Regioselective Radical Arylation of 3-Hydroxypyridines

Article abstract of DOI:10.1021/acs.joc.6b00894

The titanium(III)-mediated radical arylation of 3-hydroxypyridines was found to proceed with high regioselectivity for the 2-position. Using aryldiazonium chlorides, which were prepared from the corresponding anilines, as aryl radical sources, a range of 3-hydroxy-2-phenylpyridines were obtained in moderate to good yields under simple reaction conditions. Reactions of ortho-carboxylic ester substituted phenyldiazonium salts directly provided tricyclic benzopyranopyridinones.

Full text of DOI:10.1021/acs.joc.6b00894

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Note
Regioselective radical arylation of 3-hydroxypyridines
Michael Carl Dieter Fürst, Leonard R. Bock, and Markus Rolf Heinrich
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00894 • Publication Date (Web): 03 Jun 2016
Downloaded from http://pubs.acs.org on June 3, 2016
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Regioselective radical arylation of 3-hydroxypyridines
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Michael C. D. Fürst, Leonard R. Bock, Markus R. Heinrich*
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Department of Chemistry and Pharmacy, Pharmaceutical Chemistry, FriedrichꢀAlexanderꢀ
Universität ErlangenꢀNürnberg, Schuhstraße 19, 91052 Erlangen, Germany
markus.heinrich@fau.de
Abstract
The titanium(III)ꢀmediated radical arylation of 3ꢀhydroxypyridines was found to proceed with
high regioselectivity for the 2ꢀposition. Using aryldiazonium chlorides, which were prepared
from the corresponding anilines, as aryl radical sources, a range of 3ꢀhydroxyꢀ2ꢀphenylpyridines
was obtained in moderate to good yields under simple reaction conditions. Reactions of orthoꢀ
carboxylic ester substituted phenyldiazonium salts directly provided tricyclic benzopyranoꢀ
pyridinones.
O
O
HO
TiCl3
(1 equiv)
R1 =
COOMe
R1
TiCl3
(1 equiv)
HO
H
N2 Cl
R1
R2
+
N
N
R2
R2
2
N
4 examples
47-57% yield
16 examples
32-74% yield
Radical arylation reactions have recently become increasingly popular for the synthesis of biaryl
compounds.1 Due to the fact that such transformations are formally comparable to aromatic CꢀH
activation reactions, less demanding starting materials can be used than in established Suzukiꢀ
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type and related transitionꢀmetal catalyzed crossꢀcoupling reactions. On the other hand, many
radical arylations of substituted benzenes still suffer from insufficient regioselectivity,2 so that
unsubstituted benzene remains to be a commonly preferred substrate.3,4 Notable exceptions are
arylations of anilines5 and phenols,6 for which comparably good selectivities were recently
observed. A further, and rather general drawback of most radical arylation reactions is that the
reactant acting as radical acceptor has to be employed in large excess to counterbalance the
relatively low rate of addition of aryl radicals to benzenes.7
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Regarding regioselectivity in particular, good results can be obtained in arylations of electronꢀ
rich heterocycles such as furans8 and pyrrols,9 which are attacked with high selectivity at the
carbon atoms adjacent to the heteroatom (2ꢀ and/or 5ꢀposition). The radical arylation of pyridine,
in contrast, was found to be strongly dependent on the reaction conditions. While reactions in
acidic media favor arylation in the 2ꢀ and 4ꢀpositions of the pyridine core,10 the free base is
commonly converted to all three possible regioisomers in reactions proceeding via aryl
radicals.2b,11 Recent examples are shown in Scheme 1.12ꢀ14
Scheme 1. Radical arylation of pyridines.
Following the pHꢀcontrolled selectivity profile outlined above, all three isomers were obtained
from the tertꢀbutoxide mediated reaction of iodobenzene with pyridine (Scheme 1, (1)).12 The
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photocatalyzed arylation (Scheme 1, (2)),13,15 in which a pyridinium ion assumed the role of aryl
radical acceptor, proceeded with full selectivity for the 2ꢀposition due to the presence of a
blocking substituent in the 4ꢀposition.
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Having previously noticed the highly directing effect of hydroxy groups in titanium(III)ꢀ
mediated radical arylations of phenols,6,8 it was of interest to investigate how the regioꢀ
selectivity controlling properties of this strongly electronꢀdonating substituent would interact
with those of the aromatic core of pyridine. Although basically four regioisomers can be
expected from the arylation of 3ꢀhydroxypyridine, the results of this work demonstrate that such
arylations can be conducted with exceptionally high regioselectivity (Scheme 1, (3)). Until now,
biaryl compounds derived from an arylꢀaryl coupling of 3ꢀhydroxypyridine at its 2ꢀposition have
been performed via Negishiꢀ or Suzukiꢀtype crossꢀcoupling reactions,16,17 or via rearrangement
of benzoylfurane derivatives.18
3ꢀHydroxypyridine (1a) was chosen for optimization experiments since the matched effects of a
protonated pyridine nitrogen and that of a ortho/paraꢀdirecting hydroxy group should favor aryl
radical attack in the 2ꢀ, 4ꢀ and 6ꢀpositions of the pyridine core. Thus, basically three regioisomers
were expected from the reaction of 1a and 4ꢀchlorophenyldiazonium chloride (2a) under acidic
conditions, which would also be in agreement with the product distribution earlier observed in
the arylations of 3ꢀmethylpyridine (2/4/6 = 30:42:28) and 3ꢀfluoropyridine (2/4/6 = 26:50:24).13
Selected results from a series of experiments with 1a and 2a are summarized in Table 1 (see also
Supporting Information).
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Table 1. Reductive titanium(III)ꢀmediated arylation of 3ꢀhydroxypyridine (1a): optimization of
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reaction conditions.
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pyridine
1a
(equiv)
time of addition
of 2a
(min)
TiCl3
(equiv)
yield 3a
entry
(%)a,b
1
2
3
4
5
6
5
2
15 min
15 min
15 min
15 min
7.5 min
30 min
62
80
80
63
71
55
10
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10
10
10
2
1
0.5
2
2
aGeneral conditions: Slow addition of 2a (2 mmol in 5 mL 3
bYields determined by 1HꢀNMR using maleic acid as internal standard.
N HCl) to a mixture of 1a (3ꢀ10 mmol) and TiCl3 (1ꢀ3 mmol) over 7.5ꢀ30 min at r.t.
The reactions were generally performed under slow addition of a freshly prepared solution of
aqueous 4ꢀchlorophenyldiazonium chloride (2a) to a mixture containing pyridine 1a and the
reductant titanium(III) chloride. Slow addition of 2a is known to be an effective measure to
avoid homocoupling of aryl radicals to unreacted diazonium ions.19 A rise in the excess of 3ꢀ
hydroxypyridine (1a) from five to ten equivalents led to a significant increase in yield from 62%
to 80% (entries 1 and 2). This yield fortunately remained unchanged upon reduction of the
amount of titanium(III) chloride from two to only one equivalent (entries 2 and 3). A further
decrease to 0.5 equivalents of reductant per diazonium ion led to 63% yield (entry 4). This
observation shows that the arylation partially proceeds as a chain process, as the theoretical yield
for a nonꢀchain reaction with 0.5 equivalents of titanium(III) chloride would be only 50%. The
fact that a faster as well as a slower addition of the diazonium salt 2a to the reaction mixture
leads to decreased yields has already been observed in earlier studies (entries 5 and 6).6b Faster
addition of 2a can thereby be associated with increased homocoupling,19 whereas the negative
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effect of a prolonged addition time again points to some participation of a radical chain process
(see Scheme 2).
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An analysis of the product mixture (entry 3, Table 1) by HPLC revealed a 10:1.4:1 ratio of
regioisomers with compound 3a as the major product (see Supporting Information). Due to an
overlap of signals, only one of the minor isomers, namely the 6ꢀisomer, could be detected by 1H
NMR of the crude reaction mixture in a comparable ratio of 3a to 6ꢀisomer of 8:1. While 3a and
the 6ꢀisomer were obtained after column chromatography in 76% and 9% yield, respectively, the
missing 4ꢀisomer could not be isolated, which HPLC analysis had suggested to be formed as
minor isomer as well.
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In a second series of experiments, whether the regioselectivity for 3a could also be observed in
radical arylations starting from 4ꢀchlorophenylhydrazine (4a) as alternative aryl radical precursor
(Table 2) was evaluated. Hydrazine 4a was again slowly added to the reaction mixture under
conditions adopted from earlier studies on the radical arylation of anilines and phenols.5b,c The
manganese(IV)ꢀmediated reaction under strongly basic conditions, which had been successful for
the arylation of phenol,5b gave 3a only in a yield lower than 10% (entry 1). Weakly acidic
conditions with manganese dioxide as oxidant increased the yield of 3a to 33% (entry 2), which
is however still significantly lower than what can be achieved in a comparable titanium(III)ꢀ
mediated reaction with only three equivalents of pyridine 1a (50%, see Supporting Information).
The third attempt (entry 3), being basically attractive as only air is used as oxidant,5c was again
unsuccessful, but confirmed that basic conditions are most probably unfavorable for the radical
arylation of 3ꢀhydroxypyridine (1a).
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Table 2. Oxidative arylation of 3ꢀhydroxypyridine (1a): optimization of reaction conditions.
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time of
addition
of 4a
yield
entry (min)
reaction conditionsa
3a (%)c
1
2
3
10b
60
MnO2 (5 equiv), NaOH
(10 equiv), CH3CN, 10 min
< 10
33
MnO2 (5 equiv), HOAc
(2 equiv), CH3CN, 60 min
540
Air (O2), NaOH, 24 h
11
aGeneral conditions: Slow addition of 4a to 1a (3 equiv). bHydrazine 4a added as hydrochloride. cYields determined by 1HꢀNMR using maleic
acid as internal standard.
With these results from preliminary studies, and with optimized conditions available (Table 1,
entry 3), an investigation of the scope and limitations of the regioselective radical arylation of 3ꢀ
hydroxypyridine (1a) (Table 3) was initiated. The summarized results show that the
titanium(III)ꢀmediated reductive radical arylation of 3ꢀhydroxypyridine (1a) can be carried out
with a wide range of aryldiazonium salts. All halogenated and methylated derivatives 2aꢀk
(entries 1ꢀ11) gave moderate to good yields. Among the electronꢀdonating substituents (entries
12ꢀ15), only the 4ꢀdimethylamino compound 2o failed to give the desired biaryl 3o (entry 15).
The fact that most electronꢀdonating (entries 12ꢀ14) and electronꢀaccepting substitutents (entries
16 and 17) were tolerated, is in agreement with an, if at all, only minor participation of a radical
chain process. Radical arylations proceeding via chain processes usually show some preference
for acceptorꢀsubstituted aryldiazonium salts,20 since the cyclohexadienyl radical adduct arising
from the addition step is then more easily oxidized by the diazonium ion in the radical transfer
step.21 The lower yield obtained for 3m (40%, entry 13) can be explained by a particular
instability of diazonium salt 2m, which partially decomposed in the syringe during addition to
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the reaction mixture. A short series of experiments with diazonium salts 2r-u bearing a methyl
ester functionality in the orthoꢀposition to the diazonium unit (entries 18ꢀ21) directly provided
tricyclic benzopyranopyridinones 5a-d via a sequence of radical arylation and lactonization.
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Table 3. Titanium(III)ꢀmediated arylation of 3ꢀhydroxypyridine (1a): scope of diazonium salts.
HO
R1
N
R2
TiCl3
R1
HO
H
N2 Cl
(1 equiv)
H2O/HCl
3a-n,p,q
R2
+
2
O
O
N
2a-u
(slow addition)
1a
(10 equiv)
R1
2-CO2Me
=
N
R2
5a-d
diazonium salt
yield
entry 2: R1, R2 =
3 or 5 (%)a,b,c
1
2a: 4ꢀCl, H
3a: 74
3b: 64
3c: 56
3d: 52
3e: 50
3f: 48
3g: 56
3h: 47
3i: 43
3j: 64
3k: 58
3l: 65
3m: 40
3n: 32
3o: ꢀꢀ
2
2b: 4ꢀF, H
3
2c: 4ꢀBr, H
4
2d: 3ꢀF, H
5
2e: 3ꢀCl, H
6
2f: 3ꢀBr, H
7
2g: 2ꢀF, H
8
2h: 2ꢀCl, H
9
2i: 2ꢀBr, H
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21
2j: 4ꢀMe, H
2k: 3ꢀMe, H
2l: 4ꢀOMe, H
2m: 3ꢀOMe, H
2n: 4ꢀNHAc, H
2o: 4ꢀNMe2, H
2p: 4ꢀCF3, H
2q: 4ꢀCOOMe, H
2r: 2ꢀCOOMe, H
2s: 2ꢀCOOMe, 4ꢀF
3p: 49
3q: 55
5a: 57
5b: 50
5c: 52
5d: 47
2t: 2ꢀCOOMe, 4ꢀCl
2u: 2ꢀCOOMe, 4ꢀBr
aGeneral conditions: Slow addition of diazonium salt 2a-u (1 mmol, in 2.5 mL, 1 equiv) to a mixture of 1a and TiCl3 in a mixture of water (5 ml)
and HCl (3
TLC.
N
, 2.5 ml) at rt over 15 min. bYields after purification by column chromatography. cMinor 6ꢀisomer detected in small amounts by
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In the next part of the study, the applicability of the reaction conditions for the transformation of
additional pyridine derivatives was investigated (Figure 1). 5ꢀHydroxyꢀ2ꢀmethylpyridine (1b)
provided the arylated product 6 in 76% yield, thereby showing that benzylic positions are
tolerated, although they could basically complicate the arylation through hydrogen abstraction by
the aryl radical.1a Arylation of 4ꢀhydroxypyridine afforded an inseparable mixture of the two
regioisomers 7a (14%) and 7b (6%). While the isomeric distribution of 7a and 7b indicates that
the directing effect of the hydroxy group is stronger than that of the protonated pyridine
nitrogen,22 the low combined yield demonstrates the strong advantage of matched directing
substituent effects in radical arylations. The main conclusion that can be drawn from the
experiments with 2ꢀ, 3ꢀ and 4ꢀmethoxypyridine is that a methoxy group has a significantly
weaker ability to direct the radical arylation than the hydroxy functionality.23 The structures of
biaryls 824 and 1025 clearly point to the now predominant effect of the pyridinium core on
product formation, which also becomes apparent from the comparison of the structures of biaryls
7a and 10. The fact that a complex mixture of at least eight minor products was obtained from
the arylation of 3ꢀmethoxypyridine, with biaryl 9 not being detectable after column
chromatography, suggests that the radical addition step did occur, but that subsequent
rearomatization might be more complicated with a methoxy than with an hydroxy group.
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Figure 1. Arylation of hydroxyꢀ and methoxypyridines.
OH
Cl
HO
OH
3
2
N
2
N
N
Cl
Cl
+
6 (76%)
7a (14%)
7b (6%)
OMe
N
MeO
N
4
2
N
OMe
2
Cl
Cl
Cl
8 (23%)
9 (0%)
10 (25%)
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In the next step, the biaryl synthesis was carried out on a larger scale leading to 3a in a yield of
59% with regioselectivity identical to that observed on smaller scale (Scheme 2). Regarding the
overall process, it is currently assumed that the high regioselectivity of the aryl radical attack on
a 3ꢀhydroxypyridinium ion is due to a particularly good stabilization of the resulting adduct 11.
The increased importance of product stabilization in radical arylations of arenes in comparion
with the aryl radical addition to alkenes has been noted previously.26
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Scheme 2. Large scale arylation of 3ꢀhydroxypyridine (1a) and possible mode of reaction.
The exceptional capabilities of 3ꢀhydroxypyridine (1a) as an aryl radical acceptor were finally
confirmed in a two competition experiments. The titanium(III)ꢀmediated reaction of 4ꢀchloroꢀ
phenyldiazonium chloride (2a) with equal amounts of 1a and 4ꢀmethoxyaniline (each 5
equivalents) provided 3a exclusively in a yield of 56%, which is only slightly less the yield
reported in Table 1 (entry 1). Even more surprisingly, 3ꢀhydroxypyridine (1a) was able to
outperform furan as a radical acceptor. Conducted under identical conditions as described above,
but with five equivalents of furan instead of 4ꢀmethoxyaniline, this competition experiment led
to 3a in 58% yield and no detectable amount of 2ꢀ(4ꢀchlorophenyl)furan.
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In summary, it has been shown that the radical arylation of 3ꢀhydroxypyridine can be carried out
with high regioselectivity for the 2ꢀposition. Using titanium(III) chloride as a stoichiometric
reductant under simple reaction conditions, a variety of diazonium salts could be employed for
the synthesis of the corresponding biaryl compounds. Taking advantage of the high reactivity of
3ꢀhydroxypyridine as an aryl radical acceptor, this methodology provides a new straightforward
access to biaryl compounds for medicinal chemistry purposes16b and to benzopyranopyridinones
described as ligands in organic light emitting diodes.27,28
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Experimental Section
General Experimental:
1
Solvents and reagents were obtained from commercial sources and used as received. H NMR
and 13C NMR spectra were recorded using 600 MHz (13C: 151 MHz), 400 MHz (13C: 101 MHz)
and 360 MHz (13C: 91 MHz) spectrometers. For 1H NMR spectra CDCl3, CD3OD and (CD3)2SO
were used as solvents referenced to TMS (0 ppm), CHCl3 (7.26 ppm), CD3OH (3.31 ppm) and
(CD3)2SO (2.50 ppm). Chemical shifts are reported in parts per million (ppm). Coupling
constants are in Hertz (Hz). The following abbreviations are used for the description of signals: s
13
(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), bs (broad singlet). C NMR spectra
were recorded in CDCl3, CD3OD and (CD3)2SO using CDCl3 (77.0 ppm), CD3OD (49.05 ppm)
and (CD3)2SO (39.43 ppm) as standard. Chemical shifts are reported in parts per million (ppm).
Mass spectra were recorded using electron spray ionization (ESI) and a sector field mass
analyzer for HRMS measurements. Analytical TLC was carried out on silica gel plates using
short wave (254 nm) UV light to visualize components. Silica gel (Kieselgel 60, 40ꢀ63mm) was
used for flash column chromatography. HPLC analysis was carried out on a LCꢀMS system with
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a C18 analytical column (4.6×50 mm, 3.5 µm, flow rate: 1:23 ml/min) coupled to a QDa mass
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detector equipped with an ESIꢀtrap. Parameters: CH3CN in H2O 10ꢀ90% in 24 min, 0.1% formic
acid.
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General procedure for synthesis of 3-hydroxy-2-phenylpyridines 3 and benzopyrano-
pyridinones 5 (GP1): To an iceꢀcooled degassed solution of the respective aniline (10.0 mmol)
in HCl (3N, 10 mL) and water (10 mL) a degassed solution of sodium nitrite (0.69 g, 10.0 mmol)
in water (5 mL) was added dropwise by syringe pump over a period of 10 minutes. After stirring
for additional 20 minutes at 0 °C, the 0.4
M
solution of diazonium chloride 2 (10 mmol/25 mL)
aryldiazonium chloride
was used for the arylation reactions. A 2.5 mL aliquot of the 0.4
M
solution 2 (1 mmol, 1 equiv.) was added dropwise by syringe pump to a vigorously stirred
solution of 3ꢀhydroxypyridine (1a) (10.0 mmol, 951 mg, 10 equiv.) in water (5 mL), HCl (3 N,
2.5 mL) and titanium(III) chloride (1 mL, approximately 1M solution in 3N hydrochloric acid, 1
mmol) under nitrogen atmosphere over 15 min. After the addition was complete, the mixture was
left to stir for further 10 minutes. Then water (100 mL) and saturated sodium carbonate solution
(25 mL) were added. After extraction with ethyl acetate (3 × 150 mL), the combined organic
phases were washed with saturated aqueous sodium chloride (100 mL) and dried over anhydrous
sodium sulfate. Concentration at reduced pressure gave the desired crude product.
General procedure for synthesis of 6-10 (GP2): 4ꢀChlorophenyldiazonium chloride (2a) (2.5
mL of a 0.4
M solution, 1 mmol, 1 equiv., for preparation see GP1 above) was added dropwise by
syringe pump to a vigorously stirred solution of the respective pyridine derivative (10.0 mmol,
10 equiv.) in water (5 mL), HCl (3 N, 2.5 mL) and titanium(III) chloride (1 mL, approximately
1M solution in 3N hydrochloric acid, 1 mmol) under nitrogen atmosphere over 15 min. After the
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addition was complete, the mixture was left to stir for further 10 min. Then water (100 mL) and
saturated sodium carbonate solution (25 mL) were added. After extraction with ethyl acetate (3 ×
150 mL), the combined organic phases were washed with saturated aqueous sodium chloride
solution (100 mL) and dried anhydrous over sodium sulfate. Concentration at reduced pressure
provided the desired crude product.
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Procedure for large scale experiment: 4ꢀChlorophenyldiazonium chloride (2a) (12.5 mL of a
0.4
M solution, 5 mmol, for preparation see GP 1 above) were added dropwise by syringe pump
to a vigorously stirred solution of 3ꢀhydroxypyridine (1a) (50.0 mmol, 4.76 g, 10 equiv.) in water
(25 mL), HCl (3 N, 12.5 mL) and titanium(III) chloride (5 mL, approximately 1M solution in 3N
hydrochloric acid, 5 mmol) under nitrogen atmosphere within 15 min. After the addition was
complete, the mixture was left to stir for further 10 min. Then water (500 mL) and saturated
sodium carbonate solution (125 mL) were added. After extraction with ethyl acetate (3 × 300
mL), the combined organic phases were washed with saturated aqueous sodium chloride solution
(200 mL) and dried over sodium sulfate. Concentration at reduced pressure afforded the desired
crude product.
Procedure for competition experiments: 4ꢀChlorophenyldiazonium chloride (2a) (2.5 mL of a
0.4
M solution, 1 mmol, 1 equiv., for preparation see GP 1 above) were added dropwise by using
a syringe pump to a vigorously stirred solution of 3ꢀhydroxypyridine (1a) (476 mg, 5.0 mmol,
5 equiv.) and 4ꢀmethoxyaniline (616 mg, 5.0 mmol, 5 equiv.) or furan (364 µL, 5.0 mmol,
5 equiv.) in water (5 mL), HCl (3 N, 2.5 mL) and titanium(III) chloride (1 mL, approximately
1M solution in 3N hydrochloric acid, 1 mmol) under nitrogen atmosphere over 15 min. After the
addition was complete, the mixture was left to stir for further 10 minutes. Then water (100 mL)
and saturated sodium carbonate solution (25 mL) were added. After extraction with ethyl acetate
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(3 × 150 mL), the combined organic phases were washed with saturated aqueous sodium
chloride solution (100 mL) and dried over anhydrous sodium sulfate. After concentration at
reduced pressure, the product mixture was analyzed by 1H NMR spectroscopy. The yields of 3a
and other products were determined by using maleic acid as internal standard.
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2-(4-Chlorophenyl)pyridin-3-ol (3a): Compound 3a was prepared according to GP1 using 4ꢀ
chlorophenyldiazonium chloride (2a). Purification by column chromatography (chloroform /
diethyl ether 10:1 to 1:1) gave 3a (152 mg, 0.74 mmol, 74%) as a white solid. Rf = 0.4 (5:1
chloroform / diethyl ether) [UV]; mp = 231 °C; IR (NaCl, cmꢀ1) ν; 1577, 1459, 1363, 1308,
~
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1297, 1281, 1240, 1183, 1118, 1077, 1008, 831, 751; H NMR (360 MHz, CD3OD) δ 8.10 (dd, J
= 4.6, J = 1.4 Hz, 1H), 7.91ꢀ7.84 (m, 2H), 7.47ꢀ7.39 (m, 2H), 7.33 (dd, J = 8.2, J = 1.4 Hz, 1H),
7.23 (dd, J = 8.2, J = 4.6 Hz, 1H) ; 13C NMR (151 MHz, CD3OD) δ 153.4, 146.0, 141.2, 137.5,
135.1, 131.9, 129.1, 125.3, 125.1; HRMS (ESI), calcd. for C11H9ClNO [M+ + H]: 206.0367,
found: 206.0369. The melting point obtained is in agreement with the value previously
reported.29
2-(4-Fluorophenyl)pyridin-3-ol (3b): Compound 3b was prepared according to GP1 using 4ꢀ
fluorophenyldiazonium chloride (2b). Purification by column chromatography (chloroform /
diethyl ether 10:1 to 1:1) gave 3b (121 mg, 0.64 mmol, 64%) as a white solid. Rf = 0.5 (5:1
chloroform / diethyl ether) [UV]; mp = 228°C; IR (NaCl, cmꢀ1) ν; 2417, 1574, 1510, 1460,
~
1
1358, 1280, 1221, 1181, 1156, 1118, 1078, 835, 797, 761; H NMR (600 MHz, (CD3)2SO) δ
10.21 (s, 1H), 8.14 (dd, J = 4.5, J = 1.4 Hz, 1H), 8.08 (dd, J = 9.1 Hz, JHF = 5.8 Hz, 2H), 7.33
(dd, J = 8.2 Hz, J = 1.5 Hz, 1H), 7.24 (t, JHF = 9.0 Hz, J = 9.0 Hz, 2H), 7.20 (dd, J = 8.2, J = 4.5
Hz, 1H); 13C NMR (151 MHz, (CD3)2SO) δ 161.7 (d, JCF = 244.9 Hz), 151.3, 143.1, 140.1, 134.3
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(d, JCF = 3.0 Hz), 130.7 (d, JCF = 8.2 Hz), 123.6, 123.5, 114.4 (d, JCF = 21.1 Hz); HRMS (ESI),
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calcd. C11H9FNO [M+ + H]: 190.0663, found: 190.0662. The melting point obtained is in
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agreement with the value previously reported.32 1H NMR and C NMR data are in agreement
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with those previously reported.29
2-(4-Bromophenyl)pyridin-3-ol (3c): Compound 3c was prepared according to GP1 using 4ꢀ
bromophenyldiazonium chloride (2c). Purification by column chromatography (chloroform /
diethyl ether 10:1 to 1:1) gave 3c (140 mg, 0.56 mmol, 56%) as a light yellow solid. Rf = 0.4 (5:1
chloroform / diethyl ether) [UV]; mp = 232 °C; IR (NaCl, cmꢀ1) ν; 2466, 1575, 1457, 1364,
~
1310, 1297, 1283, 1274, 1240, 1184, 1117, 1077, 832, 761; 1H NMR (400 MHz, CD3OD) δ 8.10
(dd, J = 4.6, J = 1.4 Hz, 1H), 7.85ꢀ7.76 (m, 2H), 7.63ꢀ7.54 (m, 2H), 7.33 (dd, J = 8.2, J = 1.4 Hz,
13
1H), 7.23 (dd, J = 8.2, J = 4.6 Hz, 1H); C NMR (101 MHz, CD3OD) δ 153.5, 146.1, 141.3,
138.1, 132.2, 132.2, 125.4, 125.2, 123.4; HRMS (ESI), calcd. for C11H9BrNO [M+ + H]
249.9862; found: 249.9868.
2-(3-Fluorophenyl)pyridin-3-ol (3d): Compound 3d was prepared according to GP1 using 3ꢀ
fluorophenyldiazonium chloride (2d). Purification by column chromatography (chloroform /
diethyl ether 10:1 to 1:1) gave 3d (98.0 mg, 0.52 mmol, 52%) as a light brown solid. Rf = 0.4
(5:1 chloroform / diethyl ether) [UV]; mp = 193 °C; IR (NaCl, cmꢀ1) ν; 2511, 1583, 1430, 1359,
~
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1305, 1293, 1271, 1170, 1119, 1071, 874, 850, 790, 758; H NMR (600 MHz, CD3OD) δ 8.11
(dd, J = 4.6, J = 1.3 Hz, 1H), 7.72 (dd, JHF = 7.8, J = 0.9 Hz, 1H), 7.65ꢀ7.61 (m, 1H), 7.47ꢀ7.40
(m, 1H), 7.34 (dd, J = 8.2, J = 1.3 Hz, 1H), 7.25 (dd, J = 8.2, J = 4.6 Hz, 1H), 7.15ꢀ7.07 (m, 1H);
13C NMR (151 MHz, CD3OD) δ 164.1 (d, JCF = 242.9 Hz), 153.6, 145.9 (d, JCF = 2.6 Hz), 141.4,
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141.3, 130.7 (d, JCF = 8.3 Hz), 125.6, 125.3, 126.2 (d, JCF = 2.8 Hz), 117.0 (d, JCF = 23.1 Hz),
115.9 (d, JCF = 21.3 Hz); HRMS (ESI), calcd. for C11H9FNO [M+ + H] 190.0663; found:
190.0662.
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2-(3-Chlorophenyl)pyridin-3-ol (3e): Compound 3e was prepared according to GP1 using 3ꢀ
chlorophenyldiazonium chloride (2e). Purification by column chromatography (chloroform /
diethyl ether 10:1 to 1:1) gave 3e (103 mg, 0.50 mmol, 50%) as a light brown solid. Rf = 0.4 (5:1
chloroform / diethyl ether) [UV]; mp = 226 °C; IR (NaCl, cmꢀ1) ν; 1577, 1350, 1300, 1267,
~
1
1179, 1118, 1074, 883, 785, 750; H NMR (400 MHz, CD3OD) δ 8.11 (dd, J = 4.6, J = 1.4 Hz,
1H), 7.90 (t, J = 1.8 Hz, 1H), 7.82 (dt, J = 7.5, J = 1.5 Hz, 1H), 7.41 (t, J = 7.7 Hz, 1H), 7.39ꢀ
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7.32 (m, 2H), 7.24 (dd, J = 8.2, J = 4.6 Hz, 1H); C NMR (101 MHz, CD3OD) δ 153.5, 145.6,
141.3, 140.9, 134.9, 130.5, 130.2, 129.1, 128.7, 125.5, 125.4; HRMS (ESI), calcd. for
C11H9ClNO [M+ + H] 206.0367; found: 206.0369. The melting point obtained is in agreement
with the value previously reported.29
2-(3-Bromophenyl)pyridin-3-ol (3f): Compound 3f was prepared according to GP1 using 3ꢀ
bromophenyldiazonium chloride (2f). Purification by column chromatography (chloroform /
diethyl ether 10:1 to 1:1) gave 3f (121 mg, 0.48 mmol, 48%) as a light brown solid. Rf = 0.4 (5:1
chloroform / diethyl ether) [UV]; mp = 220 °C; IR (NaCl, cmꢀ1) ν; 2413, 1575, 1458, 1351,
~
1
1300, 1267, 1178, 1116, 1073, 795, 747; H NMR (400 MHz, CD3OD): δ 8.11 (dd, J = 4.6, J =
1.4 Hz, 1H), 8.05 (ddd, J = 2.1, J = 1.6, J = 0.4 Hz, 1H), 7.87 (ddd, J = 7.8, J = 1.6, J = 1.1 Hz,
1H), 7.52 (ddd, J = 8.0, J = 2.1, J = 1.1 Hz, 1H), 7.38ꢀ7.32 (m, 2H), 7.24 (dd, J = 8.2, J = 4.6
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Hz, 1H); 13C NMR (101 MHz, CD3OD): δ 153.5, 145.4, 141.2, 141.1, 133.1, 132.0, 130.7, 129.0,
125.4, 125.3, 122.8; HRMS (ESI), calcd. for C11H9BrNO [M+ + H]: 249.9862, found: 249.9859.
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2-(2-Fluorophenyl)pyridin-3-ol (3g): Compound 3g was prepared according to GP1 using 2ꢀ
fluorophenyldiazonium chloride (2g). Purification by column chromatography (chloroform /
diethyl ether 10:1 to 1:1) gave 3g (106 mg, 0.56 mmol, 56%) as a light brown solid. Rf = 0.4 (5:1
chloroform / diethyl ether) [UV]; mp = 178 °C; IR (NaCl, cmꢀ1) ν; 1575, 1449, 1368, 1307,
~
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1293, 1262, 1218, 1181, 1120, 1102, 819, 801, 755; H NMR (600 MHz, CD3OD) δ 8.08 (dd, J
= 4.6, J = 1.1 Hz, 1H), 7.48ꢀ7.40 (m, 2H), 7.34 (dd, J = 8.3, J = 1.4 Hz, 1H), 7.29 (dd, J = 8.3, J
= 4.6 Hz, 1H), 7.27ꢀ7.24 (m, 1H), 7.19ꢀ7.14 (m, 1H); 13C NMR (101 MHz, CD3OD) δ 161.8 (d,
JCF = 248.1 Hz), 153.9, 144.1, 140.7, 132.7 (d, JCF = 3.6 Hz), 131.4 (d, JCF = 8.2 Hz), 126.9 (d,
JCF = 15.9 Hz), 125.6, 125.0 (d, JCF = 3.6 Hz), 124.9, 116.5 (d, JCF = 22.2 Hz); HRMS (ESI),
calcd. for C11H9FNO [M+ + H] 190.0663; found: 190.0668.
2-(2-Chlorophenyl)pyridin-3-ol (3h): Compound 3h was prepared according to GP1 using 2ꢀ
chlorophenyldiazonium chloride (2h). Purification by column chromatography (chloroform /
diethyl ether 10:1 to 1:1) gave 3h (96.2 mg, 0.47 mmol, 47%) as a yellow solid. Rf = 0.3 (5:1
chloroform / diethyl ether) [UV]; mp = 243 °C; IR (NaCl, cmꢀ1) ν; 1559, 1456, 1434, 1367,
~
1303, 1283, 1245, 1181, 1114, 1085, 752, 745; 1H NMR (600 MHz, CD3OD) δ 8.06 (dd, J = 4.6,
J = 1.5 Hz, 1H), 7.51ꢀ7.45 (m, 1H), 7.41ꢀ7.35 (m, 3H), 7.35ꢀ7.33 (m, 1H), 7.31 (dd, J = 8.3, J =
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4.6 Hz, 1H); C NMR (151 MHz, CD3OD) δ 153.6, 147.0, 140.4, 138.2, 134.9, 132.5, 130.8,
130.5, 127.8, 125.8, 125.0; HRMS (ESI), calcd. for C11H9ClNO [M+ + H] 206.0367; found:
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2-(2-Bromophenyl)pyridin-3-ol (3i): Compound 3i was prepared according to GP1 using 2ꢀ
bromophenyldiazonium chloride (2i). Purification by column chromatography (chloroform /
diethyl ether 10:1 to 1:1) gave 3i (107 mg, 0.43 mmol, 43%) as a light brown solid. Rf = 0.4 (5:1
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chloroform / diethyl ether) [UV]; mp = 246 °C; IR (NaCl, cmꢀ1) ν; 1572, 1456, 1370, 1303,
~
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1280, 1252, 1184, 1110, 1082, 1011, 799, 773, 750, 721, H NMR (600 MHz, CD3OD) δ 8.05
(dd, J = 4.5, J = 1.6 Hz, 1H), 7.69ꢀ7.66 (m, 1H), 7.45ꢀ7.41 (m, 1H), 7.35ꢀ7.29 (m, 4H); 13C NMR
(101 MHz, CD3OD) δ 153.3, 148.4, 140.2, 133.7, 132.4, 130.9, 128.4, 125.8, 125.0, 124.5 (one
signal missing due to overlap); HRMS (ESI), calcd. for C11H9BrNO [M+ + H] 249.9862; found:
249.9857.
2-(p-Tolyl)pyridin-3-ol (3j): Compound 3j was prepared according to GP1 using 4ꢀ
methylphenyldiazonium chloride (2j). Purification by column chromatography (chloroform /
diethyl ether 10:1 to 1:1) gave 3j (119 mg, 0.64 mmol, 64%) as a light brown solid. Rf = 0.3 (5:1
chloroform / diethyl ether) [UV]; mp = 199 °C; IR (NaCl, cmꢀ1) ν; 2919, 1577, 1454, 1300,
~
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1280, 1242, 1183, 1109, 1017, 824, 800, 760; H NMR (400 MHz, CD3OD) δ 8.06 (d, J = 4.1
Hz, 1H), 7.75ꢀ7.69 (m, 2H), 7.31 (dd, J = 8.2, J = 1.4 Hz, 1H), 7.23ꢀ7.26 (m, 2H), 7.19 (dd, J =
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8.2, J = 4.7 Hz, 1H), 2.38 (s, 3H); C NMR (101 MHz, CD3OD) δ 153.3, 147.7, 140.8, 139.3,
136.0, 130.2, 129.6, 125.2, 124.5, 21.4; HRMS (ESI), calcd. for C12H12NO [M+ + H] 186.0913;
found: 186.0917. The melting point obtained is in agreement with the value previously
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2-(m-Tolyl)pyridin-3-ol (3k): Compound 3k was prepared according to GP1 using 3ꢀ
methylphenyldiazonium chloride (2k). Purification by column chromatography (chloroform /
diethyl ether 10:1 to 1:1) gave 3k (107 mg, 0.58 mmol, 58%) as a white solid. Rf = 0.4 (5:1
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chloroform / diethyl ether) [UV]; mp = 172 °C; IR (NaCl, cmꢀ1) ν; 3021.4, 2918.7, 2624.2,
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1573.6, 1454.1, 1364.9, 1303.6, 1281.0, 1203.9, 1116.1, 802.2, 755.5, 698.6; H NMR (600
MHz, CD3OD ) δ 8.07 (dd, J = 4.6, J = 1.0 Hz, 1H), 7.72ꢀ7.54 (m, 2H), 7.37ꢀ 7.25 (m, 2H), 7.21ꢀ
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7.17 (m, 2H), 2.39 (s, 3H); C NMR (151 MHz, CD3OD) δ 153.3, 147.8, 140.8, 138.7, 138.6,
130.9, 129.9, 128.9, 127.5, 125.3, 124.7, 21.6; HRMS (ESI), calcd. for C12H12NO [M+ + H];
186.0913 found: 186.0919. The melting point obtained is in agreement with the value previously
reported.29
2-(4-Methoxyphenyl)pyridin-3-ol (3l): Compound 3l was prepared according to GP1 using 4ꢀ
methoxyphenyldiazonium chloride (2l). Purification by column chromatography (chloroform /
diethyl ether 10:1 to 1:1) gave 3l (131 mg, 0.65 mmol, 65%) as a light brown solid. Rf = 0.3 (5:1
chloroform / diethyl ether) [UV]; mp = 186 °C; IR (NaCl, cmꢀ1) ν; 2918, 1610, 1570, 1514,
~
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1457, 1374, 1282, 1250, 1179, 1109, 1024, 837, 799, 766; H NMR (600 MHz, CD3OD) δ 8.05
(dd, J = 4.7, J = 1.3 Hz, 1H), 7.84ꢀ7.77 (m, 2H), 7.32ꢀ7.27 (m, 1H), 7.17 (dd, J = 8.2, J = 4.7 Hz,
1H), 7.01ꢀ6.95 (m, 2H), 3.84 (s, 3H); 13C NMR (101 MHz, CD3OD) δ 161.3, 153.1, 147.4,
140.8, 131.6, 131.2, 125.1, 124.2, 114.4, 55.8; HRMS (ESI), calcd. for C12H12NO2 [M+ + H]
202.0863; found: 202.0858. The melting point obtained is in agreement with the value previously
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2-(3-Methoxyphenyl)pyridin-3-ol (3m): Compound 3m was prepared according to GP1 using 3ꢀ
methoxyphenyldiazonium chloride (2m). Purification by column chromatography (chloroform /
diethyl ether 10:1 to 1:1) gave 3m (80 mg, 0.40 mmol, 40%) as a white solid. Rf = 0.3 (5:1
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chloroform / diethyl ether) [UV]; mp = 181 °C; IR (NaCl, cmꢀ1) ν; 2935, 1582, 1457, 1424,
~
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1283, 1229, 1170, 1116, 1031, 801, 760, 695; H NMR (600 MHz, CD3OD) δ 8.08 (dd, J = 4.7,
J = 1.3 Hz, 1H), 7.44ꢀ7.38 (m, 2H), 7.36 ꢀ7.30 (m, 2H), 7.22 (dd, J = 8.2, J = 4.7 Hz, 1H), 6.95
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(ddd, J = 8.2, J = 2.6, J = 1.0 Hz, 1H), 3.84 (s, 3H); C NMR (151 MHz, CD3OD) δ 160.9,
153.3, 147.3, 140.9, 140.1, 129.9, 125.4, 124.9, 122.8, 115.8, 115.0, 55.7; HRMS (ESI), calcd.
for C12H12NO2 [M+ + H]; 202.0863 found: 202.0866. The melting point obtained is in agreement
with the value previously reported.29
N-(4-(3-Hydroxypyridin-2-yl)phenyl)acetamide (3n): Compound 3n was prepared according to
GP1 using 4ꢀacetamidobenzenediazonium chloride (2n). Purification by column chromatography
(chloroform / methanol 15:1 to 7:1) gave 3n (73.0 mg, 0.32 mmol, 32%) as a light orange solid.
Rf = 0.3 (10:1 chloroform / methanol) [UV]; mp = 106 °C; IR (NaCl, cmꢀ1) ν; 3434, 1646, 1535,
~
1455, 1402, 1371, 1318, 1282, 1182, 1111, 1013, 767; 1H NMR (600 MHz, CD3OD) δ 8.07 (dd,
J = 4.6, J = 1.1 Hz, 1H), 7.86ꢀ7.81 (m, 2H), 7.66ꢀ7.61 (m, 2H), 7.31 (dd, J = 8.2, J = 1.4 Hz,
13
1H), 7.19 (dd, J = 8.2, J = 4.7 Hz, 1H), 2.14 (s, 3H). C NMR (151 MHz, CD3OD) δ 170.3,
145.5, 139.5, 138.6, 133.1, 129.4, 123.8, 123.1, 118.9, 22.5. HRMS (ESI), calcd. for C13H13N2O2
[M+ + H]: 229.0971, found: 229.0972.
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2-(4-(Trifluoromethyl)phenyl)pyridin-3-ol (3p): Compound 3p was prepared according to GP1
using 4ꢀ(trifluoromethyl)phenyldiazonium chloride (2p). Purification by column chromatography
(chloroform / diethyl ether 10:1 to 1:1) gave 3p (119 mg, 0.49 mmol, 49%) as a light brown
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solid. Rf = 0.4 (5:1 chloroform / diethyl ether) [UV]; mp = 240 °C; IR (NaCl, cmꢀ1) ν; 1578,
~
1461, 1327, 1283, 1183, 1160, 1107, 1069, 1012, 845, 719; 1H NMR (400 MHz, CD3OD) δ 8.14
(d, J = 4.0 Hz, 1H), 8.11ꢀ8.04 (m, 2H), 7.70ꢀ7.75 (m, 2H), 7.36 (dd, J = 8.3, J = 1.4 Hz, 1H),
7.27 (dd, J = 8.3, J = 4.6 Hz, 1H); 13C NMR (151 MHz, CD3OD) δ 153.8, 145.5, 142.8, 141.4,
133.9, 130.9 (q, JCF = 32.2 Hz), 130.9, 125.8 (q, JCF = 3.8 Hz), 125.9 (d, JCF = 271.3 Hz), 125.6,
125.5, 123.2; HRMS (ESI), calcd. for C12H9F3NO [M+ + H] 240.0631; found: 240.0637.
Methyl 4-(3-hydroxypyridin-2-yl)benzoate (3q): Compound 3q was prepared according to GP1
using 4ꢀ(methoxycarbonyl)benzenediazonium chloride (2q). Purification by column
chromatography (chloroform / diethyl ether 10:1 to 1:1) gave 3q (126 mg, 0.55 mmol, 55%) as a
light brown solid. Rf = 0.3 (5:1 chloroform / diethyl ether) [UV]; mp = 222 °C; IR (NaCl, cmꢀ1)
1
~
ν; 1722, 1577, 1461, 1354, 1279, 1178, 1104, 797, 744; H NMR (600 MHz, CD3OD) δ 8.13
(dd, J = 4.6, J = 1.3 Hz, 1H), 8.11ꢀ8.05 (m, 2H), 8.02ꢀ7.98 (m, 2H), 7.35 (dd, J = 8.2, J = 1.4 Hz
13
,1H), 7.26 (dd, J = 8.2, J = 4.6 Hz, 1H), 3.93 (s, 3H); C NMR (151 MHz, CD3OD) δ 168.5,
153.8, 145.9, 143.7, 141.4, 130.7, 130.4, 130.1, 125.6, 125.5, 52.7; HRMS (ESI), calcd. for
C13H12NO3 [M+ + H] 230.0812; found: 230.0815.The melting point obtained is in agreement
with the value previously reported.29
6H-Isochromeno[4,3-b]pyridin-6-one (5a): Compound 5a was prepared according to GP1 using
2ꢀ(methoxycarbonyl)benzenediazonium chloride (2r). Purification by column chromatography
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(chloroform / diethyl ether 10:1 to 5:1) gave 5a (113 mg, 0.57 mmol, 57%) as a white crystalline
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solid. Rf = 0.8 (5:1 chloroform / diethyl ether) [UV]; mp = 138 °C; IR (NaCl, cmꢀ1) ν; 1741,
~
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1703, 1589, 1428, 1270, 1244, 1224, 1073, 1024, 772, 728; H NMR (400 MHz, CDCl3) δ 8.67
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(dd, J = 8.0, J = 0.6 Hz, 1H), 8.61 (dd, J = 4.5, J = 1.1 Hz, 1H), 8.42ꢀ8.31 (m, 1H), 7.91 (ddd, J =
8.0, J = 7.4, J = 1.3 Hz, 1H), 7.72ꢀ7.68 (m, 1H), 7.66 (dd, J = 8.3, J = 1.4 Hz, 1H), 7.43 (dd, J =
13
8.3, J = 4.5 Hz, 1H); C NMR (101 MHz, CDCl3) δ 160.2, 147.8, 146.0, 136.8, 135.6, 135.2,
130.6, 130.1, 124.9, 124.8, 123.4, 122.5; HRMS (ESI), calcd. for C12H8NO2 [M+ + H] 198.0550;
found: 198.0555.
8-Fluoro-6H-isochromeno[4,3-b]pyridin-6-one (5b): Compound 5b was prepared according to
GP1 using 4ꢀfluoroꢀ2ꢀ(methoxycarbonyl)benzenediazonium chloride (2s). Purification by
column chromatography (hexane / ethyl acetate 8:1 to 4:1) gave 5b (108 mg, 0.50 mmol, 50%)
as a white solid. Rf = 0.5 (2:1 hexane / ethyl acetate) [UV]; mp = 206 °C; IR (NaCl, cmꢀ1) ν;
~
1
3086, 1740, 1503, 1447, 1407, 1331, 1265, 1236, 1066, 927, 846, 806, 752, 738; H NMR (600
MHz, CDCL3) δ 8.70 (dd, J = 8.8, J = 5.2 Hz, 1H), 8.60 (dd, J = 4.5, J = 1.4 Hz, 1H), 8.01 (dd, J
= 8.4, J = 2.6 Hz, 1H), 7.67 (dd, J = 8.3, J = 1.4 Hz, 1H), 7.61 (ddd, J = 8.8, J = 8.1, J = 2.7 Hz,
1H), 7.43 (dd, J = 8.3, J = 4.5 Hz, 1H); 13C NMR (151 MHz, CDCl3) δ 163.72 (d, J = 252.7 Hz),
159.23 (d, J = 3.5 Hz), 147.3, 146.2, 136.2, 132.18 (d, J = 3.1 Hz), 126.36 (d, J = 8.4 Hz), 124.9,
124.8, 124.39 (d, J = 8.6 Hz), 123.47 (d, J = 22.9 Hz), 115.83 (d, J = 23.7 Hz); HRMS (ESI),
calcd. for C12H7FNO2 [M+ + H] 216.0455; found: 216.0461.
8-Chloro-6H-isochromeno[4,3-b]pyridin-6-one (5c): Compound 5c was prepared according to
GP1 using 4ꢀchloroꢀ2ꢀ(methoxycarbonyl)benzenediazonium chloride (2t). Purification by
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column chromatography (hexane / ethyl acetate 8:1 to 4:1) gave 5c (120 mg, 0.52 mmol, 52%) as
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a white solid. Rf = 0.5 (2:1 hexane / ethyl acetate) [UV]; light yellow solid, mp = 168 °C; IR
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(NaCl, cmꢀ1) ν; 3075.9, 1744, 1591, 1443, 1289, 1253, 1239, 1223, 1100, 1073, 1020, 905, 839,
~
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803, 750; H NMR (600 MHz, CDCl3) δ 8.63 (d, J = 8.5 Hz, 1H), 8.61 (dd, J = 4.5, J = 1.4 Hz,
1H), 8.34 (d, J = 2.2 Hz, 1H), 7.85 (dd, J = 8.5, J = 2.2 Hz, 1H), 7.67 (dd, J = 8.3, J = 1.4 Hz,
13
1H), 7.45 (dd, J = 8.3, J = 4.5 Hz, 1H); C NMR (151 MHz, CDCl3) δ 159.0, 147.7, 146.3,
137.0, 136.1, 135.6, 134.0, 129.6, 125.3, 125.2, 125.0, 123.7; HRMS (ESI), calcd. for
C12H7ClNO2 [M+ + H]: 232.0160; found: 232.0165.
8-Bromo-6H-isochromeno[4,3-b]pyridin-6-one (5d): Compound 5d was prepared according to
GP1 using 4ꢀbromoꢀ2ꢀ(methoxycarbonyl)benzenediazonium chloride (2u). Purification by
column chromatography (hexane / ethyl acetate 8:1 to 4:1) gave 5d (129 mg, 0.47 mmol, 47%)
as a white solid. Rf = 0.6 (2:1 hexane / ethyl acetate) [UV]; mp = 175 °C; IR (NaCl, cmꢀ1) ν;
~
3071, 1733, 1588, 1440, 1390, 1315, 1289, 1253, 1239, 1223, 1194, 1098, 1080, 826, 802, 750;
1H NMR (600 MHz, CDCl3) δ 8.59 (dd, J = 4.5, J = 1.4 Hz, 1H), 8.52 (d, J = 8.5 Hz, 1H), 8.47
(d, J = 2.0 Hz, 1H), 7.98 (dd, J = 8.5, J = 2.1 Hz, 1H), 7.65 (dd, J = 8.3, J = 1.4 Hz, 1H), 7.45
13
(dd, J = 8.3, J = 4.5 Hz, 1H); C NMR (151 MHz, CDCl3) δ 158.9, 147.7, 146.3, 138.4, 136.1,
134.4, 132.6, 125.3, 125.2, 125.0, 124.9, 123.8; HRMS (ESI), calcd. for C12H6BrNNaO2 [M+ +
Na]: 297.9474; found: 297.9473.
2-(4-Chlorophenyl)-6-methylpyridin-3-ol (6): Compound 6 was prepared according to GP2 using
5ꢀhydroxyꢀ2ꢀmethylpyridine (1b) (1.09 g, 10 mmol, 10 equiv.). Purification by column
chromatography (chloroform / diethyl ether 10:1 to 1:1) gave 6 (167 mg, 0.76 mmol, 76%) as a
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white solid. Rf = 0.6 (2:1 hexane / ethyl acetate) [UV]; mp = 179 °C; IR (NaCl, cmꢀ1) ν; 3388,
~
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2949, 2844, 1480, 1454, 1389, 1269, 1090, 1053, 1033, 1015, 835, 773, 735; H NMR (600
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MHz, CD3OD) δ 7.88ꢀ7.82 (m, 2H), 7.46ꢀ7.40 (m, 2H), 7.23 (d, J = 8.3 Hz, 1H), 7.09 (d, J = 8.3
Hz, 1H), 2.47 (s, 3H); 13C NMR (151 MHz, CD3OD) δ 150.9, 150.0, 145.0, 137.8, 134.9, 132.0,
129.0, 125.9, 124.6, 22.9; HRMS (ESI), calcd. For C12H11ClNO [M+ + H]: 220.0524; found:
220.0522.
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3-(4-Chlorophenyl)pyridin-4-ol (7a) and 2-(4-chlorophenyl)pyridin-4-ol (7b): Compounds 7a
and 7b were prepared according to GP2 using 4ꢀhydroxypyridine (951 mg, 10 mmol, 10 equiv.).
Purification by column chromatography (hexane / ethyl acetate 4:1 to 1:1) gave an inseperable
mixture of regioisomers 7a and 7b (41.0 mg, 0.20 mmol, 20% overall yield) as a light brown
solid. Rf = 0.2 (2:1 hexane / ethyl acetate) [UV]; NMR analysis revealed a mixture of 14% of 7a
and 6% of 7b. 1H NMR of 7a: (600 MHz, CD3OD) δ 7.90 (s, 1H), 7.76 (d, J = 6.7 Hz, 1H), 7.58ꢀ
7.56 (m, 2H), 7.43ꢀ7.38 (m, 2H), 6.55 (d, J = 7.1 Hz, 1H); 1H NMR of 7b: (600 MHz, CD3OD) δ
7.88 (d, J = 7.1 Hz, 1H), 7.71ꢀ7.67 (m, 2H), 7.57ꢀ7.55 (m, 2H), 6.74 (d, J = 1.7 Hz, 1H), 6.52
13
(dd, J = 7.1, J = 2.4 Hz, 1H); C NMR of mixture of both regioisomers: (151 MHz, CD3OD) δ
138.8, 138.5, 137.8, 135.0, 134.5, 131.5, 130.5, 129.8, 129.6, 129.4, 118.7, signals missing due
to overlap; HRMS (ESI), calcd. for C11H9ClNO [M+ + H] 206.0367; found: 206.0368.
4-(4-Chlorophenyl)-2-methoxypyridine (8): Compound 8 was prepared according to GP2 using
2ꢀmethoxypyridine (1.05 mL, 10 mmol, 10 equiv.). Purification by column chromatography
(hexane / ethyl acetate 16:1 to 4:1) gave 8 (50.3 mg, 0.23 mmol, 23%) as a yellow oil. Rf = 0.5
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(8:1 hexane / ethyl acetate) [UV]; IR (NaCl, cmꢀ1) ν; 2945, 1609, 1546, 1476, 1405, 1386, 1326,
~
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1252, 1209, 1093, 1056, 1033, 1023, 1012, 812, 771, H NMR (600 MHz, CDCl3) δ 8.22 (d, J =
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5.3 Hz, 1H), 7.57ꢀ7.50 (m, 2H), 7.46ꢀ7.42 (m, 2H), 7.07 (dd, J = 5.4, 1.6 Hz, 1H), 6.92 (d, J =
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0.9 Hz, 1H), 3.99 (s, 3H); C NMR (151 MHz, CDCl3) δ 164.9, 150.1, 147.3, 136.7, 135.2,
129.3, 128.3, 115.1, 108.4, 53.7; HRMS (ESI), calcd. for C12H11ClNO [M+ + H]: 220.0524,
found: 220.0528.
2-(4-Chlorophenyl)-4-methoxypyridine (10): Compound 10 was prepared according to GP2
using 4ꢀmethoxypyridine (1.01 mL, 10 mmol, 10 equiv.). Purification by column
chromatography (hexane / ethyl acetate 8:1 to 2:1) gave 10 (55.8 mg, 0.25 mmol, 25%) as a light
yellow oil. Rf = 0.3 (4:1 hexane / ethyl acetate) [UV]; IR (NaCl, cmꢀ1) ν; 3011, 2969, 2940,
~
1
1597, 1577, 1562, 1496, 1472, 1442, 1312, 1216, 1091, 1033, 1012, 831; H NMR (400 MHz,
CDCl3) δ 8.50 (d, J = 5.7 Hz, 1H), 7.97ꢀ7.85 (m, 2H), 7.47ꢀ7.38 (m, 2H), 7.19 (d, J = 2.2 Hz,
13
1H), 6.78 (dd, J = 5.7, J = 2.4 Hz, 1H), 3.90 (s, 3H); C NMR (151 MHz, CDCl3) δ 166.6,
157.9, 150.9, 137.8, 135.2, 128.9, 128.3, 108.3, 106.9, 55.3; HRMS (ESI), calcd. for
C12H11ClNO [M+ + H]: 220.0524, found: 220.0529. H NMR data are in agreement with those
1
previously reported.25
Acknowledgments
The authors would like to thank the Studienstiftung des deutschen Volkes (M. C. D. F.) and the
Deutsche Forschungsgemeinschaft (DFG) for financial support of this project (HE 5413/2ꢀ2).
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Supporting Information
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Optimization of reaction conditions, analysis of regioisomeric distribution and copies of H and
13C NMR spectra of compounds 3a-3n, 3p, 3q, 5a-5d, 6, 7a, 7b, 8 and 10. This material is
available free of charge via the Internet at http://pubs.acs.org.
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References and footnotes
(1) For review articles on radical arylation, see: (a) Galli, C. Chem. Rev. 1988, 88, 765. (b)
Studer, A.; Bossart, M. in Radicals in Organic Synthesis, eds. Renaud, P.; Sibi, M. 1st ed.,
WileyꢀVCH 2001, vol. 2, 62. (c) Bowman, W. R.; Storey, J. M. D. Chem. Soc. Rev. 2007, 36,
1803. (d) Studer, A.; Curran, D. Angew. Chem. Int. Ed. 2011, 50, 5018. (e) Pratsch, G.; Heinrich,
M. R. in Radicals in Synthesis III, Topics in Current Chemistry, eds. Gansäuer, A.; Heinrich, M.
R., Springer 2012, vol. 320. (f) Bonin, H.; Sauthier, M.; Felpin, F.ꢀX. Adv. Synth. Catal. 2014,
356, 645.
(2) (a) Perkins, M. J. in Kochi, J. K : Free Radicals. Vol. 2, Wiley, New York 1973, 231. (b)
Baedle, J. R.; Korzeniowski, S. H.; Rosenberg, D. E.; GarciaꢀSlanga, B. J.; Gokel, G. W. J. Org.
Chem. 1984, 49, 1594.
(3) Recent radical arylations with focus on benzene: (a) Sun, C.ꢀL.; Li, H.; Yu, D.ꢀG.; Yu, M.;
Zhou, X.; Lu, X.ꢀY.; Huang, K.; Zheng, S.ꢀF.; Li, B.ꢀJ.; Shi, Z.ꢀJ. Nat. Chem. 2010, 2, 1044. (b)
Shirakawa, E.; Itoh, K.ꢀI.; Higashino, T.; Hayashi, T. J. Am. Chem. Soc. 2010, 132, 15537. (c)
Liu, W.; Cao, H.; Zhang, H.; Zhang, H.; Chung, K. H.; He, C.; Wang, H.; Kwong, F. Y.; Lei, A. J.
Am. Chem. Soc. 2010, 132, 16737. (d) Cheng, Y.; Gu, X.; Li, P. Org. Lett. 2013, 15, 2664. (e)
Dewanji, A.; Murarka, S.; Curran D.; Studer, A.; Org. Lett. 2013, 15, 6102; (f) Zhao, H.; Shen,
J.; Guo, J.; Ye, R.; Zeng, H. Chem. Commun. 2013, 49, 2323. (g) Budén, M. E.; Guastavino, J.
F.; Rossi, R. A. Org. Lett. 2013, 15, 1174. (h) Ghosh, D.; Lee, J.ꢀY.; Liu, C. Y.; Chiang, Y.ꢀH.;
Lee, H. M. Adv. Synth. Catal. 2014, 356, 406. (i) Demir, A. S.; Findik, H. Tetrahedron 2008, 64,
6196.
(4) Recent articles on radical arylation: (a) Wu, Y.; Wong, S. M.; Mao, F. ; Chan, T. L.; Kwong,
F. Y. Org. Lett. 2012, 14, 5306. (b) De, S.; Ghosh, S.; Bhunia, S.; Sheikh, J. A.; Bisai, A. Org.
Lett. 2012, 14, 4466. (c) Chen, W. C.; Hsu, Y. C.; Shih, W. C.; Lee, C. Y.; Chuang, W. H.; Tsai,
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Y. F.; Chen, P. P.; Ong, T. G. Chem. Commun. 2012, 48, 6702. (d) Chen, Z.ꢀX.; Wang, G.ꢀW. J.
Org. Chem. 2005, 70, 2380. (e) Ravi, M.; Chauhan, P.; Kant, R.; Shukla, S. K.; Yadav, P. P. J.
Org. Chem. 2015, 80, 5369. (f) Studer, A.; Curran, D. Angew. Chem. Int. Ed. 2011, 50, 5018.
(5) (a) Pratsch, G.; Wallaschkowski, T.; Heinrich, M. R. Chem. Eur. J. 2012, 18, 11555. (b)
Jasch, H.; Scheumann, J.; Heinrich, M. R. J. Org. Chem. 2012, 77, 10699.
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(c) Hofmann, J.; Jasch, H.; Heinrich, M. R. J. Org. Chem. 2014, 79, 2314. (d) Jiang, T.; Chen, S.ꢀ
Y.; Zhang, G.ꢀY.; Zeng, R.ꢀS.; Zou, J.ꢀP. Org. Biomol. Chem. 2014, 12, 6922. (e) Jiang, T.; Chen,
S.ꢀY.; Zhuang, H.; Zeng, R.ꢀS.; Zou, J.ꢀP. Tetrahedron Lett. 2014, 55, 4549.
(6) (a) Caronna, T.; Ferrario, F.; Servi, S. Tetrahedron Lett. 1979, 7, 657. (b) Wetzel, A.;
Ehrhardt, V.; Heinrich, M. R. Angew. Chem. Int. Ed. 2008, 47, 9130. (c) Pratsch, G.; Unfried, J.
F.; Einsiedel, J.; Plomer, M.; Hübner, H.; Gmeiner, P.; Heinrich, M. R. Org. Biomol. Chem.
2011, 9, 3746. (d) Fehler, S. K.; Pratsch, G.; Huber, W.; Gast, A.; Hochstrasser, R.; Hennig, M.;
Heinrich, M. R. Tetrahedron Lett. 2012, 53, 2189. (e) Kralj, A.; Kurt, E.; Tschammer, N.;
Heinrich, M. R. Chem. Med. Chem. 2014, 9, 151.
(7) Scaiano, J. C.; Stewart, L. C. J. Am. Chem. Soc. 1983, 105, 3609.
(8) (a) Wetzel, A.; Pratsch, G.; Kolb, R.; Heinrich, M. R. Chem. Eur. J. 2010, 16, 2547. (b) Hari,
D. P.; Schroll, P.; König, B. J. Am. Chem. Soc. 2012, 134, 2958.
(9) Honraedt, A.; Raux, M.ꢀA.; Le Grognec, E.; Jacquemin, D.; Felpin, F.ꢀX.; Chem, Commun.
2014, 50, 5236.
(10) (a) Pratsch, G.; Anger, C. A.; Ritter, K.; Heinrich, M. R. Chem. Eur. J. 2011, 17, 4104. (b)
Minisci, F.; Vismara, E.; Fontana F.; Morini, G.; Serravalle M. J. Org. Chem. 1987, 52, 730. (c)
Elks, J.; Hey, D. H. J. Chem. Soc. 1943, 441.
(11) (a) Crank, G.; Cately, G. E.; Makin, M. I. H. Aust. J. Chem 1984, 37, 2499. (b) Bhakuni, B.
S.; Yadav, A.; Kumar, S.; Kumar, S. New. J. Chem. 2014, 38, 827.
(12) Yanagisawa, S.; Ueda, K.; Taniguchi, T.; Itami, K. Org. Lett. 2008, 10, 4673.
(13) Xue, D.; Jia, Z.ꢀH.; Zhao, C.ꢀJ.; Zhang, Y.ꢀY.; Wang, C.; Xiao, J. Chem. Eur. J. 2014, 2960.
(14) For a related work, see: Zoller, J.; Fabry, D. C.; Rueping, M. ACS Catal. 2015, 5, 3900.
(15) For reviews on photocatalyzed reactions, see: (a) Hari, D. P.; König, B. Angew. Chem. Int.
Ed. 2013, 52, 4734. (b) Mo, F.; Dong, G.; Zhang, Y.; Wang, J. Org. Biomol. Chem. 2013, 11,
1582.
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2
3
4
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8
9
(16) (a) Shimizu, H.; Manabe, K. Tetrahedron Lett. 2006, 47, 5927. (b) Huang, B.; Li, X.; Zhan,
P.; De Clercq, E.; Daelemans, D.; Pannecouque, C.; Liu, X. Chem. Biol. Drug. Des. 2016, 87,
283.
(17) For a recent report on the arylation of pyridines via CꢀH activation, see: Guo, P.; Joo, J. M.;
Rakshit, S.; Sames, D. J. Am. Chem. Soc. 2001, 133, 16338.
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15
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(18) Leditschke, H. Chem. Ber. 1952, 85, 202.
(19) Minisci, F.; Coppa, F.; Fontana, F.; Pianese, G.; Zhao, L. J. Org. Chem. 1992, 57, 3929.
(20) (a) Bolton, R.; Williams, G. H. Chem. Soc. Rev. 1986, 15, 261. (b) Kosynkin, D.; Bockman,
T. M.; Kochi, J. K. J. Am. Chem. Soc. 1997, 119, 4846.
(21) Elofson, R. M.; Gadallah, F. F. J. Org. Chem. 1969, 34, 854.
(22) Beak, P.; Covington, J. B.; Smith, S. G.; White, J. M.; Zeigler, J. M. J. Org. Chem. 1980,
45, 1354.
(23) The weaker directing effect of a methoxy group compared to a hydroxy group has also been
observed in radical arylations of 4ꢀmethoxyphenethylamine and 4ꢀhydroxyphenethylamine
(tyramine). See ref. 11a.
(24) The structure of compound 8 was confirmed through comparison with the corresponding
phenyl derivative: Panda, S.; Coffin, A.; Nguyen, Q. N.; Tantillo, D. J.; Ready, J. M. Angew.
Chem. Int. Ed. 2016, 55, 2205
.
(25) The structure of compound 10 was confirmed through comparison with data reported by:
Masaki, T.; Kazuhiko, T. WO2000/49015 (A1), Chem. Abstr: 133:193162, 2000.
(26) Giese, B. Angew. Chem. Int. Ed. 1983, 22, 753.
(27) Ren, X.; Kondakova, M. E.; Giesen, D. J.; Rajeswaran, M.; Madaras, M.; Lenhart; W. C.
Inorg. Chem. 2010, 49, 1301.
(28) The preparation of 5a and 5b so far required two steps and more expensive starting
materials: Zhang, W.; Pugh, G. Tetrahedron 2003, 59, 3009.
(29) Huang, W.ꢀX.; Wu, B.; Gao, X.; Chen, M.W.; Wang, B.; Zhou, Y.ꢀ G. Org. Lett. 2015, 17,
1640.
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