General synthetic approach to 2-phenolic adenine derivatives

Article abstract of DOI:10.1055/s-0031-1290694

A simple and general one-pot' procedure for the synthesis of 2,9-diarylpurines with one or multiple hydroxyl groups in the 2-aryl unit is described, from the reaction of 5-amino-4-amidinoimidazoles with phenolic aldehydes. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290694

LETTER
▌1923
letter
General Synthetic Approach to 2-Phenolic Adenine Derivatives
Synthesis of 2-Phenolic Adenine Derivatives
Carla Correia, M. Alice Carvalho,* Ashly Rocha, M. Fernanda Proença
Departamento de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
Fax +351(253)678983; E-mail: mac@quimica.uminho.pt
Received: 05.05.2012; Accepted after revision: 14.05.2012
and the presence of hydroxyl groups in the aryl subunit in
C-2 was considered an important feature for activity. The
microorganism needs iron for the biochemical processes,
and multiple hydroxyl groups in the phenolic subunit
could enhance the complexation with the metal. This per-
ception prompted us to develop a new synthetic approach
that would allow the efficient synthesis of purines 6 (Ta-
ble 1) having a phenolic subunit in C-2 with two and three
hydroxyl substituents. The previous method only allowed
the introduction of phenolic units with one hydroxyl
group as the reaction with polyphenolic aldehydes, per-
formed in basic medium, was very slow (8–54 d) and ex-
tensive degradation occurred.4
Abstract: A simple and general ‘one-pot’ procedure for the synthe-
sis of 2,9-diarylpurines with one or multiple hydroxyl groups in the
2-aryl unit is described, from the reaction of 5-amino-4-amidino-
imidazoles with phenolic aldehydes.
Key words: nucleobases, phenols, condensations, aldehydes, ring
closure
Purines have attracted attention of the scientific commu-
nity mainly due to their biological activity.1 During the
last decade, purine derivatives were identified as a prom-
ising new class of antitubercular agents. The research was
focused on the synthesis of nucleoside analogues as sider-
ophore biosynthesis inhibitors2 and on non-nucleosides.3
In the non-nucleoside series, purines having an aryl, a
small alkyl, or a proton on N-9 were essentially inactive,
whereas 9-benzyl-6-(2-furyl)purines,3b,h,j 9-sulfonyl-6-
mercaptopurines, or 6-alkylthiopurines3e,k were highly po-
tent. In addition, we recently described the first example
of 2,9-diarylpurines (Figure 1) active against Mycobacte-
rium tuberculosis.4 The results from biological evaluation
showed that the potency of the compounds depends on the
substituents in N-9, C-2, and C-6 of the purine core. The
presence of a 4-tolyl group in N-9 and a 3-hydroxyphenyl
or a 4-hydroxyphenyl substituent in C-2 combined with a
secondary amine in C-6 proved to be important features
for activity (Figure 1) but a clear structure–activity corre-
lation pattern could not be identified.4
Herein we describe a new and general synthetic approach
for 6-amino-9-aryl-2-hydroxy or 2-(polyhydroxyphe-
nyl)purines 6 using imidazole 1, phenolic aldehydes 2,
and a cascade of acid and base catalysis.
When compound 1a (Scheme 1) was combined with
3,4,5-trihydroxybenzaldehyde (2a) in ethanol at 0 °C, us-
ing trifluoroacetic acid as catalyst, the starting materials
were dissolved and a new white solid precipitated after
five minutes. This compound was identified as the triflu-
oroacetate salt of starting material 3. When the reaction
was repeated using 2.0 equivalents of the acid, a yellow
solid precipitated after four hours and was identified as
4a6 (Scheme 1).
When imidazole 1b was reacted with monohydroxy or di-
hydroxyphenylaldehydes 2b or 2c, at 6 °C, no solid pre-
cipitated from the initial yellow solutions. When the TLC
showed the absence of imines 4, off-white solids were iso-
lated and identified as dihydropurines 5a,b7a (Scheme 1,
method i). Dihydropurine 5c7a was also isolated in the re-
action of imidazole 1a with 3,4,5-trihydroxyphenylalde-
hyde (2a) when the reaction was carried out at room
temperature (Scheme 1, method i). The imine 4a also
evolved to the dihydropurine 5c7b after ten days in ethano-
lic solution at 8 °C (Scheme 1, method ii).
R1
X
N
2
9N
4
5
8
R1 = 4-MeC6H4
N
N
R2 = NMe2; X = 4-HO; IC90 = 4.72 μg/mL
6
R2
R2 = piperidin-1-yl; X = 3-HO; IC90 = 3.54 μg/mL
Figure 1 Hit compounds active on Mycobacterium tuberculosis
A number of synthetic methods were developed to incor-
porate functional groups in the purine core, but costly re-
agents are usually required.5a,b In our research group
purine derivatives have been obtained by a simple and in-
expensive synthetic approach that uses the versatile reac-
tivity of a substituted imidazole.4,5c–l
The pure imine 4a showed a single spot on TLC, however,
1
by H NMR spectroscopy the spectrum obtained in
DMSO solution showed signals consistent with the pres-
ence of two compounds in a 7:3 molar ratio. The major
compound was identified as 4a (70%) and the minor com-
pound as the dihydropurine 5c (30%). These results sug-
gested that, in DMSO solution, the imine 4a was cyclizing
to the dihydropurine 5c. In order to confirm this result a
The 6-amino-2,9-diarylpurines (Figure 1) are a new prom-
ising scaffold active against Mycobacterium tuberculosis
1
new H NMR spectrum was registered after two hours.
SYNLETT 2012, 23, 1923–1926
Advanced online publication: 04.07.2012
The spectrum showed once again a mixture of 4a and 5c
but in a 1:9 molar ratio, and this ratio did not change after
one week at room temperature.
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290694; Art ID: ST-2012-D0394-L
© Georg Thieme Verlag Stuttgart · New York

1924
C. Correia et al.
LETTER
HO
OH
EtOH
TFA (cat)
0 °C, 5 min
EtOH
TFA (2 equiv)
0 °C, 4 h
O
OH
NH2
N
N
O
N
N
N
N
N
OH
O–
NH2
NH
+
+
+
NH2
R2
NH2
2a
2a
R1
CF3COO–
R1
R1
3 R1 = piperidin-1-yl (60%)
OH
1a R1 = piperidin-1-yl 2a R2 = 3,4,5-(HO)3C6H2
1b R1 = morpholin-1-yl 2b R2 = 2-HOC6H4
2c R2 = 3,4-(HO)2C6H3
4a R1 = piperidin-1-yl (82%)
ii)
i)
EtOH
TFA (1.3–2equiv)
EtOH
8 °C
10 d
6 °C, 4 d
2b, c
H
N
R2
+NH
N
N
r.t., 5 d
2a
CF3COO–
R1
5a R1 = morpholin-1-yl: R2 = 2-HOC6H4 (60%)i)
5b R1 = morpholin-1-yl; R2 = 3,4-(HO)2C6H3 (58%)i)
5c R1 = piperidin-1-yl; R2 = 3,4,5-(HO)3C6H2 (41%)i), (91%)ii)
Scheme 1 Reactions of imidazoles 1 with phenolic aldehydes 2 in acidic medium
When the solution was heated in the NMR tube at 60 °C two, or three hydroxyl groups. The purines 6a–k were ob-
during ten minutes a mixture of 4a and 5c was still pres- tained directly from the reaction mixture after 2–10 days
ent, however, new signals were observed in the spectrum, (Table 1). When degradation was observed, the pure prod-
assigned to purine 6i and to the imidazole 1a and aldehyde ucts were isolated in lower yields after dry flash chroma-
2a, the starting reagents. The hydrolysis of the imine 4a tography (compounds 6e–h).
was also observed by 1H NMR spectroscopy in an acidi-
fied solution of 4a in DMSO-d6. These results indicate
In summary this work describes a new versatile and sim-
ple ‘one-pot’ method to synthesize 6-amino-9-substituted
that in DMSO solution at room temperature the imine 4a
2-hydroxy or 2-(polyhydroxyphenyl)purines 6 starting
evolves rapidly to the dihydropurine 5c leading to an equi-
from imidazoles 1 and phenolic aldehydes 2. The forma-
librium mixture. Under heating, compound 5c evolves to
tion of the imine intermediate is favored in ethanol using
acid catalysis, however, the cyclization and oxidation, to
generate the purine core, is favored in dimethylsulfoxide
under heating using base catalysis.
generate the purine 6i. However, in acid solution hydroly-
sis of the imine regenerates the starting materials 1a and
2a.
The dihydropurine 5c was also solubilized in DMSO-d6
1
and the H NMR spectrum, acquired after five minutes,
showed that 5c was the only product present in solution.
Acknowledgment
The NMR spectrometer (Bruker 400 Avance III) is part of the Na-
tional NMR Network, supported with funds from Fundação para a
Ciência e a Tecnologia (FCT). The authors gratefully acknowledge
the financial support by F.C.T. (project n° F-COMP-01-0124-
FEDER-022716 (ref. FCT PEst-/QUI/UI0686/2011) FEDER-
COMPETE, FCT-Portugal and the PhD grant to C. Correia
(SFRH/BD/22270/2005).
However, after the addition of triethylamine and heating
at 80 °C for 20 hours only purine 6i was present in solu-
tion.
Considering that (1) the reaction of imidazoles 1 with al-
dehydes 2 led to imines 4 and dihydropurines 5 (in EtOH
in the presence of 1.3–2 equiv of TFA), and (2) com-
pounds 4 and 5 with triethylamine in DMSO solution un-
der heating generated the desired purine 6, a new ‘one pot’
synthetic procedure starting from imidazoles 1 and alde-
hydes 2 leading to purines 68 has been designed. The re-
action was initially carried out in ethanol and acid (1.3–2
equiv) until total consumption of the starting materials (by
TLC). The solvent was then removed in the rotary evapo-
rator, and the reactions proceeded in DMSO and base un-
der heating.
References and Notes
(1) Legraverend, M.; Grierson, D. S. Bioorg. Med. Chem. 2006,
14, 3987.
(2) (a) Gupte, A.; Boshoff, H. I.; Wilson, D. J.; Neres, J.;
Labello, N. P.; Somu, R. V.; Xing, C.; Barry, C. E. III.;
Aldrich, C. C. J. Med. Chem. 2008, 51, 7495. (b) Neres, J.;
Labello, N. P.; Somu, R. V.; Boshoff, H. I.; Wilson, D. J.;
Vannada, J.; Chen, L.; Barry, C. E. III.; Bennett, E. M.;
Aldrich, C. C. J. Med. Chem. 2008, 51, 5349. (c) Long,
M. C.; Shaddix, S. C.; Moukha-Chafiq, O.; Maddry, J. A.;
Nagy, L.; Parker, W. B. Biochem. Pharmacol. 2008, 75,
These experimental conditions were applied to the reac-
tion of imidazoles 1a–c with aldehydes 2a–g, having one,
Synlett 2012, 23, 1923–1926
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 2-Phenolic Adenine Derivatives
1925
Table 1 Synthesis of Purines 6
R1
R1
N
R3
O
N
N
NH2
NH
i)
+
R3
2
N
N
N
R2
1
R2
6
Imidazole
Aldehyde
Reaction conditions
Product Yield
1
R1
R2
2
R3
6
(%)
73
1b
1b
1b
1b
1b
1b
1b
1a
1a
1c
1c
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
morpholin-
1-yl
2b
2d
2e
2f
2-HOC6H4
3-HOC6H4
4-HOC6H4
2,3-
i) a) 1b (0.12 g), 2b (1.1 equiv), EtOH, TFA (1.3 equiv), 6a
11 °C, 1 d
b) DMSO (0.2 mL), Et3N (10 equiv), 40 °C, 2 d
morpholin-
1-yl
i) a) 1b (0.12 g), 2d (1.1 equiv), EtOH, TFA (1.3 equiv), 6b
11 °C, 7 d
79
78
88
58
59
50
57
57
67
60
b) DMSO (0.2 mL), Et3N (10 equiv), 40 °C, 2 d
morpholin-
1-yl
i) a) 1b (0.13 g), 2e (1.1 equiv), EtOH, TFA (1.3 equiv),
11 °C, 1 d
b) DMSO (0.2 mL), Et3N (10 equiv), 40 °C, 2 d
6c
6d
6e
morpholin-
1-yl
i) a) 1b (0.17 g), 2f (1.1 equiv), EtOH, TFA (2.0 equiv),
(HO)2C6H3 r.t., 30 min
b) DMSO, EtOH, Et3N(10 equiv), 40 °C, 6 d
morpholin-
1-yl
2c
2g
2a
2c
2a
3,4-
i) a) 1b (0.12 g), 2c (1.1 equiv), EtOH, TFA (1.3 equiv),
(HO)2C6H3 11 °C, 1 d
b) DMSO, Et3N (10 equiv), 40 °C, 4 d
morpholin-
1-yl
2,3,4-
i) a) 1b (0.30 g), 2g (1.1 equiv), EtOH, TFA (1.3 equiv), 6f
(HO)3C6H2 r.t., 1 d
b) DMSO, Et3N (10 equiv), 40 °C, 6 d
morpholin-
1-yl
3,4,5-
i) a) 1b (0.28 g), 2a (1.1 equiv), EtOH, TFA (1.3 equiv), 6g
(HO)3C6H2 r.t., 6 d
b) DMSO, Et3N (10 equiv), 40 °C, 1 d
piperidin-
1-yl
3,4-
i) a) 1a (0.21 g), 2c (1.1 equiv), EtOH, TFA (1.5 equiv),
(HO)2C6H3 r.t., 6 d
b) DMSO, Et3N (10 equiv), 40 °C, 4 d
6h
piperidin-
1-yl
3,4,5-
i) a) 1a (0.21 g), 2a (1.1 equiv), EtOH, TFA (1.5 equiv),
(HO)3C6H2 r.t., 10 d
b) DMSO, Et3N (10 equiv), 80 °C, 1 d
6i
thiomorpholin- 2a
4-yl
3,4,5-
i) a) 1c (0.16 g), 2a (1.1 equiv), EtOH, TFA (1.3 equiv),
(HO)3C6H2 r.t., 5 d
b) DMSO, Et3N (10 equiv), 80 °C, 1 d
6j
thiomorpholin- 2g
4-yl
2,3,4-
i) a) 1c (0.11 g), 2g (1.1 equiv), EtOH, TFA (1.3 equiv),
(HO)3C6H2 r.t., 4 d
b) DMSO, Et3N (10 equiv), 40 °C, 5 d
6k
1588. (d) Bisseret, P.; Thielges, S.; Bourg, S.; Miethke, M.;
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1923–1926

1926
C. Correia et al.
LETTER
Chem. Lett. 2002, 12, 567. (h) Gundersen, L.-L.; Nissen-
Meyer, J.; Spilsberg, B. J. Med. Chem. 2002, 45, 1383.
(i) Scozzafava, A.; Mastrolorenzo, A.; Supuran, C. T.
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were added to a stirred suspension of imidazole 1a (0.11 g,
0.40 mmol) in EtOH (2.0 mL) at r.t. The yellow solution
became light yellow, and when TLC showed the absence of
imine 4 (5 d), the solution was concentrated in the rotary
evaporator. The off-white solid was filtered, washed with
EtOH and Et2O and identified as compound 5c (0.09 g, 0.16
mmol, 41%).
(b) Method ii
(4) Correia, C.; Carvalho, M. A.; Proença, M. F. Tetrahedron
2009, 65, 6903.
A yellow ethanolic solution of 4a (0.09 g, 0.16 mmol) was
stirred at 8 °C until TLC showed the absence of starting
material (10 d). The solution was concentrated in the rotary
evaporator leading to an off-white solid that was filtered and
washed with Et2O and identified as compound 5c (0.08 g,
0.15 mmol, 91%); mp 218–220 °C. IR (mull): 3535, 3202,
1679, 1613, 1530 cm–1. 1H NMR (300 MHz, DMSO-d6): δ =
1.69 (s, 6 H, CH2), 2.39 (s, 3 H, CH3), 3.70 (m, 4 H, CH2),
5.71 (t, 1 H, J = 4.8 Hz, 2-H), 6.28 (s, 2 H, ArH), 7.40–7.46
(m, 4 H, ArH), 7.88 (s, 1 H, 8-H), 8.07 (d, 1 H, J = 4.8 Hz,
NH, D2O exchangeable), 8.23 (br s, 1 H, HO, D2O
exchangeable), 8.88 (d, 1 H, J = 4.8 Hz, NH, D2O
(5) (a) For a recent review, see: Legraverend, M. Tetrahedron
2008, 64, 8585. (b) Ibrahim, N.; Legraverend, M. J. Org.
Chem. 2009, 74, 463. (c) Alves, M. J.; Booth, B. L.; Freitas,
A. P.; Proença, M. F. J. Chem. Soc., Perkin Trans. 1 1992,
913. (d) Booth, B. L.; Dias, A. M.; Proença, M. F. J. Chem.
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1019. (k) Carvalho, M. A.; Álvares, Y.; Zaki, M. E.;
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2007, 4881.
(6) Procedure for the Synthesis of Imine 4a (Scheme 1)
To a stirred suspension of imidazole 1a (0.14 g, 0.49 mmol)
in EtOH (0.4 mL), aldehyde 2a (0.09 g, 1.1 equiv) and TFA
(75 μL, 2 equiv) were added at 0 °C. A yellow solution
developed, and a yellow solid started to precipitate after 25
min. When the TLC indicated the absence of starting
material (4 h), EtOH was added (0.8 mL), and the yellow
solid was filtered. The solid was washed with EtOH and
Et2O and identified as compound 4a (0.22 g, 0.40 mmol,
82%); mp 124–126 °C. IR (mull): 3498, 3352, 3210, 1665,
1626, 1604, 1586, 1521 cm–1. 1H NMR (300 MHz, DMSO-
d6): δ = 1.62 (s, 6 H, CH2), 2.37 (s, 3 H, CH3), 3.58 (br s, 4
H, CH2), 6.82 (s, 2 H, ArH), 7.30–7.45 (m, 4 H, ArH), 8.17
(s, 2 H, 2-H, N=CH), 8.80–9.60 (m, 5 H, NH, HO, D2O
exchangeable). Anal. Calcd for C23H25N5O3·TFA·H2O: C,
54.44; H, 5.08; N, 12.70. Found: C, 54.68; H, 5.41; N, 12.45.
(7) Procedure for the Synthesis of Dihydropurine 5c
(Scheme 1)
exchangeable), 8.99 (s, 2 H, HO, D2O exchangeable). 13
C
NMR (75 MHz, DMSO-d6): δ = 20.62 (CH3), 23.32, 25.80,
48.82, 64.77 (2-C), 105.12, 110.60, 124.14, 129.16, 130.32,
130.88, 133.39, 135.14 (8-C), 138.65, 145.73, 145.84,
150.00. Anal. Calcd for C23H25N5O3·TFA·2.1H2O: C, 52.56;
H, 5.29; N, 12.26. Found: C, 52.55; H, 5.10; N, 12.07.
(8) Procedure for the Synthesis of Purine 6f (Table 1)
Aldehyde 2g (0.18 g, 1.1 equiv) and TFA (166 μL, 1.3 equiv)
were added to a stirred suspension of imidazole 1b (0.30 g,
1.08 mmol) in EtOH (0.3 mL) at r.t. during 1 d. Then, the
solvent was removed in the rotary evaporator, and DMSO
(0.3 mL) was added to the crude solid followed by Et3N
(1.35 mL, 10 equiv), and the reaction was stirred at 40 °C
during 6 d. Addition of H2O and cooling for 10 min led to
a brown solid that was filtered and washed with H2O and
Et2O (0.42 g). The brown solid was purified by dry flash
chromatography on silica gel using 500 mL of Et2O as eluent
to give an off-white solid identified as 6f (0.25 g, 0.60 mmol,
59%); mp >300 °C. IR (mull): 3550, 3465, 3337, 3101,
1637, 1624, 1581, 1528 cm–1. 1H NMR (300 MHz, DMSO-
d6): δ = 2.41 (s, 3 H, CH3), 3.85 (s, 4 H, CH2), 4.30 (br s, 4
H, CH2), 6.36 (d, 1 H, J = 9.0 Hz, ArH), 7.43 (d, 2 H, J = 8.4
Hz, ArH), 7.64 (d, 2 H, J = 8.7 Hz, ArH), 7.68 (d, 1 H, J =
9.0 Hz, ArH), 8.24 (br s, 1 H, HO, D2O exchangeable), 8.45
(s, 1 H, 8-H), 9.16 (br s, 1 H, HO, D2O exchangeable), 13.45
(s, 1 H, HO, D2O exchangeable). 13C NMR (75 MHz,
DMSO-d6): δ = 20.64 (CH3), 45.52, 66.13, 107.05, 111.53,
117.57, 119.45, 123.82, 130.17, 131.99, 132.69, 137.77,
139.18 (8-C), 148.54, 148.93, 149.36, 152.66, 158.86 (2-C).
Anal. Calcd for C22H21N5O4·0.5H2O: C, 61.68; H, 5.14; N,
16.36. Found: C, 61.75; H, 5.06; N, 16.20.
(a) Method i
Aldehyde 2a (0.07 g, 1.0 equiv) and TFA (40 μL,1.3 equiv)
Synlett 2012, 23, 1923–1926
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