A cascade reaction with iminium ion isomerization as the key step leading to tetrahydropyrimido[4,5-d]pyrimidines

Article abstract of DOI:10.1021/ol703049j

A novel cascade reaction of aminopyrimidines 1 with N-alkyl amino acids or analogues was investigated. The keys to this cascade are the isomerization of an iminium ion formed between the aldehyde group in pyrimidine and the secondary amine of an amino acid, and subsequent cyclization to the neighboring amino group. This sequence could be useful in the synthesis of novel tetrahydropyrimido[4,5-d]pyrimidine libraries.

Full text of DOI:10.1021/ol703049j

ORGANIC
LETTERS
2008
Vol. 10, No. 5
889-892
A Cascade Reaction with Iminium Ion
Isomerization as the Key Step Leading
to Tetrahydropyrimido[4,5-d]pyrimidines
Lianyou Zheng, Fengzhi Yang, Qun Dang,* and Xu Bai*
The Center for Combinatorial Chemistry and Drug DiscoVery, Jilin UniVersity,
75 Haiwai Street, Changchun, Jilin 130012, People’s Republic of China
xbai@jlu.edu.cn; qdang@jlu.edu.cn
Received December 19, 2007
ABSTRACT
A novel cascade reaction of aminopyrimidines 1 with N-alkyl amino acids or analogues was investigated. The keys to this cascade are the
isomerization of an iminium ion formed between the aldehyde group in pyrimidine and the secondary amine of an amino acid, and subsequent
cyclization to the neighboring amino group. This sequence could be useful in the synthesis of novel tetrahydropyrimido[4,5-d]pyrimidine
libraries.
Pyrimidine-fused compounds are of interest in medicinal
chemistry and chemical biology due to their wide range of
biological activities.1 To develop new methodologies for
efficient synthesis of novel pyrimidine-fused heterocycles,2
we initially envisioned that a novel heterocyclic scaffold
could be accessed via an intramolecular azomethine ylide3
[3 + 2] cycloaddition reaction as the key step (path A,
Scheme 1). However, reaction of pyrimidine aldehyde 1a
and N-benzylglycine 2 in refluxing xylene unexpectedly gave
tetrahydropyrimido[4,5-d]pyrimidine 5a (path B, Scheme 1).
Investigation of this reaction led to a general synthetic
methodology to access tetrahydropyrimido[4,5-d]pyrimidines.
Herein, the preliminary results from these studies are
reported.
To test our initial design of an intramolecular [3 + 2]
cycloaddition reaction, the required pyrimidine 1a was
prepared from the readily accessible 4,6-dichloro-5-formylpy-
rimidine 64 as shown in Scheme 2. Substitution of 6 with
allylamine in the presence of triethylamine under well-
controlled reaction conditions produced the desired mono-
Scheme 1
(1) For examples, see: (a)Wang, S.; Folkes, A.; Chuckowree, I.;
Cockcroft, X.; Sohal, S.; Miller, W.; Milton, J.; Wren, S. P.; Vicker, N.;
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D.; Cocks, S. J. Med. Chem. 2004, 47, 1329-1338. (b) Perner, R. J.; Gu,
Y. G.; Lee, C. H.; Bayburt, E. K.; McKie, J.; Alexander, K. M.; Kohlhaas,
K. L.; Wismer, C. T.; Mikusa, J.; Jarvis, M. F.; Kowaluk, E. A.; Bhagwat,
S. S. J. Med. Chem. 2003, 46, 5249-5257. (c) McGuigan, C.; Pathirana,
R. N.; Snoeck, R.; Andrei, G.; DeClercq, E.; Balzarini, J. J. Med. Chem.
2004, 47, 1847-1851. (d) Gangjee, A.; Zeng, Y.; McGuire, J. J.; Mehraein,
F.; Kisliuk, R. L. J. Med. Chem. 2004, 47, 6893-6901.
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2005, 7, 1541-1543. (b) Fu, R.; Xu, X.; Dang, Q.; Bai, X. J. Org. Chem.
2005, 70, 10810-10816. (c) Che, X.; Zheng, L.; Dang, Q.; Bai, X.
Tetrahedron 2006, 62, 2563-2568. (d) Xiang, J.; Zheng, L.; Chen, F.; Dang,
Q.; Bai, X. Org. Lett. 2007, 9, 765-767.
(3) (a) Coldham, I.; Hufton, R. Chem. ReV. 2005, 105, 2765-2809. (b)
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10.1021/ol703049j CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/09/2008

dihydrofolate reductase inhibition,8 and hepatoprotective
activities.9 It is therefore logical to explore this type of
heterocyclic scaffold for various drug discovery programs.
Although numerous reports exist for the synthesis of various
keto derivatives of pyridopyrimidines10 and pyrimido[4,5-
d]pyrimidines,11 few were directed to the synthesis of
tetrahydropyrimido[4,5-d]pyrimidines.12 Thus, we set out to
optimize this new reaction and to explore its scope.
Scheme 2
Screening of various acids (e.g., TFA and CSA) including
Lewis acids (e.g., CuBr, LiBr, MgCl2, TiCl4, and CoCl2) as
well as base (e.g., Et3N) did not lead to any improvement in
the yield of 5a, while using DMF as the solvent only
produced a trace amount of 5a. Therefore, the refluxing
xylene conditions were used to explore reactions between
various N-alkyl-substituted amino acids and aldehydes 1a-d
(R ) allyl, H, Me, Ph). As evidenced in Table 1, most
substituted pyrimidine 7 in 89% yield.5 A second nucleophilic
displacement of the remaining chloro group in 7 by thiophe-
nol led to the desired precursor 1a in 90% yield.
It is interesting to note that the reaction of pyrimidine 1a
with N- benzylglycine in refluxing xylene did not give the
anticipated intramolecular cycloaddition product 4, but
instead gave a new pyrimidine derivative that was assigned
the structure of 5a based on proton NMR and MS data
(Scheme 2). The structure of compound 5a was unambigu-
ously confirmed by X-ray crystallographic analysis (Figure
1).
Table 1. Synthesis of
1,2,3,4-Tetrahydropyrimido[4,5-d]pyrimidinesa
time
(h)
yield
(%)b
entry
R1
R2
R
product 5
1
2
3
4
5
6
7
8
9
10
11
12
13
Ph
p-MeO-Ph
H
Ph
Ph
H
H
H
allyl
allyl 12.5 5b
allyl
5
5a
64
48
NRc
60
73
76
65
76
70
69
70
67
10
5
6
CH3 allyl
Bn
-(CH2)2-
-(CH2)3-
-(CH2)2-
-(CH2)2-
5c/5c′ (1:1.57)d
5d/5d′ (1:1.36)e
5e
5f
5g
allyl 30
allyl
allyl
H
CH3
CH3
4
6
4
6.5 5h
3
Ph
Ph
H
5i
CH3 CH3 10
5j/5j′ (1:2.3)d
-(CH2)2-
-CH2)3-
Ph
Ph
4
5k
4.5 5l
a 1a, R ) allyl; 1b, R ) H; 1c, R ) Me; 1d, R ) Ph. b Isolated yields.
c NR ) no reaction. d Ratio based on isolated products. e The structure of
5d′ was based on LC-MS and 1H NMR of the crude product, and the ratio
was estimated since pure 5d′ could not be obtained due to an unknown
contaminant.
Figure 1. X-ray structure of compound 5a.
We were intrigued by this new reaction since it may be
developed into a new synthetic route to tetrahydropyrimido-
[4,5-d]pyrimidines. Pyrimidopyrimidines exhibit a variety of
pharmacological activities, such as antitumor,6 antiviral,7
reactions (except with N-methylglycine, entry 3) gave
products 5a-l and/or 5a′-l′ in moderate to good yields. The
cyclic amino acids, such as proline and homoproline, yielded
a single isomer of the product as expected (entries 6-9, 12,
(4) Gomtsyan, A.; Didomenico, S.; Lee, C. H.; Matulenko, M. A.; Kim,
K.; Kowaluk, E. A.; Wismer, C. T.; Mikusa, J.; Yu, H.; Kohlhaas, K.; Jarvis,
M. F.; Bhagwat, S. S. J. Med. Chem. 2002, 45, 3639-3648.
(5) Clark, J.; Parvizi, B.; Southon, I. W. J. Chem. Soc., Perkin Trans. 1
1976, 125-130.
(6) Curtin, N. J.; Barlow, H. C.; Bowman, K. J.; Calvert, A. H.; Davison,
R.; Golding, B. T.; Huang, B.; Loughlin, P. J.; Newell, D. R.; Smith, P.
G.; Griffin, R. J. J. Med. Chem. 2004, 47, 4905-4922.
(7) Sanghvi, Y. S.; Larson, S. B.; Matsumoto, S. S.; Nord, L. D.; Smee,
D. F.; Willis, R. C.; Avery, T. H.; Robins, R. K.; Revankar, G. R. J. Med.
Chem. 1989, 32, 629-637.
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2003, 38, 719-728.
890
Org. Lett., Vol. 10, No. 5, 2008

and 13). In the reaction with N-benzylglycine, the cyclization
occurred regioselectively to produce only one product (entries
1, 2, and 10), while other N-benzyl-substituted amino acids,
such as alanine, led to two isomers without significant
selectivity (entries 4, 5, and 11). The ratios of the two
isomeric products 5 and 5′ were calculated based on their
corresponding 1H NMR spectrum. It is also noteworthy that
the reaction of homoproline with N-phenylaminopyrimidine
aldehyde 1d gave a much lower yield compared to the one
with proline (entry 13 vs 12).
It is logical that when R1 and R2 are the same (entries
6-9, 12, and 13, Table 1), only one isomer was obtained as
expected. When R1 is a carbon substituent and R2 is a proton
only isomer 5 is obtained presumably due to the formation
of the more stable rearranged benzylic iminium 10 (entries
1, 2, and 10, Table 1). However, when both R1 and R2 are
carbon substituents the competition of iminium ions 10 and
11 leads to a mixture of isomer 5 and 5′ (entries 4, 5, and
11, Table 1). In these cases, 5′ is the major isomer probably
due to the kinetic preference for trapping of 11 by the
intramolecular cyclization. Otherwise, the trapping of the
thermodynamically more stable benzylic iminium 10 would
have led to product isomer 5 as the major one.
To rationalize the above results, a possible cascade reaction
mechanism was envisioned as depicted in Scheme 3.
To gain further insights into the reaction mechanism, the
reaction of 1c with L-proline ethyl ester was tested under
the current reaction conditions, and the expected tetrahy-
dropyrimido[4,5-d]pyrimidine was still formed in good yield
(Scheme 4), suggesting that neither the formation of an
Scheme 3
Scheme 4
oxazolidinone nor the decarboxylation reaction is essential
for the production of tetrahydropyrimido[4,5-d]pyrimidine.
Moreover, the use of an amino acid ester allowed the
formation of a quarternary center and the ester group can be
used as a handle for further diversification.
Another question to address is whether the current reaction
system is only limited to an amino acid or its esters. Thus,
two N-benzyl amines were tested with compound 1c under
the current reaction conditions, and the desired tetrahydro-
pyrimido[4,5-d]pyrimidines 5i and 13 were generated in good
yields (Scheme 5), indicating that the scope of the current
Condensation of amino acid 2 with aldehyde 1 gives
oxazolidinone 8, which undergoes a decarboxylation reaction
with loss of carbon dioxide to lead to a zwitterionic species
9. The iminium ion 9 may undergo isomerization to iminium
ions 10 or 11 (via path a or b, respectively). And subsequent
intramolecular cyclization onto the neighboring amino group
forms the desired products 5 or 5′.
Scheme 5
(9) Ram, V. J.; Goel, A.; Sarkhel, S.; Maulik, P. R. Bioorg. Med. Chem.
2002, 10, 1275-1280.
(10) (a) Dabiri, M.; Arvin-Nezhad, H.; Khavasi, H. R.; Bazgir, A.
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A. J. Bioorg. Med. Chem. Lett. 2006, 16, 3537-3540. (c) Sharma, P.;
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4185-4190. (f) Devi, I.; Borah, H. N.; Bhuyan, P. J. Tetrahedron Lett.
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reaction is beyond amino acids and amino acid esters. On
the other hand, an iminium ion stabilizing group such as a
phenyl group is required since the simple N,N-diethylamine
did not produce a detectable amount of tetrahydropyrimido-
[4,5-d]pyrimidine under the current reaction conditions (not
listed).
The 4-phenylthio group in a pyrimidine ring has been
shown to function as a transition point to introduce other
Org. Lett., Vol. 10, No. 5, 2008
891

substituents such as an amino, alkoxy, and alkylthio.2b To
test the applicability of this strategy, tetrahydropyrimdo[4,5-
d]pyrimidine 5h was readily oxidized to its sulfone 14, which
was substituted by an amine13 to yield the desired compounds
15a,b (Scheme 6). This sequence of transformations con-
In conclusion, a novel methodology to prepare tetrahy-
dropyrimido[4,5-d]pyrimidine via a cascade reaction of an
6-amino-5-formylpyrimidine with a suitable secondary amine
(including amino acids and amino acid esters) has been
developed. The key step of this cascade reaction is the
iminium ion isomerization during the reaction sequence. This
method provides a convenient access to diversified 1,2,3,4-
tetrahydropyrimido[4,5-d]pyrimidines. Further transforma-
tions of the phenylthio group in these 1,2,3,4-tetrahydropy-
rimido[4,5-d]pyrimidines were demonstrated by an oxidation
and subsequent nucleophilc substitution sequence.
Scheme 6
Acknowledgment. This work was supported by grants
from the China Natural Science Foundation (20572032 and
90713008) and Changchun Discovery Sciences, Ltd.
Supporting Information Available: Experimental details
1
and H and 13C NMR and LC-MS-ELSD spectra for key
firmed the feasibility of the phenylthio group as a suitable
diversification point in the molecular system.
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) Liu, J.; Dang, Q.; Wei, Z.; Zhang, H.; Bai, X. J. Comb. Chem. 2005,
7, 627-636.
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