Synthesis, biological activity, and SAR of antimycobacterial 9-aryl-, 9-arylsulfonyl-, and 9-benzyl-6-(2-furyl)purines

Article abstract of DOI:10.1021/jm0408924

9-Aryl-, 9-arylsulfonyl- and 9-benzyl-6-(2-furyl)purines were synthesized by N-alkylation or N-arylation of the purine followed by Stille coupling to introduce the furyl substituent in the 6-position and the compounds screened for activity against Mycobac

Full text of DOI:10.1021/jm0408924

2710
J. Med. Chem. 2005, 48, 2710-2723
Synthesis, Biological Activity, and SAR of Antimycobacterial 9-Aryl-,
9-Arylsulfonyl-, and 9-Benzyl-6-(2-furyl)purines
Anne Kristin Bakkestuen, Lise-Lotte Gundersen,* and Bibigul T. Utenova
Department of Chemistry, University of Oslo, P.O. Box 1033, Blindern, N-0315 Oslo, Norway
Received October 29, 2004
9-Aryl-, 9-arylsulfonyl- and 9-benzyl-6-(2-furyl)purines were synthesized by N-alkylation or
N-arylation of the purine followed by Stille coupling to introduce the furyl substituent in the
6-position and the compounds screened for activity against Mycobacterium tuberculosis. The
9-aryl- and 9-sulfonylarylpurines exhibited weak activity toward the bacteria, but 9-benzylpu-
rines were good inhibitors especially those carrying electron-donating substituents on the phenyl
ring. A chlorine atom in the purine 2-position further enhanced activity. The high antimyco-
bacterial activity (MIC 0.39 µg/mL against M. tuberculosis), low toxicity against mammalian
cells and activity inside macrophages found for 2-chloro-6-(2-furyl)-9-(4-methoxyphenylmethyl)-
9H-purine makes this compound a highly interesting potential antituberculosis drug.
Introduction
by adenosine kinase to metabolites that affect DNA and
protein synthesis.6c We have previously reported that
6-arylpurine nucleosides are completely inactive as
inhibitors of M. tuberculosis growth,3 and it is not very
likely that our 6-aryl-9-benzylpurines exert their activ-
ity by the same mechanism as 2-methyladenine. Cyto-
toxicity toward cancer cell lines have been reported for
certain 6-arylpurines,7 but our antimycobacterial 6-aryl-
purines exhibited very little toxicity toward mammalian
cells.3 For 9-benzylpurines, anticonvulsant activity8 and
antirhinoviral activity9 are also reported. However these
compounds all carry an amino group in the purine
6-position and are structurally more related to the
6-alkylamino-9-benzylpurines4 shown in Figure 1 than
our antimycobacterials.
Today, one-third of the world population is infected
with Mycobacterium tuberculosis including those car-
rying dormant infections. It has been estimated that ca.
30 million people will die from tuberculosis in the next
10 year period. HIV infections have increased TB
morbidity and mortality, and multidrug resistant tu-
berculosis (MDR-TB) is a growing problem among HIV-
infected patients.1 There is an urgent need for new
antimycobacterial drugs especially for treatment of
MDR-TB.
We have identified certain 6-aryl-9-alkylpurines as
potent antimycobacterials.2,3 Among the aryl- or het-
eroarylpurines examined, the most effective compounds
were 6-(2-furyl)purines. Furthermore, it has been dem-
onstrated that the identity of the 9-substituent is crucial
for activity against Mycobacterium tuberculosis (Figure
1).3 Compounds without the N-9 substituent or only
small alkyl groups in the 9-position were essentially
inactive, whereas N-benzylated purines were highly
potent. When the length of the N-9 side chain was
further increased (CH2CH2Ph), activity was substan-
tially reduced. Our lead is 2-chloro-6-(2-furyl)-9-ben-
zylpurine (Figure 1). This compound exhibits relatively
low toxicity toward mammalian cells, and no acute
toxicity in rats has been detected. The lead structure is
also highly active against several singly drug resistant
strains of M. tuberculosis.3 Currently, the mechanism
of action for antimycobacterial 6-aryl-9-benzylpurines
is not known.
In the present paper we report the synthesis, anti-
mycobacterial activity, and SAR of 6-furylpurines car-
rying a substituted benzyl or an aryl substituent in the
purine 9-position. Substituents with various electronic,
steric and lipophilic properties were introduced at N-9.
Synthesis. The most commonly employed synthetic
routes to 6-aryl-9-alkylpurines are N-alkylation of a
6-halopurine, followed by Pd-catalyzed coupling with an
organometallic reagents,3 or reaction of a 5-amino-4,6-
dihalopyridine with an alkylamine followed by a ring
closing reaction employing for instance triethyl ortho-
formate,8 and again a final Pd-catalyzed coupling reac-
tion to introduce the 6-aryl substituent. In this study,
most 6-furyl-9-benzylpurines 7 and 8 were synthesized
according to the former strategy (Scheme 1.) 6-Chloro-
purine 1 or 2,6-dichloropurine 2 were reacted with the
desired benzyl halide in the presence of base. Both the
9-benzylpurines 3 or 5 and minor amounts of the
7-alkylated isomers 4 and 6 were formed in most cases.
The furyl substituents in the targets 7 and 8 were
introduced by Stille coupling. When mild reaction condi-
tions were applied, the dichloropurine 5 reacted with
almost complete regioselectivity to give the desired
coupling products 8 (Scheme 1). Further transforma-
tions in the para-position of the phenyl substituent of
In addition to our work, we are only aware of a few
other papers on antimycobacterial purine derivatives.
Weak activity has been observed for some 6-alkylamino-
9-benzylpurines.4 The natural product agelasine F5 and
certain synthetic 9-sulfonyl-6-mercaptopurines or 6-alkyl-
thiopurines are quite active against M. tuberculosis, the
same is true for 2-methyladenosine (Figure 1).6 Only
in the latter case, a mechanism of action is suggested
in the literature; 2-methyladenosine is phosphorylated
* To whom correspondence should be addressed. Phone: +47
22857019, Fax: +47 22855507, E-mail: l.l.gundersen@kjemi.uio.no.
10.1021/jm0408924 CCC: $30.25 © 2005 American Chemical Society
Published on Web 03/01/2005

Antimycobacterial 9-Aryl-6-(2-furyl)purines
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 7 2711
Figure 1. Structures of known antimycobacterial purines.
Scheme 1a
o
o
a (a) ArCH(RR)X, K2CO3, DMF; (b) 2-furylSnBu3, (Ph3P)2PdCl2, DMF, 90 C; (c) 2-furylSnBu3, [(2-furyl)3P]4Pd, DMF, 50 C.
Scheme 2a
The high antimycobacterial activity found for certain
6-mercapto-9-sulfonylpurines6a (general structure; see
Figure 1) inspired our synthesis of the 6-furyl-9-sul-
fonylpurine 13 (Scheme 4). 6-Chloropurine 1 was N-
sulfonylated with complete regioselectivity applying the
same set of reaction conditions as reported for the
sulfonylation of 6-mercaptopurine,6a and the furyl sub-
stituent was introduced by Negishi coupling. Compound
13 was not stable under our standard workup procedure
for Stille couplings.
a (a) Ac2O, DMAP, CH2Cl2; (b) 48% HBr (aq), 90 °C.
NOESY NMR spectroscopy supported the structure
of the sulfonylpurine 13 and hence the position of
N-sulfonylation. Correlations between the phenyl ortho
protons and both H-8 and H-2, but not any furyl protons,
exclude N-7 sulfonylation.
7z and 7cc to give compounds 7y and 7dd are shown
in Scheme 2.
The 6-chloropurines 3bb, 3ff and 3gg were not
available by the route depicted in Scheme 1. p-Ami-
nobenzyl halides required for the preparation 3bb are
extremely activated and difficult to handle,10 and the
enantiopure compounds 3ff and 3gg could not, of course,
be formed by alkylation with a secondary benzyl halide.
These three compounds were prepared as previously
reported for 3ff and 3gg8 (Scheme 3).
As discussed in the Introduction, much higher anti-
mycobacterial activity was found for the 9-benzyl-6-
furylpurine 7a than for the 9-phenylethyl homologue
(Figure 1).3 Hence, it was desirable to investigate if the
distance between the phenyl- and purine ring could be
shortened. We thus prepared the 9-aryl-6-(2-furyl)-
purines 16 and 17 by regioselective N-arylation on

2712 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 7
Bakkestuen et al.
Scheme 3a
a (a) Et3N, n-BuOH, 100 °C; (b) EtSO3H, CH(OEt)3.
Scheme 4a
against M. tuberculosis, but electron donating substit-
uents with largely negative π-values (7z: R4 ) OH, π
) -0.61; 7cc: R4 ) NHCOCH3, π ) -0.97; 7dd: R4 )
NH2 π ) -1.23) should be avoided. M. tuberculosis
contains a thick and waxy cell wall, which may preclude
efficient penetration of the most polar compounds. It
seems like the ideal substituent has a relatively small
positive π-value. Compounds 7o (R4 ) But, σ ) -0.20,
π ) 1.98, MIC > 6.25 µg/mL) and 7x (R4 ) OBn, σ )
-0.42, π ) 2.13, MIC ) 1.56 µg/mL) carries more
powerful electron donating substituents, but are only
less or equally effective than compounds 7n (R4 ) CH3,
σ ) -0.17, π ) 0.56, MIC ) 3.13 µg/mL) and 7p (R4 )
OCH3, σ ) -0.27, π ) 0.56, MIC ) 1.56 µg/mL),
respectively. However, it is currently not clear whether
the reduced activity is mainly a consequence of high
lipophilicity or the sterical requirements for the But and
OBn group.
a (a) KOH(aq), PhSO2Cl, acetone, 0 oC; (b) 2-furylZnBr, (Ph3P)4Pd,
o
THF, 50 C.
Scheme 5a
Replacing the methylene in the benzylpurines with a
sulfonyl group did not result in desirable activity even
though several 9-arylsulfonyl-6-mercaptopurines (Fig-
ure 1) are highly potent antimycobacterials.6a The
benzenesulfonylpurine 13 was only a very modest
inhibitor of M. tuberculosis (Table 1), and the N-sul-
fonyl-6-chloropurine 12 was completely inactive (data
not shown). Also introduction of a second phenyl sub-
stituent on the benzylic carbon, compound 7ee, resulted
in a substantial decrease in antimycobacterial activity,
but an R-methyl group resulted in only moderately
reduced inhibition of bacterial growth. The enantiomers
7ff and 7gg were equally active.
The 6-furyl-9-arylpurines 16 and 17 were substan-
tially less potent than most 9-benzylpurines compounds
7 and 8 (Table 1). In this series of compounds, a chlorine
atom in the purine 2-position had no profound effect on
activity, and no clear correlation between compounds
16 and 17 and the benzylpurines 7 and 8 with the same
substitution pattern in the phenyl ring could be found.
However, also in the 9-arylpurine series, highest activity
was observed for the p-methoxy group; compound 16e.
Toxicity toward Mammalian Cells. Potent inhibi-
tors of M. tuberculosis were tested for cytotoxicity (IC50)
in mammalian VERO cells and a selectivity index (SI),
defined as IC50:MIC, was calculated12b (Table 1). In
addition to an increase in antimycobacterial activity, the
para methoxy substituent on the benzyl group in
compounds 7p and 8g resulted in a substantial reduc-
tion of toxicity against mammalian VERO cells (Table
1). Hence these compounds have a much larger selectiv-
ity index and are safer drug candidates than the
previously reported compound 8a. Also the para methyl
group in compound 8f afforded reduced toxicity toward
a (a) 2-FurylSnBu3, (Ph3P)2PdCl2, DMF, 90 oC; (c) 2-furylSnBu3,
o
[(2-furyl)3P]4Pd, DMF, 50 C.
compounds 1 and 211 followed by Stille coupling in the
purine 6-position (Scheme 5).
Antibacterial Activity toward Mycobacterium
tuberculosis. The 9-benzylpurines 7, 8, 13, 16 and 17
were screened for antibacterial activity against Myco-
bacterium tuberculosis H37Rv according to procedures
previously published by the TAACF organization,12 and
the results are presented in Table 1.
We have previously shown that for the class of
antimycobacterial purines discussed herein, a chlorine
atom in the purine 2-position generally increases activ-
ity,2,3 and when the potent benzylpurines 7 (MIC e 3.31
µg/mL) were compared with the otherwise identical
2-chloropurines 8, compounds 8 were generally two
times more active against the bacteria. The most potent
compound identified to date is the para methoxy ben-
zylpurine 8g exhibiting a MIC very close to what was
found for the tuberculosis first-line drug rifampin.
The antimycobacterial activities found for the ben-
zylpurines 7 and 8 indicate that the ortho positions in
the phenyl ring should not be substituted. Restricted
rotation may inhibit adoption of the, yet unknown,
active conformation. Also substitution of the benzylic
methylene moiety (see below) led to reduced activity.
Strongly electron withdrawing substituents in the
para position were not tolerated (7k-m). Substituents
with negative σ-values generally increased activity

Antimycobacterial 9-Aryl-6-(2-furyl)purines
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 7 2713
Table 1. Antimycobacterial Activity against Mycobacterium tuberculosis and Cytotoxic Activity against VERO Cells for
6-(2-Furyl)purines 7, 8, 13, 16, and 17
% inhibition of
MIC
IC50
selectivity
index
(IC50: MIC)
M. tuberculosis, M. tuberculosis VERO cells
no.
X
RR
R2
R3
R4
R5
R6 6.25 µg/mL concn
H
37Rv (µg/mL)a
(µg/mL)
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
CH3
(S)
CH3
(R)
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
95b
94
95
94
90
71
17
91
93
52
52
12
23
95
98
97
82
98
99
8
88
89
97
99
32
79
98
91
0
3.13
6.25
6.25
3.13
6.25
n.d.
n.d.
6.25
6.25
n.d.
n.d.
n.d.
n.d.
3.13
12.5
1.56
n.d.
6.25
0.78
n.d.
n.d.
n.d.
3.13
1.56
n.d.
n.d.
6.25
12.5
n.d.
n.d.
n.d.
12.5
8.6
>62.5c
>10c
>10c
d
2.7
>10
>1.6
>3.2
n.d.
n.d.
n.d.
>1.6
>1.6
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
>40
n.d.
>10
n.d.
n.d.
n.d.
n.d.
12
Cl
Cl
H
Cl
Cl
H
Cl
Cl
Cl
H
F
Cl
H
H
n.d.
H
H
n.d.
H
F
>10c
>10c
n.d.
H
H
F
H
H
H
H
H
H
H
H
OCH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CF3
NO2
n.d.
H
n.d.
H
SO2CH3
CH3
C(CH3)3
OCH3
H
H
OCH3
n.d.
H
d
H
n.d.
H
>62.5c
n.d.
H
OCH3
CH3
>62.5c
n.d.
7s
7t
OCH3 OCH3
H
OCH3
H
n.d.
7u
7v
7w
7x
7y
7z
7aa
7bb
7cc
7dd
7ee
7ff
OCF3
H
OCH2CH3
OCH2Ph
OCOCH3
OH
SCH3
N(CH3)2
NHCOCH3
NH2
n.d.
OCF3
H
H
n.d.
H
37.41
1.70
n.d.
H
H
1
H
H
n.d.
n.d.
1.10
n.d.
n.d.
n.d.
n.d.
n.d.
H
H
n.d.
H
H
6.90
n.d.
H
H
H
H
n.d.
H
H
23
30
100
n.d.
H
H
H
H
n.d.
H
H
n.d.
7gg
8a
H
H
H
H
H
H
100
12.5
n.d.
n.d.
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
98b
0.78
1.56
6.25
3.13
3.13
0.78
0.39
n.d.
3.13
0.78
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
8.1
d
11
n.d.
>1.6
>3.20
n.d.
>13
>26
n.d.
8b Cl
H
H
Cl
98
98
99
96
98
98
80
99
99
14
13
17
7
8c
Cl
H
Cl
Cl
>10c
>10c
11.53
>10c
>10c
n.d.
8d Cl
H
Cl
H
8e
8f
8g
Cl
Cl
Cl
H
H
F
H
H
CH3
OCH3
H
H
H
8h Cl
OCH3
H
H
8i
Cl
Cl
H
H
H
H
H
H
OCH3
CH3
H
OCH3
>10c
>10c
n.d.
>3.20
>12.8
n.d.
8j
H
13
N9 subst: SO2Ph
16a
16b
16c
16d
16e
N9 subst: Ph
n.d.
n.d.
N9 subst: C6H4-p-Cl
N9 subst: C6H4-m-Cl
N9 subst: C6H4-p-CH3
N9 subst: C6H4-p-OCH3
n.d.
n.d.
n.d.
n.d.
24
81
2
n.d.
n.d.
n.d.
n.d.
17a Cl N9 subst: Ph
17b Cl N9 subst: C6H4-p-CH3
n.d.
n.d.
14
n.d.
n.d.
a MIC rifampicin 0.25 µg/mL. b At 12.5 µg/mL. c Low solubility precludes determination at higher concentrated. d Solubility in tissue
culture to low to determine IC50
.
VERO cells, but certain other para substituents, OBn
in 7x and SMe in 7aa, actually enhanced cytotoxicity
compared to the unsubstituted compound 7a. Unfortu-
nately, many compounds exhibited low solubility in the
tissue culture, and the IC50 could not be determined
exactly. Hence, information of SAR regarding toxicity
toward mammalian cells is currently limited.
Activity against Mycobacterium avium Complex.
Mycobacterium avium complex (MAC) consists of sev-
eral related species of mycobacterium that are ubiqui-
tous in the environment. MAC rarely causes disease in
individuals with an uncompromised immune system,
and disseminated infections are usually associated with
HIV infection. In patients with AIDS, MAC causes some
of the most common serious opportunistic in-
fections.12b,13,14 Compounds 7p, 8a and 8g were all
highly active against M. tuberculosis, but they were only
found to be weak inhibitors of the M. avium complex
(Table 2).
Activity against Mycobacterium tuberculosis in
Macrophages. The M. tuberculosis is a facultative
intracellular parasite, usually of macrophages. In the
early days of an infection the organism multiplies
virtually unrestricted within macrophages until the cell
burst. Later on activation of macrophages occur, but
inside the tubercles, many macrophages are poorly

2714 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 7
Bakkestuen et al.
Table 2. Antimycobacterial Activity against Mycobacterium avium and Efficacy in vitro in a TB-Effected [M. tuberculosis Erdman
(ATCC 35801)] Macrophage Model for Selected 6-(2-Furyl)purines 7 and 8
MIC M. avium complex
(µg/mL)
EC90 (µg/mL)
EC99 (µg/mL)
no.
X
R4
macrophage modela
macrophage modelb
EC90/MICc
7p
8a
8g
H
Cl
Cl
OCH3
H
OCH3
>32
25
>32
>12.5
0.04
>12.5
8.46
>8.01
0.05
0.05
0.02
0.67
a Concentrated effecting 90% reduction in residual mycobacterial growth after 7 days, compared with untreated controls. b Concentrated
effecting 99% reduction in residual mycobacterial growth after 7 days, compared with untreated controls. c MIC from Table 1; Compounds
with EC90 > 16 × MIC are considered inactive.
activated and the bacteria uses these cells to replicate..15
impact conditions (EI) were recorded at 70 eV ionizing voltage
with a VG Prospec instrument and are presented as m/z (%
Hence it is extremely important that a potential drug
against tuberculosis is able to penetrate macrophages
and destroy the bacteria inside. The efficacy of com-
pounds 7p, 8a and 8g in vitro in a TB-infected mac-
rophage model were examined12b (Table 2), and both
2-chloropurines 8 and especially 8g, were found to be
highly active.
rel int.). Optical rotation was recorded at 20 °C on a Perkin-
Elmer 341 polarimeter. Elemental analyses were performed
by Ilse Beetz Mikroanalytisches Laboratorium, Kronach,
Germany. Melting points were determined with a C. Reichert
melting point apparatus and are uncorrected. DMF was
distilled from BaO and stored over 4 Å mol sieves, and
dichloromethane was distilled from CaH2, and THF from Na/
benzophenone, prior to use. The following compounds were
prepared as previously described: 6-chloro-9-(phenylmethyl)-
9H-purine 3a,17 (S)-6-chloro-9-(1-phenylethyl)-9H-purine 3ff,8
(R)-6-chloro-9-(1-phenylethyl)-9H-purine 3gg,8 6-chloro-7-
(phenylmethyl)-7H-purine 4a,17 2,6-dichloro-9-(phenylmethyl)-
9H-purine 5a,18 2,6-dichloro-7-(phenylmethyl)-7H-purine 6a,18
6-(2-furyl)-9-(phenylmethyl)-9H-purine 7a,3 2-chloro-6-(2-fu-
ryl)-9-(phenylmethyl)-9H-purine 8a,18 and 9-arylpurines 14
and 15.11 All other reagents were commercially available and
used as received.
General Procedure for the Synthesis of N-Benzylpu-
rines (3-6) by N-Alkylation of 6-Chloropurine or 2,6-
Dichloropurine. A mixture of 6-chloropurine 1 or 2,6-
dichloropurine 2 (5.0 mmol) and potassium carbonate (2.07 g,
15 mmol) in DMF (20 mL) was stirred at ambient temperature
under N2 atm. for 30 min, before the benzyl halide (10 mmol)
was added. After stirring for 20 h, the reaction mixture was
filtered and evaporated in vacuo. The products were isolated
by flash chromatography on silica gel. The 9-alkylated isomers
3 or 5 eluted first.
6-Chloro-9-(4-chlorophenylmethyl)-9H-purine (3b).
EtOAc-hexane (1:1) was used as eluent for flash chromatog-
raphy; yield 953 mg (68%), mp 130-133 °C, colorless small
needles (lit.8 133-135 °C). 1H NMR (CDCl3, 200 MHz) δ 5.41
(s, 2H, CH2), 7.24 (d, J ) 8.0 Hz, 2H, Ar), 7.33 (d, J ) 8.0 Hz,
2H, Ar), 7.99 (s, 1H, H-8), 8.76 (s, 1H, H-2).
6-Chloro-7-(4-chlorophenylmethyl)-7H-purine (4b).
EtOAc was used as eluent for flash chromatography; yield 223
mg (16%), mp 167-169 °C, colorless microcrystalline solid (lit.8
168-170 °C). 1H NMR (CDCl3, 200 MHz) δ 5.65 (s, 2H, CH2),
7.09 (d, J ) 8.6 Hz, 2H, Ar), 7.35 (d, J ) 8.6 Hz, 2H, Ar), 8.22
(s, 1H, H-8), 8.89 (s, 1H, H-2).
Conclusions
6-(2-Furyl)-9-benzylpurines are shown to be excellent
inhibitors of M. tuberculosis growth, especially those
benzylpurines carrying electron donating substituents
on the phenyl ring. No modifications of the methylene
moiety in the benzyl group appear to be allowed. A
chlorine atom in the purine 2-position further enhanced
activity. The high antimycobacterial activity (MIC 0.39
µg/mL against M. tuberculosis), low toxicity against
mammalian cells and activity inside macrophages re-
ported makes 2-chloro-6-(2-furyl)-9-(4-methoxyphenyl-
methyl)-9H-purine a highly interesting potential anti-
tuberculosis drug.
Currently, the mechanism of action for the antimy-
cobacterials 7 and 8 is not known, and the same is true
for most other antimycobacterial purines shown in
Figure 1. We previously observed little cross resistance,3
which indicates a novel mode of action compared to
known antimycobacterial drugs. Also the fact that no
significant activity against Lactobacillus casei,3 and only
low activity against M. Avium, was found3 supports this
hypothesis. At this point, we can only speculate regard-
ing the mechanism of action for purines 7 and 8 as
antimycobacterials. However, certain 6-oxo-9-benzylpu-
rines and 6-oxo-9-benzyl-9-deazapurines are known to
inhibit human purine nucleoside phosphorylase (PNP).16
PNP from M. tuberculosis resembles the mammalian
structure.17 We have found 6-oxo-9-benzylpurine to be
essentially inactive toward M. tuberculosis,2 but sub-
stitution of the oxo-function with a furyl group in the
purine 6-position increases lipophilicity and may also
improve ability to penetrate the thick and waxy myco-
bacterial cell wall. Hence, it would certainly be interest-
ing to explore the ability of 6-(2-furyl)-9-benzylpurines
to inhibit mycobacterial PNP.
6-Chloro-9-(3,4-dichlorophenylmethyl)-9H-purine (3c).
EtOAc-hexane (1:1) was used as eluent for flash chromatog-
raphy; yield 1.039 g (66%), mp 150-153 °C, off-white powder
1
(lit.8 151-153 °C). H NMR (CDCl3, 200 MHz) δ 5.39 (s, 2H,
CH2), 7.13 (dd, J ) 8.0 and 2.0 Hz, 1H, Ar), 7.40 (br s, 1H,
Ar), 7.42 (d, J ) 8.0 Hz, 1H, Ar), 8.10 (s, 1H, H-8), 8.76 (s, 1H,
H-2).
6-Chloro-7-(3,4-dichlorophenylmethyl)-7H-purine (4c).
EtOAc was used as eluent for flash chromatography; yield 252
mg (16%), mp 172-174 °C, colorless crystals. 1H NMR (CDCl3,
200 MHz) δ 5.64 (s, 2H, CH2), 6.95 (dd, J ) 8.2 and 1.8 Hz,
1H, Ar), 7.24 (br s, 1H, Ar), 7.43 (d, J ) 8.2 Hz, 1H, Ar), 8.26
(s, 1H, H-8), 8.89 (s, 1H, H-2); HRMS: Found 311.9726, calcd
for C12H7Cl3N4 311.9736; Anal.(C12H7Cl3N4) C, H, N.
6-Chloro-9-(3-chlorophenylmethyl)-9H-purine (3d).
EtOAc-hexane (1:1) was used as eluent for flash chromatog-
raphy; yield 685 mg (49%), mp 94-96 °C, off-white powder
(lit.8 90-92 °C). 1H NMR (CDCl3, 200 MHz) δ 5.41 (s, 2H, CH2),
7.15-7.30 (m, 4H, Ar), 8.10 (s, 1H, H-8), 8.76 (s, 1H, H-2).
6-Chloro-7-(3-chlorophenylmethyl)-7H-purine (4d).
EtOAc was used as eluent for flash chromatography; yield 99
Experimental Section
The 1H NMR spectra were recorded at 500 MHz with a
Bruker Avance DRX 500 instrument, at 300 MHz with a
Bruker Avance DPX 300 instrument or at 200 MHz with a
Bruker Avance DPX 200 instrument or a Varian Gemini 200
instrument. The 1H decoupled 13C NMR spectra were recorded
at 125, 75 or 50 MHz using instruments mentioned above.
Unless otherwise stated, the spectra are recorded at ambient
temperature. NOESY NMR was performed on the Bruker
Avance DRX 500 instrument. Mass spectra under electron

Antimycobacterial 9-Aryl-6-(2-furyl)purines
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 7 2715
mg (7%), mp 133-136 °C, colorless needles. 1H NMR (CDCl3,
200 MHz) δ 5.65 (s, 2H, CH2), 7.00-7.02 (m, 1H, Ar), 7.15 (s,
1H, Ar), 7.30-7.33 (m, 2H, Ar), 8.24 (s, 1H, H-8), 8.89 (s, 1H,
H-2); HRMS: Found 278.0130, calcd for C12H8Cl2N4 278.0126;
Anal. (C12H8Cl2N4) C, H, N.
6-Chloro-9-(2,4-dichlorophenylmethyl)-9H-purine (3e).
EtOAc-hexane (1:2) was used as eluent for flash chromatog-
raphy; yield 994 mg (63%), mp 131-132 °C, colorless crystals.
1H NMR (CDCl3, 200 MHz) δ 5.50 (s, 2H, CH2), 7.19-7.33 (m,
2H, Ar), 7.42 (d, J ) 2.0 Hz, 1H, Ar), 8.16 (s, 1H, H-8), 8.73 (s,
1H, H-2); Anal. (C12H7Cl3N4) C, H, N.
6-Chloro-7-(2,4-dichlorophenylmethyl)-7H-purine (4e).
EtOAc was used as eluent for flash chromatography; yield 241
mg (15%), mp 179-181 °C, colorless crystals. 1H NMR (CDCl3,
200 MHz) δ 5.74 (s, 2H, CH2), 6.73 (d, J ) 8.4 Hz, 1H, Ar),
7.18-7.24 (m, 1H, Ar), 7.50 (d, J ) 2.0 Hz, 2H, Ar), 8.20 (s,
1H, H-8), 8.89 (s, 1H, H-2); HRMS: Found 311.9727, calcd for
C12H7Cl3N4 311.9736; Anal. (C12H7Cl3N4) C, H, N.
6-Chloro-9-(4-trifluoromethylphenylmethyl)-9H-pu-
rine (3k). EtOAc-hexane (3:4) was used as eluent for flash
chromatography; yield 932 mg (60%), mp 130-132 °C, colorless
crystals. 1H NMR (CDCl3, 200 MHz) δ 5.51 (s, 2H, CH2), 7.41
(d, J ) 8.1 Hz, 2H, Ar), 7.63 (d, J ) 8.1 Hz, 2H, Ar), 8.12 (s,
1H, H-8), 8.77 (s, 1H, H-2); HRMS: Found 312.0379, calcd for
C13H8F3ClN4 312.0390; Anal. (C13H8F3ClN4) C, H, N.
6-Chloro-7-(4-trifluoromethylphenylmethyl)-7H-pu-
rine (4k). EtOAc was used as eluent for flash chromatography;
yield 266 mg (17%), mp 135-136 °C, colorless crystals. 1H
NMR (CDCl3, 200 MHz) δ 5.75 (s, 2H, CH2), 7.24 (d, J ) 8.2
Hz, 2H, Ar), 7.63 (d, J ) 8.2 Hz, 2H, Ar), 8.27 (s, 1H, H-8),
8.89 (s, 1H, H-2); HRMS: Found 312.0383, calcd for C13H8F3-
ClN4 312.0390; Anal. (C13H8F3ClN4) C, H, N.
6-Chloro-9-(4-nitrophenylmethyl)-9H-purine
(3l).
EtOAc-hexane (1:1) and then EtOAc-hexane (2:1) were used
as eluents for flash chromatography; yield 538 mg (37%), mp
181-183 °C, yellow powdery crystals (lit.21 180 °C). H NMR
1
(CDCl3, 200 MHz) δ 5.56 (s, 2H, CH2), 7.46 (d, J ) 8.7 Hz, 2H,
Ar), 8.15 (s, 1H, H-8), 8.21 (d, J ) 8.7 Hz, 2H, Ar), 8.76 (s, 1H,
H-2).
6-Chloro-9-(2-chlorophenylmethyl)-9H-purine (3f).
EtOAc-hexane (1:2) was used as eluent for flash chromatog-
raphy; yield 784 mg (56%), mp 134-137 °C, colorless small
needles. 1H NMR (CDCl3, 200 MHz) δ 5.56 (s, 2H, CH2), 7.21-
7.46 (m, 4H, Ar), 8.17 (s, 1H, H-8), 8.76 (s, 1H, H-2); Anal.
(C12H8Cl2N4) C, H, N.
6-Chloro-7-(4-nitrophenylmethyl)-7H-purine (4l). EtOAc
was used as eluent for flash chromatography; yield 64 mg (4%),
1
yellow wax. H NMR (CDCl3, 200 MHz) δ 5.80 (s, 2H, CH2),
7.28 (d, J ) 8.8 Hz, 2H, Ar), 8.24 (d, J ) 8.8 Hz, 2H, Ar), 8.32
(s, 1H, H-8), 8.92 (s, 1H, H-2); NMR data were in good
agreement with those reported before.21
6-Chloro-7-(2-chlorophenylmethyl)-7H-purine (4f).
EtOAc was used as eluent for flash chromatography; yield 227
1
mg (16%), mp 186-187 °C, colorless small needles. H NMR
(CDCl3, 200 MHz) δ 5.78 (s, 2H, CH2), 6.83 (br d, J ) 7.4 Hz,
1H, Ar), 7.20-7.37 (m, 2H, Ar), 7.46-7.50 (m, 1H, Ar), 8.18
(s, 1H, H-8), 8.90 (s, 1H, H-2); HRMS: Found 278.0133, calcd
for C12H18Cl2N4 278.0126; Anal. (C12H8Cl2N4) C, H, N.
6-Chloro-9-(2,6-dichlorophenylmethyl)-9H-purine (3g).
EtOAc-hexane (1:2) and then EtOAc-hexane (1:1) were used
as eluents for flash chromatography; yield 1.026 g (66%), mp
190-192 °C, colorless needles (lit.19 186-188 °C). 1H NMR
(CDCl3, 200 MHz) δ 5.72 (s, 2H, CH2), 7.28-7.45 (m, 3H, Ar),
7.92 (s, 1H, H-8), 8.79 (s, 1H, H-2).
6-Chloro-9-(4-methylsulfonylphenylmethyl)-9H-
purine (3m). EtOAc was used as eluent for flash chromatog-
raphy; yield 937 mg (58%), mp 211-212 °C, off-white crystals.
1H NMR (CDCl3, 200 MHz) δ 3.00 (s, 3H, CH3), 5.54 (s, 2H,
CH2), 7.34 (d, J ) 8.2 Hz, 2H, Ar), 7.97 (d, J ) 8.2 Hz, 2H,
Ar), 8.15 (s, 1H, H-8), 8.76 (s, 1H, H-2); HRMS: Found
322.0282, calcd for C13H11ClN4O2S 322.0291; Anal. (C13H11-
ClN4O2S) C, H, N.
6-Chloro-7-(4-methylsulfonylphenylmethyl)-7H-
purine (4m). EtOAc was used as eluent for flash chromatog-
raphy; yield 249 mg (15%), mp 216-219 °C, off-white crystals.
1H NMR (CDCl3, 200 MHz) δ 3.07 (s, 3H, CH3), 5.82 (s, 2H,
CH2), 7.48 (d, J ) 8.2 Hz, 2H, Ar), 7.91 (d, J ) 8.2 Hz, 2H,
Ar), 8.36 (s, 1H, H-8), 8.94 (s, 1H, H-2); HRMS: Found
322.0288, calcd for C13H11ClN4O2S 322.0291; Anal. (C13H11-
ClN4O2S) C, H; N: calcd, 17.36; found, 16.88.
6-Chloro-9-(4-fluorophenylmethyl)-9H-purine (3h).
EtOAc-hexane (1:1) was used as eluent for flash chromatog-
raphy; yield 672 mg (51%), mp 129-131 °C, colorless needles
1
(lit.8 118-120 °C). H NMR (CDCl3, 200 MHz) δ 5.41 (s, 2H,
CH2), 7.00-7.08 (m, 2H, Ar), 7.27-7.34 (m, 2H, Ar), 8.07 (s,
1H, H-8), 8.77 (s, 1H, H-2).
6-Chloro-9-(4-methylphenylmethyl)-9H-purine (3n).
EtOAc-hexane (3:4) was used as eluent for flash chromatog-
raphy; yield 648 mg (50%), mp 135-136 °C, colorless small
needles (lit.8 132-134 °C). 1H NMR (CDCl3, 200 MHz) δ 2.32
(s, 3H, CH3), 5.39 (s, 2H, CH2), 7.17 (m, 4H, Ar), 8.05 (s, 1H,
H-8), 8.76 (s, 1H, H-2).
6-Chloro-7-(4-fluorophenylmethyl)-7H-purine (4h).
EtOAc was used as eluent for flash chromatography; yield 205
mg (16%), mp 161-164 °C, colorless needles. 1H NMR (CDCl3,
200 MHz) δ 5.64 (s, 2H, CH2), 7.02-7.20 (m, 4H, Ar), 8.20 (s,
1H, H-8), 8.88 (s, 1H, H-2); HRMS: Found 262.0428, calcd for
C12H8FClN4 262.0422; Anal. (C12H8ClFN4) C, H, N.
6-Chloro-7-(4-methylphenylmethyl)-7H-purine (4n).
EtOAc was used as eluent for flash chromatography; yield 235
mg (18%), mp 154-156 °C, colorless needles (lit.8 148-149 °C).
1H NMR (CDCl3, 200 MHz) δ 2.33 (s, 3H, CH3), 5.62 (s, 2H,
CH2), 7.06 (d, J ) 8.2 Hz, 2H, Ar), 7.18 (d, J ) 8.2 Hz, 2H,
Ar), 8.17 (s, 1H, H-8), 8.87 (s, 1H, H-2); MS EI m/z (rel. %):
260/258 (11/34, M+), 257 (6), 223 (2), 106 (10), 105 (100), 104
(5), 103 (7), 79 (11), 78 (4), 77 (15).
6-Chloro-9-(2-fluorophenylmethyl)-9H-purine
(3i).
EtOAc-hexane (2:3) was used as eluent for flash chromatog-
raphy; yield 800 mg (61%), mp 98-100 °C, colorless crystals
(lit.8 97-99 °C). 1H NMR (CDCl3, 200 MHz) δ 5.48 (s, 2H, CH2),
7.06-7.16 (m, 2H, Ar), 7.29-7.42 (m, 2H, Ar), 8.16 (s, 1H, H-8),
8.76 (s, 1H, H-2).
6-Chloro-7-(2-fluorophenylmethyl)-7H-purine
(4i).
EtOAc was used as eluent for flash chromatography; yield 249
mg (19%), mp 164-165 °C, colorless needles. 1H NMR (CDCl3,
200 MHz) δ 5.71 (s, 2H, CH2), 7.09 (m, 3H, Ar), 7.31-7.34 (m,
1H, Ar), 8.27 (s, 1H, H-8), 8.80 (s, 1H, H-2); HRMS: Found
262.0431, calcd for C12H8ClFN4 262.0422; Anal. (C12H8ClFN4)
C, H, N.
9-(4-tert-Butylphenylmethyl)-6-chloro-9H-purine (3o).
EtOAc-hexane (1:2) and then EtOAc-hexane (1:1) were used
as eluents for flash chromatography; yield 636 mg (42%), off-
1
white wax. H NMR (CDCl3, 200 MHz) δ 1.28 (s, 9H, t-Bu),
5.40 (s, 2H, CH2), 7.23 (d, J ) 8.4 Hz, 2H, Ar), 7.37 (d, J ) 8.4
Hz, 2H, Ar), 8.07 (s, 1H, H-8), 8.77 (s, 1H, H-2); HRMS: Found
300.1137, calcd for C16H17ClN4 300.1142; Anal. (C16H17ClN4)
C, H, N.
6-Chloro-9-(2,6-difluorophenylmethyl)-9H-purine (3j).
EtOAc-hexane (1:1) was used as eluent for flash chromatog-
raphy; yield 875 mg (62%), mp 147-149 °C, colorless powdery
crystals (lit.20 147-148 °C). 1H NMR (CDCl3, 200 MHz) δ 5.58
(s, 2H, CH2), 7.09 (t, J ) 7.6 Hz, 2H, Ar), 7.40 (m, 1H, Ar),
8.20 (s, 1H, H-8), 8.82 (s, 1H, H-2).
7-(4-tert-Butylphenylmethyl)-6-chloro-7H-purine (4o).
EtOAc was used as eluent for flash chromatography; yield 11
1
mg (0.7%), off-white wax. H NMR (CDCl3, 200 MHz) δ 1.27
(s, 9H, t-Bu), 5.63 (s, 2H, CH2), 7.11 (d, J ) 8.2 Hz, 2H, Ar),
7.37 (d, J ) 8.2 Hz, 2H, Ar), 8.07 (s, 1H, H-8), 8.77 (s, 1H,
H-2); HRMS: Found 300.1124, calcd for C16H17ClN4 300.1142.
6-Chloro-9-(4-methoxyphenylmethyl)-9H-purine (3p).
EtOAc-hexane (1:1) was used as eluent for flash chromatog-
raphy; yield 611 mg (44%), mp 127-128 °C, colorless crystals
6-Chloro-7-(2,6-difluorophenylmethyl)-7H-purine (4j).
EtOAc was used as eluent for flash chromatography; yield 139
1
mg (10%), mp 141-144 °C (dec), off-white crystals. H NMR
(CDCl3, 200 MHz) δ 5.77 (s, 2H, CH2), 7.01 (t, J ) 5.8 Hz, 2H,
Ar), 7.39 (m, 1H, Ar), 8.17 (s, 1H, H-8), 8.83 (s, 1H, H-2); Anal.
(C12H7F2ClN4) C, H, N.

2716 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 7
Bakkestuen et al.
1
(lit.8 122-124 °C). H NMR (CDCl3, 200 MHz) δ 3.78 (s, 3H,
matography; yield 338 mg (51%), mp 115-116 °C, colorless
1
CH3), 5.36 (s, 2H, CH2), 6.87 (d, J ) 8.6 Hz, 2H, Ar), 7.26 (d,
J ) 8.6 Hz, 2H, Ar), 8.04 (s, 1H, H-8), 8.77 (s, 1H, H-2).
6-Chloro-7-(4-methoxyphenylmethyl)-7H-purine (4p).
EtOAc was used as eluent for flash chromatography; yield 109
mg (8%), mp 138-140 °C, colorless needles (lit.8 134-136 °C).
1H NMR (CDCl3, 200 MHz) δ 3.79 (s, 3H, CH3), 5.60 (s, 2H,
CH2), 6.89 (d, J ) 8.8 Hz, 2H, Ar), 7.21 (d, J ) 8.8 Hz, 2H,
Ar), 8.16 (s, 1H, H-8), 8.87 (s, 1H, H-2).
6-Chloro-9-(2-methoxyphenylmethyl)-9H-purine (3q).
EtOAc-hexane (2:3) was used as eluent for flash chromatog-
raphy; yield 667 mg (49%), mp 110-112 °C, colorless crystals.
1H NMR (CDCl3, 200 MHz) δ 3.88 (s, 3H, CH3), 5.44 (s, 2H,
CH2), 6.93-7.01 (m, 2H, Ar), 7.30-7.40 (m, 2H, Ar), 8.04 (s,
1H, H-8), 8.77 (s, 1H, H-2); HRMS: Found 274.0620, calcd for
C13H11ClN4O 274.0621. Anal. (C13H11ClN4O) C, H, N.
6-Chloro-7-(2-methoxyphenylmethyl)-7H-purine (4q).
EtOAc was used as eluent for flash chromatography; yield 244
mg (18%), mp 149-151 °C, colorless needles. 1H NMR (CDCl3,
200 MHz) δ 3.75 (s, 3H, CH3), 5.57 (s, 2H, CH2), 6.79-6.86
(m, 2H, Ar), 7.03-7.07 (m, 1H, Ar), 7.21-7.29 (m, 1H, Ar),
8.20 (s, 1H, H-8), 8.76 (s, 1H, H-2); 13C NMR (CDCl3, 50 MHz)
δ 46.1 (CH2), 55.2 (CH3), 110.5 (CH in Ar), 120.6 (CH in Ar),
122.4 (C-5 and C in Ar), 129.2 (CH in Ar), 130.3 (CH in Ar),
142.7 (C-6), 149.5 (C-2/C-8), 151.6 (C-2/C-8), 156.8 (C in Ar),
161.6 (C-4); MS EI m/z (rel. %): 276/274 (29/76, M+), 245 (7),
243 (24), 122 (11), 121 (100), 91 (74), 78 (10), 65 (11); HRMS:
Found 274.0616, calcd for C13H11ClN4O 274.0621. Anal. (C13H11-
ClN4O) C, H; N: calcd, 20.40; found, 19.83.
needles. H NMR (CDCl3, 200 MHz) 5.45 (s, 2H, CH2), 7.18-
7.27 (m, 2H, Ar), 7.33-7.37 (m, 2H, Ar), 8.10 (s, 1H, H-8), 8.77
(s, 1H, H-2); HRMS: Found 328.0330, calcd for C13H18ClF3N4O
328.0339; Anal. (C13H18ClF3N4O) C, H, N.
6-Chloro-7-(4-trifluoromethoxyphenylmethyl)-7H-
purine (4u). The reaction was performed in 2.0 mmol scale,
and EtOAc was used as eluent for flash chromatography; yield
139 mg (21%), mp 111-114 °C, colorless waxy solid. 1H NMR
(CDCl3, 200 MHz) 5.68 (s, 2H, CH2), 7.21 (m, 4H, Ar), 8.24 (s,
1H, H-8), 8.89 (s, 1H, H-2); HRMS: Found 328.0335, calcd for
C13H18ClF3N4O 328.0339; Anal. (C13H18ClF3N4O) C, H, N.
6-Chloro-9-(3-trifluoromethoxyphenylmethyl)-9H-
purine (3v). The reaction was performed in 2.2 mmol scale,
and acetone-hexane (2:5) was used as eluent for flash chro-
matography; yield 343 mg (47%), colorless oil. 1H NMR (CDCl3,
200 MHz) 5.46 (s, 2H, CH2), 7.18-7.25 (m, 3H, Ar), 7.35-7.43
(m, 1H, Ar), 8.11 (s, 1H, H-8), 8.77 (s, 1H, H-2); HRMS: Found
328.0335, calcd for C13H18ClF3N4O 328.0339.
6-Chloro-9-(4-ethoxyphenylmethyl)-9H-purine (3w).
EtOAc-hexane (1:1) was used as eluent for flash chromatog-
raphy; yield 606 mg (42%), mp 110-112 °C, colorless crystals.
1H NMR (CDCl3, 200 MHz) δ 1.38 (t, J ) 7.2 Hz, 3H, CH3),
3.99 (q, J ) 7.2 Hz, 2H, OCH2), 5.35 (s, 2H, CH2), 6.85 (d, J )
8.8 Hz, 2H, Ar), 7.25 (d, J ) 8.8 Hz, 2H, Ar), 8.04 (s, 1H, H-8),
8.76 (s, 1H, H-2); HRMS: Found 288.0777, calcd for C14H13-
ClN4O 288.0778; Anal. (C14H13ClN4O) C, H; N: calcd, 19.41;
found, 18.95.
6-Chloro-7-(4-ethoxyphenylmethyl)-7H-purine (4w).
EtOAc was used as eluent for flash chromatography; yield 64
mg (4%), mp 169-171 °C, colorless crystals. 1H NMR (CDCl3,
200 MHz) δ 1.39 (t, J ) 7.0 Hz, 3H, CH3), 4.01 (q, J ) 7.0 Hz,
2H, OCH2), 5.59 (s, 2H, CH2), 6.88 (d, J ) 8.8 Hz, 2H, Ar),
7.13 (d, J ) 8.8 Hz, 2H, Ar), 8.15 (s, 1H, H-8), 8.87 (s, 1H,
H-2); HRMS: Found 288.0769, calcd for C14H13ClN4O 288.0778;
Anal. (C14H13ClN4O) C, H, N.
9-(4-Benzyloxyphenylmethyl)-6-chloro-9H-purine (3x).
EtOAc-hexane (2:1) was used as eluent for flash chromatog-
raphy; yield 1.140 g (65%), mp 127-128 °C, colorless crystals
(lit.8 121-125 °C). 1H NMR (CDCl3, 300 MHz): δ 4.90 (s, 2H,
CH2), 5.22 (s, 2H, CH2), 6.79-7.51 (m, 9H, Ar), 7.91 (s, 1H,
H-8), 8.63 (s, 1H, H-2).
6-Chloro-9-(3-methoxyphenylmethyl)-9H-purine (3r).
EtOAc-hexane (1:1) was used as eluent for flash chromatog-
raphy; yield 793 mg (58%), mp 104-105 °C, colorless crystals
1
(lit.8 103-104 °C). H NMR (CDCl3, 200 MHz) δ 3.76 (s, 3H,
CH3), 5.40 (s, 2H, CH2), 6.83-6-87 (m, 3H, Ar), 7.23-7.31
(m, 1H, Ar), 8.07 (s, 1H, H-8), 8.76 (s, 1H, H-2).
6-Chloro-7-(3-methoxyphenylmethyl)-7H-purine (4r).
EtOAc was used as eluent for flash chromatography; yield 299
mg (22%), mp 160-162 °C, colorless crystals. 1H NMR (CDCl3,
200 MHz) δ 3.76 (s, 3H, CH3), 5.63 (s, 2H, CH2), 6.69-6-74
(m, 2H, Ar), 6.85-6.89 (m, 1H, Ar), 7.24-7.32 (m, 1H, Ar),
8.20 (s, 1H, H-8), 8.88 (s, 1H, H-2); HRMS: Found 274.0616,
calcd for C13H11ClN4O 274.0621. Anal. (C13H11ClN4O) C, H;
N: calcd, 20.40; found, 19.92.
7-(4-Benzyloxyphenylmethyl)-6-chloro-7H-purine (4x).
EtOAc-hexane (2:1) was used as eluent for flash chromatog-
raphy; yield 360 mg (20%), mp 142-143 °C, colorless crystals.
1H NMR (CDCl3, 300 MHz): δ 5.04 (s, 2H, CH2), 5.59 (s, 2H,
CH2), 6.95-7.58 (m, 9H, Ar), 8.03 (s, 1H, H-8), 8.86 (s, 1H,
H-2); 13C NMR (CDCl3, 50 MHz): δ 50.3 (CH2), 70.0 (OCH2),
115.6 (CH in Ar), 126.4 (C in Ar), 127.4 (CH in Ar), 128.1 (CH
in Ar), 128.6 (CH in Ar), 128.8 (CH in Ar), 132.4 (C-5), 136.3
(C in Ar), 143.7 (C-8), 148.1 (C-6), 148.8 (C-4), 152.5 (C-2),
159.1 (C in Ar); MS EI m/z (rel. %): 352/350 (9/28, M+), 243
(5), 91 (100), 65 (6); HRMS: Found 350.0936, calcd for
C19H15N4OCl 350.0934; Anal. (C19H15N4OCl) C, H, N.
9-(4-Acetoxyphenylmethyl)-6-chloro-9H-purine (3y).
The reaction was performed in 2.5 mmol scale, and EtOAc-
hexane (1:1) was used as eluent for flash chromatography;
yield 387 mg (51%), mp 120-122 °C, colorless crystals. 1H
NMR (CDCl3, 200 MHz) δ 2.27 (s, 3H, CH3), 5.43 (s, 2H, CH2),
7.08 (d, J ) 8.6 Hz, 2H, Ar), 7.23 (d, J ) 8.6 Hz, 2H, Ar), 8.09
(s, 1H, H-8), 8.77 (s, 1H, H-2); HRMS: Found 302.0575, calcd
for C14H11ClN4O2 302.0571; Anal. (C14H11ClN4O2) C, H, N.
7-(4-Acetoxyphenylmethyl)-6-chloro-7H-purine (4y).
The reaction was performed in 2.5 mmol scale, and EtOAc was
used as eluent for flash chromatography; yield 222 mg (29%),
mp 155-157 °C, colorless crystals. 1H NMR (CDCl3, 200 MHz)
δ 2.28 (s, 3H, CH3), 5.66 (s, 2H, CH2), 7.10 (d, J ) 8.6 Hz, 2H,
Ar), 7.22 (d, J ) 8.6 Hz, 2H, Ar), 8.22 (s, 1H, H-8), 8.88 (s, 1H,
H-2); HRMS: Found 302.0580, calcd for C14H11ClN4O2 302.0571;
Anal. (C14H11ClN4O2) C, H, N.
6-Chloro-9-(4-methoxy-3-methylphenylmethyl)-9H-pu-
rine (3s). EtOAc-hexane (1:1) was used as eluent for flash
1
chromatography; yield 505 mg (35%), colorless wax. H NMR
(CDCl3, 200 MHz) δ 2.16 (s, 3H, CH3), 3.80 (s, 3H, OCH3), 5.33
(s, 2H, CH2), 6.77 (d, J ) 8.0 Hz, 1H, Ar), 7.08-7.14 (m, 2H,
Ar), 8.04 (s, 1H, H-8), 8.77 (s, 1H, H-2); HRMS: Found
288.0769, calcd for C14H13ClN4O 288.0778. Anal. (C14H13ClN4O)
C, H; N: calcd, 19.41; found, 18.94.
6-Chloro-7-(4-methoxy-3-methylphenylmethyl)-7H-pu-
rine (4s). EtOAc was used as eluent for flash chromatography;
yield 14 mg (1%), colorless wax. 1H NMR (CDCl3, 200 MHz) δ
2.16 (s, 3H, CH3), 3.80 (s, 3H, OCH3), 5.56 (s, 2H, CH2), 6.78
(d, J ) 8.0 Hz, 1H, Ar), 6.98-7.02 (m, 2H, Ar), 8.16 (s, 1H,
H-8), 8.85 (s, 1H, H-2).
6-Chloro-9-(3,4,5-trimethoxyphenylmethyl)-9H-
purine (3t). EtOAc-hexane (2:1) was used as eluent for flash
chromatography; yield 850 mg (51%), mp 115-116 °C, colorless
crystals. 1H NMR (CDCl3, 300 MHz) δ 3.75 (s, 9H, 3 × OCH3),
5.31 (s, 2H, CH2), 6.49 (s, 2H, Ar), 8.07 (s, 1H, H-8), 8.72 (s,
1H, H-2); HRMS: Found 334.0835, calcd for C15H15N4O3Cl
334.0832; Anal. (C15H15N4O3Cl) C, H, N.
6-Chloro-7-(3,4,5-trimethoxyphenylmethyl)-7H-
purine (4t). EtOAc-hexane (2:1) was used as eluent for flash
chromatography; yield 332 mg (20%), mp 121-122 °C, colorless
crystals. 1H NMR (CDCl3, 300 MHz) δ 3.73 (s, 6H, 2 × OCH3),
3.77 (s, 3H, OCH3), 5.55 (s, 2H, CH2), 6.38 (s, 2H, Ar), 8.09 (s,
1H, H-8), 8.71 (s, 1H, H-2); HRMS: Found 334.0836, calcd for
C15H15N4O3Cl 334.0832; Anal. (C15H15N4O3Cl) C, H, N.
6-Chloro-9-(4-trifluoromethoxyphenylmethyl)-9H-
purine (3u). The reaction was performed in 2.0 mmol scale,
and EtOAc-hexane (2:3) was used as eluent for flash chro-
6-Chloro-9-(4-methylthiophenylmethyl)-9H-purine
(3aa). The reaction was performed in 2.5 mmol scale, and
EtOAc-hexane (1:1) was used as eluent for flash chromatog-
raphy; yield 346 mg (49%), mp 95-97 °C, colorless needles.

Antimycobacterial 9-Aryl-6-(2-furyl)purines
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 7 2717
1H NMR (CDCl3, 200 MHz) δ 2.45 (s, 3H, CH3), 5.39 (s, 2H,
CH2), 7.22 (s, 4H, Ar), 8.07 (s, 1H, H-8), 8.77 (s, 1H, H-2);
HRMS: Found 290.0400, calcd for C13H11ClN4S 290.0393;
Anal. (C13H11ClN4S) C, H, N.
7-(3-Chlorophenylmethyl)-2,6-dichloro-7H-purine (6d).
EtOAc was used as eluent for flash chromatography; yield 221
mg (14%), mp 129-131 °C, colorless crystals. 1H NMR (CDCl3,
200 MHz) δ 5.61 (s, 2H, CH2), 6.99 (br s, 1H, Ar), 7.12 (br s,
1H, Ar), 7.22-7.32 (m, 2H, Ar), 8.24 (s, 1H, H-8); HRMS:
Found 311.9754, calcd for C12H7Cl3N4 311.9736; Anal. (C12H7-
Cl3N4) C, H, N.
2,6-Dichloro-9-(4-fluorophenylmethyl)-9H-purine (5e).
EtOAc-hexane (1:3) was used as eluent for flash chromatog-
raphy; yield 817 mg (55%), mp 120-122 °C, colorless crystals.
1H NMR (CDCl3, 200 MHz) δ 5.36 (s, 2H, CH2), 7.01-7.10 (m,
2H, Ar), 7.27-7.34 (m, 2H, Ar), 8.02 (s, 1H, H-8); HRMS:
Found 296.0019, calcd for C12H7Cl2FN4 296.0032; Anal. (C12H7-
Cl2FN4) C, H, N.
2,6-Dichloro-7-(4-fluorophenylmethyl)-7H-purine (6e).
EtOAc was used as eluent for flash chromatography; yield 319
mg (21%), mp 164-166 °C, colorless needles. 1H NMR (CDCl3,
200 MHz) δ 5.61 (s, 2H, CH2), 7.08-7.24 (m, 4H, Ar), 8.20 (s,
1H, H-8); HRMS: Found 296.0034, calcd for C12H7Cl2FN4
296.0032; Anal. (C12H7Cl2FN4) C, H, N.
2,6-Dichloro-9-(4-methylphenylmethyl)-9H-purine (5f).
EtOAc-hexane (1:2) was used as eluent for flash chromatog-
raphy; yield 772 mg (53%), mp 138-141 °C colorless micro-
crystalline solid (lit.9 147-148 °C). 1H NMR (CDCl3, 200 MHz)
δ 2.33 (s, 3H, CH3), 5.34 (s, 2H, CH2), 7.18 (m, 4H, Ar), 8.00
(s, 1H, H-8).
6-Chloro-7-(4-methylthiophenylmethyl)-7H-purine
(4aa). The reaction was performed in 2.5 mmol scale, and
EtOAc was used as eluent for flash chromatography; yield 96
1
mg (13%), mp 150-152 °C, colorless small needles. H NMR
(CDCl3, 200 MHz) δ 2.44 (s, 3H, CH3), 5.61 (s, 2H, CH2), 7.08
(d, J ) 6.8 Hz, 2H, Ar), 7.22 (d, J ) 6.8 Hz, 2H, Ar), 8.20 (s,
1H, H-8), 8.86 (s, 1H, H-2); HRMS: Found 290.0390, calcd for
C13H11ClN4S 290.0393; Anal. (C13H11ClN4S) C, H, N.
9-(4-Acetamidophenylmethyl)-6-chloro-9H-purine
(3cc). The reaction was performed in 2.3 mmol scale, and
acetone-hexane (2:3) was used as eluent for flash chroma-
tography; yield 431 mg (62%), mp 240-242 °C, colorless small
1
needles. H NMR (CDCl3, 200 MHz) δ 2.15 (s, 3H, CH3), 5.39
(s, 2H, CH2), 7.19 (br s, 1H, NH), 7.28 (d, J ) 8.0 Hz, 2H, Ar),
7.50 (d, J ) 8.0 Hz, 2H, Ar), 8.06 (s, 1H, H-8), 8.76 (s, 1H,
H-2); HRMS: Found 301.0724, calcd for C14H12ClN5O 301.0730;
Anal. (C14H12ClN5O) C, H.
6-Chloro-9-(diphenylmethyl)-9H-purine (3ee). EtOAc-
hexane (1:2) was used as eluent for flash chromatography;
yield 337 mg (21%), mp 173-175 °C, colorless crystals (lit.22
161-162 °C). 1H NMR (CDCl3, 200 MHz) δ 7.11-7.17 (s, 5H,
Ar/CH), 7.33-7.40 (m, 6H, Ar/CH), 7.92 (s, 1H, H-8), 8.71 (s,
1H, H-2).
6-Chloro-7-(diphenylmethyl)-7H-purine (4ee). EtOAc
was used as eluent for flash chromatography; yield 132 mg
(8%), pale yellow oil. 1H NMR (CDCl3, 200 MHz) δ 7.07-7.08
(s, 4H, Ar/CH), 7.36-7.39 (m, 7H, Ar/CH), 7.92 (s, 1H, H-8),
8.84 (s, 1H, H-2); HRMS: Found 320.0838, calcd for C18H13-
ClN4 320.0829.
9-(4-Chlorophenylmethyl)-2,6-dichloro-9H-purine (5b).
EtOAc-hexane (2:3) was used as eluent for flash chromatog-
raphy; yield 856 mg (55%), mp 162-164 °C, colorless small
needles (lit.9 158-160 °C). 1H NMR (CDCl3, 200 MHz) δ 5.36
(s, 2H, CH2), 7.21-7.26 (m, 2H, Ar), 7.33-7.37 (m, 2H, Ar),
8.04 (s, 1H, H-8).
7-(4-Chlorophenylmethyl)-2,6-dichloro-7H-purine (6b).
EtOAc was used as eluent for flash chromatography; yield 295
mg (19%), mp 180-182 °C, colorless crystals. 1H NMR (CDCl3,
200 MHz) δ 5.61 (s, 2H, CH2), 7.08 (d, J ) 8.2 Hz, 2H, Ar),
7.35 (d, J ) 8.2 Hz, 2H, Ar), 8.22 (s, 1H, H-8); HRMS: Found
311.9746, calcd for C12H7Cl3N4 311.9736; Anal.(C12H7Cl3N4):
C, H, N.
2,6-Dichloro-9-(3,4-dichlorophenylmethyl)-9H-
purine (5c). EtOAc-hexane (1:2) and then EtOAc-hexane
(1:1) were used as eluents for flash chromatography; yield 962
mg (56%), mp 175-177 °C, colorless crystals. 1H NMR (CDCl3,
200 MHz) δ 5.35 (s, 2H, CH2), 7.14 (dd, J ) 8.2 and 2.2 Hz,
1H, Ar), 7.39 (d, J ) 2.2 Hz, 1H, Ar), 7.44 (d, J ) 8.2 Hz, 1H,
Ar), 8.06 (s, 1H, H-8); HRMS: Found 345.9351, calcd for C12H6-
Cl4N4 345.9347; Anal. (C12H6Cl4N4) C, N; H: calcd, 1.16; found,
1.81.
2,6-Dichloro-7-(3,4-dichlorophenylmethyl)-7H-
purine (6c). EtOAc was used as eluent for flash chromatog-
raphy; yield 295 g (17%), mp 178-179 °C, colorless crystals.
1H NMR (CDCl3, 200 MHz) δ 5.73 (s, 2H, CH2), 7.18 (br d, J
) 8.4 Hz, 1H, Ar), 7.51-7.61 (m, 2H, Ar), 9.01 (s, 1H, H-8);
HRMS: Found 345.9352, calcd for C12H6Cl4N4 345.9347; Anal.
(C12H6Cl4N4) C, H, N.
2,6-Dichloro-7-(4-methylphenylmethyl)-7H-purine (6f).
EtOAc was used as eluent for flash chromatography; yield 329
1
mg (23%), mp 175-176 °C, colorless small needles. H NMR
(CDCl3, 200 MHz) δ 2.34 (s, 3H, CH3), 5.59 (s, 2H, CH2), 7.05
(d, J ) 7.8 Hz, 2H, Ar), 7.22 (d, J ) 7.8 Hz, 2H, Ar), 8.17 (s,
1H, H-8); HRMS: Found 292.0273, calcd for C13H10Cl2N4
292.0283; Anal. (C13H10Cl2N4) C, H, N.
2,6-Dichloro-9-(4-methoxyphenylmethyl)-9H-purine (5g).
EtOAc-hexane (2:3) was used as eluent for flash chromatog-
raphy; yield 837 mg (54%), mp 128-130 °C, colorless crystals
1
(lit.9 132-134 °C). H NMR (CDCl3, 200 MHz) δ 3.79 (s, 3H,
CH3), 5.32 (s, 2H, CH2), 6.88 (d, J ) 8.2 Hz, 2H, Ar), 7.26 (d,
J ) 8.2 Hz, 2H, Ar), 7.99 (s, 1H, H-8).
2,6-Dichloro-7-(4-methoxyphenylmethyl)-7H-purine (6g).
EtOAc was used as eluent for flash chromatography; yield 330
mg (21%), mp 146-148 °C, colorless crystals. 1H NMR (CDCl3,
200 MHz) δ 3.79 (s, 3H, CH3), 5.56 (s, 2H, CH2), 6.89 (d, J )
8.6 Hz, 2H, Ar), 7.13 (d, J ) 8.8 Hz, 2H, Ar), 8.16 (s, 1H, H-8);
HRMS: Found 308.0246, calcd for C13H10Cl2N4O 308.0232;
Anal. (C13H10Cl2N4) C, H, N.
2,6-Dichloro-9-(2-methoxyphenylmethyl)-9H-purine (5h).
EtOAc-hexane (2:3) was used as eluent for flash chromatog-
raphy; yield 763 mg (49%), mp 156-157 °C, colorless crystals.
1H NMR (CDCl3, 200 MHz) δ 3.84 (s, 3H, CH3), 5.36 (s, 2H,
CH2), 6.87-6.98 (m, 2H, Ar), 7.29-7.38 (m, 2H, Ar), 8.12 (s,
1H, H-8); HRMS: Found 308.0246, calcd for C13H10Cl2N4O
308.0232; Anal. (C13H10Cl2N4O) C, H, N.
2,6-Dichloro-7-(2-methoxyphenylmethyl)-7H-purine (6h).
EtOAc-hexane (1:1) was used as eluent for flash chromatog-
raphy; yield 326 mg (21%), mp 145-147 °C, colorless needles.
1H NMR (CDCl3, 200 MHz) δ 3.83 (s, 3H, CH3), 5.60 (s, 2H,
CH2), 6.90-6.99 (m, 2H, Ar), 7.17 (br d, J ) 7.4 Hz, 1H, Ar),
7.36 (td, J ) 8.4 and 1.8 Hz, 1H, Ar), 8.21 (s, 1H, H-8);
HRMS: Found 308.0245, calcd for C13H10Cl2N4O 308.0232;
Anal. (C13H10Cl2N4O) C, H, N.
2,6-Dichloro-9-(3-methoxyphenylmethyl)-9H-purine (5i).
EtOAc-hexane (1:2) was used as eluent for flash chromatog-
raphy; yield 835 mg (54%), mp 119-121 °C, colorless small
needles.1H NMR (CDCl3, 200 MHz) δ 3.79 (s, 3H, CH3), 5.35
(s, 2H, CH2), 6.83-6.89 (m, 3H, Ar), 7.28 (t, J ) 8.2 Hz, 1H,
Ar), 8.02 (H-8); HRMS: Found 308.0238, calcd for C13H10-
Cl2N4O 308.0232; Anal. (C13H10Cl2N4O) C, H, N.
2,6-Dichloro-7-(3-methoxyphenylmethyl)-7H-purine (6i).
EtOAc was used as eluent for flash chromatography; yield 377
mg (24%), mp 106-108 °C, off-white small needles.1H NMR
(CDCl3, 200 MHz) δ 3.72 (s, 3H, CH3), 5.60 (s, 2H, CH2), 6.64-
6.69 (m, 2H, Ar), 6.81-6.87 (m, 1H, Ar), 7.20-7.28 (m, 1H,
9-(3-Chlorophenylmethyl)-2,6-dichloro-9H-purine (5d).
EtOAc-hexane (1:3) was used as eluent for flash chromatog-
raphy; yield 871 mg (56%), mp 122-125 °C, colorless crystals.
1H NMR (CDCl3, 200 MHz) δ 5.36 (s, 2H, CH2), 7.18-7.32 (m,
4H, Ar), 8.05 (s, 1H, H-8); 13C NMR (CDCl3, 50 MHz) δ 47.3
(CH2), 126.0 (CH in Ar), 128.0 (CH in Ar), 129.2 (CH in Ar),
130.2 (C-5), 130.6 (CH in Ar), 135.2 (C in Ar), 135.9 (C in Ar),
145.2 (C-8), 151.9 (C-2/C-4/C-6), 153.0 (C-2/C-4/C-6), 153.2 (C-
2/C-4/C-6); MS EI m/z (rel. %): 316/314/312 (12/39/41, M+),
279 (11), 277 (18), 201 (6), 127 (31), 125 (100), 99 (7), 89 (21);
HRMS: Found 311.9737, calcd for C12H7Cl3N4 311.9736; Anal.
(C12H7Cl3N4) C, H, N.

2718 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 7
Bakkestuen et al.
Ar), 8.24 (s, 1H, H-8); HRMS: Found 308.0243, calcd for
C13H10Cl2N4O 308.0232; Anal. (C13H10Cl2N4O) C, H, N.
2,6-Dichloro-9-(4-methoxy-3-methylphenylmethyl)-9H-
purine (5j). EtOAc-hexane (1:2) was used as eluent for flash
chromatography; yield 625 mg (39%), mp 134-135 °C, colorless
powdery crystals.1H NMR (CDCl3, 200 MHz) δ 2.18 (s, 3H,
CH3), 3.81 (s, 3H, OCH3), 5.28 (s, 2H, CH2), 6.79 (d, J ) 8.2
Hz, 1H, Ar), 7.08-7.16 (m, 2H, Ar), 7.99 (s, 1H, H-8); HRMS:
Found 322.0382, calcd for C14H12Cl2N4O 322.0388; Anal.
(C14H12Cl2N4O) C, H, N.
5.43 (s, 2H, CH2), 6.66 (dd, J ) 3.4 and 1.6 Hz, 1H, H-4 in
furyl), 7.19 (m, 1H, Ar), 7.28-7.30 (m, 3H, Ar), 7.75 (m, 1H,
H-5 in furyl), 7.83 (br d, J ) 3.4, 1H, H-3 in furyl), 8.07 (s,
1H, H-8), 8.97 (s, 1H, H-2); HRMS: Found 310.0616, calcd for
C16H11ClN4O 310.06.21; Anal. (C16H10Cl2N4O) C, H, N.
9-(2,4-Dichlorophenylmethyl)-6-(2-furyl)-9H-purine (7e).
EtOAc-hexane (1:1) was used as eluent for flash chromatog-
raphy; yield 262 mg (76%), mp 178-180 °C, colorless crystals.
1H NMR (CDCl3, 200 MHz) δ 5.52 (s, 2H, CH2), 6.65 (dd, J )
3.4 and 1.6 Hz, 1H, H-4 in furyl), 7.22-7.28 (m, 2H, Ar), 7.44
(d, J ) 1.6 Hz, 1H, Ar), 7.75 (m, 1H, H-5 in furyl), 7.82 (br d,
J ) 3.4, 1H, H-3 in furyl), 8.15 (s, 1H, H-8), 8.94 (s, 1H, H-2);
HRMS: Found 344.0217, calcd for C16H10Cl2N4O 344.0232;
Anal. (C16H11Cl2N4O) C, H, N.
2,6-Dichloro-7-(4-methoxy-3-methylphenylmethyl)-7H-
purine (6j). EtOAc was used as eluent for flash chromatog-
raphy; yield 227 mg (14%), mp 153-155 °C, colorless small
1
needles. H NMR (CDCl3, 200 MHz) δ 2.17 (s, 3H, CH3), 3.81
9-(2-Chlorophenylmethyl)-6-(2-furyl)-9H-purine (7f).
13C NMR (CDCl3, 50 MHz) δ 44.8 (CH2), 112.5 (C-4 in furyl),
117.2 (C-3 in furyl), 127.3 (CH in Ar), 127.9 (C-5), 129.8 (CH
in Ar), 129.9 (CH in Ar), 130.1 (CH in Ar), 132.5 (C in Ar),
133.3 (C in Ar), 144.3 (C-8), 145.7 (C-5 in furyl), 145.8 (C-6),
149.5 (C-2 in furyl), 151.9 (C-4), 152.6 (C-2); MS EI m/z (rel.
%): 312/310 (5/14, M+), 276 (35), 275 (100), 246 (2), 220 (2),
138 (8), 127 (10), 125 (30), 99 (3), 89 (9).
(s, 3H, OCH3), 5.53 (s, 2H, CH2), 6.79 (d, J ) 8.0 Hz, 1H, Ar),
6.97-7.02 (m, 2H, Ar), 8.14 (s, 1H, H-8); HRMS: Found
322.0386, calcd for C14H12Cl2N4O 322.0388; Anal. (C14H12-
Cl2N4O) C, H, N.
6-Chloro-9-(4-dimethylaminophenylmethyl)-9H-
purine (3bb). Ethanesulfonic acid (0.010 mL, 0.12 mmol) was
added to a stirred suspension of 5-amino-4-chloro-6-(4-di-
methylaminyphenyl)pyrimidine 13 (316 mg, 1.14 mmol) in
triethyl orthoformate (15 mL). The resulting mixture was
stirred for 3 days and evaporated in vacuo. The residue was
dissolved in dichloromethane (50 mL) and washed with
saturated aqueous NaHCO3 (10 mL) and brine (2 × 10 mL),
dried (MgSO4) end evaporated in vacuo. The crude product was
purified by flash chromatography on silica gel eluting with
acetone-hexane (2:5); yield 215 mg (66%), mp 125-127 °C,
9-(2,6-Dichlorophenylmethyl)-6-(2-furyl)-9H-purine (7g).
EtOAc-hexane (1:1) and then EtOAc-hexane (2:1) were used
as eluents for flash chromatography; yield 185 mg (54%), mp
1
203-205 °C, colorless crystals. H NMR (CDCl3, 200 MHz) δ
5.73 (s, 2H, CH2), 6.64 (dd, J ) 3.4 and 1.6 Hz, 1H, H-4 in
furyl), 7.24-7.45 (m, 3H, Ar), 7.74 (m, 1H, H-5 in furyl), 7.81
(br d, J ) 3.4 Hz, 1H, H-3 in furyl), 7.88 (s, 1H, H-8), 8.99 (s,
1H, H-2); HRMS: Found 344.0227, calcd for C16H10Cl2N4O
344.0232; Anal. (C16H10Cl2N4O) C, H, N.
1
colorless crystals. H NMR (CDCl3, 200 MHz) δ 2.94 (s, 6H,
CH3), 5.32 (s, 2H, CH2), 6.68 (d, J ) 8.6 Hz, 2H, Ar), 7.22 (d,
J ) 8.6 Hz, 2H, Ar), 8.04 (s, 1H, H-8), 8.77 (s, 1H, H-2);
HRMS: Found 287.0932, calcd for C14H14ClN5 287.0938.
Stille coupling between 9-benzyl-6-chloropurines 3
and 2-furyl(tributyl)tin. A mixture of 9-substituted 6-chlo-
ropurine 3 (1.0 mmol), bis(triphenylphosphine)palladium(II)
chloride (35 mg, 0.05 mmol) and 2-furyl(tributyl)tin (0.47 mL,
1.4 mmol) in DMF (5 mL) was stirred at 90 °C under N2 atm.
for 18 h and evaporated in vacuo. A sat. solution of potassium
fluoride in methanol was added to the residue and the mixture
was stirred overnight and evaporated in vacuo together with
a small amount of silica gel. The residue was added on top of
a chromatography column, and the product was isolated by
flash chromatography on silica.
9-(4-Fluorophenylmethyl)-6-(2-furyl)-9H-purine (7h).
EtOAc-hexane (2:1) was used as eluent for flash chromatog-
raphy; yield 269 mg (91%), mp 162-164 °C, colorless crystals.
1H NMR (CDCl3, 200 MHz) δ 5.42 (s, 2H, CH2), 6.64 (dd, J )
3.4 and 1.8 Hz, 1H, H-4 in furyl), 7.03-7.12 (m, 2H, Ar), 7.32-
7.38 (m, 2H, Ar), 7.75 (m, 1H, H-5 in furyl), 7.82 (dd, J ) 3.4
and 0.6 Hz, 1H, H-3 in furyl), 8.13 (s, 1H, H-8), 8.98 (s, 1 H,
H-2); HRMS: Found 294.0889, calcd for C16H11FN4O 294.0917;
Anal. (C16H11FN4O) C, H, N.
9-(2-Fluorophenylmethyl)-6-(2-furyl)-9H-purine-9H-
purine (7i). EtOAc-hexane (3:2) was used as eluent for flash
chromatography; yield 260 mg (88%), mp 177-179 °C, colorless
1
needles. H NMR (CDCl3, 200 MHz) δ 5.55 (s, 2H, CH2), 6.69
(dd, J ) 3.4 and 1.6 Hz, 1H, H-4 in furyl), 7.11-7.16 (m, 2H,
Ar), 7.32-7.45 (m, 2H, Ar), 7.79 (m, 1H, H-5 in furyl), 7.87
(br d, J ) 3.4 Hz, 1H, H-3 in furyl), 8.19 (s, 1H, H-8), 9.01 (s,
1 H, H-2); HRMS: Found 294.0916, calcd for C16H11FN4O
294.0917; Anal. (C16H11FN4O) C, H, N.
9-(2,6-Difluorophenylmethyl)-6-(2-furyl)-9H-purine (7j).
EtOAc-hexane (1:1) was used as eluent for flash chromatog-
raphy; yield 131 mg (84%), mp 209-211 °C, colorless needles.
1H NMR (CDCl3, 200 MHz) δ 5.54 (s, 2H, CH2), 6.64 (dd, J )
3.4 and 1.6 Hz, 1H, H-4 in furyl), 6.92 (t, J ) 7.6 Hz, 2H, Ar),
7.34 (m, 1H, Ar), 7.74 (m, 1H, H-5 in furyl), 7.81 (br d, J ) 3.4
Hz, 1H, H-3 in furyl), 8.13 (s, 1H, H-8), 8.98 (s, 1 H, H-2);
HRMS: Found 312.0819, calcd for C16H10F2N4O 312.0823;
Anal. (C16H10F2N4O) C, H, N.
9-(4-Chlorophenylmethyl)-6-(2-furyl)-9H-purine (7b).
EtOAc-hexane (1:1) and then EtOAc-hexane (2:1) were used
as eluents for flash chromatography; yield 239 mg (77%), mp
1
156-159 °C, colorless crystals. H NMR (CDCl3, 200 MHz) δ
5.42 (s, 2H, CH2), 6.65 (dd, J ) 3.6 and 1.8 Hz, 1H, H-4 in
furyl), 7.23 (d, J ) 8.6 Hz, 2H, Ar), 7.32 (d, J ) 8.6 Hz, 2H,
Ar), 7.75 (br d, J ) 1.8 Hz, 1H, H-5 in furyl), 7.83 (br d, J )
3.6 Hz, 1H, H-3 in furyl), 8.05 (s, 1H, H-8), 9.06 (s, 1H, H-2);
13C NMR (CDCl3, 50 MHz) δ 46.5 (CH2), 112.6 (C-4 in furyl),
117.4 (C-3 in furyl), 129.1 (CH in Ar), 129.3 (CH in Ar), 129.6
(C-5), 133.6 (C in Ar), 134.6 (C in Ar), 144.0 (C-8), 145.9 (C-5
in furyl), 146.0 (C-6), 149.6 (C-2 in furyl), 152.0 (C-4), 152.8
(C-2); MS EI m/z (rel. %): 312/310 (37/100, M+), 281 (11), 199
(10), 138 (7), 127 (26), 126 (6), 125 (71), 199 (4), 90 (5), 89 (16);
HRMS: Found 310.0625, calcd for C16H11ClN4O 310.0621;
Anal. (C16H10Cl2N4O) C, H, N.
9-(3,4-Dichlorophenylmethyl)-6-(2-furyl)-9H-purine (7c).
EtOAc-hexane (1:1) and then EtOAc-hexane (2:1) were used
as eluents for flash chromatography; yield 282 mg (82%), mp
183-185 °C, colorless microcrystalline solid. 1H NMR (CDCl3,
200 MHz) δ 5.40 (s, 2H, CH2), 6.66 (dd, J ) 3.4 and 1.8 Hz,
1H, H-4 in furyl), 7.13 (dd, J ) 8.4 and 1.8 Hz, 1H, Ar), 7.39
(br s, 1H, Ar), 7.42 (d, J ) 8.4 Hz, 1H, Ar), 7.76 (dd, J ) 1.8
and 0.8 Hz, 1H, H-5 in furyl), 7.84 (dd, J ) 3.4 and 1.8 Hz,
1H, H-3 in furyl), 8.07 (s, 1H, H-8), 8.96 (s, 1H, H-2); Anal.
(C16H10Cl2N4O) C, H, N.
6-(2-Furyl)-9-(4-trifluoromethylphenylmethyl)-9H-pu-
rine (7k). EtOAc-hexane (2:1) and then pure EtOAc were
used as eluents for flash chromatography; yield 328 mg (95%),
mp 159-161 °C, off-white crystals. 1
H NMR (CDCl3, 200 MHz)
δ 5.52 (s, 2H, CH
2), 6.66 (dd, J ) 3.4 and 1.6 Hz, 1H, H-4 in
furyl), 7.40 (d, J ) 8.2 Hz, 2H, Ar), 7.60 (d, J ) 8.2 Hz, 2H,
Ar), 7.76 (m, 1H, H-5 in furyl), 7.84 (br d, J ) 3.4, 1H, H-3 in
furyl), 8.07 (s, 1H, H-8), 8.96 (s, 1H, H-2); HRMS: Found
344.0871, calcd for C
17H11F3N4O 344.0885. Anal. (C17H11F3N4O)
C, H, N.
6-(2-Furyl)-9-(4-nitrophenylmethyl)-9H-purine (7l).
EtOAc-hexane (2:1) and then EtOAc-hexane (5:2) and EtOAc
were used as eluents for flash chromatography; yield 215 mg
(71%), mp 229-232 °C, yellow small needles. 1H NMR (CDCl3,
200 MHz) δ 5.57 (s, 2H, CH2), 6.67 (dd, J ) 3.4 and 1.6 Hz,
1H, H-4 in furyl), 7.44 (d, J ) 8.6 Hz, 2H, Ar), 7.76 (m, 1H,
9-(3-Chlorophenylmethyl)-6-(2-furyl)-9H-purine (7d).
EtOAc-hexane (1:1) and then EtOAc-hexane (2:1) were used
as eluents for flash chromatography; yield 256 mg (83%), mp
1
175-177 °C, colorless crystals. H NMR (CDCl3, 200 MHz) δ

Antimycobacterial 9-Aryl-6-(2-furyl)purines
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 7 2719
H-5 in furyl), 7.85 (br d, J ) 3.4 Hz, 1H, H-3 in furyl), 8.11 (s,
1H, H-8), 8.20 (d, J ) 8.6 Hz, 2H, Ar), 8.95 (s, 1H, H-2);
HRMS: Found 321.0858, calcd for C16H10N5O3 321.0862; Anal.
(C16H10N5O3) C, H, N.
6-(2-Furyl)-9-(4-methylsulfonylphenylmethyl)-9H-pu-
rine (7m). EtOAc and then EtOAc-EtOH (20:1) were used as
eluents for flash chromatography; yield 288 mg (81%), mp
187-188 °C, colorless small needles. 1H NMR (CDCl3, 200
MHz) δ 3.00 (s, 3H, CH3), 5.55 (s, 2H, CH2), 6.66 (m, 1H, H-4
in furyl), 7.47 (d, J ) 8.0 Hz, 2H, Ar), 7.75 (m, 1H, H-5 in
furyl), 7.84 (br d, J ) 3.2 Hz, 1H, H-3 in furyl), 7.91 (d, J )
8.0 Hz, 2H, Ar), 8.12 (s, 1H, H-8), 8.95 (s, 1H, H-2); HRMS:
Found 354.0725, calcd for C17H14N4O3S 354.0787; Anal.
(C17H14N4O3S) C, H, N.
6-(2-Furyl)-9-(4-methylphenylmethyl)-9H-purine (7n).
EtOAc-hexane (1:1) and then EtOAc-hexane (2:1) were used
as eluents for flash chromatography; yield 245 mg (84%), mp
166-167 °C, off-white powdery crystals. 1H NMR (CDCl3, 200
MHz) δ 2.31 (s, 3H, CH3), 5.40 (s, 2H, CH2), 6.64 (dd, J ) 3.4
and 1.8 Hz, 1H, H-4 in furyl), 7.14 (d, J ) 8.4 Hz, 2H, Ar),
7.20 (d, J ) 8.4 Hz, 2H, Ar), 7.75 (m, 1H, H-5 in furyl), 7.82
(br d, J ) 3.4 Hz, 1H, H-3 in furyl), 8.04 (s, 1H, H-8), 8.96 (s,
1H, H-2); HRMS: Found 290.1167, calcd for C17H14N4O
290.1168; Anal. (C17H14N4O) C, H, N.
9-(4-tert-Butylphenylmethyl)-6-(2-furyl)-9H-purine (7o).
EtOAc-hexane (1:1) was used as eluent for flash chromatog-
raphy; yield 263 mg (79%), mp 185-187 °C, off-white crystals.
1H NMR (CDCl3, 200 MHz) δ 1.28 (s, 9H, t-Bu), 5.42 (s, 2H,
CH2), 6.65 (dd, J ) 3.4 and 1.6 Hz, 1H, H-4 in furyl), 7.23 (d,
J ) 8.4 Hz, 2H, Ar), 7.37 (d, J ) 8.4 Hz, 2H, Ar), 7.75 (m, 1H,
H-5 in furyl), 7.83 (br d, J ) 3.4, 1H, H-3 in furyl), 8.06 (s,
1H, H-8), 8.97 (s, 1H, H-2); HRMS: Found 322.1631, calcd for
C20H20N4O 322.1637; Anal. (C20H20N4O) C, H, N.
6-(2-Furyl)-9-(3,4,5-trimethoxyphenylmethyl)-9H-pu-
rine (7t). EtOAc-hexane (3:1) was used for flash chromatog-
raphy; yield 246 mg (67%), mp 195-196 °C, colorless crystals.
1H NMR (CDCl3, 300 MHz) δ 3.78 (s, 6H, 2 × CH3), 3.79 (s,
3H, CH3), 5.35 (s, 2H, CH2), 6.52 (s, 2H, Ar), 6.65 (dd, J ) 3.6
and 1.6 Hz, 1H, H-4 in furyl), 7.74 (m, 1H, furyl), 7.82 (m, 1H,
furyl), 8.06 (s, 1H, H-8), 8.96 (s, 1H, H-2); HRMS: Found
366.1323, calcd for C19H18N4O4 366.1328; Anal. (C19H18N4O4)
C, H, N.
6-(2-Furyl)-9-(4-trifluoromethoxyphenylmethyl)-9H-
purine (7u). The reaction was performed in 0.5 mmol scale,
and EtOAc-hexane (1:1) and then EtOAc-hexane (2:1) were
used as eluents for flash chromatography; yield 158 mg (88%),
mp 146-147 °C, off-white crystals. 1H NMR (CDCl3, 200 MHz)
δ 5.46 (s, 2H, CH2), 6.66 (dd, J ) 3.6 and 1.6 Hz, 1H, H-4 in
furyl), 7.19 (d, J 8.6 Hz, 2H, Ar), 7.34 (d, J ) 8.6 Hz, 2H, Ar),
7.76 (m, 1H, H-5 in furyl), 7.84 (br d, J ) 3.6 Hz, 1H, H-3 in
furyl), 8.08 (s, 1H, H-8), 8.97 (s, 1H, H-2); HRMS: Found
360.0839, calcd for C17H11F3N4O2 360.0834; Anal. (C17H11F3N4O2)
C, H, N.
6-(2-Furyl)-9-(3-trifluoromethoxyphenylmethyl)-9H-
purine (7v). The reaction was performed in 0.28 mmol scale,
and acetone-hexane (2:5) was used as eluent for flash chro-
matography; yield 72 mg (71%), mp 133-135 °C, colorless
crystals. 1H NMR (CDCl3, 200 MHz) δ 5.48 (s, 2H, CH2), 6.66
(dd, J ) 3.6 and 1.6 Hz, 1H, H-4 in furyl), 7.18-7.24 (m, 3H,
Ar), 7.34-7.38 (m, 1H, Ar), 7.77 (m, 1H, H-5 in furyl) 7.87 (br
d, J ) 3.6 Hz, 1H, H-3 in furyl), 8.09 (s, 1H, H-8), 8.98 (s, 1H,
H-2); HRMS: Found 360.0840, calcd for C17H11F3N4O2 360.0834;
Anal. (C17H11F3N4O2) C, H, N.
9-(4-Ethoxyphenylmethyl)-6-(2-furyl)-9H-purine (7w).
EtOAc-hexane (1:1) and then EtOAc-hexane (2:1) were used
as eluents for flash chromatography; yield 277 mg (87%), mp
1
165-166 °C, off-white crystals. H NMR (CDCl3, 200 MHz) δ
6-(2-Furyl)-9-(4-methoxyphenylmethyl)-9H-purine (7p).
EtOAc-hexane (1:1) and then EtOAc-hexane (2:1) were used
as eluents for flash chromatography; yield 237 mg (77%), mp
1.38 (t, J ) 7.0 Hz, 3H, CH3), 4.00 (q, J ) 7.0 Hz, 2H, OCH2),
5.37 (s, 2H, CH2), 6.65 (dd, J 3.6 and 1.6 Hz, 1H, H-4 in furyl),
6.86 (d, J ) 8.8 Hz, 2H, Ar), 7.22 (d, J ) 8.8 Hz, 2H, Ar), 7.74
(m, 1H, H-5 in furyl), 7.82 (br d, J 3.6 Hz, 1H, H-3 in furyl),
8.03 (s, 1H, H-8), 8.96 (s, 1H, H-2); HRMS: Found 320.1277,
calcd for C18H16N4O2 320.1273; Anal. (C18H16N4O2) C, H, N.
9-(4-Benzyloxyphenylmethyl)-6-(2-furyl)-9H-purine (7x).
EtOAc-hexane (3:1) was used for flash chromatography; yield
110 mg (71%), mp 145-146 °C, colorless crystals. 1H NMR
(CDCl3, 300 MHz): δ 5.03 (s, 2H, OCH2), 5.37 (s, 2H, NCH2),
6.65 (dd, J ) 3.4 and 1.6 Hz, 1H, H-4 in furyl), 6.92-6.95 (m,
2H, Ar), 7.26-7.39 (m, 7H, Ar), 7.75 (br s, 1H, H-5 in furyl),
7.81 (br d, J ) 3.4 Hz, 1H, H-3 in furyl), 8.03 (s, 1H, H-8),
8.96 (s, 1H, H-2); HRMS: Found 382.1424, calcd for C23H18N4O2
382.1429; Anal. (C23H18N4O2) C, H, N.
1
175-176 °C, colorless crystals. H NMR (CDCl3, 200 MHz) δ
3.77 (s, 3H, CH3), 5.37 (s, 2H, CH2), 6.64 (dd, J ) 3.4 and 1.6
Hz, 1H, H-4 in furyl), 6.86 (d, J ) 8.0 Hz, 2H, Ar), 7.26 (d, J
) 8.4 Hz, 2H, Ar), 7.75 (m, 1H, H-5 in furyl), 7.81 (br d, J )
3.4 Hz, 1H, H-3 in furyl), 8.02 (s, 1H, H-8), 8.96 (s, 1H, H-2);
HRMS: Found 306.1130, calcd for C17H14N4O2 306.1117; Anal.
(C17H14N4O2) C, H, N.
6-(2-Furyl)-9-(2-methoxyphenylmethyl)-9H-purine (7q).
The reaction was performed in 2 mmol scale and EtOAc-
hexane (1:1) was used as eluent for flash chromatography;
yield 538 mg (88%), mp 156-158 °C, colorless crystals. 1H
NMR (CDCl3, 200 MHz) δ 3.85 (s, 3H, CH3), 5.42 (s, 2H, CH2),
6.63 (dd, J ) 3.6 and 1.8 Hz, 1H, H-4 in furyl), 6.86-6.96 (m,
2H, Ar), 7.26-7.36 (m, 2H, Ar), 7.73 (m, 1H, H-5 in furyl),
7.79 (dd, J ) 3.6 and 0.6 Hz, 1H, H-3 in furyl), 8.16 (s, 1H,
H-8), 8.95 (s, 1H, H-2); HRMS: Found 306.1115, calcd for
C17H14N4O2 306.1117; Anal. (C17H14N4O2) C, H, N.
6-(2-Furyl)-9-(4-hydroxyphenylmethyl)-9H-purine (7z).
EtOAc-hexane (2:1) and then EtOAc was used as eluent for
flash chromatography; yield 181 mg (56%), mp 231-233 °C,
colorless crystals. 1H NMR (DMSO-d6, 200 MHz) δ 5.37 (s, 2H,
CH2), 6.70 (br d, J ) 8.4 Hz, 2H, Ar), 6.79 (dd, J ) 3.6 and 1.8
Hz, 1H, H-4 in furyl), 7.21 (br d, J 8.4 Hz, 2H, Ar), 7.81 (m,
1H, furyl), 8.04 (m, 1H, furyl), 8.70 (s, 1H, H-8), 8.88 (s, 1H,
H-2), 9.46 (s, 1H, OH); HRMS: Found 292.0972, calcd for
C16H12N4O2 292.0960; Anal. (C16H12N4O2) C, H, N.
6-(2-Furyl)-9-(4-methylthiophenylmethyl)-9H-purine
(7aa). Acetone-hexane (2:3) was used as eluent for flash
chromatography; yield 309 mg (96%), mp 157-159 °C, colorless
crystals. 1H NMR (CDCl3, 200 MHz) δ 2.50 (s, 3H, CH3), 5.40
(s, 2H, CH2), 6.65 (dd, J ) 3.6 and 1.6 Hz, 1H, H-4 in furyl),
7.22-7.24 (m, 4H, Ar), 7.75 (m, 1H, furyl), 7.82 (m, 1H, furyl),
8.05 (s, 1H, H-8), 8.96 (s, 1H, H-2); HRMS: Found 322.0898,
calcd for C17H14N4OS 322.0888; Anal. (C17H14N4OS) C, H, N.
9-(4-Dimethylaminophenylmethyl)-6-(2-furyl)-9H-pu-
rine (7bb). The reaction was performed in 0.5 mmol scale,
and acetone-hexane (2:5) was used as eluent for flash chro-
matography; yield 140 mg (88%), mp 158-160 °C, colorless
crystals. 1H NMR (CDCl3, 200 MHz) δ 2.93 (s, 6H, CH3), 5.33
(s, 2H, CH2), 6.64 (dd, J ) 3.6 and 1.6 Hz, 1H, H-4 in furyl),
6.69 (d, J ) 8.6 Hz, 2H, Ar), 7.22 (d, J ) 8.6 Hz, 2H, Ar), 7.74
(dd, J ) 1.6 and 0.6 Hz, 1H, H-5 in furyl), 7.81 (dd, J ) 3.6
6-(2-Furyl)-9-(3-methoxyphenylmethyl)-9H-purine (7r).
The reaction was performed in 2 mmol scale and EtOAc-
hexane (1:1) and then EtOAc-hexane (2:1) were used as
eluents for flash chromatography; yield 575 mg (94%), mp
1
138-139 °C, colorless crystals. H NMR (CDCl3, 200 MHz) δ
3.75 (s, 3H, CH3), 5.41 (s, 2H, CH2), 6.65 (dd, J ) 3.4 and 1.8
Hz, 1H, H-4 in furyl), 6.83-6.87 (m, 3H, Ar), 7.21-7.30 (m,
1H, Ar), 7.75 (m, 1H, H-5 in furyl), 7.83 (dd, J ) 3.4 and 0.6
Hz, 1H, H-3 in furyl), 8.06 (s, 1H, H-8), 8.97 (s, 1H, H-2);
HRMS: Found 306.1112, calcd for C17H14N4O2 306.1117; Anal.
(C17H14N4O2) C, H, N.
6-(2-Furyl)-9-(4-methoxy-3-methylphenylmethyl)-9H-
purine (7s). EtOAc-hexane (2:1) was used as eluent for flash
chromatography; yield 285 mg (89%), mp 169-170 °C, colorless
1
needles. H NMR (CDCl3, 200 MHz) δ 2.16 (s, 3H, CH3), 3.79
(s, 3H, OCH3), 5.34 (s, 2H, CH2), 6.64 (dd, J ) 3.6 and 1.6 Hz,
1H, H-4 in furyl), 6.77 (d, J ) 8.4 Hz, 1H, Ar), 7.08-7.15 (m,
2H, Ar), 7.75 (m, 1H, furyl), 7.82 (m, 1H, furyl), 8.02 (s, 1H,
H-8), 8.87 (s, 1H, H-2); HRMS: Found 320.1288, calcd for
C18H16N4O2 320.1273; Anal. (C18H16N4O2) C, H, N.

2720 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 7
Bakkestuen et al.
and 0.6 Hz, 1H, H-3 in furyl), 8.02 (s, 1H, H-8), 8.97 (s, 1H,
H-2); HRMS: Found 319.1430, calcd for C18H17N5O 319.1433;
Anal. (C18H17N5O) C, H; N: calcd, 21.93; found, 21.25.
9-(4-Acetamidophenylmethyl)-6-(2-furyl)-9H-purine (7cc).
The reaction was performed in 1.1 mmol scale and MeOH-
CHCl3 (1:15) was used as eluent for flash chromatography;
yield 335 mg (88%), mp 278-280 °C, colorless powdery
neacetone)dipalladium chloroform adduct (16 mg, 0.015 mmol)
and tri(2-furyl)phosphine (26 mg, 0.11 mmol) in DMF (4 mL)
was stirred at ambient temperature under N2 atm. for 15 min.,
before the 9-substituted 2,6-dichloropurine 5 (0.5 mmol) and
2-furyl(tributyl)tin (0.20 mL, 0.6 mmol) were added. The
resulting mixture was stirred for 8 h at 50 °C and evaporated
in vacuo, and the products were purified as described for
compounds 7.
1
crystals. H NMR (DMSO-d6, 200 MHz) δ 2.00 (s, 3H, CH3),
5.44 (s, 2H, CH2), 6.80 (dd, J ) 3.6 and 1.8 Hz, 1H, H-4 in
furyl), 7.30 (d, J ) 8.4 Hz, 2H, Ar), 7.52 (d, J ) 8.4 Hz, 2H,
Ar), 7.83 (br d, J ) 3.6 Hz, 1H, H-3 in furyl), 8.05 (m, 1H, H-5
in furyl), 8.72 (s, 1H, H-8), 8.88 (s, 1H, H-2), 9.94 (br s, 1H,
NH); HRMS: Found 333.1229, calcd for C18H15N5O2 333.1226;
Anal. (C18H15N5O2) C, H, N.
2-Chloro-9-(4-chlorophenylmethyl)-6-(2-furyl)-9H-pu-
rine (8b). 13C NMR (CDCl3, 50 MHz) δ 46.7 (CH2), 112.8 (C-4
in furyl), 118.8 (C-3 in furyl), 128.0 (C-5), 129.2 (CH in Ar),
129.3 (CH in Ar), 133.1 (C in Ar), 134.7 (C in Ar), 144.5 (C-8),
146.7 (C-5 in furyl), 147.3 (C-6), 148.7 (C-2 in furyl), 153.5 (C-
4), 156.0 (C-2); MS EI m/z (rel. %): 348/346/344 (6/53/84, M+),
343 (25), 315 (2), 309 (5), 233 (1), 127 (29), 126 (4), 125 (100),
99 (2), 90 (3).
2-Chloro-9-(3,4-dichlorophenylmethyl)-6-(2-furyl)-9H-
purine (8c). EtOAc-hexane (1:2) and then EtOAc-hexane
(1:1) were used as eluents for flash chromatography; yield 142
mg (75%), mp 191-193 °C, colorless crystals. 1H NMR (CDCl3,
200 MHz) δ 5.36 (s, 2H, CH2), 6.66 (dd, J ) 3.4 and 1.8 Hz,
1H, H-4 in furyl), 7.13 (dd, J ) 8.4 and 1.8 Hz, 1H, Ar), 7.38-
7.46 (m, 2H, Ar), 7.78 (m, 1H, H-5 in furyl), 7.87 (br d, J ) 3.4
Hz, 1H, H-3 in furyl), 8.02 (s, 1H, H-8); HRMS: Found
377.9838, calcd for C16H19Cl3N4O 377.9842; Anal. (C16H19-
Cl3N4O) C, H; N: calcd, 14.76; found, 14.16.
2-Chloro-9-(3-chlorophenylmethyl)-6-(2-furyl)-9H-pu-
rine (8d). EtOAc-hexane (2:3) were used as eluents for flash
chromatography; yield 164 mg (95%), mp 196-198 °C, off-
white crystals. 1H NMR (CDCl3, 200 MHz) δ 5.38 (s, 2H, CH2),
6.66 (dd, J ) 3.6 and 1.8 Hz, 1H, H-4 in furyl), 7.16-7.18 (m,
1H, Ar), 7.27-7.31 (m, 3H, Ar), 7.78 (m, 1H, H-5 in furyl),
7.86 (br d, J ) 3.6 Hz, 1H, H-3 in furyl), 8.01 (s, 1H, H-8);
HRMS: Found 344.0246, calcd for C16H10Cl2N4O 344.0232;
Anal. (C16H10Cl2N4O) C, H, N.
9-(Diphenylmethyl)-6-(2-furyl)-9H-purine (7ee). 13C NMR
(CDCl3, 50 MHz) δ 61.5 (CH), 112.5 (C-4 in furyl) 117.3 (C-3
in furyl), 127.9 (CH in Ar), 128.3 (C-5), 128.5 (CH in Ar), 129.0
(CH in Ar), 137.9 (C in Ar), 143.8 (C-8), 145.7 (C-5 in furyl),
146.0 (C-6), 149.6 (C-2 in furyl), 151.9 (C-4), 152.7 (C-2); MS
EI m/z (rel. %): 352 (45, M+), 168 (12), 167 (100), 166 (8), 165
(24), 152 (12), 137 (1).
(S)-6-(2-Furyl)-9-(1-phenylethyl)-9H-purine (7ff). EtOAc-
hexane (1:1) and then EtOAc-hexane (2:1) were used as
eluents for flash chromatography; yield 248 mg (86%), mp
138-140 °C, pale yellow crystals; [R]D: +44.8° (c 0.8, CHCl3);
1H NMR (CDCl3, 200 MHz) δ 1.99 (d, J ) 7.0 Hz, 3H, CH3),
5.99 (q, J ) 7.0 Hz, 1H, CHCH3), 6.62 (dd, J ) 3.4 and 1.6 Hz,
1H, H-4 in furyl), 7.31 (br s, 5H, Ar), 7.72 (m, 1H, H-5 in furyl),
7.80 (br d, J ) 3.4 Hz, 1H, H-3 in furyl), 8.06 (s, 1H, H-8),
8.92 (s, 1H, H-2); HRMS: Found 290.1164, calcd for C17H14N4O
290.1168; Anal. (C17H14N4O) C, H, N.
(R)-6-(2-Furyl)-9-(1-phenylethyl)-9H-purine
(7gg).
EtOAc-hexane (1:1) and then EtOAc-hexane (2:1) was used
as eluent for flash chromatography; yield 274 mg (94%), mp
136-139 °C, pale yellow powdery crystals. Spectral data, see
7ff. [R]D: -47.2° (c 1.2, CHCl3); Anal. (C17H14N4O) C, H, N.
9-(4-Acetoxyphenylmethyl)-6-(2-furyl)-9H-purine (7y).
Acetic anhydride (0.05 mL, 0.53 mmol) was added dropwise
to a stirred suspension of 6-(2-furyl)-9-(4-hydroxyphenyl-
methyl)-9H-purine 3z (77 mg, 0.26 mmol) and 4-N,N-(di-
methylamino)pyridine (65 mg, 0.53 mmol) in dry dichlo-
romethane (5 mL) at ambient temperature under N2-atm. The
resulting reaction mixture was stirred for 45 min, diluted with
dichloromethane (50 mL), washed with saturated aqueous
CuSO4 (2 × 10 mL), saturated aqueous NaHCO3 (2 × 10 mL)
and brine (10 mL), dried (MgSO4) and evaporated in vacuo.
The crude product was purified by flash chromatography in
silica gel eluting with EtOAc-hexane (2:1); yield 81 mg (93%),
mp 170-172 °C, colorless crystals. 1H NMR (CDCl3, 200 MHz)
δ 2.27 (s, 3H, CH3), 5.44 (s, 2H, CH2), 6.66 (dd, J ) 3.6 and
1.6 Hz, 1H, H-4 in furyl), 7.07 (d, J ) 8.2 Hz, 2H, Ar), 7.32 (d,
J ) 8.2 Hz, 2H, Ar), 7.75 (m, 1H, H-5 in furyl), 7.84 (br d, J )
3.6 Hz, 1H, H-3 in furyl), 8.07 (s, 1H, H-8), 8.96 (s, 1H, H-2);
HRMS: Found 334.1070, calcd for C18H14N4O3 334.1066; Anal.
(C18H14N4O3) C, H, N.
2-Chloro-9-(4-fluorophenylmethyl)-6-(2-furyl)-9H-pu-
rine (8e). EtOAc-hexane (2:3) was used as an eluent for flash
chromatography; yield 127 mg (77%), mp 152-155 °C, pale
yellow crystals. 1H NMR (CDCl3, 200 MHz) δ 5.38 (s, 2H, CH2),
6.65 (dd, J ) 3.6 and 1.8 Hz, 1H, H-4 in furyl), 7.01-7.09 (m,
2H, Ar), 7.24-7.34 (m, 2H, Ar), 7.77 (m, 1H, H-5 in furyl),
7.86 (br d, J ) 3.6 Hz, 1H, H-3 in furyl), 7.99 (s, 1H, H-8);
HRMS: Found 328.0517, calcd for C16H10ClFN4O 328.0527.
Anal. (C16H10ClFN4O) H, N; C: calcd, 58.46; found, 59.18.
2-Chloro-6-(2-furyl)-9-(4-methylphenylmethyl)-9H-pu-
rine (8f).23 EtOAc-hexane (1:2) was used as an eluent for
flash chromatography; yield 120 mg (74%), mp 171-173 °C,
1
colorless crystals. H NMR (CDCl3, 200 MHz) δ 2.33 (s, 3H,
CH3), 5.35 (s, 2H, CH2), 6.65 (dd, J ) 3.6 and 1.8 Hz, 1H, H-4
in furyl), 7.18 (m, 4H, Ar), 7.76 (m, 1H, H-5 in furyl), 7.84 (br
d, J ) 3.6 Hz, 1H, H-3 in furyl), 7.97 (s, 1H, H-8); HRMS:
Found 324.0775, calcd for C17H13ClN4O 3240778.
2-Chloro-6-(2-furyl)-9-(4-methoxyphenylmethyl)-9H-
purine (8g). EtOAc-hexane (1:1) was used as an eluent for
flash chromatography; yield 104 mg (61%), mp 184-186 °C,
1
9-(4-Aminophenylmethyl)-6-(2-furyl)-9H-purine (7dd).
A mixture of 9-(4-acetamidophenylmethyl)-6-(2-furyl)-9H-pu-
rine 7cc (140 mg, 0.42 mL) in 48% aqueous HBr (2 mL) was
stirred at 90 °C for 17 h and cooled to ambient temperature,
before 10% aqueous K2CO3 (10 mL) was added carefully and
the pH was adjusted to ca. 11 by addition of solid K2CO3. The
mixture was extracted with EtOAc (4 × 25 mL) and the
combined organic layers were dried (MgSO2) and evaporated
in vacuo. The crude product was purified by flash chromatog-
raphy on silica gel eluting with EtOAc; yield 82 mg (70%), mp
195-197 °C, yellow powdery crystals.1H NMR (DMSO-d6, 200
MHz) δ 5.10 (br s, 2H, NH2), 5.28 (s, 2H, CH2), 6.49 (d, J )
8.4 Hz, 2H, Ar), 6.79 (dd, J ) 3.4 and 1.6 Hz, 1H, H-4 in furyl),
7.08 (d, J ) 8.4 Hz, 2H, Ar), 7.81 (br d, J ) 3.4 Hz, 1H, H-3 in
furyl), 8.04 (br s, 1H, H-5 in furyl), 8.66 (s, 1H, H-8), 8.88 (s,
1H, H-2); HRMS: Found 291.1125, calcd for C16H13N5O
291.1120; Anal. (C16H13N5O) C, H.
colorless crystals. H NMR (CDCl3, 200 MHz) δ 3.78 (s, 3H,
CH3), 5.33 (s, 2H, CH2), 6.65 (dd, J ) 3.6 and 1.6 Hz, 1H, H-4
in furyl), 6.88 (d, J ) 8.8 Hz, 2H, Ar), 7.26 (d, J ) 8.8 Hz, 2H,
Ar), 7.76 (m, 1H, H-5 in furyl), 7.84 (dd, J ) 3.6 and 0.6 Hz,
1H, H-3 in furyl), 7.96 (s, 1H, H-8); 13C NMR (CDCl3, 50 MHz)
δ 46.7 (CH2), 55.2 (CH3), 112.7 (C-4 in furyl), 114.4 (CH in
Ar), 118.6 (C-3 in furyl), 126.4 (C-1 in Ar), 127.1 (C-5), 129.4
(CH in Ar), 144.6 (C-8), 146.5 (C-5 in furyl), 147.1 (C-6), 148.7
(C-2 in furyl), 153.5 (C-4), 154.3 (C-2), 159.7 (C-4 in Ar); MS
EI m/z (rel. %): 342/340 (12/38, M+), 222 (3) 220 (10), 192 (2),
122 (9), 121 (100) 106 (3), 91 (4), 78 (9), 77 (8); HRMS: Found
340.0735, calcd for C17H13ClN4O2 340.0727; Anal. (C17H13-
ClN4O2) C, H, N.
2-Chloro-6-(2-furyl)-9-(2-methoxyphenylmethyl)-9H-
purine (8h). EtOAc-hexane (1:1) was used as an eluent for
flash chromatography; yield 305 mg (90%), mp 168-170 °C,
1
colorless crystals. H NMR (CDCl3, 200 MHz) δ 3.85 (s, 3H,
Stille Coupling between 9-Benzyl-2,6-dichloropurines
5 and 2-Furyl(tributyl)tin. A mixture of tris(dibenzylide-
CH3), 5.37 (s, 2H, CH2), 6.63 (dd, J ) 3.4 and 1.6 Hz, 1H, H-4
in furyl), 6.87-6.97 (m, 2H, Ar), 7.27-7.37 (m, 2H, Ar), 7.74

Antimycobacterial 9-Aryl-6-(2-furyl)purines
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 7 2721
(m, 1H, H-5 in furyl), 7.81 (br d, J ) 3.4, 1H, H-3 in furyl),
8.09 (s, 1H, H-8); HRMS: Found 340.0715, calcd for C17H13-
ClN4O2 340.0727; Anal. (C17H13ClN4O2) C, H, N.
reaction mixture was allowed to reach ambient temperature.
A solution of 6-chloro-9-phenylsulfonyl-9H-purine (147 mg,
0.50 mmol) in dry THF (8 mL) was added followed by a solution
of tetrakis(triphenylphosphine)palladium(0) [generated in situ
from tris(dibenzylideneacetone)dipalladium chloroform adduct
(13 mg, 0.013 mmol) and triphenylphosphine (26 mg, 0.10
mmol)] in dry THF (2 mL). The mixture was heated at 50 °C
for 19 h and cooled to ambient temperature. Sat. aq. am-
monium chloride (10 mL) was added, and the aq. phase
extracted with EtOAc (2 × 25 mL). The combined organic
extracts were washed with brine (2 × 20 mL), dried (MgSO4)
and evaporated in vacuo. The product was purified by flash
chromatography on silica gel eluting with EtOAc-hexane (2:
2-Chloro-6-(2-furyl)-9-(3-methoxyphenylmethyl)-9H-
purine (8i). EtOAc-hexane (2:3) was used as an eluent for
flash chromatography; yield 161 mg (94%), mp 160-161 °C,
1
off-white crystals. H NMR (CDCl3, 200 MHz) δ 3.77 (s, 3H,
CH3), 5.37 (s, 2H, CH2), 6.65 (dd, J ) 3.6 and 1.8 Hz, 1H, H-4
in furyl), 6.84-6.88 (m, 3H, Ar), 7.26-7.31 (m, 1H, Ar), 7.77
(m, 1H, H-5 in furyl), 7.85 (br d, J ) 3.6 Hz, 1H, H-3 in furyl),
8.00 (s, 1H, H-8); 13C NMR (CDCl3, 50 MHz) δ 47.3 (CH2), 55.3
(CH3), 112.8 (C-4 in furyl), 113.7 (CH in Ar), 114.0 (CH in Ar),
118.7 (C-3 in furyl), 120.0 (CH in Ar), 127.1 (C-5), 130.3 (CH
in Ar), 136.0 (C in Ar), 144.8 (C-8), 146.6 (C-5 in furyl), 147.3
(C-6), 148.7 (C-2 in furyl), 153.6 (C-4), 154.4 (C-2), 160.1 (C-3
in Ar); MS EI m/z (rel. %): 342/340 (33/100, M+), 311 (7), 305
(14), 233 (7), 121 (100), 91 (27), 78 (14), 77 (10); HRMS: Found
340.0743, calcd for C17H13ClN4O2 340.0727; Anal. (C17H13-
ClN4O2) C, H, N.
1
3); yield (75 mg) 46%, colorless crystals, mp 218-220 °C. H
NMR (CDCl3, 200 MHz) δ 6.65 (dd, J ) 3.6 and 1.6 Hz, 1 H,
H-4 in furyl), 7.54-7.83 (m, 5H, Ph and furyl), 8.30 (br d, J )
6.0 Hz, 2 H, Ph), 8.53 (s, 1 H, H-8), 9.01 (s, 1 H, H-2); HRMS:
Found 326.0487, calcd for C15H10N4O3S 326.0474; Anal.
(C15H10N4O3S) C, H; N: calcd, 17.17; found, 16.52.
2-Chloro-6-(2-furyl)-9-(4-methoxy-3-methylphenyl-
methyl)-9H-purine (8j). EtOAc-hexane (2:3) was used as
an eluent for flash chromatography; yield 117 mg (66%), mp
Synthesis of 9-Aryl-6-(2-furyl)purines 16. The com-
pounds 16 were prepared by palladium catalyzed coupling
between 9-aryl-6-chloropurines 14 and 2-furyl(tributyl)tin
following the same general procedure as given for the synthesis
of the 9-benzylpurines 7 above.
6-(2-Furyl)-9-phenyl-9H-purine (16a). The reaction was
performed in 0.22 mmol scale, and MeOH-CH2Cl2 (3:100) was
used as eluent for flash chromatography; yield 35 mg (61%),
mp 190-192 °C, colorless crystals. 1H NMR (CDCl3, 500 MHz)
δ 6.67 (m, 1H, H-4 in furyl), 7.47 (m, 1H, Ph), 7.58 (m, 2H,
Ph), 7.71 (d, J ) 7.8 Hz, 2H, Ph), 7.77 (br s, 1H, H-5 in furyl),
7.88 (br d, J ) 3.4 Hz, 1H, H-3 in furyl), 8.35 (s, 1H, H-8),
8.99 (s, 1H, H-2); HRMS: Found 262.0865, calcd for C15H10-
ClN4O 262.0855; Anal. (C15H10ClN4O) C, H, N.
9-(4-Chlorophenyl)-6-(2-furyl)-9H-purine (16b). The re-
action was performed in 0.12 mmol scale, and MeOH-CHCl3
(1:100) was used as eluent for flash chromatography; yield 34
mg (94%), mp 240-242 °C, colorless crystals. 1H NMR (CDCl3,
500 MHz) δ 6.76 (m, 1H, H-4 in furyl), 7.54 (d, J ) 8.5 Hz,
2H, Ar), 7.68 (d, J ) 8.5 Hz, 2H, Ar), 7.76 (br s, 1H, H-5 in
furyl), 7.87 (br d, J ) 3.1 Hz, 1H, H-3 in furyl), 8.32 (s, 1H,
H-8), 8.96 (s, 1H, H-2); HRMS: Found 296.0456, calcd for
C15H9ClN4O 296.0465; Anal. (C15H9ClN4O) C, H; N: calcd,
18.88; found, 18.42.
9-(3-Chlorophenyl)-6-(2-furyl)-9H-purine (16c). The re-
action was performed in 0.19 mmol scale, and EtOAc-hexane
(1:1) was used as eluent for flash chromatography; yield 44
mg (80%), mp 181-183 °C, colorless crystals. 1H NMR (CDCl3,
500 MHz) δ 6.66 (m, 1H, H-4 in furyl), 7.42 (d, J ) 8.0 Hz,
1H, Ar), 7.49 (m, 1H, Ar), 7.64 (d, J ) 8.2 Hz, 2H, Ar), 7.76
(br s, 1H, H-5 in furyl), 7.78 (br s, 1H, Ar), 7.86 (br d, J ) 3.4
Hz, 1H, H-3 in furyl), 8.33 (s, 1H, H-8), 8.97 (s, 1H, H-2);
HRMS: Found 296.0452, calcd for C15H9ClN4O 296.0465.
1
177-179 °C, off-white crystals. H NMR (CDCl3, 200 MHz) δ
2.17 (s, 3H, CH3), 3.80 (s, 3H, OCH3), 5.29 (s, 2H, CH2), 6.64
(dd, J ) 3.4 and 1.8 Hz, 1H, H-4 in furyl), 6.78 (d, J ) 8.0 Hz,
1H, Ar), 7.07-7.14 (m, 2H, Ar), 7.75 (br s, 1H, H-5 in furyl),
7.83 (br d, J 3.4 Hz, 1H, H-3 in furyl), 7.96 (s, 1H, H-8); 13C
NMR (CDCl3, 50 MHz) δ 16.2 (CH3), 47.1 (CH2), 55.4 (OCH3),
110.2 (CH in Ar), 112.7 (C-4 in furyl), 118.6 (C-3 in furyl), 125.9
(C in Ar), 126.9 (CH in Ar), 127.2 (C-5), 127.6 (C in Ar), 130.5
(CH in Ar), 144.8 (C-8), 146.5 (C-5 in furyl), 147.2 (C-6), 148.8
(C-2 in furyl), 153.6 (C-4), 154.3 (C-2), 158.0 (C-4 in Ar); MS
EI m/z (rel. %): 356/354 (9/28, M+), 177 (2), 136 (9), 135 (100),
120 (2), 103 (1), 91 (6); HRMS: Found 354.0872, calcd for
C18H15ClN4O2 354.0884; Anal. (C18H15ClN4O2) C, H, N.
5-Amino-4-chloro-6-(4-dimethylaminyphenyl)pyrimi-
dine (11a). Triethylamine (1.12 mL, 8 mmol) was added to a
stirred suspension of 4-dimethyaminobenzylamine dihydro-
chloride (447 mg, 2 mmol) in n-butanol (10 mL). After stirring
for 5 min, 5-amino-4,6-dichloropyrimidine (328 mg, 2 mmol)
was added and the reaction mixture was stirred at 100 °C for
22h. Upon cooling to ambient temperature needles of triethyl-
ammonium chloride was formed. The reaction mixture was
filtered, and the solid washed with n-hexane. The combined
filtrates were evaporated in vacuo and the residue subjected
to flash chromatography on silica gel eluting with acetone-
1
hexane (2:5); yield 316 mg (57%), mp 153-156 °C. H NMR
(DMSO-d6, 200 MHz) δ 2.83 (s, 6H, CH3), 4.46 (d, J ) 5.2 Hz,
2H, CH2), 5.03 (br s, 2H, NH2), 6.66 (d, J ) 8.4 Hz, 2H, Ar),
7.11-7.15 (m, 3H, Ar and NH), 7.71 (s, 1H, H-2); MS EI m/z
(rel. %): 279/277 (2/9, M+), 134 (100), 118 (7), 91 (2); HRMS:
Found 277.1093, calcd for C13H16ClN5 277.1094; Anal. (C13H16-
ClN5) C, H.
6-(2-Furyl)-9-(4-methylphenyl)-9H-purine (16d). The
reaction was performed in 0.39 mmol scale, and EtOAc-
hexane (1:1) and then EtOAc-hexane (3:1) were used as
eluents for flash chromatography; yield 90 mg (83%), mp 184-
6-Chloro-9-phenylsulfonyl-9H-purine (12). A solution of
potassium hydroxide (360 mg, 6.0 mmol) in water (15 mL) and
then phenylsulfonyl chloride (0.38 mL, 3.0 mmol) were added
dropwise to a stirred mixture of 6-chloropurine (464 mg, 3.0
mmol) in acetone (30 mL) at 0 °C. The resulting mixture was
stirred at 0 °C for 2 h, the pH was adjusted to ca. 7 and acetone
was removed in vacuo. The solid was filtered off, washed with
water and diethyl ether and recrystallized from EtOH; yield
566 mg (64%), mp 175-176 °C (dec), colorless needles. 1H NMR
(CDCl3, 200 MHz) δ 7.59-7.75 (m, 3H, Ph), 8.28 (d, J ) 7.4
Hz, 2H, Ph), 8.56 (s, 1H, H-8), 8.84 (s, 1H, H-2); HRMS: Found
293.9964, calcd for C11H7ClN4O2S 293.9987.
6-(2-Furyl)-9-phenylsulfonyl-9H-purine (13). n-Butyl-
lithium (0.38 mL, 0.60 mmol, 1.6 M hexane solution) was
added dropwise to a stirred solution of furan (0.055 mL, 0.76
mmol) in dry THF (4 mL) under N2 at 0 °C. The resulting
mixture was stirred for 2 h at 0 °C and 1 h at ambient
temperature, before it was cooled to -78 °C. A 1 M solution of
anhydrous zinc bromide in dry THF (0.67 mL, 0.6 mmol) was
added dropwise, and the resulting mixture was stirred for 1 h
at -78 °C before the cooling bath was removed and the
1
186 °C, colorless crystals. H NMR (CDCl3, 500 MHz) δ 2.34
(s, 3H, CH3), 6.60 (m, 1H, H-4 in furyl), 7.28 (d, J ) 8.2 Hz,
2H, Ar), 7.49 (d, J ) 8.2 Hz, 2H, Ar), 7.70 (br s, 1H, H-5 in
furyl), 7.81 (br d, J ) 3.4 Hz, 1H, H-3 in furyl), 8.25 (s, 1H,
H-8), 8.91 (s, 1H, H-2); HRMS: Found 276.1011, calcd for
C16H12ClN4O 276.1010; Anal. (C16H12ClN4O) H; C: calcd, 69.55;
found, 69.09; N: calcd, 20.28; found, 19.82.
6-(2-Furyl)-9-(4-methoxyphenyl)-9H-purine (16e). The
reaction was performed in 0.17 mmol scale, and CHCl3 and
then MeOH-CHCl3 (1:100) were used as eluents for flash
chromatography; yield 37 mg (77%), mp 222-224 °C, colorless
crystals. 1H NMR (CDCl3, 500 MHz) δ 3.87 (s, 3H, CH3), 6.68
(m, 1H, H-4 in furyl), 7.08 (d, J ) 8.9 Hz, 2H, Ar), 7.58 (d, J
) 8.8 Hz, 2H, Ar), 7.78 (br s, 1H, H-5 in furyl), 7.89 (br d, J )
3.4 Hz, 1H, H-3 in furyl), 8.29 (s, 1H, H-8), 8.97 (s, 1H, H-2);
HRMS: Found: 292.0960, calcd for C16H12ClN4O2 292.0960;
Anal. (C16H12ClN4O2) C, H, N.

2722 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 7
Bakkestuen et al.
Synthesis of 9-Aryl-2-chloro-6-(2-furyl)purines 17. The
compounds 17 were prepared by palladium-catalyzed coupling
between 9-aryl-2,6-dichloropurines 15 and 2-furyl(tributyl)-
tin following the same general procedure as given for the
synthesis of the 9-benzyl-2-chloropurines 8 above.
2-Chloro-6-(2-furyl)-9-phenyl-9H-purine (17a). The re-
action was performed in 0.25 mmol scale at 40 °C, and MeOH-
CH2Cl2 (1:100) was used as eluent for flash chromatography;
yield 51 mg (69%), mp 222-223 °C, colorless crystals. 1H NMR
(CDCl3, 500 MHz) δ 6.68 (m, 1H, H-4 in furyl), 7.48 (m, 1H,
Ph), 7.58 (m, 2H, Ph), 7.68 (d, J ) 8.1 Hz, 2H, Ph), 7.80 (br s,
1H, H-5 in furyl), 7.91 (br d, J ) 3.4 Hz, 1H, H-3 in furyl),
8.32 (s, 1H, H-8); HRMS: Found 296.0470, calcd for C15H9-
ClN4O 296.0465.
2-Chloro-6-(2-furyl)-9-(4-methylphenyl)-9H-purine (17b).
The reaction was performed in 0.20 mmol scale, and MeOH-
CH2Cl2 (1:100) was used as eluent for flash chromatography;
yield 35 mg (56%), mp 265-267 °C, colorless crystals. 1H NMR
(CDCl3, 500 MHz) δ 2.43 (s, 3H, CH3), 6.68 (m, 1H, H-4 in
furyl), 7.37 (d, J ) 8.2 Hz, 2H, Ar), 7.54 (d, J ) 8.2 Hz, 2H,
Ar), 7.79 (br s, 1H, H-5 in furyl), 7.91 (br d, J ) 3.5 Hz, 1H,
H-3 in furyl), 8.28 (s, 1H, H-8); HRMS: Found 310.0621, calcd
for C16H11ClN4O 310.0621; Anal. (C16H11ClN4O) C, H, N.
Activity against Mycobacterium tuberculosis. The pri-
mary screening against Mycobacterium tuberculosis H37Rv
(ATCC 27294) was conducted at 6.25 µg/mL in BACTEC 12B
medium using the Microplate Alamar Blue Assay (MABA).12
Compounds exhibiting fluorescence were tested in the BACTEC
460-radiometric system,12 and compounds demonstrating at
least 90% inhibition in the primary screen were retested at
lower concentrations against M. tuberculosis H37Rv to deter-
mine the actual minimum inhibitory concentration (MIC) in
the MABA. MIC for rifampin was 0.25 µg/mL.
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Acknowledgment. Antimycobacterial data were
provided by the Tuberculosis Antimicrobial Acquisition
and Coordinating Facility (TAACF) through a research
and development contract with the US National Insti-
tute of Allergy and Infectious Diseases. We are grateful
for all help provided by Dr. Cecil Kwong and co-workers.
We also thank Dirk Petersen, Department of Chemistry,
University of Oslo, for performing NOESY NMR. The
Norwegian Research Council is greatly acknowledged
for partial financing of the Bruker Avance instruments
used in this study as well as for a Norwegian Govern-
ment Scholarship to B.T.U.
Supporting Information Available: Elemental analysis
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compounds described in the Experimental Section. This mate-
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