Functionalization of the imidazo[1,2-a]pyridine ring in α-phosphonoacrylates and α-phosphonopropionates via microwave-assisted Mizoroki-Heck reaction

Article abstract of DOI:10.3762/bjoc.16.3

A series of new phosphonocarboxylates containing an imidazo[1,2-a]pyridine ring has been synthesized via the microwave-assisted Mizoroki-Heck reaction. The efficient modification of the imidazo[1,2-a]pyridine ring has been achieved as late-stage functiona

Full text of DOI:10.3762/bjoc.16.3

Functionalization of the imidazo[1,2-a]pyridine ring in
α-phosphonoacrylates and α-phosphonopropionates
via microwave-assisted Mizoroki–Heck reaction
Damian Kusy, Agata Wojciechowska, Joanna Małolepsza and Katarzyna M. Błażewska*§
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 15–21.
Institute of Organic Chemistry, Faculty of Chemistry, Lodz University
of Technology, 116 Zeromskiego St, 90–924 Lodz, Poland
doi:10.3762/bjoc.16.3
Received: 06 November 2019
Accepted: 13 December 2019
Published: 03 January 2020
Email:
Katarzyna M. Błażewska* - katarzyna.blazewska@p.lodz.pl
* Corresponding author
Associate Editor: B. Stoltz
§ §Phone: 0048 426313227
© 2020 Kusy et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
α-phosphonoacrylates; α-phosphonopropionates;
imidazo[1,2-a]pyridine; microwave-assisted reaction; Mizoroki–Heck
reaction
Abstract
A series of new phosphonocarboxylates containing an imidazo[1,2-a]pyridine ring has been synthesized via the microwave-assisted
Mizoroki–Heck reaction. The efficient modification of the imidazo[1,2-a]pyridine ring has been achieved as late-stage functionali-
zation, enabling and accelerating the generation of a library of compounds from a common precursor.
Introduction
In the last few decades, the Mizoroki–Heck reaction has which exhibit many interesting biological properties. Its privi-
become one of the main tools in organic synthesis. Its use for leged character is confirmed by the presence in a number of
the functionalization of a wide range of compounds cannot be pharmaceuticals [2,3]. The imidazo[1,2-a]pyridine-ring modifi-
overrated [1]. However, as is true for many reactions, the late- cation via Pd-catalyzed reactions is broadly reported in the liter-
stage functionalization of target compounds or their advanced ature [3], however, such functionalizations for more complex
intermediates is rarely an extension of reaction conditions de- molecules are not very common. On the other hand, the
veloped for structurally simple analogs. The late-stage ap- Mizoroki–Heck reaction is rarely applied for the functionaliza-
proach is especially desirable in the synthesis of a library of tion of molecules bearing phosphonate or phosphine oxide
compounds from a common precursor and enables efficient groups, and the known reactions involve high temperatures
generation of new chemical entities.
(≈100 °C) and long reaction times (in most cases >24 h) [4-7].
Imidazo[1,2-a]pyridine constitutes an appealing scaffold in me- Herein we disclose the first method for functionalization of
dicinal chemistry. It is present in a number of compounds, molecules composed of both, an imidazo[1,2-a]pyridine ring
15

Beilstein J. Org. Chem. 2020, 16, 15–21.
and the phosphoryl group. The combination of these functional
groups can be found in bisphosphonates and phosphonocar-
boxylates [8-10] – inhibitors of the therapeutically important
enzymes, farnesyl pyrophosphate synthase (FPPS) and Rab
geranylgeranyl transferase (RGGT), respectively.
Results and Discussion
We have previously synthesized a number of phosphonocar-
boxylates (PC) to study their structure–activity relationship with
RGGT, using compounds 1 and 2 as advanced intermediates in
the synthesis of RGGT inhibitors (Figure 1) [10,11]. We have
found that the presence of a substituent at C6 position of the
imidazo[1,2-a]pyridine is favorable for retaining the activity of
PC toward RGGT. Such substituents were introduced into the
Figure 1: Substrates used for the Mizoroki–Heck reaction in this study.
heterocyclic ring via the use of appropriately substituted com- aminopyridin-3-yl)acrylate in 86% yield (see Supporting Infor-
mercially available 2-aminopyridines. Here, we propose a new maiton File 1). However, when the same conditions were
and efficient strategy, by which structurally diverse substitu- applied to alkyl 3-(6-bromoimidazo[1,2-a]pyridin-3-yl)-2-
ents can be attached to the imidazo[1,2-a]pyridine ring, being a (diethoxyphosphoryl)acrylates 1, no desired product 3 was
part of common precursors, compounds 1 and 2.
formed under standard heating conditions (Table 1, entry 1).
The Mizoroki–Heck reaction-assisted functionalization of Recently, multiple variants for the application of microwave
6-bromoimidazo[1,2-a]pyridine-3-carbaldehyde [12], a precur- heating for conducting Mizoroki–Heck reactions have been re-
sor of compounds 1 and 2, was successfully achieved. We used ported, including the use of heterogeneous and homogeneous
tri(o-tolyl)phosphine (P(o-tol)3, palladium(II) acetate catalysts, as well as continuous-flow conditions [13-15]. There-
(Pd(OAc)2) and obtained the desired product (E)-benzyl 3-(6- fore, we tested microwave heating, a technique which is known
Table 1: Summary of optimization studies.
Entrya
Base
Ligand
Pd catalyst
Solvent
T [°C]
t [min]
Yieldb
1c
2c
3f
4g
5
6
7
8
9
10
11
12
13
14
15
16
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
TEA
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(t-Bu)3
DABCO
P(Cy)3
–
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
–
Pd(OAc)2
Pd(PPh3)4
Pd(dba)2
Pd(OAc)2
Pd(OAc)2
PCN
PCN
PCN
PCN
PCN
PCN
PCN
PCN
PCN
PCN
PCN
PCN
PCN
PCN
PCN
PCN
97
24 h
40
50
50
50
50
10
50
50
50
30
30
30
30
50
50
0
100
110
110
110
150
130
110
110
110
110
110
110
110
110
110
70d,e
58
74
69
–h
51
58
49
0e
0
–
–
–
47i
17j
42j
62
67
P(o-tol)3
P(o-tol)3
Cy2NH
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Beilstein J. Org. Chem. 2020, 16, 15–21.
Table 1: Summary of optimization studies. (continued)
17
18
19
20
21
22
23
24
25
26
27
28
29
Cy2NMe
(n-Bu)3N
NMM
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
P(o-tol)3
–
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
PCN
PCN
PCN
PCN
PCN
PCN
110
110
110
110
110
110
110
110
110
110
110
110
80
50
50
30
30
30
30
50
30
30
30
30
40
25
62
69
32j
13j
4j
91
70
14h
0
K2CO3
Cs2CO3
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
Na2CO3
PCN/H2O 100:1
PCN/H2O 2:1
DMF/H2O 1:1
EtOH/H2O 2:1
dioxane/EtOH 1:1
dioxane/EtOH 1:1
toluene/EtOH/H2O 2:1:2
0
80
69
0d,e
aThe ratio for most experiments (except for those indicated below): substrate/olefin/ligand/Pd(OAc)2 = 1:1.1:0.05:0.045. bYield of the isolated com-
pound, if not stated otherwise. cSubstrate/olefin/ligand/Pd(OAc)2 = 1:1.5:0.1:0.18. dThe given value represents the degree of conversion. eSubstrate
recovered. fSubstrate/olefin/ligand/Pd(OAc)2 = 1:1.5:0.2:0.18. gSubstrate/olefin/ligand/Pd(OAc)2 = 1:1.5:0.05:0.045. hUnidentified products of decom-
position. iFifty-eight percent conversion into product were observed after 30 min. A comparable result was obtained after another 30 min under micro-
wave heating. jThis substrate is the main component of the reaction mixture; the yield was estimated based on 31P NMR.
for significant acceleration of the C–C coupling reaction [16]. lack of conversion as in the case of tricyclohexylphosphine
We carried out the optimization studies using model substrates (P(Cy)3 (Table 1, entries 8–10). Also no reaction was observed
– compound 1a and benzyl acrylate (Table 1). Compound 1a in the absence of Pd(OAc)2 and P(o-tol)3, while partial conver-
was prepared according to our previously published procedure sion into product 3 occurred in the presence of Pd(OAc)2
(see Supporting Information File 1) [10] as a mixture of dia- (Table 1, entries 11 and 12). In addition, replacing palladium
stereomers (E/Z ratio was determined by 31P NMR; the config- acetate by tetrakis(triphenylphosphine)palladium(0), Pd(PPh3)4,
uration of the double bond CH=CP was determined by 1H or bis(dibenzylideneacetone)palladium(0), Pd(dba)2, resulted in
NMR vicinal coupling constants 3JHP [10,17]). However, we a reduction in the yield and a partial recovery of substrate 1a
did not observe any change in this ratio under the applied condi- (Table 1, entries 13 and 14).
tions of the Mizoroki–Heck reaction.
In the next series of experiments, different amines were tested.
On applying microwave irradiation (100 °C, 40 min), we The use of triethylamine, dicyclohexylamine (Cy2NH), dicyclo-
achieved 70% conversion into product 3 (Table 1, entry 2). In hexylmethylamine (Cy2NMe), and tributylamine (n-Bu3N) led
order to improve the conversion into the product, we increased to 62–69% yields, while for N-methylmorpholine (NMM), the
the reaction temperature to 110 °C and prolonged the time to yield dropped to 32% (Table 1, entries 15–19). The use of inor-
50 min (Table 1, entry 3) and obtained product 3 with 58% ganic bases also led to very low yields (4–13%) and recovery of
yield. Then, we reduced the loading of the ligand, P(o-tol)3 and substrate (Table 1, entries 20 and 21). N,N-Diisopropylethyl-
catalyst Pd(OAc)2, to one fourth of the loading used in the amine (DIPEA) turned out to be the amine of choice (Table 1,
previous experiment which improved the yield of the isolated entry 5, yield 69%), because, in most cases, it could be readily
product 3 to up to 74% (Table 1, entry 4). Furthermore, separated after the reaction.
reducing the amount of acrylate from 1.5 to 1.1 equiv led to a
slight decrease in the yield (from 74% to 69%), but facilitated A significant improvement was achieved after decreasing the
the purification process (Table 1, entry 5). Therefore, we estab- reaction time from 50 to 30 min, which led to 91% yield
lished 110 °C as the optimal temperature for this reaction, (Table 1, entry 22). The shorter exposure to microwave heating
because higher temperatures led to decomposition of the probably limited the decomposition of the substrate and the
reagents (Table 1, entries 6 and 7), and full conversion into the product.
product was not achieved at lower temperatures (Table 1, entry
2).
Among the various choices of solvents, propionitrile (PCN)
delivered the highest amount of product 3, while other solvents
The use of other ligands resulted in a decreased yield (for tri- led to lower yields (Table 1, entries 23–29). As we have con-
tert-butylphosphine, (P(t-Bu)3) or DABCO), or even complete firmed on selected examples of substrates, the reaction can be
17

Beilstein J. Org. Chem. 2020, 16, 15–21.
also run in acetonitrile (49–98%), with a yield similar to that in and S33) [21]. In case of the reaction with allyl alcohol, the
the reaction in PCN (50–91%, Scheme 1). The presence of a generated products isomerized in situ to give the saturated alde-
little amount of water did not impair the reaction (Table 1, entry hydes, compounds 12, 21, and 22, a result being consistent with
23). However, when water was used as co-solvent, the yield sig- analogous reactions reported in the literature [22,23].
nificantly dropped, or no product was detected at all (Table 1,
entries 24–26).
In the reaction with acrylic acid and acrylamide, substrate 1a
was recovered, probably due to the propensity of these acrylic
Overall, the optimal conditions for the Mizoroki–Heck reaction substrates to polymerization. In case of ethyl crotonate and
of compound 1a and benzyl acrylate were established to involve methyl metacrylate, only traces of the desired products were
5 mol % of Pd(OAc)2, 4.5 mol % of P(o-tol)3, and DIPEA in formed. The structures of products 3 and 6–22 were confirmed
PCN (or acetonitrile), under microwave heating conditions for by spectroscopic methods, 1H, 13C, 31P NMR, and MS analysis.
30 min at 110 °C (Table 1, entry 22).
The stereochemistry of the newly formed double bond was
evaluated by 1H NMR spectroscopy.
During our optimization studies, we also identified two side
products (Figure 2), that were detected in up to 6% each. They Next, we determined the influence of the position of a halogen
were isolated and their identities were confirmed by NMR, MS, substituent in the imidazo[1,2-a]pyridine ring on its reactivity in
and IR analyses. Compound 4 is the product of dehalogenation the Mizoroki–Heck reaction. We confined our studies to the
reaction, which is known to be catalyzed by palladium [1,18]. analogs bearing substituents at positions 6, 7, and 8 of the six-
The second side product, compound 5, is probably the result of membered ring of the imidazo[1,2-a]pyridine (1a–f, in
the cleavage of the C–CN bond in the solvent (propionitrile or Figure 1) [24]. We found that the reaction occurred for the 6-
acetonitrile), followed by a palladium-catalyzed cyanation of and 7-substituted analogs 1a–c, but no product was observed in
substrate 1. Recently, acetonitrile was reported as a nontoxic the reaction with the 8-halogeno-imidazo[1,2-a]pyridine analog
source of cyanide [19,20].
1d [25]. As the Mizoroki–Heck reaction is sensitive to the elec-
tronic properties of the aryl halides, with electron-withdrawing
substituents imparting a smaller barrier in the oxidative addi-
tion step [26,27], we envisioned that the C8 carbon could be
more electron rich than C6 and C7, possibly due to the prox-
imity of the nitrogen atom N1. All the above reactions were run
on bromine-substituted analogs. Analogs bearing a strong car-
bon–chlorine bond did not react, as was observed for substrates
1e and 1f.
Figure 2: Structures of the identified side products 4 and 5.
Having the optimized conditions in hand, the scope of this Finally, we checked whether the method could be extended to
transformation was examined using selected olefins and the fluorinated analog 23 (Scheme 2). Unfortunately, in this case,
substrate containing imidazo[1,2-a]pyridine ring embedded the desired product constituted no more than 20% of the reac-
either within 2-(diethoxyphosphoryl)acrylate (analogs 1) or tion mixture, while the main components were the product of
2-(diethoxyphosphoryl)propanoates (analogs 2).
dealkylation of the phosphorous ester group, compound 24, and
the mixture of substrate 23 and the desired product of the
The reaction worked well for a number of acrylates (Scheme 1), Mizoroki–Heck reaction (Scheme 2 and Figures S69–S71 in
providing predominantly products with (E)-geometry of the Supporting Information File 1).
newly formed double bond (E/Z ratio is above 98:2). Only for
analog 11, the formation of the (Z)-product was observed in up Conclusion
to 30%. The configuration of the newly formed double bond In conclusion, we have developed a convenient protocol for the
was determined based on the vicinal coupling constant 3JHH be- functionalization of alkyl 3-(bromoimidazo[1,2-a]pyridin-3-yl)-
tween CH=CH [(E)-isomer: 3JHH = 16.5 Hz, (Z)-isomer: 2-(diethoxyphosphoryl)acrylates 1 and propionates 2 using
3JHH = 12.1 Hz].
microwave-assisted Mizoroki–Heck reaction. The method
worked for a number of olefins, enabling the functionalization
We also showed that the method is applicable to styrene and of the heterocyclic ring with diverse groups, which can be used
phthalylallylamine, although, for these substrates, a mixture of for further modifications. Importantly, synthesis of these com-
regioisomers, resulting from α- and β-arylation, was formed pounds by standard thermal Heck protocols was ineffective,
(see Supporting Information File 1, Figures S16 and S17, S32 thus highlighting the importance of employing microwave irra-
18

Beilstein J. Org. Chem. 2020, 16, 15–21.
Scheme 1: Scope of the method for analogs derived from 1 and 2. The ratio of isomers is given (E/Z or β/α) in red, wherever applicable. Yields are
given for reactions run at a 100 mg (0.22 mmol) scale, except for compounds 3 (0.88 mmol), 6 (0.44 mmol), 18 (0.11 mmol, 40 min, 100 °C), and 17
(1.08 mmol) as indicated below the appropriate structures. Asterisks indicate yields for the reaction carried out in acetonitrile.
Scheme 2: Dealkylation of fluorinated analog 23 under the Mizoroki–Heck reaction conditions.
19

Beilstein J. Org. Chem. 2020, 16, 15–21.
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Supporting Information
Supporting Information File 1
Full experimental details, including copies of spectra (1H
NMR, 13C NMR, 31P NMR) of all new compounds. The
experimental details and NMR description of the starting
compounds synthesized according to our previously
published procedure.
[https://www.beilstein-journals.org/bjoc/content/
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Acknowledgements
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(Lodz University of Technology, Poland) and Dr. Łukasz
Joachimiak (OncoArendi Therapeutics, Poland) for reading the
manuscript and for helpful suggestions. We thank Dr.
Agnieszka Dybała-Defratyka (Lodz University of Technology,
Poland) for helpful discussions on computational aspects of this
reaction.
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This work was financially supported by the National Science
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ORCID® iDs
Katarzyna M. Błażewska - https://orcid.org/0000-0002-1218-7111
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