1,4-Dicarbofunctionalization of 4-Fluoroaryl Grignard and Lithium Reagents with Disubstituted Malononitriles

Article abstract of DOI:10.1021/acs.joc.7b00567

An efficient one-pot 1,4-dicarbofunctionalization of 4-fluoroaryl Grignard or lithium reagents with 2,2-disubstituted malononitriles is described. The reaction proceeds by sequential transnitrilation and S_NAr 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 n-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.

Full text of DOI:10.1021/acs.joc.7b00567

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Note
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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1,4-Dicarbofunctionalization of 4-Fluoroaryl Grignard
and Lithium Reagents with Disubstituted Malononitriles
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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
jonathan.reeves@boehringer-ingelheim.com
RECEIVED DATE
TABLE OF CONTENTS/ABSTRACT GRAPHIC
transnitrilation
CN
MgX
THF, 0 °C - rt
NC
CN
R'
R
R
+
R
SNAr reaction
R'
F
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 2,2-
disubstituted 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 n-
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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.
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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-2-
yl)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
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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 1,4-
regioselectivity, 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 2,2-
disubstituted malononitrile.
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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
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aReaction 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 1,5-
substitution (entry 7) patterns. Finally, the use of 2,6-dichloroiodobenzene gave the 1,2-
difunctionalization 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
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aReaction conditions: (A) 1.0 equiv of ArX, 1.2 equiv of i-PrMgCl, THF, 0 °C, then 1.0 mmol of 2,2-
disubstituted 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
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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).
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In conclusion, the 1,4-difunctionalization of 4-fluorophenyl Grignard and lithium reagents with 2,2-
disubstituted 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.
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1
4-(2-Cyanopropan-2-yl)benzonitrile (5).10 See the representative procedure. Mp 88–90 °C; H
13
NMR (400 MHz, CDCl3) δ 7.72−7.70 (m, 2H), 7.63−7.60 (m, 2H), 1.75 (s, 6H); C 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
1
mg, 57% yield): H NMR (400 MHz, CDCl3) δ 7.71–7.68 (m, 2H), 7.56–7.53 (m, 2H), 2.90–2.82 (m,
13
2H), 2.66–2.57 (m, 2H), 2.53–2.41 (m, 1H), 2.16–2.06 (m, 1H); C 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
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mg, 85% yield): H NMR (400 MHz, CDCl3) δ 7.70–7.68 (m, 2H), 7.61–7.59 (m, 2H), 2.54–2.49 (m,
13
2H), 2.11–1.97 (m, 6H); C 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.
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4-(1-Cyanocyclohexyl)benzonitrile (10).6b According to the representative procedure, the
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reaction of 3 (5.5 mL, 5.5 mmol) and cyclohexane-1,1-dicarbonitrile12 (670 mg, 5.0 mmol) followed by
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SiO2 flash chromatography (10% MTBE/hexanes) afforded the title compound as a light brown solid
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(778 mg, 74% yield): mp 59.5–61.0 °C; H NMR (400 MHz, CDCl3) δ 7.72–7.69 (m, 2H), 7.65–7.63
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(m, 2H), 2.16–2.13 (m, 2H), 1.95–1.74 (m, 7H), 1.35-1.28 (m, 1H); 13C 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.
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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
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as a white solid (880 mg, 83% yield): mp 114–115 °C; H 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); 13C 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); 13C 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
1
mg, 70% yield): H 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);
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13C 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.
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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); 13C 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
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mg, 84% yield): H 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); 13C
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–
13
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); 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 =
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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.
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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.
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4-(2-Cyanopropan-2-yl)-3-methylbenzonitrile (16). See the representative procedure. Mp 137-
1
139 °C; H 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
1
white solid (276 mg, 75% yield): mp 49–51 °C; H NMR (400 MHz, CDCl3) δ 7.65–7.63 (m, 1H), 7.46
13
(s, 1H), 7.40–7.38 (m, 1H), 2.59 (s, 3H), 1.74 (s, 6H); 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%
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MTBE/hexanes) afforded the title compound as a tan solid (344 mg, 76% yield): mp 114–115 °C; H
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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
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(m, 2H); 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
1
solid (229 mg, 52% yield): mp 122–124 °C; H NMR (400 MHz, CDCl3) δ 8.67–8.65 (m, 1H), 8.35–
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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); C
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
1
solid (269 mg, 61% yield): mp 113–114 °C; H 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); 13C 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
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solid (237 mg, 58% yield): mp 115–118 °C; H NMR (400 MHz, CDCl3) δ 7.69–7.67 (m, 1H), 7.62–
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7.54 (m, 2H), 1.98 (s, 6H); 13C 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.
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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
1
solid (1.40 g, 70% yield): mp (MTBE/hexanes): 92-93.5 °C; H NMR (400 MHz, CDCl3) δ 7.55–7.53
13
(m, 1H), 7.08–7.06 (m, 2H), 3.95 (s, 3H), 1.72 (s, 6H); 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
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(m, 1H), 3.12 (s, 6H), 1.72 (s, 6H); 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.
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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%
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yield): mp 87–89 °C; H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 6.6 Hz, 2H), 2.28 (s, 6H); 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
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Supporting Information Available. H and C NMR spectra of all products. This material is free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*jonathan.reeves@boehringer-ingelheim.com
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.;
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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.,
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Knochel, P. J. Org. Chem. 2014, 79, 4253.
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(8) Bailey, W. F.; Patricia, J. J. J. Organomet. Chem. 1988, 352, 1.
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(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.
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1963, 85, 709.
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