Three-component synthesis of hexahydropyridopyrimidine- spirocyclohexanetriones induced by microwave

Article abstract of DOI:10.1016/j.tetlet.2005.10.120

Pyridopyrimidine-spirocyclohexanetriones (5, 6) and pyrimido[4,5-b] quinolinones (8) were obtained in a three-component microwave-assisted reaction of 6-aminopyrimidin-4-ones (1) with dimedone (2) and formaldehyde solution or paraformaldehyde, respectively. A mechanism is proposed based on the presence of a basic catalyst (triethylamine in this case) and the fact that single condensation intermediates are isolated prior to the cyclization leading to the final products.

Full text of DOI:10.1016/j.tetlet.2005.10.120

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 27–30
Three-component synthesis
of hexahydropyridopyrimidine–spirocyclohexanetriones induced
by microwave
b
a
a
Jairo Quiroga,a, Silvia Cruz, Braulio Insuasty, Rodrigo Abonıa,
*
´
Manuel Noguerasc and Justo Coboc
aGrupo de Investigacio´n de Compuestos Heterocı´clicos, Department of Chemistry, Universidad del Valle, A. A. 25360 Cali, Colombia
bDepartament of Chemistry, Universidad de Narin˜o, A.A. 1175 Pasto, Colombia
cDepartment of Inorganic and Organic Chemistry, Universidad de Jae´n, 23071 Jae´n, Spain
Received 19 September 2005; revised 20 October 2005; accepted 25 October 2005
Available online 11 November 2005
Abstract—Pyridopyrimidine–spirocyclohexanetriones (5, 6) and pyrimido[4,5-b]quinolinones (8) were obtained in a three-compo-
nent microwave-assisted reaction of 6-aminopyrimidin-4-ones (1) with dimedone (2) and formaldehyde solution or paraformalde-
hyde, respectively. A mechanism is proposed based on the presence of a basic catalyst (triethylamine in this case) and the fact
that single condensation intermediates are isolated prior to the cyclization leading to the final products.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
The preparation of bioactive nitrogen containing hetero-
cycles such as pyrido[2,3-d]pyrimidine derivatives, deaza-
analogs of pteridines and their oxoderivatives is one of
our ongoing projects due to their interesting bio-activi-
ties.3 We have already reported some procedures for
Multicomponent reactions (MCRs) by virtue of their
convergence, productivity, ease of execution and gener-
ally high yields of products have attracted considerable
attention from the point of view of combinatorial chem-
istry. Over the last few years, there has been a tremen-
dous development in three-component reactions and
great efforts to afford new and effective MCRs.1 Parall-
ely, the potential application of microwave technology
in organic synthesis,2 and particularly under free-solvent
conditions, is increasing rapidly because of its reaction
simplicity, lesser environmental impact and reduced
reaction time, providing rapid access to large libraries
of diverse molecules.
preparing
fused
dihydropyrido[2,3-d]pyrimidines,4
including microwave-induced MCRs. Additionally, we
have described a simple and efficient approach to pre-
pare interesting biological5 pyrimido[4,5-b]quinolines4c
(4) in a three-component reaction from 6-aminopyrimi-
dines (1), dimedone (2) and aromatic aldehydes (3)
(Scheme 1).
Similarly, we report here an extension of the latter reac-
tion using formaldehyde and microwave irradiation,
O
O
N
Ar
O
O
O
R
R
N
N
+ ArCH=O
+
(1)
CH3X
N
NH2
CH3X
N
H
3
1
2
4
Scheme 1.
Keywords: 6-Aminopyrimidine; Formaldehyde; Dimedone; Pyrido[2,3-d]pyrimidine; Pyrimido[4,5-b]quinoline; Basic catalyst; Microwave irradiation.
*
Corresponding author. Fax: +57 2 33392440; e-mail: jaiquir@univalle.edu.co
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.120

28
J. Quiroga et al. / Tetrahedron Letters 47 (2006) 27–30
3'
2'
O
N
O
N
O
O
4
O
5
R
O
O
4'
6'
R
R
ii
N
1'
i
N
N
2
6
+
CH3X
O
CH3X
N
NH2
7
O
CH3X
N
1
N
1a-d
O
2
OH
5a-d
6 or 7a-d
R'
R' = CH3CH2- , CH3-
Comp.
5a 5b
5c
5d
6a 6b
6c
6d
7a 7b
7c 7d
H
H
CH3 CH3
H
H
CH3 CH3
H
H
CH3 CH3
R
S
O
S
O
S
O
S
O
S
O
S
O
X
Yield (%)
70
80
75
57
55
65
60
55
75
70
75
75
Scheme 2. Reagents and conditions: (i) excess of formaldehyde (37%) and microwave irradiation during 1–3 min; (ii) reflux in absolute ethanol or
methanol.
that renders, depending on the reaction media, either
analogues of the reported pyrimido[4,5-b]quinolines
(4) or the unexpected pyridopyrimidin-spirocyclo-
hexanotriones.
hot absolute ethanol or methanol lead to formation of
compounds 6a–d and 7a–d, respectively (Scheme 2).7
Analogous reactions with paraformaldehyde in equimo-
lar amount to dimedone, instead of a large excess in
aqueous solution, yielded pyrimido[4,5-b]quinolinone
(8),8 when the mixtures were irradiated during 3–4 min
(Scheme 3). Irradiation of the mixture during 2 min or
heating in refluxing ethanol for 1 h afforded the dihydro-
pyrimido[4,5-b]quinoline (9),9 which with further heat-
ing gives the oxidized 8 (Scheme 3).
2. Results and discussion
A facile three-component one-pot cyclocondensation
takes place between 6-aminopyrimidines (1), dimedone
(2) and formaldehyde affording pyridopyrimidin–spiro-
cyclohexanetriones (5a–d) (Scheme 2). So, equimolar
amounts of starting compounds 1 and 2 with a large
excess of formaldehyde (37% in water) and triethyl-
amine as catalyst were irradiated in a domestic micro-
wave oven to give compounds 5 that were isolated in
good yields (57–80%) (see Table 1 in Scheme 2); the
reactions were repeated in different domestic microwave
ovens to prove reproducibility, and no significant devia-
tion was found.6 Treatment of compounds 5a–d with
To prove the mechanism shown in Scheme 3, intermedi-
ates 1010 and 11 were isolated and left to evolve in the
reaction conditions yielding the expected products.
Therefore, the isolation of such intermediates permitted
us to assume that the mechanism leading to the forma-
tion of 5 or 8 proceeds via an initial formation of the
2:1 dimedone/formaldehyde adduct 11, that goes to
the Knoevenagel adduct intermediate A, which suffers
OH
O
O
Et3N
HCHO
i
2
1+2
O
O
11
HO
A
O
O
iii
1
ii
iv
H3C
N
HO
O
O
CH3S
N
N
H3C
5
N
OH
O
CH3S
N
NH2
O
N
O
10
H3C
N
v
vii
CH3S
N
O
N
O
H
9
H3C
vi
N
CH3S
N
8
Scheme 3. Reagents and conditions: (i) stirred in EtOH at rt for 2 h; (ii) reflux in ethanol during 4 h or MW during 2 min; (iii) formaldehyde (37%)
and Et3N at reflux in EtOH during 4.5 h or MW during 2 min; (iv) MW during 2 min and formaldehyde (37%) excess; (v) MW during 2 min or reflux
in AcOH during 30 min; (vi) MW (2 min) or reflux in ethanol during 1 h; (vii) MW during 3–4 min.

J. Quiroga et al. / Tetrahedron Letters 47 (2006) 27–30
29
3. Lunt, E.; Newton, C. C. In Comprehensive Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Boulton, A. J.,
Mc Killop, A., Eds.; Pergamon Press: Oxford, 1984; Vol.
3, pp 199–232, and pp 260–261.
a Michael-type addition reaction of the nucleophile C-5
in 6-aminopyrimidine (1) leading to the formation of
intermediate 10. This intermediate could either undergo
cyclocondensation with excess of formaldehyde yielding
to 5 or cyclization with loss of a water molecule to ren-
der 8. The reactions to verify the evolution of 10 were
carried out either in a large excess of formaldehyde to
give 5 in 65% yield or, in its absence, to afford 8 in
40% yield.11
´
4. (a) Quiroga, J.; Cisneros, C.; Insuasty, B.; Abonıa, R.;
´
Nogueras, M.; Sanchez, A. Tetrahedron Lett. 2001, 42,
5625–5627; (b) Quiroga, J.; Rengifo, A.; Insuasty, B.;
´
´
Abonıa, R.; Nogueras, M.; Sanchez, A. Tetrahedron Lett.
2002, 43, 9061–9063; (c) Quiroga, J.; Hormaza, A.;
´
Insuasty, B.; Ortiz, A. J.; Sanchez, A.; Nogueras, M. J.
Heterocycl. Chem. 1998, 35, 231–233.
5. (a) Gangjee, A.; Ohemeng, J. K.; Tulachka, J. J.; Lin,
F.-T.; Katoh, A. A. J. Heterocycl. Chem. 1985, 22, 1149;
(b) Gangjee, A.; OꢁDonnell, J. K.; Bardos, T. J.; Kalman,
T. I. J. Heterocycl. Chem. 1984, 21, 873; (c) Stone, S. R.;
Montgomery, J. A.; Morrison, J. F. Biochem. Pharmacol.
1984, 21, 873.
When reactions were carried out with a large excess of
aqueous formaldehyde but without Et3N, a poor con-
version was achieved resulting in a mixture of com-
pounds 5 and 9. Additionally, the formation of
compound 11, isolated as crystals, was observed in all
cases.12a The intermediate 10 was also isolated by reac-
tion of 11 and 1 with Et3N as a catalyst. These findings
confirm that the key step in this reaction is the base-cat-
alyzed elimination of 11 into A, and corroborates our
previous postulation.
6. Preparation of the 8-hydroxymethyl hexahydropyrido-
[2,3-d]pyrimidine-6-spiro-10-cyclohexane-20,4,60-triones
(5a–d): Equimolar amounts of 6-aminopyrimidine
1
(2 mmol) and dimedone 2 (2 mmol), excess of aqueous
formaldehyde (30 mmol) (37%) and Et3N (0.5 mmol) were
placed into pyrex-glass open vessels and irradiated in a
domestic microwave oven for 1–3 min (at 600 Watts). The
products were washed with cold ethanol and recrystallized
from acetonitrile. Data for 5c. White solid, mp 220 °C,
The structures of all new compounds were established
by the usual spectroscopic methods, and the isolation
of single crystals for some compounds permitted us to
corroborate the postulated structures by X-ray diffrac-
tion analysis.10,12
1
(75%). H NMR (300 MHz, DMSO): d 0.79 (s, 3H), 1.05
(s, 3H), 2.62 (d, 2H), 2.51(s, 3H), 2.62 (s, 2H), 3.03 (d, 2H),
3.32 (s, 3H), 3.65 (s, 2H), 5.00 (d, 2H), 5.62 (t, 1H). 13C
NMR (DMSO): d 14.2 (CH3S), 23.2 (C-5), 26.9 (CH3),
28.5 (CH3), 29.3 (CH3N), 30.6 (C-40), 49.7 (C-7), 50.0 (C-
30 y 50), 61.7 (C-6), 70.2 (CH2OH), 90.0, 153.3, 158.5,
160.6 (C@O (4)), 205.9 (C@O). EIMS: m/z: 365 (M+, 6),
347 (10), 335 (25), 318 (35), 251 (45), 250 (100), 88 (30), 55
(40). Anal. Calcd for C17H23N3O4SÆH2O: C, 53.24; H,
6.57; N, 10.95; S, 8.36. Found: C, 52.71; H, 6.83; N, 11.05;
S, 8.10.
3. Conclusion
The reported three component one-step procedure is a
simple, practical and very regioselective method for the
preparation of novel hexahydropyridopyrimidine–spiro-
cyclohexanetriones or pyrimido[4,5-b]quinolinones from
6-aminopyrimidones, formaldehyde and dimedone,
monitoring the regioselectivity of the reaction by the
purity of formaldehyde.
7. Preparation of the 8-ethoxy (or methoxy)methylhexahy-
dropyrido[2,3-d]pyrimidine-6-spiro-10-cyclohexane-20,4,60-
triones (6 or 7): Products 5 were heated to reflux in
absolute ethanol or methanol, respectively, for 15 min.
Data for 6c. White solid, mp 280 °C, (60%) 1H NMR
(300 MHz, DMSO): d 0.78 (s, 3H), 0.97 (s, 3H), 1.03 (m,
3H), 2.38 (s, 3H), 2.86 (s, 2H), 2.93 (d, 2H), 3.34 (m, 2H),
3.55 (s, 3H), 5.70 (s, 2H). 13C NMR (DMSO): d 14.4
(CH3S), 27.0 (CH3CH2O), 27.3 (C-5), 27.6 (CH3), 28.3
(CH3), 29.5 (CH3N), 46.9 (C-7), 50.2 (C-30 and C-50), 60.6
(C-6), 87.2, 153.5, 159.7, 160.1 (C@O(4)), 203.3 (C@O).
EIMS: m/z: 393 (M+, 27), 348 (100), 250 (30), 88 (79), 83
(58), 56 (44), 41 (87).
Acknowledgements
The authors wish to thank COLCIENCIAS, Universi-
´
´
dad del Valle, the Spanish ꢀConsejerıa de Innovacion,
´
Ciencia y Empresa, Junta de Andalucıaꢁ and Servicios
´
´
Tecnicos de la Universidad de Jaen for financial sup-
port. S.C. thanks Universidad de Narino for her
˜
8. Preparation of the pyrimido[4,5-b]quinoline-4,6-diones
(8a–d): A mixture of 6-aminopyrimidine 1 (1 mmol),
dimedone 2 (2 mmol) and paraformaldehyde (2 mmol)
along with triethylamine (0.25 mmol) was placed into
pyrex-glass open vessels and irradiated in a domestic
microwave oven for 3–4 min (at 600 Watts). Products were
recrystallized from ethanol. Data for 8c. White solid, mp
254 °C, yield 45%. 1H NMR (300 MHz, DMSO): d 1.09 (s,
6H), 2.66 (s, 3H), 3.05 (d, 2H), 3.29 (d, 2H), 3.49 (s, 3H),
8.70 (s, 1H). 13C NMR (DMSO): d 15.2 (CH3S), 28.0
(CH3), 30.5 (CH3N), 32.6 (C-8), 46.3 (C-9), 51.3 (C-7),
112.7, 124.7, 135.1 (C-5), 158.1, 161.0, 165.4, 168.6
(C@O(4)), 196.2 (C@O). EIMS: m/z: 303 (M+, 39), 288
(12), 258 (100), 229 (20), 173 (11).
fellowship.
References and notes
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diones (9): A mixture of 6-aminopyrimidine 1 (1 mmol),
dimedone 2 (2 mmol), paraformaldehyde (2 mmol) and
triethylamine (0.25 mmol) was placed into pyrex-glass
open vessels and irradiated in a domestic microwave oven
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30
J. Quiroga et al. / Tetrahedron Letters 47 (2006) 27–30
for 1–2 min (at 600 Watts). Products were recrystallized
10. Low, J. N.; Cobo, J.; Cruz, S.; Quiroga, J.; Glidewell, C.
Acta Cryst. 2004, C60, 191–193.
from ethanol. Data for 9c: white solid (30% yield), mp
229 °C. 1H NMR (300 MHz, DMSO): d 0.99 (s, 6H), 2.13
(d, 2H), 2.28 (d, 2H), 2.53 (s, 3H), 3.04 (s, 2H), 3.33 (s,
3H), 9.27 (s, 1H). 13C NMR (DMSO): d 14.2 (CH3S), 19.5
(C-5), 27.8 (CH3), 29.6 (CH3N), 31.9 (C-8), 39.4 (C-7),
49.9 (C-9), 92.9, 104.9, 151.1, 151.5, 160.7 (C-4), 194.4 (C-
6). EIMS: m/z: 306 (20), 305 (M+, 97), 304 (42), 290 (100),
258 (42), 173 (26), 118 (28), 88 (84). Anal. Calcd for
C15H19N3O2S: C, 58.99; H, 6.27; N, 13.76; S, 10.50.
Found: C, 59.22; H, 6.43; N, 13.68; S, 10.03.
11. The product 5c was obtained starting from 10c and excess
of formaldehyde heated to reflux for 4 h. Alternatively the
product 8c was obtained when the compound 10c was
irradiated in microwave oven during 2 min or heated
under reflux in ethanol during 120 min.
12. (a) Low, J. N.; Cobo, J.; Cruz, S.; Quiroga, J.; Glidewell,
C. Acta Cryst. 2003, C59, 666–668; (b) Low, J. N.;
Ferguson, G.; Cobo, J.; Nogueras, M.; Cruz, S.; Quiroga,
J.; Glidewell, C. Acta Cryst. 2004, C60, 438–442.