Copper-catalyzed synthesis of N-aryl-D-glucosamines from arylboronic acids

Article abstract of DOI:10.1080/07328303.2013.816851

A convenient catalytic protocol was developed to synthesize N-aryl-D-glucosamines from the corresponding arylboronic acids. CN cross-coupling between arylboronic acids and 1,3,4,6-tetra-O-benzyl-β-D- glucosamine was realized by copper catalyst under mild conditions. Subsequent deprotection of the benzyl ethers gave the N-arylation products, N-aryl-D-glucosamines.

Full text of DOI:10.1080/07328303.2013.816851

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Copper-Catalyzed Synthesis of N-aryl-D-
Glucosamines from Arylboronic Acids
Chuanzhou Tao a b , Feng Liu a c , Bin Xu a , Zhiling Cao a b , Huiyan
Wang a & Weiwei Liu a c
a School of Chemical Engineering , Huaihai Institute of Technology ,
Lianyungang , 222005 , P.R. of China
b Jiangsu Marine Resources Development Research Institute ,
Lianyungang , 222005 , P.R. of China
c School of Chemical Engineering, China University of Mining and
Technology , XuZhou , 221116 , P.R. of China
Published online: 11 Oct 2013.
To cite this article: Chuanzhou Tao , Feng Liu , Bin Xu , Zhiling Cao , Huiyan Wang & Weiwei Liu
(2013) Copper-Catalyzed Synthesis of N-aryl-D-Glucosamines from Arylboronic Acids, Journal of
Carbohydrate Chemistry, 32:7, 411-423, DOI: 10.1080/07328303.2013.816851
To link to this article: http://dx.doi.org/10.1080/07328303.2013.816851
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Journal of Carbohydrate Chemistry, 32:411–423, 2013
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C
Copyright Taylor & Francis Group, LLC
ISSN: 0732-8303 print / 1532-2327 online
DOI: 10.1080/07328303.2013.816851
Copper-Catalyzed Synthesis
of N-aryl-D-Glucosamines
from Arylboronic Acids
Chuanzhou Tao,1,2 Feng Liu,1,3 Bin Xu,1 Zhiling Cao,1,2
Huiyan Wang,1 and Weiwei Liu1,3
1School of Chemical Engineering, Huaihai Institute of Technology, Lianyungang
222005, P.R. of China
2Jiangsu Marine Resources Development Research Institute, Lianyungang 222005,
P.R. of China
3School of Chemical Engineering, China University of Mining and Technology, XuZhou
221116, P.R. of China
A convenient catalytic protocol was developed to synthesize N-aryl-D-glucosamines
from the corresponding arylboronic acids. C N cross-coupling between arylboronic
acids and 1,3,4,6-tetra-O-benzyl-β-D-glucosamine was realized by copper catalyst un-
der mild conditions. Subsequent deprotection of the benzyl ethers gave the N-arylation
products, N-aryl-D-glucosamines.
Keywords N-aryl-D-glucosamine; Arylboronic acid; Copper catalysis; Cross-coupling
INTRODUCTION
D-Glucosamine and its N-substituted derivatives are found in numerous bio-
logically active molecules such as cell surface N-glycoproteins, proteoglycans,
glycosylphosphatidylinositol (GPI) anchors, glycosphingolipids, lipopolysac-
charides, and chitin/chitosan.[1] Synthetic chemists also used these molecules
as ligands or organocatalysts to introduce chirality in catalytic asymmetric re-
actions.[2] Recently, N-arylation derivatives from D-glucosamine (Fig. 1) were
disclosed with many utilities such as a predictive method in ecotoxicology,[3a,3b]
Received April 5, 2013; accepted June 15, 2013.
Address correspondence to Chuanzhou Tao, School of Chemical Engineering, Huaihai
Institute of Technology, Lianyungang 222005, P.R. of China, and Jiangsu Marine Re-
sources Development Research Institute, Lianyungang 222005, P.R. of China E-mail:
taocz@hhit.edu.cn.; and Weiwei Liu, School of Chemical Engineering, Huaihai Institute
of Technology, Lianyungang 222005, P.R. of China, and School of Chemical Engineer-
ing, China University of Mining and Technology, XuZhou 221116, P.R. of China. E-mail:
liuww323@yahoo.com.cn
411

C. Tao et al.
412
Figure 1: N-aryl-D-glucosamine derivatives.
cancer cell detection,[3c] a metabolic indicator for FACS analysis,[3d] and mea-
surement of glucose uptake in a single cell of living E. coli.[3e,3f] However, chem-
ical modifications of D-glucosamine at the N-position mainly rely on acyla-
tion,[4] Schiff-base formation,[5] azidation,[6] and alkylation.[7] N-Arylation of
D-glucosamine has rarely been realized due to synthetic difficulty. Only in a
few examples was N-arylation of D-glucosamine accomplished by the SNAr
reaction between D-glucosamine and ary halides containing a strong electron-
withdrawing group.[3,8]
Very recently, we developed a general protocol for synthesis of N-aryl-D-
glucosamines by the copper-catalyzed cross-coupling between aryl halides and
D-glucosamine.[9,10] With aryl halides as arylation reagents, a number of func-
tionalized N-aryl-1,3,4,6-tetra-O-benzyl-β-D-glucosamines were synthesized,
which were subsequently deprotected to give N-aryl-D-glucosamines. The re-
action represents a major advance in the N-aryl-D-glucosamines synthesis.
However, aryl halides carrying an ortho-substituent failed to participate in the
reaction. The cross-coupling had to be carried out at high temperature (130◦C)
and protected with inert gas. Besides, ligands were critical to the transforma-
tions.
Herein we report a convenient and mild protocol for synthesis of N-aryl-
D-glucosamines via copper-catalyzed cross-coupling between arylboronic acids
and D-glucosamine under ligand-free conditions, where aryl boronic acids were
used as arylation reagents instead of aryl halides. Copper-catalyzed cross-
couplings between arylboronic acids and N/O/S-nucleophiles (phenol, aniline,
or thiophenol) are known as Chan-Evans-Lam–modified Ullmann condensa-
tion, and the advantage of this reaction is that much milder reaction conditions
can be allowed such as lower temperature and aerobic environment.[10g,11,12]
Importantly, N-ortho-substituent-aryl-D-glucosamines could also be obtained
through the present method. The fact that many aryl boronic acids are now
commercially available makes this protocol more practically appealing.[13]

Synthesis of N-aryl-D-Glucosamines from Arylboronic Acids
413
RESULTS AND DISCUSSION
We commenced our study with phenylboronic acid (2a) as model substrate,
Cu(OAc)2 as catalyst, and CH2Cl2 as solvent (Scheme. 1). Initially, D-
glucosamine (1a) was selected as substrate to directly couple with phenyl-
boronic acid (2a). Nevertheless, we could not obtain the N-arylation product
3aa from D-glucosamine (1a). We speculated that the hydroxyl groups, es-
pecially 1-hydroxyl, have influence on the cross-coupling reaction. Then, we
turned to the substrates from O-protected-D-glucosamines.
Scheme 1: Copper-catalyzed arylation of D-glucosamines with arylboronic acids.
It is well known that acetyl is a versatile group for protecting hy-
droxyl in carbohydrate chemistry and can be removed under mild condi-
tions.[14] If 1,3,4,6-tetra-O-acetyl-β-D-glucosamine (1b) was used as a surro-
gate of D-glucosamine, it would probably cross-couple with phenyl boronic acid
(2a) to produce N-aryl-1,3,4,6-tetra-O-acetyl-β-D-glucosamine, which would
easily be converted into N-aryl-D-glucosamines with base. This hypothesis
prompted us to examine a roundabout process for synthesis of N-aryl-D-
glucosamines catalyzed by copper (Sch. 1). The surrogate 1,3,4,6-tetra-O-
acetyl-β-D-glucosamine (1b) was synthesized according to the literature.[15]
With our standard conditions, however, the reaction was reluctant and only 9%
of the product was obtained. On the other hand, as another protecting group
for hydroxyl, benzyl may be more stable in the catalytic system (Sch. 1). So we
turned to the benzyl-protected D-glucosamine and 1,3,4,6-tetra-O-benzyl-β-D-
glucosamine (1c)[16] was used as a model substrate. Gratifyingly, the designed
product (3ca) was obtained with 48% yield. It is noteworthy that many clas-
sic methods[14,17] are known to deprotect the benzyl group from alcohol. For

C. Tao et al.
414
instance, hydrogenolysis with H2/Pd/C can readily remove benzyl groups to
release the hydroxyl groups of glucosamine.
Subsequently, to optimize the reaction condition, 1,3,4,6-tetra-O-benzyl-β-
D-glucosamine and phenyl boronic acid were selected as model substrates. It is
reported that the undesired phenol and homocoupled biphenyl ether byprod-
ucts could be formed via copper-catalyzed C O coupling with H2O and phe-
nol.[18] So, the molecular sieves were introduced into the reaction mixture to
reduce the amount of H2O. As shown in Table 1, under a ligand-free and base-
free condition, different solvents were screened including polar solvents DMF
and MeOH and less polar solvents CHCl3, ClCH2CH2Cl, PhCl, CH3CN, and
toluene (entries 1–8). However, lower yields were obtained even when the re-
action temperature was raised to 130◦C. To our satisfaction, 65% yield was
achieved when a CH2Cl2 and CH3CN (2/1) mixture was used as cosolvent
(entry 9). Nonetheless, other cosolvents such as toluene and CH3CN slightly
increased the yield (entry 10). With CH2Cl2 and CH3CN as the solvent, we
screened the copper sources including cuprous and cupric salts (entries 11–14).
Table 1: Copper-catalyzed phenylation of 1,3,4,6-tetra-O-benzyl-β-D-glucosamine
with phenylboronic acida
Entry
Catalyst
Solvent
Temp/◦C
Yield%b
1
2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuSO4
CH2Cl2
CHCl3
65
65
48
39
36
39
45
33
29
15
65
49
0
3
ClCH2CH2Cl
PhCl
80
4
130
110
80
5
Toluene
6
CH3CN
7
DMF
120
65
8
CH3OH
9
CH2Cl2/CH3CN
Toluene/CH3CN
CH2Cl2/CH3CN
CH2Cl2/CH3CN
CH2Cl2/CH3CN
CH2Cl2/CH3CN
65
10
11
12
13
14
120
65
CuO
65
0
CuI
CuBr
65
27
32
65
aConditions: 1c 0.5 mmol; 2a 1.5 mmol; catalyst 20 mol%; 4ÅMS 400 mg; solvent = 3.0 mL (Vsol
VMeCN = 2:1); O2, 24 h.
:
bIsolated yield.

Synthesis of N-aryl-D-Glucosamines from Arylboronic Acids
415
The yields indicated that Cu(OAc)2 was the best catalyst. Therefore, our opti-
mal condition for the coupling of arylboronic acid and 1,3,4,6-tetra-O-benzyl-
β-D-glucosamine was as follows: 20 mol% Cu(OAc)2 as the catalyst relative to
1,3,4,6-tetra-O-benzyl-β-D-glucosamine, and CH2Cl2 and CH3CN mixture as
the cosolvent at 65◦C.
With the optimized catalytic system Cu(OAc)2/CH2Cl2/CH3CN, we next ex-
amined whether the same catalytic system can be applied to the coupling of
1,3,4,6-tetra-O-benzyl-β-D-glucosamine with various arylboronic acids having
different electronic and steric properties. It was found that both electron-rich
and electron-deficient arylboronic acids can be smoothly converted to the de-
sired products with satisfactory isolated yields (Sch. 2). It is noteworthy that
Scheme 2: Copper-catalyzed N-arylation of 1,3,4,6-tetra-O-benzyl-β-D-glucosamine (1c)
with arylboronic acids (2).

C. Tao et al.
416
arylboronic acids carrying an ortho-substituent were also found to readily par-
ticipate in the reaction. For instance, 2-methylphenyl boronic acid could give
an isolated yield of 54%, and the yield for 2-methoxylphenyl boronic acid is
51%.
Certainly, the above arylation products can now easily be converted
to the target N-aryl-D-glucosamines. Hydrogenolysis catalyzed by Pd/C
was employed to release the hydroxyl of N-aryl-1,3,4,6-tetra-O-benzyl-β-D-
glucosamine. As shown in Scheme 3, under the standard conditions,[17] N-
phenyl-D-glucosamine (3aa) and N-(4-methoxyl phenyl)-D-glucosamine (3ac)
were obtained with high yields (76% and 87%, respectively).
Scheme 3: Deprotection of N-aryl-1,3,4,6-tetra-O-benzyl-β-D-glucosamines.
CONCLUSIONS
To conclude, we have developed a mild and convenient catalytic protocol for the
synthesis of N-aryl-D-glucosamines. 1,3,4,6-tetra-O-benzyl-β-D-glucosamine
is used as D-glucosamine surrogate and Cu(OAc)2 was used as catalyst to
achieve the C N coupling. The efficiency and functional-group tolerance
of this procedure have been demonstrated by synthesis of various func-
tionalized N-aryl-1,3,4,6-tetra-O-benzyl-β-D-glucosamines. Furthermore, N-
ortho-substituent-aryl-1,3,4,6-tetra-O-benzyl-β-D-glucosamines were also syn-
thesized with the standard conditions. Finally, free N-aryl-D-glucosamines
were easily obtained by deprotection of the benzyl protecting group. Given the
fact that D-glucosamine derivatives play an important role in biomedical re-
search and chiral molecule design, we anticipate that the method described in
the present report will find applications in a number of fields such as pharma-
ceutical research and organic material synthesis.
EXPERIMENTAL
General Experimental Procedures
The solvents were distilled from CaH2. All chemicals were obtained
from commercial source and used without further purification. Flash column

Synthesis of N-aryl-D-Glucosamines from Arylboronic Acids
417
chromatography was performed on silica 230–400 mesh. Melting points were
determined on a Yanaco melting point apparatus and were uncorrected. IR
spectra were recorded on a Bruker Tensor 27 spectrometer with KBr pellets.
1H NMR and 13C NMR spectra were recorded on a Bruker Advance 400 spec-
trometer at ambient temperature in DMSO-d6 or D2O. Chemical shifts are
reported in ppm relative to TMS. HRMS analysis was performed on a Mariner
ESI-TOF and Finnigan LCQ advantage Max Series MS System.
Copper-catalyzed Coupling of arylboronic (2) with 1,3,4,6-
tetra-O-benzyl-β-D-glucosamine (1c): General procedure
A 100-mL oven-dried round-bottom flask, containing a magnetic stirring
bar, was charged with Cu(OAc)2 (18 mg, 20 mol%), ArB(OH)2 2 (1.5 mmol, 3
˚
eq.), and 4A MS (400 mg). The solvent of CH2Cl2/CH3CN (3.0 mL = 2.0 mL +
1.0 mL) was injected and the suspension was stirred for 10 min at rt. Then,
1,3,4,6-tetra-O-benzyl-β-D-glucosamine 1c (270 mg, 0.5 mmol) was added. The
reaction vessel was flushed with O2, sealed, and stirred at 65◦C for 24 h. The
resulting mixture was cooled to rt and filtered through a pad of silica gel with
the help of CH2Cl2 (30 mL). The filtrate was concentrated and the residue
was purified by column chromatography (silica gel, EtOAc-PE) to afford the
product 3.
(2R,3R,4R,5S,6R)-2,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)-N-
phenyltetrahydro-2H-pyran-3-amine (3ca)
m.p. = 114–117◦C. IR (KBr) ν: 3548, 3478, 3414, 1636, 1620, 1111, 1072,
1
620. H NMR (400 MHz, DMSO) δ 7.40–7.27 (m, 8H), 7.25–7.14 (m, 10H),
7.11–7.03 (m, 4H), 6.74 (d, J = 7.8 Hz, 2H), 6.54 (t, J = 7.0 Hz, 1H), 5.62
(d, J = 9.0 Hz, 1H), 4.81–4.71 (m, 3H), 4.65 (d, J = 10.8 Hz, 1H), 4.61–4.51
(m, 4H), 4.48 (d, J = 7.9 Hz, 1H), 3.76–3.63 (m, 3H), 3.59–3.51 (m, 2H),
3.47–3.37 (m, 1H). 13C NMR (100 MHz, DMSO) δ 149.08, 138.50, 138.32,
138.28, 137.84, 128.64, 128.23, 128.20, 127.98, 127.97, 127.73, 127.70, 127.58,
127.52, 127.42, 127.28, 127.16, 127.01, 115.70, 112.78, 102.56, 84.17, 77.99,
74.13, 74.09, 73.91, 72.36, 70.04, 68.92, 59.66. HRMS (ESI): m/z [M + Na]+
calcd for C40H41O5NNa: 638.2877; found: 638.2872.
(2R,3R,4R,5S,6R)-2,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)-N-p-
tolyltetrahydro-2H-pyran-3-amine (3cb)
m.p. = 115–116◦C. IR (KBr) ν: 3548, 3477, 3417, 1636, 1617, 1565, 1415,
1123, 1111, 1069, 617. 1H NMR (400 MHz, DMSO) δ 7.39–7.27 (m, 8H),
7.25–7.16 (m, 10H), 7.14–7.07 (m, 2H), 6.89 (d, J = 8.2 Hz, 2H), 6.67 (d,
J = 8.4 Hz, 2H), 4.84–4.70 (m, 3H), 4.66 (d, J = 10.9 Hz, 1H), 4.62–4.51

C. Tao et al.
418
(m, 4H), 4.48 (d, J = 8.0 Hz, 1H), 3.79–3.60 (m, 3H), 3.60–3.50 (m, 2H),
3.41–3.36 (m, 1H), 2.17 (s, 3H). 13C NMR (100 MHz, DMSO) δ 146.85, 138.57,
138.33, 138.30, 137.87, 129.09, 128.23, 128.20, 127.97, 127.73, 127.69, 127.58,
127.51, 127.42, 127.28, 127.17, 127.03, 124.11, 124.09, 113.00, 102.66, 84.19,
78.01, 74.09, 74.07, 73.91, 72.37, 70.05, 68.95, 60.17, 20.08. HRMS (ESI): m/z
[M + H]+ calcd for C41H44O5N: 630.3214; found: 630.3212.
(2R,3R,4R,5S,6R)-2,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)-N-(4-
methoxyphenyl)tetrahydro-2H-pyran-3-amine (3cc)
m.p. = 107–109◦C. IR (KBr) ν: 3548, 3474, 3417, 1637, 1618, 1562, 1516,
1
1451, 1244, 1116, 1070, 742, 694. H NMR (400 MHz, DMSO) δ 7.40–7.15 (m,
18H), 7.15–7.09 (m, 2H), 6.70 (s, 4H), 4.83–4.64 (m, 4H), 4.62–4.50 (m, 4H),
4.47 (d, J = 8.0 Hz, 1H), 3.79–3.59 (m, 6H), 3.54 (d, J = 5.2 Hz, 2H), 3.29 (dd,
J = 9.3, 8.2 Hz, 1H). 13C NMR (100 MHz, DMSO) δ 150.77, 143.36, 138.60,
138.33, 138.30, 137.88, 128.24, 128.22, 128.00, 127.99, 127.72, 127.71, 127.60,
127.53, 127.43, 127.30, 127.19, 127.04, 114.38, 113.93, 102.79, 84.23, 78.03,
74.07, 73.90, 72.37, 70.09, 68.95, 60.84, 55.36. HRMS (ESI): m/z [M + H]+
calcd for C41H44O6N: 646.3163; found: 646.3165.
(2R,3R,4R,5S,6R)-2,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)-N-(4-
chlorophenyl)tetrahydro-2H-pyran-3-amine (3cd)
m.p. = 118–120◦C. IR (KBr) ν: 3445, 3343, 3029, 2895, 2862, 1600, 1517,
1492, 1450, 1114, 1070, 995, 813, 749, 697. 1H NMR (400 MHz, DMSO)
δ 7.39–7.27 (m, 8H), 7.24–7.15 (m, 8H), 7.16 (dd, J = 7.0, 2.5 Hz, 2H),
7.12–7.05 (m, 4H), 6.74 (d, J = 8.9 Hz, 2H), 4.82–4.70 (m, 3H), 4.67 (d,
J = 10.9 Hz, 1H), 4.60–4.52 (m, 4H), 4.47 (d, J = 8.1 Hz, 1H), 3.80–3.52
(m, 5H), 3.46–3.37 (m, 1H). 13C NMR (100 MHz, DMSO) δ 148.07, 138.46,
138.32, 138.25, 137.78, 128.30, 128.24, 128.22, 128.00, 127.73, 127.67, 127.60,
127.55, 127.43, 127.34, 127.24, 127.01, 118.85, 114.15, 102.47, 84.01, 78.01,
74.18, 74.10, 73.95, 72.38, 70.11, 68.88, 59.64. HRMS (ESI): m/z [M + H]+
calcd for C40H41O5N35Cl: 650.2667; found: 650.2668; calcd for C40H41O5N37Cl:
652.2638; found: 652.2639.
(2R,3R,4R,5S,6R)-2,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)-N-(4-
bromophenyl)tetrahydro-2H-pyran-3-amine (3ce)
m.p. = 127–129◦C. IR (KBr) ν: 3345, 3061, 3029, 2895, 2866, 1578, 1485,
1
1450, 1069, 809, 745, 694. H NMR (400 MHz, DMSO) δ 7.40–7.27 (m, 8H),
7.27–7.12 (m, 12H), 7.08 (dd, J = 6.6, 3.0 Hz, 2H), 6.70 (d, J = 8.9 Hz, 2H), 5.91
(d, J = 9.1 Hz, 1H), 4.83–4.63 (m, 4H), 4.62–4.50 (m, 4H), 4.46 (d, J = 8.0 Hz,
1H), 3.78–3.50 (m, 5H), 3.40 (dd, J = 17.6, 9.0 Hz, 1H). 13C NMR (100 MHz,

Synthesis of N-aryl-D-Glucosamines from Arylboronic Acids
419
DMSO) δ 148.49, 138.44, 138.31, 138.24, 137.77, 131.12, 128.23, 128.21,
127.99, 127.73, 127.68, 127.67, 127.59, 127.54, 127.43, 127.33, 127.23, 127.01,
115.52, 114.76, 102.44, 84.00, 77.99, 74.17, 74.09, 73.93, 72.36, 70.09, 68.87,
59.55. HRMS (ESI): m/z [M + Na]+ calcd for C40H40O5NNa79Br: 716.1982;
found: 716.1992; calcd for C40H40O5NNa81Br: 718.1970; found: 718.1990.
Ethyl 4-((2R,3R,4R,5S,6R)-2,4,5-tris(benzyloxy)-6-(benzyloxyme-
thyl)tetrahydro-2H-pyran-3-ylamino)benzoate (3cf)
m.p. = 115–116◦C. IR (KBr) ν: 3468, 3420, 3353, 3029, 2900, 2866, 1700,
1
1610, 1537, 1274, 1175, 1111, 1069, 752, 694. H NMR (400 MHz, DMSO)
δ 7.69 (d, J = 8.9 Hz, 2H), 7.40–7.26 (m, 8H), 7.22–7.14 (m, 10H), 7.06
(dd, J = 7.4, 2.1 Hz, 2H), 6.77 (d, J = 8.9 Hz, 2H), 4.84–4.63 (m, 4H),
4.62–4.47 (m, 5H), 4.22 (q, J = 7.1 Hz, 2H), 3.81–3.52 (m, 6H), 1.28 (t, J =
7.1 Hz, 3H). 13C NMR (100 MHz, DMSO) δ 165.86, 153.15, 138.35, 138.31,
138.21, 137.72, 130.77, 128.25, 128.23, 128.01, 127.99, 127.76, 127.64, 127.61,
127.57, 127.44, 127.35, 127.26, 127.00, 116.33, 111.70, 102.04, 83.71, 77.96,
74.23, 74.14, 73.98, 72.39, 70.05, 68.84, 59.48, 58.69, 14.38. HRMS (ESI): m/z
[M + H]+ calcd for C43H46O7N: 688.3268; found: 688.3266.
(2R,3R,4R,5S,6R)-2,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)-N-o-
tolyltetrahydro-2H-pyran-3-amine (3cg)
Liquid, IR (KBr) ν: 3433, 3003, 2978, 2936, 2853, 1578, 1424, 1043, 1014,
649, 620. 1H NMR (400 MHz, DMSO) δ 7.49 (dd, J = 5.1, 1.8 Hz, 1H), 7.43–7.35
(m, 6H), 7.33–7.28 (m, 3H), 7.26–7.18 (m, 7H), 7.17–7.12 (m, 4H), 7.09 (dd,
J = 7.8, 1.7 Hz, 1H), 7.03 (dd, J = 7.2, 2.3 Hz, 1H), 6.84 (dd, J = 10.9, 4.4 Hz,
1H), 4.83 (m, 3H), 4.64–4.55 (m, 5H), 4.48 (dd, J = 11.0, 2.0 Hz, 1H), 3.89
(dd, J = 11.9, 9.3 Hz, 1H), 3.83–3.68 (m, 4H), 3.63 (t, J = 9.2 Hz, 1H), 2.08
(s, 3H). 13C NMR (100 MHz, DMSO) δ 146.24, 138.32, 138.25, 138.16, 137.78,
137.75, 129.20, 128.26, 128.24, 128.03, 128.01, 127.95, 127.73, 127.66, 127.62,
127.61, 127.12, 126.96, 126.36, 121.24, 115.93, 110.95, 102.54, 82.82, 79.18,
74.00, 73.65, 72.41, 70.36, 69.71, 68.77, 58.65, 30.62. HRMS (ESI): m/z [M +
Na]+ calcd for C41H43O6NNa: 652.3043; found: 652.3033.
(2R,3R,4R,5S,6R)-2,4,5-Tris(benzyloxy)-6-(benzyloxymethyl)-N-(2-
methoxyphenyl)tetrahydro-2H-pyran-3-amine (3ch)
Liquid, IR (KBr) ν: 3419, 3062, 3030, 2928, 2866, 1643, 1578, 1452, 1419,
1
1111, 1027, 734, 693. H NMR (400 MHz, DMSO) δ 7.39–7.15 (m, 18H), 7.07
(dt, J = 4.6, 3.2 Hz, 2H), 6.91–6.80 (m, 2H), 6.74 (td, J = 7.7, 1.2 Hz, 1H), 6.56
(td, J = 7.7, 1.5 Hz, 1H), 4.85–4.51 (m, 9H), 3.85 (dd, J = 17.4, 8.2 Hz, 1H),
3.80–3.66 (m, 4H), 3.64–3.51 (m, 2H), 3.40 (dd, J = 17.7, 8.5 Hz, 1H), 3.29 (dd,

C. Tao et al.
420
J = 9.4, 8.0 Hz, 1H). 13C NMR (100 MHz, DMSO) δ 163.69, 146.31, 138.48,
138.33, 138.29, 137.87, 128.24, 128.20, 128.00, 127.96, 127.70, 127.67, 127.61,
127.58, 127.42, 127.27, 127.11, 126.98, 120.89, 115.70, 110.87, 109.92, 102.28,
83.80, 78.06, 74.10, 74.08, 73.83, 72.37, 69.96, 68.95, 59.96, 55.41. HRMS (ESI):
m/z [M + Na]+ calcd for C41H43O6N+Na: 668.2983; found: 668.2987.
Deprotection of N-aryl-1,3,4,6-tetra-O-benzyl-β-D-glucosamine
(3): General procedure
Under hydrogen atmosphere, a solution of 3 (0.5 mmol) in CH3OH and
EtOAc (4 mL + 2 mL) was stirred in the presence of Pd/C (10%, 100 mg) and
trichloroacetic acid (80 mg, 0.5 mmol) at 40◦C. After 40 h the reaction mix-
ture was cooled to rt and filtered through a pad of silica gel with the help of
CH3OH. The filtrate was concentrated and the residue was purified by column
chromatography (silica gel, CHCl3 CH3OH) to afford the deprotected product.
(2R,3R,4R,5S,6R)-6-(Hydroxymethyl)-3-(phenylamino)tetrahydro-
2H-pyran-2,4,5-triol (3aa)
IR (KBr) ν: 3383, 2975, 2927, 2898, 1644, 1450, 1412, 1382, 1088, 1049,
880, 637. 1H NMR (400 MHz, D2O) δ 7.68–7.38 (m, 5H), 5.05 (s, 0.81H),
4.90–4.84 (m, 0.35H), 4.11 (t, J = 9.7 Hz, 0.85H), 4.00–3.62 (m, 4.15H), 3.55 (t,
J = 9.6 Hz, 1.04H), 3.51–3.32 (m, 0.77H). 13C NMR (100 MHz, D2O) δ 136.70,
136.23, 132.91, 132.71, 131.82, 130.71, 125.17, 125.13, 94.95, 90.38, 78.43,
74.09, 73.17, 72.78, 72.48, 72.22, 66.59, 66.24, 63.04, 62.88. HRMS (ESI): m/z
[M + Na]+ calcd for C12H17O5NNa: 278.0999; found: 278.0993.
(2R,3R,4R,5S,6R)-6-(Hydroxymethyl)-3-(4-methoxyphenylamino)
tetrahydro-2H-pyran-2,4,5-triol (3ac)
IR (KBr) ν: 3411, 2936, 2840, 1600, 1577, 1512, 1445, 1260, 1031, 759.
1H NMR (400 MHz, D2O) δ 7.45 (t, J = 9.4 Hz, 2H), 7.15 (d, J = 8.7 Hz,
2H), 5.01 (s, 0.83H), 4.08 (t, J = 9.8 Hz, 0.84H), 3.96–3.58 (m, 7.45H), 3.51 (t,
J = 9.5 Hz, 1.1H), 3.35 (s, 1.8H). 13C NMR (100 MHz, D2O) δ 162.23, 128.18,
127.89, 127.08, 118.08, 117.96, 94.17, 90.20, 78.42, 74.07, 72.78, 72.44, 72.21,
72.03, 66.99, 66.67, 62.98, 62.86, 58.30, 51.45. HRMS (ESI): m/z [M + H]+
calcd for C13H19O6N: 286.1285; found: 286.1293.
ACKNOWLEDGMENTS
We are grateful to the Priority Academic Program Development of Jiangsu
Higher Education Institutions, Scientific and Technological Research Project
of Lianyungang (CG1004), Open-end Funds of Jiangsu Key Laboratory of

Synthesis of N-aryl-D-Glucosamines from Arylboronic Acids
421
Marine Biotechnology (2009HS02), Open-end Funds of Jiangsu Marine Re-
sources R & D Institute (JSIMR10C05), China Postdoctoral Science Founda-
tion (20110491383) and Project of Natural Science Foundation of Jiangsu Ed-
ucation Committee (10KJB150001).
REFERENCES
1. (a) Varki, A.; Cummings, D. C.; Esko, J. D.; Freeze, H. H.; Stanley, P.; Bertozzi,
C. R.; Hart, G. W.; Etzler, M. E. In Essentials of Glycobiology, 2nd ed.; Cold Spring
Habor Laboratory Press: New York, 2009. (b) Gandhi, N. S.; Mancera, R. L. The struc-
ture of glycosaminoglycans and their interactions with proteins. Chem. Biol. Drug Des.
2008, 72, 455–482. (c) Paulick, M. G.; Bertozzi, C. R. The glycosylphosphatidylinositol
anchor: a complex membrane-anchoring structure for proteins. Biochemistry 2008, 47,
6991–7000. (d) Wang, L.-X.; Huang, W. Enzymatic transglycosylation for glycoconju-
gate synthesis. Curr. Opin. Chem. Biol. 2009, 13, 592–600. (e) Bryant, C. E.; Spring, D.
R.; Gangloff, M.; Gay, N. J. The molecular basis of the host response to lipopolysaccha-
ride. Nat. Rev. Microbiol. 2010, 8, 8–14. (f) Taube, S.; Jiang, M.; Wobus, C. E. Glycosph-
ingolipids as receptors for non-enveloped viruses. Viruses 2010, 2, 1011–1049. (g) Liu,
L.; Bennett, C. S.; Wong, C.-H. Advances in glycoprotein synthesis. Chem. Commun.
2006, 21–33.
2. (a) Tollabi, M.; Framery, E.; Goux-Henry, C.; Sinou, D. Palladium-catalyzed asym-
metric allylic alkylation using chiral glucosamine-based monophosphines. Tetrahe-
dron: Asymmetry. 2003, 14, 3329–3333. (b) Glegoła, K.; Framer, E.; Goux-Henry, C.;
Pietrusiewicz, K. M.; Sinou, D. Influence on the enantioselectivity in allylic alkylation
of the anomeric position of the phosphine-amide ligands derived from D-glucosamine.
Tetrahedron 2007, 63, 7133–7141. (c) Glegoła, K.; Johannesen, S. A.; Thim, L.; Goux-
Henry, C.; Skrydstrup, T.; Framery, E. Simple D-glucosamine-based phosphine-imine
and phosphine-amine ligands in Pd-catalyzed asymmetric allylic alkylations. Tetrahe-
dron Lett. 2008, 49, 6635–6638. (d) Agarwal, J.; Peddinti, R. K. Glucosamine-based
primary amines as organocatalysts for the asymmetric aldol reaction. J. Org. Chem.
2011, 76, 3502–3505.
3. (a) Winkler, R.; Sandermann, H. Jr. N-Glucosyl conjugates of chlorinated ani-
lines: spontaneous formation and cleavage. J. Agric. Food Chem. 1992, 40, 2008–2012.
(b) Margret, B.; Christiane, R.; Brigitte, T.; Thomas, J.; Burkhard, S. Uptake, translo-
cation, and metabolism of 3,4-dichloroaniline in soybean and wheat plants. Z. Natur-
forsch. C, 1995, 49, 719–726. (c) Hidenori, T.; Hiroshi, I.; Masahiro, K. 2012, Method
for detecting cancer cell. WO2012086802. (d) Hisakage, F.; Shiho, O.; Mikako, S.;
Hideaki, M. Utilization of fluorescent glucose analog 2-NBDG as a metabolic indicator
for FACS analysis during ES cell differentiation. Electrochemistry, 2012, 80, 299–301.
(e) Yamamoto, T.; Nishiuchi, Y.; Teshima, T.; Matsuoka, H.; Yamada, K. Synthesis of
2-NBDLG, a fluorescent derivative of L-glucosamine; the antipode of D-glucose tracer
2-NBDG. Tetrahedron Lett. 2008, 49, 6876–6878. (f) Jung, M. E.; Dong, T. A.; Cai,
X.-L. Improved synthesis of 4-amino-7-nitrobenz-2,1,3-oxadiazoles using NBD fluoride
(NBD-F). Tetrahedron Lett. 2011, 52, 2533–2535.
4. (a) Cheuk, N. G. S.; Wang, G. J. Synthesis and characterization of D-glucosamine-
derived low molecular weight gelators. Tetrahedron 2010, 66, 5962–5971. (b) Vendrell,
M.; Samanta, A.; Yun, S.-W. Synthesis and characterization of a cell-permeable near-
infrared fluorescent deoxyglucose analogue for cancer cell imaging. Org. Biomol. Chem.
2011, 9, 4760–4762.
5. (a) Mensah, E. A.; Yu, F.; Nguyen, H. M. Nickel-catalyzed stereoselective gly-
cosylation with C(2)-N-substituted benzylidene D-glucosamine and galactosamine

C. Tao et al.
422
trichloroacetimidates for the formation of 1,2-cis-2-amino glycosides. applications to the
synthesis of heparin disaccharides, GPI anchor pseudodisaccharides, and α-GalNAc. J.
Am. Chem. Soc., 2010, 132, 14288–14302. (b) Pe´rez, E. M. S.; a´valos, M.; Babiano,
R. Schiff bases from d-glucosamine and aliphatic ketones. Carbohydr. Res. 2010, 345,
23–32. (c) Cheng, A.; Hendel, J. L.; Colangelo, K. Convenient temporary methyl imi-
date protection of N-acetylglucosamine and glycosylation at O-4. J. Org. Chem. 2008,
73, 7574–7579.
6. Emmadi, M.; Kulkarni, S. S. Rapid transformation of D-mannose into orthogonally
protected D-glucosamine and D-galactosamine thioglycosides. J. Org. Chem. 2011, 76,
4703–4709.
7. Liberek, B.; Melcer, A.; Osuch, A.; Wakiec, R.; Milewski, S.; Wisniewski, A. N-Alkyl
derivatives of 2-amino-2-deoxy-D-glucose. Carbohydr. Res. 2005, 340, 1876–1884.
8. (a) Horton, D. The anomeric 1,3,4,6-tetra-O-acetyl-2-deoxy-2-(2,4-dinitroanilino)-
D-glucopyranoses. J. Org. Chem. 1964, 29, 1776–1782. (b) Bindscha¨dler, P.; Dialer, L.
O.; Seeberger, P. H. Synthesis of differentially protected glucosamine building blocks
and their evaluation as glycosylating agents. J. Carbohyd. Chem. 2009, 28, 395–420.
9. Tao, C.-Z.; Liu, F.; Liu, W.-W.; Zhu, Y.-M.; Li, Y.-F.; Liu, X.-L.; Zhao, J. Synthesis
of N-aryl-D-glucosamines through copper-catalyzed C–N coupling. Tetrahedron Lett.
2012, 53, 7093–7096.
10. Our other work about copper-catalyzed reactions: (a) Tao, C.-Z.; Liu, F.; Zhu, Y.-M.;
Liu, W.-W.; Cao, Z.-L. Copper-catalyzed aerobic oxidative synthesis of aryl nitriles from
benzylic alcohols and aqueous ammonia. Org. Biomol. Chem. 2013, 11, 3349–3354.
(b) Tao, C.-Z.; Lv, A.-F.; Zhao, N.; Yang, S.; Liu, X.-L.; Zhou, J.; Liu, W.-W.; Zhao,
J. Ligand-free copper-catalyzed synthesis of diaryl thioethers from aryl halides and
thioacetamide. Synlett 2011, 134–138. (c) Tao, C.-Z.; Liu, W.-W.; Lv, A.-F.; Sun, M.-
M.; Tian, Y.; Wang, Q.; Zhao, J. Room-temperature copper-catalyzed synthesis of pri-
mary arylamines from aryl halides and aqueous ammonia. Synlett 2010, 1355–1358.
(d) Tao, C.-Z.; Liu, W.-W.; Sun, J.-Y. Cao, Z.-L.; Li, H.; Zhang, Y.-F. 3-Acetyl-coumarin
as a practical ligand for copper-catalyzed C-N coupling reactions at room temperature.
Synthesis 2010, 1280–1284. (e) Tao, C.-Z.; Liu, W.-W.; Sun, J.-Y. Copper-catalyzed syn-
thesis of phenols from aryl halides and 4-methoxylbenzyl alcohol. Chin. Chem. Lett.
2009, 20, 1170–1174. (f) Tao, C.-Z.; Li, J.; Fu, Y.; Liu, L.; Guo, Q.-X. Copper-catalyzed
synthesis of primary arylamines from aryl halides and 2,2,2-trifluoroacetamide. Tetra-
hedron Lett. 2008, 49, 70–75. (g) Tao, C.-Z.; Cui, X.; Li, J.; Liu, A.-X.; Liu, L.; Guo, Q.-X.
Copper-catalyzed synthesis of aryl azides and 1-aryl-1,2,3-triazoles from boronic acids.
Tetrahedron Lett. 2007, 48, 3525–3529. (h) Tao, C.-Z.; Li, J.; Cui, X.; Fu, Y.; Guo, Q.-X.
Cu-catalyzed cross couplings under ligandless conditions. Chin. Chem. Lett. 2007, 18,
1199–1202.
11. Review: Ley, S. V.; Thomas, A. W. Modern synthetic methods for copper-mediated
C(aryl)–O, C(aryl)–N, and C(aryl)–S bond formation. Angew. Chem. Int. Ed. 2003, 42,
5400–5449.
12. Recent articles about Chan-Evans-Lam-modified Ullmann condensation reac-
tions: (a) Quach, T. D.; Batey, R. A. Ligand- and base-free copper(II)-catalyzed C−N
bond formation: cross-coupling reactions of organoboron compounds with aliphatic
amines and anilines. Org. Lett. 2003, 5, 4397–4400. (b) Zhang, L.-L; Zhang, G.-Y.;
Zhang, M. L.; Cheng, J. Cu(OTf)2-mediated Chan-Lam reaction of carboxylic acids to
access phenolic esters. J. Org. Chem. 2010, 75, 7472–7474. (c) Wu, H.; Hynes, J. Jr.
Copper-catalyzed chlorination of functionalized arylboronic acids. Org. Lett. 2010, 12,
1192–1195. (d) Xu, J.-M; Wang, X.-Y.; Shao, C.-W.; Su, D.-Y.; Cheng, G.-L.; Hu, Y.-
F. Highly efficient synthesis of phenols by copper-catalyzed oxidative hydroxylation
of arylboronic acids at room temperature in water. Org. Lett. 2010, 12, 1964–1967.
(e) Xu, H.-J.; Zhao, Y.-Q.; Feng, T.; Feng, Y.-S. Chan–Lam-Type S-arylation of thiols

Synthesis of N-aryl-D-Glucosamines from Arylboronic Acids
423
with boronic acids at room temperature. J. Org. Chem. 2012, 77, 2878–2884. (f) Li,
J.-H.; Be´bastien, S.; Neuville, L.; Zhu, J.-P. Copper catalyzed N-arylation of amidines
with aryl boronic acids and one-pot synthesis of benzimidazoles by a Chan–Lam–Evans
N-arylation and C–H activation/C–N bond forming process. Org. Lett. 2012, 14,
5980–5983.
13. (a) Dai, J.-J.; Liu, J.-H.; Luo, D.-F.; Liu, L. Pd-catalysed decarboxylative Suzuki
reactions and orthogonal Cu-based O-arylation of aromatic carboxylic acids. Chem.
Commun. 2011, 47, 677–679. (b) Yang, C.-T.; Zhang, Z.-Q.; Liu, Y.-C.; Liu, L. Copper-
catalyzed cross-coupling reaction of organoboron compounds with primary alkyl halides
and pseudohalides. Angew. Chem. Int. Ed. 2011, 50, 3904–3907. (c) Zhu, C.; Li, G.-Q.;
Ess, D. H.; Falck, J. R.; Ku¨rti, L. Elusive metal-free primary amination of arylboronic
acids: synthetic studies and mechanism by density functional theory. J. Am. Chem. Soc.
2012, 134, 18253–18256. (d) Qi, Q.-Q.; Shen, Q.-L.; Lu, L. Copper-mediated aerobic flu-
oroalkylation of arylboronic acids with fluoroalkyl iodides at room temperature. J. Am.
Chem. Soc. 2012, 134, 6548–6551. (e) Li, X.-J.; Zhang, J.-L; Geng, Y.; Jin Z. Nickel-
catalyzed suzuki–miyaura coupling of heteroaryl ethers with arylboronic acids. J. Org.
Chem. 2013, 78, 5078–5084.
14. Wuts, P. G. M.; Greene, T. W. in “Greene’s Protective Groups in Organic Synthesis.”
4nd ed., John Wiley & Sons, 2007.
15. Silva, D. J.; Wang, H.-M.; Allanson, N. M.; Jain, R. K.; Sofia, M. J. Stereospe-
cific solution- and solid-phase glycosylations. synthesis of β-linked saccharides and con-
struction of disaccharide libraries using phenylsulfenyl 2-deoxy-2-trifluoroacetamido
glycopyranosides as glycosyl donors. J. Org. Chem. 1999, 64, 5926–5929.
16. Aly, M. R. E.; Schmidt, R. R. New diacylamino protecting groups for glucosamine.
Eur. J. Org. Chem. 2005, 4382–4392.
17. (a) Heathcock, C. H.; Ratcliffe, R. Stereoselective total synthesis of the guaiazu-
lenic sesquiterpenoids .alpha.-bulnesene and bulnesol. J. Am. Chem. Soc. 1971, 93,
1746–1757. (b) Czech, B. P.; Bartsch, R. A. Effect of amines on O-benzyl group hy-
drogenolysis. J. Org. Chem. 1984, 49, 4076–4078. (c) Sajiki, H.; Hirota, K. A novel
type of PdMC-catalyzed hydrogenation using a catalyst poison: Chemoselective inhibi-
tion of the hydrogenolysis for O-benzyl protective group by the addition of a nitrogen-
containing base. Tetrahedron 1998, 54, 13981–13996.
18. (a) Quach, T. D.; Batey, R. A. Copper(II)-catalyzed ether synthesis from aliphatic
alcohols and potassium organotrifluoroborate salts. Org. Lett. 2003, 5, 1381–1384.
(b) Yamamoto, Y.; Takizawa, M.; Yu, X.-Q.; Miyaura, N. Cyclic triolborates: air- and
water-stable ate complexes of organoboronic acids. Angew. Chem. Int. Ed. 2008, 47,
928–931. (c) Tzschucke, C. C.; Murphy, J. M.; Hartwig, J. F. Arenes to anilines and aryl
ethers by sequential Iridium-catalyzed borylation and copper-catalyzed coupling. Org.
Lett. 2007, 9, 761–764.