Synthesis and in vitro activity of 6-amino-2,9-diarylpurines for Mycobacterium tuberculosis

Article abstract of DOI:10.1016/j.tet.2009.06.065

A mild method was developed to synthesize 6-amino-2-phenolic-9-alkyl and 9-arylpurines. The new compounds were screened for antibacterial activity against Mycobacterium tuberculosis strain H₃₇Rv. The?9-tolyl derivatives with a dimethylamino or

Full text of DOI:10.1016/j.tet.2009.06.065

Tetrahedron 65 (2009) 6903–6911
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and in vitro activity of 6-amino-2,9-diarylpurines
for Mycobacterium tuberculosis
*
Carla Correia, M. Alice Carvalho , M. Fernanda Proença
Departamento de Qu´ımica, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 May 2009
Received in revised form 17 June 2009
Accepted 18 June 2009
Available online 21 June 2009
A mild method was developed to synthesize 6-amino-2-phenolic-9-alkyl and 9-arylpurines. The new
compounds were screened for antibacterial activity against Mycobacterium tuberculosis strain H37Rv.
The 9-tolyl derivatives with a dimethylamino or a piperidine substituent in C6 and the 3-hydroxyphenyl
or 4-hydroxyphenyl substituent in C2 were highly active against the bacilli.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Purine
Antimicrobial agent
Tuberculosis
1. Introduction
as the N9 substituent were essentially inactive, whereas 9-benzyl-6-
(2-furyl)purines were highly potent. The target of this non nucleo-
The Mycobacterium tuberculosis, the microorganism responsible
for tuberculosis, is considered the leading cause of death world-
wide.1 It is estimated that at least one-third of the world’s pop-
ulation is infected with a latent form of this organism and about
10% of these individuals will develop the active form of the disease
during their lifetime.2 The co-infection with HIV is especially lethal
and serves as a trigger to convert latent tuberculosis into an active
transmissible infection. The current therapy requires treatment
with a combination of drugs, over 6–9 months and results in an
overall cure rate of approximately 85%.2 The emergence of multi-
drug resistant tuberculosis (MDR-TB) and extensively drug re-
sistant tuberculosis (XDR-TB) caused an urgency in the search for
new antitubercular agents.3
side analogues and the mechanism of action is still unknown.
The substituents incorporated in C2 of the purine ring, in the non
nucleoside series, were limited tohydrogen and chlorine atoms.7a As
far as we know, no further research was carried out to explore the
effect of different substituents in this position of the purine core.
This observation prompted us to design new purine derivatives
withpotentialantituberculosisactivitycombiningthepurinemoiety
with phenolic residues, which are known as excellent iron chelators.
As far as we know a phenolic substituent was never introduced
in C2 of the purine ring and the 6-amino-2,9-diarylpurines were
never evaluated as antituberculosis agents. Herein we report the
synthesis of new 6-amino-2-phenolic-purines 4 and their anti-
mycobacterial activity.
It is well known that invasive pathogens, as Mycobacterium tu-
berculosis, require iron as an essential element for numerous bio-
chemical processes. Theyobtainironfromthehost bysmallmolecule
iron chelators known as siderophores and using the cellular Fe-
siderophore uptake system.4 During last decade some purine de-
rivatives were identified as promising new drug candidates against
Mycobacterium tuberculosis.5 The research was mainly focussed on
nucleoside analogues as siderophore biosynthesis inhibitors6 and on
purine derivatives having different substituents in N9, C2, C6 and C8
of the purine ring. For non nucleoside analogues, it has been dem-
onstrated that the identity of the substituents on C6, C8 and N9 are
crucialforactivity.7 Compoundswithan aryl, a small alkyl ora proton
Having established compounds 4 as the target molecules, the
disconnection analysis (Scheme 1) shows that the compounds 3 are
convenient precursors to the purine 4.
R1
N
R1
N
R1
N
N
R2
NH2
NH
NRR´
NH2
NH
CN
O
HNRR´
+
+
N
R2
N
N
N
NRR´
3
4
1
2
R2= phenolic
Scheme 1. Disconnection analysis of the target molecule 4.
During last decade, a renewed interest in the development of new
synthetic methods to incorporate convenient substituents in the
* Corresponding author. Tel.: þ351 253 604 380; fax: þ351 253 678 983.
E-mail address: mac@quimica.uminho.pt (M.A. Carvalho).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.065

6904
C. Correia et al. / Tetrahedron 65 (2009) 6903–6911
purinenucleushasemerged,8 mainlyduetothebiologicalimportance
of these compounds.9 In ourresearch groupwe developed an efficient
method to obtain 6-aminopurines 4 (R2¼H)8l by reaction of the in-
termediate 3 with dimethylformamide diethyl acetal in acetonitrile.
The precursors1are not commerciallyavailableandweresynthesized
from diaminomaleonitrile in three consecutive steps.10
In order to prepare 6-amino-2-phenolic-purines 4 we combined
imidazoles 3 with phenolic aldehydes that incorporate one and two
hydroxyl groups. New compounds 3 were synthesized using the
reaction conditions previously established. The condensation of
imidazoles 3 with phenolic aldehydes was carefully studied.
3e was obtained under mild experimental conditions from the re-
action of 1a and 1.5 equiv of aqueous dimethylamine in acetonitrile.
The 1H NMR data obtained for these new substituted imidazoles
3 is in good agreement with that previously reported.8l A careful
study using NMR heteronuclear correlation techniques (HMQC and
HMBC) also confirmed the structure assignment. Typically, in the
1H NMR spectra of these compounds, the proton H2 appears as
a singlet in the range
d 7.0–7.4 ppm and the carbon C2 at dw128–
132 ppm. The infrared spectra confirmed the absence of the
stretching vibration of the cyano group.
In order to prepare the new purines 4, imidazoles 3 were reacted
with salicylaldehyde and 4-hydroxybenzaldehyde in a mixture of
acetonitrile and ethanol in basic medium. (Scheme 3, Table 1,
method A). The products 4 precipitated as off white solids from
a dark reaction medium and were isolated in moderate to good
yields (48–85%).
2. Results and discussion
The new substituted 4-amidinoimidazoles 3 were obtained by re-
action of imidazoles 1a–c with 5 equiv of secondary amines in aceto-
nitrile (Scheme 2). Theimidazoles3a–igradually precipitated from the
reaction medium and were isolated in good yield (64–89%). Com-
pound 3e was previously isolated from the reaction of 1a with a large
excess of gaseous dimethylamine in chloroform.8l In the present work,
When similar experimental conditions were applied to the re-
action of 3a with 3,4-dihydroxibenzaldehyde, extensive degrada-
tion of the reaction medium occurred. The TLC analysis of the
reaction mixture after 25 days at 8 ꢀC showed a complex mixture
and the absence of purine. A small amount of a solid precipitated
from the reaction mixture and was identified as compound 6a (5%).
The structure of compound 6a was assigned mainly on the basis of
R1
N
R1
N
NH2
NH
NRR´
NH2
NH
CN
NMR data. The 1H NMR spectrum shows a singlet at
typical of the H2 proton of substituted imidazoles. The amino group
in position 5 of the imidazole ring corresponds to a broad singlet at
d
¼7.30 ppm,
CH3CN, r.t.
HNRR´
+
N
N
(5 equiv)
d
¼5.69 ppm and the NH2 of the amide group appears as two very
1 a R1=4-CH3C6H4
b R1=C6H5
2
3
broad singlets at
d
¼6.76 and 6.90 ppm.
c R1=CH3
Some reactions were carried out using ethanol as solvent in
order to increase the solubility of the reagents (Scheme 3, Table 1,
method B) and the products 4 were isolated in moderate yields.
When 3,4-dihydroxybenzaldehyde was reacted with 3b in eth-
anol using DBU as base, compound 6a was again the only product
isolated in 7% yield from a very complex reaction mixture.
Compound 1
Compound 2
piperidine
Reaction time
Product
3a
Yield %
85 a)
84
1a
2h
morpholine
24h
3b
3c
thiomorpholine
pyrrolidine
HNMe2
24h
89
1h
3d
3e
60
74 a)
Methods A and B failed to generate the purines 4 with a dihy-
droxyphenyl substituent in C2 of the purine ring and this led us to
analyse some of the reaction mixtures by 1H NMR, as the reaction
proceeded. The reaction mixture of 3b and salicylaldehyde was
analysed after 10 days at 8 ꢀC (Scheme 4). The spectrum showed
a mixture of purine 4e and the corresponding dihydropurine 5e in
a 1:2 molar ratio. This assignment was based on the typical signals
of H8 of the purines 4 (dH8w8.54 ppm) and the singlet at
2 (1.5 equiv), 48h
1b
1c
piperidine
morpholine
piperidine
morpholine
24h
5h
3f
64
3g
3h
3i
78
24h
24h
68
66
a) Compounds 3a and 3e were isolated previously (reference 8l) in 67 and 87% yield,
respectively.
d
¼5.55 ppm, which can be assigned to H2 of dihydropurine 5e.
Scheme 2. Synthesis of compounds 3.
Compound 5e evolved to the purine 4e, in DMSO solution, in the
Method A: CH3CN/EtOH (1:1), Et3N (10 equiv)
R1
N
R1
N
R2
NH2
NH
NRR´
N
O
EtOH, r.t., Et3N (10 equiv)
DMSO, Et3N (10 equiv)
Method B:
+
N
R2
1.1 equiv
N
N
NRR´
3
Method C:
4
R2=3,4-(HO)2C6H3
Method A or
Method B or
EtOH, DBU (1 equiv), 17days
R1
N
NH2
NH2
N
6a
O
Scheme 3. General approaches to the synthesis of purines 4.

C. Correia et al. / Tetrahedron 65 (2009) 6903–6911
6905
Table 1
Reaction conditions to generate purines 4 and imidazole 6a
Reagent
R2 (aldehyde)
Method/reaction conditions
Product
Yield (%)
3a
2-HOC6H4
3-HOC6H4
4-HOC6H4
A: CH3CN/EtOH (1:1), Et3N (10 equiv), 8 ꢀC, 10 days
B: EtOHEt3N (10 equiv), rt, 26 days
4a
4b
4c
65
65
53
69
5
A: CH3CN/EtOH (1:1), Et3N (10 equiv), 8 ꢀC, 24 days
B: EtOH, Et3N (10 equiv), rt, 30 days
4c
3,4-(HO)2C6H3
A: CH3CN/EtOH (1:1), Et3N (10 equiv), 8 ꢀC, 25 days
C: DMSO, Et3N (10 equiv), 40 ꢀC, 45 days
C: DMSO, Et3N (10 equiv), 11 ꢀC, 48 days
C:DMSO, Et3N (10 equiv), rt, 8 days
C: DMSO, Et3N (10 equiv), rt, 30 days
B: EtOH, Et3N (10 equiv), rt, 26 days
B: EtOH, DBU (1 equiv), rt, 17days
C: DMSO, Et3N (10 equiv), rt, 41 days
C: DMSO, Et3N (10 equiv), rt, 54 days
C: DMSO, Et3N (10 equiv), rt, 18 days
A: CH3CN/EtOH (1:1), Et3N (10 equiv), 11 ꢀC, 20 days
B: EtOH, Et3N (10 equiv), rt, 30 days
A: CH3CN/EtOH (1:1), Et3N (10 equiv), 8 ꢀC, 30 days
C: DMSO, Et3N (10 equiv), 11 ꢀC, 48 days
C: DMSO, Et3N (10 equiv), 8 ꢀC, 42 days
C: DMSO, Et3N (10 equiv), rt, 46 days
C: DMSO, Et3N (10 equiv), 40 ꢀC, 51 days
A: CH3CN/EtOH (1:1), Et3N (10 equiv), 11 ꢀC, 31 days
B: EtOH, Et3N (10 equiv), rt, 20 days
A: CH3CN/EtOH (1:1), Et3N (10 equiv), 11 ꢀC, 37 days
B: EtOH, Et3N (10 equiv), rt, 13 days
B: EtOH, Et3N (10 equiv), rt, 8 days
C: DMSO, Et3N (10 equiv), rt, 18 days
A: CH3CN/EtOH (1:1), Et3N (10 equiv), rt, 6 days
A: CH3CN/EtOH (1:1), Et3N (10 equiv), rt, 27 days
A: CH3CN/EtOH (1:1), Et3N (10 equiv), rt, 24 days
C: DMSO, Et3N (10 equiv), rt, 30 days
C: DMSO, Et3N (10 equiv), rt, 30 days
C: DMSO, Et3N (10 equiv), rt, 10 days
A: CH3CN/EtOH (1:1), Et3N (10 equiv), 11 ꢀC, 41 days
C: DMSO, Et3N (10 equiv), 11 ꢀC, 42 days
C: DMSO (0.4 mL), Et3N (10 equiv), 40 ꢀC, 15 days
6a
4d
4da
4e
4g
4f
6a
4hb
4hc
4hd
4i
46
3b
3c
2-HOC6H4
4-HOC6H4
3-HOC6H4
3,4-(HO)2C6H3
79
84
63
7
32
2-HOC6H4
3-HOC6H4
4-HOC6H4
85
66
56
80
4j
4k
4k
4le
4le
4l
4m
4y
4n
4o
4p
4q
4r
3,4-(HO)2C6H3
40
45
81
54
71
66
34
61
70
47
72
82
33
3d
3e
2-HOC6H4
3-HOC6H4
4-HOC6H4
2-HOC6H4
3-HOC6H4
4-HOC6H4
2-HOC6H4
4-HOC6H4
2-HOC6H4
4-HOC6H4
3,4-(HO)2C6H3
3f
4s
4t
3g
4u
4v
4ve
4w
4x
4z
3h
3i
4-HOC6H4
4-HOC6H4
3,4-(HO)2C6H3
48
80
72
a
Isolated as a mixture of 4d and starting material in a 1:1 ratio.
Isolated as a mixture of 4h and starting material in a 2:1 ratio.
Isolated as a mixture of 4h and starting material in a 4:1 ratio.
Isolated as a mixture of 4h and starting material in a 1:1 ratio.
The crude product was contaminated with traces of the starting material.
b
c
d
e
R1
N
R1
N
R1
N
H
N
4-HOC6H4CHO
8 °C, 12 days
2-HOC6H4CHO
8 °C, 10 days
H
R2
R2
NH2
N
+
3b
+
4g
NH
N
N
N
N
N
NRR´
NRR´
4e
NRR´
5e
3b R1=4-CH3C6H4
NRR´=N(CH2)2O
Scheme 4. Composition of the reaction mixture by 1H NMR: 4e/5e (1:2 molar ratio) and 3b/4g (1:4 molar ratio).
NMR tube. The reaction mixture of 3b with 4-hydroxybenzaldehyde
medium, improve the solubility of reagents and tentatively de-
crease the reaction time.
1
was also analysed by H NMR after 12 days at 8 ꢀC. The spectrum
showed a mixture of the product 4g and starting material 3b in a 4:1
molar ratio.
When the imidazoles 3 were reacted with 2-hydroxy or 4-
hydroxybenzaldehydes in DMSO, the purines 4 were obtained in
good to excellent yield (Scheme 3, Table 1, method C) after 10–54
days, usually at room temperature.
These results indicate that both reactions are very slow. The
reaction of 3b with salicylaldehyde to generate the corresponding
dihydropurine 5e and purine 4e is slightly faster than the reaction
of 3b with 4-hydroxybenzaldehyde. The phenolic hydroxyl group in
the 2-position of the salicylaldehyde is probably involved in an
intramolecular H-bonding with the carbonyl oxygen, activating it
for nucleophilic attack. Elimination of water from the adduct will
also contribute to accelerate this reaction.
The evolution of dihydropurine 5e to purine 4e is very slow
under the reaction conditions A or B leading to moderate yields of
the product. In DMSO solution this evolution occurred without
competitive degradation. These observations prompted us to use
DMSO as solvent in order to reduce degradation of the reaction
The reaction of imidazole 3a with 3,4-dihydroxybenzaldehyde
was also carried out under these reaction conditions. After 48
days at 11 ꢀC a mixture of purine 4d and starting material 3a was
isolated in a 1:1 ratio. This is evidence that the reaction rate be-
tween imidazoles 3a and 3,4-dihydroxybenzaldehyde is slower
than that observed for 4-hydroxy or 2-hydroxybenzaldehydes.
However, purine 4 is formed, and in order to increase the reaction
rate, imidazoles 3 were combined with 3,4-dihydroxybenzalde-
hyde, in DMSO, at room temperature or at 40 ꢀC. Extensive
degradation occurred at 40 ꢀC however the products were
obtained as pure solids, in moderate yields, after dry flash

6906
C. Correia et al. / Tetrahedron 65 (2009) 6903–6911
chromatography using dichloromethane as solvent, (Scheme 3,
Table 1, method C).
All the compounds were fully characterised by analytical and
spectroscopic techniques including heteronuclear correlation tech-
niques (HMBC and HMQC). Typically, the 1H NMR spectra of purines 4
However, an alkyl group in N9 or a 2-hydroxylphenyl group in C2
have the opposite effect. Compounds having in C2 the substituents
3-hydroxyphenyl or 4-hydroxyphenyl can be highly active (4b and
4q) or weakly active (4c or 4p) and it is difficult to establish a clear
correlation between the nature of the substituents in the purine
scaffold and the antitubercular activity. Compounds having in C2
the substituent 3,4-dihydroxyphenyl are, in general, weakly active
(4d, 4h, 4l, 4v and 4x)
show a singlet at
interactionsobservedintheHMBCspectrabetweenH8andC4andC5
identifies these carbon atoms at w149–152 ppm and w117–
119 ppmrespectively. The C2carbonappearsaround w158 ppmand
dw8.0–8.6 ppm assigned to H8. The three bond
d
d
d
was unequivocally assigned from the three-bonds interaction with
the ortho protons of the substituent in position 2 of the purine ring.
3.2. Cytotoxicity
The two most active compounds were further evaluated for
their cytotoxicity (EC50) on mammalian VERO cell lines,11 by TAACF,
and showed a low selectivity index.
3. Biological activity
3.1. Antibacterial activity against M. tuberculosis
All the new 2-phenolic-6-aminopurines 4 were screened for
antimycobacterial activity on the M. tuberculosis strain H37Rv
according to procedures previously published by the TAACF
organization.11
4. Conclusions
This work describes a simple method to synthesize novel 9-alkyl
and 9-aryl-2-phenolic-6-aminopurines which proved to be active
against Mycobacterium tuberculosis.
The results, summarized in Table 2, show that most of the 6-
amino-2,9-diarylpurines
tuberculosis and the activity depends on the substituents present in
C2, C6 and N9 of the purine ring. Purines 4b (IC90¼3.543 g/mL) and
4q (IC90¼4.721 g/mL) are highly active and they both have the 4-
4
are active against Mycobacterium
The potency depends on the substituents present in N9, C2
and C6 of the purine core. The presence of a 4-tolyl group in N9 and
a 3-hydroxy or 4-hydroxyphenyl in C2 combined with a secondary
amine (piperidine or dimethylamine) in C6 proved to be important
features for activity but a clear structure–activity correlation pat-
tern could not be identified. New substituents were incorporated in
the purine scaffold leading to different derivatives 4. Compounds
4b and 4g were identified as highly active against M. tuberculosis
with a low level of cytotoxicity.
m
m
tolyl group in the N9position. The phenyl andinparticular the methyl
group in this position, lead to weakly active or inactive structures,
with a marginal dependence on the nature of the remaining sub-
stituents of the purine ring. For compound 4d, with a piperidinyl
substituent in the 6-position, the highest activity is associated with
the presence of the 3-hydroxyphenyl group in the 2-position. A poor
Further structural modifications of the identified hit are in
progress in order to enhance the efficacy of the new compounds.
activity was registered for compound 4c (IC90>100
IC50¼16.118 g/mL), with 4-hydroxyphenyl substituent in the 2-po-
sition, and compound 4d, with a 3,4-dihydroxyphenyl substituent in
mg/mL and
m
5. Experimental
this position, proved to be moderately active (IC90¼19.41
mg/mL).
5.1. General techniques
Table 2
Antibacterial activity against M. tuberculosis strain H37R and cytotoxic activity
against VERO cells of compounds 4
The 5-amino-1-aryl-4-(cyanoformimidoyl) imidazoles 1a–c
used in this work were prepared according to previously described
procedures.10 NMR spectra were recorded with a Varian Unity Plus
Compound
IC90
(
m
g/mL)
IC50
(
m
g/mL)
EC50
nd
(
mg/mL)
SI
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4y
4n
4o
4p
4q
4r
>100
3.543
>100
19.41
>100
10.649
>100
>100
>100
>100
>100
12.129
>100
>100
>100
>100
>100
4.721
>100
>100
>100
17.811
29.407
>100
>100
>100
>100
1.227
16.118
9.03
nd
1.441
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
2.439
nd
nd
nd
nd
nd
nd
nd
nd
5.106
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
11.516
nd
nd
nd
nd
nd
nd
nd
nd
(300 MHz) or with
a Bruker Avance II NMR spectrometer
(400 MHz), including the 1H and 13C correlation spectra (HMQC and
HMBC). IR spectra were recorded with a FT-IR Bomem MB 104 using
Nujol mulls and NaCl cells. The reactions were monitored by thin-
layer chromatography (TLC) with the use of silica gel 60 F254
(Merck). The melting points were determined with a Gallenkamp
melting point apparatus and are uncorrected. Elemental analysis
were performed with a LECO CHNS-932 instrument.
>100
3.839
7.564
39.946
>100
18.493
39.344
7.671
>100
1.654
>100
>100
5.2. General procedure for synthesis of imidazoles 3
The secondary amined1.5 to 5 equiv was added to a green
suspension of 1 in acetonitrile and the resulting solution was kept
under stirring, at room temperature. An off-white solid precipitated
from the solution and the reaction was monitored by TLC. When the
TLC showed absence of the starting material, the solid suspension
was filtered and washed with acetonitrile and diethyl ether to give
compounds 3.
42.044
2.61
>100
>100
>100
4.961
7.976
>100
>100
29.821
4s
4t
4u
4v
4w
4x
4z
5.2.1. 4-[Imino(piperidin-1-yl)methyl]-1-(p-tolyl)-1H-imidazol-5-
amine 3a
Compound 3a (0.53 g, 1.87 mmol, 85%), was obtained as an off-
white solid from [5-amino-1-(p-tolyl)-1H-imidazol-4-yl](imino)a-
cetonitrile 1a (0.49 g, 2.20 mmol) and piperidine (1.1 mL,
10.98 mmol).Lit. 8l
In summary, the presence of an aromatic group in N9 (4-tolyl)
and hydroxyl groups in the 3- or 4-position of the aryl substituent
R2, present in C2, seems to enhance the antitubercular activity.

C. Correia et al. / Tetrahedron 65 (2009) 6903–6911
6907
5.2.2. 4-[Imino(morpholin-4-yl)methyl]-1-(p-tolyl)-1H-imidazol-
5-amine 3b
3.67 (t, J¼4.8 Hz, 4H), 5.59 (s, 2H), 7.06 (s,1H), 7.39 (s, 1H), 7.40–7.60
(m, 5H); 13C NMR (75 MHz, DMSO-d6),
(ppm): 47.1, 66.1, 114.8,
d
Compound 3b (0.43 g, 1.51 mmol, 84%), was obtained as a white
solid from [5-amino-1-(p-tolyl)-1H-imidazol-4-yl](imino)acetoni-
trile 1a (0.41 g, 1.80 mmol) and morpholine (0.78 mL, 9.00 mmol).
Mp 203–205 ꢀC; IR (Nujol mull) 3365, 3285, 3122, 1626, 1592,
124.6, 127.9, 129.4, 129.7, 134.9, 139.4, 163.3. Anal. Calcd for
C14H17N5O (271.32): C, 61.98; H, 6.32; N, 25.81. Found: C, 62.07; H,
6.21; N, 25.68.
1519 cmꢁ1
;
1H NMR (300 MHz, DMSO-d6),
d
(ppm): 2.36 (s, 3H),
3.33 (br s, 4H), 3.66 (t, J¼4.8 Hz, 4H), 4.0–7.20 (br s, 3H), 7.33 (s, 1H),
7.35 (s, 4H); 13C NMR (75 MHz, DMSO-d6),
(ppm): 20.6, 47.2, 66.1,
5.2.8. 4-(Imino(piperidin-1-yl)methyl)-1-methyl-1H-
imidazol-5-amine 3h
d
Compound 3h (0.47 g, 2.30 mmol, 68%), was obtained as a white
solid from (5-amino-1-methyl-1H-imidazol-4-yl)(imino)acetoni-
trile 1c (0.50 g, 3.38 mmol) and piperidine (1.7 mL, 16.92 mmol).
114.2, 124.6, 130.0, 130.1, 132.3, 137.6, 139.5, 163.0. Anal. Calcd for
C15H19N5O (285.34): C, 63.14; H, 6.71; N, 24.54. Found: C, 63.20; H,
6.63; N, 24.49.
Mp 133–135 ꢀC; IR (Nujol mull) 3332, 3109; 1606, 1578, 1522 cmꢁ1
;
1H NMR (300 MHz, DMSO-d6),
(m, 7H), 4.80–6.80 (s, 3H), 7.24 (s, 1H); 13C NMR (75 MHz, DMSO-
d6), (ppm): 29.7, 45.8, 46.5, 54.6, 113.8, 130.7, 163.2. Anal. Calcd for
d (ppm): 1.57 (br s, 6H), 3.40–3.43
5.2.3. 4-[Imino(thiomorpholin-4-yl)methyl]-1-(p-tolyl)-1H-
imidazol-5-amine 3c
d
Compound 3c (0.43 g, 1.41 mmol, 89%), was obtained as an off-
white solid from [5-amino-1-(p-tolyl)-1H-imidazol-4-yl](imino)-
acetonitrile 1a (0.36 g, 1.60 mmol) and thiomorpholine (0.82 mL,
8.00 mmol). Mp 204–206 ꢀC; IR (Nujol mull) 3358, 3281, 3125,
C10H17N5 (207.28): C, 57.95; H, 8.27; N, 33.79. Found: C, 57.80; H,
8.30; N, 33.90.
5.2.9. 4-[Imino(morpholin-4-yl)methyl]-1-methyl-1H-
imidazol-5-amine 3i
1622,1588,1518 cmꢁ1; 1H NMR (300 MHz, DMSO-d6),
d
(ppm): 2.36
(s, 3H), 2.64 (m, 4H), 3.65 (m, 4H), 5.43 (s, 2H), 7.35 (s, 6H); 13C NMR
(75 MHz, DMSO-d6), (ppm): 20.7, 26.4, 49.3, 113.6, 124.8, 130.2,
Compound 3i (0.21 g, 0.99 mmol, 66%), was obtained as an off-
white solid from (5-amino-1-methyl-1H-imidazol-4-yl)(imino)-
acetonitrile 1c (0.22 g, 1.50 mmol) and morpholine (0.7 mL,
7.50 mmol). Mp 191–193 ꢀC; IR (Nujol mull) 3338, 3311, 3235, 3185,
d
130.7,132.2,137.8,139.4,162.1. Anal. Calcd for C15H19N5S (301.41): C,
59.77; H, 6.35; N, 23.24; S, 10.64. Found: C, 59.84; H, 6.35; N, 23.18;
S, 10.77.
3111, 1613, 1584, 1555, 1512 cmꢁ1 1H NMR (300 MHZ, DMSO-d6),
;
d
(ppm): 3.24 (t, J¼4.2 Hz, 4H), 3.38 (s, 3H), 3.64 (t, J¼4.2 Hz, 4H),
5.46 (s, 2H), 6.92 (s, 1H), 7.09 (s, 1H); 13C NMR (75 MHz, DMSO-d6),
(ppm): 29.7, 47.1, 66.0, 114.2, 130.4, 139.7, 163.8. Anal. Calcd for
5.2.4. 4-[Imino(pyrrolidin-1-yl)methyl]-1-(p-tolyl)-1H-
imidazol-5-amine 3d
d
Compound 3d (0.66 g, 2.44 mmol, 60%), was obtained as an
orange solid from [5-amino-1-(p-tolyl)-1H-imidazol-4-yl](imino)-
acetonitrile 1a (0.94 g, 4.16 mmol) and pyrrolidine (1.73 mL,
20.78 mmol). Mp 185–187 ꢀC; IR (Nujol mull) 3432, 3345, 3109,
C9H15N5O (209.25): C, 51.66; H, 7.23; N, 33.47. Found: C, 51.60; H,
6.97; N, 33.46.
5.3. Synthesis of compound 6a
1597,1577,1551,1518 cmꢁ1; 1H NMR (300 MHz, DMSO-d6),
d
(ppm):
1.38 (t, J¼6.3 Hz, 4H), 2.36 (s, 3H), 3.54 (t, J¼6.3 Hz, 4H), 6.11 (s, 3H),
7.26 (s, 1H), 7.36 (s, 4H); 13C NMR (75 MHz, DMSO-d6),
(ppm):
To a stirred suspension of 3b (0.12 g, 0.42 mmol) in ethanol was
added the 3,4-dihydroxybenzaldehyde (0.078 g, 1.3 equiv) and one
equiv of DBU, at room temperature. A dark brown homogeneous
solution was obtained. A solid started to precipitate after two days
from a very complex mixture (evidence by TLC). After 17 days the
solid in suspension was filtered and washed with diethyl ether and
identified as compound 6a (0.006 g, 0.028 mmol, 7%). Mp 238.1–
239.0 ꢀC. IR (Nujol mull) 3409, 3326, 3138, 1666 (C]O), 1655; 1H
d
20.6, 24.9, 47.6, 114.7, 124.3, 128.2, 130.1, 132.6, 137.3, 141.8, 158.9.
Anal. Calcd for C15H19N5 (269.34): C, 66.89; H, 7.11; N, 26.00. Found:
C, 67.17; H, 7.00; N, 25.91.
5.2.5. 5-Amino-N,N-dimethyl-1-(p-tolyl)-1H-imidazole-4-
carboximidamide 3e
Compound 3e.HCN (1.09 g; 4.04 mmol, 74%), was obtained as an
off-white solid from [5-amino-1-(p-tolyl)-1H-imidazol-4-yl](imino)-
acetonitrile 1a (1.23 g; 5.47 mmol) and a 40% aquous solution of
dimethylamine (1.04 mL; 8.20 mmol).Lit. 8l
NMR (300 MHZ, DMSO-d6),
(br s, 1H), 6.90 (br s, 1H), 7.30 (s, 1H), 7.36 (s, 4H); 13C NMR (75 MHz,
DMSO-d6), (ppm): 20.60, 112.89, 124.44, 129.64, 130.19, 132.07,
137.66, 142.61, 166.73. Anal. Calcd for C11H12N4O (216.23): C, 61.11;
H, 5.59; N, 25.91. Found: C, 61.31; H, 5.57; N, 25.63.
d (pm): 2.36 (s, 3H), 5.69 (s, 2H), 6.76
d
5.2.6. 4-[Imino(piperidin-1-yl)methyl]-1-phenyl-1H-
imidazol-5-amine 3f
5.4. General procedure for the synthesis of purines 4
Compound 3f (0.27 g, 1.02 mmol, 64%), was obtained as an off-
white solid from (5-amino-1-phenyl-1H-imidazol-4-yl)(imino)-
acetonitrile 1b (0.35 g, 1.64 mmol) and piperidine (0.8 mL,
8.20 mmol). Mp 130–132 ꢀC; IR (Nujol mull) 3353, 3286, 3119, 1624,
5.4.1. Method A
To a stirred suspension of 3 in a mixture of acetonitrile/ethanol
(1:1), 1.1 equiv of aldehyde and 10 equiv of triethylamine were
added, at room temperature. A yellow solution developed and an
off-white solid started to precipitate from solution after 10–41 days.
When the TLC indicated absence of starting material, the reaction
mixture was concentrated in the rotary evaporator and addition of
acetonitrile led to a suspension that was filtered. The solid was
washed with acetonitrile and diethyl ether and identified as com-
pound 4.
1591, 1550, 1515 cmꢁ1; 1H NMR (300 MHz, DMSO-d6),
d
(ppm): 1.56
(s, 6H), 3.31(br s, 4H), 4.50–6.50 (brs, 3H), 7.39 (s, 1H), 7.40–7.60 (m,
5H); 13C NMR (75 MHz, DMSO-d6),
(ppm): 24.4, 25.5, 47.5, 115.1,
d
124.6, 127.9, 129.7, 129.8, 135.0, 139.0, 163.3. Anal. Calcd for
C15H19N5 0.4H2O (276.54): C, 65.17; H, 7.17; N, 25.34. Found: C,
65.28; H, 6.94; N, 25.24.
5.2.7. 4-[Imino(morpholin-4-yl)methyl]-1-phenyl-1H-
imidazol-5-amine 3g
5.4.2. Method B
Compound 3g (0.29 g, 1.08 mmol, 78%), was obtained as a white
solid from (5-amino-1-phenyl-1H-imidazol-4-yl)(imino)acetoni-
trile 1b (0.29 g, 1.64 mmol) and morpholine (0.6 mL, 6.90 mmol).
Mp 181–183 ꢀC; IR (Nujol mull) 3357, 3290, 3123, 1627, 1594,
To a stirred suspension of 3 in ethanol, 1.1 equiv of aldehyde and
10 equiv of triethylamine were added, at room temperature. A
yellow solution developed and an off-white solid started to pre-
cipitate from solution after 8–30 days. When the TLC indicated
absence of starting material, the reaction mixture was concentrated
1518 cmꢁ1; 1H NMR (300 MHz, DMSO-d6),
d (ppm): 3.33 (br s, 4H),

6908
C. Correia et al. / Tetrahedron 65 (2009) 6903–6911
in the rotary evaporator and addition of acetonitrile led to a sus-
pension that was filtered. The solid was washed with acetonitrile
and diethyl ether and identified as compound 4.
flash chromatography on silica gel using 300 mL of dichloro-
methane as solvent to give 4d (0.10 g, 0.25 mmol, 46%) as an off-
white solid. Mp 233–235 ꢀC; IR (Nujol mull) 3138, 1710, 1575,
1525 cmꢁ1 1H NMR (300 MHz, DMSO-d6),
; d (ppm): 1.60–1.65 (m,
5.4.3. Method C
6H), 2.40 (s, 3H), 4.30 (s, 4H), 6.77 (d, J¼8.4 Hz, 1H), 7.42 (d,
To a stirred suspension of 3 in DMSO, 1.1 equiv of aldehyde and
10 equiv of triethylamine were added, at room temperature. An
orange solution was formed and the reaction was kept at room
temperature or at 40 ꢀC until TLC show the absence of starting
material. The triethylamine was removed under reduced pressure
and cold water was added to the solution. The crude product was
filtered and washed abundantly with water and diethyl ether. The
crude product was analysed by 1H NMR and was purified by dry
flash cromathography, when necessary, using dichloromethane as
solvent.
J¼8.1 Hz, 2H), 7.67 (dd, J¼8.4, 2.1 Hz, 1H), 7.70–7.80 (m, 3H), 8.44 (s,
1H), 9.12 (s, 2H); 13C NMR (75 MHz, DMSO-d6),
d (ppm): 20.7, 24.4,
25.8, 45.6, 115.3 (2C), 117.9, 119.7, 123.3, 129.8, 129.9, 132.8, 136.9,
138.4, 144.8, 147.4, 151.4, 153.0, 157.9. Anal. Calcd for C23H23N5O2
1.1H2O (421.26): C, 65.60; H, 5.99; N, 16.63. Found: C, 65.60; H, 5.74;
N, 16.41.
5.4.8. 2-(6-Morpholino-9-p-tolyl-9H-purin-2-yl)phenol 4e
Method C: Compond 4e (0.13 g, 0.35 mmol, 79%), was obtained
as a white solid from 3b (0.13 g, 0.44 mmol) and salicylaldehyde
(52
pressure and addition of acetonitrile to the suspension. Mp 207–
209 ꢀC; IR (Nujol mull) 3234, 1598, 1576, 1509 cmꢁ1 1H NMR
(300 MHz, DMSO-d6), (ppm): 2.42 (s, 3H), 3.79 (s, 4H), 4.30 (s, 4H),
6.85 (d, J¼7.8 Hz, 1H), 6.89 (t, J¼7.8 Hz, 1H), 7.31 (t, J¼7.8 Hz, 1H),
7.45 (d, J¼8.1 Hz, 2H), 7.65 (d, J¼8.1 Hz, 2H), 8.32 (dd, J¼7.8, 1.2 Hz,
1H), 8.54 (s, 1H), 13.32 (s, 1H); 13C NMR (75 MHz, DMSO-d6),
mL, 0.49 mmol) after triethylamine elimination under reduce
5.4.4. 2-(6-(Piperidin-1-yl)-9-p-tolyl-9H-purin-2-yl)phenol 4a
Method A: Compound 4a (0.12 g, 0.30 mmol, 65%), was obtained
as an off-white solid from 3a (0.13 g, 0.46 mmol) and salicylalde-
;
d
hyde (65
m
L, 0.51 mmol). Mp 169–171 ꢀC; IR (Nujol mull) 3106,
1698, 1589, 1574, 1513 cmꢁ1
;
1H NMR (300 MHz, DMSO-d6),
d
(ppm): 1.71 (s, 6H), 2.42 (s, 3H, CH3), 4.29 (s, 4H), 6.85 (d, J¼7.8 Hz,
1H), 6.89 (t, J¼7.8 Hz, 1H), 7.31 (dt, J¼7.8, 1.8 Hz, 1H), 7.45 (d,
J¼8.1 Hz, 2H), 7.67 (d, J¼8.1 Hz, 2H), 8.32 (dd, J¼7.8,1.8 Hz, 1H), 8.53
d (ppm): 20.6, 45.5, 66.1, 117.2, 118.2, 118.6, 119.1, 123.7, 129.0, 130.2,
131.9, 132.1, 137.9, 139.7, 148.7, 152.7, 158.0, 159.4.Anal. Calcd for
C22H21N5O2 0.35H2O (393.73): C, 67.10; H, 5.52; N, 17.80. Found: C,
66.99; H, 5.64; N, 17.43.
(s, 1H), 13.51 (s, 1H); 13C NMR (75 MHz, DMSO-d6),
d (ppm): 20.7,
24.2, 25.7, 46.2, 117.2, 118.0, 118.7, 119.3, 123.7, 128.9, 130.2, 132.1,
132.1, 137.9, 139.3, 148.8, 152.5, 158.1, 159.5. Anal. Calcd for
C23H23N5O (385.46): C, 71.67; H, 6.01; N, 18.17. Found: C, 71.66; H,
5.95; N, 18.05.
5.4.9. 3-(6-Morpholino-9-p-tolyl-9H-purin-2-yl)phenol 4f
Method B: Compound 4f (0.27 g, 0.70 mmol, 63%), was obtained
as a white solid from 3b (0.32 g, 1.12 mmol) and 3-hydroxy-
benzaldehyde (0.16 g, 1.23 mmol). Mp 257–259 ꢀC; IR (Nujol mull)
5.4.5. 3-(6-(Piperidin-1-yl)-9-p-tolyl-9H-purin-2-yl)phenol 4b
Method B: Compound 4b (0.11 g, 0.38 mmol, 65%), was obtained
as an off-white solid from 3a (0.16 g, 0.58 mmol) and 3-hydroxy-
benzaldehyde (0.08 g, 0.64 mmol). Mp 194–196 ꢀC; IR (Nujol mull)
3337, 3121, 1605, 1581, 1524 cmꢁ1 1H NMR (300 MHz, DMSO-d6),
;
d
(ppm): 2.41 (s, 3H), 3.78 (s, 4H), 4.43 (s, 4H), 6.82 (d, J¼8.1 Hz, 1H),
7.24 (t, J¼8.1 Hz, 1H), 7.44 (d, J¼8.1 Hz, 2H), 7.78 (s, 1H), 7.79 (d,
3105, 1659, 1611, 1574, 1515 cmꢁ1 1H NMR (300 MHz, DMSO-d6),
;
J¼8.1 Hz, 3H), 8.56 (s, 1H), 9.46 (s, 1H); 13C NMR (75 MHz, DMSO-
d
(ppm): 1.65 (s, 6H), 2.40 (s, 3H), 4.28 (s, 4H), 6.81 (d, J¼8.1 Hz, 1H),
7.23 (t, J¼8.1 Hz, 1H), 7.43 (d, J¼8.1 Hz, 2H), 7.79 (d, J¼8.1 Hz, 4H),
8.51 (s, 1H), 9.20 (s, 1H); 13C NMR (75 MHz, DMSO-d6),
(ppm):
d6), d (ppm): 20.6, 45.3, 66.2, 114.5, 116.9, 118.6, 118.6, 123.4, 129.2,
129.9, 132.5, 137.2, 139.4, 139.5, 151.4, 153.2, 157.3, 157.5. Anal. Calcd
for C22H21N5O2 0.2H2O (391.03): C, 67.59; H, 5.48; N, 17.92. Found:
C, 67.88; H, 5.74; N, 17.57.
d
20.6, 24.3, 25.7, 45.6, 114.5, 116.8, 118.4, 118.6, 123.3, 129.1, 129.9,
132.6, 137.0, 138.9, 139.7, 151.3, 153.0, 157.3, 157.5. Anal. Calcd for
C23H23N5O (385.46): C, 71.67; H, 6.01; N, 18.17. Found: C, 71.60; H,
5.80; N, 18.03.
5.4.10. 4-(6-Morpholino-9-p-tolyl-9H-purin-2-yl)phenol 4g
Method C: Compound 4g (0.24 g, 0.63 mmol, 84%), was obtained
as an off-white solid from 3b (0.21 g, 0.75 mmol) and 4-hydroxy-
benzaldehyde (0.10 g, 0.83 mmol). Mp 258–260 ꢀC; IR (Nujol mull)
5.4.6. 4-(6-(Piperidin-1-yl)-9-p-tolyl-9H-purin-2-yl)phenol 4c
Method A: Compound 4c (0.10 g, 0.26 mmol, 53%), was obtained
as an off-white solid from 3a (0.14 g, 0.49 mmol) and 4-hydroxy-
benzaldehyde (0.07 g, 0.54 mmol).
3382, 3124, 1597, 1575, 1521 cmꢁ1 1H NMR (300 MHz, DMSO-d6),
;
d
(ppm): 2.40 (s, 3H), 3.77 (s, 4H), 4.30 (s, 4H), 6.82 (d, J¼8.7 Hz, 2H),
7.42 (d, J¼8.4 Hz, 2H), 7.79 (d, J¼8.4 Hz, 2H), 8.19 (d, J¼8.7 Hz, 2H),
8.50 (s,1H), 9.83 (s,1H); 13C NMR (75 MHz, DMSO-d6),
(ppm): 20.6,
Method B: A first crop of compound 4c (0.11 g, 0.29 mmol, 49%),
was obtained as an off-white solid from 3a (0.16 g, 0.58 mmol) and
4-hydroxybenzaldehyde (0.08 g, 0.64 mmol). A second crop of
compound 4c (0.04 g, 0.10 mmol, 20%) was obtained as an off-white
solid by addition of acetonitrile and water to the resulting mother
liquor. Mp 243–245 ꢀC; IR (Nujol mull) 3382, 3102, 1601, 1574, 1525,
d
45.2, 66.3, 115.0, 118.1, 123.2, 129.1, 129.4, 129.9, 132.7, 137.0, 138.9,
151.5, 153.2, 157.8, 159.3. Anal. Calcd for C22H21N5O2 0.79H2O
(401.65): C, 65.80; H, 5.63; N,17.45. Found: C, 65.78; H, 5.83; N,17.44.
5.4.11. 4-(6-Morpholino-9-p-tolyl-9H-purin-2-yl)benzene-1,2-diol 4h
Method C: The crude product (0.23 g) was obtained as a brown
solid from 3b (0.18 g, 0.63 mmol) and 3,4-dihydroxybenzaldehyde
(0.10 g, 0.69 mmol). The solid was purified by dry flash chroma-
tography on silica gel using 400 mL of dichloromethane as solvent to
give 4h (0.08 g, 0.20 mmol, 32%). Mp 270–272 ꢀC; IR (Nujol mull)
3296,1710, 3226,1590,1569,1524 cm-1; 1H NMR (300 MHz, DMSO-
1513 cmꢁ1 1H NMR (300 MHz, DMSO-d6),
; d (ppm): 1.65 (s, 6H),
2.40 (s, 3H), 4.30 (s, 4H), 6.82 (d, J¼8.4 Hz, 2H), 7.42 (d, J¼8.4 Hz,
2H), 7.80 (d, J¼8.4 Hz, 2H), 8.17 (d, J¼8.4 Hz, 2H), 8.46 (s, 1H), 9.74
(s, 1H); 13C NMR (75 MHz, DMSO-d6),
d (ppm): 20.6, 24.3, 25.7, 45.6,
114.9, 117.9, 123.1, 129.3 (2C), 129.9, 132.7, 136.9, 138.3, 151.4, 153.0,
157.8, 159.1. Anal. Calcd for C23H23N5O 0.1H2O (387.26): C, 71.35; H,
6.00; N, 18.10. Found: C, 71.20; H, 6.25; N, 18.41.
d6),
d
(ppm): 2.41 (s, 3H), 3.78 (s, 4H), 4.31 (s, 4H), 6.77 (d, J¼8.1 Hz,
1H), 7.43 (d, J¼8.4 Hz, 2H), 7.68 (dd, J¼8.1, 2.1 Hz, 1H), 7.78 (d,
J¼2.1 Hz, 1H), 7.79 (d, J¼8.4 Hz, 2H), 8.50 (s, 1H), 9.03 (s, 1H), 9.19 (s,
5.4.7. 4-(6-(piperidin-1-yl)-9-p-tolyl-9H-purin-2-yl)benzene-
1,2-diol 4d
1H); 13C NMR (75 MHz, DMSO-d6),
d (ppm): 20.6, 45.3, 66.3, 115.25,
Method C: The crude product 4d (0.20 g) was obtained as
a brown solid from 3a (0.15 g, 0.54 mmol) and 3,4-dihydroxy-
benzaldehyde (0.08 g, 0.59 mmol). The solid was purified by dry
115.28, 118.1, 119.8, 123.3, 129.6, 129.9, 132.7, 137.0, 138.9, 144.8,
147.5,151.5,153.1,157.9. Anal. Calcd for C22H21N5O3 0.3H2O (408.83):
C, 64.64; H, 5.29; N, 17.14. Found: C, 64.63; H, 5.23; N, 17.16.

C. Correia et al. / Tetrahedron 65 (2009) 6903–6911
6909
5.4.12. 2-(6-Thiomorpholino-9-p-tolyl-9H-purin-2-yl)phenol 4i
Method A: Compound 4i (0.13 g, 0.32 mmol, 85%), was obtained
as a white solid from 3c (0.11 g, 0.38 mmol) and salicylaldehyde
(d, J¼8.4 Hz, 2H), 7.74 (d, J¼8.4 Hz, 2H), 8.30 (dd, J¼7.7, 1.2 Hz, 1H),
8.53 (s, 1H), 13.94 (s, 1H); 13C NMR (75 MHz, DMSO-d6),
(ppm):
20.6, 23.7, 25.8, 47.3, 48.9, 117.3, 118.3, 118.5, 119.2, 123.4, 128.7,
130.1, 132.0, 132.3, 137.5, 139.9, 149.0, 151.1, 158.3, 159.7. Anal. Calcd
for C22H21N5O 0.3H2O (376.84): C, 70.14; H, 5.74; N, 18.60. Found: C,
70.39; H, 5.75; N, 18.61.
d
(60.9
m
L, 0.57 mmol, 1.5 equiv). Mp 203–205 ꢀC; IR (Nujol mull)
3234, 1588, 1567, 1525, 1509 cmꢁ1
;
1H NMR (300 MHz, DMSO-d6),
d
(ppm): 2.42 (s, 3H), 2.80 (s, 4H), 4.60 (s, 4H), 6.86 (d, J¼8.3 Hz,1H),
6.91 (t, J¼8.3 Hz, 1H), 7.32 (dt, J¼8.3, 1.8 Hz, 1H), 7.45 (d, J¼8.7 Hz,
2H), 7.66 (d, J¼8.7 Hz, 2H), 8.32 (dd, J¼8.3, 1.8 Hz, 1H), 8.56 (s, 1H),
5.4.17. 3-(6-(Pyrrolidin-1-yl)-9-p-tolyl-9H-purin-2-yl)phenol 4y
Method B: Compound 4y (0.09 g, 0.26 mmol, 54%), was obtained
as an off-white solid from 3d (0.13 g, 0.48 mmol) and 3-hydroxy-
benzaldehyde (0.07 g, 0.53 mmol). Mp 227–229 ꢀC; IR (Nujol mull)
13.31 (s,1H); 13C NMR (75 MHz, DMSO-d6),
d (ppm): 20.6, 26.5, 47.9,
117.2, 118.2, 118.7, 119.2, 123.8, 129.0, 130.2, 131.9, 132.1, 138.0, 139.7,
148.8, 152.5, 158.0, 159.4. Anal. Calcd for C22H21N5OS 0.5H2O
(412.50): C, 64.08; H, 5.34; N,16.99; S, 7.77. Found: C, 64.00; H, 5.56;
N, 16.99; S, 7.66.
3163, 3122, 1584, 1523, 1510 cmꢁ1 1H NMR (300 MHz, DMSO-d6),
;
d
(ppm): 2.00 (s, 4H), 2.40 (s, 3H), 3.81 (s, 2H), 4.12 (s, 2H), 6.81 (dd,
J¼7.8, 1.8 Hz, 1H), 7.23 (t, J¼7.8 Hz, 1H), 7.43 (d, J¼7.8 Hz, 2H), 7.82
5.4.13. 3-(6-Thiomorpholino-9-p-tolyl-9H-purin-2-yl)phenol 4j
Method B: Compound 4j (0.16 g, 0.40 mmol, 66%), was obtained
as an off-white solid from 3c (0.18 g, 0.62 mmol) and 3-hydroxy-
benzaldehyde (0.08 g, 0.67 mmol). Mp 267–269 ꢀC; IR (Nujol mull)
(d, J¼7.8 Hz, 4H), 8.49 (s, 1H), 9.43 (s, 1H); 13C NMR (75 MHz,
DMSO-d6),
d (ppm): 20.6, 23.7, 25.8, 46.9, 48.4, 114.6, 116.7, 118.6,
118.9, 123.0, 129.0, 129.9, 132.8, 136.8, 139.2, 139.8, 150.6, 152.4,
157.2, 157.8. Anal. Calcd for C22H21N5O (371.44): C, 71.14; H, 5.70; N,
18.85. Found: C, 71.15; H, 5.92; N, 19.18.
3325, 3166, 1664, 1560, 1582, 1525 cmꢁ1
;
1H NMR (300 MHz,
DMSO-d6),
d
(ppm): 2.40 (s, 3H), 2.77 (s, 4H), 4.61 (s, 4H), 6.82 (d,
J¼7.8 Hz, 1H), 7.24 (t, J¼7.8 Hz, 1H), 7.43 (d, J¼7.8, 2H), 7.77 (s, 1H),
5.4.18. 4-(6-(Pyrrolidin-1-yl)-9-p-tolyl-9H-purin-2-yl)phenol 4n
Method A: Compound 4n (0.11 g, 0.29 mmol, 71%), was obtained
as an off-white solid from 3d (0.11 g, 0.41 mmol) and 4-hydroxy-
benzaldehyde (0.06 g, 0.45 mmol). Mp 260–262 ꢀC; IR (Nujol mull)
7.79 (d, J¼7.8 Hz, 3H), 8.54 (s, 1H), 9.48 (s, 1H); 13C NMR (75 MHz,
DMSO-d6),
d (ppm): 20.6, 26.5, 47.5, 114.5, 116.9, 118.6 (2C), 123.4,
129.2, 129.9, 132.5, 137.2, 139.4, 139.5, 151.4, 152.9, 157.3, 157.6. Anal.
Calcd for C22H21N5OS H2O (421.50): C, 62.71; H, 5.46; N, 16.60; S,
7.60. Found: C, 62.48; H, 5.59; N, 16.25; S, 7.68.
3069, 1596, 1581, 1526, 1510 cmꢁ1 1H NMR (300 MHz, DMSO-d6),
;
d
(ppm): 1.95 (s, 4H), 2.38 (s, 3H), 3.76 (s, 2H), 4.06 (s, 2H), 6.83 (d,
J¼8.7 Hz, 2H), 7.38 (d, J¼8.1 Hz, 2H), 7.81 (d, J¼8.1 Hz, 2H), 8.22 (d,
5.4.14. 4-(6-Thiomorpholino-9-p-tolyl-9H-purin-2-yl)phenol 4k
Method A: Compound 4k (0.09 g, 0.23 mmol, 56%), was obtained
as an off-white solid from 3c (0.12 g, 0.41 mmol) and 4-hydroxy-
benzaldehyde (0.06 g, 0.45 mmol).
J¼8.7 Hz, 2H), 8.39 (s, 1H), 9.74 (s, 1H); 13C NMR (75 MHz, DMSO-
d6),
d (ppm): 20.6, 23.6, 25.8, 46.9, 48.3, 114.9, 118.4, 122.7, 129.3,
129.5, 129.8, 132.9, 136.6, 138.6, 150.7, 152.4, 158.0, 159.1. Anal. Calcd
for C22H21N5O 0.44H2O (379.36): C, 69.67; H, 5.77; N, 18.47. Found:
C, 69.66; H, 5.96; N, 16.26.
Method C: Compound 4k (0.14 g, 0.35 mmol, 80%), was obtained
as an off-white solid from 3c (0.13 g, 0.44 mmol) and 4-hydroxy-
benzaldehyde (0.06 g, 0.48 mmol). Mp 264–266 ꢀC; IR (Nujol mull)
5.4.19. 2-(6-(Dimethylamino)-9-p-tolyl-9H-purin-2-yl)phenol 4o
Method B: Compound 4o (0.06 g, 0.18 mmol, 66%), was obtained
as an off-white solid from 3e (0.07 g, 0.28 mmol) and salicylalde-
3112, 1595, 1573, 1526, 1509 cmꢁ1 1H NMR (300 MHz, DMSO-d6),
;
d
(ppm): 2.40 (s, 3H), 2.77 (s, 4H), 4.60 (s, 4H), 6.82 (d, J¼8.0 Hz, 2H),
7.43 (d, J¼8.4 Hz, 2H), 7.80 (d, J¼8.4 Hz, 2H), 8.17 (d, J¼8.0 Hz, 2H),
8.51 (s, 1H), 9.81 (s, 1H); 13C NMR (75 MHz, DMSO-d6),
(ppm):
hyde (33
ture, instead of acetonitrile. Mp 212–215 ꢀC; IR (Nujol mull) 1698,
1560, 1512 cmꢁ1 1H NMR (300 MHz, DMSO-d6),
(ppm): 2.42 (s,
mL, 0.30 mmol), after addition of water to the crude mix-
d
20.6, 26.5, 47.5, 115.04, 118.10, 123.2, 129.1, 129.4, 129.9, 132.6, 137.0,
138.9, 151.5, 152.9, 157.8, 159.3. Anal. Calcd for C22H21N5OS 0.38H2O
(408.90): C, 64.41; H, 5.31; N, 17.08; S, 7.81. Found: C, 64.41; H, 5.40;
N, 16.80; S, 7.68.
;
d
3H), 3.40–4.00 (br s, 6H), 6.87 (d, J¼8.8 Hz, 1H), 6.89 (t, J¼8.8 Hz,
1H), 7.31 (dt, J¼8.0, 1.8 Hz, 1H), 7.45 (d, J¼8.4 Hz, 2H), 7.70 (d,
J¼8.4 Hz, 2H), 8.33 (dd, J¼8.0, 1.8 Hz, 1H), 8.54 (s, 1H), 13.70 (s, 1H);
13C NMR (75 MHz, DMSO-d6),
d (ppm): 20.6, 38.0, 117.2, 118.2, 118.5,
5.4.15. 4-(6-Thiomorpholino-9-p-tolyl-9H-purin-2-yl)benzene-
1,2-diol 4l
119.2, 123.5, 128.8, 130.1, 131.9, 132.1, 137.6, 139.3, 148.8, 153.3, 157.9,
159.5. Anal. Calcd for C20H19N5O (345.40): C, 69.55; H, 5.54; N,
20.28. Found: C, 69.79; H, 5.77; N, 20.41.
Method C: The crude product 4l (0.16 g) was obtained as a brown
solid from 3c (0.16 g, 0.53 mmol) and 3,4-dihydroxybenzaldehyde
(0.08 g, 0.58 mmol). The solid was purified by dry flash chroma-
tography on silica gel using 300 mL of dichloromethane as solvent
to give 4l (0.10 g, 0.24 mmol, 45%) as a white solid. Mp 275–277 ꢀC;
5.4.20. 3-(6-(Dimethylamino)-9-p-tolyl-9H-purin-2-yl)phenol 4p
Method B: Compound 4p (0.04 g, 0.10 mmol, 34%), was obtained
as an off-white solid from 3e (0.07 g, 0.30 mmol) and 3-hydroxy-
benzaldehyde (0.04 g, 0.34 mmol). Mp 184–186 ꢀC; IR (Nujol mull)
IR (Nujol mull) 3136, 1618, 1572, 1526 cmꢁ1
;
1H NMR (300 MHz,
(ppm): 2.41 (s, 3H), 2.76 (m, 4H), 4.60 (s, 4H), 6.73 (d,
DMSO-d6),
d
3333, 3106, 1647, 1585, 1530 cmꢁ1 1H NMR (300 MHz, DMSO-d6),
;
J¼8.4 Hz,1H), 7.43 (d, J¼8.1 Hz, 2H), 7.70 (dd, J¼8.4, 2.1 Hz,1H), 7.79
d
(ppm): 2.40 (s, 3H), 3.56 (s, 6H), 6.82 (dd, J¼8.1, 1.5 Hz, 1H), 7.23 (t,
J¼8.1 Hz, 1H), 7.43 (d, J¼8.1 Hz, 2H), 7.80 (s, 1H), 7.79 (d, J¼8.1 Hz,
3H), 8.51 (s,1H), 9.48 (s,1H); 13C NMR (75 MHz, DMSO-d6),
(ppm):
(d, J¼8.1 Hz, 3H), 8.53 (s, 1H), 9.05 (s, 1H), 9.23 (s, 1H); 13C NMR
(75 MHz, DMSO-d6),
d
(ppm): 20.6, 36.2, 44.5, 115.27 (2C), 118.3,
d
119.8, 123.3, 129.5, 129.9, 132.6, 137.1, 139.1, 144.9, 147.6, 151.6, 152.8,
158.0. Anal. Calcd for C22H21N5O2S 1.5H2O (446.50): C, 59.19; H,
5.38; N, 15.69; S, 7.17. Found: C, 59.37; H, 5.30; N, 15.63; S, 7.03.
20.6, 38.0, 114.6, 116.8, 118.6, 118.8, 123.2, 129.1, 129.9, 132.7, 137.0,
138.9, 139.7, 151.0, 154.2, 157.3, 157.5. Anal. Calcd for C20H19N5
0.5H2O (354.40): C, 67.79; H, 5.65; N,19.77. Found: C, 67.63; H, 5.78;
N, 19.58.
5.4.16. 2-(6-(Pyrrolidin-1-yl)-9-p-tolyl-9H-purin-2-yl)phenol 4m
Method A: Compound 4m (0.12 g, 0.33 mmol, 81%), was
obtained as a white solid from 3d (0.11 g, 0.41 mmol) and salicy-
5.4.21. 4-(6-(Dimethylamino)-9-p-tolyl-9H-purin-2-yl)phenol 4q
Method C: Compound 4q (0.12 g, 0.34 mmol, 61%), was obtained
as an off-white solid from 3e (0.14 g, 0.56 mmol) and 4-hydroxy-
benzaldehyde (0.07 g, 0.62 mmol). Mp 228–230 ꢀC; IR (Nujol mull)
3423, 3177, 1601, 1586, 1565, 1519 cmꢁ1; 1H NMR (400 MHz, DMSO-
laldehyde (48
1603, 1590, 1557, 1525, 1515 cmꢁ1
(ppm): 2.01 (s, 4H), 2.41 (s, 3H), 3.72 (s, 2H), 4.15 (s, 2H), 6.86 (d,
J¼7.7 Hz, 1H), 6.87 (t, J¼7.7 Hz, 1H), 7.30 (dt, J¼7.7, 1.2 Hz, 1H), 7.44
m
L, 0.45 mmol). Mp 235–237 ꢀC; IR (Nujol mull) 3102,
1H NMR (300 MHz, DMSO-d6),
;
d
d6),
d
(ppm): 2.39 (s, 3H), 3.54 (s, 6H), 6.82 (dd, J¼7.0, 2.0 Hz, 2H),

6910
C. Correia et al. / Tetrahedron 65 (2009) 6903–6911
7.41 (d, J¼8.0 Hz, 2H), 7.80 (d, J¼8.0 Hz, 2H), 8.20 (dd, J¼7.0, 2.0 Hz,
2H), 8.45 (s, 1H), 9.76 (s, 1H); 13C NMR (100 MHz, DMSO-d6),
as solvent to give 4v (0.09 g, 0.23 mmol, 33%). Mp 291–293 ꢀC; IR
(Nujol mull) 3321, 1577, 1515 cmꢁ1; 1H NMR (300 MHz, DMSO-d6),
d
(ppm): 20.6, 37.8,114.09, 118.24, 123.0, 129.30, 129.31, 129.9, 132.8,
d
(ppm): 3.78 (m, 4H), 4.31 (s, 4H), 6.78 (d, J¼8.1 Hz, 1H), 7.48 (t,
136.8, 138.3, 151.1, 154.1, 157.6, 159.2. Anal. Calcd for C20H19N5O
0.8H2O (359.80): C, 66.78; H, 5.73; N, 19.48. Found: C, 66.80; H,
6.01; N, 19.50.
J¼8.4 Hz, 1H), 7.64 (t, J¼8.4 Hz, 2H), 7.70 (dd, J¼8.1, 1.8 Hz, 1H), 7.79
(d, J¼1.8 Hz, 1H), 7.94 (d, J¼8.4 Hz, 2H), 8.54 (s, 1H), 13.32 (s, 1H);
13C NMR (75 MHz, DMSO-d6),
d (ppm): 20.6, 45.5, 66.1, 117.2, 118.2,
118.6, 119.1, 123.7, 129.0, 130.2, 131.9, 132.1, 137.9, 139.7, 148.7, 152.7,
158.0, 159.4. Anal. Calcd for C21H19N5O3 0.34H2O (393.53): C, 63.78;
H, 4.98; N, 17.72. Found: C, 63.77; H, 5.00; N, 17.78.
5.4.22. 2-(9-Phenyl-6-(piperidin-1-yl)-9H-purin-2-yl)phenol 4r
Method A: Compound 4r (0.14 g, 0.38 mmol, 70%), was obtained
as a white solid from 3f (0.15 g, 0.55 mmol) and salicylaldehyde
(64
m
L, 0.61 mmol). Mp 164–166 ꢀC; IR (Nujol mull) 3115, 1731,
5.4.27. 4-(9-Methyl-6-morpholino-9H-purin-2-yl)phenol 4x
Method C: Compound 4x (0.10 g, 0.31 mmol, 80%), was obtained
as an off-white solid from 3i (0.11 g, 0.39 mmol) and 4-hydroxy-
benzaldehyde (0.05 g, 0.43 mmol). Mp 247–249 ꢀC; IR (Nujol mull)
1605, 1563, 1516 cmꢁ1; 1H NMR (300 MHz, DMSO-d6),
d
(ppm): 1.71
(s, 6H), 4.29 (s, 4H), 6.86 (d, J¼8.0 Hz,1H), 6.90 (t, J¼8.0 Hz,1H), 7.31
(td, J¼8.0, 1.5 Hz, 1H), 7.53 (t, J¼7.5 Hz, 1H), 7.66 (t, J¼7.5 Hz, 2H),
7.81 (d, J¼7.5 Hz, 2H), 8.33 (dd, J¼8.0, 1.5 Hz, 1H), 8.58 (s, 1H), 13.50
3420, 3175, 1610, 1573, 1516 cmꢁ1 1H NMR (300 MHz, DMSO-d6),
;
(s, 1H); 13C NMR (75 MHz, DMSO-d6),
d
(ppm): 24.1, 25.7, 46.0, 117.2,
d
(ppm): 3.74 (s, 4H), 3.75 (s, 3H), 4.25 (s, 4H), 6.83 (d, J¼9.0 Hz, 2H),
118.0, 118.6, 119.3, 123.8, 128.1, 128.9, 129.7, 132.0, 134.5, 139.2,
148.8, 152.4, 158.1, 159.4. Anal. Calcd for C22H21N5O (371.44): C,
71.14; H, 5.70; N, 18.85. Found: C, 71.19; H, 5.72; N, 18.94.
8.09 (s, 1H), 8.24 (d, J¼8.7 Hz, 2H), 9.75 (s, 1H); 13C NMR (75 MHz,
DMSO-d6),
d (ppm): 29.3, 45.1, 66.3, 114.9, 117.6, 129.30, 129.33,
140.7, 152.2, 152.9, 157.1, 159.1. Anal. Calcd for C16H17N5O2 1.8H2O
(343.74): C, 55.91; H, 5.99; N, 20.38. Found: C, 55.92; H, 5.75; N,
20.18.
5.4.23. 4-(9-Phenyl-6-(piperidin-1-yl)-9H-purin-2-yl)phenol 4s
Method A: Compound 4s (0.08 g, 0.21 mmol, 47%), was obtained
as an off-white solid from 3f (0.15 g, .55 mmol) and 4-hydroxy-
benzaldehyde (0.06 g, 0.48 mmol). Mp 253–255 ꢀC; IR (Nujol mull)
3141, 1612, 1595, 1574, 1561, 1517 cmꢁ1; 1H NMR (300 MHz, DMSO-
5.4.28. 4-(9-methyl-6-morpholino-9H-purin-2-yl)benzene-
1,2-diol 4z
Method C: Compound 4z (0.10 g, 0.32 mmol, 72%), was obtained
as an off-white solid from 3i (0.13 g, 0.44 mmol) and 3,4-dihy-
droxybenzaldehyde (0.07 g, 0.48 mmol). Mp 264–266 ꢀC; IR (Nujol
d6),
d
(ppm): 1.65 (s, 6H), 4.30 (s, 4H), 6.83 (d, J¼8.7 Hz, 2H), 7.46 (t,
J¼7.5 Hz, 1H), 7.63 (t, J¼7.5 Hz, 2H), 7.95 (d, J¼7.5 Hz, 2H), 8.18 (d,
J¼8.7 Hz, 2H), 8.51 (s, 1H), 9.78 (s, 1H); 13C NMR (75 MHz, DMSO-
mull) 3459, 3219, 3114, 1579, 1529 cmꢁ1 1H NMR (300 MHz,
;
d6),
d
(ppm): 24.4, 25.7, 45.6, 115.0, 118.0, 123.2, 127.3, 129.2, 129.3,
DMSO-d6),
J¼8.1 Hz, 1H), 7.73 (dd, J¼8.1, 2.4 Hz, 1H), 7.85 (d, J¼2.4 Hz, 1H), 8.09
(s, 1H), 9.09 (s, 1H); 13C NMR (75 MHz, DMSO-d6),
(ppm): 29.4,
d (ppm): 3.75 (s, 4H), 3.76 (s, 3H), 4.25 (s, 4H), 6.77 (d,
129.5, 135.3, 138.3, 151.4, 153.1, 159.2. Anal. Calcd for C22H21N5O
0.2H2O (375.04): C, 70.48; H, 5.71; N, 18.69. Found: C, 70.46; H,
5.89; N, 18.43.
d
45.1, 66.3, 115.2 (2C), 117.6, 119.7, 129.8, 140.7, 144.8, 147.3, 152.2,
152.9, 157.3. Anal. Calcd for C16H17N5O3 0.27H2O (332.20): C, 57.86;
H, 5.28; N, 21.09. Found: C, 57.86; H, 5.33; N, 20.82.
5.4.24. 2-(6-Morpholino-9-phenyl-9H-purin-2-yl)phenol 4t
Method A: Compound 4t (0.14 g, 0.37 mmol, 72%), was obtained
as a white solid from 3g (0.14 g, 0.52 mmol) and salicylaldehyde
5.4.29. 4-(9-Methyl-6-(piperidin-1-yl)-9H-purin-2-yl)phenol 4w
Method A: Compound 4w (0.09 g, 0.29 mmol, 48%),
was obtained as an off-white solid from 3h (0.13 g, 0.61 mmol) and
4-hydroxybenzaldehyde (0.08 g, 0.67 mmol) after triethylamine
elimination under reduce pressure and addition of acetonitrile to
the solution. Mp 270 ꢀC (dec); IR (Nujol mull) 3210, 3125, 1596,
(62
m
L, 0.57 mmol). Mp 201–203 ꢀC; IR (Nujol mull) 3106, 1741,
1605, 1567, 1518 cmꢁ1; 1H NMR (300 MHz, DMSO-d6),
d
(ppm): 3.81
(s, 4H), 4.25 (s, 4H), 6.86 (d, J¼7.5 Hz, 1H), 6.90 (t, J¼8.0 Hz,1H), 7.32
(td, J¼8.0, 1.8 Hz, 1H), 7.54 (t, J¼7.5 Hz, 1H), 7.66 (t, J¼7.5 Hz, 2H),
7.79 (d, J¼7.2 Hz, 2H), 8.34 (dd, J¼8.0, 1.8 Hz, 1H), 8.61 (s, 1H), 13.31
(s, 1H); 13C NMR (75 MHz, DMSO-d6),
d
(ppm): 45.3, 66.1, 117.2,
1568, 1516 cmꢁ1 1H NMR (300 MHz, DMSO-d6),
; d (ppm): 1.60 (s,
118.2, 118.6, 119.1, 123.8, 128.2, 129.0, 129.8, 132.1, 134.4, 139.6, 148.7,
152.7, 158.0, 159.4. Anal. Calcd for C21H19N5O2 0.33H2O (379.35): C,
66.49; H, 5.19; N, 18.47. Found: C, 66.62; H, 5.04; N, 18.55.
6H), 3.75 (s, 3H), 4.24 (s, 4H), 6.83 (d, J¼8.4 Hz, 2H), 8.04 (s, 1H),
8.22 (d, J¼8.4 Hz, 2H), 9.73 (s, 1H); 13C NMR (75 MHz, DMSO-d6),
d
(ppm): 25.7, 24.4, 29.3, 45.5, 114.9, 117.4, 129.3, 129.5, 140.1, 152.0,
152.9, 157.1, 159.0. Anal. Calcd for C17H19N5O 0.38H2O (316.21): C,
64.59; H, 6.26; N, 22.16. Found: C, 64.59; H, 6.21; N, 21.97.
5.4.25. 4-(6-Morpholino-9-phenyl-9H-purin-2-yl)phenol 4u
Method C: Compound 4u (0.24 g, 0.65 mmol, 82%), was obtained
as an off-white solid from 3g (0.22 g, 0.80 mmol) and 4-hydroxy-
benzaldehyde (0.11 g, 0.88 mmol) after elimination of triethyl-
amine under reduced pressure and water addition. Mp 262–264 ꢀC;
Acknowledgements
Antimycobacterial data were provided by the Tuberculosis
Antimicrobial Acquisition and Coordinating Facility (TAACF)
through a research and development contract with the US National
Institute of Allergy and Infectious Diseases. The authors gratefully
acknowledge the financial support by Universidade do Minho,
IR (Nujol mull) 3535, 3090, 1595, 1579, 1518 cmꢁ1
;
1H NMR
(300 MHz, DMSO-d6),
d (ppm): 3.78 (s, 4H), 4.31 (s, 4H), 6.83 (d,
J¼6.9 Hz, 2H), 7.47 (t, J¼8.1 Hz, 1H), 7.63 (t, J¼8.1 Hz, 2H), 7.94 (d,
J¼8.1 Hz, 2H), 8.19 (d, J¼6.9 Hz, 2H), 8.56 (s, 1H), 9.78 (s, 1H); 13C
NMR (75 MHz, DMSO-d6),
d (ppm): 45.2, 66.3, 115.0, 118.2, 123.2,
´
˜
ˆ
Centro de Quımica and Fundaçao para a Ciencia e Tecnologia
(project PPCDT/QUI/59356/2004 and a PhD grant to C.C. SFRH/BD/
22270/2005).
127.5, 129.1, 129.4, 129.6, 135.2, 138.9, 151.5, 153.2, 157.8, 159.3. Anal.
Calcd for C21H19N5O2 H2O (391.41): C, 64.45; H, 5.37; N, 17.90.
Found: C, 64.37; H, 5.52; N, 17.80.
References and notes
5.4.26. 4-(6-Morpholino-9-phenyl-9H-purin-2-yl)benzene-
1,2-diol 4v
Method C: The crude product 4v (0.24 g), was obtained as
a brown solid from 3g (0.19 g, 0.71 mmol) and 3,4-dyhydroxy-
benzaldehyde (0.11 g, 0.78 mmol). The solid was purified by dry
flash chromatography on silica gel using 300 mL of dichloromethane
1. Duncan, K.; Barry, C. E., 3rd. Curr. Opin. Microbiol. 2004, 7, 460–465.
2. World Health Organization. Global Tuberculosis Control: Surveillance, Planning,
and Financing; WHO Report 2008; WHO: Geneva, Switzerland, 2008.
3. Guiterrez-Lugo, M.-T.; Bewley, C. A. J. Med. Chem. 2008, 51, 2606–2612.
4. (a) Ratledge, C.; Dover, L. G. Annu. Rev. Microbiol. 2000, 54, 881–941; (b)
Miethke, M.; Marahiel, M. A. Microbiol. Mol. Biol. Rev. 2007, 71, 413–451.

C. Correia et al. / Tetrahedron 65 (2009) 6903–6911
6911
5. Tripathi, R. P.; Tewari, N.; Dwivedi, N.; Tiwari, V. K. Med. Res. Rev. 2005, 25, 93–131.
6. (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, 7495–7507; (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,
5349–5370; (c) Long, M. C.; Shaddix, S. C.; Moukha-Chafiq, O.; Maddry, J. A.;
Nagy, L.; Parker, W. B. Biochem. Pharmacol. 2008, 75, 1588–1600; (d) Bisseret, P.;
Thielges, S.; Bourg, S.; Miethke, M.; Marahiel, M. A.; Eustachea, J. Tetrahedron
Lett. 2007, 48, 6080–6083; (e) Qiao, C.; Gupte, A.; Boshoff, H. I.; Wilson, D. J.;
Bennett, E. M.; Somu, R. V.; Barry, C. E.; Aldrich, C. C. J. Med. Chem. 2007, 50,
6080–6094; (f) Rai, D.; Johar, M.; Srivastav, N. C.; Manning, T.; Agrawal, B.;
Kunimoto, D. Y.; Kumar, R. J. Med. Chem. 2007, 50, 4766–4774; (g) Qiao, C.;
Wilson, D. J.; Bennett, E. M.; Aldrich, C. C. J. Am. Chem. Soc. 2007, 129, 6350–
6351; (h) Vannada, J.; Bennett, E. M.; Wilson, D. J.; Boshoff, H. I.; Barry, C. E.;
Aldrich, C. C. Org. Lett. 2006, 8, 4707–4710; (i) Somu, R. V.; Wilson, D. J.; Ben-
nett, E. M.; Boshoff, H. I.; Celia, L.; Beck, B. J.; Barry, C. E.; Aldrich, C. C. J. Med.
Chem. 2006, 49, 7623–7635; (j) Bennett, E. M.; Barry, C. E.; Aldrich, C. C. J. Med.
Chem. 2006, 49, 31–34.
7. (a) Bakkestuen, A. K.; Gundersen, L.-L.; Utenova, B. T. J. Med. Chem. 2005, 48,
2710–2723; (b) Braendvang, M.; Gundersen, L.-L. Bioorg. Med. Chem. 2007, 15,
7144–7165; (c) Braendvang, M.; Gundersen, L.-L. Bioorg. Med. Chem. 2005, 13,
6360–6373; (d) Bakkestuen, A. K.; Gundersen, L.-L.; Petersen, D.; Utenova, B. T.;
Vik, A. Org. Biomol. Chem. 2005, 3, 1025–1033; (e) Pathak, A. K.; Pathak, V.; Seitz,
L. E.; Suling, W. J.; Reynolds, R. C. J. Med. Chem. 2004, 47, 273–276; (f) Barrow,
E. W.; Westbrook, L.; Bansal, N.; Suling, W. J.; Maddry, J. A.; Parker, W. B.;
Barrow, W. W. J. Antimicrob. Chemother. 2003, 52, 801–808; (g) Andersen, G.;
Gundersen, L.-L.; Nissen-Meyer, J.; Rise, F.; Spilsberg, B. Bioorg. Med. Chem. Lett.
2002, 12, 567–569; (h) Gundersen, L.-L.; Nissen-Meyer, J.; Spilsberg, B. J. Med.
Chem. 2002, 45, 1383–1386; (i) Scozzafava, A.; Mastrolorenzo, A.; Supuran, C. T.
Bioorg. Med. Chem. Lett. 2001, 11, 1675–1678; (j) Bakkestuen, A. K.; Gundersen,
L.-L.; Langli, G.; Liu, F.; Nolsoe, J. M. J. Bioorg. Med. Chem. Lett. 2000, 10,
1207–1210.
8. (a) For a recent review see: Legraverend, M. Tetrahedron 2008, 64, 8585–8603;
(b) Ibrahim, N.; Legraverend, M. J. Org. Chem. 2009, 74, 463–465; (c) Alves, M. J.;
Booth, B. L.; Freitas, A. P.; Proença, M. F. J. Chem. Soc., Perkin Trans. 1 1992, 913–
917; (d) Booth, B. L.; Dias, A. M.; Proença, M. F. J. Chem. Soc., Perkin Trans. 1 1992,
2119–2126; (e) Alves, M. J.; Booth, B. L.; Proença, M. F. J. Heterocycl. Chem. 1994,
31, 345–350; (f) Booth, B. L.; Coster, R. D.; Proença, M. F. Synthesis 1988, 389–
391; (g) Alves, M. J.; Booth, B. L.; Carvalho, M. A.; Pritchard, R. G.; Proença, M. F.
J. Heterocycl. Chem. 1997, 34, 739–743; (h) Al-Azmi, A.; Booth, B. L.; Carpenter,
R. A.; Carvalho, M. A.; Marrelec, E.; Pritchard, R. G.; Proença, M. F. J. Chem. Soc.,
Perkin Trans. 1 2001, 2532–2537; (i) Booth, B. L.; Cabral, I. M.; Dias, A. M.; Freitas,
A. P.; Matos-Beja, A. M.; Proença, M. F.; Ramos-Silva, M. J. Chem. Soc., Perkin
Trans. 1 2001, 1241–1251; (j) Carvalho, M. A.; Esteves, T. M.; Proença, M. F.;
´
Booth, B. L. Org. Biomol. Chem. 2004, 2, 1019–1024; (k) Carvalho, M. A.; Alvares,
Y.; Zaki, M. E.; Proença, M. F.; Booth, B. L. Org. Biomol. Chem. 2004, 2, 2340–
2345; (l) Alves, M. J.; Carvalho, M. A.; Carvalho, S.; Dias, A. M.; Fernandes, F. H.;
Proença, M. F. Eur. J. Org. Chem. 2007, 4881–4887.
9. Legraverend, M.; Grierson, D. S. Bioorg. Med. Chem. 2006, 14, 3987–4006.
10. Alves, M. J.; Booth, B. L.; A-Duaij, O. Kh.; Eastwood, P.; Nezhat, L.; Proença, M. F.;
Ramos, A. S. J. Chem. Res., Synop. 1993, 402–403; J. Chem. Res., Miniprint 1993,
2701–2719.
11. (a) Orme, I.; Secrist, J.; Anathan, S.; Kwong, C.; Maddry, J.; Reynolds, R.; Pof-
fenberger, A.; Michael, M.; Miller, L.; Krahenbuh, J.; Adams, L.; Biswas, A.;
Franzblau, S.; Rouse, D.; Winfield, D.; Brooks, J. Antimicrob. Agents Chemother.
2001, 45, 1943–1946; (b) http://www.taacf.org.