Alkyl-alkyl Suzuki cross-couplings of unactivated secondary alkyl halides at room temperature

Article abstract of DOI:10.1021/ja074008l

A commercially available 1,2-diamine serves as an effective ligand for metal-catalyzed cross-couplings of unactivated alkyl electrophiles at room temperature. In particular, Ni/trans-N,N′-dimethyl-1,2-cyclohexanediamine provides the first method for achie

Full text of DOI:10.1021/ja074008l

Published on Web 07/12/2007
Alkyl-Alkyl Suzuki Cross-Couplings of Unactivated Secondary Alkyl Halides
at Room Temperature
Bunnai Saito and Gregory C. Fu*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received June 2, 2007; E-mail: gcf@mit.edu
Table 1. Alkyl-Alkyl Suzuki Cross-Coupling of an Unactivated
During the past several years, substantial progress has been
described in the development of palladium- and nickel-catalyzed
methodsforcross-couplingarangeofunactivatedalkylelectrophiles.1-4
Initial work focused on reactions of primary alkyl electrophiles,
but recent efforts have addressed the more difficult challenge of
coupling secondary electrophiles. To date, the only alkylmetal
species that have been effectively cross-coupled with unactivated
secondary halides are organozinc reagents.5
The Suzuki reaction is a particularly widely used carbon-carbon
bond-forming process.6 Thus far, the only reports of Suzuki cross-
couplings of unactivated secondary electrophiles have involved aryl-
and vinylboron compounds.7 The tremendous potential of coupling
reactions of alkyl halides would be enhanced considerably if
alkylboranes could be employed as partners. In this report, we
establish that a 1,2-diamine provides an active nickel-based catalyst
for Suzuki cross-couplings of unactivated secondary alkyl electro-
philes with alkylboron reagents at room temperature (eq 1).
Secondary Alkyl Bromide: Effect of Reaction Parameters
yielda
entry
variation from the “standard” conditions
(%)
1
2
3
4
5
6
7
none
83
25
<5
<5
7
53
<5
bathophenanthroline, instead of 1
trans-2-aminocyclohexanol, instead of 1
prolinol, instead of 1
s-Bu-Pybox,b instead of 1
trans-1,2-cyclohexanediamine, instead of 1
trans-N,N,N′,N′-tetramethyl-1,2-cyclohexanediamine,
instead of 1
8
9
cis isomer of 1, instead of 1
N,N′-dimethylethylenediamine, instead of 1
no 1
46
7
10
11
12
13
14
15
16
17
18
<5
<5
81
75
<5
80
47
<5
56
no NiCl2‚glyme
NiBr2‚diglyme, instead of NiCl2‚glyme
Ni(cod)2, instead of NiCl2‚glyme
NiCl2, instead of NiCl2‚glyme
THF, instead of dioxane
toluene, instead of dioxane
Et2O, instead of dioxane
3% NiCl2‚glyme and 4% 1, instead of 6% NiCl2‚glyme
and 8% 1
Unfortunately, the methods that had previously been described
for achieving Suzuki reactions of unactivated secondary halides
with aryl- and vinylboron compounds are not useful for alkylboron
species (eq 2).7 A variety of other bipyridine and aminoalcohol
ligands afforded similarly disappointing results.
19
20
no KOt-Bu
no i-BuOH
<5
<5
a Determined by GC analysis versus a calibrated internal standard
(average of two experiments). b s-Bu-Pybox ) (S,S)-2,6-bis(4-(2-butyl)-2-
oxazolin-2-yl)pyridine.
whereas trans-N,N,N′,N′-tetramethyl-1,2-cyclohexanediamine does
not (entry 7). The cis isomer of 1 is moderately useful (46%; entry
8). An acyclic 1,2-diamine, N,N′-dimethylethylenediamine, furnishes
very little of the target compound (entry 9).
In the absence of ligand 1 or of NiCl2‚glyme, essentially none
of the desired alkyl-alkyl bond formation is observed (Table 1,
entries 10 and 11). Nickel complexes such as NiBr2‚diglyme and
Ni(cod)2 can be used in place of NiCl2‚glyme, but NiCl2, which
has low solubility in dioxane, cannot (entries 12-14). The coupling
proceeds with comparable efficiency in THF as in dioxane (entry
15), whereas toluene is less suitable and Et2O is unsuitable as a
solvent (entries 16 and 17). Use of a lower catalyst loading leads
to a lower yield (entry 18).
If KOt-Bu or i-BuOH is omitted, essentially none of the target
alkyl-alkyl cross-coupling product is generated (Table 1, entries
19 and 20).8 We believe that the role of these species is to activate
the alkylborane for transmetalation with nickel.9 Indeed, when we
mix an organoborane, KOt-Bu, and i-BuOH, we observe quantita-
We therefore decided to pursue the use of new families of ligands
to accomplish our objective of Suzuki cross-couplings of secondary
alkyl electrophiles with alkylboranes. Upon examining a wide range
of structures, we determined that certain 1,2-diamines furnish
efficient catalysts for the desired alkyl-alkyl coupling. For example,
in the presence of NiCl2‚glyme and commercially available trans-
N,N′-dimethyl-1,2-cyclohexanediamine (1), bromocyclohexane
couples with an alkylborane at room temperature in good yield
(Table 1, entry 1).
Under these conditions, bathophenanthroline, trans-2-aminocy-
clohexanol, and prolinol are still ineffective (Table 1, entries 2-4),
as is s-Bu-Pybox5 (entry 5). trans-1,2-Cyclohexanediamine provides
a significant amount of the cross-coupling product (53%; entry 6),
9
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J. AM. CHEM. SOC. 2007, 129, 9602-9603
10.1021/ja074008l CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Alkyl-Alkyl Suzuki Cross-Couplings of Unactivated
Secondary Alkyl Bromides (for conditions, see eq 1)
Table 3. Alkyl-Alkyl Suzuki Cross-Couplings of Unactivated
Secondary and Primary Alkyl Electrophiles (for conditions, see
eq 1)
a Isolated yield (average of two experiments).
perature. We anticipate that the observation that simple, readily
available diamines can furnish active catalysts will greatly facilitate
the development of powerful new methods for cross-coupling alkyl
electrophiles. Efforts to substantiate this hypothesis are underway.
Acknowledgment. This paper is dedicated to the memory of
Prof. Yoshihiko Ito. Dr. Francisco Gonza´lez-Bobes is acknowledged
for preliminary studies. Support has been provided by the National
Institutes of Health (National Institute of General Medical Sciences,
R01-GM62871), the Japan Society for the Promotion of Science
(postdoctoral fellowship to B.S.), Merck Research Laboratories,
Novartis, and Boehringer Ingelheim.
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
(1) For general reviews of metal-catalyzed cross-coupling reactions, see: (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.
a Isolated yield (average of two experiments). b Diastereoselectivity )
>20:1 (exo:endo). c Ratio of trans/cis ) 65/35. d Eight equivalents of
i-BuOH was used.
(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. Topics in Organometallic Chemistry: Palla-
dium in Organic Synthesis; Tsuji, J., Ed.; Springer: New York, 2005.
(c) Netherton, M. R.; Fu, G. C. AdV. Synth. Catal. 2004, 346, 1525-
1532.
tive formation of a tetravalent -ate complex by 11B NMR spec-
troscopy (eq 3).
(3) For two pioneering investigations of palladium- and nickel-catalyzed cross-
couplings of alkyl electrophiles, see: (a) Ishiyama, T.; Abe, S.; Miyaura,
N.; Suzuki, A. Chem. Lett. 1992, 691-694. (b) Devasagayaraj, A.; Stu¨de-
mann, T.; Knochel, P. Angew. Chem., Int. Ed. Engl. 1995, 34, 2723-2725.
(4) For additional leading references, see: Terao, J.; Kambe, N. Bull. Chem.
Soc. Jpn. 2006, 79, 663-672.
(5) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 14726-14727.
(6) For reviews of the Suzuki reaction, see: (a) Reference 1. (b) Miyaura, N.
Top. Curr. Chem. 2002, 219, 11-59.
(7) (a) Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 1340-1341. (b)
Gonza´lez-Bobes, F.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 5360-5361.
(8) Notes: (a) Certain other alcohols (2,2-dimethyl-1-propanol, 2-ethyl-1-
butanol, and s-BuOH) furnish comparable or slightly diminished yields.
(b) In the presence of KOi-Bu (1.2 equiv), rather than KOt-Bu/i-BuOH,
the desired product is generated in 74% yield.
(9) For discussions of transmetalation in the context of palladium-catalyzed
Suzuki reactions, see: (a) Matos, K.; Soderquist, J. A. J. Org. Chem.
1998, 63, 461-470. (b) Miyaura, N. J. Organomet. Chem. 2002, 653,
54-57.
(10) A competition experiment among secondary alkyl halides revealed the
following reactivity order: I > Br . Cl.
(11) Preliminary experiments indicate that, under our standard reaction
conditions, alkylboranes derived from the hydroboration of more highly
substituted olefins, as well as alkylboron reagents that bear certain
nitrogen-containing functional groups, are not suitable cross-coupling
partners. Furthermore, couplings of actiVated secondary alkyl halides (i.e.,
a benzylic bromide and an R-bromoester) have not proceeded cleanly.
We intend to explore the use of different ligands and reactions conditions
to address these limitations.
(12) In the case of the coupling depicted in entry 9 of Table 2, we have
determined that undesired products from elimination, reduction, or
homocoupling of the alkyl bromide are not formed in significant yields.
(13) Notes: (a) We have not yet undertaken optimization studies for cross-
couplings of these families of electrophiles. (b) A competition experiment
among alkyl bromides revealed the following reactivity order: secondary
> primary . tertiary (under our standard conditions, the cross-coupling
of tert-butyl bromide with PhCH2CH2CH2(9-BBN) proceeds in <5%
yield).
This new method can be applied to a range of alkyl-alkyl cross-
couplings of unactivated secondary bromides with alkylboranes
(Table 2). Not only cyclohexyl (entry 1) but also cyclopentyl and
cycloheptyl (entries 2 and 3) bromide are suitable reaction partners.
Bicyclic (entries 4 and 5), as well as acyclic (entry 6), alkyl halides
can be employed. Secondary bromides cross-couple in preference
to chlorides (entry 7).10 In addition to chlorides, other functional
groups can be present in the electrophile and in the organoborane
(e.g., ethers, carbamates, and esters; entries 8-13).11,12
The utility of this Ni/diamine catalyst is not limited to alkyl-
alkyl Suzuki reactions of secondary bromides. Thus, without
modification, the method can be applied to couplings of unactivated
secondary alkyl iodides, primary bromides, and primary iodides
(Table 3).13
In summary, we have established that a commercially available
1,2-diamine serves as an effective ligand for metal-catalyzed cross-
couplings of unactivated alkyl electrophiles at room temperature.
In particular, Ni/trans-N,N′-dimethyl-1,2-cyclohexanediamine pro-
vides the first method for achieving alkyl-alkyl Suzuki reactions
of unactivated secondary alkyl halides with alkylboranes; earlier
success in Suzuki couplings of such electrophiles had been restricted
to reactions with aryl- and vinylboron reagents at elevated tem-
JA074008L
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J. AM. CHEM. SOC. VOL. 129, NO. 31, 2007 9603