A One-Pot Protocol to Substituted Azabiaryls
SCHEME 1. The DoM-Cross Coupling Nexus
the 2-pyridylboronic acid has been prepared Via a lithium-
halogen exchange procedure, but is reported to be highly prone
to protodeboronation.17 In contrast, 2-pyridyl diethylborane is
reported to be a stable compound;18 however, utility in transition
metal-catalyzed events has not been demonstrated. More
recently, the preparation and Suzuki couplings of diethanola-
mine-stabilized 2-pyridylboronates have been reported.19 3-Py-
ridylboronic acid20 is a relatively stable compound, and has
recently been prepared, as the boroxin trimer, on multigram scale
by a metal-halogen exchange procedure.21 The preparation and
Suzuki couplings of 3-pyridyltrifluoroborates have recently been
reported.22 4-Pyridylboronic acid20 has been prepared Via
lithium-halogen exchange processes.23 To conclude by way of
a new evolving perspective, Ir-catalyzed C-H coupling between
bis(pinacolato)diboron and pyridine derivatives leading to
pyridyl boronic esters has been recently reported.24
1), provides considerable tactical advantage in the construction
of polysubstituted aromatic and heteroaromatic compounds.9
Thus, two complementary 2 + 3 approaches with interchang-
ing X and Y substituents, for biaryl or heterobiaryl formation 4
(Scheme 1), while providing anticipation of a higher chance of
success, require careful consideration of substrate structure and
reactivity. Perusal of the literature suggests that this is especially
valid for cross coupling reactions in which one or both partners
(2 or 3) is heteroaromatic, whereby difficulty in preparation,
instability, and poor experience in synthesis has forced the use
of tin10,11 and, to a lesser extent, zinc,12 and magnesium13 over
borylated heterocycles.14 Although the number of well-
characterized heteroaromatic boronic acids is relatively small,
properties of boronic acid FG compatibility, air stability, low
toxicity, and expense of commercial products would forecast
that this situation will change.15 In point of fact, this deficiency
is being addressed for pyridylboronic acids and esters undoubt-
edly due to the significance of the pyridine moiety in bioactive
molecules and natural products.16 Thus for the parent derivatives,
In the domain of substituted pyridyl boronic acid derivatives,
systematic studies by Rault25 and Bryce26 have resulted in the
preparation of shelf-stable halo pyridyl boronic acids and esters
(17) Fischer, F. C.; Havinga, E. Recl. TraV. Chim. Pays-Bas 1974, 93,
21-24. The reaction of 2-pyridyl Grignard with tris(trimethylsilyl)borate
has recently been reported to yield the corresponding boronic acid in good
yield; Matondo, H.; Souirti, S.; Baboulene, M. Synth. Commun. 2003, 33,
795-800.
(18) Ishikura, M.; Mano, T.; Oda, I.; Terashima, M. Heterocycles 1984,
22, 2471-2474.
(19) N-Phenyldiethanolamine: (a) Hodgson, P.; Salingue, F. Tetrahedron
Lett. 2004, 45, 685-687. Polystyrene-supported diethanolamine: (b) Gros,
P.; Doudouh, A.; Fort, Y. Tetrahedron Lett. 2004, 45, 6239-6241. (c) Pfizer
Global R & D, Sa´ndwich, Kent, UK, U.S. Patent No. 7,026,479.
(20) 3- and 4-pyridineboronic acids (and corresponding esters) are
available in milligram to gram quantities from numerous suppliers; e.g.,
Aldrich Chemical Company, Inc., Milwaukee, WI, USA; Frontier Scientific,
Inc., Logan, Utah, USA; CombiPhos Catalysts, Inc., Princeton, NJ, USA;
and Lancaster Synthesis, Inc., Windham, NH, USA.
(21) (a) Li, W.; Nelson, D. P.; Jensen, M. S.; Hoerrner, R. S.; Dongwei,
C.; Larsen, R. D. Org. Lett. 2003, 5, 4835-4837. (b) Reider, P. J. J. Org.
Chem. 2002, 67, 5394-5397. Subsequently, 3-pyridylboroxin has been used
directly in Suzuki couplings; see: (c) Cioffi, C. L.; Spencer, W. T.; Richards,
J. J.; Herr, R. J. J. Org. Chem. 2004, 69, 2210-2212. For examples of
large-scale coupling reactions of diethyl(3-pyridyl)borane see: Wei, H.;
Sudini, R.; Yin, H. Org. Process Res. DeV. 2004, 8, 955-957. Lipton, M.
F.; Mauragis, M. A.; Maloney, M. T.; Veley, M. F.; VanderBor, D. W.;
Newby, J. J.; Appell, R. B.; Daugs, E. Org. Process Res. DeV. 2003, 7,
385-392.
(7) Rouhi, A. M. Chem. Eng. News 2004, September 6, 49-58. Carey,
J. S.; Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem. 2006,
2337-2347, especially p 2345. King, A. O.; Yasuda, N. Top. Organomet.
Chem. 2004, 6, 205.
(8) (a) Snieckus, V. Chem. ReV. 1990, 90, 879-933. (b) Hartung, C.
G.; Snieckus, V. In Modern Arene Chemistry; Astruc, D., Ed.; Wiley-
VCH: Weinheim, Germany, 2002; pp 330-367. (c) Macklin, T.; Snieckus,
V. In Handbook of C-H Transformations; Dyker, G., Ed.; Wiley: Weinheim,
Germany, 2005; pp 106-118. For metalation of sulfamates (OSO2NEt2),
see: Macklin, T.; Snieckus, V. Org. Lett. 2005, 7, 2519-2522. For
metalation of phosphorodiamidates (OPO(NEt2)2) see: Alessi, M.; Zum-
bansen, K.; Demchuk, O. M.; Blackburn, T. W.; Snieckus, V. Unpublished
results.
(9) (a) Anctil, E. J.-G.; Snieckus, V. In Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; de Meijere, A., Diederich, F., Eds.; Wiley-VCH:
Weinheim, Germany, 2004; Vol. 2, pp 761-813. (b) Anctil, E. J.-G.;
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Chauder, B.; Snieckus, V. J. Heterocycl. Chem. 1999, 36, 1453-1468.
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Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004;
pp 125-161. Stanforth, S. P. Tetrahedron 1998, 54, 263-303.
(11) Morris, G. A.; Nguyen, S. T. Tetrahedron Lett. 2001, 42, 2093-
2096. Benhida, R.; Lecubin, F.; Fourrey, J.-L.; Castellanos, L. R.; Quintero,
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Org. Chem. 1993, 58, 3550-3556. Alvarez, A.; Guzman, A.; Ruiz, A.;
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(22) For the preparation and coupling of 3-pyridyl tetrabutylammonium
trifluoroborates, see: (a) Batey, R. A.; Quach, T. D. Tetrahedron Lett. 2001,
42, 9099-9103. For coupling of 3-pyridyl potassium trifluoroborate with
5-bromopyrimidine, see: (b) Molander, G. A.; Biolatto, B. J. Org. Chem.
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(23) For lithium-iodine exchange see: Coudret, C. Synth. Commun.
1996, 26, 3543. For lithium-bromine exchange see ref 21b.
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(13) Bonnet, V.; Mongin, F.; Tre´court, F.; Breton, G.; Marsais, F.;
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(14) More recently, pyridines have been cross coupled under Hiyama
conditions: (a) Pierrat, P.; Gros, P.; Fort, Y. Org. Lett. 2005, 7, 697-700.
(b) Hiyama, T. J. Organomet. Chem. 2002, 653, 58-61. (c) Seganish, W.
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