Synthesis of N-aryl-d-glucosamines through copper-catalyzed C-N coupling

Article abstract of DOI:10.1016/j.tetlet.2012.10.069

A catalytic protocol was developed to synthesize N-aryl-d-glucosamines from the corresponding aryl halides. Cross-coupling of 1,3,4,6-tetra-O-benzyl- β-d-glucosamine with aryl iodides or bromides was catalyzed with copper. Subsequent deprotection of the benzyl group gave the arylation product N-aryl-d-glucosamines.

Full text of DOI:10.1016/j.tetlet.2012.10.069

Tetrahedron Letters 53 (2012) 7093–7096
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Tetrahedron Letters
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Synthesis of N-aryl-D-glucosamines through copper-catalyzed C–N coupling
Chuanzhou Tao a,c, , Feng Liu a,b, Weiwei Liu a,b, , Youmin Zhu a, Yafeng Li a, Xiaolang Liu a, Jing Zhao c,
⇑
⇑
⇑
a School of Chemical Engineering, Huaihai Institute of Technology, Lianyungang 222005, PR China
b School of Chemical Engineering, China University of Mining and Technology, XuZhou 221116, PR China
c State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A catalytic protocol was developed to synthesize N-aryl-
D
-glucosamines from the corresponding aryl
Received 15 July 2012
Revised 16 October 2012
Accepted 18 October 2012
Available online 24 October 2012
halides. Cross-coupling of 1,3,4,6-tetra-O-benzyl-b-
catalyzed with copper. Subsequent deprotection of the benzyl group gave the arylation product N-
aryl- -glucosamines.
D-glucosamine with aryl iodides or bromides was
D
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
N-Aryl-D-glucosamine
Copper
Catalysis
Cross-coupling
D
-Glucosamine, produced commercially by the hydrolysis of
OH
OH
OH
O
OH
O
O
crustacean exoskeletons, is one of the most abundant monosaccha-
O
O
HO
HO
HO
HO
HO
*
OH
*
* OH
*
OH
OH
HO
HO
HO
rides. D-Glucosamine and its N-substituted derivatives are found in
N
NH
NH
R
N3
numerous biologically active molecules1 such as cell surface N-
glycoproteins, proteoglycans, glycosylphosphatidylinositol (GPI)
anchors, glycosphingolipids, lipopolysaccharides, and chitin/chito-
san. Furthermore, these molecules have been used as ligands or
organocatalysts to introduce chirality in catalytic asymmetric reac-
n
p-MeO-C6H4
n=0-4
Scheme 1. Chemical modification of D-glucosamine.
tions.2 Chemical modifications of
D
-glucosamine at the N-position
mainly rely on acylation,3 Schiff-base formation4, azidation,5 and
alkylation6 (Scheme 1). However, N-arylation of
-glucosamine
has rarely been studied due to synthetic difficulty in the past. Only
in a few examples N-arylation of -glucosamine was accomplished
not obtain the N-arylation product 3a from D-glucosamine with
the reported ligands (Table 1, entries 1–3). We speculated that
the hydroxyl groups, especially the 1-hydroxyl, have influence on
the cross-coupling reaction. Then we turned to the protected
glucosamine. 1,3,4,6-Tetra-O-benzyl-b-
selected as a model substrate because the benzyl protecting group
is stable in the catalytic system and can be readily removed under
mild conditions (Scheme 2).12
The key step for the N-aryl-
Cu-catalyzed cross-coupling between 1,3,4,6-tetra-O-benzyl-b-
glucosamine (4) and aryl halides (2). Although a number of cata-
lytic systems9,10,13 have been shown to promote the Cu-catalyzed
arylation of amines, it remains unclear how the glycosyl and ben-
zyl groups would affect the efficiency. Thus we evaluate the ligands
in the cross-coupling of iodobenzene with 1,3,4,6-tetra-O-benzyl-
-glucosamine (Table 1).
As shown in Table 1, when 1,3,4,6-tetra-O-benzyl-b-
mine (4) was used as a surrogate for -glucosamine (1), the
D
D-
D
D
-glucosamine (4)11 was
by the SNAr reaction between D-glucosamine and aryl halides con-
taining a strong electron-withdrawing group.7
Recently we have been interested in the copper-catalyzed
arylation of nucleophiles.8 Herein we report the synthesis of N-
D-glucosamine (3) synthesis is the
aryl-
between aryl halides and
to develop more general and practical catalytic protocols for the
synthesis of
Initially,
as model substrates for the coupling reaction. Chemoselective cop-
per-catalyzed N- or O-arylation of amino alcohols has been
achieved with [O,O] ligands (Scheme 3).9,10 However, we could
D
-glucosamines by the copper-catalyzed cross-coupling
D
-
D
-glucosamine (Scheme 2) in the hope
D-glucosamine derivatives.
D-glucosamine (1) and iodobenzene (2a) were selected
b-
D
D
-glucosa-
D
cross-coupling could be achieved in 25 °C with CuI as catalyst
and glycol, BINOL, and 2-acetylcyclohexanone as ligands, although
the designed product is obtained in only 5–11% yield (entries 4–6).
Then we elevated the temperature to 110 °C and a satisfactory
⇑
Corresponding authors. Tel.: +86 (518)85895121 (C.T., W.L.); tel.: +86
(25)83592672 (J.Z.).
E-mail addresses: chuanzhoutao@yahoo.com.cn (C. Tao), liuww323@yahoo.com.
cn (W. Liu), jingzhao@nju.edu.cn (J. Zhao).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.069

7094
C. Tao et al. / Tetrahedron Letters 53 (2012) 7093–7096
Table 2
OH
OH
CuI/L3-catalyzed N-arylation of 1,3,4,6-tetra-O-benzyl-b-D-glucosamine (4) with aryl
O
O
iodides and aryl bromides (2)a
HO
HO
2: ArX
Cu/L/base
HO
HO
* OH
NH2HCl
*
OH
NH
Ar
OBn
OBn
3
1
O
O
BnO
BnO
BnO
Ar
I
OBn
OBn
BnO
NH
Ar
(1) p-MeOPhCHO
(2) BnBr,NaH. (3) H+
NH2HCl
Deprotection
4
2
5
OBn
OBn
O
Entry
Aryl halide
Product
Yieldb (%)
O
BnO
BnO
2: ArX
Cu/L/base
BnO
BnO
OBn
OBn
NH2HCl
NH
Ar
I
OBn
O
BnO
BnO
4
5
OBn
2a
NH
1
81
Scheme 2. Synthesis of N-aryl-
D
-glucosamines.
5a
I
OBn
O
O
O
OH
OH
BnO
BnO
O
OBn
OBn
2b
NH
OH
HO
O
O
2
72
L1
L2
L3
L4
5b
OBn
N
COOH
COOH
COOH
N
H
N
I
L5
L6
L7
O
BnO
BnO
O
NH
Scheme 3. Ligands used in this study.
2c
3
65
83
74
63
O
Table 1
Copper-catalyzed cross-coupling of D-glucosamine with iodobenzene (2a)a
5c
OBn
I
I
OR
OR
O
O
BnO
BnO
O
Cu/L
RO
RO
Cl
OBn
OBn
OBn
RO
RO
I
OR
OR
NH
2d
NH
Ph
NH
2HCl
4
5
6
2a
1: R = H
5a
4
: R = Bn
Cl
5d
OBn
Entry
R
Cat.
Ligand
Base
Sol.
Temp.
Yieldb (%)
O
BnO
BnO
1
2
3
4
5
6
7
8
H
H
H
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
L1
L2
L3
L1
L2
L3
L1
L2
L3
L4
L5
L6
L7
L3
L3
L3
L3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
DMF
25
25
25
25
25
0
0
0
5
Br
NH
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
2e
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
10
11
36
40
69 (81)c
42
45
32
44
33
46
61
34
Br
25
5e
OBn
110
110
110
110
110
110
110
110
110
110
110
I
9
O
BnO
BnO
10
11
12
13
14
15
16
17
EtOOC
NH
2f
COOEt
O
K3PO4
Cs2CO3
Cs2CO3
5f
OBn
I
Toluene
BnO
BnO
a
Reaction conditions: 0.5 mmol 1 or 4, 1.5 mmol 2a, 20 mol % CuI, 40 mol %
O2N
OBn
NH
Ligand, 1.5 mmol base, 0.25 mL solvent, 20 h.
2g
b
7
8
65
54
Isolated yields.
Reaction temperature = 130 °C.
c
NO2
5g
OBn
yield (36–69%) was obtained (entries 7–9). 3-Acetylcoumarin, a li-
gand developed by our group previously,8c was also investigated.
However, a lower yield was obtained even when the temperature
was increased to 110 °C (entry 10). Ligands from the amino acid
(Scheme 3), which are known in the copper-catalyzed arylation
of amines,13 were also evaluated. However, the yields were unsat-
MeOOC
O
BnO
BnO
I
OBn
NH
2h
MeOOC
5h
isfactory and the coupling yields from N,N-dimethylglycosine,
L-
proline, and N-methyl- -proline were 32–45% (entries 11–13).
L

C. Tao et al. / Tetrahedron Letters 53 (2012) 7093–7096
7095
aryl iodides containing electron-withdrawing groups also afforded
N-aryl-1,3,4,6-tetra-O-benzyl-b- -glucosamines in moderate to
Table 2 (continued)
Entry Aryl halide
NC
D
Product
OBn
Yieldb (%)
good isolated yields (54–83%, entries 4–9). However, aryl iodides
carrying an ortho-substituent failed to participate in the reaction
(entry 10). Functional groups including ether, halo, ester, nitro,
and cyano moieties were tolerated under the current conditions.
Satisfactory yields (36–57%) of arylation products were obtained
when the electron deficient aryl bromides (entries 11–13) were
utilized.
O
BnO
BnO
I
OBn
NH
2i
9
66
NC
5i
The above arylation products can easily be converted into the
I
OBn
target N-aryl-D
-glucosamines. Many classic methods12 are known
O
BnO
BnO
Br
OBn
Br
to deprotect the benzyl group from alcohol, and hydrogenolysis
catalyzed by Pd/C was employed to release the hydroxyl of N-
NH
2j
10
11
0
aryl-1,3,4,6-tetra-O-benzyl-b-
D
-glucosamine.
As
shown
in
Scheme 4, under the standard conditions,12 N-phenyl-
D
-glucosa-
5j
OBn
mine (3a) and N-(4-methoxyl phenyl)- D-glucosamine (3c) were
Br
obtained with high yields (76%, 87%).15
O
BnO
BnO
Cl
OBn
OBn
To conclude, we have developed a general, cheap, and practical
catalytic protocol for the synthesis of N-aryl- -glucosamines.
1,3,4,6-Tetra-O-benzyl-b- -glucosamine is used as a -glucosamine
NH
2k
40c
D
D
D
surrogate and CuI is used as the catalyst to achieve the C–N coupling.
The efficiency and functional-group tolerance of this procedure have
been demonstrated by the synthesis of a number of functionalized
Cl
5d
OBn
Br
N-aryl-1,3,4,6-tetra-O-benzyl-b-
aryl- -glucosamines were easily obtained by deprotection of the
benzyl protecting group. Given the fact that -glucosamine deriva-
D-glucosamines. The final N-
O
BnO
BnO
O2N
NC
D
NH
2l
D
12
57c
tives play an important role in biomedical research and chiral mol-
ecule design, we anticipate that the method described in the
present report will find applications in a number of fields such as
pharmaceutical research and organic material synthesis.
NO2
5g
OBn
O
BnO
BnO
Br
Acknowledgments
OBn
NH
2m
13
36c
We are grateful to the Open-end Funds of Jiangsu Key Labora-
tory of Marine Biotechnology (2009HS02), the Scientific and Tech-
nological Research Project of Lianyungang (CG1004), the Open-end
Funds of Jiangsu Marine Resources R&D Institute (JSIMR10C05), the
Project of Natural Science Foundation of Jiangsu Education Com-
mittee (10KJA170003, 10KJB150001), and China Postdoctoral Sci-
ence Foundation (20110491383).
NC
5i
a
Reaction conditions: 0.5 mmol 4, 1.5 mmol 2, 20 mol % CuI, 40 mol % 2-acetyl-
cyclohexanone, 1.5 mmol Cs2CO3, 0.25 mL DMF, 130 °C.
b
Isolated yields.
At 145 °C.
c
Supplementary data
OBn
O
OH
O
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
10.069.
HO
HO
BnO
BnO
H2, Pd/C, Cl3 CCOOH
MeOH/AcOEt, 40ഒ
OBn
* OH
NH
NH
R
R
References and notes
R =
yield%
76%
5a
5c
H
3a
3c
OCH3
87%
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7096
C. Tao et al. / Tetrahedron Letters 53 (2012) 7093–7096
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D
2
l
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