A New Convergent Synthesis of 4,4′-Bispyridyl-5,5′ -Disubstituted-2,2-Bisoxazoles and -Bisthiazoles

Article abstract of DOI:10.1055/s-2003-42085

A convergent strategy for the synthesis of 4,4′-bispyridyl-5,5′ -disubstituted-2,2′-bisoxazoles and -bisthiazoles from diamides has been achieved.

Full text of DOI:10.1055/s-2003-42085

PAPER
2211
A New Convergent Synthesis of 4,4 -Bispyridyl-5,5 -Disubstituted-2,2-Bisoxa-
zoles and -Bisthiazoles
S
ynthesis of 4,4 -B
o
ispyridyl-5,5
l
-Disu
a
bstituted-2,
n
2-Bisoxazole
d
s
and -Bisth
a
iazoles Martín-Cantalejo,*a Beatriz Sáez,a Javier Soto,a María Jesús Villa,a Miguel F. Brañab
a
Departamento de Química y Materiales, Escuela Superior Politécnica, Universidad Europea de Madrid, C/Tajo s/n, Villaviciosa deOdón,
28670, Madrid, Spain
Fax +34(916)168265; E-mail: yolanda.martin@qui.cie.uem.es
b
Departamento de Ciencias Químicas, Facultad de Ciencias Experimentales y Técnicas, Universidad San Pablo CEU, Boadilla del Monte,
28668, Madrid, Spain
Received 28 May 2003; revised 26 June 2003
Reaction of 4,4 -bis(trifluoromethyl)-substituted hetero-
1,3-dienes with tin(II) chloride provided 4,4 -trifluorome-
thyl-5,5 -difluor-2,2 -bisoxazoles and their corresponding
thiazoles in low yields.8 A series of symmetrical 5,5 -
bisoxazoles were synthesized by nucleophilic substitution
of 5-fluoroxazoles with binucleophiles.9 This methodolo-
gy has been extended to the preparation of polymers with
a 2,2 -bisoxazole structure.10
Abstract: A convergent strategy for the synthesis of 4,4 -bispy-
ridyl-5,5 -disubstituted-2,2 -bisoxazoles and -bisthiazoles from di-
amides has been achieved.
Key words: heterocycles , amides, oxazoles, thiazoles, fluorine
In recent years oxazole and thiazole moieties have been of
great interest in the field of organic synthesis as the core
of complex biologically active molecules.1 As a part of
our work related to the development of new antitumor
agents, we became interested in the synthesis of 2,2 -
bisoxazoles 1 and 2,2 -bisthiazoles 2, molecules structur-
ally related to hemicolinium 3 after quaternization of the
pyridine nitrogen, which has a potent in vitro activity
against HT-29 carcinoma cells2 (Figure 1).
In this paper, we wish to report our preliminary studies on
the conversion of symmetrical diamides into 4,4 -bispy-
ridyl-5,5 -disubstituted-2,2 -bisoxazoles 1 and -bisthia-
zoles 2 using a convergent strategy.
We devised two synthetic pathways, described in
Scheme 1.
Method A explores a synthetic strategy related to the one
described by Braña et al. to obtain 5-alkyl-2-aryl-4-py-
ridyloxazoles.11 Acylation of 4-aminomethylpyridine
with different acylating agents, either carboxylic diacids
in the presence of a condensation reagent or acid chlo-
rides,12 lead to a series of N,N -bis(4-pyridylmethylen)di-
amides 4 with different spacers Z, both alkylic and arylic.
Bisoxazole and bisthiazole cores found in nature com-
monly exhibit a 2,4 linkage, and they are generally con-
structed by a stepwise formation of the rings3,4 or by
cross-coupling of previously synthesized heterocycles.5,6
However, central to our strategy for the synthesis of 2,2 -
bisoxazoles and -bisthiazoles was the avoidance of a step-
wise methodology. Few examples of symmetrically
linked bisoxazoles and bisthiazoles have been reported,
and much more scarce are those examples of 2,2 -bisox-
azoles and -bisthiazoles in which, following a convergent
strategy, both rings are simultaneously assembled. We
must stress that the direct application of a methodology to
synthesize an oxazole does not afford necessarily the cor-
responding symmetrical bisoxazole. Thus, 5,5 -biphenyl-
2,2 -bisoxazole was obtained in a 25% yield when 5-phe-
nyloxazole-2-yllithium was reacted with tosyl fluoride.7
Then, when diamides 4 were treated with ethyl chlorofor-
mate and triethylamine in acetone, N,N -bis(1-ethoxycar-
bonyl-1,4-dihydropyridylmethylen)diamides
5
were
obtained as non-soluble products containing triethylam-
monium hydrochloride (a 1:5 relationship according to 1H
NMR).13 Although free anhydrobases 5 could be purified
and characterized,14 nucleophilic addition–cyclization
was always accomplished by refluxing non-purified anhy-
drobases 5 with acetic anhydride using SnCl4 as catalyst.
In this way, 5,5 -dimethyl-4,4 -bispyridyl-2,2 -bisox-
Z
X
X
OH
HO
O
R
O
R
N
N
H3C
N
N
CH3
CH3
CH3
N
N
3
1
2
X = O
X = S
Figure 1
Synthesis 2003, No. 14, Print: 02 10 2003. Web: 24 09 2003.
Art Id.1437-210X,E;2003,0,14,2211,2215,ftx,en;P04003SS.pdf.
DOI: 10.1055/s-2003-42085
© Georg Thieme Verlag Stuttgart · New York

2212
Y. Martín-Cantalejo et al.
PAPER
W
Z
W
N
CH2NH2
O
O
W = OH, Cl
Z = (CH3)2C, p-phenyl, p-biphenyl, p,p´-phenyloxyphenyl,
p,p´-PhC(CF3)2Ph, -CH2CH2-, (-).
O
O
N
Z
N
H
H
N
N
ClCO2Et
Et3N
4
Lawesson
reagent
H
N
H
Z
N
S
S
METHOD B
O
O
N
Z
N
H
H
N
N
5
6
N
N
CO2Et
CO2Et
Z
X
X
R
METHOD B
METHOD A
R
N
N
N
N
1 X = O
2 X = S
R = CH3, CF3, CF3CF2, CF3CF2CF2
Method A: Pyridine, (RCO)2O, (R = CF3,CF3CF2, CF3CF2CF2); Method B:SnCl4, (RCO)2O, (R = CH3)
Scheme 1
Table 1 5,5 -Dimethylbisoxazoles 1a–e
prolines and N-acyl-N-benzyl- -amino acids were treated
with trifluoroacetic anhydride.16
Entry
Compound
Z
Yield (%)
First, method A was applied by refluxing anhydrobases 5
with trifluoroacetic anhydride but, even increasing reac-
tion times and/or reaction temperatures (different solvents
were used), starting material was always recovered. A
new synthetic strategy seemed to be required. Then, meth-
od B was devised and we obtained 5,5 -bistrifluorometh-
ylbisoxazoles 1i–j, 5,5 -bispentafluoroethylbisoxazole
1k, and 5,5 -bisheptafluoropropylbisoxazole 1l in low to
excellent yields (20–98%) by treating diamide 4a with the
corresponding perfluoroalkyl anhydride and pyridine in
anhyd toluene as solvent (Table 2).
1
2
3
4
5
1a
1b
1c
1d
1e
CH3-C-CH3
p-biphenyl
p-phenyl
CH2CH2
–
80
100
32
65
47
azoles 1a–e were obtained in moderate to excellent yields
(32–100%) (Table 1).
As it has been previously mentioned, we were also inter-
ested in 2,2 -bisthiazoles as potential anticancer agents,
and we planned to extend our methodology by reaction of
thioamides with anhydrides (Scheme 1).
At this point our interest focussed on the preparation of
5,5 -bistrifluoromethyl- and 5,5 -bisperfluoroalkylbisox-
azoles. It has been reported that perfluoroalkyl substituted
derivatives sometimes exhibit advantageous chemical and
physical properties compared to those of the correspond-
ing alkyl compounds, as well as an ability to enhance bio-
logical activities.15 This behaviour has raised interest in
the development of methodologies towards their synthe-
sis. Nevertheless, the synthesis of 5-perfluoroalkylox-
azoles scarcely appears in the literature. One example is
the obtention of 5-trifluoromethyloxazoles when N-acyl-
Thus, reaction of diamides 4 with Lawesson’s reagent
(anisyldithiophosphine anhydride) in boiling tetrahydro-
furan gave the corresponding dithioamides 6 in quantita-
tive yields.17 When dithioamides 6 were reacted with
fluorinated anhydrides in anhyd toluene in the presence of
pyridine, 5,5 -bisthiazoles 2 were obtained in low to mod-
erate yields (20–52%) (Table 3).
Synthesis 2003, No. 14, 2211–2215 © Thieme Stuttgart · New York

PAPER
Synthesis of 4,4′-Bispyridyl-5,5′-Disubstituted-2,2-Bisoxazoles and -Bisthiazoles
2213
ed under reduced pressure. Cooled H2O was added (3 mL) and when
solid, the residue was filtered off and successively washed with aq
NaHCO3 (5%), H2O and acetone. The obtained crude contained the
5,5 -dimethyl bisoxazole as main product and it was always used
without a further purification.
Table 2 5,5 -Perfluoroalkyl Bisoxazoles 1f–l
Entry Com-
pound
R
Z
Yield
(%)
1
2
3
4
5
6
7
1f
1g
1h
1i
CF3
Me2C
50
48
34
30
98
40
20
2,2-Bis[5-methyl-4-(4-pyridyl)oxazolyl]propane (1a)
CF3
p-biphenylene
p,p -phenyloxyphenylene
p-phenyl
IR (KBr): 3432, 1621, 1596, 1543, 1458, 1415 cm–1.
1H NMR (300 MHz, DMSO-d6): = 2.54 (s, 6 H, CH3), 7.60 (d, 4
H, J = 6.0 Hz, Pyr), 8.57 (d, 4 H, J = 6.0 Hz, Pyr).
13C NMR:(75 MHz, DMSO-d6): = 11.8, 25.0, 38.0, 120.3, 131.3,
138.8, 147.5, 149.9, 163.3.
MS: m/z = 360 (M+, 68), 345 (47), 317 (6), 201 (100), 159 (7), 106
CF3
CF3
1j
1k
1l
CF3
p,p -PhC(CF3)2Ph
p-biphenylene
p-phenylene
CF3CF2
CF3CF2CF2
(5), 69 (81).
Anal. Calcd for C21H20N4O2: C, 69.98; H, 5.59; N, 15.55. Found: C,
69.87; H, 5.54; N, 15.49.
4,4 -Bis[5-methyl-4-(4-pyridyl)oxazolyl]biphenyl (1b)
Table 3 5,5 -Perfluoroalkylbisthiazoles 2
IR (KBr): 3436, 1670, 1622, 1452 cm–1.
Entry
Com-
pound
R
Z
Yield
(%)
1H NMR (300 MHz, DMSO-d6): = 2.72 (s, 6 H, CH3), 7.60 (d, 4
H, J = 4.1, Pyr), 7.80 (d, 4 H, J = 8.5, Ph), 8.11 (d, 4 H, J = 8.5, Ph),
8.61 (d, 4 H, J = 4.1, Pyr).
13C NMR (75 MHz, CDCl3): = 11.9, 122.3, 122.4, 122.5, 122.6,
122.7, 122.8, 122.9, 124.6, 125.3, 127.4, 127.8, 131.3, 136.3, 140.0,
143.1, 147.0, 160.0.
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
CF3
Me2C
25
31
25
25
52
20
21
CF3
p-biphenylene
p,p -phenyloxyphenylene
p-phenylene
CF3
Anal. Calcd for C30H22N4O2: C, 76.58; H, 4.71; N, 11.91. Found: C,
76.35; H, 4.69; N, 11.87.
CF3
CF3
p,p -PhC(CF3)2Ph
p-biphenylene
p-phenylene
1,4-Bis[5-methyl-4-(4-pyridyl)oxazolyl]benzene (1c)
IR (KBr): 3439, 1634, 1600, 1493, 1414 cm–1.
CF3CF2
CF3CF2
1H NMR (300 MHz, CDCl3–TFA-d1): = 2.88 (s, 6 H, CH3), 8.26
(s, 4 H, Ph), 8.35 (d, 4 H, J = 6.0, Pyr), 8.85 (d, 4 H, J = 6.0, Pyr).
2g
13C NMR (75 MHz, CDCl3): = 11.9, 122.0, 122.4, 127.5, 128.5,
131.0, 136.8, 140.1, 140.3, 150.1, 150.3, 159.7.
In summary, in this work we have described a short and
convergent new methodology to the synthesis of symmet-
ric 5,5 -disubstituted bisoxazoles and bisthiazoles with a
2,2 linkage but restricted to 4,4 -pyridyl substituents.
Moreover, in a one-pot reaction the two heterocyclic rings
are simultaneously constructed from easily available
amides or anhydrobases. Studies towards improving the
accessibility of other substituents at position 5 of the het-
erocyclic ring are now under way.
Anal. Calcd for C24H18N4O2: C, 73.08; H, 4.60; N, 14.20. Found: C,
72.86; H, 4.59; N, 14.16.
1,2-Bis[5-methyl-4-(4-pyridyl)oxazolyl]ethane (1d)
IR (KBr): 3430, 2975, 2938, 2739, 1636, 1475 cm–1.
1H NMR (300 MHz, DMSO-d6): = 2.53 (s, 6 H, CH3), 3.22 (s, 4
H, CH2), 7.57 (d, 4 H, J = 6.1, Pyr), 8.55 (d, 4 H, J = 6.1, Pyr).
13C NMR (75 MHz, DMSO-d6): = 11.8, 24.5, 120.3, 131.2, 139.1,
146.8, 150.1, 150.2, 161.0.
Anal. Calcd for C20H18N4O2: C, 69.35; H, 5.24; N, 16.17. Found: C,
69.07; H, 5.22; N, 16.10.
1
The H and 13C NMR spectra were recorded on a Brüker AC 300
spectrometer with Me4Si as internal standard. IR spectra were taken
on a Perkin–Elmer 1330 spectrometer. For purification of crude re-
action mixtures by flash chromatography, Merck silica gel (230–
240 mesh) was used as the stationary phase. Identification of prod-
ucts was made by analytical TLC (Merck Kieselgel 60F-254), UV
light ( = 254 mm). Reagents and solvents were handled by using
standard syringe techniques. Lawesson reagent., ClCO2Et, Et3N,
pyridine, SnCl4 and fluorinated anhydrides were obtained from Al-
drich Chemical Co. All of the solvents used were dried over appro-
priate drying agents and distilled under argon prior to use. Analyses
indicated by the symbols of the element were within 0.4% of the-
oretical values.
2-(5-Methyl-4-pyridyloxazolyl)-4-(4-pyridyl)-5-methyloxazol
(1e)
IR (KBr): 3396, 1653, 1611, 1592, 1559, 1542, 1498, 1417 cm–1.
1H NMR (300 MHz, DMSO-d6): = 2.75 (s, 6 H, CH3), 7.75 (d, 4
H, J = 6.1, Pyr), 8.68 (d, 4 H, J = 6.1, Pyr).
Anal. Calcd for C18H14N4O2: C, 67.92; H, 4.43; N, 17.69. Found: C,
64.44; H, 4.41; N, 17.52.
5,5 -Perfluoroalkyl Bisoxazoles 1f–l and 5,5 -Perfluoroalkyl
Bisthiazoles 2a–g; Typical Procedure
To a stirred solution of the diamide 4 or dithioamide 6 (1 mmol) in
anhyd toluene (10 mL), kept under argon atmosphere, pyridine was
added (12 mmol, 0.95 mL). The mixture was cooled to 0 ºC and the
corresponding perfluoroacetic anhydride was added dropwise (6
mmol). The mixture was left to attain r.t. and then stirred overnight
(12 h). The solvent was evaporated, aq NaHCO3 (5%; 5 mL) was
5,5 -Dimethyl Bisoxazoles 1a–e; Typical Procedure
To a stirred solution of the anhydrobase 5 (1 mmol) in acetic anhy-
dride (10 mL), kept under argon atmosphere, a solution of tin tetra-
chloride (0.6 mL, 1 M in CH2Cl2, 0.6 mmol) was added dropwise.
The mixture was refluxed for 4 h and then the solvent was evaporat-
Synthesis 2003, No. 14, 2211–2215 © Thieme Stuttgart · New York

2214
Y. Martín-Cantalejo et al.
PAPER
added and the crude product was extracted with EtOAc (3 × 15
mL). The combined organic extracts were washed (brine) and dried
(Na2SO4). The solvent was evaporated and purification was accom-
plished by flash column chromatrography (silica gel; EtOAc–hex-
ane, 9:1).
4,4 -Bis[5-pentafluoroethyl-4-(4-pyridyl)oxazolyl]biphenyl (1k)
IR (KBr): 3436, 1613, 1488, 1415 cm–1.
1H NMR (300 MHz, CDCl3): = 7.5 (d, 4 H, J = 4.4 Hz, Pyr), 7.8
(d, 4 H, J = 8.2 Hz, Ph), 8.2 (d, 4 H, J = 8.2 Hz, Ph), 8.8 (s, 4 H,
Pyr).
13C NMR (75 MHz, CDCl3): = 109.3, 118.4, 122.3, 122.4, 122.5,
122.6, 122.7, 122.8, 122.9, 124.7, 125.2, 127.8, 127.9, 130.1, 136.4,
140.1, 143.0, 150.3, 162.7.
2,2 -Bis[5-trifluoromethyl-4-(4-pyridyl)oxazolyl]propane (1f)
IR (KBr): 3447, 1622, 1594, 1570, 1545, 1500, 1418 cm–1.
1H NMR (300 MHz, CDCl3): = 2.09 (s, 6 H, CH3), 7.64 (d, 4 H,
J = 6.0 Hz, Pyr), 8.73 (d, 4 H, J = 6.0 Hz, Pyr).
13C NMR (75 MHz, CDCl3): = 25.3, 39.8, 118.9, 120.8, 136.3,
137.6, 150.1, 150.3, 165.5.
MS: m/z = 468 (M+, 81), 453 (8), 255 (100), 185 (15), 158 (7), 63
Anal. Calcd for C32H16F10N4O2: C, 56.65; H, 2.37; N, 8.26. Found:
C, 56.42; H, 2.36; N, 8.23.
1,4-Bis[5-heptafluoropropyl-4-(4-pyridyl)oxazolyl]benzene (1l)
IR (KBr): 3434, 1586, 1550, 1501, 1484, 1416 cm–1.
1H NMR (300 MHz, CDCl3): = 7.68 (d, 4 H, J = 6 Hz, Pyr), 8.31
(s, 4 H, Ph), 8.77 (d, 4 H, J = 6 Hz, Pyr).
13C NMR (75 MHz, CDCl3): = 111.4, 114.6, 119.2, 122.8, 127.0,
127.8, 127.9, 128.4, 134.4, 136.7, 143.2, 150.1, 150.2, 150.4, 162.1.
(8).
Anal. Calcd for C21H14F6N4O2: C, 53.86; H, 3.01; N, 11.96. Found:
C, 53.7; H, 2.97; N, 11.86.
4,4 -Bis[5-trifluoromethyl-4-(4-pyridyl)oxazolyl]biphenyl (1g)
Anal. Calcd for C28H12F14N4O2: C, 47.74; H, 1.72; N, 7.98. Found:
C, 47.74; H, 1.71; N, 7.96.
IR (KBr): 3436, 1614, 1592, 1551, 1485, 1412 cm–1.
1H NMR (300 MHz, CDCl3): = 7.71 (d, 4 H, J = 4.9 Hz, Pyr), 7.82
(d, 4 H, J = 8.2 Hz, Ph), 8.31 (d, 4 H, J = 8.2 Hz, Ph), 8.81 (d, 4 H,
J = 4.1 Hz, Pyr).
13C NMR (75 MHz, CDCl3): = 119.3, 122.3, 122.4, 122.5, 122.6,
122.7, 122.8, 122.9, 124.7, 125.2, 127.8, 127.9, 135.3, 136.7, 140.0,
143.1, 150.3, 161.7.
2,2 -Bis[5-trifluoromethyl-4-(4-pyridyl)thiazolyl]propane (2a)
IR (KBr): 3435, 2928, 2360, 1653, 1647, 1623, 1594, 1570, 1546,
1506, 1457, 1419 cm–1.
1H NMR (300 MHz, DMSO-d6): = 8.74 (d, 4 H, J = 6.1 Hz, Pyr),
7.61 (d, 4 H, J = 5.5 Hz, Pyr), 1.96 (s, 6 H, Me).
13C NMR (75 MHz, DMSO-d6): = 24.6, 38.2, 117.2, 120.8, 122.4,
135.0, 135.7, 138.7, 138.8, 142.5, 150.4, 150.5, 150.6, 165.8.
Anal. Calcd for C30H16F6N4O2: C, 62.29; H, 2.79; N, 9.69. Found:
C, 62.04; H, 2.78; N, 9.65.
Anal. Calcd for C21H14F6N4S2: C, 50.40; H, 2.82; N, 11.19. Found:
C, 50.24; H, 2.81; N, 11.15.
4,4 -Bis[5-trifluoromethyl-4-(4-pyridyl)oxazolyl]oxybisphenyl
(1h)
IR (KBr): 3435, 2925, 2360, 1653, 1635, 1608, 1588, 1559, 1490,
4,4 -Bis[5-trifluoromethyl-4-(4-pyridyl)thiazolyl]biphenyl (2b)
1457, 1418 cm–1.
IR (KBr): 3428, 1648, 1575, 1539, 1529, 1508, 1487, 1456 cm–1.
1H NMR (300 MHz, DMSO-d6): = 8.77 (s, 4 H, Pyr), 8.19 (d, 4 H,
J = 8.8 Hz, Ph), 7.71 (d, 4 H, J = 5.5 Hz, Pyr), 7.21 (d, 4 H, J = 8.8
Hz, Ph).
13C NMR (75 MHz, DMSO-d6): = 112.1, 116.7, 120.2, 126.1,
136.0, 137.4, 142.8, 146.4, 146.5, 146.6, 146.7, 165.8.
1H NMR (300 MHz, CDCl3): = 7.73 (d, 4 H, J = 6.0 Hz, Pyr), 7.83
(d, 4 H, J = 8.2 Hz, Ph), 8.27 (d, 4 H, J = 8.2 Hz, Ph), 8.78 (d, 4 H,
J = 6.0 Hz, Pyr).
13C NMR (75 MHz, CDCl3): = 119.3, 121.1, 122.5, 125.2, 127.8,
136.7, 140.0, 140.1, 143.1, 150.3, 161.7.
Anal. Calcd for C30H16F6N4O3: C, 60.61; H, 2.71; N, 9.42. Found:
C, 60.36; H, 2.70; N, 9.38.
Anal. Calcd for C30H16F6N4S2: C, 59.01; H, 2.64; N, 9.17. Found: C,
58.77; H, 9.13; N, 2.63.
1,4-Bis[5-trifluoromethyl-4-(4-pyridyl)oxazolyl]benzene (1i)
4,4 -Bis[5-trifluoromethyl-4-(4-pyridyl)thiazolyl]oxybisphenyl
(2c)
IR (KBr): 3446, 1625, 1591, 1549, 1497, 1415 cm–1.
IR (KBr): 3447, 1653, 1604, 1558, 1540, 1589, 1457, 1418 cm–1.
1H NMR (300 MHz, CDCl3): = 7.7 (d, 4 H, J = 4.9, Pyr), 8.3 (s, 4
H, Ph), 8.8 (d, 4 H, J = 4.9, Pyr).
13C NMR (75 MHz, CDCl3): = 119.3, 122.1, 122.4, 127.7, 128.4,
135.8, 136.08, 140.2, 140.3, 150.4, 150.3, 160.9.
1H NMR (300 MHz, DMSO-d6): = 8.79 (d, 4 H, J = 4.9 Hz, Pyr),
8.20 (d, 4 H, J = 8.5 Hz, Ph), 7.5 (d, 4 H, J = 5.5 Hz, Pyr), 7.4 (d, 4
H, J = 8.5 Hz, Pyr).
Anal. Calcd for C30H16F6N4OS2: C, 57.51; H, 2.57; N, 8.94. Found:
C, 52.27; H, 2.56; N, 8.90.
Anal. Calcd for C22H12F6N4O2: C, 57.38; H, 2.41; N, 11.15. Found:
C, 57.15; H, 2.40; N, 11.10.
1,4-Bis[5-trifluoromethyl-4-(4-pyridyl)thiazolyl]benzene (2d)
2,2 -Bis[5-trifluoromethyl-4-(4-pyridyl)oxazolyl]hexafluoro-
propane (1j)
IR (KBr): 3439, 1591, 1549, 1496, 1414 cm–1.
IR (KBr): 3436, 1675, 1618, 1599, 1551, 1506, 1420 cm–1.
1H NMR (300 MHz, CDCl3): = 8.78 (dd, 4 H, J = 1.7, 6.6 Hz,
Pyr), 8.32 (s, 4 H, Ph), 7.72 (d, 4 H, J = 6.1 Hz, Pyr).
13C NMR (75 MHz, CDCl3): = 117.4, 121.0, 122.4, 122.5, 127.7,
128.4, 135.5 136.1, 136.5, 140.2, 140.3, 150.3, 161.0.
1H NMR (300 MHz, DMSO-d6): = 8.78 (d, 4 H, J = 5.49 Hz, Pyr),
8.26 (d, 4 H, J = 8.52 Hz, Ph), 7.70 (d, 4 H, J = 5.49 Hz, Pyr), 7.64
(d, 4 H, J = 8.55 Hz, Ph).
13C NMR (75 MHz, DMSO-d6): = 120.9, 122.4, 126.2, 127.6,
130.8, 135.4, 135.8, 140.0, 150.6, 160.8.
Anal. Calcd for C24H12F6N4S2: C, 53.93; H, 2.26; N, 10.48. Found:
C, 53.71; H, 2.25; N, 10.44.
Anal. Calcd for C33H16F12N4O2: C, 54.41; H, 2.21; N, 7.69. Found:
C, 54.30; H, 2.20; N, 7.67.
2,2 -Bis[5-trifluoromethyl-4-(4-pyridyl)thiazolyl]hexafluoro-
propane (2e)
IR (KBr): 3477, 1684, 1670, 1654, 1617, 1559, 1540, 1507, 1458,
1419 cm–1.
Synthesis 2003, No. 14, 2211–2215 © Thieme Stuttgart · New York

PAPER
Synthesis of 4,4′-Bispyridyl-5,5′-Disubstituted-2,2-Bisoxazoles and -Bisthiazoles
2215
1H NMR (300 MHz, DMSO-d6): = 7.66 (d, 4 H, J = 8.5 Hz, Ph),
7.71 (d, 4 H, J = 6.1 Hz, Pyr), 8.27 (d, 4 H, J = 8.5 Hz, Ph), 8.79 (d,
4 H, J = 6.1 Hz, Pyr).
1H NMR (300 MHz, DMSO-d6): =1.45 (s, 6 H, CH3), 4.50 (d, 4
H, J = 5.5 Hz, CH2), 7.77 (d, 2 H, J = 5.5 Hz, Pyr), 8.58 (t, 2 H,
J = 5.5 Hz, NH), 8.76 (m, 4 H, Pyr).
13C NMR (75 MHz, DMSO-d6): = 47.8, 54.4, 116.9, 118.0, 120.4,
121.9, 122.0, 125.7, 127.1, 130.3, 134.9, 135.3, 139.5, 149.9, 150.0,
150.1, 160.3.
Anal. Calcd for C23H28N4O6: C, 60.52; H, 6.18; N, 12.27. Found: C,
60.28; H, 6.15; N, 12.22.
Anal. Calcd for C33H16F12N4S2: C, 52.11; H, 2.12; N, 7.36. Found:
C, 52.07; H, 2.08; N, 7.29
Acknowledgement
Support for this work from CAM (Comunidad Autónoma de Ma-
drid, Grant 08.1/0045.2/98) is acknowledged. One of us (B.S.)
thanks CAM for a post-doctoral grant.
4,4 -Bis[5-pentafluoroethyl-4-(4-pyridyl)thiazolyl]biphenyl (2f)
IR (KBr): 3434, 1684, 1653, 1627, 1534, 1508, 1477, 1456 cm–1.
1H NMR (300 MHz, CDCl3): = 7.69 (d, 4 H, J = 5.5 Hz, Pyr), 8.3
(s, 4 H, Ph), 8.77 (d, 4 H, J = 6.1 Hz, Pyr).
13C NMR (75 MHz, CDCl3): = 161.93, 150.20, 142.79, 136,74,
134.5, 128.36, 127.82, 122.85, 118.4, 109.3.
References
(1) (a) Smith, A. B. III; Minbiole, K. P.; Freeze, S. Synlett 2001,
1739; and references therein. (b) Cardwell, S. K.;
Hermitage, S. A.; Sjolin, A. Tetrahedron Lett. 2000, 41,
4239; and references therein.
Anal. Calcd for C32H16F10N4S2: C, 54.09; H, 2.27; N, 7.88. Found:
C, 53.87; H, 2.26; N, 7.85.
(2) Hernández-Alcoceba, L.; Saniger, J.; Campos, F.; Núñez,
M. C.; Khaless, M. A.; Gallo, A.; Espinosa, A.; Lacal, J. C.
Oncogene 1997, 15, 2289.
(3) (a) Li, J.; Jeong, S.; Esser, L.; Harran, P. G. Angew. Chem.
Int. Ed. 2001, 40, 4765. (b) Li, J.; Burgett, A. W. G.; Esser,
L.; Amezcua, C.; Harran, P. G. Angew. Chem. Int. Ed. 2001,
40, 4770. (c) Magnus, P.; McIver, E. G. Tetrahedron Lett.
2000, 41, 831.
1,4-Bis[5-pentafluoropropyl-4-(4-pyridyl)thiazolyl]benzene
(2g)
IR (KBr): 3442, 1695, 1684, 1674, 1653, 1638, 1565, 1539, 1508,
1487 cm–1.
1H NMR (300 MHz, CDCl3): = 7.71 (d, 4 H, J = 5.5 Hz, Pyr), 7.83
(d, 4 H, J = 8.2 Hz), 8.26 (d, 4 H, J = 8.2 Hz, Ph), 8.77 (d, 4 H,
J = 5.5 Hz, Pyr).
(4) (a) Doyle, K. J.; Moody, C. J. Tetrahedron Lett. 1992, 33,
7769. (b) Singh, S. P.; Naithami, R.; Aggarwal, R.; Prakash,
O. Synth. Commun. 2001, 31, 3747.
(5) Chittari, P.; Hamada, Y.; Shioiri, T. Synlett 1998, 1022; and
references therein.
13C NMR (75 MHz, CDCl3): = 162.71, 150.1, 143.2, 142.5, 137.0,
134.5, 127.8, 125.0, 122.9, 122.8, 118.0, 109.3.
Anal. Calcd for C26H12F10N4S2: C, 49.21; H, 1.91; N, 8.83. Found:
C, 49.01; H, 1.90; N, 8.79.
(6) Williams, D. R.; Brooks, D. A.; Meyer, K. G. Tetrahedron
Lett. 1998, 39, 8023.
(7) Schröeder, R.; Schöllkopf, U.; Blume, E.; Hoppe, I. Liebigs
Ann. Chem. 1975, 533.
(8) Burger, K.; Hülb, D.; Geith, K. Synthesis 1988, 36, 199.
(9) Burger, K.; Hülb, D.; Geith, K. Synthesis 1988, 36, 194.
(10) Helmreich, B.; Burger, K.; Maier, G.; Hecht, R.; Nuyken, O.
U.S. Patent 5300625, 1994.
Anhydrobases 5; Typical Procedure
To a stirred solution of the diamide 4 (1 mmol) in anhyd acetone (20
mL), kept under argon atmosphere, Et3N (0.42 mL, 3 mmol) was
added dropwise. After cooling to –10 ºC, ethyl chloroformate (0.28
mL, 3 mmol) in acetone (2 mL) was slowly added and the mixture
was left to attain r.t. and stirred a further 12 h. The precipitate was
filtered off and washed with acetone and H2O.
(11) Braña, M. F.; Castellano, J. M.; de Miguel, P.; Posada, P.;
Sanz, C. R.; Migallón, A. S. Tetrahedron 1994, 50, 10061.
(12) General procedures used for synthesis of diamides 4: (a)
For Z = (CH3)2C, p,p -PhOPh, p,p -PhC(CF3)2Ph, see:
Bernasconi, S.; Comini, A.; Corbella, A.; Gariboldi, P.;
Sisti, M. Synthesis 1980, 385. (b) For Z = p-phenyl, p-
biphenyl, oxalyl, CH2CH2, see: Tamiz, A. P.; Cai, S. X.;
Zhou, Z. L.; Yuen, P. W.; Schelkun, R. M.; Whittemore, E.
R.; Weber, E.; Woodward, R. M.; Keana, J. F. W. J. Med.
Chem. 1999, 42, 3412.
Representative Example of Analytical Data of Compounds 5;
N,N -Bis(1-carboxyethyl-1,4-anhydropyridylmethyliden)-2,2-
dimethylmalonamide
IR (KBr): 3304, 2979, 2945, 2604, 2497, 1713, 1678, 1634, 1610,
1568, 1502, 1400, 1307 cm–1.
1H NMR (300 MHz, DMSO-d6): = 1.24 (t, 6 H, J = 7.3 Hz,
CO2CH2CH3), 1.41 (s, 6 H, CH3), 4.21 (q, 4 H, J = 7.3 Hz,
CO2CH2CH3), 5.76 (d, 2 H, J = 7.9 Hz, NHCH=), 6.10 (br s, 2 H,
CH=CHNCO2Et), 6.13 (d, 2 H, J = 9.7 Hz, CH=CHNCO2Et), 6.70
(d, 2 H, J = 8.5 Hz, CH=CHNCO2Et), 6.87 (d, 2 H, J = 8.5 Hz,
CH=CHNCO2Et), 8.98 (d, 2 H, J = 9.7 Hz, NH).
(13) See experimental for typical procedure for the synthesis of
anhydrobases 5.
(14) See experimental for representative example of analytical
data of compounds 5.
13C NMR (75 MHz, DMSO-d6): = 14.1, 23.3, 49.9, 62.9, 107.9,
110.0, 113.1, 114.5, 121.9, 123.5, 149.9, 170.6.
(15) (a) Funabiki, K.; Noma, N.; Kuzuya, G.; Matsui, M.;
Shibata, K. J. Chem. Res., Synop. 1999, 300; and references
therein. (b) Filler, R. In Organofluorine and their Industrial
Application; Banks, R. E., Ed.; Ellis Horwood: Chichester,
1979.
(16) (a) Kawase, M.; Saito, S.; Kikuchi, H.; Miyamae, H.
Heterocycles 1997, 45, 2185. (b) Kawase, M. Tetrahedron
Lett. 1994, 35, 149. (c) Kawase, M. Heterocycles 1993, 36,
2441. (d) Kawase, M.; Miyamae, H.; Narita, M.; Kurihara,
T. Tetrahedron Lett. 1993, 34, 859.
Dithioamides 6
A solution of the diamide 4 (1 mmol) and the Lawesson’s reagent
(2 mmol) in THF (10 mL) was refluxed for 5 h and then stirred 12
h at r.t. The solid was filtered off, washed with Et2O and used with-
out further purification.
Representative Example of Analytical Data of Bisthioamides 6;
N,N -Bis(4-pyridylmethylen)-2,2-dimethylmalonathioamide
IR (KBr): 3346, 3313, 3030, 1535, 1380, 1142 cm–1.
(17) See experimental for preparation of dithioamides 6, and
representative example of analytical data.
Synthesis 2003, No. 14, 2211–2215 © Thieme Stuttgart · New York