Dearomatization of a 3-Hydroxypyridine through an Unexpected Oxidative Deformylation Process: An Entry to Azacyclohexadienones

Article abstract of DOI:10.1055/s-0040-1706870

Phenols are well-known precursors of cyclohexadienones, which have widespread applications in organic synthesis. In contrast, their hydroxypyridine counterparts have not been explored yet. An unprecedented oxidative dearomatization of a 3-hydroxypyridine involving an unexpected deformylation step is reported. The chemical reactivity of the resulting unreported azacyclohexadiene-type compound was also explored.

Full text of DOI:10.1055/s-0040-1706870

SYNLETT
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©
Georg Thieme Verlag Stuttgart · New York
2020, 31, A–D
letter
A
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Synlett
A. Mabrouki et al.
Letter
Dearomatization of a 3-Hydroxypyridine Through an Unexpected
Oxidative Deformylation Process: An Entry to Azacyclohexadien-
ones
Afef Mabroukia
O
OH
1,2-addition
Patricia Le Nahenec-Martelb
Abdelkader Kriaaa
Ahmed Hedhlia
RO
HO
ROH, PIDA
Diels–Alder reaction
N
N
1,4-addition
2
CH O
RO
Pierre-Yves Renardb
Cyrille Sabot*b
a
Laboratory of Molecular Organic Chemistry, National Higher
Engineering School of Tunis, 5 avenue Taha Hussein, Montfleury,
1
089, Tunis, Tunisia
b
Normandie Univ, CNRS, UNIROUEN, INSA Rouen, COBRA
UMR 6014), 76000 Rouen, France
(
Cyrille.sabot@univ-rouen.fr
Received: 03.06.2020
Accepted after revision: 10.06.2020
Published online: 13.07.2020
promising applications in synthesis (Scheme 1, X = N).15–19
Although an oxidative homocoupling of 3-hydroxypyri-
dines was recently described,20 the competitive oxidation of
the pyridine nitrogen and hydroxy group is a plausible is-
sue that might have prevented further studies on dearo-
matization and hydroxypyridine systems.
DOI: 10.1055/s-0040-1706870; Art ID: st-2020-d0333-l
Abstract Phenols are well-known precursors of cyclohexadienones,
which have widespread applications in organic synthesis. In contrast,
their hydroxypyridine counterparts have not been explored yet. An un-
precedented oxidative dearomatization of a 3-hydroxypyridine involv-
ing an unexpected deformylation step is reported. The chemical reac-
tivity of the resulting unreported azacyclohexadiene-type compound
was also explored.
21
As a-proof-of-concept study, we report the unexpected
formation of a 5-aza-2,5-cyclohexadien-1-one [pyridin-
3(6H)-one] through an oxidative deformylation/1,3-alkoxy
rearrangement of commercially available 2-(hydroxymeth-
yl)-6-methylpyridin-3-ol. The chemical reactivity of the
corresponding unreported dearomatized product was also
investigated.
Key words hydroxypyridines, oxidation, hypervalent iodine, phenylio-
dine diacetate, azacyclohexadienones
Hypervalent iodine reagents, such as phenyliodine(III)
The oxidative dearomatization of phenols offers a
diacetate [PIDA; PhI(OAc) ], are reagents of choice for pro-
2
straightforward entry to a variety of 4-alkoxycyclohexa-
moting the oxidation of phenols under mild and environ-
mentally friendly conditions.2
2–27
Accordingly, the oxidation
2
,5-dien-1-ones (also known as p-quinol ethers), generally
1,2
from commercially or readily available starting materials.
of commercially available 2-(hydroxymethyl)-6-methylpyr-
idin-3-ol (1) was investigated under standard alcoholic con-
ditions with the aim of providing the corresponding aza-p-
quinol ether 3. To this end, the oxidation was carried out in
the presence of one equivalent of PIDA in MeOH at room
temperature for 15 minutes (Scheme 2).
This oxidation step notably increases the scope for derivat-
ization of phenols, as their cyclohexadienone derivatives
can undergo subsequent nucleophilic 1,2- or 1,4-addi-
3
–5
6
tions,
-alkylations or -arylations, Diels–Alder reac-
7,8
9
tions, photochemical ring contractions, or dienone–phe-
6,9
nol rearrangements, among others (Scheme 1; X = CH).
Although this strategy has extensively been studied and
exploited in expedient syntheses of natural products,1
the oxidative dearomatization of the hydroxypyridine
counterparts of phenols has not been reported, despite its
OH
O
O
0–14
O
HO
PIDA
HO
N
MeOH,
rt, 15 min
N
O
N
O
1
2a
3 (not observed)
With: a) PIDA (1 equiv):
b) PIDA (2.14 equiv):
27%
60%
OH
O
1
,2-addition
α-alkylation, α-arylation
oxidation
Scheme 2 Oxidative hydroxypyridine dearomatization
X
2
X
R OH
2
1,4-addition
R O
R'
R'
Surprisingly, the expected aza-p-quinol ether 3 was not
formed but, instead, the diether 2a was obtained together
with the unreacted starting hydroxypyridine 1 in a ~2:3 ra-
X = CH, N
Scheme 1 Oxidative dearomatization of phenols and hydroxypyridines
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2020. Thieme. All rights reserved. Synlett 2020, 31, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synlett
A. Mabrouki et al.
Letter
1
tio as determined by a H NMR analysis of the crude reac-
tion mixture. Purification of the crude mixture by flash-col-
umn chromatography provided a 27% yield of compound
O
OH
O
HO
HO
PIDA (2.14 equiv)
CH Cl
2
a, the structure of which was confirmed by spectroscopic
N
N
2
2
and spectrometric analyses. Unexpectedly, the hy-
droxymethyl group in 1 was replaced by a methoxy substit-
uent in 2a. Because compound 2a is two oxidation states
higher than the parent compound 1, we used 2.14 equiva-
lents of PIDA in an attempt to drive the reaction to comple-
tion and improve the overall efficiency of this transforma-
tion. As expected, under these optimized conditions, com-
pound 2a was isolated in 60% yield (Scheme 2b).
1
4%
1
4
Scheme 3 Oxidation of compound 1 in CH Cl2
2
In contrast to alcoholic solvents, the formation of this com-
pound involves a monooxidation process.
Because no example of such unfused aza-p-quinol ether
systems had been previously reported, we examined their
reactivity by using the representative compound 2a. First,
the direct reductive aromatization of 2a to provide an elec-
tron-rich pyridine, was carried out by the action of Pd/C-
mediated hydrogenation, which delivered compound 5 in a
low 37% yield. This volatile material possessed a pleasant
fragrance (Scheme 4).
Having conducted these preliminary results, we per-
formed the reaction in other low-boiling-point alcoholic
solvents, and results obtained are presented in Table 1.28
Table 1 Solvent Scope of the Reactiona
OH
O
RO
HO
PIDA (2.14 equiv)
Solvent
O
OH
N
N
O
O
RO
Pd/C, H2
MeOH
1
2
N
N
O
37%
Entry
Solvent
R
Product
Yield (%)
2a
5
Scheme 4 Direct aromatization of aza-p-quinol ether 2a
1
2
3
4
MeOH
EtOH
i-PrOH
TFEb
Me
Et
2a
2b
2c
2d
2e
60
43
trace
11
–
Compound 2a was then subject to 1,2-nucleophilic ad-
dition conditions. In view of the operational simplicity as-
sociated with the use of nontoxic allylindium reagents,
compound 2a was treated with indium in the presence of
allyl bromide and sodium iodide to produce the corre-
sponding allylic alcohol 6 in 46% yield as a mixture of insep-
arable diastereoisomers in a 1:1 ratio (Scheme 5).
i-Pr
F
3
CCH
2
5
HFIPc
(F
3
C) CH
2
a
Reaction conditions: 1, PIDA (2.14 equiv), solvent, rt, 15 min.
b
c
TFE = F
3
CCH
C)
2
OH.
CHOH.
HFIP = (F
3
2
The yields of the dearomatized 3-hydroxypyridines de-
creased as the bulkiness of the solvent increased. In fact, a
moderate yield of 43% of 2b was obtained in ethanol (Table
Br
In, NaI,
OH
O
HO
O
O
O
1,2-shift
1
, entry 2), whereas only traces of product 2c were ob-
N
O
N
N
O
DMF, rt, 6 h
6%
aromatization
tained in isopropanol (entry 3). Moreover, the use of elec-
tron-deficient alcohols such as TFE markedly decreased the
efficiency of the transformation, with isolation of 11% of
dearomatized compound 2d, whereas product 2b was ob-
tained in 43% in the nonfluorinated analogue, ethanol (en-
try 2 versus entry 4). Unsurprisingly, no product was isolat-
ed when the reaction was conducted in HFIP, a bulky and
nonnucleophilic fluorinated alcohol. The reaction was also
explored in the nonprotic and chemically inert solvent, di-
chloromethane, to investigate whether the acetic acid re-
leased in the course of the reaction might trap the oxidized
intermediate in a similar manner to alcoholic solvents
4
2
a
6
7 (not observed)
Scheme 5 Allylindium-mediated 1,2-alkylation of 2a
It is worth mentioning that, in contrast to what has
been reported for p-quinol ether systems,29 no further an-
ionic vinylogous semipinacol-type rearrangement of 6 into
7 was observed in the present case.
An organocuprate reagent, generated in situ, did not un-
dergo conjugate addition to the ,-unsaturated system of
2a (Scheme 6a). In fact, the reaction of methylmagnesium
bromide in the presence of copper(I) bromide favored the
formation of the carbonyl addition product 8, which was
isolated in 33% yield as a ~3:1 mixture of inseparable iso-
mers.
(Scheme 3).
Under these conditions, only the deformylated monoo-
xidized compound 4 was obtained, albeit in a low 14% yield.
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

C
Synlett
A. Mabrouki et al.
Letter
O
HO
O
OH
O
O
O
O
MeMgBr, CuBr
a)
PIDA HO
MeOH
HO
HO
N
O
N
O
THF, rt, 12 h
33%
N
N
N
PhI, 2 AcOH
12
13
2a
8
OH
O
O
O
O
O
O
O
PIDA
MeOH
MeO2C
CO2Me
O
t-BuOK
N
N
N
b)
2a
N
CO2Me
CO2Me
CH2O
THF,
15
PhI, 2 AcOH 16
14
0
°C then rt, 10 min.
O
7
0%
O
9
[
1,3]-rearrangement
O
Scheme 6 Investigation of conjugate additions with methylmagne-
sium bromide or dimethyl malonate
N
O
17
Consequently, the reaction was next investigated with
the Michael donor dimethyl malonate; in this case, we ob-
tained the 1,4-addition product 9, isolated in 70% yield as a
single diastereoisomer (Scheme 6b).
Scheme 8 Proposed reaction mechanism
shows that the presence of a removable hydroxymethyl
group is necessary to ensure effective formation of the aza-
p-quinol ethers 2.
Next, the reactivity of aza-p-quinol ether as a diene in a
Diels–Alder reaction was investigated. To this end, com-
pound 2a was treated with freshly distilled cyclopenta-1,3-
diene in the presence of phosphoric acid as a catalyst
OH
O
O
30
(
Scheme 7). The corresponding cycloadduct 10 was ob-
PIDA (2.14 equiv)
PhI, 2 AcOH
tained in 23% isolated yield. This low yield might be partly
ascribed to the formation of the fused bicyclic pyridine 11,
which was formed cleanly in 77% yield from isolated com-
pound 10 in the presence of methanesulfonic acid in meth-
anol.
N
N
O
20%
18
2a
Scheme 9 Oxidation of 2-unsubstituted-3-hydroxypyridine 18
O
O
Compound 13 then undergoes a retro-aldolization-driv-
en aromatization process to provide the 2-methoxy-3-hy-
droxypyridine 14. This reaction occurs with the concomi-
tant release of formaldehyde. Note that the putative inter-
mediate 14 has not been isolated, even in the presence of
substoichiometric amounts of PIDA, presumably because
this electron-rich pyridine is more readily oxidized than is
the starting 3-hydroxypyridine 1. A second equivalent of
PIDA then oxidizes 14 to generate the aza-o-quinone mo-
noketal 16 through the regioselective addition of methanol
to the methoxy-stabilized carbocation at the -position of
the carbonyl of the intermediate 15.31 Monoketal 16 is con-
verted into enone 17 through a 1,3-methoxy rearrange-
ment process, similar to that reported for o-quinone mo-
noketals under Lewis acid catalysis.32 Accordingly, the pres-
ence of the temporary hydroxymethyl group at the 2-
position of the pyridine ring system of 1 plays an important
role in favoring the addition of methanol at this position,
due to the enhanced stability of the tertiary carbocation.
In conclusion, the first oxidative dearomatization of a
hydroxypyridine system leading to the formation of aza-p-
quinol ethers, is reported. This reaction proceeded under
mild conditions and involves a deformylation/1,3-migration
process favoring the formation of aza-p-quinol ethers. Sub-
O
O
N
O
N
O
H3PO4, CH2Cl2, rt, 48 h
23%
2a
10
OH
O
MeSO3H
N
MeOH, rt, 45 min
7%
7
11
Scheme 7 Diels–Alder reaction of aza-p-quinol ether 2a
Finally, a plausible reaction mechanism for the oxidative
deformylation process of 3-hydroxypyridine 1 can be pro-
posed (Scheme 8). The oxidation of the aromatic hydroxy
function promoted by the first equivalent of hypervalent
iodine reagent leads to the formation of the oxonium inter-
mediate 12, which is subsequently trapped by methanol to
give the transient intermediate 13.
To investigate this point, the 3-hydroxypyridine 18, un-
substituted in the 2-position, was oxidized under identical
optimized PIDA conditions (Scheme 9) to provide 2a in only
2
0% yield, instead of 60% when the 2-position was func-
tionalized by a hydroxymethyl substituent. This result
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

D
Synlett
A. Mabrouki et al.
Letter
sequent modifications of this particular azacyclohexadien-
one through 1,2-, 1,4-addition, and Diels–Alder reactions
were investigated.
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This work was funded by the Centre National de la Recherche Scien-
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We thank Albert Marcual (CNRS) for HRMS analyses.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1706870.
S
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p
p
orit
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©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–D