A concise and selective synthesis of novel 5-aryloxyimidazole NNRTIs

Article abstract of DOI:10.1021/ol060316x

A concise and efficient route to the construction of a 5-aryloxyimidazole has been developed. The key step was the selective O-arylation of a 2,4-dimethoxybenzyl-protected imidazolone. The final compound is a potent inhibitor of HIV reverse transcriptase.

Full text of DOI:10.1021/ol060316x

ORGANIC
LETTERS
2006
Vol. 8, No. 8
1725-1727
A Concise and Selective Synthesis of
Novel 5-Aryloxyimidazole NNRTIs
Lyn H. Jones,* Thomas Dupont, Charles E. Mowbray, and Sandra D. Newman
Sandwich Laboratories, Pfizer Global Research and DeVelopment, Ramsgate Road,
Sandwich, Kent CT13 9NJ, U.K.
lyn.jones@pfizer.com
Received February 6, 2006
ABSTRACT
A concise and efficient route to the construction of a 5-aryloxyimidazole has been developed. The key step was the selective O-arylation of
a 2,4-dimethoxybenzyl-protected imidazolone. The final compound is a potent inhibitor of HIV reverse transcriptase.
Reverse transcriptase (RT) is an essential enzyme in the
infectious lifecycle of HIV and noncompetitive inhibition
of this enzyme by nonnucleoside reverse transcriptase
inhibitors (NNRTIs) has shown utility in the treatment of
HIV. However, the established NNRTIs are particularly
vulnerable to the development of viral resistance caused by
amino acid mutations in RT that can retain viable enzymatic
function. As a result, there is considerable interest in
developing new, potent NNRTIs that exhibit less susceptibil-
ity to the clinically relevant RT mutations.1
retain the desirable mutant potency profile of compounds
such as capravirine.
Following our work in this area,2 we have decided to report
our successful exploits in the preparation of 5-aryloxy-
substituted imidazole derivatives 1 (Figure 1). Interestingly,
the S-linked imidazole analogues have themselves generated
great interest in the anti-HIV arena, exemplified by capra-
virine, which exhibits a balanced potency profile against
various clinically relevant RT mutations.1 We reasoned that
the corresponding O-linked imidazole derivatives 1 would
Figure 1. Imidazole NNRTIs.
At the outset we desired a facile and reliable method for
the preparation of 5-aryloxyimidazoles, which would allow
us to prepare a variety of related derivatives in this series.3
Our strategy for their preparation involves the arylation of
(1) De Clercq, E. Chem. BiodiVers. 2004, 1, 44.
(2) Edwards, P. J.; Jones, L. H.; Mowbray, C. E.; Stupple, P. A.; Tran,
I. WO2004031156. Jones, L. H.; Mowbray, C. E.; Price, D. A.; Selby, M.
D.; Stupple, P. A. WO2004029051. Barba, O.; Jones, L. H. WO2004029042.
Jones, L. H.; Mowbray, C. E.; Price, D. A.; Selby, M. D.; Stupple, P. A.
WO2002085860.
(3) Cu(I)-mediated phenol displacements of a 5-iodoimidazole (conditions
which are successful when thiophenols are used in the preparation of
S-linked imidazoles) were unsuccessful in our hands.
10.1021/ol060316x CCC: $33.50
© 2006 American Chemical Society
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imidazolones such as 2 using electron-deficient aryl fluorides
(Scheme 1). Imidazolones 2 can themselves be prepared via
cyclization of amino amides 3 with a suitable ortho ester 4.4
Scheme 3. Synthesis of 5-Aryloxyimidazole 14
Scheme 1. Retrosynthesis
Our first attempt using this strategy on a model system
gave an unexpected result (Scheme 2). Treatment of amino
Scheme 2. Undesired C-Arylation of 6
the next step. However, unlike 6, 11 was actually stable when
stored crude at room temperature for long periods (at least
2 months). Arylation of 11 using 3,5-dicyanofluorobenzene
7 proceeded regioselectively as we predicted to provide 12,
and none of the C-arylated material was detected. To aid
deprotection and to provide the desired N1-Et isomer
regioselectively, we performed the N-alkylation first. Indeed,
we have shown that if imidazole 12 is deprotected first there
is a preference for alkylation of the 5-aryloxy-NH-imidazole
to proceed via the “undesired” nitrogen regioselectively (∼3:
1). Thus, treatment of 12 with EtI provided imidazolonium
salt 13 and although the deprotection proved troublesome,
amide 55 with triethyl orthoacetate provided the known
imidazolone 6.6 However, subsequent treatment with com-
mercially available 3,5-dicyanofluorobenzene 7 surprisingly
gave a poor yield of C-arylated material 8 (proved by HMBC
and IR; see the Supporting Information) and none of the
desired adduct, despite trying various solvents and bases.
Poor yields for this reaction may be a reflection of the
instability of imidazolone 6 which slowly dimerizes when
stored at room temperature.6 We reasoned that introduction
of a protecting group to N3 would not only force the arylation
to the relatively less encumbered oxygen of the imidazolone,
but it may also improve the stability of this reactive
intermediate.
Following extensive examination of benzyl and 4-meth-
oxybenzyl protecting groups,7 we discovered that the 2,4-
dimethoxybenzyl group was ideal for our purposes as it was
resilient to the somewhat harsh conditions used for imid-
azolone formation, but which could be removed later in the
synthesis. The synthesis of 14 (Scheme 3), a representative
of this series, commenced with the known bromide 9,8 which
was reacted with 2,4-dimethoxybenzylamine to provide
amino amide 10. Cyclization with triethyl orthoformate
provided imidazolone 11, which was used immediately in
9
it could be effected using BBr3 to yield compound 14 in a
respectable overall yield.
With 14 in hand, we next turned our attention to func-
tionalization of the C1-position, which would allow us to
prepare various derivatives from a late-stage intermediate.
Reaction of 14 with paraformaldehyde proceeded smoothly
to give the hydroxymethyl derivative 15 (Scheme 4). The
hydroxy group now gives us a handle to prepare various
analogues, which is ongoing work within our group and will
Scheme 4. Preparation of Carboxamide 16
(4) For example: Maurer, F.; Hammann, I. DE 3136328.
(5) Conley, J. D.; Kohn, H. J. Med. Chem. 1987, 30, 567.
(6) Maquestiau, A.; Van Haverbeke, Y.; Flammang-Barbieux, M.;
Beaufays-Bar, F. Bull. Soc. Chim. Belg. 1976, 85, 573.
(7) These protecting groups could not be removed later in the synthesis
despite using various deprotection conditions, including BBr3, Pd-C/H2,
DDQ, CAN, and AlCl3. We believed the more electron-rich 2,4-dimethoxy-
benzyl group could be deprotected more readily later in the synthesis.
(8) Yamazaki, H.; Harada, H.; Matsuzaki, K.; Yoshioka, K.; Takase, M.;
Ohki, E Chem. Pharm. Bull. 1987, 35, 2243.
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Org. Lett., Vol. 8, No. 8, 2006

similar to capravirine and exhibits pleasing potency against
the wild-type reverse transcriptase enzyme (Table 1).
Additionally, compounds 14, 15, and 16 possess IC50
values against the most clinically relevant mutation K103N
that are within 10-fold of their wild-type potencies.
In conclusion, a concise and selective route to a novel and
potent 5-aryloxy imidazole NNRTI was developed using new
imidazolone chemistry. A detailed analysis of the biological
activity of these derivatives will appear elsewhere.
Table 1. Potencies against Wild-Type HIV Reverse
Transcriptasea
compd
IC50/nM
14
15
16
2100
476
103
93
capravirine
a Inhibition of wild-type RT with a poly(rA) ∼300 template, (dT) 16
primer, and dTTP as substrate.
Acknowledgment. We thank Chris Carr for preliminary
investigations into 5-aryloxyimidazole preparation and Torren
Peakman for HMBC experiments. We also thank Romu
Corbau, Ian Burr, Alex Martin, and Amy Thomas for
determining the potencies of these compounds.
be reported elsewhere. Noteworthy from this work has been
the facile preparation of 16 which posseses the carboxamide
(9) Workup with 1 N NaOH aq significantly improves the yield of
isolated product (compared to saturated NaHCO3 solution), suggesting this
reaction proceeds through a phenol intermediate. Indeed, we have on
occasions been able to isolate intermediate phenols following anisole
deprotection of similar substrates. The deprotection of 13 (and other similar
substrates) could not be effected using TFA, concd HCl, BuLi/O2, DDQ,
potassium persulfate, Pd-C/H2, FeCl3, AlCl3, or CAN.
Supporting Information Available: Representative pro-
cedures; spectral and analytical data. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL060316X
Org. Lett., Vol. 8, No. 8, 2006
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