Synthesis of novel annulated uracils via domino Knoevenagel-hetero-Diels-Alder reaction in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2008.09.079

An efficient synthesis of tetracyclic uracil derivatives (polycyclic pyrans) is achieved via domino Knoevenagel-hetero-Diels-Alder reactions of O-propargylated salicylaldehyde derivatives with 1,3-dimethylbarbituric acid in water as solvent in the presenc

Full text of DOI:10.1016/j.tetlet.2008.09.079

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Tetrahedron Letters 49 (2008) 6965–6968
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of novel annulated uracils via domino
Knoevenagel-hetero-Diels–Alder reaction in aqueous media
b
c
c
Malihe Javan Khoshkholgh a, Saeed Balalaie a, , Hamid Reza Bijanzadeh , Frank Rominger , Jürgen H. Gross
*
a Department of Chemistry, K.N. Toosi University of Technology, PO Box 15875-4416, Tehran, Iran
b Department of Chemistry, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
c Organisch-Chemisches Institut der Universitaet Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 28 May 2008
Revised 27 August 2008
Accepted 12 September 2008
Available online 18 September 2008
An efficient synthesis of tetracyclic uracil derivatives (polycyclic pyrans) is achieved via domino Knoeve-
nagel-hetero-Diels–Alder reactions of O-propargylated salicylaldehyde derivatives with 1,3-dimethyl-
barbituric acid in water as solvent in the presence of CuI. The products are formed in good yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Dedicated to Professor Habib Firouzabadi
on the occasion of his 65th birthday
Keywords:
Domino intramolecular Knoevenagel-
hetero-Diels–Alder
Cuprous iodide
Unactivated alkynes
Aqueous media
Tetracyclic uracil
Modern research in organic chemistry requires the synthesis of
complex organic molecules and emphasis on methods that provide
maximum synthetic efficiency. Combinatorial chemistry has
emerged as a powerful synthetic procedure in this area. Domino
reactions which result from the combination of multiple transfor-
mations in a single pot are highly efficient means for the improve-
ment of reaction efficiency.1 Among these reactions, the domino
Knoevenagel-hetero-Diels–Alder reaction, which was developed
widely by Tietze and Rackelman2 is a very efficient process in or-
ganic synthesis, especially in the area of heterocycles and natural
products.
For a long time, the use of alkynes in hetero-Diels–Alder reac-
tions was limited, because of the lower reactivity of unactivated al-
kynes compared to the corresponding alkenes. The use of different
Lewis acids3 provides new opportunities for various catalytic al-
kyne reactions. The development of copper catalysis for synthetic
X
X
D
O
O
O
N
O
O
C
X
CHO
N
N
N
A
N
B
O
+
O
O
O
O
O
N
O
3
4
1
2
Scheme 1. Retrosynthetic analysis.
* Corresponding author. Fax: +98 21 2285 3650.
E-mail addresses: balalaie@kntu.ac.ir, balalaie@yahoo.com (S. Balalaie).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.079

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M. J. Khoshkholgh et al. / Tetrahedron Letters 49 (2008) 6965–6968
Table 1
reactions, particularly for alkyne transformations, has gained
increasing attention. Copper(I) compounds are powerful catalysts
that promote a wide variety of organic transformations such as
intramolecular cyclization,4 halogen exchange,5 [3+2] cycloaddi-
tion,6 and coupling reactions.7
Our goal was to design an efficient method to prepare the tetra-
cyclic systems 3, which consist of a uracil ring (A) annulated to a
dihydropyran ring (B) (Scheme 1). It is highly desirable to develop
environmentally benign processes that can be conducted in aque-
ous media. Furthermore, using water as a solvent has advantages,
such as low cost, safety, and it is environmentally friendly.8 Tetra-
cyclic uracil derivatives have various biological activities. Herein,
Effect of catalyst and solvent on the domino Knoevenagel-hetero-Diels–Alder
reactionsa of 1 and 2a
Lewis acid
Solvent
Yield (%)
—
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Water
—
—
—
—
10
50
67
75
AgOAc (20%)
AgOTf (20%)
AuCl3 (20%)
CuI (20%)
CuI (20%)
CuI (30%)
CuI (40%)
Water
Water
a
Reaction time was 24 h.
Table 2
CuI-catalyzed domino Knoevenagel-hetero-Diels–Alder reaction of 2a–d and 1a
X
O
O
O
X
CHO
O
H3C
H3C
N
N
CuI
H2O, reflux
+
O
N
O
O
N
O
CH3
CH3
1
2a-d
3a-d
Aldehyde
Product
Time (h)
Yieldb (%)
CHO
O
O
O
75
24
N
O
O
N
2a
3a
Br
O
CHO
O
Br
O
25
73
N
2b
O
O
N
3b
O2N
NO2
CHO
O
O
N
6
85
O
O
O
N
2c
3c
OMe
CHO
O
O
N
O
10
80
N
OMe
O
O
2d
3d
a
Reactions were performed with aldehydes 2a–d (1 mmol), 1,3-dimethylbarbituric acid (1.2 mmol), and CuI (40 mol %) in water (25 ml) under reflux conditions.
Yield of isolated product.
b

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M. J. Khoshkholgh et al. / Tetrahedron Letters 49 (2008) 6965–6968
6967
we report the first domino intramolecular Knoevenagel-hetero-
Diels–Alder reaction of O-propargylated salicylaldehydes with
terminal unactivated acetylenes in the presence of CuI in aqueous
media. A retrosynthetic analysis of 3 (Scheme 1) led to alkyne 4,
which is easily accessible via a Knoevenagel reaction of propargy-
lated salicylaldehyde derivatives 2 with 1,3-dimethylbarbituric
acid.
The O-propargylated salicylaldehyde derivatives 2a–d were
prepared in high yields and excellent purity from the reaction of
substituted salicylaldehydes and propargyl bromide using potas-
sium carbonate in DMF.9
Compound 2a was used as a model system to achieve and opti-
mize the desired domino intramolecular Knoevenagel-hetero-
Diels–Alder reaction to give 3a. Heating 2a in acetonitrile under
reflux conditions for 24 h did not lead to the anticipated product.
Thus, the effect of various Lewis acids was studied. Using AgOTf,
AgOAc, AuCl3, and CuOTf as catalysts did not give the desired prod-
uct. When CuI was employed as the catalyst, the desired product
3a was formed in 10% yield. After investigation of the amount of
catalyst and solvent, CuI (40%) and water as solvent gave the best
results (Table 1).
Using these optimized conditions, the annulated uracils 3a–d
were synthesized in yields ranging between 73% and 85% (Table 2).
The structures of the products were deduced from their
elemental analyses and spectroscopic data.10 Characteristic sig-
nals for uracils 3a–d in the 1H NMR spectra are an AB quartet for
the –OCH2 group between 4.60 and 4.90 ppm and a singlet due
to the O–CH@ group at 6.65–7.18 ppm. The corresponding signals
of the O–CH2 and O–CH@ groups in the 13C NMR spectra appear at
65.3–67.6 ppm and 84.5–85.7 ppm, respectively. X-ray crystallog-
raphy data also confirmed the structure of 3d11 (Fig. 1).
The shape of 3d was confirmed by X-ray crystallography. The
angle between the two planes is 60.7° (i.e., the angle between
the planes C(8)–N(7)–C(6)–C(5)–C(10)–N(9) and C(3)–C(18)–
C(17)–C(16)–C(15)–C(2)).
A possible mechanism for the domino intramolecular Knoeven-
agel-hetero-Diels–Alder reaction is shown in Scheme 2. The initial
step is a Knoevenagel condensation between 1,3-dimethylbarbi-
turic acid and the aldehyde 2a–d. Next, the triple bond is activated
with CuI through formation of a p-complex or a copper acetylide,
which reduces the electron density of the alkyne12 and provides
the necessary conditions for the hetero-Diels–Alder reaction.
Copper acetylide is usually formed in the presence of a strong
base. The product of the Knoevenagel condensation of 2a with
1,3-dimethylbarbituric acid could be isolated. The hetero-Diels–
Alder reaction of this product was performed under reflux
conditions in the presence of CuI (20%) in acetonitrile as solvent
without additional base. The desired product 3a was formed in
45% yield under these conditions, therefore, the formation of a
copper acetylide is possible.
In conclusion, we have developed a CuI-catalyzed domino
intramolecular Knoevenagel-hetero-Diels–Alder reaction, which
provided an efficient route for the formation of tetracyclic uracil
derivatives. Further studies to extend the scope and synthetic
utility of this Cu-catalyzed domino intramolecular Knoevenagel-
hetero-Diels–Alder reaction with inactivated terminal acetylenes
are in progress in our laboratory.
Figure 1. ORTEP representation of the structure of 3d.
X
X
O
O
X
O
O
O
CHO
CuI
N
N
N
CuI
+
O
O
N
N
O
O
O
O
O
N
1
2a-d
X
X
O
O
O
O
Cu
N
N
O
O
N
O
O
N
3a-d
Scheme 2. A plausible mechanism for the formation of tetracyclic annulated uracils 3a–d.

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M. J. Khoshkholgh et al. / Tetrahedron Letters 49 (2008) 6965–6968
65.8, 85.7, 113, 116, 120, 125.6, 126.1, 127.3, 132.8, 149.7, 152.5, 152.8, 162.6.
HR-MS (70 eV, EI)
16H14N2O4 [M]+Å found 298.0926, calcd 298.0953.
Acknowledgments
C
Elemental Anal. Calcd for (C16H14N2O4): C 64.42, H: 4.73, N 9.39. Found: C
64.25, H 4.60, N 9.28.
Saeed Balalaie is grateful to the Alexander von Humboldt foun-
dation for a research fellowship and donation of equipment. We
are thankful to Prof. Rolf Gleiter for his hospitality and useful dis-
cussions. Partial support of this work by the K.N. Toosi University
of Technology Research Council is gratefully acknowledged.
11-Bromo-2,4-dimethyl-4,12b-dihydro-1H,7H-chromeno[4’,3’:4,5]pyrano [2,3-d]-
pyrimidine-1,3(2H)-dione (3b): mp = 240.5–242 °C; IR (KBr, cmꢀ1):
m = 1709,
1642; 1H NMR(500 MHz, DMSO-d6) d 3.26 (s, 3H, –NMe), 3.27 (s, 3H, –NMe),
4.63 (s, 1H, CH), 4.71 (d, J = 11.6 Hz, 1H, –CH), 4.84 (d, J = 11.6 Hz, 1H, –CH),
6.72 (d, J = 8.5 Hz, 1H, HAr), 7.12 (s, 2 H, HAr and @CH), 7.25 (d, J = 8.5 Hz, 1H,
HAr); 13C NMR (75 MHz, CDCl3) d 29.0, 29.8, 30.4, 67.1, 85.7, 112.3, 112.8,
119.7, 130.1, 130.4, 131.4, 136.0, 150.9, 153.6, 154.7, 163.9; HR-MS (70 eV, EI):
C16H13N2O479Br: [M]+Å found 376.0064, calcd 376.0059; C16H13N2O481Br
[M+2]+ꢁ found 378.0030, Calcd 378.0039. Elemental Anal. Calcd for
(C16H13N2O4Br): C, 50.95; H, 3.47; N, 7.43. Found: C, 50.75; H, 3.38; N, 7.18.
2,4-Dimethyl-11-nitro-4,12b-dihydro-1H,7H-chromeno[4’,3’:4,5]pyrano[2,3-d]pyr-
References and notes
1. (a) Tietze, L. F. Domino Reactions in Organic Synthesis; Wiley-VCH, 2006; (b)
Chapman, C. J.; Frost, C. G. Synthesis 2007, 1; (c) Enders, D.; Grondal, C.; Hüttl,
M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570; (d) Tietze, L. F. Chem. Rev. 1996,
96, 115.
imidine-1,3(2H)-dione (3c): mp = 254–255 °C, IR (KBr, cmꢀ1):
m = 1704, 1638,
1521, 1340; 1H NMR(300 MHz, DMSO-d6) d 3.27 (s, 3H, –NMe), 3.30 (s, 3H,
–NMe), 4.77 (s, 1H, –CH), 4.86 (d, J = 11.6 Hz, 1H, OCH), 4.98 (d, J = 11.6 Hz, 1H,
OCH), 6.95 (d, J = 9.0 Hz, 1H, HAr), 7.18 (s, 1H, @CH), 7.97 (br s, 1H, HAr), 8.0 (d,
J = 8.0 Hz, 1H, HAr); 13C NMR (75 MHz, DMSO-d6) d 28.6, 29.5, 30.0, 67.6, 85.2,
111.0, 118.1, 124, 124.5, 128.0, 136.4, 140.8, 150.5, 154.4, 159.8, 163; HR-MS
(70 eV, EI): C16H13N3O6 [M]+Å found 343.0805, calcd 343.0804. Elemental Anal.
Calcd for (C16H13N3O6): C, 55.98; H, 3.79; N, 12.24. Found: C, 55.75; H, 3.69; N,
12.08.
2. (a) Tietze, L. F.; Rackelman, N. In Multicomponent Reactions; Zhu, J., Bienayme,
H., Eds.; Wiley-VCH: Weinheim, 2005; pp 121–167; (b) Tietze, L. F.;
Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967; (c) Tietze, L. F. J. Heterocycl.
Chem. 1990, 27, 47; (d) Tietze, L. F.; Rackelmann, N.; Müller, I. Chem. Eur. J.
2004, 10, 2722; (e) Tietze, L. F.; Modi, A. Med. Res. Rev. 2000, 20, 304.
3. (a) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180; (b) Zhang, L.; Sun, J.; Kozmin, S.
A. Adv. Synth. Catal. 2006, 348, 2271; (c) Asao, N.; Sato, K.; Yamamoto, Y. J. Org.
Chem. 2005, 70, 3682; (d) Asao, N.; Yudha, S.; Nogami, T.; Yamamoto, Y. Angew.
Chem., Int. Ed. 2005, 44, 5526; (e) Ermolat, D. S.; Mehta, V. P.; Eycken, E. V. V.
Synlett 2007, 3117; (f) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104,
3079.
4. (a) Chen, Ch.; Dormer, P. G. J. Org. Chem. 2005, 70, 6964; (b) Evindar, G.; Batey,
R. J. Org. Chem. 2006, 71, 1802; (c) Patil, N. T.; Yamamoto, Y. J. Org. Chem. 2004,
69, 5139; (d) Zhu, W.; Ma, D. Chem. Commun. 2004, 888.
5. Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 14844.
6. (a) Sreedhar, B.; Reddy, P. S.; Kumar, N. S. Tetrahedron Lett. 2006, 47, 3055; (b)
Jin, T.; Kamijo, S.; Yamamoto, Y. Eur. J. Org. Chem. 2004, 3789; (c) Bock, V. D.;
Hiemstra, H.; Maarseveen, J. H. Eur. J. Org. Chem. 2006, 51.
7. (a) Black, D. A.; Arndtsen, B. A. Org. Lett. 2004, 6, 1107; (b) Gujadhur, R. K.;
Venkataraman, D. Tetrahedron Lett. 2003, 44, 81; (c) Rao, H.; Jin, Y.; Fu, H.; Jiang,
Y.; Zhao, Y. Chem. Eur. J. 2006, 12, 3636; (d) Cho, S. H.; Yoo, E. J.; Bae, I.;
Chang, S. J. Am. Chem. Soc. 2005, 127, 16046; (e) Zhu, W.; Ma, D. Org. Lett. 2006,
8, 261.
8. (a) Hailes, H. C. Org. Process Res. Dev. 2007, 11, 114; (b) Grieco, P. A. Organic
Synthesis in Water; Blackie Academic & Professional Publishers: London, 1998;
(c) Li, C. J. Chem. Rev. 2005, 105, 3095–3165; (d) Lindstrom, U. M. Chem. Rev.
2002, 102, 2751.
2,4-Dimethyl-9-methoxy-4,12b-dihydro-1H,7H-chromeno[4’,3’:4,5]pyrano[2,3-d]
pyrimidine-1,3(2H)-dione (3d). mp = 228.5–229.5 °C; IR (KBr, cmꢀ1):
m = 1707,
1639; 1H NMR (500 MHz, DMSO-d6) d 3.25 (s, 3H, –NMe), 3.29 (s, 3H, –NMe),
3.70 (s, 3H, –OMe), 4.55 (s, 1H, –CH), 4.69 (d, J = 11.7 Hz, 1H, OCH), 4.81 (d, 1H,
J = 11.7 Hz, 1H, OCH), 6.54 (d, J = 7.9 Hz, 1H, HAr), 6.70 (t, J = 7.9 Hz, 1H, HAr),
6.79 (d, J = 7.9 Hz, 1H, HAr), 7.0 (s, 1 H, @CH); 13C NMR (125 MHz, DMSO-d6) d
27.3, 28.1, 28.7, 54.9, 65.3, 84.5, 110.0, 112.4, 117.4, 118.9, 127.4, 133.4, 141.9,
147.4, 149.3, 152.8, 162.0; HR-MS (70 eV, EI): C17H16N2O5 [M]+Å found
328.1057, calcd 328.1059. Elemental Anal. Calcd for (C17H16N2O5): C, 62.23;
H, 4.90; N, 8.57. Found: C, 62.10; H, 4.86; N, 8.48.
11. C17H16N2O5, colorless crystal (polyhedron), dimensions 0.23 ꢂ 0.22 ꢂ
0.15 mm3, crystal system monoclinic, space group P21/n, Z = 4, a = 4.1440(1)
Å, b = 23.7340(1) Å, c = 14.9220(1) Å,
V = 1464.37(4) Å3, = 1.489 g/cm3, T = 200(2) K, hmax = 24.11°, radiation Mo
, k = 0.71073 Å, 0.3° -scans with CCD area detector, covering a whole
sphere in reciprocal space, 3471 unique reflections (R(int) = 0.0725), 2618
observed (I > 2 (I)), intensities were corrected for Lorentz and polarization
effects, empirical absorption correction was applied using SADABS based on
the Laue symmetry of the reciprocal space, Tmin = 0.97,
= 0.11 mmꢀ1
a = 90°, b = 93.8200(10)°, c = 90°,
q
K
a
x
r
l
,
Tmax = 0.98, structure solved by direct methods and refined against F2 with a
Full-matrix least-squares algorithm using the SHELXTL-PLUS (6.10) software
package, 221 parameters refined, hydrogen atoms were treated using
appropriate riding models, goodness of fit 1.08 for observed reflections, final
residual values R1(F) = 0.057, wR(F2) = 0.129 for observed reflections, residual
electron density ꢀ0.30 to 0.27 eÅꢀ3. CCDC 687800 contains supplementary
crystallographic data for this Letter. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
9. Bashiardes, G.; Safir, I.; Barbot, F.; Laduranty, J. Tetrahedron Lett. 2004, 45, 1567.
10. General procedure for the synthesis of tetracyclic uracils:
A solution of O-
propargylated salicylaldehyde 2a–d (1 mmol), 1,3-dimethylbarbituric acid
(1.2 mmol, mg), and CuI (0.4 equiv, 76 mg) in water was heated at reflux.
The progress of the reaction was monitored by TLC. The resulting precipitated
dark yellow solid was filtered and recrystallized from ethyl acetate.
2,4-Dimethyl-4,12b-dihydro-1H,7H-chromeno[40,30:4,5]pyrano[2,3-d]pyrimidine-
1,3(2H)-dione (3a). mp = 222.5–224 °C; IR (KBr, cmꢀ1 = 1704, 1632; 1H NMR
) m
(300 MHz, CDCl3) d 3.40 (s, 3H, –NMe), 3.47 (s, 3H, –NMe), 4.63 (d, 1H,
J = 11.8 Hz, CH), 4.74 (s, 1H, CH), 4.81 (d, 1H, J = 11.8 Hz, CH), 6.65 (s, 1H, @CH),
6.80 (d, J = 8.1 Hz, 1H, HAr), 6.87 (t, J = 7.5 Hz, 1H, HAr), 7.10 (d, J = 7.5 Hz, 1H,
HAr), 7.14 (d, J = 7.5 Hz, 1H, HAr); 13C NMR (75 MHz, CDCl3) d 27.7, 28.3, 29.4,
12. (a) Yamamoto, Y. J. Org. Chem. 2007, 72, 7817; (b) Wu, P.; Fokin, V. V. Aldrichim.
Acta 2007, 40, 7; (c) Fürstner, A.; Stimson, C. C. Angew. Chem., Int. Ed. 2007, 46,
8845.