Directed deprotonation-transmetalation as a route to substituted pyridines

Article abstract of DOI:10.1021/ol006986z

matrix presented Regioselective C-4 deprotonation of 3-bromopyridine, followed by Li/Zn transmetalation and Pd-mediated coupling processes, provides a flexible entry to 4-substituted and 3,4-disubstituted pyridines. Application of a similar sequence to 2-

Full text of DOI:10.1021/ol006986z

ORGANIC
LETTERS
2001
Vol. 3, No. 6
835-838
Directed Deprotonation−Transmetalation
as a Route to Substituted Pyridines
Gunter Karig, James A. Spencer, and Timothy Gallagher*
School of Chemistry, UniVersity of Bristol, Bristol BS8 1TS, U.K.
t.gallagher@bristol.ac.uk
Received December 11, 2000
ABSTRACT
Regioselective C-4 deprotonation of 3-bromopyridine, followed by Li/Zn transmetalation and Pd-mediated coupling processes, provides a
flexible entry to 4-substituted and 3,4-disubstituted pyridines. Application of a similar sequence to 2-bromopyridine (with LDA as base) provides
2,3-disubstituted pyridines, but using lithium 2,2,6,6-tetramethylpiperidide (LiTMP) provides access to both the 2,3- and 2,4-disubstituted isomers.
Transition metal-mediated cross couplings, based on the
reaction of an aryl or alkenyl halide or triflate with an
appropriate organometallic component, continue to find
important applications in heterocyclic chemistry.1-3 While
such processes have been utilized for the generation of 2-
and 3-monosubstituted pyridines, the direct synthesis of
4-substituted variants is frequently hampered by the unstable
nature of the 4-halopyridines.4 Consequently, most ap-
proaches have relied on generating a pyridyl-based organo-
metallic component5 and subsequent coupling of this species
with the appropriate aryl or alkenyl halide. Tin,6 boron,7 and
magnesium8 4-pyridyl derivatives have all been reported, and
while this strategy is flexible (given the wide range of aryl/
alkenyl halides that are also commercially accessible),
synthesis of the 4-metallo pyridine component still depends
on a halogen-metal exchange reaction that usually involves
4-bromopyridine, an unstable and problematic component.
Jetter, J. W.; Sherk, S. R.; Houghton, G. C.; Copeland, R. A.; Covington,
M. B.; Trzaskos, J. M.; Magolda, R. L. Bioorg. Med. Chem. Lett. 1999, 9,
919-924. Brill, W. K. D.; DeMesmaeker, A.; Wendeborn, S. Synlett 1998,
1085-1090. (iii) Zn derivatives: Takahashi, T.; Koga, H.; Sato, H.;
Ishizawa, T.; Taka, N.; Imagawa, J. Bioorg. Med. Chem. 1998, 6, 323-
337. For recent examples involving 3-metallo pyridines, see the following.
(i) Sn derivatives: Shen, W.; Fakhoury, S.; Donner, G.; Henry, K.; Lee, J.;
Zhang, H. C.; Cohen, J.; Warner, R.; Saeed, B.; Cherian, S.; Tahir, S.;
Kovar, P.; Bauch, J.; Ng, S. C.; Marsh, K.; Sham, H.; Rosenberg, S. Bioorg.
Med. Chem. Lett. 1999, 9, 703-708. Nicolaou, K. C.; He, Y.; Roschangar,
F.; King, N. P.; Vourloumis, D.; Li, T. H. Angew. Chem., Int. Ed. Engl.
1998, 37, 84-87. (ii) B derivatives: Li, J. J.; Yue, W. S. Tetrahedron Lett.
1999, 40, 4507-4510. Guarna, A.; Occhiato, E. G.; Machetti, F.; Giacomelli,
V. J. Org. Chem. 1999, 64, 4985-4989. (iii) Zn derivatives: Luo, F. T.;
Wang, R. T. Heterocycles 1990, 31, 1543-1548.
(1) Diederich, F.; Stang, P. J. Metal-catalyzed Cross-coupling Reactions;
Wiley-VCH: Weinheim, 1998.
(2) For organozinc-based methods, see: Knochel, P.; Singer, R. D. Chem.
ReV. 1993, 93, 2177-2188. Jackson, R. F. W. In Organozinc Reagents;
Knochel, P., Jones, P., Eds.; Oxford University Press: Oxford, 1999; Chapter
3, pp 37-56.
(3) Comins, D. L.; O’Connor, S. In AdVances in Heterocyclic Chemistry;
Katritzky, A. R., Ed.; Academic Press: San Diego, 1988; Vol. 44, pp 199-
267.
(4) Negishi, E.; Luo, F. T.; Frisbee, R.; Matsushita, H. Heterocycles 1982,
18, 117-122. Minato, A.; Tamao, K.; Hayashi, T.; Suzuki, K.; Kumada,
M. Tetrahedron Lett. 1981, 22, 5319-5322. Pridgen, L. N. J. Heterocycl.
Chem. 1975, 12, 443-444.
(6) Peters, D.; Ho¨rnfeldt, A.-B.; Gronowitz, S. J. Heterocycl. Chem. 1990,
27, 2165-2173. Yamamoto, Y.; Yanagi, A. Chem. Pharm. Bull. 1982, 30,
1731-1737.
(5) For recent examples involving 2-metallo pyridines, see the following.
(i) Sn derivatives: Arzel, E.; Rocca, P.; Marsais, F.; Godard, A.; Que´guiner,
G. Heterocycles 1999, 50, 215-226. Panetta, C. A.; Kumpaty, H. J.; Heimer,
N. E.; Leavy, M. C.; Hussey, C. L. J. Org. Chem. 1999, 64, 1015-1021.
Cockerill, G. S.; Easterfield, H. J.; Percy, J. M. Tetrahedron Lett. 1999,
40, 2601-2604. Buynak, J. D.; Doppalapudi, V. R.; Frotan, M.; Kumar,
R. Tetrahedron Lett. 1999, 40, 1281-1284. (ii) B derivatives: Pinto, D. J.
P.; Batt, D. G.; Pitts, W. J.; Petraitis, J. J.; Orwat, M. J.; Wang, S. G.;
(7) Ishikura, M.; Ohta, T.; Terashima, M. Chem. Pharm. Bull. 1985, 33,
4755-4763. Ishikura, M.; Kamada, M.; Terashima, M. Synthesis 1984,
936-938. Ishikura, M.; Kamada, M.; Ohta, T.; Terashima, M. Heterocycles
1984, 22, 2475-2478. Fischer, F. C.; Havinga, E. Recl. TraV. Chim. Pays-
Bas 1974, 93, 21-24. Fischer, F. C.; Havinga, E. Recl. TraV. Chim. Pays-
Bas 1965, 84, 439-440.
(8) Furukawa, N.; Shibutani, T.; Fujihara, H. Tetrahedron Lett. 1987,
28, 5845-5848.
10.1021/ol006986z CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/21/2001

To solve a problem associated with novel nicotinic
agonists,9 we have developed an alternative approach to
4-substituted pyridines that avoids the use of a 4-halopyridine
altogether. Instead, directed and regioselective deprotonation
and transmetalation (Li f Zn),10 rather than direct halogen-
metal exchange, has been used to provide access to the key
organometallic (zinc) component, which is then suitable for
a Pd-mediated cross coupling. Importantly, this strategy has
a more general application and has been extended to provide
a flexible entry to functionalized variants of both 3,4- and
2,3-disubstituted pyridines.
of ZnCl2 (as a THF solution) was also done at -95 °C, and
warming of the solution to room temperature provided the
corresponding zinc species 2.12 This intermediate, which is
stable at room temperature, was then used directly as the
4-pyridyl organometallic component in cross coupling reac-
tions involving aryl and alkenyl halides/triflates. The overall
yields for deprotonation, lithium-zinc exchange, and cross
coupling were generally good, and the resulting 3-bromo-
4-substituted pyridines 313 were isolated following chroma-
tography (Figure 1).
The synthesis of 4-substituted and 3,4-disubstituted py-
ridines is outlined in Scheme 1 and is based on a one-pot/
Scheme 1. Directed Deprotonation/Transmetalation Route to
4-Substituted and 3,4-Disubstituted Pyridinesa
Figure 1. 3-Bromo-4-substituted pyridines. The superscripts a-d
denote the following: (a) using the corresponding iodide; (b) using
the aryl or alkenyl bromide; (c) using the alkenyl triflate, see ref
9a; (d) Voc ) vinyloxycarbonyl.
a Reagents and conditions: (a) LDA, THF, -95 °C; (b) ZnCl2,
-95 °C to rt; (c) ArX, Pd(Ph3P)4, reflux; (d) Rieke zinc, then H2O;
(e) Ar′B(OH)2, Pd(Ph3P)4, aqueous Na2CO3, EtOH, PhMe, or
H2CdCHR, Pd(OAc)2, (o-Tol)3P, NEt3, MeCN.
Interestingly, no “homocoupled” products with 2 acting
as both the aryl zinc and aryl bromide fragments were
observed; the reactivity associated with the aryl zinc
component of 2 appears to dominate. Reduction of 3 (Ar )
Ph, 4-ClC6H4) using Rieke zinc14 followed by an aqueous
quench then allowed access to the corresponding 4-mono-
substituted pyridines 4a and 4b in 81% and 64% overall
yields, respectively, from 3-bromopyridine, as shown in
Scheme 1.
three-step sequence: (i) the kinetic C(4) lithiation of
3-bromopyridine 1; (ii) a low-temperature Li-Zn exchange;
(iii) Pd(0)-mediated cross coupling of the resulting orga-
nozinc intermediate 2 using an aryl or alkenyl halide (or
triflate). In this way, 3-bromo-4-substituted pyridines 3 are
obtained, which then provide access to both 4-substituted
pyridines 4 (following reduction of 3) and, more significantly,
3,4-disubstituted pyridines 5 via a second Pd-mediated cross
coupling, based on use of 3 as the aryl halide component.
Deprotonation of 3-bromopyridine 1 was achieved using
LDA in THF at -95 °C as reported by Gribble.11 Addition
While reduction of 3 to give 4a/b is straightforward, the
reactivity associated with the 3-bromo substituent of 3 can
be harnessed in a synthetically more versatile manner,
(11) Gribble, G. W.; Saulnier, M. G. Tetrahedron Lett. 1980, 21, 4137-
4140.
(12) The monoalkyl zinc halide species is assumed. Lithium zincates
are known, see: Isobe, M.; Kondo, S.; Nagasawa, N.; Goto, T. Chem. Lett.
1977, 679-682.
(13) 3-Bromopyridine is known to undergo N-acylation and C(4) arylation
with ArMgX, to provide an alternative source of 3-bromo-4-arylpyridines.
Comins, D. L.; Mantlo, N. B. J. Heterocycl. Chem. 1983, 20, 1239-1243.
(14) Rieke, R. D.; Hanson, M. V. In Organozinc Reagents; Knochel, P.,
Jones, P., Eds.; Oxford University Press: Oxford, 1999; Chapter 2, pp 23-
36. Zhu, L.; Wehmeyer, R. M.; Rieke, R. D. J. Org. Chem. 1991, 56, 1445-
1453.
(15) For related Heck processes, see: Anson, M. S.; Mirza, A. R.; Tonks,
L.; Williams, J. M. J. Tetrahedron Lett. 1999, 40, 7147-7150. El-Ghayoury,
A.; Ziessel, R. Tetrahedron Lett. 1998, 39, 4473-4476.
(16) Also see: Marsais, F.; Bouley, F.; Que´guiner, G. J. Organomet.
Chem. 1979, 171, 273-282. For reviews relating to the deprotonation of
azines, see: Que´guiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, J. In
AdVances in Heterocyclic Chemistry; Katritsky, A. R., Ed.; Academic
Press: San Diego, 1991; Vol. 52, pp 187-304. Que´guiner, G. J. Heterocycl.
Chem. 2000, 37, 615-621.
(9) (a) Wright, E.; Gallagher, T.; Sharples, C. G. V.; Wonnacott, S.
Bioorg. Med. Chem. Lett. 1997, 7, 2867-2870. (b) Sharples, C. G. V.;
Kaiser, S.; Soliakov, L.; Marks, M. J.; Collins, A. C.; Washburn, M.; Wright,
E.; Spencer, J. A.; Gallagher, T.; Whiteaker, P.; Wonnacott, S. J. Neurosci.
2000, 20, 2783-2791.
(10) For other examples of lithium-zinc transmetalations, see: Gros,
P.; Fort, Y. Synthesis 1999, 754-756. Kristensen, J.; Begtrup, M.; Vedsø,
P. Synthesis 1998, 1604-1608 (these authors use the term “ortho lithiation/
transmetalation”). Felding, J.; Uhlmann, P.; Kristensen, J.; Vedsø, P.;
Begtrup, M. Synthesis 1998, 1181-1184. Yagi, K.; Ogura, T.; Numata,
A.; Ishii, S.; Arai, K. Heterocycles 1997, 45, 1463-1466. Amat, M.; Hadida,
S.; Pshenichnyi, G.; Bosch, J. J. Org. Chem. 1997, 62, 3158-3175.
Anderson, B. A.; Harn, N. K. Synthesis 1996, 583-585. Sakamoto, T.;
Kondo, Y.; Takazawa, N.; Yamanaka, H. J. Chem. Soc., Perkin Trans. 1
1996, 1927-1934. Tre´court, F.; Gervais, B.; Mallet, M.; Que´guiner, G. J.
Org. Chem. 1996, 61, 1673-1676. Ennis, D. S.; Gilchrist, T. L. Tetrahedron
1990, 46, 2623-2632. Bell, A. S.; Roberts, D. A.; Ruddock, K. S.
Tetrahedron Lett. 1988, 29, 5013-5016.
836
Org. Lett., Vol. 3, No. 6, 2001

providing an entry to 3,4-disubstituted pyridines 5 (Figure
2). This has been illustrated by reaction of 3 in Suzuki
Figure 3. 2,3-Disubstituted pyridines. The superscripts a and b
denote the following: (a) yield from 8a; (b) in this case, the Heck
product 9b was accompanied by 38% of 3-(4-methoxyphenyl)-
pyridine and 26% of the product corresponding to reduction of the
alkenyl moiety of 9b.
Figure 2. 3,4-Disubstituted pyridines.
ponent and using LiTMP17 (at -78 °C) rather than LDA
provides, after transmetalation ([M] ) Li f Zn) and Pd(0)
cross coupling, an approximately 3:1 mixture of 8 (major
isomer) and the unexpected C(4) adduct 10 (minor isomer)
(Scheme 3). The ratio of 8 and 10 appears to be established
in the initial deprotonation18 and transmetalation steps, and
while there is scope to improve the level of regiocontrol
available, this observation provides a basis for a novel but,
more importantly, direct entry to 2,4-disubstituted py-
ridines: adduct 10a underwent Suzuki coupling to give the
2,4-diarylpyridine 11 in 82% yield.
couplings (to give 5a-e) and in the Heck reaction (leading
to 5f-h).15
Directed deprotonation and transmetalation has more
general utility and within the pyridine area can also be
applied successfully to the synthesis of 2,3-disubstituted
derivatives starting from 2-bromopyridine (Scheme 2).
Scheme 2. Directed Deprotonation/Transmetalation Route to
2,3-Disubstituted Pyridinesa
Scheme 3. C-3 vs C-4 Deprotonation/Transmetalation of
2-Bromopyridine. Synthesis of 2,4-Disubstituted Pyridinesa
a Reagents and conditions: (a) LDA, THF, -95 °C; (b) ZnCl2,
-95 °C to rt; (c) ArX, Pd(Ph3P)4, reflux; (d) 4-MeC6H4B(OH)2,
Pd(Ph3P)4, aqueous Na2CO3, EtOH, PhMe, or H2CdCHCO2Et,
Pd(OAc)2, (o-Tol)3P, NEt3, MeCN.
Using a similar sequence to that described above, depro-
tonation11,16 of 2-bromopyridine 6 followed by Li-Zn
exchange gave organozinc 7, and Pd-mediated coupling using
aryl iodides then provided a series of 2-bromo-3-substituted
pyridines 8a-c in good yields. Again, the 2-bromo moiety
of 8a is amenable to a second Pd-mediated process (either
Suzuki or Heck) to afford representative 2,3-disubstituted
pyridines 9a and 9b (Figure 3).
The interesting issue of the relative kinetic acidity of C-
(4) vs C(3) in 2-bromopyridine 6 has also been examined
(Scheme 3). Deprotonation of 6 using LDA (at -95 °C)
provides almost exclusively (>95:5) the C(3) derivatives 8
(see Scheme 2). However, simply changing the base com-
a Reagents and conditions: (a) LiTMP, THF, -78 °C; (b) ZnCl2,
-95 °C to rt; (c) ArX, Pd(Ph3P)4, reflux; (d) 4-MeC6H4B(OH)2,
Pd(Ph3P)4, aqueous Na2CO3, EtOH, PhMe (82%).
Org. Lett., Vol. 3, No. 6, 2001
837

In summary, exploiting the kinetic acidity associated with
3-bromopyridine provides regioselective access to the cor-
responding 4-organozinc species 2 via low-temperature
deprotonation followed by lithium-zinc transmetalation.
Using similar procedures, 2-bromopyridine provides the
corresponding 3-organozinc derivative 7, and both 2 and 7
undergo facile cross coupling reactions leading to a range
of substituted pyridines. It is important to recognize the dual
role of the halogen component in 2 and 7. This moiety not
only provides the activation for directing the initial depro-
tonation step but remains available for further manipulation
at a later stage. While a number of intriguing regiochemical
issues remain to be fully explored, the ability to combine
halogen-directed deprotonation and transmetalation provides
an effective alternative to direct halogen-metal exchange
(to provide simple variants such as 4) and a versatile entry
to variously substituted pyridines.
Acknowledgment. We thank BBSRC for financial sup-
port and acknowledge use of the EPSRC’s Chemical
Database Service at Daresbury.19
(17) For the application of LiTMP to the deprotonation of diazines, see:
Mojovic, L.; Turck, A.; Ple´, N.; Dorsy, M.; Ndzi, B.; Que´guiner, G.
Tetrahedron 1996, 52, 10417-10426. Ple´, N.; Turck, A.; Heynderickx, A.;
Que´guiner, G. Tetrahedron 1998, 54, 9701-9710. Turck, A.; Ple´, N.;
Lepretre-Gaquere, A.; Que´guiner, G. Heterocycles 1998, 49, 205-214.
(18) For the relative acidity of pyridyl protons, see: Zoltewicz, J. A.;
Smith, C. L. Tetrahedron 1969, 25, 4331. Zoltewicz, J. A.; Grahe, G.; Smith,
C. L. J. Am. Chem. Soc. 1969, 91, 5501-5505.
Supporting Information Available: General experimen-
tal procedures and 1H and 13C NMR and other characteriza-
tion data for key compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(19) Fletcher, D. A.; McMeeking, R. F.; Parkin, D. J. Chem. Inf. Comp.
Sci. 1996, 36, 746-749.
OL006986Z
838
Org. Lett., Vol. 3, No. 6, 2001