The oxidative coupling of benzylic compounds catalyzed by 2,3-dichloro-5,6-dicyano-benzoquinone and sodium nitrite using molecular oxygen as a co-oxidant

Article abstract of DOI:10.1016/j.tetlet.2015.02.018

Catalyzed by DDQ and NaNO₂, the oxidative coupling between benzylic compounds and 1,3-dicarbonyls in the presence of molecular oxygen and HCOOH was developed. The 1% catalytic amount of DDQ is enough to complete the reaction. This system shows high efficiency and the coupling products are obtained in good to excellent yields within half an hour.

Full text of DOI:10.1016/j.tetlet.2015.02.018

Tetrahedron Letters 56 (2015) 1641–1644
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Tetrahedron Letters
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The oxidative coupling of benzylic compounds catalyzed
by 2,3-dichloro-5,6-dicyano-benzoquinone and sodium nitrite
using molecular oxygen as a co-oxidant
Dongping Cheng a, Kun Yuan a, Xiaoliang Xu b, Jizhong Yan a,
⇑
a College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, People’s Republic of China
b College of Chemical Engineering and Materials Science, Zhejiang University of Technology, Hangzhou 310014, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Catalyzed by DDQ and NaNO2, the oxidative coupling between benzylic compounds and 1,3-dicarbonyls
in the presence of molecular oxygen and HCOOH was developed. The 1% catalytic amount of DDQ is
enough to complete the reaction. This system shows high efficiency and the coupling products are
obtained in good to excellent yields within half an hour.
Received 27 November 2014
Revised 30 January 2015
Accepted 6 February 2015
Available online 12 February 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
C–C coupling
DDQ
Oxidation
Molecular oxygen
The construction of C–C bond is one of the most fundamental
and important reactions in organic synthesis because it provides
key step in the synthesis of complex molecules. In the past decade,
the construction of C–C bond via C–H oxidative activation is a hot
topic owing to avoiding the use of pre-functionalized precursors
and improving the atom-economy.1,2 Oxidants such as di-
tert-butyl peroxide, tert-butyl-hydroperoxide, hydrogen peroxide,
molecular oxygen have been already proved to be efficient in the
oxidative coupling reaction. From the point of green chemistry,3
use of molecular oxygen as the terminal oxidant is the most ideal
way because of its great abundance in nature and water as the only
by-product. It is well-known that molecular oxygen is almost inert
under mild conditions due to the energy barrier between substrate
and molecular oxygen. To accomplish the oxidation, transition
metals or transition-metal complexes have been usually required
to active molecular oxygen.4–6 However, transition metals are
generally expensive and potentially toxic and especially some
transition-metal complexes are not easily available. Thus, transi-
tion-metal-free coupling reaction which simultaneously employs
molecular oxygen as oxidizing reagent has attracted increasing
interest in recent years.
reactions.7–31 Unfortunately, a stoichiometric or excess amount
of DDQ is usually required in order to make the reaction to fully
complete and the by-product DDQ-H2 causes the purification diffi-
culty. A practical way to solve this problem is to develop a method
in which only a catalytic amount of DDQ is needed.32–41 In 2010,
Floreancig reported that several oxidative reactions including the
coupling of acetophenone with isochroman, were catalyzed by
15–20 mol % of DDQ with up to 6 equiv of MnO2 as a co-oxidant.36
The amount of DDQ is greatly decreased, but the use of excess
amounts of co-oxidant generates larger amounts of unwanted
by-product. Molecular oxygen is a terminal oxidant and it is ideal
if molecular oxygen can be employed as co-oxidant in DDQ-medi-
ated reactions. However, molecular oxygen cannot directly trans-
form the in situ formed DDQ-H2 to DDQ under mild conditions,
which means that an additional compound should act as the bridge
between molecular oxygen and the cycle of DDQ-H2 and DDQ. Very
recently, Prabhu published the first report of regenerating DDQ by
using catalytic amount of azobisisobutyronitrile and molecular
oxygen.39 In order to complete the coupling reaction of N-aryltet-
rahydroisoquinoline, the catalytic amount of DDQ is up to
10 mol %. With the interest of applying of catalytic DDQ in the oxi-
dative reaction, herein, we wish to report an efficient coupling
reaction of benzylic compounds and 1,3-dicarbonyls catalyzed by
DDQ (1 mol %) and NaNO2 in the atmosphere of molecular oxygen.
Firstly, catalyzed by 10 mol % DDQ and 10 mol % NaNO2,
1,3-diphenyl 1,3-propanedione 1a, and 1,3-diphenyl propene 2a
were chosen as model substrates at room temperature in the
2,3-Dichloro-5,6-dicyano-benzoquinone (DDQ), being a well-
known oxidant, has been widely applied in oxidative coupling
⇑
Corresponding author. Fax: +86 571 8832 0913.
E-mail address: yjz@zjut.edu.cn (J. Yan).
http://dx.doi.org/10.1016/j.tetlet.2015.02.018
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

1642
D. Cheng et al. / Tetrahedron Letters 56 (2015) 1641–1644
presence of O2. To our delight, the coupling product could be
obtained although the yield was only 15% (Table 1, entry 1). The
yield was increased to 28% when acetic acid was added to the
system. The reason may be that the acid could promote the decom-
position of NaNO2 to NO which rapidly reacted with O2 to form
NO2.42,43 Other acids were surveyed and similar results were
observed (Table 1, entries 2–6). The yield was up to 78% when a
mixture of HCOOH/CH2Cl2 was used. Then a number of solvents
were examined (Table 1, entries 7–10). The reaction could proceed
in DCE, CHCl3, and CH3CN, but the yield was low. CH3NO2 was a rel-
atively suitable solvent for the reaction. No product was obtained
when the reaction was performed in the absence of DDQ (Table 1,
entry 11). In the absence of HCOOH, NaNO2, or molecular oxygen,
the catalytic system showed poor reactivity (Table 1, entries
12–14). To decrease the amount of DDQ, 1 mol % of DDQ was
examined and the product was obtained in 76% yield (Table 1,
entry 15). When the reaction was carried out at 40 °C, the yield
was improved to 98% (Table 1, entry 16). However, the yield was
decreased if the temperature was increased to 60 or 80 °C (Table 1,
entries 17–18). The reason might be that NaNO2 decomposed
rapidly under high temperatures.
With the best reaction conditions in hand, various substrates
were subjected to the coupling reaction (Table 2). It was shown
that the catalytic system exhibits high reactivity toward the
examined compounds. As far as the active compounds 1 were con-
cerned, obvious electron effect was observed. The benzene ring
with electron-donating group such as methyl, methoxyl gave the
corresponding products in 82–99% yields (Table 2, entries 2–3,
5–6). In comparison, a moderate yield was obtained when benzene
ring had fluorine substituent (Table 2, entry 7). In the reaction, it
was found that 1,3-diphenyl propene was converted to allyl alco-
hol which was further oxidized to the corresponding ketone. When
substrate 1g reacted with 1,3-diphenyl propene 2a, the by-product
1,3-diphenyl propen-3-one was given in 44% yield. Heteroaryl spe-
cies were acted as well and afforded the coupling products in
excellent yields (Table 2, entries 8–9). b-Keto esters such as ethyl
benzoylacetate, ethyl acetoacetate were compatible with the cata-
lytic system (Table 2, entries 12–13). It should be pointed out that
the products 3b–3m were mixtures of diastereoisomers when
nonsymmetrical b-diketones or b-ketoesters were used as
substrates. To expand the scope of the substrate, different 1,3-
diaryl propenes were investigated (Table 2, entries 14–18). As for
the asymmetrical substituted substrates 2b, 2d, 2e, and 2f, both
a- and c-products were obtained. The ratios of a- and c-products
were 3:2, 7:3, 2:3, and 9:11 for 3n, 3p, 3q, and 3r according to
NMR, respectively.
Finally, the gram-scale application of this catalytic system is
investigated.44
A reaction of 5 mmol (1.12 g) 1,3-diphenyl
1,3-propanedione 1a and 6 mmol (1.16 g) 1,3-diphenyl propene
2a was carried out with 1 mol % DDQ, 10 mol % NaNO2 in CH3NO2
(15 mL) and HCOOH (7.5 mL) under oxygen balloon at 40 °C. The
coupling product was obtained in 88% yield, which indicated that
our catalytic system was an efficient and practical process for the
oxidative coupling reaction of benzylic compounds with
1,3-dicarbonyls.
On the base of our results and literatures35,40 an additional
experiment was tested. 0.5 mmol DDQ-H2 and 0.05 mmol NaNO2
were mixed and stirred in CH3NO2/HCOOH under oxygen balloon.
DDQ-H2 was completely oxidized to DDQ in ten minutes. It shows
that NO can be oxidized to NO2 in the presence of O2 and NO2 can
readily oxidize DDQ-H2 to DDQ.
A possible mechanism for the coupling reaction was proposed
in Scheme 1. The reaction may proceed through three pathways.
One is a one-step hydride transfer to DDQ; the other two are
hydrogen atom abstraction or proton abstraction followed by a
second electron transfer after an initial electron transfer.16 In the
experiment, we obtained the 1,3-diphenyl propen-3-one which
should be in situ formed by further oxidation of 1,3-diphenyl
propene. The diastereoisomer products were given in the reaction
of 1,3-diphenylpropene with nonsymmetrical b-diketones or b-
ketoesters. The asymmetrical 1,3-diarylpropene 2b, 2d, 2e, and 2f
coupled with 1,3-diphenyl 1,3-propanedione to generate a mixture
of the corresponding
indicated the allylic cation with itself being rearranged between
- and -positions involved in the coupling reaction. The attack
of the nucleophile to - or -position gave the isomerized prod-
ucts. The -products were more stable than the -products when
2b and 2d were chosen as the substrates. As for 2e and 2f, the
a- and c-products. The above results
a
c
a
c
a
c
Table 1
Optimization of the oxidative couplinga
O
O
Ph
Ph
DDQ/NaNO2
O
O
Ph
Ph
+
Ph
Ph
Ph
Solvent
Ph
O2 (balloon)
1a
2a
3a
Entry
DDQ (mol %)
NaNO2 (mol %)
Acid/solvent
CH2Cl2
CH3COOH/CH2Cl2
(COOH)2/CH2Cl2
HCl/CH2Cl2
C6H5CO2H/CH2Cl2
HCOOH/CH2Cl2
HCOOH/DCE
HCOOH/CHCl3
HCOOH/CH3CN
HCOOH/CH3NO2
HCOOH/CH3NO2
CH3NO2
HCOOH/CH3NO2
HCOOH/CH3NO2
HCOOH/CH3NO2
HCOOH/CH3NO2
HCOOH/CH3NO2
HCOOH/CH3NO2
Temp (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14c
15
16
17
18
10
10
10
10
10
10
10
10
10
10
0
10
10
10
1
1
1
10
10
10
10
10
10
10
10
10
10
10
10
0
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
40
60
80
15
28
21
22
29
78
53
25
26
86
0
16
9
10
10
10
10
10
10
76
98
91
80
1
a
b
c
1a (0.5 mmol, 0.112 g), 2a (0.6 mmol, 0.128 g), solvent (2.5 mL), acid (0.25 mL), O2 balloon, 0.5 h.
Isolation yield.
In the absence of molecular oxygen.

D. Cheng et al. / Tetrahedron Letters 56 (2015) 1641–1644
1643
Table 2
The oxidative coupling of 1,3-diarylpropenesa
O
O
DDQ (1 mol %)/
O
O
NaNO2 (10 mol %)
R1
R3
R2
R4
+
R3
R2
R4
CH3NO2/HCOOH
O2 (balloon)
R1
1
2
3
Entry
R1, R2
1
R3, R4
2
Product 3
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13c
14
15
16
17
18
C6H5, C6H5 (1a)
C6H5, 2-CH3C6H4 (1b)
C6H5, 3-CH3OC6H4 (1c)
C6H5, 3-BrC6H4 (1d)
C6H5, 4-CH3OC6H4 (1e)
C6H5, 4-CH3C6H4 (1f)
C6H5, 4-FC6H4 (1g)
C6H5, Thienyl (1h)
C6H5, Furanyl (1i)
C6H5, CH3 (1j)
CH3, CH3 (1k)
C6H5, OCH2CH3 (1l)
CH3, OCH2CH3 (1m)
1a
C6H5, C6H5 (2a)
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3nd
3o
3pd
3qd
3rd
98
99
82
91
99
88
48
99
99
94
80
91
83
84
41
86
86
72
2a
C6H5, 4-CH3OC6H4 (2b)
1a
1a
1a
1a
4-CH3OC6H4, 4-CH3OC6H4 (2c)
C6H5, 4-CH3C6H4 (2d)
C6H5, 4-BrC6H4 (2e)
4-CH3OC6H4, C6H5 (2f)
a
b
c
1 (0.5 mmol), 2 (0.6 mmol), DDQ (0.005 mmol), NaNO2 (0.05 mmol), CH3NO2 (2.5 mL), HCOOH (0.25 mL), 40 °C, O2 balloon, 0.5 h.
Isolation yield.
1 (0.6 mmol), 2 (0.5 mmol).
d
For all of these substrates both
a- and
c
-products were formed. For 3n, 3p, 3q, and 3r, the ratios of the a- and c-products were separately 3:2, 7:3, 2:3, and 9:11
determined by NMR.
O
References and notes
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[O]
O
H2O
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might be owing to the small amount of HCOOH in the solvent. Then, the
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