Synthesis of cytisine derivatives of flavonoids. 2. Aminomethylation of 7-hydroxyisoflavones

Article abstract of DOI:10.1007/s10600-011-0006-2

Aminomethylation of natural 7-hydroxyisoflavones and their analogs by the alkaloid (-)cytisine was studied. Substituted 8-(cytisin-12-yl)methyl-7- hydroxyisoflavones were synthesized.

Full text of DOI:10.1007/s10600-011-0006-2

Chemistry of Natural Compounds, Vol. 47, No. 4, September, 2011 [Russian original No. 4, July-August, 2011]
SYNTHESIS OF CYTISINE DERIVATIVES OF FLAVONOIDS.
2. AMINOMETHYLATION OF 7-HYDROXYISOFLAVONES
1
2*
4
S. P. Bondarenko, M. S. Frasinyuk,
UDC 547.814.5
3
V. I. Vinogradova, and V. P. Khilya
Aminomethylation of natural 7-hydroxyisoflavones and their analogs by the alkaloid (–)cytisine was studied.
Substituted 8-(cytisin-12-yl)methyl-7-hydroxyisoflavones were synthesized.
Keywords: isoflavone, cytisine, electrophilic substitution, aminomethylation.
Considering the valuable biological properties of cytisine and its alkyl derivatives [1], the search for new pathways
for chemical modification of this alkaloid is certainly timely. The combination in one molecule of various fragments of natural
compounds stimulates interest in studying their mutual influence on the biological activity. Therefore, our goal was to investigate
the possibility of using cytisine for aminomethylation of natural 7-hydroxyisoflavones and their analogs methylated on ring B
that are known to be natural antioxidants [2], are used to treat cardiovascular diseases [3], and exhibit hypolipidemic activity
[4].
We found earlier that aminomethylation of 3-hetaryl-7-hydroxycoumarins and 3-hetaryl-7-hydroxychromones occurred
via reaction with the aminal synthesized using cytisine [5, 6]. We studied the aminomethylation of analogs of natural
7-hydroxy-3-arylcoumarins by this alkaloid [7].
Considering the complexity of isolating the desired 8-cytisinylmethylbenzopyranones upon reaction with methylene-
bis-cytisine, we decided to study aminomethylation of natural isoflavones and their analogs using cytisine and formalin because
the presence of electron-donating substituents in their molecules favored the occurrence of the electrophilic substitution reaction.
The starting natural 7-hydroxyisoflavones 1a [8], 1b [9], and 2a [10] and their analogs 1c [11], 2b [12], and 3a and
3b [13] were synthesized from the corresponding 2-hydroxydeoxybenzoins that were prepared under Hoesch reaction conditions
by acylation of the methylene using Vilsmeier reagent or acetic or trifluoroacetic anhydrides with subsequent heterocyclization
that formed the chromone ring.
The search for the optimum conditions for performing the aminomethylation of the natural flavonoids and their
analogs by cytisine consisted of selecting the appropriate solvent and catalyst.
It is known that the Mannich reaction can occur under base- or acid-catalyzed conditions [14]. The most satisfactory
results for introducing cytisine via aminomethylation of the natural isoflavones and their analogs, like for 7-hydroxy-
3-arylcoumarins [7], were obtained using 4-N,N-dimethylaminopyridine (DMAP) as the catalyst. The most suitable solvent in
this instance was propanol-2.
Aminomethylation of the chromone ring occurred upon heating 1a–c, 2a, 2b, 3a, or 3b, cytisine, and formalin in
propanol-2 in the presence of a catalytic amount of DMAP. This formed 8-(cytisin-12-yl)methyl-7-hydroxyisoflavones 4a–c,
5a, 5b, 6a, and 6b.
As we supposed, a 3-aryl substituent with electron-donating methoxyls increased significantly the reactivity of the
chromone ring to electrophilic attack. The reaction of 7-hydroxyisoflavones 1a–c, 2a, 2b, 3a, or 3b with formalin and cytisine
occurred in 3–7 h. This provided evidence of the significant reactivity of the benzopyrone ring in the Mannich reaction.
1) National University of Food Technology, 01601, Ukraine, Kiev, ul. Vladimirskaya, 68; 2) Institute of Bioorganic
and Petroleum Chemistry, National Academy of Sciences of Ukraine, 02094, Ukraine, Kiev, e-mail: mfras@i.kiev.ua;
3) S. Yu. Yunusov Institute of the Chemistry of Plant Substances, Academy of Sciences, Republic of Uzbekistan, Tashkent;
4) Taras Shevchenko Kiev National University, 01033, Ukraine, Kiev, ul. Vladimirskaya, 64. Translated from Khimiya
Prirodnykh Soedinenii, No. 4, July–August, 2011, pp. 536–538. Original article submitted January 31, 2011.
©
604
0009-3130/11/4704-0604 2011 Springer Science+Business Media, Inc.

N
N
HO
O
O
R
4
HO
O
O
R
4
O
R
R
R
R
3
3
R
1
R
1
2
2
4a - c, 5a,b, 6a,b
1a, 4a: R = R = R = H, R = OCH ; 1b, 4b: R = R = H, R = R = OCH ; 1c, 4c: R = OCH , R = R = R = H
1a - c, 2a,b, 3a,b
1
3
4
2
3
1
4
2
3
3
1
3
2
3
4
2a, 5a: R = R = R = H, R = CH ; 2b, 5b: R = H, R = R = OCH , R = CH ; 3a, 6a: R = R = H, R = OCH , R = CF
1
2
3
4
3
1
2
3
3
4
3
1
3
2
3
4
3
3b, 6b: R = OCH , R = R = H, R = CF
1
3
2
3
4
3
We showed previously that aminomethylation of 5,7-dihydroxyisoflavones [15] using aminals formed
6,8-bis-aminomethyl derivatives. We used 5-methylformononetin (1d) to study the influence of the substituents in ring A on
the course of the aminomethylation of the natural isoflavones and their analogs.
As it turned out, the presence of the electron-donating methyl in 1d accelerated its reaction with cytisine and formalin.
The 8-cytisinylmethyl derivative 4d was formed exclusively.
N
N
HO
O
HO
O
O
O
CH
O
3
CH
3
OCH
3
OCH
3
1d
4d
The structures of the synthesized compounds were confirmed by PMR spectroscopy. Thus, PMR spectra of 4–6
contained resonances for protons of both cytisine and the isoflavone fragments. Resonances of the CH -8 protons were
2
observed as two doublets with SSCC 14.9–16.5 Hz, indicating that they were diastereomeric because of the optical centers in
the cytisine fragment.
Thus, we developed the optimum conditions for aminomethylation of natural isoflavones and their analogs by cytisine.
This enabled compounds containing pharmacophores of these natural compounds in one molecule to be synthesized. This
opened new possibilities for chemical modification of the alkaloid cytisine.
EXPERIMENTAL
The course of reactions and purity of products were monitored by TLC on plates (Merck, Germany) with elution by
CHCl :MeOH:Et NH (88:10:2) and EtOAc. PMR spectra of 4–6 were measured in CDCl on a VXR-300 instrument (Varian,
3
2
3
300 MHz) vs. TMS (internal standard) on the ꢀ-scale. Elemental analysis of all compounds agreed with those calculated.
General Method for Preparing 3-Aryl-7-hydroxy-8-(cytisin-12-yl)methylchromones 4a–d, 5a, 5b, 6a, and 6b.
A refluxing solution of 7-hydroxyisoflavone 1a–d, 2a, 2b, 3a, or 3b (2 mmol) in propanol-2 (30 mL) was treated with cytisine
(2.5 mmol), formalin (1 mL, 35%), and DMAP (5 mg), refluxed for 3–7 h (end of reaction determined by TLC), cooled, and
diluted with hexane. The precipitate was filtered off, dried, and crystallized from propanol-2 or propanol-2:hexane.
(1R,5S)-3-{[7-Hydroxy-3-(4-methoxyphenyl)-4-oxo-4H-chromen-8-yl]methyl}-1,2,3,4,5,6-hexahydro-1,5-
methano-8H-pyrido[1,2-a][1,5]diazocin-8-one (4a). Yield 78%, C H N O , mp 196–198°C.
28 26
2 5
PMR spectrum (300 MHz, CDCl , ꢀ, ppm, J/Hz): cytisine protons: 1.84–2.08 (2H, m, CH -8), 2.45–2.65 (3H, m,
3
2
2
3
4
H-9, 11, 13), 3.03–3.18 (3H, m, H-11, 13, 7), 3.86, 3.98 (2H, 2d, J = 15.3, CH -10), 6.01 (1H, dd, J = 6.9, J = 1.2, H-5), 6.55
(1H, dd, J = 8.7, J = 1.2, H-3), 7.32 (1H, dd, J = 6.9, J = 8.7, H-4); isoflavone protons: 3.83 (3H, s, OMe-4ꢁ), 3.95, 4.19 (2H,
2d, J = 14.9, CH -8), 6.79 (1H, d, J = 9.0, H-6), 6.96 (2H, d, J = 9.0, H-3ꢁ, 5ꢁ), 7.47 (2H, d, J = 9.0, H-2ꢁ, 6ꢁ), 7.85 (1H, s,
2
3
4
3
3
2
3
3
3
2
3
H-2), 8.06 (1H, d, J = 9.0, H-5).
605

(1R,5S)-3-{[7-Hydroxy-3-(3,4-dimethoxyphenyl)-4-oxo-4H-chromen-8-yl]methyl}-1,2,3,4,5,6-hexahydro-1,5-
methano-8H-pyrido[1,2-a][1,5]diazocin-8-one (4b). Yield 82%, C H N O , mp 200–201°C.
29 28
2 6
PMR spectrum (300 MHz, CDCl , ꢀ, ppm, J/Hz): cytisine protons: 1.85–2.08 (2H, m, CH -8), 2.46–2.67 (3H, m,
3
2
2
3
4
H-9, 11, 13), 3.05–3.21 (3H, m, H-11, 13, 7), 3.87, 3.98 (2H, 2d, J = 15.3, CH -10), 6.03 (1H, dd, J = 6.9, J = 1.2, H-5), 6.55
(1H, dd, J = 8.7, J = 1.2, H-3), 7.32 (1H, dd, J = 6.9, J = 8.7, H-4); isoflavone protons: 3.90, 3.92 (6H, 2s, OMe-3ꢁ,
2
3
4
3
3
2
3
3
3
OMe-4ꢁ), 3.92, 4.19 (2H, 2d, J = 15.4, CH -8), 6.80 (1H, d, J = 9.0, H-6), 6.92 (1H, d, J = 8.4, H-5ꢁ), 7.02 (1H, dd, J = 8.4,
2
4
4
3
J = 1.8, H-6ꢁ), 7.19 (1H, d, J = 1.8, H-2ꢁ), 7.89 (1H, s, H-2), 8.07 (1H, d, J = 9.0, H-5).
(1R,5S)-3-{[7-Hydroxy-3-(2-methoxyphenyl)-4-oxo-4H-chromen-8-yl]methyl}-1,2,3,4,5,6-hexahydro-1,5-
methano-8H-pyrido[1,2-a][1,5]diazocin-8-one (4c). Yield 77%, C H N O , mp 236–237°C.
28 26
2 5
PMR spectrum (300 MHz, CDCl , ꢂꢀ, ppm, J/Hz): cytisine protons: 1.82–2.07 (2H, m, CH -8), 2.45–2.63 (3H, m,
3
2
2
3
4
H-9, 11, 13), 3.03–3.19 (3H, m, H-11, 13, 7), 3.87, 3.97 (2H, 2d, J = 15.3, CH -10), 6.00 (1H, dd, J = 6.9, J = 1.2, H-5), 6.54
(1H, dd, J = 8.7, J = 1.2, H-3), 7.29 (1H, dd, J = 6.9, J = 8.7, H-4); isoflavone protons: 3.78 (3H, s, OMe-2ꢁ), 3.89, 4.18 (2H,
2d, J = 15.3, CH -8), 6.78 (1H, d, J = 9.0, H-6), 6.98 (2H, m, H-3ꢁ, 5ꢁ), 7.35 (2H, m, H-4ꢁ, 6ꢁ), 7.85 (1H, s, H-2), 8.04 (1H, d,
2
3
4
3
3
2
3
2
3
J = 9.0, H-5).
(1R,5S)-3-{[7-Hydroxy-5-methyl-3-(4-methoxyphenyl)-4-oxo-4H-chromen-8-yl]methyl}-1,2,3,4,5,6-hexahydro-
1,5-methano-8H-pyrido[1,2-a][1,5]diazocin-8-one (4d). Yield 63%, C H N O , mp 164–166°C.
29 28
2 5
PMR spectrum (300 MHz, CDCl , ꢂꢀ, ppm, J/Hz): cytisine protons: 1.84–2.06 (2H, m, CH -8), 2.43–2.67 (3H, m,
3
2
2
3
4
H-9, 11, 13), 2.98–3.22 (3H, m, H-11, 13, 7), 3.82, 3.92 (2H, 2d, J = 14.3, CH -10), 6.01 (1H, dd, J = 6.9, J = 1.2, H-5), 6.54
(1H, dd, J = 8.7, J = 1.2, H-3), 7.32 (1H, dd, J = 6.9, J = 8.7, H-4); isoflavone protons: 2.74 (3H, s, Me-5), 3.82 (3H, s,
2
3
4
3
3
2
3
3
OMe-4ꢁ), 3.90, 4.19 (2H, 2d, J = 15.4, CH -8), 6.57 (1H, s, H-6), 6.95 (2H, d, J = 9.0, H-3ꢁ, 5ꢁ), 7.42 (2H, d, J = 9.0, H-2ꢁ,
2
6ꢁ), 7.75 (1H, s, H-2).
(1R,5S)-3-[(7-Hydroxy-2-methyl-3-phenyl-4-oxo-4H-chromen-8-yl)methyl]-1,2,3,4,5,6-hexahydro-1,5-methano-
8H-pyrido[1,2-a][1,5]diazocin-8-one (5a). Yield 82%, C H N O , mp 246–248°C.
28 26
2 4
PMR spectrum (300 MHz, CDCl , ꢀ, ppm, J/Hz): cytisine protons: 1.87–2.02 (2H, m, CH -8), 2.44–2.61 (3H, m,
3
2
2
3
4
H-9, 11, 13), 3.03–3.18 (3H, m, H-11, 13, 7), 3.83, 3.93 (2H, 2d, J = 15.4, CH -10), 5.94 (1H, dd, J = 6.9, J = 1.2, H-5), 6.50
(1H, dd, J = 8.7, J = 1.2, H-3), 7.30 (1H, dd, J = 6.9, J = 8.7, H-4); isoflavone protons: 2.25 (3H, s, Me-2), 3.89, 4.16 (2H,
2d, J = 15.4, CH -8), 6.73 (1H, d, J = 9.0, H-6), 7.21, 7.27, 7.38 (5H, m, Ph-3), 7.95 (2H, d, J = 9.0, H-5).
2
3
4
3
3
2
3
3
2
(1R,5S)-3-{[7-Hydroxy-2-methyl-3-(3,4-dimethoxyphenyl)-4-oxo-4H-chromen-8-yl]methyl}-1,2,3,4,5,6-
hexahydro-1,5-methano-8H-pyrido[1,2-a][1,5]diazocin-8-one (5b). Yield 78%, C H N O , mp 229–230°C.
30 30
2 6
PMR spectrum (300 MHz, CDCl , ꢀ, ppm, J/Hz): cytisine protons: 1.84–2.09 (2H, m, CH -8), 2.47–2.66 (3H, m,
3
2
2
3
4
H-9, 11, 13), 3.05–3.22 (3H, m, H-11, 13, 7), 3.86, 3.98 (2H, 2d, J = 15.3, CH -10), 6.01 (1H, dd, J = 6.9, J = 1.2, H-5), 6.55
(1H, dd, J = 8.7, J = 1.2, H-3), 7.33 (1H, dd, J = 6.9, J = 8.7, H-4); isoflavone protons: 2.28 (3H, s, Me-2), 3.86, 3.90 (6H,
2s, OMe-3ꢁ, OMe-4ꢁ), 3.91, 4.20 (2H, 2d, J = 15.4, CH -8), 6.75 (1H, d, J = 9.0, H-6), 6.81 (2H, m, H-2ꢁ, 6ꢁ), 6.92 (1H, d,
J = 8.4, H-5), 7.98 (1H, d, J = 9.0, H-5).
2
3
4
3
3
2
3
2
3
3
(1R,5S)-3-{[7-Hydroxy-3-(4-methoxyphenyl)-4-oxo-2-trifluoromethyl-4H-chromen-8-yl]methyl}-1,2,3,4,5,6-
hexahydro-1,5-methano-8H-pyrido[1,2-a][1,5]diazocin-8-one (6a). Yield 56%, C H F N O , mp 228-230°C.
29 25 3
2 5
PMR spectrum (300 MHz, CDCl , ꢀ, ppm, J/Hz): cytisine protons: 1.87–2.09 (2H, m, CH -8), 2.54–2.69 (3H, m,
3
2
2
3
4
H-9, 11, 13), 3.13–3.22 (3H, m, H-11, 13, 7), 3.87, 3.99 (2H, 2d, J = 14.2, CH -10), 6.03 (1H, dd, J = 6.9, J = 1.2, H-5), 6.55
(1H, dd, J = 8.7, J = 1.2, H-3), 7.34 (1H, dd, J = 6.9, J = 8.7, H-4); isoflavone protons: 3.84 (3H, s, OMe-4ꢁ), 3.92, 4.21 (2H,
2d, J = 16.5, CH -8), 6.84 (1H, d, J = 9.0, H-6), 6.95 (2H, d, J = 8.2, H-3ꢁ, 5ꢁ), 7.17 (2H, d, J = 8.2, H-2ꢁ, 6ꢁ), 7.99 (1H, d,
2
3
4
3
3
2
3
3
3
2
3
J = 9.0, H-5).
(1R,5S)-3-{[7-Hydroxy-3-(2-methoxyphenyl)-4-oxo-2-trifluoromethyl-4H-chromen-8-yl]methyl}-1,2,3,4,5,6-
hexahydro-1,5-methano-8H-pyrido[1,2-a][1,5]diazocin-8-one Hydrochloride (6b). Yield 47%, C H F N O ·HCl,
29 25 3
2 5
mp 291–292°C.
PMR spectrum (300 MHz, DMSO-d , ꢀ, ppm, J/Hz): cytisine protons: 1.72–2.03 (2H, m, CH -8), 2.73 (3H, m, H-9,
6
2
2
3
11, 13), 3.12–3.62 (3H, m, H-11, 13, 7), 3.83, 4.03 (2H, 2d, J = 15.3, CH -10), 6.32 (2H, m, H-3, 5), 7.47 (1H, dd, J = 6.9,
J = 8.7, H-4); isoflavone protons: 3.80 (3H, s, OMe-2ꢁ), 4.36 (2H, s ,CH -8), 6.40 (1H, d, J = 9.0, H-6), 7.13 (2H, m, H-3ꢁ,
5ꢁ), 7.44 (2H, m, H-4ꢁ, 6ꢁ), 8.05 (1H, d, J = 9.0, H-5).
2
3
3
2
3
606

REFERENCES
1.
2.
C. C. Boido, B. Tasso, V. Boido, and F. Sparatore, Farmaco, 58, 265 (2003).
J. Torel, J. Gillard, and P. Gillard, Phytochemistry, 25, 383 (1986).
3.
4.
P. Da Re, L. Verlicchi, and I. Setniker, J. Med. Chem., 10, 266 (1966).
M. T. Siddiqui and M. Siddiqui, Lipids, 11, 243 (1976).
5.
6.
7.
8.
V. I. Vinogradova, M. S. Frasinyuk, A. V. Turov, and V. P. Khilya, Khim. Prir. Soedin., 145 (2007).
M. S. Frasinyuk, V. I. Vinogradova, A. V. Turov, and V. P. Khilya, Khim. Prir. Soedin., 237 (2007).
S. P. Bondarenko, M. S. Frasinyuk, V. I. Vinogradova, and V. P. Khilya, Khim. Prir Soedin., 649 (2010).
E. T. Bailey, Aust. J. Agric. Res., 22, 731 (1971).
9.
M. Shamma and L. D. Stiver, Tetrahedron, 25, 3887 (1969).
10.
11.
12.
13.
14.
15.
D. K. Bhardwaj, R. Murari, T. R. Seshadri, and R. Singh, Phytochemistry, 15, 352 (1976).
Y. Kawase, K. Ogawa, S. Miyoshi, and K. Fukui, Bull. Chem. Soc. Jpn., 33, 1240 (1960).
A. S. Kukla and T. R. Seshadri, Indian J. Chem., 1, 343 (1963).
M. S. Frasinyuk, S. P. Bondarenko, and V. P. Khilya, Khim. Prir. Soedin., 117 (2006).
M. Tramontini, Synthesis, 12, 703 (1973).
S. P. Bondarenko, A. V. Levenets, M. S. Frasinyuk, and V. P. Khilya, Khim. Prir. Soedin., 211 (2003).
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