Heterocyclic ortho-aminocarbonyl compounds in the friedl?nder reaction promoted by chlorotrimethylsilane

Article abstract of DOI:10.3987/com-07-11128

A possibility of introduction of heterocyclic ortho-aminoketones into promoted by TMSCI Friedl?nder reaction with a wide set of α-methylenecarbonyl compounds was studied. A convenient synthetical method to obtain heterofused pyridine systems was elaborate

Full text of DOI:10.3987/com-07-11128

HETEROCYCLES, Vol. 71, No. 11, 2007
2397
HETEROCYCLES, Vol. 71, No. 11, 2007, pp. 2397 - 2411. © The Japan Institute of Heterocyclic Chemistry
Received, 3rd June, 2007, Accepted, 18th July, 2007, Published online, 25th July, 2007. COM-07-11128
HETEROCYCLIC ORTHO-AMINOCARBONYL COMPOUNDS IN THE
FRIEDLÄNDER REACTION PROMOTED BY
CHLOROTRIMETHYLSILANE
Sergey V. Ryabukhin,a,b* Andrey S. Plaskon,b Vasiliy S. Naumchik,b
Dmitriy M. Volochnyuk,a,c Sergey E. Pipko,a and Andrey A. Tolmachevb
aEnamine Ltd. 23 A. Matrosova st., 01103 Kyiv, Ukraine
bNational Taras Shevchenko University, 62 Volodymyrska st., 01033 Kyiv,
Ukraine
cInstitute of Organic Chemistry, National Academy of Sciences of Ukraine,
Murmanska 5, 02094 Kyiv, Ukraine
Fax: +380 44 5373253
E-mail: Ryabukhin@mail.enamine.net
Abstract – A possibility of introduction of heterocyclic ortho-aminoketones into
promoted by TMSCl Friedländer reaction with a wide set of α-methylenecarbonyl
compounds was studied. A convenient synthetical method to obtain heterofused
pyridine systems was elaborated; its scope and limitations were established as well.
A set of derivatives of thieno[2,3-b]pyridines, [1]benzofuro[3,2-b]pyridines,
5H-chromeno[2,3-b]pyridin-5-ones, pyrido[2,3-d]pyrimidin-2,4(1H,3H)-diones
was obtained in high preparative yields.
INTRODUCTION
The Friedländer reaction is a facile direct method to obtain the pyridine ring in the quinoline and other
heterofused systems.1 The diversity of α-methyleneketones available nowadays provides a possibility to
vary easily the substituents in the formed compounds. In our previous work2 we described a possibility to
use TMSCl3 in DMF solution as a condensating agent for the synthesis of quinoline derivatives. That let
extending the scope of the Friedländer reaction for different ortho-aminoketones I on α-methyleneketones
II. During the investigation mentioned a range of diverse derivatives of quinoline III was synthesized, that
demonstrated a possilbility to introduce different substituents into the quinoline system.
In present paper we report the results of studying the subjection of heterocyclic aminoketones IV to the
Friedländer reaction using TMSCl/DMF system (Scheme 1).

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HETEROCYCLES, Vol. 71, No. 11, 2007
In present paper we report the results of studying the subjection of heterocyclic aminoketones IV to the
Friedländer reaction using TMSCl/DMF system (Scheme 1).
O
R2
R2
R4
R3
R4
R3
II
O
R1
R1
TMSCl
DMF
N
NH2
R2
I
III
O
R2
R4
R3
R4
II
O
Het
Het
TMSCl
DMF
NH2
R3
N
IV
V
Scheme 1.
The corresponding aminoaldehydes and aminoketones depicted on the Figure 1 were chosen to be model
objects for the investigation.
O
R2
R2
R2
O
O
R1a
O
N
O
O
O
O
Het
=
O
N
NH2
R1b
NH2
NH2
NH2
S
O
NH2
IV
1a-b
2a-b
4a
3a
1a: R1aR1b=(CH2)4 R2=Ph
2a: R2=CH3
2b: R2=2-Furyl
1b: R1aR1b=(CH2)3 R2=Tolyl
Figure 1.
The
heterofused
systems
(V)
of
thieno[2,3-b]pyridine,
furo[3,2-b]pyridine,
5H-chromeno[2,3-b]pyridin-5-one, pyrido[2,3-d]pyridin-2,4(1H,3H)-dione, which are formed in the
reaction of ortho-aminocarbonyl compounds with ꢀ-methyleneketones (II) are common among natural
and synthetic chemical substances, and their derivatives exhibit a wide spectra of farmacological activity.
The thieno[2,3-b]pyridine derivatives are known as specific antagonists of LHRH receptors.4 Some
derivatives of furo[3,2-b]pyridine reveal anticonvulsive action.5 Among the 5H-chromeno[2,3-b]pyridin-5-one
derivatives there are many substances which have found an application as antiallergic and antiulcer drugs.6
The derivatives of pyrido[2,3-d]pyridin-2,4(1H,3H)-dione exhibit antibacterial,7a antitumor,7b
anticonvulsant7c and other therapeutic activities.7d-h Till the moment, there is a quite wide range of reagents,
systems and conditions for subjecting heterocyclic ortho-aminocarbonyl compounds to the Friedländer
reaction,5,8,9,10 however they are not sufficient to cover all the variety of ꢀ-methyleneketones which could

HETEROCYCLES, Vol. 71, No. 11, 2007
2399
be used in this reaction. Therefore, the search for new preparative procedures for the Friedländer reaction
and enlarging its scope and limitations by introducing more and more new substances remains still actually.
RESULTS AND DISCUSSION
Among the selected model compounds (IV), thiophene aminoketones (1a-b) are the closest analogues of
the aromatic aminoketones (I). Therefore, for the elucidation of the possibility of using
2-aminothiophenes as substrates for the Friedländer reaction in TMSCl/DMF system, we used the
conditions found to be the best for o-aminoacetophenone. Heating 1 equivalent of aminoketones (1a-b)
with 1 equivalent of ꢀ-methyleneketone (5-11) and 4 equivalents of TMSCl at 100 °C led to the
formation of a set of thieno[2,3-b]pyridines (Table 1).
Table 1. TMSCl Promoted Synthesis of thieno[2,3-b]pyridinesa
R2
R2
R1a
R4
R4
R3
O
TMSCl
DMF
R1a
+
R3
R1b
O
NH2
R1b
S
N
S
1a-b
5-11
12-18
Yiel
d
E
nt
ry
Tim Yiel
da
(h) (%) ry
E
nt
Tim
e
(h)
Carbonyl
compound
Carbonyl
compound
1
Product
1
Product
e
(%)
b
Ph
O
Ph
CN
O
CN
COOH
S
N
CO2H
10a
S
1
2
1a
1a
10
10
94 15 1a
89 16 1a
N
14
12
86
85
Cl
Cl
17aa
5a
12aa
Ph
O
O
O
O
N
Ph
N
CF3
S
S
CF3
S
N
S
N
Ph
11a
18aa
12ab
5b
Ph
O
Ph
O
O
O
O
O
NH2
S
CF3
S
N
NH2
3
4
1a
1a
10
12
93 17 1a
S
12
10
81
92
N
CF3
S
6a
7a
11b
5a
18ab
13aa
Ph
O
CN
96 18 1b
S
N
S
N
Cl
14aa
12ba
Ph
O
COOMe
N
S
N
S
5
1a
12
84 19 1b
5b
10
87
S
O
N
Ph
O
7b
12bb
14ab

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HETEROCYCLES, Vol. 71, No. 11, 2007
Ph
N
O
O
O
COOEt
OEt
6
1a
1a
12
12
87 20 1b
10
12
88
90
S
S
N
6b
7c
14ac
13bb
O
Ph
O
S
N
7
8
88 21 1b
S
N
14ad
7d
14be
7e
7f
Ph
O
Me
S
S
N
1a
1a
14
79 22 1b
12
87
S
O
S
N
15aa
8a
14bf
Ph
O
Me
O
S
N
NH
9
14
14
81 23 1b
12
12
84
80
N
O
O
S
N
7g
15ab
8b
14bg
Ph
O
Me
N
H
S
N
N
10 1a
11 1a
77 24 1b
N
N
O
S
N
7h
15ac
8c
14bh
Ph
Me
S
N
14
14
86 25 1b
8e
14
82
O
S
N
8d
15ad
15be
Ph
Me
S
N
12 1a
83 26 1b
10a
14
12
86
88
COOH
O
S
N
15ae
8e
17ba
O
Ph
O
O
Cl
Cl
O
CF3
CF3
S
CF3
13 1a
14 1a
14
14
82 27 1b
N
Ph
S
N
CF3
11c
8f
15af
18bc
O
Ph
OEt
87
S
N
COOEt
O
16aa
aSatisfactory microanalysis obtained C ± 0.33; H ± 0.45; N ± 0.25
9a
bYields refer to pure isolated products
Analyzing the results obtained, it should be noted that, in general more drastical conditions are required for
aminothiophenes 1a-b in comparison with o-aminoacetophenone for the Friedländer reaction. Thus, even in
the case of the most reactive ꢀ-methylenecarbonyl compounds such as ꢁ-ketonitriles (5), ꢁ-diketones (6,
11) and cyclic ketones (7) which were subjected to the similar cyclizations before,8 the optimal heating time
remains to be 10-12 hours. In the case of less active substrates such as acyclic methylketones (8),

HETEROCYCLES, Vol. 71, No. 11, 2007
2401
dialkylketones with additional functional groups (9-10), even more prolonged heating time is required (14
hours).
In the reaction of aminothiophene 1a with unsymmetrical ꢀ-CF3-ꢁ-diketones, either thienopyridine 18aa
or 18ab are formed depending on the substituents, what is in agreement with previously obtained by us
results concerning its behavior in the Friedländer reaction with ortho-aminobenzophenone2 (Scheme 2).
Ph
O
R = Me
CF3
O
S
N
R
O
Ph
O
O
TMSCl
DMF
18aa
+
NH2
CF3
R
S
Ph
1a
11a-b
R
CF3
R = 2-Thienyl
S
N
18ab
Scheme 2
Changing from aminothiophenes to aminoketones of [1]benzofuran 2a-b led to a significant narrowing
the set of ꢀ-methylenecarbonyl compounds which could be subjected to the reaction and more drastical
reaction conditions.
We succeeded in reacting aminoketones 2a-b with ꢁ-ketonitriles (5), ꢁ-diketones (6) and cyclic ketones
(7) by heating their mixtures in the TMSCl/DMF system for 12-14 hours. An attempt to subject acyclic
ketones 8-10 to the same conversion resulted in the formation of only trace amounts of products. All the
[1]benzofuro[3,2-b]pyridines obtained are listed in Table 2.
Table 2. TMSCl Promoted Synthesis of [1]benzofuro[3,2-b]pyridinesa
R2
R2
R4
R4
R3
O
O
O
TMSCl
DMF
+
O
R3
NH2
N
2a-b
19-23
5-7
Yiel
d
E
nt
ry
Tim Yiel
da
(h) (%) ry
E
nt
Tim
e
(h)
Carbonyl
compound
Carbonyl
compound
2
Product
2
Product
e
(%)
b
O
CN
O
O
O
O
O
N
28 2a
5a
12
90 33 2b
14
88
N
Cl
6c
19aa
22bc

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HETEROCYCLES, Vol. 71, No. 11, 2007
O
O
COOEt
O
O
N
29 2a
30 2a
6b
7a
14
14
87 34 2b
92 35 2b
14
14
92
90
N
O
O
20ab
6d
7a
22bd
O
O
O
N
N
21aa
23aa
O
O
O
N
31 2a
32 2a
7c
14
14
83 36 2b
81 37 2b
7d
7f
14
14
83
86
N
21ac
23ad
O
O
O
N
7d
N
21ad
23af
aSatisfactory microanalysis obtained C ± 0.33; H ± 0.45; N ± 0.25
bYields refer to pure isolated products
It should be noted that only ethyl acetoacetate was subjected to the Friedländer reaction with
[1]benzofuro[3,2-b]pyridines before.5
The derivatives of 2-amino-3-uracil-carbaldehyde 3 and 2-amino-3-chromone-carbaldehyde 4 appeared to
be even less active in the Friedländer reaction using our system in comparison with aminoketones of
thiophene and furan. In this case we succeded in reacting only ꢀ-methyleneketones 5 with
aminoaldehydes 3 and 4 using more prolonged heating (Table 3).
Table 3. TMSCl Promoted Synthesis of 5H-chromeno[2,3-b]pyridin-5-ones,
pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones.a
O
O
R4
O
NH2
O
O
N
R3
24
R4
R3
3
TMSCl
DMF
+
O
O
N
O
R4
N
N
O
NH2
5
O
N
N
R3
O
25
4
Yiel
d
E
nt
ry
Tim Yiel
da
(h) (%) ry
E
nt
Tim
e
(h)
Carbonyl
compound
Carbonyl
compound
3
Product
4
Product
e
(%)
b
O
O
CN
CN
38 3a
5a
41 4a
5a
N
O
N
O
N
N
16
90
16
89
Cl
Cl
24aa

HETEROCYCLES, Vol. 71, No. 11, 2007
2403
25aa
S
O
O
O
CN
O
N
39 3a
40 3a
42 4a
5b
5c
CN
S
N
N
N
O
N
16
16
86
83
16
16
84
S
24ac
5c
25ab
O
O
O
CN
43 4a
CN
CN
N
O
O
N
S
O
O
N
N
81
24ad
5d
25ac
aSatisfactory microanalysis obtained C ± 0.33; H ± 0.45; N ± 0.25
bYields refer to pure isolated products
In conclusion, we described an efficient route for the synthesis of different heteroannelated pyridines
using Me3SiCl as a promoter and water scavenger via Friedländer annulation. The methodology is
applicable to a wide variety of ꢀ-methylene ketones and delivers targeted products in good yields,
excellent homogeneity and often in analytically pure form. The procedure is very simple and could be
easily adapted to semi-automated solution-phase parallel synthesis of such libraries.
EXPERIMENTAL
General Data: All chemicals were obtained from commercially available sources (Aldrich, Fluka,
Enamine Ltd.) and used without further purification. DMF was freshly distilled and dried by standard
methods; monitoring of water concentration in solvents (the solvent contained < 0.05%, usually 0.02% of
water) was performed using Mettler Toledo DL31 KF Titrator. All solvents for the crystallizations were
used without additional purification.
Melting points were measured with a Buchi melting points apparatus and are uncorrected. The 1H, 13C and
19F NMR spectra (500, 125 and 470 MHz, respectively) were recorded on a Bruker Avance drx 500 with
DMSO-d6 as a solvent, TMS (1H and 13C) and CFCl3 (19F) were used as internal standards. LC/MS spectra
were recorded using chromatography/mass spectrometric system that consists of high-performance liquid
chromatograph “Agilent 1100 Series” equipped with diode-matrix and mass-selective detector “Agilent
LC/MSD SL”. According to HPLC MS data all the synthesized compounds have purity > 95%. BRANSON
2510E-MT ultrasonic bath and autoclave BERGHOF HR-500 were used.
General procedure for the preparation of thieno[2,3-b]pyridines, [1]benzofuro[3,2-b]pyridines,
5H-chromeno[2,3-b]pyridin-5-ones, pyrido[2,3-d]pyrimidine-2,4(1H,3H)-diones (12-25).
An appropriate aminocarbonyl compound 1-4 (1 mmol) and an appropriate carbonyl component 5-11 (1
mmol) were placed in 8 mL pressure tube and dissolved in DMF (2 mL). Chlorotrimethylsilane (4 mmol)
was added dropwise to the solution. The tube was thoroughly sealed and heated on a water-bath for a
particular time. (For the heating time see Tables 1-3.) After cooling the flask was opened (caution!

2404
HETEROCYCLES, Vol. 71, No. 11, 2007
Excessive pressure inside); the reaction mixture was poured into water (5 mL) and allowed to stand at 20 °C
in ultrasonic bath for 1h. The precipitate formed was filtered and washed with small amount of MeOH (or
MeCN). Recrystallization from an appropriate solvent yielded the target compound.
2-(4-Chlorophenyl)-4-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine-3-carbonitrile (12aa)
mp 201 °C. 1H NMR (DMSO-d6) ꢀ 1.53 (m, 2H), 1.75 (m, 2H), 1.85 (m, 2H), 2.87 (m, 2H), 7.49 (m, 2H),
7.56 (m, 3H), 7.61 (d, J = 7.7 Hz, 2H), 7.92 (d, J = 7.7 Hz, 2H). [M+1]=402. Anal. Calcd for
C24H17ClN2S: C, 71.90; H, 4.27; N, 6.99. Found: C, 71.75; H, 4.30; N, 6.90.
3-(1,3-Benzothiazol-2-yl)-2,4-diphenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine (12ab)
mp 178 °C. 1H NMR (DMSO-d6) ꢀ 1.49 (m, 2H), 1.72 (m, 4H), 2.86 (m, 2H), 7.2 (m, 5H), 7.28 (m, 3H),
7.37 (t, J = 7.5 Hz, 1H), 7.42 (m, 3H), 7.83 (t, J = 7.5 Hz, 2H). [M+1]=476. Anal. Calcd for C30H22N2S2:
C, 75.92; H, 4.67; N, 5.90. Found: C, 75.86; H, 4.58; N, 6.06.
2-Methyl-4-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine-3-carboxamide (13aa)
mp 254 °C. 1H NMR (DMSO-d6) ꢀ 1.45 (m, 2H), 1.69 (m, 4H), 2.57 (s, 3H), 2.77 (m, 2H), 7.29 (m, 3H),
13
7.39 (m, 3H), 7.67 (s, 1H) C NMR (DMSO-d6) ꢀ = 22.2, 22.5, 22.6, 25.9, 26.1, 127.7, 128.3, 128.6,
128.7, 129.8, 131.1, 136.4, 137.0, 141.7, 149.5, 158.4, 169.2. [M+1]=323. Anal. Calcd for C19H18N2OS: C,
70.78; H, 5.63; N, 8.69. Found: C, 70.89; H, 5.52; N, 8.54.
11-Phenyl-1,2,3,4,7,8,9,10-octahydro[1]benzothieno[2,3-b]quinoline (14aa)
mp 190-191 °C. 1H NMR (DMSO-d6) ꢀ 1.46 (m, 2H), 1.69 (m, 6H), 1.81 (m, 2H), 2.32 (t, J = 6.2 Hz, 2H),
2.74 (m, 2H), 2.94 (t, J = 6.2 Hz, 2H), 7.21 (m, 2H), 7.47 (m, 3H) . [M+1]=320. Anal. Calcd for
C21H21NS: C, 78.95; H, 6.63; N, 4.38. Found: C, 78.77; H, 6.57; N, 4.32.
Methyl 12-phenyl-2,3,4,7,8,9,10,11-octahydro-1H-[1]benzothieno[2,3-b]cyclohepta[e]pyridine-7-
carboxylate (14ab)
mp 121 °C. 1H NMR (DMSO-d6) ꢀ 1.43 (m, 1H), 1.49 (m, 2H), 1.51 (m, 1H), 1.75 (m, 8H), 1.98 (m, 1H),
2.39 (m, 1H), 2.73 (m, 2H), 3.67 (s, 3H), 4.31 (m, 1H), 7.21 (m, 2H), 7.45 (m, 3H). [M+1]=393. Anal.
Calcd for C24H25NO2S: C, 73.62; H, 6.44; N, 3.58. Found: C, 73.90; H, 6.39; N, 3.68.
13-Phenyl-1,2,3,4,7,8,9,10,11,12-decahydro[1]benzothieno[2,3-b]cycloocta[e]pyridine (14ac)
mp 243 °C. 1H NMR (DMSO-d6) ꢀ 1.29 (m, 2H), 1.38 (m, 6H), 1.66 (m, 4H), 1.82 (m, 2H), 2.61 (m, 2H),
2.81 (m, 2H), 3.24 (m, 2H), 7.32 (m, 2H), 7.51 (m, 3H) 13C NMR (DMSO-d6) ꢀ = 22.3, 22.4, 25.4, 25.6,
25.9, 26.2, 26.9, 30.9, 31.0, 33.3, 128.3, 128.4, 128.8, 129.1, 131.4, 131.7, 137.1, 137.9, 147.3, 153.2,
155.6. [M+1]=349. Anal. Calcd for C23H25NS: C, 79.49; H, 7.25; N, 4.03. Found: C, 79.37; H, 7.36; N,
4.11.
17-Phenyl-1,2,3,4,7,8,9,10,11,12,13,14,15,16-tetradecahydro[1]benzothieno[2,3-b]cyclododeca[e]pyri
dine (14ad)

HETEROCYCLES, Vol. 71, No. 11, 2007
2405
mp 175-176 °C. 1H NMR (DMSO-d6) ꢀ 1.24 (m, 2H), 1.51 (m, 14H), 1.68 (m, 2H), 1.78 (m, 2H), 1.96 (m,
2H), 2.46 (m, 2H), 2.82 (m, 2H), 2.88 (m, 2H), 7.21 (m, 2H), 7.46 (m, 3H) 13C NMR (DMSO-d6) ꢀ 22.7,
22.8, 23.3, 23.8, 26.1, 26.7, 26.9, 27.3, 27.5, 27.7, 29.3, 32.9, 128.1, 128.3, 129.7, 130.3, 136.1, 138.4,
144.8, 146.6, 155.4, 157.2, 181.9, 208.3, 212.9. [M+1]=405. Anal. Calcd for C27H33NS: C, 80.35; H, 8.24;
N, 3.47. Found: C, 80.02; H, 8.53; N, 3.58.
4-Phenyl-2-thien-2-yl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine (15aa)
1
mp 190 °C. H NMR (DMSO-d6) ꢀ 1.52 (m, 2H), 1.74 (m, 2H), 1.92 (m, 2H), 2.81 (m, 2H), 7.13 (t, J =
3.4 Hz, 1H), 7.42 (m, 2H), 7.48 (m, 3H), 7.63 (d, J = 4.4 Hz 1H), 7.68 (s, 1H), 7.87 (d, J = 2.7 Hz, 1H).
[M+1]=349. Anal. Calcd for C21H17NS2: C, 72.58; H, 4.93; N, 4.03. Found: C, 72.44; H, 4.76; N, 4.19.
2-(2-Furyl)-4-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine (15ab)
mp 199 °C. 1H NMR (DMSO-d6) ꢀ 1.52 (m, 2H), 1.74 (m, 2H), 1.94 (m, 2H), 2.82 (m, 2H), 6.65 (m, 1H),
7.22 (d, J = 3 Hz, 1H), 7.42 (m, 2H), 7.48 (m, 4H), 7.82 (s, 1H). [M+1]=332. Anal. Calcd for C21H17NOS:
C, 76.10; H, 5.17; N, 4.23. Found: C, 76.32; H, 5.05; N, 4.39.
4-Phenyl-2-(1H-pyrrol-2-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine (15ac)
mp 215 °C. 1H NMR (DMSO-d6) ꢀ 1.51 (m, 2H), 1.73 (m, 2H), 1.91 (m, 2H), 2.79 (m, 2H), 6.14 (s, 1H),
6.89 (s, 2H), 7.40 (s, 2H), 7.49 (s, 3H), 11.75 (s, 1H). [M+1]=331. Anal. Calcd for C21H18N2S: C, 76.33;
H, 5.49; N, 8.48. Found: C, 76.21; H, 5.63; N, 8.37.
2-tert-Butyl-4-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine (15ad)
mp 120 °C. 1H NMR (DMSO-d6) ꢀ 1.35 (s, 9H), 1.51 (m, 2H), 1.74 (m, 2H), 1.93 (m, 2H), 2.87 (m, 2H),
7.12 (s, 1H), 7.36 (m, 2H), 7.44 (m, 3H). [M+1]=322. Anal. Calcd for C21H23NS: C, 78.46; H, 7.21; N,
4.36. Found: C, 78.37; H, 7.30; N, 4.29.
2-(1-Adamantyl)-4-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine (15ae)
mp 181 °C. 1H NMR (DMSO-d6) ꢀ 1.50 (m, 2H), 1.72 (m, 8H), 1.97 (m, 8H), 2.03 (m, 3H), 2.49 (m, 2H),
7.04 (s, 1H), 7.33 (m, 2H), 7.43 (m, 3H). [M+1]=401. Anal. Calcd for C27H29NS: C, 81.16; H, 7.32; N,
3.51. Found: C, 81.05; H, 7.77; N, 3.41.
3-(2-Chloroethyl)-2,4-diphenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine (15af)
Mp 146-147 °C. 1H NMR (DMSO-d6) ꢀ 1.48 (m, 2H), 1.71 (m, 4H), 2.79 (m, 2H), 2.88 (m, 2H), 3.22 (m,
2H), 7.41 (m, 2H), 7.52 (m, 8H). [M+1]=405. Anal. Calcd for C25H22ClNS: C, 74.33; H, 5.49; N, 3.47.
Found: C, 74.45; H, 5.65; N, 3.32.
Ethyl 3-methyl-4-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine-2-carboxylate (16aa)
mp 130 °C. 1H NMR (DMSO-d6) ꢀ 0.84 (t, J = 7.2 Hz, 3H), 1.47 (m, 2H), 1.80 (m, 4H), 2.54 (s, 3H), 2.80
13
(m, 2H), 3.92 (q, J = 7.2 Hz, 2H), 7.24 (m, 2H), 7.45 (m, 3H). C NMR (DMSO-d6) ꢀ 13.8, 22.4, 22.5,

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22.7, 25.9, 26.2, 61.3, 126.8, 128.0, 128.2, 128.3, 128.9, 129.4, 136.2, 137.7, 142.2, 149.8, 160.5, 168.1.
[M+1]=352. Anal. Calcd for C21H21NO2S: C, 71.77; H, 6.02; N, 3.99. Found: C, 71.58; H, 6.15; N, 4.13.
(2-Methyl-4-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)acetic acid (17aa)
mp 276 °C. 1H NMR (DMSO-d6) ꢀ 1.43 (m, 2H), 1.44 (m, 4H), 2.54 (s, 3H), 2.75 (m, 2H), 3.42 (s, 2H),
7.17 (m, 2H), 7.41 (m, 3H). [M+1]=338. Anal. Calcd for C20H19NO2S: C, 71.19; H, 5.68; N, 4.15. Found:
C, 71.35; H, 5.47; N, 4.26.
2,2,2-Trifluoro-1-(2-methyl-4-phenyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)ethanone
(18aa)
mp 111 °C. 1H NMR (DMSO-d6) ꢀ 1.50 (m, 2H), 1.71 (m, 2H), 1.82 (m, 2H), 2.49 (s, 3H), 2.83 (m, 2H),
7.29 (m, 2H), 7.49 (m, 3H). 13C NMR (DMSO-d6) ꢀ 22.35, 22.44, 22.7, 26.0, 26.4, 114.9 (q, 1JCF = 292.7
2
Hz), 126.5, 128.2, 128.36, 128.40, 129.9, 130.3, 134.2, 139.0, 142.8, 149.0, 162.5, 189.9 (q, JCF = 37.2
Hz). 19F NMR (DMSO-d6) ꢀ -76.3. [M+1]=376. Anal. Calcd for C20H16F3NOS: C, 63.99; H, 4.30; N, 3.73.
Found: C, 64.12; H, 4.24; N, 3.62.
4-Phenyl-2-(trifluoromethyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl](thien-2-yl)meth-
anone (18ab)
mp 210 °C. 1H NMR (DMSO-d6) ꢀ 1.51 (m, 2H), 1.71 (m, 3H), 1.90 (m, 1H), 2.91 (m, 2H), 7.08 (m, 1H),
13
7.15 (m, 2H), 7.21 (m, 1H), 7.33 (m, 2H), 7.47 (d, J = 5.1 Hz, 1H), 7.97 (d, J = 5.1 Hz, 1H). C NMR
1
(DMSO-d6) ꢀ 22.25, 22.28, 26.0, 26.4, 122.1 (q, JCF = 275.6 Hz), 127.5, 128.0, 128.9, 129.2, 129.3,
2
19
130.0, 130.3, 130.5, 133.3, 134.2, 137.5, 137.6, 143.8 (q, JCF = 33.0 Hz), 144.6, 160.1, 185.9. F NMR
(DMSO-d6) ꢀ -62.0. [M+1]=445. Anal. Calcd for C23H16F3NOS2: C, 62.29; H, 3.64; N, 3.16. Found: C,
62.43; H, 3.57; N, 3.26.
2-(4-Chlorophenyl)-4-(4-methylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridine-3-
carbonitrile (12ba)
1
mp 216 °C. H NMR (DMSO-d6) ꢀ 2.18 (m, 2H), 2.24 (m, 2H), 2.42 (s, 3H), 3.01 (m, 2H), 7.37 (d, J =
8.0 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H) 7.63 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H). [M+1]=402. Anal.
Calcd for C24H17ClN2S: C, 71.90; H, 4.27; N, 6.99. Found: C, 71.76; H, 4.15; N, 6.85.
3-(1,3-Benzothiazol-2-yl)-4-(4-methylphenyl)-2-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]
pyridine (12bb)
1
mp 250 °C. H NMR (DMSO-d6) ꢀ 2.06 (m, 2H), 2.22 (m, 5H), 2.99 (m, 2H), 7.06 (d, J = 7.3 Hz, 2H),
7.17 (m, 5H), 7.32(t, J = 8 Hz, 1H), 7.41 (m, 3H), 7.86 (t, J = 8 Hz, 2H). [M+1]=476. Anal. Calcd for
C30H22N2S2: C, 75.92; H, 4.67; N, 5.90. Found: C, 76.06; H, 4.53; N, 5.82.
Ethyl 2-methyl-4-(4-methylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridine-3-carbo-

HETEROCYCLES, Vol. 71, No. 11, 2007
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xylate (13bb)
mp 99 °C. 1H NMR (DMSO-d6) ꢀ 0.96 (t, J = 7.2 Hz, 3H), 2.18 (m, 2H), 2.29 (m, 2H), 2.46 (s, 3H), 2.61
(s, 3H), 3.01 (m, 2H), 3.99 (q, J = 7.2 Hz, 2H), 7.15 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H)
13C NMR (DMSO-d6) ꢀ 13.9, 21.3, 22.8, 27.1, 29.8, 29.9, 61.4, 125.9, 126.2, 128.7, 129.2, 133.0, 137.4,
138.2, 141.9, 142.8, 150.0, 165.8, 168.2. [M+1]=352. Anal. Calcd for C21H21NO2S: C, 71.77; H, 6.02; N,
3.99. Found: C, 71.64; H, 6.18; N, 4.09.
8-tert-Butyl-10-(4-methylphenyl)-2,3,6,7,8,9-hexahydro-1H-cyclopenta[4,5]thieno[2,3-b]quinoline
(14be)
mp 193 °C. 1H NMR (DMSO-d6) ꢀ 0.85 (s, 9H), 1.44 (m, 2H), 1.97 (m, 1H), 2.05 (m, 2H), 2.21 (m, 3H),
2.49 (s, 3H), 2.51 (m, 1H), 2.92 (m, 3H), 3.07 (m, 1H), 7.06 (m, 2H), 7.23 (d, J = 8.4 Hz, 2H). 13C NMR
(DMSO-d6) 21.3, 24.2, 27.0, 27.4, 28.2, 29.4, 29.9, 32.6, 33.8, 44.5, 126.6, 126.8, 126.9,.128.9, 129.0,
134.2, 137.2, 137.4, 140.7, 143.7, 163.0. [M+1]=377. Anal. Calcd for C25H29NS: C, 79.95; H, 7.78; N,
3.73. Found: C, 80.05 H, 7.63; N, 3.65.
6-Methyl-10-(4-methylphenyl)-2,3,6,7,8,9-hexahydro-1H-cyclopenta[4,5]thieno[2,3-b]quinoline
(14bf)
1
mp 179 °C. H NMR (DMSO-d6) ꢀ 1.36 (d, J = 4.7 Hz, 3H), 1.60 (m, 2H), 1.72 (m, 1H), 1.95 (m, 3H),
13
2.14 (m, 2H), 2.37 (s, 3H), 2.45 (m, 2H), 2.87 (m, 2H), 3.06 (m, 1H), 7.11 (m, 2H), 7.27 (m, 2H). C
NMR (DMSO-d6) 20.4, 21.3, 21.8, 27.0, 27.6, 29.3, 29.9, 31.0, 35.9, 126.5, 127.0, 129.01, 129.05, 129.1,
134.2, 137.1, 137.5, 141.4, 157.0, 169.5. [M+1]=335. Anal. Calcd for C22H23NS: C, 79.23; H, 6.95; N,
4.20. Found: C, 79.17 H, 7.04; N, 4.33.
10-(4-Methylphenyl)-2,3,4,7,8,9-hexahydro-1H-cyclopenta[4,5]thieno[2,3-b]-1,6-naphthyridine
(14bg)
1
mp 258-259 °C. H NMR (DMSO-d6) ꢀ 2.02 (m, 2H), 2.17 (m, 2H), 2.40 (s, 3H) 2.92 (m, 2H), 3.25 (m,
2H), 3.46 (m, 2H), 3.99 (m, 2H), 7.19 (d, J = 7.3 Hz, 2H), 7.35 (d, J = 7.3 Hz, 2H). [M+1]=321. Anal.
Calcd for C20H20N2S: C, 74.96; H, 6.29; N, 8.74. Found: C, 75.15 H, 6.34; N, 8.56.
2-Ethyl-10-(4-methylphenyl)-2,3,4,7,8,9-hexahydro-1H-cyclopenta[4,5]thieno[2,3-b]-1,6-naphthyridi
ne (14bh)
mp 239-240 °C. 1H NMR (DMSO-d6) ꢀ 1.21 (m, 3H), 2.03 (m, 2H), 2.17 (m, 2H), 2.40 (s, 3H), 2.91 (m,
2H), 3.02 (m, 2H), 3.23 (m, 4H), 4.09 (m, 2H), 7.53 (m, 2H), 7.35 (m, 2H), 8.94 (br s, 1H), 11.69 (br s,
1H). [M+1]=350. Anal. Calcd for C22H24N2S: C, 75.82; H, 6.94; N, 8.04. Found: C, 75.87 H, 6.81; N,
7.80.
2-(1-Adamantyl)-4-(4-methylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridine (15be)
mp 195 °C. 1H NMR (DMSO-d6) ꢀ 1.71 (m, 6H), 2.03 (m, 11H), 2.21 (m, 2H), 2.38 (s, 3H) 2.94 (m, 2H),

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7.17 (d, J = 7.3 Hz, 2H), 7.31 (d, J = 7.3 Hz, 2H). [M+1]=401. Anal. Calcd for C27H29NS: C, 81.16; H,
7.32; N, 3.51. Found: C, 80.98 H, 7.51; N, 3.42.
[2-Methyl-4-(4-methylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetic acid
(17ba)
mp 141 °C. 1H NMR (DMSO-d6) ꢀ 1.92 (m, 2H), 2.05 (m, 2H), 2.38 (s, 3H), 2.52 (s, 3H), 2.87 (m, 2H),
3.44 (s, 2H), 7.06 (d, J = 7.0 Hz, 2H), 7.28 (d, J = 7.0 Hz, 2H), 12.30 (br s, 1H). [M+1]=338. Anal. Calcd
for C20H19NO2S: C, 71.19; H, 5.68; N, 4.15. Found: C, 71.28 H, 5.53; N, 4.28.
2,2,2-Trifluoro-1-[4-(4-methylphenyl)-2-(trifluoromethyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-
b]pyridin-3-yl]ethanone (18bc)
1
mp 147 °C. H NMR (DMSO-d6) ꢀ 2.18 (m, 2H), 2.24 (m, 2H), 2.39 (s, 3H), 3.07 (m, 2H), 7.25 (d, J =
13
1
8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H). C NMR (DMSO-d6) ꢀ 21.4, 27.2, 29.5, 30.6, 114.7 (q, JCF =
1
2
292.8 Hz), 118.7, 121.6 (q, JCF = 274.6 Hz), 129.2, 129.6, 129.8, 130.4, 138.0, 140.1, 143.3 (q, JCF =
32.6 Hz), 143.5, 150.8, 166.7, 186.6 (q, 2JCF = 38.9 Hz). 19F NMR (DMSO-d6) ꢀ -76.3, -62.3. [M+1]=430.
Anal. Calcd for C20H13F6NOS: C, 55.95; H, 3.05; N, 3.26. Found: C, 56.16 H, 3.23; N, 3.16.
2-(4-Chlorophenyl)-4-methyl[1]benzofuro[3,2-b]pyridine-3-carbonitrile (19aa)
1
mp 220-221 °C. H NMR (DMSO-d6) ꢀ 2.73 (s, 3H), 7.55 (t, J = 7.3 Hz, 1H), 7.68 (d, J = 8.5 Hz, 2H),
7.78 (t, J = 7.3 Hz, 1H), 7.91 (m, 3H), 8.23 (d, J = 7.3 Hz, 1H). [M+1]=320. Anal. Calcd for
C19H11ClN2O: C, 71.59; H, 3.48; N, 8.79. Found: C, 71.45 H, 3.58; N, 8.65.
Ethyl 2,4-dimethyl[1]benzofuro[3,2-b]pyridine-3-carboxylate (20ab)
mp 167 °C. 1H NMR (DMSO-d6) ꢀ 1.35 (t, J = 7.3 Hz, 3H ), 2.54 (s, 3H), 3.63 (s, 3H), 4.45 (q, J = 7.3
Hz, 2H), 7.49 (t, J = 7.5 Hz, 1H), 7.67 (t, J = 7.5 Hz, 1H), 7.82 (d, J = 7.5 Hz, 1H), 8.21 (d, J = 7.5 Hz,
1H) . [M+1]=270. Anal. Calcd for C16H15NO3: C, 71.36; H, 5.61; N, 5.20. Found: C, 71.25 H, 5.50; N,
5.15.
11-Methyl-1,2,3,4-tetrahydro[1]benzofuro[3,2-b]quinoline (21aa)
mp 284 °C. 1H NMR (DMSO-d6) ꢀ 1.86 (m, 4H), 2.87 (s, 3H), 2.87 (m, 2H), 3.19 (m, 2H), 7.56 (t, 1H , J
= 7.2 Hz ), 7.75 (t, 1H , J = 7.2 Hz ), 7.88 (d, 1H , J = 7.2 Hz ), 8.53 (m, 1H). [M+1]=238. Anal. Calcd for
C16H15NO: C, 80.98; H, 6.37; N, 5.90. Found: C, 81.06 H, 6.52; N, 5.98.
6-Methyl-7,8,9,10,11,12-hexahydro[1]benzofuro[3,2-b]cycloocta[e]pyridine (21ac)
mp 268 °C. 1H NMR (DMSO-d6) ꢀ 1.29 (m, 2H), 1.41 (m, 2H), 1.71 (m, 2H), 1.83 (m, 2H), 2.69 (s, 3H),
3.32 (m, 2H), 3.33 (m, 2H), 7.57 (t, 1H , J = 7.3 Hz ), 7.76 (t, 1H , J = 7.3 Hz ), 7.91 (d, 1H , J = 7.3 Hz ),
8.60 (m, 1H). [M+1]=266. Anal. Calcd for C18H19NO: C, 81.48; H, 7.22; N, 5.28. Found: C, 81.59 H,
7.10; N, 5.35.
6-Methyl-7,8,9,10,11,12,13,14,15,16-decahydro[1]benzofuro[3,2-b]cyclododeca[e]pyridine (21ad)

HETEROCYCLES, Vol. 71, No. 11, 2007
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1
mp 265 °C. H NMR (DMSO-d6) ꢀ 1.7 (m, 6H), 1.53 (m, 8H), 1.84 (m, 2H), 2.79 (s, 3H), 2.96 (m, 2H),
2.97 (m, 2H), 7.45 (t, 1H , J = 7.5 Hz ), 7.65 (t, 1H , J = 7.5 Hz ), 7.79 (d, 1H , J = 7.5 Hz ), 8.50 ( br s,
1H). [M+1]=322. Anal. Calcd for C22H27NO: C, 82.20; H, 8.47; N, 4.36. Found: C, 82.06 H, 8.31; N,
4.24.
1-[4-(2-Furyl)-2-methyl[1]benzofuro[3,2-b]pyridin-3-yl]ethanone (22bc)
mp 245 °C. 1H NMR (DMSO-d6) ꢀ 2.51 (s, 3H), 2.59 (s, 3H), 6.87 (s, 1H), 7.52 (t, J = 8.2 Hz, 1H ), 7.58
(s, 1H), 7.70 (t, J = 7.4 Hz, 1H), 7.87 (d, J = 8.2 Hz, 1H), 8.04 (s, 1H), 8.26 (d, J = 7.4 Hz, 1H).
[M+1]=292. Anal. Calcd for C18H13NO3: C, 74.22; H, 4.50; N, 4.81. Found: C, 74.11 H, 4.45; N, 4.93.
11-(2-Furyl)-3,3-dimethyl-3,4-dihydro[1]benzofuro[3,2-b]quinolin-1(2H)-one (22bd)
mp 220 °C. 1H NMR (DMSO-d6) ꢀ 1.07 (s, 6H), 2.19 (s, 2H), 2.56 (s, 2H), 6.86 (m, 1H), 7.42 (t, J = 7.8
Hz, 1H),7.63 (t, J = 7.8 Hz, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.91 (m, 1H), 8.17 (m,
1H) . [M+1]=332. Anal. Calcd for C21H17NO3: C, 76.12; H, 5.17; N, 4.23. Found: C, 76.28 H, 5.04; N,
4.38.
11-(2-Furyl)-1,2,3,4-tetrahydro[1]benzofuro[3,2-b]quinoline (23aa)
mp 266 °C. 1H NMR (DMSO-d6) ꢀ 1.84 (m, 4H), 3.08 (m, 2H), 3.17(m, 2H), 6.87 (m, 1H), 7.49 (m, 2H),
7.68 (m, 1H), 7.78 (m, 1H), 8.13 (m, 1H), 8.45 (m, 1H), 8.96 ( br s, 1H). [M+1]=290. Anal. Calcd for
C19H15NO2: C, 78.87; H, 5.23; N, 4.84. Found: C, 78.77 H, 5.15; N, 4.94.
6-(2-Furyl)-7,8,9,10,11,12,13,14,15,16-decahydro[1]benzofuro[3,2-b]cyclododeca[e]pyridine (23ad)
mp 160 °C. 1H NMR (DMSO-d6) ꢀ 1.35 (m, 6H), 1.50 (m, 8H), 1.86 (m, 2H), 2.94 (m, 2H), 3.00 (m, 2H),
6.78 (m, 1H), 7.19 (d, J = 3.0 Hz, 1H), 7.46 (t, J = 7.3 Hz, 1H), 7.61 (t, J = 7.3 Hz, 1H), 7.76 (d, J = 7.3
Hz, 1H), 8.00 (s, 1H), 8.11 (d, J = 7.3 Hz, 1H). [M+1]=375. Anal. Calcd for C25H27NO2: C, 80.40; H,
7.29; N, 3.75. Found: C, 80.52 H, 7.18; N, 3.62.
11-(2-Furyl)-4-methyl-1,2,3,4-tetrahydro[1]benzofuro[3,2-b]quinoline (23af)
1
mp 252 °C. H NMR (DMSO-d6) ꢀ 1.50 (d, J = 6.5 Hz, 3H), 1.71 (m, 1H), 1.87 (m, 2H), 2.02 (m, 1H),
3.04 (m, 1H), 3.16 (m, 1H), 3.47 (m, 1H), 6.87 (s, 1H), 7.51 (s, 2H), 7.70 (t, J = 7.2 Hz, 1H), 7.81 (d, J =
7.2 Hz, 1H), 8.13 (s, 1H), 8.59 (s, 1H). [M+1]=304. Anal. Calcd for C20H17NO2: C, 79.19; H, 5.65; N,
4.62. Found: C, 79.01 H, 5.56; N, 4.74.
2-(4-Chlorophenyl)-5-oxo-5H-chromeno[2,3-b]pyridine-3-carbonitrile (24aa)
mp 266 °C. 1H NMR (DMSO-d6) ꢀ 7.24 (m, 3H), 7.55 (d, J = 7.2 Hz, 1H), 7.65 (t, J = 7.2 Hz, 1H), 7.83
(d, J = 6.0 Hz, 2H), 8.33 (d, J = 7.2 Hz, 1H), 9.05 (s, 1H). [M+1]=334. Anal. Calcd for C19H9ClN2O2: C,
68.58; H, 2.73; N, 8.42. Found: C, 68.43 H, 2.80; N, 8.39.
5-Oxo-2-thien-2-yl-5H-chromeno[2,3-b]pyridine-3-carbonitrile (24ac)

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mp 260 °C. 1H NMR (DMSO-d6) ꢀ 7.33 (m, 1H), 7.53 (t, J = 7.3 Hz, 1H), 7.72 (d, J = 7.3 Hz, 1H), 7.91 (t,
J = 7.3 Hz, 1H) 8.00 (m, 1H), 8.15 (d, J = 7.3 Hz, 1H), 8.34 (m, 1H), 8.94 (s, 1H). [M+1]=305. Anal.
Calcd for C17H8N2O2S: C, 67.09; H, 2.65; N, 9.20. Found: C, 67.21 H, 2.79; N, 9.15.
2-(1-Benzofuran-2-yl)-5-oxo-5H-chromeno[2,3-b]pyridine-3-carbonitrile (24ad)
1
mp 295 °C. H NMR (DMSO-d6) ꢀ 7.38 (d, J = 7.2 Hz, 1H), 7.54 (m, 2H), 7.72 (m, 2H), 7.86 (m, 1H),
7.93 (m, 1H), 8.05 (m, 1H), 8.19 (d, J = 7.2 Hz, 1H), 9.00 (s, 1H). [M+1]=339. Anal. Calcd for
C21H10N2O3: C, 74.55; H, 2.98; N, 8.28. Found: C, 74.43 H, 2.77; N, 8.17.
7-(4-Chlorophenyl)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-
carbonitrile (25aa)
1
mp 222 °C. H NMR (DMSO-d6) ꢀ 0.90 (d, J = 9.6 Hz, 6H), 2.25 (m, 1H), 3.32 (s, 3H), 4.11 (m, 2H),
7.71 (m, 2H), 7.98 (d, J = 6.9 Hz, 2H), 8.85 (s, 1H). [M+1]=370. Anal. Calcd for C19H17ClN4O2: C, 61.88;
H, 4.65; N, 15.19. Found: C, 61.76 H, 4.73; N, 15.26.
6-(1,3-Benzothiazol-2-yl)-1-isobutyl-3-methyl-7-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione
(25ab)
mp 220 °C. 1H NMR (DMSO-d6) ꢀ 0.92 (d, J = 9.6 Hz, 6H), 2.07 (m, 1H), 3.35 (s, 3H), 4.13 (d, J = 10.0
Hz, 2H), 7.52 (m, 7H), 7.99 (m, 2H), 8.83 (s, 1H). [M+1]=444. Anal. Calcd for C25H22N4O2S: C, 67.85; H,
5.01; N, 12.66. Found: C, 67.73 H, 4.92; N, 12.78.
1-iso-Butyl-3-methyl-2,4-dioxo-7-thien-2-yl-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbo-
nitrile (25ac)
1
mp 200 °C. H NMR (DMSO-d6) ꢀ 0.95 (d, J= 6.3 Hz, 6H), 2.15 (m, 1H), 3.31 (s, 3H), 4.07 (d, J = 7.2
Hz, 2H), 7.35 (t, J = 4.1 Hz, 1H), 8.29 (d, J = 4.1 Hz, 1H ), 8.04 (d, J = 4.1 Hz, 1H), 8.70 (s, 1H).
[M+1]=341. Anal. Calcd for C17H16N4O2S: C, 59.98; H, 4.74; N, 16.46. Found: C, 59.86 H, 4.84; N,
16.53.
ACKNOWLEDGEMENTS
The authors acknowledge Polovinko V. V. (Enamine LTD) for spectral measurements and Dontsova D. A.
for discussion of the paper.
REFERENCES
1. (a) P. Friedländer, Ber., 1882, 15, 2572. (b) C. C. Cheng and S.-J. Yan, Org. React., 1982, 28, 37. (c)
S. Gladiali, G. Chelucci, M. S. Mudadu, M.-A. Gastaut, and R. P. Thummel, J. Org. Chem., 2001,
66, 400.
2. S. V. Ryabukhin, D. M. Volochnyuk, A. S. Plaskon’, V. S. Naumchik, and A. A. Tolmachev,
Synthesis, 2007, 1214.

HETEROCYCLES, Vol. 71, No. 11, 2007
2411
3. For using Me3SiCl as condensation agent see: (a) S. V. Ryabukhin, A. S. Plaskon, A. V.
Tverdokhlebov, and A. A. Tolmachev, Synth. Commun., 2004, 34, 1483. (b) S. V. Ryabukhin, A. S.
Plaskon, D. M. Volochnyuk, and A. A. Tolmachev, Synlett, 2004, 2287. (c) H. Heaney, G.
Papageorgeogu, and R. F. Wilkins, Tetrahedron, 1997, 53, 2941. For using Me3SiI as condensation
agent see: (d) G. Sabitha, G. S. K. K. Reddy, K. B. Reddy, and J. S. Yadav, Synthesis, 2004, 263. (e)
G. Sabitha, G. S. K. K. Reddy, C. S. Reddy, and J. S. Yadav, Synlett, 2003, 858. (f) G. Sabitha, G. S. K.
K. Reddy, C. S. Reddy, and J. S. Yadav, Tetrahedron Lett., 2003, 44, 4129. (g) S. V. Ryabukhin,
A. S. Plaskon, D. M. Volochnyuk, and A. A. Tolmachev, Synthesis, 2006, 3715. (h) S. V. Ryabukhin,
A. S. Plaskon, E. N. Ostapchuk, D. M. Volochnyuk, and A. A. Tolmachev, Synthesis, 2007, 417.
4. N. Cho, M. Harada, T. Imaeda, T. Imada, H. Matsumoto, Y. Hayase, S. Sasaki, S. Furuya, N. Suzuki,
S. Okubo, K. Ogi, S. Endo, H. Onda, and M. Fujino, J. Med. Chem., 1998, 41, 4190.
5. E. G. Paronikyan, A. Kh. Oganisyan, A. S. Noravyan, R. G. Paronikyan, and I. A. Dzhagatspanyan,
Khim. Farm. Zh., RU, 2002, 36, 17.
6. (a) Y. Isoda, H. Fujiwara, and T. Hosogami, Chem. Abstr., 1991, 115, 183264z. (b) A. Nohara, T.
Ishiguro, K. Ukawa, H. Sugihara, Y. Maki, and Y. Sanno, J. Med. Chem., 1985, 28, 559. (c) A.
Nohara, H. Kuriki, T. Sajio, H. Sugihara, M. Kanno, and Y. Sanno, J. Med. Chem., 1977, 20, 141.
(d) A. Nohara, H. Sugihara, and K. Ukawa, Chem. Abstr., 1981, 94, 192310m. (e) K. Ukawa, T.
Ishiguro, H. Kuriki, and A. Nohara, Chem. Pharm. Bull., 1985, 33, 4432. (f) G. Singh, R. Singh, N.
K. Girdhar, and M. P. S. Ishar, Tetrahedron, 2002, 58, 2471. (g) P. Langer and B. Apple,
Tetrahedron Lett., 2003, 44, 5133.
7. (a) N. Suzuki, Chem. Pharm. Bull., 1980, 28, 761. (b) E. M. Grivsky, S. Lee, C. W. Sigel, D. S.
Duch, and C. A. Nichol, J. Med. Chem., 1980, 23, 327. (c) E. Kretzchmar, Farmazie, 1980, 35, 253.
(d) R. K. Robins and G. H. Hitchings, J. Am. Chem. Soc., 1958, 80, 3449. (e) D. A. Vanden Berghe
and A. J. Vlietinck, J. Heterocycl. Chem., 1988, 25, 217. (f) W. I. Irwin and D. G. Webberley, Adv.
Heterocycl. Chem., 1969, 10, 146. (g) S. Minamis, Chem. Pharm. Bull., 1971, 19, 1426. (h) A. D.
Broom, J. L. Shim, and G. L. Anderson, J. Org. Chem., 1976, 41, 1095.
8. S. Schefer, K. Gewald, and H. Hartman, J. Prakt. Chem., 1974, 316, 169.
9. A-R. H. Abdel-Rahman, M. M. Girges, A-A. S. El-Ahl, and L. M. Sallam, Heteroatom Chem., 2006,
17, 2.
10. (a) P. Matyus, P. Sohar, and H. Wamhoff, Liebigs Ann. Chem., 1984, 10 1653. (b) A. Sivaprasad, J.
S. Sandhu, and J. N. Baruah, Indian J. Chem. Sect. B, 1985, 24, 305.