Enantioselective alkyl-alkyl suzuki cross-couplings of unactivated homobenzylic halides

Article abstract of DOI:10.1021/ja8013677

The first effective method for asymmetric cross-couplings of unactivated alkyl electrophiles has been developed, specifically, a nickel-based catalyst for stereoconvergent Suzuki reactions of homobenzylic bromides with alkylboranes. To the best of our knowledge, there are no previous examples of enantioselective Suzuki couplings of alkyl electrophiles (activated or unactivated). Both of the catalyst components are commercially available. Copyright

Full text of DOI:10.1021/ja8013677

Published on Web 05/01/2008
Enantioselective Alkyl-Alkyl Suzuki Cross-Couplings of Unactivated
Homobenzylic Halides
Bunnai Saito and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received February 23, 2008; E-mail: gcf@mit.edu
Table 1. An Asymmetric Suzuki Reaction of an Unactivated Alkyl
Progress in the development of palladium- and nickel-catalyzed
methods for cross-coupling alkyl electrophiles that bear ꢀ hydrogens
has increased significantly in recent years.1,2 For reactions of
secondary alkyl halides, nickel-based catalysts have proved to be
unusually effective.2a,c,3 Advances have also been described in the
development of chiral catalysts that achieve cross-couplings of
secondary electrophiles with high enantioselectivity, although to
date these have been limited to couplings of activated electrophiles
(e.g., allylic, benzylic, or R-halocarbonyl) with either organozinc
or organosilicon reagents.4,5 In this report, we expand upon the
scope of both reaction partners, specifically, we establish that a
chiral nickel catalyst can cross-couple certain unactiVated alkyl
electrophiles with organoboron compounds6 in good enantiomeric
excess (eq 1).
Bromide: Effect of Reaction Parametersa
entry
variation from the standard conditions
ee (%) yield (%)
1
2
3
4
5
6
7
8
9
none
no (R,R)-1
(R,R)-3, instead of (R,R)-1
(R,R)-4, instead of (R,R)-1
(R,R)-5, instead of (R,R)-1
(S,S)-6, instead of (R,R)-1
rt, instead of 5 °C
dioxane at rt, instead of i-Pr2O at 5 °C
5% Ni(cod)2 and 6% (R,R)-1, instead of 10%/12%
89
–
85
85
<2
76
66
46
72
76
32
70
88
-6
-80
87
60
89
a The yield was determined by GC versus a calibrated internal standard.
A negative ee value signifies that the opposite enantiomer of the product
was formed preferentially.
The conditions that we had employed for asymmetric Negishi
and Hiyama reactions were ineffective at cross-coupling 2-bromo-
3-phenylpropane with an alkyl-(9-BBN).4,5 We recently described
a method that achieves alkyl-alkyl couplings of secondary elec-
trophiles with organoboron reagents,3d and we were pleased to
determine that this catalyst can accomplish an asymmetric cross-
coupling with promising ee (58% ee; eq 2).
furnishes slightly to modestly lower enantioselectivities and yields
(e.g., entries 3, 4, and 6), whereas the presence of a hindered mesityl
groupleadstonearlyracemicproductandlessefficientcarbon-carbon
bond formation (entry 5). If the cross-coupling is conducted at room
temperature, rather than at -5 °C, a small erosion in yield is
observed (entry 7), and replacement of i-Pr2O with dioxane is
deleterious (entry 8).7 Finally, if half of the “standard” catalyst
loading is employed, the yield of the coupling is somewhat
diminished.
We have examined the scope of this asymmetric Suzuki cross-
coupling process with respect to the electrophile (Table 2). For alkyl
groups that range in steric demand from methyl to isopropyl, very
good ee is generally observed (e.g., entries 1-4). The presence of an
electron-rich aromatic group leads to higher ee than an electron-poor
substituent (entry 5 vs entry 6), and a hindered o-tolyl group is tolerated
(entry 7). It is noteworthy that these asymmetric Suzuki reactions of
unactivated alkyl bromides proceed under unusually mild conditions
(i.e., below room temperature).8,9
Our current hypothesis is that the chiral Ni/1 complex differentiates
between the two alkyl groups (CH2Ar vs alkyl in Table 2) of the
unactivated halide via a secondary interaction between the CH2Ar
substituent and the catalyst. Consistent with the suggestion that proper
positioning of the aromatic group is important for obtaining good ee,
Optimization of this initial lead provided a method that achieves
the desired carbon-carbon bond formation in a stereoconvergent
process in very good ee and yield (89% ee, 85% yield; Table 1,
entry 1). From a practical point of view, it is noteworthy that both
of the catalyst components, Ni(cod)2 and (R,R)-1, are commercially
available. In the absence of the diamine, essentially no cross-
coupling occurs (entry 2). An array of related ligands in which the
aromatic ring is unsubstituted, para-substituted, or meta-substituted
9
6694 J. AM. CHEM. SOC. 2008, 130, 6694–6695
10.1021/ja8013677 CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Asymmetric Suzuki Reactions of Unactivated Alkyl
Bromides: Variation of the Electrophile
2-7), although the reactions generally proceed in somewhat lower ee
than for less functionalized substrates.11,12
In summary, we have developed the first effective method for
asymmetric cross-couplings of unactiVated alkyl electrophiles, specif-
ically, a nickel-based catalyst for stereoconvergent Suzuki reactions
of homobenzylic bromides with alkylboranes. It is noteworthy that
there are no other examples of enantioselective Suzuki couplings of
alkyl electrophiles and that the catalyst components are commercially
available. Although the process has limitations, its discovery demon-
strates that unactivated alkyl electrophiles, a very important family of
coupling partners, can begin to be considered as potential substrates
for enantioselective cross-couplings. In view of the potential impact
of such reactions on organic synthesis, efforts to develop more versatile
catalysts are underway.
Acknowledgment. Support has been provided by the National
Institutes of Health (National Institute of General Medical Sciences,
Grant R01-GM62871), the Japan Society for the Promotion of Science
(postdoctoral fellowship to B.S.), Merck Research Laboratories, and
Novartis.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
a Isolated yield. All data are the average of two experiments.
bromides 7 and 8 undergo Suzuki cross-coupling with low enantiose-
lectivity under our standard conditions.10
References
(1) For two of the pioneering investigations of palladium- and nickel-catalyzed
cross-couplings of unactivated alkyl electrophiles, 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.
(2) For reviews of cross-coupling reactions of alkyl electrophiles, see: (a) Frisch,
A. C.; Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674–688. (b) Netherton,
M. R.; Fu, G. C. In 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.
Additional examples that illustrate the scope of this method for
asymmetric Suzuki reactions of unactivated alkyl halides are provided
in Table 3. Thus, a range of heteroatom-containing electrophiles and
alkylboranes serve as suitable cross-coupling partners (e.g., entries
(3) For additional reports of non-asymmetric cross-couplings of unactivated
electrophiles, see: (a) Powell, D. A.; Maki, T.; Fu, G. C. J. Am. Chem. Soc.
2005, 127, 510–511. (b) Gonza´lez-Bobes, F.; Fu, G. C. J. Am. Chem. Soc.
2006, 128, 5360–5361. (c) Strotman, N. A.; Sommer, S.; Fu, G. C. Angew.
Chem., Int. Ed. 2007, 46, 3556–3558. (d) Saito, B.; Fu, G. C. J. Am. Chem.
Soc. 2007, 129, 9602–9603.
Table 3. Asymmetric Suzuki Reactions of Unactivated Alkyl
Bromides
(4) For asymmetric Negishi reactions of activated alkyl electrophiles, see: (a)
R-Bromo amides: Fischer, C.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 4594–
4595. (b) Benzylic bromides and chlorides: Arp, F. O.; Fu, G. C. J. Am.
Chem. Soc. 2005, 127, 10482–10483. (c) Allylic chlorides: Son, S.; Fu,
G. C. J. Am. Chem. Soc. 2008, 130, 2756–2757.
(5) For asymmetric Hiyama reactions of R-bromo esters, see: Dai, X.; Strotman,
N. A.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 3302–3303.
(6) For reviews of the Suzuki reaction, see: (a) Miyaura, N. In Metal-Catalyzed
Cross-Coupling Reactions; de Meijere, A., Diederich, F., Eds.; Wiley-VCH:
New York, 2004; Chapter 2. (b) Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E.-i., Ed.; Wiley-Interscience: New York,
2002. (c) Miyaura, N. Top. Curr. Chem. 2002, 219, 11–59.
(7) In initial studies, related solvents such as t-BuOMe and glyme were inferior
to i-Pr2O.
(8) To the best of our knowledge, these are the first examples of nickel-catalyzed
Suzuki reactions of unactivated alkyl electrophiles that proceed below room
temperature.
(9) Notes: (a) In a gram-scale reaction, the asymmetric Suzuki cross-coupling
illustrated in entry 1 of Table 2 was accomplished in 89% ee and 95% yield.
(b) During the course of a coupling reaction, the ee of the starting material is
less than 10%, and the ee of the product is essentially constant. (c) The ee of
the product correlates linearly with the ee of the ligand. (d) For the cross-
couplings depicted in Table 2, all of the alkyl bromide has been consumed.
(10) For the substrate illustrated in entry 3 of Table 2, the catalyst is effectively
differentiating between a benzyl and a homobenzyl substituent.
(11) Under our standard conditions, alkylboranes derived from the hydroboration
of disubstituted olefins are not suitable reaction partners, and the cross-coupling
of a phthalimide-containing alkylborane proceeded in modest yield (∼40%).
(12) We speculate that the modest ee observed in entry 4 of Table 3 may be due
to competitive coordination of the ether oxygen to the catalyst. Studies directed
at exploring this hypothesis are underway.
a Isolated yield. b Run at 5 °C. c Run at rt. All data are the average of
two experiments.
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