A novel one-pot and efficient procedure for the synthesis of 3H-spiro[isobenzofuran-1,6′-pyrrolo[2,3-d]pyrimidine]-2′,3,4′, 5′-tetraones

Article abstract of DOI:10.1016/j.tetlet.2010.08.113

A novel and practical one-pot procedure is described for the preparation of several new of 3H-spiro[isobenzofuran-1,6′-pyrrolo[2,3-d]pyrimidine]- 2′,3,4′,5′-tetraones based on the addition reaction of ninhydrin and 6-aminouracils followed by oxidative cleavage of their corresponding dihydroxyindenopyrrolopyrimidines.

Full text of DOI:10.1016/j.tetlet.2010.08.113

Tetrahedron Letters 51 (2010) 5807–5809
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Tetrahedron Letters
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A novel one-pot and efficient procedure for the synthesis
of 3H-spiro[isobenzofuran-1,60-pyrrolo[2,3-d]pyrimidine]-20,3,40,50-tetraones
⇑
Mohammad Reza Mohammadizadeh , Mojtaba Bahramzadeh, S. Zainabkhatoon Taghavi
Chemistry Department, Faculty of Sciences, Persian Gulf University, Bushehr 75169, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and practical one-pot procedure is described for the preparation of several new of 3H-spiro[iso-
benzofuran-1,60-pyrrolo[2,3-d]pyrimidine]-20,3,40,50-tetraones based on the addition reaction of ninhydrin
and 6-aminouracils followed by oxidative cleavage of their corresponding dihydroxyindenopyrrolopyr
imidines.
Received 15 June 2010
Revised 2 August 2010
Accepted 31 August 2010
Available online 7 September 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Ninhydrin
6-Aminouracils
Dihydroxyindenopyrrolopyrimidines
Oxidative cleavage
3H-Spiro[isobenzofuran-1,60-pyrrolo[2,3-d]-
pyrimidine]-20,3,40,50-tetraones
Oxygen- and nitrogen-containing heterocycles are important in
the area of pharmaceuticals and agrochemicals.1 Substituted
phthalides [isobenzofuran-1(3H)-ones)] represent an important
class of natural products that possess interesting biological proper-
ties.1 In particular, 3-substituted phthalides are vital heterocyclic
motifs in many bioactive compounds, such as isocoumarins,
anthraquinones, anthracyclines, and several alkaloids.2 Their nota-
ble characteristics include anti-bacterial, anti-convulsant, anti-HIV,
anti-asthmatic, anti-tumor and anti-platelet activities, anesthesia
40,50-tetraones 2. We found that addition of lead tetraacetate to a
solution of dihydroxyindenopyrrolopyrimidine 1a in acetic acid
at room temperature resulted in the formation of 3H-spiro[iso-
benzofuran-1,60-pyrrolo[2,3-d]pyrimidine]-20,3,40,50(10H,30H,70H)-
tetraone (2a) in excellent yield (Scheme 1).
Toexplorethescopeandversatilityofthismethod,andinorderto
optimize the reaction conditions, various solvents and temperatures
were investigated for the synthesis of 2a. We found that using acetic
acid (AcOH) as the solvent gave the best result. To further optimize
the conditions, the samereaction was carried out in AcOH at temper-
atures ranging from 25 to 65 °C, at 10 °C intervals. The reaction time
was shortened slightly as the temperature increased from 25 to
45 °C. However, further increasing the temperature to 65 °C failed
to decrease the reaction time further, however, the amount of by-
products were increased. Therefore, a reaction temperature of
25 °C was chosen for all further AcOH-mediated reactions.
As the synthesis of dihydroxyindenopyrrolopyrimidine 1a, from
the addition reaction of ninhydrin (3) and aminouracil 4a,9 is fast
and quantitative, we decided to study the one-pot synthesis of
2a. We found that the one-pot reaction of ninhydrin (3), aminoura-
cil 4a and lead tetraacetate in acetic acid at room temperature gave
product 2a in a 92% yield, which was comparable to the above de-
scribed two-step procedure (Scheme 1). In addition, the separation
and purification steps for 1a were eliminated.
prolongation, and PGF2
isobenzofurans is important as they represent 10
with quinoid nature, which makes them attractive as a building
units for oligomeric and polymeric
-conjugated compounds.4,5
a
inhibitory properties.3 The chemistry of
electron systems
p
p
Pyrrolo[2,3-d]pyrimidines are reported to possess biological
activities such as anti-HCV, anti-HIV type 1, anti-HSV, adenosine
kinase inhibition, Aurora-A kinase inhibition, and cAMP phospho-
diesterase inhibition. Many naturally occurring compounds, such
as mycalisine A, cadeguomycin, and 2-deoxycadeguomycin pos-
sess a pyrrolo[2,3-d]pyrimidine moiety.6,7
In continuation of our programs to develop more efficient
processes for the synthesis of biologically important oxygen- and
nitrogen-containing heterocycles,8 herein, we describe a novel
and practical one-pot procedure for the preparation of several
new 3H-spiro[isobenzofuran-1,60-pyrrolo[2,3-d]pyrimidine]-20,3,
The optimized one-pot conditions were applied to the synthesis
of 3H-spiro[isobenzofuran-1,60-pyrrolo[2,3-d]pyrimidine]-20,3,40,
50-tetraones 2a–l10 starting from ninhydrin (3) and aminouracils
4a–l,11 (Scheme 2). The results shown in Table 1 indicate that all
⇑
Corresponding author. Tel./fax: +98 7714541494.
E-mail addresses: mrmohammadizadeh@pgu.ac.ir, mrmohamadizadeh@gmail.
com (M.R. Mohammadizadeh).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.113

5808
M. R. Mohammadizadeh et al. / Tetrahedron Letters 51 (2010) 5807–5809
O
O
O
O
O
O
conditions
Pb(OAc)4
OH
NH
NH
O
HO
O
HN
N
N
3.5-4 h, 35-95%
N
H
H
H
2a
1a
Scheme 1. Optimization of the reaction conditions for the synthesis of 3H-spiro[isobenzofuran-1,60-pyrrolo[2,3-d]pyrimidine]-20,3,40,50-tetraone (2a).
O
O
O
O
O
O
O
R3
O
R3
1. AcOH, r.t., 1 h
OH
OH
N
N
+
N
N
R2
2. Pb(OAc)4
r.t. 4 h
R1
HN
R1
N
R2
O
2a-l
4a-l
3
Scheme 2. One-pot synthesis of 3H-spiro[isobenzofuran-1,60-pyrrolo[2,3-d]pyrimidine]-20,3,40,50-tetraones 2a–j.
Table 1
Table 1 (continued)
Synthesis of 3H-spiro[isobenzofuran-1,60-pyrrolo[2,3-d]pyrimidine]-20,3,40,50-tetra-
ones 2a–l
Entry
Aminouracila
Product
Yieldb (%)
O
N
O
O
O
O
Entry
1
Aminouracila
Product
Yieldb (%)
N
O
O
O
O
9
94
N
O
H
HN
Bn
N
O
4i
N
H
N
O
O
N
Bn
72
2i
N
H
2a
H2N
N
H
O
4a
N
O
O
N
O
O
H
O
N
O
O
O
O
O
10
N
92
O
N
HN
p -MeO-C6H4
O
H
H
N
N
N
N
4j
p -MeO-C6H4
2
3
89
88
O
N
2j
O
N
H2N
H2N
N
O
O
O
H
O
N
O
O
2b
4b
O
O
O
N
N
N
O
H
11
12
92
96
Ph
N
N
H
N
O
4k
N
O
S
H
N
H
N
O
Ph
N
2k
O
O
N
O
4c
Ph
Ph
O
N
O
O
2c
O
O
O
O
O
O
H
H
H2N
N
S
4l
N
N
N
N
H
4
5
95
90
N
2l
N
H2N
N
O
O
H
2dBn
Bn
4d
a
6-Aminouracils 4a and 4e were purchased from Merck and used without fur-
ther purification. 6-Aminouracil derivatives 4b–d and 4l,11a and 4f–k,11b–e were
O
O
O
O
prepared according to published procedures.
b
N
Isolated yields.
N
H
H2N
N
O
N
O
4e
2e
the substituted aminouracils undergo effectively the addition and
oxidation reactions. Even with sterically hindered aminouracils
4g–k there was no significant increase in the reaction time or de-
crease in the yield.
O
O
O
O
O
O
O
O
O
H
O
H
N
N
N
N
6
7
8
83
85
86
N
HN
Ph
N
H
N
O
Ph
H
4f
2f
O
The structures of the products were established by spectro-
scopic and analytical techniques.12 The 1H NMR spectrum of 2e
exhibited two sharp singlets at d 3.12 and 3.67 due to the methyl
protons, along with multiplets at d 7.69–7.87 for the aromatic pro-
tons. A singlet at d 8.30 was identified as the N–H proton. On the
other hand, the N–H proton signal for product 2i was not observed,
while two diastereotopic benzylic protons resonated as two dis-
tinct doublets at d 4.58 and 5.00 (J = 18.6 Hz). The 1H decoupled
13C NMR spectrum of 2e showed 15 distinct resonances, in agree-
ment with the proposed structure. The signal at d 94.6 or 99.1 was
consistent with the presence of a spiro carbon.8a
O
O
O
H
H
N
N
N
HN
N
O
N
O
Ph
Ph Bn
Bn
4g
2g
O
O
H
H
N
HN
N
O
N
O
Bn
4h
Bn
2h

M. R. Mohammadizadeh et al. / Tetrahedron Letters 51 (2010) 5807–5809
5809
O
O
O
O
O
O
O
O
OH
R3
O
R3
O
NH
OH
OH
N
N
HO
O
+
N
HN
R1
N
R2
4
N
R2
N
H
N
R1
H
1
O
3
5
H2O
OH
O
O
O
O
O
O
O
O
OH
O
O
R3
H2O
R3
O
R3
O
N
H
N
N
2
-H2O
N
N
R1
-H2O
N
R2
O
N
R2
O
HN
R1
R1
N
R2
O
8
7
6
Scheme 3. Mechanism proposed for the one-pot synthesis of 3H-spiro[isobenzofuran-1,60-pyrrolo[2,3-d]pyrimidine]-tetraones 2a–l.
6. (a) Ramesh, E.; Raghunathan, R. Tetrahedron Lett. 2008, 49, 2583; (b) Ramesh,
E.; Raghunathan, R. Tetrahedron Lett. 2008, 49, 1812; (c) Fischer, R. W.; Misun,
M. Org. Process Res. Dev. 2001, 5, 581.
7. (a) Seela, F.; Soulimane, T.; Mersmann, K.; Jürgens, T. Helv. Chim. Acta 2004, 73,
1879; (b) Ramasamy, K.; Imamura, N.; Robins, R. K.; Revankar, G. R. J.
Heterocycl. Chem. 2009, 25, 1893.
8. (a) Mohammadizadeh, M. R.; Firoozi, N. Tetrahedron Lett. 2010, 51, 2467; (b)
Mohammadizadeh, M. R.; Bahramzadeh, M.; Mohammadi, A.; Karimi, A. R. Helv.
Chim. Acta 2010, 93, 153.
9. (a) Azizian, J.; Hatamjafari, F.; Karimi, A. R.; Shaabanzadeh, M. Synthesis 2006,
765; (b) Joullié, M. M.; Thompson, T. R.; Nemeroff, N. H. Tetrahedron 1991, 47,
8791.
A
plausible mechanism involving oxidative cleavage of
dihydroxyindenopyrrolopyrimidine 1 to pyrimidobenzazocine 5 is
proposed in Scheme 3. Intermediate 5 rearranges to the product 2,
by hydrolysis to 2-[(2-(6-amino-1,2,3,4-tetrahydro-2,4-dioxopyr-
imidin-5-yl)-2-oxoacetyl)]benzoic acid 6 followed by cyclization.
However, it is also reasonable to propose that pyrimidobenzazocine
5 undergoes an intramolecular reaction to give reactive intermedi-
ates, 7,8a which subsequently convert into product 2 via rapid
hydrolysis to 2-(6-hydroxy-1H-pyrrolo[2,3-d]pyrimidin-6-yl)ben-
zoic acid 8 followed by intramolecular cyclization.
In summary, we have reported a new, one-pot procedure
involving the addition reaction of ninhydrin and 6-aminouracils,
which leads to dihydroxyindenopyrrolopyrimidines, and their sub-
sequent rearrangement into 3H-spiro[isobenzofuran-1,60-pyrrol-
o[2,3-d]pyrimidine]-20,3,40,50-tetraones in the presence of lead(IV)
acetate. The combination of generality, high yields, short reaction
times, and mild conditions makes this method a useful procedure.
10. General procedure for the one-pot synthesis of 3H-spiro[isobenzofuran-1,60-
pyrrolo[2,3-d]pyrimidine]-20,3,40,50-tetraones 2a–l: A mixture of ninhydrin (3)
(1 mmol) and 6-aminouracil 4 (1 mmol) in AcOH (3 mL) was stirred at room
temperature for 1 h. Pb(OAc)4 (1.1 mmol) was added and stirring continued for
a further 4 h ,and then H2O (10 mL) was added. The reaction mixture was
filtered, washed with hot H2O (2 ꢀ 5 mL), and the obtained product 2a–l was
further purified by recrystallization from EtOH.
11. (a) Sariri, R.; Khalili, G. Russ. J. Org. Chem. 2003, 38, 1053; (b) Whitehead, C. W.;
Traverso, J. J. J. Am. Chem. Soc. 1960, 82, 3971; (c) Yoneda, F.; Shinozuka, K.;
Tsukuda, K.; Koshiro, A. J. Heterocycl. Chem. 1979, 16, 1365; (d) Ishikawa, I.;
Itoh, T.; Melik-Ohanjanian, R. G.; Takayanagi, H.; Mizuno, Y.; Ogura, H.
Heterocycles 1990, 31, 1641; (e) El-Emam, A. A.; Massoud, M. A. M.; El-
Bendary, E. R.; El-Sayed, M. A. Bull. Korean Chem. Soc. 2004, 25, 991.
12. Spectroscopic and analysis data for some selected products: 3H-Spiro[isobenzofu-
Acknowledgment
ran-1,60-pyrrolo[2,3-d]pyrimidine]-20,3,40,50(10H,30H,70H)-tetraone
(2a):
mp
The authors thank the Research Council of the Persian Gulf Uni-
versity of Bushehr for financial support of this work.
>300 °C; IR (KBr): 3298, 3213, 3086, 1770, 1705, 1562; 1H NMR (500 MHz,
DMSO-d6): d 7.64 (t, J = 6.6 Hz, 1H, arom), 7.71 (d, J = 16.4 Hz, 1H, arom), 7.82
(m, 2H, arom), 8.11 (s, 1H, NH), 11.20 (s, 1H, NH), 12.90 (s, 1H, NH); 13C NMR
(125 MHz, DMSO-d6): d 93.1, 97.0, 125.3, 125.9, 130.6, 132.2, 136.7, 144.3,
151.0, 158.6, 165.9, 167.6, 186.2; MS (70 eV): m/z (%) = 285 (M+, 75), 257 (100),
229 (97), 186 (65), 105 (55). Anal. Calcd for C13H7N3O5: C, 54.74; H, 2.47; N,
14.73. Found: C, 54.81; H, 2.39; N, 14.70. 3H-10,30-Dimethyl-spiro[isobenzofuran-
1,60-pyrrolo[2,3-d]pyrimidine]-20,3,40,50(10H,30H,70H)-tetraone (2e): mp >300 °C;
IR (KBr): 3379, 1764, 1743, 1666, 1601, 1520; 1H NMR (500 MHz, DMSO-d6): d
3.12 (s, 3H, CH3), 3.67 (s, 3H, CH3), 7.69 (dt, J1 = 7.5 Hz, J2 = 1 Hz, 1H, arom),
7.80 (t, J = 7.2 Hz, 2H, arom), 7.87 (dt, J1 = 7.5 Hz, J2 = 1 Hz, 1H, arom), 8.30 (s,
1H, NH); 13C NMR (125 MHz, DMSO-d6): d 28.4, 37.6, 94.6, 99.1, 125.4, 125.9,
130.5, 132.4, 136.8, 143.2, 151.8, 157.2, 166.4, 168.1, 186.4; MS (70 eV): m/z
(%) = 313 (M+, 55), 285 (100), 257 (98), 200 (84), 105 (80). Anal. Calcd for
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.08.113.
References and notes
1. Lin, G.; Chan, S. S.-K.; Chung, H.-S.; Li, S.-L. Chemistry and Biological Action of
Naturally Occurring Phthalides. In Studies in Natural Products Chemistry; Atta-
ur-Rahman, Ed.; Elsevier: Amsterdam, 2005; Vol. 32, p 611.
2. Mal, D.; Pahari, P.; De, S. R. Tetrahedron 2007, 63, 11781.
3. (a) Safari, J.; Naeimi, H.; Khakpour, A. A.; Jondani, R. S.; Khalili, S. D. J. Mol. Catal.
A 2007, 270, 236; (b) Yang, H.; Hu, G.-Y.; Chen, J.; Wang, Y.; Wang, Z.-H. Bioorg.
Med. Chem. Lett. 2007, 17, 5210; (c) Mor, S.; Dhawan, S. N.; Kapoor, M.; Kumar,
D. Tetrahedron 2007, 63, 594.
4. (a) Patil, A. O.; Heeger, A. J.; Wudl, F. Chem. Rev. 1988, 88, 183; (b) Roncali, J.
Chem. Rev. 1997, 97, 173.
5. Zhang, H.; Wakamiya, A.; Yamaguchi, S. Org. Lett. 2008, 10, 3591. and
references cited therein.
C
15H11N3O5: C, 57.51; H, 3.54; N, 13.41. Found: C, 57.62; H, 3.54; N, 13.36. 3H-
70-Benzyl-10,30-dimethyl-spiro[isobenzofuran-1,60-pyrrolo[2,3-d]pyrimidine]-20,3,
40,50(10H,30H,70H)-tetraone (2i): mp 204–206 °C; IR (KBr): 3401, 1772, 1720,
1706, 1678, 1581; 1H NMR (500 MHz, DMSO-d6): d 3.20 (s, 3H, CH3), 3.45 (s,
3H, CH3), 4.58 (d, J = 18.6 Hz, 1H, CH2), 5.00 (d, J = 18.6 Hz, 1H, CH2), 7.24–7.29
(m, 5H, arom), 7.71 (m, 1H, arom), 7.80 (m, 2H, arom), 7.91 (m, 1H, arom); 13
C
NMR (125 MHz, DMSO-d6): d 28.4, 33.3, 48.6, 91.2, 97.7, 124.3, 126.4, 126.8,
128.3, 129.5, 130.5, 132.7, 136.4, 137.5, 142.8, 152.0, 156.5, 167.4, 169.2,
182.6; MS (70 eV): m/z (%) = 403 (M+, 5), 346 (63), 288 (95), 199 (100), 105
(52). Anal. Calcd for C22H17N3O5: C, 65.50; H, 4.25; N, 10.42. Found: C, 65.39;
H, 4.20; N, 10.31.