Hiyama reactions of activated and unactivated secondary alkyl halides catalyzed by a nickel/norephedrine complex

Article abstract of DOI:10.1002/anie.200700440

(Chemical Equation Presented) An active partner: Nickel in combination with an amino alcohol ligand (norephedrine) was found to provide the most versatile and efficient catalyst for Hiyama cross-coupling reactions of alkyl electrophiles that has been described to date. Unprecedented Hiyama reactions of activated secondary alkyl bromides were achieved, as were the first Hiyama couplings of (activated) alkyl chlorides (see scheme, X = Br, Cl; HMDS = 1,1,1,3,3,3-hexamethyldisilazane, DMA = N,N-dimethylacetamide).

Full text of DOI:10.1002/anie.200700440

Communications
DOI: 10.1002/anie.200700440
Homogeneous Catalysis
Hiyama Reactions of Activated and Unactivated Secondary Alkyl
Halides Catalyzed by a Nickel/Norephedrine Complex**
Neil A. Strotman, Stefan Sommer, and Gregory C. Fu*
We recently reported that a nickel/bathophenanthroline-
based catalyst accomplishes Hiyama couplings[1] of unacti-
vated secondary alkyl electrophiles for the first time [Eq. (1),
DMSO = dimethyl sulfoxide].[2] Although this represented a
Despite this initial discouraging result, we recognized that
a diverse array of amino alcohols are readily (and commer-
cially) available, and we decided to explore the possibility that
one such ligand might enable us to address the shortcomings
of our first-generation catalyst for Hiyama reactions of alkyl
halides. After considerable effort, we were pleased to
determine that, in the presence of norephedrine, we can
achieve the cross-coupling of cyclohexyl bromide with F3SiPh
in very good yield (Table 1, entry 1).[7] As illustrated in
Table 1: Hiyama reactions of alkyl halides: effect of the amino alcohol
ligand.[a]
step forward in the expansion of the scope of metal-catalyzed
cross-coupling reactions,[3,4] it was not an ideal solution from
at least three standpoints: First, the yields of the Hiyama
reactions were moderate (60–82%); second, the method was
not generally effective for activated secondary alkyl halides;
and third, only bipyridine-type ligands that lack a substituent
ortho to the nitrogen atom furnished useful catalysts (that is,
bathophenanthroline, 1,10-phenanthroline, and 2,2’-bipyri-
dine, but not neocuproine). This sensitivity to substitution
represented a significant impediment to our long-term goal of
achieving asymmetric Hiyama reactions, since virtually all of
the effective chiral bipyridines that have been described have
groups in the ortho position.[5]
Entry
1
Ligand
Yield [%][b]
89
2
15
3
4
14
74
In 2006 we reported that an amino alcohol can serve as a
useful ligand for cross-coupling reactions of unactivated alkyl
electrophiles [Suzuki coupling reactions: Eq. (2), HMDS =
1,1,1,3,3,3-hexamethyldisilazane].[6] Unfortunately, when we
5
6
47
53
[a] DMA=N,N-dimethylacetamide. [b] Yield determined from GC anal-
ysis against a calibrated internal standard (average of two experiments).
attempted a Hiyama reaction with trans-2-aminocyclohexanol
[cyclohexyl bromide and F3SiPh, Eq. (1)], we obtained none
of the desired cross-coupling product.
Table 1, the structure of the amino alcohol plays a critical role
in determining the efficiency of the Hiyama reaction. Thus,
substituents on the nitrogen atom (Table 1, entry 2) and
changes in the groups on the two-carbon tether (Table 1,
entries 3 and 4) had a significant impact on catalyst activity.
The two amino alcohols that we had employed in our earlier
investigation of the Suzuki reaction[2] provided only modest
yields in Hiyama cross-coupling reactions under these con-
ditions (Table 1, entries 5 and 6).[8]
[*] Dr. N. A. Strotman, Dr. S. Sommer, Prof. Dr. G. C. Fu
Department of Chemistry
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
Fax: (+1)617-324-3611
E-mail: gcf@mit.edu
The nickel/norephedrine catalyst could be applied to
Hiyama reactions of a variety of unactivated secondary alkyl
bromides (Table 2, entries 1–8).[9] As indicated in Table 2, this
method typically gave significantly higher yields than the
previously reported bathophenanthroline-based catalyst.
Both cyclic (Table 2, entries 1–5) and acyclic (entries 6–8)
[**] Support has been provided by the National Institutes of Health
(National Institute of General Medical Sciences, R01-GM62871),
the German Academic Exchange Service (postdoctoral fellowship to
S.S.), Merck Research Laboratories, and Novartis.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 2: Nickel/norephedrine-catalyzed Hiyama reactions of unactivated
Table 3: Nickel/norephedrine-catalyzed Hiyama reactions of activated
alkyl halides.
alkyl halides.[a]
Entry
1
Alkyl halide
Ar
Yield [%][b]
88
Entry
1
Alkyl halide
Ar
Yield [%][a]
78
2
59
2
3
4
5
6
7
82
3
4
85
82
83
5
6
89[c]
76[c]
92
76
7
65
80[b]
84
8
9
86
94
[a] Cbz=benzyloxycarbonyl. [b] Yield of isolated product (average of two
experiments). [c] Purity of product: 97%.
8
9
86
60
alkyl bromides were found to cross-couple with an array of
aryl silanes. The catalyst tolerated a range of functional
groups (Table 2, entries 2–4 and 6–8) and could be employed,
without modification, in Hiyama coupling reactions of
unactivated secondary alkyl iodides (Table 2, entry 9).
Although the original nickel/bathophenanthroline cata-
lyst [Eq. (1)] could achieve Hiyama reactions of unactivated
secondary alkyl bromides and iodides, it was found to be
generally not effective for cross-coupling reactions of acti-
vated halides, perhaps as a result of the propensity of the
oxidative-addition adduct to undergo b-hydride elimination
to produce a conjugated olefin. Indeed, to the best of our
knowledge, there are no reports of Hiyama couplings of
activated secondary alkyl electrophiles.
The nickel/norephedrine-based catalyst addresses this gap
in the methodology: thus, the conditions that we had
developed for Hiyama reactions of unactivated secondary
alkyl halides (Table 2) could be applied directly to cross-
coupling reactions of a range of activated electrophiles
(Table 3).[10] For example, a-brominated ketones, esters,
amides, phosphonates, and nitriles were suitable coupling
partners (Table 3, entries 1–5).[11] Interestingly, the standard
reaction conditions could also be employed for Hiyama cross-
coupling reactions of activated alkyl chlorides, including an
allylic chloride (Table 3, entries 6–11). As far as we are aware,
there is no precedent for a Hiyama coupling of an alkyl
chloride.
10
11
88
76
[a] Yield of isolated product (average of two experiments). [b] 1:1 mixture
of diastereomers.
In summary, we have established that a nickel/amino
alcohol based catalyst provides the most efficient and
versatile method that has been described to date for
Hiyama reactions of secondary alkyl electrophiles. Not only
unactivated, but also activated, halides can be employed as
coupling partners. In addition to cross-coupling reactions of
alkyl bromides and iodides, the first Hiyama reactions of
(activated) alkyl chlorides have been achieved. In combina-
tion with an earlier study of nickel/amino alcohol catalyzed
Suzuki couplings, this investigation suggests that the readily
available amino alcohols may prove to be useful ligands for a
wide range of cross-coupling reactions of alkyl electrophiles.
Efforts to substantiate this hypothesis, as well as to exploit
enantiopure amino alcohols to accomplish asymmetric pro-
cesses, are underway.
Received: January 31, 2007
Published online: April 19, 2007
Angew. Chem. Int. Ed. 2007, 46, 3556 –3558ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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Communications
PhSiCl3 nor PhSi(OMe)3 proved to be an effective coupling
partner; d) the cross-coupling reaction did occur in the absence
of 8% H2O, but less efficiently; the origin of this water (or
hydroxide) effect is not yet clear.
Keywords: amino alcohols · cross-coupling ·
homogeneous catalysis · nickel · silicon
.
[8] Bathophenanthroline proved to be ineffective (< 5% yield).
[9] a) In preliminary experiments under our standard conditions,
Hiyama cross-coupling reactions of hindered unactivated sec-
ondary bromides, unactivated secondary chlorides, and primary
halides have not been efficient (< 50% yield). We have not yet
explored the capacity of other nickel/amino alcohol catalysts to
achieve Hiyama reactions of these families of substrates; b) we
can efficiently cross-couple an unactivated secondary alkyl
bromide (> 80% yield) in the presence of an unactivated
secondary alkyl chloride (< 2% yield).
[10] a) We have established that gram-scale Hiyama cross-coupling
reactions proceed in good yield (ethyl 2-chloropropionate with
PhSiF3, 1.44 g (81%)); b) we could effect the selective cross-
coupling reaction (krel > 50) of an activated secondary bromide
(ethyl 2-bromoisovalerate) in the presence of an unactivated
secondary bromide (cyclohexyl bromide); c) a preliminary study
indicates that benzylic halides are not useful cross-coupling
partners under our standard conditions.
[11] To the best of our knowledge, no examples of nickel- or
palladium-catalyzed cross-coupling reactions of secondary a-
halocarbonyl compounds with aryl metal reagents (for example,
boron, silicon, tin, and zinc) have been described; couplings of
primary a-halocarbonyl compounds appear to be limited to
Suzuki reactions; for examples, see: a) M. Sato, N. Miyaura, A.
Suzuki, Chem. Lett. 1989, 1405 – 1408; b) L. J. Goossen, Chem.
Commun. 2001, 669 – 670; c) X.-x. Liu, M.-z. Deng, Chem.
Commun. 2002, 622 – 623; d) T.-Y. Lu, C. Xue, F.-T. Luo,
Tetrahedron Lett. 2003, 44, 1587 – 1590; e) Y.-Z. Duan, M.-Z.
Deng, Tetrahedron Lett. 2003, 44, 3423 – 3426.
[1] For reviews of the Hiyama reaction, see: a) S. E. Denmark, R. F.
Sweis in Metal-Catalyzed Cross-Coupling Reactions (Eds.: A.
de Meijere, F. Diederich), Wiley-VCH, New York, 2004, chap. 4;
b) T. Hiyama, E. Shirakawa, Top. Curr. Chem. 2002, 219, 61 – 85.
[2] D. A. Powell, G. C. Fu, J. Am. Chem. Soc. 2004, 126, 7788 – 7789;
See also: J.-Y. Lee, G. C. Fu, J. Am. Chem. Soc. 2003, 125, 5616 –
5617.
[3] For reviews of metal-catalyzed cross-coupling reactions, see:
a) Metal-Catalyzed Cross-Coupling Reactions (Eds.: A. de Mei-
jere, F. Diederich), Wiley-VCH, New York, 2004; b) Handbook
of Organopalladium Chemistry for Organic Synthesis (Ed.: E.-i.
Negishi), Wiley Interscience, New York, 2002.
[4] For recent reviews of cross-coupling reactions of alkyl electro-
philes, see: a) A. C. Frisch, M. Beller, Angew. Chem. 2005, 117,
680 – 695; Angew. Chem. Int. Ed. 2005, 44, 674 – 688; b) M. R.
Netherton, G. C. Fu, Topics in Organometallic Chemistry:
Palladium in Organic Synthesis (Ed.: J. Tsuji), Springer, New
York, 2005; c) M. R. Netherton, G. C. Fu, Adv. Synth. Catal.
2004, 346, 1525 – 1532.
[5] For reviews of chiral bipyridine and phenanthroline ligands, see:
a) G. Chelucci, R. P. Thummel, Chem. Rev. 2002, 102, 3129 –
3170; b) A. V. Malkov, P. Kocovsky, Curr. Org. Chem. 2003, 7,
1737 – 1757; c) N. C. Fletcher, J. Chem. Soc. Perkin Trans. 1 2002,
1831 – 1842; d) E. Schoffers, Eur. J. Org. Chem. 2003, 1145 –
1152.
[6] F. Gonzµlez-Bobes, G. C. Fu, J. Am. Chem. Soc. 2006, 128, 5360 –
5361.
[7] a) In the absence of NiCl2·glyme or of norephedrine, no cross-
coupling was observed; b) the Hiyama reaction proceeded best
at high concentrations (0.5m); c) under these conditions, neither
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