Cross-Couplings of Alkyl Electrophiles under Ligandless Conditions: Negishi Reactions of Organozirconium Reagents

Article abstract of DOI:10.1021/ja0393729

This report establishes that simple, ligandless palladium complexes can catalyze the first zirconium-Negishi reactions of alkyl electrophiles. In view of the attractiveness of ligandless catalysts (cost, simplicity, and ease of purification), these observations add a significant and intriguing new dimension to the development of effective palladium-based processes for coupling alkyl electrophiles. Copyright

Full text of DOI:10.1021/ja0393729

Published on Web 12/16/2003
Cross-Couplings of Alkyl Electrophiles under “Ligandless” Conditions:
Negishi Reactions of Organozirconium Reagents
Sheryl L. Wiskur, Alexander Korte, and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received November 1, 2003; E-mail: gcf@mit.edu
Table 2. Zirconium-Negishi Cross-Couplings of Alkyl Bromides
During the past few years, considerable effort has been devoted
to expanding the scope of palladium- and nickel-catalyzed cross-
coupling reactions1 so as to include unactivated, â-hydrogen-
containing alkyl electrophiles as partners.2 For such processes,
wheareas the composition of nickel-based catalysts has been
diverse,3,4 with the exception of an early report by Suzuki describing
the use of Pd(PPh3)4 for couplings of alkyl iodides with organo-
boranes,5 all effective palladium-based catalysts have employed very
bulky, electron-rich ligands (i.e., trialkylphosphines,6,7 alkyl-
diaminophosphines,8 and carbenes9).
under Ligandless Conditionsa
In this Communication, we provide an impetus for looking
beyond such ligands in future efforts at catalyst development.
Specifically, we establish that simple, “ligandless” palladium
complexes10 can catalyze the first zirconium-Negishi reactions11,12
of alkyl electrophiles (eq 1). Such ligandless processes are attractive
from the standpoints of cost, simplicity, and ease of purification.
As illustrated in Table 1, we have determined that Pd(acac)2 is
effective for the cross-coupling of 1-bromodecane with an alkenyl-
zirconium reagent (entry 1). Other palladium complexes can also
be employed (entries 2 and 3), but nickel complexes are only
modestly efficient under these conditions (entries 4 and 5); without
Pd(acac)2, no cross-coupling is observed (entry 6). A halide source
other than LiBr can be used (e.g., LiI; entry 7), whereas the coupling
proceeds poorly if no activator is present (entry 8). Finally, the
cross-coupling is less effective at lower temperature (entry 9) or
with less catalyst (entry 10).13
Table 1. Effect of Reaction Parameters on the Cross-Coupling of
an Alkyl Bromide with an Organozirconium Reagent
change from the
“standard conditions”
a All yields are isolated yields (average of two runs). b 5% Pd(acac)2
was used. c 5% Pd(acac)2 was used. Reaction time: 48 h.
entry
yield (%)a
1
2
3
4
5
6
7
8
9
none
PdBr2
99
100
100
57
62
0
100
20
14
Pd(acac)2 is effective for cross-coupling a range of functionalized
alkyl bromides and alkenylzirconium reagents in generally good
yield (Table 2). A variety of groups are compatible with the reaction
conditions, including esters, alkyl and silyl ethers, nitriles, amides,
acetals, and olefins. A somewhat hindered, â-branched alkyl
bromide can be coupled, albeit in more modest yield (entry 13).
Furthermore, sterically demanding alkenylzirconium reagents that
are derived from the hydrozirconation of internal alkynes can be
cross-coupled (entries 14 and 15).14 When the coupling illustrated
Pd2(dba)3
NiBr2
Ni(cod)2
no Pd(acac)2
LiI
no LiBr
room temp
1.0% Pd(acac)2
10
80
a Yield according to GC, versus a calibrated internal standard (average
of two runs).
9
82
J. AM. CHEM. SOC. 2004, 126, 82-83
10.1021/ja0393729 CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Zirconium-Negishi Cross-Couplings of Other Alkyl
Wiley-VCH: New York, 1998. (b) Cross-Coupling Reactions: A Practical
Guide; Miyaura, N., Ed.; Topics in Current Chemistry Series 219;
Springer-Verlag: New York, 2002. (c) Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E.-i., Ed.; Wiley-Interscience:
New York, 2002.
Electrophiles under Ligandless Conditionsa
3
(2) For overviews of the difficulty of achieving coupling reactions of Csp -X
electrophiles, see: Ca´rdenas, D. J. Angew. Chem., Int. Ed. 2003, 42, 384-
387. Ca´rdenas, D. J. Angew. Chem., Int. Ed. 1999, 38, 3018-3020. See
also: Luh, T.-Y.; Leung, M.-k.; Wong, K.-T. Chem. ReV. 2000, 100,
3187-3204.
(3) (a) Devasagayaraj, 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.; Knochel, P. J. Am. Chem. Soc. 1998, 120, 11186-
11187. (d) Giovannini, R.; Stu¨demann, T.; Devasagayaraj, A.; Dussin,
G.; Knochel, P. J. Org. Chem. 1999, 64, 3544-3553. (e) Piber, M.; Jensen,
A. E.; Rottla¨nder, M.; Knochel, P. Org. Lett. 1999, 1, 1323-1326. (f)
Jensen, A. E.; Knochel, P. J. Org. Chem. 2002, 67, 79-85.
(4) (a) Terao, J.; Watanabe, H.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am.
Chem. Soc. 2002, 124, 4222-4223. (b) Terao, J.; Ikumi, A.; Kuniyasu,
H.; Kambe, N. J. Am. Chem. Soc. 2003, 125, 5646-5647.
a All yields are isolated yields (average of two runs).
(5) Ishiyama, T.; Abe, S.; Miyaura, N.; Suzuki, A. Chem. Lett. 1992, 691-
694.
in entry 1 is conducted under microwave conditions (100 °C, 15
min; 30 W), an excellent isolated yield of the product is obtained
(94%).
(6) (a) Netherton, M. R.; Dai, C.; Neuschu¨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. (e) Menzel, K.; Fu, G. C. J. Am. Chem. Soc. 2003, 125,
3718-3719. (f) Lee, J.-Y.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 5616-
5617. (g) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 12527-12530.
The activity of this simple, ligandless catalyst for zirconium-
Negishi couplings is not limited to reactions of alkyl bromides.
Under the same set of conditions, functionalized alkyl iodides and
alkyl tosylates undergo clean cross-coupling with alkenylzirconium
reagents (Table 3, entries 1 and 2).15 Finally, reactions of alkyl
chlorides can also be achieved, although less efficiently (entry 3).
At this stage, we have not determined the nature of the active
catalyst. Interestingly, we have found that the addition of mercury
to a cross-coupling shuts down the process, an observation
consistent with the presence of a heterogeneous species in the
reaction mixture.16,17
(7) Frisch, A. C.; Shaikh, N.; Zapf, A.; Beller, M. Angew. Chem., Int. Ed.
2002, 41, 4056-4059.
(8) Tang, H.; Menzel, K.; Fu, G. C. Angew. Chem., Int. Ed. 2003, 42, 5079-
5082.
(9) Eckhardt, M.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 13642-13643.
(10) By “ligandless”, we are simply indicating that typical ligands such as
phosphines are not present. For a discussion of other ligandless catalysts
for cross-coupling reactions, see: Metal-Catalyzed Cross-Coupling Reac-
tions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998;
pp 26, 208, 214, 233.
In conclusion, we have described the first ligandless palladium-
based method for cross-coupling alkyl electrophiles: Pd(acac)2-
catalyzed reactions of functionalized alkyl halides/tosylates with
organozirconium reagents. In view of the attractiveness of ligandless
catalysts (cost, simplicity, and ease of purification), these observa-
tions add a significant and intriguing new dimension to the
development of effective processes for coupling alkyl electrophiles.
(11) For reviews of the zirconium-Negishi reaction, see: (a) Negishi, E.-i. In
Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J.,
Eds.; Wiley-VCH: New York, 1998; pp 1-47. (b) Negishi, E.-i. In
Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi,
E.-i., Ed.; Wiley-Interscience: New York, 2002; pp 229-247.
(12) For an example of a natural-product synthesis that employs a zirconium-
Negishi reaction, see: Ribe, S.; Kondru, R. K.; Beratan, D. N.; Wipf, P.
J. Am. Chem. Soc. 2000, 122, 4608-4617.
(13) Notes: (a) The cross-coupling proceeds efficiently in NMP alone, but
not in THF. (b) Under otherwise identical conditions, if the alkenyl-
zirconium reagent is replaced with nonylzinc bromide, we observe
essentially no cross-coupling (<2%). (c) In addition to zirconium-Negishi
reactions of primary alkyl electrophiles, these conditions are also effective
for couplings of aryl bromides (but not aryl chlorides).
(14) Under these conditions, secondary alkyl bromides are not suitable
substrates.
(15) Under the cross-coupling conditions, some RCH2X (X ) Br, I, OTs) is
converted to RCH2Cl (the chloride originates from the alkenylzirconium
reagent). We believe that one of the roles of LiBr is to tranform RCH2Cl
into more reactive RCH2Br.
(16) (a) For example, see: Whitesides, G. M.; Hackett, M.; Brainard, R. L.;
Lavalleye, J. P. P. M.; Sowinski, A. F.; Izumi, A. N.; Moore, S. S.; Brown,
D. W.; Staudt, E. M. Organometallics 1985, 4, 1819-1830. Pd/C catalyzes
these zirconium-Negishi cross-couplings, although less effectively than
Pd(acac)2. Visually, the Pd(acac)2-catalyzed reactions appear to be
homogeneous. For an excellent discussion, including leading references,
of approaches to distinguishing between homogeneous and heterogeneous
catalysis, see: Widegren, J. A.; Bennett, M. A.; Finke, R. G. J. Am. Chem.
Soc. 2003, 125, 10301-10310. (b) For an example of a coupling catalyzed
by palladium nanoparticles, see: Reetz, M. T.; Westermann, E. Angew.
Chem., Int. Ed. 2000, 39, 165-168.
Acknowledgment. This paper is dedicated to the memory of
Professor Satoru Masamune. We thank Jianrong Zhou for helpful
discussions and Ivory Hills for assistance in preparing the manu-
script. Support has been provided by the National Institutes of
Health (National Institute of General Medical Sciences, R01-
GM62871), the Studienstiftung des Deutschen Volkes (support for
A.K.), Merck, and Novartis. We thank Johnson Matthey for
supplying palladium compounds. Funding for the MIT Department
of Chemistry Instrumentation Facility has been furnished in part
by NSF CHE-9808061 and NSF DBI-9729592.
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.
References
(17) The cross-coupling proceeds in the presence of radical traps.
(1) For reviews of metal-catalyzed cross-coupling reactions, see: (a) Metal-
Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
JA0393729
9
J. AM. CHEM. SOC. VOL. 126, NO. 1, 2004 83