Facile deoxygenation of hydroxylated flavonoids by palladium-catalysed reduction of its triflate derivatives

Article abstract of DOI:10.1515/znb-2005-0716

An efficient procedure to deoxygenate hydroxy substituted flavonoids, isoflavonoids and related compounds via their trifluoromethanesulfonates is presented. Their reduction with formic acid in the presence of a catalytic amount of palladium acetate, triethylamine and 1,3-bis(diphenyl-phosphanyl) propane (dppp) in DMF results in their des-hyaroxy derivatives without affecting other functional groups.

Full text of DOI:10.1515/znb-2005-0716

Facile Deoxygenation of Hydroxylated Flavonoids by
Palladium-Catalysed Reduction of its Triflate Derivatives
Jo´zsef Ko¨ve´r and Sa´ndor Antus
Department of Organic Chemistry, University of Debrecen, H-4010 Debrecen, P. O. Box 20, Hungary
Reprint requests to Sa´ndor Antus. Fax: +36-52-453-836. E-mail: antuss@tigris.klte.hu
Z. Naturforsch. 60b, 792 – 796 (2005); received November 12, 2004
Dedicated to Professor Andra´s Lipta´k on the occasion of his 70th birthday
An efficient procedure to deoxygenate hydroxy substituted flavonoids, isoflavonoids and related
compounds via their trifluoromethanesulfonates is presented. Their reduction with formic acid
in the presence of a catalytic amount of palladium acetate, triethylamine and 1,3-bis(diphenyl-
phosphanyl)propane (dppp) in DMF results in their des-hydroxy derivatives without affecting other
functional groups.
Key words: Flavonoids, Reduction, Palladium(II) Acetate
Flavonoids and isoflavonoids possessing a 2- and
3-aryl substituted 1-benzopyran skeleton with various
levels of saturation and oxidation, respectively, belong
to the class of naturally occuring O-heterocyclic com-
pounds [1] with wide range of biological importance
due to their significant antioxidant [2], hepatoprotec-
tive [3], antifungal [4], antibacterical [5] and antiviral
[6] activities.
Although, there are numerous independent meth-
ods available for the preparation of these natural prod-
ucts and the procedures of synthetic importance have
been reviewed extensively [1, 7, 8], these conditions
are mostly suitable for direct synthesis of their 7-
hydroxy- or 5,7-dihydroxy derivatives and hence syn-
thetic accessibility of their des-7-hydroxy derivatives
is strongly limited. To overcome this problem sev-
eral methods such as catalytic hydrogenation of O-
aryl-N,N-dialkylisoureas by Pd/C [9], desulfurization
of S-aryl-N,N-dialkyl thiocarbamates (prepared by
Newman-Kwart rearrangement of O-aryl-N,N-dialkyl
thiocarbamates) by Raney nickel [10] and reduction
of O-aryl (or methyl)-p-toluenesulfonates by NaBH4–
NiCl2 [11] or Raney nickel [12] have been recently in-
troduced by Patonay et al. [13] in this field using 2,2-
dimethyl-7-hydroxychromanone ( 1a) as the substrate.
Scheme 1.
neous conditions. As a continuation of our research
program aiming at the application of Pd(0)-catalyzed
transformation for the synthesis of O-heterocyclic
compounds [18 – 20], it seemed promising to study
also the deoxygenation of hydroxybenzopyranoid tri-
flates by Pd(0)-catalyzed reduction.
In order to compare our results with those publish-
ed by Patonay et al. [13], 2,2-dimethyl-7-hydroxy-
chromanone (1a) and its derivatives 1b – h were cho-
sen as model compounds (Scheme 1) whose cor-
Efficient procedures for the deoxygenation of sim- responding triflates 2a – h were prepared in high
ple phenols have been reported via their trifluoro- yields (85 – 94%) by treatment with trifluoromethane-
methanesulfonates (triflates) by hydrogenolysis under sulfonic anhydride in the◦presence of triethylamine in
heterogeneous conditions (Pd/C) [14] and Ni(0)- [15] dichloromethane at −15 C. When the reaction of 2,2-
or Pd(0)-catalyzed [16, 17] reduction under homoge- dimethyl-chromanon-7-yl triflate (2a) with 1 equiv-
c
0932–0776 / 05 / 0700–0792 $ 06.00 ꢀ 2005 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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J. Ko¨ve´r – S. Antus · Facile Deoxygenation of Hydroxylated Flavonoids
Table 1. Compounds 3a – h prepared. Table 2. Compounds 4c – 11c prepared.
793
Sub- Product Time Yielda
M. p.
[◦C]
Lit. m. p.
[◦C]
Lit. yieldb
Sub-
strate
4b
5b
6b
7b
8b
9b
10b
Product
Time
[min]
60
90
60
30
60
60
30
Yielda
[%]
83
83
85
90
93
90
94
M. p.
[◦C]
Lit. m. p.
strate
2a
[min] [%]
[%]
80
82
80
83
80
78
41
70
[◦C]
3a
3b
3c
3d
3e
3f
50
25
30
70
30
20
15
30
93 88.5 – 89 89 – 90 [13]
4c
5c
6c
7c
8c
9c
10c
11c
57 – 58
56 – 57
96 – 97
134 – 135
108 – 109
150 – 151
75 – 76
66 – 67
60 – 62 [25]
60 – 62 [25]
97 [26]
133 – 134 [27]
86 – 87 [28]
154 – 156 [29]
75 – 78 [30]
64 – 65 [31]
2b
2c
90
91
68 – 69
oil
96.5 [21]
oil [22]
2d
2e
2f
95 124 – 125 118 – 119 [23]
92 75 – 76 71 – 72 [23]
91 132 – 133 126 – 127 [23]
2g
2h
3g
3h
70.4
75
oil
88 – 89
oil [24]
89 – 90 [13]
11b
90
79
Isolated yields; b ref. [13].
Isolated yields.
a
a
but our procedure is significantly milder and simpler.
Moreover, it has been also recognized that triflates 2a
and 2g were less reactive towards the catalytic system
using PPh3 instead of dppp. In both cases, hydroly-
sis of triflates 2a, g to 1a, g, respectively, could also
be observed besides their deoxygenation (2a → 3a,
2g → 3g). In order to determine the scope and limi-
tation of this deoxygenation procedure the transforma-
tion of the chalcones 4b and 5b, the flavone 6b, the
isoflavones 7b – 9b, the coumarin 10b and chromone
derivatives 11b was also studied (Scheme 2). The re-
duction of these compounds took place very smoothly
to give the desired deoxygenated derivatives 4c – 11c,
respectively, in good yields (79– 94%) and no byprod-
ucts could be detected (TLC) in any cases (Table 2).
In conclusion, these results have clearly indi-
cated that the palladium(II) acetate/1,3-bis(diphenyl-
phosphanyl)propane (dppp)/formic acid/triethylamine
system in DMF is an efficient agent for deoxygenation
of hydroxysubstitutedflavonoids, isoflavonoids and re-
lated compounds via their trifluoromethanesulfonates.
Experimental Section
Scheme 2.
Melting points were determined on a Bu¨chi 535 appara-
alent of formic acid as a reducing agent was co◦n- tus and are not corrected. 1H NMR spectra were obtained
on a Varian Gemini 200 NMR spectrometer in CDCl3 with
TMS as internal standard. EI-MS (70 eV) spectra were ob-
tained with a VG TRIO-2 instrument. TLC was performed
on Merck Kieselgel 60 F254 pre-coated aluminium plates.
Elemental analyses (C, H) were conducted using Carlo
Erba 1106 EA instrument. 7-Hydroxyflavone (6a) was pur-
chased from Sigma-Aldrich. The preparation of the fol-
lowing derivatives was described earlier: 1a [22], 1b [32],
1c [22], 1d [13], 1e [33], 1f [13], 1g [34], 1h [35], 4a, 5a [36],
7a, 8a, 9a [37], 10a [38], 11a [39].
ducted in N,N-dimethyl formamide (DMF) at 60 C
in the presence of palladium(II) acetate (2.2 mol-%)
and triphenylphosphane (PPh3) (4.2 mol-%) according
to the method described by Cacchi et al. [17], quanti-
tative formation of 2,2-dimethylchromanone (1c) was
observed within 15 minutes. As shown in Table 1, the
other related derivatives 2b – g reacted readily to af-
ford the corresponding reduction products 3b – g, re-
spectively, in excellent yields (70– 95%). Ditriflate 2h
required the use of twice the amounts of the reagents to
convert efficiently into 3a. It is noteworthy that chloro
and carbonyl groups are completely unaffected under
these conditions and the yields have been found to be
Aryl triflates. General procedure: 2,2-Dimethyl-7-(trifluoro-
methylsulfonyloxy)chromanone (2a)
To a solution of 7-hydroxy-2,2-dimethylchromanone [22]
comparable with those published by Patonay et al. [13] (2.40 g, 12.50 mmol) in 20 ml of dichloromethane and
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794
J. Ko¨ve´r – S. Antus · Facile Deoxygenation of Hydroxylated Flavonoids
◦
3 ml of triethylamine at −15 C was slowly added trifluo- m/e (%) = 354 (M+, 8), 339 (15), 299 (8), 206 (5), 165 (6),
romethanesulfonic anhydride (2.15 ml, 3.70 g, 13.10 mmol). 138 (32), 69 (100). – C13H13F3O6S (354.30): calcd. C 44.07,
The mixture was stirred at this temperature for 5 minutes H 3.69; found C 44.50, H 3.59.
◦
and then was allowed to warm to 23 C and stirred un-
til no starting material could be detected by TLC (30 min-
utes). The mixture was washed with conc. NaHCO3 solution
(2 × 30 ml) and conc. NaCl solution, dried (MgSO4), and
concentrated. The residue was purified by chromatography
[silica gel, elution with n-hexane : ethyl acetate (3:1)] to af-
ford 2a as white crystals (3.80 g, 94%); m. p. 29 – 30 ◦C. –
1H NMR: δ = 1.45 (s, 6H, 2-H), 2.75 (s, 2H, 3-H), 6.90 (m,
2H, 6-H, 8-H), 7.95 (d, J = 9.28 Hz, 1H, 5-H). – MS: m/e
(%) = 324 (M+, 8), 309 (22), 269 (12), 176 (19), 149 (19),
107 (39), 79 (32), 69 (100). – C12H11F3O5S (324.29): calcd.
C 44.45, H 3.42; found C 44.40, H 3.49.
2,2-Dimethyl-8-methoxy-7-(trifluoromethylsulfonyloxy)-
chromanone (2f)
(15 min, yield: 88%, oil). – 1H NMR: δ = 1.55 (s, 6H,
2,2-CH3), 2.80 (s, 2H, 3-H), 4.05 (s, 3H, 8-OMe), 6.85 (d,
J = 8.80 Hz, 1H, 6-H), 7.65 (d, J = 8.80 Hz, 1H, 5-H). – MS:
m/e (%) = 354 (M+, 30), 339 (41), 299 (31), 206 (25), 107
(100), 109 (28), 69 (100). – C13H13F3O6S (354.30): calcd.
C 44.07, H 3.69; found C 44.32, H 3.70.
6-Chloro-2,2-dimethyl-7-(trifluoromethylsulfonyloxy)chrom-
anone (2g)
The compounds 2b – h and 4b – 11b were prepared in an
analogous manner.
(30 min, yield: 92%, white crystals, m. p. 58 – 58.5 ◦C). –
1H NMR: δ = 1.45 (s, 6H, 2,2-CH3), 2.75 (s, 2H, 3-H),
7.00 (s, 1H, 8-H), 8.00 (s, 1H, 5-H). – MS: m/e (%) = 358
(M+, 6), 343 (12), 303 (6), 210 (10), 141 (12), 113 (9), 69
(100). – C12H10ClF3O5S (358.72): calcd. C 40.17, H 2.80;
found C 40.30, H 2.95.
7-Trifluoromethylsulfonyloxy-2,2,5-trimethylchromanone
(2b)
1
(20 min, yield: 93%, oil). – H NMR: δ = 1.45 (s, 6H,
2,2-CH3), 2.65 (s, 3H, 5-CH3), 2.75 (s, 2H, 3-H), 6.65 (d,
J = 2.80 Hz, 1H, 6-H or 8-H), 6.75 (d, J = 2.80 Hz, 1H, 6-H
or 8-H). – MS: m/e (%) = 338 (M+, 26), 323 (10), 283 (16),
121 (25), 93 (11), 69 (100). – C13H13F3O5S (338.30): calcd.
C 46.15, H 3.87; found C 46.91, H 3.81.
5,7-Bis(trifluoromethylsulfonyloxy)-2,2-dimethylchrom-
anone (2h)
(30 min, yield: 85%, white crystals, m. p. 123 – 124 ◦C). –
1H NMR: δ = 1.51 (s, 6H, 2,2-CH3), 2.80 (s, 2H, 3-H),
6.73 – 6.74 (d, J = 2.20 Hz, 1H, 6-H or 8-H), 6.97 – 6.99 (d,
J = 2.29 Hz, 1H, 6-H or 8-H). – C13H10F6O8S2 (472.26):
calcd. C 33.06, H 2.11; found C 33.21, H 2.16.
7-Trifluoromethylsulfonyloxy-2,2,8-trimethylchromanone
(2c)
◦
(10 min, yield: 90%, white crystals, m. p. 53 – 54 C). –
1H NMR: δ = 1.50 (s, 6H, 2,2-CH3), 2.25 (s, 3H, 8-CH3),
2.75 (s, 2H, 3-H), 6.90 (d, J = 9.13 Hz, 1H, 5-H or 6-H), 7.80
(d, J = 9.10 Hz, 1H, 5-H or 6-H). – MS: m/e (%) = 338
(M+, 20), 323 (51), 283 (22), 190 (25), 149 (29), 93 (11),
69 (100). – C13H13F3O5S (338.30): calcd. C 46.15, H 3.87;
found C 46.31, H 3.60.
4’-(Trifluoromethylsulfonyloxy)chalcone (4b)
◦
(20 min, yield: 94%, white crystals, m. p. 96 – 97 C). –
1H NMR: δ = 7.14 − 7.55 (m, 6H, aromatic-H, α-CH),
7.60 – 7.75 (m, 2H, aromatic-H), 7.80 – 8.15 (m, 3H,
aromatic-H, β-CH). – MS: m/e (%) = 356 (M+, 42), 253
(76), 131 (100), 69 (72). – C16H11F3O4S (356.32): calcd.
C 53.93, H 3.11; found C 53.90, H 3.18.
2,2-Dimethyl-5-methoxy-7-(trifluoromethylsulfonyloxy)-
chromanone (2d)
4-(Trifluoromethylsulfonyloxy)chalcone (5b)
1
(10 min, yield: 93%, oil). – H NMR: δ = 1.45 (s, 6H,
◦
2,2-CH3), 2.70 (s, 2H, 3-H), 3.90 (s, 3H, 5-OMe), 6.35 (d,
J = 2.17 Hz, 1H, 6-H or 8-H), 6.50 (d, J = 2.15 Hz, 1H, 6-H
or 8-H). – MS: m/e (%) = 354 (M+, 11), 339 (10), 299 (39),
206 (7), 138 (10), 83 (8), 69 (100). – C13H13F3O6S (354.30):
calcd. C 44.07, H 3.69; found C 44.25, H 3.62.
(15 min, yield: 95%, white crystals, m. p. 60 – 61 C). –
1H NMR: δ = 7.35 (d, J = 8.72 Hz, 2H, aromatic-H),
7.50 (d, J = 5.99 Hz, 2H, aromatic-H), 7.56 – 7.66 (m, 5H,
aromatic-H, α- and β-CH), 8.03 (dd, J1 = 1.37 Hz, J2 =
8.71 Hz, 2H, aromatic-H). – MS: m/e (%) = 356 (M+,
25), 223 (66), 131 (77), 105 (100), 69 (82). – C16H11F3O4S
(356.32): calcd. C 53.93, H 3.11; found C 53.19, H 3.08.
2,2-Dimethyl-6-methoxy-7-(trifluoromethylsulfonyloxy)-
chromanone (2e)
7-(Trifluoromethylsulfonyloxy)flavone (6b)
◦
(10 min, yield: 89%, white crystals, m. p. 87 – 88 C). –
1H NMR: δ = 1.45 (s, 6H, 2,2-CH3), 2.75 (s, 2H, 3-H), 3.90
(30 min, yield: 78%, white crystals, m. p. 137 – 138 ◦C). –
(s, 3H, 6-OMe), 6.90 (s, 1H, 8-H), 7.45 (s, 1H, 5-H). – MS: 1H NMR: δ = 6.87 (s, 1H, 3-H), 7.35 (dd, J1 = 2.25 Hz, J2 =
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J. Ko¨ve´r – S. Antus · Facile Deoxygenation of Hydroxylated Flavonoids
795
8.82 Hz, 1H, 6-H), 7.51 – 7.59 (m, 4H, aromatic-H), 7.91 – 2.32 Hz, J2 = 8.83 Hz, 1H, 6-H), 7.46 (d, J = 2.32 Hz, 1H,
7.96 (m, 2H, aromatic-H), 8.35 (d, J = 8.80 Hz, 1H, 5-H). – 8-H), 8.02 (s, 1H, 2-H), 8.42 (d, J = 8.83 Hz, 1H, 5-H). –
MS: m/e (%) = 370 (M+, 80), 273 (57), 268 (54), 237 (100), MS: m/e (%) = 414 (M+, 38), 281 (88), 268 (75), 252 (72),
135 (55), 69 (75). – C16H9F3O5S (370.30): calcd. C 51.89, 146 (51), 69 (100). – C17H9F3O7S (414.32): calcd. C 49.28,
H 2.74; found C 51.01, H 2.79.
H 2.18; found C 49.57 H 2.23.
4-Methyl-7-(trifluoromethylsulfonyloxy)coumarin (10b)
7-(Trifluoromethylsulfonyloxy)isoflavone (7b)
◦
(45 min, yield: 89%, white crystals, m. p. 146 – 147 ◦C). –
1H NMR: δ = 7.26 − 7.57 (m, 7H, aromatic-H), 8.06 (s,
1H, 2-H), 8.43 (d, J = 8.84 Hz, 1H, 5-H). – MS: m/e
(%) = 370 (M+, 52), 273 (72), 268 (88), 237 (72), 135 (82),
69 (100). – C16H9F3O5S (370.30): calcd. C 51.89, H 2.74;
found C 52.01, H 2.86.
(30 min, yield: 91%, white crystals, m. p. 83 – 84 C). –
1H NMR: δ = 2.47 (d, J = 1.18 Hz, 3H, 4-CH3), 6.36 – 6.38
(q, J = 1.18 Hz, 1H, 3-H), 7.22 (d, J = 2.45 Hz, 1H, 8-H),
7.29 (dd, J1 = 2.45 Hz, J2 = 8.60 Hz, 1H, 6-H), 7.70 (d,
J = 8.60 Hz, 1H, 5-H). – MS: m/e (%) = 308 (M+, 46), 239
(40), 175 (74), 69 (100). – C11H7F3O5S (308.23): calcd.
C 42.86, H 2.29; found C 42.57, H 2.25.
5-Hydroxy-2-methyl-7-(trifluoromethylsulfonyloxy)-
isoflavone (8b)
Ethyl 7-(trifluoromethylsulfonyloxy)chromone-2-carboxylate
(11b)
(30 min, yield: 68%, white crystals, m. p. 128 – 129 ◦C). –
1H NMR: δ = 2.30 (s, 3H, CH3), 7.02 (s, 1H, 8-H), 7.35 –
7.44 (m, 6H, aromatic-H), 13.14 (s, 1H, 5-OH). – MS: m/e
(%) = 400 (M+, 32), 331 (44), 303 (63), 284 (58), 267 (88),
151 (77), 69 (100). – C17H11F3O6S (400.33): calcd. C 51.00,
H 2.76; found C 51.17, H 2.85.
(30 min, yield: 66%, white crystals, m. p. 127 – 128 ◦C). –
1H NMR: δ = 1.45 (t, J = 7.14 Hz, 3H, ethyl-CH3), 4.49
(q, J = 7.14 Hz, 2H, ethyl-CH2), 7.16 (s, 1H, 3-H), 7.37
(dd, J1 = 2.34 Hz, J2 = 8.87 Hz, 1H, 6-H), 7.65 (d, J =
2.34 Hz, 1H, 8-H), 8.31 (d, J = 8.87 Hz, 1H, 5-H). – MS:
m/e (%) = 336 (M+, 20), 297 (62), 268 (82), 233 (54),
69 (100). – C13H9F3O7S (366.27): calcd. C 42.63, H 2.47;
found C 42.17, H 2.50.
3’,4’-Methylenedioxy-7-(trifluoromethylsulfonyloxy)-
isoflavone (9b)
(30 min, yield: 73%, white crystals, m. p. 174 – 175 ◦C). –
1H NMR: δ = 6.01 (s, 2H, −OCH2O−), 6.89 (d, J =
8.01 Hz, 1H, 5’-H), 6.98 (dd, J1 = 1.66 Hz, J2 = 8.01 Hz,
1H, 6’-H), 7.08 (d, J = 1.66 Hz, 1H, 2’-H), 7.35 (dd, J1 =
Acknowledgement
We wish to thank the National Science Fundation (OTKA
T049436) for financial support.
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