Reactions of 4-unsubstituted 4,5-dihydro-1H-indeno[1,2-b]pyridines

Article abstract of DOI:10.1007/s10593-009-0270-2

Alkylation of 3-methoxycarbonyl-2-methyl-5-oxo-4,5-dihydro-1H-indeno[1,2-b] pyridine and 12-oxo-12,13-dihydro-7H-7azaindeno[1,2-b]phenanthrene using methyl iodide or allyl bromide in DMF solution in the presence of NaH occurs with high selectivity and giv

Full text of DOI:10.1007/s10593-009-0270-2

Chemistry of Heterocyclic Compounds, Vol. 45, No. 3, 2009
REACTIONS OF 4-UNSUBSTITUTED
4,5-DIHYDRO-1H-INDENO[1,2-b]PYRIDINES
D. Tanaev1, V. Lusis1, and D. Muceniece1*
Alkylation of 3-methoxycarbonyl-2-methyl-5-oxo-4,5-dihydro-1H-indeno[1,2-b]pyridine and 12-oxo-
12,13-dihydro-7H-7azaindeno[1,2-b]phenanthrene using methyl iodide or allyl bromide in DMF
solution in the presence of NaH occurs with high selectivity and gives the corresponding C-alkyl
derivatives in high yield. The acid cleavage of the 4a-alkylated 3-methoxycarbonyl-2-methyl-5-oxo-
4a,5-dihydroindeno[1,2-b]pyridines has been studied.
Keywords: 12,13- and 12,12a-dihydro-7-azaindenophenanthrenes, 4,5- and 4a,5-dihydroindeno-
pyridines.
We have previously shown [1] that alkylation of 4-aryl-4,5-dihydro-1H-indeno[1,2-b]pyridines in the
anionic form using dimethyl sulfate or methyl p-toluenesulfonate gives the N-methyl derivatives exclusively
while the reaction with methyl iodide shows a dual nature and gives a mixture of the N- and C-methyl products.
When allyl and propargyl bromides or ethyl bromoacetate are used as alkylating agents in an aprotic medium in
the presence of NaH a high selectivity is shown towards C-alkylation [2]. These results agree well with
principles of hard and soft acids and bases. Mild alkylating agents (including reagents containing readily
polarizable multiple bonds) react principally at the C-4a atom, i.e. the softer center of the ambident anion.
In this work we consider the alkylation reactions and acid cleavage of derivatives unsubstituted at atom
C-4 in 5-oxodihydroindeno[1,2-b]pyridine 1 and the analogous indeno[1,2-b]phenanthrenone 2.
Alkylation of compounds 1 and 2 using methyl iodide in DMF solution in the presence of NaH occurred
with highly selective C-alkylation and the methyl derivatives 3a and 5a were obtained in 69 and 96% yield
respectively. The N-methyl derivatives 4a and 6a formed upon alkylation were separated in 6 and about 1%
yield respectively from the reaction mixture.
We have previously used KOH [1] instead of NaH for formation of the dihydropyridine anion but Na+
binds more strongly at the hard reaction center and this shields the nitrogen atom. However, the ratio of C- and
N-methyl derivatives (~ 10:1) in the case of the 4-unsubstituted indenopyridine 1 is clearly greater than in the
alkylation of 4-phenylindenopyridine for which the ratio of C- and N-methylation products is 2.2:1. Evidently
the absence of a substituent at atom C-4 allows formation of the 4a-methyl derivative 3a. The high selectivity
towards C-alkylation was also confirmed in the synthesis of the C-allyl derivatives 3b and 5b (71 and 86% yield
respectively). The yield of the corresponding N-allyl derivatives 4b and 6b is 13 and 4.3%.
_______
* To whom correspondence should be addressed, e-mail: muceniece@osi.lv.
1Latvian Institute of Organic Synthesis, Riga LV-1006, Latvia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 415-420, March, 2009. Original
article submitted November 10, 2008.
336
0009-3122/09/4503-0336©2009 Springer Science+Business Media, Inc.

O
O
O
1. NaH
2. MeI or BrCH2CH=CH2
R
COOMe
Me
COOMe
Me
COOMe
Me
+
N
R
N
N
H
3 a,b
1
4 a,b
O
O
O
R
1. NaH
2. MeI or BrCH2CH=CH2
+
N
N
R
N
H
5 a,b
2
6 a,b
3–6 a R = Me, b R = CH2CH=CH2
It is interesting to note that allylation of the dihydroindenopyridine 1 gave an unexpected side product,
i.e. the 5-allyl derivative of indenopyridine 7. It can be assumed that compound 7 is the result of a
rearrangement of the allyl derivative 3b but the mechanism of the reaction is unknown.
O
H
HO
COOMe
Me
COOMe
Me
N
N
3b
7
Due to the rather slow reaction rate there also occurs a side oxidation reaction of the alkylated anion
involving atmospheric oxygen, hence it has to be carried out in an inert atmosphere.
O
O
H+
R
COOMe
COOMe
COMe
3 a,b
R
Me
O
O H2N
8 a,b
O
O
R
R
BnNH3OAc
COOMe
NHBn
COOMe
OH
+
9 a,b
10 b
8–10 a R = Me, b R = CH2CH=CH2
According to [3, 4] the 4a-substituted 4-phenyldihydroindenopyridines undergo acid cleavage and as a result
of an intramolecular condensation give fluorenone derivatives but this was not observed in the case of the
4-unsubstituted indenopyridines 3a,b. The products of acid hydrolysis of the 4a-alkyl derivatives of the
4-unsubstituted dihydroindenopyridines 3a,b are the α-acetyl-β-(1,3-dioxo-2,3-dihydro-1H-inden-2-yl)propionic
acid derivatives 8a,b. However, it was interesting to note that the reactions of these 2,2-dialkyl-substituted
1,3-indanediones with benzylamine acetate give fluorenone derivatives. The main cyclization products are the
3-benzylamino derivatives 9a and 9b with the 3-hydroxyfluorenone 10b as a by-product.
337

EXPERIMENTAL
1H NMR spectra were recorded on a Varian Mercury-200 (200 MHz) instrument using CDCl3
(compounds 3a,b-6a,b, 7, 8a,b, 9a,b and 10b) or DMSO-d6 (compounds 1 and 2) with TMS as internal
standard. Mass spectra were taken on an HP 6890 GCMS chromato-mass spectrometer with ionization energy
70 eV. Acros Kieselgel grade silica gel (0.035-0.070 mm) was used for preparative column chromatography.
3-Methoxycarbonyl-2-methyl-5-oxo-4,5-dihydro-1H-indeno[1,2-b]pyridine (1) was prepared by
analogy with [5]. Yield 27%; mp 265-267ºC (AcOH). 1H NMR spectrum, δ, ppm: 2.30 (3H, s, CH3); 3.10 (2H,
s, 4-CH2); 3.63 (3H, s, OCH3); 7.28-7.55 (4H, m, C6H4); 9.76 (1H, br. s, NH). Found, %: C 70.42; H 5.01;
N 5.28. C15H13NO3. Calculated, %: C 70.58; H 5.13; N 5.49.
12-Oxo-12,13-dihydro-7-aza-7H-indeno[1,2-b]phenanthrene (2). A mixture of 2-naphthylamine
(6.00 g, 42 mmol) and paraformaldehyde (1.26 g, 42 mmol) in ethanol (75 ml) was heated to reflux and a
solution of indane-1,3-dione (6.10 g, 42 mmol) in ethanol (75 ml) was added. The reaction mixture was cooled
and the precipitate filtered off and recrystallized from acetic acid. Mp 258-264ºC. Yield 5.64 g (47%). 1H NMR
spectrum, δ, ppm: 3.92 (2H, s, 13-CH2); 7.29-7.92 (10H, m, Ar); 9.40 (1H, br. s, NH). Found, %: C 84.30;
H 4.50; N 4.73. C20H13NO. Calculated, %: C 84.78; H 4.62; N 4.94.
Reaction of Methyl 2-Methyl-5-oxo-4,5-dihydro-1H-indeno[1,2-b]pyridine-3-carboxylate with
Methyl Iodide (General Method). Starting compound 1 (1.50 g, 5.88 mmol) was dissolved with stirring in
DMF (80 ml) under an argon atmosphere and NaH (0.28 g, 1.2 eq., 7.06 mmol) as a 60% suspension in oil was
added. When evolution of hydrogen had ceased methyl iodide (0.73 ml, 11.76 mmol) was added and the reaction
mixture was stirred at room temperature for 1 h. Solvent was evaporated and the residue was column
chromatographed using hexane–acetone (4:1) as eluent. The following fractions were separated:
1
3-Methoxycarbonyl-2-methyl-5-oxoindeno[1,2-b]pyridine. Yield 0.10 g (6.8%); mp 185ºC. H NMR
spectrum, δ, ppm: 2.96 (3H, s, CH3); 3.94 (3H, s OCH3); 7.43-7.96 (4H, m, Ar); 8.4 (1H, s, 4-CH). Found, %:
C 70.60; H 4.21; N 5.40. C15H11NO3. Calculated, %: C 71.14; H 4.38; N 5.53.
3-Methoxycarbonyl-2,4a-dimethyl-5-oxo-4a,5-dihydro-4H-indeno[1,2-b]pyridine (3a). Yield 1.10 g
(69%); mp 165-170ºC. 1H NMR spectrum, δ, ppm (J, Hz): 1.16 (3H, s, 4a-CH3); 2.25 (1H, dd, J = 17.7 and J = 2.7,
4-CH2); 2.50 (3H, dd, J = 1.0 and J = 2.7, CH3); 2.98 (1H, dd, J = 17.7 and J = 1.0, 4-CH2); 3.80 (3H, s, OCH3);
7.61-8.07 (4H, m, Ar). Found, %: C 71.89; H 5.08; N 5.22. C16H15NO3. Calculated, %: C 71.36; H 5.61; N 5.20.
3-Methoxycarbonyl-1,2-dimethyl-5-oxo-4,5-dihydroindeno[1,2-b]pyridine (4a). Yield 0.10 g (6.3%), red
oil. 1H NMR spectrum, δ, ppm (J, Hz): 2.42 (3H, t, J = 1.1, CH3); 3.20 (2H, br. s, CH2); 3.54 (3H, s, N–CH3); 3.69
(3H, s, OCH3); 7.17-7.46 (4H, m, Ar).
Reaction of Methyl 2-Methyl-5-oxo-4,5-dihydro-1H-indeno[1,2-b]pyridine-3-carboxylate with
Allyl Bromide. Similarly to the above from the indenopyridine 1 (2.0 g, 7.8 mmol), NaH (0.37 g, 9.3 mmol),
and allyl bromide (1.35 ml, 15.6 mmol) in DMF (80 ml) to give compounds 3b, 4b and 7.
4a-Allyl-3-methoxycarbonyl-2-methyl-5-oxo-4a,5-dihydro-4H-indeno[1,2-b]pyridine (3b). Yield
1.64 g (71%); mp 78-80ºC. 1H NMR spectrum, δ, ppm (J, Hz): 2.22 (1H, dd, J = 2.6 and J = 18.0, 4-CH2); 2.32
(2H, d, J = 7.5, CH2–CH=); 2.57 (3H, dd, J = 1.1 and J = 2.6, CH3); 3.10 (1H, dd J = 1.1 and J = 18.0, 4-CH2);
3.79 (3H, s, OCH3); 4.88-5.00 (2H, m, –CH=CH2); 5.49 (1H, m, –CH=CH2); 6.66-8.12 (4H, m, Ar). Found, %:
C 73.16; H 5.80; N 4.59. C18H17NO3. Calculated, %: C 73.20; H 5.80; N 4.74.
1-Allyl-3-methoxycarbonyl-2-methyl-5-oxo-4,5-dihydroindeno[1,2-b]pyridine (4b). Yield 0.13 g
(13%), red oil. 1H NMR spectrum, δ, ppm (J, Hz): 1.57 (3H, s, CH3); 2.21 (1H, d, J = 14.6, 4-CH2); 2.92 (1H, d,
J = 14.6, 4-CH2); 3.81 (3H, s, OCH3); 3.92 (2H, m, CH2–CH=); 5.10-5.25 (2H, m, –CH=CH2); 5.96-6.20 (1H,
m, –CH=CH2); 7.48-7.86 (4H, m, Ar).
5-Allyl-5-hydroxy-2-methoxycarbonylindeno[1,2-b]pyridine (7). Yield 0.36 g (15%); mp 160ºC.
1H NMR spectrum, δ, ppm: 1.60 (1H, br. s, OH); 2.70-2.96 (2H, m, CH2–CH=); 2.82 (3H, s, CH3); 3.93 (3H, s,
OCH3); 4.90-5.05 (2H, m, CH=CH2); 5.45-5.70 (1H, m, CH2–CH=); 7.36-7.88 (4H, m, Ar); 8.23 (1H, s, 4-CH).
Found, %: C 72.76; H 5.69; N 4.61. C18H17NO3. Calculated, %: C 73.20; H 5.80; N 4.74.
338

Reaction of 12-Oxo-12,13-dihydro-7H-7-azaindeno[1,2-b]phenanthrene with Methyl Iodide. From
the phenanthrene 2 (2.0 g, 7.0 mmol), NaH (0.33 g, 8.4 mmol), and methyl iodide (0.87 ml, 14 mmol) in DMF
(80 ml) by analogy with the reaction of indenopyridine 1 to give compounds 5a, 6a.
12a-Methyl-12-oxo-12,12a-dihydro-13H-7-azaindeno[1,2-b]phenanthrene (5a). Yield 2.00 g (96%);
mp 148-149ºC. 1H NMR spectrum, δ, ppm (J, Hz): 1.17 (3H, s, CH3); 2.95 (1H, d, J = 16.6, 4-CH2); 3.73 (1H, d,
J = 16.6, 4-CH2); 7.43-8.42 (10H, m, Ar). Found, %: C 84.89; H 5.00; N 4.69. C21H15NO. Calculated, %:
C 84.82; H 5.08; N 4.71.
7-Methyl-12-oxo-12,13-dihydro-7-azaindeno[1,2-b]phenanthrene (6a). Yield 0.01 g (0.48%);
mp 243-247ºC. 1H NMR spectrum, δ, ppm (J, Hz): 3.31 (3H, s, CH3); 3.85 (1H, d, J = 10.1, 4-CH2); 4.02 (1H, d,
J = 10.1, 4-CH2); 7.26-9.19 (10H, m, Ar).
Reaction of 12-Oxo-12,13-dihydro-7H-7-azaindeno[1,2-b]phenanthrene with Allyl Bromide. From
the starting material 2 (1.38 g, 4.8 mmol), NaH (0.2 g, 5.0 mmol) and allyl bromide (0.83 ml, 9.6 mmol) in DMF
(70 ml) similarly to the preparation and separation of compounds 5b, 6b.
12a-Allyl-12-oxo-12,12a-dihydro-13H-indeno[1,2-b]phenanthrene (5b). Yield 1.33 g (86%);
1
mp 112-114ºC. H NMR spectrum, δ, ppm (J, Hz): 2.25 (2H, d, J = 7.3, CH2–CH=); 2.87 (1H, d, J = 16.8,
4-CH2); 3.83 (1H, d, J = 16.8, 4-CH2); 4.66-4.93 (2H, m, –CH=CH2); 5.40-5.65 (1H, m, CH2–CH=); 7.42-8.30
(10H, m, Ar). Found, %: C 85.46; H 5.27; N 4.32. C23H17NO. Calculated, %: C 85.42; H 5.30; N 4.33.
7-Allyl-12-oxo-12,13-dihydro-7-azaindeno[1,2-b]phenanthrene (6b). Yield 0.06 g (4.3%), red oil.
1H NMR spectrum, δ, ppm (J, Hz): 4.10 (2H, s, 4-CH2); 4.79-4.85 (2H, m, CH2–CH=); 5.37-5.53 (2H, m,
CH=CH2); 6.11-6.31 (1H, m, CH2–CH=); 7.23-8.00 (10H, m, Ar).
Methyl α-Acetyl-β-(2-methyl-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)propionate (8a). A suspension
of indenopyridine 3a (0.36 g, 1.3 mmol) in 80% ethanol (75 ml) and 0.1 M HCl (0.6 ml, 15 eq.) was refluxed for
5 h. The reaction mixture was diluted with water (40 ml), extracted with chloroform (3×40 ml), and dried over
sodium sulphate. Solvent was evaporated off under reduced pressure and the residue was fractionated on a silica
gel column using hexane–acetone (4:1) as eluent. Yield 0.33 g (90%); mp 96-98ºC. 1H NMR spectrum, δ, ppm
(J, Hz): 1.30 (3H, s, CH3); 2.20 (3H, s, COCH3); 2.35 (1H, d, J = 6.4; CH2); 2.40 (1H, d, J = 6.4, CH2); 3.63
(3H, s, COOCH3); 3.69 (1H, t, J = 6.4, CH); 7.83-8.00 (4H, m, Ar).
Methyl α-Acetyl-β-(2-allyl-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)propionate (8b). The starting
material 3b (1.31 g, 4.4 mmol) was dissolved in glacial acetic acid (40 ml), conc. H2SO4 (4 ml) was added, and
the product was stirred at room temperature for 2 days. It was then diluted with water (50 ml), neutralized with
sodium carbonate (pH 8), and extracted with ethyl acetate (3×100 ml). The extract was dried over sodium
sulphate, solvent was evaporated at reduced pressure, and the residue was fractionated on a silica gel
1
chromatographic column using hexane–acetone (4:1) as eluent. Yield of product 8b 1.06 g (77%). H NMR
spectrum, δ, ppm (J, Hz): 2.14 (3H, s, COCH3); 2.31 (1H, dd, J = 6.8 and J = 14.8, CH2); 2.38 (1H, dd, J = 6.1 and
J = 14.8, CH2); 2.48 (1H, ddd, J = 2.9, 7.4 and J = 13.4, CH2–CH=); 2.51 (1H, ddd, J = 1.2, 7.4, and J = 13.4, CH2–
CH=); 3.58 (3H, s, OCH3); 3.61 (1H, dd, J = 6.8 and J = 6.1, CH); 4.87 (1H, dt, J = 1.2 and J = 10.0, CH=CH2);
4.99 (1H, ddd, J = 1.2, J = 3.0, and J =16.9, CH=CH2); 5.40 (1H, ddt, J = 7.4, J = 10.0, and J =16.9, CH2–CH=);
7.76-7.95 (4H, m, Ar).
3-(Benzylamino)-2-methoxycarbonyl-9a-methyl-9-oxo-9,9a-dihydro-1H-fluorene (9a). Benzyl-
amine acetate (0.33 g, 2 mmol) was added to a solution of compound 8a (0.05 g, 0.17 mmol) in glacial acetic
acid (20 ml). The product was stirred for 6 h at 50ºC, diluted with water (40 ml), and extracted with
dichloromethane (3×40 ml). The extract was dried over sodium sulphate, solvent was evaporated under reduced
pressure, and the residue was fractionated on a silica gel chromatography column using hexane–acetone (4:1) as
eluent. Yield of 9a 0.04 g (66%), yellow oil. 1H NMR spectrum, δ, ppm (J, Hz): 1.17 (3H, s, CH3); 2.26 (1H, d,
J = 15.9, 1-CH2); 3.02 (1H, d, J = 15.9, 1-CH2); 3.73 (3H, s, OCH3); 4.60 (2H, d, J = 6.2, NH–CH2–Ph); 6.62
(1H, s, 4-CH); 7.28-7.90 (9H, m, Ar); 9.27 (1H, br. t, J = 6.2, NH).
339

Reaction of Methyl α-Acetyl-β-(2-allyl-1,3-dioxo-2,3-dihydro-1H-inden-2-yl)propionate with
Benzylamine Acetate. A solution of compound 8b (0.62 g, 1.9 mmol) and benzylamine acetate (0.33 g,
2 mmol) was stirred at 50ºC in glacial acetic acid (20 ml) for 6 h. The reaction mixture was diluted with water
(40 ml), extracted with dichloromethane (3×40 ml), and dried over sodium sulphate. Solvent was evaporated and
the residue was fractionated as in the preceding example to give compounds 10b and 9b as low melting solids.
Methyl 9a-Allyl-3-hydroxy-9-oxo-9,9a-dihydro-1H-fluorene-2-carboxylate (10b). Yield 0.02 g
1
(3.5%). H NMR spectrum, δ, ppm (J, Hz): 2.32 (1H, d, J = 16.4, 1-CH2); 2.31-2.40 (2H, m, CH2–CH=); 3.03
(1H, d, J = 16.4, 1-CH2); 3.82 (3H, s, OCH3); 4.84-4.98 (2H, m, CH=CH2); 5.39-5.63 (1H, d, –CH=CH2); 6.51
(1H, s, 4-CH); 7.33-7.90 (4H, m, Ar); 12.17 (1H, s, OH).
Methyl 3-Benzylamino-9a-allyl-9-oxo-9,9a-dihydro-1H-fluorene-2-carboxylate (9b). Yield 0.27 g
(37%). 1H NMR spectrum, δ, ppm (J, Hz): 2.23 (1H, d, J = 16.1, 1-CH2); 2.35 (2H, d, J = 7.4, CH2–CH=); 3.12
(1H, d, J = 16.1, 1-CH2); 3.72 (3H, s, OCH3); 4.60 (2H, d, J = 6.4, N–CH2); 4.74-4.87 (2H, m, CH=CH2);
5.30-5.54 (1H, m, CH=CH2); 6.65 (1H, s, 4-CH); 7.20-7.80 (9H, m, Ar); 9.28 (1H, br. t, J = 6.4, NH). ESI-MS,
m/z: 386 [M+H]+.
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