Halogen dance and sequential cross-coupling on 2-anilinothiazoles

Article abstract of DOI:10.2174/157017809787582780

A series of 4-bromo-5-halo and 4-bromo-5-organometal-2-anilinothiazole derivatives were prepared via the halogen dance (HD) reaction. Subsequent Pd-catalyzed Stille and Suzuki-Miyaura cross-coupling reactions were performed in a sequential manner to obtai

Full text of DOI:10.2174/157017809787582780

Letters in Organic Chemistry, 2009, 6, 171-174
171
Halogen Dance and Sequential Cross-Coupling on 2-Anilinothiazoles
Ather Farooq Khan, Michael Schnürch*, Marko D. Mihovilovic and Peter Stanetty
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163-OC, A-1060 Vienna,
Austria
Received November 12, 2008: Revised November 28, 2008: Accepted December 18, 2008
Abstract: A series of 4-bromo-5-halo and 4-bromo-5-organometal-2-anilinothiazole derivatives were prepared via the
halogen dance (HD) reaction. Subsequent Pd-catalyzed Stille and Suzuki-Miyaura cross-coupling reactions were per-
formed in a sequential manner to obtain novel 4,5-diarylated-2-anilinothiazoles.
Keywords: Pd-catalysis, cross-couplings, thiazole, halogen dance, sequential cross-couplings.
The chemistry of heterocycles is one of the most impor-
tant fields of chemistry since heterocycles are found in such
diverse compounds as pharmaceuticals, agrochemicals, natu-
ral compounds, organic materials, and many more [1].
Within the family of heterocycles, thiazole is a prominent
member. Substituted thiazoles are present in many natural
products [2], pharmaceuticals and agrochemicals [3]. The
synthesis of thiazole compounds is often achieved via cycli-
zation methods [4] such as the classical Hantzsch synthesis
[5]. The decoration of thiazole compounds is an important
area in thiazole chemistry since via cyclization strategies not
all desired substitution patterns are accessible. For arylation
reactions transition metal-catalyzed cross-coupling protocols
[6] proved to be successful and have been reported in the
literature [7].
reagent with 1 and two new species are obtained, namely II
and III. In principle, all lithiated intermediates can act them-
selves as lithiation agents. The dibrominated intermediate III
is so converted to the key intermediate IV, either by reaction
with I or II. This intermediate IV can then be quenched with
different electrophiles to obtain 4,5-disubstituted thiazoles.
N
N
1) BOC-Protection (i)
2) Bromination (ii)
Br
N
S
N
S
H
BOC
1
1A
Br
LDA
E+
N
E
S
N
In the present contribution the use of the halogen dance
(HD) [8, 9] reaction for the preparation of various 4,5-
disubstituted thiazoles along with their use in sequential
cross-coupling reactions is reported. As starting material 1,1-
dimethylethyl-N-(5-bromothiazol-2-yl)-N-phenylcarbamate
(1) was prepared from 2-anilinothiazole in two steps. Ini-
tially, the amine functionality was BOC-protected before
bromine was introduced via a lithiation strategy (over all
yield 71%). By applying the HD reaction to 1 a new reactive
center is generated in 4-position for further manipulations
(e.g. cross-coupling). Additionally, quenching the intermedi-
ate with different electrophiles leads to the formation of new
functionalities in the 5-position, which initially carried the
bromine atom (Scheme 1). When halide-electrophiles are
used, 4,5-dihalocompounds are accessible which give the
opportunity to perform sequential cross-coupling reactions.
The big advantage of the HD methodology is that the num-
ber of reactive centers is increased and further decoration or
manipulations on the molecule are facilitated.
BOC
2a-e
i) (BOC)2O, THF, DMAP, reflux, 16h; ii) n-BuLi, Br2, THF, -80°C
Scheme 1. General scheme for the halogen dance reaction on 1.
The results obtained are summarized in Table 1. The
highest yield was obtained when intermediate IV was
quenched with water (H2O) leading to 97% of the 4-bromo
compound 2a (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 2c is an interesting substrate for further cross-
coupling reactions. Unfortunately, the introduction of bro-
mine to obtain 4,5-dibrominated product 2b worked only in
low yields.
Br2 gave the best yield with respect to electrophiles
investigated for incorporation of a bromo-substituent and
50% of 2b were obtained (entries 2&3). On the other hand,
the introduction of tributyltin (with Bu3SnCl) worked well
and the desired compound 2e was isolated in 65% yield
(entry 6). Compound 2e is another interesting starting
material for sequential cross-coupling reactions since it
enables a potential Stille reaction in 5-position followed by
any other coupling method in the 4-position.
The general mechanism for this transformation is pre-
sented in Scheme 2. Initially, the 4-position in 1 is lithiated
with LDA as it carries the most acidic proton available. The
so obtained lithiated intermediate I can react as lithiating
*Address correspondence to this author at the Institute of Applied Synthetic
Chemistry, Vienna University of Technology, Getreidemarkt 9/163-OC,
1060 Vienna, Austria; Tel: ++43 (0)1 58801 15440; Fax: ++43 (0)1 58801
15499; E-mail: mschnuerch@ioc.tuwien.ac.at
As already mentioned above, heterocyclic compounds,
especially polyarylated ones, are of considerable interest in
many different research fields. Therefore, also the formation
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

172 Letters in Organic Chemistry, 2009, Vol. 6, No. 2
Khan et al.
Scheme 2. Mechanism of the halogen dance on 1.
of arylated 2-anilinothiazoles is of considerable interest since
they might show interesting properties or biological activity.
Therefore, compounds 2a, 2c, and 2e were then used in Pd-
catalyzed cross-coupling reactions with aromatic systems.
Initially, 2a was cross-coupled with either phenylboronic
acid or tributyl(phenyl)stannane. Both, the Stille [10] and
Suzuki-Miyaura [11] protocols gave good results (60% and
61%, respectively) (Scheme 3). For Stille cross-coupling a
procedure previously optimized for arylation of thiazoles
was applied [12].
Subsequently, compounds 2c and 2e were investigated in
sequential cross-coupling reactions. Initially, Stille cross-
coupling was performed on 2e with iodobenzene as coupling
partner. This represents a challenging starting material since
an organometal- (i.e. tributyltin in 5-position) and a halide-
species (Br in 4-position) are present in the same molecule.
Therefore, it can basically react with itself as an undesired
side reaction. Performing a cross-coupling reaction with io-
dobenzene on 2e only 22% of the pure product 4 was iso-
lated. Due to the “bivalent” nature of starting material 2e this
result was not too surprising. Debrominated 2a was obtained
as a major side product (39%) which shows the instability of
2e under the reaction conditions.
Table 1. Electrophiles Introduced at 5-Position of 1
Entry
E
Electrophile
Products
Yield (%)
Starting material 2c on the other hand is actually well set
up for sequential cross-coupling reactions. The iodine in 5-
position should further increase the selectivity in cross-
coupling reactions since it was found that this position is
slightly favored over the 4-position in cross-coupling reac-
tions [11]. The remaining bromine in 4-position could then
be coupled in a second step as already demonstrated above.
Indeed, the 5-position was selectively cross-coupled with
phenylboronic acid and 80% of the desired product 4 was
isolated. The second cross-coupling step on 4 was then per-
formed under the same conditions again with phenylboronic
and the diarylated thiazole 5, was obtained in 90% yield
(Scheme 4).
1
2
3
4
5
6
H
Br
H2O
Br2
2a
2b
2b
2c
2d
2e
97
50
30
70
70
65
Br
C2Br2Cl4
I2
I
Cl
C2Cl6
Bu3SnCl
SnBu3
Suzuki-Miyaura
reaction (i)
or
Br
N
N
Stille reaction (ii)
N
S
CONCLUSION
N
BOC
S
In conclusion, the HD reaction proved to be an efficient
method for the synthesis of starting materials for sequential
cross-coupling reactions in 4- and 5-position of protected 2-
anilinothiazoles. The initial cross-coupling experiments were
performed on the halogen-danced products (2a, 2c & 2e).
Compounds 2a and 2c proved to be good substrates for
cross-coupling reactions whereas 2e gave only low yields
BOC
3
2a
i) Phenylboronic acid, H2O, DME, NaHCO3, reflux, 3h, 61% yield
ii) Tributyl(phenyl)stannane, toluene, CsF, reflux, 8h, 60% yield
Scheme 3. Cross-coupling reactions at 4-position of 2a.

HD and Cross-coupling on Thiazoles
Letters in Organic Chemistry, 2009, Vol. 6, No. 2
173
PTC Int. Appl. WO2006061215, 2006; Chem. Abstr., 145, 62881.
(b) Murakami, H.; Takii, S.; Mizuno, M. Jpn. Kokai Tokkyo Koho
JP 200466855, 2005; Chem. Abstr., 143, 306303. (c) Mueller, U.;
Eberle, M.; Pillonel, C.; Lutz, W.; Stanetty, P. PCT Int. Appl.
WO2003029249, 2003; Chem. Abstr. 138, 304297. (d) Doemling,
A.; Kolb, J. Ger. Offen. DE10134478, 2003; Chem. Abstr., 138,
137301
Br
Br
N
N
I
N
Bu3Sn
N
S
S
BOC
BOC
2e
2c
[4]
[5]
(a) Schaumann, E., Ed.; Science of Synthesis, Five-Membered
Hetarenes with One Chalcogen and One Additional Heteroatom;
Georg Thieme Verlag, Stuttgart, Germany, 2002, Vol. 11, p. 627.
Hantzsch, A. Ber. Dtsch. Chem. Ges., 1888, 21, 942. (b) Prakash,
R.; Kumar, A.; Aggarwal, R.; Prakash, O.; Singh, S. P. Synth.
Commun., 2007, 37, 2501. (c) Egan, R. S.; Tadanier, J.; Garmaise,
D. L.; Gaunce, A. P. J. Org. Chem., 1968, 33, 4422. (d) Babadja-
mian, A.; Metzger, J.; Chanon, M. J. Heterocycl. Chem., 1975, 12,
643.
Phenylboronic acid
DME, H2O, NaHCO3,
Pd(PPh3)4, 3h
Iodobenzene,
Pd(PPh3)4, CsF,
toluene, reflux, 24h
80%
22%
Br
N
[6]
[7]
(a) Negishi, E.; de Meijere, A., Eds.; Handbook of Organopalla-
dium Chemistry for Organic Synthesis, John Wiley & Sons, Inc.,
Hoboken, N. J. 2002, Vol. 1&2. b) Meijere, A.; Diederich, F. Eds.;
Metal-Catalyzed Cross-Coupling Reactions 2nd ed, Wiley-VCH
Verlag GmbH & Co. KGaA, Weinheim, Germany 2004; Vol. 1&2.
(a) Prasad, A. S. B.; Stevenson, T. M.; Citineni, J. R.; Nyzam, V.;
Knochel, P. Tetrahedron, 1997, 53, 7237. (b) Bach, T.; Heuser, S.
Angew. Chem. Int. Ed., 2001, 40, 3184. (c) Stanetty, P; Schnürch,
M; Mihovilovic, M. D. J. Org. Chem. 2006, 71, 3754. (d) Hodgetts,
K. J; Kershaw, M. T. Org. Lett., 2002, 4, 1363. (e) Nicolaou, K. C;
Ritzen, A; Namoto, K; Buey, R. M; Diaz, J. F.; Andreu, J. M.;
Wartmann, M; Altmann, K. H; O´Brate, A; Giannakakou, P. Tetra-
hedron, 2002, 58, 6413. (f) Ganesh, T; Schilling, J. K; Palakodety,
R. K; Ravindra, R; Shanker, N; Bane, S; Kingston, D. G. I. Tetra-
hedron, 2003, 59, 9979. (g) Moreno I.; Tellitu, I; Dominguez, E;
SanMartin, R. Eur. J. Org. Chem., 2002, 2126. (h) Schnürch, M.;
Spina, M.; Khan, A. F.; Flasik, R.; Mihovilovic M. D.; Stanetty, P.
Eur. J. Org. Chem., 2006, 3283.
N
S
BOC
4
Phenylboronic acid,
DME, H2O, NaHCO3,
Pd(PPh3)4, 3h
N
N
S
[8]
For reviews on the HD reaction see: (a) Bunnett, J. F. Acc. Chem.
Res. 1972, 5, 139. b) Fröhlich, J. Prog. Het. Chem. 1994, 6, 1. c)
Duan, X; Zhang, Z. Heterocycles, 2005, 65, 2005. d) Schnürch, M.;
Spina, M; Khan, A. F; Mihovilovic, M. D; Stanetty, P. Chem. Soc.
Rev., 2007, 36, 1046.
For HD reactions on thiazole see a) Stangeland, E. L.; Sammakia,
T. J. Org. Chem., 2004, 69, 2381. b) Holzweber, M.; Schnürch, M.;
Stanetty, P. Synlett, 2007, 19, 3016. c) Stanetty, P.; Schnürch, M.;
Mereiter, K.; Mihovilovic, M. D. J. Org. Chem., 2005, 70, 567.
(a) Nicolaou, K. C; Ritzen, A; Namoto, K; Buey, R. M; Diaz, J. F.;
Andreu, J. M.; Wartmann, M; Altmann, K. H; Brate, A;
Giannakakou, P. Tetrahedron, 2002, 58, 6413. b) Ganesh, T;
Schilling, J. K; Palakodety, R. K; Ravindra, R; Shanker, N; Bane,
S; Kingston, D. G. I. Tetrahedron, 2003, 59, 9979. c) Milstein, D.;
Stille, J. K. J. Am. Chem. Soc., 1978, 100, 3636. d) Stille, J. K.
Angew. Chem. Int. Ed., 1986, 25, 508. e) Espinet, P.; Echavarren,
A. M. Angew. Chem. Int. Ed., 2004, 43, 4704.
BOC
5
(90%)
Scheme 4. Cross-coupling reactions leading to 4,5-bisarylated thia-
zoles.
[9]
which were somehow expected since the compound was
challenging due to its “bivalent” nature as halide and or-
ganometal species. Further applications of the HD process
and extension of the cross-coupling methodology are cur-
rently under investigation in our laboratory.
[10]
ACKNOWLEDGEMENTS
[11]
[12]
(a) Lisowski, V.; Robba, M.; Rault, S. J. Org. Chem., 2000, 65,
4193. b) Hodgetts, K. J; Kershaw, M. T. Org. Lett., 2002, 4, 1363.
c) Hodgetts, K. J; Kershaw, M. T. Org. Lett., 2003, 5, 2911. d)
Miyaura, N.; Suzuki, A. J. Chem. Soc. Chem. Commun., 1979, 866-
867. e) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett.,
1979, 3437. f) Miyaura, N.; Suzuki, A. Chem. Rev., 1995, 95, 2457.
Hämmerle, J.; Spina, M; Schnürch, M.; Mihovilovic, M. D.; Sta-
netty, P. Synthesis, 2008, 3099.
General Procedure for the Halogen Dance: The freshly prepared
LDA (3.3 equiv.) was added drop-wise to the halide in dry THF
(10mL) at -85oC. The reaction mixture was allowed to warm up to -
60oC and stirred at this temperature until TLC showed complete
HD reaction. The corresponding electrophile (3.3 equiv.) was
added at -90oC and the reaction mixture was allowed to reach am-
bient temperature within 1 hour. The reaction mixture was diluted
with EtOAc, washed with 2N HCl, water, and brine and the organic
phase dried over Na2SO4. The solvent was evaporated and the
crude product purified by MPLC or recrystallization.
A.F.K. would like to thank the Higher Education Com-
mission of Pakistan and OEAD (Austria Student Exchange
Programme) for granting a fellowship to conduct his PhD
thesis.
REFERENCES
[1]
Heterocycles in Life and Society: An Introduction to Heterocyclic
Chemistry and Biochemistry and the Role of Heterocycles in Sci-
ence, Technology, Medicine, and Agriculture; Pozharsky, A. F.;
Soldatenkov, A. T.; Katritzky, A. R. Eds.; John Wiley and Sons,
Chichester, England, 1997.
[2]
(a) Takayama, H.; Kato, K.; Kimura, M.; Akita, H. Heterocycles,
2007, 71, 75. (b) Altmann, K.-H.;Pfeiffer, B.;Arseniyadis,S.; Pratt,
B. A.; Nicolaou, K. C. ChemMedChem, 2007, 2, 396. (c) Mueller, H.
M.; Delgado, O.; Bach, T. Angew. Chem. Int. Ed., 2007, 46, 4771.
(d) Delgado, O.; Heckmann, G.; Mueller, H. M.; Bach, T. J. Org.
Chem., 2006, 71, 4599. (e) Jin, Z. Nat. Prod. Rep., 2006, 23, 464.
(f) de Souza, M J. Sulfur Chem., 2005, 26, 429. (g) Hughes, R. A.;
Thompson, S. P.; Alcarez, L.; Moody, C. J. J. Am. Chem. Soc.,
2005, 127, 15644. (h) Jin, Z. Nat. Prod. Rep., 2005, 22, 196.
(a) Dunkel, R.; Elbe, H.-L.; Greul, J. N.; Hartmann, B.; Gayer, H.;
Seitz, T.; Wachendorff,-Neumann, U.; Dahmen, P.; Kuck, K.-H.
1,1-Dimethylethyl
N-(4-bromo-5-iodothiazol-2-yl)-N-
phenylcarbamate 2c: colorless crystals (70%), mp 144-147oC. 1H-
NMR (200MHz, CDCl3) ꢀ 1.41 (s, 9H, C(CH3)3), 7.16-7.21 (m, 2H,
H2´/H6´), 7.35-7.48 (m, 3H, H3´/H5´ & H4´). 13C-NMR (50MHz,
CDCl3): ꢀ 27.9 (q, C(CH3)3), 67.1 (s, C5), 84.3 (s, C(CH3)3), 128.3
(d, C2´/C6´), 128.4 (d, C4´), 129.2 (d, C3´/C5´), 130.2 (s, C4),
137.9 (s, C1´), 152.8 (s, CO), 165.7 (s, C2) Anal. Calcd. for
[3]

174 Letters in Organic Chemistry, 2009, Vol. 6, No. 2
Khan et al.
C14H14BrIN2O2S: C, 34.95; H, 2.93; N, 5.82. Found: C, 34.94; H,
2.76; N; 5.75.
crude mixture was purified by MPLC. The product fractions were
collected and solvent evaporated to obtain pure compound.
1,1-Dimethylethyl N-(4-bromo-5-phenylthiazol-2-yl)-N-phenyl-
carbamate 4: colorless powder, mp 173-176oC. 1H-NMR
(200MHz, CDCl3): ꢀ 1.18 (s, 9H, C(CH3)3) , 7.24-7.30 (m, 2H,
H4´, H4´´), 7.39-7.44 (m, 4H, H2´/H6´, H3´´/H5´´) 7.50-7.54 (m,
4H, H3´/H5´, H2´´/H6´´). 13C NMR (50MHz, CDCl3): 28.0 (q,
C(CH3)3), 83.9 (s, C(CH3)3), 117.9 (s, C5), 128.1 (d), 128.2 (d),
128.5 (d), 128.6 (d), 128.9 (d), 129.1 (d), 130.7 (s, C4), 138.3 (s,
Cl´), 152.8 (s, CO). Anal. Calcd. C, 55.69; H, 4.44; N, 6.49. Found
C, 55.96; H, 4.44; N, 6.36.
General Procedure for Cross-Coupling Reactions:
Stille Cross-Coupling: The stannane (1 equiv) and corresponding
halide (1 equiv) were refluxed in dry toluene with the catalyst
[Pd(PPh3)4, 0.05equiv] and CsF (2.2 equiv). The reaction was
monitored by TLC.
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 the mixture of DME and H2O
(2:1) until the TLC showed the completion of the reaction.
General Workup Procedure for Cross-Coupling Reactions: The
reaction mixture was filtered and the filtrate was concentrated. The