Alternative Synthesis of Isoguvacine and Its N-(2-Aryl-2-hydroxyethyl) Derivatives

Article abstract of DOI:10.1134/S1070428018040139

Isonicotinic acid ethyl ester reacted with substituted phenacyl bromides to give the corresponding quaternary salts which were reduced with sodium tetrahydridoborate to ethyl 1-(2-aryl-2-hydroxyethyl)-1,2,3,6- tetrahydropyridine-4-carboxylates. The presence of an electron-donating substituent in the benzene ring of the latter is a necessary condition for their acid hydrolysis with cleavage of the C–N bond and formation of isoguvacine. Analogous derivatives with electron-withdrawing substituents are not converted to isoguvacine under similar conditions.

Full text of DOI:10.1134/S1070428018040139

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2018, Vol. 54, No. 4, pp. 593–600. © Pleiades Publishing, Ltd., 2018.
Original Russian Text © M.G. Abramyants, D.A. Lomov, S.N. Lyashchuk, O.O. Zaporozhets, 2018, published in Zhurnal Organicheskoi Khimii, 2018,
Vol. 54, No. 4, pp. 591–598.
Alternative Synthesis of Isoguvacine
and Its N-(2-Aryl-2-hydroxyethyl) Derivatives
M. G. Abramyants, D. A. Lomov,* S. N. Lyashchuk, and O. O. Zaporozhets
Litvinenko Institute of Physical Organic and Coal Chemistry, ul. R. Lyuksemburg 70, Donetsk, 283114 Ukraine
*
e-mail: lomov_dmitrii@mail.ru
Received June 28, 2017
Abstract—Isonicotinic acid ethyl ester reacted with substituted phenacyl bromides to give the corresponding
quaternary salts which were reduced with sodium tetrahydridoborate to ethyl 1-(2-aryl-2-hydroxyethyl)-1,2,3,6-
tetrahydropyridine-4-carboxylates. The presence of an electron-donating substituent in the benzene ring of the
latter is a necessary condition for their acid hydrolysis with cleavage of the C–N bond and formation of
isoguvacine. Analogous derivatives with electron-withdrawing substituents are not converted to isoguvacine
under similar conditions.
DOI: 10.1134/S1070428018040139
A number of tetrahydropyridine alkaloids, includ-
ing arecoline (1), arecaidine (2), isoguvacine (3),
guvacoline (4), and guvacine (5, 1,2,5,6-tetrahydro-
nicotinic acid), have been isolated from the nuts of the
Areca catechu palm growing in India, Ceylon, and the
Philippines [1]. These compounds can be regarded as
cyclic analogs of γ-aminobutyric acid (6, GABA) and
are GABA receptor agonists [2], except for isoguva-
cine. The latter exhibits properties of GABA mimetic
An alternative procedure utilizing difficultly accessible
N-benzylpiperidine-2,6-dione derivative has been
proposed later [6, 7].
Unfortunately, despite valuable pharmacological
properties, isoguvacine is characterized by high toxic-
ity, which stimulates search for its various biologically
active low-toxic derivatives. A number of structurally
complex derivatives of isoguvacine [8–10] and its
esters [11, 12] have been synthesized and shown to act
as GABA mimetics. All known methods of synthesis
of isoguvacine and its derivatives are laborious, and
the reactions require anhydrous inert media and highly
expensive metal complex catalysts.
–
6
–5
at a concentration of 3×10 to 3× 10 M, causing
inhibitory effect on spinal motor neurons (isolated
cord) with simultaneous primary afferent depolariza-
tion [3, 4]. Guvacine, being an inhibitor of GABA
–6
–3
neuronal seizure at a concentration of 10 to 10 M,
reduces its absorption by cerebral cortex slices. Guva-
cine and isoguvacine are used in experimental medi-
cines as tools for studying CNS functions [4].
We have developed a new practical procedure for
the synthesis of isoguvacine from accessible com-
pounds and determined factors responsible for its
formation. The starting compounds for the synthesis of
isoguvacine (3) and its N-(2-aryl-2-oxoethyl) deriva-
tives were isonicotinic acid ethyl ester (7) and phen-
acyl bromides 8a–8h containing various substituents in
the aromatic ring. The reaction of equimolar amounts
of 7 and 8a–8h in acetone at room temperature
afforded quaternary salts 9a–9h in 60‒95% yield
Isoguvacine was synthesized for the first time in
1
996 via a complicated three-step protocol starting
from N-(tert-butoxycarbonyl)piperidin-4-one [5].
COOH
COOR'
COOH
(
Scheme 1).
N
R
N
NH2
Compounds 9a–9h were isolated as colorless high-
H
1
melting water-soluble solids. Their H NMR spectra
displayed signals from protons in the pyridinium frag-
ment, methylene group (a singlet at δ 6.61‒6.71 ppm),
and aromatic ring. The carbonyl carbon signal was ob-
1
, 2, 4, 5
3
6
1
, R = R′ = Me; 2, R = Me, R′ = H; 4, R = H, R′ = Me;
, R = R′ = H.
5
5
93

5
94
ABRAMYANTS et al.
Scheme 1.
O
O
HO
COOEt
Br
N
N
NaBH4
COOEt
COOEt
+
R
R
R
Br–
N
7
8a–8h
9a–9h
10a–10h
2
R = H (a), 4-Me (b), 4-Cl (c), 4-Br (d), 4-MeO (e), 3-MeO (f), 2-Br-4-MeO (g), 4-O N (h).
1
3
served in the C NMR spectra of 9a–9h at δ 188.5–
1
(yield 80–87%; Scheme 2). The product was isolated
by evaporation of the reaction mixture to dryness and
subsequent removal of tarry impurities by washing
with anhydrous acetone and recrystallization from
C
90.8 ppm, and the neighboring methylene carbon
atom resonated at δ 66.8‒67.4 ppm.
C
It is known that complex boron hydrides reduce
quaternized pyridine derivatives with an electron-with-
drawing substituent or fused aromatic ring to the cor-
responding tetrahydropyridines [13] with the remain-
ing double bond localized at the carbon atom bearing
electron-withdrawing substituent or at the fusion atom.
Salts 9a–9h were also reduced in this way. Treatment
of 9a–9h with excess sodium tetrahydridoborate in
aqueous methanol at room temperature gave ethyl
-(2-aryl-2-hydroxyethyl)-1,2,3,6-tetrahydropyridine-
-carboxylates 10a–10h in 70‒97% yield (Scheme 1).
Compounds 10a–10h are colorless or slightly colored
solids melting at much lower temperatures than quater-
1
ethanol. The H NMR spectrum of hydrochloride 3
contained a signal of the COOH proton at δ 12.77 ppm,
+
a broadened singlet of the N H protons (δ 9.53 ppm),
2
a signal of the olefinic proton at δ 6.77 ppm, and
a group of signals from the methylene protons at
2
3
6
δ 3.15 (C H ), 2.44 (C H ), and 3.71 ppm (C H ). Its
2
2
2
1
3
C NMR spectrum displayed signals of the carbonyl
carbon atom (δ 166.9 ppm) and C (δ 129.1 ppm). In
the DEPT-135 spectrum of 3, a positive peak of C H
δ 131.6 ppm) and three negative methylene carbon
signals at δ 39.3 (C H ), 21.2 (C H ), and 41.4 ppm
4
C
C
5
1
4
(
C
2
3
C
2
2
6
(
C H ) were observed in agreement with its structure.
2
1
nary salts 9a–9h. The H NMR spectra of 10a–10h
Under analogous conditions, the acid hydrolysis of
lacked signals of pyridinium fragment, but broadened
two-proton singlets appeared at δ 2.61‒2.69, 2.46‒
compounds 10a, 10c, 10d, 10f, and 10h (R = H or
electron-withdrawing substituent) involved only the
ester group, and the products were the corresponding
carboxylic acids 11a, 11c, 11d, 11f, and 11h
2
.48, and 2.55‒2.61 ppm due to tetrahydropyridine
1
3
ring. The DEPT-135 C NMR spectra of 10a–10h
1
showed negative upfield signals of three methylene
(Scheme 3) whose H NMR spectra showed no signals
2
3
carbons at δ 49.4‒51.7 (C H ), 25.1‒25.2 (C H ), and
of the ester ethoxy group.
C
2
2
6
1
3
5
2.4‒52.5 ppm (C H ). The reduction of the pyridi-
2
The C NMR and DEPT-135 spectra of carboxylic
nium ring was accompanied by reduction of the car-
bonyl group to hydroxy. This followed from the
acids 11 showed signals (positive peaks in the DEPT-
1
1
35 spectrum) of the carboxy group (δ 168.2‒
C
1
13
5
H NMR and C DEPT-135 data. Protons of the exo-
68.3 ppm), C (δ 130.9‒131.6 ppm), and CHOH
C
cyclic methylene group resonated as two symmetrical
(
δC 66.8‒66.9 ppm), as well as signals (negative peaks)
doublets at δ 3.39‒3.43 and 3.19‒3.22 ppm with
at δ 60.9‒61.3 (exocyclic methylene group), 39.5‒40.0
C
2
2
3
6
a geminal coupling constant J of 18.0‒18.8 Hz,
(
C H ), 21.1‒21.7 (C H ), and 40.8‒41.4 ppm (C H ).
2 2 2
the CHOH proton resonated as a quartet at δ 2.71‒
Presumably, the mechanism of acid hydrolysis of
β-amino alcohols 10b, 10e, and 10g involves two
competing paths, “enamine” (a) and “glycol” (b)
2
.91 ppm, and the hydroxy proton gave rise to
a doublet at δ 4.71‒4.78 ppm. In the DEPT-135 spec-
trum, a positive signal appeared as δ 68.2‒69.1 ppm
C
due to the CHOH carbon.
Scheme 2.
The acid hydrolysis of 10a–10h followed two
different paths. Heating of compounds 10b, 10e, and
HO
COOH
N
H
2
O, HCl
EtOH, ∆
1
0g containing electron-donating substituents in the
·HCl
COOEt
R
para-position of the benzene ring in aqueous–alcoholic
HCl for 10–12 h resulted in not only hydrolysis of the
ester group but also cleavage of the exocyclic C–N
bond with formation of isoguvacine hydrochloride
N
H
1
0b, 10e, 10g
3
R = 4-Me (b), 4-MeO (e), 2-Br-4-MeO (g).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 4 2018

ALTERNATIVE SYNTHESIS OF ISOGUVACINE
595
Scheme 3.
HO
HO
N
H
2
O, HCl
N
·HCl
EtOH, ∆
COOEt
COOH
R
R
1
0a, 10c, 10d, 10f, 10h
11a, 11c, 11d, 11f, 11h
R = H (a), 4-Cl (c), 4-Br (d), 3-MeO (f), 4-O
2
N (h).
1
3
(
Scheme 4). These paths leading to the formation of
charges on the C and O atoms and that increase of
the electron-donating power of the R substituent is
substituted arylacetaldehyde which rapidly polymer-
izes under the given conditions were discussed in
3
accompanied by increase of the electron density on O
[
14, 15] where the hydrolysis of β-amino alcohols was
(Table 1). The computational data are consistent with
both enamine and glycol paths. In the two cases, intro-
duction of an electron-withdrawing substituent into the
benzene ring should strongly inhibits acid hydrolysis.
In fact, this is confirmed experimentally by published
data on the hydrolysis of β-amino alcohols [15], as
well as by the results of the present study.
studied. Electron-donating substituents in the benzene
ring favor the reaction to proceed along both paths,
whereas path a predominates under more severe acidic
conditions. The formation of glycol intermediate via
nucleophilic substitution at C (path b) is facilitated by
intramolecular general base assistance of the hydroxy
group in the corresponding transition state.
2
EXPERIMENTAL
The results of PM7 semiempirical quantum chem-
ical calculations [16] (MOPAC2016 [17]) with full
geometry optimization of the most energetically favor-
able conformations showed that variation of the R
substituent causes the strongest change of effective
1
13
The H and C NMR spectra were recorded on
a Bruker Avance II 400 spectrometer (400 MHz for
1
13
H and 100 MHz for C) using tetramethylsilane as
internal standard. The purity of the isolated compounds
Scheme 4.
HO
HO
N
N
+
H , H O
H
2
COOEt
COOH
–EtOH
fast
COOH
R
R
1
0
11
COOH
COOH
+
CHO
H , H O
H O
2
2
N
H
N
N
–
H O
–H O
–H+
2
2
H
H
H
–
H N
COOH
2
R
a
b
H
O
R
R
R
≠
H
Oδ–
δ+
OH
OH
H
H
HO
H5 δ–O3
C2
OH
H
H6
+
δ+
C
H O
H , H O
2
2
1
N4
–H+
–
H O
2
R
H
– H
2
N
COOH
R
R
R
COOH
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 4 2018

5
96
ABRAMYANTS et al.
Table 1. Effective charges on some atoms of compounds 10a–10h calculated for fully optimized geometry by the PM7
semiempirical approximation
H5
O3
C1
R
H
H
C2 N4
H H6
COOEt
Effective charges, a.u.
0
R
σ
1
2
3
4
5
6
C
C
O
N
H
H
4
4
4
-MeO
‒0.15
‒0.10
‒
+0.172
+0.157
+0.172
+0.148
+0.144
+0.151
+0.152
+0.137
‒0.227
‒0.224
‒0.222
‒0.224
‒0.221
‒0.223
‒0.222
‒0.222
‒0.626
‒0.620
‒0.617
‒0.616
‒0.615
‒0.614
‒0.614
‒0.608
‒0.085
‒0.084
‒0.085
‒0.083
‒0.083
‒0.085
‒0.085
‒0.086
+0.374
+0.373
+0.371
+0.373
+0.374
+0.373
+0.373
+0.373
+0.320
+0.319
+0.318
+0.319
+0.319
+0.319
+0.319
+0.319
-Me
-MeO-2-Br
H
0.00
0.08
0.30
0.28
0.81
3
4
4
4
-MeO
-Br
-Cl
-NO
2
was checked by TLC on Silufol UV-254 plates using
methanol–chloroform (1:10) as eluent; spots were
visualized by treatment with iodine vapor or under
ultraviolet light.
CH ), 4.46 q (2H, CH CH , J = 6.7 Hz), 6.61 s (2H,
3 2 3
CH CO), 7.48 d (2H, 3′-H, 5′-H, J = 7.0 Hz), 7.97 d
2
(2H, 2′-H, 6′-H, J = 7.2 Hz), 8.64 d (2H, 3-H, 5-H, J =
1
3
4.6 Hz), 9.23 d (2H, 2-H, 6-H, J = 4.8 Hz). C NMR
spectrum (DMSO-d ), δ , ppm: 14.4 (CH CH ), 21.8
Quaternary salts 9a–9h (general procedure). A so-
lution of 11 mmol of substituted phenacyl bromide 8a–
6
C
2
3
(
CH ), 63.4 (CH CH ), 67.0 (CH CO), 127.4, 128.9,
3 2 3 2
1
30.3, 131.4, 145.1, 145.9, 148.3, 162.5 (OCO), 190.2
8
1
h in 10 mL of acetone was added to a solution of
0 mmol of ethyl pyridine-4-carboxylate (7) in 12 mL
(
CH CO). Found, %: C 56.00; H 5.01; N 3.78.
2
C H BrNO . Calculated, %: C 56.06; H 4.98; N 3.85.
of acetone. The mixture was kept for 24 h at room
temperature, and the precipitate was filtered off,
washed with acetone, and recrystallized from ethanol.
17 18
3
1
-[2-(4-Chlorophenyl)-2-oxoethyl]-4-(ethoxycar-
bonyl)pyridinium bromide (9c). Yield 65%, mp 183‒
1
4
-(Ethoxycarbonyl)-1-(2-oxo-2-phenylethyl)-
185°C. H NMR spectrum (DMSO-d
(3H, CH CH , J = 6.9 Hz), 4.46 q (2H, CH
6.9 Hz), 6.66 s (2H, CH CO), 7.75 d (2H, 3′-H, 5′-H,
6
), δ, ppm: 1.39 t
pyridinium bromide (9a). Yield 69%, mp 189‒190°C.
2
3
2
CH , J =
3
1
H NMR spectrum (DMSO-d ), δ, ppm: 1.38 t (3H,
2
6
CH CH , J = 7.1 Hz), 4.46 q (2H, CH CH , J =
J = 8.1 Hz), 8.08 d (2H, 2′-H, 6′-H, J = 8.2 Hz), 8.65 d
(2H, 3-H, 5-H, J = 5.7 Hz), 9.24 d (2H, 2-H, 6-H,
2
3
2
3
7
.0 Hz), 6.67 s (2H, CH CO), 7.66 t (2H, 3′-H, 5′-H,
2
1
3
J = 7.6 Hz), 7.79 t (1H, 4′-H, J = 7.3 Hz), 8.07 d (2H,
J = 5.9 Hz). C NMR spectrum (DMSO-d
ppm: 14.4 (CH CH ), 63.5 (CH CH ), 67.1 (CH
127.4, 129.8, 130.7, 132.7, 140.0, 145.2, 148.3, 162.5
(OCO), 190.0 (CH CO). Found, %: C 49.87; H 4.01;
N 3.72. C16 15BrClNO . Calculated, %: C 49.96;
H 3.93; N 3.84.
6
), δ
CO),
2
C
,
2
6
′-H, 6′-H, J = 7.6 Hz), 8.65 d (2H, 3-H, 5-H, J =
.1 Hz), 9.25 d (2H, 2-H, 6-H, J = 6.2 Hz). C NMR
2
3
2
3
1
3
spectrum (DMSO-d ), δ , ppm: 14.4 (CH CH ), 63.5
2
6
C
2
3
(
CH CH ), 67.2 (CH CO), 127.4, 128.8, 129.6, 133.9,
H
3
2
3
2
1
35.2, 145.1, 148.3, 162.3 (OCO), 190.8 (CH CO).
2
Found, %: C 54.72; H 4.63; N 3.97. C H BrNO .
1
6
16
3
1-[2-(4-Bromophenyl)-2-oxoethyl]-4-(ethoxycar-
Calculated, %: C 54.87; H 4.61; N 4.00.
-(Ethoxycarbonyl)-1-[2-(4-methylphenyl)-
-oxoethyl]pyridinium bromide (9b). Yield 75%,
bonyl)pyridinium bromide (9d). Yield 88%, mp 200‒
1
4
203°C. H NMR spectrum (DMSO-d
6
), δ, ppm: 1.38 t
2
(3H, CH CH , J = 7.0 Hz), 4.46 q (2H, CH CH , J =
2 3 2 3
1
mp 196‒198°C. H NMR spectrum (DMSO-d ), δ,
6.9 Hz), 6.61 s (2H, CH CO), 7.89 d (2H, 3′-H, 5′-H,
6
2
ppm: 1.40 t (3H, CH CH , J = 6.3 Hz), 2.44 s (3H,
J = 8.1 Hz), 7.99 d (2H, 2′-H, 6′-H, J = 8.1 Hz), 8.65 d
2
3
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 4 2018

ALTERNATIVE SYNTHESIS OF ISOGUVACINE
597
1
(
2H, 3-H, 5-H, J = 5.8 Hz), 9.21 d (2H, 2-H, 6-H,
190°C. H NMR spectrum (DMSO-d ), δ, ppm: 1.39 t
6
1
3
J = 5.7 Hz). C NMR spectrum (DMSO-d ), δ ,
(3H, CH CH , J = 7.1 Hz), 4.47 q (2H, CH CH , J =
6
C
2
3
2
3
ppm: 14.4 (CH CH ), 63.4 (CH CH ), 67.1 (CH CO),
7.0 Hz), 6.71 s (2H, CH CO), 8.30 d (2H, 2′-H, 6′-H,
2
3
2
3
2
2
1
27.4, 129.3, 130.7, 132.7, 133.0, 145.2, 148.3, 162.5
J = 8.5 Hz), 8.47 d (2H, 3′-H, 5′-H, J = 8.5 Hz), 8.68 d
(2H, 3-H, 5-H, J = 6.1 Hz), 9.24 d (2H, 2-H, 6-H,
(
OCO), 190.2 (CH CO). Found, %: C 44.70; H 3.61;
2
1
3
N 3.22. C H Br NO . Calculated, %: C 44.78;
J = 6.2 Hz). C NMR spectrum (DMSO-d ), δ ,
1
6
15
2
3
6
C
H 3.52; N 3.26.
-(Ethoxycarbonyl)-1-[2-(4-methoxyphenyl)-
-oxoethyl]pyridinium bromide (9e). Yield 80%,
ppm: 14.4 (CH
2
CH
3
), 63.5 (CH
2
CH
3
), 67.4 (CH
2
CO),
1
24.6, 127.5, 130.3, 138.7, 144.2, 145.3, 148.3, 162.5
4
(
OCO), 190.2 (CH CO). Found, %: C 48.52; H 3.87;
2
2
1
N 7.04. C H BrN O . Calculated, %: C 48.63;
16 15 2 5
mp 186‒188°C. H NMR spectrum (DMSO-d ), δ,
6
H 3.83; N 7.09.
ppm: 1.39 t (3H, CH CH , J = 7.0 Hz), 2.44 s (3H,
2
3
OCH ), 4.46 q (2H, CH CH , J = 6.9 Hz), 6.62 s (2H,
Reduction of quaternary salts 9a–9h (general
procedure). Sodium tetrahydridoborate, 30 mmol, was
added in portions over a period of 2 h to a solution of
10 mmol of quaternary salt 9a–9h in 70 mL of aqueous
methanol (1:1) with stirring at room temperature. The
reduction product was filtered off and recrystallized
from aqueous ethanol.
3
2
3
CH CO), 7.47 d (2H, 3′-H, 5′-H, J = 7.8 Hz), 7.97 d
2
(
6
2H, 2′-H, 6′-H, J = 7.8 Hz), 8.65 d (2H, 3-H, 5-H, J =
.0 Hz), 9.23 d (2H, 2-H, 6-H, J = 6.1 Hz). C NMR
1
3
spectrum (DMSO-d ), δ , ppm: 14.4 (CH CH ), 56.3
6
C
2
3
(
OCH ), 63.5 (CH CH ), 67.0 (CH CO), 114.9, 127.4,
3 2 3 2
1
28.9, 130.1, 131.4, 146.0, 148.3, 162.5 (OCO), 190.3
(
CH CO). Found, %: C 53.64; H 4.79; N 3.51.
2
Ethyl 1-(2-hydroxy-2-phenylethyl)-1,2,3,6-tetra-
C H BrNO . Calculated, %: C 53.70; H 4.77; N 3.68.
1
7
18
4
hydropyridine-4-carboxylate (10a). Yield 70%,
1
4
-(Ethoxycarbonyl)-1-[2-(3-methoxyphenyl)-
mp 77‒80°C. H NMR spectrum (CDCl
3
), δ, ppm:
2
-oxoethyl]pyridinium bromide (9f). Yield 95%,
1.30 t (3H, CH
2.61 br.s (2H, 2-H), 2.63 br.s (2H, 6-H), 2.91 q (1H,
2
CH
3
, J = 7.0 Hz), 2.48 br.s (2H, 3-H),
1
mp 214‒216°C. H NMR spectrum (DMSO-d ), δ,
6
ppm: 1.39 t (3H, CH CH , J = 6.5 Hz), 3.86 s (3H,
CHOH, J = 16.0 Hz), 3.22 d and 3.42 d (1H each,
2
3
OCH ), 4.46 q (2H, CH CH , J = 6.7 Hz), 6.66 s (2H,
1-CH
, J = 18.4 Hz), 4.23 q (2H, CH CH , J = 7.1 Hz),
2 2 3
3
2
3
CH CO), 7.38 d (1H, 4′-H, J = 6.5 Hz), 7.55‒7.61 m
4.80 d (1H, OH, J = 8.2 Hz), 6.92 br.s (1H, 5-H), 7.30–
2
1
3
(
(
4
1
2H, 2′-H, 5′-H), 7.67 d (1H, 6′-H, J = 6.4 Hz), 8.66 d
2H, 3-H, 5-H, J = 5.0 Hz), 9.23 d (2H, 2-H, 6-H, J =
7.39 m (5H, Ph). C NMR spectrum (CDCl ), δ ,
3 C
3
2
6
ppm: 14.3 (CH
60.5 (CH CH ), 65.6 (1-CH
127.6, 128.4, 128.8, 136.3 (C ), 141.9, 167.0 (C=O).
CH
), 25.1 (C ), 49.5 (C ), 52.5 (C ),
2
3
13
.9 Hz). C NMR spectrum (DMSO-d ), δ , ppm:
2
3
2
), 69.1 (CHOH), 125.8,
6
C
5
4.4 (CH CH ), 56.1 (OCH ), 63.5 (CH CH ), 67.2
2
3
3
2
3
(
1
CH CO), 113.4, 121.0, 121.2, 127.4, 130.9, 135.2,
Found, %: C 69.71; H 7.72; N 5.03. C16
culated, %: C 69.79; H 7.69; N 5.09.
H21NO . Cal-
3
2
45.2, 148.2, 160.0, 162.5 (OCO), 190.7 (CH CO).
2
Found, %: C 53.61; H 4.82; N 3.53. C H BrNO .
Calculated, %: C 53.70; H 4.77; N 3.68.
1
7
18
4
Ethyl 1-[2-hydroxy-2-(4-methylphenyl)ethyl]-
1
,2,3,6-tetrahydropyridine-4-carboxylate (10b).
1
1
-[2-(2-Bromo-4-methoxyphenyl)-2-oxoethyl]-
Yield 72%, mp 59‒60°C. H NMR spectrum (CDCl
δ, ppm: 1.30 t (3H, CH
3
),
, J = 6.9 Hz), 2.36 s (3H,
), 2.47 br.s (2H, 3-H), 2.61 br.s (4H, 2-H, 6-H),
2.89 q (1H, CHOH, J = 11.2 Hz), 3.20 d (1H, J =
18.4 Hz) and 3.43 d (1H, J = 18.3 Hz) (1-CH ), 4.23 q
(2H, CH CH , J = 6.8 Hz), 4.77 d (1H, CHOH, J =
4
6
-(ethoxycarbonyl)pyridinium bromide (9g). Yield
CH
2 3
1
0%, mp 217‒220°C. H NMR spectrum (DMSO-d ),
CH
3
6
δ, ppm: 1.39 t (3H, CH CH , J = 6.9 Hz), 4.00 s (3H,
2
3
OCH ), 4.46 q (2H, CH CH , J = 6.9 Hz), 6.55 s (2H,
2
3
2
3
CH CO), 7.38 d (1H, 5′-H, J = 8.5 Hz), 8.09 d (1H,
2
3
2
6
5
′-H, J = 8.6 Hz), 8.25 s (1H, 3′-H), 8.64 d (2H, 3-H,
-H, J = 5.9 Hz), 9.17 d (2H, 2-H, 6-H, J = 6.2 Hz).
C NMR spectrum (DMSO-d ), δ , ppm: 14.4
5.6 Hz), 6.91 br.s (1H, 5-H), 7.17 d (2H, 3′-H, 5′-H,
J = 6.5 Hz), 7.28 d (2H, 2′-H, 6′-H, J = 7.2 Hz).
1
3
13
C NMR spectrum (CDCl
), δ
), 25.2 (C ), 51.7 (C ), 52.4 (C ), 60.3
), 65.6 (1-CH ), 68.9 (CHOH), 125.8, 129.0,
135.9, 136.3 (C ), 137.2, 138.9, 166.5 (C=O). Found,
, ppm: 14.2 (CH CH ),
6
C
3
C 2 3
3
2
6
(
(
CH CH ), 57.5 (OCH ), 63.5 (CH CH ), 66.8
CH CO), 111.6, 113.2, 127.5, 127.8, 130.7, 133.5,
21.0 (CH
(CH CH
3
2
3
3
2
3
2
2
3
2
5
1
45.2, 148.2, 160.7, 162.5 (OCO), 188.5 (CH CO).
2
Found, %: C 44.39; H 3.75; N 3.01. C H Br NO .
%: C 70.52; H 8.03; N 4.79. C17
%: C 70.56; H 8.01; N 4.84.
H23NO . Calculated,
3
1
7
17
2
4
Calculated, %: C 44.47; H 3.73; N 3.05.
-(Ethoxycarbonyl)-1-[2-(4-nitrophenyl)-2-oxo-
ethyl]pyridinium bromide (9h). Yield 72%, mp 188‒
4
Ethyl 1-[2-(4-chlorophenyl)-2-hydroxyethyl]-
1,2,3,6-tetrahydropyridine-4-carboxylate (10c).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 4 2018

5
98
ABRAMYANTS et al.
1
Yield 87%, mp 63‒65°C. H NMR spectrum (CDCl ),
(2H, 3-H), 2.59 br.s (2H, 2-H), 2.64 br.s (2H, 6-H),
3
δ, ppm: 1.31 t (3H, CH CH , J = 7.1 Hz), 2.47 br.s
2.88 q (1H, CHOH, J = 16.0 Hz), 3.20 d (1H, J =
2
3
(
2
(
2H, 3-H), 2.60 br.s (2H, 2-H), 2.63 br.s (2H, 6-H),
.89 q (1H, CHOH, J = 11.2 Hz), 3.19 d and 3.41 d
1H each, 1-CH , J = 18.4 Hz), 4.22 q (2H, CH CH ,
18.4 Hz) and 3.40 d (1H, J = 18.8 Hz) (1-CH ), 3.82 s
2
(3H, OCH ), 4.22 q (2H, CH CH , J = 6.8 Hz), 4.77 d
3
2
3
(1H, CHOH, J = 9.2 Hz), 6.82 d (1H, 4′-H, J =
8.0 Hz), 6.90 br.s (1H, 5-H), 6.95 t (1H, 5′-H, J =
2
2
3
J = 7.1 Hz), 4.76 d (1H, CHOH, J = 7.6 Hz), 6.90 br.s
(
1H, 5-H), 7.32 s (4H, 2′-H, 3′-H, 5′-H, 6′-H).
7.5 Hz), 6.97 s (1H, 2′-H), 7.27 d (1H, 6′-H, J =
1
3
13
C NMR spectrum (CDCl ), δ , ppm: 14.3 (CH CH ),
7.1 Hz). C NMR spectrum (CDCl
3
), δ
, ppm: 14.3
C
3
C
2
3
3
2
6
3
2
6
2
5.1 (C ), 49.5 (C ), 52.5 (C ), 60.5 (CH CH ), 65.5
(CH CH ), 25.1 (C ), 49.5 (C ), 52.5 (C ), 55.1 (OCH ),
2
3
2
3
3
(
1
NCH ), 68.4 (CHOH), 127.2, 128.5, 133.2, 135.8,
36.1 (C ), 140.5, 166.4 (C=O). Found, %: C 61.97;
60.6 (CH CH ), 65.5 (1-CH ), 68.9 (CHOH), 111.2,
2 3 2
2
5
5
112.9, 118.2, 129.3, 130.9, 135.9 (C ), 137.8, 145.3,
161.3 (C=O). Found, %: C 66.80; H 7.63; N 4.54.
C H NO . Calculated, %: C 66.86; H 7.59; N 4.59.
H 6.55; N 4.48. C H ClNO . Calculated, %: C 62.03;
H 6.51; N 4.52.
16
20
3
1
7
23
4
Ethyl 1-[2-(2-bromo-4-methoxyphenyl)-2-hy-
Ethyl 1-[2-(4-bromophenyl)-2-hydroxyethyl]-
droxyethyl]-1,2,3,6-tetrahydropyridine-4-carbox-
1
,2,3,6-tetrahydropyridine-4-carboxylate (10d).
1
1
ylate (10g). Yield 70%, mp 108‒110°C. H NMR
Yield 97%, mp 68‒70°C. H NMR spectrum (CDCl ),
3
spectrum (CDCl ), δ, ppm: 1.31 t (3H, CH CH , J =
δ, ppm: 1.31 t (3H, CH CH , J = 7.1 Hz), 2.47 br.s
3
2
3
2
3
6
2
3
(
6
.9 Hz), 2.46 br.s (2H, 3-H), 2.58 br.s (2H, 2-H),
.62 br.s (2H, 6-H), 2.88 q (1H, CHOH, J = 11.6 Hz),
.20 d (1H, J = 18.4 Hz) and 3.39 d (1H, J = 18.8 Hz)
(
2
1
(
1
2H, 3-H), 2.61 br.s (2H, 2-H), 2.64 br.s (2H, 6-H),
.88 q (1H, CHOH, J = 11.4 Hz), 3.20 d (1H, J =
8.0 Hz) and 3.40 d (1H, J = 18.4 Hz) (1-CH ), 4.21 q
2
1-CH ), 3.90 s (3H, OCH ), 4.22 q (2H, CH CH , J =
2 3 2 3
2H, CH CH , J = 7.1 Hz), 4.75 d (1H, CHOH, J =
2 3
.9 Hz), 4.71 d (1H, CHOH, J = 9.6 Hz), 6.87 br.s
0.0 Hz), 6.90 br.s (1H, 5-H), 7.27 d (2H, 2′-H, 6′-H,
J = 8.0 Hz), 7.48 d (2H, 3′-H, 5′-H, J = 8.0 Hz).
(
1H, 5-H), 6.88 d (1H, 5′-H, J = 8.8 Hz), 7.28 d (1H,
1
3
1
3
6′-H, J = 8.0 Hz), 7.58 s (1H, 3′-H). C NMR spec-
C NMR spectrum (CDCl ), δ , ppm: 15.8 (CH CH ),
3
C
2
3
3
3
2
6
trum (CDCl ), δ , ppm: 14.2 (CH CH ), 25.1 (C ),
3
C
2
3
2
(
1
5.1 (C ), 49.5 (C ), 52.5 (C ), 60.6 (CH CH ), 66.9
2 3
2
6
4
9.5 (C ), 52.5 (C ), 56.2 (OCH ), 60.5 (CH CH ),
3 2 3
1-CH ), 68.5 (CHOH), 122.8, 127.5, 130.6, 131.5,
2
5
65.5 (1-CH ), 68.2 (CHOH), 111.7, 111.8, 126.0,
2
35.7 (C ), 142.5, 168.0 (C=O). Found, %: C 54.20;
5
1
30.8, 130.9, 135.6, 135.8 (C ), 155.3, 166.5 (C=O).
H 5.72; N 3.93. C H BrNO . Calculated, %: C 54.25;
1
6
20
3
Found, %: C 53.08; H 5.81; N 3.63. C H BrNO .
1
7
22
4
H 5.69; N 3.95.
Calculated, %: C 53.14; H 5.77; N 3.65.
Ethyl 1-[2-hydroxy-2-(4-methoxyphenyl)ethyl]-
Ethyl 1-[2-hydroxy-2-(4-nitrophenyl)ethyl]-
1
,2,3,6-tetrahydropyridine-4-carboxylate (10e).
1
,2,3,6-tetrahydropyridine-4-carboxylate (10h).
1
Yield 73%, mp 83‒85°C. H NMR spectrum (CDCl ),
1
3
Yield 80%, mp 100‒102°C. H NMR spectrum
δ, ppm: 1.31 t (3H, CH CH , J = 7.1 Hz), 2.46 br.s
2
3
(
CDCl ), δ, ppm: 1.31 t (3H, CH CH , J = 7.1 Hz),
3 2 3
(
2
(
4
2H, 3-H), 2.58 br.s (2H, 2-H), 2.63 br.s (2H, 6-H),
.89 q (1H, CHOH, J = 11.6 Hz), 3.20 d and 3.40 d
1H each, 1-CH , J = 18.4 Hz), 3.90 s (3H, OCH ),
2
6
3
.48 br.s (2H, 3-H), 2.55 br.s (2H, 2-H), 2.69 br.s (2H,
-H), 2.71 q (1H, CHOH, J = 12.4 Hz), 3.22 d and
2
3
.42 d (1H each, 1-CH , J = 18.0 Hz), 4.23 q (2H,
2
.23 q (2H, CH CH , J = 6.9 Hz), 4.76 d (1H, CHOH,
2 3
CH CH , J = 7.1 Hz), 4.88 d (1H, CHOH, J =
2
3
J = 10.6 Hz), 6.89 d (2H, 3′-H, 5′-H, J = 8.4 Hz),
1
0.4 Hz), 6.90 br.s (1H, 5-H), 7.57 d (2H, 2′-H, 6′-H,
J = 8.4 Hz), 8.22 d (2H, 3′-H, 5′-H, J = 8.5 Hz).
6
8
(
(
1
(
.91 br.s (1H, 5-H), 7.30 d (2H, 2′-H, 6′-H, J =
1
3
1
3
.4 Hz). C NMR spectrum (CDCl ), δ , ppm: 14.3
3
C
C NMR spectrum (CDCl ), δ , ppm: 14.3 (CH CH ),
3 C 2 3
3
2
6
3
2
6
CH CH ), 25.2 (C ), 49.5 (C ), 52.4 (C ), 55.2
2 3
25.1 (C ), 49.4 (C ), 52.5 (C ), 60.6 (CH CH ),
2 3
OCH ), 60.5 (CH CH ), 65.7 (1-CH ), 68.8 (CHOH),
3
2
3
2
65.0 (1-CH ), 68.3 (CHOH), 123.7, 126.5, 129.2,
2
5
5
13.9, 127.1, 129.1, 134.0, 135.9 (C ), 159.1, 166.5
1
35.5 (C ), 147.4, 149.6, 166.4 (C=O). Found, %:
C=O. Found, %: C 66.83; H 7.64; N 4.55. C H NO .
17
23
4
C 59.92; H 6.33; N 8.70. C H N O . Calculated, %:
1
6
20
2
5
Calculated, %: C 66.86; H 7.59; N 4.59.
C 59.99; H 6.29; N 8.74.
Ethyl 1-[2-hydroxy-2-(3-methoxyphenyl)ethyl]-
Isoguvacine hydrochloride (3) and 1-(2-aryl-2-
hydroxyethyl)-1,2,3,6-tetrahydropyridine-4-carbox-
ylic acids 11a, 11c, 11d, 11f, and 11h (general proce-
dure). Compound 10a–10h, 1 mmol, was dissolved in
1
,2,3,6-tetrahydropyridine-4-carboxylate (10f).
1
Yield 95%, mp 42‒45°C. H NMR spectrum (CDCl ),
3
δ, ppm: 1.31 t (3H, CH CH , J = 7.0 Hz), 2.46 br.s
2
3
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 4 2018

ALTERNATIVE SYNTHESIS OF ISOGUVACINE
mL of ethanol, 5 mL of concentrated aqueous HCl
599
3
2
6
5
(DMSO-d ), δ , ppm: 21.7 (C ), 39.5 (C ), 40.8 (C ),
6
C
5
was added, and the mixture was refluxed for 10 h. The
solvent was distilled off under reduced pressure, and
the residue was thoroughly washed with acetone and
recrystallized from ethanol.
61.3 (1-CH ), 66.9 (CHOH), 122.8, 128.7, 130.9 (C ),
131.7, 132.4, 143.2, 168.2 (C=O). Found, %:
C 46.30; H 4.75; N 3.84. C H BrClNO . Calcu-
2
1
4
17
3
lated, %: C 46.37; H 4.72; N 3.86.
1
,2,3,6-Tetrahydropyridine-4-carboxylic acid
1-[2-Hydroxy-2-(3-methoxyphenyl)ethyl]-1,2,3,6-
tetrahydropyridine-4-carboxylic acid hydrochloride
(11f). Yield 53%, mp 205‒210°C (decomp.). H NMR
(
isoguvacine) hydrochloride (3). Yield 80‒87%,
mp 278‒280°C (decomp.). H NMR spectrum
DMSO-d ), δ, ppm: 2.43 br.s (2H, 3-H), 3.17 br.s (2H,
-H), 3.71 br.s (2H, 6-H), 6.76 br.s (1H, 5-H), 9.53 br.s
2H, NH ), 12.77 br.s (1H, COOH). C NMR spec-
1
1
(
2
(
spectrum (DMSO-d
3.28 br.s (2H, 2-H), 3.55 br.s (2H, 6-H), 3.74 s (3H,
OCH ), 4.09 br.s (2H, NCH ), 5.22 br.s (1H, CHOH),
6
), δ, ppm: 2.53 br.s (2H, 3-H),
6
+
2
13
3
2
3
2
trum (DMSO-d ), δ , ppm: 21.2 (C ), 40.0 (C ), 41.4
6.32 br.s (1H, CHOH), 6.77 br.s (1H, 5-H), 6.86‒
7.01 m (3H, 4′-H, 5′-H, 6′-H), 7.28 s (1H, 2′-H).
6
C
6
5
(
C ), 129.1, 131.6 (C ), 166.8 (C=O). Found, %:
1
3
3
C 44.01; H 6.22; N 8.52. C H ClNO . Calculated, %:
C 44.05; H 6.16; N 8.56.
C NMR spectrum (DMSO-d
6
), δ
40.0 (C ), 41.4 (C ), 57.1 (OCH ), 62.7 (1-CH
CHOH), 112.0, 113.6, 115.2, 118.6, 120.1, 130.0,
C
, ppm: 23.3 (C ),
6
10
2
2
6
), 69.0
3
2
(
1
1
-(2-Hydroxy-2-phenylethyl)-1,2,3,6-tetrahydro-
5
30.5 (C ), 145.5, 168.2 (C=O). Found, %: C 57.40;
pyridine-4-carboxylic acid hydrochloride (11a).
Yield 78%, mp 215‒217°C (decomp.). H NMR spec-
trum (DMSO-d ), δ, ppm: 2.52 br.s (2H, 3-H), 3.28 br.s
2H, 2-H), 3.70 br.s (2H, 6-H), 4.06 br.s (2H, 1-CH2),
.22 d (1H, CHOH, J = 6.1 Hz), 6.27 br.s (1H,
CHOH), 6.77 br.s (1H, 5-H), 7.28‒7.41 m (5H, Ph).
C NMR spectrum (DMSO-d ), δ , ppm: 21.3 (C ),
9.8 (C ), 41.2 (C ), 61.3 (1-CH ), 66.7 (CHOH),
1
H 6.45; N 4.44. C15
H 6.42; N 4.46.
H20ClNO . Calculated, %: C 57.42;
4
6
1
-[2-Hydroxy-2-(4-nitrophenyl)ethyl]-1,2,3,6-
(
5
tetrahydropyridine-4-carboxylic acid hydrochloride
1
(
11h). Yield 81%, mp 233‒235°C (decomp.). H NMR
1
3
3
spectrum (DMSO-d ), δ, ppm: 2.59 br.s (2H, 3-H),
6
6
C
2
6
3
1
.31 br.s (2H, 2-H), 3.40 br.s (2H, 6-H), 4.08 br.s (2H,
-CH ), 5.40 d (1H, CHOH, J = 5.2 Hz), 6.62 br.s (1H,
3
1
2
5
23.4, 127.2, 130.1, 131.6 (C ), 142.6, 168.3 (C=O).
Found, %: C 59.20; H 6.41; N 4.90. C H ClNO .
2
CHOH), 6.79 br.s (1H, 5-H), 7.73 d (2H, 2′-H, 6′-H,
J = 7.6 Hz), 8.26 d (2H, 3′-H, 5′-H, J = 7.6 Hz),
1
4
18
3
Calculated, %: C 59.26; H 6.39; N 4.94.
-[2-(4-Chlorophenyl)-2-hydroxyethyl]-1,2,3,6-
tetrahydropyridine-4-carboxylic acid hydrochloride
1
3
1
(
6
1
0.77 br.s (1H, COOH). C NMR spectrum
1
3
2
6
DMSO-d ), δ , ppm: 21.7 (C ), 40.0 (C ), 41.2 (C ),
6 C
5
0.9 (1-CH ), 66.9 (CHOH), 125.5, 129.4, 130.9 (C ),
32.5, 149.0, 151.4, 168.3 (C=O). Found, %:
1
2
(
11c). Yield 63%, mp 223‒225°C (decomp.). H NMR
spectrum (DMSO-d ), δ, ppm: 2.54 br.s (2H, 3-H),
.28 br.s (2H, 2-H), 3.72 br.s (2H, 6-H), 4.05 br.s (2H,
-CH ), 5.21 br.s (1H, CHOH), 6.37 br.s (1H, CHOH),
.78 br.s (1H, 5-H), 7.46 s (4H, 2′-H, 3′-H, 5′-H, 6′-H),
.37 br.s (1H, NH), 10.59 br.s (1H, COOH). C NMR
spectrum (DMSO-d ), δ , ppm: 21.2 (C ), 39.9 (C ),
1.4 (C ), 61.3 (1-CH ), 66.8 (CHOH), 128.4, 128.8,
6
C 51.11; H 5.24; N 8.49. C H ClN O . Calculated,
1
4
17
2
5
3
1
6
9
%: C 51.15; H 5.21; N 8.52.
2
REFERENCES
1
3
3
2
6
C
1. The
Alkaloids:
Chemistry
and
Physiology,
6
4
1
Manske, R.H.F. and Holmes, H.L., Eds., New York:
Academic, 1950, vol. 1, p. 171.
2
5
31.6 (C ), 133.1, 134.3, 142.7, 168.4 (C=O). Found,
%
: C 52.78; H 5.43; N 4.36. C H Cl NO . Calculat-
2. Progress in Medicinal Chemistry, Ellis, G.P. and
14
17
2
3
West, G.B., Amsterdam: Elsevier, 1985, vol. 22, p. 67.
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3
. Kharkevich, D.A., Farmakologiya: uchebnik (Pharma-
1
-[2-(4-Bromophenyl)-2-hydroxyethyl]-1,2,3,6-
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tetrahydropyridine-4-carboxylic acid hydrochloride
1
0th ed., p. 185.
1
(
11d). Yield 91%, mp 235‒238°C (decomp.). H NMR
4
5
. Advances in Drug Research, Testa, B., Ed., London:
Academic, 1988, vol. 17, p. 382.
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p. 2131.
spectrum (DMSO-d ), δ, ppm: 2.57 br.s (2H, 3-H),
6
3
1
.29 br.s (2H, 2-H), 3.40 br.s (2H, 6-H), 4.06 br.s (2H,
-CH ), 5.22 d (1H, CHOH, J = 8.0 Hz), 6.38 br.s (1H,
2
CHOH), 6.77 br.s (1H, 5-H), 7.39 d (2H, 2′-H, 6′-H,
J = 8.0 Hz), 7.58 d (2H, 3′-H, 5′-H, J = 8.0 Hz),
6
. Chang, M.-Y., Chen, Sh.-T., and Chang, N.-Ch., Hetero-
cycles, 2002, vol. 57, p. 2321.
1
3
1
0.72 br.s (1H, COOH). C NMR spectrum
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 4 2018

6
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ABRAMYANTS et al.
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8
9
. Chang, M.-Y., Chen, Ch.-Y., Tasi, M.-R., Tseng, T.-W.,
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011, vol. 13, p. 2495.
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p. 1857.
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0. Kehler, J., Ebert, B., Dahl, O., and Krogsgaard-
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 54 No. 4 2018