Intramolecular annulation of aromatic rings with N-sulfonyl 1,2,3-triazoles: divergent synthesis of 3-methylene-2,3-dihydrobenzofurans and 3-methylene-2,3-dihydroindoles

Abstract

The controllable synthesis of 3-methylene-2,3-dihydrobenzofurans 2 and 3-methylene-2,3-dihydroindoles 5 has been developed through Rh-catalyzed intramolecular annulation of aromatic rings with azavinyl carbenes.

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Benzofuran and indole containing molecules are very important heterocycles which can serve as versatile building blocks and are found in a number of natural products with a wide range of biological activities.^1,2 Not surprisingly, numerous efforts have been made to synthesize such compounds.^3,4 On the other hand, less attention has been paid to the chemoselective synthesis of 3-methylene-2,3-dihydrobenzofurans and 3-methylene-2,3-dihydroindoles, which are also very important due to the fact that the exocyclic double bonds can be easily transformed to other useful functional groups for rapid construction of molecular complexity. The challenge relies on the 1,3-H shift driven by the aromatization process. Therefore, many reported synthetic methods showed no chemoselectivity in the synthesis of such exo-methylene heterocyclic compounds, or suffered from very limited substrate scopes.⁵ Only one selective synthesis of both 3-methylene-2,3-dihydrobenzofurans and 3-methylene-2,3-dihydroindoles was accomplished by means of the cycloisomerization of dienes in the presence of Ru complex and trimethylsilyl vinyl ether.⁶ Therefore, developing new methodologies to chemoselectively construct such compounds is highly desirable and urgent.

Recently, the Rh(II) catalyzed ring-opening reactions of N-sulfonyl 1,2,3-triazoles⁷ have emerged as a powerful tool for many useful transformations, including annulation with unsaturated compounds,⁸ X–H bond insertion or functionalization (X = heteroatoms or carbon),⁹ ring expansion or carbene induced other transformations.¹⁰ Previously, we also developed the intramolecular annulation of carbonyl-triazoles for the facile construction of 8-aza bridged benzodioxepines through Rh azavinyl carbene intermediates (Scheme 1a).¹¹ Herein, we wish to report the substrate-dependent divergent synthesis of 3-methylene-2,3-dihydrobenzofurans and 3-methylene-2,3-dihydroindoles (Scheme 1b).

Scheme 1 Intramolecular annulations of triazoles.

Our initial work started with the annulation reaction of 4-(phenyloxymethyl)-1-tosyl-1,2,3-triazole 1a, which was readily available from Cu(I)-catalyzed azide–alkyne cycloaddition (CuAAC),¹² in the presence of Rh₂(Piv)₄ catalyst. To our delight and surprise, an unprecedented 3-methylene-2,3-dihydrobenzofuran 2a was obtained and unequivocally confirmed by X-ray diffraction.¹³ Moreover, when nitrogen tethered substrates 4 were employed as the substrate, the reaction gave indole derivatives (see Table 3).

After evaluation of the catalysts, solvent effect, temperature and reaction time, we found that 2a could be formed in 95% yield in DCE upon heating at 90 °C for 3 h (see ESI,† Table S1).

With the optimized reaction conditions in hand, we next investigated the generality of this method with respect to various 4-(aryloxymethyl)-1-tosyl-1,2,3-triazoles 1 (Table 1). As for substrates 1b–1d with electron-withdrawing Cl and Br atoms on the benzene ring, the corresponding products 2b–2d were isolated in 43–72% yield (Table 1, entries 1–3). On the other hand, upon variation of the substituents by different electron-donating groups, the reactions also proceeded smoothly to give the corresponding 2-aminobenzofuran derivatives 2e–2j in moderate to excellent yield (65–99%) (Table 1, entries 4–9). However, when a strongly electron-withdrawing CN group was introduced at the para position of the phenyl ring, the reaction became sluggish to give complex product mixtures, and no desired product 2k was observed (Table 1, entry 10). Next, several substrates with 4-naphthyloxymethyl substituted 1l–1o were investigated under the standard reaction conditions, delivering the corresponding 3-methylenenaphthofuran derivatives 2l–2o in 72–85% yield (Table 1, entries 11–14). For 7-hydroxycoumarin derived N-sulfonyl triazole 1p, the reaction also proceeded smoothly to give the desired product 2p in 61% yield (Table 1, entry 15).

Table 1 Scope of the reaction for the synthesis of 2^a

a 0.2 mmol scale. Reaction conditions: under Ar, triazole, Rh₂(Piv)₄ and DCE (2.0 mL) were stirred in a sealed tube at 90 °C for 3 h. b Isolated yields. c The reaction temperature was decreased to 80 °C to avoid the formation of 1,3-H shift product 3.

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During the reaction scope investigation, we found that in some cases (see Table 1, substrates 1i and 1l–1o), the temperature has to be decreased to 80 °C to get pure product 2, and higher temperature (90 °C) resulted in the 1,3-H shift relevant 3, which could not be isolated from 2. The structure was also confirmed by X-ray diffraction of 3e.¹³ We were pleased to find that products 3a–3e could be exclusively formed at 120 °C in moderate to good yield (50–88%) (Table 2, entries 1–5). However, for most of 4-aryloxymethyl-1,2,3-triazoles, conducting the reaction at 120 °C led to the formation of both 2 and 3 together with increased β-H elimination byproduct acrolein imines, suggesting that temperature significantly affects the reaction pathways. Fortunately, by carefully tuning the temperature, the reactions of 1g and 1i proceeded smoothly at 120 °C and 90 °C, furnishing the corresponding products 3f and 3g in 64% and 71% yield, respectively (Table 2, entry 6).

Table 2 Rearrangement of 1 at high temperature^a

a 0.2 mmol scale. Procedure: under Ar, triazole, Rh₂(Piv)₄ and DCE (2.0 mL) were stirred in a sealed tube at 120 °C for 3 h. b Isolated yields. c Starting material is 1q. d The reaction temperature was 90 °C.

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Next, we also turned our effort to study the reaction of N-tethered substrate 4. However, upon treatment of N-tosyl tethered substrate 4a with Rh₂(Piv)₄ at 90 °C in DCE for 3 h, product 5a¹⁴ was obtained in 55% yield, together with the formation of indolyl imine product 6a′ (β-H elimination) and acrolein imine 7a (carbene induced 1,2-H shift) in 30% and 11% yield, respectively (Scheme 2). The identification of 6a′¹³ and 7a¹³ was established by single-crystal X-ray analysis. It is reported that LiCl could suppress β-H elimination by coordination with metal catalyst.¹⁵ Therefore, 5 eq. of LiCl was used in the reaction. By conducting the reaction at 60 °C, we were glad to find that 5a was exclusively formed in 82% yield (Scheme 2).

Scheme 2 Inhibition of β-H elimination/1,2-H shift. ^a N.D.: not determined.

As we successfully solved the problem of β-H elimination and 1,2-H shift, various N-sulfonyl tethered triazoles were synthesized to test the generality of this reaction (Table 3). All substrates employed were suitable for this cyclization reaction, giving the corresponding products 5 in 41–71% yield (Table 3, entries 1–6). Interestingly, when substrate 4h with 3,5-dimethoxy substituents was treated under the standard reaction conditions, indolyl methanamine product 6a was obtained in 85% yield after aromatization (Table 3, entry 7). It is worth mentioning that gram scale reaction of 4b also gives 5b in 65% yield (608 mg) (Table 3, entry 1).

Table 3 Scope of the reaction for the synthesis of 5^a

a 0.2 mmol scale. b Isolated yields. c 2 mmol scale; 992 mg of 4i and 608 mg of 5b were obtained.

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For N-alkyl group tethered triazoles, the reactions gave 3-indolylimines 6′ and 3-indolylmethanamines 6 together, and finally, the mixture could be converted to 3-indolylmethanamines 6 after a one-pot reduction (Scheme 3) (for the substrate scope study, see Table S2 in the ESI†).¹⁶

Scheme 3 One-pot synthesis of 6.

Several control experiments were conducted and carbene induced 1,2-H shift or 1,2-phenyl migration was observed (for details, see Scheme S1 in the ESI†). The deuterium labeling isotopic experiments revealed that the alkyl methylene carbon migrates to the terminal alkene in the final products (for details, see Scheme S2 in ESI†).

The deuterium kinetic isotope effects were also investigated. The obtained intra- and intermolecular k_H/k_D values were 0.89 and 0.77 (for details, see ESI†), respectively, suggesting that C–H functionalization is a Friedel–Crafts type reaction.¹⁷ This result is also consistent with the electronic effect observed in the substrate scope study.

In view of the control experiments and kinetic studies, an explanation of the reaction sequence is depicted in Scheme 4. First, in the presence of Rh(II) catalyst, an azavinyl carbene intermediate A is formed after denitrogenation, followed by a Friedel–Crafts type nucleophilic attack of the aryl ring on the Rh azavinyl carbenoid to give a zwitterionic intermediate B. The elimination of the Rh(II) catalyst together with the cleavage of the C–O bond delivers an acrolein imine C and its resonance structure C′. Finally, product 2 is formed via 1,2-addition, which is more favored than 1,4-addition probably due to the fact that the intramolecular H bonding can pull the imine group more closely to the oxygen atom. Upon heating, the thermodynamically more stable product 3 is formed after 1,3-H shift.

Scheme 4 Proposed catalytic cycle for the synthesis of 2 and 3.

A plausible mechanism for the synthesis of 5 is also outlined in Scheme 5. First, in the presence of Rh(II) complex, compound 4 generates an azavinyl carbene intermediate D, and then the Rh imino carbenoid accepts a nucleophilic attack from the aryl ring to give zwitterionic intermediate E. After aromatization and protonation, product 5 is formed. In the case of substrate 4h with two strongly electron-donating groups on the benzene ring, 6b is obtained after the 1,3-H shift.

Scheme 5 Proposed catalytic cycle for the formation of 5.

According to the DFT calculation, the 1,3-H shift process of 5a needs a relatively high energy barrier of 67.1 kcal mol⁻¹, indicating that this 1,3-H shift process is hard to take place under normal reaction conditions, which may account for why only product 5a is obtained (for details, see Fig. S1 in ESI†).

The gram scale reaction of 1a was conducted and 2a was obtained in 90% yield (for details, see Scheme S3 in the ESI†). It was also found that 2a could be readily converted to the corresponding ketone and indoline after ozonization and hydrogenation (for details, see Scheme S4 in the ESI†). Other aromatic systems, such as indoles and pyroles, will be investigated and reported in due course.

Furthermore, upon treatment of 2a with 2 equiv. of m-nitrobenzaldehyde in the presence of BF₃·Et₂O (1.1 equiv.), a 3,3′-spirobi[benzofuran]2-one derived imine 8¹⁸ was isolated in 52% yield (Scheme 6) and its structure was confirmed by X-ray diffraction.¹³ Notably, the 3,3′-spirobi[benzofuran]-2-one structure is found to exist in a natural product family of phenolics (Yuccaol A–E and Larixinol), which are extracted from Yucca schidigera Roezl and have been used in folk medicine, food and pharmaceutical industries.¹⁹

Scheme 6 Further derivatization of 2a to synthesize imine 8.

In conclusion, the controllable and chemoselective synthesis of 3-methylene-2,3-dihydrobenzofurans and 3-methylene-2,3-dihydroindoles has been established through two types of annulations of aromatic rings with N-sulfonyl 1,2,3-triazoles. For benzofuran synthesis, temperature plays an important role in controlling the exocyclic double bond and intramolecular hydrogen bonding facilitates the 1,2-addition. On the other hand, in indole synthesis, the big challenges are the β-H elimination and 1,2-H shift, which are successfully solved by the combination of additive (LiCl) and temperature, and this finding may be helpful for those reactions in which the triazole ring has adjacent beta-protons. Several derivatizations of 2a were conducted to access biologically and medicinally valuable molecules, such as the analog of phenolics. Further investigations to examine the mechanistic details more extensively are currently underway in our laboratory.

We are grateful for the financial support from the National Basic Research Program of China (973)-2015CB856603, the Shanghai Municipal Committee of Science and Technology (11JC1402600), and the National Natural Science Foundation of China (20472096, 21372241, 21361140350, 20672127, 21102166, 21121062, 21302203 and 20732008).

Notes and references

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18. Proposed mechanism for the formation of 8 is presented in the ESI†.
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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, characterization data of new compounds, and CCDC 966827, 969393, 969179, 1012006 and 989483. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc08343a

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