LETTER
Halogen-Dance Reaction in Thiazole Chemistry
3017
the dibromo product 2c in good yield (69%). Introduction can undergo metal–halogen exchange reactions for the
of alcohol functionalities with benzaldehyde and cyclo- subsequent introduction of electrophiles. Chlorine in a 2-
hexanone generated the corresponding products 2e and 2f position is readily attacked by nucleophiles as already re-
both in 77% yield. A carbonyl functionality could also be ported (Scheme 3). Finally, the electrophiles introduced
introduced by conversion of IV with DMF to give the cor- to the 5-position can also be further manipulated. Such ap-
responding aldehyde 2g in 56% yield. Transformation to plications are currently under investigation in our labora-
the silyl compound 2h (71%) is a useful option to block tories (Figure 1).
position 5 temporarily for further synthetic purposes.
Table 1 Introduction of Electrophiles into the 5-Position9
metal–halogen exchange
cross-coupling reaction
if E = Br, I:
metal–halogen exchange
cross-coupling reaction
Br
Yield (%)a
N
Electrophile
EtOH
E
Product
2a
nucleophilic substitution
cross-coupling reaction
E
Cl
if E = functional group:
transformation of this group
S
H
75
Cl3CCCl3
BrCl2CCCl2Br
I2
Cl
2b
61
Figure 1 Further synthetic possibilities
Br
2c
69
I
2d
7610
77
Acknowledgment
benzaldehyde
cyclohexanone
DMF
PhCH(OH)
C6H10OH
CHO
TMS
SMe
2e
We thank the Hochschuljubiläumsstiftung der Stadt Wien for finan-
cial support of this project (H 1478/2006).
2f
77
2g
5611
71
References and Notes
TMSCl
2h
(1) (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.
DMDS
3b
88
a Average of two runs.
b See Scheme 3.
ChemMedChem 2007, 2, 396. (c) Müller, H. M.; Delgado,
O.; Bach, T. Angew. Chem. Int. Ed. 2007, 46, 4771.
(d) Delgado, O.; Heckmann, G.; Müller, 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.; Alcaraz, L.;
Moody, C. J. J. Am. Chem. Soc. 2005, 127, 15644. (h) Jin,
Z. Nat. Prod. Rep. 2005, 22, 196.
In an attempt to apply dimethyldisulfide (DMDS) for the
introduction of a sulfur electrophile, we did not obtain the
expected product. The HD reaction took place as expected
and the MeS group was introduced in 5-position, but the
methylthiolate formed in situ also replaced the chlorine at
the 2-position to form 4-bromo-2,5-bis(methylthio)thi-
azole (3) in excellent yield (88%, Scheme 3).
(2) (a) Dunkel, R.; Elbe, H.-L.; Greul, J. N.; Hartmann, B.;
Gayer, H.; Seitz, T.; Wachendorff-Neumann, U.; Dahmen,
P.; Kuck, K.-H. WO 2006061215, 2006; Chem. Abstr. 2006,
145, 62881. (b) Murakami, H.; Takii, S.; Mizuno, M. JP
200466855, 2005; Chem. Abstr. 2005, 143, 306303.
(c) Mueller, U.; Eberle, M.; Pillonel, C.; Lutz, W.; Stanetty,
P. WO 2003029249, 2003; Chem. Abstr. 2003, 138,
304297. (d) Doemling, A.; Kolb, J. DE 10134478, 2003;
Chem. Abstr. 2003, 138, 137301.
Br
Br
N
MeS–
1. LDA
N
N
Br
Cl
2. Me2S2
S
S
S
S
Cl
S
S
(3) Five-Membered Hetarenes with One Chalcogen and One
Additional Heteroatom, In Science of Synthesis, Vol. 11;
Schaumann, E., Ed.; Georg Thieme Verlag: Stuttgart, 2002,
627.
3
1
Scheme 3 Subsequent nucleophilic substitution in 2-position
(4) (a) 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) Babadjamian, A.; Metzger, J.;
Chanon, M. J. Heterocycl. Chem. 1975, 12, 643.
(5) (a) Schröter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61,
2245; and references cited therein. (b) Schnürch, M.; Flasik,
R.; Khan, A. F.; Spina, M.; Mihovilovic, M. D.; Stanetty, P.
Eur. J. Org. Chem. 2006, 3283; and references cited therein.
(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) Hodgetts, K. J.; Kershaw, M. T.
Org. Lett. 2003, 5, 2911.
In conclusion, we have demonstrated the utility of the HD
reaction for the synthesis of polyhalogenated thiazoles as
precursors for cross-coupling reactions as well as for the
introduction of electrophiles in the 5-position. Generally
good, although not optimized, yields were obtained (56–
88%). Once again it must be emphasized that, via this
method, mixed 2,4- and 2,4,5-trihalogenated thiazoles can
be easily obtained from readily available 5-bromo-2-chlo-
rothiazole (1). Compounds 2a–h offer several possibili-
ties for further transformations. Halides in the 2-, 4-, and
5-position can be used as aryl donors in cross-coupling re-
actions. Alternatively, Br and I in the 4- and 5-position
Synlett 2007, No. 19, 3016–3018 © Thieme Stuttgart · New York