Highly diastereoselective Michael reaction under solvent-free conditions using microwaves: Conjugate addition of flavanone to its chalcone precursor

Article abstract of DOI:10.1016/S0040-4039(00)02264-4

Microwave-assisted reaction of 2′-hydroxychalcones in the presence of DBU resulted in the formation of hitherto unknown dimers by conjugate addition of the intermediate cyclic ketone to the starting enone.

Full text of DOI:10.1016/S0040-4039(00)02264-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1403–1406
Highly diastereoselective Michael reaction under solvent-free
conditions using microwaves: conjugate addition of flavanone to
its chalcone precursor
Tama´s Patonay,a,* Rajender S. Varma,b Andra´s Vass,c Albert Le´vaia and Jo´zsef Duda´sc
aDepartment of Organic Chemistry, University of Debrecen, H-4010 Debrecen, Hungary
bNational Risk Management Research Laboratory, US Environmental Protection Agency, Cincinnati, OH 45268, USA
cResearch Institute of Chemical and Process Engineering, University of Kaposva´r, H-8201 Veszpre´m, Hungary
Received 31 October 2000; accepted 8 December 2000
Abstract—Microwave-assisted reaction of 2%-hydroxychalcones in the presence of DBU resulted in the formation of hitherto
unknown dimers by conjugate addition of the intermediate cyclic ketone to the starting enone. © 2001 Published by Elsevier
Science Ltd.
Microwave (MW)-accelerated solvent-free organic syn-
theses are of great interest and importance in view of
their simplicity, high and tunable selectivities, easy
work-up and time- and energy-saving protocols. Recy-
lability of the solid supports employed and the dimin-
ished amount of solvent usage also renders this
technique truly, an environmental friendly procedure.1
Numerous papers have been published on the MW-pro-
moted deprotection, condensation, oxidation, reduction
and rearrangements.1f–h With the exception of the
preparation of heteroaromatic systems much less has
been reported on the cyclizations, especially on the
effect of MW on the stereoselectivity. During our pro-
ject on the development of new MW-assisted, solvent-
free methods for the stereoselective synthesis of
heterocyclic compounds we decided to investigate the
cyclization of 2%-hydroxychalcones 1. Our earlier suc-
cess in MW-induced cyclization of 2%-aminochalcones
on montmorillonite K-10 clay leading to 2-aryl-1,2,3,4-
tetrahydro-4-quinolones2 prompted us to explore this
approach.
Systematic studies on the MW-induced solvent-free
cyclization of chalcones 1 on various supports (silica,
K-10 clay, non-MW-absorbing materials such as
Na2SO4 or CaCO3) revealed that the reaction results in
the formation of an equilibrium mixture of the corre-
sponding flavanone 2, and the starting material 1. No
significant difference was found between the equi-
librium ratio, 2:1, of MW-assisted or conventional ther-
mal cyclization,3 the only advantage of the former
procedure was the much shorter reaction period. The
Table 1. Products from MW-assisted and thermal reaction of chalcones 1 in the presence DBU/Na2SO4
Entry
Starting material
Mode
Tmax (°C)
Convn (%)
Isolated yields (%)
2
3
4
5
1
2
3
4
5
6
1a
1a
1b
1c
1d
1e
MW
Thermal
MW
MW
MW
110
110
100
100
105
95
100
100
93
100
94
0
3.0
22
5.4
27
4.8
56
28
25
17
18
28
17
13
5.9
7
11
11
0
11
Trace
28
0
MW
86
0
Keywords: addition reactions; chalcones; dimers; flavanones; microwave heating.
* Corresponding author. Tel.: +36 52 512 900; fax: +36 52 453 836; e-mail: tpatonay@tigris.klte.hu
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(00)02264-4

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T. Patonay et al. / Tetrahedron Letters 42 (2001) 1403–1406
use of acidic or basic additives such as tartaric acid,
N-benzyl-1-phenylethyl amine or DABCO did not
change the 2:1 ratio.
disubstituted flavanone structure of 5a could be
unequivocally excluded on the basis of the lack of any
flavanone CꢀO and the presence of six aliphatic methine
unit and one aliphatic quaternary carbon in the 13C and
1H NMR spectra. The formation of 5a could be ratio-
nalized in terms of a second conjugate addition of a
a-carbanion formed from dimer 3 or 4 and a subsequent
intramolecular addition in the intermediate B. (Scheme
2). An electron-withdrawing chloro substituent appar-
ently increases the trimerisation (Table 1, entry 4).
However, irradiation4 of chalcones 1a–e in the presence
of Na2SO4 as a support and the strong base 1,8-diazabi-
cyclo[5.4.0]undec-7-ene (DBU) as an additive resulted in
the formation of diastereomeric dimers 3a–e and 4a–e5
which obviously are originating via the conjugate addi-
tion of the carbanion A generated from primary product
flavanone 2 to the a,b-enone 1 (Table 1, Scheme 1). The
intermediacy of 2 was unequivocally proven by the
kinetic curves determined by densitometrical analysis of
TLC chromatograms of the reaction mixture. Electron-
donating substituents such as methoxy and methyl slow
down the cyclization and dimerization (Table 1, entries
3,5,6), this influence is more pronounced in the case of
substitution in ring A. Dimers 3 and 4 have not been
reported in the literature so far. In a previous paper6 the
formation of analogous but trimeric products, 3,3-dis-
ubstituted chromanones, from chromanone and a,b-
unsaturated ketones and acid derivatives under basic
conditions was published. In the light of the known7
difficulties in the preparing of 3-alkylated chromanones
and related derivatives from chromanone our MW-
induced monosubstitution in position 3 has remarkable
synthetic value.
The relative configuration of the major product 3a was
determined by X-ray analysis.8 The crystal structure of
3a, shown in Fig. 1, revealed an interesting and rare
2,3-trans diaxial arrangement of the substituents in the
chromanone skeleton. {1H}–[1H] NOE measurements
provided that the same conformation exists in solution.
Irradiation of H-2 resulted in 0.9 and 0.7% difference,
respectively, on signals of H-3 and Hb but irradiation of
H-3 resulted in 0.9% difference on signal H-2 only and
1
no NOE was found with Hb. According to their H
NMR spectra the minor dimers 4 also should have
2,3-trans relative configuration but with two equatorial
substituents (J2,3=9.6–11.2 Hz). Thus, dimers 3 and 4
should differ in the stereochemistry of the b carbon of
the dihydrochalcone unit. The dimerization occurred
with remarkable diastereoselectivity; only two isomers
of the possible four diastereomers formed with
diastereomeric ratio between 62:38 and 81:19. The
observed selectivity can be explained by the attack of
carbanion A to the chalcone 1 from the less hindered
side opposite to 2-phenyl group and the face selectivity
of a,b-enone.
The comparison of the MW-induced and conventional
thermal heating (Table 1, entries 1 and 2) clearly show
the advantageous effect of MW since in the latter case
dimers 3a and 4a were obtained in lower yields beside
considerable amount of trimer 5a.5 An alternative 3,3-
Scheme 1. Formation of dimers 3 and 4 from 2%-hydroxychalcones 1.

T. Patonay et al. / Tetrahedron Letters 42 (2001) 1403–1406
1405
Scheme 2. Formation of trimer 5.
Figure 1. X-ray crystal structure of dimer 3a.
Experiments to extend this MW-assisted protocol to the
synthesis of various a-substituted benzo(hetera)-
cyclanones are in progress.
J. Chem. 1995, 48, 1665–1692; (c) Galema, S. A. Chem.
Soc. Rev. 1997, 26, 233–238; (d) Langa, F.; de la Cruz, P.;
de la Hoz, A.; D´ıaz-Ortiz, A.; D´ıez-Barra, E. Contemp.
Org. Chem. 1997, 4, 373–386; (e) Loupy, A.; Petit, A.;
Hamelin, J.; Texier-Boullet, F.; Jacqualt, P.; Mathe, D.
Synthesis 1998, 1213–1234; (f) Varma, R. S. Green Chem-
istry 1999, 43–55; (g) Varma, R. S. Clean Products Pro-
cesses 1999, 1, 132–147; (h) Varma, R. S. In Green Chem.:
Challenging Perspectives; Tundo, P.; Anastas, P.; Eds.
Environmentally benign organic transformations using
microwave irradiation under solvent-free conditions.
Oxford University Press: Oxford, 2000; pp. 221–244.
2. Varma, R. S.; Saini, R. K. Synlett 1997, 857–858.
3. Sangwan, N. K.; Varma, B. S.; Dhindsa, K. S. Chem. Ind.
(London) 1984, 271–272.
Acknowledgements
This work was financially supported by NATO
(HTECH.LG 97.4558) and Hungarian Scientific
Research Found (OTKA T22290). Special thanks are
due to Dr. A. Be´nyei for the X-ray analysis, to
´
K. Fehe´r for NOE measurements and to E. Rima´n for
her technical help.
4. Typical procedure: A mixture of substituted 2%-hydroxy-
chalcone (1 mmol), the corresponding support (5 g) and
the additive (5 mg) in a pyrex tube was subjected to
irradiation at 45 W for 20 min in a Maxidigest 350
Prolabo monomode, focused MW (2.45 GHz) reactor with
References
1. For recent reviews, see: (a) Caddick, S. Tetrahedron 1995,
51, 10403–10432; (b) Strauss, C. R.; Trainor, R. W. Aust.

1406
T. Patonay et al. / Tetrahedron Letters 42 (2001) 1403–1406
312 (8), 223 (83), 147 (28), 121 (100), 120 (30), 104 (18), 92
(25), 77 (26).
continuous rotation. The cooled mixture was washed with
methylene chloride (2×10 mL) and concentrated in vacuo.
5a: white crystals; mp 253–255°C (hexane–EtOAc). 1H
NMR (CDCl3, 200 MHz): 3.34 (dd, J=12.1, 11.6 Hz, 1H,
5-H), 3.41 (dd, J=11.8, 4.0 Hz, 1H, 3-H), 3.98 dd, J=
12.1, 1.8 Hz, 1H, 6-H), 4.98 (d, J=4.0 Hz, 1H, 2-H), 5.28
(br s, 1H, 7-H), 5.45 (dd, J=11.8, 11.6 Hz, 1H, 4-H),
6.55–7.53 (m, 25H, Ar-H), 7.78 (dd, J=7.7, 1.5 Hz, 1H,
6%-H), 8.18 (br d, Jꢀ6 Hz, 1H, 6%%-H), 12.00, 12.54 (2×s,
2×1H, 2%-OH+2%%-OH). 13C NMR (CDCl3, 50 MHz): 46.1,
46.7, 46.9, 49.2, 52.8 (C-3, C-4, C-5, C-6, C-7), 71.4 (C-8),
74.2 (C-2), 117.7, 118.4, 118.9, 120.6, 122.3, 123.1, 124.3,
125.0, 125.7, 127.3, 127.5, 127.6, 128.6, 129.2, 130.4, 130.7,
131.3, 136.1, 136.3, 138.8, 140.4, 141.1, 153.4 (C-12a),
162.2, 162.3 (C-2%, C-2%%), 209.6, 209.7 (2×CꢀO).
6. Padfield, E. M.; Tomlinson, M. L. J. Chem. Soc. 1950,
2272–2277.
The residue was purified by two subsequent column chro-
matography (silica gel) by using hexane–acetone (4:1, v/v)
and toluene or toluene–ethyl methyl ketone (30:1, v/v) as
eluent.
1
5. All isolated compounds were characterized by H and 13C
NMR, MS and elemental analysis. Representative data are
given as follows. 3a: white crystals; mp 142–144°C (hex-
ane–EtOAc). 1H NMR (CDCl3, 200 MHz): 3.31 (dd,
J=10.5, 2.6 Hz, 1H, 3-H), 3.46 (dd, J=16.9, 5.0 Hz, 1H,
a-H), 3.59 (dd, J=16.9, 8.9 Hz, 1H, a-H%), 3.97 (m, 1H,
b-H), 5.29 (d, J=2.6 Hz, 1H, 2-H), 6.79–7.79 (m, 18H,
Ar-H), 11.92 (s, 1H, 2%%-OH). 13C NMR (CDCl3, 50 MHz):
39.5 (Ca), 41.8 (Cb), 79.0 (C-2), 118.2, 118.5, 118.9, 119.4,
120.8, 126.4, 127.2, 127.6, 128.1, 128.3, 128.7, 129.2, 129.8,
136.4, 136.9 (C-7, C-4%%), 137.9, 141.4 (C-1%, C-1%%), 159.6,
7. Lockhart, I. M. In Chromenes, Chromanones and
Chromones; Ellis, G. P., Ed. 4-Chromanones. Wiley: New
York, 1977; pp. 207–428.
162.5 (C-8a, C-2%%), 193.8 (C-4), 203.8 (CꢀO); MS (EI, 70
+
’
eV): 448 (M , 4), 431 (M-OH, 9), 357 (M-Bn, 14), 312
(24), 224 (retro-Michael fragment, 71), 191 (19), 147 (57),
121 (100), 120 (78), 105 (42), 92 (48).
8. Colourless block crystals (0.9×0.72×0.55 mm) of
,
C30H23O4, M=447.48, monoclinic, a=11.0472(10) A, b=
4a: white crystals; mp 155–156°C (hexane–EtOAc). 1H
NMR (CDCl3, 200 MHz): 3.54–3.66 (overlapping m’s, 2H,
a-H, b-H), 3.79 (dd, J=10.2, 4.2 Hz, 1H, 3-H), 4.39 (dd,
J=18.6, 9.6 Hz, 1H, a-H%), 5.26 (d, J=10.2 Hz, 1H, 2-H),
6.83–7.17, 7.43, 7.85 (m’s, 18H, Ar-H), 12.16 (s, 1H,
2%%-OH). 13C NMR (CDCl3, 50 MHz): 40.1 (Cb), 42.7 (Ca),
52.9 (C-3), 82.8 (C-2), 117.8, 118.4, 118.9, 119.5, 121.5,
121.9, 127.0, 127.1, 128.2, 128.3, 128.9, 129.2, 130.3, 136.1,
136.3 (C-7, C-4%%), 137.0, 140.2 (C-1%, C-1%%), 160.5, 162.4
(C-8a, C-2%%), 194.4 (C-4), 204.9 (CꢀO); MS (EI, 70 eV):
,
,
15.6808(10) A, c=13.0609(10) A, i=93.73(1)°, V=
3
,
2257.7(3) A , Z=4, space group: P21/n, zcalc=1.316 g
cm−3. Data were collected at 293(1) K, Enraf Nonius
,
MACH3 diffractometer, Mo Ka radiation u=0.71073 A,
v–2q motion, qmax=25.5°, 3535 reflections were measured
of which 2761 reflections were unique with I>2|(I), decay:
1%. The structure was solved using the SIR-92 software
and refined on F2 using the SHELXL-97 program, R(F)=
0.051 and wR(F2)=0.141 for 3535 reflections, 307 parame-
−3
,
ters. Residual electron density: 0.403/−0.248 e A
.
.