Rearrangement of 5-O-prenyl flavones: A regioselective access to 6-C-(1,1-dimethylallyl)- and 8-C-(3,3-dimethylallyl)-flavones

Article abstract of DOI:10.1016/S0040-4039(01)01503-9

Regioselective control of the Claisen rearrangement of 7-MEM-5-prenyl chrysin was achieved by microwave irradiation. The nature of the products was influenced by the irradiation power and the type of solvent. Irradiation at 750 W in N,N-diethylaniline specifically yielded the 8-(3,3-dimethylallyl) para-rearranged product while refluxing in N,N-diethylbutylamine gave selective access to the 6-(1,1-dimethylallyl) ortho-rearranged compound.

Full text of DOI:10.1016/S0040-4039(01)01503-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7241–7244
Rearrangement of 5-O-prenyl flavones: a regioselective access to
6-C-(1,1-dimethylallyl)- and 8-C-(3,3-dimethylallyl)-flavones
Jean-Baptiste Daskiewicz, Christine Bayet and Denis Barron*
Laboratoire des Produits Naturels, Baˆtiment Chevreul, Universite´ Claude Bernard-Lyon 1, 43 Bd. du 11 Novembre 1918,
69622 Villeurbanne, France
Received 10 August 2001; accepted 17 August 2001
Abstract—Regioselective control of the Claisen rearrangement of 7-MEM-5-prenyl chrysin was achieved by microwave irradia-
tion. The nature of the products was influenced by the irradiation power and the type of solvent. Irradiation at 750 W in
N,N-diethylaniline specifically yielded the 8-(3,3-dimethylallyl) para-rearranged product while refluxing in N,N-diethylbutylamine
gave selective access to the 6-(1,1-dimethylallyl) ortho-rearranged compound. © 2001 Elsevier Science Ltd. All rights reserved.
Flavones have been recognized1 as efficient in vitro
effectors of P-glycoprotein (Pgp), one of the trans-
porters involved in multidrug resistance (MDR).2
Recently, C-isoprenylation has been shown to enhance
the binding affinity of the flavone chrysin towards Pgp.3
In addition, only isoprenoid derivatives were able to
inhibit Pgp-mediated daunomycin efflux from leukemic
K562/R7 cells. In fact, 8-prenyl chrysin displayed a
stronger effect than cyclosporin A, one of the most
potent modulators available.3 Isoprenoid chrysins have
been obtained in the past by direct C-alkylation in
aqueous alkaline medium and in catalytic phase trans-
fer conditions.3 However, the yields of isoprenoid
derivatives were in the 20–30% range and chromato-
graphic separation of the isomers was necessary.3 This
prompted us to develop more efficient and more
regioselective methods for the preparation of isoprenoid
flavones, providing easier access to the amounts
required for in vivo studies. Claisen rearrangements are
usually the method of choice for the regioselective
isoprenylation of phenolic natural products.4 Recently,5
the rearrangement of 7-acetyl-5-prenyl naringenin has
been studied in the presence of catalytic amounts of
Eu(fod)3. However, this approach failed to produce the
6-(1,1-dimethylallyl) ortho-rearranged product selec-
tively, and there has been no report of para rearrange-
silica gel, submitted to recrystallization, or heated.
Therefore, under the conditions of a thermal Claisen
rearrangement, elimination of the 5-O-prenyl chain
with no rearrangement may largely prevail. Our strat-
egy is based on two points: improved preparation of
5-O-prenyl chrysin, and microwave-assisted rearrange-
ment ensuring excellent control of the nature of the
products.
The syntheses of C-prenyl chrysins is a three-step pro-
cess, which involves (Fig. 1): (i) protection of the 7-
hydroxyl; (ii) O-alkylation of the 5-hydroxyl group,
and (iii) C-alkylation at the 6- or 8-positions by Claisen
rearrangement. Protection of the 7-hydroxyl by the
methoxyethoxymethyl (MEM) group proceeded
smoothly, leading to 7-MEM chrysin 26 in very good
yield (82%). Alkylation of flavone 2 was performed in
the presence of tetrabutylammonium hydroxide as a
base, yielding the 5-O-alkylated product 37 in 89%
yield. On the COLOC 2D NMR spectrum of 3, a
strong correlation was visible between C-5 at 160.05
ppm and H-1%% at 4.64 ppm, confirming the success of
5-O-prenylation. Subsequent rearrangements of 3 were
carried out under microwave irradiation using either
N,N-dimethylaniline or N,N-diethylaniline as solvents.8
All compounds have been fully characterized on the
1
basis of their elemental analyses, HRMS, H and 13C
ment in the flavone series. Indeed, such
a
rearrangement will be difficult, because the 5-O-prenyl-
ated intermediate, the substrate of the rearrangement,
is unstable in solution, and when chromatographed on
NMR spectroscopic properties. The nature of the prod-
uct(s) of the microwave-induced rearrangement was
highly influenced by two factors: the type of the sol-
vent, and the irradiation power (Table 1). Decreasing
microwave irradiation power was associated with
longer reaction times (Table 1, entries 1 to 3). When the
rearrangement was performed in diethylaniline and at
* Corresponding author. Tel.: +33 472 431 421; fax: +33 472 431 557;
e-mail: denis.barron@univ-lyon1.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01503-9

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J.-B. Daskiewicz et al. / Tetrahedron Letters 42 (2001) 7241–7244
Figure 1. Strategy for the regioselective syntheses of 6-(1,1-dimethylallyl)- and 8-(3,3-dimethylallyl)-chrysins. 2: MEM-Cl,
iPr2NEt, DMF, 82%; 3: 1-bromo-3-methyl-2-butene, tetrabutylammonium hydroxide, toluene/CH2Cl2, 89%; 5 and 7: see Table 1.
Table 1. Parameters influencing Claisen rearrangement of flavone 3
Entry no.
Solvent
1
2
3
4
5
N,N-Diethylaniline N,N-Diethylaniline
N,N-Diethylaniline
N,N-Dimethylaniline
N,N-Diethylbutylamine
Conditions
Microwave
750
2×15
5 (1.4), 7 (82)
0.02
Microwave
620
4×15
5 (14), 7 (76)
0.18
Microwave
570
6×15
5 (30), 7 (60)
0.5
Microwave
570
10×15
5 (39), 7 (48)
0.81
Oil bath 160°C, 72 h
–
–
5 (81), 7 (5)
16.2
Irradiation power (W)
Irradiation time (min)
Products formed (%)
5/7 Ratio
Total 5+7
83%
90%
90%
87%
86%
maximum irradiation power, the isoprenoid chrysin 79
was the major product, formed after only 30 min
irradiation (Table 1, entry 1). The occurrence of a
C-(3,3-dimethylallyl) chain in 7 was demonstrated by
the presence of the usual signals for C-prenyl chrysin
154.47 (C-9) and 108.72 ppm (C-8) correlated with the
H-1%% signal at 3.53 ppm. Therefore, compound 7 was
identified as 7-MEM-8-prenyl-chrysin. When lower
irradiation power was used, compound 512 was detected
in addition to 7. NMR data for 5 showed the presence
of a C-(1,1-dimethylallyl) residue (H-2%%: 6.30, dd, J=
17.4 and 10.6 Hz; H-3%%: 4.83, dd, J=10.6 and 1.3 Hz;
H-3%%: 4.87, dd, J=17.4 and 1.3 Hz; H-4%%/5%%: 1.62, s;
C-1%%: 41.50; C-2%%:150.56; C-3%%: 106.91; C-4%%/5%%: 29.05),
in accordance with published values.10 The 5-phenolic
hydroxyl of 5 appeared at higher chemical shift (12.96
ppm) than that of 7 (12.66 ppm). Taking into account
previous observations in the flavone3 and flavanone
series,13 this suggested that compound 5 was C-alkyl-
ated at the 6-position. This was confirmed by the
results of a 2D HMBC NMR experiment. In fact, the
singlet at 6.82 ppm (H-8) was correlated with the
quaternary carbons at 162.70 (C-7), 156.05 (C-9) and
118.80 (C-6), but not with that at 160.91 ppm (C-5).
Finally the double doublet at 6.30 ppm (H-2%%)
crosslinked with C-6 at 118.80 ppm. Therefore, the
structure 6-(1,1-dimethylallyl)-7-MEM-chrysin was
1
derivatives,3,10 both on its H- (H-2%%: 5.19, brt, J=6.8
Hz; H-4%%: 1.66, s; H-5%%: 1.79, s) and 13C NMR (C-1%%:
21.99; C-2%%: 122.22; C-3%%: 131.90; C-4%%: 25.66; C-5%%:
17.91) spectra. In addition, the chemical shift of the
benzylic methylene carbon of the prenyl group (C-1%%)
confirmed the presence of oxygen substituents in the
two positions ortho to the C-prenyl group.11 This
located the 3,3-dimethylallyl chain at either the 6- or
8-positions, but not at the 3-position.11 Final assign-
ment of the position of prenylation was derived from
the analysis of the 2D COLOC experiment. The
methine carbon at 97.97 ppm was found to correlate
with the 5-phenolic hydroxyl at 12.66 ppm, while its
associated proton at 6.62 ppm displayed a cross peak
with the C-5 signal at 160.20 ppm. This clearly demon-
strated that the 6-position of chrysin was free of substi-
tution. On the other hand, the signals at 160.46 (C-7),

J.-B. Daskiewicz et al. / Tetrahedron Letters 42 (2001) 7241–7244
7243
assigned to compound 5. The amount of 5 increased
with decreasing power (Table 1, entries 1 to 3) and
solvent boiling point (entries 3 and 4). It is noteworthy
that, modification of the parameters only affected the
5/7 ratio, but not the total amount of C-isoprenoid
flavones 5+7 which was found to stay in the 83–90%
range (Table 1). Selected preparation of the 6-(1,1-
dimethylallyl) isomer 5 was not achieved by microwave
irradiation. The latter compound, however, was synthe-
sized in 81% yield by refluxing compound 3 in N,N-
diethylbutylamine (Table 1, entry 5). It is likely that
both compounds 5 and 7 are formed from a common
intermediate 414 (Fig. 1). In relatively mild rearrange-
ment conditions (route 1), aromatisation of 4 would
preferably give rise to 5. Under more drastic conditions
(route 2), intermediate 4 would undergo a second rear-
rangement, leading to 7, possibly though a second
intermediate 6. The use of intermediate conditions
(lower irradiation power or lower solvent boiling point)
would furnish a mixture of both compounds. By proper
adjustment of the conditions of the rearrangement, the
formation of one of the two compounds can be
favored. In this respect, microwave irradiation repre-
sents a fast and simple method for the regioselective
C-isoprenylation of flavonoids. In addition, appropri-
ate conditions for the selective preparation of 6-(1,1-
dimethylallyl)-flavonoids are reported here for the first
time.
otte, A. M. Heterocycles 1996, 43, 277–285 (Prenyl
flavones).
5. Gester, S.; Metz, P.; Zierau, O.; Vollmer, G. Tetrahedron
2001, 57, 1015–1018.
6. 7-MEM-Chrysin 2. To a solution of 5 g of chrysin 1 (19.6
mmol, 1 equiv.) in 110 ml of dry DMF were added
N,N-diisopropylethylamine (7 ml, 39.5 mmol, 2 equiv.).
The mixture was cooled (ice bath) and 4.4 ml of MEM
chloride (39.3 mmol, 2 equiv.) were added dropwise
under stirring. After complete addition of the reagent, the
mixture was stirred for 15 min at room temperature. The
medium was diluted with water and left overnight at 4°C.
The resulting precipitate of crude flavone 2 was isolated
by filtration and recrystallized in EtOH, yielding 5.5 g (16
1
mmol, 82%) of pure 2. H NMR (CDCl3, 200 MHz): l
12.62 (s, 5-OH), 7.83 (m, H-2%/6%), 7.48 (m, H-3%/4%/5%),
6.66 (d, J=2.2 Hz, H-8), 6.61 (s, H-3), 6.44 (d, J=2.2
Hz, H-6), 5.30 (s, H-1%%%), 3.81 (m, H-2%%%), 3.54 (m, H-3%%%),
3.35 (s, H-4%%%). 13C NMR (CDCl3, 50 MHz): l 182.41
(C-4), 163.93 (C-2), 162.98 (C-7), 161.94 (C-5), 157.52
(C-9), 131.75 (C-4%), 131.11 (C-1%), 128.96 (C-3%/5%), 126.17
(C-2%/6%), 106.27 (C-10), 105.72 (C-3), 100.09 (C-6), 94.28
(C-8), 93.19 (C-1%%%), 71.42 (C-3%%%), 68.15 (C-2%%%), 58.94
(C-4%%%). MS (EI) m/z: 342 (M+), 283 (M+−MeOCH2CH2),
267 (M+−MeOCH2CH2O), 254 (M+−MeOCH2CH2-
OCH2+H). HRMS (EI): m/z calcd for C19H18O6,
342.1103, found 342.1104. Anal. calcd for C19H18O6: C,
66.66; H, 5.30. Found C, 66.71; H, 5.34.
7. 7-MEM-5-Prenyl chrysin 3. To a solution of 1 g of
flavone 2 (2.9 mmol, 1 equiv.) in 15 ml CH2Cl2 and 10 ml
toluene at 0°C (ice bath), were directly added (stirring)
solid tetrabutylammonium hydroxide 30 hydrate (4.6 g,
5.8 mmol, 2 equiv.). After complete dissolution of the
base, 0.5 ml of 3,3-dimethylallyl bromide (4.4 mmol, 1.5
equiv.) were added dropwise under stirring at 0°C. Reac-
tion was allowed to proceed at room temperature for 2 h
(stirring). After dilution with water and acidification (1N
HCl) the products of the reaction were extracted with
EtOAc. HPLC dosage (silica, 10% isopropanol in hexane)
of the extract revealed that flavone 3 has been prepared
in 89% yield. After evaporation of the solvent, the residue
was taken up in minimum acetone, and hexane was
added dropwise until the solution started to become
cloudy. Leaving the solution overnight at 4°C lead to
crystallization of pure flavone 3 (0.8 g, 69%). 1H NMR
(CDCl3, 200 MHz): l 7.82 (m, H-2%/6%), 7.44 (m, H-3%/4%/
5%), 6.76 (d, J=2.2 Hz, H-8), 6.59 (s, H-3), 6.43 (d, J=2.2
Hz, H-6), 5.54 (brt, J=6.4 Hz, H-2%%), 5.31 (s, H-1%%%), 4.64
(d, J=6.3 Hz, H-1%%), 3.82 (m, H-2%%%), 3.54 (m, H-3%%%),
3.34 (s, H-4%%%), 1.75 (brs, H-4%%), 1.72 (brs, H-5%%). 13C
NMR (CDCl3, 50 MHz): l 177.23 (C-4), 161.26 (C-7),
160.43 (C-2), 160.05 (C-5), 159.45 (C-9), 137.35 (C-3%%),
131.46 (C-1%), 130.97 (C-4%), 128.75 (C-3%/5%), 125.82 (C-2%/
6%), 119.36 (C-2%%), 110.19 (C-10), 108.84 (C-3), 98.40
(C-6), 95.60 (C-8), 93.24 (C-1%%%), 71.41 (C-3%%%), 68.07
(C-2%%%), 66.50 (C-1%%), 58.90 (C-4%%%), 25.66 (C-4%%), 18.27
(C-5%%). MS (FAB) m/z: 411 (M+H+), 343 (M+H−C5H8+).
HRMS (FAB): m/z calcd for C24H27O6, 411.1808, found
411.1795. Anal calcd for C24H26O6: C, 70.23; H, 6.38.
Found C, 70.35; H, 6.21.
Acknowledgements
This work was supported by grants from the EU frame-
work V (Polybind project QLK1-1999-00505). Jean-
Baptiste Daskiewicz was the recipient of a fellowship
from the French Ministry of Research and Education.
We are grateful to Professor M. N. Clifford, University
of Surrey, for revising the English.
References
1. Conseil, G.; Beaubichon-Cortay, H.; Dayan, G.; Jault, J.
M.; Barron, D.; Di Pietro, A. Proc. Natl. Acad. Sci. USA
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2. (a) Gottesman, M. M.; Pastan, I. Annu. Rev. Biochem.
1993, 62, 385–427; (b) Gros, P.; Buschman, E. Int. Rev.
Cytol. 1993, 137C, 169–197.
3. Comte, G.; Daskiewicz, J. B.; Barron, D.; Bayet, C.;
Conseil, G.; Viornery-Vanier, A.; Dumontet, C.; Di
Pietro, A. J. Med. Chem. 2001, 44, 763–768.
4. (a) Lutz, R. P. Chem. Rev. 1984, 84, 205–247 (Review on
Claisen rearrangements); (b) Muray, R. D. H.; Mendez,
J.; Brown, S. The Natural Coumarins, Occurrence, Chem-
istry and Biochemistry; Wiley & Sons: Chichester, 1982;
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Orr, A. J. Chem. Soc. Perkin Trans 1. 1994, 3095–3100
(Synthesis of prenyl coumarins); (d) ElSohly, H. N.; Ma,
G. E.; Turner, C. E.; ElSohly, M. A. J. Nat. Prod. 1984,
47, 445–452 (Prenyl dihydrostilbene); (e) Patel, G. N.;
Trivedi, K. N. J. Indian Chem. Soc. 1988, 65, 192–193
(Prenyl xanthones); (f) Raguenet, H.; Barron, D.; Mari-
8. Example of typical procedure for microwave-induced
rearrangement: Preparation of 7 (Table 1, entry 1).
Flavone 3 (0.2 g, 0.49 mmol) was dissolved in 4 ml of
freshly distilled N,N-diethylaniline. The solution was

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J.-B. Daskiewicz et al. / Tetrahedron Letters 42 (2001) 7241–7244
placed in a well-stoppered 10 ml teflon bottle and submit- calcd for C24H26O6: C, 70.23; H, 6.38. Found C, 69.93;
ted to successive 15 min microwave irradiations at 750 W
(with 10 min intervals between treatments) using a
domestic Bluewind 1797 oven. Evolution of the reaction
was monitored by the disappearance of the blue fluores-
cent starting compound 3. For selective preparation of 7,
two successive irradiations were necessary. After com-
plete cooling, the reaction medium was diluted with H2O,
acidified (1N HCl), extracted with EtOAc and the prod-
ucts of the reaction quantified by HPLC on diol-bonded
silica using 0.5% isopropanol in hexane as solvent.
H, 6.39.
10. Barron, D.; Mariotte, A. M. Nat. Prod. Lett. 1994, 4,
21–28.
11. Fukai, T.; Nomura, T. Heterocycles 1996, 42, 911–941.
1
12. 6-(1,1-Dimethylallyl-7-MEM chrysin 5. H NMR (CDCl3,
200 MHz): l 12.96 (s, 5-OH), 7.90 (m, H-2%/6%), 7.53 (m,
H-3%/4%/5%), 6.82 (s, H-8), 6.67 (s, H-3), 6.30 (dd, J=17.4
and 10.6 Hz, H-2%%), 5.31 (s, H-1%%%), 4.87 (dd, J=17.4 and
1.3 Hz, H-3%%a), 4.83 (dd, J=10.6 and 1.3 Hz, H-3%%b),
3.84 (m, H-2%%%), 3.60 (m, H-3%%%), 3.41 (s, H-4%%%), 1.62 (s,
H-4%%+H-5%%). 13C NMR (CDCl3, 50 MHz): l 183.03 (C-
4), 163.80 (C-2), 162.70 (C-7), 160.91 (C-5), 156.05 (C-9),
150.56 (C-2%%), 131.74 (C-4%), 131.24 (C-1%), 129.05 (C-3%/
5%), 126.27 (C-2%/6%), 118.80 (C-6), 106.91 (C-10+C-3%%),
105.82 (C-3), 93.36 (C-8), 93.26 (C-1%%%), 71.48 (C-3%%%),
68.28 (C-2%%%), 59.03 (C-4%%%), 41.50 (C-1%%), 29.05 (C-4%%+C-
5%%). MS (EI) m/z: 410 (M+), 335 (M+−MeOCH2CH2O),
322 (M+−MeOCH2CH2OCH2+H), 321 (M+−MeOCH2-
CH2OCH2). HRMS (EI): m/z calcd for C24H26O6,
410.1729, found 410.1731. Anal. calcd for C24H26O6+0.1
hexane: C, 70.50; H, 6.59. Found C, 70.63; H, 6.40.
13. Fukai, T.; Nomura, T. Heterocycles 1990, 31, 1861–1872.
14. Harwood, L. M.; Loftus, G. C.; Oxford, A.; Thomson,
C. Synth. Commun. 1990, 20, 649–657.
9. 7-MEM-8-Prenyl chrysin 7. 1H NMR (CDCl3, 200 MHz):
l 12.66 (s, 5-OH), 7.86 (m, H-2%/6%), 7.49 (m, H-3%/4%/5%),
6.62 (s, H-6), 6.61 (s, H-3), 5.33 (s, H-1%%%), 5.19 (brt,
J=6.8 Hz, H-2%%), 3.80 (m, H-2%%%), 3.53 (m, H-3%%%+H-1%%),
3.36 (s, H-4%%%), 1.79 (s, H-5%%), 1.66 (s, H-4%%).). 13C NMR
(CDCl3, 50 MHz): l 182.89 (C-4), 163.86 (C-2), 160.46
(C-7), 160.20 (C-5), 154.47 (C-9), 131.90 (C-3%%), 131.69
(C-1%+C-4%), 129.03 (C-3%/5%), 126.23 (C-2%/6%), 122.22 (C-
2%%), 108.72 (C-8), 105.91 (C-10), 105.44 (C-3), 97.97 (C-
6), 93.34 (C-1%%%), 71.46 (C-3%%%), 68.17 (C-2%%%), 59.01
(C-4%%%), 25.66 (C-4%%), 21.99 (C-1%%), 17.91 (C-5%%). MS (EI)
m/z: 410 (M+), 322 (M+−MeOCH2CH2OCH2+H),
321 (M+−MeOCH2CH2OCH2). HRMS (EI): m/z
calcd for C24H26O6, 410.1729, found 410.1735. Anal.