Palladium-catalyzed benzylic arylation of 2-methyl azaarenes

Article abstract of DOI:10.1021/ol102276e

A palladium-catalyzed benzylic sp³ direct arylation of electron-deficient heterocycles is reported. The method described enables the introduction of electron-rich and -poor aromatics at the benzylic position of heterocycles without the need for

Full text of DOI:10.1021/ol102276e

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5359-5361
Palladium-Catalyzed Benzylic Arylation
of 2-Methyl Azaarenes
Paul M. Burton and James A. Morris*
Syngenta Ltd., Jealott’s Hill International Research Centre, Bracknell,
Berkshire RG42 6EY, U.K.
james.morris@syngenta.com
Received September 22, 2010
ABSTRACT
A palladium-catalyzed benzylic sp3 direct arylation of electron-deficient heterocycles is reported. The method described enables the
introduction of electron-rich and -poor aromatics at the benzylic position of heterocycles without the need for preactivation or the use
of directing groups.
Naphthyridine derivatives show an exceptionally broad
range of biological activities, ranging from the treatment
of human diseases to their use as pesticides.1a Of the many
isomeric pyridopyridines, the 1,8-naphthyridines have been
by far the most studied subclass (Figure 1).1 Synthetic
methodologies that allow the rapid and late-stage deriva-
tization of this class of molecule are thus highly attractive
in research and optimization of new pharmaceuticals and
agrochemicals.
Transition-metal-catalyzed direct arylation of C-H bonds
is now a well-established method for the formation of
sp2C-sp2C bonds and enjoys a broad reaction scope.2 In
contrast, the direct arylation of sp3C-H bonds is less widely
established. Examples are generally limited to either chela-
tion-assisted sp3C-H arylation3 or preactivation of het-
eroaromatic systems through the use of N-oxides4 or N-imino
ylides.5
Figure 1. Bioactive 1,8-naphthyridines.
Due to our ongoing interest in naphthyridines,1d we sought
to prepare 2-benzyl-1,8-naphthyridine analogues by a route
amenable to 2-methyl-arylation at a late stage in the
synthesis. To this end, we report herein a general palladium-
catalyzed direct arylation of 2-methyl naphthyridines which
can be extended to sp3C-H arylation in other electron-
deficient heteroaryl scaffolds.
Exploratory studies for the coupling of substituted 2-meth-
yl-1,8-naphthyridines with aryl halides under palladium
catalysis were promising. We established dioxane to be the
preferred solvent and found cesium carbonate to be a suitable
(1) (a) Litvinov, V. P. AdV. Heterocycl. Chem. 2006, 91, 189–300. (b)
Atack, J. R. Curr. Drug Target CNS Neurol. Disord. 2003, 2, 213–232. (c)
Fuller, R. W.; Bymaster, F. P.; Perry, K. W.; Wong, D. T. J. Pharm.
Pharmacol. 1978, 30, 464–466. (d) Mitchell, G.; Salmon, R.; Bacon, D. P.;
Aspinall, I. H.; Briggs, E.; Avery, A. J.; Morris, J. A.; Russell, C. J. W.O.
Patent No. 2009/115788, 2009.
(2) For selected reviews in this area, see: (a) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. ReV. 2007, 107, 174–238. (b) Daugulis, O.; Do, H.-Q.;
Shabashov, D. Acc. Chem. Res. 2009, 42, 1074–1086. (c) Ackermann, L.;
Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792–9826.
(d) Lyons, T. W.; Sanford, M. S. Chem. ReV. 2010, 110, 1147–1169.
10.1021/ol102276e  2010 American Chemical Society
Published on Web 11/02/2010

and mild base.6 The use of stronger bases such as potassium
t-butoxide gave a complex mixture of products.
We initiated a ligand screen employing equimolar amounts
of the naphthyridine 11d and 1-bromo-4-fluorobenzene as
model coupling partners (table 1). For these exploratory
aryl bromide was used, the selectivity for monoarylation
diminished in favor of bisarylation. However, employing
equimolar amounts of the coupling partners is particularly
attractive when one or both substrates are valuable late-stage
intermediates. We found the desired monoarylation adduct
to be readily separable by chromatography from both
unreacted starting material and any bisarylated product that
may have formed.
Table 1. Effect of the Palladium Ligand on the Ratio of Mono-
The nature of the palladium source was found to be less
vital, with similar results found for Pd2(dba)3, Pd(dba-
3,5,3′,5′-OMe)2, Pd(OAc)2, and (MeCN)2PdCl2 for most
substrates. The commercially available Fairlamb catalyst,
Pd(dba-3,5,3′,5′-OMe)2,9 was selected due to a marginally
higher selectivity for the desired monoarylation product when
coupling with the most electron-deficient aryl halides.
Reducing the catalyst/ligand loading to 2.5 mol % had no
detrimental effect, and switching from microwave irradiation
to thermal conditions gave a cleaner, higher-yielding reaction.
Our optimum conditions were thus found to be 1 equiv each
of the methyl naphthyridine and aryl bromide, 2 equiv of
Cs2CO3, 2.5 mol % of Pd(dba-3,5,3′,5′-OMe)2, and 2.5 mol
% of Xantphos, heated to reflux for 16 h in dioxane. The
reaction is experimentally simple and does not require strict
anhydrous conditions, with reagents and solvents used as
purchased.10
The scope of the reaction with respect to the aryl coupling
partner was then investigated by subjecting 2-methyl-1,8-
naphthyridine 411 and a range of commercially available aryl
halides and triflates to our optimum reaction conditions
(Table 2). Both electron-rich (entries 1-5) and -deficient
(entries 6-13) aryl bromides were found to couple well.
However, a lower selectivity for monoarylation was observed
with the strongly mesomerically withdrawing p-cyano group
(entry 10). The tolerance of the reaction to ortho substituents
(entries 3 and 4), esters (entries 6 and 9), nitriles (entry 11),
and even aliphatic ketones (entry 12) was demonstrated. The
latter was particularly interesting because no R-arylation of
the ketone was observed.12 Aryl iodides and triflates could
also be successfully reacted (entries 15 and 16). Employing
an aryl chloride as the coupling partner failed to afford any
product (entry 17), which we used to our advantage to
chemoselectively functionalize an aryl bromide with chloride
substituents (entry 8).
to Bisarylationa
entry
ligand
Xantphos
BINAP
S-Phos
t-Bu-XPHOS
P(t-Bu)3·HBF4
DPPF
product ratio (1:2:3)b
1
2
3
4
5
6
7
11:83:6
94:6:0
19:53:28
92:8:0
49:14:37
43:49:8
38:46:16
dicyclohexyl JohnPhos
a All reactions performed in a sealed tube under microwave irradiation.
Determined by analysis of the crude H NMR spectra.
b
1
experiments, we employed a 5 mol % catalyst loading and
performed the reactions under microwave irradiation (30 min
at 150 °C). The nature of the ligand on palladium had a
significant effect on the ratio of mono- to bisarylation.
Xantphos7 (entry 1) clearly showed the highest combination
of reactivity and selectivity for monoarylation and was used
for all subsequent studies. One can postulate that the second
arylation, reacting with a more acidic C-H bond than the
starting material, would be favored electronically but disfa-
vored by steric factors.8 As expected, when an excess of the
(3) For selected examples of chelation-assisted arylation of sp3C-H
bonds, see: (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem.
Soc. 2005, 127, 13154–13155. (b) Shabashov, D.; Daugulis, O. Org. Lett.
2005, 7, 3657–3659. (c) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2010, 132, 3965–3972. (d) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford,
M. S. J. Am. Chem. Soc. 2005, 127, 7330–7331. (e) Giri, R.; Maugel, N.;
Li, J.-J.; Wang, D.-H.; Breazzano, S. P.; Saunders, L. B.; Yu, J.-Q. J. Am.
Chem. Soc. 2007, 129, 3510–3511. (f) Wasa, M.; Engle, K. M.; Yu, J.-Q.
J. Am. Chem. Soc. 2009, 131, 9886–9887. (g) Niwa, T.; Yorimitsu, H.;
Oshima, K. Angew. Chem., Int. Ed. 2007, 46, 2634–2645. (h) Shang, R.;
Yang, Z.-W.; Wang, Y.; Zhang, S.-L.; Liu, L. J. Am. Chem. Soc. 2010,
132, 14391–14393.
(9) Fairlamb, I. J. S.; Kapdi, A. R.; Lee, A. F. Org. Lett. 2004, 6, 4435–
4438.
(10) Typical procedure: A 25 mL RBF or a carousel tube was charged
with the methyl heterocycle (1.00 mmol), caesium carbonate (650 mg, 2.00
mmol), Pd(3,5,3′,5′-OMe-dba)2 (20 mg, 0.025 mmol), and Xantphos (15
mg, 0.025 mmol). 1,4-Dioxane (8 mL) was then added, followed by the
aryl bromide, iodide or triflate (1.00 mmol), and a stirrer bar. A reflux
condenser was fitted; the atmosphere was replaced with nitrogen; and
the reaction was heated to 100 °C (reflux) and left overnight. After 16
h, the reaction was allowed to cool and then filtered, washing with EtOAc.
The filtrate was then concentrated under reduced pressure onto silica, then
purified by chromatography.
(4) (a) Campeau, L.-C.; Schipper, D. J.; Fagnou, K. J. Am. Chem. Soc.
2008, 130, 3266–3267. (b) Schipper, D. J.; Campeau, L.-C.; Fagnou, K.
Tetrahedron 2009, 65, 3155–3164.
(5) Mousseau, J. J.; Larive´e, A.; Charette, A. B. Org. Lett. 2008, 10,
1641–1643.
(6) At least 2 equiv of base was necessary for the reaction to go to
completion. For a discussion on the role of base in the palladium-catalyzed
arylation of carbanions, see: Mitin, A. V.; Kashin, A. N.; Beletskaya, I. P.
J. Organomet. Chem. 2004, 689, 1085–1090.
(11) Prepared by the piperidine-catalyzed Friedlander condensation of
2-aminonicotinaldehyde with acetone: Hawes, E. M.; Wibberley, D. G.
J. Chem. Soc. (C) 1966, 315–321.
(12) Selected examples of R-arylation of carbonyls: (a) Kawatsura, M.;
Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473–1478. (b) Fox, J. M.;
Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360–
1370. (c) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234–
245. (d) For a review, see: Johansson, C. C. C.; Colacol, T. J. Angew. Chem.,
Int. Ed. 2010, 49, 676–707.
(7) Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J. Organometallics 1995, 14,
3081–3089.
(8) Arylation of aryl(azaaryl)methanes: Niwa, T.; Yorimitsu, H.; Oshima,
K. Org. Lett. 2007, 9, 2373–2375.
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Table 2. Pd-Catalyzed sp3 C-H Arylation of
Table 3. Pd-Catalyzed sp3 C-H Arylation of Electron-Deficient
2-Methyl-[1,8]-naphthyridine: Scope of ArXa
Heterocyclesa
a All reactions performed on a 1.0 mmol scale in 8 mL of solvent. b 5
mol % of Pd(dba-3,5,3′,5′-OMe)2 and Xantphos used.
a All reactions performed on a 1.0 mmol scale in 8 mL of solvent.
b Isolated yield of product after chromatography.
to the success of the reaction, with the successful arylation
of 6-cyanoquinaldine and 4-methylpyrimidine further il-
lustrating this point (entries 10 and 12).14,15
In conclusion, we have developed a new direct arylation
procedure for benzylic sp3C-H’s adjacent to electron-
deficient heteroaromatics, with the mild conditions allowing
for a wide functional group tolerance. The application of
this methodology to the discovery of novel agrochemicals
is ongoing within our laboratories.
With a broad scope of electrophiles established, we were
particularly interested in extending the direct arylation to
other methyl heteroaromatics (Table 3). Ester, trifluorometh-
yl, and chloride substituents on the 1,8-naphthyridine core
had no detrimental effect on the arylation (entries 1-3).
Isomeric 1,6- and 1,7-naphthyridines (entries 3 and 6) and
the addition of core nitrogens in the form of pyridopyrim-
idines and pyridopyrazines (entries 4 and 5) were also
coupled successfully. Unsubstituted 2-methylpyridine failed
to give any of the desired product (entry 7), but the
introduction of an electron-withdrawing group to the 5-posi-
tion allowed the reaction to proceed well (entries 8 and 9).13
These results suggest the acidity of the methyl C-H is crucial
Acknowledgment. We thank John Popplestone and Cliff
Kanhoye (Syngenta) for mass spectrometry assistance.
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL102276E
(13) However, no reaction occurred for 2-methyl pyridines with electron-
withdrawing groups (e.g., esters) in the 3-position. Potentially, the 3-sub-
stituent would in this case be twisted out of conjugation with the pyridine
ring due to steric factors, thereby limiting its ability to acidify the methyl
C-H bonds.
(14) For the sp3 bisarylation of 4-methylpyrimidine, see: Inoh, J.-I.;
Satoh, T.; Pivsa-Art, S.; Miura, M.; Nomura, M. Tetrahedron Lett. 1998,
39, 4673–4676
.
(15) On the other hand, 2-methylpyrimidine derivatives gave no reac-
tion.
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