Synthesis of imidazole derivatives with antimycobacterial activity

Article abstract of DOI:10.1002/ardp.200900149

4-Substituted 1-(p-methoxybenzyl)imidazoles were designed and synthesized in order to mimic parts of the structure of highly potent antimycobacterial 6-aryl-9-(p-methoxybenzyl)purines. 4-Haloimidazoles were subjected to Pd-catalyzed cross-coupling in order to introduce a (hetero)-aryl group, or they were converted to Grignard reagents and reacted with (hetero)arylaldehydes. Further transformations of the adducts gave a variety of potential antimycobacterials with different "spacers" between the imidazole and (hetero)aryl group. The adduct from furfural was rearranged to a cyclopentenone derivative when treated with methanol under acidic conditions. Several target compounds exhibited antimycobacterial activity in vitro (IC₉₀ 13 μg/mL for the best inhibitors), but they were not as active as the most potent purines and pyrimidines synthesized before.

Full text of DOI:10.1002/ardp.200900149

40
Arch. Pharm. Chem. Life Sci. 2010, 343, 40–47
Full Paper
Synthesis of Imidazole Derivatives with Antimycobacterial
Activity
Pedro O. Miranda and Lise-Lotte Gundersen
Department of Chemistry, University of Oslo, Blindern, Oslo, Norway
4-Substituted 1-(p-methoxybenzyl)imidazoles were designed and synthesized in order to mimic
parts of the structure of highly potent antimycobacterial 6-aryl-9-(p-methoxybenzyl)purines. 4-
Haloimidazoles were subjected to Pd-catalyzed cross-coupling in order to introduce a (hetero)-
aryl group, or they were converted to Grignard reagents and reacted with (hetero)arylaldehydes.
Further transformations of the adducts gave a variety of potential antimycobacterials with
different “spacers” between the imidazole and (hetero)aryl group. The adduct from furfural was
rearranged to a cyclopentenone derivative when treated with methanol under acidic conditions.
Several target compounds exhibited antimycobacterial activity in vitro (IC90 13 lg/mL for the best
inhibitors), but they were not as active as the most potent purines and pyrimidines synthesized
before.
Keywords: Antimycobacterial activity / Cross-coupling / Imidazole / Metallation /
Received: June 26, 2009; accepted: September 27, 2009
DOI 10.1002/ardp.200900149
intact purines (Fig. 1), we now focus on non-purine ana-
Introduction
logs [11, 12], and recently reported high antimycobacte-
rial activities in vitro for certain 5-formylamino-4-(2-furyl)-
pyrimidines (Fig. 2) [12]. Herein, we report the synthesis
and antimycobacterial activities for imidazole analogs of
antimycobacterial purines. A general structure is shown
in Fig. 2.
We have previously reported that certain 6,9-disubsti-
tuted purines are potent inhibitors of Mycobacterium
tuberculosis (Mtb) in vitro [1–5]. These compounds display
several properties which make them highly interesting
as potential drugs against tuberculosis: high selectivity
towards Mtb compared to other microorganisms, activity
against several drug-resistant strains of Mtb, generally
low toxicity towards mammalian cells, and ability to
affect Mtb inside macrophages. A summary of the current
SAR knowledge as well as the structures of some of the
most active compounds identified in this series is shown
in Fig. 1.
It has been estimated that approximately 30 million
people will die from tuberculosis in about ten years.
Agents that reduce the duration and complexity of the
current therapy would have a major impact on the over-
all cure rate, meaning, there is an urgent need for new
antimycobacterials [6–10]. After exploring the SAR of
Results and discussion
Imidazoles can be conveniently N-alkylated when treated
with base followed by an alkyl halide or sulfonate [13–
20]. However, N-alkylation of 4(5)-substituted imidazoles
gives both regioisomers in most cases. The ratio of iso-
mers is difficult to predict, as the regiochemical outcome
generally is dependent on the structure of both imid-
azole and alkylating agent as well as the exact reaction
conditions used [15–20]. However, some 1,4-disubsti-
tuted imidazoles are available in high yields when the
parent imidazole is alkylated in the presence of base and
alkylating agent followed by an alkyl-halide-induced iso-
merization of the 1,5- to 1,4-disubstituted isomer [21].
This strategy was attempted for the synthesis of the 1,4-
Correspondence: Lise-Lotte Gundersen, Department of Chemistry, Uni-
versity of Oslo, P.O. Box 1033, Blindern, N-0315 Oslo, Norway.
E-mail: l.l.gundersen@kjemi.uio.no
Fax: +47 228 55507
i 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2010, 343, 40–47
Antimycobacterial imidazoles
41
Figure 1. SAR summary for antimycobacterial purines and structures of some of the most active compounds.
Figure 2. General structure of recently reported antimycobacterial pyrimidines and general structure of the target imidazoles in this
study.
Reactions and conditions: (a) p-MeO-C6H4-CH2Cl, NaH, DMF, 08C to r.t.; (b) p-MeO-C6H4-CH2Cl (10%), DMF, 758C.
Scheme 1. Synthesis of compounds 1a–d and 2a–d.
disubstituted imidazoles 2b–2d, whereas compound 2a Stille coupling on iodo compound 2c (Scheme 2). The
was synthesized as described before (Scheme 1) [14]. N- reactive catalyst [(2-furyl)3P]4Pd and a relatively high tem-
Alkylation of the haloimidazoles 1b and 1c, gave the 1,4- perature (908C) are the requirements for the Stille cou-
substituted regioisomer 2b and 2c as the major product pling in order to obtain product 2b in a reasonable yield.
and these were present as the only isomers after the
In the parent purines (Fig. 1), the furyl group is sepa-
alkyl-halide-catalyzed isomerization. N-Alkylation of the rated from the imidazole part of the purine by one car-
formylimidazole 1d, on the other hand, resulted in a 1:1 bon (the purine C-6); this led us to synthesize the imid-
mixture of the regioisomers 2d and 3d, and no isomeriza- azole derivatives 5–11 (Scheme 2). Synthesis of com-
tion took place when the mixture was treated with a cata- pounds 6 by Pd-catalyzed coupling reactions on the halo-
lytic amount of the benzylic chloride at 758C for 24 h.
imidazoles 2 met with little success. Instead, compounds
Aryl groups could be introduced directly in the imid- 6 were synthesized via the alcohols 5. 4(5)-Bromoimida-
azole 4-position, by Pd-catalyzed coupling reactions on 4- zole 1b has been effectively lithiated by treatment with t-
iodoimidazole 2c. Different strategies were applicable as BuLi and subsequently trapped with aldehydes [22–23].
illustrated by the formation of the phenylimidazole 4a Having the desired substitution pattern in the N-alky-
by coupling between phenyl iodide and zincated imid- lated 4-halopurines 2b and 2c, we preferred to metallate
azole, and the synthesis of the 4-(2-furyl)imidazole by these compounds, and various conditions were tried
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P. O. Miranda and L.-L. Gundersen
Arch. Pharm. Chem. Life Sci. 2010, 343, 40–47
Reactions and conditions: (a) 1.) MeMgI, 2.) ZnCl2, 3.) PhI, Pd(PPh3)4, THF, D; (b) (2-Furyl)SnBu3, [(2-furyl)3P]4Pd, DMF, 908C; (c) 1.) MeMgI, CH2Cl2, 2.) ArCHO; (d) Et3SiH,
TFA, CH2Cl2; (e) MnO2, CH2Cl2; (f) 1.) MeMgI, CH2Cl2, 2.) excess ArCHO; (g) MeMgI, THF; (h) 10% HCl (aq), 708C.
Scheme 2. Synthesis of compounds 4a–b, 5a–b, 6a–b, 7a–b, 9a–b, 10a–b, and 11.
Table 1. Metallation conditions employed in the synthesis of
compounds 5 from compounds 2.
Table 2. Reaction conditions employed in the synthesis of com-
pounds 7 from compounds 5.
Starting
materia
Compound 2
RMet
ArCHO
Yield (%)
Compound 5 starting
material (%)
Recovered
Ar
Reagents Solvent
Yield (%)
Compound 7 Compound 9
Yield (%)
Compound 2
p-MeO-C6H4-
2-Furyl-
p-MeO-C6H4-
2-Furyl-
p-MeO-C6H4-
2-Furyl-
p-MeO-C6H4-
2-Furyl-
NaH, MeI DMF
NaH, MeI DMF
NaH, MeI THF
NaH, MeI THF
NaH, MeI THF-DMF (2:1) 39, 7a
NaH, MeI THF-DMF (2:1) 51, 7b
–
–
–
59, 9a
56, 9b
70, 9a
–
–
–
2b
2b
2b
2c
2c
2c
t-BuLi
(p-MeO-C6H4)CHO
(p-MeO-C6H4)CHO
(p-MeO-C6H4)CHO
(p-MeO-C6H4)CHO
(p-MeO-C6H4)CHO 63, 5a
(2-Furyl)CHO 81, 5b
–
–
–
–
70
63
82
76
–
EtMgBr
MeMgI
EtMgBr
MeMgI
MeMgI
52, 7b
Ag2O, MeI CH2Cl2
Ag2O, MeI CH2Cl2
_
_
68, 9a
88, 9b
–
p-MeO-C6H4-
2-Furyl-
HCl (aq)
HCl (aq)
MeOH
MeOH
33
–
–
–
a)
(Table 1). Metallation with t-BuLi failed. It was also previ-
ously reported that the protocol is only applicable for
imidazoles, which are not N-alkylated [22]. N-Trityl pro-
tected 4-iodoimidazole successfully underwent metal-
halogen exchange when treated with EtMgBr [24–26],
but, in our hands, compounds 5 were only formed when
the iodoimidazole 2c was metallated with MeMgI. Imid-
azolylcarbinols related to compounds 5 have also been
prepared by addition of organometallic compounds to N-
trityl-4-formylimidazole [27], but synthesis of compounds
5 from the formylimidazole 2d was not attempted since
the latter compound was not easily available in pure
form (Scheme 1).
a)
Compound 8 (48%) was isolated.
the 4-position. The exact amount of TFA (trifluoroacetic
acid) required for each substrate was fine-tuned in order
to facilitate the desired reduction, and not oxidation to
ketones 9. Compound 6a has previously been synthetized
by a N-alkylation of N-protected (SEM-protection) 5-(p-
methoxybenzyl)-1H-imidazole [28] or in several steps
from tyrosine [29].
O-Methylation of the alcohols 5 employing MeI/NaH
was sensitive to the solvent used. When the reaction was
carried out in DMF, only the ketones 9 could be isolated
(Table 2). Both methoxy ethers 7 were formed in a mix-
ture of DMF and THF, and the furylalcohol 5b could also
The alcohols 5 were subsequently reduced by Et3SiH to
give the imidazoles 6 carrying benzylic substituents in
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Arch. Pharm. Chem. Life Sci. 2010, 343, 40–47
Antimycobacterial imidazoles
43
Table 3. Antibacterial activity against M. tuberculosis compounds 2 and 4–11.a)
Compound
Ar-
-X-
IC90 M. tuberculosis
IC50 M. tuberculosis
H37Rv (lg/mL)b)
H37Rv (lg/mL)a)
2a
2b
2c
_
_
_
Ph-
2-Furyl-
p-MeO-C4H6-
2-Furyl-
p-MeO-C4H6-
2-Furyl-
p-MeO-C4H6-
2-Furyl-
H-
Br-
I-
_
n.d.d)
A100
A100
13
A100
16
28
13
36
27
76
A50
46
A50
14
32
n.d.d)
99
89
7.8
48
11
24
12
21
18
53
A50
29
A50
12
16
4a
4b
5a
5b
6a
6b
7a
7b
8
9a
9b
10a
10b
11
_
-CH(OH)-
-CH(OH)-
-CH2-
-CH2-
-CH(OMe)-
-CH(OMe)-
–
-CO-
-CO-
e)
p-MeO-C4H6-
2-Furyl-
p-MeO-C4H6-
2-Furyl-
-CMe(OH)-
-CMe(OH)-
-(C=CH2)-
p-MeO-C4H6-
A100
A100
a)
For a general structure of compounds 2–11, see Fig. 2 and Scheme 2.
IC90 amicain 0.13 lg/mL.
IC50 amicain 0.07.
0% inhibition at 6.25 lg/mL.
For detailed structure, see Scheme 2.
b)
c)
d)
e)
be O-methylated in pure THF. O-Metylation with MeI in in pure form failed as well due to severe instability of the
the presence of Ag2O afforded only the ketones 9 when product.
employed on alcohols 5. Reaction between the com-
The target compounds 2 and 4–11 were screened for
pounds 5 and methanol in the presence of acid was also antibacterial activity against M. tuberculosis H37Rv and
attempted. Ether 9a was isolated in a moderate yield, but the results are presented in Table 3. N-(p-Methoxybenzyl)
the acid-labile furan derivative rearranged to compound imidazole 2a itself and the 4-halo derivatives 2b and 2c
8. Related formation of 4-methoxy-cyclopent-2-en-1-ones were without any significant activity. However, attaching
from furylcarbinols has been reported, but not in one sin- a phenyl group in the imidazole 4-position had a pro-
gle step [30].
found positive effect and compound 4a were among the
Alcohols 5 were oxidized by MnO2 to give ketones 9 in most active compounds examined in this study (IC90 13
high yields. One-step formation of the ketones 9 was also lg/mL and IC50 7.8 lg/mL) and significantly more active
attempted employing Magnesium-Oppenauer oxidation than the corresponding 4-furylimidazole 4b. Compounds
[31] of alcohols 5 formed in situ. Compound 9a was avail- 5–7 and 9–11 were designed with different “spacers” (X
able by this route, whereas in similar attempts to prepare in the general structure in Fig. 2) between the imidazole
compound 9b, only carbinol 5b was isolated (80%).
and the (hetero)aryl rings. In all cases examined, the com-
Methylene derivatives 11 were formed directly from pounds with the p-methoxyphenyl groups were more
ketones 9 under Wittig conditions, but the complete sep- active than the 2-furyl derivatives when compounds with
aration of the products from triphenylphosphine oxide identical spacers were compared. This is in contrast to
was not achieved. Also, reaction of ketones 9 with the what we have previously observed in the purine series [4].
Petasis reagent (Cp2TiMe2) was attempted, but in these The -CH2- (compounds 6), -CH(OH)- (compounds 5), and
cases no desired products were observed. Instead a two- -CMe(OH)- (compounds 10) spacers resulted in the most
step strategy for the formation of compounds 11 was active compounds, IC90: 13-16 lg/mL in the p-methoxy-
employed. Both ketones reacted readily with MeMgI to phenyl series and IC90: 28–36 lg/mL in the 2-furyl series.
give the tertiary carbinols 10. Elimination of water to
In summary, 4-substituted 1-(p-methoxybenzyl)imid-
give compound 11 was achieved when the adduct formed azoles were designed and synthesized in order to mimic
by reaction of MeMgI with ketone 9a, was heated directly parts of the structure of highly potent antimycobacterial
with dilute acid. Several other attempts to form the corre- 6-aryl-9-(p-methoxybenzyl)purines. Several of the imid-
sponding methylene compound from the furylketone 9b azoles exhibited antimycobacterial activity, but they
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44
P. O. Miranda and L.-L. Gundersen
Arch. Pharm. Chem. Life Sci. 2010, 343, 40–47
7.38 (br s, 1H, H-2), 7.08 (d, J = 8.6 Hz, 2H, Ar), 6.84 (d, J = 8.6 Hz,
2H, Ar), 6.80 (s, 1H, H-5), 4.96 (s, 2H, CH2), 3.75 (s, 3H, CH3); 13C-
NMR (CDCl3, 75 MHz) d: 160.2 (C-4 in Ar), 139.1 (C-2), 129.6 (CH in
Ar), 127.5 (C-1 in Ar), 125.1 (C-5), 114.9 (CH in Ar), 82.3 (C, C-4),
55.8 (CH3), 51.2 (CH2); MS EI m/z (rel.%): 314 (20) [M+], 121 (100), 78
(5). HRMS calcd. for C11H11N2IO: 313.9916. Found: 313.9907. Anal.
calc. for C11H11N2IO: C, 42.06; H, 3.53; N, 8.92. Found: C, 42.24; H,
3.43; N, 8.66.
were not as active as the most potent purines and pyrimi-
dines synthesized before.
Experimental
General
1
The H-NMR spectra were recorded at 300 MHz with a Bruker
1-(4-Methoxybenzyl)-4-phenyl-1H-imidazole 4a [32]
Avance DPX 300 instrument or at 200 MHz with a Bruker Avance
DPX 200 instrument (Bruker, Bioscience). The decoupled 13C-
NMR spectra were recorded at 75 or 50 MHz using instruments
mentioned above. Mass spectra under electron-impact condi-
tions were recorded with a VG Prospec instrument (Fison Instru-
ments) at 70 eV ionizing voltage, and are presented as m/z (% rel.
int.). Elemental analyses were performed by the School of Chem-
istry, University of Birmingham, UK. Melting points were deter-
mined with a C. Reichert melting point apparatus (C. Reichert,
Vienna, Austria) or a Bꢀchi Melting Point B-545 apparatus (Bꢀchi
Labortechnik, Flawil, Switzerland) and are uncorrected. DMF
was distilled from BaO, CH2Cl2 from CaH2, and THF from Na/ben-
zophenone. Silica gel for flash chromatography was purchased
from Merck, Darmstadt, Germany (Merck No. 09385). All other
reagents were commercially available and used as received.
Compounds synthesized by literature procedures: 4(5)-iodoimid-
azole 1c [27] and 1-(4-methoxybenzyl)-1H-imidazole 2a [14].
Methylmagnesium iodide (0.20 mL, 0.61 mmol, 3.0 M in Et2O)
was added to a solution of 2c (160 mg, 0.51 mmol) in dry THF (5
mL) at 08C under argon (Ar) atmosphere. The reaction was
stirred at ambient temperature for 30 min, before ZnCl2 (139
mg, 1.02 mmol) was added. The mixture was stirred for an addi-
tional 1 h, before iodobenzene (70 lL, 0.61 mmol) followed by
Pd(PPh3)4 (29 mg, 0.03 mmol) were added. The reaction mixture
was heated at reflux for 16 h. After cooling, the mixture was
quenched with sat. aq. NH4Cl (20 mL), the phases were separated,
and the organic phase was washed with water (20 mL), dried
(MgSO4), and evaporated in vacuo. The residue was purified by
flash chromatography on a silica gel column eluting with
EtOAc/hexane (1:1); yield: 90 mg (68%), yellow solid. M.p.: 121–
1
1248C; H-NMR (CDCl3, 300 MHz) d: 7.73 (d, J = 7.3 Hz, 2H, Ph),
7.68 (br s, 1H, H-2), 7.33 (d, J = 7.3 Hz, 2H, Ph), 7.21 (br s, 1H, H-5),
7.18–7.13 (m, 3H, 1H in Ph and 2H in Ar), 6.88 (d, J = 8.7 Hz, 2H,
Ar), 5.06 (s, 2H, CH2), 3.78 (s, 3H, CH3); 13C-NMR (CDCl3, 75 MHz) d:
160.1 (C-4 in Ar), 142.3 (C-4), 137.6 (C-2), 133.8 (C-1 in Ph), 129.4
(CH in Ar), 129.0 (CH in Ph), 128.0 (C-1 in Ar), 127.4 (C-4 in Ph),
125.2 (CH in Ph), 115.3 (C-5), 114.8 (CH in Ar), 55.7 (CH3), 51.2
(CH2); MS EI m/z (rel.%): 264 (31) [M+], 122 (10), 121 (100), 77 (5).
HRMS calcd. for C17H16N2O: 264.1263. Found: 264.1259.
Chemistry
4-Bromo-1-(4-methoxybenzyl)-1H-imidazole 2b
4-Bromoimidazole 1b (100 mg, 0.680 mmol) was dissolved in dry
DMF (6 mL) under an Argon atmosphere. The mixture was cooled
to 08C before NaH (41 mg, ca. 60% in mineral oil, ca. 1.0 mmol)
was added. After stirring for 30 min., 4-methoxybenzyl chloride
(46 lL, 0.34 mmol) was added, the mixture was allowed to warm
to ambient temperature and was then stirred for 18 h. After
quenching with a small amount of water, the solvent was
removed in vacuo. The residue was dissolved in CH2Cl2 (20 mL),
and washed with H2O (10 mL) and brine (5 mL), dried (MgSO4),
and concentrated in vacuo. The ratio between isomers 2b and 3b
was 1.0:0.2 according to 1H-NMR (CH2 in 2b 4.95 ppm, CH2 in 3b
5.03 ppm). A mixture of 2b and 3b (190 mg, 0.600 mmol) was dis-
solved in dry DMF (3 mL), 4-methoxybenzyl chloride (8 lL, 0.06
mmol) was added and the resulting mixture was heated at 758C
for 24 h. After cooling, a small amount of water was added and
the solvent was removed in vacuo. The residue was purified by
flash chromatography on a silica gel column eluting with
4-(2-Furyl)-1-(4-methoxybenzyl)-1H-imidazole 4b
A solution of Pd[P(2-furyl)3]4 [generated in situ from Pd(dba)3 (13
mg, 0.013 mmol) and tri(2-furyl)phosphine (31 mg, 0.14 mmol)
in dry DMF (2 mL)] was added to a stirring solution of 2c (140 mg,
0.45 mmol) in dry DMF (4 mL) at ambient temperature under N2.
Subsequently, (2-furyl)tributyltin (0.25 mL, 0.68 mmol) was
added and the mixture was stirred at 908C under nitrogen for 18
h, and evaporated in vacuo. The residue was dissolved in sat. KF
in MeOH (10 mL), stirred at ambient temperature for 16 h, and
evaporated in vacuo together with a small amount of SiO2. The
residue was placed on top of a flash chromatography column
and the product was eluted with EtOAc; yield: 50 mg (44%), oil.
1H-NMR (CDCl3, 300 MHz) d: 7.51 (s, 1H, H-2), 7.31 (br s, 1H, H-5 in
furyl), 7.12 (d, J = 8.6 Hz, 2H, Ar), 7.08 (s, 1H, H-5), 6.85 (d, J = 8.6
Hz, 2H, Ar), 6.60 (br d, J = 3.3 Hz, 1H, H-3 in furyl), 6.39 (dd, J = 3.3
and 1.8 Hz, 1H, H-4 in furyl), 5.02 (s, 2H, CH2), 3.78 (s, 3H, CH3);
13C-NMR (CDCl3, 75 MHz) d: 160.1 (C-4 in Ar), 150.3 (C-2 in furyl),
141.2 (C-5 in furyl), 137.7 (C-2), 135.4 (C-4), 129.4 (CH in Ar), 128.0
(C-1 in Ar), 115.1 (C-5), 114.8 (CH in Ar), 111.6 (C-4 in furyl), 104.6
(C-3 in furyl), 55.8 (CH3), 51.0 (CH2); MS EI m/z (rel.%): 254 (35) [M+],
122 (9), 121 (100), 78 (6). HRMS calcd. for C15H14N2O2: 254.1055.
Found: 254.1055.
1
EtOAc/hexane (8:2); yield: 80 mg (88%), pale yellow oil. H-NMR
(CDCl3, 200 MHz) d: 7.34 (d, J = 1.3 Hz, 1H, H-2), 7.06 (d, J = 8.7 Hz,
2H, Ar), 6.78–6.87 (m, 3H, 2H in Ar and H-5), 4.95 (s, 2H, CH2),
3.76 (s, 3H, CH3); 13C-NMR (CDCl3, 75 MHz) d: 160.2 (C-4 in Ar),
137.1 (C-2), 129.6 (CH in Ar), 127.6 (C-1 in Ar), 118.7 (C-5), 115.8 (C-
4), 114.9 (CH in Ar), 55.7 (CH3), 51.4 (CH2); MS EI m/z (rel.%): 268/
266 (5/5) [M+], 122 (9), 121 (100), 106 (1), 91 (3), 90 (2), 89 (2), 78 (8),
77 (6). HRMS calcd. for C11H11BrN2O: 266.0055. Found: 266.0058.
4-Iodo-1-(4-methoxybenzyl)-1H-imidazole 2c
[1-(4-Methoxybenzyl)-1H-imidazol-4-yl](4-
methoxyphenyl)methanol 5a
MeMgI in Et2O (0.13 mL, 0.38 mmol, 3.0 M in Et2O) was added to
a solution of 2c (100 mg, 0.318 mmol) in dry CH2Cl2 (1 mL) under
Ar atmosphere at ambient temperature, and the resulting mix-
The title compound was prepared from 4-iodoimidazole 1c (1.20
g, 6.19 mmol) and 4-methoxybenzyl chloride as described for
compound 2b above. The product was purified by flash chroma-
tography on a silica gel column eluting with EtOAc/hexane (1:1);
1
yield: 740 mg (76%), colorless oil. H-NMR (CDCl3, 300 MHz) d:
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Arch. Pharm. Chem. Life Sci. 2010, 343, 40–47
Antimycobacterial imidazoles
45
ture was stirred for 5 h, before anisaldehyde (40 lL, 0.38 mmol)
was added. The reaction mixture was stirred for 18 h, quenched
by the addition of sat. aq. NH4Cl (5 mL), and extracted with
CH2Cl2 (2640 mL). The combined organic layers were washed
with water (10 mL), dried (MgSO4), and evaporated in vacuo. The
residue was purified by flash chromatography on a silica gel col-
umn eluting with MeOH/EtOAc (1:19); yield: 63 mg, (63%), color-
less solid. M.p.: 134–1368C; 1H-NMR (CDCl3, 300 MHz) d: 7.47 (br
s, 1H, H-2), 7.34 (d, J = 8.7 Hz, 2H, Ar), 7.05 (d, J = 8.7 Hz, 2H, Ar),
6.84 (d, J = 8.7 Hz, 2H, Ar), 6.83 (d, J = 8.7 Hz, 2H, Ar), 6.49 (br s,
1H, H-5), 5.72 (s, 1H, CHOH), 4.91 (s, 2H, CH2), 4.02 (br s, 1H, OH),
3.77 (s, 6H, 26CH3); 13C-NMR (CDCl3, 75 MHz) d: 160.0 (C-4 in Ar),
159.4 (C-4 in Ar), 146.6 (C-4), 137.3 (C-2), 135.5 (C-1 in Ar), 129.4
(CH in Ar), 128.3 (CH in Ar), 128.1 (C-1 in Ar), 116.4 (C-5), 114.8
(CH in Ar), 114.1 (CH in Ar), 70.6 (CHOH), 55.7 (26CH3), 50.9
(CH2); MS EI m/z (rel.%): 324 (24) [M+], 216 (6), 203 (15), 188 (10),
122 (9), 121 (100), 77 (6). HRMS calcd. for C19H20N2O3: 324.1474.
Found: 324.1472. Anal. calcd. for C19H20N2O3: C, 70.35; H, 6.21; N,
8.64. Found: C, 70.61, H, 6.44; N, 8.36.
4-(2-Furylmethyl)-1-(4-methoxybenzyl)-1H-imidazole 6b
Triethylsilane (0.70 mL, 4.2 mmol) and trifluoroacetic acid (1.3
mL, 17 mmol) were added to a stirred solution of 5b (150 mg,
0.528 mmol) in CH2Cl2 (10 mL) at 08C under N2. The solution was
stirred for 12 h at ambient temperature and quenched by the
addition of water (10 mL) followed by Na2CO3 (s) to basic pH. The
layers were separated and the organic layer was washed with
brine (5 mL), dried (MgSO4), and evaporated in vacuo. The residue
was purified by flash chromatography on a silica gel column
eluting with EtOAc; yield: 57 mg (40%), oil. 1H-NMR (CDCl3, 300
MHz) d: 7.42 (br s, 1H, H-2), 7.28 (br s, 1H, H-5 in furyl), 7.06 (d, J =
8.7 Hz, 2H, Ar), 6.84 (d, J = 8.7 Hz, 2H, Ar), 6.62 (br s, 1H, H-5), 6.24
(dd, J = 3.1 and 1.8 Hz, 1H, H-4 in furyl), 6.04 (br d, J = 3.1, 1H, H-3
in furyl), 4.92 (s, 2H, CH2N), 3.89 (s, 2H, CH2), 3.76 (s, 3H, CH3);13C-
NMR (CDCl3, 75 MHz) d: 159.9 (C-4 in Ar), 154.1 (C-2 in furyl),
141.6 (C-5 in furyl), 139.9 (C-4), 137.0 (C-2), 129.3 (CH in Ar), 128.6
(C-1 in Ar), 116.6 (C-5), 114.7 (CH in Ar), 110.7 (C-4 in furyl), 106.4
(C-3 in furyl), 55.7 (CH3), 50.8 (CH2N), 28.2 (CH2); MS EI m/z (rel.%):
268 (26) [M+], 121 (100), 122 (8), 78 (6); HRMS calcd. for
C16H16N2O2: 268.1212. Found: 268.1217. Anal. calcd. for
C16H16N2O2: C, 71.62, H, 6.01; N, 10.44. Found: C, 71.38; H, 6.09;
N, 10.22.
(2-Furyl)[1-(4-methoxybenzyl)-1H-imidazol-4-yl]methanol
5b
1-(4-Methoxybenzyl)-4-[methoxy(4-
methoxyphenyl)methyl]-1H-imidazole 7a
The title compound was prepared from 2c (750 mg, 2.39 mmol),
MeMgI (1.0 mL, 3.0 mmol, 3.0 M in Et2O) and furfural (0.25 mL,
2.9 mmol) as described for the synthesis of 5a; yield: 550 mg
(81%), oil. 1H-NMR (CDCl3, 300 MHz) d: 7.40 (br s, 1H, H-2), 7.32 (br
s, 1H, H-5 in furyl), 7.05 (d, J = 8.7 Hz, 2H, Ar), 6.82 (d, J = 8.7 Hz,
2H, Ar), 6.75 (br s, 1H, H-5), 6.28–6.23 (m, 2H, H-4 and H-3 in
furyl), 5.75 (s, 1H, CHOH), 4.92 (s, 2H, CH2), 4.71 (s, 1H, OH), 3.75
(s, 3H, CH3); 13C-NMR (CDCl3, 75 MHz) d: 160.5 (C-4 in Ar), 156.5 (C-
2 in furyl), 143.9 (C-4), 142.9 (C-5 in furyl), 137.7 (C-2), 129.9 (CH
in Ar), 128.6 (C-1 in Ar), 117.3 (C-5), 115.3 (CH in Ar), 111.1 (C-4 in
furyl), 107.9 (C-3 in furyl), 65.3 (CHOH), 56.2 (CH3), 51.4 (CH2); MS
EI m/z (rel.%): 284 (40) [M+], 122 (10), 121 (100), 78 (5). HRMS calcd.
for C16H16N2O3: 284.1161. Found: 284.1165. Anal. calcd. for
C16H16N2O3: C, 67.59; H, 5.67; N, 9.85. Found: C, 67.76; H, 5.77; N,
9.62.
Imidazole 5a (160 mg, 0.537 mmol) was dissolved in a mixture of
THF (4 mL) and DMF (2 mL) and stirred under N2 at 08C, before
NaH (32 mg, ca. 0.81 mmol, ca. 60% in oil) was added. After 15
min, MeI (37 lL, 0.64 mmol) was added, and the resulting mix-
ture was stirred for 1 h at 08C. The reaction mixture was
quenched by the addition of water (2 mL), and extracted with
EtOAc (2640 mL). The combined organic extracts were washed
with brine (10 mL), dried (MgSO4), and evaporated in vacuo. The
residue was purified by flash chromatography on a silica gel col-
umn eluting with EtOAc; yield: 70 mg (39%), yellow solid. M.p.:
62–658C. 1H-NMR (CDCl3, 300 MHz) d: 7.42 (br s, 1H, H-2), 7.30 (d,
J = 8.7 Hz, 2H, Ar), 7.05 (d, J = 8.7 Hz, 2H, Ar), 6.85 (d, J = 8.7 Hz,
2H, Ar), 6.82 (d, J = 8.7 Hz, 2H, Ar), 6.59 (br s, 1H, H-5), 5.19 (s, 1H,
CHOCH3), 4.91 (s, 2H, CH2), 3.77 (s, 3H, CH3), 3.76 (s, 3H, CH3), 3.32
(s, 3H, CH3);13C-NMR (CDCl3, 75 MHz) d: 159.9 (C-4 in Ar), 159.5 (C-
4 in Ar), 144.8 (C-4), 137.2 (C-2), 133.3 (C-1 in Ar), 129.3 (CH in Ar),
128.8 (CH in Ar), 128.2 (C-1 in Ar), 117.0 (C-5), 114.7 (CH in Ar),
114.1 (CH in Ar), 80.6 (CHOCH3), 57.1 (CH3), 55.7 (26CH3), 50.8
(CH2); MS EI m/z (rel.%): 338 (11) [M+], 308 (24), 307 (62), 187 (16),
122 (10), 121 (100). HRMS calcd. for C20H22N2O3: 338.1630. Found:
338.1634. Anal. calcd. for C20H22N2O3: C, 70.99; H, 6.55; N, 8.28.
Found: C, 71.12, H, 6.54; N, 8.20.
1,4-Bis(4-methoxybenzyl)-1H-imidazole 6a
Triethylsilane (0.32 mL, 2.0 mmol) and trifluoroacetic acid (0.15
mL, 2.0 mmol) were added to a stirred solution of 5a (120 mg,
0.403 mmol) in CH2Cl2 (5 mL) at 08C under N2. The solution was
stirred for 3 h at ambient temperature and quenched by the
addition of sat. aq. NaHCO3 (5 mL). The mixture was extracted
with EtOAc (2620 mL) and the combined organic layers were
dried (MgSO4) and evaporated in vacuo. The residue was purified
by flash chromatography on a silica gel column eluting with
EtOAc; yield: 90 mg (73%), yellow solid. M.p.: 87–908C (Lit. [29]:
83.5–868C). 1H-NMR (CDCl3, 300 MHz) d: 7.42 (br s, 1H, H-2), 7.16
(d, J = 8.7 Hz, 2H, Ar), 7.05 (d, J = 8.7 Hz, 2H, Ar), 6.83 (d, J = 8.7 Hz,
2H, Ar), 6.79 (d, J = 8.7 Hz, 2H, Ar), 6.46 (br s, 1H, H-5), 4.91 (s, 2H,
CH2N), 3.82 (s, 2H, CH2), 3.77 (s, 3H, CH3), 3.74 (s, 3H, CH3); 13C-
NMR (CDCl3, 75 MHz) d: 159.9 (C-4 in Ar), 158.3 (C-4 in Ar), 143.6
(C-4), 137.0 (C-2), 132.8 (C-1 in Ar), 130.2 (CH in Ar), 129.2 (CH in
Ar), 128.6 (C-1 in Ar), 116.3 (C-5), 114.7 (CH in Ar), 114.2 (CH in
Ar), 55.7 (26CH3), 50.7 (CH2N), 34.6 (CH2); MS EI m/z (rel.%): 308
(43) [M+], 187 (9), 122 (10), 121 (100). HRMS calcd. for C19H20N2O2:
308.1525. Found: 308.1518. Anal. calcd. for C19H20N2O2: C, 74.00,
H, 6.54; N, 9.08. Found: C, 74.07; H, 6.49; N, 9.09.
4-[2-Furyl(methoxy)methyl]-1-(4-methoxybenzyl)-1H-
imidazole 7b
The title compound was prepared from 5b (110 mg, 0.390
mmol), NaH (24 mg, ca. 0.59 mmol, ca. 60% in oil), and MeI (27
lL, 0.43 mmol) in dry THF (4 mL) as described for the synthesis of
compound 7a; yield: 60 mg (52%), oil. 1H-NMR (CDCl3, 300 MHz)
d: 7.43 (br s, 1H, H-2), 7.37 (br d, J = 1.3 Hz, 1H, H-5 in furyl), 7.09
(d, J = 8.7 Hz, 2H, Ar), 6.89 (br s, 1H, H-5), 6.84 (d, J = 8.7 Hz, 2H,
Ar), 6.31 (m, 2H, H-4 and H-3 in furyl), 5.31 (s, 1H, CHOCH3), 4.97
(s, 2H, CH2), 3.77 (s, 3H, CH3), 3.34 (s, 3H, CH3); 13C-NMR (CDCl3, 75
MHz) d: 160.0 (C-4 in Ar), 153.6 (C-2 in furyl), 142.9 (C-5 in furyl),
141.4 (C-4), 137.2 (C-2), 129.4 (CH in Ar), 128.2 (C-1 in Ar), 117.7 (C-
5), 114.8 (CH in Ar), 110.5 (C-4 in furyl), 109.1 (C-3 in furyl), 74.3
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46
P. O. Miranda and L.-L. Gundersen
Arch. Pharm. Chem. Life Sci. 2010, 343, 40–47
(CHOCH3), 57.0 (CH3), 55.8 (CH3), 50.9 (CH2); MS EI m/z (rel.%): 298
(10) [M+], 267 (42), 121 (100). HRMS calcd. for C17H18N2O3:
298.1317. Found: 298.1322. Anal. calcd. for C17H18N2O3: C, 68.44,
H, 6.08; N, 9.32. Found: C, 68.45; H, 5.80; N, 9.62.
due was purified by flash chromatography on a silica gel column
eluting with EtOAc/hexane (9:1); yield: 450 mg (62%).
(2-Furyl)[1-(4-methoxybenzyl)-1H-imidazol-4-yl]
methanone 9b
4-Methoxy-2-[1-(4-methoxybenzyl)-1H-imidazol-4-yl]
The title compound was prepared from 5b (220 mg, 0.70 mmol)
and MnO2 (103 mg, 1.19 mmol) as described for the synthesis of
9a (method A). EtOAc/hexane (8:2) was used as eluent for flash
chromatography; yield 190 mg (91%), yellow solid. M.p.: 126–
1288C. 1H-NMR (CDCl3, 300 MHz) d: 7.88 (d, J = 3.5 Hz, 1H, H-5 in
furyl), 7.77 (br s, 1H, H-2), 7.59 (br s, 1H, H-3 in furyl), 7.55 (br s,
1H, H-5), 7.11 (d, J = 8.7 Hz, 2H, Ar), 6.82 (d, J = 8.7 Hz, 2H, Ar), 6.50
(dd, J = 3.5 and 1.7 Hz, 1H, H-4 in furyl), 5.04 (br s, 2H, CH2), 3.73
(s, 3H, CH3); 13C-NMR (CDCl3, 75 MHz) d: 175.0 (C=O), 160.7 (C-4 in
Ar), 152.7 (C-2 in furyl), 147.4 (C-3 in furyl), 141.6 (C-4), 138.5 (C-
5), 130.1 (CH in Ar), 127.7 (C-2), 126.9 (C-1 in Ar), 121.9 (C-5 in
furyl), 115.4 (CH in Ar), 113.0 (C-4 in furyl), 56.2 (CH2), 51.8 (CH3);
MS EI m/z (rel.%): 282 (23) [M+], 122 (8), 121 (100), 78 (6). HRMS
calcd. for C16H14N2O3: 282.1004. Found: 282.1007. Anal. calcd. for
C16H14N2O3: C, 68.07; H, 5.00; N, 9.92%. Found: C, 68.88, H, 5.07;
N, 9.62.
cyclopent-2-enone 8
A mixture of 5b (400 mg, 1.41 mmol), MeOH (25 mL), and conc.
HCl (aq) (10 drops) was heated under reflux for 20 h under N2
atmosphere and evaporated in vacuo. The residue was parti-
tioned between water (20 mL) and EtOAc (40 mL). The aqueous
layer was basified with NaOH (s), the phases were separated and
the organic layer was dried (MgSO4) and evaporated in vacuo. The
residue was purified by flash chromatography on a silica gel col-
umn eluting with EtOAc; yield: 190 mg (45%), yellow solid. M.p.:
90–928C. 1H-NMR (CDCl3, 300 MHz) d: 7.88 (d, J = 2.5 Hz, 1H, H-3
in c-pent), 7.63 (br s, 1H, H-2), 7.48 (br s, 1H, H-5), 7.07 (d, J = 8.6
Hz, 2H, Ar), 6.82 (d, J = 8.6 Hz, 2H, Ar), 4.99 (s, 2H, CH2), 4.57 (m,
1H, H-4 in c-pent), 3.75 (s, 3H, CH3), 3.40 (s, 3H, CH3), 2.84–2.72
(dd, J = 18.4 and 5.9 Hz, 1H, H-5A in c-pent), 2.45–2.35 (dd, J = 18.4
and 2.1 Hz, 1H, H-5B in c-pent); 13C-NMR (CDCl3, 75 MHz) d: 204.0
(C=O), 160.0 (C-4 in Ar), 150.4 (C-3 in c-pent), 139.8 (C-2 in c-pent),
137.8 (C-5), 133.0 (C-4), 129.3 (CH in Ar), 128.0 (C-1 in Ar), 120.4 (C-
2), 114.8 (CH in Ar), 77.1 (C-4 in c-pent), 57.0 (CH3), 55.7 (CH3), 51.0
(CH2), 42.9 (C-5 in c-pent); MS EI m/z (rel.%): 298 (24) [M+], 177 (12),
122 (10), 121 (100). HRMS calcd. for C17H18N2O3: 298.1317. Found:
298.1317. Anal. calcd. for C17H18N2O3: C, 68.44; H, 6.08; N, 9.39.
Found: C, 68.25, H, 5.98; N, 9.35.
1-[1-(4-Methoxybenzyl)-1H-imidazol-4-yl]-1-(4-
methoxyphenyl)ethanol 10a
MeMgI (0.8 mL, 2.5 mmol, 3 M in Et2O) was added to a solution of
9a (360 mg, 1.12 mmol) in dry THF (12 mL) at 08C under Ar
atmosphere. The reaction was stirred at ambient temperature
for 30 min and quenched with water. The phases were separated
and the aqueous phase was extracted with EtOAc (2620 mL).
The combined organic extracts were dried (MgSO4) and evapo-
rated in vacuo. The residue was purified by flash chromatogra-
phy on a silica gel column eluting with MeOH/EtOAc (1:9); yield:
[1-(4-Methoxybenzyl)-1H-imidazol-4-yl](4-
methoxyphenyl)methanone 9a
Method A
1
269 mg (69%), colorless solid. M.p.: 97–1008C. H-NMR (CDCl3,
A mixture of 5a (50 mg, 0.15 mmol) and MnO2 (23 mg, 0.26
mmol) in dry CH2Cl2 (2 mL) was stirred for 18 h at ambient tem-
perature under Ar atmosphere. The solution was filtered
through a pad of Celite and evaporated in vacuo. The residue was
purified by flash chromatography on a silica gel column eluting
with EtOAc/hexane (9:1); yield: 42 mg (85%), pale yellow solid.
M.p.: 100–1038C. 1H-NMR (CDCl3, 300 MHz) d: 8.29 (d, J = 8.8 Hz,
2H, Ar), 7.67 (br s, 1H, H-2), 7.61 (br s, 1H, H-5), 7.15 (d, J = 8.6 Hz,
2H, Ar), 6.93 (d, J = 8.8 Hz, 2H, Ar), 6.88 (d, J = 8.6 Hz, 2H, Ar), 5.08
(s, 2H, CH2), 3.84 (s, 3H, CH3), 3.78 (s, 3H, CH3); 13C-NMR (CDCl3, 75
MHz) d: 186.1 (C=O), 163.0 (C-4 in Ar), 159.9 (C-4 in Ar), 142.3 (C-
4), 137.3 (C-5), 132.6 (CH in Ar), 130.5 (C-1 in Ar), 129.9 (CH in Ar),
126.9 (C-1 in Ar), 126.0 (C-2), 114.6 (CH in Ar), 113.4 (CH in Ar),
55.4 (26CH3), 51.0 (CH2); MS EI m/z (rel.%): 322 (29) [M+], 175 (14),
122 (9), 121 (100), 77 (6). HRMS calcd. for C19H18N2O3: 322.1317.
Found: 322.1318. Anal. calcd. for C19H18N2O3: C, 70.79; H, 5.63; N,
8.69. Found: C, 70.50, H, 5.48; N, 8.71.
300 MHz) d: 7.52 (br s, 1H, H-2), 7.35 (d, J = 8.7 Hz, 2H, Ar), 7.10 (d,
J = 8.7 Hz, 2H, Ar), 6.85 (d, J = 8.7 Hz, 2H, Ar), 6.80 (d, J = 8.7 Hz,
2H, Ar), 6.64 (br s, 1H, H-5), 4.96 (s, 2H, CH2), 3.78 (s, 1H, OH), 3.75
(s, 3H, OCH3), 3.74 (s, 3H, OCH3), 1.80 (s, 3H, CH3);13C-NMR (CDCl3,
75 MHz) d: 160.0 (C-4 in Ar), 158.8 (C-4 in Ar), 149.6 (C-4), 139.9 (C-
1 in Ar), 136.9 (C-2), 129.4 (CH in Ar), 127.9 (C-1 in Ar), 127.0 (CH
in Ar), 115.4 (C-5), 114.8 (CH in Ar), 113.7 (CH in Ar), 72.7 (COH),
55.7 (26OCH3), 51.1 (CH2), 30.5 (CH3); MS EI m/z (rel.%): 338 (8)
[M+], 323 (24), 320 (100), 122 (10), 121 (100). HRMS calcd. for
C20H22N2O3: 338.1630. Found: 338.1633.
1-(2-Furyl)-1-[1-(4-methoxybenzyl)-1H-imidazol-4-yl]
ethanol 10b
The title compound was prepared from 9b (200 mg, 0.708 mmol)
and MeMgI (0.3 mL, 0.9 mmol, 3 M in Et2O) as described for the
1
synthesis of 10a; yield: 125 mg (59%), oil. H-NMR (CDCl3, 300
MHz) d: 7.43 (br s, 1H, H-2), 7.29 (br s, 1H, H-5 in furyl), 7.08 (d, J =
8.7 Hz, 2H, Ar), 6.84 (d, J = 8.7 Hz, 2H, Ar), 6.72 (br s, 1H, H-5), 6.24
(dd, J = 3.1 and 1.8 Hz, 1H, H-4 furyl), 6.17 (br d, J = 3.1 Hz, 1H, H-3
in furyl), 4.94 (s, 2H, CH2), 3.92 (br s, 1H, OH), 3.76 (s, 3H, OCH3),
1.83 (s, 3H, CH3); 13C-NMR (CDCl3, 75 MHz) d: 160.0 (C-4 in Ar),
159.3 (C-2 in furyl), 147.4 (C-4), 142.0 (C-5 in furyl), 136.8 (C-2),
129.4 (CH in Ar), 128.0 (C-1 in Ar), 115.2 (C-5), 114.8 (CH in Ar),
110.5 (C-4 in furyl), 105.7 (C-3 in furyl), 69.7 (COH), 55.7 (OCH3),
50.9 (CH2), 27.3 (CH3); MS EI m/z (rel.%): 298 (4) [M+], 280 (44), 230
(8), 121 (100). HRMS calcd. for C17H18N2O3: 298.1317. Found:
Method B
MeMgI in Et2O (0.90 mL, 2.7 mmol, 3.0 M in Et2O) was added to a
solution of 2c (700 mg, 2.26 mmol) in dry CH2Cl2 (20 mL) under
Ar atmosphere at ambient temperature, and the resulting mix-
ture was stirred for 5 h, before anisaldehyde (2.7 mL, 23 mmol)
was added. The reaction was stirred for 18 h, quenched by the
addition of sat. aq. NH4Cl (5 mL), and extracted with CH2Cl2
(2640 mL). The combined organic layers were washed with
water (10 mL), dried (MgSO4), and evaporated in vacuo. The resi-
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Arch. Pharm. Chem. Life Sci. 2010, 343, 40–47
Antimycobacterial imidazoles
47
298.1310. Anal. calcd. for. C17H18N2O3: C, 68.44, H, 6.08; N, 9.39.
Found: C, 68.33; H, 6.38; N, 9.33.
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1-(4-Methoxybenzyl)-4-[1-(4-methoxyphenyl)vinyl]-1H-
[6] K. Duncan, Chem. Ind. 1997, 861–865.
imidazole 11
MeMgI (0.4 mL, 1.2 mmol, 3 M in Et2O) was added to a solution of
9a (190 mg, 0.589 mmol) in dry THF (6 mL) at 08C under Ar
atmosphere. The reaction was stirred at ambient temperature
for 30 min and 10% aq. HCl (5 drops) were added. The resulting
mixture was heated at 708C for 12 h and quenched by the addi-
tion of sat. aq. NaHCO3 (5 mL). The phases were separated and
the aqueous phase was extracted with EtOAc (2620 mL). The
combined organic layers were dried (MgSO4) and evaporated in
vacuo. The residue was purified by flash chromatography on a
silica gel column eluting with EtOAc/hexane (6:4); yield: 120 mg
(65%), yellow oil. 1H-NMR (CDCl3, 300 MHz) d: 7.50 (d, J = 1.2 Hz,
1H, H-2), 7.34 (d, J = 8.7 Hz, 2H, Ar), 7.05 (d, J = 8.7 Hz, 2H, Ar), 6.84
(d, J = 8.7 Hz, 2H, Ar), 6.80 (d, J = 8.7 Hz, 2H, Ar), 6.67 (d, J = 1.2 Hz,
1H, H-5), 5.84 (d, J = 1.8 Hz, 1H, HA in =CH2), 5.11 (d, J = 1.8 Hz, 1H,
HB in =CH2), 4.94 (s, 2H, CH2), 3.77 (s, 3H, CH3), 3.75 (s, 3H, CH3);
13C-NMR (CDCl3, 75 MHz) d: 159.4 (C-4 in Ar), 159.0 (C-4 in Ar),
142.6 (C-4), 141.5 (C=), 137.2 (C-2), 133.5 (C-1 in Ar), 129.1 (CH in
Ar), 128.6 (CH in Ar), 127.8 (C-1 in Ar), 117.7 (C-5), 114.2 (CH in
Ar), 113.4 (CH in Ar), 110.9 (=CH2), 55.2 (26CH3), 50.3 (CH2); MS EI
m/z (rel.%): 320 (40) [M+], 122 (9), 121 (100). HRMS calcd. for
C20H20N2O2: 320.1525. Found: 320.1529. Anal. calcd. for
C20H20N2O2: C, 74.98, H, 6.29; N, 8.74. Found: C, 74.58; H, 6.17; N,
8.94.
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Antimycobacterial data were provided by the Tuberculosis
Antimicrobial Acquisition and Coordinating Facility (TAACF,
USA) 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. The Norwegian Research Council is gratefully
acknowledged for a grant to POM (KOSK II, project number
177368) as well as for partial financing of the Bruker Avance
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