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Article

Efficient Synthesis of 1H-Benzo[4,5]imidazo[1,2-c][1,3]oxazin-1-one Derivatives Using Ag2CO3/TFA-Catalyzed 6-endo-dig Cyclization: Reaction Scope and Mechanistic Study

by
Abdelkarim El Qami
1,2,
Badr Jismy
1,*,
Mohamed Akssira
2,
Johan Jacquemin
3,
Abdellatif Tikad
4,* and
Mohamed Abarbri
1,*
1
Laboratoire de Physico-Chimie des Matériaux et des Electrolytes pour l’Energie (PCM2E), EA 6299, Faculté des Sciences et Techniques, Avenue Monge, Faculté des Sciences, Université de Tours, Parc de Grandmont, 37200 Tours, France
2
Laboratoire de Chimie Physique et Biotechnologies des Biomolécules et des Matériaux (LCP2BM), FSTM, Université Hassan II de Casablanca, B.P. 146, Mohammedia 28800, Morocco
3
Materials Science and Nano-Engineering (MSN) Department, Mohammed VI Polytechnic University (UM6P), Lot 660–Hay Moulay Rachid, Benguerir 43150, Morocco
4
Laboratoire de Chimie Moléculaire et Substances Naturelles, Faculté des Sciences, Université Moulay Ismail, B.P. 11201, Zitoune, Meknès 50050, Morocco
*
Authors to whom correspondence should be addressed.
Molecules 2023, 28(5), 2403; https://doi.org/10.3390/molecules28052403
Submission received: 9 February 2023 / Revised: 27 February 2023 / Accepted: 28 February 2023 / Published: 6 March 2023
(This article belongs to the Special Issue Recent Progress in Heteroorganic Chemistry)
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Abstract

:
A small library of 1H-benzo[4,5]imidazo[1,2-c][1,3]oxazin-1-one derivatives was prepared in good to excellent yields, involving a Ag2CO3/TFA-catalyzed intramolecular oxacyclization of N-Boc-2-alkynylbenzimidazole substrates. In all experiments, the 6-endo-dig cyclization was exclusively achieved since the possible 5-exo-dig heterocycle was not observed, indicating the high regioselectivity of this process. The scope and limitations of the silver catalyzed 6-endo-dig cyclization of N-Boc-2-alkynylbenzimidazoles as substrates, bearing various substituents, were investigated. While ZnCl2 has shown limits for alkynes with an aromatic substituent, Ag2CO3/TFA demonstrated its effectiveness and compatibility regardless of the nature of the starting alkyne (aliphatic, aromatic or heteroaromatic), providing a practical regioselective access to structurally diverse 1H-benzo[4,5]imidazo[1,2-c][1,3]oxazin-1-ones in good yields. Moreover, the rationalization of oxacyclization selectivity in favor of 6-endo-dig over 5-exo-dig was explained by a complementary computational study.

Graphical Abstract

1. Introduction

Fused heteropolycycles containing nitrogen and oxygen in the skeleton constitute an important class of heterocyclic compounds that can be found in numerous biologically active compounds [1,2,3] and natural products [4,5]. Among them, the structural motif 1H-benzo[4,5]imidazo[1,2-c][1,3]oxazin-1-one is present in pharmacologically interesting molecules, which display fungicidal activity (compound A, Figure 1) [6]. In addition, compound B (Figure 1) has been known as a potent recognition site for the detection of the highly toxic phosgene gas [7].
Functionalized alkynes at the ortho position of the carboalkoxy group are among the most common substrates used by organic chemists to generate new polycyclic heterocycles [8,9,10,11,12,13,14,15,16,17,18,19,20]. Thus, the electrophilic activation of a triple bond under acidic conditions or in the presence of a transition metal triggers heterocyclization by intramolecular nucleophilic attack. In most cases, these processes involve the regioselective 6-endo-dig cyclization, as opposed to 5-exo-dig, providing, for example, the total synthesis of several natural products such as Scoparine A and B [21], Thunberginol A [22], (−)-Citreoisocoumarinol, (−)-Citreoisocoumarin, (−)-12-epi-Citreoisocoumarinol and (−)-Mucorisocoumarins A and B [23].
Although the activation of 2-alkynylbenzoates has been extensively studied using a series of metal species including Au [23,24,25,26], Ag [17,27,28], Pt [29,30], In [31], B [15,32], Cu [33,34,35] and Fe [20,36], a limited number of heterocyclizations starting from alkynyl O-alkylcarbamates have been reported in the literature, which have been promoted with only three transition metal catalysts: gold [19,37,38,39], silver [40] and zinc [41,42].
Recently, we have developed Ag2CO3/TFA as a new tandem catalyst for intramolecular oxacyclization of N-Boc-2-alkynyl-4-bromo(alkynyl)-5-methylimidazole producing 3-methylimidazo[1,2-c][1,3]oxazin-5-one derivatives (Figure 2a) [40]. In order to study the efficiency of Ag2CO3/TFA as a catalytic system to promote heterocyclization from other substrates, herein we report the extension of our approach to N-Boc-2-alkynylbenzimidazoles, giving access to 1H-benzo[4,5]imidazo[1,2-c][1,3]oxazin-1-one derivatives (Figure 2c). It is noteworthy that the synthesis of benzimidazoxazinone derivatives has been already described in the literature using ZnCl2-mediated deprotective annulation (Figure 2b) [41]. However, this methodology was limited to aliphatic alkyne since alkynes with an aromatic substituent were not cyclized in this study.
During the preparation of the desired 1H-benzo[4,5]imidazo[1,2-c][1,3]oxazin-1-one 5, the byproduct AgTFA may be recycled from the Ag2CO3/TFA system catalyst for other applications. Considering the environmental impact, the Ag2CO3/TFA is an environmentally benign system catalyst.

2. Results and Discussion

Our synthesis begins with the generation of 2-brominated benzimidazole 2, starting from 2-mercaptobenzimidazole 1, following the known reported procedure [18]. Selective bromination of 1 was performed with bromine and hydrogen bromide in acetic acid at room temperature according to a literature procedure [19], providing 85% yield. Compound 2 was subsequently protected by a tert-butoxycarbonyl group using (Boc)2O as the reagent in the presence of triethylamine in a mixture of MeCN/DMF (1:1) at room temperature leading to compound 3 in 76% yield (Scheme 1). The N-Boc-2-bromobenzimidazole 3 served as a building block to introduce substituted alkynes at the C-2 position via the Sonogashira cross-coupling reaction.
In order to prepare a series of N-Boc-2-alkynylbenzimidazoles 4 as substrates which could undergo intramolecular cyclization, compound 3 was engaged in Sonogashira cross-coupling with several alkynes.
After screening the various conditions, the use of phenylacetylene (1.5 equiv.), Pd(OAc)2 (10 mol%), PPh3 (20 mol%) and CuI (15 mol%) in triethylamine at room temperature proved to be the most appropriate choice conditions for obtaining alkynylated product 4b in excellent yield (Scheme 2).
The scope and limitation of the Sonogashira cross-coupling were investigated starting from N-Boc-2-bromobenzimidazole 3 with various terminal alkynes (Scheme 2). As illustrated in Scheme 2, it was found that the nature of terminal alkynes (aliphatic, aromatic or heteroaromatic) did not dramatically affect the efficiency of this cross-coupling, since, in all cases, the expected compounds were obtained in moderate to good yields. Thus, this procedure is compatible with several substituents (electron-donating or electron-withdrawing groups) on the aryl rings (methoxy, methyl, chlorine, nitro, ester and fluorine groups). Moreover, under the same conditions, alkynes bearing an heteroaryl groups, such as 2-thienyl or 2-pyridyl, were also able to be introduced in satisfactory yields [4k (54%) and 4l (63%)].
Initially, the treatment of N-Boc-2-hexynylbenzimidazole 4a with ZnCl2 (1.5 equiv.) in dichloromethane at 40 °C gave successfully and exclusively the tricyclic core 5a in 80% isolated yield. However, the reaction starting from N-Boc-2-phenylethynylbenzimidazole 4b required a longer time and gave a mixture of the expected product 5b along with the starting material 4b in a 60/40 ratio, respectively (Table 1, entry 2). Increasing the temperature to 60 °C slightly improved the 4b/5b ratio from (60:40) to (50:50) (Table 1, entry 3). These results clearly indicate the inefficiency of ZnCl2 to promote intramolecular cyclization from N-Boc-2-alkynylbenzimidazole derivatives when the substituent of alkyne is an aromatic ring, such as phenyl.
To our delight, the combination of a catalytic amount of Ag2CO3 (0.1 equiv.) and TFA (2 equiv.) significantly improved the conversion of the starting material to 85% while the reaction time decreased to 24 h (Table 1, entry 4). Performing the reaction with dichloroethane as a solvent, instead of dichloromethane, resulted in a complete conversion of the starting material 4b to the target heterocycle 5b, which was isolated in an excellent yield of 90% after purification by silica-gel column chromatography (Table 1, entry 5). Otherwise, dichloroethane has a greater impact on the conversion rate of the reaction, which could be related to its higher boiling point compared to dichloromethane. A suitable solvent is crucial to this reaction. Under the same conditions, decreasing the temperature to 40 °C significantly affected the formation of the desired product 5b, since the conversion of substrate 4b remained incomplete, despite a longer reaction time of 24 h, proving the importance of heating at 60 °C to obtain a full conversion (Table 1, entry 6).
The best results in terms of the time and yields were obtained with Ag2CO3/TFA as a catalytic system. Having established the required conditions for efficient annulation, various N-Boc-2-alkynyl(arylethynyl)benzimidazoles 4a–o, which are suitable substrates to undergo intramolecular cyclization, were subjected to these optimized reaction conditions in order to study the scope and limitations of our process (Scheme 3). All reaction mixtures were stirred at 60 °C until the starting material was completely consumed, monitored by thin-layer chromatography (TLC) using a mixture of petroleum ether/ethyl acetate (v/v = 8/2) as the eluent. The oxacyclization conditions were found to be compatible with a variety of R groups in starting materials 4a–o, such as alkyl, cycloalkyl, aryl and heteroaryl, bearing electron-withdrawing or -donating substituents.
The nature of the substituents on the phenyl ring slightly affected the outcome of the cyclization. As given in Scheme 3, the reactions with the substrates having electron-donating groups, such as methoxy and methyl, were performed efficiently, affording the expected compounds 5c–e in good yields. Benzimidazoles containing chlorine atom as an electron-withdrawing group at the ortho, meta or para position 4f–h were successfully cyclized, giving access to the desired products 5f (51%), 5g (80%) and 5h (92%). As observed, the steric hindrance of the ortho-position seems to substantially influence the cyclization efficiency.
The presence of a strong electron-withdrawing group, such as nitro or carbomethoxy function on the phenylethynyl group, promote the 6-endo-dig cyclization, leading to new fused benzimidazoles in excellent yields [5i (84%) and 5j (95%)]. Encouraged by the good results obtained with different aryl R groups, benzimidazoles bearing ethynylheteroaryl were exposed under the same silver-catalyzed oxacyclization conditions. Interestingly, substrates having an heteroaromatic ring on the triple bond, such as 3-thienyl and 2-pyridyl, were found to also be compatible and exclusively provided the corresponding heterocycles 5k and 5l in 78% and 71% yields, respectively. The intramolecular cyclization of substrates bearing a fluorine atom on the phenyl ring, R = 2-fluorophenyl and R = 4-fluorophenyl, works well, giving the desired compounds in good yields [5m (88%) and 5n (68%)]. When the alkyne substituent is a bulky cyclohexyl group, the cyclization proceeded smoothly and provided the desired heterocycle 5o in excellent 90% yield. It is noteworthy that among the two possible oxacyclization products 5 and 6, only the 6-endo-dig cyclization heterocycle 5 was formed in all experiments, with variations mainly in the isolated yields.

Theoretical Calculation (Computational Studies)

To investigate the reaction pathway, and in particular, to understand the mechanism and stereoselectivity of the annulation reaction catalyzed by Ag2CO3 and TFA, a series of computational experiments were performed by density functional theory (DFT) calculations. The proposed mechanism for the competing intramolecular cyclization pathways of the target benzimidazoxazinone 5b is outlined in Scheme 4.
In order to justify the expected 6-endo annulation, the intermediates and the transition states (TS) of both cyclization pathways [6-endo-dig (path a, blue) or 5-exo-dig (path b, red)] were computed. All the structures were optimized at the B3LYP level in the gas phase and then in DCE (see the Supplementary Materials for details). The energy profiles of different reaction pathways are depicted in Figure 3.
As shown in Figure 3, the energy barriers of the transition states TSIIaendo–TSII’aendo, the intermediate Iaendo and the product 5b for 6-endo-dig oxacyclization (path a, blue) are much lower than those of 5-exo-dig (path b, red). This suggests that the preferential 6-endo-dig lactonization of compound 4b is favored both kinetically and thermodynamically.
To confirm our mechanistic hypothesis, we extended the earlier studies to the calculated natural population analysis (NPA) of each carbon in the alkyne group for all starting materials 4a–o (Table 2).
The calculated NPA revealed that the positive charge is located on the carbon atom denoted β leading to the 6-endo-dig cyclization, while the Cα leading to the undesired annulation (5-exo-dig) product 6b is negatively charged, which is in excellent agreement with the experiment, regardless of the nature of the alkyne substituent.

3. Materials and Methods

3.1. General Information

All reactions were performed under an inert atmosphere of argon in oven-dried glassware equipped with a magnetic stir bar. Solvents for reactions were obtained from Thermo Fisher Scientific in extra dry quality and stored under argon over activated 3 Å sieves. All reagents were purchased from Fluorochem and used as received without additional purification. Reactions were monitored by thin-layer chromatography (TLC) analysis using silica gel 60 F254 plates. All products were visualized by exposure to UV light (longwave at 365 nm or shortwave at 254 nm). Column chromatography was performed using silica gel 60 (230–400.13 mesh, 0.040–0.063 mm). Eluents were distilled by the standard methods before each use. All new compounds were characterized by NMR spectroscopy (1H, 19F and 13C), high-resolution mass spectroscopy (HRMS) and melting point (if solids). NMR spectra were recorded at 300 MHz for 1H, 282 MHz for 19F, and 75 MHz for 13C with a Bruker® 300 MHz NMR spectrometer. Proton and carbon magnetic resonance spectra (1H NMR and 13C NMR) were recorded using tetramethylsilane (TMS) as an external standard and CDCl3 (7.28 ppm for 1H NMR and 77.04 ppm for 13C NMR) or DMSO-d6 (2.50 ppm for 1H NMR and 40.0 ppm for 13C NMR) as internal standards. 19F spectra were unreferenced. Data for NMR are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, sep = septet, m = multiplet and br = broad resonance) and coupling constants J are reported in Hertz (Hz). All NMR spectra were processed in MestReNova. HRMS experiments were performed on a hybrid tandem quadrupole/time-of-flight (Q-TOF) instrument, equipped with a pneumatically assisted electrospray (Z-spray) ion source (Micromass, Manchester, UK) operated in the positive mode. The melting points (Mp [°C]) of samples were measured using open capillary tubes and recorded on a StuartTM melting point apparatus SMP3.
2-Bromobenzimidazole (2).
Compound 2 was prepared from 2-mercaptobenzimidazole according to a reported procedure [43]. Mp 195−196 °C (lit. [44] 191−193 °C, lit. [45] 190–192 °C). 1H NMR (300 MHz, Methanol-d4): δ = 7.52 (dd, J = 6.0, 3.3 Hz, 2H), 7.29−7.23 (m, 2H).
The experimental data are in accordance with the previously reported data [44,45].
2-Bromo-1-tertbutoxycarbonylbenzimidazole (3).
Compound 3 was prepared according to a literature procedure [46]. Mp 64−65 °C. 1H NMR (300 MHz, CDCl3): δ = 7.96−7.92 (m, 1H), 7.72−7.69 (m, 1H), 7.39−7.34 (m, 2H), 1.75 (s, 9H). 13C NMR (75 MHz, CDCl3): δ = 147.3, 142.7, 133.8, 126.9, 125.1, 124.5, 119.4, 114.7, 86.8, 28.0 (3C).
Spectroscopic data are in accordance with the previously reported data [46].

3.2. General Procedure for the Synthesis of Tert-butyl 2-alkynyl-1H-benzimidazole-1-carboxylate (4a–o)

An oven dried 25 mL Schlenk tube equipped with a magnetic stir bar was charged with tert-butyl 2-bromobenzimidazole-1-carboxylate 3 (300 mg, 1.01 mmol), PPh3 (53 mg, 0.2 mmol), Pd(OAc)2 (23 mg, 0.1 mmol), CuI (29 mg, 0.15 mmol) and triethylamine (8 mL). The vial was sealed with a septum-lined pierceable cap, evacuated and backfilled with argon (×3). Then, a solution of alkyne (1.5 mmol, 1.5 equiv.) in 2 mL of Et3N was added dropwise to the reaction mixture via a syringe. The reaction mixture was stirred at room temperature for 20 h under an argon atmosphere. After completion of the reaction (monitored by TLC), the solution was filtered through a plug of celite eluting with ethyl acetate (25 mL) and the combined filtrate was dried with MgSO4 and concentrated under vacuum. The crude product was directly purified by column chromatography using a mixture petroleum ether/EtOAc as an eluent to give the pure desired products 4a–o.
2-Hexynyl-1-tertbutoxycarbonylbenzimidazole (4a).
The crude product was purified by column chromatography on silica gel (PE/EtOAC, 9.8:0.2), followed by recrystallization from Et2O to afford compound 4a as a grey solid (270.7 mg, 90%). Mp 58−59 °C. 1H NMR (300 MHz, CDCl3): δ = 7.99 (dd, J = 6.0, 2.1 Hz, 1H), 7.75 (dd, J = 6.0, 2.1 Hz, 1H), 7.40 (td, J = 7.2, 1.8 Hz, 1H), 7.37 (td, J = 7.2, 1.8 Hz, 1H), 2.55 (t, J = 7.2, 3H), 1.73 (s, 9H), 1.73−1.65 (m, 2H), 1.54 (sext, J = 7.5 Hz, 2H), 0.97 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ = 147.9, 142.5, 136.3, 132.0, 125.6, 124.6, 120.0, 114.8, 98.0, 85.6, 72.3, 30.0, 28.1 (3C), 22.1, 19.5, 13.6. HRMS (ESI): m/z [M+H]+ calcd for C18H23N2O2: 299.1760; found: 299.1755.
2-Phenylethynyl-1-tertbutoxycarbonylbenzimidazole (4b).
The crude product was purified by column chromatography on silica gel (PE/EtOAC, 9.8:0.2), followed by recrystallization from Et2O to afford compound 4b as a beige solid (296 mg, 92%). Mp 108−109 °C. 1H NMR (300 MHz, CDCl3): δ = 8.04 (dd, J = 7.2, 1.8 Hz, 1H), 7.78 (dd, J = 7.2, 1.8 Hz, 1H), 7.70−7.67 (m, 2H), 7.57−7.51 (m, 5H), 1.75(s, 9H). 13C NMR (75 MHz, CDCl3): δ = 147.8, 142.9, 136.1, 132.3, 132.2 (2C), 129.7, 128.5 (2C), 125.9, 124.8, 121.6, 120.3, 114.9, 95.0, 85.9, 80.7, 28.2 (3C). HRMS (ESI): m/z [M+H]+ calcd for C20H19N2O2,: 319.1447; found: 319.1442.
Spectroscopic data are in accordance with the previously reported data [47].
2-(4-Methoxyphenylethynyl)-1-tertbutoxycarbonylbenzimidazole (4c).
The crude product was purified by column chromatography on silica gel (PE/EtOAC, 9:1) followed by recrystallization from Et2O afforded compound 4c as a yellow solid (275.08 mg, 78%). Mp 93−94 °C. 1H NMR (300 MHz, CDCl3): δ = 8.01 (dd, J = 6.9, 2.1 Hz, 1H), 7.79 (dd, J = 6.9, 2.1 Hz, 1H), 7.64−7.60 (m, 2H), 7.41 (td, J = 7.5, 1.8 Hz, 1H), 7.38 (td, J = 7.5, 1.8 Hz, 1H), 7.47 (dt, J = 9.0, 2.1 Hz, 2H), 3.87 (s, 3H), 1.75 (s, 9H). 13C NMR (75 MHz, CDCl3): δ = 160.7, 147.9, 142.9, 136.4, 133.9 (2C), 132.2, 125.7, 124.7, 120.1, 114.9, 114.2 (2C), 113.5, 95.6, 85.8, 79.8, 55.4, 28.2 (3C). HRMS (ESI): m/z [M+H]+ calcd for C21H21N2O3: 349.1552; found: 349.1547.
2-(3-Methylphenylethynyl)-1-tertbutoxycarbonylbenzimidazole (4d).
The crude product was purified by column chromatography on silica gel (PE/EtOAC, 9.8:0.2), followed by recrystallization from Et2O to afford compound 4d as a yellow oil (282.63 mg, 84%). 1H NMR (300 MHz, CDCl3): δ = 8.02 (dd, J = 7.8, 1.8 Hz, 1H), 7.78 (dd, J = 7.8, 1.8 Hz, 1H), 7.50−7.47 (m, 2H), 7.43 (td, J = 7.2, 1.5 Hz, 1H), 7.33−7.24 (m, 2H), 2.40 (s, 3H), 1.75 (s, 9H). 13C NMR (75 MHz, CDCl3): δ = 147.8, 142.9, 138.2, 136.1, 132.7, 132.2, 130.6, 129.3, 128.4, 125.9, 124.8, 121.3, 120.2, 114.9, 95.3, 85.9, 80.4, 28.2 (3C), 21.3. HRMS (ESI): m/z [M+H]+ calcd for C21H21N2O2: 333.1603; found: 333.1597.
2-(4-Methylphenylethynyl)-1-tertbutoxycarbonylbenzimidazoe (4e).
The crude product was purified by column chromatography on silica gel (PE/EtOAC, 9.6:0.4), followed by recrystallization from Et2O to afford compound 4e as a white solid (283 mg, 84%). Mp 61−62 °C. 1H NMR (300 MHz, CDCl3): δ = 8.02 (dd, J = 6.9, 2.1 Hz, 1H), 7.76 (dd, J = 6.9, 2.1 Hz, 1H), 7.57 (d, J = 8.1 Hz, 2H), 7.43−7.37 (m, 2H), 7.22 (d, J = 8.1 Hz, 1H), 2.42 (s, 3H), 1.74 (s, 9H). 13C NMR (75 MHz, CDCl3): δ = 147.9, 142.9, 140.1, 136.2, 132.3, 132.1 (2C), 129.3 (2C), 125.8, 124.3, 102.2, 118.5, 114.9, 95.4, 85.8, 80.2, 28.2 (3C), 21.7. HRMS (ESI): m/z [M+H]+ calcd for C21H21N2O2: 333.1603; found: 333.1602.
2-(2-Chlorophenylethynyl)-1-tertbutoxycarbonylbenzimidazole (4f).
The crude product was purified by column chromatography on silica gel (PE/EtOAC, 9.8:0.2) followed by recrystallization from Et2O afforded compound 4f as a white solid (270 mg, 76%). Mp 110−111 °C. 1H NMR (300 MHz, CDCl3): δ = 8.02 (dd, J = 7.2, 1.8 Hz, 1H), 7.80 (dd, J = 7.2, 1.8 Hz, 1H), 7.70 (dd, J = 7.5, 1.8 Hz, 1H), 7.50−7.29 (m, 5H), 1.73 (s, 9H). 13C NMR (75 MHz, CDCl3): δ = 147.1, 142.9, 136.6, 135.6, 133.9, 132.2, 130.6, 129.6, 126.6, 126.1, 124.9, 121.7, 120.4, 114.9, 91.4, 86.1, 85.0, 28.1 (3C). HRMS (ESI): m/z [M+H]+ calcd for C20H18ClN2O2: 353.1057; found: 353.1053.
2-(3-Chlorophenylethynyl)-1-tertbutoxycarbonylbenzimidazole (4g).
The crude product was purified by column chromatography on silica gel (PE/EtOAC, 9.8:0.2), followed by recrystallization from Et2O to afford compound 4g as a white solid (211 mg, 59%). Mp 102−103 °C. 1H NMR (300 MHz, CDCl3): δ = 8.01 (dd, J = 7.2, 1.5 Hz, 1H), 7.47−7.33 (m, 4H), 7.56 (dt, J = 7.5, 1.5 Hz, 1H), 1.75 (s, 9H). 13C NMR (75 MHz, CDCl3): δ = 147.7, 142.9, 135.6, 134.4, 132.2, 131.9, 130.3, 130.0, 129.8, 126.3, 124.9, 123.3, 120.4, 114.9, 93.2, 86.2, 81.7, 28.2 (3C). HRMS (ESI): m/z [M+H]+ calcd for C20H18ClN2O2: 353.1057; found: 353.1053.
2-(4-Chlorophenylethynyl)-1-tertbutoxycarbonylbenzimidazole (4h).
The crude product was purified by column chromatography on silica gel (PE/EtOAC, 9.8:0.2), followed by recrystallization from Et2O to afford compound 4h as a white solid (340 mg, 95%). Mp 130−131 °C. 1H NMR (300 MHz, CDCl3): δ = 8.02 (dd, J = 7.2, 1.8 Hz, 1H), 7.78 (dd, J = 7.2, 1.8 Hz, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.49−7.39 (m, 2H), 7.34 (d, J = 8.4 Hz, 2H), 1.74 (s, 9H). 13C NMR (75 MHz, CDCl3): δ = 147.8, 142.9, 135.9, 133.7, 133.4 (2C), 132.2, 129.0 (2C), 126.0, 124.9, 120.3, 120.1, 114.9, 93.7, 86.0, 81.6, 28.2 (3C). HRMS (ESI): m/z [M+H]+ calcd for C20H18ClN2O2: 353.1057; found: 353.1053.
2-(3-Nitrophenylethynyl)-1-tertbutoxycarbonylbenzimidazole (4i).
The crude product was purified by column chromatography on silica gel (PE/EtOAC, 9.6:0.4), followed by recrystallization from Et2O to afford compound 4i as a yellow solid (221 mg, 60%). Mp 152−153 °C. 1H NMR (300 MHz, CDCl3): δ = 8.53 (t, J = 1.8 Hz, 1H), 8.30 (ddd, J = 8.1, 2.4, 1.2 Hz, 1H), 8.03−7.95 (m, 2H), 7.81 (d, J = 7.2 Hz, 1H), 7.63 (t, J = 8.1 Hz, 1H), 7.49−7.41 (m, 2H), 1.77 (s, 9H). 13C NMR (75 MHz, CDCl3): δ = 148.2, 147.7, 142.9, 137.7, 135.2, 132.2, 129.7, 126.9, 126.4, 125.1, 124.3, 123.4, 120.6, 115.0, 91.8, 86.3, 82.8, 28.2 (3C). HRMS (ESI): m/z [M+H]+ calcd for C20H18N3O4: 364.1297; found: 364.1298.
2-(4-Methoxycarbonyl-phenylethynyl)-1-tertbutoxycarbonylbenzimidazole (4j).
The crude product was purified by column chromatography on silica gel (PE/EtOAC, 9.6:0.4), followed by recrystallization from Et2O to afford compound 4j as a white solid (190.6 mg, 50%). Mp 157−158 °C. 1H NMR (300 MHz, CDCl3): δ = 8.09 (d, J = 8.7, 2H), 8.04−8.01 (m, 1H), 7.80−7.77 (m, 1H), 7.74 (d, J = 8.7 Hz, 2H), 7.48−7.38 (m, 2H), 3.96 (s, 3H), 1.75 (s, 9H). 13C NMR (75 MHz, CDCl3): δ = 166.3, 147.7, 142.9, 135.5, 132.2, 132.1 (2C), 130.8, 129.6 (2C), 126.2, 126.1, 124.9, 120.4, 114.9, 93.7, 86.1, 83.2, 52.3, 28.1 (3C). HRMS (ESI): m/z [M+H]+ calcd for C22H21N2O4: 377.1501; found: 377.1503.
2-Thiophen-3-ylethynyl-1-tertbutoxycarbonylbenzimidazole (4k).
The crude product was purified by column chromatography on silica gel (PE/EtOAC, 9.8:0.2), followed by recrystallization from Et2O to afford compound 4k as a white solid (178 mg, 54%). Mp 137−138 °C. 1H NMR (300 MHz, CDCl3): δ = 8.05−8.02 (m, 1H), 7.78−7.74 (m, 2H), 7.43−7.31 (m, 4H), 1.75 (s, 9H). 13C NMR (75 MHz, CDCl3): δ = 147.8, 142.9, 136.0, 132.2, 131.4, 129.9, 125.9, 125.8, 124.8, 120.7, 120.2, 114.9, 90.4, 85.9, 80.5, 28.2 (3C). HRMS (ESI): m/z [M+H]+ calcd for C18H17N2O2S: 325.1011; found: 325.1005.
2-(Pyridin-2-ylethynyl)-1-tertbutoxycarbonylbenzimidazole (4l).
The crude product was purified by column chromatography on silica gel (PE/EtOAC, 8:2), followed by recrystallization from Et2O to afford compound 4l as a white solid (204 mg, 63%). Mp 142−143 °C. 1H NMR (300 MHz, CDCl3): δ = 8.69 (d, J = 4.5 Hz, 1H), 8.05 (dd, J = 6.9, 1.5 Hz, 1H), 7.81−7.68 (m, 3H), 7.48−7.31 (m, 3H), 1.75 (s, 9H). 13C NMR (75 MHz, CDCl3): δ = 150.4, 147.7, 142.9, 142.1, 136.1, 135.3, 132.3, 128.2, 126.3, 124.9, 123.8, 120.5, 115.0, 93.2, 86.4, 79.7, 28.1 (3C). HRMS (ESI): m/z [M+H]+ calcd for C19H18N3O2: 320.1399; found: 320.1398.
2-(2-Fluorophenylethynyl)-1-tertbutoxycarbonylbenzimidazole (4m).
The crude product was purified by column chromatography on silica gel (PE/EtOAC, 9.8:0.2), followed by recrystallization from Et2O to afford compound 4m as a yellow solid (283 mg, 84%). Mp 107−108 °C. 1H NMR (300 MHz, CDCl3): δ = 8.06−8.02 (m, 1H), 7.79 (dd, J = 6.9, 1.8 Hz, 1H), 7.67 (td, J = 7.5, 1.8 Hz, 1H), 7.47−7.38 (m, 3H), 7.23−7.14 (m, 2H), 1.73 (s, 9H). 13C NMR (75 MHz, CDCl3): δ = 163.0 (d, J = 252.0 Hz), 147.8, 142.9, 135.6, 134.0, 132.3, 131.5 (d, J = 7.5 Hz), 126.1, 124.9, 124.2 (d, J = 3.5 Hz), 120.4, 115.8 (d, J = 20.2 Hz), 114.9, 110.4 (d, J = 15.7 Hz), 88.4, 86.2, 85.2 (d, J = 3 Hz), 28.0 (3C). 19F NMR (282 MHz, CDCl3): δ = −107.57. HRMS (ESI): m/z [M+H]+ calcd for C20H18FN2O2: 337.1352; found: 337.1346.
2-(4-Fluorophenylethynyl)-1-tertbutoxycarbonylbenzimidazole (4n).
The crude product was purified by column chromatography on silica gel (PE/EtOAC, 9.8:0.2), followed by recrystallization from Et2O to afford compound 4n as a beige solid (262 mg, 77%). Mp 99−100 °C. 1H NMR (300 MHz, CDCl3): δ = 8.01 (dd, J = 6.9, 2.1 Hz, 1H), 7.78 (dd, J = 6.9, 2.1 Hz, 1H), 7.70−7.65 (m, 2H), 7.46−7.37 (m, 2H), 7.15−7.09 (m, 2H), 1.75 (s, 9H). 13C NMR (75 MHz, CDCl3): δ = 163.4 (d, J = 250.5 Hz), 147.8, 142.9, 135.9, 134.3 (d, J = 8.2 Hz, 2C), 132.2, 126.0, 124.9, 120.3, 117.7 (d, J = 3 Hz), 116.0 (d, J = 22.5 Hz, 2C), 114.9, 93.9, 85.9, 80.5 (d, J = 1.5 Hz), 28.15 (3C). 19F NMR (282 MHz, CDCl3): δ = −108.15. HRMS (ESI): m/z [M+H]+ calcd for C20H18FN2O2: 337.1352; found: 337.1346.
2-Cyclohexylethynyl-1-tertbutoxycarbonylbenzimidazole (4o).
The crude product was purified by column chromatography on silica gel (PE/EtOAC, 9.8:0.2), followed by recrystallization from Et2O to afford compound 4o as a beige solid (243 mg, 74%). Mp 79−80 °C. 1H NMR (300 MHz, CDCl3): δ = 7.96 (dd, J = 6.9, 3.3 Hz, 1H), 7.71 (dd, J = 6.9, 2.4 Hz, 1H), 7.41−7.32 (m, 2H), 2.70 (quint, J = 5.7 Hz, 1H), 1.99−1.94 (m, 2H), 1.83−1.77 (m, 2H), 1.73 (s, 9H), 1.71−1.59 (m, 3H), 1.45−1.34 (m, 3H). 13C NMR (75 MHz, CDCl3): δ = 147.9, 142.6, 136.4, 132.1, 125.5, 124.6, 120.0, 114.8, 101.5, 85.6, 72.3, 31.9 (2C), 30.0, 28.1 (3C), 25.7, 24.9 (2C). HRMS (ESI): m/z [M+H]+ calcd for C20H25N2O2: 325.1916; found: 325.1911.

3.3. General Procedure for the Synthesis of Benzo[1′,2′:4,5]imidazo[1,2-c][1,3]oxazin-1-one (5a–o)

To an oven-dried Schlenk tube containing the appropriate N-Boc-2-alkynyl benzimidazole (4a–o) (100 mg, 1 equiv.) in dichloroethane DCE (6 mL), silver carbonate Ag2CO3 (0.1 equiv.) and trifluoroacetic acid TFA (2 equiv.) were added. The reaction mixture was stirred at 60 °C for 6 h under an argon atmosphere. The progress of the reaction was monitored by TLC. After cooling to room temperature, the mixture was concentrated under vacuum. Then, the residue was dissolved in ethyl acetate and washed with water (2 × 30 mL). The combined organic layers were dried with MgSO4 and concentrated under reduced pressure. The crude was purified by column chromatography to give the pure desired benzo[1′,2′: 4,5]imidazo[1,2-c][1,3]oxazin-1-one (5a–o).
3-Butylbenzo[1′,2′:4,5]imidazo[1,2-c][1,3]oxazin-1-one (5a).
Compound 5a was prepared according to the general procedure using 4a (100 mg, 0.34 mmol), Ag2CO3 (9.2 mg, 0.034 mmol) and TFA (76.50 mg, 0.67 mmol). The crude reaction mixture was purified by column chromatography silica gel (PE/EtOAC, 9:1) to provide the product as a white solid (65.77 mg, 81%). Mp 97−98 °C. (lit.17a 92–94 °C). IR (ATR): υ 3056, 2932, 2863, 1755, 1663, 1550, 1447, 1369, 1176, 1094 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.25 (dd, J = 7.2, 1.5 Hz, 1H), 7.81 (dd, J = 7.2, 1.8 Hz, 1H), 7.51 (td, J = 7.5 Hz, 1.8 Hz, 1H), 7.46 (td, J = 7.5, 1.5 Hz, 1H), 6.54 (s, 1H), 2.65 (t, J = 7.5 Hz, 2H), 1.76 (quint, J = 7.5 Hz, 2H), 1.47 (sext, J = 7.2 Hz, 2H), 1 (t, J = 7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ = 162.9, 147.4, 144.1, 129.4, 126.3, 124.9 (2C), 119.7, 114.6, 96.6, 32.8, 28.5, 22.0, 13.7. HRMS (ESI): m/z [M+H]+ calcd for C14H15N2O2: 243.1134; found: 243.1128. The experimental data are in accordance with the previously reported data [41].
3-Phenylbenzo[1′,2′:4,5]imidazo[1,2-c][1,3]oxazin-1-one (5b).
Compound 5b was prepared according to the general procedure using 4b (100 mg, 0.31 mmol), Ag2CO3 (8.67 mg, 0.03 mmol) and TFA (71.83 mg, 0.63 mmol). The crude reaction mixture was purified by column chromatography silica gel (PE/EtOAC, 9:1) to provide the product as a white solid (75.78 mg, 92%). Mp 244−245 °C. IR (ATR): υ 3079, 1760, 1635, 1606, 1543, 1447, 1368, 1171, 1101 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.30 (dd, J = 6.3, 2.1 Hz, 1H), 7.96−7.94 (m, 2H), 7.86 (dd, J = 6.3, 2.1 Hz, 1H), 7.57−7.51 (m, 5H), 7.21 (s, 1H). 13C NMR (75 MHz, CDCl3): δ = 157.5, 147.6, 144.4, 143.5, 131.7, 129.7, 129.5, 129.2 (2C), 126.5, 125.8 (2C), 125.3, 119.8, 114.7, 94.5. HRMS (ESI): m/z [M+H]+ calcd for C16H11N2O2: 263.0821; found: 263.0816.
3-(4-Methoxyphenyl)benzo[1′,2′:4,5]imidazo[1,2-c][1,3]oxazin-1-one (5c).
Compound 5c was prepared according to the general procedure using 4c (100 mg, 0.29 mmol), Ag2CO3 (7.92 mg, 0.029 mmol) and TFA (65.50 mg, 0.57 mmol). The crude reaction mixture was purified by column chromatography silica gel (PE/EtOAC, 8:2) to provide the product as a yellow solid (80 mg, 95%). Mp 225−226 °C. IR (ATR): υ 3041, 2960, 2839, 1751, 1634, 1602, 1506, 1370, 1241, 1181, 1107 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.29 (dd, J = 7.2, 1.5 Hz, 1H), 7.91−7.87 (m, 2H), 7.84 (d, J = 9.0 Hz, 1H), 7.54 (td, J = 7.2, 1.5 Hz, 1H), 7.49 (t, J = 7.2 Hz, 1H), 7.08 (s, 1H), 7.07−7.03 (m, 2H), 3.91 (s, 3H). 13C NMR (75 MHz, CDCl3): δ = 162.4, 157.4, 148.0, 144.6, 143.7, 134.1, 127.5 (2C), 126.4, 125.0, 122.0, 119.7, 114.6 (3C), 92.6, 55.5. HRMS (ESI): m/z [M+H]+ calcd for C17H13N2O3: 293.0926; found: 293.0921.
3-(3-Methylphenyl)benzo[1′,2′:4,5]imidazo[1,2-c][1,3]oxazin-1-one (5d).
Compound 5d was prepared according to the general procedure using 4d (100 mg, 0.30 mmol), Ag2CO3 (8.3 mg, 0.03 mmol) and TFA (68.7 mg, 0.60 mmol). The crude reaction mixture was purified by column chromatography silica gel (PE/EtOAC, 9:1) to provide the product as a white solid (57.07 mg, 79%). Mp 222−223 °C. IR (ATR): υ 3056, 2922, 1755, 1644, 1549, 1447, 1372, 1278, 1174, 1101 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.32 (dd, J = 6.9, 1.8 Hz, 1H), 7.88 (dd, J = 6.9, 1.8 Hz, 1H), 7.75 (d, J = 9.3 Hz, 2H), 7.57 (td, J = 7.5, 1.5 Hz, 1H), 7.53 (td, J = 7.5, 1.5 Hz, 1H), 7.47−7.37 (m, 2H), 7.25 (s, 1H), 2.49 (s, 3H). 13C NMR (75 MHz, CDCl3): δ = 157.7, 147.7, 144.2, 143.6, 139.1, 132.5, 129.6, 129.4, 129.1, 126.5, 126.3, 125.3, 123.0, 119.8, 114.7, 94.3, 21.5. HRMS (ESI): m/z [M+H]+ calcd for C17H13N2O2: 277.0977; found: 277.0971.
3-(4-Methylphenyl)benzo[1′,2′:4,5]imidazo[1,2-c][1,3]oxazin-1-one (5e).
Compound 5e was prepared according to the general procedure using 4e (100 mg, 0.30 mmol), Ag2CO3 (8.30 mg, 0.03 mmol) and TFA (68.65 mg, 0.60 mmol). The crude reaction mixture was purified by column chromatography silica gel (PE/EtOAC, 9:1) to provide the product as a white solid (58 mg, 70%). Mp 246−247 °C. IR (ATR): υ 3075, 3023, 2969, 2921, 1766, 1639, 1606, 1547, 1371, 1100 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.30 (dd, J = 6.9, 1.8 Hz, 1H), 7.86−7.85 (m, 1H), 7.82 (d, J = 8.1 Hz, 2H), 7.57−7.47 (m, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.14 (s, 1H), 2.46 (s, 3H). 13C NMR (75 MHz, CDCl3): δ = 157.7, 147.8, 144.4, 143.6, 142.4, 129.9 (2C), 129.4, 126.9, 126.4, 125.7 (2C), 125.1, 119.7, 114.6, 96.6, 21.5. HRMS (ESI): m/z [M+H]+ calcd for C17H13N2O2: 277.0977; found: 277.0976.
3-(2-Chlorophenyl)benzo[1′,2′:4,5]imidazo[1,2-c][1,3]oxazin-1-one (5f).
Compound 5f was prepared according to the general procedure using 4f (100 mg, 0.28 mmol), Ag2CO3 (7.8 mg, 0.028 mmol) and TFA (64.80 mg, 0.57 mmol). The crude reaction mixture was purified by column chromatography silica gel (PE/EtOAC, 9:1) to provide the product as a white solid (43 mg, 51%). Mp 179−180 °C. IR (ATR): υ 3054, 1770, 1642, 1548, 1435, 1367, 1173, 1097 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.32 (dd, J = 6.6, 2.4 Hz, 1H), 7.88 (dd, J = 6.9, 1.8 Hz, 1H), 7.82−7.79 (m, 1H), 7.60−7.45 (m, 5H), 7.33 (s, 1H). 13C NMR (75 MHz, CDCl3): δ = 155.1, 143.7 (2C), 132.8, 132.0, 131.9, 131.2, 130.5, 129.4, 127.4, 127.3, 126.6, 125.6, 120.1, 114.9, 100.8. HRMS (ESI): m/z [M+H]+ calcd for C16H10ClN2O2: 297.0431; found: 297.0427.
3-(3-Chlorophenyl)benzo[1′,2′:4,5]imidazo[1,2-c][1,3]oxazin-1-one (5g).
Compound 5g was prepared according to the general procedure using 4g (100 mg, 0.28 mmol), Ag2CO3 (7.8 mg, 0.028 mmol) and TFA (64.8 mg, 0.57 mmol). The crude reaction mixture was purified by column chromatography silica gel (PE/EtOAC, 9:1) to provide the product as a white solid (66 mg, 80%). Mp 201−202 °C. IR (ATR): υ 3070, 1768, 1640, 1569, 1367, 1098 cm–1. 1H NMR (300 MHz, DMSO-d6): δ = 8.18−8.15 (m, 1H), 8.11 (s, 1H), 8.01 (d, J = 6.9 Hz, 1H), 7.91 (s, 1H), 7.86−7.82 (m, 1H), 7.64−7.51 (m, 4H). 13C NMR (75 MHz, CDCl3): δ = 166.6, 155.8, 135.5, 133.3, 131.6, 131.5, 130.5, 129.4, 126.7, 125.8, 125.6, 123.8, 120.1, 120.0, 114.7, 95.5. HRMS (ESI): m/z [M+H]+ calcd for C16H10ClN2O2: 297.0431; found: 297.0428.
3-(4-Chlorophenyl)benzo[1′,2′:4,5]imidazo[1,2-c][1,3]oxazin-1-one (5h).
Compound 5h was prepared according to the general procedure using 4h (100 mg, 0.28 mmol), Ag2CO3 (7.8 mg, 0.028 mmol) and TFA (64.8 mg, 0.57 mmol). The crude reaction mixture was purified by column chromatography silica gel (PE/EtOAC, 9:1) to provide the product as a white solid (77.34 mg, 92%). Mp 256−257 °C. IR (ATR): υ 3080, 1766, 1640, 1540, 1408, 1113 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.29 (d, J = 7.5 Hz, 1H), 7.87 (d, J = 8.7 Hz, 3H), 7.53 (d, J = 8.7 Hz, 4H), 7.17 (s, 1H). 13C NMR (75 MHz, CDCl3): δ = 163.3, 156.2, 147.3, 144.6, 143.3, 137.9, 129.6 (2C), 128.2, 127.0 (2C), 126.6, 125.4, 120.0, 114.6, 94.9. HRMS (ESI): m/z [M+H]+ calcd for C16H10ClN2O2: 297.0431; found: 297.0427.
3-(3-Nitrophenyl)benzo[1′,2′:4,5]imidazo[1,2-c][1,3]oxazin-1-one (5i).
Compound 5i was prepared according to the general procedure using 4i (100 mg, 0.28 mmol), Ag2CO3 (7.6 mg, 0.028 mmol) and TFA (62.8 mg, 0.55 mmol). The crude reaction mixture was purified by column chromatography silica gel (PE/EtOAC, 6:4) to provide the product as a yellow solid (71 mg, 84%). Mp 284−285 °C. IR (ATR): υ 3090, 1749, 1644, 1525, 1367, 1173, 1101 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.8 (s, 1H), 8.42 (d, J = 8.1 Hz, 1H), 8.35−8.33 (m, 1H), 8.26 (d, J = 8.1 Hz, 1H), 7.92−7.90 (m, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.58−7.56 (m, 2H), 7.36 (s, 1H). 13C NMR (75 MHz, CDCl3/TFA-d1): δ = 162.0, 149.0, 147.0, 139.9, 132.6, 131.7, 131.2, 130.2, 129.2, 129.1, 128.5, 126.8, 122.0, 115.8, 115.7, 91.0. HRMS (ESI): m/z [M+H]+ calcd for C16H9N3O4: 308.0666; found: 308.0663.
3-(4-Methoxycarbonylphenyl)benzo[1′,2′:4,5]imidazo[1,2-c][1,3]oxazin-1-one (5j).
Compound 5j was prepared according to the general procedure using 4j (100 mg, 0.27 mmol), Ag2CO3 (7.3 mg, 0.027 mmol) and TFA (60.6 mg, 0.53 mmol). The crude reaction mixture was purified by column chromatography silica gel (PE/EtOAC, 7:3) to provide the product as a white solid (81 mg, 95%). Mp 262−263 °C.IR (ATR): υ 3080, 2949, 2846, 1763, 1718, 1639, 1542, 1413, 1376, 1270, 1106 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.31 (d, J = 6.6 Hz, 1H), 8.21(d, J = 8.1 Hz, 2H), 8.01 (d, J = 8.1 Hz, 2H), 7.88 (d, J = 6.6 Hz, 1H), 7.59−7.52 (m, 2H), 7.31 (s, 1H), 3.99 (s, 3H). 13C NMR (75 MHz, CDCl3/ TFA-d1): δ = 166.6, 163.2, 147.2, 140.3, 134.7, 131.4 (2C), 130.8, 130.0, 128.8, 127.2 (2C), 127.0, 126.8, 115.9, 115.7, 90.7, 53.2. HRMS (ESI): m/z [M+H]+ calcd for C16H10ClN2O2: 321.0875; found: 321.0875.
3-(2-Thiophenyl)benzo[1′,2′:4,5]imidazo[1,2-c][1,3]oxazin-1-one (5k).
Compound 5k was prepared according to the general procedure using 4k (100 mg, 0.31 mmol), Ag2CO3 (8.5 mg, 0.031 mmol) and TFA (70.4 mg, 0.62 mmol). The crude reaction mixture was purified by column chromatography silica gel (PE/EtOAC, 9:1) to provide the product as a white solid (64.5 mg, 78%). Mp 239−240 °C. IR (ATR): υ 3096, 1760, 1637, 1548, 1368, 1246, 1099 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.28 (d, J = 7.2 Hz, 1H), 8.03 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.56−7.47 (m, 4H), 7.0 (s, 1H). 13C NMR (75 MHz, CDCl3): δ = 153.7, 147.8, 144.6, 132.0, 129.6, 127.8, 126.6, 126.4, 125.2, 124.0, 124.4, 119.8, 114.6, 94.0. HRMS (ESI): m/z [M+H]+ calcd for C14H9N2O2S: 269.0385; found: 269.0379.
3-Pyridin-2-ylbenzo[1′,2′:4,5]imidazo[1,2-c][1,3]oxazin-1-one (5l).
Compound 5l was prepared according to the general procedure using 4l (100 mg, 0.31 mmol), Ag2CO3 (8.6 mg, 0.031 mmol) and TFA (71.50 mg, 0.63 mmol). The crude reaction mixture was purified by column chromatography silica gel (PE/EtOAC, 6:4) to provide the product as a white solid (59 mg, 71%). Mp 240−241 °C. IR (ATR): υ 3060, 1762, 1644, 1575, 1464, 1364, 1171, 1101 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.76 (d, J = 3.9 Hz, 1H), 8.31 (dd, J = 6.6, 1.2 Hz, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.94−7.88 (m, 3H), 7.58−7.51 (m, 1H), 7.54 (s, 1H), 7.44 (ddd, J = 7.8, 4.8, 1.2 Hz). 13C NMR (75 MHz, CDCl3): δ = 155.8, 150.3, 147.6, 147.3, 144.7, 143.4, 137.2, 129.5, 126.5, 125.5, 125.4, 120.5, 120.2, 114.7, 96.7. HRMS (ESI): m/z [M+H]+ calcd for C15H10N3O2: 264.0773; found: 264.0771.
3-(2-Fluorophenyl)benzo[1′,2′:4,5]imidazo[1,2-c][1,3]oxazin-1-one (5m).
Compound 5m was prepared according to the general procedure using 4m (100 mg, 0.30 mmol), Ag2CO3 (8.2 mg, 0.030 mmol) and TFA (67.8 mg, 0.6 mmol). The crude reaction mixture was purified by column chromatography silica gel (PE/EtOAC, 9:1) to provide the product as a yellow solid (73.32 mg, 88%). Mp 180−181 °C. IR (ATR): υ 3090, 1767, 1631, 1539, 1445, 1369, 1217, 1036 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.30 (dd, J = 6.0, 2.1 Hz, 1H), 8.05 (td, J = 7.8, 1.5 Hz, 1H), 7.87 (dd, J = 6.0, 1.8 Hz, 1H), 7.58−7.52 (m, 3H), 7.49 (s, 1H), 7.36 (td, J = 7.8, 0.9 Hz, 1H), 7.31−7.24 (m, 1H). 13C NMR (75 MHz, CDCl3): δ = 160.5 (d, J = 253.5 Hz), 151.8, 147.4, 144.6, 143.3, 132.8 (d, J = 9.0 Hz), 129.4, 128.3, 126.5, 125.42, 124.9 (d, J = 3.7 Hz), 120.0, 118.2 (d, J = 9.7 Hz), 116.8 (d, J = 22.5 Hz), 114.7, 99.8 (d, J = 17.2 Hz). 19F NMR (282 MHz, CDCl3): δ = −110.17. HRMS (ESI): m/z [M+H]+ calcd for C16H10FN2O2: 281.0726; found: 281.0722.
3-(4-Fluorophenyl)benzo[1′,2′:4,5]imidazo[1,2-c][1,3]oxazin-1-one (5n).
Compound 5n was prepared according to the general procedure using 4n (100 mg, 0.30 mmol), Ag2CO3 (8.2 mg, 0.03 mmol) and TFA (67.80 mg, 0.6 mmol). The crude reaction mixture was purified by column chromatography silica gel (PE/EtOAC, 9:1) to provide the product as a white solid (57 mg, 68%). Mp 239−240 °C. IR (ATR): υ 3089, 3022, 1770, 1635, 1601, 1508, 1449, 1238, 1101 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.30 (dd, J = 6.0, 1.8 Hz, 1H), 7.97−7.93 (m, 2H), 7.86 (dd, J = 6.0, 1.8 Hz, 1H), 7.56 (td, J = 7.2, 1.5 Hz, 1H), 7.52 (td, J = 7.5, 1.5 Hz, 1H), 7.29−7.23 (m, 2H), 7.17 (s, 1H). 13C NMR (75 MHz, CDCl3): δ = 164.2 (d, J = 249.0 Hz), 155.9, 148.8, 144.7, 144.0, 129.8, 128.7 (d, J = 8.2 Hz, 2C), 127.1 (d, J = 3 Hz), 126.4, 125.1, 119.9, 116.8 (d, J = 21.7 Hz, 2C), 114.5, 95.4. 19F NMR (282 MHz, CDCl3): δ = −106.68. HRMS (ESI): m/z [M+H]+ calcd for C16H10FN2O2: 281.0726; found: 281.0722.
3-Cyclohexylbenzo[1′,2′:4,5]imidazo[1,2-c][1,3]oxazin-1-one (5o).
Compound 5o was prepared according to the general procedure using 4o (100 mg, 0.31 mmol), Ag2CO3 (8.5 mg, 0.031 mmol) and TFA (70.3 mg, 0.62 mmol). The crude reaction mixture was purified by column chromatography silica gel (PE/EtOAC, 9:1) to provide the product as a white solid (74.43 mg, 90%). Mp 160−161 °C. IR (ATR): υ 3090, 2925, 2855, 1765, 1665, 1554, 1449, 1366, 1155, 1088 cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.26 (d, J = 7.5 Hz, 1H), 7.82 (d, J = 7.2 Hz, 1H), 7.51 (td, J = 7.5, 1.5 Hz, 1H), 7.46 (t, J = 7.2 Hz, 1H), 6.54 (s, 1H), 2.60−2.51 (m, 1H), 2.12−2.08 (m, 2H), 1.94−1.90 (m, 2H), 1.82−1.78 (m, 1H), 1.57−1.27 (m, 5H). 13C NMR (75 MHz, CDCl3): δ = 166.7, 147.7, 144.2, 129.5, 126.2, 124.9 (2C), 119.7, 114.6, 94.8, 41.5, 30.1 (2C), 25.7 (2C), 25.6. HRMS (ESI): m/z [M+H]+ calcd for C16H17N2O2: 269.1290; found: 269.1286.

3.4. Details of DFT Calculations

The structure of each studied species was optimized by using the Turbomole 7.4 program package [48]. Before their visualization using TmoleX (version 4.5.3), the structure of each individual species was optimized in the gas phase, with a convergence criterion of 10−8 Hartree, using the hybrid functional B3LYP and the triplet-ζ basis set 6-311 + G* [49] to collect its more stable 3D conformer. The stability of each structure was then investigated during further DFT calculations. During this step, the energy of each species was then minimized again using DFT calculations combining the Resolution of Identity (RI) approximation [50,51], within the Turbomole 7.4 program package using the B3LYP function with the def2-TZVP basis set [52,53,54]. All minimum energy structures were obtained with full optimization, without constraints. Corrections for long-range non-bonding interactions were given using the Grimme D3 dispersion model [54,55]. An implicit solvent model was additionally undertaken, using the COSMO Model implemented in Turbomole to determine thermodynamic and charge population properties in DCE. Analytical frequencies were then run on each structure at 1 atm and 298.15 K to finally calculate each energy.

4. Conclusions

In conclusions, we have reported an efficient and general access to 1H-benzo[4,5]imidazo[1,2-c][1,3]oxazin-1-ones, involving an intramolecular deprotective heterocyclization sequence catalyzed by a combination between Ag2CO3 and TFA in dichloroethane at 60 °C. While this procedure is compatible with a wide range of aliphatic, aromatic and heteroaromatic alkynes, ZnCl2-mediated heterocyclization showed a limitation when the starting alkyne was aromatic. In all experiments, no trace of 5-exo-dig heterocycles was observed, since only the 6-endo-dig products were obtained exclusively in good to excellent yields, proving the high selectivity of this silver-catalyzed oxacyclization. In addition, a computational study was performed in order to rationalize the mechanism of 6-endo-dig oxacyclization and it was found that experimental results are in a good agreement with the theoretical calculation. The synthetic potential of our catalytic system (Ag2CO3/TFA) to promote intramolecular 6-endo-dig cyclization showed that N-Boc-2-alkynyl-imidazole and N-Boc-2-alkynyl-benzimidazole substrates are interesting for the synthesis of other new polycyclic heterocycles.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules28052403/s1, Section S1. Copies of 1H, 13C and 19F NMR spectra, Section S2. Details of DFT calculations, Section S3. References.

Author Contributions

Conceptualization, A.E.Q. and B.J.; methodology, A.E.Q. and B.J.; software, J.J. and B.J.; validation, B.J. and M.A. (Mohamed Abarbri); formal analysis, J.J., A.E.Q. and B.J.; investigation, B.J. and M.A. (Mohamed Abarbri); resources, M.A. (Mohamed Abarbri); data curation, A.E.Q. and B.J.; writing—original draft preparation, A.T. and B.J.; writing—review and editing, M.A. (Mohamed Abarbri); visualization, A.T., B.J. and M.A. (Mohamed Abarbri); supervision, M.A. (Mohamed Abarbri), B.J. and M.A. (Mohamed Akssira); project administration, B.J. and M.A. (Mohamed Abarbri); funding acquisition, M.A. (Mohamed Abarbri). All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data set presented in this study is available in this article.

Acknowledgments

We thank the “Departement d’Analyses Chimiques et Medicales” (Tours, France) for the chemical analyses.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds 1–3, 4a–o and 6a–o are available from the authors.

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Molecules 28 02403 g001 550
Figure 1. Several fused active heterocycles containing the 1H-benzo[4,5]imidazo[1,2-c][1,3]oxazin-1-one core.
Figure 1. Several fused active heterocycles containing the 1H-benzo[4,5]imidazo[1,2-c][1,3]oxazin-1-one core.
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Molecules 28 02403 g002 550
Figure 2. Known procedures for the cyclization of N-Boc-2-alkynylimidazoles and N-Boc-2-alkynylbenzimidazoles. (a) [40]; (b) [41]; (c) This work.
Figure 2. Known procedures for the cyclization of N-Boc-2-alkynylimidazoles and N-Boc-2-alkynylbenzimidazoles. (a) [40]; (b) [41]; (c) This work.
Molecules 28 02403 g002
Molecules 28 02403 sch001 550
Scheme 1. Synthesis of N-Boc-2-bromobenzimidazole 3.
Scheme 1. Synthesis of N-Boc-2-bromobenzimidazole 3.
Molecules 28 02403 sch001
Molecules 28 02403 sch002 550
Scheme 2. Scope of the Sonogashira coupling of N-Boc-2-bromobenzimidazole 3 with various alkynes.
Scheme 2. Scope of the Sonogashira coupling of N-Boc-2-bromobenzimidazole 3 with various alkynes.
Molecules 28 02403 sch002
Molecules 28 02403 sch003 550
Scheme 3. Ag2CO3/TFA-mediated annulation of N-Boc-2-alkynyl-benzimidazoles 4a–o.
Scheme 3. Ag2CO3/TFA-mediated annulation of N-Boc-2-alkynyl-benzimidazoles 4a–o.
Molecules 28 02403 sch003
Molecules 28 02403 sch004 550
Scheme 4. Projected computational reaction mechanism.
Scheme 4. Projected computational reaction mechanism.
Molecules 28 02403 sch004
Molecules 28 02403 g003 550
Figure 3. DFT-computed relative free energy of each intermediate and transition state.
Figure 3. DFT-computed relative free energy of each intermediate and transition state.
Molecules 28 02403 g003
Table
Table 1. Optimization of oxacyclization reaction conditions.
Table 1. Optimization of oxacyclization reaction conditions.
Molecules 28 02403 i001
EntryRSolventCatalyst (Equiv.)Additive (Equiv.)T (°C)Time (h)Ratio (%) a
4/5
1n-BuDCMZnCl2 (1.5) [41]-4030/100 b
2PhDCMZnCl2 (1.5)-404860/40
3PhDCMZnCl2 (1.5)-604850/50
4PhDCMAg2CO3 (0.1)TFA (2)602415/85
5PhDCEAg2CO3 (0.1) [40]TFA (2)6060/100 c
6PhDCEAg2CO3 (0.1)TFA (2)40245/95
a The ratio of mixture (4/5) was calculated from the crude 1H NMR spectrum. b Compound 5a was isolated in 80% yield after purification by silica-gel column chromatography. c Compound 5b was isolated in 90% yield after purification by silica-gel column chromatography.
Table
Table 2. NPA charges for the alkyne carbons Cα and Cβ of compounds 4a–o.
Table 2. NPA charges for the alkyne carbons Cα and Cβ of compounds 4a–o.
Molecules 28 02403 i002
EntryComp.ChargeEntryComp.Charge
14aα = −0.100
β = +0.125		94iα = −0.012
β = +0.064
24bα = −0.041
β = +0.078		104jα = −0.020
β = +0.069
34cα = −0.057
β = +0.082		114kα = −0.018
β = +0.038
44dα = −0.045
β = +0.081		124lα = −0.017
β = +0.059
54eα = −0.049
β = +0.080		134mα = −0.023
β = +0.070
64fα = −0.018
β = +0.071		144nα = −0.038
β = +0.075
74gα = −0.026
β = +0.070		154oα = −0.095
β = +0.130
84hα = −0.032
β = +0.073		------
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El Qami, A.; Jismy, B.; Akssira, M.; Jacquemin, J.; Tikad, A.; Abarbri, M. Efficient Synthesis of 1H-Benzo[4,5]imidazo[1,2-c][1,3]oxazin-1-one Derivatives Using Ag2CO3/TFA-Catalyzed 6-endo-dig Cyclization: Reaction Scope and Mechanistic Study. Molecules 2023, 28, 2403. https://doi.org/10.3390/molecules28052403

AMA Style

El Qami A, Jismy B, Akssira M, Jacquemin J, Tikad A, Abarbri M. Efficient Synthesis of 1H-Benzo[4,5]imidazo[1,2-c][1,3]oxazin-1-one Derivatives Using Ag2CO3/TFA-Catalyzed 6-endo-dig Cyclization: Reaction Scope and Mechanistic Study. Molecules. 2023; 28(5):2403. https://doi.org/10.3390/molecules28052403

Chicago/Turabian Style

El Qami, Abdelkarim, Badr Jismy, Mohamed Akssira, Johan Jacquemin, Abdellatif Tikad, and Mohamed Abarbri. 2023. "Efficient Synthesis of 1H-Benzo[4,5]imidazo[1,2-c][1,3]oxazin-1-one Derivatives Using Ag2CO3/TFA-Catalyzed 6-endo-dig Cyclization: Reaction Scope and Mechanistic Study" Molecules 28, no. 5: 2403. https://doi.org/10.3390/molecules28052403

APA Style

El Qami, A., Jismy, B., Akssira, M., Jacquemin, J., Tikad, A., & Abarbri, M. (2023). Efficient Synthesis of 1H-Benzo[4,5]imidazo[1,2-c][1,3]oxazin-1-one Derivatives Using Ag2CO3/TFA-Catalyzed 6-endo-dig Cyclization: Reaction Scope and Mechanistic Study. Molecules, 28(5), 2403. https://doi.org/10.3390/molecules28052403

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