Cleavage∕cross-coupling strategy for converting β-O-4 linkage lignin model compounds into high valued benzyl amines via dual C–O bond cleavage

Article abstract of DOI:10.1016/j.cclet.2021.08.125

Lignin is the most recalcitrant of the three components of lignocellulosic biomass. The strength and stability of the linkages have long been a great challenge for the degradation and valorization of lignin biomass to obtain bio-fuels and commercial chemicals. Up to now, the selective cleavage of C–O linkages of lignin to afford chemicals contains only C, H and O atoms. Our group has developed a cleavage/cross-coupling strategy for converting 4-O-5 linkage lignin model compounds into high value-added compounds. Herein, we present a palladium-catalyzed cleavage/cross-coupling of the β-O-4 lignin model compounds with amines via dual C–O bond cleavage for the preparation of benzyl amine compounds and phenols.

Full text of DOI:10.1016/j.cclet.2021.08.125

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Cleavage/cross-coupling strategy for converting β-O-4 linkage lignin
model compounds into high valued benzyl amines via dual C–O bond
cleavage
Le Jia , Chao-Jun Li , Huiying Zeng
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DOI:
Reference:
S1001-8417(21)00707-5
https://doi.org/10.1016/j.cclet.2021.08.125
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30 August 2021
Please cite this article as: Le Jia , Chao-Jun Li , Huiying Zeng , Cleavage/cross-coupling strategy for
converting β-O-4 linkage lignin model compounds into high valued benzyl amines via dual C–O bond
cleavage, Chinese Chemical Letters (2021), doi: https://doi.org/10.1016/j.cclet.2021.08.125
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Communication
Cleavage/cross-coupling strategy for converting β-O-4 linkage lignin model
compounds into high valued benzyl amines via dual C–O bond cleavage
Le Jiaa, Chao-Jun Lib, Huiying Zenga, 
a The State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
b Department of Chemistry and FQRNT Centre for Green Chemistry and Catalysis, McGill University, Montreal, Quebec H3A 0B8, Canada
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Lignin is the most recalcitrant of the three components of lignocellulosic biomass. The strength and stability of
the linkages have long been a great challenge for the degradation and valorization of lignin biomass to obtain
bio-fuels and commercial chemicals. Up to now, the selective cleavage of C–O linkages of lignin to afford
chemicals contains only C, H, and O atoms. Our group has developed a cleavage/cross-coupling strategy for
converting 4-O-5 linkage lignin model compounds into high value-added compounds. Herein, we present a
palladium-catalyzed cleavage/cross-coupling of the β-O-4 lignin model compounds with amines via dual C–O
bond cleavage for the preparation of benzyl amine compounds and phenols.
Available online
Keywords:
β-O-4 Linkage
Lignin
C-O bond cleavage
Cross-coupling reaction
Palladium-catalyzed
Conversion of renewable biomass to chemicals and fuels is
becoming an ideal way to build a sustainable development due to
the gradual depletion of fossil resources and environmental
pollution concerns [1-5]. Lignocellulose (cellulose, hemicellulose
and lignin) is the most representative biomass resources [6].
Among them, due to the complexity of lignin structure, the
utilization of lignin is the most challenge [7,8]. Until now, lignin
has been discarded as a waste product of the pulp and paper
industry, and is generally burned to supply thermal energy. From
the perspective of sustainable development, lignin is a unique
candidate for the sustainable production of organic aromatic
molecules [9-11]. The development of effective methods to
access valuable chemicals from lignin is not only highly
desirable but also challenging. More recently, some impressive
achievements have been made. The selective cleavage of C–O or
C–C linkages to obtain oxygen-containing compounds (phenols
[12-14], ketone [15,16], acids [17,18] and aldehydes [19-21]) and
alkane (cycloalkanes [22,23], alkene [24] and other small
molecules compounds [25]) has been reported (Scheme 1a).
However, these transformations typically afford chemicals
containing only C, H, and O atoms. For converting lignin to high
value-added compounds, cross-coupling reaction of lignin and its
model compounds is highly desirable.
Nitrogen-containing compounds are important organic
building block for synthetic dyes, pharmaceuticals and
polyurethane precursors, which are usually generated from non-
renewable fossil resource [26-29]. For sustainable development
of resource and society, synthesis of nitrogen-containing
compounds from renewable biomass is highly desirable. Toward
to this aim, our group has developed a cleavage/cross-coupling
strategy for converting lignin 4-O-5 linkage model compounds to
high value-added nitrogen-containing compounds via dual C–O
bond cleavage (Scheme 1b) [30,31]. Due to the continuing
interest of our research group on the degradation and valorization
of renewable lignin and its model compounds [32-42], it is highly
desirable to use the cleavage/cross-coupling strategy to convert
other lignin linkage to high value-added compounds. Meanwhile,
considering that the β-O-4 structural motifs are the most
abundant in all the linkages of lignin [43,44], its efficient
cleavage is of great significance to the degradation of lignins.
Herein, we present a palladium-catalyzed direct cross-coupling of
the β-O-4 lignin model compounds with amines via dual C–O
bond cleavages for the preparation of benzyl amine compounds
and phenols (Scheme 1c). Very recently, Li and co-workers
reported similar method during the preparation of the current
report [45].
———
 Corresponding author.
E-mail address: zenghy@lzu.edu.cn

Scheme 1. Cleavage strategy vs. cleavage/cross-coupling strategy for valorization of lignin model compounds.
Initially, we started our investigation using β-O-4 model
compound 1a and 1-heptanamine 2a as model substrates to
optimize the reaction conditions. Several palladium catalysts
were examined using toluene as the solvent (Table 1, entries 1-3).
When the reaction was performed in the presence of Pd/C (10
mol%), HCO2Na (3 equiv.), cross-coupling product 3a and
phenol 4a were obtained in 67% and 93% yield, respectively
(entry 1). Other palladium catalysts, such as Pd(OH)2/C and
Pd/Al2O3 showed lower catalytic activity than Pd/C (entries 2 and
3). When the reaction was explored under air atmosphere, the
yield was slightly decreased (entry 4). As expected, the reaction
did not occur without the catalyst (entry 5). When the reaction
was performed in the absence of hydrogen donor, the yield of 4a
was reduced to 42%, with cross-coupling product 3a being only a
trace amount together with a large amount of unreduced imine
product (entry 6). A variety of hydrogen sources (HCO2H,
HCO2NH4, NaBH4, isopropanol and H2) were investigated,
giving lower yield than HCO2Na (entries 7-11). Adjusting the
amount of HCO2Na, we found that a lower yield was obtained
when it was reduced to 2 equiv. (entry 12). On the contrary, the
best yield (87% and 95%) was obtained when the amount of
HCO2Na was increased to 5 equiv. (entry14). Increasing the
amount of 2a to 2 equiv. gave the highest yields (entry 16).
Further increasing the amount of 2a led to a lower yield (entry
17). The yield of 3a and 4a did not increase when the
temperature was raised or lowered (entries 18-20). Adjusting the
loading of the catalyst led to lower yields (entry 21) (see
Supporting information for details).

b
Yields were determined by 1H NMR spectroscopy using
Table 1
Optimization of the reaction conditions.a
dibromomethane as an internal standard.
c 2a (0.375 mmol).
d 2a (0.5 mmol).
e 2a (0.75 mmol).
f
Pd/C (5 mol%).
Yield (%)b
T
(ºC)
Entry
Catalyst
[H] (equiv.)
With the optimized reaction conditions in hand, we explored
the substrate scope of various lignin β-O-4 model compounds
(Table 2). The simplest model compounds 2-phenoxy-1-
phenylethan-1-ol (1b) was successfully cleaved and cross-
coupled with 1-heptanamine to generate desired products 3a and 4b
in high yields (entry 1). A methoxy group substituted on different
position (ortho-, para- and meta-position) of the phenyl ring
(phenolic part) has no effect, obtaining the corresponding
products with good to high yields (entries 2-4). Methoxyl group
substituted on both aromatic rings or another aromatic ring (left
part) also successfully reacted to form desired products (entries
5-8). Aromatics (1i and 1j) with a weak electron-donating methyl
substituent were used in the reaction, generating target product in
moderate to high yield (entries 9-10). Model compounds with
hydroxymethyl substituent on β-position was the most similar to
lignin, which was also successfully cleaved by the ether bond to
form C-C bond cleavage products (entries 11-14, 3a and 3c) and
phenols (4a-b and 4d). The C-C bond cleavage may be the result
of a retro-aldol process when the benzyl alcohol part was
oxidized to the corresponding ketone by palladium catalyst.
3a
67
43
8
4a
93
61
23
82
1
2
3
4
Pd/C
Pd(OH)2/C
Pd/Al2O3
HCO2Na
HCO2Na
HCO2Na
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
160
130
110
150
Pd/C (in air) HCO2Na
39
5
6
7
8
/
HCO2Na
/
HCO2H
HCO2NH4
NaBH4
Isopropanol
H2 (1 atm)
HCO2Na (2.0)
HCO2Na (4.0)
HCO2Na (5.0)
HCO2Na (5.0)
HCO2Na (5.0)
HCO2Na (5.0)
HCO2Na (5.0)
HCO2Na (5.0)
HCO2Na (5.0)
HCO2Na (5.0)
n.d.
trace
trace
trace
trace
n.d.
trace
53
84
87
89
95
n.d.
42
91
67
56
60
66
93
>95
>95
>95
>95
60
92
76
80
83
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
9
10
11
12
13
14
15c
16d
17e
18d
19d
20d
21d, f
67
91
64
40
80
a
Reaction conditions: 1a (0.25 mmol), 2a (0.25 mmol), Pd/C (10
mol%, 10 wt%), HCO2Na (3.0 equiv.) in toluene (1.0 mL) was
heated under argon atmosphere for 12 h.

Table 2
Cleavage/cross-coupling of lignin β-O-4 model compounds with 1-heptanamine.a
Entry
1
1
Yield 3 (%)
Yield 4 (%)
1b
1a
3a, 80
3a, 90
4b, 84
4a, 91
2
3b
4
1c
3a, 55
3a, 73
4c, 53
4d, 57
1d
5
6
7
8
1e
1f
3b, 52
3c, 71
3c, 53
3b, 81
4b, 61
4b, 62
4d, 57
4a, 90
1g
1h
9
1i
3a, 52
3d, 51
3a, 56
4e, 76
4b, 58
4a, 79
10
11c
1j
1k
12b
13d
14d
1l
3a, 41
3a, 58
3c, 40
4b, 62%
4d, 82%
4a, 65
1m
1n
a Reaction conditions: 1a (0.25 mmol), 2a (0.5 mmol), Pd/C (10 mol%), HCO2Na (5.0 equiv.) in toluene (1.0 mL) were heated at 150 oC under
argon atmosphere for 12 h; isolated yields were given.
b HCO2Na (7.0 equiv.).
c HCO2Na (2.0 equiv.).
d HCO2Na (1.5 equiv.).

Table 3
Cleavage/cross-coupling of lignin β-O-4 model compound 1a with amines.a
Entry
1
Yield 3 (%)
Yield 4a/5 (%)
91
Entry
10
Yield 3 (%)
Yield 4a/5 (%)
82
3a, 89
3e, 75
3m, 70
3n, 67
92
72
2
11c
3f, 62
3g, 65
3h, 52
3i, 71
77
3o, 73
3p, 63
3q, n.d.
3r, n.d
84
3
12
13d
14b
70
88
4
93/51
82
88/58
85/69
5b
6
7
15b
16b
3j, 71
3k, 67
82
88
3s, 11
3t, 23
91/67
83/59
8
9
17b
3l, 70
81
3u, n.d.
31/19
18b,e
a Reaction conditions: 1a (0.25 mmol), 2a (0.5 mmol), Pd/C (10 mol%), HCO2Na (5.0 equiv.) in toluene (1.0 mL) were heated at 150 ºC under
argon atmosphere for 12 h; isolated yields were given.
b Yields were determined by 1H NMR spectroscopy using bibromomethane as an internal standard.
c HCO2Na (3.0 equiv.), 130 ºC.
d HCO2Na (3.0 equiv.)
e NH3·H2O (2.0 equiv.) was used instead of amine 2.
We also investigated the scope of various amines for this
cleavage/cross-coupling reaction (Table 3). First, the
transformation of lignin β-O-4 model compounds 1a with
different primary amines was tested, delightfully, obtaining good
to excellent yields for all these primary amines (Table 3, entries
1-10). It is interesting to note that the use of
cyclopropylmethylamine as substrate did not generate any three-
membered rings opening product under the palladium-catalyzed
reductive condition (entry 3). Trifluoromethyl group also
remained intact in the product without further reduction (entry 7).
In addition, secondary amines such as pyrrolidine, piperidine and
morpholine also successfully coupled to afford the corresponding
product (3n, 3o and 3p) with good to high yields (entries 11-13).
When bezylamine, acyclic secondary amines (such as
dipentylamine and dipropylamine) and anilines (such as aniline
and N-methylaniline) were successfully cleaved the C-O ether
bond, phenols 4a was obtained with high yields (83%-93%)
(entries 5 and 14-17). However, the corresponding cross-
coupling products amines were generated in lower yields (0-32%)
instead of acetophenone 5 with medium to good yields. Inorganic
nitrogen resource, ammonia, was used instead of organic amines,
generating C-O ether bond cleavage product acetophenone and
guaiacol in lower yields (entry 18).
tertiary alcohol 7 did not generate the desired product indicating
that the hydrogen of hydroxyl and benzyl position was very
important, which benefited the reaction via dehydrogenation to
give a ketone intermediate (Schemes 2a and b). When we used
the ketone 8, mimicking the possible intermediate under standard
conditions, the cross-coupling product and phenol were obtained
with excellent yields (Scheme 2c). This result demonstrated that
the ketone was the intermediate for this transformation. To
further investigate the cleavage of the ether bond via enol or
enamine, beta-dimethyl substituted compound 9 was used for this
transformation under standard conditions, cross-coupling product
10 (31% yield), C–O bond cleavage product 11 (15% yield) and
phenol 4a (41% yield) were obtained (Scheme 2d). This
information excluded C–O bond cleavage via enol or enamine
process. alpha D-isotope labeling compound 12 was then chosen
as substrate for investigating the whereabouts of D atom (Scheme
2e). The result showed that no D atom was incorporated into the
product. Based on our previous work [42], we propose that D
atom maybe exchange with solvent. Therefore, we used
deuterated toluene-d8 as a solvent. It was found that there was D
atom in the product, indicating that the deuterium atoms in
toluene participated in the reaction and transferred to the
amination product and guaiacol.
To investigate the reaction mechanism, a series of control
experiments were carried out. Methyl ether compounds 6 and

Scheme 2. Control experiments.
According to above the experimental results, a possible
mechanism for the cleavage/cross-coupling reaction of lignin
model compound with amine is proposed in Scheme 3. The
alcohol A was dehydrogenatively oxidized by palladium to
and phenols. This method provides a novel avenue in the
exploitation of novel sustainable feedstocks for chemical
production and represents a particularly difficult transformation.
Further efforts will be made to apply the present strategy to
obtain high-valued chemicals from natural lignins.
generate ketone intermediate
B and simultaneously form
palladium hydrogen species. The ketone B may condense with
amine to generate imine C. Next, palladium is inserted to the C-
O bonds of the ketone B or imine C via O-oriented or N-oriented
process to form intermediate D or E. Finally, the intermediate D
or E is reduced by a hydrogen source to obtain phenol H, and
ketone F or imine G, as well as regenerates palladium catalyst.
The ketone F is condensed with amine and reduced by palladium
hydrogen species to obtain the cross-coupling product J. The
imine G is also reduced to generate product J.
Acknowledgments
we thank the National Natural Science Foundation of China
(NSFC, No. 21971093), the International Joint Research Centre for
Green Catalysis and Synthesis (Nos. 2016B01017 and 18JR4RA003),
the 111 project and Post-doctoral Foundation Project of Shenzhen
Polytechnic (No. 6021330006K) for support of our research. We also
thank the Canada Research Chair (Tier I) foundation, the E.B. Eddy
Endowment Fund, the Canada Foundation for Innovation, The
Natural Sciences and Engineering Research Council (NSERC), and
Le Fonds Québécois de la Recherche sur la Nature et les
Technologies (FQRNT) to C.-J. Li.
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