Ni- or Cu-catalyzed cross-coupling reaction of alkyl fluorides with grignard reagents

Article abstract of DOI:10.1021/ja034201p

n-Octyl fluoride underwent a cross-coupling reaction with n-propylmagnesium bromide in the presence of 1,3-butadiene using NiCl₂ as a catalyst at room temperature to give undecane in moderate yields. This alkyl-alkyl cross-coupling proceeded more efficiently when CuCl₂ was employed instead of NiCl₂. Addition of 1,3-butadiene dramatically improved the yields of the coupling products from primary alkyl Grignard reagents in both Ni- and Cu-catalyzed reactions. Alkyl fluorides efficiently reacted with tertiary alkyl and phenyl Grignard reagents using CuCl₂ in the absence of 1,3-butadiene to afford the coupling products in high yields. The competitive reaction of a mixture of alkyl halides (R-X; X = F, Cl, Br) with nC5H11MgBr showed that the reactivities of the halides increase in the order R-Cl < R-F < R-Br. In contrast, in the Cu-catalyzed reaction with PhMgBr, the reactivities increase in the order R-Cl < R-Br < R-F. Copyright

Full text of DOI:10.1021/ja034201p

Published on Web 04/22/2003
Ni- or Cu-Catalyzed Cross-Coupling Reaction of Alkyl Fluorides with Grignard
Reagents
Jun Terao, Aki Ikumi, Hitoshi Kuniyasu, and Nobuaki Kambe*
Department of Molecular Chemistry and Frontier Research Center, Graduate School of Engineering,
Osaka UniVersity, Suita, Osaka 565-0871, Japan
Received January 16, 2003; E-mail: kambe@chem.eng.osaka-u.ac.jp
Table 1. Cross-Coupling Reaction of nC8H17-F with nC3H7-MgBra
Carbon-fluorine bonds are the strongest single bonds in organic
product yield (%)b
compounds and have been thought to be inert toward many re-
agents.1 Therefore, developing reactions that replace fluorine atoms
in organic molecules with other atoms or functional groups is a
challenging theme in organic chemistry. As for metal-mediated
transformations involving cleavage of sp2C-F bonds, several reac-
tions using fluoroarenes have already been developed, employing
catalytic2 or stoichiometric3 amounts of transition metal complexes.
On the other hand, examples of aliphatic sp3C-F bond fission by use
of transition metal complexes are very rare. They are limited to the
following two types of reactions: (i) catalytic defluorination of
saturated perfluoroalkanes leading to the corresponding olefins or
arenes,4 and (ii) hydrodefluorination (i.e., reduction) of fluoroalkanes
with Cp2*ZrH2, which proceeds only in a stoichiometric manner.5
During our study on the synthetic application of alkyl halides in
transition metal chemistry,6 we have recently revealed that Ni
catalyzes cross-coupling reactions of alkyl chlorides, bromides, and
tosylates with Grignard reagents in the presence of a 1,3-butadiene
derivative under mild conditions.7 As an extension of this study,
we disclose herein the first example of a catalytic C-C bond-
forming reaction using nonactivated alkyl fluorides8 (eq 1).
entry
catalyst
NiCl2
(PPh3)2NiCl2 none
(dppp)NiCl2 none
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
NiCl2
additive (mol %)
undecane octane octenesc
1
2
3
4
5
6
7
8
9
none
0
0
0
0
0
0
1
2
2
4
3
0
0
0
0
3
3
0
0
1
0
0
0
0
0
0
0
1
2
2
1
0
0
0
0
2
2
0
0
4
0
0
0
1,3-butadiene (10)
1,3-butadiene (50)
1,3-butadiene (70)
1,3-butadiene (100)
1,3-butadiene (200)
9
44
50
64
67
47
0
0
0
8
57
0
isoprene (100)
10 NiCl2
11 NiCl2
12 NiCl2
13 (PPh3)2NiCl2 1,3-butadiene (100)
14 (dppp)NiCl2 1,3-butadiene (100)
15 FeCl2
16 CoCl2
17 PdCl2
18 CuCl2
19 CuCl
2,3-methyl-1,3-butadiene (100)
1,5-cyclooctadiene (100)
diphenylacetylene (100)
1,3-butadiene (100)
1,3-butadiene (100)
1,3-butadiene (100)
1,3-butadiene (100)
1,3-butadiene (100)
1,3-butadiene (100)
0
23
97
94
30
20 Li2CuCl4
a Conditions: nOct-F (2 mmol), 3 mol % catalyst, additive (mol % based
on the substrate), and nPr-MgBr (2 equiv, 1 M), in THF, 25 °C, 3 h.
b Determined by GC. c A mixture of 1-octene and 2-octenes.
tively, in the presence of 1,3-butadiene (entries 13 and 14). FeCl2
and CoCl2 did not give any products (entries 15 and 16), whereas
PdCl2 afforded undecane in 23% yield (entry 17). Surprisingly,
copper salts, such as CuCl2 and CuCl, showed the highest activities
for this cross-coupling reaction with complete suppression of forma-
tion of octane and octenes (entries 18 and 19). When Li2CuCl4 was
used, only a moderate yield of undecane was obtained (entry 20).
Representative results of the CuCl2-catalyzed cross-coupling
Table 1 summarizes the results of cross-coupling reactions of
n-octyl fluoride (2 mmol) with n-propylmagnesium bromide (0.93
M, 4.3 mL, 2.0 equiv), performed at 25 °C for 6 h using various
catalysts (3 mol %) and additives. As shown in entries 1-3,
nC8H17-F did not react at all when no additive is employed, even
in the presence of Ni catalyst. However, addition of 10 mol % 1,3-
butadiene based on nC8H17-F enabled alkyl-alkyl cross-coupling
to proceed in the presence of NiCl2 as a catalyst, giving rise to a
9% yield of undecane accompanied by a small amount of octane
(entry 4). On increasing the amount of 1,3-butadiene up to 100
mol %, the yield of undecane improved to 64% (entry 7). However,
further increase of 1,3-butadiene did not lead to significant
improvement of the yield (entry 8).
n
reaction of C8H17-F with some Grignard reagents are shown in
Table 2. It was found that 1.3 equiv of R-MgX and 10 mol %
1,3-butadiene (based on the halide, 0.07 M in THF) are sufficient
to promote the primary alkyl-alkyl coupling reaction efficiently
(Table 2, entry 1). Isoprene (entry 2), diphenylacetylene, and
m-CF3C6H4CHdCH2 were less effective under these conditions.
1-Octene and 1,5-cyclooctadiene were ineffective.
It should be noted that the coupling product, undecane, was
obtained in 20% yield in the presence of CuCl2 in the absence of
1,3-butadiene at 25 °C for 6 h (entry 3). Prolonged reaction time
did not improve the yield (25% for 20 h). Interestingly, when the
reaction was performed at -20 °C, the coupling reaction proceeded
slowly without significant loss of catalytic activity (entries 4 and
5) even in the absence of 1,3-butadiene, resulting in the formation
of undecane in 68% yield after 48 h (entry 6). This reaction did
not proceed at -40 °C (entry 7). The coupling reaction of
iPr-MgBr was also facilitated by 1,3-butadiene at ambient tem-
perature (entries 8 and 9). These results may imply that 1,3-
butadiene plays an important role in stabilizing an active species
in the Cu-catalyzed cross-coupling reaction.
When 100 mol % isoprene was employed instead of 1,3-
butadiene, undecane was obtained in 47% yield (entry 9). However,
2,3-dimethyl-1,3-butadiene, 1,5-cyclooctadiene, and diphenylacety-
lene did not promote this coupling reaction (entries 10-12). As
proposed in our previous paper,7 bisallyl Ni complexes would play
an important role as active catalytic species. The ineffectiveness
of 2,3-dimethyl-1,3-butadiene may be ascribed to lower stability
and/or reactivity of its complex due to steric reasons. Under the
same conditions as in entry 7, reactions of nC8H17F with iPr-MgBr,
tBu-MgCl, and Ph-MgBr afforded coupling products in 3%, 6%,
and 31% yield, respectively.
Ni complexes bearing phosphine ligands, such as (PPh3)2NiCl2
and (dppp)NiCl2, afforded undecane in 8% and 57% yield, respec-
9
5646
J. AM. CHEM. SOC. 2003, 125, 5646-5647
10.1021/ja034201p CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Cu-Catalyzed Cross-Coupling Reaction of nOct-F with
Grignard Reagents
diene revealed that fluoride was the most reactive halide (eq 4).
Such high reactivities of fluorides cannot reasonably be explained
yet9 because the mechanistic details are not known.10
When the Ni- and Cu-catalyzed cross-coupling reactions depicted
in eq 5 were run employing 6-fluoro-1,1-diphenyl-1-hexene, 1 was
obtained as the sole coupling product in 72% and 98% yield,
respectively, without formation of 2, which may arise from
intramolecular cyclization of a 6,6-diphenyl-5-hexenyl radical.11
This result would rule out this radical mechanism.
In conclusion, we revealed the first example of a metal-catalyzed
cross-coupling reaction of alkyl fluorides with Grignard reagents.
These reactions proceed efficiently between primary alkyl fluorides
and various Grignard reagents under mild conditions in the presence
of nickel or copper salts.
additive
(0.2 mmol)
temp
(°C)
time
(h)
GC yield
(%)
entry
R−MgX
1
2
nC3H7-MgBr 1,3-butadiene
25
25
25
6
6
94
34
20
38
36
68
3
81
35
99
99
38
53
99
isoprene
none
3
6
4
1,3-butadiene -20
6
5
none
-20
-20
-40
25
6
6
none
48
6
7
none
8
iC3H7-MgBr
tC4H9-MgCl
Ph-MgBr
1,3-butadiene
none
6
9
25
6
10
11
12
13
14
1,3-butadiene
none
1,3-butadiene
none
none
25
6
25
6
Acknowledgment. This research was supported financially in
part by a grant from the Ministry of Education, Culture, Sports,
Science, and Technology of Japan and by the JSPS COE program.
We thank the Instrumental Analysis Center, Faculty of Engineering,
Osaka University, for HRMS and elemental analysis.
25
6
25
6
67 (reflux)
1
In contrast to the reactions involving the primary and secondary
alkyl Grignard reagents mentioned above, 1,3-butadiene exerted
little effect in the reaction using tertiary alkyl and phenyl Grignard
reagents. These reactions gave rise to the corresponding coupling
products in good to high yields without additives (entries 10-14).
Cyclohexyl fluoride and bis(p-trifluoromethylphenyl)-methane could
not be alkylated under similar conditions.
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
References
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When n-octyl bromide was allowed to react with nPr-MgBr or
Ph-MgBr under identical conditions (entries 1 and 14 in Table 2,
respectively), the corresponding coupling products were obtained
in high yields. In contrast, n-octyl chloride gave poor to moderate
yields of products (eq 2).
(3) (a) Harrison, R. G.; Richmond, T. G. J. Am. Chem. Soc. 1993, 115, 5303-
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We also examined the relative reactivities of alkyl halides (RX;
X ) F, Cl, Br) by competitive experiments using C5H11-MgBr.
n
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To a mixture of 1,3-butadiene and equimolar amounts of n-nonyl
fluoride, n-octyl chloride, and n-decyl bromide were added a THF
solution of nC5H11-MgBr and 3 mol % NiCl2 or CuCl2 (eq 3). For
both catalysts, the reactivity of alkyl halides was observed to be in
the order chloride < fluoride < bromide. Interestingly, similar
experiments using Ph-MgBr and CuCl2 in the absence of 1,3-buta-
(5) Kraft, B. M.; Lachicotte, R. J.; Jones, W. D. J. Am. Chem. Soc. 2000,
122, 8559-8560.
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Terao, J.; Watanabe, T.; Saito, K.; Kambe, N.; Sonoda, N. Tetrahedron
Lett. 1998, 39, 9201-9204. (b) Terao, J.; Saito, K.; Nii, S.; Kambe, N.;
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(8) R-Alkoxy or phenoxy substituted akyl fluorides react with Grignard
reagents, see: (a) Yokoyama, M.; Toyoshima, H.; Shimizu, M.; Mito, J.;
Togo, H. Synthesis 1998, 409-412. (b) Ringom, R.; Benneche, T. Acta
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theoretical calculations were performed using the G2 method of the
Gaussian 98 program. Calculated bond energies of X-MgCl are 142, 112,
101 kcal/mol, and those of X-CH3 are 112, 85, 74 kcal/mol for X ) F,
Cl, Br, respectively. Energy differences between these two bonds for F,
Cl, Br are similar (30, 28, 27 kcal/mol, respectively), indicating that the
reaction of alkyl fluorides is not disfavored energetically.
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(RX) are known to react with R′2CuLi via an SN2 mechanism. A theoretical
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7294-7307.
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the 6,6-diphenyl-5-hexenyl radical to the cyclopentyldiphenylmethyl
radical has been reported: Newcomb, M.; Choi, S.-Y.; Horner, J. H. J.
Org. Chem. 1999, 64, 1225-1231.
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