Pd(PPh3)4 or trans-PdCl2(PPh3)2 in THF (entries 1 and 2).
Although each reaction led to a mixture of products,
including significant amounts of protio-quench product 3
and/or homocoupling products 4,4,5 almost complete re-
tention of geometry in the resulting Z-olefin 2 was ob-
served. However, in efforts to improve the otherwise poor
yields of desired product Z-2, screening commercially
available phosphine- or carbene-based ligands of more
recent vintage revealed a most unexpected finding:
Z-olefin geometry can be easily lost even at room tem-
perature (entries 5ꢀ8).
TMEDA in these Negishi couplings was investigated.
Remarkably, in the presence of TMEDA under otherwise
identical (standard) Negishi conditions, virtually complete
maintanence of olefin geometry was realized, as was the
preference for adduct Z-2 (Table 1, entry 10). The amount
of TMEDA (1.1 equiv) is critical for controlling selectivity.
Presumably, the presence of an additive in stoichiometric
amounts provides a coordinating ligand for both catalytic
palladium and stoichiometric zinc. Addition of triethyla-
mine also had a beneficial impact on product ratios, but
not to the extent seen with TMEDA (compare entry 2 vs
11).
The powerful combination of PdCl2(PPh3)2 as a catalyst
and TMEDA as a complexing agent could be applied to a
variety of (functionalized) reaction partners (Table 2).
Notably, sterically hindered (Z)-1-iodo-3,3-dimethylbut-
1-ene afforded stereoisomerically pure cross-coupled pro-
ducts 8 and 9 in good yields, while PdCl2(PPh3)2 as a
catalyst alone led to low conversions even after 48 h. It
should also be noted that in the coupling of phenethylzinc
iodide with (Z)-1-iodooct-1-ene (giving product 5) and
coupling of n-decylzinc iodide with (Z)-1-iodo-3,3-di-
methylbut-1-ene (giving product 8), in the absence of
TMEDA, byproducts were observed in which the double
bond had partly migrated.8 By contrast, these undesired
products were not seen using cat. PdCl2(PPh3)2/TMEDA.
Alkenylbromidescould alsobe successfully coupledwith
alkylzinc reagents. Coupling of n-decylzinc iodide with Z-
1-bromooct-1-ene led to the desired isomerically pure
product 10 in high yield (entry 13). In general, use of
TMEDA tends to slow rates of cross-couplings run at
room temperature. When performed at 60 °C, however,
they are complete in 2ꢀ3 h, require less catalyst (only 1%
of PdCl2(PPh3)2), and lead to stereoisomerically clean
products 10 and 11 in close to quantitative yield (entries
14 and 17). Cross-couplings of both (Z)-1-iodo- and (Z)-1-
bromooct-1-enes with secondary cyclohexylzinc iodide,
however, resulted in less than 50% conversion in each case
under a variety of conditions. Interestingly, although
PdCl2(Amphos)2 catalyzed the alkylation and arylation
of Z-β-bromostyrene in high yields, complete isomeriza-
tion to the E-product took place (entries 18, 22). The
presence of TMEDA, however, negates this pathway
(compare entry 18 vs 19). Best results are again obtained
using cat. PdCl2(PPh3)2/TMEDA to afford products 11
and 12 (entries 17 and 21).
Table 1. Effects of Catalyst and Additive on Z/E Ratios in 2a
a Conditions: alkylzinc iodide (1.1 mmol, 1.0 M in THF), vinyl iodide
(1 mmol), Pd catalyst (2 mol %). Reactions were run at 0.33 M at rt, 4 h
(24 h for entries 10 and 11). b By GC. c Z/E-ratio determined by NMR or
GC on crude material. d Defined as dichloro-bis(p-dimethylaminophe-
nyl-di-tert-butylphosphine) palladium(II). e 1.1 equiv. f 2.2 equiv.
Maintenance of stereoselectivity and high levels of de-
sired product formation6 are apparently favored by bulky
aromatic phosphine ligands (entry 4). An attempt to
combine the benefits in yield imparted by tricyclohexyl-
phosphine(entry 7) withthe stereoselectivity maintainedin
the presence of triphenylphosphine was unsuccessful at
preventing significant amounts of side-products 3 and 4
(entry 9).
On the basis of the critical role played by N,N,N0,N0-
tetramethylethylenediamine (TMEDA) in Zn-mediated
cross-couplings between two halides performed in water
at room temperature observed previously,7 the impact of
A controlled Z-to-E isomerization can be used to syn-
thetic advantage, in particular when starting with a mix-
ture of E/Z-isomers of β-bromostyrenes (Scheme 2). Using
PdCl2(Amphos)2 as a catalyst only the E-products are
obtained. Likewise, a mixture of E/Z-isomers of (2-
bromovinyl)trimethylsilane led to E-14 in good yield
(Scheme 2). Retention or inversion of configuration could
(3) Loss of olefin geometry in Negishi couplings has been noted
previously; however, these tend to be special cases: (a) Zhao, J.; Yu, Y.;
Ma, S. Chem.;Eur. J. 2010, 16, 74. (b) Fauvarque, J. F.; Jutand, A.
J. Organomet. Chem. 1981, 209, 109.
(4) (a) Jin, L.; Zhang, H.; Sowa, J. R.; Lei, A. J. Am. Chem. Soc. 2009,
131, 9892. (b) Liu, Q.; Lan, Y.; Liu, J.; Li, G.; Wu, Y.-D.; Lei, A. J. Am.
Chem. Soc. 2009, 131, 10201.
also be achieved for the coupling of PhZnI LiCl9 with an
3
unbiased alkenyl iodide, depending upon the catalyst
(5) Negishi, E.-I. Acc. Chem. Res. 1982, 15, 340.
(6) Tamaru, Y.; Ochiai, H.; Nakamura, T.; Yoshida, Z. Tetrahedron
Lett. 1986, 27, 955.
(8) See Supporting Information.
(9) Krasovskiy, A.; Malakhov, V.; Gavryushin, A.; Knochel, P.
Angew. Chem., Int. Ed. 2006, 45, 6040.
(7) (a) Krasovskiy, A.; Lipshutz, B. H. Org. Lett. 2010, 12, 4742. (b)
Krasovskiy, A.; Duplais, C.; Lipshutz, B. H. J. Am. Chem. Soc. 2009,
131, 15592.
Org. Lett., Vol. 13, No. 15, 2011
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