[3+3]-Annulation of Cyclic Nitronates with Vinyl Diazoacetates: Diastereoselective Synthesis of Partially Saturated [1,2]Oxazino[2,3-b][1,2]oxazines and Their Base-Promoted Ring Contraction to Pyrrolo[1,2-b][1,2]oxazine Derivatives

A rhodium(II)-catalyzed reaction of cyclic nitronates (5,6-dihydro-4H-1,2-oxazine N-oxides) with vinyl diazoacetates proceeds as a [3+3]-annulation producing bicyclic unsaturated nitroso acetals (4a,5,6,7-tetrahydro-2H-[1,2]oxazino[2,3-b][1,2]oxazines). Optimization of reaction conditions revealed the use of Rh(II) octanoate as the preferred catalyst in THF at room temperature, which allows the preparation of target products in good yields and excellent diastereoselectivity. Under basic conditions, namely, the combined action of DBU and alcohol, these nitroso acetals undergo ring contraction of an unsaturated oxazine ring into the corresponding pyrrole. Both transformations can be performed in a one-pot fashion, thus constituting a quick approach to oxazine-annulated pyrroles from available starting materials, such as nitroalkenes, olefins, and diazo compounds.

With the optimized conditions in hand, an evaluation of the substrate scope was performed (Scheme 2). Diazoacetates possessing various ester groups were successfully involved in the reaction. Alkyl (Me, 3b; Et, 3c), benzyl (3d), p-nitrobenzyl (3e), and phenyl (3f) esters gave corresponding products in good yields. However, better results were achieved for electron-accepting 2,2,2-trichloroethyl (3a) and p-nitrobenzyl (3e) moieties, which is in line with the previously reported advantages of these substituents in C-H functionalization and cyclopropanation [53][54][55][56]. Poor yields and/or conversions were observed for vinyl diazoacetates with bulky tert-butyl (2g) or BHT (2,6-di-tert-butyl-4-methylphenyl, 2h) ester groups [57]. Unfortunately, complex mixtures were observed when employing substituted (β-phenyl or γ-phenyl) vinyl diazoacetates. Regarding the scope of nitronates 1, the reaction tolerates various aryl groups at the C4 of starting nitronate. Meta-(3i)and para-(3a,g,h)-substituted substrates gave products 3 smoothly, while for ortho-substituent (3j) a diminished yield was attained, presumably, due to steric hindrance. Importantly, no influence of the electronic effect of aromatic substituent was observed as electronaccepting (NO 2 , 3h), halogen (3g,j), as well as pharmaceutically attractive dihydroxylated aromatics [58,59] (3k) gave comparable outcomes. Apart from aryl-, 5-benzoyloxy-(3l), 5-alkyl-(3m), and 7-ethoxy-(3o) products were obtained, thus demonstrating the possibility of incorporation of different functionalities in the target structures. Poor yield was attained for cyclohexane-annulated product 3p, while a complex product mixture was observed for nitronate 1q. When more sterically encumbered camphene-derived (1r) or 3-methylsubstituted nitronate (1s) was involved, the reaction was decelerated and starting materials were observed even after 4 days. Structures of the obtained products were supported by their NMR (1D and 2D) and HRMS data. Gratifyingly, in all examined cases, the annulation was found to be stereoselective producing only one diastereomer of products 3. The relative configuration of stereocenters was also deduced on the basis of the coupling constant between C(4a)-H and C(5)-H. Its high value of 9-11 Hz evidenced about (pseudo)axial positions of both protons. This conclusion was supported by the X-ray analysis for products 3b and 3p ( Figure 1). Notably, the cis-junction of two oxazine rings was observed, which can be favored by anomeric interaction within O-N-O moiety [60]. However, we should mention the conformational lability of products 3, as many signals in their NMR spectra were broadened. Especially notable was product 3p possessing three contiguous annulated six-membered rings. In its case, a lot of the 13 C signals were of low intensity and were assigned only with the aim of 1 H-13 C HSQC spectra (see Supplementary Materials). Structures of the obtained products were supported by their NMR (1D and 2D) and HRMS data. Gratifyingly, in all examined cases, the annulation was found to be stereoselective producing only one diastereomer of products 3. The relative configuration of stereocenters was also deduced on the basis of the coupling constant between C(4a)-H and C(5)-H. Its high value of 9-11 Hz evidenced about (pseudo)axial positions of both protons. This conclusion was supported by the X-ray analysis for products 3b and 3p ( Figure 1). No-tably, the cis-junction of two oxazine rings was observed, which can be favored by anomeric interaction within O-N-O moiety [60]. However, we should mention the conformational lability of products 3, as many signals in their NMR spectra were broadened. Especially notable was product 3p possessing three contiguous annulated six-membered rings. In its case, a lot of the 13 C signals were of low intensity and were assigned only with the aim of 1 H-13 C HSQC spectra (see Supplementary Materials). Mentioned effects can be attributed to both inversion of six-membered rings and to nitrogen inversion [41,61]. Based on the obtained and the literature [42,43,62] data, the following for the annulation was proposed (Scheme 3). In the first step, electrophilic noid species A is generated from vinyl diazo compound 2 and a rhodium c cleophilic attack of the oxygen atom of N-oxide at the unhindered =CH2 te produces zwitterion B that undergoes ring closure with the expulsion of the formation of target cycloadduct (path a). Observed stereochemistry can be e an approach of the bulky vinyl-rhodium moiety from the face of the dipole substituent R 1 . Hence, low yields in the case of product 3p and the messy rea tronate 1q can be attributed to the presence of a relatively bulky substituent a nitronate, which together with the substituent at C(4) may block both sides o thus preventing the annulation. Interestingly, the observed [3+3]-annulation nates differs from the reaction of vinyl diazoacetates with nitrones, which oft via a [3+2]-pathway and subsequent carbene reactions (cf. path b) [63][64][65][66], w spective [3+3]-pathway was rarely observed [62]. Based on the obtained and the literature [42,43,62] data, the following mechanism for the annulation was proposed (Scheme 3). In the first step, electrophilic vinyl carbenoid species A is generated from vinyl diazo compound 2 and a rhodium catalyst. Nucleophilic attack of the oxygen atom of N-oxide at the unhindered =CH 2 terminus in A produces zwitterion B that undergoes ring closure with the expulsion of the catalyst and formation of target cycloadduct (path a). Observed stereochemistry can be explained by an approach of the bulky vinyl-rhodium moiety from the face of the dipole opposite to substituent R 1 . Hence, low yields in the case of product 3p and the messy reaction for nitronate 1q can be attributed to the presence of a relatively bulky substituent at C(6) of the nitronate, which together with the substituent at C(4) may block both sides of the dipole, thus preventing the annulation. Interestingly, the observed [3+3]-annulation with nitronates differs from the reaction of vinyl diazoacetates with nitrones, which often proceeds via a [3+2]-pathway and subsequent carbene reactions (cf. path b) [63][64][65][66], while the respective [3+3]-pathway was rarely observed [62].
Aiming at the subsequent functionalization of product 3b, we attempted a Michael addition of dimethyl malonate across the C=C double bond. However, none of the desired transformation was observed, albeit ring contraction occurred providing pyrrolo[1,2b]oxazine derivative 4b. This process has some precedents in the literature [67][68][69][70][71][72][73][74][75], with the closest analogue observed by Kerr et al. for non-annulated oxazines under the treatment with DBU in MeCN [67]. The proposed mechanism starts with the deprotonation at C(2), which is facilitated by the conjugation of the formed anion with C=C-CO 2 moiety in D (Scheme 4). Subsequent cleavage of the N-O bond, formation of an aldehyde group, and recyclization produce hydroxypyrroline E, upon which dehydration furnishes the target pyrrole ring (path a). Some optimization of reaction conditions was performed (Scheme 5) and a combination of base (DBU) and protic additive (alcohol) was found optimal, instead of the use of a base alone (cf. yields for DBU and DBU/TCEOH). We attribute it to two main reasons. First, N-O bonds in nitroso acetals are also susceptible to basic cleavage (e.g., Scheme 4, path b) [76,77], which can lead to the formation of side products. The use of alcohol promotes the elimination of the hydroxyl group from intermediate E via hydrogen bonding, thus facilitating pyrrole formation (path a). Secondly, the presence of alcohol diminishes the amount of carboxylic acid 5, which originates from the hydrolysis of product 4a by water. Particularly, relatively large amounts of product 5 were observed when a strong base, namely, sodium tert-butylate was used. Similarly, in the excess of methanol, transesterification was observed (Scheme 6).
The literature provides limited data on the preparation of pyrrolo[1,2-b]oxazine derivatives [78,79], especially possessing an unsaturated pyrrole core [80,81]. Therefore, we elucidated the scope of the found transformation. Since the reagents used for the [3+3]annulation should not interfere with the ring contraction, we decided to make a one-pot protocol for the synthesis of pyrrolooxazines 4 from oxazine N-oxides 1 and vinyl diazoacetates 2. For this purpose, the reaction mixture was evaporated after the annulation step and redissolved in CH 2 Cl 2 , followed by the addition of other reagents. This worked well providing target products 4 in reasonable yields for the whole two-step sequence (Scheme 7). Based on the obtained and the literature [42,43,62] data, the following mechanism for the annulation was proposed (Scheme 3). In the first step, electrophilic vinyl carbenoid species A is generated from vinyl diazo compound 2 and a rhodium catalyst. Nucleophilic attack of the oxygen atom of N-oxide at the unhindered =CH2 terminus in A produces zwitterion B that undergoes ring closure with the expulsion of the catalyst and formation of target cycloadduct (path a). Observed stereochemistry can be explained by an approach of the bulky vinyl-rhodium moiety from the face of the dipole opposite to substituent R 1 . Hence, low yields in the case of product 3p and the messy reaction for nitronate 1q can be attributed to the presence of a relatively bulky substituent at C(6) of the nitronate, which together with the substituent at C(4) may block both sides of the dipole, thus preventing the annulation. Interestingly, the observed [3+3]-annulation with nitronates differs from the reaction of vinyl diazoacetates with nitrones, which often proceeds via a [3+2]-pathway and subsequent carbene reactions (cf. path b) [63][64][65][66], while the respective [3+3]-pathway was rarely observed [62]. Aiming at the subsequent functionalization of product 3b, we attempted a Michael addition of dimethyl malonate across the C=C double bond. However, none of the desired transformation was observed, albeit ring contraction occurred providing pyrrolo[1,2-b]oxazine derivative 4b. This process has some precedents in the literature [67][68][69][70][71][72][73][74][75], with the closest analogue observed by Kerr et al. for non-annulated oxazines under the treatment with DBU in MeCN [67]. The proposed mechanism starts with the deprotonation at C(2), which is facilitated by the conjugation of the formed anion with C=C-CO2 moiety in D (Scheme 4). Subsequent cleavage of the N-O bond, formation of an aldehyde group, and recyclization produce hydroxypyrroline E, upon which dehydration furnishes the target pyrrole ring (path a). Some optimization of reaction conditions was performed (Scheme 5) and a combination of base (DBU) and protic additive (alcohol) was found optimal, instead of the use of a base alone (cf. yields for DBU and DBU/TCEOH). We attribute it to two main reasons. First, N-O bonds in nitroso acetals are also susceptible to basic cleavage (e.g., Scheme 4, path b) [76,77], which can lead to the formation of side products. The use of alcohol promotes the elimination of the hydroxyl group from intermediate E via hydrogen bonding, thus facilitating pyrrole formation (path a). Secondly, the presence of alcohol diminishes the amount of carboxylic acid 5, which originates from the hydrolysis of product 4a by water. Particularly, relatively large amounts of product 5 were observed when a strong base, namely, sodium tert-butylate was used. Similarly, in the excess of methanol, transesterification was observed (Scheme 6). The literature provides limited data on the preparation of pyrrolo[1,2-b]oxazine rivatives [78,79], especially possessing an unsaturated pyrrole core [80,81]. Therefore, elucidated the scope of the found transformation. Since the reagents used for [3+3]-annulation should not interfere with the ring contraction, we decided to mak one-pot protocol for the synthesis of pyrrolooxazines 4 from oxazine N-oxides 1 and nyl diazoacetates 2. For this purpose, the reaction mixture was evaporated after the nulation step and redissolved in CH2Cl2, followed by the addition of other reagents. T worked well providing target products 4 in reasonable yields for the whole two-s sequence (Scheme 7).

Scheme 6.
Formation of pyrrole 4b from nitroso acetal 3a by sequential ring contraction/transesterification. The literature provides limited data on the preparation of pyrrolo[1,2-b]oxazine d rivatives [78,79], especially possessing an unsaturated pyrrole core [80,81]. Therefore, w elucidated the scope of the found transformation. Since the reagents used for t [3+3]-annulation should not interfere with the ring contraction, we decided to make one-pot protocol for the synthesis of pyrrolooxazines 4 from oxazine N-oxides 1 and nyl diazoacetates 2. For this purpose, the reaction mixture was evaporated after the a nulation step and redissolved in CH2Cl2, followed by the addition of other reagents. Th worked well providing target products 4 in reasonable yields for the whole two-st sequence (Scheme 7).

General Experiment
All reactions were performed in oven-dried (150 °C) glassware. Most of the chem cals were acquired from commercial sources (Sigma-Aldrich, St. Louis, MI, USA; Acr Organics, Geel, Belgium; Alfa Aesar, Heysham, UK; ABCR, Karlsruhe, Germany; a P&M Invest, Moscow, Russia) with purities >95% and used as received. Petroleum eth (PE) and ethyl acetate were distilled. THF, CH3CN, CH2Cl2, and DBU were distilled fro CaH2. Brine refers to the saturated aqueous solution of NaCl. TLC was performed

Conclusions
In conclusion, an approach was developed for the synthesis of bicyclic nitroso acetals (4a,5,6,7-tetrahydro-2H- [1,2]oxazino [2,3-b] [1,2]oxazines) via an Rh(II)-catalyzed annulation of six-membered cyclic nitronates with vinyl diazoacetates. Target products were obtained in good yields with excellent diastereoselectivity. These nitroso acetals undergo smooth ring contraction under the action of the DBU/alcohol system. Combined with a [3+3]-annulation in a one-pot protocol, it represents a quick approach to the assembly of pyrrolooxazines and complements already known approaches to this relatively rare heterocyclic core.
Supplementary Materials: The following supporting information can be downloaded at https: //www.mdpi.com/article/10.3390/molecules28073025/s1, Table S1: Preparation of starting compounds, crystal data, optimization, Tables S2 and S3: Tables for the synthesis of