Pd-arylurea complexes for the Heck arylation of crotonic and cinnamic substrates

Article abstract of DOI:10.1016/j.tetlet.2013.01.077

A catalyst consisting of the 1:2 complex of Pd(OAc)₂ (1 mol %) with N-(4-carbethoxy)-phenylurea promotes the Heck arylation of a range of crotonic and cinnamic substrates, including aldehydes, ketones, esters, and nitriles, with electron-rich - but not electron-deficient - aryl iodides.

Full text of DOI:10.1016/j.tetlet.2013.01.077

Tetrahedron Letters 54 (2013) 2042–2045
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Tetrahedron Letters
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Pd–arylurea complexes for the Heck arylation of crotonic and
cinnamic substrates
⇑
Matthew R. Smith, Jung Yun Kim, Marco A. Ciufolini
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, Canada BC V6T 1Z1
a r t i c l e i n f o
a b s t r a c t
Article history:
A catalyst consisting of the 1:2 complex of Pd(OAc)2 (1 mol %) with N-(4-carbethoxy)-phenylurea pro-
motes the Heck arylation of a range of crotonic and cinnamic substrates, including aldehydes, ketones,
esters, and nitriles, with electron-rich—but not electron-deficient—aryl iodides.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 15 January 2013
Accepted 17 January 2013
Available online 25 January 2013
Keywords:
Arylation
Arylureas
Ligands
Heck reaction
Palladium
Liu and Guo reported1 that N-phenylurea is an effective substi-
tute for phosphine ligands in Pd-catalyzed processes such as
Mizoroki–Heck2 and Suzuki3 reactions. Our own experience has
shown that the Liu–Guo ligand is superior even to efficacious,
but costly, S-Phos4 in the Heck arylation of amino acid-derived ole-
fins.5 As a consequence, we have become interested in evaluating
the use of phenylureas as ligands in other Pd-mediated reactions.
An opportunity in that sense arose when a need materialized for
quantities of amino acids 1 (Fig. 1). These are special cases of
3,3-diarylalanines, which are of interest in peptide research6 and
in medicinal chemistry,7 and that may be prepared enantioselec-
tively by phase-transfer alkylation of glycine enolates,8 or by Evans
azidation9 of acids 2.10 The latter, or their esters, are available by
ally unchanged, even though they do arylate plain acrylate esters
in excellent yield under identical conditions.1
The influence of heretofore unexplored electronic factors on the
performance of the ligand was examined with 4-carbethoxy-phe-
nyl urea (‘CEPU’) and 4-methoxyphenyl urea in lieu of phenylurea.
The yield of 4 increased from 46% to 75% with CEPU as the ligand.
Further work revealed that 1 mol % of the 1:2 complex of Pd(OAc)2
with CEPU is generally effective in the arylation of cinnamic and
crotonic esters, aldehydes, and nitriles, as well as chalcone, but,
again, only with electron-rich aryl iodides. Tables 2 and 3 summa-
rize the results of Heck reactions of oxygen- and nitrogen-substi-
tuted aryl iodides promoted by the Pd(OAc)2–CEPU complex.
Yields were generally good to excellent, except when 4-(pivaloyl-
oxy)-iodobenzene was used as the halide. Reactions of the latter
returned the free phenolic forms of products 6g–l.13 Control exper-
iments showed that reactions carried out with unprotected 4-iodo-
phenol yielded no Heck product, even though the halide was
consumed. The lower yields obtained with 4-(pivaloyloxy)-iodo-
benzene must thus be due to premature depivaloylation of a por-
tion of the halide and consumption of the resultant iodophenol
through side reactions. In accord with precedent,14 most Heck
products were obtained as mixtures of geometric isomers, the
dominant one being that in which the entering Ar group and the
hydrogenation of
a
,b-unsaturated congeners,11 which can be
reached by Heck arylation of cinnamic substrates. Such a reaction
is much less facile than that of simple acrylate systems (vide infra);
it thus seemed interesting to evaluate the Liu–Guo complex in such
a context.
The effectiveness of the Pd(OAc)2 N-phenylurea system in the
Heck arylation of ethyl cinnamate was comparable to that of the
Pd(OAc)2–PPh3 catalyst,12 but in either case yields were moderate.
Moreover, the Liu–Guo complex performed adequately only in
donor solvents such as DMF or NMP (the solvent of choice) and,
interestingly, only with deactivated, electron-rich aryl iodides such
as 3 (Table 1). Activated, electron-deficient halides, for example,
methyl 4-iodobenzoate, failed to react and were recovered virtu-
⇑
Corresponding author. Tel.: +1 604 822 2419; fax: +1 604 822 8710.
E-mail address: ciufi@chem.ubc.ca (M.A. Ciufolini).
Figure 1. Structure of acids 1 and 2.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.077

M. R. Smith et al. / Tetrahedron Letters 54 (2013) 2042–2045
2043
Table 1
Table 3
Liu–Guo arylation of ethyl cinnamate
Heck arylation of cinnamic and crotonic substrates with nitrogen-substituted aryl
iodides
Entry
Catalysta
Solvent
Yieldb
E/Zc
Entry
R1
R2
EWG
Yielda
E/Zb
a
b
c
d
e
f
a
b
c
d
e
f
DMF
DMF
DMF
NMP
NMP
NMP
35
33
31
46
29
75
2.6:1
2.5:1
2.6:1
2.6:1
2.1:1
2.1:1
a
b
c
d
e
f
g
h
i
Me2N
Me2N
Me2N
Me2N
Me2N
Me2N
BOCHIN
BOCHIN
BOCHIN
BOCHIN
BOCHIN
BOCHIN
Ph
COOEt
COOMe
CN
CHO
CHO
COPh
COOMe
CN
CHO
CHO
51
41
84
71
98
99
51
99
50
99
71
77
4.0:1
1.0:1
2.9:1
5.3:1
2.3:1
2.0:1
1.0:1
2.7:1
92:1
Me
Me
Me
Ph
Ph
Me
Ph
Me
Ph
Ph
a
Catalyst (a) 5 mol % [Pd(OAc)2(PPh3)2]; (b) 1 mol % [Pd(OAc)2(PPh3)2]; (c)
1 mol % Pd(OAc)2ꢀ[N-phenylurea]2; (d) 1 mol % Pd(OAc)2[N-(4-meth-oxyphe-
nyl)urea]2; (e) 1 mol% Pd(OAc)2[N-(4-carbethoxyphenyl)urea]2.
b
Yields of products purified by flash chromatography.
Proton NMR.
j
k
l
3.0:1
3.0:1
3.0:1
c
COOEt
COPh
Ph
a
Yields of products purified by flash chromatography.
Proton NMR.
Table 2
b
Heck arylation of cinnamic and crotonic substrates with oxygen-substituted aryl
iodides
Table 4
Heck arylation of cinnamic and crotonic substrates with miscellaneous aryl halides
Entry
R1
R2
EWG
Yielda
E/Zb
a
b
c
d
e
f
g
h
i
MeO
MeO
MeO
MeO
MeO
MeO
PivOc
PivOc
PivOc
PivOc
PivOc
PivOc
Ph
COOEt
COOMe
CHO
CN
CHO
COPh
COOMe
CHO
CN
CHO
75
97
76
92
84
66
45
47
56
36
28
35
2.1:1
1.0:1
3.0:1
3.5:1
2.6:1
2.2:1
1.0:1
1.6:1
5.5:1
7.3:1
1.3:1
1.7:1
Entry
R1
X
R2
EWG
Yielda
E/Zb
Me
Me
Me
Ph
Ph
Me
Ph
Me
Me
Ph
a
b
c
d
e
f
H
H
H
H
I
I
I
I
Br
Br
Br
Cl
Ph
Me
Me
Ph
Ph
Ph
Ph
Ph
COOEt
COOMe
CHO
72
57
34
80
15
12
17
nr
—
1.0:1
6.3:1
—
CHO
H
COOEt
COOEt
COOEt
COOEt
—
MeO
Me2N
Me2N
1.0:1
1.7:1
—
g
h
j
k
l
COOEt
COPh
Ph
a
Yields of products purified by flash chromatography.
Proton NMR.
b
a
b
c
Yields of products purified by flash chromatography, except for entry i.
Proton NMR.
Reactions of 4-pivaloylophenyl iodide returned the free phenolic form of the
product. The stated yields are those of the free phenols. For ease of purification and
characterization, the latter were converted back into the pivalate ester.
electron-withdrawing group (EWG) are trans. The results of Table 4,
underscore the fact that plain iodobenzene reacted normally to
give the expected products in 55–70% yield, but that, as indicated
earlier, aryl bromides reacted poorly, while an aryl chloride failed
altogether to react.
Scheme 1 shows some reactions of cinnamate esters 11–13,
which were made in high yield by arylation of tert-butyl acrylate
by the Liu–Guo procedure,1 or by the use of the Pd/CEPU system
described herein. Thus, just as the original Liu–Guo catalyst, the
Pd/CEPU system performs normally in the Heck reaction of simple
acrylate esters with aryl halides carrying electron-withdrawing
Scheme 1. Heck arylation of substituted cinnamic esters.

2044
M. R. Smith et al. / Tetrahedron Letters 54 (2013) 2042–2045
Table 5
Comparison of Heck arylation by the Buchwald method versus the Pd(OAc)2–CEPU
procedure
Scheme 2. Catalytic reduction of 15 and 19.
Entry
R
Ar
EWG
Product
Yieldb,c
(70% vs 50%; Table 5), but it provided 15 in lower yield (41% vs
54%); furthermore, it was uniformly less satisfactory with other
crotonic/cinnamic substrates. For instance, the arylation of
crotononitrile proceeded to afford 6d in 77% yield (vs 92% with
the Pd–CEPU system, Table 5), but the reaction also afforded
4,40-dimethoxy-1,10-biphenyl, the product of homo-coupling of
the aryl halide, in 19% yield relative to the starting halide. No such
homo-coupling product was observed in CEPU-mediated reactions.
It is worth noting that either system performed better than the
Jiang-Cai catalyst21 (Pd on zeolites, 50% yield) in the arylation of
crotononitrile. Chalcone and cinnamaldehyde did undergo aryla-
tion in moderate yield under Buchwald conditions, but they also
yielded significant amounts of products of ‘reductive Heck’ reac-
tion (Table 6).22 Such byproducts were not detected in arylation
reactions carried out with the Pd–CEPU system.
a
b
c
d
e
4-Me2NC6H4
4-MeOC6H4
Me
Me
Me
4-Me2NC6H4
4-MeOC6H4
4-MeOC6H4
Ph
COOt-Bu
COOt-Bu
CN
CHO
CHO
19
15
6d
10c
6e
70 (50)
41 (54)
77d (92)
— (34)
— (76)
4-MeOC6H4
a3% Pd(OAc)2, 1 equiv Cy2NMe, 1.1 equiv Ar–I, DMA, 85 °C, 16 h (Ref. 20).
b
Yields of products purified by flash chromatography.
Yields in parentheses are those of products obtained by the CEPU procedure.
c
d
This reaction also afforded the product of homocoupling of the aryl iodide, that
is, 4,40-dimethoxy-1,10-biphenyl, in 19% yield.
groups, even though it fails to induce arylation of cinnamic/croton-
ic substrates with such halides.
Relative to alternative methods for the arylation of cinnamic/
crotonic systems, the Pd/CEPU procedure seems advantageous in
terms of ease of preparation of the catalyst and—especially—scope
with respect to the olefinic substrate. For instance, the arylation of
cinnamic esters has been carried out with palladacycle catalysts,15
or Pd complexes of highly electron-rich16 or polydentate17 phos-
phines, possibly with microwave irradiation,18 or with supported
Pd nanoparticles.19 A more practical, phosphine-free catalyst for
this process has been described by Buchwald.20 Relative to the
Pd–CEPU complex, the Buchwald system exhibits a broader scope
with respect to the aryl halide, in that it works well with aryl io-
dides and bromides carrying electron donating or electron-with-
drawing groups, and it employs the aryl halide in only 10%
excess relative to the olefinic substrate. Conversely, it requires
more Pd (3 mol % vs 1 mol %), and it was demonstrated only with
esters. This provided an incentive to examine the relative perfor-
mance of the two catalytic systems. In our hands, the Buchwald
procedure afforded 19 in higher yield relative to the CEPU method
The notoriously problematic arylation of crotonaldehyde23
failed altogether with the Buchwald system, returning instead mix-
tures containing mostly the product of reductive Heck reaction,
accompanied by unidentified byproducts (1H NMR; Table 5). By
contrast, the Pd–CEPU catalyst induced the formation of 6c, 8d,
and 8i in satisfactory yield. List24 has described a variant of the
Buchwald procedure that achieves the efficient arylation of croton-
aldehyde and other enals, which however are employed in twofold
molar excess with respect to the aryl halide. On the other hand, no
indication is available regarding the performance of the List system
with other olefinic systems. The same is true for a Pd(0)–NHC com-
plex developed by Minnaard25 (1.5 mol % of Pd) for the arylation of
chalcones.26 At this time, it would seem that the Pd(OAc)2–CEPU
system accepts a broader range of crotonic/cinnamic substrates
than other known Heck catalysts.
On a final note, the catalytic reduction of products 15 and 19 oc-
curred uneventfully (Scheme 2), thereby realizing our original
objective.27
In summary, this work shows that previously unexplored elec-
tronic effects can be harnessed to modulate the properties of arylu-
rea ligands in Pd-mediated reactions. A Pd–arylurea complex for
the Heck arylation of diverse crotonic and cinnamic systems in
synthetically useful yield has thus resulted. Good results are gener-
ally observed with a diversity of such acceptors, most notably with
crotonaldehyde. This catalytic system exhibits an unusual prefer-
ence for deactivated, electron-rich aryl iodides. Studies centering
on further applications of Pd–arylurea complexes are underway,
and pertinent results will be disclosed in due course.
Table 6
Heck arylation of cinnamaldehyde and chalcone by the Buchwald method versus the
Pd(OAc)2–CEPU procedure
Product and yieldb,c
Yield of 20b,c
Acknowledgments
Entry
Ar
EWG
a
b
c
4-MeOC6H4
Ph
4-MeOC6H4
CHO
CHO
COPh
6e 45 (84)
10d 23 (80)
6f 58 (66)
14 (–)d
22 (–)d
38 (–)e
We thank the University of British Columbia, the Canada Re-
search Chair Program, NSERC, CIHR, CFI, and BCKDF for financial
support.
a3% Pd(OAc)2, 1 equiv Cy2NMe, 1.1 equiv Ar–I, DMA, 85 °C, 16 h (Ref. 20).
b
Yields of products purified by flash chromatography.
Yields in parentheses are those of products obtained by the Pd/CEPU procedure.
Compounds 6e–20a and 10d–20b had similar chromatographic mobilities and
c
Supplementary data
d
were not separated: yields of individual products were calculated based on the ratio
of the two (1H NMR) in the material obtained after chromatographic purification of
the crude reaction mixture.
The numbers given correspond to the yield of individual products, which in this
case were readily separated by chromatography.
Supplementary data (experimental procedures, characteriza-
tion data for new compounds, 1H and 13C NMR spectra.) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2013.01.077.
e

M. R. Smith et al. / Tetrahedron Letters 54 (2013) 2042–2045
2045
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