Isoindole Synthesis Essay


The synthesis of 1H-benzo[f]isoindole derivatives was achieved by the cascade radical cyclization–cyclization reaction of the active methine substrate having an allyl group and phenyl group as different two radical acceptors. This oxidative transformation proceeded by using iron(III) chloride FeCl3 as a mild oxidant via the intramolecular radical addition to the allyl group followed by the second radical addition to the phenyl group. View Full-Text

Keywords: radical; cyclization; benzoisoindole; iron; oxidationradical; cyclization; benzoisoindole; iron; oxidation

►▼ Figures

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

Share & Cite This Article

MDPI and ACS Style

Yoshioka, E.; Miyabe, H. Oxidative Radical Cyclization–Cyclization Reaction Leading to 1H-Benzo[f]isoindole Derivatives. Molbank2017, 2017, M929.

AMA Style

Yoshioka E, Miyabe H. Oxidative Radical Cyclization–Cyclization Reaction Leading to 1H-Benzo[f]isoindole Derivatives. Molbank. 2017; 2017(1):M929.

Chicago/Turabian Style

Yoshioka, Eito; Miyabe, Hideto. 2017. "Oxidative Radical Cyclization–Cyclization Reaction Leading to 1H-Benzo[f]isoindole Derivatives." Molbank 2017, no. 1: M929.

Show more citation formatsShow less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

1. Introduction

One of the research activities of our laboratory in the domain of heterocyclic chemistry deals with the 1,3-dipolar cycloaddition of nitrile oxides and azides as dipoles across the double or triple bonds of dipolarophiles [1,2,3]. A very recent example is the 1,3-dipolar cycloaddition of aryl nitrile oxides to the allyl group of ethyl 1-allyl-2-benzyl-3-oxo-2,3-dihydro-1H-isoindole-1-carboxylate providing a series of isoxazolines [4]. This versatile strategy for the synthesis of heterocyclic compound is more and more used in materials chemistry, drug discovery, and chemical biology [5,6,7]. Since the pioneering work of Huisgen, the contributions of Sharpless to “click chemistry” have given an additional impetus for the advancement of cycloaddition reactions [5,6,7,8,9,10,11,12,13,14,15] which are nowadays a trusted tool in targeted synthesis, especially for those involving the construction of heterocyclic systems [6]. The aim of this present work focuses on the synthesis of N-heterocyclic compounds, namely the synthesis of substituted isoxazole and triazole derivatives, since an important number of compounds containing the isoxazole and the triazole scaffold are known to exhibit a variety of biological activities in the pharmaceutical [16] and medicinal areas [17]. Representative examples of synthetic drugs incorporating these motifs are Tazobactam I [18,19,20,21,22], Rufinamide II [23,24,25], phenylisoxazole derivatives III [26,27], and Bextra (Valdecoxib) IV [28,29,30].

On the other hand, the dihydroisoindolin-1-one ring system is present in numerous synthetic and natural compounds, which exhibit interesting biological properties. For example, 3-substituted dihydroisoindolin-1-ones such as Pazinaclone V [31] and Zoplicone VI [32,33,34] possess a pharmaceutical profile similar to that of the benzodiazepines [17] (sedatives, hypnotics) and have been commercialized as anxiolytics (Figure 1). Dihydroisoindolin-1-one derivatives have been extensively studied, but to the best of our knowledge there are no reports on dihydroisoindolin-1-ones incorporating an isoxazole or triazole moiety.

A classical route for the preparation of isoxazole or triazole is the reaction of alkynes with nitrile oxides and aryl azides, respectively [35,36,37]. In this context and in connection with our current research interest in the preparation of biologically relevant nitrogenated and oxygenated compounds by 1,3-dipolar cycloaddition on unsaturated systems with several 1,3-dipoles [38,39] we wish to describe in this paper an efficient synthesis of a series of novel 3,5-disubstituted isoxazoles and 1,4-disubstituted 1,2,3-triazoles by regioselective reaction of arylnitrile oxides 1ad and azides 2ad with the dihydroisoindolin-1-one-derived terminal alkyne 3. For comparison, we have performed these 1,3-dipolar cycloadditions under non-catalyzed thermal activation in toluene or alternatively in the presence of the simple and inexpensive catalysts CuI and Ag2CO3. As well established for many other click reactions [40] catalyzed by Cu(I) salts, we obtained the best results using CuI as catalyst.

2. Results and Discussion

As previously described by our group [41] the dipolarophile 3 was prepared through an efficient four-step procedure starting from commercially available homophthalic acid, affording the desired bicyclic acetylenic lactam 3 in high yield. We have then examined the 1,3-dipolar cycloaddition reactions of propargyl-substituted dihydroisoindolin-1-one 3 as dipolarophile across aryl nitrile oxides 1ad (Ar: a: C6H5, b: p-MeC6H4, c: p-OMeC6H4, d: p-ClC6H4), generated in situ from aromatic oximes precursors [42] and azides [43] 2ad (Ar: a: C6H5, b: p-MeC6H4, c: p-MeOC6H4, d: p-ClC6H4), under conventional conditions (without catalyst) according to Scheme 1.

To find suitable reaction conditions, we conducted first the cycloaddition reaction in various solvents such as dichloromethane, acetonitrile, toluene and DMF both at room temperature and under reflux. Without catalyst, the targeted cycloadducts were only obtained in refluxing toluene, albeit in moderate amounts. The examination of the TLC of the reactions mixtures indicated the presence of only one product, which, after classical workup, was identified as cycloadducts 4 or 6 resulting from the thermal cycloaddition of the acetylene function and the 1,3-dipoles in accordance with the literature [44,45,46]. After optimization of the reactions conditions, we then performed all the cycloaddition reactions in presence of Ag2CO3 (10 mol %) using the same protocol given above.

Table 1 reveals that the silver-catalyzed reaction allowed us to obtain the corresponding isoxazoles 4ad and triazoles 6ad within a considerably shorter reaction time (24 h) in improved isolated yields (50%–73%) as colorless or yellowish solids. It is worth noting that, as far as we know, this is the first report on an efficient Ag2CO3-catalyzed 1,3-dipolar cycloaddition with a propargyl-substituted dihydroisoindolin-1-one as dipolarophile. The reaction times could be further shortened to only 6–8 h using 10 mol % of CuI as catalyst. Moreover, all [3+2] cycloadditions involving dipolarophile 3 and arylnitrile oxides 1ad or azides 2ad furnished the desired isoxazoles 4ad or triazoles 6ad (Ar: a: C6H5, b: p-MeC6H4, c: p-OMeC6H4, d: p-ClC6H4) in even superior yields (63%–89%) compared with the Ag2CO3-catalyzed syntheses.

The structures of adduct 4ad and 6ad were confirmed through X-ray structure elucidation, or by XH correlation and HMBC spectra. It is noteworthy that, independently of the reaction temperature and catalyst ratio, TLC and NMR analysis indicated that the reaction seems to be highly regioselective. In all the cycloaddition tests, exclusively 3,5-disubstituted isoxazoles 4ad and 1,4-disubstituted 1,2,3-triazoles 6ad products were obtained (Figure 2).

2.1. Spectroscopic and Crystallographic Characterization of Isoxazole 4a

The analytical and spectroscopic data are in agreement with the proposed structures illustrated in Scheme 1. The IR spectrum of compound 4a (Ar = C6H5) contains an absorption band at νmax = 1607 cm−1 characteristic of the isoxazole C=N group. The other absorptions at νmax = 1744 and 1717 cm−1 are attributed to the ester C=O and lactam C=O stretching vibrations. The regiochemistry of this adduct was deduced from the 1H-NMR spectrum, which display the resonance of the isoxazole proton (4-H) as a singlet at δ = 5.18 ppm. This value of the chemical shift clearly confirms the regiochemistry of the cycloaddition and is in line with the values reported by Fokin, Sharpless [47,48,49] and our previous work; i.e., the oxygen atom is bonded to more substituted carbon of an unsymmetrical double or triple bond. In the case of the hypothetical reverse regioisomer 5a, one should expect a chemical shift value for the 5-H proton higher than 6 ppm due to the proximity of the isoxazolinic oxygen atom [50]. The two diastereotopic 6-H protons appear as two doublets at δ = 3.78 and 3.84 ppm with a 2J coupling constant of 15.3 Hz. No allylic coupling with 4-H was noticed. The second set of doublets at 4.74 (d, 1H, J = 15.2 Hz) and 4.85 ppm (d, 1H, J = 15.2 Hz) is attributed to the methylenic protons 6′-H, which are non-equivalent due to hindered rotation. Particularly characteristic are the 13C-NMR isoxazole ring resonances with three peaks at δ = 101.0, δ = 161.9 ppm and δ = 166.3 ppm for the isoxazole carbons 4-C, 5-C and 3-C. The carbon 7-C resonates at δ = 70.2 ppm and the two secondary carbons 6-C and 6′-C are observed at δ = 62.6 and 44.9 ppm, in accordance with the data reported by Fokin and Sharpless [47,48,49]. A further proof of our structural assignment stems from an X-ray structure determination [50] performed on 4a, confirming unambiguously the stereochemistry of the product. Two independent molecules are present in the asymmetric unit of the P21/c space group (Figure 3). The intrinsic racemic property of this space group (presence of improper symmetry operations: inversion and reflections) doesn’t need the presence of two independent molecules in the asymmetric unit for the overall racemic nature of the crystal. Such a presence of two chiral molecules in the asymmetric unit of the centrosymmetric space group is not a common feature of racemic crystals of chiral molecules. It is rather an indication of the low energy barrier upon S/R isomerization. Such a kind of isomerization in 4a may occur during the crystallization process, but it may be also expected that both the relative S and R chiralities centered on the C4 and C34 atoms in two independent molecules should be already present in their solution before crystallization. The metric parameters (bond lengths and angles) observed for both isomers are found in the expected ranges and do not need further comments (Figure 3).

There is a kind of intermolecular hydrogen bonds in the structure of 4a consisting of weak C-H···O interactions leading to the formation of 1D arrays running along the x direction in the xz plane of the crystal lattice. Four associated molecules are shown in Figure 4. The two central ones are present in the asymmetric unit and the two lateral ones stem from the neighboring asymmetric units. The intra asymmetric unit (central) O···H–C (O2···C45/C49) distances are 3.253 and 3.302 Å, respectively. The O···H–C (O5···C5/C26) contacts within the inter-asymmetric unit (external) fall in the similar range of 3.213 and 3.304 Å.

2.2. Spectroscopic Characterization of Triazole 6a

The IR spectrum of 6a shows C=O absorptions bands at 1738 and 1701 cm−1 due to the ester and lactam carbonyls. The combination of 1H- and 13C-NMR spectroscopy allows one to deduce in an unambiguously manner the exclusive formation of triazolic regioisomers 6 as exemplified for 6a. The characteristic signal of triazole proton 5-H appears as a singlet at δ = 6.34 ppm. Moreover, the presence of the 2J coupling constant of 15.2 Hz between the two diastereotopic protons 6-H at δ = 3.66–3.76 and 3.85–3.96 ppm on the one hand and the non-equivalent methylene protons 6′-H at δ = 4.75 and 4.90 ppm on the other hand as observed in the case of the cycloaddition of propargyl-substituted dihydroisoindolin-1-one 3 with arylnitrile oxides 1ad corroborating the structural assignment. An additional proof concerning the regiochemistry of the copper-catalyzed [3+2] cycloaddition reaction is provided by the 13C-NMR data. The chemicals shifts of the carbon atom 5-C at δ = 120.0 ppm and that of carbon 4-C at δ = 143.8 ppm are characteristic for 1,4-disubstituted-1H-1,2,3-triazoles [47,48,49,50,51]. The C atom 4-C of the hypothetical isomeric compound 7a should appear at around 133 ppm [51]. Formation of these regioisomeric 1,5-disubstituted-1H-1,2,3-triazoles has been reported to occur by Ru-catalyzed cycloaddition [52,53], but we are not aware of copper-catalyzed reactions leading to these isomers. The carbon 7-C resonates at δ = 71.5 ppm, and the secondary carbon 6′-Cat δ = 62.7 ppm is downfield-shifted due to of deshielding effect of the nitrogen atom. The XH correlation spectrum of 6a reveals a 1J correlation between the carbon 5-C and the 5-H proton, characteristic of a triazole cycle. The structural assignment of 6a was furthermore confirmed by the analysis of its HMBC spectrum, where a 2J correlation between the proton 5-H and its adjacent carbon 4-C has been established (Figure 5 and Figure 6). The similarity of the spectroscopic data of derivatives 6b, 6c and 6d with those of 6a allows to conclude that all compounds of series 6 are isostructural, regardless of the electron-withdrawing or electron-donating propensity of the substituent at the para-position of the aryl group of azides 2ad.

Leave a Comment


Your email address will not be published. Required fields are marked *