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Article
Preparation of 5-Substituted 1H-Tetrazoles from Nitriles in Water
Zachary P. Demko, and K. Barry Sharpless
J. Org. Chem., 2001, 66 (24), 7945-7950 DOI: 10.1021/jo010635w
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Articles
Preparation of 5-Substituted 1H-Tetrazoles fromNitriles in Water

Zachary P. Demko and K. Barry Sharpl ess*


,
Department of Chemistry and TheSkaggs I nstituteof Chemical Biology, TheScripps Research I nstitute,
10550 North Torrey Pines Road, La J olla, California 92037
sharples@scripps.edu
Received J une21, 2001
The addi ti on of sodi um azi de to ni tri l es to gi ve 1H-tetrazol es i s shown to proceed readi l y i n water
wi th zi nc sal ts as catal ysts. The scope of the reacti on i s qui te broad; a vari ety of aromati c ni tri l es,
acti vated and unacti vated al kyl ni tri l es, substi tuted vi nyl ni tri l es, thi ocyanates, and cyanami des
have al l been shown to be vi abl e substrates for thi s reacti on.
The l i terature on tetrazol es i s expandi ng rapi dl y.
1
Thi s
functi onal group has rol es i n coordi nati on chemi stry as
a l i gand, i n medi ci nal chemi stry as a metabol i cal l y stabl e
surrogate for a carboxyl i c aci d group,
2
and i n vari ous
materi al s sci ence appl i cati ons, i ncl udi ng speci al ty expl o-
si ves.
3
Less appreci ated, but of enormous potenti al , are
the many useful transformati ons that make tetrazol es
versati l e i ntermedi ates en route to substi tuted tetrazol es,
and especi al l y to other 5-ri ng heterocycl es vi a the Hui s-
gen rearrangement.
4
The pri me reason for the scarci ty
of practi cal appl i cati ons for these sophi sti cated tetrazol e-
based reacti ons i s the l ack of appeal i ng syntheti c routes
to the key i ntermedi ates, RCN
4
H (2). We report here a
safer and excepti onal l y effi ci ent process for transformi ng
ni tri l es i nto tetrazol es i n water; the onl y other reagents
are sodi um azi de and a zi nc sal t (eq 1).
The most conveni ent route to 5-substi tuted 1H-tetra-
zol es (2) i s the addi ti on of azi de i on to ni tri l es (1).
5
The
l i terature i s repl ete wi th methods to perform thi s trans-
formati on; they fal l i nto three mai n categori es: those that
make use of ti n or si l i con azi des,
6
those that use strong
Lewi s aci ds,
7
and those that are run i n aci di c medi a.
8
Each of these has one or more of the fol l owi ng draw-
backs: expensi ve and toxi c metal s, severe water sensi ti v-
i ty, and the presence of hydrazoi c aci d, whi ch i s hi ghl y
toxi c and expl osi ve as wel l as vol ati l e. The few methods
that seek to avoi d hydrazoi c aci d l i berati on duri ng the
reacti on, by avoi di ng aci di c condi ti ons, requi re a very
l arge excess of sodi um azi de.
9
I n addi ti on, al l of the
known methods use organi c sol vents, i n parti cul ar,
di pol ar aproti c sol vents such as DMF. Thi s i s one of the
sol vent cl asses that process chemi sts woul d rather not
use.
10
We sought to fi nd a method that avoi ded these
drawbacks and was easy to use on both a l aboratory and
i ndustri al scal e.
Water i s rarel y used or even consi dered as a sol vent
for organi c reacti ons. The two foremost reasons why
chemi sts shy away from water i s the l ack of sol ubi l i ty of
most organi c compounds i n thi s medi um and/or concerns
that the hi gh aci d/base reacti vi ty wi l l i nterfere wi th the
desi red reacti on.
However, i t i s hard to i gnore water as a sol vent.
Beyond bei ng envi ronmental l y beni gn, i ts extraordi nary
physi cal properti es are wi del y appreci ated.
11
Whi l e the

Dedi cated to Professor Harry H. Wasserman on the occasi on of


hi s 80th bi rthday.

Reci pi ent of the 2001 Nobel Pri ze i n Chemi stry.


(1) Butl er, R. N. I n ComprehensiveHeterocyclic Chemistry; Katri tz-
ky, A. R., Rees, C. W., Scri ven, E. F. V., Eds.; Pergamon: Oxford, U.K.,
1996; Vol . 4.
(2) Si ngh, H.; Chawl a, A. S.; Kapoor, V. K.; Paul , D.; Mal hotra, R.
K. Prog. Med. Chem. 1980, 17, 151-183.
(3) (a) Ostrovski i , V. A.; Pevzner, M. S.; Kofmna, T. P.; Shcherbi ni n,
M. B.; Tsel i nski i , I . V. Targets Heterocycl. Syst. 1999, 3, 467-526. (b)
Hi skey, M.; Chavez, D. E.; Naud, D. L.; Son, S. F.; Berghout, H. L.;
Bome, C. A. Proc. I nt. Pyrotech. Semin 2000, 27, 3-14.
(4) Moderhack, D. J . Prakt. Chem. 1988 340, 687-709.
(5) Wi ttenberger, S. J. Org. Prep. Proced. I ntl. 1994, 26(5), 499-
531.
(6) (a) Duni ca, J. V.; Pi erce, M. E.; Santel l a, J. B., I I I . J . Org. Chem.
1991, 56, 2395. (b) Wi ttenberger, S. J.; Donner, B. G. J . Org. Chem.
1993, 58, 4139-4141. (c) Curran, D. P.; Hadi da, S.; Ki m, S.-Y.
Tetrahedron 1999, 55, 8997-9006.
(7) (a) Wi berg, V. E.; Mi chaud, H. Z. Naturforsch., Teil B 1954, 9,
497. (b) Grzonka, Z.; Li berek, 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) Mi hi na, J. S.; Herbst, R. M. J . Org. Chem. 1950, 15, 1082-
1092. (b) Fi nnegan, W. G.; Henry, R. A.; Lofqui st, R. J . Am. Chem.
Soc. 1958, 80, 3908-3911. (c) Ostrovski i , V. A.; Popl avski i , V. S.;
Kol dobski i , G. I .; Erusal i nki i , G. B. Khim. Geterotsikl. Soedin. 1992,
1214-1217. (d) Koguro, K.; Oga, T.; Mi tsui , S.; Ori ta, R. Synthesis
1998, 910-914.
(9) For exampl es, see: (a) Sauer, J.; Hui sgen, R.; Strum, H. J.
Tetrahedron 1960, 11, 241-251. (b) Gal l ante, R. J. U.S. Patent
5,502,191, 1995. (c) Tokuhara, G.; Yamaguchi , T.; I wasaki , T. WO
Patent 1996-37481, 1996. A good method for the amel i orati on of the
excess azi de/hydrazoi c aci d wi th sodi um ni tri te was fi rst reported i n
Rei th, J. F.; Bowman, J. H. A. Pharm. Weekbl. 1930, 67, 600. A good
revi ew can be found i n: Federoff, B. T., Ed. Encyclopedia of Explosives
and Related I tems; Pi cati nny Arsenal : Dover, NJ, 1960; Vol . 1, p A574.
(10) Anderson, N. Practical Process Research & Development; Aca-
demi c Press: San Di ego, CA, 2000; Chapter 4.
(11) (a) Rei chardt, C. Solvents and Sovent Effects in Organic
Chemistry; VCH Verl agsgesel l schaft mbH: Wei nhei m, Germany 1988.
(b) Brack, A Adv. SpaceRes. 1999, 24(4), 417-433.
7945 J . Org. Chem. 2001, 66, 7945-7950
10.1021/jo010635w CCC: $20.00 2001 Ameri can Chemi cal Soci ety
Publ i shed on Web 11/03/2001
tradi ti onal concerns (vi de supra) seem wel l founded,
there are many exampl es demonstrati ng that reacti ons
commonl y performed usi ng organi c sol vents work equal l y
wel l , i f not better, i n water. Over the past few years, we
have encountered numerous exampl es of water as the
perfect sol vent: e.g., i n (1) osmi um-catal yzed di hy-
droxyl ati on and ami nohydroxyl ati on,
12
(2) nucl eophi l i c
openi ng of epoxi des and azi ri di nes,
13
(3) cycl oaddi ti on
reacti ons of al l ki nds,
13
(4) most oxi me ether, hydrazone,
and aromati c heterocycl e condensati on processes,
14
and
(5) the formati on of an ami de from a pri mary ami ne and
an aci d chl ori de usi ng aqueous Schotten-Baumann
condi ti ons.
15
I n many of these cases, ei ther the starti ng
materi al , product, or both are rel ati vel y i nsol ubl e i n
water; i n others, the reagents are of a water-sensi ti ve
nature, yet the reacti ons proceed wi th hi gh yi el d and
fewer si de products than when organi c sol vents are used.
Thus encouraged, we envi si on a speci al styl e of organi c
synthesi s, one based on an enti re fami l y of reacti ons for
whi ch water i s the best sol vent.
As a resul t of these endeavors, we have found that i n
the presence of zi nc sal ts
9b,c
tetrazol e formati on proceeds
wi th excel l ent yi el ds and scope i n refl uxi ng water.
16
Thanks to the l ow pK
a
of 1H-tetrazol es (ca. 3-5) and thei r
hi ghl y crystal l i ne nature, a si mpl e aci di fi cati on i s usual l y
suffi ci ent to provi de the pure tetrazol es.
Another goal was to create a procedure that avoi ds the
rel ease of hydrazoi c aci d. An aqueous sol uti on of 1 M zi nc
bromi de has ca. pH 7, and when sodi um azi de i s added
(1 M), i t i s sl i ghtl y al kal i ne, ca. pH 8; consequentl y, even
at 100 C, rel ease of hydrazoi c aci d i s mi ni mi zed. Sti l l ,
as the pK
a
of hydrazoi c aci d i s 4.7, one mi ght expect a
smal l amount of hydrazoi c aci d to be l i berated duri ng the
reacti on at the temperatures and concentrati ons i nvol ved.
I ndeed, when the reacti ons were run at a concentrati on
of 1 M i n sodi um azi de and 1 M i n ZnBr
2
, we were abl e
to detect a smal l amount of l i berated hydrazoi c aci d i n
the headspace above the refl uxi ng sol vent;
17
when the
concentrati on was dropped to 0.5 M, no hydrazoi c aci d
coul d be detected. On the contrary, i n the headspace
above a sol uti on of 0.5 M sodi um azi de and 0.5 M
ammoni um chl ori de i n di methyl formami de at 100 C,
hydrazoi c aci d was cl earl y present i n much hi gher
concentrati ons and even more so at 125 C, the condi ti ons
used i n the most common procedure for maki ng tet-
razol es.
8b
By onl y usi ng 1.05 equi v of sodi um azi de, the
ri sk of hydrazoi c aci d l i berati on upon workup i s mi ni mal .
However, i n some cases such as benzoni tri l e (1a), the
yi el ds were l ower; compare a 76% yi el d of 5-phenyl tet-
razol e when 1.05 equi v of sodi um azi de i s used wi th a
93% yi el d when 1.50 equi v i s used.
A wi de vari ety of ni tri l es were converted to tetrazol es
on a 20 mmol scal e. Other thi ngs bei ng equal , the more
el ectron-poor a ni tri l e, the faster i t reacts. Aromati c
ni tri l es (see Tabl e 1) wi th a vari ety of substi tuents
(1a,b,c,i) reach compl eti on wi thi n several days at refl ux.
El ectron-poor aromati c and heteroaromati c ni tri l es, such
as 2-cyanopyri di ne and cyanopyrazi ne (1d,e), are com-
pl ete wi thi n a few hours. Some el ectron-ri ch aromati c
ni tri l es (1f,g) requi re hi gher temperatures, whi ch are
achi eved usi ng a seal ed gl ass pressure reactor. Ortho-
substi tuted aromati c ni tri l es are the most chal l engi ng,
someti mes proceedi ng at refl ux (1h), but often requi ri ng
much hi gher temperatures (1j). We have not been abl e
to achi eve si gni fi cant conversi on of any aromati c ni tri l es
beari ng an sp
3
-hybri di zed substi tuent i n the ortho posi -
ti on.
18
Unacti vated al kyl ni tri l es (see Tabl e 2) al so requi re
very hi gh temperatures (1k,l), but wi th el ectron-wi th-
(12) (a) Kol b, H. C.; VanNi euwenhze, M. S.; Sharpl ess, K. B. Chem.
Rev. 1994, 94(8), 2483-2547. (b) Wang, Z. M.; Sharpl ess, K. B. J . Org.
Chem. 1994, 59(26), 8302-8303. (c) Foki n, V. V.; Sharpl ess, K. B.
Angew. Chem., I nt. Ed. 2001, 40(18), 3455-3457.
(13) Kol b, H. C.; Fi nn, M. G.; Sharpl ess, K. B. Angew. Chem., I nt.
Ed. 2001, 40(11), 2004-2021.
(14) (a) Patai , S., Ed. TheChemistryof theCarbon-Nitrogen Double
Bond; I ntersci ence Publ i shers: London, U.K., 1070. (b) Gi l chri st, T.
L. Heterocyclic Chemistry, 3rd ed.; Addi son-Wesl ey Longman Ltd:
Harl ow, U.K., 1997.
(15) Sonntag, N. O. V. Chem. Rev. 1953, 52, 237-416.
(16) Note that the hi gh heat capaci ty of water when used as a
sol vent strongl y mi ti gates the expl osi on hazards from endergoni c
groups such as aromati c azi des and ni tro compounds. I n the present
system, i t i s i mportant that an aqueous sodi um azi de sol uti on i s very
stabl e at refl ux. For exampl e, thi s system has been used, under R
4N
+
X
-
catal ysi s, to di spl ace two chl ori des from neat 3,3-bi s(choromethyl )-
oxetane so that the organi c phase becomes pure 3,3-bi s(azi domethyl )-
oxetane pl us a few percent water. Thi s i s run on a several hundred
ki l ogram scal e, and the crude materi al i s di rectl y transferred to 55
gal l on drums for shi pment. See: Mal i k, A. A.; Manser, G. E.; Carson,
R. P.; Archi bal d, T. G. U. S. Patent US 5,523,424, 1996.
(17) A stri p of paper was soaked i n a 10 M i ron(I I I ) chl ori de sol uti on
and then dri ed. I n the presence of hydrazoi c aci d, the col or changes
from yel l ow to a bri ght red. See: Fei gl , F. Spot Tests in Organic
Analysis; El sevi er Sci enti fi c Publ i shi ng Co.: Amsterdam, 1975. Above
a 1 M aqueous sol uti on of sodi um azi de at refl ux, the stri p turned red
sl owl y over about 10 s, and usi ng the 0.5 M azi de modi fi cati on no
hydrazoi c aci d was detected. I n contrast, above the 1 M sol uti on of
sodi um azi de and 0.5 M ZnBr
2 i n DMF at 100 C, the stri p turned
bri ght red before i t coul d even be i nserted i n the fl ask. (18) Fl i ppi n, L. Tetrahedron Lett. 1991, 47, 6857-6860.
Table 1. Aromatic Tetrazoles
a
These reacti ons were run on 20 mmol scal e.
7946 J . Org. Chem., Vol. 66, No. 24, 2001 Demko and Sharpl ess
drawi ng substi tuents at the R-posi ti on (1m,n), temper-
atures can be l ower. At one extreme, tri fl uoroacetoni tri l e
has been shown to react rapi dl y wi th sodi um azi de i n
acetoni tri l e sol uti on at room temperature i n the absence
of any catal yst.
19
Al kyl ni tri l es wi th a hydroxy group at
the R-posi ti on (1o) al so proceed at l ower temperatures;
i n the anal ogous case wi th an ami no group i n pl ace of
the hydroxy group the reacti on proceeded wel l , but
puri fi cati on was very di ffi cul t. Presumabl y, thi s accel era-
ti on i s due to a combi nati on of the substi tuents i ntramo-
l ecul ar hydrogen bondi ng and -el ectroni c effects. Some
R,-unsaturated vi nyl ni tri l es (1p,q) are good substrates,
but si mpl e al kyl acryl oni tri l e deri vati ves onl y decomposed
under the reacti on condi ti ons and the tetrazol es were not
detected. Thi ocyanates gave the 5-thi otetrazol es 2r and
2s, and a di al kyl ated cyanami de al so reacted, furni shi ng
the 5-ami notetrazol e 2t. Ni tri l es attached to oxygen, as
i n cyanates (ROCN), have been shown to react wi th
sodi um azi de i n water at room temperature i n the
absence of catal yst.
20
Ki neti c studi es usi ng the water-sol ubl e ni tri l e 1i
reveal ed fi rst-order dependence i n both ni tri l e and azi de
and one-hal f order dependence for zi nc bromi de. The
mechani sm of the addi ti on of hydrazoi c aci d/azi de i on to
a ni tri l e to gi ve a tetrazol e has been debated, wi th
evi dence supporti ng both a two-step mechani sm
8b,21
and
a concerted [2 + 3] cycl oaddi ti on
22
(Chart 1, eq 2). Our
mechani sti c studi es to date i mpl y that the rol e of zi nc i s
not si mpl y that of a Lewi s aci d; a number of other Lewi s
aci ds were tested and caused l i ttl e to no accel erati on of
the reacti on.
23
I n contrast, Zn
2+
exhi bi ted a 10-fol d rate
accel erati on at 0.03 M, whi ch corresponds to a rate
accel erati on of approxi matel y 300 at the concentrati ons
typi cal l y used. The exact rol e of zi nc i s not yet cl ear.
Empi ri cal l y, we found that to ensure compl ete reacti on
one needs a 0.5 mol ar equi v of the zi nc sal t (ZnX
2
);
however, i n many cases, l ower l oadi ngs of zi nc may be
used.
24
The chi ef competi ng reacti on i s hydrol ysi s of the
ni tri l e to the pri mary ami de; therefore, i n cases where
the tetrazol e-formi ng reacti on i s suffi ci entl y fast, namel y
wi th el ectron-poor ni tri l es, l ower zi nc l oadi ngs di d not
entai l si gni fi cant formati on of the ami de byproduct.
Other zi nc sal ts such as zi nc perchl orate and zi nc tri fl ate
al so work; zi nc chl ori de, whi l e l ess expensi ve, l ed to more
of the ami de byproduct. Zi nc bromi de was chosen as the
best compromi se between cost, sel ecti vi ty, and reacti vi ty
(see Tabl e 3).
The process became even more attracti ve for l arge-
scal e appl i cati ons when we found that i t coul d be run at
hi gher concentrati on wi thout sacri fi ci ng yi el d and wi th-
out the use of organi c sol vents i n the workup or i sol ati on
phases. The resul ti ng products were spectroscopi cal l y
i denti cal by
1
H NMR and
13
C NMR to those synthesi zed
by the general method outl i ned bel ow; however, the
mel ti ng poi nts were sl i ghtl y l ower.
(19) Norri s, W. P. J . Org. Chem. 1962, 27, 3248-3251.
(20) Gri gat, E.; Putter, R.; Muhl bauer, E. Chem. Ber. 1965, 12,
3777-3785.
(21) Jursi c, E.; Zdravkovski , Z. THEOCHEM 1994, 118, 11-22.
(22) (a) Ti tova, I . E.; Popl avski i , V. S.; Kol dobski i , G. I .; Ostrovski i ,
V. A.; Ni kol aev, V. D.; Erusal i mski i , G. B. Khim. Geterosikl. Soedin.
1986, 8, 1086-1089. (b) Ostrovski i , V. A.; Popl avski i , V. S.; Kol dobski i ,
G. I .; Erusal i mski i , G. B. Khim. Geterosikl. Soedin. 1992, 9, 1214-
1219.
(23) Some of the metal s tested i ncl ude Li , K, Cs, Mg, Ca, Ba, Fe,
Co, Ni , Cu, Ag, Zn, Ce, Sm, Yb, B, Al , and Bi .
(24) We found that heterocycl i c ni tri l es woul d proceed to compl eti on,
al bei t i n l ower yi el ds, wi th onl y sodi um azi de i n refl uxi ng water (Eppl e,
R., unpubl i shed work) but that zi nc was necessary to coax the majori ty
of ni tri l es i nto reacti ng wi th azi de.
Table 2. Other Tetrazoles
a
These reacti ons were run on 20 mmol scal e.
b
These reacti ons
were run wi th
i
PrOH as a cosol vent (10% v/v).
Chart 1
Table 3. Mole-Scale Reactions
entry NaN3 (mol ) ZnX2 (0.50 mol ) yi el d (g)
1 1.05 ZnCl 2 98.0 (67%)
2 1.05 Zn(Cl O4)2 101.2 (70%)
3 1.05 ZnBr2 111.1 (76%)
4 1.50 ZnBr2 135.2 (93%)
Preparati on of 5-Substi tuted 1H-Tetrazol es J . Org. Chem., Vol. 66, No. 24, 2001 7947
I n summary, we have demonstrated an exceedi ngl y
si mpl e protocol for transformi ng a wi de vari ety of ni tri l es
i nto the correspondi ng 1H-tetrazol es. By usi ng zi nc sal ts
as catal ysts, we showed that water can be used as the
sol vent despi te the rel ati ve i nsol ubi l i ty of the starti ng
materi al s. Thi s di scovery shoul d faci l i tate the prepara-
ti on of tetrazol es i n the l aboratory.
Experimental Section
Al l
1
H NMR spectra taken on a Bruker AMX-400 spectrom-
eter i n DMSO-d6 wi th DMSO as a standard at 2.50 ppm. Al l
13
C NMR spectra taken on the same machi ne at 100 MHz i n
DMSO-d6 wi th DMSO as a standard at 39.50 ppm, unl ess
otherwi se noted. Al l mel ti ng poi nts were taken on a Thomas-
Hoover Uni -mel t mel ti ng poi nt apparatus. Reagents were used
unpuri fi ed, and dei oni zed water was used as sol vent.
Large-Scale, Organic Solvent FreeProcedurefor the
Synthesis of Tetrazoles. To a three-necked 3 L round-
bottomed fl ask equi pped wi th a mechani cal sti rrer was added
benzoni tri l e (103.1 g, 1.00 mol ), 1 L of water, sodi um azi de
(68.2 g, 1.05 mol ), and 68.1 g. (0.50 mol ) zi nc chl ori de. The
reacti on was refl uxed i n a hood, but open to the atmosphere,
for 24 h wi th vi gorous sti rri ng. After the mi xture was cool ed
to room temperature, the pH was adjusted to 1.0 wi th
concentrated HCl (120 mL), and the reacti on was sti rred for
30 mi n to break up the sol i d preci pi tate, presumabl y (PhCN
4)2-
Zn. The new preci pi tate was then fi l tered, washed wi th 2
200 mL of 1 N HCl , and dri ed i n a dryi ng oven at 90 C
overni ght to gi ve 98.0 g of 5-phenyl tetrazol e as a whi te powder
(67% yi el d, mp 211 C (l i t.
25
mp 216 C)).
General Procedurefor theTransformationof Nitriles
into Tetrazoles. To a 250 mL round-bottomed fl ask was
added the ni tri l e (20 mmol ), sodi um azi de (1.43 g, 22 mmol ),
zi nc bromi de (4.50 g, 20 mmol ), and 40 mL of water.
26
The
reacti on mi xture was refl uxed for 24 h; vi gorous sti rri ng i s
essenti al . HCl (3 N, 30 mL) and ethyl acetate (100 mL) were
added, and vi gorous sti rri ng was conti nued unti l no sol i d was
present and the aqueous l ayer had a pH of 1. I f necessary,
addi ti onal ethyl acetate was added. The organi c l ayer was
i sol ated and the aqueous l ayer extracted wi th 2 100 mL of
ethyl acetate. The combi ned organi c l ayers were evaporated,
200 mL of 0.25 N NaOH was added, and the mi xture was
sti rred for 30 mi n, unti l the ori gi nal preci pi tate was di ssol ved
and a suspensi on of zi nc hydroxi de was formed. The suspen-
si on was fi l tered, and the sol i d washed wi th 20 mL of 1 N
NaOH. To the fi l trate was added 40 mL of 3 N HCl wi th
vi gorous sti rri ng causi ng the tetrazol e to preci pi tate. The
tetrazol e was fi l tered and washed wi th 2 20 mL of 3 N HCl
and dri ed i n a dryi ng oven to furni sh the tetrazol e as a whi te
or sl i ghtl y col ored powder.
Modifications. For tetrazol es that do not show si gni fi cant
reacti on after 1 day at refl ux, the reacti on i s run i n a pressure
tube submerged up to the neck i n an oi l bath at 140 C or, i f
necessary, 170 C. I n ei ther case, i f the extent of reacti on i s
l ess than 50% after 1 day, i t i s conti nued for an addi ti onal 1
day. The ti mes gi ven for reacti on may be sl i ghtl y l onger than
necessary, but not more than twi ce the ti me needed. As the
tetrazol e products are qui te stabl e, no decrease i n yi el d was
observed from excess reacti on ti mes, so the ti mes were not
opti mi zed beyond a factor of 2. I f, duri ng the reacti on, the
ni tri l e i s not di spersed wel l (e.g., ni tri l e cl umps up), 5-10 mL
of
i
PrOH i s added to the reacti on mi xture. I n cases where a
basi c ni trogen was present i n the mol ecul e, the i ni ti al aci di -
fi cati on and extracti on i nto ethyl acetate was foregone, and
the fi nal aci di fi cati on was onl y taken to pH 6.5, at whi ch poi nt
the zwi tteri on preci pi tated. I f l i ttl e or no preci pi tate was
formed upon fi nal aci di fi cati on, the aqueous l ayer was satu-
rated wi th NaCl and extracted wi th 3 100 mL of ethyl
acetate; the organi c l ayer was dri ed wi th sodi um sul fate and
evaporated to dryness. I n some cases, extremel y nonpol ar
tetrazol es may requi re col umn puri fi cati on. Modi fi cati ons to
the general method are gi ven for i ndi vi dual tetrazol es bel ow.
5-Phenyltetrazole(2a). The product 2a(2.20 g; 75%yi el d)
had the fol l owi ng data: mp 215-216 C;
1
H NMR 8.04 (m,
2H), 7.61 (m, 3H);
13
C NMR 155.2 (br), 131.28, 129.45, 127.02,
124.17; HRMS (MALDI ) cal cd for C7H7N4 (MH
+
) 147.0665,
found 147.0666. Anal . Cal cd for C7H6N4: C, 57.53; H, 4.14; N,
38.34. Found: C, 57.65; H, 4.17; N, 38.04.
5-(4-Nitrophenyl)tetrazole(2b). The product 2b(3.42 g;
94% yi el d) had the fol l owi ng data: mp 220 C;
1
H NMR 8.44
(m, 2H), 8.29 (m, 2H);
13
C NMR 155.4 (br), 148.74, 130.60,
128.22, 124.64; HRMS (MALDI ) cal cd for C7H4N5O2 (M - H)
-
190.0360, found 190.0363. Anal . Cal cd for C7H5N5O2: C, 43.98;
H, 2.64; N, 36.64. Found: C, 44.10; H, 2.63; N, 36.37.
5-(4-Methoxyphenyl)tetrazole (2c). The reacti on was
refl uxed for 48 h. The product 2c (3.04 g; 86% yi el d) had the
fol l owi ng data: mp 231-232 C;
1
H NMR 7.97 (d, 2H, J ) 8.8
Hz), 7.14 (d, 2H, J ) 8.8 Hz), 3.83 (s, 3H);
13
C NMR 161.47,
154.6 (br), 128.66, 116.28, 114.86, 55.45; HRMS (MALDI ) cal cd
for C8H9N4O (MH
+
) 177.0771, found 177.0777.
5-(2-Pyridyl)tetrazole(2d). Workup excl uded i ni ti al aci di -
fi cati on and extracti on; the reacti on mi xture was si mpl y
basi fi ed by addi ti on of 2.5 equi v of NaOH, fi l tered, aci di fi ed
to pH )6.5, and fi l tered, and the sol i d was washed wi th water.
The product 2d(2.31 g; 79%yi el d) had the fol l owi ng data: mp
211 C;
1
H NMR 8.79 (m, 1H), 8.22 (d, 1H, J ) 7.6 Hz), 8.08
(m, 1H), 7.62 (m, 1H);
13
C NMR 154.9 (br), 150.10, 143.76,
138.29, 126.11, 122.62; HRMS (MALDI ) cal cd for C6H6N5
(MH
+
) 148.0618, found 149.0617.
5-Pyrazinetetrazole (2e). Workup excl uded i ni ti al aci di -
fi cati on and extracti on; the reacti on mi xture was si mpl y
basi fi ed by addi ti on of 2.5 equi v of NaOH, fi l tered, aci di fi ed
to pH )6.5, and fi l tered, and the sol i d was washed wi th water.
The product 2e(2.44 g; 83%yi el d) had the fol l owi ng data: mp
193-195 C;
1
H NMR 9.38 (m, 1H), 8.82 (m, 1H), 8.58 (br, 1H);
13
C NMR 154.9 (br), 146.83, 143.93, 143.07, 140.37; HRMS
(MALDI ) cal cd for C5H5N6 (MH
+
) 149.0570, found 149.0569.
5-(4-Hydroxyphenyl)tetrazole(2f). The reacti on mi xture
was sti rred i n a pressure tube submerged i n an oi l bath at
140 C. The product 2f (3.11 g; 96% yi el d) had the fol l owi ng
data: mp 234-236 C;
1
H NMR 10.20 (br, 1H), 7.86 (d, 2H, J
) 8.5 Hz), 6.95 (d, 2H, J ) 8.5 Hz);
13
C NMR 160.22, 154.7
(br), 128.89, 116.25, 114.68; HRMS (MALDI ) cal cd for C7H7N4O
(MH
+
) 163.0614, found 163.0612.
5-(2-Naphthyl)tetrazole (2g). The reacti on mi xture was
sti rred i n a pressure tube submerged i n an oi l bath at 140 C
for 48 h. The product 2g(2.85 g; 73% yi el d) had the fol l owi ng
data: mp 205-207 C;
1
H NMR 8.67 (m, 1H), 8.12 (m, 2H),
8.06 (m, 1H), 7.99 (m, 1H), 7.61 (m, 2H);
13
C 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 ) cal cd for C11H9N4 (MH
+
)
197.0822, found 197.0829.
1,2-Bis(5-tetrazolyl)benzene(2h). The reacti on mi xture
was refl uxed for 48 h. The product 2h (2.75 g; 64% yi el d) had
the fol l owi ng data: mp 228-230 C;
1
H NMR 7.89 (m, 2H),
7.82 (m, 2H);
13
C NMR 154.8 (br), 131.37, 130.78, 124.53;
HRMS (MALDI ) cal cd for C8H6N8Na (MNa
+
) 237.0608, found
237.0609.
4-(5-Tetrazolyl)(2-hydroxyethyloxy)ethylbenzamide
(2i). After fi nal aci di fi cati on, reacti on mi xture was set asi de
unti l product crystal l i zed from the sol uti on (2 days). The
product 2i (3.35 g; 67%yi el d) had the fol l owi ng data: mp 158-
160 C;
1
H 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);
13
C NMR 165.60, 155.0 (br), 136.70, 128.32,
126.61, 72.24, 68.91, 68.89, 60.32; HRMS (MALDI ) cal cd for
C12H15N5O3Na (MNa
+
) 300.1067, found 300.1059.
5-(2-(4-Methyl)biphenyl)tetrazole(2j). The reacti on was
sti rred i n a pressure tube submerged i n an oi l bath at 170 C
for 48 h. Si l i ca gel col umn chromatography was used to puri fy
(25) Note that the l i terature mel ti ng poi nt of 216 C was obtai ned
when the general procedure outl i ned i n the Experi mental Secti on,
whi ch i ncl udes an organi c extracti on, was used.
(26) As menti oned i n the text, the 1:1 mol ar rati o of NaN3/ZnBr2 i s
more general . Note that the four 1.0 M scal e reacti ons run wi th
benzoni tri l e (vi de supra) were al l performed wi th a NaN3/ZnX2 mol ar
rati o of 2:1.
7948 J . Org. Chem., Vol. 66, No. 24, 2001 Demko and Sharpl ess
the fi nal product. The product 2j (3.16 g; 67% yi el d) had the
fol l owi ng data: mp 150 C;
1
H 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);
13
C 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 ) cal cd for C14H13N4 (MH
+
) 237.1135, found 237.1142.
5-n-Heptyltetrazole (2k). The reacti on was sti rred i n a
pressure tube submerged i n an oi l bath at 170 C. Upon fi nal
aci di fi cati on, the product separated as an oi l ; after addi ti on
of NaCl , the aqueous l ayer was extracted wi th 3 200 mL of
ethyl acetate. The combi ned organi c l ayers were dri ed (Na2-
SO4) and evaporated to gi ve the crude product, whi ch was
puri fi ed by col umn chromatography. The product 2k (2.75 g.;
82% yi el d) had the fol l owi ng data: mp 36-38 C;
1
H NMR
(CDCl 3, usi ng 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);
13
C NMR (CDCl 3 usi ng CDCl 3 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 ) cal cd for C8H17N4 (MH
+
) 169.1448, found 169.1451.
5-Methyltetrazole(2l). The reacti on mi xture was sti rred
i n a pressure tube submerged i n an oi l bath at 170 C. Upon
compl eti on of the reacti on, the product was made basi c wi th
2.5 equi v of 1 N NaOH, sti rred, and fi l tered. Fol l owi ng
aci di fi cati on wi th HCl , the sol uti on was saturated wi th
magnesi um sul fate and extracted wi th 6 200 mL ethyl
acetate, whi ch was dri ed and evaporated to gi ve the crude
product. The product 2l (1.37 g; 75% yi el d) had the fol l owi ng
data: mp 146 C;
1
H NMR 2.48 (s, 3H);
13
C NMR 152.2 (br),
8.43. Anal . Cal cd for C2H4N4: C, 28.57; H, 4.79; N, 66.63.
Found: C, 28.49; H, 4.61; N, 62.76.
5-(2-(N-Benzylacetamido)tetrazole(2m). 2-Propanol (5
mL) was added to the reacti on mi xture to faci l i tate di spersal
of the ni tri l e. Due to rel ati ve i nsol ubi l i ty of the tetrazol e i n
al kal i ne water, the i ni ti al organi c extracts were combi ned,
dri ed (Na
2SO4), and evaporated to gi ve the product. The
product 2m (3.55 g; 82% yi el d) had the fol l owi ng data: mp
162-163 C;
1
H NMR 8.85 (br, 1H), 7.36-7.23 (m, 5H), 4.33
(d, 2H, J ) 5.56 Hz), 3.98 (s, 2H);
13
C NMR 166.21, 151.10
(br), 138.92, 128.43, 127.44, 127.05, 42.57, 30.56; HRMS
(MALDI ) cal cd for C10H12N5O (MH
+
) 218.1036, found 218.1041.
2,2-Bis(5-tetrazolyl)propane(2n). 2-Propanol (5 mL) was
added to the reacti on mi xture to faci l i tate di spersal of the
ni tri l e. Upon fi nal aci di fi cati on, the product separated as an
oi l ; after addi ti on of NaCl , the aqueous l ayer was extracted
wi th 3 200 mL of ethyl acetate. The combi ned organi c l ayers
were dri ed (Na
2SO4) and evaporated to gi ve the product. The
product 2n (3.20 g; 89% yi el d) had the fol l owi ng data: mp
178-179 C;
1
H NMR 1.87 (s, 6H);
13
C NMR 160.9 (br), 33.21,
26.70; HRMS (MALDI ) cal cd for C14H13N4 (M - H)
-
179.0799,
found 179.0800.
5-(Hydroxybenzyl)tetrazole (2o). Upon fi nal aci di fi ca-
ti on, the product separated as an oi l ; after addi ti on of NaCl ,
the aqueous l ayer was extracted wi th 3 200 mL of ethyl
acetate. The combi ned organi c l ayers were dri ed (Na
2SO4) and
evaporated to gi ve the product. The product 2o (3.14 g; 89%
yi el d) had the fol l owi ng data: mp 178-179 C;
1
H NMR 7.44
(m, 2H), 7.37 (m, 2H), 7.30 (m, 1H), 6.81 (br, 1H), 6.15 (s, 1H);
13
C NMR 159.2 (br), 140.99, 128.49, 128.05, 126.44, 66.46;
HRMS (MALDI ) cal cd for C8H8N4ONa (MNa
+
) 199.0590, found
199.0596.
Cinnamyltetrazole(2p). The reacti on was refl uxed for 48
h. The product 2p (2.71 g; 79% yi el d) had the fol l owi ng data:
mp 155-156 C;
1
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);
13
C NMR
154.1 (br), 137.85, 134.88, 129.63, 128.99, 127.49, 110.41;
HRMS (MALDI ) cal cd for C9H9N4 (MH
+
) 173.0822, found
173.0829.
Fumaryltetrazole (2q). The reacti on was refl uxed for 48
h. The product 2q (2.10 g; 64% yi el d) defl agrated at 273 C:
1
H NMR 7.65 (s, 2H);
13
C NMR 153.4 (br), 119.51; HRMS
(MALDI ) cal cd for C4H3N8 (M -H)
-
163.0486, found 163.0488.
5-(Benzylthio)tetrazole (2r). 2-Propanol (5 mL) was
added to the reacti on mi xture to faci l i tate di spersal of the
ni tri l e. The product 2r (2.19 g; 57% yi el d) had the fol l owi ng
data: mp 150-151 C;
1
H NMR 7.39 (m, 2H), 7.34-7.24 (m,
Figure 1. Order of reacti on i n azi de, zi nc, and ni tri l e and
overal l order of reacti on.
Preparati on of 5-Substi tuted 1H-Tetrazol es J . Org. Chem., Vol. 66, No. 24, 2001 7949
3H), 4.50 (s, 2H);
13
C NMR 153.7 (br), 136.70, 128.93, 128.58,
127.67, 35.98; HRMS (MALDI ) cal cd for C8H9N4S (MH
+
)
193.0542, found 193.0539.
5-(Methylthio)tetrazole(2s). Upon fi nal aci di fi cati on, the
product separated as an oi l ; after addi ti on of NaCl , the aqueous
l ayer was extracted wi th 3 200 mL of ethyl acetate. The
combi ned organi c l ayers were dri ed (Na2SO4) and evaporated
to gi ve the product. The product 2s (2.07 g; 89% yi el d) had
the fol l owi ng data: mp 150-151 C;
1
H NMR 2.69 (s, 3H);
13
C
NMR 155.1 (br), 14.43. Anal . Cal cd for C2H4N4S: C, 20.68; H,
3.47; N, 47.61. Found: C, 20.89; H, 3.40; N, 47.61.
5-(Diethylamino)tetrazole (2t). Gl ycerol (5 mL) was
added to the reacti on mi xture to faci l i tate di spersal of the
ni tri l e. Upon fi nal aci di fi cati on, the product separated as an
oi l ; after addi ti on of NaCl , the aqueous l ayer was extracted
wi th 3 200 mL of ethyl acetate. The combi ned organi c l ayers
were dri ed (Na
2SO4) and evaporated to gi ve the product. The
product 2t (1.99 g; 72%yi el d) had the fol l owi ng data: mp 120-
122 C;
1
H NMR 3.37 (q, 2H, J ) 7.0 Hz), 1.09 (t, 3H, J ) 7.0
Hz);
13
C NMR 157.4 (br), 43.38, 12.69; HRMS (MALDI ) cal cd
for C5H12N5 (MH
+
) 142.1087, found 142.1089.
4-Cyano(2-hydroxyethyloxy)ethylbenzamide (1i). A
500 mL round-bottomed fl ask was charged wi th a sti r bar,
4-cyanobenzoi c aci d (14.7 g., 100 mmol ), and 100 mL of CH2-
Cl 2. To the sti rri ng suspensi on were added oxal yl chl ori de (12
mL, 135 mmol ) and a catal yti c amount of di methyl formami de
(200 L). After 2 h, the suspended sol i d had di ssol ved; to thi s
mi xture was sl owl y added a sol uti on of 2-(2-ami noethoxy)-
ethanol (11.55 g, 110 mmol ) and sodi um carbonate (12.5 g, 120
mmol ) i n 100 mL of water. After 1 h, the organi c l ayer was
separated, and the aqueous l ayer was aci di fi ed to a pH of 1
wi th 3 N HCl , saturated wi th magnesi um sul fate, and ex-
tracted wi th 3 200 mL of ethyl acetate. The combi ned organi c
l ayers were washed wi th saturated sodi um bi carbonate sol u-
ti on (20 mL) and 3 N HCl (20 mL), dri ed wi th sodi um sul fate,
and evaporated to gi ve 1i (22.9 g; 98% yi el d) as a l i ght yel l ow
sol i d. The product had the fol l owi ng data: mp 85-86 C;
1
H
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);
13
C NMR 164.95, 138.40, 132.45,
128.08, 118.39, 113.58, 72.17, 68.71 (2), 60.22; HRMS (MALDI )
cal cd for C12H14N2O3Na (MNa
+
) 257.0897, found 257.0899.
Kinetic Studies. Aqueous sol uti ons (2 mL) of the three
reactants i n appropri ate proporti ons were prepared. To mea-
sure the i ndi vi dual orders of reacti on, the concentrati on of the
target reactant was vari ed from 400 to 12.5 mM i n factors of
2, whi l e the other reagents were both hel d constant at 50 mM.
For the overal l reacti on, the reactants were al l vari ed from
400 to 12.5 mM i n factors of 2.
The vi al s were pl aced i n a heati ng bl ock set to 90 C, and
at regul ar i nterval s 100 L al i quots were taken out and di l uted
10-fol d wi th a sol uti on of 50% acetoni tri l e and 50% 0.2 N
aqueous HCl . These sampl es were then anal yzed by LCMS
and cal i brated usi ng sampl es of known concentrati on. The
rates of reacti on were cal cul ated from onl y those data poi nts
correspondi ng to reacti ons that were l ess than 10% compl ete.
The l og of the rates were then pl otted agai nst the l og of the
concentrati ons for each seri es, and the sl opes were cal cul ated
by l i near regressi on to gi ve the order of the reacti on. These
pl ots are shown i n Fi gure 1.
Acknowledgment. We thank the Nati onal I nsti tute
of General Medi cal Sci ences, Nati onal I nsti tutes of
Heal th (GM-28384), the Nati onal Sci ence Foundati on
(CHE-9985553), the Nati onal Sci ence Foundati on gradu-
ate fel l owshi p (DGE-9616174) (Z.D.), the Skaggs Pre-
doctoral Fel l owshi p (Z.D.), and the W. M. Keck Foun-
dati on for fi nanci al support.
SupportingInformationAvailable: The data poi nts and
anal ysi s for the ki neti c studi es. Thi s materi al i s avai l abl e free
of charge vi a the I nternet at http://pubs.acs.org.
JO010635W
7950 J . Org. Chem., Vol. 66, No. 24, 2001 Demko and Sharpl ess