Heteroarylation of azine N-oxides

Article abstract of DOI:10.1021/ol203388j

Azine N-oxides undergo highly regioselective metalation with TMPZnCl·LiCl under mild conditions. A palladium-catalyzed Negishi cross-coupling reaction of the resulting organozinc species with heteroaromatic bromides provides heterobiaryls specifically oxidized at one nitrogen position in up to 95% yield.

Full text of DOI:10.1021/ol203388j

ORGANIC
LETTERS
2012
Vol. 14, No. 3
862–865
Heteroarylation of Azine N-Oxides
Francis Gosselin,*,† Scott J. Savage,† Nicole Blaquiere,‡ and Steven T. Staben‡
Small Molecule Process Chemistry and Discovery Chemistry, Genentech Inc., 1 DNA
Way, South San Francisco, California 94080, United States
gosselin.francis@gene.com
Received December 19, 2011
ABSTRACT
Azine N-oxides undergo highly regioselective metalation with TMPZnCl LiCl under mild conditions. A palladium-catalyzed Negishi cross-
3
coupling reaction of the resulting organozinc species with heteroaromatic bromides provides heterobiaryls specifically oxidized at one nitrogen
position in up to 95% yield.
Heterobiaryls containingazinesareimportantstructural
components of pharmaceutically relevant small-molecules
and catalysts.1,2 Inthe context ofa researchprogramin our
laboratories, we required access to a number of hetero-
biaryl motifs where one of the azine nitrogens was specifi-
cally oxidized (Figure 1). The lack of stability of 2-pyridyl
organometallics combined with the requirement for a
challenging late-stage site-selective nitrogen oxidation pro-
mpted us to examine the metalation/heteroarylation of
azine N-oxides. This approach would provide a stable or-
ganometallic species and would enable complete control
over the site of nitrogen oxidation. The regioselective
arylation ofazineshasbeen achievedthrough Pd-catalyzed
direct arylation of the corresponding N-oxides and
N-iminopyridinium-ylides.3 Although attractive, direct
arylation methods based on azine N-oxides have been re-
ported to provide unsatisfactory yields of coupling products
with heteroaryl halides.3a Furthermore, reactions performed
on substituted azine N-oxides can result in diminished yields of
desired arylation products.3b,4 Alternative approaches invol-
ving halogen-metal exchange of 2-bromo-pyridine N-oxides
under cryogenic conditions followed by Pd-catalyzed cross-
coupling have also been reported.5ꢀ8 Inspired by the recent
work of Knochel and co-workers, we envisioned that tetra-
methylpiperidinylzinc chloride lithium chloride (TMPZnCl
3
LiCl, TMP = 2,2,6,6-tetramethylpiperidide) could perform
selective metalation of azine N-oxides under mild condi-
tions.9ꢀ11 We report herein the regioselective metalation/
heteroarylation of both simple and highly substituted azine
(4) Direct arylation of pyridine N-oxides with bromopyridines pro-
ceeds in modest yields, see: Duric, S.; Tzschucke, C. C. Org. Lett. 2011,
13, 2310–2313.
(5) Duan, X.-F.; Ma, Z.-Q.; Zhang, F.; Zhang, Z.-B. J. Org. Chem.
2009, 74, 939–942.
(6) Lack of selectivity in lithiation of substituted azine N-oxides has
been noted, see: (a) Garcıa-Flores, F.; Flores-Michel, L. S.; Juaristi, E.
´
† Small Molecule Process Chemistry.
‡ Discovery Chemistry.
(1) Capdeville, R.; Buchdunger, E.; Zimmermann, J.; Matter, A.
Tetrahedron Lett. 2006, 47, 8235–8238. (b) Abramovitch, R. A.; Smith,
E. M.; Knaus, E. E.; Saha, M. J. Org. Chem. 1972, 37, 1690–1696.
(7) For an alternative approach involving ring-opening organome-
tallic addition on pyridine N-oxides followed by ring-closure, see:
Andersson, H.; Almqvist, F.; Olsson, R. Org. Lett. 2007, 9, 1335–1337.
(8) For addition of organomagnesium reagents to nitropyridine
N-oxides, see: Zhang, F.; Duan, X.-F. Org. Lett. 2011, 13, 6102–6105.
(9) For metalation of pyridine N-oxide using Zn(TMP)2 see: (a)
Hlavinka, M. L.; Hagadorn, J. R. Organometallics 2007, 26, 4105–
4108. Cross-coupling of the resulting diarylzinc species with PhBr was
reported, albeit without isolated yield. For metalation with LiTMP
under cryogenic conditions, see: (b) Denmark, S. E.; Fan, Y. Tetrahe-
dron: Asymmetry 2006, 17, 687–707.
Nature 2002, 1, 493–502.
(2) Malkov, A. V.; Dufkova, L.; Farrugia, L.; Kocovsky, P. Angew.
ꢀ
Chem., Int. Ed. 2003, 42, 3674–3677.
(3) For direct arylation of azine N-oxides, see: (a) Campeau, L.-C.;
Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005, 127, 18020–18021.
(b) Campeau, L.-C.; Stuart, D. R.; Leclerc, J.-P.; Bertrand-Laperle, M.;
Villemure, E.; Sun, H.-Y.; Lasserre, S.; Guimond, N.; Lecavallier, M.;
Fagnou, K. J. Am. Chem. Soc. 2009, 131, 3291–3306. (c) Campeau
L.-C.; Schipper, D. J.; Fagnou, K. J. Am. Chem. Soc. 2008, 130
3266–3267. (d) Schipper, D. J.; Campeau, L.-C.; Fagnou, K. Tetrahe-
dron 2009, 65, 3155–3164. For direct arylation of N-iminopyridinium
(10) (a) Mosrin, M.; Knochel, P. Org. Lett. 2009, 11, 1837–1840. (b)
Bresser, T.; Mosrin, M.; Monzon, G.; Knochel, P. J. Org. Chem. 2010,
75, 4686–4695. (c) Bresser, T.; Monzon, G.; Mosrin, M.; Knochel, P.
Org. Process Res. Dev. 2010, 14, 1299–1303.
ꢀ
ylides, see: (e) Larivee, A.; Mousseau, J. J.; Charette, A. B. J. Am. Chem.
Soc. 2008, 130, 52–54. Reviewed in: (f) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. Rev. 2007, 107, 174–238.
r
10.1021/ol203388j
Published on Web 01/19/2012
2012 American Chemical Society

Table 2. Cross-coupling of Pyridine N-Oxidesa
Figure 1. Target heterobiaryl motifs.
Table 1. Regioselective Metalation of Azine N-Oxidesa
a Conditions: TMPZnCl LiCl (100 mol %), THF, rt then quench
with 35 wt % DCl in D2O.
3
Scheme 1. Metalation/Negishi Cross-coupling
N-oxides that affords heterobiaryl motifs under mild condi-
tions with complete control over the site of nitrogen oxidation.
Metalation of representative azine N-oxides 1a and 1b using
commercially available TMPZnCl LiCl (100ꢀ150 mol %)
3
proceeded cleanly at rt. The resulting organozinc species
1
were quenched with deuterium chloride in D2O and H
NMR analysis of the crude products indicated the forma-
tion of deuterio-1a/1b with >95:5 selectivity for the aro-
matic CꢀH vs benzylic CꢀH (Table 1).12 Even upon ex-
a Conditions: (a) Azine N-oxide (150 mol %), TMPZnCl LiCl
(150 mol %, heteroaryl bromide (100 mol %), 3.5 mol % PdCl2(dppf)
CH2Cl2, THF, rt to 60 °C, 18 h. (b) Isolatedyields. (c) The corresponding
2,6-diarylation product 10b was also isolated in 15% yield (see Support-
ing Information).
tended contact (18ꢀ24 h) with excess TMPZnCl LiCl, we
3
3
found no detectable metalation at the benzylic position in
deuterio-1a.
A Negishi cross-coupling reaction of the organozinc
species proceeded smoothly under mild conditions with
PdCl2(dppf)13 as catalyst in THF at 60 °C (Scheme 1,
3
Tables 2ꢀ5).14 The compatibility of TMPZnCl LiCl with
3
the reaction components is remarkable since we found no
(11) Metalations using hindered metal amide bases are reviewed in:
Haag, B; Mosrin, M.; Hiriyakkanavar Ila, H.; Malakhov, V.; Knochel,
P. Angew. Chem., Int. Ed. 2011, 50, 9794–9825.
(12) In our hands, iodination (0.5 M I2 in THF) of the resulting
organozincspecies led to erratic results as ascertained by HPLC analysis.
(13) dppf = 1,10-bis(diphenylphosphino)ferrocene.
(14) (a) Negishi, E.-i. Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley: New York, 1998; chap. 1. (b)
Negishi, E.-i.; Valente, L. F.; Kobayashi, M. J. Am. Chem. Soc. 1980, 102,
3298–3299. (c) Negishi, E.-i. Acc. Chem. Res. 1982, 15, 340–348.
Org. Lett., Vol. 14, No. 3, 2012
863

Table 3. Cross-coupling of Picoline N-Oxidesa
Table 4. Cross-coupling of Quinoline N-Oxidesa
a Conditions: (a) Azine N-oxide (150 mol %), TMPZnCl LiCl (150
mol %), heteroaryl bromide (100 mol %), 3.5 mol % PdCl2(dppf)
3
3
CH2Cl2, THF, rt to 60 °C, 18 h. (b) Isolated yields. (c) Pd(dba)2 (5 mol %)/
Cy3P (10 mol %) as catalyst.
Table 5. Cross-coupling of Diazine N-Oxidesa
a Conditions: (a) Azine N-oxide (150 mol %), TMPZnCl LiCl
(150 mol %), heteroaryl bromide (100 mol %), 3.5 mol % PdCl2(dppf)
3
3
CH2Cl2, THF, rt to 60 °C, 18 h. (b) Isolated yields.
requirement for a separate metalation step prior to the
cross-coupling.15
Reactions of 3-fluoropyridine N-oxide 1c with 2-
bromopyridines and 2-bromopyrimidine gave the cross-
coupling products 2ꢀ4 in 59ꢀ83% isolated yield (Table 2,
entries 1ꢀ3). In comparison, cross-coupling reactions with
methyl nicotinate N-oxide 1d and 4-cyanopyridine N-oxide
1e proved more challenging and afforded products 5ꢀ9 in
moderate yields ranging from 30 to 53%. Cross-coupling of
pyridine N-oxide 1f with 2-bromoquinoline afforded the
desired heteroarylation product 10a in 70% yield along with
the corresponding 2,6-diarylation byproduct 10b in 15%
yield. We found that purification of these products was
a Conditions: (a) Azine N-oxide (150 mol %), TMPZnCl LiCl (150
mol %), heteroaryl bromide (100 mol %), 3.5 mol % PdCl2(dppf)
3
3
CH2Cl2, THF, rt to 60 °C, 18 h. (b) Isolated yields. (c) TMPZnCl LiCl
3
(110 mol %), THF:NMP (1:1). (d) Azine N-oxide (300 mol %)
was used.
challenging because of their highly polar nature. In addition,
competing diarylation often led to reduced yields of desired
products for simple pyridine N-oxides.
(15) Both TMPZnCl LiCl and (TMP)2Zn LiCl metalated azine N-
3
3
oxides but in our hands the subsequent Negishi cross-coupling was more
sluggish with the diarylzinc species.
864
Org. Lett., Vol. 14, No. 3, 2012

Next we investigated the metalation and cross-coupling
of picoline N-oxides 1g, 1a and 1h under the same reaction
conditions (Table 3). Consistent with our deuteration
experiments, we observed that metalation and arylation
of the 2-methyl group of picolines was not a competing
pathway under the reaction conditions.16 2-Picoline N-
oxide 1g underwent cross-coupling to furnish 11 in 88%
yield. It is also noteworthy that, in contrast toPd-catalyzed
direct arylation, the present Negishi cross-coupling of
highly substituted picoline N-oxides 1a and 1h proceeded
in consistently high yields to afford highly functionalized
heterobiaryls 12ꢀ17 in 81ꢀ95% yields.
We also found that diazine N-oxides performed well in
the reaction (Table 5). Pyridazine N-oxide 1j underwent
reaction with 2-bromoquinoline to give 21 in 77% yield.
Cross-couplingwith4-bromopyrrolo-[1,2-f][1,2,4]-triazine
gave 22 in 66% yield. Similarly, pyrazine N-oxide 1k and
quinoxaline N-oxide 1l afforded the desired heterobiaryl
products 23ꢀ25 in 78ꢀ84% yield.17,18
Scheme 2. Multi-gram Scale Reaction
Cross-coupling of quinoline N-oxide 1b with both 2- and
3-bromopyridine gave the desired heterobiaryls 18ꢀ19 in 74
and 73% yield, respectively (Table 4, entries 1ꢀ2). Methoxy-
quinoline N-oxide 1i afforded heterobiaryl 20 in 49% yield.
(16) Although it has been reported that picolines are metalated
smoothly with TMPZnCl LiCl at rt, the N-oxide group in the present
3
system appears to direct the deprotonation at the aromatic CꢀH
selectively. For metalation and benzylic cross-coupling of picolines
under similar conditions, see: Duez, S.; Steib, A. K.; Manolikakes,
S. M.; Knochel, P. Angew. Chem., Int. Ed. 2011, 50, 7686–7690.
(17) At the present time cross-coupling with 5-membered hetero-
cycles represents a limitation to this method. Cross-coupling of N-oxide
1h with 4-bromothiazole and 2-bromothiophene gave the corresponding
products in 30ꢀ35% yields (see Supporting Information).
Finally, as demonstrated in Scheme 2, this process is
preparatively useful as the desired cross-coupling product
17 was isolated in 93% yield on multigram scale.19
In summary, we have developed a mild and practical
protocol for the heteroarylation of azine N-oxides via a Pd-
catalyzed Negishi cross-coupling using in situ generated
organozinc intermediates. This approach also unambigu-
ously positions the N-oxide group as a handle for further
functionalization.20 Further studies are underway and will
be reported in due course.
(18) In contrast, pyrimidine N-oxide failed to provide any desired
products and apparent ring-opening byproduct were observed under the
reaction conditions.
(19) Multigram scale procedure: To a solution of 2-methyl-3-me-
thoxy-4-chloropyridine N-oxide 1h (5.21 g, 30 mmol, 150 mol %) and
2-bromo-6-methoxypyridine (2.46 mL, 3.76 g, 20 mmol) in THF (52 mL,
10 mL/g) was added TMPZnCl LiCl (43 mL, 30 mmol, 150 mol %, 0.69
3
M in THF) over 2 min. The internal temperature increased from 23.4 to
30.0 °C during the addition. A thin slurry formed after 1ꢀ2 min. The
slurry was sparged with N2 bubbles for 5 min and solid dichloro-1,10-[bis-
Acknowledgment. We thank Dr. Alan Deese for help
with NMR analysis, Dr. Christine Gu for HRMS anal-
ysis, and Dr. Sushant Malhotra and Dr. Chong Han
(Genentech) for helpful discussions and careful review of
the manuscript.
(diphenylphosphino)ferrocene]palladium CH2Cl2 (219 mg, 0.3 mmol,
3
1 mol %) was added. The resulting tan-orange slurry was then heated
at60°C(internal temperature) for 18 h. LC-MS analysis showedcomplete
conversion to 16. The deep red reaction mixture was cooled to rt and
quenched with saturated aqueous NH4Cl (100 mL) and diluted with 50%
aqueous acetonitrile (50 mL). The solution was extracted with dichlor-
omethane (2 ꢁ 100 mL), dried with Na2SO4 and concentrated. The
residue was chromatographed (0ꢀ100% EtOAc in hexanes) and the
combined fractions were concentrated to afford the desired product
4-chloro-3-methoxy-6-(6-methoxypyridin-2-yl)-2-methylpyridine1-oxide
17 as a free-flowing white solid (5.32 g, 93% yield): mp = 117ꢀ118 °C; 1H
NMR (CDCl3) δ 8.68 (d, 1H, J = 7.5 Hz), 8.22 (s, 1H), 7.68 (app t, 1H,
J = 8.0 Hz), 6.79 (d, 1H, J = 8.0 Hz), 3.98 (s, 3H), 3.90 (s, 3H), 2.56 (s, 3H);
13C NMR (CDCl3) δ 163.3, 151.5, 147.3, 145.7, 144.5, 139.3, 125.9, 124.6,
118.6, 112.4, 61.4, 53.5, 12.5; HRMS calcd for C13H14ClN2O3 [M þ H] =
281.0687, found 281.0695.
Supporting Information Available. Experimental pro-
cedures and characterization of compounds 2ꢀ27. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(20) Recent examples of nucleophilic addition to pyridine N-oxides
include: (a) Londregan, A. T.; Jennings, S.; Wei, L. Org. Lett. 2011, 13,
1840–1843. (b) Yin, J.; Xiang, B.; Huffman, M. A.; Raab, C. E.; Davies,
I. W. J. Org. Chem. 2007, 72, 4554–4557.
Org. Lett., Vol. 14, No. 3, 2012
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