Diversity-oriented synthesis toward aryl- And phosphoryl-functionalized imidazo[1,2-a]pyridines

Functionalized Imidazo[1,2 ‑a ]pyridines

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Diversity-Oriented Synthesis toward Aryl- and Phosphoryl-

Aurelie Gernet, Nicolas Sevrain, Jean-Noel Volle, Tahar Ayad, Jean-Luc Pirat,* and David Virieux*

Cite This: https://dx.doi.org/10.1021/acs.joc.0c02059

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sı Supporting Information

ABSTRACT: We report herein an eﬃcient synthesis of diversely polysub-

stituted imidazo[1,2-a]pyridines, a family of aza-heterocycles endowed with

numerous biological properties, through a sequence involving two consecutive

palladium-catalyzed cross-coupling reactions. First, we demonstrated that a

Hirao coupling occurred straightforwardly in high yields at positions 3, 5, and 6

of imidazopyridine derivatives, giving access to a wide variety of substituted

phosphonates, phosphinates, and phosphine oxides. In a second step, direct

CH-arylation of phosphorylimidazopyridines with aryl halides was found to be eﬀective and fully selective, leading to 3-aryl-

substituted imidazopyridines in moderate to high yields depending on steric hindrance.

INTRODUCTION

Diversity-oriented synthesis (DOS) is an aﬀordable method-

ology to explore the chemical space for the identiﬁcation of

■

new and potentially biologically active molecules. In spite of

the emergence of biologics, small molecules still carry

promising novelties for medicinal applications. To meet such

demands in molecular diversity, DOS is probably one of the

best approaches to keep the doors open for fast hit and lead

discovery. The term “diversity” is somewhat subjective.

Nevertheless, there is a consensus around the structural

modiﬁcations of skeletal, appendages, functional groups, and

stereochemistry. These principal structural features already

identiﬁed can be used in a build, couple, and pair approach

when complex polycyclic molecules, i.e., natural product like

compounds, are targeted. Consequently, DOS methodology

Figure 1. Representative marketed and bioactive imidazo[1,2-

has allowed the eﬃcient construction of many chemical

a]pyridines.

libraries feeding the ﬁeld of drug discovery.

Imidazo[1,2-a]pyridines are a family of aza-heterocycles

oﬀering peculiar interest in medicinal chemistry (Figure 1).

imidazo[1,2-a]pyridine derivatives. Another interesting feature

The imidazo[1,2-a]pyridine heterocyclic core is naturally

of these heterocyclic scaﬀolds can be associated with their

occurring, and several commercial drugs are already on the

market. For instance, alpidem and zolpidem are widely used in

multifaceted chemical behavior. Imparted by their structure

and their reactivity, imidazo[1,2-a]pyridine cores are perfectly

adequate motifs allowing the introduction of molecular

adornments using transition-metal-catalyzed reactions. These

the treatment of anxiety and insomnia. Minodronate is a

representative member of a larger family of nitrogen-based

bisphosphonates (third generation bisphosphonate) for the

features make them particularly attractive for DOS approaches

treatment of osteoporosis. More recently, GlaxoSmithKline

(

Figure 2). When designing new libraries, labeled fragments

developed a potent noncompetitive CXCR4 receptor antago-

for NMR-based screening may greatly facilitate hit or lead

nist, namely GSK812397, that proved to be eﬃcient for the

treatment of HIV infection, while trisubstituted-imidazopyr-

Special Issue: The New Golden Age of Organo-

phosphorus Chemistry

idines revealed targeting of the Snake Venom Phospholipase

A2. Zolimidine is a gastroprotective drug used for the

treatment of peptic ulcer and gastroesophageal reﬂux.

Received: August 26, 2020

Owing to their broad biological importance, it is therefore

not surprising that the synthetic community has spearheaded

many eﬀorts toward the synthesis and functionalization of

XXXX American Chemical Society

The Journal of Organic Chemistry

J. Org. Chem. XXXX, XXX, XXX−XXX

Article

Figure 2. Imidazo[1,2-a]pyridines as scaﬀold for DOS.

optimizations. As a result, P NMR screening of compounds

that incorporated a phosphorus atom proved to be a highly

Table 1. Optimization of the Reaction Conditions for Hirao

Coupling

valuable approach for medicinal chemists.

In our previous studies on the synthesis of bioactive and

neutral phosphorus-based molecules, we designed two families

of compounds with potent biological activities as anticancer

drugs or as neuroactive agents. Continuing our research

program aimed at the synthesis of biologically relevant

molecules, we investigated a diversity-oriented synthesis of

aryl- and phosphoryl-decorated imidazo[1,2-a]pyridines as a

central core.

yield (%)

RESULTS AND DISCUSSION

entry

cat. [Pd]

ligand

conditions

of 3a/4

■

^P^d⁽^O^A^c⁾2

Xantphos KOAc , THF, reﬂux,

0/75

Palladium-catalyzed cross-coupling reactions are exceptionally

6 h

powerful and reliable synthetic methods to build C−C or C-

Pd(OAc)

Xantphos KOAc , THF, μW, 90 0/100

C, 10 min

heteroatom bonds. Searching for highly convergent syn-

theses, we have designed a sequential approach allowing the

consecutive formation of both P−C and C−C bond, linking

PdCl (PPh )

PhMe, 110 °C, 24 h

Xantphos PhMe, 110 °C, 21 h

Xantphos PhMe, 110 °C, 4 h

dppf

dppp

SPhos

0/100

60/20

72/17

Pd dba₃

easily independent subunits to diﬀerently substituted imidazo-

Pd dba₃

[

1,2-a]pyridines. First, the sequence involves the P−C(sp )

Pd dba₃

PhMe, 110 °C, 46 h

PhMe, 110 °C, 4 d

0/11 (53)

bond formation through Hirao-coupling reaction, and

second, it involves a highly regioselective and then a direct

C−H arylation of imidazopyridines.

Pd dba₃

0/100

Pd dba₃

0/100

Reaction conditions: 1a (0.366 mmol), 2a (0.366 mmol, 1 equiv),

Pd] (10 mol %), ligand (20 mol %), and NEt (0.732 mmol, 2 equiv)

in 3.6 mL of solvent; the reactions were stopped after the total

consumption of reagent 1a, determined by TLC. 10 mol % of KOAc

was added. Indicated by TLC. Reaction conditions with 1.1 equiv of

Easily available 3-bromo-2-phenylimidazo[1,2-a]pyridine

[

9,20

and diethyl phosphite as phosphorylating agent were

chosen for preliminary optimization of the Hirao coupling

reactions. Palladium acetate and xantphos were used as the

catalytic system along with triethylamine as a base. This system

proved to be eﬃcient when nitrogen-based heterocycles were

the substrates of the reaction. The solvent and the

temperature of the reaction failed to give the expected

phosphonate, and only the reduced imidazopyridine 4 was

formed and isolated almost quantitatively (Table 1, entries 1

and 2). Similarly, changing the palladium source by palladium

dichloride bis(triphenylphosphine) did not improve the

reaction outcome (entry 3). Gratefully, the use of tris-

with various phosphites and secondary phosphine oxides 2a−f.

As can be seen in Scheme 1, the reaction appeared to be poorly

general, and it turns out that the nature of the substituents at

the phosphorus atom has a dramatic inﬂuence on the reaction.

Only diethyl phosphonate derivative 3a and diphenylphos-

phine oxide 3b were isolated in 72% and 27% yield,

respectively, whereas the unwanted reduced products were

observed in all the other reactions. Phosphorylation of

imidazopyridines at position 3 using Hirao coupling also

appeared to be poorly eﬃcient, and the reduction of the

bromide derivative was the main reaction. It should be noted

that such a reduction process mediated by H-phosphoryl

(

dibenzylideneacetone)dipalladium(0) and xantphos furnished

the diethyl imidazopyridylphosphonate 3a in 60% yield along

with 20% of the debrominated secondary product 4 (entry 4).

Reducing the reaction time from 21 to 4 h signiﬁcantly

improved the yield of the targeted phosphonate 3a up to 72%,

suggesting that the phosphonate product is prone to

degradation over the course of the reaction. From the results

depicted in Table 1, it is also clear that the outcome of this

Hirao coupling is highly ligand dependent. Indeed, only the

reduced imidazopyridine 4 was formed when the reaction was

performed with other bidentate ligands such as dppf, dppp or

SPhos (Table1, entries 6 to 8).

derivatives was already observed for aryl halides. Moreover

and to the best of our knowledge, only two papers dealing with

the phosphorylation at position 3 of imidazopyridines were

III

reported in the literature. Singh et al. disclosed a Mn -

mediated regioselective method for the direct C−H phospho-

nation of imidazo[1,2-a]pyridines in good to moderate

yields, while Marugan et al. showed that highly reactive

and electrophilic diphenyliodophosphine smoothly reacted

with imidazo[1,2-a]pyridine and 2-methylimidazo[1,2-a]-

Under the optimal operating conditions, 3-bromo-2-

phenylimidazo[1,2-a]pyridine 1a was subsequently reacted

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Scheme 1. Phosphorylation at Position 3 of

Imidazopyridines 1a and 1b

52%). It is worth noting that even the sterically hindered di-

tert-butyl phosphite gave the expected phosphonate in 52%

yield. However, the reaction failed when using dibenzyl

phosphite as no phosphonate derivative 5b was observed.

This result may be attributed to the high instability of the

dibenzyl moiety under such conditions leading to the cleavage

of the benzyl as previously reported by Virieux et al. As

outlined in Scheme 2, secondary phosphine oxides reacted

smoothly, aﬀording the tertiary phosphine oxides 5e−f in 68%

to quantitative yields. When the reactions were conducted with

aryl H-phosphinates 2g−j, the corresponding cross-coupling

products 5g−j were isolated in yields ranging from 70 to 76%.

Our studies also revealed that the electronic nature of the

substituents on aryl H-phosphinates had only a small inﬂuence

on the yield of the reaction. Both electron-donating and

-withdrawing groups were well tolerated. Finally, a coupling

reaction was attempted on 2-methylimidazopyridine 1d. The

resulting phosphine oxide 5k was isolated in a disappointing

0% yield, contrasting with the expected good result based on

pyridine leading to the corresponding 3-(diphenylphosphino)-

the in situ monitoring of the reaction by P NMR which

highlighted a complete and clean conversion of the starting

material. To the best of our knowledge, only one paper

described the phosphorylation of related heterocycles at

position 5 in low to moderate yields. Moreover, the reaction

has a relatively narrow substrate scope and required the

presence of a cyano group at position 8 for the direct

nucleophilic aromatic substitution of the bromide. Conse-

quently, the above-described Hirao coupling reaction clearly

appeared as an eﬃcient approach for the direct introduction of

a phosphorus-based functional group at position 5 of

imidazopyridines. For example, our method was successfully

applied for the gram-scale synthesis of compound 5e without

imidazo[1,2-a]pyridines in moderate yields. Since the best

results were obtained with diethyl phosphite 2a and

diphenylphosphine oxide 2b, we used them for the

phosphorylation of the 3-bromoimidazo[1,2-a]pyridine 1b.

The corresponding diethyl phosphonate 3c was obtained in

1% yield and the diphenylphosphine oxide derivative 3d in

8% yield.

By contrast, 5-bromoimidazo[1,2-a]pyridines 1c and 1d

proved to be suitable partners in such coupling reactions as

outlined in Scheme 2. Using the previously developed

conditions, 5-bromoimidazo[1,2-a]pyridine 1c (R = H) was

reacted with various dialkyl phosphites 2. The resulting

phosphonates 5a−d were obtained in moderate yields (43−

Scheme 2. Scope of the Palladium Coupling Reactions of 5-Bromoimidazopyridine 1c and 1d

Reaction conditions: under nitrogen atmosphere, 1c (0.508 mmol, 1.1 equiv), 2a−j (0.462 mmol, 1 equiv), [Pd] (10 mol %), ligand (20 mol %),

and NEt (0.924 mmol, 2 equiv) in 4.6 mL of dry toluene; the reactions were stopped after the total consumption of reagent 1c, determined by

TLC. Reaction conditions: under nitrogen atmosphere, 1d (1.10 mmol, 1.1 equiv), 2e (1.00 mmol, 1 equiv), [Pd] (10 mol %), ligand (20 mol %)

and NEt (2.0 mmol, 2 equiv) in 25 mL of dry toluene; the reaction was stopped after the total consumption of reagent 1c, determined by TLC.

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a,b

Scheme 3. Scope of the Palladium Coupling Reactions of 6-Bromoimidazopyridines 1e−h

Reaction conditions: under nitrogen atmosphere, 1e−f (0.403−0.508 mmol, 1.1equiv), 2a−j (0.366−0.462 mmol, 1 equiv), [Pd] (10 mol %),

ligand (20 mol %) and NEt (2 equiv) in dry toluene (c = 1 M); the reactions were stopped after the total consumption of reagent 1e,f, determined

by TLC. Reaction conditions: under nitrogen atmosphere, 1g−h (1.10 mmol, 1.1equiv), 2e (1.00, 1 equiv), [Pd] (10 mol %), ligand (20 mol %),

and NEt (2 equiv) in dry toluene (c = 1 M), the reactions were stopped after the total consumption of reagent 1g,h, determined by TLC.

erosion of the chemical yield, thus demonstrating the

practicality and the usefulness of the herein reported protocol.

Having validated the Hirao coupling reaction for 5-

bromoimidazo[1,2-a]pyridine derivatives 1c,d, we next exam-

ined the reaction of 6-bromoimidazo[1,2-a]pyridines 1e−h,

and the results of these experiments are reported in Scheme 3.

It turned out that under the optimized conditions imidazopyr-

idine derivatives 1e−h were also suitable substrates for this

palladium-catalyzed coupling process, irrespective of the

substitution patterns. As mentioned before, when dibenzyl

phosphite was used as the coupling partner, only a low yield

high to quantitative yields, regardless of the nature of the

substituent at position 2. A noticeable exception was the

reaction between the dimethylphosphine oxide 2f and the

imidazopyridine 1f that furnished the corresponding derivative

6f in nonreproducible 21% yield. Here again, the robustness of

the Hirao protocol for the direct introduction of phosphorus-

based functional group at position 6 of imidazopyridines was

demonstrated by the gram-scale synthesis of several

phosphoryl imidazopyridines (6a, 6f, 6k, 6o, 6p).

3-Aryl-substituted imidazo[1,2-a]pyridines attracted sub-

stantial interest in the design of new potent drugs. They

revealed nanomolar bioactivities acting as potent γ-secretase

(

36%) of the phosphonate 6b was obtained, while no reaction

occurs with the imidazopyridine 1e. Nonetheless, we were

gratiﬁed to ﬁnd that for all other substrates the reactions

proceeded smoothly giving the expected phosphonate,

phosphine oxide, and phosphinate products 6a−v in generally

modulators or antitumor agents. Having phosphorus-

functionalized imidazopyridines in hand, we decided to take

advantage of the inherent reactivity of such nitrogen-based

heterocycles, and more speciﬁcally, we turned our attention to

J. Org. Chem. XXXX, XXX, XXX−XXX

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the direct C−H bond activation at position 3. Several papers

validated this approach. For instance, the Doucet group

reported the selective direct 3-CH-arylation of imidazo[1,2-

a]pyridines with aryl bromides through a phosphine-free

assess the inﬂuence of substituents on the course of the

reaction, i.e., at position 2 and 5 or 6, imidazopyridine 7 (R =

R = H) was reacted with either bromobenzene or ortho-

sterically hindered aryl bromides, leading to CH-coupling

products 9a−g. Steric hindrance carried by the aromatic halide

has a strong inﬂuence on the reaction. All the resulting

coupling products 9c−g showed signiﬁcantly lower yields

compared to imidazopyridine 9a (Scheme 4, compare 9a vs 9c-

g). No coupling reaction (9f) was observed when 1-bromo-2-

methylnaphthalene was used as substrate of the reaction.

Introducing a phenyl substituent at position 2 of the

palladium-catalyzed reaction. Various other catalytic systems

were subsequently developed for the coupling of aryl halides

including supported catalysts on magnetically recyclable

nanoparticles, coupling reactions in PEG-medium, or in

water.

Therefore, we ﬁrst optimized the reaction on model

substrates, using either imidazopyridine 7 or diphenylphos-

phine oxide derivative 6o and bromobenzene 8a arylating

reagent, to explore the diﬀerence in reactivity induced by the

presence of a phosphoryl group starting from the conditions

imidazopyridine (R = H, R = Ph) resulted in even more

diﬃcult coupling reactions. Only the 2,3-diphenyl- and 2-

phenyl-3-naphthylimidazopyridines 9h and 9i were isolated in

59% and 80% yields, respectively, meaning that steric strains

were too important to form derivatives 9j and 9k from 2-

bromotoluene and 2-bromoanisole. Having the vision of the

limits for this CH-coupling, we next attempted to generate the

developed by Doucet. As illustrated in Table 2, 3-

Table 2. Optimization of the Reaction Conditions for Direct

C−H Bond Activation at Position 3

phosphine oxides 9b and 9l−o from imidazopyridine 6o (R =

Ph P(O), R = H) and 6p (R = Me P(O), R = H). Similarly,

to the naked imidazopyridine 7, the reactions were successful

for phenyl and 1-naphthyl bromides, and the resulting

products 9b and 9l−o were obtained in yields ranging from

8% to 75%. Noticeably, the reaction carried out with 2-

bromoanisole failed to give the corresponding anisyl derivative

m, probably due to steric reasons as mentioned before. For

comparison, the unsubstituted analogue 9e was only obtained

in low yield (21%). Then the last series was formed from

imidazopyridine 6e (R = Ph P(O), R = Ph), resulting in the

formation of the desired coupling products 9p−s with

disparate success. Indeed, 2-phenylimidazopyridine 9p and

naphthyl derivative 9q were obtained in 100% and 50% yields,

respectively, while the reaction completely failed to provide

either imidazopyridine derivative 9r or 9s.

entry substrate Pd(OAc) (mol %)

conditions

140 °C, 4 h

170 °C, 30 min

MW, 150 °C, 30 min

MW 150 °C, 30 min

MW 170 °C, 30 min

MW, 170 °C, 30 min

yield (%)

2.5 mol %

10 mol %

100

In contrast with all the synthesized 2-arylimidazopyridines 9,

it can be noticed that imidazopyridine 9q is the unique

compound that exhibits diastereotopic atoms. Due to the

complex proton NMR, this eﬀect was only and clearly visible in

C NMR. All of the carbons of the diphenylphosphinyl group

phenylimidazo[1,2-a]pyridine 9a was obtained quantitatively

after 4 h of heating at 140 °C using 2.5 mol % of palladium

acetate as catalyst in the presence of potassium acetate as a

base (Table 2, entry 1). Increasing the temperature from 140

to 170 °C undergoes rapid product formation in only 30 min

while maintaining 100% yield. Similar high results were

obtained using microwave activation at 150 °C, also giving

compound 9a in quantitative yield after 30 min (Table 2,

entries 2 and 3). We then moved to imidazo[1,2-a]pyridin-6-

yldiphenylphosphine oxide 6o. The ﬁrst trial was conducted

using 2.5 mol % of palladium acetate under microwave

activation. After 30 min at 150 °C, the 3-phenylimidazopyr-

idine 9b was isolated in 86% (Table 2, entry 4). Increasing the

temperature to 170 °C while keeping the ratio of palladium

unchanged increased the yield to 89% (Table 2, entry 5). The

best conditions were observed with heating at 170 °C under

microwave activation using 10 mol % of palladium acetate. The

imidazopyridine 9a was then isolated in 96% yield after

puriﬁcation by silica gel chromatography (Table 2, entry 6).

To shorten the reaction time, it was necessary to increase the

amount of palladium acetate from 2.5 to 10 mol % while

maintaining temperature to 170 °C. Fortunately, phosphine

oxide 9b was stable enough and no degradation was observed.

With these conditions in hand, the scope of the CH-

coupling reaction was explored as illustrated in Scheme 4. To

presented diﬀerent chemical shifts. The magnitude of

diastereotopic splitting appears small, with Δδ ranging from

0.01 to 0.13 ppm, and it mainly depends on that how far the

stereogenic element from the considered diastereotopic atoms.

These splittings are consistent with axial chirality. Compounds

i, 9l, and even 9o may also exhibit reduced rotation due to

steric hindrance, but there is no eligible atom to observe such

phenomena by NMR.

CONCLUSIONS

■

In conclusion, imidazo[1,2-a]pyridines are an exceptional and

versatile platform for medicinal chemistry. These aza-hetero-

cycles have played important roles in many FDA-approved

drugs leading to various medicinally active series of molecules.

In this context, we have developed a general and aﬀordable

approach to introduce diversity in dedicated positions. First,

we demonstrated that Hirao coupling occurred straightfor-

wardly in high yields at positions 3, 5, and 6 of various

imidazopyridines leading to a wide range of substituted

phosphonates, phosphinates, and phosphine oxides. For

position 3, the coupling was impeded by the concurrent

reduction of the 3-bromoimidazopyridine. If such a reaction

was already observed, the reduced products were obtained

sometimes almost quantitatively. In a second step, using a

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Scheme 4. Direct C−H Palladium-Coupling Reactions of Imidazopyridines with Aryl Bromides 9a−s

The reactions were stopped after the total consumption of reagent 7 or 6o. Method A was carried out under thermal conditions. Method B was

carried out under microwave heating. NR = no reaction.

Avance 400 ( H: 400 MHz, ¹³C: 100.61 MHz, ³¹P: 161.97 MHz).

Chemical shifts are reported in delta (δ) units, part per million (ppm)

downﬁeld from tetramethylsilane (TMS) relative to the residual

deuterated solvent peaks. Coupling constants are reported in hertz

(

simple palladium catalytic system, direct CH coupling of

phosphorylimidazopyridines with aryl halides was found to be

eﬀective and fully selective leading to several 3-aryl-substituted

imidazopyridines in moderate to high yields. Although this

CH-activation is highly selective, steric hindrance is a critical

parameter and only some combinations of reactants were

eﬀective.

Hz). The following abbreviations are used: s = singlet, d = doublet, t

triplet, q = quartet, m = multiplet, br = broad signal. High-

resolution mass spectroscopic (HRMS) analyses were measured on a

Xevo G2 Q TOF spectrometer using the electrospray method by the

Laboratoire de Mesures Physiques of the University of Montpellier.

Typical Procedure for the Preparation of 3-Phosphoryl-2-

phenylimidazo[1,2-a]pyridines 3a,b. Under nitrogen atmosphere, a

mixture of 3-bromo-2-phenylimidazo[1,2-a]pyridine 1a (110 mg,

EXPERIMENTAL SECTION

■

Measurements. All experiments were carried out under nitrogen

atmosphere. All commercially available materials were used as

received without further puriﬁcation. Imidazopyridines 7 and 1a−h

were, respectively, obtained from known procedures by reaction of 2-

aminopyridine, 2-amino-5-bromopyridine, and 2-amino-6-bromopyr-

idine with chloroacetaldehyde, chloroacetophenone, or chloroace-

.403 mmol), phosphorus derivatives (2a−f) (0.366 mmol), Pd dba

34 mg, 0.037 mmol), xantphos (42 mg, 0.073 mmol), and

(

triethylamine (102 μL, 0.732 mmol) in dry toluene (3.6 mL) was

stirred at reﬂux. After completion of the reaction indicated by TLC,

the mixture was cooled to room temperature, ﬁltered on Celite, and

washed with ethyl acetate (20 mL), and the ﬁltrate was concentrated

under vacuum. The crude residue was then puriﬁed by ﬂash

chromatography (silica gel, cyclohexane/ethyl acetate (80/20 to

50/50)) to give the desired products (3a,b).

tone. Bromination at position 3 was accomplished using N-

bromosuccinimide. Microwave reactions were performed using

CEM Discover apparatus using 10 and 35 mL sealed reactors for

respectively small- and large-scale synthesis. Reactions were

performed by maintaining the temperature to the set point.

NMR, ¹³C NMR, and P NMR spectra were measured on a Bruker

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Diethyl (2-phenylimidazo[1,2-a]pyridin-3-yl)phosphonate (3a):

and concentrated under vacuum. The crude residue was then puriﬁed

by ﬂash chromatography (silica gel, dichloromethane/(dichloro-

methane/MeOH 10%) (90/10 to 70/30)) to give the desired

product (5a−j).

orange oil, (87 mg, yield = 72%, cyclohexane/ethyl acetate (80/20 to

0/50)); H NMR (400 MHz, CDCl ) δ 9.19 (dt, J = 7.0, 1.2 Hz,

H), 7.90−7.82 (m, 2H), 7.72 (ddt, J = 9.0, 1.8, 1.1 Hz, 1H), 7.48−

.35 (m, 4H), 6.95 (td, J = 6.9, 1.3 Hz, 1H), 4.18−4.04 (m, 2H), 3.91

Diethyl imidazo[1,2-a]pyridin-5-ylphosphonate (5a): orange oil

(

ddq, J = 10.0, 8.0, 7.1 Hz, 2H), 1.13 (td, J = 7.1, 0.7 Hz, 6H);

(50 mg, yield = 43%, cyclohexane/ethyl acetate (80/20 to 50/50));

C{ H} NMR (101 MHz, CDCl ) δ 155.2 (d, J = 17.6 Hz, C), 148.3

H NMR (400 MHz, CDCl ) δ 7.98 (dd, J = 1.3, 0.8 Hz, 1H), 7.77

(

d, J = 14.4 Hz, C), 133.8 (s, C), 129.9 (s, CH), 129.0 (s, CH), 128.6

s, CH), 128.0 (s, CH), 127.6 (s, CH), 117.5 (s, CH), 113.6 (s, CH),

(ddt, J = 9.1, 2.2, 1.0 Hz, 1H), 7.67 (d, J = 1.3 Hz, 1H), 7.50 (ddd, J =

11.6, 6.9, 1.2 Hz, 1H), 7.17 (ddd, J = 9.1, 6.9, 3.6 Hz, 1H), 4.20 (ddq,

J = 10.2, 8.2, 7.1 Hz, 2H), 4.07 (ddq, J = 10.2, 8.5, 7.1 Hz, 2H), 1.27

07.4 (d, J = 226.9 Hz, PC), 62.6 (d, J = 5.0 Hz, CH ), 16.0 (d, J =

.3 Hz, CH ); P{ H} NMR (162 MHz, CDCl ) δ 8.17; HR-MS

(td, J = 7.1, 0.6 Hz, 6H); C{ H} NMR (101 MHz, CDCl ) δ 145.2

(m/z) [M + H] calcd for C H N O P = 331.1212, found =

(d, J = 5.9 Hz, C), 134.2 (s, CH), 126.2 (d, J = 207.5 Hz, PC), 122.6

(d, J = 13.5 Hz, CH), 122.2 (d, J = 15.2 Hz, CH), 122.1 (s, CH), 63.3

31.1215.

Diphenyl (2-phenylimidazo[1,2-a]pyridin-3-yl)phosphine oxide

3b): yellow oil, (39 mg, yield = 27%, cyclohexane/ethyl acetate (80/

(d, J = 5.3 Hz, CH ), 16.2 (d, J = 6.3 Hz, CH ); P{ H} NMR (162

(

MHz, CDCl ) δ 7.71; HR-MS (m/z) [M + H]

calcd for

0 to 50/50)); H NMR (400 MHz, CDCl ) δ 8.74 (dt, J = 7.0, 1.2

C H N O P = 255.0899, found = 255.0905.

11 16

Hz, 1H), 7.71 (dq, J = 9.0, 1.2 Hz, 1H), 7.56−7.50 (m, 4H), 7.42−

Diisopropyl imidazo[1,2-a]pyridin-5-ylphosphonate (5c): orange

.30 (m, 3H), 7.29−7.20 (m, 4H), 7.13−7.07 (m, 2H), 7.02−6.99

oil (66 mg, yield = 51%, cyclohexane/ethyl acetate (80/20 to 50/

(

m, 1H), 6.96−6.88 (m, 2H), 6.77 (td, J = 6.9, 1.3 Hz, 1H); C{ H}

50)); H NMR (400 MHz, CDCl ) δ 7.95 (dd, J = 1.3, 0.8 Hz, 1H),

NMR (101 MHz, CDCl ) δ 155.7 (d, J = 13.2 Hz, C), 148.1 (d, J =

7.74 (ddt, J = 9.0, 2.1, 1.0 Hz, 1H), 7.65 (d, J = 1.3 Hz, 1H), 7.50

(ddd, J = 11.6, 6.9, 1.3 Hz, 1H), 7.16 (ddd, J = 9.1, 6.9, 3.5 Hz, 1H),

4.69 (dhept, J = 7.8, 6.2 Hz, 2H), 1.35 (d, J = 6.2 Hz, 6H), 1.10 (d, J

0.2 Hz, C), 133.7 (s, C), 132.2 (d, J = 2.9 Hz, CH), 131.8 (d, J =

0.4 Hz, CH), 131.4 (d, J = 111.9 Hz, PC), 129.5 (d, J = 0.7 Hz,

CH), 128.6 (d, J = 12.8 Hz, CH), 128.4 (d, J = 0.7 Hz, CH), 127.7 (s,

= 6.2 Hz, 6H); C{ H} NMR (101 MHz, CDCl ) δ 145.2 (d, J = 5.9

Hz, C), 134.0 (CH), 127. Five (d, J = 207.3 Hz, PC), 122.7 (d, J =

13.5 Hz, CH), 121.8 (d, J = 12.7 Hz, CH), 121.8 (d, J = 3.0 Hz, CH),

114.2 (CH), 72.6 (d, J = 5.4 Hz, CH

), 24.1 (d, J = 4.1 Hz, CH

); P{ H} NMR (162 MHz, CDCl ) δ 5.07;

P = 283.1212, found

23.5 (d, J = 4.9 Hz, CH

HR-MS (m/z) [M + H] calcd for C13H N O

20 2 3

= 283.1218.

bromoimidazo[1,2-a]pyridine 1b (217 mg, 1.10 mmol), phosphorus

derivatives (2a, 2b) (1.00 mmol), Pd dba (92 mg, 0.1 mmol),

Di-tert-butyl imidazo[1,2-a]pyridin-5-ylphosphonate (5d): or-

ange oil (75 mg, yield = 52%, cyclohexane/ethyl acetate (80/20 to

xantphos (116 mg, 0.2 mmol), and triethylamine (280 μL, 2.00

mmol) in dry toluene (10 mL) was stirred at reﬂux. After completion

of the reaction indicated by TLC, the mixture was cooled to room

temperature, ﬁltered on Celite, and washed with ethyl acetate (50

mL), and the ﬁltrate was concentrated under vacuum. The crude

residue was puriﬁed by ﬂash chromatography (silica gel, cyclohexane/

ethyl acetate (80/20 to 50/50)) to give the desired product (3c,d).

Diethyl imidazo[1,2-a]pyridin-3-ylphosphonate (3c): yellow oil

50/50)); H NMR (400 MHz, CDCl ) δ 7.94 (dd, J = 1.3, 0.8 Hz,

1H), 7.70 (ddt, J = 9.0, 2.1, 1.0 Hz, 1H), 7.65 (d, J = 1.3 Hz, 1H),

7.47 (ddd, J = 11.9, 6.9, 1.3 Hz, 1H), 7.15 (ddd, J = 9.0, 6.9, 3.6 Hz,

1H), 1.40 (s, 18H); C{ H} NMR (101 MHz, CDCl ) δ 145.3 (d, J

= 5.8 Hz, C), 133.7 (S, CH), 131.0 (d, J = 211.4 Hz, PC), 123.0 (d, J

= 13.9 Hz, CH), 121.0 (d, J = 3.1 Hz, CH), 120. Five (d, J = 13.6 Hz,

CH), 114.1 (S, CH), 84.7 (d, J = 7.6 Hz, OC), 30.2 (d, J = 4.1 Hz,

CH ); P{ H} NMR (162 MHz, CDCl ) δ −2.32; HR-MS (m/z)

(

180 mg, yield = 71%, cyclohexane/ethyl acetate (80/20 to 50/50));

[M + H] calcd for C H N O P = 311.1519, found = 311.1528.

15 24 2 3

H NMR (400 MHz, CDCl ) δ 8.59 (bd, J = 6.9 Hz, 1H), 8.02 (s,

Imidazo[1,2-a]pyridin-5-yldiphenylphosphine oxide (5e): pale

H), 7.64 (ddt, J = 9.1, 2.2, 1.2 Hz, 1H), 7.29 (ddd, J = 9.1, 6.8, 1.3

brown solid (1.47 g, yield = 100% for 1.00 g of 5-bromoimidazo-

Hz, 1H), 6.89 (td, J = 6.9, 1.2 Hz, 1H), 4.18−4.07 (m, 2H), 4.07−

[1,2-a]pyridine, cyclohexane/ethyl acetate (80/20 to 50/50)); H

.97 (m, 2H), 1.24 (td, J = 7.1, 0.6 Hz, 6H); C{ H} NMR (101

NMR (400 MHz, CDCl ) δ 8.12 (t, J = 1.1 Hz, 1H), 7.80 (dddd, J =

MHz, CDCl ) δ 149.0 (d, J = 13.5 Hz, C), 143.7 (d, J = 18.8 Hz,

9.1, 2.1, 1.2, 0.8 Hz, 1H), 7.76−7.67 (m, 4H), 7.67−7.60 (m, 3H),

7.57−7.48 (m, 4H), 7.10 (ddd, J = 9.3, 6.9, 2.5 Hz, 1H), 6.65 (ddd, J

CH), 127.2 (s, CH), 127.1 (s, CH), 117.9 (d, J = 0.8 Hz, CH), 113.8

(

10.7, 6.9, 1.2 Hz, 1H); C{ H} NMR (101 MHz, CDCl ) δ 145.2

(

s, CH), 111.7 (d, J = 229.1 Hz, PC), 62.7 (d, J = 5.2 Hz, CH ), 16.2

d, J = 3.4 Hz, C), 134.5, (s, CH), 133.2 (d, J = 2.9 Hz, CH), 132.1

d, J = 10.3 Hz, CH), 130.4 (d, J = 109.4 Hz, PC), 129.2 (d, J = 12.7

(

d, J = 6.8 Hz, CH ); P{ H} NMR (162 MHz, CDCl ) δ 7.05; HR-

MS (m/z) [M + H] calcd for C H N O P = 255.0893, found =

Hz, CH), 129.1 (d, J = 109.3 Hz, PC), 122.4 (d, J = 11.1 Hz, CH),

21.8 (d, J = 2.4 Hz, CH), 121.7 (d, J = 12.6 Hz, CH), 114.6 (s, CH);

55.0901.

Imidazo[1,2-a]pyridin-3-yldiphenylphosphine oxide (3d): yellow

oil (153 mg, yield = 48%, cyclohexane/ethyl acetate (80/20 to 50/

P{ H} NMR (162 MHz, CDCl ) δ 25.17; HR-MS (m/z) [M + H]

0)); H NMR (400 MHz, CDCl ) δ 8.58 (dt, J = 6.9, 1.4 Hz, 1H),

calcd for C19H N OP = 319.0995, found = 319.1006.

16 2

.74−7.61 (m, 5H), 7.59−7.49 (m, 2H), 7.49−7.40 (m, 4H), 7.38 (s,

Imidazo[1,2-a]pyridin-5-yldimethylphosphine oxide (5f): brown

H), 7.32−7.22 (m, 1H), 6.77 (tt, J = 6.8, 1.7 Hz, 1H); C{ H}

solid (666 mg, yield = 68% for 1.00 g of 5-bromoimidazo[1,2-

NMR (101 MHz, CDCl ) δ 149.7 (d, J = 9.5 Hz, C), 143.9 (d, J =

a]pyridine, cyclohexane/ethyl acetate (80/20 to 50/50)); H NMR

5.5 Hz, CH), 132.6 (d, J = 2.9 Hz, CH), 131.7 (d, J = 10.6 Hz, CH),

31.1 (d, J = 111.9 Hz, PC), 128.9 (d, J = 12.8 Hz, CH), 127.5 (s,

(400 MHz, CDCl ) δ 8.38 (t, J = 1.0 Hz, 1H), 7.80 (ddt, J = 8.9, 1.9,

1.0 Hz, 1H), 7.76 (d, J = 1.3 Hz, 1H), 7.21 (ddd, J = 9.1, 6.9, 2.5 Hz,

1H), 7.14 (ddd, J = 9.9, 6.9, 1.2 Hz, 1H), 1.94 (d, J = 13.3 Hz, 6H);

CH), 127.4 (s, CH), 118.0 (s, CH), 115.5 (d, J = 125.0 Hz, PC),

13.7 (s, CH); ³P{ H} NMR (162 MHz, CDCl ) δ 16.87; HR-MS

(

C{ H} NMR (101 MHz, CDCl ) δ 145.4 (d, J = 3.4 Hz, C), 134.7

m/z) [M + H]⁺calcd for C H N OP = 319.0995, found =

(s, CH), 131.8 (d, J = 101.8 Hz, PC), 122.8 (d, J = 10.4 Hz, CH),

121.6 (d, J = 2.4 Hz, CH), 117.7 (d, J = 11.6 Hz, CH), 113. Five (s,

19.1007.

Typical Procedure for the Preparation of 5-Phosphorylimidazo-

CH), 16.3 (d, J = 74.2 Hz, PCH ); P{ H} NMR (162 MHz,

[1,2-a]pyridines 5a−k. Under nitrogen atmosphere, a mixture of 5-

CDCl ) δ 31.02; MS (ESI+) m/z = [M + H] calcd for C H N OP

bromoimidazo[1,2-a]pyridine 1c (100 mg, 0.508 mmol), phosphorus

derivatives (2a−j) (0.462 mmol), Pd dba (42 mg, 0.046 mmol),

= 195.0682, found = 195.0688.

Ethyl imidazo[1,2-a]pyridin-5-yl(m-tolyl)phosphinate (5g):

xantphos (53 mg, 0.092 mmol), and triethylamine (129 μL, 0.924

mmol) in dry toluene (4.6 mL) was stirred at reﬂux. After completion

of the reaction indicated by TLC, the mixture was cooled to room

temperature, ﬁltered on Celite, washed with ethyl acetate (20 mL),

brown oil, (100 mg, yield = 72%, cyclohexane/ethyl acetate (80/20

to 50/50)); H NMR (400 MHz, CDCl ) δ 7.99 (t, J = 1.0 Hz, 1H),

7.70 (ddt, J = 9.1, 2.0, 1.0 Hz, 1H), 7.59−7.49 (m, 3H), 7.43 (ddd, J

= 10.0, 6.9, 1.2 Hz, 1H), 7.29−7.21 (m, 2H), 7.14 (ddd, J = 9.4, 6.9,

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

.7 Hz, 1H), 4.19 (ddq, J = 10.1, 8.1, 7.1 Hz, 1H), 4.07 (ddq, J = 10.0,

.8, 7.0 Hz, 1H), 2.25 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H); C{ H}

crude residue was then puriﬁed by ﬂash chromatography (silica gel,

cyclohexane/ethyl acetate 50/50) to give the desired products (6a−

j).

NMR (101 MHz, CDCl ) δ 145.2 (d, J = 1.6 Hz, C), 138.7 (d, J =

3.5 Hz, C), 134.9 (s, CH), 133.4 (d, J = 3.0 Hz, CH), 131.9 (d, J =

7.3 Hz, CH), 131.9 (d, J = 10.4 Hz, CH), 130.5 (d, J = 142.5 Hz),

28.7 (d, J = 14.2 Hz, CH), 128.5 (d, J = 10.0 Hz, CH), 124.4 (d, J =

.1 Hz, CH), 118.0 (d, J = 12.5 Hz, CH), 116.6 (d, J = 142.0 Hz,

Diethyl (2-phenylimidazo[1,2-a]pyridin-6-yl)phosphonate (6a):

orange oil (142 mg, yield = 100%, cyclohexane/ethyl acetate 50/50).

Large-scale synthesis was accomplished starting from imidazopyridine

1f (1.1 g, 3.66 mmol), diethyl phosphite 2a (429 μL, 3.33 mmol),

Pd dba (305 mg, 0.33 mmol), xantphos (385 mg, 0.667 mmol), and

PC), 113.4 (s, CH), 61.5 (d, J = 5.9 Hz, CH ), 21.3 (d, J = 0.9 Hz,

CH ), 16.5 (d, J = 6.5 Hz, CH ); P{ H} NMR (162 MHz, CDCl )

δ 22.63; MS (ESI+) m/z = [M + H] calcd for C H N O P =

triethylamine (928 μL, 6.67 mmol) in dry toluene (35 mL) aﬀording

1.11 g of 6a (yield = 100%): H NMR (400 MHz, CDCl ) δ 8.71

01.1106, found = 301.1114.

Ethyl imidazo[1,2-a]pyridin-5-yl(3-methoxyphenyl)phosphinate

5h): orange oil (102 mg, yield = 70%, cyclohexane/ethyl acetate (80/

(ddd, J = 11.2, 1.5, 1.0 Hz, 1H), 7.99−7.94 (m, 2H), 7.93 (d, J = 0.7

Hz, 1H), 7.72 (ddt, J = 9.2, J = 3.4, J = 0.9 Hz, 1H), 7.48−7.42 (m,

2H), 7.39−7.32 (m, 2H), 4.27−4.06 (m, 4H), 1.35 (td, J = 7.1, 0.6

(

0 to 50/50)); H NMR (400 MHz, CDCl ) δ 8.02 (dd, J = 1.3, 0.7

Hz, 6H); C{ H} NMR (101 MHz, CDCl ) δ 147.1 (s, C), 145.5 (d,

Hz, 1H), 7.72 (dddd, J = 9.1, 2.0, 1.2, 0.8 Hz, 1H), 7.58 (d, J = 1.3

Hz, 1H), 7.44 (ddd, J = 10.1, 6.9, 1.2 Hz, 1H), 7.33−7.27 (m, 3H),

J = 1.5 Hz, C), 132.8 (s, C), 131.9 (d, J = 19.8 Hz, CH), 129.0 (s,

CH), 128.8 (s, CH), 126.4 (s, CH), 125.3 (d, J = 7.2 Hz, CH), 117.7

(d, J = 13.9 Hz, CH), 113.74 (d, J = 198.0 Hz, PC), 108.9 (s, CH),

.16 (ddd, J = 9.0, 6.9, 2.8 Hz, 1H), 7.03−7.00 (m, 1H), 4.22 (ddq, J

10.1, 8.0, 7.1 Hz, 1H), 4.11 (ddq, J = 10.1, 7.9, 7.0 Hz, 1H), 3.72 (s,

62.8 (d, J = 5.4 Hz, CH ), 16.5 (d, J = 6.4 Hz, CH ); P{ H} NMR

2 3

(162 MHz, CDCl ) δ 16.28; HR-MS (m/z) [M + H] calcd for

H), 1.33 (td, J = 7.1, 0.4 Hz, 3H); C{ H} NMR (101 MHz,

CDCl ) δ 159.7 (d, J = 17.5 Hz, C), 145.2 (d, J = 4.4 Hz, C), 134.2

C H N O P = 331.1212, found = 331.1216.

17 20

(

s, CH), 130.2 (d, J = 16.5 Hz, CH), 129.1 (d, J = 145.1 Hz, PC),

Dibenzyl (2-phenylimidazo[1,2-a]pyridin-6-yl)phosphonate (6b):

29.0 (d, J = 146.9 Hz, PC), 123.6 (d, J = 10.5 Hz, CH), 122.7 (d, J =

1.2 Hz, CH), 121.8 (d, J = 2.7 Hz, CH), 121.4 (d, J = 11.0 Hz, CH),

19.1 (d, J = 3.0 Hz, CH), 116.5 (d, J = 12.1 Hz, CH), 113.5 (s, CH),

2.4 (d, J = 5.9 Hz, CH ), 55.4 (s, OCH ), 16.3 (d, J = 6.4 Hz, CH );

yellow solid (59 mg, yield = 36%, cyclohexane/ethyl acetate 50/50);

H NMR (400 MHz, CDCl ) δ 8.58 (dd, J = 11.4, 1.5, 1.0 Hz, 1H),

.97−7.94 (m, 2H), 7.85 (d, J = 0.6 Hz, 1H), 7.60 (ddt, J = 9.3, 3.6

Hz, 0.9 Hz, 1H), 7.48−7.42 (m, 2H), 7.40−7.27 (m, 2H), 5.15 (dd, J

= 11.7, 8.6 Hz, 1H), 5.10 (dd, J = 11.7, 8.2 Hz, 1H); C{ H} NMR

13 1

P{ H} NMR (162 MHz, CDCl ) δ 22.26; HR-MS (m/z) [M + H]

calcd for C H N O P = 317.1055, found = 317.1065.

(101 MHz, CDCl ) δ 147.5 (s, C), 145.7 (d, J = 1.6 Hz, C), 135.8 (d,

Ethyl (3-ﬂuorophenyl)(imidazo[1,2-a]pyridin-5-yl)phosphinate

J = 6.5 Hz, C), 133.2 (s, C), 132.0 (d, J = 20.2 Hz, CH), 129.0 (s,

CH), 128.8 (s, CH), 128.8 (s, CH), 128.7 (s, CH), 128.3 (s, CH),

126.4 (s, CH), 124.8 (d, J = 7.6 Hz, CH), 117.7 (d, J = 14.3 Hz, CH),

(

5i): brown oil (99 mg, yield = 72%, cyclohexane/ethyl acetate (80/

0 to 50/50)); H NMR (400 MHz, CDCl ) δ 7.99 (dd, J = 1.3, 0.7

Hz, 1H), 7.74 (dddd, J = 9.1, 2.0, 1.2, 0.8 Hz, 1H), 7.59 (d, J = 1.3

Hz, 1H), 7.53 (ddt, J = 12.8, 7.6, 1.2 Hz, 1H), 7.48 (ddd, J = 9.9, 6.8,

13.1 (d, J = 200.6 Hz, PC), 108.9 (s, CH), 68.3 (d, J = 5.3 Hz,

CH ); P{ H} NMR (162 MHz, CDCl ) δ 17.49; HR-MS (m/z) [M

.2 Hz, 1H), 7.50−7.43 (m, 1H), 7.38 (ddddd, J = 8.1, 7.5, 5.1, 4.6,

.4 Hz, 1H), 7.21−7.14 (m, 2H), 4.24 (ddq, J = 10.1, 8.0, 7.1 Hz,

H), 4.12 (ddq, J = 10.1, 8.0, 7.0 Hz, 1H), 1.34 (td, J = 7.0, 0.4 Hz,

H] calcd for C H N O P = 455.1525, found = 455.1526.

27 24 2 3

Diisopropyl (2-phenylimidazo[1,2-a]pyridin-6-yl)phosphonate

(6c): brown solid (118 mg, yield = 90%, cyclohexane/ethyl acetate

H); ¹³C{ H} NMR (101 MHz, CDCl ) δ 162.5 (dd, J = 251.1, 19.7

50/50); H NMR (400 MHz, CDCl ) δ 8.70 (ddd, J = 11.2, 1.5, J =

Hz, CF), 145.1 (s, C), 134.4 (s, CH), 131.4 (dd, J = 145.9, 5.9 Hz,

PC), 131.02 (dd, J = 16.3, 7.5 Hz, CH), 128.4 (d, J = 148.5 Hz, PC),

1.0 Hz, 1H), 7.99−7.93 (m, 2H), 7.91 (d, J = 0.7 Hz, 1H), 7.66 (ddt,

J = 9.2, J = 3.4, J = 0.9 Hz, 1H), 7.49−7.42 (m, 2H), 7.39−7.30 (m,

2H), 4.73 (dhept, J = 8.0, 6.2 Hz, 2H), 1.41 (d, J = 6.2 Hz, 6H), 1.26

27.2 (dd, J = 10.3, 3.3 Hz, CH), 122.6 (d, J = 11.2 Hz, CH), 122.1

(

d, J = 2.7 Hz, CH), 121.7 (d, J = 10.8 Hz, CH), 120.5 (dd, J = 21.1,

(d, J = 6.2 Hz, 6H); C{ H} NMR (101 MHz, CDCl ) δ 147.4 (s,

.9 Hz, CH), 118.28 (dd, J = 22.6, 11.4 Hz, CH), 113.35 (s, CH),

C), 145.7 (d, J = 1.6 Hz, C), 133.2 (s, C), 131.7 (d, J = 19.9 Hz, CH),

129.0 (s, CH), 128.6 (s, CH), 126.3 (s, CH), 125.2 (d, J = 7.3 Hz,

CH), 117.7 (d, J = 13.8 Hz, CH), 114.8 (d, J = 198.5 Hz, PC), 108.9

2.70 (d, J = 5.9 Hz, CH ), 16.29 (d, J = 6.3 Hz, CH ); P{ H}

NMR (162 MHz, CDCl ) δ 20.34 (d, J = 7.4 Hz); MS (ESI+) m/z =

[

M + H] ⁺calcd for C H FN O P = 305.0855, found = 305.0866.

Ethyl imidazo[1,2-a]pyridin-5-yl(3-(triﬂuoromethyl)phenyl)-

(s, CH), 71.6 (d, J = 5.5 Hz, CH), 24.2 (d, J = 4.0 Hz, CH ), 24.0 (d,

J = 4.9 Hz, CH ); P{ H} NMR (162 MHz, CDCl ) δ 14.17; HR-

MS (m/z) [M + H] calcd for C H N O P = 359.1525, found =

19 24 2 3

phosphinate (5j): brown oil (125 mg, yield = 76%, cyclohexane/

ethyl acetate (80/20 to 50/50)); H NMR (400 MHz, CDCl ) δ 8.07

359.1528.

(

d, J = 13.1 Hz, 1H), 8.02 (s, 1H), 7.92 (dd, J = 12.8, 7.7 Hz, 1H),

.79−7.72 (m, 2H), 7.60 (d, J = 1.3 Hz, 1H), 7.54 (td, J = 7.8, 3.4 Hz,

H), 7.50 (ddd, J = 10.1, 6.9, 1.2 Hz, 1H), 7.19 (ddd, J = 9.0, 6.9, 2.9

Di-tert-butyl (2-phenylimidazo[1,2-a]pyridin-6-yl)phosphonate

(6d): orange oil (135 mg, yield = 89%, cyclohexane/ethyl acetate

50/50); H NMR (400 MHz, CDCl ) δ 8.65 (ddd, J = 11.4, 1.5, 1.0

Hz, 1H), 4.27 (ddq, J = 10.1, 8.1, 7.1 Hz, 1H), 4.16 (ddq, J = 10.1,

Hz, 1H), 7.97−7.94 (m, 2H), 7.90 (d, J = 0.7 Hz, 1H), 7.63 (ddt, J =

.1, 7.0 Hz, 1H), 1.36 (td, J = 7.1, 0.4 Hz, 3H); C{ H} NMR (101

MHz, CDCl ) δ 145.2 (d, J = 4.1 Hz, C), 134.7 (dq, J = 10.9, 1.3 Hz,

9.2, 3.3, 0.9 Hz, 1H), 7.47−7.42 (m, 2H), 7.37−7.30 (m, 2H), 1.50

(d, J = 0.4 Hz, 18H); C{ H} NMR (101 MHz, CDCl ) δ 147.1 (s,

CH), 134.55 (s, CH), 131.5 (qd, J = 33.0, 14.2 Hz, C), 130.51 (d, J =

C), 145.7 (d, J = 1.5 Hz, C), 133.4 (s, C), 130.9 (d, J = 20.7 Hz, CH),

128.9 (s, CH), 128.4 (s, CH), 126.3 (s, CH), 125.7 (d, J = 6.6 Hz,

CH), 118.7 (d, J = 203.2 Hz, PC), 117.3 (d, J = 13.8 Hz, CH), 108.9

46.6 Hz, PC), 129.88 (qd, J = 3.4, 3.4 Hz, CH), 129.60 (d, J = 13.8

Hz, CH), 128.25 (dq, J = 11.5, 3.8 Hz, CH), 128.14 (d, J = 148.9 Hz,

PC), 127.4 (qd, J = 272.9, 2.2 Hz, CF ), 122.67 (d, J = 11.3 Hz, CH),

(s, CH), 83.5 (d, J = 7.7 Hz, C), 30.6 (d, J = 4.1 Hz, CH ); P{ H}

22.30 (d, J = 2.7 Hz, CH), 121.90 (d, J = 11.0 Hz, CH), 113.27 (s,

NMR (162 MHz, CDCl ) δ 7.10; HR-MS (m/z) [M + H] calcd for

CH), 62.94 (d, J = 5.9 Hz, CH ), 16.30 (d, J = 6.3 Hz, CH ); P{ H}

NMR (162 MHz, CDCl ) δ 20.13; MS (ESI+) m/z = [M + H] calcd

C H N O P = 387.1838, found = 387.1834.

21 28

Diphenyl (2-phenylimidazo[1,2-a]pyridin-6-yl)phosphine oxide

(6e): yellow powder (115 mg, yield = 80%, cyclohexane/ethyl acetate

50/50). Large-scale synthesis was accomplished starting from

imidazopyridine 1f (2.00 g, 7.32 mmol), diphenylphosphine oxide

2b (673 mg, 6.67 mmol), Pd dba (606 mg, 0.667 mmol), xantphos

for C H F N O P = 355.0823, found = 355.0829.

Typical Procedure for the Preparation of 6-Phosphoryl-2-

phenylimidazo[1,2-a]pyridines 6a−j. Under nitrogen atmosphere,

a mixture of 6-bromo-2-phenylimidazo[1,2-a]pyridine 1f (110 mg,

.403 mmol), P−H derivatives (2a−j) (0.366 mmol), Pd dba (34

(772 mg, 1.33 mmol), and triethylamine (1.90 mL, 13.3 mmol) in dry

toluene (50 mL) aﬀording 2.44 g of 6e (yield = 93%): H NMR (400

mg, 0.037 mmol), xantphos (42 mg, 0.073 mmol), and triethylamine

102 μL, 0.732 mmol) in dry toluene (3.6 mL) was stirred at reﬂux.

(

MHz, CDCl ) δ 8.64 (ddd, J = 9.9, 1.6 Hz, 1.0 Hz, 1H), 7.97−7.92

After completion of the reaction indicated by TLC, the mixture was

cooled to room temperature, ﬁltered on Celite, and washed with ethyl

acetate (20 mL), and the ﬁltrate was concentrated under vacuum. The

(m, 2H), 7.90 (d, J = 0.7 Hz, 1H), 7.76−7.70 (m, 4H), 7.65 (ddt, J =

9.3, 2.6, 0.9 Hz, 1H), 7.63−7.58 (m, 2H), 7.54−7.49 (m, 4H), 7.47−

7.42 (m, 2H), 7.37−7.33 (m, 1H), 7.16 (td, J = 9.0, 1.6 Hz, 1H);

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

C{ H} NMR (101 MHz, CDCl ) δ 147.6 (s, C), 145.5 (d, J = 1.4

cyclohexane/ethyl acetate 50/50); H NMR (400 MHz, CDCl ) δ

Hz, C), 133.2 (s, C), 132.7 (d, J = 2.8 Hz, CH), 132.1 (d, J = 10.2 Hz,

CH), 131.8 (d, J = 15.8 Hz, CH), 131.7 (d, J = 107.3 Hz, PC), 129.0

8.81 (ddd, J = 10.2, 1.5, 1.0 Hz, 1H), 8.13 (dddt, J = 12.7, 2.1, 1.4, 0.7

Hz, 1H), 8.07−7.98 (m, 1H), 7.98−7.93 (m, 3H), 7.82 (ddtd, J = 7.9,

1.9, 1.2, 0.6 Hz, 1H), 7.70−7.60 (m, 2H), 7.49−7.41 (m, 2H), 7.40−

7.33 (m, 1H), 7.25 (td, J = 9.3, 1.5 Hz, 1H), 4.30−4.11 (m, 2H), 1.43

(

d, J = 12,4 Hz, CH), 129.0 (s, CH), 128.6 (s, CH), 126.4 (s, CH),

25.2 (d, J = 9.3 Hz, CH), 117.6 (d, J = 11.8 Hz, CH), 117.3 (d, J =

08.2 Hz, PC), 109.1 (s, CH); P{ H} NMR (162 MHz, CDCl ) δ

(td, J = 7.1, 0.3 Hz, 3H); C{ H} NMR (101 MHz, CDCl ) δ 147.

6.84; HR-MS (m/z) [M + H] calcd for C H N OP = 395.1313,

Eight (s, C), 145.6 (d, J = 1.5 Hz, C), 134.8 (d, J = 10.1 Hz, CH),

133.1 (s, C), 132.7 (d, J = 143.8 Hz, PC), 132.1 (d, J = 17.5 Hz, CH),

131.5 (dd, J = 33.1, 13.9 Hz, C), 129.6 (d, J = 13.3 Hz, CH), 129.4

(quint, J = 3.3, 3.3 Hz, CH), 129.0 (s, CH), 128.7 (s, CH), 128.4 (dq,

J = 11.0, 3.6 Hz, CH), 126.4 (s, CH), 124.3 (d, J = 9.1 Hz, CH),

118.1 (d, J = 12.7 Hz, CH), 115.5 (d, J = 144.5 Hz, PC), 109.1 (s,

found = 395.1317.

Dimethyl (2-phenylimidazo[1,2-a]pyridin-6-yl)phosphine oxide

(

6f): green powder (25 mg, yield = 21%, cyclohexane/ethyl acetate

0/50); H NMR (400 MHz, CDCl ) δ 8.75 (dt, J = 9.9, 1.3 Hz,

H), 7.97−7.91 (m, 3H), 7.66 (dd, J = 9.5, 2.4 Hz, 1H), 7.45−7.38

m, 2H), 7.36−7.30 (m, 1H), 7.11 (td, J = 9.0, 1.5 Hz, 1H), 1.76 (d, J

CH), 62.2 (d, J = 5.9 Hz, CH

NMR (162 MHz, CDCl ) δ 26.91 (q, J = 1.0 Hz); HR-MS (m/z) [M

P = 431.1136, found = 431.1137.

), 16.7 (d, J = 6.5 Hz, CH ); P{ H}

13.2 Hz, 6H); ¹³C{ H} NMR (101 MHz, CDCl ) δ 147.3 (s, C),

45.4 (d, J = 1.3 Hz, C), 133.1 (s, C), 130.5 (d, J = 14.3 Hz, CH),

28.9 (s, CH), 128.5 (s, CH), 126.3 (s, CH), 122.9 (d, J = 10.5 Hz,

+ H] calcd for C22H F N O

19 3 2 2

Typical Procedure for the Preparation of 6-Phosphorylimidazo-

[

1,2-a]pyridines 6k−t. Under nitrogen atmosphere, a mixture of 6-

CH), 118.9 (d, J = 102.2 Hz, PC), 117.9 (d, J = 11.7 Hz, CH), 109.2

bromoimidazo[1,2-a]pyridine (1e) (100 mg, 0.508 mmol), phospho-

(

s, CH), 18.2(d, J = 73.0 Hz, CH ); P{ H} NMR (162 MHz,

rus derivatives (2a−j) (0.462 mmol), Pd dba (42 mg, 0.046 mmol),

CDCl ) δ 33.82; HR-MS (m/z) nd.

xantphos (53 mg, 0.092 mmol), and triethylamine (129 μL, 0.924

mmol) in dry toluene (4.6 mL) was stirred at reﬂux. After completion

of the reaction indicated by TLC, the mixture was cooled to room

temperature, ﬁltered on Celite, and washed with ethyl acetate (20

mL), and the ﬁltrate was concentrated under vacuum. The crude

residue was then puriﬁed by ﬂash chromatography (silica gel,

dichloromethane/(dichloromethane/MeOH 10%) (90/10 to 70/

30)) to give the desired products (6k-t).

Diethyl imidazo[1,2-a]pyridin-6-ylphosphonate (6k): brown oil

(82 mg, yield = 70%, dichloromethane/(dichloromethane 90/MeOH

10) (90/10 to 70/30)). Large-scale synthesis was accomplished

starting from imidazopyridine 1e (1.00 g, 5.08 mmol), diethyl

Ethyl (2-phenylimidazo[1,2-a]pyridin-6-yl)(m-tolyl)phosphinate

(

6g): orange solid (111 mg, yield = 80%, cyclohexane/ethyl acetate

0/50); H NMR (400 MHz, CDCl ) δ 8.76 (dt, J = 10.0, 1.3 Hz,

H), 7.97−7.93 (m, 2H), 7.92 (d, J = 0.5 Hz, 1H), 7.71−7.59 (m,

H), 7.47−7.41 (m, 2H), 7.39−7.32 (m, 3H), 7.29 (td, J = 9.2, J = 1.5

Hz, 1H), 4.27−4.07 (m, 2H), 2.39 (d, J = 0.7 Hz, 3H), 1.41 (t, J = 7.1

Hz, 3H); ¹³C{ H} NMR (101 MHz, CDCl ) δ 147.5 (s, C), 145.6 (d,

J = 1.4 Hz, C), 138. Nine (d, J = 13.5 Hz, C), 133.6 (d, J = 3.0 Hz,

CH), 133.2 (s, C), 132.1 (d, J = 10.3 Hz, CH), 131.7 (d, J = 17.4 Hz,

CH), 130.6 (d, J = 142.6 Hz, PC), 128.9 (s, CH), 128.8 (d, J = 14.2

Hz, CH), 128.6 (d, J = 10.1 Hz, CH), 128.6 (s, CH), 126.3 (s, CH),

24.9 (d, J = 9.0 Hz, CH), 117.8 (d, J = 12.6 Hz, CH), 116.7 (d, J =

42.0 Hz, PC), 109.0 (s, CH), 61.7 (d, J = 5.8 Hz, CH ), 21.5 (s,

phosphite 2a (595 μL, 4.62 mmol), Pd dba (211 mg, 0.231 mmol),

2 3

CH ), 16.7 (d, J = 6.7 Hz, CH ); P{ H} NMR (162 MHz, CDCl )

xantphos (267 mg, 0.462 mmol), and triethylamine (1.30 mL, 9.24

δ 29.22; HR-MS (m/z) [M + H] calcd for C H N O P =

mmol) in dry toluene (50 mL) aﬀording 1.19 g of 6k (yield = 100%):

77.1419, found = 377.1422.

H NMR (400 MHz, CDCl ) δ 8.66 (ddd, J = 11.3, 1.5, 1.0 Hz, 1H),

Ethyl (3-methoxyphenyl)(2-phenylimidazo[1,2-a]pyridin-6-yl)-

7.63−7.54 (m, 3H), 7.24 (ddd, J = 10.1, 9.2, J = 1.5 Hz, 1H), 4.16−

13 1

phosphinate (6h): orange oil (128 mg, yield = 89%, cyclohexane/

3.96 (m, 4H), 1.25 (td, J = 7.1, 0.6 Hz, 6H); C{ H} NMR (101

ethyl acetate 50/50); H NMR (400 MHz, CDCl ) δ 8.75 (ddd, J =

MHz, CDCl ) δ 145.3 (s, CH), 134.9 (s, CH), 132.1 (d, J = 19.7 Hz,

0.1, 1.5, 1.0 Hz, 1H), 7.97−7.93 (m, 2H), 7.92 (d, J = 0.7 Hz, 1H),

.64 (ddt, J = 9.2, 3.1, 0.9 Hz, 1H), 7.47−7.32 (m, 6H), 7.29 (td, J =

.3, 1.5 Hz, 1H), 7.11−7.06 (m, 1H), 4.23−4.09 (m, 2H), 3.84 (s,

CH), 124.4 (d, J = 7.6 Hz, CH), 118.0 (d, J = 14.0 Hz, CH), 113.3 (s,

CH), 113.2 (d, J = 198.3 Hz, PC), 62.5 (d, J = 5.4 Hz, CH ), 16.3 (d,

J = 6.5 Hz, CH ); P{ H} NMR (162 MHz, CDCl ) δ 16.44; HR-

MS (m/z) [M + H] calcd for C H N O P = 255.0899, found =

H), 1.41 (t, J = 7.1 Hz, 3H); C{ H} NMR (101 MHz, CDCl ) δ

11 16 2 3

59.8 (d, J = 16.9 Hz, C), 147.5, 145.6 (d, J = 1.5 Hz, C), 133.2 (s,

255.0904.

Diisopropyl imidazo[1,2-a]pyridin-6-ylphosphonate (6m): brown

oil (122 mg, yield = 94%, dichloromethane/(dichloromethane 90/

MeOH 10) (90/10 to 70/30)); H NMR (400 MHz, DMSO-d ) δ

9.04 (dt, J = 11.3, 1.3 Hz, 1H), 8.13 (s, 1H), 7.69−7.66 (m, 2H), 7.27

(td, J = 9.6, 1.6 Hz, 1H), 4.59 (dhept, J = 8.0 Hz, 6.1 Hz, 2H), 1.29

(d, J = 6.2 Hz, 6H), 1.17 (d, J = 6.2 Hz, 6H); C{ H} NMR (101

MHz, DMSO-d ) δ 144.3 (s, C), 134.3 (s, CH), 132.7 (d, J = 20.5 Hz,

93.1368, found = 393.1372.

Ethyl (3-ﬂuorophenyl)(2-phenylimidazo[1,2-a]pyridin-6-yl)-

CH), 124.2 (d, J = 7.9 Hz, CH), 117.2 (d, J = 14.0 Hz, CH), 114.4 (s,

CH), 113.6 (d, J = 196.9 Hz, C), 70.6 (d, J = 5.5 Hz, CH), 23.7 (d, J

phosphinate (6i): brown oil (106 mg, yield = 76%, cyclohexane/

ethyl acetate 50/50); H NMR (400 MHz, CDCl ) δ 8.78 (ddd, J =

= 4.0 Hz, CH ), 23.5 (d, J = 4.9 Hz, CH ); P{ H} NMR (162 MHz,

3 3

DMSO-d ) δ 14.38; HR-MS (m/z) [M + H]

calcd for

0.1, 1.5, 1.0 Hz, 1H), 7.97−7.94 (m, 2H), 7.93 (d, J = 0.7 Hz, 1H),

.68−7.59 (m, 2H), 7.56 (dddd, J = 13.6, 8.4, 2.7, 1.2 Hz, 1H), 7.51−

.42 (m, 3H), 7.38−7.33 (m, 1H), 7.29−7.22 (m, 3H), 4.25−4.10

C H N O P = 283.1212, found = 283.1218.

Di-tert-butyl imidazo[1,2-a]pyridin-6-ylphosphonate (6n):

brown oil (75 mg, yield = 50%, dichloromethane/(dichloromethane

(

m, 2H), 1.42 (t, J = 7.1 Hz, 3H); C{ H} NMR (101 MHz, CDCl )

90/MeOH 10) (90/10 to 70/30)); H NMR (400 MHz, CDCl ) δ

8.64 (d, J = 11.5 Hz, 1H), 7.66 (s, 1H), 7.64−7.58 (m, 2H), 7.31 (td,

J = 10.4, 1.5 Hz, 1H), 1.47 (s, 18H); C{ H} NMR (101 MHz,

CDCl ) δ 145.4 (s, C), 134.7 (s, CH), 131.1 (d, J = 20.7 Hz, CH),

125.4 (d, J = 6.6 Hz, CH), 118.4 (d, J = 202.6 Hz, PC), 117.7 (d, J =

13.8 Hz, CH), 113.3 (s, CH), 83.4 (d, J = 7.8 Hz, C), 30.5 (d, J = 4.1

Hz, CH ); P{ H} NMR (162 MHz, CDCl ) δ 7.05; HR-MS (m/z)

[M + H] calcd for C H N O P = 311.1519, found = 311.1526

15 24 2 3

Imidazo[1,2-a]pyridin-6-yldiphenylphosphine oxide (6o): Large-

scale synthesis was accomplished starting from imidazopyridine 1e

(500 mg, 2.54 mmol), diphenylphosphine oxide 2b (467 mg, 2.31

mmol), Pd dba (212 mg, 0.231 mmol), xantphos (267 mg, 0.462

2 3

mmol), and triethylamine (0.644 mL, 4.62 mmol) in dry toluene (25

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

mL) aﬀording an orange powder (667 mg, yield = 91%, dichloro-

methane/(dichloromethane 90/MeOH 10) (90/10 to 70/30)): H

NMR (400 MHz, CDCl ) δ 8.79 (dt, J = 10.2, 1.3 Hz, 1H), 8.04 (d, J

= 12.6 Hz, 1H), 7.93 (dd, J = 12.2, 7.6 Hz, 1H), 7.74−7.60 (m, 3H),

NMR (400 MHz, CDCl ) δ 8.65 (ddd, J = 10.0, 1.6, 1.0 Hz, 1H),

7.60−7.51 (m, 2H), 7.18 (td, J = 9.3, 1.6 Hz, 1H), 4.19−4.00 (m,

.75−7.67 (m, 5H), 7.67−7.62 (m, 2H), 7.62−7.56 (m, 2H), 7.53−

2H), 1.33 (t, J = 7.1 Hz, 3H); C{ H} NMR (101 MHz, CDCl ) δ

.47 (m, 4H), 7.15 (ddd, J = 9.4, 8.7, 1.6 Hz, 1H); C{ H} NMR

145.1 (d, J = 1.4 Hz, C), z135.1 (s, CH), 134.6 (dq, J = 10.2, 1.3 Hz,

CH), 132.5 (d, J = 143.5 Hz, PC), 132.4 (d, J = 17.5 Hz, CH), 131.2

(qd, J = 33.0, 13.9 Hz, C), 129.4 (d, J = 13.2 Hz, CH), 129.2 (qd, J =

3.5, 2.7 Hz, CH), 128.1 (dq, J = 11.3, 3.8 Hz, CH), 123.8 (d, J = 9.3

(

101 MHz, CDCl ) δ 145.3 (d, J = 1.4 Hz, C), 135.3 (s, CH), 132.7

d, J = 2.8 Hz, CH), 132.2 (s, CH), 132.1 (d, J = 10.2 Hz, CH), 131.7

s, J = 12.4 Hz, PC), 129.0 (d, J = 12.4 Hz, CH), 124.9 (d, J = 9.4 Hz,

CH), 118.1 (d, J = 11.8 Hz, CH), 117.4 (d, J = 107.9 Hz, PC), 113.6

Hz, CH), 123.4 (qd, J = 272.8, 2.1 Hz, CF ), 118.3 (d, J = 12.7 Hz,

s, CH); ³¹P{ H} NMR (162 MHz, CDCl ) δ 26.74; MS (ESI+) m/z

CH), 115.4 (d, J = 144.5 Hz, PC), 113.6 (s, CH), 62.0 (d, J = 5.9 Hz,

(

[M + H] ⁺calcd for C H N OP = 319.1000, found = 319.1006.

CH ), 16.4 (d, J = 6.4 Hz, CH ); P{ H} NMR (162 MHz, CDCl )

Imidazo[1,2-a]pyridin-6-yldimethylphosphine oxide (6p): brown

δ 26.86 (q, J = 1.0 Hz); HR-MS (m/z) [M + H] calcd for C H

16 15

powder (360 mg, yield = 77% for 500 mg of 6-bromoimidazo[1,2-

F N O P = 355.0823, found = 355.0835.

3 2 2

Typical Procedure for the Phosphorylation of 5-Bromo- and 6-

Bromoimidazo[1,2-a]pyridine Derivatives 1d,g,h. Under nitrogen

atmosphere, a mixture of bromoimidazo[1,2-a]pyridine derivatives

(1d,g,h) (1.10 mmol), diphenylphosphine oxide (1.00 mmol),

Pd dba (92 mg, 0.1 mmol), xantphos (116 mg, 0.2 mmol), and

2 3

22.4 (d, J = 10.6 Hz, CH), 118.8 (d, J = 101.7 Hz, PC), 118. Six (d, J

triethylamine (280 μL, 2.00 mmol) in dry toluene (10 mL) was

stirred at reﬂux. After completion of the reaction indicated by TLC,

the mixture was cooled to room temperature, ﬁltered on Celite,

washed with ethyl acetate (50 mL), and concentrated under vacuum.

The crude residue was then puriﬁed by ﬂash chromatography (silica

gel, ethyl acetate 100%) to give the desired product (5k, 6u, 6v).

11.6 Hz, CH), 113.6 (s, CH), 18.2 (d, J = 73.1 Hz, CH ); P{ H}

NMR (162 MHz, CDCl ) δ 32.88; MS (ESI+) m/z = [M + H] calcd

for C H N OP = 195.0687, found = 195.0690.

Ethyl imidazo[1,2-a]pyridin-6-yl(m-tolyl)phosphinate (6q): or-

ange oil (138 mg, yield = 99%, dichloromethane/(dichloromethane

0/MeOH 10) (90/10 to 70/30)); H NMR (400 MHz, CDCl ) δ

(2-Methylimidazo[1,2-a]pyridin-5-yl)diphenylphosphine oxide

(

5k): beige powder (214 mg, yield = 30%, ethyl acetate 100%); H

.73 (dt, J = 10.1, 1.3 Hz, 1H), 7.63−7.50 (m, 5H), 7.33−7.24 (m,

NMR (400 MHz, CDCl ) δ 7.89 (bs, 1H), 7.73−7.65 (m, 5H), 7.65−

H), 7.22 (td, J = 9.2, 1.5 Hz, 1H), 4.16−3.97 (m, 2H), 2.29 (s, 3H),

.59 (m, 2H), 7.55−7.45 (m, 4H), 7.03 (ddd, J = 9.0, 7.0, 2.5 Hz,

.32 (t, J = 7.1 Hz, 3H); C{ H} NMR (101 MHz, CDCl ) δ 145.1

H), 6.55 (ddd, J = 10.6, 7.0, 1.2 Hz, 1H), 2.36 (d, J = 0.9 Hz, 3H);

(

d, J = 1.2 Hz, C), 138.6 (d, J = 13.5 Hz, C), 134.8 (s, CH), 133.4 (d,

J = 3.0 Hz, CH), 131.9 (d, J = 17.1 Hz, CH), 131.8 (d, J = 10.5 Hz,

CH), 130.4 (d, J = 142.5 Hz, PC), 128.6 (d, J = 14.2 Hz, CH), 128.4

C{ H} NMR (101 MHz, CDCl

) δ 144.7 (d, J = 3.6 Hz, C), 144.5

(s, C), 133.1 (d, J = 2.9 Hz, CH), 132.1 (d, J = 10.3 Hz, CH), 129.3

(d, J = 109.9 Hz, PC), 129.2 (d, J = 109.3 Hz, PC), 129.2 (d, J = 12.7

Hz, CH), 121.9 (d, J = 11.1 Hz, CH), 121.1 (d, J = 12.9 Hz, CH),

(

d, J = 10.1 Hz, CH), 124.3 (d, J = 9.0 Hz, CH), 117.9 (d, J = 12.5

Hz, CH), 116.5 (d, J = 142.0 Hz, PC), 113.4 (s, CH), 61.4 (d, J = 5.8

Hz, CH ), 21.3 (s, CH ), 16.4 (d, J = 6.5 Hz, CH ); P{ H} NMR

120.5 (d, J = 2.4 Hz, CH), 111.8 (s, CH), 14.5 (s, CH ); P{ H}

(

162 MHz, CDCl ) δ 29.16; MS (ESI+) m/z = [M + H] calcd for

NMR (162 MHz, CDCl

OP = 333.1151, found = 333.1168.

(2-(2,5-Dimethoxyphenyl)imidazo[1,2-a]pyridin-6-yl)-

diphenylphosphine oxide (6u): yellow powder (344 mg, yield = 76%,

) δ 25.46; HR-MS (m/z) [M + H] calcd for

C H N O P = 301.1106, found = 301.1117

C H N

20 18 2

Ethyl imidazo[1,2-a]pyridin-6-yl(3-methoxyphenyl)phosphinate

(

6r): green oil (45 mg, yield = 31%, dichloromethane/(dichloro-

methane 90/MeOH 10) (90/10 to 70/30)); H NMR (400 MHz,

ethyl acetate 100%); H NMR (400 MHz, CDCl ) δ 8.55 (ddd, J =

10.0, 1.6, 1.0 Hz, 1H), 8.24 (d, J = 0.8 Hz, 1H), 7.95 (d, J = 3.0 Hz,

1H), 7.77−7.68 (m, 4H), 7.63 (ddt, J = 9.3, 2.6, 0.9 Hz, 1H), 7.61−

7.56 (m, 2H), 7.55−7.47 (m, 4H), 7.17 (td, J = 9.1, 1.6 Hz, 1H), 6.93

(d, J = 8.9 Hz, 1H), 6.87 (dd, J = 8.9, 3.1 Hz, 1H), 3.92 (s, 3H), 3.87

.60 (ddt, J = 9.2, 3.0, 0.9 Hz, 1H), 7.39−7.29 (m, 3H), 7.25 (td, J =

(s, 3H); C{ H} NMR (101 MHz, CDCl ) δ 154.1 (s, C), 151.5 (s,

C), 144.2 (d, J = 1.4 Hz, C), 142.8 (s, C), 132.6 (d, J = 2.8 Hz, CH),

132.1 (d, J = 10.2 Hz, CH), 131.8 (d, J = 16.5 Hz, CH), 131.7 (d, J =

107.1 Hz, PC), 128.9 (d, J = 12.4 Hz, CH), 125.0 (d, J = 9.1 Hz,

CH), 122.5 (s, C), 117.3 (d, J = 11.8 Hz, CH), 116.9 (d, J = 108.9

Hz, PC), 115.5 (s, CH), 113.6 (s, CH), 113.3 (s, CH), 112.4 (s, CH),

56.1 (s, 2 OCH

); P{ H} NMR (162 MHz, CDCl

) δ 26.99; HR-

MS (m/z) [M + H] calcd for C27H N O P = 455.1519, found

24 2 3

Ethyl (3-ﬂuorophenyl)(imidazo[1,2-a]pyridin-6-yl)phosphinate

455.1534.

(

6s): green oil (118 mg, yield = 86%, dichloromethane/(dichloro-

(2-Methylimidazo[1,2-a]pyridin-6-yl)diphenylphosphine oxide

(6v): brown powder (710 mg, yield = 99%, ethyl acetate 100%); H

methane 90/MeOH 10) (90/10 to 70/30)); H NMR (400 MHz,

CDCl ) δ 8.76 (ddd, J = 10.2, 1.6, 1.0 Hz, 1H), 7.63 (bs, 2H), 7.60−

NMR (400 MHz, CDCl ) δ 8.54 (ddd, J = 10.0, 1.6 Hz, 1.0 Hz, 1H),

.51 (m, 2H), 7.51−7.43 (m, 1H), 7.50−7.43 (m, 1H), 7.19 (td, J =

7.74−7.66 (m, 4H), 7.62−7.55 (m, 2H), 7.55−7.46 (m, 5H), 7.39−

.2, 1.5 Hz, 1H), 7.19−7.12 (m, 1H), 4.17−3.99 (m, 2H), 1.33 (td, J

7.36 (m, 1H), 7.09 (td, J = 9.0, 1.6 Hz, 1H), 2.46 (d, J = 0.9 Hz, 3H);

7.0, 0.3 Hz, 3H); ¹³C{ H} NMR (101 MHz, CDCl ) δ 162.5 (dd, J

C{ H} NMR (101 MHz, CDCl ) δ 145.2 (s, C), 144.8 (d, J = 1.3

250.5, 19.0 Hz, C), 145.1 (s, C), 135.1 (s, CH), 133.4 (dd, J =

Hz, C), 132.6 (d, J = 2.8 Hz, CH), 132.0 (d, J = 10.2 Hz, CH), 131.6

(d, J = 155.8 Hz, PC), 131.3 (d, J = 16.0 Hz, CH), 128.9 (d, J = 12.4

Hz, CH), 124.6 (d, J = 9.5 Hz, CH), 116.8 (d, J = 11.9 Hz, CH),

42.7, 5.8 Hz, PC), 132.2 (d, J = 17.4 Hz, CH), 130.8 (dd, J = 15.8,

.4 Hz, CH), 127.1 (dd, J = 9.7, 3.3 Hz, CH), 124.0 (d, J = 9.2 Hz,

CH), 119.7 (dd, J = 21.1, 2.8 Hz, CH), 118.2 (dd, J = 22.3, 10.9 Hz,

CH), 118.2 (d, J = 12.7 Hz, CH), 115.7 (d, J = 144.3 Hz, PC), 113.5

116.4 (d, J = 109.0 Hz, PC), 110.6 (s, CH), 14.4 (s, CH ); P{ H}

NMR (162 MHz, CDCl ) δ 26.99; HR-MS (m/z) [M + H] calcd for

(

s, CH), 61.8 (d, J = 5.9 Hz, CH ), 16.4 (d, J = 6.5 Hz, CH );

C H N OP = 333.1151, found = 333.1164.

20 18

P{ H} NMR (162 MHz, CDCl ) δ 27.09 (d, J = 7.1 Hz); MS (ESI

Typical Procedure for the Arylation of Imidazo[1,2-a]pyridine

Derivatives. Method A. In a Schlenk ﬂask under nitrogen

atmosphere, a mixture of imidazo[1,2-a]pyridine derivative 7 or 6

(100−500 mg, 1−1.5 equiv), aryl bromide derivatives 8a−f (1 equiv),

) m/z = [M + H] calcd for C H FN O P = 305.0855, found =

05.0862.

Ethyl imidazo[1,2-a]pyridin-6-yl(3-(triﬂuoromethyl)phenyl)-

phosphinate (6t): green oil (153 mg, yield = 93%, dichloro-

methane/(dichloromethane 90/MeOH 10) (90/10 to 70/30)); H

KOAc (2 equiv), and Pd(OAc) (2.5−10 mol %) in dry DMAc (0.1

M) was stirred at 140 or 160 °C. After completion of the reaction

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

indicated by TLC or ³¹P NMR, the mixture was cooled to room

temperature. Water was added, and the solution was extracted three

times with dichloromethane. The combined organic layers were dried

over magnesium sulfate, ﬁltered, and concentrated under vacuum.

The crude residue was puriﬁed by ﬂash chromatography. Method B.

A mixture of imidazo[1,2-a]pyridine derivative 7 or 6 (100−500 mg,

3-(naphthalen-1-yl)-2-phenylimidazo[1,2-a]pyridine (9i). The

crude residue was puriﬁed by ﬂash chromatography eluted with

cyclohexane/ethyl acetate (80/20 to 50/50): brown oil (method B:

120 mg, yield = 80% for 150 mg of imidazo[1,2-a]pyridine). Known

compound: H NMR (400 MHz, CDCl ) δ 8.05 (dd, J = 8.0, 1.5

Hz, 1H), 8.00 (dt, J = 8.4, 1.1 Hz, 1H), 7.78 (dt, J = 9.1, 1.1 Hz, 1H),

7.64−7.52 (m, 5H), 7.42 (dt, J = 6.9, 1.2 Hz, 1H), 7.41−7.37 (m,

2H), 7.23 (ddd, J = 9.1, 6.7, 1.3 Hz, 1H), 7.20−7.15 (m, 3H), 6.64

(td, J = 6.8, 1.2 Hz, 1H).

1−1.5 equiv), aryl bromide derivatives 8a−f (1 equiv), KOAc (2

equiv), Pd(OAc) (2.5−10 mol %), and dry DMAc (0.1 M) was

introduced in a microwave 35-ML sealed tube equipped with a

magnetic stirrer. The tube was saturated with a nitrogen atmosphere

and stirred at room temperature for 5 min, then the tube was

subjected to MW heating at 170 or 190 °C for 30 min or 1 h. The

temperature of the reaction rose gradually in less than 1 min to the set

point. After a return to room temperature, water was added, and the

solution was extracted three times with dichloromethane. The

combined organic layers were dried over magnesium sulfate, ﬁltered,

and concentrated under vacuum. The crude residue was then puriﬁed

by ﬂash chromatography.

Diphenyl(3-phenylimidazo[1,2-a]pyridin-6-yl)phosphine Oxide

9b). The crude residue was puriﬁed by ﬂash chromatography eluted

(

with dichloromethane/MeOH 10% (90/10 to 50/50): yellow oil

method B: 158 mg, yield = 96% for 200 mg of imidazo[1,2-

(

a]pyridin-6-yldiphenylphosphine oxide); H NMR (400 MHz,

CDCl ) δ 8.83 (ddd, J = 10.3, 1.6, 1.0 Hz, 1H), 7.77 (s, 1H),

.73−7.66 (m, 5H), 7.62−7.55 (m, 2H), 7.53−7.44 (m, 8H), 7.43−

13 1

.37 (m, 1H), 7.17 (ddd, J = 9.3, 8.7, 1.5 Hz, 1H); C{ H} NMR

(

101 MHz, CDCl ) δ 145.9 (d, J = 2.6 Hz, C), 133.9 (s, CH), 132.6

d, J = 2.8 Hz, CH), 132.1 (d, J = 10.1 Hz, CH), 131.8 (d, J = 107.1

3-Phenylimidazo[1,2-a]pyridine (9a). The crude residue was

Hz, PC), 129.9 (d, J = 16.3 Hz, CH), 129.5 (s, CH), 128.9, (d, J =

2.4 Hz, CH), 128.8 (s, CH), 128.3 (s, C), 128.2 (s, CH), 124.7 (d, J

9.7 Hz, CH), 118.4 (d, J = 11.8 Hz, CH), 117.6 (d, J = 107.9 Hz,

puriﬁed by ﬂash chromatography eluted with cyclohexane/ethyl

acetate (50/50): brown oil (method A: 631 mg, yield = Q for 500 mg

of imidazo[1,2-a]pyridine; method B: 323 mg, yield = Q for 250 mg

PC); P{ H} NMR (162 MHz, CDCl ) δ 27.15; HR-MS (m/z) [M

of imidazo[1,2-a]pyridine). Known compound:

H NMR (400

H] calcd for C H N OP = 395.1313, found = 395.1315.

25 20 2

MHz, CDCl ) δ 8.34 (dt, J = 7.0, 1.2 Hz, 1H), 7.70 (bs, 1H), 7.68

(

3-(Naphthalen-1-yl)imidazo[1,2-a]pyridin-6-yl)-

(

dt, J = 9.1, 1.2 Hz, 1H), 7.59−7.48 (m, 4H), 7.45−7.38 (m, 1H),

diphenylphosphine Oxide (9l). The crude residue was puriﬁed by

ﬂash chromatography eluted with cyclohexane/ethyl acetate (50/50

to 0/100): yellow oil (method B: 94 mg, yield = 58% for 100 mg of

.20 (ddd, J = 9.1, 6.7, 1.3 Hz, 1H), 6.80 (td, J = 6.8, 1.2 Hz, 1H);

C{ H} NMR (101 MHz, CDCl ) δ 146.2 (s, C), 132.6 (s, CH),

29.4 (s, C), 129.4 (s, CH), 128.3 (s, CH), 128.2 (s, CH), 125.9 (s,

imidazo[1,2-a]pyridin-6-yldiphenylphosphine oxide); H NMR (400

C), 124.4 (s, CH), 123.5 (s, CH), 118.4 (s, CH), 112.7 (s, CH).

MHz, CDCl ) δ 8.09 (ddd, J = 10.2, 1.5, 1.0 Hz, 1H), 7.95−7.89 (m,

3-(Naphthalen-1-yl)imidazo[1,2-a]pyridine (9c). The crude resi-

H), 7.85 (s, 1H), 7.75 (ddd, J = 9.3, 2.5, 1.0 Hz, 1H), 7.61−7.43 (m,

0H), 7.41−7.33 (m, 5H), 7.24 (ddd, J = 9.3, 8.8, 1.6 Hz, 1H);

due was puriﬁed by ﬂash chromatography eluted with cyclohexane/

ethyl acetate (50/50): brown oil (method B: 1.44 g, yield = 77% for

C{ H} NMR (101 MHz, CDCl ) δ 145.7 (d, J = 1.7 Hz, C), 135.4

.00 g of imidazo[1,2-a]pyridine). Known compound:

H NMR

(

s, CH), 134.1 (s, C), 132.5 (d, J = 2.8 Hz, CH), 132.0 (d, J = 10.1

Hz (s, CH)), 131.9 (s, C), 131.5 (d, J = 106.8 Hz, PC), 130.3 (d, J =

7.2 Hz, CH), 130.1 (s, CH), 129.2 (s, CH), 129.0 (s, CH), 128.8 (d,

J = 12.4 Hz, CH), 127.2 (s, CH), 126.6 (s, CH), 125.7 (s, CH), 125.2

(

400 MHz, CDCl ) δ 8.01−7.93 (m, 2H), 7.80 (bs, 1H) 7.43 (ddd, J

8.5, 6.6, 1.3 Hz, 1H), 7.71 (dt, J = 6.9, 1.2 Hz, 1H), 7.62−7.56 (m,

H), 7.56−7.48 (m, 2H), 7.43 (ddd, J = 8.5, 6.6, 1.3 Hz, 1H), 7.24

ddd, J = 9.1, 6.7, 1.3 Hz, 1H), 6.72 (td, J = 6.8, 1.2 Hz, 1H).

-(o-tolyl)imidazo[1,2-a]pyridine (9d). The crude residue was

(

s, C), 125.0 (s, C), 124.9 (d, J = 9.3 Hz, CH), 124.8 (s, CH), 118.3

d, J = 11.7 Hz, CH), 117.5 (d, J = 108.1 Hz, PC). P{ H} NMR

puriﬁed by ﬂash chromatography eluted with cyclohexane/ethyl

162 MHz, CDCl ) δ 27.14; HR-MS (m/z) [M + H] calcd for

acetate (50/50): brown solid (method B: 114 mg, yield = 71% for

C H N OP = 445.1464, found = 445.1482.

29 22

00 mg of imidazo[1,2-a]pyridine). Known compound: H NMR

Dimethyl(3-phenylimidazo[1,2-a]pyridin-6-yl)phosphine Oxide

9n). The crude residue was puriﬁed by ﬂash chromatography eluted

(

400 MHz, CDCl ) δ 7.68 (dt, J = 6.9, 1.2 Hz, 1H), 7.63 (dt, J = 9.1,

(

.2 Hz, 1H), 7.56 (bs, 1H), 7.36−7.20 (m, 4H), 7.12 (ddd, J = 9.1,

.7, 1.3 Hz, 1H), 6.69 (td, J = 6.8, 1.2 Hz, 1H), 2.09 (s, 3H).

with dichloromethane/MeOH 10% (90/10 to 50/50): yellow oil

method B: 70 mg, yield = 75% for 100 mg of imidazo[1,2-a]pyridin-

(

-(2-Methoxyphenyl)imidazo[1,2-a]pyridine (9e). The crude

-yldimethylphosphine oxide); H NMR (400 MHz, CDCl ) δ 8.83

residue was puriﬁed by ﬂash chromatography eluted with cyclo-

hexane/ethyl acetate (80/20 to 50/50): brown solid (method B: 52

mg, yield = 21% for 200 mg of imidazo[1,2-a]pyridine). Known

(

d, J = 10.1 Hz, 1H), 7.74−7.66 (m, 2H), 7.54−7.43 (m, 4H), 7.42−

.34 (m, 1H), 7.09 (td, J = 8.9, 1.5 Hz, 1H), 1.72 (d, J = 13.2 Hz,

H); C{ H} NMR (101 MHz, CDCl ) δ 145.7 (s, C), 133.7 (s,

compound: H NMR (400 MHz, CDCl ) δ 7.82 (dt, J = 6.9, 1.1,

CH), 129.5 (s, CH), 128.8 (s, CH), 128.3 (d, J = 13.6 Hz (s, CH),

27.7 (d, J = 109.7 Hz, PC), 127.1 (s, CH), 122.2 (d, J = 10.8 Hz,

CH), 118.9 (d, J = 101.5 Hz, PC), 118.8 (d, J = 11.8 Hz, CH), 18.1

H), 7.68−7.64 (m, 2H), 7.47−7.38 (m, 2H), 7.18 (ddd, J = 9.1, 6.7,

.3, 1H), 7.10−7.02 (m, 2H), 6.75 (td, J = 6.8, 1.2, 1H), 3.79 (s, 3H).

-(2-Methoxynaphthalen-1-yl)imidazo[1,2-a]pyridine (9g). The

(

d, J = 73.0 Hz, PCH ); P{ H} NMR (162 MHz, CDCl ) δ 33.04;

crude residue was puriﬁed by ﬂash chromatography eluted with

cyclohexane/ethyl acetate (50/50 to 0/100): brown solid (method A:

HR-MS (m/z) [M + H] calcd for C H N OP = 271.1000, found =

71.1006.

79 mg, yield = 50% for 748 mg of imidazo[1,2-a]pyridine; method

Dimethyl(3-(naphthalen-1-yl)imidazo[1,2-a]pyridin-6-yl)-

B: 41 mg, yield = 35% for 75 mg of imidazo[1,2-a]pyridine). Known

phosphine Oxide (9o). The crude residue was puriﬁed by ﬂash

chromatography eluted with dichloromethane/MeOH 10% (90/10 to

50/50): brown oil (method B: 82 mg, yield = 75% for 100 mg of

compound: H NMR (400 MHz, CDCl ) δ 8.01 (dd, J = 9.2, 0.7

Hz, 1H), 7.89−7.84 (m, 1H), 7.80−7.74 (m, 2H), 7.61−7.54 (m,

H), 7.45−7.35 (m, 3H), 7.23 (ddd, J = 9.1, 6.7, 1.3 Hz, 1H), 6.72

imidazo[1,2-a]pyridin-6-yldimethylphosphine oxide); H NMR (400

(

td, J = 6.8, 1.2 Hz, 1H), 3.84 (s, 3H).

MHz, CDCl ) δ 8.27 (ddd, J = 10.0, 1.6, 1.0 Hz, 1H), 8.00−7.94 (m,

2,3-Diphenylimidazo[1,2-a]pyridine (9h). The crude residue was

1H), 7.94−7.89 (m, 1H), 7.83 (s, 1H), 7.79 (ddd, J = 9.2, 2.7, 1.0 Hz,

1H), 7.57 (s, 1H), 7.56 (d, J = 1.6 Hz, 1H), 7.53−7.46 (m, 2H), 7.40

(ddd, J = 8.6, 6.6, 1.3 Hz, 1H), 7.19 (td, J = 9.0, 1.6 Hz, 1H), 1.66 (d,

puriﬁed by ﬂash chromatography eluted with cyclohexane/ethyl

acetate (90/10 to 50/50): brown oil (method A: 70 mg, yield = 38%

for 200 mg of 2-phenylimidazo[1,2-a]pyridine; method B: 109 mg,

yield = 59% for 200 mg of 2-phenylimidazo[1,2-a]pyridine). Known

J = 13.1 Hz, 6H, 2 CH ); C{ H} NMR (101 MHz, CDCl ) δ 145.5

(d, J = 0.9 Hz, C), 135.2 (s, CH), 134.0 (s, C), 132.2 (s, C), 130.2 (s,

CH), 129.2 (s, CH), 128.8 (s, CH), 128.5 (d, J = 15.0 Hz, CH), 127.2

(s, CH), 126.6 (s, CH), 125.6 (s, CH), 125.1 (s, C), 124.8 (d, PC one

transition is missing), 124.7 (s, CH), 122.6 (d, J = 10.5 Hz, CH),

119.0 (d, J = 101.7 Hz, PC), 118.6 (d, J = 11.6 Hz, CH), 18.05 (d, J =

compound: H NMR (400 MHz, CDCl ) δ 7.96 (dt, J = 7.0, 1.2

Hz, 1H), 7.71−7.64 (m, 3H), 7.56−7.43 (m, 5H), 7.31−7.26 (m,

H), 7.26−7.22 (m, 1H), 7.20 (ddd, J = 9.1, 6.7, 1.3 Hz, 1H), 6.73

(

td, J = 6.8, 1.2 Hz, 1H).

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Complete contact information is available at:

Article

(

3.0 Hz, PCH ); ³¹P{ H} NMR (162 MHz, CDCl ) δ 33.11; HR-MS

https://pubs.acs.org/10.1021/acs.joc.0c02059

m/z) [M + H] calcd for C H N OP = 321.1151, found =

19 18 2

21.1166.

(

2,3-Diphenylimidazo[1,2-a]pyridin-6-yl)diphenylphosphine

Notes

Oxide (9p). The crude residue was puriﬁed by ﬂash chromatography

The authors declare no competing ﬁnancial interest.

eluted with cyclohexane/ethyl acetate (50/50 to 0/100): yellow oil

(

method B: 159 mg, yield = 100% for 200 mg of diphenyl(2-

ACKNOWLEDGMENTS

A.G. gratefully acknowledges ﬁnancial support from the Centre

National de la Recherche Scientiﬁque (CNRS) and the

̀ ́

Ministere de l’Enseignement Superieur, de la Recherche et

de l’Innovation.

phenylimidazo[1,2-a]pyridin-6-yl)phosphine oxide); H NMR (400

■

MHz, CDCl ) δ 8.53 (ddd, J = 10.2, 1.6, 1.0 Hz, 1H), 7.76−7.66 (m,

H), 7.64−7.56 (m, 2H), 7.55−7.46 (m, 7H), 7.44−7.39 (m, 2H),

13 1

.36−7.28 (m, 3H), 7.18 (td, J = 9.0, 1.6 Hz, 1H); C{ H} NMR

(

101 MHz, CDCl ) δ 144.6 (d, J = 1.5 Hz, C), 143.9 (s, C), 133.6 (s,

C), 132.6 (d, J = 2.8 Hz, CH), 132.1 (d, J = 10.1 Hz, CH), 131.8 (d, J

125.2 Hz, PC), 129.9 (s, CH), 129.8 (d, J = 16.8 Hz, CH), 129.4 (s,

CH), 128.9 (d, J = 12.4 Hz, CH), 128.8 (s, C),128.5 (s, CH), 128.3

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■

(

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(

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Nicolas Sevrain − ICGM, Univ. Montpellier, CNRS, ENSCM,

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Jean-Noel Volle − ICGM, Univ. Montpellier, CNRS, ENSCM,

4296 Montpellier, France

Tahar Ayad − PSL University, Chimie ParisTech, CNRS,

Institute of Chemistry for Life and Health Sciences, CSB2D

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