Synthesis of 5-Substituted 1-Hydroxy-1,2,3-triazoles through Directed Lithiation of 1-(Benzyloxy)-1,2,3-triazole

Article abstract of DOI:10.1021/jo971313o

1-(Benzyloxy)-1,2,3-triazole, prepared by selective benzylation of 1-hydroxy-1,2,3-triazole or by oxidative cyclization of 2-hydrazonoglyoxal O-benzyloxime, was metalated exclusively at the 5-position upon treatment with n-butyllithium. The anion formed reacted with a series of electrophiles. In this way carbon, halogen, sulfur, silicon, and tin substituants could be introduced at the 5-position. Subsequent removal of the benzyl group by palladium-catalyzed hydrogenolysis or by treatment with hydrochloric acid afforded the corresponding 5-substituted 1-hydroxy-1,2,3- triazoles.

Full text of DOI:10.1021/jo971313o

J . Org. Chem. 1997, 62, 9177-9181
9177
Syn th esis of 5-Su bstitu ted 1-Hyd r oxy-1,2,3-tr ia zoles th r ou gh
Dir ected Lith ia tion of 1-(Ben zyloxy)-1,2,3-tr ia zole
Peter Uhlmann, J akob Felding, Per Vedsø, and Mikael Begtrup*
Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Universitetsparken 2,
DK-2100 Copenhagen, Denmark
Received J uly 18, 1997X
1-(Benzyloxy)-1,2,3-triazole, prepared by selective benzylation of 1-hydroxy-1,2,3-triazole or by
oxidative cyclization of 2-hydrazonoglyoxal O-benzyloxime, was metalated exclusively at the
5-position upon treatment with n-butyllithium. The anion formed reacted with a series of
electrophiles. In this way carbon, halogen, sulfur, silicon, and tin substituents could be introduced
at the 5-position. Subsequent removal of the benzyl group by palladium-catalyzed hydrogenolysis
or by treatment with hydrochloric acid afforded the corresponding 5-substituted 1-hydroxy-1,2,3-
triazoles.
In tr od u ction
by de-methoxybenzylation of 2- or 3-(p-methoxybenzyl)-
triazole 1-oxides accomplished by treatment with con-
centrated sulfuric acid.16 The limitation of this method
is the availability of the triazole 1-oxides used as the
starting material.
1-Hydroxybenzotriazole (HOBt) is an important cata-
lyst for acylations and phosporylations.1,2 It is widely
used in peptide 3-7 and nucleotide synthesis.8 In peptide
synthesis the requirements of the catalyst are maximum
reactivity combined with minimum racemization of chiral
amino acids during the coupling. To improve the cata-
lytic properties substituted 1-hydroxybenzotriazoles3,9
and aza-substituted 1-hydroxybenzotriazoles have been
prepared.10 Introduction of substituents in the benzene
ring gave only moderate changes in the catalytic proper-
ties since these substituents are remote to the N-OH
functionality. A higher sensitivity to the nature of
substitution is possible in the uncondensed, parent
1-hydroxy-1,2,3-triazole11 (3).
Only a few uncondensed 1-hydroxytriazoles have been
reported. The 4,5-dicarboxylic acid derivative was pre-
pared by oxidation of 1-hydroxybenzotriazole.12 The
5-methyl 4-carboxylic acid, the 4-benzoyl-5-methyl, and
the 4-benzoyl 5-carboxylic acid were obtained through
reaction between diazoketone and hydroxylamine.13 The
5-tert-butylcarbonyl derivative was formed in a ring
transformation of 4-amino-5-tert-butylisoxazole effected
by diazotization.14 The parent 1-hydroxytriazole (3) has
been synthesized recently by direct oxidation of 1,2,3-
triazole.15 Finally, 1-hydroxytriazoles were prepared by
debenzylation of 2-benzyltriazole 1-oxides effected with
concentrated hydrobromic acid or iodotrimethylsilane or
A more general approach to substituted 1-hydroxytria-
zoles would be introduction of substituents in the parent
1-hydroxytriazole (3). Recently substituents were intro-
duced in 1-hydroxypyrazole which was first alkylated or
carbamoylated at the oxygen atom. The N-alkoxy or
carbamoyloxy groups formed displayed strong ortho-
directing power in lithiation reactions. Lithiation was
followed by addition of electrophiles to give a series of
5-substituted derivatives.17 If this strategy is applied to
1-hydroxytriazoles, different 5-substituents can be intro-
duced. The proximity of the substituent makes possible
effective control of the acidity of the N-hydroxy group
which is crucial for the catalytic properties in acylation
reactions.3 In addition substituents can be introduced
which can effect hydrogen bonding to the activated
complex during the peptide coupling. It has been sug-
gested that hydrogen bonding to N-7 is responsible for
the increased catalytic effect of 7-aza 1-hydroxybenzo-
triazoles as compared to the parent 1-hydroxybenzotria-
zoles.10
Resu lts a n d Discu ssion
P r ep a r a tion of Tr ia zole, 1-Hyd r oxytr ia zole, a n d
O-P r otected 1-Hyd r oxytr ia zoles. 1-Hydroxytriazole
was prepared by oxidation of triazole or by palladium-
catalyzed hydrogenolysis of 1-(benzyloxy)triazole ob-
tained by oxidative cyclization of 2-hydrazonoglyoxal
O-benzyloxime (8). In the first approach a new method
for the preparation of 1,2,3-triazole useful for larger scale
preparations was developed. In addition, the previously
described procedure for oxidation of the triazole was
optimized and modified to be suitable for medium scale
batches.
1,2,3-Triazole has been prepared by 1,3-dipolar cy-
cloaddition of azides, like azo imide or trimethylsilyl
azide, to acetylenes, like acetylene, propiolic acid, or
acetylenedicarboxylic acid (or the corresponding esters).18
With propiolic acid or acetylenedicarboxylic acid, car-
X Abstract published in Advance ACS Abstracts, November 15, 1997.
(1) Wreesmann, C. T. J .; Fidder, A.; Veeneman, G. H.; van der Marel,
G. A.; van Boom, J . H. Tetrahedron Lett. 1985, 26, 933.
(2) van Boeckel, C. A. A.; van der Marel, G. A.; Westerduin, P.; van
Boom, J . H. Synthesis 1982, 399.
(3) Ko¨nig, W.; Geiger, R. Chem. Ber. 1970, 103, 788.
(4) Ko¨nig, W.; Geiger, R. Chem. Ber. 1970, 103, 2024.
(5) Castro, B.; Dormoy, J . R.; Evin, G.; Selve, C. J . Chem. Res. (S)
1977, 182.
(6) Kim, S.; Chang, H.; Ko, Y. K. Tetrahedron Lett. 1985, 26, 1341.
(7) Nguyen, D. L.; Seyer, R.; Heitz, A.; Castro, B. J . Chem. Soc.,
Perkin Trans. 1 1985, 1025.
(8) Marugg, J . E.; Tromp, M.; J hurani, P.; Hoyng, C. F.; van der
Marel, G. A.; van Boom, J . H. Tetrahedron 1984, 40, 73.
(9) Kehler, J .; Pu¨schl, A.; Dahl, O. Acta Chem. Scand. 1996, 50,
1171.
(10) Carpino, L. A. J . Am. Chem. Soc. 1993, 115, 4397.
(11) In the following triazole refers to 1,2,3-triazole.
(12) Zincke, T.; Schwartz, P. Liebigs Ann. Chem. 1900, 311, 329.
(13) Wolff, L. Liebigs Ann. Chem. 1902, 325, 129.
(14) L′abbe´, G.; Godts, F.; Toppet, S. Tetrahedron Lett. 1983, 24,
3149.
(15) Begtrup, M.; Vedsø, P. J . Chem. Soc., Perkin Trans. 1 1995,
243.
(16) Begtrup, M.; Vedsø, P. Acta Chem. Scand. 1996, 50, 549.
(17) Vedsø, P.; Begtrup, M. J . Org. Chem. 1995, 60, 4995.
S0022-3263(97)01313-3 CCC: $14.00 © 1997 American Chemical Society

9178 J . Org. Chem., Vol. 62, No. 26, 1997
Uhlmann et al.
Sch em e 1
Sch em e 2
Sch em e 3
boxytriazoles were formed and then decarboxylated. To
develop a safer procedure, benzyl azide has been reacted
with acetylenedicarboxylic acid. Subsequent decarboxyl-
ation produced 1-benzyltriazole which was then deben-
zylated by hydrogenolysis at high pressure or by treat-
ment with sodium in liquid ammonia.19
To avoid the inconvenient debenzylation of 1-benzyl-
triazole instead, 1-(4-methoxybenzyl)triazole (1) was de-
methoxybenzylated (Scheme 1) by treatment with 47%
aqueous HBr to give 1,2,3-triazole (2) in 89% yield. The
1-(4-methoxybenzyl)triazole (1) was readily prepared by
decarboxylation of 4,5-dicarboxy-1-(4-methoxybenzyl)tria-
zole obtained by cycloaddition of 4-methoxybenzyl azide
with acetylenedicarboxylic acid as previously described.16
The yield by oxidation (Scheme 1) of triazole to 1-hy-
droxytriazole (3) was increased from 39% reported in ref
15 to 65% by adding the oxidant portionwise over 30 days.
The pure 1-hydroxytriazole (3) was isolated by continuous
extraction with Et2O over 3 weeks.
The preparation of 1-(benzyloxy)triazole (5) by N-
oxidation of triazole (2) followed by O-benzylation re-
quired ca. 2 months effort. More conveniently, 5 could
be obtained via a one-pot process by addition of glyoxal
O-benzyloxime (7)21 to a 10-fold excess of hydrazine22
followed by oxidative cyclization of the 2-hydrazonogly-
oxal O-benzyloxime (8) formed in situ (Scheme 2).
Several oxidants were tried. Copper(II) sulfate proved
to be the best, but also manganese dioxide and nickel
peroxide served well. The effectiveness of these oxidants
indicates that the cyclization takes place by a one-
electron mechanism as shown in Scheme 2.23,24 This
route to 1-(benzyloxy)triazole (5) is superior since (i) the
total process can be carried out in 2-3 days starting from
readily available starting materials; (ii) the protected
species (5), which is easily isolated by flash chromatog-
raphy,25 is obtained directly; and (iii) the reaction can
be performed in a 20 g scale. If desired, 1-(benzyloxy)-
triazole (5) could be converted to 1-hydroxytriazole (3)
in 96% yield by palladium-catalyzed hydrogenolysis.
Lith ia tion a n d Rea ction w ith Electr op h iles. The
lithiation of 1-(benzyloxy)-1,2,3-triazole (5) with n-BuLi
in THF at -78 °C for 5 min followed by quenching with
D2O resulted in quantitative incorporation of deuterium
at C-5 to give 1-(benzyloxy)-5-deuterio-triazole (12) in
90% isolated yield (Scheme 4). The position of the
O-Benzyl- and O-carbamoyl-protected N-hydroxypyra-
zoles have been prepared earlier in good yields and were
used successfully in metalation reactions.17 Therefore
these groups were selected to protect the N-hydroxy
group of 1-hydroxy-1,2,3-triazole (3) before deprotonation
at the ring carbon atoms. The protection of 3 with N,N-
diethylcarbamoyl chloride in dichloromethane using N-
ethyldiisopropylamine as the base gave exclusively the
O-protected product 4 in 92% yield. In contrast, the
benzylation under similar conditions with benzyl bromide
gave a 4:1 mixture of the O-benzylated product 5 and
the known 3-benzyl-1,2,3-triazole-1-oxide (6)20 resulting
from the attack of N-3 (Scheme 1). The ratio 5/6 was
improved when the reaction was carried out in DMF
using NaH as the base. Finally, the best result was
obtained under mild conditions using BaO/Ba(OH)2‚8
H2O in DMF. Only traces of 6 (<5%) were detected in
1
deuteration was proven by the H and 13C NMR spectra
of 12. In the carbon spectra, the C-5 signal at 118.4 ppm
was converted to a triplet (J C-5,D ) 30.7 Hz), while in
the proton spectra, the H-5 signal at 7.14 ppm of 5 was
absent. If the lithiation time of 5 was extended, or the
1
the H NMR spectrum of the crude product, and 1-(ben-
zyloxy)triazole (5) could be isolated in 87% yield. The
structure of the O- and the N-benzylated products 5 and
6 was evidenced in the 13C NMR spectra by the charac-
teristic shift of the CH2 carbon signals (82.1 ppm for 5
and 55.0 ppm for 6). The chemical shifts of C-4 and C-5
and the C-H coupling constants of 5 are in good
agreement with the values reported for 1-methoxy-1,2,3-
triazole.16
(21) Zimmerman, B.; Lerche, H.; Severin, T. Chem. Ber. 1986, 119,
2848.
(22) If addition was reversed and 1 equiv of hydrazine was used,
bis(glyoxal (benzyloxy)oxime) hydrazone was obtained in quantitative
yield: mp 140-141 °C; 1H NMR (CDCl3) δ 8.10 (d, J ) 9.1 Hz, 1H),
7.95 (d, J ) 9.1 Hz, 1H), 7.50-7.20 (m, 5H), 5.20 (s, 2H); 13C NMR
(CDCl3) δ 157.93 (d), 147.70 (d), 136.38 (s), 128.42 (d), 128.31 (d), 128.22
(d), 77.39 (t). Anal. Calcd for C18H18N4O2: C, 67.07; H, 5.63; N, 17.38.
Found: C, 67.10; H, 5.69; N, 17.49.
(23) Konaka, R.; Terabe, S.; Kuruma, K. J . Org. Chem. 1969, 34,
1334.
(24) Mineo, S.; Kawamura, S.; Nakagawa, K. Synth. Commun. 1976,
6, 69.
(25) Distillation of 1-alkoxytriazoles has been avoided since violent
explosions of alkoxyimidazoles and alkoxypyrazoles have been reported
(Flynn, A. P. Chem. Br. 1984, 20, 30).
(18) Wamhoff, H. in Comprehensive Heterocyclic Chemistry, 1st ed.;
Potts, K. T., Ed.; Pergamon: Oxford, 1984; Vol. 5, p 669.
(19) Wiley: R. H.; Hussung, K. F.; Moffat, J . J . Org. Chem. 1956,
21, 190.
(20) Begtrup, M.; Vedsø, P. J . Chem. Soc., Perkin Trans. 1 1993,
625.

Synthesis of 5-Substituted 1-Hydroxy-1,2,3-triazoles
J . Org. Chem., Vol. 62, No. 26, 1997 9179
Sch em e 4
Con clu sion
A new route to 5-substituted 1-hydroxy-1,2,3-triazoles
using ortho lithiation of 1-(benzyloxy)triazoles as the key
step has been developed. 1-(Benzyloxy)-1,2,3-triazole (5)
was obtained by oxidative cyclization of 2-hydrazonogly-
oxal O-benzyloxime (8), prepared in situ. The 1-benzyl-
oxy or 1-carbamoyloxy group in 1,2,3-triazoles served as
an effective ortho director in metalation reactions by
treatment with n-butyllithium. The 5-lithiotriazole thus
formed reacted with a series of electrophiles. In this way
carbon, halogen, sulfur, silicon, and tin substituents could
be introduced at the 5-position. It was demonstrated that
the benzyl group could be selectively removed by pal-
ladium-catalyzed hydrogenolysis affording the corre-
sponding 5-substituted 1-hydroxy-1,2,3-triazoles in ex-
cellent yields even in the presence of sensitive chlorine
or formyl substituents at the 5-position.
Exp er im en ta l Section
Gen er a l Meth od s a n d Ma ter ia ls. See ref 17.
temperature increased, significant amounts of 1,2,3-
triazole (2) and 1-phenyl-1-pentanol could be detected in
the 1H NMR spectra of the crude product. The formation
of these products can be explained by an inter- or
intramolecular rearrangement of 9 into 10 followed by
cleavage of the N-O bond which produces 1-lithiotriazole
(11) and benzaldehyde (Scheme 3). The latter compound
upon addition of n-BuLi gives 1-phenyl-1-pentanol. Hence,
the lithiation should be conducted at low temperature
and the electrophile added shortly after.
1,2,3-Tr ia zole (2). A solution of 1-(4-methoxybenzyl)-1,2,3-
triazole (1) (24 g, 0.13 mol) in HBr (47%, 100 mL) was stirred
for 3 h at 120 °C. The aqueous phase was washed with CH2-
Cl2 (2 × 100 mL), treated with trisodium phosphate dodecahy-
drate (20 g), and adjusted to pH 9 with NaOH. Continuous
extraction with Et2O for 16 h gave 7.8 g (89%) of 1,2,3-triazole
(2).
1-Hyd r oxy-1,2,3-tr ia zole (3). A mixture of 1,2,3-triazole
(2) (15.9 g, 0.23 mol), formic acid (22 mL), and hydrogen
peroxide (60%, 30 mL) was stirred at 0 °C for 1 h and then at
20 °C for 3 d. Within the next 30 d, seven portions of formic
acid (11 mL) and hydrogen peroxide (60%, 15 mL) were added,
and 71% of 2 was converted to 1-hydroxy-1,2,3-triazole (3)
according to 1H NMR spectroscopy. Purification using the
procedure described in ref 15 extending the time for the
continuous extraction to 3 weeks afforded 12.7 g (65%) of pure
3.
The lithiation of 5, followed by quenching with carbon,
halogen, sulfur, silicon, and tin electrophiles, led to the
expected 5-substituted 1-(benzyloxy)triazoles 12-22 in
good to excellent yields (Scheme 4). The electrophiles
were added in an excess of 1.5-5 equiv; only Bu3SnCl
was used in an equimolar amount since the separation
of 22 from Bu3SnCl was difficult. The products 12-22
were characterized by NMR spectroscopy and elemental
analysis. In the 13C NMR spectra of 12-22, C-4 reso-
nates at 130-139 ppm. The signals of C-5 can be
observed at 121-129 ppm, except for the 5-bromo and
the 5-iodo compounds (18 and 19, respectively), where
the strong shielding effect of the halogens leads to a shift
of the signals to a higher field (106.4 ppm for 18, 72.6
ppm for 19). Similar to 5, lithiation of 1-((N,N-diethyl-
carbamoyl)oxy)-1,2,3-triazole (4) followed by quenching
with iodine gave 1-((N,N-diethylcarbamoyl)oxy)-5-iodo-
1,2,3-triazole (23) in 87% yield.
P r otection . 1-(Ben zyloxy)-1,2,3-tr ia zole (5). Meth od
a . A suspension of 1-hydroxy-1,2,3-triazole (3) (7.4 g, 87
mmol), barium hydroxide octahydrate (6.4 g, 20 mmol), and
barium oxide (26.8 g, 175 mmol) in DMF (400 mL) was treated
with three portions of benzyl bromide (12.5 mL, 105 mmol;
additional 5 mL, 42 mmol, after 8 and 16 h, respectively) and
stirred vigorously for 24 h. The mixture was diluted with
CHCl3 (1 L), filtered over Celite, and concentrated. Flash
chromatography (AcOEt-heptane 1:1) gave 13.3 g (87%) of 5
1
as an oil: Rf (AcOEt-heptane 1:1) 0.35; H NMR (CDCl3) δ
7.51 (d, J ) 1.0 Hz, H-4), 7.42-7.26 (m, 5H), 7.24 (d, J ) 1.0
Hz, H-5), 5.39 (s, 2H); 13C NMR (CDCl3) δ 132.4 (s), 131.7 (dd,
J C-4,H-4 ) 197.0, J C-4,H-5 ) 9.9 Hz, C-4), 129.4 (d), 129.4 (d),
128.4 (d), 118.5 (dd, J C-5,H-5 ) 201.0, J C-5,H-4 ) 15.4 Hz, C-5),
82.2 (t). Anal. Calcd for C9H9N3O: C, 61.70; H, 5.18; N, 23.99.
Found: C, 62.00; H, 5.33; N, 23.81.
Dep r otection . The benzyl group of 1-(benzyloxy)tria-
zole (5) and of its 5-methyl, 5-formyl, 5-methoxycarbonyl,
and 5-(dimethylamino)carbonyl substituted derivatives
(13-16) could be removed readily by mild hydrogenolysis
(10% Pd/C at 0 °C) to give 3 and 24-27, respectively, in
96-100% yields. 1-(Benzyloxy)-5-chlorotriazole (17) was
debenzylated at -5 °C in order to avoid dechlorination.
Alternatively, 1-(benzyloxy)-5-chlorotriazole (17) could be
debenzylated by treatment with concentrated hydrochlo-
ric acid.
(Ben zyloxy)a m m on iu m Ch lor id e. The reported proce-
dure26 was improved as follows. N-Hydroxyphthalimide (98.0
g, 0.60 mol) and Na2CO3 (171 g, 0.598 mol) were dissolved in
a mixture of DMF (800 mL), acetonitrile (150 mL), and water
(800 mL). Benzyl chloride (80.5 g 0.636 mol) was added, and
the mixture was stirred for 4 h. Filtration and washing with
water (3 × 200 mL) and with 0 °C methanol (2 × 150 mL)
yielded 149.4 g (94%) of N-(benzyloxy)phthalimide, mp 143-
144 °C (reported26 mp 143-144 °C). The N-(benzyloxy)phthal-
imide was treated with hydrazine as described previously26
to give crude (benzyloxy)ammonium chloride which was
recrystallized from 1-propanol to give 93% of (benzyloxy)am-
monium chloride.
Some 1-hydroxytriazoles have been prepared earlier
by the debenzylation of 2-benzyltriazole 1-oxides.16 How-
ever the synthesis via 1-(benzyloxy)triazoles offers an
efficient and more general alternative. The resulting
5-substituted 1-hydroxytriazoles are of particular inter-
est, and their properties as catalysts in peptide coupling
reactions are currently being investigated.
1-(Ben zyloxy)-1,2,3-tr ia zole (5). Meth od b. Hydrazine
hydrate (86.5 g, 1.71 mol) was dissolved in MeOH (500 mL)
and cooled to 0 °C. A solution of 7 (28.7 g, 0.176 mol), prepared
from (benzyloxy)amine and glyoxal as described previously,21
(26) Rougny, A.; Daudon, M. Bull. Soc. Chim. Fr. 1976, 833.

9180 J . Org. Chem., Vol. 62, No. 26, 1997
Uhlmann et al.
in MeOH (1000 mL) was then added dropwise during 15 min.
The reaction mixture was stirred for 30 min and then
evaporated in vacuo to yield a colorless oil. The oil was
redissolved in pyridine (1000 mL), and the mixture was heated
to 100 °C. CuSO4‚5H2O (87.7 g, 0.351 mol) was added, and
after 30 min the black reaction mixture was evaporated in
vacuo. Water (1000 mL) was added and the aqueous phase
extracted with diethyl ether (5 × 200 mL). The organic
extracts were combined and washed with water (3 × 300 mL),
dried over MgSO4, and filtered, and the solvent was then
removed in vacuo to afford a brown oil. Purification by flash
chromatography (EtOAc-heptane 1:1) yielded 16.0-19.4 g
(52-63%) of 1-(benzyloxy)-1,2,3-triazole (5) identical with the
material above.
(s), 130.0 (d), 129.7 (d), 128.5 (d), 122.9 (s), 83.3 (t), 52.4 (q).
Anal. Calcd for C11H11N3O3: C, 56.65; H, 4.75; N, 18.02.
Found: C, 56.94; H, 4.75; N, 18.00.
1-(Ben zyloxy)-5-((d im eth yla m in o)ca r bon yl)-1,2,3-tr ia -
zole (16). Using the general procedure, the reaction of 5 (362
mg, 2.07 mmol) with dimethylcarbamoyl chloride (1.27 g, 11.82
mmol) as the electrophile gave after flash chromatography
(AcOEt-heptane 2:1) 494 mg (97%) of 16 as an oil: Rf (AcOEt-
heptane 1:1) 0.11; 1H NMR (CDCl3) δ 7.75-7.60 (s br, 1H),
7.53-7.25 (m, 5H), 5.50 (s, 2H), 3.00 (s, 3H), 2.74 (s, 3H); 13
C
NMR (CDCl3) δ 157.1 (s), 131.8 (s), 131.0 (br d), 129.5 (d), 129.1
(d), 128.1 (d), 125.8 (br s), 82.8 (t), 37.6 (q), 34.4 (q). Anal.
Calcd for C12H14N4O2: C, 58.53; H, 5.73; N, 22.75. Found: C,
58.56; H, 5.88; N, 22.51.
1-(Ben zyloxy)-5-ch lor o-1,2,3-tr ia zole (17). Using the
general procedure, the reaction of 5 (245 mg, 1.40 mmol) with
hexachloroethane (662 mg, 2.80 mmol) dissolved in THF (2
mL) as the electrophile gave after flash chromatography
(AcOEt-heptane 1:2) 257 mg (88%) of 17 as a solid. Recrys-
tallization (AcOEt-heptane) gave mp 39 °C: Rf (AcOEt-
1-((N,N-Dieth ylca r ba m oyl)oxy)-1,2,3-tr ia zole (4). A so-
lution of 1-hydroxy-1,2,3-triazole (3) (260 mg, 3.06 mmol) and
N-ethyldiisopropylamine (0.55 mL, 3.21 mmol) in dry CH2Cl2
(3 mL) was cooled to 0 °C. N,N-Diethylcarbamoyl chloride (4.3
mL, 3.39 mmol) was added and the mixture stirred for 18 h.
The mixture was concentrated and flash chromatographed
(AcOEt-heptane 1:1) to give 520 mg (92%) of 4 as an oil.
Recrystallization (AcOEt-heptane) gave mp 26 °C: Rf (AcOEt-
heptane 1:1) 0.21; 1H NMR (CDCl3) δ 7.73 (d, J ) 1.1 Hz, 1H),
7.72 (d, J ) 1.1 Hz, 1H), 3.49 (q, J ) 7.1 Hz, 2H), 3.39 (q, J )
7.1 Hz, 2H), 1.31 (t, J ) 7.1 Hz, 3H), 1.22 (t, J ) 7.1 Hz, 3H);
13C NMR (CDCl3) δ 151.1 (s), 132.2 (d, C-4), 120.4 (d, C-5),
43.5 (t), 41.9 (t), 13.8 (q), 12.7 (q). Anal. Calcd for C7H12N4O2:
C, 45.65; H, 6.57; N, 30.42. Found: C, 45.55; H, 6.51; N, 30.61.
Lith ia tion of 1-((N,N-Dieth ylca r ba m oyl)oxy)-1,2,3-tr i-
a zole (4) a n d 1-(Ben zyloxy)-1,2,3-tr ia zole (5) follow ed by
Rea ction w ith a n Electr op h ile. Gen er a l P r oced u r e.
Under N2 at -78 °C, a 0.1 M solution of 1-(benzyloxy)-1,2,3-
triazole (5) in dry THF was treated dropwise with 1.2 equiv
of n-BuLi (1.6 M in hexane). After 5 min the electrophile was
added (neat or dissolved in THF) and, stirring was continued
for 1 h at -78 °C and 1 h at rt. The mixture was then
quenched with saturated NH4Cl, and the product was ex-
tracted with CH2Cl2. The organic phase was washed with
H2O, dried (MgSO4), and concentrated.
1
heptane 1:1) 0.44; H NMR (CDCl3) δ 7.48 (s, 1H), 7.73-7.33
(m, 5H), 5.41 (s, 2H); 13C NMR (CDCl3) δ 131.7 (s), 130.0 (d),
129.8 (d), 129.7 (d), 128.6 (d), 121.0 (s), 82.8 (t). Anal. Calcd
for C9H8ClN3O: C, 51.56; H, 3.85; N, 20.04. Found: C, 51.36;
H, 3.80; N, 20.11.
1-(Ben zyloxy)-5-br om o-1,2,3-tr ia zole (18). Using the
general procedure, the reaction of 5 (124 mg, 0.71 mmol) with
bromine (55 mL, 1.07 mmol) as the electrophile gave after flash
chromatography (AcOEt-heptane 1:2) 155 mg (86%) of 18 as
a solid. Recrystallization (AcOEt-heptane) gave mp 67 °C:
Rf (AcOEt-heptane 1:1) 0.44; 1H NMR (CDCl3) δ 7.55 (s, 1H),
7.41-7.38 (m, 5H), 5.42 (s, 2H); 13C NMR (CDCl3) δ 133.1 (d),
131.7 (s), 130.1 (d), 129.9 (d), 128.7 (d), 106.1 (s), 82.9 (t). Anal.
Calcd for C9H8BrN3O: C, 42.54; H, 3.17; N, 16.54. Found: C,
42.56; H, 3.19; N, 16.54.
1-(Ben zyloxy)-5-iod o-1,2,3-tr ia zole (19). Using the gen-
eral procedure, the reaction of 5 (100 mg, 0.57 mmol) with
iodine (224 mg, 0.88 mmol) dissolved in THF (1 mL) as the
electrophile gave after flash chromatography (AcOEt-heptane
1:2) 165 mg (96%) of 19 as a solid. Recrystallization (AcOEt-
1-(Ben zyloxy)-5-d eu ter io-1,2,3-tr ia zole (12). Using the
general procedure, lithiation of 5 was followed by quenching
with deuterium oxide (15 equiv). Flash chromatography
1
heptane) gave mp 105 °C: Rf (AcOEt-heptane 1:1) 0.43; H
NMR (CDCl3) δ 7.50 (s, 1H), 7.33-7.27 (m, 5H), 5.33 (s, 2H);
13C NMR (CDCl3) δ 138.9 (d), 131.8 (s), 130.2 (d), 129.9 (d),
128.7 (d), 82.9 (t), 72.7 (s). Anal. Calcd for C9H8IN3O: C,
35.90; H, 2.68; N, 13.96. Found: C, 35.99; H, 2.71; N, 13.94.
1-(Ben zyloxy)-5-(m eth ylth io)-1,2,3-tr ia zole (20). Using
the general procedure, the reaction of 5 (237 mg, 1.35 mmol)
with dimethyl disulfide (0.24 mL, 2.71 mmol) as the electro-
phile gave after flash chromatography (AcOEt-heptane 1:2)
201 mg (67%) of 20 as a solid. Recrystallization (AcOEt-
heptane) gave mp 45 °C: Rf (AcOEt-heptane 1:1) 0.31; 1H
NMR (CDCl3) δ 7.48 (s, 1H), 7.43-7.34 (m, 5H), 5.41 (s, 2H),
2.32 (s, 3H); 13C NMR (CDCl3) δ 132.6 (d), 132.0 (s), 129.8 (d),
129.5 (d), 128.4 (d), 128.0 (s), 82.1 (t), 16.7 (q). Anal. Calcd
for C10H11N3OS: C, 54.28; H, 5.01; N, 18.99. Found: C, 54.29;
H, 5.07; N, 19.17.
1
(AcOEt-heptane 1:1) gave 90% of 12 as an oil. The H NMR
spectrum was identical with that of the starting material 5
except that the signal at 7.24 ppm was absent, indicating
quantitative deuteration at the 5-position.
1-(Ben zyloxy)-5-m eth yl-1,2,3-tr ia zole (13). Using the
general procedure, the reaction of 5 (84 mg, 0.48 mmol) with
methyl iodide (0.09 mL, 1.44 mmol) as the electrophile gave
after flash chromatography (Et2O-pentane 2:1) 84 mg (93%)
of 13 as an oil. Recrystallization (AcOEt-heptane) gave mp
34 °C: Rf (AcOEt-heptane 1:1) 0.23; 1H NMR (CDCl3) δ 7.41-
7.24 (m, 6H), 5.41 (s, 2H), 1.84 (s, 3H); 13C NMR (CDCl3) δ
132.7 (s), 130.8 (d), 130.0 (d), 129.7 (d), 128.7 (d), 128.0 (s),
81.9 (t), 6.7 (q). Anal. Calcd for C10H11N3O: C, 63.48; H, 5.86;
N, 22.21. Found: C, 63.46; H, 5.97; N, 22.20.
1-(Ben zyloxy)-5-for m yl-1,2,3-tr ia zole (14). The general
procedure was used for the reaction of 5 (1.75 g, 10 mmol) with
DMF (3.7 mL, 50 mmol) as the electrophile. The crude mixture
was stirred for 15 min with 2 M HCl (50 mL) before workup.
Flash chromatography (AcOEt-heptane 1:2) gave 1.77 g (87%)
of 14 as a solid. Recrystallization (CH2Cl2-pentane) gave mp
56 °C: Rf (AcOEt-heptane 1:1) 0.31; 1H NMR (CDCl3) δ 9.50
(s, 1H), 8.04 (s, 1H), 7.43-7.27 (m, 5H), 5.58 (s, 2H); 13C NMR
(CDCl3) δ 176.5 (d), 134.9 (d), 131.4 (s), 130.2 (d), 130.0 (d),
129.4 (s), 128.8 (d), 83.4 (t). Anal. Calcd for C10H9N3O: C,
59.11; H, 4.46; N, 20.68. Found: C, 59.18; H, 4.63; N, 20.54.
1-(Ben zyloxy)-5-(tr im eth ylsilyl)-1,2,3-tr ia zole (21). Us-
ing the general procedure, the reaction of 5 (120 mg, 0.68
mmol) with trimethylsilyl chloride (0.52 mL, 0.81 mmol) as
the electrophile gave after flash chromatography (AcOEt-
heptane 1:2) 158 mg (93%) of 21 as a solid. Recrystallization
(AcOEt-heptane) gave mp 51 °C: Rf (AcOEt-heptane 1:1)
1
0.42; H NMR (CDCl3) δ 7.55 (s, 1H), 7.39 (br s, 5H), 5.50 (s,
2H), 0.25 (s, 9H); 13C NMR (CDCl3) δ 138.6 (d), 132.7 (s), 129.6
(d), 129.4 (d), 129.0 (s), 128.7 (d), 81.5 (t), -2.0 (q). Anal. Calcd
for C12H17N3OSi: C, 58.26; H, 6.93; N, 16.99. Found: C, 58.44;
H, 6.94; N, 17.10.
1-(Ben zyloxy)-5-(tr ibu tylstan n yl)-1,2,3-tr iazole (22). Us-
ing the general procedure, the reaction of 5 (119 mg, 0.68
mmol) with tributylstannyl chloride (0.18 mL, 0.69 mmol) as
the electrophile gave after flash chromatography (AcOEt-
heptane 1:2) 287 mg (91%) of 22 as a colorless oil: Rf (AcOEt-
1-(Ben zyloxy)-5-(m eth oxyca r bon yl)-1,2,3-tr ia zole (15).
Using the general procedure, the reaction of 5 (260 mg, 1.48
mmol) with methyl chloroformate (885 mg, 9.37 mmol) as the
electrophile gave after flash chromatography (AcOEt-heptane
1:1) 263 mg (76%) of 15 as a solid. Recrystallization (AcOEt-
heptane) gave mp 62.5-63.5 °C: Rf (AcOEt-heptane 1:1) 0.44;
1H NMR (CDCl3) δ 8.03 (s, 1H), 7.54-7.32 (m, 5H), 5.50 (s,
2H), 3.89 (s, 3H); 13C NMR (CDCl3) δ 156.6 (s), 136.1 (d), 131.8
1
heptane 1:1) 0.51; H NMR (CDCl3) δ 7.50 (s, 1H), 7.37 (br s,
5H), 5.49 (s, 2H), 1.51-0.98 (m, 18H), 9.86 (t, J ) 7.1 Hz, 9H);
13C NMR (CDCl3) δ 139.1 (d, J Sn,C ) 31 Hz), 132.9 (s), 129.4
(d), 129.2 (d), 128.5 (d), 127.5 (s), 81.1 (t), 28.5 (t, J Sn,C ) 21

Synthesis of 5-Substituted 1-Hydroxy-1,2,3-triazoles
J . Org. Chem., Vol. 62, No. 26, 1997 9181
Hz), 26.9 (t, J Sn,C ) 63 Hz), 13.4 (q), 10.2 (t, J Sn,C ) 356 Hz).
Anal. Calcd for C21H35N3OSn: C, 54.33; H, 7.60; N, 9.05.
Found: C, 54.32; H, 7.60; N, 9.37.
1,2,3-triazole (26). Recrystallization (acetone) gave mp 126-
127 °C: 1H NMR (CD3OD) δ 8.27 (1H, s), 3.96 (3H, s); 13C NMR
(CD3OD) δ 159.7 (s), 136.8 (d), 124.9 (s), 53.9 (q). Anal. Calcd
for C4H5N3O3: C, 33.57; H, 3.52; N, 29.36. Found: C, 33.11;
H, 3.61; N, 28.21.
5-((Dim et h yla m in o)ca r b on yl)-1-h yd r oxy-1,2,3-t r ia z-
ole (27). Similar to 26 5-((dimethylamino)carbonyl)-1-hy-
droxy-1,2,3-triazole (27) was obtained in 98% yield. Recrys-
tallization (methanol) gave mp 127-128 °C: 1H NMR (CD3OD)
δ 8.03 (s, 1H), 3.15 (s, 3H), 3.10 (s, 3H); 13C NMR (CD3OD) δ
161.5 (s), 132.5 (d), 128.1 (s), 39.6 (q), 36.4 (q). Anal. Calcd
for C4H8N4O2: C, 38.46; H, 5.16; N, 35.88. Found: C, 38.74;
H, 4.98; N, 35.93.
5-Ch lor o-1-h ydr oxy-1,2,3-tr iazole (28). Meth od a. Simi-
lar to 13, 1-(benzyloxy)-5-chloro-1,2,3-triazole (17) (200 mg,
0.95 mmol) was debenzylated at -5 °C for 15 min27 to give
114 mg (100%) of 28, mp 128 °C (CHCl3-acetone), identical
with the material described previously.16 Anal. Calcd for
C2H2ClN3O: C, 20.10; H, 1.69; N, 35.16. Found: C, 20.12; H,
1.74; N, 35.34.
5-Ch lor o-1-h yd r oxy-1,2,3-t r ia zole (28). Met h od b . 1-
(Benzyloxy)-5-chloro-1,2,3-triazole (17) (200 mg, 0.95 mmol)
and aqueous hydrogen chloride (37%, 3 mL) were stirred at
60 °C for 10 h. The mixture was washed with CH2Cl2 (5 × 5
mL) and the product isolated using the workup procedure
described in ref 16 for a similar debenzylation. This afforded
97 mg (85%) of 28, identical with the material above.
1-((N,N-Dieth ylcar bam oyl)oxy)-5-iodo-1,2,3-tr iazole (23).
Using the general procedure, the reaction of 4 (88 mg, 0.48
mmol) with iodine (181 mg, 0.72 mmol) dissolved in THF (2
mL) as the electrophile gave after flash chromatography
(AcOEt-heptane 1:2) 129 mg (87%) of 23, mp 67-68 °C: Rf
(AcOEt-heptane 1:1) 0.42; 1H NMR (CDCl3) δ 7.68 (s, 1H),
3.44 (q, J ) 7.1 Hz, 2H), 3.34 (q, J ) 7.0 Hz, 2H), 1.29 (t, J )
7.1 Hz, 3H), 1.17 (t, J ) 7.1 Hz, 3H); 13C NMR (CDCl3) δ 150.4
(s), 139.3 (d), 74.9 (s), 43.9 (t), 42.2 (t), 14.1 (q), 12.9 (q). Anal.
Calcd for C7H11IN4O2: C, 27.11; H, 3.58. Found: C, 27.06; H,
3.49.
Deben zyla tion of 1-(Ben zyloxy)-1,2,3-tr ia zoles. 1-Hy-
d r oxy-1,2,3-tr ia zole (3). 1-(Benzyloxy)-1,2,3-triazole (5) (200
mg, 1.14 mmol) was dissolved in MeOH (10 mL), the solution
was cooled to 0 °C and then 10% Pd on activated carbon (40
mg) was added, and the reaction mixture was stirred in an
atmosphere of hydrogen (1 atm) at 0 °C for 15 min. Filtration
through Celite and removal of the methanol gave 93 mg (96%)
of 1-hydroxy-1,2,3-triazole (3), identical with the material
described previously.15
1-Hydr oxy-5-m eth yl-1,2,3-tr iazole (24). Similarly, 1-(ben-
zyloxy)-5-methyl-1,2,3-triazole (13) (200 mg, 1.06 mmol) gave
104 mg (99%) of 24. Recrystallization (acetone) gave mp 143
°C (dec): 1H NMR (acetone-d6) δ 8.87 (br s, OH), 7.51 (s, 1H),
2.23 (s, 3H); 13C NMR (DMSO-d6) δ 130.5 (d), 127.1 (s), 7.2
(q). Anal. Calcd for C3H5N3O: C, 36.35; H, 5.09; N, 42.42.
Found: C, 36.28; H, 5.07; N, 42.72.
5-For m yl-1-h ydr oxy-1,2,3-tr iazole (25). Similarly, 1-(ben-
zyloxy)-5-formyl-1,2,3-triazole (14) (200 mg, 0.99 mmol) was
debenzylated to give 111 mg (100%) of 25. Recrystallization
(acetone) gave mp 179 °C (dec). 1H NMR (acetone-d6) δ 10.43
(s, 1H), 8.69 (s, 1H), 6.02 (br s, OH); 13C NMR (DMSO-d6) δ
180.1 (s), 133.4 (d), 128.9 (s). Anal. Calcd for C3H3N3O2: C,
31.85; H, 2.68; N, 37.17. Found: C, 31.72; H, 2.77; N, 37.06.
1-H yd r oxy-5-(m et h oxyca r b on yl)-1,2,3-t r ia zole (26).
Similarly, 1-(benzyloxy)-5-(methoxycarbonyl)-1,2,3-triazole (15)
(205 mg, 0.88 mmol) was debenzylated in EtOH at 0 °C for 30
min to give 124 mg (99%) of 1-hydroxy-5-(methoxycarbonyl)-
Ack n ow led gm en t. This work was supported by the
Danish Council for Technical and Scientific Research
and the Lundbeck Foundation. The NMR spectrometer
is a gift from the Velux Foundation of 1981, The Danish
Council for Technical and Scientific Research, The Ib
Henriksen Foundation, and the Torkil Steenbeck
Foundation.
J O971313O
(27) Increasing the temperature or the reaction time led to sub-
stantial dechlorination.