The regioselective homocoupling of meta-hydroxypyridines with hypervalent iodine(iii)

Article abstract of DOI:10.1002/asia.201403359

The C-H homocoupling of meta-hydroxypyridines with phenyliodine(III) diacetate (PIDA) was carried out in dichloromethane at room temperature in the presence of cesium carbonate. The coupling reaction is highly regioselective with respect to the hydroxy group at the pyridine ring. Comparative control experiments with meta-alkoxypyridine suggest that the meta-hydroxy group at the pyridine ring plays a key role during the homocoupling reaction.

Full text of DOI:10.1002/asia.201403359

DOI: 10.1002/asia.201403359
Communication
Homocoupling Reactions
The Regioselective Homocoupling of meta-Hydroxypyridines with
Hypervalent Iodine(III)
Ping Syun Yang, Mi Ting Tsai, Meng Han Tsai, and Chi Wi Ong*[a]
appropriate choice of ligands, such as Buchwald phosphanes,[6]
Abstract: The CÀH homocoupling of meta-hydroxypyri-
bulky tri-alkylphosphanes,[7] and other di-alkylarylphosphanes.[8]
dines with phenyliodine(III) diacetate (PIDA) was carried
Recently, hypervalent iodine(III) reagents have been used
out in dichloromethane at room temperature in the pres-
successfully for the metal-free oxidative coupling between two
ence of cesium carbonate. The coupling reaction is highly
unfunctionalized electron-rich arenes and heteroarenes for the
regioselective with respect to the hydroxy group at the
direct synthesis of biaryls. However, the direct coupling of two
pyridine ring. Comparative control experiments with
unfunctionalized electron-deficient heteroarenes using hyper-
meta-alkoxypyridine suggest that the meta-hydroxy group
valent iodine(III) has not been reported. Herein, we chose to
at the pyridine ring plays a key role during the homocou-
study the homocoupling reaction of hydroxypyridine deriva-
pling reaction.
tives. Hydroxypyridine was chosen to mimic the known homo-
coupling reaction of phenol derivatives using hypervalent iodi-
ne(III) reagents. The phenolic oxygen has been reported to
Biaryls containing the 2,2’-bipyridine motif have become ex-
tremely important building blocks for supramolecular chemis-
try, macromolecular chemistry, as well as nanoscience due to
their interesting chemical and material properties.[1] Especially
important is the 3,3’-dihydroxy-2,2’-bipyridine framework,
whereby the OÀH proton is hydrogen bonded to the nitrogen
atom of the pyridyl ring in the ground state. It has been
widely used for studying excited-state intramolecular proton
transfer processes, which play an important role in many
chemical and biological systems. Moreover, 6,6’-dimethyl-3,3’-
dihydroxy-2,2’-bipyridine is an important intermediate for elab-
oration of more complex ligands with potential application in
medicinal diagnostics, biological labeling, molecular detection,
and optoelectronic materials due to their intense fluorescent
properties.[2] The conventional synthesis of bipyridine by a cou-
pling reaction using transitional metals generally requires the
prefunctionalization of the pyridine (e.g., halide or metal).[3] Re-
cently, the direct oxidative coupling of unfunctionalized pyri-
dine derivatives using Raney nickel and palladium on carbon
(Pd/C) has also been achieved.[4] One of the major limitations
of using transitional metals as catalysts for the oxidative cou-
pling reaction for nitrogen-containing heteroarenes is the cata-
lyst deactivation, thus leading to a slow reaction and low
yield.[5] Therefore, the coupling of pyridine derivatives to form
bipyridines remains a significant challenge. As such, extensive
research has been carried out to develop new protocols based
on transitional metals for the coupling of heteroaryls by the
react with phenyliodine(III) diacetate (PIDA) and phenyliodi-
ne(III) bis(trifluoroacetate) (PIFA) to increase the electrophilicity
of the ring which can be attacked by another electron-rich aro-
matic ring to give biaryl.[9] We therefore envisaged that hydrox-
ypyridine derivatives can also undergo a similar oxidative CÀH/
CÀH homocoupling reaction using hypervalent iodine(III) to
form dihydroxy-2,2’-bipyridine derivatives. The number of pos-
sible homocoupling products from the reaction of a substituted
meta-hydroxy pyridine are shown in Scheme 1. Herein, we
report on the highly regioselective homocoupling reaction of
meta-hydroxypyridine derivatives using phenyliodine(III) diace-
tate (PIDA) to yield 3,3’-dihydroxy-2,2’-bipyridine derivatives
with high efficiency.
Among the hypervalent iodine(III) reagents, we chose to use
PIDA as it is cheap and less air-sensitive. Initial experiments
were conducted in the search for a suitable solvent (acetone,
benzene, dichloromethane, ether, ethyl acetate, 1,1,1-trifluoroe-
thanol, tetrahydrofuran) for the homocoupling reaction of 2-
methyl-5-hydroxypyridine at room temperature. Dichlorome-
thane was found to be the best solvent, albeit low yields (20–
30%) were obtained. Next, we examined the effect of reaction
temperature using PIDA (Table 1, entries 2, 4, 5), and room
temperature afforded the best yield. Assessment of the various
base additives that have been studied[10] for coupling reactions
using PIDA indicated Cs2CO3 to be more favorable (Table 1, en-
tries 6–8). We found that 0.5 equivalent of Cs2CO3 was suffi-
cient for the reaction. Under optimum conditions, the homo-
coupling product, 6,6’-dimethyl-(2,2’-bipyridine)-3,3’-diol (2)
could be obtained in 70% yield and with high regioselectivity,
as determined by NMR spectroscopy (Table 1, entry 11).
[a] P. S. Yang, M. T. Tsai, M. H. Tsai, Prof. C. W. Ong
National Sun Yat Sen University
Department of Chemistry
70 Lienhai Rd., Kaohsiung 80424 (Taiwan)
E-mail: cong@mail.nsysu.edu.tw
The scope and regioselectivity of the homocoupling reaction
for a variety of hydroxy-pyridines and their derivatives were
then investigated under the optimal conditions as outlined in
Table 2. 2- and 4-Hydroxypyridine, (Table 2, entries 3, 4) did not
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(Table 2, entry 10). Furthermore,
we could synthesize poly-un-
fused aromatic rings readily from
the homocoupling of 2-phenyl-
5-hydroxypyridine
(Table 2,
entry 9). In the context of the
ortho-regioselective homocou-
pling of 3-hydroxypyridine with
respect to the hydroxy group,
one may ask the question
whether blocking this position
would hamper the reaction.
Here we found that no homo-
Scheme 1. Possible homocoupling product of substituted meta-hydroxypyridine.
Table 1. Optimization of the reaction conditions.
coupling product was obtained
using 2-substituted-3-hydroxy-
pyridine (Table 2, entries 11, 12).
These results imply that substitution at the ortho-position with
respect to the hydroxy group blocks the homocoupling reac-
tion.
Two mechanisms may be postulated for the homocoupling
reaction of hydroxypyridine with PIDA. One involves the reac-
tion at the oxygen of the hydroxy group and the second in-
volves the nitrogen of the pyridine ring to form the iodo(III) in-
termediates (Scheme 2). To gain further insights into the mech-
anism of the reaction, the hydroxy group was converted into
the corresponding alkoxy derivatives. It was found that these
ether derivatives did not undergo the homocoupling reaction
(Table 3). The use of 2-methylpyridine itself also did not give
rise to any coupling product. Based on this observation, we
concluded that the hydroxy group at the meta-position of pyri-
dine is essential for the homocoupling reaction with PIDA.
We further suggests a plausible mechanism to address the
issue of regioselectivity (Scheme 2). The fact that the homo-
coupling reaction proceeded with excellent chemo- and regio-
selectivity suggests that the mechanism possibly involves an
intramolecular concerted-like reaction, through the formation
of intermediate III (Scheme 2). The intermediate II formed from
the reaction of the hydroxy group with PIDA can coordinate
with another molecule of the hydroxypyridine to form interme-
Entry Pyridine [equiv] PIDA [equiv] T [oC] Additives/ equiv Yield [%][a]
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
1
2
3
4
0.5
1
2
1
1
1
1
1
1
rt
rt
rt
none
none
none
20
30
13
15
26
36
24
41
47
52
70
72
08C none
408C none
rt
rt
rt
rt
rt
rt
rt
Na2CO3/1 eq
K2CO3/1 eq
Cs2CO3/1.0 eq
Cs2CO3/0.5 eq
Cs2CO3/0.5 eq
Cs2CO3/0.5 eq
Cs2CO3/0.5 eq
9
10
11
12
1
1
1
[a] Yield estimated directly from the crude product by 1H NMR spectro-
scopic analysis using 1,1,2,2-tetrachloroethane as an internal standard.
give rise to the homocoupling product dihydroxybipyridine,
whereas 3-hydroxypyridine underwent a regioselective homo-
coupling reaction to give 3,3’-di-
hydroxy 2,2’-bipyridine (Table 2,
entry 2). Thus, the homocou-
pling reaction is chemo- and re-
gioselective for 3-hydroxypyri-
dine. Next, various substituted
meta-hydroxypyridines were ex-
amined for the homocoupling
reaction under the same reac-
tion conditions. Interestingly, all
the 2-substituted-5-hydroxypyri-
dine reacted smoothly to give
regioselectively 6,6’-substituted-
(2,2’-bipyridine)-3,3’-diol (Table 2,
entries 1, 2, 5–10, and 13). The
presence of an electron-with-
drawing group at the 2-position
slightly affected the reaction Scheme 2. Plausible mechanism for the homocoupling.
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Table 2. Substrate scope of unactivated hydroxypyridyls for the homo-
coupling reaction.[a]
Table 3. Investigation of the homocoupling reaction for the phenolic
protection of hydroxypyridines.
Entry Substrate
Product
Yield [%][a]
70 (85)
1
Entry
R
Yield
1
2
3
4
5
H
No reaction
No reaction
No reaction
No reaction
No reaction
2
32 (60)
OMOM
OnBu
Oallyl
OBn
3
4
0[b]
0[b]
oethanol, which can disrupt the hydrogen-bonding pyridine
coordination, was found to suppress the reaction. We also ex-
cluded the possibility of a radical reactivity through hyperva-
lent iodine(III) induced single electron transfer (SET) because
the addition of a radical scavenger such as 2,6-di-tert-butyl-4-
methylphenol (BHT), TEMPO, and diphenylethylene (DPE) had
no influence on the yield of the reaction.
5
6
7
49 (70)
69 (80)
64 (75)
Next, we performed a cross-over homocoupling reaction by
using two different 6-substituted 3-hydroxypyridines
(Scheme 3). We obtained three products that correspond to
two homocoupling and one cross-coupling in a nearly 2:2:1
ratio. When the reaction was performed using a 6-substituted
3-hydroxypyridine and a differently 6-substituted 3-alkoxypyri-
dine, only the homocoupling product from the 6-substituted
3-hydroxypyridine was obtained. These results of our cross-
over coupling experiments clearly show that the reaction takes
place intramolecularly and concerted-like.
8
66 (72)
9
66 (76)
46 (65)
In summary, a new metal-free selective homocoupling of
meta-hydroxypyridine using iodine(III) has been developed. In
this methodology, prefunctionalization of the pyridine is not
required, and the coupling takes place exclusively at the ortho-
position with respect to the hydroxypyridine. The 3,3’-dihy-
droxy-2,2’-bipyridine derivatives have been widely applied as li-
gands for coordination of transitional metals for many applica-
tions.
10
11
12
0[b]
0[b]
13
53 (70)
Experimental Section
General procedure for the preparation of pyridol derivatives (2a–i).
To a stirred solution of the pyridinol (1a–i, 4.14 mmol, 3.0 equiv) in
CH2Cl2 (8 mL) were added Cs2CO3 (0.69 mmol, 0.5 equiv) and PIDA
(1.38 mmol, 1.0 equiv) at room temperature for 2 h. The solution
was then filtered and washed with hot hexane, and then concen-
trated in vacuo. Purification of the residue by column chromatog-
raphy on silica gel gave the corresponding bipyridium.
[a] Unless otherwise mentioned, all reactions were carried out using sub-
strate 1–8 (3.0 equiv), PIDA (1.0 equiv), and Cs2CO3 (0.5 equiv). Isolated
yields. Yields estimated directly from the crude product by 1H NMR spec-
troscopic analysis using 1,1,2,2-tetrachloroethane as an internal standard
are given in parenthesis. [b] No coupling products were obtained.
diate III, which can then undergo a regioselective intramolecu-
lar reaction to form the product. The favorable coordination of
the iodine group to the nitrogen of pyridine has been report-
ed.[11] Thus, although the ortho-ortho regioselectivity of the ho-
mocoupling reaction seems surprising, it can be clearly ex-
plained. The addition of a protic polar solvent such as trifluor-
Acknowledgements
I would like to thank the National Science Council of Taiwan
for financial support and Prof. Koichi Narasaka for the com-
ments and discussion for this manuscript.
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Keywords: 3,3’-dihydroxy-2,2’-bipyridine · direct CÀC bond
formation
· hypervalent iodine · meta-hydroxypyridines ·
metal-free CÀH homocoupling reaction
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Received: November 30, 2014
Published online on && &&, 0000
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Communication
COMMUNICATION
Homocoupling Reactions
Ping Syun Yang, Mi Ting Tsai,
Meng Han Tsai, Chi Wi Ong*
&& – &&
The CÀH homocoupling of meta-hy-
droxypyridines with phenyliodine(III) di-
acetate (PIDA) was carried out in di-
chloromethane at room temperature in
the presence of cesium carbonate. The
coupling reaction was found to be
highly regioselective with respect to the
hydroxy group at the pyridine ring.
The Regioselective Homocoupling of
meta-Hydroxypyridines with
Hypervalent Iodine(III)
Chem. Asian J. 2014, 00, 0 – 0
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