Novel quinine, lupinine, and anabasine derivatives containing dithiophosphinate groups

Article abstract of DOI:10.1007/s10593-012-1013-3

A three-component, atom-economic reaction between natural quinine, lupinine, or anabasine, secondary phosphines, and elemental sulfur occurs under mild conditions to yield previously unknown optically active dithiophosphinates.

Full text of DOI:10.1007/s10593-012-1013-3

Chemistry of Heterocyclic Compounds, Vol. 48, No. 3, June, 2012 (Russian Original Vol. 48, No. 3, March, 2012)
NOVEL QUININE, LUPININE, AND ANABASINE DERIVATIVES
CONTAINING DITHIOPHOSPHINATE GROUPS
A. V. Artem'ev1, S. F. Malysheva1, N. K. Gusarova1, N. A. Belogorlova1,
S. V. Fedorov1, B. V. Timokhin1, V. I. Smirnov1, and B. A. Trofimov1*
A three-component, atom-economic reaction between natural quinine, lupinine, or anabasine,
secondary phosphines, and elemental sulfur occurs under mild conditions to yield previously unknown
optically active dithiophosphinates.
Keywords: anabasine, bis(2-arylethyl)phosphines, dithiophosphinates, elemental sulfur, lupinine,
quinine, synthesis, three-component reaction.
The alkaloids quinine, lupinine, and anabasine are readily isolated from natural sources and possess a
broad spectrum of biological activity [1-4]. They are used in the design of pharmacological preparations and
pesticides. Derivatives of these alkaloids are also being actively studied including analgesic compounds with
markedly greater activity than cocaine and procaine (lupinine derivatives [5]), agents lowering the desire to
smoke (anabasine hydrochloride [6]), antimalarial medications (quinine sulfate and hydrochloride [7]), and
substances possessing antitumor, antituberculous, hepatoprotective, antiviral, antibacterial, anticholinesterase
and antifungal activity (phosphorylated derivatives of lupinine and anabasine [8]). Anabasine sulfate is an
efficient insecticide used in agriculture [9, 10].
The search for novel synthetic intermediates in the design of biologically active alkaloid-based
preparations is also continuing to develop. In this regard, modification of alkaloids via the introduction of
pharmacophoric functional groups into these molecules is particularly promising.
_______
*To whom correspondence should be addressed, e-mail: gusarova@irioch.irk.ru.
1
A. E. Favorsky Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 1 Favorsky St.,
Irkutsk 664033, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 478-482, March, 2012. Original
article submitted January 11, 2011.
448
0009-3122/12/4803-0448©2012 Springer Science+Business Media, Inc.

Investigating the modification of alkaloids, we have carried out a targeted synthesis of the previously
unknown dithiophosphinates of quinine, lupinine, and anabasine via a three-component, atom-economic
reaction between the indicated alkaloids, secondary phosphines, and elemental sulfur. It is known that
-
compounds containing the dithiophosphinate group (PS2 ) show marked biological activity [11, 12].
Experiments have shown that natural quinine (1) reacts with the secondary phosphines 2a,b and
elemental sulfur (molar ratio of reagents 1.0:1.1:0.25) under mild conditions (60ºC, 20 min, EtOH) to give the
quinine dithiophosphinates 3a,b in 90% and 84% yield, respectively.
A three-component reaction of natural lupinine (4), the secondary phosphine 2a, and elemental sulfur
proceeds under analogous conditions to give the lupinine dithiophosphinate 5 in 95% yield.
The anabasine dithiophosphinate 7 was prepared by the same scheme from natural anabasine (6), the
secondary phosphine 2a, and elemental sulfur in 87% yield.
The choice of the secondary phosphines 2a,b was not accidental: they are readily prepared from red
phosphorus and styrene or 2-vinylpyridine [13-15].
1
Assignment of the H and 13C NMR signals in the synthesized quinine, lupinine, and anabasine
derivatives was based on the known spectroscopic data for the previously studied salts of these alkaloids
(sulfates, halides, perchlorates etc.). Analysis of the spectroscopic data for the latter showed that exchange of the
counter-ion has practically no effect on the NMR parameters of the cations of the protonated alkaloids. Hence the
1H and 13C NMR spectroscopic parameters for the cationic part of the obtained quinine dithiophosphinates 3a,b
agree well with the NMR data for quinine hydrochloride. The 1H-1H and 1H-13C 2D NMR spectra of the quinine
dithiophosphinates 3a,b also confirm the correctness of the assignments given. The HSQC and HMBC
correlation results for the quinine bis(2-phenylethyl)dithiophosphinate 3a are given in Table 1.
Thus based on a three-component, atom-economic reaction between natural lupinine, anabasine, or
quinine, available secondary phosphines, and elemental sulfur we have developed an efficient one-pot method
of synthesis of the previously unknown pharmacophoric dithiophosphinates which are of promise for creating
pharmacologically active preparations and pesticides.
EXPERIMENTAL
IR spectra were recorded on a Bruker Vertex 70 spectrometer using KBr pellets. 1H, 13C, and 31P NMR
spectra were obtained on a Bruker DPX-400 spectrometer (400, 102, and 162 MHz, respectively) for CDCl3
solutions with HMDS (0.05 ppm) as internal standard and 85% H3PO4 as external standard for the 31P NMR
449

TABLE 1. Results of the HSQC and HMBC Experiments for Salt 3a
Atom or group
δ, ppm
HSQC
HMBC
H-2
3.39-3.56
2.08-2.15
1.95-2.00
2.66-2.77
3.39-3.56
4.61-4.68
2.08-2.15
4.01
59.9
37.2; 45.1; 65.7
26.7; 143.8
3-CH2
H-4
19.1
26.7
—
—
H-5
37.2
6-CH2
7-CH2
8-CH2
CH3O
CH2=
CH2=CH
CHOH
H-2'
54.7
37.2; 45.1; 65.7; 137.2
—
45.1
24.5
—
57.2
100.5; 131.4; 158.5
37.2; 137.2
5.01; 5.05
5.53
117.1
137.2
65.7
27.6; 37.2; 54.7
119.1; 125.6
6.85
8.72
147.1
122.5
100.5
119.1
131.4
119.1; 125.6
H-3'
7.66
65.7; 125.6; 143.7; 147.1; 158.5
131.4; 143.7; 143.8; 158.5
100.5; 125.6; 143.7; 158.5
119.1; 125.6; 143.7; 158.5
—
H-5'
7.47
H-7'
7.33
H-8'
7.98
NH, OH
CH2P
CH2Ph
C6H5
10.98
—
2.34-2.41
3.04-3.11
7.11-7.25
43.7
29.8
29.8; 141.8
128.3
141.8 (i-С); 128.3 (m-С);
125.8 (p-С); 128.2 (o-С)
29.8; 125.8; 128.2; 141.8
spectra. Assignment of the signals in the 1H and 13C NMR spectra was made using COSY, NOESY, HSQC, and
HMBC homo- and heteronuclear experiments. Specific optical rotations were determined on a Polamat A
polarimeter using EtOH. Elemental analysis was performed on a Flash EA 1112 instrument. The secondary
phosphines 2a,b were synthesized from red phosphorus and styrene [14] or 2-vinylpyridine [15], respectively.
Technical grade ethanol (96%) was used as solvent. All of the experiment stages were carried out under an inert
argon atmosphere.
Synthesis of Dithiophosphinates 3a,b, 5, 7 (General Method). Orthorhombic sulfur (0.064 g, 0.25 mmol)
was added to a solution of the secondary phosphine 2a,b (1.10 mmol) and quinine, lupinine, or anabasine
(1.0 mmol) in EtOH (10 ml) at 23-25ºC. The suspension obtained was stirred at 60ºC to dissolution of the sulfur
precipitate (about 20 min) to form a colorless, transparent solution. The solvent was evaporated, and the residue
was washed with hexane (2×15 ml) and ether (5 ml) and dried in vacuo at 40-45ºC (1 mm Hg).
(2S,4S,5R)-2-[(R)- Hydroxy(6-methoxyquinolin-4-yl)methyl]-2-methyl-5-vinylquinuclidinium Bis-
(2-phenylethyl)dithiophosphinate (3a). Yield 0.57 g (90%) Colorless powder, mp 138-140ºC (Et2O),
D23 -228º (c = 2.0). IR spectrum, , cm-1: 3422, 3278, 3082, 3060, 3024, 2999, 2929, 2905, 2831, 2750, 2576,
2541, 2492, 2376, 2346, 1947, 1638, 1620, 1602, 1590, 1509, 1495, 1473, 1453, 1431, 1400, 1364, 1339, 1320,
1301, 1258, 1241, 1228, 1206, 1173, 1131, 1094, 1082, 1028, 1000, 947, 919, 879, 855, 831, 801, 751, 718,
698, 670, 639, 613, 574, 553, 529, 511, 488, 467. 1H NMR spectrum, , ppm (J, Hz): 1.18-1.26 (1H, m, H-3-е);
1.77-1.85 (1H, s, H-8-e); 1.95-2.00 (1H, m, H-4); 2.08-2.15 (2H, m, H-3-a, 8-a); 2.34-2.41 (4H, m, 2CH2P);
2.66-2.77 (1H, m, H-5); 3.04-3.11 (4H, m, 2CH2Ph); 3.26-3.32 (1H, m, H-6-e); 3.39-3.56 (3H, m, H-2,6-a,7-e);
3
3
4.01 (3H, s, CH3O); 4.61-4.68 (1H, m, H-7-a); 5.01 (1H, d, J = 11.6) and 5.05 (1H, d, J = 17.1, H2C=); 5.53
(1H, dd, 3J = 10.6, 3J = 17.1, HC=CH2); 6.85 (1H, s, CHOH); 7.11-7.25 (10H, m, Н Ph); 7.33 (1H, dd, 3J = 2.3,
3J = 9.1, H-7'); 7.47 (1H, d, 3J = 2.2, H-5'); 7.66 (1H, d, 3J = 4.4, H-3'); 7.98 (1H, d, 3J = 9.1, H-8'); 8.72 (1H, d,
3J = 4.4, H-2'); 10.98 (2Н, br. s, NH, OH). 13C NMR spectrum, , ppm (J, Hz): 19.1 (C-3); 24.5 (C-8); 26.7
(C-4); 29.8 (CH2Ph); 37.2 (C-5); 43.7 (d, 1JC–P = 50.5, CH2P ); 45.1 (C-7); 54.7 (C-6); 57.2 (CH3O); 59.9 (C-2);
65.7 (CHOH); 100.5 (C-5'); 117.1 (=CH2); 119.1 (C-7'); 122.5 (C-3'); 125.6 (C-9'); 125.8 (C-p); 128.2 (C-o);
3
128.3 (C-m); 131.4 (C-8'); 137.2 (CH=CH2); 141.8 (d, JC–P = 17, C-i); 143.7 (C-10'); 143.8 (C-4'); 147.1 (C-2');
450

1
158.5 (C-6'). 31P NMR spectrum, , ppm (J, Hz): 69.2 (satellite d, JC–P = 49.3). Found, %: C 68.50; H 6.68;
N 4.37; P 4.98; S 9.98, C36H43N2O2PS2. Calculated, %: C 68.54; H 6.87; N 4.44; P 4.91; S 10.17.
(2S,4S,5R) 2-[(R)-Hydroxy(6-methoxyquinolin-4-yl)methyl]-2-methyl-5-vinylquinuclidinium Bis-
23
[2-(2-pyridyl)ethyl]dithiophosphinate (3b). Yield 0.53 g (84%). Colorless, viscous liquid, D = -225º
(c = 2.1). IR spectrum, , cm-1: 3439, 1641, 1622, 1600, 1569, 1510, 1475, 1434, 1367, 1344, 1241, 1228, 1131,
1
1051, 1028, 1003, 948, 855, 832, 763, 718, 668, 616, 520, 468. H NMR spectrum, , ppm (J, Hz): 1.33-1.40
(1H, m, H-3-e); 1.91-1.98 (1H, m, H-8-e); 2.15-2.25 (3H, m, H-3-a,4,8-a); 2.57-2.70 (4H, m, 2CH2P); 2.76-2.84
(1H, m, H-5); 3.32-3.56 (5H, m, 2CH2Py, H-6-e); 3.65-3.71 (2H, m, H-2,7-e,); 3.88-3.94 (1H, m, H-6-a); 4.09
3
3
(3H, s, CH3O); 4.75-4.82 (1H, m, H-7-a); 5.10 (1H, d, J = 10.4) and 5.15 (1H, d, J = 17.1, H2C=); 5.61-5.69
(1H, dd, 3J = 10.4, 3J = 17.1, HC=CH2); 7.08 (1H, s, CHOH); 7.15 (1H, dd, 3J = 2.3, 3J = 9.1, H-7'); 7.25 (2Н, d,
3
3
3J = 7.6, H-3 Py); 7.41-7.43 (2H, m, H-5 Py); 7.52 (1H, s, H-5'); 7.64 (2H, dd, J = 7.6 and J = 7.6, H-4 Py);
7.88 (1H, d, 3J = 4.4, H-3'); 8.07 (1H, d, 3J = 9.1, H-8'); 8.48 (2H, d, 3J = 4.2, H-6 Py); 8.87 (1H, d, 3J = 4.4, H-
13
2'). C NMR spectrum, , ppm (J, Hz): 19.4 (C-3); 24.7 (C-8); 27.0 (C-4); 32.7 (CH2Py); 37.2 (C-5); 41.6 (d,
1JC–P = 51.3, CH2P); 45.3 (C-7); 54.7 (C-6); 57.2 (CH3O); 59.7 (C-2); 66.1 (CHOH); 100.6 (C-5'); 116.9
(=CH2), 119.0 (C-7'); 121.1(C-3 Py); 122.6 (C-3'); 123.0 (C-5 Py); 125.9 (C-9'); 131.7 (C-8'); 136.6 (C-4 Py);
137.6 (CH=CH2); 144.3 (C-10'); 144.5 (C-4'); 147.3 (C-2'); 148.7 (C-6 Py); 158.5 (C-6'); 161.5 (d, 3JC–P = 17.3, C-
2 Py). 31P NMR spectrum, , ppm (J, Hz): 70.0 (satellite d, 1JC–P = 50.0). Found, %: C 64.41; H 6.28; N 8.60; P
4.78; S 10.22. C34H41N4O2PS2. Calculated, %: C 64.53; H 6.53; N 8.85; P 4.89; S 10.13.
(1R,9aR)-1-(Hydroxymethyl)octahydro-2H-quinolizinium
Bis(2-phenylethyl)dithiophosphinate
(5). Yield 0.454 g (95%). Needle crystals, mp 186-188ºC (EtOH), D23 = -19.0º (c = 2.0). IR spectrum, , cm-1:
3348, 3311, 3106, 3084, 3061, 3023, 3000, 2941, 2865, 2766, 2719, 2594, 2512, 1957, 1939, 1885, 1868, 1709,
1656, 1601, 1583, 1495, 1452, 1426, 1401, 1378, 1364, 1349, 1335, 1314, 1270, 1262, 1240, 1214, 1191, 1159,
1124, 1107, 1077, 1057, 1050, 1030, 1015, 996, 988, 948, 931, 905, 878, 859, 837, 766, 754, 739, 695, 609,
1
569, 537, 517, 509, 472. H NMR spectrum, , ppm (J, Hz): 1.15-1.25 (1H, m, H-8-a); 1.38–2.05 (11H, m,
H-2,3,7,9-CH2, Н-4-а,6-а,8-е); 2.31-2.38 (4H, m, 2CH2P); 2.48-2.61 (1H, m, H-1); 2.67-2.75 (1H, m, H-9a);
3.06–3.13 (4H, m, 2CH2Ph); 3.57-3.62 (1H, m, H-6-е); 3.77-3.83 (1H, m, H-4-е); 3.94-3.97 (1Н, m) and
4.10-4.14 (1H, m, CH2OH); 7.23-7.37 (10H, m, Н Ph); 10.02 (2H, br. s, NH, OH). 13C NMR spectrum, , ppm
(J, Hz): 17.4; 18.3 (C-3); 19.6 (C-8); 22.1 (C-7); 22.2; 23.0 (C-9); 27.7; 28.0 (C-2); 30.0 (CH2Ph); 39.7 (C-1);
1
43.9 (d, JC–P = 50.0, CH2P); 45.1; 53.3 (C-6); 56.3; 57.1 (C-4); 58.9 (C-10); 61.4 (C-9a); 62.7 (C-10); 67.1
(C-9a); 125.7 (C-p); 128.2 (C-o); 128.3 (C-m); 142.4 (d, 3JC–P = 16.9, С-i). 31P NMR spectrum, , ppm (J, Hz):
1
68.6 (satellite d, JC–P = 49.3). Found, %: C 65.70; H 8.08; N 2.85; P 6.40; S 13.44. C26H38NOPS2. Calculated,
%: C 65.65; H 8.05; N 2.94; P 6.51; S 13.48.
(S)-2-(3-Pyridyl)piperidinium Bis(2-phenylethyl)dithiophosphinate (7). Yield 0.41 g (87%).
Colorless powder, mp 159-161ºC (EtOH–hexane), D = -4.5º (c = 2.0). IR spectrum, , cm-1: 3484, 3055,
23
3023, 2999, 2943, 2928, 2861, 2753, 2677, 2542, 2446, 1986, 1958, 1873, 1813, 1756, 1600, 1578, 1547, 1495,
1482, 1452, 1424, 1403, 1360, 1339, 1223, 1204, 1278, 1267, 1258, 1240, 1222, 1205, 1192, 1155, 1122, 1103,
1076, 1048, 1029, 1019, 1005, 948, 904, 870, 852, 838, 808, 799, 766, 743, 712, 699, 583, 571, 517, 490, 443.
1H NMR spectrum, , ppm (J, Hz): 1.66-2.10 (6H, m, 3,4,5-СН2); 2.19–2.24 (4H, m, 2CH2P); 2.89-2.96 (4H, m,
2
3
3
2
2CH2Ph); 3.06 (1H, ddd, J = 12.3, J = 9.1, J = 3.4, H-6-a); 3.88 (1H, d, J = 12.3, H-6-е); 4.19 (1H, dd,
3J = 11.2, 3J = 4.6, H-2); 7.13-7.29 (11H, m, Н Ph, H-5 Py); 8.24 (1H, d, 3J = 7.8, H-4 Py); 8.47 (1H, d, 3J = 4.0,
H-6 Py); 8.74 (1H, s, H-2 Py); 9.20 (2H, br. s, NH2 ). 13C NMR spectrum, , ppm (J, Hz): 22.2 (C-4); 22.9
(C-5); 29.7 (CH2Ph); 30.7 (C-3); 43.5 (d, JC–P = 49.8, CH2P); 45.5 (C-6); 58.8 (C-2); 124.0 (C-5 Py); 125.8
+
1
3
(C-p); 128.3 (C-o); 128.3 (C-m); 132.1 (C-3 Py); 136.2 (C-4 Py); 142.1 (d, JC–P = 17.0, C-i); 148.9 (C-2 Py);
150.3 (C-6 Py). 31P NMR spectrum, , ppm (J, Hz): 68.0 (satellite d, 1JC–P = 49.9). Found, %: C 66.51; H 7.18;
N 5.78; P 6.47; S 13.54. C26H33N2PS2. Calculated, %: C 66.63; H 7.10; N 5.98; P 6.61; S 13.68.
This work was carried out with the financial support of the Russian Foundation for Basic Research
(grant No. 11-03-00334) and the Grants Council of the President of the Russian Federation (grant NSh-3230-
2010.3).
451

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