Improvements in aldol reactions with diketopiperazines

Article abstract of DOI:10.1081/SCC-120030746

Precipitation of products by using dichloromethane as solvent permits an efficient aidol-type reaction between 1,4-diacetyl-2,5-piperazinedione and aromatic aldehydes catalyzed by K^tBuO/^tBuOH independently of the electrophilic character of the aryl ring. A simple method to obtain 3-methyl-2,4,5-trimethoxybenzaldehyde is also reported.

Full text of DOI:10.1081/SCC-120030746

This article was downloaded by: [Illinois State University Milner Library]
On: 10 December 2012, At: 06:27
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Improvements in Aldol Reactions with
Diketopiperazines
Juan Francisco González a , Elena de la Cuesta a & Carmen Avendaño a
a Departamento de Química Orgánica y Farmacéutica, Facultad de Farmacia, Universidad
Complutense, Madrid, 28040, Spain
Version of record first published: 16 Aug 2006.
To cite this article: Juan Francisco González, Elena de la Cuesta & Carmen Avendaño (2004): Improvements in Aldol
Reactions with Diketopiperazines, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 34:9, 1589-1597
To link to this article: http://dx.doi.org/10.1081/SCC-120030746
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to
anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the contents
will be complete or accurate or up to date. The accuracy of any instructions, formulae, and drug doses
should be independently verified with primary sources. The publisher shall not be liable for any loss, actions,
claims, proceedings, demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 9, pp. 1589–1597, 2004
Improvements in Aldol Reactions
with Diketopiperazines
´
Juan Francisco Gonzalez, Elena de la Cuesta,
*
and Carmen Avendan˜o
´ ´ ´
Departamento de Quımica Organica y Farmaceutica, Facultad de
Farmacia, Universidad Complutense, Madrid, Spain
ABSTRACT
Precipitation of products by using dichloromethane as solvent permits an
efficient aldol-type reaction between 1,4-diacetyl-2,5-piperazinedione
and aromatic aldehydes catalyzed by KtBuO/tBuOH independently of
the electrophilic character of the aryl ring. A simple method to obtain
3-methyl-2,4,5-trimethoxybenzaldehyde is also reported.
Key Words: Aldol reaction; Diketopiperazines; Ortho-directed
lithiation.
*
´ ´
Correspondence: Carmen Avendan˜o, Departamento de Quımica Organica y Farma-
´
ceutica, Facultad de Farmacia, Universidad Complutense, Madrid 28040, Spain;
Fax: 34-91-394-18-22; E-mail: avendano@farm.ucm.es.
1589
DOI: 10.1081/SCC-120030746
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

ORDER
REPRINTS
´
Gonzalez, de la Cuesta, and Avendan˜o
1590
INTRODUCTION
Many derivatives of 3-arylmethylene- or 3,6-bis-arylmethylene-2,5-
piperazinedione are natural products with antibacterial and/or cytotoxic
activity.[1] Albonoursin,[2] piperafizines,[3] TDD,[4] and neoechinulines,[5]
are some representative examples. On the other hand, 1-acetyl-3-arylmethy-
lene-2,5-piperazinediones have been used as starting materials to achieve
more complex structures. Fukuyama and Kubo approaches to antitumor anti-
biotics (+)-saframycin A and B[6,7] are representative.
The most general method to obtain 3-arylalkylidene-2,5-piperazine-
diones is the aldol-type reaction between an aromatic aldehyde and the cor-
responding N-acetyl or N,N0-diacetyl-2,5-piperazinedione. In the original
protocol, the acylation was performed in situ, but it is more convenient to
isolate the N-acetyl derivatives.[8] The N-acylation of the heterocycle
enhances the acidity of the vicinal methylene protons, favors the conden-
sation by the anchimeric assistance of the vicinal N-acetyl group through
an intramolecular N–O shift displacement, and permits several base-solvent
combinations suitable for aldol condensation. The reactions with KtBuO as a
t
base and BuOH–DMF as solvents take place at room temperature and with
high diastereoselectivity in favor to the Z-isomers, being a very common
procedure since the pioneering work of Gallina.[9] However, the conden-
sation yields with aromatic aldehydes are very dependent on the electronic
character of their substituents, being much better for electron-withdrawing
groups.
Although the basicity of KtBuO is highly dependent on the choice of the
reaction solvent[10] and the differences in solubility between the products and
the starting compounds could help in the equilibrium displacement, the role of
the solvent has received very little attention. Replacement of DMF by THF
in the reactions of N,N0-diacetylpiperazine-2,5-dione 1[11] with a variety of
aromatic aldehydes was recently applied to obtain 3-arylmethylene-1-acetyl-
piperazine-2,5-diones as starting compounds in the synthesis of plasminogen
activator inhibitors. In this solvent, formation of the bis-alkylidene derivatives
was prevented but the reported yields were modest.[12]
In the search of simple and flexible methods to obtain saframycin-related
compounds, we have recently shown that 2,5-dimethoxybenzylidene (2b)
may be easily transformed through previous hydrogenation of the double
bond into pyrazinoisoquinoline derivatives, compounds that were proposed
as precursors of the pentacyclic saframycins system.[13] To extend this meth-
odology to any type of aromatic rings we needed to optimize the yields of
compounds 2, including those containing several electron-donating groups.
For this proposal, we studied the use of dry dichloromethane as solvent in
the aldol reaction.

ORDER
REPRINTS
Aldol Reactions with Diketopiperazines
1591
Most of the selected aldehydes were commercially available, but
3-methyl-2,4,5-trimethoxybenzaldehyde whose substituents are adequate to
be incorporated in saframycin rings A and E was not. Among the published
synthetic approaches to this compound the formylation of 2,3,6-trimethoxy-
toluene with hexamethylenetetramine and trifluoroacetic acid may be used to
get it in 58% yield. However, the starting compound of this method is not
commercially available and is derived from 2-methylresorcinol in five steps:
O-methylation, acetylation, Baeyer–Villiger oxidation, acetate hydrolysis, and
O-methylation; or from 2-methyl-6-nitrophenol in five steps: O-methylation,
reduction of the nitro group, oxidation to the benzoquinone, reduction to
hydroquinone, and O-methylation.[14] Other four-step alternative was devel-
oped by Kubo by starting from p-benzoquinone. This compound is trans-
formed with H2SO4/Ac2O into 1,2,4-benzenetriol and this intermediate, by
subsequent O-methylation, lithium-directed methylation, and formylation
with TiCl4/Cl2CHOCH3, give the desired aldehyde in 55% yield.[15] We
considered more convenient to study a two-step procedure based on the regio-
selective lithium-directed methylation of the dimethylacetal of 2,4,5-
trimethoxybenzaldehyde, which is commercially available (Sch. 1). The initial
transformation was successfully carried out by using methanol/methyl
orthoformate and ammonium chloride[16] and the crude acetal thus obtained
was transformed in 70% yield through a standard tandem ortho-lithiation–
alkylation reaction.[17]
When aldol reactions of 1 with the aromatic aldehydes were performed in
KtBuO as a base and a tBuOH–CH2Cl2 mixture as solvent (method A, Sch. 2)
the products 2 precipitated during the reaction, being finally collected by
Scheme 1.

ORDER
REPRINTS
´
Gonzalez, de la Cuesta, and Avendan˜o
1592
Scheme 2.
filtration after treatment of the reaction suspension with an ammonium chloride
solution. The subsequent catalytic hydrogenation of compounds 2 afforded
near quantitatively the saturated derivatives 3.
In conclusion, the use of DCM instead of DMF in the aldol reactions of 1
with unsubstituted and highly oxygenated benzaldehydes, as well as other
electron-rich aromatic aldehydes, has a significant influence on the reaction
yields, as compared to the classical method by using tBuOH–DMF as solvents
(method B). Additionally, we have developed a simple procedure to obtain
3-methyl-2,4,5-trimethoxybenzaldehyde.
EXPERIMENTAL
All reagents were of commercial quality (Aldrich, Fluka, SDS, Panreac)
and were used as received. Solvents (SDS) were dried and purified using
standard techniques. Reactions were monitored by thin layer chromatography,
on aluminum plates coated with silica gel with fluorescent indicator
(Macherey–Nagel Alugram Sil G/UV254). Separations by flash chromato-
graphy were performed on silica gel (SDS 60 ACC, 230–40 mesh). Melting

ORDER
REPRINTS
Aldol Reactions with Diketopiperazines
1593
d
d

ORDER
REPRINTS
´
Gonzalez, de la Cuesta, and Avendan˜o
1594
d
d

ORDER
REPRINTS
Aldol Reactions with Diketopiperazines
1595
points were measured with a Reichert 723 hot stage microscope, and are
uncorrected. Infrared spectra were recorded on a Perkin Elmer Paragon
1000 FT-IR spectrophotometer, with all compounds examined in KBr pellets.
NMR spectra were obtained on a Bruker AC-250 spectrometer (Servicio de
´
Espectroscopıa, Universidad Complutense).
3-Methyl-2,4,5-trimethoxybenzaldehyde. 2,4,5-Trimethoxybenzaldehyde
(1 g, 5.1 mmol) was added under N2 to a suspension of NH4Cl (15 mg,
0.3 mmol) in a solution of HC(OCH3)3 (2 mL, 18.3 mmol) in MeOH
(2 mL), and the mixture was stirred and refluxed for 3 hr. After cooling
to r.t., Et3N (0.15 mL, 1.1 mmol) was added, followed after a few minutes
of stirring, by addition of H2O (10 mL). The mixture was extracted with
EtOAc (3 ꢀ 30 mL), and the organic phase was washed with saturated
aqueous NaHCO3 (10 mL), H2O (10 mL), and brine (10 mL) and was
finally dried (Na2SO4). After evaporation of the solvent 1.12 g (92%) of
the crude 2,4,5-trimethoxybenzaldehyde dimethylacetal was obtained. To
a stirred dry THF solution (20 mL) of this product (1.026 g, 4.24 mmol)
under Ar at 2788C was added by syringe a solution of n-BuLi (3.2 mL
of 1.6 M solution in THF) and TMEDA (0.82 mL, 5.4 mmol). When the
addition was complete, the reaction mixture was stirred for 1 hr, quenched
with ICH3 (0.29 mL, 4.7 mmol) and allowed to stir for 40 min. The reac-
tion mixture was warmed to 08C, poured into H2O and extracted with
EtOAc (3 ꢀ 30 mL). The combined extracts were washed with aqueous
HCl 1 N solution (30 mL), H2O (20 mL) and brine (10 mL), and were
finally dried with anhydrous Na2SO4, filtered, and concentrated at reduced
pressure to afford the crude reaction product. An analytical sample was
obtained by column chromatography (silica gel, hexane/EtOAc 7 : 3).
Yield 630 mg (70%).
(Z)-1-Acetyl-3-arylmethylene-2,5-piperazinediones (2) (Method A). A
t
1 M solution of KtBuOH in BuOH (21 mL, 1.2 eq.) was added to a stirred
solution of aromatic aldehyde (5.5mmol, 1.1 eq.) and 1,4-diacetyl-2,5-pipera-
zinedione (1) (5.05 mmol, 1 eq.) in dry DCM (20 mL) under Ar atmosphere.
After being stirred for 4 hr at room temperature, the formed suspension
was acidified with a saturated solution of ammonium chloride (10 mL) and
the precipitate was filtered and washed with cold hexane and DCM, giving
compounds 2.
1-Acetyl-3-arylmethyl-2,5-piperazinediones (3). Compounds 2 (1.5 mmol)
were dissolved in AcOEt and hydrogenated over 10% palladium on carbon
(150 mg) at 1 atm. The solution was stirred at room temperature for 15 hr.
After removal of the catalyst by filtration over celite and washing with
DCM, the filtrate was evaporated giving compounds 3. All compounds gave
satisfactory (+0.3%) combustion microanalyses.
Characterization data of compounds 2 and 3 are given in Table 1.

ORDER
REPRINTS
´
Gonzalez, de la Cuesta, and Avendan˜o
1596
ACKNOWLEDGMENT
Financial support of this research from CICYT (SAF2000-0130/99) and a
´
FPI fellowsip (J. F. Gonzalez) is gratefully acknowledged.
REFERENCES
1. Shin, C. Heterocycles 1983, 20, 1407–1433.
2. (a) Brown, R.; Kelley, C.; Wiberley, S.E. J. Org. Chem. 1965, 30,
277–280; (b) Fukushima, K.; Yawaka, K.; Arai, T. J. Antibiot. 1973,
26, 175–176.
3. Kamei, H.; Oka, M.; Hamagishi, Y.; Tomita, H.; Konishi, H.; Oki, T.
J. Antibiot. 1990, 43, 1018–1020.
4. The structure shown for TDD is under discussion. See: (a) Isolation:
Kakinuma, K.; Rinchart, K.L. J. Antibiot. 1974, 27, 733–737;
(b) Biological activity: Komagata, D.; Sawa, T.; Muroka, Y.; Imada, C.;
Okami, Y.; Takcuchi, T. J. Antibiot. 1992, 45, 1117–1121; (c) Synthetic
´
studies: Santamarıa, A.; Cabezas, N.; Avendan˜o, C. Tetrahedron 1999,
55, 1173–1186.
5. See for instance: (a) Barbetta, M.G.; Casnati, G.; Pochini, A.; Silva, A.
Tetrahedron Lett. 1969, 4457–4460; (b) Shinichi, N.; Hidcki, M.;
Toshio, G. Tetrahedron Lett. 1980, 21, 2817–2820.
6. Fukuyama, T.; Yang, L.; Ajeck, K.L.; Sachleben, R.A. J. Am. Chem. Soc.
1990, 112, 3712–3713.
7. Kubo, A.; Saito, N.; Yamoto, H.; Masubuchi, K.; Nakamura, M. J. Org.
Chem 1998, 53, 4295–4310.
8. Katritzky, A.R.; Fan, W.Q.; Szajda, M.; Li, Q.L.; Caster, K.S.
J. Heterocyclic Chem. 1988, 25, 591–597.
9. (a) Gallina, C.; Liberatori, A. Tetrahedron Lett. 1973, 1135–1136; (b)
Gallina, C.; Liberatori, T. Tetrahedron 1974, 667–673; (c) Clark, J.H.
Chem. Rev. 1980, 80, 429–452; (d) Fukuyama, F.; Nunes, J.J. J. Am.
Chem. Soc. 1988, 110, 5196–5198.
10. Caine, D. Encyclopaedia of Reagents for Organic Synthesis;
Paquette, L.A., Ed.; Wiley; 1995; Vol. 6, 4189–4203.
11. Saski, T. Chem. Ber. 1921, 54, 163–171.
12. Folkes, A.; Roc, M.B.; Sohal, S.; Golec, J.; Faint, R.; Brooks, T.;
Charlton, P. Bioor. Med. Chem. 2001, 5, 2589–2592.
´
13. Gonzalez, J.F.; de la Cuesta, E.; Avendan˜o, C. Tetrahedron Lett. 2003, 44,
4395–4398.

ORDER
REPRINTS
Aldol Reactions with Diketopiperazines
1597
14. (a) Matsuo, K.; Okumura, M.; Tanaka, T. Chem. Pharm. Bull. 1982, 30,
4170–4174; (b) Weygand, F.; Vogelbach, K.; Zimmermann, K. Chem.
Ber. 1947, 80, 391–401.
15. Kubo, A.; Saito, N.; Yamato, H.; Kawakami, Y. Chem. Pharm. Bull.
1987, 35, 2525–2532.
16. Azzena, J.; Denurra, T.; Melloni, G.; Piroddi, A.M. Synthesis 1990,
313–317.
17. For alkylation at C-3 of 1,2,4-trimethoxybenzene with n-BuLi/Me2SO4
see: (a) Danishefsky, S.; Berman, E.; Cvetovich, T.; Minamikawa, J. Tet-
rahedron Lett. 1980, 21, 4819–4822; (b) Winkle, M.R.; Ronald, R.C. J.
Org. Chem. 1982, 47, 2101–2108.
18. Peters, D.A.; Beddoes, R.L.; Joule, J.A. J. Chem. Soc. Perkin Trans. 1
1993, 11, 1217–1224.
19. Yokoi, T.; Yang, L.-M.; Yokoi, T.; Wu, R.-Y.; Lee, K.-H. J. Antibiot.
1998, 41, 494–501.
20. Ong, Ch.W.; Lee, H.Ch. Aust J. Chem. 1990, 43, 773–775.
Received in the UK October 7, 2003

Request Permission or Order Reprints Instantly!
Interested in copying and sharing this article? In most cases, U.S. Copyright
Law requires that you get permission from the article’s rightsholder before
using copyrighted content.
All information and materials found in this article, including but not limited
to text, trademarks, patents, logos, graphics and images (the "Materials"), are
the copyrighted works and other forms of intellectual property of Marcel
Dekker, Inc., or its licensors. All rights not expressly granted are reserved.
Get permission to lawfully reproduce and distribute the Materials or order
reprints quickly and painlessly. Simply click on the "Request Permission/
Order Reprints" link below and follow the instructions. Visit the
U.S. Copyright Office for information on Fair Use limitations of U.S.
copyright law. Please refer to The Association of American Publishers’
Fair Use in the Classroom.
(AAP) website for guidelines on
The Materials are for your personal use only and cannot be reformatted,
reposted, resold or distributed by electronic means or otherwise without
permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the
limited right to display the Materials only on your personal computer or
personal wireless device, and to copy and download single copies of such
Materials provided that any copyright, trademark or other notice appearing
on such Materials is also retained by, displayed, copied or downloaded as
part of the Materials and is not removed or obscured, and provided you do
not edit, modify, alter or enhance the Materials. Please refer to our
Website
User Agreement for more details.
Request Permission/Order Reprints
Reprints of this article can also be ordered at
http://www.dekker.com/servlet/product/DOI/101081SCC120030746