Trimethylsilyl-1,3,4-oxadiazoles-new useful synthons for the synthesis of various 2,5-disubstituted-1,3,4-oxadiazoles

Article abstract of DOI:10.1016/j.tet.2008.08.040

The reactivity of 2-aryl-5-trimethylsilyl-1,3,4-oxadiazoles toward different types of electrophiles was investigated. These silanes readily react with chlorine, bromine, aliphatic acyl chlorides, 2-nitrobenzenesulfenyl chloride, and some reactive isocyana

Full text of DOI:10.1016/j.tet.2008.08.040

Tetrahedron 64 (2008) 10431–10442
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Tetrahedron
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Trimethylsilyl-1,3,4-oxadiazolesdnew useful synthons for the synthesis
of various 2,5-disubstituted-1,3,4-oxadiazoles
,
a
a
Evgenij V. Zarudnitskii a, Igor I. Pervak a , Anatolij S. Merkulov , Aleksandr A. Yurchenko ,
*
Andrej A. Tolmachev b
a Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street, 5, Kyiv-94 02094, Ukraine
b Research and Development Center for Chemistry and Biology, National Taras Shevchenko University, Volodymyrska Street, 62, Kyiv-33 01033, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 May 2008
Received in revised form 31 July 2008
Accepted 14 August 2008
Available online 16 August 2008
The reactivity of 2-aryl-5-trimethylsilyl-1,3,4-oxadiazoles toward different types of electrophiles was
investigated. These silanes readily react with chlorine, bromine, aliphatic acyl chlorides, 2-nitro-
benzenesulfenyl chloride, and some reactive isocyanates affording the corresponding substituted 1,3,4-
oxadiazoles. The reactions with carbonyl compounds proceed only in the presence of Fꢀ anions.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Electrophilic substitution
C-Silyl azoles
1,3,4-Oxadiazoles
Heterocycles
1. Introduction
common because of the opening of the heterocycle. Thus, the
synthesis of the substituted 1,3,4-oxadiazoles via lithium deriva-
1,3,4-Oxadiazoles1 have attracted an interest in medicinal
chemistry as ester and amide bioisoesters for a number of biological
targets.2 Moreover, these compounds have also demonstrated
a broad spectrum of biological properties in both pharmaceutical
and agrochemical fields such as antibacterial, anti-inflammatory,
antimitotic, antiarrhythmic, and insecticidal activities.3 Also, 1,3,4-
oxadiazole derivatives are among the most widely employed
electron-transporting and hole-blocking materials in the de-
velopment of organic light-emitting diodes (OLEDs) used in energy
efficient, full-color, flat-panel displays.4
The classical synthetic routes to substituted 1,3,4-oxadiazoles
involve ring-forming reactions. Widely used methods are cyclo-
dehydratation of 1,2-diacylhydrazines with various reagents such
as thionyl chloride, phosphorus oxychloride, PPA or sulfuric acid;5
oxidation of N-acylhydrazones with different oxidizing agents;6
and direct reaction of acyl chlorides or carboxylic acids with
hydrazine or acid hydrazides.7 Another convenient method of 1,3,4-
oxadiazole synthesis is the thermal recyclization of N-acylte-
trazoles, which are commonly generated in situ from appropriate
N-unsubstituted tetrazoles and acyl chlorides.8 Preparative
methods via ring-metalated 1,3,4-oxadiazoles are much less
tives was described for the first time only several years ago.9 Only
a few examples of direct electrophilic substitution reactions in
1,3,4-oxadiazole ring is knowndacylation,10 phosphorylation,11
and silylation.12 Therefore, the elaboration of new methods for
1,3,4-oxadiazoles functionalization is of interest.
Over the last years, C-silyl azoles have gained an increasing
importance in heterocyclic chemistry. They provide a convenient
alternative to organometallic compounds as they easily enter into
electrophilic substitution with a wide range of electrophiles.13 Thus,
commercially available 2-(trimethylsilyl)thiazole is widely used in
asymmetric syntheses with chiral aldehydes affording amino hy-
droxy aldehydes and C-glycosyl amino acidsdprecursors to modi-
fied peptides.14
Recently, we have developed a new synthetic approach to
2-aryl-5-trimethylsilyl-1,3,4-oxadiazoles via direct silylation of
2-aryl-1,3,4-oxadiazoles with bromotrimethylsilane in the pres-
ence of triethylamine.12 With a ready source of these compounds at
hand, their reactivity toward electrophiles was explored and the
results are presented in this paper.
2. Results and discussion
2-Phenyl-5-trimethylsilyl-1,3,4-oxadiazole (1a) reacted with Cl2
or Br2 in hexane at 0 ꢁC for 0.25–1.5 h affording the corresponding
2-halogen-5-phenyl-1,3,4-oxadiazoles 2 and 3, which precipitated
* Corresponding author.
E-mail address: pervak@ioch.kiev.ua (I.I. Pervak).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.08.040

10432
E.V. Zarudnitskii et al. / Tetrahedron 64 (2008) 10431–10442
from the reaction mixture and were isolated in good yields (74%
and 84%, respectively) (Scheme 1). A simple synthetic procedure
makes this method complementary to known synthetic pathways
to chloro- and bromosubstituted 1,3,4-oxadiazoles.15 Sulfuryl
chloride could also be employed in the reaction with 1a but in this
case the yield of 2 was lower (45%). Unfortunately, our attempts to
use I2 or ICl in this reaction failed.
chloride (4b) was carried out in toluene under reflux to give
compound 5b in moderate yield. When we tried to conduct the
reactions of 1a with aromatic acyl chlorides under such drastic
conditions inseparable mixture of products were formed.
The reaction of 1a with 2-nitrobenzenesulfenyl chloride (6) in
diethyl ether at room temperature for 9 days afforded 7 in 82% yield
(Scheme 1). Less reactive tosyl chloride even under drastic condi-
tions (6 h in toluene under reflux) does not enter into the reaction
with 1a.
Then, we tried to introduce heterocumulenes to the reaction
with 2-aryl-5-trimethylsilyl-1,3,4-oxadiazoles. Unfortunately, none
of the desired products was obtained when acyl and aryl iso-
cyanates or isothiocyanates were employed, even under Fꢀ catal-
ysis. Only such activated isocyanates as tosyl isocyanate (8) and
isocyanatophosphoryl dichloride (10) were found to react with
2-aryl-5-trimethylsilyl-1,3,4-oxadiazoles 1a,b. Thus, tosyl isocyanate
(8) was cleanly converted into the corresponding sulfonamides
9a,b. These reactions were carried out in toluene under reflux.
More reactive isocyanatophosphoryl dichloride (10) readily reacted
with 1a at room temperature followed by treatment with dime-
thylamine or morpholine affording phosphoric triamides 11a,b
(Scheme 2).
Hal2, hexane, 0 °C or
SO2Cl2, toluene, 110 °C
N
N
Ph
Hal
O
2: Hal = Cl (45 - 74%)
3: Hal = Br (84%)
N
N
RCOCl (4a-f), hexane or Et2O, rt
N
N
R
Ph
Ph
SiMe3
O
O
O
5a-f
(54 - 81%)
1a
ClS
O2N
(6), Et2O, rt
N
N
S
Ph
O
NO2
7
(82%)
Scheme 1.
1. TosNCO (8), toluene,110 °C
2. MeOH, H2O
N
N
H
N
O
S
Treatment of 1a with acyl chlorides (4a–f) at ambient temper-
Ar
O
ature gave the corresponding ketones 5a–f in moderate to good
yields (Scheme 1, Table 1). Hexane and diethyl ether were found to
be the best solvents for running the reaction as ketones 5a–f pre-
cipitated from the reaction mixture and byproducts remained in
solution. While aliphatic acyl chlorides reacted with 1a at room
temperature, their aromatic counterparts remained intact under
these conditions. The reaction of 1a with cyclopropanecarbonyl
O
O
9a,b
(55 - 80%)
O
P
Cl
Cl
N
O
N
N
toluene, rt
1.
(10),
Ar
SiMe3
O
2. HNR2
3. H2O
N
N
H
N
O
P
NR2
1a,b
NR2
Ph
O
O
11a,b
1a, 9a: Ar = Ph
(52 - 66%)
11a: NR2= NMe2
Table 1
Yields of products of the reaction of silane 1a with acyl chlorides
N
O
1b, 9b: Ar = 4-FC6H4 11b: NR2=
Scheme 2.
Entry
Acyl chloride
Product
Solvent
Reaction Yielda (%)
time (h)
In contrast to such silylazoles as 2-trimethylsilylthiazole,16
N
N
O
1-alkyl-2-trimethylsilylimidazoles17 and 2-trimethylsilyl substituted
oxazoles,18 2-phenyl-5-trimethylsilyl-1,3,4-oxadiazole (1a) did not
react with carbonyl compounds in the absence of a catalyst, even
with an active ones (such as trifluoromethylketones). However, alkyl
and aryl aldehydes (12a–i), isatins (12j–n), carbocyclic (12o,p) and
diaryl (or aryl-hetaryl) ketones (12q–u), chalcones (12v,w), and
trifluoromethylkethones (12x,y) react smoothly with 1a in the
presence of Fꢀ anion to give trimethylsilyl ethers of 1,3,4-oxadi-
azolylcarbinoles 13a–y, which in most cases were directly converted
into the corresponding alcohols 14a–y (Scheme 3, Table 2). KF/
dibenzo-18-crown-6 system was used as the Fꢀ anion source. The
reaction was carried out in toluene or xylene under reflux. In al-
most all cases, excess amounts of silane 1a were required to obtain
14a–y in high yields. It is noteworthy that the treatment of 1a with
chalcones gave only the 1,2-addition products 14v and 14w. It was
found that trimethylsilyl ethers 13a–y are considerably stable in
protic solvents and need Fꢀ catalysis for solvolysis. In one case, the
initial trimethylsilyl ether 13a was isolated and characterized by 1H
and 13C NMR spectroscopy.
Me
Ph
1
Hexane
96
2
61
57
54
56
O
Me
4a
Cl
O
O
5a
O
N N
Ph
2
3
4
5
Tolueneb
Cl
O
4b
5b
N
N
O
Ph
Ph
Ph
5c
Et2O
24
96
O
Cl
O
4c
N
N
N
Ph
O
Ph
Et2O
O
Cl
Ph
4d
O
5d
N
O
Ph
O
O
Ph
Hexane
Et2O
18
18
81
67
O
Cl
Ph
O
4e
5e
3. Conclusion
N
N
O
Cl
Cl
4f
Ph
5f
6
O
Cl
The reactions of 2-aryl-5-trimethylsilyl-1,3,4-oxadiazoles with
different electrophiles, such as chlorine, bromine, aliphatic acyl
chlorides, 2-nitrobenzenesulfenyl chloride, isocyanates, and vari-
ous carbonyl compounds were investigated. It has been found that
O
a
Isolated yield of analytically pure product.
The reaction was run under reflux.
b

E.V. Zarudnitskii et al. / Tetrahedron 64 (2008) 10431–10442
10433
N
N
OH
Ph
N
N
O
N
N
OH
OH
N
Ph
Ph
O
R''
O
R'' = Alk
O
R
14a-i
R'
(61 - 84%)
14j-n
b
b
b
R'' = H, Me 14o,p
R = Alk, Ar
(41 - 87%)
(15 - 34%)
N
N
N
N
N
N
a
OH
Ar
b
b
R
Ph
Ph
OSiMe3
Ph
SiMe3
Ph
O
O
O
R'
13a-y
Ar'
14q-s
(17 - 70%)
1a
b
b
N
N
N
N
N
OH
Ar
OH
Ar
N
N
OH
Ph
O
O
N
Me
Ar
Ph
CF3
O
Ar'
14v,w
(61 - 71%)
N
14t,u
14x,y
N (65 - 87%)
Ar = Ph,
(17 - 27%)
Scheme 3. (a) RCOR0 (12a–y), KF, DB-18-C-6, toluene or xylene, reflux; (b) MeOH, RbF (5% solution in water), rt.
in most cases the reactions proceed under mild conditions in av-
erage to good yields, while the reactions with carbonyl compounds
need Fꢀ catalysis. Readily available starting materials and simple
synthetic procedures make these methods very attractive and
convenient for the synthesis of various 2,5-disubstituted-1,3,4-
oxadiazoles.
15 min. The precipitate formed was filtered and washed with
hexane affording 2 (1.338 g, 74%) as colorless crystals.
Method B. To a solution of 1a (0.980 g, 4.49 mmol) in toluene
(5 mL) was added SO2Cl2 (0.606 g, 0.36 mL, 4.49 mmol) at room
temperature. The reaction mixture warmed up and gas evolution
was observed. The reaction mixture was left for 96 h at room
temperature and then was heated to reflux for 2 h. The solvent was
removed in vacuo and the residue crystallized from heptane and
then from aqueous ethanol affording 2 (0.502 g, 45%) as colorless
4. Experimental
4.1. General
crystals. Mp 77–78 ꢁC. 1H NMR (C6D6):
6.91 (m, 3H). 13C NMR (C6D6):
166.4, 152.3, 131.9, 129.1, 126.8,
d
7.67 (d, J¼7.1 Hz, 2H), 7.03–
d
123.6. IR nmax (cmꢀ1): 3065, 1607, 1558, 1510, 1484, 1452, 1293, 1215,
1185, 1090, 1077, 1020, 978, 961, 780, 710, 698, 505. MS m/z (%): 182
(Mþþ2, 17), 180 (Mþ, 56), 145 (45), 126 (12), 124 (39), 105 (15), 103
(25), 89 (30), 77 (100), 76 (10), 63 (25), 62 (7), 51 (27), 50 (16), 39
(16), 37 (9), 31 (25). Anal. Calcd for C8H5ClN2O: C, 53.21; H, 2.79; Cl,
19.63; N, 15.51. Found: C, 53.18; H, 2.80; Cl, 19.58; N, 15.53.
All reagents were used as received unless otherwise noted. All
reactions were conducted in flame-dried glassware under dry ar-
gon. Melting points (mp) were determined with electrothermal
capillary melting point apparatus. 1H, 19F, and 13C NMR spectra were
recorded on a Varian VXR-300 (300 MHz for 1H, 282 MHz for 19F,
and 75 MHz for 13C) spectrometer. Chemical shifts are reported in
parts per million (d) downfield relative to internal standard (tet-
4.3. 2-Bromo-5-phenyl-1,3,4-oxadiazole (3)15
ramethylsilane for 1H and 13C, C6F6 for 19F NMR spectra). Abbrevi-
ations are as follows: s, singlet; d, doublet; t, triplet; m, multiplet;
br s, broad singlet. J values are in hertz. IR spectra were recorded on
a Nexus-470 spectrometer for samples in KBr disks. Mass spectra
were obtained on a ‘Hewlett-Packard’ HP GS/MS 5890/5972 in-
strument (EI, 70 eV) by GS inlet, on VG 70–70EQ, VG Analytical
(FAB) for substances 9a and 9b or a MX-1321 instrument (EI, 70 eV)
by direct inlet for all other substances. Microanalyses were per-
formed in the Microanalytical Laboratory of the Institute of Organic
Chemistry, National Academy of Sciences of Ukraine. 2-Phenyl-5-tri-
methylsilyl-1,3,4-oxadiazole (1a) and 2-(4-fluorophenyl)-5-trime-
thylsilyl-1,3,4-oxadiazole (1b),12 isocyanatophosphoryl dichloride.19
1-methyl-2-aroylimidazoles,20 2,2,2-trifluoro-1-(1-methyl-1H-imi-
dazol-2-yl)ethanone,20 N-alkylisatins21 were prepared according to
the literature. Hexane, toluene, xylene, diethyl ether were distilled
from P4O10. KF was dried at 120 ꢁC under high vacuum for 4 h. All acyl
chlorides and all liquid aldehydes and ketones were freshly distilled.
Yields refer to pure isolated products.
A solution of anhydrous Br2 (3.119 g, 19.5 mmol) in hexane
(5 mL) was added dropwise to a stirred solution of 1a (4.260 g,
19.5 mmol) in hexane (45 mL) at 0 ꢁC. When the addition of Br2 was
complete the reaction mixture was allowed to warm to room
temperature and stirred for 1.5 h. The precipitate formed was fil-
tered and washed with hexane affording 3 (3.695 g, 84%) as yel-
lowish solid. For further purification substance
3 could be
crystallized from cyclohexane. Mp 104–105 ꢁC. 1H NMR (C6D6):
d
7.68 (d, J¼6.6 Hz, 2H), 7.02–6.90 (m, 3H). 13C NMR (C6D6):
d 167.8,
139.1, 131.9, 129.0, 126.8, 123.6. IR nmax (cmꢀ1): 1610, 1555, 1487,
1449, 1178, 1077, 1038, 1003, 965, 890, 610, 594, 503, 485. MS m/z
(%): 226 (Mþþ1, 31), 224 (Mþꢀ1, 32), 162 (22), 145 (71), 105 (11),
103 (22), 89 (11), 77 (100), 63 (12), 51 (18). Anal. Calcd for
C8H5BrN2O: C, 42.70; H, 2.24; Br, 35.51; N, 12.45. Found: C, 42.74; H,
2.31; Br, 35.44; N, 12.48.
4.4. Typical experimental procedure for the reaction of 1a
with acyl chlorides 4a–f
4.2. 2-Chloro-5-phenyl-1,3,4-oxadiazole (2)15
To a solution of 2-phenyl-5-trimethylsilyl-1,3,4-oxadiazole 1a
(2.5 mmol) in hexane or Et2O (5 mL) the corresponding acyl chlo-
rides (2.5 mmol) were added. The reaction mixture was left for the
Method A. To a cold (0 ꢁC) stirring solution of 1a (2.18 g,
10 mmol) in hexane (20 mL) was bubbled dry Cl2 over a period of

10434
E.V. Zarudnitskii et al. / Tetrahedron 64 (2008) 10431–10442
Table 2
Yields of products of the reaction of silane 1a with carbonyl compounds
Entry
Carbonyl compound
Product
Mol ratio: 1a/carbonyl
compd/KF/DB-18-C-6
Solvent
Reaction
time (h)
Yielda (%)
N
N
Ph
Benzene
1
5
50
O
O
SiMe3
13a
CHO
1
1/1/0.1/0.04
N
N
12a
Ph
MeOH
90
60
O
OH
14a
N
N
CHO
Ph
Ph
O
2
3
1/1/0.1/0.04
Toluene
1.33
OH
12b
14b
Me
CHO
N
N
1.2/1/0.1/0.04
Toluene
Toluene
Toluene
1
76
64
87
Me
Ph
O
12c
OH
OH
14c
F
CHO
N
N
4
5
1/1/0.1/0.02
1
1
F
12d
Ph
O
14d
Cl
CHO
N
N
1.2/1/0.1/0.04
Cl
Ph
O
12e
OH
OH
14e
OBn
CHO
N
N
6
7
1.2/1/0.1/0.03
1.2/1/0.1/0.04
Toluene
Toluene
1
1
75
71
BnO
12f
Ph
O
14f
OMe
N
N
MeO
CHO
CHO
OMe
Ph
O
OMe
OH
12g
14g
NMe2
N
N
8
1/1/0.1/0.04
1.2/1/0.1/0.04
1.2/1/0.1/0.04
Toluene
Toluene
Toluene
1.5
1
41
68
72
Me2N
Ph
O
OH
12h
14h
N
N
S
CHO
9
S
Ph
14i
O
OH
OH
12i
O
N
N
O
Ph
14j
10
1
O
N
N
Me
O
Me
Ph
12j
O
N
N
OH
O
Ph
O
11
12
1/1/0.1/0.04
Toluene
Toluene
3.5
61
72
N
N
O
Ph
14k
12k
O
N
N
OH
Ph
O
O
1.2/1/0.1/0.04
1
N
N
O
i-Pr
i-Pr
12l
14l

E.V. Zarudnitskii et al. / Tetrahedron 64 (2008) 10431–10442
10435
Table 2 (continued )
Entry
Carbonyl compound
Product
Mol ratio: 1a/carbonyl
compd/KF/DB-18-C-6
Solvent
Toluene
Reaction
time (h)
Yielda (%)
O
N
N
N
OH
O
N
n-Bu
Ph
O
13
1.1/1/0.1/0.04
3
84
N
n-Bu
i-Bu
O
14m
12m
O
N
OH
Ph
O
N
O
14
15
1.2/1/0.1/0.04
1/1/0.1/0.04
Toluene
Toluene
1
4
83
34
N
O
i-Bu
12n
14n
N
N
O
OH
Ph
O
12o
14o
N
N
O
OH
Ph
16
17
1.1/1/0.1/0.04
1.5/1/0.1/0.04
Toluene
Toluene
4.5
4
15
50
O
Me
12p
Me
Ph
14p
N
N
O
OH
Ph
Ph
Ph
12q
Ph
O
14q
O
N
N
F
OH
Ph
Ph
Ph
18
19
1/1/0.2/0.04
1/1/0.1/0.04
Toluene
Toluene
6
5
17
70
O
F
14r
12r
O
N
N
OH
Ph
O
12s
14s
N
N
N
N
OH
F
Ph
O
N
Me
N
20
21
1.2/1/0.1/0.04
1.2/1/0.1/0.04
Xylene
Xylene
5.5
27
17
N
O
Me
F
14t
12t
N
N
Me
Me
OH
Ph
O
N
N
Me
8
N
O
Me
Me
Me
12u
14u
N
N
OH
O
Ph
O
22
2/1/0.1/0.04
Toluene
1
71
Me
F
12v
F
14v
N
N
F
OH
O
Ph
O
23
2/1/0.1/0.04
Toluene
1
61
F
F
12w
F
14w
(continued on next page)

10436
E.V. Zarudnitskii et al. / Tetrahedron 64 (2008) 10431–10442
Table 2 (continued )
Entry
Carbonyl compound
Product
Mol ratio: 1a/carbonyl
compd/KF/DB-18-C-6
Solvent
Toluene
Reaction
time (h)
Yielda (%)
N
N
O
OH
Ph
Ph
24
1.2/1/0.1/0.04
1/1/0.1/0.04
1
87
O
Ph
12x
CF3
CF3
14x
N
N
N
N
O
OH
N
Me
Ph
14y
25
Toluene
1.75
65
O
N
Me
CF3
CF3
12y
a
Isolated yield of analytically pure product.
time indicated in Table 1 (18–96 h) at room temperature. The
precipitated ketone was filtered and washed with hexane.
3H), 7.35–7.19 (m, 5H), 3.56 (t, J¼7.5 Hz, 2H), 3.14 (t, J¼7.5 Hz, 2H).13
C
NMR (CDCl3):
d 186.4, 166.3, 160.8, 139.9, 132.9, 129.2, 128.6, 128.4,
127.7,126.4,122.8, 41.3, 29.4. IR nmax (cmꢀ1): 3070, 3035, 2950,1712,
1605, 1545, 1488, 1453, 1397, 1360, 1300, 1080, 1032, 998, 980, 798,
752, 722, 717, 696, 552, 547, 499, 460. MS m/z (%): 278 (Mþ, 2), 251
(17), 250 (100), 249 (27), 173 (16), 131 (10), 105 (29), 104 (63), 103
(47), 91 (59), 77 (33), 65 (10), 51 (13). Anal. Calcd for C17H14N2O2: C,
73.37; H, 5.07; N, 10.07. Found: C, 73.25; H, 5.03; N, 10.13.
4.4.1. 1-(5-Phenyl-1,3,4-oxadiazol-2-yl)ethanone (5a)
Prepared according to Section 4.4. Reaction of 1a (0.669 g,
3.06 mmol) and acetyl chloride 4a (0.184 g, 3.06 mmol) in hexane
(5 mL) gave 0.350 g (61%) of ketone 5a as colorless crystals. Mp
81–82 ꢁC. 1H NMR (DMSO-d6):
3H), 2.70 (s, 3H). 13C NMR (DMSO-d6):
d
8.11–8.08 (m, 2H), 7.74–7.62 (m,
184.3, 165.1, 160.9, 132.8,
d
129.4, 127.1, 122.5, 27.0. IR nmax (cmꢀ1): 3460 (br), 3412, 3068, 3008,
2924,1716,1606,1541,1524,1479,1450,1406,1354,1296,1271,1132,
1097, 1072, 955, 785, 717, 694, 633, 550, 453. MS m/z (%): 188 (Mþ,
75),145 (100),105 (19), 77 (74), 43 (80). Anal. Calcd for C10H8N2O2: C,
63.82; H, 4.28; N, 14.89. Found: C, 63.88; H, 4.35; N, 14.85.
4.4.5. 2-Phenoxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethanone (5e)
Prepared according to Section 4.4. Reaction of 1a (0.546 g,
2.5 mmol) and phenoxyacetyl chloride 4e (0.427 g, 2.5 mmol) in
hexane(5 mL)gave0.567 g(81%)ofketone5e ascolorlesscrystals.Mp
146–147 ꢁC.1H NMR (CDCl3):
d
8.19 (d, J¼7.5 Hz, 2H), 7.63 (distorted t,
J¼7.5 Hz,1H), 7.56 (distorted t, J¼7.5 Hz, 2H), 7.35–7.30 (m, 2H), 7.05–
6.99 (m, 3H), 5.52 (s, 2H). 13C NMR (CDCl3):
181.5, 166.7, 159.2, 157.6,
4.4.2. Cyclopropyl(5-phenyl-1,3,4-oxadiazol-2-yl)methanone (5b)
To a solution of 1a (1.000 g, 4.58 mmol) in toluene (5 mL) was
added cyclopropanecarbonyl chloride 4b (0.527 g, 5.04 mmol) and
the mixture was heated to reflux for 2 h. The solvent was removed
in vacuo and the residue was crystallized from MeOH. Yellowish
d
133.3,129.8,129.4,128.0,122.5,122.2,115.0, 70.4.IRnmax (cmꢀ1):3445,
3085, 2915, 1725, 1600, 1495, 1450, 1430, 1410, 1367, 1297, 1253, 1182,
1115,1045, 998, 980, 878, 798, 766, 727, 694, 555, 515, 460. MS m/z (%):
280 (Mþ, 37), 251 (10),145 (14),119 (17),107 (26),105 (37), 79 (11), 77
(100), 56 (27), 51 (16), 32 (31), 31 (39). Anal. Calcd for C16H12N2O3: C,
68.56; H, 4.32; N, 9.99. Found: C, 68.57; H, 4.32; N, 10.04.
crystals (0.558 g, 57%). Mp 99–100 ꢁC. 1H NMR (CDCl3):
J¼8.1 Hz, 2H), 7.62–7.53 (m, 3H), 3.18 (m, 1H), 1.43 (m, 2H), 1.26 (m,
2H). 13C NMR (CDCl3):
187.4, 166.4, 161.5, 132.9, 129.4, 127.9, 123.0,
d 8.18 (d,
d
19.4, 13.9. IR nmax (cmꢀ1): 3460 (br), 3361, 3086, 3064, 3008, 1778,
1686, 1605, 1539, 1520, 1446, 1410, 1099, 1053, 1024, 991, 972, 958,
727, 714, 688. MS (FAB) m/z (%): 214 (Mþ, 67), 186 (23), 185 (17), 145
(58), 105 (39), 104 (15), 103 (46), 77 (64), 69 (100), 55 (43), 51 (14),
41 (81), 39 (42). Anal. Calcd for C12H10N2O2: C, 67.28; H, 4.71; N,
13.08. Found: C, 67.30; H, 4.72; N, 13.03.
4.4.6. 2-Chloro-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethanone (5f)
Prepared according to Section 4.4. Reaction of 1a (2.45 g,
11.2 mmol) and chloroacetyl chloride 4f (1.27 g, 11.2 mmol) in Et2O
(20 mL) gave 1.678 g (67%) of ketone 5f as colorless crystals. Mp
121–122 ꢁC. 1H NMR (CDCl3):
d
8.18 (d, J¼7 Hz, 2H), 7.64 (distorted t,
J¼7.5 Hz, 1H), 7.57 (distorted t, J¼7 Hz, 2H), 4.95 (s, 2H). 13C NMR
(CDCl3): d 178.3, 166.9, 159.4, 133.3, 129.4, 127.9, 122.3, 46.0. IR nmax
4.4.3. 2-Phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethanone (5c)
Prepared according to Section 4.4. Reaction of 1a (0.662 g,
3.03 mmol) and phenylacetyl chloride 4c (0.469 g, 3.03 mmol) in
Et2O (5 mL) gave 0.430 g (54%) of ketone 5c as colorless crystals. Mp
(cmꢀ1): 3083, 3015, 2962, 1730, 1607, 1542, 1488, 1453, 1400, 1298,
1258, 1110, 1061, 1038, 982, 799, 755, 722, 695, 535, 458. MS (FAB)
m/z (%): 224 (Mþþ2, 6), 222 (Mþ, 22), 145 (100), 105 (11), 103 (11),
77 (55). Anal. Calcd for C10H7ClN2O2: C, 53.95; H, 3.17; Cl, 15.92; N,
12.58. Found: C, 53.84; H, 3.14; Cl, 15.98; N, 12.49.
107–108 ꢁC. 1H NMR (CDCl3):
d
8.16 (d, J¼8.4 Hz, 2H), 7.63–7.51 (m,
3H), 7.42–7.26 (m, 5H), 4.48 (s, 2H). 13C NMR (CDCl3):
d
184.4, 166.6,
160.8, 132.9, 132.1, 130.0, 129.3, 128.9, 127.8, 127.6, 122.8, 46.3. IR
nmax (cmꢀ1): 3415, 3055, 3030, 2902, 1718, 1605, 1541, 1514, 1485,
1452, 1400, 1389, 1342, 1292, 1074, 1041, 1030, 997, 970, 779, 731,
714, 690, 580, 532, 517, 478, 449. MS m/z (%): 264 (Mþ, 50), 118 (59),
91 (100), 77 (17), 65 (17). Anal. Calcd for C16H12N2O2: C, 72.72; H,
4.58; N, 10.60. Found: C, 72.81; H, 4.61; N, 10.52.
4.5. 2-[(2-Nitrophenyl)thio]-5-phenyl-1,3,4-oxadiazole (7)
To a solution of 1a (0.658 g, 3.01 mmol) in Et2O (5 mL) was
added 2-nitrobenzenesulfenyl chloride 6 (0.476 g, 2.51 mmol). The
reaction mixture was left for 9 days at room temperature. The
precipitate formed was filtered affording 7 (0.616 g, 82%) as yellow
Note. In the 1H NMR spectra recorded in DMSO-d6, a mixture of
keto and enolic forms of substance 4c was observed.
crystals. Mp 112–113 ꢁC. 1H NMR (CDCl3):
d
8.30 (dd, J¼8.1, 1.3 Hz,
1H), 8.07 (dd, J¼8.4, 1.5 Hz, 2H), 7.62–7.43 (m, 5H), 7.36 (d, J¼8.1 Hz,
1H). 13C NMR (CDCl3):
167.8, 160.1, 146.2, 134.5, 132.5, 130.3, 129.8,
d
4.4.4. 3-Phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propan-
1-one (5d)
129.2, 128.0, 127.1, 126.1, 123.0. IR nmax (cmꢀ1): 3454 (br), 3099,
1605, 1591, 1570, 1543, 1525, 1504, 1479, 1448, 1338, 1309, 1153,
1113, 1082, 1068, 1055, 1041, 962, 854, 783, 731, 719, 690, 526. MS
m/z (%): 299 (Mþ, 15), 146 (10), 145 (98), 105 (86), 103 (14), 77 (100).
Anal. Calcd for C14H9N3O3S: C, 56.18; H, 3.03; N, 14.04; S, 10.71.
Found: C, 56.25; H, 3.07; N, 13.93; S, 10.78.
Prepared according to Section 4.4. Reaction of 1a (0.546 g,
2.5 mmol) and 3-phenylpropanoyl chloride 4d (0.423 g, 2.5 mmol)
in Et2O (5 mL) gave 0.388 g (56%) of ketone 5d as colorless crystals.
Mp 94–95 ꢁC.1H NMR (CDCl3):
d
8.17 (d, J¼6.9 Hz, 2H), 7.65–7.52 (m,

E.V. Zarudnitskii et al. / Tetrahedron 64 (2008) 10431–10442
10437
4.6. 4-Methyl-N-[(5-phenyl-1,3,4-oxadiazol-2-yl)-
carbonyl]benzenesulfonamide (9a)
The resulting mixture was left for 72 h at room temperature. The
solvent was removed in vacuo and the residue was treated with
water. The precipitate formed was filtered and crystallized from
ethanol affording 11b (0.658 g, 52%) as colorless crystals. Mp 206–
To a solution of 1a (0.630 g, 2.89 mmol) in toluene (5 mL) was
added p-toluenesulfonyl isocyanate 8 (0.518 g, 2.63 mmol) and the
mixture was heated to reflux for 2 h. The solvent was removed in
vacuo and the residue was treated with MeOH. The precipitate
formed was filtered affording 9a (0.716 g, 80%) as colorless solid.
207 ꢁC. 1H NMR (DMSO-d6):
d
9.99 (br s, 1H), 8.14 (d, J¼8.1 Hz, 2H),
7.72–7.61 (m, 3H), 3.57 (t, J¼4.5 Hz, 8H), 3.13 (m, 8H). 13C NMR
(DMSO-d6):
d
165.1, 157.9 (d, JCP¼12.4 Hz), 154.3, 132.6, 129.3, 127.1,
122.5, 66.2 (d, JCP¼5.5 Hz), 44.2. 31P NMR (DMSO-d6):
d 8.7. IR, nmax
Mp 214–216 ꢁC. 1H NMR (CDCl3):
d
9.56 (br s,1H), 8.10–8.06 (m, 4H),
(cmꢀ1): 3463 (br), 3396, 3112 (br), 2975, 2958, 2910, 2856, 1704,
1546, 1488, 1436 (br), 1369, 1259, 1207, 1174, 1132, 1112, 1081, 977
(br), 912, 860, 811, 707, 684, 636, 499. MS m/z (%): 407 (Mþ, 16), 362
(14), 322 (13), 321 (18), 230 (10), 218 (10), 204 (25), 147 (12), 146
(27), 105 (15), 87 (27), 86 (100), 85 (12), 77 (13), 57 (16), 56 (19), 42
(11). Anal. Calcd for C17H22N5O5P: C, 50.12; H, 5.44; N, 17.19; P, 7.60.
Found: C, 49.93; H, 5.51; N, 17.08; P, 7.72.
7.63–7.50 (m, 3H), 7.38 (d, J¼8.2 Hz, 2H), 2.45 (s, 3H). 13C NMR
(DMSO-d6):
d 165.4, 157.1, 152.0, 144.7, 136.0, 132.8, 129.6, 129.4,
127.9, 127.2, 122.5, 21.1. IR nmax (cmꢀ1): 3442, 3043 (br), 2877, 2724,
1731, 1606, 1540, 1461 (br), 1386, 1348, 1189, 1172, 1130, 1087, 881,
808, 713, 690, 661, 570, 545, 545. MS (FAB) m/z (%): 344 (MþþH,
100), 307 (13), 289 (10), 154 (59), 136 (49), 107 (21), 105 (16), 92
(21), 90 (21), 75 (22). Anal. Calcd for C16H13N3O4S: C, 55.97; H, 3.82;
N, 12.24; S, 9.34. Found: C, 56.11; H, 3.86; N, 12.17; S, 9.23.
4.10. Typical experimental procedures for the reaction of 1a
with carbonyl compounds 12a–y
4.7. N-{[5-(4-Fluorophenyl)-1,3,4-oxadiazol-2-yl]carbonyl}-4-
methyl-benzenesulfonamide (9b)
Method A. To a stirred solution of the corresponding carbonyl
compound (3.00 mmol) and 1a (3.00 mmol) in toluene (5 mL)
were added KF (0.016 g, 0.30 mmol) and dibenzo-18-crown-6
(0.12 mmol). The mixture was heated to reflux for the time in-
dicated in Table 2 (1–4 h) and then placed into a freezer. The pre-
cipitate was filtered off and washed with toluene. The combined
filtrate and washings were evaporated in vacuo, methanol (10 mL)
and RbF (5% solution inwater, 0.5 mL) were added to the residual oil,
and the mixture was allowed to stand for 24 h. In some cases pure
product was precipitated. In other cases, solvent was removed in
vacuo and the residue was crystallized from an appropriate solvent.
Method B. To a stirred solution of the corresponding carbonyl
compound (3.00 mmol) and 1a (3.60 mmol) in toluene or xylene
(5 mL) were added KF (0.016 g, 0.30 mmol) and dibenzo-18-crown-
6 (0.12 mmol). The mixture was heated to reflux for the time
indicated in Table 2 (1–8 h) and then placed into a freezer. The
precipitate was filtered off and washed with toluene. The combined
filtrate and washings were evaporated in vacuo, methanol (10 mL)
and RbF (5% solution in water, 0.5 mL) were added to the residual
oil, and the mixture was allowed to stand for 24 h. In some cases
pure product was precipitated. In other cases, solvent was removed
in vacuo and the residue was crystallized from an appropriate
solvent.
To a solution of 1b (0.466 g, 1.97 mmol) in toluene (5 mL) was
added p-toluenesulfonyl isocyanate 8 (0.388 g, 1.97 mmol) and the
mixture was heated to reflux for 1 h. The solvent was removed in
vacuo and the residue was treated with MeOH. The precipitate
formed was filtered and crystallized from MeCN affording 9b
(0.395 g, 55%) as colorless solid. Mp >245 ꢁC. 1H NMR (CDCl3):
d
9.48 (br s, 1H), 8.12 (m, 2H), 8.06 (d, J¼8 Hz, 2H), 7.39 (d, J¼8 Hz,
2H), 7.24 (m, 2H), 2.46 (s, 3H). 13C NMR (DMSO-d6):
d
164.6 (d,
JCF¼251 Hz), 164.5, 157.3, 152.1, 144.6, 136.2, 130.0 (d, JCF¼9.4 Hz),
129.5, 127.9, 119.2 (d, JCF¼2.9 Hz), 116.8 (d, JCF¼22.8 Hz), 21.1. 19F
NMR (DMSO-d6):
d
ꢀ106.2. IR nmax (cmꢀ1): 3550–3350 (br), 3250,
1736,1606,1537,1493,1446,1419,1383,1350,1240,1227,1192,1176,
1161, 1126, 1088, 874, 850, 812, 739, 700, 669, 619, 571, 544, 523.
Anal. Calcd for C16H12FN3O4S: C, 53.18; H, 3.35; N, 11.63; S, 8.87.
Found: C, 53.14; H, 3.42; N, 11.71; S, 8.73.
4.8. N,N,N0,N0-Tetramethyl-N00-[(5-phenyl-1,3,4-oxadiazol-2-
yl)carbonyl]-phosphoric triamide (11a)
To a solution of 1a (0.675 g, 3.09 mmol) in toluene (5 mL) was
added isocyanatophosphoryl dichloride 10 (0.495 g, 3.09 mmol) at
room temperature. After 1 h the reaction mixture was cooled down
to ꢀ30 ꢁC and dimethylamine (0.697 g, 15.47 mmol) was added.
The resulting mixture was left for 16 h at room temperature. The
solvent was removed in vacuo and the residue was treated with
water. The precipitate formed was filtered and crystallized from
ethyl acetate affording 11a (0.665 g, 66%) as colorless crystals. Mp
4.10.1. 2-Phenyl-5-{1-[(trimethylsilyl)oxy]pentyl}-1,3,4-
oxadiazole (13a)
To a stirred solution of valeraldehyde 12a (0.86 g, 10 mmol) and
1a (2.18 g, 10 mmol) in benzene (10 mL) were added KF (0.058 g,
1 mmol) and dibenzo-18-crown-6 (0.144 g, 0.4 mmol). The mixture
was heated to reflux for 1 h and then placed into a freezer. The
precipitate was filtered off and washed with toluene. The combined
filtrate and washings were evaporated under reduced pressure. The
residue was distilled in vacuo to give 13a (1.536 g, 50%) as colorless
165–167 ꢁC. 1H NMR (DMSO-d6):
2H), 7.73–7.62 (m, 3H), 2.67 (s, 6H), 2.63 (s, 6H).13C NMR (DMSO-d6):
d
9.94 (br s, 1H), 8.14 (d, J¼6.6 Hz,
d
165.2,158.1 (d, JCP¼11.7 Hz),154.4,132.7,129.4,127.2,122.7, 36.1 (d,
JCP¼4.3 Hz). 31P NMR (DMSO-d6):
d
14.3. IR nmax (cmꢀ1): 3473 (br),
3398, 3070, 3059, 2999, 2947, 2885, 2827, 2814, 1705, 1608, 1547,
1481, 1450, 1365, 1304, 1257, 1207, 1173, 1093, 1074, 1028, 997, 964,
858, 816, 783, 769, 715, 694, 661, 634, 546, 511, 476, 426. MS m/z (%):
323 (Mþ, 18), 295 (26), 280 (15), 279 (28), 278 (55), 250 (5), 147 (9),
133 (9), 77 (7), 44 (100). Anal. Calcd for C13H18N5O3P: C, 48.30; H,
5.61; N, 21.66; P, 9.58. Found: C, 48.42; H, 5.63; N, 21.60; P, 9.54.
oil. Bp 122–124 ꢁC/0.05 Torr. 1H NMR (C6D6):
d
8.03 (d, J¼6.6 Hz,
2H), 7.01 (m, 3H), 4.93 (m, 1H), 2.03–1.85 (m, 2H), 1.46–1.19 (m, 4H),
0.81 (t, J¼7 Hz, 3H), 0.09 (s, 9H). 13C NMR (C6D6):
d 167.5, 165.1,
131.5, 129.2, 127.1, 124.8, 66.8, 35.8, 27.7, 22.7, 14.1, ꢀ0.1. 29Si NMR
(C6D6):
d
20.0. IR nmax (film, cmꢀ1): 3077, 2970 (br), 2881, 1612,
1560,1489,1456,1375,1262,1100 (br),1034, 970, 949, 870 (br), 778,
757, 716, 697, 508. MS (FAB) m/z (%): 304 (Mþ, 8), 290 (20), 289
(100), 248 (10), 247 (41), 100 (34), 77 (14), 75 (20), 73 (78). Anal.
Calcd for C16H24N2O2Si: C, 63.12; H, 7.95; N, 9.20. Found: C, 63.31; H,
7.88; N, 9.28.
4.9. N-(Dimorpholin-4-ylphosphoryl)-5-phenyl-1,3,4-
oxadiazole-2-carboxamide (11b)
To a solution of 1a (0.675 g, 3.09 mmol) in toluene (5 mL) was
added isocyanatophosphoryl dichloride 10 (0.495 g, 3.09 mmol) at
room temperature. After 5.5 h the reaction mixture was cooled
down to ꢀ30 ꢁC and morpholine (1.348 g, 15.47 mmol) was added.
4.10.2. 1-(5-Phenyl-1,3,4-oxadiazol-2-yl)pentan-1-ol (14a)
To a solution of 13a (0.680 g, 2.23 mmol) in methanol (10 mL)
was added 5% water solution of RbF (0.5 mL). The reaction mixture

10438
E.V. Zarudnitskii et al. / Tetrahedron 64 (2008) 10431–10442
was left for 5 h at room temperature. Solvent was evaporated in
vacuo and the residue oil was treated with water. The precipitate
formed was filtered affording 14a (0.466 g, 90%) as colorless solid.
m/z (%): 271 (MþþH, 18), 270 (Mþ, 100), 147 (17), 145 (48), 125 (71),
124 (11), 123 (48), 105 (56), 104 (27), 103 (15), 97 (34), 95 (38), 77
(69), 51 (14). Anal. Calcd for C15H11FN2O2: C, 66.66; H, 4.10; N, 10.37.
Found: C, 66.48; H, 3.98; N, 10.25.
Mp 59–60 ꢁC.1H NMR (CDCl3):
d
8.05 (d, J¼6.8 Hz, 2H), 7.56–7.48 (m,
3H), 5.02 (t, J¼6.8 Hz,1H), 3.08 (br s,1H), 2.02 (m, 2H),1.55–1.36 (m,
4H), 0.93 (t, J¼7.1 Hz, 3H).13C NMR (CDCl3):
d
168.1,165.1,131.9,129.1,
4.10.6. (4-Chlorophenyl)(5-phenyl-1,3,4-oxadiazol-2-yl)-
methanol (14e)
127.1, 123.7, 65.9, 34.9, 27.2, 22.4, 14.0. IR nmax (cmꢀ1): 3500–3000
(br), 2970, 2880,1565, 1495, 1455, 1395, 1325, 1085,1040, 1020, 985,
915, 835, 795, 715, 695, 555. MS m/z (%): 232 (Mþ, 28), 189 (17), 188
(36),187 (100),176 (80),175 (30),173(39),147 (16),105(44),104 (53),
103 (19), 77 (62), 41 (22), 32 (19), 31 (32). Anal. Calcd for C13H16N2O2:
C, 67.22; H, 6.94; N, 12.06. Found: C, 67.13; H, 6.98; N, 12.09.
Prepared according to Section 4.10, Method B. Reaction of 1a
(0.712 g, 3.26 mmol), 4-chlorobenzaldehyde 12e (0.381 g,
2.72 mmol), KF (0.016 g, 0.27 mmol), and dibenzo-18-crown-6
(0.039 g, 0.11 mmol) in toluene (5 mL) gave 0.680 g (87%) of 14e as
colorless crystals. Mp 167–168 ꢁC. 1H NMR (DMSO-d6):
d 7.98 (d,
J¼7.8 Hz, 2H), 7.66–7.56 (m, 5H), 7.49 (d, J¼8.4 Hz, 2H), 6.92 (d,
4.10.3. Phenyl(5-phenyl-1,3,4-oxadiazol-2-yl)methanol (14b)
Prepared according to Section 4.10, Method A. Reaction of 1a
(0.618 g, 2.83 mmol), benzaldehyde 12b (0.300 g, 2.83 mmol), KF
(0.016 g, 0.28 mmol), and dibenzo-18-crown-6 (0.041 g, 0.11 mmol)
in toluene (5 mL) gave 0.428 g (60%) of 14b as colorless crystals
(crystallized from ethyl acetate/cyclohexane). Mp 151–152 ꢁC. 1H
J¼5.1 Hz, 1H), 6.14 (d, J¼5.1 Hz, 1H). 13C NMR (DMSO-d6):
d 167.1,
164.3, 138.3, 132.8, 132.1, 129.4, 128.5, 128.4, 126.5, 123.1, 65.7. IR
nmax (cmꢀ1): 3250 (br), 3068, 2906, 1610, 1568, 1552, 1483, 1446,
1406, 1375, 1296, 1254, 1238, 1194, 1169, 1088, 1063, 1012, 976, 849,
783, 748, 710, 687, 540, 499. MS m/z (%): 288 (Mþþ2, 19), 287
(MþþH, 10), 286 (Mþ, 55), 147 (13), 145 (46), 143 (13), 141 (56), 139
(34), 113 (10), 105 (12), 104 (27), 103 (16), 77 (100), 51 (16). Anal.
Calcd for C15H11ClN2O2: C, 62.84; H, 3.87; Cl, 12.37; N, 9.77. Found:
C, 62.98; H, 3.95; Cl, 12.24; N, 9.61.
NMR (DMSO-d6):
d
7.96 (d, J¼6.5 Hz, 2H), 7.65–7.51 (m, 5H), 7.43–
7.31 (m, 3H), 6.81 (d, J¼4.6 Hz, 1H), 6.09 (d, J¼4.6 Hz, 1H). 13C NMR
(DMSO-d6):
d 167.4, 164.2, 139.4, 131.9, 129.3, 128.4, 128.1, 126.5,
126.4, 123.2, 66.6. IR nmax (cmꢀ1): 3442 (br), 1610, 1570, 1552, 1491,
1452, 1213, 1194, 1092, 1065, 1018, 957, 775, 742, 702, 685, 627. MS
m/z (%): 253 (MþþH, 14), 252 (Mþ, 95), 147 (22), 145 (29), 107 (53),
106 (14), 105 (100), 104 (17), 103 (13), 79 (32), 78 (10), 77 (70), 51
(19). Anal. Calcd for C15H12N2O2: C, 71.42; H, 4.79; N,11.10. Found: C,
71.42; H, 4.79; N, 11.10.
4.10.7. [4-(Benzyloxy)phenyl](5-phenyl-1,3,4-oxadiazol-2-yl)-
methanol (14f)
To a stirred solution of 4-benzyloxybenzaldehyde 12f (0.730 g,
3.44 mmol) and 1a (0.902 g, 4.13 mmol) in toluene (5 mL) were
added KF (0.020 g, 0.34 mmol) and dibenzo-18-crown-6 (0.036 g,
0.10 mmol). The mixture was heated to reflux for 1 h and then
placed into a freezer. The precipitate was filtered off and washed
with toluene. The combined filtrate and washings were evaporated
in vacuo, hot methanol (10 mL) and RbF (5% solution in water,
0.5 mL) were added to the residual oil, and the mixture was allowed
to stand for 2.5 h. The precipitate formed was filtered affording 14f
(0.930 g, 75%) as colorless crystals. Mp 193–194 ꢁC. 1H NMR (DMSO-
4.10.4. (4-Methylphenyl)(5-phenyl-1,3,4-oxadiazol-2-yl)-
methanol (14c)
Prepared according to Section 4.10, Method B. Reaction of 1a
(3.745 g, 17.15 mmol), p-tolualdehyde 12c (1.717 g, 14.29 mmol), KF
(0.083 g,1.43 mmol), and dibenzo-18-crown-6 (0.206 g, 0.57 mmol)
in toluene (20 mL) gave 2.910 g (76%) of 14c as colorless crystals
(crystallized from ethyl acetate/cyclohexane). Mp 125–126 ꢁC. 1H
d6):
(d, J¼8.7 Hz, 2H), 6.68 (d, J¼5 Hz, 1H), 6.02 (d, J¼5 Hz, 1H), 5.10 (s,
2H). 13C NMR (DMSO-d6):
167.6, 164.1, 158.2, 137.0, 132.0, 131.7,
d
7.96 (d, J¼8 Hz, 2H), 7.66–7.55 (m, 3H), 7.47–7.29 (m, 7H), 7.04
NMR (DMSO-d6):
J¼8 Hz, 2H), 7.21 (d, J¼8 Hz, 2H), 6.73 (d, J¼5 Hz,1H), 6.05 (d, J¼5 Hz,
1H), 2.30 (s, 3H). 13C NMR (DMSO-d6):
167.6, 164.2, 137.4, 136.5,
d
7.96 (d, J¼8.1 Hz, 2H), 7.64–7.56 (m, 3H), 7.42 (d,
d
d
129.4, 128.4,128.0, 127.8, 127.6, 126.5, 123.2, 114.7, 69.2, 66.2. IR nmax
(cmꢀ1): 3500–3100 (br), 3061, 3030, 2947, 2891, 1610, 1585, 1568,
1554,1510,1485,1450,1323,1304,1259,1225,1204,1174,1082,1011,
957, 849, 796, 775, 741, 708, 696, 687, 638, 615, 588, 544, 517, 438. MS
m/z (%): 358 (Mþ, 8), 92 (7), 91 (100). Anal. Calcd for C22H18N2O3: C,
73.73; H, 5.06; N, 7.82. Found: C, 73.92; H, 5.17; N, 7.69.
132.0, 129.4, 129.0, 126.5, 126.4, 123.2, 66.4, 20.7. IR nmax (cmꢀ1):
3435 (br), 3066, 2922, 1608, 1574, 1556, 1514, 1489, 1450, 1267, 1217,
1180, 1084, 1070, 1018, 957, 924, 847, 789, 771, 708, 687, 584, 530,
509. MS m/z (%): 266 (Mþ, 100), 147 (14), 121 (54), 119 (57), 105 (40),
93 (22), 91 (32), 77 (57), 65 (10). Anal. Calcd for C16H14N2O2: C, 72.17;
H, 5.30; N, 10.52. Found: C, 72.30; H, 5.24; N, 10.38.
4.10.8. (2,3-Dimethoxyphenyl)(5-phenyl-1,3,4-oxadiazol-2-yl)-
methanol (14g)
4.10.5. (4-Fluorophenyl)(5-phenyl-1,3,4-oxadiazol-2-yl)-
methanol (14d)
Prepared according to Section 4.10, Method B. Reaction of 1a
(0.889 g, 4.07 mmol), 2,3-dimethoxybenzaldehyde 12g (0.564 g,
3.39 mmol), KF (0.020 g, 0.34 mmol), and dibenzo-18-crown-6
(0.049 g, 0.14 mmol) in toluene (5 mL) gave 0.752 g (71%) of 14g as
colorless crystals (crystallized from 2-propanol). Mp 129–130 ꢁC. 1H
To a stirred solution of 4-fluorobenzaldehyde 12d (0.618 g,
4.98 mmol) and 1a (1.088 g, 4.98 mmol) in toluene (5 mL) were
added KF (0.029 g, 0.50 mmol) and dibenzo-18-crown-6 (0.036 g,
0.10 mmol). The mixture was heated to reflux for 1 h and then
placed into a freezer. The precipitate was filtered off and washed
with toluene. The combined filtrate and washings were evaporated
in vacuo, ethanol (10 mL) and KF (5% solution in water, 1 mL) were
added to the residual oil, and the mixture was allowed to stand for
2 h. The solvent was removed in vacuo and the residue was crys-
tallized from ethanol/cyclohexane affording 14d (0.864 g, 64%) as
NMR (DMSO-d6):
d
7.97 (d, J¼8.1 Hz, 2H), 7.64–7.56 (m, 3H), 7.26 (d,
J¼8.1 Hz, 1H), 7.16 (t, J¼8.1 Hz, 1H), 7.07 (d, J¼8.1 Hz, 1H), 6.72 (d,
J¼5.3 Hz,1H), 6.25 (d, J¼5.3 Hz,1H), 3.81 (s, 3H), 3.66 (s, 3H).13C NMR
(DMSO-d6):
d 167.4, 163.9, 152.0, 145.5, 132.8, 131.9, 129.4, 126.4,
124.0, 123.2, 119.0, 112.9, 61.3, 60.1, 55.7. IR nmax (cmꢀ1): 3213 (br),
2995, 2960, 2933, 2831,1608,1591,1560,1552,1485,1450,1431,1279,
1261,1221,1088,1051,1005, 962, 831, 773, 754, 714, 692. MS m/z (%):
312 (Mþ, 16), 160 (100),151 (10), 77 (19). Anal. Calcd for C17H16N2O4:
C, 65.38; H, 5.16; N, 8.97. Found: C, 65.14; H, 5.25; N, 8.81.
colorless crystals. Mp 133–134 ꢁC. 1H NMR (DMSO-d6):
d 7.97 (d,
J¼7.6 Hz, 2H), 7.65–7.58 (m, 5H), 7.26–7.22 (m, 2H), 6.84 (d, J¼4 Hz,
1H), 6.11 (d, J¼4 Hz, 1H). 13C NMR (DMSO-d6):
d 167.3, 164.2, 161.9
(d, JCF¼244.1 Hz), 135.6 (d, JCF¼2.7 Hz), 132.1, 129.4, 128.7 (d,
JCF¼8.4 Hz), 126.5, 123.1, 115.2 (d, JCF¼21.7 Hz), 65.8. 19F NMR
4.10.9. [4-(Dimethylamino)phenyl](5-phenyl-1,3,4-oxadiazol-2-yl)-
methanol (14h)
Prepared according to Section 4.10, Method A. Reaction of 1a
(0.564 g, 2.58 mmol), 4-(dimethylamino)benzaldehyde 12h (0.385 g,
(DMSO-d6):
d
ꢀ114.4. IR nmax (cmꢀ1): 3230 (br), 3074, 2895, 1892,
1608,1552,1508,1485,1450,1414,1298,1255,1219,1190,1157,1109,
1068, 1011, 976, 860, 849, 783, 734, 708, 690, 579, 525, 496, 469. MS

E.V. Zarudnitskii et al. / Tetrahedron 64 (2008) 10431–10442
10439
2.58 mmol), KF (0.015 g, 0.26 mmol), and dibenzo-18-crown-6
4.10.13. 3-Hydroxy-1-isopropyl-3-(5-phenyl-1,3,4-oxadiazol-2-yl)-
(0.037 g, 0.10 mmol) in toluene (5 mL) gave 0.310 g (41%) of 14h as
1,3-dihydro-2H-indol-2-one (14l)
colorless crystals (crystallized from ethyl acetate). Mp 155–157 ꢁC.1H
Prepared according to Section 4.10, Method B. Reaction of 1a
(0.815 g, 3.73 mmol), 1-isopropylisatin 12l (0.588 g, 3.11 mmol), KF
(0.018 g, 0.31 mmol), and dibenzo-18-crown-6 (0.045 g, 0.12 mmol)
in toluene (5 mL) gave 0.755 g (72%) of 14l as colorless crystals
(crystallized from aqueous ethanol). Mp 185–186 ꢁC. 1H NMR
NMR (CDCl3):
J¼8.6 Hz, 2H), 6.70 (d, J¼8.6 Hz, 2H), 6.02 (s, 1H), 3.62 (s, 1H), 2.94 (s,
6H). 13C NMR (CDCl3):
167.2, 165.2, 150.9, 131.7, 128.9, 127.8, 127.0,
d
7.99 (d, J¼7.3 Hz, 2H), 7.51–7.43 (m, 3H), 7.37 (d,
d
125.6, 123.7, 112.4, 68.5, 40.4. IR nmax (cmꢀ1): 3439 (br), 3066, 2920,
2883, 2850, 2800,1616,1570,1556,1525,1483,1450,1354,1207,1186,
1165, 1080,1070,1018, 957, 947, 924, 793, 737, 706, 688, 577, 534. MS
m/z (%): 296 (MþþH, 15), 295 (Mþ, 74), 278 (12), 150 (77), 149 (100),
148 (41), 122 (11), 120 (10), 105 (13), 77 (23). Anal. Calcd for
(DMSO-d6):
d
8.01 (d, J¼7.8 Hz, 2H), 7.73 (s, 1H), 7.70–7.59 (m, 3H),
7.54 (d, J¼7.5 Hz,1H), 7.42 (t, J¼7.8 Hz,1H), 7.30 (d, J¼7.8 Hz,1H), 7.12
(t, J¼7.5 Hz,1H), 4.55 (septet, J¼7 Hz,1H),1.49–1.45 (m, 6H).13C NMR
(DMSO-d6):
d 171.8, 164.7, 164.5, 142.0, 132.2, 130.6, 129.4, 128.0,
C
17H17N3O2: C, 69.14; H, 5.80; N, 14.23. Found: C, 68.97; H, 5.89; N,
126.6, 125.3, 122.8, 122.6, 110.5, 72.2, 44.0, 18.9, 18.7. IR nmax (cmꢀ1):
3286 (br), 3049, 2966, 2933, 1703 (br), 1610, 1554, 1543, 1489, 1470,
1448, 1383, 1367, 1354, 1325, 1300, 1194, 1115, 1080, 1026, 970, 922,
827, 764, 725, 687, 658, 505. MS m/z (%): 336 (MþþH, 11), 335 (Mþ,
53), 293 (15), 292 (28), 264 (15),147 (10),146 (100),145 (12),119 (12),
105 (35), 90 (12), 77 (27). Anal. Calcd for C19H17N3O3: C, 68.05; H,
5.11; N, 12.53. Found: C, 68.22; H, 5.18; N, 12.31.
14.13.
4.10.10. (5-Phenyl-1,3,4-oxadiazol-2-yl)(thien-2-yl)methanol (14i)
Prepared according to Section 4.10, Method B. Reaction of 1a
(0.887 g, 4.06 mmol), 2-thiophenecarboxaldehyde 12i (0.380 g,
3.39 mmol), KF (0.020 g, 0.34 mmol), and dibenzo-18-crown-6
(0.049 g, 0.14 mmol) in toluene (5 mL) gave 0.598 g (68%) of 14i as
yellowish crystals. Mp 152–153 ꢁC. 1H NMR (DMSO-d6):
d
7.98 (d,
4.10.14. 1-Butyl-3-hydroxy-3-(5-phenyl-1,3,4-oxadiazol-2-yl)-1,3-
dihydro-2H-indol-2-one (14m)
J¼7 Hz, 2H), 7.66–7.56 (m, 4H), 7.17 (d, J¼3.5 Hz, 1H), 7.08 (s, 1H),
7.03 (t, J¼3.5 Hz, 1H), 6.37 (s, 1H). 13C NMR (DMSO-d6):
d
166.7,
To a stirred solution of 1-butylisatin 12m (0.525 g, 2.58 mmol)
and 1a (0.620 g, 2.84 mmol) in toluene (5 mL) were added KF
(0.015 g, 0.26 mmol) and dibenzo-18-crown-6 (0.037 g, 0.10 mmol).
The mixture was heated to reflux for 3 h and then placed into
a freezer. The precipitate was filtered off and washed with toluene.
The combined filtrate and washings were evaporated in vacuo,
methanol (10 mL) and RbF (5% solution in water, 0.5 mL) were
added to the residual oil, and the mixture was allowed to stand for
24 h. The solvent was removed in vacuo and the residue was
crystallized from ethyl acetate/cyclohexane affording 14m (0.757 g,
164.3, 142.7, 132.2, 129.5, 126.8, 126.6, 126.5, 125.8, 123.1, 62.9. IR
nmax (cmꢀ1): 3425 (br), 3105, 3066, 2920, 1606, 1572, 1554, 1481,
1450, 1433, 1346, 1225, 1173, 1086, 1070, 1016, 957, 858, 802, 773,
704, 687, 644. MS m/z (%): 260 (Mþþ2, 5), 259 (MþþH,17), 258 (Mþ,
97), 145 (34), 113 (100), 112 (17), 111 (44), 104 (20), 103 (20), 85 (33),
51 (12), 45 (21). Anal. Calcd for C13H10N2O2S: C, 60.45; H, 3.90; N,
10.85; S, 12.41. Found: C, 60.59; H, 3.94; N, 10.71; S, 12.24.
4.10.11. 3-Hydroxy-1-methyl-3-(5-phenyl-1,3,4-oxadiazol-2-yl)-
1,3-dihydro-2H-indol-2-one (14j)
84%) as colorless crystals. Mp 155–156 ꢁC. 1H NMR (CDCl3):
d 7.96
Prepared according to Section 4.10, Method B. Reaction of 1a
(0.655 g, 3.00 mmol), 1-methylisatin 12j (0.403 g, 2.50 mmol), KF
(d, J¼7.3 Hz, 2H), 7.59(d, J¼7.3 Hz,1H), 7.49(distortedt, J¼7.3 Hz,1H),
7.43–7.39 (m, 3H), 7.14 (distorted t, J¼7.5 Hz, 1H), 6.93 (d, J¼7.9 Hz,
1H), 5.55 (s,1H), 3.85–3.67 (m, 2H),1.71 (m, 2H),1.42 (m, 2H), 0.95 (t,
(0.015 g,
0.25 mmol),
and
dibenzo-18-crown-6
(0.036 g,
0.10 mmol) in toluene (5 mL) gave 0.555 g (72%) of 14j as colorless
J¼7.3 Hz, 3H). 13C NMR (CDCl3):
d 172.9, 165.9, 164.1, 143.2, 132.0,
crystals (crystallized from 2-propanol). Mp 178–179 ꢁC. 1H NMR
131.2, 128.9, 127.2, 126.7, 125.8, 123.7, 123.4, 109.5, 73.0, 40.4, 29.3,
20.0,13.7. IR nmax (cmꢀ1): 3396 (br), 3300 (br), 2958, 2931, 2972,1709
(br), 1612, 1564, 1551, 1487, 1468, 1448, 1383, 1352, 1223, 1188, 1128,
1066, 918, 766, 756, 710, 688. MS m/z (%): 350 (MþþH, 23), 349 (Mþ,
100), 292 (16),148 (21),146 (71),145 (61),132 (39),119 (16),105 (64),
104(12), 90(14), 77(71), 41(16). Anal. CalcdforC20H19N3O3:C, 68.75;
H, 5.48; N, 12.03. Found: C, 68.51; H, 5.59; N, 11.94.
(DMSO-d6):
7.54 (d, J¼7.5 Hz, 1H), 7.45 (t, J¼7.5 Hz, 1H), 7.15–7.12 (m, 2H), 3.22
(s, 3H). 13C NMR (DMSO-d6):
172.1, 164.9, 164.5, 143.4, 132.2, 130.8,
d
8.01 (d, J¼7.5 Hz, 2H), 7.75 (s, 1H), 7.68–7.61 (m, 3H),
d
129.4, 127.7, 126.7, 125.1, 123.1, 122.9, 109.4, 72.3, 26.4. IR nmax
(cmꢀ1): 3448 (br), 3217 (br), 3070, 2931, 1736, 1614, 1556, 1491,
1470,1373,1350,1209,1119,1086,1061,1016, 922, 764, 756, 692. MS
m/z (%): 308 (MþþH, 19), 307 (Mþ, 100), 251 (11), 250 (14), 162 (40),
146 (17), 145 (74), 134 (11), 133 (21), 105 (49), 104 (19), 103 (13), 90
(11), 78 (14), 77 (85), 51 (13). Anal. Calcd for C17H13N3O3: C, 66.44;
H, 4.26; N, 13.67. Found: C, 66.62; H, 4.35; N, 13.53.
4.10.15. 3-Hydroxy-1-isobutyl-3-(5-phenyl-1,3,4-oxadiazol-2-yl)-
1,3-dihydro-2H-indol-2-one (14n)
Prepared according to Section 4.10, Method B. Reaction of 1a
(0.784 g, 3.59 mmol), 1-isobutylisatin 12n (0.608 g, 2.99 mmol), KF
(0.017 g, 0.30 mmol), and dibenzo-18-crown-6 (0.043 g, 0.12 mmol) in
toluene (5 mL) gave 0.863 g (83%) of 14n as colorless crystals. Mp 177–
4.10.12. 1-Benzyl-3-hydroxy-3-(5-phenyl-1,3,4-oxadiazol-2-yl)-
1,3-dihydro-2H-indol-2-one (14k)
Prepared according to Section 4.10, Method A. Reaction of 1a
(0.782 g, 3.58 mmol), 1-benzylisatin 12k (0.850 g, 3.58 mmol),
KF (0.021 g, 0.36 mmol), and dibenzo-18-crown-6 (0.052 g,
0.14 mmol) in toluene (5 mL) gave 0.840 g (61%) of 14k as colorless
crystals (crystallized from acetonitrile). Mp 184–185 ꢁC. 1H NMR
178 ꢁC. 1H NMR (DMSO-d6):
d
8.00 (d, J¼7.5 Hz, 2H), 7.81 (s, 1H), 7.69–
7.59 (m, 3H), 7.54 (d, J¼7.5 Hz, 1H), 7.43 (t, J¼7.8 Hz, 1H), 7.20 (d,
J¼7.8 Hz, 1H), 7.13 (t, J¼7.5 Hz, 1H), 3.65–3.49 (m, 2H), 2.16–2.05 (m,
1H), 0.95 (m, 6H).13CNMR(DMSO-d6):
d172.4,164.7,164.6,142.9,132.2,
130.7,129.4,127.6,126.6,125.0,122.9,122.8,109.8, 72.3, 46.8, 26.5,19.8,
19.7. IR nmax (cmꢀ1): 3356 (br), 3298 (br), 3059, 2962, 2937, 2873, 1707
(br), 1612, 1547, 1489, 1468, 1448, 1385, 1356, 1196, 1122, 1059, 1026,
1012, 922, 760, 706, 687, 656, 571, 507, 494. MS m/z (%): 350 (MþþH,
27), 349 (Mþ, 83), 293 (18), 250 (30), 148 (23), 147 (18), 146 (68), 145
(55), 133 (14), 132 (93), 105 (89), 104 (20), 103 (17), 90 (18), 78 (11), 77
(100), 57 (16), 51 (12), 41 (28), 39 (13). Anal. Calcd for C20H19N3O3: C,
68.75; H, 5.48; N, 12.03. Found: C, 68.63; H, 5.41; N, 11.91.
(DMSO-d6):
d
8.00 (d, J¼6.9 Hz, 2H), 7.91 (s, 1H), 7.69–7.62 (m, 3H),
7.55 (d, J¼7.1 Hz, 1H), 7.42–7.29 (m, 6H), 7.11 (distorted t, J¼7.1 Hz,
1H), 7.02 (d, J¼8.1 Hz, 1H), 5.00 (m, 2H). 13C NMR (DMSO-d6):
d
172.3, 164.7, 164.4, 142.2, 135.7, 132.3, 130.7, 129.4, 128.6, 127.7,
127.5, 127.1, 126.6, 125.1, 123.2, 122.8, 110.0, 72.4, 42.9. IR nmax
(cmꢀ1): 3288 (br), 3062, 2926, 1726 (br), 1610, 1552, 1487, 1468,
1450, 1369, 1221, 1178, 1124, 1080, 1057, 920, 758, 694. MS m/z (%):
384 (MþþH, 10), 383 (Mþ, 37), 293 (9), 292 (55), 264 (13), 147 (8),
146 (100),145 (5),105 (9), 92 (5), 91 (52), 90 (9), 77 (16), 65 (6). Anal.
Calcd for C23H17N3O3: C, 72.05; H, 4.47; N, 10.96. Found: C, 72.31; H,
4.62; N, 10.84.
4.10.16. 1-(5-Phenyl-1,3,4-oxadiazol-2-yl)cyclohexanol (14o)
Prepared according to Section 4.10, Method A. Reaction of 1a
(0.930 g, 4.26 mmol), cyclohexanone 12o (0.418 g, 4.26 mmol), KF

10440
E.V. Zarudnitskii et al. / Tetrahedron 64 (2008) 10431–10442
(0.025 g, 0.43 mmol), and dibenzo-18-crown-6 (0.061 g, 0.17 mmol)
in toluene (5 mL) gave 0.352 g (34%) of 14o as colorless crystals
(crystallized from ethyl acetate). Mp 137–138 ꢁC. 1H NMR (DMSO-
solution in water, 0.5 mL) were added to the residual oil and the
mixture was allowed to stand for 24 h. The solvent was removed in
vacuo and the residue was treated with water. Resulted solidified
oil was crystallized from ethanol affording 14r (0.155 g, 17%) as
d6):
(m, 2H), 1.95–1.84 (m, 2H), 1.78–1.65 (m, 2H), 1.53–1.32 (m, 4H). 13
NMR (CDCl3): 170.5, 164.7, 131.7, 128.9, 127.0, 123.8, 69.7, 36.1, 25.1,
d
8.01 (d, J¼7.5 Hz, 2H), 7.67–7.57 (m, 3H), 5.74 (s,1H), 2.11–1.99
C
colorless crystals. Mp 143–144 ꢁC. 1H NMR (DMSO-d6):
d
7.97 (d,
J¼7.2 Hz, 2H), 7.65–7.58 (m, 4H), 7.49–7.32 (m, 7H), 7.21 (t, J¼8.4 Hz,
2H). 13C NMR (CDCl3):
d
21.6. IR nmax (cmꢀ1): 3263 (br), 2953, 2935, 2854, 1608, 1562,
1551, 1485, 1452, 1419, 1371, 1354, 1267, 1244, 1159, 1142, 1074, 1043,
982, 974, 926, 852, 785, 741, 710, 690. MS m/z (%): 244 (Mþ, 32), 202
(12), 201 (15),187 (14),174 (15),173 (100),160 (66),147 (19),105 (26),
104 (10), 103 (12), 77 (38), 55 (22), 41 (21). Anal. Calcd for
d
168.9, 165.7, 162.7 (d, JCF¼248 Hz), 142.3,
138.2 (d, JCF¼3.2 Hz), 132.1, 129.3, 129.2, 129.1, 128.7, 128.6, 127.1 (d,
JCF¼4.9 Hz), 123.4, 115.3 (d, JCF¼22 Hz), 77.2. 19F NMR (DMSO-d6):
d
ꢀ115.1. IR nmax (cmꢀ1): 3236 (br), 3061, 1605, 1556, 1508, 1491,
1450, 1363, 1227, 1223, 1180, 1159, 1086, 1065, 1016, 895, 825, 812,
779, 754, 708, 688, 663, 582, 534, 496. MS m/z (%): 346 (Mþ, 22),
269 (11), 241 (20), 223 (23), 213 (8), 200 (19), 146 (10), 123 (97), 105
(100), 95 (32), 77 (60), 51 (16). Anal. Calcd for C21H15FN2O2: C,
72.82; H, 4.37; N, 8.09. Found: C, 72.69; H, 4.43; N, 8.18.
C
14H16N2O2: C, 68.83; H, 6.60; N, 11.47. Found: C, 68.71; H, 6.72; N,
11.29.
4.10.17. 4-Methyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)-
cyclohexanol (14p)
To a stirred solution of 4-methylcyclohexanone 12p (0.390 g,
3.47 mmol) and 1a (0.834 g, 3.82 mmol) in toluene (5 mL) were
added KF (0.020 g, 0.35 mmol) and dibenzo-18-crown-6 (0.050 g,
0.14 mmol). The mixture was heated to reflux for 4.5 h and then
placed into a freezer. The precipitate was filtered off and washed
with toluene. The combined filtrate and washings were evaporated
in vacuo, methanol (10 mL) and RbF (5% solution in water, 0.5 mL)
were added to the residual oil, and the mixture was allowed to
stand for 24 h. The solvent was removed in vacuo and the residue
was crystallized from ethyl acetate/cyclohexane affording 14p
(0.132 g, 15%) as colorless crystals. Mp 149–150 ꢁC. 1H NMR (DMSO-
4.10.20. 9-(5-Phenyl-1,3,4-oxadiazol-2-yl)-9H-fluoren-9-ol (14s)
Prepared according to Section 4.10, Method A. Reaction of 1a
(0.923 g, 4.23 mmol), 9-fluorenone 12s (0.762 g, 4.23 mmol), KF
(0.025 g, 0.42 mmol), and dibenzo-18-crown-6 (0.061 g, 0.17 mmol)
in toluene (5 mL) gave 0.970 g (70%) of 14s as colorless crystals.
Mp 217–218 ꢁC. 1H NMR (DMSO-d6):
d
8.03 (d, J¼8.1 Hz, 2H), 7.87
(d, J¼7.5 Hz, 2H), 7.81 (d, J¼7.2 Hz, 2H), 7.68–7.59 (m, 3H), 7.50
(t, J¼7.5 Hz, 2H), 7.41 (t, J¼7.2 Hz, 2H), 7.27 (s, 1H). 13C NMR (DMSO-
d6):
d 167.3, 164.5, 145.0, 139.2, 131.9, 129.7, 129.3, 128.0, 126.4,
125.5, 123.0, 120.2, 77.3. IR nmax (cmꢀ1): 3247 (br), 3054, 2811, 1606,
1556,1540,1483,1450,1415,1191,1103,1062,1016, 960, 921, 771, 736,
725, 707, 696, 690, 588, 424. MS m/z (%): 326 (Mþ, 73), 195 (9), 181
(100), 152 (42), 145 (27), 105 (26), 77 (35), 51 (6). Anal. Calcd for
d6):
d
8.00 (d, J¼7.5 Hz, 2H), 7.64–7.58 (m, 3H), 5.90 (s, 1H), 2.41 (m,
2H), 1.67 (m, 4H), 1.46 (m, 1H), 0.99 (m, 2H), 0.81 (d, J¼6 Hz, 3H). 13
C
NMR (DMSO-d6):
d
169.0, 163.7, 131.9, 129.4, 126.4, 123.4, 68.8, 35.9,
C21H14N2O2: C, 77.29; H, 4.32; N, 8.58. Found: C, 77.21; H, 4.38; N,
31.1, 30.6, 21.2. IR nmax (cmꢀ1): 3294 (br), 2951, 2933, 2862, 1560,
1487, 1450, 1400, 1365, 1342, 1103, 1059, 1018, 1012, 966, 783, 748,
706, 696. MS m/z (%): 258 (Mþ, 17), 201 (30), 189 (16), 188 (17), 187
(100), 173 (30), 161 (10), 160 (78), 147 (24), 105 (25), 104 (11), 103
(12), 77 (30), 55 (29), 43 (10), 41 (17). Anal. Calcd for C15H18N2O2: C,
69.74; H, 7.02; N, 10.84. Found: C, 69.52; H, 7.15; N, 10.63.
8.45.
4.10.21. (4-Fluorophenyl)(1-methyl-1H-imidazol-2-yl)(5-phenyl-
1,3,4-oxadiazol-2-yl)methanol (14t)
Prepared according to Section 4.10, Method B. Reaction of 1a
(0.689 g, 3.16 mmol), (4-fluorophenyl)(1-methyl-1H-imidazol-2-
yl)methanone 12t (0.537 g, 2.63 mmol), KF (0.015 g, 0.26 mmol),
and dibenzo-18-crown-6 (0.038 g, 0.11 mmol) in xylene (5 mL) gave
0.303 g (27%) of 14t as colorless crystals (crystallized from acetoni-
4.10.18. Diphenyl(5-phenyl-1,3,4-oxadiazol-2-yl)methanol (14q)22
To a stirred solution of benzophenone 12q (0.396 g, 2.17 mmol)
and 1a (0.711 g, 3.26 mmol) in toluene (5 mL) were added KF
trile). Mp 212–213 ꢁC.1H NMR (DMSO-d6):
d
8.03–7.96 (m, 3H), 7.65–
7.60 (m, 3H), 7.39 (m, 2H), 7.27–7.20 (m, 3H), 6.80 (s,1H), 3.39 (s, 3H).
13C NMR (DMSO-d6):
(0.013 g,
0.22 mmol)
and
dibenzo-18-crown-6
(0.031 g,
0.09 mmol). The mixture was heated to reflux for 4 h and then
placed into a freezer. The precipitate was filtered off and washed
with toluene. The combined filtrate and washings were evaporated
in vacuo, methanol (10 mL) and RbF (5% solution in water, 0.5 mL)
were added to the residual oil, and the mixture was allowed to
stand for 24 h. The solvent was removed in vacuo and the residue
was treated with water affording the crude product as colorless
solidified oil. Flash chromatography using ethyl acetate/hexane
(1:3) as the eluant afforded the title compound 14q (0.360 g, 50%)
d
168.0, 164.5, 161.8 (d, JCF¼244.7 Hz), 146.3,
136.0 (d, JCF¼3.2 Hz), 132.0,129.4,128.5 (d, JCF¼8.3 Hz), 126.4, 125.8,
123.9, 123.2, 114.8 (d, JCF¼21.5 Hz), 73.2, 33.6 (d, J¼1.8 Hz). 19F NMR
(DMSO-d6):
d
ꢀ114.6. IR nmax (cmꢀ1): 3442 (br), 2920 (br), 2698 (br),
1605,1549,1508,1487,1448,1410,1356,1286,1225,1178,1161,1080,
1020, 914, 904, 835, 781, 764, 733, 712, 704, 696, 687, 596, 559, 526,
478. MS m/z (%): 351 (MþþH, 11), 350 (Mþ, 54), 255 (13), 205 (25),
204 (34), 203 (80),189 (10),188 (88),187 (100),176 (32),175 (72),146
(52),124(19),123 (92),109 (49),105 (41),103 (15), 95(68), 90 (15), 82
(15), 77 (40), 75 (15), 51 (11), 42 (9). Anal. Calcd for C19H15FN4O2: C,
65.14; H, 4.32; N, 15.99. Found: C, 64.89; H, 4.18; N, 16.11.
as colorless solid. Mp 153–154 ꢁC. 1H NMR (DMSO-d6):
d 7.96 (d,
J¼7.5 Hz, 2H), 7.65–7.58 (m, 3H), 7.43–7.30 (m, 11H). 13C NMR
(DMSO-d6):
d 169.1, 164.3, 143.4, 131.9, 129.3, 127.8, 127.6, 126.5,
126.4, 123.1, 76.1. IR nmax (cmꢀ1): 3433 (br), 3062, 1610, 1560, 1547,
1493, 1448, 1362, 1344, 1234, 1169, 1053, 1009, 891, 779, 760, 750,
741, 698, 690, 634, 530, 472. MS m/z (%): 328 (Mþ, 16), 251 (16), 223
(44), 105 (100), 77 (43). Anal. Calcd for C21H16N2O2: C, 76.81; H,
4.91; N, 8.53. Found: C, 76.88; H, 4.85; N, 8.44.
4.10.22. (3,4-Dimethylphenyl)(1-methyl-1H-imidazol-2-yl)-
(5-phenyl-1,3,4-oxadiazol-2-yl)methanol (14u)
Prepared according to Section 4.10, Method B. Reaction of 1a
(0.737 g, 3.38 mmol), (3,4-dimethylphenyl)(1-methyl-1H-imida-
zol-2-yl)methanone 12u (0.602 g, 2.81 mmol), KF (0.016 g,
0.28 mmol), and dibenzo-18-crown-6 (0.041 g, 0.11 mmol) in xy-
lene (5 mL) gave 0.171 g (17%) of 14u as colorless crystals (crystal-
lized from ethyl acetate). Mp 193–194 ꢁC. 1H NMR (DMSO-d6):
4.10.19. (4-Fluorophenyl)(phenyl)(5-phenyl-1,3,4-oxadiazol-2-
yl)methanol (14r)
To a stirred solution of 4-fluorobenzophenone 12r (0.527 g,
2.63 mmol) and 1a (0.575 g, 2.63 mmol) in toluene (7 mL) were
added KF (0.030 g, 0.52 mmol) and dibenzo-18-crown-6 (0.038 g,
0.11 mmol). The mixture was heated to reflux for 6 h and then the
solvent was removed in vacuo. Methanol (20 mL) and NaF (5%
d
7.95 (d, J¼6.5 Hz, 2H), 7.76 (s, 1H), 7.66–7.57 (m, 3H), 7.16 (m, 3H),
7.01 (d, J¼7.8 Hz, 1H), 6.77 (s, 1H), 3.36 (s, 3H), 2.23 (s, 3H), 2.21 (s,
3H). 13C NMR (DMSO-d6):
168.4, 164.3, 146.7, 137.3, 136.1, 135.7,
d
131.9, 129.4, 129.1, 127.2, 126.4, 125.6, 123.7, 123.6, 123.3, 73.4, 33.6,
19.6,19.0. IR nmax (cmꢀ1): 3439 (br), 3059 (br), 2760 (br),1558,1549,

E.V. Zarudnitskii et al. / Tetrahedron 64 (2008) 10431–10442
10441
1487, 1450, 1389, 1362, 1284, 1201, 1144, 1124, 1068, 1020, 908,
4.10.25. 2,2,2-Trifluoro-1-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-
yl)ethanol (14x)
876, 841, 818, 769, 706, 692. MS m/z (%): 361 (MþþH, 18), 360 (Mþ,
75), 255 (37), 215 (15), 214 (24), 213 (43),199 (11),198 (45),197 (12),
186 (23), 185 (36), 184 (14), 183 (100), 146 (20), 133 (39), 124 (12),
109 (38), 105 (50), 103 (16), 79 (14), 77 (35). Anal. Calcd for
Prepared according to Section 4.10, Method B. Reaction of 1a
(1.050 g, 4.81 mmol), 2,2,2-trifluoroacetophenone 12x (0.698 g,
4.01 mmol), KF (0.023 g, 0.40 mmol), and dibenzo-18-crown-6
(0.058 g, 0.16 mmol) in toluene (5 mL) gave 1.118 g (87%) of 14x as
colorless solid (crystallized from cyclohexane). Mp 106–108 ꢁC. 1H
C
21H20N4O2: C, 69.98; H, 5.59; N, 15.54. Found: C, 70.11; H, 5.51; N,
15.38.
NMR (DMSO-d6):
d
8.59 (br s, 1H), 7.97 (d, J¼7.5 Hz, 2H), 7.68–7.55
4.10.23. (2E)-1-(4-Fluorophenyl)-3-(4-methylphenyl)-1-(5-phenyl-
1,3,4-oxadiazol-2-yl)prop-2-en-1-ol (14v)
(m, 5H), 7.49 (m, 3H). 13C NMR (DMSO-d6):
d
164.9, 163.2, 134.2,
132.5, 129.7, 129.5, 128.5, 126.8, 126.7, 123.6 (q, JCF¼287 Hz), 122.6,
To a stirred solution of (2E)-1-(4-fluorophenyl)-3-(4-methyl-
phenyl)prop-2-en-1-one 12v (0.462 g, 1.92 mmol) and 1a (0.840 g,
3.85 mmol) in toluene (5 mL) were added KF (0.011 g, 0.19 mmol)
and dibenzo-18-crown-6 (0.028 g, 0.08 mmol). The mixture was
heated to reflux for 1 h and then placed into a freezer. The pre-
cipitate was filtered off and washed with toluene. The combined
filtrate and washings were evaporated in vacuo, methanol (10 mL)
and RbF (5% solution in water, 0.5 mL) were added to the residual
oil, and the mixture was allowed to stand for 72 h. The precipitate
formed was filtered affording 14v (0.530 g, 71%) as colorless crys-
74.7 (q, JCF¼30.6 Hz). 19F NMR (DMSO-d6):
d
ꢀ76.6. IR nmax (cmꢀ1):
3300–2950 (br), 2810 (br), 2640 (br), 1608, 1557, 1490, 1458, 1417,
1373, 1280, 1197, 1183, 1130, 1104, 1080, 1037, 1001, 959, 929, 732,
717, 702, 671, 608, 525. MS m/z (%): 321 (MþþH, 6), 320 (Mþ, 11),
252 (6), 251 (38), 145 (13), 106 (8), 105 (100), 103 (8), 77 (39), 51 (6).
Anal. Calcd for C16H11F3N2O2: C, 60.00; H, 3.46; N, 8.75. Found: C,
59.89; H, 3.55; N, 8.63.
4.10.26. 2,2,2-Trifluoro-1-(1-methyl-1H-imidazol-2-yl)-1-
(5-phenyl-1,3,4-oxadiazol-2-yl)ethanol (14y)
tals. Mp 161–162 ꢁC. 1H NMR (DMSO-d6):
d
7.97 (d, J¼8.3 Hz, 2H),
Prepared according to Section 4.10, Method A. Reaction of 1a
(0.740 g, 3.39 mmol), 2,2,2-trifluoro-1-(1-methyl-1H-imidazol-2-
yl)ethanone 12y (0.603 g, 3.39 mmol), KF (0.020 g, 0.34 mmol), and
dibenzo-18-crown-6 (0.049 g, 0.14 mmol) in toluene (5 mL) gave
0.717 g (65%) of 14y as colorless crystals (crystallized from ethyl
7.64–7.56 (m, 5H), 7.42 (d, J¼7.8 Hz, 2H), 7.27–7.21 (m, 3H), 7.16 (d,
J¼7.8 Hz, 2H), 6.99 (d, J¼16 Hz, 1H), 6.71 (d, J¼16 Hz, 1H), 2.29 (s,
3H). 13C NMR (DMSO-d6):
d
168.7, 164.5, 161.7 (d, JCF¼244.3 Hz),
138.5 (d, JCF¼3.1 Hz), 137.5, 133.0, 132.1, 130.5, 129.4, 129.3, 129.0,
128.1 (d, JCF¼8.3 Hz), 126.8, 126.6, 123.2, 115.1 (d, JCF¼21.4 Hz), 73.5,
acetate/cyclohexane). Mp 170 ꢁC (dec). 1H NMR (DMSO-d6):
d
8.97
(br s, 1H), 8.00 (d, J¼6.9 Hz, 2H), 7.71–7.60 (m, 3H), 7.32 (s, 1H), 6.88
(s, 1H), 3.79 (s, 3H). 13C NMR (DMSO-d6):
165.0, 162.3, 138.8, 132.5,
20.8. 19F NMR (DMSO-d6):
d
ꢀ115.2. IR nmax (cmꢀ1): 3282 (br), 1605,
1545, 1508, 1485, 1450, 1227, 1161, 1082, 1038, 1009, 976, 918, 841,
816, 748, 708, 685, 548, 530, 505. MS m/z (%): 387 (MþþH, 10), 386
(Mþ, 41), 358 (12), 263 (10), 241 (11), 240 (32), 239 (37), 225 (57),
213 (11), 212 (48), 197 (14), 145 (41), 136 (21), 132 (20), 120 (20), 119
(14), 117 (24), 115 (28), 105 (100), 104 (12), 103 (37), 95 (52), 92 (22),
91 (26), 90 (12), 89 (11), 77 (43), 76 (12), 75 (10), 51 (14), 39 (14).
Anal. Calcd for C24H19FN2O2: C, 74.60; H, 4.96; N, 7.25. Found: C,
74.44; H, 5.08; N, 7.13.
d
129.5, 127.0, 126.8, 125.3, 123.2 (q, JCF¼285.5 Hz), 122.7, 74.0 (q,
JCF¼32 Hz), 34.5. 19F NMR (DMSO-d6):
d
ꢀ75.2. IR nmax (cmꢀ1): 3425
(br), 3118, 1610, 1560, 1552, 1489, 1448,1396, 1362, 1279, 1244,1196,
1182,1165,1117,1088,1018, 955, 931, 906, 768, 712, 685, 523. MS m/z
(%): 324 (Mþ, 4), 255 (62), 179 (58), 145 (16), 109 (100), 103 (14), 81
(13), 77 (49), 54 (18), 42 (18). Anal. Calcd for C14H11F3N4O2: C, 51.86;
H, 3.42; N, 17.28. Found: C, 51.74; H, 3.48; N, 17.19.
4.10.24. (2E)-1,3-Bis(4-fluorophenyl)-1-(5-phenyl-1,3,4-oxadiazol-
2-yl)prop-2-en-1-ol (14w)
Acknowledgements
To a stirred solution of (2E)-1,3-bis(4-fluorophenyl)prop-2-en-
1-one 12w (0.425 g, 1.74 mmol) and 1a (0.760 g, 3.48 mmol) in
toluene (5 mL) were added KF (0.010 g, 0.17 mmol) and dibenzo-
18-crown-6 (0.025 g, 0.07 mmol). The mixture was heated to reflux
for 1 h and then placed into a freezer. The precipitate was filtered
off and washed with toluene. The combined filtrate and washings
were evaporated in vacuo, methanol (10 mL) and RbF (5% solution
in water, 0.5 mL) were added to the residual oil, and the mixture
was allowed to stand for 72 h. The solvent was removed in vacuo
and the residue was treated with water. The precipitate formed was
crystallized from 2-propanol and then subjected to column chro-
matography over silica gel affording 14w (0.414 g, 61%) as colorless
We thank Enamine Co., Ukraine for the financial support of this
work.
References and notes
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solid. Mp 148–149 ꢁC. 1H NMR (DMSO-d6):
d
7.98 (d, J¼7.5 Hz, 2H),
7.66–7.57 (m, 7H), 7.30 (s, 1H), 7.26–7.17 (m, 4H), 7.03 (d, J¼16 Hz,
1H), 6.78 (d, J¼16 Hz, 1H). 13C NMR (DMSO-d6):
d 168.5, 164.5, 161.9
(d, JCF¼245.2 Hz), 161.6 (d, JCF¼244.7 Hz), 138.3 (d, JCF¼3.2 Hz),
132.4 (d, JCF¼3.2 Hz), 132.1, 131.4 (d, JCF¼1.8 Hz), 129.4, 128.8 (d,
JCF¼8.2 Hz), 128.1 (d, JCF¼8.2 Hz), 127.9, 126.6, 123.1, 115.5 (d,
JCF¼21.5 Hz), 115.1 (d, JCF¼21.5 Hz), 73.4. 19F NMR (DMSO-d6):
d
ꢀ114.2, ꢀ115.1. IR nmax (cmꢀ1): 3321 (br), 3066, 1603, 1558, 1508,
1483, 1448, 1414, 1365, 1346, 1306, 1230, 1159, 1093, 1068, 1045,
1011, 972, 924, 866, 843, 822, 783, 750, 708, 694, 667, 596, 530, 505,
492. MS m/z (%): 391 (MþþH, 11), 390 (Mþ, 44), 362 (24), 267 (21),
244 (42), 243 (28), 217 (15), 216 (76), 215 (15),150 (11),149 (52),148
(14), 146 (26), 136 (74), 124 (19), 123 (100), 122 (14), 121 (36), 109
(48), 105 (37), 104 (14), 103 (30), 101 (31), 95 (55), 77 (52), 75 (17),
51 (15). Anal. Calcd for C23H16F2N2O2: C, 70.76; H, 4.13; N, 7.18.
Found: C, 70.85; H, 4.12; N, 7.01.
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