Practical One-Pot Multistep Synthesis of 2H-1,3-Benzoxazines Using Copper, Hydrogen Peroxide and Triethylamine

Abstract

In this article, we describe simple one-pot syntheses of 2H-1,3-benzoxazines from ketones utilizing an imino-pyridine directing group (R¹R²-C=N-CH₂-Pyr), which promotes a Cu-directed sp² hydroxylation using H₂O₂ as oxidant and followed by an oxidative intramolecular C-O bond formation upon addition of NEt₃. This synthetic protocol is utilized in the gram scale synthesis of the 2H-1,3-benzoxazine derived from benzophenone. Mechanistic studies reveal that the cyclization occurs via deprotonation of the benzylic position of the directing group to produce a 2-azallyl anion intermediate, which is oxidized to the corresponding 2-azaallyl radical before the C-O bond formation event. Understanding of the cyclization mechanism also allowed us to develop reaction conditions that utilize catalytic amounts of Cu.

Graphical Abstract

Here, we describe a simple one-pot synthesis of 2H-1,3-benzoxazines from imino-pyridines substrates using Copper, H₂O₂ and NEt₃. Mechanistic studies were performed and suggested that cyclization occurred via the formation of 2-azallyl intermediates. Understanding of the cyclization mechanism allowed for developing reaction conditions with using catalytic amounts of Cu.

2H-1,3-Benzoxazines are common motifs in bioactive molecules that have multiple applications including pharmaceutics (e.g., TCV-295 is used as a potassium channel-activating agent to treat asthma, hypertension, etc.) and as bactericides (Figure 1A).^[1] Despite their relevance only a handful of synthetic routes have been reported, which usually entail tedious multistep procedures with poor overall yields and limited product scope.^[2] Our research lab is interested in developing practical synthetic protocols inspired by the oxygenase and oxidase reactivity of Cu-dependent metalloenzymes by which challenging functionalization reactions (e.g., selective C-H hydroxylation) can be achieved using cheap reagents under mild conditions (e.g., Cu and H₂O₂ at room temperature).^[3] In 2017, we reported the intramolecular ɣ-hydroxylation of sp³ C-H bonds via installation of a directing group (DG) to ketone substrates and selective hydroxylation using Cu^II and H₂O₂ (Figure 1B).^[4] To our delight, this protocol has been recently used in the total synthesis of nortriterpenoids and ritterazine B.^[5] In 2019, we described that this methodology can also be applied to the β-hydroxylation of sp³ C-H bonds and the ɣ-hydroxylation of sp² C-H bonds.^[6] In the hydroxylation of substrate-ligand derived from benzophenone using Cu, H₂O₂ and triethylamine (NEt₃), we observed the formation of an unknown product. This unidentified product, which is formed by exposing the hydroxylation product to NEt₃ in the presence of Cu^II, was characterized by NMR as the 2H-1,3-benzoxazine heterocycle produced via intramolecular C-O bond formation between the benzylic position of the DG and the phenolic moiety (Figure 1C). This serendipitous finding triggered the work that we present in this paper, in which describe that 2H-1,3-benzoxazine products can be generated in one-pot syntheses using cheap reagents (Cu^II, H₂O₂ and NEt₃) under mild and practical reaction conditions.

Figure 1.

Structure of relevant 2H-1,3-benzoxazines (A), Cu-directed hydroxylation of C-H bonds (B) and serendipitous Cu-promoted hydroxylation/cyclization reactions observed in the oxidation of L1 (C).

The cyclization reaction was optimized for the substrate-ligand derived from 2-hydroxybenzophenone PL1 (Figure 2). The reactions were carried out at room temperature and under air by mixing solutions of PL1 with the metal source and base. We found that 1 equiv. of Cu^II(CF₃SO₃)₂ and 5 equiv. of NEt₃ were optimal for the formation of the cyclic product (Figure 2, entries 1 to 4). We also observed that other bases such as TMG (1,1,3,3-tetramethylguanidine), DBU (1,8-diazabicyclo[5,4,0]undec-7-ene), TBD (1,5,7-triazabicyclo[4,4,0]dec-5-ene) or pyridine produced the 2H-1,3-benzoxazine product with smaller yields (Figure 2, entries 5 to 8). Other Cu^II sources were also utilized and we found that Cu^II(NO₃)₂·3H₂O (cheapest Cu salt) reached the highest yields. Other metal sources (Fe^II, Mn^II, Ni^II, Zn^II and Pd^II) did not form the cyclization product or did in very minor yields. Interesting, cyclization in other solvents (THF, CH₂Cl₂ and CH₃CN) led to similar yields to the ones obtained in acetone.

Figure 2.

Optimization of the cyclization reaction conditions.

After optimizing the cyclization reaction, we decided to develop a one-pot synthetic protocol to oxidize a series of substrate-ligands (LX) to the corresponding hydroxylation products (PLX) and cyclization products (CX) (Figure 3A). The hydroxylation of the LX systems was performed utilizing 1 equiv. of Cu^II(NO₃)₂·3H₂O, 1 equiv. of NMe₄OH and 5 equiv. of H₂O₂, which allowed to obtain the PLX products with good yields. 4,4’-substituted benzophenones were oxidized with yields similar to the ones reported in our previous work (see PL1-PL5 in Figure 3A). In this paper, we also analyzed the hydroxylation of unsymmetric 2-susbtituted benzophenones (PL6-PL9), which were functionalized at the ortho-position of the unsubstituted ring in a selective fashion (see S.I. for synthesis of L6-L9). The hydroxylation products derived from 4-substituted acetophenones (PL10-PL13) and acetonaphthones (PL14 and PL15) were also obtained with moderate yields (20–40%). 4-substituted benzaldehydes could also be oxidized but did not produce the resulting PL products (PL16-PL18) since these were hydrolyzed to the corresponding 4-substituted 2-hydroxy-benzaldehydes (see S.I. for details). The products derived from sp² C-H hydroxylation of butyrophenone (PL19) and 2-methyl-1-tetralone (PL20) were obtained with excellent selectivity (i.e., no sp³ C-H hydroxylation).

Figure 3.

(A) One-pot hydroxylation of LX to PLX and hydroxylation/cyclization of LX to CX using Cu^II, hydroxide, H₂O₂ and NEt₃. (B) Gram-scale synthesis of cyclization products C1 and subsequent hydroxylation to PC1 based on the X-ray diffraction structure of [(C1)Cu^I(CH₃CN)](PF₆) (see S.I. for details).

The one-pot sequential hydroxylation-cyclization of the LX systems to CX was accomplished by performing the hydroxylation with Cu^II, NMe₄OH and H₂O₂ and, after 30 minutes, adding 5 equiv. of NEt₃ (Figure 3A). The cyclization products were obtained with modest overall yields (ca. 35%) partially attributed to hydrolysis of the imine bond in LX and PLX. These overall yields are also in agreement with the average yield obtained in the sp² hydroxylation (ca. 60%) and the optimized cyclization (ca. 70%). Despite the yields, the CX products were obtained as sole products by filtering the solutions obtained after work-up through a basic alumina plug. Using this one-pot methodology, we synthesized and characterized 15 novel 2-H-1,3-benzoxazines derived from 4-substituted benzophenones (C1-C5), 2-substituted benzophenones (C6-C9), 4-substituted acetophenones (C10-C13), acetonaphthones (C14 and C15), butyrophenone (C19) and 2-methyl-1-tetralone (C20) (see Figure 3). For 4-substituted benzaldehydes, we did not observe the formation of the corresponding cyclization products (C16-C18) since we believe the PLX imine products are hydrolyzed in the reaction crude. We attempted to carry out the cyclization of the independently synthesized PL16 using Cu^II and NEt₃ but no cyclization was observed and only the products derived from PL16 hydrolysis could be isolated (see S.I.).

We also performed the one-pot synthesis of C1 from L1 at a gram scale (Figure 3B). After hydroxylation with copper, tetramethylammonium hydroxide and hydrogen peroxide and cyclization with triethylamine, we were able to isolate C1 by stirring the reaction crude overnight with a saturated aqueous solution of Na₄EDTA and purifying the resulting organic products by flash column chromatography in basic alumina (yield: 26%, 575 mg). The isolated C1 product was transferred inside the glovebox and it was reacted with 1 equiv. of [Cu^I(CH₃CN)₄]PF₆ to produce the corresponding cuprous complex (Figure 3B, right). The resulting complex, [(C1)Cu^I(CH₃CN)]PF₆, was characterized by X-ray diffraction analysis and the C-N distances and N-C-O angles measured were consistent with the formulation of C1 as 2H-1,3-benzoxazine product.^[7] We also noticed that in this cuprous complex, the directing group and the Cu ion were oriented towards the phenyl ring that was not oxidized, which suggested that after the cyclization reaction a second hydroxylation process could be promoted. In fact, hydroxylation of the cyclization product of C1 to PC1 was accomplished by adding stoichiometric amounts of [Cu^I(CH₃CN)₄](PF₆) and 5 equiv. of H₂O₂ (Figure 3B). PC1 could be isolated after Na₄EDTA (pH:11)/EtOAc work-up followed by flash column chromatography (Figure 3B).

We have previously reported that for the sp² substrate-ligands (e.g. L1), the Cu-promoted hydroxylation of sp² C-H bonds involves the formation of mononuclear Cu^II-hydroperoxo species.^[6] The proposed mechanism for the cyclization reaction is depicted in Figure 4A. Deprotonation of the Cu^II-PLX complex (A) by NEt₃ is proposed to produce a 2-azaallyl anion (B) that undergoes an intermolecular 1e− oxidation event to generate a 2-azaallyl radical (C) before imine isomerization (D) and radical-radical C-O bond formation (E).^[8] In order to support the mechanism, we performed the oxidation of PL1 under different reaction conditions (Figure 4B). We found that when the reactions were carried out under anaerobic conditions, the reactions yield diminished (from 67% to 25%) but C1 was still formed, which suggested that the oxidation of intermediate B did not require O₂. When the reaction was done under N₂ using 2 equiv. of Cu^II the yields were restituted, implying that the 1e− oxidation of B did not involve the formation of a Cu/O₂ intermediate and that Cu^II could also act as 1e− oxidant. In fact, the cyclization of PL1 under anaerobic conditions using 1 equiv. of Cu^II and 1 equiv. of AgNO₃ (1e− oxidant) produced C1 with excellent yields (72%).

Figure 4.

(A) Mechanistic proposal for the cyclization of PLX substrates. (B) Cyclization of PL1 using stoichiometric and catalytic amounts of Cu^II. (C) Cyclizaton of PL10 and its isomer PL10-b to C10.

The formation of the proposed 2-azaallyl radical was supported by the fact that the substrate derived from 2-hydroxyacetophenone PL10 and its isomer PL10-b produced the same cyclization product (Figure 4C). For both substrates, the oxidation of the corresponding benzylic position generates a common 2-azaallyl radical intermediate that will undergo intramolecular C-O bond formation to product the same cyclic product.^[9] Our mechanistic proposal also suggests that after C-O bond formation, the resulting cuprous product E can be oxidized and release copper(II), which could potentially oxidize another molecule of PLX. When the cyclization of PL1 was carried out using catalytic amounts of Cu^II (10 mol%) under air, small amounts of C1 were formed (Figure 4B, entry 5). However, when the reaction was performed with 0.1 equiv of Cu^II under anaerobic conditions and using Ag⁺ as oxidant, the product C1 could be produced catalytically (Figure 4B, entry 6 and 7). For practical purposes, the reaction with Cu^II and Ag⁺ was performed under air and we were able to utilize small amounts of Cu^II catalyst (1 mol%) to reach notable turnover numbers (Figure 4B, entry 10).

The development of these catalytic conditions, which required small amounts of Cu^II, prompted us to test if these could be applied in the cyclization of sensitive substrates such as PL10 (Figure 4C). While in the cyclization of PL10 performed using stoichiometric amounts of Cu^II and air we observed small yields (20%), when the reactions were done using 10 mol% of Cu^II and 5 equiv. of AgNO₃ the yields improved (45%).

To summarize, we have developed a one-pot practical and cheap method for the synthesis of 2H-1,3-benzoxazines utilizing a directing group as building block, Cu^II, H₂O₂ and NEt₃. Our findings suggest that the cyclization reactions entail the formation of Cu/2-azaallyl intermediates, which can also be formed using stoichiometric one-electron oxidants and catalytic amounts of Cu. Our current efforts are focused on expanding these one-pot cyclization reactions to substrate-ligands derived from alkylic ketones, aldehydes and other directing groups, along with the umpolung functionalization of amines and imines.