A facile synthesis of new substituted spiropyrimidine-2,4-diones

Article abstract of DOI:10.3184/174751913X13783169779948

An efficient and short route to synthesise spiropyrimidine-2,4-diones was achieved using 1,3-dipolar cycloaddition followed by a cyclisation reaction. The reaction is regiospecific in all cases.

Full text of DOI:10.3184/174751913X13783169779948

592 RESEARCH PAPER
OCTOBER, 592–595
JOURNAL OF CHEMICAL RESEARCH 2013
A facile synthesis of new substituted spiropyrimidine-2,4-diones
Amira Bahy, Nafâa Jegham, Yakdhane Kacem and Béchir Ben Hassine*
Laboratoire de Synthèse Organique Asymétrique et Catalyse Homogène (O1UR1201), Faculté des Sciences, Avenue de l’environnement, 5019
Monastir, Tunisia
An efficient and short route to synthesise spiropyrimidine-2,4-diones was achieved using 1,3-dipolar cycloaddition followed by
a cyclisation reaction. The reaction is regiospecific in all cases.
Keywords: spiropyrimidine-2,4-dione, 1,3-dipolar cycloaddition, cyclisation reaction, regiospecific reaction
Table 1 Yields of adducts 4 and 5
Pyrimidine systems have attracted much attention owing to
their wide range of biological activities, particularly in cancer
research. Among these heterocycles, the pyridopyrimidine class
is also of great interest because of its dihydrofolate reductase
inhibiting, antibacterial,1,2 antitumour3 and antiepileptic
activities.4
On the other hand, pyrimidine-2,4-diones are a class of
bioactive heterocyclic molecules, the most famous examples
being uracil and thymine, which form part of the nucleotides
of RNA and DNA, respectively.5 Pyrimidine-2,4-diones have
attracted considerable attention in the pharmaceutical industry
as anti-inflammatory agents,6 dopamine receptor agonists,7
serotonin uptake inhibitors8 and antiepileptic agents.9 A good
example of a pyrimidine-2,4-dione derivative with a medicinal
application is zidovudine (AZT, Fig. 1), used as an anti-AIDS
agent.10 This moiety is also the core structural element of some
fungicides11 and herbicides.12
1,3-Dipolar cycloaddition reactions are the most important
and versatile methods to build five-membered heterocycles.13–15
They have been applied to the synthesis of natural products
such as sugar derivatives,16 β-lactams,17 amino acids18 and
alkaloids.19
We now report the synthesis of new spiropyrimidine-2,4-
dione derivatives via 1,3-dipolar cycloaddition with nitrones in
good yield.
Entry
Amine
R
Bn
Bn
Bn
i-Pr
i-Pr
i-Pr
i-Bu
i-Bu
i-Bu
Nitrone Product Yields/% Product Yields/%
R’
1
2
3
4
5
6
7
8
9
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
77
65
60
70
57
60
63
68
62
5a
5b
5c
5d
5e
5f
5g
5h
5i
84
75
79
72
82
70
80
75
78
i-Pr
t-Bu
Ph
i-Pr
t-Bu
Ph
i-Pr
t-Bu
formation of the ethyl 2-(aminomethyl)acrylate 2 in 50–73%
yields. Compound 2 with isopropyl isocyanate were placed
in anhydrous toluene.21 The resulting mixture was stirred and
heated to reflux under an argon atmosphere until complete
consumption of the starting materials to furnish the product
3 in 65–80% yields. The next step in this synthesis was the
formation of the isoxazolidine-core structures 4 by a 1,3-dipolar
cycloaddition reaction22 using three nitrones. This reaction is an
important method for the formation of isoxazolidines20 and has
been used in the synthesis of natural products.25,28 Two possible
regioisomers of the cycloadducts can be theoretically obtained:
the 5,5-disubstituted isoxazolidine and/or the 4,4-disubstituted
isoxazolidines. In practice, we have obtained only one product.
The structure of each cycloadduct was confirmed by NMR (1H
and 13C) spectra of the crude cycloaddition reaction mixture.
Comparison of the 13C NMR data of adducts 4 suggests that
these compounds possess the same regiochemistry. The
chemical shift of carbon C5 of the isoxazolidine ring of all
adducts appears between 84 and 86 ppm. This value located
the carbon C5 near the very electronegative oxygen atom of the
isoxazolidine ring.23–25 Yields of 4 ranges between 62 and 77%.
Finally, the synthesis of 5 could be achieved by the cyclisation
of the ureido intermediate 4. Compound 4 was dissolved in
THF and a solution of tBuOK in THF (1 M) was added.29–30
The reaction was stirred at room temperature for 1 h. The
spiropyrimidine-2,4-dione 5 was obtained in good yield
(Scheme 1, Table 1).
Results and discussion
The synthesis of spiro-compound 5 commenced by the
condensation reaction20 of ethyl 2-(bromomethyl)acrylate
1 with primary amines. Three amines were selected for the
H
O
N
O
N
O
HO
Me
N3
Fig. 1 Structure of zidovudine (AZT).
R'
Ph
H
O
O
O
O
O
N
C
N
O
iPr-N=C=O
R-NH2
R
R
O
R'
O
Br
O
N
H
O
N
O
Ph
Toluene
NEt3 / CHCl3
Toluene , 80°C
H
N
N
NH
3a-c
R
O
4a-i
1
2a-c
tBuOK (1M) / THF
rt , 1 h
R'
O
Scheme 1 Synthetic route to spiropyrimidine-2,4-dione 5.
N
O
N
Ph
N
R
O
5a-i
* Correspondent. E-mail: bechirbenhassine@yahoo.fr
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JOURNAL OF CHEMICAL RESEARCH 2013 593
NMR (75.5 MHz, CDCl3): 13.8 (CH3), 23.0 (2CH3–iPr), 42.7 (C4), 46.9
(CH–iPr), 51.2 (C7), 51.4 (C6), 62.0 (CH2), 69.8 (C3), 86.2 (C5), 116.4–150.2
(Carom), 158.7 (N–C=O), 171.6 (O–C=O); HRMS Calcd for C30H36N3O4
[M+H]+: 502.2706; found: 502.2707; IR (KBr) cm–1: 1252, 1531, 1645,
1737, 2966, 3368.
Conclusions
In summary, we have developed a facile route for the synthesis
of new substituted spiropyrimidine-2,4-diones by a 1,3-dipolar
cycloaddition reaction with nitrones, followed by cyclisation of
a ureido intermediate. All spiroadducts were formed via a very
high regioselectivity pathway, and the spirocarbon atom was
linked to the isoxazolidine oxygen atom.
Ethyl 5-{[benzyl(N-isopropylcarbamoyl)amino]methyl}-2-isopropyl-
3-phenylisoxazolidine-5-carboxylate (4b): Yellow liquid; 1H NMR
(300 MHz, CDCl3): 1.04 (m, 2CH3–iPr), 1.20 (t, CH3), 1.84 (s, NH), 2.35
(dd, H4a, J=12.9 Hz, J=9.6 Hz), 2.88 (d, H4b, J=12.9 Hz, J=7.5 Hz), 2.96
(m, CH–iPr), 3.51 (d, CH2–N), 3.74 (m, CH–iPr), 4.03 (dd, H3, J=9.6 Hz,
J=7.5 Hz), 4.16 (q, CH2), 4.50 (d, CH2–Bn), 4.53 (d, CH2–Bn), 7.14–7.42
(m, 10Harom); 13C NMR (75.5 MHz, CDCl3): 14.0 (CH3), 19.1 (2CH3–iPr),
23.2 (2CH3–iPr), 43.1 (C4), 43.6 (CH–iPr), 51.2 (C7), 55.8 (C6), 60.5 (CH–
iPr), 61.4 (CH2), 66.6 (C3), 84.1 (C5), 126.0–140.8 (Carom), 159.5 (N–C=O),
171.0 (O–C=O); HRMS Calcd for C27H38N3O4 [M+H]+: 468.2863;
found: 468.2865; IR (KBr) cm–1 : 1256, 1535, 1647, 1740, 2970, 3369.
Ethyl 5-{[benzyl(N-isopropylcarbamoyl)amino]methyl}-2-tert-butyl-
3-phenylisoxazolidine-5-carboxylate (4c): Yellow liquid; 1H NMR
(300 MHz, CDCl3): 1.08 (d, 2CH3–iPr), 1.12 (s, 3CH3–tBu), 1.22 (t,
CH3), 1.83 (s, NH), 2.34 (dd, H4a, J=12.9 Hz, J=9.6 Hz), 2.93 (d, H4b,
J=12.9 Hz, J=7.5 Hz), 2.96 (m, CH–iPr), 3.55 (d, CH2–N), 3.73 (m,
CH–iPr), 4.16 (q, CH2), 4.50 (d, CH2–Bn), 4.29 (d, CH2–Bn), 4.54 (dd,
H3, J=9.6 Hz, J=7.5 Hz), 7.12–7.43 (m, 10Harom); 13C NMR (75.5 MHz,
CDCl3): 14.0 (CH3), 23.2 (2CH3–iPr), 26.2 (3CH3–tBu), 43.7 (C4), 52.2
(C7), 55.8 (C6), 60.5 (CH–iPr), 61.4 (CH2), 61.8 (C–tBu), 64.9 (C3), 83.8
(C5), 126.8–140.9 (Carom), 159.5 (N–C=O), 168.4 (O–C=O); HRMS Calcd
Experimental
All reactions were monitored by TLC Merck 60F-254 silica gel plates
(layer thickness 0.25 mm). Column chromatography was performed
on silica gel (70–230 mesh) using ethyl acetate and cyclohexane
mixture as eluents. NMR spectra were recorded on a Bruker AC-300
spectrometer [300 MHz (1H) and 75 MHz (13C)]. All chemical shifts
were reported as δ values (ppm) relative to internal tetramethylsilane.
IR spectra (KBr) were recorded on
spectrophotometer. High resolution mass spectra (HR-MS) were
obtained on a Waters Micromass Q-Tof Micro instrument.
a FTIR-8400 Shimadzu
Synthesis of compounds 3a–c; general procedure
A solution of compound 2 (10 mmol) with isopropyl isocyanate
(10 mmol) were placed in anhydrous toluene (10 mL). The resulting
mixture was stirred and heated to reflux under an argon atmosphere
until complete consumption of the starting materials (TLC analysis).
The reaction mixture was allowed to cool to room temperature
and concentrate. The residue obtained was purified by column
chromatography [SiO2/cyclohexane:ethyl acetate (90:10)] to furnish the
products 3.
for C28H40N3O4 [M+H]+: 482.3019; found: 482.3021; IR (KBr) cm–1
1255, 1532, 1649, 1739, 2969, 3368.
:
Ethyl 2-{[benzyl(N-isopropylcarbamoyl)amino]methyl}acrylate (3a):
Yellow liquid (80%); H NMR (300 MHz, CDCl3): 1.08 (d, 2CH3–iPr),
Ethyl 5-{[isopropyl(isopropylcarbamoyl)amino]methyl}-2,3-
diphenylisoxazolidine-5-carboxylate (4d): Yellow liquid; 1H NMR
(300 MHz, CDCl3): 1.10 (d, 2CH3–iPr), 1.18 (d, 2CH3–iPr), 1.20 (t,
CH3), 1.71 (s, NH), 2.22 (dd, H4a, J=12.9 Hz, J=9.6 Hz), 2.83 (d, H4b,
J=12.9 Hz, J=7.5 Hz), 3.42 (d, CH2–N), 3.86 (m, CH–iPr), 4.16 (q,
CH2), 4.26 (m, CH–iPr), 4.89 (dd, H3, J=9.6 Hz, J=7.5 Hz), 6.74–7.52
(m, 10Harom); 13C NMR (75.5 MHz, CDCl3): 13.8 (CH3), 20.2 (2CH3–iPr),
23.3 (2CH3–iPr), 42.4 (CH–iPr), 43.2 (C4), 50.4 (CH–iPr), 52.3 (C6), 61.4
(CH2), 69.9 (C3), 86.4 (C5), 115.8–150.0 (Carom), 160.2 (N–C=O), 168.0
(O–C=O); HRMS Calcd for C26H36N3O4 [M+H]+: 454.2706; found:
454.2709; IR (KBr) cm–1 : 1252, 1534, 1645, 1740, 2965, 3370.
Ethyl 5-{[isopropyl(isopropylcarbamoyl)amino]methyl}-2-isopropyl-
3-phenylisoxazolidine-5-carboxylate (4e): Yellow liquid; 1H NMR
(300 MHz, CDCl3): 1.06 (m, 2CH3–iPr), 1.13 (m, 2CH3–iPr), 1.20
(m, 2CH3–iPr), 1.24 (t, CH3), 1.80 (s, NH), 2.06 (dd, H4a, J=12.9 Hz,
J=9.6 Hz), 2.62 (d, H4b, J=12.9 Hz, J=7.5 Hz), 2.90 (m, CH–iPr), 3.51
(d, CH2–N), 3.86 (m, CH–iPr), 4.04 (dd, H3, J=9.6 Hz, J=7.5 Hz), 4.16
(q, CH2), 4.28 (m, CH–iPr), 7.27–7.37 (m, 5Harom); 13C NMR (75.5 MHz,
CDCl3): 14.0 (CH3), 19.0 (2CH3–iPr), 20.3 (2CH3–iPr), 23.1 (2CH3–iPr),
42.4 (CH–iPr), 43.3 (C4), 52.4 (CH–iPr), 52.3 (C6), 60.5 (CH–iPr), 61.4
(CH2), 66.0 (C3), 86.4 (C5), 127.1–140.1 (Carom), 160.2 (N–C=O), 169.0
(O–C=O); HRMS Calcd for C23H37N3O4 [M+H]+: 420.2863; found:
420.2864; IR (KBr) cm–1 : 1253, 1534, 1646, 1739, 2968, 3369.
Ethyl 5-{[isopropyl[(isopropyl carbamoyl)amino]methyl}-2-tert-
butyl-3-phenylisoxazolidine-5-carboxylate (4f): Yellow liquid; 1H
NMR (300 MHz, CDCl3): 1.13 (s, 3CH3–tBu), 1.15 (d, 2CH3–iPr), 1.20
(d, 2CH3–iPr), 1.24 (t, CH3), 1.85 (s, NH), 2.08 (dd, H4a, J=12.9 Hz,
J=9.6 Hz), 2.63 (d, H4b, J=12.9 Hz, J=7.5 Hz), 3.54 (d, CH2–N), 3.86
(m, CH–iPr), 4.17 (q, CH2), 4.29 (m, CH–iPr), 4.57 (dd, H3, J=9.6 Hz,
J=7.5 Hz), 7.28–7.34 (m, 5Harom); 13C NMR (75.5 MHz, CDCl3): 14.1
(CH3), 20.1 (2CH3–iPr), 23.4 (2CH3–iPr), 26.4 (3CH3–tBu), 42.4 (CH–
iPr), 43.9 (C4), 50.5 (CH–iPr), 52.3 (C6), 61.6 (CH2), 61.9 (C–tBu), 65.0
(C3), 86.1 (C5), 126.9–140.1 (Carom), 160.2 (N–C=O), 169.3 (O–C=O);
HRMS Calcd for C24H40N3O4 [M+H]+: 434.3019; found: 434.3022; IR
(KBr) cm–1 : 1250, 1533, 1647, 1739, 2966, 3370.
1
1.16 (t, CH3), 3.61 (m, CH–iPr), 4.03 (q, CH2), 4.26 (d, CH2–Bn), 4.28 (d,
CH2–Bn),4.30 (s, NH), 4.34 (s, CH2–N), 5.84 (d, CH=), 6.11 (d, CH=),
7.12–7.46 (m, 5Harom); 13C NMR (75.5 MHz, CDCl3): 14.2 (CH3), 22.5
(2CH3–iPr), 45.1 (CH–iPr), 52.1 (CH2–N), 52.3 (CH2–Bn), 60.0 (CH2–O),
122.1 (CH2=), 126.4–135.4 (Carom), 136.5 (C=), 159.9 (N–C=O), 172.0 (O–
C=O); HRMS Calcd for C17H25N2O3 [M+H]+: 305.1865; found: 305.1867.
Ethyl
2-{[isopropyl(N-isopropylcarbamoyl)amino]methyl}acrylate
(3b): Yellow liquid (65%); 1H NMR (300 MHz, CDCl3): 1.07 (d, 2CH3–
iPr), 1.18 (t, CH3), 1.22 (d, 2CH3–iPr), 3.59 (m, CH–iPr), 4.05 (q, CH2),
4.13 (m, CH–iPr), 4.13 (s, NH), 4.24 (s, CH2–N), 5.75 (d, CH=), 6.37 (d,
CH=); 13C NMR (75.5 MHz, CDCl3): 14.3 (CH3), 19.9 (2CH3–iPr), 22.7
(2CH3–iPr), 45.7 (CH–iPr), 48.6 (CH2–N), 50.2 (CH–iPr), 60.1 (CH2–O),
118.8 (CH2=), 138.1 (C=), 159.7 (N–C=O), 171.7 (O–C=O); HRMS Calcd
for C13H25N2O3 [M+H]+: 257.1865; found: 257.1866.
Ethyl 2-{[isobutyl(N-isopropylcarbamoyl)amino]methyl}acrylate (3c):
Yellow liquid (72%); 1H NMR (300 MHz, CDCl3): 1H NMR (300 MHz,
CDCl3): 0.84 (d, 2CH3–iBu), 1.01 (m, CH–iBu), 1.06 (d, 2CH3–iPr), 1.16
(t, CH3), 3.27 (m, CH2–iBu), 3.60 (m, CH–iPr), 4.03 (q, CH2), 4.30 (s,
CH2–N), 4.35 (s, NH), 5.82 (d, CH=), 6.05 (d, CH=); 13C NMR (75.5 MHz,
CDCl3): 14.1 (CH3), 20.1 (2CH3–iBu), 22.6 (2CH3–iPr), 26.6 (CH–iBu),
45.2 (CH–iPr), 51.7 (CH2–N), 57.2 (CH2–iBu), 60.2 (CH2–O), 122.1
(CH2=), 137.1 (C=), 160.2 (N–C=O), 172.1 (O–C=O); HRMS Calcd for
C14H27N2O3 [M+H]+: 271.2022; found: 271.2023.
1,3-Dipolar cycloaddition reactions of 4a–i; general procedure
A solution of nitrone (1 mmol) and compound 3 (1 mmol) in toluene
(3 mL) was stirred at 80°C under an argon atmosphere for 24 h. The
solvent was then removed, and the residue was purified by column
chromatography [SiO2/cyclohexane:ethyl acetate (90:10)] to give the
compounds 4.
Ethyl 5-{[benzyl(N-isopropylcarbamoyl)amino]methyl}-2,3-
diphenylisoxazolidine-5-carboxylate (4a): Yellow liquid; 1H NMR
(300 MHz, CDCl3): 1.06 (d, 2CH3–iPr), 1.18 (t, CH3), 1.85 (s, NH), 2.51
(dd, H4a, J=12.9 Hz, J=9.6 Hz), 3.14 (d, H4b, J=12.9 Hz, J=7.5 Hz), 3.50
(d, CH2–N), 3.71 (m, CH–iPr), 4.14 (q, CH2), 4.49 (d, CH2–Bn), 4.53 (d,
Ethyl
5-{[isobutyl[(isopropyl
carbamoyl)amino]methyl}-2,3-
CH2–Bn), 5.42 (dd, H3, J=9.6 Hz, J=7.5 Hz), 6.94–7.43 (m, 15Harom); 13
C
diphenylisoxazolidine-5-carboxylate (4g): Yellow liquid; 1H NMR
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594 JOURNAL OF CHEMICAL RESEARCH 2013
(300 MHz, CDCl3): 0.85 (d, 2CH3–iBu), 1.07 (d, 2CH3–iPr), 1.11 (m, CH-
iBu), 1.20 (t, CH3), 1.68 (s, NH), 2.50 (dd, H4a, J=12.9 Hz, J=9.6 Hz),
3.07 (d, H4b, J=12.9 Hz, J=7.5 Hz), 3.29 (d, CH2–iBu), 3.52 (d, CH2–N),
3.74 (m, CH–iPr), 4.15 (q, CH2), 4.90 (dd, H3, J=9.6 Hz, J=7.5 Hz),
6.73–7.53 (m, 10Harom); 13C NMR (75.5 MHz, CDCl3): 13.9 (CH3), 20.1
(2CH3–iBu), 23.2 (2CH3–iPr), 26.3 (CH–iBu), 43.0 (C4), 43.6 (CH–iPr),
50.4 (CH–iPr), 55.4 (C6), 57.1 (CH2–iBu), 61.6 (CH2), 69.8 (C3), 88.4 (C5),
115.7–150.8 (Carom), 159.8 (N–C=O), 169.1 (O–C=O); HRMS Calcd for
C27H38N3O4 [M+H]+: 468.2863; found: 468.2864; IR (KBr) cm–1 : 1250,
1532, 1648, 1738, 2969, 3368.
Ethyl 5-{[isobutyl[(isopropyl carbamoyl)amino]methyl}-2-isopropyl-
3-phenylisoxazolidine-5-carboxylate (4h): Yellow liquid; 1H NMR
(300 MHz, CDCl3): 0.86 (d, 2CH3–iBu), 1.08 (m, CH3–iPr), 1.12 (m, CH–
iBu), 1.21 (t, CH3), 1.66 (s, NH), 2.35 (dd, H4a, J=12.9 Hz, J=9.6 Hz),
2.89 (d, H4b, J=12.9 Hz, J=7.5 Hz), 3.30 (d, CH2–iBu), 3.54 (d, CH2–N),
3.78 (m, CH–iPr), 4.05 (dd, H3, J=9.6 Hz, J=7.5 Hz), 4.13 (q, CH2), 7.29–
7.35 (m, 5Harom); 13C NMR (75.5 MHz, CDCl3): 14.1 (CH3), 19.1 (2CH3–
iPr), 20.2 (2CH3–iBu), 23.0 (2CH3–iPr), 26.5 (CH–iBu), 43.2 (C4), 43.6
(CH–iPr), 55.4 (C6), 57.2 (CH2–iBu), 60.6 (CH–iPr), 61.3 (CH2), 66.1 (C3),
88.5 (C5), 127.2–140.8 (Carom), 159.8 (N–C=O), 169.5 (O–C=O); HRMS
Calcd for C24H40N3O4 [M+H]+: 434.3019; found: 434.3018; IR (KBr)
cm–1 : 1251, 1532, 1649, 1740, 2969, 3369.
Ethyl 5-{[isobutyl[(isopropyl carbamoyl)amino]methyl}-2-tert-butyl-
3-phenylisoxazolidine-5-carboxylate (4i): Yellow liquid; 1H NMR
(300 MHz, CDCl3): 0.84 (d, 2CH3–iBu), 1.06 (d, 2CH3–iPr), 1.11 (s,
3CH3–tBu), 1.13 (m, CH–iBu), 1.24 (t, CH3), 1.70 (s, NH), 2.33 (dd, H4a,
J=12.9 Hz, J=9.6 Hz), 2.91 (d, H4b, J=12.9 Hz, J=7.5 Hz), 3.30 (d,
CH2–iBu), 3.56 (d, CH2–N), 3.73 (m, CH–iPr), 4.17 (q, CH2), 4.55 (dd,
H3, J=9.6 Hz, J=7.5 Hz), 7.28–7.34 (m, 5Harom); 13C NMR (75.5 MHz,
CDCl3): 14.0 (CH3), 20.2 (2CH3–iBu), 23.0 (2CH3–iPr), 26.2 (3CH3–tBu),
26.4 (CH–iBu), 43.5 (CH–iPr), 43.7 (C4), 55.5 (C6), 57.3 (CH2–iBu), 61.5
(CH2), 65.0 (C3), 88.2 (C5), 126.8–140.9 (Carom), 159.9 (N–C=O), 169.3
(O–C=O); HRMS Calcd for C25H42N3O4 [M+H]+: 448.3176; found:
448.3179; IR (KBr) cm–1 : 1251, 1533, 1648, 1739, 2967, 3368.
(300 MHz, CDCl3): 1.14 (s, 3CH3–tBu), 1.25 (d, 2CH3–iPr), 2.43 (dd,
H4a, J=12.9 Hz, J=9.6 Hz), 2.93 (d, H4b, J=12.9 Hz, J=7.5 Hz), 3.73 (m,
CH–iPr), 3.84 (dd, H3, J=9.6 Hz, J=7.5 Hz), 3.86 (d, CH2–N), 4.64 (d,
CH2–N), 4.66 (d, CH2–Bn), 4.75 (d, CH2–Bn), 7.08–7.52 (m, 10Harom); 13
C
NMR (75.5 MHz, CDCl3): 20.0 (2CH3–iPr), 26.4 (3CH3–tBu), 43.7 (C4),
43.9 (CH–iPr), 50.0 (C6), 52.3 (C7), 61.7 (C–tBu), 64.2 (C3), 80.8 (C5),
126.6–139.9 (Carom), 155.1 (N–C=O), 168.7 (O–C=O); HRMS Calcd for
C26H34N3O3 [M+H]+: 436.2600; found: 436.2601; IR (KBr) cm–1 : 1169,
1335, 1341, 1640, 2978.
7,9-Diisopropyl-2,3-diphenyl-1-oxa-2,7,9-triazaspiro[4.5]decane-
1
6,8-dione (5d): Yellow liquid; H NMR (300 MHz, CDCl3): 1.10 (d,
2CH3–iPr), 1.24 (d, 2CH3–iPr), 2.29 (dd, H4a, J=12.9 Hz, J=9.6 Hz), 2.81
(d, H4b, J=12.9 Hz, J=7.5 Hz), 3.47 (m, 2CH–iPr), 3.64 (d, CH2–N), 4.39
(d, CH2–N), 4.75 (dd, H3, J=9.6 Hz, J=7.5 Hz), 6.92–7.68 (m, 10Harom);
13C NMR (75.5 MHz, CDCl3): 19.9 (2CH3–iPr), 21.6 (2CH3–iPr),
43.2 (C4), 44.8 (CH–iPr), 47.0 (C6), 47.8 (CH–iPr), 69.2 (C3), 83.4 (C5),
115.6–149.0 (Carom), 155.8 (N–C=O), 169.7 (O–C=O); HRMS Calcd for
C24H30N3O3 [M+H]+: 408.2287; found: 408.2290; IR (KBr) cm–1: 1166,
1334, 1340, 1638, 2979.
2,7,9-Triisopropyl-3-phenyl-1-oxa-2,7,9-triazaspiro[4.5]decane-6,8-
dione (5e): Yellow liquid; 1H NMR (300 MHz, CDCl3): 1.06 (d, 2CH3–
iPr), 1.10 (d, 2CH3–iPr), 1.24 (d, 2CH3–iPr), 2.14 (dd, H4a, J=12.9 Hz,
J=9.6 Hz), 2.64 (d, H4b, J=12.9 Hz, J=7.5 Hz), 2.77 (m, CH–iPr), 3.50
(m, 2CH–iPr), 3.64 (d, CH2–N), 3.87 (dd, H3, J=9.6 Hz, J=7.5 Hz), 4.38
(d, CH2–N), 7.17–7.50 (m, 5Harom); 13C NMR (75.5 MHz, CDCl3): 19.4
(2CH3–iPr), 19.8 (2CH3–iPr), 21.6 (2CH3–iPr), 43.4 (C4), 44.9 (CH–iPr),
46.5 (C6), 47.8 (CH–iPr), 60.1 (CH–iPr), 65.4 (C3), 83.4 (C5), 127.0–139.2
(Carom), 155.8 (N–C=O), 169.9 (O–C=O); HRMS Calcd for C21H32N3O3
[M+H]+: 374.2444; found: 374.2446; IR (KBr) cm–1 : 1167, 1334, 1341,
1638, 2978.
2-Tert-butyl-7,9-diisopropyl-3-phenyl-1-oxa-2,7,9-triazaspiro[4.5]
decane-6,8-dione (5f): Yellow liquid; 1H NMR (300 MHz, CDCl3):
1.07 (d, 2CH3–iPr), 1.13 (s, 3CH3–tBu), 1.24 (d, 2CH3–iPr), 2.15 (dd, H4a,
J=12.9 Hz, J=9.6 Hz), 2.66 (d, H4b, J=12.9 Hz, J=7.5 Hz), 3.47 (m,
2CH–iPr), 3.64 (d, CH2–N), 3.37 (dd, H3, J=9.6 Hz, J=7.5 Hz), 4.40
(d, CH2–N), 7.17–7.46 (m, 5Harom); 13C NMR (75.5 MHz, CDCl3): 19.8
(2CH3–iPr), 21.8 (2CH3–iPr), 26.3 (3CH3–tBu), 43.8 (C4), 44.9 (CH–iPr),
46.5 (C6), 47.8 (CH–iPr), 61.9 (C–tBu), 64.4 (C3), 83.1 (C5), 126.5–139.2
(Carom), 155.8 (N–C=O), 169.6 (O–C=O); HRMS Calcd for C22H34N3O3
[M+H]+: 388.2600; found: 388.2602; IR (KBr) cm–1 : 1165, 1331, 1339,
1640, 2981.
9-Isobutyl-7-isopropyl-2,3-diphenyl-1-oxa-2,7,9-triazaspiro[4.5]
decane-6,8-dione (5g): Yellow liquid; 1H NMR (300 MHz, CDCl3):
0.90 (d, 2CH3–iBu), 1.25 (d, 2CH3–iPr), 1.30 (d, CH–iBu), 2.59 (dd, H4a,
J=12.9 Hz, J=9.6 Hz), 3.10 (d, H4b, J=12.9 Hz, J=7.5 Hz), 3.41 (d,
CH2–iBu), 3.73 (m, CH–iPr), 3.78 (d, CH2–N), 4.54 (d, CH2–N), 4.76 (dd,
H3, J=9.6 Hz, J=7.5 Hz), 6.93–7.69 (m, 10Harom); 13C NMR (75.5 MHz,
CDCl3): 19.8 (2CH3–iBu), 19.9 (2CH3–iPr), 26.5 (CH–iBu), 43.1 (C4),
43.8 (CH–iPr), 50.0 (C6), 61.3 (CH2–iBu), 69.3 (C3), 85.4 (C5), 115.7–149.7
(Carom), 155.4 (N–C=O), 168.9 (O–C=O); HRMS Calcd for C25H32N3O3
[M+H]+: 422.2444; found: 422.2445; IR (KBr) cm–1 : 1166, 1335, 1336,
1639, 2980.
Cyclisation of spiropyrimidine-2,4-dione (5a–I); general procedure
A solution of 1 M tBuOK in THF was added to a solution of
intermediate 4 (0.10 mmol) in THF (3 mL). The reaction mixture was
then stirred at room temperature for 1 h. A brine solution was added
and the layer was extracted with CH2Cl2 (3×10 mL), and the combined
organic fractions were dried over MgSO4 and concentrated under
reduced pressure.
9-Benzyl-7-isopropyl-2,3-diphenyl-1-oxa-2,7,9-triazaspiro[4.5]
decane-6,8-dione (5a): Yellow liquid; 1H NMR (300 MHz, CDCl3):
1.42 (d, 2CH3–iPr), 2.57 (dd, H4a, J=12.9 Hz, J=9.6 Hz), 3.12 (d, H4b,
J=12.9 Hz, J=7.5 Hz), 3.75 (m, CH–iPr), 3.86 (d, CH2–N), 4.63 (d,
CH2–N), 4.66 (d, CH2–Bn), 4.74 (d, CH2–Bn), 4.72 (dd, H3, J=9.6 Hz,
J=7.5 Hz), 6.93–7.69 (m, 15Harom); 13C NMR (75.5 MHz, CDCl3): 19.9
(2CH3–iPr), 43.1 (C4), 43.8 (CH–iPr), 46.9 (C6), 52.4 (C7), 69.3 (C3), 81.0
(C5), 115.7–149.7 (Carom), 155.1 (N–C=O), 170.0 (O–C=O); HRMS Calcd
for C28H30N3O3 [M+H]+: 456.2287; found: 456.2289; IR (KBr) cm–1
1166, 1334, 1340, 1639, 2980.
:
9-Benzyl-2,7-diisopropyl-3-phenyl-1-oxa-2,7,9-triazaspiro[4.5]
decane-6,8-dione (5b): Yellow liquid; 1H NMR (300 MHz, CDCl3): 1.06
(d, 2CH3–iPr), 1.24 (d, 2CH3–iPr), 2.42 (dd, H4a, J=12.9 Hz, J=9.6 Hz),
2.78 (m, CH–iPr), 2.95 (d, H4b, J=12.9 Hz, J=7.5 Hz), 3.75 (m, CH–iPr),
3.84 (dd, H3, J=9.6 Hz, J=7.5 Hz), 3.87 (d, CH2–N), 4.63 (d, CH2–N),
4.66 (d, CH2–Bn), 4.75 (d, CH2–Bn), 7.09–7.51 (m, 10Harom); 13C NMR
(75.5 MHz, CDCl3): 19.1 (2CH3–iPr), 19.9 (2CH3–iPr), 43.2 (C4),
43.9 (CH–iPr), 49.9 (C6), 52.5 (C7), 60.1 (CH–iPr), 65.3 (C3), 81.1 (C5),
126.9–139.5 (Carom), 155.2 (N–C=O), 169.5 (O–C=O); HRMS Calcd for
C25H32N3O3 [M+H]+: 422.2444; found: 422.2446; IR (KBr) cm–1 : 1167,
1338, 1340, 1637, 2981.
9-Isobutyl-2,7-diisopropyl-3-phenyl-1-oxa-2,7,9-triazaspiro[4.5]
decane-6,8-dione (5h): Yellow liquid; 1H NMR (300 MHz, CDCl3): 0.90
(d, 2CH3–iBu), 1.07 (d, 2CH3–iPr), 1.26 (d, 2CH3–iPr), 1.31 (d, CH–iBu),
2.42 (dd, H4a, J=12.9 Hz, J=9.6 Hz), 2.77 (m, CH–iPr), 2.92 (d, H4b,
J=12.9 Hz, J=7.5 Hz), 3.40 (d, CH2–iBu), 3.75 (m, CH–iPr), 3.80 (d,
CH2–N), 3.88 (dd, H3, J=9.6 Hz, J=7.5 Hz), 4.56 (d, CH2–N), 7.17–7.52
(m, 5Harom); 13C NMR (75.5 MHz, CDCl3): 19.1 (2CH3–iPr), 19.9 (2CH3–
iBu), 20.1 (2CH3–iPr), 26.7 (CH–iBu), 43.2 (C4), 43.9 (CH–iPr), 50.1 (C6),
60.2 (CH–iPr), 61.4 (CH2–iBu), 69.4 (C3), 85.4 (C5), 126.8–139.9 (Carom),
155.3 (N–C=O), 168.8 (O–C=O); HRMS Calcd for C22H34N3O3 [M+H]+:
388.2600; found: 388.2602; IR (KBr) cm–1 : 1165, 1333, 1341, 1638, 2977.
2-tert-Butyl-9-isobutyl-7-isopropyl-3-phenyl-1-oxa-2,7,9-
triazaspiro[4.5]decane-6,8-dione (5i): Yellow liquid; 1H NMR
9-Benzyl-2-tert-butyl-7-isopropyl-3-phenyl-1-oxa-2,7,9-
triazaspiro[4.5]decane-6,8-dione (5c): Yellow liquid; 1H NMR
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JOURNAL OF CHEMICAL RESEARCH 2013 595
8
9
S. Mignani, D. Damour, A. Doble, R. Labaudinière, J.-L. Malleron, O. Plot
and C. Gueremy, Bioorg. Med. Chem. Lett., 1993, 3, 1913.
K.A. Jones, D.F. Weaver, K.E. Tiedje, WO 2004009559, January 29, 2004;
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(300 MHz, CDCl3): 0.89 (d, 2CH3–iBu), 1.12 (s, 3CH3–tBu), 1.23 (d,
2CH3–iPr), 1.28 (d, CH–iBu), 2.44 (dd, H4a, J=12.9 Hz, J=9.6 Hz), 2.90
(d, H4b, J=12.9 Hz, J=7.5 Hz), 3.39(d, CH2–iBu), 3.72 (m, CH–iPr),
3.80 (d, CH2–N), 4.38 (dd, H3, J=9.6 Hz, J=7.5 Hz), 4.56 (d, CH2–N),
7.16–7.46 (m, 5Harom); 13C NMR (75.5 MHz, CDCl3): 19.9 (2CH3–iPr),
26.5 (3CH3–tBu), 27.0 (CH–iBu), 43.8 (C4), 44.1 (CH–iPr), 49.5 (C6),
61.3 (CH2–iBu), 61.8 (C–tBu), 64.3 (C3), 85.2 (C5), 126.5–140.0 (Carom),
155.3 (N–C=O), 168.9 (O–C=O); HRMS Calcd for C23H36N3O3 [M+H]+:
402.2757; found: 402.2759; IR (KBr) cm–1 : 1164, 1335, 1340, 1638, 2980.
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The authors are grateful to DGRSRT (Direction Générale de la
Recherche Scientifique et de la Rénovation Technologique) of
the Tunisian Ministry of Higher Education, Scientific Research,
and Technology for the financial support.
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Received 12 May 2013; accepted 10 July 2013
Paper 1301944 doi: 10.3184/174751913X13783169779948
Published online: 7 October 2013
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