Preparation of 5-substituted 1H-tetrazoles from nitriles in water

Article abstract of DOI:10.1021/jo010635w

The addition of sodium azide to nitriles to give 1H-tetrazoles is shown to proceed readily in water with zinc salts as catalysts. The scope of the reaction is quite broad; a variety of aromatic nitriles, activated and unactivated alkyl nitriles, substituted vinyl nitriles, thiocyanates, and cyanamides have all been shown to be viable substrates for this reaction.

Full text of DOI:10.1021/jo010635w

J . Org. Chem. 2001, 66, 7945-7950
7945
Articles
P r ep a r a tion of 5-Su bstitu ted 1H-Tetr a zoles fr om Nitr iles in Wa ter †
Zachary P. Demko and K. Barry Sharpless*,‡
Department of Chemistry and The Skaggs Institute of Chemical Biology, The Scripps Research Institute,
10550 North Torrey Pines Road, La J olla, California 92037
sharples@scripps.edu
Received J une 21, 2001
The addition of sodium azide to nitriles to give 1H-tetrazoles is shown to proceed readily in water
with zinc salts as catalysts. The scope of the reaction is quite broad; a variety of aromatic nitriles,
activated and unactivated alkyl nitriles, substituted vinyl nitriles, thiocyanates, and cyanamides
have all been shown to be viable substrates for this reaction.
The literature on tetrazoles is expanding rapidly.1 This
functional group has roles in coordination chemistry as
a ligand, in medicinal chemistry as a metabolically stable
surrogate for a carboxylic acid group,2 and in various
materials science applications, including specialty explo-
sives.3 Less appreciated, but of enormous potential, are
the many useful transformations that make tetrazoles
versatile intermediates en route to substituted tetrazoles,
and especially to other 5-ring heterocycles via the Huis-
gen rearrangement.4 The prime reason for the scarcity
of practical applications for these sophisticated tetrazole-
based reactions is the lack of appealing synthetic routes
to the key intermediates, RCN4H (2). We report here a
safer and exceptionally efficient process for transforming
nitriles into tetrazoles in water; the only other reagents
are sodium azide and a zinc salt (eq 1).
Lewis acids,7 and those that are run in acidic media.8
Each of these has one or more of the following draw-
backs: expensive and toxic metals, severe water sensitiv-
ity, and the presence of hydrazoic acid, which is highly
toxic and explosive as well as volatile. The few methods
that seek to avoid hydrazoic acid liberation during the
reaction, by avoiding acidic conditions, require a very
large excess of sodium azide.9 In addition, all of the
known methods use organic solvents, in particular,
dipolar aprotic solvents such as DMF. This is one of the
solvent classes that process chemists would rather not
use.10 We sought to find a method that avoided these
drawbacks and was easy to use on both a laboratory and
industrial scale.
Water is rarely used or even considered as a solvent
for organic reactions. The two foremost reasons why
chemists shy away from water is the lack of solubility of
most organic compounds in this medium and/or concerns
that the high “acid/base” reactivity will interfere with the
desired reaction.
However, it is hard to ignore water as a solvent.
Beyond being environmentally benign, its extraordinary
physical properties are widely appreciated.11 While the
The most convenient route to 5-substituted 1H-tetra-
zoles (2) is the addition of azide ion to nitriles (1).5 The
literature is replete with methods to perform this trans-
formation; they fall into three main categories: those that
make use of tin or silicon azides,6 those that use strong
(7) (a) Wiberg, V. E.; Michaud, H. Z. Naturforsch., Teil B 1954, 9,
497. (b) Grzonka, Z.; Liberek, B. Roczniki Chemii 1971, 45, 967-980.
(c) Huff, B. E.; Staszak, M. A. Tetrahedron Lett. 1993, 34, 8011-8014.
(d) Kumar, A.; Narayanan, R.; Shechter, H. J . Org. Chem. 1996, 61,
1(13), 4462-4465.
(8) (a) Mihina, J . S.; Herbst, R. M. J . Org. Chem. 1950, 15, 1082-
1092. (b) Finnegan, W. G.; Henry, R. A.; Lofquist, R. J . Am. Chem.
Soc. 1958, 80, 3908-3911. (c) Ostrovskii, V. A.; Poplavskii, V. S.;
Koldobskii, G. I.; Erusalinkii, G. B. Khim. Geterotsikl. Soedin. 1992,
1214-1217. (d) Koguro, K.; Oga, T.; Mitsui, S.; Orita, R. Synthesis
1998, 910-914.
(9) For examples, see: (a) Sauer, J .; Huisgen, R.; Strum, H. J .
Tetrahedron 1960, 11, 241-251. (b) Gallante, R. J . U.S. Patent
5,502,191, 1995. (c) Tokuhara, G.; Yamaguchi, T.; Iwasaki, T. WO
Patent 1996-37481, 1996. A good method for the amelioration of the
excess azide/hydrazoic acid with sodium nitrite was first reported in
Reith, J . F.; Bowman, J . H. A. Pharm. Weekbl. 1930, 67, 600. A good
review can be found in: Federoff, B. T., Ed. Encyclopedia of Explosives
and Related Items; Picatinny Arsenal: Dover, NJ , 1960; Vol. 1, p A574.
(10) Anderson, N. Practical Process Research & Development; Aca-
demic Press: San Diego, CA, 2000; Chapter 4.
† Dedicated to Professor Harry H. Wasserman on the occasion of
his 80th birthday.
‡ Recipient of the 2001 Nobel Prize in Chemistry.
(1) Butler, R. N. In Comprehensive Heterocyclic Chemistry; Katritz-
ky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, U.K.,
1996; Vol. 4.
(2) Singh, H.; Chawla, A. S.; Kapoor, V. K.; Paul, D.; Malhotra, R.
K. Prog. Med. Chem. 1980, 17, 151-183.
(3) (a) Ostrovskii, V. A.; Pevzner, M. S.; Kofmna, T. P.; Shcherbinin,
M. B.; Tselinskii, I. V. Targets Heterocycl. Syst. 1999, 3, 467-526. (b)
Hiskey, M.; Chavez, D. E.; Naud, D. L.; Son, S. F.; Berghout, H. L.;
Bome, C. A. Proc. Int. Pyrotech. Semin 2000, 27, 3-14.
(4) Moderhack, D. J . Prakt. Chem. 1988 340, 687-709.
(5) Wittenberger, S. J . Org. Prep. Proced. Intl. 1994, 26(5), 499-
531.
(6) (a) Dunica, J . V.; Pierce, M. E.; Santella, J . B., III. J . Org. Chem.
1991, 56, 2395. (b) Wittenberger, S. J .; Donner, B. G. J . Org. Chem.
1993, 58, 4139-4141. (c) Curran, D. P.; Hadida, S.; Kim, S.-Y.
Tetrahedron 1999, 55, 8997-9006.
(11) (a) Reichardt, C. Solvents and Sovent Effects in Organic
Chemistry; VCH Verlagsgesellschaft mbH: Weinheim, Germany 1988.
(b) Brack, A Adv. Space Res. 1999, 24(4), 417-433.
10.1021/jo010635w CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/03/2001

7946 J . Org. Chem., Vol. 66, No. 24, 2001
Demko and Sharpless
Ta ble 1. Ar om a tic Tetr a zoles
traditional concerns (vide supra) seem well founded,
there are many examples demonstrating that reactions
commonly performed using organic solvents work equally
well, if not better, in water. Over the past few years, we
have encountered numerous examples of water as the
“perfect” solvent: e.g., in (1) osmium-catalyzed dihy-
droxylation and aminohydroxylation,12 (2) nucleophilic
opening of epoxides and aziridines,13 (3) cycloaddition
reactions of all kinds,13 (4) most oxime ether, hydrazone,
and aromatic heterocycle condensation processes,14 and
(5) the formation of an amide from a primary amine and
an acid chloride using aqueous Schotten-Baumann
conditions.15 In many of these cases, either the starting
material, product, or both are relatively insoluble in
water; in others, the reagents are of a water-sensitive
nature, yet the reactions proceed with high yield and
fewer side products than when organic solvents are used.
Thus encouraged, we envision a special style of organic
synthesis, one based on an entire family of reactions for
which water is the best “solvent”.
As a result of these endeavors, we have found that in
the presence of zinc salts9b,c tetrazole formation proceeds
with excellent yields and scope in refluxing water.16
Thanks to the low pKa of 1H-tetrazoles (ca. 3-5) and their
highly crystalline nature, a simple acidification is usually
sufficient to provide the pure tetrazoles.
Another goal was to create a procedure that avoids the
release of hydrazoic acid. An aqueous solution of 1 M zinc
bromide has ca. pH 7, and when sodium azide is added
(1 M), it is slightly alkaline, ca. pH 8; consequently, even
at 100 °C, release of hydrazoic acid is minimized. Still,
as the pKa of hydrazoic acid is 4.7, one might expect a
small amount of hydrazoic acid to be liberated during the
reaction at the temperatures and concentrations involved.
Indeed, when the reactions were run at a concentration
of 1 M in sodium azide and 1 M in ZnBr2, we were able
to detect a small amount of liberated hydrazoic acid in
the headspace above the refluxing solvent;17 when the
concentration was dropped to 0.5 M, no hydrazoic acid
could be detected. On the contrary, in the headspace
above a solution of 0.5 M sodium azide and 0.5 M
ammonium chloride in dimethyl formamide at 100 °C,
a
These reactions were run on 20 mmol scale.
hydrazoic acid was clearly present in much higher
concentrations and even more so at 125 °C, the conditions
used in the most common procedure for making tet-
razoles.8b By only using 1.05 equiv of sodium azide, the
risk of hydrazoic acid liberation upon workup is minimal.
However, in some cases such as benzonitrile (1a ), the
yields were lower; compare a 76% yield of 5-phenyltet-
razole when 1.05 equiv of sodium azide is used with a
93% yield when 1.50 equiv is used.
A wide variety of nitriles were converted to tetrazoles
on a 20 mmol scale. Other things being equal, the more
electron-poor a nitrile, the faster it reacts. Aromatic
nitriles (see Table 1) with a variety of substituents
(1a ,b,c,i) reach completion within several days at reflux.
Electron-poor aromatic and heteroaromatic nitriles, such
as 2-cyanopyridine and cyanopyrazine (1d ,e), are com-
plete within a few hours. Some electron-rich aromatic
nitriles (1f,g) require higher temperatures, which are
achieved using a sealed glass pressure reactor. Ortho-
substituted aromatic nitriles are the most challenging,
sometimes proceeding at reflux (1h ), but often requiring
much higher temperatures (1j). We have not been able
to achieve significant conversion of any aromatic nitriles
bearing an sp3-hybridized substituent in the ortho posi-
tion.18
(12) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94(8), 2483-2547. (b) Wang, Z. M.; Sharpless, K. B. J . Org.
Chem. 1994, 59(26), 8302-8303. (c) Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2001, 40(18), 3455-3457.
(13) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2001, 40(11), 2004-2021.
(14) (a) Patai, S., Ed. The Chemistry of the Carbon-Nitrogen Double
Bond; Interscience Publishers: London, U.K., 1070. (b) Gilchrist, T.
L. Heterocyclic Chemistry, 3rd ed.; Addison-Wesley Longman Ltd:
Harlow, U.K., 1997.
(15) Sonntag, N. O. V. Chem. Rev. 1953, 52, 237-416.
(16) Note that the high heat capacity of water when used as a
solvent strongly mitigates the explosion hazards from endergonic
groups such as aromatic azides and nitro compounds. In the present
system, it is important that an aqueous sodium azide solution is very
stable at reflux. For example, this system has been used, under R4N+X-
catalysis, to displace two chlorides from neat 3,3-bis(choromethyl)-
oxetane so that the organic phase becomes pure 3,3-bis(azidomethyl)-
oxetane plus a few percent water. This is run on a several hundred
kilogram scale, and the crude material is directly transferred to 55
gallon drums for shipment. See: Malik, A. A.; Manser, G. E.; Carson,
R. P.; Archibald, T. G. U. S. Patent US 5,523,424, 1996.
(17) A strip of paper was soaked in a 10 µM iron(III) chloride solution
and then dried. In the presence of hydrazoic acid, the color changes
from yellow to a bright red. See: Feigl, F. Spot Tests in Organic
Analysis; Elsevier Scientific Publishing Co.: Amsterdam, 1975. Above
a 1 M aqueous solution of sodium azide at reflux, the strip turned red
slowly over about 10 s, and using the 0.5 M azide modification no
hydrazoic acid was detected. In contrast, above the 1 M solution of
sodium azide and 0.5 M ZnBr2 in DMF at 100 °C, the strip turned
bright red before it could even be inserted in the flask.
Unactivated alkyl nitriles (see Table 2) also require
very high temperatures (1k ,l), but with electron-with-
(18) Flippin, L. Tetrahedron Lett. 1991, 47, 6857-6860.

Preparation of 5-Substituted 1H-Tetrazoles
J . Org. Chem., Vol. 66, No. 24, 2001 7947
Ta ble 2. Oth er Tetr a zoles
Ch a r t 1
a concerted [2 + 3] cycloaddition22 (Chart 1, eq 2). Our
mechanistic studies to date imply that the role of zinc is
not simply that of a Lewis acid; a number of other Lewis
acids were tested and caused little to no acceleration of
the reaction.23 In contrast, Zn2+ exhibited a 10-fold rate
acceleration at 0.03 M, which corresponds to a rate
acceleration of approximately 300 at the concentrations
typically used. The exact role of zinc is not yet clear.
Empirically, we found that to ensure complete reaction
one needs a 0.5 molar equiv of the zinc salt (ZnX2);
however, in many cases, lower loadings of zinc may be
used.24 The chief competing reaction is hydrolysis of the
nitrile to the primary amide; therefore, in cases where
the tetrazole-forming reaction is sufficiently fast, namely
with electron-poor nitriles, lower zinc loadings did not
entail significant formation of the amide byproduct.
Other zinc salts such as zinc perchlorate and zinc triflate
also work; zinc chloride, while less expensive, led to more
of the amide byproduct. Zinc bromide was chosen as the
best compromise between cost, selectivity, and reactivity
(see Table 3).
a
b
These reactions were run on 20 mmol scale. These reactions
i
were run with PrOH as a cosolvent (10% v/v).
Ta ble 3. Mole-Sca le Rea ction s
drawing substituents at the R-position (1m ,n ), temper-
atures can be lower. At one extreme, trifluoroacetonitrile
has been shown to react rapidly with sodium azide in
acetonitrile solution at room temperature in the absence
of any catalyst.19 Alkyl nitriles with a hydroxy group at
the R-position (1o) also proceed at lower temperatures;
in the analogous case with an amino group in place of
the hydroxy group the reaction proceeded well, but
purification was very difficult. Presumably, this accelera-
tion is due to a combination of the substituents’ intramo-
lecular hydrogen bonding and σ-electronic effects. Some
R,â-unsaturated vinyl nitriles (1p ,q) are good substrates,
but simple alkylacrylonitrile derivatives only decomposed
under the reaction conditions and the tetrazoles were not
detected. Thiocyanates gave the 5-thiotetrazoles 2r and
2s, and a dialkylated cyanamide also reacted, furnishing
the 5-aminotetrazole 2t. Nitriles attached to oxygen, as
in cyanates (ROCN), have been shown to react with
sodium azide in water at room temperature in the
absence of catalyst.20
entry
NaN3 (mol)
ZnX2 (0.50 mol)
yield (g)
1
2
3
4
1.05
1.05
1.05
1.50
ZnCl2
Zn(ClO4)2
ZnBr2
98.0 (67%)
101.2 (70%)
111.1 (76%)
135.2 (93%)
ZnBr2
The process became even more attractive for large-
scale applications when we found that it could be run at
higher concentration without sacrificing yield and with-
out the use of organic solvents in the workup or isolation
phases. The resulting products were spectroscopically
1
identical by H NMR and 13C NMR to those synthesized
by the general method outlined below; however, the
melting points were slightly lower.
Kinetic studies using the water-soluble nitrile 1i
revealed first-order dependence in both nitrile and azide
and one-half order dependence for zinc bromide. The
mechanism of the addition of hydrazoic acid/azide ion to
a nitrile to give a tetrazole has been debated, with
evidence supporting both a two-step mechanism8b,21 and
(21) J ursic, E.; Zdravkovski, Z. THEOCHEM 1994, 118, 11-22.
(22) (a) Titova, I. E.; Poplavskii, V. S.; Koldobskii, G. I.; Ostrovskii,
V. A.; Nikolaev, V. D.; Erusalimskii, G. B. Khim. Geterosikl. Soedin.
1986, 8, 1086-1089. (b) Ostrovskii, V. A.; Poplavskii, V. S.; Koldobskii,
G. I.; Erusalimskii, G. B. Khim. Geterosikl. Soedin. 1992, 9, 1214-
1219.
(23) Some of the metals tested include Li, K, Cs, Mg, Ca, Ba, Fe,
Co, Ni, Cu, Ag, Zn, Ce, Sm, Yb, B, Al, and Bi.
(24) We found that heterocyclic nitriles would proceed to completion,
albeit in lower yields, with only sodium azide in refluxing water (Epple,
R., unpublished work) but that zinc was necessary to coax the majority
of nitriles into reacting with azide.
(19) Norris, W. P. J . Org. Chem. 1962, 27, 3248-3251.
(20) Grigat, E.; Pu¨tter, R.; Mu¨hlbauer, E. Chem. Ber. 1965, 12,
3777-3785.

7948 J . Org. Chem., Vol. 66, No. 24, 2001
Demko and Sharpless
the zwitterion precipitated. If little or no precipitate was
formed upon final acidification, the aqueous layer was satu-
rated with NaCl and extracted with 3 × 100 mL of ethyl
acetate; the organic layer was dried with sodium sulfate and
evaporated to dryness. In some cases, extremely nonpolar
tetrazoles may require column purification. Modifications to
the general method are given for individual tetrazoles below.
5-P h en yltetr a zole (2a ). The product 2a (2.20 g; 75% yield)
had the following data: mp 215-216 °C; 1H NMR 8.04 (m,
2H), 7.61 (m, 3H); 13C NMR 155.2 (br), 131.28, 129.45, 127.02,
124.17; HRMS (MALDI) calcd for C7H7N4 (MH+) 147.0665,
found 147.0666. Anal. Calcd for C7H6N4: C, 57.53; H, 4.14; N,
38.34. Found: C, 57.65; H, 4.17; N, 38.04.
In summary, we have demonstrated an exceedingly
simple protocol for transforming a wide variety of nitriles
into the corresponding 1H-tetrazoles. By using zinc salts
as catalysts, we showed that water can be used as the
solvent despite the relative insolubility of the starting
materials. This discovery should facilitate the prepara-
tion of tetrazoles in the laboratory.
Exp er im en ta l Section
1
All H NMR spectra taken on a Bruker AMX-400 spectrom-
eter in DMSO-d6 with DMSO as a standard at 2.50 ppm. All
13C NMR spectra taken on the same machine at 100 MHz in
DMSO-d6 with DMSO as a standard at 39.50 ppm, unless
otherwise noted. All melting points were taken on a Thomas-
Hoover Uni-melt melting point apparatus. Reagents were used
unpurified, and deionized water was used as solvent.
La r ge-Sca le, Or ga n ic Solven t F r ee P r oced u r e for th e
Syn th esis of Tetr a zoles. To a three-necked 3 L round-
bottomed flask equipped with a mechanical stirrer was added
benzonitrile (103.1 g, 1.00 mol), 1 L of water, sodium azide
(68.2 g, 1.05 mol), and 68.1 g. (0.50 mol) zinc chloride. The
reaction was refluxed in a hood, but open to the atmosphere,
for 24 h with vigorous stirring. After the mixture was cooled
to room temperature, the pH was adjusted to 1.0 with
concentrated HCl (∼120 mL), and the reaction was stirred for
30 min to break up the solid precipitate, presumably (PhCN4)2-
Zn. The new precipitate was then filtered, washed with 2 ×
200 mL of 1 N HCl, and dried in a drying oven at 90 °C
overnight to give 98.0 g of 5-phenyltetrazole as a white powder
(67% yield, mp 211 °C (lit.25 mp 216 °C)).
Gen er a l P r oced u r e for th e Tr a n sfor m a tion of Nitr iles
in to Tetr a zoles. To a 250 mL round-bottomed flask was
added the nitrile (20 mmol), sodium azide (1.43 g, 22 mmol),
zinc bromide (4.50 g, 20 mmol), and 40 mL of water.26 The
reaction mixture was refluxed for 24 h; vigorous stirring is
essential. HCl (3 N, 30 mL) and ethyl acetate (100 mL) were
added, and vigorous stirring was continued until no solid was
present and the aqueous layer had a pH of 1. If necessary,
additional ethyl acetate was added. The organic layer was
isolated and the aqueous layer extracted with 2 × 100 mL of
ethyl acetate. The combined organic layers were evaporated,
200 mL of 0.25 N NaOH was added, and the mixture was
stirred for 30 min, until the original precipitate was dissolved
and a suspension of zinc hydroxide was formed. The suspen-
sion was filtered, and the solid washed with 20 mL of 1 N
NaOH. To the filtrate was added 40 mL of 3 N HCl with
vigorous stirring causing the tetrazole to precipitate. The
tetrazole was filtered and washed with 2 × 20 mL of 3 N HCl
and dried in a drying oven to furnish the tetrazole as a white
or slightly colored powder.
5-(4-Nitr op h en yl)tetr a zole (2b). The product 2b (3.42 g;
1
94% yield) had the following data: mp 220 °C; H NMR 8.44
(m, 2H), 8.29 (m, 2H); 13C NMR 155.4 (br), 148.74, 130.60,
128.22, 124.64; HRMS (MALDI) calcd for C7H4N5O2 (M - H)-
190.0360, found 190.0363. Anal. Calcd for C7H5N5O2: C, 43.98;
H, 2.64; N, 36.64. Found: C, 44.10; H, 2.63; N, 36.37.
5-(4-Meth oxyp h en yl)tetr a zole (2c). The reaction was
refluxed for 48 h. The product 2c (3.04 g; 86% yield) had the
following data: mp 231-232 °C; 1H NMR 7.97 (d, 2H, J ) 8.8
Hz), 7.14 (d, 2H, J ) 8.8 Hz), 3.83 (s, 3H); 13C NMR 161.47,
154.6 (br), 128.66, 116.28, 114.86, 55.45; HRMS (MALDI) calcd
for C8H9N4O (MH+) 177.0771, found 177.0777.
5-(2-P yr id yl)tetr a zole (2d ). Workup excluded initial acidi-
fication and extraction; the reaction mixture was simply
basified by addition of 2.5 equiv of NaOH, filtered, acidified
to pH ) 6.5, and filtered, and the solid was washed with water.
The product 2d (2.31 g; 79% yield) had the following data: mp
1
211 °C; H NMR 8.79 (m, 1H), 8.22 (d, 1H, J ) 7.6 Hz), 8.08
(m, 1H), 7.62 (m, 1H); 13C NMR 154.9 (br), 150.10, 143.76,
138.29, 126.11, 122.62; HRMS (MALDI) calcd for C6H6N5
(MH+) 148.0618, found 149.0617.
5-P yr a zin etetr a zole (2e). Workup excluded initial acidi-
fication and extraction; the reaction mixture was simply
basified by addition of 2.5 equiv of NaOH, filtered, acidified
to pH ) 6.5, and filtered, and the solid was washed with water.
The product 2e (2.44 g; 83% yield) had the following data: mp
193-195 °C; 1H NMR 9.38 (m, 1H), 8.82 (m, 1H), 8.58 (br, 1H);
13C NMR 154.9 (br), 146.83, 143.93, 143.07, 140.37; HRMS
(MALDI) calcd for C5H5N6 (MH+) 149.0570, found 149.0569.
5-(4-Hyd r oxyp h en yl)tetr a zole (2f). The reaction mixture
was stirred in a pressure tube submerged in an oil bath at
140 °C. The product 2f (3.11 g; 96% yield) had the following
data: mp 234-236 °C; 1H NMR 10.20 (br, 1H), 7.86 (d, 2H, J
) 8.5 Hz), 6.95 (d, 2H, J ) 8.5 Hz); 13C NMR 160.22, 154.7
(br), 128.89, 116.25, 114.68; HRMS (MALDI) calcd for C7H7N4O
(MH+) 163.0614, found 163.0612.
5-(2-Na p h th yl)tetr a zole (2g). The reaction mixture was
stirred in a pressure tube submerged in an oil bath at 140 °C
for 48 h. The product 2g (2.85 g; 73% yield) had the following
1
data: mp 205-207 °C; H NMR 8.67 (m, 1H), 8.12 (m, 2H),
Mod ifica tion s. For tetrazoles that do not show significant
reaction after 1 day at reflux, the reaction is run in a pressure
tube submerged up to the neck in an oil bath at 140 °C or, if
necessary, 170 °C. In either case, if the extent of reaction is
less than 50% after 1 day, it is continued for an additional 1
day. The times given for reaction may be slightly longer than
necessary, but not more than twice the time needed. As the
tetrazole products are quite stable, no decrease in yield was
observed from excess reaction times, so the times were not
optimized beyond a factor of 2. If, during the reaction, the
nitrile is not dispersed well (e.g., nitrile clumps up), 5-10 mL
8.06 (m, 1H), 7.99 (m, 1H), 7.61 (m, 2H); 13C NMR 155.5 (br),
133.89, 132.59, 129.19, 128.63, 127.89, 127.86, 127.27, 127.04,
123.69, 121.54; HRMS (MALDI) calcd for C11H9N4 (MH+)
197.0822, found 197.0829.
1,2-Bis(5-tetr a zolyl)ben zen e (2h ). The reaction mixture
was refluxed for 48 h. The product 2h (2.75 g; 64% yield) had
1
the following data: mp 228-230 °C; H NMR 7.89 (m, 2H),
7.82 (m, 2H); 13C NMR 154.8 (br), 131.37, 130.78, 124.53;
HRMS (MALDI) calcd for C8H6N8Na (MNa+) 237.0608, found
237.0609.
4-(5-Tet r a zolyl)(2-h yd r oxyet h yloxy)et h ylb en za m id e
(2i). After final acidification, reaction mixture was set aside
until product crystallized from the solution (∼2 days). The
product 2i (3.35 g; 67% yield) had the following data: mp 158-
160 °C; 1H NMR 8.69 (t, 1H, J ) 5.2 Hz), 8.13 (d, 2H, J ) 8.5
Hz), 8.05 (d, 2H, J ) 8.5 Hz), 3.56 (t, 2H, J ) 5.6 Hz), 3.51 (m,
2H), 3.46 (m, 2H); 13C NMR 165.60, 155.0 (br), 136.70, 128.32,
126.61, 72.24, 68.91, 68.89, 60.32; HRMS (MALDI) calcd for
i
of PrOH is added to the reaction mixture. In cases where a
basic nitrogen was present in the molecule, the initial acidi-
fication and extraction into ethyl acetate was foregone, and
the final acidification was only taken to pH 6.5, at which point
(25) Note that the literature melting point of 216 °C was obtained
when the general procedure outlined in the Experimental Section,
which includes an organic extraction, was used.
(26) As mentioned in the text, the 1:1 molar ratio of NaN3/ZnBr2 is
more general. Note that the four 1.0 M scale reactions run with
benzonitrile (vide supra) were all performed with a NaN3/ZnX2 molar
ratio of 2:1.
C
12H15N5O3Na (MNa+) 300.1067, found 300.1059.
5-(2-(4′-Meth yl)bip h en yl)tetr a zole (2j). The reaction was
stirred in a pressure tube submerged in an oil bath at 170 °C
for 48 h. Silica gel column chromatography was used to purify

Preparation of 5-Substituted 1H-Tetrazoles
J . Org. Chem., Vol. 66, No. 24, 2001 7949
the final product. The product 2j (3.16 g; 67% yield) had the
following data: mp 150 °C; 1H NMR 7.66 (m, 2H), 7.55 (m,
2H), 7.11 (d, 2H, J ) 7.9 Hz), 6.97 (d, 2H, J ) 7.9 Hz), 2.28 (s,
3H); 13C NMR 154.8 (br), 141.51, 136.81, 136.32, 131.12,
130.63, 130.56, 128.94, 128.68, 127.56, 123.36, 20.65; HRMS
(MALDI) calcd for C14H13N4 (MH+) 237.1135, found 237.1142.
5-n -Hep tyltetr a zole (2k ). The reaction was stirred in a
pressure tube submerged in an oil bath at 170 °C. Upon final
acidification, the product separated as an oil; after addition
of NaCl, the aqueous layer was extracted with 3 × 200 mL of
ethyl acetate. The combined organic layers were dried (Na2-
SO4) and evaporated to give the crude product, which was
purified by column chromatography. The product 2k (2.75 g.;
82% yield) had the following data: mp 36-38 °C; 1H NMR
(CDCl3, using TMS as a standard at 0.0 ppm) 3.12 (t, 2H, J )
7.6 Hz), 1.88 (m, 2H), 1.43-1.22 (m, 8H), 0.83 (t, 3H, J ) 7.0
Hz); 13C NMR (CDCl3 using CDCl3 as a standard at 77.0 ppm)
156.9, 31.52, 28.94, 28.70, 27.65, 23.42, 22.51, 13.99; HRMS
(MALDI) calcd for C8H17N4 (MH+) 169.1448, found 169.1451.
5-Meth yltetr a zole (2l). The reaction mixture was stirred
in a pressure tube submerged in an oil bath at 170 °C. Upon
completion of the reaction, the product was made basic with
2.5 equiv of 1 N NaOH, stirred, and filtered. Following
acidification with HCl, the solution was saturated with
magnesium sulfate and extracted with 6 × 200 mL ethyl
acetate, which was dried and evaporated to give the crude
product. The product 2l (1.37 g; 75% yield) had the following
1
data: mp 146 °C; H NMR 2.48 (s, 3H); 13C NMR 152.2 (br),
8.43. Anal. Calcd for C2H4N4: C, 28.57; H, 4.79; N, 66.63.
Found: C, 28.49; H, 4.61; N, 62.76.
5-(2-(N-Ben zyla ceta m id o)tetr a zole (2m ). 2-Propanol (5
mL) was added to the reaction mixture to facilitate dispersal
of the nitrile. Due to relative insolubility of the tetrazole in
alkaline water, the initial organic extracts were combined,
dried (Na2SO4), and evaporated to give the product. The
product 2m (3.55 g; 82% yield) had the following data: mp
1
162-163 °C; H NMR 8.85 (br, 1H), 7.36-7.23 (m, 5H), 4.33
(d, 2H, J ) 5.56 Hz), 3.98 (s, 2H); 13C NMR 166.21, 151.10
(br), 138.92, 128.43, 127.44, 127.05, 42.57, 30.56; HRMS
(MALDI) calcd for C10H12N5O (MH+) 218.1036, found 218.1041.
2,2-Bis(5-tetr a zolyl)p r op a n e (2n ). 2-Propanol (5 mL) was
added to the reaction mixture to facilitate dispersal of the
nitrile. Upon final acidification, the product separated as an
oil; after addition of NaCl, the aqueous layer was extracted
with 3 × 200 mL of ethyl acetate. The combined organic layers
were dried (Na2SO4) and evaporated to give the product. The
product 2n (3.20 g; 89% yield) had the following data: mp
178-179 °C; 1H NMR 1.87 (s, 6H); 13C NMR 160.9 (br), 33.21,
26.70; HRMS (MALDI) calcd for C14H13N4 (M - H)- 179.0799,
found 179.0800.
5-(Hyd r oxyben zyl)tetr a zole (2o). Upon final acidifica-
tion, the product separated as an oil; after addition of NaCl,
the aqueous layer was extracted with 3 × 200 mL of ethyl
acetate. The combined organic layers were dried (Na2SO4) and
evaporated to give the product. The product 2o (3.14 g; 89%
yield) had the following data: mp 178-179 °C; 1H NMR 7.44
(m, 2H), 7.37 (m, 2H), 7.30 (m, 1H), 6.81 (br, 1H), 6.15 (s, 1H);
13C NMR 159.2 (br), 140.99, 128.49, 128.05, 126.44, 66.46;
HRMS (MALDI) calcd for C8H8N4ONa (MNa+) 199.0590, found
199.0596.
Cin n a m yltetr a zole (2p ). The reaction was refluxed for 48
h. The product 2p (2.71 g; 79% yield) had the following data:
1
mp 155-156 °C; H NMR 7.71 (m, 2H), 7.65 (d, 1H, J ) 16.7
Hz), 7.46-7.36 (m, 3H), 7.33 (d, 1H, J ) 16.7 Hz); 13C NMR
154.1 (br), 137.85, 134.88, 129.63, 128.99, 127.49, 110.41;
HRMS (MALDI) calcd for C9H9N4 (MH+) 173.0822, found
173.0829.
F u m a r yltetr a zole (2q). The reaction was refluxed for 48
h. The product 2q (2.10 g; 64% yield) deflagrated at 273 °C:
1H NMR 7.65 (s, 2H); 13C NMR 153.4 (br), 119.51; HRMS
(MALDI) calcd for C4H3N8 (M - H)- 163.0486, found 163.0488.
5-(Ben zylth io)tetr a zole (2r ). 2-Propanol (5 mL) was
added to the reaction mixture to facilitate dispersal of the
nitrile. The product 2r (2.19 g; 57% yield) had the following
F igu r e 1. Order of reaction in azide, zinc, and nitrile and
overall order of reaction.
1
data: mp 150-151 °C; H NMR 7.39 (m, 2H), 7.34-7.24 (m,

7950 J . Org. Chem., Vol. 66, No. 24, 2001
Demko and Sharpless
3H), 4.50 (s, 2H); 13C NMR 153.7 (br), 136.70, 128.93, 128.58,
127.67, 35.98; HRMS (MALDI) calcd for C8H9N4S (MH+)
193.0542, found 193.0539.
NMR 8.78 (t, 1H, J ) 5.6 Hz), 7.99 (d, 2H, J ) 8.5 Hz), 7.95
(d, 2H, J ) 8.5 Hz), 4.61 (br, 1H), 3.54 (t, 2H, J ) 5.6 Hz),
3.49 (m, 2H), 3.44 (m, 4H); 13C NMR 164.95, 138.40, 132.45,
128.08, 118.39, 113.58, 72.17, 68.71 (2), 60.22; HRMS (MALDI)
calcd for C12H14N2O3Na (MNa+) 257.0897, found 257.0899.
Kin etic Stu d ies. Aqueous solutions (2 mL) of the three
reactants in appropriate proportions were prepared. To mea-
sure the individual orders of reaction, the concentration of the
target reactant was varied from 400 to 12.5 mM in factors of
2, while the other reagents were both held constant at 50 mM.
For the overall reaction, the reactants were all varied from
400 to 12.5 mM in factors of 2.
The vials were placed in a heating block set to 90 °C, and
at regular intervals 100 µL aliquots were taken out and diluted
10-fold with a solution of 50% acetonitrile and 50% 0.2 N
aqueous HCl. These samples were then analyzed by LCMS
and calibrated using samples of known concentration. The
rates of reaction were calculated from only those data points
corresponding to reactions that were less than 10% complete.
The log of the rates were then plotted against the log of the
concentrations for each series, and the slopes were calculated
by linear regression to give the order of the reaction. These
plots are shown in Figure 1.
5-(Meth ylth io)tetr a zole (2s). Upon final acidification, the
product separated as an oil; after addition of NaCl, the aqueous
layer was extracted with 3 × 200 mL of ethyl acetate. The
combined organic layers were dried (Na2SO4) and evaporated
to give the product. The product 2s (2.07 g; 89% yield) had
the following data: mp 150-151 °C; 1H NMR 2.69 (s, 3H); 13
C
NMR 155.1 (br), 14.43. Anal. Calcd for C2H4N4S: C, 20.68; H,
3.47; N, 47.61. Found: C, 20.89; H, 3.40; N, 47.61.
5-(Dieth yla m in o)tetr a zole (2t). Glycerol (5 mL) was
added to the reaction mixture to facilitate dispersal of the
nitrile. Upon final acidification, the product separated as an
oil; after addition of NaCl, the aqueous layer was extracted
with 3 × 200 mL of ethyl acetate. The combined organic layers
were dried (Na2SO4) and evaporated to give the product. The
product 2t (1.99 g; 72% yield) had the following data: mp 120-
122 °C; 1H NMR 3.37 (q, 2H, J ) 7.0 Hz), 1.09 (t, 3H, J ) 7.0
Hz); 13C NMR 157.4 (br), 43.38, 12.69; HRMS (MALDI) calcd
for C5H12N5 (MH+) 142.1087, found 142.1089.
4-Cya n o(2-h yd r oxyet h yloxy)et h ylb en za m id e (1i). A
500 mL round-bottomed flask was charged with a stir bar,
4-cyanobenzoic acid (14.7 g., 100 mmol), and 100 mL of CH2-
Cl2. To the stirring suspension were added oxalyl chloride (12
mL, 135 mmol) and a catalytic amount of dimethyl formamide
(200 µL). After 2 h, the suspended solid had dissolved; to this
mixture was slowly added a solution of 2-(2-aminoethoxy)-
ethanol (11.55 g, 110 mmol) and sodium carbonate (12.5 g, 120
mmol) in 100 mL of water. After 1 h, the organic layer was
separated, and the aqueous layer was acidified to a pH of 1
with 3 N HCl, saturated with magnesium sulfate, and ex-
tracted with 3 × 200 mL of ethyl acetate. The combined organic
layers were washed with saturated sodium bicarbonate solu-
tion (20 mL) and 3 N HCl (20 mL), dried with sodium sulfate,
and evaporated to give 1i (22.9 g; 98% yield) as a light yellow
Ack n ow led gm en t. We thank the National Institute
of General Medical Sciences, National Institutes of
Health (GM-28384), the National Science Foundation
(CHE-9985553), the National Science Foundation gradu-
ate fellowship (DGE-9616174) (Z.D.), the Skaggs Pre-
doctoral Fellowship (Z.D.), and the W. M. Keck Foun-
dation for financial support.
Su p p or tin g In for m a tion Ava ila ble: The data points and
analysis for the kinetic studies. This material is available free
of charge via the Internet at http://pubs.acs.org.
1
solid. The product had the following data: mp 85-86 °C; H
J O010635W