Generation of pyrrolo[2,3-d]pyrimidines. Unexpected products in the multicomponent reaction of 6-aminopyrimidines, dimedone, and arylglyoxal

Article abstract of DOI:10.1016/j.tetlet.2010.08.021

A series of 6-aryl-5-(1-cyclohexen-1-yl)pyrrolo[2,3-d]pyrimidines 9a-q were obtained by the three-component reaction between 6-aminopyrimidines 6, 7, 8, dimedone 2, and arylglyoxal 5a,b. The unexpected cyclization process was established by NMR and X-ray diffraction measurements.

Full text of DOI:10.1016/j.tetlet.2010.08.021

Tetrahedron Letters 51 (2010) 5443–5447
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Generation of pyrrolo[2,3-d]pyrimidines. Unexpected products in the
multicomponent reaction of 6-aminopyrimidines, dimedone, and arylglyoxal
Jairo Quiroga a, , Paola A. Acosta a, Silvia Cruz b, Rodrigo Abonía a, Braulio Insuasty a, Manuel Nogueras c,
,
⇑
⇑
Justo Cobo c
a Grupo de Investigación de Compuestos Heterocíclicos, Department of Chemistry, Universidad del Valle, A.A. 25360, Cali, Colombia
b Department of Chemistry, Universidad de Nariño, A.A. 1175, Pasto, Colombia
c Department of Inorganic and Organic Chemistry, Universidad de Jaén, 23071 Jaén, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 6-aryl-5-(1-cyclohexen-1-yl)pyrrolo[2,3-d]pyrimidines 9a–q were obtained by the three-com-
ponent reaction between 6-aminopyrimidines 6, 7, 8, dimedone 2, and arylglyoxal 5a,b. The unexpected
cyclization process was established by NMR and X-ray diffraction measurements.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 25 May 2010
Revised 2 August 2010
Accepted 6 August 2010
Available online 12 August 2010
Keywords:
Pyrrolopyrimidines
Multicomponent reaction
Aminopyrimidines
Arylglyoxal
Dimedone
The pyrrolo[2,3-d]pyrimidine ring system is a common motif in
several natural products and biologically active molecules.1a Re-
cently there has been a great interest in the synthesis of pyrrol-
o[2,3-d]pyrimidines due to their proven biological activity and
medicinal utility. A number of pyrrolopyrimidine derivatives struc-
turally related to toyocamycin, sangivamycin, and the seco nucleo-
sides of tubercidin have antiviral activity.1
As the pyrrolo[2,3-d]pyrimidine heterosystem represents a 7-
deazaanalogue of biogenic purine, it is an important class of com-
pounds possessing notable biological activity.2,3
which yields pyrimido[4,5-b]quinolines4 4 via a simple, practical,
and a very regioselective procedure (Scheme 1).
In the course of our research aimed at the preparation of bioac-
tive nitrogen-containing heterocycles, we addressed the multicom-
ponent synthesis of fused pyrido[2,3-d]pyrimidines.5
We report herein an extension of this three-component reaction
with aminopyrimidines 1, dimedone 2, and arylglyoxales 5, which
yielded the formation of unexpected several pyrrolo[2,3-d]pyrimi-
dine derivatives 9a–q (Scheme 2, Table 1).
The structure of all new compounds was determined on the ba-
sis of their analytical techniques, 1D and 2D-NMR spectra, and MS,
which agree with the proposed structures. Single crystal X-ray dif-
We recently reported a three component one-step reaction of 6-
aminopyrimidin-4-ones 1 with dimedone 2 and benzaldehydes 3,
O
O
N
Ar
O
O
O
R
R
N
N
+ ArCH=O
+
H3CX
N
1
NH2
H3CX
N
H
3
2
4
Scheme 1.
⇑
Corresponding authors. Fax: +57 2 33392440 (J.Q.); fax: +34 618907111 (M.N.).
E-mail addresses: jaiquir@univalle.edu.co (J. Quiroga), mmontiel@ujaen.es (M.
Nogueras).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.021

5444
J. Quiroga et al. / Tetrahedron Letters 51 (2010) 5443–5447
4´
5´
3´
2´
O
O
R
N
O
1´
6´
OH
Ar
4
4a
R
X
5
N
3
X
N
6
NH2
6
2
N
N
H
1
R = H, CH3
X = OCH3, SCH3, NH2
9a-i
4´
5´
3´
2´
O
NH2
N
NH2
1´
O
O
O
6´
OH
Ar
4a
5
3
+
+
O
N
Ar
6
H2N
N
7
NH2
N
H
2
H2N
N
5
1
2
9j-k
4´
5´
3´
O
2´
R1
O
O
N
1´
6´
OH
Ar
R1
4
4a
5
N
3
X
N
R2
8
NH2
6
N
2
X
N
H
R2
9l-q
R1 = H, CH3; R2 = H, CH3
X = O
Scheme 2.
p
m
o
i
O
O
C
O
8
O
O
+
O
O
NH2
C
6,7,8
-H2O
HO
9
HO
CH
7
OH
1
CH
2
3
H
N
6
5
5
2
O
Y
O
N
4
10
X
11
Scheme 3.
fraction analysis of compounds 9b6 was used to corroborate the
postulated structures.7
A possible mechanism route for the described three-component
reaction is outlined in Scheme 3. We consider that initially the
dimedone reacts with the arylglyoxal to give the intermediate 10.
The last one reacts with the 6-aminopyrimidine leading to the for-
mation of intermediate 11, which suffers the cyclation with loss of a
water molecule, to form final pyrrolopyrimidine 9. As an evidence of
this is the fact that the reaction of dimedone with phenylglyoxal led
to the formation of product 10, which was isolated and character-
Table 1
Pyrrolo[2,3-d]pyrimidine derivatives
Entry
Pyrimidine
Product
Mp (°C)
%
m/z
O
HN
H3CS
O
O
N
9a
280–282
50
395
N
NH2
OH
Ph
HN
N
H
H3CS
O
N
H3C
N
O
O
N
9b
294–295
60
410
H3C
H3CS
NH2
OH
Ph
N
N
H
H3CS

J. Quiroga et al. / Tetrahedron Letters 51 (2010) 5443–5447
5445
Table 1 (continued)
Entry
Pyrimidine
Product
Mp (°C)
%
m/z
O
HN
H3CO
O
O
9c
9d
9e
278–280
46
379
N
NH2
OH
HN
Ph
N
H
H3CO
N
O
N
H3C
N
O
O
N
296–298
328–329
60
46
393
364
H3CO
NH2
H3C
OH
Ph
N
N
H
H3CO
O
HN
H2N
O
O
N
NH2
OH
Ph
HN
H2N
N
N
H
O
HN
O
O
O
O
9f
9g
9h
9i
H3CS
N
NH2
299–301
292–293
262–263
286–288
43
39
38
43
429/431
443/445
413/415
OH
HN
N
H3CS
N
H
Cl
O
N
H3C
N
O
N
H3C
H3CS
NH2
OH
N
N
H
H3CS
Cl
O
N
HN
H3CO
O
N
NH2
OH
HN
H3CO
N
H
Cl
O
HN
O
O
N
398/400
H2N
N
NH2
OH
HN
H2N
N
H
Cl
NH2
N
N
N
O
O
N
9j
242–243
279–281
41
41
363
H2N
NH2
OH
Ph
HN
H2N
N
H
NH2
N
O
NH2
N
9k
397/399
H2N
NH2
OH
N
H
H2N
Cl
(continued on next page)

5446
J. Quiroga et al. / Tetrahedron Letters 51 (2010) 5443–5447
Table 1 (continued)
Entry
Pyrimidine
Product
Mp (°C)
%
m/z
O
HN
O
O
9l
246–248
44
381
S
N
H
NH2
OH
HN
Ph
N
S
N
H
H
O
N
H3C
O
N
O
O
N
NH2
H3C
O
9m
299–300
55
393
OH
Ph
N
O
CH3
N
H
CH3
O
N
HN
O
O
NH2
9n
9o
9p
296–298
308–309
306–308
53
43
40
379
OH
Ph
HN
O
CH3
N
N
H
CH3
O
HN
S
O
O
415/417
N
H
NH2
OH
HN
S
N
N
H
H
Cl
O
N
H3C
O
O
O
N
N
NH2
H3C
O
427/429
OH
CH3
N
H
N
CH3
Cl
O
HN
O
O
O
N
NH2
9q
295–297
54
413/415
OH
HN
O
CH3
N
N
H
CH3
Cl
ized.8 The compound 10 was submitted to the reaction with amino-
pyrimidines 6 under the same conditions to give compounds 9.9
The described three-component one-step procedure is a simple,
practical, and a very regioselective method for the preparation of
novel pyrrolo[2,3-d]pyrimidines. The biological properties of the
new compounds obtained in this research are under investigation.
2. (a) Townsend, L. B.; Lewis, A. F.; Roti Roti, L. W. US 804601, 1977; Chem. Abstr.
1978, 89, 44130.; (b) Porcari, A. R.; Ptak, R. G.; Borysko, K. Z.; Breitenbach, J. M.;
Vittori, S.; Wotring, L. L.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 2000, 43,
2438; (c) Gangjee, A.; Jain, H. D.; Phan, J.; Lin, X.; Song, X.; McGuire, J. J.; Kisliuk,
R. L. J. Med. Chem. 2006, 49, 1055; (d) Gangjee, A.; Lin, X.; Queener, S. F. J. Med.
Chem. 2004, 47, 3689; (e) Taylor, E. C.; Kuhnt, D.; Shih, C.; Rinzel, S. M.; Grindey,
G. B.; Barredo, J.; Jannatipour, M.; Moran, R. G. J. Med. Chem. 1992, 35, 4450; (f)
Edstrom, E. D.; Wei, I. J. Org. Chem. 1993, 58, 403.
3. (a) Seela, F.; Zulauf, M. Helv. Chim. Acta 1999, 82, 1878; (b) Zhang, L.; Zhang, Y.;
Li, X.; Zhang, L. Bioorg. Med. Chem. 2002, 10, 907; (c) Taylor, E. C.; Jennings, L. D.;
Mao, Z.; Hu, B.; Jun, J.-G.; Zhou, P. J. Org. Chem. 1997, 62, 5392; (d) Taylor, E. C.;
Chaudhuri, R. P.; Watson, S. E. Tetrahedron 1999, 55, 1631; (e) Gangjee, A.; Yu,
J.; McGuire, J. J.; Cody, V.; Galitsky, N.; Kisliuk, R. L.; Queener, S. F. J. Med. Chem.
2000, 43, 3837.
Acknowledgements
Authors wish to thank COLCIENCIAS, Universidad del Valle, the
Spanish ‘Consejería de Innovación, Ciencia y Empresa, Junta de
Andalucía’, and the Servicios Técnicos de Investigación de la Uni-
versidad de Jaén for the financial support. SC thanks the Universi-
dad de Nariño for her fellowship.
4. (a) Quiroga, J.; Hormaza, A.; Insuasty, B.; Ortiz, A. J.; Sánchez, A.; Nogueras, M. J.
Heterocycl. Chem. 1998, 35, 231–233; For
a review on multi-component
reactions with 1,3-dicarbonyl compounds, see: (b) Simon, C.; Constantieux,
T.; Rodriguez, J. Eur. J. Org. Chem. 2004, 4957–4980.
5. (a) Quiroga, J.; Cisneros, C.; Insuasty, B.; Abonía, R.; Nogueras, M.; Sánchez, A.
Tetrahedron Lett. 2001, 42, 5625–5627; (b) Quiroga, J.; Rengifo, A.; Insuasty, B.;
Abonía, R.; Nogueras, M.; Sánchez, A. Tetrahedron Lett. 2002, 43, 9061–9063; (c)
Quiroga, J.; Insuasty, B.; Abonía, R.; Hernández, P.; Nogueras, M.; Sánchez, A.
Heterocycl. Commun. 2000, 6, 345–350.
References and notes
1. (a) Gupta, P. K.; Daunert, S.; Nassiri, M. R.; Wotring, L. L.; Drach, J. C.; Townsend,
L. B. J. Med. Chem. 1989, 32, 402; (b) Gupta, P. K.; Nassiri, M. R.; Coleman, L. A.;
Wotring, L. L.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 1989, 32, 1420.
6. Cruz, S.; Quiroga, J.; de la Torre, J.; Cobo, J.; Low, J. N.; Glidewell, C. Acta
Crystallogr., Sect. C 2006, 62, 554–556.

J. Quiroga et al. / Tetrahedron Letters 51 (2010) 5443–5447
5447
7. General procedure for the preparation of pyrrolo[2,3-d]pyrimidines 9. A solution of
equimolar amounts of 6-aminopyrimidine 6, 7, 8, dimedone 2, and arylglyoxal
5 in ethanol (15 mL) and amounts of catalytic acetic acid was heated for 9 h.
Then, the reaction mixture was allowed to cool to ambient temperature, and
the resulting solid products were collected by filtration, washed with ethanol,
dried in air, and recrystallized from ethanol. Data for 5-(2-hydroxy-4,4-
dimethyl-6-oxo-1-cyclohexen-1-yl)-2-(methylsulfanyl)-6-phenyl-3,7-dihydro-4H-
pyrrolo[2,3-d]-pyrimidin-4-one 9a: White solid, yield 50%, 280–282 °C. 1H NMR
(400 MHz DMSO-d6) d: 1.05 (s, 3H, CH3), 1.50 (s, 3H, CH3), 2.16 (s, 2H, H-50),
2.37 (s, 2H, H-30), 2.54 (s, 3H, SCH3), 7.19 (t, 1H, Hp, J = 7.36), 7.28 (t, 2H, Hm
dimedone 2, arylglyoxal 5, and amounts of catalytic CdI2 was subjected to
microwave irradiation for 20 s at a temperature of 80 °C (CEM-Discovery).
Then, the product obtained is treated with a mixture of ethanol–water, and the
resulting solid products were collected by filtration, washed with ethanol,
dried in air, and recrystallized from ethanol. White solid, yield 47%, 165–67 °C.
1H NMR (400 MHz CDCl3) d: 1.09 (s, 6H, CH3), 1.13 (s, 6H, CH3), 2.25 (s, 4H, H-
4), 2.50 (s, 4H, H-6), 5.42 (s, 1H, H-7), 7.49 (d, 2H, Ho), 7.56 (t, 2H, Hm), 8.28 (d,
1H, Hp). 13C NMR (100 MHz CDCl3) d: 27.4 (CH3), 29.0 (CH3), 32.3 (C-4), 34.2 (C-
7), 40.9 (C-5), 50.4 (C-3), 113.1 (C-1), 128.1 (Cm), 129.3 (Co) 132.8(Cp), 137.3
(Ci), 164.4 (C-2), 196.7 (C-6), 201.5 (C-8). IE EM: m/z: 396 (M+, 1), 273 (100).
Anal. Calcd for C24H28O5: C, 72.71; H, 7.12. Found: C, 72.45; H, 6.78.
00
J = 7.67), 7.47 (d, 2H, Ho , J = 7.47), 9.86 (s, 1H, OH), 11.73 (s, 1H, H-3), 11.88 (s,
1H, H-7). 13C NMR (100 MHz DMSO-d6) d: 13.4 (SCH3), 28.3 (CH3), 28.9 (CH3),
32.1 (C-40), 43.4 (C-30), 51.1 (C-50), 106.2 (C-5), 108.1 (C-4a), 109.5 (C-10), 126.5
(Co), 126.9 (Cp), 128.6 (Cm), 129.7 (C-6), 133.0 (Ci), 148.9 (C-7a), 154.5 (C-2),
158.8 (C-4), 171.4 (C-20), 196.4(C-60). IE EM: m/z: 395 (M+, 98), 380 (100,
M+ꢀCH3), 297 (34), 270 (48), 167 (31), 140 (35). Anal. Calcd for C21H21N3O3S: C,
63.78; H, 5.35; N, 10.623; Found: C, 63.59; H, 5.18; N, 10.51.
9. General procedure for the preparartion of pyrrolo[2,3-d]pyrimidines 9a (R = H,
X = SCH3) from the intermediate 10 (di-component reaction).
A solution of
equimolar amounts of 6-aminopyrimidine 6 and intermediate 10 in ethanol
(15 mL) and amounts of catalytic acetic acid was heated for 9 h. Then, the
reaction mixture was allowed to cool to ambient temperature, and the
resulting solid products were collected by filtration, washed with ethanol,
dried in air, and recrystallized from ethanol. Yield 45%.
8. Preparation of the intermediate 2,20-(2-oxo-2-phenyl-1,1-ethanediyl)bis(3-
hydroxy-5,5-dimethyl-2-cyclohexen-1-one 10. This compound was obtained by
a modified method described in Ref. 10. A mixture of equimolar amounts of
10. Prajapati, D.; Sandhu, J. S. J. Chem. Soc., Perkin Trans. 1 1993, 739–740.