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Synthesis 2020; 52(02): 239-245
DOI: 10.1055/s-0039-1690220
paper
© Georg Thieme Verlag Stuttgart · New York

Silver-Promoted Regioselective Oxidative Decarboxylative C–H Alkylation of Phenanthridines with Carboxylic Acids

Tianyin Huang
a   Department of Chemistry, Innovative Drug Research Center, Qianweichang College, School of Life Science, Shanghai University, Shanghai 200444, P. R. of China   Email: dingchanghua@shu.edu.cn   Email: junjiexiao@live.cn   Email: xubin@shu.edu.cn
,
Yang Yu
a   Department of Chemistry, Innovative Drug Research Center, Qianweichang College, School of Life Science, Shanghai University, Shanghai 200444, P. R. of China   Email: dingchanghua@shu.edu.cn   Email: junjiexiao@live.cn   Email: xubin@shu.edu.cn
,
Hui Wang
a   Department of Chemistry, Innovative Drug Research Center, Qianweichang College, School of Life Science, Shanghai University, Shanghai 200444, P. R. of China   Email: dingchanghua@shu.edu.cn   Email: junjiexiao@live.cn   Email: xubin@shu.edu.cn
,
Yifan Lin
a   Department of Chemistry, Innovative Drug Research Center, Qianweichang College, School of Life Science, Shanghai University, Shanghai 200444, P. R. of China   Email: dingchanghua@shu.edu.cn   Email: junjiexiao@live.cn   Email: xubin@shu.edu.cn
,
Yurui Ma
a   Department of Chemistry, Innovative Drug Research Center, Qianweichang College, School of Life Science, Shanghai University, Shanghai 200444, P. R. of China   Email: dingchanghua@shu.edu.cn   Email: junjiexiao@live.cn   Email: xubin@shu.edu.cn
,
Haoyu Wang
a   Department of Chemistry, Innovative Drug Research Center, Qianweichang College, School of Life Science, Shanghai University, Shanghai 200444, P. R. of China   Email: dingchanghua@shu.edu.cn   Email: junjiexiao@live.cn   Email: xubin@shu.edu.cn
,
Chang-Hua Ding  ∗
a   Department of Chemistry, Innovative Drug Research Center, Qianweichang College, School of Life Science, Shanghai University, Shanghai 200444, P. R. of China   Email: dingchanghua@shu.edu.cn   Email: junjiexiao@live.cn   Email: xubin@shu.edu.cn
,
Junjie Xiao∗
a   Department of Chemistry, Innovative Drug Research Center, Qianweichang College, School of Life Science, Shanghai University, Shanghai 200444, P. R. of China   Email: dingchanghua@shu.edu.cn   Email: junjiexiao@live.cn   Email: xubin@shu.edu.cn
,
Bin Xu∗
a   Department of Chemistry, Innovative Drug Research Center, Qianweichang College, School of Life Science, Shanghai University, Shanghai 200444, P. R. of China   Email: dingchanghua@shu.edu.cn   Email: junjiexiao@live.cn   Email: xubin@shu.edu.cn
b   State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. of China
› Author Affiliations

We thank the National Natural Science Foundation of China (No. 21672136, 21871174, 21772215) and Innovation Program of Shanghai Municipal Education Commission (No. 2019-01-07-00-09-E00008) for financial support.
Further Information

Publication History

Received: 12 September 2019

Accepted after revision: 02 October 2019

Publication Date:
29 October 2019 (online)

 
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§ These authors contributed equally to this manuscript

Abstract

A novel oxidative decarboxylative C–H alkylation of phenanthridines with carboxylic acids was developed for the efficient synthesis of multi-substituted phenanthridine derivatives. The given method features easy availability of starting materials, high regioselectivity, and mild conditions. Furthermore, a one-pot synthesis of multi-substituted phenanthridine derivatives was realized by the reaction of biphenyl isocyanides and carboxylic acid.


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Key words

phenanthridine - decarboxylation - silver acetate - C–H alkylation­ - potassium persulfate - late-stage modification
Zoom Image
Scheme 1 Typical approaches to phenanthridines

Phenanthridines are important nitrogen-containing heterocyclic compounds which exist widely in some natural products, pharmaceuticals, and materials science.[1] They could affect the functions of central nervous system and cardiovascular system, and has antineoplastic, antimicrobial, and antiviral activities.[2] Accordingly, the synthesis of phenanthridines has attracted great attention due to their biological activities. Therefore, it is of great significance to explore efficient and selective synthetic methods for phenanthridines in the field of medicinal chemistry and materials science. At present, intramolecular cyclization of α-substituted diaryl compounds and tandem reactions of oxime or N-arylimidoyl chloride are two of the main methods for the synthesis of phenanthridine compounds (Scheme [1a]).[3] [4] Among them, biphenyl isonitriles are used as substrates frequently to synthesize C6-substituted phenanthridine derivatives.[4] Thus, different groups such as acyl, trifluoromethyl, aryl, and phosphatidyl could be introduced successfully at the 6-position of phenanthridine ring accordingly. Despite these significant advancements, some methods suffered from substrates that have to be prepared by multiple steps, or the use of expensive transition-metal catalysts such as iridium salts. Furthermore, substituents located at the other positions, including the 9-position of phenanthridine products, need to be pre-positioned in the starting materials for these methods (Scheme [1a]). Notably, the protocol for regioselective synthesis of phenanthridines through a late-stage C–H functionalization approach is not available so far.

Oxidative decarboxylative coupling reaction of simple carboxylic acids has evolved as a powerful strategy for the formation of carbon–carbon and carbon–heteroatom bonds.[5] [6] Since the pioneering work on Ag-catalyzed decarboxylative alkylation of pyridines by Minisci in the 1970s,[7] the reaction has been widely used to introduce diverse substituents into heteroaromatic compounds.[5] However, the direct C–H alkylation of polycyclic heteroaromatics, especially in the absence of directing groups, is challenging due to the presence of multiple C–H bonds, which makes the control of regioselectivity to be difficult without the aid of the directing group. During our studies on the application of isocyanides for the synthesis of heterocycles,[8] we observed a rare regioselective C–H alkylation of phenanthridine via Ag-promoted oxidative decarboxylation of carboxylic acids (Scheme [1b]), which offers a direct C–H alkylation approach to prepare 9-substituted phenanthridines. Herein, we report our preliminary results.

At the outset of this investigation, we commenced our study by exploring the reaction of 6-tert-butylphenanthridine (1a) with 1-adamantane (Ad) carboxylic acid (2a) in the presence of silver acetate and potassium persulfate in MeCN under air atmosphere at 50 °C. Delightfully, the desired product 3a was isolated in 23% yield and the starting material 1a was recovered in 26% yield (Table [1], entry 1). Various polar solvents commonly used in decarboxylation reactions were then examined (entries 2–6). A mixed solvent of acetone and water in a 1:1 ratio proved to be the most suitable reaction medium to furnish product 3a in 60% yield (entry 6). Better results were not observed when other silver salts or oxidants were employed instead of AgOAc or K2S2O8 (entries 7–13 vs entry 6). Likewise, increasing or lowering the reaction temperature did not improve the reaction yield (entries 14–15 vs entry 6). Further study indicated beneficial effect on the reaction by increasing the loading of AgOAc to 30 mol%, affording product 3a in 77% yield (entry 16 vs entry 6). The reaction did not occur in the absence of silver salt, suggesting the crucial role of silver salt (entry 17). Decreasing the loading of K2S2O8 to 2.0 equivalents resulted in a reduced yield (60%) (entry 18).

Table 1 Optimization of Reaction Conditionsa

Entry

Ag salt

Solvent (v/v)

Oxidant

Temp (°C)

Yield (%)b

 1

AgOAc

MeCN

K2S2O8

50

23

 2

AgOAc

1,4-dioxane

K2S2O8

50

N.R.

 3

AgOAc

THF

K2S2O8

50

N.R.

 4

AgOAc

DMSO

K2S2O8

50

<5

 5

AgOAc

MeCN/H2O (1:1)

K2S2O8

50

19

 6

AgOAc

acetone/H2O (1:1)

K2S2O8

50

60

 7

AgNO3

acetone/H2O (1:1)

K2S2O8

50

50

 8

AgF

acetone/H2O (1:1)

K2S2O8

50

56

 9

Ag2CO3

acetone/H2O (1:1)

K2S2O8

50

44

10

AgOAc

acetone/H2O (1:1)

Na2S2O8

50

53

11

AgOAc

acetone/H2O (1:1)

(NH4)2S2O8

50

57

12

AgOAc

acetone/H2O (1:1)

TBHP

50

N.R.

13

AgOAc

acetone/H2O (1:1)

BQ

50

N.R.

14

AgOAc

acetone/H2O (1:1)

K2S2O8

40

45

15

AgOAc

acetone/H2O (1:1)

K2S2O8

60

54

16

AgOAcc

acetone/H2O (1:1)

K2S2O8

50

77

17

–

acetone/H2O (1:1)

K2S2O8

50

N.R.

18

AgOAcc

acetone/H2O (1:1)

K2S2O8 d

50

60

a Reaction conditions: 1a (0.3 mmol), 2a (0.6 mmol), oxidant (0.9 mmol), solvent (3.0 mL), under air atmosphere; Ad: 1-adamantyl; BQ: 1,4-benzoquinone; TBHP: tert-butyl hydroperoxide.

b Isolated yield. N.R.: No reaction.

c AgOAc used: 30 mol%.

d K2S2O8 (0.6 mmol) was used.

The substrate scope of phenanthridines was next examined under the optimized reaction conditions (Scheme [2]). The substituent effect of 6-tert-butylphenanthridines was investigated first. For 6-tert-butylphenanthridines bearing either electron-donating group (3b) or electron-withdrawing group (3c) at the 2-position, the reaction proceeded smoothly to afford the corresponding products in good yields. However, product 3d was obtained in low yield by using phenanthridine with a 3-methoxy substituent as the reactant. For 8-substituted phenanthridines, electron-withdrawing group favored the reaction with product 3f obtained in 73% yield, while electron-donating group had inferior impact on the reaction with product 3e isolated in a slight low yield.

Zoom Image
Scheme 2 Substrate scope of the reaction. Reagents and conditions: 1 (0.3 mmol), 2 (0.6 mmol), K2S2O8 (0.9 mmol), acetone/H2O (3.0 mL), 50 °C, under air atmosphere. Isolated yields are shown.

These results suggested a profound substituent effect of phenanthridine ring on the reaction. Then, different carboxylic acids were examined. The reaction of 1a with trimethylacetic acid and cyclohexanecarboxylic acid provided the products in low yield due to incomplete conversion of substrates (→ 3g–i). With 1-adamantanecarboxylic acid as the reactant, the reaction of phenanthridine compounds with different substituents at the 6-position were performed. Using 6-adamantylphenanthridine as the substrate led to product 3j in 53% yield. For 6-adamantylphenanthridines containing different substituents at the 2-position, the substrate with electron-donating group gave better yield than that with electron-withdrawing group (3k vs 3l and 3m). The structure of product 3k was unequivocally determined by X-ray crystallographic analysis.[9] However, when using 2-methyl-6-phenylphenanthridine as the substrate, product 3n was isolated in 28% yield. It should be noted that the cases with low yields (3d,e,g–i,l–n) were due to the formation of undetermined side products. Additionally, when 2-phenylacetic acid or 2-methoxypropionic acid was treated with phenanthridine 1a under the optimized reaction conditions, no corresponding product could be isolated.

Because of the fact that 6-substituted phenanthridines could be easily synthesized through an oxidative decarboxylation/cyclization of 2-isocyanobiphenyls with carboxylic acids,[4] we envisioned to develop a one-pot synthesis of 6,9-bis-substituted phenanthridines starting from 2-isocyanobiphenyls and carboxylic acids through a tandem oxidative decarboxylation, cyclization, and decarboxylative alkylation reaction. With this idea in mind, biphenyl isocyanides were treated with 1-adamantanecarboxylic acid by using potassium persulfate as the oxidant, acetone and water as mixed solvents under the effect of 30 mol% silver acetate (Scheme [3]). The reaction indeed proceeded smoothly to furnish 3j in 55% yield. Similarly, 6,9-bis-adamantyl phenanthridines 3k and 3l could be also obtained in 73% and 41% yield, respectively.

Zoom Image
Scheme 3 One-pot synthesis of multi-substituted phenanthridines from biphenyl isocyanides
Zoom Image
Scheme 4 Radical trapping experiment

To understand the mechanism of this reaction, preliminary mechanistic investigation was carried out, as shown in Scheme [4]. The reaction was completely suppressed upon the addition of 2,2,6,6-tetramethylpiperidine-1-oxy (TEMPO) or 2,6-di-tert-butyl-p-cresol (BHT) under the standard conditions, which implied that the reaction may experience a radical pathway. On the basis of the experimental results and the literature precedents,[10] a postulated reaction pathway is tentatively proposed as shown in Scheme [5]. Under the combined action of silver acetate and potassium persulfate, the carboxylic acid undergoes an oxidative decarboxylation to generate an alkyl radical. The alkyl radical regioselectively attacks the C9 position of phenanthridine to form the corresponding free radical intermediate. Then the intermediate is oxidized by Ag(II), generated in situ via the oxidation of Ag(I) by persulfate,[10a] to produce the corresponding carbon cationic intermediate. Finally, the deprotonation affords product 3.

Zoom Image
Scheme 5 Postulated reaction mechanism

In conclusion, we have successfully developed an efficient method for the synthesis of multi-substituted phenanthridine derivatives through a novel decarboxylative C–H alkylation with carboxylic acids. The given method has the advantages of easy availability of starting materials, high regioselectivity, and mild conditions. Furthermore, a one-pot synthesis of multi-substituted phenanthridine derivatives was realized by the reaction of biphenyl isocyanides and carboxylic acid. The protocol may find application in the late-stage modification of phenanthridines. Further studies on the biological applications of multi-substituted phenanthridines and the extension of the substrate scope are currently underway in our laboratory.

All reagents and metal catalysts were obtained from commercial sources without further purification, and commercially available solvents were purified before use. Melting points were taken on a WRS-1A or a WRS-1B Digital Melting Point Apparatus without correction. IR spectra were obtained using an AVATAR 370 FT-IR spectrophotometer. 1H, 13C, and 19F NMR spectra were recorded with a Bruker AV-500 spectrometer operating at 500 MHz, 125 MHz, and 470 MHz, respectively, with chemical shift values being reported in ppm relative to CHCl3 (δ = 7.26) or TMS (δ = 0.00) for 1H NMR; chloroform (δ = 77.16) for 13C NMR; and C6F6 (δ = –164.9) for 19F NMR. Mass spectra (MS) and high-resolution mass spectra (HRMS) were recorded with an Agilent 5975C, Waters Micromass GCT Premier, or JEOL AccuTOF-MS using an electron impact (EI), electrospray ionization (ESI), or direct analysis in real-time (DART) techniques.

The preparation of starting phenanthridines 1 is described in the Supporting Information.


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Oxidative Decarboxylative C–H Alkylation of Phenanthridines with Carboxylic Acids; General Procedure

To a dry test tube was added phenanthridine 1 (0.3 mmol), carboxylic acid 2 (0.6 mmol, 2.0 equiv), K2S2O8 (243 mg, 0.9 mmol, 3.0 equiv), AgOAc (15.0 mg, 0.09 mmol, 0.3 equiv), acetone (1.5 mL), and H2O (1.5 mL). The reaction mixture was stirred at 50 °C under air balloon. Upon completion as monitored by TLC (about 22 h), the mixture was cooled down to r.t. and H2O (5 mL) was added. The mixture was extracted with CH2Cl2 (3 × 10 mL) and the combined organic layers were dried (anhyd Na2SO4). The volatiles were removed under reduced pressure and the residue was purified by flash column chromatography on alkaline aluminum oxide (200–300 mesh) (eluent: PE/CH2Cl2 50:1 to 20:1) to afford product 3.


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9-[(3r,5r,7r)-Adamantan-1-yl]-6-(tert-butyl)phenanthridine (3a)

White solid; yield: 85.2 mg (77%); mp 161–164 °C.

IR (KBr): 2904, 2847, 1614, 1570, 1450, 758 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 8.63 (d, J = 1.8 Hz, 1 H), 8.58 (dd, J = 7.7, 4.0 Hz, 2 H), 8.11 (dd, J = 8.1, 0.8 Hz, 1 H), 7.72–7.67 (m, 2 H), 7.62–7.59 (m, 1 H), 2.20 (s, 3 H), 2.11 (d, J = 2.3 Hz, 6 H), 1.89–1.83 (m, 6 H), 1.74 (s, 9 H).

13C NMR (CDCl3, 125 MHz): δ = 166.47, 152.23, 143.15, 133.94, 130.29, 128.09, 128.01, 126.16, 123.84, 123.70, 122.48, 121.55, 118.36, 43.09, 40.12, 36.84, 36.79, 31.17, 28.93.

ESI-MS (C27H31N): m/z = 369 [M]+.

HRMS (ESI): m/z [M]+ calcd for C27H31N: 369.2456; found: 369.2454.


#

9-[(3r,5r,7r)-Adamantan-1-yl]-6-(tert-butyl)-2-methylphenanthridine (3b)

White solid; yield: 71.2 mg (62%); mp 145–148 °C.

IR (KBr): 2908, 2851, 1617, 1570, 1450, 817, 487 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 8.59 (s, 1 H), 8.55 (d, J = 8.9 Hz, 1 H), 8.33 (s, 1 H), 7.99 (d, J = 8.3 Hz, 1 H), 7.69 (dd, J = 9.0, 2.0 Hz, 1 H), 7.49 (dd, J = 8.3, 1.5 Hz, 1 H), 2.63 (s, 3 H), 2.21 (s, 3 H), 2.11 (d, J = 2.5 Hz, 6 H), 1.89–1.86 (m, 6 H), 1.71 (s, 9 H).

13C NMR (CDCl3, 125 MHz): δ = 165.44, 151.99, 141.44, 135.85, 133.70, 130.03, 129.80, 127.97, 123.62, 123.52, 122.53, 121.09, 118.26, 43.09, 39.97, 36.82, 36.80, 31.18, 28.94, 22.01.

ESI-MS (C28H33N): m/z = 383 [M]+.

HRMS (ESI): m/z [M]+ calcd for C28H33N: 383.2613; found: 383.2637.


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9-[(3r,5r,7r)-Adamantan-1-yl]-6-(tert-butyl)-2-fluorophenanthridine (3c)

White solid; yield: 80.1 mg (69%); mp 127–131 °C.

IR (KBr): 2904, 2851, 2654, 1616, 1571, 1191, 812 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 8.58 (d, J = 9.0 Hz, 1 H), 8.47 (s, 1 H), 8.18 (dd, J =10.3, 2.5 Hz, 1 H), 8.10 (dd, J = 8.9, 5.8 Hz, 1 H), 7.74 (dd, J = 8.9, 1.5 Hz, 1 H), 7.41 (td, J = 8.6, 2.3 Hz, 1 H), 2.20 (s, 3 H), 2.10 (s, 6 H), 1.89–1.83 (m, 6 H), 1.72 (s, 9 H).

13C NMR (CDCl3, 125 MHz): δ = 165.69, 161.99, 160.05, 152.40, 139.96, 133.42 (d, J = 3.8 Hz), 132.40 (d, J = 8.8 Hz), 128.07, 125.07 (d, J = 8.8 Hz), 124.39, 122.50, 118.55, 116.82 (d, J = 23.8 Hz), 106.45 (d, J = 23.8 Hz), 43.06, 40.05, 36.83, 36.75, 31.12, 28.90.

19F NMR (CDCl3, 470 MHz): δ = –114.39 to –114.44 (m).

ESI-MS (C27H30FN): m/z = 387 [M]+.

HRMS (ESI): m/z [M]+ calcd for C27H30FN: 387.2362; found: 387.2387.


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9-[(3r,5r,7r)-Adamantan-1-yl]-6-(tert-butyl)-3-methoxyphenanthridine (3d)

White solid; yield: 38.3 mg (32%); mp 198–200 °C.

IR (KBr): 2910, 2847, 1615, 1459, 1215, 1036, 825 cm–1.

H NMR (CDCl3, 500 MHz): δ = 8.54 (d, J = 9.0 Hz, 1 H), 8.51 (s, 1 H), 8.47 (d, J = 9.0 Hz, 1 H), 7.63 (dd, J = 8.8, 1.4 Hz, 1 H), 7.52 (d, J = 7.4 Hz, 1 H), 7.24 (dd, J = 9.2, 2.5 Hz, 1 H), 4.00 (s, 3 H), 2.19 (s, 3 H), 2.10 (s, 6 H), 1.88–1.82 (m, 6 H), 1.73 (s, 9 H).

13C NMR (CDCl3, 125 MHz): δ = 167.15, 159.76, 152.28, 144.69, 134.18, 128.03, 122.84, 122.68, 121.58, 117.93, 117.85, 117.30, 109.90, 55.53, 43.06, 40.11, 36.82, 36.80, 31.21, 28.93.

ESI-MS (C28H33NO): m/z = 399 [M]+.

HRMS (ESI): m/z [M]+ calcd for C28H33NO: 399.2562; found: 399.255.


#

9-[(3r,5r,7r)-Adamantan-1-yl]-6-(tert-butyl)-8-methoxyphenanthridine (3e)

White solid: yield: 38.3 mg (32%); mp 219–221 °C.

IR (KBr): 2959, 1718, 1483, 1225, 1178, 1152, 1021, 758, 738 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 8.50 (d, J = 3.9 Hz, 1 H), 8.48 (s, 1 H), 8.08 (d, J = 8.3 Hz, 1 H), 7.92 (s, 1 H), 7.63–7.56 (m, 2 H), 4.04 (s, 3 H), 2.27 (s, 6 H), 2.16 (s, 3 H), 1.85–1.82 (m, 6 H), 1.74 (s, 9 H).

13C NMR (CDCl3, 125 MHz): δ = 165.22, 157.09, 142.40, 142.19, 130.24, 127.94, 127.10, 126.24, 123.89, 123.65, 121.08, 120.82, 108.49, 55.04, 40.55, 39.87, 37.90, 37.11, 30.91, 29.04.

HRMS (DART): m/z [M + H]+ calcd for C28H34NO: 400.2635; found: 400.2633.


#

9-[(3r,5r,7r)-Adamantan-1-yl]-6-(tert-butyl)-8-fluorophenanthridine (3f)

White solid; yield: 84.8 mg (73%); mp 92–95 °C.

IR (KBr): 2904, 2853, 1573, 1474, 1143, 756 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 8.55 (d, J = 8.4 Hz, 1 H), 8.51 (d, J = 7.8 Hz, 1 H), 8.17 (d, J = 15.6 Hz, 1 H), 8.12 (dd, J = 8.1, 5.8 Hz, 1 H), 7.67 (td, J = 7.1, 1.1 Hz, 1 H), 7.60 (td, J = 8.2, 1.1 Hz, 1 H), 2.23 (s, 6 H), 2.20 (s, 3 H), 1.89–1.87 (m, 6 H), 1.72 (s, 9 H).

13C NMR (CDCl3, 125 MHz): δ = 165.51 (d, J = 3.8 Hz), 161.17, 159.18, 142.77, 140.58 (d, J = 12.5 Hz), 130.47 (d, J = 5.0 Hz), 127.96, 126.57, 123.63 (d, J = 8.8 Hz), 123.37, 121.57 (d, J = 7.5 Hz), 121.33, 114.10 (d, J = 26.3 Hz), 41.07 (d, J = 3.8 Hz), 40.08, 37.27 (d, J = 2.5 Hz), 36.85, 30.95, 28.84.

19F NMR (CDCl3, 470 MHz): δ = –109.61 to –109.66 (m).

ESI-MS (C27H30FN): m/z = 387 [M]+.

HRMS (ESI): m/z [M]+ calcd for C27H30FN: 387.2362; found: 387.2366.


#

6,9-Di-tert-butylphenanthridine (3g)

White solid; yield: 24.9 mg (29%); mp 119–121 °C.

IR (KBr): 2962, 1618, 1571, 1259, 1087, 1015, 795, 757 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 8.66 (s, 1 H), 8.56 (d, J = 8.6 Hz, 2 H), 8.10 (d, J = 8.0 Hz, 1 H), 7.72–7.66 (m, 2 H), 7.61 (t, J = 7.3 Hz, 1 H), 1.72 (s, 9 H), 1.50 (s, 9 H).

13C NMR (CDCl3, 125 MHz): δ = 166.45, 152.13, 143.17, 133.87, 130.29, 128.14, 128.03, 126.19, 124.25, 123.74, 122.38, 121.50, 118.50, 40.10, 35.30, 31.26, 31.15.

HRMS (DART): m/z [M + H]+ calcd for C21H26N: 292.2059; found: 292.2063.


#

6,9-Di-tert-butyl-2-methylphenanthridine (3h)

Colorless oil; yield: 30.1 mg (33%).

IR (KBr): 2960, 2919, 1616, 1573, 1459, 1260, 1022, 819, 797 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 8.63 (s, 1 H), 8.54 (d, J = 8.9 Hz, 1 H), 8.31 (s, 1 H), 7.98 (d, J = 8.3 Hz, 1 H), 7.69 (d, J = 8.8 Hz, 1 H), 7.49 (d, J = 8.1 Hz, 1 H), 2.63 (s, 3 H), 1.71 (s, 9 H), 1.51 (s, 9 H).

13C NMR (CDCl3, 125 MHz): δ = 165.42, 151.88, 141.47, 135.88, 133.63, 130.03, 129.84, 127.98, 124.06, 123.52, 122.43, 121.06, 118.42, 39.96, 35.29, 31.30, 31.16, 22.00.

HRMS (DART): m/z [M + H]+ calcd for C22H28N: 306.2216; found: 306.2217.


#

6-(tert-Butyl)-9-cyclohexylphenanthridine (3i)

White solid; yield: 33.3 mg (35%); mp 105–107 °C.

IR (KBr): 2922, 2852, 1713, 1569, 1449, 1356, 761 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 8.54 (d, J = 8.6 Hz, 2 H), 8.49 (s, 1 H), 8.09 (d, J = 8.1 Hz, 1 H), 7.67 (t, J = 7.1 Hz, 1 H), 7.59 (t, J = 7.4 Hz, 1 H), 7.51 (d, J = 8.5 Hz, 1 H), 2.81–2.76 (m, 1 H), 2.02 (d, J = 11.4 Hz, 2 H), 1.93 (d, J = 12.8 Hz, 2 H), 1.83 (d, J = 13.4 Hz, 1 H), 1.72 (s, 9 H), 1.64–1.57 (m, 2 H), 1.53–1.45 (q, J = 12.8 Hz, 2 H), 1.38–1.33 (m, 1 H).

13C NMR (CDCl3, 125 MHz): δ = 166.54, 149.16, 143.11, 134.19, 130.24, 128.25, 128.15, 126.16, 125.49, 123.57, 122.80, 121.59, 120.34, 53.44, 45.00, 40.11, 34.38, 31.18, 26.88, 26.16.

ESI-MS (C23H27N): m/z = 317 [M]+.

HRMS (ESI): m/z [M]+ calcd for C23H27N: 317.2143; found: 317.2123.


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6,9-Di-[(3r,5r,7r)-adamantan-1-yl]phenanthridine (3j)

White solid; yield: 71.4 mg (53%); mp 139–141 °C.

IR (KBr): 2900, 2847, 1619, 1570, 1452, 1100, 805, 748, 727 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 8.80 (d, J = 9.0 Hz, 1 H), 8.62 (s, 1 H), 8.56 (d, J = 8.1 Hz, 1 H), 8.09 (d, J = 8.1 Hz, 1 H), 7.71–7.65 (m, 2 H), 7.59 (t, J = 8.0 Hz, 1 H), 2.48 (s, 6 H), 2.21 (d, J = 16.8 Hz, 6 H), 2.10 (s, 6 H), 1.94–1.82 (m, 12 H).

13C NMR (CDCl3, 125 MHz): δ = 165.90, 152.10, 143.35, 134.02, 130.26, 128.09, 127.76, 126.15, 123.73, 123.50, 122.61, 121.57, 118.48, 43.08, 42.90, 42.05, 37.29, 36.83, 36.81, 29.31, 28.95.

HRMS (DART): m/z [M + H]+ calcd for C33H38N: 448.2998; found: 448.3002.


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6,9-Di-[(3r,5r,7r)-adamantan-1-yl]-2-methylphenanthridine (3k)

White solid; yield: 83.8 mg (60%); mp 285–286 °C.

IR (KBr): 2900, 2847, 1617, 1447, 1350, 809, 757, 556 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 8.78 (d, J = 9.0 Hz, 1 H), 8.58 (s, 1 H), 8.32 (s, 1 H), 7.98 (d, J = 8.2 Hz, 1 H), 7.68 (dd, J = 9.0, 1.9 Hz, 1 H), 7.49 (dd, J = 8.3, 1.4 Hz, 1 H), 2.63 (s, 3 H), 2.47 (d, J = 1.8 Hz, 6 H), 2.20 (d, J = 10.3 Hz, 6 H), 2.10 (d, J = 2.3 Hz, 6 H), 1.94–1.83 (m, 12 H).

13C NMR (CDCl3, 125 MHz): δ = 164.88, 151.85, 141.63, 135.83, 133.75, 129.98, 129.79, 127.69, 123.47, 123.31, 122.64, 121.10, 118.34, 43.07, 42.72, 42.01, 37.27, 36.80, 29.29, 28.93, 22.02.

ESI-MS (C34H39N): m/z = 461 [M]+.

HRMS (ESI): m/z [M]+ calcd for C34H39N: 461.3083; found: 461.3107.


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6,9-Di-[(3r,5r,7r)-adamantan-1-yl]-2-fluorophenanthridine (3l)

White solid; yield: 41 mg (29%); mp 251–253 °C.

IR (KBr): 2908, 2884, 1621, 1568, 1497, 1211, 846, 812, 785 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 8.80 (d, J = 9.5 Hz, 1 H), 8.45 (s, 1 H), 8.15 (dd, J = 10.5, 2.2 Hz, 1 H), 8.07 (dd, J = 8.9, 5.8 Hz, 1 H), 7.73 (d, J = 8.9 Hz, 1 H), 7.40 (td, J = 8.6, 2.5 Hz, 1 H), 2.46 (s, 6 H), 2.21 (d, J = 13.0 Hz, 6 H), 2.09 (s, 6 H), 1.94–1.82 (m, 12 H).

13C NMR (CDCl3, 125 MHz): δ = 165.11, 161.79 (d, J = 202.5 Hz), 152.25, 140.15, 133.46, 132.35 (d, J = 7.5 Hz), 127.79, 124.94, 124.15, 122.58, 118.60, 116.88 (d, J = 20.0 Hz), 106.50 (d, J = 18.7 Hz), 43.04, 42.80, 41.99, 37.23, 36.82, 36.75, 29.24, 28.89.

19F NMR (CDCl3, 470 MHz): δ = –114.45 to –114.50 (m).

HRMS (DART): m/z [M + H]+ calcd for C33H37FN: 466.2904; found: 466.2906.


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6,9-Di-[(3r,5r,7r)-adamantan-1-yl]-8-fluorophenanthridine (3m)

White solid: yield: 50.2 mg (36%); mp 229–231 °C.

IR (KBr): 2901, 2846, 1486, 1421, 1202, 1154, 846, 712, 677 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 8.54 (d, J = 8.4 Hz, 1 H), 8.49 (d, J = 8.1 Hz, 1 H), 8.37 (d, J = 15.9 Hz, 1 H), 8.10 (d, J = 8.0 Hz, 1 H), 7.66 (t, J = 7.3 Hz, 1 H), 7.59 (t, J = 7.6 Hz, 1 H), 2.45 (s, 6 H), 2.22 (s, 6 H), 2.19 (s, 6 H), 1.95–1.87 (m, 12 H).

13C NMR (CDCl3, 125 MHz): δ = 164.93, 160.91, 158.93, 142.93, 140.45 (d, J = 12.5 Hz), 130.46 (d, J = 18.8 Hz), 127.94, 126.53, 123.65 (d, J = 8.8 Hz), 123.22, 121.62 (d, J = 6.3 Hz), 121.33, 113.88 (d, J = 27.5 Hz), 42.82, 41.80, 41.05 (d, J = 3.8 Hz), 37.25 (d, J = 3.8 Hz), 37.18, 36.83, 29.17, 28.82.

19F NMR (CDCl3, 470 MHz): δ = –109.61 to –109.66 (m).

HRMS (DART): m/z [M + H]+ calcd for C33H37FN: 466.2904; found: 466.2907.


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9-[(3r,5r,7r)-Adamantan-1-yl)-2-methyl-6-phenylphenanthridine (3n)

White solid; yield: 33.9 mg (28%); mp 168–169 °C.

IR (KBr): 2908, 2894, 1614, 1563, 1447, 1275, 959, 827, 766, 718, 697 cm–1.

1H NMR (CDCl3, 500 MHz): δ = 8.61 (s, 1 H), 8.42 (s, 1 H), 8.12 (d, J = 8.3 Hz, 1 H), 8.03 (d, J = 8.7 Hz, 1 H), 7.73 (d, J = 7.0 Hz, 2 H), 7.66 (d, J = 8.7 Hz, 1 H), 7.57–7.49 (m, 4 H), 2.67 (s, 3 H), 2.20 (s, 3 H), 2.11 (s, 6 H), 1.89–1.83 (m, 6 H).

13C NMR (CDCl3, 125 MHz): δ = 160.04, 153.65, 142.32, 140.09, 136.49, 133.08, 130.31, 130.12, 129.75, 128.55, 128.49, 128.36, 124.81, 123.95, 123.49, 121.39, 117.57, 43.13, 37.06, 36.75, 28.92, 22.04.

HRMS (DART): m/z [M + H]+ calcd for C30H30N: 404.2373; found: 404.2375.


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One-Pot Synthesis of Multi-Substituted Phenanthridines 3j–l from Biphenyl Isocyanides; General Procedure

To a dry test tube was added the respective biphenyl isocyanide (0.2 mmol), carboxylic acid 2 (1.0 mmol, 5.0 equiv), K2S2O8 (162 mg, 0.6 mmol, 3.0 equiv), AgOAc (10.0 mg, 0.06 mmol, 0.3 equiv), acetone (1.0 mL), and H2O (1.0 mL). The reaction mixture was stirred at 70 °C under air balloon. Upon completion as monitored by TLC (about 22 h), the mixture was cooled down to r.t. and H2O (5 mL) was added to the mixture. The mixture was extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried (anhyd Na2SO4), and the volatiles were removed under reduced pressure. The residue was purified by flash column chromatography on alkaline aluminum oxide (200–300 mesh) (eluent: PE/CH2Cl2 50:1 to 20:1) to afford product 3.

3j: Yield: 49.4 mg (55%).

3k: Yield: 67.8 mg (73%).

3l: Yield: 38.2 mg (41%).


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Acknowledgment

The authors thank Prof. Bingxin Liu and Prof. Qitao Tan for their helpful discussion, and Prof. Hongmei Deng (Laboratory for Microstructures, SHU) for NMR spectroscopic measurements.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0039-1690220.
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Scheme 1 Typical approaches to phenanthridines
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Scheme 2 Substrate scope of the reaction. Reagents and conditions: 1 (0.3 mmol), 2 (0.6 mmol), K2S2O8 (0.9 mmol), acetone/H2O (3.0 mL), 50 °C, under air atmosphere. Isolated yields are shown.
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Scheme 3 One-pot synthesis of multi-substituted phenanthridines from biphenyl isocyanides
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Scheme 4 Radical trapping experiment
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Scheme 5 Postulated reaction mechanism