Room-temperature alkyl-alkyl Suzuki cross-coupling of alkyl bromides that possess β hydrogens [1]

Full text of DOI:10.1021/ja011306o

J. Am. Chem. Soc. 2001, 123, 10099-10100
10099
Communications to the Editor
Table 1. Suzuki Coupling of an Alkyl Bromide: Ligand Surveya
Room-Temperature Alkyl-Alkyl Suzuki
Cross-Coupling of Alkyl Bromides that Possess â
Hydrogens
Matthew R. Netherton, Chaoyang Dai, Klaus Neuschu¨tz, and
Gregory C. Fu*
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, Massachusetts 02139
ReceiVed May 30, 2001
Palladium-catalyzed couplings of organometallic reagents with
aryl and vinyl electrophiles (eq 1) have become classic methods
for generating carbon-carbon bonds.1 Not only sp2-hybridized
but also sp3-hybridized organometallics can be employed. On the
other hand, palladium-catalyzed couplings in which the halide/
triflate is sp3-hybridized are rather uncommon.1-3
a In the case of bidentate ligands, 4% of the ligand was used.
plings, due in part to a reluctance to undergo oxidative addition.6
In view of recent reports that the use of bulky, electron-rich
phosphines can lead to palladium catalysts effective for reactions
of aryl chlorides,7 we decided to pursue the possibility that such
ligands might also be useful in couplings of alkyl halides. As a
test reaction, we chose to examine the unprecedented Suzuki
cross-coupling of an alkyl bromide that contains â hydrogens (1-
bromododecane) with an alkylborane (B-n-octyl-9-BBN).
We were pleased to discover that Pd(OAc)2/PCy3, in the
presence of K3PO4‚H2O, serves as an efficient catalyst for this
alkyl-alkyl coupling process (Table 1, entry 1). Among the
ligands that we have investigated, PCy3 is uniquely effective
(entries 2-13). Under otherwise identical conditions, we observe
no cross-coupling in the presence of triarylphosphines (mono-
dentate: entries 2-5; bidentate: entries 6-7), a phosphite (entry
8), and an arsine (entry 9). Other electron-rich trialkylphosphines
are also markedly less useful than PCy3 (cone angle: 170°).8 For
Slow oxidative addition of alkyl halides/triflates to palladium
and facile â-hydride elimination (eq 2) are two likely causes for
this comparative lack of success. Indeed, to date most palladium-
catalyzed couplings of alkyl electrophiles have involved substrates
that are activated toward oxidative addition and that lack â
hydrogens (e.g., benzyl halides). For the Suzuki reaction in
particular, among alkyl halides/triflates, only iodides have been
shown to couple with any generality (Pd(PPh3)4, 60 °C; 45-71%
yield).4,5 On the other hand, to the best of our knowledge, there
are no examples of Suzuki reactions of alkyl bromides that possess
â hydrogens. In this communication, we describe a method for
achieving Suzuki cross-couplings of a variety of alkyl bromides
under surprisingly mild conditions (room temperature; eq 3).
(2) (a) Luh, T.-Y.; Leung, M.-K.; Wong, K.-T. Chem. ReV. 2000, 100,
3187-3204. (b) Ca´rdenas, D. J. Angew. Chem., Int. Ed. 1999, 38, 3018-
3020.
(3) Knochel has described a nickel-catalyzed method for effecting sp3-
sp3 couplings of primary alkyl iodides and organozinc reagents: (a) Devasa-
gayaraj, A.; Stu¨demann, T.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1995,
34, 2723-2725. (b) Giovannini, R.; Stu¨demann, T.; Dussin, G.; Knochel, P.
Angew. Chem., Int. Ed. 1998, 37, 2387-2390. (c) Giovannini, R.; Stu¨demann,
T.; Devasagayaraj, A.; Dussin, G.; Knochel, P. J. Org. Chem. 1999, 64, 3544-
3553.
(4) For reviews of the Suzuki reaction, see: (a) Miyaura, N.; Suzuki, A.
Chem. ReV. 1995, 95, 2457-2483. (b) Suzuki, A. J. Organomet. Chem. 1999,
576, 147-168. (c) Suzuki, A. In Metal-Catalyzed Cross-Coupling Reactions;
Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998; Chapter 2.
(5) (a) Ishiyama, T.; Abe, S.; Miyaura, N.; Suzuki, A. Chem. Lett. 1992,
691-694. Under these conditions, “alkyl bromides [...] never provide the
corresponding coupling products.” (b) For couplings of iodocyclopropanes,
for which â-hydride elimination is precluded, see: Charette, A. B.; Giroux,
A. J. Org. Chem. 1996, 61, 8718-8719. Charette, A. B.; De Freitas-Gil, R.
P. Tetrahedron Lett. 1997, 38, 2809-2812. Martin, S. F.; Dwyer, M. P.
Tetrahedron Lett. 1998, 39, 1521-1524.
(6) (a) Grushin, V. V.; Alper, H. In ActiVation of UnreactiVe Bonds and
Organic Synthesis; Murai, S., Ed.; Springer-Verlag: Berlin, 1999; pp 193-
226. (b) Grushin, V. V.; Alper, H. Chem. ReV. 1994, 94, 1047-1062.
(7) For leading references, see: Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2001,
123, 2719-2724.
Like alkyl halides/triflates, aryl chlorides were long considered
to generally be unsuitable partners in palladium-catalyzed cou-
(1) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P.
J., Eds.; Wiley-VCH: New York, 1998.
10.1021/ja011306o CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/21/2001

10100 J. Am. Chem. Soc., Vol. 123, No. 41, 2001
Communications to the Editor
Table 2. Room-Temperature Suzuki Cross-Coupling of Alkyl
Bromides (eq 3): Reaction Scope
functional groups, including amines, alkenes, esters, alkynes,
ethers, and nitriles (entries 2-7). Furthermore, alkyl bromides
can be coupled selectively in the presence of alkyl chlorides (entry
8), and vinylboranes can serve as coupling partners (entry 9).
As is the case for Suzuki reactions of sp2-hybridized halides/
triflates, our cross-couplings of alkyl bromides are not highly
moisture-sensitive. In fact, water (from K3PO4‚H2O) is an
important component of the reaction systemsessentially no
coupling occurs when anhydrous K3PO4, rather than K3PO4‚H2O,
is employed. By adding 1 equiv of water to reactions with
anhydrous K3PO4, we obtain the reactivity afforded by K3PO4‚
H2O.11
By 11B NMR spectroscopy, we have investigated the role of
water in our Suzuki cross-coupling system. When we introduce
anhydrous K3PO4 into a THF solution of B-n-hexyl-9-BBN, the
11B NMR spectrum does not change (δ 78). On the other hand,
when we mix B-n-hexyl-9-BBN with K3PO4‚H2O (1:1), the
resonance at δ 78 is replaced by a signal at δ 4, which corresponds
to the hydroxyl-bound “ate” complex.12,13 For Suzuki reactions,
such four-coordinate boron adducts are believed to play a key
role in transmetalation (R-PdLn-X + R1 B(OH)- f R-PdLn-
3
R1).4,14
In summary, we have developed the first method for achieving
Suzuki cross-couplings of alkyl bromides that contain â hydro-
gens, under surprisingly mild conditions (room temperature). This
work represents a significant expansion in the scope of the Suzuki
reaction. We are currently exploring other palladium-catalyzed
couplings of alkyl halides and triflates.
a Prepared by hydroboration with 9-BBN of the corresponding
alkene/alkyne and used without purification. b Isolated yield, average
of two runs. c 1.05 equiv of R-(9-BBN) was used.
Acknowledgment. Support has been provided by Bristol-Myers
Squibb, Merck, the National Institutes of Health (National Institute of
General Medical Sciences, R01-GM62871), the Natural Sciences and
Engineering Research Council of Canada (Postdoctoral Fellowships to
M.R.N. and C.D.), Novartis, the Novartis Foundation (Postdoctoral
Fellowship to K.N.), Pfizer, and the Swiss National Science Foundation
(Postdoctoral Fellowship to K.N.).
example, more hindered P(t-Bu)3 (entry 10; cone angle: 182°),
less hindered P(n-Bu)3 (entry 11; cone angle: 132°), and bidentate
dcpe (entry 12) afford little or none of the desired product. In
fact, among the other trialkylphosphines that we have examined,
only P(i-Pr)3 furnishes a significant amount of the target
compound (entry 13; cone angle: 160°).
We have established that Pd(OAc)2/PCy3/K3PO4‚H2O catalyzes
the room-temperature Suzuki cross-coupling of an array of
â-hydrogen-bearing alkyl bromides with alkyl- and vinylboranes
(Table 2).9,10 The mildness of these conditions for coupling alkyl
bromides contrasts with the higher temperatures employed in
Suzuki’s reactions of alkyl iodides (60 °C).5a As shown in entry
1, Pd(OAc)2/PCy3 cross-couples unfunctionalized partners in
excellent yield (93%). The process tolerates a wide range of
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.
JA011306O
(10) Notes: (a) Dioxane and DME can also be employed as solvents. (b)
Carbonates may be used as the base. (c) A 1:1 ratio of Pd:PCy3 provides
comparable results. (d) Pd(OAc)2(PCy3)2 (Neilan, J. P.; Laine, R. M.; Cortese,
N.; Heck, R. F. J. Org. Chem. 1976, 41, 3455-3460) and commercially
available, air-sensitive Pd(PCy3)2 are comparable in effectiveness to Pd(OAc)2/
PCy3. We chose to focus our study on Pd(OAc)2/PCy3 because both
components are commercially available and easily handled in air. (e) Under
these conditions, boronic acids, secondary alkyl bromides, and secondary alkyl-
9-BBN reagents are not suitable coupling partners.
(8) (a) For a compilation of cone angles, see: Rahman, M. M.; Liu, H.-
Y.; Eriks, K.; Prock, A.; Giering, W. P. Organometallics 1989, 8, 1-7. (b)
Tolman, C. A. Chem. ReV. 1977, 77, 313-348.
(9) General procedure: In air, Pd(OAc)2 (9.0 mg, 0.040 mmol), PCy3 (22.4
mg, 0.080 mmol), and K3PO4‚H2O (276 mg, 1.20 mmol) are added to a reaction
vessel equipped with a stir bar. The vessel is sealed with a septum and purged
with argon for 15 min. The trialkylborane (1.2 mmol; 0.50 M solution in
THF) and then the alkyl bromide (1.0 mmol) are added by syringe. The
resulting heterogeneous reaction mixture is stirred vigorously at room
temperature for 16-24 h. At the conclusion of the reaction, the mixture is
diluted with Et2O, filtered through silica gel with copious washings (Et2O),
concentrated, and then purified by flash column chromatography.
(11) With <1 equiv of water, decreased activity is observed. With 1, 4, 7,
and 10 equiv of water, essentially identical results are obtained.
(12) (a) Matos, K.; Soderquist, J. A. J. Org. Chem. 1998, 63, 461-470.
(b) Ko¨ster, R.; Seidel, G.; Wrackmeyer, B. Chem. Ber. 1992, 125, 617-625.
(13) As expected, we have determined that KOH can be employed as the
base in alkyl-alkyl Suzuki cross-coupling reactions (e.g., 1-bromododecane
couples with B-n-hexyl-9-BBN in 92% yield).
(14) According to 31P NMR, during the course of the cross-coupling
reaction, Pd(PCy3)2 (δ 40) is the predominant phosphorus-containing species.