Efficient, single-step access to imidazo[1,5-a]pyridine N-heterocyclic carbene precursors

Article abstract of DOI:10.1021/ol202134n

The three-component coupling reaction of substituted picolinaldehydes, amines, and formaldehyde to produce imidazo[1,5-a]pyridinium ions is reported, providing an efficient method for the preparation of N-heterocyclic carbenes (NHCs). Reactions proceed in

Full text of DOI:10.1021/ol202134n

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5256–5259
Efficient, Single-Step Access to
Imidazo[1,5-a]pyridine N-Heterocyclic
Carbene Precursors
Johnathon T. Hutt and Zachary D. Aron*
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington,
Indiana 47405-7102, United States
zaron@indiana.edu
Received August 5, 2011
ABSTRACT
The three-component coupling reaction of substituted picolinaldehydes, amines, and formaldehyde to produce imidazo[1,5-a]pyridinium ions is
reported, providing an efficient method for the preparation of N-heterocyclic carbenes (NHCs). Reactions proceed in high yields under mild
conditions, allowing the incorporation of diverse functionality and chiral substituents. Higher order condensations are also described that provide
access to multidentate NHC ligands useful for a variety of applications.
In the past 20 years, the strong σ-donor capacities, low
dissociation rates and unique geometries of N-heterocyclic
carbenes (NHCs) have made them invaluable ligands for
homogeneous catalysis.1À5 Of particular interest are un-
symmetrical NHCs that frame the carbene with differen-
tiated substituents to provide tunable control of metal
ligand sphere geometry. Unfortunately, the range of these
structures available through straightforward and practical
methods is limited. Here, we report a three-component
coupling reaction that simplifies the synthesis of imidazo-
[1,5-a]pyridinium salts, providing unprecedented access to
variously substituted, chelating, and oligomeric unsym-
metrical NHC precursors in a single transformation.
Figure 1. Catalytically relevant complexes of imidazo[1,5-a]pyrid-
ine-based NHC ligands.
Imidazo[1,5-a]pyridine-derived NHCs are well-estab-
lished in homogeneous catalysis, as exemplified by appli-
cations in asymmetric allylic alkylations and SuzukiÀ
Miyaura and related cross-coupling reactions (Figure 1).6,7
Among the strongest heteroaromatic σ-donors,7 imidazo-
[1,5-a]pyridine-derived NHCs place substituents directly
in the nodal plane of the carbene π-system, facilitating the
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r
10.1021/ol202134n
Published on Web 09/09/2011
2011 American Chemical Society

creation of a unique steric environment. General synthetic
approaches to these ligands involve alkylations of com-
mercially available imidazo[1,5-a]pyridines with reactive
electrophiles,7a dehydrative cyclizations of N-formylpico-
line derivatives,7a and condensations of picolinealdehyde
Schiff bases with activated bis-electrophiles.7b The harsh
conditions, poor yields, and constrained scope of these
methods limit the range of available analogs.
Table 1. Initial Optimizationa,b
entry
equiv acid
solvent
methoda
yield (%)b
1
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
2.0
0.5
0.5
ethanol
ethanol
MeCN
MeCN
MeOH
MeOH
H2O
B
A
B
A
B
A
B
A
B
A
B
A
>99
94
97
97
95
91
91
>99
71
85
34
25
Scheme 1. Campbell’s approach to imidazo1,5-a]pyridinium
2
ions.8
3
4
5
6
7c
8c
9
H2O
ethanol
ethanol
ethanol
ethanol
10
11
12
Inspired by the related reports of Campbell8 and
Chakravarty9 (Scheme 1), we sought to explore condensa-
tions of amines with picolinaldehyde and formaldehyde to
directly access imidazopyridinium ions. Initial efforts to
establish the desired three-component coupling examined
the ethanolic reaction of picolinaldehyde with paraformal-
dehyde and benzylamine in the presence of acid. These
transformations involved premixing the amine with par-
aformaldehyde to avoid double condensations of picoli-
naldehyde with the amine in a manner analogous to the
previously reported reactions (Scheme 1).8,9 Gratifyingly,
rapid reaction was observed at rt to provide salt 4 in 91%
isolated yield (Table 1, entry 1). Reaction optimization
revealed that using aqueous formaldehyde circumvented
picolinaldehyde self-condensation, allowing us to directly
combine the reagents in a single reaction without attenua-
tion of yield (Table 1, entry 2). Solvent screens revealed
excellent reactivity in a variety of polar solvents with both
approaches (Table 1, entries 1À8). Solubility issues in water
required the use of polar substrates, but no loss in efficiency
was observed (Table 1, entries 7 and 8). Superstoichiometric
quantities of acid slowed the reaction, likely impacting the
reactivity of the pyridine nitrogen (Table 1, entries 9 and 10).
In contrast, substoichiometric quantities of acid revealed the
acid as a limiting reagent (Table 1, entries 11 and 12).
Following initial optimizations, we screened several
amines to explore the scope of the reaction (Table 2).
a Method A: Reactions maintained for 2 h with 1.5 equiv of formalin
in solvent (0.5 M), anhydrous HCl in ethanol, and 1 equiv of picolinal-
dehyde. Method B: Benzyl amine was stirred with 1.5 equiv of paraf-
ormaldehyde in solvent (0.5 M) for 1À4 h, at which point HCl and 1
equiv of picolinaldehyde were added, and the solutions were maintained
at rt for 2 h. b Yields determined by 1H NMR spectroscopy with an
internal standard (phenol). c Reactions performed using aqueous HCl
(conc) and ethanolamine in lieu of benzylamine.
The condensation proceeds in excellent yields with simple,
functionalized, and sterically encumbered primary amines
and anilines. Substrates containing secondary amines,
pyridyl moieties, alcohols, thioethers, and esters proceeded
with excellent conversions, although substrates bearing an
additional basicnitrogen requiredanadditional equivalent
of acid (Table 2, entries 1À7). The condensation proceeds
at a slower rate in the presence of sterically encumbered
amines, requiring prolonged reaction times in some cases
(Table 2, entries 8 and 9). Substrates bearing stabilized
nitrogens revealed excellent reactivity in the case of elec-
tron-rich and -poor anilines (Table 2, entries 10À13).
However, no products were observed in reaction attempts
with amides or sulfonamides.
Amino acid derived amines exhibited no epimerization
during the condensation reaction, facilitating the incorpora-
tion of chirality into imidazopyridinium salts (Table 2,
entries 6 and 7). Functionalized nonracemic NHCs are
powerful tools for homogeneous catalysis,10 inducing chir-
ality in numerous reactions including hydrogenation, hydro-
silylation, and alkylation (among many others).11
Unfortunately, unsymmetrically functionalized NHCs are
generally prepared through a tandem condensation/
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Org. Lett., Vol. 13, No. 19, 2011
5257

Table 2. Amine Substrate Scopea,b
Table 3. Bis- and Poly-NHCsa
a Compounds purified as described in note b of Table 2. b Reaction
performed at 0.35 M in ethanol. c Reaction run as described for Method B,
Table 1 using 3 equivalents of paraformaldehyde. d Reaction performed
using the bis-HCl salt of the starting diamine with no additional HCl added.
Reactions of polyamines provide facile access to bis- and
tris-NHCs (Table 3). The reaction works exceedingly well
with simple diamines, para-phenylene diamine, chiral bis-
amines, and polyamines. The successful reaction of 1,2-cyclo-
hexyldiamine (Table 3, entry 3) demonstrated our ability to
access chiral bis-NHCs possessing two R-stereocenters.
Synthesis of the analogous imidazolium salt 5 requires a
three-step procedure with the key cycloaddition step invol-
ving long reaction times and exhibiting low yields (Scheme
2a).13 The straightforward synthesis of tris-NHCs such as
entry 4 (Table 3) is notable as current approaches center on a
harsh alkylation strategy that limits access to these materials
(Scheme 2b).12 Although tris-NHCs remain rare in the
literature, they exhibit significant synthetic potential. For
example, ligands such as the TIMEN-derived imidazolium
NHCs (6), developed by Meyer et al., bind first row transition
metals (Cu, Fe, Ni, and Co) in a 1:1 fashion, with cobalt com-
plexes of 6 displaying activity in small-molecule activation.14
Notable exceptions to the polyamine condensations were
a Reactions run as described in Table 1, using varying times (1À12 h) for
different amines. b Chloride salts isolated through recrystallization or
filtration; hexafluorophosphate salts isolated through salt metathesis with
KPF6. c Reactions required 2 equiv of HCl. d Reactions performed for 4 d.
alkylation aproach, making access to R-chiral compounds of
high optical purity both costly and time-consuming.12 Our
procedure simplifies access to these compounds, allowing the
incorporation of R-chiral amines without epimerization or
loss of chirality in the corresponding NHCs.
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2003, 22, 4384–4386.
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Soc. 2004, 125, 12237–12245. (b) Hu, X. L.; Castro-Rodriguez, I.;
Meyer, K. J. Am. Chem. Soc. 2004, 126, 13464–13473. (c) Vogel, C.;
Heinemann, F. W.; Sutter, J.; Anthon, C.; Meyer, K. Angew. Chem., Int.
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Chem. 2009, 1700–1716.
5258
Org. Lett., Vol. 13, No. 19, 2011

Table 4. Carbonyl Substrate Scopea,b
Scheme 2. (a) Representative Synthetic Approach to Chiral Bis-
NHCs;13 (b) Synthesis of the TIMEN Tris-NHC Ligand14
entry
carbonyl donor
methoda product yield (%)b
1
2
3
4
5
5-methoxypicolinaldehyde
5-cyanopicolinaldehyde
6-methylpicolinaldehyde
2-acetylpyridine
A
A
A
B
B
7a
7b
7c
7d
7e
78
43
92
88
70
2-acetyl-6-
observed for ortho-phenylenediamine, which condenses with
formaldehyde to produce the corresponding dihydrobenzi-
midazole, and meta-phenylenediamine, which reacted with
formaldehyde to produce an intractable red solid. Consider-
ing the wealth of commercially available diamines and poly-
amines, this method allows for the facile construction of a
library of imidazo[1,5-a]pyridine bis- and poly-NHC analogues.
Reactions of substituted picolinaldehydes and related
ketones with n-butylamine and formaldehyde further es-
tablished the scope of this condensation. Electron-rich
pyridines react smoothly (Table 4, entry 1); however
electron-poor systems led to attenuated yields (Table 4,
entry 2). Pyridine substitution at C-5 had no notable effect
on reactivity, despite steric interactions introduced by the
substituent (Table 4, entry 3). 2-Acetyl-pyridine, 2-ben-
zoylpyridine, and 6-methyl-2-acetyl-pyridine also react
well, allowing for placement of substituents at both the 1
and 5 positions. The incorporation of substituents at C5
allows us to increase the effective steric bulk of these
ligands. Moreover, substitution at C1 potentially restricts
bond rotation at N-substituted stereocenters, further rigi-
difying the system.15 To the best of our knowledge, this
chemistry is the first reported method that provides access
to unsymmetrical NHCs that vary in substitution at both
sides of the carbene carbon in a single transformation.
One plausible mechanism for this condensation is shown
below (Scheme 3). In our mechanistic rationalization, the
protonated Schiff base 9 is attacked by picolinaldehyde (8),
leading to condensation intermediate 10. Cyclization of 10
occurs through nucleophilic attack of the amine nitrogen
onto the aldehyde, and the reaction is driven to completion by
an irreversible dehydration to provide aromatic imidazo[1,5-
a]pyridinium ion 12. Our proposed mechanism is consistent
with observations that both an excess of acid and the use of
electron-poor pyridines inhibit the process, as the nucleo-
philicity of the pyridine is critical to the initial step.
methylpyridine
6
2-benzoylpyridine
A
7f
91
a Reactions run as described in Table 1, using varying times (2À12 h)
for different amines. b Chloride salts were isolated by recrystallization,
whereas PF6 and BPh4 salts were isolated through salt metathesis with
KPF6 and NaBPh4.
Scheme 3. Proposed Mechanism of Condensation
In conclusion, an efficient method for the general
preparation of imidazo[1,5-a]pyridine salts has been
developed. This method represents a new avenue for
directly accessing unsymmetrical NHCs that vary in
substitution at both sides of the carbene carbon. Using
this chemistry, a library of structurally diverse com-
pounds can be quickly assembled to access new and
potentially valuable N-heterocyclic carbene ligands. On-
going studies in our laboratory are directed at develop-
ing catalytic systems that incorporate imidazo[1,5-
a]pyridine based NHC ligands.
Acknowledgment. We acknowledge the financial sup-
port of Indiana University.
Supporting Information Available. Experimental pro-
cedures and spectral data for all compounds generated
through this work. This material is available free of
charge via the Internet at http://pubs.acs.org.
(15) Schmidt, M. A.; Movassaghi, M. Tetrahedron Lett. 2007, 48,
101–104.
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