Synthesis of novel 6-substituted sulfur-containing derivatives of pyridoxine

Article abstract of DOI:10.1016/j.tetlet.2012.05.086

An efficient synthesis of novel 6-substituted derivatives of pyridoxine was achieved. The reactions of various thiols with mono-, bis-, and tris(hlorine) derivatives of 6-methyl-2,3,4-tris(hydroxymethyl)pyridin-5-ol (6-hydroxymethylpyridoxine) gave sulfur

Full text of DOI:10.1016/j.tetlet.2012.05.086

Tetrahedron Letters 53 (2012) 3967–3970
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Tetrahedron Letters
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Synthesis of novel 6-substituted sulfur-containing derivatives of pyridoxine
Nikita V. Shtyrlin a, Roman S. Pavelyev a, Mikhail V. Pugachev a, Lubov P. Sysoeva a, Rashid Z. Musin b,
Yurii G. Shtyrlin a,
⇑
a Research and Educational Center of Pharmacy, Kazan Federal University, Kazan 420008, Russian Federation
b A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Centre of the Russian Academy of Sciences, Kazan 420088, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of novel 6-substituted derivatives of pyridoxine was achieved. The reactions of var-
ious thiols with mono-, bis-, and tris(chlorine) derivatives of 6-methyl-2,3,4-tris(hydroxymethyl)pyridin-
5-ol (6-hydroxymethylpyridoxine) gave sulfur-containing derivatives of pyridoxine.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 6 April 2012
Revised 10 May 2012
Accepted 17 May 2012
Available online 31 May 2012
Keywords:
Pyridoxine
Nucleophilic substitution
Sulfur nucleophiles
Thioethers
Protecting groups
Chemical modification of biologically active compounds of nat-
ural origin is one of the most efficient approaches in drug develop-
ment. A promising starting compound is vitamin B6 (pyridoxine)
which participates in over a hundred enzyme reactions involved
in biosynthesis, metabolism, and regulatory functions in living
organisms.1
A complicated problem in pyridoxine chemistry is its function-
alization at C-6. Only a few reports have been published that con-
sider the synthesis of such compounds and their biological
activity.2 In particular, arylazo derivatives act as selective antago-
nists of P2X1 and P2Y13 receptors,2e,2f whereas, aminopyridinol
derivatives exhibit antioxidant properties.2g
Jones obtained 6-hydroxymethylpyridoxine through initial for-
mation of the pyridine ring from ethyl hydroxymethyleneoxalace-
tate and iminoacetylacetone followed by its functionalization in
five steps.2c,2d This method was laborious and not effective. Re-
cently, we described an efficient method for the synthesis of 6-
hydroxymethylpyridoxine from pyridoxine hydrochloride in three
steps.3
In continuation of our studies on pyridoxine derivatives, it was
interesting (for the first time) to produce thioethers of 6-hydrox-
ymethylpyridoxine via nucleophilic substitution reactions.
Thioethers are an important class of diverse organic compounds
that are used widely in medicine,4 agriculture,5 and industry.6
Moreover, thioethers can be used for the asymmetric synthesis of
sulfoxides as well as for the production of sulfones.7
The most straightforward method for the synthesis of thio-
ethers is based on nucleophilic substitution reactions. In order to
involve the hydroxy groups in the reaction they need to be con-
verted into a good leaving group using activating agents such as al-
kyl- or arylsulfonates.8 Activation of the hydroxymethyl groups of
pyridoxine derivatives was achieved by reaction with thionyl chlo-
ride9 or methanesulfonyl chloride.10
We achieved selective activation of the hydroxymethyl groups
of 6-methyl-2,3,4-tris(hydroxymethyl)pyridin-5-ol using isomeric
six- and seven-membered ketals 1 and 2, which we obtained ear-
lier in two or three steps from pyridoxine hydrochloride.11 Chlo-
rination of the hydroxymethyl group of seven-membered ketal 1
by the reaction with thionyl chloride occurred via isomerization
of the seven-membered ketal into six-membered derivative 3
with a yield of 62% (Scheme 1). In this case, a large number of
by-products formed which is typical for reactions of alcohols
with thionyl chloride in the absence of a hydrogen acceptor.12
Attempts to block isomerization of the seven-membered ketal
into the six-membered product with triethylamine or pyridine
as the acceptors of hydrogen chloride failed. However, the reac-
tion of six-membered ketal 2 with thionyl chloride occurred un-
der mild conditions and resulted in the desired product 3 in 85%
yield.
The lower yield of six-membered ketal 3 in the chlorination
reaction of compound 1 in comparison with 2 can be explained
by the occurrence of a side process involving dehydrochlorination
of the hydroxymethyl group at the para-position to the aromatic
hydroxy group with the formation of a p-quinone methide which
participates in different side reactions.13
⇑
Corresponding author. Tel./fax: +7 843 233 75 31.
E-mail address: Yurii.Shtyrlin@ksu.ru (Y.G. Shtyrlin).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.086

3968
N. V. Shtyrlin et al. / Tetrahedron Letters 53 (2012) 3967–3970
CH3
H3C
O
H3C
O
CH3
CH3
CH3
SPh
OH
OH
O
OH
OH
O
O
O
2 steps
MsCl (2 equiv)
Et3N
HO
MsO
H3C
HO
MsO
H3C
MsO
H3C
PhSNa (1 equiv)
HCl
CHCl3, 0 oC to r.t.,
10 h
MeOH, r.t.,
EtOH/H2O,
SPh
OH
Cl
H3C
N
N
6
H3C
N
1
N
4
N
5
12 h
50 oC, 8 h
HCl
(82%)
(81%)
(66%)
NaOH,
NaOH,
SOCl2,
r.t., 4 h
EtOH/H2O,
60 oC, 20 h
EtOH/H2O,
60 oC, 20 h
3 steps
H3C
O
CH3
O
CH3
O
CH3
SPh
OH
OH
H3C
H3C
O
HO
O
HO
O
HCl
SOCl2
OH
OH
Cl
Cl
CH2Cl2
EtOH/H2O,
SPh
0 oC to r.t., 5 h
50 oC, 5 h
H3C
N
H3C
N
N
3
H3C
N
H3C
2
(62% from 1)
7a (54%)
8a (52% from 6)
(67% from 7a)
(85% from 2)
Scheme 1. Synthesis of compounds 3 and 8a.
In order to activate the unprotected hydroxymethyl group of se-
ven-membered ketal 1, we used another activating agent–meth-
anesulfonyl chloride in the presence of triethylamine. This
allowed us to avoid isomerization of the ketal group and isolate
compound 4 in 81% yield.
Thioethers based on the seven-membered ketal 1 were synthe-
sized in three steps as shown by the example involving the reac-
tion with thiophenol (Scheme 1). In the first step, derivative 4
reacts with an equimolar amount of thiophenolate at 40 °C. Subse-
quent cleavage of the ketal group of compound 5 under acidic con-
ditions led to the formation of diol 6. In the last step, mesylate
deprotection in the presence of sodium hydroxide or sodium meth-
oxide was performed. The overall yield of thioether 8a over three
steps, starting from compound 4, was 28%.
When we changed the sequence of deprotection steps to ini-
tially remove the mesyl group under basic conditions followed
by hydrolysis of the ketal group, the total yield of the target prod-
uct was found to be lower (about 24%).
Unexpectedly, we found that the reaction of chlorine deriva-
tives 4 with a twofold molar excess of thiophenolate at 50 °C for
six hours led not only to nucleophilic substitution of the chlorine
atom, but to removal of the mesylate group as well, and the reac-
tion took place under much milder conditions than those of the
mesylate hydrolysis using alkali or sodium methoxide. This al-
Table 1
Preparation of compounds 8a–8c
H3C
CH3
H3C
CH3
O
OH
O
O
OH
O
HO
HO
MsO
H3C
RSNa (2 equiv)
HCl
Cl MeOH, 40-50 oC,
SR
SR
EtOH/H2O,
50-60 oC, 4-6 h
N
4
H3C
N
7
H3C
N
8
4-6 h
Entry
R
Product
Yield of 7 (%)
Product
Yielda of 8 (%)
1
2
3
Ph
Bu
Bn
7a
7b
7c
79
54
68
8a
8b
8c
67
64
55
a
Isolated yield.
Table 2
Preparation of compounds 10a–e
H3C
H3C
H3C
H3C
HO
HO
O
O
O
O
RSNa (2 equiv)
HCl
SR
SR
Cl
Cl
SR
SR
MeOH, 25-50 o
3-24 h
C
EtOH/H2O,
H3C
N
H3C
N
H3C
N
25-50 oC, 10-48 h
9
10
3
Entry
R
Product
Yield of 9 (%)
Product
Yielda of 10 (%)
1
2
3
4
Ph
Bu
Bn
9a
9b
9c
9d
92
77
72
74
10a
10b
10c
10d
92
93
84
75
CH2CH2OH
N
5
9e
77
10e
67
S
a
Isolated yield.

N. V. Shtyrlin et al. / Tetrahedron Letters 53 (2012) 3967–3970
3969
H3C
H3C
H3C
O
O
HO
HO
H3C
S
S
S
O
O
NaSCH2CH2SNa (1 equiv)
MeOH, 50 oC, 10 h
Cl
Cl
HCl
EtOH/H2O,
H3C
N
H3C
N
H3C
N
9f
50 oC, 10 h
S
3
(52%)
10f(71%)
Scheme 2. Synthesis of compound 10f.
H3C
O
CH3
OH
Cl
SR
OH
O
Cl
SR
SR
MsCl (2 equiv)
Et3N
0 oC to r.t.,10 h
MsO
H3C
MsO
H3C
MsO
H3C
HO
HCl
RSNa (4 equiv)
Cl
MeOH, 30-55 oC,
CHCl3,
EtOH/H2O,
Cl
Cl
50 oC, 8 h
N
N
N
H3C
N
48-96 h
4
11(90%)
(98%)
12
14
SOCl2
CH2Cl2, r.t., 5 h
O
S
O
O
MsO
H3C
Cl
N
(75%)
13
Scheme 3. Synthesis of thioethers 14a–d.
lowed us to reduce the number of steps to form thioether 8a by
one, as well as to increase significantly the overall yield of the final
product up to 53% (Table 1). Similarly, thioethers 8b and 8c were
obtained by reactions with 1-butanethiol and benzyl mercaptan.
In the case of compound 3, bis-thioethers were formed in two
steps: (i) the reaction with a twofold molar excess of thiolate, fol-
lowed by (ii) hydrolysis of the ketal protecting group under acidic
conditions. We have performed these reactions with five different
thiols: thiophenol, 1-butanethiol, benzyl mercaptan, 2-mercap-
toethanol, and 2-mercaptobenzothiazole (Table 2). In all cases
the reaction yield was satisfactory (67–92%).
Using equimolar ratios of chlorine derivative 3 and thiolate an-
ions (thiophenol or 1-butanethiol) did not lead to any regioselec-
tivity being observed. We observed the formation of two
products in almost equal ratio, the structures of which were con-
firmed from NMR spectra. On reaction of 3 with an equimolar
amount of 1,2-ethanedithiol followed by acidic deprotection of
the ketal group, we obtained the corresponding cyclic sulfide 10f
(Scheme 2).
Tris-thioethers 14 were obtained in one step by reaction of 12
with a fourfold molar excess of thiolate anion. Nucleophilic substi-
tution of the three chlorine atoms and simultaneous removal of the
mesyl group occurred. The synthesis of four such thiols was
achieved in high yields (Table 3). The regioselectivity of the nucle-
ophilic substitution reactions of compound 12 will be considered
elsewhere.
In conclusion, we have developed an efficient method for the
synthesis of mono-, bis-, and tris-thioethers from 6-hydroxymeth-
ylpyridoxine using nucleophilic substitution reactions. This meth-
od allowed modification of the hydroxymethyl groups at the
second, third, and fourth positions of 6-methyl-2,3,4-tris(hydroxy-
methyl)pyridin-5-ol. The developed method should be of consider-
able interest for the selective introduction of various functional
groups on 6-hydroxymethylpyridoxine to generate new and poten-
tially biologically active compounds on the basis of vitamin B6.
Supplementary data
For the synthesis of tris-thioethers (on the basis of 6-methyl-
2,3,4-tris(hydroxymethyl)pyridin-5-ol), the trischloride 12 was ob-
tained in two steps starting from compound 4 (Scheme 3). Initially,
the ketal protecting group was hydrolyzed under acidic conditions.
In the second step, chlorination of the two hydroxy groups in com-
pound 11 was carried out using methanesulfonyl chloride as the
chlorinating agent. The corresponding trichloride 12 was obtained
in almost quantitative yield. However, when thionyl chloride was
used as the chlorinating agent, we observed the formation of an-
other product–cyclic sulfite 13.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.05.086.
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