A general synthetic method for the formation of substituted 5-aminotetrazoles from thioureas: a strategy for diversity amplification.

Article abstract of DOI:10.1021/ol006465b

A general method for the synthesis of 5-aminotetrazoles is outlined using the mercury(II)-promoted attack of azide anion on a thiourea. The reaction proceeds through a guanyl azide intermediate, which undergoes electrocyclization to the tetrazole. The method is high yielding and provides access to mono-, di-, and trisubstituted 5-aminotetrazoles, targets of potential interest for combinatorial library development.

Full text of DOI:10.1021/ol006465b

ORGANIC
LETTERS
2000
Vol. 2, No. 20
3237-3240
A General Synthetic Method for the
Formation of Substituted
5-Aminotetrazoles from Thioureas: A
Strategy for Diversity Amplification
Robert A. Batey* and David A. Powell
Department of Chemistry, Lash Miller Chemical Laboratories, UniVersity of Toronto,
Toronto, ON, Canada M5S 3H6
rbatey@chem.utoronto.ca
Received August 15, 2000
ABSTRACT
A general method for the synthesis of 5-aminotetrazoles is outlined using the mercury(II)-promoted attack of azide anion on a thiourea. The
reaction proceeds through a guanyl azide intermediate, which undergoes electrocyclization to the tetrazole. The method is high yielding and
provides access to mono-, di-, and trisubstituted 5-aminotetrazoles, targets of potential interest for combinatorial library development.
Combinatorial chemistry is now an indispensable technique
in the pharmaceutical and agrochemical industries.1 The
ability to synthesize and test compounds in a high-throughput
manner offers many advantages, but new synthetic methods
are required to meet the demands of creating highly diverse
compound libraries.2 Diversity is usually created through the
combination of a scaffold synthesis and the functionalization
of pendant reactive groups such as amines, alcohols, thiols,
carboxylic acids, etc. An example of a widely used func-
tionalization procedure is the formation of thioureas through
the coupling of amines with isothiocyanates. The resultant
thiourea functionality may be present in the target structure,
but can also be used for further synthetic transformations
such as guanidine formation. As part of an interest in such
“diversity amplifying” (DA) reactions, we have initiated a
project on the synthesis of 5-aminotetrazoles 1 and their use
in peptidomimetic structures. We envisaged that thioureas
could serve as versatile intermediates for the synthesis of
highly substituted 5-aminotetrazoles 1, in a transformation
which can be viewed as both a functionalization and a
scaffold synthesis reaction.
There is considerable interest in the medicinal and biologi-
cal applications of tetrazoles 2,3 particularly those containing
a ring N-H (2, R2 ) H), as they are isosteric with carboxylic
acids. The comparable acidity and increased metabolic
stability of tetrazoles 2 (R2 ) H) has resulted in their use in
a variety of pharmacologically active compounds.3,4 1,5-
Disubstituted tetrazoles 2 have also been incorporated into
biologically active peptides such as bradykinin5 and de-
(1) Dolle, R. E.; Nelson, K. H., Jr. J. Comb. Chem. 1999, 1, 235-282.
(2) Weber, L. Curr. Opin. Chem Biol. 2000, 4, 295-302.
(4) For a few recent examples, see (a) White, A. D.; Creswell, M. W.;
Chucholowski, A. W.; Blankley, C. J.; Wilson, M. W.; Bousley, R. F.;
Essenburg, A. D.; Hamelehle, K. L.; Krause, B. R.; Stanfield, R. L.;
Dominick, M. A.; Neub, M. J. Med. Chem. 1996, 39, 4382-4395. (b)
Larsen, R. D.; King, A. O.; Chen, C. Y.; Corley, E. G.; Foster, B. S.;
Roberts, F. E.; Yang, C.; Lieberman, D. R.; Reamer, R. A.; Tschaen, D.
M.; Verhoeven, T. R.; Reider, P. J. J. Org. Chem. 1994, 59, 6391-6394.
(5) Zabrocki, J.; Dunbar, J. B.; Marshall, K. W.; Toth, M. V.; Marshall,
G. R. J. Org. Chem. 1992, 57, 202-209.
(3) For reviews of tetrazole chemistry see: (a) Moderhack, D. J. Prakt.
Chem. 1998, 340, 687-709. (b) Butler, R. N. ComprehensiVe Heterocyclic
Chem. II; Katrinsky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon
Press: New York, 1996; Vol. 4; pp 621-678. (c) Wittenberger, S. J. Org.
Prep. Proced. Int. 1994, 26, 499-531. (d) Butler, R. N. ComprehensiVe
Heterocyclic Chemistry; Potts, K. T., Ed.; Pergamon Press: New York,
1984; Vol 5; pp 791-838.
10.1021/ol006465b CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/13/2000

aminooxytocin,6 acting as cis-amide bond mimics.7 Our
interest is in the utility of highly substituted 5-aminotetrazoles
1, which are less common targets. Although there a variety
of procedures for the synthesis of 2,3 currently the only
method for the direct construction of trisubstituted 5-amino-
tetrazoles 1, with potentially general applicability, requires
a three-step procedure involving diazotization under relatively
harsh conditions.8,9 Disubstituted 5-aminotetrazoles 1 (R1/
R2 * H, R3 ) H) can be similarly accessed, or can be
generated through the addition of hydrazoic acid to cyan-
amides at high temperatures.10 Disubstituted 5-aminotetra-
zoles 1 (R1/R3 * H, R2 ) H) are typically prepared from
aminoguanidines through the diazotization method,11 or from
the reaction of carbodiimides with sodium azide or hydrazoic
acid.12 A modification of the latter method involving tandem
acylation has led to a synthesis of trisubstituted 5-amino-
tetrazoles 1 (R1/R3 ) aryl, R2 ) benzoyl).13 Generally,
however, selective alkylation of aminotetrazoles is not pos-
sible because of competitive formation of 1- and 2-alkylated-
5-aminotetrazoles.4a
commercially available amines and aryl, alkyl, and acyl
isothiocyanates make this approach all the more appealing.
Phenyl-n-propylthiourea was chosen as a test substrate for
the synthesis of a disubstituted 5-aminotetrazole and was
prepared from the reaction of n-propylamine with phenyl
isothiocyanate. Reaction with mercury(II) chloride, sodium
azide, and triethylamine in DMF15 at room temperature
furnished exclusively the 1-phenyl 5-propylaminotetrazole
in quantitative yield (Table 1, entry 1).16 The regioselectivity
Table 1. Formation of Mono- and Disubstituted
5-aminotetrazoles 1 via Thioureas 5a
yield of 5
yield of 1
entry
R1
R2
R3
Ph
Bn
Bz
COOEt
Ph
[%]
[%]
1
2
3
4
5
Pr
Pr
Pr
H
H
H
H
H
99
99
63
96
72
99
89b
0
0
76
MeOOC(CH2)3
H
There is clearly a need for a general method for the
synthesis of 5-aminotetrazoles 1 of any substitution pattern,
using readily available starting materials, which can be
efficiently coupled under mild conditions. We envisaged that
such a method would allow us to use the 5-aminotetrazole
moiety as a scaffold for combinatorial elaboration. By
analogy with the mercury(II)-promoted guanadinylation of
di-Boc-protected thioureas with primary or secondary amines,
developed by Kim and Qian,14 we reasoned that the use of
sodium azide as a nucleophile would allow for the synthesis
of 5-aminotetrazoles 1. Thus, displacement by sodium azide
of a mercury(II)-activated thiourea would generate an
intermediate guanyl azide 7, which upon electrocyclization
would render the 5-aminotetrazole 1 (Scheme 1). It is known
a For experimental conditions, see ref 16. b 1:1 Mixture of regioisomeric
tetrazoles obtained.
of the electrocyclization step is in accordance with earlier
results, leading to the product having the tetrazole and phenyl
rings conjugated.12a Benzyl-n-propylthiourea was subjected
(8) A trisubstituted thiourea is first S-methylated, converted to the
aminoguanidine (hydrazine hydrate in ethanol at reflux), and then converted
to the tetrazole using concentrated HCl/NaNO2. See Atherton, F. R.;
Lambert, R. W. Tetrahedron 1983, 39, 2599-2608.
(9) For other less general methods utilizing harsh conditions, see (a)
Imhof, R.; Ladner, D. W.; Muchowski, J. M. J. Org. Chem. 1977, 42, 3709-
3713. (b) Boyd, G. V.; Cobb, J.; Lindley, P. F.; Mitchell, J. C.; Nicolaou,
G. A. J. Chem. Soc., Chem. Commun. 1987, 99-101. (c) Gupton, J. T.;
Idoux, J. P.; Baker, G.; Colon, C.; Crews, A. D.; Jurss, C. D.; Rampi, R.
C. J. Org. Chem. 1983, 48, 2933-2936.
(10) (a) Garbrecht, W. L.; Herbst, R. M. J. Org. Chem. 1953, 18, 1003-
1010. (b) Castro, J. L.; Ball, R. G.; Broughton, H. B.; Russell, M. G. N.;
Rathbone, D.; Watt, A. P.; Baker, R.; Chapman, K. L.; Fletcher, A. E.;
Patel, S.; Smith, A. J.; Marshall, G. R.; Ryecroft, W.; Matassa, V. G. J.
Med. Chem. 1996, 39, 842-849.
Scheme 1
(11) Kurzer, F.; Godfrey, L. E. A. Angew. Chem., Int. Ed. Engl. 1963,
2, 459-476.
(12) (a) Svetlik, J.; Hrusovsky, I.; Martvon, A. Coll. Czech. Chem.
Commun. 1979, 44, 2982-2986. (b) Habich, D. Synthesis 1992, 358-360.
(13) Ding, Y.-X.; Weber, W. P. Synthesis 1987, 823-824.
(14) Kim, K. S.; Qian, L. Tetrahedron Lett. 1993, 34, 7677-7680. The
scope of this reaction has been expanded by Levallet, C.; Lerpiniere, J.;
Ko, Y. S. Tetrahedron 1997, 53, 5291-5304.
(15) Kadaba, P. K. J. Org. Chem. 1976, 41, 1073-1075.
(16) Representative procedure for the preparation of tetrazoles (1)
via thioureas (5). A solution of amine 3 (6.0 mmol, 1.0 equiv) in 15 mL
of dry CH2Cl2 was treated dropwise with isothiocyanate 4 (6.0 mmol, 1.0
equiv). The resulting solution was stirred at room temperature for 16 h and
then diluted with H2O (50 mL) and extracted with 3 × 15 mL of CH2Cl2.
The combined organics were washed with brine, dried over MgSO4, filtered,
and concentrated. The residue was purified by recrystallization (CH2Cl2:
hexanes) or column chromatography through silica gel to give thiourea 5.
To a suspension of 5 (1.25 mmol, 1.0 equiv), sodium azide (244 mg, 3.75
mmol, 3.0 equiv), and mercuric chloride (373 mg, 1.38 mmol, 1.1 equiv)
in 5 mL of dry DMF was added triethylamine (503 µL, 3.75 mmol, 3.0
equiv). The resulting suspension was stirred for 3 h at room temperature or
until TLC indicated complete consumption of starting material. The
suspension was filtered through a pad of Celite, washing with CH2Cl2. The
filtrate was diluted with water and extracted with 3 × 15 mL of CH2Cl2,
the combined organics were dried over MgSO4, filtered, and concentrated
under reduced pressure. The resulting residue was purified by silica gel
chromatography to give tetrazole 1.
that the imino nitrogen must have sufficient electron density
for electrocyclization to occur.3d Thioureas 5 serve as ideal
intermediates, as they are easily accessible from the reaction
of amines 3 with isothiocyanates 4. The wide range of
(6) Lebl, M.; Slaninova, J.; Johnson, R. L. Int. J. Pept. Protein Res. 1990,
33, 16.
(7) (a) Satoh, Y.; De Lombaert, S.; Marcopulos, N.; Moliterni, J.; Moskal,
M.; Tan, J.; Wallace, E. Tetrahedron Lett. 1998, 39, 3367-3370. (b) Beusen,
D. D.; Zabrocki, J.; Slomczynska, U.; Head, R. D.; Kao, J. L. F.; Marshall,
G. R. Biopolymers 1995, 36, 181-200. (c) Boteju, L. W.; Hruby, V. J.;
Tetrahedron Lett. 1993, 34, 1757-1760. (d) Zabrocki, J.; Smith, G. D.;
Dunbar, J. B.; Iijima, H.; Marshall, G. R. J. Am. Chem. Soc. 1988, 110,
5875-5880.
3238
Org. Lett., Vol. 2, No. 20, 2000

to the above conditions to give a 1:1 mixture of tetrazole
isomers, resulting from competitive cyclization of the guanyl
azide (Table 1, entry 2). More electron-deficient thioureas
failed to give the desired tetrazoles (Table 1, entries 3 and
4). Both of these substrates reacted with mercury but failed
to convert to the tetrazole, and no other intermediates or
products were detected. The method can also be used for
the synthesis of monosubstituted 5-aminotetrazoles from the
terminal phenylthiourea (Table 1, entry 5). By contrast,
terminal arylthioureas and amines do not react in Hg(II)-
promoted guanadinylation reactions.14
corresponding 5-aminotetrazole in 89% yield (Table 2, entry
1), the structure of which was unambiguously confirmed by
X-ray crystallography (Figure 1).17 Other pyrrolidine-derived
Of greater significance is the synthesis of trisubstituted
5-aminotetrazoles 1 (Table 2), products which are not
Table 2. Formation of Trisubstituted 5-aminotetrazoles 1 via
Thioureas 5a
Figure 1. ORTEP drawing of 1-benzyl-5-pyrrolidin-1-yl-1H-
tetrazole (from Table 2, entry 1) with 30% thermal ellipsoids.
thioureas gave similarly high yields of the tetrazole substrates
(Table 2, entries 2-4). For the allyl isothiocyanate derived
thiourea, lower yields were obtained, presumably because
of competitive reaction of mercury(II) with the terminal
alkene (Table 2, entry 3).18 Other N,N,N′-trisubstituted
thioureas also gave 5-aminotetrazoles in good to excellent
yields (Table 2, entries 5-9). Notably the more electron-
deficient pyrrolidinone substituent could also be used, albeit
with somewhat lower efficiency. All of the above reactions
were complete within 3 h or less at room temperature.
Tetrazole formation was not possible from N,N-disubstituted
thioureas or N,N-disubstituted N′-acylthioureas,19 where the
imino lone pair on the guanyl azide lacks sufficient electron
density to cyclize.
A preliminary screen revealed that other mercury(II) salts
also promote the reaction with trisubstituted thioureas,
including HgBr2, HgI2, and Hg(OAc)2. However, reaction
did not occur with red HgO, Zn(II), Cu(I), or Cu(II) salts or
in the absence of mercury(II) salts. The reaction can also be
conducted in the absence of triethylamine, although at a
significantly slower rate, requiring 3 h for 30% conversion
a For experimental conditions, see ref 16. b This thiourea was prepared
by deprotonation of 2-pyrrolidinone with NaH, followed by reaction with
BnNCS. c Recovered thiourea (26%) was also obtained.
1
and 16 h for 50%, as determined by H NMR. Since the
accessible through the conventional reaction of sodium azide
or hydrazoic acid with carbodiimides. Thus, the thiourea
obtained from pyrrolidine and benzyl isothiocyanate reacted
with mercury(II) chloride and sodium azide to give the
electrocyclization of guanyl azides is known to be inhibited
under acidic conditions, the role of the triethylamine is
presumably to neutralize the HCl produced during the
formation of 6.3b
(17) Crystal data for 1-benzyl-5-pyrrolidin-1-yl-1H-tetrazole (Table 2,
entry 1): C12H15N5; FW ) 229.29, orthorhombic, space group Pna21 [no.
33], block cut from colorless needles, a ) 8.1926(3) Å, b ) 12.2982(4) Å,
c ) 11.3204(5) Å, V ) 1140.58(8) Å3, Z ) 4, Dcalcd ) 1.335 Mg/m3, µ(Mo
KR) ) 0.86 cm-1, Nonius Kappa-CCD diffractometer, λ ) 0.71073 Å, φ
scans and ω scans with κ offsets, 2θmax ) 60.16°, 3122 reflections (unique),
R1 ) 0.00493, wR2 ) 0.1094, GOF ) 1.006.
(18) Larock, R. C. Organomercury Compounds in Organic Synthesis;
Springer: Berlin, 1985.
(19) For the reaction of N-(pyrrolidine-1-carbothioyl)benzamide, we may
have obtained a bis-thiomercury(II) complex. See Richter, R.; Seiler, J.;
Beyer, L.; Lindqvist, O.; Andersen, L. Z. Anorg. Allg. Chem. 1985, 522,
171-183.
Org. Lett., Vol. 2, No. 20, 2000
3239

The mercury-promoted dehydration of thioureas to give
carbodiimides is well-known,20 and for N,N′-disubstituted
thioureas, carbodiimide intermediacy is likely (i.e., reaction
occurs through coordination of Hg(II) to give 6 followed by
an elimination-addition mechanism). Ko and co-workers
have observed these intermediates in the mercury-promoted
guanadinylation reaction,14 and reagents such as EDCI21 or
Mukaiyama’s reagent22 which are known to react with thio-
ureas to give carbodiimides, have also been explored in the
context of guanadinylations. The mechanism of 5-amino-
tetrazole formation from trisubstituted thioureas is not as
clear. Although carbodiimidium compounds are known,23
they are difficult to synthesize requiring long reaction times
and high temperatures. As powerful electrophiles they readily
react with even sterically hindered alcohols.21 However, when
sodium azide is replaced with an amine as the nucleophile,
the corresponding guanidine is not obtained.14,24 Thus, it is
unlikely that a reactive carbodiimidium moiety is an inter-
mediate, since reaction with weaker nucleophiles would be
expected to occur. Furthermore, such an intermediate would
be severely destabilized for substrates bearing electron-
withdrawing groups, yet the reaction works even when R2
is an acyl or aromatic group (Table 2, entries 5 and 7). The
most likely mechanism therefore involves Hg(II) coordination
to give 6, followed by attack of azide anion to give 7, via
an addition-elimination pathway, a mechanism that will only
operate with strong sterically unencumbered nucleophiles
such as azide anion. A similar mechanism has been proposed
in the reaction of thioamides with mercury carboxylates to
give imides.25
In conclusion, we have developed a new method for the
mild and efficient preparation of mono-, di-, and tri
substituted 5-aminotetrazoles from amines, isothiocyanates,
and azide anion. Further examination of the scope and
mechanism of the reaction and the identification of mercury
free conditions which are amenable to the generation of com-
binatorial libraries of 5-aminotetrazole-containing peptido-
mimetics is currently underway in our laboratories.
Acknowledgment. AstraZeneca, the Natural Science and
Engineering Research Council (NSERC) of Canada and the
Ontario Research and Development Challenge Fund sup-
ported this work. D.A.P. thanks AstraZeneca and the NSERC
for an Industrial Postgraduate Scholarship. R.A.B gratefully
acknowledges receipt of an Astra Award, a Bio-Me´ga/
Boehringer Ingelheim Young Investigator Award, a Premier’s
Research Excellence Award, and additional funding from
Merck-Frosst, Uniroyal Chemicals Inc., and the Environ-
mental Science and Technology Alliance of Canada. We
thank Dr. A. B. Young for mass spectroscopic analyses and
Dr. A. J. Lough for X-ray crystallographic analysis.
(20) For a review of carbodiimides, see (a) Williams, A.; Ibrahim, I. T.
Chem. ReV. 1981, 81, 589-636. (b) Mikolajczyk, M.; Kielbasinski, P.
Tetrahedron 1981, 37, 233-284.
Supporting Information Available: X-ray crystallo-
graphic data for 1-benzyl-5-pyrrolidin-1-yl-1H-tetrazole and
characterization data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(21) (a) Poss, M. A.; Iwanowicz, E.; Reid, J. A.; Lin, J.; Gu, Z.
Tetrahedron Lett. 1992, 33, 5933-5936. (b) Linton, B. R.; Carr, A. J.;
Orner, B. P.; Hamilton, A. D. J. Org. Chem. 2000, 65, 1566-1568.
(22) Yong, Y. F.; Kowalski, J. A.; Lipton, M. A. J. Org. Chem. 1997,
62, 1540-1542.
(23) (a) Scheffold, R.; Saladin, E. Angew. Chem., Int. Ed. Engl. 1972,
11, 229-231. (b) Hartke, K.; Rossbach, F.; Radau, M. Justus Liebigs Ann.
Chem. 1972, 762, 167-177.
OL006465B
(24) We have confirmed the results of Ko and co-workers (ref 14) in
the reaction of thiourea 5 (Table 2, entry 1) with benzylamine in the presence
of HgCl2, which did not give any guanidine product, even after heating to
60 °C for 24 h.
(25) Avalos, M.; Babiano, R.; Cintas, P.; Duran, C. J.; Higes, F. J.;
Jimenez, J. L.; Lopez, I.; Palacios, J. C. Tetrahedron 1997, 53, 14463-
14480.
3240
Org. Lett., Vol. 2, No. 20, 2000