Synthesis and alkylation of 4-aryl-5-oxo-1h-2,3,4,5-tetrahydroindeno[1,2-b] pyridines

Article abstract of DOI:10.1007/s10593-010-0595-x

Reduction of 5-oxo-4-phenyl-1H-4,5-dihydroindeno[1,2-b]pyridines with triethylsilane in trifluoro-acetic acid gave the corresponding 1,2,3,4-tetrahydroindeno[1,2-b]pyridines predominatly with the trans-configured substituents at atoms C(2), C(3), and C(4)

Full text of DOI:10.1007/s10593-010-0595-x

Chemistry of Heterocyclic Compounds, Vol. 46, No. 7, 2010
SYNTHESIS AND ALKYLATION OF 4-ARYL-5-OXO-
1H-2,3,4,5-TETRAHYDROINDENO[1,2-b]PYRIDINES*
S. Stupnikova1, E. Petushkova1, D. Tanajev1, V. Lusis1**, and D. Muceniece1
Reduction of 5-oxo-4-phenyl-1H-4,5-dihydroindeno[1,2-b]pyridines with triethylsilane in trifluoro-
acetic acid gave the corresponding 1,2,3,4-tetrahydroindeno[1,2-b]pyridines predominatly with the
trans-configured substituents at atoms C(2), C(3), and C(4). Alkylation of the anionic form of the
tetrahydroindenopyridines gives the N- and C(4a)-alkyl derivatives.
Keywords: 5-oxo-4,5-dihydro-1H- and 2,3,4,5-tetrahydro-1H-indeno[1,2-b]pyridines, N- and C(4a)-
alkylation of 5-oxo-2,3,4,5-tetrahydro-1H-indeno[1,2-b]pyridine, triethylsilane reduction.
Depending on the reaction conditions, the reduction of Hantzsch type 1,4-dihydropyridine esters using
triethylsilane in trifluoroacetic acid medium gives the trans isomers of the corresponding 1,2,3,4-tetra-
hydropyridines or piperidines [1]. Only certain representatives of the 1,2,3,4-tetrahydroindeno[1,2-b]pyridine
series are known and they are prepared by a complex route including photosynthesis, even though they are
beginning to attract interest as potential antiparasitic agents [2]. We have found that reduction of the 4-aryl-
5-oxo-4,5-dihydro-1H-indeno[1,2-b]pyridines 1a-h to the corresponding tetrahydroindenopyridines can also be
carried out using Et3SiH in CF3COOH. Under these conditions selective reduction of the C(2)=C(3) bond occurs
and the main products are the trans isomers of the 1,2,3,4-tetrahydroindenopyridines 2a-h. Only in the single
case of the reduction of compound 1b was it possible to separate the reduction product of the C(4a)=C(9b) bond
(compound 5) in low yield (5%).
As expected, the trans isomer was formed as a result of the reduction since protonation of the enamine
fragment as also the addition of hydride ion generated by Et3SiH can occur at both sides of the pyridine ring
plane and a trans orientation of all of the bulky substituents at atoms C(2), C(3), and C(4) is energetically more
favored. The cis isomers 3a-h are formed as minor reduction products. The remaining two possible
diastereomers with reduced bond C(2)=C(3) were not observed.
Protonation of the enamine fragment at atom C(3) leads to formation of a cyclic immonium ion. Thanks
to the presence of the C=C and C=N double bonds the conformation of the pyridine ring is comparatively
planar, the ring atoms forming two planar fragments C(3)–C(2)=N–C(9b) and C(4)–C(4a)=C(9b)–N, the
terminal atoms of which (C(3) and C(4)) are shifted to opposite sides of the mean ring plane by twisting along
the C(9b)–N single bond. Such a ring conformation markedly decreases the CH3–C(2)–C(3)–R(H) dihedral
angle and makes the conformation with an axial arrangement of the substituent at C(3) more favored due to a
____
* Dedicated to the memory of Reva S. Sagitullin.
** To whom correspondence should be addressed, e-mail: lusis@osi.lv.
1 Latvian Institute of Organic Synthesis, Riga LV-1006, Latvia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1062-1072, July, 2010. Original
article submitted June 17, 2010.
0009-3122/10/4607-0859©2010 Springer Science+Business Media, Inc.
859

decreased Me/3-R gauche interaction. More preferred are conformation B with protonation on the side of the
4-phenyl substituent and conformation C with protonation on the side of the opposite substituent at position 4.
Conformation B ensures free approach of the hydride-bearing agent to atom C(2) while in conformation C the
approach is hindered by the axially placed 4-Ph group. These steric factors limit the ratio of diastereomers
trans >> cis and the insignificant fraction of conformations A and D results in the absence of other
stereoisomers.
R1
O
Ph
R1
O
Ph
R2
R2
R3
R
R
Et3SiH
+
3
R
CF3COOH
N
H
Me
N
H
Me
R4
O
R4
1 a–h
2 a–h
R1
R1
O
Ph
Ph
Ph
O
H
H
R2
R2
R3
R
COOEt
Me
R
+
+
+
R3
N
N
N
H
Me
Me
H
R4
R4
3 a–h
5
4a–c,e
14 ac R2 = R3 = R4 = H, a R = COMe, R1 = H; b R = CO2Et, R1 = H; c R = CO2Pr-i;
R1 = H; 13 d R = CO2Me, R1 = Me, R2 = R3 = R4 = H; 14 e R = CO2Et, R1 = NH2,
R2 = R3 = R4 = H; 13 f R = CO2Et, R1 =R2 = R3 = H, R4 = NO2; g R = CO2Me, R1 =R2 =H,
R3 = OMe, R4 = OEt; h R = CO2Et, R1 = R4 = H, R2 = R3 = Cl
It was interesting to note that the substituent in the indene part of the molecule affects the trans/cis
isomers ratio. On comparing the yields of the trans and cis isomers of the compounds 2b,f the trans/cis ratio are
72:12 and 86:4. Reduction of the dihydroindenopyridines with Et3SiH/CF3COOH is accompanied by partial
oxidation of the dihydropyridine derivative to a pyridine, even though the reduction is carried out under an
argon atmosphere. The tetrahydroindenopyridines are not oxidized by atmospheric oxygen to indenopyridines
but undergo a rearrangement which will be reported separately. Hence the source of the oxidized form is the
starting dihydropyridine and the oxidant may be the atmospheric oxygen in the reaction medium. We were
unable to avoid this side reaction by either simple passage of argon through the reaction vessel or by repeated
freeze/evacuation/argon fill. It can be proposed that, along with the Et3SiH, the hydride ion donor may be the
dihydropyridine when converted to the indenopyridine. This hypothesis is indirectly confirmed by the absence
of the oxidized form in the case of reduction of indenopyridines having acceptor substituents in the indane ring
(1f,h) since such a substitution must lower the reductive ability of the dihydropyridine.
H
H
H
Ph
Me
Me
N
N
R
H
R
Ph
B
A
H
R
R
Ph
Me
Me
N
N
H
H
H
Ph
C
D
860

The 3-acetyl derivative of dihydroindenopyridine 1a undergoes reduction in the same way as the
dihydroindenopyridine-3-carboxylates but we were unable to reduce the corresponding 3-cyano derivative with
Et3SiH in trifluoroacetic acid.
The structures of the diastereomers 2a-h and 3a-h and the reduction product 5 were proved using NMR
1
spectroscopy and X-ray structural analysis (compounds 2b, 3b and 5, see Figs. 1-3 respectively). Hence the H
NMR spectra of the trans isomers 2a-h show a large proton spin-spin coupling constants for the protons of the
pyridine ring with J2,3  J3,4 = 9.4-10.0 Hz and this agrees well with an antiperiplanar arrangement of H(2),
Fig. 1. Structure of ethyl (2R*,3S*,4R*)-2-methyl-5-oxo-4-phenyl-2,3,4,5-tetra-
hydro-1H-indeno[1,2-b]pyridine-3-carboxylate (2b).
Fig. 2. Structure of ethyl (2R*,3R*,4R*)-2-methyl-5-oxo-4-phenyl-2,3,4,5-tetra-
hydro-1H-indeno[1,2-b]pyridine-3-carboxylate (3b).
861

H(3), and H(4) protons. Hence all of the bulky groups in the tetrahydropyridine ring occupy equatorial positions.
The spin-spin couplings constants of the isomers 3a-h occur in the range J2,3 = 3.3-3.6 and J3,4 = 6.3-6.7 Hz,
corresponding to a cis arragement of the H(2), H(3), and H(4) protons. An increased value for the
J
3,4 constant points to a decrease in the H–C(3)–C(4)–H dihedral angle due to flattening of the ring
conformation.
Fig. 3. Structure of ethyl (4R*,4aR*,9bS*)-2-methyl-5-oxo-4-phenyl-4,4a,5,9b-tetra-
hydro-1H-indeno[1,2-b]pyridine-3-carboxylate (5).
Alkylation of the tetrahydroindenopyridine 2b using iodomethane, allyl bromide, or ethyl bromoacetate
was carried out in DMF in the presence of sodium hydride. The action of NaH on the tetrahydroindenopyridine
2b forms an anion, the ambidentate properties of whose enamino ketone fragment are similar to those of
dihydroindenopyridine anions [3]. Reaction of the tetrahydropyridine anion with an alkylating agent gives a
mixture of the N- and C-alkylated products 7a,b and 8a-c. Similar methylation of the diastereomer 3b gave the
N-isomer 10 as the main product.
O
Ph
O
Ph
O
Ph
R
COOEt
Me
COOEt
Me
COOEt
Me
RHal
+
N
H
N
R
N
2b
7a,b
8a–c
7 a R = Me, b R = CH2CO2Et; 8 a R = Me, b R = CH2CO2Et, c R = CH2CH=CH2
The spatial positioning of the substituent in the alkylation product 8c was determined from the results of
a 2D NOESY correlation spectroscopic experiment. This spectrum clearly showed an interaction between the
4a-allyl substituent and the H(4) proton and the complete absence of corresponding cross peak with the phenyl
group. Hence the substituent R on atom C(4a) had added to the ring plane opposite to the 4-Ph substituent. In the
spectra of compounds 7a,b the spin-spin couplings J2,3  J3,4 = 2.3-3.0 Hz are nontypical for trans-orientated
substituents at atoms C(2), C(3), and C(4).
862

Selective reduction of the C(2)=C(3) bond occurs upon reduction of 1-methyl-5-oxo-4,5-dihydro-
indeno[1,2-b]pyridine 9 and the main product is the trans isomer of 1,2,3,4-tetrahydroindenopyridine 7a, the
fraction of the cis isomer 10 being markedly greater when compared with the N-unsubstituted analogs.
O
Ph
O
Ph
O
Ph
COOEt
Me
COOEt
Me
COOEt
Me
Et3SiH
+
CF3COOH
N
N
N
Me
Me
9
Me
7a
10
TABLE 1. Physicochemical Characteristics of the Compounds Prepared
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, оС
Yield, %
С
Н
N
2b
2c
2d
2e
2f
С22Н21NO3
75.96
76.06
6.08
6.09
4.04
4.03
227-227.5
230
23
67
80
50
86
83
24
12
6
С23Н23NO3
С22Н21NO3
С22Н22N2O3
С22Н20N2O5
С24Н25NO5
С21Н19NO2
С22Н21NO3
С23Н23NO3
С22Н20N2O5
C23H19NO3
C22H22N2O3
С22Н21NO3
С23Н23NO3
C26H27NO5
C23H23NO3
C26H27NO5
C25H25NO3
С23Н23NO3
76.18
76.43
6.23
6.41
3.81
3.88
75.62
76.06
5.98
6.09
3.93
4.03
345-347
193-195
148
72.51
72.91
5.59
6.12
7.39
7.73
67.32
67.34
5.07
5.14
7.09
7.14
2g
3a
3b
3c
3f
70.44
70.75
6.12
6.18
3.32
3.44
116-118
158-159
251-252
212
79.70
79.47
6.15
6.03
4.20
4.41
75.80
76.06
6.03
6.09
3.98
4.03
76.21
76.43
6.26
6.41
3.67
3.88
67.09
67.34
5.32
5.14
6.92
7.14
148
4
4c
4e
5
76.99
77.29
5.30
5.36
3.75
3.92
124
17
11
5
73.58
73.73
4.84
5.06
7.61
7.82
262-265
201
75.82
76.06
6.02
6.09
3.98
4.03
7a
7b
8a
8b
8c
10
76.42
76.43
6.45
6.41
3.77
3.88
168-170
148-150
140-141
140-141
77-79
35*,
65*2
71.84
72.04
6.27
6.28
3.09
3.23
14
27
61
54
76.29
76.43
6.42
6.41
3.81
3.88
71.86
72.04
6.24
6.28
3.10
3.23
77.41
77.49
6.49
6.50
3.58
3.60
76.01
76.43
6.41
6.41
3.79
3.88
149-150
48*,
32*2
_______
* Yield in the alkylation reaction.
*2 Yield in the reduction reaction.
863

TABLE 2. 1H NMR Spectra of the Compounds Prepared
Com-
pound
Chemical shifts, δ, ppm (J, Hz)*
2
1
2a
1.30 (3H, d, J = 6.5, 2-CH3); 1.72 (3H, s, COCH3); 2.78 (1H, dd, J = 9.5, J = 9.4, H-3);
3.12 (1H, dq, J = 9.4, J = 6.5, H-2); 3.91 (1H, d, J = 9.5, H-4); 5.27 (1H, br. s, NH);
6.87-7.82 (9H, m, Ar)
2b
2c
1.01 (3H, t, J = 7.0, OCH2CH3); 1.33 (3H, d, J = 6.4, 2-CH3); 2.53 (1H, t, J = 9.7, H-3);
3.80 (1H, m, H-2); 3.97 (2H, q, J = 7.0, OCH2CH3), 4.01(1H, d, J = 9.7, H-4);
5.31 (1H, br. s, NH); 7.00-7.38 (9H, m, Ar)
0.86 (3H, d, J = 6.3, CH(CH3)2); 1.15 (3H, d, J = 6.3, CH(CH3)2);
1.35 (3H, d, J = 6.4, 2-CH3); 2.48 (1H, dd, J = 9.8, J = 9.7, H-3); 3.90 (1H, m, H-2);
4.01 (1H, d, J = 9.8, H-4); 4.89 (1H, sept, J = 6.3, CH(CH3)2); 5.47 (1H, br. s, NH);
7.02-7.35 (9H, m, Ar)
2d
1.18 (3H, d, J = 6.4, 2-CH3); 2.33 (3H, s, 6-CH3); 2.43-2.51 (1H, m, H-3);
3.43 (3H, s, ОСH3); 3.69-3.78 (1H, m, H-2); 3.83 (1Н, d, J = 9.4, Н-4);
6.98-7.07 (3H, m, Ar); 7.10-7.24 (4H, m, Ar); 7.34 (1H, d, J = 7.0, Ar);
8.60 (1H, br. s, NH)
2e
2f
1.00 (3H, t, J = 7.1, OCH2CH3); 1.32 (3H, d, J = 6.5, 2-CH3);
2.50 (1H, dd, J = 9.9, J = 9.8, H-3); 3.76-4.05 (3H, m, OCH2CH3, Н-2); 4.25 (1H, m, H-4);
4.98 (2H, br. s, NH2); 5.05 (1H, br. s, NH); 6.50 (2H, m, Н-7,8); 6.90-7.53 (6H, m, Ar)
1.02 (3H, t, J = 7.1, OCH2CH3); 1.40 (3H, d, J = 6.5, 2-CH3);
2.55 (1H, t, J= 10.0, J = 9.8, H-3); 3.85-4.08 (3H, m, OCH2CH3, Н-2);
4.10 (1H, d, J = 10.0, H-4); 7.13-7.66 (8H, m, Аr)
2g
1.30 (3H, d, J = 6.4, 2-CH3); 1.41 (3H, t, J = 7.0, СН2СН3); 2.52 (1H, t, J = 9.6, Н-3);
3.52 (3H, s, COOCH3); 3.81-3.95 (4H, m, H-2, OCH3); 4.02 (1Н, d, J = 9.6, Н-4);
4.14-4.41 (2H, m, CH2CH3); 6.20 (1H, br. s, NH); 6.65 (1H, d, J = 7.7, Н-7);
7.04 (1H, d, J = 7.7, Н-6); 7.09-7.37 (5H, m, Ar)
2h,3h 0.83 (0.5H, t, J = 7.1, cis-OCH2CH3); 1.01 (2.5H, t, J = 7.1, trans-OCH2CH3);
1.31 (2.5H, d, J = 6.5, trans-2-CH3); 1.40 (0.5H, d, J = 6.9, cis-2-CH3);
2.51 (0.83H, t, J = 9.6, trans-H-3); 3.06 (0.17H, m, cis-H-3);
3.67-4.08 (3.83H, m, trans-H-2, cis-Н-2, trans-H-4, cis-OCH2CH3, trans-OCH2CH3);
4.22 (0.17H, d, J = 6.6, cis-H-4); 5.47 (0.17H, br. s, NH); 5.52 (0.83H, br. s, NH);
7.08-7.38 (7H, m, Н-6,9, Ar)
3a
3b
1.37 (3H, d, J = 6.5, 2-CH3); 1.91 (3H, s, COCH3); 3.30 (1H, m, H-3); 3.94 (1H, m, H-2);
4.28 (1H, d, J = 6.5, H-4); 5.23 (1H, br. s, NH); 7.047.67 (9H, m, Ar)
0.85 (3H, t, J = 7.0, OCH2CH3); 1.41 (3H, d, J = 6.8, 2-CH3);
3.08 (1H, dd, J = 6.6, J = 3.5, H-3); 3.74 (2H, m, OCH2CH3); 3.98 (1H, m, H-2);
4.26 (1H, d, J = 6.6, H-4); 5.22 (1H, br. s, NH); 7.02-7.42 (9H, m, Ar)
3c
3d
3e
0.65 (3H, d, J = 6.3, CH(CH3)2); 1.05 (3H, d, J = 6.3, CH(CH3)2);
1.40 (3H, d, J = 6.9, 2-CH3); 3.04 (1H, dd, J = 6.6, J = 3.6, H-3);
3.96 (1H, qd, J = 6.9, J = 3.6, H-2); 4.23 (1H, d, J = 6.6, H-4);
4.62 (1H, sept, J = 6.3, CH(CH3)2); 5.27 (1H, br. s, NH); 7.02-7.42 (9H, m, Ar)
1.21 (3H, d, J = 6.8, 2-CH3); 2.37 (3H, s, 6-CH3); 3.03 (1H, dd, J = 6.4, J = 3.5, H-3);
3.15 (3H, s, ОСH3); 3.86-3.94 (1H, m, H-2); 4.12 (1Н, d, J = 6.4, Н-4);
6.99-7.07 (3H, m, Ar); 7.08-7.23 (4H, m, Ar); 7.31 (1H, d, J = 7.0, Ar);
8.27 (1H, br. s, NH)
0.73 (3H, t, J = 7.0, OCH2CH3); 1.20 (3H, d, J = 6.8, 2-CH3);
2.97 (1H, dd, J = 6.3, J = 3.3, H-3); 3.52-3.69 (2H, m, OCH2CH3); 3.79-3.90 (1Н, m, Н-2);
4.09 (1H, d, J = 6.3, H-4); 5.75 (2H, br. s, NH2); 6.55 (1H, d, J = 8.2, Ar);
6.75 (1H, d, J = 6.8, Ar); 6.93-7.24 (6H, m, Ar); 8.03 (1H, br. s, NH)
3f
0.86 (3H, t, J = 7.1, OCH2CH3); 1.45 (3H, d, J = 6.9, 2-CH3);
3.10 (1H, dd, J = 6.7, J = 3.6, H-3); 3.76 (2H, m, OCH2CH3); 4.00 (1Н, m, Н-2);
4.28 (1H, d, J = 6.7, H-4); 7.08-8.03 (9H, m, NH, Аr)
3g
1.33 (3H, d, J = 6.8, 2-CH3); 1.39 (3H, t, J = 7.0, СН2СН3); 3.03-3.08 (1H, m, Н-3);
3.26 (3H, s, COOCH3); 3.84 (3H, s, OCH3); 3.90-3.96 (1Н, m, Н-2);
4.16-4.33 (3Н, m, CH2CH3, Н-4); 6.23 (1H, br. s, NH); 6.64 (1H, d, J = 7.6, Н-7);
7.05 (1H, d, J = 7.6, Н-6); 7.10-7.26 (5H, m, Ar)
4c
4e
0.97 (3H, d, J = 6.3, CH(CH3)2); 2.68 (3H, s, 2-CH3); 4.93 (1H, sept, J = 6.3, CH(CH3)2);
7.32-7.94 (9H, m, Ar)
0.93 (3H, t, J = 7.1, CH2CH3); 2.68 (3H, s, 2-CH3); 4.02 (2H, q, J = 7.1, CH2CH3);
5.50 (2H, br. s, NH2); 6.62 (1Н, dd, J = 6.0, J = 2.4, Н-7); 7.19-7.48 (7H, m, Ar)
864

TABLE 2 (continued)
2
1
5
1.12 (3H, t, J = 7.1, CH2CH3); 2.55 (3H, s, 2-CH3); 3.32 (1Н, t, J = 7.4, J = 7.1, Н-4а);
3.98 (2H, m, CH2CH3); 4.65 (1H, d, J = 7.4, Н-4); 4.94-5.06 (2Н, m, NH, H-9b);
6.73-6.78 (5Н, m, Ar); 7.10-7.17 (2H, m, Н-6,8); 7.46-7.51 (2Н, m, Н-7,9)
7a
7b
0.90 (3H, d, J = 7.1, 2-CH3); 1.22 (3H, t, J = 7.1, OCH2CH3); 1.14 (1H, t, J = 2.3, H-3);
3.60 (3Н, s, N-CH3); 3.91 (1H, m, H-2); 4.12 (1H, q, J = 7.1, OCH2CH3);
4.14 (1H, q, J = 7.1, OCH2CH3); 4.57 (1H, m, H-4); 7.10-7.50 (9H, m, Ar)
0.98 (3H, d, J = 7.1, 2-CH3); 1.21 (3H, t, J = 7.1, OCH2CH3);
1.29 (3H, t, J = 7.1, OCH2CH3); 3.11 (1H, t, J = 3.0, H-3);
3.98 (1H, qd, J = 7.1, J = 3.0, H-2); 4.13 (2H, q, J = 7.1, OCH2CH3);
4.27 (1H, q, J = 7.1, OCH2CH3); 4.28 (1H, q, J = 7.1, OCH2CH3);
4.33 (1H, d, J = 18.5, СH2СО); 4.54 (1Н, d, J = 3.0, H-4); 4.76 (1H, d, J = 18.5, СH2СО);
7.05 (1H, m, Ar); 7.14-7.35 (7H, m, Ar); 7.45 (1H, m, Ar)
8a
8b
1.26 (3H, t, J = 7.0, OCH2CH3) ; 1.49 (3H, s, 4a-CH3); 1.64 (3H, d, J = 6.6, 2-CH3);
2.64 (1H, dd, J = 9.9, J = 5.1, H-3); 3.64 (1H, d, J = 5.1, H-4);
4.05-4.29 (1H, m, H-2) and (2H, q, J = 7.0, OCH2CH3); 6.86 (2H, m, Ar);
7.05 (3H, m, Ar); 7.49-7.78 (3H, m, H-7,8,9); 8.11 (1H, m, H-6)
0.87 (3H, t, J = 7.1, OCH2CH3); 1.28 (3H, t, J = 7.1, OCH2CH3);
1.68 (3H, d, J = 7.1, 2-CH3); 2.77 (1H, dd, J = 10.0, J = 4.0, H-3);
3.21 (1H, d, J = 16.0, СН2СО); 3.42 (1H, d, J = 16.0, СН2СО); 3.64 (1Н, d, J = 4.0, H-4);
3.79 (2H, q, J = 7.1, OCH2CH3); 4.18 (1Н, qd, J = 10.0, J = 6.5, H-2);
4.23 (2H, q, J = 7.1, OCH2CH3); 6.85 (2H, m, Ar); 6.99 (3H, m, Ar); 7.48 (2H, m, Ar);
7.67 (1H, ddd, J = 7.6, J = 6.0, J = 2.4, H-8);
8.07 (1H, ddd, J = 7.6, J = 6.0, J = 2.4, H-7)
8c
1.25 (3H, t, J = 7.1, OCH2CH3) ; 1.63 (3H, d, J = 6.6, 2-CH3);
2.66 (1H, dd, J = 9.9, J = 5.2, H-3); 2.74 (1Н, dd, J = 14.0, J = 7.0, СН2СН=);
2.90 (1Н, dd, J = 14.0, J = 7.0, СН2СН=); 3.63 (1H, d, J = 5.2, H-4);
4.17 (1H, qd, J = 9.9, J = 6.6, H-2); 4.20 (2H, q, J = 7.1, OCH2CH3);
4.84 (1Н, dd, J = 9.9, J = 1.8, СН2=); 5.01 (1Н, dd, J = 16.9, J = 1.8, СН2=);
5.31 (1Н, ddt, J = 16.9, J = 9. 9, J = 7.0, СН=); 6.85 (2H, m, Ar); 7.03 (3H, m, Ar);
7.53 (2H, m, Ar); 7.70 (1H, ddd, J = 7.6, J = 6.0, J = 2.2, H-7); 8.08 (1H, d, J = 7.6, H-6)
10
1.18 (3H, d, J = 6.8, 2-CH3); 1.29 (3H, t, J = 7.1, OCH2CH3);
3.29 (1H, dd, J = 6.2, J = 3.9, H-3); 3.57 (3Н, s, N-CH3); 3.80 (1H, m, H-2);
4.19 (2H, m, OCH2CH3); 4.65 (1H, d, J = 6.2, H-4); 7.11-7.49 (9H, m, Ar)
_______
* The spectra of compounds 2a-c,e,f,h, 3a-c,f,h, 4c,e, 5, 7a,b, 8a-c (in
CDCl3) were recorded on a Varian Mercury 200 (200 MHz) and
compounds 2, 3d (in DMSO-d6) and 2g, 3e,g (in CDCl3) on a Varian
Mercury 400 (400 MHz) instrument.
1
The structure of the cis-1-methyl-1,2,3,4-tetrahydroindenopyridine 10 was proved by H NMR
spectroscopy. The spin-spin couplings constants in compound 10 are close to those in the N-unsubstituted
analogs 3a-h (J2,3 = 3.3-3.6, J3,4 = 6.3-6.7 Hz). As noted above, this spin-spin coupling in the N-methyl-trans
isomer 7a contrasts strongly with the measured constants in the precursor compounds 2a-h. This is explained by
the fact that, in the conformations with equatorial substituents at the C(2)–C(4) atoms, the NCH3 and 2-CH3
groups occupy an almost screened orientation. The unfavorable steric interaction is decreased by rotation around
the N–C(2) bond so leading to a tetrahydropyridine ring conformation with an axial orientation of the C(2) and
C(3) substituents.
Me
H
R
H
N
Ph
H
R1 = Me
R1 = H
Ph
H
R1
N
R1
Me
H
H
R
865

TABLE 3. 13C NMR Spectra of the Compounds Prepared
Com
pound
Chemical shifts, δ, ppm ( J, Hz)*
2b
2c
2e
2f
14.25 (CH2CH3); 19.46 (CH3); 41.99 (C-4); 50.74 (C-2); 56.93 (C-3); 60.91 (CH2CH3);
103.69 (C-4a); 117.07; 120.64; 126.99; 127.94; 128.47; 130.50; 130.54; 136.10; 136.61;
140.86; 162.09; 173.01 (COOCH2); 189.08 (C=O)
19.43 (CH3); 21.26 (CH(CH3)2); 22.00 (CH(CH3)2); 42.06 (C-4); 50.80 (C-2); 57.01 (C-3);
68.37 (CH(CH3)2); 104.12; 116.75; 120.74; 126.98; 128.04; 128.45; 130.50; 130.52;
136.12; 136.51; 140.73; 172.49; 189.05 (COOPr-2); 201.95 (C=O)
14.03 (CH2CH3); 19.50 (CH3); 41.95 (C-4); 50.43 (C-2); 56.71 (C-3); 60.60 (CH2CH3);
103.61 (C-4a); 106.96; 114.03; 120.30; 126.82; 127.73; 128.21; 131.42; 136.87; 140.74;
143.36; 159.57; 172.87 (COOCH2); 192.07 (C=O)
14.09 (CH2CH3); 19.27 (CH3); 42.05 (C-4); 50.76 (C-2); 50.81 (C-3); 61.65 (CH2CH3);
119.60 (C-4a); 121.79; 127.99; 128.31; 129.10; 132.44; 133.28; 135.55; 144.45; 147.10;
161.20; 163.62; 167.68 (COOCH2); 187.54 (C=O)
2g
15.9; 19.6; 41.7; 50.1; 51.7; 55.9; 56.5; 69.3; 103.4; 111.4; 116.9; 126.5; 126.6; 127.5;
128.2; 129.2; 140.6; 141.6; 155.3; 160.5; 173.3 (COOMe); 187.70 (C=O)
3а
18.08 (COCH3); 31.19 (CH3); 40.90 (C-4); 52.42 (C-2); 56.34 (C-3); 117.26 (C-4a);
120.46; 127.05; 128.10; 128.42; 128.76; 130.50; 136.17; 138.54; 143.65; 162.77; 164.10;
176.71 (COCH3); 208.40 (C=O)
3b
3c
20.84 (CH2CH3); 21.27 (CH3); 39.33 (C-4); 40.58 (C-2); 40.63 (C-3); 45.70 (CH2CH3);
116.35 (C-4a); 126.10; 127.48; 127.55; 128.36; 128.47; 128.77; 132.01; 145.36; 149.48;
152.97; 155.38; 174.20(COOCH2); 192.89 (C=O)
18.36 (CH3); 21.34 (CH(CH3)2); 22.03 (CH(CH3)2); 42.21 (C-4); 50.04 (C-2); 51.78 (C-3);
67.59 (CH(CH3)2); 101.93 (C-4a); 116.78; 120.52; 126.90; 128.02; 128.94; 130.40;
130.42; 136.29; 136.84; 138.80; 163.64; 169.41 (COOPr-2); 189.53 (C=O)
3e
3f
14.1; 18.1; 49.3; 51.3; 59.3; 98.6; 108.2; 120.1; 126.3; 127.6; 129.0; 131.2; 137.5; 140.5;
143.8; 162.1; 169.8 (COOEt); 191.3 (C=O)
14.56 (CH2CH3); 19.18 (CH3); 41.77 (C-4); 51.10 (C-2); 56.23 (C-3); 60.85 (CH2CH3);
102.90 (C-4a); 121.69; 124.10; 127.09; 128.40; 128.63; 132.96; 138.15; 141.38; 143.85;
161.13; 164.22; 166.88 (COOCH2); 172.75 (C=O)
3g
15.8; 18.4; 40.1; 49.1; 50.8; 51.4; 55.9; 69.4; 101.3; 111.2; 116.7; 126.6; 127.0; 127.8;
128.4; 129.6; 138.7; 141.5; 155.3; 162.0; 170.0 (COOMe); 188.0 (C=O)
_______
* The spectra of compounds 2b,c and 3a,c,f (in CDCl3) were recorded on a
Varian Mercury 200 (200 MHz) and compounds 3e (in DMSO-d6) and
2e,f,g, 3b,g (in CDCl3) on a Varian Mercury 400 (400 MHz) instrument.
The N-methyltetrahydroindenopyridine 7a was prepared by two independent methods, i.e. by reduction
of the dihydroindeno[1,2-b]pyridine 9 and by alkylation of the tetrahydroindenopyridine 2b and this is an
additional confirmation of its steric structure.
EXPERIMENTAL
1H and 13C NMR spectra were obtained on Varian Mercury 200 and 400 MHz instruments using TMS as
internal standard and mass spectra on a Micromass Q-TOF mass spectrometer. X-ray structural investigation
was carried out on a Bruker-Nonius Kappa automatic X-ray diffractometer using a CCD detector. Preparative
column chromatography was performed on Acros Kieselgel (0.035-0.070 mm) grade silica gel.
Synthesis of the 5-Oxo-4-phenyl-1H-2,3,4,5-tetrahydroindeno[1,2-b]pyridines 2a-h, 3a-h, 7a, 10
(General Method). Triethylsilane (1.0 ml) was added to a solution of the dihydropyridines 1a-h, 9 (4.3 mmol)
in trifluoroacetic acid (5 ml). The reaction mixture was stirred under an argon atmosphere for 1 h and added to a
mixture of ice (100 g) and bicarbonate (15 g). The precipitate formed was filtered off, dried, and placed on a
chromatographic column. The cis and trans isomers 3a-c,f, 10 and 2a-g, 7a were separated using the following
eluents: ethyl acetate–petroleum ether (6:1), methylene chloride–acetone (20:1), and methylene chloride–
866

petroleum ether–acetone (9:7:1). The cis isomers 3d,e,g were separated after a repeated chromatography, their
yields not exceeding 5% (3d, mp 347-348ºC; 3g, mp 191-193ºC; 3e, mp 176-178ºC (sinters), 178-180ºC (melts).
Mass spectra: 3d, m/z 348 [M+1]+; 3e, m/z 363 [M+1]+. The mixture of 2h, 3h trans and cis isomers (in the ratio
5:1) could not be separated, the overall yield being 66%. Compound 2a was separated in 45% yield and had m/z
318 [M+1]+.
Alkylation of (2R*,3S*,4R*)-5-Oxo-4-phenyl-1H-2,3,4,5-tetrahdroindeno(1,2-b)pyridines (General
Method). A suspension of sodium hydride (0.26 g) in mineral oil (60%) was added with stirring to a solution of the
tetrahydroindenopyridines 2b or 3b (4.3 mmol) in DMF (15 ml) and stirred for a further 0.5 h. The reaction mixture
was then treated with the alkylating agent (12.9 mmol) and monitored using TLC. The reaction mixture was poured
into an aqueous solution of sodium chloride at the end of the reaction. The oily precipitate formed was separated,
dried, and placed on a silica gel chromatographic column. The C- and N-isomers 8a-c and 7a,b, 10 were separated
using the following eluents: ethyl acetate – petroleum ether (1:1) or petroleum ether–acetone (4:1).
The authors thank S. Belyakov for carrying out the X-ray structural analysis.
REFERENCES
1.
2.
3.
U. Rosentreter, Synthesis, 210 (1985).
C. Taberez, V. Waterman, A. L. Rapp, P. Moyna, and G. Moyna, Tetrahedron Lett., 50, 7128 (2009).
D. Muceniece, S. Stupnikova, and V. Lusis, Khim. Geterotsikl. Soedin., 1071 (2001). [Chem.
Heterocycl. Comp., 37, 982 (2001)].
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