Synthesis of Nitrogen Heterocycles from Methyl α- and β-D-Glucopyranosides

Article abstract of DOI:10.1081/CAR-120025329

Eight nitrogen heterocycles, mono and disubstituted tetrazoles and oxadiazoles, were synthesized from methyl D-glucopyranoside anomers. The monosubstituted tetrazoles resulted from the reaction of 6-cyanoglucopyranoside derivatives with sodium azide. By a

Full text of DOI:10.1081/CAR-120025329

This article was downloaded by: [University of Windsor]
On: 17 November 2014, At: 01:00
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Journal of Carbohydrate Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lcar20
Synthesis of Nitrogen Heterocycles from Methyl α‐ and
β‐d‐Glucopyranosides
Maria Teresa Capanema Pedrosa a , Rosemeire Brondi Alves a , Maria Auxiliadora Fontes
Prado b , José Dias de Souza Filho a , Ricardo José Alves b & Norma Beatriz D'Accorso c
a Departamento de Química , Instituto de Ciências Exatas , Universidade Federal de Minas
Gerais , Avenida Antônio Carlos 6627, Belo Horizonte, 31.270‐901, Brazil
b Departamento de Produtos Farmacêuticos , Faculdade de Farmácia , Universidade Federal
de Minas Gerais , Avenida Olegário Maciel 2360, Belo Horizonte, 30.180‐112, Brazil
c Departamento de Química Orgânica , Facultad de Ciências Exactas y Naturales ,
Universidad de Buenos Aires , Pabellón II, 3° Piso, C.P. 1428, Buenos Aires, Argentina
Published online: 23 Aug 2006.
To cite this article: Maria Teresa Capanema Pedrosa , Rosemeire Brondi Alves , Maria Auxiliadora Fontes Prado , José Dias
de Souza Filho , Ricardo José Alves & Norma Beatriz D'Accorso (2003) Synthesis of Nitrogen Heterocycles from Methyl α‐ and
β‐d‐Glucopyranosides, Journal of Carbohydrate Chemistry, 22:6, 433-442, DOI: 10.1081/CAR-120025329
To link to this article: http://dx.doi.org/10.1081/CAR-120025329
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

JOURNAL OF CARBOHYDRATE CHEMISTRY
Vol. 22, No. 6, pp. 433–442, 2003
Synthesis of Nitrogen Heterocycles from Methyl
- and -D-Glucopyranosides
Maria Teresa Capanema Pedrosa,1 Rosemeire Brondi Alves,1,
*
Maria Auxiliadora Fontes Prado,2 Jose´ Dias de Souza Filho,1
Ricardo Jose´ Alves,2 and Norma Beatriz D’Accorso3
1Departamento de Qu´ımica, Instituto de Cieˆncias Exatas and
2Departamento de Produtos Farmaceˆuticos, Faculdade de Farma´cia,
Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
3Departamento de Qu´ımica Orgaˆnica, Facultad de Cieˆncias Exactas y Naturales,
Universidad de Buenos Aires, Buenos Aires, Argentina
ABSTRACT
Eight nitrogen heterocycles, mono and disubstituted tetrazoles and oxadiazoles, were
synthesized from methyl D-glucopyranoside anomers. The monosubstituted tetrazoles
resulted from the reaction of 6-cyanoglucopyranoside derivatives with sodium azide.
By alkylation of the monosubstituted tetrazoles, the 1,5 and 2,5 disubstituted tet-
razoles were obtained. The monosubstituted tetrazoles were reacted with acetic an-
hydride to give the oxadiazoles.
Key Words: Tetrazole; Oxadiazole; Heterocycle.
*
Correspondence: Rosemeire Brondi Alves, Departamento de Qu´ımica, Instituto de Cieˆncias
Exatas, Universadade Federal de Minas Gerais, Avenida Antoˆnio Carlos 6627, Belo Horizonte
31.270-901, Brazil; E-mail: brondi@dedalus.1cc.ufmg.br.
433
DOI: 10.1081/CAR-120025329
0732-8303 (Print); 1532-2327 (Online)
www.dekker.com
Copyright D 2003 by Marcel Dekker, Inc.

434
Pedrosa et al.
INTRODUCTION
Tetrazoles are an increasingly popular structural unit, often used as metabolically
stable surrogates for carboxylic acid groups, and as convenient lipophilic spacers in
pharmaceuticals.[1] This unit also has roles in coordination chemistry as a ligand, and in
various material science applications, including in specialty explosives.[2] There have
been considerable achievements in the practical application of tetrazoles, especially in
medicine and biochemistry.[3–5] Recent publications include the use of tetrazoles as
inhibitors of monoamine oxidase,[6] as antiviral and antibacterial agents,[7,8] and an-
tagonists of cerebellum-specific GABAA receptors[9] and angiotensin II.[10] The oxa-
diazoles also display biological activities such as fungicidal,[11] antibacterial[12] and
glycosidase inhibitors.[13] We are interested in the synthesis of heterocycles using car-
bohydrates as starting materials, a strategy that offers the possibility of synthesis of
compounds possessing chiral centers with the necessary enantiomeric purity required
for active biological compounds. In this context, we synthesized some heterocycles
using carbohydrates as starting materials.[14–17]
RESULTS AND DISCUSSION
The initial work centered on the preparation of methyl 2,3,4-tri-O-benzyl-6-cyano-6-
deoxy-D-glucopyranoside anomers 1 and 1 in five conventional synthesis steps starting
from methyl a(b)-D-glucopyranosides (Scheme 1). The starting materials were protected
as 4,6-di-O-benzylidene derivatives[18] and then the C-2 and C-3 hydroxyl groups were
O-benzylated.[19] Removal of the benzylidene group under LiAlH4 reduction con-
ditions[20] and replacement of the hydroxy group at C-6 by iodine[21] afforded the methyl
2,3,4-tri-O-benzyl-6-deoxy-6-iodo-a(b)-D-glucopyranosides (4 and 4 ). Treatment of
4
and 4 with potassium cyanide in DMF[22] gave nitriles 1 and 1 , respectively.
After the preparation of these compounds, we went on to obtain the target tetrazoles.
Several methods of tetrazole synthesis are known,[2,4,5,23] but the most conve-
nient method of synthesis of substituted tetrazoles involves the reaction of nitriles
with salts of hydrazoic acid.[2,5] Thus, products 1 and 1 were submitted to reaction
with sodium azide and ammonium chloride in DMF[16,17] to give 5-(methyl a/b-
2,3,4-tri-O-benzyl-6-deoxy-D-glucopyranos-6-yl)tetrazole 2 and 2 in 81% and 73%
yields, respectively.
Distinct oxadiazoles can be obtained by many methods.[12,24] In this work, we
synthesized 1,3,4-oxadiazoles 3 and 3 in 84% and 60% yields, respectively, by the
reaction of tetrazoles 2 and 2 with acetic anhydride and pyridine[12,16,17] at 110°C.
To construct disubstituted tetrazoles, the alkylation reactions of tetrazole anions are
often used.[25] However, due to the existence of the tetrazole tautomeric forms, al-
kylation gives mixtures of N(1)- and N(2)-alkylation isomers.[25] The ratio of these
regioisomers is affected by the electronic and steric effect of the substituent.[25] Due to
the two tautomeric forms of tetrazole, tetrazole 2 when reacted with iodine derivative
4 in the presence of anhydrous potassium carbonate in acetone,[6,17] gave a mixture of
the two alkylated tetrazoles: 2,5-bis(methyl 2,3,4-tri-O-benzyl-6-deoxy-a-D-glucopyra-
nos-6-yl)-2H-tetrazole (5 ) (31%) and 1,5-bis(methyl 2,3,4-tri-O-benzyl-6-deoxy-a-D-

Synthesis of Nitrogen Heterocycles
435
Scheme 1. Reagents, conditions and yields: i, NaN3, DMF, NH4Cl, 95°C, 192 h (a) and 144 h (b),
81% (a) and 73% (b); ii, acetic anhydride, pyridine, 110°C, 96 h (a) and 144 h (b), 84% (a) and
60% (b); iii, K2CO3, acetone, compounds 2 and 4 , 70°C, 120 h, 5 (31%), 6 (34%);
compounds 2 e 4 , 70°C, 64 h, 5 (50%) and 6 (25%).
glucopyranos-6-yl)-1H-tetrazole (6 ) (34%) in an approximate 1:1 ratio. Tetrazole 2
by reaction with 4 under the same conditions described for 2 gave the regioisomers
5
(50%) and 6 (25%) in a 2:1 ratio. In a preliminary systematic conformational
research (Hyperchem Pro 6.0 – Molecular Mechanics), it was observed that when the
anomeric methoxy group is in the b position, there is a steric repulsion with the
nucleophilic glycoside moiety, and the alkylation on the tetrazolic ring occurs
preferentially at position 2. In contrast, when the anomeric methoxy group is a, the
cited repulsive interaction is absent, and alkylation occurs at positions 1 and 2 in the
same ratio (Scheme 1).
The structures of all the compounds obtained were confirmed by NMR
spectroscopy. However, it is interesting to remark on the unequivocal characterization
of the isomeric tetrazoles 5 and 6. The literature reports that tetrazole isomers with
1
methyl or alkyl substituents at positions 1 and 2 are readily distinguished by the H and
13C chemical shifts of the N-alkyl group. Alkyl groups bonded to N-1 are more shielded
1
by ca. 0.15–0.35 ppm in the H spectra and by ca. 2–6 ppm in the 13C spectra relative
to their corresponding N-2 isomers. However, HMBC experiments were carried out for
confirmation and revealed that the cross correlation of H6@ with tetrazolic carbon
occurs solely in derivatives 6 because of the J coupling constant.
3

436
Pedrosa et al.
EXPERIMENTAL
General procedures. Melting points were determined on a Mettler FP80HT
apparatus and are uncorrected. Optical rotation was determined with a Perkin-Elmer
1
341 Polarimeter at 25°C. 13C and H NMR spectra were recorded on a Bruker Avance
DRX-400 spectrometer. Chemical shifts are reported in d units downfield from Me4Si.
Elemental analyses were carried out using a Perkin-Elmer 2400 CHN apparatus.
Column chromatography was performed with silica gel 60, 70-230 mesh (Merck). The
term ‘‘standard work-up’’ means that the organic layer was washed with satd NaCl
solution, dried over anhydrous Na2SO4, filtered, and the solvent was removed under
reduced pressure. Dry solvents were prepared as follows. DMF was dried over
potassium hydroxide and stirred for 24 hours at room temperature. The solution was
filtered and distilled under reduced pressure. Dry pyridine was prepared after agitation
with KOH for 17 h at room temperature, and then distilled. Potassium permanganate
was added to refluxing acetone until its color remained purple. The solution was
refluxed for 6 h more and distilled. Dry acetone was collected under desiccated K2CO3.
Methyl 2,3,4-tri-O-benzyl-6-cyano-6-deoxy- -D-glucopyranoside 1 .[22] To a
solution of methyl 2,3,4-tri-O-benzyl-6-deoxy-6-iodo-b-D-glucopyranoside (4 ) (1.00
g, 1.74 mmol) in dry DMF (25 mL), KCN (0.38 g, 5.85 mmol) was added and the
reaction mixture stirred at rt for 65 h. DMF was removed under reduced pressure,
giving a residue. Water was added, the aqueous solution extracted with CH2Cl2
(4 Â 30 mL), and the combined organic extracts submitted to standard work-up. The
crude product was purified by column chromatography (10% EtOAc in hexane,
gradually increasing the percentage of EtOAc) to give product 1 (0.61 g, 74%) as a
1
white solid: [a]D + 32 (c 1.3, CHCl3); mp 69–73°C; H NMR (CDCl3, 400 MHz): d
7.37–7.23 (m, 15H, Ar), 4.96 (d, 1H, Jgem 10.9 Hz, 1 Â PhCH2), 4.92 (d, 1H, Jgem
11.0 Hz, 1 Â PhCH2), 4.91 (d, 1H, Jgem 11.2 Hz, 1 Â PhCH2), 4.78 (d, 1H, Jgem 10.9
Hz, 1 Â PhCH2), 4.70 (d, 1H, Jgem 11.0 Hz, 1 Â PhCH2), 4.60 (d, 1H, Jgem 11.2 Hz,
1 Â PhCH2), 4.35 (d, 1H, J1,2 7.8 Hz, H1), 3.65 (t, 1H, J3,4 9.1 Hz, H3), 3.58 (s, 3H,
MeO), 3.49 (ddd, 1H, J5,4 9.1, J5,6@ 7.7, J5,6’ 3.2 Hz, H5), 3.45 (dd, 1H, H2), 3.36 (t,
1H, H4), 2.70 (dd, 1H, Jgem 16.8 Hz, H6’), 2.43 (dd, 1H, H6@); 13C NMR (CDCl3, 100
MHz): d 138.3, 138.2, 137.5 (3 Â C ipso), 128.6, 128.4, 128.3, 128.2, 128.1, 127.9,
127.7 (15 Â Ar), 116.8 (CN), 104.6 (C1), 84.2 (C3), 82.2 (C2), 79.8 (C4), 75.6, 75.2,
74.8 (3 Â PhCH2), 70.5 (C5), 57.2 (MeO), 21.0 (C6).
Anal. Calcd for C29H31NO5: C, 73.55; H, 6.60; N, 2.96. Found: C, 73.14; H, 6.59;
N, 2.86.
Treating the epimer 4 (3.15 g, 6.79 mmol) with KCN as described above for 4 ,
1
product 1 (2.36 g, 91%) was obtained as a whitish oil: [a]D + 46.8 (c 1.1, CHCl3); H
NMR (CDCl3, 400 MHz): d 7.36–7.24 (m, 15H, Ar), 5.01 (d, 1H, Jgem 10.9 Hz,
1 Â PhCH2), 4.93 (d, 1H, Jgem 11.2 Hz, 1 Â PhCH2), 4.80 (d, 1H, Jgem 10.9 Hz,
1 Â PhCH2), 4.79 (d, 1H, Jgem 12.1 Hz, 1 Â PhCH2), 4.65 (d, 1H, Jgem 12.1
Hz, 1 Â PhCH2), 4.60 (d, 1H, Jgem 11.2 Hz, 1 Â PhCH2), 4.57 (d, 1H, J1,2 3.6 Hz,
H1), 3.98 (t, 1H, J3,4 9.6 Hz, H3), 3.79 (ddd, 1H, J5,4 9.6, J5,6’ 7.0, J5,6@ 3.4 Hz, H5),
3.55 (dd, 1H, H2), 3.39 (s, 3H, MeO), 3.33 (t, 1H, H4), 2.62 (dd, 1H, Jgem 16.8 Hz,
H6’), 2.42 (dd, 1H, H6@); 13C NMR (CDCl3, 50 MHz): d 138.3, 137.7, 137.5 (3 Â C
ipso), 128.5, 128.4, 128.3, 128.1, 128.0, 127.9, 127.8, 127.7 (15 Â Ar), 116.9 (CN),

Synthesis of Nitrogen Heterocycles
437
98.0 (C1), 81.5 (C3), 79.8 (C2 or C4), 79.7 (C2 or C4), 75.6, 75.1, 73.4 (3 Â PhCH2),
66.2 (C5), 55.4 (MeO), 20.7 (C6).
Anal. Calcd for C29H31NO5: C, 73.55; H, 6.60; N, 2.96. Found: C, 72.95; H, 6.59;
N, 2.99.
5-(Methyl 2,3,4-tri-O-benzyl-6-deoxy- -D-glucopyranos-6-yl)tetrazole 2 .[16,17]
To a solution of methyl 2,3,4-tri-O-benzyl-6-cyano-6-deoxy-b-D-glucopyranoside (1 )
(0.17 g, 0.36 mmol) in dry DMF (10 mL), NaN3 (0.28 g, 4.31 mmol) and NH4Cl (0.23
g, 4.30 mmol) were added. The solution was stirred at 95°C for 144 h. DMF was
removed under reduced pressure, giving a residue. Aqueous H2SO4 (3 mol.LÀ 1) was
added until pH 1 was reached. Water was added, the aqueous solution extracted with
CH2Cl2 (4 Â 25 mL), and the combined organic extracts submitted to standard work-
up. The crude product was purified by column chromatography (30% EtOAc in hexane,
gradually increasing the percentage of EtOAc) to give product 2 (0.14 g, 73%) as a
white solid: [a]D + 2 (c 1.2, Me2SO); mp 217–219°C; 1H NMR (Me2SO-d6, 400
MHz): d 16.03 (br s, 1H, NH), 7.89–7.26 (m, 15H, Ar), 4.83 (d, 1H, Jgem 11.1 Hz,
1 Â PhCH2), 4.82 (d, 1H, Jgem 11.1 Hz, 1 Â PhCH2), 4.78 (d, 1H, Jgem 11.5 Hz,
1 Â PhCH2), 4.73 (d, 2H, Jgem 11.1 Hz, 2 Â PhCH2), 4.62 (d, 1H, Jgem 11.5
Hz, 1 Â PhCH2), 4.32 (d, 1H, J1’,2’ 7.8 Hz, H1’), 3.72 (td, 1H, J5’,6@ 9.1, J5’,6’ 3.0 Hz,
H5’), 3.65 (t, 1H, J3’,4’ 9.1 Hz, H3’), 3.42 (t, 1H, H4’), 3.36 (dd, 1H, Jgem 15.1 Hz, H6’),
3.29–3,25 (m, 1H, H2’), 3.25 (s, 3H, MeO), 3.09 (dd, 1H, H6@); 13C NMR (Me2SO-d6,
100 MHz): d 153.0 (C5), 138.5, 138.4, 138.1 (3 Â C ipso), 128.2, 128.1, 128.0, 127.9,
127.8, 127.6, 127.5, 127.3 (15 Â Ar), 103.3 (C1’), 83.5 (C3’), 81.6 (C2’), 80.6 (C4’),
74.4, 74.0, 73.5 (3 Â PhCH2), 71.7 (C5’), 56.0 (MeO), 25.8 (C-6’).
Anal. Calcd for C29H32N4O5: C, 67.43; H, 6.24; N, 10.85. Found: C, 67.13; H,
6.36; N, 11.25.
Treatment of product 1 (2.21 g, 4.66 mmol) as described above for 1 gave
product 2 (1.94 g, 81%) as a white solid: [a]D + 13.6 (c 1.2, CHCl3); mp 218–223°C;
1H NMR (CDCl3, 400 MHz): d 13.23 (br s, 1H, NH), 7.34–7.24 (m, 15H, Ar), 4.97 (d,
1H, Jgem 10.9 Hz, 1 Â PhCH2), 4.89 (d, 1H, Jgem 11.0 Hz, 1 Â PhCH2), 4.80 (d, 1H,
Jgem 10.9 Hz, 1 Â PhCH2), 4.76 (d, 1H, Jgem 12.0 Hz, 1 Â PhCH2), 4.65 (d, 1H, Jgem
11.0 Hz, 1 Â PhCH2), 4.62 (d, 1H, Jgem 12.0 Hz, 1 Â PhCH2), 4.60 (d, 1H, J1’,2’ 3.6
Hz, H1’), 4.00–3.93 (m, 1H, H5’), 3.99 (t, 1H, J3’,4’ 9.7 Hz, H3’), 3.56 (dd, 1H, H2’),
3.48 (dd, 1H, Jgem 15.3, J6’,5’ 3.6 Hz, H6’), 3.22 (s, 3H, MeO), 3.19 (t, 1H, J4’,5’ 9.7 Hz,
H4’), 3.14 (dd, 1H, J6@,5’ 9.7 Hz, H6@); 13C NMR (CDCl3, 50 MHz): d 153.3 (C5),
138.3, 137.8, 137.6 (3 Â C ipso), 128.6, 128.5, 128.4, 128.3, 128.1, 128.0, 127.9,
127.8, 127.7 (15 Â Ar), 98.0 (C1’), 81.5 (C3’), 80.3 (C4’), 79.9 (C2’), 75.7, 75.1, 73.3
(3 Â PhCH2), 67.9 (C5’), 55.4 (MeO), 25.9 (C6’).
Anal. Calcd for C29H32N4O5: C, 67.43; H, 6.24; N, 10.85. Found: C, 67.19; H,
5.99; N, 10.89.
2-Methyl-5-(methyl 2,3,4-tri-O-benzyl-6-deoxy- -D-glucopyranos-6-yl)-1,3,4-
oxadiazole 3 .[12,16,17] To a stirred solution of 5-(methyl 2,3,4-tri-O-benzyl-6-deoxy-
b-D-glucopyranos-6-yl)tetrazole (2 ) (0.15 g, 0.29 mmol) in dry pyridine (3 mL), acetic
anhydride (9 mL, 99.10 mmol) was added. The solution was stirred at 110°C for 144 h,
then cooled to rt and cold aq HCl (19 mL, 3 mol.LÀ 1) was added. Water was added,
the aqueous solution extracted with CH2Cl2 (4 Â 25 mL), and the combined organic

438
Pedrosa et al.
extracts submitted to standard work-up. The crude product was purified by column
chromatography (40% EtOAc in hexane, gradually increasing the percentage of EtOAc)
to give product 3 (0.09 g, 60%) as a white solid: [a]D + 13.2 (c 0.6, CHCl3); mp 101–
1
105°C; H NMR (CDCl3, 400 MHz): d 7.34–7.25 (m, 15H, Ar), 4.95 (d, 1H, Jgem 10.9
Hz, 1 Â PhCH2), 4.93 (d, 1H, Jgem 11.5 Hz, 1 Â PhCH2), 4.90 (d, 1H, Jgem 11.7 Hz,
1 Â PhCH2), 4.78 (d, 1H, Jgem 10.9 Hz, 1 Â PhCH2), 4.69 (d, 1H, Jgem 11.7 Hz,
1 Â PhCH2), 4.66 (d, 1H, Jgem 11.5 Hz, 1 Â PhCH2), 4.30 (d, 1H, J1’,2’ 7.8 Hz, H1’),
3.75 (td, 1H, J5’,6@ 8.8 Hz, J5’,6’ 3.8, H5’), 3.68 (t, 1H, J3’,4’ 8.8 Hz, H3’), 3.45 (s, 3H,
MeO), 3.45–3.39 (m, 1H, H2’), 3.41 (t, 1H, H4’), 3.26 (dd, 1H, Jgem 15.4 Hz, H6’),
2.93 (dd, 1H, H6@), 2.43 (s, 3H, Me); 13C NMR (CDCl3, 100 MHz): d 164.2 (C5),
163.7 (C2), 138.5, 138.4, 137.9 (3 Â C ipso), 128.5, 128.4, 128.3, 128.1, 128.0, 127.9,
127.8, 127.7 (15 Â Ar), 104.5 (C1’), 84.5 (C3’), 82.4 (C2’), 80.7 (C4’), 75.7, 74.9, 74.7
(3 Â PhCH2), 72.0 (C5’), 56.9 (MeO), 28.3 (C6’), 10.8 (Me).
Anal. Calcd for C31H34N2O6: C, 70.17; H, 6.46; N, 5.28. Found: C, 69.97; H, 6.29;
N, 5.32.
The treatment of tetrazole 2 (0.20 g, 0.39 mmol) as described above for 2 gave
product 3 (0.17 g, 84%) as a whitish oil: [a]D + 42.7 (c 1.2, CHCl3); 1H NMR
(CDCl3, 400 MHz): d 7.36–7.25 (m, 15H, Ar), 5.01 (d, 1H, Jgem 10.8 Hz, 1 Â PhCH2),
4.95 (d, 1H, Jgem 10.8 Hz, 1 Â PhCH2), 4.81 (d, 1H, Jgem 10.8 Hz, 1 Â PhCH2), 4.78
(d, 1H, Jgem 12.2 Hz, 1 Â PhCH2), 4.66 (d, 1H, Jgem 10.8 Hz, 1 Â PhCH2), 4.63 (d,
1H, Jgem 12.2 Hz, 1 Â PhCH2), 4.50 (d, 1H, J1’,2’ 3.6 Hz, H1’), 4.12–4.02 (m, 1H,
H5’), 4.01 (t, 1H, J3’,4’ 9.6 Hz, H3’), 3.50 (dd, 1H, H2’), 3.34 (t, 1H,J4’,5’ 9.6 Hz, H4’),
3.29 (s, 3H, MeO), 3.19 (dd, 1H, Jgem 15.4, J6’,5’ 3.7 Hz, H6’), 2.89 (dd, 1H, J6@,5’ 8.4
Hz, H6@), 2.42 (s, 3H, Me); 13C NMR (CDCl3, 50 MHz): d 164.2 (C5), 163.6 (C2),
138.4, 137.9, 137.8 (3 Â C ipso), 128.3, 128.0, 127.9, 127.8, 127.7, 127.6 (15 Â Ar),
97.8 (C1’), 81.7 (C3’), 80.6 (C4’), 79.8 (C2’), 75.6, 74.8, 73.2 (3 Â PhCH2), 67.5 (C5’),
55.2 (MeO), 27.9 (C6’), 10.7 (Me).
Anal. Calcd for C31H34N2O6: C, 70.17; H, 6.46; N, 5.28. Found: C, 69.98; H, 6.44;
N, 5.33.
2,5-Bis(methyl 2,3,4-tri-O-benzyl-6-deoxy- -D-glucopyranos-6-yl)-2H-tetrazole
5
and 1,5-Bis(methyl 2,3,4-tri-O-benzyl-6-deoxy-b-D-glucopyranos-6-yl)-1H-tetra-
zole 6 .[6,17] To a solution of 5-(methyl 2,3,4-tri-O-benzyl-6-deoxy-b-D-glucopyranos-
6-yl)tetrazole (2 ) (0.35 g, 0.68 mmol) and methyl 2,3,4-tri-O-benzyl-6-deoxy-6-iodo-
b-D-glucopyranoside (4 ) (0.39 g, 0.68 mmol) in dry acetone (120 mL), anhydrous
K2CO3 (0.94 g, 6.81 mmol) was added. The solution was stirred at 70°C for 64 h in a
pressure reactor. After cooling to rt, the solvent was removed, water was added, the
aqueous solution was extracted with EtOAc (4 Â 20 mL) and the combined organic
extracts were submitted to standard work-up. The crude product was purified by
column chromatography (10% EtOAc in hexane, gradually increasing the percentage of
EtOAc) to give product 5 (0.33 g, 50%) and 6 (0.16 g, 25%) as white solids.
1
Compound 5 : [a]D + 18 (c 1.0, CHCl3); mp 122–123°C; H NMR (CDCl3, 400
MHz): d 7.32–7.27 (m, 30H, Ar), 4.95 (d, 1H, Jgem 10.9 Hz, 1 Â PhCH2), 4.94 (d, 1H,
Jgem 10.9 Hz, 1 Â PhCH2), 4.93 (d, 1H, Jgem 10.9 Hz, 1 Â PhCH2), 4.92 (d, 1H, Jgem
11.2 Hz, 1 Â PhCH2), 4.88 (d, 1H, Jgem 11.1 Hz, 1 Â PhCH2), 4.86 (d, 1H, Jgem 11.1
Hz, 1 Â PhCH2), 4.78 (d, 2H, Jgem 10.9 Hz, 2 Â PhCH2), 4.73 (dd, 1H, J6b@,6a@ 13.9,
J6b@,5@ 3.1 Hz, H-6b@), 4.72 (d, 1H, Jgem 11.2 Hz, 1 Â PhCH2), 4.71 (d, 1H, Jgem 10.9

Synthesis of Nitrogen Heterocycles
439
Hz, 1 Â PhCH2), 4.67 (d, 1H, Jgem 11.1 Hz, 1 Â PhCH2), 4.65 (d, 1H, Jgem 11.1 Hz,
1 Â PhCH2), 4.56 (dd, 1H, J6a@,5@ 7.6 Hz, H-6a@), 4.27 (d, 1H, J1,2 7.8 Hz, H1’ or H1@),
4.21 (d, 1H, J1,2 7.7 Hz, H1’ or H1@), 3.86–3.80 (m, 2H, H5’, H-5@), 3.68 (t, 1H, J3,4
9.1 Hz, H3’ or H3@), 3.67 (t, 1H, J3,4 9.1, H3’ or H3@), 3.48 (t, 1H, J4’,5’ 9.1 Hz, H4’),
3.47 (t, 1H, J4@,5@ 9.1 Hz, H4@), 3.42–3.34 (m, 2H, H2’, H2@), 3.38 (s, 3H, MeO’ or
MeO@), 3,35 (dd, 1H, J6b’,6a’ 15.3, J6b’,5’ 3.6 Hz, H6b’), 3.32 (s, 3H, MeO’ or MeO@),
3.08 (dd, 1H, J6a’,5’ 8.1 Hz, H6a’); 13C NMR (CDCl3, 100 MHz): d 163.4 (C-5), 138.6,
138.4, 138.3, 138.2, 137.8 (6 Â C ipso), 128.6, 128.5, 128.4, 128.3, 128.2, 128.1,
128.0, 127.9, 127.8, 127.7, 127.6, 127.5 (30 Â Ar), 104.5, 104.4 (C1’, C1@), 84.7, 84.5
(C3’, C3@), 82.5, 82.2 (C2’, C2@), 81.0, 78.4 (C4’, C4@), 75.7, 75.6, 75.0, 74.9, 74.7
(6 Â PhCH2), 72.6 (C5’), 72.4 (C5@), 56.8, 56.7 (MeO’, MeO@), 53.5 (C6@), 28.2 (C6’).
Anal. Calcd for C57H62N4O10: C, 71.08; H, 6.49; N, 5.82. Found: C, 69.97; H,
6.29; N, 5.32.
1
Compound 6 : [a]D + 14 (c 0.9, CHCl3); mp 110–114°C; H NMR (CDCl3, 400
MHz): d 7.36–7.25 (m, 30H, Ar), 4.97 (d, 1H, Jgem 10.8 Hz, 1 Â PhCH2), 4.96 (d, 1H,
Jgem 10.8 Hz, 1 Â PhCH2), 4.95 (d, 1H, Jgem 10.8 Hz, 1 Â PhCH2), 4.94 (d, 1H, Jgem
10.5 Hz, 1 Â PhCH2), 4.87 (d, 1H, Jgem 11.0 Hz, 1 Â PhCH2), 4.86 (d, 1H, Jgem 11.0
Hz, 1 Â PhCH2), 4.81 (d, 1H, Jgem 10.8 Hz, 1 Â PhCH2), 4.79 (d, 1H, Jgem 10.5 Hz,
1 Â PhCH2), 4.78 (d, 2H, Jgem 10.8 Hz, 2 Â PhCH2), 4.71 (dd, 1H, J6b@,6a@ 14.5, J6b@,5@
2.8 Hz, H6b@), 4.67 (d, 1H, Jgem 11.0 Hz, 1 Â PhCH2), 4.66 (d, 1H, Jgem 11.0 Hz,
1 Â PhCH2), 4.38 (dd, 1H, J6a@,5@ 7.5 Hz, H6a@), 4.22 (d, 1H, J1’,2’ 7.9 Hz, H1’), 4.18
(d, 1H, J1@,2@ 7.9 Hz, H1@), 3.74 (ddd, 1H, J5’,4’ 9.7, J5’,6a’ 8.2, J5’,6b’ 3.2 Hz, H5’), 3.72–
3.66 (m, 1H, H5@), 3.69 (t, 1H, J3,4 9.0 Hz, H3’ or H3@), 3.68 (t, 1H, J3,4 9.1 Hz, H3’ or
H3@), 3.47 (dd, 1H, J6b’,6a’ 15.1 Hz, H6b’), 3.45–3.34 (m, 4H, H2’, H2@, H4’, H4@), 3.33
(s, 3H, MeO’ or MeO@), 3.29 (s, 3H, MeO’ or MeO@), 3.07 (dd, 1H, H6a’); 13C NMR
(CDCl3, 100 MHz): d 153.8 (C5), 138.4, 138.3, 138.2, 138.1, 138.0, 137.8 (6 Â C
ipso), 128.6, 128.5, 128.4, 128.3, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 127.5
(30 Â Ar), 104.6, 104.5 (C1’, C1@), 84.4, 84.3 (C3’, C3@), 82.2, 82.0, 80.2, 78.1 (C2’,
C2@, C4’, C4@), 75.6, 74.9, 74.8, 74.7 (6 Â PhCH2), 73.4 (C5@), 73.1 (C5’), 57.0
(MeO’), 57.0 (MeO@), 47.7 (C6@), 25.7 (C6’).
Anal. Calcd for C57H62N4O10: C, 71.08; H, 6.49; N, 5.82. Found: C, 70.60; H,
6.31; N, 5.76.
By treatment of tetrazole 2 (1.00 g, 1.94 mmol) with 4 (1.10 g, 1.92 mmol) as
described above for 2 , product 5 (0.57 g, 31%) and 6 (0.64g, 34%) were obtained
as whitish oils.
1
Compound 5 : [a]D + 47.1 (c 1.0, CHCl3); H NMR (CDCl3, 400 MHz): d 7.33–
7.28 (m, 30H, Ar), 5.00 (d, 1H, Jgem 10.8 Hz, 1 Â PhCH2), 4.98 (d, 1H, Jgem 10.8 Hz,
1 Â PhCH2), 4.96 (d, 1H, Jgem 11.1 Hz, 1 Â PhCH2), 4.95 (d, 1H, Jgem 11.7 Hz, 1 Â
PhCH2), 4.81 (d, 1H, Jgem 10.8 Hz, 1 Â PhCH2), 4.80 (d, 1H, Jgem 10.8 Hz,
1 Â PhCH2), 4.75 (d, 1H, Jgem 12.1 Hz, 1 Â PhCH2), 4.74 (d, 1H, Jgem 12.0 Hz, 1 Â
PhCH2), 4.72 (d, 1H, Jgem 11.1 Hz, 1 Â PhCH2), 4.71 (d, 1H, Jgem 11.7 Hz,
1 Â PhCH2), 4.70 (dd, 1H, J6b@,6a@ 14.7, J6b@,5@ 2.8 Hz, H6b@), 4.61 (d, 1H, Jgem 12.1
Hz, 1 Â PhCH2), 4.59 (d, 1H, Jgem 12.0 Hz, 1 Â PhCH2), 4.57 (dd, 1H, J6a@,5@ 8.3 Hz,
H6a@), 4.44 (d, 1H, J1@,2@ 3.5 Hz, H1@), 4.43 (d, 1H, J1’,2’ 3.5 Hz, H1’), 4.17–4.07 (m,
2H, H5’ and H5@), 4.01 (t, 1H, J3@,4@ 9.4 Hz, H3@), 4.00 (t, 1H, J3’,4’ 9.4 Hz, H3’), 3.45
(dd, 1H, H2@), 3.41 (dd, 1H, H2’), 3.35 (t, 1H, J4’,5’ 9.4 Hz, H4’), 3.37–3.31 (m, 1H,
H4@), 3.30 (dd, 1H, J6b’,6a’ 14.7, J6b’,5’ 3.4 Hz, H6b’), 3.19 (s, 3H, MeO’ or MeO@), 3.11

440
Pedrosa et al.
(s, 3H, MeO’ or MeO@), 3.00 (dd, 1H, J6a’,5’ 8.5 Hz, H6a’); 13C NMR (CDCl3, 100
MHz): d 163.5 (C5), 138.6, 138.3, 138.2, 138.0, 137.8 (6 Â C ipso), 128.6, 128.5,
128.4, 128.3, 128.2, 128.0, 127.9, 127.8, 127.7, 127.6, 127.5, 127.4 (30 Â Ar), 97.8
(C1’ or C1@), 97.7 (C1’ or C1@), 81.9 (C3@), 81.8 (C3’), 81.0 (C4’), 80.0 (C2’), 79.7
(C2@), 78.3 (C4@), 75.8, 75.7, 74.9, 74.8, 73.4, 73.3 (6 Â PhCH2), 68.4 (C5’), 68.2
(C5@), 55.2 (MeO’ or MeO@), 55.1 (MeO’ or MeO@), 53.4 (C6@), 27.9 (C6’).
Anal. Calcd for C57H62N4O10: C, 71.08; H, 6.49; N, 5.82. Found: C, 70.89; H,
6.32; N, 5.65.
1
Compound 6 : [a]D + 51.3 (c 1.0, CHCl3); H NMR (CDCl3, 400 MHz): d 7.34–
7.26 (m, 30H, Ar), 4.99 (d, 1H, Jgem 10.9 Hz, 1 Â PhCH2), 4.98 (d, 1H, Jgem 11.0 Hz,
1 Â PhCH2), 4.96 (d, 1H, Jgem 12.3 Hz, 1 Â PhCH2), 4.95 (d, 1H, Jgem 12.5 Hz,
1 Â PhCH2), 4.81 (d, 1H, Jgem 10.9 Hz, 1 Â PhCH2), 4.80 (d, 1H, Jgem 11.0 Hz, 1 Â
PhCH2), 4.76 (d, 1H, Jgem 11.7 Hz, 1 Â PhCH2), 4.74 (d, 1H, Jgem 11.7 Hz,
1 Â PhCH2), 4.73 (d, 1H, Jgem 12.3 Hz, 1 Â PhCH2), 4.72 (d, 1H, Jgem 12.5 Hz,
1 Â PhCH2), 4.63 (d, 1H, Jgem 11.7 Hz, 1 Â PhCH2), 4.60 (d, 1H, Jgem 11.7 Hz, 1 Â
PhCH2), 4.48 (dd, 1H, J6b@,6a@ 14.4, J6b@,5@ 2.5 Hz, H6b@), 4.39 (d, 1H, J1’,2’ 3.6 Hz,
H1’), 4.38 (d, 1H, J1@,2@ 3.6 Hz, H1@), 4.15 (dd, 1H, J6a@,5@ 8.0 Hz, H6a@), 4.00–3.86 (m,
2H, H5’ and H5@), 3.96 (t, 2H, J3’,4’ 9.4 Hz, H3’ and H3@), 3.43 (dd, 1H, H2’), 3.40 (dd,
1H, H2@), 3.32–3.23 (m, 3H, H4’, H4@ and H6b’), 3.09 (s, 3H, MeO’ or MeO@), 2.98 (s,
3H, MeO’ or MeO@), 2.81 (dd, 1H, J6a’,6b’ 15.1, J6a’,5’ 8.8 Hz, H6a’); 13C NMR (CDCl3,
100 MHz): d 153.7 (C5), 138.5, 138.3, 138.2, 138.0, 137.9, 137.8 (6 Â C ipso), 128.6,
128.5, 128.4, 128.3, 128.0, 127.9, 127.8, 127.7, 127.6 (30 Â Ar), 97.8 (C1’ or C1@),
97.7 (C1’ or C1@), 81.8 (C3’ and C3@), 80.3 (C4’), 79.8 (C2’ or C2@), 79.7 (C2’ or C2@),
78.1 (C4@), 75.7, 75.6, 74.7, 74.6, 73.3, 73.2 (6 Â PhCH2), 69.1 (C5@), 68.7 (C5’), 55.1
(MeO’ or MeO@), 55.0 (MeO’ or MeO@), 47.5 (C6@), 25.3 (C6’).
Anal. Calcd for C57H62N4O10: C, 71.08; H, 6.49; N, 5.82. Found: C, 70.91; H,
6.35; N, 5.72.
ACKNOWLEDGMENTS
The authors thank Coordenac¸a˜o de Aperfeic¸oamento de Pessoal de N´ıvel Superior
(Capes) and Conselho Nacional de Desenvolvimento Cient´ıfico e Tecnolo´gico (CNPq)
for the fellowships (Maria T. C. Pedrosa, Rosemeire B. Alves and Maria A. F. Prado).
REFERENCES
1. Demko, Z.P.; Sharpless, K.B. An intramolecular [2 + 3] cycloaddition route to
fused 5-heterosubstituted tetrazoles. Org. Lett. 2001, 3 (25), 4091–4094.
2. Demko, Z.P.; Sharpless, K.B. Preparation of 5-substituted 1H-tetrazoles from
nitriles in water. J. Org. Chem. 2001, 66, 7945–7950.
3. Singh, H.; Chawla, A.S.; Kapoor, V.K.; Paul, D.; Malhotra, R.K. Medicinal
chemistry of tetrazoles. In Progress in Medicinal Chemistry; Ellis, G.P., West, G.B.,
Eds.; North-Holland Biomedical Press: Holland, 1980; Vol. 17, 151–176.
4. Butler, R.N. Tetrazoles. In Comprehensive Heterocyclic Chemistry: The Structure,

Synthesis of Nitrogen Heterocycles
441
Reactions, Synthesis and Uses of Heterocyclic Compounds; Katritzky, A.R., Rees,
C.W., Eds.; Imprenta Pergamon Press: Oxford, 1984; Vol. 4, 791–838.
5. Koldobskii, G.I.; Ostrovskii, V.A. Tetrazoles. Russ. Chem. Rev. 1994, 63 (10),
797–814.
6. Harfenist, M.; Heuser, D.J.; Joyner, C.T.; Batchelor, J.F.; White, H.L. Selective
inhibitors of monoamine oxidase. 3. Structure-activity relationship of tricyclics
bearing imidazoline, oxadiazole, or tetrazole groups. J. Med. Chem. 1996, 39 (9),
1857–1863.
7. Ogilvie, W.W.; Yoakim, C.; Doˆ, F.; Hache´, B.; Lagace´, L.; Naud, J.; O’Meara, J.A.;
De´ziel, R. Synthesis and antiviral activity of monobactams inhibiting the human
cytomegalovirus protease. Bioorg. Med. Chem. 1999, 7, 1521–1531.
8. Genin, M.J.; Allwine, D.A.; Anderson, D.J.; Barbachyn, M.R.; Emmert, D.E.;
Garmon, S.A.; Graber, D.R.; Grega, K.C.; Hester, J.B.; Hutchinson, D.K.; Morris,
J.; Reischer, R.J.; Ford, C.W.; Zurenko, G.E.; Hamel, J.C.; Schaadt, R.D.; Stapert,
D.; Yagi, B.H. Substituent effects on the antibacterial activity of nitrogen-carbon-
linked (azolylphenyl)oxazolidinones with expanded activity against the fastidious
gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis. J.
Med. Chem. 2000, 43 (5), 953–970.
9. Lu¨ddens, H.; Lang, H.J.; Korpi, E.R. Structure-activity relationship of furosemide-
derived compounds as antagonists of cerebellum-specific GABAA receptors. Eur. J.
Pharm. 1998, 344, 269–277.
10. Middlemiss, D.; Watson, S.P. A medicinal chemistry case study: an account of an
angiotensin II antagonist drug discovery programme. Tetrahedron 1994, 50 (46),
13049–13080.
11. Cannizzaro, C.E.; Thiel, I.M.E.; D’Accorso, N.B. Synthesis and debenzoylation
products of two perbenzoylated 2-substituted 5-D-galactosyl-1,3,4-oxadiazoles. J.
Heterocyclic Chem. 1998, 35 (2), 481–484.
12. Fascio, M.L.; D’Accorso, N.B. Synthesis of some oxadiazole derivatives of
D-mannose. J. Heterocyclic Chem. 1995, 32, 815–818.
13. Martins Alho, M.A.; D’Accorso, N.B. Synthesis and characterization of some
heterocyclic derivatives from 1,2:3,4-di-O-isopropylidene-a-D-galacto-1,6-hexa-
dialdo-1,5-pyranose oxime. J. Heterocyclic Chem. 1999, 36, 177–182.
14. Binatti, I.; Prado, M.A.F.; Alves, R.J.; Souza Filho, J.D. Synthesis of
benzomacrolactam by 11-endo selective aryl radical cyclization of 2-iodobenz-
amide derived from D-galactose. J. Br. Chem. Soc. 2002, 13 (5), 570–575.
15. Prado, M.A.F.; Alves, R.J.; Souza Filho, J.D.; Alves, R.B.; Pedrosa, M.T.C.; Prado,
R.F.; Faraco, A.A.G. Synthesis of benzolactams by 11-endo selective aryl radical
cyclisation of 2-iodobenzamides. J. Chem. Soc., Perkin Trans. 1 2000, 12, 1853–
1857.
16. Faraco, A.A.G.; Prado, M.A.F.; D’Accorso, N.B.; Alves, R.J.; Souza Filho, J.D.;
Prado, R.F. Synthesis and characterization of some nitrogen heterocycles from
D-galactose derivatives. J. Heterocyclic Chem. 1999, 36, 1129–1133.
17. Klier, A.H.; Alves, R.J.; Prado, M.A.F.; Souza Filho, J.D.; D’Accorso, N.B. Syn-
thesis of new five membered nitrogen containing heterocycles bearing D-galactose
side chains. Synth. Commun. 2000, 30 (23), 4361–4374.
18. Hall, D.M. A practical synthesis of methyl 4,6-O-benzylidene-a- and -b-D-
glucopyranoside. Carbohydr. Res. 1980, 86, 158–160.

442
Pedrosa et al.
19. Pietraszkiewicz, M.; Jurczak, J. Synthesis of chiral diaza-crown ethers incorporat-
ing carbohydrate units. Tetrahedron 1984, 40 (15), 2967–2970.
20. Lipta´k, A.; Joda´l, I.; Na´na´si, P. Stereoselective ring-cleavage of 3-O-benzyl- and
2,3-di-O-benzyl-4,6-O-benzylidenehexopyranoside derivatives with the LiAlH4-
AlCl3 reagent. Carbohydr. Res. 1975, 44, 1–11.
21. Kohn, A.; Schmidt, R.R. Untersuchungen zur synthese von C1-verzweigten cycliten
aus D-glucose. Liebigs Ann. Chem. 1987, 12, 1045–1054.
22. Sugihara, J.M.; Teerlink, W.J.; MacLeod, R.; Dorrence, S.M.; Springer, C.H. Direct
syntheses of some cyano and nitro derivatives of carbohydrates by nucleophilic
displacement. J. Chem. Soc. 1963, 28, 2079–2082.
23. Duncia, J.V.; Pierce, M.E.; Santella, J.B. Three synthetic routes to a sterically
hindered tetrazole. A new one-step mild conversion of an amide into a tetrazole. J.
Org. Chem. 1991, 56, 2395–2400.
24. Clapp, L.B. 1,2,3- and 1,2,4-oxadiazoles. In Comprehensive Heterocyclic
Chemistry: The Structure, Reactions, Synthesis and Uses of Heterocyclic
Compounds; Katritzky, A.R., Rees, C.W., Eds.; Imprenta Pergamon Press: Oxford,
1984; Vol. 6, 365–391.
25. Gyoung, Y.S.; Shim, J.; Yamamoto, Y. Regiospecific synthesis of 2-allylated-5-
substituted tetrazoles via palladium-catalyzed reaction of nitriles, trimethylsilyl
azide, and allyl acetates. Tetrahedron Lett. 2000, 41, 4193–4196.
Received April 10, 2003
Accepted July 14, 2003