Regioselective synthesis of 2-(2-hydroxyaryl)pyridines from the reactions of benzynes with pyridine N-oxides

Article abstract of DOI:10.1039/c2ob26130h

By modifying the conditions from those in Larock's reported synthesis of 3-(2-hydroxyaryl)pyridines from benzynes, and pyridine N-oxides, we altered the regioselectivity of the reaction toward an efficient synthesis of 2-substituted pyridines. The presenc

Full text of DOI:10.1039/c2ob26130h

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COMMUNICATION
Regioselective synthesis of 2-(2-hydroxyaryl)pyridines from the reactions of
benzynes with pyridine N-oxides†
Balagopal S. Shaibu, Rahul Kisan Kawade and Rai-Shung Liu*
Received 13th June 2012, Accepted 19th July 2012
DOI: 10.1039/c2ob26130h
By modifying the conditions from those in Larock’s reported
synthesis of 3-(2-hydroxyaryl)pyridines from benzynes, and
pyridine N-oxides, we altered the regioselectivity of the reac-
tion toward an efficient synthesis of 2-substituted pyridines.
The presence of ethyl propiolate altered the regioselectivity
to afford 3-substituted pyridine products instead. We con-
ducted appropriate control experiments that enable a full
understanding of the mechanism.
Results and discussion
Eqn (4) was our original target involving a synthesis of benzo-
furan derivatives through a [2 + 2 + 1]-cycloaddition among
benzyne,2 electron-deficient alkyne and organic oxides (eqn (4)).
Treatment of 2-(trimethylsilyl)phenyl triflate 1a (1.0 equiv.),
pyridine N-oxide 2a (1.5 equiv.), ethyl propiolate (1.0 equiv.) and
Bu4NF (1.5 equiv.) in DCM–THF (4 : 1) delivered a 3-phenyl-
pyridine-based enol ether 3a in 58% yield (eqn (5)). We thought
that this enol ether was produced from a Michael-type reaction11
on initial 3-(2-hydroxyphenyl)pyridine in Larock’s reaction (eqn
(2)). But a control experiment (eqn (6)) gave an astonishing
result that 2-(2-hydroxyphenyl)pyridine 4a was produced exclu-
sively in the absence of ethyl propiolate; more importantly, com-
pounds 3a and 4a have distinct pyridine frameworks. The
regioselectivity in Larock’s reaction10 is easily affected by
unknown factors.
Introduction
The generation of benzyne intermediates is a powerful tool for
the synthesis of 1,2-difunctionalized benzenes.1 Preparations of
benzynes are commonly from o-(trimethylsilyl)aryl triflates and
fluoride.2 Benzynes are reactive toward 4π-electron donors
through various [4 + 2]-cycloaddition reactions.3 A more
common difunctionalization of benzynes occurs through a
sequential treatment with a nucleophile, followed by an electro-
phile, as depicted in eqn (1).4,5 2- and 3-Aryl-substituted pyri-
dines are commonly used in organic light-emitting diode
(OLED) materials, including green phosphorous emitters6 and
electron-transport layers.7 The preparation of these arylpyridines
relies mainly on metal-catalyzed coupling reactions.8 Abramo-
vitch and Shinkai reported9 that benzynes reacted with pyridine
N-oxides to give a mixture of 2- and 3-(2-hydroxyphenyl)pyri-
dines, albeit in low yields. Larock developed a regioselective
synthesis of 3-(2-hydroxyphenyl)pyridines using CsF in aceto-
nitrile (eqn (2)).10 As 2-phenylpyridine derivatives (ppy)
provide an important ligand in green phosphor emitters such as
Ir(ppy)3,6 a selective synthesis of 2-aryl-substituted pyridines
from readily available benzyne precursors is desired. Herein, we
report a chemoselectivity toward 2-(2-hydroxyphenyl)pyridines
effectively through modified experimental conditions (eqn (3));
the success of this reaction enabled us to explore the behavior of
key intermediates.
ð1Þ
ð2Þ
ð3Þ
ð4Þ
Department of Chemistry, National Tsing-Hua University, Hsinchu,
Taiwan, ROC. E-mail: rsliu@mx.nthu.edu.tw; Fax: +88635711082;
Tel: +88635721424
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c2ob26130h
ð5Þ
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Table 1 Optimized conditions for production of 2-(2-hydroxyphenyl)pyridines
Yieldsb (%)
Entry
N-Oxide (equiv.)
Base (equiv.)
Additive
Time (h)
Solvent
4a
5a
1
2
3
4
5
6
7
8
1.5
1.5
1.5
1.5
0.5
0.5
0.5
1.5
1.5
1.5
0.5
1.5
1.5
TBAF (1.5)c
TBAF (1.5)
TBAF (1.5)
TBAF (1.5)
TBAF (1.8)
CsF (2.0)
CsF (6.0)
CsF (2.0)
CsF (6.0)
CsF (12)
—
—
—
2
2
2
DCM
CH3CN
THF
DCM
THF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
71
41
60
51
11
4
18
13
21
55
31
48
53
—
12
6
LiPF6 (0.1)
18
24
24
3
24
24
24
2
13
69
79
23
54
53
15
4
—
—
—
—
—
—
—
—
—
9
10
11
12
13
TBAF (5.4)
TBAF (1.8)
TBAF (5.4)
3
2
THF
THF
18
12
a [1a] = 0.016 M. b Product yields are reported after separation from a silica column. c TBAF = 1 M solution in THF.
We examined the scope of this regioselective synthesis over
various pyridine-based N-oxides 2b–2h and benzyne precursors
1b–1f; the results are shown in Table 2. Structural assignment of
products relies on the NMR data of pyridine, in which the C(2)
and C(6) protons have downfield chemical shifts (8.0–9.0 ppm).
All these reactions were performed using a molar ratio N-oxide/
Bu4NF/benzyne = 1.5 : 1.5 : 1.0 in dichloromethane/THF = 4 : 1
(28 °C, 3 h) except entry 1 for which the reaction was run for
24 h. We obtained 2-(2-hydroxyaryl)pyridines 4b–4m exclu-
sively. We tested the reactions between 2-substituted pyridine
N-oxides 2b–c (R1 = Br, Me; R2 = R3 = H) and benzyne precursor
1a; the corresponding products 4b and 4c were obtained in 29%
and 66% yields respectively. The reactions were extendable to
4-substituted pyridine oxides (R3 = Me, OMe, CN; R1 = R2 = H),
giving the desired 2-arylpyridine derivatives 4d–4f in 69–81%
yields. The structures of compounds 4d–4f are readily assigned
ð6Þ
Shown in Table 1 are our efforts to understand the regiochemi-
stry toward 2- and 3-substituted regioisomers 4a or 5a. The
reactions were conducted according to the same procedure as
described by Larock and coworkers.10 Entry 1 depicts our
success (eqn (6)) to obtain 2-substituted pyridine 4a exclusively
using a reagent ratio 1a/2a/TBAF = 1 : 1.5 : 1.5 in dichloro-
methane/THF = 4 : 1. Entries 2–3 show the solvent effects; we
obtained 2-substituted pyridine 4a (41–60%) as the major
species, together with its regioisomer 5a (6–12%) in CH3CN
and THF. The presence of LiPF6 (10 mol%) additive in dichloro-
methane gave 3-substituted pyridine 5a in minor proportion
(13%, entry 4). We repeated Larock’s conditions using a ratio of
benzyne/oxide = 2.0 (entries 5–6); we confirmed their results
that 3-substituted isomer 5a was produced predominantly from
both Bu4NF and CsF. As depicted in entries 1–4, we suspected
that an excess proportion of basic N-oxide 2a or fluoride (1.5
equiv.) over benzyne (1.0 equiv.) is crucial for the formation of
2-substituted regioisomer 4a. We thus altered Larock’s condition
(entry 6) by steadily increasing the proportion of CsF and
N-oxide 2a in CH3CN whereas benzyne 1a was kept at 1.0 equiv.
The results in entries 7–10 reveal that increasing proportions of
oxide 2a and CsF significantly enhanced 2-substituted isomer
4a. We also observed similar phenomena in entries 11–13 that
excess proportions of either N-oxide 2a or TBAF gave enhanced
yields of 2-substituted regioisomer 4a. Among these parameters,
the use of a less polar solvent like dichloromethane is the best
choice so that a 1.5 equimolar proportion of pyridine N-oxide 2a
and TBAF completely alters the regioselectivity in favor of com-
pound 4a.
1
according to their H NMR spectra showing only one C(6)–H
proton resonance in the downfield region (8.0–9.0 ppm). The use
of quinoline N-oxides 2g–2h is also compatible with this reac-
tion to give the desired products 4g–4h in 69–81% yields
(entries 6–7). Entries 8–12 show the suitability of this reaction to
various benzyne precursors 2b–2f bearing either electron-donat-
ing or withdrawing groups, giving 2-(2-hydroxyaryl) pyridines
4i–4m in 71–86% yields.
As shown in eqn (5), the presence of ethyl propiolate (10 mol
%) completely altered the regioselectivity to give enol ether 3a
exclusively. We tested this behavior on additional electron-
deficient alkynes under our conditions (N-oxide/Bu4NF/benzyne
= 1.5 : 1.5 : 1); the results are summarized in Table 3. We
selected THF as the reaction solvent because it gave a better
yield (72%, entry 1) of enol ether 3a than DCM (53%) and
CH3CN (51%). As shown in entries 2–4, we obtained similar
products 3b–c in 62–76% yields from buty-3-yn-2-one, non-1-
yn-3-one, and diethyl acetylenedicarboxylate (entries 2–4). We
tested the reaction on reactive alkenes including methyl acrylate
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Table 2 Synthesis of 2-(2-hydroxyaryl)pyridines over various
benzyne precursors and N-oxidesa,b
Scheme 1 A deuterium-labeling experiment.
Scheme 2 Reaction routes toward 2- and 3-substituted pyridines.
a [1] = 0.016 M, 1 (1.0 equiv.), 2 (1.5 equiv.), TBAF (1.5 equiv.).
compound 5a was recovered exclusively. This observation
suggests that compound d5-3a was not produced from ethyl pro-
piolate and undeuterated 3-(2-hydroxyphenyl)pyridine 5a.
b Product yields are reported after separation using a silica column.
Our results provide new insight into the reaction regioselectiv-
ity. Scheme 2 shows a plausible mechanism involving well
accepted intermediates A and B.9,10 In Larock’s condition, bases
like pyridine N-oxide and fluoride were used in a deficient pro-
portion; the transformation of intermediate A into 2-(2-hydroxy-
phenyl)pyridine 4a is thereby unlikely to occur because there is
no sufficient base to intercept species A through a deprotonation
Table 3 An alteration of regioselectivity with electron-deficient
alkynesa,b
reaction. Thus, the regioselectivity proceeded through
a
rearrangement of intermediate B to 3-(2-hydroxyphenyl)pyridine
5a, via a loss of the cyclopropyl CH′ proton that is more acidic
than the other C–H proton.10 We used N-oxide and fluorides in
an excess proportion (1.5 equiv.) in dichloromethane to enable
the interception of initial intermediate A to give 2-substituted
pyridine product 4a predominantly. This regioselectivity became
invalid in the presence of ethyl propiolate or Li+, which reacts
with the carbonyl of species B to give cyclohexadienyl cation C.
In this manner, the CH′ acidity of this cationic intermediate is
greatly enhanced by its adjacent cationic character, thus inducing
a quick proton dissociation to accelerate the B → 5a (or 3a)
transformation.
a [1a] = 0.016 M, 1a (1 equiv.), 2a (1.5 equiv.), alkyne or alkene
(1 equiv.), Bu4NF (1.5 equiv.). b Product yields are reported after
separation using a silica column.
Conclusions
and maleic anhydride (entries 5–6), we obtained no addition pro-
ducts, but 2-or 3-substituted regioisomers 4a–5a.
Following Larock reporting the synthesis of 3-(2-hydroxy-
phenyl)pyridines from the reaction of benzynes with pyridine
N-oxide,10 we report here an efficient regioselective synthesis of
2-substituted pyridine isomers with N-oxides and fluoride in
excess proportions in dichloromethane. With suitable experimen-
tal results, we postulate that the presence of N-oxides accelerates
the formation of 2-substituted pyridine products via deprotona-
tion of an initial intermediate A whereas an electrophile
Shown in Scheme 1 is a deuterium-labelling experiment invol-
ving a reaction between benzyne precursor 1a (1 equiv.), d5 pyri-
dine N-oxide (d5-2a, 1.5 equiv.), TBAF (1.5 equiv.), ethyl
propiolate (1.0 equiv.) and 3-(2-hydroxyphenyl)pyridine 5a (0.5
equiv.); we found that a deuterated pyridine moiety was included
only in enol ether product d5-3a whereas undeuterated
6836 | Org. Biomol. Chem., 2012, 10, 6834–6839
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accelerates the formation of 3-substituted pyridine via intercep-
tion of a cyclopropyl ketone intermediate B. The utility of this
reaction is highlighted by a widespread application of 2-phenyl-
pyridine ligands in many green phosphor emitters.6
159.1, 152.5, 149.7, 148.5, 136.4, 132.5, 130.9, 129.8, 129.5,
125.7, 123.0, 119.2, 102.3, 59.9, 14.1; HRMS calcd for
C16H15NO3: 269.1052; found: 269.1046.
Synthesis of 2-(2-hydroxyphenyl)pyridine (4a). To a reaction
flask were added pyridine N-oxide 2a (47.8 mg, 0.5 mmol), sily-
laryl triflate 1a (100 mg, 0.34 mmol), DCM (2 mL) and TBAF
(0.5 mL, 0.5 mmol), and this mixture was stirred for 3 h at room
temperature. The resulting solution was filtered over a short
silica bed, and the filtrate was concentrated under reduced
pressure. The residue was eluted through a silica column to give
the desired 4a (41 mg, 0.23 mmol) in 71% yield. IR (neat,
Experimental
General methods
Unless otherwise noted, all the reactions for the preparation of
the substrates were performed in oven-dried glassware under a
nitrogen atmosphere with freshly distilled solvents. The catalytic
reactions were performed under a nitrogen atmosphere. Toluene,
DCE and methanol were distilled from CaH under nitrogen.
Methanol and triethylamine (Et3N) were stored over 4 Å molecu-
lar sieves prior to use. TBAF used was a commercially available
1 M solution in THF. All other commercial reagents were used
without further purification, unless otherwise indicated. 1H
NMR and 13C NMR spectra were recorded on Varian 400 MHz,
Bruker 400 and 600 MHz spectrometers using CDCl3 as the
internal standard.
1
cm−1): 3039, 1750, 1338, 788; H NMR (600 MHz, CDCl3):
δ 8.52–8.51 (m, 1 H), 7.92 (d, J = 8.2 Hz, 1 H), 7.85–7.84 (m,
1 H), 7.78 (dd, J = 8.0, 1.0 Hz, 1 H), 7.29–7.28 (m, 1 H),
7.26–7.24 (m, 1 H), 7.03 (dd, J = 8.0, 1.0 Hz, 1 H), 6.91–6.89
(m, 1 H); 13C NMR (100 MHz, CDCl3): δ 159.8, 157.6, 145.5,
138.2, 131.7, 126.3, 121.6, 119.5, 118.8, 118.7 (one carbon
merged to others); HRMS calcd for C11H9NO: 171.0684; found:
171.0687.
Spectral data for 4,5-dimethyl-2-(trimethylsilyl)phenyl tri-
fluoromethane sulfonate (1b). Yellow oil, IR (neat, cm−1): 3029,
1608, 1350, 1160; 1H NMR (400 MHz, CDCl3): δ 7.21 (s, 1 H),
7.07 (s, 1 H), 2.26 (s, 3 H), 2.24 (s, 3 H), 0.32 (s, 9 H); 13C
NMR (100 MHz, CDCl3): δ 153.1, 140.3, 136.9, 136.0, 129.1,
120.5, 116.9, 19.9, 19.1, −0.76; HRMS calcd for
C12H17F3O3SSi: 326.0620; found: 326.0627.
Synthesis of 2-(trimethylsilyl)phenyl trifluoromethanesulfo-
nate (1a). A mixture of 2-bromophenol (1 g, 5.7 mmol) and
HMDS (1.21 g, 7.5 mmol) in THF was heated at 85 °C for 2 h.
The mixture was dried in vacuum to afford the compound
(2-bromophenoxy)trimethylsilane as a yellow oil (1.27 g, 94%).
(2-Bromophenoxy)trimethylsilane (2.0 g, 8.6 mmol) was dis-
solved in THF (20 mL), and the solution was cooled to −80 °C
before n-BuLi (2.5 M, 3.91 mL, 12.2 mmol) was added. The
reaction was maintained at the same temperature for a further
20 min before Tf2O (1.90 mL, 12.2 mmol) was added dropwise.
The reaction was stirred for 30 min at room temperature. The sol-
ution was quenched with NaHCO3, and extracted with ethyl
acetate (2 × 20 mL). After removal of the solvent in vacuo, the
crude material was purified by flash column chromatography on
silica gel to afford 2-(trimethylsilyl)phenyl trifluoromethanesul-
fonate 1a (1.97 g, 81%) as a yellow oil.2 IR (neat, cm−1): 3078,
1621, 1335; 1H NMR (400 MHz, CDCl3): δ 7.53–7.50 (m, 1 H),
7.44–7.40 (m, 1 H), 7.34–7.30 (m, 2 H), 0.35 (s, 9 H); 13C
NMR (100 MHz, CDCl3): 155.1, 136.2, 132.5, 131.2, 127.4,
119.5, 116.9, −0.87; HRMS calcd for C10H13F3O3SSi:
298.0307; found: 298.0310.
Spectral data for 4,5-dimethoxy-2-(trimethylsilyl)phenyl tri-
fluoromethane sulfonate (1c). Pale yellow oil; IR (neat, cm−1):
1
3068, 1610, 1335, 1236; H NMR (400 MHz, CDCl3): δ 6.88
(s, 1 H), 6.83 (s, 1 H), 3.88 (s, 3 H), 3.86 (s, 3 H), 0.33 (s, 9 H);
13C NMR (100 MHz, CDCl3): δ 150.6, 148.2, 147.9, 123.1,
120.1, 116.9, 116.6, 104.2, 56.1, 56.0, −0.7; HRMS calcd for
C12H17F3O5SSi: 358.0518; found: 358.0512.
Spectral data for 4,5-difluoro-2-(trimethylsilyl)phenyl trifluoro-
methane sulfonate (1d). Pale yellow solid; IR (neat, cm−1):
3051, 1607, 1319, 1089; 1H NMR (400 MHz, CDCl3):
δ 7.29–7.19 (m, 2 H), 0.33 (s, 9 H); 13C NMR (100 MHz,
CDCl3): δ 150.6 (dd, J = 252.8, 14.4 Hz), 149.3 (dd, J = 250.5,
11.6 Hz), 130.1, 123.5 (d, J = 17.2 Hz), 120.0, 116.8, 110.4 (d,
J = 21.2 Hz), −0.823; HRMS calcd for C10H11F5O3SSi:
334.0118; found: 334.0113.
Synthesis of (E)-ethyl 3-(2-(pyridin-3-yl)phenoxy)acrylate
(3a). A reaction flask was charged with pyridine N-oxide 2a
(47.8 mg, 0.5 mmol), followed by THF (2.0 mL) and TBAF
(0.5 mL, 0.5 mmol). To this solution was added a mixture of
silylaryl triflate 1a (100 mg, 0.34 mmol) and ethyl propiolate
(32 mg, 0.34 mmol) via a syringe pump over a period of 1 h; the
resulting solution was stirred at 25 °C for 3 h. The reaction
mixture was filtered over a short silica bed; the filtrate was con-
centrated under reduced pressure. The residue was eluted
through a silica column to give the desired 3a (65 mg,
0.24 mmol) in 72% yield. IR (neat, cm−1): 3021, 1726, 1330,
795; 1H NMR (400 MHz, CDCl3): δ 8.67 (s, 1 H), 8.55 (dd, J =
4.8, 0.8 Hz, 1 H), 7.76–7.74 (m, 1 H), 7.66–7.63 (m, 1 H),
7.41–7.38 (m, 2 H), 7.33–7.26 (m, 2 H), 7.13 (d, J = 8.0 Hz,
1 H), 5.36 (d, J = 12.4 Hz, 1 H), 4.10 (q, J = 7.1 Hz, 2 H), 1.21
(t, J = 7.1 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ 166.7,
Spectral data for 6-(trimethylsilyl)-2,3-dihydro-1H-inden-5-yl
trifluoromethanesulfonate (1e). Yellow oil; IR (neat, cm−1):
3027, 1611, 1354, 1130; 1H NMR (400 MHz, CDCl3): δ 7.33 (s,
1 H), 7.17 (s, 1 H), 2.94–2.87 (m, 4 H), 2.15–2.07 (m, 2 H),
0.34 (s, 9 H); 13C NMR (100 MHz, CDCl3): δ 153.9, 148.3,
143.6, 131.3, 129.4, 115.7, 33.1, 32.1, 25.7, −0.7; HRMS calcd
for C13H17F3O3SSi: 338.0620; found: 338.0625.
Spectral data for 3-(trimethylsilyl)naphthalen-2-yl trifluoro-
methanesulfonate (1f). Yellow oil; IR (neat, cm−1): 3070, 1601,
1353, 1301; 1H NMR (400 MHz, CDCl3): δ 7.99 (s, 1 H),
7.86–7.80 (m, 2 H), 7.78 (s, 1 H), 7.56–7.50 (m, 2 H), 0.42 (s, 9
H); 13C NMR (100 MHz, CDCl3): δ 152.6, 137.5, 134.1, 131.8,
131.0, 127.9, 127.8, 127.7, 126.9, 120.1, 116.5, −0.75; HRMS
calcd for C14H15F3O3SSi: 348.0463; found: 348.0467.
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Spectral data for 2-(6-bromopyridin-2-yl)phenol (4b). Yellow
oil; IR (neat, cm−1): 3035, 1743, 1351, 754; 1H NMR
(600 MHz, CDCl3): δ 7.93–7.91 (m, 1 H), 7.86–7.84 (m, 1 H),
7.79–7.77 (m, 1 H), 7.31–7.23 (m, 2 H), 7.03–7.02 (m, 1 H),
6.92–6.88 (m, 1 H); 13C NMR (100 MHz, CDCl3): δ 159.2,
152.8, 139.3, 132.2, 131.2, 130.7, 127.9, 125.7, 119.6, 117.9
(one carbon merged to others); HRMS calcd for C11H8BrNO:
248.9789; found: 248.9795.
1 H), 7.60–7.58 (m, 1 H), 7.44 (t, J = 7.3 Hz, 1 H), 7.38–7.34
(m, 1 H), 7.09 (dd, J = 8.2, 1.2 Hz, 1 H), 6.97–6.93 (m, 1 H),
2.78 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ 161.1, 156.8,
143.9, 138.0, 134.9, 131.9, 130.8, 126.8, 126.4, 125.6, 118.9,
118.6, 118.5, 116.8, 18.3 (one carbon merged to others); HRMS
calcd for C16H13NO: 235.0997; found: 235.0998.
Spectral data for 4,5-dimethyl-2-(pyridin-2-yl)phenol (4i).
1
Yellow oil; IR (neat, cm−1): 3034, 1748, 1336, 789; H NMR
Spectral data for 2-(6-methylpyridin-2-yl)phenol (4c). Yellow
oil; IR (neat, cm−1): 3035, 1743, 1351, 754; 1H NMR
(600 MHz, CDCl3): δ 7.76 (d, J = 7.8 Hz, 1 H), 7.71–7.70 (m,
1 H), 7.32–7.25 (m, 2 H), 7.08–7.06 (m, 1 H), 6.98 (d, J = 8.0
Hz, 1 H), 6.87 (t, J = 7.6 Hz, 1 H), 2.58 (s, 3 H); 13C NMR
(150 MHz, CDCl3): δ 160.1, 157.3, 155.0, 138.0, 131.3, 127.4,
126.1, 121.1, 118.6, 116.0, 22.6 (one carbon merged to others);
HRMS calcd for C12H11NO: 185.0841; found: 185.0845.
(600 MHz, CDCl3): δ 8.46–8.45 (m, 1 H), 7.85 (d, J = 8.2 Hz,
1 H), 7.79–7.76 (m, 1 H), 7.51 (s, 1 H), 7.18–7.16 (m, 1 H),
6.80 (s, 1 H), 2.22 (s, 6 H); 13C NMR (150 MHz, CDCl3):
δ 158.0, 157.9, 145.8, 140.7, 137.5, 130.6, 126.6, 120.9, 119.6,
118.6, 116.2, 19.9, 19.1; HRMS calcd for C13H13NO: 199.0997;
found: 199.0994.
Spectral data for 4,5-dimethoxy-2-(pyridin-2-yl)phenol (4j).
1
Yellow oil; IR (neat, cm−1): 3036, 1752, 1339, 786; H NMR
Spectral data for 2-(4-methylpyridin-2-yl)phenol (4d). Yellow
oil; IR (neat, cm−1): 3035, 1743, 1351, 754; 1H NMR
(400 MHz, CDCl3): δ 8.34 (d, J = 5.2 Hz, 1 H), 7.78 (d, J = 8.2
Hz, 1 H), 7.71 (s, 1 H), 7.28 (t, J = 7.8 Hz, 1 H), 7.05 (d, J =
5.2 Hz, 1 H), 7.00 (d, J = 8.2 Hz, 1 H), 6.88 (t, J = 7.8 Hz, 1 H),
2.43 (s, 3 H); 13C NMR (100 MHz, CDCl3): δ 160.1, 157.5,
149.0, 145.4, 131.3, 125.9, 122.6, 119.6, 118.8, 118.6, 118.5,
21.6; HRMS calcd for C12H11NO: 185.0841; found: 185.0845.
(600 MHz, CDCl3): δ 8.45–8.44 (m, 1 H), 7.78–7.77 (m, 1 H),
7.72–7.71 (m, 1 H), 7.24 (s, 1 H), 7.21 (s, 1 H), 6.56 (s, 1 H),
3.89 (s, 3 H), 3.88 (s, 3 H); 13C NMR (150 MHz, CDCl3):
δ 157.6, 155.9, 152.4, 145.8, 142.0, 137.6, 128.4, 123.4, 120.4,
118.2, 101.9, 56.9, 55.9 (2 C); HRMS calcd for C13H13NO3:
231.0895; found: 231.0897.
Spectral data for 4,5-difluoro-2-(pyridin-2-yl)phenol (4k).
1
Yellow oil; IR (neat, cm−1): 3035, 1756, 1332, 788; H NMR
Spectral data for 2-(4-methoxypyridin-2-yl)phenol (4e).
(600 MHz, CDCl3): δ 8.49–8.48 (m, 1 H), 7.86–7.83 (m, 1 H),
7.73–7.72 (m, 1 H), 7.57–7.54 (m, 1 H), 7.28–7.26 (m, 1 H),
6.80–6.77 (m, 1 H); 13C NMR (150 MHz, CDCl3): δ 157.0,
156.9, 156.3, 151.8 (dd, J = 250.6, 14.1), 145.8, 143.7 (dd,
J = 235.8, 13.9), 138.1, 121.9, 119.0, 113.7 (d, J = 14.1), 106.9
(d, J = 13.9); HRMS calcd for C11H7F2NO: 207.0496; found:
207.0491.
1
Yellow oil; IR (neat, cm−1): 3035, 1743, 1351, 754; H NMR
(600 MHz, CDCl3): δ 8.32 (d, J = 5.9 Hz, 1 H), 7.72 (dd, J =
8.0, 1.4 Hz, 1 H), 7.35 (d, J = 2.4 Hz, 1 H), 7.29–7.26 (m, 1 H),
7.00 (d, J = 8.0 Hz, 1 H), 6.89–6.86 (m, 1 H), 6.77–6.76 (m,
1 H), 3.92 (s, 3 H); 13C NMR (150 MHz, CDCl3): δ 166.9, 160.2,
159.5, 147.2, 131.4, 125.9, 118.8, 118.7, 118.6, 108.3, 104.3,
55.3; HRMS calcd for C12H11NO2: 201.0790; found: 201.0790.
Spectral data for 6-(pyridin-2-yl)-2,3-dihydro-1H-inden-5-ol
(4l). Yellow oil; IR (neat, cm−1): 3035, 1743, 1351, 754; 1H
NMR (600 MHz, CDCl3): δ 8.46–8.44 (m, 1 H), 7.85 (d, J = 8.2
Hz, 1 H), 7.78–7.76 (m, 1 H), 7.62 (s, 1 H), 7.18–7.16 (m, 1 H),
6.88 (s, 1 H), 2.89–2.86 (m, 4 H), 2.09–2.04 (m, 2 H); 13C
NMR (150 MHz, CDCl3): δ 158.9, 158.3, 148.6, 145.7, 137.5,
134.4, 121.1, 120.8, 118.7, 116.6, 114.1, 33.1, 32.0, 25.7;
HRMS calcd for C14H13NO: 211.0997; found: 211.0998.
Spectral data for 2-(4-cyanopyridin-2-yl)phenol (4f). Yellow
oil; IR (neat, cm−1): 3035, 1743, 1351, 754; 1H NMR
(400 MHz, CDCl3): δ 8.66 (d, J = 5.2 Hz, 1 H), 8.11 (s, 1 H),
7.73 (d, J = 7.8 Hz, 1 H), 7.43 (d, J = 5.2 Hz, 1 H), 7.36 (t, J =
7.8 Hz, 1 H), 7.03 (d, J = 7.8 Hz, 1 H), 6.95 (t, J = 7.8 Hz, 1 H);
13C NMR (100 MHz, CDCl3): δ 159.9, 159.2, 147.2, 132.9,
126.3, 122.3, 121.4, 119.4, 118.9, 117.3, 116.2 (one carbon
merged to others); HRMS calcd for C12H8N2O: 196.0637;
found: 196.0631.
Spectral data for 3-(pyridin-2-yl)naphthalen-2-ol (4m).
1
Yellow oil; IR (neat, cm−1): 3039, 1746, 1355, 752; H NMR
Spectral data for 2-(quinolin-2-yl)phenol (4g). Yellow oil; IR
(neat, cm−1): 3036, 1756, 1338, 796; 1H NMR (600 MHz,
CDCl3): δ 8.23 (d, J = 8.8 Hz, 1 H), 8.03–7.98 (m, 2 H), 7.90
(dd, J = 8.0, 1.5 Hz, 1 H), 7.79 (d, J = 8.2 Hz, 1 H), 7.72–7.70
(m, 1 H), 7.53–7.50 (m, 1 H), 7.35–7.32 (m, 1 H), 7.10 (d, J =
8.2 Hz, 1 H), 6.94–6.92 (m, 1 H); 13C NMR (150 MHz,
CDCl3): δ 160.9, 157.8, 144.4, 137.8, 132.1, 130.6, 127.5,
127.2, 127.0, 126.7, 126.5, 118.8, 118.6, 117.4 (one carbon
merged to others); HRMS calcd for C15H11NO: 221.0841;
found: 221.0839.
(400 MHz, CDCl3): δ 8.42–8.41 (m, 1 H), 8.18 (s, 1 H), 7.97 (d,
J = 8.2 Hz, 1 H), 7.75–7.71 (m, 1 H), 7.66 (d, J = 8.2 Hz,
1 H),7.56 (d, J = 8.2 Hz, 1 H), 7.32–7.28 (m, 2 H), 7.18–7.13
(m, 2 H); 13C NMR (100 MHz, CDCl3): 157.5, 156.8, 145.9,
137.8, 135.7, 128.3, 127.4, 127.2, 126.8, 125.8, 123.1, 122.0,
121.4, 119.9, 112.0; HRMS calcd for C15H11NO: 221.0841;
found: 221.0836.
Spectral data for (E)-4-(2-(2,6-dimethylpyridin-3-yl)phenoxy)-
but-3-en-2-one (3b). Yellow oil; IR (neat, cm−1): 3021, 1726,
1
1330, 795; H NMR (400 MHz, CDCl3): δ 8.67 (d, J = 2.2 Hz,
Spectral data for 2-(8-methylquinolin-2-yl)phenol (4h).
1 H), 8.56 (dd, J = 4.8, 1.5 Hz, 1 H), 7.78–7.75 (m, 1 H), 7.58
(d, J = 12.4 Hz, 1 H), 7.36–7.34 (m, 2 H), 7.32–7.24 (m, 2 H),
7.16–7.14 (m, 1 H), 5.73 (d, J = 12.4 Hz, 1 H), 2.13 (s, 3 H);
13C NMR (150 MHz, CDCl3): δ 196.9, 159.1, 152.4, 149.5,
1
Yellow oil; IR (neat, cm−1): 3033, 1750, 1339, 758; H NMR
(400 MHz, CDCl3): δ 8.24 (d, J = 8.9 Hz, 1 H), 8.04 (d, J = 8.9
Hz, 1 H), 7.96 (dd, J = 8.0, 1.6 Hz, 1 H), 7.66 (d, J = 8.1 Hz,
6838 | Org. Biomol. Chem., 2012, 10, 6834–6839
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2 This benzyne formation was first reported by Kobayashi, see:
Y. Hemishima, T. Sonoda and H. Kobayashi, Chem. Lett., 1983, 1211.
3 (a) U. K. Tambar and B. M. Stoltz, J. Am. Chem. Soc., 2005, 127, 5340–
5341; (b) U. K. Tambar, D. C. Ebner and B. M. Stoltz, J. Am. Chem.
Soc., 2006, 128, 11752–11753; (c) J. Zhao and R. C. Larock, Org. Lett.,
2005, 7, 701–704; (d) K. Okuma, A. Nojima, N. Matsunaga and
K. Shioji, Org. Lett., 2009, 11, 169–171; (e) M. Alajarin,
C. L. Leonardo, R. Raja and R. A. Orenes, Org. Lett., 2011, 13, 5668–
5671 and references cited therein.
4 (a) E. K. Fields and S. Meyerson, J. Org. Chem., 1966, 31, 3307–3309;
(b) N. Dennis, A. R. Katritzky and S. K. Parton, J. Chem. Soc., Perkin
Trans. 1, 1976, 2285–2288; (c) E. Ihara, A. Kurokawa, T. Koda,
T. Muraki, T. Itoh and K. Inoue, Macromolecules, 2005, 38, 2167–2172;
(d) G. Wittig and B. Reichl, Chem. Ber., 1963, 96, 2815;
(e) L. A. Carpino and D. E. Barr, J. Org. Chem., 1966, 31, 764–767;
(f) V. Nair and K. H. Kim, J. Org. Chem., 1975, 40, 3784–3786;
(g) H. Yoshida, S. Sugiura and A. Kunai, Org. Lett., 2002, 4, 2767–
2769; (h) J. Zhao, C. Wu, P. Li, W. Ai, H. Chen, C. Wang, R. C. Larock
and F. Shi, J. Org. Chem., 2011, 76, 6837–6843; (i) C. Wu, Y. Fang,
R. C. Larock and F. Shi, Org. Lett., 2010, 12, 2234–2237.
5 (a) Z. Liu, X. Zhang and R. C. Larock, J. Am. Chem. Soc., 2005, 127,
15716–15717; (b) Z. Liu and R. C. Larock, J. Am. Chem. Soc., 2005,
127, 13112–13113; (c) J. Zhao and R. C. Larock, Org. Lett., 2005, 7,
4273–4275; (d) X. Zhang and R. C. Larock, Org. Lett., 2005, 7, 3973–
3976; (e) Z. Liu and R. C. Larock, Org. Lett., 2004, 6, 3739–3741;
(f) Z. Liu and R. C. Larock, Org. Lett., 2004, 6, 99–102; (g) Z. Liu and
R. C. Larock, Org. Lett., 2003, 5, 4673–4675; (h) Z. Liu, F. Shi,
P. D. G. Martinez, C. Raminelli and R. C. Larock, J. Org. Chem., 2008,
73, 219–226.
6 (a) Y. Sun, N. C. Giebink, H. Kanno, B. Ma, M. E. Thompson and
S. R. Forrest, Nature, 2006, 440, 908–912; (b) T. Tsutsui, M. Yang,
M. Yahiro, K. Nakamura, T. Watanabe, T. Tsuji, Y. Fukuda, T. Wakimoto
and S. Miyaguchi, Jpn. J. Appl. Phys., 1999, 38, 1502–1504;
(c) K. A. King, P. J. Spillane and R. J. Watts, J. Am. Chem. Soc., 1985,
107, 1431–1432; (d) W. Zhu, Y. Mo, M. Yuan, W. Yang and Y. Cao,
Appl. Phys. Lett., 2002, 80, 2045–2047.
148.4, 136.6, 132.6, 131.1, 130.4, 129.9, 126.0, 123.2, 119.2,
111.7, 28.2; HRMS calcd for C15H13NO2: 239.0946; found:
239.0939.
Spectral data for (E)-1-(2-(pyridin-3-yl)phenoxy)non-1-en-3-
one (3c). Yellow oil; IR (neat, cm−1): 3021, 1726, 1330, 795; 1H
NMR (600 MHz, CDCl3): δ 8.69 (s, 1 H), 8.57 (d, J = 4.3 Hz, 1
H), 7.75 (dd, J = 4.3, 1.7 Hz, 1 H), 7.60 (d, J = 12.3 Hz, 1 H),
7.43–7.40 (m, 2 H), 7.34–7.29 (m, 2 H), 7.15 (d, J = 8.3 Hz, 1
H), 5.76 (d, J = 12.3 Hz, 1 H), 2.37 (t, J = 7.4, 2 H), 1.53 (m, 2
H), 1.28–1.23 (m, 6 H), 0.85 (t, J = 6.8 Hz, 3 H); 13C NMR
(150 MHz, CDCl3): δ 199.8, 158.2, 152.7, 149.7, 148.6, 136.6,
132.7, 131.1, 129.9, 129.5, 125.9, 123.2, 119.1, 110.8, 41.8,
31.5, 28.8, 24.2, 22.4, 14.
Spectral data for (d5-3a). Yellow oil; IR (neat, cm−1): 3021,
1
1726, 1330, 795; H NMR (600 MHz, CDCl3): δ 7.62 (d, J =
12.3 Hz, 1 H), 7.38–7.36 (m, 2 H), 7.27–7.25 (m, 1 H),
7.13–7.11 (m, 1 H), 5.34 (d, J = 12.3 Hz, 0.5 H), 4.08 (q, J =
7.1 Hz, 2 H), 1.18 (t, J = 7.1 Hz, 3 H); 13C NMR (150 MHz,
CDCl3): δ 166.7, 159.1, 152.4, 149.3 (t, J = 27.4), 148.1 (t, J =
27.4), 135.9 (t, J = 24.6), 132.2, 130.9, 129.7, 129.4, 125.7,
122.5 (t, J = 24.6), 119.1, 102.3, 59.9, 14.1; HRMS calcd for
C16H11D4NO3: 273.1303; found: 273.1295.
Acknowledgements
We thank the National Science Council and Education of
Ministry, Taiwan, for financial support of this work.
7 (a) C. Wu, H.-F. Chen, K.-T. Wong and M. E. Thompson, J. Am. Chem.
Soc., 2010, 132, 3133–3139; (b) A. Sarkar and C. Sankar, J. Lumin.,
1995, 65, 163–168; (c) T. Tsuzuki, Y. Nakayama, J. Nakamura, T. Iwata
and S. Tokito, Appl. Phys. Lett., 2006, 88, 243511; (d) S. Sprouse,
K. A. King, P. J. Spellane and R. J. Watts, J. Am. Chem. Soc., 1984, 106,
6647–6653.
8 (a) F. Diederich and P. J. Stang, Metal-catalysed cross-coupling reactions,
Wiley-VCH, Weinheim, 1998; (b) K. Yoon, S. M. Ha and K. Kim,
J. Org. Chem., 2005, 70, 5741–5744; (c) G. Karig, J. A. Spencer and
T. Gallagher, Org. Lett., 2001, 3, 835–838; (d) S. P. Stanforth, Tetra-
hedron, 1998, 54, 263–303.
9 R. A. Abramovitch and I. Shinkai, J. Am. Chem. Soc., 1974, 96, 5265–
5267.
10 C. Raminelli, Z. Liu and R. C. Larock, J. Org. Chem., 2006, 71, 4689–
4691.
11 Strong bases are known to implement the addition of phenol to ethyl
propiolate; see: M. J. Fan, G. Q. Li, L. H. Li, S. D. Yang and
Y. M. Liang, Synthesis, 2006, 14, 2286–2292.
Notes and references
1 For reviews, see: (a) R. W. Hoffmann, Dehydrobenzene and Cycloalk-
ynes, Academic Press, New York, 1967; (b) D. Penam, D. Perez and
E. Guitian, Angew. Chem., Int. Ed., 2006, 45, 3579–3581; (c) Y. Chen,
H. H. Wenk, M. Winkler and W. Sander, Angew. Chem., Int. Ed., 2003,
42, 502–528; (d) H. Pellissier and M. Santelli, Tetrahedron, 2003, 59,
701–730; (e) R. Sanz, Org. Prep. Proced. Int., 2008, 40, 215;
(f) R. C. Larock, Arylation reactions involving the formation of arynes,
in Modern Arylation Methods, ed. L. Ackermann, Wiley-VCH,
New York, 2009, ch. 12, p. 401; (g) M. C. Carre, B. Gregoire and
P. Caubere, J. Org. Chem., 1984, 49, 2050–2052; S. Cossu and O. De
Lucchi, Tetrahedron, 1996, 52, 14247–14252; (h) S. S. Bhojgude and
A. T. Biju, Angew. Chem., Int. Ed., 2012, 51, 1520–1522;
(i) S. Escudero, D. Perez, E. Guitian and L. Castedo, Tetrahedron Lett.,
1997, 38, 5375–5378.
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