Selective Reactivity of sp3and sp2 Carbanions of 1-Substituted 1,2,4-Triazoles. A Comparative Approach

Article abstract of DOI:10.1021/jo9800659

The regioselectivity of lithiation reactions of 1-n-alkyl-, 1-allyl-, and 1-propargyl-1H-1,2,4-triazoles was studied in terms of the products formed by sequential treatment with BuLi and a range of electrophiles.

Full text of DOI:10.1021/jo9800659

J . Org. Chem. 1998, 63, 4323-4331
4323
Selective Rea ctivity of sp 3 a n d sp 2 Ca r ba n ion s of 1-Su bstitu ted
1,2,4-Tr ia zoles. A Com p a r a tive Ap p r oa ch
Alan R. Katritzky,* Mircea Darabantu, Diana C. Aslan, and Daniela C. Oniciu
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
Received J anuary 13, 1998
The regioselectivity of lithiation reactions of 1-n-alkyl-, 1-allyl-, and 1-propargyl-1H-1,2,4-triazoles
was studied in terms of the products formed by sequential treatment with BuLi and a range of
electrophiles.
In tr od u ction
N-methylene group of a 1H-1,2,4-triazole was previously
reported only for 1-benzyl-1H-1,2,4-triazole, and only
when benzyl halides were used as an electrophile.10
Substitution at an exocyclic N-methine group in 1-(R-
ethoxyallyl)-11a and 1-(R-ethoxypropynyl)-1H-1,2,4-
triazole11b has been developed as an important synthetic
procedure in our group.
Many heteroaromatic ring systems which contain
electronegative heteroatoms (N, S, O) are long known to
undergo facile C-metalations of two distinct types: (i) at
a sp2-hybridized carbon atom adjacent to a heteroatom1-4
and (ii) at an R-sp3-hybridized carbon atom of C-alkyl
substituents. In recent years, considerable attention has
been paid to a third type of C-metalation, that is, that at
the R-position of N-alkyl groups.5
There is much practical interest in triazole deriva-
tives,12-14 but mechanistic aspects have been relatively
neglected. We now present a comparative study of the
C-metalation and subsequent treatment with electro-
philes of 1-alkyl-, 1-allyl-, and 1-propargyl-1H-1,2,4-
triazoles to evaluate their substitution patterns and to
help to expand the functionalization routes in this class.
The 1H-1,2,4-triazole derivatives 1-5 used as sub-
strates for the present study are known compounds and
were prepared by previously described methods. 1-n-
Butyl- (1) and 1-n-octyl-1,2,4-triazole (2) were made by
direct alkylation of 1H-1,2,4-triazole with haloalkanes.15
1-(1-Pyrrolidinomethyl)-1H-1,2,4-triazole (3) was ob-
tained by a Mannich-type reaction of 1,2,4-triazole with
formaldehyde and pyrrolidine.8 1-Allyl-1,2,4-triazole (4)
was prepared by reacting 1H-1,2,4-triazole with allyl
bromide,16 while 1-propargyl-1H-1,2,4-triazole (5)17 was
obtained by adapting the method described for the
preparation of 1-propargylbenzotriazole.18
The aforementioned considerations apply to substi-
tuted 1H-1,2,4-triazoles. The similar properties of C-
alkyl substituents on triazoles to those on benzene are
widely recognized.6 By contrast, the reactivity of N-
substituents on triazoles, as with N-substituents on
heterocycles in general, has until recently been much less
investigated.6 Most studies of the lithiation of N-substi-
tuted triazoles have been in connection with the protec-
tion of the 1-NH during C-lithiation at C-5 and subse-
quent reaction with electrophiles.3 5-Metalated 1N-
protected 1H-1,2,4-triazoles were used as nucleophiles in
reactions with various electrophiles to give the corre-
sponding 1,5-disubstituted triazoles, which were further
deprotected to 3(≡5)-substituted derivatives.7,8 In the
course of such work, rearrangements between 5-C and
3-C isomers have appeared to occur readily: thus,
lithiated 1-(pyrrolidinomethyl)-1H-1,2,4-triazole reacted
with electrophiles to afford the 1,5-disubstituted product,
which underwent isomerization to produce an equilibri-
um mixture in which the less sterically hindered 1,3-
disubstituted derivative prevailed.8 However, in fact
such rearrangements involve movement of the N-sub-
stituent from 1-N to 2-N, while the C-substituent remains
attached to the same ring carbon;8 for similar behavior
see ref 9. To our knowledge, substitution at the exocyclic
These substrates were lithiated and subsequently
reacted with D2O (or H2O), iodomethane, benzophenone,
and phenyl isocyanate, by some or all of five standardized
procedures of lithiation/treatment with electrophile which
are classified below as A-E. These procedures were
(10) (a) Cuberes, M. R.; Moreno-MaAÄ as, M.; Trius, A. Synthesis
1985, 302. (b) Moreno-Manˇas, M.; Bassa, J .; Llado, N.; Pleixats, R. J .
Heterocycl. Chem. 1990, 27, 673.
(11) (a) Katritzky, A. R.; Feng, D.; Lang H. J . Org. Chem. 1997, 62,
706. (b) Katritzky, A. R.; Feng, D.; Lang H. J . Org. Chem. 1997, 62,
715.
(1) Shirley, D. A.; Gross, B. H.; Roussel, P. A. J . Org. Chem. 1955,
20, 225.
(12) Potts, K. T. Chem. Rev. 1961, 61, 87.
(2) Chadwick, D. J .; Cliffe, I. A. J . Chem. Soc., Perkin Trans. 1 1979,
2845.
(3) Rewcastle, G. W.; Katritzky, A. R. Adv. Heterocycl. Chem. 1993,
56, 208.
(4) Kessar, S. V.; Singh, P. Chem. Rev. 1997, 97, 721.
(5) Katritzky, A. R.; Oniciu, D. C.; Serdyuk, L.; Ghiviriga, I. J . Org.
Chem. 1995, 60, 1244.
(6) Katritzky, A. R. Handbook of Heterocyclic Chemistry; Pergamon
Press: Oxford, 1985.
(13) Polya, J . B. In Comprehensive Heterocyclic Chemistry; Katritz-
ky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford; 1984, Vol. 5, p
733.
(14) Garratt, P. J . in Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford; 1996; Vol. 4, p
127.
(15) Zhang, H.; Liao, L.; Guo, Q. Youji Huaxue 1986, 108; Chem.
Abstr. 1986, 105, 226456b.
(16) Gasparini, J . P.; Gassend, R.; Maire, J . C.; Elguero, J . J .
Organomet. Chem. 1980, 188, 141.
(7) Humburg, G.; Mildenberger, H. Liebigs Ann. Chem. 1982, 1387.
(8) Katritzky, A. R.; Lue, P.; Yannakopoulou, K. Tetrahedron 1990,
46, 641.
(17) Diez-Barra, E.; de la Hoz, A.; Loupy, A.; Sanchez-Migallon, A.
Heterocycles 1994, 38, 1367.
(9) Katritzky, A. R.; Aslan, D. C.; Leeming, P.; Steel, P. J . Tetra-
hedron: Asymmetry 1997, 8, 1491.
(18) Katritzky, A. R.; Li, J .; Malhotra, N. Liebigs Ann. Chem. 1992,
843.
S0022-3263(98)00065-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/05/1998

4324 J . Org. Chem., Vol. 63, No. 13, 1998
Katritzky et al.
Sch em e 1
aimed at the elucidation of the regioselectivity of the first
and subsequent lithiations, along with the determination
of the regioselectivity of the ambident carbanions in their
reactions with electrophiles.
(A) For compounds 1-5: reaction with 1 equiv of BuLi
and subsequently with 1 equiv of electrophile. These
experiments established that, for 1-alkyl- and 1-allyl-1H-
1,2,4-triazoles, the carbanion was formed at 5-C, the
position already reported as the most reactive lithiation
site,14 while for 1-propargyl-1H-1,2,4-triazole the first
lithiation occurred at the alkyne hydrogen.
Sch em e 2
(B) For compounds 2, 4, and 5: two consecutive
sequences of reactions, each consisting of treatment with
1 equiv of BuLi, and subsequently 1 equiv of electrophile.
These experiments showed the orientation of the second
lithiation and provided information on the relative re-
activities of the centers.
(C) For compounds 4 and 5: reaction with 2 equiv of
BuLi, and subsequent treatment with 2 equiv of electro-
phile.
(D) For compounds 4 and 5: reaction with 2 equiv of
BuLi and then with 1 equiv of an electrophile, followed
by quenching with water.
(E) For compound 5: reaction with 3 equiv of BuLi,
and then 1 equiv of an electrophile (i.e., benzophenone),
followed by quenching with water.
raphy). A second lithiation obviously occurred at the
5-CH3 of the intermediate 11. Compound 13 was prob-
ably formed via 1-iodobutane, which results from ex-
change between BuLi and iodomethane.
The results depicted in Schemes 1-7 and Tables 1-4
1
are based on preparative yields and on H and 13C NMR
The structures of products 6a -c, 8-10, 12, and 13
1
were confirmed by H and 13C NMR assignments: the
evaluation of the crude reaction mixtures. In all cases,
GC/MS data were supported by NMR measurements.
1H NMR spectra provided evidence for the presence of a
hydrogen atom at 3-C of the triazole ring (at ca. 8 ppm),
while the 13C NMR spectra revealed the signals for the
corresponding carbon atoms (3-CdN at ca. 125 ppm). The
substitution at 5-C was confirmed by the disappearance
of the signal characteristic for the 5-CH proton. More-
over, the attached proton test (APT) showed the corre-
sponding carbon atoms to be quaternary.
Resu lts
1-Alk yl-1H-1,2,4-tr ia zoles 1 a n d 2. Previous studies
of the lithiation of 1-alkyl-substituted 1H-1,2,4-triazoles
are related to the functionalization of the triazole ring.14
Various alkyl substituents were used as protective groups
for the 1-NH of 1H-1,2,4-triazole to induce lithiation at
C-5. Previous examples of substitution at the exocyclic
carbon of the N-substituent are uncommon.3
Treatment of 1-n-butyl-1,2,4-triazole (1) with BuLi and
subsequently with D2O, iodomethane, or benzophenone
gave exclusively the corresponding 5-substituted deriva-
tives 6a -c, as expected. The reaction of lithiated 1 with
1 equiv of benzyl bromide followed an unexpected route,
giving compound 10 with a conversion of 32% (conversion
of benzyl bromide 100%), while 68% of the starting
material was recovered (Scheme 1). The monoalkylated
derivative 7 initially formed was not detected in the crude
reaction mixture. The product 10 evidently originated
from the double deprotonation of lithiated 7. The reac-
tion of lithiated 1 with 1 equiv of 1-iodohexane gave a
mixture of the 5-monoalkylated derivative 8 and the
dialkylated product 9, in a ratio of 3:1.
1-(1-P yr r olid in om eth yl)-1H-1,2,4-tr ia zole (3). The
pyrrolidinomethyl synthon is utilized as a protective
group for the 1-NH of 1H-1,2,4-triazoles when synthetic
purposes require functionalization of a 1H-1,2,4-triazole
via ring lithiation.8 In compounds of type 3 lithiation
proceeds at 5-C, but the 5-substituted products are in
mobile equilibrium with their 3-substituted regioisomers,
because of easy rearrangement of the pyrrolidinomethyl
substituent to the adjacent N-atom via cationotropy.8,9
Compound 3 was reacted using conditions A with
benzaldehyde to give the expected product as a mixture
of its 3- and 5-regioisomers 14a and 14b, respectively,
in a ratio of 1:1 (yield 76%) (Scheme 3). When reacted
with benzophenone using the same conditions (A) a
mixture of regioisomers 15a and 15b in a ratio of 1:2 was
obtained (yield 80%). The ratio of the two regioisomers
in each pair was determined by NMR by using the two
distinct singlets at ca. 8 ppm, characteristic for the two
ring hydrogen atoms.
When 1-n-octyl-1H-1,2,4-triazole (2) was reacted with
iodomethane under conditions B, products 12 and 13
were obtained in a ratio of 3:2 (Scheme 2 reports the
experimental yields, as separated by column chromatog-
1-Allyl-1H-1,2,4-tr ia zole (4). The stereochemical and
regiochemical characteristics of many reactions of reso-

Selective Reactivity of Carbanions of 1,2,4-Triazoles
J . Org. Chem., Vol. 63, No. 13, 1998 4325
Sch em e 3
With conditions B the second reaction with iodomethane
occurred exclusively at the 5-methyl group; compound 33,
resulting from the rearrangement of the double bond, was
obtained with a conversion of 80% and an isolated yield
of 53%. By contrast, under conditions C the reaction with
two molecules of iodomethane gave the disubstituted
regioisomers 25a and 26a , in a 25a :26a ratio of 1:3.
Compound 26a was isolated in 55% yield. With condi-
tions D, compounds 25a -27a were formed in a 25a :26a :
27a ratio of 1:1.5:3. Compound 27a was isolated in 35%
yield.
(c) Rea ction w ith Ben zop h en on e (Ta ble 2). Under
conditions A lithiated 4 reacted with benzophenone to
give exclusively the product 24b of substitution at 5-C
(40%, Table 2). Under conditions B the second substitu-
tion with benzophenone was directed to the allyl chain,
and compounds 25b (28.5%) and 26b (35.5%) were
obtained in a ratio of 1:1.25. Under conditions C the
isomeric ratio 25b:26b was 2:1, and the isolated yields
were 43% and 23%, respectively. Under conditions D the
major fraction separated was compound 28b (39%), and
much of the starting material was recovered.
nance-stabilized allyl organometallics have raised ques-
tions on their kinetic versus thermodynamic control.
Many experimental results,19 supported by theoretical
7
calculations20,21 and Li NMR measurements,22 suggest
a delocalized structure for allyllithiums and indicate that
the regiochemistry of their reactions with electrophiles
is strongly influenced by both electronic and solvation
effects. Most previous studies of the metalation of allyl
heterocycles have been associated with specific synthetic
applications (e.g., 1-allyl-1H-benzotriazole18).
(d ) Rea ction w ith P h en yl Isocya n a te (Ta ble 3).
Under conditions A the reaction of lithiated 4 and phenyl
isocyanate afforded the ring-substituted compound 24c
in 61% yield (Table 4). Under conditions B after the
second lithiation the anion did not react with a second
mole of phenyl isocyanate, but isomerized to yield prod-
ucts 29c and 30c, isolated and characterized as a mixture
in a 29c:30c ratio of 1:4 (by 1H NMR). However, the
overall conversion of compound 4 was only 15%, and the
major products 35 and 36 resulted from side reactions
involving phenyl isocyanate. Under conditions C the
major product in the reaction with phenyl isocyanate was
disubstituted 32c (20.2%); monosubstituted 29c was also
isolated, in a 29c:32c ratio of 1:2.
Scheme 4 summarizes the results of the present
investigation: we interpret our results in terms of initial
formation of monolithiated intermediate 16 in all four
procedures (A-D). Procedure B proceeds via further
monolithiated intermediates 20-23. Procedures C and
D give products expected to arise from dilithiated inter-
mediates of type 17-19.
(a ) Rea ction w ith Wa ter . 1-Allyl-1H-1,2,4-triazole
(4) was treated with 2 equiv of BuLi using conditions C,
and after 15 min the reaction mixture was quenched with
water. The starting material and its isomer 26d (Scheme
4) were obtained in equimolar amounts. If the reaction
mixture was left at room temperature for 12 h and then
quenched with water, compound 26d was formed as the
major product, while the minor product was its corre-
The structures of products 24-36 were confirmed by
1H and 13C NMR spectroscopy. The positions of the
protons assigned to the allyl group are relatively con-
stant: CH2d at about 5.5 ppm, CHd at 6.4 ppm, and
the allyl protons at 4.2 ppm, with coupling constants in
agreement with the literature data. The cis or trans
stereochemistry of the products was unequivocally con-
firmed by NOE experiments, as in all cases the signals
were well separated and easy to irradiate.
1
sponding trans diastereomer 32d in about 10% (by H
NMR). The reaction was performed with and without
TMEDA, and in concentrations between 10-2 and 10-3
M, and gave identical results.
1-P r op a r gyl-1,2,4-tr ia zole (5). The metalation and
functionalization of N-propargyl- and N-allenyl-pyrrole23,24
and -benzotriazole25 have been studied.26 The equilibri-
um between the allenyl and propargyl structures of such
lithiated compounds is strongly influenced by the solvent,
temperature, and substituents.26 We have shown that
1-(R-ethoxypropynyl)-1H-1,2,4-triazole11b and -benzotria-
zole27 are valuable and complementary reagents, their
lithiated derivatives reacting at the δ and R positions,
respectively. However, functionalization via metalation
of 1-propargyl-1H-1,2,4-triazole (5) or its allenyl isomer
(b) Rea ction s w ith Iod om eth a n e (Ta ble 1). Lithi-
ated 1-allyl-1,2,4-triazole (4) reacted with iodomethane
using conditions A to give 1-allyl-5-methyl-1,2,4-triazole
(24a ) as the major product (conversion 81%, yield 60%),
together with 8% of compound 27a which resulted from
the lithiation of compound 4 in the R-position of the
exocyclic chain. Additionally, products of disubstitution
at both ring and exocycle (25a and 26a ) were also isolated
(7 and 4%, respectively).
(23) Tarasova, O. A.; Taherirastgar, F.; Verkruijsse, H. D.; Mal’kina,
A. G.; Brandsma, L.; Trofimov, B. A. Recl. Trav. Chim. Pays-Bas 1996,
115, 145.
(19) Schlosser, M.; Desponds, O.; Lehmann, R.; Moret, E.; Rauch-
schwalbe, G. Tetrahedron 1993, 49, 10175.
(20) van Eikema Hommes, N. J . R.; Buhl, M.; von RaguJ Schleyer,
P.; Wu, Y.-D. J . Organomet. Chem. 1991, 409, 307.
(21) Pratt, L. M.; Khan, I. M. J . Comput. Chem. 1995, 16, 1067.
(22) Fraenkel, G.; Qiu, F. J . Am. Chem. Soc. 1997, 119, 3571.
(24) Tarasova, O. A.; Brandsma, L.; Verkruijsse, H. D.; Mal’kina,
A. G.; Trofimov, B. A. Zh. Org. Chim. 1996, 32, 1208.
(25) Katritzky, A. R.; Li, J .; Gordeev, M. F. Synthesis 1994, 93.
(26) Reich, J . H.; Holladay, J . E. Angew. Chem., Int. Ed. Engl. 1996,
35, 2365.
(27) Katritzky, A. R.; Lang H. J . Org. Chem. 1995, 60, 7612.

4326 J . Org. Chem., Vol. 63, No. 13, 1998
Katritzky et al.
Sch em e 4
Ta ble 1. Com p osition of th e Rea ction Mixtu r es in th e
Rea ction of Lith ia ted 4 w ith Iod om eth a n ea
Ta ble 2. Com p osition of th e Rea ction Mixtu r es in th e
Rea ction of Lith ia ted 4 w ith Ben zop h en on e (R )
P h 2COH)a
a
The compositions are calculated on the basis of the 1H NMR
of the crude reaction mixtures and on isolated amounts after
column chromatography. Compounds whose numbers have an
a
The reported yields are based on GC-MS values obtained from
the analysis of the crude reaction mixtures and confirmed by 1H
NMR results. Isolated yields are indicated in parentheses. Com-
b
asterisk were not fully characterized. Reaction conditions A-D
are described in detail in the Experimental Section. c Calculated
from the 1H NMR spectrum of the mixture of products 27b and
29b.
b
pound 25a was not fully characterized. Reaction conditions A-D
are described in detail in the Experimental Section. c Approxi-
mately 20% of an unidentified tris(methylated) product was also
d
1
found. Values calculated from the H NMR of the crude reaction
mixtures.
isomer was not detected in the NMR spectra of the crude
reaction mixture in any of these experiments.
has not previously been reported and could provide useful
new insights for the functionalization of 1H-1,2,4-tria-
zoles.
Experiments under conditions A, B, D, and E were
performed on compound 5 using three of the same
electrophiles as for the allyl analogue 4: water, iodo-
methane, and benzophenone. Lithiated 5 reacted slug-
gishly with electrophiles below 0 °C; the reaction mix-
tures were therefore brought to 20 °C immediately after
the addition of the electrophile.
(a) Reaction with Water . Under conditions A quench-
ing of the monolithiated 1-propargyl-1,2,4-triazole (5)
with D2O gave quantitative incorporation of deuterium
at the triple bond. When the reaction mixture was
quenched with water after 15 min at -78 °C or after 12
h at 20 °C, only compound 5 was recovered; the allenyl
(b) Rea ction w ith Iod om eth a n e (Sch em e 5). Un-
der conditions A the reaction with iodomethane gave
products 37, 38, and 39, with very similar Rf values, in
1
a ratio of 7:1:2, as determined by the H and 13C NMR
on the mixture. Well-defined signals and easily deter-
mined hyperfine coupling constants, together with het-
eronuclear correlation, allowed individual assignments.
For example, the R-methyl groups in compound 37 and
γ-proton in compound 38 are located at 1.90 ppm, while
the methinic protons were revealed as a triplet of
doublets in compound 38 and a triplet of quartets in
compound 39, at 5.1-5.3 ppm.
(c) Reaction with Ben zoph en on e (Table 4, Sch em e
6). Under conditions A, the reaction of γ-lithiated
1-propargyl-1H-1,2,4-triazole (5) with benzophenone af-
forded compound 45 in 70% yield, along with unreacted

Selective Reactivity of Carbanions of 1,2,4-Triazoles
J . Org. Chem., Vol. 63, No. 13, 1998 4327
Ta ble 3. Com p osition of th e Rea ction Mixtu r es in th e
Rea ction of Lith ia ted 4 w ith P h en yl Isocya n a te (R )
P h NHCO)a
Sch em e 6
a
Reaction conditions A-D are described in detail in the
Experimental Section. Compounds whose numbers have an as-
terisk were not fully characterized. The compositions are calcu-
b
lated on the basis of isolated amounts after column chromatog-
raphy. c Percentages calculated on the basis of 1H NMR spectra
of the mixtures of compounds 29c, 30c, and 34, as isolated by
column chromatography.
Sch em e 5
Under conditions E, compound 5 was treated with 3
equiv of BuLi and then 1 equiv of benzophenone. The
composition of the reaction mixture remained much the
same as that under conditions D, but the conversion of
1-propargyl-1H-1,2,4-triazole (5) significantly increased
from 23% (D) to 58% (E).
Ta ble 4. Com p osition of th e Rea ction Mixtu r es in th e
Rea ction of Lith ia ted 5 w ith Ben zop h en on e (R )
P h 2COH)a
1
The identification of products 45-51 was based on H
and 13C NMR assignments. The positions of the protons
characteristic for the propargyl and allenyl groups are
in the same range as indicated in the literature: allenyl
CH2d at ca. 5.5 ppm, CHt at 6.4 ppm, and the R-CH2 at
ca. 5 ppm. The signals characteristic for the 1,2,4-triazole
moiety are present at values similar to those of the other
derivatives described in this paper. Long-range HET-
COR experiments proved the structure of compounds 47
and 49 and eliminate the possibility of a 3- to 5-isomer-
ization.
a
Based on amounts isolated after column chromatography (%
mol/mol). Compounds whose numbers have an asterisk were not
fully characterized. Ratio ((% mol/mol) determined from the 1H
b
NMR spectrum of the mixture of products 47 and 48. c Recovered
after column chromatography as unreacted starting material.
starting material (Scheme 6). Conditions B gave three
disubstituted compounds 46, 47, and 48, in a total yield
of 55% and a 46:47:48 ratio of 1:3:1, along with mono-
substituted 45 (16%) and 28% of unreacted compound 5.
In a separate experiment, compound 45 was lithiated
under conditions A and reacted with benzophenone to
afford a mixture of regioisomers 46, 47, and 48 in the
same ratio as above. We hence assume that compound
45 was lithiated mostly in the ring at 5-C, while the
allenyl compound 46 resulted from the isomerization of
compound 47 during workup.29 The reaction of 1-pro-
pargyl-1H-1,2,4-triazole (5) with benzophenone at
-78 °C under conditions D afforded compounds 49, 50,
and 51 in a 49:50:51 ratio of 1:1.3:1. No allenyl deriva-
tive was identified.
Discu ssion
As expected, monolithiation of 1-alkyl-1H-1,2,4-tria-
zoles 1-3 occurred at 5-C in the ring, and 5-substituted
derivatives were generally formed in the reaction with
alkyl halides, deuterium oxide, and benzophenone
(Schemes 1 and 3). Rearrangement of the 5-C to the 3-C
isomer occurred only in the case of the pyrrolidinomethyl
derivative 3, where cationotropy is expected.8,9 Similar
isomerizations were neither expected nor found for 1-bu-
tyl- (1), 1-octyl- (2), 1-allyl- (4), and 1-propargyl-1H-1,2,4-
triazole (5). Subsequent lithiation in the 5-alkyl-1-n-
octyl-1H-1,2,4-triazoles derived from compound 2 was
directed to the R-exocyclic CH of the 5-substituent
(Scheme 2). During the monolithiation/reaction of com-
pounds 1 and 2 with electrophile, the product was
sometimes more reactive than the starting material and
underwent a second or even a third lithiation at the
5-methylene group, as shown for benzyl bromide and
(28) Macho, V.; Kralik, M.; Halmo, F. J . Mol. Catal. A 1996, 109,
119.
(29) Wiegrebe, W.; Stephan, H. M.; Fricke, J .; Schlunegger, U. P.
Helv. Chim. Acta 1976, 59, 949.

4328 J . Org. Chem., Vol. 63, No. 13, 1998
Katritzky et al.
stirred for 5 min; then iodooctane (2.4 g, 10 mmol) was added.
After 15 min, the reaction mixture was poured in water (50
mL), extracted with chloroform (3 × 50 mL), and dried
(MgSO4) and the solvent was evaporated under vacuum. The
product was purified by flash vacuum chromatography on
silica gel, using successively hexane and diethyl ether as
1-iodooctane (Schemes 1 and 2). No C-metalation at the
exocyclic N-methylene group was found for any of the
1-alkyl-substituted 1H-1,2,4-triazoles 1-3.
1-Allyl-1H-1,2,4-triazole (4) under conditions A follows
the general rule of initial lithiation at the 5-position and
thus of substitution at 5-C in the monolithiation/reaction
with electrophile. Under conditions B, the second lithia-
tion occurs either in the methyl group introduced into
the 5-position (for iodomethane giving compound 33) or
at the exocyclic N-CH2 (yielding compounds 25b and
26b). However, under conditions C and D the second
lithiation now occurs readily at the exocyclic N-CH2
leading to the formation of an ambident dianion which
can react with an electrophile at one or two of the three
alternative positions: the R-exocyclic CH in position 5
and the R- and γ-exocyclic CH at the 1-N substituent.
The reaction course was dependent on the type of
electrophile. With iodomethane, the first electrophile
mainly attacks at the γ-position to give product 27a and
the second mainly at the 5-ring position to give compound
26a . By contrast benzophenone attacks first mainly the
a-position to give compound 28b and then the 5-C of the
ring to afford product 25b. Phenyl isocyanate yields a
greater variety of products, but 31c and 32c conform to
the product orientation of iodomethane.
1
eluent: yellow oil,15 1.3 g (70%); H NMR δ 8.06 (s, 1H), 7.93
(s, 1H), 4.16 (t, J ) 6.9 Hz, 2H), 1.89 (qv, J ) 6.9 Hz, 2H),
1.32-1.20 (m, 10H), 0.87 (t, J ) 6.6 Hz, 3H); 13C NMR δ 13.7,
22.2, 26.1, 28.6, 28.7, 29.4, 31.3, 49.3, 142.4, 151.4.
1-(1-P yr r olid in om eth yl)-1H-1,2,4-tr ia zole (3). 1H-1,2,4-
Triazole (7.81 g, 0.11 mol), pyrrolidine (8.5 g, 0.12 mol), and a
solution of formaldehyde in water (37% w/w, 10 mL, 0.12 mol)
were dissolved in ethanol (50 mL). The mixture was refluxed
for 4 h; then the solvent was removed under vacuum. The
resulting residue was diluted with water (50 mL), extracted
with chloroform (3 × 25 mL), and dried (Na2SO4). The extract
was concentrated, and the residue was subjected to distillation
(bp 100 °C/1.2 mmHg) to give a colorless oil,7 14.4 g (86%):
1H NMR δ 8.15 (s, 1H), 7.95 (s, 1H), 5.14 (s, 2H), 2.74-2.69
(m, 4H), 1.79-1.74 (m, 4H); 13C NMR δ 23.6 (2C), 49.5 (2C),
66.3, 143.3, 151.3.
1-Allyl-1H-1,2,4-tr ia zole (4). 1H-1,2,4-Triazole (17.25 g,
0.25 mol) was added to a solution prepared from sodium metal
(5.75 g, 0.25 mol) in absolute EtOH (90 mL). After complete
dissolution, the reaction mixture was heated at 40 °C for 0.5
h; allyl bromide (22.7 mL, 0.26 mol) was then added in one
o
portion. The reaction mixture was stirred at 75 C for 12 h,
then cooled to rt, filtered, and concentrated under vacuum to
a semicrystalline residue which was taken up in chloroform
(100 mL). The organic extract was filtered and concentrated
under vacuum, and the residue was distilled (bp 94-95 °C/12
mmHg) to yield a colorless liquid,16 16.35 g (60%): 1H NMR δ
8.12 (s, 1H), 7.96 (s, 1H), 6.01 (ddt, J ) 6.0 Hz, J ) 10.2 Hz,
1-Propargyl-1H-1,2,4-triazole (5), unlike the other N-
substituted 1H-1,2,4-triazoles studied, initially undergoes
lithiation at the γ-exocyclic position, evidently as a result
of the high acidity of this proton. The γ-exocyclic position
is in turn attacked by each of the electrophiles (water,
iodomethane, or benzophenone), although iodomethane
also gives small quantities of other products (Scheme 5).
The second lithiation occurs at the 5-C of the ring. The
reaction of bis-lithiated 1-propargyl-1H-1,2,4-triazole (5)
with 1 equiv of benzophenone formed mixtures of mono-
and disubstitution products. A similar product distribu-
tion, but with higher yields, was obtained when 1-pro-
pargyl-1H-1,2,4-triazole (5) was reacted with 3 equiv of
BuLi (Table 4).
J ) 17.1 Hz, 1H), 5.35 (d, J cis ) 10.2 Hz, 1H), 5.28 (d, J trans
)
17.1 Hz, 1H), 4.81 (d, J ) 6.0 Hz, 2H); 13C NMR δ 51.8, 119.6,
131.0, 142.5, 151.8.
1-P r op a r gyl-1H-1,2,4-tr ia zole (5). 1H-1,2,4-Triazole (15
g, 0.217 mol) in absolute EtOH (150 mL) was cooled to 0 °C in
an ice bath, and a solution of NaOH (8.70 g, 0.217 mol, in 15
mL water) was added. When the sodium triazolate precipi-
tated, propargyl bromide (25 mL, as 80% w/w in toluene, 0.224
mol) was added dropwise at 0 °C (about 1 h). The reaction
mixture was allowed to gradually reach rt and was kept under
stirring for an additional 48 h, when the final pH was below
8.5. Water (100 mL) was added until the solution was clear,
and the reaction mixture was extracted with CH2Cl2 (3 × 150
mL). The organic solution was washed with water (50 mL, to
neutrality), dried (MgSO4), and concentrated under vacuum
to give crude product as an orange liquid (19 g), which was
purified by distillation (bp 53-55 °C/0.8-1 mmHg). The
compound solidified upon standing to give yellow crystals, mp
Exp er im en ta l Section
Gen er a l. Melting points were determined with a hot-stage
apparatus and are uncorrected. NMR spectra were recorded
in CDCl3 with tetramethylsilane as the internal standard for
1H (300 MHz) or solvent as the internal standard for 13C (75
MHz), unless otherwise stated. The abbreviations for the
multiplicity of the proton signals are as follows: q for quartet,
qv for quintet, sx for sextet, and h for heptet. GC-MS spectra
were performed on a HP5890 series II GC HP 5972 MSD
instrument, equipped with a HP5 30 m column. Retention
times (tr) are given in minutes. THF was distilled under
nitrogen immediately prior to use from sodium/benzophenone.
All reactions with air-sensitive compounds were carried out
under an argon atmosphere. Column chromatography was
conducted with silica gel 230-400 mesh. 1-n-Butyl-1H-1,2,4-
triazole (1) was prepared by a procedure previously described.14
Benzophenone, iodomethane, 1-iodohexane, 1-iodooctane, ben-
zyl bromide, and phenyl isocyanate were purchased from
Fisher.
Note. In some cases, compounds were isolated as mixtures
and, if they were not considered to present synthetical interest,
further purification was not performed. Assignments were
made on the basis of 1H and 13C NMR spectra and GC-MS
results, which are presented in the Supporting Information.
Characterization data and details regarding reactions and
separation of products are also presented in the Supporting
Information.
o
44-6 °C (lit.17 mp 45-6 C); 13.86 g (58%): 1H NMR δ 8.31 (s,
1H), 7.97 (s, 1H), 5.00 (d, J ) 2.5 Hz, 2H), 2.64 (t, J ) 2.5 Hz,
1H), 13C NMR δ 39.2, 74.9, 75.7, 142.6, 152.1.
F u n ction a lized 1-Alk yl-1H-1,2,4-tr ia zoles. Con d ition s
A: Syn t h esis of Com p ou n d s 6a -c, 7, 8, 10, 14a ,b , a n d
15a ,b. The appropriate 1-alkyl-1H-1,2,4-triazole (0.34 M in
THF) was treated at -78 °C with an equimolar amount of BuLi
(1.6 M solution in hexane) to give a yellow suspension. After
15 min, the theoretical amount of electrophile (20% in THF)
was added and the reaction was allowed to warm to rt. The
reaction was quenched with a saturated solution of NH4Cl (50
mL) and extracted with CH2Cl2 (50 mL). The organic layer
was dried (MgSO4), the solvent was evaporated in vacuo, and
the residue was subjected to column chromatography.
1-Bu tyl-5-D-1H-1,2,4-tr ia zole (6a ) was obtained as an oil
by lithiation of 1-butyl-1H-1,2,4-triazole (1) and quenching the
reaction mixture with D2O at rt (95%).
1-Bu tyl-5-m eth yl-1H-1,2,4-tr ia zole (6b) was obtained as
an oil by lithiation of 1-butyl-1H-1,2,4-triazole (1) and elec-
trophilic substitution with iodomethane (41%).
1-Octyl-1H-1,2,4-tr ia zole (2). Finely ground 1H-1,2,4-
triazole (10 mmol), NaOH (40 mmol), and DMF (10 mL) were
(1-Bu tyl-1H-1,2,4-tr ia zol-5-yl)(d ip h en yl)m eth a n ol (6c)
was obtained exclusively as the 5-isomer by lithiation of

Selective Reactivity of Carbanions of 1,2,4-Triazoles
J . Org. Chem., Vol. 63, No. 13, 1998 4329
1-butyl-1H-1,2,4-triazole (1) and electrophilic substitution with
benzophenone; mp 120-2 °C (82%).
1-Bu tyl-5-h exyl-1H-1,2,4-tr ia zole (7) was obtained as an
oil by lithiation of 1-butyl-1H-1,2,4-triazole (1) and electrophilic
substitution with iodohexane (73%).
1-Bu tyl-5-(6-d od ecyl)-1H-1,2,4-tr ia zole (9) was obtained
as an oil by lithiation of 1-butyl-1H-1,2,4-triazole (1) and
electrophilic substitution with iodohexane (10%).
5-(1-Ben zyl-1,2-d ip h en ylet h yl)-1-b u t yl-1H -1,2,4-t r ia -
zole (10) was obtained by lithiation of 1-butyl-1H-1,2,4-
triazole (1) and electrophilic substitution with benzyl bromide;
white solid, mp 89-90 °C (32%).
P h en yl[(1-p yr r olid in om eth yl)-1H-1,2,4-tr ia zol-3(5)-yl]-
m eth a n ol (14a ,b) was obtained as a mixture of 3- and
5-isomers in a 1:2 ratio by lithiation of 1-(1-pyrrolidinomethyl)-
1H-1,2,4-triazole (3) and electrophilic substitution with ben-
zaldehyde; white solid, mp 86-87 °C (lit.8 mp 87 °C) (76%).
Dip h en yl[(1-p yr r olid in om eth yl)-1H-1,2,4-tr ia zol-3(5)-
yl]m eth a n ol (15a ,b) was obtained as a mixture of 3- and
5-isomers in a ratio of 2:1 by lithiation of 1-(1-pyrrolidino-
methyl)-1H-1,2,4-triazole (3) and electrophilic substitution
with benzophenone; white solid, mp 121-122 °C (lit.9 mp
121-2 °C) (80%).
a yellow suspension. After 15 min the electrophile (2 equiv)
was added dropwise (benzophenone and phenyl isocyanate as
a solution 20% in THF) and the reaction was kept at -78 °C
for 2 h (25a , 26a ), 5 h (25b, 26b), and 6 h (24c, 29c, 30c, 32c).
The reaction mixture was allowed to reach rt, quenched with
saturated NH4Cl (50 mL), extracted with CH2Cl2 (25a , 26a ,
25b, 26b) or EtOAc (24c, 29c, 30c, 32c) (4 × 50 mL), and dried
(Na2SO4). The organic layer was worked up as described above
for the reactions performed using conditions A.
Con d ition s D: Syn th esis of Com p ou n d s 24c, 25a , 26a ,
27a , 25b, 27b, 28b, 29b, 29c, 30c, a n d 31c. 1-Allyl-1H-1,2,4-
triazole (0.34 M in THF) was lithiated at -78 °C with 2 equiv
of BuLi (1.6 M solution in hexane) to give a yellow suspension.
After 15 min the electrophile (1 equiv) was added dropwise
(benzophenone and phenyl isocyanate as a solution 20% in
THF) and the reaction was kept at -78 °C for 2 h (25a , 26a ,
27a ), 5 h (25b, 27b, 28b, 29b), and 6 h (24c, 29c, 30c, 31c).
The reaction was allowed to reach rt, quenched with saturated
NH4Cl (50 mL), extracted with CH2Cl2 (25a , 26a , 27a , 25b,
27b, 28b, 29b) or EtOAc (24c, 29c, 30c, 31c) (4 × 50 mL),
and dried (Na2SO4). The organic layer was worked up as
described above for the reactions performed using conditions
A.
Con d ition s B: Syn th esis of Com p ou n d s 12 a n d 13.
The appropriate 1-alkyl-1H-1,2,4-triazole (0.34 M in THF) was
lithiated at -78 °C with the equimolar amount of BuLi (1.6
M solution in hexane) to give a yellow suspension. After 15
min, the theoretical amount of electrophile (20% in THF) was
added dropwise and the reaction was kept at -78 °C for 2 h.
The reaction mixture was again lithiated with the equimolar
amount of BuLi (1.6 M solution in hexane), and after 15 min
the theoretical amount of electrophile (20% in THF) was added.
The reaction was allowed to warm to rt, quenched with a
saturated solution of NH4Cl (50 mL), and extracted with CH2-
Cl2 (50 mL). The organic solution was dried (MgSO4), and the
solvent was evaporated in vacuo. The residue was subjected
to column chromatography.
5-Eth yl-1-octyl-1,2,4-tr ia zole (12) was obtained by lithia-
tion of 1-octyl-1H-1,2,4-triazole (2) and electrophilic substitu-
tion with iodomethane; oil (32%).
1-Octyl-5-p en tyl-1,2,4-tr ia zole (13) was obtained by lithi-
ation of 1-octyl-1H-1,2,4-triazole (2) and electrophilic substitu-
tion with iodomethane; oil (40%).
F u n ction a lized 1-Allyl-1H-1,2,4-tr ia zoles. Con d ition s
A: Syn th esis of Com p ou n d s 24a -c. 1-Allyl-1H-1,2,4-
triazole (0.34 M in THF) was lithiated at -78 °C with an
equimolar amount of BuLi (1.6 M solution in hexane) to give
a yellow suspension. After 15 min, the theoretical amount of
electrophile was added dropwise (benzophenone and phenyl
isocyanate as 20% THF solution) and the reaction was allowed
to reach rt. The reaction mixture was quenched with a
saturated solution of NH4Cl and extracted with CH2Cl2 (24a ,b)
or EtOAc (24c) (4 × 50 mL). The organic layer was dried
(MgSO4), the solvent was evaporated in vacuo, and the residue
was subjected to column chromatography.
Isom er iza tion of 1-Allyl-1H-1,2,4-tr ia zole (4) to (Z)-1-
(P r op en -1-yl)-1H-1,2,4-tr ia zole (26d ). 1-Allyl-1H-1,2,4-tria-
zole (2.00 g, 0.0183 mol) in THF (54 mL) was lithiated with
BuLi (23 mL, 1.6 M in hexane, 0.0366 mol) at -78 °C to give
a yellow fine suspension. Eleven samples were collected at
-78 °C after 1, 2, 3, 4, 6, 9, 15, 25, 35, and 50 min and then
after 7, 8, and 9 h. The 1H NMR spectra indicated for all these
samples an equimolar ratio between 4 and 43. The reaction
mixture was then allowed to reach rt and was quenched with
saturated NH4Cl (25 mL). The aqueous layer was extracted
with EtOAc (3 × 25 mL), dried (MgSO4), and allowed to stand
at 4 °C for 24 h, when the polymeric deposits were filtered off
and the solvent was evaporated in vacuo. The oily residue
was subjected to column chromatography (40 g silica gel,
eluent EtOAc) to yield a mixture of isomers, in a 26d (Z):32d (E)
of 10:1; 1.00 g (50%): 1H NMR δ (Z) 8.26 (s, 1H), 8.02 (s, 1H),
6.82 (dq, J allylic ) 1.8 Hz, J cis ) 9.1 Hz, 1H), 5.63 (dq, J ) 7.3
Hz, J cis ) 9.1 Hz, 1H), 1.95 (dd, J ) 7.3 Hz, J ) 1.8 Hz, 3H),
(E) 8.22 (s, 1H), 7.96 (s, 1H), 6.60 (dq, J allylic ) 1.8 Hz, J trans
)
14.0 Hz, 1H), 6.31 (m, J ) 7.0 Hz, J trans ) 14.0 Hz, 1H), 1.85
(dd, J ) 7.0 Hz, J ) 1.8 Hz, 3H); 13C NMR δδ (Z) 12.5, 119.7,
123.0, 143.1 151.2; (E) 14.4, 117.5, 123.6, 140.9, 151.4; HRMS
(EI) 109.0641, calcd for C5H7N3 109.0639.
Rea ction s w ith Iod om eth a n e. Con d ition s A: 1-a llyl-
5-m eth yl-1,2,4-tr ia zole (24a ) was obtained starting from
compound 4 (1.5 g, 0.0137 mol) and separated by column
chromatography as the main fraction, using EtOAc as eluent;
yellow oil, 1.00 g (60%).
Con d ition s B: (Z)-1-a llyl-5-eth yl-1,2,4-tr ia zole (33) was
obtained from compound 4 (1.50 g, 0.0137 mol) and separated
by column chromatography as the main fraction, using as
eluent EtOAc; yellow oil, 1.00 g (53%).
Con d ition s B: Syn th esis of Com p ou n d s 24c, 25b, 26b,
29c, 30c, a n d 33. 1-Allyl-1H-1,2,4-triazole (0.34 M in THF)
was lithiated at -78 °C with the equimolar amount of BuLi
(1.6 M solution in hexane) to give a yellow suspension. After
15 min, the theoretical amount of electrophile was added
dropwise (benzophenone and phenyl isocyanate as a solution
20% in THF) and the reaction was kept at -78 °C for 2 h (33),
5 h (25b, 26b), or 6 h (24c, 29c, and 30c). The reaction
mixture was lithiated with an equimolar amount of BuLi (1.6
M solution in hexane), and after 15 min the theoretical amount
of electrophile was added (as above). The reaction was allowed
to reach rt, quenched with saturated NH4Cl (50 mL), extracted
with CH2Cl2 (33, 25b, 26c) or EtOAc (24c, 29c, 30c) (4 × 50
mL), and dried (Na2SO4). The organic layer was worked up
as described before for the reactions performed using condi-
tions A.
Con d ition s C: (Z)-1-bu ten -1-yl-5-m eth yl-1,2,4-tr ia zole
(26a ) was obtained from compound 4 (1.50 g, 0.0137 mol) and
separated by column chromatography as the main fraction,
using EtOAc as eluent; yellow oil, 1.04 g (55%). The second
fraction in the column chromatography separation was 2-(5-
m eth yl-1,2,4-tr ia zol-1-yl)-3-bu ten e (25a ), as a mixture with
26a ; yellow oil, 0.100 g (28% 25a ).
Con d ition s D: (Z)-1-bu ten -1-yl-1,2,4-tr ia zole (27a ) was
obtained from compound 4 (1.50 g, 0.0137 mol) and separated
by column chromatography as the main fraction, using as
eluent EtOAc; yellow oil, 0.57 g (35%).
Rea ction s w ith Ben zop h en on e. Con d ition s A: 1-a llyl-
5-(h yd r oxyd ip h en ylm eth yl)-1,2,4-tr ia zole (24b) was ob-
tained from compound 4 (1.50 g, 0.0137 mol) and separated
by column chromatography using as eluent hexanes-EtOAc
(2:1); white crystals, mp 151-3 °C; 1.57 g (40%).
Con d ition s C: Syn th esis of Com p ou n d s 24c, 25a , 25b,
26a , 26b, 29c, 30c, a n d 32c. 1-Allyl-1H-1,2,4-triazole (0.34
M in THF) was lithiated at -78 °C with BuLi (2 equiv, 1.6 M
solution in hexane, BuLi:substrate molar ratio of 2:1) to give
Con d ition s B: (Z)-1,1-d ip h en yl-4-(5-d ip h en ylh yd r oxy-
m eth yl-1,2,4-tr ia zol-1-yl)-3-bu ten -1-ol (26b) was obtained
from compound 4 (1.50 g, 0.0137 mol) and separated by column
chromatography (first fraction compound 25b, 1.84 g, 28.5%),

4330 J . Org. Chem., Vol. 63, No. 13, 1998
Katritzky et al.
using as eluent hexanes-EtOAc (2:1); white crystals, mp
166-8 °C; 2.30 g (35.5%).
solution was concentrated in vacuo, and the crude reaction
mixture was separated by column chromatography (37-39)
or recrystallized from methanol (45).
Con d ition s C: (r-d ip h en ylh yd r oxym eth yl)-1-a llyl-5-
(d ip h en ylh yd r oxym et h yl)-1,2,4-t r ia zole (25b ) was ob-
tained from compound 4 (1.50 g, 0.0137 mol) and separated
by column chromatography using as eluent hexanes-EtOAc
(2:1) (the second fraction compound 26b, 1.00 g, 23%); white
crystals, mp 172-4 °C, 1.86 g (43%).
Con d it ion s D: (r-d ip h en ylh yd r oxym et h yl)-1-a llyl-
1,2,4-tr ia zole (28b) was obtained from compound 4 (1.50 g,
0.0137 mol) and separated by column chromatography using
hexanes-EtOAc (2:1) as eluent; white crystals, mp 118-20
°C; 1.54 g (39%).
1,1-Dip h en yl-4-(1H -1,2,4-t r ia zol-1-yl)-(Z)-3-b u t en -1-ol
(27b) a n d (Z)-5-Dip h en ylh yd r oxym eth yl-1-p r op en -1-yl-
1,2,4-tr ia zole (29b) were obtained from compound 4 (1.50 g,
0.0137 mol) and separated by column chromatography as a
second fraction, using hexanes-EtOAc (2:1) as eluent; mixture
in a 27b:29b ratio of 2:1 (see Note); 0.25 g (6.0%). Compound
25b was also separated using conditions D (0.25 g, 4%).
Rea ction s w ith P h en yl Isocya n a te. Con d ition s A:
1-a llyl-5-N-p h en ylca r ba m oyl-1,2,4-tr ia zole (24c) was ob-
tained from compound 4 (0.95 g, 0.0087 mol), and separated
by column chromatography as the main fraction; eluent
hexanes-EtOAc (3:1); yellow oil, 1.20 g (61%).
Con d ition s B. Starting from compound 4 (1.50 g, 0.0137
mol) the following compounds were isolated after column
chromatography, using as eluent hexanes-EtOAc (3:1): (Z/
E)-1-P r open -1-yl-5-N-ph en ylcar bam oyl-1,2,4-tr iazole (29c/
30c) as a yellow oil, in a 29c:30c ratio of 3.7:1; 0.340 g (14%).
N,N-Diph en ylu r ea (35): white crystals, mp 235-7 °C (metha-
nol) (lit.28 mp 238-40 °C); 0.270 g (24.8% based on phenyl
isocyanate). N,N-Di-N-ph en ylcar bam oyl-an ilin e (36): white
crystals, mp 156-8 °C (methanol) (lit.29 mp 148 °C); 0.490 g
(44.8% based on phenyl isocyanate).
Con d ition s C. Starting from compound 4 (1.50 g, 0.0137
mol) the following compounds were isolated after column
chromatography using as eluent hexanes-EtOAc (3:1):
(Z)-1-P r op e n -1-yl-5-N -p h e n ylca r b a m oyl-1,2,4-t r ia -
zole (29c) (see conditions B above) in a mixture with N-
p h en yl n -bu tylca r ba m a te (34)30 as a reddish oil; the 29c:
34 ratio was ca. 4.5:1 (by 1H NMR); 0.440 g (11.5% 29c and
1% 34). N,N-Dip h en ylu r ea (35): 0.180 g (8% based on
phenyl isocyanate). N,N-Di-N-p h en ylca r b a m oyla n ilin e
(36): 0.680 g (30.1%, based on phenyl isocyanate).
(E)-5-N-P h en ylca r ba m oyl-1-(3-N-p h en ylca r ba m oyl-1-
p r op en -1-yl)-1,2,4-tr ia zole (32c) was isolated after column
chromatography using as eluent hexanes-diethyl ether (1:1):
yellow crystals, mp 185-7 °C; 0.96 g (20.4%).
Rea ction w ith Iod om eth a n e. Starting from compound
5 (1.50 g, 0.014 mol), a mixture of isomers 37-39 was isolated
after column chromatography (eluent EtOAc), as an oil (see
Note); 1.12 g (60%). According to the 1H NMR spectrum of
the mixture, the assignments and percentages are as follows:
1-(1,2,4-t r ia zol-1-yl)-2-b u t yn e (37), 70%; 3-(1,2,4-t r ia zol-
1-yl)-1-bu tyn e (38), 10%; 2-(1,2,4-tr ia zol-1-yl)-3-p en tyn e
(38), 20%.
Rea ction w ith Ben zop h en on e: 1,1-Dip h en yl-4-(1,2,4-
tr ia zol-1-yl)-2-bu tyn -1-ol (45): white crystals, mp 149-50
°C (methanol) (70%).
Con d ition s B: Syn th esis of Com p ou n d s 45-48. 1-Pro-
pargyl-1H-1,2,4-triazole (5) (0.28 M solution in THF) was
lithiated at -78 °C with an equimolar amount of BuLi (1.6 M
in hexane) to give an orange suspension. After 15 min
benzophenone (1 equiv as 20% THF solution) was added
dropwise. The resulted solution was further lithiated at -78
°C with BuLi (1 equiv) to give a purple solution. After 15 min
benzophenone (1 equiv as 20% THF solution) was added
dropwise. The reaction mixture was maintained at -78 °C
for 8 h and then allowed to reach rt. The reaction mixture
was quenched with saturated NH4Cl and worked up as
described in conditions A. Starting from 1.25 g (0.0117 mol)
of compound 5, the following compounds were isolated by
column chromatography, using as eluent hexanes-EtOAc
(1.5:1): 1,1-Dip h en yl-4-(5-d ip h en ylh yd r oxym eth yl-1,2,4-
tr iazol-1-yl)-2,3-bu tadien -1-ol (46): white crystals; mp 100-1
°C (ether); 0.690 g (12.3%). 1,1-Dip h en yl-4-(5-d ip h en ylh y-
d r oxym et h yl-1,2,4-t r ia zol-1-yl)-2-b u t yn -1-ol (47) a n d
1,1,4,4-t e t r a p h e n yl-1,2,4-t r ia zol-1-yl-3-b u t yn -1,4-d iol
(48): isolated as a mixture in a 47:48 ratio of 3.3:1; white
crystals, mp 120-142 °C; 2.34 g (42.5%). 1,1-Dip h en yl-4-
(1,2,4-tr ia zol-1-yl)-2-bu tyn -1-ol (45): eluted from the chro-
matography column with dry acetone (see conditions A above);
0.57 g (17%).
Con d ition s D: Syn th esis of Com p ou n d s 49-51. 1-Pro-
pargyl-1H-1,2,4-triazole (5) (0.014 mol, 0.28 M in THF) was
lithiated at -78 °C with BuLi (2 equiv, 1.6 M in hexane) to
yield an orange suspension. After 15 min, benzophenone (1
equiv as 20% in THF) was added dropwise. After 4 h the
reaction mixture (as a green solution) was quenched at -78
°C and worked up as described above to give after column
chromatography compounds 49-51. The column was finally
eluted with dry acetone to afford unreacted starting material
4, 0.97 g (77%).
1,1-Diph en yl-2-(5-diph en ylh ydr oxym eth yl-1,2,4-tr iazol-
1-yl)-3-bu tyn -1-ol (49). Hexanes-EtOAc (1.5:1) was used as
eluent to obtain white crystals, mp 142-4 °C (ether); 0.35 g
(7.4%).
Con d ition s D. Starting from compound 4 (2.00 g, 0.0183
mol) the following compounds were isolated by column chro-
matography using as eluent hexanes-EtOAc (3:1): compounds
29c, 30c, and 34 as a mixture in a 29c:30c:34 ratio of 6:1:1
1
5-Dip h e n ylh yd r oxym e t h yl-1-p r op yn -1-yl-1,2,4-t r ia -
zole (50). Hexanes-EtOAc (1.5:1) was used as eluent to
obtain white crystals, mp 170-1 °C; 0.43 g (9.0%).
1,1-Diph en yl-2-1,2,4-tr iazol-1-yl-3-bu tyn -1-ol (51). Hex-
anes-EtOAc (1.5:1) was used as eluent to obtain white
crystals, mp 165-7 °C (ether); 0.31 g (6.6%).
Con d ition s E: Alter n a tive Syn th esis of Com p ou n d s
49-51. 1-Propargyl-1H-1,2,4-triazole (5) (1.50 g, 0.014 mol,
0.28 M in THF) was lithiated at -78 °C with BuLi (3 equiv,
1.6 M in hexane) to give an orange suspension. After 15 min
benzophenone (2 equiv as 20% THF solution) was added
dropwise. The deep green reaction mixture was maintained
at -78 °C for an additional 8 h and then was quenched and
worked up as described above. Compounds 45-47 were
separated by column chromatography, using as eluent hex-
anes-EtOAc (1.5:1). The unreacted starting material was
finally eluted with dry acetone; 0.69 g (42%). 1,1-Dip h en yl-
2-(5-d ip h en ylh yd r oxym eth yl-1,2,4-tr ia zol-1-yl)-3-bu tyn -
1-ol (49): 0.755 g (17%). 5-Dip h en ylh yd r oxym eth yl-1-
pr opyn -1-yl-1,2,4-tr iazole (50): 1.16 g (26%). 1,1-Diph en yl-
2-1,2,4-tr ia zol-1-yl-3-bu tyn -1-ol (51): 0.69 g (15%).
(by H NMR); yellow oil, 0.14 g (3% 29c, 0.5% 30c, 0.5% 34).
N,N-Dip h en ylu r ea (35): 0.17 g (5% based on phenyl isocy-
anate) (see conditions B above). N,N-Di-N-(p h en ylca r ba m -
oyl)a n ilin e (36): 0.22 g (3.7% based on phenyl isocyanate).
(E)-1-(3-N-P h en ylca r ba m oyl)-1-p r op en -1-yl-1,2,4-tr ia -
zole (31c) was obtained by column chromatography using as
eluent CH2Cl2:ether (1:1); yellow crystals, mp 202-4 °C; 0.17
g (6%).
F u n ction a lized 1-P r op a r gyl-1H-1,2,4-tr ia zoles. Con d i-
tion s A. 1-Propargyl-1H-1,2,4-triazole (0.28 M solution in
THF) was lithiated at -78 °C with an equimolar amount of
BuLi (1.6 M solution in hexane) to give an orange suspension.
After 15 min the appropriate electrophile (1 equiv) was added
dropwise (iodomethane or benzophenone as 20% THF solu-
tion). The reaction mixture was allowed to warm at rt
overnight, then was quenched with saturated NH4Cl, extracted
with EtOAc (reported to the reaction volume, ca. 4-fold amount
of EtOAc is recommended), and dried (MgSO4). The organic
(30) McGhee, W.; Riley, D.; Christ, K.; Pan, Y.; Parnas, B. J . Org.
Chem. 1995, 60, 2820.

Selective Reactivity of Carbanions of 1,2,4-Triazoles
J . Org. Chem., Vol. 63, No. 13, 1998 4331
Su p p or tin g In for m a tion Ava ila ble: 1H NMR, 13C NMR,
and HRMS spectra for compounds 6a ,b, 9, 13, 24a , 26a , 27a ,
26d , and 33 and 1H and 13C NMR for compound 8 and the
mixtures of compounds referred to in Note. Characterization
data and experimental details for the following compounds:
6a -c, 7, 8-10, 12-15, 24a -c, 25a -b, 26a -b, 27a -b, 28b,
29b-c, 30c, 31c, 32c, 33-39, 45-51. This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O9800659