Metal-Free, Visible-Light-Promoted Decarboxylative Radical

Jan 4, 2018 - A visible-light-mediated decarboxylative cyclization of N-acyloxylphthalimides with vinyl azides has been developed under metal-free con...
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Cite This: J. Org. Chem. 2018, 83, 1598−1605

Metal-Free, Visible-Light-Promoted Decarboxylative Radical Cyclization of Vinyl Azides with N‑Acyloxyphthalimides Jun-Cheng Yang, Jia-Yu Zhang, Jin-Jiang Zhang, Xin-Hua Duan, and Li-Na Guo* Department of Chemistry, School of Science and MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, Xi’an Jiaotong University, Xi’an 710049, China S Supporting Information *

ABSTRACT: A visible-light-mediated decarboxylative cyclization of N-acyloxylphthalimides with vinyl azides has been developed under metal-free conditions. This protocol features mild conditions, a broad substrate scope, and an excellent functional group tolerance, thus providing a facile and efficient access to substituted phenanthridines. Control experiments revealed that the reaction proceeded via a radical process.

P

been reported.7 Very recently, Baran, Li, and Aggarwal et al. have represented the decarboxylative borylation of redox-active esters, respectively.8 Although, the redox-active NHP esters have already been well-exploited as efficient alkylating sources in Csp3−C and Csp3−heteroatom bond formations. However, as C-centered radical precursors, their applications in cyclization reactions, especially under metal-free conditions, are less reported.4g,9 Herein, we describe a metal-free, visiblelight-promoted cyclization of vinyl azides with N-acyloxyphthalimides for the synthesis of 6-alkylated phenanthridines. Compared with existing catalytic methods,3 this decarboxylative cyclization protocol takes advantages of using easily available starting materials and mild reaction conditions and avoiding the use of oxidants and metals. Initially, the reaction was carried out by treatment of vinyl azide 1a with redox-active ester 2a in the presence of 1 mol % fac-Ir(ppy)3 in 3 mL of NMP at room temperature under visible-light irradiation.5 To our delight, the desired product 3a was isolated in 48% yield along with 15% of 6-methylphenanthridine 5a as a byproduct after 24 h (Table 1, entry 1). To enhance the reaction efficiency, other visible-light photoredox catalysts were then examined (details in the Supporting Information). It was found that using the organic dye Eosin Y10 (2 mol %) instead of Ir-complex as a catalyst also resulted in 33% yield of 3a (entry 2). In view of its inexpensive and easily available merits, we chose Eosin Y as the photoredox catalyst to further optimize the reaction conditions. An extensive screening of solvents revealed that the reaction in DMF led to the best yield (entries 3−8). To scavenge the byproduct of 6-methylphenanthridine, several organic and inorganic bases were tested as an additive (entries 9−14). Satisfactorily, a base facilitated the reaction, and only a trace amount of 6-methylphenanthridine was detected in these cases (entries 9−14). Tetramethylethylenediamine (TMEDA) was

henanthridines are an important class of alkaloids, which exhibit remarkable biological activities and optoelectronic properties.1a−d Thus, many efforts have been devoted to develop efficient methods for the synthesis of these motifs.1 In this field, the radical cyclization involving an iminyl radical has been established as an efficient strategy for the construction of a phenanthridine skeleton.1e,f,2,3 For instance, the direct intramolecular cyclization of the biaryloxime derivatives has been developed to access the phenanthridine framework by different research groups.2 Besides acyl oximes, Chiba, Studer, and Yu et al. have successfully exploited vinyl azides as iminyl radical precursors to achieve these aza-heterocyles via an intermolecular addition/intramolecular cyclization process.3a−c In this aspect, our group disclosed an efficient copper-catalyzed radical cyclization of vinyl azides with benzylic Csp3−H bonds via a dual C−H functionalization process.3d Despite these important advances, most of the current protocols still suffer several drawbacks, such as the use of stoichiometric amounts of an external oxidant, an additional transition-metal catalyst, and harsh conditions. Thus, the development of more facile and mild methods for the synthesis of phenanthridine derivatives is still desirable. N-Acyloxyphthalimides, derived from alkyl carboxylic acids and N-hydroxyphthalimides, are important and useful building blocks in organic synthesis.4−8 In the early 1990s, Okada discovered first that redox-active NHP esters could undergo decarboxylative cross-coupling with electron-deficient alkenes through visible-light photocatalysis.4a Since then, several visiblelight-mediated decarboxylative cross-couplings of the redoxactive NHP esters have been developed.4b In this aspect, our group described a visible-light-induced decarboxylative coupling of NHP esters with α,β-unsaturated carboxylic acids, which provided an efficient route to substituted alkenes via a dual decarboxylation process.5 Recently, the group of Baran has successfully revealed a series of Ni-catalyzed decarboxylative cross-coupling of redox-active esters with organic zinc reagents.6 In addition, the Ni-catalyzed decarboxylative crosscoupling of redox-active esters with organic halides has also © 2018 American Chemical Society

Received: November 11, 2017 Published: January 4, 2018 1598

DOI: 10.1021/acs.joc.7b02861 J. Org. Chem. 2018, 83, 1598−1605

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The Journal of Organic Chemistry Table 1. Optimization of the Reaction Conditionsa

entry

photocatalyst (mol %)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

fac-Ir(ppy)3 (1) Eosin Y (2) Eosin Y (2) Eosin Y (2) Eosin Y (2) Eosin Y (2) Eosin Y (2) Eosin Y (2) Eosin Y (2) Eosin Y (2) Eosin Y (2) Eosin Y (2) Eosin Y (2) Eosin Y (2) Eosin Y (1) Eosin Y (5) Eosin Y (2) Eosin Y (2) Eosin Y (2) Eosin Y (2) Eosin Y (2) Eosin Y (2)

base (equiv)

Et3N (1.5) i-Pr2EtN (1.5) TMEDA (1.5) DBACO (1.5) Na2HPO4 (1.5) Cs2CO3 (1.5) TMEDA (1.5) TMEDA (1.5) TMEDA (1.5) TMEDA (1.5) TMEDA (1.5) TMEDA (1.5) TMEDA (1.0) TMEDA (2.0) TMEDA (1.5) TMEDA (2.5)

solvent

yield of 3a (%)b

yield of 5a (%)c

NMP NMP DMF acetone CH3CN 1,4-dioxane DCE toluene DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF

48 33 47 28 trace 14 0 0 68 51 75 64 41 63 72 70 nrd,e 72f 70g 43h 69 73 30 28 0

15 13 12 10 0 6 0 0 trace 5 trace trace 10 trace trace trace 0 trace trace trace trace trace trace trace 0

a

Reaction conditions: photocatalyst (1−5 mol %), 1a (0.3 mmol, 1 equiv), 2a (0.6 mmol, 2.0 equiv), solvent (3 mL), room temperature, 15 W CFL, 24 h. bYield of isolated product. cYield of 6-methylphenanthridine. dWithout CFL irradiation. enr = no reaction. fUnder green LEDs. gUnder blue LEDs (λ = 468 nm). hReaction time = 8 h.

ate to good yields. The tertiary alkyl NHP esters were efficient substrates to afford the desired products 3b−3e in 47−75% yields. Notably, the secondary alkyl NHP esters containing heteroatoms (O or N) on the aliphatic ring were also amenable to the reaction conditions, providing the desired products 3f− 3j in moderate to good yields. Furthermore, the protecting groups −Boc and −Ts on the N tether could survive well under the reaction conditions (3h and 3i). In addition to the tertiary and secondary NHP esters, the reaction of primary esters 2n− 2p also proceeded smoothly to give the corresponding phenanthridines in reasonable yields. Particularly, the primary esters 2n and 2o derived from aryloxy acetic acids showed a better reaction efficiency, producing the desired products 3n and 3o in 54% and 79% yields, respectively. Subsequently, we turned our attention to examine the scope of vinyl azides 1 with 2i (Scheme 2). A variety of biarylvinylazides 1 with p-substituted electron-donating or electron-withdrawing groups led to the desired products in moderate to good yields (4a−f). It is particularly noteworthy that functional groups such as fluoro, chloro, bromo, and cyano were well-tolerated in this reaction. Satisfactorily, the sterically hindered ortho-substituted vinyl azide 1f was also a good substrate, giving the desired product 4f in 72% yield. Furthermore, biarylvinylazides bearing a fluoro or a methoxy substituent on the other aromatic ring also worked well in the

proven to be the best additive to provide product 3a in 75% yield (entry 11). Furthermore, decreasing the catalyst loading to 1 mol % or increasing it to 5 mol % both resulted in comparable yields (entries 15 and 16). No reaction occurred without compact fluorescent light (CFL) irradiation (entry 17). Under green or blue LED irradiation, similar yields of 3a were obtained (entries 18 and 19). When the reaction time was shortened to 8 h, the product 3a was isolated in only 43% yield due to low conversion (entry 20). Furthermore, increasing or decreasing the amount of TMEDA did not further improve the yield of 3a (entries 21 and 22). The control experiment disclosed that 30% yield of 3a was still obtained in the absence of a photocatalyst, implying that direct photolysis of 1a accounts partly for the formation of 3a (entry 23).11 Without a photocatalyst, increasing the amount of TMEDA to 2.5 equiv did not obviously affect the yield of 3a (entry 24). Finally, no product was observed without a photocatalyst and base (entry 25). With the optimized reaction conditions in hand (Table 1, entry 11), the substrate scope of this transformation was investigated. First, we evaluated the scope of redox-active esters with vinyl azide 1a. As shown in Scheme 1, a series of redoxactive NHP esters derived from structurally diverse 3°, 2°, and 1° aliphatic carboxylic acids showed good reactivities and furnished the 6-substituted phenanthridines 3b−3p in moder1599

DOI: 10.1021/acs.joc.7b02861 J. Org. Chem. 2018, 83, 1598−1605

Note

The Journal of Organic Chemistry Scheme 1. Scope of Redox-Active Esters

Scheme 2. Scope of the Vinyl Azides

1600

DOI: 10.1021/acs.joc.7b02861 J. Org. Chem. 2018, 83, 1598−1605

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The Journal of Organic Chemistry Scheme 3. Investigation of the Reaction Mechanism

reaction and gave the corresponding products 4g and 4h in 80% and 68% yields, respectively. In addition, the chlorosubstituted biarylvinylazide 1i also reacted well with 2i to give the desired product 4i in 67% yield. To shed light on the mechanism of this process, several control experiments were conducted carefully (Scheme 3). When the radical scavengers such as TEMPO and BHT were added, the reaction of 1a and 2i were suppressed significantly, respectively. Fortunately, the alkyl-TEMPO adduct 6a was isolated in 20% yield when TEMPO was added (eq 1). Furthermore, the reaction of NHP ester 2q derived from cyclopropyl acetic acid, a radical clock substrate with vinyl azide 1a, led to the only ring-opening product 3q in 13% yield (eq 3). These results indicated that a radical pathway might be involved in this reaction. Additionally, in the absence of 2a, vinyl azides 1a could lead to trace amounts of 6-methylphenanthridine3a along with 17% of 2H-azirine 7a under the standard conditions (eq 4). Moreover, the treatment of 2H-azirine 7a generated by the decomposing of 1a with 2i did not afford any product of 3i (eq 5). This result suggested that 2H-azirine was not the key intermediate in this cyclization reaction. To get a better understanding of the mechanism, the quenching experiments were then performed. (For details, see the Supporting Information.) The Stern−Volmer studies indicated that the quenching of Eosin Y was performed by NHP ester 2a rather than vinyl azide 1a or TMEDA (Figure 1), suggesting that the reaction should proceed through an oxidative quenching pathway. Moreover, the electron-donor−acceptor (EDA)

Figure 1. Fluorescence quenching of Eosin Y by 1a, NHP ester 2a, and TMEDA.

complex was not observed by NMR or UV−vis spectroscopy. We speculated that the main role of TMEDA is probably to activate the Eosin Y photocatalyst.11 Furthermore, quantum yield measurements of this reaction have been conducted, and the quantum yield (14.9, λ = 468 nm) indicated that the radical chain propagation mechanism was also involved in this transformation. (For details, see the Supporting Information.) 1601

DOI: 10.1021/acs.joc.7b02861 J. Org. Chem. 2018, 83, 1598−1605

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The Journal of Organic Chemistry Scheme 4. Proposed Mechanism

Based on the above investigations and previous reports,3 a possible mechanism is proposed for this reaction (Scheme 4). Photoexcitation of Eosin Y by visible light affords the excited Eosin Y*. Oxidative quenching of Eosin Y* by single-electron transfer (SET) to NHP ester 1a generates the radical anion I along with Eosin Y•+. Fragmentation of CO2 from I gives the phthalimide anion and the corresponding alkyl radical II,4,5 which adds to the CC bond of 2a, furnishing the iminyl radical III by extrusion of N2. Subsequently, the iminyl radical III undergoes an intramolecular cyclization to produce radical intermediate IV,3 which is oxidized by Eosin Y•+ to give the corresponding carbocation V and regenerate the photocatalyst. Finally, deprotonation of intermediate V delivers the desired product 3a. Alternatively, a radical chain propagation mechanism should be involved in this reaction, wherein oxidation of radical intermediate IV by NHP ester 1a led to the desired product 3a.11 In summary, we have developed a simple and efficient visiblelight-induced decarboxylative cyclization of redox-active esters with vinyl azides. A variety of 1°, 2°, and 3° alkyl NHP esters performed well in this tandem radical addition/cyclization process to afford substituted phenanthridines in moderate to good yields. The significant advantages of this protocol are avoiding the use of an external oxidant and metal catalyst, under very mild conditions.

■

(0.3 mmol, 1.0 equiv), NHP ester 2 (0.6 mmol, 2.0 equiv), and Eosin Y (4.15 mg, 2 mol %). Then, the tube was evacuated and backfilled with nitrogen (three times). After that, 3 mL of DMF followed by TMEDA (0.45 mmol, 1.5 equiv) was added by syringe under nitrogen. The reaction was then stirred vigorously and irradiated with a 15 W compact fluorescent light bulb at room temperature for 24 h. The mixture was diluted with EtOAc and transferred to a separatory funnel. The organic phase was washed successively with H2O and brine, dried over Na2SO4, and evaporated under reduced pressure. The resulting residue was purified with chromatography column on silica gel (gradient eluent of EtOAc/petroleum ether 1/50 to 1/3) to afford the corresponding product 3 or 4 in a yield listed in Schemes 1 and 2. 6-(Cyclohexylmethyl)phenanthridine (3a): (known compound)3d yellow oil (75%, 61.9 mg); Rf 0.3 (EtOAc/petroleum ether = 1:20); 1 H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 8.4 Hz, 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.81 (t, J = 7.2 Hz, 1H), 7.74−7.66 (m, 2H), 7.61 (td, J = 8.0, 0.8 Hz, 1H), 3.26 (d, J = 7.2 Hz, 2H), 2.02 (m, 1H), 1.75−1.64 (m, 5H), 1.20−1.19 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 161.4, 143.6, 132.8, 130.1, 129.6, 128.5, 127.1, 126.6, 126.2, 125.7, 123.5, 122.3, 121.8, 43.6, 38.7, 33.6, 26.3 ppm; HRMS (ESI) calcd for C20H22N [M + H]+ 276.1747, found 276.1746. 6-((Adamantan-1-yl)methyl)phenanthridine (3b): white solid (75%, 73.6 mg), mp = 112−114 °C; Rf 0.3 (EtOAc/petroleum ether = 1:20); 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 8.0 Hz, 1H), 8.56 (d, J = 7.6 Hz, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.16 (dd, J = 8.4, 0.8 Hz, 1H), 7.82 (td, J = 8.0, 0.8 Hz, 1H), 7.75−7.61 (m, 3H), 3.22 (s, 2H), 1.92 (s, 3H), 1.71−1.55 (m, 12H); 13C NMR (100 MHz, CDCl3) δ 159.9, 143.4, 132.6, 130.0, 129.8, 128.4, 127.7, 126.9, 126.7, 126.2, 123.4, 122.2, 121.8, 48.7, 43.3, 36.8, 35.4, 28.8 ppm; IR (KBr) υmax 3072, 2901, 2846, 1612, 1570, 1450, 1357 cm−1; HRMS (ESI) calcd for C24H26N [M + H]+ 328.2060, found 328.2067. 6-(2,2-Dimethylbutyl)phenanthridine (3c): colorless oil (62%, 48.9 mg); Rf 0.37 (EtOAc/petroleum ether = 1:20); 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 8.4 Hz, 1H), 8.56 (d, J = 8.4 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 7.81 (t, J = 7.2 Hz, 1H), 7.74−7.60 (m, 3H), 3.32 (s, 2H), 1.51 (q, J = 7.6 Hz, 2H), 1.00−0.97 (m, 9H); 13C NMR (100 MHz, CDCl3) δ 160.8, 143.5, 132.7, 130.0, 129.8, 128.4, 127.4, 126.8, 126.2, 123.4, 122.3, 121.8, 45.1, 35.9, 35.8, 27.0, 8.7 ppm; IR (KBr) υmax 2961, 1612, 1571, 1461, 1361 cm−1; HRMS (ESI) calcd for C19H22N [M + H]+ 264.1747, found 264.1743. 6-Neopentylphenanthridine (3d): (known compound)12a colorless oil (69%, 51.5 mg); Rf 0.3 (EtOAc/petroleum ether = 1:20); 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 8.4 Hz, 1H), 8.56 (dd, J = 8.0, 0.8 Hz, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.15 (dd, J = 8.4, 0.8 Hz, 1H), 7.82 (td, J = 8.4, 1.2 Hz, 1H), 7.75−7.61 (m, 3H), 3.34 (s, 2H), 1.09 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 160.8, 143.4, 132.7, 130.0,

EXPERIMENTAL SECTION

General Methods. All reactions were carried out in oven-dried Schlenk tubes filled with nitrogen. Column chromatography was carried out on silica gel. 1H NMR and 13C NMR spectra were recorded on a 400 M spectrometer in solvents as indicated. Chemical shifts are reported in ppm with the solvent resonance as an internal standard (CDCl3: 1H NMR, δ = 7.26; 13C NMR, δ = 77.0). IR spectra were recorded on a spectrometer, and only major peaks are reported in cm−1. HRMS were obtained on a Q-TOF Micro spectrometer. All of the vinyl azides 1 were synthesized according to the literature, and the NMR spectra were in full accordance with the data in the literature.3a All of the N-acyloxyphthalimides 2 were synthesized according to the literature, and the NMR spectra were in full accordance with the data in the literature.6a All of the commercially available compounds were used without further purification. General Procedure for the Cyclization of Vinyl Azides with N-acyloxyphthalimides. A 10 mL oven-dried Schlenk tube equipped with a magnetic sir bar was charged with vinyl azides 1 1602

DOI: 10.1021/acs.joc.7b02861 J. Org. Chem. 2018, 83, 1598−1605

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The Journal of Organic Chemistry

1H), 3.95 (dd, J = 12.0, 2.8 Hz, 2H), 3.36 (td, J = 11.6, 2.4 Hz, 2H), 3.31 (d, J = 7.2 Hz, 2H), 2.37−2.26 (m, 1H), 1.67−1.53 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 160.2, 143.5, 132.8, 130.3, 129.6, 128.6, 127.2, 126.4, 126.2, 125.6, 123.5, 122.5, 121.9, 68.0, 42.6, 35.6, 33.3 ppm; IR (KBr) υmax 2921, 2841, 1578, 1445, 1362 cm−1; HRMS (ESI) calcd for C19H20NO [M + H]+ 278.1539, found 278.1552. 6-((4,4-Difluorocyclohexyl)methyl)phenanthridine (3k): colorless oil (65%, 60.6 mg); Rf 0.2 (EtOAc/petroleum ether = 1:20); 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 8.0 Hz, 1H), 8.55 (d, J = 8.0 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.84 (t, J = 8.0 Hz, 1H), 7.75−7.68 (m, 2H), 7.63 (t, J = 8.0 Hz, 1H), 3.31 (d, J = 7.2 Hz, 2H), 2.22−2.05 (m, 3H), 1.87−1.83 (m, 2H), 1.79−1.50 (m, 4H); 13 C NMR (100 MHz, CDCl3) δ 160.4, 143.5, 132.8, 130.3, 129.6, 128.6, 127.3, 126.4, 126.1, 125.5, 123.6 (dd, J = 238.3, 240.5 Hz), 123.5, 122.5, 121.9, 41.3 (d, J = 2.2 Hz), 36.1, 33.4 (dd, J = 22.5, 22.4 Hz), 29.2 (d, J = 9.5 Hz) ppm; IR (KBr) υmax 2932, 2860, 1612, 1584, 1448, 1358, 1112 cm−1; HRMS (ESI) calcd for C20H20F2N [M + H]+ 312.1558, found 312.1556. 6-Isobutylphenanthridine (3l): (known compound)12b colorless oil (52%, 36.7 mg); Rf 0.3 (EtOAc/petroleum ether = 1:20); 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 8.4 Hz, 1H), 8.54 (dd, J = 8.0, 0.8 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.15 (dd, J = 8.0, 0.8 Hz, 1H), 7.82 (td, J = 8.4, 1.2 Hz, 1H), 7.74−7.66 (m, 2H), 7.62 (td, J = 8.4, 1.2 Hz, 1H), 3.26 (d, J = 7.2 Hz, 2H), 2.45−2.33 (m, 1H), 1.05 (d, J = 6.8 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 161.6, 143.7, 132.8, 130.2, 129.6, 128.5, 127.1, 126.5, 126.2, 125.6, 123.5, 122.4, 121.9, 44.9, 29.2, 22.9 ppm; IR (KBr) υmax 2922, 1611, 1571, 1526, 1461, 1360 cm−1; HRMS (ESI) calcd for C17H18N [M + H]+ 236.1434, found 236.1429. 6-(2-Ethylhexyl)phenanthridine (3m): colorless oil (63%, 55.0 mg); Rf 0.3 (EtOAc/petroleum ether = 1:20); 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 8.0 Hz, 1H), 8.55 (dd, J = 8.0, 0.8 Hz, 1H), 8.26 (d, J = 8.0 Hz, 1H), 8.13 (dd, J = 8.0, 0.8 Hz, 1H), 7.83 (td, J = 8.4, 1.2 Hz, 1H), 7.74−7.67 (m, 2H), 7.62 (td, J = 8.4, 1.6 Hz, 1H), 3.35−3.26 (m, 2H), 2.13−2.06 (m, 1H), 1.49−1.38 (m, 5H), 1.29−1.23 (m, 3H), 0.93 (t, J = 7.6 Hz, 3H), 0.85 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.8, 143.7, 132.9, 130.1, 129.7, 128.5, 127.1, 126.4, 126.2, 125.6, 123.5, 122.4, 121.8, 40.8, 39.6, 32.9, 28.8, 26.1, 23.1, 14.1, 10.9 ppm; IR (KBr) υmax 2925, 1584, 1574, 1460, 1377, 1362 cm−1; HRMS (ESI) calcd for C21H26N [M + H]+ 292.2060, found 292.2051. 6-(2-(4-Chlorophenoxy)ethyl)phenanthridine (3n): white solid (54%, 51.7 mg), mp = 152−154 °C; Rf 0.2 (EtOAc/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 8.4 Hz, 1H), 8.57 (d, J = 8.4 Hz, 1H), 8.33 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.88−7.85 (m, 1H), 7.75−7.63 (m, 3H), 7.22 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 9.2 Hz, 2H), 4.65 (t, J = 7.2 Hz, 2H), 3.86 (t, J = 7.2 Hz, 2H); 13 C NMR (100 MHz, CDCl3) δ 158.2, 157.5, 143.6, 132.8, 130.5, 129.7, 129.3, 128.7, 127.4, 126.7, 126.1, 125.6, 125.5, 123.7, 122.5, 122.0, 115.9, 67.1, 34.9 ppm; IR (KBr) υmax 1588, 1492, 1244, 1096, 1018 cm−1; HRMS (ESI) calcd for C21H17ClNO [M + H]+ 334.0993, found 334.0995. 6-(2-Phenoxyethyl)phenanthridine (3o): white solid (79%, 67.6 mg), mp = 140−142 °C; Rf 0.2 (EtOAc/petroleum ether = 1:10); 1H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 8.4 Hz, 1H), 8.56 (d, J = 8.0 Hz, 1H), 8.35 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.86 (t, J = 8.0 Hz, 1H), 7.75−7.63 (m, 3H), 7.29 (t, J = 8.4 Hz, 2H), 6.98−6.93 (m, 3H), 4.68 (t, J = 7.2 Hz, 2H), 3.88 (t, J = 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 158.8, 158.5, 143.6, 132.8, 130.5, 129.7, 129.4, 128.6, 127.4, 126.6, 126.2, 125.6, 123.7, 122.4, 121.9, 120.7, 114.6, 66.7, 35.2 ppm; IR (KBr) υmax 1585, 1495, 1245, 1031 cm−1; HRMS (ESI) calcd for C21H18NO [M + H]+ 300.1383, found 300.1389. 6-(4-Chlorophenethyl)phenanthridine (3p): (known compound)3d yellow oil (32%, 30.4 mg); Rf 0.2 (EtOAc/petroleum ether = 1:20); 1 H NMR (400 MHz, CDCl3) δ 8.66 (d, J = 8.4 Hz, 1H), 8.56 (dd, J = 8.0, 0.8 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.15 (dd, J = 8.0, 0.8 Hz, 1H), 7.84 (td, J = 8.0, 1.2 Hz, 1H), 7.76−7.63 (m, 3H), 7.31−7.26 (m, 4H), 3.67−3.63 (m, 2H), 3.30−3.25 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 160.4, 143.6, 140.4, 132.9, 131.7, 130.4, 129.9, 129.6, 128.6, 128.5, 127.3, 126.5, 125.8, 125.1, 123.6, 122.6, 121.9, 37.5, 34.0 ppm. HRMS (ESI) calcd for C21H17ClN [M + H]+ 318.1044, found 318.1043.

129.7, 128.5, 127.5, 126.8, 126.6, 126.2, 123.4, 122.3, 121.8, 47.0, 33.4, 30.5 ppm; IR (KBr) υmax 2956, 1612, 1581, 1462, 1362, 1232 cm−1; HRMS (ESI) calcd for C18H20N [M + H]+ 250.1590, found 250.1587. 6-((1-Methylcyclohexyl)methyl)phenanthridine (3e): colorless oil (47%, 40.8 mg); Rf 0.3 (EtOAc/petroleum ether = 1:20); 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 8.4 Hz, 1H), 8.56 (d, J = 8.4 Hz, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.81 (t, J = 8.4 Hz, 1H), 7.74−7.60 (m, 3H), 3.34 (s, 2H), 1.60−1.41 (m, 10H), 1.01 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.6, 143.4, 132.7, 129.9, 129.8, 128.4, 127.6, 126.9, 126.7, 126.2, 123.4, 122.2, 121.8, 46.9, 38.4, 36.0, 26.3, 24.8, 22.2 ppm; IR (KBr) υmax 2925, 1611, 1571, 1459, 1362 cm−1; HRMS (ESI) calcd for C21H24N [M + H]+ 290.1903, found 290.1896. tert-Butyl 3-(Phenanthridin-6-ylmethyl)azetidine-1-carboxylate (3f): white solid (58%, 60.6 mg), mp = 125−127 °C; Rf 0.21 (EtOAc/petroleum ether = 1:5); 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 8.4 Hz, 1H), 8.52 (d, J = 8.0 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.88 (t, J = 8.0 Hz, 1H), 7.72−7.67 (m, 2H), 7.62 (td, J = 8.0, 1.2 Hz, 1H), 4.22 (t, J = 8.4 Hz, 2H), 3.84 (d, J = 8.4 Hz, 1H), 3.83 (d, J = 8.4 Hz, 1H), 3.64 (d, J = 6.4 Hz, 2H), 3.44−3.33 (m, 1H), 1.45 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 158.6, 156.4, 143.5, 132.6, 130.3, 129.9, 128.5, 127.3, 126.5, 1235.5, 125.3, 123.5, 122.5, 121.9, 79.1, 55.5, 54.2, 39.4, 28.4, 24.7 ppm; IR (KBr) υmax 2973, 1702, 1612, 1585, 1400, 1257, 1137 cm−1; HRMS (ESI) calcd for C22H25N2O2 [M + H]+ 349.1911, found 349.1905. tert-Butyl 2-(Phenanthridin-6-ylmethyl)pyrrolidine-1-carboxylate (3g): white solid (a mixture of enantiomers, total 69%, 74.9 mg); Rf 0.26 (EtOAc/petroleum ether = 1:5); 1H NMR (400 MHz, CDCl3) δ 8.79 (d, J = 7.6 Hz, 0.5H), 8.64−8.60 (m, 1H), 8.54 (d, J = 8.0 Hz, 1H), 8.48 (d, J = 8.4 Hz, 0.5H), 8.12 (d, J = 8.0 Hz, 1H), 7.85−7.59 (m, 4H), 7.62 (td, J = 8.0, 1.2 Hz, 1H), 4.48−4.43 (m, 1H), 4.19 (dd, J = 12.8, 2.8 Hz, 0.5H), 3.98 (dd, J = 12.8, 4.0 Hz, 0.5H), 3.54−3.29 (m, 3H), 3.16−3.05 (m, 1H), 2.06−2.02 (m, 2H), 1.86−1.66 (m, 2H), 1.53 (s, 4.5H), 1.50 (s, 4.5H); 13C NMR (100 MHz, CDCl3) δ 159.8, 159.4, 154.7, 154.5, 143.8, 132.8, 132.7, 130.4, 129.7, 128.6, 128.3, 127.8, 127.4, 127.1, 126.6, 126.5, 126.3, 125.7, 125.6, 123.8, 123.6, 122.4, 122.0, 121.9, 79.7, 79.0, 57.0, 56.8, 46.8, 46.4, 41.1, 40.5, 29.9, 28.8, 28.6, 23.5, 22.6 ppm; IR (KBr) υmax 2974, 1686, 1612, 1584, 1478, 1449, 1396, 1365, 1170, 1119 cm−1; HRMS (ESI) calcd for C23H27N2O2 [M + H]+ 363.2067, found 363.2079. tert-Butyl 4-(Phenanthridin-6-ylmethyl)piperidine-1-carboxylate (3h): yellow solid (54%, 60.9 mg), mp = 128−130 °C; Rf 0.24 (EtOAc/petroleum ether = 1:5); 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 8.4 Hz, 1H), 8.54 (d, J = 8.4 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.83 (t, J = 8.0 Hz, 1H), 7.73−7.67 (m, 2H), 7.62 (d, J = 7.6 Hz, 1H), 4.09 (br s, 2H), 3.29 (br s, 2H), 2.66 (t, J = 12.4 Hz, 2H), 2.27−2.18 (m, 1H), 1.72−1.69 (m, 2H), 1.45−1.37 (m, 11H); 13C NMR (100 MHz, CDCl3) δ 160.3, 154.8, 143.5, 132.8, 130.3, 129.6, 128.6, 127.2, 126.4, 126.2, 125.6, 123.5, 122.5, 121.9, 79.2, 44.0, 42.2, 36.6, 32.4, 28.4 ppm; IR (KBr) υmax 2927, 1687, 1612, 1584, 1422, 1245, 1167 cm−1; HRMS (ESI) calcd for C24H29N2O2 [M + H]+ 377.2224, found 377.2220. 6-((1-Tosylpiperidin-4-yl)methyl)phenanthridine (3i): white solid (72%, 92.9 mg), mp = 183−185 °C; Rf 0.36 (EtOAc/petroleum ether = 1:2); 1H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 8.0 Hz, 1H), 8.51 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.0 Hz, 1H), 7.81 (t, J = 7.2 Hz, 1H), 7.71−7.59 (m, 5H), 7.27 (d, J = 8.0 Hz, 2H), 3.76 (d, J = 11.6 Hz, 2H), 3.25 (d, J = 7.2 Hz, 2H), 2.39 (s, 3H), 2.21 (td, J = 8.0, 1.6 Hz, 2H), 2.06−1.99 (m, 1H), 1.80 (d, J = 11.6 Hz, 2H), 1.57 (qd, J = 12.0, 7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 159.7, 143.4, 143.3, 132.8, 132.7, 130.3, 129.5, 129.4, 128.5, 127.6, 127.2, 126.4, 125.9, 125.4, 123.4, 122.4, 121.8, 46.3, 41.4, 35.3, 31.6, 21.4 ppm; IR (KBr) υmax 2920, 2850, 1573, 1459, 1333, 1161 cm−1; HRMS (ESI) calcd for C26H27N2O2S [M + H]+ 431.1788, found 431.1789. 6-((Tetrahydro-2H-pyran-4-yl)methyl)phenanthridine (3j): colorless oil (62%, 51.5 mg); Rf 0.16 (EtOAc/petroleum ether = 1:5); 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 8.0 Hz, 1H), 8.54 (d, J = 8.0 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.13 (dd, J = 8.4, 0.8 Hz, 1H), 7.83 (td, J = 8.4, 1.2 Hz, 1H), 7.74−7.68 (m, 2H), 7.62 (td, J = 8.4, 1.2 Hz, 1603

DOI: 10.1021/acs.joc.7b02861 J. Org. Chem. 2018, 83, 1598−1605

Note

The Journal of Organic Chemistry 6-(Pent-4-en-1-yl)phenanthridine (3q): colorless oil (13%); Rf 0.23 (EtOAc/petroleum ether = 1:20); 1H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 8.4 Hz, 1H), 8.55 (dd, J = 8.0, 0.8 Hz, 1H), 8.25 (d, J = 8.4 Hz, 1H), 8.12 (dd, J = 8.0, 0.8 Hz, 1H), 7.86−7.82 (m, 1H), 7.74− 7.68 (m, 2H), 7.65−7.60 (m, 1H), 5.98−5.88 (m, 1H), 5.12−5.07 (m, 1H), 5.04−5.01 (m, 1H), 3.41−3.37 (m, 2H), 2.30 (q, J = 7.2 Hz, 2H), 2.08−2.01 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 162.1, 143.7, 138.4, 132.9, 130.3, 129.6, 128.6, 127.2, 126.3, 125.2, 123.6, 122.5, 121.9, 115.1, 35.7, 33.9, 28.6 ppm; IR (KBr) υmax 2923, 1584, 1466, 1458, 1363, 1090, 1020, 799, 757, 724 cm−1; HRMS (ESI) calcd for C18H18N [M + H]+ 248.1434, found 248.1427. 3-Fluoro-6-((1-tosylpiperidin-4-yl)methyl)phenanthridine (4a): white solid (78%, 104.8 mg), mp = 204−206 °C; Rf 0.4 (EtOAc/ petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 8.4 Hz, 1H), 8.50 (dd, J = 8.8, 5.6 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.83 (t, J = 7.2 Hz, 1H), 7.70 (dd, J = 10.0, 2.4 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.38 (td, J = 8.4, 2.4 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 3.78 (d, J = 12.0 Hz, 2H), 3.26 (d, J = 7.2 Hz, 2H), 2.42 (s, 3H), 2.24 (td, J = 12.0, 2.0 Hz, 2H), 2.10−2.02 (m, 1H), 1.81 (d, J = 11.6 Hz, 2H), 1.62−1.52 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 162.6 (JC−F = 246.4 Hz), 161.3, 144.8 (JC−F = 11.5 Hz), 143.4, 133.1, 132.6, 130.8, 129.5, 127.7, 127.1, 126.1, 125.1, 123.8 (JC−F = 9.5 Hz), 122.3, 120.2, 115.5 (JC−F = 23.6 Hz), 114.1 (JC−F = 20.4 Hz), 46.4, 41.4, 35.3, 31.7, 21.5 ppm; IR (KBr) υmax 2914, 1583, 1485, 1333, 1160, 931, 727 cm −1; HRMS (ESI) calcd for C26H26FN2O2S [M + H]+ 449.1694, found 449.1696. 3-Chloro-6-((1-tosylpiperidin-4-yl)methyl)phenanthridine (4b): white solid (68%, 94.7 mg), mp = 218−220 °C; Rf 0.4 (EtOAc/ petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 8.4 Hz, 1H), 8.43 (dd, J = 8.8, 3.6 Hz, 1H), 8.16 (d, J = 8.4 Hz, 1H), 8.05 (s, 1H), 7.83 (t, J = 7.6 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.56 (dd, J = 8.8, 2.4 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 3.78 (d, J = 11.6 Hz, 2H), 3.24 (d, J = 6.8 Hz, 2H), 2.41 (s, 3H), 2.24 (td, J = 11.6, 1.6 Hz, 2H), 2.14−2.09 (m, 1H), 1.82 (d, J = 12.4 Hz, 2H), 1.61−1.51 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 161.1, 144.2, 143.4, 134.2, 133.0, 132.4, 130.8, 129.5, 128.8, 127.7, 127.6, 127.0, 126.1, 125.4, 123.3, 122.4, 122.0, 46.4, 41.3, 35.1, 31.7, 21.5 ppm; IR (KBr) υmax 2920, 1593, 1446, 1330, 1157, 939, 722 cm−1; HRMS (ESI) calcd for C26H26ClN2O2S [M + H]+ 465.1398, found 465.1400. 3-Bromo-6-((1-tosylpiperidin-4-yl)methyl)phenanthridine (4c): white solid (63%, 90.0 mg), mp = 221−223 °C; Rf 0.4 (EtOAc/ petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 8.0 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.84 (td, J = 8.4, 1.2 Hz, 1H), 7.72−7.67 (m, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 3.78 (d, J = 11.6 Hz, 2H), 3.25 (d, J = 7.2 Hz, 2H), 2.42 (s, 3H), 2.24 (td, J = 12.0, 2.4 Hz, 2H), 2.12−2.04 (m, 1H), 1.82 (d, J = 11.2 Hz, 2H), 1.62−1.51 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 161.1, 144.5, 143.4, 133.0, 132.4, 132.1, 130.8, 129.6, 129.5, 127.7, 126.1, 125.5, 123.5, 122.4, 122.3, 46.4, 41.3, 35.1, 31.7, 21.5 ppm; IR (KBr) υmax 2920, 1597, 1447, 1331, 1159, 940, 721 cm −1; HRMS (ESI) calcd for C26H26BrN2O2S [M + H]+ 509.0893, found 509.0907. 6-((1-Tosylpiperidin-4-yl)methyl)phenanthridine-3-carbonitrile (4d): white solid (47%, 90.0 mg), mp = 215−217 °C; Rf 0.14 (EtOAc/ petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 8.0 Hz, 1H), 8.60 (d, J = 8.4 Hz, 1H), 8.38 (d, J = 1.2 Hz, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.91 (t, J = 7.2 Hz, 1H), 7.81−7.77 (m, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 3.79 (d, J = 11.6 Hz, 2H), 3.28 (d, J = 6.8 Hz, 2H), 2.42 (s, 3H), 2.26 (td, J = 12.0, 2.0 Hz, 2H), 2.17−2.08 (m, 1H), 1.84 (d, J = 11.6 Hz, 2H), 1.62−1.52 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 162.0, 143.4, 142.8, 134.7, 133.0, 131.7, 131.2, 129.6, 129.1, 128.0, 127.7, 126.8, 126.4, 126.2, 123.3, 123.0, 118.7, 111.8, 46.4, 41.3, 34.8, 31.7, 21.5 ppm; IR (KBr) υmax 2226, 1634, 1401, 1165, 728 cm−1; HRMS (ESI) calcd for C27H26N3O2S [M + H]+ 456.1740, found 456.1734. 3-Methyl-6-((1-tosylpiperidin-4-yl)methyl)phenanthridine (4e): white solid (53%, 70.6 mg), mp = 184−186 °C; Rf 0.4 (EtOAc/ petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 8.0 Hz, 1H), 8.41 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.86 (s,

1H), 7.80 (t, J = 7.2 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.45 (dd, J = 8.0, 1.2 Hz, 1H), 7.29 (d, J = 8.4 Hz, 2H), 3.76 (d, J = 11.6 Hz, 2H), 3.25 (d, J = 7.2 Hz, 2H), 2.57 (s, 3H), 2.41 (s, 3H), 2.22 (td, J = 12.0, 2.4 Hz, 2H), 2.08−1.99 (m, 1H), 1.80 (d, J = 11.6 Hz, 2H), 1.62−1.52 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 159.8, 143.6, 143.3, 138.8, 133.1, 132.9, 130.3, 129.5, 129.2, 128.2, 127.7, 126.8, 126.0, 125.2, 122.3, 121.7, 121.1, 46.4, 41.5, 35.5, 31.7, 21.5 ppm; IR (KBr) υmax 2914, 1587, 1445, 1334, 1160, 931, 730 cm−1; HRMS (ESI) calcd for C27H29N2O2S [M + H]+ 445.1944, found 445.1940. 1-Fluoro-6-((1-tosylpiperidin-4-yl)methyl)phenanthridine (4f): white solid (72%, 96.8 mg), mp = 201−203 °C; Rf 0.4 (EtOAc/ petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3) δ 9.03 (dd, J = 8.4, 2.4 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.84 (t, J = 8.0 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 7.64−7.58 (m, 3H), 7.35−7.28 (m, 3H), 3.78 (d, J = 11.6 Hz, 2H), 3.26 (d, J = 7.2 Hz, 2H), 2.40 (s, 3H), 2.23 (td, J = 12.0, 2.0 Hz, 2H), 2.10−2.01 (m, 1H), 1.81 (d, J = 11.6 Hz, 2H), 1.62−1.52 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 160.8, 160.3 (JC−F = 253.1 Hz), 145.4 (JC−F = 2.7 Hz), 143.3, 133.0, 130.9 (JC−F = 1.8 Hz), 130.8 (JC−F = 5.0 Hz), 129.5, 128.0 (JC−F = 10.8 Hz), 127.7, 127.6, 127.4, 125.8, 125.7, 125.6 (JC−F = 3.2 Hz), 113.3 (JC−F = 8.7 Hz), 112.9 (JC−F = 24.0 Hz), 46.4, 41.5, 35.1, 31.7, 21.5 ppm; IR (KBr) υmax 2918, 1587, 1445, 1335, 1262, 1162, 813 cm−1; HRMS (ESI) calcd for C26H26FN2O2S [M + H]+ 449.1694, found 449.1703. 8-Fluoro-6-((1-tosylpiperidin-4-yl)methyl)phenanthridine (4g): white solid (80%, 107.5 mg), mp = 191−193 °C; Rf 0.4 (EtOAc/ petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3) δ 8.57 (dd, J = 9.2, 5.6 Hz, 1H), 8.42 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 1.2 Hz, 1H), 7.73−7.65 (m, 2H), 7.62−7.58 (m, 3H), 7.53 (td, J = 8.8, 2.4 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 3.77 (d, J = 11.6 Hz, 2H), 3.16 (d, J = 7.2 Hz, 2H), 2.39 (s, 3H), 2.25−2.20 (m, 2H), 2.04−2.00 (m, 1H), 1.80 (d, J = 12.0 Hz, 2H), 1.60−1.52 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 161.2 (JC−F = 246.7 Hz), 158.7 (JC−F = 3.8 Hz), 143.3, 143.0, 132.9, 129.6, 129.5, 129.4 (JC−F = 1.8 Hz), 128.4, 127.6, 126.8, 126.6 (JC−F = 7.4 Hz), 125.0 (JC−F = 8.4 Hz), 122.9, 121.6, 119.4 (JC−F = 23.5 Hz), 110.4 (JC−F = 21.2 Hz), 46.3, 41.4, 34.9, 31.5, 21.4 ppm; IR (KBr) υmax 2918, 1574, 1533, 1476, 1334, 1162, 931, 725 cm−1; HRMS (ESI) calcd for C26H25FN2NaO2S [M + Na]+ 471.1513, found 471.1520. 8-Methoxy-6-((1-tosylpiperidin-4-yl)methyl)phenanthridine (4h): white solid (68%, 93.8 mg), mp = 180−182 °C; Rf 0.18 (EtOAc/ petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 8.8 Hz, 1H), 8.42 (dd, J = 8.0, 1.2 Hz, 1H), 8.02 (dd, J = 8.0, 1.2 Hz, 1H), 7.65−7.56 (m, 4H), 7.46−7.42 (m, 2H), 7.28 (d, J = 8.4 Hz, 2H), 3.96 (s, 3H), 3.77 (d, J = 11.6 Hz, 2H), 3.20 (d, J = 7.2 Hz, 2H), 2.40 (s, 3H), 2.23 (td, J = 12.0, 2.0 Hz, 2H), 2.10−2.03 (m, 1H), 1.83 (d, J = 12.8 Hz, 2H), 1.62−1.52 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 158.8, 158.5, 143.3, 142.6, 132.9, 129.5, 129.4, 127.6, 127.5, 127.0, 126.8, 126.5, 124.2, 123.5, 121.4, 120.2, 106.6, 55.5, 46.4, 41.4, 35.1, 31.7, 21.4 ppm; IR (KBr) υmax 2920, 1726, 1618, 1535, 1337, 1163, 1045, 933, 727 cm−1; HRMS (ESI) calcd for C27H29N2O3S [M + H]+ 461.1893, found 461.1894. 9-Chloro-6-((1-tosylpiperidin-4-yl)methyl)phenanthridine (4i): white solid (67%, 93.3 mg), mp = 206−208 °C; Rf 0.4 (EtOAc/ petroleum ether = 1:3); 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.43 (d, J = 8.0 Hz, 1H), 8.10−8.04 (m, 2H), 7.72 (dd, J = 8.0, 1.2 Hz, 1H), 7.65−7.59 (m, 4H), 7.29 (d, J = 8.0 Hz, 2H), 3.77 (d, J = 11.6 Hz, 2H), 3.23 (d, J = 7.2 Hz, 2H), 2.41 (s, 3H), 2.23 (td, J = 12.0, 2.0 Hz, 2H), 2.05−1.99 (m, 1H), 1.80 (d, J = 12.8 Hz, 2H), 1.61−1.52 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 159.3, 143.9, 143.4, 136.9, 134.2, 133.0, 129.7, 129.5, 129.3, 127.9, 127.7, 127.6, 126.8, 123.8, 122.5, 122.2, 122.0, 46.4, 41.4, 35.4, 31.7, 21.5 ppm; IR (KBr) υmax 2920, 1582, 1335, 1162, 1095, 935, 724 cm−1; HRMS (ESI) calcd for C26H26ClN2O2S [M + H]+ 465.1398, found 465.1394. 6-Methylphenanthridine (5a): (known compound)12c 1H NMR (400 MHz, CDCl3) δ 8.64 (d, J = 8.0 Hz, 1H), 8.55 (d, J = 8.0 Hz, 1H), 8.23 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.88−7.83 (m, 1H), 7.74−7.69 (m, 2H), 7.65−7.61 (m, 1H), 3.06 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.4, 133.3, 129.5, 127.7, 78.4, 59.7, 44.9, 40.1, 34.3, 31.1, 21.5, 20.1,17.1 ppm. 1604

DOI: 10.1021/acs.joc.7b02861 J. Org. Chem. 2018, 83, 1598−1605

Note

The Journal of Organic Chemistry 2,2,6,6-Tetramethyl-1-[1-(toluene-4-sulfonyl)-piperidin-4-yloxy]piperidine (6a): (known compound)5a 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 3.63−3.53 (m, 3H), 2.45−2.39 (m, 5H), 2.05−2.01 (m, 2H), 1.69−1.52 (m, 3H), 1.42− 1.41 (d, J = 4.0 Hz, 4H), 1.30 (m, 1H), 1.04 (s, 12H); 13C NMR (100 MHz, CDCl3) δ 158.9, 143.7, 132.6, 130.5, 129.4, 128.6, 127.3, 126.6, 126.3, 125.9, 123.8, 122.3, 121.9, 23.4 ppm. 3-([1,1′-Biphenyl]-2-yl)-2H-azirine (7a): colorless oil; Rf 0.35 (EtOAc/petroleum ether = 1:20); 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.57−7.51 (m, 2H), 7.42 (s, 3H), 7.37 (s, 1H), 1.50 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 166.1, 143.8, 138.6, 132.4, 130.7, 130.3, 129.7, 127.9, 127.7, 123.3, 21.8 ppm; IR (KBr) υmax 3035, 2974, 1738, 1595, 1475, 1461, 1450 1434, 1260, 1074, 1046, 996, 801, 776, 739, 699 cm−1; HRMS (ESI) calcd for C14H12N [M + H]+ 194.0964, found 194.0963.

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(4) For selected examples, see: (a) Okada, K.; Okamoto, K.; Morita, N.; Okubo, K.; Oda, M. J. Am. Chem. Soc. 1991, 113, 9401. (b) Schnermann, M. J.; Overman, L. E. Angew. Chem., Int. Ed. 2012, 51, 9576. (c) Pratsch, G.; Lackner, G. L.; Overman, L. E. J. Org. Chem. 2015, 80, 6025. (d) Hu, C.; Chen, Y. Org. Chem. Front. 2015, 2, 1352. (e) Schwarz, J.; König, B. Green Chem. 2016, 18, 4743. (f) Jin, Y.; Yang, H.; Fu, H. Chem. Commun. 2016, 52, 12909. (g) Cheng, W.-M.; Shang, R.; Fu, Y. ACS Catal. 2017, 7, 907. (h) Tlahuext-Aca, A.; GarzaSanchez, R. A.; Glorius, F. Angew. Chem., Int. Ed. 2017, 56, 3708. (5) (a) Zhang, J.-J.; Yang, J.-C.; Guo, L.-N.; Duan, X.-H. Chem. - Eur. J. 2017, 23, 10259. (b) Recently, a very similar work was reported by Xu and co-workers, see Xu, K.; Tan, Z.; Zhang, H.; Liu, J.; Zhang, S.; Wang, Z. Chem. Commun. 2017, 53, 10719. (6) (a) Cornella, J.; Edwards, J. T.; Qin, T.; Kawamura, S.; Wang, J.; Pan, C.-M.; Gianatassio, R.; Schmidt, M.; Eastgate, M. D.; Baran, P. S. J. Am. Chem. Soc. 2016, 138, 2174. (b) Qin, T.; Cornella, J.; Li, C.; Malins, L. R.; Edwards, J. T.; Kawamura, S.; Maxwell, B. D.; Eastgate, M. D.; Baran, P. S. Science 2016, 352, 801. (c) Edwards, J. T.; Merchant, R. R.; McClymont, K. S.; Knouse, K. W.; Qin, T.; Malins, L. R.; Vokits, B.; Shaw, S. A.; Bao, D.-H.; Wei, F.-L.; Zhou, T.; Eastgate, M. D.; Baran, P. S. Nature 2017, 545, 213. (7) (a) Huihui, K. M. M.; Caputo, J. A.; Melchor, Z.; Olivares, A. M.; Spiewak, A. M.; Johnson, K. A.; DiBenedetto, T. A.; Kim, S.; Ackerman, L. K. G.; Weix, D. J. J. Am. Chem. Soc. 2016, 138, 5016. (b) Suzuki, N.; Hofstra, J. L.; Poremba, K. E.; Reisman, S. E. Org. Lett. 2017, 19, 2150. (8) (a) Li, C.; Wang, J.; Barton, L. M.; Yu, S.; Tian, M.; Peters, D. S.; Kumar, M.; Yu, A. W.; Johnson, K. A.; Chatterjee, A. K.; Yan, M.; Baran, P. S. Science 2017, 356, 1045. (b) Hu, D.; Wang, L.; Li, P. Org. Lett. 2017, 19, 2770. (c) Fawcett, A.; Pradeilles, J.; Wang, Y.; Mutsuga, T.; Myers, E. L.; Aggarwal, V. K. Science 2017, 357, 283. (9) Tang, Q.; Liu, X.; Liu, S.; Xie, H.; Liu, W.; Zeng, J.; Cheng, P. RSC Adv. 2015, 5, 89009. (10) For recent reviews concerning application of organic dyes as photocatalyst, see: (a) Nicewicz, D. A.; Nguyen, T. M. ACS Catal. 2014, 4, 355. (b) Romero, N. A.; Nicewicz, D. A. Chem. Rev. 2016, 116, 10075. (c) Arias-Rotondo, D. M.; McCusker, J. K. Chem. Soc. Rev. 2016, 45, 5803. (d) Qin, Y.; Zhu, L.; Luo, S. Chem. Rev. 2017, 117, 9433. (11) For some elegant studies concerning mechanism of photocatalytic reactions, see: (a) Majek, M.; Filace, F.; Wangelin, A. J. Beilstein J. Org. Chem. 2014, 10, 981. (b) Cismesia, M. A.; Yoon, T. P. Chem. Sci. 2015, 6, 5426. Although the exact role of TMEDA remains unclear at present. According to the UV/vis studies and the previous studies (Refs 3. and 11), we believed that TMEDA probably served as an activator in this reaction. Eosin Y could be converted into the active species (the monoanionic or dianionic forms) by TMEDA via an acidbase equilibration process. Thus, stoichiometric amount of TMEDA is helpful to improve the yield. For the detailed UV/vis studies on the reaction mixture of TMEDA with photocatalyst, see the SI, Figure S8 and Figure S9. (12) (a) Liang, Z.; Ju, L.; Xie, Y.; Huang, L.; Zhang, Y. Chem. - Eur. J. 2012, 18, 15816. (b) Buu-Hoï, N. P.; Jacquignon, P.; Long, C. T. J. Chem. Soc. 1957, 0, 505. (c) Gerfaud, T.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2009, 48, 572.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02861. 1 H and 13C spectra of all new compounds and the primary mechanistic studies of the reaction (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Li-Na Guo: 0000-0002-9789-6952 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the Natural Science Basic Research Plan in Shaanxi Province of China (no. 2016JZ002), the National Natural Science Foundation of China (no. 21602168), and the Fundamental Research Funds of the Central Universities (nos. zrzd2017001, xjj2016056, and 2015qngz17) are greatly appreciated.

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REFERENCES

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DOI: 10.1021/acs.joc.7b02861 J. Org. Chem. 2018, 83, 1598−1605