Nickel-catalyzed monosubstitution of polyfluoroarenes with organozinc reagents using alkoxydiphosphine ligand

Article abstract of DOI:10.1021/ol301195x

A new diphosphine (POP) ligand bearing an alkoxide group allows us to synthesize partially fluorinated arenes. A nickel-catalyzed cross-coupling between a polyfluoroarene and an organozinc reagent in the presence of POP selectively produces a monosubstitution product. Aryl and alkylzinc reagents smoothly take part in the reaction. It is speculated that monosubstitution is the result of accelerated product expulsion from the product/catalyst complex.

Full text of DOI:10.1021/ol301195x

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3316–3319
Nickel-Catalyzed Monosubstitution of
Polyfluoroarenes with Organozinc
Reagents Using Alkoxydiphosphine
Ligand
Yuki Nakamura, Naohiko Yoshikai,‡ Laurean Ilies, and Eiichi Nakamura*
Department of Chemistry, School of Science, The University of Tokyo, Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
nakamura@chem.s.u-tokyo.ac.jp
Received May 10, 2012
ABSTRACT
A new diphosphine (POP) ligand bearing an alkoxide group allows us to synthesize partially fluorinated arenes. A nickel-catalyzed cross-coupling
between a polyfluoroarene and an organozinc reagent in the presence of POP selectively produces a monosubstitution product. Aryl and alkylzinc
reagents smoothly take part in the reaction. It is speculated that monosubstitution is the result of accelerated product expulsion from the product/
catalyst complex.
Partially fluorinated arenes have received much atten-
tion in drug discovery and materials science.1 However,
they are synthetically difficult to access because neither
selective partial fluorination of aromatic compounds2 nor
partial CꢀF bond activation of polyfluoroaromatics3 is easy
‡ Present address: Division of Chemistry and Biological Chemistry,
School of Physical and Mathematical Sciences, Nanyang Technological
University, Singapore 637371, Singapore.
to achieve. The conventional nickel- or palladium-catalyzed
cross-coupling reactions via CꢀF bond activation4,5 of poly-
fluoroarenes displace more than one CꢀF bond6 or they are
limited in substrate scope,7,8 respectively. The difficulty arises
from (1) robustness of the CꢀF bond to undergo oxidative
addition,9 (2) slow reductive elimination with highly electron-
deficient substrates,10 and (3) “ring walking” in the product/
catalyst complex caused by strong back-donation from a
transition metal that inhibits smooth catalyst turnover,
making it difficult to activate only one CꢀF bond in a poly-
fluoroarene (particularly problematic in nickel catalysis).11
To achieve the difficult monosubstitution of a CꢀF bond
€
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r
10.1021/ol301195x
Published on Web 06/12/2012
2012 American Chemical Society

under widely used nickel catalysis,5,12 we have designed a
new diphosphine ligand (POP) that possesses two phos-
phine units and an alkoxide group. We report herein a
nickel/POP-catalyzed selective monosubstitution reaction
of polyfluoroarenes with aryl- and alkylzinc reagents.
We previously reported that installation of an alkoxide
group in a phosphine ligand (PO) greatly enhances the
efficiency of the CꢀF bond activation reaction of a
polyfluoroarene.13 We have also demonstrated that the
alkoxide unit of the PO ligand coordinates to both nickel
and magnesium and activates the CꢀF bond through
pushꢀpull mechanism. The catalytic system exhibited high
efficiency toward CꢀF bond activation when mono- or
polyfluoroarene was used as a substrate, which resulted in
substitution of many CꢀF bonds due to the problematic
“ring walking”.14,15 We considered that destabilization of
the product/catalyst complex C through stabilization of a
nickel(0) intermediate D should promote the product
expulsion and hence promote the catalyst turnover in the
reaction between 1,3-difluorobenzene (1) and a phenylzinc
reagent (Scheme 1). We hence added an additional diphe-
nylphosphino group to make a new tridentate ligand POP
so that the nickel(0) species D can be stabilized. The POP
ligand is expected to place the alkoxide group at an apical
position of the nickel center and capture both the nickel
and zinc (or magnesium) atoms to accelerate the CꢀF
bond cleavage in a pushꢀpull manner (A). The following
transmetalation and reductive elimination would lead to
the formation of a nickel/product complex B that gives
monosubstituted product 2 upon product expulsion,
whereas the ring walking would form complex C, a com-
plex that gives disubstituted side product 3.
Scheme 1. Typical Example and a Mechanistic Rationale
To investigate the efficiency of the POP ligand for the
selective monosubstitution reaction, several reactions were
carried out using 1 as a substrate (Table 1). In the reaction
with 2.1 equiv of PhMgBr in the presence of 1 mol % of
Ni(acac)2 and PO ligand in diethyl ether, the PO ligand
was converted in situ to its magnesium salt (PO-Mg)13a
and quickly underwent nickel-catalyzed displacement of
both of the fluorine atoms in 1 to give 3 exclusively
(Table 1, entry 1). The reaction did not afford the mono-
substitution product because of quick ring walking in the
product complex.11 The use of a diarylzinc reagent
(prepared from ArMgBr and ZnCl2 TMEDA; Ar =
2-MeOC6H4) in THF at ambient temperature resulted in
low conversion (entry 2).
3
Addition of Ph3P (1.0 equiv) to 1.0 equiv of PO did not
changetheselectivity (entry3). Bycontrast, the useofPOP
in the reaction of 1 with PhMgBr (2.0 equiv) increased the
selectivity toward 2 to give 2 and 3 in a 3:2 ratio (entry 4)
and the use of the Grignard-derived diarylzinc greatly
increased the selectivity to give 2 and 3 in 73 and 10%
yields, respectively (entry 5). When 1.3 equiv16 of the
organometallicreagent wasused, the yield decreased, while
the selectivity remained the same (2: 54% yield, 3: 6%
yield). Interestingly, the use of diphenylzinc led to higher
selectivity; however, the conversion was low (entry 6).
Moreover, the organozinc reagent prepared from PhLi
or Ph2Zn gave no desired product (entries 7 and 8), and 1
was largely recovered. When MgBr2 was added to the
reaction with Ph2Zn and TMEDA, 2 was obtained in trace
amounts (4%, data not shown). The necessary presence of
both magnesium and zinc to achieve high reactivity and
high selectivity suggests cooperation of nickel, zinc, and
magnesium,17,18 thus making the picture in Scheme 1 too
simplistic.
A preligand, protonated POP was synthesized in 90%
yield by coupling a commercially available 2-(diphenyl-
phosphino)benzaldehyde with 2-(diphenylphosphino)-
phenyllithium prepared from the corresponding bromide,
which is also commercially available.
(11) (a) Yoshikai, N.; Matsuda, H.; Nakamura, E. J. Am. Chem. Soc.
2008, 130, 15258–15259. (b) Strawser, D.; Karton, A.; Zenkina, O. V.;
Iron, M. A.; Shimon, L. J. W.; Martin, J. M. L.; van der Boom, M. E.
J. Am. Chem. Soc. 2005, 127, 9322–9323. (c) Iverson, C. N.; Lachicotte,
€
R. J.; Muller, C.; Jones, W. D. Organometallics 2002, 21, 5320–5333. (d)
ꢀ
Carbo, J. J.; Eisenstein, O.; Higgitt, C. L.; Klahn, A. H.; Maseras, F.;
Oelckers, B.; Perutz, R. N. J. Chem. Soc., Dalton Trans. 2001, 1452–
€
€
1461. (e) Bach, I.; Porschke, K.-R.; Goddard, R.; Kopiske, C.; Kruger,
C.; Rufınska, A.; Seevogel, K. Organometallics 1996, 15, 4959–4966.
´
€
€
(12) (a) Bohm, V. P. W.; Grotmayr, C. W. K.; Weskamp, T.;
Herrmann, W. A. Angew. Chem., Int. Ed. 2001, 40, 3387–3389. (b)
Ackermann, L.; Born, R.; Spatz, J. H.; Meyer, D. Angew. Chem., Int. Ed.
2005, 44, 7216–7219. (c) Mongin, F.; Mojovic, L.; Giullamet, B.;
ꢀ
ꢀ
Trecourt, F.; Queguiner, G. J. Org. Chem. 2002, 67, 8991–8994. (d)
Dankwardt, J. E. J. Organomet. Chem. 2005, 690, 932–938. (e) Inamoto,
K.; Kuroda, J.; Sakamoto, T.; Hiroya, K. Synthesis 2007, 18, 2853–2861.
(f) Schaub, T.; Fischer, P.; Steffen, A.; Braun, T.; Radius, U.; Mix, A.
J. Am. Chem. Soc. 2008, 130, 9304–9317. (g) Ackermann, L.; Wechsler,
C.; Kapdi, A.; Althammer, A. Synlett 2010, 2, 294–298.
Many other mono- and diphosphine ligands were found
to be inferior to POP. For instance, the diphosphine ligand
DPEphos, in which two 2-(diphenylphosphino)phenyl
(13) (a) Yoshikai, N.; Mashima, H.; Nakamura, E. J. Am. Chem. Soc.
2005, 127, 17978–17979. (b) Yoshikai, N.; Matsuda, H.; Nakamura, E.
J. Am. Chem. Soc. 2009, 131, 9590–9599.
(14) “Ring-walking” may be caused by a catalyst/ligand complex of
bent geometry with a high π-donor character. See: (a) Yoshikai,
N.; Nakamura, E. Chem. Rev. 2012, 112, 2339–2372. (b) Mori, S.;
Nakamura, E. THEOCHEM 1999, 461ꢀ462, 167–175.
(16) A small fraction of the organometallic reagent is used for
deprotonation of POP-H and also for the reduction of Ni(II).
(17) Jin, L.; Liu, C.; Liu, J.; Hu, F.; Lan, Y.; Batsanov, A. S.;
Howard, J. A. K.; Marder, T. B.; Lei, A. J. Am. Chem. Soc. 2009, 131,
16656–16657.
(15) Zenkina, O. V.; Karton, A.; Freeman, D.; Shimon, L. J. W.;
Martin, J. M. L.; van der Boom, M. E. Inorg. Chem. 2008, 47, 5114–5121.
Org. Lett., Vol. 14, No. 13, 2012
3317

Table 1. Effect of the Ligand and of the Organometallic Reagent
on the Nickel-Catalyzed Phenylation of 1,3-Difluorobenzene 1a
Table 2. Ni/POP-Catalyzed Monofunctionalization of Poly-
fluoroarenes with Organozinc Reagentsa
entry
ligandb
organometallic reagent
2c (%)
3c (%)
1d
2
PO
PhMgBr
0
3
92
2
PO
ZnCl2 TMEDA/2ArMgBr
3
3e
4
PO/PPh3
POP
ZnCl2 TMEDA/2ArMgBr
0
8
3
PhMgBr
27
73
34
0
17
10
2
5
POP
ZnCl2 TMEDA/2ArMgBr
3
6
POP
ZnCl2 TMEDA/2PhMgBr
3
7
POP
ZnCl2 TMEDA/2PhLi
0
3
8
POP
Ph2Zn/TMEDA
0
0
9
DPEphos
dppe
ZnCl2 TMEDA/2ArMgBr
4
0
3
10
11
12
13
ZnCI2 TMEDA/2ArMgBr
1
0
3
dppp
ZnCl2 TMEDA/2ArMgBr
14
8
0
3
dppb
ZnCl2 TMEDA/2ArMgBr
<1
0
3
XPhos
ZnCl TMEDA/2ArMgBr
<1
3
a Reaction conditions: 1,3-difluorobenzene (1, 0.30 mmol) was re-
acted with diarylzinc reagent (2.0 equiv) prepared from 2-MeOC6-
H4MgBr (4.0 equiv) and ZnCl2 TMEDA (2.0 equiv) unless otherwise
3
noted in the presence of 5 mol % of Ni(acac)2 and 5 mol % of ligand
in THF for 3 h. See the Supporting Information for details. b PO =
alkoxyphosphine (or 1-(2-(diphenylphosphino)phenyl)ethanolate);
DPEphos =2,20-bis(diphenylphosphino)diphenyl ether; dppe =1,2-bis-
(diphenylphosphino)ethane; dppp =1,3-bis(diphenylphosphino)propane;
dppb =1,4-bis(diphenylphosphino)butane; XPhos =2-dicyclohexylpho-
sphine-20,40,60-triisopropylbiphenyl. c Yields were determined by gas chro-
matography (GC) using n-tridecane as an internal standard. d Reaction
was carried out with 1 mol % each of Ni(acac)2 and PO with PhMgBr
(2.1 equiv) at ambient temperature for 2 h. e PO and Ph3P (5 mol % each)
were added as ligands.
groups are connected by an ether bridge instead of the
CH2O group as in POP, was entirely ineffective (entry 9),
and the diphosphine ligands used in the literature in a
related context (entries 10ꢀ12) uniformly performed
poorly. Sterically hindered XPhos, which is known to be
useful for chloride displacement, was entirely ineffective
(entry 13).
a Reactions were performed on a 0.30ꢀ0.50 mmol scale. Substrates
were reacted with the diorganozinc reagent (2.0 equiv) in the presence of
5 mol % each of Ni(acac)2 and POP ligand in THF at rt (80 °C for
alkylzinc reagent) for 3 h. See the Supporting Information for details.
The selective monofunctionalization of various poly-
fluoroarenes in the presence of the nickel/POP was
investigated using the optimized conditions (Table 2).
1,2-Difluorobenzene was monoarylated with complete se-
lectivity, and 1,3- and 1,4-difluorobenzene also gave the
monoarylated product with good selectivity (entries 1ꢀ3).
The alkylation of 1,2- and 1,3-difluorobenzene with
n-octylzinc reagent also proceeded selectively to give the
corresponding monoalkylated products (entries 4 and 5).
1,3,5-Trifluorobenzene reacted with excellent selectivity to
give the monoarylated product in 58% yield, together with a
trace amount (4%) of diarylated product (entry 6), while a
triarylation reaction took place as a major pathway when
PO was used.13 1,2,3-Trifluorobenzene, 1,2,3,4-tetrafluoro-
benzene, and pentafluorobenzene reacted selectively on the
1-fluoro carbon rather than on the internal CꢀF bond
(entries 7ꢀ9).19
b Prepared in situ from ZnCl2 TMEDA and 2RMgBr. c Isolated yields.
3
Yields in parentheses are those of the corresponding diarylated or
dialkylated byproducts, and were estimated by GC using n-tridecane
as an internal standard. d Yields were determined by 19F NMR using R,
R,R-trifluorotoluene as an internal standard. e Reaction was carried out
at 70 °C for 1 h.
Hexafluorobenzene is a challenging substrate, and to the
best of our knowledge there has been only one report on
tantalum-catalyzed benzylation of this substrate.20 POP
effected this transformation in 52% yield with high selec-
tivity for monoarylation (entry 10).
The reaction also allows the coupling of a variety of
fluoroaromatics with aryl- and alkylzinc reagents, β-hy-
drogen-possessing alkylzinc reagents, and functionalized
alkyl reagents (Table 3). Arylzinc reagents bearing an
ortho-substituent smoothly took part in the coupling reac-
tion (entries 1, 2, 8, 10, and 12). Both dimethylzinc (entry 4)8
and dialkylzinc reagents possessing a β-hydrogen (entries 5,
(18) (a) Norinder, J.; Matsumoto, A.; Yoshikai, N.; Nakamura, E.
J. Am. Chem. Soc. 2008, 130, 5858–5859. (b) Yoshikai, N.; Matsumoto,
A.; Norinder, J.; Nakamura, E. Angew. Chem., Int. Ed. 2009, 48, 2925–
2928. (c) Yoshikai, N.; Matsumoto, A.; Norinder, J.; Nakamura, E.
Synlett 2010, 313–316.
(20) Guo, H.; Kong, F.; Kanno, K.; He, J.; Nakajima, K.; Takahashi,
T. Organometallics 2006, 25, 2045–2048.
(19) Aizenberg, M.; Milstein, D. Science 1994, 265, 359–361.
3318
Org. Lett., Vol. 14, No. 13, 2012

may inhibit the undesired β-hydride elimination, to induce
the smooth reaction of these alkylzinc reagents. A benzy-
loxy group remained intact during the reaction (entry 13).
An aryl fluoride possessing an electron-donating group
(entries 8 and 9) and naphthyl fluoride (entries 12 and 13)
reacted smoothly. 2-Fluoropyridine reacted well with o-
anisylzinc (entry 10) and also with n-octylzinc (entry 11).
The POP ligand was also effective for the reaction of aryl
iodides, bromides, and chlorides (data not shown).
Table 3. Ni/POP-Catalyzed Cross-Coupling of Aryl Fluorides
with Organozinc Reagentsa
In summary, we have developed a new ligand, POP, for
nickel catalysis that has provided a highly efficient system
for the CꢀF bond arylation and alkylation of mono- to
polyfluoroarenes. A selective CꢀF monofunctionalization
reaction was achieved for polyfluoroarenes, where product
expulsion was promoted when POP was used as a ligand.
This tripodal, tridentate ligand differs from the popular
tridentate pincer ligands21 for its noncoplanarity of the
three coordinating groups relative to the main skeleton of
the ligand. The two phosphine groups stabilize the nickel-
(0) complexand accelerate the product expulsion attheend
of the catalytic cycle, thus suppressing multisubstitution of
polyfluoroarenes caused by ring walking. The alkoxide
coordinating group is located in the apical position of the
nickel(II) intermediate and captures a Lewis acidic metal
to accelerate the CꢀF bond cleavage. We consider that the
present strategy to preserve fluorine atoms in the cross-
coupling product provides a valuable new methodology
for the chemistry of fluorous compounds.
Acknowledgment. We thank MEXT for financial sup-
port (KAKENHI Specially Promoted Research No.
22000008 to E.N., and Grant-in-Aid for Young Scientists
(B) No. 23750100 to L.I.). Y.N. thanks the Japan Society
for the Promotion of Science for the Research Fellowship
for Young Scientists (21 8591). We thank Sobi Asako for
3
a Reactions were performed on a 0.50ꢀ1.0 mmol scale. Substrates
were reacted with the diphenylzinc reagent (1.3ꢀ1.8 equiv, unless
otherwise noted) in the presence of 5ꢀ10 mol % each of Ni(acac)2 and
POP ligand in THF at 60ꢀ80 °C. See the Supporting Information for
helpful mechanistic discussions.
details. b Prepared in situ from ZnCl2 TMEDA and 2RMgBr. c Isolated
Supporting Information Available. Experimental pro-
cedures and physical properties of the compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
3
yield exceptfor entries 1 and 4ꢀ7 (GC yield based on n-tridecane internal
standard). d Product ratio: i/n = 51:49.
6, 7, 9, 11, and 13) reacted well. The reaction of i-Pr2Zn
gave the coupling products with an i-Pr/n-Pr ratio of 1:1, in
contrast to the 1:7 ratio reported in a previous nickel
catalysis (entry 7).5a We speculate that the hydroxy group
in the POP ligand placed at the apical position of nickel
ꢀ
(21) Reviews on metal pincer complexes: (a) Selander, N.; Szabo,
K. J. Chem. Rev. 2011, 111, 2048–2076. (b) van der Boom, M. E.;
Milstein, D. Chem. Rev. 2003, 103, 1759–1792.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
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