3-Bromoimidazo [1,2-a]pyridines: Bromination via in situ oxidation of HBr by nitric acid

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1 Chapter 2 3-Bromoimidazo [1,2-a]pyridines: Bromination via in situ oxidation of HBr by nitric acid 2.1 INTRODUCTION Halogenated compounds play a very important role in getting higher value added pharmaceutical and agrochemical products in medicinal science and also in material science. It is estimated that about 20 percent of all pharmaceutical small molecule drugs and about 30 percent of all active compounds in agro chemistry are halogenated (Herrera-rodriguez 2011). They play a crucial part as starting materials and key intermediates in constructing desired molecules for fine chemicals, material science and pharmaceutically active molecules (Podgorsek 2009). The prologue of a carbon halogen bond can have many effects in medicinal chemistry and two most important are: a) a raise in thermal and oxidative stability, which means less tendency towards oxidation by the liver P450 detoxification and b) an improved biological membrane permeability. Therefore halogenation is a strategy to lessen drug failure in clinical trials and increase drug efficacy (Herrera-rodriguez 2011). Among halogenated compounds, organic bromides have an extensive application in life, society and serve as herbicides (Bromoxynil), bioactive molecules, emulsifiers, fire-retardants properties of materials (tetrabromobisphenol- A), dyes (Tyrian purple-6,6-dibromoindigo) and a popular indicator (bromothymol blue) in analytical chemistry (Li 2014; Daniels 2006). In last few decades, heteroaryl/aryl bromides earned an important place in organic chemistry as precursors in carbon-carbon bond formation reactions via Heck, Stille and Suzuki cross coupling reactions (Trzeciak and Ziolkowski 2005). The functionalized imidazo[1,2-a]pyridine scaffold is a starting point for synthesis of a plethora of biologically active molecules (Katritzky 2003). The pharmacological profile of imidazo[1,2-a]pyridines depends on the nature of the substituents at 2 nd and 3 rd positions. In particularly, functionalization at 3 rd position leads to various biologically active imidazo[1,2-a]pyridine scaffolds (Kianmehr 2010). In the last couple of decades, a lot of development has taken place in synthesis and cross coupling reactions of imidazo[1,2-a]pyridines. But an 42

2 imidazo[1,2-a]pyridine functionalized with a reactive functionality in 3 rd position to enable further functionalization has a scope for further development (Koubachi 2014). Herein, we report an efficient one-pot synthesis of multifunctional 3- bromoimidazo[1,2-a]pyridine scaffold amenable for further functionalization by the nitric acid oxidation of its HBr salt. 2.2 RESULTS AND DISCUSSION 3-nitro and 3-bromoimidazo[1,2-a]pyridines are key starting materials for functionalization of imidazo[1,2-a]pyridines through metal catalyzed cross-coupling reactions like Heck, Suzuki, Stille and Buchwald reactions. As part of our medicinal chemistry program as well as research program, we set out to find efficient methods for synthesis of 3-nitroimidazo[1,2-a]pyridines. Literature method (Xia 2005), reveals that commercially available 2-amino-3-methylpyridine 2.1 was converted into ethyl 8-methylimidazo[1,2-a]pyridine-2-carboxylate.HBr 2.2 with 76% yield by refluxing in EtOH for 6 h with ethyl bromopyruvate. Nitration of 2.2 with nitrating mixture was performed at 0 C afforded ethyl 3-nitroimidazo[1,2-a]pyrine- 2-carboxylate 2.3 with yield 65% (Xia 2005). The overall yield of their transformation was moderate. As we needed 2.3 in bulk quantity, we further investigated the nitration of 2.2 using milder reagent - concentrated nitric acid (excess) in presence of acetic acid at room temperature. However, this condition led to formation of a unexpected derivative, which turned out to be ethyl 3-bromo-8- methylimidazo[1,2-a]pyridine-2-carboxylate 2.4 with 95% yield. This product was confirmed by 1 H NMR and HRMS/MS (Scheme 2.1). 43

3 Scheme 2.1 Reaction of ethyl imidazo[1,2-a]pyridine-2-carboxylate.hbr For optimization of reaction conditions for the bromination, a series of experiments were conducted with 2.2 and results are summarized in table 2.1. When we carried out the reaction in absence of conc. nitric acid, reaction not proceeded (Table 1.1, entry 1). When we tried reaction with 2.2 with conc. nitric acid without acetic acid, which gave 2.4 in 83% (Table 2.1, entry 2). The involvement of HBr salt was further confirmed by treating ethyl imidazo[1,2-a]pyridine-2-carboxylate (free base) with one equivalent of aq. HBr and excess of conc. nitric acid, which provided ethyl 3-bromoimidazo[1,2-a]pyridine-2-carboxylate 2.4 with 87% yield (Table 2.1, entry 4). We optimized the quantity of conc. nitric acid in this reaction. When bromination of 2.2 has been carried out with one equivalent of conc. nitric acid in the presence of acetic acid, reaction not completed even after 80 min (Table 2.1 entry 5). Then we performed bromination with varying amounts of conc. nitric acid and found that 5 equivalent of conc. nitric acid provided the best result. (Table 2.1 entries 6 and 7). 44

4 Table 2.1 Optimization for the synthesis of ethyl 3-bromo-8-methylimidazo[1,2- a]pyridine-2-carboxylate We choose entry 7 of table 2.1 as our optimized condition for bromination and further evaluated the scope of the reaction with other ethyl imidazo[1,2- a]pyridine-2-carboxylates 2.5 and 2.8 in scheme 2.2. Treatment of imidazo[1.2- a]pyridines 2.5 and 2.8 with nitrating mixture afforded as expected, corresponding nitro derivatives 2.6 and 2.9 in good yields. Further, 3-bromoimidazo[1,2- a]pyridines 2.7 and 2.10 were obtained in good yield by reaction of the corresponding starting materials 2.5 and 2.8 with conc. nitric acid using our optimized bromination conditions (Scheme 2.2). 45

5 Scheme 2.2 Reactions with ethyl imidazo[1,2-a]pyridine-2-carboxylate.hbr 2.5 and 2.8 Literature review revealed that procedures for the synthesis of 3- bromoimidazo[1,2-a]pyridine-2-carboxylates require at least two steps: 1. construction of an imidazo[1,2-a]pyridine ring under drastic conditions in solvents like ethanol (Xia 2005), THF (Kaizerman 2003) and acetone (Sundber 1998). 2. Subquently bromination utilizing NBS (Bellingham 2010; Rival 1991), bromine (Moreau 2002; Ager 1988), pyridiniumhydrobromide perbromide (Katsura 1991). However, our current method offers a significant advantage as it does not use an external bromine source and therefore is atom economical. Ethyl imidazo[1,2-a]pyridine-2-carboxylate.hbr 2.12a-f as the our starting materials, were prepared in moderate to good yield using a literature method (Xia 2005) by the reaction of 2-aminopyridines 2.11a-f with ethyl bromopyruvate in ethanol at reflux condition (Scheme 2.3). 46

6 Scheme 2.3 Preparation of various ethyl imidazo[1,2-a]pyridine-2-carboxylate.hbr Using our optimized bromination condition, a panel of substituted ethyl imidazo[1,2-a]pyridine-2-carboxylates 2.12a-f were converted to their corresponding ethyl 3-bromoimidazo[1,2-a]pyridine-2-caboxylates 2.13a-f in good to excellent yields. Representative bromo derivatives are illustrated in scheme

7 Scheme 2.4 Synthesis of 3-bromoimidazo[1,2-a]pyridines After the synthesis of ethyl 3-bromoimidazo[1,2-a]pyridine-2-caboxylates, we explored the synthesis of 2-aryl-3-bromoimidazo[1,2-a]pyridines as they are useful analogues which exhibit biological activity. At the beginning stage, we synthesized 8-methyl-2-(p-tolyl)imidazo[1,2-a]pyridine.HBr 2.15 with 92% yield from reaction of 3-picolylamine 2.1 with 4-methylphenacylbromide 2.14 in ethanol at reflux conditions using a literature method (Xia 2005). Using our optimized condition, treatment of 2.15 with 5 equivalents conc. nitric acid afforded the corresponding 3-bromo derivative 2.16 in 96%. Keeping in mind a one-pot synthetic approach, we carried out the reaction in ethanol replacing acetic acid and it afforded 2.17 with similar yield. With these encouraging results in hand, we decided to execute the cyclization and in situ oxidative bromination in a one-pot manner. Thus we choose to add the 5 equivalents of conc. nitric acid to the reaction mixture of cyclized product at rt without isolation. When a reaction of 2.1 with 2.14 was performed in ethanol at reflux, followed by addition of 5 equivalents of conc. nitric acid at room temperature (rt), it afforded 2.16 in 86% yield (Scheme 2.5). Using our optimized one-pot condition, a panel of 3-bromo-2-(4- nitrophenyl)imidazo[1,2-a]pyridines 2.18a-e were synthesized in good to excellent yield starting from the corresponding 2-aminopyridines 2.17a-e with 4- nitrophenacyl bromide (Scheme 2.6). 48

8 Scheme 2.5 Optimization of one-pot synthesis of 2.16 Scheme 2.6 One pot synthesis of 3-bromo-2-(4-nitrophenyl)imidazo[1,2- a]pyridines Mechanistically, condensation of 2-aminopyridine with ethyl bromopyruvate produces 3-bromo-imidazo[1,2-a]pyridine.monohydrobromide (Lombardino 1965). Reaction of HBr salt (generated in situ) with nitric acid leads to formation of bromine molecule. The bromine probably participates in the electrophilic bromination of the imidazo[1,2-a]pyridine. Regenerates HBr which is re-oxidized by nitric acid to bromine, which participates in electrophilic bromination. This cycle continues till all the HBr is used up for bromination. As a proof of this hypothesis, treatment of 4-chlorostyrene with conc. HBr: conc. HNO 3 (1:2.5 equiv.) in ethanol at rt produced 1-chloro-4-(1,2-dibromoethyl)benzene 2.20 in 46% yield. However, treatment of 4-chlorostyrene 2.19 with conc. HBr: conc. HNO 3 (2:5 equiv.) in 49

9 ethanol gave exclusively 1-chloro-4-(1,2-dibromoethyl)benzene These results show formation of bromine from oxidation of HBr salt by conc. HNO 3 (Figure 2.1). Figure 2.1 Proposed mechanism for 3-bromoimidazo[1,2-a]pyridines via in situ oxidation of HBr salt by nitric acid 2.3 CONCLUSION In conclusion, we have investigated the formation and mechanism of an unexpected product, ethyl 3-bromo-8-methylimidazo-1,2-a]pyridine-2-carboxylate during nitration of ethyl 8-methylimidazo[1,2-a]pyridine-2-carboxylate.HBr and developed an atom economical and novel method for synthesis of 3- bromoimidazo[1,2-a]pyridines via in situ oxidation of HBr salt by conc. nitric acid at room temperature. In addition, we developed a one-pot approach for synthesis of 3-bromo-2-(4-nitrophenyl)imidazo[1,2-a]pyridines from 2-aminopyridines. Further, we also studied the generation of bromine from HBr/HNO 3 by conducting an addition reaction with 4-chlorostyrene. 50

10 2.4 EXPERIMENTAL SECTION Preparation of ethyl 8-methylimidazo[1,2-a]pyridine-2- carboxylatehydrobromide (2.2) A mixture of 2-amino-3-methylpyridine 2.1 (5 g, mmol) and ethyl bromopyruvate, 95% (10.10 g, mmol) dissolved in EtOH (50 ml) was refluxed for 6 h. The reaction mass was diluted with ethyl acetate (50 ml) and the solid, on filtration afforded ethyl 8-methylimidazo[1,2-a]pyridine-2- carboxylate.hbr (2.2) as white solid (10.0 g, 76%). White solid; mp: C; 1 H NMR (300 MHz, DMSOd 6 ) δ (ppm): 1.36 (t, J = 6.9 Hz, 3H), 2.60 (s, 3H), 4.42 (q, J = 6.9 Hz, 2H), 7.29 (t, J = 6.9 Hz, 1H), 7.62 (d, J = 6.9 Hz, 1H), 8.63 (d, J = 6.9 Hz, 1H), 8.87 (s, 1H); MS (ESI): m/z [M+H] + calcd. for C 11 H 13 N 2 O 2 : found; Ethyl 8-methyl-3-nitroimidazo[1,2-a]pyridine-2-carboxylate (2.3) Yellow solid; mp: 96 C (Lit: 95 C) (Teulade 1978); 1 H NMR (300 MHz, CDCl 3 ) δ (ppm): 1.44 (t, J = 7.2 Hz, 3H), 2.71 (s, 3H), 4.54 (q, J = 7.2 Hz, 2H), 7.25 (dd, J = 6.9, 7.2 Hz, 1H), 7.47 (d, J = 7.2 Hz, 1H), 9.21 (d, J = 7.2 Hz, 1H); MS (ESI): m/z [M+H] + calcd. for C 11 H 12 N 3 O 4 : found; Ethyl 3-bromo-8-methylimidazo[1,2-a]pyridine-2-carboxylate (2.4) Pale yellow solid; mp: C; 1 H NMR (300 MHz, CDCl 3 ) δ (ppm): 1.48 (t, J = 6.9 Hz, 3H), 2.69 (s, 3H), 4.52 (q, J = 6.9 Hz, 2H), 6.95 (t, J = 6.9 Hz, 1H), 7.15 (d, J = 6.9 Hz, 1H), 8.10 (d, J = 6.9 Hz, 1H); MS (ESI): m/z [M+H] + calcd. for C 11 H 12 BrN 2 O 2 : found;

11 Ethyl 6-chloroimidazo[1,2-a]pyridine-2-carboxylatehydrobromide (2.5) Pale yellow solid; mp:117 C; 1 H NMR (300 MHz, DMSO-d 6 ) δ (ppm): 1.34 (t, J = 7.2 Hz, 3H), 4.36 (q, J = 7.2 Hz, 2H), 7.63 (m, 1H), 7.77 (d, J = 9.6 Hz, 1H), 8.63 (s, 1H), 8.96 (s, 1H); MS (ESI): m/z [M+H] + calcd. for C 10 H 10 ClN 2 O 2 : found; Ethyl 6-chloro-3-nitroimidazo[1,2-a]pyridine-2-carboxylate (2.6) Pale yellow solid; mp: C (Lit: 171 C) (Teulade 1978); 1 H NMR (300 MHz, CDCl 3 ) δ (ppm): 1.47 (t, J = 6.9 Hz, 3H), 4.56 (q, J = 6.9 Hz, 2H), 7.67 (dd, J = 1.5, 6.9 Hz, 1H), 7.85 (d, J = 9.6 Hz, 1H), 9.43 (d, J = 1.5 Hz, 1H); MS (ESI): m/z [M+H] + calcd. for C 10 H 9 ClN 3 O 4 : found; Ethyl 6-chloro-3-bromoimidazo[1,2-a]pyridine-2-carboxylate (2.7) White solid; mp: C; 1 H NMR (300 MHz, CDCl 3 ) δ (ppm): 1.48 (t, J = 7.2 Hz, 3H), 4.49 (q, J = 7.2 Hz, 2H), 7.32 (dd, J = 1.5, 9.6 Hz, 1H), 7.67 (d, J = 9.6 Hz, 1H), 8.28 (d, J = 1.5 Hz, 1H); MS (ESI): m/z [M+H] + calcd. for C 10 H 9 BrClN 2 O 2 : found; chloroimidazo[1,2-a]pyridine hydrobromide (2.8) Compound prepared according literature method (Maxwell 2005). 2-chloro-3-nitroimidazo[1,2-a]pyridine (2.9) Yellow solid; mp: C (Lit: 171 C) (Teulade 1978); 1 H NMR (300 MHz, CDCl 3 ) δ (ppm): 7.36 (dt, J = 1.2, 7.2 Hz, 1H), 7.69 (brs, 1H), 52

12 7.81 (d, J = 6.9 Hz, 1H), 9.46 (d, J = 6.9 Hz, 1H); MS (ESI): m/z [M+H] + calcd for C 7 H 5 ClN 3 O 2 : found; Bromo-2-chloroimidazo[1,2-a]pyridine (2.10) Dark Yellow solid; 1 H NMR (300 MHz, CDCl 3 ) δ (ppm): 7.00 (t, J = 6.9 Hz, 1H), 7.33 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 8.08 (d, J = 9.0 Hz, 1H); MS (ESI): m/z [M+H] + calcd. for C 7 H 5 BrClN 2 : found; Ethyl imidazo[1,2-a]pyridine-2-carboxylate hydrobromide (2.12a) White solid; mp: C; 1 H NMR (300 MHz, DMSOd 6 ) δ (ppm): 1.34 (t, J = 7.2 Hz, 3H), 4.40 (q, J = 7.2 Hz, 2H), 7.43 (t, J = 6.6 Hz, 1H), (m, 2H), 8.81 (d, J = 6.6 Hz, 1H), 8.92 (s, 1H); MS (ESI): m/z [M+H] + calcd. for C 10 H 11 N 2 O 2 : found; Ethyl 5-methylimidazo[1,2-a]pyridine-2-carboxylate hydrobromide (2.12b) White solid; mp:123 C; 1 H NMR (300 MHz, CD 3 OD) δ (ppm): 1.48 (t, J = 7.2 Hz, 3H), 2.88 (s, 3H), 4.54 (q, J = 7.2 Hz, 2H), 7.44 (t, J = 7.5 Hz, 1H), 7.83 (d, J = 9.0 Hz, 1H), 8.03 (d, J = 7.5 Hz, 1H), 8.86 (s, 1H); MS (ESI): m/z [M+H] + calcd. for C 11 H 13 N 2 O 2 : found; Ethyl 7-methylimidazo[1,2-a]pyridine-2-carboxylate hydrobromide (2.12c) White solid; mp: C; 1 H NMR (300 MHz, DMSOd 6 ) δ (ppm): 1.36 (t, J = 6.9 Hz, 3H), 2.33 (s, 3H), 4.45 (q, J = 6.9 Hz, 2H), 7.37 (dd, J = 1.5, 7.5 Hz, 1H), 7.65 (d, J = 1.5 Hz, 1H), 8.73 (d, J = 7.2 Hz, 1H), 8.88 (s, 1H); MS (ESI): m/z [M+H] + calcd. for C 11 H 13 N 2 O 2 : found;

13 Ethyl 8-(benzyloxy)imidazo[1,2-a]pyridine-2-carboxylate hydrobromide (2.12d) Brown solid; mp: C; 1 H NMR (300 MHz, CD 3 OD) δ (ppm): 1.43 (t, J = 7.2 Hz, 3H), 4.54 (q, J = 7.2 Hz, 2H), 5.47 (s, 2H), (m, 7H), 8.36 (d, J = 6.6 Hz, 1H), 8.75 (s, 1H); MS (ESI): m/z [M+H] + calcd. for C 17 H 17 N 2 O 3 : found; Ethyl 8-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylate hydrobromide (2.12e) White solid; mp: C; 1 H NMR (300 MHz, CD 3 OD) δ (ppm): 1.46 (t, J = 7.2 Hz, 3H), 4.51 (q, J = 7.2 Hz, 2H), 7.52 (t, J = 7.5 Hz, 1H), 8.28 (d, J = 7.5 Hz, 1H), 8.87 (s, 1H), 8.87 (d, J = 6.9 Hz, 1H); MS (ESI): m/z [M+H] + calcd. for C 11 H 10 F 3 N 2 O 2 : found; Ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate hydrobromide (2.12f) White solid; mp: C; 1 H NMR (300 MHz, DMSOd 6 ) δ (ppm): 1.32 (t, J = 7.2 Hz, 3H), 4.31 (q, J = 7.2 Hz, 2H), 7.48 (dd, J = 1.8, 9.6 Hz, 1H), 7.63 (d, J = 9.6 Hz, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.92 (s, 1H); MS (ESI): m/z [M+H] + calcd. for C 10 H 10 BrN 2 O 2 : found; Ethyl 3-bromoimdazo[1,2-a]pyridine-2-carboxylate (2.13a) Yellow solid; mp: 68 C; 1 H NMR (300 MHz, CDCl 3 ) δ (ppm): 1.46 (t, J = 7.2 Hz, 3H), 4.50 (q, J = 7.2 Hz, 2H), 7.01 (t, J = 6.9 Hz, 1H), 7.33 (t, J = 6.9 Hz, 1H), 7.71 (d, J = 9.3 Hz, 1H), 8.22 (d, J = 6.9 Hz, 1H); HRMS 54

14 (ESI) m/z [M+H] + calcd. for C 10 H 10 BrN 2 O 2 : , found ; HPLC: 98.4%. Ethyl 3-bromo-5-methylimidazo[1,2-a]pyridine-2-carboxylate (2.13b) Pale yellow solid; mp: C; 1 H NMR (300 MHz, CDCl 3 ) δ (ppm): 1.47 (t, J = 7.2 Hz, 3H), 3.13 (s, 3H), 4.49 (q, J = 7.2 Hz, 2H), 6.60 (t, J = 6.9 Hz, 1H), 7.27 (d, J = 6.9 Hz, 1H), 7.57 (d, J = 6.9 Hz, 1H); MS (ESI): m/z [M+H] + calcd. for C 11 H 12 BrN 2 O 2 : found; 285.0; HPLC: 97.7% Ethyl 3-bromo-7-methylimidazo[1,2-a]pyridine-2-carboxylate (2.13c) Pale yellow solid; mp: C; 1 H NMR (300 MHz, CDCl 3 ) δ (ppm): 1.48 (t, J = 7.2 Hz, 3H), 2.46 (s, 3H), 4.50 (q, J = 7.2 Hz, 2H), 6.85 (d, J = 6.9 Hz, 1H), 7.44 (s, 1H), 8.09 (d, J = 6.9 Hz, 1H); MS (ESI): m/z [M+H] + calcd. for C 11 H 12 BrN 2 O 2 : found; 285.0; HPLC: 98.4% Ethyl 8-(benzyloxy)-3-bromoimidazo[1,2-a]pyridine-2-carboxylate (2.13d) White solid; mp: C; 1 H NMR (300 MHz, CDCl 3 ) δ (ppm): 1.45 (t, J = 7.2 Hz, 3H), 4.49 (q, J = 7.2 Hz, 2H), 5.36 (s, 2H), 6.58 (d, J = 7.2 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 7.37 (m, 3H), 7.49 (bd, 2H), 7.84 (d, J = 7.2 Hz, 1H). HRMS (ESI) m/z [M+H] + calcd. for C 17 H 16 BrN 2 O 3 : , found ; HPLC: 98.1%. Ethyl 3-bromo-8-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylate (2.13e) White solid; mp: C; 1 H NMR (300 MHz, CDCl 3 ) δ (ppm): 1.49 (t, J = 7.2 Hz, 3H), 4.52 (q, J = 7.2 Hz, 2H), 7.12 (t, J = 6.9 Hz, 1H), 55

15 7.73 (d, J = 7.2 Hz, 1H), 8.42 (d, J = 6.9 Hz, 1H); MS (ESI) m/z [M+H] + calcd. for C 11 H 9 BrF 3 N 2 O 2 : 337.1, found 337.0; HPLC: 98.9%. Ethyl 3,6-dibromoimidazo[1,2-a]pyridine-2-carboxylate (2.13f) Yellow solid; mp: C; 1 H NMR (300 MHz, CDCl 3 ) δ (ppm): 1.48 (t, J = 7.2 Hz, 3H), 4.50 (q, J = 7.2 Hz, 2H), 7.43 (d, J = 9.6 Hz, 1H), 7.63 (d, J = 9.6 Hz, 1H), 8.38 (s, 1H); HRMS (ESI) m/z [M+H] + calcd. for C 10 H 9 Br 2 N 2 O 2 : , found ; HPLC: 98.3%. 8-methyl-2-(p-tolyl)imidazo[1,2-a]pyridine hydrobromide (2.15) White solid; mp: C; 1 H NMR (300 MHz, DMSO-d 6 ) δ (ppm): 2.41 (s, 3H), 2.66 (s, 3H), (m, 3H), 7.76 (d, J = 6.9 Hz, 1H), 7.90 (d, J = 8.1 Hz, 2H), 8.73 (d, J = 8.1 Hz, 2H), (br s, 1H); MS (ESI): m/z [M+H] + calcd. for C 15 H 15 N 2 : found; 223.1; HPLC: 98.6% 3-bromo-8-methyl-2-(p-tolyl)imidazo[1,2-a]pyridine (2.16) Dark brown solid; mp: C; 1 H NMR (300 MHz, CDCl 3 ) δ (ppm): 2.41 (s, 3H), 2.67 (s, 3H), 6.84 (t, J = 6.9 Hz, 1H), 7.05 (d, J = 6.9 Hz, 1H), 7.30 (d, J = 8.1 Hz, 2H), 8.02 (d, J = 8.1 Hz, 2H), 8.06 (d, J = 6.9 Hz, 1H); HRMS (ESI) m/z [M+H] + calcd. for C 15 H 14 BrN 2 : , found ; HPLC: 99.7%. 56

16 3-bromo-2-(4-nitrophenyl)imidazo[1,2-a]pyridine (2.18a) Yellow solid; mp: C; 1 H NMR (300 MHz, CDCl 3 ) δ (ppm): 7.00 (t, J = 7.2 Hz, 1H), 7.34 (t, J = 9.0 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H), 8.21 (d, J = 7.2 Hz, 1H), 8.34 (s, 4H); MS (ESI): m/z [M+H] + calcd. for C 13 H 9 BrN 3 O 2 : found; bromo-8-methyl-2-(4-nitrophenyl)imidazo[1,2-a]pyridine (2.18b) Yellow solid; mp: C; 1 H NMR (300 MHz, CDCl 3 ) δ (ppm): 2.69 (s, 3H), 6.93 (t, J = 6.9 Hz, 1H), 7.13 (d, J = 6.9 Hz, 1H), 8.10 (d, J = 6.9 Hz, 1H), 8.35(d, J = 9.0 Hz, 2H), 8.40 (d, J = 9.0 Hz, 2H); MS (ESI): m/z [M+H] + calcd. for C 14 H 11 BrN 3 O 2 : found; bromo-7-methyl-2-(4-nitrophenyl)imidazo[1,2-a]pyridine (2.18c) Yellow solid; mp: C; 1 H NMR (300 MHz, CDCl 3 ) δ (ppm): 2.45 (s, 3H), 6.81 (d, J = 6.9 Hz, 1H), 7.40 (s, 1H), 8.07 (d, J = 6.9 Hz, 1H), 8.34 (s, 4H); MS (ESI): m/z [M+H] + calcd. for C 14 H 11 BrN 3 O 2 : found; bromo-5-methyl-2-(4-nitrophenyl)imidazo[1,2-a]pyridine (2.18d) Deep yellow solid; mp: C; 1 H NMR (300 MHz, CDCl 3 ) δ (ppm): 3.12 (s, 3H), 6.58 (d, J = 6.9 Hz, 1H), 7.14 (dd, J = 6.9,

17 Hz, 1H), 7.52 (d, J = 9.0 Hz, 1H), 8.21 (d, J = 8.7 Hz, 2H), 8.31 (d, J = 8.7 Hz, 2H); MS (ESI): m/z [M+H] + calcd. for C 14 H 11 BrN 3 O 2 : found; bromo-6-chloro-2-(4-nitrophenyl)imidazo[1,2-a]pyridine (2.18e) Pale yellow solid; mp: C; 1 H NMR (300 MHz, CDCl 3 ) δ (ppm): 7.29 (dd, J = 1.8, 9.6 Hz, 1H), 7.60 (d, J = 9.6 Hz, 1H), 8.25 (d, J = 1.8 Hz, 1H), 8.33 (s, 4H); MS (ESI): m/z [M+H] + calcd. for C 13 H 8 BrClN 3 O 2 : found; chloro-4-(1,2-dibromoethyl)benzene (2.20) Colourless oil; 1 H NMR (300 MHz, CDCl 3 ) δ (ppm): 3.99 (t, J = 10.5 Hz, 1H), 4.09 (dd, J = 5.1, 5.4 Hz, 1H), 5.13 (dd, J = 5.1, 5.4 Hz, 1H), 7.38 (s, 4H); MS (ESI): m/z [M+H] + calcd. for C 8 H 8 Br 2 Cl: found; NR peak. 58