1
3
15
iodoalkanes with Grignard reagents have been reported.
raphy in several experiments. 1-Chlorooctane was also
Thus, it is reasonable to assume that cross-coupling of
nonactivated fluoroalkanes with Grignard reagents is even
less likely.
obtained in yields of 20-30% as determined by gas
chromatography. Longer reaction times did not result in
increased yields of n-octylbenzene for this reaction. Other
C-C bond-coupling isomers have not been detected in GC-
MS or NMR spectra of these crude mixtures.
Recently, several reports have shown efficient cross-
coupling reactions of fluoroalkanes with Grignard reagents
using transition metal catalysts such as nickel and copper
Secondary and tertiary fluoroalkanes, fluorocyclohexane,
and 1-fluoroadamantane were also treated with phenylmag-
nesium chloride and produced the expected cross-coupling
products phenylcyclohexane and phenyladamantane, respec-
tively (Table 1, entries 5 and 6, Scheme 1 (4) and (5)). The
reactivity of fluoroalkanes increased in the order primary <
secondary < tertiary, as was the case for substitution reactions
1
4
complexes. In this paper, we describe new C-F bond
activation and C-C and C-X bond-forming processes by
the reaction of a primary 1-fluorooctane with magnesium
reagents without using a transition metal species and under
mild conditions. We thus report the scope, limitations, and
some mechanistic considerations of the new reactions.
7
b
with aluminum reagents. The reaction rate observed when
using phenylmagnesium chloride also increased in the same
order. However, the reaction of fluorocyclohexane with
phenylmagnesium chloride formed mainly cyclohexene in
26% yield and phenylcyclohexane/chlorocyclohexane in
lower yields (Table 1, entry 5).
This reaction was discovered while screening reactions of
fluoroalkanes with Grignard reagents in the presence of
transition metal compounds. Typically, 1-fluorooctane and
phenylmagnesium chloride in THF were stirred at 60 °C for
4
days in the presence of a transition metal species. Among
the crude products, n-octylbenzene was obtained in a yield
of 28%. However, even in the absence of these transition
metal compounds n-octylbenzene was isolated at 60 °C after
Other experimental results showed further significant
features of this unexpected C-F bond cleavage reaction. The
reaction of 1-fluorooctane with methyl magnesium chloride
in THF (3.0 M) did not give the C-C bond-forming product,
n-nonane, but gave 1-chlorooctane after 24 h as a major
product (61% yield) (entry 7, Scheme 1 (2)) and trace
amounts of 2-methyl- and 3-methyloctane. These products
were detected by GC-MS and show that C-F bond cleavage
also occurs with methylmagnesium chloride and that the aryl
group that is bound to magnesium is essential for efficient
3
(
days in 29% yield after silica gel column chromatography
Table 1, entry 1). At higher temperature (80 °C) and with
a reaction time of 24 h the yield increased to about 40%
entry 2). At least 50% of the 1-fluorooctane was converted
(
into n-octylbenzene when more than 5 equiv of the Grignard
reagent was added (entry 3), as shown in Scheme 1 (1), or
when MgCl
Addition of MgF
of n-octylbenzene were 35-37% after column chromatog-
2
was added to the reaction mixture (entry 4).
2
did not change the yields. Isolated yields
1
6
C-C bond formation. Additionally, MgCl also reacted
2
efficiently with 1-fluorooctane to form 1-chlorooctane after
(
6) For examples of boron-mediated aliphatic C-F bond activation, see:
6 h (entry 8, Scheme 1 (3)). A recent report showed similar
product selectivity using aluminum reagents in fluorine
substitution reactions of alkylfluorides. We also added 1
equiv of tetramethylethylenediamine (TMEDA) to phenyl-
magnesium chloride in the reaction medium to form a
diphenyl magnesium complex bearing a TMEDA ligand and
(
a) Prakash, G. K. S.; Hu, J.; Simon, J.; Bellew, D. R.; Olah, G. A. J.
Fluorine Chem. 2004, 125, 595–601. (b) Ramchandani, R. K.; Wakharkar,
R. D.; Sudalai, A. Tetrahedron Lett. 1996, 37, 4063–4064. (c) Olah, G. A.;
Yamato, T.; Hashimoto, T.; Shih, J. G.; Trivedi, N.; Singh, B. P.; Piteau,
M.; Olah, J. A. J. Am. Chem. Soc. 1987, 109, 3708–3713. (d) Theodoridis,
G. Tetrahedron Lett. 1998, 39, 9365–9368.
7
b
(
7) Aluminum-mediated aliphatic C-F bond activation: (a) Ooi, T.;
Uraguchi, D.; Kagoshima, N.; Maruoka, K. Tetrahedron Lett. 2004, 45,
555–2557. (b) Terao, J.; Begum, S. A.; Shinohara, Y.; Tomita, M.; Naitoh,
Y.; Kambe, N. Chem. Commun. 2007, 855–857.
8) Silylcation-mediated alkyl-fluorine bond activation: (a) Scott, V. J.;
C¸ elenligil- C¸ etin, R.; Ozerov, O. V. J. Am. Chem. Soc. 2005, 127, 2852–
MgCl in situ before the reaction. No C-C bond-coupling
2
2
product was observed for this reaction, with N,N-dimethy-
loctylamine being the main product. N,N-Dimethyloctylamine
(
was probably formed by a S
N
2 reaction of in situ generated
2
9
853. (b) Panisch, R.; Bolte, M.; M u¨ ller, T. J. Am. Chem. Soc. 2006, 128,
676–9682. (c) Douvris, C.; Ozerov, O. V. Science 2008, 321, 1188–1190.
1-chlorooctane with TMEDA and a subsequent intramolecu-
(
9) Carbocation-mediated aliphatic C-F bond activation: (a) Ferraris,
lar Hoffmann degradation (Table 1, entry 9). This result
indicated that only 1-chlorooctane was formed, even in the
D.; Cox, C.; Anand, R.; Lectka, T. J. Am. Chem. Soc. 1997, 119, 4319–
320. (b) Wang, H.; Webster, C. E.; Perez, L. M.; Hall, M. B.; Gabba ¨ı ,
F. P. J. Am. Chem. Soc. 2004, 126, 8189–8196.
10) Hatakeyama, T.; Ito, S.; Nakamura, M.; Nakamura, E. J. Am. Chem.
Soc. 2005, 127, 14192–14193.
11) Weaker Lewis-acidity of magnesium in comparison with aluminum:
4
(
(15) Typical Procedure. To 1-fluorooctane (0.16 mL, 1.0 mmol) in a
20 mL Schlenk tube was added a 2.0 M tetrahydrofuran solution of
phenylmagnesium chloride (0.75 mL, 1.5 mmol) under an argon atmosphere.
The solution was warmed up to 80 °C and stirred for 24 h. After cooling
to ambient temperature, the solvent and volatile products, including
1-chlorooctane, were removed under reduced pressure, and water (20 mL)
and dichloromethane (20 mL) were added to the residual oil. The crude
organic product was extracted with dichloromethane (20 mL × 4) and dried
(
Grohmann, I.; Hess, A.; Kemnitz, E.; Fentrup, W.; Unger, W. E. S.; Wong,
J.; Rowen, M.; Tanaka, T.; Fr o¨ ba, M. J. Mater. Chem. 1998, 8, 1453–
1
457.
(
12) Trial for nucleophilic substitution of haloalkanes with Grignard
reagent: Hahn, R. C.; Tompkins, J. Tetrahedron Lett. 1990, 31, 937–940.
13) Grignard cross-coupling of haloalkanes: (a) Schleyer, P. V. R.;
(
Osawa, E.; Majerski, Z. J. Org. Chem. 1971, 36, 205–207. (b) Ohno, M.;
Shimizu, K.; Ishizaki, K.; Sasaki, T.; Eguchi, S. J. Org. Chem. 1988, 53,
4
with MgSO . The residual mixture was purified by silica gel (neutral) column
chromatography by eluting with hexane to yield n-octylbenzene (68.1 mg,
1
7
29–733.
14) Metal-catalyzed Grignard cross-coupling of fluoroalkanes: (a) Terao,
J.; Todo, H.; Watanabe, H.; Ikumi, A.; Kambe, N. Angew. Chem., Int. Ed.
004, 43, 6180–6182. (b) Terao, J.; Watabe, H.; Kambe, N. J. Am. Chem.
0.36 mmol, 36%). n-Octylbenzene was commercially available, and H and
1
3
(
C NMR spectral data of the product were in complete agreement with
those of the authentic sample.
2
(16) We have a preliminary experimental result of the reaction of
1-fluorooctane with vinylmagnesium chloride in THF. Although successful
dominant C-C bond formation to form 1-decene and also 1-chlorooctane
was detected by GC-MS analysis, determination of other products and
quantification are not successful at present.
Soc. 2005, 127, 3656–3657. (c) Terao, J.; Todo, H.; Begum, S. A.; Kuniyasu,
H.; Kambe, N. Angew. Chem., Int. Ed. 2007, 46, 2086–2089. (d) Terao, J.;
Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2003, 125, 5646–
647.
5
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Org. Lett., Vol. 11, No. 8, 2009