Synthesis of 2-(o-hydroxyaryl)-4-arylthiazoles by regioselective Pd(0)- catalyzed cross-coupling

Article abstract of DOI:10.1016/S0040-4039(00)00018-6

The difunctional substrate 2,4-dibromothiazole 2 was transformed into the title compounds 1 by consecutive Pd(0)-catalyzed cross-coupling reactions. Aryl zinc reagents which were prepared by ortho-lithiation of compounds 3 and subsequent transmetalation w

Full text of DOI:10.1016/S0040-4039(00)00018-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1707–1710
Synthesis of 2-(o-hydroxyaryl)-4-arylthiazoles by regioselective
Pd(0)-catalyzed cross-coupling
Thorsten Bach ∗ and Stefan Heuser
Fachbereich Chemie der Philipps-Universität Marburg, D-35032 Marburg, Germany
Received 29 November 1999; accepted 17 December 1999
Abstract
The difunctional substrate 2,4-dibromothiazole 2 was transformed into the title compounds 1 by consecutive
Pd(0)-catalyzed cross-coupling reactions. Aryl zinc reagents which were prepared by ortho-lithiation of com-
pounds 3 and subsequent transmetalation were used as carbon nucleophiles in the first coupling reaction. By
this means, an aryl substituent was attached to the 2-position (50–62% yield). A succeeding cross-coupling with
arylboronic acids 4 occurred at the 4-position of the intermediate 4-bromothiazoles 5 (76–97% yield). © 2000
Elsevier Science Ltd. All rights reserved.
Keywords: palladium; palladium compounds; catalysis; coupling reactions; thiazoles.
2-(o-Hydroxyaryl)-4-arylthiazoles 1 can be considered as heteroanalogous β-hydroxyenones (Scheme
1). Based on this analogy they should be able to dissipate the energy of absorbed UV-light by an
intramolecular hydrogen transfer,1 a property which would make them promising candidates to be used
in cosmetic sunscreens.2 Due to our continuing interest in the development of new UV-A-absorbers3 we
sought a facile entry into this class of compounds.
Scheme 1.
∗
Corresponding author.
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Since it was desirable to investigate the influence of various substituents R, R1, R2 and R3 on the
chromophore, a versatile synthetic strategy was mandatory to achieve the neccessary scope. Initial
attempts employing classic heterocyclic chemistry4 (Hantzsch synthesis) failed in this respect and
we, therefore, looked into regioselective bond constructions starting from the readily available 2,4-
dibromothiazole 2.5 The possibility to prepare ortho-metalated O-methoxymethyl (MOM) protected
phenols by directed metalation of arenes 36–8 led us to consider a regioselective coupling reaction at
the more electron-deficient 2-position of thiazole 2 (Scheme 2). Subsequent Suzuki cross-coupling9 at
C(4) with arylboronic acids 4 was expected to yield the target compounds after deprotection (Scheme
3). Although precedence for regioselective cross-coupling reactions of this type in the thiazole series
was rare10–12 we attempted to use a Negishi cross-coupling13 to establish the aryl–C(2) bond. To this
end, the MOM-protected phenols 3 were treated with t-butyllithium at 0°C in ether and the lithiated
arenes were transmetalated by treatment with ZnCl2 in THF. The species so obtained underwent a
regioselective Pd(0)-catalyzed C–C bond formation with substrate 2 to yield the desired intermediates
5. Some examples for the described transformation are summarized in Table 1.14 The yields of the 4-
bromothiazoles 5 were reliably in the range of 60% irrespective of the substitution pattern at the benzene
ring. In the case of substrate 3e the primary product 5e was deprotected in the course of the reaction
(entry 5) and the phenol 6e was isolated as the final product. Proof for the regioselectivity of the cross-
coupling was obtained by comparing the 13C NMR data of substrate 2 with those of the products 5.
The aryldebromination leads to a significant downfield shift of the carbon atom at which the substitution
occurs.15 In the transformation 2→5 the carbon atom C(2) clearly showed the expected shift to lower
field (∆δ›25 ppm).
Scheme 2.
Scheme 3.
As in previous examples,15,16 we ascribe the pronounced regioselectivity to the oxidative addition step,
i.e. to the insertion of Pd(0) into the carbon–bromine bond. At room temperature the insertion into the
more electron-deficient C(2)–Br bond is fast and there is no competitive reaction at C(4). The succeeding
Suzuki cross-coupling of the thiazoles 5 and 6e proceeded in high yield (76–97%).17 The higher reaction
temperature facilitates the oxidative addition of Pd(0) at the less electrophilic 4-position. Compound 6e
gave direct access to the free phenol 1e. For all other substrates, the MOM group was removed in a final
deprotection step and the desired target compounds 1 were isolated (Table 2).

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Table 1
Pd(0)-Catalyzed cross-coupling of ortho-metalated MOM-protected phenols 3 with thiazole 2
Table 2
Yields of target compounds 1 obtained by cross-coupling of arylboronic acids 4 with thiazoles 5 and
subsequent deprotection
In summary, a regioselective access to 2,4-disubstituted thiazoles has been established. The Negishi
cross-coupling of aryl zinc halides with 2,4-dibromothiazole 2 proceeded exclusively at the more
electron-deficient position thus permitting the selective installation of an aryl fragment at C(2). In
preliminary experiments, we have found that alkyl and alkenyl zinc reagents behave similarly and the
use of the described methodology for the construction of biologically active thiazoles is currently being
pursued in our laboratory.
Acknowledgements
This work was supported by the BASF AG (Ludwigshafen/Rhein) and by the Fonds der Chemischen
Industrie. We thank Drs. G. Seybold, S. Haremza, T. Habeck and F. Prechtl (BASF AG) for fruitful
discussions.
References
1. For a review, see: Klöpffer, W. Adv. Photochem. 1977, 10, 311–358.
2. Sunscreens: Development, Evaluation, and Regulatory Aspects; Lowe, N. J.; Shaath, N. A., Eds.; Dekker: New York, 1990.

1710
3. Krüger, L.; Bach, T.; Drögemüller, M.; Trentmann, B.; Fröhlich, R. J. Inf. Recording 1998, 24, 289–293.
4. For a review, see: Liebscher, J, In Methoden der Organischen Chemie (Houben-Weyl) 4te Aufl., Band E 8b; Schaumann, E.,
Ed.; Thieme: Stuttgart, 1994; 1–398.
5. Reynaud, P.; Robba, M.; Moreau, R. C. Bull. Soc. Chim. Fr. 1962, 1735–1740.
6. Snieckus, V. Chem. Rev. 1990, 90, 879–933.
7. Gschwend, H. W.; Rodriguez, H. R. Org. React. 1979, 26, 1–360.
8. Christensen, H. Synth. Commun. 1975, 5, 65–78.
9. Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-VCH: Weinheim, 1998;
49–97.
10. Wellmar, U.; Gronowitz, S.; Hörnfeldt, A.-B. J. Heterocycl. Chem. 1995, 32, 1159–1163.
11. Nicolaou, K. C.; He, Y.; Roschangar, F.; King, N. P.; Vourloumis, D.; Li, T. Angew. Chem. 1998, 110, 89–92; Angew. Chem.
Int. Ed. Engl. 1998, 37, 84–87.
12. For a review on the use of cross-coupling reactions for biaryl synthesis, see: Stanforth, S. P. Tetrahedron 1998, 54, 263–303.
13. Negishi, E.-i.; Liu, F. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 1998; pp. 1–48.
14. Representative procedure: A 1.34 M solution of t-BuLi in pentane (8.3 mL, 11 mmol) was added dropwise to a stirred
solution of 1.36 g O-methoxymethylphenol 3a (1.30 mL, 10 mmol) in 50 mL of ether at 0°C. The mixture was stirred for
another 10 min at 0°C. A 0.5 M solution of ZnCl2 in THF (30 mL, 15 mmol) was subsequently added and the resulting
solution was warmed to ambient temperature. After another 30 min at rt the solution of the aryl zinc reagent so prepared
was added dropwise to a suspension of 2.43 g 2,4-dibromothiazole5 2 (10 mmol) and 350 mg PdCl2(PPh3)2 (0.5 mmol, 5
mol%) in 50 mL of THF. The mixture was stirred at room temperature for 16 h and subsequently quenched with a saturated
aqueous solution of NH4Cl (100 mL). After extraction with ether (3×200 mL) the organic layers were combined, washed
with brine and dried over Na2SO4. After removal of the solvent the residue was purified by flash chromatography (4×20 cm
silica gel; pentane/t-butylmethyl ether=98:2) to yield 1.72 g of compound 5a (58%). 1H NMR (CDCl3, 200 MHz): δ=3.51
(s, 3 H), 5.37 (s, 2 H), 7.10–7.37 (m, 4 H), 8.40 (dd, J=8.0 Hz, J=1.7 Hz, 1 H). 13C NMR (CDCl3, 50 MHz): 57.0 (q), 94.6
(t), 114.6 (d), 118.2 (d), 122.1 (s), 122.4 (d), 125.6 (s), 128.9 (d), 131.6 (d), 154.5 (s), 163.7 (s). C11H10BrNO2S (300.17)
calcd: C, 44.02; H, 3.36; N, 4.67; found: C, 43.78; H, 3.23; N, 4.80.
15. Bach, T., Krüger, L. Eur. J. Org. Chem. 1999, 2045–2057.
16. Bach, T., Krüger, L. Tetrahedron Lett. 1998, 39, 1729–1732.
17. Representative procedure: A solution of 1.74 g K2CO3 (12.3 mmol) in 5 mL of water and a solution of 732 mg phenylboronic
acid (4, R=H) (6.15 mmol) in 5 mL of EtOH were added successively to a solution of 1.24 g 4-bromothiazole 5a (4.1 mmol)
and 140 mg Pd(PPh3)4 (0.16 mmol, 4 mol%) in 20 mL of benzene at ambient temperature. The mixture was heated to 90°C
and kept at this temperature for 72 h. Upon cooling to rt the mixture was extracted with ether (3×150 mL). The organic
layers were combined, washed with brine and dried over MgSO4. The solvent was removed in vacuo and the residue was
purified by flash chromatography (3×30 cm silica gel; pentane/t-butylmethyl ether=98:2) to yield 1.02 g of the O-MOM-
protected derivative of compound 1a (82%). 1H NMR (CDCl3, 200 MHz): δ=3.49 (s, 3 H), 5.34 (s, 2 H), 6.88–7.50 (m, 8
H), 7.65 (dd, J=7.7 Hz, J=1.5 Hz, 1 H), 7.88 (dd, J=8.0 Hz, J=1.5 Hz, 1 H). 13C NMR (CDCl3, 50 MHz): 57.0 (q), 94.7 (t),
114.6 (d), 114.8 (d), 122.6 (d), 123.5 (s), 126.9 (d), 128.4 (d), 129.2 (d), 129.3 (d), 131.0 (s), 135.4 (s), 154.5 (s), 154.8 (s),
162.4 (s). C17H15NO2S (297.37) calcd: C, 68.66; H, 5.08; N, 4.71; found: C, 68.99; H, 4.91; N, 4.36.