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1,4-Dicarbofunctionalization of 4-Fluoroaryl Grignard and Lithium Reagents with Disubstituted Malononitriles Christian A Malapit, Irungu K. Luvaga, Jonathan T. Reeves, Ivan Volchkov, Carl A. Busacca, Amy R Howell, and Chris H. Senanayake J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00567 • Publication Date (Web): 12 Apr 2017 Downloaded from http://pubs.acs.org on April 12, 2017

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The Journal of Organic Chemistry

1,4-Dicarbofunctionalization of 4-Fluoroaryl Grignard and Lithium Reagents with Disubstituted Malononitriles Christian A. Malapit, † Irungu K. Luvaga,‡ Jonathan T. Reeves,* Ivan Volchkov, Carl A. Busacca, Amy R. Howell‡ and Chris H. Senanayake Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut, 06877-0368, USA [email protected] RECEIVED DATE

TABLE OF CONTENTS/ABSTRACT GRAPHIC

transnitrilation CN

MgX R

NC +

R

F

CN

THF, 0 °C - rt

R

R' SNAr reaction

R' R CN

• Net 1,4-dicarbofunctionalization • Mild reaction conditions • Also possible with 4-fluoroaryllithiums

ABSTRACT

An efficient one-pot 1,4-dicarbofunctionalization of 4-fluoroaryl Grignard or lithium reagents with 2,2disubstituted malononitriles is described. The reaction proceeds by sequential transnitrilation and SNAr reactions. Commercial Grignard solutions, Grignard reagents prepared in situ by halogen/magnesium exchange with i-PrMgCl, or aryllithium reagents prepared in situ by bromine/lithium exchange with nACS Paragon Plus Environment

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BuLi are compatible with the reaction conditions. Moreover, 2,2-disubstituted malononitriles of diverse structures are accommodated. The reaction provides a unique approach to 1,4-dicarbofunctionalization of activated arenes in a tandem, one-pot transformation.

Recently we reported a mild, transition metal-free synthesis of aryl nitriles by “transnitrilation” of aryl Grignard or aryllithium reagents with dimethylmalononitrile (DMMN, 1).1 The reaction proceeds by attack of the aryl organometallic reagent on DMMN to give intermediate adduct A, which subsequently fragments by a retro-Thorpe type reaction to give the aryl nitrile product, as well as isobutyronitrile anion 2 (Figure 1A). During these studies, the reaction of 4-fluorophenylmagnesium bromide (3) with 1 was found to produce none of the expected 4-fluorobenzonitrile (4) but rather 4-(2-cyanopropan-2yl)benzonitrile (5) in 79% yield (Figure 1B). Presumably the transnitrilation reaction gave 4 which subsequently reacted with anion 2 (M = MgBr) by an SNAr process with the electronically activated aryl fluoride 4 to furnish 5.2

Figure 1. Transnitrilation of aryl organometallics with dimethylmalononitrile 1 normally gives aryl nitriles (A), while the reaction of 4-fluorophenylmagnesium bromide 3 with 1 gave 5 (B).

Although the tandem transnitrilation/SNAr reaction to give 5 was unexpected, a process with the ability to 1,4-dicarbofunctionalize a fluoroaryl Grignard reagent in a single step seemed worth exploring. The methods available for difunctionalization of arenes are largely limited to reactions of benzyne ACS Paragon Plus Environment

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derivatives and are, in such cases, restricted to 1,2-difunctionalization.3 Methods that can dicarbofunctionalize (as opposed to heteroatom/carbon or diheteroatom difunctionalization) with 1,4regioselectivity, as opposed to the more common 1,2-regioselectivity, are rare.4 Herein we report the scope of this transnitrilation/SNAr transformation with respect to aryl organometallic reagent and 2,2disubstituted malononitrile.

In our original report we demonstrated that the transnitrilation reaction was possible with aryllithium reagents as well as aryl Grignard reagents.1 To see if the transnitrilation/SNAr reaction was also possible with a 4-fluoroaryllithium reagent, 4-fluoro-1-bromobenzene 6 was treated with n-BuLi at –78 °C, and the resultant solution of aryllithium 7 was added to a –78 °C solution of DMMN (Scheme 1).5 Product 5 was isolated in 56% yield under these conditions. Thus the reaction was possible with aryllithium 7 generated in situ from aryl bromide 6.

Scheme 1. Transnitrilation/SNAr Reaction of Aryllithium Reagent 7 to give 5. The scope of the 1,4-dicarbofunctionalization reaction was first examined with respect to variation in the structure of the 2,2-disubstituted malononitrile (Table 1). The reaction was amenable to cyclic malononitriles, giving the cyclobutyl (8), cyclopentyl (9), cyclohexyl (10), and tetrahydropyranyl (11) adducts in good yields. The reaction with 2,2-dibenzylmalononitrile gave sterically hindered adduct 12 in 66% yield. The reaction was also applicable to non-symmetrical disubstituted malononitriles, providing adducts 13-15 in good yields. This operationally simple method can be viewed as an alternative approach to α-arylation of nitriles.6

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Table 1. Scope of Dinitrile in the Transnitrilation/SNAr Reactiona

a

Reaction conditions: 1.1 mmol of 3, 1.0 mmol of 2,2-disubstituted malononitrile, THF, 0 °C to rt, 30 min. Isolated yields.

The scope of the difunctionalization with respect to variation in the aryl Grignard reagent structure was explored next (Table 2). For aryl iodide or aryl bromide starting materials, Grignard reagent formation was done using Knochel’s procedure7 with i-PrMgCl (condition A), or for more electron-rich aryl bromides, n-BuLi at low temperature was used to generate the corresponding aryllithium reagent (condition B).8 The presence of a methyl group was tolerated either ortho to the fluorine (entry 1) or ortho to the magnesiated carbon (entries 2 and 3). Substrates bearing methoxy (entry 4) or dimethylamino (entry 5) groups ortho to bromine were converted to the aryllithium reagents using procedure B and smoothly underwent the difunctionalization in good yields. The reaction was demonstrated on a naphthalene framework, and proceeded for both 1,4-substitution (entry 6) and 1,5substitution (entry 7) patterns. Finally, the use of 2,6-dichloroiodobenzene gave the 1,2difunctionalization product 23 in modest yield (entry 8). This is a notable case in which a chloride participated in the SNAr reaction and also was the only successful case of 1,2-difunctionalization we have observed (vide infra).


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Table 2. Scope of 4-Fluoroaryl Grignard Reagent in the Transnitrilation/SNAr Reactiona

a

Reaction conditions: (A) 1.0 equiv of ArX, 1.2 equiv of i-PrMgCl, THF, 0 °C, then 1.0 mmol of 2,2disubstituted malononitrile, THF, 0 °C to rt, 30 min. (B) 1.0 equiv of ArX, 1.1 equiv of n-BuLi, THF, – 78 °C, 5 min, then 1.0 mmol of 2,2-disubstituted malononitrile, THF, –78 °C to rt, 1 h. bIsolated yield.

Although the reaction was tolerant of a single methyl group adjacent to the fluoride moiety, the presence of two neighboring methyl groups prevented the SNAr reaction (Scheme 2). In this case only


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the product of transnitrilation, compound 24, was obtained, and the difunctionalization product 25 was not detected.

Scheme 2. Steric Shielding of the Fluoride Prevents SNAr Reaction.

While the difunctionalization reaction was successful for aryl Grignard reagents bearing a para-fluoro group, the corresponding ortho- and meta-fluoro Grignard reagents displayed different reactivity (Scheme 3). The ortho-fluoro Grignard reagent was prepared from 2-iodofluorobenzene and i-PrMgCl (Scheme 3A). On trapping with DMMN, neither the cyanation product 26 nor the difunctionalization product 27 was observed. This is likely due to the known propensity of 2-fluoroaryl Grignard reagents to form benzyne derivatives.9 Similarly, attempts to convert 2-bromofluorobenzene to the corresponding lithium reagent at –78 °C and then trap it with DMMN at –78 °C also resulted in no detectable amounts of 26 or 27.10 For the meta-fluoro experiment, the commercially available Grignard reagent was employed (Scheme 3B). On reaction with DMMN, a modest 54% yield of the cyanation product 28 was obtained, along with a 12% yield of the addition product 29, resulting from hydrolysis of the initially formed ketimine adduct A (Figure 1A), which has failed to undergo fragmentation. The difunctionalization product 30 was not observed.


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Scheme 3. The Reaction of o-Fluoro (A) and m-Fluoro (B) Aryl Grignard Reagents with DMMN (1).

In conclusion, the 1,4-difunctionalization of 4-fluorophenyl Grignard and lithium reagents with 2,2disubstituted malononitriles via transnitrilation and subsequent SNAr reaction has been explored. The reaction is possible using 4-fluoroaryllithium reagents as well as Grignard reagents. The process works for both acyclic and cyclic 2,2-disubstituted malononitriles. The presence of substituents ortho to either the fluoride or the metallated carbon is tolerated. This method provides a unique avenue for the one-pot, 1,4-difunctionalization of 1-magnesiated or 1-lithiated 4-fluoroarenes.

EXPERIMENTAL SECTION General Information. All starting materials and reagents were purchased from commercial sources and used as received unless otherwise noted. NMR spectra were recorded on a 400 MHz instrument. All 1H and 13C NMR data were referenced to the internal deuterated solvent relative to TMS at 0 ppm. High resolution mass spectroscopy (HRMS) was performed on a TOF instrument with ESI in positive ionization mode. Flash chromatography was performed on an automated system with silica columns. Melting points are uncorrected. DMMN (1), 4-fluorophenylmagnesium bromide (1.0 M in THF), i-PrMgCl (2.0 M in THF), and n-BuLi (2.47 M in hexane) were purchased from commercial sources.


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Representative Procedure for the Reaction of 4-Fluorophenylmagnesium Bromide (3) with 2,2-Disubstituted Malononitriles. A reaction flask equipped with a magnetic stir bar was charged with anhydrous THF (3.5 mL) and commercial 4-fluorophenylmagnesium bromide (3) solution (5.5 mL, 5.5 mmol, 1.0 M in THF) at 0 °C. To the resulting mixture, a solution of dimethylmalononitrile (1) (471 mg, 5.0 mmol in 2 mL THF) was added and the reaction mixture was allowed to warm up to room temperature. After 30 min, TLC analysis indicated complete consumption of 1. The reaction mixture was quenched with saturated aqueous NH4Cl (10 mL) and extracted with MTBE (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on SiO2 (10% MTBE/hexanes) to provide 5 (732 mg, 86% yield) as a white solid. 4-(2-Cyanopropan-2-yl)benzonitrile (5).10 See the representative procedure. Mp 88–90 °C; 1H NMR (400 MHz, CDCl3) δ 7.72−7.70 (m, 2H), 7.63−7.60 (m, 2H), 1.75 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 146.5, 132.8, 126.1, 123.4, 118.2, 111.9, 37.5, 28.8. 4-(1-Cyanocyclobutyl)benzonitrile (8).11 According to the representative procedure, the reaction of 3 (2.2 mL, 2.2 mmol) and cyclobutane-1,1-dicarbonitrile12 (212 mg, 2.0 mmol) followed by SiO2 flash chromatography (10% MTBE/hexanes) afforded the title compound as a colorless oil (207 mg, 57% yield): 1H NMR (400 MHz, CDCl3) δ 7.71–7.68 (m, 2H), 7.56–7.53 (m, 2H), 2.90–2.82 (m, 2H), 2.66–2.57 (m, 2H), 2.53–2.41 (m, 1H), 2.16–2.06 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 144.8, 132.8, 126.6, 123.2, 118.2, 112.0, 40.2, 34.6, 17.1. 4-(1-Cyanocyclopentyl)benzonitrile (9).13 According to the representative procedure, the reaction of 3 (2.2 mL, 2.2 mmol) and cyclopentane-1,1-dicarbonitrile12 (240 mg, 2.0 mmol) followed by SiO2 flash chromatography (10% MTBE/hexanes) afforded the title compound as a colorless oil (333 mg, 85% yield): 1H NMR (400 MHz, CDCl3) δ 7.70–7.68 (m, 2H), 7.61–7.59 (m, 2H), 2.54–2.49 (m, 2H), 2.11–1.97 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 144.9, 132.5, 126.8, 123.1, 118.1, 111.6, 47.7, 40.3, 24.1; HRMS (ESI) calcd for C13H13N2 [M + H]+ m/z 197.1073, found 197.1069. ACS Paragon Plus Environment

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4-(1-Cyanocyclohexyl)benzonitrile (10).6b According to the representative procedure, the reaction of 3 (5.5 mL, 5.5 mmol) and cyclohexane-1,1-dicarbonitrile12 (670 mg, 5.0 mmol) followed by SiO2 flash chromatography (10% MTBE/hexanes) afforded the title compound as a light brown solid (778 mg, 74% yield): mp 59.5–61.0 °C; 1H NMR (400 MHz, CDCl3) δ 7.72–7.69 (m, 2H), 7.65–7.63 (m, 2H), 2.16–2.13 (m, 2H), 1.95–1.74 (m, 7H), 1.35-1.28 (m, 1H);

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C NMR (100 MHz, CDCl3) δ

146.3, 132.5, 126.5, 121.4, 118.0, 111.6, 44.5, 36.7, 24.5, 23.2. 4-(4-Cyanophenyl)tetrahydro-2H-pyran-4-carbonitrile (11). According to the representative procedure, the reaction of 3 (5.5 mL, 5.5 mmol) and tetrahydro-4H-pyran-4,4-dicarbonitrile12 (680 mg, 5.0 mmol) followed by SiO2 flash chromatography (15% MTBE/hexanes) afforded the title compound as a white solid (880 mg, 83% yield): mp 114–115 °C; 1H NMR (400 MHz, CDCl3) δ 7.76–7.73 (m, 2H), 7.65–7.63 (m, 2H), 4.14–4.10 (m, 2H), 3.94–3.88 (m, 2H), 2.18–2.03 (m, 4H);

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C NMR (100

MHz, CDCl3) δ 144.7, 133.0, 126.6, 120.7, 118.0, 112.4, 64.7, 42.2, 36.2; HRMS (ESI) calcd for C13H13N2O [M + H]+ m/z 213.1022, found 213.1027. 4-(2-Cyano-1,3-diphenylpropan-2-yl)benzonitrile (12). According to the representative procedure, the reaction of 3 (5.5 mL, 5.5 mmol) and 2,2-dibenzylmalononitrile12 (1.23 g, 5.0 mmol) followed by SiO2 flash chromatography (10% MTBE/hexanes) afforded the title compound as a colorless oil (1.06 g, 66% yield): 1H NMR (400 MHz, CDCl3) δ 7.57–7.55 (m, 2H), 7.41–7.39 (m, 2H), 7.23–7.16 (m, 6H), 7.02–7.00 (m, 4H), 3.39–3.36 (m, 2H), 3.29–3.26 (m, 2H);

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C NMR (100 MHz,

CDCl3) δ 142.7, 134.2, 132.5, 130.4, 128.5, 128.0, 127.8, 120.5, 118.3, 112.1, 51.6, 46.4; HRMS (ESI) calcd for C23H19N2 [M + H]+ m/z 323.1543, found 323.1551. 4-(2-Cyanohexan-2-yl)benzonitrile (13). According to the representative procedure, the reaction of 3 (2.2 mL, 2.2 mmol) and 2-butyl-2-methylmalononitrile (272 mg, 2.0 mmol) followed by SiO2 flash chromatography (10% MTBE/hexanes) afforded the title compound as a colorless oil (297 mg, 70% yield): 1H NMR (400 MHz, CDCl3) δ 7.72–7.70 (m, 2H), 7.59–7.57 (m, 2H), 1.99–1.85 (m, 2H), 1.73 (s, 3H), 1.50–1.39 (m, 1H), 1.38–1.25 (m, 2H), 1.21–1.10 (m, 1H), 0.87 (t, J = 7.3 Hz, 3H); ACS Paragon Plus Environment

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C NMR (100 MHz, CDCl3) δ 145.8, 132.9, 126.6, 122.6, 118.4, 112.1, 43.0, 41.8, 27.7, 27.6, 22.6,

13.9; HRMS (ESI) calcd for C14H17N2 [M + H]+ m/z 213.1386, found 213.1395. 4-(2-Cyano-1-phenylpropan-2-yl)benzonitrile (14). According to the representative procedure, the reaction of 3 (2.2 mL, 2.2 mmol) and 2-benzyl-2-methylmalononitrile (340 mg, 2.0 mmol) followed by SiO2 flash chromatography (10% MTBE/hexanes) afforded the title compound as a tan solid (380 mg, 77% yield): mp 93–94.5 °C; 1H NMR (400 MHz, CDCl3) δ 7.66–7.63 (m, 2H), 7.48–7.45 (m, 2H), 7.26–7.21 (m, 3H), 6.99–6.97 (m, 2H), 3.18 (d, J = 13.6 Hz, 1H), 3.11 (d, J = 13.6 Hz, 1H), 1.79 (s, 3H);

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C NMR (100 MHz, CDCl3) δ 144.9, 134.3, 132.7, 130.3, 128.5, 127.9, 127.1, 122.2, 118.3,

112.2, 48.4, 44.0, 26.0; HRMS (ESI) calcd for C17H15N2 [M + H]+ m/z 247.1230, found 247.1232. 4-(2-Cyanopent-4-en-2-yl)benzonitrile (15). According to the representative procedure, the reaction of 3 (2.2 mL, 2.2 mmol) and 2-allyl-2-methylmalononitrile (240 mg, 2.0 mmol) followed by SiO2 flash chromatography (10% MTBE/hexanes) afforded the title compound as a colorless oil (330 mg, 84% yield): 1H NMR (400 MHz, CDCl3) δ 7.72–7.70 (m, 2H), 7.60–7.57 (m, 2H), 5.68 (dddd, J = 17.5, 10.2, 7.3 Hz, 1H), 5.21–5.18 (m, 1H), 5.19–5.13 (m, 1H), 2.67-2.65 (m, 2H), 1.75 (s, 3H);

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C

NMR (100 MHz, CDCl3) δ 145.0, 132.7, 131.0, 126.7, 122.1, 121.0, 118.2, 112.0, 45.9, 42.5, 26.3; HRMS (ESI) calcd for C13H13N2 [M + H]+ m/z 197.1073, found 197.1077. 3-Fluorobenzonitrile (28)14 and 3-(3-fluorophenyl)-2,2-dimethyl-3-oxopropanenitrile (29). According to the representative procedure, the reaction of 3-fluorophenylmagnesium bromide (2.2 mL, 1.0 M in THF) and DMMN (1) (188 mg) followed by SiO2 flash chromatography (5% MTBE/hexanes) afforded 28 as a colorless oil (131 mg, 54% yield) and 29 as a colorless oil (46 mg, 12% yield). Data for 28: 1H NMR (400 MHz, CDCl3) δ 7.48–7.46 (m, 2H), 7.38–7.31 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 162.2 (d, J = 250 Hz), 131.2 (d, J = 8.4 Hz), 128.2 (d, J = 3.5 Hz), 120.5 (d, J = 21 Hz), 119.2 (d, J = 24.6 Hz), 117.5 (d, J = 3.2 Hz), 113.9 (d, J = 9.2 Hz). Data for 29: 1H NMR (400 MHz, CDCl3) δ 8.01– 7.99 (m, 1H), 7.82–7.78 (m, 1H), 7.53–7.48 (m, 1H), 7.35–7.31 (m, 1H), 1.72 (s, 6H);

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C NMR (100

MHz, CDCl3) δ 192.8, 162.7 (d, J = 249 Hz), 135.5 (d, J = 6.5 Hz), 130.4 (d, J = 7.6 Hz), 125.1 (d, J = ACS Paragon Plus Environment

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3.2 Hz), 122.3, 121.0 (d, J = 21.4 Hz), 116.3 (d, J = 23.2 Hz), 41.0, 25.5; HRMS (ESI) calcd for C11H11FNO [M + H]+ m/z 192.0819, found 192.0833. Representative Procedure for Aryl Grignard Formation with i-PrMgCl and Subsequent Reaction with 2,2-Disubstituted Malononitriles. A solution of i-PrMgCl (3.0 mL, 6.0 mmol, 2.0 M in THF) was charged to a THF solution of 1-fluoro-4-iodo-2-methylbenzene (1.30 g, 5.5 mmol in 5 mL THF) at 0 °C. The reaction mixture was stirred at the same temperature and monitored by HPLC for completion (30 min). To the resulting mixture, a solution of dimethylmalononitrile (1) (471 mg, 5.0 mmol in 2 mL THF) was added and the reaction mixture was allowed to warm up to room temperature. After 30 min, TLC analysis indicated complete consumption of DMMN (1). The reaction mixture was quenched with saturated aqueous NH4Cl (10 mL) and extracted with MTBE (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on SiO2 (10% MTBE/hexanes) to provide 16 (590 mg, 64% yield) as a white solid. 4-(2-Cyanopropan-2-yl)-3-methylbenzonitrile (16). See the representative procedure. Mp 137139 °C; 1H NMR (400 MHz, CDCl3) δ 7.53–7.52 (m, 2H), 7.45–7.42 (m, 1H), 2.70 (s, 3H), 1.81 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 143.3, 138.1, 136.0, 130.3, 125.9, 123.5, 118.3, 112.3, 35.3, 28.04, 28.01, 21.1; HRMS (ESI) calcd for C12H13N2 [M + H]+ m/z 185.1073, found 185.1083. 4-(2-Cyanopropan-2-yl)-2-methylbenzonitrile (17). According to the representative procedure, the reaction of i-PrMgCl (2.3 mmol), 4-fluoro-1-iodo-2-methylbenzene (520 mg) and DMMN (1) (188 mg) followed by SiO2 flash chromatography (10% MTBE/hexanes) afforded the title compound as a white solid (276 mg, 75% yield): mp 49–51 °C; 1H NMR (400 MHz, CDCl3) δ 7.65–7.63 (m, 1H), 7.46 (s, 1H), 7.40–7.38 (m, 1H), 2.59 (s, 3H), 1.74 (s, 6H);

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C NMR (100 MHz, CDCl3) δ 146.4, 143.0,

133.3, 127.4, 123.6, 123.2, 117.7, 112.6, 37.5, 29.0, 20.8; HRMS (ESI) calcd for C12H13N2 [M + H]+ m/z 185.1073, found 185.1069.


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4-(4-Cyano-3-methylphenyl)tetrahydro-2H-pyran-4-carbonitrile (18). According to the representative procedure, the reaction of i-PrMgCl (2.3 mmol), 4-fluoro-1-iodo-2-methylbenzene (520 mg) and tetrahydro-4H-pyran-4,4-dicarbonitrile (272 mg) followed by SiO2 flash chromatography (15% MTBE/hexanes) afforded the title compound as a tan solid (344 mg, 76% yield): mp 114–115 °C; 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.2 Hz, 1H), 7.48 (br s, 1H), 7.41 (dd, J = 8.2, 1.7 Hz, 1H), 4.11 (dd, J = 11.7, 3.6 Hz, 2H), 3.90 (dt, J = 12.1, 2.0 Hz, 2H), 2.60 (s, 3H), 2.17–2.09 (m, 2H), 2.06–2.02 (m, 2H);

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C NMR (100 MHz, CDCl3) δ 144.7, 143.3, 133.5, 127.8, 123.7, 121.0, 117.5, 113.1, 65.0,

42.3, 36.5, 20.9; HRMS (ESI) calcd for C14H15N2O [M + H]+ m/z 227.1179, found 227.1172. 4-(2-Cyanopropan-2-yl)-1-naphthonitrile (21). According to the representative procedure, the reaction of i-PrMgCl (2.3 mmol), 1-bromo-4-fluoronaphthalene (495 mg) and DMMN (1) (188 mg) followed by SiO2 flash chromatography (10% MTBE/hexanes) afforded the title compound as a tan solid (229 mg, 52% yield): mp 122–124 °C; 1H NMR (400 MHz, CDCl3) δ 8.67–8.65 (m, 1H), 8.35– 8.32 (m, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.77–7.74 (m, 2H), 7.57 (d, J = 7.7 Hz, 1H), 2.00 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 141.7, 133.3, 132.0, 130.1, 128.6, 128.2, 126.9, 125.4, 124.2, 122.3, 117.5, 111.9, 35.1, 29.0; HRMS (ESI) calcd for C15H13N2 [M + H]+ m/z 221.1073, found 221.1066. 5-(2-Cyanopropan-2-yl)-1-naphthonitrile (22). According to the representative procedure, the reaction of i-PrMgCl (2.3 mmol), 1-bromo-5-fluoronaphthalene (495 mg) and DMMN (1) (188 mg) followed by SiO2 flash chromatography (10% MTBE/hexanes) afforded the title compound as a white solid (269 mg, 61% yield): mp 113–114 °C; 1H NMR (400 MHz, CDCl3) δ 8.86–8.84 (m, 1H), 8.31– 8.29 (m, 1H), 7.99–7.97 (m, 1H), 7.71–7.63 (m, 3H), 1.99 (s, 6H);

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C NMR (100 MHz, CDCl3) δ

136.9, 133.7, 132.5, 130.0, 129.6, 127.9, 126.6, 125.4, 124.6, 117.7, 111.8, 34.5, 29.0; HRMS (ESI) calcd for C15H13N2 [M + H]+ m/z 221.1073, found 221.1080. 2-Chloro-6-(2-cyanopropan-2-yl)benzonitrile (23). According to the representative procedure, the reaction of i-PrMgCl (2.3 mmol), 1,3-dichloro-2-iodobenzene (600 mg) and DMMN (1) (188 mg) followed by SiO2 flash chromatography (40% MTBE/hexanes) afforded the title compound as a white ACS Paragon Plus Environment

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solid (237 mg, 58% yield): mp 115–118 °C; 1H NMR (400 MHz, CDCl3) δ 7.69–7.67 (m, 1H), 7.62– 7.54 (m, 2H), 1.98 (s, 6H);

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C NMR (100 MHz, CDCl3) δ 145.8, 140.2, 133.9, 129.7, 125.2, 122.4,

114.8, 111.1, 38.0, 27.3; HRMS (ESI) calcd for C11H10N2Cl [M + H]+ m/z 205.0527, found 205.0536. Representative Procedure for Aryl Lithium Formation with n-BuLi and Subsequent Reaction with Dimethylmalononitrile. A solution of n-BuLi (4.05 mL, 9.99 mmol, 2.47 M in hexane) was charged dropwise to a THF solution of 4-fluorobromobenzene (1.0 mL, 9.08 mmol in 10 mL THF) at –78 °C. The reaction mixture was stirred at –78 °C for 5 min. The resultant solution was slowly added via cannula to a THF solution of dimethylmalononitrile (855 mg, 9.08 mmol) in 5 mL of THF precooled to –78 °C. The reaction mixture was allowed to warm up to room temperature over 1 h and then was quenched with saturated aqueous NH4Cl and extracted with MTBE. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on SiO2 (10% MTBE/hexanes) to provide 5 (874 mg, 56% yield) as a white solid. Spectral data matched data for 5 obtained from the Grignard process. 4-(2-Cyanopropan-2-yl)-2-methoxybenzonitrile

(19).

According

to

the

representative

procedure, the reaction of 1-bromo-4-fluoro-2-methoxybenzene (2.05 g) and DMMN (1) (941 mg) followed by SiO2 flash chromatography (40% MTBE/hexanes) afforded the title compound as a yellow solid (1.40 g, 70% yield): mp (MTBE/hexanes): 92-93.5 °C; 1H NMR (400 MHz, CDCl3) δ 7.55–7.53 (m, 1H), 7.08–7.06 (m, 2H), 3.95 (s, 3H), 1.72 (s, 6H);

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C NMR (100 MHz, CDCl3) δ 161.5, 148.5,

134.3, 123.5, 117.4, 115.9, 108.7, 101.4, 56.2, 37.8, 28.8; HRMS (ESI) calcd for C12H13N2O [M + H]+ m/z 201.1022, found 201.1031. 4-(2-Cyanopropan-2-yl)-2-(dimethylamino)benzonitrile (20). According to the representative procedure, the reaction of 2-bromo-5-fluoro-N,N-dimethylaniline (2.18 g) and DMMN (1) (941 mg) followed by SiO2 flash chromatography (65% MTBE/hexanes) afforded the title compound as a brown oil (1.77 g, 83% yield): 1H NMR (400 MHz, CDCl3) δ 7.52-7.50 (m, 1H), 7.01-7.00 (m, 1H), 6.88-6.86 (m, 1H), 3.12 (s, 6H), 1.72 (s, 6H);

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C NMR (100 MHz, CDCl3) δ 155.1, 147.1, 135.7, 123.7, 119.3,


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115.2, 113.3, 99.5, 42.8, 37.7, 28.7; HRMS (ESI) calcd for C13H16N3 [M + H]+ m/z 214.1339, found 214.1347. 4-Fluoro-3,5-dimethylbenzonitrile (24).15 According to the representative procedure, the reaction of 5-bromo-2-fluoro-1,3-dimethylbenzene (2.03 g) and DMMN (1) (941 mg) followed by SiO2 flash chromatography (10% MTBE/hexanes) afforded the title compound as a white solid (1.37 g, 92% yield): mp 87–89 °C; 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 6.6 Hz, 2H), 2.28 (s, 6H);

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C NMR

(100 MHz, CDCl3) δ 162.4 (d, J = 253 Hz), 132.9 (d, J = 6.4 Hz), 126.3 (d, J = 19.6 Hz), 118.4, 107.5 (d, J = 4.5 Hz), 14.4 (d, J = 4.1 Hz).

ASSOCIATED CONTENT Supporting Information Available. 1H and

13

C NMR spectra of all products. This material is free of

charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author *[email protected] Present Address † Department of Chemistry, University of Michigan, Ann Arbor, MI 48109. ‡ Department of Chemistry, University of Connecticut, Storrs, CT 06269.

Notes The authors declare no competing financial interests. REFERENCES (1) Reeves, J. T.; Malapit, C. A.; Buono, F.; Sidhu, K. P.; Marsini, M. A.; Sader, C. A.; Fandrick, K. R.; Busacca, C. A.; Senanayake, C. H. J. Am. Chem. Soc. 2015, 137, 9481. (2) The SNAr reaction of secondary nitriles such as isobutyronitrile and aryl fluorides using KHMDS in toluene at 60-100 °C has been described: Caron, S.; Vazquez, E.; Wojcik, J. M. J. Am. Chem. Soc. 2000, 122, 712. (3) Selected arene difunctionalization reactions: a) Sumida, Y.; Sumida, T.; Hashizume, D.; Hosoya, T. Org. Lett. 2016, 18, 5600; b) Zeng, Y.; Hu, J. Synthesis 2016, 2137; c) Garcia-Lopez, J.-A.; Cetin, M.; Greaney, M. F. Angew. Chem. Int. Ed. 2015, 54, 2156; d) Melzig, L.; Rauhut, C. B.; ACS Paragon Plus Environment

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Naredi-Rainer, N.; Knochel, P. Chem. Eur. J. 2011, 17, 5362; e) Melzig, L.; Rauhut, C. B.; Knochel, P. Synthesis 2009, 1041. (4) a) Agrawal, T.; Cook, S. P. Org. Lett. 2014, 16, 5080; b) Manabe, K.; Kimura, T. Org. Lett. 2013, 15, 374. (5) This mode of addition gave the highest yield of 5. When the normal addition sequence used for aryl Grignard reagents was employed, a 47% yield of 5 was obtained. (6) For selected examples of α-arylation of nitriles, see: a) You, J.; Verkade, J. G. Angew. Chem., Int. Ed. 2003, 42, 5051; b) Wu, L.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 15824; c) Jiao, Z.; Chee, K. W.; Zhou, J. J. Am. Chem. Soc. 2016, 138, 16240. (7) a) Boymond, L.; Rottlander, M.; Cahiez, G.; Knochel, P. Angew. Chem. Int. Ed. 1998, 37, 1701; b) Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem. Int. Ed. 2003, 42, 4302; c) Klatt, T.; Markiewicz, J. T.; Samann, C.; Knochel, P. J. Org. Chem. 2014, 79, 4253. (8) Bailey, W. F.; Patricia, J. J. J. Organomet. Chem. 1988, 352, 1. (9) Wittig, G. Org. Synth., Coll. Vol. 1963, 4, 964. (10) Davies, J. W.; Durrant, M. L.; Walker, M. P.; Malpass, J. R. Tetrahedron 1992, 48, 4379. (11) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 9330. (12) Malapit, C. A.; Reeves, J. T.; Busacca, C. A.; Howell, A. R.; Senanayake, C. H. Angew. Chem. Intl. Ed. 2016, 55, 326. (13) Brown, W.; Johnstone, S.; Labrecque, D. U.S. Patent 8 093 402, 2012. (14) Taft, R. W.; Price, E.; Fox, I. R.; Lewis, I. C.; Andersen, K. K.; Davis, G. T. J. Am. Chem. Soc. 1963, 85, 709. (15) Noël, T.; Maimone, T. J.; Buchwald, S. L. Angew. Chem. Int. Ed. 2011, 50, 8900.


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1,4-Dicarbofunctionalization of 4-Fluoroaryl ... - ACS Publications

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