Organocatalytic Michael-Knoevenagel-hetero-Diels-Alder reactions: An efficient asymmetric one-pot strategy to isochromene pyrimidinedione derivatives

Article abstract of DOI:10.1021/ol202877m

Synthesis of isochromene pyrimidinedione derivatives having five stereocenters has been achieved by a one-pot Michael-Knoevenagel condensation-inverse-electron-demand hetero-Diels-Alder reaction of α, β-unsaturated aldehydes, olefinic nitroalkanes, and 1,

Full text of DOI:10.1021/ol202877m

ORGANIC
LETTERS
2012
Vol. 14, No. 2
448–451
Organocatalytic MichaelꢀKnoevenagelꢀ
Hetero-DielsꢀAlder Reactions: An Efficient
Asymmetric One-Pot Strategy to
Isochromene Pyrimidinedione Derivatives
Bor-Cherng Hong,* Nitin S. Dange, Chun-Feng Ding, and Ju-Hsiou Liao
Department of Chemistry and Biochemistry, National Chung Cheng University,
Chia-Yi, 621, Taiwan, R.O.C.
chebch@ccu.edu.tw
Received October 25, 2011
ABSTRACT
Synthesis of isochromene pyrimidinedione derivatives having five stereocenters has been achieved by a one-pot MichaelꢀKnoevenagel
condensationꢀinverse-electron-demand hetero-DielsꢀAlder reaction of r, β-unsaturated aldehydes, olefinic nitroalkanes, and 1,3-
dimethylbarbituric acid via a one-pot strategy with excellent diastereo- and enantioselectivities (up to 99% ee). The structures and absolute
configurations of the products were confirmed by X-ray analysis.
With the recent advent of cascade and sequential organo-
catalysis, stereoselective syntheses of polycycles have
entered into a new era of flourishing development. The
many examples of organocatalyzed annulations1 have
included the Michael,2 DielsꢀAlder,3 aldol,4 Moritaꢀ
BaylisꢀHillman,5 Knoevenagel,6 and Henry reactions.7
Among the strategies employed in these organocatalyzed
annulations, multicomponent approaches8 with multiple
bonds and numerous stereocenters selectively generated in
a cascade or one-pot manner stand out as particularly
attractive. These approaches are characterized by their
efficiency, versatility, and flexibility, and they remain of
great interest to the synthetic community. Molecules with
the pyrimidinedione moiety have displayed a wide range of
pharmacological activities, including anti-HIV, antiprolif-
erative, anti-inflammatory, antibacterial, anti-hepatitis B
virus, and sustained reduction of plasma DPP-4 activity,
and have attracted much attention in medicinal and
(1) For a recent review in organocatalyzed cycloadditions, see: Hong,
B.-C. In Enantioselective Organocatalyzed Reactions II; Mahrwald, R.,
Ed.; Springer: 2011; Chapter 3.
(2) (a) Enders, D.; Wang, C.; Liebich, J. X. Chem.;Eur. J. 2009, 15,
11058. (b) Albrecht, Ł.; Richter, B,; Vila, C.; Krawczyk, H.; Jørgensen,
K. A. Chem.;Eur. J. 2009, 15, 3093.
ꢀ
ꢀ
(3) For a recent review: (i) Merino, P.; Marques-Lopez, E.; Tejero,
€
T.; Herrera, R. P. Synthesis 2010, 1. For examples:(a) Enders, D.; Huttl,
M. R. M.; Runsink, J.; Gerhard, R.; Bianca, W. Angew. Chem., Int. Ed.
2007, 46, 467. (b) Hayashi, Y.; Samanta, S.; Gotoh, H.; Ishikawa, H.
Angew. Chem., Int. Ed. 2008, 47, 6634. (c) Gotoh, H.; Hayashi, Y. Org.
Lett. 2007, 9, 2859. (d) Gioia, C.; Hauville, A.; Bernardi, L.; Fini, F.;
Ricci, A. Angew. Chem., Int. Ed. 2008, 47, 9236. (e) He, H.; Pei, B.-J.;
Chou, H.-H.; Tian, T.; Chan, W. H.; Lee, A. W. M. Org. Lett. 2008, 10,
2421. (f) Xu, D.-Q.; Xia, A.-B.; Luo, S.-P.; Tang, J.; Zhang, S.; Jiang,
J.-R.; Xu, Z.-Y. Angew. Chem., Int. Ed. 2009, 48, 3821. (g) Kano, T.;
Tanaka, Y.; Osawa, K.; Yurino, T.; Maruoka, K. Chem. Commun. 2009,
45, 1956. (h) Nakano, H.; Osone, K.; Takeshita, M.; Kwon, E.; Seki, C.;
Matsuyama, H.; Takano, N.; Kohari, Y. Chem. Commun. 2010, 46,
4827. (i) Zheng, C.; Lu, Y.; Zhang, J.; Chen, X.; Chai, Z.; Ma, W.; Zhao,
G. Chem.;Eur. J. 2010, 16, 5853. (j) Jia, Z.-J.; Jiang, H.; Li, J.-L.;
Gschwend, B.; Li, Q.-Z.; Yin, X.; Grouleff, J.; Chen, Y.-C.; Jørgensen,
K. A. J. Am. Chem. Soc. 2011, 133, 5053.
ꢀ
ꢀ~
(5) (a) Aleman, J.; Nunez, A.; Marzo, L.; Marcos, V.; Alvarado, C.;
Garcıa Ruano, J. L. Chem.;Eur. J. 2010, 16, 9453. (b) Takizawa, S.;
Inoue, N.; Hirata, S.; Sasai, H. Angew. Chem., Int. Ed. 2010, 49, 9725.
(6) (a) Lee, A.; Michrowska, A.; Sulzer-Mosse, S.; List, B. Angew.
Chem., Int. Ed. 2011, 50, 1707. (b) List, B. Angew. Chem., Int. Ed. 2010,
49, 1730. (c) Hayashi, Y.; Toyoshima, M.; Gotoh, H.; Ishikawa, H. Org.
Lett. 2009, 11, 45. (d) Reference 2b.
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(7) Uehara, H.; Imashiro, R.; Hernandez-Torres, G.; Barbas, C. F.
Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 20672.
(8) For reviews: (a) Gabriela, G.; Ramon, D. J.; Yus, D. M. Tetra-
(4) (a) Notz, W.; Tanaka, F.; Barbas, C. F. Acc. Chem. Res. 2004, 37,
580. (b) Hayashi, Y.; Yasui, Y.; Kawamura, T.; Kojima, M.; Ishikawa,
H. Angew. Chem., Int. Ed. 2011, 50, 2804. (c) Rueping, M.; Kuenkel, A.;
Tato, F.; Bats, J. W. Angew. Chem., Int. Ed. 2009, 48, 3699.
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hedron: Asymmetry 2007, 18, 693. (b) Zhu, J.; Bienayme, H. Multi-
component Reactions; Wiley-VCH: Weinheim, 2005.
r
10.1021/ol202877m
Published on Web 12/23/2011
2011 American Chemical Society

Table 1. Screening of the Catalysts, Solvents, and Reaction
Conditions for the Reactionsa
Scheme 1. Retrosynthetic Analysis
synthetic studies.9 In fact, some of these derivatives are
marketed as medicinal drugs, e.g., idoxuridine, primidone,
trifluridine, fluorouracil, urapidil, zenarestat (FK 366), gem-
citabine, capecitabine, and alogliptin (SYR-322). Moreover,
several rare examples have been reported for the asymmetric
multicomponent synthesis of hydroisochromenes, a unique
skeleton possessing pharmacological activities.10 Considering
the above background in the context of organocatalytic
asymmetric annulations,11 we envisioned an approach to
the isochromene pyrimidinedione system that could be
accomplished by a MichaelꢀKnoevenagel condensationꢀ
inverse-electron-demand hetero-DielsꢀAlder reaction12,13 of
R, β-unsaturated aldehydes, olefinic nitroalkanes and 1,3-
dimethylbarbituric acid via a one-pot strategy (Scheme 1).14
Herein, we describe the details of such an approach and the
methodology that permits efficient production of isochro-
mene pyrimidinedione derivatives in excellent yields and
stereoselectivities with up to >20:1 dr and 99% ee.
a Unless otherwise noted, the reactions were performed in 0.2 M 1a
with a 1/1.2 ratio of 1a/2a at rt (∼25 °C). b Unless otherwise noted,
20 mol % of additive was used. c Reaction time for the first-step reaction
of 1a and 2a. d Isolated yields of 4a. e Determined by HPLC with a chiral
column (Chiralpak IA). f 24 h was required for the second-step reaction:
Knoevenagelꢀhetero-DielsꢀAlder reaction. nd = not determined.
g 150 mol %. h PhCO2H (30 mol %), DBU (20 mol %).
Initially, we chose 1-((E)-4-nitrobut-1-enyl)benzene 1a
and cinnamaldehyde 2a for testing the feasibility of the
proposed MichaelꢀKnoevenagelꢀhetero-DielsꢀAlder
reaction (Table 1). Gratifyingly, reaction of 1a and 2a with
20 mol % of pyrrolidine and acetic acid in ethanol for 46 h,
followed by the addition of 1.2 equiv of 1,3-dimethylbar-
bituric acid (3a) with stirring for 12 h, afforded a 47% yield
of the expected product 4a although in an ∼1:1 ratio of
diastereomers, as depicted in Table 1, with the C-8
epimer.15 Subsequently, treatment of the unpurified dia-
stereomeric mixtures with 1.5 equiv of DBU in CHCl3
resulted in an isomerization to give the product 4a as the
only observable isomer (Table 1, entry 1).16
Conducting the same MichaelꢀKnoevenagel condensa-
tionꢀinverse-electron-demand hetero-DielsꢀAlder reac-
tion with L-proline, followed by the addition of 1.5 equiv
of DBU, resulted in the formation of expected product 4a
as the only observable diastereomer in 55% yield but
with very low enantioselectivity (Table 1, entry 2). A series
of organocatalysts were then screened in the reactions
(9) Manickam, B.; Govindan, S.; Damodharan, K. Org. Lett. 2009,
11, 4466.
(10) For examples, ochratoxin A, citrinin, A-77636, galaxolide, hydran-
genol, mellein, phyllodulcin, nabilone, L-759, L-656, and HU-210.
(11) For our recent efforts in exploring new organocatalytic annula-
tions, see: (a) Hong, B.-C.; Dange, N. S.; Hsu, C.-S.; Liao, J.-H.; Lee,
G.-H. Org. Lett. 2011, 13, 1338. (b) Hong, B.-C.; Nimje, R. Y.; LinC.-W.;
Liao, J.-H. Org. Lett. 2011, 13, 1278. (c) Hong, B.-C.; Kotame, P.; Liao,
J.-H. Org. Biomol. Chem. 2011, 9, 382. (d) Hong, B.-C.; Dange, N. S.;
Hsu, C.-S.; Liao, J.-H. Org. Lett. 2010, 12, 4812. (e) Hong, B.-C.;
Kotame, P.; Tsai, C.-W.; Liao, J.-H. Org. Lett. 2010, 12, 776. (f) Hong,
B.-C.; Jan, R.-H.; Tsai, C.-W.; Nimje, R. Y.; Liao, J.-H.; Lee, G.-H. Org.
Lett. 2009, 11, 5246. (g) Hong, B.-C.; Nimje, R. Y.; Liao, J.-H. Org.
Biomol. Chem. 2009, 7, 3095. (h) Kotame, P.; Hong, B.-C.; Liao, J.-H.
Tetrahedron Lett. 2009, 50, 704. (i) Hong, B.-C.; Nimje, R. Y.; Sadani,
A. A.; Liao, J.-H. Org. Lett. 2008, 10, 2345. (j) Hong, B.-C.; Nimje,
R. Y.; Wu, M.-F.; Sadani, A. A. Eur. J. Org. Chem. 2008, 1449 and
references cited therein.
(12) For reviews in hetero-DielsꢀAlder reactions, see: (a) Bodnar,
B. S.; Miller, M. J. Angew. Chem., Int. Ed. 2011, 50, 5629. (b) Pellissier,
H. Tetrahedron 2009, 65, 2839. (c) Jørgensen, K. A. Angew. Chem., Int.
Ed. 2000, 39, 3558.
(13) For examples of the organocatalytic inverse-electron-demand
DielsꢀAlder reaction, see: (a) Xie, H.; Zu, L.; Oueis, H. R.; Li, H.;
Wang, J.; Wang, W. Org. Lett. 2008, 10, 1923. (b) Li, J.-L.; Kang, T.-R.;
Zhou, S.-L.; Li, R.; Wu, L.; Chen, Y.-C. Angew. Chem., Int. Ed. 2010, 36,
6418. (c) Xu, Z.; Liu, L.; Wheeler, K.; Wang, H. Angew. Chem., Int. Ed.
2011, 50, 3484.
(15) Unless otherwise isomerized, organocatalyzed Michael addi-
tion of nitroalkane to R,β-unsaturated aldehydes usually yields an
isomeric mixture of adducts (syn/anti). For examples, see: (a) Jakob, F.;
Herdtweck, E.; Bach, T. Chem.;Eur. J. 2010, 16, 7537. (b) Gotoh, H.;
Ishikawa, H.; Hayashi, Y. Org. Lett. 2007, 9, 5307. (c) Hojabri, L.;
Hartikka, A.; Moghaddam, F. M.; Arvidsson, P. I. Adv. Synth. Catal.
2007, 349, 740. (d) Zu, L.; Xie, H.; Li, H.; Wang, J.; Wang, W. Adv.
Synth. Cat 2007, 349, 2660. (e) Gotoh, H.; Okamura, D.; Ishikawa, H.;
Hayashi, Y. Org. Lett. 2009, 11, 4056.
(16) Reaction of the syn/anti mixtures with DBU in EtOH or
CH3CN, vide infra, gave low yields. Changing the reaction media by
evaporation of solvent followed by the addition of CHCl3 and DBU
provided better yields.
(14) For recent examples of the organocatalytic approaches to
enantiomerically pure cyclohexanes, see: (a) Inokoishi, Y.; Sasakura,
N.; Nakano, K.; Ichikawa, Y.; Kotsuki, H. Org. Lett. 2010, 12, 1616–
1619. (b) Li, J.-L.; Kang, T.-R.; Zhou, S.-L.; Li, R.; Wu, L.; Chen, Y.-C.
ꢀ
Angew. Chem., Int. Ed. 2010, 49, 6418–6420. (c) Aleman, J.; Marcos, V.;
Marzo, L.; Ruano, J. L. G. Eur. J. Org. Chem. 2010, 4482–4491.
Org. Lett., Vol. 14, No. 2, 2012
449

Table 2. Scope of the MichaelꢀKnoevenagel Condensationꢀ
Inverse-Electron-Demand Hetero-DielsꢀAlder Reactionsa
Figure 1. Stereo plots of the X-ray crystal structures of (þ)-5,
(þ)-6, and (()-9: C, gray; N, blue; O, red; Br, purple.
general with respect to the substrates tested, providing the
desired adducts with excellent enantioselectivities and
diastereomeric ratios (dr) (>20:1) in good yields. In addi-
tion, for the reaction with thioxopyrimidinedione (3b),
the second-step reaction, the Knoevenagelꢀhetero-Dielsꢀ
Alder reaction, required a longer reaction time than the
examples using 3a (48 vs 12 h), Table 2, entry 11. The
structure and the absolute configuration of the products
were assigned based on the X-ray analysis of (þ)-517 and
(þ)-6,18 which were obtained from the respective reduc-
tions of 4a and 4b by DIBAL-H (Figure 1).
To explain the stereochemistry of this transformation, a
plausible mechanism was proposed, as shown in Scheme 2.
Initial nucleophilic attack of nitroalkane 1 on the iminium-
activated cinnamaldehyde 2 from the Re face under the
control of the catalyst (TS A) gives intermediate enamine
B, which was transformed to iminium C and then reacted
with 1,3-dimethylbarbituric acid 3 via Knoevenagel con-
densation to afford pyrimidinetrione D. Subsequently, the
intermediate D underwent the intramolecular hetero-
DielsꢀAlder reaction (IMDA) via the transition state
(TS E) to give a 1:1 ratio of the diastereomeric product 4
(8,9-syn and 8,9-anti), which was subsequently isomerized
by DBU to afford 4 (8,9-anti) predominately. The intrigu-
ing and excellent diastereoselective IMDA reaction19
may arise from the severe steric hindrance conferred by
the phenyl substituents at C-9 (denoted by an asterisk
in Scheme 2), which hampers the reaction through the
transition state (TS F).20 Notably, the reaction demon-
strates a proof-of-principle of the control of facial selectiv-
ity in IMDA by the remote stereogenic center generated
in situ by the domino organocatalysis reaction.21
a Unless otherwise noted, the reactions were performed in 0.2 M 1
with a ratio of 1/1.2 of 1/2 at rt (∼25 °C). b Reaction time for the first-step
reaction of 1 and 2. c Isolated yields of product 4. d Determined by HPLC
with a chiral column (Chiralpak IA). e 48 h was required for the second-
step reaction: Knoevenagelꢀhetero-DielsꢀAlder reaction. f First-step
Michael reactions at 10 °C for 56 h.
(Table 1, entries 3ꢀ8). Among them, reactions with the
prolinol derivatives IIIꢀV, especially the Jørgensenꢀ
Hayashi catalyst IV, gave promising results with good
yields and better enantioselectivities (e.g., 68% yield and
71% ee in Table 1, entry 4). The reactions with thiourea
catalysts VIꢀVIII afforded lower yields of the product 4a
(Table 1, entries 6ꢀ8). To optimize the yields and enantio-
selectivities, the reaction was conducted in various solvents
(Table 1, entries 9ꢀ14), and the best result was obtained
with CH3CN to give a 63% yield with 96% ee (Table 1,
entry 10). To accelerate the first-step Michael reaction,
we increased the nucleophilicity of the nitroalkane by
replacing benzoic acid with a base, e.g., NaOAc, and then
screened the reactions. Although this modification facili-
tated the first-step Michael reaction, it also afforded lower
yields of product 4a, but with similar enantioselectivities
(Table 1, entries 15ꢀ16). Notably, using a combination of
acid and base additives with catalyst IV (Table 1, entry 17),
the first-step Michael reactions were facilitated and the
optimal yield (70% yield) was obtained with a slight excess
of PhCO2H to DBU (30ꢀ20 mol %).
Finally, we explored the possibility of extending the pro-
tocol to hexahydro-1H-isochromen-3(4H)-one (Scheme 3).
(17) X-ray data was deposited in data bank (CCDC-842679). These data
can be obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
(18) X-ray data was deposited in data bank (CCDC-842680).
(19) For review in IMDA, see: (a) Martin, J.; David, T. Chem. Soc.
Rev. 2009, 38, 2983. (b) Takao, K.; Munakata, R.; Tadano, K. Chem.
Rev. 2005, 105, 4779. (c) Bear, B. R.; Sparks, S. M.; Shea, K. J. Angew.
Chem., Int. Ed. 2001, 40, 821. For our previous effort in the IMDA
reaction, see:Hong, B.-C.; Chen, F.-L.; Chen, S.-H.; Liao, J.-H.; Lee,
G.-H. Org. Lett. 2005, 7, 557.
(20) In addition, the secondary orbital interaction between the
electron-rich phenyl group and the electron-poor enone may play a role
in the diastereoselective IMDA reaction.
(21) For other examples of hetero-DielsꢀAlder reactions, see: (a)
Dickmeiss, G.; Jensen, K. L.; Worgull, D.; Franke, P. T.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2011, 50, 1580–1583. (b) Jensen, K. L.;
Dickmeiss, G.; Donslund, B. S.; Poulsen, P. H.; Jørgensen, K. A. Org.
Lett. 2011, 13, 3678.
Having established the optimal reaction conditions
(Table 1, entry 17), we next examined the scope and
limitation of the above system with variants of reactants
1, 2, and 3. Despite a subtle decrease in the enantioselec-
tivity, the condition of IVꢀPhCO2HꢀDBU was selected
for these reactions since it gave the best yield as well as
included a short reaction time in the first-step Michael
reaction. As shown in Table 2, the reaction appears quite
450
Org. Lett., Vol. 14, No. 2, 2012

Scheme 2. Plausible Reaction Mechanism
electron-demand hetero-DielsꢀAlder reaction to provide
isochromene pyrimidinediones having five stereocenters
with excellent diastereo- (>20:1) and enantioselectivities
(up to 99% ee). The reaction not only adds to the limited
repertory of examples of organocatalytic one-pot four
consecutive reaction sequences but also demonstrates a
one-pot synthesis of isochromene pyrimidinediones with
an ecological and economical protocol. The methodology
also reveals a strategy and provides an example of the
control of facial selectivity of IMDA by a remote
stereogenic center generated in situ via the organocatalysis
reaction. The one-pot tactics and the benign reaction media
at ambient temperature further manifest the merit of this
strategy. The structure as well as the absolute configura-
tions of the products were confirmed by X-ray analysis of
the appropriate adducts. Further work is underway to
explore and to elaborate the synthetic applications.
Scheme 3. Synthetic Extension to 8 and 9
Replacing the 1,3-dimethylbarbituric acid 3 with Meldrum’s
acid (7), the domino reaction, after acid hydrolysis, afforded
hexahydro-1H-isochromen-3(4H)-one (8) in 54% yield.22
Treatment of the syn- and anti-8 mixture with LiOH in EtOH
followed by acidification gave the decarboxylation product 9
in 67% yield, 96% ee. The structure was confirmed by X-ray
analysis of (()-923 (Figure 1).
Acknowledgment. We acknowledge the financial support
for this study from the National Science Council, Taiwan,
ROC. Thanks to the National Center for High-Performance
Computing (NCHC) for their assistance in literature search-
ing and the instrument center of National Science Council
for compounds analysis.
In summary, we have achieved the first organocatalytic
one-pot MichaelꢀKnoevenagel condensationꢀinverse-
Supporting Information Available. Experimental pro-
cedures and characterization data for the new compounds
and X-ray crystallographic data for (þ)-5, (þ)-6, and (()-
9 (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org
(22) For the same solvent system with the subsequent ethanolysis, the
Michael reaction proceeded in EtOH at 0 °C for 110 h.
(23) X-ray data was deposited in data bank (CCDC-842838).
Org. Lett., Vol. 14, No. 2, 2012
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