2
Tetrahedron Letters
synthesis
Ortoleva-King-type
imidazo[1,2-a]pyridine
involving the reaction of active methyl or methylene compounds
with stoichiometric amounts of molecular iodine and 2-
aminopyridine is another equally important and widely used
methodology. But the major disadvantage of this methodology is
the formation of the iodide by-products leading to complex
separation procedures often resulting in lower yields. Later many
modifications were tried in this area by performing reactions in
the presence catalytic amounts of iodine, in situ generated from
iodide salts using catalysts like cerium, Graphene Oxide etc. The
oxidizing nature of catalysts in converting iodide ion to iodine
Scheme 2: Iron-Iodine catalyzed Ortoleva-King-type reaction
between 4-methylpyridin-2-amine and acetophenone
Since we found that our Fe(III)/I- system is active for this
conversion, we made further efforts to achieve the optimum
yielding condition by varying the iodide source, solvent etc. An
elevation in the temperature was found to enhance the yield to
52% in a shorter duration of 20 hours. The use of nitrogen
atmosphere provided only 13% yield which arises due to inability
of iron to restore catalytically active Fe (III) state after the initial
iodine liberation step (Equation. 1) and continue the catalytic
cycle (Scheme 4). Although we attempted the reaction in the
presence of oxygen atmosphere eyeing a more effective Fe2+ to
Fe3+ conversion step, oxidation of 1a was found to occur
furnishing unwanted side products yielding only traces of 3a.
Influence of other iodide salts were also tested where TBAI and
ZnI2 provided yields of 28% and 36% respectively (Table 1,
entry 4 & 6). Use of 1, 2-dichlorobenzene and DMF has
delivered the products with yields of 41% and 25% while ethanol
and DCE provided only traces (Table 1, entry 5, 7, 8 & 9).
Formation of 36% of 3a was observed when toluene was used as
the solvent (Table 1, entry 10). Interestingly, an enhancement of
yield to 61% was occurred when we used 20 mol% of molecular
iodine as the additive (Table 1, entry 14). The reactivity of more
easy-to-handle FeCl3.6H2O was also tested which afforded a
similar yield of 62% (Table 1, entry 15). Other iron sources
examined were Fe(NO3)2. 9H2O and Silica supported
FeCl3.6H2O; but both were met with lower yields of 32% and
33% respectively (Table 1, entry 13 & 12). Use of both iron
catalyst and iodine in 30 mol% each only provided 52% of yield
(Table 1, entry 16). Control experiments were also performed
which avoid the use of either iron or iodine (Table 1, Entry 17
& 18). No product formation was observed in the former case
while the latter furnished 18% of the desired product
corresponding to the 20 mol% of the iodine present in the
medium which could run a single catalytic cycle in the absence of
iron. Extension of duration of reaction to 24 hours only resulted
in an increment of yield by one percentage (Table 1, Entry 19).
was the key factor here and the catalytic cycle was found to be
maintained well providing more efficient conversions compared
to the original methods. These protocols were equally imperative
and analogous to that of oxidative coupling reactions between
ketones and 2-aminopyridines, which afford imidazopyridines
via α C-H functionalization (Scheme 1).14,15 Iron is a cheap and
non-toxic transition metal which is widely employed in synthetic
organic chemistry especially in heterocycle synthesis. The metal
possesses good oxidizing capability and known to liberate iodine
on reaction with iodide salts (Equation 1).
2 Fe3+ + 2 I-
2 Fe 2+ + I2… (Equation 1)
Our experience in iron-catalyzed cross-coupling reactions16
made us to study the activity of this d6 metal in the catalyzed
version of Ortoleva-King-type reactions like the above. In this
manuscript we report the first iron-catalyzed Ortoleva-King-type
imidazo[1,2-a]pyridine synthesis in the presence of catalytic
amounts of molecular iodine and the protocol have successfully
extended to demonstrate the functional group tolerance of a
variety of ketones.
These results indicate that both iron and iodine are
unavoidable constituents in this protocol and thus support the
mechanistic proposal also. Thus we have reached a conclusion
choosing the optimal conditions as Entry 15, Table 1 and carried
out the substrate scope studies. During the process we examined
the reactivity of a variety of acetophenones with 4-methyl-2-
aminopyridine and 2-aminopyridine and moderate to good yields
of the corresponding imidazo[1,2-a]pyridines were obtained
(Table 2).
Scheme 1: a, b) Copper catalyzed oxidative coupling between
2-aminopyridine and ketone c) Our protocol involving
Iron/iodine-Catalyzed Ortoleva-King type Protocol
We have also achieved a facile one step synthesis of the gastro
protective drug, Zolimidine, which demonstrates the potential
application of this protocol in the pharmaceutical industry.
The protocol was found to be general in the presence of
different substituents comprising ERGs (-Me, -OMe), halo (-I, -
Br, -F) and EWGs (-NO2, -CF3) at ortho, para and meta
positions. Electron density on the aryl ketones doesn’t made any
observable correlation with the yields where nitro group was an
exception providing the highest yield of 75% (Entry 11). The
Electron density on the amino pyridine core has some influence
as more electron rich 4-methyl-2-amino pyridine was providing
the highest yields compared to the 2-aminopyridines in the case
of all the aryl ketones investigated. Later we decided to evaluate
the possible application of this methodology in drug industry by
an attempt towards the direct synthesis of the gastro protective
drug, Zolimidine. We have found that under the optimized
2. Results and Discussion
We have started our studies by choosing 4-methylpyridin-2-
amine 1a (0.60 mmol) and acetophenone 2a (0.50 mmol) as the
model substrates. The initial reaction was carried out in
o
acetonitrile (80 C) in a sealed tube using 20 mol% of anhydrous
FeCl3 as the catalyst and KI (20 mol%) as the iodine source
(Scheme 2). The progress of the reaction was monitored by TLC
and after 45 hours the reaction mixture was quenched with water
and extracted with ethyl acetate (3x15mL). The solvent was later
evaporated in vaccuo. The crude mixture was purified by
performing silica gel column chromatography using Hexane-
Ethyl acetate mixture to furnish a white powder which was
characterized to be the desired product 3 using characterization
techniques such as NMR and GC-MS. (Table 1, Entry 1)
conditions,
2-aminopyridine
(1b)
and
1-(4-
(methylsulfonyl)phenyl)ethanone react to furnish the desired
drug, 3s in 65% yield (Scheme 3).
Ujwaldev, Sankuviruthiyil Mohanan
