Regioselective synthesis of benzonitriles via amino-catalyzed [3+3] benzannulation reaction

Abstract

A straightforward synthesis of benzonitriles is achieved via amino-catalyzed [3+3] benzannulation of α,β-unsaturated aldehydes and 4-arylsulfonyl-2-butenenitriles. Using pyrrolidine as an organocatalyst via iminium activation, a series of substituted benzonitriles were obtained in good to high yields in a regioselective manner. This reaction can proceed smoothly under mild reaction conditions and without the aid of any metals, additional oxidants, or strong bases, thus making this an efficient and environmentally friendly method to access benzonitriles.

Keywords

α,β-unsaturated aldehyde 4-arylsulfonyl-2-butenenitrile aminocatalysis benzannulation benzonitrile

Introduction

Benzonitriles are privileged structural elements found in a number of pharmaceuticals, agrochemicals, and natural products.¹ Diverse biological activities render this kind of molecule therapeutically important agents in medicinal chemistry. For example, citalopram has been used as an antidepressant in clinical practice (Figure 1).² Letrozole has been ratified as a marked drug to treat breast cancer.³ Bicalutamide, as a nonsteroidal antiandrogen, has been approved by Food and Drug Administration (FDA) for the treatment of prostate cancer.⁴ Cromakalim, which could open the potassium channel, is a potential drug used in therapy of high blood pressure.⁵ Apart from these, the cyano group in benzonitriles also plays as an important functional group in organic synthesis due to the multiple possibilities of transforming into other functional groups such as carboxylic acids, amide, and amine.⁶

Figure 1.

Examples of pharmaceutically important benzonitriles.

Owing to the importance and noteworthy utility of aromatic nitriles, numerous efforts are devoted for their synthesis. One of the most representative methods is the traditional S_NAr reactions, in which aromatics such as sodium benzenesulfonates, benzenediazonium chlorides, and bromobenzenes react with cyanides via a C–C bond formation process.⁷ Although S_NAr approach has long been proved to be efficient in incorporating a cyano group into aromatic rings, it suffers from the common drawbacks of employing toxic cyanide sources and harsh reaction conditions and generating a stoichiometric amount of heavy metal waste. On the other hand, transition-metal-catalyzed cross-coupling reactions with a variety of cyanating reactants have been established as well.⁸ However, requiring expensive reagents and contamination with heavy metal residues restrict their practical applicability.

In recent years, benzannulation reaction, an assembly of readily available acyclic precursors into polysubstituted arenes, has received much attention due to its high efficiency, functional flexibility, and superior control of regiochemical outcome.^9,10 In this area, formation of benzonitrile cores relies largely on the rational integration of acyclic building blocks which bear one or more cyano groups into aromatic scaffolds. Hence, synthesis of benzannulated benzonitriles to a great extent avoids introducing toxic cyanide sources and provides much broader substrate scope. Despite being more in line with the requirements of environmental concern, the examples of building benzonitrile backbones via metal-free benzannulation are still relatively few compared to those by transition-metal catalysis.¹¹ In 2007, the Deng group reported the base-mediated [4+2] benzannulation of vinyl malononitriles and nitroolefins.¹² Since then, various types of benzannulation such as [3+2+1],^13,14 [3+3],^15–17 and [4+2]¹⁸ have been uncovered. As an alternative, Wang¹⁹ and Ye²⁰ groups independently reported a benzannulation route by N-heterocyclic carbene catalysis. However, we notice that most of these metal-free cases require the attendance of added strong bases for nucleophilic activation in mechanism. In view of the synthetic value and inspired by the growing demand for developing new benzannulation strategies to diversify substituted benzonitriles, we report here the synthesis of substituted benzonitriles via amino-catalyzed regioselective [3+3] benzannulation of enals and 4-arylsulfonyl-2-butenenitriles.

Results and discussion

To obtain the optimized benzannulation conditions for substituted benzonitriles, we selected (E)-cinnamaldehyde 1a and (E/Z)-4-phenylsulfonyl-2-butenenitrile 2a as model substrates. As shown in Table 1, the benzannulation was first treated with different kinds of nucleophilic aminocatalysts in air. To our delight, the expected [3+3] benzannulation could smoothly proceed under the catalysis of 20 mol% of pyrrolidine 3a, furnishing a sulfonyl benzonitrile 4a as a sole isomer in 77% yield within 5 h in chloroform at room temperature (Table 1, entry 1). Other nucleophilic catalysts like piperidine 3b, morpholine 3c, pyridine 3d, and 4-dimethylaminopyridine (DMAP) 3e all produced inferior results (Table 1, entries 2–5). All the tested catalysts produced complete conversion of 2a accompanied by various levels of inseparable byproducts, which seemed to be derived from some unwanted condensation of 2a. With pyrrolidine as catalyst, increasing the catalytic amount to 30 mol% could improve the yield to 83% (Table 1, entry 6), whereas the decrease of catalyst loading to 10 mol% had a deleterious effect on reaction yield and caused significantly prolonged reaction time (69%, 12 h, Table 1, entry 7). Next, the reaction was carried out in different solvents such as dichloroethane (DCE), tetrahydrofuran (THF) and benzotrifluoride, and the efficiency was less than that in chloroform (Table 1, entries 8–12). Then, we turned our attention to the effect of reaction temperature. It was found that the yield benefited from elevating reaction temperature to 40 °C (86%; Table 1, entry 13). Further elevating temperature led to a diminution of the yield (80%; Table 1, entry 14). Moreover, albeit with a longer reaction time, the yield seemed slightly improved when diluting the concentration of 2a to 0.05 M (88%; Table 1, entry 15). It was observed that acetic acid as additive²¹ brought down product yield (75%; Table 1, entry 16), whereas the addition of 4Å molecular sieves (4Å MS) as a water scavenger offered a slightly higher yield (89%; Table 1, entry 17). Finally, the conditions outlined in entry 17 were identified as optimal.

Table 1.

Optimization of reaction conditions.^a


Entry	Catalyst (3)	Solvent	T (°C)	t (h)	Yield (%)^b
1^c	Pyrrolidine (3a)	CHCl₃	25	5	77
2^c	Piperidine (3b)	CHCl₃	25	5	70
3^c	Morpholine (3c)	CHCl₃	25	5	38
4^c	Pyridine (3d)	CHCl₃	25	5	52
5^c	DMAP (3e)	CHCl₃	25	5	63
6	Pyrrolidine (3a)	CHCl₃	25	5	83
7^d	Pyrrolidine (3a)	CHCl₃	25	12	69
8	Pyrrolidine (3a)	DCE	25	5	60
9	Pyrrolidine (3a)	CH₃CN	25	5	62
10	Pyrrolidine (3a)	Toluene	25	5	56
11	Pyrrolidine (3a)	THF	25	5	73
12	Pyrrolidine (3a)	PhCF₃	25	5	48
13	Pyrrolidine (3a)	CHCl₃	40	3	86
14	Pyrrolidine (3a)	CHCl₃	50	3	80
15^e	Pyrrolidine (3a)	CHCl₃	40	5	88
16^e,f	Pyrrolidine (3a)	CHCl₃	40	5	75
17^e,g	Pyrrolidine (3a)	CHCl₃	40	5	89

DMAP: dimethylaminopyridine; DCE: dichloroethane; THF: tetrahydrofuran.

Reaction conditions: unless otherwise noted, [3+3] benzannulation was conducted with (E)-cinnamaldehyde 1a (0.15 mmol), (E/Z)-4-phenylsulfonyl-2-butenenitrile 2a (0.1 mmol) and catalyst 3 (30 mol%) in solvent (1 mL) at indicated reaction temperature.

Yield of isolated product.

20 mol% of catalyst.

10 mol% of catalyst.

2 mL of solvent.

0.03 mmol of AcOH was added.

50 mg 4Å MS was added.

With the optimized reaction conditions in hand, we evaluated the substrate scope of this amino-catalyzed [3+3] benzannulation reaction. As depicted in Table 2, through reaction with 4-arylsulfonyl-2-butenenitrile 2, a large range of aromatic enals 1 could be regioselectively converted into functionalized benzonitriles 4 under current established reaction conditions. Among them, α,β-unsaturated aldehydes bearing a halogen functional group (Cl or Br) at the ortho, meta, or para position of benzene moiety were suitable substrates to furnish corresponding products 4b–g in 71%–79% yields (Table 2, entries 2–7). Enals with stronger electron-withdrawing groups such as trifluoromethyl, nitro or dichloro rendered somewhat lower yield (4h–k, Table 2, entries 8–11). In comparison, cinnamaldehyde derivatives which bear electron-donating substituents such as methyl, methoxy or dimethoxy gave higher yields (4l–o, Table 2, entries 12–15). Moreover, a sterically encumbered 1-naphthyl counterpart also showed favorable reactivity, giving 4p in 82% yield (Table 2, entry 16). Similarly, heteroaromatic enals were well tolerated with present reaction system, affording 4q and 4r in 82% and 78% yields, respectively (Table 2, entries 17 and 18). As anticipated, 4-p-(toluenesulfonyl)-2-butenenitrile 2b was smoothly converted into target product 4s in 85% yield (Table 2, entry 19). Unfortunately, inseparable mixture was obtained from trans-crotonaldehyde engaged reaction. We speculated it might be resulted from the co-existent dienamine activation, which would complicate the reaction pathways. To further evaluate the generality of this process, we carried out a gram-scale reaction under the standard conditions. The desired 4a was afforded in 85% yield, which was approximately the same with that obtained in small-scale reaction.

Table 2.

Substrate scope of the [3+3] benzannulation.^a


Entry	Ar	Ar′	4	Yield (%)^b
1	Ph	Ph	4a	89 (85)^c
2	p-ClC₆H₄	Ph	4b	76
3	p-BrC₆H₄	Ph	4c	71
4	m-ClC₆H₄	Ph	4d	79
5	m-BrC₆H₄	Ph	4e	74
6	o-ClC₆H₄	Ph	4f	76
7	o-BrC₆H₄	Ph	4g	72
8	p-CF₃C₆H₄	Ph	4h	66
9	p-NO₂C₆H₄	Ph	4i	69
10	m-NO₂C₆H₄	Ph	4j	73
11	3,4-Cl₂C₆H₃	Ph	4k	71
12	p-MeC₆H₄	Ph	4l	88
13	m-MeC₆H₄	Ph	4m	86
14	p-MeOC₆H₄	Ph	4n	85
15	3,4-(MeO)₂C₆H₄	Ph	4o	80
16	1-naphthyl	Ph	4p	82
17	2-furyl	Ph	4q	82
18	2-thienyl	Ph	4r	78
19	Ph	p-MeC₆H₄	4s	85

Reaction conditions: all reactions were carried out with 1 (0.15 mmol), 2 (0.1 mmol), 3a (30 mol%), and 4Å MS (50 mg) in CHCl₃ (2 mL) at 40 °C for 5 h.

Yield of isolated product.

A gram-scale reaction of 1a (7.5 mmol) and 2a (5 mmol) was carried out under the optimal reaction conditions.

The structure of benzannulated benzonitrile 4g was determined by detailed one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) spectroscopic analysis see supplemental material).

On the basis of the above results and earlier report,²² a possible mechanism for this amino-catalyzed [3+3] benzannulation reaction is proposed in Scheme 1. Upon treatment of catalytic amount of pyrrolidine 3a, cinnamaldehyde 1a is first activated into the form of iminium ion 5. Although the subsequent conjugate addition may take place at either C₁ or C₃ site of 2a to generate zwitterionic intermediate 6′ (route a) or 6 (route b), respectively, the observed absolute regioselectivity proves the latter site is preferred. We speculate that the steric repulsion between bulky phenylsulfonyl group of 2a and phenyl moiety of 5 presumbly prevents C₁ site from participating Michael addition. Thus, the reaction proceeds in a highly regioselective manner at the less hindered C₃ site to afford 6. Subsequently, sequential intramolecular 1,3-H-shift and C=C double bond migration of 6 results in the formation of 7, which undergoes intramolecular imino-aldol reaction followed by release of 3a to give cyclohexadiene 8. Finally, benzonitrile 4a, rather than 4a′ (through sterically disfavored transformation pathway), is formed via oxidative aromatizaion of 8 in the presence of molecular oxygen from air.

Scheme 1.

Proposed reaction mechanism.

Conclusion

In summary, we have described an efficient method for the regioselective synthesis of multi-substituted benzonitriles via [3+3] benzannulation of α,β-unsaturated aldehydes with 4-arylsulfonyl-2-butenenitriles. Promoted by iminium activation of nucleophilic amonicatalyst, the benzannulation reaction proceeds with absolute regioselectivity and displays good substrate scope, and generates a series of benzonitriles bearing a sulfonyl group rapidly in good to high yields under the optimized reaction conditions. Compared with previous reports, this methodology involves no transition-metal catalysts or any added strong bases. Thus, it has the advantages of environmentally benign, mild reaction conditions and convenient in application. Further studies on organocatalytic benzannulation reactions are currently underway.

Experiment

¹H NMR and ¹³C NMR spectra were recorded on a Bruker AV 400 MHz spectrometer with tetramethylsilane (TMS) as internal reference. High-resolution electrospray ionization mass spectrometry (ESI HRMS) was recorded on a Waters SYNAPT G2 mass spectrometer. Melting points were determined in open capillary tubes and were uncorrected. Flash column chromatography was performed on silica gel (200–300 mesh). All solvents were dried and redistilled before use. Chemical reagents were used as commercially available and without further purification, unless otherwise stated.

Synthesis of 4-arylsulfonyl-2-butenenitrile (2a, 2b); general procedure

Synthetic procedure was based on the literature with little modification.^23,24 To a solution of 3-butenenitrile (5 g, 74.5 mmol) in CCl₄ (50 mL) was added bromine (4.1 mL, 78.2 mmol) in CCl₄ (20 mL) dropwise with stirring at 0 °C over 10 min. Stirring was continued at room temperature for 1 h. After the completion of the reaction, the reaction was quenched with saturated aqueous Na₂S₂O₃ and then extracted with CH₂Cl₂ (25 mL × 3). The combined organic phase was washed sequentially with water, saturated brine and dried over anhydrous Na₂SO₄ and concentrated in vacuum. The crude adduct, 3,4-dibromobutanenitrile (16.1 g, 95%), was used without further purification.

To a solution of 3,4-dibromobutanenitrile (16.1 g, 70.8 mmol) in dry THF (80 mL) was added Et₃N (10.3 mL, 74.3 mmol) dropwise in a period of 0.5 h at 0 °C. Then the reaction was stirred at the same temperature for 0.5 h. After the completion of the reaction, the reaction was quenched with saturated aqueous NH₄Cl and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed sequentially with water, saturated brine, and dried over anhydrous Na₂SO₄ and concentrated in vacuum to yield crude 4-bromobut-2-enenitrile (8.5 g, 82%), which was used without further purification.

Sodium sulfinate (69.7 mmol) was added in one portion to a solution of 4-bromobut-2-enenitrile (8.5 g, 58.1 mmol) in ethanol (100 mL). The reaction mixture was reflux for 4 h. After consumption of the 4-bromobut-2-enenitrile monitored by thin-layer chromatography (TLC) analysis, the solvent was removed in vacuum. The mixture was added water and extracted with CH₂Cl₂ (25 mL × 3). The combined organic phase was washed sequentially with water, saturated brine and dried over anhydrous Na₂SO₄ and concentrated in vacuum. The residue was recrystallized from ethanol to give the desired 4-arylsulfonyl-2-butenenitrile 2.

4-Phenylsulfonyl-2-butenenitrile (2a): White solid; yield 69% (for three steps); Z/E = 1:1; m.p. 70 °C–72 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.92–7.86 (m, 2H), 7.74–7.70 (m, 1H), 7.63–7.58 (m, 2H), 6.56, 6.55 (2dt, J = 16.0 Hz, 4.0 Hz; 16.0 Hz, 8.0 Hz, 1H), 5.58, 5.43 (2d, J = 8.0 Hz; 16.0 Hz, 1H), 4.17, 3.94 (2d, J = 8.0 Hz; 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 140.0 (139.5), 138.0 (137.8), 134.7 (134.7), 129.7 (129.7), 128.5 (128.5), 115.7 (114.0), 108.3 (107.3), 59.6 (58.5); ESI HRMS: calcd for C₁₀H₉NO₂S+Na 230.0252; found: 230.0260.

4-p-(Toluenesulfonyl)-2-butenenitrile (2b): White solid; yield 73% (for three steps); Z/E = 1:1; m.p. 74 °C–76 °C; ¹H NMR (400 MHz, CDCl₃): δ 7.76, 7.73 (2d, J = 8.0 Hz, 12.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H), 6.54, 6.53 (2dt, J = 16.0 Hz, 8.0 Hz; 12.0 Hz, 8.0 Hz, 1H), 5.60, 5.46 (2d, J = 12.0 Hz; 16.0 Hz, 1H), 4.16, 3.96 (2d, J = 8.0 Hz; 8.0 Hz, 2H), 2.46 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 145.7 (145.6), 140.2 (139.5), 134.8 (134.6), 130.1 (130.1), 128.2 (128.2), 115.8 (114.0), 107.9 (107.0), 59.3 (58.3), 21.6 (21.6); ESI HRMS: calcd for C₁₁H₁₁NO₂S+Na 244.0408; found: 244.0415.

Synthesis of benzonitriles (4a–s): general procedure

To a mixture of α,β-unsaturated aldehyde 1 (0.15 mmol) and 4-arylsulfonyl-2-butenenitrile 2 (0.1 mmol) in dry chloroform (2 mL) was added pyrrolidine 3a (2.5 µL, 0.03 mmol) and 4Å molecular sieves (50 mg). The reaction mixture was stirred at 40 °C for 5 h. After consumption of 2 monitored by TLC analysis, the reaction mixture was directly purified by flash column chromatography on silica gel using petroleum/ethyl acetate as eluent to afford the benzonitrile 4.

4-(Phenylsulfonyl)-[1,1′-biphenyl]-2-carbonitrile (4a): White solid; yield 89%; m.p. 131 °C–134 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.31 (s, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.67–7.63 (m, 2H), 7.60–7.56 (m, 2H), 7.55–7.50 (m, 5H); ¹³C NMR (100 MHz, CDCl₃): δ 150.0, 141.6, 140.6, 136.5, 134.1, 133.2, 131.5, 131.3, 130.0, 129.8, 129.2, 128.8, 128.1, 117.2, 112.8; ESI HRMS: calcd for C₁₉H₁₃NO₂S+Na 342.0565; found: 342.0569.

4′-Chloro-4-(phenylsulfonyl)-[1,1′-biphenyl]-2-carbonitrile (4b): White solid, yield 76%; m.p. 144 °C–146 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.31 (d, J = 4.0 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 4.0 Hz, 2H), 7.65–7.62 (m, 2H), 7.60–7.56 (m, 2H), 7.50–7.45 (m, 4H); ¹³C NMR (100 MHz, CDCl₃): δ 148.6, 142.0, 140.5, 136.5, 134.9, 134.2, 133.2, 131.7, 131.2, 130.1, 129.9, 129.5, 128.1, 116.9, 112.7; ESI HRMS: calcd for C₁₉H₁₂ClNO₂S+Na 376.0175; found: 376.0177.

4′-Bromo-4-(phenylsulfonyl)-[1,1′-biphenyl]-2-carbonitrile (4c): White solid, yield 71%; m.p. 141 °C–143 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.31 (d, J = 4.0 Hz, 1H), 8.18 (dd, J = 8.0 Hz, 4.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.66–7.62 (m, 4H), 7.59–7.55 (m, 2H), 7.40 (d, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 148.6, 142.0, 140.4, 135.3, 134.1, 133.1, 132.4, 131.7, 131.1, 130.3, 129.8, 128.1, 124.7, 116.9, 112.6; ESI HRMS: calcd for C₁₉H₁₂BrNO₂S+Na 419.9670; found: 419.9673.

3′-Chloro-4-(phenylsulfonyl)-[1,1′-biphenyl]-2-carbonitrile (4d): White solid; yield 79%; m.p. 142 °C–144 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.32 (d, J = 4.0 Hz, 1H), 8.19 (dd, J = 8.0 Hz, 4.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.67–7.63 (m, 2H), 7.59–7.56 (m, 2H), 7.48–7.43 (m, 4H); ¹³C NMR (100 MHz, CDCl₃): δ 148.2, 142.2, 140.4, 138.1, 135.1, 134.2, 133.1, 131.7, 131.2, 130.4, 130.0, 129.8, 128.8, 128.1, 127.0, 116.7, 112.8; ESI HRMS: calcd for C₁₉H₁₂ClNO₂S+Na 376.0175; found: 376.0172.

3′-Bromo-4-(phenylsulfonyl)-[1,1′-biphenyl]-2-carbonitrile (4e): White solid; yield 74%; m.p. 155 °C–157 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.31 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.68–7.63 (m, 4H), 7.60–7.56 (m, 2H), 7.49 (d, J = 8.0 Hz, 1H), 7.41–7.37 (m, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 148.1, 142.2, 140.3, 138.3, 134.1, 133.0, 132.9, 131.6, 131.5, 131.1, 130.5, 129.7, 128.0, 127.3, 123.1, 116.6, 112.8; ESI HRMS: calcd for C₁₉H₁₂BrNO₂S+Na 419.9670; found: 419.9673.

2′-Chloro-4-(phenylsulfonyl)-[1,1′-biphenyl]-2-carbonitrile (4f): White solid; yield 76%; m.p. 140 °C–142 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.31 (d, J = 4.0 Hz, 1H), 8.19 (dd, J = 8.0 Hz, 4.0 Hz, 1H), 8.01 (d, J = 8.0 Hz, 2H), 7.68–7.65 (m, 1H), 7.62–7.57 (m, 3H), 7.53 (d, J = 8.0 Hz, 1H), 7.45–7.36 (m, 2H), 7.29 (d, J = 8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 147.6, 142.5, 140.3, 135.5, 134.2, 132.7, 132.2, 132.2, 131.1, 131.1, 130.9, 130.4, 129.9, 128.2, 127.3, 116.3, 114.7; ESI HRMS: calcd for C₁₉H₁₂ClNO₂S+Na 376.0175; found: 376.0177.

2′-Bromo-4-(phenylsulfonyl)-[1,1′-biphenyl]-2-carbonitrile (4g): White solid; yield 72%; m.p. 149 °C–152 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.30 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.69–7.65 (m, 1H), 7.62–7.58 (m, 3H), 7.45–7.42 (m, 1H), 7.37–7.33 (m, 1H), 7.27 (d, J = 8.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 149.2, 142.5, 140.4, 137.5, 134.2, 133.6, 132.2, 132.2, 131.2, 131.1, 130.7, 129.9, 128.2, 127.9, 122.4, 116.2, 114.6; ESI HRMS: calcd for C₁₉H₁₂BrNO₂S+H 397.9850; found: 397.9856.

4-(Phenylsulfonyl)-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carbonitrile (4h): White solid; yield 66%; m.p. 147 °C–149 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.34 (s, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.77 (d, J = 8.0 Hz, 2H), 7.68–7.64 (m, 4H), 7.60–7.57 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 148.2, 142.7, 140.4, 134.3, 133.2, 131.8, 131.3, 129.9, 129.3, 128.1, 126.2, 116.7, 113.0; ESI HRMS: calcd for C₂₀H₁₂F₃NO₂S+H 388.0619; found: 388.0610.

4′-Nitro-4-(phenylsulfonyl)-[1,1′-biphenyl]-2-carbonitrile (4i): White solid; yield 69%; m.p. 162 °C–164 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.39–8.35 (m, 3H), 8.25 (d, J = 12.0 Hz, 1H), 8.01 (d, J = 8.0 Hz, 2H), 7.72–7.65 (m, 4H), 7.62–7.58 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 148.7, 147.3, 143.2, 142.5, 140.2, 134.4, 133.2, 131.9, 131.3, 130.0, 130.0, 128.2, 124.4, 116.5, 113.0; ESI HRMS: calcd for C₁₉H₁₂N₂O₄S+Na 387.0415; found: 387.0418.

3′-Nitro-4-(phenylsulfonyl)-[1,1′-biphenyl]-2-carbonitrile (4j): White solid; yield 73%; m.p. 162 °C–164 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.39–8.36 (m, 3H), 8.26 (dd, J = 8.0 Hz, 4.0 Hz, 1H), 8.01 (d, J = 8.0 Hz, 2H), 7.91 (d, J = 8.0 Hz, 1H), 7.76–7.70 (m, 2H), 7.69–7.65 (m, 1H), 7.62–7.58 (m, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 148.7, 147.1, 143.1, 140.3, 138.0, 134.7, 134.4, 133.2, 132.0, 131.3, 130.4, 130.0, 128.2, 124.7, 123.9, 116.5, 113.1; ESI HRMS: calcd for C₁₉H₁₂N₂O₄S+Na 387.0415; found: 387.0415.

3′,4′-Dichloro-4-(phenylsulfonyl)-[1,1′-biphenyl]-2-carbonitrile (4k): White solid; yield 71%; m.p. 153 °C–155 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.32 (d, J = 4.0 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.67–7.62 (m, 2H), 7.60–7.56 (m, 4H), 7.40 (d, J = 12.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 147.2, 142.6, 140.3, 136.2, 134.7, 134.3, 133.7, 133.2, 131.8, 131.2, 131.1, 130.7, 129.9, 128.1, 128.0, 116.6, 112.8; ESI HRMS: calcd for C₁₉H₁₁Cl₂NO₂S+Na 409.9785; found: 409.9780.

4′-Methyl-4-(phenylsulfonyl)-[1,1′-biphenyl]-2-carbonitrile (4l): White solid; yield 88%; m.p. 114 °C–116 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.30 (d, J = 4.0 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.66–7.62 (m, 2H), 7.59–7.55 (m, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 2.42 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 148.9, 140.2, 139.6, 139.1, 132.9, 132.5, 132.0, 130.3, 130.0, 128.7, 128.7, 127.6, 126.9, 116.2, 111.4, 20.3; ESI HRMS: calcd for C₂₀H₁₅NO₂S+Na 356.0721; found: 356.0723.

3′-Methyl-4-(phenylsulfonyl)-[1,1′-biphenyl]-2-carbonitrile (4m): White solid; yield 86%; m.p. 116 °C–118 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.30 (s, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.67–7.63 (m, 2H), 7.60–7.56 (m, 2H), 7.41–7.37 (m, 1H), 7.34–7.29 (m, 3H), 2.42 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 150.1, 141.5, 140.6, 139.0, 136.5, 134.1, 133.1, 131.5, 131.3, 130.7, 129.8, 129.4, 129.0, 128.0, 125.9, 117.2, 112.7, 21.5; ESI HRMS: calcd for C₂₀H₁₅NO₂S+Na 356.0721; found: 356.0725.

4′-Methoxy-4-(phenylsulfonyl)-[1,1′-biphenyl]-2-carbonitrile (4n): Yellow solid; yield 85%; 132 °C–134 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.28 (s, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.66–7.62 (m, 2H), 7.59–7.55 (m, 2H), 7.50 (d, J = 4.0 Hz, 2H), 7.02 (d, J = 8.0 Hz, 2H), 3.86 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 161.1, 149.7, 140.9, 140.7, 134.0, 133.3, 131.5, 131.0, 130.3, 129.8, 128.7, 128.0, 117.5, 114.7, 112.3, 55.6; ESI HRMS: calcd for C₂₀H₁₅NO₃S+Na 372.0670; found: 372.0673.

3′,4′-Dimethoxy-4-(phenylsulfonyl)-[1,1′-biphenyl]-2-carbonitrile (4o): Yellow solid; yield 80%; m.p. 139 °C–141 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.29 (d, J = 4.0 Hz, 1H), 8.14 (d, J = 12.0 Hz, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.67–7.62 (m, 2H), 7.59–7.55 (m, 2H), 7.12 (d, J = 8.0 Hz, 1H), 7.08 (d, J = 4.0 Hz, 1H), 6.98 (d, J = 8.0 Hz, 1H), 3.93 (s, 3H), 3.93 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 150.7, 149.7, 149.4, 141.1, 140.7, 134.0, 133.3, 131.5, 129.8, 128.0, 121.9, 112.4, 111.9, 111.6, 56.3, 56.2; ESI HRMS: calcd for C₂₁H₁₇NO₄S+H 380.0957; found: 380.0952.

2-(Naphthalen-1-yl)-5-(phenylsulfonyl)benzonitrile (4p): White solid; yield 82%; m.p. 131 °C–133 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.35 (s, 1H), 8.21 (d, J = 8.0 Hz, 1H), 8.03–8.01 (m, 3H), 7.98 (d, J = 8.0 Hz, 1H), 7.93–7.89 (m, 2H), 7.76 (d, J = 8.0 Hz, 1H), 7.65–7.56 (m, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 149.9, 141.6, 140.6, 134.1, 133.8, 133.6, 133.2, 133.1, 131.6, 131.5, 129.8, 129.1, 128.8, 128.7, 128.1, 127.9, 127.6, 127.1, 125.7, 117.2, 112.9; ESI HRMS: calcd for C₂₃H₁₅NO₂S+Na 392.0721; found: 392.0726.

2-(Furan-2-yl)-5-(phenylsulfonyl)benzonitrile (4q): Yellow solid; yield 82%; m.p. 126 °C–128 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.23 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 8.02 (d, J = 8.0 Hz, 1H), 7.96 (d, J = 8.0 Hz, 2H), 7.64–7.61 (m, 2H), 7.57–7.53 (m, 2H), 7.50 (d, J = 4.0 Hz, 1H), 6.59 (s, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 148.4, 145.1, 140.6, 140.3, 136.8, 134.0, 133.7, 131.7, 129.8, 127.9, 126.7, 117.6, 113.7, 113.1, 107.5; ESI HRMS: calcd for C₁₇H₁₁NO₃S+Na 332.0357; found: 332.0358.

5-(Phenylsulfonyl)-2-(thiophen-2-yl)benzonitrile (4r): Yellow solid; yield 78%; m.p. 128 °C–130 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.27 (d, J = 4.0 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.99–7.96 (m, 1H), 7.77–7.75 (m, 2H), 7.66–7.62 (m, 1H), 7.59–7.53 (m, 4H), 7.20–7.18 (m, 1H); ¹³C NMR (100 MHz, CDCl₃): δ 141.8, 141.0, 140.6, 137.7, 134.1, 133.9, 131.7, 130.5, 129.8, 129.6, 129.4, 129.0, 128.0, 117.5, 110.8; ESI HRMS: calcd for C₁₇H₁₁NO₂S₂+H 326.0309; found: 326.0313.

4-Tosyl-[1,1′-biphenyl]-2-carbonitrile (4s): White solid; yield 85%; m.p. 143 °C–145 °C; ¹H NMR (400 MHz, CDCl₃): δ 8.28 (d, J = 4.0 Hz, 1H), 8.16 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.54–7.49 (m, 5H), 7.37 (d, J = 8.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃): δ 149.7, 145.3, 142.0, 137.6, 136.6, 133.0, 131.4, 131.2, 130.4, 129.9, 129.1, 128.8, 128.1, 117.2, 112.7, 21.8; ESI HRMS: calcd for C₂₀H₁₅NO₂S+Na 356.0721; found: 356.0726.

Supplemental Material

Lin_Jiang-SUPPLEMENTARY_INFORMATION-200103 – Supplemental material for Regioselective synthesis of benzonitriles via amino-catalyzed [3+3] benzannulation reaction

Supplemental material, Lin_Jiang-SUPPLEMENTARY_INFORMATION-200103 for Regioselective synthesis of benzonitriles via amino-catalyzed [3+3] benzannulation reaction by Lin Jiang, Wen-Fei Jin, Liu-Dong Yu, Ming-Wei Yuan, Hong-Li Li, Deng-Bang Jiang and Ming-Long Yuan in Journal of Chemical Research

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was financially supported by the National Natural Science Foundation of China (21302163).

ORCID iD

Lin Jiang

Supplemental material

Supplemental material for this article is available online.

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