3140
M. Brad Nolt et al. / Tetrahedron Letters 49 (2008) 3137–3141
Table 1
spectroscopy. Discussions with James J. Mulhearn
prompted the investigation of a one-pot, sequential
Development of cross-coupling conditions
Entry
Boronic acid
(equiv)
Reaction
conditions
21:23: double
arylationa
functionalization of 21.
1
2
3
4
5
6
7
8
a
1.2
1.2
1.2
1.2
2
1.2
1.2
1.2
60 °C, 10 min
70 °C, 10 min
80 °C, 10 min
90 °C, 15 min
90 °C, 10 min
100 °C, 10 min
120 °C, 10 min
35 °C, 72 h
46:54:0
34:66:0
26:74:0
0:99:1b
0:87:13
0:82:18
0:77:23
References and notes
1. (a) Gola, M.; Bonadonna, S.; Mazziotti, G.; Amato, G.; Giustina, A.
J. Endocrinol. Invest. 2006, 29, 86; (b) Ma, P.; Wang, Y.; van der
Hoek, J.; Nedelman, J.; Schran, H.; Tran, L.-L.; Lamberts, S. W. J.
Clin. Pharmacol. Ther. 2005, 78, 69.
2. (a) Mastrodimou, N.; Kiagiadaki, F.; Hodjarova, M.; Karagianni, E.;
Thermos, K. Regul. Peptides 2006, 133, 41; (b) Grant, M. B.;
Caballero, S. Drugs Today 2002, 38, 783; (c) Higgins, R. D.; Yan, Y.;
Schrier, B. K. Exp. Eye Res. 2002, 74, 553; (d) Boehm, B. O.; Lang, G.
K.; Jehle, P. M.; Feldmann, B.; Lang, G. E. Horm. Metab. Res. 2001,
33, 300; (e) Smith, L. E. H.; Kopchick, J. J.; Chen, W.; Knapp, J.;
Kinose, F.; Daley, D.; Foley, E.; Smith, R. G.; Schaeffer, J. M.
Science 1997, 276, 1706.
b
—
Arylation of both the quinoline 3- and 6-position; ratios determined by
LCMS analysis of reaction mixtures, ELSD integration.
b
78% isolated yield.
at the bromine-substituted carbon of 22 proceeded only in
a low yield, and major side products from competing reac-
tion at the quinoline 4-chloride were observed. In contrast,
selective coupling occurred in the case of 23 (160 °C,
15 min, microwave) to form 25 in a moderate yield.
In the third sequential Suzuki reaction, the 4-chloride of
25 was converted to a phenyl substituent in good yield by
heating with 5,5-dimethyl-2-phenyl-1,3,2-dioxaborinane at
160 °C for 30 min. Conversion of 21 to 26 represents the
successful distinction among four halogens within a single
quinoline ring system. Impressively, the same catalyst,
base, and solvent combination (Cl2Pd(dppf), aq Cs2CO3/
THF) was effective in each of these transformations, and
selectivity could be tuned by varying time and
temperature.13
While not investigated in detail, the generation of 26
from 21 in one-pot, via sequential heating of a single reac-
tion mixture with addition of the respective boronic acid/
ester coupling partners was possible.14 Three arylation
cycles were completed using the optimal stepwise condi-
tions to furnish, after purification of a relatively complex
reaction mixture, 26 in 20% yield.
In summary, we have developed useful microwave-
assisted protocols for selective, sequential cross-coupling
of tri- and tetrahalogenated quinoline precursors.15 Use
of catalytic Cl2Pd(dppf), aq Cs2CO3, and THF with
microwave heating proved amenable to the selective cou-
plings investigated, and with a variety of commercially
available boronic acids and esters as coupling partners.
Excellent regio- and chemoselectivity were observed in
the course of our studies through careful manipulation of
reaction temperature and time. These procedures were
effectively utilized as part of an iterative analogue library
approach to the identification of potent and selective sst2
agonists.16
3. (a) Name Reactions in Heterocyclic Chemistry; Li, J. J., Ed.; Wiley:
Hoboken, 2005; pp 375–494. For recent examples, see: (b) Hu, Y.-Z.;
Zhang, G.; Thummel, R. P. Org. Lett. 2003, 5, 2251; (c) Takamura,
M.; Funabashi, K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc.
2001, 123, 6801.
4. Manley, P. J.; Bilodeau, M. T. Org. Lett. 2004, 6, 2433.
5. (a) Young, J. R.; Huang, S. X.; Chen, I.; Walsh, T. F.; DeVita, R. J.;
Wyvratt, M. J., Jr.; Goulet, M. T.; Ren, N.; Lo, J.; Yang, Y. T.;
Yudkovitz, J. B.; Cheng, K.; Smith, R. G. Bioorg. Med. Chem. Lett.
2000, 10, 1723; (b) Wash, T. F.; Toupence, R. B.; Young, R. J.;
Huang, S. X.; Ujjainwalla, F.; DeVita, R. J.; Goulet, M. T.; Wyvratt,
M. J., Jr.; Fisher, M. H.; Lo, J.-L.; Ren, N.; Yudkovitz, J. B.; Yang,
Y. T.; Cheng, K.; Smith, R. G. Bioorg. Med. Chem. Lett. 2000, 10,
443.
6. (a) Reitsema, R. H. Chem. Rev. 1948, 47, 47. For recent examples, see:
(b) Berbasov, D. O.; Soloshonok, V. A. Synthesis 2003, 13, 2005; (c)
Guay, V.; Brassard, P. J. Heterocycl. Chem. 1986, 24, 1649; (d)
Merchant, J. R.; Martyres, G.; Koshti, N. M. J. Heterocycl. Chem.
1983, 20, 775.
7. All reported yields are for isolated, analytically pure material.
8. Zhao, Z.; Leister, W. H.; Robinson, R. G.; Barnett, S. F.; Defeo-
Jones, D.; Jones, R. E.; Hartman, G. D.; Huff, J. R.; Huber, H. E.;
Duggan, M. E.; Lindsley, C. W. Bioorg. Med. Chem. Lett. 2005, 15,
905–909.
9. Not surprisingly, double arylation of 15a was also possible by heating
at 160 °C for 10 min with an excess of arylboronic acid.
10. Deprotection (TFA) of the Boc-protected piperidine nitrogen was
required in parallel, and was technically non-demanding.
11. 6-Bromo-4,7-dichloro-3-iodoquinoline (20): 1H NMR (CDCl3): 9.11
(s, 1H), 8.56 (s, 1H), 8.22 (s, 1H); 3-bromo-4,7-dichloro-6-iodoquino-
line (21): 1H NMR (CDCl3): 8.93 (s, 1H), 8.78 (s, 1H), 8.19 (s, 1H); 6-
bromo-4,7-dichloro-3-(3,5-dimethylphenyl)quinoline
(22):
TLC
Rf = 0.47 (95:5 EtOAc/hexanes); 1H NMR (CDCl3): 8.83 (s, 1H),
8.64 (s, 1H), 8.26 (s, 1H), 7.11 (s, 3H), 2.40 (s, 6H); 13C NMR
(CDCl3): 153.25, 147.11, 138.52, 138.48, 136.48, 135.66, 134.54,
130.58, 129.54, 127.63, 126.23, 123.07, 104.57, 21.57; HRMS: calcd
for C17H12BrCl2N (M+H+) 379.9603, found 379.9604.
12. 3-(3-Bromo-4,7-dichloroquinolin-6-yl)-N,N-dimethylbenzenamine
(23): TLC Rf = 0.45 (95:5 EtOAc/hexanes); 1H NMR (CDCl3): 8.99
(s, 1H), 8.27 (s, 1H), 8.20 (s, 1H), 7.57–7.63 (m, 1H), 7.5 (s, 2H), 7.41–
7.44 (m, 1H), 3.22 (s, 6H); 13C NMR (CDCl3): 152.9, 146.3, 145.5,
142.0, 140.3, 140.0, 135.5, 130.2, 130.1, 127.2, 126.7, 126.1, 119.4,
118.8, 118.2, 44.6; HRMS: calcd for
394.9712, found 394.9716.
C
17H14BrCl2N2 (M+H+)
Acknowledgments
13. While further improvements in selectivity could be expected by
screening various catalyst, ligand, and base combinations this work
was limited to exploration of the Cl2Pd(dppf)/Cs2CO3 system.
14. For each sequential Suzuki–Miyaura coupling step, 10 mol % of fresh
Cl2Pd(dppf) was added to the reaction mixture.
We thank Brian Eastman for early experiments, John
Swestock for the preparation of 5a and 5b, and Joan
Murphy and Charles W. Ross, III for high-resolution mass