Abstract
The efficient visible-light-promoted cyanomethylation of 2H-indazoles in the presence of Ir(ppy)3 as the photocatalyst and bromoacetonitrile as the cyanomethyl radical source was achieved under mild conditions, providing a series of C3-cyanomethylated derivatives in good yields.
Introduction
The cyanomethylation of (hetero)aromatic rings is of great research interest to organic and medicinal chemists due to the prevalence of cyano groups in biologically active molecules.1 Moreover, the cyano group can easily be converted to many other functional groups, such as primary amines, amides, carboxylic acids, esters, aldehydes, and heterocycles.2 Commonly, (hetero)arylacetonitriles are prepared through the cyanation of benzyl halides,3 the dehydration of arylacetaldoximes or amides,4 or the metal-catalyzed cross-coupling of aryl halides with functionalized acetonitriles.5 The radical cross-dehydrogenative coupling reaction of acetonitrile with a heterocycle developed in recent years also provides an alternative strategy for heteroarylacetonitrile synthesis.6 However, these strategies usually require the prefunctionalization of substrates, highly toxic cyanidation reagents, excess oxidants, or a high reaction temperature. Consequently, the exploration of highly efficient methods to access (hetero)arylacetonitriles is still highly desirable.
In the past years, visible-light photocatalysis has provided another suitable approach to installing the cyanomethyl group into the molecules of interest, benefiting from the advantages of its high efficiency, mild reaction conditions, energy-saving ability, and operation simplicity.7 Bromoacetonitrile is a cheap and commercially available compound that can be activated by visible-light catalyst to form the acetonitrile radical. It has been used as a cyanomethyl radical source for the cyanomethylation of activated alkenes, alkynes, and aldehydes via a radical pathway.8 However, few studies have focused on the dehydrogenative Csp2–H cyanomethylation of heterocycles with bromoacetonitrile through visible-light catalysis.9 On the other hand, indazoles, an important class of N-heterocycles, play an important role in organic synthesis and medical chemistry exhibiting a wide range of biological activities such as antitumor, antimicrobial, anti-inflammatory, antiplatelet, and anticontraceptive activity while being also applied in HIV protease inhibition.10 Many strategies have been developed to synthesize such important molecules.11 For example, the direct C3–H phosphonylation, amination, arylation, alkylation, and alkoxylation of 2H-indazole by visible-light photoredox have been reported previously.12 However, efficient protocols for various functionalizations of 2H-indazole are still urgently needed. With our continuous study on the sustainable modification of heterocycles,13 we herein present the efficient visible-light-promoted cyanomethylation of 2H-indazoles in the presence of Ir(ppy)3 as the photocatalyst and bromoacetonitrile as an inexpensive and readily available cyanomethyl radical source under mild conditions.
Results and Discussion
Initially, 2-phenyl-2H-indazoles (1a) with bromoacetonitrile (2) were selected as the model substrates. The reaction proceeded with 2 mol % Ir(ppy)3 as the photocatalyst and 2 equiv of K2HPO4 as the base in MeCN with 5 W blue LED irradiation at room temperature under argon atmosphere and provided the C3-cyanomethylated 2H-indazole 3a in 67% yield (Table 1, entry 1). Then, a series of photocatalysts were screened. Ru(bpy)3Cl2 and [Ir(dtbbpy)(ppy)2]PF6 only gave trace amounts of the product, while organic photocatalysts, such as rose bengal, methylene blue, and rhodamine 6G, did not show any catalytic activity in this reaction (Table 1, entries 2–6). Using Ir(ppy)3 as the photocatalyst, several commonly used bases such as K2CO3, Na2CO3, K3PO4, 2,6-lutidine, and N,N-diisopropylethylamine (DIPEA), were also studied, with K2HPO4 providing the best results this reaction system. (Table 1, entries 7–12). Different solvents (i.e., DMF, DCE, DCM, MeOH, DMSO, and acetone) were then evaluated (Table 1, entries 13–18), with DMSO providing the highest yield of the desired product 3a (73% yield, entry 17). No reaction happened without base (Table 1, entry 19). Improving the loading of photocatalyst or bromoacetonitrile did not improve the yield (Table 1, entries 20 and 21). The formation of product 3a was suppressed when the reaction was performed under air instead of argon (Table 1, entry 22). Notably, control experiments conducted in the absence of light or photocatalyst did not generate the target product (entries 23 and 24), indicating that both irradiation and photoredox catalysts are necessary.
Table 1. Optimization of Reaction Conditionsa.
| entry | catalyst | base | solvent | yieldb (%) |
|---|---|---|---|---|
| 1 | Ir(ppy)3 | K2HPO4 | MeCN | 67 |
| 2 | Ru(bpy)2Cl2 | K2HPO4 | MeCN | trace |
| 3 | [Ir(dtbbpy)(ppy)2]PF6 | K2HPO4 | MeCN | trace |
| 4 | Rhodamine 6Gh | K2HPO4 | MeCN | N.R. |
| 5 | Rose Bengalh | K2HPO4 | MeCN | N.R. |
| 6 | Methylene bluei | K2HPO4 | MeCN | N.R. |
| 7 | Ir(ppy)3 | K2CO3 | MeCN | trace |
| 8 | Ir(ppy)3 | Na2CO3 | MeCN | 48 |
| 9 | Ir(ppy)3 | NaHCO3 | MeCN | 11 |
| 10 | Ir(ppy)3 | K3PO4 | MeCN | 19 |
| 11 | Ir(ppy)3 | 2,6-lutidine | MeCN | 35 |
| 12 | Ir(ppy)3 | DIPEA | MeCN | trace |
| 13 | Ir(ppy)3 | K2HPO4 | DMF | N.R. |
| 14 | Ir(ppy)3 | K2HPO4 | DCE | 45 |
| 15 | Ir(ppy)3 | K2HPO4 | DCM | 28 |
| 16 | Ir(ppy)3 | K2HPO4 | MeOH | N.R. |
| 17 | Ir(ppy)3 | K2HPO4 | DMSO | 73 |
| 18 | Ir(ppy)3 | K2HPO4 | acetone | 61 |
| 19 | Ir(ppy)3 | DMSO | N.R. | |
| 20 | Ir(ppy)3 | K2HPO4 | DMSO | 73c |
| 21 | Ir(ppy)3 | K2HPO4 | DMSO | 63d |
| 22 | Ir(ppy)3 | K2HPO4 | DMSO | N.R.e |
| 23 | Ir(ppy)3 | K2HPO4 | DMSO | N.R.f |
| 24 | - | K2HPO4 | DMSO | N.R.g |
1a (0.2 mmol), 2a (0.4 mmol), photocatalyst (2 mol %), base (0.4 mmol), solvent (1.0 mL), under Ar atmosphere performed in a 25 mL sealed tube with a 5 W blue LED irradiation, r.t., for 24 h.
Isolated yield.
3 mol % Ir(ppy)3.
Bromoacetonitrile (0.8 mmol).
Under air.
In the dark.
Without photocatalyst.
With a 5 W green LED irradiation.
With a 5 W red LED irradiation.
With the optimized reaction conditions in hand, we next examined the scope of this protocol with different functionalities in the 2H-indazole system (Table 2). 2-Phenyl-2H-indazoles bearing an electron-donating group such as Me-, Et-, or MeO- on the 4- or 3-position of the N-2-phenyl ring reacted efficiently to produce C3-cyanomethylated 2H-indazoles in good yields (3a–3f). 2H-Indazoles containing an electron-withdrawing group, such as F–, Cl–, Br–, CF3–, CN–, and NO2–, also reacted smoothly, providing the respective products in 32–71% yields (3g–3p). Among them, 2H-indazoles with halogens such as F–, Cl–, and Br– substituted on the 4- or 3-position of the N-2-phenyl ring successfully reacted under the present reaction conditions to give the desired products 3g–3l in good yields. The products 3m–3o, respectively containing 4-CF3–, 3-CF3–, or 3-CN– substituents, were obtained in 55–71% yields. The nitro group was tolerated in the current reaction, and the product (3p) was obtained in 32% yield. Substrates with substituents on the ortho-position of the phenyl ring had relatively low yields of 34–40% (3q–3t), likely due to steric hindrance. In addition, disubstituted 2H-indazoles with substituents on the N-2-phenyl ring also provided the corresponding products 3u–3x in moderate yields. 2H-Indazoles bearing electron-donating groups (i.e., OMe– and Me−) as well as electron-withdrawing groups (i.e., F–, Cl–, and Br−) on the indazole ring efficiently reacted with 2 to produce the C3-cyanomethylated derivatives 3y–3ae in 44–65% yields. nBu- and Bn- groups at N-2 position of 2H-indazole afforded provided the desired products 3af–3ag in relatively low yields. N-2-Pyridyl-substituted 2H-indazole, 1-Me-1H-indazole, and 1-Ph-1H-indazole were unreactive under the standard reaction conditions.
Table 2. Substrate Scopea,b.
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), Ir(ppy)3 (2 mol%), K2HPO4 (0.4 mmol), DMSO (1 mL) under Ar atmosphere 24 h with 5 W blue LED irradiation.
Isolated yields are given.
To further demonstrate the viability of this approach, we transformed the nitrile group into an amide in the presence of K2CO3 and H2O2, obtaining the target product 4 in 80% yield (Scheme 1).
Scheme 1. Transformation of the C3-Cyanomethylated Compound 3b.
To gain insight into the mechanism of this transformation, we performed the reaction under standard conditions with the addition of the radical scavenger 2,2,6,6-tetramethylpiperidinooxyl (TEMPO) and obtained trace amounts of product 3a (Scheme 2). However, the coupling product 5 of TEMPO-CH2CN was captured by high-resolution mass spectrometry. These results indicated that the radical process may be involved in the cyanomethylation reaction.
Scheme 2. Radical-Trapping Experiments.
The Stern–Volmer fluorescence quenching experiments were conducted by mixing the photocatalyst Ir(ppy)3 with BrCH2CN, K2HPO4 and 1a, respectively, and these results are shown in Figure 1 (see the SI for details). We disclosed that the fluorescence of the excited photocatalyst could be remarkably quenched by BrCH2CN, while being rarely influenced by K2HPO4 and 1a. Moreover, the luminescence intensities exhibited an obvious linear correlation with the concentration of BrCH2CN, which indicated that BrCH2CN acted as an important quencher in this visible-light-promoted system.
Figure 1.
Luminescence quenching studies.
Based on these observations and literature, a plausible mechanism for the C3-cyanomethylation of 2H-indazoles with bromoacetonitrile is proposed (Scheme 3). Initially, the excited state [Ir(III)(ppy)3]* was formed under blue LED irradiation. Then, the excited [Ir(III)(ppy)3]* undergoes a single-electron transfer (SET) with 2 to generate radical A and [Ir(IV)(ppy)3]+. Subsequently, radical A attacks the π electrons at the C3-position of 1a to construct intermediate B, which is converted into intermediate C by undergoing single-electron oxidation. Finally, the radical intermediate C is deprotonated under the action of a base to produce 3a, during which [Ir(III) (ppy)3] is regenerated.
Scheme 3. Proposed Reaction Mechanism.
Conclusions
In summary, we successfully achieved the efficient visible-light-induced C3-cyanomethylation of 2H-indazoles using bromoacetonitrile as the cyanomethyl radical source and Ir(ppy)3 as the photocatalyst. Various cyanomethylated 2H-indazoles derivatives were prepared in moderate yields with a wide range of functional group tolerance at room temperature. This new protocol features a short synthetic route, green chemistry, low cost, and mild reaction conditions, making it an attractive strategy for installing cyanomethyl groups on 2H-indazoles.
Experimental Section
General Information
All catalytic reactions were carried out under argon atmosphere. Unless otherwise stated, all reagents were purchased without further purification. Analytical thin-layer chromatography (TLC) was performed on precoated silica gel GF254 plates. Visualization on TLC was achieved using UV light (254 nm). Column chromatography was undertaken on silica gel (200–300 mesh) using a proper eluent system. 1H, 13C, and 19F NMR spectra were recorded at 400, 101, and 376 MHz, respectively, with CDCl3 or DMSO-d6 as solutions. The chemical shifts δ are reported in ppm relative to tetramethylsilane or residual CHCl3 (δc = 77.00 ppm). The following abbreviations were used to describe peak splitting patterns when appropriate: s (singlet), d (doublet), t (triplet), q (quartet) m (multiplet), dd (doublet of doublet), ddd (doublet of doublet of doublet), td (triplet of doublet). Coupling constants, J, are reported in hertz (Hz). High-resolution mass spectrometry (HRMS) was performed on a Q-TOF spectrometer with micromass MS software using electrospray ionization (ESI). Emission intensities were recorded using an Edinburgh UK FLS100 photoluminescence spectrometer from 450 to 750 nm. Substituted 2H-indazole derivatives were prepared according to the published procedure.14
General Catalytic Procedure
Under argon atmosphere, a reaction tube (25 mL) equipped with a magnetic stirrer bar was charged with 2H-indazole (1, 0.2 mmol), bromoacetonitrile (2, 0.4 mmol, 28 uL), Ir(ppy)3 (0.004 mmol, 2 mol %, 2.6 mg), K2HPO4 (0.4 mmol, 55.3 mg), and DMSO (1.0 mL). The reaction mixture was stirred with a 5 W blue LED irradiation at room temperature for 24 h, filtered through a pad of celite, and then washed with ethyl acetate (3 × 10 mL). The solvent was removed under reduced pressure, and the residue was purified by chromatography on silica gel (eluent: EA/PE) to give the desired product 3.
2-(2-Phenyl-2H-indazol-3-yl)acetonitrile (3a)
34 mg, 73% yield, red oil. 1H NMR (400 MHz, CDCl3) δ 7.75 (dd, J = 8.7, 4.2 Hz, 2H), 7.62–7.48 (m, 5H), 7.37 (dd, J = 8.3, 7.0 Hz, 1H), 7.19 (dd, J = 8.3, 7.0 Hz, 1H), 4.05 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 148.7, 138.6, 129. 8, 129.7, 127.3, 125.8, 123.0, 122.8, 121.4, 118.9, 118.1, 115.0, 15.0. HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H12N3 234.1026, found 234.1024.
2-(2-(p-Tolyl)-2H-indazol-3-yl)acetonitrile (3b)
35 mg, 71% yield, pale red solid; mp 69–71 °C. 1H NMR (400 MHz, CDCl3) δ 7.75 (dd, J = 8.7, 4.0 Hz, 2H), 7.56–7.28 (m, 5H), 7.19 (dd, J = 8.5, 6.6 Hz, 1H), 4.05 (s, 2H), 2.46 (s, 3H).13C{1H} NMR (101 MHz, CDCl3) δ 148.6, 140.1, 136.1, 130.3, 127.1, 125.6, 122.9, 122.8, 121.3, 118.8, 118.1, 115.1, 21.3, 15.0. HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H14N3 248.1182, found 248.1180.
2-(2-(4-Ethylphenyl)-2H-indazol-3-yl)acetonitrile (3c)
33 mg, 63% yield; red oil. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 9.4 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H), 7.42–7.35 (m, 3H), 7.23–7.15 (m, 1H), 4.08 (s, 2H), 2.77 (q, J = 7.6 Hz, 2H), 1.31 (t, J = 7.6 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 148.6, 146.3, 136.2, 129.2, 127.2, 125.8, 122.9, 122.7, 121.3, 118.8, 118.2, 115.1, 28.6, 15.4, 15.1. HRMS (ESI-TOF) m/z [M + H]+ calcd for C17H16N3 262.1339, found 262.1341.
2-(2-(4-Methoxyphenyl)-2H-indazol-3-yl)acetonitrile (3d)
32 mg, 61% yield, pale yellow solid; mp 97–99 °C. 1H NMR (400 MHz, CDCl3) δ 7.75 (dd, J = 8.7, 3.3 Hz, 2H), 7.51–7.42 (m, 2H), 7.40–7.34 (m, 1H), 7.23–7.17 (m, 1H), 7.11–7.03 (m, 2H), 4.05 (s, 2H), 3.89 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.5, 148.5, 131.4, 127.2, 127.1, 122.9 (2C), 121.2, 118.8, 118.1, 115.1, 114.8, 55.7, 15.0. HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H14N3O 264.1131, found 264.1130.
2-(2-(m-Tolyl)-2H-indazol-3-yl)acetonitrile (3e)
30 mg, 61% yield, red oil. 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 9.4 Hz, 2H), 7.46 (m, 1H), 7.39–7.35 (m, 3H), 7.31 (d, J = 7.7 Hz, 1H), 7.20 (dd, J = 8.9, 6.7 Hz, 1H), 4.08 (s, 2H), 2.46 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 148.7, 140.2, 138.6, 130.6, 129.5, 127.3, 126.6, 123.0, 122.8, 122.7, 121.4, 118.9, 118.2, 115.1, 21.4, 15.1. HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H14N3 248.1182, found 248.1179.
2-(2-(3-Methoxyphenyl)-2H-indazol-3-yl)acetonitrile (3f)
34 mg, 65% yield, yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.75 (dd, J = 8.7, 4.2 Hz, 2H), δ 7.47 (t, J = 8.2 Hz, 1H), 7.41–7.35 (m, 1H), 7.23–7.17 (m, 1H), 7.09 (dd, J = 6.9, 3.7 Hz, 3H), 4.09 (s, 2H), 3.87 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 160.6, 148.7, 139.6, 130.5, 127.3, 123.1, 122.8, 121.4, 118.9, 118.2, 117.8, 116.1, 115.1, 111.4, 55.7, 15.1. HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H14N3O 264.1131, found 264.1131.
2-(2-(4-Fluorophenyl)-2H-indazol-3-yl)acetonitrile (3g)
33 mg, 65% yield, pale yellow solid; mp 111–113 °C. 1H NMR (400 MHz, CDCl3) δ 7.75 (dd, J = 8.7, 4.2 Hz, 2H), 7.58–7.51 (m, 2H), 7.43–7.36 (m, 1H), 7.32–7.26 (m, 2H), 7.22 (dd, J = 8.4, 6.7 Hz, 1H), 4.06 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 163.1 (d, J = 251.1 Hz), 148.7, 134.7 (d, J = 3.2 Hz), 127.9 (d, J = 8.9 Hz), 127.5, 123.3, 123.0, 121.4, 118.8, 118.2, 116.9 (d, J = 23.2 Hz), 114.9, 15.0. 19F NMR (376 MHz, CDCl3) δ −110.02. HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H11FN3 252.0932, found 252.0930.
2-(2-(3-Fluorophenyl)-2H-indazol-3-yl)acetonitrile (3h)
33 mg, 66% yield, pale yellow solid; mp 108–110 °C. 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 9.5 Hz, 2H), 7.57 (td, J = 8.3, 6.2 Hz, 1H), 7.42–7.32 (m, 3H), 7.31–7.26 (m, 1H), 7.24–7.17 (m, 1H), 4.11 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 162.9 (d, J = 250.4 Hz), 148.9, 139.9 (d, J = 9.7 Hz), 131.2 (d, J = 9.0 Hz), 127.7, 123.4, 122.8, 121.6, 121.5 (d, J = 3.4 Hz), 118.9, 118.2, 117.0 (d, J = 21.0 Hz), 114.8, 113.8 (d, J = 24.5 Hz), 15.1. 9F NMR (376 MHz, CDCl3) δ −109.25. HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H11FN3 252.0932, found 252.0931.
2-(2-(4-Chlorophenyl)-2H-indazol-3-yl)acetonitrile (3i)
38 mg, 70% yield, pale red solid; mp 143–145 °C. 1H NMR (400 MHz, CDCl3) δ 7.75 (dd, J = 8.7, 4.6 Hz, 2H), 7.60–7.47 (m, 4H), 7.42–7.35 (m, 1H), 7.21 (dd, J = 8.6, 6.3 Hz, 1H), 4.07 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 148.9, 137.1, 136.0, 130.0, 127.6, 127.1, 123.4, 122.9, 121.6, 118.8, 118.2, 114.9, 15.0. HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H11ClN3 268.0636, found 268.0634.
2-(2-(3-Chlorophenyl)-2H-indazol-3-yl)acetonitrile (3j)
33 mg, 61% yield, yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 9.5 Hz, 2H), 7.63–7.59 (m, 1H), 7.58–7.50 (m, 2H), 7.49–7.44 (m, 1H), 7.42–7.36 (m, 1H), 7.25–7.19 (m, 1H), 4.11 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 148.9, 139.6, 135.6, 130.7, 130.0, 127.6, 126.4, 123.9, 123.4, 122.8, 121.6, 118.8, 118.2, 114.8, 15.1. HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H11ClN3 268.0636, found 268.0633.
2-(2-(4-Bromophenyl)-2H-indazol-3-yl)acetonitrile (3k)
42 mg, 67% yield, pale red solid; mp 152–154 °C. 1H NMR (400 MHz, CDCl3) δ 7.79–7.68 (m, 4H), 7.48–7.42 (m, 2H), 7.41–7.36 (m, 1H), 7.22 (dd, J = 8.6, 6.4 Hz, 1H), 4.08 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 148.9, 137.7, 133.0, 127.6, 127.4, 124.0, 123.4, 122.8, 121.6, 118.8, 118.2, 114.9, 15.0. HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H11BrN3 312.0131, found 312.0129.
2-(2-(3-Bromophenyl)-2H-indazol-3-yl)acetonitrile (3l)
40 mg, 64% yield, pale red solid; mp 115–117 °C. 1H NMR (400 MHz, CDCl3) δ 7.76 (dd, J = 5.7, 3.7 Hz, 3H), 7.70 (dt, J = 7.6, 1.6 Hz, 1H), 7.54–7.43 (m, 2H), 7.42–7.33 (m, 1H), 7.25–7.17 (m, 1H), 4.11 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 148.9, 139.7, 133.0, 130.9, 129.2, 127.6, 124.3, 123.4, 123.3, 122.9, 121.6, 118.8, 118.2, 114.8, 15.1. HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H11BrN3 312.0131., found 312.0130.
2-(2-(4-(Trifluoromethyl)phenyl)-2H-indazol-3-yl)acetonitrile (3m)
31 mg, 55% yield, pale red solid; mp 115–117 °C. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.4 Hz, 2H), 7.77 (dd, J = 2.7, 1.8 Hz, 1H), 7.76–7.70 (m, 3H), 7.41 (ddd, J = 8.7, 6.6, 0.9 Hz, 1H), 7.26–7.19 (m, 1H), 4.12 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 149.1, 141.5, 131.8 (q, J = 33.3 Hz), 127.8, 127.1 (q, J = 3.7 Hz), 126.3, 123.6, 123.5 (q, J = 273.7 Hz), 122.9, 121.8, 118.8, 118.3, 114.8, 15.1. 19F NMR (376 MHz, CDCl3) δ −62.67. HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H11F3N3 302.0900, found 302.0901.
2-(2-(3-(Trifluoromethyl)phenyl)-2H-indazol-3-yl)acetonitrile (3n)
42 mg, 69% yield, red oil. 1H NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.83 (d, J = 6.9 Hz, 1H), 7.80–7.72 (m, 4H), 7.40 (ddd, J = 8.7, 6.6, 0.8 Hz, 1H), 7.23 (dd, J = 8.6, 6.5 Hz, 1H), 4.10 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 149.1, 139.2, 132.6 (q, J = 33.5 Hz), 130.5, 129.0 (d, J = 0.7 Hz), 127.8, 126.6 (q, J = 3.6 Hz), 123.6, 123.2 (q, J = 273.7 Hz), 123.2 (q, J = 3.8 Hz), 123.0, 121.7, 118.8, 118.2, 114.7, 15.1. 19F NMR (376 MHz, CDCl3) δ −62.72. HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H11F3N3 302.0900, found 302.0904.
2-(3-(Cyanomethyl)-2H-indazol-2-yl)benzonitrile (3o)
37 mg, 71% yield, pale red solid; mp 136–138 °C. 1H NMR (400 MHz, CDCl3) δ 7.90 (t, J = 1.6 Hz, 1H), 7.87–7.82 (m, 2H), 7.75 (dd, J = 12.9, 5.1 Hz, 3H), 7.43–7.38 (m, 1H), 7.26–7.21 (m, 1H), 4.13 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 149.2, 139.6, 133.2, 130.9, 130.0, 129.4, 128.0, 123.8, 123.1, 121.8, 118.9, 118.2, 117.2, 114.6, 114.3, 15.1. HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H11N4 259.0978, found 259.0975.
2-(2-(3-Nitrophenyl)-2H-indazol-3-yl)acetonitrile (3p)
18 mg, 32% yield, pale yellow solid; mp 174–176 °C. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (t, J = 2.1 Hz, 1H), 8.46 (ddd, J = 8.3, 2.2, 0.9 Hz, 1H), 8.19 (ddd, J = 8.0, 2.0, 0.9 Hz, 1H), 8.01–7.91 (m, 2H), 7.74 (d, J = 8.8 Hz, 1H), 7.41 (ddd, J = 8.8, 6.6, 1.0 Hz, 1H), 7.23 (dd, J = 8.5, 6.6 Hz, 1H), 4.75 (s, 2H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 148.8, 148.7, 140.0, 132.5, 131.7, 128.0, 125.9, 124.6, 123.0, 121.7, 121.2, 120.5, 118.1, 116.9, 14.9.
2-(2-(o-Tolyl)-2H-indazol-3-yl)acetonitrile (3q)
18 mg, 36% yield, yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.83–7.74 (m, 2H), 7.50 (t, J = 7.5 Hz, 1H), 7.46–7.37 (m, 3H), 7.33 (d, J = 7.7 Hz, 1H), 7.25–7.19 (m, 1H), 3.92 (s, 2H), 2.05 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 148.7, 137.3, 135.9, 131.6, 130.6, 127.3, 127.1, 127.1, 123.5, 123.0, 120.5, 118.8, 118.3, 114.6, 17.1, 14.6. HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H14N3 248.1182, found 248.1180.
2-(2-(2-Fluorophenyl)-2H-indazol-3-yl)acetonitrile (3r)
20 mg, 40% yield, pale red solid; mp 133–135 °C. 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.6 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.64 (td, J = 7.7, 1.7 Hz, 1H), 7.58 (tdd, J = 6.9, 5.0, 1.7 Hz, 1H), 7.43–7.31 (m, 3H), 7.22 (dd, J = 8.5, 6.7 Hz, 1H), 4.06 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 156.3 (d, J = 252.3 Hz), 149.3, 132.0 (d, J = 7.9 Hz), 129.3, 127.5, 126.5 (d, J = 12.0 Hz), 125.5 (d, J = 3.9 Hz), 124.5, 123.2, 120.9, 118.9, 118.2, 116.9 (d, J = 19.5 Hz), 114.5, 14.7 (d, J = 4.9 Hz). 19F NMR (376 MHz, CDCl3) δ −122.24. HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H11FN3 252.0932, found 252.0930.
2-(2-(2-Chlorophenyl)-2H-indazol-3-yl)acetonitrile (3s)
18 mg, 34% yield, red oil. 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 8.6 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.63 (m, 1H), 7.60–7.48 (m, 3H), 7.40 (m, 1H), 7.25–7.21 (m, 1H), 3.99 (dd, J = 83.7, 18.0 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 149.1, 136.2, 131.9, 131.6, 130.6, 129.7, 128.2, 127.5, 124.4, 123.2, 120.6, 119.0, 118.4, 114.5, 14.8. HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H11ClN3 268.0636 found 268.0636.
2-(2-(2-Bromophenyl)-2H-indazol-3-yl)acetonitrile (3t)
21 mg, 34% yield, yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.83-7.76 (m, 3H), 7.57-7.55 (m, 2H), 7.53–7.46 (m, 1H), 7.44–7.37 (m, 1H), 7.25-7.21 (m, 1H), 3.98 (dd, J = 90.4, 18.5 Hz, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 149.0, 137.7, 133.7, 132.1, 129.8, 128.8, 127.5, 124.2, 123.3, 121.4, 120.6, 119.0, 118.3, 114.5, 14.9. HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H11BrN3 312.0131, found 312.0131.
2-(2-(3,4-Dimethylphenyl)-2H-indazol-3-yl)acetonitrile (3u)
28 mg, 54% yield, pale yellow solid; mp 89–91 °C. 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 9.1 Hz, 2H), 7.40–7.34 (m, 1H), 7.32 (d, J = 7.9 Hz, 2H), 7.24 (dd, J = 8.0, 2.0 Hz, 1H), 7.20 (dd, J = 8.6, 6.4 Hz, 1H), 4.08 (s, 2H), 2.36 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 148.6, 138.8, 138.6, 136.3, 130.6, 127.1, 126.9, 122.9, 122.9, 122.7, 121.3, 118.8, 118.2, 115.2, 19.9, 19.6, 15.1. HRMS (ESI-TOF) m/z [M + H]+ calcd for C17H16N3 262.1339, found 262.1338.
2-(2-(3-Fluoro-4-methylphenyl)-2H-indazol-3-yl)acetonitrile (3v)
31 mg, 58% yield, pale red solid; mp 82–84 °C. 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 8.8 Hz, 1H), 7.60-7.55 (m, 2H), 7.46 (dd, J = 8.1, 2.1 Hz, 1H), 7.38 (m, 1H), 7.19 (dd, J = 9.2, 6.6 Hz, 1H), 4.68 (s, 2H), 2.37 (d, J = 1.6 Hz, 3H).13C{1H} NMR (101 MHz, DMSO-d6) δ 160.8 (d, J = 245.0 Hz), 148.4, 138.2 (d, J = 10.2 Hz), 132.8 (d, J = 6.0 Hz), 127.6, 126.3 (d, J = 17.0 Hz), 125.2, 122.7, 122.0 (d, J = 3.4 Hz), 121.5, 120.4, 118.0, 116.9, 113.3 (d, J = 25.7 Hz), 14.8, 14.5 (d, J = 2.9 Hz). 19F NMR (376 MHz, DMSO-d6) δ −114.77. HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H13FN3 266.1088, found 266.1089.
2-(2-(3-Chloro-4-methylphenyl)-2H-indazol-3-yl)acetonitrile (3w)
31 mg, 55% yield, red oil. 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 9.5 Hz, 2H), 7.58 (d, J = 2.1 Hz, 1H), 7.47–7.32 (m, 3H), 7.24–7.17 (m, 1H), 4.09 (s, 2H), 2.48 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 148.8, 138.3, 137.2, 135.5, 131.7, 127.5, 126.6, 123.8, 123.3, 122.8, 121.5, 118.8, 118.2, 114.9, 20.0, 15.1. HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H13ClN3 282.0793, found 282.0789.
2-(2-(3-Bromo-4-methylphenyl)-2H-indazol-3-yl)acetonitrile (3x)
36 mg, 55% yield, pale red solid; mp 102–104 °C. 1H NMR (400 MHz, CDCl3) δ 7.75 (t, J = 5.7 Hz, 3H), 7.47–7.34 (m, 3H), 7.24–7.18 (m, 1H), 4.09 (s, 2H), 2.51 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 148.8, 140.2, 137.2, 131.5, 129.7, 127.5, 125.5, 124.4, 123.3, 122.9, 121.5, 118.8, 118.2, 114.9, 22.8, 15.1. HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H13BrN3 326.0287, found 326.0285.
2-(6-Methoxy-2-phenyl-2H-indazol-3-yl)acetonitrile (3y)
34 mg, 65% yield, pale red solid; mp 141–143 °C. 1H NMR (400 MHz, CDCl3) δ 7.66 (d, J = 9.3 Hz, 1H), 7.58 (dt, J = 7.7, 2.0 Hz, 2H), 7.56–7.51 (m, 3H), 7.08 (dd, J = 9.3, 2.3 Hz, 1H), 6.90 (d, J = 2.2 Hz, 1H), 4.05 (s, 2H), 3.89 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 156.0, 145.6, 138.8, 129.8, 129.6, 125.8, 122.6, 121.5, 121.3, 119.6, 115.2, 94.6, 55.5, 15.1. HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H14N3O 264.1131, found 264.1129.
(6-Fluoro-2-phenyl-2H-indazol-3-yl)acetonitrile (3z)
27 mg, 54% yield, pale red solid; mp 124–126 °C. 1H NMR (400 MHz, CDCl3) δ 7.75 (dd, J = 9.4, 4.6 Hz, 1H), 7.64–7.56 (m, 3H), 7.56–7.52 (m, 2H), 7.35 (dd, J = 8.8, 2.3 Hz, 1H), 7.18 (td, J = 9.2, 2.4 Hz, 1H), 4.05 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 158.8 (d, J = 243.0 Hz), 146.1, 138.5, 130.0, 129.9, 125.8, 122.9 (d, J = 8.8 Hz), 120.8 (d, J = 11.5 Hz), 120.5 (d, J = 9.8 Hz), 119.1 (d, J = 29.1 Hz), 114.8, 101.5 (d, J = 24.9 Hz), 15.1.19F NMR (376 MHz, CDCl3) δ −117.02. HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H11FN3 252.0932, found 252.0927.
2-(6-Chloro-2-phenyl-2H-indazol-3-yl)acetonitrile (3aa)
30 mg, 56% yield, pale yellow solid; mp 133–135 °C. 1H NMR (400 MHz, CDCl3) δ 7.77–7.69 (m, 2H), 7.65–7.57 (m, 3H), 7.54 (dd, J = 7.7, 2.0 Hz, 2H), 7.31 (dd, J = 9.2, 1.9 Hz, 1H), 4.06 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 147.1, 138.3, 130.1, 129.9, 128.9, 128.8, 125.8, 122.6, 121.8, 119.8, 117.6, 114.7, 15.1. HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H11ClN3 268.0636, found 268.0635.
2-(6-Bromo-2-phenyl-2H-indazol-3-yl)acetonitrile (3ab)
36 mg, 58% yield, pale red solid; mp 137–139 °C. 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 1.5 Hz, 1H), 7.65 (d, J = 9.2 Hz, 1H), 7.61-7.58 (m, 3H), 7.55-7.53 (m, 2H), 7.43 (dd, J = 9.2, 1.7 Hz, 1H), 4.05 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 147.2, 138.3, 131.1, 130.1, 129.9, 125.8, 122.6, 122.4, 121.1, 120.0, 116.7, 114.7, 15.1. HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H11BrN3 312.0131, found 312.0127.
2-(5-Methoxy-2-phenyl-2H-indazol-3-yl)acetonitrile (3ac)
23 mg, 44% yield, pale yellow solid; mp 125–127 °C. 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 9.2 Hz, 1H), 7.56 (dt, J = 11.0, 7.6 Hz, 5H), 6.98 (d, J = 1.7 Hz, 1H), 6.90 (dd, J = 9.1, 1.9 Hz, 1H), 4.05 (s, 2H), 3.89 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 159.7, 149.9, 138.7, 129.8, 129.6, 125.8, 122.9, 119.7, 118.5, 117.3, 115.0, 94.7, 55.4, 15.1. HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H14N3O 264.1131, found 264.1129.
2-(5-Methyl-2-phenyl-2H-indazol-3-yl)acetonitrile (3ad)
28 mg, 57% yield, pale red solid; mp 118–120 °C. 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.7 Hz, 1H), 7.61–7.56 (m, 2H), 7.53 (dt, J = 7.4, 2.3 Hz, 4H), 7.05 (dd, J = 8.7, 1.1 Hz, 1H), 4.06 (s, 2H), 2.48 (s, 3H).13C{1H} NMR (101 MHz, CDCl3) δ 149.3, 138.7, 137.4, 129.7, 129.7, 126.1, 125.9, 122.6, 119.9, 118.3, 116.3, 115.1, 22.2, 15.1. HRMS (ESI-TOF) m/z [M + H]+ calcd for C16H14N3 248.1182, found 248.1181.
2-(5-Chloro-2-phenyl-2H-indazol-3-yl)acetonitrile (3ae)
27 mg, 50% yield, pale yellow solid; mp 129–131 °C. 1H NMR (400 MHz, CDCl3) δ 7.78–7.74 (m, 1H), 7.73 (d, J = 9.0 Hz, 1H), 7.64–7.56 (m, 3H), 7.53 (dd, J = 7.7, 1.9 Hz, 2H), 7.16 (dd, J = 9.0, 1.7 Hz, 1H), 4.08 (s, 2H). 13C{1H} NMR (101 MHz, CDCl3) δ 148.9, 138.3, 133.3, 130.1, 129.9, 125.8, 124.7, 123.5, 120.2, 119.9, 117.2, 114.8, 15.2. HRMS (ESI-TOF) m/z [M + H]+ calcd for C15H11ClN3 268.0636, found 268.0634.
2-(2-Butyl-2H-indazol-3-yl)acetonitrile (3af)
15 mg, 36% yield, yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.37–7.27 (m, 1H), 7.18–7.11 (m, 1H), 4.46–4.38 (m, 2H), 4.12 (s, 2H), 2.05–1.95 (m, 2H), 1.47–1.38 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H).13C{1H} NMR (101 MHz, CDCl3) δ 147.9, 126.4, 122.4, 121.3, 120.9, 118.3, 117.8, 114.8, 50.9, 32.5, 20.0, 14.1, 13.6. HRMS (ESI-TOF) m/z [M + Na]+ calcd for C13H15N3Na 236.1158, found 236.1158.
2-(2-Benzyl-2H-indazol-3-yl)acetonitrile (3ag)
12 mg, 25% yield, yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.38–7.31 (m, 4H), 7.20–7.12 (m, 3H), 5.74 (s, 2H), 3.92 (s, 2H).13C{1H} NMR (101 MHz, CDCl3) δ 147.8, 134.8, 129.3, 128.6, 127.0, 126.7, 122.7, 121.9, 121.6, 118.4, 118.0, 114.5, 55.5, 14.3. HRMS (ESI-TOF) m/z [M + Na]+ calcd for C16H13N3Na 270.1002, found 270.1005.
Procedure for the Derivatization Reaction
Compound 4 was synthesized according to the procedure reported.15 K2CO3 (0.1 mmol, 13.8 mg) and 1 mL of DMSO were added to a tube with substrate 3b (0.2 mmol). Then, 1.2 mL of aq. H2O2 (1.2 mmol, 30%) was dropped at room temperature. The mixture was stirred for 30 min and then the reaction mixture was added to 1 mL of saturated Na2S2O3 and 10 mL of saturated NaHCO3 at 0 °C. The resulting mixture was subjected to extraction with ethyl acetate (2 × 15 mL). The combined organic phase was washed with brine (2 × 10 mL), dried over anhydrous Na2SO4, concentrated in vacuo, and the residue was subjected to flash chromatography (ethyl acetate/petroleum ether 1:2) to give amide 4.
2-(2-(p-Tolyl)-2H-indazol-3-yl)acetamide (4)
41 mg, 80% yield, pale white solid; mp 219–221 °C. 1H NMR (400 MHz, CDCl3) δ 7.77 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.42 (d, J = 8.3 Hz, 2H), 7.39–7.30 (m, 3H), 7.17 (dd, J = 8.1, 6.9 Hz, 1H), 5.59 (s, 1H), 5.52 (s, 1H), 3.97 (s, 2H), 2.45 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 170.1, 148.7, 139.6, 136.7, 130.1, 128.7, 127.1, 125.6, 122.6, 121.7, 119.2, 118.1, 33.0, 21.3. HRMS (ESI-TOF) m/z [M + Na]+ calcd for C16H15N3ONa 288.1107, found 288.1111.
Procedure for the Radical-Trapping Experiment
Two equivalents of radical scavenger (2,2,6,6-tetramethylpiperidinoxy, TEMPO) were added to the reaction of 1a with 2 in the standard conditions. After 1 h, the reaction mixture was stopped. Then, the crude reaction mixture was detected by HRMS.
Acknowledgments
This work was financially supported by the Foundation for University Key Teachers from the Education Department of Henan Province (no. 2020GGJS107) and the National Natural Science Foundation of China (no. 21602046).
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c08094.
1H, 19F, and 13C NMR spectra of compounds 3 and 4 (PDF)
The authors declare no competing financial interest.
Supplementary Material
References
- a Fleming F. F.; Fleming F. F. Nitrile-Containing Natural Products. Nat. Prod. Rep. 1999, 16, 597–606. 10.1039/a804370a. [DOI] [Google Scholar]; b Fleming F. F.; Yao L.; Ravikumar P. C.; Funk L.; Shook B. C. Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore. J. Med. Chem. 2010, 53, 7902–7917. 10.1021/jm100762r. [DOI] [PMC free article] [PubMed] [Google Scholar]
- a Rappoport Z.The Cyano Group; Wiley-Interscience: New York, 1970. [Google Scholar]; b Larock R. C.Comprehensive Organic Transformations: A Guide to Functional Group Preparations; VCH: New York, 2018. [Google Scholar]; c Luo F. T.; Jeevanandam A. Simple Transformation of Nitrile into Ester by the Use of Chlorotrimethylsilane. Tetrahedron Lett. 1998, 39, 9455–9456. 10.1016/S0040-4039(98)02143-1. [DOI] [Google Scholar]; d Miura T.; Harumashi T.; Murakami M. Cyclization Reaction of Cyano-Substituted Unsaturated Esters Prompted by Conjugate Addition of Organoborons. Org. Lett. 2007, 9, 741–743. 10.1021/ol062882y. [DOI] [PubMed] [Google Scholar]; e Sakai T.; Danheiser R. L. Cyano Diels–Alder and Cyano Ene Reactions. Applications in A Formal [2 + 2+ 2] Cycloaddition Strategy for the Synthesis of Pyridines. J. Am. Chem. Soc. 2010, 132, 13203–13205. 10.1021/ja106901u. [DOI] [PMC free article] [PubMed] [Google Scholar]; f Ramadhar T. R.; Bansagi J.; Batey R. A. Mild Double Allylboration Reactions of Nitriles and Acid Nnhydrides Using Potassium Allyltrifluoroborate. J. Am. Chem. Soc. 2013, 78, 1216–1221. [DOI] [PubMed] [Google Scholar]; g Wang M.-X. Enantioselective Biotransformations of Nitriles in Organic Synthesis. Acc. Chem. Res. 2015, 48, 602–611. 10.1021/ar500406s. [DOI] [PubMed] [Google Scholar]; h Xu X.; Li B.; Zhao Y.; Song Q. Aerobic Oxidative Decyanation–Amidation of Arylacetonitriles with Urea as A Nitrogen Source. Org. Chem. Front. 2017, 4, 331–334. 10.1039/C6QO00635C. [DOI] [Google Scholar]
- a Soli E. D.; Manoso A. S.; Patterson M. C.; DeShong P.; Favor D. A.; Hirschmann R.; Smith A. B. Azide and Cyanide Displacements via Hypervalent Silicate Intermediates. J. Org. Chem. 1999, 64, 3171–3177. 10.1021/jo982302d. [DOI] [PubMed] [Google Scholar]; b Neetha M.; Afsina C. M. A.; Aneeja T.; Anilkumar G. Recent Advances and Prospects in the Palladium-Catalyzed Cyanation of Aryl Halides. RSC Adv. 2020, 10, 33683–33699. 10.1039/D0RA05960A. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Mills L. R.; Graham J. M.; Patel P.; Rousseaux S. A. L. Ni-Catalyzed Reductive Cyanation of Aryl Halides and Phenol Derivatives via Transnitrilation. J. Am. Chem. Soc. 2019, 141, 19257–19262. 10.1021/jacs.9b11208. [DOI] [PubMed] [Google Scholar]
- Narsaiah A. V.; Nagaiah K. An Efficient and Improved Method for the Preparation of Nitriles from Primary Amides and Aldoximes. Adv. Synth. Catal. 2004, 346, 1271–1274. 10.1002/adsc.200404059. [DOI] [Google Scholar]
- a Kosugi M.; Ishiguro M.; Negishi Y.; Sano H.; Migita T. Palladium Catalyzed Reaction of Aryl Bromides with Cyanomethyltributyltin, Aromatic Cyanomethylation. Chem. Lett. 1984, 13, 1511–1512. 10.1246/cl.1984.1511. [DOI] [Google Scholar]; b Fredj T.; Klingstedt T. Nickel-Catalyzed Synthesis of Arylacetonitriles from Arylzinc Chlorides and Bromoacetonitrile. Synthesis 1987, 1, 40–42. 10.1055/s-1987-27834. [DOI] [Google Scholar]; c Culkin D. A.; Hartwig J. F. Synthesis, Characterization, and Reactivity of Arylpalladium Cyanoalkyl Complexes: Selection of Catalysts for the α-Arylation of Nitriles. J. Am. Chem. Soc. 2002, 124, 9330–9331. 10.1021/ja026584h. [DOI] [PubMed] [Google Scholar]; d Wu L.; Hartwig J. F. Mild Palladium-Catalyzed Selective Monoarylation of Nitriles. J. Am. Chem. Soc. 2005, 127, 15824–15832. 10.1021/ja053027x. [DOI] [PubMed] [Google Scholar]; e Yang Y.; Tang S.; Liu C.; Zhang H.; Sun Z.; Lei A. Novel α-Arylnitriles Synthesis via Ni-Catalyzed Cross-Coupling of α-Bromonitriles with Arylboronic Acids Under Mild Conditions. Org. Biomol. Chem. 2011, 9, 5343–5345. 10.1039/c1ob05326d. [DOI] [PubMed] [Google Scholar]; f Shang R.; Ji D.-S.; Chu L.; Fu Y.; Liu L. Synthesis of α-Aryl Nitriles through Palladium-Catalyzed Decarboxylative Coupling of Cyanoacetate Salts with Aryl Halides and Triflates. Angew. Chem. 2011, 123, 4562–4566. 10.1002/ange.201006763. [DOI] [PubMed] [Google Scholar]
- a Zhang W.; Yang S.; Shen Z. Copper-Catalyzed Cyanomethylation of Substituted Tetrahydroisoquinolines with Acetonitrile. Adv. Synth. Catal. 2016, 358, 2392–2397. 10.1002/adsc.201600050. [DOI] [Google Scholar]; b Liu Z.-Q.; Li Z. Radical-Promoted Site-Specific Cross Dehydrogenative Coupling of Heterocycles with Nitriles. Chem. Commun. 2016, 52, 14278–14281. 10.1039/C6CC08213K. [DOI] [PubMed] [Google Scholar]; c Su H.; Wang L.; Rao H.; Xu H. Iron-Catalyzed Dehydrogenative sp3–sp2 Coupling via Direct Oxidative C–H Activation of Acetonitrile. Org. Lett. 2017, 19, 2226–2229. 10.1021/acs.orglett.7b00678. [DOI] [PubMed] [Google Scholar]; d Qiao K.; Zhang D.; Zhang K.; Yuan X.; Zheng M.-W.; Guo T.-F.; Fang Z.; Wan L.; Duo K. Iron (II)-Catalyzed C-2 Cyanomethylation of Indoles and Pyrroles via Direct Oxidative Cross-Dehydrogenative Coupling with Acetonitrile Derivatives. Org. Chem. Front. 2018, 5, 1129–1134. 10.1039/C7QO01086A. [DOI] [Google Scholar]; e Chauhan P. M.; Morja M. I.; Asamdi M.; Chikhalia K. H. Copper Catalyzed Cyanomethylation Reaction of 4-Thiazolidinone. Tetrahedron Lett. 2020, 61, 152601–152605. 10.1016/j.tetlet.2020.152601. [DOI] [Google Scholar]; f Hong G.; Nahide P. D.; Kozlowski M. C. Cyanomethylation of Substituted Fluorenes and Oxindoles with Alkyl Nitriles. Org. lett. 2020, 22, 1563–1568. 10.1021/acs.orglett.0c00160. [DOI] [PMC free article] [PubMed] [Google Scholar]; g Liu D.; Xia Z.; Xiao Y.; Yu Y.; Yu L.; Song Z.; Wu Q.; Zhang J.; Tan Z. Transition-Metal-Free Cross-Dehydrogenative Couplings of 8-Aminoquinoline Amides at C5 Position with Acetonitrile, Ethers or Acetone. Eur. J. Org. Chem. 2021, 2021, 5012–5016. 10.1002/ejoc.202100953. [DOI] [Google Scholar]; h Yao H.; Zhong X.; Wang B.; Lin S.; Yan Z. Cyanomethylation of the Benzene Rings and Pyridine Rings via Direct Oxidative Cross-Dehydrogenative Coupling with Acetonitrile. Org. Lett. 2022, 24, 2030–2034. 10.1021/acs.orglett.2c00498. [DOI] [PubMed] [Google Scholar]
- For review, see:; a Narayanam J. M. R.; Stephenson C. R. J. Visible Light Photoredox Catalysis: Applications in Organic Synthesis. Chem. Soc. Rev. 2011, 40, 102–113. 10.1039/B913880N. [DOI] [PubMed] [Google Scholar]; b Xuan J.; Xiao W.-J. Visible-Light Photoredox Catalysis. Angew. Chem., Int. Ed. 2012, 51, 6828–6838. 10.1002/anie.201200223. [DOI] [PubMed] [Google Scholar]; c Prier C. K.; Rankic D. A.; MacMillan D. W. C. Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis. Chem. Rev. 2013, 113, 5322–5363. 10.1021/cr300503r. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Romero N. A.; Nicewicz D. A. Organic Photoredox Catalysis. Chem. Rev. 2016, 116, 10075–10166. 10.1021/acs.chemrev.6b00057. [DOI] [PubMed] [Google Scholar]; e Shaw M. H.; Twilton J.; MacMillan D. W. C. Photoredox Catalysis in Organic Chemistry. J. Org. Chem. 2016, 81, 6898–6926. 10.1021/acs.joc.6b01449. [DOI] [PMC free article] [PubMed] [Google Scholar]; f Wang C.-S.; Dixneuf P. H.; Soule J.-F. Photoredox Catalysis for Building C-C Bonds from C(sp2)-H Bonds. Chem. Rev. 2018, 118, 7532–7585. 10.1021/acs.chemrev.8b00077. [DOI] [PubMed] [Google Scholar]
- a Yi H.; Zhang X.; Qin C.; Liao Z.; Liu J.; Lei A. Visible Light-Induced γ-Alkoxynitrile Synthesis via Three-Component Alkoxycyanomethylation of Alkenes. Adv. Synth. Catal. 2014, 356, 2873–2877. 10.1002/adsc.201400548. [DOI] [Google Scholar]; b Fumagalli G.; Boyd S.; Greaney M. F. Exploiting Photoredox Catalysis for the Synthesis of Tetra-and Di-Hydrofurans. Tetrahedron. Lett. 2015, 56, 2571–2573. 10.1016/j.tetlet.2015.03.124. [DOI] [Google Scholar]; c Gao X.; Dong W.; Hu B.; Gao H.; Yuan Y.; Xie X.; Zhang Z. Visible-light Induced Tandem Radical Cyanomethylation and Cyclization of N-Aryl Acrylamides: Access to Cyanomethylated Oxindoles. RSC Adv. 2017, 7, 49299–49302. 10.1039/C7RA10090F. [DOI] [Google Scholar]; d Voutyritsa E.; Triandafillidi I.; Kokotos C. G. Expanding the Scope of Photocatalysis: Atom Transfer Radical Addition of Bromoacetonitrile to Aliphatic Olefins. Chem. Cat. Chem. 2018, 10, 2466–2470. 10.1002/cctc.201800110. [DOI] [Google Scholar]; e Sun S.; Zhou C.; Cheng J. Synthesis of 4-Cyanoethylated Benzoxazines by Visible-Light-Promoted Radical Oxycyanomethylation of Olefinic Amides with Bromoacetonitrile. Tetrahedron Lett. 2019, 60, 150926–150930. 10.1016/j.tetlet.2019.07.017. [DOI] [Google Scholar]; f Liu L.; Yang D.-Y.; He Y.-H.; Gyan Z. Redox-Neutral Photocatalytic Radical Cascade Cyclization for the Synthesis of CH2CN/CF2COOEt/CF3-Containing Benzo[4,5]imidazo[2,1-a]isoquinolin-6(5H)-One Derivatives. J. Org. Chem. 2020, 85, 11892–11901. 10.1021/acs.joc.0c01688. [DOI] [PubMed] [Google Scholar]; g Inprung N.; Ho H. E.; Rossi-Ashton J. A.; Epton R. G.; Whitwood A. C.; Lynam J. M.; Taylor R. J. K.; James M. J.; Unsworth W. P. Indole-ynones as Privileged Substrates for Radical Dearomatizing Spirocyclization Cascades. Org. Lett. 2022, 24, 668–674. 10.1021/acs.orglett.1c04098. [DOI] [PubMed] [Google Scholar]; h Welin E. R.; Warkentin A. A.; Conrad J. C.; MacMillan D. W. C. Enantioselective α-Alkylation of Aldehydes by Photoredox Organocatalysis: Rapid Access to Pharmacophore Fragments from β-Cyanoaldehydes. Angew. Chem., Int. Ed. 2015, 54, 9668–9672. 10.1002/anie.201503789. [DOI] [PMC free article] [PubMed] [Google Scholar]
- a Chang Q.; Liu Z.; Liu P.; Yu L.; Sun P. Visible-light-induced Regioselective Cyanomethylation of Imidazopyridines and Its Application in Drug Synthesis. J. Org. Chem. 2017, 82, 5391–5397. 10.1021/acs.joc.7b00750. [DOI] [PubMed] [Google Scholar]; b O’Brien C. J.; Droege D. G.; Jiu A. Y.; Gandhi S. S.; Paras N. A.; Olson S. H.; Conrad J. Photoredox Cyanomethylation of Indoles: Catalyst Modification and Mechanism. J. Org. Chem. 2018, 83, 8926–8935. 10.1021/acs.joc.8b01146. [DOI] [PMC free article] [PubMed] [Google Scholar]
- a Rodgers J. D.; Johnson B. L.; Haisheng W.; Erickson-Viitanen S.; Klabe R. M.; Bacheler L.; Cordova B. C.; Chang C.-H. Potent Cyclic Urea HIV Protease Inhibitors with 3-Aminoindazole P2/P2′ Groups. Bioorg. Med. Chem. Lett. 1998, 8, 715–720. 10.1016/S0960-894X(98)00118-8. [DOI] [PubMed] [Google Scholar]; b Chen H.-S.; Kuo S.-C.; Teng C.-M.; Lee F.-Y.; Wang J.-P.; Lee Y.-C.; Kuo C.-W.; Huang C.-C.; Wu C.-C.; Huang L.-J. Synthesis and Antiplatelet Activity of Ethyl 4-(1-benzyl-1H-Indazol-3-yl)benzoate (YD-3) Derivatives. Bioorg. Med. Chem. 2008, 16, 1262–1278. 10.1016/j.bmc.2007.10.070. [DOI] [PubMed] [Google Scholar]; c Cerecetto H.; Porcal W. Pharmacological Properties of Furoxans and Benzofuroxans: Recent Developments. Mini-Rev. Med. Chem. 2005, 5, 57–71. 10.2174/1389557053402864. [DOI] [PubMed] [Google Scholar]; d Govek S. P.; Nagasawa J. Y.; Douglas K. L.; Lai A. G.; Kahraman M.; Bonnefous C.; Aparicio A. M.; Darimont B. D.; Grillot K. L.; Joseph J. D.; Kaufman J. A.; Lee K.-J.; Lu N.; Moon M. J.; Prudente R. Y.; Sensintaffar J.; Rix P. J.; Hager J. H.; Smith N. D. Optimization of An Indazole Series of Selective Estrogen Receptor Degraders: Tumor Regression in A Tamoxifen-Resistant Breast Cancer Xenograft. Bioorg. Med. Chem. Lett. 2015, 25, 5163–5167. 10.1016/j.bmcl.2015.09.074. [DOI] [PubMed] [Google Scholar]; e Avvisati R.; Meringolo M.; Stendardo E.; Malavas E.; Marinelli S.; Badiani A. Intravenous Self-Administration of Benzydamine, A Non-Steroidal Anti-Inflammatory Drug with A Central Cannabinoidergic Mechanism of Action. Addict. Biol. 2018, 23, 610–619. 10.1111/adb.12516. [DOI] [PubMed] [Google Scholar]; f Yakaiah T.; Lingaiah B. P. V.; Narsaiah B.; Kumar K. P.; Murthy U. S. N. GdCl3 Catalysed Grieco Condensation: A Facile Approach for the Synthesis of Novel Pyrimidine and Annulated Pyrimidine Fused Indazole Derivatives in Single Pot under Mild Conditions and Their Anti-Microbial Activity. Eur. J. Med. Chem. 2008, 43, 341–347. 10.1016/j.ejmech.2007.03.031. [DOI] [PubMed] [Google Scholar]
- Ghosh S.; Mondal S.; Hajra A. Direct Catalytic Functionalization of Indazole Derivatives. Adv. Synth. Catal. 2020, 362, 3768–3794. 10.1002/adsc.202000423. [DOI] [Google Scholar]
- For review, see:; a Ghosh D.; Ghosh S.; Ghosh A.; Pyne P.; Majumder S.; Hajra A. Visible light-induced functionalization of indazole and pyrazole: a recent update. Chem. Commun. 2022, 58, 4435–4455. 10.1039/D2CC00002D. [DOI] [PubMed] [Google Scholar]; For examples, see:; b Singsardar M.; Dey A.; Sarkar R.; Hajra A. Visible-Light-Induced Organophotoredox-Catalyzed Phosphonylation of 2H-Indazoles with Diphenylphosphine Oxide. J. Org. Chem. 2018, 83, 12694–12701. 10.1021/acs.joc.8b02019. [DOI] [PubMed] [Google Scholar]; c Aganda K. C. C.; Kim J.; Lee A. Visible-Light-Mediated Direct C3-Arylation of 2H-Indazoles Enabled by An Electron-Donor–Acceptor Complex. Org. Biomol. Chem. 2019, 17, 9698–9702. 10.1039/C9OB02074H. [DOI] [PubMed] [Google Scholar]; d Neogi S.; Ghosh A. K.; Majhi K.; Samanta S.; Kibriya G.; Hajra A. Organophotoredox-Catalyzed Direct C–H Amination of 2H-Indazoles with Amines. Org. Lett. 2020, 22, 5605–5609. 10.1021/acs.orglett.0c01973. [DOI] [PubMed] [Google Scholar]; e Saritha R.; Annes S. B.; Ramesh S. Metal-Free, Regioselective, Visible Light Activation of 4CzIPN for the Arylation of 2H-Indazole Derivatives. RSC Adv. 2021, 11, 14079–14084. 10.1039/D1RA02372A. [DOI] [PMC free article] [PubMed] [Google Scholar]; f Ma C.; Feng Z.; Li J.; Zhang D.; Li W.; Jiang Y.; Yu B. Photocatalytic Transition-Metal-Free Direct 3-Alkylation of 2-Aryl-2H-Indazoles in Dimethyl Carbonate. Org. Chem. Front. 2021, 8, 3286–3291. 10.1039/D1QO00064K. [DOI] [Google Scholar]; g Sun M.; Li L.; Wang L.; Huo J.; Sun M.; Li P. Controllable Chemoselectivity in the Reaction of 2H-Indazoles with Alcohols under Visible-Light Irradiation: Synthesis of C3-Alkoxylated 2H-Indazoles and Ortho-Alkoxycarbonylated Azobenzenes. Org. Chem. Front. 2021, 8, 4230–4236. 10.1039/D1QO00592H. [DOI] [Google Scholar]
- a Mi X.; Kong Y.; Yang H.; Zhang J.; Pi C.; Cui X. Visible-Light-Promoted Metal-Free C-H Trifluoromethylation of Imidazopyridines. Eur. J. Org. Chem. 2020, 2020, 1019–1022. 10.1002/ejoc.201901860. [DOI] [Google Scholar]; b Mi X.; Cui B.; Zhang J.; Pi C.; Cui X. Visible-Light Induced C3-H Trifluoromethylation of Quinoxalin-2 (1H)-Ones with CF3SO2Cl under External Photocatalyst-Free Conditions. Tetrahedron Lett. 2022, 93, 153693–153696. 10.1016/j.tetlet.2022.153693. [DOI] [Google Scholar]; c Mi X.; Kong Y.; Zhang J.; Pi C.; Cui X. Visible-light-promoted Sulfonylmethylation of Imidazopyridines. Chin. Chem. Lett. 2019, 30, 2295–2298. 10.1016/j.cclet.2019.09.040. [DOI] [Google Scholar]
- Rodríguez-Villar K.; Hernández-Campos A.; Yépez-Mulia L.; Sainz-Espuñes T. D. R.; Soria-Arteche O.; Palacios-Espinosa J. F.; Cortés-Benítez F.; Leyte-Lugo M.; Varela-Petrissans B.; Quintana-Salazar E. A.; Pérez-Villanueva J. Design, Synthesis and Anticandidal Evaluation of Indazole and Pyrazole Derivatives. Pharmaceuticals 2021, 14, 176–194. 10.3390/ph14030176. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhang W.; Zheng H.; Liu Y.; Yu A.; Yang C.; Li X.; Cheng J. Catalyst-Free Amination of α-Cyanoarylacetates Enabled by Single-Electron Transfer. Org. Chem. Front. 2019, 6, 1900–1904. 10.1039/C9QO00346K. [DOI] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.