Alkyl-alkyl Suzuki cross-coupling of unactivated secondary alkyl chlorides

Article abstract of DOI:10.1002/anie.201003272

No such thing as a problem substrate! In a reaction designed specifically for the title substrates C-C coupling with alkyl boranes occurred in good yield at room temperature with commercially available catalyst components (see scheme). This versatile method is also suitable for Suzuki reactions of secondary and primary alkyl bromides and iodides, as well as primary alkyl chlorides.

Full text of DOI:10.1002/anie.201003272

Communications
DOI: 10.1002/anie.201003272
Cross-Coupling
Alkyl–Alkyl Suzuki Cross-Coupling of Unactivated Secondary Alkyl
Chlorides**
Zhe Lu and Gregory C. Fu*
Table 1: Effect of reaction parameters on an alkyl–alkyl Suzuki cross-
coupling reaction of an unactivated secondary alkyl chloride.
Among cross-coupling processes that form carbon–carbon
bonds, the Suzuki reaction is perhaps the most widely used,
owing to considerations such as functional-group tolerance,
the accessibility of organoboron coupling partners, and
toxicity issues.[1] Most early investigations of Suzuki cross-
coupling focused on reactions of aryl and vinyl electrophiles.
Of course, the ability to also couple a wide range of alkyl
electrophiles would significantly enhance the utility of Suzuki
reactions, and advances toward this goal have been de-
scribed.[2,3] Despite this progress, many classes of alkyl–alkyl
Suzuki cross-coupling reactions still have not been achieved,
including reactions of unactivated secondary alkyl chlor-
ides.[4,5] Herein, we establish that this family of electrophiles
can indeed serve as suitable partners in alkyl–alkyl Suzuki
coupling reactions under mild conditions through the use of
an appropriate nickel catalyst [Eq. (1)].
Entry
Nickel source
Ligand
Solvent
Yield [%][a]
1
2
3
4
NiCl2·glyme
2
2
1
1
dioxane
dioxane
dioxane
iPr2O
9
14
43
86
NiBr2·diglyme
NiBr2·diglyme
NiBr2·diglyme
[a] Determined by GC with a calibrated internal standard (average of two
experiments).
ining the various reaction parameters, we determined that the
desired cross-coupling of an unactivated secondary alkyl
chloride can in fact be carried out efficiently at room
temperature. Specifically, by altering the nickel source
(Table 1, entry 1!entry 2), the ligand (entry 2!entry 3),
and the solvent (entry 3!entry 4), we developed a method
that furnished the target coupling product in good yield
(Table 1, entry 4: 86%). Furthermore, all of the catalyst
components are commercially available.
One practical drawback of our previous procedures for
alkyl–alkyl Suzuki reactions of secondary bromides/iodides[4]
was our observation that cross-coupling reactions that were
set up without a glove box proceeded in lower yield than
reactions conducted in a glove box. When we attempted to
employ the method illustrated in entry 4 of Table 1 without a
glove box, the product was also obtained in diminished yield.
We hypothesized that adventitious water might be the culprit
and therefore added powdered 4 ꢀ molecular sieves to the
reaction mixture. Indeed, with this modification, we obtained
the Suzuki coupling product of the secondary chloride in good
yield (83%) without the use of a glove box.
In the case of our previously described method for the
alkyl–alkyl Suzuki cross-coupling of secondary bromides and
iodides,[4a] we observed that the corresponding chlorides are
much less reactive. For example, the coupling illustrated in
entry 1 of Table 1 proceeded in poor yield (9%) when that
procedure was applied. Nevertheless, by systematically exam-
[*] Z. Lu, 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
[**] Support has been provided by the National Institutes of Health
(National Institute of General Medical Sciences, grant R01-
GM62871), Eli Lilly (fellowship to Z.L.), the Martin Family Society of
Fellows for Sustainability (fellowship to Z.L.), Merck Research
Laboratories, and Novartis. We thank Dr. Bunnai Saito for
preliminary studies and Dr. Jeffrey H. Simpson for assistance with
NMR spectroscopy.
The scope of this new cross-coupling method is fairly
broad.[6] Both cyclic secondary alkyl chlorides (Table 2,
entries 1–6), including nitrogen and oxygen heterocycles
(entries 5 and 6), and acyclic secondary alkyl chlorides
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201003272.
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Table 2: Alkyl–alkyl Suzuki cross-coupling reactions of unactivated
Table 3: Alkyl–alkyl Suzuki cross-coupling reactions of unactivated alkyl
secondary alkyl chlorides [for reaction conditions, see Equation (1)].
halides [for reaction conditions, see Equation (1)].
1
1
Entry R Cl
9-BBN R
Yield [%][a]
Entry
9-BBN R
Yield [%][a]
ꢀ
ꢀ
ꢀ
R X
ꢀ
1
2
3
4
5
6
7
8
X=Br: 75
X=I: 75
X=Br: 65
X=I: 64
X=Br: 74
X=I: 76
X=Br: 75
X=I: 76
1
2
80
69[b]
53[b]
3
4
9
63
70
67[c]
10
11
78
5
6
70
71
[a] Yield of the isolated product (average of two experiments). Ts=p-
toluenesulfonyl.
7
8
9
72
64
64
bromide underwent cross-coupling at comparable rates,
whereas the alkyl chloride reacted more slowly.
10
11
74
72
12
13
81
83
[a] Yield of the isolated product (average of two experiments). [b] Dia-
stereoselectivity: trans/cis >20:1 (relative to the proximal substituent).
[c] Diastereoselectivity: b/a 2:1. Cbz=carbobenzyloxy, TBS=tert-butyl-
dimethylsilyl, TIPS=triisopropylsilyl.
Interestingly, in competition experiments between pairs of
cyclohexyl electrophiles, the catalyst differentiated effectively
between alkyl halides [Eq. (3)].[8] Collectively, these data are
consistent with oxidative addition not being the turnover-
limiting step of the catalytic cycle in the case of cyclohexyl
iodide and bromide.[9]
(entries 7–13) are suitable substrates. A variety of functional
groups are compatible with the reaction conditions, such as
alkyl and silyl ethers (Table 2, entries 2, 6, 8, 9, and 13),
alkenes (entry 4), carbamates (entry 5), esters (entries 11 and
12), and acetals (entries 12 and 13).
This method for alkyl–alkyl Suzuki cross-coupling, which
we optimized for a new family of substrates (unactivated
secondary alkyl chlorides), can be applied without modifica-
tion to an array of other reaction partners. Thus, secondary
alkyl bromides and iodides, both cyclic (including hetero-
cyclic) and acyclic, are suitable electrophiles (Table 3,
entries 1–8).[7] Furthermore, primary alkyl chlorides, bro-
mides, and iodides underwent the Suzuki coupling in good
yield (entries 9–11).
We determined that, for the reaction of cyclohexyl
bromide, the rate law is first-order in the catalyst
(NiBr2·diglyme/ligand 1), first-order in the alkyl borane, and
zeroth-order in the electrophile. These data are also consis-
tent with oxidative addition not being the turnover-limiting
We examined the relative reactivity of cyclohexyl halides
in Suzuki cross-coupling reactions with an alkyl borane under
this set of conditions [Eq. (2)]. The alkyl iodide and the alkyl
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[3] For examples of applications of alkyl–alkyl Suzuki cross-coupling
reactions in the total synthesis of natural products, see: a) K. A.
Keaton, A. J. Phillips, Org. Lett. 2007, 9, 2717 – 2719; b) N. D.
Griggs, A. J. Phillips, Org. Lett. 2008, 10, 4955 – 4957.
[4] For alkyl–alkyl Suzuki reactions of unactivated secondary alkyl
bromides and/or iodides, see: a) B. Saito, G. C. Fu, J. Am. Chem.
Soc. 2007, 129, 9602 – 9603; b) B. Saito, G. C. Fu, J. Am. Chem.
Soc. 2008, 130, 6694 – 6695.
step for this Suzuki reaction of cyclohexyl bromide. In
contrast, for cyclohexyl chloride, the rate of cross-coupling
is dependent on the concentration of the electrophile.
In conclusion, we have developed the first alkyl–alkyl
Suzuki reaction of unactivated secondary alkyl chlorides.
Carbon–carbon bond formation occurs under mild conditions
(at room temperature) with the aid of commercially available
catalyst components. This method, although developed for
the cross-coupling of unactivated secondary chlorides, has
proved to be versatile: without modification, it can be applied
to Suzuki reactions of secondary and primary alkyl bromides
and iodides, as well as primary alkyl chlorides. Mechanistic
investigations suggest that oxidative addition is not the
turnover-limiting step of the catalytic cycle for unactivated
secondary alkyl iodides and bromides, whereas it may be
(partially) for the corresponding alkyl chlorides. Additional
mechanistic and catalyst-development studies of a wide array
of alkyl–alkyl cross-coupling reactions are under way.
[5] For alkyl–aryl Suzuki reactions of unactivated secondary alkyl
iodides, bromides, and chlorides at 608C, see: F. Gonzꢁlez-Bobes,
G. C. Fu, J. Am. Chem. Soc. 2006, 128, 5360 – 5361; see also: J.
Zhou, G. C. Fu, J. Am. Chem. Soc. 2004, 126, 1340 – 1341.
[6] Additional details about the reaction: 1) In the absence of
NiBr2·diglyme or ligand 1, essentially none of the desired product
was formed (< 1%). 2) On a gram scale, the Suzuki reaction in
entry 1 of Table 2 proceeded in 79% yield (yield of the isolated
product, average of two experiments). 3) Under our standard
conditions, secondary alkyl boranes, primary alkyl boronate
esters, primary alkyl boronic acids, and primary alkyl trifluor-
oborates did not undergo cross-coupling in good yield. 4) By
11B NMR spectroscopy, we determined that the potassium
alkoxide reacts with the alkyl-9-BBN reagent to form a tetrava-
lent boron complex. This interaction not only activates the trialkyl
borane reagent, but also attenuates the Brønsted basicity of the
reaction mixture. 5) On a 1 mmol scale in a microwave (608C for
3.5 h), the cross-coupling reaction in entry 1 of Table 2 proceeded
in 74% yield. 6) When tBuOMe or Et2O was used as the solvent
in place of iPr2O, product yields were slightly lower, whereas the
use of THF led to a greatly diminished yield.
Received: May 30, 2010
Published online: August 16, 2010
Keywords: alkyl halides · boron · cross-coupling ·
.
homogeneous catalysis · nickel
[7] Under our standard conditions, attempts to cross-couple an
unactivated tertiary chloride, bromide, and iodide led to essen-
tially none of the desired products.
[1] For leading references, see: a) Metal-Catalyzed Cross-Coupling
Reactions (Eds.: A. de Meijere, F. Diederich), Wiley-VCH,
Weinheim, 2004; b) Handbook of Organopalladium Chemistry
for Organic Synthesis (Ed.: E.-i. Negishi), Wiley-Interscience,
New York, 2002; c) Cross-Coupling Reactions: A Practical Guide,
Topics in Current Chemistry Series 219 (Ed.: N. Miyaura),
Springer, New York, 2002.
[8] High selectivity (I > Br> Cl) is often observed in oxidative
addition/abstraction processes that proceed through an inner-
sphere electron-transfer pathway; see, for example: S. L. Scott,
J. H. Espenson, Z. Zhu, J. Am. Chem. Soc. 1993, 115, 1789 – 1797.
[9] For mechanistic proposals for nickel-catalyzed Negishi reactions
of alkyl electrophiles, see: a) G. D. Jones, J. L. Martin, C. McFar-
land, O. R. Allen, R. E. Hall, A. D. Haley, R. J. Brandon, T.
Konovalova, P. J. Desrochers, P. Pulay, D. A. Vicic, J. Am. Chem.
Soc. 2006, 128, 13175 – 13183; b) X. Lin, D. L. Phillips, J. Org.
Chem. 2008, 73, 3680 – 3688.
[2] a) For a pioneering study of Suzuki reactions of primary alkyl
electrophiles, see: T. Ishiyama, S. Abe, N. Miyaura, A. Suzuki,
Chem. Lett. 1992, 691 – 694; b) for a review of cross-coupling
reactions of secondary alkyl electrophiles, see: A. Rudolph, M.
Lautens, Angew. Chem. 2009, 121, 2694 – 2708; Angew. Chem. Int.
Ed. 2009, 48, 2656 – 2670.
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