One step synthesis of imidazole and benzimidazole acycloaromatic nucleoside analogs

Article abstract of DOI:10.1016/S0040-4020(02)01415-1

A facile and rapid method for the synthesis of novel imidazole and benzimidazole aromatic acyclic nucleosides is described. Synchronous N-alkylation of imidazole or benzimidazole and potassium aryloxide with methylene iodide in the presence of triethylami

Full text of DOI:10.1016/S0040-4020(02)01415-1

Tetrahedron 58 (2002) 10341–10344
One step synthesis of imidazole and benzimidazole acycloaromatic
nucleoside analogs
a
b
a
A. Khalafi-Nezhad,a M. N. Soltani Rad, G. H. Hakimelahi and B. Mokhtari
,
*
aDepartment of Chemistry, Faculty of Science, College of Science, Shiraz University, Shiraz 71454, Iran
bTaiGen Biotechnology, Taipei 114, Taiwan, ROC
Received 28 March 2002; revised 7 October 2002; accepted 31 October 2002
Abstract—A facile and rapid method for the synthesis of novel imidazole and benzimidazole aromatic acyclic nucleosides is described.
Synchronous N-alkylation of imidazole or benzimidazole and potassium aryloxide with methylene iodide in the presence of triethylamine
and a catalytic amount of tetrabutylammonium bromide (TBAB) in dry acetonitrile or acetone gave moderate yields of the acycloaromatic
nucleoside analogs. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
and intermediates, poor yield, tedious workups and harsh
reaction conditions. Here we describe a simple and rapid
method for the one step synthesis of acyclic nucleoside
analogs.
Given the significance of imidazole and benzimidazole as a
part of the purine nucleobase framework, drug design based
on imidazole or benzimidazole is an interesting topic
for synthetic medicinal chemists. The unique biological
activity of N-alkylated imidazoles and benzimidazoles on
remedying diseases such as protozoal infections, like
trichomoniasis1,2 as well as nucleoside analogs in inhibiting
viral infections, like TCRB3–5 and ribovirin6 encouraged us
to prepare novel derivatives which could show useful
pharmaceutical properties. In continuation of our previous
work on the synthesis of aromatic acyclic nucleosides with
miscellaneous purine and pyrimidine nucleobases7 (1)
which led to introduction of 1-(phenoxymethyl)-6-azauracil
(2) as an active chemotherapeutic agents for inhibiting the
growth of myeloid cell and useful in the treatment of
leukemia.8 This synthesis7 had a number of drawbacks
including multi-step synthesis sequence, harmful reagents
2. Results and discussion
The synthesis of compounds (3) and (4) was achieved using
1 equiv. of each of methylene iodide, potassium aryloxide,
imidazole (Scheme 1) or benzimidazole (Scheme 2),
triethylamine and catalytic tetrabutylammonium bromide
(TBAB) in dry acetonitrile or acetone and refluxed for
1.5–2.5 h.
Reaction of potassium aryloxide with methylene iodide and
imidazole (Scheme 1) or benzimidazole (Scheme 2) was
expected to give three products in each case. In the case of
imidazole, the reaction gave compound (3) as major product
and a trace amount of 1-(phenoxymethoxy) benzene (,%6)
but it did not give the third possible product namely 1-(1H-
imidazol-1-ylmethyl)-1H-imidazole. For benzimidazole
(Scheme 2) compound (4) was obtained as the main product
but in contrast to imidazole (Scheme 1) a trace amount of
1-(1H-benzimidazol-1-ylmethyl)-1H-benzimdazole was
observed but not 1-(phenoxymethoxy) benzene. The reason
for this difference is not fully understood. Semi-empirical
quantum mechanic calculations (MNDO/3) gave a mechan-
istic point of view. The calculated data have illustrated a
negative value for the heat of formation for in situ generated
1-(iodomethoxy) benzene (E¼20.02346 kcal/mol) with
respect to other possible intermediates such as nucleophilic
N-alkylation of imidazole or benzimidazole with methyl-
eneiodide, although formation of 1-(iodomethoxy) benzene
was not detected through the reaction progress.
Keywords: imidazole; benzimidazole; acycloaromatic nucleosides.
*
Corresponding author. Tel.: þ98-711-2282380; fax: þ98-711-2280926;
e-mail: khalafi@chem.susc.ac.ir
0040–4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01415-1

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A. Khalafi-Nezhad et al. / Tetrahedron 58 (2002) 10341–10344
Scheme 1.
Because of the low solubility of imidazole in non-nucleophilic
solvents, polar protic solvents are usually used but these
solvents themselves can act as nucleophiles in the reaction
with active substrates. Phase transfer catalyst (PTC) systems
are often advantageous in these cases and such a system has
been employed for imidazole9 therefore using non-nucleo-
phile solvents are possible for this purpose. So, for this
reason TBAB was used as PTC in dry acetonitrile or
acetone. The one step synthesis of imidazole acycloaro-
matic nucleosides with non-symmetrical imidazoles (4 or 5
substituted) are usually accompanied with the formation of
multiple by-products.
Scheme 2.

A. Khalafi-Nezhad et al. / Tetrahedron 58 (2002) 10341–10344
10343
In the case of 2-methyl-4(5)-nitroimidazole derivatives
which possess considerable medical and potential agri-
cultural interest as chemotherapeutic agents and potential
biocides, compound (3h) was synthesized. Analyzing the
spectroscopic data10 has revealed to us the formation of
2-methyl-4-nitro-1-phenoxymethyl-1H-imidazole (3h) as
the main product and trace amounts of the 5-nitro isomer
(,5%). This is completely in agreement with the litera-
ture,11 where the 1-alkyl-2-methyl-4-nitro derivative is
obtained under basic conditions, while the 1-alkyl-2-
methyl-5-nitro derivative is the major product under neutral
or acidic conditions.12 The same results were also obtained
for 4(5)-methylimidazole, entry (3i).
OCH2N). Anal. calcd for C10H10N2O: C, 68.95; H, 5.79; N,
16.08. Found: C, 68.87; H, 5.86; N, 16.19.
4.1.2. 1-(4-Chloro-phenoxymethyl)-1H-imidazole (3b).
Column chromatography on silica gel elution with EtOAc
gave pale yellow crystals (1.27 g, 61%); Rf (EtOH) 0.8; mp
72–738C; IR (potassium bromide): nmax 3100, 2900, 1600–
1540, 1220, 1160, 750 cm21; MS: m/z (%) 208 (Mþ, 12.1);
dH (250 MHz, CDCl3) 7.70 (1H, s, C(2), imidazole),
7.50–6.80 (6H, m, aromatic), 5.80 (2H, s, OCH2N). Anal.
calcd for C10H9N2O: C, 57.57; H, 4.35; N, 13.43. Found: C,
57.44; H, 4.36; N, 13.36.
4.1.3. 1-[(2,4-Dichloro-phenoxy) methyl]-1H-imidazole
(3c). Column chromatography on silica gel elution with
EtOAc/EtOH (5:2) gave pale yellow crystals (1.43 g, 59%);
Rf (EtOH) 0.83; mp 80–828C; IR (potassium bromide): nmax
3130, 2900, 1620–1540, 1210, 1140, 800–650 cm21; MS:
m/z (%) 243 (Mþ, 29.1); dH (250 MHz, CDCl3) 7.73 (1H, s,
C(2), imidazole), 7.50–6.80 (5H, m, aromatic), 5.78 (2H, s,
OCH2N). Anal. calcd for C10H8Cl2N2O: C, 49.41; H, 3.32;
N, 11.52. Found: C, 49.58; H, 3.21; N, 11.40.
3. Conclusion
The one step synthesis of imidazole or benzimidazole
acycloaromatic nucleosides in which the sugar moiety is
replaced by an aromatic side-chain may show interesting
biological activity. The explained method has superiority
with respect to the previous methods. Glycoside linkage i.e.
O–CH2–N as a part of nucleosides is directly interacted
with aromatic p-electron systems and this special case may
create interesting biological activity.
4.1.4. 1-(2,3-Dichloro-phenoxymethyl-1H-imidazole
(3d). Column chromatography on silica gel elution with
EtOAc/EtOH (5:2) gave pale yellow crystals (1.45 g, 60%);
Rf (EtOH) 0.81; mp 70–728C; IR (potassium bromide): nmax
3130, 2900, 1620–1540, 1210, 1140, 800–650 cm21; MS:
m/z (%) 243 (Mþ, 29.1); dH (250 MHz, CDCl3) 7.58 (1H, s,
C(2), imidazole), 7.46–6.74 (5H, m, aromatic), 5.79 (2H, s,
OCH2N). Anal. calcd for C10H8Cl2N2O: C, 49.41; H, 3.32;
N, 11.52. Found: C, 49.29; H, 3.24; N, 11.38.
4. Experimental
4.1. General
The chemicals were obtained from Fluka or Merck chemical
companies except for potassium aryloxides that were
prepared using 1 equiv. of KOH and 1 equiv. of related
phenols in a minimum amount of distilled water, which is
evaporated to dryness under vacuum. Purification and
dehydration of solvents were done using the reported
methods13 and stored over molecular sieves. TLC using
silica gel SILG/UV 254 plates followed reaction progress.
IR spectra were run on a Perkin–Elmer 781 Spectro-
4.1.5. 1-p-Tolyloxymethyl-1H-imidazole (3e). Column
chromatography on silica gel elution with EtOAc gave
white crystals (1.01 g, 54%); Rf (EtOH) 0.73; mp 70–718C;
IR (potassium bromide): nmax 3100, 2960, 1600–1500,
1200, 1040 cm21; MS: m/z (%) 188 (Mþ, 32.6); dH
(250 MHz, CDCl3) 7.48 (1H, s, C(2), imidazole), 7.19–
6.71 (6H, m, aromatic), 5.75 (2H, s, OCH2N), 2.21 (3H, s,
Me). Anal. calcd for C11H12N2O: C, 70.19; H, 6.43; N,
14.88. Found: C, 70.05; H, 6.33; N, 14.68.
1
photometer. The H NMR spectra were run on a Bruker
Advanced DPX-250, FT-NMR spectrometer. Mass spectra
were recorded on a Shimadzu GC MS-QP 1000EX.
Microanalyses were performed on a Perkin–Elmer 240-B
microanalyzer. Melting points were determined on a Bu¨chi
510 in open capillary tubes and are uncorrected.
4.1.6. 1-(4-Chloro-3-methyl-phenoxymethyl)-1H-imida-
zole (3f). Column chromatography on silica gel elution
with EtOAc/EtOH (5:2) gave pale yellow crystals (1.37 g,
62%); Rf (EtOH) 0.76; mp 68–728C; IR (potassium
bromide): nmax 3130, 2900, 1600–1530, 1140, 690 cm21
;
4.1.1. 1-Phenoxymethyl-1H-imidazole (3a). In a round
bottomed flask (100 mL) a mixture of imidazole (0.68 g,
0.01 mol), methylene iodide (2.68 g, 0.01 mol), potassium
phenoxide (1.32 g, 0.01 mol), dry triethylamine (1.01 g,
0.01 mol) and catalytic amount of TBAB (0.1 g) were
dissolved in dry acetonitrile (40 mL). The solution was
refluxed for 2 h. Evaporation of solvent gave an oil, which
was dissolved in CHCl3 (150 mL) and washed with water
(2£200 mL). The organic layer was dried with anhydrous
sodium sulfate, filtered and evaporated to give an oily crude
product. Using column chromatography on silica gel and
EtOAc as eluent gave a brown–yellow, syrupy product
(0.99 g, 57%); Rf (EtOH) 0.7; IR (potassium bromide): nmax
3150, 2980, 1620–1500, 1200, 1150 cm21; MS: m/z (%)
174 (Mþ, 58.2); dH (250 MHz, CDCl3) 7.69 (1H, s, C(2),
imidazole), 7.60–7.04 (7H, m, aromatic), 5.79 (2H, s,
MS: m/z (%) 243 (Mþ, 29.1); dH (250 MHz, CDCl3) 7.57
(1H, s, C(2), imidazole), 7.57–7.03 (5H, m, aromatic),
6.04 (2H, s, OCH2N), 2.21 (3H, s, Me). Anal. calcd for
C11H11ClN2O: C, 59.33; H, 4.98; N, 12.58. Found: C, 59.29;
H, 5.08; N, 12.68.
4.1.7. 1-(4-Allyl-2-methoxy-phenoxymethyl)-1H-imida-
zole (3g). Column chromatography on silica gel elution
with EtOAc gave a yellow oily product (1.58 g, 65%); Rf
(EtOH) 0.84; IR (potassium bromide): nmax 3200, 2900,
1600–1500, 1240–1210, 1100 cm21; MS: m/z (%) 245
(Mþ, 60.3); dH (250 MHz, CDCl3) 7.80 (1H, s, C(2),
imidazole), 7.20–6.50 (5H, m, aromatic), 6.02–5.81 (1H,
m, vinylic), 5.80 (2H, s, OCH2N), 5.21–4.9 (2H, dd,
vinylic, J¼10.3, 16.8 Hz), 3.91 (3H, s, OCH3), 3.43 (2H, d,

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A. Khalafi-Nezhad et al. / Tetrahedron 58 (2002) 10341–10344
allylic, J¼6.6 Hz). Anal. calcd for C14H16N2O2: C, 68.83;
C, 70.85; H, 5.55; N, 11.02. Found: C, 70.81; H, 5.60; N,
10.96.
H, 6.60; N, 11.47. Found: C, 68.91; H, 6.71; N, 11.59.
4.1.8. 2-Methyl-4-nitro-1-phenoxymethyl-1H-imidazole
(3h). Column chromatography on silica gel elution with
EtOAc/EtOH (5:3) gave pale yellow crystals (1.32 g, 57%);
Rf (EtOH) 0.85; mp 91–938C; IR (potassium bromide): nmax
3100, 2890, 1600–1560, 1550–1350 (two bands), 1200,
1100 cm21; MS: m/z (%) 233 (Mþ, 41.8); dH (250 MHz,
CDCl3) 7.82 (1H, s, C(5), imidazole), 7.42–6.71 (5H, m,
aromatic), 5.80 (2H, s, OCH2N), 2.62 (3H, s, Me). Anal.
calcd for C11H11N3O3: C, 56.85; H, 4.75; N, 18.02. Found:
C, 56.93; H, 4.88; N, 17.94.
4.1.13. 1-(p-Tolyloxymethyl)-1H-benzimidazole (4c).
Column chromatography on silica gel elution with EtOAc
gave white crystals (1.10 g, 49%); Rf (EtOH) 0.73; mp 101–
1128C; IR (potassium bromide): nmax 3100, 2900, 1600–
1500, 1200, 1100 cm21; MS: m/z (%) 238 (Mþ, 40.1);dH
(250 MHz, CDCl3) 8.13 (1H, s, C(2), benzimidazole),
7.86–7.26 (8H, m, aromatic), 6.77 (2H, s, OCH2N), 2.26
(3H, s, CH3). Anal. calcd for C15H14N2O: C, 75.63; H, 5.46;
N, 11.83. Found: C, 75.54; H, 5.39; N, 11.96.
4.1.14. 1-(p-Tolyloxymethyl)-2-methyl-1H-benzimida-
zole (4d). Column chromatography on silica gel elution
with EtOAc gave white crystals (1.36 g, 54%); Rf (EtOH)
0.71; mp 92–948C; IR (potassium bromide): nmax 3100,
2850, 1600–1500, 1210, 1100 cm21; MS: m/z (%) 252
(Mþ, 35.3); dH (250 MHz, CDCl3) 7.08–6.51 (8H, m,
aromatic), 5.92 (2H, s, OCH2N), 2.50 (3H, s, C(2), CH3),
2.20 (3H, s, CH3 (aryl)). Anal. calcd for C16H16N2O: C,
76.16; H, 6.39; N, 11.10. Found: C, 76.21; H, 6.46; N, 11.29.
4.1.9. 1-(4-Phenyl-phenoxymethyl)-4-methyl-1H-imida-
zole (3i). Column chromatography on silica gel elution
with EtOAc/EtOH (5:2) gave white crystals (1.37 g, 53%);
Rf (EtOH) 0.5; mp 120–1258C; IR (potassium bromide):
nmax 3100, 2890, 1600–1500, 1210, 1100 cm21; MS: m/z
(%) 264 (Mþ, 24.9); dH (250 MHz, CDCl3) 7.43 (1H, s,
C(2), imidazole), 7.43–6.87 (12H, m, aromatic), 5.66 (2H,
s, OCH2N), 2.09 (3H, s, Me). Anal. calcd for C17H16N2O: C,
77.27; H, 6.06; N, 10.60. Found: C, 77.21; H, 5.98; N, 10.63.
4.1.10. 2-Methyl-1-b-naphthoxymethyl-1H-imidazole
(3j). Column chromatography on silica gel elution with
EtOAc/EtOH (5:2) gave white crystals (1.23 g, 52%); Rf
(EtOH) 0.7; mp 109–1118C; IR (potassium bromide): nmax
3100, 2900, 1600–1550, 1200, 1140 cm21; MS: m/z (%)
238 (Mþ, 35.8); dH (250 MHz, CDCl3) 8.06–7.02 (9H, m,
aromatic), 5.89 (2H, s, OCH2N), 2.65 (3H, s, Me). Anal.
calcd for C15H14N2O: C, 75.61; H, 5.92; N, 11.76. Found: C,
75.72; H, 6.07; N, 11.84.
Acknowledgements
We appreciate Shiraz University research council for the
financial support for this work. We also thank Mr Sajedian
Fard for running the NMR spectra.
References
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L. B. J. Med. Chem. 1997, 40, 785.
4.1.11. 1-Phenoxymethyl-1H-benzimidazole (4a). In a
round bottomed flask (100 mL) a mixture of benzimidazole
(1.18 g, 0.01 mol), methylene iodide (2.68 g, 0.01 mol),
potassium phenoxide (1.32 g, 0.01 mol), dry triethylamine
(1.01 g, 0.01 mol) and catalytic amount of TBAB (0.1 g)
were dissolved in dry acetonitrile (40 mL). The solution was
refluxed for 2.5 h. Evaporation, dissolving in CHCl3
(150 mL) washing with water (2£200 mL) afforded the
crude solid product which, purified with column chroma-
tography on silica gel EtOAc/EtOH (8:1) gave white
crystals (1.18 g, 53%); Rf (EtOH) 0.76; mp 105–1078C;
IR (potassium bromide): nmax 3180, 2800, 1610–1500,
1200, 1160 cm21; MS: m/z (%) 224 (Mþ, 34.2); dH
(250 MHz, CDCl3) 8.33 (1H, s, C(2), benzimidazole),
7.92–6.92 (9H, m, aromatic), 5.99 (2H, s, OCH2N). Anal.
calcd for C14H12N2O: C, 74.98; H, 5.39; N, 12.49. Found: C,
75.07; H, 5.46; N, 12.57.
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4.1.12. 1-(2-Methoxy-phenoxymethyl)-1H-benzimida-
zole (4b). Column chromatography on silica gel elution
with EtOAc gave a bright brown oil (1.27 g, 50%); Rf
(EtOH) 0.84; IR (potassium bromide): nmax 3150, 2900,
1600–1550, 1240–1210, 1100 cm21; MS: m/z (%) 254
(Mþ, 20.3); dH (250 MHz, CDCl3) 7.96 (1H, s, C(2),
benzimidazole), 7.70–6.71 (8H, m, aromatic), 5.93 (2H, s,
OCH2N), 3.64 (3H, s, OCH3). Anal. calcd for C15H14N2O2:
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