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Synthesis 2022; 54(10): 2480-2486
DOI: 10.1055/a-1731-9464
paper

FeCl3-Promoted Facile Synthesis of Multiply Arylated Nicotinonitriles

Kento Iwai  ∗
a   School of Environmental Science and Engineering, Kochi University of Technology, Kami, Kochi 782-8502, Japan
b   Research Center for Molecular Design, Kochi University of Technology, Kami, Kochi 782-8502, Japan
,
Haruka Yamauchi
a   School of Environmental Science and Engineering, Kochi University of Technology, Kami, Kochi 782-8502, Japan
,
Soichi Yokoyama
a   School of Environmental Science and Engineering, Kochi University of Technology, Kami, Kochi 782-8502, Japan
b   Research Center for Molecular Design, Kochi University of Technology, Kami, Kochi 782-8502, Japan
c   SANKEN, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047, Japan
,
Nagatoshi Nishiwaki  ∗
a   School of Environmental Science and Engineering, Kochi University of Technology, Kami, Kochi 782-8502, Japan
b   Research Center for Molecular Design, Kochi University of Technology, Kami, Kochi 782-8502, Japan
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Abstract

Many biologically active nicotinonitriles have been reported to date. Consequently, the development of synthetic methods for multiply arylated/alkylated nicotinonitriles remains a sought-after field of research. In the present work, a new synthetic strategy for multi-substituted nicotinonitriles is described. A FeCl3-promoted condensation–cyclization reaction of an enamino nitrile and α,β-unsaturated ketones proceeded efficiently with a wide range of substrates. It is noteworthy that this method facilitates access to fully and differently substituted nicotinonitriles, including tetra-arylated nicotinonitriles, in only three steps. Using the functionality of the cyano group, the copper-catalyzed annulation reaction of the nicotinonitrile was achieved to yield benzo­[c][2,7]naphthyridin-5(6H)-one.


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Key words

polysubstituted nicotinonitrile - iron(III) chloride - enamino nitrile - α,β-unsaturated ketone

A pyridine framework is often found in medicine, agrochemicals, natural products, and functional materials. Accordingly, the development of versatile and concise synthetic methods to access pyridines has been one of the main topics in heterocyclic chemistry, and it remains important. Among numerous pyridine derivatives, 3-cyano­pyridines (nicotinonitriles) are known to exhibit anticancer, antitumor, and antimicrobial activities,[1] and nicotino­nitriles also serve as precursors for various bioactive nicotinates and nicotinamides through the conversion of its cyano group.[2] Thus, multiply substituted nicotinonitriles are desired for drug discovery applications.

The modification of a nicotinonitrile scaffold[3] and direct cyanation of a pyridine ring[4] are straightforward strategies; however, these methods often require preliminary halogenation or metalation.[3] [4] Alternatively, condensation–­cyclization reactions are employed using a nitrile compound as the building block. This strategy is advantageous from the perspective of simple experimental alterations and availability of diverse cyano compounds and their counterparts, which enables the synthesis of a variety of multi-substituted nicotinonitriles.

Zoom Image
Figure 1 Conventional synthetic methods used to access nicotino­nitriles and major synthetic components

Commonly used condensation–cyclization reactions can be categorized into four types, based on the component pattern (Figure [1]), in which malononitrile (C–C–N source), enamino nitriles (C–C–N source), and keto nitriles (C–C source) are mainly used as a nitrile source. A combination of [C–C–N+C+C–C] (pattern a)[5] is the most familiar. This method uses aldehydes as a C unit, and the substituent at the 4- or 6-position can be easily modified. Similarly, a combination of the [2C–C+C+N] (pattern b) is represented by the Hantzsch type reaction,[6] in which enamines are generated in situ from carbonyl compounds with an N-source such as ammonia or ammonium acetate. 1,3-Dicarbonyls and α,β-unsaturated carbonyl compounds serve as an excellent C–C–C unit, which condense with a C–C–N unit (pattern c) [7] or with a combination of C–C and N unit (pattern d)[8] to construct pyridine frameworks. Although many useful methods for synthesizing nicotinonitriles have been reported, the development of a versatile synthetic method to introduce desired substituents at target positions remains an important topic of research. In particular, alkylation and/or arylation methods are limited, and few methods are known for synthesizing fully and differently substituted nicotinonitriles.[8a]

In our previous paper, we demonstrated a condensation–cyclization of an enamino ester and α,β-unsaturated ketones, leading to multiply substituted nicotinates.[9] Although this method suffered from the inert nature of β-aryl-α,β-unsaturated ketones due to steric hindrance, the use of FeCl3 was found to be effective to yield versatile nicotinates on demand. Under these conditions, FeCl3 served as both Lewis acid and oxidant. Based on these results, we investigated the synthesis of multiply substituted nicotinonitriles 3 through FeCl3-promoted condensation–cyclization reaction of an enamino nitrile 1 and an α,β-unsaturated ketone 2 (Scheme [1]).

Zoom Image
Scheme 1 Synthetic strategy for multi-substituted nicotinonitriles using FeCl3 as both an activator and an oxidant

When enamino nitrile 1a was allowed to react with α,β-unsaturated ketone 2a in the presence of FeCl3 under microwave heating, triarylnicotinonitrile 3a was obtained with 36% yield (Table [1], entry 1). Increasing the reaction temperature was effective for enhancing the yield of 3a to 42% (entry 2). In this reaction, considerable amounts of α-cyanoacetophenone 4a, the hydrolyzed product of 1a, was formed. Hence, increasing the amount of 1a, rather than the amount of FeCl3, was crucial to improve the yield of 3a, which was obtained in up to 80% yield (entries 3–5). Since addition of 1 equivalent of FeCl3 was enough to enable the reaction, the conditions shown in entry 5 were used for subsequent studies.

Table 1 Optimization of Reaction Conditions

Entry

Temp (°C)

1a (equiv)a

FeCl3 (equiv)a

Yield (%)a

Recovery (%)

3a

4a

1a

2a

1

150

2

1

36

30

15

50

2

180

2

3

42

31

 0

31

3

180

3

3

66

40

 0

12

4

180

5

3

80

36

 0

 5

5

180

5

1

80

28

17

 8

a The yield and equivalent were calculated based on the amount of 2a.

The structural determination of 3a was performed by 1H/13C NMR, IR spectroscopy and HRMS. A singlet signal at δ = 7.75 ppm was assigned to the ring proton at the 5-position of the pyridine ring in the 1H NMR spectrum. A 13C NMR signal at δ = 103.7 ppm and an IR absorption band at 2219 cm–1 revealed that the cyano group of 1a was retained, while the carbonyl group of 2a disappeared. In addition, new signals attributed to the pyridine ring appeared in the low field. A HRMS peak at m/z 375.1856 was consistent with the calculated formula weight of 3a (m/z 375.1855 [M+H]).

Based on the optimized conditions, the substrate scope of the reaction was studied (Scheme [2]). First, the substituent effect of 1 was studied. While phenyl- and electron-donating 4-methoxyphenyl-substituted enamino nitriles, 1b and 1c, underwent the reaction efficiently, an electron-withdrawing 4-(trifluoromethyl)phenyl group decreased the yield of 3d to a moderate level, which is presumably due to the lower nucleophilicity. The electronic properties of the β-substituent in 2 did not affect the reactivity towards the corresponding nicotinonitriles 3e–g, respectively; however, the reaction mixture became complex in the case of 4-nitrophenyl-substituted enone 2h. A 2-bromophenyl group was found to suppress this reaction because of congestion around the reaction site. When the substituent at the benzoyl group was changed, no significant difference in yield was observed between electron-donating and -withdrawing groups, and the corresponding nicotinonitriles 3j–l were obtained in moderate to good yields. In addition, a differently triaryl-substituted nicotinonitrile 3m was also synthesized with 89% yield. In the case of low-yield reactions, the starting materials 1 and 2 were completely consumed, but no by-products could be determined except for keto nitrile 4.

Zoom Image
Scheme 2 Scope and limitations. a Changes to conditions: 2 equiv of 1, 150 °C (MW).

The major advantage of this protocol is that substituents on the pyridine ring are easily modified by altering the substrates of enamino nitriles 1 and enones 2. Thus, it is possible to introduce an alkyl group. Indeed, 2,4-diarylated 6-methylnicotinonitriles 3n and 3o were synthesized in good yields under milder conditions when chalcones 2n and 2o were employed as the substrates, respectively. The synthesis of a fully substituted nicotinonitrile 3p was achieved under the same reaction conditions. Notably, fully and differently arylated nicotinonitrile 3q was successfully synthesized with 11% yield, which is the first synthesis of a differently tetra-arylated nicotinonitrile. The wide scope of substrates has high synthetic utility and facilitates tailor-made, molecular design.

Since the cyano group exhibited good chemical reactivity, a copper-catalyzed intramolecular cyclization of 3i was performed according to Hsieh’s procedure.[10] When a solution of nicotinonitrile 3i in t-BuOH was heated at 60 °C in the presence of NaOH and a catalytic amount of CuI, the hydration of the cyano group proceeded followed by the subsequent copper-catalyzed annulation to yield benzo­[c][2,7]naphthyridin-5(6H)-one 5 at 48% (Scheme [3]).

Zoom Image
Scheme 3 Copper-catalyzed annulation reaction of 3i

In summary, a versatile synthetic method of multiply substituted nicotinonitriles 3 was investigated by the FeCl3-promoted condensation–cyclization reaction of enamino nitriles 1 with α,β-unsaturated ketones 2. This reaction showed a wide substrate scope, which facilitated the successful synthesis of fully and differently substituted nicotinonitrile 3n and 3o in only three steps, including the preparation of substrates 1 and 2. Furthermore, nicotinonitrile 3i was transformed into benzo[c][2,7]naphthyridin-5(6H)-one 5 by connecting the cyano and the vicinal aryl group.

All reagents were purchased from commercial sources and used without further purification. 1H and 13C NMR spectra were recorded with Bruker DPX-400 and JEOL JMN-ECZ400S spectrometer (400 MHz and 100 MHz, respectively) in CDCl3 using TMS as internal standard. The assignments of the 13C NMR spectra were performed based on DEPT experiments. IR spectra were recorded with a JASCO FT/IR-4200 spectrophotometer equipped with an ATM detector. High-resolution mass spectra were obtained with an AB SCEIX Triplet TOF 4600 mass spectrometer. Melting points were recorded with an SRS-Optimelt automated melting-point system and are uncorrected. Microwave heating was performed with an Anton-Paar Microwave 300 (850 W, 2455 MHz) using a 10 mL glass vessel.


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Synthesis of Polysubstituted Pyridines 3; Typical Procedure

To a solution of 3-amino-3-(4-methylphenyl)-2-propenenitrile 1a (96.0 mg, 0.5 mmol) in acetonitrile (0.5 mL), were added 1,3-bis(4-methylphenyl)-2-propene-1-one 2a (76.6 mg, 0.1 mmol) and iron(II) chloride (147.1 mg, 0.1 mmol), and the resultant solution was heated at 180 °C for 1 h under microwave irradiation. After filtering through a silica gel short column (eluent: EtOAc), the eluted solution was evaporated under reduced pressure. The residue was dissolved in EtOAc (20 mL), the mixture was washed with water (3 × 20 mL), and the combined organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluent: chloroform) to afford the nicotinonitrile 3a.


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3-Cyano-2,4,6-tris(4-methylphenyl)pyridine (3a)

Yield: 30.0 mg (0.08 mmol, 80%); white solid; mp 82.5–83.4 °C.

1H NMR (400 MHz, CDCl3): δ = 2.43 (s, 3 H), 2.44 (s, 3 H), 2.45 (s, 3 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.37 (d, J = 8.0 Hz, 2 H), 7.38 (d, J = 8.0 Hz, 2 H), 7.59 (d, J = 8.0 Hz, 2 H), 7.75 (s, 1 H), 7.96 (d, J = 8.0 Hz, 2 H), 8.08 (d, J = 8.0 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 21.3 (CH3), 21.4 (CH3), 21.4 (CH3), 103.7 (C), 117.9 (CH), 118.2 (C), 127.5 (CH), 128.6 (CH), 129.2 (CH), 129.3 (CH), 129.6 (CH), 129.7 (CH), 134.1 (C), 135.0 (C), 135.5 (C), 140.0 (C), 140.1 (C), 140.8 (C), 155.3 (C), 159.0 (C), 162.3 (C).

IR (ATR): 2219 cm–1.

HRMS (ESI/TOF): m/z [M + H]+ calcd. for C27H22N2: 375.1855; found: 375.1856.


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3-Cyano-4,6-bis(4-methylphenyl)-2-phenylpyridine (3b)

Yield: 26.6 mg (74%); white solid; mp 157.8–158.6 °C.

1H NMR (400 MHz, CDCl3): δ = 2.43 (s, 3 H), 2.46 (s, 3 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.37 (d, J = 8.0 Hz, 2 H), 7.54–7.57 (m, 3 H), 7.59 (d, J = 8.0 Hz, 2 H), 7.78 (s, 1 H), 8.04 (dd, J = 8.0, 8.0 Hz, 2 H), 8.08 (d, J = 8.0 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 21.4 (CH3), 21.4 (CH3), 103.9 (C), 118.0 (C), 118.2 (CH), 127.5 (CH), 128.5 (CH), 128.6 (CH), 129.4 (CH), 129.6 (CH), 129.7 (CH), 129.9 (CH), 134.0 (C), 134.9 (C), 138.2 (C), 140.1 (C), 140.9 (C), 155.3 (C), 159.1 (C), 162.4 (C).

IR (KBr): 2220 cm–1.

HRMS (ESI/TOF): m/z [M + H]+ calcd. for C26H20N2: 361.1699; found: 361.1695.


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3-Cyano-2-(4-methoxyphenyl)-4,6-bis(4-methylphenyl)pyridine (3c)

Yield: 31.2 mg (80%); white solid; mp 178.6–179.3 °C.

1H NMR (400 MHz, CDCl3): δ = 2.43 (s, 3 H), 2.45 (s, 3 H), 3.90 (s, 3 H), 7.06 (d, J = 9.2 Hz, 2 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.36 (d, J = 8.0 Hz, 2 H), 7.57 (d, J = 8.0 Hz, 2 H), 7.72 (s, 1 H), 8.04 (d, J = 9.2 Hz, 2 H), 8.07 (d, J = 8.0 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 21.4 (CH3), 21.4 (CH3), 55.4 (CH3), 103.3 (C), 113.9 (CH), 117.6 (CH), 118.4 (C), 127.4 (CH), 128.5 (CH), 128.6 (CH), 128.7 (CH), 130.7 (C), 130.9 (CH), 134.2 (C), 135.0 (C), 140.0 (C), 140.7 (C), 155.4 (C), 158.9 (C), 161.2 (C), 161.8 (C).

IR (KBr): 2220 cm–1.

HRMS (ESI/TOF): m/z [M + H]+ calcd. for C27H22N2O: 391.1805; found: 391.1795.


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3-Cyano-4,6-bis(4-methylphenyl)-2-[4-(trifluoromethyl)phenyl]pyridine (3d)

Yield: 20.5 mg (48%); white solid; mp 207.1–207.9 °C.

1H NMR (400 MHz, CDCl3): δ = 2.44 (s, 3 H), 2.47 (s, 3 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.38 (d, J = 8.0 Hz, 2 H), 7.59 (d, J = 8.0 Hz, 2 H), 7.82 (d, J = 8.0 Hz, 2 H), 7.83 (s, 1 H), 8.07 (d, J = 8.0 Hz, 2 H), 8.15 (d, J = 8.0 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 21.3 (CH3), 21.4 (CH3), 104.1 (C), 117.6 (C), 118.7 (CH), 124.1 (q, J = 270.8 Hz, CF3), 125.5 (q, J = 3.6 Hz, CH), 127.5 (CH), 128.6 (CH), 129.7 (CH), 129.8 (CH), 129.8 (CH), 131.7 (q, J = 32.4 Hz, C), 133.7 (C), 134.5 (C), 140.4 (C), 141.2 (C), 141.5 (C), 155.5 (C), 159.3 (C), 160.9 (C).

IR (ATR): 2223 cm–1.

HRMS (ESI/TOF): m/z [M + H]+ calcd. for C27H19F3N2: 429.1573; found: 429.1573.


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3-Cyano-4-(4-methoxyphenyl)-2,6-bis(4-methylphenyl)pyridine (3e)

Yield: 25.0 mg (64%); yellow solid; mp 140.5–141.4 °C.

1H NMR (400 MHz, CDCl3): δ = 2.41 (s, 3 H), 2.44 (s, 3 H), 3.87 (s, 3 H), 7.05 (d, J = 8.8 Hz, 2 H), 7.29 (d, J = 8.0 Hz, 2 H), 7.34 (d, J = 8.4 Hz, 2 H), 7.63 (d, J = 8.8 Hz, 2 H), 7.71 (s, 1 H), 7.93 (d, J = 8.4 Hz, 2 H), 8.06 (d, J = 8.0 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 21.4 (CH3), 21.5 (CH3), 55.5 (CH3), 103.5 (C), 114.4 (CH), 117.6 (CH), 118.4 (C), 127.5 (CH), 129.1 (CH), 129.2 (C), 129.3 (CH), 129.7 (CH), 130.2 (CH), 135.0 (C), 135.5 (C), 140.1 (C), 140.7 (C), 154.9 (C), 158.9 (C), 161.0 (C), 162.4 (C).

IR (KBr): 2216 cm–1.

HRMS (ESI/TOF): m/z [M + H]+ calcd. for C27H23N2O: 391.1805; found: 391.1798.


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3-Cyano-4-(3-methoxyphenyl)-2,6-bis(4-methylphenyl)pyridine (3f)

Yield: 23.4 mg (60%); white solid; mp 120.0–121.0 °C.

1H NMR (400 MHz, CDCl3): δ = 2.44 (s, 3 H), 2.46 (s, 3 H), 3.90 (s, 3 H), 7.07 (ddd, J = 8.0, 1.6, 0.8 Hz, 1 H), 7.20 (dd, J = 1.6, 1.6 Hz, 1 H), 7.25 (ddd, J = 8.0, 1.6, 0.8 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.37 (d, J = 8.0 Hz, 2 H), 7.47 (dd, J = 8.0, 8.0 Hz, 1 H), 7.77 (s, 1 H), 7.96 (d, J = 8.0 Hz, 2 H), 8.09 (d, J = 8.0 Hz, 2 H).

13C NMR (101 MHz, CDCl3): δ = 21.5 (CH3), 21.5 (CH3), 55.6 (CH3), 103.8 (C), 114.3 (CH), 115.6 (CH), 118.0 (CH), 118.1 (CH), 121.1 (CH), 127.6 (CH), 129.3 (CH), 129.4 (CH), 129.8 (CH), 130.1 (CH), 134.9 (C), 135.4 (C), 138.3 (C), 140.3 (C), 141.0 (C), 155.2 (C), 159.1 (C),159.9 (C), 162.4 (C).

HRMS (ESI/TOF): m/z [M + H]+ calcd. for C27H23N2O: 391.1805; found: 391.1805.


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3-Cyano-2,6-bis(4-methylphenyl)-4-[4-(trifluoromethyl)phenyl]pyridine (3g)

Yield: 28.3 mg (66%); white solid; mp 215.8–216.8 °C.

1H NMR (400 MHz, CDCl3): δ = 2.44 (s, 3 H), 2.46 (s, 3 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.37 (d, J = 8.0 Hz, 2 H), 7.75 (s, 1 H), 7.79 (d, J = 8.4 Hz, 2 H), 7.83 (d, J = 8.4 Hz, 2 H), 7.96 (d, J = 8.0 Hz, 2 H), 8.08 (d, J = 8.0 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 21.5 (CH3), 21.5 (CH3), 103.5 (C), 117.6 (C), 117.7 (CH), 123.8 (q, J = 271.0 Hz, CF3), 126.0 (q, J = 3.6 Hz, CH), 127.5 (CH), 129.2 (CH), 129.3 (CH), 129.3 (CH), 129.8 (CH), 131.8 (q, J = 32.8 Hz, C), 134.5 (C), 135.1 (C), 140.4 (C), 140.5 (C), 141.2 (C), 153.8 (C), 159.4 (C), 162.4 (C).

IR (KBr): 2220 cm–1.

HRMS (ESI/TOF): m/z [M + H]+ calcd. for C27H19F3N2: 429.1573; found: 429.1571.


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3-Cyano-2,6-bis(4-methylphenyl)-4-(4-nitrophenyl)pyridine (3h)

Yield: 19.0 mg (47%); white solid; mp 265.7–266.5 °C.

1H NMR (400 MHz, CDCl3): δ = 2.44 (s, 3 H), 2.46 (s, 3 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.37 (d, J = 8.0 Hz, 2 H), 7.74 (s, 1 H), 7.84 (d, J = 8.4 Hz, 2 H), 7.96 (d, J = 8.0 Hz, 2 H), 8.09 (d, J = 8.0 Hz, 2 H), 8.42 (d, J = 8.4 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 21.4 (CH3), 21.4 (CH3), 103.2 (C), 117.4 (C), 117.5 (CH), 124.2 (CH), 127.5 (CH), 129.3 (CH), 129.4 (CH), 129.8 (CH), 129.9 (CH), 134.4 (C), 134.9 (C), 140.7 (C), 141.4 (C), 143.1 (C), 148.6 (C), 152.9 (C), 159.6 (C), 162.5 (C).

IR (KBr): 1345, 1516, 2220 cm–1.

HRMS (ESI/TOF): m/z [M + H]+ calcd. for C26H19N3O2: 406.1550; found: 406.1550.


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3-Cyano-4-(2-bromophenyl)-2,6-bis(4-methylphenyl)pyridine (3i)

Yield: 14.9 mg (34%); white solid; mp 120.0–121.0 °C.

1H NMR (400 MHz, CDCl3): δ = 2.44 (s, 3 H), 2.47 (s, 3 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.38 (ddd, J = 8.0, 8.0, 2.0 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 2 H), 7.44 (dd, J = 8.0, 2.0 Hz, 1 H), 7.49 (ddd, J = 8.0, 8.0, 1.2 Hz, 1 H), 7.72 (s, 1 H), 7.78 (dd, J = 8.0, 1.2 Hz, 1 H), 8.01 (d, J = 8.0 Hz, 2 H), 8.10 (d, J = 8.0 Hz, 2 H).

13C NMR (101 MHz, CDCl3): δ = 21.6 (CH3), 105.2 (C), 117.3 (C), 118.7 (C), 122.3 (C), 127.6 (C), 127.9 (C), 129.35 (C), 129.39 (C), 129.8 (C), 130.6 (C), 131.0 (C), 133.5 (C), 134.8 (C), 135.2 (C), 138.1 (C), 140.5 (C), 141.1 (C), 154.7 (C), 159.0 (C), 161.6 (C).

HRMS (ESI/TOF): m/z [M + H]+ calcd. for C26H20BrN2: 439.0804; found: 439.0801.


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3-Cyano-2,4-bis(4-methylphenyl)-6-phenylpyridine (3j)

Yield: 24.5 mg (68%); pale-yellow solid; mp 213.3–214.2 °C.

1H NMR (400 MHz, CDCl3): δ = 2.46 (s, 3 H), 2.46 (s, 3 H), 7.36 (d, J = 8.4 Hz, 2 H), 7.37 (d, J = 8.0 Hz, 2 H), 7.48–7.54 (m, 3 H), 7.59 (d, J = 8.4 Hz, 2 H), 7.78 (s, 1 H), 7.95 (d, J = 8.0 Hz, 2 H), 8.18 (dd, J = 7.2 Hz, J = 8.0 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 21.4 (CH3), 21.5 (CH3), 104.1 (C), 118.1 (C), 118.3 (CH), 127.5 (CH), 128.6 (CH), 128.9 (CH), 129.2 (CH), 129.3 (CH), 129.7 (CH), 130.4 (CH), 134.0 (C), 135.3 (C), 137.7 (C), 140.1 (C), 140.2 (C), 155.5 (C), 159.0 (C), 162.4 (C).

IR (KBr): 2219 cm–1.

HRMS (ESI/TOF): m/z [M + H]+ calcd. for C26H20N2: 361.1699; found: 361.1699.


#

3-Cyano-2,4-bis(4-methylphenyl)-6-(4-nitrophenyl)pyridine (3k)

Yield: 26.3 mg (65%); pale-yellow solid; mp 227.5–228.3 °C.

1H NMR (400 MHz, CDCl3): δ = 2.47 (s, 6 H), 7.38 (d, J = 8.0 Hz, 2 H), 7.39 (d, J = 8.0 Hz, 2 H), 7.59 (d, J = 8.0 Hz, 2 H), 7.85 (s, 1 H), 7.94 (d, J = 8.0 Hz, 2 H), 8.30–8.40 (m, 4 H).

13C NMR (100 MHz, CDCl3): δ = 21.4 (CH3), 21.5 (CH3), 105.5 (C), 117.6 (C), 119.0 (CH), 124.1 (CH), 128.4 (CH), 128.6 (CH), 129.3 (CH), 129.4 (CH), 129.8 (CH), 133.5 (C), 134.8 (C), 140.6 (C), 140.7 (C), 143.5 (C), 148.9 (C), 156.1 (C), 156.3 (C), 162.8 (C).

IR (KBr): 1345, 1532, 2220 cm–1.

HRMS (ESI/TOF): m/z [M + H]+ calcd. for C26H19N3O2: 406.1550; found: 406.1551.


#

3-Cyano-6-(4-methoxyphenyl)-2,4-bis(4-methylphenyl)pyridine (3l)

Yield: 23.8 mg (61%); yellow solid; mp 159.2–160.1 °C.

1H NMR (400 MHz, CDCl3): δ = 2.45 (s, 3 H), 2.45 (s, 3 H), 3.88 (s, 3 H), 7.01 (d, J = 8.8 Hz, 2 H), 7.35 (d, J = 8.4 Hz, 2 H), 7.36 (d, J = 8.4 Hz, 2 H), 7.57 (d, J = 8.4 Hz, 2 H), 7.70 (s, 1 H), 7.93 (d, J = 8.4 Hz, 2 H), 8.14 (d, J = 8.8 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 21.4 (CH3), 21.4 (CH3), 55.4 (CH3), 103.2 (C), 114.3 (CH), 117.4 (CH), 118.3 (C), 128.6 (CH), 129.1 (CH), 129.2 (CH), 129.3 (CH), 129.6 (CH), 130.2 (C), 134.2 (C), 135.5 (C), 140.0 (C), 140.1 (C), 155.2 (C), 158.5 (C), 161.7 (C), 162.3 (C).

IR (KBr): 2216 cm–1.

HRMS (ESI/TOF): m/z [M + H]+ calcd. for C27H22N2O: 391.1805; found: 391.1805.


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4-(4-Chlorophenyl)-3-cyano-2-(4-methylphenyl)-6-phenylpyridine (3m)

Yield: 33.8 mg (89%); pale-yellow solid; mp 256.0–256.7 °C.

1H NMR (400 MHz, CDCl3): δ = 2.45 (s, 3 H), 7.36 (d, J = 8.0 Hz, 2 H), 7.50–7.52 (m, 3 H), 7.54 (d, J = 8.4 Hz, 2 H), 7.62 (d, J = 8.8 Hz, 2 H), 7.75 (s, 1 H), 7.95 (d, J = 8.0 Hz, 2 H), 8.16–8.18 (m, 2 H).

13C NMR (100 MHz, CDCl3): δ = 21.5 (CH3), 103.9 (C), 117.7 (C), 118.1 (CH), 127.6 (CH), 129.0 (CH), 129.3 (CH), 129.3 (CH), 129.3 (CH), 130.0 (CH), 130.6 (CH), 135.1 (C), 135.3 (C), 136.3 (C), 137.5 (C), 140.5 (C), 154.2 (C), 159.3 (C), 162.5 (C).

IR (KBr): 2220 cm–1.

HRMS (ESI/TOF): m/z [M + H]+ calcd. for C25H17ClN2: 381.1153; found: 381.1152.


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3-Cyano-6-methyl-2-(4-methylphenyl)-4-phenylpyridine (3n)

Yield: 15.6 mg (55%); pale-yellow solid; mp 130.1–130.9 °C.

1H NMR (400 MHz, CDCl3): δ = 2.42 (s, 3 H), 2.71 (s, 3 H), 7.23 (s, 1 H), 7.32 (d, J = 8.0 Hz, 2 H), 7.51–7.53 (m, 3 H), 7.60–7.62 (m, 2 H), 7.80 (d, J = 8.0 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 21.4 (CH3), 25.1 (CH3), 103.5 (C), 117.8 (C), 121.7 (CH), 128.7 (CH), 128.9 (CH), 129.1 (CH), 129.3 (CH), 129.8 (CH), 135.2 (C), 136.6 (C), 140.1 (C), 154.6 (C), 161.2 (C), 162.5 (C).

IR (ATR): 2218 cm–1.

HRMS (ESI/TOF): m/z [M + H]+ calcd. for C20H16N2: 285.1386; found: 285.1387.


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3-Cyano-6-methyl-4-phenyl-2-[4-(trifluoromethyl)phenyl]pyridine (3o)

Yield: 15.2 mg (45%); colorless solid; mp 178.3–179.3 °C.

1H NMR (400 MHz, CDCl3): δ = 2.73 (s, 3 H), 7.32 (s, 1 H), 7.53–7.55 (m, 3 H), 7.61–7.63 (m, 2 H), 7.79 (d, J = 8.4 Hz, 2 H), 8.02 (d, J = 8.4 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 25.1 (CH3), 103.9 (C), 117.2 (C), 122.7 (CH), 124.0 (q, J = 270.7 Hz, C), 128.9 (q, J = 3.8 Hz, CH), 128.6 (CH), 129.0 (CH), 129.7 (CH), 130.0 (CH), 131.8 (q, J = 32.6 Hz, C), 136.2 (C), 141.3 (C), 154.7 (C), 160.9 (C), 162.3 (C).

IR (KBr): 2216 cm–1.

HRMS (ESI/TOF): m/z [M + H]+ calcd. for C20H13F3N2: 339.1103; found: 339.1103.


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4-(4-Chlorophenyl)-3-cyano-5-methyl-2-(4-methylphenyl)-6-phenylpyridine (3p)

Yield: 15.0 mg (38%); yellow solid.

1H NMR (400 MHz, CDCl3): δ = 2.15 (s, 3 H), 2.41 (s, 3 H), 7.30 (d, J = 8.0 Hz, 2 H), 7.37 (d, J = 8.8 Hz, 2 H), 7.45–7.51 (m, 3 H), 7.53 (d, J = 8.8 Hz, 2 H), 7.62 (dd, J = 8.0 Hz, J = 8.0 Hz, 2 H), 7.87 (d,, J = 8.0 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 18.1 (CH3), 21.4 (CH3), 106.0 (C), 117.3 (C), 127.5 (C), 128.3 (CH), 128.9 (CH), 129.0 (CH), 129.2 (CH), 129.4 (CH), 129.9 (CH), 134.8 (C), 135.1 (C), 135.4 (C), 139.7 (C), 140.1 (C), 154.6 (C), 158.6 (C), 162.1 (C).

IR (KBr): 2224 cm–1.

HRMS (ESI/TOF): m/z [M + H]+ calcd. for C26H19ClN2: 395.1309; found: 395.1308.


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4-(4-Chlorophenyl)-3-cyano-2,5-bis(4-methylphenyl)-6-phenyl­pyridine (3q)

Yield: 5.2 mg (11%); white solid.

1H NMR (400 MHz, CDCl3): δ = 2.24 (s, 3 H), 2.44 (s, 3 H), 6.72 (d, J = 8.0 Hz, 2 H), 6.88 (d, J = 7.6 Hz, 2 H), 7.10 (d, J = 8.4 Hz, 2 H), 7.22 (d, J = 8.4 Hz, 2 H), 7.26 (d, J = 8.0 Hz, 2 H), 7.36 (dt, J = 1.2 Hz, J = 8.0 Hz, 4 H), 7.96 (d, J = 8.0 Hz, 2 H).

13C NMR (100 MHz, CDCl3): δ = 21.2 (CH3), 21.4 (CH3), 106.4 (C), 117.5 (C), 124.2 (C), 127.6 (CH), 128.5 (CH), 128.5 (CH), 128.8 (CH), 129.2 (CH),129.3 (CH), 130.1 (CH), 130.8 (CH), 130.8 (CH), 132.9 (C), 133.2 (C), 134.7 (C), 134.8 (C), 137.1 (C), 140.3 (C), 154.1 (C), 157.2 (C), 160.1 (C), 160.6 (C).

IR (KBr): 2224 cm–1.

HRMS (ESI/TOF): m/z [M + Na]+ calcd. for C32H23ClN2Na: 493.1442; found: 493.1447.


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Synthesis of Benzo[c][2,7]naphthyridin-5(6H)-one (5)

To a solution of nicotinonitrile 3i (18.7 mg, 0.04 mmol) in t-BuOH (1 mL), were added sodium hydroxide (6.8 mg, 0.16 mmol) and copper(I) iodide (1 mg, 0.004 mmol), and resultant solution was heated at 60 °C for 2 d. The solution was poured into the water (5 mL), and extracted with CH2Cl2 (3 × 5 mL). The combined organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was reprecipitated with (CH2Cl2/hexane) to afford benzo­[c][2,7]naphthyridin-5(6H)-one 5.


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2,4-Bis(4-methylphenyl)benzo[c][2,7]naphthyridin-5(6H)-one (5)

Yield: 7.1 mg (0.019 mmol, 48%); white solid; mp 356 °C (decomp.).

1H NMR (400 MHz, DMSO-d 6): δ = 2.38 (s, 6 H), 7.21 (d, J = 8.0 Hz, 2 H), 7.31 (d, J = 7.6, 7.6 Hz, 1 H), 7.35 (d, J = 8.0 Hz, 2 H), 7.36 (d, J = 7.2 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.60 (dd, J = 7.6, 8.0 Hz, 4 H), 8.26 (d, J = 8.0 Hz, 2 H), 8.72 (d, J = 8.0 Hz, 1 H), 8.70 (s, 1 H), 11.5 (s, 1 H).

13C NMR (101 MHz, DMSO-d 6): δ = 21.2 (CH3), 110.3 (CH), 122.5 (CH), 116.0 (CH), 116.4 (C), 116.9 (C), 125.1 (CH),127.5 (CH), 127.9 (CH), 129.4 (CH),129.7 (CH), 132.0 (CH), 135.2 (C), 137.2 (C), 138.7 (C), 139.9 (C), 140.0 (C), 144.2 (C), 156.2 (C), 160.0 (C), 162.0 (C).

HRMS (ESI/TOF): m/z [M–H]– calcd. for C26H19N2O: 375.1503; found: 375.1518.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1731-9464.
  • Supporting Information

Corresponding Authors

Kento Iwai
Research Center for Material Science and Engineering, Kochi University of Technology
Kami, Kochi 782-8502
Japan   

Nagatoshi Nishiwaki
Research Center for Material Science and Engineering, Kochi University of Technology
Kami, Kochi 782-8502
Japan   

Publication History

Received: 09 December 2021

Accepted after revision: 05 January 2022

Accepted Manuscript online:
05 January 2022

Article published online:
09 February 2022

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Zoom Image
Figure 1 Conventional synthetic methods used to access nicotino­nitriles and major synthetic components
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Scheme 1 Synthetic strategy for multi-substituted nicotinonitriles using FeCl3 as both an activator and an oxidant
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Scheme 2 Scope and limitations. a Changes to conditions: 2 equiv of 1, 150 °C (MW).
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Scheme 3 Copper-catalyzed annulation reaction of 3i