S. T. Handy et al. / Tetrahedron Letters 44 (2003) 427–430
429
H.; Fenical, W. J. Org. Chem. 1997, 62, 3254–3262 and
references cited therein.
4. For a discussion of dehalogenations in Stille couplings,
see: Farina, V.; Krishnamurthy, V.; Scott, W. J. Organic
Reactions; John Wiley & Sons: New York, 1997; Vol. 50.
5. Banwell, M. G.; Flynn, B. L.; Hamel, E.; Hockless, D. C.
R. Chem. Commun. 1997, 207–208.
6. Wang, J.; Scott, A. I. Tetrahedron Lett. 1996, 37, 3247–
3250.
7. Remarkably few reports provide any details regarding
dehalogenations in Suzuki coupling reactions, although a
few comment simply that dehalogenation is observed as a
secondary product. Two major exceptions are: Haseltine,
J.; Wang, D. J. Heterocyclic Chem. 1994, 31, 1637–1639
and Ref. 15.
8. For references to cross-coupling reactions with pyrroles,
see Refs. 5, 10, 12–15 and: Liu, J.-H.; Yang, Q.-C.; Mak,
T. C. W.; Wong, H. N. C. J. Org. Chem. 2000, 65,
3587–3595; Zhou, X.; Tse, M. K.; Wan, T. S. M.; Chan,
K. S. J. Org. Chem. 1996, 61, 3590–3593; Alvarez, A.;
Guzman, A.; Ruiz, A.; Velarde, E.; Muchowski, J. M. J.
Org. Chem. 1992, 57, 1653–1656; Banwell, M.; Edwards,
A.; Smith, J.; Hamel, E.; Verdier-Pinard, P. J. Chem.
Soc., Perkin Trans. 1 2000, 1497–1499; Dupont, C.;
Guenard, D.; Thal, C.; Thoret, S.; Gueritte, F. Tetra-
hedron Lett. 2000, 41, 5853–5856.
Scheme 3. Couplings with 3-halo, 5-halo, and 4,5-dihalo
pyrrole esters.
In light of these results, there are still a number of
questions concerning the electronic and regiochemical
features that facilitate the dehalogenation reaction of
halopyrrole esters. What can be stated with assurance is
that the 4 position of unsubstituted pyrrole-2-carboxyl-
ates is particularly prone to dehalogenation under
cross-coupling conditions. This dehalogenation can be
avoided by use of a protecting group on the pyrrole
nitrogen. With a BOC group, the protecting group is
also cleaved under the coupling conditions, thereby
avoiding a separate deprotection step. The mechanism
of this facile dehalogenation and its implications for
Suzuki couplings of halopyrroles in general is currently
under investigation and will be reported in due course.
9. Interestingly, as we were pursuing these investigations,
Dr. Cai of Hoffmann-La Roche informed us of a similar
observation that they have made in the coupling of
3-bromoindoles in which protection of the indole nitro-
gen is required to avoid extensive dehalogenation.
10. This deprotection appears to be a thermal reaction. We
have noted that simply heating a solution of pyrrole ester
1 in DMF to 120°C for 6 h is sufficient to completely
remove the BOC group. Lower temperatures (100°C) do
not cleave the BOC group. For similar observations, see:
(BOC removal), Fuerstner, A.; Grabowski, J.; Lehmann,
C. W. J. Org. Chem. 1999, 64, 8275–8280. (BOC
retained), Johnson, C. K.; Stemp, G.; Anand, N.;
Stephen, S. C.; Gallagher, T. Synlett 1998, 1025–1027.
11. General procedure for the coupling reaction: To a round-
bottom flask was added 100 mg (0.32 mmol) of BOC-pro-
tected pyrrole ester 1. DMF (2.5 mL) was added and the
mixture stirred under argon. To this solution was then
added sequentially 33 mg (0.016 mmol) of palladium
tetrakis-triphenylphosphine and 167 mg (0.79 mmol) of
2,3,4-trimethoxyphenylboronic acid. The mixture was
heated to 70°C and 540 mg (2.88 mmol) of sodium
carbonate dissolved in minimal water added. The reac-
tion was then heated to 110°C for 14 h. After cooling to
rt, the reaction was diluted with water (15 mL) and
extracted with diethyl ether (3×15 mL). The organic
layers were dried with magnesium sulfate, filtered, and
concentrated in vacuo. Chromatography (20% ethyl ace-
tate/hexanes) afforded 82.0 mg (84%) of ethyl 4-(2%,3%,4%-
trimethoxyphenyl)pyrrole-2-carboxylate as a white solid.
1H NMR (360 MHz, CDCl3) 9.16 (br s, 1H), 7.41 (m,
1H), 7.20 (m, 1H), 7.18 (d, 7.2 Hz, 1H), 6.70 (d, J=7.2
Hz, 1H), 4.33 (q, 2H), 3.91 (s, 3H), 3.87 (s, 3H), 3.81 (s,
3H), 1.37 (t, 3H); 13C NMR (90 MHz, CDCl3) 161.14,
152.11, 150.87, 142.77, 122.66, 122.15, 122.09, 121.60,
121.40, 113.69, 107.69, 60.86, 60.34, 60.24, 55.98, 14.43.
Spectral data for other coupling products: ethyl 4-(4%-iso-
Acknowledgements
The authors thank the State University of New York at
Binghamton and the Research Foundation for financial
support of this work. The authors also thank Dr.
Jianping Cai at Hoffmann-La Roche for comments and
suggestions regarding the dehalogenation results.
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