Vinylation of aryl bromides using an inexpensive vinylpolysiloxane

Article abstract of DOI:10.1021/ol052517r

(Chemical Equation Presented) A mild and general method for the palladium-catalyzed vinylation of aryl bromides has been developed. The use of tetrabutylammonium fluoride (TBAF) as the activator and an inexpensive and nontoxic vinyl donor, 1,3,5,7-tetramethyl-1,3,5,7-tetravinylcyclotetrasiloxane (D₄^V, 1), allows for a general and high-yielding preparation of substituted styrenes.

Full text of DOI:10.1021/ol052517r

ORGANIC
LETTERS
2
006
Vol. 8, No. 1
3-66
Vinylation of Aryl Bromides Using an
Inexpensive Vinylpolysiloxane
6
Scott E. Denmark* and Christopher R. Butler
Roger Adams Laboratory, Department of Chemistry, UniVersity of Illinois,
600 South Mathews AVenue, Urbana, Illinois 61801
denmark@scs.uiuc.edu
Received October 17, 2005
ABSTRACT
A mild and general method for the palladium-catalyzed vinylation of aryl bromides has been developed. The use of tetrabutylammonium
V
fluoride (TBAF) as the activator and an inexpensive and nontoxic vinyl donor, 1,3,5,7-tetramethyl-1,3,5,7-tetravinylcyclotetrasiloxane (D
allows for a general and high-yielding preparation of substituted styrenes.
4
, 1),
7
8
9
10
Substituted styrenes are important building blocks in fine
nesium-, boron-, silicon-, and tin-based vinyl donors that
can couple to a variety of aryl halides. However, these vinyl
donors also suffer from a number of drawbacks, including
1
2
chemical and polymer synthesis. In addition, the emergence
of important transformations over the last two decades such
3
4
11
12
as olefin metathesis, asymmetric hydrogenation, and het-
high reactivity, cost, or toxicity.
5
erocycle construction, along with dramatic advances in
Recent reports from these laboratories have demonstrated
the successful palladium-catalyzed vinylation of aryl and
vinyl iodides using inexpensive, readily available, nontoxic
polyvinylsiloxanes with tetrabutylammonium fluoride (TBAF)
as an activator (Scheme 1). Although a variety of poly-
vinysiloxanes served successfully as donors, it was shown
polymer chemistry, has driven the demand for mild and
efficient access to substituted styrenes. The classical prepara-
6
tions of styrenes involve either strongly basic dehydration
1
3
or Hoffman elimination conditions and are therefore incom-
patible with many functional groups. In contrast, the advent
of transition-metal-catalyzed, cross-coupling reactions which
take place under milder conditions has allowed the prepara-
tion of styrenes bearing sensitive functionality. These
methods include the vinylation of aryl halides using mag-
(7) Bumagin, N. A.; Luzikova, E. V. J. Organomet. Chem. 1997, 532,
2
71-273.
8) (a) Kerins, F.; O’Shea, D. F. J. Org. Chem. 2002, 67, 4968-4971.
b) Peyroux, E.; Berthiol, F.; Doucet, H.; Santelli, M. Eur. J. Org. Chem.
004, 1075-1082. (c) Darses, S.; Michaud, G.; Genet, J.-P. Eur. J. Org.
Chem. 1999, 1875-1883. (d) Stewart, S. K.; Whiting, A. J. Organomet.
Chem. 1994, 482, 293-300. (e) Lightfoot, A. P.; Twiddle, S. J. R.; Whiting,
A. Synlett 2005, 529-531. (f) Molander, G. A.; Rivero, M. R. Org. Lett.
2002, 4, 107-109.
(9) (a) Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 53, 918-920. (b)
Jeffery, T. Tetrahedron Lett. 1999, 40, 1673-1676.
(10) (a) Littke, A. F.; Schwarz, L.; Fu, G. C. J. Am. Chem. Soc. 2002,
124, 6343-6348. (b) Grasa, G. A.; Nolan, S. P. Org. Lett. 2001, 3, 119-
122. (c) McKean, D. R.; Parrinello, G.; Renaldo, A. F.; Stille, J. K. J. Org.
Chem. 1987, 52, 422-424.
(11) (a) 2,4,6-Trivinylcyclotriboroxane (Aldrich, catalog no. 637998):
$3851/mol. (b) Tributyl(vinyl)tin (Aldrich, catalog no. 271438): $3032/
mol.
(
(
2
(
1) (a) Agbossou, F.; Carpentier, J.-F.; Mortreux, A. Chem. ReV. 1995,
9
5, 2485-2506. (b) Crudden, C. M.; Hleba, Y. B.; Chen, A. C. J. Am.
Chem. Soc. 2004, 126, 9200-9201. (c) RajanBabu, T. V.; Nomura, N.;
Jin, J.; Nandi, M.; Park, H.; Sun, X. J. Org. Chem. 2003, 68, 8431-
8
446.
(2) (a) Modern Styrenic Polymers: Polystyrenes and Styrenic Copoly-
mers; Scheirs, J., Priddy, D. B., Eds.; John Wiley & Sons: Chichester,
UK, 2003. (b) Hirao, A.; Loykulnant, S.; Ishizone, T. Prog. Polym. Sci.
2
002, 27, 1399-1471. (c) Schellenberg, J.; Tomotsu, N. Prog. Polym. Sci.
2
002, 27, 1925-1982.
(3) (a) Grubbs, R. H. Tetrahedron 2004, 60, 7117-7140. (b) Handbook
of Metathesis; Grubbs, R. H., Ed.; John Wiley & Sons: Ltd.: Weinheim,
2
003.
(
4) Noyori, R.; Kitamura, M.; Ohkuma, T. Proc. Natl. Acad. Sci. U.S.A.
(12) National Institute of Occupational Health and Safety; Pub. No. 77-
115; U.S. Government Printing Office: Washington, 1976.
(13) (a) Denmark, S. E.; Wang, Z. Synthesis 2000, 999-1003. (b)
Denmark, S. E.; Wang, Z. J. Organomet. Chem. 2001, 621, 372-375.
2
004, 101, 5356-5362.
(
(
5) Dieters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199-2238.
6) Emerson, W. S. Chem. ReV. 1949, 49, 347-383.
1
0.1021/ol052517r CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/13/2005

Scheme 1. Vinylation of Aryl Iodides
Table 1. Survey of Catalysts and Ligands
that one of the most inexpensive agents, 1,3,5,7-tetramethyl-
V
14
1
,3,5,7-tetravinylcyclotetrasiloxane (D
4
, 1), was optimal.
is active for transfer
V
Each of the four vinyl groups in D
under the described conditions.
4
The application of this technology to include aryl bromides
would significantly broaden its utility. Aryl bromides present
numerous advantages over aryl iodides, including increased
stability, lower cost, and wider availability. The increased
stability, however, implies a decreased inherent reactivity,
and therefore requires more vigorous cross-coupling condi-
tions to engage this class of acceptors. Such modifications
usually involve ligands that aid in the oxidative addition of
palladium to the carbon-bromine bond. Herein, we report
a
Yield based on GC analysis relative to an internal standard. b Yield of
4
in parentheses. c Not determined.
the successful extension of the vinylation reaction using this
V
inexpensive reagent D
4
to include the less reactive but more
widely available aryl bromides.
hexylphosphino)biphenyl, 6, provided none of the product
entry 9). Increasing the temperature to 50 °C in the presence
of 5 provided complete reaction in 3 h with only a 5 mol %
loading of PdBr (entry 10). On the basis of these experi-
ments, we chose to use the air stable biphenyl-derived ligand
As point of entry, we chose 4-bromoacetophenone (2a), a
very active substrate, to establish the viability of the method.
We examined the role of solvents, palladium sources, and
ligands to elucidate the general reaction conditions with the
goal of high yields (>80% isolated) for a wide survey of
substrates. We hoped to achieve good reactivity (complete
reaction in less than 3-4 h) with this active substrate and
then apply these conditions to more difficult substrates.
(
2
5
5
as it afforded the product within the desired time frame at
0 °C.
Gratifyingly, these optimized conditions translated well
to the preparative scale (2 mmol), providing an 85% yield
of 4-vinylacetophenone (Table 2, entry 1). However, a brief
substrate survey performed under these conditions revealed
a surprising lack of generality. Although 2-bromonaphthalene
The optimal conditions developed from the vinylation of
aryl iodides (Pd(dba) , (5 mol %), TBAF (2.0 equiv), D
2 4
V
(0.3 equiv), THF, Scheme 1) afforded a suitable starting point
for our investigation. Employing these conditions provided
none of the desired styrene and returned only starting material
(
(
2b) afforded an 82% yield of the corresponding styrene
entry 2), extension to electron-rich bromides, such as
(Table 1, entry 1). Orienting experiments using allylpalla-
4
-bromoanisole (2c) or 2-bromotoluene (2d), afforded re-
dium chloride dimer (APC) led to competitive reduction of
the aryl bromide (entry 2). This unwanted process presum-
ably arises from the ability of ethereal solvents to act as
hydride donors. Alternate solvents suppressed the reduction
process but also did not provide any of the desired product
duced yields of the corresponding styrenes (entry 3 and 4).
Ultimately, it was found that the lower yields resulted from
15
Table 2. Initial Survey of Aryl Bromides
(entries 3 and 4). The use of phosphine or arsine ligands
also prevented reduction, but again without productive
coupling (entries 5 and 6). However, the use of 2-(di-tert-
butylphosphino)biphenyl (BPTBP, 5) as the ligand did
provide the desired product albeit rather slowly (entry 7).
a
Changing the palladium(II) source to PdBr
2
(10 mol %)
entry
R
series
yield, %
afforded complete conversion to the corresponding styrene
in 18 h at rt (entry 8). Surprisingly, the use of 2-(dicyclo-
1
2
3
4
4-COMe
2-naphthyl
4-OMe
a
b
c
85
82
32
b
(
14) 1,3,5,7-Tetramethyl-1,3,5,7-tetravinylcyclotetrasiloxane (Lancaster,
catalog no. 16645): $176/mol.
15) (a) Kabir-ud-Din; Plesch, P. H. J. Chem. Soc., Perkin Trans. 2 1978,
2-Me
d
(75)
a
Yields of chromatographically homogeneous material. b Conversion by
H NMR analysis relative to starting material.
(
1
9
37-938. (b) Melikyan, G. G.; Deravakian, A. J. Organomet. Chem. 1997,
5
44, 143-145.
64
Org. Lett., Vol. 8, No. 1, 2006

consumption of the products in a subsequent Heck reaction
with a second molecule of aryl bromide to afford the
corresponding stilbene.
Scheme 2. Phosphine Dependence
To suppress the formation of the stilbene byproduct, the
V
influence of temperature, D
4
and TBAF stoichiometry, were
examined (Table 3). Increasing the temperature, either in
THF (entry 2), dimethoxyethane (entry 3), or dioxane (entry
4
), left the styrene-to-stilbene ratio essentially unchanged.
V
However, increasing the loading of D
4
and TBAF and
raising the temperature concomitantly did show a marked
decrease in stilbene formation (entry 5). Further increase to
V
0.9 equiv of D
4
(3.6 vinyl groups) and 6.0 equiv of TBAF
eliminated the stilbene formation (entry 6). In an effort to
minimize cost, we lowered the TBAF loading to be equimo-
lar with the number of vinyl equiv used (entry 7). Although
the yield remained about the same, a small amount of stilbene
reemerged. Raising the amount of TBAF to 4.0 equiv was
sufficient to suppress stilbene formation and still deliver the
product in high yield (entry 8).
ratio of styrene to stilbene, although the reaction was
considerably slower (6 h, entry 1). Increasing the temperature
to 50 °C provided a shorter reaction time, but a decrease in
selectivity (entry 2). The use of a “pre-reduced” Pd(0) source
1
6
led to a significantly slower reaction (entry 3). As before,
Table 3. Stilbene Minimization
V
only an increase in the amount of D
to 0.5 equiv (1.6 and 2.0 vinyl groups, respectively, entries
and 5), satisfactorily eliminated the stilbene side product.
4
, first to 0.4 and further
4
The final conclusions of these optimizations are that (1) the
formation of stilbene could be nearly completely suppressed
vinyl, TBAF, yield,a
styrene/
stilbene
V
by increasing the level of D
4
and (2) the use of 2.0 equiv
b
entry T, °C
solvent
equiv
equiv
%
of 5 leads to faster reactions at lower temperature and also
1
2
3
4
5
6
7
8
50
70
85
100
70
70
THF
THF
DME
dioxane
THF
THF
THF
THF
1.2
1.2
1.2
1.2
2.4
3.5
3.6
3.6
2.0
2.0
2.0
2.0
4.0
6.0
3.6
4.0
32c
67
64
70
74
93
94
94
V
allows for the D
4
and TBAF stoichiometry to be kept to
5:1
5:1
6:1
synthetically practical levels.
27:1
>99:1
38:1
>99:1
Table 4. Optimization of D V
Loading
4
70
70
a
1
b
Yield based on H NMR analysis relative to an internal standard. Ratio
1
c
determined by H NMR spectroscopy, comparing relative integration. Yield
of chromatographically homogeneous material.
For the next phase in the optimization, we examined the
more conventional use of 2.0 equiv of phosphine ligand with
respect to palladium and were delighted to discover that a
second equivalent of phosphine allowed for a decrease in
reaction temperature and reaction time (Scheme 2). Most
likely, the first equivalent of phosphine is consumed in the
reduction of the palladium(II) source and the second is the
entry D4V (vinyl equiv) Pd source T, °C time , h 3b/7b
a
1
2
3
4
5
0.3 (1.2)
0.3 (1.2)
0.3 (1.2)
0.4 (1.6)
0.5 (2.0)
PdBr2
PdBr2
Pd(dba)2
PdBr2
PdBr2
25
50
50
50
50
6
10:1
6:1
20:1
24:1
30:1
0.5
d
c
6
1
e
2.5
a
1
b
Time to 100% conversion, determined by H NMR analysis. Ratio
determined by H NMR spectroscopy, comparing relative integration.
mol % of phosphine 5 was used. Reaction did not go to 100% conversion;
“
active” ligand. An additional benefit from using 2 equiv of
1
c
5
V
ligand 5 is that the loading of both D
4
and TBAF could be
d
9% of 2b remains. e 3% of 2b remains.
reduced to their original levels (1.2 and 2.0 equiv, respec-
tively) without compromising the styrene/stilbene ratio.
In view of the importance of phosphine stoichiometry, we
decided to re-optimize the reaction conditions to eliminate
the stilbene. We chose initially to minimize the amount of
To establish the generality of the vinylation protocol, a
variety of aromatic bromides were tested under the optimized
fluoride used in the reaction, limiting ourselves to only 2.0
V
equiv of fluoride, varying only the amount of D
4
(Table
(16) The origin of the decreased reaction rate is ambiguous. This may
arise from the dba ligand as an inhibitor or there may be a beneficial effect
of having both phosphine and phosphine oxide in the mixture for enhanced
reaction rate.
V
4
4). Using the original stoichiometry of D (0.3 equiv, 1.2
equiv of vinyl groups) at room temperature provided a 10:1
Org. Lett., Vol. 8, No. 1, 2006
65

Figure 1. Vinylation of various aryl bromides. Key: (a) yields of chromatographically homogeneous, isolated products; (b) contains 10%
dimethylaniline; (c) contains 5% bromomesitylene.
V
conditions. The survey was designed to probe the compat-
ibility of common functional groups under the coupling
conditions and also test the effects of steric hindrance and
electronic character of the aryl group on the rate and yield
of the vinylation. The results of this survey (Figure 1) show
good functional compatibility with the ketone, ester, ether,
hydroxyl and nitro groups. Although 4-bromoaniline pro-
vided a less than desirable yield (32%), other bromides which
bear nitrogen-containing functional groups such as the
acetamide and quinoline did participate in the coupling well.
The dimethylamino group was also compatible, but it was
not possible to remove a small amount of the reduction
byproduct.
TBAF and D
4
to adequately suppress the stilbene formation.
For substrates less prone to the Heck process, the increased
V
level of D
4
may not be needed, and reducing the amount
and TBAF will provide adequate yield and selectivity.
V
of D
4
In conclusion, we have developed a general method for
the vinylation of aryl bromides using an inexpensive, readily
available, nontoxic vinylpolysiloxane. The conditions are
mild and allow for the facile introduction of a vinyl group
in the presence of a variety of common functional groups.
Current work is focused on the development of fluoride-
free vinylation conditions as well as the extension to aryl
chlorides and aryl triflates.
In general, electron-deficient aryl bromides react faster
than electron-rich substrates, but yields are not affected.
Steric effects are evident and decrease the reaction rate, but
again yields remain high.
Acknowledgment. We are grateful for the National
Institutes of Health for generous financial support (R01
GM63167-01A1). C.R.B. acknowledges Procter & Gamble
and Abbott Laboratories for graduate fellowships.
This substrate survey was perfomed using reaction condi-
tions designed to minimize cost (TBAF) and which were
optimized to suppress the formation of stilbene with 1-bro-
Supporting Information Available: Key optimization
experiments, detailed procedures, and characterization of all
products are provided. This material is available free of
charge via the Internet at http://pubs.acs.org.
monaphthalene. Other substrates may require modulation of
V
the D
4
/TBAF levels for optimization. For example, electron-
rich bromides, whose products are more prone to the
secondary Heck reaction, may require an increased level of
OL052517R
66
Org. Lett., Vol. 8, No. 1, 2006