Spirooxindoles: reaction of 2,6-diaminopyrimidin-4(3H)-one and isatins

Article abstract of DOI:10.1016/j.tet.2009.01.013

A simple and efficient cyclocondensation reaction of 2,6-diaminopyrimidin-4(3H)-one and isatins for the synthesis of spiro[pyrimido[4,5-b]quinoline-5,5′-pyrrolo[2,3-d]pyrimidine] and spiro[indoline-pyrido[2,3-d:6,5-d′]dipyrimidine] derivatives is reported

Full text of DOI:10.1016/j.tet.2009.01.013

Tetrahedron 65 (2009) 2005–2009
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Spirooxindoles: reaction of 2,6-diaminopyrimidin-4(3H)-one and isatins
*
Khosrow Jadidi, Ramin Ghahremanzadeh, Ayoob Bazgir
Department of Chemistry, Shahid Beheshti University, G.C., PO Box 19396-4716, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient cyclocondensation reaction of 2,6-diaminopyrimidin-4(3H)-one and isatins for the
synthesis of spiro[pyrimido[4,5-b]quinoline-5,50-pyrrolo[2,3-d]pyrimidine] and spiro[indoline-pyr-
ido[2,3-d:6,5-d0]dipyrimidine] derivatives is reported.
Received 19 October 2008
Received in revised form 16 December 2008
Accepted 5 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Available online 10 January 2009
Keywords:
Isatin
2,6-Diaminopyrimidin-4(3H)-one
Spiro[pyrimidoquinoline-
pyrrolopyrimidine]
Spirooxindole
1. Introduction
developed for constructing these spirocycles, most of which were
based on cycloaddition or condensation reactions.15–23
Polyfunctionalized heterocyclic compounds play important
roles in the drug discovery process, and analysis of drugs in late
development or on the market shows that 68% of them are hetero-
cycles.1,2 Therefore, it is not surprising that research on the syn-
thesis of polyfunctionalized heterocyclic compounds has received
significant attention.
Benzo- and hetero-fused pyrimidines are known to exhibit
promising antiviral,3 antibacterial,4 anti-AIDS5 and antino-
ciceptive6 activities. Fused pyrimidines are selective inhibitors for
multidrug resistance (MDR).7 The relevance of fused pyrimidines as
antiplatelet and antithrombotic drugs8 has been firmly established
by clinical trials. Thus, further exploration of pyrimidine chemistry
appears to be worthwhile.
Consideringtheabovereports,thedevelopmentofnewandsimple
synthetic methods for the efficient preparation of spiro heterocycles
containing pyrimidine ring fragments is therefore an interesting
challenge. Very recently, we have reported a synthesis of spiro[pyr-
imido[4,5-b]quinoline-5,50-pyrrolo[2,3-d]pyrimidine] derivatives by
the reaction of 6-amino-uracils and isatins in refluxing ethanol.24 Due
to the biological activity of fused pyrimidines, and our interest in the
synthesis of heterocyclic compounds,25–31 herein, we report a simple
and efficient method for the preparation of new spiro[pyr-
imido[4,5-b]quinoline-5,50-pyrrolo[2,3-d] pyrimidine] derivatives. To
the bestof ourknowledge, this isthe second reporton the synthesis of
spiro[pyrimido[4,5-b]quinoline-5,50-pyrrolo[2,3-d]pyrimidine]s.
Spirocyclic systems containing one carbon atom common to two
rings are structurally interesting.9 The asymmetric characteristic of
the molecule due to the chiral spiro carbon is one of the important
criteria of the biological activities. The presence of the sterically
constrained spiro structure in various natural products also adds to
the interest in the investigations of spiro compounds.10 Spiro
compounds represent an important class of naturally occurring
substances characteristic by their highly pronounced biological
properties.11,12 Similarly, functionalized spiro cycloalkyloxindoles
are found in a variety of natural products and bioactive mole-
cules.13,14 Consequently, many synthetic methodologies have been
2. Results and discussion
After some preliminary experimentation, it was found that
a mixture of 2,6-diaminopyrimidin-4(3H)-one 1 and isatin 2a, in
the presence of a catalytic amount of p-toluene sulfuonic acid
(p-TSA) as an inexpensive and readily available catalyst, afforded
2,20-diamino-3H-spiro[pyrimido[4,5-b]quinoline-5,50-pyrrolo[2,3-
d]pyrimidine]-4,40,60(30H,70H,10H)-trione 3a in 85% yield after
refluxing in ethanol for 8 h (Scheme 1).
Encouraged by this success, we have extended this reaction to
various isatins 2b–d under similar conditions (using EtOH/p-TSA),
furnishing the respective 2,20-diamino-3H-spiro[pyrimido[4,5-
b]quinoline-5,50-pyrrolo[2,3-d]pyrimidine]-4,40,60(30H,70H,10H)-
triones 3b–d in good yields (Scheme 2). The optimized results are
summarized in Table 1.
* Corresponding author. Fax: þ98 21 22431661.
E-mail address: a_bazgir@sbu.ac.ir (A. Bazgir).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.01.013

2006
K. Jadidi et al. / Tetrahedron 65 (2009) 2005–2009
H2N
HN
O
O
NH
O
O
N
O
N
HO
H+
1
X
+
NH2
NH
O
N
H+
NH
HN
H2N
HN
O
O
N
O
O
HN
N
N
EtOH/Reflux
H2N
NH2
HN
+
NH2
O
NH
NH2
2
H
1
2
X
NH2
NH
p-TSA/ 8 h
N
H2N
N
H
N
H
X
NH2
N
1
2a
3a
O
O
O
N
O
O
X
Scheme 1.
HN
HN
H2N
N
O
N
H
NH2
NH2
NH2
H2N
H2N
4
5
-NH3
H2N
HN
Product 3
N
Scheme 3.
O
NH
O
O
X
+
NH2
O
HN
O
X
EtOH/Reflux
O
NH
NH2
2
p-TSA/ 8 h
N
H2N
N
H
N
N
H
3a-d
1
2a-d
X
O
N
Scheme 2.
O
NR
H
N
X
O
N
O
N
EtOH/Reflux
p-TSA/ 8 h
+
NH2
2
O
O
H2N
HN
H2N
NH
N
R
N
H
NH2
1
6a-g
7a-g
Table 1
Synthesis of spiro[pyrimido[4,5-b]quinoline-5,50-pyrrolo[2,3-d]pyrimidine]-trione 3
Scheme 4.
Entry
Isatin 2
Product 3
Yielda (%)
H2N
HN
O
N
We have not established the exact mechanism for the formation
of spiro[pyrimido[4,5-b]quinoline-5,50-pyrrolo[2,3-d]pyrimidine]-
triones 3, however, a reasonable suggestion is offered in Scheme 3.
The reaction may have proceeded through intermediate 4, formed
in situ by reaction of isatins 2 with 2,6-diaminopyrimidin-4(3H)-
one 1, then, intermediate 4 was converted to intermediate 5 and
which cyclized to afford the corresponding product 3 and ammonia
(Scheme 3).
NH
O
O
N
O
O
NH
NH2
1
85
N
H
N
H
2a
3a
Finally, to further explore the potential of this protocol for spiro-
heterocyclic synthesis, we investigated the reaction of 2,6-di
aminopyrimidin-4(3H)-one 1 and N-alkylisatins 6a–g. Surprisingly,
it was found that under similar conditions, different products 20,
80-diamino-spiro[indoline-3,50-pyrido[2,3-d:6,5-d0]dipyrimidine]-
2,40,60(30H,70H,100H)-triones 7a–g were formed in 78–87% yields
(Scheme 4, Table 2). In previous work, we found that N-alkylisatin
and isatins reacted similarly.24 To the best of our knowledge, this
new procedure provides the first example of an efficient method
for the synthesis of spiro[indoline-3,50-pyrido[2,3-d:6,5-d0]-
dipyrimidine]triones.
H2N
N
HN
O
NH
O
O
N
O2N
O
O2N
O
NH
NH2
2
90
N
H
N
H
2b
3b
H2N
HN
O
N
Compounds 7 may result from the initial addition of 2,6-di-
NH
O
O
aminopyrimidin-4(3H)-one 1 to N-alkylisatins
6 to yield in-
Br
O
Br
termediate 8, which reacted further with another molecule of 1 and
cyclized to afford the corresponding product 7 (Scheme 5).
Compounds 3a–d and 7a–g are stable solids whose structures
are fully supported by IR, 1H and 13C NMR spectroscopy, mass
spectrometry and elemental analysis.
O
NH
NH2
3
88
N
H
N
H
N
2c
3c
H2N
HN
O
N
3. Conclusion
O
NH
Me
O
N
O
In conclusion, we have described an efficient and simple
method for the preparation of spiro[pyrimido[4,5-b]quinoline-
5,50-pyrrolo[2,3-d]pyrimidine] and spiro[indoline-pyrido[2,3-
d:6,5-d0]dipyrimidine] derivatives via
reaction of 2,6-diaminopyrimidin-4(3H)-one and isatins in
refluxing ethanol.
O
4
Me
85
NH
NH2
N
H
N
H
2d
a
cyclocondensation
3d
a
Isolated yields.

K. Jadidi et al. / Tetrahedron 65 (2009) 2005–2009
2007
O
NR
O
O
N
O
HO
Table 2
H+
1
X
+
NH2
Synthesis of spiro[indoline-pyrido[2,3-d:6,5-d0]dipyrimidine] 7
HN
H+
HN
O
Entry
Isatin 2
Product 7
Yield (%)
N
H2N
N
1
H2N
NH2
X
6
R
MeN
R
O
N
O
O
O
N
X
O
O
O
N
HN
H2N
NH
NH2
O
1
81
NH
-NH3
HN
H2N
N
Product 7
N
N
H
Me
H2N
N
NH2
NH2
8
6a
7a
Scheme 5.
EtN
O
O
O
O
N
4. Experimental
HN
H2N
NH
NH2
O
2
3
4
80
78
87
N
4.1. Typical procedure for the preparation of 2,20-diamino-
3H-spiro[pyrimido[4,5-b]quinoline-5,50-pyrrolo[2,3-
d]pyrimidine] 4,40,60(30H,70H,10H)-trione (3a)
N
N
H
Et
6b
7b
A mixture of 2,6-diaminopyrimidin-4(3H)-one (2 mmol), isatin
(1 mmol) and p-TSA (0.5 mmol) in refluxing EtOH (5 mL) was stir-
red for 8 h (TLC). After completion of reaction, the reaction mixture
was filtered and the precipitate washed with water and then with
EtOH to afford the pure product 3a as a white powder (0.31 g, 85%).
Mp>320 ꢀC. IR (KBr) (nmax/cmꢁ1): 3393, 3152, 1681, 1658, 1637. 1H
NMR (300 MHz, DMSO-d6): dH (ppm) 6.26 (2H, br s, NH2), 6.65–7.04
(6H, m, NH2 and H–Ar), 9.21 (1H, s, NH), 10.07 (1H, s, NH), 10.18 (1H,
s, NH), 10.43 (1H, s, NH). 13C NMR (75 MHz, DMSO-d6): dC (ppm)
50.5, 56.5, 85.4, 101.7, 115.5, 121.7, 122.3, 126.3, 127.7, 137.9, 154.4,
155.7, 157.3, 160.9, 163.4, 182.7. MS, m/z (%): 364 (Mþ, 15), 323 (23),
236 (50), 149 (100). Anal. Calcd for C16H12N8O3: C, 52.75; H, 3.32; N,
30.76%. Found: C, 52.69; H, 3.37; N, 30.69%.
PhH2CN
O
N
O
O
O
N
O
HN
H2N
NH
NH2
CH2Ph
N
N
H
6c
7c
MeN
NO2
O
O
O
O
N
O2N
HN
H2N
NH
NH2
O
N
N
N
H
Me
6d
7d
4.2. 2,20-Diamino-7-nitro-3H-spiro[pyrimido[4,5-
b]quinoline-5,50-pyrrolo[2,3-d]pyrimidine]-
4,40,60(30H,70H,10H)-trione (3b)
EtN
NO2
O
O
O
O
N
White powder (0.37 g, 90%); mp>300 ꢀC. IR (KBr) (nmax/cmꢁ1):
3363, 3152, 1733, 1699, 1658. 1H NMR (300 MHz, DMSO-d6): dH
(ppm) 6.42 (2H, s, NH2), 6.72 (2H, s, NH2), 7.07 (1H, d, 3JHH¼9.0 Hz,
O2N
HN
H2N
NH
NH2
O
5
86
N
N
N
H
Et
3
6e
H–Ar), 7.47 (1H, s, H–Ar), 7.97 (1H, d, JHH¼9.0 Hz, H–Ar), 10.05
7e
(1H, s, NH), 10.26 (1H, s, NH), 10.35 (1H, s, NH), 10.66 (1H, s, NH).
MS, m/z (%): 409 (Mþ, 10), 236 (52), 149 (100). Anal. Calcd for
C16H11N9O5: C, 46.95; H, 2.71; N, 30.80%. Found: C, 46.89; H, 2.76;
N, 30.87%.
MeN
Br
O
Due to very low solubility of products 3b and 3c, we can0t report
the 13C NMR data for these products.
O
O
O
N
Br
HN
H2N
NH
NH2
O
6
88
N
N
N
H
Me
6f
7f
4.3. 2,20-Diamino-7-bromo-3H-spiro[pyrimido[4,5-
b]quinoline-5,50-pyrrolo[2,3-d]pyrimidine]-
4,40,60(30H,70H,10H)-trione (3c)
EtN
Br
O
O
O
White powder (0.39 g, 88%); mp>300 ꢀC. IR (KBr) (nmax/cmꢁ 1):
3342, 3168, 1660, 1658. 1H NMR (300 MHz, DMSO-d6): dH (ppm)
6.28 (2H, s, NH2), 6.66 (2H, s, NH2), 6.68–7.21 (3H, m, H–Ar), 9.37
(1H, s, NH),10.11 (1H, s, NH),10.22 (1H, s, NH),10.49 (1H, s, NH). MS,
m/z (%): 444 (Mþ, 12), 442 (Mþ, 12), 236 (100), 149 (97). Anal. Calcd
for C16H11BrN8O3: C, 43.36; H, 2.50; N, 25.28%. Found: C, 43.42; H,
2.44; N, 25.36%.
O
N
Br
O
7
83
HN
H2N
NH
NH2
N
Et
N
N
H
6g
7g

2008
K. Jadidi et al. / Tetrahedron 65 (2009) 2005–2009
4.4. 2,20-Diamino-7-methyl-3H-spiro[pyrimido[4,5-
b]quinoline-5,50-pyrrolo[2,3-d]pyrimidine]-
4,40,60(30H,70H,10H)-trione (3d)
(1H, d, 3JHH¼8.5 Hz, H–Ar), 9.71 (1H, s, NH), 10.46 (2H, s, 2NH). 13
C
NMR (75 MHz, DMSO-d6): dC (ppm): 12.3, 30.5, 48.4, 89.3, 106.9,
118.0, 125.2, 137.8, 142.2, 150.8, 155.1, 155.6, 160.6, 179.6. MS, m/z
(%): 437 (Mþ, 4), 368 (22), 313 (31), 264 (15), 236 (40), 149 (100).
Anal. Calcd for C18H15N9O5: C, 49.43; H, 3.46; N, 28.82%. Found: C,
49.49; H, 3.40; N, 28.76%.
White powder (0.32 g, 85%); mp>320 ꢀC. IR (KBr) (nmax/cmꢁ1):
3360, 3193, 1714, 1653. 1H NMR (300 MHz, DMSO-d6): dH (ppm)
2.09 (3H, s, CH3), 6.19 (2H, s, NH2), 6.45 (1H, s, H–Ar), 6.59 (2H, s,
NH2), 6.79–6.82 (2H, m, H–Ar), 9.10 (1H, s, NH), 9.98 (1H, s, NH),
10.15 (1H, s, NH), 10.38(1H, s, NH). 13C NMR (75 MHz, DMSO-d6): dC
(ppm) 20.8, 50.5, 85.2, 101.6, 115.4, 122.1, 126.3, 128.4, 130.2, 135.6,
154.3, 155.8, 157.2, 160.9, 163.4, 182.8. MS, m/z (%): 378 (Mþ, 8), 368
(100), 313 (42), 236 (57), 149 (78). Anal. Calcd for C17H14N8O3: C,
53.97; H, 3.73; N, 29.62%. Found: C, 53.92; H, 3.69; N, 29.69%.
4.10. 20,80-Diamino-5-bromo-spiro[1-methylindoline-3,50-
pyrido[2,3-d:6,5-d0]dipyrimidine]-2,40,60(30H,70H,100H)-
trione (7f)
White powder (0.40 g, 88%); mp>320 ꢀC; IR (KBr) (nmax/cmꢁ1):
3361, 3164, 1656, 1606. 1H NMR (300 MHz, DMSO-d6): dH (ppm)
3.05 (3H, s, CH3), 6.76 (4H, br s, 2NH2), 6.78–6.99 (3H, m, H–Ar),
9.62 (1H, s, NH),10.39 (2H, s, 2NH). 13C NMR (75 MHz, DMSO-d6): dC
(ppm) 26.7, 48.5, 89.8, 108.9, 113.2, 125.5, 129.9, 138.9, 144.7, 154.9,
155.2, 160.2, 179.4. MS, m/z (%): 458 (Mþ, 8), 456 (Mþ, 8), 236 (50),
149 (100). Anal. Calcd for C17H13BrN8O3: C, 44.66; H, 2.87; N,
24.51%. Found: C, 44.70; H, 2.84; N, 24.56%.
4.5. 20,80-Diamino-spiro[1-methylindoline-3,50-pyrido[2,3-
d:6,5-d0]dipyrimidine]-2,40,60(30H,70H,100H)-trione (7a)
White powder (0.31 g, 81%); mp>300 ꢀC; IR (KBr) (nmax/cmꢁ1):
3358, 3173, 1653, 1607. 1H NMR (300 MHz, DMSO-d6): dH (ppm)
3.05 (3H, s, CH3), 6.62 (4H, br s, 2NH2), 6.75–7.11 (4H, m, H–Ar), 9.48
(1H, s, NH), 10.26 (2H, s, 2NH). MS, m/z (%): 378 (Mþ, 5), 368 (100),
236 (50). Anal. Calcd for C17H14N8O3: C, 53.97; H, 3.73; N, 29.62%.
Found: C, 53.91; H, 3.78; N, 29.54%.
4.11. 20,80-Diamino-5-bromo-spiro[1-ethylindoline-3,50-
pyrido[2,3-d:6,5-d0]dipyrimidine]-2,40,60(30H,70H,100H)-
trione (7g)
Due to very low solubility of products 7a–d and 7g, we can’t
report the 13C NMR data for these products.
White powder (0.39 g, 83%); mp>320 ꢀC; IR (KBr) (nmax/cmꢁ1):
3363, 3162, 1652, 1604. 1H NMR (300 MHz, DMSO-d6): dH (ppm)
1.15 (3H, br s, CH3), 3.62 (2H, br s, CH2), 6.75 (4H, br s, 2NH2),
6.97–7.46 (3H, m, H–Ar), 9.56 (1H, s, NH), 10.36 (2H, s, 2NH). MS,
m/z (%): 472 (Mþ, 10), 470 (Mþ, 10), 236 (100), 149 (100). Anal. Calcd
for C18H15BrN8O3: C, 45.87; H, 3.21; N, 23.78%. Found: C, 45.82; H,
3.25; N, 23.73%.
4.6. 20,80-Diamino-spiro[1-ethylindoline-3,50-pyrido[2,3-
d:6,5-d0]dipyrimidine]-2,40,60(30H,70H,100H)-trione (7b)
White powder (0.31 g, 80%); mp>320 ꢀC; IR (KBr) (nmax/cmꢁ1):
3440, 3168, 1702, 1643. 1H NMR (300 MHz, DMSO-d6): dH (ppm)
3
3
1.18 (3H, t, JHH¼6.2 Hz, CH3), 3.63 (2H, q, JHH¼6.3 Hz, CH2), 6.72
(4H, br s, 2NH2), 6.75–710 (4H, m, H–Ar), 9.54 (1H, s, NH),10.33 (2H,
s, 2NH). MS, m/z (%): 392 (Mþ, 8), 264 (25), 236 (50),149 (100). Anal.
Calcd for C18H16N8O3: C, 55.10; H, 4.11; N, 28.56%. Found: C, 55.04;
H, 4.06; N, 28.64%.
Acknowledgements
We gratefully acknowledge financial support from the Research
Council of Shahid Beheshti University.
4.7. 20,80-Diamino-spiro[1-benzylindoline-3,50-pyrido[2,3-
d:6,5-d0]dipyrimidine]-2,40,60(30H,70H,100H)-trione (7c)
References and notes
White powder (0.35 g, 78%); mp>320 ꢀC; IR (KBr) (nmax/cmꢁ1):
3342, 3203, 1719, 1659. 1H NMR (300 MHz, DMSO-d6): dH (ppm)
4.82 (2H, s, CH2), 6.75 (4H, br s, 2NH2), 6.35–768 (9H, m, H–Ar), 9.61
(1H, s, NH), 10.54 (2H, s, 2NH). MS, m/z (%): 454 (Mþ, 10), 264 (45),
149 (100). Anal. Calcd for C23H18N8O3: C, 60.79; H, 3.99; N, 24.66%.
Found: C, 60.75; H, 3.94; N, 24.60%.
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17. Jiang, T.; Kuhen, K. L.; Wolff, K.; Yin, H.; Bieza, K.; Caldwell, J.; Bursulaya, B.; Wu,
T. Y.-H.; He, Y. Bioorg. Med. Chem. Lett. 2006, 16, 2105.
18. Robertson, D. W.; Krushinski, J. H.; Pollock, G. D.; Wilson, H.; Kauffman, R. F.;
Hayes, J. S. J. Med. Chem. 1987, 30, 824.
White powder (0.37 g, 87%); mp>320 ꢀC; IR (KBr) (nmax/cmꢁ1):
3373, 3163, 1716, 1668. 1H NMR (300 MHz, DMSO-d6): dH (ppm)
3.04 (3H, s, CH3), 6.75 (4H, br s, 2NH2), 6.76–7.26 (3H, m, H–Ar),
9.61 (1H, s, NH), 10.37 (2H, s, 2NH). MS, m/z (%): 423 (Mþ, 5), 264
(35), 236 (100), 149 (90). Anal. Calcd for C17H13N9O5: C, 48.23; H,
3.10; N, 29.78%. Found: C, 48.29; H, 3.16; N, 29.86%.
4.9. 20,80-Diamino-5-nitro-spiro[1-ethylindoline-3,50-
pyrido[2,3-d:6,5-d0]dipyrimidine]-2,40,60(30H,70H,100H)-
trione (7e)
19. Yong, S. R.; Williams, M. C.; Pyne, S. G.; Ung, A. T.; Skelton, B. W.; White, A. H.;
Turner, P. Tetrahedron 2005, 61, 8120.
20. Feldman, K. S.; Vidulova, D. B.; Karatjas, A. G. J. Org. Chem. 2005, 70, 6429.
21. Osman, F. H.; El-Samahy, F. A. Tetrahedron 2000, 56, 1863.
22. Mao, Z.; Baldwin, S. W. Org. Lett. 2004, 6, 2425.
White powder (0.38 g, 86%); mp>320 ꢀC; IR (KBr) (nmax/cmꢁ1):
3360, 3166,1714,1661. 1H NMR (300 MHz, DMSO-d6): dH (ppm) 1.20
(3H, t, 3JHH¼6.5 Hz, CH3), 3.75 (2H, q, 3JHH¼6.5 Hz, CH2), 6.79 (4H, br
23. Feldman, K. S.; Karatjas, A. G. Org. Lett. 2006, 8, 4137.
24. Dabiri, M.; Azimi, S. C.; Khavasi, H. R.; Bazgir, A. Tetrahedron 2008, 64, 7307.
3
s, 2NH2), 7.08 (1H, d, JHH¼8.5 Hz, H–Ar), 7.71 (1H, s, H–Ar), 8.11

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