Palladium-catalyzed synthesis of 4-cyclohexylmorpholines from reductive coupling of aryl ethers and lignin model compounds with morpholines

Article abstract of DOI:10.1039/d0gc03188g

This work describes the highly efficient Pd-catalyzed direct coupling of aryl ethers (including the typical lignin model compounds) and morpholines to produce 4-cyclohexylmorpholines, a useful class of fine chemicals. Without employing any acidic additives, various 4-cyclohexylmorpholines could be synthesized with good yields from a variety of aryl ethers using H2 as a hydrogen resource. A mechanism study revealed that the desired product was formed via the cleavage of the C(Ar)-O bonds to generate the corresponding cyclohexanones and subsequent reductive amination. This journal is

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DOI: 10.1039/D0GC03188G
COMMUNICATION
Palladium-Catalyzed Synthesis of 4-Cyclohexylmorpholines from
Reductive Coupling of Aryl Ethers and Lignin Model Compounds
with Morpholines
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
a
b
a*
a
a
a
a
Bingxiao Zheng, Jinliang Song, Haihong Wu, Shitao Han, Jianxin Zhai, Kaili Zhang, Wei Wu,
a
a
a,b*
Caiyun Xu, Mingyuan He, and Buxing Han
4-Cyclohexylmorpholines are an important class of N-
coupling of aryl ethers (including the typical lignin model containing compounds. As valuable fine chemicals, 4-
compounds) and morpholines to produce 4- cyclohexylmorpholines have been diversely employed as
cyclohexylmorpholines, a useful type of fine chemicals. Without emulsifier, corrosion inhibitor, and the catalyst for
employing any acidic additives, various of 4- polyurethane foam, etc. In general, 4-cyclohexylmorpholines
cyclohexylmorpholines with good yields could be synthesized can be synthesized through the reaction between diethylene
from a variety of aryl ethers using H as hydrogen resource. glycol and cyclohexylamine or the reductive amination of
Mechanism study revealed that the desired product was formed cyclohexanone and morpholine, etc.
This work described the highly efficient Pd-catalyzed direct
2
2
1-26
Considering that the
via the cleavage of the C(Ar)-O bonds to generate the cyclohexanone could be potentially generated from the
corresponding cyclohexanones and subsequent reductive selective hydrogenolytic cleavage of the aryl ethers, some of
amination.
which could be derived from lignin, it would be a sustainable
strategy for the synthesis of 4-cyclohexylmorpholines from aryl
Transformation of renewable lignocellulose has been ethers and morpholines by a successive process involving the
recognized as an alternative strategy to relieve the excessive cleavage of aryl ethers and the reductive amination.1
5-17
reliance on depleting fossil resources (e.g., petroleum, coal
and natural gas) for the production of chemicals and fuels. In cyclohexylamines could be synthesized from the coupling of
this context, lignin, one of the three main components of lignin-derived phenols with amines in the catalytic systems of
It has been reported that various aryl amines or
1
-3
2
7
lignocellulose, has gained significant research interest as a Pd/C-sodium formate-trifluoroacetic acid or Pd/C-sodium
4
-9
28,29
renewable aromatic carbon resource. Current researches formate.
However, the use of sodium formate usually
mainly focus on the synthesis of various oxygenates from resulted in the generation of some salt wastes. More
lignin.1
0-17
In contrast, the strategies for the production of importantly, it is highly different between the conversion of
valuable nitrogen-containing compounds from lignin are still phenol and transformation of lignin into small molecules.
very limited.1
8-20
To convert lignin into small molecules, Owing to the plenty of aryl C-O bonds in lignin, synthesis of
efficient cleavage of aromatic ether bonds (aryl C-O bonds) is substituted amines by the reductive coupling of aryl ethers
the key. However, lignin has very complex structure, resulting with amines would provide knowledge to study the catalytic
in difficult for efficient and selective conversion of lignin. systems for lignin conversion. In recent years, several catalytic
Alternatively, various aromatic ethers, including the motifs in systems have been developed for the synthesis of amines from
lignin, were employed to study the cleavage of aromatic ether aryl ethers (including the typical linkage in lignin).30,31 For
bonds, with the purpose of providing useful/potential methods example, various diaryl ethers, which was 4-O-5 linkage in
for lignin conversion.
lignin, could be directly converted into amine derivatives (e.g.,
aryl amines and cyclohexylamines) over Pd(OH) /C in the
Moreover, various cyclohexylamines
2
3
0
4
presence of NaBH .
could be prepared from aryl ethers in the catalytic system of
a. Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of Pd/C-Lewis acid using H
as the hydrogen resource. In this
31
2
Chemistry and Molecular Engineering, East China Normal University, Shanghai
catalytic system, the role of acidic additives was to activate the
C-O bond, which was helpful for its cleavage. These results
imply that the syntheses of 4-cyclohexylmorpholines from the
direct reaction of morpholines and aryl ethers are feasible.
2
00062, China. E-mail: hhwu@chem.ecnu.edu.cn; hanbx@iccas.ac.cn
b.
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Colloid
and Interface and Thermodynamics, CAS Research/Education Center for
Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of
Sciences, Beijing 100190, China.
Electronic Supplementary Information (ESI) available: [details of any However, these developed catalytic systems were hindered by
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
4
the use of salt-type reductants (e.g., NaBH ) accompanied by
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the generation of salt wastes30 or homogeneous acidic the hydrogenation of phenol under the employed reaction
View Article Online
3
1
DOI: 10.1039/D0GC03188G
conditions, which could be verified by several control experiments
additives that are difficult to be separated or recycled.
Therefore, it is highly desirable to develop simple and robust (Scheme S1). To our delight, the yield of 4-cyclohexylmorpholine
catalytic systems for the syntheses of 4-cyclohexylmorpholines could reach 99% with a complete conversion of benzyl phenyl ether
by direct conversion of aryl ethers, including the typical lignin over Pd/C (Table 1, entry 4). Additionally, although small amount of
model compounds.
benzyl phenyl ether was converted into toluene and phenol over
, no 4-cyclohexylmorpholine was generated
Inspired by the achievements on the synthesis of amines homogeneous Pd(acac)
2
from lignin derivatives, herein, we reported for the first time (Table 1, entry 5) because the generated phenol could not be
that 4-cyclohexylmorpholines could be efficiently synthesized transformed into cyclohexanone (the intermediate for the desired
via the direct reaction of morpholines with various aryl ethers, product) in this catalytic system. From the above discussion, we
including several lignin model compounds, e.g., benzyl phenyl could find that the intrinsic nature of the catalyst affected the
ether, phenethyl phenyl ether, and 2-phenoxyacetophenone, reactivity of the reaction, and Pd/C was the best choice among the
over Pd/C using molecular H
the absence of any acidic additives (Scheme 1). The fact that
using H at the feasible pressure (e.g., 1 MPa) to generate with Pd/C as the catalyst. First, it was found that the molar
2
of moderate pressure (1 MPa) in studied catalysts.
Various reaction parameters were subsequently optimized
2
more active H could promote the hydrogenolysis of the C-O ratio of morpholine and benzyl phenyl ether could affect the
bond, which could replace the role of homogeneous acidic product distribution (Fig. 1A). With a molar ratio of 1.5:1 or
additives, thereby having some obvious advantages from more, the products were 4-cyclohexylmorpholine and toluene.
green chemistry points of views. The new class of useful N- In contrast, phenol or methylcyclohexane would be detected
containing compounds (4-cyclohexylmorpholines) and more when the molar ratio was decreased to less than 1.5:1 (e.g.,
applicability of lignin model compounds further confirms the 1:1, 0.5:1), and the amount of phenol or methylcyclohexane
great potential of this catalytic system.
increased with the decrease of the molar ratio. These results
indicated that 1.5:1 was the optimal molar ratio of morpholine
and benzyl phenyl ether in our reaction system. Second, the
influence of Pd usage was investigated. There was no obvious
difference in the yield when the amount of Pd decreased from
6 to 3 mol% (Fig. 1B). However, the yield of the product
decreased with reducing the amount of the catalyst when the
Pd amount was less than 3 mol%, suggesting that the suitable
R3
R3
Pd/C, No additive
H2
n
+
HN
O
N
O
O
R2
R1
R1
R4
R4
Scheme 1. Synthesis of 4-cyclohexylmorpholines from the direct coupling of
lignin model compounds and morpholines.
2
Pd usage was 3 mol%. Third, too low H pressure was not
favorable to the reaction (Fig. 1C). For example, the yield of 4-
cyclohexylmorpholine was only 58.6% when the reaction was
conducted at 0.5 MPa. When the reaction was carried out at 1
MPa, the benzyl phenyl ether would be completely converted
with a high yield of 4-cyclohexylmorpholine (>99%). These
results were probably caused by the amount of active H
Table 1. Catalytic activity of various catalysts for the conversion of benzyl
phenyl ether with morpholine.a
OH
O
Pd/C
+
N
O
+
+
O
H2
N
H
1a
2a
3a
4a
5a
Yield (%)b
Conversion (%)b
Entry
Catalyst
3
a
4a
---
5a
formed on the Pd surface under different H
2
pressure.
1
2
3
4
5
---
---
---
---
---
---
---
Generally, higher H pressure was beneficial for the formation
2
Pt/C
Ru/C
Pd/C
---
18
of active H, which could improve the reactivity of the
hydrogenolysis of the C-O bond to form phenol and toluene.
Thus, 1 MPa was selected as the optimal pressure for
18.4
100
10.9
9.8
> 99
---
8.5
---
> 99
9.6
2
subsequent studies. Through a moderate H pressure (1 MPa),
Pd(acc)
2
9.8
the use of homogeneous acidic additives was avoided. Forth,
kinetic experiments indicated that the reaction could be
completed in 6 h (Fig. 1D). In the reaction process, the yields of
a
Reaction conditions: 1a, 1.0 mmol; 2a, 3.5 mmol; catalyst, 6 mol% metal
o
based on 1a; m-xylene, 3.5 mL; reaction temperature, 90 C; H
MPa; reaction time, 8 h. The conversion and yield were determined by GC
using dodecane as a standard.
2
pressure, 3
b
4
-cyclohexylmorpholine and toluene increased with the
prolonging reaction time, while the yield of phenol was sharply
increased first and then gradually decreased. Finally, it was
observed that the reaction temperature had significant impact
on the reactivity (Fig. 1E). When the reaction temperature
Initially, the conversion of benzyl phenyl ether (the typical α-O-
linkage in lignin) with morpholine to synthesize 4-
4
cyclohexylmorpholine was selected as a model reaction to evaluate
the catalytic activity of various catalysts (Table 1). No reaction
occurred in the absence of a catalyst (Table 1, entry 1). Pt/C was
inactive for the reaction (Table 1, entry 2) because it generally
showed lower activity on the hydrogenolytic cleavage of C-O ether
o
increased from 60 to 90 C, both the conversion and the yield
increased, while the yield of the desired 4-
cyclohexylmorpholine was constant when the reaction
o
o
temperature was higher than 90 C. Therefore, 90 C was the
optimal reaction temperature for our reaction system.
Additionally, the recyclability of the catalyst was studied under
both 99% yield and lower yield (about 40%) of the product.
1
6
bonds. Moreover, the yield of 4-cyclohexylmorpholine was very
low over Ru/C (Table 1, entry 3) because of the low activity of Ru/C
for both the cleavage of the ether bonds in benzyl phenyl ether and
2
| J. Name., 2012, 00, 1-3
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The results indicated that Pd/C could be reused at least three (about 86%) of the desired products (Table 2, entrViieews A6rticalenOdnl7in)e.
catalytic cycles with no obvious change in both substrate Second, the reactivity of various ethers wiDthOIm: 1o0.r1p0h3o9/liDn0eG(C20a3)18w8aGs
conversion and product (i.e., 4-cyclohexylmorpholine and investigated (Table 2, entries 8-19). When the substituents were on
toluene) yields with a reaction time of 6 h (Fig. 1F) or 1.6 h the benzyl group (Table 2, entries 9-14), there was no significant
(Fig. 1G), indicating that Pd/C was stable under the reaction difference in the yield of 4-cyclohexylmorpholine. High yields
conditions. As characterized by TEM (Fig. S1), the recovered (>93%) were achieved for all the substrates with substituents on the
o
Pd/C had the same morphology as the original Pd/C.
benzyl group when the reactions were conducted at 90 C with the
reaction time of 6 h. In contrast, when the substituents were on the
phenyl part (Table 2, entries 15-18), 4-cyclohexylmorpholines was
o
not generated at 90 C because the cleavage of the C-O bond to
form the corresponding phenols and subsequent hydrogenation of
these substituted phenols were both difficult at a low temperature
o
like 90 C. To obtain satisfactory yields (>85%) of the corresponding
o
4
-cyclohexylmorpholine, high reaction temperature (150 C) should
be employed for the substrates with substituents on the phenyl
part (Table 2, entries 15-18). Herein, it should be pointed out that it
was a mixture of cis/trans isomers for the products 3f, 3g-3j.
Furthermore, phenethyl phenyl ether and 2-phenoxyacetophenone
(Table 2, entries 19 and 20), the most abundant C-O linkage (β-O-4)
in lignin, could react with morpholine to generate 4-
cyclohexylmorpholine with a yield of 39% and 35%. These results
above indicated that the developed catalytic system was highly
applicable in the synthesis of 4-cyclohexylmorpholine through the
direct cleavage of the ether bonds.
Table 2. Pd-catalyzed reductive coupling of morpholines with various aryl
a
ethers.
O
R3
n2
Pd/C
H2
n2
n1
+
R3
N
O
+
+
O
R2
N
H
R1
R4
R2
R1
R4
R2
1a-1l
2a-2g
3a-3j
n2 = 0 or 1
n2 = 0 or 1
n1 = 1 or 2
Entry
1
Substrates
Products
Yields (%)b
> 99
O
H
N
N
O
2a
2b
3
a
H
O
N
N
2
3
> 99
> 99
O
3
b
H
N
O
N
O
2c
2d
2e
3
3
c
Fig. 1. Effect of various reaction parameters. (A) Morpholine amount, (B)
Catalyst amount, (C) H pressure, (D) Reaction time, (E) Effect of reaction
2
temperature, (F) Reusability of Pd/C (6 h) and (G) Reusability of Pd/C (1.6 h).
Other conditions were the same as entry 4 of Table 1.
H
O
N
4
5
N
> 99
> 99
O
d
H
N
O
N
O
3
e
O
H
N
Delighted by the excellent result in the reaction of benzyl
phenyl ether and morpholine, the scope of the substrates (both
morpholines and the ethers) was explored to show the applicability
of this strategy to synthesize 4-cyclohexylmorpholines (Table 2).
First, it was found that various morpholines with different
substituents could efficiently react with benzyl phenyl ether (1a) to
generate the corresponding 4-cyclohexylmorpholines (Table 2,
entries 1-7), and the position of the substituent would affect the
reactivity of the morpholines. The yields of the desired products
would be quantitative when the substituent was on the meta-
position of the amine group (Table 2, entries 2-5). In comparison,
when the substituent was on the ortho-position of the amine group,
the reactivity of the morpholines decreased, and the reaction
N
6c
7c
8
86.1
85.9
> 99
97.0
97.4
O
2f
3f
1
O
H
N
N
O
2g
3f
2
O
O
N
1
a
3a
3a
3a
3a
O
O
O
N
N
N
O
9
1
b
O
1
1
0
1
1
c
O
98.1
93.3
1
d
O
O
N
o
temperature would be increased to 120 C to achieve a good yield
12
3
a
1
e
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O
O
O
In addition, control experiment indicated that substituted
O
N
N
View Article Online
DOI: 10.1039/D0GC03188G
1
1
3
4
98.7
> 99
>99
F
1f
benzenes could not be hydrogenated under the standard conditions
3
3
a
a
o
(
90 C with morpholine, Scheme S2). Thus, the yields of the
O
substituted benzenes were quantitative in the reactions conducted
under standard conditions. However, very small part of the
substituted benzenes would be hydrogenated when more extreme
F3C
1g
N
5d
O
1
1
h
1
o
3
g
conditions (e.g., 120, 150, and 170 C) were involved (Table 3,
O
O
N
entries 5, 6 and 13-20). Thus, their yields were no longer
quantitative (Table S1).
6d
7d
O
>99
1
1
i
O
3h
3i
O
N
N
O
84.7
1
j
O
OH
3
mol% Pd/C;1 MPa H2
O
O
0 oC; 6 h
+
+
+
(a)
9
1
8d
O
96.5
6
3.6%
36.4%
77.9%
21.1%
1
k
3j
O
O
H
N
OH
O
N
N
3mol% Pd/C;1 MPa H2
9e
N
O
+
+
(b)
1
2
39.4
35.0
O
+
90 oC; 40 min
1
l
3
a
O
8
.7%
91.3%
> 99%
O
O
OH
H
0e
3
mol % Pd/C; 1 MPa H2
0 oC;6 h
1
m
3a
+
N
O
(c)
9
O
a
Reaction conditions: 1, 1.0 mmol; 2, 1.5 mmol; catalyst, 3 mol% metal based
on 1; m-xylene, 3.5 mL; reaction temperature, 90 C; H
reaction time, 6 h. The yield were determined by GC using dodecane as a
standard. Reaction temperature, 120 oC; reaction time,12 h. Catalyst, 6
mol% metal based on 1, reaction temperature,150 C; H
reaction time 12 h.
temperature, 170 C; H
> 99%
o
2
pressure, 1 MPa;
O
H
N
b
3mol % Pd/C; 1 MPa H2
+
+
N
O
(d)
(e)
c
d
90
oC;6 h
O
o
> 99%
2
pressure, 3 MPa;
Catalyst, 9 mol% metal based on 1, reaction
pressure, 3 MPa; reaction time, 24 h.
e
OH
H
N
o
3mol % Pd/C; 1 MPa H2
2
No Reaction
9
0 oC;6 h
O
To reveal the reaction mechanism, several control experiments
were conducted. First, benzyl phenyl ether could be transformed Scheme 2. Control experiments performed under specific conditions.
into cyclohexanone, cyclohexanol, toluene, and methylcyclohexane
over Pd/C (3 mol% Pd) under the above optimal reaction conditions
R3
O
o
H
N
2
(90 C, 6 h, and 1 MPa H ) in the absence of morpholine (Scheme
Pd/C
H2
N
n
+
2
a), indicating that the C-O in the benzyl phenyl ether could be
O
R2
R4
R3
R4
R1
O
R1
cleaved at the used conditions. Second, in the presence of
morpholine, the hydrogenation of toluene could not occur (Scheme
[
Pd]/[H]
n
[
Pd]/[H]
2
b) due to the negative effect of nitrogen-containing compounds.
R1
H
N
This result also provided the reason why there was no
hydrogenation of toluene observed in the process to produce 4-
cyclohexylmorpholine. Third, phenol and cyclohexanone could be
quantitatively converted to generate 4-cyclohexylmorpholine
R3
O
OH
O
R3
R4
[Pd]/[H]
O
R1
R1
N
R4
R1
Phenols
cyclohexanones
A
H2O
Scheme 3. Proposed reaction pathway for cross-coupling of ethers with
(Scheme 2c and Scheme 2d), while no product was detected when
morpholines.
using cyclohexanol (Scheme 2e). These results indicated that
cyclohexanone from the hydrogenation of phenol could be rapidly
consumed, and thus, no cyclohexanol was formed in the process
with morpholine.
Based on the above experimental results and some reported
knowledge, a possible reaction mechanism was proposed for the
formation of 4-cyclohexylmorpholines from the reaction of aryl
Conclusions
In conclusion, we have developed a direct route to synthesize
-cyclohexylmorpholines from morpholines and aryl ethers
over Pd/C with H as the hydrogen resource. Various aryl
4
2
ethers, including several lignin model compounds, e.g., benzyl
phenyl ether (α-O-4 linkage in lignin), phenethyl phenyl ether
and 2-phenoxyacetophenone (β-O-4 linkage in lignin), could be
efficiently and directly transformed into the corresponding 4-
cyclohexylmorpholines without using any acidic additives.
More importantly, it was found that ethers with substituents
on the benzyl group showed higher reactivity than those with
substituents on the phenyl part. We believe that this
methodology has great potential in the cleavage of C-O bond
in aryl ethers, and also shows a promising application to
upgrade renewable lignin derivatives into high-valuable
2
ethers and morpholines (Scheme 3). Initially, H was activated to
form active H on the surface of Pd particles. Then, hydrogenolytic
transformation of the aryl ethers to form phenols and substituted
benzene occurred because of the higher bonding energy of
2
3
32
aromatic C(sp )-O bond than the alkyl C(sp )-O bond. The
generated phenols would be hydrogenated to generate the
corresponding cyclohexanones, which could react with morpholines
to form the intermediate A. Finally, the desired 4-
cyclohexylmorpholines was formed by the hydrogenation of the
intermediate A.
4
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1
1
1
1
1
1
2
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nitrogen-containing chemicals. However, it should be pointed
out that there is significant difference between the used aryl
ethers and raw lignin, although they both contain aryl C-O
bonds. This strategy shows very low reactivity when using raw
lignin as the reactant, which probably caused by the complex
structure of raw lignin. Direct and efficient conversion of raw
lignin into N-containing compounds is a great challenge, and
more efforts still need to be paid on developing robust
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Supporting Information Summary
Detailed experimental section with materials, general
procedures for the coupling of morpholines with ethers, NMR
data and HR-MS data.
2
2
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2 D. Crozet, M. Urrutigoity and P. Kalck, ChemCatChem, 2011,
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