Nickel-catalyzed Negishi cross-couplings of secondary nucleophiles with secondary propargylic electrophiles at room temperature

Article abstract of DOI:10.1002/anie.200802784

(Chemical Equation Presented) Mild thing: The first nickel-based catalysts for cross-couplings of secondary organometallic nucleophiles with secondary alkyl electrophiles have been developed. Thus, Negishi reactions proceed under mild conditions (at room temperature with no basic activators) in the presence of NiCl₂·glyme and a tridentate ligand (see scheme).

Full text of DOI:10.1002/anie.200802784

Communications
DOI: 10.1002/anie.200802784
Homogeneous Catalysis
Nickel-Catalyzed Negishi Cross-Couplings of Secondary Nucleophiles
with Secondary Propargylic Electrophiles at Room Temperature**
Sean W. Smith and Gregory C. Fu*
Table 1: Negishi reactions of secondary nucleophiles with secondary
propargylic electrophiles: Effect of reaction parameters.
In recent years, significant progress has been made in the
development of metal-catalyzed cross-couplings of alkyl
electrophiles.[1] A number of substantial challenges have not
yet been met, including the coupling of sterically demanding
partners. For example, to our knowledge, palladium- or
nickel-catalyzed cross-couplings of secondary alkyl electro-
philes with secondary organometallic nucleophiles have not
been reported.[2] Recognizing the importance of overcoming
Entry Variation from the “standard” conditions
Yield [%][a]
this limitation, we have recently turned our attention to
addressing such deficiencies. The ease of synthesis and
functional-group compatibility of alkylzinc reagents led us
to focus our efforts on Negishi reactions.[3–5] Herein, we
describe the first nickel-based catalysts for cross-couplings of
secondary nucleophiles with secondary electrophiles [Eq. 1;
X = Br, Cl].
1
2
3
4
5
6
7
8
9
none
no NiCl2·glyme
no terpyridine
TMS, instead of TIPS
89
<5
<5
48
15
<5
10
62
11
9
Me, instead of TIPS
bipyridine, instead of terpyridine
isopropyl pybox, instead of terpyridine
2,6-bis(N-pyrazolyl)pyridine, instead of terpyridine
THF, instead of DMA
DMF, instead of DMA
DMI, instead of DMA
10
11
4
[a] The yield was determined by GC, calibrated using an internal
standard. DMI=1,3-dimethyl-2-imidazolidinone.
As part of our initial investigation, we explored the
Negishi reaction illustrated in Table 1.[6] Unfortunately, none
of the previously reported methods for cross-couplings of
secondary alkyl electrophiles with primary alkylzinc reagents
furnished the desired product in substantial yield (< 20%).[7,8]
By optimizing the various reaction parameters, we were able
to develop a catalyst system that achieves this Negishi cross-
coupling with good efficiency at room temperature (89%
yield; Table 1, entry 1).[9] In the absence of NiCl2·glyme or
terpyridine, essentially no carbon–carbon bond formation
occurs (Table 1, entries 2 and 3). If the bulky TIPS substituent
is replaced with a smaller silyl or alkyl group, the yield of the
cross-coupling decreases, as a result of the formation of a
substantial amount of homocoupled electrophile (Table 1,
entries 4 and 5).[10] The other ligands, both bidentate and
tridentate, that we have examined are less useful than
terpyridine (Table 1, entries 6–8), as are solvents other than
N,N-dimethylacetamide (DMA; Table 1, entries 9–11).
Our optimized method (NiCl2·glyme/terpyridine/DMA)
can be applied to cross-couplings of a range of secondary
propargylic bromides with secondary alkylzinc reagents
(Table 2). Esters, olefins (no E/Z isomerization), ethers, and
carbamates are compatible with the reaction conditions.[11]
Although our primary objective was to develop a method
for secondary–secondary cross-couplings, we were also inter-
ested in exploring the versatility of this catalyst. We have
determined that, without modification, NiCl2·glyme/terpyr-
idine/DMA can also be applied to Negishi reactions of less-
hindered coupling partners, for example, primary alkylzinc
reagents with secondary/primary propargylic bromides
(Table 3). Cross-couplings proceed in very good yield in the
presence of an unactivated primary alkyl chloride, an ether,
and an ester.[12]
[*] S. W. Smith, 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
If the alkyl group of the organozinc reagent is more
hindered than cyclohexyl or isopropyl, the efficiency of
NiCl2·glyme/terpyridine/DMA diminishes significantly (e.g.,
Table 4, entry 1, L = terpyridine: 20% yield). However, by
replacing terpyridine with a related ligand, 2,6-bis(N-pyrazo-
[**] Support has been provided by the NIH (National Institute of
General Medical Sciences, R01-GM62871), Merck Research Labo-
ratories, and Novartis.
Supporting Information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200802784.
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Table 2: Room-temperature Negishi reactions of secondary nucleophiles
with secondary propargylic electrophiles.
Table 4: Room-temperature Negishi reactions of secondary nucleophiles
with secondary propargylic electrophiles.
1
Yield [%][a]
ꢀ
Entry
R
Alkyl
R
ZnI
1
2
3
4
5
TIPS
TIPS
TIPS
TIPS
TIPS
nBu
88
72
72
70
76
1
ꢀ
Entry
1
Alkyl
R ZnI
Yield [%][a]
86
nBu
2
3
78
82
nBu
Me
6
TIPS
63
4
81
7
8
tBu
tBu
72
73
5
6
nBu
76[b]
50[b]
[a] Yield of purified product (average of two experiments). Cbz=carbo-
benzyloxy.
[a] Yield of purified product (average of two experiments). [b] Equivalents
of organozinc reagent: 3.0.
Table 3: Negishi reactions of primary nucleophiles with secondary and
primary propargylic electrophiles.
1
Yield [%][a]
97
ꢀ
Entry
1
R
R
ZnBr
2
3
96
90
H
We applied our method for secondary–secondary cross-
couplings to the formal total synthesis of a-cembra-2,7,11-
triene-4,6-diol (Scheme 1), a cembranoid diterpene with
antitumor activity, which has been synthesized by the
groups of Marshall[16] and Thomas.[17] We envisioned that
the isopropyl substituent could be installed by a Negishi
reaction of propargylic bromide 1, which can be generated
from farnesyl acetate; indeed, using our nickel/terpyridine
method, we achieved the desired cross-coupling in 61% yield
on a gram scale. In preliminary studies, we converted coupling
product 2 into 14-membered macrocycle 3, which served as an
intermediate in the Thomas synthesis of a-cembra-2,7,11-
triene-4,6-diol.[17,18]
[a] Yield of purified product (average of two experiments).
lyl)pyridine, and using THFas the solvent, the desired Negishi
cross-coupling can be achieved in good yield (e.g., Table 4,
entry 1: 86% yield).[13,14] Many functional groups, such as
alkynes, unactivated alkyl chlorides, and ethers, are tolerated
by this method (Table 4).[15]
We have determined that our coupling conditions can be
employed not only for propargylic bromides, but also for
propargylic chlorides (also at room temperature; [Eqs. 2 and
3]).
In conclusion, we have developed the first method for
secondary–secondary cross-couplings with a Group 10 tran-
sition-metal catalyst, specifically, a nickel-based system for
coupling propargylic halides with alkylzinc reagents that
proceeds under mild conditions (at room temperature and
with no basic activators). Future efforts will focus on further
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Jones, D. A. Vicic, J. Am. Chem. Soc. 2004, 126, 8100 – 8101;
b) X. Lin, D. L. Phillips, J. Org. Chem. 2008, 73, 3680 – 3688.
[6] Palladium-catalyzed cross-coupling reactions of propargylic
electrophiles with organometallic reagents typically provide
the allene, rather than the alkyne, as the predominant product.
See: a) J. Tsuji, T. Mandai in Metal-Catalyzed Cross-Coupling
Reactions (Eds.: A. de Meijere, F. Diederich), Wiley-VCH, New
York, 2004, chap. 10; b) S. Ma, Eur. J. Org. Chem. 2004, 1175 –
1183. The regioselectivity of the corresponding nickel-catalyzed
processes has not been well-studied.
[7] For some recent examples, see: a) unactivated electrophiles: J.
Zhou, G. C. Fu, J. Am. Chem. Soc. 2003, 125, 14726 – 14727;
b) activated electrophiles: S. Son, G. C. Fu, J. Am. Chem. Soc.
2008, 130, 2756 – 2757; F. O. Arp, G. C. Fu, J. Am. Chem. Soc.
2005, 127, 10482 – 10483; C. Fischer, G. C. Fu, J. Am. Chem. Soc.
2005, 127, 4594 – 4595.
[8] In addition, we explored previously reported methods for
Negishi reactions of primary alkyl electrophiles. For example,
see: a) Reference [5a]; b) A. E. Jensen, P. Knochel, J. Org.
Chem. 2002, 67, 79 – 85.
Scheme 1. Application of a secondary–secondary Negishi cross-cou-
pling in a formal total synthesis of a-cembra-2,7,11-triene-4,6-diol.
TBDPS=tert-butyldiphenylsilyl.
[9] For the use of [Ni(cod)2]/terpyridine (and terpyridine deriva-
tives; cod = 1,5-cyclooctadiene) in THF as a catalyst for Negishi
reactions of primary alkyl halides with primary alkylzinc
reagents, see: a) Reference [5a]; b) G. D. Jones, C. McFarland,
T. J. Anderson, D. A. Vicic, Chem. Commun. 2005, 4211 – 4213.
For the Negishi reaction depicted in Table 1, Vicicꢁs procedure
furnished the desired cross-coupling product in low yield
(< 20%).
expanding the scope of cross-coupling reactions of alkyl
electrophiles.
[10] Homocoupling of the propargylic halide to generate a bis-
(allene) or an allene–alkyne is the major side reaction. No other
undesired product (e.g., from cross-coupling of the propargylic
bromide with the organozinc reagent to form an allene, or from
b-hydride elimination) has been identified. For all of the
reactions that are reported in Tables 2–4, the starting propargylic
halide is consumed.
[11] Notes: a) In the absence of NiCl2·glyme or terpyridine, essen-
tially no cross-coupling occurs; b) Organozinc iodides, rather
than bromides, were employed owing to ease of synthesis;
c) Attempts to cross-couple an acetone-protected (i.e., R =
CMe2OH in [Eq. (1)]) or an aryl-substituted alkyne were not
successful; d) Under our standard conditions, Negishi reactions
of hindered electrophiles (e.g., alkyl = iPr in Table 2) proceed in
low yield, and unactivated alkyl chlorides are not suitable cross-
coupling partners.
[12] A Negishi cross-coupling of a primary propargylic bromide with
a secondary alkylzinc reagent proceeded in low yield.
[13] For the Negishi reaction illustrated in Table 4, entry 1, the
change in solvent (THF instead of DMA) and the change in
ligand (2,6-bis(N-pyrazolyl)pyridine in place of terpyridine)
contribute comparably to the increase in yield (20!86%).
[14] Vicic et al have reported that [Ni(cod)2]/2,6-bis(N-pyrazolyl)-
pyridine in THF catalyzes the Negishi coupling of a primary
alkylzinc reagent with a primary alkyl bromide (45% yield) and
with a primary alkyl iodide (67% yield): Reference [5a].
[15] Notes: a) Under these conditions, tBuZnI is not a suitable cross-
coupling partner; b) For Negishi reactions of less-hindered
alkylzinc reagents (e.g., those illustrated in Table 2),
NiCl2·glyme/2,6-bis(N-pyrazolyl)pyridine/THF is not as effec-
tive as NiCl2·glyme/terpyridine/DMA.
Received: June 12, 2008
Revised: July 13, 2008
Published online: October 29, 2008
Keywords: alkynes · cross-coupling · homogeneous catalysis ·
.
nickel · zinc
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117, 680 – 695; Angew. Chem. Int. Ed. 2005, 44, 674 – 688;
b) M. R. Netherton, G. C. Fu, Topics in Organometallic Chemis-
try: Palladium in Organic Synthesis (Ed.: J. Tsuji), Springer, New
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Synth. Catal. 2004, 346, 1525 – 1532.
[2] Malosh and Ready reported copper-catalyzed couplings of
secondary a-chloroketones with secondary alkylzinc reagents.
It is postulated that, unlike typical palladium- and nickel-
catalyzed cross-couplings, these reactions proceed without
oxidative addition of the electrophile to the catalyst. See: C. F.
Malosh, J. M. Ready, J. Am. Chem. Soc. 2004, 126, 10240 – 10241.
[3] For a review of the Negishi reaction, see: E.-i. Negishi, Q. Hu, Z.
Huang, G. Wang, N. Yin in The Chemistry of Organozinc
Compounds (Eds.: Z. Rappoport, I. Marek), Wiley, New York,
2006, chap. 11.
[4] For pioneering studies of nickel-catalyzed Negishi reactions of
alkyl electrophiles, see: a) A. Devasagayaraj, T. Stꢀdemann, P.
Knochel, Angew. Chem. 1995, 107, 2952 – 2954; Angew. Chem.
Int. Ed. Engl. 1995, 34, 2723 – 2725; b) R. Giovannini, T.
Stꢀdemann, A. Devasagayaraj, G. Dussin, P. Knochel, J. Org.
Chem. 1999, 64, 3544 – 3553.
[16] J. A. Marshall, E. D. Robinson, J. Lebreton, J. Org. Chem. 1990,
55, 227 – 239.
[17] P. C. Astles, E. J. Thomas, J. Chem. Soc. Perkin Trans. 1 1997,
845 – 856.
[5] For mechanistic studies of 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. See also: T. J. Anderson, G. D.
[18] For additional details, see the Supporting Information.
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