C O M M U N I C A T I O N S
Table 1. Conversion of Arylboronic Esters to Aryl Bromides
Scheme 1
A formal iridium-catalyzed synthesis of this material is shown
in Scheme 1. The iridium-catalyzed borylation of (L)-nicotine
occurred in high yield with exclusive selectivity for reaction at the
5-position, as determined by 1H NMR spectroscopy. Treatment of
this crude material with aqueous copper(II) bromide at 85 °C for 6
h formed 5-bromonicotine in 61% yield. The conversion of this
halide to Altinicline has previously been reported in 89% yield by
Sonogashira coupling with 2-methyl-3-butyn-2-ol, followed by
deprotection with NaH (Scheme 1).18
In summary, we have shown that a variety of 3,5-disubstituted
aryl bromides and chlorides can be synthesized in one-pot using a
sequence of iridium-catalyzed arene borylation, followed by ipso
halogenation with copper(II) salts. Ongoing work is being performed
to extend this methodology for the synthesis of aryl iodides and
aryl fluorides.
a Average isolated yield for the two-step process from two experiments.
Reactions were run on a 2.0 mmol scale. b Reaction run using 0.5 mol %
[Ir(COD)(OMe)]2 and 1.0 mol % dtbpy. c Contained 2% pinacol by 1H NMR
spectroscopy. d Reaction run using 3.0 mol % 1 and 6.0 mol % 2. e Reaction
run using 1.0 mol % 1 and 2.0 mol % 2. Yield in parentheses was obtained
when conducting the reaction without a glove box using Schlenk techniques.
See Supporting Information for details.
Acknowledgment. We thank the NSF (Grant CHE-03019071)
for support of this work, Johnson-Matthey for [Ir(COD)(OMe)]2,
and Allychem and Frontier Scientific for gifts of B2pin2.
f
Supporting Information Available: Complete ref 18. Procedures
for synthesis and characterization of reaction products. This material
Table 2. Conversion of Arylboronic Esters to Aryl Chlorides
References
(1) Smith, M. B.; March, J., March’s AdVanced Organic Chemistry, 5th ed.;
John Wiley and Sons: New York, 2001.
(2) Snieckus, V., Chem. ReV. 1990, 90, 879.
(3) Arisawa, M.; Suwa, A.; Ashikawa, M.; Yamaguchi, M., ARKIVOC 2003,
8, 24.
(4) (a) Takagi, J.; Sato, K.; Hartwig, J. F.; Ishiyama, T.; Miyaura, N.,
Tetrahedron Lett. 2002, 43, 5649. (b) Ishiyama, T.; Takagi, J.; Ishida,
K.; Miyaura, N.; Anastasi, N.; Hartwig, J. F., J. Am. Chem. Soc. 2002,
124, 390. (c) Takagi, J.; Sato, K.; Hartwig, J. F.; Ishiyama, T.; Miyaura,
N., Tetrahedron Lett. 2002, 43, 5649. (d) Ishiyama, T.; Takagi, J.;
Yonekawa, Y.; Hartwig, J. F.; Miyaura, N., AdV. Synth. Catal. 2003, 345,
1103. (e) Ishiyama, T.; Nobuta, Y.; Hartwig, J. F.; Miyaura, N., Chem.
Commun. 2003, 2924. (f) Boller, T. M.; Murphy, J. M.; Hapke, M.;
Ishiyama, T.; Miyaura, N.; John F. Hartwig, J. Am. Chem. Soc. 2005,
127, 14263.
(5) (a) Iverson, C. N.; Smith, M. R., III, J. Am. Chem. Soc. 1999, 121, 7696.
(b) Cho, J. Y.; Iverson, C. N.; Smith, M. R., J. Am. Chem. Soc. 2000,
122, 12868.
(6) (a) Cho, J. Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E.; Smith, M. R.,
Science 2002, 295, 305. (b) Chotana, G. A.; Rak, M. A.; Smith, M. R., J.
Am. Chem. Soc. 2005, 127, 10539.
(7) Maleczka, R. E.; Shi, F.; Holmes, D.; Smith, M. R., J. Am. Chem. Soc.
2003, 125, 7792.
(8) Holmes, D.; Chotana, G. A.; Maleczka, R. E., Jr., Org. Lett. 2006, 8, 1407.
(9) Tzschucke, C. C.; Murphy, J. M.; Hartwig, J. F., Org. Lett. 2007, 9, 761.
(10) Murphy, J. M.; Tzschucke, C. C.; Hartwig, J. F., Org. Lett. 2007, 9, 757.
(11) Thompson, A. L. S.; Kabalka, G. W.; Akula, M. R.; Huffman, J. W.,
Synthesis 2005, 4, 547.
(12) (a) Kabalka, G. W.; Mereddy, A. R., Organometallics 2004, 23, 4519.
(b) Theibes, C.; Praskash, G. K. S.; Petasis, N. A.; Olah, G. A., Synlett
1998, 2, 141.
(13) Szumigala, R. H. J.; Devine, P. N.; Gauthier, D. R. J.; Volante, R. P., J.
Org. Chem. 2004, 69, 566.
a Average isolated yield for the two-step process from two experiments.
All reactions were run on a 2.0 mmol scale. b Reaction run using 0.5 mol
1
% 1 and 1.0 mol % 2. c Contained 2% pinacol by H NMR spectroscopy.
d Reaction run using 3.0 mol % 1 and 6.0 mol % 2. e Reaction run using
1.0 mol % 1 and 2.0 mol % 2.
(14) (a) Matteson, D. S.; Kim, G. Y., Org. Lett. 2002, 4, 2153. (b) Yuen, A.
K. L.; Hutton, C. A., Tetrahedron Lett. 2005, 46, 7899. (c) Lawrence, J.
D.; Takahashi, M.; Bae, C.; Hartwig, J. F., J. Am. Chem. Soc. 2004, 126,
15334.
(15) (a) McDonald, I. A.; Cosford, N. D. P.; Vernier, J. M., Annu. Rep. Med.
Chem. 1995, 30, 41. (b) McDonald, I. A.; Vernier, J. M.; Cosford, N. D.
P.; Corey-Naeve, J., Curr. Pharm. Des. 1996, 2, 357.
(16) Dukat, M.; Ramunno, A.; Banzi, R.; Damaj, M. I.; Martin, B.; Glennon,
R. A., Bioorg. Med. Chem. Lett. 2005, 15, 4308.
(17) Wagner, F. F.; Comins, D. L., J. Org. Chem. 2006, 71, 8673.
(18) Cosford, N. D. P.; et al. J. Med. Chem. 1996, 39, 3235.
is an intermediate in the synthesis of a member of a class of
compounds that act as neuronal nicotinic acetylcholine receptors,15
and a precursor to other derivatives by cross-coupling methods.
Among the derivatives of 5-substituted nicotine,16 Altinicline (5-
ethynyl-nicotine) has been investigated for the treatment for
Parkinson’s disease. The most efficient synthesis of Altinicline is
a five-step route starting from (L)-nicotine with an overall yield of
32%.17
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