0)
/TBHP (4.0)
trace
<10
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
-
ꢀ
ꢀ
ꢀ
O
9c
120
120
120
120
120
120
120
130
100
36
47
65
67
60
68
58
64
18
<10
<10
<5
MeO
10c
11c
12c
13c
14c
15c,d
16c
17c
3la trace
3ia 54%
3ja 80%
3ka 72%
3hc 71%
O
O
<5
3ab 32%
3jc 81%
<10
trace
<5
3ac 61%
3ae 48%
3ad 23%
aReaction conditions: 1 (0.5 mmol), 2 (2.0 mL), DTBP (1.0 equiv.), TBHP
<5
(4.0 equiv., 70% aqueous solution) and 4A MS (200 mg) in a sealed tube
under N2 at 120 °C for 24 h. The yields are isolated one based on cinnamic
acids.
b
<5
aUnless otherwise specified, the reactions were carried out in a sealed
tube in the presence of 1a (0.5 mmol), 2a (2 mL), catalyst (20 mol%) and
Unlike the above decarboxylative carbonylation, only in the
presence of DTBP, cinnamic acids reacted with alkanes to form
alkenes via the decarboxylative alkylation. To most of the cinnamic
acids we used, the reaction gave the corresponding coupling results
in moderate to good yields and exactly with (E)ꢀconfiguration (Table
3). The results showed that the presence of electronꢀdonating group
methoxy on benzene ring did not act as a disincentive to this
transformation (4la and 4ma). Specially, the heterocyclic derivative,
3ꢀ(pyridinꢀ2ꢀyl)acrylic acid also gave a high yield of 90% (4na).
When adamantane (2g) was used as the coupling partner, a mixture
of coupling on 3o (C(1)) and 2o (C(2)) carbon was obtained, and the
ratio was determined by 1H NMR to be 83:17 (4ag). A mixture was
also obtained for the decarboxylative coupling of cinnamic acid (1a)
with hexane (2h) in a total yield of 65% (4ah).
b
c
peroxide under N2 for 24 h. Isolated yield, based on 1a. 4A MS (200
mg) was added. dUnder air.
Using the optimized reaction conditions, we firstly tested the
scope of the decarboxylative alkylation coupling of cinnamic acid
derivatives with alkanes to form aryl ketones, as shown in Table 2.
The electronꢀdonating substituents on the benzene ring of cinnamic
acids seemed to be disadvantageous to the reaction. For example,
using cyclohexane as the coupling partner, the metaꢀ or paraꢀmethyl
substrates were compatible with the process and afforded ketone
products in moderate yields (3baꢀ3da), but the reactant with a
methoxy group only gave trace amount of the product (3la). On the
contrary, the orthoꢀ, metaꢀ or paraꢀhalogenated substrates were
tolerated, and the reaction proceeded smoothly and gave moderate to
high yields (3eaꢀ3ja). The strong electronꢀwithdrawing group
trifluoromethyl seemed to be favorable to this transformation and
gave the desired product in 72% yield (3ka), which might due to the
formation of more stable radical intermediates. Several other
cycloalkanes were then examined as the coupling partners, and
similar reactivity was found from cyclooctane (3ac, 3hc, 3jc).
However, cyclopentane which has low boilingꢀpoint showed less
reactive and led to a lower yield (3ab). Surprisingly, the reaction of
1,4ꢀdioxane only gave 23% yield (3ad). To our delight, the reaction
of ethylbenzene was uneventful, and furnished the ketone product at
αꢀposition with high regioselectivity (3ae).
Table 3 Decarboxylative alkylation of cinnamic acids to form alkenesa,b
COOH
R2
DTBP (2.0 eq.)
R1
R1
R2
+
H
120 o
C
1
2
4
4aa 75%
4ea 70%
4ia 74%
4ba 73%
4ha 80%
4fa 68%
4ja 68%
4na 90%
4ga 50%
4ka 78%
Table 2 Decarboxylative alkylation of cinnamic acids to form ketonesa,b
O
R2
COOH
DTBP (1 eq.), TBHP (4 eq.)
R2
H
R1
R1
4A MS, 120 o
C
4ma 83%
4ac 81%
4la 71%
4ab 74%
1
2
3
4oa 72%
4af 77%c
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1
2
Further studies on the cascade addition reaction of cinnamic acids
with other radical sources and the mechanism are in progress in our
group.
3
4ag 59%c
4ah 65%
(C(1):C(2) =
This work was supported by the National Natural Science
Foundation of China (Project 21272117) and the Priority Academic
Program Development of Jiangsu Higher Education Institutions. The
authors also thank Mr. Zilie Liu for the determination of HRMS.
83:17)d
(C(1):C(2):C(3)
= 10:50:40)d
aReaction conditions: 1 (0.5 mmol), 2(aꢀc) (2.0 mL), DTBP (2.0 equiv.) in a
sealed tube under N2 at 120 °C for 24 h. bThe yields are isolated one based on
cinnamic acids. 2(f and g) (3.0 equiv.) in DCE (2.0 mL). dThe ratio was
c
determined by 1H NMR.
Notes and references
College of Chemistry and Materials Science, Nanjing Normal University;
Jiangsu Provincial Key Laboratory of Material Cycle Processes and
Pollution Control; Jiangsu Collaborative Innovation Center of
Biomedical Functional Materials, Nanjing 210097, China
Eꢀmail: sunpeipei@njnu.edu.cn
The
presence
of
radical
scavenger
TEMPO
(2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy) had obvious suppression to
both reactions above. CO2 was detected via GC−FTIR in the gas
generated from the reaction using air as blank (see electronic
supplementary information). And also, from compound 4aa, we did
not observe the formation of 3aa under the standard reaction
conditions which were used to form 3aa from cinnamic acid. Based
on above results and the related reports,9,14 we proposed the
mechanism referring to radical oxidative coupling process (Scheme
1). Initially, thermal homolysis of DTBP produced tertꢀbutoxyl
radical A, which could abstract a hydrogen radical from cyclohexane
and generated cyclohexanyl radical B, followed by addition to
cinnamic acid 1a and produced radical intermediate C. Next,
decarboxylative alkenylation took place to form 4aa with the aid of
another tertꢀbutoxyl radical. The combination of radical intermediate
†
Electronic supplementary information (ESI) available. See
DOI: 10.1039/c000000x/
1
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∆
1a
O
O
2
O
A
B
t-BuOH
COOH
4aa
CO2 + t-BuOH
3
4
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∆
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Scheme 1 Plausible mechanisms for the two different oxidative
coupling reactions.
In summary, we have developed a tunable method for the
synthesis of alkenes and ketones via the oxidative alkylation of
cinnamic acids with alkanes under transition metalꢀfree conditions.
Peroxide DTBP and DTBP/TBHP were proved to be efficient
oxidants respectively for these transformations. Alkanes and various
substituents on the aryl ring of cinnamic acids tolerated the reactions
and gave the corresponding products in moderate to good yields.
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