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Synthesis 2023; 55(06): 877-891
DOI: 10.1055/a-1957-4343
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Tf2O-Promoted Morgan–Walls Reaction: From a Flexible Approach to Functionalized Phenanthridines and Quinazolines to the Short and Divergent Total Syntheses of Alkaloids

Xiao-Yu Su
,
Pei-Qiang Huang∗

This work was supported by the National Natural Science Foundation of China (No. 21931010).
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Abstract

A new protocol for the direct transformation of secondary amides (N-acyl-o-xenylamines) to phenanthridines under mild conditions is reported. The method features trifluoromethanesulfonic anhydride (Tf2O)/2-fluoropyridine as the efficient amide activation system and MeCN or CH2Cl2 as the solvent. For some substrates, MeCN participated in the reaction, which affords a mild access to polysubstituted quinazolines. By employing a Tf2O/2,4,6-tri-tert-butylpyrimidine (TTBP) combination, the method was extended to an N-formyl-o-xenylamine, which represents a recalcitrant amide substrate type for the dehydrative cyclization reaction. More importantly, a one-pot method was established for the direct and divergent synthesis of four types of phenanthridinoids from o-xenylamines, which features both a tert-N-formyl-o-xenylamine and phenanthridinium salt as key and versatile intermediates. The investigation has resulted in one of the shortest and the most efficient total syntheses of the three natural products trisphaeridine, 5,6-dihydrobicolorine, and N-methylcrinasiadine, and in the formal total syntheses of three other ones: 3-hydroxytrisphaeridine, bicolorine, and zephycandidine A.


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Key words

amide activation - N-heterocycles - cyclization - step-economy - chemoselectivity - alkaloids - total synthesis - Morgan–Walls reaction

Biographical Sketches

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Xiao-Yu Su received her BE from Wuhan University of Science and Technology in 2019. She is currently a master’s student at Xiamen University under the supervision of Professor Pei-Qiang Huang. Her research focuses on the development of synthetic methods based on amide activation, and synthesis of natural products.

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Pei-Qiang Huang is a Professor at the College of Chemistry and Chemical Engineering at Xiamen University (China). He received his DEA in 1984 from the Université de Montpellier II (France) under the direction of Professor B. Castro (INSERM-CNRS). He completed the research work at the Institut de Chimie des Substances Naturelles (ICSN), CNRS under the direction of Professor H.-P. Husson, and received his PhD from the Université de Paris-Sud (Orsay) (France) in 1987. In 1988, he joined Professor W.-S. Zhou’s group at the Shanghai Institute of Organic Chemistry (SIOC), CAS as a postdoctoral fellow. In 1990, he returned to Xiamen University. Between 2003 and 2012 he served as Dean of his faculty, and in 2006 and 2021, he was elected as a Fellow of the Royal Society of Chemistry (RSC) and Chinese Chemical Society­ (CCS). Professor Huang’s research interests are the development of novel and efficient synthetic methodologies, the total synthesis of bioactive natural products, and chemical biology.

Phenanthridine (1, Figure [1]) is a privileged azaheterocyclic motif that has attracted the attention of scientists of several fields. As early as 1938, it was reported that phenanthridine compounds display outstanding trypanocidal activities.[1] Ethidium bromide (2·HBr), a common and versatile DNA/RNA intercalator, has been used for many decades as a gold-standard DNA and RNA fluorescent marker.[2] More recently, it was reported that phenanthriplatin (3), a representative of monofunctional platinum anticancer complexes, shows a distinct spectrum of action.[3] In addition, the phenanthridine motif is found in a number of alkaloids (e.g., 4–10; Figure [1]) that show a broad spectrum of bioactivities.[4] For example, trisphaeridine[5] (trispheridine, 4), 5,6-dihydrobicolorine[5e] [6] (6), bicolorine[5b] [6a] (7), N-methylcrinasiadine[5b] [d] (8), zephycandidine A[7] (9), and sanguinarine[8a] (10) exhibit antitumor,[5c] [h] [8] antipolioviral, neuroprotective,[5e] antimigratory, strong acetylcholinesterase (AChE) inhibitory,[5e] [7] and Bcl-XL inhibitory activities.[8b] Moreover, phenanthridine derivatives serve, on one hand, as versatile building blocks for the synthesis of functional materials,[9] and on the other hand, as a new kind of chiral NAD(P)H model.[10] In this context, Fan and co-workers have developed a highly enantioselective catalytic hydrogenation protocol for the transformation of 6-alkylphenanthridines to 6-alkyl-5,6-dihydrophenanthridines, and demonstrated that 6-methyl-5,6-dihydrophenanthridine could be applied for the organocatalytic asymmetric transfer hydrogenation of 3-phenyl-2H-1,4-benzoxazine.[10c]

Consequently, much effort has been devoted to the synthesis of phenanthridines,[2] which has resulted in many elegant approaches.[11] However, due to the high toxicities, the phenanthridine class of natural products and derivatives has not yet found applications in human medicine.[2] Thus, the flexible synthesis of diverse non-natural phenanthridine derivatives has become imperative. In this regard, simplified derivatives such as 10A (Figure [1]) were identified as more potent Bcl-XL inhibitors than the natural product sanguinarine (10).[8b] On the other hand, derivatives 6A were identified as potent anti-PEDV agents[12a] and Wnt/β-catenin signaling pathway agonists.[12b] More recently, a method for the in-cell generation of anticancer 6-alkylphenanthridine derivatives through bioorthogonal cyclization of antitumor prodrugs has been disclosed.[5h] The aforementioned achievements highlight, on one hand, the high potential of phenanthridine derivatives for medicinal applications, and on the other hand, the need to develop mild and versatile methods for their synthesis.

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Figure 1 Representative bioactive natural and non-natural phenanthridinoids

Because of their ready availability and high stability, amides are a class of very attractive starting materials in organic synthesis.[13] However, the high stability renders the direct transformation of amides quite challenging, which requires either harsh reaction conditions,[11f] [14] [15a] or multistep transformations,[15b] or a lack of functional group tolerance/chemoselectivity, or being limited in scope.[14] This is the case of the Morgan–Walls reaction[14a] that involves the dehydrative cyclization of acyl-o-xenylamines in refluxing neat phosphorus oxychloride (POCl3) (Scheme [1, 1]), which failed with formyl-o-xenylamine. In 2007, during the development of a direct synthesis of pyridine derivatives from secondary amides, Movassaghi and Hill obtained an unexpected Morgan–Walls cyclization product in high yield.[16a] In a subsequent investigation, this result was confirmed (Scheme [1, 2]), and it was demonstrated that a trifluoromethanesulfonic anhydride (Tf2O)/2-chloropyridine (2-Cl-Pyr.) combination is superior to other amide activation reagents/systems such as POCl3 and Tf2O/4-(dimethylamino)pyridine.[16b]

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Scheme 1 Reported and current methods for the synthesis of phenanthridines from amides

In 2010, the Yao group established a flexible synthesis of phenanthridines from secondary amides using a Hendrickson­ reagent initiated cascade reaction.[17] Their protocol allowed for the reaction to be run under very mild conditions and showed good functional group tolerance for bromo and nitro groups (Scheme [1, 3]). During the last decade, our group has been engaged in the development of mild methods for the direct transformation of amides and applications in the total synthesis of natural products.[18] [19] One of our strategies features the use of Tf2O[20] as a convenient and highly efficient amide activation reagent. Herein, we report our findings gained during the investigation of the Tf2O/2-fluoropyridine (2-F-Pyr.)-promoted Morgan–Walls reaction (Scheme [1, 4]). The results include a mild, versatile, and chemoselective entrance to functionalized phenanthridines from secondary amides 11. Significantly, from o-arylanilines 14a–14c, a one-pot protocol has been established for the efficient total and formal syntheses of three types of phenanthridine alkaloids: trisphaeridine[21] (4), 3-hydroxy-8,9-methylenedioxyphenanthridine (3-hydroxytrisphaeridine)[22] (5), 5,6-dihydrobicolorine[23] (6), bicolorine[5b] [6a] (7), and N-methylcrinasiadine[24] (8), as well as C6-functionalized derivatives. In addition, we found that for some substrates, acetonitrile, the solvent used in our methodology, served as a nucleophilic partner to yield polysubstituted quinazolines.

In our previous work, the Tf2O/2-fluoropyridine combination has proved to be an effective amide activation system for several types of transformations of secondary amides.[18c] , [18`] [g] [h] We envisaged extending this strategy to the synthesis of natural phenanthridines and non-natural derivatives. For this purpose, we opted for N-acetyl-o-xenylamine (11a) as the model substrate and dichloromethane as the solvent to screen different Tf2O/base combinations (Table [1]).

Table 1 Screening of Reaction Conditionsa

a Reaction conditions: amide 11a (0.2 mmol), Tf2O (0.22 mmol), base (0.24 mmol), solvent, T1, 30 min; then T1 to T2, 3 h.

b Yields determined by 1H NMR analysis using 1,3,5-trimethoxybenzene as an internal standard.

Indeed, among the five Tf2O/base combinations [Tf2O/2-fluoropyridine, Tf2O/triethylamine, Tf2O/2-bromopyridine, Tf2O/2,6-dichloropyridine, and Tf2O/2,4,6-tri-tert-butyl­pyrimidine (TTBP)[18g]] examined for the tandem amide activation and dehydrative cyclization (Table [1], entries 1–5), an optimal yield of 68% was obtained when the Tf2O/2-fluoropyridine activation system was used (entry 5). Next, the use of acetonitrile to replace dichloromethane as the solvent was attempted, which gave 1a in a diminished yield of 58% (Table [1], entry 6). Given the solidification phenomenon of MeCN at –78 °C, the amide activation step at a higher temperature was envisaged. Delightedly, when the secondary amide 11a was exposed to Tf2O/2-fluoropyridine at –40 °C, and the subsequent cyclization run at 40 °C for 3 hours, 6-methylphenanthridine (1a) was obtained in an excellent yield of 93% (Table [1], entry 7). Further elevating the temperature for the amide activation to 0 °C, or lowering or elevating the temperature for the cyclization, resulted in inferior yields (Table [1], entries 8–11). Increasing the concentration to 0.2 M also led to a deteriorated reaction yield (entry 12). Thus, the optimal reaction conditions were defined as those shown in entry 7.

Table 2 Substrate Scopea,b

a The structures of all amides 11 are listed in the Supporting Information.

b Isolated yields.

c Yield determined by 1H NMR analysis.

Table 3 Unexpected Formation of Polysubstituted Quinazolines from Some o-Phenylanilidesa

a Isolated yields.

With the optimal reaction conditions in hand, we proceeded to investigate the substrate scope, and the results are summarized in Table [2]. The reactions of N-alkoyl-o-xenyl­amines 11a–11f (the structures of all amides are listed in the Supporting Information) proceeded smoothly to yield the corresponding 6-alkylphenanthridines 1a–1f in good to excellent isolated yields (87–98%). Similarly, N-aroyl-o-xenylamines 11g–11l are also venerable substrates which cyclized to yield 6-arylphenanthridines 1g–1l in 82–98% yield. Even at a gram scale, the desired phenanthridine 1i was obtained in excellent yield. The reaction tolerates both electron-donating groups such as methoxy and electron-withdrawing groups such as fluoro in the o-xenylamine moiety of N-aroyl-o-xenylamines 11m–11p. Significantly, the reaction also tolerates an ester group, and the corresponding 6-substituted phenanthridine 1q was obtained in 68% yield. To demonstrate the utility of the method for late-stage functionalization of drug molecules,[25] an amide derivative 11r of Gemfibrozil, a blood lipid-lowering drug for fibrates, was prepared, and its dehydrative cyclization proceeded smoothly to afford the hybrid[26] drug-like molecule 1r in 97% yield.

Interestingly, for N-aroyl-o-xenylamines bearing an electron-withdrawing group such as NO2 or CF3 in the N-aroyl moiety (11w and 11v), the reaction afforded, instead of the expected phenanthridines, quinazolines 13a and 13b in 85% and 86% yield, respectively (Table [3]). For substrates bearing a more reactive carboxylic acid derivative moiety such as ester or nitrile group, the reaction occurred chemoselectively at the more stable amide group to provide quinazolines 13c and 13d in 88% and 63% yield, respectively. More intriguingly, benzo[b]thiophene-2-carboxamide 11aa, which bears an electron-donating group, also reacted with MeCN to afford quinazoline 13e in 64% yield.

Mechanistically, this unexpected reaction reflects the competing intermolecular nucleophilic addition of the non-innocent solvent MeCN over the expected intramolecular Friedel–Crafts-type cyclization onto nitrilium intermediate I to generate iminonitrilium intermediate II (Figure [2]). An intramolecular Friedel–Crafts-type cyclization then occurs to yield quinazoline 13a. This chemoselectivity outcome is of value because Mayr and co-workers have reported that N-isopropylbenzonitrilium reacted with 2-methylthiophene in acetonitrile at 20 °C to yield a cycloaddition product in a high yield, in which 2-methylthiophene served as a more efficient nucleophile in competing with the solvent (MeCN).[27] It is worth noting that Movassaghi and Hill have systematically investigated the synthesis of pyrimidine and quinazoline derivatives based on the Tf2O/2-chloro­pyridine-mediated condensation reactions of secondary amides with nitriles.[19e] However, their method involved neither an N-acyl-o-xenylamine substrate, nor acetonitrile as a nucleophilic partner. Moreover, they found that with recalcitrant amide substrates such as electron-deficient N-aryl amides, the condensation reaction required more forcing conditions to proceed effectively, namely by heating with microwave irradiation to 140 °C for 20 minutes.[19i] Our discovery of the use of cheap and easily available MeCN solvent as a nucleophilic partner allows a mild synthesis of quinazolines, and thus complements Movassaghi’s synthesis of pyrimidine derivatives.

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Figure 2 Proposed mechanism for the formation of quinazolines

Although the formation of polysubstituted quinazolines 13a–13e is of value for both organic synthesis and medicinal chemistry, we envisioned that the desired synthesis of phenanthridines 1s–1aa could be achieved by switching the solvent from MeCN to CH2Cl2. Indeed, under the standard reaction conditions, except that CH2Cl2 was used as the solvent, the reactions of amides 11s–11aa afforded the corresponding phenanthridines 1s–1aa in good to excellent yields (70–98%) except CF3- and NO2-substituted derivatives 1v and 1w and benzo[b]thiophen-2-yl derivative 1aa for which low to modest yields were obtained (39–52%) (Table 4). It is worth mentioning that the reactions of cyano and ester group bearing substrates afforded phenanthridines 1x and 1y in almost quantitative yields (98% and 97%).

Table 4 Tf2O/2-Fluoropyridine-Mediated Dehydrative Cyclization of Secondary Amides in Dichloromethanea

a Isolated yields.

Given the important bioactivities reported for trisphaeridine (4) and 5,6-dihydrobicolorine (6), we turned our attention to the total syntheses of these two natural products. The synthesis of trisphaeridine (4) requires the cyclization of o-formamido-1,1′-biphenyl 11ab (see Scheme [2]). However, this type of formamide has proved to be challenging.[14a] Even by employing the modern Hendrickson reagent based method, the reaction of N-[4′-methoxy-(1,1′-biphenyl)-2-yl]formamide afforded 8-methoxyphenanthridine in a low yield of 30%.[17]

To address this issue, we first secured a high-yielding two-step synthesis of o-formamidobiphenyl 11ab, which consisted of a Suzuki coupling and N-formylation (Scheme [2]). A screening of reaction conditions allowed achievement of the challenging dehydrative cyclization of 11ab to afford trisphaeridine (4) in a high yield of 90%. The protocol features both the employment of TTBP as a beneficial base in partner with Tf2O,[18g] and running the reaction in CH2Cl2.

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Scheme 2 Three-step total synthesis of trisphaeridine

To further improve the step-economy[28] and thus the synthetic efficiency of the total synthesis,[29] we envisioned a one-pot protocol. To this end, after the formylation of 14a, run in CH2Cl2, the resulting mixture was exposed to Tf2O and TTBP at –40 °C, and stirred at 40 °C for 3 hours. In this manner, the expected one-pot reaction was achieved in 90% yield (Scheme [3]). With an overall yield of 85% from commercially available reagents, this two-step total synthesis of trisphaeridine stands as one of the shortest and the most efficient total synthesis of trisphaeridine (4) to date.[21] Moreover, since alkaloid trisphaeridine (4) has been converted into alkaloid zephycandidine A (9) in two steps,[30] our synthesis of 4 constitutes a formal total synthesis of the latter alkaloid.[7]

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Scheme 3 One-pot synthesis of trisphaeridine (4) from 14a and formal total synthesis of zephycandidine A (10)

Having established an efficient total synthesis of trisphaeridine (4), we anticipated the total synthesis of 3-hydroxy-8,9-methylenedioxyphenanthridine (3-hydroxytrisphaeridine, 5), an alkaloid isolated from whole plants of Crinum firmifolium var. hygrophilum.[22] Different from trisphaeridine (4) and 5,6-dihydrobicolorine (6), for which many total syntheses have been documented, only one total synthesis of 5 has been reported.[22] Our synthesis started with the Suzuki coupling of commercially available 15 and 16b to afford 14b in 90% yield (Scheme [4]). Subjecting the latter to the aforementioned one-pot tandem N-formylation–cyclodehydration produced 17 in 75% yield. The spectroscopic data of our synthetic compound 17 are identical with those reported previously.[22] Since 17 has been converted into 3-hydroxy-8,9-methylenedioxyphenanthridine (5) by Pd/C-catalyzed hydrogenolysis of 17, our work constitutes a formal total synthesis of this natural product.[22]

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Scheme 4 Formal total synthesis of alkaloid 3-hydroxy-8,9-methylenedioxyphenanthridine (5)

Next, we turned our attention to the total synthesis of another natural product, 5,6-dihydrobicolorine (6), which represents the N-alkyl-5,6-dihydrophenanthridine type. We envisioned a one-pot synthesis from 14a through the capture of in situ formed trisphaeridine (4) by the Borch reductive methylation method. For this purpose, after the one-pot transformation of 14a to trisphaeridine (4), the resultant mixture was subjected to Borch’s conditions by treating with formaldehyde and NaBH3CN in MeOH and AcOH (Scheme [5]). In this fashion, the desired 5,6-dihydrobicolorine (6) was obtained in 60% yield. We were pleased to find that the highly toxic NaBH3CN could be replaced by NaBH4 while 5,6-dihydrobicolorine (6) was obtained in a slightly higher yield of 63%. Thus, we have established a two-step total synthesis of 5,6-dihydrobicolorine (6) with an overall yield of 59%.

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Scheme 5 First-generation synthesis of alkaloid 5,6-dihydrobicolorine (6)

In our aforementioned investigations, only secondary amides (N-acyl-o-xenylamines) were employed as the starting materials. To expand this methodology, and develop a more efficient approach to the 5,6-dihydrobicolorine type of phenanthridines and non-natural derivatives, the Tf2O-mediated dehydrative cyclization of tertiary amides was envisaged. Focusing on the synthesis of 5,6-dihydrobicolorine (6) and derivatives, we selected commercially available 2-bromo-N-methylaniline (16c) as the starting material (Scheme [6]). Its coupling with commercially available benzo[d][1,3]dioxol-5-ylboronic acid (15) under Suzuki coupling conditions produced o-xenylamine derivative 14c in 94% yield. In the presence of formic acid and acetic anhydride, 14c reacted to yield the N-formylation product 12. After completion of the reaction, the reaction mixture was concentrated, and the residue was subjected to Tf2O-mediated dehydrative cyclization to yield the presumed iminium ion intermediate III, which was reduced in situ with NaBH4 in MeOH to yield 6. This one-pot reaction proceeded in an excellent yield of 91%. Thus, starting from commercially available reagents, we have established one of the shortest and the most efficient two-step total synthesis of 5,6-dihydro­bicolorine (6) with an overall yield of 86%.

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Scheme 6 One-pot, divergent syntheses of alkaloids 5,6-dihydro­bicolorine (6), N-methylcrinasiadine (8), and C6-functionalized derivatives

The successful in situ reduction of iminium ion intermediate III with NaBH4 prompted us to explore the synthesis of non-natural 6-substituted derivatives of 5,6-dihydrobicolorine. Thus, after the stage of the Tf2O-mediated dehydrative cyclization, iminium ion intermediate III was exposed to HPO(OEt)2 and K2CO3, which afforded α-aminophosphonate 6a in 85% yield (Scheme [6]). On the other hand, the addition of methylmagnesium bromide yielded the methylated derivative 6b of 5,6-dihydrobicolorine, in 90% yield. Similarly, interception of iminium ion intermediate III with ethyl and benzyl Grignard reagents furnished the 6-alkylated products 6c and 6d in 87% and 82% yield, respectively. Moreover, subjecting phenanthridinium salt III [24g] to K3Fe(CN)6/NaOH[31] in aqueous THF at room temperature for 12 hours produced N-methylcrinasiadine (8), another alkaloid isolated from Lapiedra martinezii (Amaryllidaceae)[5b] and Zephyranthes candida,[5d] in 89% yield. Since phenanthridinium salt III has been converted into bicolorine (7, see Figure [1]),[24g] our work could be considered as a formal total synthesis of this alkaloid.[5b] [6a] It is worth noting that all the one-pot transformations from o-arylanilide 14c do not require the use of a stoichiometric base additive as a partner of Tf2O.

In summary, we have demonstrated that by employing different Tf2O/base/solvent combinations, the Morgan–Walls reaction could be achieved for a wide range of amides including the recalcitrant N-formyl-o-xenylamines and tertiary amides. Moreover, by telescoping N-acylation and the Tf2O-promoted Morgan–Walls reaction, as well as nucleophilic addition, we have established a divergent, one-pot approach to three types of phenanthridine alkaloids from primary or secondary amines. The reactions are run under mild conditions and show good functional group tolerance and chemoselectivity. The value of the methodology is highlighted by the highly efficient total syntheses and formal total syntheses of six alkaloids 4–9 from commercially available compounds. In addition, for some substrates, the methodology affords a mild entrance to polysubstituted quinazolines.

Tf2O was distilled over phosphorus pentoxide and was stored for no more than a week before use. CH2Cl2 was distilled over calcium hydride under N2 atmosphere. All other commercially available compounds were used as received. Silica gel (300–400 mesh) was used for flash column chromatography. NMR spectra were recorded on a Bruker Avance 400 MHz or 500 MHz instrument and were calibrated using residual undeuterated solvent (CHCl3 7.26 ppm 1H NMR, 77 ppm 13C NMR). IR spectra were recorded on a Nicolet iS50 FT-IR spectrophotometer using film KBr pellet techniques. High-resolution mass spectrometry was performed using positive electrospray ionization (ESI+) on a single quadrupole Exactive LC/MS system with Orbitrap mass detector.


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Phenanthridines 1a–1r and Quinazolines 13a–13e; General Procedure A

To a solution of an N-acyl-o-xenylamine 11 (0.20 mmol) in MeCN (2 mL) was added 2-fluoropyridine (14 μL, 0.24 mmol) at room temperature under an argon atmosphere. After 10 min, Tf2O (37 μL, 0.22 mmol) was slowly added, and the mixture was stirred at –40 °C for 30 min before being warmed to 40 °C and stirred for 3 h. The reaction was quenched with saturated aqueous NH4Cl solution (5 mL). The mixture was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (FC) on silica gel to afford the desired compound.


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6-Methylphenanthridine (1a)

Yield: 34 mg (87% from 11a); pale yellow solid; purified by FC on silica gel (EtOAc/hexane, 1:5).

Mp 79.5–80.0 °C (Lit.[11k] 79.0–81.0 °C).

IR (KBr): 3070, 2918, 1612, 1585, 1485, 1447, 1375, 1350, 1320, 1035, 754, 723, 614 cm–1.

1H NMR (400 MHz, CDCl3): δ = 3.05 (s, 3 H), 7.62 (t, J = 7.1 Hz, 1 H), 7.66–7.76 (m, 2 H), 7.85 (t, J = 7.6 Hz, 1 H), 8.10 (d, J = 8.0 Hz, 1 H), 8.23 (d, J = 8.1 Hz, 1 H), 8.54 (d, J = 8.0 Hz, 1 H), 8.63 (d, J = 8.3 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 23.4, 121.9, 122.2, 123.7, 125.8, 126.2, 126.4, 127.2, 128.5, 129.2, 130.4, 132.5, 143.6, 158.8.

HRMS (ESI): m/z [M + H]+ calcd for C14H11N: 194.0964; found: 194.0965.


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6-Isopropylphenanthridine (1b)

Yield: 38 mg (87% from 11b); pale yellow oil; purified by FC on silica gel (EtOAc/hexane, 1:5).

IR (KBr): 2965, 2926, 1583, 1486, 1458, 1382, 1359, 1084, 1007, 760, 726 cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.52 (d, J = 6.7 Hz, 6 H), 3.94–4.06 (m, 1 H), 7.60 (t, J = 7.7 Hz, 1 H), 7.66–7.73 (m, 2 H), 7.81 (s, 1 H), 8.14 (d, J = 8.1 Hz, 1 H), 8.32 (d, J = 8.2 Hz, 1 H), 8.54 (d, J = 8.1 Hz, 1 H), 8.66 (d, J = 8.3 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 21.9, 31.5, 121.8, 122.6, 123.4, 124.7, 125.7, 126.2, 127.1, 128.4, 129.9, 133.1, 165.8.

HRMS (ESI): m/z [M + H]+ calcd for C16H15N: 222.1277; found: 222.1277.


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6-(tert-Butyl)phenanthridine (1c)

Yield: 45 mg (98% from 11c); pale yellow oil; purified by FC on silica gel (EtOAc/hexane, 1:5).

IR (KBr): 2967, 2922, 1568, 1476, 1458, 1441, 1411, 1365, 1188, 1163, 1150, 1092, 1033, 986, 759, 729 cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.73 (s, 9 H), 7.56–7.74 (m, 3 H), 7.78 (t, J = 7.6 Hz, 1 H), 8.12 (d, J = 8.1 Hz, 1 H), 8.52 (d, J = 8.1 Hz, 1 H), 8.63 (d, J = 8.5 Hz, 1 H), 8.69 (d, J = 8.3 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 31.2, 40.2, 121.6, 123.0, 123.4, 124.3, 125.9, 126.4, 128.2, 128.3, 129.2, 130.2, 134.0, 142.9, 166.6.

HRMS (ESI): m/z [M + H]+ calcd for C17H17N: 236.1434; found: 236.1433.


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6-Cyclopropylphenanthridine (1d)

Yield: 43 mg (98% from 11d); pale yellow oil; purified by FC on silica gel (EtOAc/hexane, 1:5).

IR (KBr): 3073, 3005, 1610, 1582, 1571, 1487, 1462, 1446, 1398, 1294, 1214, 1027, 1012, 887, 758, 724 cm–1.

1H NMR (500 MHz, CDCl3): δ = 1.08–1.22 (m, 2 H), 1.30–1.41 (m, 2 H), 2.71–2.80 (m, 1 H), 7.55 (t, J = 7.6 Hz, 1 H), 7.62–7.72 (m, 2 H), 7.80 (dd, J = 8.3, 7.0 Hz, 1 H), 8.04 (d, J = 8.1 Hz, 1 H), 8.48 (d, J = 8.1 Hz, 1 H), 8.52 (d, J = 8.2 Hz, 1 H), 8.59 (d, J = 8.2 Hz, 1 H).

13C NMR (125 MHz, CDCl3): δ = 8.4, 14.3, 121.8, 122.3, 123.4, 125.9, 126.0, 126.2, 127.1, 128.4, 129.6, 130.1, 132.6, 143.8, 161.4.

HRMS (ESI): m/z [M + H]+ calcd for C16H13N: 220.1121; found: 220.1122.


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6-Cyclopentylphenanthridine (1e)

Yield: 42 mg (85% from 11e); pale yellow oil; purified by FC on silica gel (EtOAc/hexane, 1:5).

IR (KBr): 3072, 2950, 2866, 1611, 1583, 1527, 1486, 1461, 1445, 1375, 1295, 1209, 759, 726 cm–1.

1H NMR (500 MHz, CDCl3): δ = 1.71–1.85 (m, 2 H), 1.86–1.99 (m, 2 H), 2.13–2.32 (m, 4 H), 3.98–4.08 (m, 1 H), 7.52–7.70 (m, 3 H), 7.75 (t, J = 7.6 Hz, 1 H), 8.11 (d, J = 8.2 Hz, 1 H), 8.28 (d, J = 8.1 Hz, 1 H), 8.47 (d, J = 8.0 Hz, 1 H), 8.57 (d, J = 8.2 Hz, 1 H).

13C NMR (125 MHz, CDCl3): δ = 26.0, 32.2, 43.5, 121.8, 122.4, 123.4, 125.6, 126.0, 126.2, 127.0, 128.3, 129.9, 129.9, 132.9, 143.7, 164.1.

HRMS (ESI): m/z [M + H]+ calcd for C18H17N: 248.1434; found: 248.1433.


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6-Cyclohexylphenanthridine (1f)

Yield: 51 mg (98% from 11f); pale yellow oil; purified by FC on silica gel (EtOAc/hexane, 1:5).

IR (KBr): 2925, 2850, 1581, 1573, 1486, 1461, 1448, 1379, 1347, 988, 757, 725 cm–1.

1H NMR (500 MHz, CDCl3): δ = 1.23–1.49 (m, 1 H), 1.49–1.63 (m, 2 H), 1.77–1.87 (m, 1 H), 1.87–2.02 (m, 4 H), 2.07 (d, J = 10.2 Hz, 2 H), 3.50–3.69 (m, 1 H), 7.56 (t, J = 7.6 Hz, 1 H), 7.60–7.70 (m, 2 H), 7.75 (t, J = 7.6 Hz, 1 H), 8.13 (d, J = 8.1 Hz, 1 H), 8.27 (d, J = 8.2 Hz, 1 H), 8.48 (d, J = 8.6 Hz, 1 H), 8.59 (d, J = 8.3 Hz, 1 H).

13C NMR (125 MHz, CDCl3): δ = 26.3, 26.8, 32.3, 41.9, 121.8, 122.5, 123.3, 124.7, 125.5, 126.0, 127.0, 128.3, 129.8, 129.9, 132.9, 143.8, 165.2.

HRMS (ESI): m/z [M + H]+ calcd for C19H19N: 262.1590; found: 262.1591.


#

6-Phenylphenanthridine (1g)

Yield: 45 mg (89% from 11g); pale yellow solid; purified by FC on silica gel (EtOAc/hexane, 1:5).

Mp 109.0–109.3 °C (Lit.[11k] 99.0–101.0 °C).

IR (KBr): 3061, 1581, 1560, 1483, 1458, 1444, 1406, 1360, 1328, 1136, 1074, 1032, 781, 763, 726, 700, 671 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.48–7.63 (m, 4 H), 7.70–7.64 (m, 1 H), 7.70–7.78 (m, 3 H), 7.80–7.86 (m, 1 H), 8.09 (dd, J = 8.3, 1.2 Hz, 1 H), 8.25 (dd, J = 8.3, 1.3 Hz, 1 H), 8.60 (d, J = 8.1 Hz, 1 H), 8.68 (d, J = 8.3 Hz, 1 H).

13C NMR (125 MHz, CDCl3): δ = 121.9, 122.1, 123.7, 125.2, 126.9, 127.1, 128.4, 128.7, 128.8, 128.9, 129.7, 130.3, 130.5, 133.4, 139.8, 143.8, 161.2.

HRMS (ESI): m/z [M + H]+ calcd for C19H13N: 256.1121; found: 256.1120.


#

6-(p-Tolyl)phenanthridine (1h)

Yield: 50 mg (92% from 11h); pale yellow solid; purified by FC on silica gel (EtOAc/hexane, 1:5).

Mp 79.0–80.7 °C (Lit.[11k] 80.0–82.0 °C).

IR (KBr): 3067, 3027, 1609, 1581, 1560, 1483, 1458, 1358, 1327, 960, 823, 761, 728 cm–1.

1H NMR (400 MHz, CDCl3): δ = 2.46 (s, 3 H), 7.35 (d, J = 7.8 Hz, 2 H), 7.58 (t, J = 7.6 Hz, 1 H), 7.61–7.69 (m, 3 H), 7.69–7.77 (m, 1 H), 7.77–7.86 (m, 1 H), 8.12 (d, J = 8.2 Hz, 1 H), 8.23 (d, J = 8.1 Hz, 1 H), 8.58 (d, J = 7.9 Hz, 1 H), 8.66 (d, J = 8.3 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 21.3, 121.8, 122.1, 123.6, 125.2, 126.7, 126.9, 128.7, 128.9, 129.0, 129.6, 130.2, 130.4, 133.3, 136.8, 138.5, 143.8, 161.2.

HRMS (ESI): m/z [M + H]+ calcd for C20H15N: 270.1277; found: 270.1276.


#

6-(o-Tolyl)phenanthridine (1i)

Yield: 53 mg (98% from 11i); pale yellow oil; purified by FC on silica gel (EtOAc/hexane, 1:5).

IR (KBr): 2920, 1459, 1445, 1358, 1142, 1081, 1038, 761, 728 cm–1.

1H NMR (500 MHz, CDCl3): δ = 2.10 (s, 3 H), 7.32–7.41 (m, 4 H), 7.50–7.57 (m, 1 H), 7.63–7.71 (m, 2 H), 7.71–7.77 (m, 1 H), 7.77–7.84 (m, 1 H), 8.25 (d, J = 8.1 Hz, 1 H), 8.60 (d, J = 7.9 Hz, 1 H), 8.66 (d, J = 8.3 Hz, 1 H).

13C NMR (125 MHz, CDCl3): δ = 22.4, 123.6, 124.4, 125.3, 125.3, 127.1, 127.6, 127.9, 128.8, 130.9, 134.0, 138.2, 140.7, 141.7, 147.7, 157.9, 168.7.

HRMS (ESI): m/z [M + H]+ calcd for C20H15N: 270.1277; found: 270.1276.


#

6-(4-Methoxyphenyl)phenanthridine (1j)

Yield: 47 mg (83% from 11j); pale yellow oil; purified by FC on silica gel (EtOAc/hexane, 1:5).

IR (KBr): 1608, 1578, 1562, 1511, 1483, 1459, 1405, 1359, 1328, 1302, 1285, 1248, 1171, 1106, 1032, 958, 832, 762, 732 cm–1.

1H NMR (400 MHz, CDCl3): δ = 3.89 (s, 3 H), 7.08 (d, J = 8.6 Hz, 2 H), 7.55–7.78 (m, 5 H), 7.82 (t, J = 7.6 Hz, 1 H), 8.15 (d, J = 8.2 Hz, 1 H), 8.22 (d, J = 8.1 Hz, 1 H), 8.58 (d, J = 8.1 Hz, 1 H), 8.66 (d, J = 8.3 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 55.4, 113.9, 121.9, 122.2, 123.6, 125.4, 126.7, 127.0, 128.8, 128.9, 130.3, 130.4, 131.2, 132.3, 133.5, 143.9, 160.1.

HRMS (ESI): m/z [M + H]+ calcd for C20H15NO: 286.1226; found: 286.1225.


#

6-(3,5-Dimethylphenyl)phenanthridine (1k)

Yield: 46 mg (82% from 11k); pale yellow oil; purified by FC on silica gel (EtOAc/hexane, 1:5).

IR (KBr): 2917, 1602, 1579, 1567, 1558, 1524, 1484, 1460, 1435, 1407, 1383, 1360, 1346, 1264, 1035, 852, 761, 728, 715, 704 cm–1.

1H NMR (500 MHz, CDCl3): δ = 2.43 (s, 6 H), 7.15 (s, 1 H), 7.32 (s, 2 H), 7.58–7.65 (m, 1 H), 7.66–7.72 (m, 1 H), 7.72–7.80 (m, 1 H), 7.82–7.91 (m, 1 H), 8.11 (d, J = 8.2 Hz, 1 H), 8.25 (d, J = 8.1 Hz, 1 H), 8.61 (d, J = 7.8 Hz, 1 H), 8.69 (d, J = 8.2 Hz, 1 H).

13C NMR (125 MHz, CDCl3): δ = 21.4, 121.9, 122.1, 123.7, 125.4, 126.8, 127.0, 127.4, 128.8, 129.1, 130.3, 130.3, 130.5, 133.4, 137.9, 139.6, 143.8, 161.7.

HRMS (ESI): m/z [M + H]+ calcd for C21H17N: 284.1434; found: 284.1434.


#

6-(2,6-Dichlorophenyl)phenanthridine (1l)

Yield: 54 mg (84% from 11l); white soild; purified by FC on silica gel (EtOAc/hexane, 1:5).

Mp 158.0–158.3 °C.

IR (KBr): 1611, 1585, 1572, 1486, 1447, 1430, 1359, 1322, 1191, 1145, 957, 800, 788, 774, 760, 737, 726 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.44 (t, J = 8.1 Hz, 1 H), 7.54 (d, J = 8.0 Hz, 2 H), 7.59–7.70 (m, 2 H), 7.73–7.87 (m, 2 H), 7.87–7.96 (m, 1 H), 8.32 (d, J = 8.0 Hz, 1 H), 8.73 (dd, J = 23.9, 8.2 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 122.2, 122.4, 124.2, 125.1, 127.1, 127.6, 127.7, 128.3, 128.9, 130.3, 130.5, 131.0, 133.1, 135.2, 137.0, 143.8, 157.3.

HRMS (ESI): m/z [M + H]+ calcd for C19H11Cl2N: 324.0341; found: 324.0342.


#

8-Methoxy-6-(p-tolyl)phenanthridine (1m)

Yield: 50 mg (83% from 11m); pale yellow solid; purified by FC on silica gel (EtOAc/hexane, 1:5).

Mp 117.0–117.5 °C (Lit.[11k] 118.0–120.0 °C).

IR (KBr): 2919, 1616, 1532, 1479, 1461, 1418, 1372, 1327, 1289, 1244, 1215, 1181, 1133, 1095, 1040, 1000, 820, 761, 737 cm–1.

1H NMR (400 MHz, CDCl3): δ = 2.48 (s, 3 H), 3.84 (s, 3 H), 7.37 (d, J = 7.8 Hz, 2 H), 7.44–7.54 (m, 2 H), 7.60–7.73 (m, 4 H), 8.20 (dd, J = 8.0, 1.3 Hz, 1 H), 8.51 (dd, J = 7.9, 1.7 Hz, 1 H), 8.60 (d, J = 8.9 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 21.4, 55.4, 109.0, 120.9, 121.4, 123.8, 123.9, 126.6, 126.8, 127.8, 127.8, 129.2, 129.4, 130.2, 137.0, 138.5, 143.0, 158.4, 160.5.

HRMS (ESI): m/z [M + H]+ calcd for C21H17NO: 300.1383; found: 300.1384.


#

8-Methoxy-6-(o-tolyl)phenanthridine (1n)

Yield: 54 mg (91% from 11n); pale yellow oil; purified by FC on silica gel (EtOAc/hexane, 1:5).

IR (KBr): 2958, 2932, 1616, 1567, 1533, 1480, 1461, 1373, 1325, 1290, 1244, 1214, 1142, 1092, 1041, 894, 830, 764, 736 cm–1.

1H NMR (400 MHz, CDCl3): δ = 2.17 (s, 3 H), 3.80 (s, 3 H), 7.08 (s, 1 H), 7.30 (d, J = 1.8 Hz, 1 H), 7.34–7.49 (m, 3 H), 7.49–7.56 (m, 1 H), 7.67–7.79 (m, 2 H), 8.25 (d, J = 7.3 Hz, 1 H), 8.59 (d, J = 7.3 Hz, 1 H), 8.66 (d, J = 9.1 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 19.8, 55.4, 108.6, 121.0, 121.5, 123.8, 123.9, 125.9, 127.0, 127.2, 127.4, 127.8, 128.6, 129.2, 130.2, 130.4, 136.3, 139.2, 143.0, 158.6, 161.1.

HRMS (ESI): m/z [M + H]+ calcd for C21H17NO: 300.1383; found: 300.1384.


#

3-Fluoro-6-(p-tolyl)phenanthridine (1o)

Yield: 57 mg (99% from 11o); pale yellow oil; purified by FC on silica gel (EtOAc/hexane, 1:5).

IR (KBr): 3425, 2920, 1682, 1610, 1597, 1528, 1512, 1493, 1481, 1461, 1446, 1423, 1361, 1297, 1281, 1252, 1187, 1161, 1117, 974, 767, 744, 705 cm–1.

1H NMR (400 MHz, CDCl3): δ = 2.48 (s, 3 H), 7.34–7.50 (m, 3 H), 7.56–7.73 (m, 3 H), 7.81–7.97 (m, 2 H), 8.14 (d, J = 8.2 Hz, 1 H), 8.52–8.70 (m, 2 H).

13C NMR (100 MHz, CDCl3): δ = 21.4, 114.5, 114.7, 115.8, 116.0, 120.4, 122.0, 123.8, 123.9, 124.8, 126.9, 129.1, 129.2, 129.7, 130.9, 133.3, 136.4, 138.9, 161.5, 162.6, 164.0.

HRMS (ESI): m/z [M + H]+ calcd for C20H14FN: 288.1183; found: 288.1183.


#

3-Fluoro-6-isopropylphenanthridine (1p)

Yield: 40 mg (84% from 11p); pale yellow oil; purified by FC on silica gel (EtOAc/hexane, 1:5).

IR (KBr): 2967, 2928, 1619, 1581, 1485, 1457, 1383, 1360, 1283, 1245, 1205, 1166, 1144, 1132, 1116, 1009, 963, 874, 822, 763, 723, 680 cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.49 (d, J = 6.8 Hz, 6 H), 3.90–4.02 (m, 1 H), 7.27–7.37 (m, 1 H), 7.59–7.69 (m, 1 H), 7.73–7.82 (m, 2 H), 8.27 (d, J = 8.3 Hz, 1 H), 8.44 (dd, J = 9.0, 5.9 Hz, 1 H), 8.51 (d, J = 8.3 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 21.9, 31.5, 114.2, 114.4, 114.9, 115.2, 120.0, 120.1, 122.3, 123.6, 123.7, 124.2, 125.8, 126.9, 130.3, 132.7, 145.0, 145.1, 161.3, 163.8, 167.3.

HRMS (ESI): m/z [M + H]+ calcd for C16H14FN: 240.1183; found: 240.1182.


#

Ethyl 3-(Phenanthridin-6-yl)propanoate (1q)

Yield: 38 mg (68% from 11q); pale yellow solid; purified by FC on silica gel (EtOAc/hexane, 1:5).

Mp 70.2–70.3 °C.

IR (KBr): 2980, 2926, 1732, 1612, 1587, 1530, 1487, 1463, 1447, 1416, 1370, 1348, 1324, 1299, 1256, 1236, 1209, 1162, 1096, 1036, 1009, 754, 724 cm–1.

1H NMR (500 MHz, CDCl3): δ = 1.27 (t, J = 7.1 Hz, 3 H), 3.07 (t, J = 7.3 Hz, 2 H), 3.70 (t, J = 7.3 Hz, 2 H), 4.15–4.23 (m, 2 H), 7.60 (t, J = 7.2 Hz, 1 H), 7.68 (t, J = 7.5 Hz, 2 H), 7.81 (t, J = 7.6 Hz, 1 H), 8.08 (d, J = 8.1 Hz, 1 H), 8.26 (d, J = 8.1 Hz, 1 H), 8.51 (d, J = 8.1 Hz, 1 H), 8.61 (d, J = 8.2 Hz, 1 H).

13C NMR (125 MHz, CDCl3): δ = 14.3, 29.9, 31.8, 60.4, 121.9, 122.4, 123.6, 125.3, 125.6, 126.4, 127.3, 128.5, 129.7, 130.3, 132.7, 143.4, 149.1, 159.1, 173.6.

HRMS (ESI): m/z [M + H]+ calcd for C18H17NO2: 280.1332; found: 280.1329.


#

6-(5-(2,5-Dimethylphenoxy)-2-methylpentan-2-yl)phenanthridine (1r)

Yield: 74 mg (97% from 11r); pale yellow oil; purified by FC on silica gel (EtOAc/hexane, 1:5).

IR (KBr): 2923, 2867, 1612, 1580, 1569, 1508, 1485, 1458, 1440, 1412, 1387, 1284, 1265, 1156, 1129, 1041, 1000, 803, 760, 729 cm–1.

1H NMR (500 MHz, CDCl3): δ = 1.57–1.70 (m, 2 H), 1.75 (s, 6 H), 2.09 (s, 3 H), 2.23 (s, 3 H), 2.33–2.42 (m, 2 H), 3.82 (t, J = 6.2 Hz, 2 H), 6.47 (s, 1 H), 6.60 (d, J = 7.4 Hz, 1 H), 6.95 (d, J = 7.4 Hz, 1 H), 7.57–7.66 (m, 2 H), 7.70 (t, J = 7.1 Hz, 1 H), 7.78 (t, J = 7.5 Hz, 1 H), 8.15 (s, 1 H), 8.52 (d, J = 7.9 Hz, 1 H), 8.67 (t, J = 9.0 Hz, 2 H).

13C NMR (125 MHz, CDCl3): δ = 15.8, 21.3, 25.3, 29.7, 39.6, 43.5, 68.0, 111.7, 120.4, 121.6, 123.0, 123.4, 123.4, 124.6, 126.2, 126.6, 127.6, 128.4, 129.4, 130.1, 133.9, 136.3, 156.9, 165.4.

HRMS (ESI): m/z [M + H]+ calcd for C27H29NO: 384.2322; found: 384.2322.


#

4-Methyl-2-(4-nitrophenyl)-8-phenylquinazoline (13a)

Yield: 58 mg (85% from 11w); yellow solid; purified by FC on silica gel (EtOAc/hexane, 1:5).

Mp 218.0–218.3 °C.

IR (KBr): 1599, 1576, 1556, 1521, 1440, 1386, 1351, 1340, 1105, 869, 849, 777, 764, 751, 721 cm–1.

1H NMR (400 MHz, CDCl3): δ = 3.09 (s, 3 H), 7.43–7.53 (m, 1 H), 7.56 (t, J = 7.4 Hz, 2 H), 7.68–7.77 (m, 1 H), 7.77–7.84 (m, 2 H), 7.98 (dd, J = 7.2, 1.2 Hz, 1 H), 8.15 (dd, J = 8.3, 1.2 Hz, 1 H), 8.31 (d, J = 9.0 Hz, 2 H), 8.72 (d, J = 9.0 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 22.4, 123.6, 124.4, 127.6, 127.8, 128.0, 129.3, 130.9, 134.2, 138.0, 144.2, 149.0, 157.1, 169.0.

HRMS (ESI): m/z [M + H]+ calcd for C21H15N3O2: 342.1237; found: 342.1236.


#

4-Methyl-8-phenyl-2-(4-(trifluoromethyl)phenyl)quinazoline (13b)

Yield: 63 mg (86% from 11v); yellow solid; purified by FC on silica gel (EtOAc/hexane, 1:5).

Mp 132.2–132.3 °C.

IR (KBr): 2917, 2849, 1483, 1437, 1385, 1359, 1161, 1124, 1101, 1064, 1017, 946, 762, 698 cm–1.

1H NMR (400 MHz, CDCl3): δ = 3.08 (s, 3 H), 7.48 (t, J = 7.2 Hz, 1 H), 7.55 (t, J = 7.5 Hz, 2 H), 7.64–7.75 (m, 3 H), 7.81 (d, J = 7.5 Hz, 2 H), 7.94–7.98 (m, 1 H), 8.09–8.20 (m, 1 H), 8.66 (d, J = 8.1 Hz, 2 H).

13C NMR (125 MHz, CDCl3): δ = 22.4, 123.6, 124.4, 125.3, 125.4, 125.4, 127.1, 127.7, 127.9, 128.8, 131.0, 134.0, 138.2, 140.7, 141.7, 147.8, 158.0, 168.7.

HRMS (ESI): m/z [M + H]+ calcd for C22H15F3N2: 365.1260; found: 365.1258.


#

Methyl 4-(4-Methyl-8-phenylquinazolin-2-yl)benzoate (13c)

Yield: 62 mg (88% from 11y); white solid; purified by FC on silica gel (EtOAc/hexane, 1:5).

Mp 140.0–140.7 °C.

IR (KBr): 1723, 1608, 1577, 1552, 1481, 1435, 1342, 1274, 1114, 1018, 773, 761, 728, 699 cm–1.

1H NMR (400 MHz, CDCl3): δ = 3.09 (s, 3 H), 3.94 (s, 3 H), 7.42–7.52 (m, 1 H), 7.55 (t, J = 7.5 Hz, 2 H), 7.65–7.71 (m, 1 H), 7.79–7.90 (m, 2 H), 7.96 (dd, J = 7.2, 1.0 Hz, 1 H), 8.13 (dd, J = 8.4, 1.9 Hz, 3 H), 8.62 (d, J = 8.4 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 25.1, 52.2, 111.9, 125.5, 127.7, 127.9, 128.1, 129.1, 129.6, 130.7, 131.0, 131.9, 134.7, 134.8, 139.7, 150.7, 163.8, 165.5, 166.9.

HRMS (ESI): m/z [M + H]+ calcd for C23H18N2O2: 355.1441; found: 355.1440.


#

4-(4-Methyl-8-phenylquinazolin-2-yl)benzonitrile (13d)

Yield: 40 mg (63% from 11x); yellow oil; purified by FC on silica gel (EtOAc/hexane, 1:5).

IR (KBr): 2225, 1576, 1543, 1481, 1458, 1441, 1430, 1385, 1342, 1098, 1022, 856, 773, 756, 746, 690 cm–1.

1H NMR (400 MHz, CDCl3): δ = 3.08 (s, 3 H), 7.49 (d, J = 7.5 Hz, 1 H), 7.55 (t, J = 7.5 Hz, 2 H), 7.70 (d, J = 7.4 Hz, 1 H), 7.74 (d, J = 8.2 Hz, 2 H), 7.79 (d, J = 7.5 Hz, 2 H), 7.97 (d, J = 7.2 Hz, 1 H), 8.13 (d, J = 8.3 Hz, 1 H), 8.65 (d, J = 8.2 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 22.4, 113.4, 119.0, 123.6, 124.4, 127.5, 127.7, 127.9, 129.0, 130.9, 132.3, 134.3, 138.1, 140.8, 142.4, 147.7, 157.3, 168.9.

HRMS (ESI): m/z [M + H]+ calcd for C22H15N3: 322.1339; found: 322.1344.


#

2-(Benzo[b]thiophen-2-yl)-4-methyl-8-phenylquinazoline (13e)

Yield: 45 mg (64% from 11aa); yellow solid; purified by FC on silica gel (EtOAc/hexane, 1:5).

Mp 211.3–211.4 °C.

IR (KBr): 1576, 1551, 1481, 1463, 1432, 1384, 1346, 1152, 772, 749, 724, 697 cm–1.

1H NMR (400 MHz, CDCl3): δ = 3.10 (s, 3 H), 7.34–7.44 (m, 2 H), 7.53 (t, J = 7.4 Hz, 1 H), 7.58–7.72 (m, 3 H), 7.90 (t, J = 6.2 Hz, 4 H), 7.99 (d, J = 7.2 Hz, 1 H), 8.11 (d, J = 8.3 Hz, 1 H), 8.39 (s, 1 H).

13C NMR (100 MHz, CDCl3): δ = 22.2, 122.6, 123.3, 124.4, 124.5, 124.7, 125.4, 125.8, 126.8, 127.6, 127.9, 131.1, 134.2, 137.9, 140.1, 140.3, 142.1, 144.5, 147.7, 156.3, 168.6.

HRMS (ESI): m/z [M + H]+ calcd for C23H16N2S: 353.1107; found: 353.1104.


#

Phenanthridine Derivatives 1s–1aa; General Procedure A′

Phenanthridine derivatives 1s–1aa were prepared according to general procedure A except that CH2Cl2 instead of MeCN was used as the solvent.


#

6-(4-(tert-Butyl)phenyl)phenanthridine (1s)

Yield: 44 mg (71% from 11s); colourless oil; purified by FC on silica gel (EtOAc/hexane, 1:5).

IR (KBr): 2962, 1610, 1577, 1548, 1482, 1458, 1441, 1402, 1384, 1361, 1342, 1328, 1142, 1110, 1024, 836, 775, 761, 745, 727, 617 cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.40 (s, 9 H), 7.54–7.61 (m, 3 H), 7.62–7.70 (m, 3 H), 7.73 (t, J = 7.5 Hz, 1 H), 7.82 (t, J = 7.6 Hz, 1 H), 8.17 (d, J = 8.2 Hz, 1 H), 8.24 (d, J = 8.1 Hz, 1 H), 8.58 (d, J = 8.1 Hz, 1 H), 8.66 (d, J = 8.2 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 31.3, 34.7, 121.9, 122.1, 123.6, 125.3, 125.4, 126.7, 127.0, 128.7, 129.0, 129.4, 130.3, 130.4, 133.4, 136.9, 143.9, 151.7, 161.3.

HRMS (ESI): m/z [M + H]+ calcd for C23H21N: 312.1747; found: 312.1744.


#

6-(4-Chlorophenyl)phenanthridine (1t)

Yield: 48 mg (83% from 11t); white solid; purified by FC on silica gel (EtOAc/hexane, 1:5).

Mp 152.5–153.0 °C (Lit.[11k] 151.0–152.0 °C).

IR (KBr): 2918, 1609, 1457, 1396, 1359, 1205, 1151, 1104, 1090, 1068, 1039, 830, 753, 723 cm–1.

1H NMR (500 MHz, CDCl3): δ = 7.55 (d, J = 8.1 Hz, 2 H), 7.63 (t, J = 7.6 Hz, 1 H), 7.70 (t, J = 7.8 Hz, 3 H), 7.77 (d, J = 7.6 Hz, 1 H), 7.87 (t, J = 7.7 Hz, 1 H), 8.06 (d, J = 8.2 Hz, 1 H), 8.23 (d, J = 8.1 Hz, 1 H), 8.62 (d, J = 8.1 Hz, 1 H), 8.71 (d, J = 8.2 Hz, 1 H).

13C NMR (125 MHz, CDCl3): δ = 121.9, 122.3, 123.7, 124.9, 127.1, 127.2, 128.4, 128.6, 128.9, 130.3, 130.6, 131.1, 133.4, 134.8, 138.1, 143.6, 159.9.

HRMS (ESI): m/z [M + H]+ calcd for C19H12ClN: 290.0731; found: 290.0729.


#

6-(4-Fluorophenyl)phenanthridine (1u)

Yield: 38 mg (70% from 11u); white solid; purified by FC on silica gel (EtOAc/hexane, 1:5).

Mp 124.8–125.1 °C.

IR (KBr): 1600, 1564, 1509, 1483, 1459, 1402, 1358, 1327, 1223, 1157, 1137, 1094, 837, 761, 729, 625 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.26 (d, J = 17.3 Hz, 2 H), 7.63 (t, J = 7.6 Hz, 1 H), 7.67–7.80 (m, 4 H), 7.83–7.92 (m, 1 H), 8.07 (d, J = 8.2 Hz, 1 H), 8.23 (d, J = 8.1 Hz, 1 H), 8.62 (d, J = 8.2 Hz, 1 H), 8.71 (d, J = 8.2 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 115.3, 115.5, 121.9, 122.3, 123.7, 125.1, 127.0, 127.2, 128.6, 128.9, 130.3, 130.6, 131.6, 131.6, 133.5, 135.8, 143.7, 160.1, 161.9, 164.4.

HRMS (ESI): m/z [M + H]+ calcd for C19H12FN: 274.1027; found: 274.1024.


#

6-(4-(Trifluoromethyl)phenyl)phenanthridine (1v)

Yield: 34 mg (52% from 11v); yellow solid; purified by FC on silica gel (EtOAc/hexane, 1:5).

Mp 164.0–164.5 °C.

IR (KBr): 2919, 1654, 1632, 1612, 1519, 1459, 1405, 1350, 1327, 1168, 1135, 1106, 1067, 1020, 841, 757, 727, 619 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.71 (t, J = 7.6 Hz, 1 H), 7.76–8.12 (m, 7 H), 8.31 (dd, J = 15.1, 8.0 Hz, 1 H), 8.48 (d, J = 8.7 Hz, 1 H), 8.70 (d, J = 8.1 Hz, 1 H), 8.79 (d, J = 8.3 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 122.1, 122.5, 122.6, 123.7, 123.9, 124.7, 125.5, 125.6, 127.6, 127.7, 127.8, 128.0, 128.6, 129.3, 129.4, 129.8, 130.2, 130.3, 130.9, 131.2, 131.4, 133.7, 142.8, 159.7.

HRMS (ESI): m/z [M + H]+ calcd for C20H12F3N: 324.0995; found: 324.0992.


#

6-(4-Nitrophenyl)phenanthridine (1w)

Yield: 28 mg (46% from 11w); yellow solid; purified by FC on silica gel (EtOAc/hexane, 1:5).

Mp 183.5–183.9 °C.

IR (KBr): 2918, 2849, 1517, 1350, 1101, 846, 760, 726, 697 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.66–7.74 (m, 1 H), 7.74–7.89 (m, 2 H), 7.91–8.06 (m, 4 H), 8.28 (d, J = 8.1 Hz, 1 H), 8.48 (d, J = 8.7 Hz, 2 H), 8.69 (d, J = 8.3 Hz, 1 H), 8.79 (d, J = 8.3 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 122.1, 122.6, 123.7, 124.6, 127.6, 127.7, 127.9, 129.2, 130.4, 130.9, 131.0, 133.6, 143.6, 146.1, 158.7.

HRMS (ESI): m/z [M + H]+ calcd for C19H12N2O2: 301.0972; found: 301.0971.


#

4-(Phenanthridin-6-yl)benzonitrile (1x)

Yield: 54 mg (98% from 11x); white solid; purified by FC on silica gel (EtOAc/hexane, 1:5).

Mp 174.9–175.0 °C.

IR (KBr): 2227, 1654, 1610, 1579, 1484, 1459, 1441, 1402, 1384, 1360, 1328, 1136, 1095, 1032, 842, 762, 732, 725 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.65 (t, J = 7.6 Hz, 1 H), 7.69–7.82 (m, 2 H), 7.82–7.94 (m, 5 H), 7.98 (d, J = 8.2 Hz, 1 H), 8.23 (d, J = 8.0 Hz, 1 H), 8.63 (d, J = 8.1 Hz, 1 H), 8.73 (d, J = 8.3 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 112.5, 118.7, 122.0, 122.5, 123.8, 124.5, 127.5, 127.6, 128.0, 129.1, 130.3, 130.6, 131.0, 132.2, 133.5, 143.5, 144.2, 159.0.

HRMS (ESI): m/z [M + H]+ calcd for C20H12N2: 281.1073; found: 281.1071.


#

Methyl 4-(Phenanthridin-6-yl)benzoate (1y)

Yield: 60 mg (97% from 11y); yellow solid; purified by FC on silica gel (EtOAc/hexane, 1:5).

Mp 158.8–158.9 °C.

IR (KBr): 1723, 1611, 1581, 1459, 1435, 1402, 1359, 1277, 1137, 1113, 1103, 1020, 759, 727, 706 cm–1.

1H NMR (400 MHz, CDCl3): δ = 3.99 (s, 3 H), 7.63 (t, J = 7.6 Hz, 1 H), 7.72 (t, J = 7.5 Hz, 1 H), 7.76–7.81 (m, 1 H), 7.83 (d, J = 8.2 Hz, 2 H), 7.89 (t, J = 7.6 Hz, 1 H), 8.03 (dd, J = 8.2, 1.1 Hz, 1 H), 8.22–8.30 (m, 3 H), 8.64 (d, J = 8.0 Hz, 1 H), 8.73 (d, J = 8.2 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 52.3, 122.0, 122.4, 123.8, 124.9, 127.4, 128.5, 129.1, 129.7, 129.9, 130.2, 130.4, 130.9, 133.5, 160.1, 166.8.

HRMS (ESI): m/z [M + H]+ calcd for C21H15NO2: 314.1176; found: 314.1173.


#

6-(Naphthalen-1-yl)phenanthridine (1z)

Yield: 44 mg (73% from 11z); white solid; purified by FC on silica gel (EtOAc/hexane, 1:5).

Mp 148.0–148.7 °C.

IR (KBr): 2917, 1654, 1578, 1561, 1457, 1407, 1384, 1323, 1263, 1196, 1137, 1094, 1032, 745, 726 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.52–7.68 (m, 3 H), 7.68–7.84 (m, 2 H), 7.84–7.93 (m, 2 H), 7.93–8.01 (m, 2 H), 8.04 (d, J = 8.5 Hz, 1 H), 8.17 (d, J = 8.1 Hz, 1 H), 8.25 (s, 1 H), 8.34 (d, J = 7.8 Hz, 1 H), 8.66 (d, J = 7.5 Hz, 1 H), 8.74 (d, J = 8.2 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 122.0, 122.3, 123.8, 125.3, 126.4, 126.6, 127.0, 127.2, 127.3, 127.8, 128.1, 128.5, 129.0, 129.0, 129.3, 130.2, 130.7, 133.2, 133.4, 133.5, 161.2.

HRMS (ESI): m/z [M + H]+ calcd for C23H15N: 306.1277; found: 306.1276.


#

6-(Benzo[b]thiophen-2-yl)phenanthridine (1aa)

Yield: 24 mg (39% from 11aa); yellow solid; purified by FC on silica gel (EtOAc/hexane, 1:5).

Mp 145.0–145.9 °C.

IR (KBr): 1611, 1577, 1561, 1484, 1454, 1433, 1384, 1356, 1319, 1155, 1119, 1093, 1032, 761, 746, 723 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.37–7.47 (m, 2 H), 7.64–7.80 (m, 3 H), 7.83–7.98 (m, 4 H), 8.24 (d, J = 8.0 Hz, 1 H), 8.59 (d, J = 8.2 Hz, 1 H), 8.64 (d, J = 8.3 Hz, 1 H), 8.70 (d, J = 8.3 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 121.9, 122.3, 122.4, 123.6, 124.3, 124.5, 124.8, 125.1, 126.0, 127.4, 127.6, 128.0, 129.0, 130.4, 130.7, 133.6, 140.0, 140.7, 142.6, 143.6, 154.0.

HRMS (ESI): m/z [M + H]+ calcd for C21H13NS: 312.0841; found: 312.0840.


#

Trisphaeridine (4)[5a]

o-Arylanilide 14a (0.0426 g, 0.2 mmol) was dissolved in dry CH2Cl2 (1 mL), formic acetic anhydride [prepared by heating formic acid (33 μL, 0.88 mmol) and acetic anhydride (75 μL, 0.8 mmol) at 55 °C with stirring for 2 h] was added at 0 °C, then the mixture was allowed to warm to rt and stirred for 2 h. The reaction mixture was concentrated under vacuum, then dissolved in dry CH2Cl2 (2 mL). TTBP (0.0298 g, 0.12 mmol) was added at rt, and Tf2O (37 μL, 0.22 mmol) was added at –40 °C and the mixture stirred for 30 min, then warmed to 40 °C and stirred for 3 h. The reaction was quenched with saturated aqueous NH4Cl solution (5 mL). The mixture was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/hexane, 1:1) to afford 4.

Yield: 40 mg (90%); white crystals (CH2Cl2/petroleum ether).

Mp 141.0–141.1 °C (Lit.[21a] 144.5–145.0 °C, Lit.[5a] 138.0 °C).

IR (KBr): 2921, 1618, 1581, 1501, 1484, 1464, 1384, 1254, 1226, 1097, 1039, 939, 759 cm–1.

1H NMR (400 MHz, CDCl3): δ = 6.18 (s, 2 H), 7.35 (s, 1 H), 7.64 (t, J = 7.2 Hz, 1 H), 7.70 (t, J = 7.0 Hz, 1 H), 7.92 (s, 1 H), 8.17 (d, J = 8.1 Hz, 1 H), 8.38 (d, J = 8.5 Hz, 1 H), 9.10 (s, 1 H).

13C NMR (100 MHz, CDCl3): δ = 100.0, 102.0, 105.6, 122.0, 123.0, 124.3, 126.8, 128.1, 129.8, 130.4, 143.6, 148.3, 151.5, 151.7.

HRMS (ESI): m/z [M + H]+ calcd for C14H9NO2: 224.0706; found: 224.0705.


#

3-(Benzyloxy)[1,3]dioxolo[4,5-j]phenanthridine (17)[22]

Following the procedure for the synthesis of trisphaeridine (4), compound 17 was prepared from o-arylanilide 14b (0.0639 g, 0.2 mmol).

Yield: 49 mg (75%); orange solid.

Mp 200.3–200.5 °C.

IR (KBr): 2918, 1958, 1471, 1384, 1362, 1180, 1150, 1129, 1081, 1036, 851, 767 cm–1.

1H NMR (400 MHz, CDCl3): δ = 5.24 (s, 2 H), 6.14 (s, 2 H), 7.29 (s, 1 H), 7.31–7.37 (m, 2 H), 7.41 (t, J = 7.5 Hz, 2 H), 7.51 (d, J = 7.4 Hz, 2 H), 7.61 (s, 1 H), 7.79 (s, 1 H), 8.25 (d, J = 9.0 Hz, 1 H), 9.03 (s, 1 H).

13C NMR (100 MHz, CDCl3): δ = 70.2, 99.4, 101.8, 105.4, 110.6, 118.5, 118.7, 122.1, 123.3, 127.7, 128.1, 128.6, 130.6, 136.6, 145.5, 147.5, 151.6, 152.0, 158.7.

HRMS (ESI): m/z [M + H]+ calcd for C21H15NO3: 330.1125; found: 330.1121.


#

Phenanthridinium Salt III; Procedure B

To o-arylanilide 14c (0.0454 g, 0.2 mmol) in CH2Cl2 (1.0 mL), formic acetic anhydride [prepared by heating formic acid (33 μL, 0.88 mmol) and acetic anhydride (75 μL, 0.8 mmol) at 55 °C with stirring for 2 h] was added at 0 °C, then the mixture was allowed to warm to rt and stirred for 2 h. The reaction mixture was concentrated under vacuum, then dissolved in dry CH2Cl2 (2 mL). Tf2O (37 μL, 0.22 mmol) was added at –40 °C for 30 min. Then the mixture was warmed to 40 °C and stirred for 3 h. The reaction mixture was used for the subsequent reactions.


#

5,6-Dihydrobicolorine (6)[6b]

A reaction mixture containing phenanthridinium salt III, prepared according to procedure B, was concentrated under reduced pressure, and NaBH4 (0.0304 g, 0.8 mmol) was added. The resulting mixture was dissolved in MeOH at 0 °C, then warmed to rt, and stirred for 2 h. The reaction was quenched with saturated aqueous NaHCO3 solution (5 mL). The mixture was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/hexane, 1:10) to afford 6.

Yield: 44 mg (91%); orange solid.

Mp 82.3–82.4 °C (Lit.[6b] 77.0–81.0 °C).

IR (KBr): 2918, 2849, 1633, 1578, 1484, 1463, 1410, 1394, 1314, 1261, 1181, 1081, 1037, 933, 750 cm–1.

1H NMR (400 MHz, CDCl3): δ = 2.90 (s, 3 H), 4.08 (s, 2 H), 5.96 (s, 2 H), 6.62 (s, 1 H), 6.73 (d, J = 8.1 Hz, 1 H), 6.85 (t, J = 7.5 Hz, 1 H), 7.20 (t, J = 8.4 Hz, 2 H), 7.54 (d, J = 7.6 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 38.6, 55.1, 100.9, 103.2, 106.1, 112.2, 118.7, 123.0, 123.6, 126.2, 127.2, 128.4, 146.5, 146.8, 147.5.

HRMS (ESI): m/z [M + H]+ calcd for C15H13NO2: 240.1019; found: 240.1014.


#

Diethyl (5-Methyl-5,6-dihydro[1,3]dioxolo[4,5-j]phenanthridin-6-yl)phosphonate (6a)

A reaction mixture containing phenanthridinium salt III, prepared according to procedure B, was allowed to warm to rt, then K2CO3 (0.0553 g, 0.4 mmol) and HPO(OEt)2 (39 μL, 0.3 mmol) were added at 0 °C. The mixture was allow to warm to rt, and stirred for 10 h. The reaction mixture was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc­/hexane, 1:10) to afford 6a.

Yield: 60 mg (85%); yellow oil.

IR (KBr): 2918, 2849, 1959, 1658, 1633, 1488, 1471, 1423, 1384, 1181, 1150, 1094, 1033, 747, 617 cm–1.

1H NMR (400 MHz, CDCl3): δ = 0.98–1.17 (m, 6 H), 3.13 (d, J = 2.7 Hz, 3 H), 3.48–3.68 (m, 1 H), 3.69–3.92 (m, 3 H), 4.59 (d, J = 9.2 Hz, 1 H), 5.92–6.03 (m, 2 H), 6.63–6.74 (m, 2 H), 6.80 (t, J = 7.5 Hz, 1 H), 7.12–7.24 (m, 2 H), 7.49 (dd, J = 7.7, 1.5 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 16.2, 16.3, 16.4, 39.1, 62.2, 63.6, 101.2, 103.0, 107.8, 107.8, 112.5, 118.4, 122.5, 123.1, 123.4, 126.6, 128.7, 144.1, 146.8.

31P NMR (162 MHz, CDCl3): δ = 22.0.

HRMS (ESI): m/z [M + Na]+ calcd for C19H22NO5P: 398.1128; found: 398.1127.


#

5,6-Dimethyl-5,6-dihydro[1,3]dioxolo[4,5-j]phenanthridine (6b)

To a reaction mixture containing phenanthridinium salt III, prepared according to procedure B, was added MeMgBr (0.3 mmol) at 0 °C, then the mixture was allowed to warm to rt, and stirred for 1 h. The reaction was quenched with saturated aqueous NH4Cl solution (5 mL). The mixture was extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/hexane, 1:10) to afford 6b.

Yield: 46 mg (90%); pale yellow oil.

IR (KBr): 2918, 1597, 1500, 1488, 1455, 1427, 1376, 1297, 1286, 1250, 1232, 1211, 1179, 1128, 1095, 1037, 934, 860, 749, 726 cm–1.

1H NMR (400 MHz, CDCl3): δ = 1.08 (d, J = 6.5 Hz, 3 H), 2.95 (s, 3 H), 4.23–4.32 (m, 1 H), 5.93 (dd, J = 6.2, 1.2 Hz, 2 H), 6.56 (s, 1 H), 6.64 (d, J = 8.1 Hz, 1 H), 6.77–6.86 (m, 1 H), 7.14–7.23 (m, 2 H), 7.51–7.58 (m, 1 H).

13C NMR (100 MHz, CDCl3): δ = 16.6, 36.7, 59.8, 100.9, 103.0, 105.7, 112.8, 117.8, 122.5, 122.6, 124.6, 128.4, 132.1, 143.8, 146.7, 147.3.

HRMS (ESI): m/z [M + H]+ calcd for C16H15NO2: 254.1176; found: 254.1173.


#

6-Ethyl-5-methyl-5,6-dihydro[1,3]dioxolo[4,5-j]phenanthridine (6c)

Prepared according to the procedure for the synthesis of 6b except that EtMgBr was used as the Grignard reagent.

Yield: 46 mg (87%); pale yellow oil.

IR (KBr): 2962, 2918, 2850, 1959, 1599, 1504, 1488, 1456, 1431, 1382, 1320, 1283, 1253, 1230, 1211, 1180, 1127, 1095, 1038, 937, 862, 820, 749 cm–1.

1H NMR (400 MHz, CDCl3): δ = 0.75 (t, J = 7.5 Hz, 3 H), 1.41–1.53 (m, 1 H), 1.57–1.65 (m, 1 H), 3.02 (s, 3 H), 4.00 (dd, J = 8.6, 4.5 Hz, 1 H), 5.89–6.01 (m, 2 H), 6.56 (s, 1 H), 6.63 (d, J = 8.1 Hz, 1 H), 6.79 (td, J = 7.5, 1.2 Hz, 1 H), 7.13–7.24 (m, 2 H), 7.54 (dd, J = 7.7, 1.5 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 10.4, 24.3, 37.5, 65.7, 100.9, 103.2, 107.0, 112.3, 117.4, 122.6, 125.2, 128.4, 129.7, 144.4, 146.3, 147.3.

HRMS (ESI): m/z [M + H]+ calcd for C17H17NO2: 268.1332; found: 268.1329.


#

6-Benzyl-5-methyl-5,6-dihydro[1,3]dioxolo[4,5-j]phenanthridine (6d)

Prepared according to the procedure for the synthesis of 6b except that BnMgCl was used as the Grignard reagent.

Yield: 54 mg (82%); pale yellow oil.

IR (KBr): 2917, 2849, 1958, 1632, 1599, 1501, 1488, 1454, 1432, 1384, 1301, 1274, 1232, 1180, 1125, 1095, 1038, 938, 740, 699 cm–1.

1H NMR (400 MHz, CDCl3): δ = 2.60 (dd, J = 12.9, 8.1 Hz, 1 H), 2.93 (s, 4 H), 4.29 (t, J = 6.9 Hz, 1 H), 5.87–5.95 (m, 2 H), 6.04 (d, J = 1.6 Hz, 1 H), 6.66 (d, J = 8.1 Hz, 1 H), 6.85 (t, J = 7.5 Hz, 1 H), 6.92 (d, J = 7.4 Hz, 2 H), 7.11–7.28 (m, 5 H), 7.60 (d, J = 7.6 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 37.9, 38.2, 66.7, 100.8, 103.1, 106.9, 112.8, 117.8, 122.7, 125.0, 126.2, 128.2, 128.5, 129.3, 129.7, 143.6, 146.1, 147.3.

HRMS (ESI): m/z [M + H]+ calcd for C22H19NO2: 330.1489; found: 330.1486.


#

N-Methylcrinasiadine (8)[21a]

A reaction mixture containing phenanthridinium salt III, prepared according to procedure B, was concentrated under vacuum, K3Fe(CN)6 (0.2634 g, 0.8 mmol) and NaOH (0.0480 g, 1.2 mmol) were added, and the mixture was dissolved in THF/H2O (2:1) (THF 2 mL) at rt and stirred for 12 h. The reaction mixture was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromato­graphy on silica gel (EtOAc/hexane, 1:5) to afford 8.

Yield: 45 mg (89%); yellow needle crystals (CH2Cl2/petroleum ether).

Mp 246.4–246.5 °C [Lit.[24c] 239.0 °C; Lit.[5a] 250–255 °C, yellow crystals (acetone)].

IR (KBr): 2920, 1958, 1649, 1468, 1259, 1179, 1035, 751, 638 cm–1.

1H NMR (400 MHz, CDCl3): δ = 3.81 (s, 3 H), 6.12 (s, 2 H), 7.27–7.34 (m, 1 H), 7.40 (d, J = 8.4 Hz, 1 H), 7.47–7.56 (m, 1 H), 7.62 (s, 1 H), 7.91 (s, 1 H), 8.09 (d, J = 8.1 Hz, 1 H).

13C NMR (100 MHz, CDCl3): δ = 30.0, 100.4, 101.9, 107.0, 115.0, 119.2, 121.3, 122.3, 122.9, 128.9, 130.4, 137.5, 148.4, 152.2, 161.0.

HRMS (ESI): m/z [M + H]+ calcd for C15H11NO3: 254.0812; found: 254.0814.


#
#

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

We thank Mr. Yi Ruan for the preparation of some starting materials, and Ms. Yan-Jiao Gao for assistance in the preparation of the manuscript.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1957-4343.
  • Supporting Information

Corresponding Author

Pei-Qiang Huang
Department of Chemistry, Fujian Provincial Key Laboratory of Chemical Biology, College of Chemistry and Chemical Engineering, Xiamen University
Xiamen, Fujian 361005
P. R. of China   

Publication History

Received: 14 September 2022

Accepted: 07 October 2022

Accepted Manuscript online:
07 October 2022

Article published online:
10 November 2022

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Figure 1 Representative bioactive natural and non-natural phenanthridinoids
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Scheme 1 Reported and current methods for the synthesis of phenanthridines from amides
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Figure 2 Proposed mechanism for the formation of quinazolines
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Scheme 2 Three-step total synthesis of trisphaeridine
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Scheme 3 One-pot synthesis of trisphaeridine (4) from 14a and formal total synthesis of zephycandidine A (10)
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Scheme 4 Formal total synthesis of alkaloid 3-hydroxy-8,9-methylenedioxyphenanthridine (5)
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Scheme 5 First-generation synthesis of alkaloid 5,6-dihydrobicolorine (6)
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Scheme 6 One-pot, divergent syntheses of alkaloids 5,6-dihydro­bicolorine (6), N-methylcrinasiadine (8), and C6-functionalized derivatives