Suzuki-Miyaura cross-coupling reactions of potassium vinyltrifluoroborate with aryl and heteroaryl electrophiles

Article abstract of DOI:10.1021/jo0617013

We have previously reported that the palladium-catalyzed cross-coupling reaction of potassium vinyltrifluoroborate with aryl electrophiles proceeds with good yields. Herein, we describe recent progress in optimizing the reaction, as well as outlining the scope and limitations of the reaction. The cross-coupling reaction can generally be effected using 2 mol % of PdCl₂ and 6 mol % of PPh₃ as a catalyst system in THF/H₂O with Cs ₂CO₃ as a base. Moderate to good yields are obtained in the presence of a variety of functional groups.

Full text of DOI:10.1021/jo0617013

Suzuki-Miyaura Cross-Coupling Reactions of Potassium
Vinyltrifluoroborate with Aryl and Heteroaryl Electrophiles
Gary A. Molander* and Adam R. Brown
Roy and Diana Vagelos Laboratories, Department of Chemistry, UniVersity of PennsylVania, Philadelphia,
PennsylVania 19104-6323
gmolandr@sas.upenn.edu
ReceiVed August 16, 2006
We have previously reported that the palladium-catalyzed cross-coupling reaction of potassium
vinyltrifluoroborate with aryl electrophiles proceeds with good yields. Herein, we describe recent progress
in optimizing the reaction, as well as outlining the scope and limitations of the reaction. The cross-
coupling reaction can generally be effected using 2 mol % of PdCl2 and 6 mol % of PPh3 as a catalyst
system in THF/H2O with Cs2CO3 as a base. Moderate to good yields are obtained in the presence of a
variety of functional groups.
Introduction
Although the palladium-catalyzed Heck reaction of aryl halides
with ethylene provides access to substituted styrenes,5 the high
pressures required for the reaction and the tendency for further
reaction to give stilbenes make it undesirable.6 This problem
has prompted the development of organometallic vinylating
agents for use in transition-metal-mediated cross-coupling
reactions. These reactions generally involve vinylmagnesium,7
-tin,8 -silicon,9 or -boron10 compounds that couple with aryl
electrophiles to form the desired styrene product.
Substituted styrene starting materials have seen extensive use
in both specialty chemical and polymer syntheses. Not only can
styrenes be used in transformations such as olefin metathesis1
or Heck-type reactions2 but also the alkene can be employed
as a platform on which to introduce a variety of functionalities.3
In regard to polymer synthesis, a multitude of transformations
exist for polymerizing styrenes.4 The utility of such transforma-
tions has dramatically increased the demand for facile routes
to substituted styrenes.
Transition-metal-mediated cross-coupling reactions provide
efficient routes to functionalized styrenes that complement
traditional methods such as dehydration or Hoffman elimination,
both of which are incompatible with sensitive functional groups.
(5) Plevyak, J. E.; Heck, R. F. J. Org. Chem. 1978, 43, 2454-2456.
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122. (c) McKean, D. R.; Parrinello, G.; Renaldo, A. F.; Stille, J. K. J. Org.
Chem. 1987, 52, 422-424. (d) Shirakawa, E.; Yamasaki, K.; Tamerjiro,
H. Synthesis 1998, 1544-1549. (e) Krolski, M. E.; Renaldo, A. F.; Rudisill,
D. E.; Stille, J. K. J. Org. Chem. 1988, 53, 1170-1176.
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Denmark, S. E.; Wang, Z. Synthesis 2000, 999-1003. (c) Denmark, S. E.;
Wang, Z. J. Organomet. Chem. 2001, 624, 372-375. (d) Hatanaka, Y.;
Hiyama, T. J. Org. Chem. 1988, 53, 918-920. (e) Jeffrey, T. Tetrahedron
Lett. 1999, 40, 1673-1676.
(10) (a) Kerins, F. O.; O’Shea, D. F. J. Org. Chem. 2002, 67, 4968-
4971. (b) Peyroux, E.; Berthiol, F.; Doucet, H.; Santelli, M. Eur. J. Org.
Chem. 2004, 1075-1082. (c) Darses, S.; Michaud, G.; Genet, J.-P. Eur. J.
Org. Chem. 1999, 1875-1883. (d) Darses, S.; Michaud, G.; Genet, J.-P.
Tetrahedron Lett. 1998, 39, 5045-5048. (e) Stewart, S. K.; Whiting, A.
J. Organomet. Chem. 1994, 482, 293-300. (f) Lightfoot, A. P.; Twiddle,
S. J. R.; Whiting, A. Synlett 2005, 529-531. (g) Molander, G. A.; Rivero,
M. R. Org. Lett. 2002, 4, 107-109. (h) Grisorio, R.; Mastrorillo, C.
F. N.; Romanazzi, G.; Suranna, G. P. Tetrahedron Lett. 2005, 46, 2555-
2558.
(1) Grubbs, R. H. Tetrahedron 2004, 60, 7117-7140.
(2) (a) Heck, R. F. J. Am. Chem. Soc. 1968, 90, 5518-5526. (b) Braese,
S.; de Meijere, A. In Metal-Catalyzed Cross-Coupling Reactions; de Meijere,
A., Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004; pp 217-315. (c)
Beller, M.; Zapf, A.; Riermeier, T. H. In Transition Metals for Organic
Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim, 2004; pp
271-305.
(3) (a) Rodriguez, A. L.; Bunlaksananusorn, T.; Knochel, P. Org. Lett.
2000, 2, 3285-3287. (b) Ikeda, Y.; Nakamaru, T.; Yorimitsu, H.; Oshima,
K. J. Am. Chem. Soc. 2002, 124, 6514-6515. (c) Terao, J.; Saito, K.; Nii,
S.; Kambe, N.; Sonada, N. J. Am. Chem. Soc. 1998, 120, 11822-11823.
(d) Crudden, C. M.; Hleba, Y. B.; Chen, A. C. J. Am. Chem. Soc. 2004,
126, 9200-9201. (e) RajanBabu, T. V.; Nomura, N.; Jin, J.; Nandi, M.;
Park, H.; Sun, X. J. Org. Chem. 2003, 68, 8431-8446. (f) Agbossou, F.;
Carpentier, J.-F.; Mortreux, A. Chem. ReV. 1995, 95, 2485-2506.
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126, 6542-6543.
10.1021/jo0617013 CCC: $33.50 © 2006 American Chemical Society
Published on Web 12/01/2006
J. Org. Chem. 2006, 71, 9681-9686
9681

Molander and Brown
TABLE 1. Optimization of Conditions for Cross-Coupling Reaction
catalyst
loading
reaction
time (h)
isolated
yield
ratio
entry
catalyst system
solvent
molarity
base
5a/6aa
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
PdCl2(dppf)‚CH2Cl2
2 mol %
2 mol %
2 mol %
5 mol %
2 mol %
2 mol %
2 mol %
2 mol %
2 mol %
2 mol %
2 mol %
2 mol %
2 mol %
2 mol %
2 mol %
2 mol %
2 mol %
THF/H2O (9:1)
i-PrOH/H2O (9:1)
toluene/H2O (9:1)
THF/H2O (9:1)
THF/H2O (9:1)
THF/H2O (9:1)
THF/H2O (9:1)
THF/H2O (9:1)
THF/H2O (9:1)
THF/H2O (9:1)
THF/H2O (9:1)
THF/H2O (9:1)
THF/H2O (9:1)
THF/H2O (9:1)
THF/H2O (9:1)
THF/H2O (9:1)
THF/H2O (9:1)
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.5
0.5
0.5
0.5
0.5
0.5
0.5
Cs2CO3
NEt3
22
22
22
18
40
45
45
45
45
45
22
22
22
22
22
22
22
63
23
100:0
100:0
20:80
100:0
100:0
92:8
97:3
95:5
96:4
95:5
100:0
100:0
92:8
82:18
97:3
PdCl2(dppf)‚CH2Cl2
PdCl2(dppf)‚CH2Cl2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
PdCl2(dppf)‚CH2Cl2
30
62
78
72
69
70
72
72
68
67
62
67
Pd(PPh3)4
Pd(OAc)2 + 2 equiv of PPh3
Pd(OAc)2 + 3 equiv of PPh3
PdCl2(CN)2 + 2 equiv of PPh3
PdCl2(CN)2 + 3 equiv of PPh3
PdCl2 + 2 equiv of PPh3
PdCl2 + 3 equiv of PPh3
PdCl2 + 2 equiv of PPh3
PdCl2 + 3 equiv of PPh3
PdCl2 + 3 equiv of PPh3
PdCl2 + 3 equiv of PPh3
PdCl2 + 3 equiv of PPh3
PdCl2 + 3 equiv of PPh3
KHCO3
K2CO3
pyridine
NEt3
20:80
55:45
a Ratio of 5a/6a in isolated material by GC assay.
The use of vinyltributyltin in the palladium-catalyzed Stille
reaction is arguably the most developed of the cross-coupling
reactions to access substituted styrenes.8 Making use of fluoride
as an activator, conditions have been developed that successfully
couple even deactivated aryl chlorides with vinyltributyltin in
good yields.8a However, the use of vinyltributyltin also has
several drawbacks. Vinyltributyltin suffers from toxicity and
can be difficult to remove from the styrene product.10a In
addition, vinyltributyltin is quite expensive, and its use con-
tributes to a lack of atom economy.
The problems associated with the use of traditional orga-
noboron compounds can be solved with the use of potassium
organotrifluoroborate salts. These compounds can be readily
prepared via the addition of KHF2 to a variety of organoboron
intermediates.12 More specifically, potassium vinyltrifluorobo-
rate can be prepared in good yields on a large scale through the
addition of vinylmagnesium bromide to trimethyl borate fol-
lowed by treatment with inexpensive KHF2 (eq 1).10c
Vinyltrimethylsilanes9d,e and vinylpolysiloxanes9a-c have also
seen use in the palladium-catalyzed vinylation of aryl halides.
Using fluoride as an activating agent, vinyltrimethylsilanes can
be used in the vinylation of aryl iodides in good yields,9d,e and
vinylpolysiloxanes can be used in the vinylation of aryl bromides
and aryl iodides in good yields.9a-c
The use of potassium vinyltrifluoroborate in Suzuki-Miyaura
coupling reactions with arenediazonium salts to form styrenes
was first reported by Genet in 1998.10d Later, preliminary results
of Suzuki-Miyaura cross-coupling reactions between potassium
vinyltrifluoroborate and aryl bromides were reported by our
research group.10g Herein, we provide a full account of our
exploration of these reactions, including further optimization
of the reaction conditions and expansion of the reaction scope.
The palladium-catalyzed Suzuki-Miyaura reaction provides
another method for the vinylation of aryl halides. Organoboron
compounds such as dialkylboranes, boronic acids, and boronate
esters can generally be utilized for Suzuki-Miyaura cross-
coupling reactions. However, vinylboron analogues of such
organoboron compounds have notable limitations. For example,
vinylboronic acid readily polymerizes and cannot be isolated.11
However, this problem can be solved by converting the
vinylboronic acid into its anhydride form, the 2,4,6-trivinylcy-
clotriboroxane-pyridine complex, which can be used to generate
vinylboronic acid in situ for use in the coupling reaction.10a
Although this method furnishes the desired styrene product in
good yields, a 1:1 ratio of halide to the 2,4,6-trivinylcyclotri-
boroxane-pyridine complex is used, equating to three equiva-
lents of vinylating agent. Alternatively, vinyl boronate esters
have been shown to participate selectively in Suzuki-type
reactions with aryl halides to form styrenes.10f Unfortunately,
the diols used to make the boronate esters add considerable
expense to the process and also contribute to a lack of atom
economy.
Results and Discussion
Initially, we focused on optimization of the reaction conditions
of the cross-coupling reaction of potassium vinyltrifluoroborate
and p-bromoanisole. The cross-coupling conditions were opti-
mized using a variety of palladium sources [PdCl2(dppf)‚CH2-
Cl2, PdCl2, Pd(OAc)2, Pd(PPh3)4, PdCl2(CN)2], bases (Cs2CO3,
K2CO3, KHCO3, K3PO4, NEt3, pyridine), and solvent systems
(i-PrOH/H2O, THF/H2O, toluene/H2O). PPh3 was used as a
ligand for the Pd(II) sources (Table 1).
The reaction proceeded most effectively using 2 mol % of
PdCl2 and 6 mol % of PPh3 as a catalyst system in THF/H2O
(12) (a) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf,
M. R. J. Org. Chem. 1995, 60, 3020-3027. (b) Vedejs, E.; Fields, S. C.;
Hayashi, R.; Hitchcock, S. R.; Powell, D. R.; Schrimpf, M. R. J. Am. Chem.
Soc. 1999, 121, 2460-2470.
(11) Matteson, D. S. J. Am. Chem. Soc. 1960, 82, 4228-4233.
9682 J. Org. Chem., Vol. 71, No. 26, 2006

Suzuki-Miyaura Cross-Coupling Reactions
TABLE 2. Cross-Coupling of Electron-Deficient Bromides with
Potassium Vinyltrifluoroborate 1
TABLE 3. Cross-Coupling of Electron-Rich Bromides with
Potassium Vinyltrifluoroborate 1
a 8 mmol scale reaction.
a 7% o-bromotoluene was present. b RuPhos was used as a ligand.
(9:1) in the presence of 3 equiv of Cs2CO3 as a base to furnish
4-methoxystyrene in 72% yield (entry 11).
a number of substrates (Table 4). The increased rate of the
electron-deficient bromides in comparison to the electron-rich
bromides is presumably due to the fact that electron-deficient
bromides undergo oxidative addition more rapidly than electron-
rich bromides.
Through the investigation of functional group tolerance, we
found the optimized conditions to be quite general, affording
good yields of the desired products in almost all cases. A few
cases, however, required further ligand optimization. Following
the general procedure and using PPh3 as the ligand, entries 7
and 8 of Table 3 only afforded 35% and 40% conversion,
respectively, to the desired product by a gas chromatography
assay. This poor conversion was most likely due to the extremely
electron-rich nature of both bromides and the steric hindrance
of the mesityl bromide.13 Using the highly hindered mesityl
bromide, Buchwald’s SPhos, XPhos, and RuPhos ligands
(Figure 1) were screened (Table 5).14
Through the optimization process, it was observed that the
reaction was rather specific to the THF/H2O solvent system, as
it was the only system tested that offered satisfactory results.
In contrast, a number of catalyst systems tested provided
satisfactory results. Using 2 mol % of PdCl2(dppf)‚CH2Cl2 as
a catalyst system with the optimized solvent and base conditions
furnished the desired 4-methoxystyrene product in 63% yield,
and using 2 mol % of Pd(OAc)2 and 6 mol % of PPh3 as a
catalyst system with the optimized solvent and base conditions
furnished the desired 4-methoxystyrene in a 72% yield. The
PdCl2 system was chosen over the Pd(OAc)2 system because
of its lower price. With regard to the base, only Cs2CO3 and
K2CO3 provided acceptable results.
With the optimized conditions in hand, we explored the scope
of the cross-coupling reaction in the presence of a variety of
functional groups. As shown in Tables 2 and 3, the cross-
coupling reaction proceeds with good to excellent yields in the
presence of a large variety of functional groups including nitriles,
ketones, esters, aldehydes, alcohols, and nitro groups. Further-
more, both electron-deficient and electron-rich bromides react
with the vinyltrifluoroborate to yield the desired products in
good yields; however, the rate of reaction of the electron-
deficient bromides is higher than that of the electron-rich
bromides. Although the reaction time for each bromide tested
was not optimized and the general protocol was to run the
reactions for 22 h, minimized reaction times were compiled for
In all three cases, nearly all of the mesityl bromide was
consumed. Although the reaction employing RuPhos gave
almost entirely the desired product, the reactions employing
SPhos and XPhos gave significant amounts of both the desired
product and the Heck product resulting from the reaction of
the Suzuki-Miyaura coupling product with the mesityl bromide.
(13) Carter, R. R.; Wyatt, J. K. Tetrahedron Lett. 2006, 47, 6091-6094.
(14) (a) Milne, J. E.; Buchwald, S. L. J. Am. Chem. Soc. 2004, 126,
13028-13032. (b) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald,
S. L. J. Am. Chem. Soc. 2005, 127, 4685-4696.
J. Org. Chem, Vol. 71, No. 26, 2006 9683

Molander and Brown
TABLE 4. Minimized Reaction Times for Cross-Coupling of
Representative Aryl Bromides with Potassium Vinyltrifluoroborate 1
FIGURE 1. Buchwald ligands.
TABLE 6. Cross-Coupling of Ortho-, Meta-, and
Para-Functionalized Bromides with Potassium Vinyltrifluoroborate
1
TABLE 5. Ligand Screening for 2-Bromomesitylene
entry
ligand
ratio of 6g/7g/7ja
1
2
3
4
PPh3
3.5:6.5:0
0:3:1
0:1:1
SPhos
XPhos
RuPhos
1:20:1
a By GC assay.
No homocoupled product was observed in any case, most likely
due to the steric hindrance. Clearly, the RuPhos ligand was the
most desirable for the reaction and subsequently supplied the
desired product in good yields (entry 7, Table 3). The successful
coupling of the mesityl bromide prompted the use of RuPhos
in the coupling of the bromoaniline, which also yielded the
desired product in excellent yields (entry 8, Table 3).
At this point, the viability of the cross-coupling reaction was
tested on a larger scale. Although the general protocol was to
run the reaction on a 1 mmol scale, the cross-coupling reaction
of 4-bromoacetophenone and potassium vinyltrifluoroborate was
found to be comparable in utility on a gram scale, as an 8 mmol
reaction afforded the desired product in 79% yield.
Having demonstrated the utility of the cross-coupling reaction
conditions on a number of functional groups, mostly at the para
position, we chose to test the generality of the functional group
tolerance at the ortho and meta positions. As shown in Table 6,
the acetyl- and nitrile-substituted bromides were chosen as
a 8% 2′-bromoacetophenone was present.
representative electron-deficient bromides, and the methoxy-
substituted bromide was chosen as a representative electron-
rich bromide.
In all cases, the tolerance of the functional group was general
as the desired product was obtained in comparable yields at all
three positions for each functional group tested.
9684 J. Org. Chem., Vol. 71, No. 26, 2006

Suzuki-Miyaura Cross-Coupling Reactions
TABLE 7. Cross-Coupling of Heteroaryl Bromides with Potassium
Vinyltrifluoroborate 1
TABLE 8. Electrophile Compatibility
TABLE 9. Ligand Screening for Chloroacetophenone
entry
ligand
ratio of 2d/3a/3b/3ca
1
2
3
4
PPh3
1:0:0:0
SPhos
XPhos
RuPhos
0:20:4:3
0:27:8:3
0:17:4:1.5
a By GC assay.
reactivity of all three protecting groups indicates that the poor
results seen in the case of the unprotected indole were a result
of the N-H functionality and not the electron-rich nature of
the system (entries 9-11, Table 7).
With the generality of the coupling demonstrated in the
presence of diverse functionality, we focused our attention on
the scope of the leaving group. As outlined in Table 8, iodide,
triflate, bromide, and chloride were all tested as leaving groups.
Although the triflate, iodide, and bromide all afforded compa-
rable yields of the desired product, the chloride failed to produce
any of the desired product.
The poor conversion observed using the chloride (entry 4)
prompted the screening of alternative ligands for the coupling
reaction. In this case, again, Buchwald’s SPhos, XPhos, and
RuPhos were examined (Table 9).
Although all of the Buchwald ligands tested were far more
effective than PPh3, all three of these ligands yielded not only
the desired product but also two undesired byproducts. Byprod-
uct 3b is a result of homocoupling between two chloroacetophe-
none molecules, and byproduct 3c is a result of a Heck-type
reaction between the desired product and chloroacetophenone.
The screening process showed RuPhos as the most effective
a 2% THF and 8% 3-bromothiophene were present. b Contaminated by
unknown impurity.
We continued our investigation by exploring the reaction of
potassium vinyltrifluoroborate with heteroaryl bromides. A
variety of diverse heteroaryl bromides were reacted with
potassium vinyltrifluoroborate (Table 7).
As shown in Table 7, the cross-coupling reaction of potassium
vinyltrifluoroborate proceeds with a wide variety of heteroaryl
bromides to give the desired product in good yields. Although
the unprotected indole (entry 8) does not provide the desired
product in acceptable yields, simple Boc, tosylate, or benzyl
protection15 allows the cross-coupling reaction to proceed,
furnishing good yields of the desired product. The desirable
(15) (a) Prieto, M.; Zurita, E.; Rosa, E.; Munoz, L.; Loyd-Williams, P.;
Giralt, E. J. Org. Chem. 2004, 69, 6812-6820. (b) Evans, D. A.; Fandrick,
K. R.; Song, H.-J. J. Am. Chem. Soc. 2005, 127, 8942-8943.
J. Org. Chem, Vol. 71, No. 26, 2006 9685

Molander and Brown
ligand for the coupling reaction, and upon isolation, the desired
product was obtained in 65% yield (eq 2). The yield is
Experimental Section
General Procedure for Suzuki-Miyaura Cross-Coupling
Reactions. Preparation of 1-(4-Vinylphenyl)-ethanone (3a). A
solution of potassium vinyltrifluoroborate (134 mg, 1.00 mmol),
PdCl2 (3.5 mg, 0.02 mmol), PPh3 (16 mg, 0.06 mmol), Cs2CO3
(978 mg, 3.00 mmol), and 4′-bromoacetophenone (199 mg, 1.00
mmol) in THF/H2O (9:1) (2 mL) was heated at 85 °C under an N2
atmosphere in a sealed tube. The reaction mixture was stirred at
85 °C for 22 h, then cooled to room temperature and diluted with
H2O (3 mL) followed by extraction with CH2Cl2 (10 mL × 3).
The solvent was removed in vacuo, and the crude product was
purified by silica gel chromatography (eluting with 20:1 n-pentane/
ether) to yield 1-(4-vinylphenyl)-ethanone as a pale yellow solid
(123 mg, 0.848 mmol, 85%, mp 33-34 °C). The spectral data were
in accordance with those described in the literature.9a
significantly reduced due to the subsequent homocoupling and
Heck chemistry.
Although the cross-coupling proceeded readily with the
activated, electron-deficient chloroacetophenone, the conditions
utilizing RuPhos as the ligand were not general for deactivated,
electron-rich chlorides. Neither 4-chloroanisole nor 4-chloro-
toluene reached completion after 22 h at 85 °C.
Acknowledgment. The authors thank the NIH (GM35249),
Amgen, Merck Research Laboratories, and the Vagelos Program
in the Molecular Life Sciences for support. We thank Johnson
Matthey for the donation of catalysts and Prof. Stephen L.
Buchwald (MIT) for a donation of ligands.
Conclusions
The Suzuki-Miyaura cross-coupling reaction of aryl and
heteroaryl electrophiles with potassium vinyltrifluoroborate has
proven to be an efficient route for accessing functionalized
styrenes. The reaction proceeds readily in the presence of a wide
variety of functional groups and can be used with iodides,
bromides, chlorides, and triflates as electrophiles.
Supporting Information Available: Full experimental details
and copies of all NMR spectra (1H and 13C). This material is
available free of charge via the Internet at http://pubs.acs.org.
JO0617013
9686 J. Org. Chem., Vol. 71, No. 26, 2006