A comprehensive study of the heterocyclizations of N-arylmaleimides and 6-aminouracils

Article abstract of DOI:10.1055/s-0030-1260163

Heterocyclization reactions between N-arylmaleimides and 6-aminouracils were studied in detail. It was established that several directions are possible depending on the nature of reaction medium and the substituent character in the uracil component. The synthetic procedure leading to N-phenyl-2,4,7- trioxopyrido[2,3-d]pyrimidine-5-carboxamides in good-to-high yields was developed and key stages of the corresponding reaction were established. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1260163

PAPER
3161
A Comprehensive Study of the Heterocyclizations of N-Arylmaleimides and
6-Aminouracils
Roman V. Rudenko,a Sergey A. Komykhov,*a Sergey M. Desenko,a,b Yulia V. Sen’ko,a Oleg V. Shishkin,a,b
Irina S. Konovalova,a Svetlana V. Shishkina,a Valentin A. Chebanov*a
a
State Scientific Institution, ‘Institute for Single Crystals’ of National Academy of Sciences of Ukraine, Lenin Ave. 60, 61001 Kharkiv,
Ukraine
Fax +38(57)3410273; E-mail: komykhov@isc.kharkov.com; E-mail: chebanov@isc.kharkov.com
Karazin Kharkiv National University, Svobody sq. 4, 61077 Kharkiv, Ukraine
b
Received 31 May 2011; revised 8 July 2011
synthetic analogue of maleimides, yields pyrrolo[4,3-
Abstract: Heterocyclization reactions between N-arylmaleimides
c]pyridines III or IV.9
and 6-aminouracils were studied in detail. It was established that
several directions are possible depending on the nature of reaction
medium and the substituent character in the uracil component. The
synthetic procedure leading to N-phenyl-2,4,7-trioxopyrido[2,3-
d]pyrimidine-5-carboxamides in good-to-high yields was devel-
oped and key stages of the corresponding reaction were established.
In our previous research it was shown that in the reaction
of maleimides with 3-amino-1,2,4-triazole depending on
the solvent applied the formation of either triazolo[4,3-
c]pyridine V or triazolo[1,5-a]pyridine VI11 (Scheme 1)
was observed, while the reactions involving substituted 3-
aminopyrazoles led to pyrazolo[4,3-b]pyridines VII or
pyrazolo[1,5-a]pyrimidines VIII.12
Key words: heterocycles, nucleophilic addition, ring opening, py-
ridines, pyrroles, annulation, regioselectivity
Thus, synthetic approaches based on reactions of dinu-
cleophiles and maleimides seem to be quite convenient for
the preparation of new pyridine and pyrimidine deriva-
tives. On the other hand, such methods are not sufficiently
developed which makes study in this area promising.
Fused heterocyclic systems containing partially hydroge-
nated pyridine and pyrimidine moieties possess different
types of biological activity1 and, therefore, are of interest
as potential objects for investigations in medicinal chem-
istry. Important systems of this kind are derivatives of py-
ridopyrimidines based on 6-aminouracils, which can be
synthesized by their condensation with different unsatur-
ated carbonyl compounds or with CH acids and alde-
hydes.2
In the present article we disclose our recent results regard-
ing the behavior of N-arylmaleimides in their reactions
with substituted 6-aminouracils.
It was found that the reaction of 6-aminouracil (1a;
R1 = R2 = H) with maleimide 2b (Scheme 2) carried out
under conditions described by Velchinskaya et al.,10 by re-
fluxing in ethanol or propan-2-ol for 10 hours, yielded
quantitatively only the starting 6-aminouracil. No com-
pound like II (Scheme 1) was found in the reaction medi-
um. In our opinion, it can be explained both by the low
temperature of the medium being insufficient for the reac-
tion to proceed and by the poor solubility of 6-aminouracil
(1a) in these alcohols.
N-Substituted maleimides are well-known polyelectro-
philic compounds, which can react either as dienophiles/
dipolarophiles with dienes/1,3-dipoles or as 1,2- and 1,3-
dinucleophiles with different mono- and dinucleophiles.
From the viewpoint of synthetic organic chemistry, the re-
actions of maleimides as 1,2- or 1,3-dinucleophiles lead-
ing to several classes of heterocyclic compounds are of
special interest. However, only a relatively small number
of such transformations were described. Among them the
heterocyclization of maleimides with thiourea and its de-
rivatives are most frequently encountered3 while there are
only a few examples of reactions with another dinucleo-
philes. For example, the reactions involving o-amino-
thiophenols,4 2,4-diamino-5-hydroxypyrimidines,5 alipha-
tic 1,4-diamines,6 2-mercapto-1,2,4-triazole,7 3-amino-
crotonates8 have been described. It is also known that the
reaction of 6-aminouracils and maleimides leads either to
Michael adducts I9 (Scheme 1) or to compounds II
formed with participation of an exocyclic amino group.10
In turn, similar reaction with maleic anhydride, being a
The same reactions of aminouracil (1a) carried out in boil-
ing acetonitrile, under conditions described by Cobo et
al.,9 also allowed to isolate only the starting materials. On
the other hand, in the case of 1b after 12 hours of heating,
the formation of a mixture of several products was ob-
served. Three of them were identified as compounds 3, 4,
and 5 (Scheme 2) in ca. 1:1:1 ratio.
In order to improve yields and selectivity, we studied the
reaction specified in solvents with different nature, specif-
ically acetic acid and N,N-dimethylformamide.
The outcome of the reaction between 6-aminouracils and
maleimides in acetic acid depended on the nature of R1
and R2 substituents in the azine component. Thus, reflux-
ing of equimolar mixture of aminouracil (1a) and N-phe-
nylmaleimide (2a) in acetic acids for eight hours led to the
isolation of a mixture of fused pyridine derivative 3a and
SYNTHESIS 2011, No. 19, pp 3161–3167
x
x.
x
x
.
2
0
1
1
Advanced online publication: 09.08.2011
DOI: 10.1055/s-0030-1260163; Art ID: T56611SS
© Georg Thieme Verlag Stuttgart · New York

3162
R. V. Rudenko et al.
PAPER
O
O
R2
X
O
N
HN
O
O
O
N
R3
NH2
R1
N
R1
N
R2
N
X
N
H
NH2
HN
R1
O
O
N
O
MeCN
i-PrOH
X
N
H
N
H
X
N
R3
NH2
O
II
I
HO
O
OH
O
O
O
O
O
O
O
O
O
O
O
O
R1
X
R1
2
Me
N
O
N
N
O
O
MeCN
MeCN
N
H
N
H
O
N
N
R2
X
N
R2
NH2
Me
IV
III
R1, R2 = H, Me; X = O, S
H
Ar
N
Ar
N
H
N
O
N
N
O
N
Ar
O
Ar
O
O
O
O
O
H
N
N
N
N
NH2
N
AcOH, DMF, Δ
i-PrOH, 1,4-dioxane, Δ
N
N
N
H
N
H
VI
V
R3
NH
R3
R3
N
R3
N
O
O
N
NH
R2
R1
O
O
O
O
N
N
N
N
NH2
R2
N
R1
AcOH, Δ
DMF, Δ
N
O
R2
N
H
O
H
VII
VIII
Scheme 1 Some examples of the reactions of maleimides (maleic anhydride) with 6-aminouracils and aminoazoles
the adduct 5a in a 1:2 ratio in a general yield of 20% These experimental facts allow us to propose that the re-
(Scheme 2). In the mother liquor sufficient amounts of the action takes place by an attack of the C=C bond of male-
starting materials were found as well.
imide at the CH reaction center of 6-aminouracil with
formation of adduct 5 and its further recyclization into the
target compound 3 as key steps of the reaction studied.
Reaction of 1,3-dimethyl-6-aminouracil (1b) and N-aryl-
maleimides 2a,c,f,g under the same conditions allowed to
obtain a mixture of pyrimidopyridones 3f–i and pyrimi- The structures of compounds 3, 4, and 5 were established
dopyrrolones 4f–i in a 4:1 ratio while treatment involving with help of elemental analyses, MS, and NMR (1H and
aminouracils 1c,d (R1 = H, R2 = Bn or PhCH2CH2) yield- 13C) spectra. For instance, the mass spectra of 3a–q and 5a
ed fused pyrimidines 3k–q as sole reaction products.
contain peaks of molecular ions, while their elemental
analyses confirms the quantitative content of the com-
pounds synthesized.
The best results from the viewpoint of yields, selectivity,
and universality of the procedure were obtained when the
reaction studied was carried out in N,N-dimethylform- 1H NMR spectra of compounds 3 exhibit signals being
amide. Heterocyclization of 6-aminouracils 1a,b with typical for the ABX system with AB part at 2.60–2.90
maleimides 2a–h in boiling N,N-dimethylformamide for ppm, while the chemical shift of X-proton is within 3.80–
three hours led to the formation of pyrimidopyridones 3a–j 4.06 ppm, broad singlets at 9.0–11.5 ppm corresponding
in 54–68% yields (Scheme 2, Table 1).
to NH protons, signals of aromatic protons, and their ter-
minal substituents. The spectra of heterocycles 4, which
were not isolated in individual state, are very similar to the
spectra described above for compounds 3; however, AB
part of ABX spin system shifted downfield to 2.60–2.80
ppm while the doublet of doublet of X proton shifted up-
field to 3.60–3.70 ppm.
It was also found that decreasing the duration of the reac-
tion of 6-aminouracil (1a) with N-phenylmaleimide (2a)
in N,N-dimethylformamide led to the formation of mix-
tures of pyrimidopyridone 3a and compound 5a. The
same treatment carried out for 15 minutes yielded mainly
Michael adduct 5a followed with impurities of starting
materials and compound 3a (up to 10%). Additionally, ad- However, these spectral data are insufficient to make a fi-
duct 5a underwent recyclization into heterocycle 3a by nal decision about the structure of the compounds ob-
heating in N,N-dimethylformamide for three hours.
tained. In addition several NOE experiments were carried
out, which showed differences in the spatial location of
Synthesis 2011, No. 19, 3161–3167 © Thieme Stuttgart · New York

PAPER
Heterocyclizations of N-Arylmaleimides and 6-Aminouracils
3163
O
H
O
N
R3
O
O
N
Ph
R1 = R2 = H
HN
HN
+
O
N
H
N
H
O
N
H
O
O
NH2
3a
5a
20%
R3
H
N
HN
O
O
R3
O
R3
N
O
O
R1
O
Me
O
Me
AcOH, Δ
R
1 = R2 = Me
N
N
N
O
O
O
+
+
3 h
N
H
N
N
H
O
O
N
N
NH2
R2
Me
Me
3f–j
52–80%
R3
4f–j
1a–d
2a–k
H
N
O
O
R1 = H; R2 = Bn or
2 = CH2CH2Ph
R1
R
N
O
N
R2
N
O
H
3k–q
63–73%
DMF, Δ
3a–j 54–68%
1a,b
+
2a–h
3h
O
R1 = R2 = H;
3 = H
R
O
N
Ph
DMF, Δ
DMF, Δ
3 h
HN
O
15 min
O
N
NH2
H
5a
Scheme 2
methine CH and amide NH for heterocycles 3 and 4 mation with deviation of the N3 atom from mean plane of
(Figure 1).
remaining atoms of ring by 0.08 Å. Such a nonplanar
geometry of the uracil fragment is caused by its high con-
formational flexibility.14
The 1H NMR spectra of 5a contain, in addition to signals
of an ABX system, aromatic protons and other substitu-
ents, a broad singlet of NH2 group at 6.36 ppm, which The substituent at the C3 atom has axial orientation and is
confirms that the reaction proceeds with participation of turned to a relatively bicyclic fragment [the C10–C3–C4–
uracil CH but not with the NH2 reaction center.
C5 and C4–C3–C10–O4 torsion angles are –96.3(3)° and
106.8(3)°, respectively]. Such orientation of this substitu-
ent is stabilized additionally by formation of intramolecu-
lar hydrogen bond N4-H···O3 (H···O 2.14 Å N-H···O
143°). Difluoro-substituted phenyl ring has an ap-confor-
mation relative to the C3–C10 bond [the C11–N4–C10–
The structure of heterocycles 3 was also proven with the
help of X-ray diffraction data obtained for compound 3j
(Figure 2).
The X-ray diffraction study reveals that the tetrahydropy-
ridone ring of bicyclic fragment adopts an intermediate
conformation between chair and twist-boat, which is typ-
ical for this ring13 conformation. Deviations of the C1 and
C2 atoms from the mean plane of remaining atoms of the
ring are 0.26 Å and 0.63 Å, respectively. Tetrahydropy-
dropyrimidindione ring adopts a flattened chair confor-
X
Ph
O
HN Ph
HN
O
O
H
H
Me
O
Me
O
O
O
N
N
N
N
N
N
O
H
H
Me
Me
3f
4f
Figure 2 Molecular structure of compound 3j (X-ray diffraction
data)
Figure 1 Some data of NOE experiments for compounds 3f and 4f
Synthesis 2011, No. 19, 3161–3167 © Thieme Stuttgart · New York

3164
R. V. Rudenko et al.
PAPER
Table 1 Synthesis of Compounds 3a–q
6-Aminouracil 1 R1 R2
N-Arylmaleimide 2 R3
Product
3a
Yield (%)
54a
1a
H
H
2a
2b
2c
2d
2e
2a
2f
Ph
1a
H
H
4-ClC6H4
2,4-Me2C6H3
4-MeO-3-ClC6H3
4-CF3C6H4
Ph
3b
3c
58a
1a
H
H
62a
1a
H
H
3d
3e
60a
1a
H
H
65a
1b
Me
Me
Me
Me
Me
H
Me
3f
57a
1b
Me
2-MeOC6H4
2,4-Me2C6H3
4-MeOC6H4
3,4-F2C6H3
Ph
3g
68a
1b
Me
2c
2g
2h
2a
2f
3h
3i
59a
1b
Me
58a
1b
Me
3j
64a
1c
Bn
3k
3l
70b
63b
71b
73b
63b
65b
66b
1c
H
Bn
2-MeOC6H4
2-ClC6H4
2,4-Cl2C6H3
Ph
1c
H
Bn
2i
3m
3n
3o
1c
H
Bn
2j
1d
H
PhCH2CH2
PhCH2CH2
PhCH2CH2
2a
2f
1d
H
2-MeOC6H4
2-FC6H4
3p
3q
1d
H
2k
a Reaction in DMF.
b Reaction in AcOH.
Varian 1200L (ionizing voltage 70 eV). Elemental analysis was
made on a EuroVector EA-3000. TLC analyses were performed on
precoated (silica gel 60 HF254) plates. All solvents and chemicals
were obtained from standard commercial vendors and were used
without any additional purification.
C3 torsion angle is 178.4(2)°] and is noncoplanar to car-
bamide fragment [the C10–N4–C11–C12 torsion angle is
27.2(4)°] in spite of the presence of the weak hydrogen
bond C12–H···O2 (H···O 2.42 Å C–H···O 115°).
In summary, the heterocyclizations between N-arylmale-
imides and 6-aminouracils were studied in detail. An in-
fluence of the reaction parameters and the structure of the
azine component on their directions were established. It
was found that the treatment carried out in low-boiling
solvents like ethanol, propan-2-ol, or acetonitrile deliv-
ered either no product or complicated mixtures. The reac-
tion in boiling acetic acid can yield several different
compounds and their mixtures depending on the substitu-
ents character in aminouracil. Application of N,N-dimeth-
N-Aryl-2,4,7-trioxo-1,2,3,4,5,6,7,8-octahydropyrido[2,3-d]pyri-
midine-5-carboxamides 3a–q; General Procedure
A mixture of the 6-aminouracil 1 (0.003 mol) and the corresponding
N-arylmaleimide 2 (0.003 mol) in the noted solvent (3 mL, Table 1)
was heated at reflux for 3 h. After cooling, the precipitate formed
was filtered and if needed recrystallized from acetone, and air dried
(Table 1).
N-Phenyl-2,4,7-trioxo-1,2,3,4,5,6,7,8-octahydropyrido[2,3-
d]pyrimidine-5-carboxamide (3a)
Colorless solid; mp >300 °C.
ylformamide as
a
medium to carry out the
2
1H NMR (200 MHz, DMSO-d6): d = 2.59 (dd, JAB = 16.7 Hz,
heterocyclization permitted obtaining individual N-aryl-
2,4,7-trioxopyrido[2,3-d]pyrimidine-5-carboxamides in
good-to-high yields. 6-Amino-5-(2,5-dioxo-1-arylpyrro-
lidin-3-yl)pyrimidine-2,4-diones were found to be the in-
termediates of the reaction studied that allowed to propose
the key stages.
3JAX = 0.9 Hz, 1 H, 6-Ha), 2.92 (dd, 3JBX = 7.7 Hz, 1 H, 6-Hb), 3.82
(dd, 1 H, 5-Hx), 7.03–7.53 (m, 5 Harom), 9.89 (br s, 1 H, NH), 9.5–
10.5 (br s, 2 H, NH), 11.03 (br s, 1 H, NHpyr).
13C NMR (50 MHz, DMSO-d6): d = 170.4, 168.4, 162.9, 149.7,
147.3, 137.3, 128.2, 126.8, 120.7, 84.9, 35.7, 32.8.
MS (EI, 70 eV): m/z (%) = 300 (2, [M+]), 180 (100), 179 (76), 151
(53).
Melting points were obtained on a standard melting point apparatus
in open capillary tubes. The 1H and 13C NMR spectra were recorded
in DMSO-d6 at 200 MHz (50 MHz for 13C) on Varian Mercury VX-
200 spectrometers. Mass spectra were measured on a GC-MS
Anal. Calcd for C14H12N4O4: C, 56.00; H, 4.03; N, 18.66. Found: C,
55.9; H, 4.1; N, 18.7.
Synthesis 2011, No. 19, 3161–3167 © Thieme Stuttgart · New York

PAPER
Heterocyclizations of N-Arylmaleimides and 6-Aminouracils
3165
N-(4-Chlorophenyl)-2,4,7-trioxo-1,2,3,4,5,6,7,8-octahydropyri-
do[2,3-d]pyrimidine-5-carboxamide (3b)
Yellow solid; mp >300 °C.
1,3-Dimethyl-2,4,7-trioxo-N-phenyl-1,2,3,4,5,6,7,8-octahydro-
pyrido[2,3-d]pyrimidine-5-carboxamide (3f)
Colorless solid; mp 275–276 °C.
2
2
1H NMR (200 MHz, DMSO-d6): d = 2.59 (dd, JAB = 15.7 Hz,
1H NMR (200 MHz, DMSO-d6): d = 2.62 (dd, JAB = 16.3 Hz,
3JAX = 1.3 Hz, 1 H, 6-Ha), 2.90 (dd, 3JBX = 7.7 Hz, 1 H, 6-Hb), 3.19
(s, 3 H, CH3), 3.38 (s, 3 H, CH3), 3.93 (dd, 1 H, 5-Hx), 7.00–7.55 (m,
5 Harom), 9.86 (br s, 1 H, NH), 10.53 (br s, 1 H, NHpyr).
3JAX = 1.3 Hz, 1 H, 6-Ha), 2.93 (dd, 3JBX = 7.5 Hz, 1 H, 6-Hb), 3.80
(dd, 1 H, 5-Hx), 7.32–7.60 (m, 4 Harom), 10.04 (br s, 1 H, NH), 9.6–
10.4 (br s, 2 H, NH), 11.03 (br s, 1 H, NHpyr).
13C NMR (50 MHz, DMSO-d6): d = 170.2, 168.5, 163.0, 149.6,
147.1, 138.4, 128.3, 123.1, 119.1, 85.1, 35.6, 32.9.
13C NMR (50 MHz, DMSO-d6): d = 170.1, 169.7, 161.1, 150.5,
147.3, 138.4, 128.3, 123.2, 119.3, 86.8, 36.5, 33.0, 30.0, 27.5.
MS (EI, 70 eV): m/z (%) = 335 (2, [M+ – 1]), 333 (2, [M+ – 1]), 179
MS (EI, 70 eV): m/z (%) = 327 (2), 328 (3, [M+ – 1]), 208 (6).
(29), 178 (67), 150 (59), 149 (32).
Anal. Calcd for C16H16N4O4: C, 58.53; H, 4.91; N, 17.06. Found: C,
58.5; H, 5.1; N, 17.0.
Anal. Calcd for C14H11ClN4O4: C, 50.24; H, 3.31; N, 16.74. Found:
C, 50.1; H, 3.3; N, 16.8.
N-(2-Methoxyphenyl)-1,3-dimethyl-2,4,7-trioxo-1,2,3,4,5,6,7,8-
octahydropyrido[2,3-d]pyrimidine-5-carboxamide (3g)
Colorless solid; mp 265–266 °C.
N-(2,4-Dimethylphenyl)-2,4,7-trioxo-1,2,3,4,5,6,7,8-octahydro-
pyrido[2,3-d]pyrimidine-5-carboxamide (3c)
Colorless solid; mp 275–276 °C.
1H NMR (200 MHz, DMSO-d6): d = 2.11 (s, 3 H, CH3), 2.22 (s, 3
H, CH3), 2.65 (dd, 2JAB = 16.4 Hz, 3JAX = 1.3 Hz, 1 H, 6-Ha), 2.83
(dd, 3JBX = 7.6 Hz, 1 H, 6-Hb), 3.87 (dd, 1 H, 5-Hx), 6.9–7.44 (m, 3
Harom), 9.04 (br s, 1 H, NH), 9.7–10.3 (br s, 2 H, NH), 11.09 (br s, 1
H, NHpyr).
2
1H NMR (200 MHz, DMSO-d6): d = 2.67 (dd, JAB = 16.4 Hz,
3JAX = 3.3 Hz, 1 H, 6-Ha), 2.75 (dd, 3JBX = 5.6 Hz, 1 H, 6-Hb), 3.24
(s, 3 H, CH3), 3.37 (s, 3 H, CH3), 3.83 (s, 3 H, CH3O), 4.06 (dd, 1
H, 5-Hx), 6.85–8.05 (m, 4 Harom), 9.16 (br s, 1 H, NH), 10.54 (br s,
1 H, NHpyr).
13C NMR (50 MHz, DMSO-d6): d = 169.7, 169.6, 161.4, 150.3,
148.4, 146.8, 127.5, 123.5, 120.2, 119.7, 111.2, 86.5, 55.8, 35.9,
31.9, 30.0, 27.5.
MS (EI, 70 eV): m/z (%) = 358 (3), 357 (18, [M+ – 1]), 208 (7), 207
(45), 206 (100), 149 (16), 148 (19).
13C NMR (50 MHz, DMSO-d6): d = 169.9, 168.7, 163.4, 149.8,
147.2, 133.5, 133.4, 130.4, 129.6, 126.1, 122.9, 85.1, 35.0, 32.5,
20.0, 17.0.
MS (EI, 70 eV): m/z (%) = 327 (2, [M+ – 1]), 326 (3, [M+ – 2]), 179
(33), 178 (100), 177 (74), 150 (73), 149 (60).
Anal. Calcd for C17H18N4O5: C, 56.98; H, 5.06; N, 15.63. Found: C,
57.1; H, 4.9; N, 15.7.
Anal. Calcd for C16H16N4O4: C, 58.53; H, 4.91; N, 17.06. Found: C,
58.6; H, 5.1; N, 17.0.
N-(2,4-Dimethylphenyl)-1,3-dimethyl-2,4,7-trioxo-
1,2,3,4,5,6,7,8-octahydropyrido[2,3-d]pyrimidine-5-carbox-
amide (3h)
N-(3-Chloro-4-methoxyphenyl)-2,4,7-trioxo-1,2,3,4,5,6,7,8-oc-
tahydropyrido[2,3-d]pyrimidine-5-carboxamide (3d)
Yellow solid; mp >300 °C.
Colorless solid; mp 269–270 °C.
2
1H NMR (200 MHz, DMSO-d6): d = 2.58 (dd, JAB = 17.2 Hz,
1H NMR (200 MHz, DMSO-d6): d = 2.11 (s, 3 H, CH3), 2.23 (s, 3
H, CH3), 2.70 (dd, 2JAB = 16.0 Hz, 3JAX = 1.3 Hz, 1 H, 6-Ha), 2.84
(dd, 3JBX = 7.2 Hz, 1 H, 6-Hb), 3.22 (s, 3 H, CH3), 3.37 (s, 3 H, CH3),
3.95 (dd, 1 H, 5-Hx), 6.9–7.4 (m, 3 Harom), 9.0 (br s, 1 H, NH), 10.5
(br s, 1 H, NHpyr).
13C NMR (50 MHz, DMSO-d6): d = 169.7, 169.6, 161.28, 161.27,
150.4, 147.1, 133.4, 130.4, 129.7, 126.1, 123.0, 86.8, 35.8, 32.6,
30.0, 27.4, 20.0, 17.0.
3JAX = 1.3 Hz, 1 H, 6-Ha), 2.92 (dd, 3JBX = 8.0 Hz, 1 H, 6-Hb), 3.76
(dd, 1 H, 5-Hx), 3.80 (s, 3 H, CH3O), 7.06–7.72 (m, 3 Harom), 9.91
(br s, 1 H, NH), 9.7–10.4 (br s, 2 H, NH), 11.0 (br s, 1 H, NHpyr).
13C NMR (50 MHz, DMSO-d6): d = 170.1, 168.8, 163.5, 149.8,
148.6, 145.5, 136.1, 121.0, 120.6, 119.3, 113.0, 85.3, 55.1, 35.3,
32.6.
MS (EI, 70 eV): m/z (%) = 364 (2, [M+]), 180 (27), 142 (100), 114
(50).
MS (EI, 70 eV): m/z (%) = 356 (2), 355 (3, [M+ – 1]), 207 (61), 206
(100), 149 (14), 148 (13).
Anal. Calcd for C15H13ClN4O5: C, 49.39; H, 3.59; N, 15.36. Found:
C, 49.4; H, 3.6; N, 15.2.
Anal. Calcd for C18H20N4O4 (%): C, 60.66; H, 5.66; N, 15.72.
Found: C, 60.7; H, 5.6; N, 15.8.
2,4,7-Trioxo-N-[4-(trifluoromethyl)phenyl]-1,2,3,4,5,6,7,8-oc-
tahydropyrido[2,3-d]pyrimidine-5-carboxamide (3e)
Colorless solid; mp >300 °C.
N-(4-Methoxyphenyl)-1,3-dimethyl-2,4,7-trioxo-1,2,3,4,5,6,7,8-
octahydropyrido[2,3-d]pyrimidine-5-carboxamide (3i)
Colorless solid; mp 279–280 °C.
2
1H NMR (200 MHz, DMSO-d6): d = 2.63 (dd, JAB = 17.0 Hz,
3JAX = 1.3 Hz, 1 H, 6-Ha), 2.95 (dd, 3JBX = 8.2 Hz, 1 H, 6-Hb), 3.84
(dd, 1 H, 5-Hx), 7.63–7.78 (m, 4 Harom), 10.29 (br s, 1 H, NH), 9.8–
10.5 (br s, 2 H, NH), 11.04 (br s, 1 H, NHpyr).
1H NMR (200 MHz DMSO-d6): d = 2.61 (dd, JAB = 16.3 Hz,
2
3JAX = 1.4 Hz, 1 H, 6-Ha), 2.89 (dd, 3JBX = 7.6 Hz, 1 H, 6-Hb), 3.19
(s, 3 H, CH3), 3.37 (s, 3 H, CH3), 3.70 (s, 3 H, CH3O), 3.88 (dd, 1
H, 5-Hx), 6.83–7.47 (m, 4 Harom), 9.71 (br s, 1 H, NH), 10.54 (br s,
1 H, NHpyr).
13C NMR (50 MHz, DMSO-d6): d = 171.0, 168.4, 163.0, 149.7,
147.4, 142.0, 126.6, 125.0 (1 C, q, 1JCF = 271.2 Hz, CF3), 124.4 (1
C, q, 2JCF = 32.2 Hz, CCF3), 120.1, 85.8, 36.8, 33.8.
MS (EI, 70 eV): m/z (%) = 368 (2, [M+]), 367 (3), 180 (25), 179
(100), 150 (38).
13C NMR (50 MHz, DMSO-d6): d = 169.65, 169.6, 161.0, 155.3,
150.5, 147.2, 131.6, 120.9, 113.7, 86.9, 55.0, 36.3, 33.1, 30.0, 27.4.
MS (EI, 70 eV): m/z (%) = 358 (7), 357 (30, [M+ – 1]), 356 (28), 208
(5), 207 (56), 206 (100), 149 (51), 148 (64).
Anal. Calcd for C15H11F3N4O4: C, 48.92; H, 3.01; N, 15.21. Found:
C, 49.1; H, 3.0; N, 15.3.
Anal. Calcd for C17H18N4O5: C, 56.98; H, 5.06; N, 15.63. Found: C,
57.1; H, 5.1; N, 15.6.
Synthesis 2011, No. 19, 3161–3167 © Thieme Stuttgart · New York

3166
R. V. Rudenko et al.
PAPER
N-(3,4-Difluorophenyl)-1,3-dimethyl-2,4,7-trioxo-
1,2,3,4,5,6,7,8-octahydropyrido[2,3-d]pyrimidine-5-carbox-
amide (3j)
13C NMR (50 MHz, DMSO-d6): d = 169.9, 169.6, 162.1, 150.0,
148.4, 147.5, 135.9, 128.3, 127.5, 127.0, 126.0, 123.7, 120.2, 119.7,
111.1, 87.7, 55.9, 43.8, 35.4, 31.8.
Colorless solid; mp 282–283 °C.
MS (EI, 70 eV): m/z (%) = 420 (2, [M+]), 270 (4), 269 (9), 178 (7),
91 (100).
1H NMR (200 MHz, DMSO-d6): d = 2.63 (dd, JAB = 16.3 Hz,
2
3JAX = 1.4 Hz, 1 H, 6-Ha), 2.91 (dd, 3JBX = 7.8 Hz, 1 H, 6-Hb), 3.18
(s, 3 H, CH3), 3.38 (s, 3 H, CH3), 3.89 (dd, 1 H, 5-Hx), 7.22–7.80 (m,
3 Harom), 10.14 (br s, 1 H, NH), 10.55 (br s, 1 H, NHpyr).
Anal. Calcd for C22H20N4O5: C, 62.85; H, 4.79; N, 13.33. Found: C,
62.9; H, 4.7; N, 13.4.
13C NMR (50 MHz, DMSO-d6): d = 170.3, 169.3, 160.8, 150.3,
148.6 (1 C, dd, 1JCF = 244 Hz, 2JCF = 13.3 Hz, CAr), 147.2, 145.2 (1
C, dd, 1JCF = 242 Hz, 2JCF = 12.3 Hz, CAr), 135.3 (1 C, dd, 3JCF = 9.4
1-Benzyl-N-(2-chlorophenyl)-2,4,7-trioxo-1,2,3,4,5,6,7,8-oc-
tahydropyrido[2,3-d]pyrimidine-5-carboxamide (3m)
Colorless solid; mp 291–292 °C.
2
Hz, 4JCF = 3.1 Hz, CAr), 116.8 (1 C, dd, JCF = 17.7 Hz, 3JCF = 1.0
2
1H NMR (200 MHz, DMSO-d6): d = 2.68 (dd, JAB = 16.5 Hz,
Hz, CAr), 115.6 (1 C, dd, 3JCF = 5.1 Hz, 4JCF = 3.1 Hz, CAr), 108.3 (1
C, d, 2JCF = 21.9 Hz, CAr), 86.5, 36.4, 32.8, 29.9, 27.3.
MS (EI, 70 eV): m/z (%) = 364 (3, [M+]), 208 (56), 207 (100), 150
3JAX = 2.0 Hz, 1 H, 6-Ha), 2.83 (dd, 3JBX = 7.1 Hz, 1 H, 6-Hb), 4.06
(dd, 1 H, 5-Hx), 5.13 (d, 2JAB = 17.0 Hz, 1 H, CH-2a), 5.33 (d, 2JAB
=
17.0 Hz, 1 H, CH-2b), 7.1–8.0 (m, 9 Harom), 9.37 (br s, 1 H, NH),
10.53 (br s, 1 H, NH), 11.65 (br s, 1 H, NH).
(51), 148 (64).
Anal. Calcd for C16H14F2N4O4: C, 52.75; H, 3.87; N, 15.38. Found:
C, 52.7; H, 3.8; N, 15.5.
13C NMR (50 MHz, DMSO-d6): d = 170.1, 169.8, 162.2, 150.1,
147.7, 135.9, 134.7, 129.1, 128.3, 127.3, 127.0, 126.0, 125.3, 124.1,
123.3, 87.4, 43.8, 35.4, 31.9.
X-ray Structural Analysis of 3j15
MS (EI, 70 eV): m/z (%) = 424 (2, [M+]), 272 (11), 271 (17), 270
The colorless crystals of 3j (C16H14F2N4O4) are triclinic. At 293 K,
a = 8.205(3), b = 8.977(3), c = 12.096(4) Å, a = 90.30(2)°,
b = 109.68(3)°, g = 110.04(3)°, V = 780.7(4) Å3, Mr = 364.31,
Z = 2, space group P1, dcalc = 1.550 g/cm3, m(MoKa) = 0.129 mm–1,
F(000) = 376. Intensities of 5770 reflections (2671 independent,
Rint = 0.057) were measured on the ‘Xcalibur-3’ diffractometer
(graphite monochromated MoKa radiation, CCD detector, w-scan-
ning, 2qmax = 50°). The structure was solved by direct method us-
ing SHELXTL package.16 Positions of the hydrogen atoms were
located from electron density difference maps and refined by
‘riding’ model with Uiso = nUeq of the carrier atom (n = 1.5 for me-
thyl groups and n = 1.2 for other hydrogen atoms). Full-matrix
least-squares refinement against F2 in anisotropic approximation
for non-hydrogen atoms using 2635 reflections was converged to
wR2 = 0.099 (R1 = 0.045 for 1397 reflections with F >4s(F),
S = 0.861).
(32), 180 (17), 127 (100), 126 (56), 101 (18), 77 (44).
Anal. Calcd for C21H17ClN4O4: C, 59.37; H, 4.03; N, 13.19. Found:
C, 59.3; H, 4.1; N, 13.0
1-Benzyl-N-(2,4-dichlorophenyl)-2,4,7-trioxo-1,2,3,4,5,6,7,8-oc-
tahydropyrido[2,3-d]pyrimidine-5-carboxamide (3n)
Colorless solid; mp 300–301 °C.
2
1H NMR (200 MHz, DMSO-d6): d = 2.70 (dd, JAB = 16.4 Hz,
3JAX = 1.3 Hz, 1 H, 6-Ha), 2.81 (dd, 3JBX = 7.2 Hz, 1 H, 6-Hb), 4.06
(dd, 1 H, 5-Hx), 5.14 (d, 2JAB = 17.2 Hz, 1 H, CH-2a), 5.32 (d, 2JAB
=
17.2 Hz, 1 H, CH-2b), 7.18–8.01 (m, 8 Harom), 9.4 (br s, 1 H, NH),
10.47 (br s, 1 H, NH), 11.58 (br s, 1 H, NH).
13C NMR (50 MHz, DMSO-d6): d = 169.9, 169.5, 162.0, 149.9,
147.6, 135.8, 134.6, 128.9, 128.1, 127.1, 126.9, 125.9, 125.1, 123.9,
123.1, 87.3, 43.7, 35.3, 31.8.
MS (EI, 70 eV): m/z (%) = 458 (5, [M+]), 460 (2), 272 (13), 271
(12), 270 (100), 180 (47), 154 (18), 153 (28), 91 (98).
1-Benzyl-2,4,7-trioxo-N-phenyl-1,2,3,4,5,6,7,8-octahydropyri-
do[2,3-d]pyrimidine-5-carboxamide (3k)
Colorless solid; mp 295–296 °C.
Anal. Calcd for C21H16Cl2N4O4: C, 54.92; H, 3.51; N, 12.2. Found:
C, 54.8; H, 3.45; N, 12.3.
2
1H NMR (200 MHz, DMSO-d6): d = 2.56 (dd, JAB = 16.5 Hz,
3JAX = 0.9 Hz, 1 H, 6-Ha), 2.92 (dd, 3JBX = 7.7 Hz, 1 H, 6-Hb), 3.91
(dd, 1 H, 5-Hx), 5.16 (d, 2JAB = 17.2 Hz, 1 H, CH2a), 5.36 (d, 2JAB
=
N-Phenyl-2,4,7-trioxo-1-(2-phenylethyl)-1,2,3,4,5,6,7,8-octahy-
dropyrido[2,3-d]pyrimidine-5-carboxamide (3o)
Colorless solid; mp 278–279 °C.
17.2 Hz, 1 H, CH2b), 7.01–7.57 (m, 10 Harom), 9.93 (br s, 1 H, NH),
10.52 (br s, 1 H, NH), 11.51 (br s, 1 H, NH).
2
1H NMR (200 MHz, DMSO-d6): d = 2.54 (dd, JAB = 16.2 Hz,
13C NMR (50 MHz, DMSO-d6): d = 170.0, 169.7, 161.6, 150.1,
147.9, 138.4, 135.9, 128.3, 128.2, 127.0, 126.0, 123.2, 119.2, 88.0,
43.7, 35.9, 32.8.
MS (EI, 70 eV): m/z (%) = 389 (2, [M+ – 1]), 270 (4), 269 (14), 268
(100), 178 (16).
3JAX = 1.2 Hz, 1 H, 6-Ha), 2.78 (dd, 3JBX = 7.1 Hz, 1 H, 6-Hb), 2.83
(t, 3J = 7.1 Hz, 2 H, CH2), 3.87 (dd, 1 H, 5-Hx), 4.21 (m, 2 H, CH2),
6.98–7.52 (m, 10 Harom), 9.77 (br s, 1 H, NH), 10.48 (br s, 1 H, NH),
11.30 (br s, 1 H, NH).
13C NMR (50 MHz, DMSO-d6): d = 169.9, 169.6, 161.6, 149.8,
147.8, 138.4, 137.5, 128.6, 128.3, 127.9, 126.0, 123.1, 119.2, 87.6,
42.1, 35.7, 33.3, 32.6.
Anal. Calcd for C21H18N4O4 (%): C, 64.61; H, 4.65; N, 14.35.
Found: C, 64.3; H, 4.6; N, 14.3
MS (EI, 70 eV): m/z (%) = 404 (2, [M+]), 284 (7), 283 (15), 282
(23), 180 (2), 179 (10), 178 (27), 177 (21), 100 (100).
1-Benzyl-2,4,7-trioxo-N-(2-methoxyphenyl)-1,2,3,4,5,6,7,8-oc-
tahydropyrido[2,3-d]pyrimidine-5-carboxamide (3l)
Colorless solid, mp 288–289 °C.
Anal. Calcd for C22H20N4O4: C, 65.34; H, 4.98; N, 13.85. Found: C,
65.3; H, 5.1; N, 13.7.
2
1H NMR (200 MHz, DMSO-d6): d = 2.67 (dd, JAB = 16.4 Hz,
3JAX = 2.0 Hz, 1 H, 6-Ha), 2.75 (dd, 3JBX = 6.6 Hz, 1 H, 6-Hb), 3.83
(s, 3 H, CH3O), 4.03 (dd, 1 H, 5-Hx), 5.13 (d, 2JAB = 17.1 Hz, 1 H,
CH2a), 5.32 (d, 2JAB = 17.1 Hz, 1 H, CH2b), 6.85–8.08 (m, 9 Harom),
9.12 (br s, 1 H, NH), 10.41 (br s, 1 H, NH), 11.56 (br s, 1 H, NH).
N-(2-Methoxyphenyl)-2,4,7-trioxo-1-(2-phenylethyl)-
1,2,3,4,5,6,7,8-octahydropyrido[2,3-d]pyrimidine-5-carbox-
amide (3p)
Colorless solid; mp 282–283 °C.
1H NMR (200 MHz, DMSO-d6): d = 2.66 (m, 2 H, 6-Ha + Hb), 2.81
(t, 3J = 7.3 Hz, 2 H, CH2), 3.82 (s, 3 H, CH3O), 3.98 (dd,
Synthesis 2011, No. 19, 3161–3167 © Thieme Stuttgart · New York

PAPER
Heterocyclizations of N-Arylmaleimides and 6-Aminouracils
3167
3J = 6.6, 2.2 Hz, 1 H, 5-Hx), 4.16 (m, 2 H, CH2), 6.87–8.07 (m, 9
arom), 9.12 (br s, 1 H, NH), 10.50 (br s, 1 H, NH), 11.48 (br s, 1 H,
NH).
13C NMR (50 MHz, DMSO-d6): d = 169.7, 169.5, 161.9, 149.6,
148.3, 147.3, 137.4, 128.5, 127.8, 127.5, 126.0, 123.4, 120.1, 119.6,
111.2, 87.2, 55.8, 42.0, 35.2, 33.3, 31.6.
1986, 104, 207298. (e) Tsuda, Y.; Mishina, T.; Obata, M.;
H
Araki, K.; Inui, J.; Nakamura, T. Japanese Patent JP
61227584, 1986; Chem. Abstr. 1988, 109, 120988.
(f) Tsuda, Y.; Mishina, T.; Obata, M.; Araki, K.; Inui, J.;
Nakamura, T. European Patent EP 0217142, 1987; Chem.
Abstr. 1987, 106, 213976. (g) Atwal, K. S.; Vaccaro, W.;
Lloyd, J.; Finlay, H.; Yan, L.; Bhandaru, R. S. Patent WO
0140231, 2001; Chem. Abstr. 2003, 135, 19660. (h) Atwal,
K. S.; Moreland, S. Bioorg. Med. Chem. Lett. 1991, 1, 291.
(i) Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043.
(j) Ram, V. J.; Goel, A.; Sarkhel, S.; Maulik, P. R. Bioorg.
Med. Chem. 2002, 10, 1275. (k) Tenser, R. B.; Gaydos, A.;
Hay, K. A. Antimicrob. Agents Chemother. 2001, 45, 3657.
(l) Gready, J. E.; McKinlay, C.; Gebauer, M. G. Eur. J. Med.
Chem. 2003, 38, 719.
MS (EI, 70 eV): m/z (%) = 434 (2, [M+]), 284 (12), 283 (17), 282
(10), 180 (2), 179 (5), 103 (93), 102 (96), 101 (100).
Anal. Calcd for C23H22N4O5: C, 63.59; H, 5.10; N, 12.90. Found: C,
63.5; H, 5.2; N, 13.0
N-(2-Fluorophenyl)-2,4,7-trioxo-1-(2-phenylethyl)-
1,2,3,4,5,6,7,8-octahydropyrido[2,3-d]pyrimidine-5-carbox-
amide (3q)
(2) See, for example: (a) Quiroga, J.; Insuasty, B.; Sanchez, A.
J. Heterocycl. Chem. 1992, 29, 1045. (b) Rodrigues, R.;
Suarez, M.; Ochoa, E. J. Heterocycl. Chem. 1996, 33, 45.
(c) Powers, D. G.; Casebier, D. S.; Fokas, D. Tetrahedron
1998, 54, 4085. (d) Takahashi, M.; Nagaoka, H.; Inoue, K.
J. Heterocycl. Chem. 2004, 41, 525. (e) Chebanov, V. A.;
Saraev, V. E.; Gura, E. A.; Desenko, S. M.; Musatov, V. I.
Collect. Czech. Chem. Commun. 2005, 70, 350. (f) Hassan,
N. A.; Hegab, M. I.; Hashem, A. I. J. Heterocycl. Chem.
2007, 44, 775. (g) Shi, D.-Q.; Ni, S.-N.; Yang, F.
J. Heterocycl. Chem. 2008, 45, 693. (h) Shi, D.-Q.; Niu, L.-
H.; Yao, H. J. Heterocycl. Chem. 2009, 46, 237.
(3) (a) Marrian, D. H. J. Chem. Soc. 1949, 1797. (b) Augustin,
M.; Rudorf, W.-D.; Pasche, R. Z. Chem. 1974, 14, 434.
(c) Shimo, T.; Matsuda, Y.; Iwanaga, T.; Shinmyozu, T.;
Somekawa, K. Heterocycles 2007, 71, 1053. (d)Havrylyuk,
D.; Zimenkovsky, B.; Lesyk, R. Phosphorus, Sulfur Silicon
Relat. Elem. 2009, 184, 638. (e) Rudenko, R. V.;
Colorless solid; mp 281–282 °C.
1H NMR (200 MHz, DMSO-d6): d = 2.67 (m, 2 H, 6-Ha + Hb), 2.83
(t, 3J = 7.2 Hz, 2 H, CH2), 4.00 (t, 3J = 4.6 Hz, 1 H, 5-Hx), 4.18 (m,
2 H, CH2), 7.06–8.0 (m, 9 Harom), 9.43 (br s, 1 H, NH), 10.47 (br s,
1 H, NH), 11.40 (br s, 1 H, NH).
13C NMR (50 MHz, DMSO-d6): d = 170.1, 169.6, 162.1, 152.5 (1
C, d, 1JCF = 244 Hz, CAr), 149.7, 147.7, 137.5, 128.6, 127.9, 126.1,
2
3
126.0 (1 C, d, JCF = 19.2 Hz, CAr), 124.4 (1 C, d, JCF = 7.4 Hz,
3
CAr), 124.0 (1 C, d, JCF = 2.7 Hz, CAr), 122.3, 114.8 (1 C, d,
2JCF = 19.3 Hz, CAr), 87.0, 42.1, 35.2, 33.3, 31.8.
MS (EI, 70 eV): m/z (%) = 422 (3, [M+]), 284 (37), 283 (100), 282
(13), 178 (2), 177 (6), 103 (40), 102 (26), 100 (2).
Anal. Calcd for C22H19FN4O4: C, 62.55; H, 4.53; N, 13.26. Found:
C, 62.3; H, 4.6; N, 13.1
6-Amino-5-(2,5-dioxo-1-phenylpyrrolidin-3-yl)pyrimidine-
2,4(1H,3H)-dione (5a)
Komykhov, S. A.; Desenko, S. M. Chem. Heterocycl.
Compd. 2009, 45, 1017.
(4) Augustin, M.; Mueller, W. J. Prakt. Chem. 1985, 327, 789.
(5) Ito, I.; Oda, N.; Kato, T. Chem. Pharm. Bull. 1976, 24, 1189.
(6) Abelman, M. M.; Fisher, K. J.; Doerffler, E.; Edwards, P. J.
Tetrahedron Lett. 2003, 44, 1823.
A mixture of 6-aminouracil (1a; 0.003 mol) and N-phenylmaleim-
ide (2a; 0.003 mol) in DMF (2 mL) was refluxed for 15 min. After
cooling, EtOH (10 mL) was added. The reaction mixture was al-
lowed to stand at r.t. for ~4 h and then the precipitate formed was
filtered. The solid product was washed with EtOH (10 mL) and
dried on air at r.t.
(7) Lesyk, R.; Vladzimirska, O.; Holota, S.; Zaprutko, L.;
1H NMR (200 MHz, DMSO-d6): d = 2.56 (dd, JAB = 18.1 Hz,
2
Gzella, A. Eur. J. Med. Chem. 2007, 42, 641.
3JAX = 4.8 Hz, 1 H, Ha), 3.05 (dd, 3JBX = 9.8 Hz, 1 H, Hb), 3.98 (dd,
1 H, 4-Hx), 6.36 (br s, 2 H, NH2), 7.20–7.50 (m, 5 Harom), 10.18 (br
s, 1 H, NHpyr), 10.46 (br s, 1 H, NHpyr).
(8) Shah, K. R.; Blanton, C. D. J. Org. Chem. 1982, 47, 502.
(9) Cobo, J.; Sánchez, A.; Nogueras, M. Tetrahedron 1998, 54,
5753.
(10) (a) Velchinskaya, E.; Kuz’menko, I.; Kulik, L. Pharm.
Chem. J. 1999, 33, 155. (b)Velchinskaya, E.; Petsushak, B.;
Rogal, A. Chem. Heterocycl. Compd. 2007, 43, 695.
(11) Rudenko, R. V.; Komykhov, S. A.; Musatov, V. I.;
Konovalova, I. S.; Shishkin, O. V.; Desenko, S. M.
J. Heterocycl. Chem. 2011, 48, 888.
(12) Rudenko, R. V.; Komykhov, S. A.; Desenko, S. M.;
Musatov, V. I.; Shishkin, O. V.; Konovalova, I. S.;
Vashchenko, E. V.; Chebanov, V. A. Synthesis 2011, 783.
(13) Shishkin, O. V. Russ. Chem. Bull. 1997, 46, 1510.
(14) (a) Shishkin, O. V.; Gorb, L.; Hobza, P.; Leszczynski, J. Int.
J. Quantum Chem. 2000, 80, 1116. (b) Isayev, O.;
Furmanchuk, A.; Shishkin, O. V.; Gorb, L.; Leszczynski, J.
J. Phys. Chem. B. 2007, 111, 3476.
13C NMR (50 MHz, DMSO-d6): d = 178.2, 176.0, 163.8, 152.6,
150.2, 133.2, 128.8, 127.3, 125.5, 83.7, 34.4, 32.5.
MS (EI, 70 eV): m/z (%) = 300 (3, [M+]), 180 (100), 179 (56), 151
(43).
Transformation of 5a into 3a
The pyrimidine dione 5a (0.003 mol) and DMF (2 mL) were placed
in a flask and the mixture refluxed for 5 h. The mixture was poured
into H2O (20 mL) and the precipitated compound 3a was filtered
and dried at r.t. under air.
References
(15) The final atomic coordinates and crystallographic data for
molecule 3j have been deposited at the Cambridge
Crystallographic Data Centre, 12 Union Road, CB2 1EZ,
UK [fax: +44(1223)336033; e-mail:
deposit@ccdc.cam.ac.uk] and are available on request
quoting the deposition number CCDC 824124.
(16) Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112.
(1) See, for example: (a) Alajarin, R.; Avarez-Buila, J.;
Vaquero, J. J.; Sunkel, C.; Fau, J.; Statkov, P.; Sanz, J.
Tetrahedron: Asymmetry 1993, 4, 617. (b) Bossert, F.;
Vater, W. Med. Res. Rev. 1989, 9, 291. (c) Trigle, D. J.;
Langs, D. A.; Janis, R. A. Med. Res. Rev. 1989, 9, 123.
(d) Tsuda, Y.; Mishina, T.; Obata, M.; Araki, K.; Inui, J.;
Nakamura, T. Patent WO 8504172, 1985; Chem. Abstr.
Synthesis 2011, No. 19, 3161–3167 © Thieme Stuttgart · New York