Visible‐Light‐Mediated Heterocycle Functionalization via Geometrically Interrupted [2+2] Cycloaddition

Abstract The [2+2] photocycloaddition is the most valuable and intensively investigated photochemical process. Here we demonstrate that irradiation of N‐acryloyl heterocycles with blue LED light (440 nm) in the presence of an IrIII complex leads to efficient and high yielding fused γ‐lactam formation across a range of substituted heterocycles. Quantum calculations show that the reaction proceeds via cyclization in the triplet excited state to yield a 1,4‐diradical; intersystem crossing leads preferentially to the closed shell singlet zwitterion. This is geometrically restricted from undergoing recombination to yield a cyclobutane by the planarity of the amide substituent. A prototropic shift leads to the observed bicyclic products in what can be viewed as an interrupted [2+2] cycloaddition.

Abstract: The [2+2] photocycloaddition is the most valuable and intensively investigated photochemical process. Here we demonstrate that irradiation of N-acryloyl heterocycles with blue LED light (440 nm) in the presence of an Ir III complex leads to efficient and high yielding fused g-lactam formation across a range of substituted heterocycles. Quantum calculations show that the reaction proceeds via cyclization in the triplet excited state to yield a 1,4-diradical; intersystem crossing leads preferentially to the closed shell singlet zwitterion. This is geometrically restricted from undergoing recombination to yield a cyclobutane by the planarity of the amide substituent. A prototropic shift leads to the observed bicyclic products in what can be viewed as an interrupted [2+2] cycloaddition.
The [2+2] photocycloaddition is arguably the most important photochemical transformation in synthetic chemistry. [1] In recent years, a number of visible-light [2+2] processes that operate by electron or energy transfer have been disclosed. Elegant approaches by the groups of Bach and Yoon have enabled efficient construction of polycyclic cyclobutane architectures and have also led to advances in the enantioselective catalysis of such reactions. [2] Within this field, the visible-light-enabled [2+2] photocycloaddition of indole substrates has received significant recent attention. You demonstrated that indoles bearing a C-3 tethered alkene could undergo efficient and diastereoselective cycloaddition in the presence of an iridium sensitizer to yield fused cyclobutanes (Scheme 1). [3] In a related transformation disclosed by Oderinde, [4] alkenes tethered through an indole C-2 amide were demonstrated to be viable substrates for the [2+2] cycloaddition under similar visible-light conditions. We reasoned that distinct reactivity could be attained through Nfunctionalization of heterocycles (such as indole) with an aaryl acryloyl derivative. [5] This would provide an alkene with a triplet energy of about 50 kcal mol À1 , similar in magnitude to the triplet energies of a number of excited state photo-catalysts. We envisaged that excitation to the triplet (T 1 ) state via triplet energy transfer (TET) from an appropriate sensitizer and addition to the indole alkene would generate a 1,4-diradical intermediate, which in a conventional [2+2] process would generate cyclobutane products via intersystem crossing (ISC) to the singlet state. Once in the singlet state, this intermediate may adopt an open shell diradical or zwitterionic closed shell electronic configuration. Both types of electronic configuration have been recognised in thermal and photochemical cyclobutane formation and in other processes. [6] However, the geometry of the 5,5-bicyclic lactam ring system means that this route is challenging and hence can be interrupted via proton transfer to afford the functionalized aromatic heterocycle. [7] Owing to the electronwithdrawing nature of the amide group, we envisioned that this reaction intermediate could possess significant zwitterionic character, further facilitating the proposed proton transfer event.
The resulting pyrrolo [1,2-a]indole scaffold is an important motif found in numerous natural products. [8] Although photochemically mediated electron-transfer processes have been used in the past to enable generation of these structures, there are, to our knowledge, no examples employing energy transfer. [9] To probe the feasibility of this approach, we prepared a test acryloyl substrate 1 through N-acylation of 5-cyano indole and examined its reactivity in the presence of a range of photocatalysts under irradiation with blue LED light (Table 1). A ruthenium(II) catalyst proved to be ineffective ( Table 1, entry 1), and hence we examined iridium photocatalysts with increasingly higher triplet energies (entries 2-6). [Ir(dtbbpy)(ppy) 2 ]PF 6 (entry 3) afforded a trace of product 2. Significantly higher conversion was observed with fac-Ir(ppy) 3 (71 % conversion, entry 4) and similar results were obtained using [Ir(dF(CF 3 )ppy) 2 -(dtbbpy)]PF 6 (81 % yield), while Ir(dFppy) 3 gave complete conversion and an 85 % yield of 2. Furthermore, addition of a catalytic amount of NaOAc further increased the isolated yield to 93 %. With a working substrate synthesis and cyclization procedure in hand, we examined the scope and limitations of this visible light mediated process (Table 2).
We initially explored cyclization of substrates with different substituents on the indole. The parent substrate in which indole is N-functionalized with 2-phenyl acrylic acid cyclized smoothly to afford bicyclic lactam 3 in 98 % isolated yield. The reaction is remarkably tolerant of different substituents around the pyrroloindole core. Substrates with 8-substituents cyclize successfully including electron-donating groups such as O-tert-butyldimethylsilyl (4, 85 % yield) and electronwithdrawing groups such as halogens (8-chloro 5, 79 % yield; 8-bromo 6, 94 % yield). More reactive groups such as 8-Omethanesulfonyl 7 also cyclize successfully, albeit in lower yield (52 %). Introducing substituents in the 7-position does not have any deleterious effects on the reaction. Halogen substituted indoles cyclize in good to excellent yields: 7-fluoro 8 (95 % yield), 7-bromo 9 (94 % yield) and 7-iodo 10 (83 % yield) groups are all well-tolerated. Electron-withdrawing groups such as a cyano 2 (93 % yield) or a methyl ester 11 (62 % yield) were both tolerated at C-7 without incident, and electron rich pyrroloindoles were synthesized with equal facility (12, 70 % yield). Pyrroloindoles bearing pinacol boronic acid esters were also demonstrated to be viable substrates for the reaction, cyclizing in 66 % isolated yield to afford 13. 6-Bromo and 6-trifluoromethyl substituted indole derivatives also cyclized effectively to afford product in good yields (14, 94 % yield and 15, 74 % yield, respectively). We were also able to demonstrate that performing the reaction on a substrate bearing an aldehyde in the 6-position was also possible, albeit affording product 16 in a moderate yield of 32 %; in this case the remaining material is likely consumed via polymerization of the starting acrylic acid derivative. 5-Substitution on the pyrroloindole core was exemplified through the synthesis of the 5-fluoro derivative 17 in 82 % yield. We were also able to perform the reaction efficiently on a series of azaindoles: 6-azaindole derivative 18 (77 % yield), 5-azaindole 19 (90 % yield) and 4-azaindole 20 were all generated in good to excellent yields. The transformation is also tolerant of other changes to the backbone of the heterocycle; bicyclic pyrrole derivatives such as 21 could also be generated in 83 % yield while bicyclic imidazole derivative 22 was obtained in 21 % yield as a mixture of regioisomers. Substitution is also tolerated in the 9-position of the pyrroloindole as demonstrated by the successful conversion of substrates bearing cyanomethyl 23 (92 % yield) and methyl ester groups (24, 84 % yield). We also probed the potential to make changes to the substrate via modification of the N-acyl portion of the molecule. Replacement of the aphenyl group on the N-acyl moiety by a methoxy ether was well tolerated and led to the desired photo-cyclised product in high yield (25, 74 %), while modification of the phenyl group itself by the addition of a p-OMe substituent also gave an excellent yield (26, 92 %). Similarly, addition of a p-t Bu (27, 91 %) and p-CF 3 (28, 68 %) are well tolerated. Addition of an alkyl substituent at the terminal end of the alkene had no deleterious effect; however, the product was obtained with minimal control over diastereoselectivity (29, 88 %, 1.2:1 dr). Finally, we turned our attention to modifying more complex products containing indoles. Camalexin, a simple alkaloid that is cytotoxic against aggressive prostate cancer, [10] and melatonin, an important sleep-regulating hormone, [11] were acylated and found to be compatible with the photochemical transformation, leading to the formation of their corresponding pyrrolo [1,2-a]indole containing products 30 (50 % yield) and 31 (50 % yield) respectively.
To probe the practical utility of this transformation, a gram scale synthesis of 6-bromo substrate 14 was performed. By starting with 4.6 mmol of the appropriate precursor, 1.39 g of 14 were obtained (93 %), thus demonstrating that the reaction is scalable without affecting the overall yield.
Our proposed mechanism is pictured in Figure 1. After singlet-to-triplet excitation of the initial substrate by the excited state catalyst ( 1 A to 3 A), a 5-exo-trig cyclization takes place to produce intermediate 3 B. 3 B undergoes an intersystem crossing (ISC) and generates the corresponding singlet species 1 B; this species is better described as a closed-shell singlet zwitterion rather than a singlet diradical (hŜ 2 i = 0 in the wavefunction stability checks). This zwitterionic species undergoes a proton transfer to form final product C. The reaction activation barriers of the main pathway, which range from 3.2 to 10.6 kcal mol À1 (Figure 1 B) are easily accessible at room temperature. The barrier to ISC is particularly low owing to the small structural reorganization needed from 3 B to reach the geometry observed in the ISC (Supporting Information, Figure S7). The calculated energy profile also indicates the presence of a retrocyclization process (from 1 B back to 1 A) with an activation barrier of 9.7 kcal mol À1 ; this is somewhat higher than the barrier required to form the reaction product C (3.3 to 7.6 kcal mol À1 ). When we performed the reaction on substrate 1 in the presence of acetone, the adduct 32 was isolated (11 % yield), along with the pyrroloindole product, consistent with the presence of an enolate-like intermediate. The last step of the proposed mechanism involves transformation of the zwitterion 1 B into the final product C. We reasoned initially that this could occur via stepwise deprotonation/reprotonation events or by a direct hydrogen shift from C 9a of 1 B to C 2 . To probe this, we subjected deuterated substrate 33 to the reaction con-  Under these conditions only a small amount of deuterium in the C 2 position was observed in 34. This result implies that the H atom from C 9a is not directly transferred to the C 2 position, which agrees with the prohibitively high calculated barrier of the intramolecular H-shift (31.7 kcal mol À1 ; Supporting Information, Figure S6 A). We did, however, observe 17 % incorporation of deuterium at C 9 , which is consistent with a minor 1,2-shift pathway; this was also observed computationally (8.9 kcal mol À1 ; Supporting Information, Figure S6 B). Conversely, when using D 2 O as co-solvent with a non-deuterated indole 1, the C 2 position of product 35 showed significant deuterium incorporation (80 %); control experiments also demonstrated that the pyrroloindole 2 is unreactive under these conditions and no deuterium incorporation is observed. This is consistent with a pathway whereby the C 2 hydrogen comes from solvent. We probed this with further calculation and found that the stepwise solvent mediated deprotonation/ reprotonation pathway is feasible with a barrier of 7.6 kcal mol À1 (Supporting Information, Figure S6 C). We also discovered an alternative lower energy pathway that could operate in the presence of water (5.7 kcal mol À1 , Figure 1 C). In this scenario, the water co-solvent acts to shuttle a proton from C 9a to C 2 leading to the product. However, when a base such as AcONa is used or the concentration of water as a cosolvent is low, other pathways might become the preferred routes to promote this 1,3-shift (Supporting Information, Figure S6 C,D).
In conclusion, we have discovered an operationally simple and functional-group-tolerant synthesis of pyrroloindoles that proceeds in the presence of visible light and an iridium(III) sensitizer. The reaction proceeds via cyclization in the triplet excited state to yield a 1,4-diradical; intersystem crossing leads preferentially to a closed shell singlet zwitterion that is geometrically restricted from undergoing recombination to yield a cyclobutane, leading to the preferential formation of a 5,5-bicyclic lactam ring system.