Development of a new approach to generation of dihydropyridine ring: First representative of 2-alkylsulfanyl-5,6-dihydropyridin-3(4H)-ones

Full text of DOI:10.1134/S1070428007030311

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 3, pp. 478–481. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © N.A. Nedolya, S.V. Tolmachev, L. Brandsma, 2007, published in Zhurnal Organicheskoi Khimii, 2007, Vol. 43, No. 3, pp. 477–480.
SHORT
COMMUNICATIONS
Development of a New Approach to Generation
of Dihydropyridine Ring: First Representative of 2-Alkylsulfanyl-
5,6-dihydropyridin-3(4H)-ones
N. A. Nedolyaa, S. V. Tolmacheva, and L. Brandsmab
a Favorskii Irkutsk Institute of Chemistry, Siberian Division, Russian Academy of Sciences,
ul. Favorskogo 1, Irkutsk, 664033 Russia
e-mail: nina@irioch.irk.ru
b Utrecht University, Utrecht, The Netherlands
Received September 28, 2006
DOI: 10.1134/S1070428007030311
Pyridines and their hydrogenated derivatives are
typical structural units of many natural compounds
which play an exceptionally important role in the vital
activity [1]. We recently showed for the first time [2]
that reactions of metalated 1,2- and 1,3-dienes and
alkynes with aliphatic isothiocyanates provide a direct
synthetic route to hitherto unknown or difficultly
accessible 6-alkylsulfanyl-substituted 1,2- and 2,3-di-
hydropyridines.
solution (including nonpolar solvents); according to
the IR and NMR data, the fraction of the oxo tautomer,
1-methyl-2-methylsulfanyl-2,3-dihydro-1H-pyrrol-3-
one (VI), did not exceed 5–10% [4] (Scheme 1). How-
ever, cyclization of the alkylated adduct of lithioallene
II with methoxymethyl isothiocyanate (III, R =
MeOCH2), regardless of the conditions, leads exclu-
sively to 5-(1-ethoxyethoxy)-2-methoxy-6-methylsul-
fanyl-2,3-dihydropyridine (VIII) (yield 84%) through
intermediate VII. Heating of compound VIII for ~1 h
at 120–130°C results in elimination of methanol with
formation of previously unknown 3-(1-ethoxyethoxy)-
2-methylsulfanylpyridine (IX) in quantitative yield.
Mild hydrolysis of pyridine IX afforded 84% of
2-methylsulfanylpyridin-3-ol (X) (Scheme 1) [5]
which can be regarded as a first synthetic analog of
natural aromatizing component of smoking fluids [6].
The use in such reactions of a protected allenyl
alcohol, 1-(1-ethoxyethoxy)allene (I) which is readily
available from commercial starting materials (prop-2-
yn-1-ol and ethoxyethene) in the presence of an acid
catalyst and subsequent isomerization of 3-(1-ethoxy-
ethoxy)prop-1-yne thus formed [3], ensured simple
syntheses of new families of 3-hydroxypyrroles [4]
and 3-hydroxypyridines [5]. It turned out that the size
of the heteroring being formed (five- or six-membered)
depends not only on the reaction conditions but also
on the structure of isothiocyanate, which considerably
extends the synthetic potential of the proposed ap-
proach. For example, S-alkylation followed by CuBr-
catalyzed (50–55°C, 0.5 h) cyclization of the adduct of
1-lithio-1-(1-ethoxyethoxy)allene (II) (prepared by de-
protonation of allene I with butyllithium in THF–
hexane) with methyl isothiocyanate (III, R = Me) gave
more than 75% of previously unknown 3-[1-(1-ethoxy-
ethoxy)]-1-methyl-2-methylsulfanyl)pyrrole (IV), and
mild alcoholysis of IV (MeOH, H+) afforded ~75% of
1-methyl-2-methylsulfanyl-1H-pyrrol-3-ol (V). Com-
pound V is the first representative of hydroxypyrroles;
it exists exclusively in the OH form both neat and in
We have continued studies in this line and devel-
oped a simple and nontrivial synthetic route to previ-
ously unknown and inaccessible 2-methylsulfanyl-5,6-
dihydropyridin-3(4H)-ones from carbo- and hetero-
cumulene precursors, 1-(1-ethoxyethoxy)-1-lithioal-
lene (II) and alkyl isothiocyanates.
1-Aza-1,3,4-triene III prepared by reaction of
lithioallene II with, e.g., ethyl isothiocyanate, under-
goes thermal transformation (in the absence of CuBr)
to give mainly intermediate 2-aza-1,3,5-triene XI, and
electrocyclization of the latter on heating for a short
time to ~120°C results in the formation of previously
unknown 5-(1-ethoxyethoxy)-2-methyl-6-methylsul-
fanyl)-2,3-dihydropyridine (XII) (Scheme 2). Isomeric
3-(1-ethoxyethoxy)-1-ethyl-2-methylsulfanyl-1H-pyr-
478

DEVELOPMENT OF A NEW APPROACH TO GENERATION
479
Scheme 1.
SMe
(1) RNCS, –100 to –60°C
(2) MeI
BuLi, THF–hexane
–100 to –60°C
CH2
CH2
EtO
O
R
EtO
O
·
EtO
O
·
N
Me
·
Me
Me
Li
CH2
I
II
III
OEt
O
OH
O
CuBr
H+, MeOH
Me
R = Me
–MeOCH(Me)OEt
SMe
N
SMe
SMe
Me
N
N
Me
Me
Me
IV
V
VI
Me
OEt
Me
OEt
OEt
[1,5]-H shift
Δ
Δ
O
O
O
H2C
–MeOH
R = MeOCH2
MeO
N
SMe
MeO
N
SMe
N
SMe
VII
VII
IX
OH
H+/H2O
–EtOH
N
SMe
–MeCHO
X
role (XIII) formed via concurrent intramolecular
nucleophilic 1,5-cyclization of 1-aza-1,3,4-triene III is
the minor product (according to the NMR data, the
ratio XII:XIII is ~6:1).
from allenes and isothiocyanates. Among compounds
of the dihydropyridine series, 3,6-dihydropyridin-
2(1H)-ones [7] and 5,6-dihydropyridin-2(1H)-ones [8]
were studied most extensively; increased interest in
these compounds that can be obtained in several ways
originates mainly from their wide application as key
intermediates and building blocks in fine organic
synthesis, including syntheses of biologically active
structures.
Separation of the products by treatment of their
mixture with dilute hydrochloric acid is accompanied
by removal of the acetal protection from dihydropyri-
dine XII, so that the synthesis of target 3-hydroxy-
dihydropyridines is strongly simplified. After neutral-
ization with aqueous potassium hydroxide of the acid
aqueous phase, 6-methyl-2-methylsulfanyl-5,6-dihy-
dropyridin-3(4H)-one (XIV) is extracted into an organ-
ic solvent. The corresponding enol tautomer, 6-methyl-
2-methylsulfanyl-5,6-dihydropyridin-3-ol (XV) was
not identified by spectral data (IR and NMR in CDCl3
and DMSO). Interestingly, pyrrole XIII isolated from
the organic phase, in contrast to dihydropyridine XII,
remains unchanged on treatment with dilute hydro-
chloric acid for a short time. Apart from less favorable
conditions for the protolysis, another reason may be
relatively higher hydrolytic stability of acetals of the
pyrrole series.
Thus we were the first to demonstrate that com-
mercially available prop-2-yn-1-ol, ethoxyethene, alkyl
isothiocyanates, and alkyl halides (or other alkylating
agents) constituted a new and promising source of new
families of previously unknown 2-alkylsulfanyl-5,6-di-
hydropyridin-3(4H)-ones which attract interest as
models for biological studies and reagents for the pre-
paration of biologically active compounds. Obviously,
the potential of the developed synthetic approach to
5,6-dihydropyridin-3(4H)-ones is not limited to the
example described above.
5-(1-Ethoxyethoxy)-2-methyl-6-methylsulfanyl-
2,3-dihydropyridine (XII). A solution of 59.2 mmol
of butyllithium in a mixture of 37 ml of hexane and
70 ml of THF was cooled to –95°C, and 7.15 g
It should be noted that there are no published data
on the synthesis of 5,6-dihydropyridin-3(4H)-ones
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 3 2007

NEDOLYA et al.
480
Scheme 2.
OEt
O
Me
SMe
EtO
Me
N
SMe
Et
O
R
Δ
XIII
N
Me
OEt
Me
OEt
·
CH2
O
O
OH
[1,5]-H shift
H+/H2O
Δ
H2C
III
–EtOH
–MeCHO
Me
N
SMe
Me
N
SMe
Me
N
SMe
XI
XII
XV
O
Me
N
SMe
XIV
chloric acid in 35 ml of cold water (~5°C), and the
organic and aqueous layers were quickly separated.
Pyrrole XIII was extracted from the aqueous layer
with diethyl ether (4×40 ml), the extracts were com-
bined with the organic layer and treated with a small
amount of concentrated aqueous potassium hydroxide
(to neutral reaction), and the organic phase was sepa-
rated, dried over potassium carbonate, and evaporated
(55.8 mmol) of allene I was added under nitrogen. The
mixture warmed up to –55°C. It was stirred for 15 min
at −95 to −55°C and cooled to –100°C, and 4.54 g
(52.2 mmol) of ethyl isothiocyanate was added under
stirring. The mixture warmed up to –65°C. It was
stirred for 10 min at that temperature, and 15.1 g
(106.3 mmol) of methyl iodide was added. The mix-
ture was allowed to warm up to room temperature and
treated with ~100 ml of cold water, the organic phase
was separated, the aqueous phase was extracted with
diethyl ether (2×50 ml) and pentane (2×50 ml), the
extracts were combined and dried over K2CO3, and the
solvent was evaporated under reduced pressure to iso-
late 13 g (100%) of a mixture of azatrienes III and XI,
dihydropyridine XII, and pyrrole XIII (according to
the NMR data). The product mixture was heated to
~120°C (to effect cyclization of the azatrienes) and
distilled under reduced pressure to obtain a mixture of
dihydropyridine XII and pyrrole XIII at a ratio of
~6:1 (98.8% of the main substances, according to the
GLC data); boiling point of the azeotrope 86–100°C
1
to isolate pyrrole XIII. H NMR spectrum, δ, ppm:
6.59 d (1H, 5-H), 5.91 d (1H, 4-H), 5.17 q (1H,
OCHO), 3.98 q (2H, NCH2Me), 3.91 m and 3.60 m
(2H, OCH2Me), 2.17 s (3H, SMe), 1.34 t (3H,
NCH2Me), 1.33 d (3H, CHMe), 1.22 t (3H, OCH2Me).
13C NMR spectrum (CDCl3), δC, ppm: 146.56 (C2),
119.21 (C5), 108.86 (C3), 101.86 (C4), 99.23 (OCHO),
62.18 (OCH2Me), 41.45 (NCH2Me), 20.31 (SMe),
20.25 (CHMe), 16.60 (NCH2Me), 14.95 (OCH2Me).
The acidic aqueous layer was treated in succession
with a solution of 1.7 g of potassium hydroxide in
25 ml of cold water (to neutralize HCl) and with
diethyl ether (5×40 ml), the combined extracts were
dried over potassium carbonate, and the solvent was
removed on a rotary evaporator to isolate 5,6-dihydro-
pyridin-3(4H)-one XIV. Compound XIV was addi-
tionally purified by flash chromatography on alumi-
num oxide using diethyl ether as eluent. Yield 2.34 g
(30%), nD20 = 1.5362. IR spectrum (film), ν, cm–1: 510,
530 sh, 540, 650, 825, 910, 940, 960, 980, 1020, 1120,
1175, 1190, 1250, 1300 sh, 1310, 1320, 1370, 1410,
1450, 1570 s, 1630, 1700 s (C=O), 2850, 2920, 2960,
1
(1.8 mm), nD22 = 1.5045. H NMR spectrum of com-
pound XII, δ, ppm: 5.34 q (1H, 4-H), 4.91 q (1H,
OCHO), 3.75 m (1H, NCH), 3.55 m (1H, OCH2),
3.45 m (1H, OCH2), 2.24 s (3H, SMe), 2.00 m (2H,
3-H), 1.42 d (3H, MeCHO), 1.29 t (3H, MeCH2O),
1.19 m (3H, MeCHN).
6-Methyl-2-methylsulfanyl-5,6-dihydropyridin-
3(4H)-one (XIV). A 5-g portion of the product mixture
was dissolved in 60 ml of diethyl ether, the solution
was treated with a solution of 3.3 g of 33% hydro-
1
3140. H NMR spectrum (CDCl3), δ, ppm: 3.83 m
(1H, NCH), 2.66 t, 2.62 t (1H, CH2), 2.56–2.47 m (1H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 3 2007

DEVELOPMENT OF A NEW APPROACH TO GENERATION
481
2. Nedolya, N.A., Ph.D. Thesis of Utrecht University,
Utrecht (The Netherlands), 1999; Brandsma, L., Eur. J.
Org. Chem., 2001, p. 4569; Brandsma, L. and Nedo-
lya, N.A., Synthesis, 2004, p. 735; Nedolya, N.A., Brand-
sma, L., van der Kerk, A.H.T.M., Vvedensky, V.Yu., and
Trofimov, B.A., Tetrahedron Lett., 1998, vol. 39, p. 1995;
Nedolya, N.A., Brandsma, L., Zinov’eva, V.P., and
Trofimov, B.A., Russ. J. Org. Chem., 1998, vol. 34,
p. 1494; Nedolya, N.A., Brandsma, L., and Trofi-
mov, B.A., Dokl. Ross. Akad. Nauk, 1996, vol. 350,
p. 68; Nedolya, N.A., Brandsma, L., and Trofimov, B.A.,
Izv. Ross. Akad. Nauk, Ser. Khim., 1996, p. 2813.
3. Hoff, S., Brandsma, L., and Arens, J.F., Recl. Trav. Chim.
Pays–Bas, 1968, vol. 87, p. 916.
4. Brandsma, L., Nedolya, N.A., and Trofimov, B.A., Izv.
Ross. Akad. Nauk, Ser. Khim., 2000, p. 1645.
5. Nedolya, N.A., Brandsma, L., Shlyakhtina, N.I., and
Fedorov, S.V., Khim. Geterotsikl. Soedin., 2002, p. 707;
Nedolya, N.A., Schlyakhtina, N.I., Klyba, L.V., Usha-
kov, I.A., Fedorov, S.V., and Brandsma, L., Tetrahedron
Lett., 2002, vol. 43, p. 9679.
6. Potthast, K. and Eigner, G., Fleischwirtschaft, 1988,
vol. 68, p. 651; Ref. Zh., Khim., 1988, no. 19R276;
Potthast, K., Eichner, R., and Fischer, K., Fleischwirt-
schaft, 1988, vol. 68, p. 991; Chem. Abstr., 1989,
vol. 110, no. 56208f.
CH2), 2.22 s (3H, SMe), 2.18 m (1H, CH2), 1.85–
1.75 m (1H, CH2), 1.38 d (3H, Me). 13C NMR spec-
trum, δC, ppm: 188.41 (C=O), 162.52 (C2), 56.09 (C6),
35.44 (C4), 30.58 (C5), 25.96 (Me), 11.85 (SMe).
Found, %: C 53.55; H 6.89; N 9.08; S 20.10.
C7H11NOS. Calculated, %: C 53.47; H 7.05; N 8.91;
S 20.39.
The IR spectra were recorded on a Specord 75IR
1
13
spectrophotometer. The H and C NMR spectra were
measured from ~5–10% solutions in CDCl3 on
a Bruker DPX-400 instrument (400.13 MHz for 1H and
100.61 MHz for 13C) using HMDS as internal refer-
ence. 1-(1-Ethoxyethoxy)allene (II) was synthesized
by the procedure described in [3]. All reactions were
carried out under argon using liquid nitrogen as cool-
ing agent. Tetrahydrofuran was purified by treatment
with mechanically dispersed KOH (~50 g/l), followed
by distillation over LiAlH4 in the presence of benzo-
phenone under argon. Butyllithium (a ~1.6 M solution
in hexane) and the other reagents and solvents were
commercial products.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
nos. 05-03-32578, 01-03-32698).
7. Knight, J.G. and Tchabanenko, K., Tetrahedron, 2003,
vol. 59, p. 281; Anderson, T.F., Knight, J.G., and
Tchabanenko, K., Tetrahedron Lett., 2003, vol. 44,
p. 757; Knight, J.G., Ainge, S.W., Baxter, C.A., East-
man, T.P., and Harwood, S.J., J. Chem. Soc., Perkin
Trans. 1, 2000, p. 3188; Baures, P.W., Eggleston, D.S.,
Erhard, K.F., Cieslinski, L.B., Torphy, T.J., and Christen-
son, S.B., J. Med. Chem., 1993, vol. 36, p. 3274.
8. Nedolya, N.A., Albanov, A.I., Klyba, L.V., and Zhanchi-
pova, E.R., Russ. J. Org. Chem., 2006, vol. 42, p. 455;
Senda, T., Ogasawara, M., and Hayashi, T., J. Org.
Chem., 2001, vol. 66, p. 6852; Arrayas, R.G., Alcudia, A.,
and Liebeskind, L.S., Org. Lett., 2001, vol. 3, p. 3381;
Casamitjana, N., Lopez, V., Jorge, A., Bosch, J., Mo-
lins, E., and Roig, A., Tetrahedron, 2000, vol. 56,
p. 4027; Casamitjana, N., Jorge, A., Perez, C.G., Bosch, J.,
Espinosa, E., and Molins, E., Tetrahedron Lett., 1997,
vol. 38, p. 2295; Marson, C.M., Grabowska, U., Fal-
lah, A., Walsgrove, T., Eggleston, D.S., and Baures, P.W.,
J. Org. Chem., 1994, vol. 59, p. 291.
REFERENCES
1. Lounasmaa, M. and Tolvanen, A., Comprehensive
Heterocyclic Chemistry. II, Katritzky, A.R., Rees, C.W.,
and Scriven, E.F.V., Eds., Oxford: Pergamon, 1996,
vol. 5, p. 135; Balasubramanian, M. and Keay, J.G., Com-
prehensive Heterocyclic Chemistry. II, Katritzky, A.R.,
Rees, C.W., and Scriven, E.F.V., Eds., Oxford: Pergamon,
1996, vol. 5, p. 245; Lavilla, R., J. Chem. Soc., Perkin
Trans. 1, 2002, p. 1142; Stout, D. and Meyers, A., Chem.
Rev., 1982, vol. 82, p. 223; Eisner, U. and Kuthan, J.,
Chem. Rev., 1972, vol. 72, p. 1; Yu, L.-B., Chen, D.,
Li, J., Ramirez, J., and Wang, P.G., J. Org. Chem., 1997,
vol. 62, p. 208; Wang, Y.-X. and Castagnoli, N., Jr.,
J. Med. Chem., 1995, vol. 38, p. 1904; Kuthan, J. and
Kurfurst, A., Ind. Eng. Chem. Prod. Res. Dev., 1982,
vol. 21, p. 191; Zhang, W., Xie, W., Wang, J., Chen, X.,
Fang, J., Chen, Y., Li, J., Yu, L., Chen, D., and
Wang, P.G., Curr. Org. Chem., 1999, vol. 3, p. 241.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 3 2007