Convenient Synthesis of β-Alkyl-Substituted Dihydrochalcones

Full text of DOI:10.1021/jo980769i

5730
J . Org. Chem. 1998, 63, 5730-5731
in THF the (E)-1,3-diphenyl-2-propen-1-ol, 2, is the main
product, (yields >95%), and (E)-chalcone, 3, and (E)-1,3-
diphenyl-1-propanone, 4, were found as traces. Neverthe-
less, by a careful choice of reaction conditions, the product
distribution in the reaction mixture can be changed to give
a high yield of 4, the optimum conditions being [PhLi]:[1] )
2:1 and 7 h reaction time. Under these conditions, a brillant
deep violet solution is formed and 4 is obtained in 97% yield
(eq 1). The precursor of 4 is shown to be a â-lithiated
Con ven ien t Syn th esis of â-Alk yl-Su bstitu ted
Dih yd r och a lcon es
Norma Sbarbati Nudelman,* Graciela V. Garc´ıa, and
Hernan G. Schulz
Depto. de Quı´mica Orga´nica, Fac. de Ciencias Exactas y
Naturales, Universidad de Buenos Aires, Ciudad Universitaria,
1428, Buenos Aires, Argentina
Received April 28, 1998
The chalcone system is the subject of renewed interest
because it has been found to be a useful intermediate for
the synthesis of compounds containing the benzopyran ring
system and for other related substances.1a Several substi-
tuted chalcones have been found to exhibit pharmacological
properties, and they seem to be involved in the biosynthesis
of flavonoids.1b There is an ever-increasing concern about
how the specific structure of organolithiums in solution,2 and
especially their degree of association,3,4 affects the reactiv-
ity2,5,6 and in many cases also the regio-7,8 and stereochem-
istry9 of their reactions. It was usually assumed by synthetic
chemists that the “naked” carbanion (the monomer) was
more reactive than higher oligomeric states;10 nevertheless,
different complexation effects could lead to a decrease in the
reactivity of lower aggregates.11
We have recently shown how the special aggregation
features of lithium amides can be constructively used to lead
their reactions toward the desired synthetic goal, in cases
where different products can be obtained.7 On other cases,
the complex-induced proximity effects (CIPE) observed in
some conveniently substituted substrates have been suc-
cessfully used to promote remote directed lithiation, thus
providing an expanded synthetic methology for â-substitu-
tion.9,12 In this paper, the aggregation features of the
organolithium reagent are conveniently used to promote
addition of phenyllithium to (E)-cinnamyl aldehyde, 1,
â-lithiation, and subsequent electrophilic substitution, thus
providing a convenient one-pot one-step methodology for the
synthesis of a wide variety of â-alkyl-substituted dihydro-
chalcones.
(1)
intermediate, since treatment of the reaction mixture with
D2O gives 4 in 95% yield and 99% d1. (When the isolated
alcohol 2 was treated with PhLi, 79% of 4 and 21% of 3 were
obtained.)
Addition of an electrophile to the reaction mixture and
allowing the reaction to stand at 20 °C until decoloration of
the solution is observed (2-8 h depending on RX) give the
â-substituted dihydrochalcone (eq 2). A wide range of
(2)
electrophiles have been assayed, and formation of the
products is summarized in Table 1. Most of these electro-
philic substitutions proceed in good yield, giving only one
product, the corresponding dihydrochalcone (products 5-11),
in 77-100% yields. Table 1 shows that alkylation can be
afforded with alkyl chlorides as well as with bromides; allyl
bromide gave a very good yield of 11 (95%). Benzyl and
hindered alkyl bromides, such as isopropyl and cyclohexyl,
also gave good yields of the â-substituted dihydrochalcone.14
No detectable addition to the R-carbon was observed.
Addition of alkyllithiums on the R-carbon of cinnamyl alcohol
has received a great deal of interest in recent years,15,16 and
the reaction has been recently applied to the synthesis of
asymmetric cinnamyl derivatives17a and chiral disubstituted
cyclopropanes17b by running the reaction in the presence of
A mechanistic study of the addition of phenyllithium to 1
has been recently reported.13 This work showed that the
reaction is highly sensitive to the reaction conditions; thus,
* To whom correspondence should be addressed. Fax: +541 7820529.
E-mail: nudelman@qo.fcen.uba.ar.
(1) (a) Hepworth, J . D.; Gabbutt, C. D.; Heron, M. Pyrans and their Benzo
Derivatives: Synthesis. In Comprehensive Heterocyclic Chemistry II; Katritz-
ky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996;
Vol. 5, Chapter 5. (b) Harborne, H. B., Ed. The Flavonoids: Advances in
Research since 1986; Chapman and Hall: London, 1994.
(2) For pertinent reviews see: (a) Lambert, C.; Schleyer, P. v. R. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1129-1140. (b) Nudelman, N. S. Carbo-
nylation of Main-Group Organometal Compounds. In The Chemistry of
Double Bonded Functional Groups; Patai, S., Rappoport, Z., Eds.; Wiley:
Chichester, 1989; Chapter 13 and references therein.
(3) Remenar, J . F.; Collum, D. B. J . Am. Chem. Soc. 1997, 119, 5573.
(4) J edlicka, B.; Crabtree, R. H.; Siegbahn, P. E. M. Organometallics
1997, 16, 6021-6023.
(5) Kingsbury, C. L.; Smith, R. A. J . J . Org. Chem. 1997, 62, 4629-4634.
(6) Stanetty, P.; Mihovilovic, M. D. J . Org. Chem. 1997, 62, 1514-1515.
(7) Nudelman, N. S.; Schulz, H. G.; Garc´ıa Lin˜ares, G. E.; Bonatti, A.
E.; Boche, G. Organometallics 1998, 17, 146.
(8) Nudelman, N. S.; Lewkowicz, E.; Furlong, J . J . P. J . Org. Chem. 1993,
58, 1847.
(9) Pippel, D. J .; Curtis, M. D.; Du, H.; Beak, P. J . Org. Chem. 1998, 63,
2-3.
(10) Williard, P. G. In Comprehensive Organic Synthesis; Trost, B.,
Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 1 and references
therein.
(11) Collum, D. B. Acc. Chem. Res. 1992, 25, 448-454.
(12) Gallagher, D. J .; Du, H.; Long, S. A.; Beak, P. J . Am. Chem. Soc.
1996, 118, 11391-11398.
(13) Nudelman, N. S.; Schulz, H. G.; Garc´ıa, G. V. J . Phys. Org. Chem.
1998, in press.
(14) In a typical procedure, 3 mL of 1 M PhLi in anhyd THF was placed
in a septum-capped round-bottomed reaction flask at 20 °C under a nitrogen
atmosphere. Then 12 mL of THF and 132 mg (1 mmol) of (E)-cinnamalde-
hyde (freshly distilled) were added at once to the stirred solution. After 7
h, 1 mmol of the electrophile was added; the solution was allowed to stir
until decoloration occurred and treated with 0.2 mL of methanol. The
resulting dihydrochalcone was crystallized from methanol-water. The
compounds were fully characterized by melting point, 1H and 13C NMR
spectroscopy, and HRMS.
(15) Marumoto, S.; Kuwajima, I. J . Am. Chem. Soc. 1993, 115, 9021-
9024 and references therein.
(16) Cohen, T.; Bhupathy, M. Acc. Chem. Res. 1989, 22, 152-161.
(17) (a) Klein, S.; Marek, I.; Poisson, J . F.; Normant, J . F. J . Am. Chem.
Soc. 1995, 117, 8853-8854. (b) Norsikian, S.; Marek, I.; Poisson, J . F.;
Normant, J . F. J . Org. Chem. 1997, 62, 4898-4899.
S0022-3263(98)00769-5 CCC: $15.00 © 1998 American Chemical Society
Published on Web 08/06/1998

Communications
J . Org. Chem., Vol. 63, No. 17, 1998 5731
°C,18 and this finding was corroborated by 13C NMR (35:
65).19 Recent studies on the reactions of lithiated pheny-
lacetonitrile with R,â-unsaturated carbonyl compounds show
that aggregation effects strongly influences the 1,2- vs 1,4-
regioselectivity in THF and in THF-binary solvent mix-
tures.20
Ta ble 1. Ad d ition of P h Li to (E)-Cin n a m a ld eh yd e, 1, in
THF a t 20 °C. Rea ction w ith Electr op h iles, RXa
In the present case, the reaction works well even with a
ratio of [PhLi]:[1] ) 2:1 with RX ) PhCH2Br, but in the other
cases the best results and higher yields of â-alkyl-substituted
dihydrocalcones were obtained with a ratio of [PhLi]:[1] )
3:1. Although additional experimental evidence is needed,
theoretical calculations on the likely intermediates using
dimeric PhLi gives a real transition state for the formation
of the precursor of 4.21
Ack n ow led gm en t. H.S. and G.G. are grateful recipi-
ents of fellowships from the Universidad de Buenos Aires
(UBA) and from the National Research Council (CONICET)
from Argentina, respectively. Financial support from the
UBA, the CONICET, and the European Community is
gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: Experimental details for
the preparation and reactions of 1-11, characterization data for
all new compounds 5-11, and copies of their NMR spectra (11
pages).
J O980769I
a
b
[PhLi]0 ) 0.21 M and [1]0 ) 0.07 M. Determined by quan-
titative GC using Decalin as internal standard.
(18) Bauer, W.; Seebach, D. Helv. Chim. Acta 1984, 67, 1972.
(19) Bauer, W.; Winchester, W. R.; Schleyer, P. v. R. Organometallics
1987, 6, 2371-2379.
(-)-sparteine. In light of the different products obtained and
the sensitivity to the reaction conditions, a different mech-
anism in which the dimer of the reagent is involved is
suspected in the present case. In relatively dilute THF
solution (260 mM), phenyllithium was established to be in
a monomer-dimer equilibrium (39:61) by cryoscopy at -103
(20) Strzalko, T.; Seyden-Penne, J .; Wartski, L. J . Org. Chem. 1998, 63,
3295-3301.
(21) The transition state was searched and its geometry optimized by
MNDO and PM3 methods. Calculations show that it is a real transition
state, having only one negative vibrational frecuency corresponding to the
reaction coordinate. Nudelman, N. S.; Schulz, H. G.; Garc´ıa, G. V. Submitted
to J . Chem. Soc., Perkin Trans. 2, 1998.