A new, fast and efficient synthesis of 3-aryl indenones: Intramolecular cyclization of 1,3-diarylpropynones in superacids

Article abstract of DOI:10.1016/j.tetlet.2004.03.026

1,3-Diarylpropynones were cleanly converted to the corresponding 3-arylindenones in various superacidic media. This new, simple, one-pot reaction proved to be efficient (yields up to 95%) and very fast (reaction time less than 30min).

Full text of DOI:10.1016/j.tetlet.2004.03.026

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3379–3381
A new, fast and efficient synthesis of 3-aryl indenones:
intramolecular cyclization of 1,3-diarylpropynones in superacids
a,
a
b,
a,
*
*
Aleksander V. Vasilyev, St ꢀe phane Walspurger, Patrick Pale and Jean Sommer
a
Laboratoire de physico-chimie des hydrocarbures, associ ꢀe au CNRS, Institut Le Bel, Universit ꢀe L. Pasteur, 67000 Strasbourg, France
Laboratoire de synth ꢁe se et r ꢀe activit ꢀe organique, associ ꢀe au CNRS, Institut Le Bel, Universit ꢀe L. Pasteur, 67000 Strasbourg, France
b
Received 9 February 2004; accepted 5 March 2004
Abstract—1,3-Diarylpropynones were cleanly converted to the corresponding 3-arylindenones in various superacidic media. This
new, simple, one-pot reaction proved to be efficient (yields up to 95%) and very fast (reaction time less than 30 min).
Ó 2004 Elsevier Ltd. All rights reserved.
The indenone motif can be found in some natural
indenones A (Scheme 2). Indeed, protonation in strong
1;2
3–6
15
16
products and in man made compounds. Indenones
have also been used as starting materials either towards
biologically active molecules such as C-nor-D-homo-
acids would in situ generate a vinyl cation (B in
Scheme 2), which should be trapped by the adjacent aryl
group leading to indenone.
7
8
9
steroids, estrogen-binding receptors, gibberellins or
3
4
towards indanones, indenes, photochromic indenone
5
In this communication, we described our preliminary
results based on such process and showed that aryl
propynones are indeed converted to indenones in strong
acid media.
6
oxides, 2,4- and 3,4-disubstituted 1-naphthols (Scheme
).
1
Due to their importance, various syntheses of indenones
have been reported. Classical Friedel–Crafts and
10
14
To investigate this cyclization process, we prepared
11
Grignard reactions have mostly been used but more
recently, cross-coupling methods have been applied to
various 1,3-diarylpropynones carrying or not various
substituents on one or both aromatic rings. Dissolved in
triflic acid at ꢀ30 °C or room temperature, these com-
pounds exhibited interesting reactivities and could be
distinguished into two categories (Table 1).
12
indenones synthesis. Organometallics and/or metal
activators have therefore always been required.
13
14
Based on our work on propynones, we reasoned that
arylpropynones C could be precursors of choice towards
The 1,3-diphenyl propynone 1a and its substituted
3 3
analogues 1b–c do not react in neat CF SO H even at
room temperature and after prolonged time (Table 1,
entries 1, 3 and 5) while the methoxy substituted deriv-
atives 1d–f were cleanly converted to the corresponding
3-arylindenones 2d–f (Table 1, entries 8–10). For the
latter, quantitative transformation occurred as judged
from NMR when the reaction was performed and
OH
O
2
R
4
R
O
1
3
O
R
R
OH
O
Euplectin Me
C-Nor-D-homo Steroid System
Scheme 1.
O
OH
R
H
O
R
R
*
Corresponding authors. Tel./fax: +33-03-90-24-15-17 (P.P.), tel.:
33-03-90-24-14-86; fax: +33-03-90-24-14-87 (J.S.); e-mail addresses:
+
X
X
ppale@chimie.u-strasbg.fr; sommer@chimie.u-strasbg.fr
On leave from: Saint-Petersburg State Forest Technical Academy,
Department of Organic Chemistry, Institutsky per. 5, Saint-Peters-
burg, 194021 Russia.
A
B
X
C
Scheme 2. Mechanistic hypothesis for the cyclization of propynones to
indanones.
0
040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.026

3380
A. V. Vasilyev et al. / Tetrahedron Letters 45 (2004) 3379–3381
Table 1. Synthesis of the 3-arylindenones 2a–f from the 1,3-diarylpropynones 1a–g
O1
O
7
4
8
9
6
R2
R1
2
2
3
5
R
1
a-g
2
a-f
R1
Reaction conditions
Entry
1,3-Diarylpropynones
3-Arylindenones
1
2
1
2
a
Compound
no.
R
R
Acidic medium
Time (min) Temperature Compound
(°C)
R
R
Yields
no.
b
1
1a
1a
H
H
H
H
CF
CF
3
SO
SO
3
3
H
H/SbF
30
30
25
25
–––
2a
––
H
––
H
––
43
2
3
5
5
5
(
17 mol %)
b
3
1b
1b
H
H
3-MeO
3-MeO
CF
CF
3
SO
SO
3
3
H
30
30
25
25
––
2b
––
H
––
6-MeO
––
61
4
3
H/SbF
(
17 mol %)
b
5
1c
1c
4-Me
4-Me
H
H
CF
CF
3
SO
SO
3
3
H
30
30
25
25
––
2c
––
4-Me
––
H
––
75
6
3
H/SbF
(
HF/SbF
17 mol %)
7
1c
4-Me
H
5
30
0
2c
4-Me
H
H
60
(
2 mol %)
8
9
1d
1e
1f
4-MeO
4-MeO
4-MeO
4-MeO
H
CF
CF
CF
CF
3
3
3
3
SO
SO
SO
SO
3
3
3
3
H
H
H
H
15
15
15
30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
2d
2e
2f
4-MeO
54
95
95
––
3-MeO
3,4-Me
4-MeO
4-MeO 6-MeO
4-MeO 5,6-Me
2
1
0
1
2
c
1
1g
––
––
––
a
b
c
Yields after preparative isolation of reaction products.
No transformation, the unchanged starting compound was quantitatively isolated after reaction.
No 3-arylindenone formation, the 1,3-diarylpropynone was completely transformed into mixture of oligomeric material.
followed in NMR tubes. The products were isolated
with yields up to 95% after reaction time of only 15 min,
even at low temperature (ꢀ30 °C).
positions of both aromatic substituents and submitted it
to triflic acid. In a few minutes at ꢀ30 °C, 1g was
completely consumed but a mixture of oligomeric
materials was produced from which it was impossible to
detect the expected indenone. It seems that such meth-
oxy substitution renders the propynone system too
reactive.
This discrepancy can be correlated with the electron
density of the propynone system. When located on the
aromatic group adjacent to the acetylenic group like in
1
d–f, the strong electron-donating property of the
methoxy group induces an increase of the propynone
electron density. This effect would thus favor the O,C-
It is worth noting that a single regioisomer is always
formed when the aromatic ring is not symmetrically
substituted. The diarylpropynones 1b,e,f only gave the
indenones 2b,e,f, although two compounds could have
been produced (Scheme 3).
17
diprotonation of the propynone system (proposed
intermediate B in Scheme 2) and facilitate the sub-
sequent cyclization to indenones 2d–f. On the other
hand, the unsubstituted 1a or derivatives substituted by
a less donating group (1b–c) may lack electron density
and are thus not basic enough to be additionally C-
protonated at the acetylene group by triflic acid.
In conclusion, we have developed a new, simple and
efficient method for the synthesis of 3-arylindenones by
intramolecular cyclization of 1,3-diarylpropynones in
superacidic media. Moreover, this one-pot reaction does
not require metal catalysts or reagents and is very fast,
If this is true, acids stronger than triflic acid would
nevertheless O,C-diprotonate the propynone fragment
and induce the expected ring closure. Increasing the
5
acidity of the reaction medium from H
neat CF SO H up to H ¼ ꢀ19 or ꢀ20 for mixtures of
0
¼ ꢀ14.1 for
R2
15
3
3
0
O
O
CF
(
3
SO
2 mol %), respectively, indeed allows the reaction to
3
H and SbF
5
(17 mol %) or of HFand SbF
5
R1
R2
O
R2
R1
proceed. The indenones 2a–c were thus obtained but the
yield was slightly lower than for the formation of 2e–f
Ar
R1
Ar
1
b,e,f
2b,e,f
Ar
(
Table 1, entries 2, 4, 6 and 7 vs 9 and 10). We found
1
2
that such compounds are surprisingly sensitive, espe-
cially to nucleophiles, heat and light.
1b Ar = Ph;R = OMe, R = H
1
2
1e Ar = 4-MeOC H ; R = OMe, R = H
6
4
1
2
1
f Ar = 4-MeOC H ; R = R = Me
6 4
To further check the effect of methoxy substituent, we
prepared 1g bearing a methoxy group at both para-
Scheme 3.

A. V. Vasilyev et al. / Tetrahedron Letters 45 (2004) 3379–3381
3381
with reaction times lower than 30 min (usually 15 min).
Mechanistic studies are now underway in order to detect
the in situ formation of vinyl cation.
4. Alesso, E. N.; Tombardi, D. G.; Ibanez, A. F.; Moltrasio
Iglesias, G. Y.; Aguirre, J. M. Can. J. Chem. 1991, 69,
1
166.
. Ulman, E. F.; Henderson, W. A. J. J. Am. Chem. Soc.
966, 88, 4942.
. Buggle, K.; Ghogain, U. N.; O’Sullivan, D. J. Chem. Soc.,
Perkin Trans. 1 1983, 2075.
. (a) Chatterjee, A.; Banerjee, S. Tetrahedron 1970, 26, 2599;
(b) Ceustermans, R. A. E.; Martens, H. J.; Hoornaert, G. J.
J. Org. Chem. 1979, 44, 1388; (c) Jammaer, G.; Martens, H.
J.; Hoornaert, G. J. J. Org. Chem. 1974, 39, 1325.
. (a) Anstead, G. M.; Altenbach, R. J.; Scott, R. W.;
Katzenellenbogen, J. A. J. Med. Chem. 1988, 31, 1316; (b)
Anstead, G. M.; Wilson, S. R.; Katzenellenbogen, J. A.
J. Med. Chem. 1989, 32, 2163.
5
6
7
1
Typical procedure
Propynone 1a–f (0.5 mmol) was added to a mixture of
triflic acid CF SO H (2 mL, 3.4 g, 22.5 mmol) and SbF
3
3
5
(
SbF ) or to triflic acid CF SO H (2 mL, 3.4 g,
980 mg, 4.5 mmol, 17 mol % in the mixture CF
3
SO
3
H–
8
9
5
3
3
2
1
2.5 mmol) at ꢀ30 °C or at room temperature (see Table
) with vigorous magnetic stirring. Color of solutions
became intensively red or violet. After stirring during
5–30 min (see Table 1), the reaction mixture was slowly
added dropwise to a vigorously stirred ice–water mix-
. House, H. O.; Larson, J. K. J. Org. Chem. 1968, 33, 448.
1
1
0. (a) Frank, R. L.; Eklund, H.; Richter, J. W.; Vanneman,
C. R.; Wennerberg, A. N. J. Am. Chem. Soc. 1944, 66, 1;
(b) Feeman, J. F.; Amstutz, E. D. J. Am. Chem. Soc. 1950,
72, 1522; (c) Floyd, M. B.; Allen, G. R. J. J. Org. Chem.
ture (ꢁ30 mL). The product 2a–f was then isolated
2 2
either after extraction with CH Cl and flash-chroma-
1
970, 35, 2647; (d) Martens, H. J.; Jammaer, G.; Hoor-
tography on silica gel or after filtration when a solid
formed after water quenching. This solid was then
naert, G. J. Tetrahedron 1975, 31, 2293; (e) Martens, H. J.;
Hoornaert, G. J. Tetrahedron Lett. 1970, 21, 1821; (f)
Martens, H. J.; Hoornaert, G. J. Synth. Commun. 1972, 2,
recrystallized from MeOH/CH
2
Cl
2
.
1
47.
6
-Methoxy-3-(4-methoxyphenyl)indenone 2e: Yield 95%.
H
1
1. (a) Manning, C.; McClory, M. R.; McCullough, J. J.
J. Org. Chem. 1981, 46, 919; (b) Anstead, G. M.; Ensign, J.
L.; Peterson, C. S.; Katzenellenbogen, J. A. J. Org. Chem.
1989, 54, 1485.
12. (a) Tao, W.; Silverberg, L. J.; Rheingold, A. L.; Heck,
R. F. Organometallics 1989, 8, 2550; (b) Vicente, J.; Abad,
J.-A.; Gil-Rubio, J. J. Organometal. Chem. 1992, C9, 436;
1
Red-orange crystals, mp 155–157 °C.
NMR
(
300 MHz, CDCl ): d 3.82 (s, 3H), 3.86 (s, 3H), 5.84 (s,
3
1
2
7
5
1
1
H), 6.77 (dd, J ¼ 8:1, 2.5 Hz, 1H), 6.98 (d, J ¼ 8:9 Hz,
H), 7.08 (d, J ¼ 2:5 Hz, 1H), 7.26 (d, J ¼ 8:1 Hz, 1H),
13
.62 (d, J ¼ 8:9 Hz, 2H). C NMR (75 MHz, CDCl ): d
3
5.44, 55.73, 110.24, 114.34, 115.32, 120.22, 122.60,
25.74, 129.13, 135.14, 135.53, 161.16, 161.63, 163.32,
96.67. MS: m/z (Irel:, %) 266 (100) M , 159 (72), 135
(c) Larock, R. C.; Doty, M. J. J. Org. Chem. 1993, 58,
4579; (d) Vicente, J.; Abad, J.-A.; Lopez-Pelaez, B.;
þ
Martinez-Viviente, E. Organometallics 2002, 21, 58;
(
(59). Anal. Calcd for C H O : C, 76.68; H, 5.30.
17 14 3
Found: C, 76.76; H, 5.27.
e) Liebeskind, L. S.; South, M. S. J. Org. Chem. 1980,
5, 5426; (f) Hong, P.; Cho, B.-R.; Yamazaki, H. Chem.
4
Lett. 1979, 339; (g) Kim, D. H.; Son, S. U.; Chung, Y. K.
Org. Lett. 2003, 5, 3151; (h) M u€ nzenmaier, W.; Straub, H.
Synthesis 1976, 49.
1
3. Electron transfer reagents have also been described as
promoter for the cyclization of 1,2-dialkynylbenzene
derivatives to aroylindenones; see: Schmittel, M.; Kian,
S. Liebigs Ann. Recl. 1997, 1391.
4. Vasilyev, A. V.; Rudenko, A. P.; Grinenko, E. V. Russ. J.
Org. Chem. 2000, 36, 1157.
5. Olah, G. A.; Prakash, G. K. S.; Sommer, J. Superacids;
Wiley: New York, 1985.
6. (a) Olah, G. A.; Spear, R. J. J. Am. Chem. Soc. 1975, 97,
Acknowledgements
A.V. thanks the NATO for a postdoctoral fellowship.
S.W. thanks Loker Hydrocarbon Institute, USC, Los-
Angeles for financial support. P.P. and J.S. thank the
CNRS for financial support.
1
1
1
1845; (b) Siehl, H.-U.; Kaufman, F.-P.; Hori, K. J. Am.
Chem. Soc. 1992, 114, 9343.
References and notes
1
7. Similar processes of O,C-diprotonation of enone systems
were investigated previously; see: (a) Koltunov, K. Y.;
Repinskaya, I. B. Russ. J. Org. Chem. 1994, 30, 97; (b)
Koltunov, K. Y.; Prakash, G. K. S.; Rasul, G.; Olah,
G. A. J. Org. Chem. 2002, 67, 8943, and references cited
therein.
1
2
3
. Ernst-Russel, M. A.; Chai, C. L. L.; Wardlaw, J. H.; Elix,
J. A. J. Nat. Prod. 2000, 63, 129.
. Arnone, A.; Camarda, L.; Merlini, L.; Nashini, G. Gazz.
Chim. Ital. 1975, 105, 1093.
. Zimmerman, H. E. J. Am. Chem. Soc. 1956, 78, 1168.