Synthesis of a 2-aminoimidazole library for antibiofilm screening utilizing the sonogashira reaction

Article abstract of DOI:10.1021/jo800618q

(Chemical Equation Presented) The divergent synthesis of a 21-member library composed of 2-aminoimidazole compounds for evaluation as novel antibiofilm molecules is presented. The Sonogashira reaction was employed with three regioisomeric aryl iodides and 11 different alkynes to generate variously substituted diverse ring systems. Good to excellent yields (80-97%) for the reaction were obtained, and the products provide adequate handles for further manipulation into more advanced analogues.

Full text of DOI:10.1021/jo800618q

Synthesis of a 2-Aminoimidazole Library for
Antibiofilm Screening Utilizing the Sonogashira
Reaction
Justin J. Richards and Christian Melander*
FIGURE 1. Previously reported 2-AI biofilm modulators.
Department of Chemistry, North Carolina State UniVersity,
Our group has been actively investigating the effects that
simple sponge-derived marine alkaloids and their derivatives
have upon biofilm development and maintenance in medically
relevant bacteria.8,9 The 2-aminoimidazole (2-AI) motif, preva-
lent in all members of the oroidin family of natural products,10
serves as the inspiration in the design and evaluation of these
analogues (Figure 1). In order to generate additional diversity
around the 2-AI scaffold, new avenues for the synthesis of large
numbers of compounds are needed.
Raleigh, North Carolina 27695
christian_melander@ncsu.edu
ReceiVed March 18, 2008
Despite this need for 2-AI based motifs that would provide
a suitable handle for rapid analogue construction and evaluation
as antibiofilm agents, there remains a lack of known methods
for their quick generation. It was therefore a goal to take
advantage of palladium-catalyzed cross-coupling reactions in
aiding the synthesis of these aforementioned chemical libraries.
Among the known palladium-catalyzed carbon-carbon bond-
forming reactions, the Sonogashira reaction11 is known to
proceed under fairly mild conditions12,13 and would give the
option of simultaneously providing entrance into further ad-
vanced analogues through exploitation of the triple bond into
alkene and alkane based derivatives. It was also envisioned that
by performing the couplings at various positions along the core
phenyl ring, the position effect of the alkynyl appendage on
activity could be evaluated. Herein we report the synthesis of a
21-member library that employs a high-yielding Sonogashira
reaction on three aryl iodide protected 2-aminoimidazole
scaffolds to generate novel small molecules applicable for
screening as antibiofilm agents.
Access to the desired aryl halide intermediates for the
Sonogashira coupling was executed through the commercially
available ortho, meta, and para substituted iodobenzoic acid
derivatives 3-5 (Scheme 1). Each was first transformed into
its acid chloride before being sequentially reacted with diaz-
omethane and quenched with concentrated HBr. This afforded
the requisite R-bromo ketones 6-8 in excellent yields. Instal-
lation of the 2-aminoimidazole subunit was achieved through
condensation with Boc-guanidine14 in the presence of NaI.
Attempts at performing the Sonogashira reaction with interme-
The divergent synthesis of a 21-member library composed
of 2-aminoimidazole compounds for evaluation as novel
antibiofilm molecules is presented. The Sonogashira reaction
was employed with three regioisomeric aryl iodides and 11
different alkynes to generate variously substituted diverse
ring systems. Good to excellent yields (80-97%) for the
reaction were obtained, and the products provide adequate
handles for further manipulation into more advanced
analogues.
Bacterial biofilms have recently been estimated by the NIH
as being responsible for upward of 80% of microbial infections
in the human body.1 They also possess increased resistance to
basic host immune responses, antiseptics, and antibiotics, often
representing a significant challenge to overcome as evident by
the increased morbidity and mortality rates of numerous biofilm-
mediated diseases.2,3 Biofilms are described as highly organized
structures composed of a complex matrix of bacteria and
biomolecules.4 They form when planktonic bacteria irreversibly
bind to a surface suitable for growth and initiate the formation
of a microcolony. On a global scale, biofilm-related costs incur
billions of dollars to the agricultural, engineering, and medical
sectors of the economy. Recently, there has been an intense
effort to investigate small molecules that either retard biofilm
development or, more importantly, disperse existing biofilms
in hopes of providing a therapeutic tool in combating the serious
problems they underpin.5–7
(6) Hu, J. F.; Garo, E.; Goering, M. G.; Pasmore, M.; Yoo, H. D.; Esser, T.;
Sestrich, J.; Cremin, P. A.; Hough, G. W.; Perrone, P.; Lee, Y. S. L.; Le, N. T.;
O’Neil-Johnson, M.; Costerton, J. W.; Eldridge, G. R. J. Nat. Prod. 2006, 69,
118–120.
(7) Junker, L. M.; Clardy, J. Antimicrob. Agents Chemother. 2007, 51, 3582–
3590.
(8) Huigens, R. W.; Richards, J. J.; Parise, G.; Ballard, T. E.; Zeng, W.;
Deora, R.; Melander, C. J. Am. Chem. Soc. 2007, 129, 6966–6967.
(9) Richards, J. J.; Huigens, R. W.; Ballard, T. E.; Basso, A.; Cavanagh, J.;
Melander, C. Chem. Commun. 2008, 1698–1700.
(1) Davies, D. Nat. ReV. Drug DiscoVery 2003, 2, 114–122.
(2) Costerton, J. W.; Stewart, P. S.; Greenberg, E. P. Science 1999, 284,
1318–1322.
(10) Hoffmann, H.; Lindel, T. Synthesis 2003, 1753–1783.
(11) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467–
4470.
61.(3) Rasmussen, T. B.; Givskov, M. Int. J. Med. Microbiol. 2006, 296, 149–
(4) Musk, D. J.; Hergenrother, P. J. Curr. Med. Chem. 2006, 13, 2163–2177.
(5) Geske, G. D.; Wezeman, R. J.; Siegel, A. P.; Blackwell, H. E. J. Am.
Chem. Soc. 2005, 127, 12762–12763.
(12) Chinchilla, R.; Najera, C. Chem. ReV. 2007, 107, 874–922.
(13) Schnurch, M.; Flasik, R.; Khan, A. F.; Spina, M.; Mihovilovic, M. D.;
Stanetty, P. Eur. J. Org. Chem. 2006, 3283–3307.
10.1021/jo800618q CCC: $40.75
Published on Web 06/04/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5191–5193 5191

SCHEME 1. Construction of 2-AI Scaffolds
SCHEME 3. Library Synthesis
SCHEME 2. Sonogashira Optimization
diate 11 proved futile due to its relative insolubility in all organic
solvents except DMF. Low yields and difficulty in purification
of the desired product were observed, however, when DMF was
used in the reaction. It therefore became necessary to protect
the exocyclic amine functionality, and this was accomplished
by reaction of derivatives 9-11 with LiHMDS in the presence
of Boc anhydride.15 Despite the need for the extra synthetic
step, scaffolds 12-14 were quickly prepared on multigram
scales in just three synthetic operations.
Attention then was turned to a suitable catalyst system for
the Sonogashira reaction. Lindel previously reported the use of
PdCl2(PPh3)2 as a catalyst for Heck- and Sonogashira-type
reactions employing an imidazole-based iminophosphorane
intermediate,16 and this provided the starting point for catalyst
screening and reaction condition optimization (Scheme 2).
Conditions were screened using the p-iodo scaffold 14 and
phenyl acetylene 15 as the alkyne. PdCl2(PPh3)2 was found to
be a better catalyst at promoting the coupling than Pd(PPh3)4
in every condition analyzed. Increasing the catalyst load to 10
mol% was found to be optimal, leading to complete consumption
of the aryl iodide starting material. This was essential because
incomplete conversion led to difficulty in removing unreacted
starting material, which was laborious and led to reduced
reaction yields. THF was the best solvent among the three
scanned. Minor adjustments were also made in the amount of
DIPEA used (10 equiv) and the alkyne coupling partner (5
equiv). With the conditions optimized on the trial system, the
yield for the Sonogashira coupling was 90% and was deemed
acceptable for the synthesis of the library.
to generate a small library of 2-AI analogues using the optimized
coupling conditions (Scheme 3). Yields for all reactions were
good to excellent (80-97%). The highest yielding reactions
were those involving the 2,5-diflourophenyl alkyne derivative
19 (entries 3-5). TMS acetylene (entry 14) and propargyl
alcohol (entries 15 and 16) were also shown to be suitable
coupling partners under the extremely mild reaction conditions.
Furthermore, consistently high yields were obtained when a
single alkyne was coupled to all three regioisomers, thus
indicating the robustness of the system.
In summary, the Sonogashira reaction was used to build a
unique library of 21 complex 2-aminoimidazole based com-
pounds that have the potential to provide access to numerous
other more advanced analogues. The reaction proceeds in
excellent yield regardless of the alkyne and aryl halide scaffold
used. The biological screening of the analogues as modulators
of biofilm growth and maintenance is currently underway, and
our findings will be reported in due course. Additionally, other
conditions are being investigated that take advantage of pal-
ladium-catalyzed cross-couplings to make other libraries of 2-AI
based molecules for evaluation as novel antibiofilm agents.
Ten electronic and sterically diverse alkynes incorporating a
number of synthetically relevant functionalities were then used
(14) Zapf, C. W.; Creighton, C. J.; Tomioka, M.; Goodman, M. Org. Lett.
2001, 3, 1133–1136.
(15) Ando, N.; Terashima, S. Synlett 2006, 2836–2840.
(16) Poeverlein, C.; Jacobi, N.; Mayer, P.; Lindel, T. Synthesis 2007, 3620–
3626.
5192 J. Org. Chem. Vol. 73, No. 13, 2008

16 (0.085 g, 90%) as a yellow solid: mp ) 131-132 °C; 1H NMR
(400 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.00 (s, 1H), 7.86 (d, 2H, J
) 7.6 Hz), 7.42 - 7.57 (m, 7H), 1.58 (s, 9H), 1.44 (s, 9H); 13C
NMR (100 MHz, DMSO-d6) δ 152.9, 146.8, 139.9, 136.3, 133.0,
131.7, 131.4, 128.8, 124.9, 122.6, 126.8, 120.9, 113.7, 89.9, 89.5,
85.4, 80.1, 27.9, 27.3; HRMS (ESI) calcd for C27H29N3O4Na
(MNa+) 482.2050, found 482.2051.
Experimental Section
Representative Procedure for Optimized Sonogashira Cou-
pling. Aryl iodide 14 (0.100 g, 0.206 mmol) was dissolved in
anhydrous THF (8 mL), and to this solution was added DIPEA
(0.359 mL, 2.06 mmol), CuI (0.004 g, 0.021 mmol), and
PdCl2(PPh3)2 (0.014 g, 0.021 mmol). The solution was then
degassed at ambient temperature for 10 min. During this time a
solution of phenyl acetylene 15 (0.105 g, 1.03 mmol) in anhydrous
THF (3 mL) was also degassed. The solution of alkyne was added
dropwise to the solution of aryl iodide, and the reaction was stirred
at room temperature for 12 h. The reaction was filtered through a
Celite pad, and the filter cake rinsed with EtOAc (10 mL). The
filtrate was washed with saturated NH4Cl (2 × 10 mL) and brine
(2 × 10 mL), and dried (Na2SO4). Filtration and evaporation
afforded the crude product, which was purified via flash column
chromatography (1:5 EtOAc/hexanes) to obtain the target product
Acknowledgment. Financial support from NCSU and Agile
Sciences is gratefully acknowledged.
Supporting Information Available: Experimental proce-
dures, spectral characterization, and copies of NMR spectra for
all compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO800618Q
J. Org. Chem. Vol. 73, No. 13, 2008 5193