Ni-catalyzed alkenylation of triazolopyridines: Synthesis of 2,6-disubstituted pyridines

Article abstract of DOI:10.1021/ol301606y

A synthetic strategy to access 2,6-disubstituted pyridines from triazolopyridines through a regioselective nickel-catalyzed alkenylation reaction of the C7-H bond is described. The N₂ fragment embedded in the resulting C-H functionalized triazolopyridine can be readily excised using acidic or oxidative conditions to unmask the pyridine.

Full text of DOI:10.1021/ol301606y

ORGANIC
LETTERS
2012
Vol. 14, No. 14
3744–3747
Ni-Catalyzed Alkenylation of
Triazolopyridines: Synthesis
of 2,6-Disubstituted Pyridines
Sheng Liu, James Sawicki, and Tom G. Driver*
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061, United States
tgd@uic.edu
Received June 11, 2012
ABSTRACT
A synthetic strategy to access 2,6-disubstituted pyridines from triazolopyridines through a regioselective nickel-catalyzed alkenylation reaction of
the C7ÀH bond is described. The N2 fragment embedded in the resulting CÀH functionalized triazolopyridine can be readily excised using acidic
or oxidative conditions to unmask the pyridine.
Achieving selective transition-metal-catalyzed CÀH bond
functionalization of N-heterocycles1 continues to inspire
research groups worldwide because these structural motifs
are ubiquitous in compounds with significant biological
activity or in materials with promising electronic pro-
perties.2,3 Pyridines have proved to be recalcitrant substrates
in CÀH bond functionalization processes because of their
electron-poor π-system and Lewis basic N-atom, which
together thwart the use of electrophilic CÀH bond activa-
tion transition metal complexes.4 While metal-catalyzed
CÀH functionalization methods have emerged that over-
come these challenges,5 these methods are generally re-
stricted to pyridines lacking a 2-substituent; the presence
of this group often significantly reduces the yield of the 2,6-
disubstituted product.6 To diminish the detrimental effect of
the Lewis basic pyridine nitrogen, pyridine N-oxides7 or N-
imines8 were used as protected pyridines. While these meth-
ods exhibit a greater tolerance to transition metals, the
scope of the reaction is attenuated by the solubility of the
substrate, and removal of the N-protecting group requires
a separate step, which does not not result in new bond
(1) For recent reviews, see: (a) Dick, A. R.; Sanford, M. S. Tetra-
hedron 2006, 62, 2439. (b) Zhang, M. Adv. Synth. Catal. 2009, 351, 2243.
(c) Chen, X.; Engle, K.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed.
2009, 48, 5094. (d) Ackermann, L.; Vicente, R.; Kapdi, K. P. Angew.
Chem., Int. Ed. 2009, 52, 9792. (e) Driver, T. G. Eur. J. Org. Chem. 2011,
2011, 4071. (f) Du Bois, J. Org. Process Res. Dev. 2011, 15, 758.
(2) Cf. (a) Pigolitazone: (a) Momose, Y.; Meguro, K.; Ikeda, H.;
Hatanaka, C.; Oi, S.; Sohda, T. Chem. Pharm. Bull. 1991, 39, 1440.
(b) Esomeprazole: Cotton, H.; Elebring, T.; Larsson, M.; Li, L.;
€
Sorensen, H.; von Unge, S. Tetrahedron: Asymmetry 2000, 11, 3819.
(c) Imatinib: Druker, B. J.; Lydon, N. B. J. Clin. Invest. 2000, 105, 3.
(3) Cf. (a) Zhang, X.; Jenekhe, S. A.; Perlstein, J. Chem. Mater. 1996,
8, 1571. (b) Izuhara, D.; Swager, T. M. J. Am. Chem. Soc. 2009, 131,
17724. (c) Izuhara, D.; Swager, T. M. Macromolecules 2011, 44, 2678.
(4) For recent reviews on pyridine syntheses, see: (a) Varela, J. A.;
(6) For notable exceptions, see: (a) Jordan, R. F.; Taylor, D. F.
J. Am. Chem. Soc. 1989, 111, 778. (b) Lewis, J. C.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2007, 129, 5332. (c) Yotphan, S.;
Bergman, R. G.; Ellman, J. A. Org. Lett. 2010, 12, 2978. (d) Tobisu, M.;
Hyodo, I.; Chatani, N. J. Am. Chem. Soc. 2009, 131, 12070.
ꢀ
Saa, C. Chem. Rev. 2003, 103, 3787. (b) Zeni, G.; Larock, R. C. Chem.
(7) Cf. (a) Campeau, L.-C.; Rousseaux, S.; Fagnou, K. J. Am. Chem.
Soc. 2005, 127, 18020. (b) Kanyiva, K. S.; Nakao, Y.; Hiyama, T. Angew.
Chem., Int. Ed. 2007, 46, 8872. (c) Hwang, S. J.; Cho, S. H.; Chang, S.
Rev. 2006, 106, 4644. (c) Bull, J. A.; Mousseau, J. J.; Pelletier, G.;
Charette, A. B. Chem. Rev. 2012, 112, 2642.
ꢀ
J. Am. Chem. Soc. 2008, 130, 16158. (d) Liegault, B.; Lapointe, D.;
(5) Cf. (a) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S.
J. Am. Chem. Soc. 2005, 127, 7330. (b) Nakao, Y.; Kanyiva, K. S.;
Hiyama, T. J. Am. Chem. Soc. 2008, 130, 2448. (c) Do, H.-Q.; Khan,
R. M. K.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 15185. (d) Nakao,
Y.; Yamada, Y.; Kashihara, N.; Hiyama, T. J. Am. Chem. Soc. 2010,
132, 13666. (e) Ye, M.; Gao, G.-L.; Yu, J.-Q. J. Am. Chem. Soc. 2011,
133, 6964.
Caron, L.; Vlassova, A.; Fagnou, K. J. Org. Chem. 2009, 74, 1826.
(e) Sun, H.-Y.; Gorelsky, S. I.; Stuart, D. R.; Campeau, L.-C.; Fagnou,
K. J. Org. Chem. 2010, 75, 8180.
ꢀ
(8) (a) Larivee, A.; Mousseau, J. J.; Charette, A. B. J. Am. Chem. Soc.
2008, 130, 52. (b) Mousseau, J. J.; Bull, J. A.; Charette, A. B. Angew.
Chem., Int. Ed. 2010, 49, 1115.
r
10.1021/ol301606y
Published on Web 07/03/2012
2012 American Chemical Society

formation. We anticipated that these drawbacks might be
surmounted using triazolopyridines as pyridine surrogates:9
a new CÀO bond is produced upon excision of the em-
bedded N2 molecule to produce a 2,6-disubstituted pyridine
(Scheme 1).10 Despite the potential for triazolopyridines to
function as masked pyridines, no CÀH bond activation
methodology exists that employs them as substrates. Here-
in, we report the development of a general, regiospecific
Ni-catalyzed heteroarylation of internal acetylenes with
triazolopyridines.
triazolopyridine was premixed with AlMe3 before addition
of a solution of phosphine and Ni(COD)2. The optimal
solvent was found to be toluene; diminished yields were
observed using ethereal or chlorinated solvents.11 While
alkenylation could potentially occur at either the C3 or
C7 position, reaction occurred exclusively at C7 to afford
only 4 as a single isomer. This reactivity is orthogonal to
KOH-mediated iodination, which occurs exclusively at
C3.12 In contrast to previous studies on the alkenylation
of pyridine,5c we observed only the insertion of a single
diphenylacetylene molecule.
Scheme 1. Synthesis of 2,6-Disubstituted Pyridines from CÀH
Bond FunctionalizationÀDenitrogenation of Triazolopyridines
Table 1. Optimization of C7-Alkenylation of Triazolopyridine
Ni(COD)2
(mol %)
Lewis
acid
% yield
4a,b
entry
ligand
mol %
In search of a general set of conditions, a range of transi-
tion metal complexes and ligands were screened for the
alkenylation of triazolopyridine 3 with diphenylacetylene.
Triazolopyridine 3 was selected because either the C3ÀH
or C7ÀH bond could potentially be functionalized, and
diphenylacetylene was chosen as the alkyne because it
performs poorly in existing methods for the alkenylation
of pyridine.5c We anticipated if optimal conditions were
found to achieve the regiospecific functionalization of 3
with diphenylacetylene that a general alkenylation method
would result. Established transition metal CÀH bond
activation catalysts were first examined,11 and Ni(COD)2
emerged as a potential catalyst from this initial screen.
No productive reaction was observed with Rh(I) or Ir(I)
complexes, all potent heteroarylation catalysts. While no
reaction was observed using Ni(COD)2 and bidentate
phosphine ligands, the desired alkenylation could be trig-
gered using monodentate phosphines withthe highest yield
obtained using the inexpensive, air stable triphenylphos-
phine (Table 1, entries 2À6). The catalyst loading could be
reduced to 3 mol % without attenuation of the yield of the
reaction (entries 6À8). The identity of the Lewis acid was
crucial to the success of this reaction with the best conver-
sions using AlMe3; reduced conversion was observed using
substoichiometric amounts of AlMe3, and using weaker
Lewis acids such as triphenylborane or dimethylzinc re-
sulted in no reaction (entries 11À13). The success of our
reaction depended on the order of addition of the Lewis
acid: high yields were obtained reproducibly only when the
1
10
10
10
10
10
5
À
À
5
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
AlMe3
AlCl3
n.r.
n.r.
56
2
dppb
3
PCy3
PPhCy2
PPh2Cy
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
10
10
10
10
5
4
73
5
85
6
>95
>95
>95
71
7
5
8
3
3
9
2
2
10c
11
12
13
3
3
64
3
3
14
3
3
BPh3
<5
3
3
ZnMe2
<5
a As determined using 1H NMR spectroscopy using CH2Br2 as an
internal standard. b E/Z = >95:5. c 0.2 equiv of AlMe3 used.
A series of triazolopyridines 3 were examined to determine
the scope and limitations of our Ni-catalyzed alkenylation
reaction (Table 2).13 Our reaction proved robust tolerating
alkyl substitution at any position on triazolopyridine without
diminishment of the reaction yield (entries 1À6). Electron-
donating or -withdrawing groups could be appended to the
triazolopyridine without adversely affecting the yield of the
alkenylation (entries 7À10). While our alkenylation reaction
tolerated the presence of a tertiary amine, the olefin E/Z
selectivity was attenuated (entry 8). In contrast, the olefin
selectivity was not diminished when the steric or electronic
environment around the C7ÀH bond was modified with a C6-
methyl or C6-F substituent (entries 9 and 10). In both cases,
triazolopyridines 4i and 4j were obtained as single isomers.
The effect of changing the identities of the alkyne sub-
stituents on the C7-alkenylation reaction was investigated
(9) (a) Jones, G.; Sliskovic, D. R. Tetrahedron Lett. 1980, 21, 4529. (b)
Jones, G.; Mouat, D. J.; Tonkinson, D. J. J. Chem. Soc., Perkin Trans. 1
1985, 2719.
(10) For related strategies of traceless bond construction, see: (a)
Zhang, H.-C.; Ye, H.; Moretto, A. F.; Brumfield, K. K.; Maryanoff,
B. E. Org. Lett. 2000, 2, 89. (b) Guo, F.; Konkol, L. C.; Thomson, R. J.
J. Am. Chem. Soc. 2010, 133, 18. (c) Mundal, D. A.; Avetta, C. T.;
Thomson, R. J. Nat. Chem. 2010, 2, 294.
(12) Abarca, B.; Aucejo, R.; Ballesteros, R.; Blanco, F.; Garcıa-
~
(13) To simplify the manipulation of Ni(COD)2 and Ph3P when
0.2 mmol of the triazolopyridine was used, our investigations into the
scope of our reaction were performed using 10 mol % of catalyst and
phosphine.
Espana, E. Tetrahedron Lett. 2006, 47, 8101.
(11) Refer to the Supporting Information for a complete listing of the
reaction conditions that were screened.
Org. Lett., Vol. 14, No. 14, 2012
3745

Table 2. Scope of the Ni-Catalyzed C7-Alkenylation Reaction
Table 3. Regioselective C7-Alkenylation of Triazolopyridine
a Isolated yield of 4 after silica gel chromatography, E/Z > 95:5.
b 92:8 mixture of olefins.
next (Table 3). While no insertion was observed with
terminal- or silyl-substituted acetylenes,14 the reaction tol-
erated a range of aryl- and alkyl-substituted alkynes. A
slight attenuation of the reaction yield was observed with
dialkyl acetylenes in comparison to diaryl acetylenes (entries
1À3). To our delight, alkyne insertion into the C7ÀH bond
proved to be regioselective.15 Triazolopyridine 6d was for-
med as a single alkene isomer from the insertion of 4-methyl-
pent-2-yne (entry 4). Regioselective alkyne insertion was
also observed for aryl acetylenes with slightly higher selec-
tivities observed for electron-rich arenes (entries 5À8). In
each case the alkyne insertion occurred to form a new bond
between C7 and the methyl-substituted acetylenic carbon.
The sensitivity of our alkenylation reaction to the electronic
nature of the alkyne is illustrated in the lower conversions
observed with electron-deficient aryl acetylenes (entries 8
and 9). The regioselectivity of alkyne insertion was reversed
when the methyl was replaced with an ethyl group to favor
the formation of triazolopyridine 7j (entry 10). If alkyne
insertion is under steric control,15 then this process finds
phenyl to be smaller than the ethyl group.
a Isolated yield of 6 and 7 after silica gel chromatography, E/Z >
95:5. b 10 mol % of PCy3 used.
occurs through a Ni-catalyzed CÀH bond activation path-
way (Scheme 2). Before entering the catalytic cycle, the
triazolopyridine 3 coordinates to AlMe3 to produce 8.16
Coordination of the nickel catalyst with the aluminate
positions it for selective oxidative addition of the C7ÀH
bondin9.16d,17 Oxidativeaddition thenproducesnickel(II)
10, which undergoes regioselective alkyne insertion to form
11, where the new CÀC bond is formed between the smaller
The reactivity trends of our substrates in combination
with the reported mechanism studies of nickel(0) com-
plexes suggest that C7-alkenylation of triazolopyridines
(14) Precipitation of nickel black was observed when these acetylenes
were used.
(15) The regioselectivity of alkyne insertion mirrors that of other Ni-
catalyzed processes. For example, see: (a) Nakao, Y.; Kashihara, N.;
Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc. 2008, 130, 16170.
(b) Miura, T.; Yamauchi, M.; Murakami, M. Org. Lett. 2008, 10,
3085. (c) Malik, H. A.; Sormunen, G. J.; Montgomery, J. J. Am. Chem.
Soc. 2010, 132, 6304. (d) Kumar, P.; Louie, J. Org. Lett. 2012, 14, 2026.
(16) (a) Tolman, C. A.; Seidel, W. C.; Druliner, J. D.; Domaille, P. J.
Organometallics 1984, 3, 33. (b) Brunkan, N. M.; Brestensky, D. M.;
Jones, W. D. J. Am. Chem. Soc. 2004, 126, 3627. (c) Hratchian, H. P.;
Chowdhury, S. K.; Gutierrez-Garcia, V. M.; Amarasinghe, K. K. D.;
Heeg, M. J.; Schlegel, H. B.; Montgomery, J. Organometallics 2004, 23,
4636. (d) Ogoshi, S.; Ueta, M.; Arai, T.; Kurosawa, H. J. Am. Chem.
Soc. 2005, 127, 12810. (e) Tsai, C.-C.; Shih, W.-C.; Fang, C.-H.; Li,
C.-Y.; Ong, T.-G.; Yap, G. P. A. J. Am. Chem. Soc. 2010, 132, 11887.
(17) For related mechanistic studies on the oxidative addition of
CÀH bonds to Ni(0) complexes, see: (a) Clement, N. D.; Cavell, K. J.
Angew. Chem., Int. Ed. 2004, 43, 3845. (b) Reinhold, M.; McGrady, J. E.;
Perutz, R. N. J. Am. Chem. Soc. 2004, 126, 5268. (c) Normand, A. T.;
Hawkes, K. J.; Clement, N. D.; Cavell, K. J.; Yates, B. F. Organome-
tallics 2007, 26, 5352. (d) Kanyiva, K. S.; Kashihara, N.; Nakao, Y.;
Hiyama, T.; Ohashi, M.; Ogoshi, S. Dalton Trans. 2010, 39, 10483.
(18) For computational studies on the origin of the regioselectivity of
Ni-promoted alkynyl processes, see: (a) Liu, P.; McCarren, P.; Cheong,
P. H.-Y.; Jamison, T. F.; Houk, K. N. J. Am. Chem. Soc. 2010, 132, 2050.
(b) Liu, P.; Montgomery, J.; Houk, K. N. J. Am. Chem. Soc. 2011, 133,
6956.
3746
Org. Lett., Vol. 14, No. 14, 2012

alkynyl substituent and C7 of the triazolopyridine.15,18
Reductive elimination then produces 12.19 Our data point
to coordination of the substrate with the Lewis acid occurs
first because successful C7-alkenylation requires preincuba-
tion of the triazolopyridine with AlMe3 before addition of
the nickel catalyst.
without affecting the alkenyl substituent using either aqu-
eous HCl to afford alcohol 13a or HOAc to afford acetate
14a, whereas oxidation with SeO2 produced aldehyde 15a.
A one-flask hydrogenationÀhydrolysis sequence was also
achieved to produce alkyl-substituted pyridine 16a.
Scheme 3. Conversion of Triazolopyridine 4a into 2,6-Disub-
stituted Pyridines
Scheme 2. Potential Catalytic Cycle
In conclusion, we have developed a synthetic strategy to
access 2,6-disubstituted pyridines from triazolopyridines
through a regioselective Ni-catalyzed alkenylation of the
C7ÀH bond. The N2 fragment embedded in the resulting
CÀH functionalized triazolopyridine can be readily ex-
cised using acidic or oxidative conditions without destruc-
tion of the C7-alkene substituent. Our nickel alkenylation
method employs the cheap and air stable triphenylphos-
phine ligand and a slight excess of the acetylene. It is toler-
ant of a range of functionality on either the triazolopyr-
idine or alkyne without attenuation of the reaction yield.
Importantly, alkyne insertion into the C7ÀH triazolopyr-
idine bond is regioselective. Together, we believe that these
attributes produce an attractive solution to the synthesis of
polysubstituted pyridines.
To gain insight into the catalytic cycle, we examined the
reactivity of C7-labeled triazolopyridine 3a-d1 toward our
reaction conditions. A kinetic isotope effect of 3.0 was
observed for an intermolecular competition experiment
between 3a-d0 and 3a-d1. This primary kinetic isotope
effect indicates that CÀH bond activation is the turn-
over-limiting step in the catalytic cycle.20 No H/D ex-
change was observed in either the reisolated substrates or
the product triazolopyridines. This absence indicates that
proton exchange processes are not occurring between the
nickel hydride and AlMe3 or another substrate molecule.21
We next sought to demonstrate that our triazolopyri-
dines functioned as masked pyridines through denitro-
genation (Scheme 3). While our attempts to excise the N2
fragment of the triazolopyridine using transition metal
complexes were unsuccessful,22 exposure of 4a to acid or
an oxidant produced the desired 2,6-disubstituted pyridine
(Scheme 3).9 A new CÀO bond could be introduced
Acknowledgment. We are grateful to the University of
Illinois at Chicago for their generous support. We thank
Prof. L. Anderson (UIC) for insightful discussions.
Supporting Information Available. Complete experi-
mental procedures, spectroscopic and analytical data for
the products (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
(22) cf. (a) Chuprakov, S.; Hwang, F. W.; Gevorgyan, V. Angew.
Chem., Int. Ed. 2007, 46, 4757. (b) Horneff, T.; Chuprakov, S.;
Chernyak, N.; Gevorgyan, V.; Fokin, V. V. J. Am. Chem. Soc. 2008,
130, 14972. (c) Miura, T.; Yamauchi, M.; Murakami, M. Chem. Commun.
2009, 1470. (d) Nakamura, I.; Nemoto, T.; Shiraiwa, N.; Terada, M. Org.
Lett. 2009, 11, 1055. (e) (Review) Chattopadhyay, B.; Gevorgyan, V.
Angew. Chem., Int. Ed. 2012, 51, 862.
(19) AlMe3 could also accelerate reductive elimination; see: Shen, Q.;
Hartwig, J. F. J. Am. Chem. Soc. 2007, 129, 7734.
(20) In contrast, a KIE of 1 was observed for Ni(0)-catalyzed hydro-
fluoroarylation of alkynes. See ref 17d.
(21) H/D exchange processes are common in Pt-mediated CÀH bond
activation processes; see: Stahl, S. S.; Labinger, J. A.; Bercaw, J. E.
J. Am. Chem. Soc. 1996, 118, 5961.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 14, 2012
3747