LETTER
Synthesis of -Substituted Chalcones
1677
(13b and 13c), which is consistent with the known prefer-
ence of pyrrole to undergo electrophilic substitution at the
2-position rather than the 3-position.14 It is noteworthy
that the present method affords good yields of trisubstitut-
ed olefins from phenones, which are typically difficult
substrates in the context of Wittig or aldol transforma-
tions.
References and Notes
(1) Smith, M. A.; Neumann, R. M.; Webb, R. A. J. Heterocycl.
Chem. 1968, 5, 425.
(2) Patil, C. B.; Mahajan, S. K.; Katti, S. A. J. Pharm. Sci. Res.
2009, 1, 11.
(3) Dhar, D. N. The Chemistry of Chalcones and Related
Compounds; Wiley: New York, 1981.
(4) (a) Claisen, L.; Claparede, A. Ber. Dtsch. Chem. Ges. 1881,
14, 2460. (b) Schmidt, J. G. Ber. Dtsch. Chem. Ges. 1881,
14, 1459. (c) Kumar, S. K.; Hager, E.; Pettit, C.;
Gurulingappa, H.; Davidson, N. E.; Khan, S. R. J. Med.
Chem. 2003, 46, 2813. (d) Sashidhara, K. V.; Rosaiah, J. N.;
Kumar, A. Synth. Commun. 2009, 39, 2288.
Table 3 Formation of β-Aryl-Substituted Chalcones from Propar-
gylic Alcohols 3b and 3c Using Ferric Chloride as Catalyst
O
OEt
H
OH
Ar
(5) Modern Carbonyl Olefination; Takeda, T., Ed.; Wiley-
VCH: Weinheim, 2004.
FeCl3
(0.05 equiv)
ArH
(6) (a) Wadsworth, W. S. Jr.; Emmons, W. D. J. Am. Chem. Soc.
1961, 83, 1733. (b) Wadsworth, W. S. Jr. In Organic
Reactions; Vol. 25; Dauben, W. G., Ed.; John Wiley & Sons:
New York, 1977, Chap. 2. (c) Boutagy, J.; Thomas, R.
Chem. Rev. 1974, 74, 87.
(7) (a) Kocienski, P. J.; Lythgoe, B.; Waterhouse, I. J. Chem.
Soc., Perkin Trans. 1 1980, 1045. (b) Kumar, A.; Sharma, S.;
Tripathi, S. D.; Srivastava, S. Tetrahedron 2010, 66, 9445.
(8) Meyer, K. H.; Schuster, K. Ber. Dtsch. Chem. Ges. 1922, 55,
819.
+
r.t.,
MeCN
R
R
R
R
3b, R = H
3c, R = OMe
10b,c–13b,c
Entry ArH
Substrate Time (h) Product Yield (%)
H
N
1
2
3b
3c
22
24
10b
10c
81
83
(9) Acid-catalyzed as well as transition-metal-catalyzed
substitution reactions have been recently reviewed; see, for
example: (a) Detz, R. J.; Hiemstra, H.; van Maarseveen, J.
H. Eur. J. Org. Chem. 2009, 6263. (b) Miyake, Y.; Uemura,
S.; Nishibayashi, Y. ChemCatChem 2009, 1, 342.
(10) (a) Tankard, M. H.; Whitehurst, J. S. J. Chem. Soc., Perkin
Trans. 1 1973, 615. (b) Engel, D. A.; Dudley, G. B. Org.
Lett. 2006, 8, 4027. (c) Crich, D.; Natarajan, S.; Crich, J. Z.
Tetrahedron 1997, 53, 7139.
H
Me
3
4
3b
3c
23
24
11b
11c
84
90
N
H
O
5
6
3b
3c
1
0.5
12b
12c
58
25
H
H
H
N
(11) Preparation of Propargylic Alcohols; Typical Procedure:
At –78 °C, n-BuLi (2.5 M in hexanes, 400 μL, 1.00 mmol)
was added dropwise to a solution of ethoxyacetylene (40%
in hexanes, 240 μL, 1.00 mmol) in anhydrous THF (3 mL).
The solution was stirred for 5 min, warmed slowly to 0 °C
over 1 h and stirred for 30 min. After cooling to –78 °C,
acetophenone (50 μL, 0.43 mmol) was added in one portion.
The solution was warmed to r.t. over 1 h and stirred for 1.5 h.
Saturated aqueous NH4Cl was added, the aqueous phase was
extracted with EtOAc, and the combined organic layers were
dried with MgSO4 and concentrated under reduced pressure.
The crude material was purified by flash chromatography on
silica gel (hexanes–EtOAc, 95:5→75:25) to afford the
desired compound 3a (65 mg, 80%) as a yellow oil.
(12) Preparation of β-Substituted Chalcones; Typical
Procedure: To a solution of propargylic alcohol (3a; 26.6
mg, 0.140 mmol) in anhydrous acetonitrile (0.7 mL), indole
(49 mg, 0.42 mmol) and FeCl3 (1 mg, 0.007 mmol) were
added. The solution was stirred for 24 h, then the solvent was
evaporated under vacuum. Analysis of the crude reaction
mixture by NMR indicated an E/Z ratio of 1.2:1. The crude
mixture was purified by flash chromatography on silica gel
(hexanes–EtOAc, 90:10→60:40) to afford the corre-
sponding β-substituted chalcones (E)-10a (14.3 mg, 39%)
and (Z)-10a (11.9 mg, 33%), respectively, as white and
yellowish solids.
7
8
3b
3c
23
20
13b
13c
85
87
In conclusion, a practical and new method for the synthe-
sis of β-substituted chalcones from propargylic alcohols
and electron-rich aromatic systems has been developed.
This transformation combines an electrophilic aromatic
substitution together with the activation of propargylic al-
cohols under acidic conditions. The transformation, in ad-
dition to affording a new route to flavonoids, thus
provides a new strategic opportunity that could be applied
to the synthesis of chalcones in general.
Acknowledgment
The authors wish to acknowledge Prof. S. Canesi, Dr. R. Rej, and
Dr E. Bourque for their assistance in the preparation of this manu-
script, as well as NSERC (Canada) and FQRNT (Quebec) for their
financial support.
Supporting Information for this article is available online at
m
iotSrat
ungIifoop
r
t
(13) Stereochemistry was established by NOE experiments.
(14) The regioisomers were separable by chromatography; see
the Supporting Information.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1675–1677