Intermolecular palladium-catalyzed coupling of 2-halopyridines and alcohols for the preparation of pyridine ether PPAR agonists

Article abstract of DOI:10.1016/j.tetlet.2006.05.133

A series of pyridine ether PPAR agonists were synthesized through intermolecular palladium-catalyzed coupling of 2-halopyridines and alcohols. This method proved to be versatile, efficient, and amenable to parallel synthesis.

Full text of DOI:10.1016/j.tetlet.2006.05.133

Tetrahedron Letters 47 (2006) 5333–5336
Intermolecular palladium-catalyzed coupling of 2-halopyridines
and alcohols for the preparation of pyridine ether PPAR agonists
Paul S. Humphries,* Simon Bailey,* Quyen-Quyen T. Do, Jack H. Kellum,
Guy A. McClellan and David M. Wilhite
Pfizer Global R&D, Department of Medicinal Chemistry, 10614 Science Center Drive, San Diego, CA 92121, USA
Received 2 May 2006; revised 17 May 2006; accepted 18 May 2006
Available online 12 June 2006
Abstract—A series of pyridine ether PPAR agonists were synthesized through intermolecular palladium-catalyzed coupling of
2-halopyridines and alcohols. This method proved to be versatile, efficient, and amenable to parallel synthesis.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Peroxisome proliferator-activated receptors (PPARs)
are pharmaceutical targets of great importance. Their
wide-ranging effects on key transcriptional pathways
for lipid handling, insulin sensitivity, inflammation,
and other functions have led to marketed drugs and vast
clinical and preclinical research efforts.1–4
In 1991, a series of PPAR analogues were disclosed,
which for the first time did not contain a thiazolidine-
2,4-dione pharmacophore.5 These were propanoic acid
derivatives with a substituent placed in the a-position
such that the whole group could mimic the thiazol-
idine-2,4-dione ring. Based on the above and a knowl-
Figure 1. Thiazolidine-2,4-dione mimic and chosen lead scaffold.
mary alcohols.8,9 Prior to this work, successful
edge of PPAR ligands publicly disclosed, we wished to
synthesize compounds represented by the general struc-
ture 1 (Fig. 1). We envisaged the pyridyl ether moiety of
1 to be efficiently formed via intermolecular palladium-
catalyzed coupling of the requisite 2-halopyridines and
alkyl alcohols.
intermolecular palladium-catalyzed C–O bond forming
processes were limited to the reactions of activated aryl
halides and alcohols lacking b-hydrogens.10 This new
general procedure minimizes b-hydride elimination from
A, thus allowing the productive reductive elimination
step to occur at a faster rate (Scheme 1).11 This is made
possible by the use of bulky phosphine ligand 2, which
balances the subtle interplay of both sterics and elec-
tronics, allowing for successful C–O bond formation.
Aromatic ethers are structural motifs in many naturally
occurring and medicinal compounds.6 Although there
are numerous methods for their synthesis,7 a mild and
general method remained elusive for a considerable per-
iod of time. Recently, the Buchwald group developed an
efficient catalyst for the palladium-catalyzed intermole-
cular coupling of aryl bromides and chlorides and pri-
In the original publication, only one example of the use
of a 2-halopyridine was described. We felt that this effi-
cient and practically simple protocol had utility as a ver-
satile method. Our first attempt at this reaction involved
the coupling of 2-chloropyridine 3 and alcohol 4 to
afford pyridyl ether 5 in good yield (Scheme 2).12
Keywords: PPAR; Halopyridine; Buchwald; Pyridine ether; Palladium.
With the above result in hand, we then pursued a variety
of targets by performing the intermolecular palladium-
catalyzed coupling of bromopyridine 6 and a variety
*
Corresponding authors. Tel.: +1 858 622 7956; fax: +1 858 526 4438
(P.S.H.); tel.: +1 858 526 4692; fax: +1 858 526 4315 (S.B.); e-mail
addresses: paul.humphries@pfizer.com; simon.bailey@pfizer.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.133

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P. S. Humphries et al. / Tetrahedron Letters 47 (2006) 5333–5336
Scheme 1. Mechanism of intermolecular palladium-catalyzed synthesis of aryl ethers.
of primary alcohols (Table 1).13,14 In general, a variety
of diverse alcohols afforded the expected products in
excellent yield. As expected, alcohols containing oxa-
zoles, thiazoles, and pyridines are tolerated in this chem-
istry. In a limited number of cases, functionality (e.g.,
basic amines, pyrazoles, benzimidazoles, indoles) caused
palladium sequestration and no reaction occurred (data
not shown).
We then shifted our attention to variation of halopyr-
idine, whilst holding constant the 2-(5-methyl-2-
phenyl-1,3-oxazol-4-yl)ethanol reactant 19 (Table 2).
Scheme 2. Reagents and conditions: (a) Pd(OAc)2 (cat.), racemic-2-
(di-tert-butylphosphino)-1,10-binaphthyl
2 (cat.), Cs2CO3, PhMe,
reflux, 16 h, 58%.
Table 1. Intermolecular palladium-catalyzed coupling of bromopyridine 6 and a variety of primary alcoholsa
Entry
1
Alcohol
Product
Yield (%) Entry
Alcohol
Product
Yield (%)
69
O
N
O
N
7
85
7
13
OH
OH
O
N
N
N
OH
2
8
79
8
14
90
OH
O
O
N
S
N
Cl
3
4
9
56
67
9
15
16
68
59
OH
OH
O
O
N
F3C
10
10
N
OH
OH

P. S. Humphries et al. / Tetrahedron Letters 47 (2006) 5333–5336
5335
Table 1 (continued)
Entry
Alcohol
Product
Yield (%) Entry
Alcohol
Product
Yield (%)
PhO
N
N
5
11
79
11
17
64
OH
OH
Et
F3CO
6
12
100
12
18
67
N
OH
OH
a Reactions were run using 0.5 mmol halopyridine, 1.0 mmol alcohol, 1.5 mmol cesium carbonate, 8 mol % Pd(OAc)2, 10 mol % racemic-2-(di-tert-
butylphosphino)-1,10-binaphthyl 2 and 5 mL toluene.
Table 2. Intermolecular palladium-catalyzed coupling of alcohol 19 and a variety of halopyridinesa
Entry
1
Halopyridine
CO2Et
Product
Yield (%)
93
Entry
3
Halopyridine
Product
Yield (%)
74
CO2Me
OMe
20
22
Cl
N
Br
Br
N
N
CO2Et
O
CO2Et
2
21
72
4
23
70
O
Br
N
a Reactions were run using 0.5 mmol halopyridine, 1.0 mmol alcohol, 1.5 mmol cesium carbonate, 8 mol % Pd(OAc)2, 10 mol % racemic-2-(di-tert-
butylphosphino)-1,10-binaphthyl 2 and 5 mL toluene.
Switching from 2-bromopyridines to 2-chloropyridines
had no effect on isolated yields. Similarly, variation of
the 5-substituent of the pyridine ring resulted in equally
high yields.
24) could be obtained in a matter of minutes.15 The sig-
nificant reduction in reaction time resulted in a produc-
tivity enhancement due to increased sample processing.
In summary, we have expanded the scope of the inter-
molecular palladium-catalyzed synthesis of aryl ethers.
Utilization of this method resulted in a rapid, conve-
nient, and high-yielding two step protocol for the prep-
aration of PPAR agonists. In particular, the
intermolecular palladium-catalyzed coupling of 2-halo-
pyridines and alcohols proved to be versatile, efficient,
and amenable to parallel synthesis. A full account of
the medicinal chemistry of these compounds will be
given elsewhere.
Having efficiently synthesized a diverse set of interme-
diate esters, we then sought an expedient method for
obtaining the final carboxylic acids. We opted for a
microwave-assisted procedure for this basic hydrolysis
step. As shown in Scheme 3, the carboxylic acids (e.g.,
Acknowledgments
The authors would like to thank John Tatlock for stim-
ulating discussions and feedback on this manuscript.
References and notes
1. For recent reviews, see: (a) Ram, V. J. Drugs Today 2003,
39, 609; (b) Sternbach, D. D. Ann. Rep. Med. Chem. 2003,
38, 71; (c) Miller, A. R.; Etgen, G. J. Expert Opin. Invest.
Scheme 3. Reagents and conditions: (a) 1 N aq NaOH, MeCN,
100 ꢁC, lW, 10 min, 92%.

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P. S. Humphries et al. / Tetrahedron Letters 47 (2006) 5333–5336
Drugs 2003, 12, 1489; (d) Willson, T. M.; Brown, P. J.;
Sternbach, D. D.; Henke, B. R. J. Med. Chem. 2000, 43,
527.
(di-tert-butylphosphino)-1,10-binaphthyl 2 (10 mol %) and
cesium carbonate (3 equiv). The flask was then evacuated
and back-filled with nitrogen and fitted with a rubber
septum. Anhydrous toluene (2.5 mL) followed by halo-
2. For PPARa, see: (a) van Raalte, D. H.; Li, M.; Pritchard,
P. H.; Wasan, K. M. Pharm. Res. 2004, 21, 1531; (b)
Miyachi, H. Expert Opin. Ther. Pat. 2004, 14, 607.
3. For PPARc, see: (a) Henke, B. R. Prog. Med. Chem. 2004,
42, 1; (b) Fajas, L.; Auwerx, J. Handbook of Obesity, 2nd
ed.; Marcel Dekker: New York, 2004; p 559; (c) Evans, R.
M.; Barish, G. D.; Wang, Y.-X. Nat. Med. 2004, 10, 355;
(d) Pershadsingh, H. A. Expert Opin. Invest. Drugs 2004,
13, 215.
4. For PPARd, see: Tan, N. S.; Michalik, L.; Desvergne, B.;
Wahli, W. Expert Opin. Ther. Targets 2004, 8, 39.
5. Hulin, B. WO 91/19702 A1, 1991; Chem. Abstr. 1991, 117,
26552.
pyridine
6 (0.144 g, 0.5 mmol), alcohol 4 (0.203 g,
1.0 mmol) and additional anhydrous toluene (2.5 mL)
was added via a syringe. The flask was then sealed under
nitrogen and placed in a pre-heated oil bath to allow the
solution to reflux for 16 h. The reaction mixture was
cooled to ambient temperature, diluted with diethyl ether
(2 mL), and filtered through a pad of Celite, washing with
additional diethyl ether (10 mL). The filtrate was then
concentrated in vacuo and purified (Biotage Sp4) by silica
gel chromatography (hexanes to ethyl acetate over 10
column volumes) to afford ester 7 as a pale yellow oil
1
(0.174 g, 85%). H NMR (300 MHz, CDCl3) d 7.97–7.95
6. Czarnik, A. W. Acc. Chem. Res. 1996, 29, 112.
7. (a) Lindley, J. Tetrahedron 1984, 40, 1433; (b) Keegstra,
M. A.; Peters, T. H. A.; Brandsma, L. Tetrahedron 1992,
48, 3633; (c) Capdevielle, P.; Maumy, M. Tetrahedron
Lett. 1993, 34, 1007; (d) Lee, S.; Frescas, S. P.; Nichols, D.
E. Synth. Commun. 1995, 25, 2775; (e) Fagan, P. J.;
Hauptman, E.; Shapiro, R.; Casalnuovo, A. J. Am. Chem.
Soc. 2000, 122, 5043.
8. Torraca, K. E.; Huang, X.; Parrish, C. A.; Buchwald, S. L.
J. Am. Chem. Soc. 2001, 123, 10770.
9. For an excellent review, see: Littke, A. F.; Fu, G. C.
Angew. Chem., Int. Ed. 2002, 41, 4176.
10. (a) Palucki, M.; Wolfe, J. P.; Buchwald, S. L. J. Am.
Chem. Soc. 1996, 118, 10333; (b) Mann, G.; Hartwig, J. F.
J. Am. Chem. Soc. 1996, 118, 13109; (c) Watanabe, M.;
Nishiyama, M.; Koie, Y. Tetrahedron Lett. 1999, 40, 8837;
(d) Shelby, Q.; Kataoka, N.; Mann, G.; Hartwig, J. F. J.
Am. Chem. Soc. 2000, 122, 10718; (e) Torraca, K. E.;
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12907; (f) Parrish, C. A.; Buchwald, S. L. J. Org. Chem.
2001, 66, 2498.
11. Han, R. Y.; Hillhouse, G. L. J. Am. Chem. Soc. 1997, 119,
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12. All new compounds were characterized by full spectro-
scopic data, yields refer to chromatographed material with
purity >95%.
(m, 1H), 7.92 (d, J = 2.1 Hz, 2H), 7.43–7.39 (m, 4H), 6.63
(d, J = 8.5 Hz, 1H), 4.52 (t, J = 6.8 Hz, 2H), 3.70 (s, 3H),
3.32–3.28 (m, 3H), 2.96–2.90 (m, 4H), 2.33 (s, 3H), 1.33 (s,
3H). ESIMS (m/z): 411 (M+H).
14. A modified microwave-assisted intermolecular palladium-
catalyzed procedure was never attempted during these
investigations.
15. General procedure for the microwave-assisted hydrolysis
reaction. A Smith Process Vial (2–5 mL) was charged,
under nitrogen, with a stir bar, methyl ester 7 (0.174 g,
0.42 mmol), 1 N aq sodium hydroxide (1.26 mL,
1.26 mmol), and acetonitrile (2 mL). The reaction vessel
was sealed and heated at 100 ꢁC for 10 min (fixed hold
time) in a Biotage Emrys Creator. After cooling, the vessel
was uncapped and the reaction mixture acidified to pH 5–7
with 1 N aq hydrochloric acid. The resulting mixture was
extracted with ethyl acetate (3 · 15 mL) and the combined
organic extracts were dried (anhydrous magnesium sul-
fate), filtered, and concentrated in vacuo. Purification
(Biotage Sp4) by silica gel chromatography (ethyl acetate
to 50% methanol/ethyl acetate over 10 column volumes)
1
afforded acid 24 as a white solid (0.153 g, 92%). H NMR
(300 MHz, DMSO-d6) d 7.93–7.89 (m, 3H), 7.52–7.46 (m,
4H), 7.42–7.38 (m, 3H), 6.69 (d, J = 8.5 Hz, 1H), 4.44 (t,
J = 6.7 Hz, 2H), 3.45–3.43 (m, 2H), 3.18 (s, 3H), 2.91–2.87
(m, 2H), 2.31 (s, 3H), 1.19 (s, 3H). ESIMS (m/z): 395
(MꢀH). Anal. Calcd for C22H24N2O5: C, 66.65; H, 6.10;
N, 7.07. Found: C22H24N2O5.0.06H2O: C, 66.16; H, 6.15;
N, 6.96.
13. General procedure for the intermolecular palladium-cat-
alyzed synthesis of pyridyl ethers. An oven-dried flask was
charged with palladium(II) acetate (8 mol %), racemic-2-