Metal-Free Aerobic Oxidative C–O Coupling of C(sp3)–H with Carboxylic Acids Catalyzed by DDQ and tert-Butyl Nitrite

Article abstract of DOI:10.1002/ejoc.201900773

The formation of the C–O bond is one of the hot topics in the area of C(sp³)–H bond functionalization. A metal-free oxidative cross-coupling between benzylic C(sp³)–H bond and carboxylic acids has been developed. The reactions were performed with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as the catalyst, tert-butyl nitrite (TBN) as the co-catalyst, and molecular oxygen as the terminal oxidant. A variety of diarylmethanes could be successfully coupled with various carboxylic acids to obtain diarylmethanol esters in good to excellent yields. In addition, 2-benzylbenzoic acids could be converted into phthalides in moderate yields through an intramolecular oxidative cyclization.

Full text of DOI:10.1002/ejoc.201900773

A Journal of
Accepted Article
Title: Metal-Free Aerobic Oxidative C−O Coupling of C(sp3)−H with
Carboxylic Acids Catalyzed by DDQ/tert-Butyl nitrite
Authors: Decheng Pan, Zilong Pan, Zhiming Hu, Meichao Li, Xinquan
Hu, Liqun Jin, Nan Sun, Baoxiang Hu, and Zhenlu Shen
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900773
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10.1002/ejoc.201900773
European Journal of Organic Chemistry
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Metal-Free Aerobic Oxidative C−O Coupling of C(sp3)−H with
Carboxylic Acids Catalyzed by DDQ/tert-Butyl nitrite
Decheng Pan,[a] Zilong Pan,[a] Zhiming Hu,[a] Meichao Li,*[a] Xinquan Hu,[a] Liqun Jin,[a] Nan Sun,[a]
Baoxiang Hu,[a] Zhenlu Shen*[a]
Abstract: The formation of C−O bond is one of the hot topics in the
area of C(sp3)−H bond functionalization. A metal-free oxidative
cross-coupling between benzylic C(sp3)−H bond and carboxylic
acids has been developed. The reactions were performed with 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as the catalyst, tert-
butyl nitrite (TBN) as the co-catalyst, and molecular oxygen as the
terminal oxidant. A variety of diarylmethanes could successfully
couple with various carboxylic acids to obtain diarylmethanol esters
in good to excellent yields. In addition, 2-benzylbenzoic acids could
be converted into phthalides in moderate yields via intramolecular
oxidative cyclization.
molecular oxygen to oxidize common singlet organic compounds
directly.[12] To clear up the high energy barrier between
molecular oxygen and organic substrates, a practical way is to
construct an aerobic oxidation system with
a
catalyst
combination of DDQ and a co-catalyst. Prabhu et al reported the
aerobic oxidation system DDQ/AIBN/O2, which was applied to
oxidative C-C coupling.[13] Our group has also developed an
efficient oxidation system DDQ/tert-butylnitrite (TBN)/O2,[14] and
this oxidation system has been successfully used for oxidation of
[15]
C(sp3)−H bond
and oxidative C-N coupling.[16] These
strategies have significant economic and environmental benefits
due to the use of catalytic amount of DDQ and the natural
abundance of molecular oxygen.
Introduction
Direct C−H bond functionalization is a powerful and robust
strategy in organic synthesis. Simple raw materials with C−H
bond can be directly converted into more valuable products
through carbon-carbon (C−C) bond or carbon-heteroatom (C−X)
bond formations.[1] During the past several years, the C−H bond
functionalization has made great progress through the way of
oxidative cross-coupling.[2] While most of the C−H bond
functionalization reactions are catalyzed by the transition
metals,[3] such as Cu, Ni, Fe, Ru, Pd, etc. Unfortunately, these
methods are always unable to avoid metal residue, especially in
the pharmaceutical industry. With the merits of metal-free and
mild reaction conditions, organocatalysis has become a new
strategy for the formation of C−C/C-X bonds.[4]
Scheme 1. Aerobic oxidative C−O coupling of benzylic C(sp3)−H bonds with
carboxylic acids.
[5]
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)
is
a
Diarylmethanol esters are an important class of organic
molecules which can be served as pharmaceutical precursors
and functional molecules,[17] and they could be hydrolyzed into
diarylmethanols which are also important pharmaceutical
substructures.[18] Although some examples of oxidative C−O
coupling reactions with benzylic C(sp3)−H bond have been
reported for synthesis of diarylmethanol esters and other
compounds,[9,19] to the best of our knowledge, there is no report
of metal-free oxidative C−O coupling with molecular oxygen as
the terminal oxidant.
powerful oxidant which has been successfully employed in many
C−H bond functionalizations including C(sp3)−H oxidation to
form C=O bond [6], and oxidative coupling of C(sp3)−H to form
C−C,[7] C−N,[8] C−O,[9] C−P[10] bonds and et al. This is mainly
attributed to its single electron transfer (SET) ability and
hydrogen abstraction capacity.[11] Most of these reactions require
stoichiometric DDQ or a combination of catalytic amount of DDQ
and a stoichiometric metal oxidant (MnO2).[7d,9d] As we known,
molecular oxygen (O2 or air) is considered as an ideal oxidant
due to its economic and green characteristics with the sole by-
product H2O after oxidation. However, it is difficult for triplet
Inspired by the aforementioned works and our previous works,
herein we report a DDQ/TBN-catalyzed aerobic oxidative C−O
coupling of C(sp3)−H with carboxylic acids (Scheme 1).
[a]
D. Cheng, Z. Pan, Z. Hu, Prof. Dr. M. Li, Prof. Dr. X. Hu, Prof. Dr. L.
Jin, Prof. Dr. N. Sun, Prof. B. Hu, Prof. Dr. Z. Shen
College of Chemical Engineering
Zhejiang University of Technology
Results and Discussion
No. 18, Chaowang Road, Hangzhou 310014 (P.R. China)
E-mail: limc@zjut.edu.cn; zhenlushen@zjut.edu.cn
http://www.ce.zjut.edu.cn/jsp/teacher.jsp?wcId=36&teacher_id=00218
http://www.ce.zjut.edu.cn/jsp/teacher.jsp?wcId=36&teacher_id=03541
We set out to evaluate reaction parameters with the coupling of
diphenylmethane (1a) and AcOH (2a) to form benzhydryl
acetate (3aa) as the model reaction (Table 1).
Diphenylmethanone is the
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201900773
European Journal of Organic Chemistry
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Table 1. Optimization of the Reaction Conditions. [a]
Entry
Solvent
T
DDQ
(mol%)
TBN
(mol%)
AcOH
(equiv)
Conv. [b]
(%)
Yield [c]
(%)
(oC)
1
Toluene
EtOH
THF
100
100
100
100
100
100
80
20
20
20
20
20
20
20
20
10
-
20
20
20
20
20
20
20
20
20
20
10
-
5
5
5
-
8
5
2
N.R.
N.R.
72
96
98
69
3
-
3
-
4
AcOH
PhCl
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
70 (67)
5
5
5
5
5
5
5
5
5
5
3
1
5
84 (81)
6
96 (92)
7
65
8
60
3
9
100
100
100
100
100
100
100
rt
71
7
61
10
11
12
13
14
15
16[d]
0
20
20
-
70
13
N.R.
97
90
92
66
13
-
-
20
20
20
20
20
20
82 (77)
70 (64)
78
[a] Reaction conditions: 1a (0.5 mmol), 2a, DDQ, TBN, solvent (4.0 mL), O2 (0.1 Mpa),36 h. [b] Determined by GC with area normalization
method. [c] GC yields (the data in the parenthesis are isolated yields). [d] Photooxygenation conditions: 1a (0.5 mmol), 2a (2.5 mmol), DDQ
and TBN, DCE (4.0 mL), 18 W blue LED, O2 (0.1 Mpa), rt, reaction time 36 h.
sole by-product in this oxidative cross-coupling reaction. The
reaction of 1a and 2a (5 equiv) was performed with DDQ (20
mol%) and TBN (20 mol%) in the solution of toluene under 0.1
DDQ, TBN and AcOH were further examined. When the loading
of DDQ was reduced to 10 mol%, the conversion of 1a was
decreased to 71% (Table 1, entry 9). When DDQ was
completely removed, the conversion of 1a is only 7% and no 3aa
was detected (Table 1, entry 10). Similarly, decreasing the
loading of TBN to 10 mol% led to 70% conversion of 1a; and
when TBN was completely removed, 3aa could be obtained in
13% GC yield (Table1, entries 11 and 12). Then the oxidative
coupling reaction was performed in the absence of DDQ and
TBN, as we expected, no reaction took place (Table 1, entry 13).
Notably, reducing the loading of AcOH from 5 equiv led to a
lower yield of 3aa although the conversion of 1a was still
relatively high (Table 1, entries 14 and 15). It could be found that
as the amount of AcOH decreased, the by-product
benzophenone increased. At last, we tried the photocatalytic
strategy, but the selectivity to 3aa was not as good
o
MPa of oxygen at 100 C. After 36 h, the conversion of 1a was
only 8% and the GC yield of 3aa was only 5% (Table 1, entry 1).
In polar solvent EtOH and THF, the oxidative C−O coupling
reaction was obviously inhibited (Table 1, entries 2 and 3).
When acetic acid was used as both solvent and reactant, 72%
conversion of 1a and 67% isolated yield of 3aa could be
obtained (Table 1, entry 4). To our delight, when the reaction
was performed in chlorobenzene and 1,2-dichloroethane (DCE),
the conversion of 1a was higher than 95% (Table 1, entries 5
and 6). Especially in DCE, 92% isolated yield of 3aa could be
achieved.
Then the reaction temperature was tested. Decreasing the
reaction temperature from 100 oC to 60 oC led to lower
conversions (Table 1, entries 7 and 8). Later on, the loadings of
as that of thermal method (Table 1, entry 16).
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(30 mol% DDQ and 30 mol% TBN) were required, also a longer
reaction time (48 h) was needed. Nevertheless, the isolated
yields of the corresponding esters 3ha and 3ia were still
excellent (90% and 87%). The C−O bond coupling reaction of 2a
with multi-substituted diphenylmethane 1j containing methyl and
methoxy should performed at room temperature with 2a as the
solvent, and 86% isolated yield of 3ja could be obtained.
Moreover, diphenylmethanes bearing both electron-donating
and electron-withdrawing substituents could react efficiently with
2a, and afforded their corresponding esters 3ka-3ma in 85-88%
isolated yields. Polycyclic aromatic substrates 1n-1r could also
be converted into their corresponding products 3na-3ra in 84-
95% isolated yields. Lower temperature (80 oC) and less
amounts of DDQ (10 mol%) and TBN (10 mol%) were needed in
the coupling of 1-(4-methoxybenzyl)naphthalene (1o) with 2a.
Substrate 1s containing a heterocyclic thiophene was also
explored, the product 3sa could be obtained in 81% isolated
yield. However, the presence of strong electron-withdrawing
group (4-CN and 4-NO2) on diphenylmethane would hinder the
reaction. The isolated yield of (4-cyanophenyl)(phenyl)methyl
acetate (3ta) was only 20%, and (4-nitrophenyl)(phenyl)methyl
acetate (3ua) could not be obtained in the reaction.
Scheme 2. DDQ/TBN-catalyzed aerobic oxidative C−O coupling of
diarylmethanes with AcOH.[a] [a] Standard reaction conditions: 1 (0.5 mmol),
2a (2.5 mmol), DDQ (20 mol%), TBN (20 mol%), DCE (4.0 mL), O2 (0.1 MPa),
100 oC (bath oil). [b] DDQ (30 mol%), TBN(30 mol%). [c] AcOH (2.0 mL) as
the solvent, rt. [d] DDQ (10 mol%), TBN (10 mol%), 80 oC.
Upon exploring the general applicability of this protocol, the
oxidative C−O coupling of a number of diarylmethanes 1 with 2a
were investigated under the optimal reaction conditions
(Scheme 2). The results in Scheme 2 demonstrated the yields of
desired diarylmethyl acetates to be good to excellent. This C−O
bond coupling reaction was compatible with different functional
groups including electron-donating groups and electro-
withdrawing groups. Substrate 1b containing o-methyl reacted
smoothly with 2a to give the corresponding phenyl(o-tolyl)methyl
acetate (3ba) in 91% isolated yield. It is clear that the reactivities
of diphenylmethanes bearing an electro-donating group (m-
methyl, p-methyl, m-methoxy, p-methoxy or p-tert-butyl) were
improved. The required reaction time was shortened to less than
15 h, and the isolated yields of 3ca-3ga were 88-94%. When
diphenylmethanes with an electron-withdrawing group (p-F and
p- Cl) were used as the substrates, higher loadings of catalysts
Scheme 3. DDQ/TBN-catalyzed aerobic oxidative C−O coupling of
diphenylmethanes with carboxylic acids.[a] [a] Standard reaction conditions: 1
(0.5 mmol), 2 (2.5 mmol), DDQ (20 mol%), TBN (20 mol%), DCE (4.0 mL), O2
(0.1 MPa), 100 oC (bath oil).
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Next, we tried to investigated DDQ/TBN-catalyzed aerobic
oxidative C−O coupling of diphenylmethanes with various
carboxylic acids (Scheme 3). Initially, some common carboxylic
acids, including isobutyric acid (2b), benzoic acid (2c),
cyclohexanecarboxylic acid (2d), and p-tolylacetic acid (2e),
successfully coupled with diphenylmethanes (1a and 1d) in 61-
91% isolated yields (3ab-3de). It is obvious that the yields of
diphenylmethanol esters were depended on the activity of
diphenylmethanes and the acidity of carboxylic acids. When the
low-activity 1a coupled with 2c, it was difficult to achieve high
yield of 3ac. Then heteroaromatic acid (thiophene-3-carboxylic
system for the intramolecular oxidative cyclization of 2-
benzylbenzoic acids, 40-51% isolated yields of phthalides (5a-
5d) were obtained. According to our previous research work and
the experimental results, we believed that H2O produced in the
reaction could react with the intermediates (diphenylmethyliums)
to form by-products. Hence, stoichiometric DDQ was used in
order to reduce the effect of H2O. The results in Scheme 5
demonstrated that the isolated yields of the oxidative cyclization
products have been significantly improved (66-76%). Although
only moderate yields of phthalides can be obtained, this DDQ-
mediated oxidative lactonization of 2-benzylbenzoic acids
acid 2f) and cinnamic acid (2g) were submitted to couple with 1d, strategy still has application value in the synthesis of
the isolated yields of 83% (3df) and 82% (3dg) were also
pharmaceutical intermediates.
satisfactory.
Evidence for a radical pathway was obtained by performing the
aerobic oxidative C−O coupling of 1a with 2a in the presence of
excess TEMPO (2 equiv.) as a radical scavenger [E1. (2)]. In
this case, no reaction was observed, suggesting that a radical
mechanism was plausible (Scheme 5). In the DDQ/TBN/O2
system, DDQ is employed as the main catalyst, oxygen as the
terminal oxidant, and TBN as the co-catalyst which serves as an
equivalent of nitric oxide.[22] The reaction of 1a and DDQ
generates alkyl radical (I) and DDQH· via hydrogen atom
transfer (HAT). Subsequent single electron transfer (SET) led to
diphenylmethylium (II) and DDQH-.[9a] The cation II can react
with AcOH (2a) to give the corresponding product 3aa.
Meanwhile, DDQH- is protonated to the hydroquinone DDQH2,
which could be re-oxidized to DDQ by NO2.
In order to examine the practicability of this aerobic oxidative
C−O coupling reaction, gram-scale reaction was performed
under the optimized conditions (6 mmol of 1-benzyl-4-
methoxybenzene (1f)). The corresponding product 3fa could be
isolated in 90% yield [Eq. (1)].
Scheme 4. DDQ/TBN-catalyzed intramolecular aerobic oxidative C−O
coupling.[a] [a] Reaction conditions: 4 (0.5 mmol), DDQ (30 mol%), TBN (30
mol%), DCE (4.0 mL), O2 (0.1 MPa), 100 oC (bath oil). [b] Reaction conditions:
4 (0.5 mmol), DDQ (1.2 equiv), DCE (4.0 mL), N2, 100 oC (bath oil).
According to above results, the metal-free DDQ/TBN catalytic
system exhibited a strong catalytic ability in intermolecular
oxidative cross-coupling between benzylic C(sp3)−H bond and
carboxylic acid. We turned our attention to intramolecular
oxidative cyclization of 2-benzylbenzoic acids (Scheme 4).
Phthalides have great potential in pharmaceutical and biological
application, and have been used from academic to industry.[20]
Varieties synthetic methods of phthalides have been reported,
such as reduction of phthalic anhydrides or phthalaldehydic
acids, coupling of phthalaldehyde and arylboronic acids, and
photocyclization.[21] When we explore this DDQ/TBN catalytic
Scheme 5. Plausible reaction mechanism.
Conclusions
In summary, we have developed a metal-free aerobic oxidative
cross-coupling between benzylic C(sp3)−H bond and carboxylic
acids catalyzed by DDQ/TBN. A range of diarylmethanes could
successfully couple with various carboxylic acids, and
diarylmethanol esters could be obtained in good to excellent
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European Journal of Organic Chemistry
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synthesized via intramolecular oxidative cyclization mediated by
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Experimental Section
General experimental procedure (3): A 25-mL tube equipped with a
magnetic stirrer bar was added diphenylmethanes 1 (0.5 mmol), dry
carboxylic acid 2 (2.5 mmol), DDQ (22.7 mg, 20 mol%) and 4.0 mL of dry
DCE. After the air in the tube was replaced with O2, TBN (12 μL, 20
mol%) was added and the tube was sealed. The sealed tube was
placed in an oil-bath and heated at 100 oC until the reaction was
completed. Then the mixture was concentrated on a rotary evaporator.
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by-product (diarylketones) was completely converted into oxime. Then
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chromatography (silica gel, PE-EtOAc) to afford the title compound.
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General experimental procedure (5): Method (1): A 25-mL tube
equipped with a magnetic stirrer bar was charged with 2-benzylbenzoic
acid 5 (0.5 mmol), DDQ (34.0 mg, 30 mol%) and dry DCE (4.0 mL). After
the air in the tube was replaced with O2, TBN (18 μL, 30 mol%) was
added and the tube was sealed. The sealed tube was placed in an oil-
bath and heated at 100 oC until the reaction was completed. The mixture
was then concentrated on a rotary evaporator, and the residue was
purified by column chromatography (silica gel, PE-EtOAc) to afford the
title compound. Method (2): A 25-mL tube equipped with a magnetic
stirrer bar was charged with 2-benzylbenzoic acid 5 (0.5 mmol), DDQ
(136.2 mg, 1.2 equiv) and dry DCE (4.0 mL). The tube was sealed after
the air in it was replaced with N2. The sealed tube was placed in an oil-
bath and heated at 100 oC until the reaction was completed. The mixture
was then concentrated on a rotary evaporator, and the residue was
purified by column chromatography (silica gel, PE-EtOAc) to afford the
title compound.
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This project was supported by the National Natural Science
Foundation of China (21776260, 21773211 and 21773210) and
Natural
Science
Foundation
of
Zhejiang
Province
(LY17B060007).
Keywords: 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone •
Oxidation • Cross-coupling • Oxygen • Diarylmethanol ester
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Entry for the Table of Contents
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Decheng Pan, Zilong Pan, Zhiming Hu,
Meichao Li,* Xinquan Hu, Liqun Jin, Nan
Sun, Baoxiang Hu, Zhenlu Shen*
Page No. – Page No.
Metal-Free Aerobic Oxidative C−O
Coupling of C(sp3)−H with Carboxylic
Acids Catalyzed by DDQ/tert-Butyl
nitrite
Aerobic C−O coupling: A metal-free aerobic oxidative cross-coupling between
benzylic C(sp3)−H bond and carboxylic acids catalyzed by 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone / tert-butyl nitrite has been developed. This protocol provides a
mild and efficient route to obtain diarylmethanol esters and phthalides. It can be
regarded as a typical example of green chemistry in oxidative C−O coupling.
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