A general route to 5-aminotetrazoles

Article abstract of DOI:10.1021/jo0266543

Various di- and trisubstituted (benzotriazolyl)- carboximidamides were used for the preparation of N,N-di-and 1,N,N-trisubstituted 5-aminotetrazoles 3a-e and 6a-d under mild conditions in good to excellent yields.

Full text of DOI:10.1021/jo0266543

SCHEME 1
A Gen er a l Rou te to 5-Am in otetr a zoles
Alan R. Katritzky,* Boris V. Rogovoy, and
Katherine V. Kovalenko
Center for Heterocyclic Compounds,
Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
katritzky@chem.ufl.edu
Received November 4, 2002
Abstr a ct: Various di- and trisubstituted (benzotriazolyl)-
carboximidamides were used for the preparation of N,N-di-
and 1,N,N-trisubstituted 5-aminotetrazoles 3a -e and 6a -d
under mild conditions in good to excellent yields.
Tetrazoles exhibit a wide scope of biological activity.1
In particular, 5-aminotetrazoles show anti-allergic and
anti-asthmatic,2 antiviral and anti-inflammatory,3 anti-
neoplastic,4 and cognition disorder activities.5a Activity
as CCK antagonists5b and antibiotics against a range of
bacteria6 has been observed.
Syntheses of substituted 5-aminotetrazole derivatives
fall into four main types (Scheme 1): (1) amino group or
ring functionalization of 5-aminotetrazole,2d,7a,b which
often results in mixtures of isomers;6,7c (2) the substitu-
tion of a leaving group in the tetrazole 5-position with
amines;8 (3) reactions of aminoguanidine derivatives with
sodium nitrite;9 and (4) various azide-mediated tetrazole
ring constructions.
diimides9c,10a or cyanamides;11 and (ii) nucleophilic sub-
stitution by N3- of (a) chlorine in R-chloroformamidines,12a
which can be obtained from nitriles and alkyl halides,12b-d
(b) the sulfite anion in aminoiminomethanesulfonic
acids,12e and (c) sulfur from thioureas in the presence of
mercury12f or lead salts9a (Scheme 1).
We now report an efficient preparation of substituted
5-aminotetrazoles by a variation of route 4(ii) starting
from 1-(benzotriazolyl)carboximidamides. 1-(Benzotria-
zolyl)carboximidamides and their acyl derivatives were
previously demonstrated to be efficient reagents for the
preparation of polysubstituted guanidines,13 1,2,4-tria-
zoles,14 1,3,5-triazin-2-ones and 1,3,5-triazine-2-thiones,15
and 2-amino-1,3-quinazoline-4-thiones.16
Formations of 5-aminotetrazole rings using azide anion
include the following: (i) addition of NaN3 to carbo-
(1) (a) Wittenberger, S. J . Org. Prep. Proced. Int. 1994, 26, 499. (b)
Butler, R. N. In Comprehensive Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996;
Vol. 4, p 674.
N,N-Disubstituted (benzotriazolyl)carboximidamides
and their acyl derivatives were obtained by a known
procedure13,14 starting from di(benzotriazolyl)methan-
imine 1 in reactions with an appropriate secondary amine
(Scheme 2). N,N′-Di- and N,N,N′-trisubstituted 1-(benzo-
triazolyl)carboximidamides were obtained from the re-
spective (benzotriazolyl)carboximidoyl chlorides.16 N,N-
Disubstituted (benzotriazolyl)carboximidamides were
treated with sodium azide in chloroform in the presence
(2) (a) Yoshinaga, J .; Shogaki, T.; Kakita, T.; Ozeki, H.; Sugimoto,
N.; Kato, Y. Eur. Patent EP 262873, 1988; Chem. Abstr. 1988, 109,
54782. (b) Cetenko, W. A.; Connor, D. T.; Mullican, M. D.; Sorenson,
R. J . Eur. Patent EP 249236, 1987; Chem. Abstr. 1988, 108, 150482.
(c) Connor, D. T.; Unangst, P. C.; Weikert, R. J . Eur. Patent EP 279466,
1988; Chem. Abstr. 1988, 109, 231035. (d) Ford, R. E.; Knowles, P.;
Lunt, E.; Marshall, S. M.; Penrose, A. J .; Ramsden, C. A.; Summers,
A. J . H.; Walker, J . L.; Wright, D. E. J . Med. Chem. 1986, 29, 538. (e)
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Olberding, E. L.; Shah, D. N. J . Med. Chem. 1986, 29, 2403.
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W. Eur. Patent EP 274867, 1988; Chem. Abstr. 1989, 110, 23890.
(4) (a) Akimoto, H.; Ootsu, K.; Itoh, F. Eur. Patent EP 530537, 1993;
Chem. Abstr. 1993, 119, 226417. (b) Taveras, A. G.; Mallams, A. K.;
Afonso, A. Int. Patent WO 9811093, 1998; Chem. Abstr. 1998, 128,
230253.
(10) Ding, Y.-X.; Weber, W. P. Synthesis 1987, 823.
(11) (a) Moderhack, D.; Goos, K.-H.; Preu, L. Chem. Ber. 1990, 123,
1575. (b) Garbrecht, W. L.; Herbst, R. M. J . Org. Chem. 1953, 18, 1014.
(c) Herbst, R. M.; Roberts, C. W.; Harvill, E. J . J . Org. Chem. 1951,
16, 139. (d) Marchalin, M.; Martvon, A. Collect. Czech. Chem. Commun.
1980, 45, 2329.
(5) (a) Mitch, C. H.; Quimby, S. J . Int. Patent WO 9851312, 1998;
Chem. Abstr. 1998, 130, 13997. (b) Castro Pineiro, J . L.; Chambers,
M. S.; Hobbs, S. C.; Matassa, V. G. Int. Patent WO 9319052, 1993;
Chem. Abstr. 1994, 120, 134543.
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Tetrahedron Lett. 1984, 25, 911.
(7) (a) Peet, N. P. J . Heterocycl. Chem. 1987, 24, 223. (b) Kato, T.;
Chiba, T.; Daneshtalab, M. Chem. Pharm. Bull. 1976, 24, 2549. (c)
Butler, R. N.; Scott, F. L. J . Org. Chem. 1966, 31, 3182.
(8) (a) Klich, M.; Teutsch, G. Tetrahedron 1986, 42, 2677. (b) Barlin,
G. B. J . Chem. Soc. B 1967, 641.
(9) (a) Finnegan, W. G.; Henry, R. A.; Lieber, E. J . Org. Chem. 1953,
18, 779. (b) J ensen, K. A.; Holm, A.; Rachlin, S. Acta Chem. Scand.
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22, 925.
(12) (a) Ried, W.; Erle, H.-E. Liebigs Ann. Chem. 1982, 201. (b) Ried,
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Anders, B.; Klauke, E.; Tarnow, H.; Zumach, G. Angew. Chem., Int.
Ed. Engl. 1969, 8, 20. (d) Ku¨hle, E.; Anders, B.; Zumach, G. Angew.
Chem., Int. Ed. Engl. 1967, 6, 649. (e) Miller, A. E.; Feenay, D. J .; Ma,
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217. (f) Batey, R. A.; Powell, D. A. Org. Lett. 2000, 2, 3237.
(13) Katritzky, A. R.; Rogovoy, B. V.; Chassaing, C.; Vvedensky, V.
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(14) Katritzky, A. R.; Rogovoy, B. V.; Vvedensky, V. Y.; Kovalenko,
K.; Steel, P. J .; Markov, V. I.; Forood, B. Synthesis 2001, 897.
(15) Katritzky, A. R.; Rogovoy, B. V.; Vvedensky, V. Y.; Hebert, N.;
Forood, B. J . Org. Chem. 2001, 66, 6797.
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10.1021/jo0266543 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/09/2003
J . Org. Chem. 2003, 68, 4941-4943
4941

TABLE 1. Syn th esis of 5-Am in otetr a zoles 3a -e a n d 6a -d
entry
compd
R1
HNR2
yield, %
mp [lit. mp] (°C)
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
6a
6b
6c
6d
H
H
H
H
H
morpholine
N-methylpiperazine
pyrrolidine
piperidine
diethylamine
morpholine
pyrrolidine
morpholine
diethylamine
80
27
60
73
61
89
71
41
62
168.0-169.0 [180.5-181.018
270.0 dec [-]
]
]
227.0 dec [231 dec18
]
195.0 dec [199.0-199.518
]
121.5-122.5 [124.0-125.018
148.0-150.0 [-]
160.0-161.0 [-]
201.0 dec [-]
TsCH2
TsCH2
4-NO2C6H4
TsCH2
77.0-79.0 [-]
SCHEME 2
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were determined using a
capillary melting point apparatus equipped with digital
a
thermometer and are uncorrected. 1H and 13C NMR spectra were
recorded on a 300 MHz NMR spectrometer (300 and 75 MHz,
respectively) using CDCl3 or DMSO-d6 as a solvent with tet-
ramethylsilane as an internal standard. Column chromatogra-
phy was conducted with silica gel 230-400 mesh. All other
reagents were of reagent grade and were used without purifica-
tion.
SCHEME 3
Di(1H-ben zotr ia zol-1-yl)m eth a n im in e (1) a n d 1H-Ben -
zotr ia zol-1-yl(2H-ben zotr ia zol-2-yl)m eth a n im in e (1′) (uti-
lized as a 2:1 mixture of isomers) were prepared and character-
ized according to the previously published procedure.13
(1-Ben zotr ia zolyl)ca r boxim id a m id es 2a-e were prepared
according to a previously published procedure13 and were used
as crude products without purification as follows: To a suspen-
sion of di(1H-benzotriazol-1-yl)methanimine 1 (1.67 g, 0.006 mol)
in dichloromethane (30 mL) was added dropwise the appropriate
amine (0.006 mol, 1 equiv) under vigorous stirring. Completion
of the reaction was monitored by TLC. Upon completion, the
reaction mixture was washed twice with a 10% solution of Na2-
CO3, dried over MgSO4, and filtered. The solvent was evaporated
under reduced pressure to afford compounds 2a -e in analytical
purity.
Gen er a l P r oced u r e for th e P r ep a r a tion of 5-Am in otet-
r a zoles 3a -e. To a solution of starting (1-benzotriazolyl)-
carboximidamide 2 (1 equiv) in chloroform were added subse-
quentially sodium azide (1 equiv) and acetic acid (1 equiv). The
mixture obtained was allowed to react overnight at room
temperature with stirring. Upon completion (TLC monitoring),
the solvent was evaporated under reduced pressure and the
desired aminotetrazole 3 was isolated by gradient column
chromatography with a mixture of ethyl acetate with hexanes
as eluent (from 5% to 50% of ethyl acetate, step 5%).
5-(4-Mor p h olin yl)-1H-1,2,3,4-tetr a zole (3a ): white prisms;
1H NMR δ 3.34-3.37 (m, 4H), 3.70-3.73 (m, 4H); 13C NMR δ
46.9, 65.2, 159.7. Anal. Calcd for C5H9N5O: N, 45.14. Found:
N, 44.77.
of acetic acid to give the desired N,N-disubstituted
5-aminotetrazoles 3a -e in moderate to high yields
(Scheme 2). Reactions were performed at room temper-
ature and stirred overnight. Signals ranging from 156
to 159 ppm (depending on the nature of the substituents
in the amino functionality) in the 13C spectra were
assigned to the tetrazole carbon atoms.
According to the 1H NMR spectra, the amount of
compound 3b in the crude reaction mixture was about
70%. However, due to its low solubility and high polarity,
only 27% of the desired compound 3b was isolated after
gradient column chromatography (Table 1).
Di- and trisubstituted (benzotriazolyl)carboximida-
mides 5a ,b, obtained from (benzotriazolyl)carboximidoyl
chlorides 4a ,b,16 provide access to 1,N,N-trisubstituted
5-aminotetrazoles 6a -d (Scheme 3). The versatility of
intermediates 4a ,b is demonstrated by the variety of
substituents (alkyl, aryl, heteroaryl) that can be intro-
duced at all three possible sites of the molecule. Reactions
were performed at room temperature, and the desired
compounds 6a -d were obtained in 41-90% yield.
In conclusion, in this work we have developed an
efficient procedure for the preparation of substituted
5-aminotetrazoles. Unlike previously described methods,
which frequently require unstable and/or moisture-sensi-
tive starting materials, such as isocyanide dichlorides,12c,d
chloroformamidines,12c or aminoiminomethanesulfonic
acids,12b our method uses (benzotriazolyl)carboximida-
mides as starting compounds, which are relatively stable
and can be prepared in high yields. The reaction condi-
tions for the formation of the final 5-aminotetrazoles are
mild and purification is simple. Benzotriazole is a good
leaving group that is easily introduced to form intermedi-
ates that are typically stable and nonvolatile. Benzo-
triazole formed during the substitution step of the
reaction sequence is environmentally safe and can be
recycled.17
5-(4-Meth ylp ip er a zin e)-1H-1,2,3,4-tetr a zole (3b): white
1
microcrystals; H NMR δ 2.17 (s, 3H), 2.34-2.37 (m, 4H), 3.18
(s, 4H); 13C NMR δ 46.1, 48.3, 54.5, 168.2; HRMS (EI) calcd for
C6H12N6 (M) 168.1123, found 168.1113.
5-(1-P yr r olid in yl)-1H-1,2,3,4-tetr a zole (3c): white prisms;
1H NMR δ 1.92 (s, 4H), 3.33 (s, 4H); 13C NMR δ 25.1, 48.2, 156.8.
Anal. Calcd for C5H9N5: C, 43.16; H, 6.52; N, 50.33. Found: C,
43.44; H, 6.60; N, 50.02.
5-(1-P ip er id in yl)-1H-1,2,3,4-tetr a zole (3d ): white micro-
1
crystals; H NMR δ 1.55 (s, 6H), 3.35 (s, 4H); 13C NMR δ 23.4,
24.3, 47.7, 159.4. Anal. Calcd for C6H11N5: N, 45.72. Found: N,
45.82.
N,N-Dieth yl-1H-1,2,3,4-tetr a zol-5-a m in e (3e): white flakes;
1H NMR δ 1.23 (t, 6H, J ) 7.1 Hz), 3.58 (q, 4H, J ) 7.1 Hz); 13
NMR δ 12.8, 44.4, 157.7.
C
P r ep a r a tion of Com p ou n d s 6a -d . Compounds 4a ,b and
5a -d were prepared according to a previously reported proce-
(17) Katritzky, A. R.; Lan, X.; Yang, J . Z.; Denisko, O. V. Chem.
Rev. 1998, 98, 409.
(18) Garbrecht, W. L.; Herbst, R. M. J . Org. Chem. 1953, 18, 1003.
4942 J . Org. Chem., Vol. 68, No. 12, 2003

dure16 and were used without isolation and purification for the
preparation of 1,N,N-trisubstituted-1H-tetrazoles.
5-(P yr r olid in -1-yl)-1-(tolu en e-4-su lfon ylm eth yl)-1H-tet-
r a zole (6b): white microcrystals; 1H NMR δ 2.04-2.08 (m, 4H),
2.46 (s, 3H), 3.68-3.72 (m, 4H), 5.55 (s, 2H), 7.35 (d, 2H, J )
8.1 Hz), 7.58 (d, 2H, J ) 8.1 Hz); 13C NMR δ 21.8, 25.7, 49.4,
To a solution of (benzotriazolyl)carboximidoyl chloride 4
(0.0026 mol) in chloroform (20 mL) was added the amine (0.0026
mol) followed by the addition of triethylamine (0.0026 mol) at
room temperature with vigorous stirring. The reaction was
monitored by TLC. Upon completion, the reaction mixture was
washed twice with water, dried over MgSO4, and filtered. The
solvent was partially removed under reduced pressure.
65.5, 129.0, 130.2, 132.7, 146.5, 155.0. Anal. Calcd for C13H17
-
N5O2S: C, 50.80; H, 5.57; N, 22.78. Found: C, 50.58; H, 5.88;
N, 22.72.
5-(Mor p h olin -4-yl)-1-(4-n it r op h en yl)-1H-t et r a zole (6c):
white prisms; 1H NMR δ 3.16-3.19 (m, 4H), 3.66-3.69 (m, 4H),
8.02 (d, 2H, J ) 8.8 Hz), 8.48 (d, 2H, J ) 8.9 Hz); 13C NMR δ
48.7, 65.1, 125.1, 125.4, 139.2, 147.5, 157.4. Anal. Calcd for
To a solution of obtained (benzotriazolyl)carboximidamide 5
in chloroform (20 mL) was added sodium azide (0.0031 mol)
followed by the addition of acetic acid (0.0031 mol). During the
reaction, the formation of a cloudy white precipitate was
observed. Upon completion (TLC monitoring), the reaction
mixture was washed twice with 10% Na2CO3. The organic layer
was separated, dried over MgSO4, and concentrated. The final
1,N,N-trisubstituted 5-aminotetrazoles 6a -d were isolated by
gradient column chromatography (eluent: EtOAc/hexanes).
5-(Mor p h olin -4-yl)-1-(tolu en e-4-su lfon ylm eth yl)-1H-tet-
r a zole (6a ): white microcrystals; 1H NMR δ 2.48 (s, 3H), 3.44-
3.47 (m, 4H), 3.83-3.86 (m, 4H), 5.45 (s, 2H), 7.39 (d, 2H, J )
8.1 Hz), 7.65 (d, 2H, J ) 8.2 Hz); 13C NMR δ 21.8, 50.1, 65.2,
C
11H12N6O3: C, 47.83; H, 4.38; N, 30.42. Found: C, 47.89; H,
4.30; N, 30.54.
5-(N,N-Dieth yla m in o)-1-(tolu en e-4-su lfon ylm eth yl)-1H-
1
tetr a zole (6d ): white microcrystals; H NMR δ 1.22 (t, 6H, J
) 7.1 Hz), 2.46 (s, 3H), 3.52 (q, 4H, J ) 7.1 Hz), 5.45 (s, 2H),
7.36 (d, 2H, J ) 8.2 Hz), 7.61 (d, 2H, J ) 8.4 Hz); 13C NMR δ
13.0, 21.7, 45.7, 65.7, 128.9, 130.2, 132.8, 146.5, 157.3. Anal.
Calcd for C13H19N5O2S: C, 50.47; H, 6.19; N, 22.64. Found: C,
50.77; H, 6.34; N, 22.95.
66.0, 129.1, 130.3, 132.7, 146.8, 158.9. Anal. Calcd for C13H17
N5O3S: C, 48.28; H, 5.30. Found: C, 48.57; H, 5.62.
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