Regioselective synthesis of 3-(2-hydroxyaryl)pyridines via arynes and pyridine N-oxides

Article abstract of DOI:10.1021/jo060523a

A variety of substituted 3-(2-hydroxyphenyl)pyridines have been prepared regioselectively by a transition-metal-free, mild, one-step route, which involves the reaction of pyridine N-oxides with silylaryl triflates in the presence of CsF in acetonitrile at

Full text of DOI:10.1021/jo060523a

TABLE 1. Optimization of the Synthesis of
3-(2-Hydroxyphenyl)Pyridine (3a) (Eq 1)a
Regioselective Synthesis of
3-(2-Hydroxyaryl)pyridines via Arynes and
Pyridine N-Oxides
Cristiano Raminelli, Zhijian Liu, and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity,
2a
(equiv)
base
(equiv)
temp
(°C)
% isolated
yield
Ames, Iowa 50011
entry
solvent
1
2
3
4
5
6
1.5
1.5
2
2
2
CsF (3)
CsF (3)
CsF (3)
CsF (4)
MeCN
MeCN
MeCN
MeCN
MeCN
THF
rt
80
rt
rt
rt
rt
74
65
78
88
0
larock@iastate.edu
ReceiVed March 9, 2006
1.5
Bu4NF (1.8)
64
a Reaction conditions: 0.2 mmol of pyridine N-oxide (1a), the indicated
amount of benzyne precursor 2a, the indicated amount of base, and 3 mL
of solvent were stirred at the temperature shown for 24 h.
ments based on prior literature (see the later mechanistic
discussion). Considering the importance of such pyridine
derivatives, a method to generate only one single isomer,
namely, 3-(2-hydroxyphenyl)pyridines, in high yields in a single
step would be highly desirable.
A variety of substituted 3-(2-hydroxyphenyl)pyridines have
been prepared regioselectively by a transition-metal-free,
mild, one-step route, which involves the reaction of pyridine
N-oxides with silylaryl triflates in the presence of CsF in
acetonitrile at room temperature. These reactions proceed
in good yields through what appears to be a series of
rearrangements.
In view of our recent success using arynes prepared from
o-(trimethylsilyl)aryl triflates and CsF in organic synthesis,6 we
decided to examine their reaction with pyridine N-oxide because
this approach generates benzyne under very mild reaction
conditions.7 Allowing pyridine N-oxide (1a) to react with 2
equiv of o-(trimethylsilyl)phenyl triflate (2a) and 3 equiv of
CsF in MeCN at room temperature, we obtained 3-(2-hydroxy-
phenyl)pyridine (3a) in a 74% yield as a single isomer (Table
1, entry 1). The formation of regioisomers was not observed.
In an attempt to improve the yield, subsequent work focused
on optimization of these reaction conditions (Table 1). When
the transformation was performed at 80 °C, compound 3a was
obtained in a lower yield (65%) (entry 2) because of the
formation of byproducts. No attempts were made to identify
the byproducts. By using 2 equiv of benzyne precursor 2a at
room temperature, we isolated 3a in a slightly better yield of
78% (entry 3). Treatment of pyridine N-oxide (1a) with 2 equiv
of benzyne precursor 2a and 4 equiv of CsF in acetonitrile at
room temperature gave 3-(2-hydroxyphenyl)pyridine (3a) in an
88% yield (entry 4). As can be seen in Table 1, entry 5, the
heterobiaryl 3a was not obtained and the starting materials 1a
and 2a were recovered when the reaction was carried out in
the absence of CsF. This experiment shows that the success of
our reaction depends dramatically on the presence of fluoride.
To explore the effect of the fluoride source on the reaction,
tetrabutylammonium fluoride (TBAF) was added to a mixture
of pyridine N-oxide (1a) and silylaryl triflate 2a in THF at room
temperature. After 24 h, heterobiaryl 3a was obtained in a 64%
isolated yield (entry 6). No further attempts were made to
optimize this TBAF procedure.
Heterocycles are considered a very important class of organic
compounds because of their wide application in medicine,
agriculture, and technology.1 Among nitrogen heterocycles,
alkaloids stand out as biologically active compounds presenting
a broad spectrum of activities.1,2 Accordingly, synthetic methods
for the construction of alkaloids are particularly valuable.
3-Arylpyridines are a particularly interesting class of alka-
loids, which can be prepared via intermolecular radical addition
using pyridine derivatives.3 However, transition-metal-catalyzed
cross-coupling reactions have more commonly been chosen to
prepare such heterobiaryls.4 Some time ago, Abramovitch
reported that benzyne reacts with pyridine N-oxides to afford
mixtures of 3- and 2-(2-hydroxyphenyl)pyridines in low yields.5
Several approaches to the generation of benzyne were explored,
and a mechanism was proposed involving a series of rearrange-
(1) Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R. In Heterocycles
in Life and Society - An Introduction to Heterocyclic Chemsitry and
Biochemistry and the Role of Heterocycles in Science, Technology, Medicine
and Agriculture; John Wiley & Sons: Chichester, England, 1997.
(2) Foye’s Principles of Medicinal Chemistry; Williams, D. A., Lemke,
T. L., Eds.; Lippincott Williams & Wilkins: Baltimore, 2002.
(3) (a) McLoughlin, P. T. F.; Clyne, M. A.; Aldabbagh, F. Tetrahedron
2004, 60, 8065. (b) Nu´n˜es, A.; Sa´nchez, A.; Burgos, C.; Alvarez-Builla, J.
Tetrahedron 2004, 60, 6217. (c) Crich, D.; Patel, M. Heterocycles 2004,
64, 499. (d) Mart´ınez-Barrasa, V.; Viedma, A. G.; Burgos, C.; Alvarez-
Builla, J. Org. Lett. 2000, 2, 3933.
(4) (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang
P. J., Eds.; Willey-VCH: Weinheim, 1998. (b) Metal-Catalyzed Cross-
Coupling Reactions; Meijere, A., Diederich, F., Eds.; Willey-VCH: Wein-
heim, 2004; Vols. 1 and 2. (c) Karig, G.; Spencer, J. A.; Gallagher, T.
Org. Lett. 2001, 3, 835. (d) Stanforth, S. P. Tetrahedron 1998, 54, 263.
(5) Abramovitch, R. A.; Shinkai, I. J. Am. Chem. Soc. 1974, 96, 5265.
(6) (a) Liu, Z.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2005, 127,
15716. (b) Liu, Z.; Larock, R. C. J. Am. Chem. Soc. 2005, 127, 13112. (c)
Zhao, J.; Larock, R. C. Org. Lett. 2005, 7, 4273. (d) Zhang, X.; Larock, R.
C. Org. Lett. 2005, 7, 3973. (e) Liu, Z.; Larock, R. C. Org. Lett. 2004, 6,
3937. (f) Liu, Z.; Larock, R. C. Org. Lett. 2004, 6, 99-102. (g) Liu, Z.;
Larock, R. C. Org. Lett. 2003, 5, 4673.
(7) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211.
10.1021/jo060523a CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/10/2006
J. Org. Chem. 2006, 71, 4689-4691
4689

TABLE 2. Synthesis of 3-(2-Hydroxyphenyl)pyridines by the Reaction of Pyridine N-Oxides and Aryne Precursors in the Presence of CsFa
a Reaction conditions: 0.2 mmol of pyridine N-oxide 1, 0.4 mmol of benzyne precursor 2, 0.8 mmol of CsF, and 3 mL of MeCN were stirred at room
1
temperature for 24 h. b The ratio was determined by H NMR spectroscopy.
Employing the optimal conditions shown in Table 1, entry
4, we examined the scope of this process using various aryne
precursors and aromatic N-oxides (Table 2). The reaction
between pyridine N-oxide (1a) and the electron-rich benzyne
precursor 2b gave the biaryl 3b in an 84% isolated yield (Table
2, entry 1). The same yield was obtained for biaryl 3c, when
the reaction was carried out using the silylaryl triflate 2c bearing
two methoxy groups (entry 2). By performing the reaction
between 1a and the benzyne precursor 2d derived from
5-indanol, we prepared compound 3d in a 90% yield (entry 3).
4690 J. Org. Chem., Vol. 71, No. 12, 2006

SCHEME 1
SCHEME 2
resonance structure B′ (Scheme 2) is unfavorable when the
cyano-substituted amine oxide 1e is employed and compound
3q is formed instead. For this reaction, the hydrogen next to
the nitrogen atom is more acidic, and formation of a 2-substi-
tuted pyridine takes place.
The structures of the biaryls have been assigned on the basis
of a variety of spectroscopic techniques. The structure of
When the electron-poor benzyne precursor 2e was allowed to
react with pyridine N-oxide (1a), compound 3e was isolated in
a 92% yield. The high yields indicate that both electron-rich
and electron-poor arynes can be successfully utilized in this
chemistry.
1
compound 3a was assigned according to its HRMS, IR, H,
and 13C NMR spectra and confirmed afterward by X-ray
analysis. The structures for compounds 3b-p were assigned
by carefully comparing their spectral data with the spectral data
obtained for 3a. The structure of compound 3q was assigned
To better understand the regioselectivity of the reaction when
unsymmetrical arynes are employed, pyridine N-oxide (1a) was
allowed to react with 4-methyl-2-(trimethylsilyl)phenyl triflate
(2f), using our optimized conditions. A mixture of two isomers
3f and 3g was obtained in a 1.4:1 ratio in a total yield of 77%
(Table 2, entry 5). When the reaction was carried out using the
4-methoxy silylaryl triflate 2g, a 1:1 mixture of heterobiaryls
3h and 3i was isolated in a 75% yield (entry 6). For entries 5
and 6, only a slight or no effect of the electron-donating groups
present in the aryne was observed on the ratio of the isomers.
On the other hand, when the reaction between pyridine N-oxide
(1a) and the 4-fluoro aryne precursor 2h was performed, this
electron-withdrawing group produced a 2:1 mixture of isomers
3j and 3k in an 83% yield (entry 7). In this case, the major
product was the heterobiaryl 3j with the fluoro substituent in
the 5-position. When pyridine N-oxide (1a) was subjected to
the reaction with the 3-methoxy aryne precursor 2i, the product
of attack of the oxygen at the less electron-rich position of the
benzyne was formed as the only regioisomer in an 82% isolated
yield (entry 8).
Turning our attention to the effect of substituted N-oxides
on the reaction course, we treated 2-picoline N-oxide (1b) with
benzyne precursor 2a to give a 6.7:1 mixture of two regioiso-
mers 3m and 3n in an overall 81% yield (entry 9). Presumably,
the regioselectivity for this transformation is governed by the
steric bulk of the methyl group present in substrate 1b. When
the coupling between 2,6-lutidine N-oxide (1c) and silylaryl
triflate 2a was performed, the desired product 3o was still
isolated in an excellent 78% yield (entry 10). A moderate yield
of 52% was obtained when 4-picoline N-oxide (1d) was treated
with benzyne precursor 2a. In this case, the electron-donating
effect of the methyl group at the 4-position of the pyridine ring
may have disfavored the sequence of rearrangements necessary
to form the biaryl product (see the later mechanistic discussion).
Interestingly, the treatment of 4-cyanopyridine N-oxide (1e) with
silylaryl triflate 2a gave only the regioisomer 3q in a respectable
42% yield (entry 12).
1
on the basis of HRMS, IR, H, and 13C NMR spectra and
confirmed by X-ray analysis.
In summary, a simple, regioselective coupling reaction
between pyridine N-oxides and arynes has been developed,
which provides hydroxyphenylpyridines in excellent yields.
Through this transition-metal-free process, a carbon-carbon
bond is formed presumably by means of a series of rearrange-
ments. The synthetic method described in this manuscript
provides an alternative preparation of aryl-substituted pyridines
and should find use in the construction of molecules with
interesting biological properties and applications in material
science.
Experimental Section
To a vial (20 mL) were added the appropriate pyridine N-oxide
1a-e (0.2 mmol), the appropriate silylaryl triflate 2a-i (0.4 mmol),
acetonitrile (3 mL), and CsF (0.1215 g, 0.8 mmol). The vial was
sealed using a cap, and the mixture was stirred for 24 h at room
temperature. Afterward, brine (20 mL) was added to the mixture,
which was extracted with ethyl acetate (3 × 20 mL). The organic
phase was dried over MgSO4. After filtration, the solvent was
evaporated under reduced pressure. The residue was impregnated
with silica gel and purified by column chromatography on silica
gel using 2:1 hexane/acetone as eluent unless otherwise indicated,
affording the desired products 3a-q.
3-(2-Hydroxyphenyl)pyridine (3a):7 yield 30.0 mg (88%); light
1
yellow solid; mp 173-175 °C (lit.7 mp 171-172 °C); H NMR
(DMSO-d6) δ 9.77 (s, 1H), 8.75 (d, J ) 1.5 Hz, 1H), 8.50 (dd, J
) 4.8, 1.5 Hz, 1H), 7.95 (dt, J ) 7.8, 1.9 Hz, 1H), 7.43 (ddd, J )
7.9, 4.8, 0.7 Hz, 1H), 7.32 (dd, J ) 7.5, 1.5 Hz, 1H), 7.22 (td, J )
7.6, 1.5 Hz, 1H), 6.99 (dd, J ) 8.2, 0.7 Hz, 1H), 6.92 (td, J ) 7.5,
1.2 Hz, 1H); 13C NMR (DMSO-d6) δ 154.5, 149.5, 147.5, 136.3,
134.1, 130.3, 129.3, 124.3, 123.1, 119.6, 116.1; IR (KBr, cm-1
)
3445, 3039-2426, 1450, 1394, 1267, 758; HRMS calcd for C11H9-
NO 171.0684, found 171.0687.
Acknowledgment. We gratefully acknowledge the National
Science Foundation for support of this research. C.R. thanks
CAPES (Brazil) for a fellowship.
Compounds 3a-p are presumably obtained through the
proposed mechanism illustrated in Scheme 1.5 To explain the
formation of the observed products, it is necessary to consider
the resonance structures B and B′ shown in Scheme 2. Through
the positive charge present in B′, one would expect that
hydrogen H′ is more acidic than H. Thus, the carbonyl group
present in the intermediate B attacks the hydrogen H′, instead
of H, affording 3-substituted pyridines. On the other hand, the
Supporting Information Available: General methods, experi-
1
mental procedures, characterization data, as well as copies of H
and 13C NMR spectra for compounds 3a-q and crystallographic
information files (CIF) are available. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO060523A
J. Org. Chem, Vol. 71, No. 12, 2006 4691