A regioselective etherification of pyridoxine via an ortho-pyridinone methide intermediate

Article abstract of DOI:10.1016/j.tetlet.2017.04.082

The catalyst-free, regioselective synthesis of 4′-O-substituted pyridoxine derivatives under solventless conditions is described. The methodology relies on the highly regioselective formation of the ortho-pyridinone methide from pyridoxine and subsequent oxa-Michael addition of alcohol nucleophiles. This methodology provides good to excellent yields for primary and secondary alcohols and moderate yields for tertiary alcohols.

Full text of DOI:10.1016/j.tetlet.2017.04.082

Accepted Manuscript
A regioselective etherification of pyridoxine via an ortho-pyridinone methide
intermediate
Jessica A. Yazarians, Brian L. Jiménez, Gregory R. Boyce
PII:
S0040-4039(17)30536-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.082
TETL 48874
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 March 2017
18 April 2017
24 April 2017
Please cite this article as: Yazarians, J.A., Jiménez, B.L., Boyce, G.R., A regioselective etherification of pyridoxine
via an ortho-pyridinone methide intermediate, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.
2017.04.082
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A regioselective etherification of pyridoxine
via an ortho-pyridinone methide
intermediate
Leave this area blank for abstract info.
Jessica A. Yazarians, Brian L. Jiménez, and Gregory R. Boyce
OR
OH
OH
OH
OH
catalyst-free
OH
ROH
N
N
13 examples

1
Tetrahedron Letters
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A regioselective etherification of pyridoxine via an ortho-pyridinone methide
intermediate
Jessica A. Yazarians, Brian L. Jiménez, and Gregory R. Boyce∗
Department of Chemistry and Physics, Florida Gulf Coast University, Fort Myers, Florida 33965, United States
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The catalyst-free, regioselective synthesis of 4’-O-substituted pyridoxine derivatives under
solventless conditions is described. The methodology relies on the highly regioselective
formation of the ortho-pyridinone methide from pyridoxine and subsequent oxa-Michael
addition of alcohol nucleophiles. This methodology provides good to excellent yields for
primary and secondary alcohols and moderate yields for tertiary alcohols.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Pyridoxine
o-Pyridinone methide
Ginkgotoxin
Catalyst-free
Oxa-Michael
Introduction
Pyridoxine 1, a vitamer of B6, is one of the eight water-soluble
B vitamins and is an important nutrient. Of the six forms of the
vitamin, the main active vitamer, pyridoxal 5-phosphate, is a
cofactor in over 100 enzyme-catalyzed reactions involved in
metabolism and regulatory functions.1 Pyridoxine 1 possesses
significant biological activity in its own right as a cofactor for
several enzymes and a participant in the biosynthesis of
neurotransmitters and the production of nucleic acids. Recently,
pyridoxine’s potent antioxidant activity against superoxide2 and
singlet oxygen3 has been documented. Additionally, pyridoxine
can be prescribed to treat certain medical disorders. It is used as
an antidote for hydrazine exposure from incidents involving
isoniazid (INH) overdose and Gyromitra mushroom poisoning.4
Pyridoxine is also administered to treat ginkgotoxin 2 induced
seizures that can be caused from consumption of ginkgo biloba
seeds.5
Figure 1. Pyridoxine and selected biologically active
derivatives
The derivatization of the vitamin B6 3-pyridinol core has
generated considerable interest due to the broad range of
biological activity displayed with instructive examples
highlighted in Figure 1. The aminomethylated derivative,
pyridoxamine 3, is used to treat diabetic kidney disease.6 Bananin
4 has been shown to inhibit SARS-CoV ATPase activity and
viral replication leading to its investigation as an anti-SARS
agent.7 Other derivatives have demonstrated utility as HIV-
integrase inhibitors,8 antibiotics9 and enzyme mimics.10
The functionalization of pyridoxine can be challenging. As
a practical consideration, the high water-solubility of pyridoxine
can be problematic in extractions leading to significant mass
loss.11 Pyridoxine is not soluble in many conventional organic
solvents which can complicate reaction optimization. A key
selectivity issue is the differentiation of the two primary alcohols.
Obtaining regioselectivity at the 4- and 5-hydroxymethyl groups
typically requires a ketalization protection strategy of the 4-
hydroxymethyl and the phenol.9 A rare example of selective
derivatization at the 5-hydroxymethyl moiety without the use of
protecting groups is the lipase-catalyzed acylation of pyridoxine
———
∗ Corresponding author. Tel.: +1-239-590-1471; fax: +1-239-590-7200; e-mail: gboyce@fgcu.edu

2
Tetrahedron
reported by Sun and coworkers.11 Pyridinone methide chemistry
A series of conditions was screened with instructive examples
highlighted in Table 1. Pyridoxine 1 in n-butanol at 105 °C
provided 5c in a 51% yield after 24 hours (entry 1) with
significant unreacted starting material isolated during
purification. Allowing the control to run to completion by TLC
analysis provided an 83% yield (entry 2) over 96 hours. Despite
the long reaction time, the reaction provides clean conversion to
the ether products and avoids the dimerization and byproducts
formation that occurs at higher temperatures.16 No reactivity was
observed for temperatures under 100 °C regardless of reaction
time. Increasing the temperature to 120-160 °C shortened the
reaction time; however, this led to a higher degree of
decomposition and a lower selectivity ratio of the ortho- to meta-
substitution. We then sought to employ a catalyst to expedite the
reaction time.
holds promise as a potential method for protecting group-free
derivatization of pyridoxine since theoretical studies have shown
that the energy barrier for the ortho-pyridinone methide is 8
kcal/mol lower than the meta-pyridinone methide.12 While this
reactivity has been noted prior to this report, only three primary
alcohol substrates have been synthesized in the past 75 years and
in low to moderate yields. Herein, we investigate the scope and
limitations of the catalyst-free13 synthesis of 4’-O-substituted
pyridoxine derivatives via thermal formation of a highly
regioselective o-pyridinone methide (o-PM) intermediate and
subsequent oxa-Michael addition of alcohol nucleophiles
(Scheme 1).
Scheme 1. Thermal ortho-pyridinone methide formation and
Table 1. Optimization Screen
trapping with alcohols
Entry catalyst
time (h)
24
temp (°C) yield (%)
While o-quinone methide chemistry is well-precedented in the
literature,14 examples of o-pyridinone methides are rare. The
thermal o-pyridinone methide reactivity of pyridoxine was first
noted by Harris who synthesized ginkgotoxin HCl salt in a 12%
yield by heating in the presence of sodium methoxide in 1940.15
This reactivity was further developed by Frater-Schröder and
Mahrer-Busato in conjunction with toxicological studies in 1975.
They demonstrated that heating pyridoxine to 120-130 °C in the
presence of n-butanol and isoamyl alcohol with tetralin as a
cosolvent provided the 4’-O-substituted products albeit in a 49%
and 36% yield, respectively.16 This report is significant as the
first catalyst-free formation of these products; however, the
report is limited to two substrates and the authors note the
presence of dimerization of pyridoxine and other byproducts at
such high temperatures. Recently, a microwave-assisted p-
toluenesulfonic acid-catalyzed synthesis of ginkgotoxin was
accomplished providing 56% yield.18 The low to moderate yields
might be caused by the weak nucleophilicity of the alcohols as
well as the observed reversibility of the C-O bond formation in
the presence of water.16
1
2
3
4
5
6
7
none
none
105
105
50
51
83
0
96
dibenzoyl peroxide 96
dibenzoyl peroxide 96
105
50
65
0
AIBN, hv
phenylboronic acid 96
p-TSA 96
48
105
105
58
53
a
All reactions were conducted [1]0= 0.2 M on a 0.3 mmol
scale under air.
Using 0.2 M n-butanol and pyridoxine for the synthesis of 5c
as a model system, an investigation to identify a suitable catalyst
was undertaken. Since pyridoxine has been noted to form radicals
in biological systems,19 we began the study with an analysis of
radical initiators. Of the radical initiators attempted, dibenzoyl
peroxide provided the highest yields and facilitated product
formation below 100 °C; however, the catalyst provided less 5c
than the uncatalyzed conditions at both lower temperatures (entry
3) and at 105 °C (entry 4). Several boronic acid catalysts were
also screened as they have been demonstrated as efficient
promoters of o-quinone methide formation;20 these attempts
provided lower yields than the uncatalyzed conditions (entry 6).
A series of Brönsted and Lewis acid catalysis were attempted and
most hindered the desired reactivity or provided a lower
selectivity ratio of the ortho- to meta-substitution. p-
Toluenesulfonic acid (entry 7), the catalyst used in the
microwave-assisted synthesis of ginkgotoxin,18 provided a 53%
yield. Basic conditions, as utilized by Harris,10 provided a faster
reaction, but favored decomposition with trace product
formation. With suitable solventless, catalyst-free conditions in
hand, an examination of the allowable steric and electronic
parameters with respect to the alcohol coupling partner was
undertaken. A variety of primary, secondary, and tertiary
alcohols were submitted to the reaction conditions with the
results compiled in Table 2.
Due to the biological importance of pyridoxine analogs, we
sought to investigate the feasibility of expanding this
alkoxylation reactivity to generate a broad scope of 4’-O-
substituted ether derivatives. In particular, a scalable synthesis of
ginkgotoxin was desired since the natural product is required as
an analytic standard for GC-MS analysis of ginkgo biloba.
Currently, ginkgotoxin is only available in limited quantities
commercially (63.50 USD/10 mg, Sigma-Aldrich). An evaluation
of the steric and functional group limitations of the reaction was
desired to generate a library of analogs to facilitate the study of
the biological activity of this intriguing class of compounds.
Results and discussion
An examination to determine the most suitable reaction
parameters commenced with an analysis of solvent and
temperature. Without the use of a catalyst, the temperature
required to achieve formation of the o-pyridinone methide was
determined to be 105 °C in protic solvents. In aprotic solvents,
the o-pyridinone methide did not form to an appreciable extent at
comparable temperatures. The high solubility of pyridoxine in
alcohols enabled the coupling partner to be utilized without the
need for a traditional organic solvent.

3
Table 2. Synthesis of 4’-O-pyridoxine derivatives via thermal
o-PMa
Acknowledgments
The project described was supported by Award No. CHE-
1530959 from the National Science Foundation. GRB is grateful
to Florida Gulf Coast University for the startup funds that support
research.
Supplementary Material
Entry
1
Product
2
R
Mec
Etc
Yield (%)b
Supplementary data associated with this article can be found,
in the online version, at
57
58
44
83
38
79
55
46
70
82
38
72
2
5a
5b
5c
References and notes
3
i-Prc
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n-Bu
NIH, Office of dietary supplements. Dietary Supplement Fact
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−237.
Vitamin
B6
(accessed
Nov
20,
2016).
5
t-Bu
5d
5e
6
i-Amyl
s-Amyl
t-Amyl
Bn
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56
aAll reactions were conducted [1]0= 0.2 M. Isolated yield.
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Conclusion
The general synthesis of 4’-O-substituted pyridoxine
derivatives with high regioselectivity under catalyst-free
conditions is disclosed. This operationally-simple methodology
enables access to a broad scope of ether analogs from
inexpensive, commercially available pyridoxine and alcohols in
moderate to excellent yields via the rare ortho-pyridinone
methide intermediate. The substrate scope demonstrated good
functional group compatibility with primary, secondary, and
tertiary alcohols and ether and olefin moieties being well-
tolerated. The analysis of the biological activities of these
compounds and the incorporation of additional nucleophilic
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A Regioselective Etherification of Pyridoxine via an ortho-Pyridinone Methide
Intermediate
Jessica A. Yazarians, Brian L. Jiménez, and Gregory R. Boyce*
Department of Chemistry and Physics, Florida Gulf Coast University, Fort Myers, Florida 33965, USA
e-mail: gboyce@fgcu.edu
Highlights
A catalyst-free regioselective etherification of pyridoxine was described.
The natural product, ginkgotoxin, was synthesized using this methodology in a 57% yield.
The steric and electronic parameters of the reaction were investigated using 13 substrates.