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D. R. Williams et al. / Tetrahedron Letters 51 (2010) 121–124
Table 1 (continued)
Entry
Alkenyl fluoride
Coupling partnera
Productb
Conditions (yield)c
F
H3C
F
F
Br
N
HO
N
Boc
B
Boc
12
13
A (71%)
HO
1e
1e
38
39
24
N
N
N
N
N
N
N
N
F
Br
HO
N
H
N
B
H
HO
A (70%)
25
Reaction conditions: (A) Pd(dppf)Cl2 10 mol %; CsCO3; THF, sealed tube at 90 °C/8 h. (B) Pd(PPh3)4 10 mol %; CsCO3; THF, sealed tube at 90 °C/8 h. (C) Pd(PPh3)4 10 mol %;
toluene, sealed tube at 90 °C/10 h. Notes: (a) All coupling partners are commercially available from Frontier Scientific, Inc. (b) Products were purified by flash silica gel
chromatography. (c) Yields are provided for purified products and are based on reactions of 1:1 stoichiometry of coupling reactants.
in the presence of HFꢂpyridine to regioselectively produce b,b-di-
bromo-
-fluorophenyl-ethanes.10 Elimination with potassium
isosteres for the design of peptidomimetics. The differential reac-
tivity of aryl iodide and alkenylbromide moieties in 1a facilitates
an efficient modular synthesis of peptidomimetics allowing for ra-
pid screening of cross-coupling partners.
a
tert-butoxide in THF proceeded smoothly to give the desired (Z)-
1-fluoro-2-bromostyrenes 1a, 1b, 1c, and 1d (yields 70–75%) as
the only observed alkene isomers.11 Substituted (Z)-1-fluoro-2-
bromostyrenes, such as 1e of Table 1, are available from aryl
iodides as illustrated for 1a (see Scheme 2). The trans geometry
of the fluoro and vinylic hydrogen substituents was confirmed
via the characteristically large coupling constants (JHF 38–40 Hz)
apparent in the H NMR spectra of the products.
Acknowledgments
We acknowledge Indiana University and the National Institutes
of Health (GM42897) for generous support. We also thank Nicholas
Chow and Richard Lord for calculations of 3.
Results of the palladium cross-coupling reactions of the (Z)-1-
fluoro-2-bromostyrenes 1b, 1c, 1d, and 1e are compiled in Table
1. Commercially available aryl and heteroaryl boronic acids were
surveyed utilizing Suzuki conditions. Reactions proceeded with
complete retention of olefin geometry to consistently provide
70–80% yields of cross-coupled (Z)-1-fluorostilbenes (Table 1, en-
tries 1–13). Experiments were conducted in resealable Carius tubes
in refluxing THF at 90 °C for 8–12 h in the presence of 10 mol %
Pd(dppf)Cl2. Reactions were monitored for consumption of the
starting alkenyl bromides. Subsequently, we found that 10 mol %
Pd(PPh3)4 could be used in many cases with similar results. The
availability of boronic acids provides convenient access to hetero-
cyclic derivatives, and the inclusion of isoxazole, pyrrole, indole,
and pyrimidine systems offers opportunities for further elabora-
tions. However, sluggish reactions were observed for cross-cou-
pling of the electron-rich styrene 1c and 3-fluorophenyl boronic
acid giving rise to a modest 40% yield of the desired stilbene
product.
Supplementary data
Supplementary information provides a description of general
reaction procedures and a listing of spectral data of products of
Schemes 1, 2 and 3, and Table 1. Supplementary data associated
with this Letter can be found, in the online version, at doi:10.1016/
References and notes
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