Visible light-induced photocatalytic C–H ethoxycarbonylmethylation of imidazoheterocycles with ethyl diazoacetate

A visible light-mediated regioselective C3-ethoxycarbonylmethylation of imidazopyridines with ethyl diazoacetate (EDA) was achieved under mild reaction conditions. In contrast to the carbene precursors from α-diazoester a first C3-ethoxycarbonylmethylation of imidazopyridines via a radical intermediate has been established. The present methodology provides a concise route to access pharmacologically useful esters with wide functional group tolerance in high yields.

A visible light-mediated regioselective C3-ethoxycarbonylmethylation of imidazopyridines with ethyl diazoacetate (EDA) was achieved under mild reaction conditions. In contrast to the carbene precursors from a-diazoester a first C3-ethoxycarbonylmethylation of imidazopyridines via a radical intermediate has been established. The present methodology provides a concise route to access pharmacologically useful esters with wide functional group tolerance in high yields.
Ester groups are a most powerful and versatile synthetic building block in natural products as well as in organic synthesis since they can be derivatized to diverse functional groups such as carbonyl, hydroxymethyl, and amide, etc. 1 Beside the traditional methods of using xanthates for ethoxycarbonylmethylation, 2 the introduction of diazoesters represents a very important strategy for the synthesis of acetate derivatives. 3 Generally, thermal, 4a photoinduced, 4b or metal catalyzed 4c reactions of diazo compounds produce reactive carbene precursors which further undergo an addition reaction, insertion reaction, cyclopropanation, Wolff rearrangement, etc. (Scheme 1a). 4 In contrast to the carbene precursors from a-diazoester, a new methodology is always highly desirable especially with a signicantly different mode of activation under a distinct mechanism. 5 In this context, a new strategy for installation of alkyl radicals from diazo compounds under photoredox-catalysis is very important. 6 Recently, visible light-mediated photoredox catalyzed direct C-H bond functionalization reactions have come to the forefront in synthetic organic chemistry 7 where Ru(II)-polypyridyl complexes have been extensively used as photoredox-catalysts due to their unique photo-physical properties. 8 Imidazo[1,2-a]pyridines, an important class of nitrogenbased privileged structural motifs widely found in a variety of natural products and alkaloids. 9 In pharmaceutical chemistry, it possesses large number of biological activities like antitumor, antibacterial, antifungal, antipyretic, analgesic, antiin-ammatory, etc. 10a It is also important in material sciences due to its unique excited state intramolecular proton transfer phenomena (ESIPT). 10b In particular, ethoxycarbonylmethylated imidazopyridines are the core structure of several marketed drugs such as alpidem, zolpidem, saripidem, etc. 11 Therefore, practical methodologies for the synthesis of alkylated ester substituted imidazoheterocycles are highly desirable and will be of great interest to the synthetic chemists. 11 However, to the best of our knowledge there is no such method for the direct photoinitiated ethoxycarbonylmethylation reaction of imidazoheterocycles with diazo compounds through distinct radical pathway. 11-13 As part of our ongoing research on photoredoxcatalyzed C-H functionalization reactions, 13 herein we describe an environmentally benign visible light-promoted ethoxycarbonylmethylation for the synthesis of alkyl substituted imidazopyridines by the coupling between imidazopyridines and ethyl diazoacetate using Ru(bpy) 3 Cl 2 as photoredox-catalyst under argon atmosphere at room temperature (Scheme 1b).
To begin, the reaction was carried out using 2-phenylimidazo [1,2-a]pyridine (1a) and ethyl diazoacetate (EDA) (2) (2.0 equiv.) in presence of 0.2 mol% of Ru(bpy) 3 Cl 2 as a photoredox-catalyst under the irradiation of 34 W blue LED lamp in methanol at room temperature. To our delight, 49% yield of the ethyl 2-(2phenylimidazo[1,2-a]pyridin-3-yl)acetate (3a) was obtained aer 36 h under argon atmosphere. However, no desired product was formed in aerobic conditions (Table 1, entry 1). Next, we screened the effect of different solvents such as EtOH, DCM, MeCN, and toluene but these were not suitable like MeOH (Table 1, entries 2-5). Interestingly, the binary solvent mixture (MeOH and H 2 O, 1 : 1) was found to be effective for the formation of alkylated product in 76% yield (Table 1, entry 6). The yield of the reaction was increased using a binary mixture of MeOH : H 2 O (2 : 1) ( Table 1, entry 7). However, only a trace amount of product was detected with the mixture of (1 : 2) MeOH : H 2 O and no product was observed in H 2 O (Table 1, entries 8 and 9). Instead of MeOH : H 2 O (2 : 1) by using EtOH : H 2 O (2 : 1) desired product (3a) was obtained in 68% yield aer 36 h (Table 1 entry 10). The reaction did not proceed at all in presence of other classical photoredox-catalysts like Ir(ppy) 3 , rose bengal, eosin Y, eosin B, and rhodamine B (Table  1, entries 11-15). Moreover, no product was formed in absence of photoredox-catalyst as well as light source (Table 1, entries 16 and 17) which conrm that photo-catalyst and light source are essential for this transformation. We also performed the reaction in thermal condition at 60 C (Table 1, entry 18). The desired product (3a) was not formed which indicated that the reaction probably go through the charge transfer/EDA-type complex not via carbene pathway. The yield of the reaction decreased when the amount of ethyl diazoacetate was either lowered or increased (Table 1, entry 19). In addition, 56% yield of the desired product was obtained under the irradiation of 20 W blue LED and no alkylated product was observed using 30 W white LED (Table 1, entry 20). From this experiment, we conrmed that the probable reaction pathway via chargetransfer/EDA-type complex absorbs wave length only from the emitted blue LED light not from the emitted 30 W white LED. Finally, optimized yield (89%) was achieved using 0.2 mol% Ru(bpy) 3 Cl 2 and 2.0 equiv. ethyl diazoacetate in 2.0 mL mixture of MeOH : H 2 O (2 : 1) with the irradiation of 34 W blue LED for 36 h at room temperature under argon atmosphere (Table 1,  entry 7).
With the optimized reaction conditions in hand we explored the substrate scope of this methodology with various substituted imidazopyridines. At rst we checked the effect of various substituents on the pyridine ring of imidazopyridine derivatives and the results are summarized in Scheme 2. Imidazopyridine containing various electron-donating groups (8-Me and 7-OMe) efficiently reacted with ethyl diazoacetate to provide the desired products in good yields (3b and 3c). It is important to note that substrates bearing electron-withdrawing groups did not afford alkylated products under the optimized reaction condition. However, addition of 10 mol% N,Ndimethyl-m-toluidine as a redox-active additive gave a satisfactory yield of the desired products (see ESI †). Therefore in modied reaction conditions, halogens containing imidazopyridines like -F, -Br, -I and strong electron-withdrawing group such as -CF 3 , -CN containing substrates were successfully afforded the desired products in 67-90% yields (3d-3h). Next, we examined the substrate scope with various substitutions in phenyl part of imidazo[1,2-a]pyridine. Imidazopyridine with electron-releasing (4-Me, and 4-OMe), halogens (4-F, 4-Cl, and 3-Br) and strong electron-withdrawing group (4-CF 3 , and 4-CN) containing substrates produced the desired products with good to excellent yields (3i-3p). 2-Hydroxy substituted imidazo[1,2-a] pyridine was also worked well in this transformation (3k). In addition, disubstituted imdazopyridines with different substituents at both the phenyl and pyridine ring underwent the reaction very smoothly (3q, and 3r). Heteroaryl and naphthyl substituted imidazopyridines produced the desired products without any difficulties (3s-3u). However, unsubstituted imidazo[1,2-a]pyridine did not produce the desired product in this protocol. To highlight the applicability of the present protocol a gram-scale reaction was carried out taking 1a in 6.0 mmol scale under normal laboratory setup. The yield of ethyl 2-(2phenylimidazo[1,2-a]pyridin-3-yl)acetate (3a) was slightly diminished to 70% aer 36 h along with the recovery of excess starting material. Next, to show the generality of this present methodology, we investigated the reaction taking other imidazoheterocycles like imidazo[2,1-b]thiazole and benzo[d]imidazo[2,1-b]thiazoles (Scheme 3). 6-Phenylimidazo-[2,1-b]thiazole reacted smoothly to afford 5a in 66% yield. Benzo[d]imidazo[2,1-b]thiazole containing -Me, -OMe, and -Cl substituted derivatives were well tolerable under the present reaction conditions (5b-5e). The structure of ethyl 2-(7-methoxy-2-phenylbenzo[d]imidazo[2,1-b] thiazol-3-yl)acetate (5c) was conrmed by X-ray crystallography. 14 In addition, thiophene substituted benzo[d]imidazo [2,1-b]thiazole furnished the corresponding alkylated product in good yield (5f).
Aer that, we have directly modied the synthesized ethoxycarbonylmethylated product (3q) to amide derivative (6q) in 56% yield using benzylamine in the presence of La(OTf) 3 as a catalyst under ambient air at rt to 70 C as shown in Fig. 1.
Based on the above mechanistic studies and previous literature reports, 7,8,13 a possible radical mechanism was proposed for the formation of ethyl 2-(2-phenylimidazo[1,2a]pyridin-3-yl)acetate (3a)   In case of halogen or electron-withdrawing substituted imidazoheterocycles a possible mechanism for the radical alkylation reaction is illustrated in Scheme 6. 6b,c Reductive quenching of *Ru(bpy) 3 2+ by SET oxidation of aniline derivatives affords radical cation E and Ru(bpy) 3 + . Then reduced photocatalyst Ru(bpy) 3 + comes back to ground state with the generation of radical intermediate B via the elimination of N 2 . Subsequently, radical intermediate B reacts with imidazopyridine 1 to produce radical intermediate C 0 . Finally, the desired product 3 0 is produced through the hydrogen atom transfer (HAT) process between radical cation E and radical intermediate C 0 .

Conclusions
In summary, we have developed an efficient photoredoxcatalyzed ethoxycarbonylmethylation of imidazoheterocycles with ethyl diazoester as an alkylating reagent under the irradiation of blue LED at room temperature. A wide variety of functionalized imidazoheterocycles were well tolerated under the mild reaction conditions. A gram-scale synthesis was also performed to demonstrate the potential synthetic application of this new method. In contrast to the carbene precursors from adiazoester a rst C3-ethoxycarbonylmethylation of imidazopyridines via radical intermediate has been established. We believe the present protocol to be of signicant applicability for the diversication of heterocyclic moieties in a multitude of medicinal applications.

Conflicts of interest
There are no conicts to declare.