Intramolecular hetero-Diels-Alder reaction of 1-oxa-1,3-butadienes with terminal acetylenes in aqueous media using CuI

Article abstract of DOI:10.1016/j.tet.2008.08.056

A new method for the preparation of tetracyclic uracils (oxa-helicene) 4 was developed. The intramolecular hetero-Diels-Alder reaction of 1-oxa-1,3-butadiene 3 and an unactivated alkyne in the presence of CuI led to tetracyclic uracils 4 in aqueous media

Full text of DOI:10.1016/j.tet.2008.08.056

Tetrahedron 64 (2008) 10924–10929
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Intramolecular hetero-Diels–Alder reaction of 1-oxa-1,3-butadienes with
terminal acetylenes in aqueous media using CuI
,
b
b
Malihe Javan Khoshkholgh a, Saeed Balalaie a , Rolf Gleiter , Frank Rominger
*
a Department of Chemistry, K. N. Toosi University of Technology, P.O. Box 15875-4416, Tehran, Iran
b Organisch-Chemisches Institut der Universita¨t Heidelberg, Im Neuenheimer Feld 270, D-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 12 May 2008
Received in revised form 5 August 2008
Accepted 21 August 2008
Available online 27 August 2008
A new method for the preparation of tetracyclic uracils (oxa-helicene) 4 was developed. The intra-
molecular hetero-Diels–Alder reaction of 1-oxa-1,3-butadiene 3 and an unactivated alkyne in the pres-
ence of CuI led to tetracyclic uracils 4 in aqueous media with good yields. The 1-oxa-1,3-butadiene 3 was
prepared through Knoevenagel reaction of O-propargylated salicylaldehyde derivatives and barbituric
acid or 1,3-dimethylbarbituric acid.
Ó 2008 Published by Elsevier Ltd.
Keywords:
Intramolecular hetero-Diels–Alder reaction
Cuprous iodide
1,3-Oxa-butadienes
Aqueous media
Unactivated acetylene
Oxa-helicene
1. Introduction
so far.6 Recently, different Lewis acids7 provide new opportunities
for various catalytic alkyne reactions. Some of the most frequently
One of the important objectives in organic synthesis is the de-
velopment of highly efficient synthetic procedures toward complex
molecules. The hetero-Diels–Alder reaction represents one of the
most effective methods for the synthesis of heterocyclic
compounds, especially for natural products synthesis.1,2 In recent
years, intramolecular hetero-Diels–Alder (IMHDA) reactions have
been used widely in numerous reactions of prominence in organic
synthesis, because of their economical and stereocontrolled na-
ture.3 These reactions allow the formation of two or more rings at
once, avoiding sequential chemical transformations. Among these
reactions, the 1-oxa-1,3-butadiene Diels–Alder reaction provides
a means for the synthesis of pyran moieties. The 1-oxa-1,3-buta-
diene cycloaddition with dienophiles, usually an alkene, has been
described in the literature.1b,4
used transition metal catalysts are copper(I) compounds. These are
useful catalysts for a wide variety of organic transformations such
as intramolecular cyclizations,8 halogen exchange,9 [3þ2] cyclo-
additions,10and coupling reactions.11 The significant catalytic effect
of specific transition metal complexes for activating the triple bond,
made the utilization of alkynes in the hetero-Diels–Alder reaction
possible.
In this paper, a new and efficient strategy for the preparation of
the cyclic compounds 4 via the catalytic intramolecular hetero-
Diels–Alder cycloaddition of 1-oxa-1,3-butadiene derivatives 3 is
reported (Scheme 1). Reactions were carried out in the presence of
CuI (40%), and water as the solvent. The use of water as solvent has
been an active area of research in Green Chemistry and has been
usually applied for HAD reactions.12
Due to the lower reactivity of unactivated alkynes in comparison
to the corresponding alkenes, only a few examples of hetero-Diels–
Alder reactions with unactivated acetylenes have been reported.
The examples given in the literature are restricted to 1-aza-1,3-
butadienes,5 no hetero-Diels–Alder reaction of 1-oxa-1,3-butadi-
enes with unactivated alkynes has been reported; only cycloaddi-
tions of alkynes with donor–acceptor substituents were described
X
X
X
D
O
O
O
O
O
O
C
O
O
N
N
N
A
N
B
O
N
O
O
O
O
N
4
3
1
2
* Corresponding author. Fax: þ98 21 2285 3650.
E-mail address: balalaie@kntu.ac.ir (S. Balalaie).
Scheme 1. Retrosynthetic analysis of the synthesis.
0040-4020/$ – see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tet.2008.08.056

M.J. Khoshkholgh et al. / Tetrahedron 64 (2008) 10924–10929
10925
Our goal was to design an efficient way to prepare the tetracyclic
systems 4, which consist of a uracil ring (A) annulated to a dihy-
dropyran ring (B) (Scheme 1). System 3 seemed to be very suitable
for a ring closure using the Diels–Alder reaction as the key step. It
could be readily available from barbituric acid or its 1,3-dimethyl
derivatives, and O-propargylated salicylaldehyde compounds 2a–e.
2. Results and discussion
2.1. Preparation of substrates for the hetero-Diels–Alder
reaction
The O-propargylated salicylaldehydes 2a–e were prepared13
from the corresponding substituted salicylaldehydes with good to
excellent yields by applying Williamsons ether synthesis (Scheme
2).
A Knoevenagel condensation between barbituric acid or
1,3-dimethylbarbituric acid and the aldehydes 2a–e afforded
compounds 3a–i (Scheme 3, Table 2) in yields between 75 and 94%.
X-ray crystallography data confirm the structure of 3a. In Figure 1,
the molecular structure of 3a is shown.
Figure 1. ORTEP representation of the structure of 3a.
Table 1
Effect of solvent and catalyst in the hetero-Diels–Alder reaction of 3a
CHO
OH
CHO
O
K2CO3
Br
+
DMF, rt
Lewis acid
Lewis acid (%)
Solvent
Time (h)
Yield (%)
X
X
d
d
Toluene
72
24
24
24
6
24
20
20
20
20
d
d
d
d
40
45
53
68
76
84
2a-e
Ag(OTf)
AuCl3
Cu(OTf)
CuI
CuI
CuI
CuI
CuI
CuI
20
20
20
20
20
20
25
30
40
Acetonitrile
Acetonitrile
Acetonitrile
Toluene
Acetonitrile
Water
Water
Water
Water
Scheme 2. Synthesis of O-propargylated aldehydes at room temperature.
2.2. Intramolecular hetero-Diels–Alder reaction of 1-oxa-1,3-
butadienes with terminal acetylene
The intramolecular hetero-Diels–Alder reaction of several
1-oxa-1,3-butadienes with terminal acetylenes was investigated. At
first, compound 3a was used as the model system to achieve and
optimize the desired Diels–Alder reaction. Heating 3a in toluene
under reflux for 72 h did not provide our goal. After this failure, we
tried various Lewis acids; we only got satisfactory results with CuI.
By variation of CuI ratios and the solvent type, we obtained good
yields with 30 and 40% CuI and boiling water as reaction medium.
The results are summarized in Table 1.
OCH] groups in the 13C NMR spectra appear at 67 ppm and
85 ppm, respectively.
The helical shape of 4a was confirmed by X-ray crystallography
(Fig. 2). The angle between two planes is 66.3ꢀ (the angle between
the two planes C (1) N (2) C (3) C (4) C (17) N (18) and C (6) C (7) C
(8) C (9) C (10) C (11)).
It seems that the initial step is probably the formation of a
p
-complex with CuI. Research has shown that copper(I) salts can be
Using these optimized conditions, we investigated the intra-
molecular hetero-Diels–Alder reaction of compounds 3a–i (Scheme
3, Table 2). Compounds 4a–i have been prepared in 70–84% yields.
The results are summarized inTable 2. The structures of the products
were deduced from their elemental analysis and spectroscopic data.
The characteristic peaks for 4a–i in the 1H NMR spectra are an
AB quartet for the –OCH2 group between 4.6 and 4.9 ppm followed
closely by a singlet for the OCH] group. The diastereotopicity of
the two protons of the OCH2– groups is due to the helical shape of
rings A–D in 4a–i. The corresponding signals of the OCH2 and
coordinatedtothetriplebondandactasa
p
-electrophilicLewisacid.14
This complexation likely increases alkyne activity toward cyclization.
In conclusion, we have developed a general method for the
synthesis of tetracyclic uracil derivatives via the intramolecular
hetero-Diels–Alder cyclization in water. The investigation proceeds
using unactivated alkynes as dienophiles and 1-oxa-1,3-butadienes
as dienes in the presence of CuI. The research for finding novel
hetero-Diels–Alder reaction with unactivated alkynes using differ-
ent Lewis acids is still in progress in our laboratory.
X
X
O
O
O
X
O
O
R
O
CHO
O
R
O
R
O
H2O
i or ii
N
Cul (40 mol%)
H2O, Reflux
N
N
+
N
R
1
O
N
R
O
N
R
O
2a-e
3a-i
4a-i
i: R= H, 10% HCl
ii: R= Me, 20% (NH4)2HPO4
Scheme 3.

10926
M.J. Khoshkholgh et al. / Tetrahedron 64 (2008) 10924–10929
Table 2
Table 2 (continued)
Synthesis of annulated uracil derivatives using CuI
Entry
Alkene
Yield (%)
Product
Time (h) Yielda (%)
Entry
Alkene
Yield (%)
Product
Time (h) Yielda (%)
OMe
O
OMe
O
O
O
O
O
O
O
H
H
N
N
N
N
N
8
94
13
82b
1
84
20
84
O
O
N
H
O
N
H
O
N
O
O
H
O
N
O
4a
3a
4h
3h
O
O
O
O
O
O
H
O
O
N
H
H
N
72b
N
2
90
28
73
9
93
15
O
N
H
O
O
N
H
O
O
O
O
N
H
O
N
H
3b
4b
Br
O
4i
3i
Br
O
Reactions were performed with alkenes 3a–i (1 mmol) and CuI (40 mol %) in water
at reflux.
a
Yields of isolated product.
The solvent was toluene.
O
O
b
N
N
3
88
25
30
6
70
76
81
3. Experimental
3.1. General
O
N
O
O
H
N
3c
Br
O
O
4c
Br
O
Commercially available materials were used without further pu-
rification. Compounds 2a–e were prepared in excellent purity.13
Melting points were determined on an Electrothermal 9100 apparatus
and were uncorrected. IR spectra were obtained on an ABB FTIR (FTLA
2000)spectrometer.1HNMR and 13C NMRspectrawererunonBruker
DRX-300 and DRX-500 AVANCE spectrometers at 300 and 500 MHz
for 1H NMR, and 125 and 75 MHz for 13C NMR. CDCl3 and DMSO-d6
were usedassolvents. High resolution mass spectrawererecorded on
JEOL JMS-700 (HR-EI) spectrometer. Elemental analyses for C, H, and
N were performed using a Heraeus CHN–O rapid analyzer. X-ray
structure determinations were carried out on Bruker Smart (3a) and
APEX (4a) diffractometers. CCDC676951 (3a)and 635913(4a)contain
the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
O
O
H
O
N
N
4
86
O
O
N
H
O
N
H
3d
4d
O2N
O2N
O
N
O
O
N
O
5
80
O
N
O
N
O
O
4e
3e
O2N
O2N
O
N
O
O
N
O
H
O
H
6
91
10
75
O
N
H
O
N
H
O
3f
4f
OMe
O
OMe
O
O
O
N
N
7
75
10
80
O
N
O
O
N
O
3g
4g
Figure 2. ORTEP representation of the structure of 4a.

M.J. Khoshkholgh et al. / Tetrahedron 64 (2008) 10924–10929
10927
3.2. General procedure for the synthesis of starting materials
for hetero-Diels–Alder reaction
propargylated aldehydes 2a–e (1 mmol) at room temperature. Af-
ter stirring for 2–10 h, the precipitated material was filtered and
washed with water and ethanol.
3.2.1. O-Propargylation of salicylaldehyde derivatives 2a–e
3.2.2.2.1. 1,3-Dimethyl-5-{[2-(2-propynyloxy)phenyl]methylene}-
2,4,6(1H,3H,5H)-pyrimidinetrione(3a). Yellow solid, yield¼84%; mp
142.5–143.5 ꢀC; nmax (KBr) 3245, 2115, 1684; dH (300 MHz, CDCl3)
2.49 (1H, t, J 2.3 Hz, H-acetylenic), 3.3 (3H, s, NMe), 3.37 (3H, s,
NMe), 4.73 (2H, d, J 2.3 Hz, OCH2), 7.00 (2H, m, HAr), 7.45 (1H, dt, J
8.2, 1.4 Hz, HAr), 7.93 (1H, d, J 7.6 Hz, HAr), 8.79 (1H, s, ]CH); dC
(75 MHz, CDCl3) 28.3, 28.9, 56.3, 76.3, 77.8, 1141.4, 117.9, 120.6,
122.8, 132.6, 134.0, 151.4, 154.8, 157.3, 160.3, 162.4; HRMS (EI): [M]þ,
found 298.0938. C16H14N2O4 requires 298.0953.
3.2.2.2.2. 5-{[2-(2-Propynyloxy)phenyl]methylene}-2,4,6(1H,3H,5H)-
pyrimidinetrione (3b). Yellow solid, yield¼90%; mp 296–298 ꢀC;
nmax (KBr) 3281, 3203, 3060, 1742, 1663; dH (300 MHz, DMSO-d6)
3.64 (1H, d, J 1.8 Hz, H-acetylenic), 4.95 (2H, br s, OCH2), 7.01 (1H, t, J
7.6 Hz, HAr), 7.17 (1H, d, J 8.1 Hz, HAr), 7.52 (1H, t, J 8.1 Hz, HAr), 7.97
(1H, d, J 7.6 Hz, HAr), 8.45 (1H, s, ]CH), 11.18 (1H, s, NH), 11.37 (1H, s,
NH); dC (75 MHz, DMSO-d6) 56.2, 78.8, 112.3, 119.0, 120.2, 122.1,
132.5, 133.6, 149.6,150.2, 156.8,161.4, 163.3; HRMS (EI): [M]þ, found
270.0636. C14H10N2O4 requires 270.0641.
To a stirred solution of salicylaldehyde derivative (5 mmol) and po-
tassium carbonate (5 mmol, 0.069 g) in DMF (25 ml) was added prop-
argyl bromide (6 mmol, 0.071 g). After stirring for 4–24 h, water was
added and the precipitated solid was filtered and washed with water.
3.2.1.1. 2-(2-Propynyloxy)benzaldehyde (2a). White solid, yield¼
90%; mp 69–70 ꢀC (lit.15 66–68 ꢀC); nmax (KBr) 3271, 2120, 1689; dH
(300 MHz, CDCl3) 2.59 (1H, t, J 2.4 Hz, H-acetylenic), 4.86 (2H, d, J
2.4 Hz, OCH2), 7.11 (1H, t, J 7.7 Hz, HAr), 7.14 (1H, d, J 8.5 Hz, HAr),
7.60 (1H, dt, J 8.5, 1.5 Hz, HAr), 7.90 (1H, dd, J 7.7, 1.8 Hz, HAr), 10.50
(1H, d, J 0.5 Hz, HC]O); dC (75 MHz, DMSO-d6) 56.4, 78.6, 79.0,
114.3, 121.5, 124.8, 127.8, 136.2, 159.5, 188.9; HRMS (EI): [M]þ, found
160.0501. C10H8O2 requires 160.0524.
3.2.1.2. 5-Bromo-2-(2-propynyloxy)benzaldehyde (2b). White solid,
yield¼94%; mp 94–96 ꢀC (lit.15 89–91 ꢀC); nmax (KBr) 3281, 2120,
1684; dH (300 MHz, CDCl3) 2.60 (t, 1H, J 2.4 Hz, H-acetylenic), 4.84
(2H, d, J 2.4 Hz, OCH2), 7.05 (1H, d, J 8.9 Hz, HAr), 7.66 (1H, dd, J
8.9, 2.6 Hz, HAr), 7.97 (1H, d, J 2.6 Hz, HAr), 10.41 (1H, s, HC]O); dC
(75 MHz, DMSO-d6) 56.8, 78.2, 79.4, 113.4, 117.0, 126.3, 130.0,
138.2, 158.5, 187.8; HRMS (EI): [M]þ, found 237.9602. C10H7O729Br
requires 237.9625; [Mþ2]þ, found 239.9606. C10H7O821Br requires
239.9609.
3.2.2.2.3. 5-{[5-Bromo-2-(2-propynyloxy)phenyl]methylene}-1,3-
dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione
(3c). Yellow
solid,
yield¼88%; mp 156–156.5 ꢀC (decomp.); nmax (KBr) 3260, 2115,
1679; dH (300 MHz, CDCl3) 2.56 (1H, br s, H-acetylenic), 3.36 (3H, s,
NMe), 3.43 (3H, s, NMe), 4.77 (2H, d, J 2.1 Hz, OCH2), 6.97 (1H, d, J
8.9 Hz, HAr), 7.58 (1H, dd, J 8.9, 2.3 Hz, HAr), 8.08 (1H, d, J 2.3 Hz,
HAr), 8.69 (1H, s, ]CH); dC (75 MHz, DMSO-d6) 28.0, 28.5, 56.6, 78.4,
79.1, 111.7, 114.7, 120.2, 124.4, 133.9, 135.2, 148.4, 151.1, 155.6, 160.1,
161.8; HRMS (EI): [M]þ, found 376.0058. C16H13N2O749Br requires
376.0059; [MþH]þ, found 378.0027. C16H13N2O481Br requires
378.0038.
3.2.1.3. 5-Nitro-2-(2-propynyloxy)benzaldehyde (2c). White solid,
yield¼92%; mp 91.5–93 ꢀC; nmax (KBr) 3245, 2125, 1684; dH
(300 MHz, CDCl3) 2.68 (1H, t, J 2.4 Hz, H-acetylenic), 4.99 (2H, d, J
2.4 Hz, OCH2), 7.30 (1H, d, J 9.2 Hz, HAr), 8.47 (1H, dd, J 9.2, 2.9 Hz,
HAr), 8.47 (1H, d, J 2.9 Hz, HAr), 10.48 (1H, s, HC]O); dC (75 MHz,
DMSO-d6) 57.4, 77.6, 80.0,115.2,123.6,124.4,130.6,141.3,163.3,187.6;
HRMS (EI): [M]þ, found 205.0356. C10H7NO4 requires 205.0375.
3.2.2.2.4. 5-{[5-Bromo-2-(2-propynyloxy)phenyl]methylene}-
2,4,6(1H,3H,5H)-pyrimidinetrione (3d). Yellow solid, yield¼86%;
mp 226–228 ꢀC; nmax (KBr) 3291, 3204, 3091, 2115, 1740, 1684; dH
(300 MHz, DMSO-d6) 3.67 (1H, s, H-acetylenic), 4.96 (2H, s, OCH2),
7.15 (1H, d, J 8.9 Hz, HAr), 7.68 (1H, d, J 8.9 Hz, HAr), 8.09 (1H, s, HAr),
8.28 (1H, s, ]CH), 11.24 (1H, s, NH), 11.42 (1H, s, NH); dC (75 MHz,
DMSO-d6) 56.5, 78.4, 79.1,11.7, 114.7, 120.4, 124.2,134.2, 135.2,147.3,
150.2, 155.7, 161.4, 163.0; HRMS (EI): [M]þ, found 347.9742.
C14H9N2O749Br requires 347.9746; [Mþ2]þ, found 349.9717.
C14H9N2O481Br requires 349.9725.
3.2.2.2.5. 1,3-Dimethyl-5-{[5-nitro-2-(2-propynyloxy)phenyl]-
methylene}2,4,6(1H,3H,5H)-pyrimidinetrione (3e). Yellow solid,
yield¼80%; mp 177–178.6 ꢀC; nmax (KBr) 3286, 2125, 1689, 1519,
1350; dH (300 MHz, CDCl3) 2.63 (1H, t, J 2.3 Hz, H-acetylenic), 3.36
(3H, s, NMe), 3.44 (3H, s, NMe), 4.90 (2H, d, J 2.3 Hz, OCH2), 7.19 (1H,
d, J 9.2 Hz, HAr), 8.37 (1H, dd, J 9.2, 2.8 Hz, HAr), 8.67 (1H, s, ]CH),
8.81 (1H, d, J 2.8 Hz, HAr); dC (75 MHz, CDCl3) 28.5, 29.0, 57.0, 76.4,
77.5, 11.9, 120.3, 123.2, 128.0, 128.0, 128.2, 141.1, 151.0, 151.4, 159.8,
160.7, 161.5; HRMS (EI): [M]þꢂ found 343.0784. C16H13N3O6 requires
343.0804.
3.2.2.2.6. 5-{[5-Nitro-2-(2-propynyloxy)phenyl]methylene}2,4,6
(1H,3H,5H)-pyrimidinetrione (3f). Yellow solid, yield¼91%; mp
236–238 ꢀC; nmax (KBr) 3286, 3209, 3082, 2115, 1745, 1684, 1537,
1355; dH (300 MHz, DMSO-d6) 3.46 (1H, s, H-acetylenic), 5.12 (2H,
s, OCH2), 7.38 (1H, d, J 9.3 Hz, HAr), 8.26 (1H, s, ]CH), 8.40 (1H, d, J
9.3 Hz, HAr), 8.81 (1H, s, ]CH), 11.30 (1H, s, NH), 11.46 (1H, s, NH);
dC (75 MHz, DMSO-d6) 57.3, 77.9, 79.7, 113.0, 121.7, 122.6, 127.8,
128.0, 140.3, 146.2, 150.2, 160.9, 161.4, 162.8; HRMS (EI): [M]þ,
found 315.0453. C14H9N3O6 requires 315.0492.
3.2.2.2.7. 1,3-Dimethyl-5-{[3-methoxy-2-(2-propynyloxy)phenyl]-
methylene}-2,4,6(1H,3H,5H)-pyrimidinetrione (3g). Yellow solid,
yield¼75%; mp 131–132 ꢀC, nmax (KBr) 3258, 2116, 1684; dH
(500 MHz, DMSO-d6) 3.14 (3H, s, NMe), 3.22 (3H, s, NMe), 3.48 (1H,
t, J 4 Hz, H-acetylenic), 3.84 (3H, s, OMe), 4.77 (2H, d, J 4 Hz, OCH2),
3.2.1.4. 3-Methoxy-2-(2-propynyloxy)benzaldehyde (2d). White solid,
yield¼80%; mp 51–52.5 ꢀC (lit.16 oil); nmax (KBr) 3271, 2125, 1684; dH
(500 MHz, CDCl3) 2.52 (1H, t, J 2.4 Hz, H-acetylenic), 3.96 (3H, s, OMe),
4.93 (2H, d, J 2.4 Hz, OCH2), 7.22 (2H, m, HAr), 7.51 (1H, dd, J 1.9, 7.4 Hz,
HAr), 10.54 (1H, s, HC]O); dC (75 MHz, DMSO-d6) 56.1, 60.5, 78.8, 79.6,
117.9, 118.6, 125.1, 130.5, 148.9, 152.8, 189.9; HRMS (EI): [M]þ, found
190.0645. C14H10O3 requires 190.0630.
3.2.1.5. 2-(2-Propynyloxy)-1-naphthaldehyde
(2e). Red-brown
solid, yield¼72%; mp 109.5–110.5 ꢀC (lit.16 116 ꢀC); nmax (KBr, cmꢁ1
)
3248, 2119, 1656; dH (500 MHz, CDCl3) 2.63 (1H, t, J 2.4 Hz, H-
acetylenic), 5.0 (2H, d, J 2.4 Hz, OCH2), 7.43 (1H, d, J 9.1 Hz, HAr), 7.50
(1H, dt, J 1.0, 7.6 Hz, HAr), 7.68 (1H, dt, J 1.3, 7.6 Hz, HAr), 7.84 (1H, d, J
8.1 Hz, HAr), 8.12 (1H, d, J 9.1 Hz, HAr), 9.32 (1H, d, J 8.1 Hz, HAr),
10.95 (1H, s, HC]O); dC (75 MHz, DMSO-d6) 57.4, 78.6, 79.3, 115.2,
116.8, 124.0, 125.0, 128.6, 129.8, 130.5, 137.6, 162.0, 191.2; HRMS (EI):
[M]þ, found 210.0692. C14H10O2 requires 210.0681.
3.2.2. The synthesis of the uracil derivatives
3.2.2.1. Procedure A: preparation of the uracil derivatives at room
temperature (3a, c, e, g). To a stirred solution of N,N0-dime-
thylbarbituric acid (187 mg, 1.2 mmol) in water (20 ml) containing
(NH4)2HPO4 (20 mol %, 0.014 g) were added propargylated aldehydes
2a–c (1 mmol) at room temperature. After stirring for 4–15 h, the
yellow precipitated was filtered and washed with water and ethanol.
3.2.2.2. Procedure B: preparation of the uracil derivatives at room
temperature (3b, d, f, h, i). To a stirred solution of barbituric acid
(153 mg, 1.2 mmol) in aqueous HCl (25 ml, 10%) were added

10928
M.J. Khoshkholgh et al. / Tetrahedron 64 (2008) 10924–10929
7.11 (1H, t, J 8.3 Hz, HAr), 7.20 (1H, d, J 8.3 Hz, HAr), 7.41 (1H, d, J
8.3 Hz, HAr), 8.59 (1H, s, ]CH); dC (75 MHz, DMSO-d6) 28.2, 28.7,
56.2, 59.8, 78.9, 79.2, 116.5, 120.7, 123.5, 123.6, 128.5, 145.9, 150.5,
151.0, 152.1, 151.2, 163.5; HRMS (EI): [M]þ, found 328.1058.
C17H16N2O5 requires 328.1059.
3.2.2.2.8. 5-{[3-Methoxy-2-(2-propynyloxy)phenyl]methylene}-
2,4,6(1H,3H,5H)-pyrimidinetrione (3h). Yellow solid, yield¼94%;
mp 197–199 ꢀC; nmax (KBr) 3271, 3122, 3060, 2120, 1745, 1684; dH
(500 MHz, DMSO-d6) 3.51 (1H, t, J 2.3 Hz, H-acetylenic), 3.86 (3H, s,
OMe), 4.79 (2H, d, J 2.3 Hz, OCH2), 7.12 (1H, t, J 7.7 Hz, HAr), 7.22 (1H,
d, J 7.7 Hz, HAr), 7.49 (1H, d, J 7.7 Hz, HAr), 8.52 (1H, s, ]CH), 11.18
(1H, s, NH), 11.38 (1H, s, NH); dC (75 MHz, DMSO-d6) 55.9, 59.8, 78.8,
79.1, 116.0, 120.2, 123.3, 123.5, 128.1, 145.7, 150.2, 150.8, 151.8, 161.1,
163.0; HRMS (EI): [M]þ, found 300.0746. C15H16N2O5 requires
300.0732.
3.2.2.2.9. 5-{[2-(2-Propynyloxy)-1-naphthyl]methylene}-2,4,6-
(1H,3H,5H)-pyrimidinetrione (3i). Red solid, yield¼93%; mp 157–
159 ꢀC; nmax (KBr) 3510, 3502, 3271, 2118, 1679; dH (300 MHz,
DMSO-d6) 3.60 (1H, t, J 2.2 Hz, H-acetylenic), 4.94 (1H, d, J 16.2 Hz,
CHO), 5.02 (1H, d, J 16.2 Hz, CHO), 7.41 (1H, dt, J 7.5,1.0 Hz, HAr), 7.46
(1H, dt, J 1.0, 7.5 Hz, HAr), 7.53 (1H, d, J 9 Hz, HAr), 7.68 (1H, d, J
7.5 Hz, HAr), 7.91 (1H, d, J 7.5 Hz, HAr), 8.05 (1H, d, J 9 Hz, HAr), 8.52
(1H, s, ]CH), 11.11 (1H, s, NH), 11.44 (1H, s, NH); dC (75 MHz, DMSO-
d6) 56.9, 78.6, 79.2,114.3, 118.4, 123.1,124.1,127.1, 128.3, 128.4, 130.7,
131.6, 148.5, 150.3, 153.0, 160.6, 162.6; HRMS (EI): [M]þ, found
320.0797. C18H12N2O4 requires 320.0797.
CH), 4.84 (1H, d, 1H, J 11.6 Hz, –CH), 6.72 (1H, d, J 8.5 Hz, HAr), 7.12
(2H, s, HAr and ]CH), 7.25 (1H, d, J 8.5 Hz, HAr); dC (75 MHz, CDCl3)
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; HRMS (EI): [M]þ, found 376.0064.
C16H13N2O749Br requires 376.0059; [Mþ2]þ, found 376.0030.
C16H13N2O481Br requires 376.0039.
3.3.4. 11-Bromo-4,12b-dihydro-1H,7H-chromeno[40,30:4,5]pyrano-
[2,3-d]pyrimidine-1,3(2H)-dione(4d)
Following general procedure C in water, compound 4d was
produced (264.5 mg, 76%) as a dark yellow solid; mp 295–297 ꢀC;
[Found: C, 48.07; H, 2.53; N, 7.96. C14H9N2O4Br requires C, 48.16; H,
2.60; N, 8.02%.] nmax (KBr) 3115, 3004, 1699, 1627; dH (500 MHz,
DMSO-d6) 4.56 (1H, s, –CH), 4.67 (1H, d, J 11.5 Hz, CH), 4.78 (1H, d, J
11.5 Hz, CH), 6.71 (1H, d, J 8.7 Hz, HAr), 7.04 (1H, s, ]CH), 7.23 (1H, s,
HAr), 7.25 (1H, d, J 8.7 Hz, HAr), 11.28 (1H, s, NH), 11.90 (1H, s, NH);
HRMS (EI): [M]þ, found 347.9710. C14H9N2O749Br requires 347.9746;
[Mþ2]þ, found 349.9692. C14H9N2O481Br requires 347.9725.
3.3.5. 2,4-Dimethyl-11-nitro-4,12b-dihydro-1H,7H-chromeno-
[40,30:4,5]pyrano[2,3-d]pyrimidine-1,3(2H)-dione (4e)
Following general procedure C in water, compound 4e was
produced (302.2 mg, 81%) as a dark yellow solid; mp 254–255 ꢀC;
[Found: C, 55.75; H, 3.69; N, 12.08. C16H13N3O6 requires C, 55.98; H,
3.79; N, 12.24%.] nmax (KBr) 1704, 1638, 1521, 1340; dH (300 MHz,
DMSO-d6) 3.27 (3H, s, NMe), 3.30 (3H, s, NMe), 4.77 (1H, s, CH), 4.86
(1H, d, J 11.6 Hz, CH), 4.98 (1H, d, J 11.6 Hz, CH), 6.95 (1H, d, J 9.0 Hz,
HAr), 7.18 (1H, s, ]CH), 7.97 (1H, s, HAr), 8.02 (1H, d, J 8.0, HAr); dC
(75 MHz, DMSO-d6) 28.6, 29.5, 30.0, 67.6, 85.2, 111.0, 118.0, 124.0,
124.5,128.0,136.4,140.8,150.5,154.4,159.8,163.6; HRMS (EI): [M]þ,
found 343.0805. C16H13N3O6 requires 373.0804.
3.3. General procedure C for the intramolecular hetero-Diels–
Alder reaction
A solution of compound 4a–i (1 mmol), CuI (0.4 equiv, 76 mg) in
water (25 ml) or toluene was heated to reflux for 6–30 h. The
progress of reaction was monitored by TLC. The precipitated dark
yellow solid was filtered and recrystallized in ethyl acetate.
3.3.6. 11-Nitro-4,12b-dihydro-1H,7H-chromeno[40,30:4,5]pyrano-
[2,3-d]pyrimidine-1,3(2H)-dione (4f)
Following general procedure C in water, compound 4f was
produced (236.2 mg, 75%) as a dark yellow solid; mp >350 ꢀC
(decomp.); [Found: C, 53.28; H, 2.69; N,13.21. C14H9N3O6 requires C,
53.34; H, 2.88; N, 13.33%.] nmax (KBr) 1699, 1632, 1530, 1350; dH
(500 MHz, DMSO-d6) 4.69 (1H, s, CH), 4.82 (1H, d, J 11.6 Hz, CH),
4.93 (1H, d, J 11.6 Hz, CH), 6.94 (1H, d, J 8.7 Hz, HAr), 7.12 (1H, s,
]CH), 8.01 (1H, d, J 8.7 Hz, HAr), 8.11 (1H, s, HAr), 11.39 (1H, s, NH),
11.96 (1H, s, NH); HRMS (EI): [M]þ, found 315.0488. C14H9N3O6
requires 315.0491.
3.3.1. 2,4-Dimethyl-4,12b-dihydro-1H,7H-chromeno[40,30:4,5]-
pyrano[2,3-d]pyrimidine-1,3(2H)-dione (4a)
Following general procedure C in water, compound 4a was
produced (250.4 mg, 84%) as a dark primrose solid; mp 222.5–
224 ꢀC; [Found: C, 64.25; H, 4.60; N, 9.28. C16H14N2O4 requires C,
64.42; H, 4.73; N, 9.39%.] nmax (KBr) 1704, 1632; dH (300 MHz,
CDCl3) 3.40 (3H, s, NMe), 3.47 (3H, s, NMe), 4.63 (1H, d, J 11.8 Hz,
CH), 4.74 (1H, s, CH), 4.81 (1H, d, J 11.8 Hz, CH), 6.65 (1H, s, ]CH),
6.80 (1H, d, J 8.1 Hz, HAr), 6.87 (1H, t, J 7.5 Hz, HAr), 7.10 (2H, m, HAr);
dC (75 MHz, CDCl3) 27.7, 28.3, 29.4, 65.8, 85.7, 113.0, 116.1, 120.1,
125.6, 126.1, 127.3, 132.8, 149.7, 152.5, 152.8, 162.6; HRMS (EI): [M]þ,
found 298.0926. C16H14N2O4 requires 298.0953.
3.3.7. 2,4-Dimethyl-9-methoxy-4,12b-dihydro-1H,7H-chromeno-
[40,30:4,5]pyrano[2,3-d]pyrimidine-1,3(2H)-dione (4g)
Following general procedure C in water, compound 4g was
produced (262.5 mg, 80%) as a poor red solid; yield¼80%; mp
228.5–229.5 ꢀC; [Found: C, 62.10; H, 4.86; N, 8.48. C17H16N2O5 re-
quires C, 62.23; H, 4.90; N, 8.57%.] nmax (KBr) 1707, 1639; dH
(500 MHz, DMSO-d6) 3.25 (3H, s, NMe), 3.26 (3H, s, NMe), 3.70 (3H,
s, OMe), 4.55 (1H, s, CH), 4.69 (1H, d, J 11.7 Hz, CH), 4.81 (1H, d, J
11.7 Hz, CH), 6.54 (1H, d, J 7.9 Hz, HAr), 6.70 (1H, t, J 7.9 Hz, HAr), 6.79
(1H, d, J 7.9 Hz, HAr), 7.03 (1H, s, ]CH); dC (125 MHz, DMSO-d6) 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; HRMS (EI): [M]þ, found 328.1057.
C17H16N2O5 requires 328.1059.
3.3.2. 4,12b-Dihydro-1H,7H-chromeno[40,30:4,5]pyrano[2,3-d]pyrimidine-
1,3(2H)-dione (4b)
Following general procedure C in water, compound 4b was
produced (197.2 mg, 73%) as a dark yellow solid; mp 265–267 ꢀC;
[Found: C, 62.13; H, 3.70; N, 10.26. C14H10N2O4 requires C, 62.23; H,
3.73; N,10.37%.] nmax (KBr) 1735,1699; dH (500 MHz, DMSO-d6) 4.50
(1H, s, CH), 4.64 (1H, d, J 10.7 Hz, –CH), 4.77 (1H, d, J 10.7 Hz, –CH),
6.71 (1H, d, J 7.2 Hz, HAr), 6.78 (1H, s, ]CH), 7.05 (3H, m, HAr), 11.24
(1H, s, NH), 11.83 (1H, s, NH); HRMS (EI): [M]þ, found 270.0628.
C14H10N2O4 requires 270.0641.
3.3.8. 9-Methoxy-4,12b-dihydro-1H,7H-chromeno[40,30:4,5]pyrano-
[2,3-d]pyrimidine-1,3(2H)-dione(4h)
3.3.3. 11-Bromo-2,4-dimethyl-4,12b-dihydro-1H,7H-chromeno-
[40,30:4,5]pyrano[2,3-d]pyrimidine-1,3(2H)-dione (4c)
Following general procedure C in toluene, compound 4b was
produced (264.0 mg, 82%) as a dark yellow solid; mp 266.5–268 ꢀC;
[Found: C, 59.78; H, 4.00; N, 9.16. C15H12N2O5 requires C, 60.00; H,
4.03; N, 9.33%.] nmax (KBr) 3276, 3194, 1751, 1640; dH (500 MHz,
DMSO-d6) 3.71 (3H, s, OMe), 4.47 (1H, s, CH), 4.66 (1H, d, J 11.7 Hz,
CH), 4.77 (1H, d, J 11.7 Hz, CH), 6.63 (1H, d, J 7.8 Hz, HAr), 6.74 (1H, t, J
Following general procedure C in water, compound 4c was
produced (263.2 mg, 70%) as a dark yellow solid; mp 240.5–242 ꢀC;
[Found: C, 50.75; H, 3.38; N, 7.18. C16H13N2O4Br requires C, 50.95; H,
3.47; N, 7.43%.] nmax (KBr) 1709, 1642; dH (300 MHz, DMSO-d6) 3.26
(3H, s, NMe), 3.27 (3H, s, NMe), 4.63 (1H, s, CH), 4.71 (1H, d, J 11.6 Hz,

M.J. Khoshkholgh et al. / Tetrahedron 64 (2008) 10924–10929
10929
7.8 Hz, HAr), 6.81 (1H, d, J 7.8 Hz, HAr), 6.97 (1H, s, ]CH),11.23 (1H, s,
References and notes
NH), 11.83 (1H, s, NH); dC (125 MHz, DMSO-d6) 29.45, 56.4, 67.0,
86.0, 111.4, 113.6, 119.1, 120.6, 129.0., 135.1, 143.5, 148.9, 150.4, 155.6,
165.8; HRMS (EI): [M]þ, found 300.0702. C15H12N2O5 requires
300.0747.
1. (a) Nicolaou, K. C.; Snyder, S. A.; Vassilikogiannakis, G.; Montagnon, T. Angew.
Chem., Int. Ed. 2002, 41, 1668–1698 and references cited therein; (b) Tietze, L. F.;
Kettschau, G. Top. Curr. Chem. 1997, 189, 1–120; (c) J4rgensen, K. A. Eur. J. Org.
Chem. 2004, 2093–2102; (d) Palacios, F.; Herran, E.; Rubiales, G.; Ezpeleta, J. M.
J. Org. Chem. 2002, 67, 2131–2135; (e) Behforouz, M.; Ahmadian, M. Tetrahedron
2000, 56, 5259–5288.
2. (a) Osborn, H. M. I.; Coisson, D. Mini Rev. Org. Chem. 2004, 1, 41–45; (b) Schmidt,
R. R. Acc. Chem. Res. 1986, 19, 250–259; (c) Kende, A. S.; Fan, J.; Chen, Z. Org. Lett.
2003, 5, 3205–3208; (d) Crimmins, M. T.; Smith, A. C. Org. Lett. 2006, 8 1003–
1006; (e) Hughes, R. A.; Thompson, S. P.; Alcaraz, L.; Moody, C. J. J. Am. Chem.
Soc. 2005, 127, 15644–15651; (f) Chao, W.; Mahajan, Y. R.; Weinreb, S. M.
Tetrahedron Lett. 2006, 47, 3815–3818.
3. (a) Amos, D. T.; Renslo, A. R.; Danheiser, R. L. J. Am. Chem. Soc. 2003, 125, 4970–
4971; (b) Bland, D. C.; Raudenbush, B. C.; Weinreb, S. M. Org. Lett. 2000, 2,
4007–4009; (c) Ho, T.-L.; Kung, L.-R.; Chein, R.-J. J. Org. Chem. 2000, 65, 5774–
5779; (d) Snyder, S. A.; Vosburg, D. A.; Jarvis, M. G.; Markgral, J. H. Tetrahedron
2000, 56, 5329–5335; (e) Thomas, E. J. Acc. Chem. Res. 1991, 24, 229–235; (f)
Tanaka, N.; Suzuki, T.; Hosoya, Y.; Nakada, M. Tetrahedron Lett. 2007, 48, 6488–
6492.
3.3.9. 7,8-Naphtyl-4,12b-dihydro-1H,7H-chromeno[40,30:4,5]
pyrano[2,3-d]pyrimidine-1,3(2H)-dione (4i)
Following general procedure C in toluene, compound 4i was
produced (230.4 mg, 72%) as a dark red solid; mp 243–244.5 ꢀC;
[Found: C, 67.04; H, 3.56; N, 8.55. C18H12N2O4 requires C, 67.54; H,
3.78; N, 8.75%.] nmax (KBr) 3178, 3019, 1720, 1617; dH (500 MHz,
DMSO-d6) 4.66 (1H, s, CH), 4.73 (1H, d, 1H, J 12.7 Hz, CH), 4.93 (1H,
d, J 12.7 Hz, CH), 6.94 (1H, s, ]CH), 7.25 (1H, t, J 7.4 Hz, HAr), 7.3 (1H,
t, J 7.4 Hz, HAr), 7.35 (1H, d, J 7.7 Hz, HAr), 7.75 (1H, d, J 8.1 Hz, HAr),
7.81 (d, 1H, J 7.7 Hz, HAr), 7.98 (1H, d, J 8.1 Hz, HAr), 11.30 (1H, s, NH),
11.98 (1H, s, NH); dC (125 MHz, DMSO-d6) 28.3, 66.7, 85.6, 116.5,
119.1, 121.9, 125.0, 125.6, 128.3, 129.1, 131.2, 133.3, 149.2, 153.1, 155.2,
164.1; HRMS (EI): [M]þ, found 320.0781. C18H12N2O4 requires
320.0797.
4. Tietze, L. F.; Rackelman, N. In Multicomponent Reactions; Zhu, J., Bienayme, H.,
Eds.; Wiley-VCH: Weinheim, Germany, 2005; pp 121–167.
5. (a) Palacios, F.; Alonso, C.; Ameezua, P.; Rubiales, G. J. Org. Chem. 2002, 67, 1941–
1946; (b) Zhou, H.-B.; Liu, G.-S.; Yao, Z.-J. Org. Lett. 2007, 9, 2003–2006; (c)
Twin, H.; Batey, R. A. Org. Lett. 2004, 6, 4913–4916; (d) Boger, D. L.; Corbett, W.
L. J. Org. Chem. 1993, 58, 2068–2074; (e) Lu, J.-Y.; Arndt, H.-D. J. Org. Chem. 2007,
72, 4205–4212.
6. (a) Dell, C. P. Tetrahedron Lett. 1992, 33, 699–700; (b) Mantani, T.; Konno, T.;
Ishihara, T.; Yamanaka, H. Chem. Lett. 2000, 666–667; (c) Back, T. G.; Bethell,
R. J.; Parvez, M.; Taylor, J. A.; Wehrli, D. J. Org. Chem. 1999, 64, 7426–7432.
7. (a) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180–3211; (b) Zhang, L.; Sun, J.;
Kozmin, S. A. Adv. Synth. Catal. 2006, 348 2271–2296; (c) Asao, N.; Sato, K.;
Yamamoto, Y. J. Org. Chem. 2005, 70, 3682–3685; (d) Asao, N.; Yudha, S.; No-
gami, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2005, 44, 5526–5528; (e) Ermolat,
D. S.; Mehta, V. P.; Eycken, E. V. V. Synlett 2007, 3117–3122; (f) Alonso, F.;
Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104 3079–3159.
8. (a) Chen, Ch.; Dormer, P. G. J. Org. Chem. 2005, 70, 6964–6967; (b) Evindar, G.;
Batey, R. J. Org. Chem. 2006, 71, 1802–1808; (c) Patil, N. T.; Yamamoto, Y. J. Org.
Chem. 2004, 69, 5139–5142; (d) Zhu, W.; Ma, D. Chem. Commun. 2004, 888–889.
9. Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 14844–14845.
10. (a) Sreedhar, B.; Reddy, P. S.; Kumar, N. S. Tetrahedron Lett. 2006, 47, 3055–3058;
(b) Jin, T.; Kamijo, S.; Yamamoto, Y. Eur. J. Org. Chem. 2004, 3789–3791; (c) Bock,
V. D.; Hiemstra, H.; Maarseveen, J. H. Eur. J. Org. Chem. 2006, 51–68.
11. (a) Black, D. A.; Arndtsen, B. A. Org. Lett. 2004, 6, 1107–1110; (b) Rao, H.; Jin, Y.;
Fu, H.; Jiang, Y.; Zhao, Y. Chem.dEur. J. 2006, 12, 3636–3646; (c) Cho, S. H.; Yoo,
E. J.; Bae, I.; Chang, S. J. Am. Chem. Soc. 2005, 127, 16046–16047; (d) Zhu, W.; Ma,
D. Org. Lett. 2006, 8, 261–263.
3.4. Crystal structure
3.4.1. Crystal data of the 3a
Compound 3a: (CCDC 676951) C16H14N2O4, yellow crystals,
triclinic, P1, Z¼2, a¼3.9693(1) Å, b¼11.4451(1) Å, c¼15.3766(3) Å,
a
¼81.049(1)ꢀ,
b
¼88.767(1)ꢀ,
g
¼87.394(1)ꢀ, V¼689.25(2) Å3,
Dcal¼1.44 g/cm3,
m
¼0.10 m mꢁ1, 6929 reflections collected, 3108
independent (Rint¼0.0360), 2195 observed, R1¼0.048, wR2¼
0.105(I>2s(I)).
3.4.2. Crystal data of the 4a
Compound 4a: (CCDC 635913) C16H14N2O4, colorless
crystals, monoclinic, P21/n, Z¼4, a¼4.2581(9) Å, b¼21.678(5) Å,
c¼14.571(3) Å,
a
¼90ꢀ,
b
¼92.391(6)ꢀ,
g
¼90ꢀ. V¼1343.8(5) Å3,
Dcal¼1.47 g/cm3,
m
¼0.11 m mꢁ1, 6280 reflections collected, 2810 in-
dependent
wR2¼0.149(I>2
(Rint¼0.0361),
(I)).
1871
observed,
R1¼0.064,
12. (a) Grieco, P. A. Organic Synthesis in Water; Blacky academic & professional:
London, 1998; pp 82–141; (b) Li, C. J.; Chan, T. H. Organic Reaction in
Aqueous Media; Wiley: New York, NY, 1997; (c) Li, C. J. Chem. Rev. 2005,
105, 3095–3165.
13. Bashiardes, G.; Safir, I.; Barbot, F.; Laduranty, J. Tetrahedron Lett. 2004, 45, 1567–
1570.
14. (a) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H. Eur. J. Org. Chem. 2006, 51–
68; (b) Yamamoto, Y. J. Org. Chem. 2007, 72, 7817–7831.
15. Janietz, D.; Rudorf, W. D. Tetrahedron 1989, 45, 1661–1666.
s
Acknowledgements
S.B. is grateful to the Alexander von Humboldt foundation for
the research fellowship and equipment donation. Partial support of
this work by the K. N. Toosi University of Technology Research
Council is appreciatively acknowledged.
16. Mathur, S. S.; Suschitzky, H. J. Chem. Soc., Perkin Trans. 1 1975, 2479–2483.