N derivatives, sharing structural analogies with omeprazole, a eukaryotic efflux pump inhibitor (EPI) used as an antiulcer agent. But instead of cyclisating with triphosgene they used chloroacetyl chloride and POCl3 to obtain the target structures as drawn in Scheme 2.8.75
Scheme 2.8. Synthesis of pyrrolo[1,2-a]quinoxalines by Vidaillac et. al..
In 2009, For the first time, Patil et. al. has developed an efficient method for Markownikoff‟s hydroamination-hydroarylation of alkynols using PtBr2 as catalyst. The platinum-catalyzed reactions of alkynols with amino group containing aromatics were achieved in methanol over a reaction time of 6-24 h and temperature ranging from r.t to 80 oC in Scheme 2.9.76
Scheme 2.9. Synthesis of pyrrolo[1,2-a]quinoxalines by PtBr2 catalysedreaction by Patil et. al.
N H2N +
5 mol% AuCl DCE, rt-12 h
N
N Ph
O H
96 % yield
NH2 N
+ nHex
2 mol% Ph3PAuNTf2, toluene
100 oC N
NH Me
nHex
90 % yield
Subsequently in 2010, Patil et. al. has developed a gold(I)-catalyzed, coupling–
cyclization technique for the synthesis of isoquinoline- fused polycyclic compounds. The reaction composed of o-alkynylbenzaldehydes and aromatic amines having tethered nucleophiles in Scheme 2.10.77
Scheme 2.10. AuCl catalysed synthesis of pyrrolo[1,2-a]quinoxalines
In the same year, Patil et. al. has developed an efficient method for formal Markownikoff hydroamination/ hydroarylation and double hydroamination of terminal alkynes using 2–
5 mol-% of Ph3PAuNTf2 in toluene at 100 °C has been developed scheme 2.11. 78
Scheme 2.11. Synthesis of pyrrolo[1,2-a]quinoxalines by Au catalysed reaction
In 2011, Liu et. al. has developed an efficient tandem process of hydroamination and hydroarylation using a gold catalyst to enable and study the reactions between
pyrrole-N NH2 R3
R4
R1 R2 Au catalyst Toluene 80 oC, 1-6 hrs
R3
NH N
R1R2 R4
R1= aryl, alkyl R2=H, aryl, alkyl R3=H, Me, OMe, CN R4=H, Me, Et, OMe, CN, F
substituted anilines and alkynes. The gold (I)-catalyzed reactions were accomplished in toluene at 80 oC over a reaction time of 1-6 h in scheme 2.12. 79
Scheme 2.12. Synthesis of pyrrolo[1,2-a]quinoxalines by Au catalysed reaction
In 2010, Our lab has described the synthesis diverse indolo-fused pyrazino-/diazepinoquinoxalinones using amino acid and indoline-substituted dinitrobenzene on a soluble polymer support (PEG) and its further reductive double-ring closure to afford structurally diverse final compounds. To furnish these novel scaffolds traceless synthesis of quinoxalinones coupled with application of the Pictet-Spengler-type condensation reaction uder microwave irradiation has been developed in Scheme 2.13. 80
N
Scheme 2.13. Synthesis of indolo-fused pyrazino-/diazepinoquinoxalinones on PEG support
In 2011, Our lab has developed the diversity-oriented synthesis of novel benzimidazole linked indolo-benzodiazepine/quinoxaline ring systems using poly-(ethylene glycol) as soluble polymer support. To construct these types of privileged heterocyles commercially available 4-fluoro-3-nitrobenzoic acid and indoline were along with focused microwave irradiation in Scheme 2.14. 81
Scheme 2.14. Synthesis of benzimidazole linked indolo-benzodiazepine/quinoxaline on PEG support.
However, it has observed that for the construction of both tetrahydro-β-carbolines and tetrahydroisoquinolines the Pictet-Spengler reaction,82a which entails the cyclization of electron-rich aryl or heteroaryl groups onto imine or iminium ion electrophiles, has long been a standard method.82b For assemble diverse benzimidazole-pyrrolo[1,2-a]quinoxaline core small molecules, here for the first time we have described an application of SNAr reaction and subsequent Pictet-Spengler cyclization involving electron-rich heteroaryl pyrrole groups onto iminium ion electrophiles. To the best of our knowledge, no research group ever reported the nucleophilic aromatic substitution reaction of pyrrole ring to the aromatic substrate directly and subsequent Pictet-spengler reaction. Prompted by this observation, we undertook the present investigation and the results of our studies are reported herein.
2.16. Results and Discussions
The present approach initiated with the synthesis of polymer immobilized o-phenylene diamine 3 from 4-fluoro-3-nitrobenzoic acid 1 with built-in structural diversity (R1) through three step protocol as developed by our group previously.83
Scheme 2.15. PEG supported synthesis of o-phenylenediamine 4.
PEG 4000
N C N
The synthetic method depicted in Scheme 2.15 was utilized HO-PEG-OH (MW: 4000) as a soluble support was reacted with the commercially available 4-fluoro-3-nitrobenzoic acid 1 through the N,N'-dicyclohexylcarbodiimide (DCC) and catalytic amount of 4-dimethylaminopyridine (DMAP) activation to afford the polymer immobilized o-fluoronitrobenzene 2 as pale yellow compounds in quantitative yields. However, we have observed that completion of the reaction was achieved in 1 day at room temperature condition. But with the application of sealed vessel microwave irradiation (80 °C, 2 bar), the same reaction completed in 20 minutes. After completion of the reaction time, the insoluble DCU was filtered off and purified by precipitating out the reaction mixtures with cold ether. The mechanism of the formation of compound 2 was explained in Scheme 2.16.
Scheme 2.16. Mechanism of formation of compound 2 on soluble support
The first point of structural diversity was introduced by nucleophilic aromatic substitution (SnAr) of readily available primary amines with 1 via an ipso-fluoro
displacement to give polymer bound yellow nitroaniline compound 2. NMR analysis of 2 showed complete conversion to 3 after a reaction time of 12 h at room temperature. The reaction proceeded efficiently with various amines without cleavage of the ester bond at the polymer attached site. With the application of microwave irradiation (100 °C, 2 bar) reduced the reaction time to 10 minutes. Purification was achieved by the precipitation with cold ether. Reduction of the aryl nitro group in the resulting polymer immobilized nitro derivative 3 was successfully accomplished with a suspension of Zn/HCOONH4 in methanol to afford immobilized diamine 4 at room temperature for 20 minutes.
Formation of the amine conjugates 4 was confirmed from change of yellow to blue color upon spotting on the TLC plate. Upon completion of the reaction, reaction mixtures were filtered through fritted funnel to get rid of the Zn. The reaction mixtures were evaporated and dichloromethane was added to salt out the ammonium formate to obtain the colourless compound 4. The exact mechanism reharding the formation of compound 4 was observed in Scheme 2.17.
Scheme 2.17. Mechanism of formation of compound 4 on soluble support.
R N
OH e, H
R NH OH
e, H -H2O
e, H
R N O OH
R NO2 e, H
-H2O R NO e, H
R N
H e, H
R NH2
1eq. Zinc 1eq. Zinc
1eq. Zinc
4 3
To construct the benzimidazole ring in the present synthesis another molecule of 4-fluoro-3-nitrobenzoic acid 1 has been used in presence of DCC/DMAP coupling reagent to afford the polymer immobilized 5 as pale brownish compounds in quantitative yields in Scheme 2.18.
Scheme 2.18. PEG supported synthesis of o-nitrofluoro benzimidazol derivatives 6.
However, we have observed that completion of the reaction was achieved in 2 day at room temperature condition. But with the application of sealed vessel microwave irradiation (85 °C, 2 bar), the same reaction completed in 15 minutes. After completion of the reaction time, the insoluble DCU was filtered off and purified by precipitating out the reaction mixtures with cold ether. The mechanism of the formation of compound 5 was explained in Scheme 2.19.
NH
Scheme 2.19. Mechanism of formation of compound 5 on soluble support
The obtained anilide conjugates 5 were converted into benzimidazoles 6 by an intramolecular ring closure through the nucleophilic attack of the secondary amine on to the amide carbonyl which was induced by a mild acid (12 % TFA). Addition of anhydrous magnesium sulphate in this transformation reduced the reaction time, by facilitating the removal of water during this step, which needed 15 h under refluxing conditions in dichloroethane. The time for the formation of benzimidazole was reduced to 15 minutes by domestic MW reactor. However, the reaction time was reduced to 5 minutes in sealed vessel MW conditions (5 bar, 100 0C). Magnesium sulphate was filtered off and the polymer conjugate 6 was purified by precipitating out the reaction mixtures with excess of cold ether. The mechanism of the formation of the compound was described in Scheme 2.20.
N
Scheme 2.20. Mechanism of formation of compound 6 on soluble support
We envisioned applying the aromatic nucleophilic substitution (SNAr) reaction by pyrrole moiety at the aromatic fluoride position of polymer immobilized substrate 6. Our synthetic strategy is depicted in Scheme 17. The nitro group in the polymer conjugates 7 could be reduced to deliver 8. Pictet-Spengler reaction is planned to use for ring closure to generate pyrrole fused quinoxaline skeleton 9 in Scheme 2.21.
Scheme 2.21. Retrosynthetic pathway for the synthesis of pyrrolo[1,2-a]quinoxalines
In an effort to attain the target molecule as per our synthetic plan, compound 6 was subjected to SNAr reaction with pyrrole Table 2.1. For preliminary optimization of the
SNAr reaction conditions, the present coupling reactions were conducting by conventional thermal heating for 24 h, as well as microwave irradiation at 135 °C for 10 min in dichloromethane resulting into no desired product (entry 1). The main purpose to implement microwave irradiation was investigated with the aim to reduce reaction time and to increase reaction efficiency. Subsequently, addition of triethyl amine as a base also failed to generate the polymer immobilized compound 7 (entry 2). We further observed that the use of polar aprotic solvent acetonitrile (entry 3) or non-polar solvent toluene with triethyl amine (entry 4) under refluxing conditions for 24 h or microwave irradiation at 135 °C for 10 min did not generate any coupling product. We then focused our investigation on the scope of inorganic base catalyzed SNAr reaction of polymer immobilized substrate 6 with pyrrole. The addition of inorganic base such as Cs2CO3 in dichloromethane (entry 5) solution under the same reaction conditions also failed to produce the desired results. This could be attributed to the insolubility of inorganic base into dichloromethane solvent. Surprisingly, the desired product 7 was finally obtained in 80 % yield in refluxing conditions of DMF with K2CO3 after 18 h and microwave irradiation at 135 °C in 10 min (entry 6). Furthermore, the use of Cs2CO3 in DMF solvent produces the polymer immobilized compound 7 with significantly improved yield up to 95 % in 16 h under refluxing conditions and 10 min under microwave irradiation at 135 °C (entry 7).
Table 2.1. Reaction optimization for the SNAr reaction of pyrrole on compound 6
PEG O
O
N N
R1
NO2 F
HN
PEG O O
N N
R1
NO2 N
6 7
For the synthesis of pyrrole attached polymer immobilized compound 7, we found that cesium carbonate was effective base in SNAr reaction with DMF solvent. Polar, aprotic, high boiling DMF absorbs microwave energy efficiently, under microwave irradiation conditions, and allows the facile product formation. After completion of the reaction, the polymer conjugates were purified by precipitation of the reaction mixture with cold ether to remove the excess pyrrole and side products without the need of regular column purification. However, in an attempt to increase the structural diversity for the target library, the nitro group ortho to the pyrrole moiety of polymer ester conjugates 7 was
reduced with zinc dust in methanol buffered with ammonium formate. Formation of the amine conjugates 8 was achieved at room temperature for 30 minutes however, microwave irradiation condition reduced the reaction time to 10 min. After completion of the reaction, excess zinc dust and ammonium formate was removed by successive filtration to obtain the compound 8. The structrure of compound 8 was confirmed by proton NMR spectroscopy of PEG supported compound 8.
N
Scheme 2.22 Acid catalyzed Pictet-Spengler cyclization.
The relative structural study revealed the resemblance between the polymer conjugates 8 and tryptophan derivatives for Pictet-Spengler reaction in Scheme 2.22. In the polymer conjugates 8, the aromatic amine functionality originated from C-1 of the aromatic ring as an analogy of tryptophan derivatives where aliphatic amine originates from C-4 of the heteroaromatic ring. In addition to these similarities, we assume that the C-4 required for the desired C-C bond formation is contiguous to the nitrogen atom of the aromatic moiety in the polymer conjugates 8 which is similar to the C-1 of the tryptophan derivative. All there analogy gratifies the elementary precondition for the Pictet-Spengler cyclization.
Based on these correlation, we envisaged to utilize the amine functionality of polymer
PEG
conjugates 8 for the ring closure using Pictet-Spengler reaction with various ketones. The use of ketones in Pictet-Spengler reaction of aromatic amines with pyrrole moiety is unlikeness to a traditional Pictet-Spengler reaction which involve a reactive aldehydes with the aliphatic amine connected to the carbon of an activated aromatic moiety.
Scheme 2.23. Novel microwave assisted polymer supported approach for the synthesis of benzimidazole-pyrrolo [1,2-a] quinoxalines.
Accordingly, the polymer conjugates 8 were treated with various ketones using 1 % TFA as an acid catalyst in chloroform under refluxing condition in Scheme 2.23. The desired polymer conjugates 9 were furnished after 12 h. However, the same Pictet-Spengler reaction was achieved under pressured microwave irradiation at 85 °C within 12 min.
The polymer conjugates 9 were separated by precipitation and purified by washing with cold ether to remove excess reagents. The Pictet-Spengler reaction was confirmed by
proton NMR spectrums of compound 9. The peak corresponds to the proton at 2-possition on pyrrol ring was absent along with one of the amine proton peak. Also the introduction of peaks corresponds to keto-alkyl chain were clearly indicates the Pictet-Spengler cyclization. Here we developed the new application of the Pictet-Pictet-Spengler cyclization at pyrrole moiety of the conjugates 8 to provide a hitherto unknown bi-heterosystem of pyrroloquinoxalines 9. The generalization of this methodology and the expansion of the skeletal diversity was achieved using various symmetrical and unsymmetrical ketones in Pictet-Spengler cyclization. Moreover, the spiro element has been successfully introduced as an additional feature of the structural diversity on the pyrrolo[1,2-a]quinoxaline skeleton by using the cyclic ketones.
O
Scheme 2.24. Plausible Pictet-Spengler like cyclization mechanism towards the formation of pyrrolo[1,2-a]quinoxalines 9 on polymer support.
The cyclization products 9 were obtained through an iminium intermediate and then preceded non-traditional Pictet-Spengler reactions, as shown in Scheme 2.24.84 Polymer conjugates 8 reacts with ketones in the presence of TFA as an acid catalyst to give an iminium ion with the liberation of water. The iminium ion derived from aniline moiety is going to be more electrophilic than that of aliphatic amines. This enhances carbon-carbon bond formation with the C-4 of the pyrrole ring because the nature of electron-deficient imines provides a driving force for cyclization. The endo cyclization to create a new carbon-carbon bond between a carbon nucleophile of unreactive aromatic pyrrole and the electrophilic Schiff‟s base is successful to deliver an N-heterocyclic ring of polymer bound benzimidazole-pyrrolo quinoxalines 9.
Highly substituted pyrrolo[1,2-a]quinoxalines were finally cleaved from polymer support using 1 % KCN solution in MeOH at room temperature for 24 hours. The PEG was precipitated out from reaction mixtures by addition of cold ether and removed by filtration. The filtrates were evaporated to provide polymer free benzimidazole-pyrrolo[1,2-a]quinoxaline derivatives 10 of 75-99 % purity as assessed by HPLC analysis in Table 2.2. The removal of polymer support was confirmed by the proton NMR spectrum where the characteristic peaks of polyethylene glycol at 3.5 ppm were absent in figure 2.12. Additionally, mass spectroscopy also confimers the structures of final products. It is worth to note that, diverse benzimidazole-pyrroloquinoxaline small molecule analogues have been synthesized via a novel SNAr/Pictet-Spengler cyclization under focused microwave irradiation.
A
B
C
D
E
Figure 2.12. Stepwise Monitoring towards the Formation of Benzimidazole-pyrrolo[1,2-a]quinoxaline on PEG Support in CDCl3 as solvent at 25 0C.
R1NH2 Isolated yieldb
Table 2.2. Synthesis of benzimidazole-pyrrolo[1,2-a]quinoxaline derivatives (10a-10r).
N O N
O
N HN
O 10h
N N
O O
O NH
N
10g
aLRMS were detected with ESI ionization source. bDetermined based on the weight of crude samples (%).
cDetermined by HPLC analysis (UV detection at 254 nm of the crude product (%).
Furthermore, the structure of the present skeleton is confirmed by single crystal X-ray analysis. The ORTEP diagram for compound 10h is depicted in figure. 2.13. In present biheterocyclic configuration, the pyrrolo-quinoxaline moiety and benzimidazole moiety remain perpendicular to each other whereas spiro ethyl cyclohexane ring acquires chair conformation.
Figure 2.13. ORTEP diagram of compound 10h and 10g.
After the successful synthesis of benzimidazole-pyrrolo[1,2-a]quinoxaline derivatives 10a-r, we then turned our attention to use the indole instead of pyrrole as a nucleophile for the aromatic nucleophilic substitution reaction on polymer immobilzed
substrate 6a as shown in Scheme 2.25. However quick search revealed that to construct benzimidazole-indolo [1,2-a]quinoxaline moiety few lituratures is there where indoline has been used as a nucleophile and further oxidation of indoline to indole moiety and subsequent pictet-spengler reaction has been described. In our case to deversify the methodology we have incorporated the indole moiety instead of pyrrole moity by SnAr reaction in to the aromatic ring system. However, the desired reaction proceeded smoothly to generate the polymer immobilzed substrate 11, which further underwent the reduction of nitro group ortho to the indole N1 of the aromatic substrate 11 to obtained the PEG supported compound 12. With the PEG supported compound 12, we then carried out the Pictet-Spengler reactions with 4-methylcyclohexanone under microwave irradiations at 85 °C within 12 min using 1 % TFA as an acid catalyst in chloroform solution. After completion of the reaction, the polymer conjugates 13 were separated by precipitation and purified by washing with cold ether to remove excess reagents. The desired indolo [1,2-a] quinoxalines were finally cleaved from polymer support using 1 % KCN solution in MeOH at room temperature for 24 hours. The polymeric support was precipitated out from reaction mixtures by addition of cold ether and removed by filtration. The filtrates were evaporated and subsequently purified by column chromatography to provide polymer free benzimidazole-indolo [1,2-a]quinoxaline derivative 14 in good yields.
PEG
Scheme 2.25. Novel microwave assisted polymer supported approach for the synthesis of benzimidazole-indolo [1,2-a] quinoxalines.
To explore further application scopes of the polymer immobilized substrate 8a, we carried out the transition metal catalysed organic transformations using various alkyne as shown in the Scheme 2.26. Treatment of the polymer immobilized substrates 8a with pent-4-yne-1-ol in the presence of 5 mol % of PtCl4 at reflux temperature for 24 hrs using dry MeOH as solvent generated the substituted pyrrolo[1,2-a]quinoxalines derivatives.85a Subsequent cleavage of polymer support from the substrates using 1 % KCN in methanol at room temperature for 24 hours to obtain the benzimidazole-pyrrolo[1,2-a]quinoxaline derivatives 15 in good yields. Subsequently, we have investigated that Au and Ag metal catalysed transformation can be used to prepare benzimidazole-pyrrolo[1,2-a]quinoxaline derivatives by the treatment of polymer
PEG
immobilized substrate 8a and 1-alkynylbenzaldehyde and phenyl acetylene respectively under the optimized reaction conditions.85b,c We have observed good yields under the optimal conditions, a relatively longer time (18 h) was needed to complete the starting material. After cessation of the reaction, the desired pyrrolo[1,2-a] quinoxalines were finally cleaved from polymer support using 1 % KCN solution in MeOH at room temperature for 24 hours to obtain the different derivatives of benzimidazole-pyrrolo[1,2-a]quinoxalines 16 and 17 in good yields.
Scheme 2.26. Synthesis of benzimidazole-pyrrolo[1,2-a]quinoxalines via metal-mediated one-pot domino reactions
2.17. Pyrrolo[1,2-a]quinoxalinones its importance and synthesis:
Numerous pharmaceutically important molecules, including antipsychotic agent A,86 anti-HIV agent B,87 adenosine A3 receptor modulator C,88 and antitumor agent D in Figure 2.1489 contains pyrrolo[1,2-a]quinoxalineone moiety as key constituents. In addition, pyrrolo[1,2-a]quinoxalineone compounds have afford as key intermediates for the congregation of numerous heterocycles that exhibited a wide range of biological activities. Beside this Pyrrolo[1,2-a]quinoxalines moiety are best known for antiviral and antiallergic activity. 90-91
Figure 2.14. Representative examples of biologically active pyrrolo[1,2-a]quinoxalineone.
To construct the pyrrolo[1,2-a]quinoxalinone moiety very few literature methods are there. The general method for the building of pyrrolo[1,2-a]quinoxalineones initiates
NH
NO2 NH2
NO2 N
NH2
N
N NH
O
MeO O OMe SnCl2
Triphosgene
from 2-nitroanilines and proceeds in three steps pyrrole ring construction, nitro group reduction, and cyclization with triphosgene. In 2004 Guillon et. al. has constructed pyrrole moiety by reaction with o-nitro aniline with DMT group. To construct the privileged heterocyles pyrrolo[1,2-a]quinoxalinone they reduced nitro group by SnCl2 cyclised by triphosgene to provides the desired building block pyrrolo[1,2-a]quinoxalinone in Scheme 2.27.92
Scheme 2.27. Synthesis of benzimidazole-pyrrolo[1,2-a]quinoxalinones Gullion et. al.
In 2004 Varvounis et. al. has described the synthesis of pyrrolo[1,2-a]quinoxalinone
In 2004 Varvounis et. al. has described the synthesis of pyrrolo[1,2-a]quinoxalinone