Fe-catalyzed double cross-dehydrogenative coupling of 1,3-dicarbonyl compounds and arylmethanes

Article abstract of DOI:10.1021/ol503556x

Fe-catalyzed tandem cross-dehydrogenative coupling of the methyl group in arylmethanes with 1,3-dicarbonyl compounds has been developed. The reaction affords one new C(sp³)-C(sp²) bond and one new C(sp³)-C(sp³)

Full text of DOI:10.1021/ol503556x

Letter
pubs.acs.org/OrgLett
Fe-Catalyzed Double Cross-Dehydrogenative Coupling of 1,3-
Dicarbonyl Compounds and Arylmethanes
Kai Yang and Qiuling Song*
Institute of Next Generation Matter Transformation, College of Chemical Engineering, Huaqiao University, 668 Jimei Boulevard,
Xiamen, Fujian 361021, China
S
* Supporting Information
ABSTRACT: Fe-catalyzed tandem cross-dehydrogenative
coupling of the methyl group in arylmethanes with 1,3-
dicarbonyl compounds has been developed. The reaction
affords one new C(sp3)−C(sp2) bond and one new C(sp3)−
C(sp3) bond in a one-pot protocol. Further study suggests that
this reaction might start with a Friedel−Crafts-type reaction
(cross-dehydrogenative arylation) followed by cross-dehydrogenative coupling with an activated methylene group under mild
oxidative conditions.
1);8d,10 Shi et al. described an Fe-catalyzed cross-dehydrogen-
elective functionalization of C−H bonds for the con-
Sstruction of new C−C bonds has attracted great attention ative arylation between a benzylic C(sp3)−H bond and the
arene C(sp2)−H bond (Scheme 1, eq 2).11 However, in these
reported examples, only one C−C bond was formed. A cascade
or tandem reaction is an easy and efficient way to construct
several new bonds in a one-pot protocol; therefore, a tandem
cross-dehydrogenative coupling (CDC) is very attractive and
desirable. To the best of our knowledge, there is no example for
the construction of two new different types of C−C bonds via
CDC under Fe-catalyzed reaction. Herein, we disclose the first
example of Fe-catalyzed double CDC between two arylmethane
molecules and activated dicarbonyl compounds to construct
one new C(sp3)−C(sp2) and one new C(sp3)−C(sp3)
simultaneously in a tandem pattern.
We commenced our study with p-xylene (1a) and diethyl
malonate (2a) with FeCl2 as catalyst under air as a model
reaction (Table 1). To our delight, the desired product 3aa was
formed in 36% isolated yield (Table 1, entry 1) with 20 mol %
of FeCl2 and 2.5 equiv of 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ) as oxidant at 100 °C in a sealed tube.
When the oxidant was increased to 3 equiv, the isolated yield of
desired product was increased to 52% (Table 1, entry 2); when
DDQ was increased to 4 equiv, 68% of desired product was
obtained (Table 1, entry 3). Yet 5 equiv of DDQ did not show
superiority to 4 equiv of oxidant (Table 1, entry 4), and only
67% of desired product was obtained. Further iron salt
screening suggested that FeCl2 is the best among FeBr2,
Fe(OAc)2, and FeCl3 (Table 1, entries 5−7). When the
temperature was decreased to 90 °C, surprisingly, 75% of
desired product 3a was obtained, higher than the 100 °C one.
Yet when the reaction temperature was dropped to 80 and 70
°C, the isolated yields of desired products were dropped to 60
and 51%, correspondingly (Table 1, entries 8−10). When the
from the synthetic community in the past decade.1,2 Through
C−H functionalization, preactivation of cheap and readily
available starting material could be avoided, thus improving
reaction atom-efficiency and shortening synthetic steps, making
C−H functionalization potentially applicable in the synthesis of
complex molecules. Great progress has been achieved in this
area, especially transition-metal-catalyzed C−H functionaliza-
tion.3−7 Among all of the reported transition metals, Fe gets
more attention due to its nontoxicity, low cost, and
environmentally benign features, which gives Fe-catalyzed C−
H activation many advantages over other transition metals.1b,8,9
Many research groups greatly contributed to this field; for
instance, Li and co-workers reported Fe-catalyzed activation of
a benzylic C−H bond with an active dicarbonyl methylene
compound to form a new C(sp3)−C(sp3) bond (Scheme 1, eq
Scheme 1. Transition-Metal-Catalyzed C−C Bond
Formation Reaction between a Benzylic C−H Bond and an
Activated C−H Bond
Received: December 9, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ol503556x
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Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Tandem Cross-Dehydrogenative Coupling of 1,3-
Dicarbonyl Compounds with Arylmethanes
a
catalyst
(mol %)
oxidant
(equiv)
temp
(°C)
time
(h)
yield
b
entry
solvent
(%)
1
2
3
4
5
6
FeCl2 (20)
FeCl2 (20)
FeCl2 (20)
FeCl2 (20)
FeBr2 (20)
DDQ (2.5)
DDQ (3)
DDQ (4)
DDQ (5)
DDQ (4)
DDQ (4)
DCE
DCE
DCE
DCE
DCE
DCE
100
100
100
100
100
100
24
24
24
24
24
24
36
52
68
67
29
Fe(OAc)2
(20)
trace
7
8
FeCl3 (20)
FeCl2 (20)
FeCl2 (20)
FeCl2 (20)
FeCl2(10)
FeCl2 (20)
FeCl2 (20)
FeCl2 (20)
FeCl2 (20)
FeCl2 (20)
FeCl2 (20)
FeCl2 (20)
DDQ (4)
DDQ (4)
DDQ (4)
DDQ (4)
DDQ (4)
DDQ (4)
DDQ (4)
DDQ (4)
DDQ (4)
DDQ (4)
DDQ (4)
DCE
100
90
80
70
90
90
90
90
90
90
90
90
24
24
24
24
24
24
24
24
24
24
24
24
40
75
60
51
52
DCE
9
DCE
10
11
12
13
14
15
16
17
18
DCE
DCE
c
CH2Cl2
CHCl3
dioxane
CH3CN
DMSO
DMF
61
trace
0
0
0
0
0
TBHP (70%) DCE
(4)
19
20
FeCl2 (20)
FeCl2 (20)
DTBP (4)
K2S2O8 (4)
DCE
DCE
90
90
24
24
0
0
a
Reaction conditions: toluene derivatives 1 (1.25 mmol), 1,3-
a
Reaction conditions: diethyl malonate (0.25 mmol), p-xylene (5
equiv), Fe salt (20 mol %), DDQ, in corresponding solvent (1 mL) in
dicarbonyl compounds 2 (0.25 mmol), FeCl2 (20 mol %), DDQ (1
mmol), DCE (1 mL) in air in a sealed tube, corresponding
temperature, 24 h. Isolated yield based on 2. The ratio of the two
diastereomers is given in the parentheses.
b
c
a sealed tube under air. Isolated yield. GC yield.
catalyst loading was reduced to 10 mol %, only 52% of the
desired product was obtained (Table 1, entry 11). Solvent and
oxidant screening indicated that dichloroethane (DCE) and
DDQ are the best choices (Table 1, entry 8), while other
solvents, such as CH2Cl2, chloroform, dioxane, MeCN,
dimethylsulfoxide (DMSO), dimethylformamide (DMF), and
other oxidants, like tert-butyl hydroperoxide (TBHP) (70% in
aqueous solution), di-tert-butyl peroxide (DTBP), and K2S2O8,
were not effective in this transformation (Table 1, entries 12−
20). After sufficient screening, the optimal condition eventually
emerged as toluene derivative 1a (5 equiv), malonate 2a (0.25
mmol), FeCl2 (20 mol %), DDQ (4 equiv), and DCE (1 mL)
at 90 °C under air.
With the optimized conditions available, we explored the
substrate scope (Scheme 2). As shown in Scheme 2, 1a works
very well with a variety of dicarbonyl compounds 2 under
standard conditions to afford moderate to good yields of
desired products (Scheme 2, 3aa−3ai): 1,3-diesters (2a−c),
1,3-diketone (2e), and β-keto esters (2d, 2f−i) were all found
to react smoothly with p-xylene to afford corresponding desired
products, and the substituents on the aromatic rings of aryl β-
ketone esters survived well (Scheme 2, 2f, 2h, and 2i). Dialkyl
2e was also a suitable dicarbonyl substrate to smoothly generate
the desired product (Scheme 2, 3ae). Besides, 1a, p-tert-butyl
toluene (1b), m-xylene (1c), mesitylene (1d), and o-xylene
(1e) were all good candidates for this reaction, although 3ca
was obtained only in 22% yield and 3da needs a higher
temperature to process smoothly. For 1e, two regioisomers
were obtained with a total isolated yield of 34% under the
standard conditions. Yet surprisingly, if amide 2j was used or
ether ester 2k was involved in the reaction, no desired products
were formed (Scheme 2, 3aj and 3ak).
For the mechanism of the novel tandem reaction, we
hypothesize that cross-dehydrogenative arylation of two
arylmethane molecules should be performed first to afford
diaryl methylene compounds, which further couples with 1,3-
dicarbonyl compounds to generate desired products. To verify
our hypothesis, diphenylmethane 4 was directly treated with
1,3-diester 2 under the standard conditions. The desired
product 3fa was obtained just as we expected. After simple
modification (Table S2, Supporting Information), such as
reduction of the amount of diaryl compounds and DDQ,
compound 3fa was obtained in 70% yield (Scheme 3, 3fa).
Further exploration showed that diaryl compounds could react
with various dicarbonyl compounds, for instance, 1,3-diester
(2a−c), 1,3-diketone (dialkyl 2e or alkyl aryl 2l), β-keto ester
(alkyl 2d and aryl 2h), to afford corresponding products in
good yields. In contrast to Li’s method, which mainly focused
on 3-oxo-3-phenylpropanoate (β-ketone ester) and no alkyl β-
ketone ester, dialkyl 1,3-diketone, or 1,3-diester involved, our
method widely expanded the substrate scope of dicarbonyl
compounds. At the same time, DDQ has many advantages over
peroxide, which Li and co-workers used in their method in
terms of safety; therefore, our work could be a complementary
strategy to Li’s method.
To illustrate the further synthetic utility of this novel method,
desired product 3aa, which was made from a scaled-up reaction
B
DOI: 10.1021/ol503556x
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Letter
Scheme 3. Alkylation of Diaryl C−H Bonds with 1, 3-
Scheme 5. Control Experiments under Standard Conditions
a
Dicarbonyl Compounds
with its corresponding oxidized product 4a′ (Scheme 5, eq 3),
and the two compounds 4a and 4a′ were also detected in the
model reaction under the standard conditions (Figure S1,
Supporting Information). Interestingly, Shi and co-workers
mentioned one similar reaction in their cross-dehydrogenative
arylation of a benzylic compound with an electron-rich arene, in
which the benzylic compound and electron-rich arene are the
same: mesitylene was dimerized into product at 150 °C for 36 h
with TON = 11. Compared to our condition, their’s was very
harsh and needs a very long reaction time.11
a
Reaction conditions: toluene derivatives 4 (0.75 mmol), 1,3-
dicarbonyl compounds 2 (0.25 mmol), FeCl2 (20 mol %), DDQ
(0.75 mmol), DCE (1 mL) in air in a sealed tube, corresponding
temperature, 18 h. Isolated yield based on 2.
(1 mmol, based on 1,3-diethyl ester 2a), was treated with
sodium hydroxide in MeOH/H2O. After being acidified by
acetic acid, eventually acid 5, a key intermediate for the
synthesis of hexahydropyrroloisoquinoline compounds, which
are useful for the treatment of histamine H3 receptor- and
serotonin-mediated diseased,12 was easily obtained from readily
available starting materials in two steps (Scheme 4, eq 1). Acid
Further kinetic study was also conducted under various
reaction times: when the reaction was conducted at the
standard condition of 15 min, GC yield of product 3aa was
20%, 30 min was 27%, and 1 and 2 h gave the same GC yields
of product with 36%. This revealed that the reaction was
initiated by SET process very quickly, yet later, it was slowed.
Since dimer 4a and its corresponding oxidized compound 4a′
were both detected besides the desired product 3aa under the
standard conditions (Table S1, Supporting Information) and
no dimerization of 1,3-diketone product was ever detected,
based on the previous literature report3c,11,13 and our
observations, as well as the above experimental results, we
gave a proposed mechanism: the reaction was initiated by
FeCl2-catalyzed SET oxidation of one arylmethane molecule to
generate a benzylic cation M, a subsequent Friedel−Crafts-type
process with another molecule of arylmethane, and further
proton abstraction of hydroquinone to afford dimer 4a (cycle
A), which served as a new benzylic compound and started a
new cycle (cycle B) to generate a new benzyl cation N; the new
cation N reacted with iron-chelated the 1,3-dicarbonyl
compound to produce the desired product 3aa (Scheme 6).
In conclusion, a novel Fe-catalyzed double C−C bond
formation via a tandem CDC of dicarbonyl compounds with
arylmethanes has been developed under mild conditions. This
novel reaction has many advantages with double C−H
activation in a one-pot protocol to generate two new types of
C−C bonds. Substrate scope exploration suggested that this
method was complementary to the exisiting method in terms of
safer oxidant and wider substrate functionalities. Further
investigation on the mechanism, scope, and synthetic
application of this reaction are ongoing in our laboratory.
a
Scheme 4. Synthetic Utility of the Current Method
a
Reaction conditions: (a) FeCl2 (20 mol %), DDQ (4 equiv), DCE,
90 °C; (b) (1) NaOH (3 equiv), 90 °C, 18 h, MeOH (2 mL), H2O (1
mL); (2) AcOH (2 mL), 90 °C, 12 h; (c) LiAIH4, THF.
5 was difficult to access by other methods. When 3aa was
applied with LiAlH4 in THF, 1,3-diol 6, which is a very useful
building block in organic synthesis, was formed in 71% yield
(Scheme 4, eq 2).
Several control experiments were conducted to get further
insights into the reaction mechanism. First, radical trapping
experiments were carried out by employing 2,2,6,6-tetramethyl-
1-piperidinyloxy (TEMPO) and butylated hydroxytoluene
(BHT) with 1a and 2a under the standard conditions. As
shown in Scheme 2, the reactions were totally inhibited by
TEMPO and BHT, suggesting a radical pathway might be
involved in this reaction (Scheme 5, eqs 1 and 2). When p-
xylene was used under the standard conditions, 11% of cross-
dehydrogenative arylation product (dimer) 4a was obtained
C
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ASSOCIATED CONTENT
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Ed. 2009, 48, 3817−3820.
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S
* Supporting Information
Experimental procedures, analytical data for products, NMR
spectra of products. This material is available free of charge via
the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: qsong@hqu.edu.cn. Fax: 86-592-6162990.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the National Science Foundation of
China (21202049), the Recruitment Program of Global Experts
(1000 Talents Plan), Fujian Hundred Talents Program and
Program for Innovative Research Team of Huaqiao University
is gratefully acknowledged. We also thank Prof. Zhiping Li from
Renmin University of China for helpful discussions.
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D
DOI: 10.1021/ol503556x
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