1-Alkoxy-7-hydroxy-1,3-dihydrofuro[3,4-c]pyridinium Salts

Article abstract of DOI:10.1134/S1070428018040103

New salt structures have been synthesized from pyridoxal and various organic and inorganic acids.

Full text of DOI:10.1134/S1070428018040103

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 4, pp. 578–581. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © R.Kh. Bagautdinova, L.K. Kibardina, M.A. Pudovik, E.M. Pudovik, A.R. Burilov, A.V. Trifonov, A.B. Dobrynin, 2018, published in
Zhurnal Organicheskoi Khimii, 2018, Vol. 54, No. 4, pp. 577–580.
1-Alkoxy-7-hydroxy-1,3-dihydrofuro[3,4-c]pyridinium Salts
a
a
a
b
a
R. Kh. Bagautdinova , L. K. Kibardina , M. A. Pudovik ,* E. M. Pudovik , A. R. Burilov ,
a,c
a
A. V. Trifonov , and A. B. Dobrynin
a
Arbuzov Institute of Organic and Physical Chemistry, Kazan Scientific Center, Russian Academy of Sciences,
ul. Arbuzova 8, Kazan, 420088 Tatarstan, Russia
*
e-mail: pudovik@iopc.ru
b
Kazan (Volga Region) Federal University, ul. Kremlevskaya 18, Kazan, 420008 Tatarstan, Russia
c
Kazan National Research Technological University, ul. Karla Marksa 68, Kazan, 420015 Tatarstan, Russia
Received June 28, 2017
Abstract—New salt structures have been synthesized from pyridoxal and various organic and inorganic acids.
DOI: 10.1134/S1070428018040103
Pyridoxal (3-hydroxy-5-hydroxymethyl-2-methyl-
such strong acids as sulfuric, trifluoromethanesulfonic,
and trifluoroacetic in alcohol afforded alkoxyfuropyri-
dinium salts 2a–2c (Scheme 1). The structure of 2a–2e
pyridine-4-carbaldehyde) is a form of vitamin B ; it
6
plays an important role in biochemical processes
occurring in living organisms. Its catalytically active
coenzyme) form, pyridoxal phosphate, is involved in
1
was confirmed by elemental analyses and IR, H and
1
3
1
(
C NMR, and mass spectra. According to the H NMR
many reactions. Pyridoxal is a polyfunctional com-
pound possessing reactive phenolic, pseudo alcohol,
and formyl groups together with basic pyridine nitro-
gen atom which is capable of forming salt structures.
Pyridoxal is fairly unstable and is therefore commer-
cially produced as pyridoxal hydrochloride. Analogous
salt structures are formed in many reactions. We
previously studied alkylation of a series of phenols and
polyphenols with pyridoxal. The reactions were carried
out in the presence of HCl, and the products were the
corresponding hydrochlorides [1]. Pyridoxal reacted
with dialkyl hydrogen phosphites to give inner salts
data, compounds 2a–2e contained an ethoxy group,
protons of the endocyclic methylene group (3-H)
resonated as two doublets with fairly similar chemical
shifts (J = 13.10–14.10 Hz), and the OCHO signal
(1-H) was a singlet. The 4-H signal was observed in
a weaker field than the corresponding signal of free
pyridoxal, and the OH signal appeared as a broadened
singlet. The IR spectra of 2a–2e showed a number of
–
1
absorption bands in the region 1800–2500 cm , which
+
are typical of N –H group. The salt structure of 2a–2e
is indirectly supported by their solubility in water.
The reaction of 1 with weaker acids, such as acetic
acid or phenol, gave a different result. In these cases,
the product was neutral acetal 3 (Scheme 2), and acetic
acid or phenol acted as catalyst. No alkoxyfuropyri-
dines were formed in the absence of acid catalyst.
Compound 1 could be expected to react with dicar-
boxylic acids to give 2 :1 adducts; however, these
[2]. Ammonium moiety often constitutes a necessary
structural unit of potentially biologically active com-
pounds [3–5].
In this work we made an attempt to obtain onium
salts from pyridoxal (1) and some mineral, carboxylic,
and phosphorus acids. The reaction of pyridoxal with
Scheme 1.
OH
OH
OEt
O
Me
CHO
OH
EtOH
Me
+
X–H
X–
N
N
H
1
2a–2e
–
4
–
2
–
–
–
2
, X = HSO
(a), CF
3
SO
(b), CF
3
COO (c) , HOC(O)C(O)O (d), HOC(O)CH=CHC(O)O (e).
5
78

1
-ALKOXY-7-HYDROXY-1,3-DIHYDROFURO[3,4-c]PYRIDINIUM SALTS
579
Scheme 2.
OH
OH
OEt
O
Me
CHO
OH
EtOH
Me
+
Y–H
N
N
1
3
Y–H = PhOH, AcOH.
Scheme 3.
OH
OH
OR
Me
CHO
OH
ROH
Z–H
Me
+
Z–
O
N
N
H
1
4a–4c
4
, R = Et, Z = (ClCH
2
)
2
P(O)O (a), (HO)
2
2 2
P(O)C(Me)(OH)P(O)(OH)O (b); R = Me, Z = (ClCH ) P(O)O (c).
Scheme 4.
O–
O
OH
OH
P
OMe
OH
OMe
O
Me
CHO
OH
MeOH
Me
H
Me
+
(PhO) P(O)H
OH
OH
+
2
N
N
N
1
5
6
reactions involved only one carboxy group with forma-
EXPERIMENTAL
tion of 1:1 acid salts 2d and 2e (Scheme 1).
–
1
The IR spectra (400–3600 cm ) were recorded in
We previously showed that pyridoxal forms salt
structures with phosphorous acid; the reactions were
carried out in alcohols, and pyridoxal was converted to
the corresponding acetal, alkoxyfuropyridine [6]. Bis-
1
13
KBr on a Bruker Tensor-27 spectrometer. The H, C,
and P NMR spectra were measured on a Bruker
Avance 400 spectrometer at 400.13, 100.61, and
61.98 MHz, respectively. The mass spectra (MALDI-
TOF) were obtained on a Bruker Ultraflex III TOF/
TOF instrument using 4-nitroaniline as matrix.
3
1
1
(
chloromethyl)phosphinic and 1-hydroxyethane-1,1-di-
ylphosphonic acids reacted with pyridoxal (1) in
ethanol or methanol to give alkoxyfuropyridinium salts
4
a–4c (Scheme 3). The structure of 4a was proved by
X-ray analysis (Fig. 1). The bond lengths in molecule
a conform to the corresponding standard values. The
4
pyridine heterocycle is planar, and the dihydrofuran
ring has an O-envelope conformation with the
1
8
9
3
C C C C fragment planar within 0.024(6) Å and the
1
O atom deviating from that plane by 0.320(3) Å; the
ethoxy group occupies the axial position.
The reaction of pyridoxal with a weak phosphorus
acid, diphenyl hydrogen phosphite, in methanol gave
a mixture of inner salt 5 and acetal 6. Presumably,
compound 5 is formed as a result of replacement of
phenoxy groups on the phosphorus by methoxy and
addition of phosphorus to the carbonyl carbon atom
with formation of dialkyl α-hydroxyphosphonate
which (as shown in [2]) is very readily hydrolyzed to
α-hydroxyphosphonate 5.
Fig. 1. Structure of the molecule of 1-ethoxy-7-hydroxy-6-
methyl-1,3-dihydrofuro[3,4-c]pyridin-5-ium bis(chlorometh-
yl)phosphinate (4a) according to the X-ray diffraction data.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 4 2018

5
80
BAGAUTDINOVA et al.
The X-ray diffraction study of a single crystal of 4c
was performed at the Diffraction Methods Laboratory
Arbuzov Institute of Organic and Physical Chemistry,
7.0 Hz), 2.51 s (3H, CH
and 5.17 d (1H each, 3-H, J = 14.0 Hz), 6.42 s (1H,
), 3.73 m (2H, OCH ), 5.11 d
3 2
1
3
(
1-H), 8.34 s (1H, 4-H). C NMR spectrum
(DMSO-d ), δ , ppm: 15.26, 15.63, 64.02, 70.01,
103.87, 126.07, 138.66, 138.87, 143.93, 149.34. Found,
%: C 37.99; H 4.24; N 3.99; S 9.11. C11 NO S.
Calculated, %: C 38.26; H 4.09; N 4.06; S 9.28.
-Ethoxy-7-hydroxy-6-methyl-1,3-dihydrofuro-
3,4-c]pyridin-5-ium trifluoroacetate (2c). Yield
Kazan Scientific Center, Russian Academy of
Sciences). Monoclinic crystal system, space group
C2/c; C H NO ·C H Cl O P, M 358.14; unit cell
6
C
H F
14
1
0
14
3
2
4
2
2
3
6
parameters (296 K): a = 18.4814(16), b = 9.9639(7),
3
c = 19.9972(17) Å; β = 115.096(4)°; V = 3334.8(5) Å ;
1
3
–1
Z = 8; dcalc = 1.427 g/cm ; μ = 0.503 mm ; F(000) =
488. The data were obtained on a Bruker Smart
[
–
1
1
1
.02 g (87%), mp 110–113°C. IR spectrum, ν, cm :
+
1
APEX II CCD automated diffractometer (Mo K radia-
α
3063 (OH), 2549–2104 (NH ). H NMR spectrum
tion, λ 0.71073 Å, graphite monochromator; ω-scan-
ning, 2θ < 52°). Total of 14222 reflection intensities
were measured, including 3264 independent reflections
(
DMSO-d ), δ, ppm: 1.14 t (3H, CH , J = 7.0 Hz),
6
3
2
.53 s (3H, CH ), 3.70 m (2H, OCH ), 5.07 d and
3 2
5
.13 d (1H each, 3-H, J = 13.7 Hz), 6.40 s (1H, 1-H),
1
3
(
Rint = 0.094) and 1682 reflections with I> 2σ(I). Final
8.24 s (1H, 4-H).
C NMR spectrum (DMSO-d6),
divergence factors: R = 0.0539, wR = 0.1602; good-
2
δC, ppm: 15.67, 16.10, 63.82, 70.02, 104.06, 127.50,
37.00, 138.14, 144.42, 148.87, 159.09. Found, %:
C 46.54; H 4.27; N 4.43. C H F NO . Calculated, %:
ness of fit 1.01; 138 variables. A correction for absorp-
tion was applied using SADABS program [7]. The
structure was solved by the direct method (SIR [8])
and was refined first in isotropic and then in aniso-
tropic approximation (SHELXL-97 [9]). All hydrogen
atoms were placed in geometrically calculated posi-
tions which were refined according to the riding
model. All calculations were carried out using WinGX
1
1
2
14
3
5
C 46.60; H 4.57; N 4.53.
-Ethoxy-7-hydroxy-6-methyl-1,3-dihydrofuro-
3,4-c]pyridin-5-ium carboxymethanoate (2d). Yield
1
[
–1
0
.83 g (77%), mp 149°C. IR spectrum, ν, cm : 3063
+
1
(
OH), 2552–2112 (NH ), 1726 (C=O). H NMR spec-
trum (DMSO-d ), δ, ppm: 1.13 t (3H, CH CH , J =
6
2
3
[10] and APEX2 [11]. The X-ray diffraction data for
7
4
.1 Hz), 2.41 s (3H, CH ), 3.65 m (2H, CH CH ),
3 2 3
.95 d and 5.05 d (1H each, 3-H, J = 13.1 Hz), 6.29 s
compound 4c were deposited to the Cambridge Crys-
tallographic Data Centre (CCDC entry no. 1813446)
and are available at http://www.ccdc.cam.ac.uk.
(
1H, 1-H), 8.00 s (1H, 4-H), 9.53 br.s (2H, OH). Mass
+
spectrum: m/z 195 [M – HOCOCOOH] . Found, %:
1
-Ethoxy-7-hydroxy-6-methyl-1,3-dihydrofuro-
3,4-c]pyridin-5-ium hydrogen sulfate (2a). A mix-
ture of 0.72 g (4 mmol) of pyridoxal (1) and 0.42 g
4 mmol) of sulfuric acid in 20 mL of anhydrous
C 50.45; H 5.34; N 4.64. C H NO . Calculated, %:
1
2
15
7
[
C 50.53; H 5.26; N 4.91.
-Ethoxy-7-hydroxy-6-methyl-1,3-dihydrofuro-
3,4-c]pyridin-5-ium 3-carboxyprop-2-enoate (2e).
1
(
[
ethanol was refluxed for 2 h. The solvent was
removed, the residue was treated with 20 mL of diethyl
ether, and the precipitate was filtered off and dried
under reduced pressure. Yield 1.17 g (97%), mp 110–
–1
Yield 0.60 g (47%), mp 139°C. IR spectrum, ν, cm :
3
+
1
061 (OH), 2591–2122 (NH ), 1694 (C=O). H NMR
spectrum (DMSO-d ), δ, ppm: 1.13 t (3H, CH CH ,
6
2
3
J = 7.0 Hz), 2.43 s (3H, CH ), 3.65 m (2H, CH CH ),
3
2
3
–
1
1
(
12°C. IR spectrum, ν, cm : 3074 (OH), 2600–2500
4
(
9
.98 d and 5.07 d (1H each, 3-H, J = 13.2 Hz), 6.19 s
2H, CH=CH), 6.31 s (1H, 1-H), 8.06 s (1H, 4-H),
.53 br.s (1H, OH). Mass spectrum: m/z 195 [M –
+
1
NH ). H NMR spectrum (DMSO-d ), δ, ppm: 1.15 t
6
(
3H, CH , J = 7.0 Hz), 2.58 s (3H, CH ), 3.74 m (2H,
OCH ), 5.12 d and 5.16 d (1H each, 3-H, J = 14.0 Hz),
.43 s (1H, 1-H), 8.35 s (1H, 4-H). Found, %: C 40.75;
H 5.06; N 4.44; S 11.12. C H NO S. Calculated, %:
3
3
+
2
HOC(O)CH=CHC(O)OH] . Found, %: C 53.90;
H 5.38; N 4.24. C H NO . Calculated, %: C 54.19;
6
1
4
17
7
1
0
15
7
H 5.16; N 4.52.
C 40.94; H 5.16; N 4.78; S 10.93.
1
-Ethoxy-7-hydroxy-6-methyl-1,3-dihydrofuro-
Compounds 2b–2e and 4a–4c were synthesized in
a similar way.
[
(
3,4-c]pyridin-7-ol (3). a. A mixture of 0.69 g
4 mmol) of pyridoxal (1) and 0.25 g (4 mmol) of
1
-Ethoxy-7-hydroxy-6-methyl-1,3-dihydrofuro-
acetic acid in 20 mL of anhydrous ethanol was re-
fluxed for 2 h. The mixture was cooled, the solvent
was removed, the residue was treated with 20 mL of
anhydrous diethyl ether, and the precipitate was
filtered off. Yield 0.55 g (69%), mp 118–121°C [2].
[
(
3,4-c]pyridin-5-ium trifluoromethanesulfonate
2b). Yield 1.26 g (85%), mp 123–126°C. IR spectrum,
ν, cm : 3154 (OH), 2750–2600 (NH ). H NMR spec-
trum (DMSO-d ), δ, ppm: 1.15 t (3H, CH , J =
–
1
+
1
6
3
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 4 2018

1
-ALKOXY-7-HYDROXY-1,3-DIHYDROFURO[3,4-c]PYRIDINIUM SALTS
581
1
1
H NMR spectrum (DMSO-d ), δ, ppm: 1.13 t (3H,
Yield 0.16 g (25%), mp 300°C. H NMR spectrum
6
CH , J = 7.1 Hz), 2.37 s (3H, CH ), 3.65 m (2H,
(DMSO-d ), δ, ppm: 2.43 s (3H, CH ), 3.56 d (3H,
3
3
6
3
OCH ), 4.93 d and 5.03 d (1H each, 3-H, J = 12.9 Hz),
CH , J = 10.1 Hz), 4.66 d and 4.76 d (1H each, 5-CH ,
2
3
2
6
.27 s (1H, 1-H), 7.93 s (1H, 4-H).
J = 14.4 Hz), 5.05 d (1H, PCH, J = 16.5 Hz), 7.94 s
3
1
(
1H, 6-H). P NMR spectrum (DMSO-d ):
P
6
b. When the reaction was carried out with phenol,
+
δ 18.51 ppm. Mass spectrum: m/z 263 [M] . Found,
the yield of 3 was 0.65 g (81%), mp 118–120°C.
%
: C 41.13; H 5.34; N 5.72. C H NO P. Calculated,
9 14 6
1
-Ethoxy-7-hydroxy-6-methyl-1,3-dihydrofuro-
%
: C 41.06; H 5.32; N 5.32.
-Methoxy-6-methyl-1,3-dihydrofuro[3,4-c]-
pyridin-7-ol (6) was isolated from the filtrate. Yield
[
(
3,4-c]pyridin-5-ium bis(chloromethyl)phosphinate
4a). Yield 1.29 g (87%), mp 135–137°C. IR spectrum:
1
–
1
+
1
ν 2353–2086 cm (NH ). H NMR spectrum
1
0
.21 g (48%), mp 167–170°C. H NMR spectrum
(
DMSO-d ), δ, ppm: 1.13 t (3H, CH , J = 7.0 Hz),
6
3
(
DMSO-d ), δ, ppm: 2.42 s (3H, CH ), 3.34 s (3H,
6
3
2
5
.47 s (3H, CH ), 3.68 d (4H, ClCH , J = 8.0 Hz),
3 2
OCH ), 4.98 d and 5.06 d (1H each, 3-H, J = 13.3 Hz),
3
.00 d and 5.08 d (1H each, 3-H, J = 13.3 Hz), 6.37 s
3
1
6.27 s (1H, 1-H), 8.01 s (1H, 4-H). Mass spectrum:
(
(
1H, 1-H), 8.08 s (1H, 4-H). P NMR spectrum
DMSO-d ): δ 26.85 ppm. Found, %: C 39.99; H 4.21;
+
m/z 181 [M] . Found, %: C 59.44; H 6.16; N 7.57.
6
P
C H NO . Calculated, %: C 59.67; H 6.08; N 7.73.
9
11
3
Cl 20.09; N 3.93; P 8.62. C H Cl NO P. Calculated,
11
16
2
5
%
: C 40.24; H 4.40; Cl 19.79; N 3.91; P 8.65.
-Ethoxy-7-hydroxy-6-methyl-1,3-dihydrofuro-
3,4-c]pyridin-5-ium hydrogen (1-hydroxy-1-phos-
phonoethyl)phosphonate (4b). Yield 1.32 g (85%),
REFERENCES
1
[
1. Kibardina, L.K., Chumakova, L.V., Gazizov, A.S.,
Burilov, A.R., and Pudovik, M.A., Synthesis, 2015,
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Burilov, A.R., Pudovik, M.A., and Sinyashin, O.G.,
Heteroatom Chem., 2016, vol. 27, no. 4, p. 221.
–
1
mp 171–173°C. IR spectrum: ν 2520–2151 cm
+
1
2
(NH ). H NMR spectrum (DMSO-d ), δ, ppm: 1.13 t
6
(
3H, CH , J = 7.1 Hz), 1.44 t (3H, CH , J = 15.6 Hz),
3
3
2
4
.42 s (3H, CH ), 3.65 m (2H, CH ), 4.76 s (4H, OH),
.97 d and 5.06 d (1H each, 3-H, J = 13.1 Hz), 6.29 s
3 2
3
4
. Bogdanov, A.V., Kutuzova, T.A., and Mironov, V.F.,
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3
1
(
(
1H, 1-H), 8.01 s (1H, 4-H). P NMR spectrum
DMSO-d ): δ 20.65 ppm. Found, %: C 35.76;
. Vagapova, L.I., Amirova, L.R., Burilov, A.R., and
Pudovik, M.A., Russ. J. Gen. Chem., 2016, vol. 86,
no. 3, p. 725.
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Chem., 2015, vol. 51, no. 10, p. 1510.
6
P
H 5.32; N 3.82; P 15.43. C H NO P . Calculated, %:
C 35.91; H 5.29; N 3.49; P 15.44.
12
21
10 2
5
7
-Hydroxy-1-methoxy-6-methyl-1,3-dihydro-
furo[3,4-c]pyridin-5-ium bis(chloromethyl)phos-
phinate (4c). Yield 1.17 g (83%), mp 138–141°C. IR
spectrum: ν 2349–2082 cm (NH ). H NMR spec-
trum (DMSO-d ), δ, ppm: 2.44 s (3H, CH ), 3.35 s
–
1
+
1
6
3
(
5
8
3H, OCH ), 3.64 d (4H, CH , J = 8.0 Hz), 5.00 d and
7. Sheldrick, G.M., SADABS, Madison, Wisconsin, USA:
3
2
Bruker AXS, 1997.
.08 d (1H each, 3-H, J = 13.3 Hz), 6.26 s (1H, 1-H),
3
1
.06 s (1H, 4-H). P NMR spectrum (DMSO-d6):
8. Altomare, A., Cascarano, G., Giacovazzo, C., and
Viterbo, D., Acta Crystallogr., Sect. A, 1991, vol. 47,
p. 744.
δP 28.09 ppm. Found, %: C 38.19; H 4.61; Cl 20.29;
N 3.93; P 8.82. C H Cl NO P. Calculated, %:
C 38.37; H 4.70; Cl 20.60; N 4.07; P 9.00.
1
1
16
2
5
9
. Sheldrick, G.M., SHELX-97. Programs for Crystal
Structure Analysis (Release 97-2), Göttingen: University
of Göttingen, 1997.
Methyl [hydroxy(3-hydroxy-5-hydroxymethyl-2-
methylpyridin-1-ium-4-yl)methyl]phosphonate (5).
A mixture of 0.4 g (2 mmol) of pyridoxal, 0.56 g
1
0. Farrugia, L.J., J. Appl. Crystallogr., 1999, vol. 32,
p. 837.
(
2 mmol) of diphenyl hydrogen phosphite, and 10 mL
1
1. APEX2 (Version 2.1), SAINTPlus. Data Reduction and
of anhydrous methanol was refluxed for 3 h. The
mixture was left to stand for 24 h, and the precipitate
was filtered off and washed with diethyl ether.
Correction Program (Version 7.31A), Bruker Advanced
X-ray Solutions, Madison, Wisconsin, USA: Bruker
AXS, 2006.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 4 2018