TFA-mediated tandem Friedel-Crafts alkylation/cyclization/hydrogen transfer process for the synthesis of flavylium compounds

Article abstract of DOI:10.1021/jo7015604

(Chemical Equation Presented) The tandem reaction of phenols and chalcones in refluxing TFA gave the flavylium species of 2-hydroxy-2-phenyl-2H-chromenes in moderate to good isolated yields. The reaction was proposed to involve a tandem transformation of

Full text of DOI:10.1021/jo7015604

TABLE 1. The Reaction of Phenol 1a with Chalcone 2a under
Different Conditions
TFA-Mediated Tandem Friedel-Crafts
Alkylation/Cyclization/Hydrogen Transfer
Process for the Synthesis of Flavylium
Compounds
Yan-Chao Wu, Li Liu,* Yu-Liang Liu, Dong Wang, and
Yong-Jun Chen*
Beijing National Laboratory for Molecular Science (BNLMS),
Center for Chemical Biology, Institute of Chemistry, Chinese
Academy of Sciences, Beijing 100080, People’s Republic of
China
entry
reagent
timea (d)
yieldb of 3a (%)
1
2
3
4
5
6
7
8
9
TFA
TFA
TFA
TFA
1
2
3
4
1
1
3
3
3
44
62
73
71
<5
45
<5
<5
<5
lliu@iccas.ac.cn; yjchen@iccas.ac.cn
Pd(OAc)2, TFAc
Pd(OAc)2, TFAd
HCle
ReceiVed August 2, 2007
f
H2SO4
AcOH
a 1a:2a ) 1:2. Reaction temperature ) 72 °C. b Isolated yield. c P-
d(OAc)2: 10 mol %. Reaction temperature ) room temperature. d Pd(OAc)2:
10 mol %. e Aqueous hydrochloric acid (37%). f Concentrated sulfonic
acid (98%).
The tandem reaction of phenols and chalcones in refluxing
TFA gave the flavylium species of 2-hydroxy-2-phenyl-2H-
chromenes in moderate to good isolated yields. The reaction
was proposed to involve a tandem transformation of Friedel-
Crafts alkylation, dehydrative cyclization, intermolecular
hydrogen transfer, and hydration. As a multifunctional
catalyst, TFA mediated the processes efficiently and cleanly.
FIGURE 1. The structure of 4a and 5.
suitable catalysts for the Friedel-Crafts-type reaction. Fujuwara
reported that the Friedel-Crafts C-alkylation of phenols with
R,â-unsaturated esters could be catalyzed by Pd(II) in TFA to
give coumarin derivatives.8 On the other hand, the reaction of
phenols with R,â-unsaturated ketones could provide flavylium
compounds.9 However, under such conditions, the substrates
were limited to reactive phenols; furthermore, an additional
oxidant such as DDQ was normally necessary for the formation
of flavylium salts in the final step. Flavylium salts, e.g.,
anthocyanins, have long been considered as ubiquitous pigments
responsible for the various colors in fruits and flowers,10
effective food colorants,11 and biologically active substances.12
The Friedel-Crafts alkylation reactions of phenols have been
widely employed to construct numerous aromatic heterocyclics
possessing special properties.1 Among them, the addition
reactions of phenols to R,â-unsaturated carbonyl compounds
provide various benzopyran derivatives.2 Phenols can react with
R,â-unsaturated ester or acids through C-alkylation/O-acylation
or C-acylation/O-alkylation to form coumarins, chromanones,
chromones, etc.3 Many Lewis acids, such as Cu(OTf)24 and BF3‚
OEt2,5 and protic acids, such as HCl6 and sulfuric acid,7 were
(6) Singh, I.; Prasad, A. K.; Sharma, A. K.; Saxena, R. K.; Olsen, C.;
Cholli, A. L.; Samuelson, L. A.; Kumar, J.; Watterson, A. C.; Parmar, V.
S. Bioorg. Med. Chem. 2003, 11, 529 - 538.
(7) Buu-Hoi, N. P.; Le Bihan, N.; Binon, F.; Maleyran, P. J. Org. Chem.
1952, 17, 1122-1127.
(8) (a) Jia, C. G.; Piao, D. G.; Oyamada, J.; Lu, W. J.; Kitamura, T.;
Fujuwara, Y. Science 2000, 287, 1992-1995. (b) Tunge, J. A.; Foresee, L.
N. Organometallics 2005, 24, 6440-6444.
(9) (a) Hill, D. W. Chem. ReV. 1936, 19, 27-54. (b) Broadbent, P.;
Roberrtson, A.; Whalley, W. B. J. Chem. Soc. 1952, 4957-4959. (b)
Robinson, R.; Walker, J. J. Chem. Soc. 1934, 1435-1440. (c) Johnson, A.
W.; Melhuish, R. R. J. Chem. Soc. 1947, 346-350. (d) Chassaing, S.;
Kueny-Stotz, M.; Isorez, G.; Brouillard, R. Eur. J. Org. Chem. 2007, 15,
2438-2448.
(10) (a) Goto, T.; Kondo, T. Angew. Chem., Int. Ed. 1991, 30, 17-33.
(b) Santos, H.; Turner, D. L.; Lima, J. C.; Figueiredo, P.; Pina, F.;
Macu¨anita, A. L. Phytochemistry 1993, 33, 1227-1232. (c) Brouillard, R.;
Dangles, O. In The FlaVonoids, AdVances in Research since 1986; Harborne,
J. B., Ed.; Chapman and Hall: London, UK, 1993.
(1) (a) Rappoport, Z. The chemistry of phenols; John Wiley and Sons:
New York, 2003. (b) Heaney, H. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds; Pergamon Press: Oxford, UK, 1991; Vol.
2, pp 733-752. (c) Olah, G. A.; Krishnamurti, R.; Prakash, G. K. S. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds; Pergamon
Press: Oxford, UK, 1991; Vol. 3, pp 293-339.
(2) (a) Ellis, G. P. Chromenes, chromanones, and chromones; Wiley-
Interscience: New York, 1977. (b) Ellis, G. P.; Lockhart, I. M. Chromans
and Tocopherols; Wiley-Interscience: New York, 1981.
(3) (a) Fillion, E.; Dumas, A. M.; Kuropatwa, B. A.; Malhotra, N. R.;
Sitler, T. C. J. Org. Chem. 2006, 71, 409-412. (b) Krawczyk, H.; Bodalski,
R. J. Chem. Soc., Perkin Trans. I 2001, 1559-1565. (c) Gunnewegh, E.
A.; Hoefnagel, A. J.; vanBekkum, H. J. Mol. Catal. A: Chem. 1995, 100,
87-92.
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Jorgensen, K. A. Org. Biol. Chem. 2003, 1, 1953-1958.
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F.; De Keukeleire, D. E. J. Med. Chem. 2005, 40, 1042-1051.
10.1021/jo7015604 CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/01/2007
J. Org. Chem. 2007, 72, 9383-9386
9383

TABLE 2. Reaction of Phenols (1a-f) with Chalcones (2a-e)a
a Reaction condition: in refluxed TFA for 3 d. b Isolated yield.
The multistate/multifunctional chemical system existing in
flavylium compounds has attracted considerable attention in
molecular information processing, optical memories, and logic
gates.
The development of tandem reactions in which one catalyst
promotes all transformation in a one-pot process is a challenging
task for synthetic chemists. Inspired by the tandem reaction
involving the Friedel-Crafts reaction of phenols with R,â-
unsaturated carbonyl compounds providing various heteroaro-
(11) (a) Markakis, P. Anthocyanins as Food Additives. In Anthocyanins
as Food Colors; Markakis, P., Ed.; Academic Press: New York, 1982. (b)
Timberlake, C. F.; Henry, B. S. Anthocyanins as Natural Food Colorants.
In Plant FlaVonoids in Biology and Medicine II Biochemical, Cellular and
Medicinal Properties; Cody, V., Middleton, E., Harborne, J. B., Beretz,
A., Alan, R., Eds.; Liss: New York, 1988.
(12) (a) Harborne, J. B.; Grayer, R. J. The Anthocyanins. In The
FlaVonoids: AdVances in Research Since 1980; Harborne, J. B., Ed.;
Chapman and Hall: London, 1988. (b) Costantino, L.; Rastelli, G.; Albasini,
A. Pharmazie 1995, 50, 573-574. (c) Tamura, H.; Yamagami, A. J. Agric.
Food Chem. 1994, 42, 1612-1615.
9384 J. Org. Chem., Vol. 72, No. 24, 2007

SCHEME 1. The Reaction of Phenols 1 with Chalcones 2 in
TFA
maticyclics, we would like to report the Friedel-Crafts alky-
lation of phenols with chalcone derivatives in TFA without the
use of other catalysts for the direct synthesis of flavylium
compounds in a one-pot process.
FIGURE 2. Reaction intermediates.
SCHEME 2. Hydrogen Transfer between 7 and 2e in
TFA-d
Reaction of 4-tert-butylphenol (1a) and 4-chloro-trans-
chalcone (2a) was carried out initially at room temperature in
trifluoroacteic acid (TFA) in the presence of Pd(OAc)2 (10 mol
%) as a catalyst.8 However, no flavylium product was detected
(Table 1, entry 5). Then, the reaction of 1a and 2a (1a/2a )
1:2) was performed in refluxing TFA for 1 day in the absence
of Pd (OAc)2 (entry 1). To our delight, the product of the desired
tandem reaction, 6-tert-butyl-4-(4-chlorophenyl)-2-hydroxy-2-
phenyl-2H-chromene 3a, was obtained in 44% yield, together
with the corresponding reduction product, 3-(4-chlorophenyl)-
1-phenylpropan-1-one 4a (45% yield on the basis of 1a used,
Figure 1). The same results were obtained when 10 mol % of
Pd(OAc)2 in refluxing TFA was used, which indicated that Pd-
(OAc)2 was not essential in this reaction (entry 6 vs entry 1 in
Table 1). The yield of 3a was increased to 73% by prolonging
the reaction time (Table 1, entries 1-3). No further increase
was observed when the reaction time exceeded 3 days (entry
4). In this case, the yield of the reduction product 4a was
increased to 70% (Table 1, entry 3 and Table 2, entry 1).
Hydrochloric acid, sulfuric acid, and acetic acid were ineffective
for this reaction (entries 7-9). TFA appeared to serve the dual
role of catalyst and solvent. However, if TFA was mixed with
organic solvents (v/v ) 1:1) such as dichloromethane, water,
and toluene, the yields of 3a decreased dramatically, and only
a trace amount of the product 3a was detected. The structure of
3a was supported by X-ray crystallographic analysis of 6-tert-
butyl-4-(p-chlorophenyl)-2-ethoxy-2-phenyl-2H-chromene 5 (see
the Supporting Information), which was obtained from 3a by
etherification with ethanol.
The interesting preliminary results encouraged us to examine
the scope of substrates suitable to this tandem reaction. Various
phenols (1a-f) and chalcones (2a-e) were employed. It was
found in Table 2 that a wide range of 1 and 2 subjected to this
procedure (1/2 ) 1:2) could afford the corresponding flavylium
compounds (3a-j) in moderate to good yields (Scheme 1).
4-Chloro-trans-chalcone (2a), 4,4′-dichloro-trans-chalcone (2b),
and 4′-chloro-trans-chalcone (2c) provided similar yields of the
flavylium products (3a-c) in yields of 68-73% (entries 1-3).
4-Methyl-trans-chalcone (2d) and chalcone (2e) were relatively
less reactive than 2a (entries 4 and 5). In the selected halogen-
substituted phenols (1e,f) (entries 9-11), 4-bromophenol (1f)
was the most reactive one. It is worth mentioning that no metal
catalyst was required in the reaction. Furthermore, after the
reaction TFA could be distilled out for reuse. In addition, the
reduction products (4a-e) of chalcones (2) were also isolated
from the product mixture in yields almost equal to that of the
flavylium compounds (3) (Table 2).
to trap the reaction intermediates. When the reaction of phenol
1g with 2e in refluxing TFA was quenched after only 1 day,
apart from the isolation of the product 3k in 13% yield, a small
amount of the Friedel-Crafts alkylation product 6 and the
related cyclization product 7, 2,4-diphenyl-4H-chromene, were
also isolated in 6% and 1% yields, respectively (Figure 2). The
structure of intermediate 7 was determined by spectroscopy and
X-ray crystallographic analysis.
In a separate reaction, 6 could be converted to 7 in almost
quantitative yield after 12 h in refluxing TFA. The conversion
of 7 into 3k involved a dehydrogenation process, whereas during
the reaction chalcone 2e was reduced to 4e. A reasonable
postulation was the conversion of 7 to 3k would be through an
intermolecular hydrogen shift process, in which 2e was involved
as a hydrogen acceptor.13 Indeed, when 7 was reacted with 2e
in refluxing TFA for 3 days, followed by quenching with water,
the product 3k could be obtained in 72% yield.
The intermolecular hydrogen transfer between 7 and 2e was
further proved by hydrogen/deuterium (H/D) exchange experi-
ments (Scheme 2). The mixture of 7 and 2e in refluxing
deuteriotrifluoroacetic acid (CF3CO2D, TFA-d) was stirred for
3 days, followed by hydration with water to afford 2,2-
dideuterio-1,3-diphenylpropan-1-one (8, 71%) and 3k (70%).
The generation of 8 as the sole deuterio product demonstrated
that the hydrogen transfer proceeded with high chemoselectivity.
The hydrogen transfer is proposed to take place as shown in
Scheme 2. In the initial step, hydrogen is selectively transferred
To obtain further information on the reaction mechanism, the
tandem reaction was quenched under certain reaction conditions
(13) Mishrikey, M. M.; Østensen, E. T. Acta Chem. Scand. B 1976, 30,
329-335.
J. Org. Chem, Vol. 72, No. 24, 2007 9385

SCHEME 3. Reaction Mechanism
4H-chromenes (7), (c) intermolecular hydrogen transfer between
2 and 7 to form 2-arylbenzopyryliums ion 11 and 1,3-bisaryl-
propan-1-ones 4, and (d) reaction of 11 with a molecule of water
to form 3. Unlike stepwise approaches, this tandem process
efficiently avoids the handling of multiple intermediates.
Experiment Section
General Procedure for the Synthesis of 2-Hydroxy-2-phenyl-
2H-chromenes. A mixture of phenols 1 (0.2 mmol) and chalcones
2 (0.4 mmol) in TFA (2 mL) under atmospheric N2 was stirred at
reflux for 3 d, after which TFA was distilled out for reuse. The
residue was redissolved in CH2Cl2 (30 mL), and the solution was
washed with 5 mL of saturated aqueous NaHCO3 and 5 mL of
water, dried over anhydrous Na2SO4, filtered, and evaporated under
reduced pressure at a bath temperature of <30 °C. The crude
products were isolated by flash chromatography on silica gel (200-
300 mesh) (eluent: ethyl acetate/petroleum ether ) 1:10) to obtain
the products 3 and 4.
from the 4-position of 7 to the â-carbon of the enone 2e to
afford 2-deuterio-1,3-diphenylpropan-1-one (9). The latter is
subsequently converted to 8 by further hydrogen/deuterium
exchange.14 Transfer hydrogenation reactions of R,â-unsaturated
ketones catalyzed by Ru-complex are known to proceed chemo-
selectively for CdO function, and CdC bonds are unaffected.15
In contrast, under refluxing TFA conditions, the hydrogen
transfer process involved in the tandem reaction of phenols with
chalcones took place exclusively for the reduction of the CdC
bond. The result might provide an approach to the development
of new methods of selective reductions of the CdC bond in
R,â-unsaturated ketones via transfer hydrogenation.
On the basis of the foregoing results we propose the putative
general mechanism in Scheme 3 for the TFA-mediated synthesis
of 2-aryl-2-hydroxy-2H-chromenes such as 3: (a) Friedel-
Crafts alkylation of chalcones (2) with phenols (1) to form the
alkylation products (6),16 (b) dehydrative cyclization of 6 to form
6-tert-Butyl-4-(4-chlorophenyl)-2-phenyl-2H-chromen-2-ol (3a):
1
73%, foam; H NMR (300 MHz, CDCl3) δ 7.71 (dd, J ) 7.8, 1.1
Hz, 2H), 7.44-7.33 (m, 8H), 7.19 (d, J ) 2.3 Hz, 1H), 7.09 (d, J
) 8.5 Hz, 1H), 5.86 (s, 1H), 3.25 (s, 1H), 1.25 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 149.2, 144.4, 143.1, 136.1, 135.9, 134.2, 130.2,
128.7, 128.6, 128.4, 127.2, 125.8, 124.2, 122.7, 119.2, 117.0, 96.5,
34.4, 31.5; IR (film) ν (cm-1) 3407, 3035, 2961, 1489, 1258, 1088,
1015, 825, 763, 699. Anal. calcd for C25H23ClO2: C, 76.81; H,
5.93. Found: C, 76.85; H, 6.17.
Acknowledgment. We thank the National Natural Science
Foundation of China and the Chinese Academy of Sciences for
financial support.
Supporting Information Available: Experimental procedures;
characterization data; copies of 1H and 13C NMR spectra; and X-ray
crystallographic data of 5 and 7 in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) When trityl fluoroborate (Ph3CBF4) (1 equiv) was added in the
reaction of phenol 1a with chalcone 2a (1a:2a ) 1:1), 3a was obtained in
70% yield by saving 1 equiv of 2a.
(15) Xue, D.; Chen, Y.-C.; Cui, X.; Wang, Q.-W.; Zhu, J.; Deng, J.-G.
J. Org. Chem. 2005, 70, 3584-3591.
JO7015604
(16) Aoki, S.; Amamoto, C.; Oyamada, J.; Kitamura, T. Tetrahedron
2005, 61, 9291-9297.
9386 J. Org. Chem., Vol. 72, No. 24, 2007