Polyarylated thiazoles via a combined halogen dance - Cross-coupling strategy

Article abstract of DOI:10.1002/ejoc.200900092

The application of the halogen dance reaction for the synthesis of starting materials for cross-coupling reactions is reported. The obtained compounds were then successfully applied, in sequential Stille and Suzuki-Miyaura cross-coupling reactions to obta

Full text of DOI:10.1002/ejoc.200900092

FULL PAPER
DOI: 10.1002/ejoc.200900092
Polyarylated Thiazoles via a Combined Halogen Dance – Cross-Coupling
Strategy
Michael Schnürch,*[a] Ather Farooq Khan,[a][‡] Marko D. Mihovilovic,[a] and Peter Stanetty[a]
Keywords: Protein kinase inhibitor analogues / Halogen dance / Cross-coupling / Palladium / Polyarylated thiazoles
The application of the halogen dance reaction for the synthe-
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
sis of starting materials for cross-coupling reactions is re- Germany, 2009)
ported. The obtained compounds were then successfully ap-
plied in sequential Stille and Suzuki–Miyaura cross-coupling
reactions to obtain novel thiazole derivatives.
The halogen dance (HD) reaction for the synthesis of
Introduction
various di- and trisubstituted heterocycles was reported in
the literature.[8] It represents a base-induced reaction of a
haloaromatic compound in which the position of the halo-
gen atom differs from its position in the starting material.
Additionally, quenching the intermediate with different
electrophiles leads to the introduction of a new function-
ality at the position where the halogen was present initially.
In summary, the big advantage of the HD methodology is
that the number of reactive centers is increased and further
manipulations on the molecule are facilitated. HD reactions
were successfully performed on a number of heterocyclic
systems[8] but only recently oxazole[9] and thiazole have
been added to this list. The first HD on thiazole was per-
formed by Stangeland and Sammakia[10] and recently two
more examples, from our group, were published.[11] In a
very recent example, we reported preliminary data on the
formation of polyhalogenated thiazoles via the HD reaction
as starting materials for cross-coupling reactions. Within
this contribution we have extended our investigations and
significantly broadened the substrate scope of the method-
ology.[12]
Simple and convenient methods for the synthesis and
decoration of heterocycles are always desirable due to the
importance of heterocyclic compounds as agrochemicals,
pharmaceuticals, natural products, materials and in many
other areas of interest.[1] Thiazole can be considered as an
important member of the heterocyclic family and substi-
tuted thiazoles can be found in a number of molecules with
interesting properties.[2,3] Principally, substituted thiazoles
can be prepared by two methods: directly via cyclization
reactions[4] or via decoration of simple thiazole building
blocks. For the synthesis of complex thiazole derivatives,
the latter approach is usually the more convenient one, es-
pecially, when libraries of compounds have to be prepared.
Transition metal catalyzed cross-coupling reactions have
proved to be very useful for developing syntheses of com-
plex heterocyclic compounds.[5] They are nowadays well es-
tablished methods for the formation of C–C and C–X (X =
N, O, and S) bonds.[6] In cross-coupling reactions thiazole
building blocks can either be used as the organometallic
species[7] or as the halogenated counterpart. Therefore, de-
veloping methods for the efficient synthesis of halogenated/
metallated thiazoles, as valuable building blocks, are highly
desirable. Within this contribution, transition metal-cata-
lyzed cross-coupling strategies were applied to decorate the
thiazole building block 1, obtained via a cyclization strat-
egy, with various aryl and heteroaryl substituents. In the
present case a cyclization strategy would not be versatile
enough since only a limited number of substituents can be
introduced and for each substitution pattern different
thioamides and α-halo ketones have to be prepared.
In the present contribution the HD reaction on 2-anilino-
thiazole was investigated. Additionally, the 4-halogenated
and 4,5-dihalogenated/metallated thiazoles, obtained after
a HD on thiazole 2, were then cross-coupled with different
aromatic systems in a sequential manner leading finally to
[a] Vienna University of Technology, Institute of Applied Synthetic
Chemistry,
Getreidemarkt 9/163, 1060 Vienna, Austria
E-mail: mschnuerch@tuwien.ac.at
[‡] Present address: Department of Chemistry, COMSATS Insti-
tute of Information Technology, Abbottabad 22060, Pakistan
Figure 1. Related protein kinase inhibitors.
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Polyarylated Thiazoles
a variety of 2,4,5-trisubstituted thiazoles. These compounds
are of interest since they are structurally related to sub-
stances reported as potential protein kinase inhibitors
(PKIs, Figure 1).[13]
Results and Discussion
Synthesis of Starting Materials
Scheme 2. Synthesis of 1 via Hantzsch cyclization.
2-Anilinothiazole (1) was first prepared according to the
Due to its possible interference in forthcoming reactions
the free amine functionality had to be protected. The BOC
group was chosen[11a] due to its lower tendency to migrate
under lithiation conditions compared to the pivaloyl
group.[17] Compound 7 was prepared via a standard proto-
col.[11a] Introduction of bromine in the 5-position of thi-
azoles was achieved via lithiation using nBuLi and quench-
ing with Br2 (Scheme 3). Lithiation conditions were used
as bromination under conventional bromination conditions
(i.e. Br2 in CHCl3) resulted in partial removal of the BOC
group and only 53% yield of product 2 were isolated. How-
ever, under lithiation conditions the desired product 2 was
obtained in 86% yield.
method reported in the literature starting from
3
(Scheme 1).[14] Although the starting materials were cheap,
this method has the disadvantage that it is a two step pro-
cess leading to only 48% of 1, a yield which was considered
as unsatisfactory especially for the first step of a reaction
sequence. Therefore, two alternative strategies for the syn-
thesis of 1 were investigated: a) nucleophilic substitution b)
Hantzsch synthesis[15] with N-phenylthiourea.
Scheme 1. Synthesis of 1.
Commercially available 2-bromothiazole (5) was selected
for nucleophilic substitution with aniline. Due to the low
nucleophilicity of aniline, activation of 5 via protonation
was necessary. Consequently, pTosOH was used as acid and
an appreciable yield of 60% was obtained when equimolar
amounts of pTosOH were used (iPrOH as solvent). Incom-
plete conversion was observed when substoichiometric
amounts of pTosOH were used and in the absence of pTos-
OH no product was formed. Unfortunately, the expectation
Scheme 3. Synthesis of precursor 2.
Halogen Dance Reaction
Compound 2 was then used as starting material for HD
that the higher boiling solvent sec-BuOH would lead to reactions. The reason why an HD takes place on 2 can be
higher product yields was not fulfilled and 56% of the prod- explained on the basis of differences in acidity. The 5-posi-
uct was isolated in that case. Although higher yielding, we tion, in this particular case, is more acidic than the 4-posi-
did not consider this process as ideal due to the rather ex- tion therefore favoring lithiation at the 5-position rather
pensive starting material 5.
than in 4-position. However, when LDA is used as base the
The Hantzsch synthesis was used by Kaye et al.[16] for initially formed lithiated species is I. This intermediate I can
the synthesis of various thiazole derivatives with yields up react by itself as a lithiating reagent but in contrast to LDA
to 94%. When this method was applied for the synthesis of it gives a metal–halogen exchange starting a cascade of
1, using commercially available N-phenylthiourea (6) and 2- metal–halogen exchange reactions which ultimately leads to
chloro-1,1-diethoxyethane, 84% of the desired product was the most stable lithiated species IV: First, I reacts with still
obtained (Scheme 2). Therefore, this cyclization strategy be- present starting material 2 which leads to the intermediates
came ultimately the method of choice for the synthesis of II and III. Then again, these two species can react with each
starting material 1.
other and metal–halogen exchange on III takes place in 5-
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M. Schnürch, A. F. Khan, M. D. Mihovilovic, P. Stanetty
FULL PAPER
position leading to the most stable lithiated species IV on Table 1. Optimization of HD conditions.
the one hand and on the other hand starting material 2 is
Entry
Temperature
LDA [equiv.] % of 2
% of 8a
recovered. Key intermediate IV can also be formed upon
reaction of intermediate I with intermediate III whereby I
is transformed to III and III into IV. It can be seen that all
lithiated intermediates (I, II, IV) can react with the interme-
diate halide species (2, III) ultimately leading to the thermo-
dynamically most stable compound IV. The suggested
mechanism is summarized in Scheme 4.
1
2
3
4
–85 °C to –70 °C
–85 °C to –50 °C
–85 °C to –60 °C
–85 °C to –60 °C
1.1
1.1
2.2
3.3
80
–
35
–
10
–
60
97
These optimized conditions were then used to obtain dif-
ferent 4,5-disubstituted thiazoles. 4-Bromo-5-lithiated inter-
mediate IV was trapped with various electrophiles and sev-
eral substituents were introduced at 5-position in good
yields (43–97%; Table 2, Scheme 5). The highest yield was
obtained when intermediate IV was quenched with water
(H2O) leading to 97% of 4-bromo compound 8a (entry 1).
Also iodine (70% with I2, entry 4) and chlorine (70% with
hexachloroethane, entry 5) were introduced with good
yields. Especially the 5-iodo-4-bromo compound 8c is an
interesting substrate for further cross-coupling reactions.
Unfortunately, the introduction of bromine to obtain 4,5-
dibrominated product 8b worked only in comparably mod-
erate yields (50%). Even by applying 1,2-dibromo-1,1,2,2-
tetrachloroethane instead of Br2, a method successful in the
oxazole series,[10] did not improve the yield (30%). On the
other hand, the introduction of tributyltin (with Bu3SnCl)
worked well and the desired compound 8e was isolated in
65% yield (entry 6). Compound 8e is another interesting
starting material for sequential cross-coupling reactions
since it enables a potential Stille reaction in 5-position fol-
lowed by any other cross-coupling method in the 4-posi-
tion. However, attempts to introduce a boronic acid or ester
via this methodology were unsuccessful. This is not too sur-
prising since in our previous research we already found a
very limited stability of thiazole-boron compounds. We
could never isolate a free boronic acid and only pinacol
esters, obtained via immediate transesterification with pina-
col proved to be accessible in some cases.[18] Introduction
of an alcohol with benzophenone resulted in the formation
of product 8g in 43% yield. The lower yield in the case
of benzophenone compared to other electrophiles can be
explained by steric reasons. A formyl group could also be
introduced by using DMF as an electrophile (8f, 97% yield)
as well as TMS using TMSCl (8h, 97%), which provides an
interesting option to block position 5 temporarily.
Scheme 4. The mechanism of the HD reaction. Structures with ro-
man numbers are not isolated reaction intermediates.
To optimize HD reaction conditions, the conversion of
the 5-bromo compound 2 to the 4-bromo compound 8a was
investigated in detail (Table 1). In first attempts 1.1 equiv.
of LDA were added dropwise to a solution of 2 at –80 °C
over a period of 15 min. Then the reaction mixture was
stirred for 1 h keeping the temperature below –70 °C.
Quenching the reaction with H2O (1.1 equiv.) in 5 mL of
THF gave only 10% of the desired product with 80% recov-
ery of starting material. When the temperature was elevated
to –50 °C, decomposition of the product was observed and
no product was obtained after workup. By using an excess
of LDA (2.2 equiv.), an improvement in the yield was ob-
Table 2. Electrophiles introduced at 5-position of thiazole.
served and 60% of product 8a was obtained. Further in- Entry
E
Electrophile
Product
Yield (%)
creasing the amount of LDA to 3.3 equiv. resulted in the
complete conversion of the starting material and 97% of
the product 8a was obtained. These results were comparable
to the previously reported[11a] HD reaction on a thiazole
derivative, where 3.3 equiv. of base (LDA) were required as
well to give complete HD. We also observed that “in-
verse”[8b] addition of base was not necessary and similar
yields were obtained when the halide was added to the LDA
solution.
1
2
3
4
5
6
7
8
9
10
H
Br
Br
I
H2O
Br2
C2Br2Cl4
I2
C2Cl6
Bu3SnCl
B(OiPr)3
DMF
benzophenone
TMSCl
8a
8b
8b
8c
8d
8e
–
8f
8g
8h
97
50
30
70
70
65
–
97
43
97
Cl
SnBu3
Bpin/B(OH)2
CHO
C(OH)(C6H5)2
TMS
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Polyarylated Thiazoles
however, in case of (4-methoxyphenyl)boronic acid only
39% of the desired compound 12 was obtained. However,
similar observations were reported in the literature[18,23] for
aryl-donors with electron donating substituents. Somewhat
remarkable was that the sterically demanding (2-meth-
ylphenyl)boronic acid gave the best yield, even better than
the simple phenylboronic acid. An explanation for that
might be the lower tendency to form a biphenyl by-product
than in the other cases.
Scheme 5. Introduction of electrophiles via HD.
After investigating aryl coupling partners, the cross-cou-
pling of heteroaryl donors with 8a was investigated. (2-
Fluoropyridin-3-yl)- and (2-fluoropyridin-4-yl)boronic acid
were chosen for cross-couplings since those compounds
were available in our lab and of interest in the context of
potential PKIs. These two boronic acids were prepared
from 2-fluoropyridine by following the literature pro-
cedure.[24] Applying these compounds in the cross-coupling
protocol, (2-fluoropyridin-3-yl)boronic acid gave a good
yield of 64% of 13, and in the case of (2-fluoropyridin-4-
yl)boronic acid an excellent yield of 80% of 14 was ob-
tained. The higher yields in the case of heteroaromatic part-
ners are quite encouraging as heteroaromatic moieties are
key structural features of many biologically active com-
pounds.
Cross-Coupling Reactions
As already mentioned above, heterocyclic compounds,
especially polyarylated ones, are of considerable interest in
many different research fields.[1] Therefore, compounds 8a,
8c, and 8e were then used in Pd-catalyzed cross-coupling
reactions with aromatic and heteroaromatic systems (see
Schemes 6, 7 and 9).
Initially, 8a was cross-coupled with either phenylboronic
acid or tributyl(phenyl)stannane. Both, the Stille[19–21]
[Pd(PPh3)4, CsF, toluene] and Suzuki–Miyaura[22] protocols
[Pd(PPh3)4, NaHCO3, DME, H2O] gave the same result
(product 9 in 60% and 61%, respectively). Additionally, we
also investigated the effect of different substituents on the
benzene ring on the outcome of Suzuki–Miyaura cross-cou-
pling reactions. The Stille protocol was excluded from this
survey due to the high toxicity of tin compounds and the
limited commercial availability of arylstannanes in com-
parison to aryl boronic acids. (4-Methoxyphenyl)boronic
acid, (4-methylphenyl)boronic acid and (2-methylphenyl)-
Sequential Cross-Coupling Reactions
Subsequently, starting materials 8c and 8e were used in
boronic acid were selected as aryl donors. The best yields sequential cross-coupling reactions. Initially, 8e a vicinal
were obtained in the case of (2-methylphenyl)boronic acid bromostannane, was selected for cross-coupling reactions.
i.e. 77%. (4-Methylphenyl)boronic acid gave a yield of 58%, It represents a challenging compound for cross-coupling re-
Scheme 6. Suzuki–Miyaura cross-coupling reactions with 8a.
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M. Schnürch, A. F. Khan, M. D. Mihovilovic, P. Stanetty
FULL PAPER
Scheme 7. Cross-couplings with vicinal (bromostannyl)thiazole 8e.
actions since an organometal and a halide-species are pres- i.e. starting from 17, improved the yield and the required
ent in the same molecule (tributyltin in 5-position and Br in product 19 was obtained in 76% overall yield over two steps
4-position). Therefore, there are more possibilities for side (Scheme 8).[25] However, when this strategy was applied to
reactions since 8e can potentially react with itself. When the 8e, an overall yield of 15% was obtained. These lower yields
cross-coupling reaction of iodobenzene with 8e was per- with vicinal bromostannanes of azoles were not surprising.
formed only 22% of product 15 (Scheme 7) was isolated. Revesz and co-workers[26] reported imidazole examples
Compound 8a was obtained as a major side product (39%) which gave similar low yields (24–55%). Only in one case
which shows the instability of 8e under the reaction condi- the desired product was obtained in 74% yield.
tions. In another project a similar reaction was performed
It was mentioned above that better yields were obtained
on the oxazole derivative 18 (Scheme 8). There, 43% of the in cross-coupling reactions of 8a with heterocyclic boronic
desired product 19 was obtained upon cross-coupling with acids. Therefore, also in the sequential case 2-fluoro-3-iodo-
iodobenzene. However, performing the reaction in one-pot pyridine was cross-coupled with 8e. The yields were slightly
better but again not more than 37% of the desired product
16 (Scheme 7) was obtained along with 30% of side product
8a.
In comparison to 8e, starting material 8c is actually well
set up for sequential cross-coupling reactions as it was
found that the 5-position is slightly favored over the 4-posi-
tion in cross-coupling reactions.[19] The iodine in 5-position
should further increase the selectivity in cross-coupling re-
actions. Indeed, when the cross-coupling was performed be-
tween 8c and phenylboronic acid, the 5-position was selec-
tively cross-coupled to give 80% of the desired product 15
(Scheme 9). The second cross-coupling step was then per-
formed on 15 at 4-position and 90% of product 20 were
obtained. When sterically hindered (2-methylphenyl)bor-
onic acid was used in the second cross-coupling step 50%
of the desired product 21 were isolated. This lower yield
Scheme 8. Cross-coupling with vicinal (bromostannyl)oxazole 17.
Scheme 9. Sequential cross-couplings with thiazole 8c.
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Polyarylated Thiazoles
Table 3. Sequential cross-couplings with thiazole 8c.
Entry
Step 1
Coupling partner
Step 2
Coupling partner
Overall
Yield (%) Yield (%)
Product
Yield (%)
Product
1
2
3
phenylboronic acid
phenylboronic acid
(2-methylphenyl)boronic acid 22
15
15
80
80
59
phenylboronic acid
(2-methylphenyl)boronic acid 21
phenylboronic acid 23
20
90
50
90
72
40
53
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. Ele-
mental analyses were carried out in the Microanalytical Labora-
tory, Institute of Physical Chemistry, Vienna University.
can be explained by steric reasons. A slightly better yield
was obtained when (2-methylphenyl)boronic acid was used
in the first cross-coupling step on 8c (59% yield of 22).
Compound 22 was then again cross-coupled in 4-position
with phenylboronic acid to give product 23 in an excellent
yield of 90%. In summary, compound 20 was prepared in
72% yield over two cross-coupling steps starting from 8c.
The synthesis of 21 and 23 was not as efficient but still 40%
resp. 53% were obtained. In both cases cross-coupling with
(2-methylphenyl)boronic acid was the step which lowered
the yield of the overall process (Table 3).
N-Phenylthiazol-2-amine (1). Method I: 2-Bromothiazole (1 equiv.,
3.00 g, 18.2 mmol) was dissolved in iPrOH (50 mL). Then aniline
(1.5 equiv., 2.54 g, 27.3 mmol) and pTosOH (1.0 equiv., 3.12 g,
18.2 mmol) were added to the reaction mixture. After refluxing for
60 h the reaction mixture was diluted with EtOAc and washed with
satd. NaHCO3, water and brine. The organic layer was dried with
Na2SO4, filtered and the solvent was evaporated. Recrystallization
from DIPE gave pure 1 (yield 60%, 1.93 g, 1.09 mmol, yellow so-
lid).
Conclusions
Method II: N-Phenylthiourea (1 equiv., 1.00 g, 6.57 mmol), 2-
chloro-1,1-diethoxyethane (1 equiv., 0.82 g, 6.57 mmol) and few
drops of concd. aqueous HCl were mixed in water (100 mL). After
refluxing for 4 h the reaction mixture was diluted with water
(100 mL) followed by aq. NaOH (2 ) to make the solution alka-
line. The resulting precipitate was collected by filtration, washed
with water and dried at 80 °C. Recrystallization from DIPE gave 1
(yield 84%, 0.97 g, 0.55 mmol, yellow solid).
In conclusion we found that the HD reaction can be used
as an efficient method for the synthesis of starting materials
for sequential cross-coupling reactions. Additionally, a
series of electrophiles can be introduced in 5-position. HD
reactions were performed on 1,1-dimethylethyl N-(5-bro-
mothiazol-2-yl)-N-phenylcarbamate (2), which in turn was
synthesized from commercially available 2-phenylthiourea 6
in three steps with an overall yield of 60%, improving pre-
vious routes significantly. Depending on the nature of the
electrophile, moderate to excellent yields were obtained (43–
97%). Subsequently, cross-coupling reactions were then
performed on products 8a, 8c and 8e. Reactions with 8a
gave yields in the range of 40–77% when cross-coupled with
aryl systems. In case of heteroaryl systems slightly better
yields were obtained (64–80%). Compound 8c also proved
to be a good substrate for sequential cross-coupling reac-
tions and different aryl groups were introduced selectively
at 5- and subsequently at 4-position in good yields (60–
90%). Compound 8e on the other hand gave only low yields
in sequential reactions, which was somehow expected since
the compound was challenging due to its “bivalent” nature
as halide and organometal species.
Melting point and NMR spectroscopic data matched literature re-
ports.[27]
1,1-Dimethylethyl N-(5-Bromothiazol-2-yl)-N-phenylcarbamate (2):
nBuLi (1.1 equiv., 2.38  in hexane, 5.03 mL) was added dropwise
to a stirred solution of 3 (1.0 equiv., 3.00 g, 10.9 mmol) in dry THF
(50 mL) under argon atmosphere at –80 °C. Stirring at –80 °C was
continued for 30 min, then Br2 (1.1 equiv., 1.91 g, 11.94 mmol) was
added below –70 °C. The reaction mixture was stirred for ad-
ditional 30 min at –80 °C and then slowly warmed to ambient tem-
perature. The reaction solution was then poured onto water, diluted
with EtOAc, washed with water and brine. The organic layer was
dried with Na2SO4, filtered and the solvent was evaporated to give
2. The crude product was purified by MPLC (LP:EtOAc 10:1) to
give 86% yield (3.32 g, 9.3 mmol) of 2 as colorless crystals.
Melting point and NMR spectroscopic data match with corre-
sponding values in the literature.[11a] C14H15BrN2O2S (355.2): C
47.33, H 4.26, N 7.89; found C 47.55, H 4.11, N 7.87.
Experimental Section
General Procedure for the Halogen Dance: Freshly prepared LDA
(3.3 equiv. as 10% solution in THF) was added dropwise to the
halide (200 mg) in dry THF (10 mL) at –85 °C. The reaction mix-
ture was warmed to –70 °C and stirred at this temperature until
TLC showed complete HD reaction. The corresponding electro-
phile (3.3 equiv.) [15% sol. in THF in case of solids and neat in
case of liquid] was added at –90 °C and the reaction mixture was
allowed to reach ambient temperature within 1 h. The reaction
mixture was diluted with EtOAc, washed with 2  HCl, water, and
brine and the organic phase dried with Na2SO4. The solvent was
evaporated and the crude product was purified by MPLC or
recrystallization.
General Methods: All lithiation reactions were conducted under ar-
gon using dried glassware and magnetic stirring. Unless otherwise
noted, chemicals were purchased from commercial suppliers and
used without further purification. All solvents were dried with
Al2O3 cartridges prior to use. Flash column chromatography was
performed on silica gel 60 from Merck (40–63 µm) using a Büchi
Sepacore preparative column. The ratio of crude product to silica
gel was 1:30. For thin-layer chromatography (TLC) aluminum
backed silica gel was used. The solvent mixture used for TLC was
also used for column chromatography. Kugelrohr distillation was
carried out using a Büchi GKR-51 apparatus. Melting points were
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1,1-Dimethylethyl
N-(4-Bromothiazol-2-yl)-N-phenylcarbamate
General Procedure for Cross-Coupling Reactions
(8a): M.p. 117–119 °C; yield 97% (194 mg, 0.54 mmol, colorless
crystals) MPLC LP/DIPE, 10:1, H NMR (CDCl3, 200 MHz): δ =
Stille Cross-Coupling: The stannane (1 equiv.) and corresponding
halide (1 equiv.) were refluxed in dry toluene (15 mL) with the cata-
lyst [Pd(PPh3)4, 0.05 equiv.] and CsF (2.2 equiv.). The reaction was
monitored by TLC.
1
1.42 (s, 9 H), 6.85 (s, 1 H), 7.19–7.24 (m, 2 H), 7.33–7.45 (m, 3 H)
ppm. 13C NMR (CDCl3, 50 MHz): δ = 27.9 (q), 83.8 (s), 111.8 (d),
120.9 (s), 128.2 (d), 128.3 (d), 129.1 (d), 138.6 (s), 152.7 (s), 162.2
(s) ppm. C14H15BrN2O2S (355.25): calcd. C 47.33, H 4.26, N 7.89;
found C 47.40, H 4.12, N 7.79.
Suzuki–Miyaura Cross-Coupling: The boronic acid (1 equiv.), the
halide (1 equiv.), the catalyst [Pd(PPh3)4, 0.05equiv] and the base
NaHCO3 (3.3 equiv.) were refluxed in a mixture of DME and H2O
(2:1, 10% solution) until the TLC showed the completion of the
reaction.
1,1-Dimethylethyl N-(4,5-Dibromothiazol-2-yl)-N-phenylcarbamate
(8b): M.p. 106–109 °C; yield 50% (121 mg, 0.28 mmol, colorless
1
crystals) MPLC LP/DIPE, 20:1, H NMR (CDCl3, 200 MHz): δ =
1.41 (s, 9 H), 7.16–7.21 (m, 2 H), 7.39–7.45 (m) ppm. 13C NMR
(CDCl3, 50 MHz): δ = 27.9 (q), 84.3 (s), 101.8 (s), 123.9 (s), 128.4
(d), 128.5 (d), 129.2 (d), 137.6 (s), 152.8 (s), 161.3 (s) ppm.
C14H14Br2N2O2S (434.15): calcd. C 38.73, H 3.25, N 6.45; found
C 38.93, H 3.30, N 6.34.
General Workup Procedure for Cross-Coupling Reactions: The reac-
tion mixture was filtered and the filtrate was concentrated in vacuo.
The crude mixture was purified by MPLC. The product fractions
were collected and the solvent evaporated to obtain pure com-
pound.
1,1-Dimethylethyl
N-(4-Bromo-5-iodothiazol-2-yl)-N-phenylcarb-
1,1-Dimethylethyl N-(4-Phenylthiazol-2-yl)-N-phenylcarbamate (9):
M.p. 128–130 °C; yield 61% (120 mg, 0.34 mmol, colorless crys-
tals), MPLC LP/DIPE, 20:1, 1H NMR (CDCl3, 200 MHz): δ =
1.43 (s, 9 H), 7.15 (s, 1 H), 7.22–7.32 (m, 5 H), 7.40–7.46 (m, 3 H),
7.61–7.65 (m, 2 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 28.6
(q), 83.8 (s), 108.4 (d), 126.4 (d), 128.1 (d), 128.3 (d), 129.0 (d),
129.1 (d), 129.3 (d), 135.1 (s), 140.1 (s), 150.4 (d), 153.4 (s), 162.0
(s) ppm. C20H20N2O2S (352.45): calcd. C 68.16, H 5.72, N 7.95;
found C 68.07, H 5.60, N 7.78.
amate (8c): M.p. 144–147 °C; yield 70% (189 mg, 0.39 mmol, color-
less crystals) MPLC LP/DIPE, 20:1, 1H NMR (CDCl3, 200 MHz):
δ = 1.41 (s, 9 H), 7.16–7.21 (m, 2 H), 7.35–7.48 (m, 3 H) ppm. 13C
NMR (CDCl3, 50 MHz): δ = 27.9 (q), 67.1 (s), 84.3 (s), 128.3 (d),
128.4 (d), 129.2 (d), 130.2 (s), 137.9 (s), 152.8 (s), 165.7 (s) ppm.
C14H14BrIN2O2S (481.15): calcd. C 34.95, H 2.93, N 5.82; found
C 34.94, H 2.76, N 5.75.
1,1-Dimethylethyl N-(4-Bromo-5-chlorothiazol-2-yl)-N-phenylcarb-
amate (8d): M.p. 136–138 °C; yield 70% (153 mg, 0.39 mmol, yel-
low crystals) MPLC LP/DIPE, 20:1, 1H NMR (CDCl3, 200 MHz):
δ = 1.35 (s, 9 H), 7.10–7.14 (m, 2 H), 7.31–7.38 (m, 3 H) ppm. 13C
NMR (CDCl3, 50 MHz): δ = 28.0 (q), 84.3 (s), 117.2 (s), 120.7 (s),
128.4 (d), 128.5 (d), 129.2 (d), 137.4 (s), 152.8 (s), 158.8 (s) ppm.
C14H14BrClN2O2S (389.70): calcd. C 43.15, H 3.62, N 7.19; found
C 43.14, H 3.53, N 6.99.
1,1-Dimethylethyl N-[4-(2-Methylphenyl)thiazol-2-yl]-N-phenylcarb-
amate (10): M.p. 80–82 °C; yield 77% (158 mg, 0.43 mmol, color-
less powder), MPLC LP/DIPE, 20:1, 1H NMR (CDCl3, 200 MHz):
δ = 1.45 (s, 9 H), 2.97 (s, 3 H), 6.94 (s, 1 H), 7.10–7.14 (m, 3 H),
7.22–7.44 (m, 6 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 21.3
(q), 28.6 (q), 83.2 (s), 110.9 (d), 125.6 (d), 127.6 (d) 127.7 (d), 128.5
(d), 128.8 (d), 129.3 (d), 130.8 (d) 134.7 (s), 136.3 (s), 139.7 (s),
150.7 (s), 152.9 (s), 160.6 (s) ppm. C21H22N2O2S (366.48): calcd. C
68.82, H 6.05, N 7.64; found C 68.87, H 5.87, N 7.69.
1,1-Dimethylethyl
N-[4-Bromo-5-(tributylstannyl)thiazol-2-yl]-N-
phenylcarbamate (8e): M.p. 35–37 °C; yield 65% (235 mg,
0.36 mmol, colorless crystals) MPLC LP/DIPE, 20:1, 1H NMR
(CDCl3, 200 MHz): δ = 0.89 (t, J = 7 Hz, 3 H), 1.15–1.23 (m, 6
H), 1.27–1.38 (m, 6 H), 1.42 (s, 9 H) 1.44–1.52 (m, 6 H), 7.19–7.25
(m, 2 H), 7.35–7.47 (m, 3 H) ppm. 13C NMR (CDCl3, 50 MHz): δ
= 11.0 (t), 13.6 (q), 27.2 (t), 28.0 (t), 28.9 (q), 83.4 (s), 121.7 (s),
128.0 (s), 128.3 (d), 129.0 (d), 139.2 (s), 152.8 (s), 166.7 (s) ppm.
1,1-Dimethylethyl N-[4-(4-Methylphenyl)thiazol-2-yl]-N-phenylcarb-
amate (11): M.p. 96–98 °C, yield 58% (119 mg, 0.32 mmol, color-
less powder), MPLC LP/DIPE, 20:1, 1H NMR (CDCl3, 200 MHz):
δ = 1.49 (s, 9 H), 2.32 (s, 3 H), 7.27–7.31 (m, 3 H), 7.32–7.58 (m,
7 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 21.2 (q), 28.1 (q), 83.2
(s), 107.1 (d), 125.8 (d), 127.7 (d) 128.6 (d), 128.7 (d), 129.1 (d),
131.9 (s), 137.3 (s), 139.7 (s), 150.0 (s), 152.9 (s), 161.4 (s) ppm.
C21H22N2O2S (366.48): calcd. C 68.82, H 6.05, N 7.64; found C
68.37, H 5.86, N 7.65.
1,1-Dimethylethyl N-(4-Bromo-5-formylthiazol-2-yl)-N-phenylcarb-
amate (8f): M.p. 152–154 °C; yield 97% (215 mg, 0.56 mmol, color-
less crystals) MPLC LP/DIPE, 4:1, H NMR (CDCl3, 200 MHz):
1
δ = 1.35 (s, 9 H), 7.10–7.14 (m, 2 H), 7.31–7.38 (m, 3 H), 9.88 (s,
1 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 27.8 (q), 85.2 (s), 126.9
(s), 128.1 (d), 128.7 (d), 129.3 (d), 133.1 (s), 137.4 (s), 152.3 (s),
167.0 (s), 183.7 (d) ppm. C15H15BrN2O3S (383.26): calcd. C 47.01,
H 3.94, N 7.31; found C 46.95, H 3.82, N 7.15.
1,1-Dimethylethyl N-[4-(4-Methoxyphenyl)thiazol-2-yl]-N-phenyl-
carbamate (12): M.p. 124–126 °C; yield 39% (83 mg, 0.22 mmol,
colorless powder), MPLC LP/DIPE, 20:1, 1H NMR (CDCl3,
200 MHz): δ = 1.45 (s, 9 H), 3.77 (s, 3 H), 6.78–6.84 (m, 2 H), 7.01
(s, 1 H), 7.27–7.60 (m, 7 H) ppm. 13C NMR (CDCl3, 50 MHz): δ
= 28.0 (q), 55.2 (q), 83.2 (s), 106.0 (d), 113.7 (d), 127.1 (d) 127.6
(s), 127.7 (d), 128.5 (d), 128.7 (d), 139.6 (s), 149.6 (s), 152.8 (s),
159.1 (s), 161.4 (s) ppm. C21H22N2O3S (382.48): calcd. C 65.95, H
5.80, N 7.32; found C 65.72, H 5.64, N 7.40.
1,1-Dimethylethyl N-[4-Bromo-5-(hydroxydiphenylmethyl)thiazol-2-
yl]-N-phenylcarbamate (8 g): M.p. 184–187 °C; yield 43% (130 mg,
0.24 mmol, colorless crystals) MPLC LP:EtOAc 10:1, 1H NMR
(CDCl3, 200 MHz): δ = 1.35 (s, 9 H), 3.82 (br. s, 1 H), 7.17–7.22
(m, 2 H), 7.31–7.38 (m, 13 H) ppm. 13C NMR (CDCl3, 50 MHz):
δ = 27.9 (q), 78.1 (s), 83.8 (s), 119.1 (s), 127.9 (d), 126.5 (d), 127.4
(d), 127.5 (s), 128.0 (d), 128.1 (d), 128.2 (d), 128.4 (d), 129.1 (d),
133.9 (s), 138.2 (s), 143.8 (s), 144.8 (d) 152.5 (s), 160.3 (s) ppm.
C27H25BrN2O3S (537.47): calcd. C 60.34, H 4.69, N 5.21; found C
60.09, H 4.52, N 5.15.
1,1-Dimethylethyl N-[4-(2-Fluoropyridin-3-yl)thiazol-2-yl]-N-phenyl-
carbamate (13): M.p. 159–161 °C, yield 64% (134 mg, 0.37 mmol,
colorless powder) MPLC LP/EtOAc, 15:1, 1H NMR (CDCl3,
50 MHz): δ = 1.39 (s, 9 H), 6.98–7.05 (m, 1 H), 7.19–7.24 (m, 2
H), 7.33–7.47 (m, 4 H), 7.92–7.96 (m), 7.98–8.07 (m, 1 H) ppm.
4
13C NMR (CDCl3, 50 MHz): δ = 28.0 (q), 83.6 (s), 114.1 (d, JC,F
2
4
1,1-Dimethylethyl
N-[4-Bromo-5-(trimethylsilyl)thiazol-2-yl]-N-
= 14.8 Hz), 117.6 (d, JC,F = 26.5 Hz), 121.7 (d, JC,F = 4.2 Hz),
3
phenylcarbamate (8h): Yield 97% (233 mg, 0.54 mmol, yellow pow-
127.9 (d), 128.5 (d), 128.9 (d), 139.4 (s), 139.6 (d, JC,F = 4.2 Hz),
der) Data matched with the literature.[18]
141.7 (d, 3JC,F = 7.1 Hz), 145.3 (d, 3JC,F = 15.2 Hz), 152.8 (s), 160.2
3234
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 3228–3236

Polyarylated Thiazoles
1
(d, JC,F = 240.9 Hz), 161.3 (s) ppm. C19H18FN3O2S (371.43):
H), 7.21–7.48 (m, 11 H) ppm. 13C NMR (CDCl3, 50 MHz): δ =
20.1 (q), 28.0 (q), 83.3 (s), 126.0 (d), 126.2 (s), 127.0 (d), 127.3 (d),
127.7 (d), 127.9 (d), 128.5 (d), 128.6 (d), 128.8 (d), 130.4 (d), 131.4
(d), 131.5 (s), 135.1 (s), 138.0 (s), 139.3 (s), 144.2 (s), 152.9 (s),
159.5 (s) ppm.
calcd. C 61.44, H 4.88, N 11.31; found C 61.29, H 4.84, N 11.03.
1,1-Dimethylethyl N-[4-(2-Fluoropyridin-4-yl)thiazol-2-yl]-N-phenyl-
carbamate (14): M.p. 126–128 °C, yield 80% (167 mg, 0.45 mmol,
yellow powder). MPLC LP/EtOAc, 5:1, 1H NMR (CDCl3,
200 MHz): δ = 1.38 (s, 9 H), 7.03 (s, 1 H), 7.19–7.22 (m, 3 H), 7.29
(dd, JHF = 1.4, JH5ЈЈЈ = 4.8 Hz, 1 H), 7.34–7.42 (m, 3 H), 8.03 (d,
Acknowledgments
JH5ЈЈЈ = 5.3 Hz, 1 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 28.0
(q), 83.8 (s), 105.7 (d, 2JC,F = 39.0 Hz), 112.6 (d), 117.9 (d, JC,F
=
=
4
A. F. K. would like to thank the Higher Education Commission
(HEC) of Pakistan and Austria Student Exchange Program
(OEAD) for granting a fellowship to conduct his PhD Thesis.
4
3.8 Hz), 128.1 (d), 128.4 (d), 128.9 (d), 139.0 (s), 146.3 (d, JC–F
3.9 Hz), 146.9 (d, 3JC,F = 8.7 Hz), 147.7 (d, 3JC,F = 15.4 Hz), 152.9
1
(s), 162.1 (s), 164.5 (d, JC,F = 234.6 Hz) ppm. C19H18FN3O2S
(371.43): calcd. C 61.44, H 4.88, N 11.31, S 8.63; found C 61.21,
H 5.03, N 10.81, S 8.30.
[1] Heterocycles in Life and Society: An Introduction to Heterocy-
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ester, England, 1997 .
1,1-Dimethylethyl N-(4-Bromo-5-phenylthiazol-2-yl)-N-phenylcarb-
amate (15): M.p. 173–176 °C; yield 80% (143 mg, 0.33 mmol, color-
less powder), 1H NMR (CDCl3, 200 MHz): δ = 1.18 (s, 9 H), 7.24–
7.30 (m, 2 H), 7.39–7.44 (m, 4 H) 7.50–7.54 (m, 4 H) ppm. 13C [2] a) H. Takayama, K. Kato, M. Kimura, H. Akita, Heterocycles
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Chem. 2005, 26, 429–449; g) R. A. Hughes, S. P. Thompson, L.
Alcarez, C. J. Moody, J. Am. Chem. Soc. 2005, 127, 15644–
15651; h) Z. Jin, Nat. Prod. Rep. 2005, 22, 196–229.
[3] a) R. Dunkel, H.-L. Elbe, J. N. Greul, B. Hartmann, H. Gayer,
T. Seitz, U. Wachendorff, Neumann, P. Dahmen, K.-H. Kuck,
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Tokkyo Koho JP 200466855, 2005 [Chem. Abstr. 143:306303];
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Int. Appl. WO 2003029249, 2003 [Chem. Abstr. 138:304297]; d)
A. Doemling, J. Kolb, Ger. Offen. DE 10134478, 2003 [Chem.
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[4] Science of Synthesis, vol. 11: Five-Membered Hetarenes with
One Chalcogen and One Additional Heteroatom (Ed.: E. Schau-
mann), Georg Thieme Verlag, Stuttgart, Germany, 2002, p.
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[5] a) Handbook of Organopalladium Chemistry for Organic Syn-
thesis (Eds: E. Negishi, A. de Meijere), John Wiley & Sons,
Hoboken, NJ, 2002, vol. 1 and 2; b) Metal-Catalyzed Cross-
Coupling Reactions, 2nd ed., vol. 1 and 2 (Eds: A. de Meijere,
F. Diederich), Wiley-VCH, Weinheim, Germany, 2004.
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Chemist (Eds: J. J. Li, G. W. Gribble), Elsevier, Amsterdam,
The Netherlands, 2007.
NMR (CDCl3, 50 MHz): δ = 28.0 (q), 83.9 (s), 117.9 (s), 128.1 (d),
128.2 (d), 128.5 (d), 128.6 (d), 128.9 (d), 129.1 (d), 130.7 (s), 138.3
(s), 152.8 (s) ppm. C20H19BrN2O2S (431.35): calcd. C 55.69, H 4.44,
N 6.49; found C 55.96, H 4.44, N 6.36.
1,1-Dimethylethyl N-[4-Bromo-5-(2-fluoropyridin-3-yl)thiazol-2-yl]-
N-phenylcarbamate (16): M.p. 156–158 °C, yield 37% (69 mg,
0.15 mmol, yellow powder), MPLC LP/EtOAc, 4:1, 1H NMR
(CDCl3, 200 MHz): δ = 1.43 (s, 9 H), 7.23–7.31 (m, 3 H), 7.37–
7.52 (m, 3 H), 8.04 (dt, JH6ЈЈ = 7.4, JH4ЈЈ = 1.9 Hz, 1 H), 8.24 (d,
JH5 = 4.8 Hz, 1 H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 27.9
2
3
(q), 84.3 (s), 114.0 (d, JC,F = 30.3 Hz), 119.0 (d, JC,F = 6.4 Hz),
4
121.4 (d, JC,F = 4.3 Hz), 121.9 (s), 128.4 (d), 128.4 (d), 129.1 (d),
138.1 (s), 142.3 (d, 3JC,F = 3.5 Hz), 147.6 (d, 3JC,F = 14.4 Hz), 152.7
1
(s), 160.0 (d, JC,F = 241.6 Hz), 162.2 (s) ppm.
1,1-Dimethylethyl N-(4,5-Diphenylthiazol-2-yl)-N-phenylcarbamate
(20): M.p. 168–172 °C, yield 90% (160 mg, 0.37 mmol, colorless
1
powder), MPLC LP/EtOAc, 20:1, H NMR (CDCl3, 200 MHz): δ
= 1.45 (s, 9 H), 7.09–7.16 (m, 3 H), 7.27–7.48 (m, 12 H) ppm. 13C
NMR (CDCl3, 50 MHz): δ = 28.0 (q), 83.3 (s), 127.2 (d), 127.6 (d),
127.7 (d), 127.9 (d), 128.6 (d), 128.7 (d), 128.8 (d), 129.6 (d) 132.3
(s), 135.0 (s), 139.2 (s), 144.2 (s), 152.9 (s), 159.3 (s) ppm.
1,1-Dimethylethyl N-[4-(2-Methylphenyl)-5-(phenyl)thiazol-2-yl]-N-
phenylcarbamate (21): M.p. 158–161 °C; yield 50% (91 mg, 0.20,
colorless powder) MPLC LP/DIPE, 15:1, 1H NMR (CDCl3,
200 MHz): δ = 1.46 (s, 9 H), 2.02 (s, 3 H) 6.01–7.41 (m, 14 H) ppm.
13C NMR (CDCl3, 50 MHz): δ = 20.1 (q), 28.0 (q), 83.3 (s), 125.3
(d), 127.0 (s), 127.7 (d), 127.8 (d), 128.4 (d), 128.5 (d), 128.8 (d),
130.3 (d), 130.6 (d), 132.3 (s), 135.1 (s), 137.4 (s), 139.2 (s), 145.3
(s), 152.9 (s), 158.8 (s) ppm. C27H26N2O2S (442.57): calcd. C 73.27,
H 5.92, N 6.33; found C 72.73, H 5.57, N 6.16.
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1,1-Dimethylethyl N-[4-Bromo-5-(2-methylphenyl)thiazol-2-yl]-N-
phenylcarbamate (22): M.p. 160–162 °C; yield 59% (109 mg,
0.24 mmol, colorless powder) MPLC LP/DIPE, 15:1, 1H NMR
(CDCl3, 200 MHz): δ = 1.42 (s, 9 H), 2.32 (s, 3 H) 7.25–7.50 (m, 9
H) ppm. 13C NMR (CDCl3, 50 MHz): δ = 20.3 (q), 28.0 (q), 83.9
(s), 120.2 (s), 125.7 (d), 126.8 (s), 128.2 (d), 128.5 (d), 129.1 (d),
129.2 (d), 129.6 (s), 130.3 (d), 131.4 (d), 138.2 (s), 138.4 (s), 152.7
(s), 161.2 (s) ppm. C21H21BrN2O2S (445.37): calcd. C 56.63, H 4.75,
N 6.29; found C 57.17, H 4.63, N 6.30.
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(CDCl3, 200 MHz): δ = 1.45 (s, 9 H), 2.11 (s, 3 H) 7.03–7.10 (m, 3
Eur. J. Org. Chem. 2009, 3228–3236
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3235

M. Schnürch, A. F. Khan, M. D. Mihovilovic, P. Stanetty
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Published Online: May 14, 2009
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Eur. J. Org. Chem. 2009, 3228–3236