Synthesis of 6-Arylpyridin-3-ols by Oxidative Rearrangement of (5-Arylfurfuryl)amines

Article abstract of DOI:10.1002/ejoc.201600377

The synthesis of 6-arylpyridin-3-ols and their 2,4-dibrominated analogues has been achieved by the oxidative rearrangement of (5-arylfurfuryl)amines. The desired arylpyridols were obtained in good to high yields, and the reactions were shown to be suitable for preparation on a gram scale.

Full text of DOI:10.1002/ejoc.201600377

DOI: 10.1002/ejoc.201600377
Communication
Heterocycles
Synthesis of 6-Arylpyridin-3-ols by Oxidative Rearrangement of
(5-Arylfurfuryl)amines
Michael C. D. Fürst,[a] Caroline S. Sauer,[a] Takaaki Moriyama,[a,b] Akio Kamimura,[b] and
Markus R. Heinrich*[a]
Abstract: The synthesis of 6-arylpyridin-3-ols and their 2,4-di- were obtained in good to high yields, and the reactions were
brominated analogues has been achieved by the oxidative re-
arrangement of (5-arylfurfuryl)amines. The desired arylpyridols
shown to be suitable for preparation on a gram scale.
Introduction
As for a wide range of other biaryls, the synthesis of phenyl-
pyridol building blocks today mainly relies on Suzuki aryl–aryl
coupling reactions, which, however, require comparably de-
manding starting materials as well as an expensive catalyst.[7,8]
Regarding palladium-free routes to the target compounds, the
preparation of phenylpyridol 3 from 4-fluorobenzaldehyde even
required eight steps, of which the final one was a Kolbe–
Schmitt reaction to introduce the carboxylic acid.[5] Against this
background, it was a challenging question whether the prepa-
ration of 6-arylpyridin-3-ol derivatives could also be achieved
by a short sequence involving a radical arylation step. Radical
arylations for the synthesis of biaryls have recently gained
much interest,[9] but reactions of substituted benzenes are of-
ten not easy to conduct due to low rate constants in the addi-
tion step[10] and insufficient regioselectivity.[11] Similarly difficult
are direct arylations of pyridine, which commonly give moder-
ate yields and insufficient regioselectivities in the case of the
free base.[11a] Arylations of pyridinium salts usually require a
blocking substituent in 4-position to selectively give 2-arylpyr-
idines.[12] Comparably good results in terms of yield and select-
ivity can be obtained with anilines,[13] phenols,[14] and espe-
cially electron-rich heterocycles such as furans[14b,15] and
pyrroles.[16] Starting from aryldiazonium salts,[12,13a,14,15] aryl
halides[17] or aryl hydrazines[13b–13e,18] as aryl radical sources,
typical reaction conditions include stoichiometric oxidants, re-
ductants or bases, and alternatively photo- or base catalysis.
Arylpyridines are a common structural motif in medicinal chem-
istry research.[1] A particularly interesting subgroup of such
compounds are 6-arylpyridin-3-ol derivatives (Figure 1). Phenyl-
pyridyl ether 1 has recently been found to be an Hsp90 C-
terminal inhibitor. The inhibition of Hsp90 represents a promis-
ing strategy for the treatment of breast cancer and neurode-
generative diseases.[2] Pyridol 2 has been described as a niacin
receptor agonist for the treatment of lipometabolic disorders.[3]
Furthermore, 6-arylpyridin-3-ol derivatives have been discov-
ered as remedies for diseases attributable to abnormal plasma
uric acid levels,[4] and, as exemplified by the comparably simple
heterobiaryl 3, also as antiinflammatory agents.[5] Arylpyridyl
ether 4 shows antiinfective properties and was investigated as
an antitubercolosis agent.[6]
In the overall context it was interesting to notice that the
oxidative rearrangement of furfurylamine to 3-pyridol is
known,[19,20] with a number of applications in total synthesis,[21]
medicinal chemistry[22] and food chemistry.[23] However, no ex-
amples have yet been reported for the oxidative ring-opening
of 5-arylated furfurylamines to give 6-arylpyridin-3-ol deriva-
tives after cyclization involving the originally exocyclic amino
group. Such a reaction could – in combination with previous
radical arylation of furfurylamine – allow an expedient access
to the desired target molecules. Moreover, the advantageous
tolerance of radical arylations towards halogens such as
chlorine and bromine would provide substituted arylpyridols,
Figure 1. 6-Arylpyridin-3-ol derivatives as anticancer, antineurodegenerative,
lipometabolic, antiinflammatory and antituberculosis agents.
[a] Department of Chemistry and Pharmacy, Pharmaceutical Chemistry,
Friedrich-Alexander-Universität Erlangen-Nürnberg
Schuhstraße 19, 91052 Erlangen, Germany
E-mail: markus.heinrich@fau.de
http://www.medchem.uni-erlangen.de/heinrichlab/
[b] Department of Applied Molecular Bioscience, Graduate School of Medicine,
Yamaguchi University
Ube 755-8611, Japan
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600377.
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which are not easy to prepare by transition-metal-catalyzed re-
actions.
Table 2. Variation of substituents of the benzene core.
Results and Discussion
Radical arylation of furfurylamine occurs with high regioselect-
ivity for the 5-position, and yields in the range of 70–80 % can
be obtained with typical aryldiazonium salts by using titanium-
(III) chloride as a reductant.[14b] Based on this straightforward
access to the required starting materials, a series of optimiza-
tion experiments with [5-(4-chlorophenyl)furfuryl]amine (5a)
was carried out (Table 1). A control reaction to probe the direct
arylation of 3-hydroxypyridine with 4-chlorophenyldiazonium
chloride and titanium(III) chloride had provided only trace
amounts of arylpyridol 6a.
Entry
Furfurylamine
Pyridol
Entry
Furfurylamine
Pyridol
5: R =
6: [%][a]
5: R =
6: [%][a]
1
2
3
4
5a: 4-Cl
5b: 4-F
5c: 4-Br
5d: 3-F
6a: 69
6b: 62
6c: 86
6d: 70
5
6
7
8
5e: 3-Cl
5f: 3-Br
5g: 2-Cl
5h: 2-Br
6e: 68
6f: 66
6g: 58
6h: 60
[a] For reaction conditions, see Exp. Sect. Yields determined after purification
by column chromatography.
building blocks, since substitution of the bromine atoms can
often be achieved with high regioselectivity.[28] Results from the
related optimization experiments are summarized in Table 3.
Analysis of the reaction time dependent product distribution
An initial attempt with N-bromosuccinimide under typical
Achmatowicz[24,25] conditions failed completely and did not
even give traces of the desired product 6a (Entry 1).[26] Based
on a moderately successful experiment with bromine as an al-
ternative oxidant (Entry 2),[20d] it was possible to improve the revealed that the monobrominated arylpyridol 7a cannot be
yield of 6a to 69 % by variation of reaction time and solvent obtained in a sufficiently high yield (Entries 1–6). The maximum
mixture (Entries 3 and 4). A further prolongation of the reaction yield of the dibrominated product 8a of 48 % (Entry 5) could
time combined with a large excess of bromine led to a mixture not be further increased by reaction under argon (Entry 7), but
of 6a (21 %) and its mono- and dibrominated analogues 7a and by the addition of hydrobromic acid (Entries 8 and 9). Hydro-
8a. With suitable conditions available, we turned to investigate bromic acid thereby appears to slow down the third bromation
the reaction scope with different substituents on the benzene step converting 8a into 9a (Entries 6, 8 and 9), which enables
core. The results of this study are summarized in Table 2.
yields for 8a of up to 60 %.
All desired 6-arylpyridin-3-ols 6a–h were obtained in good
The results obtained with various (5-arylfurfuryl)amines un-
yields with a maximum yield of 86 % (Entry 3) for the 4-bromo- der the optimized conditions (Table 3, Entry 8) are summarized
phenyl derivative 6c; ortho substitution, which could compli- in Table 4. In this study, all halogenated (5-arylfurfuryl)amines
cate the rearrangement, did only have a marginal effect on the 5a–5i (Entries 1–9) were tolerated with no remarkable negative
outcome (Entries 7 and 8). From a synthetic point of view, the effect of ortho substitution (Entries 7–9). Electon-withdrawing
brominated compounds 6c,f,h are of particular value, since they groups on the phenyl ring led to a slightly increased average
cannot be easily prepared by Pd-catalyzed coupling reac- yield among the products 8j–8m (Entries 10–13), which can be
tions.[27]
The formation of the mono- and dibrominated pyridols 7a
and 8a within the original optimization (Table 1, Entry 5)
explained by smaller amounts or the absence of the tribromin-
ated analogues 9. By conjugation, electron acceptors thereby
appear to retard the third bromination step.
prompted us to investigate whether the oxidative rearrange-
Finally, two representative reactions were carried out on a
ment could be combined with selective bromination of the larger scale (Scheme 1) under conditions identical to those used
pyridol core. Polybrominated pyridines are versatile synthetic for the syntheses summarized in Tables 2 and 4. The desired
Table 1. Optimization experiments: Oxidative rearrangement of (5-arylfurfuryl)amine 1a to 6-arylpyridin-3-ol derivatives 6a–8a.
Entry
Reagent[a]
(equiv.)
Solvent system
(ratio, reaction time)
6a/7a/8a[b]
[%/%/%]
1
2
3
4
5
NBS (1.1)
Br2 (1.1)
Br2 (1.1)
Br2 (1.2)
Br2 (4.0)
THF/H2O (1:1, 24 h)
MeOH (1.5 h), MeOH/H2O (1:1, 1.5 h)
MeOH (15 h), MeOH/H2O (1:1, 2 h)
MeOH/H2O (2:1, 18 h)
–/–/–
34/–/–
41/–/–
69/–/–
21/32/37
MeOH/H2O (4:1, 24 h)
[a] Reagent added at 0 °C, mixture then left to warm to room temperature. Reactions conducted under air. NBS: N-bromosuccinimide. [b] Yields determined
by 1H NMR spectroscopy using dimethyl terephthalate as internal standard.
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Table 3. Optimization experiments: Oxidative rearrangement of 5a combined with bromination of the pyridol core.
Entry
Conditions[a]
6a/7a/8a/9a[b]
[%/%/%/%]
1
2
3
4
5
6
7
8
9
Br2 (4.0 equiv.), MeOH/H2O (4:1), 3 h
Br2 (4.0 equiv.), MeOH/H2O (4:1), 6 h
Br2 (4.0 equiv.), MeOH/H2O (4:1), 12 h
Br2 (4.0 equiv.), MeOH/H2O (4:1), 24 h
Br2 (4.0 equiv.), MeOH/H2O (4:1), 36 h
32/10/9/7
24/14/27/9
22/19/30/10
21/32/37/12
15/20/48/14
1/2/41/38
–/–/35/30
–/–/60/28
–/–/59/32
Br2 (4.0 equiv.), MeOH/H2O (4:1), 48 h
Br2 (4.0 equiv.), MeOH/H2O (4:1), argon, 48 h
Br2 (5.0 equiv.), HBr (1 equiv.), MeOH/H2O (6:1), 72 h
Br2 (5.0 equiv.), HBr (2 equiv.), MeOH/H2O (6:1), 72 h
[a] Reagent added at 0 °C, mixture then left to warm to room temperature. Reactions conducted under air except for Entry 7. [b] Yields determined by 1H
NMR spectroscopy using dimethyl terephthalate as internal standard.
Table 4. Oxidative rearrangement combined with bromination of the pyridol
core: variation of substituents.
Entry
Furfurylamine
Dibromopyridol
Tribromopyridol
5: R =
8: [%][a]
9: [%][a]
1
2
3
4
5
6
7
8
9
10
11
12
13
5a: 4-Cl
5b: 4-F
5c: 4-Br
5d: 3-F
5e: 3-Cl
5f: 3-Br
5g: 2-F
5h: 2-Cl
5i: 2-Br
5j: 4-CN
5k: 4-NO2
5l: 4-CO2Me
5m: 3-CN
8a: 60
8b: 50
8c: 63
8d: 44
8e: 52
8f: 55
8g: 54
8h: 56
8i: 70
8j: 54
8k: 67
8l: 68
8m: 71
9a: 28
9b: 23
9c: 33
9d: 21
9e: 35
9f: 31
9g: 33
9h: 35
9i: 23
9j: –
Scheme 1. Reactions on larger scales and intermediates.
9k: –
9l: 18
9m: –
Conclusions
We have shown that the oxidative rearrangement of furfuryl-
amines to pyridols allows a straightforward access to 6-aryl-
pyridin-3-ols. The reaction could be extended to dibrominated
analogues, and both transformations were conducted on a
larger scale.
[a] For reaction conditions, see Exp. Sect. Yields determined after purification
by column chromatography.
pyridols 6a and 8l were obtained in yields of 74 % and 68 %,
which demonstrates the synthetic applicability. Scheme 1 fur-
ther shows plausible intermediates occurring in the reaction
course to 6a.[20d,25] Oxidation of (5-arylfurfuryl)amine 5a leads
to dihydrofurans 10, which can undergo ring-opening to diket-
one 11 by hydrolysis. Pyridol 6a is obtained in a final condensa-
tion step.
Experimental Section
General Procedure for the Synthesis of 6-Arylpyridin-3-ol Deriv-
atives: Table 2. (5-Arylfurfuryl)amine 5 (1.0 mmol, 1 equiv.) was
dissolved in MeOH (6 mL) and H2O (3 mL), and the mixture was
cooled to 0 °C. Then Br2 (1.2 mmol, 61 μL, 1.2 equiv.) was added.
The mixture was warmed to room temperature and stirred for 18 h.
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Communication
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mixture until pH 7, and the aqueous phase was extracted with ethyl
acetate (3 × 50 mL). The combined organic phases were dried with
Na2SO4, filtered, and the solvent was removed under reduced pres-
sure. Purification by column chromatography (Hex/EtOAc, 8:1 → 2:1
→ 0:1) provided the arylpyridoles 6a–h.
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General Procedure for the Synthesis of 6-Aryl-2,4-dibromopyr-
idin-3-ol Derivatives: Table 4: (5-Arylfurfuryl)amine 5 (1.0 mmol,
1 equiv.) was dissolved in MeOH (6 mL) and H2O (1 mL), and the
mixture was cooled to 0 °C. Then HBr (48 %, 1.0 mmol, 112 μL,
1 equiv.) and Br2 (5.0 mmol, 256 μL, 5 equiv.) were added. The
mixture was warmed to room temperature and stirred for 72 h.
After the reaction had been quenched with saturated aqueous NaH-
SO3 (3 mL), saturated aqueous Na2CO3 was added until pH 7, and
the aqueous phase was extracted with ethyl acetate (3 × 50 mL).
The combined organic phases were dried with Na2SO4, filtered, and
the solvent was removed under reduced pressure. Purification by
column chromatography (Hex/EtOAc, 8:1 → 2:1 → 0:1) provided
the dibrominated arylpyridoles 8a–m along with tribrominated ana-
logues 9a–i and 9l.
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Acknowledgments
The authors would like to thank the Studienstiftung des deut-
schen Volkes (M. C. D. F.) as well as the Deutsche Forschungsge-
meinschaft (DFG) (HE5413/2-2) for financial support. We are fur-
ther grateful for a travel grant (New Choshu-five scholarship) by
Yamaguchi University (T. M.) and for the experimental assist-
ance by Laura Hofmann (FAU Erlangen-Nürnberg).
Keywords: Rearrangement · Furan · Pyridine · Bromine ·
Oxidation
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Received: March 26, 2016
Published Online: ■
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Communication
Heterocycles
M. C. D. Fürst, C. S. Sauer,
T. Moriyama, A. Kamimura,
M. R. Heinrich* .................................... 1–6
Synthesis of 6-Arylpyridin-3-ols by
Oxidative Rearrangement of (5-Aryl-
furfuryl)amines
A new straightforward access to 6-aryl- arrangement of readily available (5--
pyridin-3-ols and their 2,4-dibromi- arylfurfuryl)amines are accurately de-
nated analogues has been developed. fined reaction conditions, which in-
Key to the successful oxidative re- clude bromine as oxidant.
DOI: 10.1002/ejoc.201600377
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim