C O M M U N I C A T I O N S
Table 2. NiI2/trans-2-Aminocyclohexanol-Catalyzed Suzuki
Cross-Couplings of Secondary Alkyl Iodides, as Well as Primary
Alkyl Iodides and Bromides (reaction conditions: eq 2)
Capitalizing on the ready availability of structurally diverse amino
alcohols, we surveyed a variety of ligands and discovered a method
that achieves the desired objective (Table 3). Thus, when prolinol,
rather than trans-2-aminocyclohexanol, is employed as a ligand,
nickel-catalyzed Suzuki cross-couplings of unactivated secondary
and primary alkyl chlorides proceed in good yield.12 Acyclic as
well as cyclic chlorides are suitable reaction partners, as are
electron-poor and electron-rich arylboronic acids.
In conclusion, we have demonstrated that Suzuki cross-coupling
reactions of an unprecedented array of unactivated primary and
secondary alkyl halides (including challenging alkyl chlorides) can
be accomplished through the use of nickel/amino alcohol-based
catalysts. Both the nickel precatalyst and the amino alcohols
(prolinol and trans-2-aminocyclohexanol) are commercially avail-
able and air-stable. In view of the remarkable diversity of amino
alcohols that are readily accessible, we believe that the door is now
open to the rapid development of versatile catalysts for a wide range
of cross-coupling processes.
a Isolated yield (average of two experiments). b With 2.0 equiv of the
boronic acid used. c With 1.1 equiv of the boronic acid used.
Table 3. NiCl2‚Glyme/Prolinol-Catalyzed Suzuki Cross-Couplings
of Secondary and Primary Alkyl Chlorides (reaction conditions: eq
3)
Acknowledgment. We thank Frontier Scientific for boronic
acids and CEM for a microwave apparatus. Support has been
provided by the National Institutes of Health (NIGMS, R01-
GM62871), Merck Research Laboratories (including a postdoctoral
fellowship to F.G.-B.), and Novartis. Funding for the MIT Depart-
ment of Chemistry Instrumentation Facility has been furnished in
part by the National Science Foundation (CHE-9808061 and DBI-
9729592).
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). This material is available free
References
(1) (a) Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich,
F., Eds.; Wiley-VCH: New York, 2004. (b) Handbook of Organopalla-
dium Chemistry for Organic Synthesis; Negishi, E.-i., Ed.; Wiley-
Interscience: New York, 2002.
(2) For pioneering studies, see: (a) Ishiyama, T.; Abe, S.; Miyaura, N.; Suzuki,
A. Chem. Lett. 1992, 691-694. (b) Devasagayaraj, A.; Stu¨demann, T.;
Knochel, P. Angew. Chem., Int. Ed. Engl. 1995, 34, 2723-2725.
(3) For recent reviews, see: (a) Frisch, A. C.; Beller, M. Angew. Chem., Int.
Ed. 2005, 44, 674-688. (b) Netherton, M. R.; Fu, G. C. Topics in
Organometallic Chemistry: Palladium in Organic Synthesis; Tsuji, J.,
Ed.; Springer: New York, 2005. (c) Netherton, M. R.; Fu, G. C. AdV.
Synth. Catal. 2004, 346, 1525-1532.
a Isolated yield (average of two experiments). b Yield of the trans isomer
(yield of the mixture of isomers: 65%, according to GC analysis versus a
calibrated standard). The starting material was 95:5 trans:cis; the product
was 78:22 trans:cis. c With 2.0 equiv of the boronic acid used.
(4) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340-1341.
(5) For asymmetric Negishi reactions of alkyl halides, see: (a) Fischer, C.;
Fu, G. C. J. Am. Chem. Soc. 2005, 127, 4594-4595. (b) Arp, F. O.; Fu,
G. C. J. Am. Chem. Soc. 2005, 127, 10482-10483.
involved in the oxidative-addition step of the nickel-catalyzed
processes.11
(6) For a review of chiral bipyridine and phenanthroline ligands, see: Chelucci,
G.; Thummel, R. P. Chem. ReV. 2002, 102, 3129-3170.
(7) Notes: (a) The hydrochloride salt of trans-2-aminocyclohexanol was
employed since that is the form in which it is commonly supplied. (b) In
a 10 mmol experiment, the coupling depicted in entry 6 of Table 1
proceeds in 85% yield (1.6 g of product). (c) For cross-couplings of
electron-rich arylboronic acids, 2 equiv of the boronic acid was used, due
to competitive protodeborylation. (d) The coupling of cyclohexyl bromide
with phenylboronic acid can be achieved under microwave conditions
under air (57% yield according to GC analysis versus a calibrated internal
standard; 80 °C, 250 W, 5 min; not extensively optimized). (e) Reactions
of several heteroaryl-, vinyl-, and alkylboronic acids proceeded in relatively
poor yield (<30%). We have not yet examined the capacity of other nickel/
amino alcohol catalysts to achieve Suzuki cross-couplings of these families
of substrates.
(8) For the Suzuki reaction illustrated in entry 2 of Table 1, the Ni/
bathophenanthroline catalyst (eq 1) furnishes <5% of the cross-coupling
product.
(9) For the cross-coupling depicted in entry 5 of Table 1, we have not detected
the formation of any product resulting from reaction of the secondary
alkyl chloride.
(10) (a) Pandey, G.; Rao, K. S. S. P.; Palit, D. K.; Mittal, J. P. J. Org. Chem.
1998, 63, 3968-3978. (b) Hackmann, C.; Scha¨fer, H. J. Tetrahedron 1993,
49, 4559-4574. (c) Mayer, S.; Prandi, J.; Bamhaoud, T.; Bakkas, S.;
Guillou, O. Tetrahedron 1998, 54, 8753-8770.
(11) For an earlier discussion, see: Powell, D. A.; Maki, T.; Fu, G. C. J. Am.
Chem. Soc. 2005, 127, 510-511. Under our standard conditions, alkyl
tosylates are essentially unreactive (<10% yield), presumably due to their
reluctance to undergo oxidative addition via a radical pathway.
(12) Notes: (a) Future studies will be directed at gaining an understanding of
the interplay among various reaction parameters and their impact on the
efficiency of these cross-coupling processes. (b) This method is not
effective for ortho-substituted arylboronic acids (<30% yield).
We were pleased to determine that the NiI2/trans-2-aminocy-
clohexanol-based method that we had developed for Suzuki
reactions of secondary alkyl bromides (Table 1) can be applied
without modification to secondary alkyl iodides, primary iodides,
and primary bromides (Table 2). The previously described nickel/
bathophenanthroline catalyst (eq 1) is ineffective for primary alkyl
bromides and displays inferior functional-group compatibility.
As suggested by entry 4 of Table 2 and entry 5 of Table 1, Ni/
trans-2-aminocyclohexanol is significantly more reactive toward
alkyl bromides than alkyl chlorides. Nevertheless, this catalyst does
exhibit slight activity for Suzuki reactions of alkyl chlorides (e.g.,
cyclohexyl chloride cross-couples with phenylboronic acid in 7%
yield under the conditions described in eq 2). In view of the lack
of precedent for Suzuki couplings of unactivated secondary alkyl
chlorides, we chose to pursue the development of the first effective
catalyst for such processes.
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J. AM. CHEM. SOC. VOL. 128, NO. 16, 2006 5361