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On Homothiopterocarpan.

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Valenti, Rampa, Barili and Da Re
Arch. Pharm.
Arch. Pharm. (Weinheim) 318, 744-747 (1985)
On Homothiopterocarpan
Piero Valenti, Angela Rampa, Pier L. Barili+) and Paolo Da Re*
Institute of Pharmaceutical Chemistry, University of Bologna, 40126 Bologna, Italy and
+) Institute of Organic Chemistry, University of Pisa
Eingegangen am 11. Mai 1984
The synthesis and some spectral data of a new type of heterocyclic ring system (c@,c$,c6,c6,
homothiopterocarpan) are describcd.
Uber Hornothiopterocarpan
Die Synthese und einige spektrale Daten einer neuen Art von Cs0,C5S, C6,C6-hetcrozyclischem
Ringsystem wird beschrieben.
Due to our interest in the chemistry of flavonoids, we report in this paper the synthesis
and some spectral data of a new prototype of benzothiopyranobenzopyran type structure
belonging to c5o,c5s,c6,c6 ring system. The new compound isolated as (k) cis
6a, 12a-dihydro-6H,7H-[ l]benzothiopyrano[4,3-b]-[l]benzopyran(l) (homothiopterocarpan) is the sulfur analogue of the earlier described') homopterocarpan ( c ~ o , c ~ o , c ~ , c ~
ring system) 2.
& &
Compound 1 has been prepared in three steps by condensing thiochromanone with
salicylaldehyde to the 3-(2-hydroxybenzyl) intermediate 3, which after reduction with
NaBH, to the corresponding sec. alcohol 4, was cyclized by 50 % AcOH to 1.It may be of
interest to remark that in the first step of the synthesis, unlike that observed with
chromanone, the 3-benzyl rather than 3-benzylidene derivative was isolated. The IH NMR
and I3C NMR data comparison between 3 and the analogous oxygen intermediate 5
previously described'), strongly supports this conclusion'). Moreover compound 3, unlike
5, shows a typical ally1 coupling (1.8 Hz) between CH, (exo) protons and =CH vinyl
Tablel: ' H NMR and 13C N M R Data of 3 and 5 [ b (ppm)]
0 VCH Verlagsgesellschaft mbH, D-6940Weinheim, 1985
On Homothiopterocarpan
'H NMR: H(5)8.60 (lH, m)
CH2 3.94 (2H, s)
"C NMR: C(2) 136.6
C(3) 34.0
8.04 (lH, m)
5.21 (2H, d, J = 1.8 Hz)
The structure of 1 is consistent with its mass spectrum in which the molecular ion at m/e
254 and two characteristic fragments at m/e 148 and 147 attributable to benzothiopyrylium
ions are recognizable.
m / r 148
m / e 147
100 %
lo3 115
(7891 1107
1 1
The 'H NMR and 13CNMR spectra (see Exp. Part) also are consistent with the above
structure. As observed with homopterocarpan (2) the coupling constant value between
H(6a) and H(12a) of 1 is consistent with the value given by Karpfus3)for the cis
configuration of vicinal protons. This stereochemistry is also confirmed on the basis of the
known additivity rule4)of 13Cchemical shift applied to the significative carbons of 1 and 2
which gives similar values.
Experimental Part
A solution of 16.4 g (0.1 mole) of thiochromanone and 12.2g (0.1 mole) of salicylaldehyde in 200 ml of
Valenti, Ramva, Barili and Da Re
Arch. Pharm.
85 % H3P04was heated at 80" for 6 h. After cooling the mixture was poured into ice-water and the
separated solid washed (H20) and dried. The crude product on crystallizing from EtOH gave 21.4 g
(80 % yield) of solid m.p. 177-178'. 'H NMR: 6 (ppm) = 8.60 (lH, m) H(5); 8.04 (lH, s) H(2);
7.60-6.90 (7H, m) aromatic protons; 3.94 (2H, s) H(3a). 13C NMR: 6 (ppm) = 180.7 C(4); 154.9
C(2'); 137.8 C(8a); 136.6 C(2); 136.1 C(3); 131.4 C(7); 130.7 C(4a); 130.2, 129.0 C(4') and C(6');
128.4C(8); 127.7,126.3 C(5) and C(6); 125.5C(1'); 120.3C(5'); 118.1C(3'); 34.0 C(3a). C,,H,,O,S
(268.2). Calcd.: C 71.6 H 4.51; Found: C 71.8 H 4.48.
Reduction of 3 with NaBH4. homothiopterocarpan (l),3-(2-hydroxybenzyl)-thiochromane (6),
To a solution of 5.4 g (0.02 mole) of 3 in 100 ml dioxane, 1.5 g (0.04 mole) NaBH, were added. The
reaction mixture was stirred for 5 d at room temp. and then quenched by the addition of 20 ml solution
saturated NaCI. After dilution with 150 ml of H20, the solution was extracted with three 50 ml
portions CHCI, and the organic layer washed (H20,saturated NaCI), dried (MgSO,) and evaporated
to dryness. The residue was chromatographated on silica gel (ethyl acetate/petroleum ether, 1 : 4) and
four products were separated (order of elution) and identified:
1) 0.25 g (5 %) of 1, m.p. 110-113" (AcOH-H,O).
2) 1 g (20 %) of 3-(2-hydroxybenzyl)thiochromane(6), m.p. 117-120" (AcOH-H20). 'H NMR: 6
(ppm) = 7.25-6.70 (8H, m) aromatic protons; 3.00-2.45 (7H, m) aliphatic protons. 13C NMR: 6
(ppm) = 153.7C(2'); 132.6,132.1C(8a) and C(4a); 131.1, 130.4C(7) and C(4'); 127.5,126.3,126.1,
124.0 C(6'), C(8), C(6) and C(5); 125.6 C(1'); 120.6 C(5'); 115.5 C(3'); C(4) and C(3a);
33.2 C(3); 31.5 C(2). C,,HI60S (256.2). Calcd.: C 74.9 H 6.30; Found: C 74.8 H 6.41.
3) 2.2 g (40 %) of 3-(2-hydroxybenzyl)thiochroman-4-o1(7), m.p. 104-106 (ligroin). 'H NMR: 6
(ppm) = 7.20-6.80 (8H, m) aromatic protons; 4.46 (lH, d, J = 2 Hz) H(4); 3.46-2.06 (SH, m) H(2),
H(3) and H(3a). 13CNMR: 6 (ppm) = 154.5C(2'); 133.2, 133.0 C(8a) and C(4a); 131.8,131.1 C(7)
andC(4'); 128.8,127.9,126.3,124.1C(6'), C(8), C(6)andC(5); 124.8C(lf);lZO.SC(5'); 116.4C(3');
67.7C(4);40.3C(3); 32.1 C(3a);26.0C(2). CI6HlhO2S(272.2). Calcd.: C70.5 H5.93; Found: C70.6
H 5.88.
4) 1.1 g (20 %) of 3-(2-hydroxybenzyl)-thiochromanone(3) m.p. 177-178" (EtOH).
(+) Cis 6a, 12a-dihydro-6H,7H-[l]benzothiopyrano[4,3-b]-[l]benzopyran:Homothiopterocarpan
A solution of 1.35 g (5 mmole) of 5 in 40 ml50 % AcOH was refluxed for 1 h and then evaporated to
dryness. The residue on crystallizing from 50 % AcOH gave 1 g (80 %) of white product m.p.
110-113". 'H NMR: 6 (ppm) = 7.40-6.80 (8H, m) aromatic protons; 5.03 (lH, d, J = 2 Hz) H(12a);
3.40-2.60(5H,m) H(6),H(7)andH(6a). ''CNMR: 6(ppm) = 152.7C(lla); 133.1,131.0C(4a)and
C(12b); 131.5,129.5, 128.8,127.4,126.0 C(3), C(10), C(8). C(l) and C(2); 124.0C(8a); 120.7,119.6
C(4) and C(9); 116.9 C(11); 73.3 C(12a); 30.3 C(7); 30.1 C(6a); 26.1 C(6). C16H140S(254.2). Calcd.:
C 75.5 H 5.55; Found: C 75.4 H 5.62.
1 P.Valenti, P.Montanari, P.L. Barili and P.Da Re, Arch. Pharm. (Weinheim) 313, 289
2 A. Levai, 2.Dinya, J. B. Schag, G. Toth and A. Szollosy, Pharmazie 36, 465 (1981).
3 L. M. Jackman and S. Sternhell, Application of NMR Spectroscopyin Organic Chemistry, p. 280,
Pergamon Press, Oxford 1969.
4 E. Pretsch, E.T. Clerc, J. Seibl and W. Simon, Tabellen zur Strukturaufklarung organischer
Verbindungen mit spektroskopischen Methoden, S. 90, Springer-Verlag, Berlin 1976.
[Ph 9541
Arch. Pharm. (Weinheim) 318, 747-753 (1985)
Hydroxyalkoxyflavonoide, 1. Mitt.
Regioselektive 0-Hydroxyethylierung von Quercetin
Gotthard Wurm* und Dieter Rehn
Institut fur Pharmazic der Freien Universitat Berlin, Konigin-Luise-Str. 2 + 4, 1000Berlin 33
Eingegangen am 23. Januar 1984
Neben Ethylenchlorhydrin eignet sich besonders Ethylencarbonat zur effektiven quantitativen und
partiellen 0-Hydroxyethylierung des Quercetins (1, R’=H). Hierbei wurden Pentahydroxyethyl-(4),
3,3’,4’,7-Tetrahydroxyethyl-(3)und 4‘,7-Dihydroxyethylquercetin (7) als Hauptprodukte und 8
sowie 9 und 10 - neuartige Flavonoidtypen - als Nebenprodukte isoliert und charakterisiert. Die
Ubertragung der Reaktionen auf Propylencarbonat als Alkylierungsreagens miBlang, es konnten
lediglich unbedeutende Mengen eines schwer trennbaren Gemischs von 11 und U gewonnen
Hydroxyalkoxyflavonoids, I: Regioselective Syntheses of 0-Hydroxyethylquercetin Derivatives
Besides ethylene chlorohydrine, ethylene carbonate is an efficient reagent for the quantitative and
partial 0-hydroxyethylation of quercetin (1, R’=H). With this reagent pentakis (hydroxyethy1)-(4).
3,3’,4‘,7-tetrakis(hydroxyethyl)-(3) and 4’,7-bis(hydroxyethyI)quercetin (7) as the main products
and 8or9 and 10- new types of flavonoids- as by-products were isolated and characterised. The use of
propylene instead of ethylene carbonate as an alkylating reagent was a failure. Only very small
quantities of a cristalline mixture of 11,12 and other bis-(P-hydroxypropy1)derivatives was obtained.
This mixture was difficult to separate. Its constituents, beside 11 and U ,were not characterised.
0-P-Hydroxyethylrutinderivate(Troxerutin und Venoruton@))sind Arzneistoffe zur Behandlung
der venosen Insuffizienz. Die hervorragend wasserloslichen Glykoside werden schlecht resorbiert
und in erheblichem AusmaB durch die Darmflora zu den 0-P-Hydroxyethylquercetinderivaten
hydrolysiert, die besser als die Rutoside resorbiert werden”. Bei i. v. Injektion erleiden die Rutoside
bei der Leberpassage ebenfalls Glykosidspaltung als ersten Metabolisierungsschritt”. Es ist noch
nicht endgiiltig geklart, ob die 0-P-Hydroxyethylrutoside die eigentlichen Wirkstoffe sind oder
lediglich Prodrugfunktion besitzen. 1973 publizierten Courbar et al. die gezielte Synthese von
0-f3-Hydroxyethylquercetinderivatendurch Einleiten von Ethylenoxid in stark alkalische Quercetinlosungen”. Wir benotigten ebenfalls unterschiedlich aber einheitlich hydroxyethylierte Quercetinderivate, um durch weitere Umsetzungen freier phenolischcr OH-Gruppen die hydrophilen bzw.
0 VCH Verlagsgesellschaft mbH, D-6940 Weinheim, 1985
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