Domino 'Michael-retro-Michael-aldol' reactions of 1,3-bis-silyl enol ethers with 3-formylchromones

Article abstract of DOI:10.1016/j.tetlet.2003.09.008

Functionalized benzophenones were prepared by domino 'Michael-retro-Michael-aldol' reactions of 1,3-bis-silyl enol ethers with 3-formylchromones.

Full text of DOI:10.1016/j.tetlet.2003.09.008

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7921–7923
Domino ‘Michael-retro-Michael-aldol’ reactions of 1,3-bis-silyl
enol ethers with 3-formylchromones
Peter Langer* and Bettina Appel
Institut fu¨r Chemie und Biochemie der Ernst-Moritz-Arndt-Universita¨t Greifswald, Soldmannstr. 16, D-17487 Greifswald,
Germany
Received 2 July 2003; revised 16 August 2003; accepted 3 September 2003
Abstract—Functionalized benzophenones were prepared by domino ‘Michael-retro-Michael-aldol’ reactions of 1,3-bis-silyl enol
ethers with 3-formylchromones.
© 2003 Elsevier Ltd. All rights reserved.
Functionalized benzophenones are of considerable
interest as pharmacologically relevant natural products
and natural product analogues and represent versatile
synthetic building blocks.1,2 Classical syntheses of ben-
zophenone derivatives mainly rely on the Friedel–
Crafts acylation.3 However, unsatisfactory results are
frequently obtained when this method is applied to the
synthesis of functionalized or substituted derivatives.
Major drawbacks result from the drastic reaction con-
ditions and from the low chemo- and regioselectivity.
Therefore there is a need for the development of alter-
native methods which allow the convenient and selec-
tive synthesis of a wide range of functionalized
benzophenones under mild conditions.4,5 We have
recently reported the base-mediated synthesis of 4-(2%-
hydroxybenzoyl)salicylic esters from (2,4-dioxobutyli-
These reactions allow a convenient, regio- and
chemoselective synthesis of a great variety of function-
alized benzophenones from readily available starting
materials.
dene)triphenylphosphoranes.6
Unfortunately,
the
preparative scope of this method is severely limited by
the fact that substituted, functionalized and 1,3-dike-
tone derived phosphoranes are not readily available. In
addition, the reactivity of substituted phosphoranes is
very low and their application to the synthesis of
benzophenones was unsuccessful. Herein, we wish to
report a new and more general method for the synthesis
of functionalized benzophenones. This methodology
relies on what is, to the best of our knowledge, the first
domino ‘Michael-retro-Michael-aldol’ reactions7 of 1,3-
9
bis-silyl enol ethers8
with 3-formylchromones.10–12
Keywords: benzophenones; cyclizations; chromones; domino reac-
tions; silyl enol ethers.
* Corresponding author. Fax: (+49) 3834-864373; e-mail:
peter.langer@uni-greifswald.de
Scheme 1. Synthesis of functionalized benzophenone 3a.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.008

7922
P. Langer, B. Appel / Tetrahedron Letters 44 (2003) 7921–7923
Table 1. Products and yields
Our starting point was the development of a new
method for the synthesis of the interesting benzoyl
substituted benzophenone 3a. Complex mixtures were
obtained in the reaction of chromone 2a with the
dianion of benzoylacetone. The problem was solved by
employment of the 1,3-bis-silyl enol ether 1a which is
available from benzoylacetone in one or two steps.8b
The reaction of 1a with 2a in the presence of TMSOTf
afforded the desired benzophenone 3a.13 During the
optimization of the reaction, the use of TMSOTf (0.3
equiv.) proved to be an important parameter.10o The
use of stoichiometric amounts of the Lewis acid did not
result in an increase of the yield. The reaction was very
robust against minor changes of the conditions (reac-
tion time and temperature).
1
2
3
R1
R2
R3
R4
R5
3 (%)a
a
a
b
b
c
c
c
d
e
e
e
e
e
e
e
f
a
b
a
b
a
c
b
a
a
b
d
e
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
H
Cl
H
Cl
H
Cl
Cl
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
Cl
H
H
Cl
H
H
Cl
Me
H
H
H
H
H
H
H
H
Me
Et
Et
Et
Et
Et
Et
Et
Allyl
Allyl
Allyl
n-Butyl
n-Butyl
n-Octyl
n-Octyl
Bn
Ph
Ph
Me
Me
61
55
43
52
51
46
82
56
53
42
46
51
55
54
63
42
47
44
68
43
43
56
48
OEt
OEt
OEt
OMe
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
H
Cl
Me
Cl
Cl
Br
NO2
H
Me
Cl
H
c
f
H
Br
H
g
a
d
b
a
b
a
b
a
The formation of 3a can be explained by a domino
‘Michael-retro-Michael-aldol’ reaction (Scheme 1). The
reaction of 3-formylchromone with TMSOTf afforded
the benzopyrylium triflate A. The reaction of A with the
terminal carbon atom of 1a gave intermediate B which
underwent a retro-Michael reaction to give the polyke-
tide C. An intramolecular aldol reaction afforded inter-
mediate D which was transformed into the product 3a
by elimination of siloxane.
H
f
f
Me
Cl
H
Cl
H
g
g
h
h
i
s
t
u
v
w
Cl
H
Cl
H
Cl
H
a Yields of isolated products.
To study the preparative scope of our methodology the
substituents of the starting materials were systemati-
cally varied (Scheme 2, Table 1). The reaction of ben-
zoylacetone derived 1,3-bis-silyl enol ether 1a with
chloro-substituted 3-formylchromone 2b afforded the
functionalized benzophenone 3b with very good
chemoselectivity. The cyclization of 1,3-bis-silyl enol
ether 1b, prepared from acetylacetone, with 2a and 2b
afforded the acetyl-substituted benzophenones 3c and
3d, respectively. The ethoxycarbonyl substituted ben-
zophenones 3e–g were prepared from the ethyl acetoac-
etate-derived silyl enol ether 1c. The reaction of
3-formylchromone 2a with 1,3-bis-silyl enol ether 1d,
containing a methyl group at the terminal carbon atom,
afforded the methyl-substituted benzoylacetone 3h. The
cyclization of the ethyl-substituted silyl enol ether 1e,
prepared from ethyl 3-oxohexanoate, with 3-
formylchromones 2a–g afforded the respective substi-
tuted benzophenones 3i–o. The allyl-, n-butyl-, n-octyl-
and benzyl-substituted benzophenones 3p–w were pre-
pared by cyclization of the corresponding 1,3-bis-silyl
enol ethers 1f–i with the 3-formylchromones 2a,b,d. All
cyclization reactions proceeded with very good
chemoselectivity.
Acknowledgements
Financial support from the Deutsche Forschungsge-
meinschaft (Heisenberg-scholarship for P.L. and Nor-
malverfahren) is gratefully acknowledged.
References
1. For salicylic esters and salicylic glycosides (e.g. sal-
icortin), see for example: Ro¨mpp Lexikon Naturstoffe;
Steglich, W.; Fugmann, B.; Lang-Fugmann, S., Eds.:
Thieme, Stuttgart: 1997.
2. For anthracyclines, pyoluteorin, pyrrolomycines, anthra-
noids and their analogues, see: (a) Ezaki, N.; Shomura,
T.; Koyama, M.; Niwa, T.; Kojima, M.; Inouye, S.;
Niida, T. J. Antibiot. 1981, 34, 1363; (b) Kaneda, M.;
Nakamura, S.; Ezaki, N.; Iitaka, Y. J. Antibiot. 1981, 34,
1366; (c) Ezaki, N.; Koyama, M.; Shomura, T.; Tsu-
ruoka, T.; Inouye, S. J. Antibiot. 1983, 36, 1263; (d)
Carter, G. T.; Nietsche, J. A.; Goodman, J. J.; Torrey,
M. J.; Dunne, T. S.; Siegel, M. M.; Borders, D. B. J.
Chem. Soc., Chem. Commun. 1989, 1271; (e) Mu¨ller, K.;
Leukel, P.; Ziereis, K.; Gawlik, I. J. Med. Chem. 1994,
37, 1660; (f) Barton, D. H. R.; Challis, J. A.; Magnus, P.
D.; Marshall, J. P. J. Chem. Soc. (C) 1971, 2241.
3. Buchta, E.; Egger, H. Chem. Ber. 1957, 90, 2760.
4. For the SmI2 mediated reaction of benzaldehydes with
benzylhalides and subsequent oxidation, see: Shiue, J.-S.;
Lin, M.-H.; Fang, J.-M. J. Org. Chem. 1997, 62, 4643.
Scheme 2. Synthesis of the functionalized benzophenones 3a–
w.

P. Langer, B. Appel / Tetrahedron Letters 44 (2003) 7921–7923
7923
5. For the synthesis of salicylic esters from silyl enol ethers,
see: (a) Chan, T. H.; Brownbridge, P. J. Am. Chem. Soc.
1980, 102, 3534; from 1,3-dicarbonyl dianions: (b) Harris,
T. M.; Wittek, P. J. J. Am. Chem. Soc. 1975, 97, 3270;
from alkynals and alkynones, see: (c) Covarrubias-
Zu´niga, A.; R´ıos-Barrios, E. J. Org. Chem. 1997, 62, 5688
and references cited therein.
168; (b) synthesis of benzopyrano[2,3-b]pyridines:
Langer, P.; Appel, B. Tetrahedron Lett. 2003, 44, 5133.
12. The reaction of 3-formylchromone with 1,3-dicarbonyl
compounds has been reported to result in attack of the
central carbon atom of the nucleophile onto the aldehyde
(aldol condensation) and formation of open-chain prod-
ucts: (a) Ghosh, C. K.; Khan, S. Synthesis 1981, 903; (b)
Hass, G.; Stanton, J. L.; von Sprecher, A.; Wenk, P. J.
Heterocycl. Chem. 1981, 18, 607; (c) Prousek, J. Coll.
Czech. Chem. Commun. 1991, 1361; (d) Ghosh, C. K.;
Bandyopadhyay, C.; Biswas, S.; Chakravarty, A. K. Ind.
J. Chem. Sect. B 1990, 29, 814; a cyclization with ring
opening of the chromone system was observed only in
specific cases: (e) Bandyopadhyay, C.; Sur, K. R.; Patra,
R. J. Chem. Res. (S) 1998, 12, 802.
6. Langer, P.; Holtz, E. Synlett 2003, 402.
7. For reviews of domino reactions, see: (a) Tietze, L. F.;
Beifuss, U. Angew. Chem. 1993, 105, 137; Angew. Chem.,
Int. Ed. Engl. 1993, 32, 131; (b) Tietze, L. F. Chem. Rev.
1996, 96, 115.
8. These reagents can be regarded as masked 1,3-dicarbonyl
dianions: (a) Chan, T.-H.; Brownbridge, P. J. Chem.
Soc., Chem. Commun. 1979, 578; (b) Molander, G. A.;
Cameron, K. O. J. Am. Chem. Soc. 1993, 115, 830.
9. Review: Langer, P. Synthesis 2002, 441.
13. Synthesis of (2-hydroxyphenyl)-(3%-acetyl-4%-hydroxy-
phenyl)-methanone 3c: To a CH2Cl2 solution (10 ml) of
3-formylchromone 2a (200 mg, 1.15 mmol) was added
Me3SiOTf (0.06 ml, 0.35 mmol) at 0°C. After stirring for
1 h at 20°C, CH2Cl2 (10 ml) and 1b (365 mg, 1.50 mmol)
were added at 0°C. The mixture was stirred for 12 h at
20°C and subsequently poured into an aqueous solution
of hydrochloric acid (10%, 80 ml). The organic and the
aqueous layer were separated and the latter was extracted
with ether (3×80 ml). The combined organic layers were
washed with water, dried (Na2SO4), filtered and the
filtrate was concentrated in vacuo. The residue was
purified by column chromatography (silica gel, EtOAc/n-
hexane=1:15) to give 3c as a colourless solid (127 mg,
10. For reactions of 3-formylchromones, see: (a) Nohara, A.;
Umetani, T.; Sanno, Y. Tetrahedron 1974, 30, 3553; (b)
Jones, W. D.; Albrecht, W. L. J. Org. Chem. 1976, 41,
706; the cyclization of 3-formylchromones with amidines
afforded 5-(2-hydroxybenzoyl)-pyrimidines: (c) Lo¨we, W.
Synthesis 1976, 274, and (d) Petersen, U.; Heitzer, H.
Liebigs Ann. Chem. 1976, 1663; with enamines: (e) Heber,
D. Synthesis 1978, 691; with hydrazines: (f) Eiden, F.;
Haverland, H. Arch. Pharm. (Weinheim, Ger.) 1968, 301,
819, and (g) Ghosh, C. K.; Mukhopadhyay, K. K. J. Ind.
Chem. Soc. 1978, 55, 386; with H2NOHHCl: (h) Hsung,
R. P.; Zificsak, C. A.; Wei, L.-L.; Zehnder, L. R.; Park,
F.; Kim, M.; Tran, T.-T. T. J. Org. Chem. 1999, 64, 8736;
with o-phenylenediamine: (i) Ghosh, C. K.; Khan, S.
Synthesis 1980, 701; for conversions into pyrroles and
thiophenes: (j) Fitton, A. O.; Frost, J. R.; Suschitzky, H.;
Hougton, P. G. Synthesis 1977, 133; for a review, see: (k)
Ellis, G. P. Heterocyclic Compounds; Weisberger, A., Ed.,
1977, 35, 921; see also: (l) Ghosh, C. K.; Ghosh, C. Ind.
J. Chem. 1997, 36B, 968; for reactions with ketene
acetals: (m) Wallace, T. W.; Wardell, I.; Li, K.-D.; Leem-
ing, P.; Redhouse, A. D.; Challand, S. R. J. Chem. Soc.,
Perkin Trans. 1 1995, 2293; with dienes: (n) Sandulache,
A.; Silva, A. M. S.; Cavaleiro, J. A. S. Tetrahedron 2002,
58, 105; for the activation of chromones towards conju-
gate addition by the formation of silylated benzopyrylium
triflates, see: (o) Lee, Y.-G.; Ishimaru, K.; Iwasaki, H.;
Ohkata, K.; Akiba, K. J. Org. Chem. 1991, 56, 2058.
11. For other reactions of chromone derivatives from our
laboratory, see: (a) synthesis of biaryl lactones: Langer,
P.; Saleh, N. N. R.; Freifeld, I. Chem. Commun. 2002,
1
43%). H NMR (CDCl3, 300 MHz): l 2.69 (s, 3H, CH3),
6.92 (m, 1H, 5-H), 7.09 (d, 3J=8.7 Hz, 1H, 5%-H), 7.10
(dd, 3J=9.2 Hz, 4J=0.8 Hz, 1H, 3-H), 7.53 (m, 1H, 4-H),
7.58 (dd, 3J=9.6 Hz, 4J=1.6 Hz, 1H, 6-H), 7.86 (dd,
3J=8.7 Hz, 4J=2.1 Hz, 1H, 6%-H), 8.21 (d, 4J=2.1 Hz,
1H, 2%-H), 11.78 (s, 1H, OH), 12.68 (s, 1H, OH). 13C
NMR (75.5 MHz, CDCl3): l 26.76 (CH3), 118.50, 118.70,
118.80 (CH), 119.01, 119.27, 128.82 (C), 132.75, 133.21,
136.33, 137.40 (CH), 163.05, 165.52 (C-OH), 198.88,
204.47 (CꢀO). IR (KBr, cm−1): w˜ 3081 (m), 2973 (m), 2925
(m), 1644 (s), 1626 (s), 1588 (s), 1482 (m), 1440 (m), 1423
(m), 1363 (s), 1295 (s), 1241 (s), 1221 (s). umax (CH3CN,
nm, log m): 425 (3.16), 403 (3.17), 323 (3.93), 285 (4.02),
250 (4.30). m/z (EI, 70 eV): 256 (M+, 100), 241 (20), 213
(15), 163 (23), 145 (10), 121 (90). Calcd. for C15H12O4
(256.1): C 70.31, H 4.72; found C 70.04, H 4.89. All new
compounds gave satisfactory spectroscopic and analytical
and/or high resolution mass data.