Solid-state melt reaction for the domino process: highly efficient synthesis of fused tetracyclic chromenopyran pyrimidinediones using baylis hillman derivatives

Article abstract of DOI:10.1021/ol901228j

A solid-state melt reaction (SSMR) has been demonstrated via a domino process for the synthesis of tetracyclic chromenopyran pyrimidinedione frameworks using Baylis Hillman derivatives through in situ formation of an olefin followed by an Intramolecular [

Full text of DOI:10.1021/ol901228j

ORGANIC
LETTERS
2009
Vol. 11, No. 19
4466-4469
Solid-State Melt Reaction for the
Domino Process: Highly Efficient
Synthesis of Fused Tetracyclic
Chromenopyran Pyrimidinediones Using
Baylis-Hillman Derivatives†
Manickam Bakthadoss,* Govindan Sivakumar, and Damodharan Kannan
Department of Organic Chemistry, UniVersity of Madras, Guindy Campus,
Chennai-600 025, Tamilnadu, India
bhakthadoss@yahoo.com
Received August 11, 2009
ABSTRACT
A solid-state melt reaction (SSMR) has been demonstrated via a domino process for the synthesis of tetracyclic chromenopyran pyrimidinedione
frameworks using Baylis-Hillman derivatives through in situ formation of an olefin followed by an intramolecular [4 + 2] cycloaddition
reaction sequence. The tetracyclic frameworks were obtained without using catalyst and solvent in a highly stereoselective and stereospecific
fashion. The isolated yield is excellent and does not require column chromatography purification to obtain the pure product.
Synthesis of complex heterocyclic compounds is very
challenging in the field of organic chemistry.1 Usually,
complex organic molecules are synthesized by a multistep
reaction sequence. Recently, domino reactions have become
very attractive and a useful strategy which minimizes the
reaction steps to achieve the target complex organic com-
pounds2 with high yields. The domino Knoevenagel intramo-
lecular hetero-Diels-Alder reaction is one of the most
powerful synthetic routes for the synthesis of various
heterocycles and natural products.2a,c,3 The domino Knoev-
enagel intramolecular hetero-Diels-Alder reaction has also
been extensively employed for the synthesis of polycyclic
compounds, especially for the synthesis of chromenopyran
pyrimidinedione ring systems.2a,3b,d,f,4
There has been a flurry of activity in the synthesis of
pyrimidine derivatives due to their proven biological activity
(2) (a) Tietze, L. F. Chem. ReV. 1996, 96, 115–136. (b) Tietze, L. F.;
Beifuss, U. Angew. Chem., Int. Ed. 1993, 32, 131–163. (c) Pellissier, H.
Tetrahedron 2006, 62, 1619–1665. (d) Pellissier, H. Tetrahedron 2006, 62,
2143–2173. (e) Tietze, L. F.; Rackelmann, N. Pure Appl. Chem. 2004, 76,
1967–1983. (f) Tietze, L. F.; Kinzel, T.; Brazel, C. C. Acc. Chem. Res.
2009, 42, 367–378. (g) Enders, D.; Wang, C.; Bats, J. W. Angew. Chem.,
Int. Ed. 2008, 47, 7539–7542. (h) Zhang, Z.; Zhang, Q.; Sun, S.; Xiong,
T.; Liu, Q. Angew. Chem., Int. Ed. 2007, 46, 1726–1729. (i) Enders, D.;
Grondal, C.; Hutt, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570–1581.
(j) Yadav, A. K.; Peruncheralathan, S.; Ila, H.; Junjappa, H. J. Org. Chem.
† Dedicated to Prof. D. Basavaiah.
(1) (a) Nicolaou, K. C.; Synder, S. A.; Montagnon, T.; Vassilikogian-
nakis, G. Angew. Chem., Int. Ed. 2002, 41, 1668–1698. (b) Takao, K.;
Munakata, R.; Tadano, K. Chem. ReV. 2005, 105, 4779–4807. (c) Bur, S. K.;
Padwa, A. Chem. ReV. 2004, 104, 2401–2432. (d) Chen, F.; Huang, J. Chem.
ReV. 2005, 105, 4671–4706. (e) Coldham, I.; Hufton, R. Chem. ReV. 2005,
105, 2765–2809. (f) Hudlicky, T. Chem. ReV. 1996, 96, 3–30.
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.
10.1021/ol901228j CCC: $40.75
Published on Web 09/01/2009
 2009 American Chemical Society

and medicinal utility. 5-Substituted uracils and their nucleo-
sides are of immense biological significance because of their
use in chemotherapy of cancer.5a Some of the pyrimidine
derivatives also have anti viral and anti-HIV activities.5b-e
The Baylis-Hillman reaction is one of the most important
reactions in the field of organic synthesis.6 In fact, the
Baylis-Hillman adducts and their derivatives are useful
intermediates for the synthesis of many natural products and
biologically active molecules.6a-c,7 To the best of our
knowledge, Baylis-Hillman derivatives have not been
utilized for the domino Knoevenagel intramolecular hetero-
Diels-Alder reaction to date. In continuation of our interest
in the field of Baylis-Hillman chemistry,8 herein for the
first time we report a novel solid state melt reaction (SSMR)
via a domino reaction for the synthesis of complex tetracyclic
chromenopyran pyrimidinedione frameworks in a highly
stereoselectiveandstereospecificfashionusingBaylis-Hillman
derivatives involving in situ formation of olefin followed by
an intramolecular [4 + 2] cycloaddition reaction.
or microwave irradiation.2a,c,d,9 We envisaged that the
domino Knoevenagel intramolecular hetero-Diels-Alder
reaction can be conducted without the above-mentioned
essential reaction components/conditions which are very
important criteria in green synthesis.
To execute our idea, first we selected methyl (2Z)-2-
(bromomethyl)-3-arylprop-2-enoates, bromo derivatives of
the Baylis-Hillman adducts and salicyladehyde to generate
the required precursor (1) to obtain the desired tetracyclic
chromenopyran pyrimidinedione compounds (4) via a tandem
Knoevenagel intramolecular hetero-Diels-Alder reaction
according to the retrosynthetic strategy shown in Scheme 1.
Scheme 1. Retrosynthetic Strategy for the Synthesis of
Tetracyclic Frameworks with Angular Substitution
Generally domino Knoevenagel intramolecular hetero-
Diels-Alder reactions are carried out with catalyst, solvent
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Meervelt, L. V.; Dehaen, W. Tetrahedron 2002, 58, 531–544. (b) Dat, N. T.;
Lee, J.; Lee, K.; Hong, Y.; Kim, Y. H.; Lee, J. J. J. Nat. Prod. 2008, 71,
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Brumby, T.; Fennen, J. Angew. Chem., Int. Ed. 1990, 29, 665–667. (h)
Sinder, B. B.; Lu, Q. J. Org. Chem. 1994, 59, 8065–8070.
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Kim, Y. M.; Kim, S. H. Tetrahedron 2009, 65, 101–108. (c) Sabitha, G.;
Reddy, E. V.; Fatima, N.; Yadav, J. S.; Krishna, K. V. S. R.; Kunwar,
A. C. Synthesis 2004, 1150–1154. (d) Tietze, L. F.; Bachmann, J.;
Wichmann, J.; Burkhardt, O. Synthesis 1994, 1185–1194.
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P. A.; St Clair, M. H.; Lehrman, S. N.; Gallo, R. C.; Bolognesi, D.; Barry,
D. W.; Broder, S. Proc. Natl. Acad. Sci. U.S.A. 1985, 82, 7096–7100. (c)
Griengl, H.; Bodenteich, M.; Hayden, W.; Wanek, E.; Streicher, W.; Stutz,
P.; Bachmayer, H.; Ghazzouli, I.; Rosenwirth, B. J. Med. Chem. 1985, 28,
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R. T.; Balzarini, J.; DeClercq, E. J. Med. Chem. 1989, 32, 2507–2509. (e)
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To prepare the desired tetracyclic chromenopyran pyrim-
idinedione compound (4), we first treated N,N-dimethylbar-
bituric acid and the Baylis-Hillman derivative 1a8a with a
catalytic amount of ethylenediammonium diacetate (EDDA)
catalyst in toluene under reflux temperature for 6 h. However,
the reaction did not provide the anticipated product (4). The
reaction was carried out with other catalysts such as AlCl3,
BF3(OEt)2, and cerium(IV) ammonium nitrate (CAN), but
they too failed to provide the desired product (Table 1, entries
1-4).
However, best results were obtained when the Baylis-
Hillman derivative 1a melted with N,N-dimethylbabituric
acid (2) in a round-bottom flask at 180 °C for 1 h in solvent
and catalyst-free conditions, yielding the desired angularly
substituted (ester moiety) tetracyclic chromenopyran pyri-
midinedione 4a in 98% yield without column chromatog-
raphy purification (pure product obtained after washing with
ethylacetate and hexane mixture in a 1:49 ratio). Decreasing
(6) (a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. ReV. 2003,
103, 811–891. (b) Declerck, V.; Martinez, J.; Lamaty, F. Chem. ReV. 2009,
109, 1–48. (c) Basavaiah, D.; Rao, K. V.; Reddy, R. J. Chem. Soc. ReV.
2007, 36, 1581–1588. (d) Singh, V.; Batra, S. Tetrahedron 2008, 64, 4511–
4574. (e) Basavaiah, D.; Rao, P. D.; Hyma, S. R. Tetrahedron 1996, 52,
8001–8062. (f) Ciganek, E. In Org. Reactions; Paquette, L. A., Ed.; Wiley:
New York, 1997; Vol. 51, pp 201-350.
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7379–7382. (b) Basavaiah, D.; Krishnamacharyula, M.; Hyma, R. S.; Sarma,
P. K. S.; Kumaragurubaran, N. J. Org. Chem. 1999, 64, 1197–1200. (c)
Basavaiah, D.; Reddy, R. M.; Kumaragurubaran, N.; Sharada, D. S.
Tetrahedron 2002, 58, 3693–3697. (d) Basavaiah, D.; Sarma, P. K. S.
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Tetrahedron Lett. 2008, 49, 820–823. (b) Bakthadoss, M.; Sivakumar, N.
Synlett 2009, 1014–1018. (c) Basavaiah, D.; Bakthadoss, M.; Pandiaraju,
S. Chem. Commun. 1998, 1639–1640. (d) Basavaiah, D.; Bakthadoss, M.;
Jayapal Reddy, G. Synth. Commun. 2002, 35, 689–697. (e) Bakthadoss,
M.; Murugan, G. Synth. Commun. 2008, 38, 3406–3413. (f) Basavaiah, D.;
Bakthadoss, M.; Jayapal Reddy, G. Synthesis 2001, 919–923. (g) Baktha-
doss, M.; Murugan, G. Synth. Commun. 2009, 39, 1290–1298.
(9) (a) Tietze, L. F.; Geissler, H.; Fennen, J.; Brumby, T.; Brand, S.;
Schulz, G. J. Org. Chem. 1994, 59, 182–191. (b) Tietze, L. F.; Zhou, Y.
Angew. Chem., Int. Ed. 1999, 38, 2045–2047. (c) Matiychuk, V. S.; Lesyk,
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Kryshchyshyn, A. P. Tetrahedron Lett. 2008, 49, 4648–4651. (d) Khosh-
kholgh, M. J.; Balalaie, S.; Gleiter, R.; Rominger, F. Tetrahedron 2008,
64, 10924–10929. (e) Alonso, S. J.; Braun, A. E.; Ravelo, A. G.; Zarate,
R.; Lopez, M. Tetrahedron 2007, 63, 3066–3074
.
Org. Lett., Vol. 11, No. 19, 2009
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Table 1. Optimization for the Formation of Tetracyclic
Compound Using Various Catalysts and Conditions
Table 2. Synthesis of Tetracyclic Frameworks Using
N,N-Dimethylbarbituric Acid/Cyclohexane-1,3-dione/
5,5-Dimethylcyclohexane-1,3-dione and Baylis-Hillman
Derivatives 1a-j
producta (%)
catalyst
entry (20 mol %) T (°C) solvent time (h)
3a
4a
entry substrate
R
producta time (h) yieldb, c (%)
1
2
3
4
5
6
7
8
EDDA
AlCl3
BF3(OEt)2
CAN
110
110
110
110
toluene
toluene
toluene
toluene
toluene
6
6
6
6
6
1
1
1
1
1
57
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
H
4ad
4b
4c
4d
4e
4f
1
1
1
1
1
1
1
1
1
1
1
1
98
92
98
97
98
97
92
93
96
94
96
95
2-Me
4-Me
4-Et
4-iPr
4-OMe
2-Cl
3-Cl
4-Cl
2-NO2
H
29
24
57
86
72
23
110
100b
120b
140b
160b
180b
21
72
98
7
8
9
1g
1h
1i
4g
4h
4i
4j
7
9
10
a Isolated yield of the pure product. b Solid reactants melted at the
mentioned temperature without solvent.
10
11
12
1j
1a
1a
H
10
a All reactions were carried out on a 1 mmol scale of O-alkylated
compound (1a-j) with 1 mmol of N,N-dimethylbarbituric acid/cyclohexane-
1,3-dione/5,5-dimethylcyclohexane-1,3-dione by melting at 180 °C for 1 h.
b Isolated yield of the pure product. c All compounds were fully characterized
(see the Supporting Information). d The structure of the molecule was further
confirmed by single-crystal X-ray data (see the Supporting Information).10
the reaction temperature from 180 °C led to incompletion
of the reaction (Table 1, entries 6-9). It is worth mentioning
that this is the first solid-state melt reaction (SSMR) for the
domino Knoevenagel intramolecular hetero-Diels-Alder
reaction. Utilization of the Baylis-Hillman derivatives for
such domino hetero-Diels-Alder reactions is new in the field
of Baylis-Hillman chemistry.
Encouraged by this result, we treated a variety of
Baylis-Hillman derivatives (1b-j) with N,N-dimethylbar-
bituric acid which successfully yielded the desired fused
tetracyclic chromenopyran pyrimidinedione derivatives 4b-j
in 92-98% yields (Table 2).
To understand the reaction further, we also melted
cyclohexane-1,3-dione (5) and 5,5-dimethylcyclohexane-1,3-
dione (8) with a Baylis-Hillman derivative (1a) in catalyst-
and solvent-free conditions for 1 h at 180 °C, which
successfully led to the corresponding fused tetracyclic
chromenopyran pyrimidinedione compounds 7 and 10,
respectively, in excellent yields (96% and 95%).
To check the generality of the reaction, we melted the
various Baylis-Hillman derivatives derived from acryloni-
trile (11a-j)8a with N,N-dimethylbarbituric acid for 1 h at
180 °C which successfully provided the desired angularly
substituted (cyano group) fused tetracyclic chromenopyran
pyrimidinedione compounds 13a-j in 92-98% yields. The
isolated yields of the pure products (13a-j) are summarized
in Table 3.
It is worth mentioning that the highly stereoselective and
stereospecific nature of the reaction was clearly evidenced
1
by H NMR data and X-ray crystal analyses. Comparison
of the 1H NMR spectra of the crude products and recrystal-
lized products showed them to be identical, which confirms
the highly stereoselective nature of the reaction. Furthermore,
the stereochemistry of compound 4a was confirmed by X-ray
crystallographic analysis (Figure 1). The crystal structure of
compound 4a shows that the relative stereochemistry of the
phenyl group and the adjacent ester moiety are in the anti
orientation, which is presumably due to the initial trans
geometry of the phenyl group and ester moiety present in
the double bond at Vicinal positions of compound 1a, thus
confirming the stereospecificity of the reaction. Similarly,
the relative stereochemistry of compound 13a was confirmed
by X-ray crystallographic analysis (Figure 2). The crystal
(10) Structures were confirmed by single-crystal X-ray data. CCDC
numbers for 4a and 13a are 682089 and 682090, respectively.
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Org. Lett., Vol. 11, No. 19, 2009

Table 3. Synthesis of Tetracyclic Frameworks Using
N,N-Dimethylbarbituric Acid and Baylis-Hillman Derivatives
11a-j
Figure 2. X-ray crystal structure of 13a.
presumably due to the initial cis geometry of the phenyl
group and nitrile moiety present in the double bond at Vicinal
positions of compound 11a, thus confirming the stereospeci-
ficity of the reaction. Hence, the starting material having a
trans geometry (aryl and ester groups present in the Vicinal
positions of compound 1a) led to the anti product and starting
material having a cis geometry (aryl and nitrile moieties
present in the Vicinal positions of compound 11a), which
led to the syn product which clearly shows the high
stereospecific nature of the reaction.
In conclusion, we have successfully developed a simple
and novel protocol for the facile synthesis of complex
angularly substituted tetracyclic frameworks containing a
chromenopyran pyrimidinedione ring system via a solid-state
melt reaction (SSMR) through a domino process using
Baylis-Hillman derivatives. Notable features include the
following: (a) catalyst and solvent are not required even for
solid reactants; (b) the products are obtained in a highly
stereoselective and stereospecific fashion; (c) column chro-
matography purification is not required to obtain the pure
products; and (d) products are obtained with excellent yields.
This strategy opens new opportunities for the preparation of
libraries of a wide variety of chromenopyran pyrimidinedione
derivatives for biological screening.
entry substrate
R1
producta time (h) yieldb, c (%)
1
2
3
4
5
11a
11b
11c
11d
11e
11f
H
13ad
13b
13c
13d
13e
13f
1
1
1
1
1
1
1
1
1
1
97
98
98
96
95
98
94
92
93
92
2-Me
4-Me
4-Et
4-iPr
4-OMe
2-Cl
6
7
8
9
11g
11h
11i
13g
13h
13i
3-Cl
4-Cl
10
11j
2,4-dichloro
13j
a All reactions were carried out on a 1 mmol scale of O-alkylated
compound (11a-j) with 1 mmol of N,N-dimethylbarbituric acid by melting
at 180 °C for 1 h. b Isolated yield of the pure product. c All compounds
were fully characterized (see the Supporting Information). d The structure
of the molecule was further confirmed by single-crystal X-ray data (see
the Supporting Information).10
Acknowledgment. We thank CSIR, UGC (New Delhi),
for financial support. We also thank DST-FIST for the NMR
facility. G.S. thanks CSIR for his SRF, and D.K. thanks UGC
for his JRF.
Supporting Information Available: Experimental pro-
cedures (with all spectral data), 1H and 13C NMR spectra of
all compounds 3a, 4a-j, 7, 10, and 13a-j, CIF files, and
ORTEP diagrams. This material is available free of charge
via the Internet at http://pubs.acs.org.
Figure 1. X-ray crystal structure of 4a.
structure of compound 13a shows that the phenyl group and
adjacent nitrile moiety are in syn orientation which was
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4469