Synthesis of trifluoromethylated 2-benzoyl- and 2-aminoimidazoles from ring rearrangement of 1,2,4-oxadiazole derivatives

Article abstract of DOI:10.1016/j.tet.2008.02.047

Fluoroalkylated 2-ylamino-imidazoles have been synthesized by reaction of 3-amino-5-phenyl-1,2,4-oxadiazole with fluorinated β-dicarbonyl compounds and subsequent base-induced Boulton-Katritzky Rearrangement (BKR) of the isolated β-enaminocarbonyl interme

Full text of DOI:10.1016/j.tet.2008.02.047

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4004e4010
www.elsevier.com/locate/tet
Synthesis of trifluoromethylated 2-benzoyl- and 2-aminoimidazoles
from ring rearrangement of 1,2,4-oxadiazole derivatives
Antonio Palumbo Piccionello a, Andrea Pace a, Silvestre Buscemi a,
*
,
a
Nicolo Vivona , Marcella Pani
b
`
a Dipartimento di Chimica Organica ‘E. Paterno`’, Universita` degli Studi di Palermo, Viale delle Scienze, Parco d’Orleans II, I-90128 Palermo, Italy
b Dipartimento di Chimica e Chimica industriale, Universita` di Genova, Via Dodecaneso 31, I-16146 Genova, Italy
Received 8 November 2007; received in revised form 25 January 2008; accepted 14 February 2008
Available online 6 March 2008
Abstract
Fluoroalkylated 2-ylamino-imidazoles have been synthesized by reaction of 3-amino-5-phenyl-1,2,4-oxadiazole with fluorinated b-dicar-
bonyl compounds and subsequent base-induced BoultoneKatritzky Rearrangement (BKR) of the isolated b-enaminocarbonyl intermediate.
Alternatively, one-pot reactions performed in the presence of Montmorillonite K10 favoured the condensation at the 3-amino moiety of the
oxadiazole and, in some cases, allowed the direct synthesis of 2-benzoylamino-imidazoles. Hydrolysis of 2-benzoylamino-imidazoles easily
yielded fluorinated 2-amino-imidazoles targets.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: 1,2,4-Oxadiazole; Montmorillonite; Imidazoles; b-Dicarbonyls; b-Enaminoketones; Crystal structure
1. Introduction
[containing a tertiary amino moiety on the C(2) of the fluori-
nated imidazole nucleus], which have been recently reported
as corticotropin-releasing factor 1 receptor (CRF1R) antago-
nists for the treatment of depression, anxiety and stress-related
disorders.8
The imidazole ring plays a critical role in many aspects of
biological structure and function. For example, the imidazole
ring of the aminoacid histidine is often found in the active cata-
lytic site of enzymes. Considering the important function of
this heterocycle, it is not surprising that many ring-fluorinated
imidazoles possess quite interesting biological properties.1
Moreover, perfluoroalkylated imidazoles have been used as
19F NMR spectroscopic probes for biomimetic studies2 and
intracellular pH determinations,3 ionic liquids4 and lightfast
optical recording media.5 In turn, 2-amino-imidazole moieties
are present in several biologically active marine alkaloids6 and
this prompted research into efficient and general methodol-
ogies for the synthesis of these target molecules.7
We therefore decided to synthesize a series of trifluorome-
thylated imidazole derivatives by following the Ring-Rear-
rangement Approach, which takes advantage of the thermal
and photochemical reactivities of suitable heterocyclic syn-
thons and is a very versatile approach to fluorinated heterocy-
cles.9 In this context, it is worth remarking that the presence of
a fluorinated moiety [either as a fluorine atom, as a per(poly)-
fluoroalkyl or as a per(poly)fluoroaryl group] can strongly af-
fect such reactivity or the outcome of the reaction with respect
to the results obtained with non-fluorinated analogues.9 In the
last decade, we have been revisiting several reactions of the
1,2,4-oxadiazole, a heterocycle, which is very likely to un-
dergo ring rearrangement into the more stable heterocycles,
with the aim of synthesizing fluorinated heterocyclic targets.9
An interesting example of the reactivity of 1,2,4-oxadiazoles is
afforded by N-(1,2,4-oxadiazol-3-yl)-b-enaminoketones 1. For
these systems, two different rearrangements have been shown
Nevertheless, despite their potential interest as bioactive
molecules, to the best of our knowledge, no fluoroalkylated
2-aminoimidazole has been ever reported. The only example
regards trifluoromethylated imidazo[1,2-a]benzimidazoles
* Corresponding author. Fax: þ39 091 596825.
E-mail address: sbuscemi@unipa.it (S. Buscemi).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.047

A. Palumbo Piccionello et al. / Tetrahedron 64 (2008) 4004e4010
4005
as a function of the experimental conditions (Scheme 1): (i) in
acidic media, a four-atom side-chain rearrangement yields
2-amino-pyrimidine-N-oxides 4 through a bicyclic cation
intermediate 2;10a,b (ii) in the presence of a base, a three-atom
side-chain rearrangement is observed, yielding the correspond-
ing 2-(N-acylamino)imidazoles 310c,d in accordance with the
general scheme of the BoultoneKatritzky Rearrangement
(BKR).11,12 Subsequent hydrolysis of compounds 3 gives
access to 2-amino-imidazoles 5.
involving the CH3CO carbonyl, according to a previous
report.13
Attempting to improve the yields of 11b, the reaction was
performed at 100 ꢀC in toluene/Mont-K10 in a sealed tube
for 6 h. Under these conditions, compound 11b was obtained
in 25% yield (with 73% of recovered starting compound 6);
however, prolonged heating lowered the yield and led to the
formation of decomposition products.
These conditions were then adopted as a general procedure
for the reaction of amine 6 with fluorinated 1,3-dicarbonyl
compounds 7aed, as well as for a comparison with the non-
fluorinated diketone 7e. Interestingly, for the reactions of 6
with compounds 7a,c, besides the expected b-enaminocarb-
onyl compounds 12a and 11c, were also isolated 4(5)-tri-
fluoromethyl-2-(N-benzoylamino)-imidazoles 16a,c while in
the reaction with diketone 7d, only the imidazole 16d was ob-
tained (see Table 1). In order to assess the role of the fluori-
nated group on the observed reactivity, reaction of amine 6
with the non-fluorinated symmetric diketone 7e was per-
formed, resulting in the formation of enaminoketone 11e
(43%) together with the corresponding imidazole 16e (15%).
It is important to remark that the regiochemistry of the re-
action of amino compound 6 with unsymmetrical diketones
might depend on several factors such as: (i) the ketoeenolic
equilibrium of the diketonic reagent,15 (ii) the electrophilic
character of the two carbonyls on the diketone and (iii) the sta-
bility of the carbinolamine intermediate in either its keto (8 or
9) or its enol (10 or 13) form.16 These factors, together with
the presence of trifluoromethyl groups and a possible involve-
ment of the heterogeneous catalyst used, play an important
role in driving the reaction either towards the formation of
the enaminoketones (11 or 12) or towards the acylimidazole
(16 or 17). In the latter case, this reaction represents the first
example of an acid catalyzed BoultoneKatritzky rearrange-
ment (BKR) involving an NCC side chain. In order to assess
whether the imidazoles originate directly from a BKR of the
corresponding enaminoketone precursors, a separate experi-
ment has been conducted by reacting compounds 11c,e and
12a in refluxing toluene in the presence of Montmorillonite
K10. In all the cases, ready hydrolysis to amine 6 was ob-
served; moreover, in the case of 11c, only a small amount of
the corresponding imidazole 16c (15%) was isolated; interest-
ingly, in the reaction of 12a both imidazole regioisomers 16a
(20%) and 17a (5%) were formed. These results (the lower
yields in imidazole with respect to the one-pot reaction and
the formation of the two regioisomers 16a and 17a) clearly
rule out any role of the enaminoketone as a reaction interme-
diate in the reaction with Mont-K10.
R1
H
N
N
N
R2
Base
O
R
O
R
O
1
H+
R1
R1
N
N
R2
N
O
R
N
H
N
H
N
O
R2
H+
2
3
H+
H2O
H2O
N
R1
N
R1
H2N
O
R2
N
H2N
N
H
5
O
R2
4
Scheme 1.
In a recent paper,13 we have reported on the reactivity of
3-amino-5-methyl-1,2,4-oxadiazole with trifluoromethylated
diketones under acidic conditions, leading to fluorinated 2-
amino-pyrimidine N-oxides and 2-hydroxyaminopyrimidines.
In this paper, we report the reaction of 3-amino-5-phenyl-1,2,4-
oxadiazole 6 with some trifluoromethylated 1,3-dicarbonyl
compounds and the base-induced BKR of some trifluoromethyl-
ated N-(1,2,4-oxadiazol-3-yl)-b-enaminoketones as an attrac-
tive synthetic strategy for the synthesis of trifluoromethylated
2-N-benzoylamino- and 2-amino-imidazole derivatives.
2. Results and discussion
The reaction of 3-amino-1,2,4-oxadiazole 6 with trifluoro-
methylated 1,3-diketones 7a,b was initially performed in re-
fluxing toluene in the presence of p-toluenesulfonic acid
following the conventional procedure used for the synthesis
of non-fluorinated 1,2,4-oxadiazol-3-yl-enaminoketones.13
However, under these conditions, the substrate remained es-
sentially unchanged; moreover, due to the volatility of 7a,b
loss of the diketone in the DeaneStark apparatus was experi-
enced. The reaction was then performed at rt, in petroleum
ether and in the presence of Montmorillonite K10 (Mont-
K10) as an heterogeneous acid catalyst.14 Under these condi-
tions, enaminoketone 12a (80%) was obtained in good yields
from 7a (Scheme 2), while only a small amount of enamino-
ketone 11b (5%) was obtained from reaction with 7b. The
structure of compound 12a was confirmed by X-ray data
(see Fig. 1) and is in agreement with a condensation reaction
An intriguing mechanistic hypothesis considers the Mont-
morillonite activation of the oxadiazole ring towards the nu-
cleophilic attack by the enol moiety of the side chain. Thus
the carbinolamine intermediate 10 (or 13) undergoes an acid
catalyzed BKR into imidazoline 14 (or 15), which can be
easily dehydrated to the corresponding aromatic imidazole
16 (or 17).
In their turn, the b-enaminocarbonyl compounds 11b,c and
12a were refluxed in DMF and in the presence of an excess of

4006
A. Palumbo Piccionello et al. / Tetrahedron 64 (2008) 4004e4010
R
NH2
R
R'
CH3
CF3
OEt
Ph
CH3
O
N
a
b
c
CF3
CF3
CF3
CF3
CH3
N
Ph
O
O
6
R'
7a-e
d
e
Mont-K10
Ph
R' OH
HN
R
OH
O
R
HN
O
N
N
R'
N
N
Ph
O
O
8
9
- H2O + H2O
R'
- H2O + H2O
R
R' OH
HN
R
OH
OH
R
R'
N
O
+ H2O
- H2O
HN
OH
R'
+ H2O
- H2O
R
N
O
N
H
N
N
H
N
Ph
N
O
N
Ph
N
O
Ph
N
O
Ph
Δ
10
Δ
O
11b,c,e
13
12a
HO
N
R'
HO
N
O
R
O
R
Ph
R'
N
H
Ph
N
H
15
N
H
N
H
O
O
14
-H2O
R'
-H2O
R
O
N
O
N
R
Ph
R'
N
H
Ph
N
H
N
H
N
H
16a-e
O
O
17a
Scheme 2.
t-BuOK to obtain the corresponding 2-(N-benzoylamino)-im-
idazoles 16b,c, and 17a (Scheme 3). It is worth noting that
this rearrangement allows one to complete the series of
imidazole targets considering that imidazoles 16b and 17a
were not obtained through the Mont-K10 catalyzed one-pot
reaction.
The regio-chemical issue for compounds 16a,d and 17a
1
was unambiguously resolved by means of H NMR spectro-
scopic determination of their reduction products 18aec,
respectively (Scheme 4).
Table 1
Product distribution for Montmorillonite K10 catalyzed reaction of oxadiazole
6 with 1,3-dicarbonyls 7aee in toluene at 100 ꢀC
Reagent Reaction Recovered Yield of Yield of Yield of Yield of
17 (%)
time (h) 6 (%)
11 (%)
12 (%)
16 (%)
7a
7b
7c
7d
7e
a
24
6
5
73
16
36
10
d
25
57
d
43
44
a
29
d
27
23
15
d
a
24
72
8
d
d
d
d
a
a
For reaction with a symmetrical diketone, product 12 is identical to 11 and
product 16 is identical to 17.
Finally, all the obtained fluorinated 2-benzoylamino-imid-
azoles 16aed and 17a were easily hydrolyzed, under
acidic conditions, to the corresponding trifluoromethylated
2-amino-imidazoles 19aee (Scheme 5), whose structure was
confirmed by spectroscopic (IR, 1H NMR, HRMS) and
X-ray (for representative 19d, see Fig. 2) data.
3. Conclusions
The synthesis of a series of trifluoromethylated 2-benzoyl-
amino-imidazoles, hydrolyzed into their corresponding
Figure 1. ORTEP drawing of compound 12a.

A. Palumbo Piccionello et al. / Tetrahedron 64 (2008) 4004e4010
4007
CF3
O
the isolation of imidazoles 16a,d, whose enaminoketone pre-
cursors 11a,d were not accessible.
H3C
N
CH3
O
O
H
N
N
CF3
t-BuOK
DMF / Δ
N
H
N
H
N
4. Experimental
O
12a
17a (75 %)
4.1. General methods and materials
R'
Melting points were determined on a REICHART-THER-
MOVAR hot-stage apparatus. FTIR spectra (Nujol) were de-
termined with a SHIMADZU FTIR-8300 instrument; 1H
NMR spectra were recorded on a BRUKER 300 Avance spec-
trometer and were taken with TMS as an internal standard.
Flash chromatography was performed by using silica gel
(Merck, 0.040e0.063 mesh) and mixtures of light petroleum
(fraction boiling in the range of 40e60 ꢀC) and ethyl acetate
in varying ratios. Compound 617 was prepared as reported pre-
viously. Montmorillonite K10 was purchased and used without
further treatment. For X-ray analysis details, see Supplemen-
tary data.
R
N
O
H
R
N
O
N
R'
t-BuOK
DMF / Δ
N
H
N
H
N
O
O
11b,c
b: R=R' = CF3
c: R= CF3; R' = OEt
16b (69 %)
16c (51 %)
Scheme 3.
R
O
N
NaBH4
THF/ Δ
R'
16a,d,17a
Ph
N
H
N
H
OH
18a-c
a: R = CF3; R'= CH3 (50%)
b: R = CF3; R'= C6H5 (72%)
c: R = CH3; R'= CF3 (51%)
4.2. Reaction of 3-amino-5-phenyl-1,2,4-oxadiazole 6 with
fluorinated b-dicarbonylic compounds 7aee: general
procedure
Scheme 4.
Montmorillonite K10 (2 g) was suspended in a stirred solu-
tion of 6 (1.5 mmol) in AcOEt. The solvent was eliminated un-
der reduced pressure and the residue suspended in petroleum
ether or toluene (10 mL), and was added the appropriate b-
dicarbonylic compound 7 (3 mmol). The obtained suspension
was allowed to stir at rt using petroleum ether or 100 ꢀC with
toluene. The suspension was then filtered and the solid washed
with AcOEt several times. The filtrate was dried over Na2SO4
and evaporated.
R
a: R = CF3; R'= CH3 (90%)
N
b: R = R'= CF3
(86%)
R'
HCl
EtOH / Δ
c: R = CF3; R'= OEt (50%)
d: R = CF3; R'= C6H5 (75%)
e: R = CH3; R'= CF3 (88%)
16a-d, 17a
H2N
N
O
H
19a-e
Scheme 5.
2-amino derivatives, was achieved through BoultoneKatritzky
rearrangements of 1,2,4-oxadiazoles bearing an NCC side
chain. Besides the classic base-promoted BKR of b-enamino-
carbonyl compounds in their anionic form, an acid-catalyzed
BKR has been pointed out, likely involving the enolic form
of a carbinolamine intermediate and a Montmorilloniteeoxa-
diazole complex. In some cases these appear to be two com-
plementary synthetic approaches. For instance, one-pot
reactions with the appropriate 1,3-dicarbonyl reagent allowed
4.2.1. Reaction of 3-amino-5-phenyl-1,2,4-oxadiazole 6
with 1,1,1-trifluoro-2,4-pentanedione 7a
4.2.1.1. Petroleum ether, rt. Chromatography of the residue
gave 12a (79%) and recovered 6 (20%). 1,1,1-Trifluoro-N-
(50-phenyl-1,2,4-oxadiazol-3-yl)-4-amino-pent-3-en-2-one 12a
had mp 127e128 ꢀC (white crystals, from ethanol). FTIR (Nu-
1
jol) n: 1635 cmꢁ1. H NMR (CDCl3) d: 2.59 (s, 3H), 5.73 (s,
1H), 7.51e7.67 (m, 3H), 8.09e8.14 (m, 2H), 12.45 (s, 1H,
exch. with D2O). HRMS found: 297.0725; C13H10F3N3O2
requires: 297.0725.
4.2.1.2. Toluene, 100 ꢀC. Chromatography of the residue gave
12a (44%), 16a (29%) and recovered 6 (5%). 2-N-Benzoyl-
amino-4(5)-trifluoromethyl-5(4)-acetyl-imidazole 16a had mp
249e251 ꢀC (white crystals, from EtOAc). FTIR (Nujol) n:
1
3389, 3293, 1667, 1638 cmꢁ1. H NMR (DMSO-d6) d: 2.57
(s, 3H), 7.49e7.71 (m, 3H), 8.08e8.12 (m, 2H), 12.10 (br s,
1H, exch. with D2O), 12.68 (br s, 1H, exch. with D2O).
HRMS found: 297.0724; C13H10F3N3O2 requires: 297.0725.
Figure 2. ORTEP drawing of compound 19d.

4008
A. Palumbo Piccionello et al. / Tetrahedron 64 (2008) 4004e4010
4.2.2. Reaction of 3-amino-5-phenyl-1,2,4-oxadiazole 6
with 1,1,1,5,5,5-hexafluoro-2,4-pentanedione 7b
EtOAc. The organic layer was dried over Na2SO4 and
evaporated.
4.2.2.1. Petroleum ether, rt. Chromatography of the residue
gave 11b (5%) and recovered 6 (94%). 1,1,1,5,5,5-Hexa-
fluoro-N-(50-phenyl-1,2,4-oxadiazol-3-yl)-4-amino-pent-3-en-2-
one 11b had mp 80e82 ꢀC (white crystals, from petroleum
4.3.1. Rearrangement of 1,1,1,5,5,5-hexafluoro-N-
(50-phenyl-1,2,4-oxadiazol-3-yl)-4-amino-pent-3-en-
2-one 11b
Chromatography of the residue gave recovered 11b (6%),
16b (69%) and 6 (15%). 2-N-Benzoylamino-4(5)-trifluoro-
methyl-5(4)-trifluoroacetyl-imidazole 16b had mp 41e3 ꢀC
(white crystals, from petroleum ether). FTIR (Nujol) n:
1
ether). FTIR (Nujol) n: 1674 cmꢁ1. H NMR (CDCl3) d: 6.33
(s, 1H), 7.53e7.70 (m, 3H), 8.11e8.15 (m, 2H), 11.73 (s,
1H, exch. with D2O). HRMS found: 351.0444; C13H7F6N3O2
requires: 351.0443.
1
3441, 3413, 1680 cmꢁ1. H NMR (DMSO-d6) d: 7.57e7.70
(m, 3H), 8.10e8.12 (m, 2H), 8.31 (s, 2H, exch. with D2O, hy-
drated form), 11.85 (s, 1H, exch. with D2O), 11.97 (s, 1H,
exch. with D2O). HRMS found: 351.0448; C13H7F6N3O2
requires: 351.0443.
4.2.2.2. Toluene, 100 ꢀC. Chromatography of the residue gave
11b (25%) and recovered 6 (73%).
4.2.3. Reaction of 3-amino-5-phenyl-1,2,4-oxadiazole 6
with ethyl 4,4,4-trifluoroacetoacetate 7c
4.3.2. Rearrangement of 4,4,4-trifluoro-N-(50-phenyl-1,2,
4-oxadiazol-3-yl)-3-amino-but-2-enoic acid ethyl ester 11c
Chromatography of the residue gave 16c (51%) and 6
(12%).
Chromatography of the residue gave 11c (57%), 16c (27%)
and recovered 6 (16%). 4,4,4-Trifluoro-N-(50-phenyl-1,2,4-ox-
adiazol-3-yl)-3-amino-but-2-enoic acid ethyl ester 11c had
mp 88e90 ꢀC (white crystals, from petroleum ether). FTIR
1
(Nujol) n: 1676 cmꢁ1. H NMR (DMSO-d6) d: 1.08 (t, 3H,
4.3.3. Rearrangement of 1,1,1-trifluoro-N-(50-phenyl-1,2,4-
oxadiazol-3-yl)-4-amino-pent-3-en-2-one 12a
Chromatography of the residue gave 17a (75%) and recov-
ered 12a (9%). 2-N-Benzoylamino-4(5)-methyl-5(4)-trifluoro-
acetyl-imidazole 17a had mp 88e90 ꢀC (white crystals, from
ethanol/water). FTIR (Nujol) n: 3303, 1694, 1680 cmꢁ1. H
J¼8.5 Hz), 3.98 (q, 2H, J¼8.5 Hz), 6.13 (s, 1H), 7.65e7.80
(m, 3H), 8.05e8.14 (m, 2H), 10.43 (s, 1H, exch. with D2O).
HRMS found: 327.0831; C14H12F3N3O3 requires: 327.0831.
2-N-Benzoylamino-4(5)-trifluoromethyl-5(4)-carboxyethyl-im-
idazole 16c had mp 203e5 ꢀC (white crystals, from ethanol).
FTIR (Nujol) n: 3377, 3317, 1694, 1664 cmꢁ1 1H NMR
.
1
(CDCl3) d: 1.40 (t, 3H, J¼8.5 Hz), 4.41 (q, 2H, J¼8.5 Hz),
7.51e7.69 (m, 3H), 7.89e7.92 (m, 2H), 9.79 (s, 1H, exch.
with D2O), 11.56 (br s, 1H, exch. with D2O). HRMS found:
327.0831; C14H12F3N3O3 requires: 327.0831.
NMR (DMSO-d6) d: 2.64 (s, 3H), 7.55e7.71 (m, 3H), 8.11e
8.15 (m, 2H), 11.84 (s, 1H, exch. with D2O), 13.07 (s, 1H,
exch. with D2O). HRMS found: 297.0725; C13H10F3N3O2
requires: 297.0725.
4.2.4. Reaction of 3-amino-5-phenyl-1,2,4-oxadiazole 6
with 4,4,4-trifluoro-1-phenyl-1,3-butanedione 7d
Chromatography of the residue gave 16d (23%) and recov-
ered 6 (36%). 2-N-Benzoylamino-4(5)-trifluoromethyl-5(4)-
benzoyl-imidazole 16d had mp 165e167 ꢀC (white crystals,
from EtOAc). FTIR (Nujol) n: 3231, 1657, 1642 cmꢁ1. H
NMR (DMSO-d6) d: 7.54e7.73 (m, 6H), 7.81e7.89 (m,
2H), 8.07e8.09 (m, 2H), 12.09 (br s, 1H, exch. with D2O),
12.92 (br s, 1H, exch. with D2O). HRMS found: 359.0883;
C18H12F3N3O2 requires: 359.0882.
4.4. Reduction of 2-N-benzoylamino-5(4)-acyl-imidazoles
16a,d and 17a: general procedure
2-N-Benzoylamino-5(4)-acyl-imidazole (1 mmol) was
added to a solution of NaBH4 (2 mmol) in THF (10 mL).
The solution was refluxed for 2 h and then the solvent was
eliminated under reduced pressure. The residue was treated
with 1 M HCl (100 mL), refluxed for 30 min, neutralized
with NaOH and extracted with EtOAc. The combined organic
layers were dried over Na2SO4 and evaporated.
1
4.2.5. Reaction of 3-amino-5-phenyl-1,2,4-oxadiazole 6
with 2,4-pentanedione 7e
Chromatography of the residue gave 11e (43%, mp 112e
113 ꢀC, lit.10d 112 ꢀC), 16e (13%, mp 222e3 ꢀC, lit.10d 221 ꢀC)
and recovered 6 (10%).
4.4.1. Reduction of 2-N-benzoylamino-4(5)-trifluoromethyl-
5(4)-acetyl-imidazole 16a
Chromatography of the residue gave 18a (50%) and recov-
ered 16a (31%). 2-N-Benzoylamino-4(5)-trifluoromethyl-5(4)-
(1-hydroxyethyl)-imidazole 18a had mp 175e177 ꢀC (white
crystals, from EtOAc). FTIR (Nujol) n: 3371, 3276, 3245,
4.3. Rearrangement of N-(1,2,4-oxadiazol-3-yl)-
b-enaminocarbonyls 11b,c and 12a: general procedure
3165, 1665 cmꢁ1 1H NMR (DMSO-d6) d: 1.47 (d, 3H,
.
1
2
J¼6.6 Hz), 5.03 (dq, 1H, J¼6.6 Hz, J¼6 Hz), 6.43 (d, 1H,
J¼6 Hz, exch. with D2O), 7.57e7.71 (m, 3H), 8.10e8.12 (m,
2H), 11.78 (s, 1H, exch. with D2O), 12.06 (s, 1H, exch. with
D2O). HRMS found: 299.0883; C13H12F3N3O2 requires:
299.0882.
To a solution of b-enaminocarbonyls (1 mmol) in dry DMF
(2 mL), t-BuOK (1,2 mmol) was added and the solution re-
fluxed for 2 h. The mixture was diluted with water
(100 mL), neutralized with HCl and then extracted with

A. Palumbo Piccionello et al. / Tetrahedron 64 (2008) 4004e4010
4009
4.4.2. Reduction of 2-N-benzoylamino-4(5)-trifluoromethyl-
5(4)-benzoyl-imidazole 16d
Chromatography of the residue gave 18b (72%). 2-N-Benz-
oylamino-4(5)-trifluoromethyl-5(4)-hydroxy(phenyl)methyl-imid-
azole 18b had mp 178e180 ꢀC (white crystals, from water).
FTIR (Nujol) n: 3270, 3225, 3065, 1679 cmꢁ1 1H NMR
.
(DMSO-d6) d: 5.99 (d, 1H, J¼6 Hz, as singlet after exch.
with D2O), 6.36 (d, 1H, J¼6 Hz, exch. with D2O), 7.27e
7.39 (m, 5H), 7.51e7.65 (m, 3H), 8.03e8.04 (m, 2H), 11.76
(s, 1H, exch. with D2O), 12.04 (s, 1H, exch. with D2O).
HRMS found: 361.1039; C18H14F3N3O2 requires: 361.1038.
1676, 1640 cmꢁ1 1H NMR (DMSO-d6) d: 1.11 (t, 3H,
.
J¼7.2 Hz), 4.08 (q, 2H, J¼7.2 Hz), 5.83 (s, 2H, exch. with
D2O), 11.50 (s, 1H, exch. with D2O). HRMS found:
223.0562; C7H8F3N3O2 requires: 223.0568.
4.5.4. 2-Amino-4(5)-trifluoromethyl-5(4)-benzoyl-imidazole
19d
Compound 19d (75%) had mp 218e220 ꢀC (white crystals,
from ethanol). FTIR (Nujol) n: 3461, 3245, 3164, 1652,
1
1610 cmꢁ1. H NMR (DMSO-d6) d: 6.21 (s, 2H, exch. with
D2O), 7.54e7.74 (m, 5H), 11.66 (s, 1H, exch. with D2O).
HRMS found: 255.0622; C11H8F3N3O requires: 255.0619.
4.4.3. Reduction of 2-N-benzoylamino-4(5)-methyl-5(4)-
trifluoroacetyl-imidazole 17a
4.5.5. 2-Amino-4(5)-methyl-5(4)-trifluoroacetyl-imidazole
19e
Chromatography of the residue gave 18c (51%) and recov-
ered 17a (5%). 2-N-Benzoylamino-4(5)-methyl-5(4)-(1-hy-
droxy-2,2,2-trifluoro-ethyl)-imidazole 18c had mp 242e5 ꢀC
(white crystals, from EtOAc). FTIR (Nujol) n: 3310, 3273,
Compound 19e (88%) had mp 199e201 ꢀC (white crystals,
from ethanol). FTIR (Nujol) n: 3450, 3263, 3055, 1682 cmꢁ1
.
1H NMR (DMSO-d6) d: 2.41 (s, 3H), 6.54 (s, 2H, exch. with
D2O), 11.01 (s, 1H, exch. with D2O). HRMS found:
193.0464; C6H6F3N3O requires: 193.0463.
1
3184, 1654 cmꢁ1. H NMR (DMSO-d6) d: 2.26 (s, 3H), 5.10
(br s, 1H), 6.43 (br s, 1H, exch. with D2O), 7.53e7.67 (m,
3H), 8.09e8.12 (m, 2H), 11.61e11.73 (br s, 2H, exch. with
D2O). HRMS found: 299.0881; C13H12F3N3O2 requires:
299.0882.
Acknowledgements
Financial support through University of Palermo and Gen-
ova is gratefully acknowledged.
4.5. Hydrolysis of 2-N-benzoylamino-imidazoles 16aed
and 17a: general procedure
Supplementary data
To a solution of 2-N-benzoylamino-imidazole (1 mmol) in
ethanol (10 mL), hydrochloric acid (0.5 mL) was added and
the mixture was refluxed for 24 h. After removal of the sol-
vent, the residue was treated with water, neutralized with solid
NaHCO3 and extracted with EtOAc. The combined organic
layers were dried over Na2SO4 and evaporated. Crystallization
of the residue from ethanol gave the corresponding 2-amino-
imidazole 19.
Supplementary data associated with this article can be
found in the online version, at doi:10.1016/j.tet.2008.02.047.
References and notes
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Compound 19a (90%) had mp 230 ꢀC (dec, white crystals,
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1
1659 cmꢁ1. H NMR (DMSO-d6) d: 6.88 (s, 2H, exch. with
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247.0177; C6H3F6N3O requires: 247.0180.
4.5.3. 2-Amino-4(5)-trifluoromethyl-5(4)-carboxyethyl-
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