Preparation of Phenanthridines from o-Cyanobiaryls via Addition of

Article Cite This: J. Org. Chem. 2018, 83, 11080−11088

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Preparation of Phenanthridines from o‑Cyanobiaryls via Addition of Organic Lithiums to Nitriles and Imino Radical Cyclization with Iodine Atsushi Kishi,† Katsuhiko Moriyama,†,‡ and Hideo Togo*,† †

Graduate School of Science and ‡Molecular Chirality Research Center, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan

J. Org. Chem. 2018.83:11080-11088. Downloaded from pubs.acs.org by UNIV OF SOUTH DAKOTA on 09/21/18. For personal use only.

S Supporting Information *

ABSTRACT: Simple treatment of 2-cyanobiaryls with methyllithium, ethylmagnesium bromide, butyllithium, phenyllithium, p-methylphenyllithium, etc., followed by the reaction with water and then with molecular iodine at 60 °C provided efficiently 6methyl-, 6-ethyl-, 6-butyl-, 6-phenyl, 6-(p-methylphenyl)phenanthridines, etc., in good yields, respectively. Here, imines formed through the addition of carbanion onto the nitriles reacted with molecular iodine to form N-iodoimines smoothly, and their warming treatment induced the formation of imino radicals that smoothly cyclized onto the aryl group to give 6-alkyl- and 6-arylphenanthridines.

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INTRODUCTION Phenanthridine is an important nitrogen-containing heteroaromatic base that is found in some natural products and biologically active alkaloids bearing antibacterial and antitumoral properties, functional materials, and pharmaceuticals.1 In addition, it is well-known that phenanthridines and bisphenanthridines exhibit strong affinity for DNA through intercalation because of their having pH-induced positive charge, high polarizability, and high electron affinity, as shown in Figure 1.2

Scheme 1. Construction of Phenanthridine Core

Figure 1. Phenanthridines having specific binding ability to DNA.

(trifluoromethyl)phenanthridines from 2-isocyanobiaryls with Togni reagent5a and with TMSCF3 and PhI(OAc)2 (DIB)5b and the preparation of 6-alkylphenanthridines or 6-arylphenanthridines from 2-isocyanobiaryls with BPO in CCl4,5c with PhSO 2 CF 2 H, DIB, and t-BuONa 5d and with azobis(isobutyronitrile) (AIBN).5e As photochemical methods, the preparation of 6-alkylphenanthridines or 6-arylphenanthridines from 2-isocyanobiaryls with α-bromoacetate ester and facIr(ppy)3,6a with ArSO2Cl and Eosin Y,6b with THF, TBHP, and [Ru(bpy)3]Cl2,6c with NH2NHCO2R, Eosin Y, and TBHP,6d with RfI and N,N,N′,N′-tetra(ethyl)-

Naturally occurring benz[c]phenanthridines and their Nmethylammonium salts also exhibit biological activities, such as antitumor activity.3 Therefore, synthetic studies of the phenanthridine core have been carried out extensively. Under transition-metal-free conditions, the reductive construction of phenanthridines from o-(o′-nitrophenyl)benzaldehydes with zinc in acetic acid under refluxing conditions4a and the preparation of 6-alkylphenanthridines by the condensation of o-aminobiphenyl with cyclic ketones/ aza-triene electrocyclization/ring fisson at 250−300 °C4b were reported. As the most popular method, the radical-mediated cyclization of 2-isocyanobiaryls via imino carbon-centered radical (Scheme 1, eq 1) has been extensively studied, and some examples are as follows: the preparation of 6© 2018 American Chemical Society

Received: July 4, 2018 Published: August 17, 2018 11080

DOI: 10.1021/acs.joc.8b01688 J. Org. Chem. 2018, 83, 11080−11088

The Journal of Organic Chemistry

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ethylenediamine,6e and with ArBr and N,N-di(isopropyl)ethylamine6f was also reported. As examples of transitionmetal-catalyzed formation of 6-substituted phenanthridines from 2-isocyanobiaryls, the reactions with ArB(OH)2 and Mn(acac)2,7a with ArCHO, TBHP, and FeCl3,7b with ether, TBHP, and Fe(acac)2,7c with R2P(=O)H and Mn(OAc)2,7d and with RCO2H, K2S2O8, and Ag2CO3,7e are known. Most of those reactions5−7 proceed via the formation of imino carboncentered radicals and their cyclization onto the aromatic ring, as shown in Scheme 1 (eq 1). Other methods for the preparation of the phenanthridine core are as follows: the preparation of 6-phenylphenanthridines from benzophenone O-aroyl oximes, O-(trimethylsilyl)phenyl triflate, and [{(allyl)PdCl}2];8a the preparation of phenanthridines from N-aryl-(2-iodobenzyl)amines under irradiation with Hg-lamp; 8b the preparation of 6-(t-butylamino)phenanthridines from 2-aminobiaryls, t-BuNC, and Co(acac)2;8c the preparation of phenanthridines from 2bromobenzyl bromide, N-aryl methanesulfonamides, and Pd(O2CCF3)2;8d the preparation of 6-thioarylphenanthridines from 2-biaryl isothiocyanates, diaryliodonium salts, and CuCl;8e the preparation of 9-acylphenanthridines from 1,5diyne-3-enes, 2-alkynylanilines, PdCl2, and CuI;8f and the electrosynthesis of phenanthridines from biaryl-2-carboaldehydes and ammonia.8g On the other hand, synthetic studies of phenanthridine via imino nitrogen-centered radical (Scheme 1, eq 2) are extremely limited.9 Typically, the cascade formation of the phenanthridine core from N-(2-cyano-[1,1′-biaryl-3-yl]-Nmethylmethacrylamide with α-bromoacetonitrile in the presence of fac-Ir(ppy)3 through the addition of a cyanomethyl radical to the olefinic group,9f and with trifluoromethanesulfonyl chloride in the presence of Ru(phen)2Cl2 through the addition of a trifluoromethyl radical to the olefinic group,9g both of which are followed by 6-endo-trig cyclization of the formed carbon-centered radicals onto the nitrile groups and then the cyclization of the formed imino nitrogen-centered radicals onto the phenyl rings under visible-light irradiation conditions, respectively, was reported very recently. As a related reaction to that shown in eq 2, the preparation of phenanthridines by the visible-light irradiation of biaryl-2carboaldehyde O-aroyl oximes in the presence of fac-Ir(ppy)3 through N−O bond cleavage and formation of the imino nitrogen-centered radical, followed by the cyclization onto the aromatic ring, was reported.10 With regard to the synthesis of 6-aryl- and 6-alkylphenanthridines from 2-cyanobiaryls, the reactions of 2-bromo-2′cyanobiaryls with RMgBr in the presence of Cu2O at 100 °C via an intramolecular coupling reaction on copper atom between imino nitrogen and C−Br groups11a and with LiEt3BH at 100 °C via a SNAr pathway onto the bromoaryl group by the formed imino anion group11b were also reported. Thus, to the best of our knowledge, the synthesis of phenanthridines from 2-cyanobiaryls based on eq 2 has been little studied. Here, we would like to report a simple preparation of 6-alkyl- and 6-arylphenanthridines from 2cyanobiaryls with alkyllithiums or aryllithiums, followed by the reaction with water and then molecular iodine through the formation of imino nitrogen-centered radical and its cyclization onto the aromatic ring based on eq 2 under transition-metalfree conditions.

RESULTS AND DISCUSSION First, to research the chemical behavior of imines with iodines based on our synthetic studies of molecular iodine and related iodine reagents, such as N-iodosuccinimide (NIS) and 1,3diiodo-5,5-dimethylhydantoin (DIH),12 phenylimine 1Ad (1.0 mmol), which was prepared from the reaction of 2-cyano-4′methylbiphenyl 2A with PhLi, was treated with NIS (1.1 equiv) in 1,2-dichloroethane (DCE, 4.0 mL) under irradiation with a tungsten lamp (200 W) for 1 h to give 3-methyl-6phenylphenanthridine 3Ad in 37% yield together with recovered imine 1Ad in 51% yield, as shown in Table 1 Table 1. Optimization for Reaction Conditions from Imines 1A to Phenanthridines 3A

time (h)

entry

1

reagent

solvent

condition

yield (%)

1

1Ad

DCE

1

W-hva

2

″

DCE

1

W-hva

37 (51)b (3Ad) 56 (3Ad)

3

″

THF

1

W-hva

77 (3Ad)

4

″

CH3CN

1

a

W-hv

54 (3Ad)

5

″

benzene

1

W-hva

50 (3Ad)

6

″

dioxane

1

W-hva

74 (3Ad)

7

″

ether

1

W-hva

55 (3Ad)

THF

1

a

W-hv

71 (3Aa)

THF

1

W-hva

68 (3Ab)

THF

1

W-hva

85 (3Ae)

THF

1

60 °C

80 (3Ad)

THF

1

60 °C

80 (3Ad)

THF

5

60 °C

31 (3Ad)

5 3.5

60 °C 60 °C

88 (3Ad) 79 (3Ad)

1.5

60 °C

95 (3Ad)

8

1Aa

9

1Ab

10

1Ae

11

1Ad

12

″

13

″

14 15

″ ″

NIS (1.1 equiv) NIS (2.1 equiv) NIS (2.1 equiv) NIS (2.1 equiv) NIS (2.1 equiv) NIS (2.1 equiv) NIS (2.1 equiv) NIS (2.1 equiv) NIS (2.1 equiv) NIS (2.1 equiv) NIS (2.1 equiv) DIH (1.1 equiv) I2 (1.5 equiv) I2, K2CO3c I2, K2CO3b

16

″

I2, K2CO3b

THF THF:H2 O = 9:1 THF:H2 O = 1:1

The mixture was irradiated with a tungsten lamp (200 W) at 30 °C for 1 h. b1Ad was recovered. cI2 (1.5 equiv) and K2CO3 (3.0 equiv) were used. a

(entry 1). When phenylimine 1Ad was treated with NIS (2.1 equiv) under the same conditions, the yield of phenanthridine 3Ad was increased to 56% (entry 2). When the solvent was changed from DCE to THF, acetonitrile, benzene, 1,4-dioxane, and diethyl ether under the same conditions, THF showed the best result, giving phenanthridine 3Ad in 77% yield (entry 3 in entries 3−7). Then, methylimine 1Aa, ethylimine 1Ab, and p11081


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The Journal of Organic Chemistry methylphenylimine 1Ae were treated with NIS (2.1 equiv) using the same conditions as those in entry 3 to provide 3,6dimethylphenanthridine 3Aa, 6-ethyl-3-methylphenanthridine 3Ab, and 3-methyl-6-(4′-methylphenyl)phenanthridine 3Ae in 71%, 68%, and 85% yields, respectively (entries 8−10). On the other hand, when the reaction of phenylimine 1Ad with NIS (2.1 equiv) in THF was carried out at 60 °C for 1 h instead of the irradiation with a tungsten lamp (200 W), the yield of 3methyl-6-phenylphenanthridine 3Ad was slightly increased to 80% (entry 11 and entry 3). Thus, warming conditions at 60 °C were better than irradiation conditions at room temperature. When DIH (1.1 equiv) was used instead of NIS (2.1 equiv), 3-methyl-6-phenylphenanthridine 3Ad was obtained in 80% yield (entry 12). However, NIS and DIH were rather expensive, and therefore, the cyclization of phenylimine 1Ad with molecular iodine was studied. Treatment of phenylimine 1Ad with I2 (1.5 equiv) in THF at 60 °C for 5 h gave 3methyl-6-phenylphenanthridine 3Ad in 31% yield together with the recovery of starting phenylimine 1Aa (entry 13). When the oxidative cyclization of phenylimine 1Ad was carried out in the presence of I2 (1.5 equiv) and K2CO3 (3.0 equiv) in THF at 60 °C for 5 h, the yield of 3-methyl-6-phenylphenanthridine 3Ad was increased to 88% (entry 14). Moreover, the reaction of phenylimine 1Ad (1.0 mmol) with I2 (1.5 equiv) and K2CO3 (3.0 equiv) was carried out in a 9:1 mixture (4.0 mL) of THF and water at 60 °C, and a 1:1 mixture (4.0 mL) of THF and water at 60 °C, 3-methyl-6phenylphenanthridine 3Ad was obtained in 79% and 95% yields, respectively (entries 15, 16). Thus, the treatment of phenylimine 1Ad (1.0 mmol) with I2 (1.5 equiv) and K2CO3 (3.0 equiv) in a 1:1 mixture (4.0 mL) of THF and water at 60 °C for 1.5 h gave 3-methyl-6-phenylphenanthridine 3Ad in the best yield (entry 16). The structure of 3-methyl-6-phenylphenanthridine 3Ad was supported by X-ray crystallographic analysis, as shown in Table 1. Based on those results, the direct transformation of 2-cyano4′-methylbiphenyl 2A (1.0 mmol) into 3-methyl-6-phenylphenanthridine 3Ad was carried out by the reaction with PhLi, followed by the reaction with water, and then with I2 (1.5 equiv) and K2CO3 (3.0 equiv) in a 1:1 mixture of THF (4.0 mL) and water (4.0 mL) at 60 °C for 2 h to give 3-methyl-6phenylphenanthridine 3Ad in 96% yield, as shown in Table 2 (entry 1). As a gram-scale experiment, the treatment of compound 2A (6.0 mmol) under the same procedure and conditions provided compound 3Ad in 98% yield, as shown in Table 2 (entry 1). When the present reaction with 2A was carried out in the presence of 2,6-di-t-butyl-p-cresol (BHT, 3.0 equiv) and 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxy radical (4-hydroxy-TEMPO, 3.0 equiv) at the third step under the same procedure and conditions, the yield of 3-methyl-6phenylphenanthridine 3Ad was 0% and 32% together with phenylimine 1Ad in 58% yield, respectively (entries 2, 3). Here, 3 equiv each of BHT and 4-hydroxy-TEMPO were used to retard the rapid intramolecular cyclization of the imino group to the p-methylphenyl group to form phenanthridine 3Ad. Thus, these results indicate that the third reaction step for the construction of phenanthridine 3Ad from phenylimine 1Ad with I2 is a radical-mediated reaction. Practically, the formation of N-iodophenylimine 1Ad-I was observed by the reaction of phenylimine 1Ad and NIS, and the thermal treatment of N-iodophenylimine 1Ad-I at 60 °C in THF gave 3-methyl-6-phenylphenanthridine 3Ad in 77% yield.

Table 2. Transformation of Nitrile 2A to 6Phenylphenanthridine 3Ad

entry

reagents

additive

yield (%)

1 2 3 4 5

I2, K2CO3a I2, K2CO3a I2, K2CO3a NBSb NCSc

BHT (3.0 equiv) 4-OH-TEMPO (3.0 equiv) -

96 (98d) 0 32 (58e) 0 (85f) 0 (49g)

a

l2 (1.5 equiv) and K2CO3 (3.0 equiv) were used. bNBS (2.1 equiv) was used. cNCS (2.1 equiv) was used. dReaction was carried out with 2A (6.0 mmol). e Yield of phenylimine 1Ad. f Yield of Nbromophenylimine. gYield of N-chlorophenylimine.

On the other hand, when the present reactions of 2A with N-bromosuccinimide (NBS) and N-chlorosuccinimide (NCS) instead of NIS at the third step were carried out under the same procedure and conditions, phenanthridine 3Ad was not obtained at all in both reactions, and N-bromophenylimine 1Ad-Br and N-chlorophenylimine 1Ad-Cl were obtained in 85% and 49% yields, respectively, together with hydrolyzed 2benzoyl-4′-methylbiphenyl after quenching with aq. Na2SO3. Here, the same treatment of phenylimine 1Ad with NBS and NCS generated N-bromophenylimine 1Ad-Br and N-chlorophenylimine 1Ad-Cl in quantitative yields, respectively. However, the same thermal treatment of 1Ad-Br and 1AdCl at 60 °C in THF did not generate 3-methyl-6-phenylphenanthridine 3Ad at all. Based on those results, the one-pot transformation of 2cyano-4′-methylbiphenyl 2A (1.0 mmol) with methyllithium (a), ethylmagnesium bromide (b), n-butyllithium (c), phenyllithium (d), p-methylphenyllithium (e), p-methoxyphenyllithium (f), and p-chlorophenyllithium (g) at 0 °C in THF (4.0 mL, first step), and the addition of water (4.0 mL) (second step), and the reaction with I2 (1.5 equiv) and K2CO3 (3.0 equiv) at 60 °C for 2 h (third step) were carried out to give 3,6-dimethylphenanthridine 3Aa, 6-ethyl-3-methylphenanthridine 3Ab, 6-butyl-3-methylphenanthridine 3Ac, 3-methyl6-phenylphenanthridine 3Ad, 3-methyl-6-(4′-methylphenyl)phenanthridine 3Ae, 6-(4′-methoxyphenyl)-3-methylphenanthridine 3Af, and 6-(4′-chlorophenyl)-3-methylphenanthridine 3Ag in good yields, respectively, as shown in Scheme 2. Similarly, the same treatment of 2-cyanobiaryls 2 (1.0 mmol), such as 2-cyanobiphenyl 2B, 2-cyano-4′-methoxybiphenyl 2C, and 4′-chloro-2-cyanobiphenyl 2D, with methyllithium (a), ethylmagnesium bromide (b), n-butyllithium (c), phenyllithium (d), p-methylphenyllithium (e), p-methoxyphenyllithium (f), and p-chlorophenyllithium (g) at 0 °C in THF (first step), the addition of water (4.0 mL) (second step), and the reaction with I2 (1.5 equiv) and K2CO3 (3.0 equiv) at 60 °C for 2 h (third step) were carried out to give 6-substituted phenanthridines 3Ba−3Bg, 6-substituted 3-methoxyphenanthridines 3Ca−3Cg, and 6-substituted 3-chlorophenanthridines 3Da−3Dg in good yields, respectively (Scheme 2). 2Cyano-3′-methylbiphenyl 2E could be also used under the 11082


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(second step), such as benzonitrile, p-methylbenzonitrile, pmethoxybenzonitrile, p-chlorobenzonitrile, p-bromobenzonitrile, isobutyronitrile, cyclohexanecarbonitrile, and pivalonitrile, followed by quenching with water (4 mL, third step) and the reaction with I2 (1.5 equiv) and K2CO3 (3.0 equiv) at 60 °C for 2 h (4th step) gave 6-phenylphenanthridine (3Bd), 6-(4′methylphenyl)phenanthridine (3Be), 6-(4′-methoxyphenyl)phenanthridine (3Bf), 6-(4′-chlorophenyl)phenanthridine (3Bg), 6-[4′-bromophenyl]phenanthridine (3Bh), 6-isopropylphenanthridine (3Bi), and 6-cyclohexylphenanthridine (3Bj) in good to moderate yields, respectively, as shown in Scheme 3. However, when pivalonitrile was used under the

Scheme 2. Scope for Transformation of 2-Cyanobiaryls 2 to Phenanthridines 3

Scheme 3. Preparation of Phenanthridines 3B from 2Bromobiphenyl 4B

an

BuLi (1.1 equiv) was used. bYield of 2-cyanobiphenyl.

same procedure and conditions, 6-t-butylphenanthridine (3Bk) was not obtained at all, and instead 2-cyanobiphenyl was obtained in 79% yield. A possible reaction pathway for the present one-pot preparation of phenanthridines 3 from 2-cyanobiaryls 2 is shown in Scheme 4. 2-Cyanobiaryl 2 reacts with alkyllithium Scheme 4. Possible Reaction Pathway

a

C2H5MgBr was used instead of C2H5Li. NIS (2.1 equiv) was used instead of I2 and K2CO3. The mixture was irradiated with a tungsten lamp (200 W) at 30 °C for 1 h. b2-Cyano-3′-methylbiphenyl 2E was used.

or aryllithium to form an imino anion that is converted into imine 1 by quenching with water. Treatment of imine 1 with I2 in the presence of K2CO3 gives N-iodoimine I that smoothly generates reactive imino nitrogen-centered radical II. Once imino nitrogen-centered radical II is formed, it rapidly cyclizes onto the aromatic ring to form stabilized radical III that would be smoothly oxidized to phenanthridine 3 by I2. Practically, Niodoimine 1Ad-I could be observed by the reaction of phenylimine 1Ad and NIS, and the thermal treatment of N-

same procedure and conditions to form 4-methyl-6-phenylphenanthridine 3Ed in 67% yield (Scheme 2). On the other hand, the one-pot treatment of 2bromobiphenyl 4B with n-butyllithium (first step) and nitriles 11083


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The Journal of Organic Chemistry iodoimine 1Ad-I at 60 °C generated phenanthridine 3Ad. In addition, the present cyclization was completely retarded by the addition of BHT (3.0 equiv), and the yield of phenanthridine was decreased by the addition of 4-hydroxyTEMPO (3.0 equiv). Moreover, treatment of N-iodo compound derived from 2-biphenyl t-butyl imine formed from the reaction of 2-biphenyllithium and pivalonitrile at 60 °C did not generate 6-t-butylphenanthridine (3Bk) at all (Scheme 3), and instead 2-cyanobiphenyl was obtained in good yield. This result suggests that β-cleavage of the formed imino radical would occur to form 2-cyanobiphenyl and stable t-butyl radical that would react with molecular iodine to form tbutyl iodide. Very recently, the β-cleavage of cyclic imino radicals to form cyano derivatives was reported.13 On the other hand, the same treatment of phenylimine 1Ad with NBS and NCS via N-bromophenylimine and N-chlorophenylimine did not generate phenanthridine at all under warming conditions or irradiation with a tungsten lamp.

aqueous solution (20 mL) was added to the reaction mixture, and the product was extracted with EtOAc (10 mL × 3). The organic layer was purified by silica gel column chromatography (eluent: nhexane:EtOAc = 6:1) to give 3-methyl-6-phenylphenanthridine 3Ad (258.5 mg 96%). 3,6-Dimethylphenanthridine (3Aa). Yield: 193.5 mg (93%); yellow solid; Mp: 92−93 °C; IR (neat) 1585, 1486, 1375, 822, 724, 628 cm−1; 1H NMR (400 MHz, CDCl3): δ = 2.57 (s, 3H), 3.04 (s, 3H), 7.44−7.47 (m, 1H), 7.65−7.68 (m, 1H), 7.80 (t, 1H, J = 8.4 Hz) 7.90 (s, 1H), 8.21 (d, 1H, J = 8.0 Hz), 8.43 (d, 1H, J = 8.4 Hz), 8.59 (d, 1H, J = 8.0 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 21.5, 23.3, 121.3, 121.6, 122.0, 125.5, 126.4, 126.7, 127.9, 128.9, 130.2, 132.5, 138.6, 143.7, 158.7; HRMS (ESI) Calcd for C15H14N [M + H]+ = 208.1121, Found = 208.1120. 6-Ethyl-3-methylphenanthridine (3Ab). Yield: 182.7 mg (82%); yellow solid; Mp: 80−81 °C; IR (neat) 1585, 1485, 1373, 818, 763, 727 cm−1; 1H NMR (400 MHz, CDCl3): δ = 1.50 (t, 3H, J = 7.8 Hz), 2.58 (s, 3H), 3.39 (q, 2H, J = 7.8 Hz), 7.44 (d, 1H, J = 8.4 Hz), 7.65 (t, 1H, J = 8.0 Hz), 7.80 (t, 1H, J = 8.0 Hz), 7.92 (s, 1H), 8.23 (d, 1H, J = 8.4 Hz), 8.41 (d, 1H, J = 8.4 Hz), 8.59 (d, 1H, J = 8.4 Hz); 13 C{1H}NMR (100 MHz, CDCl3): δ = 13.2, 21.2, 29.2, 120.9, 121.3, 121.9, 124.6, 125.7, 126.3, 127.5, 128.9, 129.7, 132.5, 138.2, 143.6, 162.6; HRMS (ESI) Calcd for C16H16N [M + H]+ = 222.1277, Found = 222.1272. 6-Butyl-3-methylphenanthridine (3Ac). Yield: 168.5 mg (67%); yellow solid; Mp: 38−39 °C; IR (neat) 2954, 1584, 1486, 817, 760, 727 cm−1; 1H NMR (400 MHz, CDCl3): δ = 1.00 (t, 3H, J = 7.8 Hz), 1.50−1.60 (m, 2H), 1.87−1.92 (m, 2H), 2.57 (s, 3H), 3.35 (t, 2H, J = 8.0 Hz), 7.43 (d, 1H, J = 8.4 Hz), 7.64 (t, 1H, J = 7.8 Hz), 7.79 (t, 1H, J = 7.8 Hz), 7.92 (s, 1H), 8.22 (d, 1H, J = 8.4 Hz), 8.41 (d, 1H, J = 8.4 Hz), 8.58 (d, 1H, J = 8.4 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 14.0, 21.5, 23.1, 31.7, 36.1, 121.2, 121.6, 122.2, 124.8, 126.2, 126.6, 127.8, 129.1, 130.1, 132.9, 138.5, 143.7, 162.3; HRMS (ESI) Calcd for C18H20N [M + H]+ = 250.1590, Found = 250.1591. 3-Methyl-6-phenylphenanthridine (3Ad). Yield: 258.5 mg (95%); yellow solid; Mp: 110−111 °C; IR (neat) 1559, 1444, 1362, 771, 700, 668 cm−1; 1H NMR (400 MHz, CDCl3): δ = 2.61 (s, 3H), 7.50−7.60 (m, 5H), 7.71−7.74 (m, 2H), 7.84 (t, 1H, J = 8.4 Hz), 8.05 (s, 1H), 8.09 (d, 1H, J = 8.4 Hz), 8.51 (d, 1H, J = 8.4 Hz), 8.67 (d, 1H, J = 8.4 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 21.5, 121.3, 121.6, 121.9, 124.8, 126.6, 128.3 (2C), 128.5, 128.6, 128.8, 129.6 (2C), 129.8, 130.4, 133.4, 138.9, 139.8, 143.8, 161.2; HRMS (ESI) Calcd for C20H16N [M + H]+ = 270.1277, Found = 270.1274. 3-Methyl-6-(4′-methylphenyl)phenanthridine (3Ae). Yield: 246.5 mg (87%); white solid; Mp: 90−91 °C; IR (neat) 1482, 1360, 1325, 820, 759, 726 cm−1; 1H NMR (400 MHz, CDCl3): δ = 2.47 (s, 3H), 2.59 (s, 3H), 7.36 (d, 2H, J = 8.4 Hz), 7.50 (d, 1H, J = 8.8 Hz), 7.56 (t, 1H, J = 8.0 Hz), 7.63 (d, 2H, J = 8.4 Hz), 7.81 (t, 1H, J = 8.0 Hz), 8.03 (s, 1H), 8.11 (d, 1H, J = 8.4 Hz), 8.47 (d, 1H, J = 8.4 Hz), 8.64 (d, 1H, J = 8.8 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 21.3, 21.5, 121.3, 121.6, 121.9, 124.9, 126.5, 128.5, 128.9, 129.0 (2C), 129.6 (2C), 129.8, 130.3, 133.4, 137.0, 138.4, 138.8, 143.9, 161.2; HRMS (ESI) Calcd for C21H18N [M + H]+ = 284.1434, Found = 284.1429. 6-(4′-Methoxyphenyl)-3-methylphenanthridine (3Af). Yield: 236.6 mg (83%); yellow solid; Mp: 154−155 °C; IR (neat) 1249, 1173, 1021, 835, 730, 506 cm−1; 1H NMR (400 MHz, CDCl3): δ = 2.60 (s, 3H), 3.92 (s, 3H), 7.09 (d, 2H, J = 8.8 Hz), 7.51 (d, 1H, J = 8.8 Hz), 7.59 (t, 1H, J = 8.0 Hz), 7.70 (d, 2H, J = 8.8 Hz), 7.84 (t, 1H, J = 8.0 Hz), 8.03 (s, 1H), 8.14 (d, 1H, J = 8.0 Hz), 8.49 (d, 1H, J = 8.8 Hz), 8.66 (d, 1H, J = 8.0 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 21.5, 55.4, 113.8 (2C), 121.2, 121.7, 122.0, 124.9, 126.5, 128.4, 128.8, 129.7, 130.3, 131.1 (2C), 132.3, 133.5, 138.9, 144.1, 160.0, 160.8; HRMS (ESI) Calcd for C21H18NO [M + H]+ = 300.1383, Found = 300.1383. 6-(4′-Chlorophenyl)-3-methylphenanthridine (3Ag). Yield: 260.8 mg (84%); yellow solid; Mp: 170−171 °C; IR (neat) 1479, 1361, 827, 759, 725 cm−1; 1H NMR (400 MHz, CDCl3): δ = 2.60 (s, 3H), 7.52−7.61 (m, 4H), 7.66−7.69 (m, 2H), 7.82−7.86 (m, 1H), 8.03 (d, 2H, J = 9.6 Hz), 8.50 (d, 1H, J = 8.8 Hz), 8.66 (d, 1H, J = 8.8 Hz);

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CONCLUSION Treatment of 2-cyanobiaryls with alkyllithiums and aryllithiums, followed by the reaction with water and then with molecular iodine and K2CO3 at 60 °C for 2 h, provided the corresponding 6-alkylphenanthridines and 6-arylphenanthridines in good yields, respectively, through the formation of imino nitrogen-centered radicals and their cyclization onto the aromatic ring. We believe that the present method would be useful not only for the preparation of 6-substituted phenanthridines from 2-cyanobiaryls but also for the synthetic use of the imino nitrogen-centered radical.

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EXPERIMENTAL SECTION

General. 1H NMR spectra were measured on 500 MHz spectrometers. Chemical shifts were recorded as follows: chemical shift in ppm from internal tetramethylsilane on the δ scale, multiplicity (s = singlet; d = doublet; t = triplet; q = quartet; m = multiplet; br = broad), coupling constant (Hz), integration, and assignment. 13C NMR spectra were measured on 125 MHz spectrometers. Chemical shifts were recorded in ppm from the solvent resonance employed as the internal standard (deuterochloroform at 77.0 ppm). Characteristic peaks in the infrared (IR) spectra were recorded in wavenumber, cm−1. High-resolution mass spectra were measured with Thermo Fisher Scientific Exactive Orbitrap mass spectrometers. Melting points were uncorrected. Thin-layer chromatography (TLC) was performed using 0.25 mm silica gel plates (60F254). The products were purified by column chromatography on silica gel 60 (63−200 mesh). Typical Procedure for Transformation of Imines 1A into Phenanthridines 3A. To a solution of phenylimine 1Ad (1.0 mmol, 271.13 mg) in a mixture of THF (2.0 mL) and water (2.0 mL) were added I2 (1.5 mmol, 380.7 mg) and K2CO3 (3.0 mmol, 414.6 mg). The obtained mixture was stirred for 1.5 h at 60 °C under argon atmosphere. Saturated Na2SO3 aqueous solution (20 mL) was added to the reaction mixture, and the product was extracted with EtOAc (10 mL × 3). The organic layer was dried over Na2SO4. After removal of the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent: n-hexane:EtOAc = 6:1) to give 3-methyl-6-phenylphenanthridine 3Ad (255.1 mg, 95%). Typical Procedure for Transformation of o-Cyanobiaryls into Phenanthridines. To a solution of 2-cyano-4′-methylbiphenyl 2A (1.0 mmol, 193.2 mg) in THF (4.0 mL) was added PhLi (2.0 mmol, 1.88 mL) at 0 °C. The obtained mixture was stirred for 15 min at room temperature under argon atmosphere. H2O (4.0 mL) was added to the mixture, and then I2 (1.5 mmol, 380.7 mg) and K2CO3 (3.0 mmol, 414.6 mg) were added to the mixture at 0 °C, and the obtained mixture was stirred for 2 h at 60 °C. Saturated Na2SO3 11084


Article

The Journal of Organic Chemistry C{1H}NMR (100 MHz, CDCl3): δ = 21.5, 121.3, 121.7, 122.0, 124.6, 126.7, 128.3, 128.6 (2C), 128.8, 129.8, 130.5, 131.1 (2C), 133.4 134.7, 138.2, 139.1, 143.7, 159.8; HRMS (ESI) Calcd for C20H15ClN [M + H]+ = 304.0888, Found = 304.0888. 6-Methylphenanthridine (3Ba). Yield: 166.8 mg (86%); yellow solid; Mp: 80−81 °C; IR (neat) 1371, 1239, 750, 720, 503 cm−1; 1H NMR (400 MHz, CDCl3): δ = 3.05 (s, 3H), 7.63 (t, 1H, J = 8.4 Hz), 7.68−7.73 (m, 2H), 7.85 (t, 1H, J = 8.4 Hz), 8.11 (d, 1H, J = 8.4 Hz), 8.23 (d, 1H, J = 8.4 Hz), 8.55 (d, 1H, J = 8.4 Hz), 8.63 (d, 1H, J = 8.4 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 23.3, 121.8, 122.2, 123.6, 125.7, 126.2, 126.4, 127.2, 128.5, 129.2, 130.3, 132.4, 143.5, 158.7; HRMS (ESI) Calcd for C14H12N [M + H]+ = 194.0964, Found = 194.0958. 6-Ethylphenanthridine (3Bb). Yield: 174.2 mg (84%); yellow solid; Mp: 56−57 °C; IR (neat) 1584, 1373, 1268, 748, 723 cm−1; 1H NMR (400 MHz, CDCl3): δ = 1.51 (t, 3H, J = 7.8 Hz), 3.41 (q, 2H, J = 7.8 Hz), 7.61 (t, 1H, J = 8.4 Hz), 7.67−7.73 (m, 2H), 7.82 (t, 1H, J = 8.4 Hz), 8.12 (d, 1H, J = 8.4 Hz), 8.26 (d, 1H, J = 8.4 Hz), 8.54 (d, 1H, J = 8.4 Hz), 8.64 (d, 1H, J = 8.4 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 13.1, 29.1, 121.7, 122.2, 123.4, 124.9, 125.9, 126.0, 127.0, 128.3, 129.3, 130.0, 132.6, 143.5, 162.9; HRMS (ESI) Calcd for C15H14N [M + H]+ = 208.1121, Found = 208.1117. 6-Butylphenanthridine (3Bc). Yield: 197.3 mg (83%); yellow oil; IR (neat) 2955, 1584, 1485, 1362, 753, 723 cm−1; 1H NMR (400 MHz, CDCl3): δ = 1.01 (t, 3H, J = 7.6 Hz), 1.52−1.61 (m, 2H), 1.87−1.95 (m, 2H), 3.38 (t, 2H, J = 8.2 Hz), 7.62 (t, 1H, J = 7.6 Hz), 7.67−7.73 (m, 2H), 7.84 (t, 1H, J = 7.6 Hz), 8.12 (d, 1H, J = 8.4 Hz), 8.26 (d, 1H, J = 8.4 Hz), 8.55 (d, 1H, J = 8.4 Hz), 8.65 (d, 1H, J = 8.4 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 13.9, 23.0, 31.7, 36.2, 121.7, 122.2, 123.4, 125.0, 126.0, 126.1, 126.9, 128.3, 129.4, 130.0, 132.6, 143.5, 162.2; HRMS (ESI) Calcd for C17H18N [M + H]+ = 236.1434, Found = 236.1433. 6-Phenylphenanthridine (3Bd). Yield: 243.6 mg (95%); yellow solid; Mp: 99−101 °C; IR (neat) 1360, 1137, 960, 1758, 695 cm−1; 1 H NMR (400 MHz, CDCl3): δ = 7.50−7.65 (m, 4H), 7.67−7.78 (m, 4H), 7.85 (t, 1H, J = 7.6 Hz), 8.10 (d, 1H, J = 8.4 Hz), 8.23 (d, 1H, J = 8.4 Hz), 8.61 (d, 1H, J = 8.4 Hz), 8.70 (d, 1H, J = 8.4 Hz); 13 C{1H}NMR (100 MHz, CDCl3): δ = 121.8, 122.1, 123.6, 125.1, 126.8, 127.0, 128.3 (2C), 128.6, 128.7, 128.8, 129.6 (2C), 130.2, 130.4, 133.3, 139.7, 143.7, 161.1; HRMS (ESI) Calcd for C19H14N [M + H]+ = 256.1121, Found = 256.1121. 6-(4′-Methylphenyl)phenanthridine (3Be). Yield: 185.6 mg (68%); white solid; Mp: 80−82 °C; IR (neat) 1357, 960, 822, 754, 726 cm−1; 1H NMR (400 MHz, CDCl3): 2.48 (s, 3H), 7.37 (d, 2H, J = 8.4 Hz), 7.59−7.70 (m, 4H), 7.75 (t, 1H, J = 7.6 Hz), 7.86 (t, 1H, J = 7.6 Hz), 8.14 (d, 1H, J = 8.4 Hz), 8.24 (d, 1H, J = 8.4 Hz), 8.62 (d, 1H, J = 8.4 Hz), 8.70 (d, 1H, J = 8.4 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 21.3, 121.8, 122.1, 123.6, 125.2, 126.7, 127.0, 128.7, 128.9, 129.0 (2C), 129.6 (2C), 130.2, 130.4, 133.3, 136.9, 138.5, 143.7, 161.2; HRMS (ESI) Calcd for C20H16N [M + H]+ = 270.1277, Found = 270.1273. 6-(4′-Methoxyphenyl)phenanthridine (3Bf). Yield: 232.7 mg (81%); yellow solid; Mp: 144−146 °C; IR (neat) 1509, 1247, 1171, 1028, 828, 759 cm−1; 1H NMR (400 MHz, CDCl3): δ = 3.92 (s, 3H), 7.09 (d, 2H, J = 8.4 Hz), 7.60−7.77 (m, 5H), 7.82 (t, 1H, J = 8.4 Hz), 8.16 (d, 1H, J = 8.4 Hz), 8.23 (d, 1H, J = 8.4 Hz), 8.60 (d, 1H, J = 8.4 Hz), 8.70 (d, 1H, J = 8.4 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 55.4, 113.8 (2C), 121.8, 122.1, 123.5, 125.2, 126.6, 127.0, 128.7, 128.8, 130.2, 130.3, 131.1 (2C), 132.2, 133.4, 143.8, 160.3, 160.8; HRMS (ESI) Calcd for C20H16NO [M + H]+ = 286.1226, Found = 286.1227. 6-(4′-Chlorophenyl)phenanthridine (3Bg). Yield: 186.3 mg (64%); yellow solid; Mp: 151−152 °C; IR (neat) 1359, 1089, 1014, 829, 752, 722 cm−1; 1H NMR (400 MHz, CDCl3): δ = 7.51− 7.56 (m, 2H), 7.62−7.79 (m, 5H), 7.88 (t, 1H, J = 7.6 Hz), 8.07 (d, 1H, J = 8.8 Hz), 8.23 (d, 1H, J = 8.4 Hz), 8.63 (d, 1H, J = 8.4 Hz), 8.72 (d, 1H, J = 8.8 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 122.0, 122.3, 123.7, 124.4, 127.1, 127.4, 128.4, 128.6 (2C), 128.9, 130.3, 130.6, 131.1 (2C), 133.4, 134.8, 138.1, 143.6, 159.9; HRMS

(ESI) Calcd for C19H13ClN [M + H]+ = 290.0731, Found = 290.0728. 6-(4′-Bromophenyl)phenanthridine (3Bh). Yield: 133.6 mg (40%); yellow solid; Mp: 160−162 °C; IR (neat) 1482, 1389, 1010, 823, 754, 723 cm−1; 1H NMR (400 MHz, CDCl3): δ = 7.52 (m, 1H), 7.61−7.78 (m, 6H), 7.85−7.90 (m, 1H), 8.06 (d, 1H, J = 8.0 Hz), 8.23 (d, 1H, J = 8.0 Hz), 8.63 (d, 1H, J = 8.0 Hz), 8.71 (d, 1H, J = 8.0 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 121.9, 122.3, 123.1, 123.7, 124.8, 127.1, 127.2, 128.4, 128.9, 130.2, 130.6, 131.3 (2C), 131.5 (2C), 133.4, 138.6, 143.6, 159.9; HRMS (ESI) Calcd for C19H13BrN [M + H]+ = 334.0226, Found = 334.0227. 6-Isopropylphenanthridine (3Bi). Yield: 157.2 mg (71%); colorless oil; IR (neat) 2964, 1582, 1006, 756, 724, 677 cm−1; 1H NMR (400 MHz, CDCl3): δ = 1.51 (d, 6H, J = 6.8 Hz), 3.99 (m, 1H), 7.60 (t, 1H, J = 7.6 Hz), 7.65−7.71 (m, 2H), 7.80 (t, 1H, J = 7.6 Hz), 8.14 (d, 1H, J = 7.6 Hz), 8.30 (d, 1H, J = 8.4 Hz), 8.53 (d, 1H, J = 8.4 Hz), 8.64 (d, 1H, J = 8.4 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 22.6 (2C), 31.4, 121.7, 122.5, 123.3, 124.6, 125.6, 126.1, 127.0, 128.3, 129.8 (2C), 132.9, 143.7, 166.7; HRMS (ESI) Calcd for C16H16N [M + H]+ = 222.1277, Found = 222.1278. 6-Cyclohexylphenanthridine (3Bj). Yield: 228.6 mg (87%); yellow oil; IR (neat) 2927, 2852, 1581, 1447, 987, 756, 725 cm−1; 1H NMR (400 MHz, CDCl3): δ = 1.11−2.14 (m, 10H), 3.61 (m, 1H), 7.59 (t, 1H, J = 7.6 Hz), 7.69 (m, 2H), 7.80 (t, 1H, J = 8.4 Hz), 8.13 (d, 1H, J = 8.4 Hz), 8.31 (d, 1H, J = 8.4 Hz), 8.53 (d, 1H, J = 8.4 Hz), 8.65 (d, 1H, J = 8.4 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 13.9, 26.2, 26.8 (2C), 32.2 (2C), 41.9, 121.7, 122.5, 123.2, 124.6, 125.5, 126.1, 127.0, 128.3, 129.8, 132.9, 143.8, 165.2; HRMS (ESI) Calcd for C19H20N [M + H]+ = 262.1590, Found = 262.1590. 3-Methoxy-6-methylphenanthridine (3Ca). Yield: 136.1 mg (71%); yellow solid; Mp: 78−79 °C; IR (neat) 1616, 1484, 1213, 1030, 843, 755 cm−1; 1H NMR (400 MHz, CDCl3): δ = 3.04 (s, 3H), 3.89 (s, 3H), 7.26 (dd, 1H, J = 8.8, 2.8 Hz), 7.52 (d, 1H, J = 2.8 Hz), 7.62 (t, 1H, J = 7.6 Hz), 7.80 (t, 1H, J = 7.6 Hz), 8.19 (d, 1H, J = 8.4 Hz), 8.42 (d, 1H, J = 8.8 Hz), 8.52 (d, 1H, J = 8.4 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 23.0, 55.2, 108.9, 116.9, 117.3, 121.4, 122.8, 124.5, 125.7, 126.1, 130.1, 132.3, 144.8, 158.9, 159.7; HRMS (ESI) Calcd for C15H14NO [M + H]+ = 224.1070, Found = 224.1067. 6-Ethyl-3-methoxyphenanthridine (3Cb). Yield: 129.2 mg (54%); yellow solid; Mp: 45−46 °C; IR (neat) 1597, 1492, 1447, 1025, 746, 693 cm−1; 1H NMR (400 MHz, CDCl3): δ = 1.49 (t, 3H, J = 7.8 Hz), 3.37 (q, 2H, J = 7.8 Hz), 3.96 (s, 3H), 7.20−7.23 (m, 1H), 7.52 (d, 1H, J = 2.8 Hz), 7.56 (t, 1H, J = 7.6 Hz), 7.73 (t, 1H, J = 7.6 Hz), 8.18 (d, 1H, J = 8.4 Hz), 8.36 (d, 1H, J = 9.2 Hz), 8.47 (d, 1H, J = 8.4 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 13.6, 29.3, 55.4, 109.2, 117.1, 117.4, 121.8, 123.0, 123.8, 125.9, 126.0, 130.1, 132.9, 145.2, 159.9, 163.6; HRMS (ESI) Calcd for C16H16NO [M + H]+ = 238.1226, Found = 238.1226. 6-Butyl-3-methoxyphenanthridine (3Cc). Yield: 162.4 mg (61%); yellow oil; IR (neat) 2956, 1615, 1214, 1038, 750, 724 cm−1; 1H NMR (400 MHz, CDCl3): δ = 1.01 (t, 3H, J = 7.6 Hz), 1.56 (m, 2H), 1.90 (m, 2H), 3.35 (t, 2H, J = 8.0 Hz), 3.97 (s, 3H), 7.23−7.26 (m, 1H), 7.53 (d, 1H, J = 2.8 Hz), 7.59 (t, 1H, J = 7.8 Hz), 7.76 (t, 1H, J = 7.8 Hz), 8.20 (d, 1H, J = 8.8 Hz), 8.39 (d, 1H, J = 8.8 Hz), 8.50 (d, 1H, J = 8.8 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 14.0, 23.1, 31.9, 36.2, 55.4, 109.2, 117.2, 117.5, 121.8, 123.0, 124.1, 125.9, 126.2, 130.2, 133.0, 145.2, 160.0, 163.0; HRMS (ESI) Calcd for C18H20NO [M + H]+ = 266.1539, Found = 266.1537. 3-Methoxy-6-phenylphenanthridine (3Cd). Yield: 226.1 mg (79%); yellow solid; Mp: 107−108 °C; IR (neat) 1617, 1203, 1035, 768, 706, 673 cm−1; 1H NMR (400 MHz, CDCl3): δ = 3.98 (s, 3H), 7.32 (dd, 1H, J = 9.2, 2.8 Hz), 7.50−7.59 (m, 4H), 7.66 (d, 1H, J = 2.8 Hz), 7.71−7.74 (m, 2H), 7.81 (t, 1H, J = 7.8 Hz), 8.06 (d, 1H, J = 8.4 Hz), 8.50 (d, 1H, J = 9.2 Hz), 8.60 (d, 1H, J = 8.0 Hz); 13 C{1H}NMR (100 MHz, CDCl3): δ = 55.3, 109.7, 117.5, 117.9, 121.4, 122.9, 124.0, 125.7, 128.2 (2C), 128.4, 128.6, 129.5 (2C), 130.3, 133.6, 139.6, 145.1, 160.0, 161.4; HRMS (ESI) Calcd for C20H16NO [M + H]+ = 286.1226, Found = 286.1225. 3-Methoxy-6-(4′-methylphenyl)phenanthridine (3Ce). Yield: 234.2 mg (78%); white solid; Mp: 118−120 °C; IR (neat) 1203,

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The Journal of Organic Chemistry 1039, 821, 760, 721, 599 cm−1; 1H NMR (400 MHz, CDCl3): δ = 2.48 (s, 3H), 3.98 (s, 3H), 7.32 (dd, 1H, J = 9.2, 2.8 Hz), 7.37 (d, 2H, J = 8.0 Hz), 7.54 (t, 1H, J = 8.0 Hz), 7.61−7.65 (m, 3H), 7.81 (t, 1H, J = 8.0 Hz), 8.10 (d, 1H, J = 8.4 Hz), 8.50 (d, 1H, J = 9.0 Hz), 8.59 (d, 1H, J = 8.0 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 21.2, 55.3, 109.7, 117.5, 117.7, 121.4, 122.9, 124.1, 125.7, 128.7, 128.9 (2C), 129.4 (2C), 130.2, 133.4, 136.8, 138.2, 145.2, 159.9, 161.5; HRMS (ESI) Calcd for C21H18NO [M + H]+ = 300.1383, Found = 300.1379. 3-Methoxy-6-(4′-methoxyphenyl)phenanthridine (3Cf). Yield: 218.9 mg (69%); white solid; Mp: 141−143 °C; IR (neat) 1607, 1244, 1027, 832, 766 cm−1; 1H NMR (400 MHz, CDCl3): δ = 3.92 (s, 3H), 3.98 (s, 3H), 7.07−7.11 (m, 2H), 7.31 (dd, 1H, J = 8.4, 2.8 Hz), 7.55 (t, 1H, J = 7.8 Hz), 7.64 (d, 1H, J = 2.4 Hz), 7.68−7.71 (m, 2H), 7.82 (t, 1H, J = 7.8 Hz), 8.13 (d, 1H, J = 8.4 Hz), 8.50 (d, 1H, J = 8.4 Hz), 8.59 (d, 1H, J = 8.4 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 55.1, 55.2, 109.6, 113.6 (2C), 117.3, 117.6, 121.4, 122.8, 124.5, 125.6, 128.6, 130.1, 130.9 (2C), 132.1, 133.4, 145.2, 159.8, 159.9, 161.0; HRMS (ESI) Calcd for C21H18NO2 [M + H]+ = 316.1332, Found = 316.1331. 6-(4′-Chlorophenyl)-3-methoxyphenanthridine (3Cg). Yield: 191.4 mg (59%); white solid; Mp: 143−145 °C; IR (neat) 1617, 1204, 1044, 757, 719, 502 cm−1; 1H NMR (400 MHz, CDCl3): δ = 3.98 (s, 3H), 7.33 (dd, 1H, J = 8.4, 2.8 Hz), 7.52−7.69 (m, 6H), 7.84 (t, 1H, J = 7.2 Hz), 8.02 (d, 1H, J = 8.4 Hz), 8.51 (d, 1H, J = 8.4 Hz), 8.61 (d, 1H, J = 8.4 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 55.5, 110.0, 117.7, 118.3, 121.7, 123.1, 123.9, 126.1, 128.4, 128.6 (2C), 130.7, 131.0 (2C), 133.6, 134.8, 138.2, 145.2, 160.2, 160.3; HRMS (ESI) Calcd for C20H15ClNO [M + H]+ = 320.0837, Found = 320.0834. 3-Chloro-6-methylphenanthridine (3Da). Yield: 170.1 mg (74%); yellow solid; Mp: 120−122 °C; IR (neat) 1370, 876, 755, 727, 720, 627 cm−1; 1H-NMR (400 MHz, CDCl3): δ = 3.04, (s, 3H), 7.58 (dd, 1H, J = 8.0 Hz, 2.4 Hz), 7.72 (t, 1H, J = 7.6 Hz), 7.86(t, 1H, J = 7.6 Hz), 8.01 (d, 1H, J = 2.4 Hz), 8.23 (d, 1H, J = 8.0 Hz), 8.46 (d, 1H, J = 8.0 Hz), 8.57 (d, 1H, J = 8.0 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 23.3, 122.1 (2C), 123.2, 125.7, 126.6, 126.7, 127.5, 128.6, 130.8, 130.9, 134.1, 144.3, 160.2; HRMS (ESI) Calcd for C14H11ClN [M + H]+ = 228.0575, Found = 228.0573. 3-Chloro-6-ethylphenanthridine (3Db). Yield: 143.9 mg (59%); yellow solid; Mp: 100−102 °C; IR (neat) 1583, 1476, 1080, 771, 750, 727 cm−1; 1H NMR (400 MHz, CDCl3): δ = 1.50 (t, 3H, J = 7.6 Hz), 3.78 (q, 2H, J = 7.6 Hz), 7.54 (m, 1H), 7.69 (t, 1H, J = 7.6 Hz), 7.82 (t, 1H, J = 7.6 Hz), 8.10 (d, 1H, J = 2.0 Hz), 8.24 (d, 1H, J = 8..4 Hz), 8.41 (d, 1H, J = 8.8 Hz), 8.53 (d, 1H, J = 8.8 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 13.2, 29.2, 122.0, 122.3, 123.2, 124.8, 126.1, 126.6, 127.4, 128.7, 130.1, 132.2, 134.0, 144.6, 164.3; HRMS (ESI) Calcd for C15H13ClN [M + H]+ = 242.0731, Found = 242.0731. 3-Chloro-6-butylphenanthridine (3Dc). Yield: 195.5 mg (72%); yellow solid; Mp: 62−64 °C; IR (neat) 2952, 1478, 1078, 885, 752, 726 cm−1; 1H NMR (400 MHz, CDCl3): δ = 1.01 (t, 3H, J = 7.6 Hz), 1.53−1.59 (m, 2H), 1.94−1.86 (m, 2H), 3.37 (t, 2H, J = 8.0 Hz), 7.57 (dd, 1H, J = 9.2, 2.4 Hz), 7.71 (t, 1H, J = 8.0 Hz), 7.85 (t, 1H, J = 8.0 Hz), 8.12 (d, 1H, J = 2.4 Hz), 8.26 (d, 1H, J = 8.4 Hz), 8.45 (d, 1H, J = 9.2 Hz), 8.58 (d, 1H, J = 8.4 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 14.1, 23.0, 31.4, 36.0, 121.9, 122.2, 123.1, 124.9, 126.2, 126.5, 127.3, 128.7, 130.4, 132.2, 133.9, 144.3, 163.6; HRMS (ESI) Calcd for C17H17ClN [M + H]+ = 270.1043, Found = 270.1044. 3-Chloro-6-phenylphenanthridine (3Dd). Yield: 238.7 mg (82%); yellow solid; Mp: 132−134 °C; IR (neat) 1443, 1360, 1074, 765, 668 cm−1;1H NMR (400 MHz, CDCl3): δ = 7.51−7.65 (m, 5H), 7.70− 7.75 (m, 2H), 7.87 (t, 1H, J = 8.8 Hz), 8.12 (d, 1H, J = 9.2 Hz). 8.24 (d, 1H, J = 2.4 Hz), 8.53 (d, 1H, J = 9.2 Hz), 8.64 (d, 1H, J = 8.8 Hz); 13 C{1H}NMR (100 MHz, CDCl3): δ = 122.1, 122.2, 123.3, 125.1, 127.4 (2C), 128.4 (2C), 128.9, 129.0, 129.5, 129.6 (2C), 130.9, 133.0, 134.4, 139.3, 144.4, 162.4; HRMS (ESI) Calcd for C19H13ClN [M + H]+ = 290.0731, Found = 290.0730. 3-Chloro-6-(4′-methylphenyl)phenanthridine (3De). Yield: 272.9 mg (89%); white solid; Mp: 128−129 °C; IR (neat) 1078, 905, 819, 746, 719, 671 cm−1; 1H NMR (400 MHz, CDCl3): δ = 2.48 (s, 3H),

7.37 (d, 2H, J = 8.0 Hz), 7.65−7.10 (m, 4H), 7.86 (t, 1H, J = 8.0 Hz), 8.15 (d, 1H, J = 8.4 Hz), 8.22 (d, 1H, J = 2.0 Hz), 8.52 (d, 1H, J = 8.8 Hz), 8.63 (d, 1H, J = 8.4 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 21.4, 122.0, 122.1, 123.2, 125.1, 127.2, 127.3, 129.1 (3C), 129.4, 129.6 (2C), 130.8, 133.0, 134.3, 136.4, 138.9, 144.4, 162.4; HRMS (ESI) Calcd for C20H15ClN [M + H]+ = 304.0888, Found = 304.0887. 3-Chloro-6-(4′-methoxyphenyl)phenanthridine (3Df). Yield: 244.8 mg (76%); white solid; Mp: 133−135 °C; IR (neat) 1360, 1248, 1031, 828, 761, 598 cm−1; 1H NMR (400 MHz, CDCl3): δ = 3.92 (s, 3H), 7.10 (d, 2H, J = 8.8 Hz), 7.61−7.72 (m, 4H), 7.88 (t, 1H, J = 8.4 Hz), 8.18 (d, 1H, J = 8.4 Hz), 8.21 (d, 1H, J = 2.4 Hz), 8.52 (d, 1H, J = 8.8 Hz), 8.63 (d, 1H, J = 8.4 Hz), 13C{1H}NMR (100 MHz, CDCl3): δ = 55.3, 113.8 (2C), 121.9, 122.0, 123.2, 125.1, 127.1, 127.2, 129.0, 129.3, 130.7, 131.2 (2C), 131.7, 132.9, 134.2, 144.4, 160.2, 161.9; HRMS (ESI) Calcd for C20H15ClNO [M + H]+ = 320.0837, Found = 320.0836. 3-Chloro-6-(4′-chlorophenyl)phenanthridine (3Dg). Yield: 313.2 mg (96%); white solid; Mp: 210−212 °C; IR (neat) 1359, 1078, 831, 765, 722 cm−1; 1H NMR (400 MHz, DMSO-d6): δ = 7.72 (d, 2H, J = 8.4 Hz), 7.83−7.93 (m, 4H), 8.13 (d, 1H, J = 8.4 Hz), 8.19 (t, 1H, J = 8.4 Hz), 8.26 (d, 1H, J = 2.0 Hz), 8.97 (d, 1H, J = 9.2 Hz), 9.02 (d, 1H, J = 8.4 Hz); 13C{1H}NMR (100 MHz, CDCl3 and CF3CO2H): δ = 121.1, 123.1, 123.2, 123.3, 124.6, 127.4, 130.0 (2C), 130.7, 131.3 (2C), 131.8, 132.2, 133.3, 135.8, 138.1, 139.0, 140.4, 160.6; HRMS (ESI) Calcd for C19H12Cl2N [M + H]+ = 324.0341, Found = 324.0340. 4-Methyl-6-phenylphenanthridine (3Ed). Yield: 181.7 mg (67%); pale yellow solid; Mp: 108−110 °C; IR (neat) 1566, 1466, 1360, 744, 687, 667 cm−1; 1H NMR (400 MHz, CDCl3): δ = 2.88 (s. 3H), 7.50− 7.62 (m, 6 H), 7.80−7.84 (m, 3 H), 8.18 (d, 1H, J = 8.4 Hz), 8.46 (d, 1H, J = 8.0 Hz), 8.69 (d, 1H, J = 8.4 Hz); 13C{1H}NMR (100 MHz, CDCl3): δ = 18.4, 119.6, 122.4, 123.4, 124.7, 126.4, 126.8, 128.2 (2C), 128.5, 129.4, 130.1, 130.2 (2C), 133.8, 140.2, 142.5, 159.2; HRMS (ESI) Calcd for C20H16N [M + H]+ = 270.1277, Found = 270.1278. Crystal Data of 3-methyl-6-phenylphenanthridine 3Ad. Recrystallized from a mixture of ethyl acetate and hexane. Formula: C20H15N, crystal color: colorless, crystal dimensions: 0.20 0.20 0.20 mm3, crystal shape: needle, Bravais lattice: monoclinic, space group: P121/n1′, a = 9.6849(8) Å, b = 14.6284(11) Å, c = 20.1462(16) Å, α = 90°, β = 98.8224(11) °, γ = 90°, V = 2820.4(4) Å3, Z = 8, ρcalc = 1.269 g cm−3, F(000) = 1136, μ(MoKα) = 0.073 mm−1, T = 173 K, reflections collected 16 048, 6431 independent reflections with I > 2σ (2θmax = 27.51°), 381 parameters were used for the solution of the structure, R1 = 0.0484, wR2 = 0.1148, GOF = 1.043. Crystallographic data (excluding structure factors) for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-1853388. Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, U.K. [Fax: int. code +44(1223)336-033; E-mail: [email protected]].

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01688.

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NMR charts of all phenanthridines 3; X-ray analytical data of 3Ad (PDF) Crystallographic data of 3Ad (CIF)

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Katsuhiko Moriyama: 0000-0001-8443-3599 11086


Article

The Journal of Organic Chemistry Notes

Synthesis of Cyano-Containing Phenanthridine Derivatives via Catalyst-, Base-, and Oxidant-Free Direct Cyanoalkylarylation of Isocyanides. J. Org. Chem. 2017, 82, 4444−4448. (6) (a) Jiang, H.; Cheng, Y.; Wang, R.; Zheng, M.; Zhang, Y.; Yu, S. Synthesis of 6-Alkylated Phenanthridine Derivatives Using Photoredox Neutral Somophilic Isocyanide Insertion. Angew. Chem., Int. Ed. 2013, 52, 13289−13292. (b) Gu, L.; Jin, C.; Liu, J.; Ding, H.; Fan, B. Synthesis of 6-Alkylated Phenanthridine Derivatives Using Photoredox Neutral Somophilic Isocyanide Insertion. Chem. Commun. 2014, 50, 4643−4645. (c) Feng, S.; Li, T.; Du, C.; Chen, P.; Song, D.; Li, J.; Xie, X.; She, X. Visible-light-mediated Radical Insertion/ cyclization Cascade Reaction: Synthesis of Phenanthridines and Isoquinolines from Isocyanides. Chem. Commun. 2017, 53, 4585− 4588. (d) Li, X.; Fang, X.; Zhuang, S.; Liu, P.; Sun, P. Photoredox Catalysis: Construction of Polyheterocycles via Alkoxycarbonylation/ Addition/Cyclization Sequence. Org. Lett. 2017, 19, 3580−3583. (e) Wang, Y.; Wang, J.; Li, G.; He, G.; Chen, G. Halogen-BondPromoted Photoactivation of Perfluoroalkyl Iodides: A Photochemical Protocol for Perfluoroalkylation Reactions. Org. Lett. 2017, 19, 1442−1445. (f) Li, X.; Liang, D.; Huang, W.; Sun, H.; Wang, L.; Ren, M.; Wang, B.; Ma, Y. Metal-free Photocatalyzed Cross Coupling of Aryl(heteroaryl)bromides with Isonitriles. Tetrahedron 2017, 73, 7094−7099. (7) (a) Tobisu, M.; Koh, K.; Furukawa, T.; Chatani, N. Modular Synthesis of Phenanthridine Derivatives by Oxidative Cyclization of 2-Isocyanobiphenyls with Organoboron Reagents. Angew. Chem., Int. Ed. 2012, 51, 11363−11366. (b) Leifert, D.; Daniliuc, C. G.; Studer, A. 6-Aroylated Phenanthridines via Base Promoted Homolytic Aromatic Substitution (BHAS). Org. Lett. 2013, 15, 6286−6289. (c) Xu, Y.; Chen, Y.; Li, W.; Xie, W.; Shao, L. Microwave-Assisted Synthesis of Phenanthridines by Radical Insertion/Cyclization of Biphenyl Isocyanides. J. Org. Chem. 2016, 81, 8426−8435. (d) Guo, W.; Dou, Q.; Hou, J.; Wen, L.; Li, M. Synthesis of 6-Phosphorylated Phenanthridines by Mn(II)-Promoted Tandem Reactions of 2-Biaryl Isothiocyanates with Phosphine Oxides. J. Org. Chem. 2017, 82, 7015−7022. (e) Yao, Q.; Zhou, X.; Zhang, X.; Wang, C.; Wang, P.; Li, M. Convenient Synthesis of 6-Alkylphenanthridines and 1Alkylisoquinolines via Silver-catalyzed Oxidative Radical Decarboxylation. Org. Biomol. Chem. 2017, 15, 957−971. (8) (a) Gerfaud, T.; Neuville, L.; Zhu, J. Palladium-catalyzed Annulation of Acyloximes with Arynes (or Alkynes): Synthesis of Phenanthridines and Isoquinolines. Angew. Chem., Int. Ed. 2009, 48, 572−577. (b) Linsenmeier, A. M.; Williams, C. M.; Bräse, S. Synthesis of Phenanthridine Derivatives via Photolysis. J. Org. Chem. 2011, 76, 9127−9132. (c) Zhu, T.; Wang, S.; Tao, Y.; Wei, T.; Ji, S. Co(acac)2/O2-Mediated Oxidative Isocyanide Insertion with 2Arylanilines: Efficient Synthesis of 6-Aminophenanthridine Derivatives. Org. Lett. 2014, 16, 1260−1263. (d) Han, W.; Zhou, X.; Yang, S.; Xiang, G.; Cui, B.; Chen, Y. Palladium-catalyzed Nucleophilic Substitution/C−H Activation/Aromatization Cascade Reaction: One Approach To Construct 6-Unsubstituted Phenanthridines. J. Org. Chem. 2015, 80, 11580−11587. (e) Guo, W.; Li, S.; Tang, L.; Li, M.; Wen, L.; Chen, C. Synthesis of 6-(Arylthio)phenanthridines by Copper-Catalyzed Tandem Reactions of 2-Biaryl Isothiocyanates with Diaryliodonium Salts. Org. Lett. 2015, 17, 1232−1235. (f) Liu, X.; Mao, R.; Ma, C. Crossover-Annulation/Oxygenation Approach to Functionalized Phenanthridines by Palladium−Copper Relay Catalysis. Org. Lett. 2017, 19, 6704−6707. (g) Zhao, H.; Liu, Z.; Song, J.; Xu, H. Reagent-Free C-H/N-H Cross-coupling: Regioselective Synthesis of N-Heteroaromatics from Biarylaldehydes and NH3. Angew. Chem., Int. Ed. 2017, 56, 12732−12735. (9) Reviews: (a) Jackman, M. M.; Cai, Y.; Castle, S. L. Recent Advances in Iminyl Radical Cyclizations. Synthesis 2017, 49, 1785− 1795. (b) Tumir, L. M.; Radic-Stojkovic, M.; Piantanida, I. Comeback of Phenanthridine and Phenanthridinium Derivatives in the 21st Century. Beilstein J. Org. Chem. 2014, 10, 2930−2954. (c) Zhang, B.; Studer, A. Recent Advances in the Synthesis of Nitrogen Heterocycles via Radical Cascade Reactions Using Isonitriles as Radical Acceptors. Chem. Soc. Rev. 2015, 44, 3505−3521. (d) Lei, J.; Huang, J. B.; Zhu,

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support in the form of a Grant-in−Aid for Scientific Research (No. 18K05118) from the Ministry of Education, Culture, Sports, Science, and Technology in Japan is gratefully acknowledged.

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Preparation of Phenanthridines from o-Cyanobiaryls via Addition of

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