Iron fluoride/N-heterocyclic carbene catalyzed cross coupling between deactivated aryl chlorides and alkyl grignard reagents with or without β-hydrogens

Article abstract of DOI:10.1055/s-0034-1380361

High-yielding cross-coupling reactions of various combinations of aryl chlorides and alkyl Grignard reagents have been developed by using an iron(III) fluoride/1,3-bis(2,6-diisopropylphenyl)imidazolin-2-ylidene (SIPr) catalyst composite. The iron(III) fluoride/SIPr-catalyzed aryl-alkyl coupling demonstrates unprecedented scope for both aryl chlorides and alkyl Grignard reagents, thus enabling the first efficient coupling of electron-rich (deactivated) aryl chlorides with alkyl Grignard reagents without β-hydrogens. The present reaction is also effective for diverse alkyl Grignard reagents such as (trimethylsilyl)methyl, primary, and secondary alkyl Grignard reagents.

Full text of DOI:10.1055/s-0034-1380361

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 1733–1740
paper
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Synthesis
Iron Fluoride/N-Heterocyclic Carbene Catalyzed Cross Coupling
between Deactivated Aryl Chlorides and Alkyl Grignard Reagents
with or without β-Hydrogens
Ryosuke Agataa,b
cat. FeF3, SIPr•HCl
AlkylMgX
(X = Cl, Br)
Takahiro Iwamotoa,b,c
Naohisa Nakagawaa,b
Katsuhiro Isozakia,b
Takuji Hatakeyamaa,d,e
Hikaru Takayaa,b
+
ArCl
Ar Alkyl
up to >99% yield
broad scope!
ArCl: including deactivated electron-rich aryl chlorides
OMe
Cl
MeO
MeO
Masaharu Nakamura*a,b
MeO
Cl
Cl
a International Research Center for Elements Science,
Institute for Chemical Research (ICR), Kyoto University,
Uji, Kyoto 611-0011, Japan
AlkylMgX: Me, Me3SiCH2, 1° alkyl, 2° alkyl Grignard reagents even without b-hydrogen
masaharu@scl.kyoto-u.ac.jp
b Department of Energy and Hydrocarbon Chemistry,
Graduate School of Engineering, Kyoto University,
Nishikyo-ku, Kyoto 615-8510, Japan
c CRESTJapan Science and Technology Agency (JST), 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan
d Elements Strategy Initiative for Catalysts and Batteries (ESICB), Kyoto University, Nishikyo-ku, Kyoto 615-8520, Japan
e Current address: Department of Chemistry, School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo 669-1337, Japan
Received: 08.01.2015
Accepted: 17.02.2015
Published online: 08.04.2015
DOI: 10.1055/s-0034-1380361; Art ID: ss-2015-c0013-st
catalyzed cross coupling of sp2-carbon (alkenyl) halides
with an alkyl Grignard reagent initially developed by
Kochi.5
Fürstner thus reported the first iron-catalyzed aryl–
alkyl coupling reaction,6a where aryl chlorides and alkyl
Grignard reagents could be efficiently cross-coupled by us-
ing a simple catalyst system of iron(III) acetylacetonate or
iron(III) chloride and an excess of 1-methylpyrrolidin-2-
one (NMP) as a cosolvent.6a–c,7 Although this was a clearly
promising discovery showing the unprecedented reactivity
of the iron catalyst, it had obvious limitations. Because of
the limited reactivity of Grignard reagents without β-hy-
drogens,6d which is attributed to their inability to generate
low-valent organoiron species,6e,8 the methyl group9 could
be introduced only into activated aryl and alkenyl electro-
philes such as highly electron-deficient heteroaromatics10a,b
or enol triflates.10c In addition, even with reactive Grignard
reagents carrying β-hydrogens, aryl chlorides bearing elec-
tron-donating alkoxy or alkyl substituents (deactivated aryl
chlorides) were reluctant to participate in the aryl–alkyl
coupling.6b
Considerable research efforts have been made to over-
come the aforesaid limitations, and several modifications
have been reported, such as the use of aryl carbamates11a or
sulfamates11 and sulfonates6b,11b,c instead of chlorides, and
the use of different iron salts and modifiers.12,13 Despite the
partial solutions derived from these studies, no cross cou-
plings between unreactive alkyl Grignard reagents and de-
activated aryl chlorides have been realized, for example, the
simple methylation of 1-chloro-4-methoxybenzene with a
methyl Grignard reagent. In this paper, we report the effec-
Abstract High-yielding cross-coupling reactions of various combina-
tions of aryl chlorides and alkyl Grignard reagents have been developed
by using an iron(III) fluoride/1,3-bis(2,6-diisopropylphenyl)imidazolin-
2-ylidene (SIPr) catalyst composite. The iron(III) fluoride/SIPr-catalyzed
aryl–alkyl coupling demonstrates unprecedented scope for both aryl
chlorides and alkyl Grignard reagents, thus enabling the first efficient
coupling of electron-rich (deactivated) aryl chlorides with alkyl Grignard
reagents without β-hydrogens. The present reaction is also effective for
diverse alkyl Grignard reagents such as (trimethylsilyl)methyl, primary,
and secondary alkyl Grignard reagents.
Key words C–C bond formation, cross coupling, iron fluoride, N-het-
erocyclic carbene, aryl chloride
Transition-metal-catalyzed cross coupling is one of the
most powerful C–C bond forming processes. Specifically,
aryl–alkyl coupling reactions are of high importance in the
synthesis and mass production of functional aromatic com-
pounds.1 Such aryl–alkyl coupling reactions have been typ-
ically carried out between aryl halides and alkyl Grignard
reagents in the presence of nickel, and occasionally, palladi-
um catalysts; this is because of the relatively poor efficien-
cy of palladium when used in conjunction with an alkyl
Grignard reagent.1c,2 Iron catalysts have regained consider-
able attention in cross-coupling chemistry because of their
low toxicity and cost effectiveness.3 Their use in aryl–alkyl
coupling has increased since Fürstner renovated4 the iron-
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tiveness of a catalyst composite of iron(III) fluoride and 1,3-
bis(2,6-diisopropylphenyl)imidazolin-2-ylidene (SIPr) for
the cross coupling of various combinations of aryl chlorides
and alkyl Grignard reagents, especially for the coupling of
deactivated aryl chlorides with the unreactive methyl
Grignard reagent.
We began our study by screening catalyst composites of
iron salts, specifically, iron fluorides, and N-heterocyclic
carbene (NHC) ligands.14 We envisaged that these compos-
ites would work well with the unreactive Grignard re-
agents, because they were effective even in the cross cou-
pling between aryl chlorides with aryl Grignard reagents.15
The reaction of 1-chloro-4-methoxybenzene (1) with
methylmagnesium bromide was examined in the presence
of various combinations of iron salts and NHC precursor
salts (Table 1, Figure 1).
1-methoxy-4-methylbenzene in 92% yield (entries 1–3). To
the best of our knowledge, this is the first example of meth-
ylation of deactivated aryl chlorides under iron catalysis.10a,b
Iron(III) chloride with SIPr could also catalyze the methyla-
tion, but the reaction was very sluggish and afforded the
desired product in only 21% yield under the same condi-
tions, showing the uniqueness of the fluoride (entry 4). In
the absence of a ligand, the reaction did not proceed at all
(entry 5). Notably, N,N,N′,N′-tetramethylethylenediamine
(TMEDA) was ineffective in this reaction (entry 6).12
Table 2 demonstrates the substrate scope for the aryl
chloride in the iron(III) fluoride/SIPr-catalyzed methylation.
A more challenging substrate, the electronically and steri-
cally demanding 1-chloro-2-methoxybenzene, participated
in the coupling to give the desired product in 93% yield (en-
try 1). The present protocol is scalable: the reaction of 1-
chloro-2-methoxybenzene (20 mmol) with methylmagne-
sium bromide (30 mmol) provided the corresponding
methylation product in quantitative yield (>99% NMR yield).
After purification, 1.92 g of 1-methoxy-2-methylbenzene
was isolated (79% yield). The reaction with the more elec-
tron-rich 1-chloro-3,5-dimethoxybenzene was very slow,
providing the desired product in poor yield (entry 3). How-
ever, the yield was dramatically improved to 72% by in-
creasing the catalyst loading (15 mol%) (entry 4). Electron-
deficient as well as electronically neutral aryl chlorides
were effectively converted into the corresponding methyla-
tion products (entries 5 and 6).16 The dimethylamino group
did not interfere in the coupling reaction, and the desired
product was obtained in 93% yield (entry 7). A heteroaro-
matic chloride, 2-chloroquinoline, underwent the methyla-
tion in moderate yield (entry 8).
Table 1 Catalyst Screening on Cross Coupling of 1-Chloro-4-methoxy-
benzene (1) with Methylmagnesium Bromide (See Figure 1)a
iron salt (5 mol%)
ligand (15 mol%)
MeO
Cl
MeO
Me
+ MeMgBr
(1.5 equiv)
THF, 80 °C, 24 h
Entry
Iron salt
Ligand
Yieldb
(%)
Recovered 1b
(%)
1
2
3
4
5
6
FeF3
FeF3
FeF3
FeCl3
FeF3
FeF3
SIPr·HCl
SIMes·HCl
IPr·HCl
92
0
57
29
57
94
94
33
58
21
0
SIPr·HCl
none
TMEDAc
1
Table 3 summarizes the reaction of diverse alkyl
Grignard reagents with the electron-rich deactivated 1-
chloro-4-methoxybenzene (1) and an electronically neutral
aryl chloride, 4-chlorobiphenyl (2). The reaction with an
unreactive Grignard reagent, (trimethylsilyl)methylmagne-
sium chloride17 proceeded using similar reaction conditions
to those in Tables 1 and 2, although the yield was moderate
(entry 1). Among alkylmagnesium reagents possessing β-
hydrogens, octyl and cyclohexyl Grignard reagents reacted
smoothly with 1-chloro-4-methoxybenzene (1) even at
25 °C to give the desired compounds in excellent yields (en-
tries 218 and 3). The reaction with isopropylmagnesium
chloride proceeded quantitatively, and a 38:62 mixture of
branch- and linear-alkylated compounds was obtained (en-
try 4).19
a Reactions were carried out on a 1-mmol scale.
b Determined by GC analysis using undecane as an internal standard.
c TMEDA (1.5 equiv) was used.
Cl
Cl
N
N
N
N
SIPr·HCl
SIMes·HCl
Cl
N
N
When using 4-chlorobiphenyl (2), all the Grignard re-
agents examined underwent the coupling smoothly to fur-
nish the corresponding alkylated products in excellent
yields (entries 5–8). It should be noted that the cross cou-
pling of (trimethylsilyl)methyl magnesium chloride with
IPr·HCl
Figure 1
Screening of NHC ligands in the presence of iron(III) flu-
oride revealed that the 1,3-bis(2,6-diisopropylphenyl)imid-
azolin-2-ylidene (SIPr) ligand was the best, affording
this electronically neutral aryl chloride 2 proceeded
smoothly to give the corresponding coupling product in
quantitative yield (entry 5). The reaction with isopropyl-
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Table 2 Scope of Aryl Chlorides in Iron(III) Fluoride/SIPr-Catalyzed Cross Coupling with Methylmagnesium Bromidea
Entry
Aryl chloride
Temp (°C), time (h)
Product
Yield (%)
OMe
OMe
Me
1
2
80, 24
80, 15
93b
>99c,d
Cl
MeO
MeO
3e
80, 48
80, 58
30d
72b
Cl
Me
4e,f
MeO
Ph
MeO
Ph
5
6
60, 24
60, 48
>99d
81d
Me
Cl
F3C
Cl
F3C
Me
Me2N
Me2N
7
80, 36
93d
53b
Me
Cl
Cl
Me
8
60, 26
N
N
a Reactions were carried out on a 1-mmol scale using FeF3 (5 mol%) and SIPr·HCl (15 mol%) in THF, for the indicated temperature and time.
b Determined by GC analysis using undecane as an internal standard.
c Reaction was performed on a 20-mmol scale.
d Determined by 1H NMR analysis using 1,1,2,2-tetrachloroethane.
e MeMgBr (2 equiv) was used.
f FeF3 (15 mol%) and SIPr·HCl (45 mol%) were used.
FeF3 (5 mol%)
SIPr·HCl (15 mol%)
magnesium chloride again afforded the branch and linear
isomers in 1:1 ratio. Isomerization of the isopropyl group
indicated the formation of iron hydride species via β-hydro-
gen elimination from an alkyliron intermediate during the
coupling. However, side reactions such as reduction of aryl
chlorides were almost negligible (<2%) in all cases.
MeMgBr
+
60 °C, 36 h
Cl
(1.5 equiv)
(1.0 mmol)
A brief mechanistic study was performed by using a
radical probe substrate, 1-(but-3-enyl)-2-chlorobenzene.20
The cross coupling with methylmagnesium bromide pro-
ceeded to give the methylation product in quantitative
yield, and no cyclization products were formed (Scheme 1).
This result suggests that the present coupling proceeded by
a two-electron mechanism14 rather than the radical mecha-
nism proposed for iron-catalyzed cross coupling of alkyl ha-
lides.5,21
+
+
Me
Me
Me
not observed
not observed
>99%
(NMR yield)
Scheme 1
In summary, we have demonstrated that the iron(III)
fluoride/SIPr catalyst composite is effective for the cross
coupling between aryl chlorides and alkyl Grignard re-
agents, with unprecedented substrate/reagent scope as
compared to previously reported aryl–alkyl coupling reac-
tions under iron catalysis. The developed reaction is thus
applicable to the efficient coupling of electron-rich deacti-
vated aryl chlorides with the methyl Grignard reagent, as
well as various alkyl Grignard reagents, offering a practical
alternative to conventional nickel- and palladium-catalyzed
aryl–alkyl couplings. Further studies to clarify the effect of
fluoride ion and the reaction mechanism are underway in
our laboratory, and the results will be reported in due
course.
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Table 3 Scope of Alkyl Grignard Reagents in Iron(III) Fluoride/SIPr-Catalyzed Cross Couplinga
MeO
Alkyl
FeF3 (5 mol%)
SIPr·HCl (15 mol%)
or
+
1 or 2
AlkylMgX
(X = Br or Cl)
Alkyl
Entry
1
AlkylMgX (equiv)
Temp (°C), time (h)
80, 84
Product
Yield (%)
SiMe3
Me3SiCH2MgCl (2.0)
60b,c
96c
MeO
2
3
C8H17MgBr (1.5)
CyMgCl (1.5)
25, 24
25, 14
MeO
MeO
MeO
C8H17
>99c
4d
5
i-PrMgCl (2.0)
30, 61
80, 36
97c (38:62)e
(major product)
SiMe3
Me3SiCH2MgCl (2.0)
>99c
6
7
C8H17MgBr (1.5)
CyMgCl (1.5)
40, 24
25, 28
>99c
92f
C8H17
8d
i-PrMgCl (2.0)
30, 48
>99c (48:52)e
(major product)
a Reactions were carried out on a 1-mmol scale in THF for the indicated temperature and time.
b The starting material was recovered in 20% yield. Determined by GC analysis using undecane as an internal standard.
c Determined by 1H NMR analysis using 1,1,2,2-tetrachloroethane as an internal standard.
d FeF3 (10 mol%) and SIPr·HCl (30 mol%) were used.
e Branch/linear ratio was determined by 1H NMR analysis by using 1,1,2,2-tetrachloroethane as an internal standard.
f Isolated yield.
All reactions were carried out in dry vessels under a positive pressure
of argon. Preparative recycling gel permeation chromatography (GPC)
was performed on a Japan Analytical Industry LC-9204 instrument
equipped with JAIGEL-1H-20/JAIGEL-2H-20 columns, using CHCl3 as
the eluent. 1H and 13C NMR spectra were recorded on a JEOL ECS-
400NR NMR spectrometer referenced to TMS (δ = 0.00) and CDCl3 (δ =
77.16), respectively. The NMR yields were determined for crude prod-
ucts by 1H NMR analysis using 1,1,2,2-tetrachloroethane or pyrazine
as an internal standard. GC analysis was conducted on a Shimadzu
GC-2010 instrument equipped with an FID detector and a capillary
column, ZB-1MS (Phenomenex, 10 m × 0.10 mm i.d., 0.10-μm film
thickness). HRMS were obtained in fast atom bombardment (FAB)
ionization or electron ionization (EI) mode on a JEOL JMS-700 mass
spectrometer. IR spectra were recorded on a PerkinElmer Spectrum
One FT-IR spectrophotometer. THF was purchased from Wako Pure
Chemical Industries, Ltd. (Wako) and distilled from benzophenone
ketyl at ambient pressure. Alkylmagnesium bromides and chlorides
were prepared from the corresponding aryl halides and magnesium
(turnings). MeMgBr was purchased from Tokyo Chemical Industry.
1-Methoxy-4-methylbenzene; Typical Procedure
A 0.94 M soln of MeMgBr in THF (1.59 mL, 1.5 mmol) was added to a
mixture of FeF3 (5.7 mg, 0.050 mmol) and 1,3-bis(2,6-diisopropylphe-
nyl)imidazolinium chloride (64.4 mg, 0.15 mmol) in THF (2.0 mL) at 0
°C; 1-chloro-4-methoxybenzene (143 mg, 1.0 mmol) and undecane
were then added at r.t. The mixture was stirred at 80 °C for 24 h. The
mixture was cooled to r.t. and an aliquot of the mixture was filtered
through a Florisil pad. The product yield was determined by GC anal-
ysis (92% yield) using undecane as an internal standard. 1-Methoxy-
4-methylbenzene is volatile, hence isolation was performed for the
large-scale experiment using starting aryl chloride (5.6 mmol). The
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crude product was purified by column chromatography (silica gel,
pentane, Rf = 0.06) and subsequent GPC to obtain the title compound
(78.7 mg, 11%) as a colorless oil.
1H NMR (392 MHz, CDCl3): δ = 2.29 (s, 3 H, CH3), 3.78 (s, 3 H, OCH3),
6.80 (d, J = 8.6 Hz, 2 H, H2Ar, H6Ar), 7.09 (d, J = 7.8 Hz, 2 H, H3Ar, H5Ar).
13C NMR (99 MHz, CDCl3): δ = 20.59, 55.43, 113.84 (2 C), 129.98,
130.03 (2 C), 157.61.
1-Methyl-4-(trifluoromethyl)benzene
The product yield (81%) was determined by 1H NMR analysis using
1,1,2,2-tetrachloroethane as an internal standard. 1-Methyl-4-(triflu-
oromethyl)benzene is volatile, hence isolation was performed on a
10-mmol scale. The reaction was carried out at 80 °C, and MeMgBr
(20 mmol, 2 equiv). The crude product was purified by distillation at
r.t. under reduced pressure (0.133 bars) to obtain the title compound
(260 mg, 16%) as a colorless oil.
HRMS (EI): m/z [M]+ calcd for C8H10O: 122.0732; found: 122.0730.
1H NMR (392 MHz, CDCl3): δ = 2.41 (s, 3 H, CH3), 7.27 (d, J = 8.2 Hz, 2
H, H2Ar, H6Ar), 7.50 (d, J = 8.2 Hz, 2 H, H3Ar, H5Ar).
Anal. Calcd for C8H10O: C, 78.65; H, 8.25. Found: C, 78.81; H, 8.17.
13C NMR (99 MHz, CDCl3): δ = 21.56, 124.58 (q, JC-F = 273 Hz, CF3),
125.27 (q, JC-F = 3.9 Hz, 2 C), 128.00 (q, JC-F = 32 Hz), 129.45 (2 C),
142.21.
1-Methoxy-2-methylbenzene
The reaction was carried out according to the typical procedure on a
1.0-mmol scale. The large-scale synthesis was also carried out ac-
cording to the typical procedure on a 20-mmol scale. After the mix-
ture was heated at 80 °C for 15 h, sat. aq sodium potassium tartrate
and 1 M aq HCl were added. The aqueous layer was extracted with
Et2O (4 ×). The organic layers were combined, washed with brine,
dried (Na2SO4), and filtered through a Florisil pad. After solvent re-
moval at 50 °C under ambient pressure, the product yield was deter-
mined by 1H NMR analysis (>99% yield) using 1,1,2,2-tetrachlo-
roethane as an internal standard. The crude product was purified by
GPC to obtain the title compound (1.92 g, 79%) as a colorless oil.
N,N,3-Trimethylaniline
The product yield (93%) was determined by 1H NMR analysis using
1,1,2,2-tetrachloroethane as an internal standard. N,N,3-Trimeth-
ylaniline is volatile, hence isolation was performed on a 5.4-mmol
scale. The crude product was purified by column chromatography
(silica gel, hexane–EtOAc, 10:1, Rf = 0.38), and subsequent GPC, to ob-
tain the title compound (318 mg, 44%) as a brown oil.
1H NMR (392 MHz, CDCl3): δ = 2.32 (s, 3 H, CH3), 2.93 [s, 6 H,
N(CH3)2,], 6.55–6.58 (m, 3 H, H2Ar, H4Ar, H6Ar), 7.13 (dd, J = 10.6, 7.1
Hz, 1 H, H5Ar).
1H NMR (392 MHz, CDCl3): δ = 2.22 (s, 3 H, CH3), 3.82 (s, 3 H, OCH3),
6.82 (d, J = 8.2 Hz, 1 H, H6Ar), 6.85 (t, J = 7.5 Hz, 1 H, H4Ar), 7.13 (d, J =
7.4 Hz, 1 H, H3Ar), 7.16 (t, J = 7.1 Hz, 1 H, H5Ar).
13C NMR (99 MHz, CDCl3): δ = 20.34, 40.82 (2 C), 110.05, 113.58,
117.74, 129.05, 138.83, 150.89.
13C NMR (99 MHz, CDCl3): δ = 16.35, 55.35, 110.01, 120.38, 126.72,
126.93, 130.74, 157.85.
HRMS (EI): m/z [M]+ calcd for C8H10O: 122.0732; found: 122.0730.
2-Methylquinoline
The product yield (53%) was determined by GC analysis using undec-
ane as an internal standard. 2-Methylquinoline is volatile, hence iso-
lation was performed on a 5.2-mmol scale. The crude product was
purified by column chromatography (silica gel, hexane–EtOAc, 5:1,
Rf = 0.19) to obtain the title compound (300 mg, 40%) as a colorless oil.
1H NMR (392 MHz, CDCl3): δ = 2.74 (s, 3 H, CH3), 7.26 (d, J = 8.6 Hz, 1
H, H3), 7.46 (td, J = 8.2, 1.2 Hz, 1 H, H7), 7.67 (td, J = 8.2, 1.2 Hz, 1 H,
H8), 7.75 (d, J = 8.2 Hz, 1 H, H6), 8.01 (d, J = 8.2 Hz, 1 H, H9), 8.03 (d, J =
8.2 Hz, 1 H, H4).
Anal. Calcd for C8H10O: C, 78.65; H, 8.25. Found: C, 78.40; H, 8.25.
1,3-Dimethoxy-5-methylbenzene
The product yield (72%) was determined by GC analysis using undec-
ane as an internal standard. The crude product was purified by GPC to
obtain the title compound (32.3 mg, 21%) as a colorless oil.
1H NMR (392 MHz, CDCl3): δ = 2.30 (d, J = 0.6 Hz, 3 H, CH3), 3.77 (s, 6
H, OCH3), 6.28 (t, J = 2.1 Hz, 1 H, H2Ar), 6.33 (dd, J = 2.3, 0.6 Hz, 2 H,
H4Ar ,H6Ar).
13C NMR (99 MHz, CDCl3): δ = 25.47, 122.06, 125.73, 126.56, 127.72,
128.72, 129.49, 136.22, 147.97, 159.06.
13C NMR (99 MHz, CDCl3): δ = 21.96, 55.37 (2 C), 97.66, 107.22 (2 C),
140.36, 160.84 (2 C).
HRMS (EI): m/z [M]+ calcd for C9H12O2: 152.0837; found: 152.0839.
HRMS (FAB): m/z [M + H]+ calcd for C10H10N: 144.0813; found:
144.0813.
4-Methylbiphenyl
(4-Methoxybenzyl)trimethylsilane
The product yield (>99%) was determined by 1H NMR analysis using
1,1,2,2-tetrachloroethane as an internal standard. The crude product
was purified by column chromatography (silica gel, hexane, Rf = 0.23)
to obtain the title compound (143 mg, 85%) as a white solid.
The product yield (60%) was determined by 1H NMR analysis using
1,1,2,2-tetrachloroethane as an internal standard. The crude product
was purified by GPC and column chromatography (silica gel, hexane,
Rf = 0.14) to obtain the title compound (102 mg, 59%) as a colorless oil.
1H NMR (392 MHz, CDCl3): δ = 2.40 (s, 3 H, CH3), 7.25 (d, J = 8.2 Hz, 2
H, H3Ar, H5Ar), 7.32 (tt, J = 7.4, 1.2 Hz, 1 H, H4′), 7.42 (t, J = 7.8 Hz, 2 H,
H3′Ar, H5′Ar), 7.50 (d, J = 8.2 Hz, 2 H, H2Ar, H6Ar), 7.57–7.59 (m, 2 H,
H2′Ar, H6′Ar).
1H NMR (392 MHz, CDCl3): δ –0.015 [s, 9 H, Si(CH3)3], 2.01 (s, 2 H,
CH2TMS), 3.78 (s, 3 H, OCH3), 6.78 (d, J = 9.0 Hz, 2 H, H3Ar, H5Ar), 6.92
(d, J = 9.0 Hz, 2 H, H2Ar, H6Ar).
13C NMR (99 MHz, CDCl3): δ = –1.80 (3 C), 25.83, 55.37, 113.77 (2 C),
128.93 (2 C), 132.48, 156.62.
13C NMR (99 MHz, CDCl3): δ = 21.24, 127.12 (5 C), 128.85 (2 C), 129.63
(2 C), 137.17, 138.51, 141.31.
HRMS (EI): m/z [M]+ calcd for C13H12: 168.0939; found: 168.0934.
1-Methoxy-4-octylbenzene
The product yield (96%) was determined by 1H NMR analysis using
1,1,2,2-tetrachloroethane as an internal standard. The crude product
was purified by GPC and column chromatography (silica gel, hexane,
Rf = 0.15) to obtain the title compound (216 mg, 93%) as a colorless oil.
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1H NMR (392 MHz, CDCl3): δ = 0.88 [t, J = 7.1 Hz, 3 H, (CH2)7CH3],
1.26–1.31 [m, 10 H, (CH2)2(CH2)5CH3], 1.53–1.61 [m, H,
CH2CH2(CH2)5CH3], 2.53 [t, J = 7.4 Hz, 2 H, CH2(CH2)6CH3], 3.78 (s, 3 H,
OCH3), 6.81 (d, J = 8.6 Hz, 2 H, H2Ar, H6Ar), 7.08 (d, J = 8.6 Hz, 2 H, H3Ar,
H5Ar).
13C NMR (99 MHz, CDCl3): δ = 14.25, 22.83, 29.44 (2 C), 29.65, 31.93,
32.05, 35.20, 55.32, 113.76 (2 C), 129.36 (2 C), 135.17, 157.72.
4-Octylbiphenyl
The product yield (>99%) was determined by 1H NMR analysis using
1,1,2,2-tetrachloroethane as an internal standard. The crude product
was purified by GPC and column chromatography (silica gel, hexane,
Rf = 0.46) to obtain the title compound (257 mg, 97%) as a white solid.
1H NMR (392 MHz, CDCl3): δ = 0.88 [t, J = 6.7 Hz, 3 H, (CH2)7CH3],
1.28–1.38 [m, 10 H, (CH2)2(CH2)5CH3], 1.65 [quint, J = 7.4 Hz, 2 H,
CH2CH2(CH2)5CH3], 2.64 [t, J = 7.8 Hz, 2 H, CH2CH2(CH2)5CH3], 7.25 (d,
J = 7.8 Hz, 2 H, H3Ar, H5Ar), 7.32 (tt, J = 7.1, 1.2 Hz, 1 H, H4′Ar), 7.42 (tt,
J = 8.2, 2.0 Hz, 2 H, H3′Ar, H5′Ar), 7.50 (dt, J = 8.2, 2.0 Hz, 2 H, H2Ar,
H6Ar), 7.57–7.60 (m, 2 H, H2′Ar, H6′Ar).
2
HRMS (FAB): m/z [M]+ calcd for C15H24O: 220.1827; found: 220.1827.
Anal. Calcd for C15H24O: C, 81.76; H, 10.98. Found: C, 81.53; H, 10.97.
1-Cyclohexyl-4-methoxybenzene
13C NMR (99 MHz, CDCl3): δ = 14.26, 22.83, 29.43, 29.54, 29.64, 31.67,
32.05, 35.77, 127.09, 127.13, (4 C), 128.83 (2 C), 128.96 (2 C), 138.67,
141.34, 142.27.
The product yield (>99%) was determined by 1H NMR analysis using
1,1,2,2-tetrachloroethane as an internal standard. The crude product
was purified by GPC and column chromatography (silica gel, hexane,
Rf = 0.23) to obtain the title compound (190 mg, 94%) as a colorless oil.
1H NMR (392 MHz, CDCl3): δ = 1.18–1.29 (m, 1 H, H4′ax), 1.32–1.44
(m, 4 H, H2′ax, H3′ax, H5′ax, H6′ax), 1.70–1.76 (m, 1 H, H4′eq), 1.81–1.89
(m, 4 H, H2′eq, H3′eq, H5′eq, H6′eq), 2.44 (tt, Jax–ax = 11.0 Hz, Jax–eq = 3.1
Hz, 1 H, H1′ax), 3.78 (s, 3 H, OCH3), 6.83 (dt, J = 9.0, 2.7 Hz, 2 H, H3Ar,
H5Ar), 7.12 (dt, J = 9.0, 2.4 Hz, 2 H, H2Ar, H6Ar).
4-Cyclohexylbiphenyl
The reaction was carried out according to the typical procedure on a
1.0-mmol scale. The crude product was purified by column chroma-
tography (silica gel, hexane, Rf = 0.18) to obtain the title compound
(216 mg, 92%) as a white solid.
1H NMR (392 MHz, CDCl3): δ = 1.23–1.33 (m, 1 H, H4′′ax), 1.36–1.51
(m, 4 H, H2′′ax, H3′′ax, H5′′ax, H6′′ax), 1.74–1.80 (m, 1 H, H4′′eq), 1.84–
13C NMR (99 MHz, CDCl3): δ = 26.32, 27.10 (2 C), 34.86 (2 C), 44.83,
55.38, 113.78 (2 C), 127.76 (2 C), 140.52, 157.77.
1.94 (m, 4 H, H2′′eq, H3′′eq, H5′′eq, H6′′eq), 2.55 (tt, Jax-ax = 11.8 Hz, Jax-eq
=
3.1 Hz, 1 H, H1′′ax), 7.29 (d, J = 8.2 Hz, 2 H, H3Ar, H5Ar), 7.32 (tt, J = 7.4,
1.6 Hz, 1 H, H4′Ar), 7.42 (t, J = 8.2 Hz, 2 H, H3′Ar, H5′Ar), 7.52 (d, J = 8.2
Hz, 2 H, H2Ar, H6Ar), 7.57–7.59 (m, 2 H, H2′Ar, H6′Ar).
13C NMR (99 MHz, CDCl3): δ = 26.33, 27.07 (2 C), 34.62 (2 C), 44.39,
127.08, 127.17 (4 C), 127.38 (2 C), 128.82 (2 C), 138.87, 141.34,
147.38.
1-Isopropyl-4-methoxybenzene and 1-Methoxy-4-propylbenzene
The product yield (97%) and the ratio of branched to linear (38:62)
were determined by 1H NMR analysis using 1,1,2,2-tetrachloroethane
as an internal standard. The crude product was purified by GPC and
column chromatography (silica gel, hexane, Rf = 0.16) to obtain a mix-
ture of the title compounds (139 mg, 86%, 37:63) as a colorless oil.
HRMS (FAB): m/z [M]+ calcd for C18H20: 236.1565; found: 236.1564.
1-Isopropyl-4-methoxybenzene
4-Isopropylbiphenyl and 4-Propylbiphenyl
1H NMR (392 MHz, CDCl3): δ = 1.22 [d, J = 7.1 Hz, 6 H, CH(CH3)2], 2.86
[sept, J = 7.1 Hz, 1 H, CH(CH3)2], 6.84 (d, J = 9.4 Hz, 2 H, H3Ar, H5Ar),
7.14 (d, J = 8.6 Hz, 2 H, H2Ar, H6Ar).
The product yield (>99%) and the ratio of branched to linear (48:52)
were determined by 1H NMR analysis using 1,1,2,2-tetrachloroethane
as an internal standard. After purification by GPC and column chro-
matography (silica gel, hexane, Rf = 0.34), a mixture of the title com-
pounds was obtained (184 mg, 94%, 49:51) as a colorless oil.
1-Methoxy-4-propylbenzene
1H NMR (392 MHz, CDCl3): δ = 0.92 [t, J = 7.4 Hz, 3 H, (CH2)2CH3], 1.60
(sext, J = 8.2 Hz, 2 H, CH2CH2CH3), 2.52 (t, J = 7.8 Hz, 2 H, CH2CH2CH3),
6.82 (d, J = 8.6 Hz, 2 H, H2Ar, H6Ar), 7.08 (d, J = 8.2 Hz, 2 H, H3Ar, H5Ar).
4-Isopropylbiphenyl
1H NMR (392 MHz, CDCl3): δ = 1.29 [d, J = 7.5 Hz, 6 H, CH(CH3)2], 2.95
[sept, J = 7.1 Hz, 1 H, CH(CH3)2], 7.22–7.59 (m, 9 H).
1-Isopropyl-4-methoxybenzene and 1-Methoxy-4-propylbenzene
13C NMR (99 MHz, CDCl3): δ = 13.92, 24.35, 24.93, 33.40, 37.28, 55.38,
113.76, 113.81, 127.38, 129.44, 134.95, 141.19, 157.76.
4-Propylbiphenyl
1H NMR (392 MHz, CDCl3): δ = 0.97 [t, J = 7.1 Hz, 3 H, (CH2)2CH3], 1.68
(sext, J = 7.4 Hz, 2 H, CH2CH2CH3), 2.62 (t, J = 7.5 Hz, 2 H, CH2CH2CH3),
7.22–7.59 (m, 9 H).
(Biphenyl-4-ylmethyl)trimethylsilane
The product yield (>99%) was determined by 1H NMR analysis using
1,1,2,2-tetrachloroethane as an internal standard. The crude product
was purified by GPC and column chromatography (silica gel, hexane,
Rf = 0.22) to obtain the title compound (231 mg, 96%) as a white solid.
1H NMR (392 MHz, CDCl3): δ = 0.02 [s, 9 H, Si(CH3)3], 2.12 (s, 2 H,
CH2TMS), 7.07 (d, J = 7.8 Hz, 2 H, H3Ar, H5Ar), 7.31 (td, J = 7.3, 1.7 Hz, 1
H, H4′Ar), 7.40–7.47 (m, 4 H, H2Ar, H6Ar, H3′Ar, H5′Ar), 7.58 (dt, J = 7.1,
1.6 Hz, 2 H, H2′Ar, H6′Ar).
13C NMR (99 MHz, CDCl3): δ = –1.72 (3 C), 26.90, 126.88, 126.93 (2 C),
126.96 (2 C), 128.58 (2 C), 128.81 (2 C), 136.87, 139.90, 141.35.
HRMS (FAB): m/z [M]+ calcd for C16H20Si: 240.1334; found: 240.1336.
4-Isopropylbiphenyl and 4-Propylbiphenyl
13C NMR (99 MHz, CDCl3): δ = 14.04, 24.15 (2 C), 24.70, 33.94, 37.84,
126.98, 127.10, 127.13, 127.16, 127.20, 128.82, 129.02, 138.72,
138.88, 141.32, 141.98, 148.13.
1-(But-3-enyl)-2-methylbenzene
The product yield (>99%) was determined by 1H NMR analysis using
pyrazine as an internal standard. The crude product was purified by
GPC to obtain the title compound (47.9 mg, 34%) as a colorless oil.
IR (neat): 3076, 3017, 2977, 2932, 2367, 1892, 1829, 1641, 1605,
Anal. Calcd for C16H20Si: C, 79.93; H, 8.39. Found: C, 79.98; H, 8.11.
1493, 1459, 1379, 995, 911, 752 cm–1
.
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1H NMR (392 MHz, CDCl3): δ = 2.31 (s, 3 H, CH3), 2.30–2.36 (m, 2 H,
CH2CH2C2H3), 2.67–2.72 (m, 2 H, CH2CH2C2H3), 4.99 (d, J = 10.2 Hz, 1
H, CH=CHtransHcis), 5.06 (d, 1 H, J = 17.0 Hz, CH=CHtransHcis), 5.90 (ddt, 1
H, J = 17.0, 10.2, 6.7 Hz, CH2CH2CH=CH2), 7.08–7.15 (m, 4 H, HAr).
13C NMR (99 MHz, CDCl3): δ = 19.46, 32.87, 34.45, 114.95, 126.04,
126.10, 128.92, 130.27, 136.04, 138.43, 140.19.
(8) (a) Aleandri, L. E.; Bogdanović, B.; Bons, P.; Dürr, C.; Gaidies, A.;
Hartwig, T.; Huckett, S. C.; Lagarden, M.; Wilczok, U.; Brand, R.
A. Chem. Mater. 1995, 7, 1153. (b) Siedlaczek, G.; Schwickardi,
M.; Kolb, U.; Bogdanović, B.; Blackmond, D. G. Catal. Lett. 1998,
55, 67. (c) Bogdanović, B.; Schwickardi, M. Angew. Chem. Int. Ed.
2000, 39, 4610.
(9) For recent review showing the importance of introduction of
methyl group in medicinal compounds, see: (a) Barreiro, E. J.;
Kümmerle, A. E.; Fraga, C. A. M. Chem. Rev. 2011, 111, 5215.
(b) Schonherr, H.; Cernak, T. Angew. Chem. Int. Ed. 2013, 52,
12256.
HRMS (EI): m/z [M]+ calcd for C11H14: 146.1096; found: 146.1094.
Anal. Calcd for C11H14: C, 90.35; H, 9.65. Found: C, 90.10; H, 9.77.
(10) (a) Hocek, M.; Dvoráková, H. J. Org. Chem. 2003, 68, 5773.
(b) Malhotra, S.; Seng, P. S.; Koenig, S. G.; Deese, A. J.; Ford, K. A.
Org. Lett. 2013, 15, 3698. (c) Scheiper, B.; Bonnekessel, M.;
Krause, H.; Fürstner, A. J. Org. Chem. 2004, 69, 3943.
(11) (a) Silberstein, A. L.; Ramgren, S. D.; Garg, N. K. Org. Lett. 2012,
14, 3796. (b) Agrawal, T.; Cook, S. P. Org. Lett. 2013, 15, 96. One
example of cross-coupling of biphenyl sulfamate with methyl
Grignard reagent in the presence of catalytic FeF3·3H2O/IPr was
reported, see: (c) Agrawal, T.; Cook, S. P. Org. Lett. 2014, 16,
5080.
(12) N,N,N′,N′-Tetramethylethylenediamine acted as a good modifier
in the iron-catalyzed aryl–alkyl coupling reaction, albeit being
limited to electron-deficient aryl chlorides with a primary alkyl
Grignard reagent, see: Rushworth, P. J.; Hulcoop, D. G.; Fox, D. J.
J. Org. Chem. 2013, 78, 9517.
(13) The FeCl2·4H2O/SIPr composite was reported to catalyze the
cross-coupling of deactivated aryl chlorides, such as p-tolyl and
p-anisyl chlorides, with primary and secondary alkyl Grignard
reagents possessing β-hydrogens: Perry, M. C.; Gillet, A. N.; Law,
T. C. Tetrahedron Lett. 2012, 53, 4436.
Acknowledgment
This work was supported by the Japan Society for the Promotion of
Science (JSPS) through the ‘Funding Program for Next-Generation
World-Leading Researchers (NEXT Program),’ initiated by the Council
for Science and Technology Policy (CSTP) and supported in part by
the Japan Science and Technology Agency (JST), the Core Research for
Evolutional Science and Technology (CREST 1102545) Program, and
MEXT program ‘Elements Strategy Initiative to Form Core Research
Center.’ T.I. and K.I. also thank RIKEN for the provision of beam time in
SPring-8 (BL14B2: 2014B1907 and 2014B1654).
Supporting Information
1H and 13C NMR spectra of the coupling products. This material is
available online at http://dx.doi.org/10.1055/s-0034-1380361.
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References
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These reactions are considered to proceed via a high-valent
organoiron(IV) species, without the need for the generation of
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catalyst also shows high activity toward the cross-coupling of
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(16) The reaction of 4-chlorobiphenyl was also catalyzed by FeCl3, to
afford the product in excellent yield (96%). The details will be
reported elsewhere in due course.
(17) (Trimethylsilyl)methyl group acts as a nontransferable or unre-
active dummy ligand in the iron-catalyzed Negishi coupling
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(octenes and hexadecane) were detected on GLC analysis. The
formation of a significant amount of hexane, which is derived
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1733–1740

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R. Agata et al.
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Synthesis
from the hydrolysis of octylmagnesium bromide, was also
observed.
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alkyl coupling of aryl sulfamates and tosylates when using FeF3
and FeCl3 as the precursor salts.10b
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9132; and references cited therein. See also selected papers
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 1733–1740