Catalyst-free tandem aldol condensation/Michael addition of 1,3-cyclohexanediones with enolizable aldehydes

Article abstract of DOI:10.1016/j.bmcl.2009.03.040

An efficient tandem aldol condensation/Michael addition process of unactivated aldehydes and 1,3-cyclohexanedione is described. This transformation proceeds without any catalyst at room temperature with high isolated yields. By a fine-tuning of reaction conditions an access to both the aldol condensation/Michael addition products or to the dehydrated cyclized 9-substituted 1,8-dioxo-xanthenes is given.

Full text of DOI:10.1016/j.bmcl.2009.03.040

Bioorganic & Medicinal Chemistry Letters 19 (2009) 3949–3951
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Catalyst-free tandem aldol condensation/Michael addition
of 1,3-cyclohexanediones with enolizable aldehydes
*
Kerstin Rohr, Rainer Mahrwald
Humboldt-University Berlin, Institute of Chemistry, Brook-Taylor Street 2, 12489 Berlin, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient tandem aldol condensation/Michael addition process of unactivated aldehydes and 1,3-cyclo-
hexanedione is described. This transformation proceeds without any catalyst at room temperature with
high isolated yields. By a fine-tuning of reaction conditions an access to both the aldol condensation/
Michael addition products or to the dehydrated cyclized 9-substituted 1,8-dioxo-xanthenes is given.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 3 February 2009
Accepted 9 March 2009
Available online 16 March 2009
Keywords:
Tandem aldol condensation/Michael
addition
Enolizable aldehydes
1,3-Cyclohexanediones
Catalyst-free
Introduction. Xanthenes are important compounds with antibac-
tericide-activities in agriculture,1 with anti-inflammatory effects2
and even with antiviral activities.3 They are being developed to
act as new clinical agents in cancer therapy.4 In addition, substi-
tuted xanthenes are structural key-units in several natural prod-
ucts.5 Many procedures exist for the synthesis of 1,8-dioxo-
xanthenes.6 However, many of these methods include strong acidic
reaction conditions,7 long reaction times,8 high temperatures9 or
they are dedicated only to the application of aromatic aldehydes.10
The important aldol reaction/Michael addition intermediates could
not be isolated under these reaction conditions. To avoid these
restrictions we have tested the scope of a new aldol addition devel-
oped in our laboratories. Herein, we describe results of these
investigations.
Results and discussion. Recently, we have reported a solvent- and
catalyst-free aldol addition of activated aldehydes to 1,3-dicarbonyl
compounds. Aldol condensation does not occurred under these
reaction conditions. This unexpected aldol reaction could be ex-
tended successfully to a variety of acyclic and cyclic b-dicarbonyl
compounds.11 In order to explore the scope and limitations of this
new aldol addition we have also used 1,3-cyclohexanediones as
substrates. In initial studies we were able to isolate xanthene-ad-
duct 4h from reaction of choroacetaldehyde with 1,3-cyclohexane-
dione 1 with 43% yield after 24 h at room temperature. When
CH2Cl2 was applied as solvent 4h was isolated with 73%. This
increasing of yield is caused by homogeneity of the reaction mix-
ture. Further studies revealed that a variety of even unactivated
enolizable aldehydes 2a–h react with 1,3-cyclohexanedione 1 to
give aldol condensation/Michael addition compounds 3a–g. Under
these catalyst-free reaction conditions we obtained the 2:1 adducts
3a–g at room temperature within 24 h in good to high isolated
yields (Table 1). When used with (R)- or (S)-configured menthylgly-
oxylates an access to optically active products 3f and 3g is given.
Dehydrations were accomplished by addition of catalytic amounts
of pyridinium p-toluenesulfonate to the reaction mixtures. Also
isolated aldol/Michael adducts 3a–g were dehydrated under these
catalytic conditions; the corresponding 1,8-dioxo-xanthenes 4a–g
were obtained in quantitative yields within 30 min (Scheme 1,
Table 1).
It is reasoned that by an initial aldol condensation 2-arylidene-
or 2-alkylidene substituted 1,3-cyclohexandiones 5a–h were
formed. These Knoevenagel products are highly reactive Michael
Table 1
Reactions of aldehydes with 1,3-cyclohexanedione
Entry
R
Compound
Yield (%)
1
2
3
4
5
6
7
8
Cy
iPr
Ph
3a
3b
3c
3d
3e
3f
81
75
69
85
87
69
PhCH@CH
PhCH2–CH2
(R)-Menthyl-CO2
(S)-Menthyl-CO2
ClCH2
3g
78
4ha
43b, 73c
a
In this reaction only xanthene-product 4b was detected.
Neat, chloroacetaldehyde—50% solution in water.
Reactions were conducted in CH2Cl2.
b
c
* Corresponding author. Tel.: +49 30 2093 8397, fax: +49 30 2093 5553.
E-mail address: rainer.mahrwald@rz.hu-berlin.de (R. Mahrwald).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.03.040

3950
K. Rohr, R. Mahrwald / Bioorg. Med. Chem. Lett. 19 (2009) 3949–3951
H+, 30 min, quant.
r.t.
O
O
O
O
R-CHO
+
O
O
R
O
R
O
O
2a-g
1
4a-g
3a-g
Scheme 1. Reactions of aldehydes with 1,3-cyclohexanedione.
acceptors capable for further reactions 1,3-cyclohexanedione 1 to
yield compounds 3a–h. Subsequent dehydration yield 1,8-dioxo-
xanthenes 4a–h. In no case were we able to detect Knoevenagel
products 5a–h (Scheme 2).
in the presence of catalytic amounts of pyridinium p-toluenesulfo-
nate as described above. In this reaction we were able to isolate
highly differently substituted and functionalized xanthene 8a in
high yields—a valuable intermediate for further transformations
to higher-substituted xanthenes.
In conclusion, the non-catalysed aldol addition of 1,3-cyclohex-
anedione with enolizable and unactivated aldehydes has been
investigated. Under catalyst-free reaction conditions we were able
to isolate aldol addition/Michael adducts of 1,3-cyclohexanediones
with high yields. This catalyst-free method should be of great
interest especially for natural product synthesis, since no compara-
bly mild access to aldol/Michael adducts of 1,3-dicarbonyl com-
pounds exists.
Experimental. General experimental procedures: NMR spectra
were recorded at 300 MHz (1H NMR) and 75 MHz (13C NMR) in
CDCl3, respectively, using an AC-300 spectrometer. Chemical shifts
are given in ppm. Purification of products was accomplished by
flash chromatography. Thin layer chromatography was performed
with Merck Silica Gel 60 F254 TLC plates. Melting points were deter-
mined in open capillary tubes on a Sanyo Gallenkamp melting
point apparatus and are uncorrected. Mass spectra were obtained
using a Hewlett–Packard GCMS 5995-A mass spectrometer operat-
ing at 70 eV.
This behaviour concurs with reports found in the literature.12
Since 2-arylidene or 2-alkylidene adducts 5a–h of 1,3-cyclohexane-
dione are not attainable by aldol methodologies so far, there are
only a few other methods for the synthesis of these compounds.13
Also, these findings strongly contrast the results we described
in Ref. 11. When used with 1,3-dicarbonyl compounds of the acy-
clic series we have detected exclusively aldol adducts (e.g., 2,4-
pentanedione, 1,3-diphenyl-1,3-propanedione, ethyl acetoacetate
or ethyl 2-cyclohexanonecarboxylate). In addition, only aldol ad-
ducts of activated aldehydes and 1,3-dicarbonyl compounds were
formed in those transformations. No reactions were observed
when used with unactivated aldehydes as they were applied in
these reactions with 1,3-cyclohexanedione 1 (Table 1, entries 1–5).
Similar results were obtained when extending this method to
other substrates. Using with 5,5-dimethyl-substituted 1,3-cyclo-
hexanedione 6 we were able to obtain aldol/Michael adducts 7a
and 7b with good to high yields (Scheme 3). Dehydrations to the
corresponding 1,8-dioxo-xanthenes 8a and 8b were carried out
General procedure of 1,8-dioxo-xanthenes 4a–h and 8a,b. (1) Aldol
condensation/Michael addition: 2.5 mmol of appropriate aldehydes
and 5.0 mmol of 1,3-cyclohexane-dione were stirred for 24 h at
room temperature in 2.0 ml CH2Cl2. The reactions were completed
after that time (DC-control) and the reaction mixture was purified
by column chromatography without any further extraction
procedures.
(2) Cyclization: 0.5 g of corresponding Michael adducts 3a-h or
7a,b were stirred in 2.0 ml CH2Cl2 at room temperature in the pres-
ence of 5 mg pyridinium p-toluenesulfonate. After 300 the reaction
mixtures were extracted three times with saturated aq NaHCO3-
solution. The organic layers were separated, dried (Na2SO4),
filtrated and evaporated i. vac.
2,2’-(2,2-Dimethoxyethane-1,1-diyl)bis(3-hydroxy-5,5-dimethyl-
cyclohex-2-enone) (7a). Yield 76%; mp 104 °C (hexane/ethyl ace-
tate); 1H NMR: d = 12.16 (br, 2H, OH), 5.58 (d, 1H, J = 9.1 Hz, CH),
4.14 (d, 1H, J = 9.5 Hz, CH), 3.27 (s, 6H, CH3), 2.28 (s, 8H, CH2),
1.06 (s, 12H, CH3); 13C NMR: d = 190.0, 114.2, 100.6, 53.2, 46.4,
33.3, 31.3; HRMS: calcd for C20H30O6 + H+: 367.2115; found:
367.2114.
neat
r.t.
O
O
R
+
R-CHO
O
1
O
5a-h
2a-h
O
O
O
O
O
O
R
OH
R
OH
O
O
3a-h
H+
O
R
4a-h
3,3,6,6-Tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xan-
thene-9-carbaldehyde (8a). Yield 98%; mp 112 °C (hexane/ethyl
acetate); 1H NMR: d = 9.90 (d, 1H, J = 0.8 Hz, CHO) 4.45 (d, 1H,
O
O
Scheme 2. Reaction mechanism.

K. Rohr, R. Mahrwald / Bioorg. Med. Chem. Lett. 19 (2009) 3949–3951
3951
OH
H+
OH
O
(MeO)2CH-CHO
O
O
O
O
O
CHO
(OMe)2
6
7a: 76%
8a: 98%
O
H+
OH
OH
O
EtO2C-CHO
O
O
O
O
O
OEt
O
OEt
8b: 99%
7b: 68%
Scheme 3. Aldol additions to 5,5-dimethyl-1,3-cyclohexanediones 6.
F.; Bordin, F. Eur. J. Med. Chem. 2000, 35, 827; (e) Anonini, I.; Polucci, P.;
Magnano, A.; Martelli, S. J. Med. Chem. 2001, 44, 3329.
J = 0.7 Hz, CH), 2.38 (s, 4H, CH2), 2.26 (s, 6H, CH3), 1.06 (s, 6H,
CH3); 13C NMR: d = 198.9, 196.6, 164.1, 111.0, 50.0, 40.6, 32.2,
28.9, 27.4; HRMS: calcd for C18H22O4 + H+: 303.1591; found:
303.1593.
5. Quinonoid xanthenes with antisnake venom activity: (a) Selvanayagam, Z. E.;
Gnanavendhan, S. G.; Balakrishna, K.; Rao, R. B.; Sivaraman, J.; Subramanian, K.;
Puri, R.; Puri, R. K. J. Nat. Prod. 1996, 59, 664; Pyridoacridine marine alkaloids:
(b) Delfourne, E.; Roubin, C.; Bastide, J. J. Org. Chem. 2000, 65, 5476;
Osajaxanthone: (c) Wolfrom, M. L.; Komitsky, F.; Looker, J. H. J. Org. Chem.
1965, 30, 144; Gum gamboge: (d) Yates, P.; Karmarkar, S. S.; Rosenthal, D.;
Stout, G. H.; Stout, V. F. Tetrahedron Lett. 1963, 4, 1623; Morellin: (e) Kartha, G.;
Ramchandran, G. N.; Bhat, H. B.; Nair, P. M.; Raghavan, V. K. V.; Ventkatamaran,
K. Tetrahedron Lett. 1963, 4, 459; Ergochrysine: (f) Apsimon, J. W.; Corran, A. J.;
Creasey, N. G.; Marlow, W.; Whalley, W. B.; Sim, K. Y. Proc. Chem. Soc., London
1963, 313.
6. Ferric hydrogen sulfate: (a) Shatterian, H. R.; Hosseinian, A.; Ghashang, M. Turk.
J. Chem. 2009, 33, 1; Montmorillonite K10: (b) Dabiri, M.; Azimi, S. C.; Bazgir, A.
Chem. Papers 2008, 62, 522; Sulfuric acid: (c) Seyyedhamzeh, M.; Mirzaei, P.;
Bazgir, A. Dyes Pigments 2008, 76, 836; DOWEX-50W: (d) Imani-Shakibaei, G.;
Mirzaei, P.; Bazgir, A. Appl. Catal. A: Gen. 2007, 325, 188; HClO4: (e) Kantevari,
R.; Bantu, R.; Nagarapu, L. J. Mol. Catal. A: Chem. 2007, 269, 53; Amberlyst-15: (f)
Das, B.; Thirupathi, P.; Mahender, I.; Reddy, V. S.; Rao, Y. K. J. Mol. Catal. A: Chem.
2006, 247, 233; TMSCl: (g) Kantevari, S.; Bantu, R.; Nagarapu, L. Arkivoc 2006,
xvi, 136; Cyanuric chloride: (h) Zhang, Z. H.; Tao, X. Y. Aust. J. Chem. 2007, 61,
77; BiCl3: (i) Li, J. J.; Tao, X. Y.; Zhang, Z. H. Phosphorus, Sulfur Silicon Relat. Elem.
2008, 183, 1672.
Acknowledgements
This work was supported by the Deutsche Forschungsgemeins-
chaft, Bayer-Schering Pharma AG, Bayer Services GmbH, BASF AG
and Sasol GmbH. Petra Neubauer and Dr. Burhard Ziemer are grate-
fully acknowledged for the X-ray structure analyses.
7. Nafion-H: (a) Lin, H.; Zhao, Q.; Xu, B.; Wang, X. J. Mol. Cat. A: Chem. 2007, 268,
221; Acidic ionic liquids: (b) Fang, D.; Gong, K.; Liu, Z. L. Catal. Lett. 2009, 127,
291; Sulfonic acid: (c) Jin, T. S.; Zhang, J. S.; Xiao, J. C.; Wang, A. Q.; Li, T. S.
Synlett 2004, 866.
8. (a) Das, B.; Thirupathi, P.; Reddy, K.; Ravikanth, B.; Nagarapu, L. Catal. Commun.
2007, 8, 535; (b) Jin, T. S.; Zhang, J. S.; Wang, A. Q.; Li, T. S. Ultrason. Sonochem.
2006, 13, 220.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2009.03.040.
9. (a) Horning, E. C.; Horning, M. J. Org. Chem. 1946, 11, 95; (b) Cremlyn, R. J.;
Saunders, D. Phosphorus, Sulfur Silicon Relat. Elem. 1993, 81, 72; (c) Singh, K.;
Singh, J.; Singh, H. Tetrahedron 1996, 52, 14273; (d) Shi, D.; Wang, Y.; Lu, Z.; Dai,
G. Synth. Commun. 2000, 30, 713; (e) Tonkikh, N. N.; Strakovs, A.; Petrova, M. V.
Chem. Heterocycl. Compd. 2004, 40, 43.
10. Venkatesan, K.; Pujar, S. S.; Lahoti, R. J.; Srinivasan, K. V. Ultrason. Sonochem.
2008, 15, 548.
11. Rohr, K.; Mahrwald, R. Adv. Synth. Catal. 2008, 350, 2877.
12. (a) Jones, G. Org. React. 1967, 15, 204; (b) Hobel, K.; Margaretha, P. Helv. Chim.
Acta 1989, 72, 975.
References and notes
1. Takeshiba, H.; Jiyoujima, T. 1981. Japan Kokai Tokkyo Koho JP 56005480.
Tokyo: Japan Patent Office.
2. Poupelin, J. P.; Saint-Ruf, G.; Foussard-Blanpin, O.; Narcisse, G.; Uchida-Ernouf,
G.; Lacroix, R. Eur. J. Med. Chem. 1978, 13, 67.
3. Lambert, R. W.; Martin, J. A.; Merrett, J. H.; Parkes, K. E. B.; Thomas, G. J., PCT Int.
Appl. WO9706178, 1997.
4. (a) Koeller, K. M.; Haggarty, S. J.; Perkins, B. D.; Leykin, I.; Wong, J. C.; Kao, M. C.
J.; Schreiber, S. L. Chem. Biol. 2003, 10, 397; (b) Dimmock, J. R.; Raghavan, S. K.;
Bigam, G. E. Eur. J. Med. Chem. 1988, 23, 111; (c) Baguley, B. C.; Ching, L. M.
Biodrugs 1997, 8, 119; (d) Ferlin, M. G.; Marzano, C.; Chiarelotto, G.; Baccichetti,
13. (a) Margaretha, P.; Polansky, O. E. Monatsh. Chem. 1970, 101, 824; (b) Eaton, P.
E.; Bunenelle, P. H. Tetrahedron Lett. 1984, 25, 23.