Furan ring recyclization in 2-furfurylthieno[2,3-b]pyridines: An intramolecular N-alkylation of pyrrole ring under acid conditions

Article abstract of DOI:10.1002/jhet.311

(Chemical Equation Presented) The preparation of new 3-amino-2- furfurylthieno[2,3-b]pyridines (1a,b, 69-80%) is described. Subsequent acidic rearrangement of 1a,b afforded two new annulated heterocyclic products, 5a,b, pyrrolothieno[2,3-b]pyridines (45-7

Full text of DOI:10.1002/jhet.311

March 2010
Furan Ring Recyclization in 2-Furfurylthieno[2,3-b]pyridines: An
Intramolecular N-alkylation of Pyrrole Ring under
Acid Conditions
309
Darya Yu. Kosulina, Vladimir K. Vasilin, Tatyana A. Stroganova,*
Tatyana Ya. Kaklyugina, and Gennady D. Krapivin
Department of Organic Chemistry, Kuban State University of Technology, Krasnodar 350072,
Russian Federation
*E-mail: tatka_s@mail.ru
Received August 9, 2009
DOI 10.1002/jhet.311
Published online 2 March 2010 in Wiley InterScience (www.interscience.wiley.com).
The preparation of new 3-amino-2-furfurylthieno[2,3-b]pyridines (1a,b, 69–80%) is described. Subse-
quent acidic rearrangement of 1a,b afforded two new annulated heterocyclic products, 5a,b, pyrrolo-
thieno[2,3-b]pyridines (45–74%), and 6, pyridothieno[2,3-b]pyrrolizine (22%), depending on reaction
conditions.
J. Heterocyclic Chem., 47, 309 (2010).
INTRODUCTION
followed by reduction of carbonyl group and alkylation
of 2-methylfuran with the alcohols obtained. A mixture
of 70% HClO4, acetic anhydride, and acetic acid
(HClO4:Ac2O:AcOH ¼ 5.6:3.3:5.2 mmoles) was used as
a catalyst for the last stage. The application of the cata-
lyst allowed to decrease undesired side-transformations
of alcohols 4a,b and 2-methylfuran during the reaction
[15].
Thieno[2,3-b]pyridine derivatives are well known to
possess varied biological and pharmacological activities,
and hence, their synthesis has been of interest to
chemists [1–7]. We have successively used different
thieno[2,3-b]pyridine derivatives as intermediates for
synthesis of some interesting conjugated and annulated
heterocyclic systems [8–11].
A new heterocyclic system—pyridothienopyrrole 5—
was made from 1 by successive treatment with concen-
trated HCl in acetic acid under heating (Scheme 3). A
cleavage of the protective acetyl group was observed
during the reaction.
Thus, continuing our investigation along this line, we
herein wish to report the synthesis and acid catalyzed
transformations of N-{2-[(5-methyl-2-furyl)(phenyl)me-
thyl]thieno[2,3-b]pyridin-3-yl}acetamides.
An attempt to recyclize 1 on heating in ethanolic HCl
solution gave the unusual results: if 1b (R ¼ Me) was
smoothly converted into the corresponding pyridothieno-
pyrrole 5b (64%), 1a (R ¼ H) gave two substances. We
found that in addition to the expected 5a (45%) another
product—a compound 6 (22%)—was isolated from the
reaction mixture (Scheme 3).
RESULTS AND DISCUSSION
The preparation and transformations of 3-amino-2-fur-
furylthieno[2,3-b]pyridines (e.g. 1, Scheme 1) under
acid conditions have attracted our attention because
these substances could be considered as heteroanalogues
of ortho-aminobenzylfurans, which were converted into
indole derivatives via the furan ring recyclization under
acid conditions [12–14] (Scheme 1).
The structure of 6 is assigned by X-ray analysis
[Fig.(1)] [16]. The crystal was grown from CH2Cl2-
petroleum ether mixture. Pyrrolidine moiety of the mol-
ecule is practically planar: the angle between planes
C(7)-N(2)-C(10)-C(6) and C(7)-C(8)-C(9) is 176.1ꢀ.
H(8b)-C(8)-C(7)-C(19), H(8a)-C(8)-C(7)-H(9a), H(9b)-
C(9)-C(8)-H(8b), and H(9a)-C(9)-C(8)-H(8a) torsion
The 3-amino-2-furfurylthieno[2,3-b]pyridines 1 were
prepared easily from 3-amino-2-benzoylthieno[2,3-b]pyr-
idines 2 according to Scheme 2. This approach included
an acetylation of aminoketones 2 with acetyl chloride
C
V
2010 HeteroCorporation

310
D. Yu. Kosulina, V. K. Vasilin, T. A. Stroganova, T. Ya. Kaklyugina, and G. D. Krapivin
Vol 47
Scheme 1
Scheme 3
angles equals 4.6, 2.4, 2.1, and 4.7ꢀ, correspondingly.
Phenyl substituent is located in a plane forming an angle
of 3.4ꢀ with the heterocyclic core.
AcOH mixture only 5a,b (74%, 61%) were formed. In
this case the Path a is predominant because of the equi-
librium between cyclic seminal B and A.
As to the recyclization of 1b, we suppose that the
Me-substituent in position 4 of the pyridine ring pre-
vents the pyrrolidine ring closure, probably, due to steric
factors. So in this case, the Path a is the only possible
way for the reaction.
We suppose that the formation of 5a and 6 proceeds
as follows: the furan ring opening leads to a diketone,
which in turn reacts with amino group to afford A
(Scheme 4). The aromatization of A leads to pyrrole
ring formation as observed earlier for benzylfurans [11–
13] to give compound 5a (Path a). Another route—pyr-
rolizine 6 formation—is a concurrent process. Probably,
compound 6 is provided by ring closure of dihydropyr-
rolothienopyridine A with side chain carbonyl group to
produce a cyclic semiaminal B (Path b). The interaction
between the semiaminal B and EtOH molecule allows
fixing the pyrrolizine ring as ethoxy derivative which
then converts into 6.
In conclusion, acid-catalyzed transformations of 2-fur-
furylthieno[2,3-b]pyridines have been studied, and the
unusual intramolecular N-alkylation of pyrrole ring
under acid condition has been disclosed. Possible mech-
anism of the reaction has been proposed.
We found that all efforts to furnish the pyrrolizine 6
by heating of the ketone 5a under identical conditions
failed. In our opinion, this result confirms the proposed
mechanism: the alkylation occurs before the aromatiza-
tion of the pyrrole ring. On treating 1a,b with HCl/
EXPERIMENTAL
1
Melting points are uncorrected. H-NMR spectra were meas-
ured in DMSO-d6 on Bruker AM 300 spectrometer using TMS
as an internal standard. Coupling constant (J) values are given
in Hz. Mass spectra were recorded on a Kratos MS-30 instru-
ment with 70 eV impact ionization. IR spectra were recorded
Scheme 2
Figure 1. ORTEP of the molecular structure of compound 6.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2010
Furan Ring Recyclization in 2-Furfurylthieno[2,3-b]pyridines: An Intramolecular
N-alkylation of Pyrrole Ring under Acid Conditions
311
Scheme 4
General procedure for the reduction of acylaminoketones
3a,b. To a vigorously stirred suspension of acylaminoketone
(3a,b) (5 mmoles) in ethanol (40 mL), NaBH4 (0.23 g, 6
mmoles) was added portion wise, and the mixture was kept at
50–60ꢀC for 2 h. After that the mixture was diluted with water
(200 mL) and a precipitate formed was separated by filtration.
The solid was recrystallized from ethanol yielding alcohols
4a,b.
N-{2-[Hydroxy(phenyl)methyl]-4,6-dimethylthieno[2,3-b]pyri-
din-3-yl}acetamide (4a). This compound was obtained as white
powder in 77% yield, mp 178–179 ꢀC; IR: OH 3280, NH
3225, 3120, CO 1652 cm–1; 1H-NMR (DMSO-d6): d 2.03 (s,
3H, COCH3), 3.35 (s, 6H, 4-,6-CH3), 5.98 (d, 1H, CHAOH, J
¼ 3.7 Hz), 6.36 (d, 1H, CHAOH, J ¼ 3.7 Hz), 7.00 (s, 1H,
H-5), 7.20–7.41 (m, 5H, phenyl protons), 9.51 ppm (s, 1H,
NH), ms: m/z 326 (0.7), 308 (20), 293 (40), 267 (100), 265
(98), 251 (12), 105 (21), 101 (10), 80 (38), 76 (17), 59 (24),
43 (59). Anal. Calcd for C18H18N2O2S: C, 66.23; H, 5.56; N,
8.58. Found: C, 66.32; H, 5.60; N, 8.69.
N-{2-[Hydroxy(phenyl)methyl]-6-methylthieno[2,3-b]pyridin-
3-yl}acetamide (4b). This compound was obtained as white
powder in 89% yield, mp 197–198ꢀC; IR: OH 3259, NH 3230,
;
3158, CO 1656 cmꢁ1 1H-NMR (DMSO-d6): d 2.06 (s, 3H,
COCH3), 2.50 (c, 3H, 6-CH3), 6.12 (d, 1H, CHAOH, J ¼ 4.4
Hz), 6.37 (d, 1H, CHAOH, J ¼ 4.4 Hz), 7.19–7.43 (m, 6H,
phenyl protons, H-5), 7.75 (d, 1H, H-4, J ¼ 8.8 Hz), 9.67 ppm
(s, 1H, NH); ms: m/z 253 (32), 252 (20), 251 (100), 134 (26),
105 (30), 91 (15), 90 (19), 77 (41), 65 (12), 63 (11), 59 (15),
43 (28). Anal. Calcd for C17H16N2O2S: C, 65.36; H, 5.16; N,
8.97. Found: C, 65.46; H, 5.24; N, 8.89.
on an InfraLUM FT-02 spectrometer, and absorptions are
given in wavenumbers (cm–1). Column chromatography was
carried out using KSK silica gel (5–40 lm) manufactured by
Sorbpolymer Ltd.
Preparation of N-{2-[(5-methyl-2-furyl)(phenyl)methyl]th-
ieno[2,3-b]pyridin-3-yl}acetamide (1a,b). To
General procedure for acetylation of amines 2a,b. A mix-
ture of amine (2a,b) (10 mmoles) and AcCl (20 mmoles) in
1,4-dioxane (60 mL) was refluxed until the complete conver-
sion of the compounds 2 (TLC). To the cooled stirred mixture,
water (10–15 mL) was added drop by drop, and the resulted
mixture was left at RT for crystallization of a product. The
precipitate thus obtained was separated with suction, washed
with aq solution of sodium hydrocarbonate, water, and air-
dried. Recrystallization of the solid from DMF yielded com-
pounds 3a,b as colorless crystals.
a solution of
4a,b (8.3 mmoles) in 1,4-dioxane (20 mL), 2-methylfuran
(1.12 mL, 12.5 mmoles) and a catalyst (0.4 mL), which was a
mixture of 70% HClO4 (2 mL), Ac2O (5.3 mL) and AcOH (3
mL), was added [15]. The mixture was refluxed for 5 h until
no initial compound remained (TLC control), then it was
poured into of cold water (100 mL), neutralized with sodium
hydrocarbonate to pH ꢂ 6–7. The crude product was filtered
with suction and recrystallized from ethanol with charcoal.
N-{6-Methyl-2-[(5-methyl-2-furyl)(phenyl)methyl]thieno[2,3-
b]pyridin-3-yl}acetamide (1a). This compound was obtained as
white powder in 80% yield, mp 186–187ꢀC; IR: NH 3247, CO
N-(2-Benzoyl-4,6-dimethylthieno[2,3-b]pyridin-3-yl)acetamide
(3a). This compound was obtained as colorless crystals in 71%
yield, mp 161–162ꢀC; IR: NH 3245, CO 1662, CO 1645
1659 cmꢁ1 1H-NMR (DMSO-d6): d 2.05 (s, 3H, COCH3),
;
1
cmꢁ1; H-NMR (DMSO-d6): d 1.50 (s, 3H, COCH3), 2.57 (s,
2.22 (s, 3H, CH3), 2.55 (s, 3H, CH3), 5.90 (s, 1H, CH), 6.00
(d, 1H, HFur, J ¼ 3.2 Hz), 6.08 (d, 1H, HFur, J ¼ 3.2 Hz), 7.26
(s, 5H, phenyl protons), 7.77 (s, 2H, H-5, H-4), 9.68 ppm (s,
1H, NH). Anal. Calcd. for C22H20N2O2S: C, 70.19; H, 5.35;
N, 7.44. Found: C, 70.21; H, 5.32; N, 7.41.
N-{4,6-Dimethyl-2-[(5-methyl-2-furyl)(phenyl)methyl]thieno[2,3-
b]pyridin-3-yl}acetamide (1b). This compound was obtained as
colorless crystals in 69% yield, mp 187–188ꢀC; IR: NH 3272,
3H, 4-CH3), 2.62 (s, 3H, 6-CH3), 7.19 (s, 1H, H-5), 7.52 (t,
2H, HPh, J ¼ 7.3 Hz), 7.62–7.74 (m, 3H, phenyl protons), 9.76
ppm (s, 1H, NH), ms: m/z 324 (29), 281 (100), 121 (11), 105
(13), 59 (25), 43 (49). Anal. Calcd for C18H16N2O2S: C,
66.65; H, 4.97; N, 8.64. Found: C, 66.80; H, 5.09; N, 8.70.
N-(2-Benzoyl-6-methylthieno[2,3-b]pyridin-3-yl)acetamide
(3b). This compound was obtained as colorless crystals in
70% yield, mp 187–188ꢀC; IR: NH 3213, 3192, CO 1705, CO
1635 cmꢁ1
;
1H-NMR (DMSO-d6): d 1.65 (s, 3H, COCH3),
CO 1654 cmꢁ1
;
1H-NMR (DMSO-d6): d 2.04 (s, 6H, 2ꢃ
2.65 (s, 3H, 6-CH3), 7.42–7.55 (m, 3H, phenyl protons), 7.60–
7.67 (m, 2H, phenyl protons), 7.72 (d, 1H, J ¼ 7.3 Hz, H-5),
8.33 (d, 1H, J ¼ 8.1 Hz, H-4), 10.51 ppm (s, 1H, NH); ms: m/
z 310 (21), 269 (12), 268 (82), 267 (94), 105 (17), 101 (13),
77 (100), 69 (12), 59 (35), 57 (17), 55 (14), 51 (18), 45 (22).
Anal. Calcd for C17H14N2O2S: C, 65.79; H, 4.55; N, 9.03.
Found: C, 65.91; H, 4.68; N, 8.91.
CH3), 2.23 (s, 6H, 2ꢃ CH3), 5.77 (s, 1H, CH), 6.02 (d, 1H,
HFur, J ¼ 3.2 Hz), 6.04 (d, 1H, HFur, J ¼ 3.2 Hz), 7.03 (s, 1H,
H-5), 7.21–7.38 (m, 5H, phenyl protons), 9.57 ppm (s, 1H,
NH); ms: m/z 390 (82), 374 (12), 332 (88), 305 (49), 303 (18),
291 (28), 289 (18), 271 (11), 265 (19), 229 (12), 184 (17), 178
(20), 171 (37), 165 (11), 155 (12), 141 (32), 127 (15), 105
(25), 101 (16), 76 (14), 59 (21), 44 (29), 43 (54). Anal. Calcd.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

312
D. Yu. Kosulina, V. K. Vasilin, T. A. Stroganova, T. Ya. Kaklyugina, and G. D. Krapivin
Vol 47
for C23H22N2O2S: C, 70.74; H, 5.68; N, 7.17. Found: C,
70.65; H, 5.78; N, 7.24.
2984, 2921, 2881, 1603, 1559, 1540, 1453, 1420, 1338, 1212,
1132, 1101, 1065, 976, 813, 761, 723, 688, 510 cmꢁ1 1H-
;
General procedure for the reaction of thieno[2,3-b]pyri-
dines 1a,b with HCl/AcOH mixture. A solution of 1a,b (2
mmoles) in a mixture of glacial acetic acid (20 mL) and hy-
drochloric acid (5 mL) was refluxed until no initial compounds
remained (TLC) and then was poured into cold water (100
mL) and neutralized with sodium hydrocarbonate to pH ꢂ 6–
7. A precipitate was collected, washed with water, and air-
dried. A hot solution of the solid in dichloromethane-petro-
leum ether mixture was filtered through a pad of silica gel to
give desired compounds 5a,b.
NMR (DMSO-d6): d 1.05 (t, 3H, OCH2CH3, J ¼ 6.6 Hz), 1.80
(s, 3H, CH3), 2.60 (c, 3H, CH3-Py), 2.98 (t, 2H, CH2, J ¼ 7.3
Hz), 3.35 (q, 2H, OCH2CH3, J ¼ 6.6 Hz), 3.59 (t, 2H, CH2, J
¼ 7.3 Hz), 7.23 (t, 1H, 4-HPh, J ¼ 7.3 Hz), 7.37 (d, 1H, HPy
,
J ¼ 8.1 Hz,), 7.48 (t, 2H, J ¼ 7.3 Hz, 3-, 5-HPh), 7.56 (d, 2H,
2-, 6-HPh, J ¼ 7.3 Hz), 8.14 ppm (d, 1H, HPy, J ¼ 8.1 Hz);
ms: m/z 362 (37), 317 (12.8), 315 (11), 301 (24), 277 (25), 96
(14), 95 (100), 43 (23). Anal. Calcd for C22H22N2OS: C,
72.89; H, 6.12; N, 7.73. Found: C, 72.91; H, 6.10; N, 7.74.
4-(6-Methyl-3-phenyl-1H-pyrrolo[20,30:4,5]thieno[2,3-b]pyr-
idin-2-yl)butan-2-one (5a). This compound was obtained as
white powder in 74% yield; mp 98–99ꢀC; IR: NH 3360, CO
REFERENCES AND NOTES
1709 cmꢁ1 1H-NMR (DMSO-d6): d 2.12 (s, 3H, COCH3),
;
[1] Dave, Ch. G.; Shah, A. B.; Shah H. C. J Heterocycl Chem
1997, 34, 937.
2.57 (s, 3H, CH3), 2.92 (t, 2H, CH2CH2COCH3, J ¼ 8.1 Hz),
3.10 (t, 2H, CH2CH2COCH3, J ¼ 8.1 Hz), 7.28 (d, 1H, H-5, J
¼ 8.1 Hz), 7.43–7.58 (m, 5H, phenyl protons), 8.04 (d, 1H, H-
4 J ¼ 7.3 Hz), 11.87 ppm (s, 1H, NH); ms: m/z 334 (54), 314
(12), 289 (12), 279 (16), 278 (30), 277 (100), 275 (19), 59
(13), 58 (15), 55 (11), 43 (26), 42 (13), 41 (12). Anal. Calcd
for C20H18N2OS: C, 71.83; H, 5.42; N, 8.38. Found: C, 71.86;
H, 5.40; N, 8.35.
[2] Bakhite, E. A.; Al-Sehemi, A. G.; Yamada, Y. J Heterocycl
Chem 2005, 42, 1069.
[3] Abdelkhalik, M. M.; Eltoukhy, A. M.; Agamy, S. M.;
Elnagdi, M. H. J Heterocycl Chem 2004, 41, 431.
[4] Al-Huniti, M. H.; El-Ababdelah, M. M.; Zahra, J. A.; Sabri,
S. S.; Ingendoh, A. Molecules 2007, 12, 497.
[5] Broggini, G.; Chiesa, K.; De Marchi, I.; Martinelli, M.;
Pilati, T.; Zecchi, G. Tetrahedron 2005, 61, 3525.
4-(4,6-Dimethyl-3-phenyl-1H-pyrrolo[20,30:4,5]thieno[2,3-b]
pyridin-2-yl)butan-2-one (5b). This compound was obtained
as white powder in 61% yield; mp 178–179ꢀC; IR: NH 3262,
[6] Yuh Wen Ho. Dyes Pigments 2005, 66, 223.
[7] Bakhite, E. A.; Abdel-Rahman, A. E.; Al-Taifi, E. A. Phos-
phorus, Sulfur, Silicon Relat Elem 2004, 179, 513.
[8] Stroganova, T. A.; Butin, A. V.; Vasilin, V. K.; Nevolina,
T. A.; Krapivin G. D. Synlett 2007, 1106.
1
CO 1715 cmꢁ1; H-NMR (DMSO-d6): d 2.11 (s, 3H, COCH3),
2.70 (s, 6H, 2ꢃ CH3), 2.92 (t, 2H, CH2CH2COCH3, J ¼ 7.3
Hz), 3.12 (t, 2H, CH2CH2COCH3, J ¼ 7.3 Hz), 7.06 (s, 1H,
H-5), 7.25–7.29 (m, 2H, phenyl protons), 7.43–7.57 (m, 3H,
phenyl protons), 11.46 ppm (s, 1H, NH); ms: m/z 348 (44),
291 (100), 151 (15), 128 (29), 115 (30), 101 (26), 89 (11), 76
(26), 66 (11), 59 (16), 58 (40), 51 (24), 45 (14). Anal. Calcd
for C21H20N2OS: C, 72.38; H, 5.79; N, 8.04. Found: C, 72.38;
H, 5.91; N, 7.94.
General procedure for the interaction of thieno[2,3-
b]pyridines 1a,b with EtOH/HCl(gas). A solution of 1a,b (2
mmoles) in EtOH saturated with dry HCl (gas) (20 mL) was
refluxed for 50 min. Then the mixture was poured into cold
water (100 mL), and neutralized with sodium hydrocarbonate
to pH ꢂ 6–7. The solid formed was filtered off, washed with
water, and air-dried. For 1b—the precipitate was purified as
described above yielding 5b in 64% yield.
[9] Abdel-Moneim Makhmud, M.; Vasilin, V. K.; Krapivin, G.
D. Khim Geterotsikl Soedin 2006, 1801 (Chem Heterocycl Comp
(Engl Ed.) 2006, 42, 1501).
[10] Vasilin, V. K.; Kaigorodova, E. A.; Firgang, S. I.; Krapivin,
G. D. Khim Geterotsikl Soedin 2004, 462 (Chem Heterocycl Comp
(Engl Ed.) 2004, 40, 377).
[11] Vasilin, V. K.; Lipunov, M. M.; Konyushkin, L. D.; Krapi-
vin, G. D. Khim Geterotsikl Soedin 2006, 1582 (Chem Heterocycl
Comp(Engl. Ed.) 2006, 42, 1368).
[12] Butin, A. V.; Stroganova, T. A.; Lodina, I. V.; Krapivin, G.
D. Tetrahedron Lett 2001, 42, 2031.
[13] Butin, A. V.; Smirnov, S. K.; Stroganova, T. A. J Hetero-
cycl Chem 2006, 43, 623.
[14] Butin, A. V.; Smirnov, S. K.; Stroganova, T. A.; Bender,
W.; Krapivin, G. D. Tetrahedron 2007, 63, 474.
[15] Kosulina, D.Yu.; Vasilin, V. K.; Stroganova, T. A.; Sbit-
neva, E. A.; Krapivin, G.D. Pat. (RU) 2346947, 2009.
[16] CCDC 693220 for 6 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge at www.ccdc.cam.ac.uk/conts/retrieving.html or from the
Cambridge Crystallographic Data Centre, 12, Union Road, Cam-
bridge CB2 1EZ, UK; fax: þ44(1223)336033; Available at:
deposit@ccdc.cam.ac.uk.
In case of 1a, the solid was separated by column chromatog-
raphy (silica gel, petroleum ether : ethyl acetate 1:2) to afford
5a and
6 as colorless crystals in 45 and 22% yield,
respectively.
9-Ethoxy-3,9-dimethyl-6-phenyl-8,9-dihydro-7H-pyrido[30,20:
4,5]thieno[2,3-b]pyrrolizine (6). This compound was obtained
as colorless crystals in 22% yield, mp 166–167ꢀC; IR: 3053,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet