Stereoselective Negishi-like couplings between alkenyl and alkyl halides in water at room temperature

Article abstract of DOI:10.1021/ol101885t

Mix in water and then stir. That is all that is required in this new approach to stereoselective sp³-sp² cross-couplings between an alkyl and alkenyl halide. Prior formation of organozinc reagents is not required.

Full text of DOI:10.1021/ol101885t

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4742-4744
Stereoselective Negishi-like Couplings
Between Alkenyl and Alkyl Halides in
Water at Room Temperature
Arkady Krasovskiy, Christophe Duplais, and Bruce H. Lipshutz*
Department of Chemistry & Biochemistry, UniVersity of California, Santa Barbara,
California 93106, United States
lipshutz@chem.ucsb.edu
Received August 17, 2010
ABSTRACT
Mix in water and then stir. That is all that is required in this new approach to stereoselective sp3-sp2 cross-couplings between an alkyl and
alkenyl halide. Prior formation of organozinc reagents is not required.
Palladium-catalyzed cross-couplings involving E- or Z-
alkenyl halides lie at the very origin of several of the most
commonly used ‘name’ reactions.1 These include Negishi
couplings between organozinc halides and alkenyl or aryl
halides, usually in THF. Recently, we have shown that by
simply combining an aryl bromide with an alkyl iodide in
the presence of zinc powder and a palladium catalyst, C-C
bond formation smoothly occurs within nanomicelles at room
temperature in water.2 In this report we disclose newly
investigated cross-couplings of alkenyl halides. Our approach
provides high levels of maintenance of both E- and Z-olefin
geometry in the products of zinc-mediated reactions, which
in some cases compare very favorably to traditional two-
step Negishi cross-couplings in ethereal media.
Crucial to the success of this technology are the following:
(a) the use of TMEDA as additive,3 presumably functioning as
both a surface-cleaning/activating agent for the metal and ligand
for the in situ-formed organozinc reagent; (b) the palladium(II)
precursor PdCl2(Amphos)2;4 other sources of Pd(0) or Pd(II)
catalysts led to inferior results; (c) the amphiphile PTS (the
diester made from PEG-600, R-Tocopherol, Sebacic acid),5
which presumably supplies the hydrophobic pocket in which
the in situ generated water-sensitive organozinc halide reacts;6
and (d) Zn dust, rather than powder. Only 2 equiv of the
corresponding alkyl halide and 1 mol % of PdCl2(Amphos)2
are required for high levels of conversion and good isolated
yields under mild, ambient temperatures.
In the case of cross-couplings of stereoisomerically pure
E-alkenyl halides (Table 1, entries 1 and 2), complete
retention of E-stereochemistry was observed. Mixtures of
(1) (a) Negishi, E.-I.; Gagneur, S. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley: New York, 2002;
Vol. 1, p 597. (b) Negishi, E.-I. Acc. Chem. Res. 1982, 15, 340. (c) Negishi,
E.-I.; Hu, Q.; Huang, Z.; Qian, M.; Wang, G. Aldrichimica Acta 2005, 38,
71. (d) Negishi, E.-I.; Huang, Z.; Wang, G.; Mohan, S.; Wang, C.; Hattori,
H. Acc. Chem. Res. 2008, 41, 1474. (e) Knochel, P.; Singer, R. D. Chem.
ReV. 1993, 93, 2117.
(3) Without TMEDA, no product is formed.
(4) PdCl2(Amphos)2 (dichlorobis(p-dimethylaminophenyl-π-di-tert-bu-
tylphosphine)palladium(II)) is commercially available from Johnson Mat-
they.
(5) Lipshutz, B. H.; Ghorai, S. Aldrichimica Acta 2008, 41, 59.
(6) In the absence of PTS, low levels of conversion (<20%) were
observed after 48 h.
(2) Krasovskiy, A.; Duplais, C.; Lipshutz, B. H. J. Am. Chem. Soc. 2009,
131, 15592.
10.1021/ol101885t  2010 American Chemical Society
Published on Web 09/30/2010

Table 1. Representative Couplings of E-Alkenyl Halides in
Table 2. Representative Couplings of Z-Alkenyl Halides in
PTS/H2Oa
PTS/H2Oa
a Conditions: alkyl halide (2 mmol), alkenyl halide (1 mmol),
PdCl2(Amphos)2 (0.01 mmol), zinc dust (3 mmol), TMEDA (2 mmol), 2%
PTS/H2O (2 mL), rt, 24 h. b Isolated yields. c Determined by proton NMR
and GC of the crude. d 12 h.
E/Z-alkenyl halides led to slight increases of the resulting
E/Z-isomer ratio in the final products (entries 3, 4). This
observation is expected based on relative rates of cross-
couplings between E- and Z-disubstituted isomers. We could
clearly observe much faster consumption of the E-isomer by
monitoring reactions by GC. A second explanation relies on
isomerization of either the starting material or final product
during the course of the reaction to the more thermodynamically
stable E-isomer. Lastly, isomerization could happen after
generation of a Pd(II) intermediate following a likely stereospe-
cific7 Pd-insertion/transmetalation.
To gain further insight, cross-couplings of Z-alkenyl
halides were studied (Table 2). In all representative cases
examined, g95% retention of Z-stereochemistry was
observed. Various functionalized Z-olefins could be
prepared in good to excellent yields (entries 1-14, Table
2). When both substrates are unactivated, the “homoha-
lide” pairs such as alkenyl iodide + alkyl iodide (entry
1) and alkenyl bromide + alkyl bromide (entry 4), led to
efficient cross-couplings with anticipated Z-stereochem-
istry (entries 1, 4). Curiously, the “mixed halide” pairs
(entries 2, 3), under otherwise identical conditions, gave
low levels of conversion and/or significant amounts of the
a Conditions: alkyl halide (2 mmol), alkenyl halide (1 mmol),
PdCl2(Amphos)2 (0.01 mmol), zinc dust (3 mmol), TMEDA (2 mmol), 2%
PTS/H2O (2 mL), rt, 48 h. b Isolated yields. c Determined by proton NMR
e
and GC of the crude. d 12 h. ∼20% reduction of alkenyl iodide. f 60%
conversion. g 81% yield with 1.5 equiv of alkyl bromide. h GC yield 94%.
i 24 h.
product of alkenyl halide reduction. In one case (entry
2), competitive zinc insertion occurs with the alkenyl
iodide, while, in the other case (entry 3), consumption of
the alkyl iodide is too rapid leading to competitive protio
quenching. Nonetheless, stereoselectivity is unaffected. As
illustrated in entries 7-9 and 11-14, functional groups
such as benzyl ether, ketone, chloride, ester, and tri-
methylsilyl are tolerated within the starting halides.8
(7) Jutand, A.; Negry, S. Organometallics 2003, 22, 4229.
Org. Lett., Vol. 12, No. 21, 2010
4743

ꢀ-Bromostyrene showed anomalous behavior in PTS/H2O,
losing 21-30% of its originally all Z constitution (Scheme
1, top). Stirring this reaction for one additional day after
Scheme 2
.
Stereoelective Coupling of 2,2-Disubstituted Alkenyl
Halides
Scheme 1. Negishi-like Couplings in Water and in THF
completion led to only 5% ZfE isomerization. Moreover,
a control experiment run in the absence of an alkyl halide
also showed insignificant isomerization of the starting
material alkenyl halide under these reaction conditions. By
way of comparison, in THF, Pd(PPh3)4 as catalyst leads
mainly to the Z-isomer, albeit in low isolated yield, while
PdCl2(Amphos)2 gaVe Virtually all E-olefinic product (Scheme
1).9 Clearly, further experimental and theoretical studies on
the role of ligands and reaction media in Negishi cross-
couplings seem warranted.
secondary alkyl halides react smoothly, although use of alkyl
bromides is preferred for more sterically hindered disubsti-
tuted alkenyl halides. In these latter cases, alkyl iodides were
readily consumed; however, a considerable amount of their
homocoupled Wurtz-type side products were formed. Under
our reaction conditions, dimerization products from starting
alkenyl halides were not observed. These overall trends seem
to be general for both alkenyl bromides and alkenyl iodides.
On the other hand, we were unable to obtain reasonable
yields with more sterically hindered R-substituted cyclic or
acyclic alkenyl halides.
In summary, a new micellar technology is described for
effecting net Negishi-like cross-couplings of stereodefined
alkenyl halides with alkyl halides. This method not only is
an alternative to the generally accepted two-step procedures
that rely on initial generation of stoichiometric organozinc
reagents but also allows replacement of organic solvent with
water as the only medium.
Also noteworthy are the couplings with unsymmetrical 2,2-
disubstituted alkenyl halides, found to readily undergo cross-
coupling reactions under our conditions with complete
retention of configuration (Scheme 2). Both primary and
(8) General Procedure: In a 5 mL round-bottom flask under argon
containing zinc dust (197 mg, 3 mmol) and PdCl2(Amphos)2 (7 mg, 0.01
mmol) was added 2% PTS solution in water (2 mL). N,N,N′,N′-Tetram-
ethylethylenediamine (TMEDA, 232 mg, 2 mmol) was added at rt followed
by the addition of the alkyl halide (2 mmol) and the vinyl halide (1 mmol).
The flask was stirred vigorously at rt for the indicated time. The product
was extracted with EtOAc. Silica gel (1 g) was added to the combined
organic phase, and solvents were removed under vacuum. The resulting
dry, crude silica was introduced on top of a silica gel chromatography
column to purify the product.
(9) Rare examples of cross-couplings between alkylzinc reagents and
Z-vinyl halides: (a) Negishi, E.-I.; Luo, F.-T.; Rand, C. L. Tetrahedron
Lett. 1982, 23, 27. (b) Koumaglo, K.; Chan, T. H. Tetrahedron Lett. 1984,
25, 717. (c) Chan, T. H.; Koumaglo, K. J. Organomet. Chem. 1985, 285,
109. (d) Nakamura, E.; Kuwajima, I. Tetrahedron Lett. 1986, 27, 83. (e)
Tamaru, Y.; Ochiai, H.; Nakamura, T.; Yoshida, Z. Tetrahedron Lett. 1986,
27, 955. (f) Millar, J. G. Tetrahedron Lett. 1989, 30, 4913. (g) Negishi,
E.-I.; Ay, M.; Gulevich, Y. V.; Noda, Y. Tetrahedron Lett. 1993, 34, 1437.
(h) Meyer, C.; Marek, I.; Courtemanche, G.; Normant, J.-F. J. Org. Chem.
1995, 60, 863. (i) Nakamura, E.; Aoki, S.; Sekiya, K.; Oshino, H.;
Kuwajima, I. J. Am. Chem. Soc. 1987, 109, 8056.
Acknowledgment. Financial support provided by the NIH
is warmly acknowledged. We are grateful to Johnson
Matthey for generously supplying catalyst PdCl2(Amphos)2
and to Boulder Scientific for the Cp2ZrCl2 used to make the
alkenyl halides.
Supporting Information Available: Experimental pro-
cedures and product spectral data are provided. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL101885T
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Org. Lett., Vol. 12, No. 21, 2010