Room-temperature Stille cross-couplings of alkenyltin reagents and functionalized alkyl bromides that possess β hydrogens

Article abstract of DOI:10.1021/ja0344563

This communication describes a significant expansion in the scope of Stille reactions of C_sp3 -X electrophiles, specifically, that Pd/P(t-Bu)₂Me catalyzes the room-temperature cross-coupling of a variety of functionalized, β-hydrogen-containing alkyl bromides with an array of alkenyltin reagents. The structure of the phosphine (P(t-Bu)₂Me) is well suited for facilitating oxidative addition and avoiding β-hydride elimination, while the fluoride serves to activate the tin reagent for efficient transmetalation. Copyright

Full text of DOI:10.1021/ja0344563

Published on Web 03/11/2003
Room-Temperature Stille Cross-Couplings of Alkenyltin Reagents and
Functionalized Alkyl Bromides that Possess â Hydrogens
Karsten Menzel and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received February 2, 2003; E-mail: gcf@mit.edu
The Stille cross-coupling reaction1,2 is a powerful method for
generating carbon-carbon bonds under conditions that are compat-
ible with a broad range of functional groups. As a consequence of
these attractive attributes, it has been applied in a wide array of
3
disciplines, spanning areas such as materials science and natural
4
products synthesis. Although innumerable reports have described
Stille reactions of Csp2-X electrophiles, there are few examples of
cross-couplings of Csp3-X electrophiles, particularly those that bear
â hydrogens;5 indeed, we are aware of only four successes:
6
7
R-bromoketones (Migita), 1-bromo-1-phenylethane (Sustmann),
8
Figure 1. Mechanism for the Stille cross-coupling reaction.
an R-chloroether (Mioskowski), and fluorinated alkyl iodides
,10
(
Fuchikami).9 In this communication, we significantly expand the
scope of Stille reactions of Csp3-X electrophiles, demonstrating that
Pd/P(t-Bu) Me catalyzes the room-temperature cross-coupling of
Table 1. Effect of Lewis-Basic Additives on the Stille Coupling of
an Alkyl Bromide
2
a variety of functionalized, unactivated, â-hydrogen-containing alkyl
bromides with an array of alkenyltin reagents (eq 1).
entry
additive
yield (%)a
1
2
3
4
5
6
7
8
none
<2
<2
7
N(i-Pr)2Et
CsOH‚H2O
NaOMe
KF
CsF
4
<2
<2
32
73
We have recently reported that bulky, electron-rich phosphines
furnish unusually effective catalysts for Suzuki reactions of Csp3-X
Bu4NF‚3H2O
Me4NF (1.9 equiv),
electrophiles with a range of organoboron reagents.11 Thus, PdL
n
3
Å molec. sieves
2 3
complexes (L ) P(t-Bu) Me or PCy ) appear to possess desirable
reactivity profiles with respect to two of the impediments to efficient
cross-coupling of Csp3-X electrophiles: relatively slow oxidative
a
Determined by GC versus a calibrated internal standard (average of
two runs).
addition and rapid â-hydride elimination (Figure 1; note that the
alkyl halides of Migita/Sustmann/Mioskowski/Fuchikami are all
either activated toward oxidative addition or stabilized against
â-hydride elimination).
3
size of just one of the cyclohexyl groups of PCy leads to a
markedly less efficient coupling catalyst (Table 2, entry 1 vs entries
, which is a useful ligand for a wide array of
2-4). P(t-Bu)
3
palladium-catalyzed couplings of Csp2-X electrophiles, is not
14
Unfortunately, when we applied Pd/PCy
the Stille coupling of n-decyl bromide with vinyl-SnBu
obtained essentially none of the desired product (Table 1, entry 1).
3
2
(or Pd/P(t-Bu) Me) to
3
, we
effective for Stille reactions of alkyl bromides (entry 5). Whereas
replacing one of the t-Bu groups of P(t-Bu) with an ethyl group
3
1a,d
Given that Pd/PCy
3
catalyzes Suzuki reactions of n-decyl bromide,1
does not lead to an appreciable enhancement in reactivity (entry
6), substitution with a methyl group furnishes an active catalyst
(entry 7). Under these conditions, other families of ligands, such
as phosphites (entry 8), triarylphosphines (entries 9-11), arsines
(entry 12), and carbenes (entry 13), afford ineffective catalysts.
we postulated that our inability to achieve Stille cross-coupling was
probably due to slow transmetalation. Because Lewis-basic additives
have been shown to facilitate certain Stille reactions, presumably
by generating hypervalent stannate complexes that are more reactive
toward transmetalation,12 we explored the utility of a variety of
potential activators, illustrative examples of which are provided in
2
With Pd/P(t-Bu) Me as the catalyst, we can cross-couple an array
of functionalized alkyl bromides with a range of alkenyltin reagents
at room temperature (Table 3). Thus, the reaction conditions are
compatible with groups such as olefins, acetals, ethers, nitriles,
esters, and amides. With respect to the tin reagent, not only is vinyl-
Table 1. Although N(i-Pr)
were largely ineffective (entries 2-6), the addition of Bu
led to the formation of an appreciable quantity of the cross-coupling
product (entry 7).13 Additional optimization revealed that Me
NF/3
2
Et, CsOH‚H
2
O, NaOMe, KF, and CsF
4
NF‚3H O
2
4
3
SnBu a suitable reactant, but a variety of compounds, including
Å molecular sieves serve as a particularly effective activator,
furnishing a 73% yield of 1-dodecene (entry 8).
We have determined that, as for Suzuki reactions of alkyl
electrophiles,11 the structure of the ligand has a remarkable influence
on Stille reactions of alkyl bromides. Decreasing or increasing the
progressively more challenging trans- (entries 1-5) and cis-
disubstituted (entries 6-8), as well as trisubstituted (entry 9),
olefins, can be cross-coupled.15
Unfortunately, the susceptibility of P(t-Bu) Me to oxidation can
2
make its handling inconvenient. As illustrated in Table 3, air- and
3718
9
J. AM. CHEM. SOC. 2003, 125, 3718-3719
10.1021/ja0344563 CCC: $25.00 © 2003 American Chemical Society

C O MMU N I C A T I O N S
Table 2. Effect of Ligand Structure on the Stille Coupling of an
Alkyl Bromide
bromides that contain â hydrogens. In view of the limited prior
success in this area, we believe that this report reveals a significant
new dimension to the Stille reaction. Our current efforts are focused
on developing catalysts that expand the scope of this and related
coupling processes, as well as on gaining a better understanding
of the origin of the unusual reactivity of Pd/trialkylphosphine-based
catalysts.
entry
ligand
PCy3
yield (%)a
1
2
3
4
5
6
7
8
9
73
17
<2
9
<2
<2
86 W
<2
<2
<2
<2
<2
<2
Acknowledgment. Support has been provided by the National
Institutes of Health (NIGMS, R01-GM62871), Merck, and Novartis.
Funding for the MIT Department of Chemistry Instrumentation
Facility has been furnished in part by NSF CHE-9808061 and NSF
DBI-9729592. We thank Johnson Matthey for supplying palladium
compounds.
PCy2Et
PCy2Me
PCy2(t-Bu)
P(t-Bu)3
P(t-Bu)2Et
P(t-Bu)2Me
P(OPh)3
PPh3
P(o-tol)3
P(2-furyl)3
AsPh3
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
1
1
1
1
0
1
2
3
b
IMesHCl
References
a
(1) (a) Kosugi, M.; Sasazawa, K.; Shimizu, Y.; Migita, T. Chem. Lett. 1977,
Determined by GC versus a calibrated internal standard (average of
301-302. (b) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100,
b
two runs). 1,3-Bis(2,4,6-trimethylphenyl)imidazolium chloride.
3636-3638.
(
2) For reviews of the Stille reaction, see: (a) Farina, V.; Krishnamurthy,
V.; Scott, W. J. Org. React. 1997, 50, 1-652. (b) Mitchell, T. N. In Metal-
Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: New York, 1998; Chapter 4. (c) Fugami, K.; Kosugi, M.
Top. Curr. Chem. 2002, 219, 87-130.
Table 3. Room-Temperature Stille Cross-Couplings of Alkyl
Bromides that Contain â Hydrogens
(
(
(
3) For a recent example, see: Yu, H.-h.; Xu, B.; Swager, T. M. J. Am. Chem.
Soc. 2003, 125, 1142-1143.
4) For a recent example, see: Kadota, I.; Takamura, H.; Sato, K.; Ohno, A.;
Matsuda, K.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 46-47.
5) For an overview of the difficulty of achieving coupling reactions of Csp3-X
electrophiles, see: Cardenas, D. J. Angew. Chem., Int. Ed. 2003, 42, 384-
3
87. See also: Luh, T.-Y.; Leung, M.-K.; Wong, K.-T. Chem. ReV. 2000,
100, 3187-3204.
(
6) Kosugi, M.; Takano, I.; Sakurai, M.; Sano, H.; Migita, T. Chem. Lett.
1984, 1221-1224.
(
(
7) Sustmann, R.; Lau, J.; Zipp, M. Tetrahedron Lett. 1986, 27, 5207-5210.
8) Bhatt, R. K.; Shin, D.-S.; Falck, J. R.; Mioskowski, C. Tetrahedron Lett.
1
992, 33, 4885-4888.
(
9) (a) Shimizu, R.; Fuchikami, T. Tetrahedron Lett. 1996, 37, 8405-8408.
(b) Shimizu, R.; Fuchikami, T. Tetrahedron Lett. 2001, 42, 6891-6894.
Fuchikami postulates, based in part on computational studies, that
undesired â-hydride elimination (see Figure 1) is disfavored due to
chelation of fluorine to palladium.
(
10) Stille has reported couplings of R-halolactones that apparently proceed
through a mixture of palladium-catalyzed and radical pathways: Simpson,
J. H.; Stille, J. K. J. Org. Chem. 1985, 50, 1759-1760.
(
11) (a) Netherton, M. R.; Dai, C.; Neusch u¨ tz, K.; Fu, G. C. J. Am. Chem.
Soc. 2001, 123, 10099-10100. (b) Kirchhoff, J. H.; Dai, C.; Fu, G. C.
Angew. Chem., Int. Ed. 2002, 41, 1945-1947. (c) Netherton, M. R.; Fu,
G. C. Angew. Chem., Int. Ed. 2002, 41, 3910-3912. (d) Kirchhoff, J. H.;
Netherton, M. R.; Hills, I. D.; Fu, G. C. J. Am. Chem. Soc. 2002, 124,
13662-13663.
(
12) For some early examples, see: (a) Vedejs, E.; Haight, A. R.; Moss, W.
O. J. Am. Chem. Soc. 1992, 114, 6556-6558. (b) Brown, J. M.; Pearson,
M.; Jastrzebski, J. T. B. H.; van Koten, G. J. Chem. Soc., Chem. Commun.
1
992, 1440-1441. (c) Martinez, A. G.; Barcina, J. O.; Cerezo, A. de F.;
Subramanian, L. R. Synlett 1994, 1047-1048. (d) Farina, V. Pure Appl.
Chem. 1996, 68, 73-78. (e) Fouquet, E.; Pereyre, M.; Rodriguez, A. L.
J. Org. Chem. 1997, 62, 5242-5243.
(
(
(
13) Tin is known to be fluorophilic. For a discussion, see: Chemistry of Tin;
Smith, P. J., Ed.; Blackie: New York, 1998.
14) For leading references, see: Littke, A. F.; Schwarz, L.; Fu, G. C. J. Am.
Chem. Soc. 2002, 124, 6343-6348.
a
Isolated yield, average of two runs.
15) Under these conditions, allyl-, aryl-, and alkynyltin reagents, as well as
more hindered alkyl bromides, are not suitable substrates.
2 4
moisture-stable [HP(t-Bu) Me]BF , which is also commercially
available, furnishes yields that are comparable to the phosphine
itself.17
In conclusion, we have established that a Pd/P(t-Bu) Me-based
2
catalyst can achieve room-temperature Stille cross-couplings of a
variety of alkenyltin reagents with a range of functionalized alkyl
(
16) Strem Chemicals catalog numbers: P(t-Bu)
2 2
Me (#15-1020); [HP(t-Bu) Me]-
16
BF (#15-1023).
4
(17) For other demonstrations that phosphines and the corresponding phos-
phonium salts can often be used interchangeably in palladium-catalyzed
coupling processes, see: (a) Netherton, M. R.; Fu, G. C. Org. Lett. 2001,
3, 4295-4298. (b) Reference 11d.
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J. AM. CHEM. SOC.
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