Efficient synthesis of purine analogues: An FeCl3-SiO2-promoted cyclization reaction of 4,5-diaminopyrimidines with aldehydes leading to 6,8,9-trisubstituted purines

Article abstract of DOI:10.1016/S0040-4039(00)01074-1

6,8,9-Trisubstituted purine analogues were efficiently synthesized via cyclization of 6-chloro-4,5-diaminopyrimidines and various aldehydes promoted by FeCl₃-SiO₂. Fe(III) chloride on silica gel has a dual role of a dehydration agent

Full text of DOI:10.1016/S0040-4039(00)01074-1

Tetrahedron Letters 41 (2000) 6559±6562
Ecient synthesis of purine analogues: an FeCl ±SiO -
3
2
promoted cyclization reaction of 4,5-diaminopyrimidines with
aldehydes leading to 6,8,9-trisubstituted purines
Qun Dang,* Brian S. Brown and Mark D. Erion
Chemistry Department, Metabasis Therapeutics, Inc., 9390 Towne Centre Drive, San Diego, CA 92121, USA
Received 24 May 2000; revised 23 June 2000; accepted 26 June 2000
Abstract
6,8,9-Trisubstituted purine analogues were eciently synthesized via cyclization of 6-chloro-4,5-diami-
nopyrimidines and various aldehydes promoted by FeCl ±SiO . Fe(III) chloride on silica gel has a dual
3
2
role of a dehydration agent and an oxidant, and was conveniently removed during work-up by ®ltration.
#
2000 Elsevier Science Ltd. All rights reserved.
Purine and pyrimidine metabolic pathways have long been the targets of many drug discovery
1
projects. In our continuing e€orts to identify purine analogues as potential ARA's (adenosine
2
regulating agents), we became interested in various 6,8,9-trisubstituted purines. In an e€ort to
explore and rapidly determine the SAR at the 6-, 8- and 9-positions of purine bases, we investigated
the strategy shown in Scheme 1, namely the reaction of 5-amino-4,6-dichloropyrimidine with an
1
amine (R -NH ) followed by a cyclization reaction between the resulting diamine and an aldehyde
2
to give 8,9-disubstituted 6-chloropurines. Further functionalization of the 6-chloro group of the
3
cyclized product can be readily achieved via a nucleophilic substitution reaction or a transition
metal-catalyzed cross-coupling reaction.4
Scheme 1.
*
Corresponding author. Tel: 858-622-5517; fax: 858-622-5573; e-mail: dang@mbasis.com
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01074-1

6
560
Cyclization reactions between 4,5-diaminopyrimidines and carboxy or cyano derivatives are
frequently used to prepare 8-substituted purines.3 Unfortunately, subjecting 6-chloro-4,5-
diaminopyrimidine to the standard reaction conditions (aqueous acid or base) often led to substantial
5
hydrolysis of the 6-chloro to give 8-substituted hypoxanthines. On the other hand, under mild
conditions cyclization reactions between aldehydes, and 4,5-diaminopyrimidines have been
6
successfully used to prepare 8-substituted xanthine analogues, for example the Traube xanthine
synthesis using Fe(III) chloride as the oxidant. Subsequent e€orts to prepare 8-substituted purines
7
using a mild one-step reaction have shown limited success. Kuznetsov and Remizov reported
that an attempted one-step cyclization between 2,4,5,6-tetraaminopyrimidine and a benzaldehyde
generated many other side products and they concluded that this method did not have any
8
preparative utility. Nagel and van der Plas reported that the cyclization of 4,5-diamino-2-
methylthio-6-phenylpyrimidine and benzaldehyde using copper(II) acetate in re¯uxing aqueous
methanol gave 6,8-diphenyl-2-methylthiopurine in good yield (61%). Recently, Gangjee et al.9
reported a successful one-step cyclization between 2,4,5,6-tetraaminopyrimidine and benzaldehydes
in the presence of aqueous hydrochloric acid to give 8-substituted purines in moderate to good
yields (12±40%). Herein, we report an FeCl ±SiO promoted cyclization reaction of 6-chloro-4,5-
3
2
diaminopyrimidines and various aldehydes that proceeds in good yields and under mild reaction
conditions.
To prepare 6,8,9-trisubstituted purines, we chose 5-amino-4,6-dichloropyrimidine as the starting
material, and reacted it with various amines to give 5-amino-6-chloro-4-alkylaminopyrimidines
(1a±f) in excellent yields (90±95%, Scheme 2).
Scheme 2.
Our initial e€ort to cyclize 1a with 2-furaldehyde using copper(II) acetate did not give the
ꢀ
desired product, while treatment of 1a and 2-furaldehyde with FeCl (4 equiv.) in DMF at 100 C
3
gave 2a in good yield (40%). Unfortunately, the reaction was complicated by the hygroscopic
nature of FeCl and the diculty in separating out the sticky iron-derived solid from the product.
3
In an e€ort to minimize these problems, we evaluated FeCl absorbed on silica gel based on its
3
favorable storage and handling properties.10 It was envisioned that silica gel could act as a water
absorbent and thereby assist the imine formation reaction step while enabling the convenient
removal of the iron-derived byproduct via a simple ®ltration. After optimization studies regarding
reaction solvent and ratios of FeCl to SiO , 3a was prepared from 1a and 3-furaldehyde using
3
2
ꢀ
5% FeCl ±SiO (dioxane, 101 C, 44 h) in excellent yield (87%).
3 2
11
1
The reaction scope was studied using both aromatic and aliphatic aldehydes with 4,5-
diaminopyrimidines (1a±f), and the results are summarized in Table 1.

6
561
It is evident from Table 1 that both aromatic and aliphatic aldehydes can be used for this
reaction to give 8-substituted purines. Since various pyrimidines (1a±f) are suitable for this
reaction, 8,9-disubstituted purine analogues are readily prepared.
Table 1
FeCl ±SiO promoted cyclization reaction of 1a±f with various aldehydes (R -CHO).
2
3
2
In conclusion, a one-step cyclization reaction of 6-chloro-4,5-diaminopyrimidines with various
aldehydes under mild conditions in the presence of FeCl ±SiO was developed. This reaction is
3
2
suitable for synthesis of 8,9-disubstituted 6-chloropurines, and should enable ecient synthesis of
other 6,8,9-trisubstituted purines (Scheme 1).
References
1
. Appleman, J. R.; Erion, M. D. Exp. Opin. Invest. Drugs 1998, 7, 225. Jacobson, K. A.; Jarvis, M. F., Eds.
Purinergic Approaches in Experimental Therapeutics; John Wiley & Sons: New York, 1997. Chu, C. K.; Baker,
D. C., Eds. Nucleosides and Nucleotides as Antitumor and Antiviral Agents; Plenum: New York, 1993. Bonnet,
P. A.; Robins, R. K. J. Med. Chem. 1993, 36, 635. Erion, M. D. Annu. Rep. Med. Chem. 1993, 28, 295. Huryn,
D. M.; Okabe, M. Chem. Rev. 1992, 92, 1745.
2
. Dang, Q.; Brown, B. S.; Erion, M. D. J. Org. Chem. 1996, 61, 5204. Dang, Q.; Liu, Y.; Erion, M. D. J. Am. Chem.
Soc. 1999, 121, 5833.
3
4
. Lister, J. H., Ed. The Purines; John Wiley & Sons: New York, 1996; Vol. 54 (Suppl. I), pp. 21±60.
. Hocek, M.; Holy, A.; Votruba, I.; Dvorakova, H. J. Med. Chem., 2000, 43, 1145, and references cited therein.

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5
6
7
8
9
. Giner-Sorolla, A.; Segarra, J. T.; Brooks, M. H. J. Med. Chem. 1978, 21, 344.
. Traube, W.; Nithack, W. Chem. Ber. 1906, 39, 227.
. Kuznetsov, V. S.; Remizov, A. L. Khim. Geterotsikl. Soed. 1972, 10, 1430.
. Nagel, A.; van der Plas, H. C. Chem. Pharm. Bull. 1975, 23, 2678.
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1
0. Although 5% FeCl
by mixing solid FeCl
with air easily and was hard to handle.
1. General procedure: A solution of 1a (4 mmol) and 3-furaldehyde (8 mmol) in anhydrous dioxane (50 mL) was
3
±SiO
2
is available from Aldrich, for our studies 15% FeCl
3
±SiO
2
was conveniently prepared
3
with SiO
2
under nitrogen. A higher content of FeCl in SiO
3
2
was also studied, but it reacted
1
o
3 2
treated with 15% FeCl ±SiO (2 equiv.) at 100 C under nitrogen for 44 h. The cooled reaction mixture was ®ltered
(
washed with EtOAc, 3Â20 mL), and the ®ltrates were evaporated and the residue was puri®ed by ¯ash
ꢀ
chromatography (SiO , 3Â15 cm, 20% EtOAc±hexane) to give 3a as a white solid (1.1 g, 87%). mp 96±97 C
2
1
(
(
toluene±hexane); H NMR (CDCl
3
, 200 MHz) ꢀ 8.67 (1H, s), 7.70 (1H, s), 7.40 (1H, m), 7.26±7.12 (5H, m), 6.67
13 4
1H, m), 4.86 (2H, t, J=7.2 Hz), 3.15 (2H, t, J=7.2 Hz); anal. calcd for C17H N OCl: C, 62.87; H, 4.03; N, 17.25.
Found: C, 62.94; H, 4.03; N, 17.27.