Five-to-six membered ring-rearrangements in the reaction of 5-perfluoroalkyl-1,2,4-oxadiazoles with hydrazine and methylhydrazine

Article abstract of DOI:10.1021/jo061251e

The hydrazinolysis reaction of 5-perfluoroalkyl-1,2,4-oxadiazoles with hydrazine or methylhydrazine as bidentate nucleophiles has been investigated. The reaction occurred through the addition of the bidentate nucleophile to the C(5)-N(4) double bond of th

Full text of DOI:10.1021/jo061251e

Five-to-Six Membered Ring-Rearrangements in the Reaction of
5-Perfluoroalkyl-1,2,4-oxadiazoles with Hydrazine and
Methylhydrazine
Silvestre Buscemi,* Andrea Pace, Antonio Palumbo Piccionello, Ivana Pibiri, and
Nicol o` Vivona
Dipartimento di Chimica Organica “E. Patern o` ”, UniVersit a` degli Studi di Palermo,Viale delle Scienzes
Parco d’Orleans II, I-90128 Palermo, Italy
Gianluca Giorgi
Dipartimento di Chimica, UniVersit a` degli Studi di Siena, Via Aldo Moro, I-53100 Siena, Italy
Andrea Mazzanti and Domenico Spinelli
Dipartimento di Chimica Organica “A. Mangini”, UniVersit a` degli Studi di Bologna,Via S. Giacomo 11,
I-40127 Bologna, Italy
sbuscemi@unipa.it
ReceiVed June 19, 2006
The hydrazinolysis reaction of 5-perfluoroalkyl-1,2,4-oxadiazoles with hydrazine or methylhydrazine as
bidentate nucleophiles has been investigated. The reaction occurred through the addition of the bidentate
nucleophile to the C(5)-N(4) double bond of the 1,2,4-oxadiazole followed by ring-opening and ring-
closure (ANRORC) involving the second nucleophilic site of the reagent. This ring-closure step could
involve either the original C(3) of the 1,2,4-oxadiazole (giving a five-to-five membered ring rearrangement)
or an additional electrophilic center linked to it (exploiting a five-to-six membered ring rearrangement).
An alternative initial nucleophilic attack may involve the additional electrophilic center linked at C(3),
that is the carbonyl group, leading to the formation of the hydrazones which undergo the Boulton-
Katritzky rearrangement (BKR). The chosen reaction path is a function of the used nucleophile and of
the nature of the substituent at C(3). At variance with previous hypotheses, when methylhydrazine was
used, the observed regiochemistry always showed the preferred initial attack by the less hindered NH
2
end of the nucleophile on C(5). Moreover, new spectroscopic evidence allowed the assignment of correct
structures to the products formed by reaction of 5-perfluoroalkyl-3-phenyl-1,2,4-oxadiazoles with
methylhydrazine.
Introduction
ANRORC reactions of π-deficient six-membered hetero-
cycles, such as di- and triazines, have been extensively studied
by Van der Plas and co-workers. On the other hand, few
Heterocyclic rearrangements represent an interesting research
field since in several cases they allow us to obtain other
heterocyclic structures which are difficult to synthesize through
the classical methodologies.1,2 In this context, ANRORC
processes (consisting of an initial nucleophilic attack followed
by ring-opening and ring-closure) represent an useful tool, in
the hand of the synthetic heterocyclic chemist, to achieve the
ring transformation of heterocyclic systems.2
2
(1) See for example: (a) Boulton, A. J.; Katritzky, A. R.; Hamid, A. M.
J. Chem. Soc. C 1967, 2005-2007. (b) Afridi, A. S.; Katritzky, A. R.;
Ramsden, C. A. J. Chem. Soc., Perkin Trans. 1 1976, 315-320. (c) Ruccia,
M.; Vivona, N.; Spinelli, D. AdV. Heterocycl. Chem. 1981, 29, 141-169.
(
d) L’abb e´ , G. J. Heterocycl. Chem. 1984, 21, 627-638. (e) Vivona, N.;
Buscemi, S.; Frenna, V.; Cusmano, G. AdV. Heterocycl. Chem. 1993, 56,
9-154. (f) Pace, A.; Pibiri, I.; Buscemi, S.; Vivona, N. Heterocycles 2004,
63, 2627-2648.
4
10.1021/jo061251e CCC: $33.50 © 2006 American Chemical Society
8
106
J. Org. Chem. 2006, 71, 8106-8113
Published on Web 09/16/2006

Ring-Rearrangements in Reactions of Oxadiazoles
SCHEME 1. Ring-Degenerate ANRORC Rearrangement of
CHART 1. ANRORC Rearrangements of 5-Perfluoroalkyl
Oxadiazoles with Bidentate Nucleophiles.
5-Perfluoroalkyl-1,2,4-oxadiazoles
examples of ANRORC rearrangements are reported for five-
membered heterocycles. These include electron poor five-
3
membered systems such as 1,3,4-oxadiazoles, 1,3,4-thiadi-
7
4
3,5
roalkyl-regioisomers (at room temperature the eventual equi-
azoles, nitroimidazoles, and the recently reported bis(1,3,4-
3
thiadiazol-2-yl)-1,3,5-triazinium halides.6
librium constant is larger than 10 ), are not activated toward
ANRORC.
In general, one may assume that the ANRORC reactivity
depends on three main factors: (i) the electrophilic character
of the heterocyclic ring which can make possible or prevent
the initial nucleophilic attack; (ii) the presence of a further
electrophilic center in the open-chain intermediate (formed
during the ring-opening stage) which allows the cyclization step;
To enlarge the synthetic applications of this ANRORC
approach, hydrazine and methylhydrazine could also be used
as bidentate nucleophiles. It is noteworthy that, besides the
regiochemistry issues due to the use of an unsymmetrical
bidentate nucleophile such as methylhydrazine, the presence of
another electrophilic center within the C(3) substituent intro-
duces other potential competitive paths such as [4 + 2]
ANRORC cyclizations (Chart 1).
Preliminary results on the reaction of 5-perfluoroalkyl-1,2,4-
oxadiazoles with hydrazine showed the formation of 1,2,4-
triazoles from a [3 + 2] ANRORC rearrangement. In the case
of 3-benzoyl-5-perfluoroalkyl-1,2,4-oxadiazoles the presence of
a side-chain electrophilic center shifted the reaction toward a
(iii) the presence of good leaving groups which allows the final
elimination processes to occur, furnishing compounds thermo-
dynamically favored with respect to the starting materials.
For five-membered heterocycles, the first factor is a function
of the number of pyridine-like nitrogens in the ring and of the
electron withdrawing ability (and location) of the substituents.
As for the electrophilic center and the leaving group, they can
either be generated during the ring-opening process or be already
part of some substituent on the starting ring.
10
[
1
4 + 2] ANRORC rearrangement into triazinone oximes (Chart
). In this work we report a complete set of reactions with
1
1
On the basis of the above considerations, we recently studied
the ring-degenerate rearrangements of 5-perfluoroalkyl-1,2,4-
oxadiazoles 1 into their corresponding 3-perfluoroalkyl-regio-
isomers 4 by performing an ANRORC reaction with hydroxy-
hydrazines, which includes the new interesting reactivity
observed for 3-ethoxycarbonyl-5-perfluoroalkyl-1,2,4-oxadi-
azoles. As for the reaction with methylhydrazine, we will discuss
the observed reactivity as a function of the substituent at C(3)
and point out the differences with respect to the reaction with
hydrazine. Moreover, a reinvestigation, based on new spectro-
scopic evidence, of the reaction of 3-phenyl-5-perfluoroalkyl-
7
lamine as a bidentate nucleophile. In this reaction, the electron-
poor and weakly aromatic 1,2,4-oxadiazole8 is even more
activated, toward a nucleophilic attack, by the presence of the
strongly electron-withdrawing perfluoroalkyl group at C(5).
,9
1
,2,4-oxadiazoles with methylhydrazine allowed an assignment
In this reaction a second electrophilic center is created, after
the ring-opening step, on the original C(3) of the starting ring.
This center is attacked, in the ring closure step, by the oxygen
end of the bidentate nucleophile. Finally, in the rearomatization
step the hydroxylamino moiety (originally part of the oxadiazole
ring) acts as the leaving group (Scheme 1). This reaction, which
can be classified as a [3 + 2] ANRORC heterocyclization (Chart
of the correct structure to the formed products.
Results and Discussion
The ANRORC behavior has been studied considering 3-sub-
stituted-5-perfluoroalkyl-oxadiazoles where the C(3) substituent
was (i) nonelectrophilic, (ii) containing an electrophilic center,
or (iii) containing a leaving group linked to an electrophilic
center. In the following paragraphs, all the possible reaction
pathways are illustrated as a function of the substituent at C(3)
or of the used nucleophile. Considering the number of possible
products that could be formed during the studied reactions, the
observed selectivity is, in some cases, extremely significant and
is discussed below.
1
), is irreversible since the obtained 3-perfluoroalkyl-1,2,4-
oxadiazoles, which are more stable than the starting 5-perfluo-
(
(
2) Van der Plas, H. C. AdV. Heterocycl. Chem. 1999, 74, 1-253.
3) (a) Hetzheim, A.; M o¨ ckel, K. AdV. Heterocycl. Chem. 1966, 7, 183-
2
9
24. (b) Reid, J. R.; Heindel, N. D. J. Heterocycl. Chem. 1976, 13, 925-
26.
(
4) Sandstr o¨ m, J. AdV. Heterocycl. Chem. 1968, 9, 165-209.
Reactions of 3-Aryl-5-perfluoroalkyl-1,2,4-oxadiazoles with
Hydrazine and Methylhydrazine. For 1,2,4-oxadiazoles 5
(5) Suwinski, J.; Pawlus, W.; Salwinska, E.; Swierczek, K. Heterocycles
1
994, 37, 1511-1520.
6) Wermann, K.; Walther, M.; G u¨ nther, W.; G o¨ rls, H.; Anders, E.
Tetrahedron 2005, 61, 673-685.
7) Buscemi, S.; Pace, A.; Pibiri, I.; Vivona, N.; Lanza, C. Z.; Spinelli,
D. Eur. J. Org. Chem. 2004, 974-980.
8) (a) Bird, C. W. Tetrahedron 1985, 41, 1409-1414. (b) Bird, C. W.
Tetrahedron 1992, 48, 335-340.
9) For aromaticity criteria of five-membered heterocycles, see also: (a)
(
(
Scheme 2), where the C(3) substituent does not contain an
electrophilic center, the initial attack of the nucleophile can occur
only at C(5) of the oxadiazole ring. In the reaction with
(
1
0,12
(
hydrazine
we have reported the formation of triazoles 8
(tautomers of 13) together with some amounts of 3-perfluoro-
(
Bean, G. P. J. Org. Chem. 1998, 63, 2497-2506. (b) Katritzky, A. R.;
Barczynski, P.; Musumarra, G.; Pisano, D.; Szafran, M. J. Am. Chem. Soc.
(10) Buscemi, S.; Pace, A.; Pibiri, I.; Vivona, N.; Spinelli, D. J. Org.
1
2
989, 111, 7-15. (c) Katritzky, A. R.; Jug, K.; Oniciu, D. C. Chem. ReV.
001, 101, 1421-1449. (d) Balaban, A. T.; Oniciu, D. C.; Katritzky, A. R.
Chem. 2003, 68, 605-608.
(11) Buscemi, S.; Pace, A.; Palumbo Piccionello, A.; Macaluso, G.;
Vivona, N.; Spinelli, D.; Giorgi, G. J. Org. Chem. 2005, 70, 3288-3291.
Chem. ReV. 2004, 104, 2777-2812.
J. Org. Chem, Vol. 71, No. 21, 2006 8107

Buscemi et al.
SCHEME 2. Hydrazinolysis of 5-Perfluoroalkyl-1,2,4-oxadiazoles 5
TABLE 1. Product Distribution (%) from the Reaction of 5 with
range coupling between the methyl signal at 4.06 ppm and the
quaternary carbon at 155.9 ppm. The same carbon has a similar
coupling with the ortho hydrogens of the phenyl group at 7.83
ppm, so it can be assigned to the phenyl-substituted C(5) of
the 1,2,4-triazole ring. On the other hand, the long range
coupling has not been observed between the methyl hydrogens
and the quaternary C(3) carbon at 150.9 ppm, easily recogniz-
Hydrazine (R ) H) and Methylhydrazine (R ) Me)
substrate
RF
Ar
R
8
9
10
a
a
a
c
10b
5
5
5
5
5
5
5
5
a
b
c
d
a
b
c
CF3
Ph
Ph
Ph
4-Py
Ph
Ph
Ph
4-Py
H
H
H
H
Me
Me
Me
Me
70
72
82
65
b
C3F7
C7F15
C7F15
CF3
C3F7
C7F15
C7F15
11
15
23
19
24
26
b
c
80d
75
b
2
b
able as a quartet because of geminal C-F coupling ( JC-F )
d
b
38.8 Hz) with the CF3. These data allow the assignment of the
1-methyl-5-phenyl-3-trifluoromethyl-1,2,4-triazole structure to
71
c,e
c
d
85
10
1
5
a
compound 9a. The assignment of the N chemical shifts of
the methyl-substituted N(1) (206.9 ppm) and pyridine-like N(2)
These results are in agreement with what previously reported within
1
0
b
See ref 7. See ref 12. See ref 10. e In this
c
d
experimental errors.
reaction, the triazole regioisomer 14d, originating from the initial attack of
the N-methylated end of the nucleophile on the C(5) of the oxadiazole, has
(
302.2 ppm) were determined by observing the long-range
1
15
coupling with the methyl hydrogens by means of
g-HMBC spectra. The remaining chemical shift of N(4) (248.9
ppm), lacking of any coupling with the protons, was determined
H
N
1
2
been isolated in 4% yield.
15
alkyl-1,2,4-oxadiazoles 10 (see Table 1) formed by the reaction
between the starting oxadiazoles 5 and the hydroxylamine
eliminated during the main process.7
15
from the N spectrum.
In the case of 14a, the 1H 13C g-HMBC spectrum showed a
,13
long range coupling between the methyl hydrogens signal at
In the case of the reaction with methylhydrazine, the
regioselectivity of the process (paths a or b in Scheme 2) is
determined by which end of the nucleophile attacks the
oxadiazole. In a previous communication we proposed the
formation of triazoles 14a-c and explained their formation
through the initial attack of the more nucleophilic end of the
nucleophile (path b in Scheme 2). However, a deeper spectro-
scopic investigation revealed that the structure of the formed
triazoles was misassigned and that the correct structure was that
of triazoles 9a-c.14 The regioselective formation of triazoles
4
.10 ppm and the trifluoromethylated quaternary carbon at 143.8
ppm, easily recognizable as a quartet because of the geminal
C-F coupling ( JC-F ) 40.6 Hz).
On the other hand, the ortho hydrogens of the phenyl group
show long-range correlation with the other quaternary carbon
2
[
i.e., the C(3) at 160.1 ppm] of the 1,2,4-triazole ring. These
data allow a satisfactory assignment of the 1-methyl-3-phenyl-
-trifluoromethyl-1,2,4-triazole structure to compound 14a (see
5
1
13
Supporting Information for the two H C g-HMBC spectra of
compounds 9a and 14a). Also in this case the assignment of
the N chemical shifts of methyl-substituted N(1) (207.9 ppm)
and pyridine-like N(2) (300.4 ppm) were obtained from H
g-HMBC, while the remaining N(4) shift (250.6 ppm) was
determined from the N NMR spectrum. The same approach
was used to determine the structures of the other pairs of
products 9b,c and 14b,c. The correct assignment has been also
definitely confirmed by X-ray diffraction in the case of 9c (see
Supporting Information), showing that the methyl group is
bonded to the nitrogen near the phenyl group, in agreement with
the 1-methyl-3-perfluoroepthyl-5-phenyl-1,2,4-triazole structure.
9
d was also observed in the case of 3-(4′-pyridyl)-1,2,4-
15
oxadiazoles 5d, confirming that the initial attack at the C(5)
preferentially involves the less hindered NH2 end of the
nucleophile (path a in Scheme 2).12
1
15
N
15
All three pairs of regioisomers (9a-c and 14a-c) were then
synthesized, through diazomethane methylation of the corre-
sponding triazoles 8a-c, for a structure correlation study. The
1
13
H
Cg-HMBC spectrum of 9a revealed the presence of a long-
(
12) Pibiri, I.; Pace, A.; Buscemi, S.; Vivona, N.; Malpezzi, L.
Heterocycles 2006, 68, 307-321.
13) In our preliminary communication this product was reported as
unidentified.
1
0
(
(15) For a comprehensive review on long-range H 15N heteronuclear
correlations and 15N chemical shifts see: Martin, G. E.; Hadden, C. E. J.
Nat. Prod. 2000, 63, 543-585
1
(
14) Moreover, the previously reported formation of demethylated product
10
8
a,c depends on the purity degree of the used methylhydrazine reagent.
8108 J. Org. Chem., Vol. 71, No. 21, 2006

Ring-Rearrangements in Reactions of Oxadiazoles
SCHEME 3. Hydrazinolysis of 5-Perfluoroalkyl-1,2,4-oxadiazoles Bearing an Electrophilic Substituent at C(3)
TABLE 2. Product Distribution (%) from the Reaction of 15 with
Hydrazine (R ) H) and Methylhydrazine (R ) Me)
Reactions of 3-Benzoyl-5-perfluoroalkyl-1,2,4-oxadiazoles
with Hydrazine and Methylhydrazine. As illustrated in the
case of compounds 15, when the 5-perfluoroalkyl-1,2,4-oxa-
diazole contained another electrophilic center on the substituent
at C(3), several reaction pathways became available (Scheme
substrate
RF
Ar
R
19
21
22
15a
CF3
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
Me
Me
Me
92a
5
24
29
a
a
a
a
15b
15c
15a
15b
C3F7
C7F15
CF3
C3F7
C7F15
70
a
65
3
). For a symmetric nucleophile such as hydrazine, paths a and
64
75
97
b in Scheme 3 indicate the attack at the C(5) or at the carbonyl
moiety, respectively. As previously reported, the reaction of
oxadiazoles 15 with hydrazine11 leads mainly to the triazinone
15c
a
See ref 11.
oxime 19 (from path a-2) and to the Boulton-Katritzky
rearrangement (BKR)1
a-c,e
product 21 (from path b). It is
noteworthy that the yield of compound 21 significantly increased
along with the steric bulkiness of the perfluoroalkyl group
otherwise confirming, in the absence of steric hindrance, that
the C(5) was the preferred site of the initial attack.1
decided to investigate the effects of the presence of a leaving
group at the carbonyl moiety and studied the reactivity of
3-carboxyethyl-5-perfluoroalkyl-1,2,4-oxadiazoles 23 with hy-
drazine and methylhydrazine (Scheme 4).
1
The use of an asymmetric nucleophile introduces two
additional possible paths (paths c and d in Scheme 3). Interest-
ingly, in the reaction with methylhydrazine, no product was
isolated from paths c or d, thus confirming that only the NH2
end of the nucleophile is involved in the first attack. However
in this case, differently from the reaction with hydrazine, the
BKR product 22 (64-97%) was the only one obtained. A
mechanistic explanation considers that in path a-2, the C(5) is
still the preferred electrophilic site during the initial nucleophilic
Despite the fact that the presence of the leaving group may
introduce additional paths, we observed in both reactions with
hydrazine and methylhydrazine, and for all oxadiazoles 23, a
surprising selectivity for the formation of triazinones 27 and
28 (from path a-2) which are isolated as the only products in
81-97% yield. Once again, the observed regioselectivity
confirms the preferential attack of the NH2 end of the methyl-
hydrazine on the C(5). Moreover, path c (and the subsequent
BKR) is shut down by the lower reactivity of the carboxyethyl
group toward hydrazines in comparison with the benzoyl group
in compound 15. The cyclization step involves the carbonyl
moiety of the open-chain intermediate 25. However, unlike
compound 18, the presence of the ethoxy leaving group allows
the final elimination process to occur independently from the
nature of the R substituent (R ) H, Me) present in the
hydrazines.
1
1
attack, while the carbonyl is the preferred cyclization site.
Probably the formation of 18 is a reversible process, that can
be driven by the formation of the stable triazinone oxime 19
from tetrahydro triazine 18 through an elimination process which
is only possible for R ) H (i.e., in the reaction with hydrazine).
Lacking this driving force, the reaction with methylhydrazine
develops through path b leading exclusively to highly stable
8
,9
triazoles 22 (see Table 2). This observation supports the
hypothesis that the 15 f 16 f 18 transformation could be, at
least in the first stage, reversible.
Both NMR spectra and X-ray analysis were employed to
unambiguously assign the structures of compounds 27a-c and
28a-c.
Reactions of 3-Carboxyethyl-5-perfluoroalkyl-1,2,4-oxa-
diazoles with Hydrazine and Methylhydrazine. The cycliza-
tion and the subsequent elimination are key reaction steps
involving the side-chain carbonyl substituent. We therefore
In the case of compounds 28a-c, crystals suitable for X-ray
diffraction were obtained for 28c (see Supporting Information).
From the X-ray data, however, the position of the NH group
was not completely clear, owing to the very weak absorption
J. Org. Chem, Vol. 71, No. 21, 2006 8109

Buscemi et al.
SCHEME 4. Hydrazinolysis of 5-Perfluoroalkyl-1,2,4-oxadiazoles Bearing an Electrophilic Substituent at C(3) Containing a
Leaving Group
a
TABLE 3. Ab initio Calculated Chemical Shift (GIAO Method at the B3LYP/6-311++G(2d,p)//B3LYP/6-311G(d) Level) and Relative
Energies Calculated for 28a
a
Reference was NH3, calculated at the same level of theory. b The reported values were obtained by the sum of the absolute value of the difference
between the calculated shift and the experimental one.
of the crystals. Since there are, in theory, three possible
tautomeric forms available to 28 (indicated as 28-2NH, 28-
the four signals of 28c were observed at 159.6, 185.4, 205.1,
1
15
and 275.2 ppm; from the H- N long-range correlation spec-
trum, the two nitrogen atoms in positions 1 and 2, because of
their long-range coupling with the methyl hydrogens, were
assigned to the signals at 185.4 and 275.2 ppm, respectively.
The latter chemical shift is typical of a pyridine-like nitrogen,
while the signal at 185.4 ppm corresponds to the methylated
4
NH, and 28-5CNHOH; see Table 3) in order to resolve this
15
1
15
ambiguity, both direct detected N spectra and H N g-HMBC
spectra were acquired for 28c, and ab initio chemical shift
calculation (GIAO method at the B3LYP/6-311G++(2d,p)//
16
B3LYP/6-311G(d) level) were obtained for all the three
tautomeric forms of 28a (see Table 3).17 In the N spectrum,
15
pyrrole-like nitrogen in position 1. The presence of the methyl
15
8110 J. Org. Chem., Vol. 71, No. 21, 2006

Ring-Rearrangements in Reactions of Oxadiazoles
in position 1 is evident from X-ray data, and also from H 13
1
C
Conclusions
HMBC spectrum, where it is evident in the long range coupling
of the methyl hydrogens with the carbonyl carbon. These data
imply that the NH group cannot be located in position 2 of the
triazinone ring, thus the 28-2NH form can be excluded.
Among the plethora of nonphotochemical heterocyclic re-
arrangements, which are usually carried out by using harsh
thermal conditions, ANRORC rearrangements on activated
5
-perfluoroalkyl-1,2,4-oxadiazoles resulted in a very versatile
In the case of the two remaining structures (i.e., 28-4NH
and 28-5CNHOH in Table 3), the main difference lies in the
electronic distribution around the oximic nitrogen. Because of
the simultaneous presence of the double bond and of the oxygen,
and mild method to synthesize fluorinated 1,2,3- and 1,2,4-
triazoles, Z-oximes of 1,2,4-triazin-5-ones and 5-hydroxylamino-
1
,2,4-triazin-6-ones.
The study, carried on different hydrazinolysis reactions with
1
8
the oximic nitrogen is usually found at very low field (from
45 to 365 ppm), while in the present case its chemical shift
hydrazine and methylhydrazine on differently substituted sub-
strates, allowed us to rationalize the results obtained considering
the factors involved in all the steps of the ANRORC process in
terms of (i) the initial attack by the less hindered side of the
bidentate nucleophile; (ii) the steric influence of the perfluo-
roalkyl group and the extent of the electronic demand in the
competition between the C(5) of the oxadiazole ring and the
side-chain carbonyl group in undergoing the initial nucleophilic
attack; (iii) the competition between the C(3) of the oxadiazole
and the side-chain carbonyl group in undergoing the second
nucleophilic attack (i.e., in the cyclization step); and (iv) the
evolution of reaction intermediates as a function of the leaving
group ability of the substituent on the side-chain electrophilic
site. Despite the fact that several paths were available, the
observed regioselectivity was fairly good and opens the way to
future developments of this strategy for the obtainment of other
fluorinated heterocycles.
3
should be assigned to one of the signals at 205.1 or 159.6 ppm.
In the case of the hydroxilaminic form 28-5CNHOH, the
expected chemical shift19 is much more compatible with the
observed spectra. Indeed, also the chemical shift obtained from
ab initio calculations for the three tautomers of 28a show the
best agreement in the case of the 28-5CNHOH structure;
incidentally this tautomer is also calculated to be the most stable.
Further support to this hypothesis comes from the comparison
between the experimentally, X-ray derived, bond distances for
2
8c and the calculated ones for 28a, from which it is evident
the single-bond nature of the C(5)-NHOH bond (see Supporting
Information for a comparison between the two structures).
In the case of compound 27c, the 1H NMR and 13C NMR
spectra show three very broad signals for the three protons and
for the three quaternary carbons, and no heteronuclear correla-
1
15
1
13
tions were observed in both H N HMBC and H C HMBC
spectra. These data indicate that a chemical exchange between
different species is fast in the NMR time scale. In the case of
Experimental Section
General Procedure for the Hydrazinolysis of 5-Perfluoro-
alkyl-3-phenyl-1,2,4-oxadiazoles 5a-c with Hydrazine or
Methylhydrazine in DMF. To a sample of compunds 5a-c (1.5
mmol) in dry DMF (2 mL) was added an excess of hydrazine or
methylhydrazine (7.5 mmol), and the mixture was left at room
temperature for 1 h (for 5a,b) or 10 h (for 5c). After dilution with
water, the mixture was extracted with EtOAc, which was dried and
evaporated, and the residue was chromatographed. Results are
reported in Table 1.
2
7c, in addition to the three tautomeric forms already shown
for 28a-c, each of them could be present in the C(6)-OH form.
Lacking any indication from NMR data, and being impossible
for us to produce good crystals for these compounds, compound
2
7b was subjected to aroylation with benzoyl chloride. The
resulting compound 30 yielded good crystals, suitable for the
X-ray diffraction analysis. X-ray data (see Supporting Informa-
tion) show that compound 30 derives from the hydroxylamino
form. The X-ray data further confirms the presence of the
hydroxylamino form in the case of 28a-c, indeed the bond
distance C-N(7) is 1.39 Å, to be compared with the experi-
mentally observed distance of 1.38 Å in the case of 28c.
Hydrazinolysis of the 5-Heptafluoropropyl-3-phenyl-1,2,4-
oxadiazole 5b with Methylhydrazine. Compound 9b is an oil.
1
H NMR (599.7 MHz, DMSO-d , 25 °C): δ 4.09 (s, 3H), 7.59-
6
13
6
7.64 (m, 3H), 7.83 (m, 2H). C NMR (150.8 MHz, DMSO-d , 25
1
1
2
°C H decoupled): δ 37.9 (Me), 108.8 (tq, JC-F ) 266.4, JC-F
3
1
)
2
1
2
7.4 Hz, CF
17.1 (qt, JC-F ) 289.3, JC-F ) 35.5 Hz, CF
2
), 110.5 (tt, JC-F ) 254.3, JC-F ) 31.5 Hz, CF
),
1
2
3
), 126.2 (Cq), 128.8
(16) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
(
1
2 CH), 128.9 (2 CH), 130.8 (CH), 150.0 (t, JC-F ) 28.2 Hz, Cq),
56.2 (Cq). 19F NMR (564.2 MHz, DMSO-d
, 25 °C): δ -126.5
bs, 2F), -112.1 (q, 2F, J ) 8.1 Hz), -79.8 (t, 3F, J ) 8.2 Hz).
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A.
D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A.
G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian
6
(
1
5
N NMR (60.8 MHz, DMSO-d
6
, 25 °C): δ 209.0, 251.6, 305.4.
HRMS: calcd for C12 , 327.06066; found, 327.05999.
8 7 3
H F N
General Procedure for the Methylation of 5-Perfluoroalkyl-
3
-phenyl-1,2,4-triazoles 8a-c with Diazomethane. To a sample
of compounds 8a-c (0.5 mmol) in diethyl ether (10 mL), an
ethereal solution of CH N was added, and the solution was allowed
2 2
to stir at room temperature for 1 h. After removal of the solvent,
the residue was chromatographed.
Methylation of 5-Trifluoromethyl-3-phenyl-1,2,4-triazole 8a.
Chromatography of the residue gave 1-methyl-3-phenyl-5-triflu-
oromethyl-1,2,4-triazole 14a (72%) and 1-methyl-3-trifluoromethyl-
0
3, revision C.02; Gaussian, Inc.: Wallingford, CT, 2004.
17) To reduce the computational time, the ab initio chemical shift
1
0
(
5-phenyl-1,2,4-triazole 9a (25%).
1
calculations were obtained for compound 28a, in which the only difference
with 28c is the presence of a CF3 group instead of the C7F15 chain.
Compound 9a. H NMR (599.7 MHz, DMSO-d
, 25 °C): δ
6
13
4
.06 (s, 3H), 7.57-7.64 (m, 3H), 7.83 (m, 2H). C NMR (150.8
(18) Kolehmainen, E.; Gawinecki, R.; Oœmialowski, B. Trezbiatowska,
1
MHz, DMSO-d
C-F ) 269.2 Hz, CF
130.7 (CH), 150.9 (q, JC-F ) 38.8 Hz, Cq), 155.9 (Cq). F NMR
(564.2 MHz, DMSO-d
, 25 °C): δ -64.4. 15N NMR (60.8 MHz,
6
, 25 °C H decoupled): δ 37.7 (Me), 119.4 (q,
K. Magn. Reson. Chem. 1997, 35, 778-784.
15
J
3
), 126.3 (Cq), 128.7 (2 CH), 128.8 (2 CH),
(
19) For example the N chemical shift of N-benzyl-hydroxylamine and
1
9
N,N-dimethyl-hydroxylamine were found to be 126.1 and 145.1 ppm,
respectively (in DMSO-d6, this work).
6
J. Org. Chem, Vol. 71, No. 21, 2006 8111

Buscemi et al.
DMSO-d
C H F N
10 8 3 3
6
, 25 °C): δ 206.9, 248.9, 302.2. HRMS: calcd for
, 227.06704; found, 227.06644.
Compound 14a. mp 83-85 °C (from light petroleum). H NMR
599.7 MHz, DMSO-d , 25 °C): δ 4.10 (s, 3H), 7.46-7.53 (m,
Anal. Calcd for C
C, 30.80; H, 1.80; N, 9.20.
-Carboxyethyl-5-pentadecafluorohepthyl-1,2,4-oxadiazole 23c.
8
H
5
N
2
O
3
F
7
: C, 30.98; H, 1.63; N, 9.03. Found:
1
3
(
3
6
1
Yield 64%; colorless oil. H NMR (CDCl
3
): δ 1.47 (t, 3H, J )
H), 8.01 (m, 2H). 13C NMR (150.8 MHz, DMSO-d
, 25 °C H
), 125.8
1
+
6
7
5
.5 Hz), 4.56 (q, 2H, J ) 7.5 Hz). GC-MS m/z 511 (M +1, 72),
decoupled): δ 37.3 (Me), 118.5 (q, JC-F ) 267.8 Hz, CF
3
+
10 (M , 11), 484 (41), 466 (88), 119 (28), 100 (36), 69 (100), 45
(2 CH), 128.9 (2 CH), 129.2 (Cq), 129.9 (CH), 143.8 (q, JC-F
)
, 25
-1
(
19). IR (Nujol) 1763 cm . Anal. Calcd for C12
8.25; H, 0.99; N, 5.49. Found: C, 28.30; H, 1.00; N, 5.30.
General Procedure for the Hydrazinolysis of 3-Benzoyl-5-
5 2 3
H N O F15: C,
19
4
°
0.6 Hz, Cq), 160.1 (Cq). F NMR (564.2 MHz, DMSO-d
6
2
C): δ -62.0. 15N NMR (60.8 MHz, DMSO-d
, 25 °C): δ 207.9,
6
2
2
50.6, 300.4. HRMS: calcd for C10
27.06654.
H F N , 227.06704; found,
8 3 3
perfluoroalkyl-1,2,4-oxadiazoles 15a-c and 3-Carboxyethyl-5-
perfluoroalkyl-1,2,4-oxadiazoles 23a-c with Hydrazine or
Methylhydrazine in DMF. To a mixture of the oxadiazole (1
mmol) in dry DMF (2 mL), hydrazine or methylhydrazine (3 mmol)
was added. After standing 1 h at rt, the mixture was diluted with
HCl 1 M and then extracted with EtOAc. The organic layer was
Methylation of 5-Heptafluoropropyl-3-phenyl-1,2,4-triazole
8
b. Chromatography of the residue gave 5-heptafluoropropyl-1-
methyl-3-phenyl-1,2,4-triazole 14b (72%) and 3-heptafluoropropyl-
-methyl-5-phenyl-1,2,4-triazole 9b (19%).
Compound 14b. mp 65-66 °C (from light petroleum). H NMR
599.7 MHz, DMSO-d , 25 °C): δ 4.12 (s, 3H), 7.47-7.53 (m,
1
1
2 4
dried over Na SO and evaporated.
(
3
6
H), 8.01 (m, 2H). 1 C NMR (150.8 MHz, DMSO-d
3
1
Reaction of 3-Benzoyl-5-trifluoromethyl-1,2,4-oxadiazole 15a
with Methylhydrazine. Chromatography of the residue gave
4-trifluoroacetylamino-2-methyl-5-phenyl-2H-1,2,3-triazole 22a:
6
, 25 °C H
1
2
decoupled): δ 37.9 (Me), 108.8 (tq, JC-F ) 266.4, JC-F ) 36.8
1
2
Hz, CF
2
), 110.5 (tt, JC-F ) 256.8, JC-F ) 32.6 Hz, CF
2
), 117.1
1
1
2
(64%) mp 109-111 °C (from H
2
O/EtOH). H NMR (DMSO-d
6
):
(
qt, JC-F ) 288.4, JC-F ) 33.4 Hz, CF
3
), 125.8 (2 CH), 128.9 (2
δ 4.28 (s, 3H), 7.44-7.57 (m, 3H), 7.72 (d, 2H, J ) 7.5 Hz), 11.83
CH), 129.0 (Cq), 130.0 (CH), 142.4 (t, JC-F ) 29.7 Hz, Cq), 160.7
Cq). 1 F NMR (564.2 MHz, DMSO-d
9
(s, 1H, exch. D O). ESI-MS m/z: 269 (M - 1, 100%, negative
2
(
6
, 25 °C): δ -126.0 (bs,
+
15
mode). 293 (M + Na , 100%, positive mode). IR (Nujol): 3240,
2
F), -110.7 (q, 2F, J ) 8.2 Hz), -79.6 (t, 3F, J ) 8.2 Hz).
, 25 °C): δ 210.6, 253.1, 302.0.
, 327.06066; found, 327.06014.
N
-
1
1
9 4 3
716 cm . Anal. Calcd for C11H N OF : C, 48.89; H, 3.36; N,
NMR (60.8 MHz, DMSO-d
8 7 3
HRMS: calcd for C12H F N
6
20.73. Found: C, 48.70; H, 3.30; N, 21.70.
Methylation of 5-Pentadecafluoroheptyl-3-phenyl-1,2,4-tri-
Reaction of 3-Benzoyl-5-heptafluoropropyl-1,2,4-oxadiazole
azole 8c. Chromatography of the residue gave 1-methyl-3-phenyl-
15b with Methylhydrazine. Chromatography of the residue gave
5
-pentadecafluoroheptyl-1,2,4-triazole 14c (72%) and 1-methyl-3-
4-heptafluorobutanoylamino-2-methyl-5-phenyl-2H-1,2,3-triazole
10
1
pentadecafluoroheptyl-5-phenyl-1,2,4-triazole 9c (25%).
22b: (75%) mp 104-105 °C (from H
6
2
O/EtOH). H NMR (DMSO-
): δ 4.27 (s, 3H), 7.51-7.57 (m, 3H), 7.68 (d, 2H, J ) 7.5 Hz),
1
Compound 9c. H NMR (599.7 MHz, DMSO-d
6
, 25 °C): δ
d
13
4
.03 (s, 3H), 7.51-7.58 (m, 3H), 7.78 (m, 2H). C NMR (150.8
11.85 (s, 1H, exch. D O); ESI-MS m/z 369 (M-1, 100%, negative
2
1
+
MHz, DMSO-d
1
Hz, Cq), 156.0 (Cq). C NMR (150.8 MHz, DMSO-d
6
, 25 °C H decoupled): δ 37.8 (Me), 126.2 (Cq),
mode); 393 (M+Na , 100%, positive mode). IR (Nujol): 3275,
1
-
28.6 (2 CH), 128.8 (2 CH), 130.7 (CH), 150.4 (t, JC-F ) 28.5
9 4 7
1717 cm . Anal. Calcd for C13H N OF : C, 42.17; H, 2.45; N,
13
19
6
, 25 °C
F
15.13. Found: C, 42.10; H, 2.50; N, 15.10.
decoupled): δ 108.5, 110.4, 110.9 (2 signals), 111.3, 112.1, 117.2
Reaction of 3-Benzoyl-5-pentadecafluoroheptyl-1,2,4-oxadi-
azole 15c with Methylhydrazine. Chromatography of the residue
gave 2-methyl-4-pentadecafluorooctanoylamino-5-phenyl-2H-1,2,3-
19
(CF
3
). F NMR (564.2 MHz, DMSO-d
6
, 25 °C): δ -126.9,
1
5
-
123.5, -122.8 (2 signals), -122.2, -112.1, -81.7 (CF
NMR (60.8 MHz, DMSO-d
HRMS: calcd for C16
Compound 14c. mp 65-67 °C (from light petroleum). H NMR
599.7 MHz, DMSO-d
H), 8.00 (m, 2H). C NMR (150.8 MHz, DMSO-d
3
).
N
, 25 °C): δ 208.5, 251.7, 305.5.
, 527.04790; found, 527.04788.
1
6
triazole 22c: (97%) mp 86-88 °C (from H
DMSO-d ): δ 4.27 (s, 3H), 7.59 (q, 3H, J ) 7.5 Hz), 7.67 (d, 2H,
J ) 7.5 Hz), 11.84 (s, 1H, exch. D O). ESI-MS m/z: 569 (M - 1,
2
O/EtOH). H NMR
H
F
8 15
N
3
(
6
1
2
(
3
6
, 50 °C): δ 4.11 (s, 3H), 7.47-7.52 (m,
+
1
00%, negative mode), 593 (M+Na , 100%, positive mode). IR
13
1
, 50 °C H
-1
6
9 4
(Nujol): 3283, 1713 cm . Anal. Calcd for C17H N OF15: C, 35.81;
decoupled): δ 37.8 (Me), 125.7 (2 CH), 128.7 (2 CH), 129.0 (Cq),
H, 1.59; N, 9.82. Found: C, 35.80; H, 1.50; N, 10.00.
Reaction of 3-Carboxyethyl-5-trifluoromethyl-1,2,4-oxadi-
azole 23a with Hydrazine. Chromatography of the residue gave
1
3
1
29.8 (CH), 142.4 (t, JC-F ) 29.9 Hz, Cq), 160.4 (Cq). C NMR
(150.8 MHz, DMSO-d
6
, 50 °C 19F decoupled): δ 107.7, 109.6,
10.1, 110.2, 110.5, 111.0, 116.4 (CF ). F NMR (564.2 MHz,
3
19
1
1
H-5-Hydroxylamino-3-trifluoromethyl-1,2,4-triazin-6-one 27a: (97%)
DMSO-d
119.7, -80.7 (CF
07.9, 250.6, 300.4. HRMS calcd for C16
found, 527.04756.
6
, 50 °C): δ -126.0, -122.7, -122.0, -121.4, -121.3,
1
mp 202-203 °C (from H
s, 1H, exch. D O), 11.72 (s, 1H, exch. D
O). IR (Nujol): 3404, 3354, 3213, 1683, 1647 cm . HRMS:
calcd for C , 196.02082; found, 196.02122.
2
O/EtOH). H NMR (DMSO-d
6
): δ 10.07
15
-
2
3
). N NMR (60.8 MHz, DMSO-d
6
, 50 °C): δ
(
D
2
2
O), 12.94 (s, 1H, exch.
8 15 3
H F N , 527.04790;
-
1
2
4
3 4 2 3
H N O F
General Procedure for the Synthesis of 3-Carboxyethyl-5-
perfluoroalkyl-1,2,4-oxadiazoles 23a-c. A mixture of carboxy-
ethyl amidoxime (1.32 g; 10 mmol) in pyridine (30 mL) and the
appropriate polyfluoroalkyl chloride (22 mmol) was stirred for 8 h
at room temperature. After removal of the solvent, the residue was
Reaction of 3-Carboxyethyl-5-heptafluoropropyl-1,2,4-oxa-
diazole 23b with Hydrazine. Chromatography of the residue gave
1
H-5-hydroxylamino-3-heptafluoropropyl-1,2,4-triazin-6-one 27b:
1
(
95%) mp 219-220 °C (from H
2
O/EtOH). H NMR (DMSO-d
6
):
δ 9.95 (s, 1H, exch. D
exch. D
2
O), 11.88 (s, 1H, exch. D O), 13.11 (s, 1H,
2
treated with water and then extracted with Et
was dried over Na SO and evaporated. Chromatography of the
residue gave the oxadiazoles 23a-c.
-Carboxyethyl-5-trifluoromethyl-1,2,4-oxadiazole 23a. Yield
2
O. The organic layer
-1
2
O). IR (Nujol): 3311, 3109, 3061, 1672, 1661, 1599 cm
, 296.01444; found, 296.01495.
.
2
4
6 3 4 2 7
HRMS: calcd for C H N O F
3
Reaction of 3-Carboxyethyl-5-pentadecafluoroheptyl-1,2,4-
oxadiazole 23c with Hydrazine. Chromatography of the residue
1
8
4
4%; colorless oil. H NMR (CDCl
3
): δ 1.46 (t, 3H, J ) 7.5 Hz),
+
.54 (q, 2H, J ) 7.5 Hz). GC-MS m/z: 211 (M + 1, 100), 183
gave 1H-5-hydroxylamino-3-pentadecafluoroheptyl-1,2,4-triazin-6-
-
1
1
(
C
2
15), 100 (12), 70 (35). IR (Nujol): 1763 cm . Anal. Calcd for
: C, 34.30; H, 2.40; N, 13.33. Found: C, 34.50; H,
.30; N, 13.20.
-Carboxyethyl-5-hepthafluoropropyl-1,2,4-oxadiazole 23b.
one 27c: (90%) mp 221-222 °C (from H
MHz, DMSO-d
(bs,1H). 13C NMR (150.8 MHz, DMSO-d
δ 141.5 (bs, Cq), 149.6 (bs, Cq), 153.2 (bs, Cq). C NMR (150.8
2
O/EtOH). H NMR (599.7
6
H
5
N
2
O F
3 3
6
, 25 °C): δ 9.89 (bs, 1H), 11.83 (bs, 1H), 13.03
1
6
, 25 °C, H decoupled):
13
3
1
19
Yield 65%; colorless oil. H NMR (CDCl
7
1
3
): δ 1.48 (t, 3H, J )
MHz DMSO-d
111.1 (2 signals), 111.9, 117.1 (CF
DMSO-d , 25 °C): δ -126.2, -122.9, -122.2. -121.7, -121.6,
6
, 25 °C, F decoupled): δ 108.3, 110.2, 110.8,
.0 Hz), 4.57 (q, 2H, J ) 7.0 Hz). GC-MS m/z: 311 (M+ + 1,
19
3
). F NMR (564.2 MHz,
00), 283 (11), 265 (59), 100 (8), 70 (28). IR (Nujol): 1763 cm-1
.
6
8112 J. Org. Chem., Vol. 71, No. 21, 2006

Ring-Rearrangements in Reactions of Oxadiazoles
). IR (Nujol): 3319, 3138, 3061, 1672, 1661,
-
114.0, -80.7 (CF
3
2.2 mmol) was added, and the stirring continued for 24 h at rt.
After removal of the solvent at reduced pressure, the residue was
treated with water and extracted with EtOAc. The organic layer
-
1
1599 cm . HRMS: calcd for C10
96.00171.
3 4 2
H N O F15, 496.00167; found,
4
Reaction of 3-Carboxyethyl-5-trifluoromethyl-1,2,4-oxadi-
2 4
was dried over Na SO and evaporated. Crystallization of the
azole 23a with Methylhydrazine. Chromatography of the residue
residue from EtOH/water gave O,N-dibenzoyl-5-hydroxylamino-
gave 1-N-methyl-5-hydroxylamino-3-trifluoromethyl-1,2,4-triazin-
3-heptafluoropropyl-1,2,4-triazin-6-one (30): (91%) mp 185-186
1
1
6
-one 28a: (81%) mp 185-186 °C (from H
2
O/EtOH). H NMR
°C (from H
2
O/EtOH). H NMR (599.7 MHz, DMSO-d
6
, 25 °C):
(DMSO-d
6
): δ 3.57 (s, 3H), 10.02 (s, 1H, exch. D
2
O), 11.91 (s,
O). IR (Nujol): 3213, 3088, 1674, 1631 cm-1
, 210.03647; found, 210.03640.
δ 7.52 (t, 2H, J ) 7.6 Hz), 7.59 (t, 2H, J ) 7.7 Hz), 7.64 (t, 1H,
1H, exch. D
2
.
J ) 7.6 Hz), 7.71 (t, 1H, J ) 7.7 Hz), 7.88 (t, 2H, J ) 7.6 Hz),
13
HRMS: calcd for C
H
5 5
N
4
O F
2 3
8.02 (t, 2H, J ) 7.7 Hz), 14.40 (bs, 1H). C NMR (150.8 MHz,
1 1 2
Reaction of 3-Carboxyethyl-5-heptafluoropropyl-1,2,4-oxa-
diazole 23b with Methylhydrazine. Chromatography of the residue
DMSO-d
) 36.8 and 32.3 Hz, CF ), 110.2 (tt, JC-F ) 258.2, JC-F ) 32.3
2
6
, 25 °C, H decoupled): δ 107.9 (ttq, JC-F)269.8, JC-F
1 2
2
1
gave 1-N-methyl-5-hydroxylamino-3-heptafluoropropyl-1,2,4-tri-
Hz, CF
2
3
), 117.1 (qt, JC-F ) 292.8, JC-F ) 36.8 Hz, CF ), 125.1
1
azin-6-one 28b: (96%), mp 99-100 °C (from H
DMSO-d ): δ 3.60 (s, 3H), 10.01 (s, 1H, exch. D
H, exch. D O). IR (Nujol) 3234, 3188, 1654, 1637, 1605 cm
HRMS: calcd for C , 310.03008; found, 310.03028.
2
O/EtOH). H NMR
(Cq), 128.9 (2CH), 129.0 (2CH), 129.2 (2CH), 129.8 (2CH), 131.5
2
(
1
6
2
O), 11.93 (s,
(Cq), 133.7 (CH), 135.1 (CH), 137.3 (t, JC-F ) 26.1 Hz, Cq),
-
1
19
2
.
149.1 (Cq), 156.1 (Cq), 163.6 (CO), 166.9 (CO). F NMR (564.2
1
5
H
7 5
N
4
O F
2 7
MHz, DMSO-d
NMR (60.8 MHz, DMSO-d
IR (Nujol): 3172, 3070, 1770, 1738, 1693 cm . HRMS: calcd
for C20 , 504.06685; found, 504.06673.
6
, 25 °C): δ -126.9, -115.7, -80.6 (CF
3
).
N
Reaction of 3-Carboxyethyl-5-pentadecafluoroheptyl-1,2,4-
oxadiazole 23c with Methylhydrazine. Chromatography of the
residue gave 1-N-methyl-5-hydroxylamino-3-pentadecafluoroheptyl-
6
, 25 °C): δ 187.8, 207.7, 263.2, 305.3.
-
1
11 7 4 4
H F N O
1
,2,4-triazin-6-one 28c: (94%), mp 140-141 °C (from H
2
O/EtOH).
IR (Nujol): 3396, 3265, 1693, 1657, 1637 cm . H NMR (599.7
MHz, DMSO-d , 25 °C): δ 3.55 (s, 3H), 9.95 (bs, 1H), 11.85 (bs,
-
1 1
Acknowledgment. Financial support from the Italian MIUR
and the Universities of Palermo, Siena, and Bologna are
gratefully acknowledged.
6
H). 13C NMR (150.8 MHz, DMSO-d
1
1
3
6
, 25 °C, H decoupled): δ
8.2 (Me), 140.4 (t, JC-F ) 25.0 Hz, Cq), 148.2 (Cq), 152.0 (Cq).
13
19
C NMR (150.8 MHz, DMSO-d
09.7, 110.3, 110.6, 110.7, 111.4, 116.6 (CF
, 25 °C): δ -126.1, -122.7, -122.0. -121.4,
6
, 25 °C, F decoupled): δ 107.9,
Supporting Information Available: General experimental
19
1
3
). F NMR (564.2
details; crystallographic data, and ORTEP drawings of compounds
MHz, DMSO-d
121.1, -113.8, -80.7 (CF
5 °C): δ 159.6, 185.4, 205.1, 275.2. HRMS: calcd for
15, 510.01732; found, 510.01729.
Benzoylation of the 1H-5-Hydroxylamino-3-heptafluoropro-
6
1
13
9
1
2
c, 28c, and 30; H C g-HMBC spectra for compounds 9a and
4a; geometry comparison between the X-ray derived structure of
8c and 30; the calculated structure of 28a; and ab initio optimized
15
-
2
3 6
). N NMR (60.8 MHz, DMSO-d ,
11 5 4 2
C H N O F
geometry and GIAO chemical shift calculations for the three
tautomers of 28a. This material is available free of charge via the
Internet at http://pubs.acs.org.
pyl-1,2,4-triazin-6-one 27b. To a mixture of 27b (296 mg, 1 mmol)
in benzene (20 mL), pyridine (0.1 mL) was added under stirring at
room temperature. After dissolution, benzoyl chloride (0.255 mL,
JO061251E
J. Org. Chem, Vol. 71, No. 21, 2006 8113