A comparative study on stille cross-coupling reactions of 2-phenylthiazoles and 2-phenyloxazoles

Article abstract of DOI:10.1055/s-2008-1067263

A systematic study of the cross-coupling capability of the 4- and 5-positions of 2-phenylthiazoles and -oxazoles under Stille conditions is presented. The azoles were both applied as stannanes and as the halide component. The obtained results were compared regarding the position of the halide and Bu₃Sn group. In order to establish a general reactivity platform for those heterocyclic systems, a broad variety of aromatic and heteroaromatic halides were coupled and some significant differences concerning the coupling properties of the investigated systems were observed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1067263

PAPER
3099
A Comparative Study on Stille Cross-Coupling Reactions of 2-Phenylthiazoles
and 2-Phenyloxazoles
Coupling
o
R
eactions of
h
2-Phenylthia
a
zoles and
-
n
oxazoles na Hämmerle, Markus Spina, Michael Schnürch, Marko D. Mihovilovic, Peter Stanetty*
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163-OC, 1060 Vienna, Austria
Fax +43(1)5880115499; E-mail: peter.stanetty@tuwien.ac.at
Received 15 April 2008; revised 12 June 2008
ganyls are stable in the 4- as well as the 5-position of such
Abstract: A systematic study of the cross-coupling capability of
heterocyclic systems and can easily be prepared and
stored for a considerable length of time. In contrast to the
Negishi protocol, the metal species do not have to be
the 4- and 5-positions of 2-phenylthiazoles and -oxazoles under
Stille conditions is presented. The azoles were both applied as stan-
nanes and as the halide component. The obtained results were com-
pared regarding the position of the halide and Bu3Sn group. In order freshly prepared for each reaction and are stable in the
to establish a general reactivity platform for those heterocyclic sys-
presence of oxygen and moisture. In order to obtain a
tems, a broad variety of aromatic and heteroaromatic halides were
range of differently substituted products starting from in-
coupled and some significant differences concerning the coupling
expensive and commercially available halides, we consid-
properties of the investigated systems were observed.
ered it beneficial to apply the metal on the azole system.
Thiazoleboronic acids seem to be a comparably unstable
class of compounds and in our hands application of thi-
Key words: cross-coupling, heterocycles, Stille reaction, oxazole,
thiazole
azoleboronic esters, which can be used instead, usually re-
sulted in lower yields than thiazolylstannanes in the
corresponding Stille reactions7 so far.
Both, substituted thiazoles and oxazoles are interesting
building blocks and frequently encountered structural mo-
tifs in a variety of natural products and synthetic bioactive
compounds useful as pharmaceuticals or plant protection
agents.1 In general, both heterocycles can be obtained via
cyclization reactions. In the case of thiazole and its deriv-
atives, the Hantzsch reaction2 (condensation of a-haloke-
tones with appropriate thioamides) is the most frequently
encountered route whereas various cyclization methodol-
ogies exist leading to interesting oxazole or oxazoline de-
rivatives.3 The described methods are useful and usually
deliver satisfying results only when a small number of
products has to be prepared. Nevertheless, substituted
starting materials have to be prepared for each single com-
pound and sometimes unwanted side reactions can lower
the obtained yields. Therefore, an alternative approach is
preferable by introducing the required substituents into
the already preformed thiazoles and oxazoles when a larg-
er number of differently substituted azoles are envisaged.
In this regard, transition-metal-catalyzed cross-coupling
reactions4 represent a very attractive alternative since sim-
ple building blocks can be decorated in a stepwise manner
allowing substitution in each position.5 Although cross-
coupling reactions on thiazole as well as on oxazole sys-
tems have already been reported1b–f,5 a more elaborate and
systematic investigation of the coupling capability as well
as the reactivity of the various positions and methods in
thiazole and oxazole cross-coupling chemistry is still
lacking. Within this contribution we wish to close this gap
with the investigation of those aspects under Stille condi-
tions. The Stille reaction6 was chosen initially since tin or-
In the thiazole series, 2-phenylthiazole (1) was obtained
via a Hantzsch cyclization.8 Functionalization of the 5-po-
sition was easily achieved via direct bromination or lithi-
ation and subsequent quenching with Bu3SnCl. By
applying the conditions specified in Scheme 1, 5-bromo-
2-phenylthiazole (2)9 as well as 5-tributylstannyl-2-phe-
nylthiazole (3) were obtained in good yields. The desired
4-bromo-2-phenylthiazole (4) was obtained via a halogen
dance reaction10 and subsequent quenching of the reaction
mixture with water. The isolated product was not only
used as coupling partner, but also as starting material for
the synthesis of 4-tributylstannyl-2-phenylthiazole (5),
which was prepared via metal–halogen exchange using t-
BuLi followed by addition of Bu3SnCl.
In the oxazole series 5-bromo-2-phenyloxazole (6) was
prepared according to a literature procedure11 and subse-
quently converted into the other desired coupling partners
under similar conditions as in the thiazole series. 5-Tribu-
tylstannyl-2-phenyloxazole (7) was obtained after metal–
halogen exchange and subsequent quenching with
Bu3SnCl. 4-Bromo-2-phenyloxazole (8) was again pre-
pared via a halogen dance reaction10 and trapping of the 4-
bromo-5-lithio species with water or MeOH. The obtained
product could then be transformed into the corresponding
4-tributylstannyl-2-phenyloxazole (9).
In both series all coupling partners were obtained in good
yields. Under halogen dance conditions the lithiated ox-
azole species turned out to be less stable than the corre-
sponding thiazoles and in some cases ring opening was
observed as well. All stannanes 3, 5, 7, and 9 were purified
by Kugelrohr distillation. A major difference in reactivity
of thiazoles vis-à-vis oxazoles was observed during the
metal–halogen exchange in the 4-position. In the oxazole
SYNTHESIS 2008, No. 19, pp 3099–3107
x
x.
x
x
.
2
0
0
8
Advanced online publication: 05.09.2008
DOI: 10.1055/s-2008-1067263; Art ID: T06108SS
© Georg Thieme Verlag Stuttgart · New York

3100
J. Hämmerle et al.
PAPER
series it was sufficient to use n-BuLi leading to full con- amount of the halide to 1.5 or 2 equivalents. However,
version to 9, whereas a mixture consisting of unreacted costs and complexity of the aryl or hetaryl halide might
starting material 4, product 5, and dehalogenated starting determine if such an excess of one reagent can be justi-
material 1 was obtained in the thiazole series under the fied. Steric and electronic effects were also explored by
same reaction conditions. Therefore, it was necessary to applying substituted coupling partners such as 2-bromo-
use t-BuLi instead of n-BuLi in order to obtain 4-tributyl- toluene, 4-bromoanisole and 4-nitrobromobenzene. Nei-
stannyl-2-phenylthiazole (5) in satisfactory yields ther coupling partners with sterical hindrance nor
(Scheme 1).
electron-withdrawing substituents led to a significant de-
crease in yield. When 2-bromotoluene was used the yield
was lowered by approximately 10% (entries 7 and 8) com-
pared to unhindered iodo- or bromobenzene, but the in-
vestigated positions still showed similar behavior.
Applying electron-poor 4-nitrobromobenzene in the cou-
pling process (entries 11 and 12) yielded 69 and 78% of
the desired coupling products 10d and 11d. In these cases,
slightly higher yields were obtained in 4- than in 5-posi-
tion. On the other hand, coupling reactions with electron-
rich 4-bromoanisole resulted in significantly lower yields
of 38% for cross-coupling in 5-position and 41% in 4-po-
sition (entries 9 and 10). Apart from the desired com-
pound 10c, 16% of starting material as well as 25% of 2,5-
diphenylthiazole (as a result of a ligand-exchange reac-
tion)14 were obtained when coupling 4-bromoanisole into
the 5-position (entry 9). When performing the reaction in
4-position the formation of considerable amounts (>10%)
of 2,4-diphenylthiazole was observed.
N
a or b
N
Y
S
X
1
c
2: X = S, Y = Br, 91%
3: X = S, Y = SnBu3, 84%
6: X = O, Y = Br
Br
N
X
b
4: X = S, 78%
8: X = O, 78%
N
Bu3Sn
O
b or d
7
86%
Bu3Sn
N
X
To further broaden the substrate scope of this transforma-
tion a series of hetaryl halides was selected as coupling
partners. As before, the coupling capabilities of position 5
as well as 4 were investigated. When 3-bromopyridine
(entries 15 and 16), 2-fluoro-4-iodopyridine (entries 17
and 18), and 4-chloro-2-methylsulfanylpyrimidine (en-
tries 19 and 20) were used similar yields compared to io-
do- and bromobenzene were obtained. Satisfying results
were also achieved with 2-bromothiophene (entries 13
and 14), but lower yields were obtained when 2,4-dichlo-
ropyrimidine was applied (entries 21 and 22). Since some
biologically active natural products contain differently
joined bisazole fragments,15 compound 3 was also cou-
pled with 5-iodo-2-phenylthiazole, 2 as well as 6 and in all
cases (entries 23–25) satisfactory yields of the coupled
products were obtained. Among the three coupling part-
ners, 5-iodo-2-phenylthiazole (entry 23) provided the
highest yield (81%) of the product, but due to decomposi-
tion under the applied conditions it had to be separated
from 13% of the dehalogenated starting material. In the
course of these reactions some side products were gener-
ated: the formation of the homocoupling product 2,2¢-
bithiophene was observed with 2-bromothiophene and in
many cases 2,5- and 2,4-diphenylthiazole14 were isolated
(4–25%). The highest amount of the latter side product
was obtained when the cross-coupling reaction was per-
formed at the 5-position with 4-bromoanisole and 3-bro-
5: X = S, 83%
9: X = O, 67%
Scheme 1 Synthesis of cross-coupling reaction partners. Reagents
and conditions: (a) Br2, CHCl3, r.t.; (b) n-BuLi, Bu3SnCl, THF,
–80 °C; (c) LDA, H2O–THF, –80 °C; (d) t-BuLi, Bu3SnCl, THF,
–80 °C.
In order to compare the results of the coupling reactions
of the two heterocyclic systems, standard conditions re-
garding solvent, reaction temperature and catalyst had to
be defined. Toluene turned out to be a good solvent in test
reactions and reaction mixtures were refluxed until com-
plete consumption of the halide (2–48 h) was observed by
TLC or GC/MS analysis. Pd(PPh3)4 was chosen as the cat-
alyst since it is commercially available or can easily be
prepared freshly in the laboratory.12 In order to avoid pu-
rification problems often encountered in cross-coupling
reactions under Stille conditions, we followed a literature
procedure13 where addition of CsF was suggested. This re-
agent not only activates the applied stannane, but also
simplifies the purification due to generation of insoluble
Bu3SnF.
Initially, the cross-coupling capability of stannane 3 and 5
was investigated by using iodo- or bromobenzene as cou-
pling partners. In all cases good yields of 10a and 11a
(Table 1, entries 1 and 4–6) were obtained. The results
showed that essentially the same yields were obtained in-
dependent of the position of the Bu3Sn group (positions 4
or 5), indicating similar coupling capabilities of these two
positions in the thiazole system. In the case of iodoben-
zene as reaction partner the yield could even be improved
to 84% (entry 2) or 89% (entry 3) by increasing the
mopyridine.
The
formation
of
2,2¢-diphen-
yl[5,5¢]bithiazolyl (10j) and 2,2¢-diphenyl[4,4¢]bithiaz-
olyl (11j) was also observed in the yield range of 2–11%.
Taken together, we have found that cross-coupling of thi-
azoles 3 and 5 with aryl and hetaryl halides can be per-
Synthesis 2008, No. 19, 3099–3107 © Thieme Stuttgart · New York

PAPER
Coupling Reactions of 2-Phenylthiazoles and -oxazoles
3101
Table 1 Stille Cross-Coupling Reactions of 3 and 5 with Various Halides
Z
ArX (1.1 equiv)
CsF (2.2 equiv)
N
N
Ar
Y
Ph
Ph
Pd(PPh3)4 (5 mol%)
toluene, reflux
S
S
3
5
10a–k
11a–i
3: Y = SnBu3, Z = H
5: Y = H, Z = SnBu3
2–48h
Entry
1
Y
Z
ArX
Product
10a
10a
10a
11a
10a
11a
10b
11b
10c
11c
10d
11d
10e
11e
10f
Ar
Yield (%)
SnBu3
SnBu3
SnBu3
H
H
iodobenzene
phenyl
78
84
89
77
76
75
68
66
38
41
69
78
67
51
75
67
76
78
2
H
iodobenzene (1.5 equiv)
iodobenzene (2 equiv)
iodobenzene
phenyl
3
H
phenyl
4
SnBu3
H
phenyl
5
SnBu3
H
bromobenzene
phenyl
6
SnBu3
H
bromobenzene
phenyl
7
SnBu3
H
2-bromotoluene
2-methylphenyl
2-methylphenyl
4-methoxyphenyl
4-methoxyphenyl
4-nitrophenyl
4-nitrophenyl
2-thienyl
8
SnBu3
H
2-bromotoluene
9
SnBu3
H
4-bromoanisole
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
SnBu3
H
4-bromoanisole
SnBu3
H
4-nitrobromobenzene
4-nitrobromobenzene
2-bromothiophene
2-bromothiophene
3-bromopyridine
SnBu3
H
SnBu3
H
SnBu3
H
2-thienyl
SnBu3
H
3-pyridinyl
3-pyridinyl
2-fluoro-4-pyridinyl
2-fluoro-4-pyridinyl
SnBu3
H
3-bromopyridine
11f
SnBu3
H
2-fluoro-4-iodopyridine
2-fluoro-4-iodopyridine
4-chloro-2-methylsulfanylpyrimidine
4-chloro-2-methylsulfanylpyrimidine
2,4-dichloropyrimidine
2,4-dichloropyrimidine
5-iodo-2-phenylthiazole
2
10g
11g
10h
11h
10i
SnBu3
H
SnBu3
H
2-methylsulfanyl-4-pyrimidinyl 73
2-methylsulfanyl-4-pyrimidinyl 61
SnBu3
H
SnBu3
H
2-chloro-4-pyrimidinyl
2-chloro-4-pyrimidinyl
2-phenyl-5-thiazolyl
2-phenyl-5-thiazolyl
2-phenyl-5-oxazolyl
48
30
81
73
70
SnBu3
H
11i
SnBu3
SnBu3
SnBu3
10j
H
10j
H
6
10k
formed in very similar yields indicating that the coupling In the oxazole series, the conditions regarding solvent, re-
capabilities of positions 4 and 5 are comparable. Electron- action temperature, and catalyst were the same as in the
poor and also sterically demanding halides can be applied thiazole series and in an initial experiment iodobenzene
and good yields are obtained, both in the carbocyclic and was coupled with both 7 and 9 (Table 2, entries 1 and 2).
heterocyclic series. Only with electron-rich halides signif- Results of the two conversions were in accordance with
icantly lower yields are encountered as it is known from the thiazole series and again very similar yields were ob-
the literature.16 In the 5- and the 4-position of 2-phenyl- tained for reactions in the 4- and in 5-positions suggesting
thiazole no significant differences in cross-coupling capa- that differences in coupling capability of these positions
bility were detected. Subsequently, an additional survey are minor. When four additional experiments were carried
on the analogous oxazole system was carried out to deter- out in order to support this observation some very unex-
mine any related trends true for this ring system.
pected and interesting results were obtained. 2-Fluoro-4-
Synthesis 2008, No. 19, 3099–3107 © Thieme Stuttgart · New York

3102
J. Hämmerle et al.
PAPER
Table 2 Stille Cross-Coupling Reactions of 7 and 9 with Various Halides
Z
ArX (1.1 equiv)
CsF (2.2 equiv)
N
N
Ar
Pd(PPh3)4 (5 mol%)
toluene, reflux
2–48 h
Y
Ph
Ph
O
O
7
9
12a–d
13a–d
7: Y = SnBu3, Z = H
9: Y = H, Z = SnBu3
Entry
Y
Z
ArX
Product
12a
Ar
Yield (%)
1
2
3
4
5
6
SnBu3
H
H
iodobenzene
iodobenzene
phenyl
74
73
80
46
75
49
SnBu3
H
13a
phenyl
SnBu3
H
2-fluoro-4-iodopyridine
2-fluoro-4-iodopyridine
12b
2-fluoro-4-pyridinyl
2-fluoro-4-pyridinyl
2-methylsulfanyl-4-pyrimidinyl
2-methylsulfanyl-4-pyrimidinyl
SnBu3
H
13b
SnBu3
H
4-chloro-2-methylsulfanylpyrimidine
4-chloro-2-methylsulfanylpyrimidine
12c
SnBu3
13c
iodopyridine and 4-chloro-2-methylsulfanylpyrimidine comparable or slightly better than when applying the thi-
were chosen as coupling partners and when they were azole or oxazole as tin compound. Since previous experi-
coupled into the 5-position almost identical yields (entries ments showed that at least iodothiazoles favor the
3 and 5) as in the thiazole series were obtained. But when formation of bithiazoles17 we only considered the bromo
coupling the two heterocyclic coupling partners into the 4- compounds within the scope of the present study.
position (entries 4 and 6) the obtained yields were signif-
Finally, a set of competition experiments was also set up
icantly lower than in the 5-position. It seems that the cou-
in order to establish the direct ranking of coupling effi-
pling capability of 5-tributylstannyl-2-phenyloxazole (7)
ciencies of the various positions in the heterocyclic sys-
is comparable to that of 5-tributylstannyl-2-phenylthiaz-
tems: 1 equivalent of 5-tributylstannyl-2-phenylthiazole
ole (3) and 4-tributylstannyl-2-phenylthiazole (5) whereas
(3) or 5-tributylstannyl-2-phenyloxazole (7), and 1 equiv-
alent of 4-tributylstannyl-2-phenylthiazole (5) or 4-tribu-
tylstannyl-2-phenyloxazole (9) were put forward
simultaneously and coupled with 1 equivalent of bro-
the coupling capability of 4-tributylstannyl-2-phenylox-
azole (9) is definitely lower, which can be observed when
more demanding coupling partners are applied.
Especially when a great number of differently substituted mobenzene under standard conditions (Table 4). The re-
thiazoles or oxazoles have to be synthesized (e.g., for a actions were run overnight and the composition of the
compound library) it is beneficial to introduce the tin on reaction mixture was determined after consumption of the
the azole system and couple it with different aryl or hetar- halide via GC/MS.
yl halides since a large number of halides are commercial-
ly available and often inexpensive. But since the synthetic
route could make it necessary to apply the azole as a ha-
lide we wanted to conclude our investigations by coupling
In the thiazole series, the ratio of 2,5-diphenylthiazole
(10a) to 2,4-diphenylthiazole (11a) was 71:29 (Table 4,
entry 1) whereas in the oxazole series 2,5-diphenylox-
azole (12a) was formed exclusively (entry 2). These re-
2, 4, 6, and 8 with commercially available tributylphenyl-
stannane (Table 3). In the thiazole as well as in the ox-
azole series the obtained yields (74–82%) were
Table 4 Competition Experiments
N
Z
Y
Ph
+
X
Table 3 Stille Cross-Coupling Reactions with Tributylphenylstan-
nane
N
Ph
1 equiv
CsF (2.2 equiv)
X
Pd(PPh3)4 (5 mol%)
toluene, reflux
overnight
Z
Y
PhSnBu3 (1.1 equiv)
CsF (2.2 equiv)
N
N
Ph
N
1 equiv
Pd(PPh3)4 (5 mol%)
toluene, reflux
2–48 h
Y
Ph
Ph
X
X
X
1 equiv
Entry
Starting
material
X
Y
Z
Product Yield
(%)
Entry Starting
X
Y
Z
Products
Ratio
materials
3 and 5
7 and 9
2 and 4
6 and 8
1
2
3
4
2
4
6
8
S
Br
H
H
10a
11a
12a
13a
74
81
76
82
1
2
3
4
S
SnBu3 Br
SnBu3 Br
10a, 11a
12a, 13a
10a, 11a
12a, 13a
71:29
100:0
82:18
96:4
S
Br
H
O
S
O
O
Br
H
Br
Br
SnBu3
SnBu3
Br
O
Synthesis 2008, No. 19, 3099–3107 © Thieme Stuttgart · New York

PAPER
Coupling Reactions of 2-Phenylthiazoles and -oxazoles
3103
(Na2SO4), filtered, and evaporated. The crude material was purified
by Kugelrohr distillation.
sults support the observed trend, indicating that the
difference in coupling reactivity between 7 and 9 is much
more pronounced than for the analogous thiazole com-
pounds 3 and 5. When the experiments were carried out
with 1 equivalent of 5-bromo-2-phenylthiazole 2 or 5-bro-
mo-2-phenyloxazole (6), and 1 equivalent of 4-bromo-2-
phenylthiazole (4) or 4-bromo-2-phenyloxazole (8) and 1
equivalent of tributylphenylstannane very similar results
were obtained and the ratio in the thiazole series was
82:18 favoring 2,5-diphenylthiazole (10a) (entry 3) and in
the oxazole series again almost no 2,4-diphenyloxazole
(13a) was formed (entry 4).
5-Tributylstannyl-2-phenylthiazole (3)
Compound 3 was prepared from 1 (1 equiv, 6.66 mmol, 1.07 g) ac-
cording to the general procedure for the preparation of stannanes us-
ing anhyd THF (20 mL), n-BuLi (1.25 equiv, 8.33 mmol, 3.33 mL,
2.5 M in hexane), and Bu3SnCl (1.15 equiv, 7.66 mmol, 2.08 mL);
yield: 2.53 g (84%); yellow oil; bp 200 °C/0.1 mbar; Rf = 0.70 (PE–
EtOAc. 10:1).
1H NMR (200 MHz, CDCl3): d = 0.91 (t, J = 7.1 Hz, 9 H, CH3),
1.16 (t, J = 7.8 Hz, 6 H, SnCH2), 1.35 (sext, J = 7.1 Hz, 6 H,
CH3CH2), 1.50–1.68 (m, 6 H, CH3CH2CH2), 7.34–7.48 (m, 3 H,
ArH), 7.81 (s, 1 H, H-4), 7.94–8.06 (m, 2 H, ArH).
The results of this study show that the Stille cross-cou-
pling reaction is generally applicable for the introduction
not only of aromatic but also various heteroaromatic sub-
stituents in the 5-position as well as the 4-position of thi-
azoles and oxazoles. Even with heterocyclic coupling
partners moderate to good yields were obtained. In the
case of thiazoles no difference concerning the coupling
capability of the 4- and 5-position could be observed
whereas significantly lower yields were obtained in the
oxazole series when heterocyclic halides were coupled
into the 4-position instead of the 5-position. Still the thia-
zolestannanes 3 and 5 as well as the oxazolestannanes 7
and 9 are very useful building blocks for the synthesis of
arylated derivatives and especially appealing when a
number of differently substituted thiazoles or oxazoles is
needed. Additionally, it has to be mentioned that the halo-
gen dance reaction proved to be a very useful tool for the
synthesis of the 4-substituted starting materials, both, ha-
lides and metal organyls.
13C NMR (50 MHz, CDCl3): d = 11.0 (t), 13.7 (q, CH3), 27.2 (t),
29.0 (t), 126.6 (d), 128.6 (s, C-5), 128.9 (d), 129.6 (d, C-4¢), 133.9
(s, C-1¢), 150.3 (d, C-4), 173.3 (s, C-2).
4-Tributylstannyl-2-phenylthiazole (5)
Compound 5 was prepared from 4 (1 equiv, 1.25 mmol, 300 mg) ac-
cording to the general procedure for the preparation of stannanes us-
ing anhyd Et2O (15 mL), t-BuLi (1.2 equiv, 1.50 mmol, 0.92 mL,
1.63 M in pentane), and Bu3SnCl (1.4 equiv, 1.75 mmol, 0.47 mL).
Since the boiling point of the product was too high, the excess of
Bu3Sn was distilled off and the then-pure residue could be used for
further reactions; yield: 466 mg (83%); yellow oil; Rf = 0.64 (PE–
THF, 50:1).
1H NMR (200 MHz, CDCl3): d = 0.71–1.83 [m, 27 H, (CH2)3CH3],
7.33 (s, 1 H, H-5), 7.38–7.51 (m, 3 H, ArH), 7.98–8.08 (m, 2 H,
ArH).
13C NMR (50 MHz, CDCl3): d = 10.4 (t), 13.7 (q, CH3), 27.3 (t),
29.1 (t), 125.3 (d, C-5), 127.1 (d), 128.8 (d), 129.4 (d, C-4¢), 134.2
(s, C-1¢), 160.9 (s, C-4), 168.3 (s, C-2).
5-Tributylstannyl-2-phenyloxazole (7)
Compound 7 was prepared from 6 (1 equiv, 2.23 mmol, 500 mg) ac-
cording to the general procedure for the preparation of stannanes us-
ing anhyd THF (25 mL), n-BuLi (1.1 equiv, 2.45 mmol, 1.34 mL,
1.83 M in hexane) and Bu3SnCl (1.1 equiv, 2.45 mmol, 0.89 mL);
yield: 830 mg (86%); colorless oil; bp 180–185 °C/0.05 mbar;
Rf = 0.29 (PE–EtOAc, 10:1).
1H NMR (200 MHz, CDCl3): d = 0.88 (t, J = 7.2 Hz, 9 H, CH3),
1.12 (t, J = 7.9 Hz, 6 H, SnCH2), 1.34 (sext, J = 7.2 Hz, 6 H,
CH3CH2), 1.47–1.68 (m, 6 H, CH3CH2CH2), 7.23 (s, 1 H, H-4),
7.33–7.54 (m, 3 H, ArH), 7.96–8.13 (m, 2 H, ArH).
All reactions were conducted under N2 or argon using dried glass-
ware and magnetic stirring. Unless otherwise noted, chemicals were
purchased from commercial suppliers and used without further pu-
rification. Petroleum ether (PE) used refers to the fraction boiling in
the range 40–60 °C. All solvents were dried over Al2O3 cartridges
prior to use. Flash column chromatography was performed on silica
gel 60 from Merck (40–63 mm) using a Büchi Sepacore preparative
column. The ratio of crude product to silica gel was 1:30 and in case
of cross-coupling products cartridges with 45 g of SiO2 were used.
Aluminum backed silica gel plates were used for TLC analyses. The
solvent mixture used for TLC was also used for column chromatog-
raphy. Kugelrohr distillation was carried out using a Büchi GKR-51
apparatus. Melting points were determined using a Kofler-type
Leica Galen III micro hot stage microscope and are uncorrected.
NMR-spectra were recorded from CDCl3 solution on a Bruker AC
200 (200 MHz) and chemical shifts are reported in ppm using TMS
as internal standard. Elemental analyses were carried out in the
Microanalytical Laboratory, Institute of Physical Chemistry,
Vienna University.
13C NMR (50 MHz, CDCl3): d = 10.3 (t), 13.6 (q, CH3), 27.1 (t),
28.9 (t), 126.3 (d), 128.1 (s, C-1¢), 128.6 (d), 129.8 (d, C-4¢), 138.7
(d, C-4), 155.5 (s, C-5), 161.9 (s, C-2).
4-Tributylstannyl-2-phenyloxazole (9)
Compound 9 was prepared from 8 (1 equiv, 0.89 mmol, 200 mg) ac-
cording to the general procedure for the preparation of stannanes us-
ing anhyd THF (20 mL), n-BuLi (1.1 equiv, 0.99 mmol, 0.42 mL,
2.4 M in hexane), and Bu3SnCl (1.1 equiv, 0.99 mmol, 0.27 mL);
yield: 260 mg (67%); colorless oil; bp 220–225 °C/0.35 mbar;
Rf = 0.31 (PE–EtOAc, 40:1).
1H NMR (200 MHz, CDCl3): d = 0.92 (t, J = 7.1 Hz, 9 H, CH3),
1.07–1.67 [m, 18 H, (CH2)3], 7.36–7.51 (m, 3 H, ArH), 7.55 (s, 1 H,
H-5), 7.99–8.15 (m, 2 H, ArH).
Stannanes of Azoles; General Procedure
The appropriate starting material was lithiated with n- or t-BuLi
(1.1–1.25 equiv) under argon at –80 °C. After complete addition,
the mixture was warmed to –50 °C and held at that temperature for
30 min. The mixture was again cooled to –80 °C and Bu3SnCl (1.1–
1.4 equiv) was added dropwise at that temperature. The mixture was
warmed to r.t. and diluted with Et2O (5 × reaction volume). The or-
ganic layer was washed with aq 2 N HCl (5 × reaction volume),
H2O (5 × reaction volume), and brine (5 × reaction volume), dried
13C NMR (50 MHz, CDCl3): d = 9.8 (t), 13.7 (q, CH3), 27.2 (t), 29.0
(t), 126.5 (d), 128.1 (s, C-1¢), 128.6 (d), 129.8 (d, C-4¢), 138.7 (s, C-
4), 144.7 (d, C-5), 162.6 (s, C-2).
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Halogen Dance Reaction; General Procedure
13C NMR (50 MHz, CDCl3): d = 21.2 (q), 126.2 (d), 126.4 (d),
128.6 (d), 129.0 (d), 130.0 (d), 130.6 (d), 131.0 (d), 133.7 (s), 136.4
(s), 137.6 (s), 142.0 (d, C-4), 167.8 (s, C-2).
A freshly prepared solution of LDA (1.5 equiv) in anhyd THF
(10%) was added to a solution of the halide (1 equiv) in anhyd THF
(20%) at –80 °C under argon. When TLC control showed complete
HD reaction, the mixture was quenched with H2O (10 mL) or
MeOH (10 mL), and allowed to warm to r.t. Brine (10 mL) was add-
ed and 2/3 of the THF was removed under reduced pressure. The
mixture was extracted with CH2Cl2 [3 × (5 × reaction volume)] and
the combined organic layers were washed with aq sat. NaHCO3
(5 × reaction volume) and brine (5 × reaction volume). The organic
layer was dried (Na2SO4), filtered, and the solvent was removed un-
der reduced pressure. The crude product was purified by column
chromatography.
Anal. Calcd for C16H13NS: C, 76.46; H, 5.21; N, 5.57. Found: C,
76.40; H, 5.14; N, 5.54.
2-Phenyl-4-o-tolylthiazole (11b)
Reaction time: 23 h; yield: 66 mg (66%); yellow oil; Rf = 0.47 (PE–
CH2Cl2, 1:1).
1H NMR (200 MHz, CDCl3): d = 2.43 (s, 3 H, CH3), 7.11–7.24 (m,
4 H, ArH, H-5), 7.29–7.40 (m, 3 H, ArH), 7.51–7.62 (m, 1 H, ArH),
7.88–7.98 (m, 2 H, ArH).
13C NMR (50 MHz, CDCl3): d = 21.2 (q, CH3), 115.8 (d, C-5),
125.9 (d), 126.6 (d), 128.3 (d), 128.9 (d), 129.9 (d), 130.0 (d), 131.0
(d), 133.8 (s), 134.7 (s), 136.4 (s), 156.7 (s, C-4), 166.9 (s, C-2).
4-Bromo-2-phenylthiazole (4)
Compound 4 was prepared from 2 (1 equiv, 12.49 mmol, 3.00 g) ac-
cording to the general procedure for the halogen dance reaction;
yield: 2.34 g (78%); colorless solid; mp 65–67 °C (Lit.18 mp 65 °C);
Rf = 0.63 (PE–THF, 10:1).
Anal. Calcd for C16H13NS: C, 76.46; H, 5.21; N, 5.57. Found: C,
76.52; H, 5.34; N, 5.64.
1H NMR (200 MHz, CDCl3): d = 7.20 (s, 1 H, H-5), 7.33–7.48 (m,
5-(4-Methoxyphenyl)-2-phenylthiazole (10c)
3 H, ArH), 7.82–7.99 (m, 2 H, ArH).
Reaction time: 48 h; yield: 38 mg (38%); colorless solid; mp 98–
100 °C (Lit.21 mp 102–103 °C); Rf = 0.35 (PE–EtOAc 10:1). NMR
data of the obtained product were in agreement with the literature.21
13C NMR (50 MHz, CDCl3): d = 116.5 (d, C-5), 126.0 (s, C-4),
126.3 (d), 129.0 (d), 130.7 (d, C-4¢), 132.5 (s, C-1¢), 169.0 (s, C-2).
4-(4-Methoxyphenyl)-2-phenylthiazole (11c)
4-Bromo-2-phenyloxazole (8)
Reaction time: 48 h; yield: 41 mg (41%); colorless solid; mp 130–
Compound 8 was prepared from 6 (1 equiv, 2.23 mmol, 500 mg) ac-
cording to the general procedure for the halogen dance reaction;
yield: 365 mg (78%); colorless oil; Rf = 0.40 (PE–EtOAc, 20:1).
1H NMR (200 MHz, CDCl3): d = 7.35–7.50 (m, 3 H, ArH), 7.65 (s,
1 H, H-5), 7.90–8.10 (m, 2 H, ArH).
13C NMR (50 MHz, CDCl3): d = 117.0 (s, C-4), 126.3 (s, C-1¢),
126.4 (d), 128.8 (d), 131.0 (d, C-4¢), 136.6 (d, C-5), 162.1 (s, C-2).
132 °C (Lit.21 mp 134.5–135 °C); Rf = 0.49 (PE–EtOAc, 30:1).
1H NMR data of the obtained product was in agreement with the lit-
erature.21
13C NMR (50 MHz, CDCl3): d = 55.3 (q, CH3), 110.9 (d, C-5),
114.1 (d), 126.6 (d), 127.5 (s, C-1¢¢), 127.7 (d), 128.9 (d), 129.9 (d,
C-4¢), 133.8 (s, C-1¢), 156.1 (s, C-4), 159.6 (s, C-4¢¢), 167.7 (s, C-2).
5-(4-Nitrophenyl)-2-phenylthiazole (10d)
Stille Cross-Coupling Reaction of Azoles; General Procedure
The stannane (1 equiv), the halide (1.1–2 equiv), CsF (2.2 equiv),
and Pd(PPh3)4 (0.05 equiv) were dissolved in anhyd toluene (12
mL) and refluxed under N2. When reaction control (TLC or GC/
MS) showed complete conversion of the halide, the mixture was fil-
tered over Celite and evaporation of the solvent in vacuum gave a
residue, which was purified by column chromatography.
Reaction time: 18 h; yield: 69 mg (69%); yellow solid; mp 191–
194 °C (Lit.22 mp 173 °C); Rf = 0.32 (PE–EtOAc, 10:1).
NMR data of the obtained product were in agreement with the liter-
ature.22
4-(4-Nitrophenyl)-2-phenylthiazole (11d)
Reaction time: 18 h; yield: 78 mg (78%); yellow solid; mp 130–
132 °C (Lit.23 mp 130–131 °C); Rf = 0.35 (PE–EtOAc, 10:1).
2,5-Diphenylthiazole (10a)
Yield: see Table 1 (entries 1–3 and entry 5) and Table 3 (entry 1);
colorless solid; mp 103–104 °C (Lit.19 mp 103–104 °C); Rf = 0.46
(PE–EtOAc, 10:1).
1H NMR data of the obtained product was in agreement with the lit-
erature.23
13C NMR (50 MHz, CDCl3): d = 116.0 (d, C-5), 124.1 (d), 126.6
(d), 126.9 (d), 129.1 (d), 130.5 (d, C-4¢), 133.1 (s, C-1¢), 140.2 (s, C-
1¢¢), 147.2 (s, C-4¢¢), 153.7 (s, C-4), 168.7 (s, C-2).
NMR data of the obtained product were in agreement with the liter-
ature.20
2,4-Diphenylthiazole (11a)
2-Phenyl-5-(2-thienyl)thiazole (10e)
Reaction time: 24 h; yield: 67 mg (67%); pale yellow solid; mp 76–
78 °C; Rf = 0.12 (PE–EtOAc, 50:1).
1H NMR (200 MHz, CDCl3): d = 7.01–7.10 (m, 1 H), 7.21 (dd,
J = 4.1, 1.0 Hz, 1 H), 7.29 (dd, J = 6.1, 1.0 Hz, 1 H), 7.39–7.49 (m,
3 H, ArH), 7.90 (s, 1 H, H-4), 7.92–8.01 (m, 2 H, ArH).
13C NMR (50 MHz, CDCl3): d = 125.5 (d), 125.6 (d), 126.4 (d),
128.0 (d), 129.0 (d), 130.1 (d), 132.5 (s), 133.3 (s), 133.5 (s), 139.4
(s, C-4), 166.6 (s, C-2).
Yield: see Table 1 (entries 4 and 6) and Table 3 (entry 2); colorless
solid; mp 75–78 °C (Lit.19 mp 93–94 °C); Rf = 0.56 (PE–EtOAc,
15:1).
1H NMR data of the obtained product were in agreement with the
literature.19
13C NMR (50 MHz, CDCl3): d = 112.7 (d, C-5), 126.5 (d), 126.6
(d), 128.2 (d), 128.8 (d), 128.9 (d), 130.0 (d), 133.8 (s), 134.5 (s),
156.3 (s, C-4), 167.9 (s, C-2).
Anal. Calcd for C13H9NS2: C, 64.16; H, 3.73; N, 5.76. Found: C,
63.97; H, 3.79; N, 5.63.
2-Phenyl-5-o-tolylthiazole (10b)
Reaction time; 18 h; yield: 68 mg (68%); colorless oil; Rf = 0.64
(PE–EtOAc, 10:1).
2-Phenyl-4-(2-thienyl)thiazole (11e)
1H NMR (200 MHz, CDCl3): d = 2.51 (s, 3 H, CH3), 7.27–7.39 (m,
3 H, ArH), 7.45–7.55 (m, 4 H, ArH), 7.86 (s, 1 H, H-4), 8.00–8.10
(m, 2 H, ArH).
Reaction time: 24 h; yield: 51 mg (51%); beige solid; mp 69–71 °C
(Lit.24 mp 77 °C); Rf = 0.61 (PE–THF, 15:1).
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Coupling Reactions of 2-Phenylthiazoles and -oxazoles
3105
1H NMR (200 MHz, CDCl3): d = 7.10 (dd, J = 3.7, 5.1 Hz, 1 H),
7.29–7.35 (m, 2 H), 7.41–7.51 (m, 3 H, ArH), 7.53 (dd, J = 3.7, 1.2
Hz, 1 H), 7.97–8.08 (m, 2 H, ArH).
13C NMR (50 MHz, CDCl3): d = 14.2 (q, SCH3), 110.8 (d), 126.7
(d), 129.1 (d), 130.8 (d), 133.2 (s), 137.5 (s), 143.7 (d), 157.2 (s),
157.4 (d), 171.6 (s), 173.2 (s).
13C NMR (50 MHz, CDCl3): d = 111.4 (d), 124.3 (d), 125.5 (d),
126.7 (d), 127.7 (d), 128.9 (d), 130.2 (d), 133.4 (s), 138.4 (s), 150.8
(s), 168.0 (s, C-2).
Anal. Calcd for C14H11N3S2: C, 58.92; H, 3.89; N, 14.72. Found: C,
58.77; H, 3.92; N, 14.45.
2-Methylsulfanyl-4-(2-phenylthiazol-4-yl)pyrimidine (11h)
Reaction time: overnight; yield: 61mg (61% mg); yellow solid; mp
127–128 °C; Rf = 0.31 (PE–EtOAc, 10:1).
1H NMR (200 MHz, CDCl3): d = 2.63 (s, 3 H, SCH3), 7.40–7.52 (m,
3 H, ArH), 7.82 (d, J = 5.1 Hz, 1 H, H-5), 7.94–8.08 (m, 2 H, ArH),
8.29 (s, 1 H, H-5¢), 8.61 (d, J = 5.1 Hz, 1 H, H-6).
3-(2-Phenylthiazol-5-yl)pyridine (10f)
Reaction time: 24 h; yield: 80 mg (75%); colorless solid; mp 90–
92 °C (Lit.22 mp 90–91 °C); Rf = 0.25 (PE–EtOAc, 1:1).
NMR data of the obtained product were in agreement with the liter-
ature.22
13C NMR (50 MHz, CDCl3): d = 14.2 (q, SCH3), 112.8 (d), 120.9
(d), 126.6 (d), 129.0 (d), 130.5 (d), 133.2 (s), 153.9 (s), 158.3 (d),
158.9 (s), 168.7 (s), 172.3 (s).
3-(2-Phenylthiazol-4-yl)pyridine (11f)
Reaction time: 24 h; yield: 67 mg (67%); beige solid; mp 81–83 °C;
Rf = 0.16 (PE–EtOAc, 3:1).
Anal. Calcd for C14H11N3S2: C, 58.92; H, 3.89; N, 14.72. Found: C,
58.56; H, 3.90; N 14.55.
1H NMR (200 MHz, CDCl3): d = 7.33 (dd, J = 4.7, 7.8 Hz, 1 H, H-
5), 7.38–7.47 (m, 3 H, ArH), 7.51 (s, 1 H, H-5¢), 7.96–8.04 (m, 2 H,
ArH), 8.24 (m, 1 H, H-4), 8.56 (dd, J = 4.7, 1.4 Hz, 1 H, H-6), 9.13–
9.24 (m, 1 H, H-2).
13C NMR (50 MHz, CDCl3): d = 113.8 (d), 123.6 (d), 126.6 (d),
129.0 (d), 130.3 (d), 133.3 (s, C-3), 133.7 (d), 147.7 (d), 149.1 (d),
153.1 (s, C-4¢), 168.5 (s, C-2¢).
2-Chloro-4-(2-phenylthiazol-5-yl)pyrimidine (10i)
Reaction time: 24 h; yield: 59 mg (48%); pale yellow solid; mp
180–183 °C; Rf = 0.33 (PE–EtOAc, 3:1).
1H NMR (200 MHz, CDCl3,): d = 7.42–7.56 (m, 4 H, ArH, H-5),
7.93–8.09 (m, 2 H, ArH), 8.47 (s, 1 H, H-4¢), 8.58 (d, J = 5.3 Hz, 1
H, H-6).
13C NMR (50 MHz, CDCl3,): d = 114.2 (d), 126.8 (d), 129.2 (d),
131.2 (d), 132.9 (s), 135.8 (s), 144.9 (d), 159.6 (d), 160.2 (s), 161.7
(s), 172.6 (s).
Anal. Calcd for C14H10N2S: C, 70.56; H, 4.23; N, 11.75. Found: C,
70.46; H, 4.02; N, 11.61.
2-Fluoro-4-(2-phenylthiazol-5-yl)pyridine (10g)
Reaction time: 21 h; yield: 76 mg (76%); beige solid; mp 126–
128 °C; Rf = 0.40 (PE–EtOAc, 1:1).
1H NMR (200 MHz, CDCl3): d = 7.07 (s, 1 H, H-4¢), 7.35 (m, 1 H),
7.41–7.51 (m, 3 H, ArH), 7.90–8.02 (m, 2 H, ArH), 8.15–8.28 (m,
2 H).
13C NMR (50 MHz, CDCl3): d = 106.0 (d, JC,F = 39.2 Hz, C-3),
118.4 (d, JC,F = 3.9 Hz, C-5), 126.6 (d), 129.1 (d), 130.9 (d), 132.9
(s), 134.9 (d, JC,F = 3.9 Hz), 142.1 (d), 144.0 (d, JC,F = 8.6 Hz),
148.5 (d, JC,F = 15.9 Hz, C-6), 164.4 (d, JC,F = 243.0 Hz, C-2), 169.8
(s, C-2¢).
Anal. Calcd for C13H8ClN3S: C, 57.04; H, 2.95; N, 15.35. Found: C,
56.84; H, 2.81; N, 14.96.
2-Chloro-4-(2-phenylthiazol-4-yl)pyrimidine (11i)
Reaction time: 24 h; yield: 30 mg (30%); colorless solid; mp 188–
190 °C; Rf = 0.68 (PE–EtOAc, 5:1).
1H NMR (200 MHz, CDCl3): d = 7.43–7.53 (m, 3 H, ArH), 8.00–
8.07 (m, 2 H, ArH), 8.12 (d, J = 5.1 Hz, 1 H, H-5), 8.39 (s, 1 H, H-
5¢), 8.69 (d, J = 5.1 Hz, 1 H, H-6).
13C NMR (50 MHz, CDCl3): d = 114.4 (d), 120.8 (d), 125.1 (d),
127.5 (d), 129.1 (d), 131.3 (s), 150.9 (s), 158.9 (s), 159.8 (s), 160.1
(s), 167.5 (s).
Anal. Calcd for C14H9FN2S: C, 65.61; H, 3.54; N, 10.93. Found: C,
65.37; H, 3.47; N, 10.86.
Anal. Calcd for C13H8ClN3S: C, 57.04; H, 2.95; N, 15.35. Found: C,
57.12; H, 3.01; N, 14.93.
2-Fluoro-4-(2-phenylthiazol-4-yl)pyridine (11g)
Reaction time: 24 h; yield: 78 mg (78%); colorless solid; mp 153–
155 °C; Rf = 0.23 (PE–EtOAc, 10:1).
1H NMR (200 MHz, CDCl3): d = 7.47 (t, J = 3.0 Hz, 3 H, ArH),
7.54 (s, 1 H, H-5¢), 7.64–7.75 (m, 2 H, ArH), 7.95–8.10 (m, 2 H,
ArH), 8.25 (d, J = 5.5 Hz, 1 H, H-6).
13C NMR (50 MHz, CDCl3): d = 106.4 (d, JC,F = 39.2 Hz, C-3),
117.1 (d, C-5¢), 118.4 (d, JC,F = 3.9 Hz, C-5), 126.7 (d), 129.1 (d),
130.6 (d), 133.0 (s), 146.7 (d, JC,F = 8.5 Hz), 148.1 (d, JC,F = 15.5
Hz, C-6), 152.4 (d, JC,F = 3.9 Hz), 164.7 (d, JC,F = 237.7 Hz, C-2),
168.9 (s, C-2¢).
2,2¢-Diphenyl[5,5¢]bithiazolyl (10j)
Yield: see Table 1, entries 23, 24; yellow solid; mp 195–197 °C
(Lit.22 mp 182 °C); Rf = 0.29 (PE–EtOAc, 10:1).
NMR data of the obtained product were in agreement with the liter-
ature.22
2,2¢-Diphenyl[4,4¢]bithiazolyl (11j)
Yield: isolated as by-product in varying trace amounts; colorless
solid; mp 179–182 °C (Lit.25 mp 185 °C); Rf = 0.65 (CH2Cl2).
Anal. Calcd for C14H9FN2S: C, 65.61; H, 3.54; N, 10.93. Found: C,
65.32; H, 3.45; N, 11.05.
1H NMR (200 MHz, CDCl3): d = 7.38–7.56 (m, 6 H, ArH), 7.92 (s,
2 H, H-5, H-5¢), 7.97–8.13 (m, 4 H, ArH).
13C NMR (50 MHz, CDCl3): d = 115.3 (d, C-5, C-5¢), 126.6 (d),
128.9 (d), 130.1 (d), 133.6 (s), 151.6 (s, C-4, C-4¢), 168.3 (s, C-2, C-
2¢).
2-Methylsulfanyl-4-(2-phenylthiazol-5-yl)pyrimidine (10h)
Reaction time: overnight; yield: 73 mg (73%); colorless solid; mp
143–144 °C; Rf = 0.06 (PE–EtOAc, 10:1).
1H NMR (200 MHz, CDCl3): d = 2.60 (s, 3 H, SCH3), 7.21 (d,
J = 5.1 Hz, 1 H, H-5), 7.37–7.52 (m, 3 H, ArH), 7.92–8.07 (m, 2 H,
ArH), 8.38 (s, 1 H, H-4¢), 8.47 (d, J = 5.1 Hz, 1 H, H-6).
5-Phenyl-2-(2-phenylthiazol-5-yl)oxazole (10k)
Reaction time: 24 h; yield: 70 mg (70%); yellow solid; mp 121–
124 °C; Rf = 0.05 (CH2Cl2).
1H NMR (200 MHz, CDCl3): d = 7.37 (s, 1 H, H-4), 7.40–7.59 (m,
6 H, ArH), 7.89–8.01 (m, 2 H, ArH), 8.02–8.19 (m, 3 H, ArH, H-4¢).
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J. Hämmerle et al.
PAPER
13C NMR (50 MHz, CDCl3): d = 124.9 (s), 125.2 (d, C-4), 126.4 (d),
126.5 (d), 126.8 (s), 128.9 (d), 129.1 (d), 130.5 (d), 130.7 (d), 133.1
(s), 140.2 (d, C-4¢), 143.8 (s), 161.5 (s), 167.8 (s).
Anal. Calcd for C14H11N3OS: C, 62.44; H, 4.12; N, 15.60. Found:
C, 62.15; H, 4.24; N, 15.31.
Acknowledgment
2,5-Diphenyloxazole (12a)
Yield: see Table 2 (entry 1) and Table 3 (entry 3); yellow solid; mp
We thank ‘Hochschuljubiläumsstiftung der Stadt Wien’ for finan-
cial support of this project (H 1478/2006) as well as Vienna Univer-
sity of Technology.
72–75 °C (Lit.26 mp 74 °C); Rf = 0.28 (PE–EtOAc, 10:1).
NMR data of the obtained product were in agreement with the liter-
ature.27
References
2,4-Diphenyloxazole (13a)
Yield: see Table 2 (entry 2) and Table 3 (entry 4); beige solid; mp
(1) Thiazoles: (a) Rivkin, A.; Cho, Y. S.; Gabarda, A. E.;
Yoshimura, F.; Danishefsky, S. J. J. Nat. Prod. 2004, 67,
139. (b) Bach, T.; Heuser, S. Angew. Chem. Int. Ed. 2001,
40, 3184. (c) Plazzi, P. V.; Bordi, F.; Silva, C.; Morini, G.;
Caretta, A.; Barocelli, E.; Vitali, T. Eur. J. Med. Chem.
1995, 30, 881. (d) Ganesh, T.; Schilling, J. K.; Palakodety,
R. K.; Ravindra, R.; Shanker, N.; Bane, S.; Kingston, D. G.
I. Tetrahedron 2003, 59, 9979. (e) Shao, J.; Panek, J. S.
Org. Lett. 2004, 6, 3083. Thiazoles and oxazoles:
(f) Nicolaou, K. C.; Roschangar, F.; Vourloumis, D. Angew.
Chem. Int. Ed. 1998, 37, 2014. (g) Zhong, J.; Zaiguo, L.;
Runqiu, H. Nat. Prod. Rep. 2002, 19, 454. (h) Lucke, A. J.;
Tyndall, J. D. A.; Singh, Y.; Fairlie, D. P. J. Mol. Graphics
Modell. 2003, 21, 341. Oxazoles: (i) Yeh, V. S. C.
Tetrahedron 2004, 60, 11995.
102–104 °C (Lit.28 mp 101–102 °C); Rf = 0.18 (PE–EtOAc, 30:1).
NMR data of the obtained product were in agreement with the liter-
ature.28
2-Fluoro-4-(2-phenyloxazol-5-yl)pyridine (12b)
Reaction time: 17 h; yield: 80 mg (80%); colorless solid; mp 110–
114 °C; Rf = 0.29 (PE–EtOAc, 20:1).
1H NMR (200 MHz, CDCl3): d = 7.23 (br s, 1 H, H-3), 7.46 (d,
J = 5.3 Hz, 1 H, H-5), 7.43–7.58 (m, 3 H, ArH), 7.69 (s, 1 H, H-4¢),
8.07–8.20 (m, 2 H, ArH), 8.29 (d, J = 5.3 Hz, 1 H, H-6).
13C NMR (50 MHz, CDCl3): d = 103.6 (d, JC,F = 40.3 Hz, C-3),
115.9 (d, JC,F = 4.2 Hz, C-5), 126.6 (s), 126.7 (d), 127.9 (d), 129.0
(d), 131.2 (d), 139.9 (d, JC,F = 8.8 Hz), 147.8 (d, JC,F = 3.9 Hz),
148.5 (d, JC,F = 15.5 Hz, C-6), 162.9 (s, C-2¢), 164.5 (d, JC,F = 238.1
Hz, C-2).
(2) (a) Hantzsch, A. Ber. Dtsch. Chem. Ges. 1888, 21, 942.
(b) Science of Synthesis, Vol. 11; Schaumann, E., Ed.; Georg
Thieme Verlag: Stuttgart, 2002, 627. (c) Ghosh, A. K.;
Bilcer, G.; Schiltz, G. Synthesis 2001, 2203. (d) List, B.;
Castello, C. Synlett 2001, 1687.
Anal. Calcd for C14H9FN2O: C, 70.00; H, 3.78; N, 11.66. Found: C,
69.76; H, 3.78; N, 11.42.
(3) (a) The Chemistry of Heterocyclic Compounds, Vol. 60;
Palmer, D. C., Ed.; Wiley: New York, 2004. (b) Hassner,
A.; Fischer, B. Heterocycles 1993, 35, 1441. (c) Turchi, I. J.
Ind. Eng. Chem. Prod. Res. Dev. 1981, 20, 32.
2-Fluoro-4-(2-phenyloxazol-4-yl)pyridine (13b)
Reaction time: 20 h; yield: 23 mg (46%); colorless solid; mp 138–
140 °C; Rf = 0.17 (PE–EtOAc, 8:1).
1H NMR (200 MHz, CDCl3): d = 7.38 (br s, 1 H, H-3), 7.43–7.60
(m, 4 H, ArH), 8.02–8.18 (m, 3 H, ArH), 8.25 (d, J = 5.1 Hz, 1 H,
H-6).
13C NMR (50 MHz, CDCl3): d = 105.6 (d, JC,F = 39.2 Hz, C-3),
117.7 (d, JC,F = 3.9 Hz, C-5), 126.6 (d), 128.9 (d), 131.0 (d), 136.1
(d), 139.0 (d, JC,F = 4.2 Hz), 144.0 (d, JC,F = 8.8 Hz), 148.1 (d,
JC,F = 15.2 Hz, C-6), 162.6 (s, C-2¢), 164.5 (d, JC,F = 237.7 Hz, C-2).
(4) (a) Handbook of Organopalladium Chemistry for Organic
Synthesis, Vol. 1; Negishi, E.; de Meijere, A., Eds.; Wiley:
Hoboken N.J., 2002. (b) Handbook of Organopalladium
Chemistry for Organic Synthesis, Vol. 2; Negishi, E.;
de Meijere, A., Eds.; Wiley: Hoboken N.J., 2002.
(c) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.,
Vol. 1; de Meijere, A.; Diederich, F., Eds.; Wiley-VCH:
Weinheim, 2004. (d) Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed., Vol. 2; de Meijere, A.; Diederich, F.,
Eds.; Wiley-VCH: Weinheim, 2004. (e) Schnürch, M.;
Flasik, R.; Khan, A.; Spina, M.; Mihovilovic, M. D.;
Stanetty, P. Eur. J. Org. Chem. 2006, 3283. (f) Schröter, S.;
Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245.
(5) Thiazoles: (a) Bach, T.; Heuser, S. Tetrahedron Lett. 2000,
41, 1707. (b) Hodgetts, K. J.; Kershaw, M. T. Org. Lett.
2002, 4, 1363.
Oxazoles: (c) Young, G. L.; Smith, S. A.; Taylor, R. J. K.
Tetrahedron Lett. 2004, 45, 3797.
(6) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
(b) Nicolaou, K. C.; He, F.; Roschangar, F.; King, N. P.;
Vourloumis, D.; Li, T. Angew. Chem. Int. Ed. 1998, 37, 84.
(c) Espinet, P.; Echavarren, A. M. Angew. Chem. Int. Ed.
2004, 43, 4704.
Anal. Calcd for C14H9FN2O·0.3 H2O: C, 68.46; H, 3.94; N, 11.40.
Found: C, 68.43; H, 3.83; N, 11.32.
2-Methylsulfanyl-4-(2-phenyloxazol-5-yl)pyrimidine (12c)
Reaction time: 18 h; yield: 125 mg (75%); colorless solid; mp 122–
124 °C; Rf = 0.14 (PE–EtOAc, 20:1).
1H NMR (200 MHz, CDCl3): d = 2.56 (s, 3 H, SCH3), 7.24 (d,
J = 5.1 Hz, 1 H, H-5), 7.40–7.50 (m, 3 H, ArH), 7.91 (s, 1 H, H-4¢),
8.01–8.13 (m, 2 H, ArH), 8.52 (d, J = 5.1 Hz, 2 H, H-6).
13C NMR (50 MHz, CDCl3): d = 14.1 (q, SCH3), 110.1 (d, C-5),
126.7 (s), 126.8 (d), 128.9 (d), 130.7 (d), 131.3 (d, C-4¢), 148.8 (s,
C-4), 153.6 (s, C-5¢), 157.9 (d, C-6), 163.4 (s, C-2¢), 173.1 (s, C-2).
2-Methylsulfanyl-4-(2-phenyloxazol-4-yl)pyrimidine (13c)
Reaction time: 18 h; yield: 30 mg (49%); beige solid; mp 138–
141 °C; Rf = 0.28 (PE–EtOAc, 8:1).
(7) Stanetty, P.; Schnürch, M.; Mihovilovic, M. D. J. Org.
Chem. 2006, 71, 3754.
(8) Erlenmeyer, H.; Becker, C.; Sorkin, E.; Bloch, H.; Suter, E.
Helv. Chim. Acta 1947, 30, 2058.
1H NMR (200 MHz, CDCl3): d = 2.53 (s, 3 H, SCH3), 7.37–7.47 (m,
3 H, ArH), 7.53 (d, J = 5.1 Hz, 1 H, H-5), 7.97–8.09 (m, 2 H, ArH),
8.35 (s, 1 H, H-5¢), 8.52 (d, J = 5.1 Hz, 1 H, H-6).
13C NMR (50 MHz, CDCl3): d = 14.1 (q, SCH3), 111.8 (d, C-5),
126.6 (d), 126.9 (s), 128.8 (d), 130.9 (d), 139.3 (d, C-5¢), 140.4 (s,
C-4), 157.9 (s, C-4¢), 158.0 (d, C-6), 162.4 (s, C-2¢), 172.4 (s, C-2).
(9) Begtrup, M.; Hansen, L. B. L. Acta Chem. Scand. 1992, 46,
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(10) For reviews of halogen dance reactions, see: (a) Schnürch,
M.; Spina, M.; Khan, A. F.; Mihovilovic, M. D.; Stanetty, P.
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Synthesis 2008, No. 19, 3099–3107 © Thieme Stuttgart · New York