Synthesis, structure, and antimycobacterial activity of 6-[1(3H)-isobenzofuranylidenemethyl]purines and analogs

Article abstract of DOI:10.1016/j.bmc.2009.08.012

6-Benzofuryl-, styryl, benzyl, and furfurylpurines as well as 6-[1(3H)-isobenzofuranylidenemethyl]purines have been synthesized and their activities against Mycobacterium tuberculosis (Mtb) determined. Several compounds displayed profound antimycobacteria

Full text of DOI:10.1016/j.bmc.2009.08.012

Bioorganic & Medicinal Chemistry 17 (2009) 6512–6516
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis, structure, and antimycobacterial activity
of 6-[1(3H)-isobenzofuranylidenemethyl]purines and analogs
*
Morten Brꢀndvang, Vebjørn Bakken, Lise-Lotte Gundersen
Department of Chemistry, University of Oslo, PO Box 1033, Blindern, N-0315 Oslo, Norway
a r t i c l e i n f o
a b s t r a c t
Article history:
6-Benzofuryl-, styryl, benzyl, and furfurylpurines as well as 6-[1(3H)-isobenzofuranylidenemeth-
yl]purines have been synthesized and their activities against Mycobacterium tuberculosis (Mtb) deter-
mined. Several compounds displayed profound antimycobacterial activity in combination with low
toxicity towards mammalian cells. NMR and X-ray crystallography were employed to determine the
detailed structures and the results were supported by quantum chemical calculations.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 7 April 2009
Revised 4 August 2009
Accepted 6 August 2009
Available online 12 August 2009
Keywords:
Purines
Cross-couplings
Antimycobacterials
X-ray
Ab initio calculations
1. Introduction
yl)purine 2b (Fig. 1) and the styryl- 5, benzyl- 6, and furfurylpurine
7. The structural relationship between compounds 5–7 and the
Tuberculosis (TB) still claims ca. two-million deaths per year
world-wide and resistance to existing drugs is a growing problem.1
We have previously reported selective antibacterial activity against
Mycobacterium tuberculosis (Mtb) for certain 9-benzylpurines.2
Fig. 1 shows examples of purines with profound antimycobacterial
activity as well as a summary of SAR knowledge. Previous results
have led us to believe that an aryl group in the purine 6-position
is a requirement for significant antimycobacterial effect,2a and
among the 6-aryl- and 6-heteroarylpurines examined, especially
high activities are found for 6-(2-furyl)purines,2e for instance com-
pounds 1a–1d (Fig. 1). The more bulky 6-(benzofur-2-yl)purine 2a
is less active than the corresponding furylpurine 1a.2d However, we
recently found MIC values for antimycobacterial activity of 6-
[1(3H)-isobenzofuranylidenemethyl]purines 3a and 4a only one ti-
ter step higher than 6-furylpurine 1a.3 Since we have shown that
compound 4a easily isomerizes into the Z-isomer 3a,3 it may be
that compound 4a also isomerizes into compound 3a in the anti-
mycobacterial assay.
(isobenzofuranylidenemethyl)purine 3b, is illustrated in Figure 2.
It was previously shown that compound 3a exists only as a (iso-
benzofuranylidenemethyl)purine, and not as an aromatic, but
quinoid, benzo[c]furylmethylpurine.3 On the other hand, the sim-
ple furyl derivative 7, may exist as tautomer 7b rather than 7a.
Hence, we included a structural study of the synthesized com-
pounds employing NMR, X-ray, and quantum chemical calcula-
tions in order to reveal their detailed structures and broaden our
SAR knowledge.
2. Synthesis
Z-6-[1(3H)-Isobenzofuranylidenemethyl]purine 3b was synthe-
sized essentially as reported for the preparation of compound 3a
before.3 When the dichloropurine 8 was reacted with the alkyne
9 under Sonogashira coupling conditions, cyclization took place
to give mainly the E-isomer 4b. The mixture of isomers was treated
with TFA to give the pure Z-6-[1(3H)-isobenzofuranylidenemeth-
yl]purine 3b (Scheme 1).
The other target molecules, 2b and 5–7, were available by reg-
ioselective Stille- or Negishi-coupling on the dichloropurine 8
(Scheme 2, Table 1) a synthetic strategy employed by us in the syn-
thesis of several 6-substituted purines.1,4 Furfuryl halides are re-
garded as unstable and difficult to utilize for synthetic purposes.5
However, we found that the desired furfurylzinc chloride could
be generated from furfuryl chloride and Rieke zinc following the
protocol previously used for generation of benzylzinc chloride.6
The profound, and somewhat unexpected, effect on Mtb growth
found for the Z-6-[1(3H)-isobenzofuranylidenemethyl]purine 3a,
prompted us to synthesize and determine antimycobacterial activ-
ity for the related compound 3b (Fig. 1) where the substitution pat-
tern elsewhere in the molecule is optimized according to our
current SAR knowledge, as well as the optimized 6-(benzofur-2-
* Corresponding author. Tel.: +47 22857019; fax: +47 22855507.
E-mail address: l.l.gundersen@kjemi.uio.no (L.-L. Gundersen).
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.08.012

M. Br
ꢀndvang et al. / Bioorg. Med. Chem. 17 (2009) 6512–6516
6513
Figure 1. Structures of antimycobacterial purines and previously reported MIC values,2a,d,e,3 summary of SAR for antimycobacterial 9-benzylpurines, and target molecules in
the study.
This constitutes the first formation and synthetic application of a
furfurylmetal reagent carrying no stabilizing groups on the furyl
ring.
4. Antimycobacterial activity
The novel purine derivatives 2b, 3b, 5, 6, and 7b were screened
for antibacterial activity against M. tuberculosis H37Rv in vitro and
the IC90 and IC50 values are presented in Table 2 together with
comparable data for the compounds 1d and 3a synthesized earlier.
Previously determined MIC values (Mtb) for compounds 1a–1d, 2a,
3a, and 4a are displayed in Figure 1.
3. Structure
In line with our previous observations on compound 3a,3 no
quinoid benzo[c]furylmethylpurine tautomer could be detected
in the 1H NMR spectrum of the Z-6-[1(3H)-isobenzofuranylide-
nemethyl]purine 3b or the isomer 4b. On the other hand, 1H
NMR revealed that compound 7 was present only as the furfurylp-
urine 7b. Electronic structure calculations supported these findings
(see Supplementary data). The furfurylpurine 7 also crystallized as
the 7b tautomer (Fig. 3). The benzyl group in crystalline compound
7b is oriented quite different from what is previously found by
X-ray crystallography for the benzylic substituent in the 6-furylp-
urine 1d7 and related structures,8 for further discussions, see
Supplementary data.
Both the 6-furyl- 1d and 6-benzofurylpurine 2b were found to be
highly potent inhibitors of Mtb (IC90 <0.20
pected, both (isobenzofuranylidenemethyl)purines 3a and 3b also
displayed considerable growth inhibition (IC90 3–5 g/mL,
8–12 M). However, the furfurylpurine 7b was essentially inactive
(IC90 >100 g/mL) whereas the benzyl- 6 and styrylpurine 5 were
only slightly weaker inhibitors (IC90 6–11 g/mL, 16–30 M) com-
lg/mL, <0.6 lM). As ex-
l
l
l
l
l
pared to the (isobenzofuranylidenemethyl)purines 3. None of the
novel compounds described herein could compete with 6-furyl- 1d
or 6-benzofurylpurine 2b where the aryl substituent is connected
Figure 2. Target molecules 5–7 and their structural relationship with target molecule 3b.

6514
M. Brꢀndvang et al. / Bioorg. Med. Chem. 17 (2009) 6512–6516
Scheme 1. Reagents and conditions: (a) (Ph3P)2PdCl2, CuI, (i-Pr)2NH, DMF, 60 °C; (b) TFA, CH2Cl2.
tra were recorded 75 MHz using the same instrument. Mass spec-
tra under electron impact conditions (EI) were recorded at 70 eV
ionizing voltage with a VG Prospec instrument, and are presented
as m/z (% rel. int.). Elemental analyses were performed by Ilse Beetz
Mikroanalytisches Laboratorium, Kronach, Germany. Melting
points were determined with a C. Reichert melting point apparatus
or a Büchi Melting Point B-545 apparatus and are uncorrected.
DMF was distilled from BaO and stored over 4 Å mol. sieve,
dichloromethane was distilled from CaH2, and THF from Na/benzo-
phenone. Antimycobacterial activity was determined as previously
reported.2 The following compounds were prepared according to
literature procedures: 2-chloro-6-(2-furyl)-9-(4-methoxyphenylm-
Scheme 2. Reagents and conditions: (a) R-Met, Pd-cat, 50 °C, for more details, see
Table 1.
ethyl)-9H-purine
1d,2d
(Z)-9-benzyl-6-[isobenzofuran-1(3H)-
Table 1
ylidenemethyl]-9H-purine 3a,2 2,6-dichloro-9-(4-methoxyphe-
nylmethyl)-9H-purine 8,2d (E)-tributyl(phenylethenyl)stannane,9
tributyl(benzo[b]fur-2-yl)stannane,10 and furfuryl chloride.11 Ben-
zylzinc chloride was generated from benzyl chloride and Rieke
zinc12 according to a published procedure6 and the concentration
of the solution was determined by hydrolysis and iodolysis.13 Fur-
furylzinc chloride was generated from furfuryl chloride following
the same protocol.
Reaction conditions applied in synthesis of compounds 5–7
–Met
Pd-catalyst
Solvent
Time (h)
Yield (%)
–SnBu3
–SnBu3
–ZnCl
[(2-Furyl)3P]4Pd
[(2-Furyl)3P]4Pd
(Ph3P)4Pd
DMF
DMF
THF
THF
8
7
5
3
78, 2b
77, 5
69, 6
59, 7
–ZnCl
(Ph3P)4Pd
directly to C-6 in the purine, with respect to inhibition of Mtb. How-
ever, and in contrast to our previous believe (Fig. 1),2 also other sub-
stituents (i.e., styryl- or isobenzofuranylidenemethyl-) in the 6-
position may result in purines with a considerable antimycobacteri-
al activity. The compounds displaying IC90 values against Mtb lower
5.1. X-ray crystallographic analysis for compound 7b
Crystals of 7b suitable for X-ray crystallography were obtained
from benzene solution at +4 °C. X-ray data were collected on a Sie-
mens SMART CCD diffractometer14 using graphite monochromated
than 10
cells (VERO cells, Table 2). All compounds examined, except 3a,
showed IC50 against VERO cells >40 g/mL. We have previously re-
lg/mL were also screened for toxicity towards mammalian
Mo Ka radiation (k = 0.71073 Å). Data collection method: x-scan,
l
step 0.3°, crystal to detector distance 5 cm. Data reduction and cell
determination were carried out with the SAINT and XPREP programs.
Absorption corrections were applied by the use of the SADABS pro-
gram.15 The structure was determined and refined using the SHELX
program package.16 The non-hydrogen atoms were refined with
isotropic thermal parameters; H atoms were positioned geometri-
cally and allowed to ride and rotate (for the CH3 group) on their
carrier atoms, with C–H bond lengths of 0.95 (aromatic C–H),
0.99 (CH2) or 0.98 Å (CH3) and with Uiso(H) = 1.2Ueq(C) for CH2
and aromatic C–H or 1.5Ueq(C) for CH3. Crystal structure data for
7b are available from the Cambridge Crystallographic Data Center,
CCDC no. 643827.
ported that compound 1c (Fig. 1) showed virtually no cross resis-
tance against a panel of drug-resistant Mtb strains.2b We assume
that the closely related structures reported herein act by the same,
currently unknown, mechanism of action as purine 1c, so we have
reasonstobelievethatcrossresistancewillnotbe anissuefortheno-
vel compounds described herein.
5. Experimental
The 1H NMR spectra were recorded at 300 MHz with a Bruker
Avance DPX 300 instrument, and the 1H decoupled 13C NMR spec-
Figure 3. X-ray structure of compound 7b, the gas-phase equilibrium structure of compound 7b, and X-ray structure of compound 1d.7

M. Br
ꢀndvang et al. / Bioorg. Med. Chem. 17 (2009) 6512–6516
6515
Table 2
(CH in benzofuryl), 123.6 (CH in benzofuryl), 126.4 (C-1 in Ar),
127.2 (CH in benzofuryl), 128.1 (C in benzofuryl), 128.4 (C-5),
129.6 (CH in Ar), 145.1 (C-8), 147.6 (C-6/C-2), 149.7 (C-2 in ben-
zofuryl), 153.7 (C-4), 154.5 (C-2/C-6), 156.0 (C in benzofuryl) and
159.9 (C-4 in Ar) ppm. MS (EI): m/z (%): 392/390 (15/42) [M]+,
234 (1), 195 (1), 181 (2), 122 (9), 121 (100). HRMS (EI): calcd for
C21H15ClN4O2 390.0884, found 390.0886. C21H15ClN4O2 (390.8):
C, 64.54; H, 3.87; N, 14.34. Found: C, 64.50; H, 3.93; N, 14.20.
Activity against M. tuberculosis for purines 1d, 2b, 3a, 3b, 5, 6, and 7b as well as
cytotoxicity against VERO cells for selected compoundsa
Compound
IC90 M. tuberculosis
IC50 M. tuberculosis
IC50 VERO
H37Rv (
l
g/mL),
l
M
H37Rv (
l
g/mL),
lM
cells (
lg/
values in bracketsb
values in bracketsb
mL)c
1d
2b
3a
3b
5
<0.20 (<0.59)
<0.20 (<0.51)
2.7 (7.9)
4.9 (12)
6.1 (16)
<0.20 (<0.59)
<0.20 (<0.51)
1.5 (4.3)
<0.20 (<0.48)
3.0 (8.0)
>40
>40
17
>40
>40
n.d.
n.d.
5.6. 2-Chloro-6-[(Z)-1(3H)-isobenzofuranylidenemethyl]-9-(met-
hoxyphenylmethyl)-9H-purine (3b)
6
7b
11 (30)
>100 (>280)
7.4 (20)
>100 (>280)
a
b
c
2,6-Dichloro-9-(4-methoxyphenylmethyl)-9H-purine 8 (155 mg,
0.50 mmol) was added to a stirring solution of CuI (9.5 mg, 0.050
mmol), bis(triphenylphosphine)palladium(II) chloride (18 mg,
Structures of compounds are shown in Schemes 1 and 2.
IC90 amicain 0.13 g/mL (0.22 M) and IC50 amicain 0.07
EC50 hyamine 0.01 g/mL.
l
l
l
lg/mL (0.12 lM).
0.025 mmol), and dry diisopropylamine (420 lL, 3.00 mmol) in dry
5.2. Crystal data for C18H15ClN4O2 7b
DMF (2.5 mL) under N2. The solution was heated to 60 °C before 2-
ethynylbenzenemethanol 9 (79 mg, 0.60 mmol) dissolved in DMF
(1 mL) was added dropwise over 1 h. After stirring for additional
4 h at 60 °C, the reaction mixture evaporated in vacuo with a small
amount of silica. The residue was added on top of a silica gel column,
and the product, as a ca. 7:3 E/Z mixture was isolated by flash chro-
matography eluting with CH2Cl2–acetone (19:1) followed by
CH2Cl2–acetone (9:1). The isomeric mixture was dissolved in CH2Cl2
M = 354.79, monoclinic, P2(1)/n a = 4.5528 (6) Å, b = 18.867(3) Å,
c = 18.955(3) Å, b = 96.486(2)°, V = 1617.8(4) Å3, Z = 4, Dx = 1.457
Mg mꢀ3 = 0.26 mmꢀ1, T = 105(2) K, measured 16,774 reflections
, l
in 2h range 6.2–60.6°, Rint = 0.032. To 128 parameters refined against
4518 F2, R = 0.0333 for 3293 Io >2
r (Io) and 0.0553 for all data.
5.3. Antimycobacterial data
(30 mL) and trifluoroacetic acid (74 lL, 0.96 mmol) was added. After
stirring for 1 h at ambient temperature the reaction mixture was
washed with satd aq NaHCO3 (2 ꢁ 20 mL), water (20 mL), brine
(20 mL), dried (MgSO4) and evaporated in vacuo. The product was
purified by flash chromatography on silica gel eluting with
CH2Cl2–acetone (9:1); yield 101 mg (50%), pale yellow crystals. 1H
NMR (300 MHz, CDCl3) d = 3.76 (s, 3H, OCH3), 5.28 (s, 2H, NCH2),
5.71 (s, 2H, OCH2), 6.72 (s, 1H, @CH), 6.87 (d, J = 8.7 Hz, 2 H, Ar),
7.25 (d, J = 8.7 Hz, 2H, Ar), 7.40–7.48 (m, 3H, Ar0), 7.79–7.82 (m,
1H, Ar0) and 7.84 (s, 1H, 8-H) ppm. 13C NMR (75 MHz, CDCl3)
d = 46.8 (NCH2), 55.3 (OCH3), 77.2 (OCH2), 88.6 (@CH), 114.5 (CH in
Ar), 121.3 (CH in Ar0), 121.8 (CH in Ar0), 126.9 (C-1 in Ar), 128.5 (CH
in Ar0), 129.0 (C-5), 129.6 (CH in Ar), 131.1 (CH in Ar0), 133.9 (C in
Ar0), 141.5 (C in Ar0), 142.7 (C-8), 152.1 (C-4), 154.6 (C-2/C-6),
156.2 (C-6/C-2), 159.8 (C-4 in Ar) and 165.7 (@C) ppm. MS (EI): m/
z (%): 406/404 (9/25) [M]+, 285 (3), 284 (2), 283 (8), 140 (2), 121
(100). HRMS (EI): calcd for C22H17ClN4O2 404.1040, found
404.1030. C22H17ClN4O2 (404.9): C, 65.27; H, 4.23; N, 13.84. Found:
C, 64.94; H, 4.16; N, 13.81.
The purines were screened for antimycobacterial activities
essentially as described before.2,17 Compounds were tested in 10
twofold dilutions, from 100 to 0.19 lg/mL, against M. tuberculosis
H37Rv (ATCC 27294) in BACTEC 12B medium using the Microplate
Alamar Blue Assay (MABA). The IC90 and IC50 values are deter-
mined from the dose–response curve as the IC90 using the curve fit-
ting program XLFIT, formula 205.
5.4. Activity against VERO cells
The compounds were screened for mammalian cell cytotoxicity
to VERO cells essentially as described before;2 after 72 h exposure,
viability is assessed using the CellTiter 96Ò Non-Radioactive Cell
Proliferation Assay (MTT) reagent from Promega. Cytotoxicity is
determined from the dose–response curve as the EC50 using the
curve fitting program XLFIT, formula 205.
5.5. 6-(Benzofuran-2-yl)-2-chloro-9-(4-methoxyphenylmeth-
yl)-9H-purine (2b)
5.7. (E)-2-Chloro-9-(4-methoxybenzyl)-6-(2-phenylethenyl)-
9H-purine (5)
A mixture of tris(dibenzylideneacetone)dipalladium, Pd2dba3
(28 mg, 0.030 mmol), and tri(2-furyl)phosphine (51 mg, 0.22 mmol)
in dry DMF (4 mL) was stirred at ambient temperature for 5 min,
The product was formed by Stille coupling between 2,6-dichloro-
9-(4-methoxyphenylmethyl)-9H-purine 8 (309 mg, 1.0 mmol) and
(E)-tributyl(phenylethenyl)stannane (1.12 g, 1.20 mmol, ca. 42%
purity) as described for compound 3b above. The reaction time
was 7 h, and the product purified by flash chromatography on silica
gel eluting with CH2Cl2–acetone (29:1), followed by CH2Cl2–acetone
(19:1) and finally CH2Cl2–acetone (9:1); yield 292 mg (77%), color-
less foam. 1H NMR (300 MHz, CDCl3) d = 3.75 (s, 3H, OCH3), 5.30 (s,
2H, NCH2), 6.88 (d, J = 8.8 Hz, 2H, Ar), 7.26 (d, J = 8.8 Hz, 2H, Ar),
7.32–7.42 (m, 3H, Ph), 7.59 (d, J = 16.1 Hz, 1H, CH@), 7.66–7.69 (m,
2H, Ph), 7.94 (s, 1H, 8-H) and 8.42 (d, J = 16.1 Hz, 1H, CH@) ppm.
13C NMR (75 MHz, CDCl3) d = 47.0 (NCH2), 55.3 (OCH3), 114.5 (CH
in Ar), 121.4 (CH@), 126.6 (C-1 in Ar), 128.1 (CH in Ph), 128.8 (CH
in Ph), 129.6 (CH in Ar), 129.8 (CH in Ph), 130.0 (C-5), 135.7 (C-1 in
Ph), 141.7 (CH@), 144.3 (C-8), 153.4 (C-4), 154.3 (C-2), 155.8 (C-6)
and 159.9 (C-4 in Ar) ppm. MS (EI): m/z (%): 378/376 (13/36) [M]+,
257 (1), 255 (4), 122 (9), 121 (100). HRMS (EI): calcd for C21H17ClN4O
376.1091, found376.1093. C21H17ClN4O(376.8): C, 66.93;H, 4.55; N,
14.87. Found: C, 66.76; H, 4.46; N, 14.71.
before
a solution of 2,6-dichloro-9-(4-methoxyphenylmethyl)-
9H-purine 8 (309 mg, 1.0 mmol) in DMF (4 mL) was added. After
an additional 5 min, tributyl(benzo[b]fur-2-yl)stannane (575 mg,
ca. 1.20 mmol, ca. 85% pure) was introduced, the resulting mixture
stirred at 50 °C for 8 h and evaporated in vacuo. A satd solution of
potassium fluoride in methanol (40 mL) was added to the residue,
the mixture was stirred over night and evaporated in vacuo to-
gether with a small amount of silica gel. The residue was added
on top of a silica gel column, and the product purified by flash
chromatography eluting with CH2Cl2–acetone (29:1), followed by
CH2Cl2–acetone (19:1); yield 303 mg (78%), mp 189 °C, colorless
crystals. 1H NMR (300 MHz, CDCl3) d = 3.75 (s, 3H, OCH3), 5.32 (s,
2H, NCH2), 6.87 (d, J = 8.7 Hz, 2H, Ar), 7.24–7.30 (m, 3H, Ar and
benzofuryl), 7.38–7.43 (m, 1H, benzofuryl), 7.67–7.70 (m, 2H, ben-
zofuryl), 8.02 (s, 1H, 8-H) and 8.28 (s, 1H, 3-H in benzofuryl) ppm.
13C NMR (75 MHz, CDCl3) d = 47.1 (NCH2), 55.3 (OCH3), 112.4 (CH
in benzofuryl), 114.6 (CH in Ar), 115.2 (CH in benzofuryl), 122.4

6516
M. Brꢀndvang et al. / Bioorg. Med. Chem. 17 (2009) 6512–6516
5.8. 6-Benzyl-2-chloro-9-(4-methoxyphenylmethyl)-9H-purine
C18H15ClN4O2 354.0884, found 354.0873. C18H15ClN4O2 (354.8):
(6)
C, 60.94; H, 4.26; N, 15.79. Found: C, 60.92; H, 4.28; N, 15.71.
2,6-Dichloro-9-(4-methoxyphenylmethyl)-9H-purine
8
(309
Acknowledgments
mg, 1.0 mmol) was added to a solution of tetrakis(triphenylphos-
phine)palladium(0) [generated in situ from tris(diphenylmethylide-
neacetone)dipalladium chloroform adduct (23 mg, 0.025 mmol)
and triphenylphosphine (53 mg, 0.20 mmol)] in dry THF (4 mL) at
ambient temperature under N2. After 10 min, a solution of benzyl-
zinc chloride (1.83 mL, 1.52 mmol, 0.83 M) in THF was added and
the mixture stirred at 50 °C for 5 h. Satd aq NH4Cl (10 mL) was added
and the resulting mixture was extracted with EtOAc (4 ꢁ 25 mL).
The combined organic extracts were washed with brine (2 ꢁ
20 mL), dried (MgSO4), and evaporatedin vacuo with a small amount
on silica. The residue was added on top of a silica gel column, and the
product purified by flash chromatography eluting with CH2Cl2–ace-
tone (29:1), followed by CH2Cl2–acetone (19:1) and finally CH2Cl2–
acetone (9:1); yield 250 mg (69%), colorless oil. 1H NMR (300 MHz,
CDCl3) d = 3.74 (s, 3H, OCH3), 4.43 (CH2), 5.25 (s, 2H, NCH2), 6.85
(d, J = 8.7 Hz, 2H, Ar), 7.11–7.27 (m, 2H, Ar and 3H, Ph), 7.45–7.48
(m, 2H, Ph) and 7.92 (s, 1H, 8-H) ppm. 13C NMR (75 MHz, CDCl3)
d = 39.5 (CH2), 47.0 (NCH2), 55.3 (OCH3), 114.5 (CH in Ar), 126.4 (C-
1 in Ar), 126.7 (CH in Ph), 128.5 (CH in Ph), 129.3 (CH in Ph), 129.6
(CH in Ar), 131.7 (C-5), 137.0 (C-1 in Ph), 144.4 (C-8), 152.8 (C-4),
154.1 (C-2), 159.9 (C-4 in Ar) and 162.8 (C-6) ppm. MS (EI): m/z
(%): 366/364 (24/60) [M]+, 245 (9), 243 (27), 207 (2), 180 (3), 153
(2), 121 (100). HRMS (EI): calcd for C20H17ClN4O 364.1091, found
364.1090. C20H17ClN4O (363.8): C, 65.84; H, 4.70; N, 15.36. Found:
C, 65.83; H, 4.84; N, 15.26.
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. We are grateful for all
help provided by Dr. Cecil Kwong and co-workers. This work has
received support through a grant of computer time from the
Research Council of Norway (Grant No. NN1118K). NFR is also
greatly acknowledged for partial financing of the Bruker Avance
instrument used in this study. We thank Dr. Osamu Sekiguchi,
Department of Chemistry, University of Oslo for the single-crystal
data collection and initial refinement and Tom Chr. Berg for the
synthesis of compound 3a.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmc.2009.08.012.
References and notes
1. See for instance: Bhowruth, V.; Dover, L. G.; Besra, G. S. Prog. Med. Chem. 2007,
45, 169. and references therein.
2. (a) Bakkestuen, A. K.; Gundersen, L.-L.; Langli, G.; Liu, F.; Nolsøe, J. M. N. Bioorg.
Med. Chem. Lett. 2000, 10, 1207; (b) Gundersen, L.-L.; Nissen-Meyer, J.;
Spilsberg, B. J. Med. Chem. 2002, 45, 1383; (c) Andresen, G.; Gundersen, L.-L.;
Nissen-Meyer, J.; Rise, F.; Spilsberg, B. Bioorg. Med. Chem. Lett. 2002, 12, 567; (d)
Bakkestuen, A. K.; Gundersen, L.-L.; Utenova, B. T. J. Med. Chem. 2005, 48, 2710;
5.9. 2-Chloro-6-(furan-2-ylmethyl)-9-(4-
(e) Brꢀndvang, M.; Gundersen, L.-L. Bioorg. Med. Chem. 2005, 13, 6360; (f)
methoxyphenylmethyl)-9H-purine (7b)
Br ndvang, M.; Gundersen, L.-L. Bioorg. Med. Chem. 2007, 15, 7144.
3. Berg, T. C.; Bakken, V.; Gundersen, L.-L.; Petersen, D. Tetrahedron 2006, 62,
6121.
4. Langli, G.; Gundersen, L.-L.; Rise, F. Tetrahedron 1996, 52, 5625.
5. Takanishi, K.; Hirokazu, U.; Kuwajima, I. Tetrahedron Lett. 1987, 28, 2281.
6. Zhu, L.; Wehmeyer, R. M.; Rieke, R. D. J. Org. Chem. 1991, 56, 1445.
ꢀ
The product was formed by Negishi coupling between 2,6-di-
chloro-9-(4-methoxyphenylmethyl)-9H-purine
8 (309 mg, 1.0
mmol) and furfurylzinc chloride (3.9 mL, 1.60 mmol, 0.41 M) as de-
scribed for compound 6 above. The reaction time was 3 h, and the
product purified by flash chromatography on silica gel eluting with
CH2Cl2–acetone (29:1), followed by CH2Cl2–acetone (19:1) and fi-
nally CH2Cl2–acetone (9:1); yield 208 mg (59%), mp 135 °C, color-
less crystals. 1H NMR (300 MHz, CDCl3) d = 3.74 (s, 3H, OCH3),
4.46 (s, 2H, CH2), 5.27 (s, 2H, NCH2), 6.22 (dd, J = 3.2 and 0.7 Hz,
1H, 3-H in furyl), 6.25 (dd, J = 3.2 and 1.9 Hz, 1H, 4-H in furyl),
6.85 (d, J = 8.7 Hz, 2H, Ar), 7.25 (d, J = 8.7 Hz, 2H, Ar), 7.28 (dd,
J = 1.8 and 0.8 Hz, 1H, 5-H in furyl) and 7.94 (s, 1H, 8-H) ppm.
13C NMR (75 MHz, CDCl3) d = 32.2 (CH2), 47.0 (NCH2), 55.3
(OCH3), 107.6 (C-3 in furyl), 110.5 (C-4 in furyl), 114.5 (CH in Ar),
126.4 (C-1 in Ar), 129.6 (CH in Ar), 131.7 (C-5), 141.9 (C-5 in furyl),
144.7 (C-8), 149.9 (C-2 in furyl), 152.9 (C-4), 154.1 (C-2), 159.8 (C-
6) and 159.9 (C-4 in Ar) ppm. MS (EI): m/z (%): 356/354 (15/43)
[M]+, 121 (100), 91 (3), 78 (5), 77 (5). HRMS (EI): calcd for
7. (a) Brꢀndvang, M.; Gundesen, L.-L. Acta. Crystallogr., Sect. C 2007, 63, o274–
o276; (b) Brꢀndvang, M.; Gundersen, L.-L. Acta. Crystallogr., Sect. E 2007, 63,
o3036.
8. Mazumdar, P. A.; Das, A. K.; Bakkestuen, A. K.; Gundersen, L.-L.; Bertolasi, V.
Acta. Crystallogr., Sect. E 2001, 57, o1052.
9. Labadie, J. W.; Tueting, D.; Stille, J. K. J. Org. Chem. 1983, 48, 4634.
10. Liebeskind, L. S.; Wang, J. J. Org. Chem. 1993, 58, 3550.
11. Chaudhari, S. S.; Akamanchi, K. G. Synlett 1999, 1763.
12. (a) Chen, T.-A.; Wu, X.; Rieke, R. D. J. Am. Chem. Soc. 1995, 117, 233–244; (b)
Rieke, R. D.; Hanson, M. V.; Brown, J. D.; Niu, Q. J. J. Org. Chem. 1996, 61, 2726.
13. Knochel, P.; Jones, P.; Langer, F. In Organozinc Reagents: A Practical Approach;
Knochel, P., Jones, P., Eds.; Oxford University Press: Oxford, 1999; p 14.
14. SMART (Version 5.625) and SAINT+ (Version 6.02). Area-Detector Control and
Integration Software, Bruker Analytical X-ray Instruments, Madison, WI, 1998.
15. Sheldrick, G. M. SADABS. Program for Empirical Correction of Area Detector Data,
University of Göttingen, Germany, 1996.
16. Sheldrick, G. M. SHELXL (release 97-2)—Programs for Crystal Structure Analysis
Structure, University of Göttingen, Germany, 1997.
17. Collins, L. A.; Franzblau, S. G. Antimicrob. Agents Chemother. 1997, 41, 1004.