Nickel-catalyzed Kumada cross-coupling reactions of tertiary alkylmagnesium halides and aryl bromides/triflates

Article abstract of DOI:10.1021/ja202769t

We report a Ni-catalyzed process for the cross-coupling of tertiary alkyl nucleophiles and aryl bromides. This process is extremely general for a wide range of electrophiles and generally occurs with a ratio of retention to isomerization >30:1. The same procedure also accommodates the use of aryl triflates, vinyl chlorides, and vinyl bromides as the electrophilic component.

Full text of DOI:10.1021/ja202769t

NickelꢀCatalyzed Kumada CrossꢀCoupling Reactions of Tertiary
Alkylmagnesium Halides and Aryl Bromides/Triflates
Amruta Joshi-Pangu, Chao-Yuan Wang, and Mark R. Biscoe*
Department of Chemistry, The City College of New York, 160 Convent Avenue, New
York, NY 10031
Supporting Information
General Reagent Information. BDH brand toluene was purchased from VWR. EMD
brand Omnisolv THF (unstabilized) was also purchased from VWR. These solvents were
transferred to separate 20L solventꢀdelivery kegs and vigorously purged with argon for 2
h. The solvents were further purified by passing them under argon pressure through two
packed columns of neutral alumina (for THF and Et2O) or through neutral alumina and
copper (II) oxide (for toluene). tꢀBuMgCl (1M in THF) was purchased from Sigmaꢀ
Aldrich. All NHC ligands were purchased form Strem. All nickel compounds with the
exception of NiCl2(H2O)6 (Fisher Scientific) were purchased from Strem. Grignard
reagents were prepared from their corresponding tꢀalkyl chlorides or bromides using a
literature procedure.1 Molarities of Grignard reagents (typically between 0.8 M and 1.0
M) were determined using iodine titration.2 Reagents and solvents were used as received
unless otherwise noted. Flash chromatography was performed using Silicylcle silica gel
(ultra pure grade).
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General Analytical Information. All compounds were characterized by H NMR and
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13C NMR spectroscopy. Copies of the H and C spectra for all new compounds can be
found at the end of the Supporting Information. All previously unreported compounds
were additionally characterized by high resolution MS. Nuclear Magnetic Resonance
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spectra were recorded on a Varian 300 or 500 MHz instrument. All H NMR
experiments are reported in δ units, parts per million (ppm), and were measured relative
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to the signals for residual chloroform (7.26 ppm). All C NMR spectra are reported in
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ppm relative to deuterochloroform (77.23 ppm), and were obtained with H decoupling.
19F NMR spectra were recorded using CFCl3 (0.00 ppm) as an internal reference. High
resolution MS analyses were performed on an Agilent 6520 QꢀTOF instrument. All GC
analyses were performed on a Shimadzu GCꢀ2010 gas chromatograph with an FID
detector using a 25 m x 0.20 mm capillary column with crossꢀlinked methyl siloxane as
the stationary phase. All GC yields were calibrated using dodecane as an internal
standard.
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General Procedural Information.
General procedure for the preparation of NiCl2•(H2O)n
NiCl2•(H2O)6 (2 g, 8.4 mmol) was finely ground using a mortar and pestle and
transferred to a 50 mL round bottom flask containing a stirbar. The flask was place under
high vacuum (0.5–1.0 torr) and immersed into a 100 ºC oil bath for 20 minutes. The
contents of the flasks were vigorously mixed to ensure homogenous heating. The color
of the nickel complex changed from bright green to yellow to yellowꢀorange as water was
removed. The flask was removed from the oil bath and allowed to cool. Loss of water
was determined by measuring mass lost during the heating process. In general, after 20
min, ca. 2 equiv water remained for each equivalent of NiCl2. After loss of 4 equivalents
of water, dehydration becomes slower. After having determined the extent of remaining
hydration, the temperature of the oil bath was increased to 120 ºC. The flask was reꢀ
immersed in the heated oil bath for 5ꢀ10 min to generate NiCl2•(H2O)n where n = 1.4–1.7.
NiCl2 samples with different extents of hydration were achieved by sampling the heated
reaction flask more frequently. In order to thoroughly dehydrate the NiCl2, the
temperature of the oil bath was increased to 150 ºC and the flask was heated for at least 2
h. In its anhydrous state, NiCl2 is orange.
General procedure for the cross-coupling of aryl/vinyl halide/triflates and tertiary
alkylmagnesium halides:
Because we are interested in developing methods of high operational simplicity as
well as generality, we performed each of the reactions on the benchtop, using readily
available disposable vials with screwꢀtop septa. NiCl2•(H2O)1.54 (16 mg, 0.1 mmol) and
NHC ligand 18 (32 mg, 0.1 mmol) were weighed out on the benchtop in an ovenꢀdried 10
mL screw top test tube with stir bar. The aryl bromide/triflate (1 mmol) was then added
to the vial. The vial was sealed using a screw cap lined with a teflon septum. The
reaction vial was evacuated and backfilled three times with argon using a needle attached
to a vacuum manifold, and cooled to –10 ºC in a NaCl/ice slurry prior to the addition of
the alkylmagnesium reagent. If the aryl bromide/triflate were a liquid, it was added via
microsyringe after having backfilled the vial with argon. The tertiary alkylmagnesium
halide (2.0 mmol) was then added via syringe under a positive pressure of argon. The
vial was sealed with electrical tape and the reaction mixture was stirred for 90 minutes on
the benchtop at –10 ºC with no additional argon pressure. The reaction mixture was
quenched through the addition of ice chips, then poured into a separatory funnel
containing saturated aqueous NH4Cl (ca. 10 mL) and extracted with EtOAc (3 x 20 mL).
The combined organic layers were washed with brine and dried over Na2SO4. The crude
product was purified by column chromatography. Extent of isomerization can be easily
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determined via H NMR spectroscopy by comparison of the intergral of the singlet from
the tꢀbutyl group (1.3ꢀ1.4 ppm, 9H) to the integral of the doublet from the benzylic
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protons of the iꢀbutyl group (2.4ꢀ2.5 ppm, 2H). The doublet from the methyls of the iꢀ
butyl group could additionally be used (ca. 0.8 ppm, 6H).
t-Bu
2-(tert-Butyl)naphthalene (Table 2, Row 1, Column 1). The general procedure
was employed. A oily, white solid was isolated by column chromatography (96:4
Hex:Ether). This product consisted of 142 mg desired product (77% yield) and 15 mg
reduction product. 1H NMR (500 MHz, CDCl3) δ: 7.77ꢀ7.84 (m, 4H), 7.57 (dd, J = 8.4,
1.9 Hz, 1H), 7.39ꢀ7.47 (m, 2H), 1.43 (s, 9H) ppm. 13C NMR (125 MHz, CDCl3) δ: 133.6,
131.9, 128.2, 127.9, 127.6, 127.5, 126.0, 125.4, 125.0, 123.1, 35.0, 31.5 ppm.
t-Bu
t-Bu
1,4-di-tert-Butylbenzene (Table 2, Row 1, Column 2). The general procedure
was employed. A oily, white solid (147 mg, 77%) was isolated by column
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chromatography (98:2 Hex:Ether). H NMR (500 MHz, CDCl3) δ: 7.34 (s, 4H), 1.34 (s,
18H) ppm. 13C NMR (125 MHz, CDCl3) δ: 148.2, 125.1, 34.5, 31.6 ppm.
t-Bu
EtO2C
Ethyl 4-(tert-butyl)benzoate (Table 2, Row 1, Column 3). The general
procedure was employed. A yellow liquid (167 mg, 81%) was isolated by column
chromatography (80:20 Hex:EtOAc). 1H NMR (500 MHz, CDCl3) δ: 7.98 (d, J = 8.6
Hz, 2H), 7.45 (d, J = 8.6 Hz, 2H), 4.36 (q, J = 7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H), 1.34
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(s, 9H) ppm. C NMR (125 MHz, CDCl3) δ: 166.7, 156.5, 129.5, 127.9, 125.4, 60.8,
35.1, 31.2, 14.5 ppm.
t-Bu
OMe
1-(tert-Butyl)-3-methoxybenzene (Table 2, Row 2, Column 1). The general
procedure was employed. A colorless liquid (138 mg, 84%) was isolated by column
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chromatography (98:2 Hex:Ether). H NMR (500 MHz, CDCl3) δ: 7.23 (t, J = 7.9 Hz,
1H), 6.99 (ddd, J = 7.8 Hz, 1.8 Hz, 0.9 Hz, 1H), 6.95 (m, 1H), 6.73 (ddd, J = 8.1 Hz, 2.6
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Hz, 0.9 Hz, 1H), 3.81 (s, 3H), 1.31 (s, 9H) ppm. C NMR (125 MHz, CDCl3) δ: 159.6,
153.1, 129.1, 118.0, 112.2, 110.1, 55.2, 34.9, 31.5 ppm.
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O
H
O
t-Bu
2-(3-(tert-butyl)phenyl)-1,3-dioxolane (Table 2, Row 2, Column 2). The general
procedure was employed. The general procedure was employed. A colorless liquid (165
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mg, 80%) was isolated by column chromatography (95:5 Hex:Ether). H NMR (500
MHz, CDCl3) δ: 7.49 (m, 1H), 7.40 (dt, J = 7.2 Hz, 1.6 Hz, 1H), 7.31 (m, 2H), 5.81 (s,
1H), 4.10 (m, 4H), 1.33 (s, 9H) ppm. 13C NMR (125 MHz, CDCl3) δ: 151.4, 137.5,
128.3, 126.5, 123.7, 123.5, 104.3, 65.5, 34.9, 31.5 ppm. HRMS (ESI+): (M+H)+:
207.1380 (calc.); 207.1382 (found); diff (ppm) = 1.31.
t-Bu
MeO
1-(tert-Butyl)-4-methoxybenzene (Table 2, Row 2, Column 3). The general
procedure was employed. A colorless liquid (126 mg, 77%) was isolated by column
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chromatography (98:2 Hex:Ether). H NMR (500 MHz, CDCl3) δ: 7.34 (d, J = 8.9 Hz,
2H), 6.88 (d, J = 8.9 Hz, 2H), 3.82 (s, 3H), 1.34 (s, 9H) ppm. 13C NMR (125 MHz,
CDCl3) δ: 157.5, 143.5, 126.4, 113.5, 55.4, 34.2, 31.7 ppm.
F3CO
t-Bu
1-(tert-Butyl)-3-(trifluoromethoxy)benzene (Table 2, Row 3, Column 1). The
general procedure was employed. A colorless liquid (153 mg, 70%) was isolated by
column chromatography (98:2 Hex:Ether). 1H NMR (500 MHz, CDCl3) δ: 7.32 (m, 2H),
7.22 (s, 1H), 7.05 (m, 1H), 1.33 (s, 9H) ppm. 13C NMR (125 MHz, CDCl3) δ: 153.9,
149.5, 129.4, 123.9, 118.4, 118.0, 35.1, 33.4 ppm. 19F NMR (282 MHz, CDCl3) δ: ꢀ58.2
ppm. HRMS (APPI+): M+: 218.0918 (calc.); 218.0915 (found); diff (ppm) = ꢀ1.49.
t-Bu
Cl
1-(tert-Butyl)-4-chlorobenzene (Table 2, Row 3, Column 2). The general
procedure was employed. A pale yellow liquid (142 mg, 84%) was isolated by column
chromatography (96:4 Hex:Ether). 1H NMR (500 MHz, CDCl3) δ: 7.33 (d, J = 8.8 Hz,
2H), 7.27 (d, J = 8.8 Hz, 2H), 1.32 (s, 9H). 13C NMR (125 MHz, CDCl3) δ: 149.8, 131.3,
128.3, 126.9, 34.7, 31.5 ppm.
t-Bu
O
O
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5-(tert-Butyl)benzo[d][1,3]dioxole (Table 2, Row 3, Column 3). The general
procedure was employed. A purple liquid was isolated by column chromatography
(90:10 Hex:EtOAc). This liquid consisted of 130 mg desired product (73% yield) and 17
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mg reduction product. H NMR (500 MHz, CDCl3) δ: 6.90 (d, J = 2.0 Hz, 1H), 6.82ꢀ6.84
(m, 2H), 5.92 (s, 2H), 1.28 (s, 9H) ppm. 13C NMR (125 MHz, CDCl3) δ: 147.6, 145.5,
145.3, 118.0, 107.8, 106.5, 100.9, 34.8, 31.8 ppm.
t-Bu
Me2N
4-(tert-Butyl)-N,N-dimethylaniline (Table 2, Row 4, Column 1). The general procedure
was employed. A pale yellow liquid was isolated by column chromatography (90:10
Hex:EtOAc). This liquid consisted of 135 mg desired product (76% yield) and 17 mg
reduction product. 1H NMR (500 MHz, CDCl3) δ: 7.39 (d, J = 8.8 Hz, 2H), 6.83 (d, J =
8.8 Hz, 2H), 3.02 (s, 6H), 1.42 (s, 9H) ppm. 13C NMR (125 MHz, CDCl3) δ: 148.7,
139.5, 126.0, 112.8, 41.2, 33.9, 31.7 ppm.
t-Bu
F3C
1-(tert-Butyl)-4-(trifluoromethyl)benzene (Table 2, Row 4, Column 2). The
general procedure was employed. A colorless liquid (164 mg, 81%) was isolated by
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column chromatography (98:2 Hex:Ether). H NMR (500 MHz, CDCl3) δ: 7.60 (d, J =
8.3 Hz, 2H), 7.54 (d, J = 8.3 Hz, 2H), 1.39 (s, 9H) ppm. 13C NMR (125 MHz, CDCl3) δ:
155.4, 128.1 (q, J = 32 Hz), 125.9, 125.2 (q, J = 4 Hz), 124.7 (q, J = 270 Hz), 35.2, 31.3
ppm.
TBDMSO
t-Bu
tert-butyl(3-(tert-butyl)phenoxy)dimethylsilane (Table 2, Row 4, Column 3).
The general procedure was employed. A colorless liquid was isolated by column
chromatography (90:10 Hex:EtOAc). This liquid consisted of 177 mg desired product
(67% yield) and 29 mg reduction product. 1H NMR (500 MHz, CDCl3) δ: 7.20 (t, J = 7.9
Hz, 1H), 7.03 (ddd, J = 7.8 Hz, 1.9 Hz, 1.0 Hz, 1H), 6.93 (app. t, J = 2.1 Hz, 1H), 6.71
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(ddd, J = 8.0 Hz, 2.4 Hz, 1.0 Hz, 1H), 1.36 (s, 9H), 1.06 (s, 9H), 0.27 (s, 6H) ppm. C
NMR (125 MHz, CDCl3) δ: 155.6, 153.0, 129.0, 120.3, 118.4, 117.6, 117.2, 34.8, 31.6,
26.0, 18.5, 4.1 ppm.
t-Bu
N
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1-(4-(tert-butyl)phenyl)-1H-pyrrole (Table 2, Row 5, Column 1). The general
procedure was employed. A pale yellow solid was isolated by column chromatography
(98:2 Hex:Ether). Mp: 55ꢀ58 ºC. This solid consisted of 149 mg desired product (75%
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yield) and 29 mg reduction product. H NMR (500 MHz, CDCl3) δ: 7.46 (d, J = 8.6 Hz,
2H), 7.34 (d, J = 8.6 Hz, 2H), 7.09 (t, J = 7.1 Hz, 2H), 6.36 (t, J = 7.1 Hz, 2H), 1.37 (s,
9H) ppm. 13C NMR (125 MHz, CDCl3) δ: 148.9, 129.7, 126.6, 120.5, 119.6, 110.2, 34.7,
31.6 ppm.
H3C
t-Bu
CH3
1-(tert-Butyl)-3,5-dimethylbenzene (Table 2, Row 6, Column 1). The general
procedure was employed with the following modification: the reaction mixture was
allowed to warm to rt and stir overnight (10h). A colorless liquid (138 mg, 85%) was
isolated by column chromatography (98:2 Hex:Ether). 1H NMR (500 MHz, CDCl3) δ:
7.21 (s, 2H), 7.02 (s, 1H), 2.52 (s, 6H), 1.51 (s, 9H) ppm. 13C NMR (125 MHz, CDCl3) δ:
151.3, 137.5, 127.3, 123.3, 34.6, 31.6, 21.7 ppm.
t-Bu
H3C
CH3
1-(tert-butyl)-2,4-dimethylbenzene (Table 2, Row 6, Column 2). The general
procedure was employed. A colorless liquid (89 mg, 55%) was isolated by column
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chromatography (98:2 Hex:Ether). H NMR (500 MHz, CDCl3) δ: 7.28 (d, J = 7.7 Hz,
1H), 6.96 (m, 2H), 2.53 (s, 3H), 2.29 (s, 3H), 1.41 (s, 9H) ppm. 13C NMR (125 MHz,
CDCl3) δ: 145.2, 136.3, 135.4, 133.8, 126.5, 126.2, 42.4, 35.7, 31.2 ppm.
t-Bu
MeO
1-(tert-Butyl)-6-methoxynaphthalene (Table 2, Row 6, Column 3). The general
procedure was employed. A white solid was isolated by column chromatography (96:4
Hex:Ether). Mp: 63ꢀ65 ºC. This white solid consisted of 184 mg desired product (86%
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yield) and 13 mg reduction product. H NMR (500 MHz, CDCl3) δ: 7.70 (app. t, J = 8.0
Hz, 3H), 7.54 (dd, J = 8.6, 2.0 Hz, 1H), 7.11ꢀ7.14 (m, 2H), 3.92 (s, 3H), 1.41 (s, 9H)
ppm. 13C NMR (125 MHz, CDCl3) δ: 157.5, 146.5, 132.8, 129.6, 129.0, 126.7, 125.5,
122.9, 118.7, 101.6, 55.5, 34.8, 31.5 ppm. HRMS (ESI+): (M+H)+: 215.1430 (calc.);
215.1432 (found); diff (ppm) = 0.70.
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Me Me
Me
Cl
1-Chloro-4-(tert-pentyl)benzene (Table 3, Column 1). The general procedure
was employed. A pale yellow liquid (133 mg, 73%) was isolated by column
chromatography (99:1 Hex:Ether). 1H NMR (500 MHz, CDCl3) δ: 7.29 (app. s, 4H), 1.66
(q, J = 7.3, 2H), 1.30 (s, 6H), 0.71 (t, J = 7.3, 3H) ppm. 13C NMR (125 MHz, CDCl3) δ:
167.4, 153.5, 129.8, 127.9, 127.2, 52.1, 41.9, 31.1, 21.7, 12.3 ppm.
Me
EtO2C
Ethyl 4-(1-methylcyclohexyl)benzoate (Table 3, Column 2). The
general procedure was employed. A colorless liquid (187 mg, 76%) was isolated by
column chromatography (90:10 Hex:EtOAc). 1H NMR (500 MHz, CDCl3) δ: 7.99 (d, J =
8.7 Hz, 2H), 7.44 (d, J = 8.7 Hz, 2H), 4.37 (q, J = 7.1, 2H), 2.02 (m, 2H), 1.55ꢀ1.61 (m,
4H), 1.39ꢀ1.50 (m, 4H), 1.38 (t, J = 7.1, 3H), 1.19 (s, 3H) ppm. 13C NMR (125 MHz,
CDCl3) δ: 166.9, 155.6, 129.7, 127.7, 126.1, 60.9, 38.6, 37.5, 33.3, 26.5, 22.8, 14.6 ppm.
HRMS (ESI+): (M+H)+: 247.1693 (calc.); 247.1696 (found); diff (ppm) = 1.22.
Me
O
H
O
Me
Me
2-(3-(3-methylpentan-3-yl)phenyl)-1,3-dioxolane (Table 3, Column 3).
The general procedure was employed with the following modification: the reaction
mixture was allowed to warm to rt and stir overnight (10h). An oily, colorless solid (121
1
mg, 51%) was isolated by column chromatography (98:2 Hex:Ether). H NMR (500
MHz, CDCl3) δ: 7.39 (s, 1H), 7.28ꢀ7.34 (m, 3H), 5.81 (s, 3H), 4.13ꢀ4.17 (m, 2H), 4.02ꢀ
4.06 (m, 2H), 1.72ꢀ1.80 (m, 2H), 1.54ꢀ1.62 (m, 2H), 1.27 (s, 3H), 0.68 (t, J = 7.4 Hz, 6H)
ppm. 13C NMR (125 MHz, CDCl3) δ: 148.0, 137.4, 128.1, 127.7, 125.0, 123.5, 104.4,
65.4, 41.5, 38.6, 35.3, 23.0, 8.9 ppm. HRMS (ESI+): (M+H)+: 235.1693 (calc.);
235.1691 (found); diff (ppm) = ꢀ0.65.
t-Bu
MeO
(E)-1-(3,3-dimethylbut-1-en-1-yl)-4-methoxybenzene (Figure 4). The general
procedure was employed. A white solid (Cl: 158 mg, 83%; Br: 133 mg, 70%) was
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isolated by column chromatography (98:2 Hex:Ether). Mp: 48ꢀ50 ºC. 1H NMR (500
MHz, CDCl3) δ: 7.30 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 6.25 (d, J = 16 Hz,
1H), 6.12 (d, J = 16 Hz, 1H), 3.80 (s, 3H), 1.11 (s, 9H) ppm. 13C NMR (125 MHz,
CDCl3) δ: 158.8, 140.0, 131.1, 127.3, 124.0, 114.1, 55.5, 33.4, 29.9 ppm.
References
1) Dragoli, D. R.; Burdett, M. T.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123, 10127.
2) Krasovskiy, A.; Knochel, P. Synthesis 2006, 5, 890.
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