Room temperature palladium-catalysed coupling of amino acid-derived organozinc reagents with aryl triflates

Article abstract of DOI:10.1016/S0040-4020(00)00362-8

Aryl triflates may be cross-coupled with the amino acid derived zinc reagents 1, 2 and 3 using palladium catalysis at room temperature, in the presence of anhydrous lithium chloride, conveniently yielding phenylalanine 4, β-homophenylalanine 5 and γ-bisho

Full text of DOI:10.1016/S0040-4020(00)00362-8

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 4539±4540
Room Temperature Palladium-Catalysed Coupling of Amino
Acid-Derived Organozinc Reagents with Aryl Tri¯ates
b
Charles S. Dexter,a Richard F. W. Jacksona, and Jason Elliott
*
aDepartment of Chemistry, Bedson Building, The University of Newcastle, Newcastle-upon-Tyne NE1 7RU, UK
bMerck Sharp & Dohme Research Laboratories, Neuroscience Research Park, Terlings Park, Eastwick Road, Harlow,
Essex CM20 2QR, UK
Received 3 March 2000; revised 5 April 2000; accepted 20 April 2000
AbstractÐAryl tri¯ates may be cross-coupled with the amino acid derived zinc reagents 1, 2 and 3 using palladium catalysis at room
temperature, in the presence of anhydrous lithium chloride, conveniently yielding phenylalanine 4, b-homophenylalanine 5 and g-bishomo-
phenylalanine 6 derivatives respectively (nine examples). q 2000 Elsevier Science Ltd. All rights reserved.
Our previous synthetic approach to substituted phenyl-
alanines, b-homophenylalanines and g-bishomophenyl-
alanines relied on coupling of zinc reagents with aryl
iodides.1,2 Given the easier access (in general)3 to aryl
tri¯ates, we have explored the coupling of the zinc reagents
1, 2 and 3 with aryl tri¯ates. Palladium catalysed coupling
of aryl (and heteroaryl) tri¯ates with alkyl,4,5 benzylic6,7 and
aryl8±10 zinc reagents has been reported, as well as a recent
example using zinc cyanide.11 Lipshutz has also recently
described a nickel catalysed cross-coupling reaction of an
organozinc reagent with a naphthyl tri¯ate.12 Several cost
effective alternatives to tri¯ates; vinyl nona¯ates13 and aryl
¯uorosulfonates14 have been examined in the context of
crosscoupling reactions with organozincs.
tic acid derived zinc reagent 2 failed to furnish any coupled
product, in contrast to the good yield of 5a (73%) obtained
when using iodobenzene as the electrophile. In general, the
literature examples referred to above required heating in
order to obtain high yields. These conditions are unsuitable
for the functionalised zinc reagents 2 and 3, which undergo
rapid b-elimination. However, after extensive screening of a
variety of catalysts, ligands and additives, a combination
which did not require elevated temperature was identi®ed,
but which had previously been employed at elevated
temperature.4 Room temperature coupling of zinc reagent
2 with phenyl tri¯ate, in the presence of three equivalents of
rigorously dried lithium chloride, resulted in an acceptable
yield (58%) of coupled product 5a. Using these optimum
conditions, cross-coupling reactions were carried out
between zinc reagents 1, 2 and 3 and phenyl, naphthyl and
p-nitrophenyl tri¯ates to furnish the coupled products shown
below (Scheme 1 and Table 1).
The yields of reaction are typically all lower than when the
corresponding aryl iodides are used as electrophiles, but the
scope of the process has been extended signi®cantly. The
role of the lithium chloride is presumably to act as source of
chloride ions to stabilise the palladium catalyst, in a manner
analogous to that postulated by Stille in the cross-coupling
of alkylstannanes with aryl tri¯ates.15 Interestingly, the
yields of coupled product obtained with the serine derived
zinc reagent 1 are signi®cantly lower than when homo-
logous zinc reagents 2 and 3 are coupled with aryl tri¯ates.
This may be a re¯ection of the internal coordination
observed between the ester and zinc,2 making this zinc
species a bulkier nucleophile, even in DMF. Alternatively,
the lower yields may be simply due to the electron with-
drawing ester group being closer to the metal bearing
carbon.
Results and Discussion
Simply replacing iodobenzene with phenyl tri¯ate under our
optimum conditions for aryl iodide coupling with the aspar-
Keywords: amino acids; palladium; cross-coupling; zinc.
* Corresponding author. Tel.: 144-191-222-7072; fax: 144-191-222-
6929; e-mail: r.f.w.jackson@ncl.ac.uk
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00362-8

4540
C. S. Dexter et al. / Tetrahedron 56 (2000) 4539±4540
Scheme 1.
Table 1. Yields of products from the palladium(0) catalysed cross-coupling
reaction of aryl tri¯ates with zinc reagents 1, 2 and 3
between ethyl acetate (50 mL) and saturated aqueous
ammonium chloride (20 mL) then ®ltered. The organic
layer was washed with water (20 mL) and brine (20 mL),
then dried and the solvent removed under reduced pressure.
Flash column chromatography yielded protected aryl amino
acids which exhibited spectroscopic characteristics identical
to the compounds prepared previously using aryl iodides as
electrophiles, and which we have already reported. For
compounds 4a±c see Ref. 1 and for compounds 5a±c and
6a±c see Ref. 2.
Ar
Zinc reagent
Coupled product
% Yielda
C6H5
C6H5
C6H5
1
2
3
4a
5a
6a
7
58
44
1-Naphth
1-Naphth
1-Naphth
1
2
3
4b
5b
6b
39
64
49
p-NO2-C6H4
p-NO2-C6H4
p-NO2-C6H4
1
2
3
4c
5c
6c
30
44
29
Acknowledgements
a Yields are based on amino acid derived iodide precursors (0.75 mmol).
We thank the EPSRC (studentship to C. S. D.) and Merck
Sharp & Dohme (CASE award to C. S. D.) for support.
It appeared from analysis of the crude NMR spectra,
especially in the case of the p-nitrophenyl tri¯ate, that a
signi®cant proportion of the corresponding biaryl product
was present. This probably arises from the presence of a
small amount of residual zinc which is present after forma-
tion of the zinc reagents. Jutand has previously commented
on the scope of forming symmetrical biaryls from the
palladium catalysed homocoupling of aryl tri¯ates in the
presence of zinc dust.16
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