Synthesis of 7,8,9-trisubstituted dihydropurine derivatives via a 'tert-amino effect' cyclization

Article abstract of DOI:10.1055/s-2008-1078212

7,8,9-Trisubstituted dihydropurine derivatives were prepared from 5-amino-4-(N,N-disubstituted)aminopyrimidines and aromatic aldehydes via a cascade of reactions. The key transformation for the reaction is a [1,6]-hydrogen shift due to a 'tert-amino effect'. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078212

LETTER
2373
Synthesis of 7,8,9-Trisubstituted Dihydropurine Derivatives via a ‘tert-Amino
Effect’ Cyclization
S
ynthesis of 7,8,9-
i
Trisub
n
C
The Center for Combinatorial Chemistry and Drug Discovery, Jilin University, 75 Haiwai St., Changchun, Jilin 130012, P. R. of China
Fax +86(431)85188900; E-mail: xbai@jlu.edu.cn; E-mail: qdang@jlu.edu.cn
Received 13 April 2008
Recently, we discovered that a Pictet–Spengler-type cy-
Abstract: 7,8,9-Trisubstituted dihydropurine derivatives were pre-
clization of pyrimidinediamine 1 with an electron-rich ar-
omatic ring (Ar = 3,5-di-MeOC6H4 or N-Me-indol-2-yl)
pared from 5-amino-4-(N,N-disubstituted)aminopyrimidines and
aromatic aldehydes via a cascade of reactions. The key transforma-
yielded novel tricyclic pyrimidine-fused eight-membered
heterocycle 2 (path a in Scheme 1).8 However, certain
substrates (e.g., when Ar was 3-methoxyphenyl and the
aldehyde was aromatic) produced 7,8,9-trisubstituted di-
hydropurine derivative 3 as the major product (path b in
Scheme 1). We reasoned that the formation of 3 was due
to the competition of the ‘tert-amino effect’ and further
investigations of this new mode of reaction may lead to a
new method for the synthesis of various dihydropurine an-
alogues. Herein, the preliminary results of this investiga-
tion are reported.
tion for the reaction is a [1,6]-hydrogen shift due to a ‘tert-amino ef-
fect’.
Key words: tert-amino effect, dihydropurine, hydrogen transfer,
imines, cyclizations
Natural products are generated via evolutionary selection
processes and represent the biologically relevant and pre-
validated fractions of chemical spaces. Dihydropurine de-
rivatives are among the natural products that exhibit
important pharmacological properties.1 7-Methylgua-
nosine is unique since it is involved in certain transfer and
messenger RNAs, and is the only naturally occurring nu-
cleoside known to exist as a zwitterion at physiological
pH.2 Methods have been reported for the synthesis of di-
hydropurine derivatives, for example, the reduction of pu-
rine by NaBH42,3 and the reaction of urea with an aldehyde
or a ketone under basic conditions.4
Suitably substituted pyrimidines 1, 4, and 5 were readily
prepared following a two-step process from commercially
available 4,6-dichloro-5-nitropyrimidine and correspond-
ing amines (Table 1).9 Their reactions with aromatic alde-
hydes proceeded smoothly in the presence of tri-
fluoroacetic acid (TFA) to give 7,8,9-trisubstituted dihy-
dropurine derivatives 3, and 6–8 (Table 2).10 The structure
of compound 8a was unequivocally determined through
an X-ray diffraction analysis (Figure 1).11
The formation of heterocycles by ring closure of ortho-
substituted N,N-dialkylanilines is known as the ‘tert-ami-
no effect’ cyclization or a-cyclization of tertiary amines.5
Viehe investigated the scope and limitations of the ‘tert-
amino effect’ for the synthesis of heterocycles.6 The ‘tert-
amino effect’ has been successfully applied to the synthe-
sis of several heterocyclic scaffolds.7
Table 1 Synthesis of Pyrimidinediamine Derivatives
Cl
Cl
NH2
NO2
Cl
i. amines, Et3N, THF
N
N
R
ii. Fe-NH4Cl, EtOH–H2O
n
N
N
N
R1
Cl
Me
1 (n = 1)
4 (n = 2)
5 (n = 3)
HN
N
Ar
Cl
N
N
N
Entry
Product
n
1
1
1
1
2
2
3
R
Yield (%)a
a
b
NH2
Me
R1CHO
N
2
+
1
2
3
4
5
6
7
1a
1b
1c
1d
4a
4b
5
3-MeO
52
65
23
38
47
90
20
R1
Cl
N
H
Ar
N
Me
N
Ar
1
4-Me
N
N
Me
3
4-F
H
Scheme 1
3,5-di-MeO
H
SYNLETT 2008, No. 15, pp 2373–2375
Advanced online publication: 22.08.2008
DOI: 10.1055/s-2008-1078212; Art ID: W05808ST
© Georg Thieme Verlag Stuttgart · New York
1
5
.0
9
.2
0
0
8
a Overall yield in two steps.

2374
X. Che et al.
LETTER
Table 2 Synthesis of 6-Chloro-7,8,9-trisubstituted Dihydropurinesa
R
R2
R1
R2
NH2
R1CHO
TFA
N
N
N
R
n–1
n
N
N
MeCN
N
N
Me
Me
1 (n = 1, R2 = Cl)
4 (n = 2, R2 = Cl)
5 (n = 3, R2 = Cl)
3 (n = 1, R2 = Cl)
7 (n = 2, R2 = Cl)
8 (n = 3, R2 = Cl)
6 (n = 2, R2 = 1-pyrrolidinyl)
9 (n = 2, R2 = 1-pyrrolidinyl)
Entry
1
Product
3a
R
R1
n
1
1
1
1
1
1
2
2
2
3
3
3
2
2
2
2
R2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Xd
X
Time (h)
Yield (%)b
67c
51
3-MeO
4-O2NC6H4
Ph
12
8
2
3b
3c
3-MeO
3
3-MeO
4-MeC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
Ph
7
68
4
3d
3e
H
12
8
68
5
4-Me
74
6
3f
4-F
12
12
8
61
7
7a
H
60
8
7b
7c
H
31
9
3,5-(MeO)2
4-O2NC6H4
4-O2NC6H4
Ph
12
12
8
35
10
11
12
13
14
15
16
8a
H
H
H
H
H
H
H
65
8b
8c
59
4-MeC6H4
4-O2NC6H4
Ph
7
64
9a
12
12
12
3
82
9b
9c
47
4-MeC6H4
n-Pr
X
37
9d
X
59
a Reagents and conditions: 1 (1.0 equiv), R1CHO (1.5–2.0 equiv) and TFA (excess) in MeCN, reflux.
b Yields are based on pure products isolated by flash chromatography.
c 7% Imine intermediate was also isolated.
d X = 1-pyrrolidinyl.
(n = 3, phenpropylamino; entries 1–6 and 10–12, Table 2)
generally gave higher yields as compared to 4 with a
phenethylamino group (n = 2; entries 7–9 and 13–16,
Table 2). However, there was no clear correlation be-
tween the electronic properties of the substituents on the
aromatic rings and product yields.
A plausible mechanism for the formation of dihydropu-
rine derivatives was proposed in Scheme 2. It was envi-
sioned that the cyclization reaction proceeded through an
imine intermediate 10 formed between the amino group of
pyrimidine 1 (or 4–6) and an aldehyde under acid-cata-
lyzed conditions. Imine 10 was protonated to iminium 11
which underwent a [1,6]-hydrogen shift to give iminium
12. Ring closure of the iminium 12 and deprotonation
generated the expected dihydropurine derivatives.
Figure 1 X-ray crystal structure of 8a
As shown in Table 2, when an aromatic aldehyde was em-
ployed, the desired product was obtained in moderate to
good yields. Pyrimidines 1 (n = 1, benzylamino) and 5
Synlett 2008, No. 15, 2373–2375 © Thieme Stuttgart · New York

LETTER
Synthesis of 7,8,9-Trisubstituted Dihydropurine Derivatives
2375
R2
(6) (a) Jiang, S.; Janousek, Z.; Viehe, H. G. Tetrahedron Lett.
1994, 35, 1185. (b) De Boeck, B.; Jiang, S.; Janousek, Z.;
Viehe, H. G. Tetrahedron 1994, 50, 7075. (c) De Boeck,
B.; Janousek, Z.; Viehe, H. G. Tetrahedron 1995, 51, 13239.
(7) (a) Ojea, V.; Peinador, C.; Vilar, J.; Quintela, J. M. Synthesis
1993, 152. (b) Ojea, V.; Maestro, M. A.; Quintela, J. M.
Tetrahedron 1993, 49, 2691. (c) Ojea, V.; Peinador, P.;
Quintela, J. M. Synthesis 1992, 798. (d) Ojea, V.; Muinelo,
I.; Figueroa, M. C.; Ruiz, M.; Quintela, J. M. Synlett 1995,
622. (e) Ojea, V.; Muinelo, I.; Quintela, J. M. Tetrahedron
1998, 54, 927. (f) Mátyus, P.; Fuji, K.; Tanaka, K.
Heterocycles 1994, 37, 171. (g) Schwartz, A.; Beke, G.;
Kovári, Z.; Böcskey, Z.; Farkas, Ö.; Mátyus, P. J. Mol.
Struct. (Theochem) 2000, 528, 49. (h) Kaval, N.; Dehaen,
W.; Mátyus, P.; Van der Eycken, E. Green Chem. 2004, 6,
125. (i) Dajka-Halász, B.; Földi, A. A.; Ludányi, K.;
Mátyus, P. ARKIVOC 2008, (iii), 102.
N
R1
N
R1CHO
1 (or 4–6)
N
N
n
Ar
Me
10
H+
R1
R2
N
NH
N
H
Ar
• •
N
n–1
Me
11
∆
[1,6]-H
R1
(8) Che, X.; Zheng, L.; Dang, Q.; Bai, X. J. Org. Chem. 2008,
R2
73, 1147.
ring
closure
(9) Yang, J.; Che, X.; Dang, Q.; Wei, Z.; Gao, S.; Bai, X. Org.
Lett. 2005, 7, 1541.
(10) General Procedure for Syntheses of 6-Chloro-7,8,9-
trisubstituted Dihydropurines
N
H
N
3 (or 7–9)
Ar
N
N+
H+
n–1
Me
12
Pyrimidinediamine 1 (0.65 mmol), the appropriate aldehyde
(0.975 mmol), and TFA (0.6 mL) were dissolved in MeCN
(10.0 mL) and stirred under reflux for 1–12 h. The reaction
mixture was concentrated in vacuo, diluted with EtOAc (15
mL), and washed with sat. NaHCO3 (3 × 15 mL). The water
layer was extracted with EtOAc (3 × 10 mL). The combined
EtOAc layer was washed with brine, dried over anhyd
Na2SO4, concentrated in vacuo, and purified by flash
chromatography on SiO2 to furnish the cyclized product 3.
6-Chloro-8-(3-methoxyphenyl)-9-methyl-7-(4-
Scheme 2 A plausible mechanism for the formation of dihydropu-
rines
In conclusion, a new method was developed for the prep-
aration of 7,8,9-trisubstituted dihydropurine derivatives
via a cascade reaction. The key transformation was a pos-
sible [1,6]-hydrogen shift or hydride transfer due to a
‘tert-amino effect’. This method complements the exist-
ing ones for the preparation of dihydropurine derivatives,
and should be applicable to preparation of diverse librar-
ies, which may be useful in field of chemical biology and
medicinal chemistry.
nitrobenzyl)-8,9-dihydro-7H-purine (3a)
Orange solid, yield 67% (elution with EtOAc–PE, 1:2); mp
119.2–120.6 °C. ES-MS: m/z = 411.8 [M + 1]+. 1H NMR
(300 MHz, CDCl3): d = 8.14 (d, J = 8.4 Hz, 2 H), 7.92 (s, 1
H), 7.30–7.35 (m, 3 H), 6.96 (dd, J = 8.4, 1.8 Hz, 1 H), 6.88
(d, J = 7.5 Hz, 1 H), 6.82 (t, J = 1.8 Hz, 1 H), 5.71 (s, 1 H),
5.05 (d, J = 16.8 Hz, 1 H), 4.32 (d, J = 16.5 Hz, 1 H), 3.80
(s, 3 H), 2.77 (s, 3 H). 13C NMR (75 MHz, CDCl3): d =
155.8, 154.2, 144.6, 142.8, 140.0, 132.6, 125.7, 124.1,
122.5, 119.3, 115.7, 111.1, 108.8, 80.4, 50.9, 43.5, 23.9.
6-Chloro-9-methyl-7-(4-nitrobenzyl)-8-phenethyl-8,9-
dihydro-7H-purine (8a)
Yellow solid, yield 65% (elution with EtOAc–PE, 1:2); mp
123–125 °C. ES-MS: m/z = 410.1 [M + 1]+. 1H NMR (500
MHz, DMSO): d = 8.23 (d, J = 8.5 Hz, 2 H), 7.70 (s, 1 H),
7.63 (d, J = 8.5 Hz, 2 H), 7.17–7.20 (m, 2 H), 7.10–7.13 (m,
1 H), 7.02–7.03 (m, 2 H), 5.32 (s, 1 H), 4.85 (d, J = 17.5 Hz,
1 H), 4.69 (d, J = 17.0 Hz, 1 H), 2.89 (s, 3 H), 2.46–2.56 (m,
1 H), 2.40–2.44 (m, 1 H), 2.05–2.10 (m, 1 H), 1.85–1.91 (m,
1 H). 13C NMR (75 MHz, CDCl3): d = 159.4, 149.6, 149.5,
147.5, 144.8, 140.4, 128.5, 128.0, 127.6, 126.2, 123.9, 82.5,
50.3, 33.0, 28.4, 27.7.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
This work was supported by the National Natural Science Founda-
tion of China (20572032 and 90713008) and Changchun Discovery
Sciences, Ltd.
References and Notes
(1) Lin, Y.-L.; Huang, R.-L.; Chang, C.-M.; Kuo, Y.-H. J. Nat.
Prod. 1997, 60, 982.
(2) Hecht, S. M.; Adams, B. L.; Kozarich, J. W. J. Org. Chem.
(11) Crystallographic data for structure 8a reported in this paper
in the form of CIF file has been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication No. CCDC-689708. Copies of the data can be
obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB2 IEZ, UK [fax: +44 (1223)336033; e-
mail: deposit @ccdc.cam.ac.uk].
1976, 41, 2303.
(3) Kelley, J. L.; Linn, J. A. J. Org. Chem. 1986, 51, 5435.
(4) Booth, B. L.; Dias, A. M.; Proenca, M. F.; Zaki, M. E. A.
J. Org. Chem. 2001, 66, 8436.
(5) (a) Meth-Cohn, O.; Suschitzky, H. Adv. Heterocycl. Chem.
1972, 14, 211. (b) Meth-Cohn, O. Adv. Heterocycl. Chem.
1996, 65, 1. (c) Mátyus, P.; Éliás, O.; Tapolcsányi, P.;
Polonka-Bálint, Á.; Halász-Dalka, B. Synthesis 2006, 2625.
Synlett 2008, No. 15, 2373–2375 © Thieme Stuttgart · New York

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