Dinuclear iron complex-catalyzed cross-coupling of primary alkyl fluorides with aryl grignard reagents

Article abstract of DOI:10.1021/om300722g

Iron-catalyzed cross-coupling of nonactivated primary alkyl fluorides with aryl Grignard reagents has been achieved by using the low-coordinate dinuclear iron complex [(IPr₂Me₂)Fe(μ₂-NDipp) ₂Fe(IPr₂Me₂)] as the catalyst. This iron-catalyzed C(sp³)-F bond arylation reaction is applicable to a variety of aryl Grignard reagents and primary alkyl fluorides. The product pattern suggests the involvement of a radical-type mechanism for its C-F bond scission step.

Full text of DOI:10.1021/om300722g

Communication
pubs.acs.org/Organometallics
Dinuclear Iron Complex-Catalyzed Cross-Coupling of Primary Alkyl
Fluorides with Aryl Grignard Reagents
Zhenbo Mo, Qiang Zhang, and Liang Deng*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai, People’s Republic of China, 200032
S
* Supporting Information
ABSTRACT: Iron-catalyzed cross-coupling of nonactivated
primary alkyl fluorides with aryl Grignard reagents has been
achieved by using the low-coordinate dinuclear iron complex
[(IPr2Me2)Fe(μ2-NDipp)2Fe(IPr2Me2)] as the catalyst. This
iron-catalyzed C(sp3)−F bond arylation reaction is applicable
to a variety of aryl Grignard reagents and primary alkyl fluorides.
The product pattern suggests the involvement of a radical-type
mechanism for its C−F bond scission step.
Chart 1. Dinuclear Iron Catalysts Used in This Study
he search for a new generation of homogeneous catalysts
Twith inexpensive, nontoxic, and environmentally benign
features has led to the fast development of iron catalysis in
organic synthesis,1 of which iron-catalyzed cross-coupling
reactions of organic electrophiles with organometallic reagents
have proved very efficient for carbon−carbon bond con-
struction.2 With continuing efforts in this area, versatile iron-
catalyzed cross-couplings of organometallic reagents with
reactive electrophiles, such as acyl halides, alkenyl and alkyl
triflates, iodides, bromides, and secondary alkyl halides, have
been successfully developed2 and applied to the synthesis of
complex organic molecules.3 However, in terms of less reactive
electrophiles, e.g., electron-rich aryl halides and primary alkyl
chlorides, only a handful of examples are known,4 and fluorides
remain rare, in sharp contrast to the plentiful Pd-, Ni-, and Cu-
based catalysts.5,6 Since the conventional iron salts-based
catalysts are not effective for these electrophiles, new iron
catalysts, which could not only mediate the activation of
carbon−halogen bonds of these less reactive halides but also
concomitantly or subsequently facilitate carbon−carbon bond
formation, are desired to address this challenge. In this regard,
we report herein our investigation on the low-coordinate
dinuclear iron complex [(IPr2Me2)Fe(μ2-NDipp)2Fe-
(IPr2Me2)] (IPr2Me2: 2,5-diisopropyl-3,4-dimethylimidazol-1-
ylidene; Dipp: 2,6-diisopropylphenyl, Chart 1),7 which is
capable of catalyzing the cross-coupling of primary alkyl
fluorides with aryl Grignard reagents in good yields. This
study represents the first example of an iron-catalyzed C−F
bond functionalization reaction and, more interestingly, has
revealed the involvement of a radical-type mechanism for the
C(sp3)−F bond activation step as shown below.
organic fluorides with organometallic reagents. Hence, we
examined the catalytic performance of some three- and four-
coordinate iron complexes in addition to simple iron salts in the
reaction of n-C8H17F with p-Me-C6H4MgBr in THF. As shown
in Table 1, the iron compounds [Fe(acac)3]4a and
(FeCl3)2(TMEDA)3 (TMEDA = N,N,N′,N′-tetramethylethyle-
nediamine),9 which are well known for catalyzing the cross-
coupling of reactive organic halides with aryl Grignard reagents,
do not promote C−F bond arylation (entries 1 and 2), but
induce defluorination of n-C8H17F. A similar situation occurred
in the cases of the low-coordinate complexes [Fe-
(NTMS2)2]2,10 [Fe(Mes)2]2,11 and (IPr2Me2)Fe(Mes)2 (en-
7
tries 3−5; TMS = trimethylsilyl; Mes = 2,4,6-trimethylphenyl).
As the defluorination products (3−5) dominate in these trials,
the iron complexes seem amenable to facilitating C−F bond
cleavage, but incapable of promoting further carbon−carbon
bond formation. The dinuclear iron complex [(IPr2Me2)Fe(μ2-
NDipp)2Fe(IPr2Me2)] (cat. 1)7 shows a different catalytic
performance. Addition of the catalyst to the reaction mixture
gave a red-brown solution. After 48 h GC-MS analyses revealed
the formation of the cross-coupling product p-methyl-n-
octylbenzene and the defluorination products in 87% and 5%
Inspired by Holland’s work on the iron-catalyzed C−F bond
hydrodefluorination reactions,8 we envisioned the potential of
low-coordinate iron complexes in catalyzing cross-coupling of
Received: July 29, 2012
Published: August 31, 2012
© 2012 American Chemical Society
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Communication
Table 1. Influence of the Iron Catalysts
Table 2. Iron-Catalyzed Arylation of n-Octyl Fluoride
a
GC yield (%)
entry
iron compound
2
3 + 4 + 5
6
1
1
2
3
4
5
6
7
8
Fe(acac)3
trace
0
75
37
79
56
23
5
trace
40
25
63
21
37
77
7
(FeCl3)2(TMEDA)3
[Fe(NTMS2)2]2
[Fe(Mes)2]2
0
trace
trace
trace
12
7
(IPr2Me2)Fe(Mes)2
0
b
cat. 1
87
71
NR
b
cat. 2
12
31
17
none
a
b
GC yields are based on the fluoride. cat. 1: [(IPr2Me2)Fe(μ2-
NDipp)2Fe(IPr2Me2)]; cat. 2: [F(IPr2Me2)Fe(μ2-NDipp)2Fe-
(IPr2Me2)F].
a
Data in parentheses are isolated yields based on the fluoride after
b
column chromatography. The reaction was run at room temperature.
a b
,
Table 3. Iron-Catalyzed C(sp3)−F Bond Phenylation
yields, respectively (entry 6). The diferric complex [F-
(IPr2Me2)Fe(μ2-NDipp)2Fe(IPr2Me2)F] (cat. 2)7 could also
catalyze the cross-coupling reaction and afforded the product in
a slightly lower yield (entry 7).
Noting Matsubara’s report on the C−F bond cleavage
reactions of alkyl fluorides with PhMgCl without a transition
metal catalyst, which gave arylation products in low yields,12 as
well as Kambe’s copper-catalyzed C(sp3)−F bond phenylation
reactions,13 the control experiment of treating p-Me-C6H4MgBr
with n-C8H17F in the absence of iron complexes was performed
(Table 1, entry 8). While atomic absorption spectroscopy
analyses on this reaction mixture indicate the presence of
copper in low concentration (less than 10 ppm),14 no reaction
was observed for this trial since GC-MS analyses show the full
retention of n-C8H17F. These results suggest the observed
C(sp3)−F bond phenylation reactions in entries 5 and 6 are less
likely facilitated by impurity or trace metal contamination and
confirm the uniqueness of the dinuclear iron complexes in
catalyzing the C(sp3)−F bond phenylation reaction.
Subsequently, we examined the impact of the arene
substituent of Grignard reagents on the reaction yields by the
reaction of n-C8H17F with two equivalents of Grignard reagents
at room temperature or at 60 °C when the rates were slow at
room temperature. As shown in Table 2, this reaction did not
exhibit a clear dependence on the electronic nature of the
substituents, as the corresponding cross-coupling products were
obtained in high yields with either electron-donating (entries
1−7) or electron-withdrawing (entries 8 and 9) groups
attached to the aryl ring.15 In addition to phenyl Grignard
reagents, naphthyl Grignard reagents could also be used as the
nucleophiles (entries 11 and 12). Notably, besides the cross-
coupling products, small amounts of n-octane and octenes were
also observed in all cases.15
The scope of fluorides was examined using p-Me-C6H4MgBr
as the nucleophile. The dinuclear iron complex can selectively
catalyze the arylation of a variety of primary alkyl fluorides
(Table 3), but is ineffective for cyclohexyl, adamantyl, and
phenyl fluorides. The selectivity might come from the different
steric properties of the alkyl fluorides and is distinct from
Kambe’s nickel- and copper-catalyzed C−F bond functionaliza-
tion reactions, which work for both primary and secondary alkyl
a
b
Ar = p-methylphenyl. Data in parentheses are isolated yields based
c
on fluorides after column chromatography. Four equivalents of
Grignard reagents was used.
fluorides.6b−d,g,13 As shown in Table 3, among the examined
primary fluorides, the phenylation of simple alkyl fluorides, n-
octyl and n-hexyl fluoride, could be accomplished in high yields
(entries 1 and 2). With 6-fluoro-1-phenyl-1-hexene, the
reaction gave both phenylation and defluorination products in
67% and 16% yields, respectively, but no cyclization product
(entry 3). When 1,6-difluorohexane was used, both the double
phenylation product, 1,6-di(p-tolyl)hexane, and monophenyla-
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Communication
tion/defluorination product, p-methylhexylbenzene, were
formed (entry 4). The reaction can also tolerate certain
functional groups. As depicted in entries 5−7, the reactions
using 3-(2′-furyl)propyl fluoride, 2-(2′-fluoroethyl)-1,3-diox-
ane, and 2-(3-fluoropropyl)-1-methylindole gave the cross-
coupling products in decent yields along with certain amounts
of the defluorination products. The increased yields of the
byproducts in entries 3−7 again suggest this iron-catalyzed
cross-coupling reaction might be sensitive to the steric
bulkiness of alkyl fluorides.
Scheme 2. Proposed Reaction Mechanism
To understand the role of the dinuclear iron catalyst, we
performed the stoichiometric reaction of [(IPr2Me2)Fe(μ2-
NDipp)2Fe(IPr2Me2)] with n-C8H17F or p-Me-C6H4MgBr in
THF, but neither reaction took place at either room
1
temperature or 60 °C, as indicated by their intact H and 19F
NMR spectra. These results indicate [(IPr2Me2)Fe(μ2-
NDipp)2Fe(IPr2Me2)] might be the resting state of genuine
catalytic species in the catalytic cycle. To shed light on the
mechanism of the C(sp3)−F bond scission step, the reaction
employing “radical clock” cyclopropylmethyl fluoride has been
performed. As shown in Scheme 1, this reaction gave not only
nucleophilic substitution reactions of alkyl fluorides have been
well documented in the literature,20 a nucleophlic substitution
mechanism, possibly via the reaction of the iron-aryl
intermediate (A) with alkyl fluorides, might also be present
as a parallel route during the reaction course.
Scheme 1. Cross-Coupling of Cyclopropylmethylene
Fluoride with p-Me-C6H4MgBr
In conclusion, by using the low-coordinate dinuclear iron(II)
complex [(IPr2Me2)Fe(μ2-NDipp)2Fe(IPr2Me2)] as the cata-
lyst we have achieved the first example of an iron-catalyzed
cross-coupling reaction with organic fluorides as the electro-
philes. This iron-catalyzed C(sp3)−F bond arylation reaction is
applicable to a variety of aryl Grignard reagents and primary
alkyl fluorides and involves a radical-type mechanism that is
distinct from the known Ni- and Cu-catalyzed C(sp3)−F bond
functionalization reactions.5b Currently, we are trying to
investigate the reaction mechanism in detail and expand the
substrate scope upon catalyst modification.
the ring-opening product 4-methyl-1-(3′-butenyl)benzene but
also the cyclopropyl derivative 4-methyl-1-cyclopropylmethyl-
benzene, along with 4,4′-dimethylbiphenyl. While our control
experiment has confirmed the inertness of cyclopropylmethyl
fluoride toward p-Me-C6H4MgBr without the addition of the
iron catalyst, the formation of both phenylation products
resembles the one-electron oxidation reaction between
(TMEDA)Fe(Mes)2 and cyclopropylmethyl bromide16 and
suggests the involvement of iron-mediated radical processes.
Based on these results, a radical-type mechanism was
proposed for this dinuclear iron complex-catalyzed cross-
coupling reactions. As shown in Scheme 2, the reaction might
proceed by the displacement of one IPr2Me2 ligand in
[(IPr2Me2)Fe(μ2-NDipp)2Fe(IPr2Me2)] by an aryl anion to
afford a low-coordinate anionic intermediate [(IPr2Me2)Fe-
(NDipp)2Fe(Ar)]− (A).17 An alkyl fluoride molecule (R-F)
might then interact with this low-coordinate intermediate in a
single electron-transfer manner to produce an alkyl radical R•
and a transient aryliron(III) fluoride (or an iron(II) species
bonding with an aryl radical (Ar•)). Subsequent coupling of
these two radicals would afford the cross-coupling product (Ar-
R) and a fluoride-bound intermediate B. B might then react
with ArMgBr to regenerate intermediate A. On the other hand,
when the rate of radical coupling is not fast enough, the side
reactions of radical decomposition may take place, generating
defluorination products and biaryls.18 This mechanism is
supported by the known capability of the dinuclear iron-
imido complex in mediating electron transfer7 and the
precedent examples of radical-type C(sp3)−F bond activation
reactions.19 Notably, as chelating- and Lewis acid-assisted
ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures; characterization data for
starting materials and cross-coupling products. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*E-mail: deng@sioc.ac.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Basic Research Program of China (973
Program, No. 2011CB808705) and the National Natural
Science Foundation of China (Nos. 20872168, 21002114,
and 21121062) for financial support.
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