Key words solvent free - grinding - regioselective substitution - in situ bromination - atom
economy
Fused N -heterocycles are an important class of molecules that exhibit not only unique bioactivities[1 ] but also interesting chemical properties that lead to broad applications in synthetic[2 ] and material chemistry.[3 ] Consequently, the synthesis of fused N -heterocycles has received much attention. The utility and activity profile of these
molecules, especially imidazo[1,2-a ]pyridine/pyrimidine has been shown to be greatly influenced by the nature of substitutions
on the C-2 and C-3 positions (Figure [1 ]). In these heterocycles the C-3 position is normally an electron-rich centre that
is susceptible to electrophilic substitution.[4 ] Substitutions at C-3 carbon of these key substrates via metal-catalyzed oxidative
C–H activation,[5 ] as well as a few organocatalyst- and organophotocatalyst-mediated[6 ] oxidative reactions have also been attempted.
Figure 1 Fused N -heterocycles used in this study
A diverse range of substitutions can be introduced on substrates through the reversal
of reactivity of reagents and/or synthons. Hypervalent iodine[7 ] reagents have been reported to promote this reversal of reactivity to facilitate
hitherto impossible substitutions on electron-rich substrates. A recent flurry of
reports on iodobenzenediacetate (IBD) mediated substitutions on electron-rich aromatic
compounds alkenes,[8 ] carbonyls,[9 ] and enamines[10 ] has prompted us to investigate hypervalent iodine mediated functionalisation of
the imidazo[1,2-a ]pyridine/pyrimidine framework. Hypervalent iodine reagents are ambiphilic in nature
and behave similar to transition-metal complexes, facilitating ligand exchange[11 ] and their subsequent transfer via reductive elimination. Though few synthetic protocols[12 ] have been devised for key substitution on fused N -heterocycles, a versatile metal-free oxidative protocol for C-3 substitution, incorporating
green chemistry principles, is highly desirable.
Table 1 Optimization of Conditions for Halogenation and Thiocyanation of 2-Phenylimidazo[1,2-a ]pyridine (1a )a
Entry
Reagent
Solvent
Oxidant
Time (min)
Yield (%)b
1
NH4 Br
H2 O
IBD (1.2)f
30
69
2
NH4 Br
neat (80 °C)
IBD (1.2)f
15
72
3
NH4 Br
grinding
IBD (1.2)f
15
71
4
NH4 Br
grinding
IBD (1.5)f
15
84
5
NH4 Br
grinding
HTIB
15
75
6
NH4 Br
grinding
K2 S2 O8
15
NRc
7
NH4 Br
CH3 CN
K2 S2 O8
360
51
8
NaBr
grinding
IBD
15
88
9
NH4 Cl
grinding
IBD
30
60
10
NaCl
grinding
IBD
30
60
11
NaI
grinding
IBD
15
78
12
HBr aq.d
H2 O(rt)
IBD
20
55
13
HCl aq.e
H2 O(rt)
IBD
20
42
14
KSCN
grinding
IBD
15
85
15
NH4 SCN
grinding
IBD
15
70
16
KSCN
grinding
HTIB
15
80
17
KSCN
grinding
K2 S2 O8
30
NRc
18
KSCN
DCE
K2 S2 O8
360
60
a Reaction conditions: 1a (1 mmol), 2 M-X (1.5 mmol), oxidant.
b Isolated yields reported.
c No reaction.
d HBr 48% solution.
e HCl 36.5% solution.
f Equivalents of halide salt and oxidant used are given in parentheses.
The reactivity of fused N -heterocycles was assessed with a range of salts in the presence of iodobenzene diacetate
(IBD) under various reaction conditions (Table [1 ], Scheme [1 ]). To begin with, the strategy was tested by subjecting imidazo[1,2-a ]pyridine to IBD-mediated bromination with NH4 Br in H2 O at room temperature (entry 1). 3-Bromo-2-phenylimidazo[1,2-a ]pyridine (3a ) precipitated from the reaction mixture within a short time (30 min) and the product
was isolated in 69% yield. Raising the temperature to 80 °C and performing reaction
under solvent-free conditions not only improved the yield of the reaction (72%) but
also reduced the reaction time by half (entry 2). The conversion yield (71%) was comparable,
when the reactants were subjected to simple grinding in a mortar and pestle under
neat conditions (entry 3). Optimum product yields were obtained by using 1.5 equivalents
of NH4 Br and IBD (entry 4). Having successfully demonstrated the formation of the required
product under solvent-free conditions, other oxidising reagents were tested for their
utility in the current protocol. Reaction was facile with NH4 Br and [hydroxy(tosyloxy)iodo]benzene (HTIB) (entry 5) by simple grinding of reactants.
On the other hand, the reaction was not successful under these conditions with K2 S2 O8 (entry 6). However, heating the reaction at 80 °C in CH3 CN for a longer time (6 h) resulted in 51% conversion into the desired product (entry
7) in the presence of K2 S2 O8 . The results establish the superiority of hypervalent iodine reagents, unequivocally.
Sodium bromide gave slightly higher yield of 3a (entry 8). The study was extended to other halide salts. The chloride salts NH4 Cl and NaCl gave the corresponding 3-chloro-2-phenylimidazo[1,2-a ]pyridine (4a ; entries 9 and 10), under similar reaction conditions, albeit in much lower yield.
Iodination with NaI in the presence of IBD was also successful, yielding 3-iodo-2-phenylimidazo[1,2-a ]pyridine (5a ; entry 11). The substrate scope of the protocol, investigated with respect to substitutions
on C-2 phenyl group of imidazopyridines, indicated that the unsubstituted phenyl ring
gave the best yields in all halogenations. Among the various halogenations attempted,
the yields were better for bromination, followed closely by iodination, and chlorination
gave lowest yield of products (Scheme [1, 3a–c, 4a–c ], and 5a –c ). Interestingly halogenations with aq. HBr (48%) and aq. HCl (36.5%) were also successful,
and the corresponding products (3a or 4a , respectively) could be obtained in moderate yields (entries 12 and 13).
Extending the protocol to other reagents was explored in an attempt to further broaden
its scope and applicability. Thiocyanation of the above heterocycles was studied under
a similar set of optimised conditions (Table [1 ], entry 4). Gratifyingly, simple grinding of imidazo[1,2-a ]pyridine and KSCN with IBD gave the corresponding 2-phenyl-3-thiocyanatoimidazo[1,2-a ]pyridine (6a ) in 85% yield (entry 14). Comparable results were obtained with NH4 SCN and imidazopyridine as reactants (entry 15). Reaction with alternative hypervalent
reagent HTIB was also facile under simple grinding conditions (entry 16). However,
when K2 S2 O8 was used, the formation of the product was possible only on refluxing in solution
in dichloroethane (DCE) at 80 °C. Thiocyanation failed to progress under simple grinding
conditions (entries 17 and 18). The substrate scope of thiocyanation was broad, as
evident from the examples depicted in Scheme [1 ] (6a –j ) and products were obtained in good yields.
Scheme 1 Substrate scope of C-3 halogenation and thiocyanation of imidazoheterocycles. Reaction
conditions for products 3a –c , 4a –c , 5a –c and 6a –j : compound 1 (1 mmol), 2 (1.5 mmol), IBD (1.5 mmol), grinding at room temperature. General procedure and data
for select compounds are provided in References and Notes.[13 ]
The success of halogenations with aqueous HCl and HBr (Table [1 ], entries 12 and 13) inspired us to investigate a cleaner and more atom-economical
method for the synthesis of 3-bromo-2-phenylimidazo[1,2-a ]pyridine (3a ). Construction of these fused rings often involves condensation of a heterocyclic
amine and α-bromoketone, resulting in generation of HBr in stoichiometric portions
as a by-product. It would be an ideal situation if the HBr generated in situ could
be used for bromination. The α-bromoketone and heterocyclic amine were stirred in
solvent for the requisite time (Scheme [2 ]) to complete ring formation and subsequently solvent was removed from the reaction
mixture. The residue was taken in a mortar and pestle and the mass was thoroughly
ground along with IBD. Continuous grinding for 15 minutes resulted in formation of
the corresponding brominated product in good yields.
Scheme 2 Synthesis of heterocyclic hydrobromides
A one-pot protocol for the synthesis of 3a by grinding heterocyclic amine and α-bromoketone under solvent-free, aerobic conditions
resulted in hydrolysis of the α-bromoketone. Therefore, a completely solvent-free
grinding protocol could not be designed. Suitable conditions for in situ bromination
protocol were arrived at by studying various reaction parameters. It was found that
bromination yields were good when the reaction residue (9 /11 ) was heated neat (melt) or by simple grinding with IBD (Table [2 ], entries 1 and 2). Both these conditions gave brominated products in yields that
were comparable to the yields obtained when brominations were performed in refluxing
aprotic solvents (entries 3 and 4). Protic solvents (entries 5–7) were not good media
for bromination. Brominations in IBD gave better yield of the product compared with
other oxidising reagents (entries 8–10).
Table 2 Optimization of Conditions for Bromination of 2-Phenylimidazo[1,2-a ]pyridine Hydrobromide to 3-Bromo-2-phenylimidazo[1,2-a ]pyridine (3a )a
Entry
Solvent
Oxidant
Time (min)
Yield (%)b
1
neat (80 °C)
IBD
15
80
2
grinding
IBD
15
85
3
dioxane
IBD
15
80
4
CH3 CN
IBD
15
78
5
H2 O
IBD
20
65
6
EtOH
IBD
15
50
7
MeOH
IBD
15
45
8
grinding
K2 S2 O8
30
NRc
9
CH3 CN
K2 S2 O8
6 h
trace
10
grinding
HTIB
6
54
a Reaction Conditions: 9a (1 mmol), oxidant (1.5 mmol).
b Isolated yields were reported.
c No reaction.
The established ideal reaction conditions for in situ bromination [hydrobromide salt
9/11 , IBD (1.5 equiv), grinding] were extended to other substrates. The substrate scope
of the protocol is broad, as a wide range of substituents are tolerated. The reaction
conditions could be used for bromination of a number of substituted imidazo[1,2-a ]pyridine, imidazo[1,2-a ]pyrimidine, as well as other fused N -heterocycles (Scheme [3 ]; 3a –r , 12a –c ).
Scheme 3 Substrate scope of in situ bromination of fused N -heterocycles. Reaction conditions: heterocyclic hydrobromide (9/11 ; 1 mmol), IBD (1.5 mmol), grinding for 15 min at room temperature. General procedure
and data for select compounds is given in References and Notes.[14 ]
Having established the scope and utility of the reaction, the mechanistic aspects
of the transformation attracted our attention. Hypervalent iodine-mediated reactions
are known to adopt two pathways: either a radical pathway[15 ] or ionic pathway.[16 ] Control experiments carried out in the presence of 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as radical scavengers
were surprisingly successful (Scheme [4 ]). This unambiguously rules out a radical pathway for the reaction. The product yield
of the reaction was susceptible to variations in the oxidant quantity and slightly
higher than stoichiometric proportions of IBD and halide/thiocaynate salts were essential
to obtain good product yields. A simple grinding of the halide salts with IBD resulted
in the liberation of distinct acetic acid odour. This indirectly indicates that a
ligand exchange mechanism is probably involved. A plausible mechanism therefore involves
ligand exchange with acetate to form in situ [acetoxy(halo/thiocyanato)iodo]benzene[17 ] from IBD and MX (Scheme [5 ]). The species, being labile, serves as a formal X+ reagent, thereby facilitating substitution on C-3 carbon.
Scheme 4 Control experiments. Reaction conditions: 1 (1 mmol), IBD (1.5 mmol) TEMPO or DDQ (1.5 mmol), NH4 Br or KSCN (1.5 mmol), grinding for 15 min at room temperature.
In summary, a highly efficient, rapid, operationally simple and facile substitution
protocol for C–H substitution of fused N -heterocycles has been established.[13 ]
[14 ]
[18 ] An inexpensive practical halogenation method has been established for imidazo[1,2-a ]pyridine/ pyrimidine using simple alkali/ammonium halides, aq. HBr / aq. HCl in the
presence of IBD. The scope of the protocol has been extended to other reagents, and
effective thiocyanation of imidazo[1,2-a ]pyridine/ pyrimidine could be achieved under solvent-free conditions. The method
has been extrapolated to an atom-economical[17 ] cleaner synthesis of brominated derivatives of fused N -heterocycles starting from heterocyclic amine and α-bromomketone. Additionally, this
in situ bromination protocol could be scaled up to a gram level synthesis (Scheme
[3 ], compound 3b ). This hypervalent iodine mediated substitution protocol, which is compatible with
a wide range of substrates, substituents and reagents, is a valuable tool for substitution
of electron-rich arene centres and N -heterocycles.
Scheme 5 Plausible route
