A Zinc-Mediated Deprotective Annulation Approach to New Polycyclic Heterocycles

A straightforward approach to new polycyclic heterocycles, 1H-benzo[4,5]imidazo[1,2-c][1,3]oxazin-1-ones, is presented. It is based on the ZnCl2-promoted deprotective 6-endo-dig heterocyclization of N-Boc-2-alkynylbenzimidazoles under mild conditions (CH2Cl2, 40 °C for 3 h). The zinc center plays a dual role, as it promotes Boc deprotection (with formation of the tert-butyl carbocation, which can be trapped by substrates bearing a nucleophilic group) and activates the triple bond toward intramolecular nucleophilic attack by the carbamate group. The structure of representative products has been confirmed by X-ray diffraction analysis.


Introduction
The development of efficient methods for the synthesis of high value added polycyclic heterocyclic derivatives by metal-promoted annulation of acyclic precursors is one of the most important area of research in heterocyclic chemistry [1][2][3][4][5]. Polycyclic heterocyclic systems, in fact, are largely present as fundamental cores in natural products and in biologically active compounds [6][7][8][9][10][11], and the possibility to obtain them by a simple cyclization process starting from readily available substrates is particularly attractive [1][2][3][4][5].

Results and Discussion
It is well known that zinc (II) compounds are able to promote Boc deprotection [49][50][51][52][53][54]. In particular, an excess of ZnBr 2 has been successfully employed for the deprotection of N-Boc secondary amines [52] as well as of tert-butyl esters [53,54]. Considering the importance of developing new approaches to the synthesis of polycyclic heterocycles by heterocyclization processes promoted by non-noble and inexpensive metal species, we have explored the possibility to access new polycyclic heterocycles, that are 1H-benzo [4,5]imidazo [1,2c] [1,3]oxazin-1-ones 2, starting from readily available N-Boc-2-alkynylbenzimidazoles 1, by Zn(II)-assisted deprotective heterocyclization (Scheme 1). According to our rationale, the zinc center should play a double role, that is, to promote deprotection to give a carbamate species A (with elimination of isobutene and H + from the ensuing tert-butyl carbocation [52][53][54]) and then assist a 6-endo-dig heterocyclization by intramolecular nucleophilic attack of the free carbamate group of species B (in equilibrium with A) on the triple bond activated by coordination to Zn 2+ (with the zinc center stabilized by chelation by the benzimidazole nitrogen). This would lead to organizinc intermediate C, whose protonolysis would then afford the polycyclic heterocycles 2 (Scheme 2; zinc counteranions have been omitted for clarity).

Results and Discussion
It is well known that zinc (II) compounds are able to promote Boc deprotection [49][50][51][52][53][54]. In particular, an excess of ZnBr2 has been successfully employed for the deprotection of N-Boc secondary amines [52] as well as of tert-butyl esters [53,54]. Considering the importance of developing new approaches to the synthesis of polycyclic heterocycles by heterocyclization processes promoted by non-noble and inexpensive metal species, we have explored the possibility to access new polycyclic heterocycles, that are 1Hbenzo [4,5]imidazo [1,2-c] [1,3]oxazin-1-ones 2, starting from readily available N-Boc-2alkynylbenzimidazoles 1, by Zn(II)-assisted deprotective heterocyclization (Scheme 1). According to our rationale, the zinc center should play a double role, that is, to promote deprotection to give a carbamate species A (with elimination of isobutene and H + from the ensuing tert-butyl carbocation [52][53][54]) and then assist a 6-endo-dig heterocyclization by intramolecular nucleophilic attack of the free carbamate group of species B (in equilibrium with A) on the triple bond activated by coordination to Zn 2+ (with the zinc center stabilized by chelation by the benzimidazole nitrogen). This would lead to organizinc intermediate C, whose protonolysis would then afford the polycyclic heterocycles 2 (Scheme 2; zinc counteranions have been omitted for clarity).
In spite of the low yield, this initial result was encouraging, since it confirmed the validity of our work hypothesis and the possibility to synthesize novel polycyclic heterocycles with a very simple approach and using an inexpensive promoter. In order to improve the reaction performance, and achieve a higher 2a yield, we then changed some operative parameters ( In spite of the low yield, this initial result was encouraging, since it confirmed the validity of our work hypothesis and the possibility to synthesize novel polycyclic heterocycles with a very simple approach and using an inexpensive promoter. In order to improve the reaction performance, and achieve a higher 2a yield, we then changed some operative parameters (  11). This result, associated with the lower cost of ZnCl 2 , made ZnCl 2 the promoter of choice for realizing the transformation of 1a into benzimidazoxazinone 2a and for the subsequent extension to other differently substituted substrates (Table 2). Thus, to assess the generality of the reaction, various N-Boc-alkynylbenzimidazoles 1 (bearing different R 1 and R 2 groups; prepared as detailed in the Supplementary Materials) were subjected to the optimized reaction conditions with ZnCl 2 as the promoter ( Table 2, entries 2-15). while more diluted conditions led to a lower 2a yield (Table 1, entry 8). Predictably, a faster reaction was observed at 40 °C rather than 25 °C, with a higher yield of 2a (Table 1, entry 9) with respect to the initial experiment (Table 1, entry 1). Under the optimized conditions (40 °C in CH2Cl2 in the presence of 1.5 equiv of ZnBr2, with a substrate concentration of 1 mmol per mL of solvent), 2a could be finally obtained in a yield as high as 79% (Table 1, entry 10).  Very interestingly, the reaction was also successful using ZnCl2 (  (Table 2). Thus, to assess the generality of the reaction, various N-Boc-alkynylbenzimidazoles 1 (bearing different R 1 and R 2 groups; prepared as detailed in the Supplementary Materials) were subjected to the optimized reaction conditions with ZnCl2 as the promoter ( Table 2, entries 2-15). Very interestingly, the reaction was also successful using ZnCl2 (  (Table 2). Thus, to assess the generality of the reaction, various N-Boc-alkynylbenzimidazoles 1 (bearing different R 1 and R 2 groups; prepared as detailed in the Supplementary Materials) were subjected to the optimized reaction conditions with ZnCl2 as the promoter ( Table 2, entries 2-15). Very interestingly, the reaction was also successful using ZnCl2 (  (Table 2). Thus, to assess the generality of the reaction, various N-Boc-alkynylbenzimidazoles 1 (bearing different R 1 and R 2 groups; prepared as detailed in the Supplementary Materials) were subjected to the optimized reaction conditions with ZnCl2 as the promoter ( Table 2, entries 2-15). Very interestingly, the reaction was also successful using ZnCl2 (  (Table 2). Thus, to assess the generality of the reaction, various N-Boc-alkynylbenzimidazoles 1 (bearing different R 1 and R 2 groups; prepared as detailed in the Supplementary Materials) were subjected to the optimized reaction conditions with ZnCl2 as the promoter (Table 2, entries 2-15). Very interestingly, the reaction was also successful using ZnCl2 (  (Table 2). Thus, to assess the generality of the reaction, various N-Boc-alkynylbenzimidazoles 1 (bearing different R 1 and R 2 groups; prepared as detailed in the Supplementary Materials) were subjected to the optimized reaction conditions with ZnCl2 as the promoter (Table 2, entries 2-15). Very interestingly, the reaction was also successful using ZnCl2 (  (Table 2). Thus, to assess the generality of the reaction, various N-Boc-alkynylbenzimidazoles 1 (bearing different R 1 and R 2 groups; prepared as detailed in the Supplementary Materials) were subjected to the optimized reaction conditions with ZnCl2 as the promoter (Table 2, entries 2-15). Very interestingly, the reaction was also successful using ZnCl2 (  (Table 2). Thus, to assess the generality of the reaction, various N-Boc-alkynylbenzimidazoles 1 (bearing different R 1 and R 2 groups; prepared as detailed in the Supplementary Materials) were subjected to the optimized reaction conditions with ZnCl2 as the promoter (Table 2, entries 2-15). Very interestingly, the reaction was also successful using ZnCl2 (  (Table 2). Thus, to assess the generality of the reaction, various N-Boc-alkynylbenzimidazoles 1 (bearing different R 1 and R 2 groups; prepared as detailed in the Supplementary Materials) were subjected to the optimized reaction conditions with ZnCl2 as the promoter (Table 2, entries 2-15). Very interestingly, the reaction was also successful using ZnCl2 (  (Table 2). Thus, to assess the generality of the reaction, various N-Boc-alkynylbenzimidazoles 1 (bearing different R 1 and R 2 groups; prepared as detailed in the Supplementary Materials) were subjected to the optimized reaction conditions with ZnCl2 as the promoter (Table 2, entries 2-15).    As can be seen from Table 2, entries 2-5, excellent results were obtained with substrates still with R 2 = Bu and bearing either electron-donating (methyl or methoxy; yields of the corresponding products 2b-d were 76-83%, Table 2, entries 2-4) or electron-withdrawing chlorine substituents (yield of 2e = 77%, Table 2, entry 5) on the aromatic ring. On the other hand, inferior results were observed with substrates 1f and 1g, bearing a strong electron-withdrawing nitro substituent (yields of 2f and 2g were 45% and 30%, Table 2, entries 6 and 7, respectively). With these substrates, complete Boc removal competed with heterocyclization, as confirmed by the formation of not negligible amounts of deprotected compounds 3f and 3g (20% and 31%, respectively, Table 2, entries 6 and 7) (Scheme 3), not observed in other cases. Clearly, the formation of these byproducts from substrates 1f and 1g is due to the diminished nucleophilicity of the carbamate intermediate B (Scheme 2) caused by the strong electron-withdrawing effect of the nitro group, which makes decarboxylation to compete with cyclization. The structures of products 2c and 2f were confirmed by XRD analysis (see the Supplementary Materials for XRD data). The X-ray structures of 2c and 2f, shown in Figures 2 and 3, respectively, allowed to unequivocally establish the positions of the methoxy and nitro substituents in regioisomeric substrates 1c/1d and 1f/1g, respectively (as 2c must be formed from 1c and 2f from 1f).
Molecules 2021, 26, x FOR PEER REVIEW 6 of 14 As can be seen from Table 2, entries 2-5, excellent results were obtained with substrates still with R 2 = Bu and bearing either electron-donating (methyl or methoxy; yields of the corresponding products 2b-d were 76-83%, Table 2, entries 2-4) or electron-withdrawing chlorine substituents (yield of 2e = 77%, Table 2, entry 5) on the aromatic ring. On the other hand, inferior results were observed with substrates 1f and 1g, bearing a strong electron-withdrawing nitro substituent (yields of 2f and 2g were 45% and 30%, Table 2, entries 6 and 7, respectively). With these substrates, complete Boc removal competed with heterocyclization, as confirmed by the formation of not negligible amounts of deprotected compounds 3f and 3g (20% and 31%, respectively, Table 2, entries 6 and 7) (Scheme 3), not observed in other cases. Clearly, the formation of these byproducts from substrates 1f and 1g is due to the diminished nucleophilicity of the carbamate intermediate B (Scheme 2) caused by the strong electron-withdrawing effect of the nitro group, which makes decarboxylation to compete with cyclization. The structures of products 2c and 2f were confirmed by XRD analysis (see the Supplementary Materials for XRD data). The X-ray structures of 2c and 2f, shown in Figures 2 and 3, respectively, allowed to unequivocally establish the positions of the methoxy and nitro substituents in regioisomeric substrates 1c/1d and 1f/1g, respectively (as 2c must be formed from 1c and 2f from 1f).   As can be seen from Table 2, entries 2-5, excellent results were obtained with substrates still with R 2 = Bu and bearing either electron-donating (methyl or methoxy; yields of the corresponding products 2b-d were 76-83%, Table 2, entries 2-4) or electron-withdrawing chlorine substituents (yield of 2e = 77%, Table 2, entry 5) on the aromatic ring. On the other hand, inferior results were observed with substrates 1f and 1g, bearing a strong electron-withdrawing nitro substituent (yields of 2f and 2g were 45% and 30%, Table 2, entries 6 and 7, respectively). With these substrates, complete Boc removal competed with heterocyclization, as confirmed by the formation of not negligible amounts of deprotected compounds 3f and 3g (20% and 31%, respectively, Table 2, entries 6 and 7) (Scheme 3), not observed in other cases. Clearly, the formation of these byproducts from substrates 1f and 1g is due to the diminished nucleophilicity of the carbamate intermediate B (Scheme 2) caused by the strong electron-withdrawing effect of the nitro group, which makes decarboxylation to compete with cyclization. The structures of products 2c and 2f were confirmed by XRD analysis (see the Supplementary Materials for XRD data). The X-ray structures of 2c and 2f, shown in Figures 2 and 3, respectively, allowed to unequivocally establish the positions of the methoxy and nitro substituents in regioisomeric substrates 1c/1d and 1f/1g, respectively (as 2c must be formed from 1c and 2f from 1f).     [4,5]imidazo [1,2-c] [1,3]oxazin-1-one 2c. Color legend: carbon (light grey), hydrogen (white), oxygen (red), nitrogen (blue) (CCDC 2051334).  High yields of the corresponding benzimidazoxazinones were obtained by changing the alkyl substituent on the triple bond R 2 to octyl (yield of 2h, 85%; Table 2, entry 8), isopentyl (yield of 2i, 82%; Table 2, entry 9), or phenethyl (yield of 2j, 80%; Table 2, entry 10), while a slightly lower yield was observed with R 2 = cyclohexylmethyl (yield of 2k, 70%; Table 2, entry 11). The use of a substrate with the triple bond conjugated with an alkenyl group, as in N-Boc-2-(cyclohex-1-en-1-ylethynyl)-1H-benzo[d]imidazole 1l, led to a satisfactory yield of the corresponding polycyclic heterocycle 2l (66%; Table 2, entry 12).

General Experimental Methods
Melting points were measured with a Leitz Laborlux 12 POL polarizing optical microscope (Leitz Italia GmbH/Srl, Lana(BZ), Italy) and are uncorrected. 1 H NMR and 13 C NMR spectra were recorded at 25 °C in CDCl3 or DMSO-d6 at 300 MHz or 500 MHz and 75 or 125 MHz, respectively, with Me4Si as internal standard, using Bruker DPX Avance 300 and Bruker DPX Avance 500 NMR spectrometers (Brucker Italia s.r.l., Milano, Italy); chemical shifts (δ) and coupling constants (J) are given in ppm and in Hz, respectively. IR spectra were taken with a JASCO FT-IR 4200 spectrometer (Jasco Europe s.r.l., Cremella, Lecco, Italy). All reactions were analyzed by TLC on silica gel 60 F254 and by GC-MS using a Shimadzu QP-2010 GC-MS apparatus (Smimadzu Italia s.r.l., Milano, Italy) at 70 eV ionization voltage equipped with a 95% methyl polysiloxane-5% phenyl polysiloxane capillary column (30 m × 0.25 mm, 0.25 μm). Column chromatography was performed on silica gel 60 (Merck, 70-230 mesh; Merck Life Science s.r.l., Milano, Italy). Evaporation refers to the removal of solvent under reduced pressure. The HRMS spectra were taken on an Agilent 1260 Infinity UHD accurate-mass Q-TOF mass spectrometer (Agilent Tech-

General Experimental Methods
Melting points were measured with a Leitz Laborlux 12 POL polarizing optical microscope (Leitz Italia GmbH/Srl, Lana(BZ), Italy) and are uncorrected. 1 H NMR and 13 C NMR spectra were recorded at 25 • C in CDCl 3 or DMSO-d 6 at 300 MHz or 500 MHz and 75 or 125 MHz, respectively, with Me 4 Si as internal standard, using Bruker DPX Avance 300 and Bruker DPX Avance 500 NMR spectrometers (Brucker Italia s.r.l., Milano, Italy); chemical shifts (δ) and coupling constants (J) are given in ppm and in Hz, respectively. IR spectra were taken with a JASCO FT-IR 4200 spectrometer (Jasco Europe s.r.l., Cremella, Lecco, Italy). All reactions were analyzed by TLC on silica gel 60 F 254 and by GC-MS using a Shimadzu QP-2010 GC-MS apparatus (Smimadzu Italia s.r.l., Milano, Italy) at 70 eV ionization voltage equipped with a 95% methyl polysiloxane-5% phenyl polysiloxane capillary column (30 m × 0.25 mm, 0.25 µm). Column chromatography was performed on silica gel 60 (Merck, 70-230 mesh; Merck Life Science s.r.l., Milano, Italy). Evaporation refers to the removal of solvent under reduced pressure. The HRMS spectra were taken on an Agilent 1260 Infinity UHD accurate-mass Q-TOF mass spectrometer (Agilent Technologies Italia s.p.a. Cernusco sul Naviglio, Milano, Italy), equipped with an electrospray ion source (ESI) operated in dual ion mode. Ten microliters of the sample solutions (CH 3 OH) were introduced by continuous infusion at a flow rate of 200 L min −1 with the aid of a syringe pump. Experimental conditions were performed as follows: capillary voltage, 4000 V; nebulizer pressure, 20 psi; flow rate of drying gas, 10 L/min; temperature of sheath gas, 325 • C; flow rate of sheath gas, 10 L/min; skimmer voltage, 60 V; OCT1 RF Vpp, 750 V; fragmentor voltage, 170 V. The spectra data were recorded in the m/z range of 100-1000 Da in a centroid pattern of full-scan MS analysis mode. The MS/MS data of the selected compounds were obtained by regulating diverse collision energy (18-45 eV).

Preparation of Substrates 1
Substrates were prepared and characterized as described in the Supplementary Materials.

General Procedure for the Synthesis of Benzimidazoxazinone Derivatives 2
See Table 2 (1 mL), and ZnCl 2 (204 mg, 1.5 mmol). The reaction mixture was heated at 40 • C and then allowed to stir at this temperature for 3 h. After cooling, the reaction mixture was diluted with CH 2 Cl 2 (5 mL) and water (5 mL) (for 2a-1, 2n, and 2o'). Alternatively, after cooling, the solvent was evaporated, and water (20 mL) was added to the residue (for 2m). Phases were separated the aqueous phase was washed with CH 2 Cl 2 (5 mL), and the combined organic phases were dried with Na 2 SO 4 . After filtration and evaporation of the solvent, the product was purified by column chromatography on silica gel using hexane/AcOEt (8:2, v/v) as the eluent (for 2a-1l, 2n, and 2o'). For the purification of 2m, the suspension obtained as seen above was filtered, the precipitate washed with water (3 × 5 mL) and then purified by column chromatography on silica gel using hexane/AcOEt (8:2, v/v) as eluent. With substrates 1f and 1g, the reaction also led to the formation of deprotected products 3f and 3g, respectively (Scheme 3) (order of elution: 3f followed by 2f; 2g followed by 3g). [4,5]imidazo [1,2-c] [1,3]oxazin-1-one 2a

Conclusions
In conclusion, we have reported that simple and inexpensive ZnCl 2 is able to promote the heterocyclization of N-Boc-2-alkynylbenzimidazoles under mild conditions (40 • C in CH 2 Cl 2 for 3h), giving access to new polycyclic heterocycles, 1H-benzo [4,5]imidazo [1,2c] [1,3]oxazin-1-ones. While in the previous literature ZnCl 2 was reported to promote complete N-Boc deprotection with elimination of isobutene and CO 2 , in the present process it assisted the 6-endo-dig heterocyclization of the carbamate intermediate with incorporation of the carbamate group into the final polyheterocyclic derivative. ZnCl 2 thus played a dual role, by promoting the Boc deprotection of the substrate with elimination of the tert-butyl carbonation (which could be trapped by substrates bearing a nucleophilic group) and activating the triple bond toward the intramolecular nucleophilic attack by the carbamate moiety. The benzimidazoxazinone derivatives have been obtained in moderate to high yields starting from differently substituted substrates, and the structure of representative products has been confirmed by X-ray diffraction analysis.

Data Availability Statement:
The data presented in this study are available on request from the corresponding authors.