Synthesis of substituted indolizino[8,7-b]indoles from harmine and their biological activity

Article abstract of DOI:10.1007/s10593-011-0698-z

The reaction of harmine with phenacyl bromides or ethyl bromoacetate gives quaternized harmine derivatives. The cyclization of the phenacylharminium salts yields the corresponding 2-aryl-11H-indolizino[8,7-b]indoles. Vilsmaier-Haack formylation of 11H-ind

Full text of DOI:10.1007/s10593-011-0698-z

Chemistry of Heterocyclic Compounds, Vol. 46, No. 12, March, 2011 (Russian Original Vol. 46, No. 12, December, 2010)
SYNTHESIS OF SUBSTITUTED INDOLIZINO[8,7-b]INDOLES
FROM HARMINE AND THEIR BIOLOGICAL ACTIVITY
Zh. S. Nurmaganbetov1, E. E. Shultz2*, S. V. Chernov2,
A. Zh. Turmukhambetov1, R. B. Seydakhmetova1,
M. M. Shakirov2, G. A. Tolstikov2, and S. M. Adekenov1
The reaction of harmine with phenacyl bromides or ethyl bromoacetate gives quaternized harmine
derivatives. The cyclization of the phenacylharminium salts yields the corresponding 2-aryl-11H-
indolizino[8,7-b]indoles. Vilsmaier-Haack formylation of 11H-indolizino[8,7-b]indoles leads to the
corresponding 3,10-bisformyl derivatives. The acylation proceeds selectively at C(3) to give 3-acetyl-
2-aryl-11H-indolizino[8,7-b]indole.
Keywords: harmine, phenacyl bromides, antimicrobial, cytotoxic, and anticholinesterase activities,
acetylation, cyclization, formylation.
Plant metabolites containing the 11H-indolizino[8,7-b]indole unit such as the alkaloids harmicidine [1]
and trichotomine [2] have valuable pharmacological properties. The tetrahydro-11H-indolizino[8,7-b]indole
fragment is a structural element of plant cytotoxic indole-containing subincanadine alkaloids [3, 4]. We attempted
to construct this heterocyclic unit by synthetic transformations of the available plant alkaloid, harmine (1). Some
reactions of this compound have been described in our previous work [5, 6].
We have shown that the reaction of harmine 1 with phenacyl bromides 2a-c in ethanol leads to the
formation of harminium salts 3a-c. Similarly, the action of ethyl bromoacetate on harmine 1 leads to quaternized
salt 4 (Scheme 1). We should point out that the preparation of 9H--carbolinium salts holds interest in light of the
high antimicrobial (including antimalarial) activity of various quaternized -carboline derivatives [7-9].
Phenacylharminium salts 3a-c undergo facile cyclization upon treatment with KOH to give 11H-indo-
lizino[8,7-b]indole derivatives 5a-c in 77-85% yield. Thus, this method reproduces a reported approach to the
synthesis of indolizines [10].
The methods described for constructing the indolizino[8,7-b]indole unit are based on the Pictet-Spengler
[11, 12] and Bischler-Napieralski reactions [13, 14] of tryptamine or tryptophan derivatives, the reaction of
3,4-dihydro--carboline with 2-acetoxyacrylates [15, 16], and the 1,3-dipolar cycloaddition of derivatives of
-carboline azomethine ylids [17]. Our method for obtaining this heterocyclic unit features a high yield of
_______
* To whom correspondence should be addressed, e-mail: schultz@nioch.nsc.ru.
1International Research and Production Holding "Phytochemistry", Karaganda 100009, Kazakhstan.
2Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk
630090, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1849-1856, December, 2010.
Original article submitted April 13, 2010, submitted after revision July 11, 2010.
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0009-3122/11/4612-1494©2011 Springer Science+Business Media, Inc.

Scheme 1
O
O
R
Br
Br
R1
EtO
O
EtOH
2a–c
+
+
N
N
N
MeO
N
H
MeO
N
H
EtOH
MeO
N
Me
EtO
Me
Me
H
1
O
4
R
R1
3a–c
2, 3 a R = R1 = H; b R = H, R1 = OMe; c R = R1 = Cl
tetracyclic derivatives of 11H-indolizino[8,7-b]indole. These results have led us to study the reactivity of products
5a-c. The Vilsmaier-Haack formylation of compound 5b led to 9-methoxy-2-(4-methoxyphenyl)-11H-
indolizino[8,7-b]indole-3,10-dicarbaldehyde (6). Harmine 1 is characteristically inert under these conditions.
Thus, the reaction reveals the effect of the indolizine fragment in the structure of compound 5b. The acetylation
of compound 5a under conditions employed for N–O-acylation with MeCOCl/pyridine proceeds readily and
selectively at C-3 of the indolizinoindole to give 3-acetyl-9-methoxy-2-phenyl-11H-indolizino[8,7-b]indole (7)
(Scheme 2). The structure of the compounds synthesized was established from the spectral data. The signals for
H-1 at  6.96-7.01 ppm and H-3 at  7.99-8.12 ppm, which appear as broadened doublets, are a distinguishing
1
feature of the H NMR spectra of 11H-indolizino[8,7-b]indoles 5a-c. The introduction of a substituent at C-3 of
the indolizinoindoles (compounds 6 and 7) leads to disappearance of the signal for H-3 proton and a characteristic
downfield shift for proton H-5. The compounds synthesized have characteristic UV spectra typical for
quaternized amines (3a-c and 4) or conjugated indolizinoindole systems (5a-c, 6, and 7).
Scheme 2
7
6
8
KOH
6b
6a
11
5
N
10
3a–c
9
MeO
N
3
1
2
H
R
3'
4'
R1
5a–c
O
C
POCl3 – DMF
AcCl – Py
5b
N
N
CHO
5a
MeO
N
H
N
H
MeO
Me
CHO
Ph
7
6
OMe
5 a R = R1 = H; b R = H, R1 = OMe; c R = R1 = Cl
Biological screening of products 3a-c, 4, and 5a-c included determination of the antimicrobial activity
relative to Gram-positive (Staphylococcus aureus and Bacillus subtilis) and Gram-negative bacteria (Escherichia
coli and Pseudomonas aeruginosa) as well as yeast fungi Candida albicans by the agar diffusion test. The
reference substances were gentamycin for bacteria and nystatin for Candida albicans. We found that
N(2)-phenacylharminium bromide (3a) and N(2)-(3,4-dichlorophenacyl)harminium bromide (3b) have marked
1495

antimicrobial activity relative to the Gram-positive species Bacillus subtilis. Bromide 3b and indole derivatives
5a-c display moderate activity relative to the Gram-positive species Staphylococcus aureus. Bromide 4 has
moderate antibacterial activity relative to the test species Bacillus subtilis. Moderate antimicrobial activity toward
yeast fungi Candida albicans was found for compounds 3a,b, 5a,b.
Cytotoxic properties have been reported for harmine and its derivatives [18]. The cytotoxicity of
compounds 3a-c, 4, and 5a-c was studied relative to the survival of larvae of brine shrimp Artemia salina (Leach).
The experiments were carried out for two-day-old larvae under conditions of in vitro cultivation. The reference
compound was 13-dimethylamino-1,10-epoxy-5,7,11(H)-guai-3,4-en-6,12-olide (the active substance of
preparation Arglabin), which has antitumor activity [19]. We found that bromide 3a has cytotoxic activity relative
to larvae of brine shrimp Artemia salina (Leach).
Harmine has tranquillizing and anesthetizing action and has been used for the treatment of Parkinson's
disease. This property has been attributed to its capacity to inhibit acetylcholinesterase. 2-Methylnorharmane [20]
and quaternized harmine derivatives display anticholinesterase activity [21]. We have found that
2-phenacylharminium bromide (3a) and its cyclization product 5a display higher anticholinesterase activity
(0.308 and 0.251 A, respectively) relative to the model inhibitor, prozerin (0.115 A). This result indicates that
the compounds synthesized may be considered as reversibly-competitive inhibitors of acetylcholinesterase.
EXPERIMENTAL
The IR spectra were taken on an Avatar 360 esp Fourier spectrometer for KBr pellets. The UV spectra
1
13
were taken on an HP 8453 UV-vis spectrometer in ethanol (c 10-4 mol/liter). The H and C NMR spectra were
taken on a Bruker AV-300 spectrometer at 300 and 75 MHz, respectively, for compounds 3a-c and 4 and on a
Bruker AV-600 spectrometer at 600 and 150 MHz, respectively, for compounds 5a-c, 6, and 7 in DMSO-d6
(compounds 3a-c, 5a-c, and 7), CD3OD (compound 4), and CDCl3 (compound 6). Different types of proton-
proton and carbon-proton shift correlations (COSY, COXH, COLOC) were used to assign the signals in the NMR
spectra of compounds 3a-c, 5, and 6. A DFS Thermo Scientific high-resolution mass spectrometer was used to
take the mass spectra and determine the molecular masses and elemental composition. The ionizing voltage was
70 eV and the injector temperature was 270-300°C. The melting points were found using a Koefler block.
The reaction course was followed by thin-layer chromatography on Silufol UV-254 plates. The reaction
products were isolated by recrystallization or chromatography on a silica gel column.
Preparation of N-Aroylmethyl Harmine Salts 3a-c (General Method). A mixture of harmine 1 (0.6 g,
0.28 mmol) and corresponding aroylmethyl bromide 2a-c (0.30 mmol) in ethanol (15 ml) was heated at reflux for
30 min until the solid was completely dissolved. The reaction mixture was evaporated to half volume. Then, ethyl
acetate (5 ml) was added to the residue. After cooling, the precipitate formed was filtered off to give salts 3a-c as
yellow crystals.
2-Phenacylharminium Bromide (3a) was obtained in 86% yield; mp 280°C (dec.). IR spectrum, , cm-1:
3057, 3014, 2951, 1691, 1633, 1595, 1565, 1530, 1469, 1434, 1340, 1296, 1228, 1164, 1134, 1079, 1026, 990,
925, 811, 796, 761, 685, 632. UV spectrum, max, nm (log ): 202 (5.30), 204 (5.31), 254 (5.53), 291 (5.67), 295
1
(5.68), 336 (5.81), 490 (4.87). H NMR spectrum, , ppm (J, Hz): 2.95 (3H, s, CH3); 3.38 (2H, br. s, CH2); 4.01
(3H, s, CH3O); 7.12 (1H, dd, J = 8.8, J = 2.1, H-6); 7.30 (1H, d, J = 2.1, H-8); 7.68 (2H, m, C6H5); 7.75 (1H, m,
C6H5); 8.18 (1H, d, J = 8.8, H-5); 8.21 (2H, m, 2H, C6H5); 8.32 (1H, d, J = 5.6, H-4); 8.42 (1H, d, J = 5.6, H-3);
12.65 (1H, s, NH). 13C NMR spectrum, , ppm: 15.22 (q, CH3); 55.79 (q, CH3O); 62.68 (t, CH2); 94.09 (d, C-8);
125.08 (d, C-5); 113.38 (d, C-4); 114.06 (d, C-6); 114.45 (s, C-4b); 124.49 (d, C-4'); 128.51 (d, C-3',5'); 129.12
(d, C-2',6'); 131.43 (s, C-9a); 133.52 (s, C-4a); 134.86 (s, C-1); 137.51 (d, C-3); 139.41 (s, C-1'); 147.96 (s, C-8a);
162.97 (s, C-7); 191.52 (s, C=O). Found, %: C 61.72; H 3.98; Br 19.91; N 7.14. C21H19BrN2O2. Calculated, %: C
61.33; H 4.66; Br 19.43; N 6.81.
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2-(4-Methoxyphenacyl)harminium Bromide (3b) was obtained in 91% yield; mp 316-318°C (dec.). IR
spectrum, , cm-1: 3404, 3082, 2972, 1664, 1601, 1515, 1437, 1355, 1213, 1167, 1128, 1009, 991, 933, 828, 799,
736, 704, 676, 612. UV spectrum, max, nm (log ): 203 (5.31), 223 (5.38), 254 (5.54), 269 (5.59), 335 (5.81), 493
(4.69). 1H NMR spectrum, , ppm (J, Hz): 2.98 (3H, s, CH3); 3.38 (2H, br. s, CH2); 3.98 (3H, s, CH3O); 4.01 (3H,
s, CH3O); 7.15 (1H, dd, J = 8.5, J = 2.1, H-6); 7.30 (1H, d, J = 2.1, H-8); 7.32 (2H, d, J = 8.0, C6H5); 7.88 (2H, d,
J = 8.0, C6H5); 8.21 (1H, d, J = 8.5, H-5); 8.30 (1H, d, J = 5.6, H-4); 8.40 (1H, d, J = 5.6, H-3); 12.65 (1H, s,
NH). 13C NMR spectrum, , ppm: 15.68 (q, CH3); 56.60 (q, CH3O); 58.22 (q, CH3O); 63.12 (t, CH2); 94.60 (d, C-8);
114.18 (d, C-4); 114.88 (s, C-4b); 115.89 (d, C-3',5'); 115.46 (d, C-6); 125.63 (d, C-5); 129.12 (d, C-2',6'); 131.12 (s,
C-9a); 132.18 (s, C-4a); 134.86 (s, C-1); 135.12 (s, C-1'); 138.62 (d, C-3); 148.06 (s, C-8a); 155.62 (s, C-4');
164.48 (s, C-7); 190.48 (s, C=O). Found, %: C 60.39; H 4.50; Br 18.54; N 6.25. C22H21BrN2O3. Calculated, %:
C 59.87; H 4.80; Br 18.11; N 6.35.
2-(3,4-Dichlorophenacyl)harminium Bromide (3c) was obtained in 84% yield; mp 310-312°C (dec.).
IR spectrum, , cm-1: 3053, 3009, 1680, 1633, 1583, 1565, 1466, 1392, 1339, 1295, 1264, 1211, 1133, 1079,
1030, 972, 934, 832, 820, 778, 675, 634, 610. UV spectrum, max, nm (log ): 201 (5.30), 257 (5.54), 338 (5.82),
414 (6.02), 422 (6.04), 427 (6.05), 490 (4.28).1H NMR spectrum, , ppm (J, Hz): 2.95 (3H, s, CH3); 3.38 (2H,
br. s, CH2); 4.01 (3H, s, CH3O); 7.16 (1H, dd, J = 8.8, J = 2.1, H-6); 7.32 (1H, d, J = 2.1, H-8); 7.68 (1H, d,
J = 8.6, H-5'); 7.95 (1H, dd, J = 8.6, J = 2.0, H-6'); 8.20 (1H, d, J = 8.8, H-5); 8.25 (1H, d, J = 2.0, H-2'); 8.33
(1H, d, J = 5.6, H-4); 8.45 (1H, d, J = 5.6, H-3); 12.70 (1H, s, NH). 13C NMR spectrum, , ppm: 15.60 (q, CH3);
49.66 (t, CH2); 56.29 (q, CH3O); 94.91 (d, C-8); 114.12 (d, C-4); 114.31 (s, C-4b); 114.93 (d, C-6); 125.09 (d,
C-5); 129.09 (d, C-6'); 131.18 (d, C-5'); 132.07 (d, C-2'); 132.66 (s, C-9a); 133.37 (s, C-4'); 134.57 (s, C-4a);
135.37 (s, C-1'); 135.56 (d, C-1); 138.66 (s, C-3'); 140.31 (d, C-3); 147.05 (s, C-8a); 164.34 (s, C-7); 190.67 (s,
C=O). Found, %: C 52.27; H 3.57; Br 17.04; Cl 15.02; N 5.51. C21H17BrCl2N2O2. Calculated, %: C 52.53; H 3.57;
Br 16.64; Cl 14.77; N 5.83.
2-(Ethoxycarbonylmethyl)harminium Bromide (4) was obtained in 80% yield by the reaction of
harmine 1 with ethyl bromoacetate according to the method described above, mp 298-300°C (dec.). IR spectrum,
, cm-1: 2996, 2904, 2785, 1731, 1680, 1634, 1582, 1566, 1515, 1453, 1377, 1294, 1261, 1209, 1164, 1132, 1023,
949, 869, 804, 736, 695, 675, 637. UV spectrum, max, nm (log ): 204 (5.31), 253 (5.53), 324 (5.78), 337 (5.82),
426 (6.06), 493 (6.20). 1H NMR spectrum, , ppm (J, Hz): 1.37 (3H, t, J = 7.0, CH3); 2.96 (3H, s, CH3); 3.95 (3H,
s, CH3O); 4.37 (2H, q, J = 7.0, OCH2CH3); 5.66 (2H, br. s, CH2); 6.91 (1H, dd, J = 8.0, J = 2.1, H-6); 7.02 (1H, d,
J = 2.1, H-8); 7.97 (1H, m, H-5); 8.12 (1H, d, J = 6.0, H-4); 8.35 (1H, d, J = 6.0, H-3); 12.65 (1H, s, NH). 13C
NMR spectrum, , ppm: 14.37 (q, CH2CH3); 15.83 (q, CH3 at C-1); 55.36 (q, CH3O); 57.92 (t, CH2); 63.90 (t,
CH2CH3); 94.87 (d, C-8); 114.53 (s, C-4b); 114.67 (d, C-4); 114.93 (d, C-6); 124.74 (d, C-5); 133.57 (s, C-4a);
135.66 (d, C-3); 135.80 (s, C-9a); 139.74 (s, C-8a); 147.75 (s, C-1); 165.14 (s, C-7); 167.62 (s, C=O). Found, %:
C 53.48; H 4.88; Br 20.74; N 7.62. C17H19BrN2O3. Calculated, %: C 53.82; H 5.01; Br 21.11; N 7.39.
Preparation of substituted 11H-indolizino[8,7-b]indoles 5a-c (General Method). A 50% aqueous
solution of KOH (3 eq.) was added to a hot saturated solution of quaternary salt 3a-c in ethanol. The reaction
mixture was maintained for 5-10 min at 65-70°C until no further precipitate formed. After cooling, the crystals
were filtered off and washed with aqueous methanol and ether to give indolizinoindoles 5a-c.
9-Methoxy-2-phenyl-11H-indolizino[8,7-b]indole (5a) was obtained in 85% yield; mp 223-225°C. IR
spectrum, , cm-1: 3080, 2969, 1622, 1581, 1537, 1497, 1438, 1400, 1326, 1309, 1239, 1220, 1158, 1026, 817,
780, 760, 730, 693, 503. UV spectrum, max, nm (log ): 209 (5.34), 221 (5.39), 223 (5.40), 241 (5.48), 273
1
(5.60), 338 (5.82), 345 (5.97). H NMR spectrum, , ppm (J, Hz): 3.81 (3H, s, OCH3); 6.78 (1H, dd, J = 8.3,
J = 2.2, H-8); 6.99 (1H, br. d, J = 1.5, H-1); 7.05 (1H, d, J = 2.2, H-10); 7.17 (1H, d, J = 7.0, H-6); 7.21 (1H, m,
H-4'); 7.39 (2H, m, H-3', H-5'); 7.70 (2H, d, J = 8.2, H-2', H-6'); 7.77 (1H, d, J = 8.3, H-7); 7.96 (1H, dd, J = 7.0,
J = 1.1, H-5); 7.99 (1H, dd, J = 1.5, J = 1.1, H-3); 11.89 (1H, s, NH). 13C NMR spectrum, , ppm: 55.63 (q,
OCH3); 93.36 (d, C-1); 95.40 (d, C-10); 105.06 (d, C-6); 109.26 (d, C-8); 109.50 (s, C-11a); 111.48 (d, C-3);
117.86 (s, C-6b); 119.26 (d, C-5); 119.84 (d, C-7); 124.93 (s, C-11b); 125.66 (d, C-2',6'); 124.65 (d, C-4');
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127.25 (s, C-2); 128.96 (s, C-6a); 129.17 (d, C-3', C-5'); 135.34 (s, C-1'); 139.30 (s, C-10a); 157.20 (s, C-9).
Mass spectrum, m/z (Irel, %): 314 (3), 313 (22), 312 [M]+ (100), 298 (17), 297 (72), 268 (14), 156 (15). Found:
m/z 312.1255 [M]+. C21H16N2O. Calculated: M 312.1257.
9-Methoxy-2-(4-methoxyphenyl)-11H-indolizino[8,7-b]indole (5b) was obtained in 80% yield; mp
245-248°C. IR spectrum, , cm-1: 3392, 3117, 3009, 2961, 2926, 2835, 1646, 1620, 1578, 1547, 1433, 1377,
1339, 1282, 1325, 1159, 1096, 949, 837, 749, 736, 648, 631. UV spectrum, max, nm (log ): 222 (5.29), 276
1
(5.62), 297 (5.69), 333 (5.80), 338 (5.82), 344 (5.84). H NMR spectrum, , ppm (J, Hz): 3.76 (3H, s, OCH3 at
C-9); 3.89 (3H, s, OCH3 at C-4'); 6.63 (1H, dd, J = 8.5, J = 2.2, H-8); 6.96 (1H, br. d, J = 1.5, H-1); 7.05 (1H, d,
J = 2.2, H-10); 7.12 (2H, m, J = 8.2, H-3',5'); 7.22 (1H, d, J = 7.0, H-6); 7.62 (2H, m, J = 8.2, H-2',6'); 7.70 (1H,
d, J = 8.5, H-7); 7.91 (1H, dd, J = 7.0, J = 1.1, H-5); 8.03 (1H, br. d, J = 1.5, H-3); 11.86 (1H, s, NH). 13C NMR
spectrum, , ppm: 55.46 (q, OCH3); 56.22 (q, OCH3); 94.08 (d, C-1); 96.03 (d, C-10); 105.12 (d, C-6); 110.42 (d,
C-8); 110.43 (s, C-11a); 111.81 (d, C-3); 114.46 (d, C-3',5'); 118.66 (s, C-6b); 119.58 (d, C-5); 120.41 (d, C-7);
125.13 (s, C-11b); 124.65 (s, C-1'); 127.18 (s, C-2); 129.45 (s, C-6a); 126.18 (d, C-2',6'); 140.15 (s, C-10a);
158.06 (s, C-9); 160.26 (s, C-4'). Mass spectrum, m/z (Irel, %): 344 (4), 343 (25), 342 [M]+ (100), 328 (13), 327
(50), 284 (13), 171 (14). Found: m/z 342.1365 [M]+. C22H18N2O2 . Calculated: M 342.1363.
2-(3,4-Dichlorophenyl)-9-methoxy-11H-indolizino[8,7-b]indole (5c) was obtained in 77% yield; mp
231-233°C. IR spectrum, , cm-1: 3647, 3385, 3124, 2962, 2833, 1191, 1555, 1498, 1466, 1327, 1220, 1078,
1025, 941, 872, 826, 787, 748, 699, 676. UV spectrum, max, nm (log ): 201 (5.30), 243 (5.49), 270 (5.59), 288
1
(5.66), 336 (5.81), 344 (5.84). H NMR spectrum, , ppm (J, Hz): 3.85 (3H, s, OCH3); 6.78 (1H, dd, J = 8.5,
J = 2.4, H-8); 7.01 (1H, br. d, J = 1.6, H-1); 7.05 (1H, d, J = 2.4, H-10); 7.22 (1H, d, J = 7.1, H-6); 7.61 (1H, d,
J = 8.4, H-5'); 7.70 (1H, dd, J = 8.4, J = 2.2, H-6'); 7.78 (1H, d, J = 8.5, H-7); 7.91 (1H, d, J = 2.2, H-2'); 7.96
(1H, dd, J = 6.8, J = 0.9, H-5); 8.12 (1H, br. d, J = 1.6, H-3); 11.88 (1H, s, NH). 13C NMR spectrum, , ppm:
55.44 (q, OCH3); 93.35 (d, C-1); 95.20 (d, C-10); 105.44 (d, C-6); 109.17 (d, C-8); 109.27 (s, C-11a); 112.16 (d,
C-3); 117.57 (s, C-6b); 119.01 (d, C-5); 119.70 (d, C-7); 124.43 (s, C-11b); 125.04 (s, C-1'); 125.55 (d, C-6');
126.88 (d, C-5'); 128.28 (s, C-2); 128.64 (s, C-6a); 131.04 (d, C-2'); 131.66 (s, C-3'); 136.19 (s, C-4'); 139.13 (s,
C-10a); 157.00 (s, C-9). Mass spectrum, m/z (Irel, %): 382 (64), 381 (25), 380 [M]+ (100), 367 (54), 366 (18), 365
(85), 337 (19). Found: m/z 380.0475 [M]+. C21H14Cl2N2O. Calculated: M 380.0478.
9-Methoxy-2-(4-methoxyphenyl)-11H-indolizino[8,7-b]indole-3,10-dicarbaldehyde (6). POCl3 (0.3 ml)
was added to DMF (5 ml) at 0°C. The solution was left for 30 min and then compound 5b (0.3 g, 0.88 mmol)
was added. The reaction mixture was left for 18 h at room temperature with periodic stirring. 10% Aqueous
sodium acetate (15 ml) was added and the mixture was stirred for an additional 1 h. The reaction mixture was
extracted with chloroform. The extract was washed with water and evaporated. The residue was subjected to
chromatography on an alumina column using methylene chloride as the eluent. The fraction containing the
product was recrystallized from ethyl acetate to give 0.21 g (65%) dialdehyde 6; mp 242-244°C. UV spectrum,

max, nm (log ): 222 (4.42), 234 (4.39), 248 (4.43), 341 (4.31), 386 (4.49), 396 (4.72). 1H NMR spectrum, , ppm
(J, Hz): 3.90 (6H, s, CH3O at C-9 and CH3O at C-4'); 6.86 (1H, d, J = 8.2, H-8); 6.95 (1H, s, H-1); 7.03 (2H, d,
J = 8.4, H-3',5'); 7.50 (2H, d, J = 8.4, H-2',6'); 7.63 (1H, d, J = 7.0, H-6); 7.85 (1H, d, J = 8.2, H-7); 9.52 (1H, d,
J = 7.0, H-5); 9.62 (1H, s, CHO at C-3); 9.66 (1H, s, CHO at C-10); 11.49 (1H, s, NH). 13C NMR spectrum, ,
ppm: 55.35 (q, OCH3); 55.47 (q, OCH3); 94.47 (d, C-1); 109.60 (d, C-6); 111.23 (d, C-8); 113.65 (s, C-10);
113.98 (d, C-3',5'); 115.54 (s, C-11a); 120.50 (s, C-6b); 120.63 (d, C-5); 121.35 (d, C-7); 121.63 (s, C-1'); 122.95
(s, C-3); 128.07 (s, C-6a); 128.19 (s, C-2); 132.56 (d, C-2',6'); 140.01 (s, C-10a); 146.38 (s, C-11b); 160.26 (s,
C-4'); 160.40 (s, C-9); 179.22 (d, CHO at C-3); 185.57 (CHO at C-10). Mass spectrum, m/z (Irel, %): 400 (5), 399
(26), 398 [M]+ (100), 383 (21), 355 (15), 353 (11), 199 (10). Found: m/z 398.1264 [M]+. C24H18N2O4. Calculated:
M 398.1268.
3-Acetyl-9-methoxy-2-phenyl-11H-indolizino[8,7-b]indole (7). Acetyl chloride (0.2 ml) was added with
stirring to a suspension of indolizine 5a (0.2 g) in a mixture of chloroform (5 ml) and pyridine (0.5 ml). The
solid dissolved to give a yellow-green solution. After 30 min, the reaction mixture was diluted by the addition of
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chloroform (10 ml). The solution was washed with three 3-ml water portions and evaporated. The residue was
1
crystallized from 1:1 ethyl acetate–methanol to give 0.15 g (72%) yellow crystalline acetate 7, mp 233°C. H
NMR spectrum, , ppm (J, Hz): 1.96 (3H, s, CH3); 3.85 (3H, s, CH3O); 6.82 (1H, s, H-1); 6.87 (1H, dd, J = 8.2,
J = 2.0, H-8); 7.09 (1H, d, J = 2.0, H-10); 7.41 (2H, m, H-2', H-6'); 7.48 (3H, m, H-3', H-4', H-5'); 7.65 (1H, d,
J = 5.6, H-5); 7.96 (1H, d, J = 8.2, H-7); 9.68 (1H, d, J = 5.6, H-5); 12.15 (1H, s, NH). 13C NMR spectrum, ,
ppm: 29.97 (q, CH3); 55.55 (q, OCH3); 95.14 (d, C-10); 101.69 (d, C-1); 107.49 (d, C-6); 109.96 (d, C-8); 114.87
(s, C-11a); 116.50 (s, C-6b); 120.49 (d, C-5); 121.14 (d, C-7); 121.43 (s, C-3); 127.33 (s, C-1'); 127.65 (s, C-6a);
127.76 (d, C-4'); 128.48 (d, C-3', C-5'); 130.05 (d, C-2', C-6'); 137.38 (s, C-11b); 138.46 (s, C-2); 140.63 (s,
C-10a); 158.57 (s, C-9); 186.88 (s, C=O). Found, %: C 77.57; H 5.05; N 7.85. C23H18N2O2. Calculated, %:
C 77.95; H 5.12; N 7.90.
This work was carried out with the financial support of the Integrated Projects of the Siberian Branch of
the Russian Academy of Sciences with the Academies of Sciences of the Commonwealth of Independent States
(Project No. 79).
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