Synthesis of β-d-glucopyranosyl-and β-d-galactopyranosylamines from 4-bromo-3-methylaniline and 2-amino-5-bromopyridine

Article abstract of DOI:10.1007/s11172-008-0350-y

The possibility of coupling of d-glucose and d-galactose with 4-bromo-3-methylaniline, 2,4,6-tribromoaniline, and 2-amino-5-bromopyridine was studied. The substituent in the aromatic ring was found to influence the conditions and possibility of the reacti

Full text of DOI:10.1007/s11172-008-0350-y

Russian Chemical Bulletin, International Edition, Vol. 57, No. 11, pp. 2443—2445, November, 2008
2443
Synthesis of βꢀDꢀglucopyranosylꢀ and βꢀDꢀgalactopyranosylamines
from 4ꢀbromoꢀ3ꢀmethylaniline and 2ꢀaminoꢀ5ꢀbromopyridine
I. V. Kulakov,a A. I. Il´in,b Zh. A. Kabyl,b and A. M. Gazalieva
aInstitute of Organic Synthesis and Coal Chemistry of the Republic of Kazakhstan,
1 ul. Alikhanova, 100008 Karaganda, Republic of Kazakhstan.
Fax: +7 (7 7212) 413 866. Eꢀmail: ivanku1@mail.ru
bScientific Center for Antiinfectious Drugs,
84 ul. Auezova, 050008 Almaty, Republic of Kazakhstan.
Fax: +7 (7 7272) 266 5229
The possibility of coupling of Dꢀglucose and Dꢀgalactose with 4ꢀbromoꢀ3ꢀmethylaniline,
2,4,6ꢀtribromoaniline, and 2ꢀaminoꢀ5ꢀbromopyridine was studied. The substituent in the
aromatic ring was found to influence the conditions and possibility of the reaction. The yields
of βꢀDꢀglucopyranosylꢀ and βꢀDꢀgalactopyranosylamines from 4ꢀbromoꢀ3ꢀmethylaniline and
2ꢀaminoꢀ5ꢀbromopyridine were 50—65%; 2,4,6ꢀtribromoaniline did not react at all.
Key words: Nꢀglycosylamines, Dꢀglucose, Dꢀgalactose, 4ꢀbromoꢀ3ꢀmethylaniline, 2,4,6ꢀtriꢀ
bromoaniline, 2ꢀaminoꢀ5ꢀbromopyridine.
Permanent development and application to clinical
practice of novel drugs, especially antibacterial and antiꢀ
viral ones, are prompted by not only a seriously deterioꢀ
rated environmental situation favoring the progressive
growth of some diseases, but also the soꢀcalled drug resisꢀ
tance of many pathogenic bacteria and viruses.1,2 It is
known that the development of drug resistance to almost
all currently existing drugs reflects the natural adaptation
of species to the environment.
with a broad spectrum of pharmacological activities.9 The
presence of halogen atoms in drug molecules strongly
influences the physiological activity by way of enhancing
the lipophilicity of drugs, which facilitates their penetraꢀ
tion through biomembranes.10 In addition, halogen deriꢀ
vatives of pyrimidineꢀbased glycosides are widely used
in medical practice as potent antiviral drugs (e.g., 5ꢀiodoꢀ
2´ꢀdeoxyuridine, or idoxuridine, is employed in the
chemotherapy of herpes11).
Functionalization of monosaccharides by way of inꢀ
troducing active pharmacophore groups into their molꢀ
ecules can serve as a tool for the design of new biologiꢀ
cally active compounds. In addition, carbohydrateꢀconꢀ
taining biologically active compounds are known to be
more soluble in water, less toxic, and more convenient for
targeted drug delivery and penetration into cells.3,4
NꢀGlycosylamines are coming into ever increasing use
for the synthesis of natural glycopeptides, their analogs,
and glycoconjugates to be employed in various biological
investigations.5—7 Much attention given by chemists,
biochemists, and biologists to Nꢀglycosylamines is due
to their formation under biological conditions from carꢀ
bohydrates and alkylꢀ and arylamines. Pharmacologists
consider Nꢀglycosylamines to be potential sources of
new drugs.8
In connection with this, we tried to obtain new haloꢀ
genꢀcontaining Nꢀglycosylamines from haloaniline and
halopyridine derivatives.
Earlier,12 we have synthesized Nꢀglycosylamines from
Dꢀglucose and Dꢀgalactose and 4ꢀbromoꢀ and 4ꢀiodoꢀ
anilines. Noncatalytic coupling of Dꢀglucose or Dꢀgalacꢀ
tose with 4ꢀiodoaniline or 4ꢀbromoaniline proceeds rather
smoothly in 95% ethanol at 60—70 °C and is completed
in 4—5 h.
To extend the range of halogenꢀcontaining Nꢀglycoꢀ
sylamines, we studied this coupling reaction with
4ꢀbromoꢀ3ꢀmethylaniline, 2,4,6ꢀtribromoaniline, and
2ꢀaminoꢀ5ꢀbromopyridine as the amine components.
Glycosylation of 4ꢀbromoꢀ3ꢀmethylaniline was catalyzed
by AcOH (Scheme 1). The yields of glycosides 1 and 2
were 60%.
The antipyretic properties of aniline are also known;
however, this compound is too toxic to be used for mediꢀ
cal purposes. By introducing various substituents (e.g.,
acetyl) into the benzene ring and the amino group, one
can appreciably reduce the toxicity and obtain derivatives
As for 2,4,6ꢀtribromoaniline, the corresponding
Nꢀglycosylamines could not be obtained even upon proꢀ
longed (for many hours) reflux in the presence of AcOH.
Coupling of Dꢀglucose and Dꢀgalactose with 2ꢀaminoꢀ
5ꢀbromopyridine in ethanol in the presence of AcOH
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2393—2395, November, 2008.
1066ꢀ5285/08/5711ꢀ2443 © 2008 Springer Science+Business Media, Inc.

2444
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008
Kulakov et al.
Scheme 1
Experimental
1H NMR spectra were recorded on a Bruker DRXꢀ500 inꢀ
strument (500 MHz) in DMSOꢀd6 with Me4Si as the internal
standard. IR spectra were recorded on an AVATARꢀ320 FTIR
spectrometer (KBr pellets). Mass spectra were recorded on a
Finnigan MATINCOS 50 instrument (EI, 70 eV, direct inlet
probe). The melting point was determined with a Boetius instruꢀ
ment. The course of the reaction was monitored and the purity
of the products was checked by TLC on Sorbfil plates in PriOH—
benzene—25% NH3 (10 : 5 : 2). Spots were visualized with the
iodine vapor. 4ꢀBromoꢀ3ꢀmethylaniline and 2ꢀaminoꢀ5ꢀbromoꢀ
pyridine (Aldrich) were used as purchased. 2,4,6ꢀTribromoꢀ
aniline was prepared according to a known procedure.
Nꢀ(4ꢀBromoꢀ3ꢀmethylphenyl)ꢀβꢀDꢀglucopyranosylamine (1).
One to two drops of glacial AcOH were added to a solution of
Dꢀglucose (3.60 g, 0.02 mol) and 4ꢀbromoꢀ3ꢀmethylaniline
(3.72 g, 0.02 mol) in ethanol (20 mL). The resulting solution
was stirred at 60—65 °C for 6 h and concentrated to one third of
its volume. The white crystalline precipitate that formed upon
cooling was filtered off, washed with cold isopropyl alcohol, and
recrystallized from 95% ethanol. The yield of compound 1 was
gave Nꢀ(5ꢀbromopyridinꢀ2ꢀyl)ꢀβꢀDꢀglucopyranosylamine
(3) and Nꢀ(5ꢀbromopyridinꢀ2ꢀyl)ꢀβꢀDꢀgalactopyranosylꢀ
amine (4), respectively, in 50—56% yields (Scheme 2).
Scheme 2
20
4.55 g (65.4%), m.p. 118—120 °C, [α]D –76 (c 1, DMSO).
Found (%): C, 45.17; H, 5.56; N, 4.33. C13H18BrNO5. Calcuꢀ
lated (%): C, 44.84; H, 5.21; N, 4.02. 1H NMR, δ: 2.25 (s, 3 H,
CH3—Ar); 3.08—3.67 (m, 6 H, H(2)—H(6)); 4.31 (t, 1 H, H(1),
J = 7.9 Hz); 6.32 (d, 1 H, NH, J = 7.9 Hz); 6.48 (d, 1 H, H(6´),
J = 7.6 Hz); 6.67 (s, 1 H, H(2´)); 7.23 (d, 1 H, H(5´)). MS, m/z
(Irel (%)): 349 [M]+ (33), 347 [M]+ (35), 227 (40), 214 (75), 198
(67), 185 (100), 60 (76).
Nꢀ(4ꢀBromoꢀ3ꢀmethylphenyl)ꢀβꢀDꢀgalactopyranosylamine (2)
was obtained as described for compound 1. The yield was 60%,
20
m.p. 130—131 °C, [α]D –33.5 (c 1, DMSO). Found (%):
C, 45.02; H, 5.44; N, 4.21. C13H18BrNO5. Calculated (%): C,
44.84; H, 5.21; N, 4.02. 1H NMR, δ: 2.25 (s, 3 H, CH3—Ar);
3.08—3.67 (m, 6 H, H(2)—H(6)); 4.31 (t, 1 H, H(1), J = 7.8 Hz);
6.32 (d, 1 H, NH, J = 7.8 Hz); 6.48 (d, 1 H, H(6´), J = 7.6 Hz);
6.67 (s, 1 H, H(2´)); 7.23 (d, 1 H, H(5´)).
Unlike compounds 1 and 2, Nꢀglycosylamines 3 and 4
are fairly stable and can easily be recrystallized.
Nꢀ(5ꢀBromopyridinꢀ2ꢀyl)ꢀβꢀDꢀglucopyranosylamine (3).
A solution of Dꢀglucose (1.80 g, 0.01 mol), 2ꢀaminoꢀ5ꢀbromoꢀ
pyridine (1.73 g, 0.01 mol), and two to three drops of glacial
AcOH in ethanol (10 mL) was stirred at 65—75 °C for 8 h. The
solution was concentrated by half. The white crystalline precipiꢀ
tate that formed was filtered off, washed with cold isopropyl
alcohol, and recrystallized from 95% ethanol. The yield of comꢀ
pound 3 was 1.65 g (50%), m.p. 197—198 °C, [α]D20 –34.5 (c 1,
DMSO). Found (%): C, 39.87; H, 4.24; N, 8.11. C11H15BrN2O5.
Calculated (%): C, 39.42; H, 4.51; N, 8.36; 1H NMR, δ:
3.05—3.62 (m, 6 H, H(2)—H(6)); 4.41 (t, 1 H, H(1), J = 8.2 Hz);
6.55 (d, 1 H, H—Ar—N, J = 8.4 Hz); 7.23 (d, 1 H, NH, J = 8.2 Hz);
7.60 (d, 1 H, H—Ar—Br); 8.08 (s, 1 H, N—HAr—Br). MS, m/z
(Irel (%)): 336 [M]+ (10), 334 [M]+ (10), 201 (100), 172 (30),
158 (22), 60 (40).
The IR spectra of Nꢀglycosylamines 1—4 show
an absorption band at 891 8 cm–1, which suggests the
βꢀconfiguration of the anomeric carbon.13 The presence
of several peaks at 1010—1090 cm–1 is due to the pyranose
form of the glycoside residue. The spectra also exhibit
bands at 600—700 cm–1 (C—Hal) and 1280—1330 cm–1
(C—N stretching) and an intense band at 3260—3380 cm–1
(OH and NH stretching). According to the IR spectra,
compounds 1—4 contain no C=N bond (i.e., they are not
Schiff bases).
1H NMR data for compounds 1—4, viz., the presence
of a signal at δ 4.30—4.50 (J1,2 = 7.8—8.2 Hz) for the
anomeric H(1) proton in the axial position, confirm that
these compounds exist in the pyranose form as βꢀanomers.
The mass spectra of compounds 1—4 contain peaks of
molecular (Irel = 10—35%) and fragmentation ions.
According to computerꢀassisted biological prediction
performed with the PASS (Prediction of Activity Spectra
for Substances) program,14 Nꢀaminoglycosides 1—4 can
be very promising antibacterial or antiviral drugs.
Nꢀ(5ꢀBromopyridinꢀ2ꢀyl)ꢀβꢀDꢀgalactopyranosylamine (4)
was obtained as described for compound 3. The yield was 56%,
20
m.p. 180—181 °C, [α]D –6.2 (c 1, DMSO). Found (%):
C, 39.60; H, 4.74; N, 8.23. C11H15BrN2O5. Calculated (%): C,
39.42; H, 4.51; N, 8.36. 1H NMR, δ: 3.35—3.80 (m, 6 H,
H(2)—H(6)); 4.50 (t, 1 H, H(1), J = 7.9 Hz); 6.58 (d, 1 H,
H(3´), J = 8.4 Hz); 7.20 (d, 1 H, NH, J = 7.9 Hz); 7.62 (d, 1 H,
H(4´)); 8.10 (s, 1 H, H(6´)).

Halogenꢀcontaining Nꢀglycosylamines
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 11, November, 2008 2445
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Received January 25, 2008;
in revised form June 16, 2008