Solid-phase synthesis of 5-aminotetrazoles

Article abstract of DOI:10.1016/j.tetlet.2004.07.160

A solid-phase synthesis of 5-aminotetrazoles is described. Resin-bound thioureas were displaced by sodium azide in the presence of HgCl₂ and following nucleophilic cyclization produced the resin-bound products. The desired 5-aminotetrazoles were cleaved from the resin using 95% trifluoroacetic acid in dichloromethane in good yield and purity.

Full text of DOI:10.1016/j.tetlet.2004.07.160

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7787–7789
Solid-phase synthesis of 5-aminotetrazoles
Yongping Yu,a,b,* John M. Ostresh and Richard A. Houghtena,*
a
a
Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, CA 92121, USA
College of Pharmaceutical Sciences, Zhejiang University, 353 Yan An Road, Hangzhou, Zhejiang 310031, PR China
b
Received 10 February 2004; revised 26 July 2004; accepted 26 July 2004
Abstract—A solid-phase synthesis of 5-aminotetrazoles is described. Resin-bound thioureas were displaced by sodium azide in the
presence of HgCl and following nucleophilic cyclization produced the resin-bound products. The desired 5-aminotetrazoles were
cleaved from the resin using 95% trifluoroacetic acid in dichloromethane in good yield and purity.
2
Ó 2004 Elsevier Ltd. All rights reserved.
5
6
The rapid synthesis of large organic compound collec-
tions by combinatorial methods using solid-phase and
solution-phase approaches facilitate the discovery of
anti-allergic,
7
activities.
antiviral,
and cognition disorder
1
pharmaceutical lead compounds. These approaches
enable the synthesis of large numbers of individual
compounds as well as mixture-based combinatorial
Recently, several reports have described syntheses of 5-
8
aminotetrazoles using azide anion in solution. As part
of our ongoing efforts directed toward the solid-phase
synthesis of small molecule heterocyclic compounds
2
libraries for use in high-throughput screening. Substi-
9
tuted heterocyclic compounds offer a high degree of
structural diversity and have proven to be broadly use-
ful as therapeutic agents. As a result, an increasing
range and number of pharmaceutically useful hetero-
cyclic compounds have been prepared using solid-
and the generation of combinatorial libraries, we report
here an efficient strategy for the solid-phase synthesis of
5-aminotetrazoles.
The parallel solid-phase synthesis of 5-aminotetrazoles
3
phase methodologies. There is considerable interest
in the medicinal and biological applications of tetra-
was carried out on the solid-phase using the ÔteabagÕ
methodology. The reaction sequence is illustrated in
Scheme 1.
1
0
4
zoles, including 5-aminotetrazoles, due to their reported
S
i
R1
ii
R2
CHO
N
H
N
R
N
H
1
3
2
1
N N
N N
R1
iii
N
N
R
iv
N
N
N
H
1
N
R2
R2
4
5
1
Scheme 1. Solid-phase synthesis of 5-aminotetrazoles 5. Reagents and conditions: (i) R NH
2
(6equiv, 0.1M), NaBH(OAc)
3
(6equiv, 0.1M) in DMF/
2
AcOH (99:1), rt, overnight; (ii) R NCS (6equiv, 0.1M) in DCM, rt, overnight; (iii) NaN
overnight; (iv) TFA/DCM (95:5), 1h.
3
(6equiv, 0.1M), HgCl (6equiv, 0.1M) in DMF, rt,
2
*
0
Corresponding authors. Tel.: +1 858 455 3803; fax: +1 858 455 3804; e-mail addresses: yyu@tpims.org; rhoughten@tpims.org
040-4039/$ - see front matter Ó 2004Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.07.160

7788
Y. Yu et al. / Tetrahedron Letters 45 (2004) 7787–7789
Table 1. Individual 5-aminotetrazoles
N N
R1
N
N
N
H
R2
1
R
2
R
a
b
c
Entry
Product
Yield
Purity
MW (found)
+
295.1 ([M + Na] )
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
C
C
C
6
6
6
H
H
H
5
5
5
CH
CH
CH
2
CH
CH
CH
2
2
2
4-CH
3-FC
CH CH
4-CH
3
OC
6
H
4
4
68
75
63
71
75
62
73
71
65
61
67
72
68
72
83
81
83
79
86
82
85
78
81
78
77
82
76
81
+
283.3 ([M + H] )
2
6
H
4
+
217.2 ([M + H] )
2
3
2
+
311.3 ([M + H] )
4-CH
4-CH
3
OC
6
H
H
4
CH
CH
2
3
OC
6
H
+
233.3 ([M + H] )
3
OC
6
4
2
CH
CH
3
CH
CH
2
+
235.3 ([M + H] )
4-FC
2-CF
2-CF
3-CF
3-CF
6
H
4
CH
2
CH
2
3
2
+
319.3 ([M + H] )
5g
5h
5i
3
C
3
C
3
C
3
C
6
H
H
H
H
4
4
4
4
CH
CH
CH
CH
2
2
2
C
CH
6
H
5
+
271.2 ([M + H] )
6
6
6
3
CH
2
+
319.3 ([M + H] )
C
6
H
5
+
217.2 ([M + H] )
1
1
1
1
1
0
1
2
3
4
5j
2
CH
3
CH
2
+
217.2 ([M + H] )
5k
5l
CH
CH
CH
CH
3
3
3
3
CH
CH
CH
2
2
3
CH
CH
2
CH
2
C
4-CH
6
H
5
+
247.3 ([M + H] )
2
CH
2
3
OC
6
H
4
+
232.1 ([M + H] )
5m
5n
NCH
CH
2
CH
2
C
C
6
H
H
5
5
+
219.1 ([M + H] )
OCH
2
2
6
+
263.1 ([M + H] )
1
1
5
6
5o
5p
2-FC
6
H
4
69
72
83
78
CH
2
O
+
257.2 ([M + H] )
CH2
C
6
H
5
a
b
c
Percent yields are based on the weight of crude material and are relative to the initial loading of the resin.
The purity of the crude material was estimated based on analytical traces at k = 214nm.
Confirmed by mass spectra (ESI).
Starting from 4-(4-formyl-3-methoxyphenoxy)butyryl
AM resin 1, reductive amination was used to attach a
primary amine to the resin in the presence of NaBH-
(OAc) in DMF. The resin-bound amine 2 was then
3
reacted with an isothiocyanate to yield the correspond-
placed by sodium azide and subsequent intramolecular
nucleophilic cyclization gave the resin-bound products
4. The resulting desired 5-aminotetrazoles 5 were
cleaved from the resin with 95% trifluoroacetic acid in
dichloromethane for 1h in good yield and purity.
The results are summarized in Table 1. The results show
1
1
ing thiourea 3. The mercury-activated thiourea was dis-
Figure 1. LC–MS of crude 5a.

Y. Yu et al. / Tetrahedron Letters 45 (2004) 7787–7789
7789
2
that either alkyl or aryl R groups on 3 gave products in
7. Mitch, C. H.; Quimby, S. J. Int. Patent WO 9851312,
998; Chem. Abstr. 1998, 130, 13997.
2
good purity independent of the nature of the R substit-
1
8
. (a) Katritzky, A. R.; Rogovoy, B. V.; Kovalenko, K. V. J.
Org. Chem. 2003, 68, 4941; (b) Batey, R. A.; Powell, D. A.
Org. Lett. 2000, 2, 3237; (c) Miller, A. E.; Feenay, D. J.;
Ma, Y.; Zarcone, L.; Aziz, M. A.; Magnuson, E. Synth.
Commun. 1990, 20, 217.
uent Figure 1 illustrates a typical LC–MS spectrum of
crude product 5a.
In conclusion, we have demonstrated an efficient
approach for the parallel solid-phase synthesis of disub-
stituted 5-aminotetrazoles from readily available amines
9
. (a) Yu, Y.; Ostresh, J. M.; Houghten, R. A. J. Org. Chem.
2
003, 68, 183; (b) Yu, Y.; Ostresh, J. M.; Houghten, R. A.
Tetrahedron Lett. 2003, 44, 2569; (c) Yu, Y.; Ostresh, J.
M.; Houghten, R. A. J. Comb. Chem. 2004, 6, 83.
1
2
(
R ) and isothiocyanates (R ) building blocks.
1
0. Houghten, R. A. Proc. Natl. Acad. Sci. U.S.A. 1985, 82,
131.
Acknowledgements
5
1
1. General procedure for the synthesis of disubstituted 5-
aminotriazoles: 110mg of 4-(4-formyl-3-methoxyphen-
oxy)butyryl AM resin (0.89mmol/g, 100–200mesh, 1%
DVB, Novabiochem, San Diego) was sealed within a
polypropylene mesh packet. Reactions were carried out in
This work was supported by National Cancer Institute
Grant No. CA78040 (Houghten) and National Institute
of Drug Abuse Grant No. DA09410 (Houghten).
References and notes
polypropylene bottles. A solution of NaBH(OAc)3
(6equiv, 0.1M) in 6mL DMF containing 1% AcOH was
1
. (a) Combinatorial Chemistry: Synthesis, Analysis, Screen-
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Wiley & Sons: New York, 1998; (c) Dolle, R. E. J. Comb.
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added to the resin, followed by the addition of an amine
(6equiv, 0.1M). The reaction was shaken at room
temperature overnight, followed by washes with DMF
(three times), DCM (two times) and methanol (three
times). The resulting resin-bound 2 was treated with an
isothiocyanate (6equiv, 0.1M) in DCM overnight to yield
the resin-bound thioureas 3. The resin was washed with
DMF (three times), DCM (two times), and methanol
(three times). Resin-bound compound 3 was reacted with
sodium azide (6equiv, 0.1M) and mercury chloride
(6equiv, 0.1M) in DMF at room temperature overnight
to afford the resin-bound 3-aminotetrazole 4. After
washing with DMF (three times), DCM (three times),
and MeOH (three times), the resin was cleaved with 95%
trifluoroacetic acid in dichloromethane for 1h to give the
corresponding crude product 5. The product was charac-
terized by electrospray LC–MS under ESI conditions.
Figure 1 illustrates a typical LC–MS spectrum of crude
product 5a. Following purification by RP-HPLC, the
2
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1
identity of the compounds was confirmed by H NMR.
[1-(4-Methoxy-phenyl)-1H-tetrazole-5-yl]-phenethylamine
+
1
(
b) Peet, N. P.; Baugh, L. E.; Sundler, S.; Lewis, J. E.;
(5a): LC–MS (ESI) m/z 318.2 (M + Na ). H NMR
(500MHz, DMSO): d 2.87 (2H, t, J = 7.8), 3.45–3.49
(2H, m), 3.83 (s, 3H), 7.12–7.14(2H, m), 7.18–7.22 (3H,
Matthews, E. H.; Olberding, E. L.; Shah, D. N. J. Med.
Chem. 1986, 29, 2403.
1
3
6
. Girijavallabhan, V. M.; Pinto, P. A.; Ganguly, A. K.;
Versace, R.W. Eur. Patent EP 274867, 1988; Chem. Abstr.
m), 7.28–7.31 (2H, m), 7.40–7.42 (2H, m). C NMR
(DMSO, 125MHz): d 34.7, 45.1, 55.6, 114.9, 125.7, 126.1,
126.5, 128.3, 128.7, 139.2, 155.1, 159.9.
1
989, 110, 23890.