Synthesis of bis(glycosylamino)alkanes and bis(glycosylamino)arenes

Article abstract of DOI:10.1007/s11172-006-0205-3

The condensation of D-mannose and D-galactose with aliphatic and aromatic diamines afforded a series of bis(glycosylamino)alkanes and-arenes. A possible mechanism was proposed for the formation of 1,2-bis(β-D-glycosylamino) benzenes.

Full text of DOI:10.1007/s11172-006-0205-3

2890
Russian Chemical Bulletin, International Edition, Vol. 54, No. 12, pp. 2890—2898, December, 2005
Synthesis of bis(glycosylamino)alkanes and bis(glycosylamino)arenes
S. V. Metlitskikh,aꢀ A. M. Koroteev,a M. P. Koroteev,a A. S. Shashkov,b
A. A. Korlyukov,c M. Yu. Antipin,c A. I. Stash,d and E. E. Nifantieva
aMoscow Pedagogical State University,
3 Nesvizhskii per., 119021 Moscow, Russian Federation.
Fax: +7 (495) 246 7766. Eꢀmail: therion@hotmail.ru
bN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 199991 Moscow, Russian Federation.
Fax: +7 (495) 135 5328. Eꢀmail: shash@ioc.ac.ru
cA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (495) 135 5085. Eꢀmail: m_antipin@yahoo.com
dL. Ya. Karpov Research Physicochemical Institute,
10 ul. Vorontsovo Pole, 105064 Moscow, Russian Federation.
Fax: +7 (495) 975 2450. Eꢀmail: asta@xray.nifhi.ac.ru
The condensation of Dꢀmannose and Dꢀgalactose with aliphatic and aromatic diamines
afforded a series of bis(glycosylamino)alkanes and ꢀarenes. A possible mechanism was proꢀ
posed for the formation of 1,2ꢀbis(βꢀDꢀglycosylamino)benzenes.
Key words: bis(glycosylamino)alkanes, bis(glycosylamino)arenes, glycosylation, diamines,
Nꢀglycosylaminobenzenes, NMR spectroscopy, IR spectroscopy, Xꢀray diffraction analysis,
chelation.
NꢀGlycosides are abundant in nature and perform variꢀ
The problem of synthesis and study of the properties
of bis(glycosylamino)alkanes and ꢀarenes remains poorly
explored. Therefore, it was of interest to study specific
features of the synthesis of bis(glycosylamino)hydroꢀ
carbons, determine their structures, and characterize the
resulting compounds. We have earlier18 synthesized a seꢀ
ries of bis(glycosylamino)benzenes, which are the disacꢀ
charide derivatives.
We performed condensation of Dꢀmannose and Dꢀgaꢀ
lactose with 1,2ꢀ, 1,3ꢀ, and 1,4ꢀdiaminobenzenes, 1,2ꢀ
diaminoethane, 1,2ꢀ and 1,3ꢀdiaminopropanes, 1,4ꢀdiꢀ
aminobutane, 1,5ꢀdiaminopentane, and 1,6ꢀdiaminoꢀ
hexane. The following compounds were isolated as the
reaction products: 1,2ꢀ (2), 1,3ꢀ (3), and 1,4ꢀbis(βꢀDꢀ
mannopyranosylamino)benzene (4), 1,2ꢀbis(βꢀDꢀmannoꢀ
pyranosylamino)ethane (5), 1,2ꢀ (6) and 1,3ꢀbis(βꢀDꢀ
mannopyranosylamino)propane (7), 1,4ꢀbis(βꢀDꢀmannoꢀ
pyranosylamino)butane (8), 1,5ꢀbis(βꢀDꢀmannopyranoꢀ
sylamino)pentane (9), and 1,6ꢀbis(βꢀDꢀmannopyranosylꢀ
amino)hexane (10), respectively, and their galactose
anologs, viz., compounds 11—19.
ous bioregulatory functions. Some of them have found
use as drugs and ligands for the synthesis of metal comꢀ
plexes.1—3 Bis(glycosylamino)ethanes, which were used
as addends for coordination with salts of some transition
metals,3 were not isolated in the free state, and it was the
condensation products of monosaccharides with ethylꢀ
enediamine that were introduced into the complexation.
Numerous glycosylamines with both aliphatic4—10 and
aromatic aglycones11—16 have been synthesized by differꢀ
ent methods. At the same time, despite a variety of the
synthesized glycosylamines,
many representatives of this
class of carbohydrates are
characterized incompletely.
Probably, this is related to
high lability of glycosylꢀ
amines, which impedes their
use and determination of
their characteristics. The
aforesaid concerns, in parꢀ
ticular, bis(glycosylamiꢀ
no)alkanes and ꢀarenes. It
was assumed that the Schiff
bases of type 1 can be the reaction products of monosacꢀ
charides with oꢀphenylenediamine (see Ref. 17).
Compounds 2—19 were synthesized by the direct conꢀ
densation of monosaccharides with 2 equiv. of diamine in
80% ethanol at room temperature in the absence of catalysts.
The reaction with aliphatic diamines is faster than that
with aromatic diamines (except for that with oꢀphenyleneꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2793—2801, December, 2005.
1066ꢀ5285/05/5412ꢀ2890 © 2005 Springer Science+Business Media, Inc.

Synthesis of bis(glycosylamino)hydrocarbons
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 12, December, 2005 2891
mꢀ and pꢀphenylenediamines with monosaccharides took
4—10 h. We believe that this difference is caused by a
higher nucleophilicity of the nitrogen atoms of diamines
of the aliphatic series. The duration of glycosylation of
oꢀphenylenediamine is virtually comparable with that for
aliphatic diamines: the process is over in 2—5 h. Probꢀ
ably, this fact is in favor of a special mechanism of formaꢀ
tion of bisglycosides 2 and 11. Perhaps, the reaction of oꢀ
phenylenediamine with monosaccharides affords the
Schiff base (А), which gives intermediate В of the aminal
nature due to the nucleophilic addition of the NH2 group
to the C=N multiple bond (Scheme 1). Subsequent transꢀ
formations of aminal В involve the attack of the OH
group at the C(5) atom, producing Nꢀglycopyranoside C.
The glycosylation of the liberated amino group gives, fiꢀ
nally, bis(glycosylamino)benzene 2.
The fact that the reaction with 1,8ꢀdiaminonaphthaꢀ
lene affords only aminals 20 (Dꢀmannose derivative)
and 21 (Dꢀgalactose derivative), regardless of the amount
of monosaccharide introduced into the reaction and the
reaction temperature, can be regarded as an indirect proof
of the proposed mechanism. The sixꢀmembered diaza rings
are, most likely, more stable than the fiveꢀmembered ring
in intermediates В. Due to this, products 20 and 21 were
isolated in the free state (Scheme 2).
The structure of aminal 20 was proved by 13C and
1H NMR spectroscopy using the C—H (HSQC) and
H—H (COSY) correlations (Fig. 1). The signal for the
C(1) atom of the saccharide fragment is observed at δ 66.7,
and the chemical shift values of the C atoms of the carboꢀ
hydrate moiety unambiguously indicate its open form.
The highꢀfield signal for C(5) (δ 71.3) seems to be the
most indicative of the formation of the open form of the
diamine). For instance, the glycosylation of diaminoꢀ
alkanes completes within 1—6 h, while the reactions of
Scheme 1

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Russ.Chem.Bull., Int.Ed., Vol. 54, No. 12, December, 2005
Metlitskikh et al.
Scheme 2
condensation of 1,8ꢀdiaminonaphthalene with one molꢀ
ecule of monosaccharide, which also agrees with the mass
spectrometric data. Note that the protons bonded to the
N atoms in compound 20 are magnetically nonequivalent,
because they appear in the spectrum as two singlet signals
(δ 5.95 and 6.27), the difference between which (∆δ) is
0.32 ppm. The NH protons are nonequivalent due to their
diastereotopicity. In addition, the diastereotopicity is exꢀ
tended to the protons of the naphthylene fragment. For
1
example, the H NMR spectrum exhibits a divergence of
signals for the C(2)H and C(7)H groups (δ 6.41 and 6.57)
with ∆δ = 0.16. The protons of C(4)H and C(5)H appear
as two superimposed doublets, and the "diastereotopic"
difference between the chemical shifts of these protons
is 0.01 ppm. The protons of the C(3)H and C(6)H groups
are also nonequivalent, and their triplet signals are also
superimposed.
A substantial difference was revealed for the reaction
rates of the monosaccharides under study with diamines.
For instance, the mannosylation of diamines is over in
1—4 h, while galactose reacts completely in 5—10 h.
Dꢀmannose fragment. In the 1H NMR spectrum, the ratio
of integral intensities of signals for the aromatic protons
and protons of the carbohydrate fragment indicate the
a
δ
a
70
δ
70
80
80
90
90
100
110
120
130
100
110
120
7
6
5
4
δ
7
6
5
4
δ
b
δ
b
3.2
δ
4
5
6
7
3.6
4.0
4.4
4.8
5.2
7
6
5
4
δ
5.2
4.8
4.4
4.0
3.6
3.2
δ
Fig. 1. HSQC (а) and COSY (b) spectra of compound 20.
Fig. 2. HSQC (а) and COSY (b) spectra of compound 2.

Synthesis of bis(glycosylamino)hydrocarbons
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 12, December, 2005 2893
Table 1. Chemical shifts (δ) in the 13C NMR spectra of compounds 2—19 (DMSOꢀd6)
Comꢀ
pound
δ
Aglycone fragment
Carbohydrate fragments
С(1)
С(2)
С(3)
С(4)
С(5)
С(6)
С(1),
С(2),
С(3),
С(4),
С(5),
С(6),
C(1´)
C(2´)
C(3´)
C(4´)
C(5´)
C(6´)
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
134.4
146.9
138.1
45.3
51.5
43.4
44.8
44.8
44.9
135.4
149.8
139.4
45.5
51.9
43.9
44.9
45.2
45.0
134.4
99.3
114.9
45.3
46.9
30.7
27.8
29.9
30.0
135.4
98.2
115.3
45.5
47.9
30.5
27.8
30.2
30.1
114.5
146.9
114.9
—
20.3
43.4
27.8
24.6
26.9
113.0
149.8
115.3
—
119.3
104.0
138.1
—
—
—
44.8
29.9
26.9
118.6
104.6
139.4
—
119.3
129.2
114.9
—
—
—
114.5
104.0
114.9
—
—
—
81.9
81.6
82.4
87.6
86.6
87.4
87.3
87.3
87.3
86.1
86.4
86.4
82.4
82.5
82.3
82.7
82.1
82.7
71.4
71.3
71.4
71.6
71.6
71.5
71.4
71.4
71.5
70.4
70.3
70.3
71.4
71.6
71.5
71.6
71.6
71.5
74.4
74.6
74.6
74.8
74.8
74.8
74.7
74.7
74.7
73.8
73.8
73.6
74.6
74.8
74.5
74.5
74.8
74.9
67.1
67.2
67.2
67.6
67.7
67.6
67.6
67.6
67.6
68.4
68.5
68.8
67.2
67.2
67.3
67.2
67.4
67.3
77.8
77.8
77.8
78.0
77.9
77.9
77.9
77.8
77.9
75.6
75.7
75.5
77.8
77.7
77.8
77.8
78.0
77.9
61.3
61.3
61.3
61.8
61.8
61.7
61.7
61.7
61.7
60.6
60.5
60.8
61.3
61.3
61.3
61.3
61.2
61.4
—
—
—
44.8
30.0
118.6
132.8
115.3
—
—
—
—
45.2
30.1
44.9
113.0
104.6
115.3
—
—
—
—
—
20.6
43.9
27.8
24.6
26.9
—
—
44.9
30.2
26.9
45.0
Usually, glycosylation products 2—19 precipitated
spontaneously from the reaction mixture as white powꢀ
ders and were isolated in the pure state in 70—80% yields.
The individual character and structures of glycosylꢀ
amines 2—21 were proved by 13C NMR and IR spectroꢀ
scopy. The 13C NMR spectra of the synthesized comꢀ
pounds contain signals for all the constituent C atoms.
The signals for the anomeric C atoms are observed at
δ 81—86 for the aromatic derivatives and at δ 82—89 in
the case of bis(glycosylamino)alkanes (Table 1). This inꢀ
dicates the formation of the β,β´ꢀisomers. The HSQC and
COSY techniques were used to assign signals for the proꢀ
tons and carbon nuclei in compound 2 (Fig. 2).
pyranose.19 Most likely, the signals in the 13C NMR specꢀ
tra of mannopyranosylamines 3—10 can be attributed
to certain carbon nuclei similarly to compound 2, while
for derivatives 11—19 they are similar to those for
βꢀDꢀgalactopyranose (see Table 1). A comparison of the
1H NMR spectra of bisglycosides 2 and 11 shows a subꢀ
stantial difference in the chemical shifts of the protons of
the NH groups (δ 3.32 and 5.18, respectively). In addiꢀ
1
tion, the H NMR spectrum of glycoside 11 exhibits the
spinꢀspin coupling with J = 8.8 Hz between the H(1) and
H(2) protons, which indicates the βꢀstructure of galactoꢀ
sylamines 11—19.
The IR spectra of the synthesized compounds exhibit
a broad intense band in the region of 3550—3000 cm–1
,
The HSQC spectrum of compound 2 shows that the
signal for the anomeric protons lies at δ 4.70—4.73 and
the nuclei of the anomeric atoms resonate at δ 81.9. An
analysis of the crossꢀpeaks suggests that the highestꢀfield
which is characteristic of stretching vibrations of the OH
and NH groups and the CH fragments of the aromatic
system of compounds 2—4 and 11—13. This band reꢀ
mains almost unchanged on going from the aromatic
to aliphatic derivatives, and its position is independent
of the nature of monosaccharide. The same concerns
the intense characteristic bands at 1500—1400 and
1400—1310 cm–1 corresponding to bending vibrations
of the OH groups of the monosaccharides. Some changes
are observed for frequencies corresponding to stretchꢀ
ing vibrations of C—O of the alcohol groups and to viꢀ
brations of the deformational character of the NH fragꢀ
ments. On going from bis(glycosylamino)benzenes to
bis(glycosylamino)alkanes, the position and width of
bands corresponding to the C—O groups change from
1120—950 cm–1 (s) to 1140—835 cm–1 (m). The intensity
1
signal in the H NMR spectrum of compound 2 belongs
to the H(5) protons (H(5)/H(6´) correlation is observed)
and the multiplet with δ 3.36—3.46 is the superposition
of signals for the H(4) (crossꢀpeak H(4)/H(5)), H(3)
(crossꢀpeak H(3)/H(4)), and H(6´) atoms (crossꢀpeaks
H(6´)/H(5) and H(6´)/H(6)). The low intensity of the
H(3)/H(2) crossꢀpeak (δH(2) 3.75) indicates a weak couꢀ
pling of the equatorial (H(2)) and axial (H(3)) protons.
Note that the crossꢀpeaks H(5)/H(6) and H(1)/H(2)
1
are absent. Thus, in the H and 13C NMR spectra of
1,2ꢀbis(βꢀDꢀmannopyranosylamino)benzene, the posiꢀ
tions (but not the chemical shifts) of signals for the proꢀ
tons and carbon nuclei are similar to those for βꢀDꢀmannoꢀ

2894
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 12, December, 2005
Metlitskikh et al.
of the band at 1640—1550 cm–1 (s) corresponding to
stretching vibrations of the NH fragment of the aromatic
derivatives increases in comparison with the intensity of a
similar band in the spectra of the derivatives of aliphatic
diamines (1600—1540 cm–1 (w)), which is, most likely, a
consequence of superposition of variableꢀintensity bands
corresponding to the vibrations of the benzene ring on
the band of stretching vibrations of the NH groups of
bis(glycosylamino)arenes. The IR spectra of compounds
5—10 and 14—19 also contain bands at 750—700 cm–1 (s).
Rocking vibrations of the CH2 groups are responsible for
C(9)
C(7)
C(10)
O(2)
C(1)
C(8)
N(1)
C(3)
O(3)
C(4)
C(2)
C(11)
C(12)
C(5)
C(15)
O(1)
O(5)
O(4)
Fig. 5. Structure of NꢀβꢀDꢀgalactopyranosylaniline (23).
the bands at 750—700 cm–1
.
have a chair conformation with deviations of the C(1) and
C(4) atoms from the C(2)C(3)C(5)O(1) plane of 0.68 and
0.66 Å on the average (for the ∆1 and ∆4 parameters, see
Table 2). The angle between the C(2)C(3)C(5)O(1) and
C(2´)C(3´)C(5´)O(1´) planes of two carbohydrate fragꢀ
ments in the molecule of 2 is 69.7°. The angles between
the C(2)C(3)C(5)O(1) planes of the carbohydrate fragꢀ
ments and phenyl substituents in molecules 22 and 23 are
42.2 and 39.3°, respectively.
In crystal, the molecules of 2, 22, and 23 form threeꢀ
dimensional frameworks linked through hydrogen bonds
between the OH and NH groups. The O...O interatomic
distances range from 2.75 to 3.07 Å, and the O—H—O
angles are 146—171°. Thus, the intermolecular hydrogen
bonds O—H...O correspond to weak bonds of this type.
The N—H—O bonds can also be characterized as weak:
the N...O distances and N—H—O bond angles in molꢀ
ecules 22 and 23 are equal to 3.061 and 3.139 Å, 176
and 130°, respectively.
The structure of product 2 was also proved by Xꢀray
diffraction analysis. The general view of a molecule of
1,2ꢀbis(βꢀDꢀmannopyranosylamino)benzene 2 is shown
in Fig. 3.
It seemed of interest to compare the geometric paꢀ
rameters of a molecule of the synthesized "crossꢀlinked"
Nꢀglycoside and Nꢀglycosides of the chosen monosacꢀ
charides with the phenyl substituent as the aglycone. For
this purpose, we obtained and characterized for the first
time by Xꢀray diffraction analysis NꢀβꢀDꢀmannopyranoꢀ
sylaniline (22) and NꢀβꢀDꢀgalactopyranosylaniline (23).
The general views of molecules of Nꢀglycosides 22 and 23
are shown in Figs 4 and 5. Selected structural parameters
and crystallographic data for compounds 2, 22, and 23
are presented in Tables 2 and 3.
The bond lengths and bond angles in compounds 2,
22, and 23 are similar to the values characteristic of subꢀ
stances of this class. In all compounds under study, the
carbohydrate fragments correspond to the βꢀform and
Bis(glycosylamino)hydrocarbons were isolated from
the reaction mixture as stable hydrates. In our opinion,
O(3´)
C(3´)
C(2´)
C(4)
Table 2. Selected bond lengths and bond angles in molecules of
glycosylamines 2, 22, and 23
O(4´)
O(2´)
O(2)
O(3)
O(6)
C(1´)
C(3)
C(4´)
C(5´)
N(1´)
C(2)
Parameter
2
22
23
N(1)
O(4)
C(6)
O(1´)
C(11)
C(10)
C(12)
Bond
d/Å
O(1)
C(5)
C(7) C(1)
C(8)
O(1)—C(5)
O(1)—C(1)
O(2)—C(2)
O(3)—C(3)
O(4)—C(4)
O(6)—C(6)
N(1)—C(1)
N(1)—C(7)
O(5)—C(15)
1.429(6)
1.445(5)
1.443(7)
1.430(6)
1.432(7)
1.412(7)
1.411(7)
1.407(3)
—
1.438(5)
1.470(5)
1.436(5)
1.435(5)
1.436(4)
—
1.412(5)
1.394(5)
1.432(5)
0.68
1.423(3)
1.450(3)
1.425(3)
1.439(3)
1.442(3)
—
1.417(3)
1.404(3)
1.428(3)
0.68
C(6´)
O(6´)
C(9)
Fig. 3. Structure of 1,2ꢀbis(βꢀDꢀmannopyranosylamino)benꢀ
zene (2).
C(9)
a
∆
C(10)
C(8)
0.65
0.69
1
b
C(1)
C(3)
∆
0.64
0.71
4
N(1)
C(2)
Angle
ω/deg
O(3)
C(4)
C(11)
C(7)
C(5)—O(1)—C(1) 111.4(5)
C(1)—N(1)—C(7) 124.2(4)
N(1)—C(1)—O(1) 110.1(4)
113.3(3)
122.2(4)
108.1(3)
112.2(2)
120.3(2)
109.3(2)
C(12)
C(5)
O(1)
O(2)
O(4)
O(5)
C(15)
a Shift of the C(1) atom from the plane.
b Shift of the C(4) atom from the plane.
Fig. 4. Structure of NꢀβꢀDꢀmannopyranosylaniline (22).

Synthesis of bis(glycosylamino)hydrocarbons
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 12, December, 2005 2895
Table 3. Selected parameters of Xꢀray diffraction experiment and crystallographic data for compounds 2, 22, and 23
Parameter
2
22
23
Molecular formula
Molecular weight
T/K
C
18H30N2O11
450.44
293
C12H17NO5
255.27
C12H16NO5
254.26
110
110
Space group
P21
P212121
P21
a/Å
b/Å
c/Å
28.518(6)
6.4402(13)
6.7366(13)
28.002(6)
4.7541(4)
8.6869(9)
13.9719(14)
96.219(2)
573.62(10)
1.472
5.2740(10)
13.708(3)
93.94(3)
2056.9(7)
1.455
β/deg
V/Å3
1214.9(4)
1.396
4
dcalc/g cm–3
Z
2
2
2θmax/deg
F(000)
64.94
960
60.12
544
60.08
270
Scan mode
θ/2θ
ω
ω
Number of collected reflections
Number of independent reflections (Rint
Number of observed reflections with I > 2σ(I )
Number of refined parameters
Absorption coefficient/cm–1
R1 (I > 2σ(I ))
2046
1958 (0.122)
1292
10116
3540 (0.0995)
1247
5534
3027 (0.0324)
2435
)
281
1.04
0.0497
0.1313
163
1.09
0.0521
0.1612
227
1.15
0.0602
0.1531
wR2
water of crystallization often serves as a causative agent
for the destruction of Nꢀglycosides on their heating and
prolong storage. These compounds can be transformed
into anhydrous forms by dissolution of Nꢀglycosides in
anhydrous DMF containing 20—25% (v/v) benzene folꢀ
lowed by vacuum azeotropic distillation of water of crysꢀ
tallization together with benzene.
compound 2 are the same as those in the complex of 2
with pyridine. The melting point of the complex differs
substantially from that for compound 2 and equals
161—164 °C (decomp.). It is most likely that DMF is also
coordinated with bisglycosides to form inclusion comꢀ
pounds. Interestingly, the "crossꢀlinked" saccharides faꢀ
vor the solubilization of alkali metal halides (e.g., NaCl,
NaBr, KCl, and KBr) in methanol and ethanol. We
found that these salts are much more rapidly dissolved
in alcoholic solutions of bis(βꢀDꢀmannopyranosylamiꢀ
no)alkanes 5—10 than in alcohols containing no comꢀ
pounds 5—10.
Prolong storage of solutions of bisglycosides results in
anomerization, whose rate decreases in the following orꢀ
der of solvents: water, pyridine, DMSO. The formation of
αꢀanomers (exemplifed by glycosides 2—4) is distinctly
observed in the 13C NMR spectra containing signals with
chemical shifts at δ 84—86. The dissolution of compounds
2—19 in water is accompanied by their gradual destrucꢀ
tion to free carbohydrates and the corresponding diamines.
The destruction is especially fast in the presence of acids.
Glycosides of the aromatic series are most stable toward
hydrolysis. Bis(galactosylamino)hydrocarbons are someꢀ
what more stable than the mannose analogs. Attempts to
determine the optical rotation values of the synthesized
compounds were unsuccessful, because the glycosylamines
are hydrolyzed in water, which is often used as the solvent
for these purposes. Complexation occurs in DMF and
pyridine. Solutions of compounds 2—19 in DMSO (at
concentrations higher than 0.5 g mL–1) are highly visꢀ
cous, which impedes strongly the determination of [α]D.
All the compounds synthesized are soluble in the same
solvents in which free monosaccharides pass into soluꢀ
tion. Note that solutions of the synthesized bisglycosides
in DMF and especially in pyridine rapidly solidify. This
can be related to the chelation of these solvents with
Nꢀglycosides to form inclusion complexes. A complex of
1,2ꢀbis(βꢀDꢀmannopyranosylamino)benzene (2) with pyꢀ
ridine was isolated in the individual state and characterꢀ
1
ized by H NMR. An analysis of the integral intensity of
signals for the protons of pyridine and bisglycoside sugꢀ
gests the ratio of the constituents of the complex to be
1
1 : 3, respectively. According to the H NMR data, coorꢀ
dination with pyridine involves protons of the C(2)OH
and C(6)OH groups and, most likely, of the NH group.
This conclusion is based on the fact that the signals for
protons of the C(2)OH and C(6)OH groups in the
1H NMR spectrum of the isolated complex differ by
0.07—0.08 ppm from the signals of the same groups in the
spectrum of compound 2. The signals for the H(1) proꢀ
tons exhibit an upfield shift by 0.09 ppm, which can be
caused by the participation of the NH groups in coordiꢀ
nation (the signal for the protons of the NH group in
the complex is also shifted toward a multiplet with
δ 3.39—3.47). The chemical shifts of other protons in

2896
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 12, December, 2005
Metlitskikh et al.
2 H(3), 2 H(6´)); 3.64 (dd, 2 H, 2 H(6)); 3.76 (dd, 2 H, 2 H(2));
4.25 (m, 2 H, 2 C(6)OH); 4.65 (m, 2 H, 2 C(4)OH); 4.69 (m,
2 H, 2 C(3)OH); 4.72 (m, 2 H, 2 H(1)); 4.81 (m, 2 H, 2 C(2)OH);
aglycone fragment: 6.65 (m, 2 H, C(3)H, C(6)H); 6.79 (m, 2 H,
C(4)H, C(5)H); pyridine: 7.36 (dd, 2 H, C(3)H, C(5)); 7.77 (m,
1 H, C(4)H); 8.57 (d, 2 H, C(2)H, C(6)H).
Thus, in the present work, we showed a possibility to
synthesize bis(glycosylamino)hydrocarbons of different
chemical nature by direct condensation in the absence of
catalysts, suggested the formation of an aminal intermeꢀ
diate in the synthesis of the oꢀphenylenediamine derivaꢀ
tives, and described some physicochemical properties of
the synthesized compounds.
1,2ꢀBis(βꢀDꢀgalactopyranosylamino)benzene (11). 1H NMR,
δ, carbohydrate fragment: 3.41—3.57 (m, 10 H, 2 H(2), 2 H(3),
2 H(4), 2 H(5), 2 H(6)); 3.74 (m, 2 H, 2 H(6´)); 4.23 (t, 2 H,
2 C(6)OH, 3JOH,H(6) = 3.6); 4.29 (dd, 2 H, 2 H(1), 3JH(1),H(2)
=
Experimental
8.8 Hz); 4.48 (m, 2 H, 2 C(4)OH)*; 4.69 (d, 2 H, 2 C(2)OH,
3
3J = 5.2 Hz)*; 4.79 (d, 2 H, 2 C(3)OH, J = 3.4 Hz)*; 5.18 (d,
13
C NMR spectra were recorded on a Bruker ACꢀ200 specꢀ
1 H, NH, 3JNH,H(1) = 9.1 Hz); aglycone fragment: 6.59 (m, 2 H,
C(3)H, C(6)H); 6.70 (m, 2 H, C(4)H, C(5)H).
trometer with an operating frequency of 50 MHz in DMSOꢀd6
1
as the solvent with Me4Si as the internal standard. H NMR
Synthesis of bis(βꢀDꢀglycopyranosylamino)alkanes 5—10 and
14—19 (general procedure). A suspension of anhydrous monosacꢀ
charide (10 g, 55.55 mmol) in 80% ethanol (250 mL) was stirred
at room temperature with a twofold excess of the corresponding
diamine. After the end of glycosylation, precipitates that formed
were filtered off, washed three times with 95.5% ethanol preꢀ
heated to 50 °C, and dried in vacuo. The resulting products were
white powders with a taste from burning to bitterꢀsweet, soluble
in pyridine, DMF, DMSO, methanol, and water (hydrolysis),
and poorly soluble in ethanol. The duration of reactions, yields,
melting points, and elemental analysis data are given in Table 4.
The spectral characteristics of the products are presented in
Tables 1 and 5.
spectra of compounds 2 and 20 were obtained on a Bruker
DRXꢀ500 spectrometer with an operating frequency of 500 MHz.
1H NMR spectra of compound 11, the complex of 2 with pyriꢀ
dine, and compound 2 (for comparison with the 1H NMR specꢀ
trum of the complex of 2 with pyridine) were measured on a
Bruker Hꢀ250 spectrometer with an operating frequency of
250 MHz in DMSOꢀd6 as the solvent with Me4Si as the internal
standard.
IR spectra were obtained on a Specord IRꢀ75 instrument
using NaCl lenses. Mass spectra were measured on a Finnigan
LCQ (electrospray, (ESI)) instrument.
Synthesis of bis(βꢀDꢀglycopyranosylamino)benzenes 2—4 and
11—13 (general procedure). A suspension of the corresponding
anhydrous monosaccharide (10 g, 55.55 mmol) in 80% ethanol
(250 mL) was stirred at room temperature with the correspondꢀ
ing phenylenediamine (3 g, 27.75 mmol). After the end of the
reaction, precipitates that formed were filtered off, washed three
times with 95.5% ethanol preheated to 50 °C, and dried in vacuo.
The glycosylation products were white powders with a very bitꢀ
ter taste, soluble in pyridine, DMF, DMSO, and water (hydroꢀ
lysis), and poorly soluble in methanol and ethanol. The duration
of reactions, yields, melting points, and elemental analysis data
are given in Table 4. The spectral characteristics of the products
are presented in Tables 1 and 5.
1 ꢀ ( 2 , 3 ꢀ D i h y d r o ꢀ 1 H ꢀ p e r i m i d i n ꢀ 2 ꢀ y l ) p e n t a n e ꢀ
1(S),2(S),3(R),4(R),5ꢀpentol (20). A suspension of anhydrous
Dꢀmannose (5 g, 27.77 mmol) in 80% ethanol (100 mL) was
stirred at room temperature with 1,8ꢀdiaminonaphthalene (4.4 g,
27.85 mmol). After the end of the reaction, the precipitate was
filtered off, washed three times with 95.5% ethanol preheated to
40 °C, and dried. A white powder soluble in pyridine, DMSO,
DMF, and water (slow hydrolysis) was obtained. 13C NMR,
δ, carbohydrate fragment: 63.8 (C(6)); 66.7 (C(1)); 69.8 (C(4));
70.6 (C(2)); 71.0 (C(3)); 71.3 (C(5)); naphthalene fragment:
104.3 (C(2)); 104.9 (C(7)); 112.8 (C(10)); 115.1 (C(4)); 115.2
(C(5)); 126.9 (C(3), C(6)); 134.4 (C(9)); 142.6 (C(8)); 142.8
(C(1)). 1H NMR, δ, carbohydrate fragment: 3.43 (m, 1 H, H(6´),
2JH(6´),H(6) = 10.3 Hz); 3.53 (m, 1 H, H(5), 3JH(5),H(4) = 8.2 Hz);
3.60—3.66 (m, 3 H, H(2), H(4), H(6)); 3.89 (t, 1 H, H(3),
1,2ꢀBis(βꢀDꢀmannopyranosylamino)benzene (2). 1H NMR
(500 MHz), δ, carbohydrate fragment: 3.15 (dd, 2 H, 2 H(5));
3.32 (s, 2 H, NH); 3.37 (m, 2 H, 2 H(4)); 3.41 (m, 2 H, 2 H(3));
3.44 (m, 2 H, 2 H(6´)); 3.66 (dd, 2 H, 2 H(6)); 3.75 (dd, 2 H,
3
3JH(3),H(2) = 7.8 Hz); 4.30 (d, 1 H, C(4)OH, J = 7.5 Hz); 4.38
3
2 H(2)); 4.33 (t, 2 H, 2 C(6)OH, J = 5.5 Hz); 4.66—4.73 (m,
3
(m, 1 H, C(6)OH); 4.44 (d, 1 H, H(1), JH(1),H(2) = 5.8 Hz);
6 H, 2 C(4)OH, 2 C(3)OH, 2 H(1)); 4.88 (d, 2 H, 2 C(2)OH,
4.46 (d, 1 H, C(5)OH, 3J = 5.4 Hz); 4. 86 (d, 1 H, C(3)OH, 3J =
7.2 Hz); 4.95 (d, 1 H, C(2)OH, 3J = 6.6 Hz); naphthalene
fragment: 5.95 (s, 1 H, H(8), NH); 6.27 (s, 1 H, H(1), NH);
3J = 5.5 Hz); aglycone fragment: 6.64 (m, 2 H, C(3)H, C(6)H);
1
6.78 (m, 2 H, C(4)H, C(5)H). H NMR (250 MHz), δ, carboꢀ
hydrate fragment: 3.14 (dd, 2 H, 2 H(5)); 3.29 (s, 2 H, NH);
3
6.41 (d, 1 H, H(2), JH(2),H(3) = 7.3 Hz)**; 6.57 (d, 1 H, H(7),
3.38—3.45 (m, 6 H, 2 H(4), 2 H(3), 2 H(6´)); 3.67 (dd, 2 H,
3JH(7),H(6) = 7.3 Hz)**; 6.94 (d, H, H(4), 3JH(4),H(3) = 7.3 Hz)**;
3
2 H(6)); 3.75 (dd, 2 H, 2 H(2)); 4.33 (t, 2 H, 2 C(6)OH, J =
3
6.96 (d, H, H(5), JH(5),H(6) = 7.3 Hz)**; 7.12 (t, H, H(3))**;
5.8 Hz); 4.62 (m, 2 H, 2 C(4)OH); 4.70 (m, 2 H, 2 C(3)OH);
7.13 (t, H, H(6))**. Mass spectrum, m/z (Irel (%)): 320.2 (14)
[М]+, 319.1 (100) [М – H]+, 259.1 (5), 211.1 (6), 202.1 (15),
169.3 (88), 168.2 (36), 115.1 (2).
1 ꢀ ( 2 , 3 ꢀ D i h y d r o ꢀ 1 H ꢀ p e r i m i d i n ꢀ 2 ꢀ y l ) p e n t a n e ꢀ
1(R),2(S),3(S),4(R),5ꢀpentol (21). 1,8ꢀDiaminonaphthalene
(4.4 g, 27.85 mmol) was added to a suspension of anhydrous
3
4.81 (d, 2 H, 2 H(1)); 4.88 (d, 2 H, 2 C(2)OH, J = 5.5 Hz);
3
aglycone fragment: 6.65 (m, 2 H, C(3)H, JH(3),H(4) = 5.8 Hz,
3JH(3),H(5) = 3.6 Hz, C(6)H); 6.80 (m, 2 H, C(4)H, C(5)H).
Complex of 2 with pyridine. Compound 2 (1 g) was dissolved
in pyridine (10 mL) at 25 °C. After 5—7 min, the solution
transformed into a gel, which was filtered off, triply washed with
ethanol, and dried in vacuo to a constant weight. The yield
was 0.68 g (66.8%); white powder with a bitter taste; m.p.
* The assignment of signals of the protons of the OH groups can
be opposite.
1
161—164 °C (decomp.). H NMR, δ, carbohydrate fragment:
3.15 (dd, 2 H, 2 H(5)); 3.39—3.47 (m, 8 H, 2 NH, 2 H(4),
** The assignment of signals can be opposite.

Synthesis of bis(glycosylamino)hydrocarbons
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 12, December, 2005 2897
Table 4. Duration of reactions (τ), yields, melting points, and elemental analysis data for compounds 2—21
Comꢀ
pound
τ/h
Yield
(%)
M.p./°C
(decomp.)
Found
Calculated
Molecular
formula
(%)
C
H
N
2
2—2.5
3.5—4
3.5—4
2—3
79
73
78
85
82
86
86
83
86
73
75
76
85
73
76
86
86
86
68
60
195—197
203—205
188—190
143—145
152—154
149—151
130—132
140—142
110—112
185—186
197—200
205—207
158—160
156—158
148—150
135—137
132—133
130—131
214—216
232—235
46.84
46.15
48.08
48.00
48.12
48.00
41.82
41.79
43.31
43.26
44.56
43.26
44.70
44.64
45.80
45.94
47.21
47.15
46.82
46.15
48.84
48.00
46.93
48.0
41.89
41.79
43.42
43.26
43.35
43.26
44.76
44.64
45.78
45.94
47.30
47.15
59.87
59.99
59.92
59.99
7.01
6.89
6.76
6.71
6.76
6.71
7.60
7.51
7.80
7.75
7.99
7.75
7.95
7.96
7.98
8.16
8.39
8.35
7.09
6.89
6.81
6.71
6.95
6.71
7.66
7.51
7.86
7.75
7.84
7.75
7.98
7.96
7.95
8.16
8.41
8.35
6.24
6.29
6.21
6.29
5.62
5.98
6.24
6.22
6.25
6.22
6.70
6.96
6.75
6.73
6.81
6.73
6.53
6.51
6.23
6.30
6.13
6.11
5.77
5.98
6.33
6.22
6.40
6.22
6.69
6.96
6.76
6.73
6.78
6.73
6.60
6.51
6.25
6.30
6.14
6.11
8.70
8.74
8.71
8.74
C18H28N2O10•2H2O
C18H28N2O10•H2O
C18H28N2O10•H2O
C14H28N2O10•H2O
C15H30N2O10•H2O
C15H30N2O10•H2O
C16H32N2O10•H2O
C17H34N2O10•H2O
C18H36N2O10•H2O
C18H28N2O10•2H2O
C18H28N2O10•H2O
C18H28N2O10•H2O
C14H28N2O10•H2O
C15H30N2O10•H2O
C15H30N2O10•H2O
C16H32N2O10•H2O
C17H34N2O10•H2O
C18H36N2O10•H2O
C16H20N2O5
3
4
5
6
2—3
7
2—3
8
2—2.5
2.5—3
2.5—3
5—5.5
8—10
8—10
6.5—6
6.5—6
5—6
9
10
11
12
13
14
15
16
17
18
19
20
21
5—6
5—6
5—6
2—3
6—7
C16H20N2O5
Dꢀgalactose (5 g, 27.77 mmol) in 80% ethanol (100 mL). The
mixture was stirred for 6 h, and then the precipitate was filtered
off, triply washed with warm ethanol, and dried. Compound 21,
which is soluble in pyridine, DMSO, DMF, and water (slow
hydrolysis), was obtained. 13C NMR, δ, carbohydrate fragment:
60.8 (C(6)); 66.6 (C(1)); 67.3 (C(4)); 71.4 (C(2)); 70.8 (C(3));
71.4 (C(5)); naphthalene fragment: 104.5 (C(2)); 104.8 (C(7));
112.6 (C(10)); 115.5 (C(4)); 115.4 (C(5)); 126.5 (C(3), C(6));
133.7 (C(9)); 142.8 (C(8)); 142.9 (C(1)).
NꢀβꢀDꢀMannopyranosylaniline (22). A mixture of anhydrous
Dꢀmannose (5 g) and aniline (2.6 g) was homogenized in water
(3 mL). Then water was slowly distilled off with weak heating
in vacuo of a waterꢀjet pump. The mixture was kept in vacuo
for 2 h. The product formed upon glycosylation was recrystalꢀ
lized from hot ethanol. The resulting white precipitate was filꢀ
tered off, washed with ethanol, and dried in vacuo. The yield was
5.6 g (79%), m.p. 219—220 °C (cf. Ref. 21: m.p. 181 °C
(decomp.)). 13C NMR, δ, carbohydrate fragment: 61.4 (C(6));
67.2 (C(4)); 71.3 (C(2)); 74.6 (C(3)); 77.9 (C(5)); 81.5 (C(1));
aglycone fragment: 113.8 (C(2), C(6)); 117.5 (C(4)); 128.9
(C(3), C(5)); 146.4 (C(1)).
NꢀβꢀDꢀGalactopyranosylaniline (23) was synthesized simiꢀ
larly to 22 from anhydrous Dꢀgalactose (5 g) and aniline (2.6 g).
The yield was 85%, white powder, m.p. 176—178 °C (cf. Ref. 11:
m.p. 159 °C (decomp.)). 13C NMR, δ, carbohydrate fragment:
60.6 (C(6)); 68.5 (C(4)); 70.3 (C(2)); 74.3 (C(3)); 75.6 (C(5));

2898
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 12, December, 2005
Metlitskikh et al.
Table 5. IR spectroscopic data for compounds 2—19
Comꢀ
pound
ν/cm–1
ν(OH), ν(NH), ν(C=C)
ν(CH arom.)
δ(NH)
δ(C=C)
δ(OH)
ν(C—O)
ν(CH2)
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
3250
3400
3400
3300
3300
3300
3300
3300
3300
3400
3400
3400
3300
3300
3300
3300
3300
3300
1650
1650
1650
—
—
—
—
—
—
1655
1650
1655
—
—
—
—
—
—
1560
1615
1615
1555
1550
1550
1550
1550
1555
1620
1610
1615
1555
1550
1550
1550
1555
1550
1470
1515
1510
—
—
—
—
—
—
1515
1510
1510
—
—
—
—
—
—
1415, 1335
1455, 1375
1450, 1370
1415, 1340
1415, 1330
1415, 1330
1410, 1330
1410, 1335
1410, 1335
1450, 1370
1455, 1370
1450, 1375
1410, 1330
1415, 1335
1410, 1335
1410, 1330
1410, 1335
1415, 1330
1020
1060
1060
1050
1055
1050
1055
1050
1050
1065
1065
1060
1050
1050
1050
1055
1050
1050
—
—
—
790, 680
795, 685
790, 680
790, 685
790, 680
795, 680
—
—
—
790, 685
790, 680
795, 685
790, 680
790, 685
790, 680
85.7 (C(1)); aglycone fragment: 113.3 (C(2), C(6)); 117.0 (C(4));
128.8 (C(3), C(5)); 147.4 (C(1)).
5. J. Erickson, J. Am. Chem. Soc., 1955, 77, 2839.
6. G. Ames and T. King, J. Org. Chem., 1962, 27, 390.
7. J. Hodge and C. Rist, J. Am. Chem. Soc., 1955, 74, 1494.
8. E. Mitts and R. Hixon, J. Am. Chem. Soc., 1944, 66, 483.
9. M. Wolfrom, R. Schütz, F. Liebe, and J. Cavalieri, J. Am.
Chem. Soc., 1949, 71, 3518.
10. F. Micheel and G. Hagemann, Ber., 1960, 93, 2381.
11. B. Sorokin, Ber., 1886, 19, 513.
12. R. Kuhn and F. Weygand, Ber., 1937, 70, 769.
13. J. Honeyman and A. Tatchell, J. Chem. Soc., 1950, 967.
14. S. Adachi, Carbohydr. Res., 1969, 10, 165.
15. F. Weygand, Ber., 1940, 73, 1259.
16. O. William, O. Joanne, and O. Charles, Carbohydr. Res.,
2000, 326, No. 104.
17. P. Griess and G. Harrow, Ber., 1887, 20, 281.
18. S. V. Metlitskikh, M. P. Koroteev, and E. E. Nifantyev, Izv.
Akad. Nauk, Ser. Khim., 2005, 1235 [Russ. Chem. Bull., Int.
Ed., 2005, 54, 1272].
Xꢀray diffraction study of crystals of 2, 22, and 23. Experiꢀ
ments were carried out on Bruker Smart CCD 1000 (for 22
and 23) and Enraf—Nonius CADꢀ4 (for glycosylamine 2)
diffractometers. The structures were solved by a direct method
and refined by the fullꢀmatrix leastꢀsquares method for F 2 in the
anisotropic approximation for nonꢀhydrogen atoms. Hydrogen
atoms of hydroxyl groups were localized from the difference
Fourier syntheses imposing additional constraints in terms of
the riding model. Attempts to localize the hydrogen atoms of the
solvate water molecule in structure 2 were unsuccessful. All
calculations were performed using the SHELXTL PLUS proꢀ
gram complex (version 5.10).20 The crystallographic parameters
and selected details of Xꢀray diffraction experiments are preꢀ
sented in Table 3. The coordinates of atoms were deposited with
the Cambridge Structure Database.
19. R. Kasai, M. Okihara, J. Asakawa, K. Mizutani, and
O. Tanaka, Tetrahedron, 1979, 35, 1427.
References
20. G. M. Sheldrick, SHELXTLꢀ97, Version 5.10, Bruker AXS
Inc., Madison, WIꢀ53719, USA, 1997.
21. F. Weygand, Ber., 1939, 72, 1663.
1. Yu. A. Zhdanov and Yu. E. Alekseev, Usp. Khim., 2002, 71,
1090 [Russ. Chem. Rev., 2002, 71 (Engl. Transl.)].
2. S. Yano, Coord. Chem. Rev., 1988, 92, 113.
3. T. Tanase, K. Mano, and Y. Yamamoto, Inorg. Chem., 1993,
32, 3995.
Received February 14, 2005;
4. J. Hodge and C. Rist, J. Am. Chem. Soc., 1953, 75, 316.
in revised form December 8, 2005