Palladium-Catalyzed Formal Cross-Coupling of Diaryl Ethers with Amines: Slicing the 4-O-5 Linkage in Lignin Models

Article abstract of DOI:10.1002/anie.201712211

Lignin is the second most abundant organic matter on Earth, and is an underutilized renewable source for valuable aromatic chemicals. For future sustainable production of aromatic compounds, it is highly desirable to convert lignin into value-added platform chemicals instead of using fossil-based resources. Lignins are aromatic polymers linked by three types of ether bonds (α-O-4, β-O-4, and 4-O-5 linkages) and other C?C bonds. Among the ether bonds, the bond dissociation energy of the 4-O-5 linkage is the highest and the most challenging to cleave. To date, 4-O-5 ether linkage model compounds have been cleaved to obtain phenol, cyclohexane, cyclohexanone, and cyclohexanol. The first example of direct formal cross-coupling of diaryl ether 4-O-5 linkage models with amines is reported, in which dual C(Ar)?O bond cleavages form valuable nitrogen-containing derivatives.

Full text of DOI:10.1002/anie.201712211

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Angewandte
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International Edition
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Accepted Article
Title: Palladium-Catalyzed Formal Cross-Coupling of Diaryl Ethers with
Amines: New Tactic to Slice 4-O-5 Linkage in Lignin Models
Authors: Huiying Zeng, Dawei Cao, Zihang Qiu, and Chao-Jun Li
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201712211
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10.1002/anie.201712211
Angewandte Chemie International Edition
COMMUNICATION
Palladium-Catalyzed Formal Cross-Coupling of Diaryl Ethers with
Amines: New Tactic to Slice 4-O-5 Linkage in Lignin Models
Huiying Zeng,[a],* Dawei Cao,[a] Zihang Qiu[b] and Chao-Jun Li[a],[b],*
OH
Abstract: Lignin, the second most abundant organic matter on Earth,
OH
is an under-utilized renewable source for valuable aromatic chemicals.

For future sustainable aromatic products, it is highly desirable to

HO
OMe
OH
O
convert lignin into higher value-added platform chemicals instead of
using the fossil-based resources. Lignins are aromatic polymers
linked by three types of ether bonds (α-O-4, β-O-4 and 4-O-5 linkages)
and other C–C bonds. Among those ether bonds, the bond
dissociation energy of 4-O-5 linkage is the highest and the most
challenging to cleave. Up to date, the 4-O-5 ether linkage model
compounds have been cleaved to obtain phenol, cyclohexane,
cyclohexanone, and cyclohexanol. Herein, we report the first example
of direct formal cross-coupling of the 4-O-5 linkage model compounds,
diaryl ethers, with amines via dual C(Ar)-O bond cleavages to
generate valuable nitrogen-containing derivatives.
HO
HO
OMe
OMe
O
O
MeO
OH
HO
O
HO
O
MeO
O
O
OMe
OMe
HO
HO
OMe
O

OMe
OH
O
MeO
O
HO
Figure 1. Common Ether Linkages in Lignins
(a) Catalytic reduction and cleavage of 4-O-5 linkage model compounds
OH
O
Lignin, the most recalcitrant of the three components of
lignocellulosic biomass,[1] accounts for ca. 30% of the organic
carbon on Earth.[2] Until now, lignin has been treated as a waste
product in the pulp and paper industry, mostly being burned to
recover its thermo-energy. Lignin has the potential to provide one
of the few renewable sources of aromatic chemicals in the
future.[3] Consequently, valorization of lignin is becoming more
and more important for social, economic, and resource
sustainability.[4] Structurally, lignin is a complex polyphenolic
substance containing a large number of C–O ether bonds
(including α-O-4, β-O-4 and 4-O-5 linkages) (Fig. 1).[5] Therefore,
cleavage of C–O ether bonds in lignins is a crucial step for the
degradation and valorization of lignin biomass to obtain bio-fuels
and commercial chemicals[6] and is challenging because of the
strength and stability of these ether linkages.[1a, 7] 2-Phenylethyl
phenyl ether, benzyl phenyl ether, and diphenyl ether have been
commonly selected as model compounds for the cleavage of β-
O-4, α-O-4 and 4-O-5 linkages, respectively.[8] Among these three
types of C–O ether bonds, the bond dissociation energy (BDE) of
diphenyl ether bond of 4-O-5 (BDE = 314 kJꞏmol-1) is much
stronger than the aliphatic ether bonds of α-O-4 (BDE =218
kJꞏmol-1) and β-O-4 (BDE = 289 kJꞏmol-1).[9] Thus, while the
cleavage of C–O aliphatic ether bond (α-O-4 linkage and β-O-4
linkage) were extensively reported through oxidation,[10]
O
OH
O
O
O
OH
OH
O
O
(b) This work: catalytic direct formal cross-coupling of 4-O-5 linkage
model compounds with amines
R1
N
R1
N
O
R2
R1
R2
R2
+
N
+
H
cross-coupling
OH
second C(Ar)-O
bond cleavage
first C(Ar)-O
bond cleavage
Scheme 1. Strategies for Cleavage of Lignin 4-O-5 Linkage Model Compounds
12]
reduction,[11] hydrolysis/solvolysis,[3a,
and others,[13] the
cleavage of diphenyl ether bond (4-O-5 linkage) is the most
challenging. A milestone to overcome the challenge of cleaving
the most difficult diphenyl ether C–O bond (4-O-5 linkage) via
[a]
[b]
Prof. Dr. H. Zeng, D. Cao and Prof. Dr. C.-J. Li
The State Key Laboratory of Applied Organic Chemistry
Lanzhou University
222 Tianshui Road, Lanzhou, 730000, P. R. China
E-mail: zenghy@lzu.edu.cn; cj.li@mcgill.ca
Z. Qiu and Prof. Dr. C.-J. Li
Department of Chemistry and FQRNT Centre for Green Chemistry
and Catalysis
McGill University
hydrogenolysis to form phenol and benzene was achieved by
8c, 8f]
Hartwig and co-workers.[8b,
Since then, several important
progresses have been made in cleavage of diaryl ether bonds to
form small molecules, including: a) phenol and benzene,[14] b)
15]
cyclohexanol,[8d] c) cyclohexane[8e,
, d) cyclohexanol and
801 Sherbrooke St. West, Montreal, Quebec H3A 0B8, Canada
cyclohexanone[8g] and e) cyclohexanone and phenol[8h] (Scheme
1a). It will be highly desirable to generate other important
structural motifs such as nitrogen-containing compounds, a
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201712211
Angewandte Chemie International Edition
COMMUNICATION
general feature shared by >90% of leading pharmaceutical
agents[16], from diaryl ethers directly.
examined for this transformation; lower conversion or no product
was obtained when Pd(OAc)2 and Pd(PPh3)2Cl2 were used as
catalysts (Table 1, entries 2-3). To our delight, higher conversion
(35%) and yield (22%) were obtained when Pd(OH)2/C was used
as catalyst (Table 1, entry 4). The addition of various additives
such as Lewis acids and Lewis bases failed to produce any
desired coupling products, with only small amounts of starting
material being converted (Table 1, entries 5-8). The reaction
showed a strong dependence on the solvent, among which o-
xylene, m-xylene and p-xylene were more effective than toluene
(Table 1, entries 9-11). It is interesting to note that the different
substituted position of xylene is important to this transformation.
The highest yield (48%) and highest conversion (71%) were
obtained when m-xylene was used as solvent (Table 1, entry 10).
More polar solvents, such as dioxane and water, were less
effective (Table 1, entries 12-13). A small amount of water (10 μL)
was found beneficial to this reaction (Table 1, entry 15), whereas
a higher or lower amount of water resulted in a lower yield (Table
1, entries 14 and 16). The ratio of pyrrolidine and diphenyl ether
at 3.5: 1 appeared to be optimal for this reaction (Table 1, entries
17-19). The amount of air was also important for both the yield
and the conversion. A higher yield (66%) and higher conversion
(93%) were achieved when 1 mL air was added in this reaction
system (Table 1, entry 20). Further increasing the amount of air
(2 mL) decreased the yield slightly (Table 1, entry 21). Decreasing
the amount of Pd(OH)2/C to 10%, both the yield and the
conversion were reduced significantly (Table 1, entry 22). No
improvement in yield was observed when increasing the amount
of catalyst; and almost the same yields were observed with 30
mol% or 40 mol% Pd(OH)2/C (Table 1, entries 23-24). For
economical reason, we choose the amount of 30 mol%
Pd(OH)2/C as the optimal conditions for the following optimization
process. It was found that much better result (77% yield, 99%
conversion) was obtained when NaBH4 was used as an
alternative hydride source (Table 1, entry 25). Further increasing
the amount of NaBH4 gave the best result in 83% yield (Table 1,
entry 26). When 1 atm H2 was used, instead of NaBH4 and argon
atmosphere, both lower yield and conversion were observed
(Table 1, entry 27). For details of studies on the reaction
temperature, reaction time and others, please see Supporting
Information.
Recently, our group reported a palladium-catalyzed formal
cross-coupling of phenols with amine to form amine derivatives
via a hydrogen-borrowing strategy.[17] Inspired by this strategy, we
contemplated the possibility of directly cleaving the most
challenging C(Ar)–O bond of diphenyl ethers to generate the
nitrogen-containing products, via the phenol intermediate
generated in situ (Scheme 1b). Herein we report, for the first time,
a palladium-catalyzed direct conversion of biaryl ethers into
amine derivatives via dual C(Ar)–O bond cleavages. The amine
derivatives are important building blocks for pharmaceuticals, fine
chemicals, and electronic materials.[18]
Diphenyl ether was used as a model compound for the 4-O-5
linkage of lignin for our investigation. The diphenyl ether was
reacted with pyrrolidine with Pd/C (20 mol%) as catalyst in toluene
at 160°C under argon atmosphere for 24h using sodium formate
as hydride source. Fortunately, the desired nitrogen-containing
compound, 1-cyclohexyl-1H-pyrrole was detected by 1H NMR in
18% yield with 26% conversion (Table 1, entry 1). Encouraged by
this result, other palladium catalysts were
N
N
+
additive, T
solvent, time
N
H
+
+
1a
2a
3a
4a
5
3ab/% 4ab/% 5c/%
Entry
Catalyst
Additive
Solvent
Conv./%
1
2
3
4
5
6
7
8
9
10
Pd/C
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
o-xylene
m-xylene
26
13
12
35
22
5
18
6
-
-
-
-
-
-
-
-
-
-
Pd(PPh3)2Cl2
Pd(OAc)2
n.p.
n.p.
22
n.p.
n.p.
5
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
AlCl3
n.p.
n.p.
n.p.
n.p.
30
n.p.
n.p.
n.p.
n.p.
22
CF3CO2H
DBU
14
8
Cs2CO3
60
71
48
20
11
12
13
14
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
p-xylene
1,4-dioxane
H2O
62
11
20
85
20
n.p.
19
n.p.
-
-
-
-
trace n.p.
H2O (5 uL)
H2O (10 uL)
H2O (15 uL)
H2O (10 uL)
H2O (10 uL)
m-xylene
47
52
42
39
57
26
25
18
23
25
15
16
17d
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
m-xylene
m-xylene
m-xylene
m-xylene
81
65
88
90
-
-
-
-
With the optimized reaction conditions in hand, the substrate
scope was explored with 3.5 equiv of pyrrolidine at 160 under
argon (with 1 mL air and 10 μL water) using 30 mol% of
Pd(OH)2/C as the catalyst and 1.5 equiv of sodium borohydride
as the hydride source in m-xylene (1 mL) for 24 h. As shown in
Table 2, symmetrical diaryl ether reacted with pyrrolidine in good
to excellent conversions and moderate to excellent yields (Table
2, entries 1-8). Various diaryl ethers bearing electron-donating
and electron-withdrawing groups at different positions were all
effective for the transformation. It is noteworthy that with strong
electron-donating group—methoxyl group substituted at different
positions (ortho-, meta- or para-) of diphenyl ether, the same
major product 1-cyclohexylpyrrole 3a was obtained with
demethoxylation at the same time, and the minor product 1-
phenylpyrrolidine 4a was also obtained with demethoxylation
(Table 2, entries 4-6). The corresponding products were obtained
in good total yield without ester-amide exchange when the
18e
19f
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
H2O (10 uL)
H2O (10 uL)
H2O (10 uL)
m-xylene
m-xylene
m-xylene
82
93
92
36
66
62
20
18
17
-
-
-
20e,g
21e,h
22e,g,i
23e,g,j
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
H2O (10 uL)
H2O (10 uL)
H2O (10 uL)
m-xylene
m-xylene
m-xylene
65
99
99
99
22
70
71
77
13
22
24
15
-
-
24e,g,k
-
25e,g,j,l
26e,g,j,m
27e,g,j,n
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
H2O (10 uL)
H2O (10 uL)
H2O (10 uL)
m-xylene
m-xylene
m-xylene
82
>99 83 (79) 13 (11) 83
93 68 10 78
1a
2a
(0.5 mmol), catalyst (20 mol%), HCO2Na (1
a. General conditions:
(0.2 mmol),
equiv), additive (0.5 equiv) and solvent (1 mL) at 160C for 24 h under argon
atmosphere. b. Yields were determined by 1H NMR with nitromethane as internal
standard; isolated yields in brackets. c. The yields of benzene and cyclohexane were
determined by GC-MS. d. Pyrrolidine (0.3 mmol). e. Pyrrolidine (0.7 mmol). f.
Pyrrolidine (0.9 mmol). g. Air (1 mL) was added. h. Air (2 mL) was added. i.
Pd(OH)2/C (10 mol%). j. Pd(OH)2/C (30 mol%). k. Pd(OH)2/C (40 mol%). l. NaBH4
was used instead of sodium formate. m. NaBH4 (1.5 equiv). n. 1 atm H2 was used
instead of argon atmosphere, in absence of sodium formate.
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10.1002/anie.201712211
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COMMUNICATION
3.5 equiv pyrrolidine
30 mol% Pd(OH)2/C
substrate contained an ester group (Table 2, entry 7). When
fluorine-containing diphenyl ether was used, defluorination
products were obtained with excellent conversion and high total
yield (Table 2, entry 8). For all substrates, the corresponding
arenes were also obtained with good to high yields (Table 2,
entries 1-8).
O
N
N
3.0 equiv NaBH4, m-xylene
1 mL air, 10L H2O, 160C, 24h
conversion > 99%
O
3a
4a
17%
153%
total yield: 170%
6
Equation 1. Cross-Coupling of Oligomeric Phenylene Oxide with Pyrrolidine
1
3
4
5
Entry
Substrate
Conversion
Products
O
>99%
>99%
1
2
N
N
major
O
1a
3a
3b
4a
4b
5a 83%c
79%
11%
N
>99%
Me
1
N
Me
O
Me
Me
Me
N
Me
N
1i
3b
4b
5a 74%c
62%
12%
Me
Me
Me
Me
d
cis/transb=1:2.4
Me
1b
57%
35%
5b
5b
87%
cis/transb=1:1.9
Me
major
O
Me
Me
O
>99%
2
3
N
N
3
>99%
N
N
1j
3c
4c
56%
15%
5a 72%d
d
1c
3c
4c
cis/transb=2.2:1
53%
40%
85%
cis/transb=1.8:1
only
O
O
4
5
6
68%
75%
70%
N
N
>99%
>99%
N
N
OMe
5c 64%e
OMe
MeO
MeO
OMe
OMe
1d
3a
4a
4a
44%
13%
e
5e
5e
15%
16%
1K
3a 80%
4a 13%
only
O
O
N
N
N
4
N
Me
Me
50%
N
14%
5c 68%e
OMe
1e
3a
Me
f
1l
3b 72%
4b 16%
OMe
OMe
cis/transb=1:2.9
O
N
only
O
5c 62%e
1f
3a 40%
4a 9%
N
N
>99%
5
Ph
g
OMe
O
Ph
O
1m
3a
4a
12%
79%
5f
11%
N
86%
N
MeO
7
8
MeO
MeO
a. Reaction conditions: diaryl ether (0.2 mmol), pyrrolidine (0.7 mmol), Pd(OH)2/C (30 mol%),
O
and NaBH4 (0.3 mmol) in m-xylene (1 mL). All reactions were carried out at 160C in a sealed
tube under argon with air (1 mL) and water (10 L)) for 24 h; yields of isolated products were
given; conversions were determined by 1H NMR with nitromethane as internal standard.
Cis/trans (isomer) ratio was determined by crude 1H NMR. c. In addition, 10% of 1-cyclohexyl-
1H-pyrrole and 9% of toluene were also obtained. d. In addition, 14% of 1-cyclohexyl-1H-
pyrrole and 10% of toluene were also obtained. e. Isolated yield, in addition, 77% of 1,2,3,4-
tetrahydronaphthalene was obtained. f. Isolated yield, in addition, 75% of 1,2,3,4-
tetrahydronaphthalene was obtained. g. Isolated yield, in addition, 85% of cyclohexylbenzene
was obtained.
O
MeO
O
O
f
4d
3d
25%
54%
1g
5d
30%
cis/transb=1:1.4
b
.
O
N
N
>99%
F
F
c
5a
79%
1h
3a
4a
15%
70%
a Reaction conditions: diaryl ether (0.2 mmol), pyrrolidine (0.7 mmol), Pd(OH)2/C (30 mol%), and NaBH4
(0.3 mmol) in m-xylene (1 mL). All reactions were carried out at 160C in a sealed tube under argon
(with air (1 mL) and water (10 L)) for 24 h; yields of isolated products were given; conversions were
determined by 1H NMR with nitromethane as internal standard.
Cis/trans (isomer) ratio was
b
determined by crude 1H NMR. c. Yields of benzene and cyclohexane were determined by GC-MS;
a
small peak of cyclohexane overlapped within the big peak of benzene. d.Yield was determined by GC-
MS; no methylcyclohexane was detected. e. Yield was determined by GC-MS; no cyclohexylmethyl
ether was detected. f. Isolated yield. In addition, 52% of methyl cyclohexanecarboxylate was obtained.
To further exploit the potentials of this method, different amines
were examined to cross-couple with diphenyl ether. Different
diaryl ethers were successfully sliced and cross-coupled with
pyrrolidine to give higher value-added nitrogen-containing
chemicals—pyrrolidines and pyrroles (Table 4). The optimized
conditions were obtained by elevating the reaction temperature to
150 , with 3.5 equiv of amines under argon using 30 mol% of
Pd(OH)2/C as the catalyst and 1.25 equiv of sodium borohydride
as the hydride source in toluene (0.5 mL) (with 10 μL water) for
24 h (Please see the details in SI). As shown in Table 4, diphenyl
ether reacted with different amines in high to excellent conversion,
to generate the corresponding anilines and cyclohexyl amines19
in high to excellent total yields. Piperidine reacted very well with
diphenyl ether, generating phenyl piperidine 7b and cyclohexyl
piperidine 8b in high conversion and excellent total yield (Table 4,
entry 1). Piperidine bearing methyl groups at different positions
(2-, 3- or 4-) were all effective for the transformation (Table 4,
entries 2-4). Excellent conversion and high yield were also
obtained with linear primary amine 2f (Table 4, entry 5).
Non-symmetrical diaryl ethers were then used to investigate the
regioselectivity of the reactions (Table 3). We found that nitrogen-
containing products were obtained with high total yields (71-74%),
excellent conversions (>99%) and highly regioselective cleavage
of C(Ar)–O bond with only a small difference in substitution of
phenyl ring (Table 3, entries 1-2). Similar excellent total yields (88-
93%), excellent conversions (>99%) and regioselective cleavage
of C(Ar)–O bond were observed for compound 1k, 1j and 1m as
starting materials (Table 3, entries 3-5).
To further investigate the scope of this catalytic system,
oligomeric phenylene oxide 6 containing four C(Ar)-O bonds was
tested under the standard reaction conditions with increasing
sodium borohydride to 3.0 equiv; 1-cyclohexyl-1H-pyrrole 3a and
1-phenylpyrrolidine 4a were obtained in high total yields (170%)
and excellent conversion (>99%) (Eq. 1).
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10.1002/anie.201712211
Angewandte Chemie International Edition
COMMUNICATION
Cyclopentylamine 2g also reacted smoothly with diphenyl ether to
afford the corresponding products in high yield (Table 4, entry 6).
Likewise, aryl amines also reacted very well with diphenyl ether
efficiently (Table 4, entries 7-8). Despite bearing two methyl
groups at 2,6-positions, the sterically hindered 2,4,6-
trimethylaniline reacted smoothly (Table 4, entry 8).
further investigate the potential pathway of C(Ar)-O cleavage,
cyclohexenyl phenyl ether (12), which was proposed as a partial
hydrogenation intermediate in the literatures[8g-h,20], was explored
under the standard reaction conditions (Scheme 2a). The direct
C=C bond hydrogenation products cyclohexanyl phenyl ether (11)
(65%) and dicyclohexanyl ether 13 (16%) were obtained as major
products with only a small amount of the cross-coupling product
3a (10%). These results suggest that the C(Ar)–O bond was
cleaved via the Pd(OH)2/C catalyzed hydrogenolysis of diphenyl
ether to form phenol and benzene instead of hydrolysis of
compound 12 under our standard conditions. The phenol can be
reduced to form to cyclohexanone.[21] The reaction of phenol (9)
and cyclohexanone (10) proceeded well under the standard
conditions (Scheme 2b and 2c) to give N-cyclohexylpyrrole (3a)
and N-phenylpyrrolidine (4a) in high total yields (99% and 97%,
respectively), suggesting their being the possible intermediates in
the conversion of diphenyl ether. N-Cyclohexylpyrrolidine 14 was
also explored under standard reaction conditions; oxidative
aromatization products 3a and 4a were also obtained with high
total yields (Scheme 2d). The cross-coupling of diphenyl ether
with pyrrolidine was then investigated in different reaction times
under the standard conditions (Figure 2b). The nitrogen-
Table 4. Direct Formal Cross-Coupling of Diphenyl Ether with Aminesa
O
H
N
N
2
R2
R2
1
7
8
5
Entry
Amines
Conversion
Products
1
>99%
N
N
HN
b
5a
5a
7b
7c
8b
8c
85%
28%
56%
2b
2c
2
HN
>99%
N
N
b
32%
53%
84%
containing
products
(N-cyclohexylpyrrolidine
and
N-
N
N
HN
HN
3
4
>99%
>99%
cyclohexylpyrrole) and hydrocarbon products (benzene and
cyclohexane) were formed in ca. 1:1 ratio. The results indicated
b
2d
2e
7d
7e
8d
8e
5a
5a
33%
54%
87%
86%
standard
condition
O
O
O
N
N
N
(a)
(b)
+
+
+
N
H
b
30%
60%
12
2a
11
13
16%
65%
N
3a 10%
H
N
H
N
H2N
7
5
6
7
>99%
>99%
>99%
7
standard
condition
7
OH
O
+
+
+
+
+
N
N
H
b
b
b
2f
7f
8f
5a
5a
5a
65%
23%
84%
82%
9
2a
3a 85%
4a 14%
H
N
H
N
H2N
standard
condition
N
N
N
H
(c)
(d)
10
2a
3a
3a
4a
7%
90%
2g
2h
7g
7h
8g
74%
2%
standard
condition
H
N
H
N
N
N
N
H2N
14
4a
10%
84%
8h
68%
22%
83%
Scheme 2. Control Experiments
H
N
H
N
H2N
8
>89%
b
2i
5a
7i
8i
26%
78%
50%
a Reaction conditions: diaryl ether (0.2 mmol), amines (0.7 mmol), Pd(OH)2/C (30
mol%), and NaBH4 (0.25 mmol) in toluene (0.5 mL). All reactions were carried out at
150C in a sealed tube under argon with water (10 L)) for 24 h; yields of isolated
products were given; conversions were determined by 1H NMR with nitromethane as
internal standard. b. Yields of benzene and cyclohexane were determined by GC-MS;
a little peak of cyclohexane overlapped with the big peak of benzene.
To explore the reaction mechanism, diphenyl ether was
examined without amine under the standard reaction conditions
(Figure 2a). Phenol (9), cyclohexanone (10), benzene (5) and a
trace amount of cyclohexane were detected by GC-MS. The total
yields of phenol (9) and cyclohexanone (10) were almost the
same as the total yields of benzene (5) and cyclohexane. To
Figure 2. Product Distributions vs Time for the Reaction of Diphenyl Ether
without Amine (a) and with Amine (b) under the Standard Reaction Conditions
that one Ar-O bond was reductively cleaved to form benzene and
cyclohexane and the remaining fragment predominantly became
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10.1002/anie.201712211
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phenol and cyclohexanone. This rationale is also in agreement
with the results in Figure 2a. Then the phenol and cyclohexanone
were transformed into the nitrogen-containing products (N-
cyclohexylpyrrolidine and N-cyclohexylpyrrole).
General procedure for the coupling of phenol with pyrrolidine:
In a 20 mL oven-dried vial was charged with a magnetic stir-bar,
Pd(OH)2/C( 42 mg, 30 mol% based on Pd contents) and NaBH4
(12 mg, 0.3 mmol). The tube was then evacuated and backfilled
with argon. The evacuation/backfill sequence was repeated two
additional times. M-xylene (1 mL), diphenyl ether (0.2 mmol) and
pyrrolidine (0.7 mmol) were added by syringe, followed by the
addition of H2O (10 uL) and air (1 mL) by syringe. The tube was
placed in a preheated oil bath at 160ºC and the mixture was
stirred under an argon atmosphere for 24 h. The reaction mixture
was cooled to room temperature and filtered through a pad of
silica gel. The filtrate was concentrated and the resulting residue
was purified by preparative thin layer chromatography to give N-
cyclohexylpyrrole and phenylpyrrolidine.
Based on these experimental results, a tentative mechanism for
this cross-coupling reaction is proposed in Figure 3: firstly, sodium
borohydride reacts with the Pd(OH)2/C catalyst to form the HPdIIH
species. Subsequently, hydrogenolysis of diphenyl ether
generates phenol A via C(Ar)–O bond cleavage, which is further
19]
reduced by HPdIIH species to form cyclohexanone B.[17a,
Intermediate B reacts with amine to form iminium intermediate C.
Intermediate C is reduced to form compound D (path a), and then
D is oxidized to generate intermediate E or H. The intermediate E,
upon loosing H+, tautomerizes to form enamine F. Finally,
enamine F is oxidatively aromatizes to form the product pyrrole G,
as well as regenerates HPdIIH species. Another intermediate H
undergoes oxidative aromatization to form product
I and
Acknowledgements
regenerates the HPdIIH species. It is also possible that
intermediate C can also undergo [1,3] hydride shift to generate
intermediate E (path b).[22] Furthermore, a small portion of
intermediate C can also tautomerize to form enamine H (path c).
We thank the Recruitment Program of Global Experts to C.-J.L.,
the Fundamental Research Funds for the Central Universities
(lzujbky-2016-53), Gansu Provincial Sci. & Tech. Department
(2016B01017) and Lanzhou University for support of our research.
We also thank the Canada Research Chair (Tier I) foundation, the
E.B. Eddy endowment fund, the CFI, NSERC, and FQRNT to C.-
J.L.
NaBH4, Pd(0)
O
N
R2
R1
HPd(II)
H
N
G
[O]
Keywords: Lignin • diaryl ethers • cross-coupling • amines • C-O
[O]
bond cleavage
I
OH
R1 R2
N
N
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Figure 3. Proposed Reaction Pathway for Cross-Coupling Diaryl Ethers with
Amines
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Entry for the Table of Contents (Please choose one layout)
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Huiying Zeng,* Dawei Cao, Zihang Qiu
and Chao-Jun Li*
Page No. – Page No.
Palladium-Catalyzed Formal Cross-
Coupling of Diaryl Ethers with
Amines: New Tactic to Slice 4-O-5
Linkage in Lignin Models
From waste to value: A potential strategy for converting renewable lignin biomass
to higher value-added nitrogen-containing chemicals is reported. The 4-O-5 linkage
model compounds of lignin was cross-coupled with amines via dual C(Ar)-O bond
cleavages to generate valuable nitrogen-containing derivatives.
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