Substituent Effects in Reductions of Heteroaromatic Cations
David Heyes, Ramesh S. Menon, C. Ian. F. Watt,† and (in part) Jake Wiseman and Przemyslaw
Kubinski.
Department of Chemistry,
University of Manchester,
Manchester M13 9PL
†Author to whom correspondence should be addressed
E.mail
Ian.Watt@man.ac.uk
Phone
0161 275 4611
Fax
0161 275 4598
Experimental Section
Samples of 2,4,6-triphenylpyrylium tetrafluoroborate, 4 (X = O), 2,4,6-triphenyl-thiopyrylium tetrafluoroborate, 4
(X = S), and 1-methyl-2,4,6-triphenylpyridinium tetrafluoroborate, 4 (X = NMe), and derivatives carrying 4-phenyl
substituents, 3, 5, 6, and 8 (X = O, S, and NMe) were available from earlier work. With the exceptions detailed
below, the chalcones required for pyrylium synthesis were known compounds and prepared by literature
methods from commercially available substituted benzaldehydes and acetophenones.
1
E-1-Phenyl-3-[3,5-bis(trifluoromethyl)phenyl]propenone:— 3,5-Bis(trifluoro-methyl)-benzaldehyde (4.13 mmol)
was stirred with acetophenone (4.13 mmol) in ethanolic sodium hydroxide solution for 15 to 30 min to give the
chalcone in 88% yield as pale green needles after recrystallisation from light petroleum m.p. 110-111 °C (Found
C, 59.25; H, 2.66. C17H10F6O requires C, 59. 31; H, 2.93%); max(cm-1) 1668, 1611, 1380, 1285, 1218, 1169,
1126, 1018 and 987; H(CDCl3) 8.05 (4 H, br s, aromatic), 7.93 (1 H, s, aromatic), 7.84 (1 H, d, J 15, vinylic) and
7.7-7.5 (4 H, m); m/z (FAB) 345 (M+H+, 100%).
E-1-[3,5-Bis(trifluoromethyl)phenyl]-3-phenylprop-2-ene-1-one :— Benzaldehyde (3.90 mmol) was stirred with
m,m-bis(trifluoromethyl)acetophenone (3.90 mmol) in ethanolic sodium hydroxide solution for 15 min to 1 h to
give the chalcone in 94% yield. Recrystallisation from light petroleum gave pale green needles m.p. 108.5-109
°C (Found C, 59.36; H,3.15. C17H10F6O requires C, 59.31; H, 2.93%); max(cm-1) 1169, 1620, 1596, 1573, 1282,
1202, 1177 and 1129; H(CDCl3) 8.45 (2 H, s, aromatic), 8.10 (1 H, s, aromatic), 7.93 (1 H, AB, JAB 16, vinylic),
7.74-7.65 (2 H, m, aromatic) and 7.55-7.45 (4 H, m, aromatic + vinylic); m/z (FAB) 345 (M+H+, 100%).
The pyrylium salts (general procedure):– The chalcone (2 equiv.) and the acetophenone (1 equiv.) in ethylene
chloride (0.35 ml per mmol chalcone) were heated to reflux temperature. Ethereal HBF 4 (54% w/w; ~7.32 M, 4
equiv.) was then added dropwise, the reaction mixture turned deep red and fluorescence became apparent
shortly after complete addition. The mixture was refluxed for 1 to 5 h depending on the reagents used, before
addition of ether to precipitate the salt which was filtered and washed thoroughly with ether.
2,4,6-Tri-(4-methylphenyl)pyrylium tetrafluoroborate, 1 (X = O):— This was prepared by literature methods 2
providing the pyrylium salt in 71% yield, m.p. 275-280 °C (decomp.; ethylene chloride) (lit., ca. 280 °C) (Found
C, 69.19; H, 5.45. C26H23BF4O.3/10CH2ClCH2Cl requires C, 68.27; H, 5.21%; strongly retaining solvent, material
heated to ~ 60-80 °C under reduced pressure darkened and consistently failed analysis.); max(CH3CN)/nm 424,
-2-
376 and 288; max(cm-1) 1625, 1599, 1494, 1193 and 1056;H(CD3CN) 8.55 (2 H, s, pyrylium ring), 8.29 (4 H, d,
J 7.5, aromatic), 8.19 (2 H, d, J 7.5, aromatic), 7.57 (6 H, d, J 7.5, aromatic) and 2.53 (9 H, s, p-Me); m/z (FAB)
351 (cation, 100%).
4-Phenyl-2,6-di-(4-methylphenyl)pyrylium tetrafluoroborate, 2 (X = O) :— 1-(4-methylphenyl)-3-phenylpropenone
(10 mmol) was refluxed with p-methylacetophenone (5 mmol) with HBF4 for 3 h to give the pyrylium salt (11; X =
O), yield (55%) m.p. 258-263 °C (decomp.; ethylene chloride/ethyl acetate/ether) (lit. 3 268-269 °C from ethanol),
(Found C, 70.82; H, 4.86. C25H21BF4O requires C, 70.78; H, 4.99%); max(CH3CN)/nm 428, 360 and 288;
max(cm-1) 1620, 1594, 1522, 1498, 1466, 1190 and 1054; H(CD3CN) 8.60 (2 H, s, pyrylium ring), 8.35-8.25 (6 H,
m, aromatic), 7.90-7.70 (3 H, m, aromatic), 7.58 (4 H, d, J 7, aromatic) and 2.54 (6 H, s, p-Me); m/z (FAB) 353
(cation + 16, 2%) and 337 (cation, 100).
4-Phenyl-2,6-di-(3-chlorophenyl)pyrylium
tetrafluoroborate,
7
(X
=
O):—
The
1-(3-Chlorophenyl)-3-
phenylpropenone4 (5.80 mmol) was refluxed with m-chloroacetophenone (2.90 mmol) with HBF 4 for 3 h to give
salt (73%) m.p. 254-262 °C (ethylene chloride/ethyl acetate with a trace of HBF 4 (Found C, 59.52; H, 3.00.
C23H15BCl2F4O requires C, 59.40; H, 3.25%); max(CH3CN)/nm 390s, 364 and 276; max(cm-1) 1628, 1592, 1569,
1511, 1460, 1246 and 1058; H(CD3CN) 8.78 (2 H, s, pyrylium ring), 8.45 (2 H, m, aromatic), 8.40-8.30 (4 H,
aromatic) and 7.95-7.72 (7 H, m, aromatic); m/z (FAB) 377, 379, 381 (cation, 100%; 8.2:5.5:1 Cl isotopes).
4-Phenyl-2,6-di-(4-trifluoromethylphenyl)pyrylium tetrafluoroborate, 9 (X = O):— 1-(4-trifluoromethylphenyl)-3phenylpropenone5 (3.62 mmol) was refluxed with p-trifluoromethylacetophenone (1.81 mmol) with HBF 4 for 2 h to
give the salt (58%) m.p. 255-263 °C (ethylene chloride/ether + a trace of HBF 4) (Found C, 56.36; H, 2.64.
C25H15BF10O requires C, 56.42; H, 2.84%); max(CH3CN)/nm 368 and 268; max(cm-1) 1625, 1594, 1580, 1524,
1505, 1324, 1171 and 1067; H(CD3CN) 8.91 (2 H, s, pyrylium ring), 8.40 (2 H, d, J 8, aromatic), 8.35 (4 H, AB,
A 8.59, B 8.11, JAB 8, aromatic) and 7.99-7.75 (3 H, m, aromatic); m/z (FAB) 977 (2 x cation +
11BF4-,
3%), 369
(cation, + 16, 3) and 445 (cation, 100).
2-Phenyl-4-(4-trifluoromethyl)phenyl-6-[3,5-bis(trifluoromethyl)phenyl]pyrylium tetrafluoroborate, 10 (X = O) :—
1-phenyl-3-(4-trifluoromethyl)phenylpropenone1
(4.33
mmol)
was
refluxed
with
3,5-bis(trifluoro-
methyl)acetophenone (2.17 mmol) with HBF 4 for 3 h to give the salt (50%), m.p. 252-257 °C (ethylene chloridelight petroleum) (Found C, 51.83; H, 2.19. C26H14BF13O requires C, 52.03; H, 2.35%); max(CH3CN)/nm 402, 338
and 274; max(cm-1) 1633, 1515, 1325, 1279, 1134, 1070, 1049, 1033 and 840;H(CD3CN) 8.94 (2 H, s, pyrylium
-3-
ring), 8.89 (2 H, s, aromatic), 8.55-8.45 (5 H, m, aromatic), 8.11 (2 H, d, J 9, aromatic) and 8.00-7.78 (3 H, m,
aromatic); F(CD3CN) -64.93 (6 F, s) and -65.36 (3 F, s); m/z (FAB) 513 (cation, 100%). [Traces of 4-(4-trifluoromethylphenyl)-2,6-diphenylpyrylium tetrafluoroborate formed from the chalcone and acetophenone (see
chalcone preparation), could be removed by recrystallising the crude product twice from ethylene
chloride/benzene (3:1).]
4-Phenyl-2,6-di-[3,5-bis(trifluoromethyl)phenyl]pyrylium
Bis(trifluoromethyl)phenyl]-3-phenylpropenone
(2.90
tetrafluoroborate,
mmol)
was
11
refluxed
(X
with
=
O):—
1-[3,5-
3,5-bis(trifluoromethyl)-
acetophenone (1.45 mmol) with HBF4 for 1 h (a pale yellow precipitate was evident within 5 min of addition of
acid) to give the salt (67%) m.p. 254-263 °C (decomp.; acetonitrile/ether + a trace of HBF 4) (Found C, 47.64; H,
1.64. C27H13BF16O.1/6HBF4 requires C, 47.49; H, 1.94%); max(CH3CN)/nm 372 and 266; max(cm-1) 1638, 1525,
1369, 1277, 1143, 1117, 1081 and 1060;H(CD3CN) 9.05 (2 H, s, pyrylium ring), 8.93 (4 H, s, aromatic), 8.538.43 (4 H, m, aromatic) and 8.02-7.88 (3 H, m, aromatic); m/z (FAB) 597 (cation + 16, 9%), 581 (cation, 100) and
241 (ArCHCH2, 44).
Thiopyrylium salts from pyrylium salts (general procedure):– The pyrylium salt (1 equiv.) was stirred in acetone
(10 ml per mmol substrate) and sodium sulphide (4 equiv.) in water (0.8 ml per mmol sulphide) was added. The
deep red solution was stirred for 30 min and then poured into aqueous HBF 4 solution (5.5 ml 50% aqueous acid
and 10ml water per mmol substrate) and stirred for 1 h. The precipitate was collected and washed with water,
ether and finally with light petroleum. The collected solid was dissolved in the minimum quantity of acetonitrile,
filtered (celite) and concentrated to give the crude thiopyrylium product contaminated with the pyrylium precursor.
The crude product was dissolved in the minimum quantity refluxing 95% ethanol, reflux was discontinued, and
ether (twice the volume of ethanol) was added to the warm solution to precipitate the product. Repeating this
precipitation two to three times gave analytically pure thiopyrylium salt.
2,4,6-Tri-(4-methylphenyl)thiopyrylium tetrafluoroborate, 1 (X = S)— This was prepared from the pyrylium salt 1
(X = O) (0.70 mmol) in 92% yield, m.p. 253-257 °C (dichloromethane-light petroleum; decomp.) (Found C, 68.57;
H, 5.15; S, 6.81. C26H23SBF4 requires C, 68.74; H, 5.10; S, 7.06%); max(CH3CN)/nm 394, 278 and 258;max
(cm-1) 1574, 1462, 1430, 1192, 1057 and 815; H(300 MHz; CD3CN) 8.90 (2 H, s, thiopyrylium ring), 7.82 (4 H,
AB, A 8.09, B 7.54, JAB 8, 4-aryl), 7.77 (8 H, AB, A 7.99, B 7.55, JAB 8, 2,6-aryl) and 2.50 (9 H, s, p-Me); m/z
(FAB) 367 (cation, 100%).
-4-
4-Phenyl-2,6-di-(4-methylphenyl)thiopyrylium tetrafluoroborate, 2 (X = S)6:— This was prepared using the
pyrylium salt 2 (X = O) (0.60 mmol) to yield the thiopyrylium salt (62%) m.p. 219-222 °C (ethylene chloride/ethyl
acetate/ether) (Found C, 68.35; H, 5.01; S, 7.50. C 25H21BF4S requires C, 68.20; H, 4.81; S, 7.28%);
max(CH3CN)/nm 430, 370 and 278; max(cm-1) 1604, 1577, 1472, 1437, 1396, 1274, 1193 and 1055; H(CD3CN)
8.94 (2 H, s, thiopyrylium ring), 8.17 (2 H, dd, J 7.5, 2, aromatic), 7.85-7.68 (3 H, m, aromatic), 7.79 (4 H, AB, A
8.02, B 7.56, JAB 8, aromatic) and 2.52 (6 H, s, p-Me); m/z (FAB) 369 (cation + 16, 3%) and 353 (cation, 100).
4-Phenyl-2,6-di-(3-chlorophenyl)thiopyrylium tetrafluoroborate, 7 (X = S):— This was prepared from the pyrylium
salt 7 (X = O) (0.60 mmol) in 51% yield, m.p. 181-187 °C (dichloromethane/ ethyl acetate/ether) (Found C, 57.47;
H, 3.03; S, 6.97. C23H15BCl2F4S requires C, 57.42; H, 3.14; S, 6.66%); max(CH3CN)/nm 380 and 276; max(cm-1)
1578, 1566, 1476, 1442 and 1055; H(CD3CN) 9.06 (2 H, s, thiopyrylium ring), 8.29-8.15 (4 H, m, aromatic), 8.087.98 (2 H, m, aromatic) and 7.89-7.68 (7 H, m, aromatic); m/z (FAB) 393, 395 and 397 (cation, 100%; 6:4.4:1, Cl
isotopes).
Thiopyrylium salts by the alternative route:– With the exceptions detailed below, distyryl ketone and necessary
substituted distyryl ketones for thiopyrylium syntheses by the alternative route were known compounds and
prepared by literature methods.7
1E,4E-1,5-Di-[3,5-bis(trifluoromethyl)phenyl]pentan-1,4-diene-3-one, 12 (P = R = m,m-(CF3)2):— Pre-mixed
3,5-bis-(trifluoromethyl)benzaldehyde (4.13 mmol, 1.0 g) and acetone (2.07 mmol) were stirred in absolute
ethanol (3.5 ml) and sodium hydroxide solution (0.05 M, 4.2 ml) was added and the mixture was stirred for 1 h,
during which time a precipitate formed. The supernatant was decanted and the solid was partitioned between
dichloromethane and water. The dried (Na 2SO4) organic portion was treated with light petroleum and the denote
precipitated as bright yellow crystals (482 mg, 46%),
m.p. 201-201.5 °C (dichloromethane/light petroleum)
(Found C, 50.02; H, 2.00. C21H10F12O requires C, 49.82; H, 1.99%); max(cm-1) 1683, 1631, 1600, 1382, 1279,
1181, 1148, 1115 and 1090; H(CDCl3) 8.05 (4 H, s, o-aromatic), 7.93 (2 H, s, p-aromatic) and 7.51 (4 H, AB, A
7.81, B 7.21, JAB 16, vinylic); m/z (FAB) 507 (M+H+, 100%).
1E,4E-1-Phenyl-5-[3,5-bis(trifluoromethyl)phenyl]pentan-1,4-diene-3-one 12 (P = H, R - m,m-(CF3)2):—
Benzalacetone (585 mg, 4.0 mmol) was stirred in ethanolic sodium hydroxide solution [95% ethanol (6.6 ml) and
NaOH (~2.8 M, 8 ml)] and 3,5-bis(trifluoromethyl)benzaldehyde (968 mg, 4.0 mmol) was added. After 15 min a
sticky precipitate had developed and the supernatant fluid was decanted. The solid was extracted into ether,
-5-
washed with water, dried (MgSO4) and recrystallised from ether/light petroleum to give bright green plates of
required dienone, (0.472 g, 32%,) m.p. 133-134.5 °C (dichloromethane–light petroleum) (Found C, 61.61; H,
3.07. C19H12F6O requires C, 61.63; H, 3.27%);max(cm-1) 1675, 1625, 1592, 1450, 1380, 1280, 1166, 1110, 1092
and 992; H(CDCl3) 8.03 (2 H, s, aryl), 7.90 (1 H, s, aryl), 7.65 (2 H, m, phenyl), 7.51 (2 H, AB, A 7.79, B 7.22,
JAB 16, vinylic; subst. side), 7.49-7.40 (3 H, m, phenyl) and 7.42 (2 H, AB, A 7.76, B 7.08, JAB 16, vinylic;
unsubst. side); m/z(FAB) 393 (M+Na+, 8%), 371 (M+H+, 100), 267 (ArCH=C=C=O+H+, 26) and 131
(PhCH=C=C=O+H+, 29). Repeating the above, using the same quantities (unless otherwise stated), but stirring
pre-mixed benzalacetone and aldehyde in 95% ethanol and then adding 0.1 M sodium hydroxide solution (8 ml)
gave a flocculent precipitate within 5 min. After 45 min (or even 17 h) the mixture was diluted with water and the
powdery precipitate was collected (wash thoroughly with water) and dried in air. Fractional crystallisation from
ether-light petroleum gave the distyryl ketone (43) 470 mg (32%) and, as a by-product, 1E-1-phenyl-5-[3,5bis(trifluoromethyl)phenyl]-5-hydroxypentan-1-ene-3-one , (0.784g 53%, as brilliant white needles) m.p. 70-72
°C (dichloromethane-light petroleum) (Found C, 58.97; H, 3.53. C19H14F6O2 requires C, 58.77; H,
3.63%);max(cm-1) 3449, 1655, 1609, 1366, 1278, 1170 and 1130; H(CDCl3) 7.91 (2 H, s, aryl), 7.83 (1 H, s,
aryl), 7.64-7.52 (2 H, m, phenyl), 7.61 (1 H, d, J 16.5, vinylic), 7.50-7.38 (3 H, m, phenyl), 6.76 (1 H, d, J 16.5,
vinylic), 5.40 (1 H, ddd, JBH 8, JAH = JH,OH 3.5; dd with D2O, CHOH), 3.97 (1 H, d, JH,OH 3.5, OH; exchanges with
D2O) and 3.11 (2 H, ABH, A 3.15, B 3.07, JAB 18, JAH 3.5, JBH 8, -CH2C(O)-); m/z(FAB) 411 (M+Na+, 41%), 389
(M+H+, 16), 243 (ArCH=O+H+, 6) and 131 (PhCH=C=C=O+H+, 100). This could be converted by stirring in
ethanolic sodium hydroxide [95% ethanol (4.5 ml) and 2.8 M NaOH (4 ml)] for 15 min to the distyryl ketone
(0.244 g, 32 % from by-product).
2,6-Di-[3,5-bis(trifluoromethyl)phenyl]-4H-tetrahydrothiopyran-4-one, 13 (P = R= m,m-(CF3)2) :— 1,5-Di-[3,5bis(trifluoromethyl)phenyl]pentan-1,4-diene-3-one (0.89 mmol, 450 mg) and anhydrous sodium acetate (3.88
mmol, 318 mg) were refluxed in aqueous ethanol (1.6 ml 95% ethanol and 0.1 ml water) and H 2S gas was
bubbled through the mixture for 50 min (the colour faded within 20 min). All solvent was removed and the residue
was partitioned between dichloromethane. The dried (Na 2SO4) organic portion was diluted with light petroleum,
concentrated and then triturated with dichloromethane and light petroleum to give 2,6-di-[3,5-bis(trifluoromethyl)phenyl]-4H-tetrahydrothiopyran-4-one,
as a white solid (395 mg, 82%),
m.p. 198-200.5 °C
(ether/light petroleum; before melting the fluffy material sublimed 159-175 °C to give new larger crystals) (Found
C, 46.55; H, 2.32; S, 5.64. C21H12F12OS requires C, 46.68; H, 2.24; S, 5.93%); max(cm-1) 1712, 1380, 1286,
-6-
1277, 1168, 1128 and 904; H(CDCl3) 7.86 (6 H, s, aromatic), 4.50 (2 H, dd, J 5, 10) and 3.17-3.00 (4 H, m);
m/z(EI) 540 (M+, 17%) and 240 (ArCH=CH2+, 100).
2-Phenyl-6-[3,5-bis(trifluoromethyl)phenyl]-4H-tetrahydrothiopyran-4-one, 13 (P = H, R - m,m-(CF3)2):—
1-
Phenyl-5-[3,5-bis(trifluoro methyl)phenyl]pentan-1,4-diene-3-one (3.1 mmol, 1.15 g) and anhydrous sodium
acetate (13.5 mmol, 1.11 g) were refluxed in aqueous ethanol (5.5 ml 95% ethanol and 0.34 ml water) and H 2S
gas was bubbled through the mixture for 1 h. All solvent was removed and the residue was partitioned between
dichloromethane. The dried (Na2SO4) organic portion was concentrated to give crude 2-phenyl-6-[3,5bis(trifluoromethyl)phenyl]-4H-tetrahydrothiopyran-4-one as an oil which was used without purification in further
reaction (1.26 g, ~ 100%); max(cm-1) 1714, 1378, 1279, 1173 and 1133; H(CDCl3) 7.85 (2 H, s, aromatic), 7.80
(1 H, s, aromatic), 7.45-7.25 (5 H, s, aromatic), 4.50-4.32 (2 H, m) and 3.24-2.92 (4 H, m); m/z(EI) 404 (M+, 72%)
and 240 (ArCH=CH2+, 17) and 104 (PhCH=CH2+, 100).
4-Phenyl-2,6-di-(4-trifluoromethylphenyl)thiopyrylium
tetrafluoroborate,
9
(X
=
S):—
2,6-Di-(4-trifluoro-
methylphenyl)-4H-tetrahydrothiopyran-4-one,8 (1.187 mmol, 480 mg) was stirred with dry pyridine (1.36 mmol,
0.11 ml) and dried NCS (1.19 mmol, 159 mg) in dry dichloromethane (3 ml) first at 0 °C for 2 h and then room
temperature over the weekend. The mixture was diluted with dichloromethane, washed thrice with water and the
dried (Na2SO4) solution was concentrated to give crude 2,6-di-(4-trifluoromethylphenyl)-4H-dihydrothiopyran-4one, 14 (P = R = p- CF3), as a light brown oil, max(cm-1)1657, 1324, 1167, 1125 and 1069; H(CDCl3) 7.83-7.48
(8 H, m, aromatic), 6.60 (1 H, s, vinylic), 4.85 (1 H, dd, J 5, 12) and 3.27-2.96 (2 H, m). This used without further
purification. Phenyl lithium (1.8 M; 1.1 ml) was added to a stirred cooled (-78 °C) solution of the dihydrothiopyran4-one (~ 1.187 mmol) in THF (3.2 ml) and after 45 min the mixture was warmed to room temperature and stirred
for a further 1 h before quenching with aq. ammonium chloride solution. The mixture was concentrated, the
residue was partitioned between ether and water and the dried (Na 2SO4) organic portion was mixed with light
petroleum. The resulting precipitate was removed and the filtrate was concentrated to give crude 2,6-di-(4trifluoromethylphenyl)-4-phenyl-4H-dihydrothiopyran-4-ol, 15 (P = R = p-CF3, S4 = H) as a dark orange foam
(516 mg, 1.07 mmol, 90%). max(cm-1) 3379, 2930, 1617, 1326, 1167, 1125 and 1069; H(CDCl3) in part 6.21 (1
H, s, vinylic), 4.23 (1 H, dd, J 3, 12) and 2.80-2.53 (2 H, m). This was refluxed with ethereal HBF4 (7.32 M; 0.4
ml) in ethylene chloride (4 ml) for 30 min and then the mixture was concentrated. The residue was refluxed with
triphenylmethanol (1.07 mmol, 280 mg) in TFA (4 ml) for 3h, the mixture was then concentrated, re-dissolved in
95% ethanol before precipitation of a solid by addition of ether and excess ethereal HBF 4. The solid was
-7-
collected and washed with ether to give required salt as orange crystals, yield (0. 247g, 38%) m.p. 221-226 °C
(dichloro-methane/light petroleum) (Found C, 55.00; H, 2.52; S, 5.90. C25H15BF10S requires C, 54.77; H, 2.76; S,
5.85%); max(CH3CN)/nm 378 and 244; max(cm-1) 1581, 1477, 1445, 1323, 1175, 1069, 1014 and 847;
H(CD3CN) 9.17 (2 H, s, thiopyrylium ring), 8.28-8.20 (2 H, m, aromatic), 8.185 (8 H, AB, AB 8.28, B 8.09, JAB 8,
aromatic) and 7.90-7.72 (3 H, m, aromatic); m/z (FAB) 461 (cation, 100).
4-Phenyl-2,6-di-[3,5-bis(trifluoromethyl)phenyl]thiopyrylium
tetrafluoroborate,
11
(X
=
S):—
2,6-Di-[3,5-
bis(trifluoromethyl)phenyl]-4H-tetrahydrothiopyran-4-one (0.70 mmol, 377 mg) was stirred with pyridine (1.24
mmol, 0.1 ml) and NCS (0.71 mmol, 95 mg) in dry dichloromethane (1.5 ml) at 0 °C 2 h then at room temperature
for 72 h. The reaction mixture was concentrated and the residue was dissolved in dichloromethane and washed
three times with water. The dried (Na2SO4) solution was diluted with light petroleum and then concentrated to
give crude 2,6-di-[3,5-bis(trifluoromethyl)phenyl]-4H-dihydrothiopyran-4-one, 13 (P = R = m,m-(CF3)2), as a
brown solid (0.38g; 92% conversion to product, 8% starting material); H(CDCl3) 8.08 (2 H, br. s, m-H on 2aromatic), 8.00 (1 H, br. s, p-H on 2-aromatic), 6.64 (1 H, s, vinylic), 4.97 (1 H, dd, J 5, 12) and 3.35-3.0 (2 H, m).
Phenyl lithium (1.8 M; 1.15 ml) was added to a stirred cooled (-78 °C) solution of the dihydrothiopyranone (0.69
mmol, 370 mg) in THF (1.7 ml) and after 1h the mixture was warmed to room temperature and stirred for a
further 1 h before quenching with ammonium chloride. The mixture was partitioned between dichloromethane
and water and the dried (Na2SO4) organic portion was concentrated to give 2,6-di-[3,5-bis(trifluoromethyl)phenyl]4H-dihydrothiopyran-4-ol, 14 (P = Q = m,m-(CF3)2, S2 = H), ( (~ 0.68 mmol); H(CDCl3) 6.28 (1 H, s, vinylic),
4.31 (1 H, dd, J 3,12) and 2.85-2.56 (2 H, m). This was refluxed with ethereal HBF 4 (7.32 M; 0.15 ml) in ethylene
chloride (2 ml) for 1.25 h and then concentrated to give a red tar which was refluxed with triphenylmethanol (0.68
mmol, 177 mg) in TFA (2.5 ml) for a further 1.5 h. The reaction mixture was concentrated and the residue
dissolved in 95% ethanol and ether with HBF 4 (7.32 M in ether; 0.2 ml) added and crystallisation initiated. The
precipitate was collected and washed with ether to give the required salt as a yellow solid, yield (0.111g, 23%
from the tetrahydrothiopyranone) m.p. 173-180 °C (dichloromethane/light petroleum) (Found C, 47.68; H, 1.78;
S, 4.95. C27H13BF16S requires C, 47.40; H, 1.91; S, 4.69%); max(CH3CN)/nm 378 and 244; max(cm-1) 1620,
1580, 1480, 1390, 1365, 1281, 1183, 1134, 1058 and 896; H(300 MHz; CD3CN) 9.27 (2 H, s, thiopyrylium ring),
8.67 (4 H, s, o-H for 2,6-aromatic), 8.45 (2 H, s, p-H for 2,6-aromatic) 8.30 (2 H, comp. d, J 7, o-H for phenyl) and
7.89-7.75 (3 H, m, m+p-H for phenyl); m/z (FAB) 597 (cation, 100%).
-8-
2-Phenyl-4-(4-trifluoromethyl)phenyl-6-[3,5-bis(trifluoromethyl)phenyl]thiopyrylium tetrafluoroborate, 10 (X = S):–
2-Phenyl-6-[3,5-bis(trifluoromethyl)phenyl]-4H-tetrahydrothiopyran-4-one (3.1 mmol, 1.25 g) was stirred with dry
pyridine (3.7 mmol, 0.3 ml) and dried NCS (3.1 mmol, 414 mg) in dry dichloromethane (8 ml) first at 0 °C for 2 h
and then overnight at room temperature. The reaction mixture was concentrated and the residue was dissolved
in dichloromethane and washed three times with water and the dried (Na 2SO4) solution was concentrated to give
a crude mixture of 2-phenyl-6-[3,5-bis(trifluoro-methyl)phenyl]-4H-2-dihydrothiopyran-4-one, 13 (P = H, R = m,m(CF3)2), and 2-phenyl-6-[3,5-bis(trifluoro-methyl)phenyl]-4H-5-dihydrothiopyran-4-one, 13 (P = m,m-(CF3)2, R = H
), as a brown oil (1.12 g, 90%); H(CDCl3) 6.58 (1 H, s, vinylic) and 4.90 and 4.84 (total 1 H; ~ 1:2, dd, J 5, 12
and J 4, 12.5 respectively). p-Trifluoro-methylphenylbromide (4.88 mmol, 0.68 ml) was stirred in THF (5 ml) at 78 °C and n-butyl lithium (1.58 M; 3.15 ml) was added. After 1 h this mixture was transferred by cannula to a
cooled (-78 °C) solution of the alkenones in THF (5 ml) and stirred for a 1 h and then for a further 30 min at room
temperature. After quenching (aq. NH4Cl), all the solvent was removed and the residue was extracted into ether,
dried (MgSO4) and concentrated before refluxing with HBF 4 (7.32 M in ether; 0.6 ml) in ethylene chloride (12 ml)
for 1.5 h, the solvent was then replaced by TFA (12 ml), triphenylmethanol (3.0 mmol, 781 mg) was added, and
the mixture was refluxed for 2 h. The reaction mixture was concentrated and the residue was dissolved in 95%
ethanol and ether. Excess ethereal fluoroboric acid was added and a yellow solid eventually precipitated to give
the required salt (0.410g, 21% from the tetrahydrothiopyranone, m.p. 207-213 °C (dichloromethane-ether)
(Found C, 50.84; H, 2.16; S, 4.98. C26H14BF13S requires C, 50.68; H, 2.29; S, 5.20%); max(CH3CN)/nm 400, 346
and 268; max(cm-1) 1585, 1474, 1379, 1324, 1281, 1178, 1135 and 1071; H(CD3CN) 9.18 and 9.17 (Total 2 H,
overlapping s, thiopyrylium ring), 8.65 (2 H, s, aromatic), 8.44 (1 H, s, aromatic) 8.22 (4 H, AB, A 8.37, B 8.08, J
AB
9, aromatic), 8.22-8.15 (2 H, m, aromatic) and 7.90-7.75 (3 H, m, aromatic); F(CD3CN) -64.86 (6 F, s) and -
65.15 (3 F, s); m/z (FAB) 529 (cation, 100%).
The pyridinium salts (general procedure):– The pyrylium salt (1 equiv.) was stirred in absolute ethanol (3.175 ml
per mmol substrate) and methylamine in IMS (33%, ~ 8.3 M; 1.25 equiv.) was added and the red reaction mixture
was stirred for 6 to 24 h. The reaction mixture was diluted with ether and the precipitated product was filtered and
washed with ether.
2,4,6-Tri-(4-methylphenyl)-N-methylpyridinium tetrafluoroborate, 1 (X = NMe):— The pyrylium salt, 1 (X = O) was
stirred with ethanolic methylamine for 5 h to give required salt (68%) m.p. 182-184 °C (dichloromethane-light
petroleum)
(Found
C,
72.10;
H,
5.92;
N,
2.96.
-9-
C27H26BF4N
requires
C,
71.86;
H,
5.81;
N,
3.10%);max(CH3CN)/nm 318; max(cm-1) 1622, 1609, 1057 and 819; H(CD3CN) 8.15 (2 H, s, pyridinium ring),
7.92 (2 H, d, J 7.5, aromatic), 7.56 (8 H, AB, A 7.61, B 7.51, JAB 7.5, aromatic), 7.43 (2 H, d, J 7.5, aromatic),
3.75 (3 H, s, N-methyl), 2.50 (6 H, s, p-Me) and 2.45 (3 H, s, p-Me); m/z(FAB) 364 (cation, 100%).
4-Phenyl-2,6-di-(4-methylphenyl)-N-methylpyridinium tetrafluoroborate, 2 (X = NMe):— The pyrylium salt (0.5
mmol) was stirred with ethanolic methylamine for 24 h to give the required salt (79%) m.p. 204-206 °C
(ether/dichloromethane) (Found C, 71.48; H, 5.69; N, 3.08. C 26H24BF4N requires C, 71.41; H, 5.53; N, 3.20 %);
max(CH3CN)/nm 306; max(cm-1) 1624, 1565, 1514 and 1057; H(CD3CN) 8.18 (2 H, s, pyridinium ring), 8.08-7.97
(2 H, m, aromatic), 7.71-7.45 (11 H, m, aromatic), 3.88 (3 H, s, N-Me) and 2.50 (6 H, s, p-Me); m/z(FAB) 787 (2 x
cation + 11BF4-, 2%), 366 (cation +16, 3) and 350 (cation, 100).
4-Phenyl-2,6-di-(3-chlorophenyl)-N-methylpyridinium tetrafluoroborate, 7 (X = NMe):— The pyrylium salt (0.52
mmol) was stirred with ethanolic methylamine for 18 h to give required salt (61%) m.p. 206-210 °C
(dichloromethane/ether) (Found C, 60.53; H, 3.56; N, 2.84. C 24H18BCl2F4N requires C, 60.29; H, 3.79; N, 2.93%);
max(CH3CN)/nm 304; max(cm-1) 1626, 1567 and 1057; H(CD3CN) 8.25 (2 H, s, and pyridinium ring), 8.12 (2 H,
m, aromatic), 7.82-7.62 (11 H, m, aromatic) and 3.78 (3 H, s, NMe); m/z(FAB) 390, 392 and 394 (cation, 100%;
8.3:5.6:1, Cl isotopes).
4-Phenyl-2,6-di-(4-trifluoromethylphenyl)-N-methylpyridinium tetrafluoroborate, 9 (X = NMe):— The pyrylium salt
(14; X = O) (0.56 mmol) was stirred with ethanolic methylamine for 5 h to give the required salt (62%) m.p. 130136 °C (dichloro-methane/light petroleum) (Found C, 57.50; H, 3.56; N, 2.52. C26H18BF10N requires C, 57.28; H,
3.33; N, 2.57%); max(CH3CN)/nm 302;max(cm-1) 1628, 1615, 1573, 1325, 1172, 1128, 1115, 1071 and 850;
H(CD3CN) 8.30 (2 H, s, pyridinium ring), 8.03 (total 6 H; 4 H, AB, J AB 8, superimposed over 2 H, aromatic), 7.93
(4 H, AB, JAB 8, aromatic), 7.72-7.58 (3 H, m, aromatic), 3.74 (3 H, s, N-methyl); m/z(FAB) 458 (cation, 100%).
2-Phenyl-4-(4-trifluoromethylphenyl)-6-[3,5-bis(trifluoromethyl)phenyl]-N-methylpyridinium tetra- fluoro-borate, 10
(X = NMe):— The pyrylium salt, 10 (X = O) was stirred with ethanolic methylamine for 22 h to give the required
salt (58%) m.p. 260-263 °C (dichloromethane-ether) (Found C, 53.17; H, 2.87; N, 2.14. C 27H17BF13N requires C,
52.88; H, 2.79; N, 2.28%);max(CH3CN)/nm 292; max(cm-1) 1629, 1388, 1326, 1282, 1177, 1133 and 1071;
H(CD3CN) 8.15 (2 H, s, pyridinium ring), 8.38-8.31 (5 H, m), 8.08 (4 H, AB, A 8.19, B 7.96, JAB 9, aromatic),
7.73 (5 H, s, aromatic) and 3.81 (3 H, s, N-methyl); F(CD3CN) -64.93 (6 F, s) and -65.11 (3 F, s);m/z(FAB) 526
(cation, 100%).
-10-
4-Phenyl-2,6-di-[3,5-bis(trifluoromethyl)phenyl]-N-methylpyridinium tetrafluoroborate, 11 ( X = NMe):— The
pyrylium salt (15; X = O) (0.67 mmol) was stirred with ethanolic methylamine for 5 h to give the required salt
(64%) m.p. 290-292 °C (chloroform/light petroleum) (Found C, 49.26; H, 2.54; N, 2.00. C 28H16BF16N requires C,
49.37; H, 2.37; N, 2.06%); max(CH3CN)/nm 304;max(cm-1) 1630, 1366, 1282, 1178, 1135, 1059 and 909;
H(CD3CN) 8.38 (2 H, s, pyridinium ring), 8.35 (6 H, s, o,p-H for 2,6-aromatic), 8.12-8.02 (2 H, m, o-H for phenyl),
7.77-7.58 (3 H, m, m,p-H for phenyl), 3.80 (3 H, s, N-methyl); m/z(FAB) 594 (cation, 100%).
2,4,6-Triphenyl-4H-thiopyran:— 2,4,6-triphenylthiopyrylium, 4(X = S), (1.81g, 4.4 mmol) was stirred in methanol
(35 ml) at -20 °C and NaBH4 (1.33 g, 35 mmol) was added gradually. 9 When hydrogen evolution had ceased,
solvent was removed and the residue was stirred in ether. The suspension was filtered (celite), the filtrate
washed thoroughly with water and then dried (MgSO 4). Concentration on the solution gave a pale green oil 1.097
g (77%) being 61% the 1,4-isomer. Trituration with acetonitrile gave a pale green solid greatly enriched in the
4H-thiopyran and recrystallisation from acetonitrile afforded 2,4,6-triphenyl-4H-thiopyran (50) as off-white
needles m.p. 112.5-114.5 °C decomp. (Lit., 110 °-112 °C10) from methanol, (Found C, 84.82; H, 5.35; S, 10.03.
C23H18S requires C, 84.62; H, 5.56; S, 9.82%); max(cm-1) 3057, 3024, 1598, 1490, 1444, 1073, 1029, 754 and
695; H(CD3CN) 7.62-7.51 (4 H, m, aromatic), 7.47-7.28 (11 H, m, aromatic), 6.15 (2 H, d, J 5) and 4.61 (1 H, t, J
5); m/z(CI) 327 (M+H+, 100%).
2,4,6-Triphenyl-2H-thiopyran (51):— From isomerisation of the 1,4-thiopyran H(CD3CN; contains 2,4,6triphenylthiopyrylium) 7.67-7.24 (15 H, m, aromatic), 6.97 (1 H, s), 6.06 (1 H, d, J 6.5) and 4.96 (1 H, d, J 6.5).
N-Methyl-2,4,6-triphenyl-4H-dihydropyridine, 17 :— A solution of the pyridinium salt, 4 (X = NMe) (0.9g, 2.2
mmol) in absolute ethanol (120 ml) was stirred over 1.2% sodium amalgam overnight (keep in dark) during which
time the UV absorption at 302 nm had decayed to a shoulder and a new maximum at 234 nm had appeared. The
solution was decanted, concentrated, extracted into ether, dried (K 2CO3) and concentrated again to give Nmethyl-2,4,6-triphenyl-4H-dihydropyridine (17) as a pale yellow oil (0.630 g, 89%) that darkened on exposure to
light and air; max(acetonitrile)/nm 234 (387000) and 280 (shoulder; 12000); max(cm-1) 3079, 3057, 3025, 2882,
2818, 1664, 1619, 1599, 1492, 1447, 1369, 1154, 1072, 1012, 756 and 699; H(CDCl3) 7.51 (4 H, d, J 8,
aromatic), 7.40-7.20 (11 H, m, aromatic), 5.10 (2 H, d, J 5), 4.45 (1 H, t, J 5) and 2.64 (3 H, s, N-Me); H(CDCl3)
147.7, 144.7, 138.1, 128.5, 128.2, 127.80, 127.76, 127.5, 126.2, 109.3, 41.2 and 38.8; m/z(CI) 324 (M+H+,
100%) (Found M+ 323.1661. C24H21N requires M+ 323.1674.).
-11-
Cyclic voltammetry:— Measurements were carried as described earlier.
Solution calorimetry:– The apparatus and method were those of Akello, Paz-Andrade and Pilcher.11 Accurately
measured amounts of the heterocyclic salt (ca 0.1 g) were dissolved in acetonitrile (100 cm 3) in the calorimeter
vessel. Samples of NaBH4- were sealed in Teflon ampoules, which were broken under the acetonitrile solution at
the appropriate time to initiate the reaction.
.Reductions with Sodium Cyanoborohydride for product analysis: —The heterocyclic cation
(0.005g) was
dissolved in 0.5 ml CD3CN in a standard NMR tube. The proton NMR spectrum of the sample was then run
before addition of an equal volume of a saturated solution of sodium cyanoborohydride in CD 3CN. The NMR
spectrum was then re-run within five minutes of mixing. For all salts except the pyridinium derivatives, the
spectroscopy showed complete reaction in this time. For details of the spectra, see main text.
Rate Measurements:- Reactions with sodium cyanoborohydride were carried as detailed earlier.
All manipulations with sodium borohydride were carried under argon atmosphere. Sodium borohydride (~
3 g NaBH4 or NaBD4) from a freshly opened bottle (Aldrich) was added to freshly distilled diglyme (40 ml) and the
mixture was heated to 50 °C in a sonic bath for 30 minutes.12 The filtered solution was cooled to 0 °C until
crystallisation had taken place (white needles 1:1 solvate 12), and the crystals were then collected and heated in
vacuo at 60 °C for 4 h to remove diglyme. The purified borohydride was dissolved in dry distilled acetonitrile to
make ca 0.05 M solution and allowed to stand overnight. The exact concentration was determined by reaction of
aliquots of the solution with a known amount of potassium iodate, followed by conversion of the excess iodate to
iodine and titration against standard thiosulphate. 13 Solutions of NaBH4 in acetonitrile, stored under argon in the
dark at room temperature, showed less than 0.2% loss of titre over a week. 14 Dilutions of these solutions were
used in the rate measurements.
Solutions of the cation (~ 1.5 x 10 -5 M) and of NaBH4 or NaBD4 (~ 2 x 10-4 M) in acetonitrile were placed in
the syringes of a Hi-Tech SF61 stopped flow UV spectrophotometer. Equal volumes of reagent were mixed and
the rate of reaction was determined by observing decrease of absorbance at the longest wavelength maximum
(see Table 1 of the main text). Each reaction was observed at five temperatures in the range of 30 <T < 60°C for
pyridiniums and -5 < T < 20°C for thiopyryliums. For the pyryliums 7, 8, and 9 (X =O), solutions of the cation were
ca 1.05 x 10-6M and borohydride were ca 2 x 10 -5M, and reactions were monitored by decrease in fluorescence
with excitation at 395, 418, and 376 nm respectively.
-12-
Reduction
of
2,4,6-Triphenylthiopyrylium
Tetrafluoroborate
to
2,4,6-Triphenyl-4H-thiapyran:—Sodium
borohydride (0.036g) was gradually added over 30 min, with stirring, to a solution of 2,4,6-triphenylthiopyrylium
tetrafluoroborate (0.1g in 30ml of dry acetonitrile). The reaction mixture was then concentrated and ether (10ml)
added. The solution was then filtered and the ethereal solution with water before drying over magnesium
sulphate and evaporation. Recrystallisation of the oily residue from methanol gave yellow crystals (0.044g,
31%), which were examined spectroscopically (see text).
References
1
Reichardt C and Müller R, Justus Liebigs Annalen Der Chemie, 1976; 1937 and references therein.
2
Schill G and Zollenkopf H, Justus Liebigs Annalen Der Chemie, 1969; 721: 53.
3
Csu’rös Z, Deák G and Sally P, Acta Chim (Budapest), 1971; 70: 123.
4
Lyle RE and Paradis LP, J. Am. Chem. Soc., 1955; 77: 6667.
5
Ash ML, Obrien FL, and Boykin DW, J. Org. Chem., 1972; 37: 106.
6
Mistr A, Vavra M, Skoupy J, and Zaharadnik R, Collect. Czech. Chem. Commun. 1972; 37: 1520. (for
the perchlorate)
7
Conrad CR and Dolliver MA, Organic Synthesis, CV 2, John Wiley and Son, New York, 1943, p. 167,
8
M. Chaykovsky, M. Lin, A. Rosowsky and E. J. Modest, J. Med. Chem, 1973, 16 ,188
9
Doddi G and Ercolani G, J. Org. Chem. 1991; 56: 1674.
10
Abdallah AA, and El-Nahas HM, J. Heterocyclic Chem. 1981; 18: 1517, and references therein.
11
Akello MJ, Paz-Andrade MI, and Pilcher G, J. Chem. Thermodynamics, 1983, 15, 949.
12
Brown HC, E. Mead J and Rao BCS, J. Am. Chem. Soc. 1955; 77: 6209.
13
Lyttle DA, Jensen EH, and Struck WA, Anal. Chem., 1952; 24: 1843.
14
Modler RF and Kreevoy MM, J. Am. Chem. Soc, 1977; 99: 2271.
-13-