Iron-catalysed fluoroaromatic coupling reactions under catalytic modulation with 1,2-bis(diphenylphosphino)benzene

Article abstract of DOI:10.1039/b820879d

A catalytic amount of 1,2-bis(diphenylphosphino)benzene (DPPBz) achieves selective cleavage of sp³-carbon-halogen bond in the iron-catalysed cross-coupling between polyfluorinated arylzinc reagents and alkyl halides, which was unachievable with

Full text of DOI:10.1039/b820879d

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Iron-catalysed fluoroaromatic coupling reactions under catalytic
modulation with 1,2-bis(diphenylphosphino)benzenew
Takuji Hatakeyama,a Yoshiyuki Kondo,a Yu-ichi Fujiwara,a Hikaru Takaya,a Shingo Ito,b
Eiichi Nakamurab and Masaharu Nakamura*a
Received (in Cambridge, UK) 24th November 2008, Accepted 9th January 2009
First published as an Advance Article on the web 3rd February 2009
DOI: 10.1039/b820879d
A catalytic amount of 1,2-bis(diphenylphosphino)benzene (DPPBz)
achieves selective cleavage of sp3-carbon–halogen bond in the iron-
catalysed cross-coupling between polyfluorinated arylzinc reagents
and alkyl halides, which was unachievable with a stoichiometric
modifier such as TMEDA; the selective iron-catalysed fluoro-
aromatic coupling provides easy and practical access to poly-
fluorinated aromatic compounds.
Fluoroaromatic rings are a key structural unit of numerous
functional molecules, such as liquid crystals, drugs, agrochemicals,
and dyes.1 Hence, it has been of great synthetic interest to develop
an efficient reaction for installing various fluorinated aryl groups
onto organic structures. The cross-coupling technology has
provided a number of powerful methods for connecting fluoro-
aromatic rings and unsaturated carbon (Csp2 or Csp) side chains;2
however, there are few coupling methods for introducing alkyl
(Csp3) substituents.
Fig. 1 Mono- and polyfluorinated arylmetal reagents used for the
iron-catalysed cross-coupling of alkyl halides.
Despite the significant progress in catalytic cross-coupling
reactions of alkyl electrophiles,3 the lability (e.g., undesired
C–F bond cleavage) and low reactivity of polyfluorinated aryl
metals under conventional reaction conditions pose a serious
synthetic challenge when catalytic C–C bond formation
technology is employed.3b,c,h,l Herein, we report that a catalytic
amount of a chelate phosphine ligand, 1,2-bis(diphenylphos-
phino)benzene (DPPBz), effects selective iron-catalysed cross-
coupling4 between fluoroaromatic zinc reagents (1) and alkyl
halides, which has not been achieved by using stoichiometric
additives, such as TMEDA.
Scheme 1 Iron-catalysed cross-coupling between bromocycloheptane
and 3,4,5-trifluorophenyl metal reagents.
ineffective, as shown in entries 1 and 2 in Table 1. Careful
GLC analysis of the relationship between the formation of
by-products and conversion of the starting bromide showed
that the desired coupling reactions stopped when the defluori-
nated products 4, 5, and 8-F5 appeared in the reaction mixture.
C–F bond cleavage of 8-F6 would give 8-F5 and fluorinated
iron species, which presumably mediated the reductive biaryl
coupling of the arylzinc reagent to yield 8-F6.5,6
We chose the coupling of bromocycloheptane (c-Hep–Br) 2
with 3,4,5-trifluorophenyl metal reagents (1f–h; Fig. 1) as a
benchmark reaction for catalyst screening in the presence of
various additives (Scheme 1 and Table 1). The diarylzinc
reagents used in the present study were prepared from
the corresponding Grignard reagents and anhydrous ZnCl2
because of their substantially higher reactivity than those
prepared from the corresponding aryllithium reagents.3k
A standard protocol using the iron-catalysed cross-coupling
of haloalkanes with an excess amount of N,N,N0,N0-tetra-
methylethylenediamine (TMEDA)3g,i–k,n,4f,h was found to be
The observed termination of the catalytic reaction can be
attributed to catalyst poisoning caused by the fluoride ion,
which is generated in situ by the side reactions between the
fluoroaromatic group and the iron catalyst.5 Assuming that
the electron-donating nature of TMEDA enhances the
reducing ability of the iron catalyst to cleave the C–F bonds,
we turned our attention to phosphine ligands to modulate the
reactivity of the iron species.7 Ligand screening eventually
revealed that a catalytic amount of DPPBz dramatically
improved the reactivity and selectivity of the iron catalyst to
give 3 with an optimum yield of 91% (entry 3).8 Formation of
defluorinated and elimination by-products was minimal, being
below 5%. Addition of one equivalent of DPPBz to FeCl3
(3 mol% each) improved the chemical yield of the cross-
coupling product, suggesting that a 1 : 1 composite of the
a International Research Center for Elements Science (IRCELS),
Institute for Chemical Research, Uji, Kyoto, 611-0011, Japan.
E-mail: masaharu@scl.kyoto-u.ac.jp; Fax: (+81)-774-38-3186;
Tel: (+81)-774-38-3180
b Department of Chemistry, The University of Tokyo, Bunkyo-ku,
Tokyo, 113-0033, Japan
w Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/b820879d
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Table 1 Cross-coupling between bromocycloheptane 2 and 3,4,5-
trifluorophenyl metal reagents (ArM) in the presence of various
additives and ligandsa
Table 2 Cross-coupling of arylzinc reagents and alkyl halidesa
a
Reactions were carried out on a 0.2–0.4 mmol scale. b The yield was
determined by GC analysis using undecane as an internal standard.
c
d
The yield was based on the amount of ArM. The reaction was
e
carried out for 24 h. The reaction was carried out for 6 h.
f
FeCl2(dppbz)2 (3 mol%) was used instead of FeCl3 and an additive.
chelate phosphine and iron should constitute a catalytically
active species (entry 4).
3,4,5-Trifluorophenylzinc chloride 1g shows much lower
reactivity than 1h, producing 3 in 18% yield under the same
conditions (entry 5). The use of 9 mol% of DPPBz with an
extended reaction time (24 h) improved the product yield to
86% (entry 6). Interestingly, defluorinated cross-coupling
products 4 and 5 were not obtained at all. E2-elimination was
predominant with 3,4,5-trifluorophenylmagnesium bromide
and DPPBz (entry 7). Without any additives, 3 was obtained
only in 3% yield (entry 8). Finally, we examined the reaction
with a structurally well-defined iron complex, FeCl2(dppbz)2,9
to obtain 3 in 93% yield with slightly higher selectivity than
with the combined use of FeCl3 and DPPBz (entry 9). One can
choose the crystalline complex, FeCl2(dppbz)2, or the combina-
tion of DPPBz and cheap FeCl3 salt as the catalyst for the cross-
coupling. We currently assume a catalytic cycle starting from
Fe(II) rather than Fe(III), which we had previously adopted to
account for the higher catalytic activity of Fe(III) salts.3g,k,10
Table 2 summarizes the scope of the present coupling reac-
tion. As shown in entries 1–6, a variety of mono-, di-, and
trifluorophenylzinc reagents can be used: 4-fluorophenyl- and
3,4-difluorophenylzinc reagents (1a and b) smoothly reacted
with bromocycloheptane 2 to give the products 9 and 4 in 92%
and 91% yield, respectively. Similarly, the reaction of 3,5-
difluorophenyl- and 3,4,5-trifluorophenylzinc reagents (1c and h)
gave the corresponding product in 84% and 90% yield,
respectively. The reaction of 2,5-difluorophenylzinc reagent
1d turned out to be less selective to give 10 in 79% yield after
12 h. Bromocycloheptane 2 was consumed completely in these
cases. While the reactions of 2,3-difluoro-4-ethoxyphenylzinc
reagent 1e with 2 were very sluggish,11 1-iododecane was
reactive enough to give the coupling product 11 in 91% yield.
The reaction of 2,3,4,5,6-pentafluorophenylzinc reagent 1i and 2
gave no coupling products, and 2 was recovered quantitatively.
It should be noted that the reaction of 1b with a secondary
alkyl chloride, chlorocycloheptane, took place smoothly
a
Reactions were carried out according to the procedure for entry 3 in
b
Table 1 on a 1.0–2.0 mmol scale. Isolated yield. c 1H NMR yield.
d
e
3 mol% of FeCl3 and 9 mol% of DPPBz were used. 1.5 equiv. of
Ar2M was used. f cis : trans = 44 : 56. g 3 mol% of FeCl2(dppbz)2 was
h
used. cis : trans = 39 : 61.
at 80 1C to give 4 in 83% yield (entry 7). Although 1-chlorodecane
was totally inert even at 80 1C, the coupling product
12 was obtained in 84% yield in both cases when 1-bromo-
or 1-iododecane was used (entries 8–10). This reactivity profile
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is similar to that commonly observed in the iron-catalysed
cross-coupling of alkyl halides.3g–p,4f,h Nitrile and indole
moieties remained intact under the reaction conditions
(entries 11 and 12).
The reaction of cis-4-bromo-trans-40-pentyl-1,10-bi(cyclo-
hexyl) 17 with 1b gave 18 in 85% yield (entry 13); likewise,
3,4,5-trifluoroarylation of 17 was accomplished by using 1h in
the presence of 3 mol% of FeCl3 and 9 mol% of DPPBz (entry
14).12 Although the reaction provided a mixture of the two
diastereomers, the effective and efficient coupling by simple use
of DPPBz suggests its potential application to the production
of widely used liquid crystal molecules.13
J. Am. Chem. Soc., 2005, 127, 510–511; (d) F. Gonzalez-Bobes and
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G. C. Fu, J. Am. Chem. Soc., 2006, 128, 5360–5361;
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The reactivity profile and nonstereoselective nature of the
iron-catalysed fluoroaromatic coupling reaction indicate inter-
mediacy of alkyl radicals. This was confirmed by the reactions
of (bromomethyl)cyclopropane 20 and 3-(1-butoxy-2-iodo-
ethoxy)-3-methylbut-1-ene 22 in the presence of 3 mol% of
FeCl2(dppbz)2, which gave ring-opening product 21 and ring-
closing product 23 in 77% and 85% yield, respectively, as we
and others have reported previously.3i–k,m
The present reaction is highly selective for Csp3–X. Thus,
1-bromo-4-(2-bromoethyl)benzene 24 possessing two potential
reactive sites, Csp2–Br and Csp3–Br, reacted with 1b via a
selective Csp3–Br bond cleavage, yielding 25 in 77% yield
(entry 17). Reductive cleavage of the Csp2–Br took place only
to a minor extent (5%).14 While a detailed mechanistic study is
required to determine the oxidation state or electronic state of
the reactive iron species, we suppose, at the present stage,
that the selective cleavage of Csp3–Br over Csp2–Br can be
explained by the radical character of the neutral organoiron
species that was proposed as a reactive intermediate of one of
the interconnected pathways of the iron-catalysed cross-coupling
of alkyl Grignard reagents.3p
Chem., Int. Ed., 2008, 47, 1305–1307; (p) A. Furstner, R. Martin,
¨
H. Krause, G. Seidel, R. Goddard and C. Lehmann, J. Am. Chem.
Soc., 2008, 130, 8773–8787.
4 Selected papers not referred to above: (a) M. Tamura and J. Kochi,
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H. Avedissian, Synthesis, 1998, 1199–1205; (c) A. Furstner,
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5 Iron fluoride showed no catalytic activity for the present reaction
but high catalytic activity for biaryl cross-coupling; see ref. 4g.
6 When the reaction was quenched with I2, iodopentafluorobiphenyl
was obtained instead of 8-F5.
7 Some examples of highly controlled C–C bond formation under
the catalysis of iron/phosphine-based ligand: (a) F. Viton,
In summary, we have developed the first direct polyfluoro-
arylation of primary and secondary alkyl halides via a selective
iron-catalysed cross-coupling reaction. A catalytic amount
of DPPBz ligand suppresses Csp2–F bond cleavage and
E2-elimination reactions. The reaction is high yielding,
chemoselective, and free of rare metals, and hence it is a
concise and versatile synthetic method for functional organic
molecules bearing various fluoroaromatic rings. Synthesis of
the DPPBz derivatives15 and their application in related iron-
catalysed reactions are being actively investigated in our
laboratories and will be reported in due course.16
G. Bernardinelli and E. P. Kundig, J. Am. Chem. Soc., 2002,
¨
Synth. Catal., 2001, 343, 51–56; (c) M. Nakamura, A. Hirai and
E. Nakamura, J. Am. Chem. Soc., 2000, 122, 978–979. See also
ref. 3m.
8 Other phosphine ligands are less effective: 1,2-bis(diphenylphos-
phino)ethylene, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenyl-
phosphino)propane, 1,2-bis(diphenylphosphino)ferrocene, and PPh3
give 3 in 60, 29, 25, 1, and 1% yield, respectively. Details are given in
Supporting Informationw.
¨
124, 4968–4969; (b) E. P. Kundig, C. M. Saudan and F. Viton, Adv.
9 J. E. Barclay, A. Hills, D. L. Hughes and G. J. Leigh, J. Chem.
Soc., Dalton Trans., 1988, 2871–2877.
10 In situ reduction of Fe(III) to Fe(II) is reported to be quite rapid in
the presence of organomagnesium or organolithium reagents; see
ref. 3p.
11 The reaction of 2 with 1e took place at 80 1C for 36 h to give the
corresponding coupling product in 60% yield. Details are given in
Supporting Informationw.
12 The reaction of 17 with 1a and 1c gave 86% and 77% yield,
respectively. Details are given in Supporting Informationw.
13 (a) D. Demus, Y. Goto, S. Sawada, E. Nakagawa, H. Saito and
R. Tarao, Mol. Cryst. Liq. Cryst., 1995, 260, 1–21; (b) M. Hird,
Chem. Soc. Rev., 2007, 36, 2070–2095.
Grants-in-Aid for Scientific Research on Priority Areas
‘‘Synergy of Elements’’ (M.N., 18064006) and ‘‘Chemistry of
Concerto Catalysis’’ (T.H., 20037033), and a Grant-in-Aid for
Young Scientists from JSPS (S, M.N., 2075003) are gratefully
acknowledged.
Notes and references
1 Organofluorine Chemistry, ed. R. E. Banks, B. E. Smart and
J. C. Tatlow, Plenum Press, New York, 1994.
14 Details are given in Supporting Informationw.
15 A patent application has been filed for the DPPBz derivatives and
their iron complexes. M. Nakamura, T. Hatakeyama and Y.
Fujiwara, JP Pat., 2008-174021.
16 After this manuscript was submitted for publication Bedford et al.
reported that the iron-DPPBz catalyst is effective for cross-
couplings of benzyl halides. R. B. Bedford, M. Huwe and
M. C. Wilkinson, Chem. Commun., 2009, 600–602.
2 (a) Metal-Catalyzed Cross-Coupling Reactions, ed. F. Diederich
and A. de Meijere, Wiley-VCH, New York, 2nd edn, 2004;
(b) Cross-Coupling Reactions: A Practical Guide, ed. N. Miyaura,
Springer, Berlin, 2002.
3 (a) J. Zhou and G. C. Fu, J. Am. Chem. Soc., 2004, 126,
1340–1341; (b) D. A. Powell and G. C. Fu, J. Am. Chem. Soc.,
2004, 126, 7788–7789; (c) D. A. Powell, T. Maki and G. C. Fu,
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