Synlett 2019; 30(13): 1573-1579
DOI: 10.1055/s-0037-1611856
letter
© Georg Thieme Verlag Stuttgart · New York

Hypervalent Iodine Mediated Efficient Solvent-Free Regioselective Halogenation and Thiocyanation of Fused N-Heterocycles

Divakar Reddy Indukuri
a  Flouro & Agrochemicals Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007, India
b  Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India   Email: [email protected]
,
Gal Reddy Potuganti
a  Flouro & Agrochemicals Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007, India
b  Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India   Email: [email protected]
,
Manjula Alla*
a  Flouro & Agrochemicals Division, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad, 500007, India
b  Academy of Scientific and Innovative Research, CSIR-Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500007, India   Email: [email protected]
› Author Affiliations
I.D.R. thanks DST and P.G.R. thanks CSIR, for a fellowship.
Further Information

Publication History

Received: 18 March 2019

Accepted after revision: 16 May 2019

Publication Date:
12 June 2019 (online)

 


Abstract

A facile, rapid, metal-free regioselective halogenation and thiocyanation of imidazo[1,2-a]pyridine/pyrimidine heterocycles has been achieved under solvent-free reaction conditions. Halogenations and thiocyanation of the heterocycles could be accomplished by simple grinding of reactants and hypervalent iodine reagents with the corresponding alkali metal or ammonium salts. The method has been extrapolated to a cleaner synthesis of brominated imidazo[1,2-a]pyridine/pyrimidine derivatives, starting from the corresponding heterocyclic amines and substituted α-bromoketones, utilising HBr generated in situ as the source of bromine.


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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.

Zoom Image
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

NH4Br

H2O

IBD (1.2)f

 30

69

 2

NH4Br

neat (80 °C)

IBD (1.2)f

 15

72

 3

NH4Br

grinding

IBD (1.2)f

 15

71

 4

NH4Br

grinding

IBD (1.5)f

 15

84

 5

NH4Br

grinding

HTIB

 15

75

 6

NH4Br

grinding

K2S2O8

 15

NRc

 7

NH4Br

CH3CN

K2S2O8

360

51

 8

NaBr

grinding

IBD

 15

88

 9

NH4Cl

grinding

IBD

 30

60

10

NaCl

grinding

IBD

 30

60

11

NaI

grinding

IBD

 15

78

12

HBr aq.d

H2O(rt)

IBD

 20

55

13

HCl aq.e

H2O(rt)

IBD

 20

42

14

KSCN

grinding

IBD

 15

85

15

NH4SCN

grinding

IBD

 15

70

16

KSCN

grinding

HTIB

 15

80

17

KSCN

grinding

K2S2O8

 30

NRc

18

KSCN

DCE

K2S2O8

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 NH4Br in H2O 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 NH4Br 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 NH4Br 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 K2S2O8 (entry 6). However, heating the reaction at 80 °C in CH3CN for a longer time (6 h) resulted in 51% conversion into the desired product (entry 7) in the presence of K2S2O8. 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 NH4Cl 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 5ac). 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 NH4SCN and imidazopyridine as reactants (entry 15). Reaction with alternative hypervalent reagent HTIB was also facile under simple grinding conditions (entry 16). However, when K2S2O8 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] (6aj) and products were obtained in good yields.

Zoom Image
Scheme 1 Substrate scope of C-3 halogenation and thiocyanation of imidazoheterocycles. Reaction conditions for products 3ac, 4ac, 5ac and 6aj: 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.

Zoom Image
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

CH3CN

IBD

15

78

 5

H2O

IBD

20

65

 6

EtOH

IBD

15

50

 7

MeOH

IBD

15

45

 8

grinding

K2S2O8

30

NRc

 9

CH3CN

K2S2O8

 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]; 3ar, 12ac).

Zoom Image
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.

Zoom Image
Scheme 4 Control experiments. Reaction conditions: 1 (1 mmol), IBD (1.5 mmol) TEMPO or DDQ (1.5 mmol), NH4Br 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.

Zoom Image
Scheme 5 Plausible route

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Acknowledgment

We would like to thank the director, CSIR-IICT, and AcSIR for facilities. Manuscript communication number IICT/Pubs./2019/018.

Supporting Information

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  • 13 Synthesis of 3-Halo/thiocyanato-2-phenylimidazo[1,2-a]pyridine Derivatives; General Procedure A mixture of 2-phenylimidazo[1,2-a]pyridine (1; 1 mmol), M-X (2ad; 1.5 mmol) and IBD (1.5 mmol) were taken in a mortar and the mixture was ground with a pestle until the solids melted (ca. 15 min). A distinction odour of acetic acid was noted. The progress of the reaction was monitored by TLC and grinding was continued until the starting materials disappeared. The reaction mixture was extracted with ethyl acetate (30 mL) and washed with water (10 mL) to remove remnant inorganic salts. The organic layer was separated and dried over Na2SO4. Solvent was removed in vacuo. The crude product thus obtained was purified by column chromatography for all halogenations (silicon 60–120 mesh; EtOAc/hexane, 5:95). Thiocyanation products could be obtained in pure form without further purification.
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  • 18 Analytical data and copies of spectra of all compounds are given in the Supporting Information. Analytical data of a selection of new compounds are given below. 3-Bromo-2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyridine (3c) Yield: 253 mg (80%); yellow solid; mp 92–94 °C; 1H NMR (500 MHz, CDCl3): δ = 8.08–8.04 (m, 1 H), 8.02 (d, J = 7.0 Hz, 1 H), 7.38 (s, 1 H), 7.03–6.99 (m, 2 H), 6.74 (dd, J = 7.0, 1.5 Hz, 1 H), 3.86 (s, 3 H), 2.42 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 159.57, 145.52, 141.94, 136.15, 129.02, 125.35, 122.96, 115.65, 115.50, 113.81, 89.96, 77.00, 55.24, 21.28. HRMS-ESI: m/z [M + H]+ calcd. for C15H14BrN2O: 317.0284; found: 317.0290. 3-Bromo-7-methyl-2-(p-tolyl)imidazo[1,2-a]pyridine (3l) Yield: 234 mg (78%); white solid; mp 176–178 °C; 1H NMR (400 MHz, CDCl3): δ = 8.00 (dd, J = 7.5, 5.8 Hz, 3 H), 7.37 (s, 1 H), 7.29–7.25 (m, 2 H), 6.70 (dd, J = 7.0, 1.5 Hz, 1 H), 2.40 (s, 6 H). 13C NMR (125 MHz, CDCl3): δ = 145.64, 142.27, 137.95, 136.02, 130.04, 129.08, 127.60, 122.98, 115.81, 115.49, 90.41, 77.00, 21.28. HRMS-ESI: m/z [M + H]+ calcd. for C15H14BrN2: 301.0348; found: 301.0340. 3-Bromo-2-(thiophen-2-yl)imidazo[1,2-a]pyrimidine (3m) Yield: 232 mg (84%); white solid; mp 150–152 °C; 1H NMR (400 MHz, CDCl3): δ = 8.56 (dd, J = 4.0, 1.8 Hz, 1 H), 8.40 (dd, J = 6.8, 1.8 Hz, 1 H), 7.95 (d, J = 3.6 Hz, 1 H), 7.45 (d, J = 5.0 Hz, 1 H), 7.20–7.14 (m, 1 H), 6.99 (dd, J = 6.8, 4.1 Hz, 1 H). 13C NMR (125 MHz, CDCl3): δ = 150.23, 147.99, 140.28, 135.12, 131.15, 127.74, 127.28, 126.71, 109.36, 89.31, 77.00. HRMS-ESI: m/z [M + H]+ calcd. for C10H7BrN3S: 279.9543; found: 279.9544. 3-Bromo-2-(3-nitrophenyl)imidazo[1,2-a]pyrimidine (3n) Yield: 214 mg (68%); white solid; mp 224–226 °C; 1H NMR (300 MHz, CDCl3+DMSO): δ = 9.12 (s, 1 H), 8.67 (dd, J = 4.1, 1.9 Hz, 1 H), 8.65–8.57 (m, 2 H), 8.27 (dd, J = 8.2, 1.2 Hz, 1 H), 7.72 (t, J = 8.0 Hz, 1 H), 7.15 (dd, J = 6.8, 4.1 Hz, 1 H). 13C NMR (75 MHz, CDCl3+DMSO): δ = 150.36, 147.28, 147.06, 139.91, 133.11, 132.40, 131.32, 128.71, 122.07, 121.29, 109.15, 90.40, 77.00. HRMS-ESI: m/z [M + H]+ calcd. for C12H8BrN4O2: 317.9749; found: 317.9752. 3-Bromo-7-methyl-2-(p-tolyl)imidazo[1,2-a]pyrimidine (3p) Yield: 241 mg (80%); brown solid; mp 180–182 °C; 1H NMR (400 MHz, CDCl3): δ = 8.28 (d, J = 7.0 Hz, 1 H), 8.14–8.10 (m, 2 H), 7.29 (d, J = 8.0 Hz, 2 H), 6.85–6.82 (m, 1 H), 2.66 (s, 3 H), 2.41 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 160.32, 148.05, 143.39, 138.52, 130.58, 129.60, 129.13, 127.73, 110.08, 88.91, 77.00, 24.84, 21.35. HRMS-ESI: m/z [M + H]+ calcd. for C13H11BrN3: 288.0140; found: 288.0136. HRMS-ESI: m/z [M + H]+, calcd. for C14H13BrN3: 302.0293; found: 302.0287. 3-Bromo-2-(4-methoxyphenyl)imidazo[1,2-a]pyrimidine (3q) Yield: 249 mg (82%); white solid; mp 154–156 °C; 1H NMR (400 MHz, CDCl3): δ = 8.57 (dd, J = 4.1, 2.0 Hz, 1 H), 8.45 (dd, J = 6.8, 2.0 Hz, 1 H), 8.22–8.16 (m, 2 H), 7.05–6.96 (m, 3 H), 3.88 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 160.16, 149.79, 148.14, 144.22, 131.18, 129.44, 124.79, 113.95, 109.14, 89.38, 77.00, 55.33. HRMS-ESI: m/z [M + H]+ calcd. for C13H10BrN3O: 304.0086; found: 304.0085. 3-Bromo-7-methoxy-2-(4-methoxyphenyl)benzo[d]imidazo [2,1-b]thiazole (12b) Yield: 251 mg (65%); white solid; mp 206–208 °C; 1H NMR (300 MHz, CDCl3): δ = 8.30 (d, J = 9.1 Hz, 1 H), 7.94 (d, J = 8.8 Hz, 2 H), 7.20 (d, J = 2.4 Hz, 1 H), 7.05–6.92 (m, 3 H), 3.87 (d, J = 4.5 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ = 159.34, 157.31, 147.08, 143.31, 131.54, 128.46, 127.18, 125.18, 114.26, 113.87, 113.06, 108.54, 90.89, 77.00, 55.88, 55.31. HRMS-ESI: m/z [M + H]+ calcd. for C17H14BrN2O2S: 388.9958; found: 388.9959. 3-Bromo-7-methoxy-2-(p-tolyl)benzo[d]imidazo[2,1-b]thiazole (12c) Yield: 260 mg (70%); pale-pink solid; mp 204–206 °C; 1H NMR (400 MHz, CDCl3): δ = 8.31 (d, J = 9.1 Hz, 1 H), 7.90 (d, J = 8.2 Hz, 2 H), 7.26 (t, J = 4.0 Hz, 2 H), 7.20 (d, J = 2.4 Hz, 1 H), 7.01 (dd, J = 9.0, 2.4 Hz, 1 H), 3.88 (s, 3 H), 2.40 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 157.27, 147.20, 143.74, 137.63, 131.56, 129.96, 129.11, 127.22, 126.99, 114.26, 112.96, 108.54, 91.33, 77.00, 55.86, 21.31. HRMS-ESI: m/z [M + H]+ calcd. for C17H14BrN2OS: 372.9967; found: 372.9954. 3-Chloro-2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyridine (4c) Yield: 155 mg (57%); brown solid; mp 122–124 °C; 1H NMR (400 MHz, CDCl3): δ = 8.09–8.04 (m, 2 H), 7.97 (d, J = 7.0 Hz, 1 H), 7.39 (s, 1 H), 7.03–6.98 (m, 2 H), 6.75 (dd, J = 7.0, 1.5 Hz, 1 H), 3.87 (s, 3 H), 2.43 (d, J = 0.6 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ = 159.60, 143.98, 139.23, 135.94, 128.75, 125.19, 121.82, 115.80, 115.45, 113.99, 104.16, 55.34, 21.41. HRMS-ESI: m/z [M + H]+ calcd. for C15H14OClN2: 273.0792; found: 273.0789. 3-Iodo-2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyridine (5c) Eluent: hexane/ethyl acetate, 90:10. Yield: 254 mg (70%); white solid; mp 118–120 °C; 1H NMR (400 MHz, CDCl3): δ = 8.06 (d, J = 7.0 Hz, 1 H), 8.00 (d, J = 8.7 Hz, 2 H), 7.35 (s, 1 H), 7.01 (d, J = 8.7 Hz, 2 H), 6.73 (d, J = 6.9 Hz, 1 H), 3.86 (s, 3 H), 2.43 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 159.56, 148.23, 147.52, 136.37, 129.59, 126.16, 125.43, 115.71, 115.45, 113.66, 77.00, 57.33, 55.22, 21.19. HRMS-ESI: m/z [M + H]+ calcd. for C15H14IN2O: 365.0146; found: 365.0151. 3-Thiocyanato-2-(p-tolyl)imidazo[1,2-a]pyrimidine (6g) Yield: 223 mg (84%); white solid; mp 208–210 °C; 1H NMR (300 MHz, CDCl3+DMSO): δ = 8.81 (ddd, J = 6.1, 5.5, 1.9 Hz, 2 H), 8.07 (d, J = 8.2 Hz, 2 H), 7.37 (d, J = 8.0 Hz, 2 H), 7.27 (dd, J = 6.7, 4.3 Hz, 1 H), 2.46 (s, 3 H). 13C NMR (75 MHz, CDCl3+DMSO): δ = 151.94, 138.92, 131.87, 128.45, 127.67, 126.76, 109.65, 77.00, 20.38. HRMS-ESI: m/z [M + H]+ calcd. for C14H11IN4S: 267.0695; found: 267.0699.

  • References and Notes

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  • 13 Synthesis of 3-Halo/thiocyanato-2-phenylimidazo[1,2-a]pyridine Derivatives; General Procedure A mixture of 2-phenylimidazo[1,2-a]pyridine (1; 1 mmol), M-X (2ad; 1.5 mmol) and IBD (1.5 mmol) were taken in a mortar and the mixture was ground with a pestle until the solids melted (ca. 15 min). A distinction odour of acetic acid was noted. The progress of the reaction was monitored by TLC and grinding was continued until the starting materials disappeared. The reaction mixture was extracted with ethyl acetate (30 mL) and washed with water (10 mL) to remove remnant inorganic salts. The organic layer was separated and dried over Na2SO4. Solvent was removed in vacuo. The crude product thus obtained was purified by column chromatography for all halogenations (silicon 60–120 mesh; EtOAc/hexane, 5:95). Thiocyanation products could be obtained in pure form without further purification.
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  • 18 Analytical data and copies of spectra of all compounds are given in the Supporting Information. Analytical data of a selection of new compounds are given below. 3-Bromo-2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyridine (3c) Yield: 253 mg (80%); yellow solid; mp 92–94 °C; 1H NMR (500 MHz, CDCl3): δ = 8.08–8.04 (m, 1 H), 8.02 (d, J = 7.0 Hz, 1 H), 7.38 (s, 1 H), 7.03–6.99 (m, 2 H), 6.74 (dd, J = 7.0, 1.5 Hz, 1 H), 3.86 (s, 3 H), 2.42 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 159.57, 145.52, 141.94, 136.15, 129.02, 125.35, 122.96, 115.65, 115.50, 113.81, 89.96, 77.00, 55.24, 21.28. HRMS-ESI: m/z [M + H]+ calcd. for C15H14BrN2O: 317.0284; found: 317.0290. 3-Bromo-7-methyl-2-(p-tolyl)imidazo[1,2-a]pyridine (3l) Yield: 234 mg (78%); white solid; mp 176–178 °C; 1H NMR (400 MHz, CDCl3): δ = 8.00 (dd, J = 7.5, 5.8 Hz, 3 H), 7.37 (s, 1 H), 7.29–7.25 (m, 2 H), 6.70 (dd, J = 7.0, 1.5 Hz, 1 H), 2.40 (s, 6 H). 13C NMR (125 MHz, CDCl3): δ = 145.64, 142.27, 137.95, 136.02, 130.04, 129.08, 127.60, 122.98, 115.81, 115.49, 90.41, 77.00, 21.28. HRMS-ESI: m/z [M + H]+ calcd. for C15H14BrN2: 301.0348; found: 301.0340. 3-Bromo-2-(thiophen-2-yl)imidazo[1,2-a]pyrimidine (3m) Yield: 232 mg (84%); white solid; mp 150–152 °C; 1H NMR (400 MHz, CDCl3): δ = 8.56 (dd, J = 4.0, 1.8 Hz, 1 H), 8.40 (dd, J = 6.8, 1.8 Hz, 1 H), 7.95 (d, J = 3.6 Hz, 1 H), 7.45 (d, J = 5.0 Hz, 1 H), 7.20–7.14 (m, 1 H), 6.99 (dd, J = 6.8, 4.1 Hz, 1 H). 13C NMR (125 MHz, CDCl3): δ = 150.23, 147.99, 140.28, 135.12, 131.15, 127.74, 127.28, 126.71, 109.36, 89.31, 77.00. HRMS-ESI: m/z [M + H]+ calcd. for C10H7BrN3S: 279.9543; found: 279.9544. 3-Bromo-2-(3-nitrophenyl)imidazo[1,2-a]pyrimidine (3n) Yield: 214 mg (68%); white solid; mp 224–226 °C; 1H NMR (300 MHz, CDCl3+DMSO): δ = 9.12 (s, 1 H), 8.67 (dd, J = 4.1, 1.9 Hz, 1 H), 8.65–8.57 (m, 2 H), 8.27 (dd, J = 8.2, 1.2 Hz, 1 H), 7.72 (t, J = 8.0 Hz, 1 H), 7.15 (dd, J = 6.8, 4.1 Hz, 1 H). 13C NMR (75 MHz, CDCl3+DMSO): δ = 150.36, 147.28, 147.06, 139.91, 133.11, 132.40, 131.32, 128.71, 122.07, 121.29, 109.15, 90.40, 77.00. HRMS-ESI: m/z [M + H]+ calcd. for C12H8BrN4O2: 317.9749; found: 317.9752. 3-Bromo-7-methyl-2-(p-tolyl)imidazo[1,2-a]pyrimidine (3p) Yield: 241 mg (80%); brown solid; mp 180–182 °C; 1H NMR (400 MHz, CDCl3): δ = 8.28 (d, J = 7.0 Hz, 1 H), 8.14–8.10 (m, 2 H), 7.29 (d, J = 8.0 Hz, 2 H), 6.85–6.82 (m, 1 H), 2.66 (s, 3 H), 2.41 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 160.32, 148.05, 143.39, 138.52, 130.58, 129.60, 129.13, 127.73, 110.08, 88.91, 77.00, 24.84, 21.35. HRMS-ESI: m/z [M + H]+ calcd. for C13H11BrN3: 288.0140; found: 288.0136. HRMS-ESI: m/z [M + H]+, calcd. for C14H13BrN3: 302.0293; found: 302.0287. 3-Bromo-2-(4-methoxyphenyl)imidazo[1,2-a]pyrimidine (3q) Yield: 249 mg (82%); white solid; mp 154–156 °C; 1H NMR (400 MHz, CDCl3): δ = 8.57 (dd, J = 4.1, 2.0 Hz, 1 H), 8.45 (dd, J = 6.8, 2.0 Hz, 1 H), 8.22–8.16 (m, 2 H), 7.05–6.96 (m, 3 H), 3.88 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 160.16, 149.79, 148.14, 144.22, 131.18, 129.44, 124.79, 113.95, 109.14, 89.38, 77.00, 55.33. HRMS-ESI: m/z [M + H]+ calcd. for C13H10BrN3O: 304.0086; found: 304.0085. 3-Bromo-7-methoxy-2-(4-methoxyphenyl)benzo[d]imidazo [2,1-b]thiazole (12b) Yield: 251 mg (65%); white solid; mp 206–208 °C; 1H NMR (300 MHz, CDCl3): δ = 8.30 (d, J = 9.1 Hz, 1 H), 7.94 (d, J = 8.8 Hz, 2 H), 7.20 (d, J = 2.4 Hz, 1 H), 7.05–6.92 (m, 3 H), 3.87 (d, J = 4.5 Hz, 6 H). 13C NMR (100 MHz, CDCl3): δ = 159.34, 157.31, 147.08, 143.31, 131.54, 128.46, 127.18, 125.18, 114.26, 113.87, 113.06, 108.54, 90.89, 77.00, 55.88, 55.31. HRMS-ESI: m/z [M + H]+ calcd. for C17H14BrN2O2S: 388.9958; found: 388.9959. 3-Bromo-7-methoxy-2-(p-tolyl)benzo[d]imidazo[2,1-b]thiazole (12c) Yield: 260 mg (70%); pale-pink solid; mp 204–206 °C; 1H NMR (400 MHz, CDCl3): δ = 8.31 (d, J = 9.1 Hz, 1 H), 7.90 (d, J = 8.2 Hz, 2 H), 7.26 (t, J = 4.0 Hz, 2 H), 7.20 (d, J = 2.4 Hz, 1 H), 7.01 (dd, J = 9.0, 2.4 Hz, 1 H), 3.88 (s, 3 H), 2.40 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 157.27, 147.20, 143.74, 137.63, 131.56, 129.96, 129.11, 127.22, 126.99, 114.26, 112.96, 108.54, 91.33, 77.00, 55.86, 21.31. HRMS-ESI: m/z [M + H]+ calcd. for C17H14BrN2OS: 372.9967; found: 372.9954. 3-Chloro-2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyridine (4c) Yield: 155 mg (57%); brown solid; mp 122–124 °C; 1H NMR (400 MHz, CDCl3): δ = 8.09–8.04 (m, 2 H), 7.97 (d, J = 7.0 Hz, 1 H), 7.39 (s, 1 H), 7.03–6.98 (m, 2 H), 6.75 (dd, J = 7.0, 1.5 Hz, 1 H), 3.87 (s, 3 H), 2.43 (d, J = 0.6 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ = 159.60, 143.98, 139.23, 135.94, 128.75, 125.19, 121.82, 115.80, 115.45, 113.99, 104.16, 55.34, 21.41. HRMS-ESI: m/z [M + H]+ calcd. for C15H14OClN2: 273.0792; found: 273.0789. 3-Iodo-2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyridine (5c) Eluent: hexane/ethyl acetate, 90:10. Yield: 254 mg (70%); white solid; mp 118–120 °C; 1H NMR (400 MHz, CDCl3): δ = 8.06 (d, J = 7.0 Hz, 1 H), 8.00 (d, J = 8.7 Hz, 2 H), 7.35 (s, 1 H), 7.01 (d, J = 8.7 Hz, 2 H), 6.73 (d, J = 6.9 Hz, 1 H), 3.86 (s, 3 H), 2.43 (s, 3 H). 13C NMR (125 MHz, CDCl3): δ = 159.56, 148.23, 147.52, 136.37, 129.59, 126.16, 125.43, 115.71, 115.45, 113.66, 77.00, 57.33, 55.22, 21.19. HRMS-ESI: m/z [M + H]+ calcd. for C15H14IN2O: 365.0146; found: 365.0151. 3-Thiocyanato-2-(p-tolyl)imidazo[1,2-a]pyrimidine (6g) Yield: 223 mg (84%); white solid; mp 208–210 °C; 1H NMR (300 MHz, CDCl3+DMSO): δ = 8.81 (ddd, J = 6.1, 5.5, 1.9 Hz, 2 H), 8.07 (d, J = 8.2 Hz, 2 H), 7.37 (d, J = 8.0 Hz, 2 H), 7.27 (dd, J = 6.7, 4.3 Hz, 1 H), 2.46 (s, 3 H). 13C NMR (75 MHz, CDCl3+DMSO): δ = 151.94, 138.92, 131.87, 128.45, 127.67, 126.76, 109.65, 77.00, 20.38. HRMS-ESI: m/z [M + H]+ calcd. for C14H11IN4S: 267.0695; found: 267.0699.

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Figure 1 Fused N-heterocycles used in this study
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Scheme 1 Substrate scope of C-3 halogenation and thiocyanation of imidazoheterocycles. Reaction conditions for products 3ac, 4ac, 5ac and 6aj: 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]
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Scheme 2 Synthesis of heterocyclic hydrobromides
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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]
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Scheme 4 Control experiments. Reaction conditions: 1 (1 mmol), IBD (1.5 mmol) TEMPO or DDQ (1.5 mmol), NH4Br or KSCN (1.5 mmol), grinding for 15 min at room temperature.
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Scheme 5 Plausible route