Direct hydroxyethylation of amines by carbohydrates: Via ruthenium catalysis

Article abstract of DOI:10.1039/c9gc01195a

An efficient and halogen-free catalytic methodology for the synthesis of β-amino alcohols from aromatic amines and biomass-derived carbohydrates is demonstrated for the first time. The activation of C5/C6 sugars by a ruthenium catalyst selectively generates the C2 alkylating reagent glycolaldehyde. The transformation involves metal-catalyzed hydrogen borrowing for the reduction of the imine intermediate. A series of arylamines bearing various substituents were successfully transformed into the desired products in good to excellent yields.

Full text of DOI:10.1039/c9gc01195a

View Article Online
View Journal
Green
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: L. Jia, M. Makha,
C. Du, Z. Quan, X. Wang and Y. Li, Green Chem., 2019, DOI: 10.1039/C9GC01195A.
This is an Accepted Manuscript, which has been through the
Volume 18 Number
7 7 April 2016 Pages 1821–2242
Royal Society of Chemistry peer review process and has been
accepted for publication.
Green
Chemistry
Accepted Manuscripts are published online shortly after
Cutting-edge research for a greener sustainable future
www.rsc.org/greenchem
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1463-9262
CRITICAL REVIEW
G. Chatel et al.
Heterogeneous catalytic oxidation for lignin valorization into valuable
chemicals: what results? What limitations? What trends?
rsc.li/green-chem

Please do not adjust margins
Page 1 of 6
Green Chemistry
View Article Online
DOI: 10.1039/C9GC01195A
Journal Name
ARTICLE
Direct hydroxyethylation of amines by carbohydrates via
ruthenium catalysis
＊b
Le Jia,ab Mohamed Makha,b Chen-Xia Du,c Zheng-Jun Quan,a Xi-Cun Wang,＊a and Yuehui Li,
Received 00th January 20xx,
Accepted 00th January 20xx
An efficient and halogen-free catalytic methodology for the synthesis of β-amino alcohols from aromatic amines and
biomass-derived carbohydrates is demonstrated for the first time. The activation of C5/C6 sugars by ruthenium catalyst
selectively generates the C2 alkylating reagent glycolaldehyde. The transformation involves metal catalyzed hydrogen
borrowing for the reduction of imine intermediate. A series of arylamines bearing various substituents were successfully
transformed to the desired products in good to excellent yields.
DOI: 10.1039/x0xx00000x
www.rsc.org/
H
H3C
N
CH3
O
Introduction
H3C
H3C
O
P
OH
N
O
O
The utilization of biomass and renewable resources has
attracted significant amounts of interests owing to the
depletion of fossil fuels and environmental protection
concerns. In this regard, biomass-derived carbohydrates
such as glucose and xylose produced from chemical or
enzymatic hydrolysis of biomass (i.e. hemicellulose and
cellulose) are emerging as promising building blocks for
value-added chemicals.1 The development of cost
effective methods to access valuable chemicals from
carbohydrates is not only highly desirable but also
challenging. More recently, some promising advances
have been made in this area.2 Importantly, biomass-
derived sugars conversion into valuable nitrogenous
compounds represents a major advance in the sustainable
synthesis of biologically active amines.3-7 β-Amino
alcohols for instance are commonly encountered moieties
in many bioactive natural products and synthetic
O
O
N
NO2
anti-cancer active
Efonidipine
O
NH
N
S
O
O
R
R = CH3, OCH3, i-Pro, t-Bu
Thiazolidinedione derivatives
Figure 1 Examples of biologically active compounds featuring β-amino alcohol building
blocks.
peroxide and ethylene carbonate based epoxide (Scheme 1A).14
In the other hand, the process of sugar and sugar alcohol
hydrogenolysis has been explored as a potential means to make
various polyols; glycerol, ethylene glycol and propylene glycol
from renewable biomass resources.15 This usually requires
high temperature and high hydrogen pressure for C-C bonds
cleavage. Catalytic methods were devised for preparing β-
amino alcohols utilizing hydrogen borrowing (HB) strategy.
This approach overcomes alcohol’s low reactivity by involving
dehydrogenative generation of aldehyde intermediate. The
aldehyde and amine forms imine intermediate, which is
hydrogenated to β-amino alcohols (Scheme 1B).16 The
transformation of polyol/carbohydrates usually involves the
formation of aldehyde intermediates from C-C bond cleavage
via retro-aldol reaction.17 For example, hydrogenolysis of
biomass-derived sugars to ethylene glycol requires cleavage of
specific C-C and C-O bonds, and generally involves the
formation of glycoaldehyde intermediate.18 In addition, sugars
have been used as C1 source to generate acyl anion
intermediate as one-carbon nucleophile in Stetter reaction.19
Due to our continuous interest in catalytic dehydrogenations,20
pharmaceutical
intermediates.8-11
Representative
examples include reactive oxygen species (ROS)-
activated agent against acute myeloid leukemia (AML),
Efonidipine and Thiazolidinedione derivatives used in the
treatment of hypertension and diabetes (Figure 1).
Conventional methods of the synthesis of β-amino alcohols
use epoxides or haloalkanols that are toxic, carcinogenic
and/or flammable.12,13 Improved methods use radical initiator
a. College of Chemistry and Chemical Engineering, Northwest Normal University,
Lanzhou, Gansu 730070, P.R. China. E-mail: wangxicun@nwnu.edu.cn
b. State Key Laboratory for Oxo Synthesis and Selective Oxidation
Suzhou Research Institute of LICP, Center for Excellence in Molecular Synthesis,
Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of Sciences,
Lanzhou 730000, P.R. China. E-mail: yhli@licp.cas.cn
c. College of Chemistry and Molecular Engineering, Zhengzhou University,
Zhengzhou, 450001, P.R. China
d. † Footnotes relating to the title and/or authors should appear here.
e. Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 2 of 6
ARTICLE
Journal Name
Table 1 Optimization of the reaction conditionsa
Previous work
A)
:
View Article Online
DOI: 10.1039/C9GC01195A
Me
Hydroxyethylating
Sources
Catalyst
H
N
OH
R
O
N
R
Ligand, Acid
N
NH
Me
OH
HO
+
HO
R'
R'
1,4-dioxane, 16 h
OH
OH
150 o
C
R = Alkyl, Benzyl, Aryl
R' = Aryl, Alkyl, H
Hydroxyethylating
Sources
1a
O
2a D(+)-Xylose
3a
OH
X
R
Yieldb
3a (%)
X = Cl, Br
Entry
1
Catalyst
RuCl2(PPh3)3
Ru(acac)3
Ligand
Acid
O
H
O
CH3OH
+
Xantphos
Xantphos
Xantphos
Xantphos
-
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
CH3COOH
-
37
56
60
87
24
n.d.
16
23
29
n.d.
15
74
46
44
O
O
2
3
Ru3(CO)12
Known methods:
B)
4
Ru(cod)(2-methylallyl)2
Ru(cod)(2-methylallyl)2
-
R'
N
molecular catalyst
+
R
R
OH
R'NH2
- H2O
R'
R
5
- H2
6
Xantphos
DPPM
H2
R
O
NR'
7
Ru(cod)(2-methylallyl)2
Ru(cod)(2-methylallyl)2
Ru(cod)(2-methylallyl)2
Ru(cod)(2-methylallyl)2
Ru(cod)(2-methylallyl)2
Ru(cod)(2-methylallyl)2
Ru(cod)(2-methylallyl)2
Ru(cod)(2-methylallyl)2
8
DPPE
C) This work:
9
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
R'
H
N
Ru(cod)(2-methylallyl)2
Xantphos
10
11
12c
13d
14e
H3PO4
N
O
R'
OH
HO
HO
+
R
R
CH3COOH
(CH3)3CCOOH
CH3COOH
CH3COOH
CH3COOH
OH
OH
1
2a
D-(+)-Xylose
(or carbohydrates
derived biomass)
3
Scheme 1 A) Selected strategies for conventional syntheses of β-amino alcohols; B)
Hydrogen borrowing (HB) process methodology; C) Ruthenium-catalyzed direct
a Reaction conditions: 1a (0.5 mmol), 2a (1.5 mmol), catalyst (2 mol%), ligand (2 mol%),
1,4-dioxane (2 mL), at 150 oC under N2 atmosphere for 16 h. bYields were determined by
GC using n-docecane as an internal standard. c 1 mol% Ru(cod)(2-Methylallyl)2, 1 mol%
Xantphos. d Ethylene glycol (1.5 mmol) instead of 2a (1.5 mmol). e Glycerol (1.5 mmol)
instead of 2a (1.5 mmol). Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene;
hydroxyethylation
of
amines
with
carbohydrates.
we
examined
biomass-derived
sugars
for
the
Ru(cod)(2-methylallyl)2
=
Bis(2-methylallyl)(1,5-cyclooctadiene)ruthenium(II).
hydroxyethylation of amines using ruthenium catalysts based
on phosphine ligands. Herein, we report the first example of
ruthenium-catalyzed hydroxyethylation of aromatic amines
using carbohydrates for the preparation of β-amino alcohols
(Scheme 1C).
Xantphos generated the desired product 3a in 87% yield.
We then tested the effect of phosphine ligand using
Ru(cod)(2-methylallyl)2. When the reaction was
performed in the absence of Xantphos, the yield of 3a
declined to 24% (Table 1, entry 5). Substituting Xantphos
with other bi-dentate phosphine ligands (DPPM or DPPE)
showed no improvement on the catalytic activity (Table1,
entries 7-8). We further investigated the reaction in the
absence of acetic acid and observed lowered yield of 29%,
too (Table1, entry 9). Hence, we investigated the effect of
inorganic acids on the reaction affording lower yields or
no reaction compared to acetic acid (Table1, entries 10-
11). The catalyst loading was also considered and found
product yield is slightly lowered by decreasing the amount
of catalyst (Table1, entry 12). Alternatively, we tested
other N-hydroxyethylating agents under similar reaction
conditions by substituting xylose with either ethylene
glycol or glycerin affording β-amino alcohols 3a in lower
yields, 46% and 44%, respectively.
Results and discussion
Initially, we started our investigation of Ru-catalyzed
hydroxyethylation using N-methylaniline (1a) as model
substrate with different carbohydrates to screen C5, C6
sugars and higher oligomeric carbohydrates. To our
delight, we found that most C5 and C6 sugars tested are
suitable N-hydroxyethylating reagents providing the
desired -amino alcohol product in 51% to 87% yields in
the presence of acid additives. Polysaccharides were less
effective for this transformation under similar reaction
conditions, understandably due to solubility constraints.
We then used xylose saccharide to further optimize the
reaction conditions. We examined several ruthenium
complexes and phosphine ligands using 1,4-dioxane as
solvent (Table 1). When the reaction was performed in the
presence of RuCl2(PPh3)3 (2.0 mol%), Xantphos (2.0
mol%) and acetic acid (30 mol%), product 3a was formed
in 37% yield (Table 1, entry 1). Other ruthenium
precursors, such as Ru(acac)3, Ru3(CO)12 and Ru(cod)(2-
methylallyl)2 were also screened and all showed
reasonable catalytic activity (56-87% yields; Table 1,
entries 2-4). Interestingly, Ru(cod)(2-methylallyl)2 with
Under the optimized reaction conditions, we explored
the substrate scope of various N-alkyl-anilines for this
ruthenium-catalyzed N-hydroxyethylation reaction (Table
2). In general, we observed that substrates bearing
electron-donating substituents on the phenyl ring proved
more reactive with yields ranging from 58%-75% (3b-d).
Fluoro-, chloro- and bromo-substituted aromatic amines
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 6
Green Chemistry
Please do not adjust margins
Journal Name
ARTICLE
Table 2 Scope of amine substratesa, b
motifs were well tolerated giving 3u-3x hydroxyethylated
products in 58% to 67% yields. Heterocyclic compounds,
benzomorpholine, benzothiazine and 5H-1-benzazepin-5-
one can also be successfully transformed to the desired
corresponding products 3y, 3aa and 3z in good to
moderate yields (63%, 55% and 56%, respectively). The
View Article Online
DOI: 10.1039/C9GC01195A
R'
N
H
Ru(cod)(2-Methylallyl)2 (2 mol%)
Xantphos (2 mol%)
N
O
R'
HO
OH
+
R
HO
R
CH3COOH (30 mol%)
1,4-dioxane, 150 C, 16 h
OH
OH
1
2a
3
D-(+)-Xylose
Me
N
Me
Me
Me Me
N
Me
Cl
N
N
OH
OH
OH
OH
OH
OH
dehydrogenative
diethanolamine with this catalytic system generates N-
substituted 2-morpholinone 3ae from 2-
lactonization
of
N-substituted
Me
3a:
3b:
3d: 58%
78%
75%
3c:
3g:
71%
Me
N
Me
N
Me
Me
N
N
OH
OH
OH
(phenylamino)ethanol 3ad. Interestingly, N-substituted 2-
morpholinone can also be obtained with D-(+)-xylose
from aniline derivatives 3ab or 3ac in good yields under
the optimized reaction conditions.
Cl
F
Br
c
3h:
57%
3e:
3i:
3f:
75%
69%
52%
Me
N
Me
N
Me
N
Me
N
OH
OH
OH
O
HOOC
F3C
To further demonstrate the generality of this strategy
with carbohydrates as hydroxyethylating reagent, we
studied a set of commercially available natural saccharides
(Table 3). The examined C6-sugars (2b-e) were effective
giving -amino alcohols product 3a in 51-84% yields.
Testing several C5-sugars and sugar alcohols (2f, 2g-h)
also showed good reactivity giving -amino alcohol
product 3a in excellent yields (64-87%). C5-sugar, D-(+)-
xylose (2a) gave near complete conversion with N-
methylaniline substrate. The reaction was efficient and
produced 3a with high purity after a simple workup.
Remarkably, both disaccharides (2i, 2j) and
polysaccharide cellulose (2k) could be used equally as
hydroxyethylating reagent, albeit with diminished yields
(8-18%). This is due to slow hydrolysis and further studies
needed to develop more practical protocols especially for
cellulose and other polysaccharides.
3k:
53%
O
O
3l:
43%
67%
3j:
58%
74%
nBu
Me
N
Et
iPr
N
N
N
OH
OH
OH
OH
OH
NC
3p:
67%
3m:
0 %
3o:
3n:
65%
Bn
N
Cy
N
OH
C12H25
N
N
OH
OH
e
d
3q:
3t:
42%
61%
58%
3r:
56%
3s:
70%
O
Me
OH
N
N
N
N
N
OH
OH
OH
OH
3x: 66%
3u:
3v:
65%
3w:
3y: 63%
67%
O
H
N
O
S
N
O
3ab
O
H
N
N
N
OH
COOH
OH
optimized
conditions
O
OH
3z:
56%
3aa:
55%
3ac
3ae:
51-64%
H
N
Interestingly, pre-treatment of α-cellulose (particle
size of ca. 25 m) with inorganic acids H2SO4/H3PO4 at
ambient temperature and further hydrolysis with water
3ad
a Reaction conditions: 1 (0.5 mmol), 2a D-(+)-xylose (1.5 mmol), Ru(cod)(2-methylallyl)2
(2 mol%), Xantphos (2 mol%), CH3COOH (0.15 mmol), 1,4-dioxane (2 mL), at 150 oC in the
b
c
d
e
nitrogen atmosphere for 16 h;
isolated yields. 170 oC.
48 h.
180 oC.
Table 3 Examples of carbohydrates screening a, b
Me
H
also underwent smooth reaction to furnish the
corresponding products in yields 52%-75% (3e-h).
However, aromatic amines bearing other electron-
withdrawing substituents such as trifluoromethyl and
acetyl groups afforded the corresponding products 3i and
3g in slightly lower yields (43-58%); while the presence
of carboxylic acid and ester substituents afforded product
3k and 3l in 53% and 67%, respectively. In addition,
aniline substrates bearing various alkyl groups (Et, iPr,
nBu, C12H25, Cy and benzyl) at the amine were smoothly
transformed to the corresponding hydroxyethylated
products in moderate to good yields (3n-3s; 56-74%). N-
Substituted anilines with bulkier groups required
prolonged reaction times (48 h) or elevated temperatures
to achieve moderate yields (3r and 3t; 56% and 42%). N-
Benzyl substitution provided the benzyl product 3s in 70%
isolated yield. Notably, 3s is a key building block for the
synthesis of the calcium channel blocker Efonidipine
which is conventionally prepared using excess amounts of
2-chloroethanol.10 Moreover, transformation of aromatic
amino compounds with pento- and benzo-fused cyclic
Ru(cod)(2-Methylallyl)2 (2 mol%)
Xantphos (2 mol%)
N
N
OH
Me
+
Carbohydrates
CH3COOH (30 mol%)
1,4-dioxane, 150 oC, 16 h
1a
2
3a
C6 sugars:
D-(+)-Glucose
D-(-)-Fructose
HO
D-(+)-Mannose
OH
D-(+)-Galactose
OH
O
OH
HO
O
OH
HO
O
O
HO
HO
OH
OH
HO
HO
OH
HO
OH
OH
2c:
OH
: 54%
OH
OH
2e
: 51%
2b
2d
84%
: 70%
C5 sugars and sugar alcohols:
C4 sugar alcohols:
D-(+)-Xylose
HO
D-Ribose
O
Xylitol
OH
Erythritol
OH
O
HO
OH
HO
OH
OH
HO
OH
HO
OH
OH OH
OH OH
2g
OH
2a
2f
: 64%
: 87%
2h
: 66%
: 67%
Di-and polysaccharides:
D-(+)-Cellobiose
Cellulose
OH
Sucrose
OH
OH
OH
OH
O
CH2OH
O
O
O
O
HO
HO
O
HO
OH
O
HO
HO
O
OH
O
H
n
HO
OH
HO
HO
OH
OH
OH
OH
O
OH
OH
2i
: 8%
2j
: 18%
2k
: trace
a Reaction conditions: 1a (0.5 mmol), 2 (1.5 mmol), Ru(cod)(2-methylallyl)2 (2 mol%),
Xantphos (2 mol%), CH3COOH (0.15 mmol), 1,4-dioxane (2 mL), N2 atmosphere. b Yields
were determined by GC using n-docecane as internal standard.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 4 of 6
ARTICLE
Journal Name
1
metal hydrides from in-situ H NMR expVeierwimAreticnletsOnlainse
DOI: 10.1039/C9GC01195A
described in Figure 2. Further evidence of the reaction
H
pathway through control experiments for this Ru-
catalyzed N-hydroxyethylation of N-methyl aniline with
D-(+)-xylose were obtained in support of the mechanism.
Components in the gas phase of the reaction mixture
were analyzed by Gas Chromatography. The results
showed that CO, CH4 and H2 were generated during the
reaction, presumably as decomposition products of the
cleaved formaldehyde in the presence of excess amounts
of sugar substrates (Figure 2b). In order to get further
insights into the mechanism of this ruthenium catalyzed
hydroxyethylation of arylamines, we conducted in-situ
NMR to detect hydride species generally involved the
hydrogen borrowing process. The phosphorus 31P NMR
showed the presence of two phosphorus environments for
the Ru-Xantphos complexes at 33.7 ppm and 35.2 ppm.
Moreover, in-situ 1H NMR showed a high field multiplet
chemical shift at around -15.6 ppm consistent with hydride
hydrogens and in line with ruthenium-Xantphos catalyst
dehydrogenative mode of action (Figure 2c).
after hydrolysis, neutralize
with 20 mol/L NaOH
solution, evaporate
and dry
powdered cellulose
H
the acidolytic liquid
of cellulose
solid mixture A
Me
Ru(cod)(2-Methylallyl)2 (4 mol%)
Xantphos (4 mol%)
N
N
Me
OH
+
CH3COOH (30 mol%)
1,4-dioxane (4 mL), 150 oC, 24 h
53%
isolated yield
0.5 mmol
3 g treated solid mixture A
is equivalent to 7 mmol cellulose
Scheme 2 Cellulose pre-treatment experiment.
followed by neutralization afforded a degradation mixture
A suitable for this reaction.21 Although the degradation of
cellulose in the pre-treatment gives a complex mixture of
oligosaccharides, the reaction performance was not
undermined and the desired product was obtained in an
appreciable yield (See Supporting information).
Specifically, N-methyl aniline reacted with solid mixture
A smoothly giving hydroxyethylated product in 53% yield
(Scheme 2).
Regarding the mechanism, it has been proposed that
polyols are dehydrogenated to the corresponding
carbonyl intermediates over metal catalysts, and their
subsequent C-C bond cleavage is likely via the retro-
aldol reaction.17 Based on the current understanding of
the mechanism, we further carried additional experiments
and we propose the reaction pathway according to the
conditions employed in this work (Scheme 3). Initially,
xylose is in equilibrium between its cyclic acetal and
acyclic aldehyde forms promoted under acidic
conditions. The initial step involves a C-C bond cleavage
through retro-aldol reaction to generate the aldehyde
intermediate. Upon condensation with the amine
substrate, the formed imine intermediate is hydrogenated
to β-amino alcohols in the presence of Ru-based catalyst.
W e a c h i e v e d e v i d e n c e o f t h e p r e s e n c e o f
Figure 2 GC analysis of gas samples (a) GC spectrum of reference gas sample, (b) GC
spectrum of gas sample taken from gas phase of the reaction and (c) 31P NMR of Ru-
Xantphos catalyst with D-(+)-xylose (inset 1H NMR of Ru-H species).
O
OH
OH
H
HO
HO
HO
HO
H
OH
2a D-(+)-Xylose
Control experiments with glycerol or with cyclic form
of glycoaldehyde afforded β-amino alcohols in good
moderate yield (Scheme 4). Under the optimized reaction
conditions, the desired N-hydroxyethylated product was
smoothly generated in moderate yield (43%). This is
further evidence of the involvement of glycoadehyde in
the reaction pathway. Moreover, we conducted
experiment with methyl group-containing L-fucopyranose
instead of D-(+)-xylose using the same reaction conditions.
We found that the reaction gave a mixture of products with
the majority include 2-(methyl(phenyl)amino)ethan-1-ol
obtained in 36% and 1-(methyl(phenylamino)propan-2-ol
in 12%. This result clearly shows the presence of retro-
aldol reaction preferring the C-C bond cleavage to
generate C2 intermediates and the potential of this
OH
O
Retro-aldol
OH
O
O
OH
+
OH
[Ru-H]
R2NH, -H2O
Retro-aldol
-HCHO
R
[Ru-H]
O
N
OH
R2NH, -H2O
R
OH
H2
CH3OH
O
H2
+
CH4
CO
H2O
H
H
[Ru]
+
H2
Scheme 3 Proposed reaction pathways
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 6
Green Chemistry
Please do not adjust margins
Journal Name
ARTICLE
methodology as a mean to generate a wide variety of vacuo and purified by column chromatography [petroleum
View Article Online
DOI: 10.1039/C9GC01195A
molecules by using different polyol substrates (Scheme 4). ether /ethyl acetate = 5:1] to give the corresponding β-
amino alcohols (2-(methyl(phenyl)amino)ethan-1-ol) in
good yields. All the prepared β-amino alcohols and related
Scheme 4 Control experimenta, b
Me
N
O
Me
N
characterisation data are available in the supporting
information. 2-(methyl(phenyl)amino)ethan-1-ol (3a):
Yield: 78% (59 mg), light yellow oil. 1H NMR (400 MHz,
CDCl3): δ (ppm) 7.24 (t, J = 7.2 Hz, 2H), 6.81-6.73 (m,
3H), 3.80 (t, J = 4.8 Hz, 2H), 3.46 (t, J = 4.8 Hz, 2H), 2.95
(s, 3H), 1.87 (br, 1H). 13C NMR (100 MHz, CDCl3): δ
(ppm) 150.1, 129.2 (2C), 117.2, 113.0 (2C), 60.0, 55.4,
38.7.
OH
OH
3a 36%
:
8%
H
H3C
HO
O
OH
OH
N
optimized
conditions
Me
Me
N
Me
N
+
OH
OH
12%
5%
L-fucopyranose
2a
1.5 mmol
0.5 mmol
Me
N
trace
Me
N
H
N
O
Me
optimized
conditions
OH
HO
OH
+
O
Conclusions
2a
0.5 mmol
Glycolaldehyde dimer
3a:
43%
0.75 mmol
In summary, this work describes the first protocol for
utilising mono- and oligosaccharides as alkylating
reagents of arylamines. In the presence of ruthenium
complexes based on Xantphos ligand under acidic
conditions, this methodology is chemo-selective and
general producing a wide variety of β-amino alcohols with
good yields. This process is also practical to access
important heterocyclic compounds and has the advantage
of minimizing chemical waste and reducing costs. These
findings extend the scope of the use of carbohydrates for
the synthesis of valuable amines from renewable
resources, as shown by the use of cellulose as source of
hydroxyethyl group. This approach opened up new line of
enquiries for other type of reactions of polyols we are
currently pursuing.
a Reaction conditions: Ru(cod)(2-Methylallyl)2 (2 mol%), Xantphos (2 mol%), CH3COOH
(0.15 mmol), 1,4-dioxane (2 mL), 150 oC, N2 atmosphere. b Yields were determined by 1H
NMR
using
dibromomethane
as
an
internal
standard.
Experimental
Reactions were carried out in moisture and oxygen
exclusion under nitrogen atmosphere and inert atmosphere
techniques in glovebox. All solvents were dried and
degassed before use by standard methods and stored under
nitrogen atmosphere. All reactions were monitored with
silica gel-coated plates (TLC). NMR spectra were
recorded on a Bruker 400 MHz spectrometer. The NMR
chemical shift values are referenced to CDCl3 (δ (1H),
7.26 ppm; δ (13C{1H}), 77.00 ppm). GC-MS data were
obtained from Shimadzu GCMS-QP2010 SE, GC data
were obtained from Shimadzu GC-2010 Plus. HRMS data
were obtained on an Agilent 6530 spectrometer at Suzhou
Research Institute of LICP.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
General procedure for synthesis of β-amino alcohols:
We are grateful for the financial supports from NSFC
(21633013, 21101109, 21602228).
The reaction of N-methylaniline and D-(+)-xylose as
representative example: Ru(cod)(2-methylallyl)2 (3.2 mg,
0.01 mmol), Xantphos (5.8 mg, 0.01 mmol) added to
anhydrous 1,4-dioxane (0.5 mL) in 15 mL pressure-
resistant tube containing magnetic stir bar. Then the
mixture was allowed to stir under nitrogen atmosphere in
the pressure-resistant tube at room temperature for 10
minutes. To the pressure-resistant tube containing pre-
prepared catalyst, representative aryl amine and
saccharide were added, N-methylaniline (53.6 mg, 0.5
mmol), D-(+)-xylose (225.0 mg, 1.5 mmol) with
CH3COOH (9.0 mg, 0.15 mmol) in anhydrous 1,4-dioxane
(1.5 mL). The reaction mixture is heated to 150 C and
allowed to stir under a nitrogen atmosphere in the closed
pressure-resistant tube for 16 h. After the reaction
finished, the reaction tube was cooled to room temperature
and the pressure was carefully released. The reactions
yield determined by GC using n-dodecane as internal
standard. The crude reaction mixture was concentrated in
Notes and references
1
(a) P. McKendry, Biores Technol., 2002, 83, 37-46; (b) P. L. Dhepe
and A. Fukuoka, ChemSusChem, 2008, 1, 969–975; (c) C. Luo, S.
Wang and H. Liu, Angew. Chem. Int. Ed., 2007, 46, 7636–7639; (d)
M. Schlaf, Dalton Trans., 2006, 4645–4653.
2
3
F. W. Lichtenthaler, Acc. Chem. Res., 2002, 35, 728-737.
L. Jia, C. M. Pedersen, Y. Qiao, T. Deng, P. Zuo, W. Ge, Z. Qin, X.
Hou and Y. Wang, Phys. Chem. Chem. Phys., 2015, 17, 23173-23182.
L. Jia, Z. Zhang, Y. Qiao, C. M. Pedersen, H. Ge, Z. Wei, T. Deng, J.
Ren, X. Liu, Y. Wang and X. Hou, Ind. Eng. Chem. Res., 2017, 56,
2925-2934.
4
5
F. M. Kerton, Y. Liu, K. W. Omari and K. Hawboldt, Green Chem.,
2013, 15, 860-871.
6
7
X. Chen, H. Yang and N. Yan, Chem. Eur. J., 2016, 22, 13402-13421.
M. Pelckmans, T. Renders, S. Van de Vyver and B. F. Sels, Green
Chem., 2017, 19, 5303-5331.
8
D. J. Ager, I. Prakash and D. R. Schaad, Chem. Rev., 1996, 96, 835-
876.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 6 of 6
ARTICLE
Journal Name
9
T. R. Bell-Horwath, A. K. Vadukoot, F. S. Thowfeik, G. Li, M
Wunderlich, J. C. Mulloy and E. J. Merino, Bioorg. Med. Chem. Lett.,
2013, 23, 2951-2954.
View Article Online
DOI: 10.1039/C9GC01195A
10 X. Hu, Q. Li, W. Li and Y. Yu, Chin. J. Pharmaceuticals, 2011, 42,
803-805.
11 H. J. Gim, B. Kang and R. Jeon, Arch Pharm Res., 2007, 30, 1055-
1061.
12 R. N. Salvatore, C. H. Yoon and K. W. Jung, Tetrahedron, 2001, 57,
7785-7781.
13 (a) X. Fu and S. Wu, Synth. Commun., 1997, 27, 1677-1683. (b) B. M.
Reddy, M. K. Patil, B. T. Reddy and S. Park, Cat. Commun., 2008, 9,
950-954. (c) C. Cojocariu and P. Rochon, Macromolecules, 2005, 38,
9526-9538; (d) W. Leng, Y Zhou, Q. Xu and J. Liu, Macromolecules,
2001, 34, 4774-4779.
14 (a) A. Shivarkar, S. Gupte and R. Chaudhari, Synlett, 2006, 9, 1374-
1378. (b) A. Clerici, A. Ghilardi, N. Pastori, C. Punta and O. Porta,
Org. Lett., 2008, 10, 5063-5066.
15 A. M. Ruppert, K. Weinberg, and R. Palkovits, Angew. Chem. Int. Ed.,
2012, 51, 2564-2601.
16 M. H. S. A. Hamid, P. A. Slatford and J. M. J. Williams, Adv. Synth.
Catal., 2007, 349, 1555-1575.
17 K. Y. Wang, M. C. Hawley and T. D. Furney, Ind. Eng. Chem. Res.,
1995, 34, 3766–3770.
18 (a) L. Zhao, J. H. Zhoub, Z. J. Sui, X. G. Zhou, Chem. Eng. Sci., 2010,
65, 30-35, (b) J. Sun and H. Liu, Green Chem., 2011, 13, 135-142.
19 J. Zhang, C. Xing, B. Tiwari and Y. Robin Chi, J. Am. Chem. Soc.,
2013, 135, 8113-8116.
20 (a) Z. Xin, J. Zhang, K. Sordakis, M. Beller, C.-X. Du, G. Laurenczy
and Y. Li, ChemSusChem, 2018, 11, 2077-2082. (b) X. Jiang, J. Zhang,
D. Zhao and Y. Li, Chem. Commun., 2019, 55, 2797-2800.
21 M. A. Harmer, A. Fan, A. Liauwa and R. K. Kumarc, Chem. Commun.,
2009, 6610-6612.
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins