N-(2-formyl-1-methylimidazol-4-yl)-2,2-dimethylpropanamide: A versatile reagent for preparing imidazole-amine ligands with variable second-coordination spheres

Article abstract of DOI:10.1016/j.tetlet.2011.07.025

Two synthetic pathways to N-(2-formyl-1-methylimidazol-4-yl)-2,2- dimethylpropanamide from 1-methyl-2-carboxaldehyde are described. The reagent serves as a useful synthon for reductive amination reactions with primary and secondary amines in the presence

Full text of DOI:10.1016/j.tetlet.2011.07.025

Tetrahedron Letters 52 (2011) 4771–4774
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Tetrahedron Letters
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N-(2-formyl-1-methylimidazol-4-yl)-2,2-dimethylpropanamide: a versatile
reagent for preparing imidazole-amine ligands with variable
second-coordination spheres
⇑
Lionel E. Cheruzel, Jinlan Cui, Mark S. Mashuta, Craig A. Grapperhaus, Robert M. Buchanan
Department of Chemistry, University of Louisville, Louisville, KY 40292, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Two synthetic pathways to N-(2-formyl-1-methylimidazol-4-yl)-2,2-dimethylpropanamide from 1-
methyl-2-carboxaldehyde are described. The reagent serves as a useful synthon for reductive amination
reactions with primary and secondary amines in the presence of sodium cyanoborohydride to yield a ser-
ies of ligands with second coordination sphere functional groups. Protocols for the syntheses of related
imidazole synthons functionalized in the 4-position with amino acids, Schiff bases, and other amides
are also reported.
Received 6 June 2011
Revised 16 June 2011
Accepted 6 July 2011
Available online 19 July 2011
Keywords:
Amide
Ó 2011 Elsevier Ltd. All rights reserved.
Imidazole
Nitroimidazole
Non-covalent interactions
The active site of several metal-containing enzymes extends be-
yond the donor atoms of the first-coordination sphere to include a
second-coordination sphere1,2 defined by functional groups that
participate in non-covalent interactions with metal-bound species,
Figure 1. The design and synthesis of organic ligands with multiple
functional group shells to represent these coordination spheres in
model complexes remain a challenge. In recent years, tripodal
nitrogen-based ligands incorporating amide pendant groups have
been reported. Masuda,3–5 Berreau,6,7 and Mareque-Rivas,8–10 em-
ployed pyridine-based ligands to stabilize reactive metal-bound
hydroperoxide or hydroxide intermediates, while Borovik and
coworkers2,11–14 have developed elegant urea-based tripods to sta-
bilize high valent metal-oxo or metal-hydroxo compounds. Addi-
tionally, Carrano and co-workers15,16 explored carboxamide and
3-carboxyethyl functionalized pyrrazolate ligands.
Our laboratory has focused on the ligand tris((1-methyl-
imidazol-2-yl)methyl)amine (tmima)17–20 as a model for metallo-
enzymes with histidine-rich primary coordination spheres. The
constrained nature of the metal binding pocket of tmima makes it
suitable for binding various metals. Recently, we have been inter-
ested in modifying the tmima metal binding pocket to include amide
pendant groups capable of stabilizing various exogenous ligands
bonded to different metals. Toward this goal, we have reported the
synthesis and characterization of L1 and its ferric complex,21 as well
as the bis-functionalized amide tripod, L2, and a series of Cu(II)
complexes.22 In the current study, we report improved syntheses
of L1 and L2 employing 1-methyl-4-pivaloylami do-imidazole-
2-carboxaldehyde as a key synthon. The methodology was then
extended to develop new ligands, L3–L5, and a small library of
amide-functionalized imidazole synthons.
A key feature of our design is the introduction of the amide pen-
dant in the 4-position of the imidazole ring. This position is crucial
to facilitate the formation of intramolecular six-member hydrogen
bonding rings upon metal-coordination, Figure 1. Our strategy
involves nitration of 1-methylimidazole-2-carboxaldehyde (1)
followed by protection (2,3), reduction (4,5), and acylation (6,7)
to yield the target compound N-(2-formyl-1-methylimidazol-
4-yl)-2,2-dimethylpropanamide (8), Scheme 1. Synthon 8 was then
employed to prepare a variety of amido-functionalized imidazole
ligands L1–L5. All intermediate species were characterized using
conventional analytical and spectroscopic methods. The X-ray
crystal structures of 1, 3, 8, and 10 are also reported, Figure 2.
The nitration of imidazole was first reported by Pyman and
coworkers over nine decades ago.23 In the 1960s the reaction
was revisited by Vaupre,24 who reported the isolation and biolog-
ical activity of 2-nitroimidazole. Since then nitroimidazoles have
been used in pharmaceuticals including metronidazole,25 in purine
synthesis,26–28 and in the syntheses of polyimidazole and polypyr-
role compounds as DNA minor groove binders.29–32 Nitration of 1-
þ
methylimidazole-2-carboxaldehyde using various NO2 sources
(HNO3/H2SO4 or NH4NO3/H2SO4)33 yields 1-methyl-4-nitroimidaz-
ole-2-carboxaldehyde (1). The HNO3 protocol gives slightly lower
yields (35% vs 45%), but allows partial recovery of unreacted 1.
⇑
Corresponding author. Tel.: +1 502 852 5635; fax: +1 502 852 8149.
E-mail address: bob.buchanan@louisville.edu (R.M. Buchanan).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.025

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L. E. Cheruzel et al. / Tetrahedron Letters 52 (2011) 4771–4774
Figure 1. Representation of [L3MX]nꢀ1 highlighting the first coordination sphere of
the M–N bonds and the second coordination sphere of H-bonding interactions
between the amide functional groups and the anionic donor X. The structure is
based on the previously reported complexes [L1FeCl]2+ and [L2CuOH]+, where L1
and L2 differ from L3 by the substitution of one and two amido functional groups by
hydrogen, respectively.
Figure 2. ORTEP representations of 1, 3, 8, and 10.
Scheme 1. Synthesis of 8. Reagents and conditions: (i) HNO3/H2SO4, 100 °C, 50 min
or NH4NO3/H2SO4, 90 °C, 12 h; (ii) N,N0-dimethyl-ethylenediamine; reflux, 2 h; (iii)
ethylene glycol, p-toluenesulfonic acid, reflux, 6 h; (iv) Pd/C/H2, dioxane, rt, 4 h (v)
NEt3, pivaloyl chloride, rt, 2 h; (vi) Pd/C/H2, toluene, rt, 24 h; (vii) NEt3, pivaloyl
chloride, rt, 4 h; (viii) 3 M HCl, acetone, rt, 2 h; (ix) glacial acetic acid, reflux, 12 h.
Compound 8 was employed to synthesize the tripodal ligands
L1–L3 with one to three amide-functionalized imidazole donors,
respectively, as shown in Scheme 2. Reductive amination of
bis((1-methyl-imidazol-2-yl)methyl)amine (bmima) with 8 in the
presence of sodium cyanoborohydride gives the monoamide-
functionalized tripod L1 in 75% yield. The diamide-functionalized
ligand L2 is prepared by reductive amination of 2-aminomethyl-
1-methylimidazole with two equivalents of 8 and sodium cyano-
borohydride in a stepwise or single pot manner. The reaction
proceeds via the amide-functionalized bmima derivative, 9, which
is isolated in the stepwise method and used in situ in the one pot
method. The overall yield for L2 ranges from 40 to 55% following
column chromatography purification. The triamide-functionalized
ligand L3 requires a slightly different approach. First, 8 is reacted
with hydroxylamine to yield oxime 10. Next, 10 is reduced to 2-
aminomethyl-1-methyl-4-pivalamidoimidazole (11), which was
isolated and stored as the hydrochloric acid salt. The free base of
11 reacts with two equivalents of 8 to yield L3 either in a stepwise
process via 12 or in a one-pot synthesis with yields of 65%.
In addition to tripodal ligands, the synthon 8 can be employed
to prepare amido-functionalized imidazole donors based on mac-
rocyclic scaffolds, Scheme 3. As a proof of concept we have isolated
L4–L5, which are derivatives of the previously reported 1-thia-4,7-
diazacyclononane (TASN) ligands with mono- and bis-imidazole
pendant arms. Reductive amination of 8 with TASN in the presence
of sodium borohydride yields L4 in 99% yield within 3 h. Isolated
L4 reacts more slowly with 8 yielding 61% L5 after 24 h in metha-
nol at 45 °C followed by reduction with sodium cyanoborohydride
for an additional 24 h at the same temperature.
þ
With either NO2 source, the reaction occurs regioselectively at the
4-position attributable to the electron-withdrawing carboxalde-
hyde in the 2-position, which strongly disfavors the cationic inter-
mediate required for nitration at the 5-position.
Several carboxaldehyde protecting methods were investigated
including the formation of an 1,3 imidazolidine34 (2), an acetal35
(3), and a thioether.36 Compounds 2 and 3 are isolated in high
yields; 99%. Although 2 is slightly more acid sensitive than 3, either
derivative is suitable for further reactions. Compound 3 is easily
crystallized from the reaction mixture upon cooling at ꢀ20 °C
overnight. Reduction of 2/3 to their corresponding amines 4/5
readily occurs in 1,4-dioxane or THF using H2/Pd/C.37 Reaction
yields as high as 95% were obtained when dried, freshly distilled
solvents are used. Reaction progress was monitored by the NMR
resonance frequency of the C5 proton, which shifts upfield by
ꢁ1 ppm upon reduction of the electron-withdrawing nitro group.
While the amine derivatives 4 and 5 are stable under a H2 atmo-
sphere, attempts to isolate analytically pure samples were unsuc-
cessful. As such, 4 and 5 are acylated in situ using pivaloyl
chloride to yield compounds 6 and 7, respectively, in 74 and 84%
yields, respectively. The direct acylation of 4/5 upon reduction of
2/3 provides a significant improvement in the reaction yield. The
acylated products 6 and 7 are deprotected using either 3 M HCl
in acetone/water for 2 h or refluxing acetic acid for 4 h to yield
the target synthon N-(2-formyl-1-methylimidazol-4-yl)-2,2-dim-
ethylpropanamide (8) as a crystalline white solid. The overall yield
from 1 is 52% for the 1,3 imidazolidine-protected route and 72% for
the acetal-protected pathway.
The development of a rational method for the preparation of
amide-functionalized imidazole ligands allows further derivation
with alternate second coordination sphere motifs. With this in

L. E. Cheruzel et al. / Tetrahedron Letters 52 (2011) 4771–4774
4773
Scheme 2. Syntheses of L1–-L3. Reagents and conditions: (i) bmima, NaBH3CN, glacial acetic acid, CH3OH, rt, 12 h; (ii) 2-aminomethyl-1-methylimidazole; NaBH4, CH3OH,
12 h; (iii) 8, NaBH3CN, CH3OH, rt, 12 h; (iv) 0.5 equiv 8, NaBH3CN, CH3OH, rt, 12 h; (v) NH2OHꢂEtOH, rt, 2 h; (vi) Pd/C/H2, CH3OH, rt, 12 h; (vii) 8, CH3OH, reflux, 30 min, NaBH4,
0 °C, 2 h; (vii) 8, NaBH3CN, CH3OH, rt, 12 h.; (ix) 2 equiv 8, NaBH3CN, CH3OH, rt, 2 h.
Scheme 3. Syntheses of L4–L5. Reagents and conditions: (i) 8, CH3OH, reflux, 3 h, NaBH4, 0 °C, 12 h; (ii) 8, CH3OH, 45 °C, 24 h, NaBH3CN, 45 °C, 24 h.
of 13, HBTU/DIEA yields 65% isolated product after 22 h.38 Simi-
larly, 6 reacts with 1-methylimidazol-2-carboxaldehyde to form
the corresponding Schiff base 14. Finally, the benzamido- (15)
and furamido- (16) analogs of 8 are prepared in 65 and 73% yields,
respectively, under similar reaction conditions.
In conclusion, a facile methodology has been developed to syn-
thesize novel and versatile amide-functionalized imidazole li-
gands. The synthetic methodology developed herein allows the
design of new metal binding pockets that can form intramolecular
six-membered hydrogen bonding rings with other endogenous li-
gands. The systems may be useful in recognition studies modeling
the second coordination sphere of metalloenzymes. The develop-
ment of new amido imidazole synthons containing carboxaldehyde
or amine functionalities permits a wide range of control over the
structure and electronic properties of metal binding pockets. The
molecular environment around the metal can be fine-tuned to in-
clude harder or softer ligands as well as ligands possessing hydro-
phobic, hydrophilic, and charged groups in the second coordination
Scheme 4. Syntheses of 13–16. Reagents and conditions: (i) N-acetyl-DL-phenylal-
anine, HBTU/DIEA, DMF, rt, 22 h; (ii) 1-methylimidazole-2-carboxaldehyde, CH3OH,
rt, 2 h; (iii) NEt3, dioxane, benzoyl chloride, rt, 2 h; (iv) NEt3, 2-furoyl chloride, rt,
2 h.
sphere. Another attractive aspect of this synthetic strategy is that
the nitration step could be used to easily introduce 15N nucleus
in the fourth position of the imidazole ring by using 15N-labeled
ammonium nitrate.
Acknowledgments
mind, we prepared a small library of functionalized imidazole syn-
thons from 5, Scheme 4, through peptide coupling reactions (13),
Schiff base condensation with aldehydes (14), and acylation with
other acyl chlorides (15, 16). Although standard peptide coupling
reagents (DCC/HOBt or EDCI/DMAP in DMF)29,31 give low yields
Acknowledgment is made to the National Science Foundation
(CHE-0749965) and the Kentucky Science and Engineering Founda-
tion (KSEF-275-RDE-003) for funding. MSM thanks the Department

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Supplementary data
Experimental procedures and NMR spectra (1H and 13C) of 1–16
and L1–L5, and X-ray crystallographic detail in PDF format and
crystallographic data in CIF format (CCDC 827412–827415) of 1,
3, 8, and 10. Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2011.07.025.
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