Polyfluorinated phosphine ligands in the room temperature Suzuki cross-coupling reactions

Article abstract of DOI:10.1016/j.tetlet.2007.09.016

Polyfluorinated phosphine ligands can be obtained by regioselective nucleophilic aromatic substitution on tetrafluoronaphthalene derivatives. The ligand efficiency has been demonstrated in the room temperature Suzuki coupling reactions of aryl bromides an

Full text of DOI:10.1016/j.tetlet.2007.09.016

Tetrahedron Letters 48 (2007) 8048–8051
Polyfluorinated phosphine ligands in the room temperature
Suzuki cross-coupling reactions
Shahla Yekta, Lawrence Cheung and Andrei K. Yudin*
Davenport Research Laboratories, Department of Chemistry, University of Toronto 80 St. George Street,
Toronto, Ontario, Canada M5S 3H6
Received 22 July 2007; revised 31 August 2007; accepted 4 September 2007
Available online 8 September 2007
Abstract—Polyfluorinated phosphine ligands can be obtained by regioselective nucleophilic aromatic substitution on tetrafluoro-
naphthalene derivatives. The ligand efficiency has been demonstrated in the room temperature Suzuki coupling reactions of aryl
bromides and aryl boronic acids. The described process allows access to a new class of highly versatile fluorinated phosphine ligands.
Ó 2007 Elsevier Ltd. All rights reserved.
The development of new ligands for transition metal
catalysis is of ever growing importance in a field search-
ing for cheaper, faster and environmentally friendlier
methods of making new molecules. A plethora of phos-
phine ligands have been designed to aid metal-catalyzed
cross-coupling reactions that form carbon–carbon as
well as carbon-heteroatom bonds.1 The most commonly
used phosphine ligands are triaryl substituted as they are
readily available and do not require inert atmosphere
for storage. Fluorinated ligands, and in particular fluo-
rinated phosphine ligands have found applications in
catalysis as fluorine substitution does not affect the steric
properties of a ligand, however, greatly modifies its elec-
tronic characteristics.2,3 Fluorine substituents have also
been shown to participate in hydrogen bonding with
neighbouring atoms.4
F
F
F
R2P
OMe
1
2
R = Cyclohexyl
R = Phenyl
Figure 1. Polyfluorinated phosphine ligands.
F
F
F
F
F
F
Ph2PH, nBuLi, THF
OMe
Ph2P
OMe
-78 ºC, 5 h
80%
F
3
2
Scheme 1.
Here, we describe the synthesis of polyfluorinated phos-
phine ligands (Fig. 1) and their application in the room
temperature Suzuki reaction of aryl bromides and boro-
nic acids. Ligands 1 and 2 are air-stable and can be
stored on the bench. We previously showed that a vari-
ety of oxygen and carbon nucleophiles regioselectively
displace fluorine at the 7-position of the 2-alkoxy substi-
tuted tetrafluorinated naphthalene rings.5 Using
lithiated phosphine nucleophiles, the ligands can be pre-
pared from the corresponding tetrafluoronaphthalene 3
(Scheme 1).
While ligand 2 can be directly synthesized from lithium
diphenylphosphide at ꢀ78 °C, dicyclohexylphosphine
needed to be protected following Grubbs’ procedure
prior to deprotonation with base.6 The metallated phos-
phine species was generated at ꢀ78 °C and then allowed
to react with 3. Since no product was observed after a few
hours at room temperature, the reaction was heated to
reflux and stirred for 16 h to give the desired product 4
in 60% yield. Unlike nucleophilic aromatic substitutions
with carbon and oxygen nucleophiles that generally
result in a mixture of 6- and 7-substituted prod-
ucts, which are often difficult to separate by flash
column chromatography, only one product, the 7-substi-
tuted phosphine was formed in this case. Phosphine
*
Corresponding author. Tel.: +1 416 946 5042; fax: +1 416 946
7676; e-mail: ayudin@chem.utoronto.ca
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.016

S. Yekta et al. / Tetrahedron Letters 48 (2007) 8048–8051
8049
Table 1. s-Character on the phosphorous lone pair
F
F
F
Cy2PH·BH3, nBuLi
-78 ºC to reflux
60%
BH3
F
F
F
Se
P
Cy2P
OMe
OMe
F
4
R
R1
3
R
morpholine
100 ºC, 3 h
quant.
Entry
1
R
R1
Ph
1J(31P–77Se)
Ph
732
743
F
2
Ph
Ph
F
S
Cy2P
OMe
F
3
754
756
1
O
Scheme 2.
F
F
4
5
6
7
Ph
OMe
deprotection occurs in the presence of morpholine at
F
110 °C (Scheme 2).
In order to determine the nucleophilicity of the phos-
phine ligands, selenium coupling constants were
obtained and compared with the literature results as well
as with other structurally related phosphine ligands
(Table 1). To our surprise, fluorinated phosphine ligand
1 is very similar in nucleophilicity to the commercially
available dicyclohexylphosphino-1,10-biphenyl (Table 1,
entries 5 and 6). The ligand 2 (R = Ph, entry 4)
exhibited a much higher value, close to diphenylthienyl
and diphenylfuryl phosphines (Table 1, entries 2 and 3).
tBu
703
PdCl2(BnCN)2 was solved using X-ray diffraction and
is shown in Figure 2. The complex has a trans, square
planar geometry with a centre of inversion about the
Pd atom in which the fluorinated aryl group of the
ligand points away from the crowded palladium centre.
The X-ray structure of 1 reveals a hydrogen bond
between the fluorine on C10 and a hydrogen of the
cyclohexyl group on phosphorous.
Interaction between the phosphorous centre of ligand 1
and Pd(OAc)2 is revealed by considering 19F and 31P
NMR shifts of the corresponding peaks.7,8 19F NMR
of the same solution after 10 h showed unaltered reso-
nances, confirming that palladium does not insert into
CAF bonds of the ligand, as has been shown possible
with some fluorinated ligands.9 The structure of a com-
plex obtained from a 1:1 mixture of ligand with
Figure 2. X-ray structure of 1 and PdCl2(BnCN)2 complex.

8050
S. Yekta et al. / Tetrahedron Letters 48 (2007) 8048–8051
Table 2. Application of polyfluorinated ligands in Suzuki-type
reactions
We opted to apply the ligand in the palladium-catalyzed
Suzuki couplings of aryl bromides and aryl boronic
acids. The reactions were found to occur at room
temperature and products were obtained in good yields
(Table 2). A GC conversion/time study shows that while
1/Pd(OAc)2 catalyzed the coupling of 4-tert-butylphenyl
bromide and phenyl boronic acid at room temperature
in 3 h, the catalyst system based on commercially avail-
able dicyclohexylphosphino-1,10-biphenyl [ligand 5,
with a similar 1J(31P–77Se)] required heating up to
80 °C for complete conversion of the starting material
(Table 2, entries 1–3).10
Ar–X þ PhBðOHÞ2 PdðOAcÞ =ligand ð1:2Þ Ph–Ar
2
ƒƒƒƒƒƒƒƒ!
K3PO4; toluene
Entry Ar–X
Time Temperature Yielda Ligand
(h)
(°C)
(%)
But
Br
Br
Br
1
3
rt
85
1
5
5
50c
88
But
But
2
3
3
5
rt
110
When smaller amounts of Pd were used, heating was
required for the reaction to go to full conversion (entry
8). Heating (50 °C) was also required for the substrates
with ortho-substituents (entries 4, 6 and 7). 2-Bromo-
thiophene reacted with phenylboronic acid at room
temperature to give the desired biaryl in excellent yield
(entry 5). When the diphenylphosphine ligand 2 was
used in the Suzuki coupling of 4-tert-butylphenyl
bromide and phenyl boronic acid, 8% conversion was
observed at room temperature after 24 h (entry 9). This
result is not surprising considering the high 1J(31P–77Se)
coupling constant of 2, as well as the need for the right
balance of electron-rich phosphines with steric hin-
drance to facilitate oxidative addition and reductive
elimination.11 Unfortunately, aryl chlorides and phenyl
boronic acid gave low conversions even at high temper-
atures (entry 10).
Me
Me
4
12
50
79
1
Me
S
Br
5
6
5
5
rt
91
78
1
1
Br
Me
50
Br
OMe
Br
7
5
50
82
1
80b
8c
1
2
1
But
But
F3C
Br
Br
8
9
8
8
50
rt
We have also demonstrated that ligand 2 can catalyze
the Suzuki cross-coupling of naphthyl bromides and
naphthyl boronic acids (Table 3). In this case, heating
to 80 °C was required and although coupling of com-
pounds with ortho-substituents was possible, full conver-
sion was not achieved. When both coupling partners
had ortho-substituents, no reaction occurred even at ele-
vated temperatures (100 °C).
10
12
80
27d
Cl
a Typical reaction condition used 5 mol % Pd(OAc)2.
b 1 mol % Pd(OAc)2 was used.
c Conversion.
d 2 mol % Pd(OAc)2 was used.
Table 3. Scope of ligand 2 in the Suzuki coupling of naphthyl bromidesa
Ar1X
PdðOAcÞ2=2 ð1:2Þ
þ Ar2BðOHÞ2
Ar1–Ar2
ƒƒƒƒƒƒƒƒ!
X ¼ OTf; Br
K3PO4; toluene
80 ꢁC; 24 h
Entry
Ar1X
Ar2B(OH)2
Product
Me
Conv. (%)
Yield (%)
Me
1
100
60
Br
Br
B(OH)2
Me
Me
2
83
51
Me
B(OH)2

S. Yekta et al. / Tetrahedron Letters 48 (2007) 8048–8051
8051
Table 3 (continued)
Entry
Ar1X
Ar2B(OH)2
Product
Conv. (%)
64
Yield (%)
F
F
F
F
3
50b
F
F
OMe
F
F
OMe
B(OH)2
Br
F
F
F
F
F
F
4
69
55
OMe
B(OH)2
F
F
OMe
OTf
a Reaction conditions: 5 mol % Pd(OAc)2/10 mol % ligand, 1 equiv Ar1Br, 1.5 equiv Ar2B(OH)2, 2 equiv K3PO4.
b GC yield (product was not separable from starting aryl bromide by flash chromatography).
Tetrahedron 1997, 53, 14437–14450; For bulky electron-
rich phosphine ligands see: (f) Grushin, V. V.; Alper, H.
Top. Organomet. Chem. 1999, 3, 193, and references
therein; (g) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed.
2002, 41, 4176, and references therein.
In conclusion, we have shown that the steric and
electronic balance at the phosphorous centre of polyflu-
orinated phosphine ligands allows for room tempera-
ture palladium-catalyzed cross-coupling reaction of
aryl bromides and aryl boronic acids. These fluorinated
ligands are readily accessible and can be synthesized on
a gram scale. The versatility of the synthetic methodol-
ogy allows access to a series of ligands with different
substituents having a variety of substitution patterns.
2. Bayardon, J.; Cavazzini, M.; Maillard, D.; Pozzi, G.;
Quici, S.; Sinou, D. Tetrahedron: Asymmetry 2003, 14,
2215–2224.
3. For a review on fluorine chemistry see: Dolbier, W. R., Jr.
J. Fluorine Chem. 2005, 126, 157–163.
4. For examples see: (a) Silva, M. R.; Paixao, J. A.; Beja, A.
˜
M.; da Veiga, L. A. J. Fluorine Chem. 2007, 113, 7–12; (b)
Kundig, E. P.; Saudan, C. M.; Bernardinelli, G. Angew.
Chem., Int. Ed. 1999, 38, 1219–1223.
¨
Acknowledgements
5. Chen, Y.; Yekta, S.; Martyn, L. J. P.; Zheng, J.; Yudin,
A. K. Org. Lett. 2000, 2, 3433–3436.
6. Mohr, B.; Lynn, D. M.; Grubbs, R. H. Organometallics
1996, 15, 4317–4325.
We thank NSERC, CFI, ORDCF, and Amgen for
financial support. We also thank Dr. A. Lough for X-
ray structure analysis.
7. A 2:1 mixture of ligand/Pd(OAc)2 was prepared in CDCl3.
8. Phosphorous NMR shifts correspond to reported litera-
ture values: (a) Power, W. P. J. Am. Chem. Soc. 1995, 117,
1800–1806; (b) Grim, S. O.; Keiter, R. L. Inorg. Chim.
Acta 1970, 4, 56–60. Also, see experimental section.
9. Kiplinger, J. L.; Richmond, T. G.; Osterberg, C. E. Chem.
Rev. 1994, 94, 373–431.
10. Less than 10% conversion is achieved in the absence of any
ligand.
11. Hartwig, J. F.; Richards, S.; Baranano, D.; Paul, F. J. Am.
Chem. Soc. 1996, 118, 3626–3633.
References and notes
1. For selected references see: (a) De Meijere, A.; Diederich,
F. Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.;
Wiley-VCH: Weinheim, 2004; (b) Grushin, V. V.; Alper,
H. Chem. Rev. 1994, 94, 1047–1062; (c) Zhang, C.;
Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem.
1999, 64, 3804–3805; (d) Shen, W. Tetrahedron Lett. 1997,
38, 5575–5578; (e) Bumagin, N. A.; Bykov, V. V.