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Synthesis 2021; 53(08): 1524-1530
DOI: 10.1055/s-0040-1706103
paper

Organophotoredox-Catalyzed C–H Alkylation of Imidazoheterocycles with Malonates: Total Synthesis of Zolpidem

Narendra R. Chaubey  ∗
a   Institute of Chemical Technology, Department of Chemistry, Nathalal Parekh Road, Matunga, Mumbai 400019, Maharashtra, India
,
Anant R. Kapdi
a   Institute of Chemical Technology, Department of Chemistry, Nathalal Parekh Road, Matunga, Mumbai 400019, Maharashtra, India
,
Biswanath Maity
b   Translational Cell Biology Unit, Centre of Biomedical Research, Raibareli Road, Lucknow, Uttar-Pradesh 226014, India
› Author Affiliations

Dr. Narendra R. Chaubey acknowledges the Research Fellowship (F. No. 45/15/2019-BIO/BMS) from Indian Council of Medical Research, Delhi, India.
› Further Information
 
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Abstract

Organophotocatalytic C–H bond functionalization has attracted a lot of attention in the past several years due to the possibility of catalyzing reactions in a metal- and peroxide-free environment. Continuing on these lines, an organophotoredox-catalyzed C–H functionalization of imidazo[1,2-a]pyridines and related heterocycles with bromomalonates under mild conditions is reported, providing excellent yields of the products at room temperature. This is the first report involving malonates as coupling partners leading to the synthesis of a range of functionalized products including total synthesis of zolpidem, a sedative­-hypnotic drug molecule.


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Key words

organophotoredox - C–H functionalization - imidazoheterocycles - zolpidem - drug prejudice

Among the all known N-heterocycles, imidazo[1,2-a]-pyridines are widely found in biologically active natural products and pharmaceuticals. It is also considered as a ‘drug prejudice’ as it shows antipyretic,[1] antiviral,[2] antibacterial,[3] anticancer,[4] antiulcer,[5] and anti-inflammatory[6] properties. There are also marketed drugs such as alpidem, zolpidem, olprinone, necopidem, saripidem, and zolimidine containing imidazo[1,2-a]pyridines as the core of the molecule. This moiety have also shown significant importance in material chemistry due to its capabilities to exhibit excited state intramolecular proton transfer.[7] Due to all these reasons, functionalization of imidazo[1,2-a]pyridines at different positions by various groups has drawn considerable attention in the last few decades.[8]

In the last few years, visible-light-promoted photoredox process has emerged as a prominent tool for carrying out novel chemical transformations at room temperature.[9] Most common photocatalysts employed to carry out such transformations are ruthenium- and iridium-based complexes. These precious metal catalysts are very expensive and potentially toxic on larger scale.[10] Therefore major efforts have been made in the last few years to use organic dyes as an alternative to these expensive complexes. Recently­, several reports have been published involving visible­-light-promoted C–H functionalization of imidazo-[1,2-a]pyridines at room temperature.[11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] However, cross coupling reaction between a moiety with C-sp3 carbon and C-sp2 carbon of imidazo[1,2-a]pyridine is still considered as a challenging task for synthetic organic chemists. Nature of the functional group or the substituent attached at the C3 position of the imidazo[1,2-a]pyridine regulates its biological activity. Many well-developed drugs contain methylene group directly attached to imidazo[1,2-a]pyridines (Figure [1]). To the best of our knowledge, there is no such method for the direct coupling between active methylene compounds and imidazo[1,2-a]pyridines. Therefore to check the impact of the presence of an active methylene carbon at the C3 position of the imidazo[1,2-a]pyridine, it was decided to carry out this challenging C–C bond formation reaction under mild and sustainable conditions.

Zoom Image
Figure 1 Drug molecules containing imidazoheterocycles

We commenced our study with 2-phenylimidazo[1,2-a]pyridine (1a; 0.5 mmol) and diethyl malonate (1 mmol) in DMSO (5 mL) as reacting partners. When 1a and diethyl malonate were made to react under 10 W blue LED in the presence of 2 mol% of eosin Y, decomposition of starting material was observed (Table [1], entry 1). No reaction was observed when 1.5 equivalents of bis(pinacolato)diboron (B2pin2) was used as an additive, but this time 1a was not decomposed and recovered from the reaction mixture (entry 2). Similar observation was reported when this reaction was carried out in acetone (entry 3). Use of N-hydroxysuccinimide (NHSI) or N-hydroxyphthalimide (NHPI) as the HAT catalyst along with eosin Y/B2pin2 system could not produce the required product (entry 4, 5). Similar result was observed with Ru(bpy)3(PF6)2 photocatalyst (entry 6). Ferrocene/TBHP and rose bengal/TBHP system were also attempted to get the required result (entries 7 and 8, respectively). Later, it was decided to attempt the desired coupling reaction by in situ conversion of diethyl malonate into its iodo derivative and a reaction was carried out in the presence of I2/K2CO3 along with B2pin2. This effort also did not produce any fruitful result (entry 9). Replacing eosin Y with Ru(bpy)3(PF6)2 along with I2/K2CO3/B2pin2 system did not yield the desired result (entry 10). After these unsuccessful efforts, it was decided to use diethyl bromomalonate (2a; 0.5 mmol) instead of diethyl malonate as the coupling partner. When 1a and 2a were subjected to Ru(bpy)3(PF6)2/NPh3/B2Pin2 system in the presence of 10 W blue LED, a poor yield of the desired coupling product was observed (entry 12). Yield of the reaction was improved to 47% in 1,4-dioxane (entry 14). The product 3a was obtained with an improved yield of 65% when rose bengal was used as the photocatalyst (entry 15). We were surprised to observe an excellent yield of 95% by using sodium bicarbonate as the base (entry 16). No reaction was observed in the absence of rose bengal or blue LED light. Hence, we were successful in developing a metal- and peroxide-free condition for coupling an active methylene carbon with 2-phenyl­imidazo[1,2-a]pyridine (1a).

Table 1 Optimization of the Reaction Conditions

Entry

Photocatalyst (2 mol%)

Additive

Solvent

Yield (%)a

 1

eosin Y

–

DMSO

N.R.

 2

eosin Y

B2pin2 (1.5 equiv)

DMSO

N.R.

 3

eosin Y

B2pin2 (1.5 equiv)

acetone

N.R.

 4

eosin Y

NHSI (0.2 equiv)/B2pin2 (1.5 equiv)

EtOAc

N.R.

 5

eosin Y

NHPI (0.2 equiv/B2pin2 (1.5 equiv)

EtOAc

N.R.

 6

Ru(bpy)3(PF)6

NHPI (0.2 equiv/B2pin2 (1.5 equiv)

EtOAc

N.R.

 7

–

TBHP (2 equiv)/ferrocene (0.2 equiv)

EtOAc

N.R.

 8

rose bengal

TBHP (2 equiv)

ClCH2CH2Cl

N.R.

 9

eosin Y

I2 (1 equiv)/ K2CO3 (1.5 equiv)/B2Pin2 (1.5 equiv)

DMSO

N.R.

10

Ru(bpy)3(PF)6

I2 (1 equiv)/ K2CO3 (1.5 equiv)/B2Pin2 (1.5 equiv)

DMSO

N.R.

11

Ru(bpy)3(PF)6

NBS (1.1 equiv)/NPh3 (2 equiv)/B2Pin2 (1.5 equiv)

DMSO

N.R.

12

Ru(bpy)3(PF)6

NPh3 (2 equiv)/B2Pin2 (1.5 equiv)

DMSO

20b

13

Ru(bpy)3(PF)6

NPh3 (2 equiv)/B2Pin2 (1.5 equiv)

MeCN

32b

14

Ru(bpy)3(PF)6

NPh3 (2 equiv)/B2Pin2 (1.5 equiv)

1,4-dioxane

47b

15

rose bengal

NPh3 (2 equiv)/B2Pin2 (1.5 equiv)

1,4-dioxane

59b

16

rose bengal

NaHCO3 (2 equiv)/B2Pin2 (1.5 equiv)

1,4-dioxane

95b

17

–

NaHCO3 (2 equiv)/B2Pin2 (1.5 equiv)

1,4-dioxane

traceb

18

rose bengal

NaHCO3 (2 equiv)/B2Pin2 (1.5 equiv)

1,4-dioxane

N.R.b,c

a Isolated yield; N.R.: no reaction.

b Reaction was carried out with diethyl bromomalonate (2a).

c Reaction was carried out in the absence of 10 W blue LED.

After achieving the optimized reaction conditions, our next move was to explore the scope of the reaction. Initially, the reaction was examined with different substituents on the phenyl ring of 2-arylimidazo[1,2-a]pyridines. For this purpose, diethyl bromomalonate (2a) was treated with different 2-arylimidazo[1,2-a]pyridines 1a–j. All the para-substituted 2-arylimidazo[1,2-a]pyridines with electron-donating substituents (such as Me, OMe, and halogens) and electron-withdrawing substituents on phenyl ring of acetophenone part (1b–g) tolerated the reaction conditions with moderate to excellent yields (68–92%) (Scheme [1]). Similarly, 2-(2-naphthyl)imidazo[1,2-a]pyridine (1h) also underwent the reaction to furnish the product 3h in 92% yield. To check the effect of meta substitution, 2-(3-bromophenyl)imidazo[1,2-a]pyridine (1i) was treated with 2a under the optimized reaction conditions. Without any surprises it also reacted smoothly to produce the product 3i in a yield of 77%. When dimethyl bromomalonate (2b) was used instead of diethyl bromomalonate (2a), it also sustained the reaction condition and yielded the products 3k (74%) and 3l (77%) in very good yields. In order to explore the scope of the protocol with another active methylene compound, 1a was treated with ethyl 2-bromo-3-oxobutanoate (2c) but no reaction was observed under the present reaction conditions.

Zoom Image
Scheme 1 Scope of the reaction with different 2-arylimidazo-[1,2-a]pyridines

In the process of further exploration of this protocol, it was decided to study the scope of the reaction with other class of imidazoheterocycles. For this purpose, different 6-arylimidazo[2,1-b]thiazoles were synthesized following the reported procedure.[22] When 6-phenylimidazo[2,1-b]thiazole (1k) was treated with 2a under present conditions, the product 3n was obtained in a very good yield (90%) (Scheme [2]). Similarly, 6-(4-methoxyphenyl)imidazo[2,1-b]-thiazole (1l) and 6-naphthylimidazo[2,1-b]thiazole (1m) also reacted well with diethyl bromomalonate (2a) to furnish the desired products 3o (88%) and 3p (89%) in excellent yields. The presence of electron-withdrawing group on phenyl ring was tolerated well under these conditions as 4-(imidazo[2,1-b]thiazol-6-yl)benzonitrile (1n) gave product 3q (83%) in a very good yield. Dimethyl bromomalonate (2b) also reacted smoothly with 6-phenylimidazo[2,1-b]thiazole (1k) under our conditions. Next, it was decided to use benzo[d]imidazo[2,1-b]thiazole as the heterocycle counterpart. For this purpose diethyl bromomalonate (2a) was treated with 7-methoxy-2-phenylbenzo[d]imidazo-[2,1-b]thiazole (1o) to produce the corresponding alkylated product 3s in 77% yield.

Zoom Image
Scheme 2 Scope of the reaction with other imidazoheterocycles

We have also proved the synthetic utility of this protocol by carrying out a total synthesis of the drug molecule zolpidem (5j) (Scheme [3]). The crude product 3j (obtained from reaction between 1j and 2a) was subjected to Krapcho decarboxylation to produce 4j (74%), which on further hydrolysis and then condensation with amine gave zolpidem (5j).[23]

Few control experiments were carried out to examine the mechanism of this reaction strategy. When 2-phenylimidazo[1,2-a]pyridine (1a) and diethyl bromomalonate (2a) were treated in the presence of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) under the proposed reaction conditions, the desired product 3a was not formed. A similar result was observed when the same reaction was carried out in the presence of 2,6-di-tert-butyl-4-methylphenol (BHT). These results clearly indicated that the reaction probably proceeds through a radical pathway. From the optimization studies it was very much clear that 2-phenylimidazo[1,2-a]pyridine (1a) decomposes in the absence of B2pin2 and is an essential additive to get desired reaction.

Zoom Image
Scheme 3 Total synthesis of zolpidem

From the above results and previous literature,[16] [24] a plausible reaction mechanism is proposed for this reaction protocol (Scheme [4]). In the presence of blue LED, rose bengal (RB) is converted into its excited state RB*, which helps in the generation of carbon radical species I from 2a. 2-Phenylimidazo[1,2-a]pyridine (1a) gets activated by B2pin2 to intermediate II. The carbon radical I reacts with intermediate II to produce the radical intermediate III, which gets converted into the intermediate IV. This intermediate IV undergoes abstraction of proton by base to produce the final product 3a.

Zoom Image
Scheme 4 Plausible reaction mechanism

In conclusion, we have developed a metal- and peroxide-free reaction strategy for the coupling of imidazohetero­cycles with malonates at room temperature.[25] This is a new reaction protocol and also the first report for the synthesis of most of these molecules. Resulting molecules of this protocol can create new possibilities for probable drug candidates as these molecules can be easily converted into new highly functionalized compounds. The substrate scope of this protocol is sufficiently good and the yields of the products are excellent. This protocol has also been applied for the total synthesis of zolpidem.

1H and 13C NMR spectra were recorded on a Varian (1H NMR at 500 or 400 MHz, 13C NMR at 125.7 or 100 MHz) FTNMR spectrometer. Chemical shifts for protons are reported in parts per million downfield from TMS and are referenced to residual deuterium in the solvent (1H NMR: CDCl3 at 7.26 ppm). Chemical shifts for carbons are reported in parts per million downfield from TMS and are referenced to the carbon resonances of the solvent peak (13C NMR: CDCl3 at 77.0 ppm). NMR data are represented as follows: chemical shift, multiplicity (standard abbreviations), coupling constant (J, Hz), and integration. Analytical TLC was performed on Merck Kieselgel 60 GF254 plates (thickness 0.25 mm). Visualization was performed with a 254 nm UV lamp and by staining in I2 chamber. Organic solutions were concentrated under reduced pressure using a Heidolph rotary evaporator. Purification of the crude products was carried out by column chromatography using silica gel (100‒200 mesh). All the reactions of the present protocol were carried out in a sealed vial. Yield refers to the isolated analytically pure material. The coupling reaction was carried out at rt under a 10 W blue LED light.

All the 2-arylimidazo[1,2-a]pyridines 1a–j were prepared from corresponding acetophenones and 2-aminopyridines following the reported procedure.[26] Similarly, different 6-arylimidazo[2,1-b]thiazoles 1k–n were synthesized from 2-aminothiazoles and the corresponding acetophenones using reported protocol.[23] 7-Methoxy-2-phenylbenzo-[d]imidazo[2,1-b]thiazole (1o) was also prepared in a similar way as their thiazole counterparts. Diethyl bromomalonate and dimethyl bromomalonate were purchased from TCI Chemicals Ltd.


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Diethyl 2-(2-Phenylimidazo[1,2-a]pyridin-3-yl)malonate (3a); Typical Procedure

To a solution of 2-phenylimidazo[1,2-a]pyridine (1a; 97 mg, 0.5 mmol) in 1,4-dioxane (5 mL), was added B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) and the resulting solution was stirred at rt for 5 min. Now diethyl bromomalonate (2a; 239 mg, 1 mmol, 2 equiv) was added followed by the addition of NaHCO3 (84 mg, 1 mmol, 2 equiv) and rose bengal (9.7 mg, 2 mol%). The resulting reaction mixture in a closed vial was stirred at rt under 10 W blue LED for 24 h. The mixture was poured into cold H2O (30 mL) and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4) and evaporated under reduced pressure. The crude residue was purified by column chromatography to obtain the desired product 3a; yield: 167 mg (95%); colorless oil.

1H NMR (CDCl3, 500 MHz): δ = 8.35 (d, J = 10.0 Hz, 1 H), 7.75 (d, J = 10.0 Hz, 2 H), 7.67 (d, J = 5.0 Hz, 1 H), 7.50 (t, J = 7.5 Hz, 2 H), 7.41 (t, J = 7.5 Hz, 1 H), 7.27–7.23 (m, 1 H), 5.41 (s, 1 H), 4.21–4.27 (m, 4 H), 1.25 (t, J = 5.0 Hz, 6 H).

13C NMR (CDCl3, 125 MHz): δ = 166.6, 146.3, 145.8, 133.8, 129.0, 128.6, 128.5, 128.2, 126.2, 125.1, 117.5, 111.9, 62.4, 49.1, 13.9.[12]


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Diethyl 2-[2-(4-Bromophenyl)imidazo[1,2-a]pyridin-3-yl]malonate (3b)

Yield: 196 mg (91%); thick colorless oil.

1H NMR (CDCl3, 500 MHz): δ = 8.26 (d, J = 10.0 Hz, 1 H), 7.57–7.61 (m, 5 H), 7.19–7.20 (m, 1 H), 6.78 (t, J = 10.0 Hz, 1 H), 5.24 (s, 1 H), 4.16–4.20 (m, 4 H), 1.19 (t, J = 7.5 Hz, 6 H).

13C NMR (CDCl3, 125 MHz): δ = 166.3, 145.8, 145.0, 132.6, 131.8, 130.5, 126.2, 125.5, 122.6, 117.5, 112.1, 111.9, 62.5, 49.0, 13.9.

HRMS: m/z calcd for C20H19BrN2O4 (M + H): 431.0606; found: 431.0603.


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Diethyl 2-[2-(4-Methoxyphenyl)imidazo[1,2-a]pyridin-3-yl]malonate (3c)

Yield: 176 mg (92%); thick colorless gum.

1H NMR (CDCl3, 500 MHz): δ = 8.33 (d, J = 5.0 Hz, 1 H), 7.65–7.71 (m, 3 H), 7.22–7.35 (m, 1 H), 7.03 (d, J = 10.0 Hz, 2 H), 6.82 (t, J = 10.0 Hz, 1 H), 5.37 (s, 1 H), 4.21–4.28 (m, 4 H), 3.87 (s, 3 H), 1.26 (t, J = 7.5 Hz, 6 H).

13C NMR (CDCl3, 125 MHz): δ = 166.7, 159.7, 146.1, 145.7, 130.3, 126.2, 126.1, 125.0, 117.3, 114.2, 111.9, 111.3, 62.4, 55.3, 49.2, 14.0.

HRMS: m/z calcd for C21H22N2O5 (M + H): 383.1607; found: 383.1644.


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Diethyl 2-[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]malonate (3d)

Yield: 147 mg (76%); colorless thick oil.

1H NMR (CDCl3, 400 MHz): δ = 8.34 (d, J = 8.0 Hz, 1 H), 7.65–7.71 (m, 3 H), 7.47 (d, J = 8.0 Hz, 2 H), 7.25–7.29 (m, 1 H), 6.83–6.87 (m, 1 H), 5.29 (s, 1 H), 4.22–4.27 (m, 4 H), 1.26 (t, J = 8.0 Hz, 6 H).

13C NMR (CDCl3, 100 MHz): δ = 166.4, 145.8, 145.1, 134.4, 132.2, 130.3, 128.9, 126.2, 125.4, 117.5, 112.2, 111.9, 62.5, 49.1, 14.0.

HRMS: m/z calcd for C20H19ClN2O4 (M + H): 387.1112; found: 387.1108.


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Diethyl 2-[2-(4-Cyanophenyl)imidazo[1,2-a]pyridin-3-yl]malonate (3e)

Yield: 128 mg (68%); colorless thick gum.

1H NMR (CDCl3, 400 MHz): δ = 8.35 (d, J = 8.0 Hz, 1 H), 7.91 (d, J = 8.0 Hz, 2 H), 7.79 (d, J = 8.0 Hz, 2 H), 7.68 (d, J = 8.0 Hz, 1 H), 7.31 (m, 1 H), 6.83–6.89 (m, 1 H), 5.31 (s, 1 H), 4.26 (m, 4 H), 1.27 (t, J = 8.0 Hz, 6 H).

13C NMR (CDCl3, 100 MHz): δ = 166.1, 146.0, 144.2, 138.4, 132.5, 129.5, 126.3, 125.9, 118.8, 117.8, 112.7, 112.5, 111.8, 62.7, 49.0, 14.0.

HRMS: m/z calcd for C21H19N3O4 (M + H): 378.1454; found: 378.1448.


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Diethyl 2-[2-(p-Tolyl)imidazo[1,2-a]pyridin-3-yl]malonate (3f)

Yield: 158 mg (86%); pale yellow thick gum.

1H NMR (CDCl3, 500 MHz): δ = 8.27 (d, J = 10.0 Hz, 1 H), 7.58 (t, J = 7.5 Hz, 3 H), 7.15–7.24 (m, 3 H), 6.74 (t, J = 7.5 Hz, 1 H), 5.32 (s, 1 H), 4.14–4.19 (m, 4 H), 2.35 (s, 3 H), 1.18 (t, J = 10.0 Hz, 6 H).

13C NMR (CDCl3, 125 MHz): δ = 166.7, 145.8, 145.3, 137.1, 129.8, 128.4, 127.9, 125.2, 124.1, 116.4, 110.9, 110.6, 61.5, 48.3, 20.5, 13.1.

HRMS: m/z calcd for C21H22N2O4 (M + H): 367.1658; found: 367.1653.


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Diethyl 2-[2-(4-Fluorophenyl)imidazo[1,2-a]pyridin-3-yl]malonate (3g)

Yield: 148 mg (80%); pale yellow thick gum.

1H NMR (CDCl3, 400 MHz): δ = 8.34 (d, J = 8.0 Hz, 1 H), 7.72–7.75 (m, 2 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.27 (t, J = 8.0 Hz, 1 H), 7.19 (t, J = 8.0 Hz, 2 H), 6.82–6.86 (m, 1 H), 5.32 (s, 1 H), 4.23–4.28 (m, 4 H), 1.25–1.29 (m, 6 H).

13C NMR (CDCl3, 100 MHz): δ = 166.48, 162.9 (d, J = 247 Hz), 145.7, 145.4, 130.8 (d, J = 9 Hz), 129.7, 126.2, 125.3, 117.9, 115.7 (d, J = 22 Hz), 112.1, 111.7, 62.4, 49.3, 13.9.

HRMS: m/z calcd for C20H19FN2O4 (M + H): 371.1407; found: 371.1400.


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Diethyl 2-[2-(Naphthalen-2-yl)imidazo[1,2-a]pyridin-3-yl]malonate (3h)

Yield: 185 mg (92%); colorless thick gum.

1H NMR (CDCl3, 400 MHz): δ = 8.40 (d, J = 8.0 Hz, 1 H), 8.24 (br s, 1 H), 7.94 (m, 4 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.51 (m, 2 H), 7.27 (m, 1 H), 6.85 (t, J = 8.0 Hz, 1 H), 5.51 (s, 1 H), 4.25 (m, 4 H), 1.28 (t, J = 6.0 Hz, 6 H).

13C NMR (CDCl3, 100 MHz): δ = 166.6, 146.3, 145.9, 133.3, 133.1, 131.2, 128.4, 128.3, 128.2, 127.7, 126.8, 126.4, 126.3, 126.2, 125.2, 117.9, 112.1, 112.0, 62.4, 49.2, 14.0.

HRMS: m/z calcd for C24H23N2O4 (M + H): 403.1658; found: 403.1651.


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Diethyl 2-[2-(3-Bromophenyl)imidazo[1,2-a]pyridin-3-yl]malonate (3i)

Yield: 166 mg (77%); yellow thick gum.

1H NMR (CDCl3, 500 MHz): δ = 8.35 (d, J = 10.0 Hz, 1 H), 7.95 (br s, 1 H), 7.68 (m, 2 H), 7.54 (m, 1 H), 7.36 (t, J = 7.5 Hz, 1 H), 7.27 (m, 1 H), 6.85 (t, J = 5.0 Hz, 1 H), 5.33 (s, 1 H), 4.25 (m, 4 H), 1.28 (t, J = 7.5 Hz, 6 H).

13C NMR (CDCl3, 125 MHz): δ = 166.4, 145.8, 144.8, 135.9, 132.1, 131.2, 130.2, 127.6, 126.3, 125.5, 122.1, 117.6, 112.3, 112.1, 62.6, 49.0, 14.0.

HRMS: m/z calcd for C20H19BrN2O4 (M + H): 431.0606; found: 431.0603.


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Dimethyl 2-(2-Phenylimidazo[1,2-a]pyridin-3-yl)malonate (3k)

Yield: 120 mg (74%); colorless thick gum.

1H NMR (CDCl3, 400 MHz): δ = 8.32 (d, J = 8.0 Hz, 1 H), 7.74 (d, J = 4.0 Hz, 2 H), 7.68 (d, J = 8.0 Hz, 1 H), 7.50 (t, J = 8.0 Hz, 2 H), 7.42 (t, J = 8.0 Hz, 1 H), 7.27 (t, J = 8.0 Hz, 1 H), 6.85 (t, J = 6.0 Hz, 1 H), 5.46 (s, 1 H), 3.78 (s, 6 H).

13C NMR (CDCl3, 100 MHz): δ = 167.0, 146.4, 145.8, 133.6, 129.0, 128.7, 128.3, 126.0, 125.2, 117.6, 112.3, 111.4, 53.1, 48.7.

HRMS: m/z calcd for C18H16N2O4 (M + H): 325.1188; found: 325.1186.


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Dimethyl 2-[2-(Naphthalen-2-yl)imidazo[1,2-a]pyridin-3-yl]malonate (3l)

Yield: 144 mg (77%); colorless thick gum.

1H NMR (CDCl3, 400 MHz): δ = 8.36 (d, J = 4.0 Hz, 1 H), 8.21 (br s, 1 H), 7.98 (d, J = 8.0 Hz, 1 H), 7.91 (m, 3 H), 7.72 (d, J = 8.0 Hz, 1 H), 7.52 (t, J = 4.0 Hz, 2 H), 7.28 (t, J = 6.0 Hz, 1 H), 6.86 (t, J = 6.0 Hz, 1 H), 5.57 (s, 1 H), 3.79 (s, 6 H).

13C NMR (CDCl3, 100 MHz): δ = 167.0, 146.3, 146.0, 133.3, 133.1, 131.1, 128.5, 128.4, 128.2, 127.7, 126.7, 126.4, 126.3, 126.1, 125.3, 118.0, 112.3, 111.7, 53.2, 48.8.

HRMS: m/z calcd for C22H18N2O4Na (M + Na): 397.1164; found: 397.1159.


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Diethyl 2-(6-Phenylimidazo[2,1-b]thiazol-5-yl)malonate (3n)

Yield: 161 mg (90%); colorless thick gum.

1H NMR (CDCl3, 500 MHz): δ = 7.68 (d, J = 10.0 Hz, 2 H), 7.33 (m, 3 H), 6.86 (d, J = 5.0 Hz, 1 H), 6.26 (d, J = 5.0 Hz, 1 H), 4.44 (s, 1 H), 4.15 (m, 2 H), 3.98 (m, 2 H), 1.19 (t, J = 7.5 Hz, 3 H), 0.93 (t, J = 7.5 Hz, 3 H);

13C NMR (CDCl3, 125 MHz): δ = 175.6, 168.4, 166.1, 165.6, 135.7, 128.7, 128.5, 126.4, 115.9, 110.9, 62.1, 61.4, 59.9, 13.8, 13.6.

HRMS: m/z calcd for C18H18N2O4S (M + H): 359.1066; found: 359.1046.


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Diethyl 2-[6-(4-Methoxyphenyl)imidazo[2,1-b]thiazol-5-yl]malonate (3o)

Yield: 171 mg (88%); yellow thick gum.

1H NMR (CDCl3, 500 MHz): δ = 7.59 (d, J = 10.0 Hz, 2 H), 6.85 (m, 3 H), 6.24 (d, J = 5.0 Hz, 1 H), 4.39 (s, 1 H), 4.13 (m, 2 H), 4.01 (m, 2 H), 3.77 (s, 3 H), 1.17 (t, J = 7.5 Hz, 3 H), 0.97 (t, J = 7.5 Hz, 3 H)

13C NMR (CDCl3, 125 MHz): δ = 175.8, 167.8, 166.1, 165.6, 159.9, 127.7, 127.4, 115.9, 113.8, 110.8, 62.0, 61.4, 59.8, 55.3, 13.8, 13.7.

HRMS: m/z calcd for C19H20N2O5S (M + H): 389.1171; found: 389.1159.


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Diethyl 2-[(6-Naphthalen-2-yl)imidazo[2,1-b]thiazol-5-yl]malonate (3p)

Yield: 182 mg (89%); yellow thick gum.

1H NMR (CDCl3, 500 MHz): δ = 8.14 (br s, 1 H), 7.83 (m, 4 H), 7.47 (m, 2 H), 6.87 (d, J = 5.0 Hz, 1 H), 6.27 (d, J = 5.0 Hz, 1 H), 4.56 (s, 1 H), 4.18 (m, 2 H), 3.93 (m, 2 H), 1.19 (t, J = 7.5 Hz, 3 H), 0.81 (t, J = 7.5 Hz, 3 H).

13C NMR (CDCl3, 125 MHz): δ = 175.5, 168.1, 166.2, 165.6, 133.2, 132.9, 132.8, 128.4, 128.3, 127.5, 126.6, 126.3, 125.9, 123.7, 115.9, 110.9, 62.1, 61.4, 59.7, 13.8, 13.5.

HRMS: m/z calcd for C22H20N2O4S (M + H): 409.1222; found: 409.1214.


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Diethyl 2-[6-(4-Cyanophenyl)imidazo[2,1-b]thiazol-5-yl]malonate (3q)

Yield: 159 mg (83%); colorless thick gum.

1H NMR (CDCl3, 500 MHz): δ = 7.81 (d, J = 10.0 Hz, 2 H), 7.75 (d, J = 10.0 Hz, 2 H), 7.67 (d, J = 5.0 Hz, 1 H), 6.86 (d, J = 5.0 Hz, 1 H), 5.16 (s, 1 H), 4.27 (m, 4 H), 1.30 (t, J = 7.5 Hz, 6 H).

13C NMR (CDCl3, 125 MHz): δ = 166.1, 151.2, 144.9, 138.5, 132.5, 128.8, 120.5, 118.8, 112.3, 111.4, 62.7, 49.8, 14.0.

HRMS: m/z calcd for C19H17N3O4SNa (M + Na): 406.0837; found: 406.0832.


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Dimethyl 2-(6-Phenylimidazo[2,1-b]thiazol-5-yl)malonate (3r)

Yield: 122 mg (74%); colorless thick gum.

1H NMR (CDCl3, 500 MHz): δ = 7.65 (d, J = 5 Hz, 2 H), 7.32 (m, 3 H), 6.85 (d, J = 5.0 Hz, 1 H), 6.24 (d, J = 5.0 Hz, 1 H), 4.44 (s, 1 H), 3.68 (s, 3 H), 3.48 (s, 3 H).

13C NMR (CDCl3, 125 MHz): δ = 175.5, 168.3, 166.5, 166.1, 135.3, 128.8, 128.6, 126.3, 115.9, 111.0, 59.8, 52.9, 52.5.

HRMS: m/z calcd for C16H14N2O4S (M + H): 331.0753; found: 331.0740.


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Diethyl 2-(7-Methoxy-2-phenylbenzo[d][2,1-b]thiazol-3-yl)malonate (3s)

Yield: 169 mg (77%); pale yellow thick gum.

1H NMR (CDCl3, 500 MHz): δ = 7.72 (m, 3 H), 7.46 (t, J = 7.5 Hz, 2 H), 7.38 (t, J = 10.0 Hz, 1 H), 7.19 (bs, 1 H), 6.96 (m, 1 H), 5.38 (s, 1 H), 4.22 (m, 4 H), 3.86 (s, 3 H), 1.20 (t, J = 7.5 Hz, 6 H).

13C NMR (CDCl3, 125 MHz): δ = 167.1, 156.8, 148.4, 147.3, 133.7, 131.4, 128.7, 128.6, 127.9, 127.4, 115.8, 115.6, 112.7, 112.7, 108.2, 62.5, 55.8, 49.6, 13.9.

HRMS: m/z calcd for C23H22N2O5S (M + H): 439.1328; found: 439.1308.


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Total Synthesis of Zolpidem (5j)

To a solution of 6-methyl-2-(p-tolyl)imidazo[1,2-a]pyridine (1j; 111 mg, 0.5 mmol) in 1,4-dioxane (5 mL), was added B2pin2 (190 mg, 0.75 mmol, 1.5 equiv) and the resulting solution was stirred at rt for 5 min. Now diethyl bromomalonate (2a; 239 mg, 1 mmol, 2 equiv) was added followed by NaHCO3 (84 mg, 1 mmol, 2 equiv) and rose bengal (9.7 mg, 2 mol%). The resulting reaction mixure in a closed vial was stirred at rt under 10 W blue LED for 24 h. The reaction mixture was poured into cold H2O (30 mL) and extracted with CH2Cl2. The combined organic layers were dried (Na2SO4) and evaporated under reduced pressure. The crude residue of 3j was dissolved in DMSO (0.3 mL) and a solution of NaCl (0.047 g, 0.8 mmol) in H2O (0.3 mL) was added. The resulting mixture was heated overnight at 160 °C (oil bath). Then, the reaction mixture was cooled to rt, quenched with H2O, and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with H2O and dried (Na2SO4). After evaporation of solvent, the crude product was purified by column chromatography (30% EtOAc in hexane) to afford 4j; yield: 114 mg (74%); off-white solid, mp 95 °C.

1H NMR (CDCl3, 500 MHz): δ = 7.81 (br s, 1 H), 7.65 (d, J = 10.0 Hz, 2 H), 7.50 (d, J = 10.0 Hz, 1 H), 7.19–7.22 (m, 2 H), 7.01 (d, J = 10.0 Hz, 1 H), 7.16 (q, J = 7.5 Hz, 2 H), 3.94 (s, 2 H), 2.34 (s, 3 H), 2.30 (s, 3 H), 1.21 (t, J = 7.5 Hz, 3 H).

13C NMR (CDCl3, 125 MHz): δ = 169.6, 143.8, 137.6, 131.0, 129.3, 128.4, 127.6, 122.0, 121.3, 116.7, 112.4, 61.5, 30.9, 21.3, 18.4, 14.1.[4]

The above ester 4j (96 mg, 0.25 mmol) was converted into zolpidem (5j) following the reported protocol;[23] yield: 65 mg (68%); off-white colored solid; mp 194 °C.

1H NMR (CDCl3, 500 MHz): δ = 7.99 (s, 1 H), 7.54 (d, J = 10.0 Hz, 3 H), 7.26 (d, J = 10.0 Hz, 2 H), 7.04 (d, J = 10.0 Hz, 1 H), 4.07 (s, 2 H), 2.94 (s, 3 H), 2.88 (s, 3 H), 2.40 (s, 3 H), 2.34 (s, 3 H).

13C NMR (CDCl3, 125 MHz): δ = 168.3, 144.1, 143.7, 137.4, 131.7, 129.3, 128.4, 127.5, 122.2, 121.7, 116.5, 113.6, 37.5, 35.8, 30.2, 21.2, 18.4.


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Acknowledgment

We are also thankful to Dr. Biswanath Maity, CBMR, Lucknow, India for providing HRMS analysis of new molecules.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0040-1706606.
  • Supporting Information

Corresponding Author

Narendra R. Chaubey
Institute of Chemical Technology, Department of Chemistry
Nathalal Parekh Road, Matunga, Mumbai 400019, Maharashtra
India   

Publication History

Received: 28 October 2020

Accepted after revision: 29 October 2020

Article published online:
02 December 2020

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Zoom Image
Figure 1 Drug molecules containing imidazoheterocycles
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Scheme 1 Scope of the reaction with different 2-arylimidazo-[1,2-a]pyridines
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Scheme 2 Scope of the reaction with other imidazoheterocycles
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Scheme 3 Total synthesis of zolpidem
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Scheme 4 Plausible reaction mechanism