Selective reactivity of electron-rich aryl iodides in the Heck arylation of disubstituted alkenes catalyzed by palladium-arylurea complexes

Article abstract of DOI:10.1016/j.tet.2013.09.019

A catalyst consisting of 1 mol % of the 1:2 complex of Pd(OAc)₂ with N-(4-carbethoxyphenyl)urea promotes the Heck arylation of 2- or 3-substituted, conjugated esters, nitriles, aldehydes, and ketones (an uncharacteristically broad range of substrates), but only with electron-rich aryl iodides (an uncharacteristically narrow range of halides).

Full text of DOI:10.1016/j.tet.2013.09.019

Tetrahedron 69 (2013) 10139e10151
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Selective reactivity of electron-rich aryl iodides in the Heck arylation
of disubstituted alkenes catalyzed by palladiumearylurea
complexes
*
Matthew R. Smith, Young Jin Jang, Jung Yun Kim, Marco A. Ciufolini
Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2013
Received in revised form 4 September 2013
Accepted 5 September 2013
Available online 13 September 2013
A catalyst consisting of 1 mol % of the 1:2 complex of Pd(OAc)2 with N-(4-carbethoxyphenyl)urea pro-
motes the Heck arylation of 2- or 3-substituted, conjugated esters, nitriles, aldehydes, and ketones
(an uncharacteristically broad range of substrates), but only with electron-rich aryl iodides (an un-
characteristically narrow range of halides).
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Arylation
Arylureas
Heck reaction
Ligands
Palladium
1. Introduction
very favorable results obtained in the arylation of protected
(S)-vinylglycinol, leading to homotyrosinol derivatives.4 Thus, the
A recent communication from this group1 describes the Mizor-
okieHeck arylation2 of crotonic and cinnamic substrates in the
presence of a LiueGuo-type3 catalyst consisting of 1 mol % of the
1:2 complex of Pd(OAc)2 and N-[4-(carbethoxy)]phenylurea (CEPU)
in N-methyl-2-pyrrolidinone (NMP) as the solvent, and the pres-
ence of K2CO3 as the base. This catalytic system produces superior
results relative to traditional Pd(PPh3)4, but it displays peculiar
behavior. First, and unlike most other catalysts, it possesses broad
scope with respect to the alkene. Thus, conjugated esters, nitriles,
ketones, and aldehydes, including the notoriously problematic
crotonaldehyde, undergo Heck reaction in generally good to ex-
cellent yields in the presence of Pd(OAc)2 and CEPU. Second, it
accepts only electron-rich aryl iodides in the arylation of the above
substrates, but it performs well with either electron-rich or
electron-deficient aryl halides in the arylation of simple acrylic
systems. This paper expands the scope of our previous work by
disclosing additional examples of Heck reactions promoted by the
Pd(OAc)2/CEPU system.
LiueGuo system outperformed even highly efficacious complexes
of Pd with costly S-Phos.5 Such a positive experience provided an
incentive to evaluate the catalytic ability of the Pd(OAc)2/NPU
system in other common Pd mediated coupling reactions. Liu and
Guo had already established that their catalyst functions well in
Suzuki processes;3 therefore, we focused our attention on Sono-
gashira6 and Negishi7 couplings. The Pd(OAc)2/NPU system gave
disappointing results in representative Sonogashira reactions, and
since superior protocols are already available for such trans-
formations, research in this area was quickly halted. The catalyst
also performed poorly in Negishi reactions involving arylzinc ha-
lides. Unexpectedly, however, the attempted Negishi coupling of
commercial alkylzinc agent 1 (Table 1) with methyl 4-iodobenzoate
afforded cinnamic-type ester 2 in low yield (the balance of the aryl
halide was recovered unchanged), while the same reaction with
4-iodoanisole produced mixtures of mono- and bis-aryl esters, 2
and 3. A plausible mechanism for the formation of such products
involves transmetallation of 1 to Pd(II), followed by b-hydrogen
The original LiueGuo catalyst [1:2 complex of Pd(OAc)2 with
elimination. The resulting ethyl acrylate may then undergo Heck-
type mono- and bis-arylation. These results captured out atten-
tion for three reasons. First, a need had recently arisen in our group
for quantities of 3,3-diarylalanines,8 which could be prepared9 from
compounds 3 by hydrogenation and Evans10 azidation.11 Second, it
seemed to us that an improved protocol for the arylation of acrylate
N-phenylurea (NPU)]3 became of interest to us as a consequence of
* Corresponding author. Tel.: þ1 604 822 2419; fax: þ1 604 822 8710; e-mail
address: ciufi@chem.ubc.ca (M.A. Ciufolini).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.09.019

10140
M.R. Smith et al. / Tetrahedron 69 (2013) 10139e10151
Table 1
Attempted Negishi reaction of organozinc compound 1 with aryl halides
R
Ar–I, 1:2 Pd(OAc)2/NPU
CO2Et
CO2Et
R = H
R = Ar
Yield:
BrZn
Ar
1
2
60 °C, solvent, time
3
Entry
Ar
% Pd
Solv.
Time (h)
Scheme 1. Proposed structure of the NPU-Pd(II) complex 4 (Ref. 3) and structures of
MPU (5) and CEPU (6).
2a
3a
a
b
c
d
e
f
g
h
i
4-C6H4COOMe
4-C6H4COOMe
4-C6H4COOMe
4-C6H4COOMe
4-MeOeC6H4
4-MeOeC6H4
4-MeOeC6H4
4-MeOeC6H4
4-MeOeC6H4
4-MeOeC6H4
100
20
5
THF
THF
DMF
THF
THF
THF
THF
THF
Toluene
THF
5
5
5
5
5
24
5
24
16
24
d
21
12
11
d
d
7
11
5
17
d
d
d
d
d
d
d
16
d
15
both afforded much improved results in the Heck reaction of cin-
namic and crotonic substrates with electron-rich aryl iodides.
Whereas CEPU was definitely superior to MPU in our test arylation of
ethyl cinnamate with 4-iodoanisole, and consequently our previous
work1 had focused exclusively on that catalyst, it ultimately tran-
spired that the efficacy of the two systems is generally comparable,
suggesting that factors other than purely electronic effects modulate
the properties of phenylurea ligands. Results obtained in the aryla-
tion of various substrates with the representative electron-rich aryl
iodides, N,N-dimethyl-4-iodoaniline, N-(tert-butoxycarbonyl)-4-
iodoaniline, and 4-iodoanisole, are summarized in Table 2.19
5
50
20
5
1
1
j
0.1
a
Yields of products purified by flash chromatography.
or cinnamate esters12 under the influence of Pd(OAc)2/NPU would
be advantageous relative to earlier methods that require catalysts
such as palladacycles,13 or Pd complexes incorporating highly
electron-rich14 or polydentate15 phosphines (sometimes aug-
mented by microwave irradiation),16 or supported Pd nano-
particles.17 Indeed, the LiueGuo complex might well embody
an alternative to an especially useful phosphine-free system de-
scribed by Buchwald.18 Third, we were struck by the fact that the
Pd(OAc)2/NPU system performed best at low metal loading
(0.1e5 mol %) and with electron-rich aryl halides. We thus
launched an investigation of the Heck reaction of cinnamic and
crotonic substrates in the presence of Pd(OAc)2/NPU.
Table 2
Comparison of the PdeCEPU versus PdeMPU catalysts in the arylation of cinnamic
and crotonic substrates with electron-rich aryl iodides
Entry
R1
R2
EWG
CEPU
E/Zb
MPU
E/Zb
Yielda
Yielda
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
Me2N
Ph
COOEt
COOMe
CN
CHO
CHO
COPh
COOMe
CN
CHO
CHO
COOEt
COPh
COOEt
COOMe
CHO
CN
CHO
COPh
51
41
84
71
98
99
51
99
50
99
71
77
75
97
76
92
84
66
4:0:1
1.0:0
31
51
81
79
98
77
55
95
55
85
77
83
29
67
54
83
99
53
4:0:1
1.0:0
2. Results and discussion
Me
Me
Me
Ph
2.9:1
5.3:1
2.3:1
2.0:1
1.0:0
2.7:1
11.5:1
3.0:1
3.0:1
2.8:1
5.4:1
5.7:1
2.0:1
1.0:0
2.6:1
11.5:1
2.5:1
3.0:1
3.0:1
2.1:1
1.0:0
3.2:1
3.4:1
2.6:1
2.3:1
As detailed previously,1 test reactions with ethyl cinnamate and
4-iodoanisole revealed that the efficacy of Pd(OAc)2/NPU was
similar to that of the customary Pd(OAc)2/PPh3 system, although in
either case the yields of Heck products were only moderate.
However, the LiueGuo complex exhibited broader substrate scope,
promoting successful arylation of a range of cinnamic and crotonic
systems, including notoriously troublesome crotonaldehyde. A
solvent switch from DMF to NMP was beneficial, as confirmed in
subsequent experiments. Electron deficient methyl 4-iodo-benzo-
ate failed to undergo Heck coupling with ethyl cinnamate in the
presence of Pd(OAc)2/NPU (essentially quantitative recovery of
unchanged substrates), even though it reacts efficiently with ethyl
acrylate under the same conditions.
The influence of the electronic properties of the ligand on the
performance of the catalyst was studied in an effort to improve the
yields of the above reactions. Liu and Guo had found an inverse
correlation between the pKa of the NeH bond of various urea ligands
and the catalytic activity of the corresponding complexes with
Pd(OAc)2 (the lower the pKa, the higher the activity).3 They attributed
the beneficial effect of phenylurea to the more facile accessibility of
its anionic form and the ability the latter to ligate arylpalladium(II)
species, leading to complexes of the type 4 (Scheme 1). On that basis,
we surmised that further lowering of the pKa of the NeH bond of the
ligand might increase the catalytic efficiency of the resulting Pd
complexes. To test this hypothesis, 4-(methoxy)phenylurea (5, MPU)
and 4-(carbethoxy) phenylurea (6, CEPU) were examined as ligands
in lieu of NPU, with the expectation that the more NeH acidic CEPU
should perform much better than MPU. Relative to the original
LiueGuo system, the 1:2 complexes of Pd(OAc)2 with CEPU or MPU
Ph
BOCHN
MeO
Me
Me
Me
Ph
Ph
Ph
3:0:1
Ph
2.1:1
1.0:0
3.0:1
3.5:1
2.6:1
2.2:1
Me
Me
Me
Ph
Ph
a
Yield of products purified by flash chromatography.
b
Ratios measured by intergration of 1H NMR spectra.
Plain iodobenzene reacted to give the expected Heck products in
moderate to good yields (Table 3). In all cases, ester, nitrile, ketone,
and aldehyde substrates participated normally in the reaction. In
particular, products arising from ‘reductive Heck’ processes20 or
homocoupling of the aryl halide (vide infra) were not apparent in
the 1H NMR spectra of crude reaction mixtures. By contrast,1 aryl
bromides reacted poorly, while aryl chlorides failed to react,21 as
did, again, electron-deficient iodides (all recovered unchanged). As
detailed previously, the arylation of substituted cinnamic esters
proceeded in a satisfactory manner, as exemplified by compounds
10 (Scheme 2, 50e54% yield),1 which are especially relevant to our
need for 3,3-diarylalanines.1

M.R. Smith et al. / Tetrahedron 69 (2013) 10139e10151
10141
Table 3
connection, List has developed a modification of the Buchwald
procedure that is quite satisfactory for the Heck reaction of enals.23
The List protocol affords higher yields relative to the PdeCEPU
method. Conversely, it employs the enal in 2-fold molar excess
relative to the aryl halide, and maintains the need for three times
more palladium. Furthermore, the authors comment that their
catalytic system does not tolerate sterically demanding sub-
Arylation of cinnamic/crotonic systems with PheI
stituents, such as an isopropyl group, at the b-position of the enal.
Entry
R
EWG
Urea
Yielda
E/Zb
This does not seem to be the case for the PdeCEPU complex, which
promotes the arylation of, e.g., (E)-3-cyclohexylacrolein in ca. 40%
yield (Table 4, entries d and e). Generally problematic methacrolein
reacts rather well under the catalytic influence of the PdeCEPU
system (Table 4, entries aec).
a
b
c
d
e
f
Me
Ph
Ph
Me
Me
Me
Ph
COOMe
COOEt
COOEt
CN
CHO
CHO
CEPU
CEPU
MPU
CEPU
CEPU
MPU
CEPU
CEPU
57
72
55
58
34
29
80
59
1.0:0
d
d
1.0:0
1.0:0
1.0:0
d
g
h
CHO
COPh
Ph
d
Table 4
a
Arylation of enals catalyzed by PdeCEPU
Yields of products purified by flash chromatography.
b
Ratios measured by intergration of 1H NMR spectra.
Entry
R1
R2
R3
Yielda
E/Zb
a
b
c
d
e
f
MeO
H
H
H
Me
Me
Me
H
H
H
70
68
56
38
42
30
30
1.0:0
1.0:0
1.0:1
Me2N
BOCHN
MeO
Me2N
MeO
cyclo-C6H11
cyclo-C6H11
n-C6H13
n-C6H13
Scheme 2. Preparation of compounds 10a,b (Ref. 1).
1.1:1
1.4:1
g
Me2N
H
a
Yields of products purified by flash chromatography.
Relative to alternative methods13e17 for the arylation of crotonic
b
Ratios measured by intergration of 1H NMR spectra.
and cinnamic systems, the advantages of the PdeCEPU protocol
include low cost, simplified workups, broad scope with respect to
the olefinic substrate, and requirement for only 1% of Pd(OAc)2. Its
disadvantages are that it is limited to electron-rich aryl iodides and
it works best in the presence of a 2-fold molar excess thereof. By
way of comparison, the Buchwald phosphine-free catalytic sys-
tem,18 exhibits broad scope relative to the aryl halide, in that it
performs equally well with electron-rich or electron-deficient io-
dides or bromides, and it employs only a 10 mol % excess of aryl
halide. However, it requires three times more palladium (3 mol % vs
1 mol %) and it has been demonstrated only with conjugated esters
as the acceptors. Given the generally excellent results available
through the Buchwald method, a comparative evaluation with the
PdeCEPU protocol was undertaken.1 Whereas the Buchwald pro-
cedure afforded 10b in higher yield relative to the Pd(OAc)2/CEPU
system, it produced 10a in lower yield.1 Furthermore, it gave con-
sistently poorer results with most other substrates. For example,
the reaction of crotonitrile with 4-iodoanisole under Buchwald
conditions returned the expected 7p in 77% yield (vs 92% with the
Pd(OAc)2/CEPU catalyst), together with a significant amount of 4,40-
dimethoxy-1,10-biphenyl (19% yield): the product of homocoupling
of the aryl halide. No such homocoupling byproducts were ever
observed with the PdeCEPU system. Chalcone and cinnamaldehyde
underwent Heck reaction with moderate efficiency, but they also
returned significant amounts of products arising from the reductive
Heck process, together with other unidentified byproducts. The use
of crotonaldehyde as the substrate resulted in formation of complex
mixtures, a major component of which was again the product of
reductive Heck reaction (see Supplementary data), but no regular
Heck product was apparent in the spectra of crude reaction
mixtures.
Dehydroaminoacid derivatives, another class of problematic
substrates,24 were more sensitive to steric effects. Thus, useful
yields were recorded in the arylation of N-BOC dehydroalanine Me
ester, but the reaction of the dehydroaminobutyrate analog
was inefficient, and that of dehydroarylanines failed altogether
(Table 5). So far as enones are concerned, it has already been seen
that the arylation of chalcones25 proceeds well without formation
of products of ‘reductive Heck’ coupling (Table 2). Benzylidenea-
cetone and dibenzylideneacetone also reacted in a satisfactory
manner under catalysis by the PdeCEPU complex. More signifi-
cantly, the notoriously difficult substrate, cyclohexenone, un-
derwent arylation in 50e70% yield (Table 6).
Table 5
Arylation of dehydroaminoacid derivatives
Entry
R1
R2
Yielda
a
b
c
d
e
f
MeO
Me2N
BOCHN
H
MeO
Me2N
MeO
Me2N
H
H
H
H
68
44
57
50
22
28
d
Me
Me
MeOeC6H4
Me2NeC6H4
g
h
The failure of crotonaldehyde to undergo arylation under
Buchwald conditions may not be surprising in light of the notorious
difficulties that affect the Heck reaction of aliphatic enals.22 In that
d
a
Yields of products purified by flash chromatography.

10142
M.R. Smith et al. / Tetrahedron 69 (2013) 10139e10151
Table 6
form catalytically active nanoparticulate metal, which may be sta-
bilized by anions29 or other ligands (e.g., phosphines)30 present in
the medium. Indeed, TEM imaging of our reaction mixtures revealed
that Pd nanoparticles in a number of sizes were present,31 even
though, of course, it is not possible to establish whether these con-
stitute the actual catalytic agents or the store thereof. It should be
noted that these images are similar in appearance to those recorded
in the literature, and that the average size of our particles is also
comparable to those previously reported.32 Second, many such
phosphine-free reactionsdincluding the ones described here-
indperform best at low catalyst loading.33 This is consistent with the
fact that increasingly larger amounts of metal in the reaction me-
dium promote the growth of initially formed, catalytically active
nanoparticles (‘Ostwald ripening’).34 As these grow, their catalytic
activity diminishes (smaller surface/volume ratio), while the ulti-
mate precipitation of finely divided metal (Pd black) deprives the
medium of catalytically active species. Third, it is established that Pd
atoms in metallic nanoparticles are electron-deficient,35 while those
in structurally defined phosphine (or NHC) complexes are regarded
as electron-rich.36 Furthermore, the smaller the nanoparticles, the
more electron-deficient the catalytically active surface atoms will be.
It therefore seems plausible that electron-deficient forms of Pd(0)
should undergo faster oxidative addition to electron-rich aryl halides
(this study), while the opposite would be true of electron-rich forms
of zerovalent metal. While these hypotheses tentatively explain the
preference of the PdeCEPU system for electron-rich aryl iodides,
other aspects of its reactivitydsuch as the reason why the catalyst
accepts electron-deficient aryl iodides in the Heck reaction of acry-
lates, but not in that of cinnamates/crotonates; or why it fails to
achieve efficient double arylation of acrylatesdremain difficult to
rationalize at this time, although there can be little doubt that they
must be related to catalyst evolution/aging.
Arylation of enones catalyzed by PdeCEPU
Entry
Enone
R1
R2
R3
Yielda
E/Zb
a
b
c
d
e
f
g
h
i
cyclo-Hexenone
MeO
(CH2)2
(CH2)2
(CH2)2
Ph
Ph
Ph
Ph
Ph
Ph
CH2
CH2
CH2
Me
Me
Me
Ph
52
76
62
83
99
30
41
50
61
d
Me2N
BOCHN
MeO
Me2N
BOCHN
MeO
d
d
Benzylideneacetone
3.0:1
2.5:1
2.7:1
2.3:1
2.0:1
2.0:1
Dibenzylideneacetone
Me2N
BOCHN
Ph
Ph
a
Yields of products purified by flash chromatography.
b
Ratios measured by intergration of 1H NMR spectra.
On a final note, it will be recalled that attempted Negishi re-
actions of zinc reagent 1 afforded some diarylated product 3 (Table
1). It seemed interesting to optimize such a transformation in order
to gain rapid access to the compounds of Table 4 via a one-pot
‘double Heck’ reaction of an acrylate ester.26 In spite of numerous
attempts, a viable method to achieve an efficient double arylation
of tert-butyl acrylate remains elusive. Results of representative
experiments appear in Table 7. Rapid (4e5 h), clean, conversion to
a product of mono-arylation was observed in all cases. Reactions
involving 4-iodoanisole (typically 2.1 equiv), and carried out at
100 ꢀC, soon began to form doubly arylated material, but then they
stalled after about one-third of the mono-aryl derivative has ad-
vanced to the bis-aryl product. A temperature increase to 150 ꢀC
translated into the formation of an approximately 1:1 mixture of
mono- and bis-arylated products before the reaction stalled. This is
the best result obtained so far (entry c). Reactions with N,N-di-
methyl-4-iodoaniline typically stopped at the stage of the mono-
aryl product, although a small amount of bis-aryl material were
observed in one reaction run with 3.5 equiv of the iodide (100 ꢀC).
3. Conclusion
The arylation chemistry detailed herein affords valuable prod-
ucts in synthetically useful yields. The preparation of the same
materials by alternative routes may require more complex/costly
catalytic systems. Broad scope with respect to the conjugated ac-
ceptor renders the PdeCEPU technique a first-choice method for
the Heck reaction with electron-rich aryl iodides.
Table 7
Double arylation of tert-butyl acrylate catalyzed by PdeCEPU
4. Experimental section
4.1. Experimental protocols
Unless otherwise indicated, 1H (300 MHz) and 13C (75 MHz)
NMR spectra were recorded at rt from CDCl3 solutions and were
calibrated using residual protio solvent as an internal reference.
Entry
R
Time (h)
Temp (ꢀC)
100
A (yield)c
B (yield)c
aa
ba
ca
db
ea
fa
MeO
5
16
9b (85)
9b (67)
9b (49)
9b (70)
9f (75)
9f (86)
9f (90)
(10b) e
10b (33)
10b (51)
10b (23)
(10f) e
Chemical shifts are reported as parts per milliom on the d scale and
150
100
coupling constants, J, are in hertz. Multiplicities are described as s
(singlet), d/dd/dt (doublet/doublet of doublets/doublet of triplets), t
(triplet), q (quartet), m (multiplet). Mass spectra were recorded on
a micromass-TOF spectrometer in ESI or APCI mode. Infrared
spectra were recorded in attenuated total reflectance mode. All
reactions were carried out under an atmosphere of argon. Com-
mercial materials, including anhydrous 99%þ N-methyl-
pyrrolidinone (NMP) and N,N-dimethylformamide (DMF), were
used as received. To avoid error in weighing small quantities of
catalyst, a standard solution of Pd(OAc)2 (concentration¼1 mg
Pd(OAc)2/mL) in dry THF (freshly distilled from Na/benzophenone),
stored at ꢁ20 ꢀC under argon, was used as the source of Pd. Melting
points are uncorrected. Chromatographic separations were effected
over silica gel 60.
Me2N
150
100
(10f) e
10f (10)
gb
a
Reaction run using 2.1 equiv ArI.
Reaction run using 3.5 equiv ArI.
Yields of products purified by flash chromatography.
b
c
In closing, we wish to state that a number of observations made in
the course of this study have led us to believe that Pd nanoparticles27
may be the actual species involved in the catalytic cycle. First, it is
generally accepted that reactions involving phosphineefree
Pd(OAc)2, and probably most other palladium catalysts,28 rapidly

M.R. Smith et al. / Tetrahedron 69 (2013) 10139e10151
10143
4.2. General procedures for the Heck arylation with
Pd(OAc)2earylurea complexes
ESI-MS: 318.4 (MþNa, 100%), 296.4 (MþH, 60%). ESIeHRMS: calcd
for C19H22NO2 [MþH]þ: 296.1651; found 296.1647. EA: (Found C,
77.29; H, 6.95; N, 4.62. C19H21NO2 requires C, 77.26; H, 7.17; N, 4.74).
Procedure A: An appropriate alkene (1 equiv) was added to
a DMF solution (enough solvent to attain an initial concentration of
alkene equal to ca. 0.1 M) of aryl iodide (2 equiv), Pd(OAc)2 (1 mol %,
delivered as a standard THF solution containing 1 mg/mL of com-
pound), phenylurea (2 mol %), and K2CO3 (2 equiv) in a thick-walled
glass reaction tube equipped with a magnetic stirring bar and fitted
with a threaded Teflon cap. The reaction tube was sealed and im-
mersed in an oil bath maintained at 100 ꢀC and stirring was started.
After 16 h, the resulting black solution was cooled to rt, diluted with
ethyl acetate, and washed sequentially with water and brine solu-
tion. The organic phase was separated, dried (Na2SO4), and con-
centrated under reduced pressure (rotary evaporator), and the
residue was purified by flash column chromatography.
4.4. (E)-Methyl 3-(4-(dimethylamino)phenyl)but-2-enoate
(7b)14
Procedure
B using 4-iodo-N,N-dimethylaniline (100 mg,
0.40 mmol), K2CO3 (56 mg, 0.40 mmol), Pd(OAc)2 (0.5 mL of THF
solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.5 mg
Pd(OAc)2), CEPU (0.8 mg), and methyl crotonate (21 mL, 0.20 mmol),
and chromatography with 5% ether in hexanes gave 7b as a yellow
solid (18 mg, 41%). Procedure C using 4-iodo-N,N-dimethylaniline
(100 mg, 0.40 mmol), K2CO3 (56 mg, 0.40 mmol), Pd(OAc)2 (0.5 mL
of THF solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.5 mg
Pd(OAc)2), MPU (0.7 mg), and methyl crotonate (21 mL, 0.20 mmol).
Procedure B: An appropriate alkene (1 equiv) was added to an
NMP solution (enough solvent to attain an initial concentration of
alkene equal to ca. 0.1 M) of aryl iodide (2 equiv), Pd(OAc)2 (1 mol %,
delivered as a standard THF solution containing 1 mg/mL of com-
pound), N-(4-carbethoxyphenyl)urea (CEPU, 2 mol %), and K2CO3
(2 equiv) in a thick-walled glass reaction tube equipped with
a magnetic stirring bar and fitted with a threaded Teflon cap. The
reaction tube was sealed and immersed in an oil bath maintained at
100 ꢀC and stirring was started. After 16 h, the resulting black so-
lution was cooled to rt, diluted with ethyl acetate, and washed
sequentially with water and brine solution. The organic phase was
separated, dried (Na2SO4), and concentrated under reduced pres-
sure (rotary evaporator), and the residue was purified by flash
column chromatography.
Procedure C. An appropriate alkene (1 equiv) was added to an
NMP solution (enough solvent to attain an initial concentration of
alkene equal to ca. 0.1 M) of aryl iodide (2 equiv), Pd(OAc)2 (1 mol %,
delivered as a standard THF solution containing 1 mg/mL of com-
pound), N-(4-methoxyphenyl)urea (MPU, 2 mol %), and K2CO3
(2 equiv) in a thick-walled glass reaction tube equipped with
a magnetic stirring bar and fitted with a threaded Teflon cap. The
reaction tube was sealed and immersed in an oil bath maintained at
100 ꢀC and stirring was started. After 16 h, the resulting black so-
lution was cooled to rt, diluted with ethyl acetate, and washed
sequentially with water and brine solution. The organic phase was
separated, dried (Na2SO4), and concentrated under reduced pres-
sure (rotary evaporator), and the residue was purified by flash
column chromatography.
Chromatography with 5% ether in hexanes gave 7b as a yellow solid
(22 mg, 50%); mp 68e70 ꢀC (lit.14 mp not given). 1H: 7.46 (d, J¼8.9,
2H), 6.69 (d, J¼8.9, 2H), 6.13 (q, J¼1.0, 1H), 3.74 (s, 3H), 3.01 (s, 6H),
2.58 (d, J¼1.0, 3H). 13C: 167.9, 155.7, 151.1, 128.9, 127.4, 112.3, 111.7,
50.9, 40.3, 17.2. IR: 2943, 1703, 1591, 1520, 1434, 1354, 1282, 1178,
1152, 1063, 1044. ESI-MS: 242.4 (MþNa, 40%), 220.4 (MþH, 100%).
4.5. 3-(4-(Dimethylamino)phenyl)but-2-enenitrile (7c)
Procedure
B using 4-iodo-N,N-dimethyl-aniline (100 mg,
0.40 mmol), K2CO3 (56 mg, 0.40 mmol), Pd(OAc)2 (0.5 mL of THF
solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.5 mg
Pd(OAc)2), CEPU (0.8 mg), and cis/trans-crotononitrile (16
mL,
0.20 mmol), and chromatography using a solvent gradient of 5e10%
ether in hexanes gave 7c as a pale yellow solid (31 mg, 84%) as
a 2.8:1 (E/Z) mixture. Procedure C using 4-iodo-N,N-dimethylani-
line (100 mg, 0.40 mmol), K2CO3 (56 mg, 0.40 mmol), Pd(OAc)
(0.5 mL of THF solution containing 1 mg/mL Pd(OAc)2, equivalent to
0.5 mg Pd(OAc)2), MPU (0.7 mg), and crotononitrile (16
mL,
0.20 mmol). Chromatography with 5% ether gave 7c as pale yellow
solid (30 mg, 81%) in a 2.8:1 (E/Z) mixture; mp 131e134 ꢀC. 1H: 7.61
(d, J¼9.0, min.) and 7.41 (d, J¼9.0, maj.; 2H), 6.70 (d, J¼9.0, min.) and
6.68 (d, J¼9.0, maj.; 2H), 5.51 (q, J¼0.6, maj.) and 5.17 (q, J¼1.3, min.;
1H), 3.03 (s, 6H), 2.43 (d, J¼0.6, maj.) and 2.25 (d, J¼1.3, min.; 3H).
13C: 159.5, 158.7, 151.7, 151.4, 128.6, 127.1, 125.0, 124.7, 119.1, 119.0,
111.6, 111.3, 90.5, 90.0, 40.1, 24.2, 19.6. IR: 2906, 2197, 1677, 1605,
1579, 1524, 1442, 1362, 1261, 1231, 1203, 1141, 1066, 1025. ESI-MS:
209.4 (MþNa, 100%), 187.4 (MþH, 10%). ESIeHRMS: calcd for
C
C
12H15N2 [MþH]þ: 187.1235; found: 187.1234. EA: calcd for
4.3. Ethyl 3-(4-(dimethylamino)phenyl)-3-phenylacrylate (7a)
12H14N2: C 77.38, H 7.58, N 15.04; found C 77.56, H 7.45, N 14.80.
Procedure
B
using 4-iodo-N,N-dimethylaniline (100 mg,
4.6. 3-(4-(Dimethylamino)phenyl)but-2-enal (7d)23
using 4-iodo-N,N-dimethylaniline2 (100 mg,
0.40 mmol), K2CO3 (56 mg, 0.40 mmol), Pd(OAc)2 (0.5 mL of THF
solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.5 mg
Procedure
B
Pd(OAc)2), CEPU (0.8 mg), and ethyl cinnamate (34
m
L, 0.20 mmol),
0.40 mmol), K2CO3 (56 mg, 0.40 mmol), Pd(OAc)2 (0.5 mL of THF
solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.5 mg
and chromatography using a solvent gradient of 5/50% ether in
hexanes gave 8a as yellow solid (30 mg, 51%) as a 4:1 mixture of E
and Z isomers. Procedure C using 4-iodo-N,N-dimethylaniline
(100 mg, 0.40 mmol), K2CO3 (56 mg, 0.40 mmol), Pd(OAc)2 (0.5 mL
of THF solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.5 mg
Pd(OAc)2), CEPU (0.8 mg), and trans-crotonaldehyde (17
mL,
0.20 mmol), and chromatography using a solvent gradient of
5e50% ether in hexanes gave 7d as a yellow solid (27 mg, 71%) as
a 5.3:1 (E/Z) mixture. Procedure C using 4-iodo-N,N-dimethylani-
line (100 mg, 0.40 mmol), K2CO3 (56 mg, 0.40 mmol), Pd(OAc)2
(0.5 mL of THF solution containing 1 mg/mL Pd(OAc)2, equivalent to
Pd(OAc)2), MPU (0.7 mg), and ethyl cinnamate (34 mL, 0.20 mmol).
Chromatography with 10% ether in hexanes gave 7a as a yellow
solid (18 mg, 31%) in a 4:1 (E/Z) mixture; mp 77e80 ꢀC. 1H:
7.39e7.14 (m, 8H), 6.70 (d, J¼8.7, min.) and 6.63 (d, J¼8.8, maj.; 2H),
6.31 (s, maj.) and 6.16 (s, min.; 1H), 4.13 (q, J¼7.1, min.) and 4.03 (q,
J¼7.1, maj.; 2H), 3.01 (s, min.) and 3.00 (s, maj.; 6H), 1.22 (t, J¼7.1,
min.) and 1.11 (t, J¼7.1, maj.; 3H). 13C: 166.6, 157.1, 151.2, 139.7, 131.2,
129.5, 129.0 (two peaks), 128.1, 127.8, 127.7, 126.0, 115.4, 112.5, 111.5,
111.0, 59.8, 59.6, 40.3, 40.2, 14.2, 14.1. IR: 2982, 2902, 2816, 1708,
1676, 1613, 1580, 1547, 1524, 1443, 1361, 1253, 1231, 1141, 1032.
0.5 mg Pd(OAc)2), MPU (0.7 mg), and trans-crotonaldehyde (17 mL,
0.20 mmol). Chromatography with 10% ether in hexanes gave 7d as
a yellow solid (30 mg, 79%) in a 5.4:1 (E/Z) mixture; mp 110e112 ꢀC
(lit.23 mp not given). 1H: 10.13 (d, J¼8.1, maj.) and 9.57 (d, J¼8.1,
min.; 1H), 7.54 (d, J¼8.9, maj.) and 7.24 (d, J¼8.9, min.; 2H), 6.70 (d,
J¼8.9, 2H), 6.44 (d, J¼8.1, maj.) and 6.06 (d, J¼8.1, min.; 1H), 3.04 (s,
maj.) and 3.02 (s, min.; 6H), 2.53 (s, maj.) and 2.30 (s, min.; 3H). 13C:
193.8, 191.2, 162.1, 157.4, 151.8, 130.3, 127.7, 127.4, 126.6, 123.3, 111.6,

10144
M.R. Smith et al. / Tetrahedron 69 (2013) 10139e10151
111.4, 40.2, 40.1, 25.8, 15.6. IR: 2858, 1633, 1605, 1578, 1523, 1430,
1403, 1365, 1330, 1257, 1232, 1205, 1157, 1147, 1057. ESI-MS: 190.4
(MþH, 100%).
(s, 3H), 2.56 (d, J¼1.0, 3H), 1.53 (s, 9H). 13C: 167.4, 155.1, 152.5, 139.3,
136.3, 127.1, 118.1, 115.3, 80.9, 51.1, 28.3, 17.6. IR: 3375, 2978, 1698,
1623, 1605, 1499, 1435, 1393, 1370, 1349, 1267, 1235, 1197, 1057,
t
1014, 1039. ESI-MS: 314.4 (MþNa, 100%), 258.3 (Mꢁ Bu, 100%).
4.7. 3-(4-(Dimethylamino)phenyl)-3-phenylacrylaldehyde
(7e)37
ESIeHRMS: calcd for C16H21NO4Na [MþNa]þ: 314.1368; found
314.1360. EA: calcd for C16H21NO4 C 65.96; H 7.27; N 4.81; found C
66.35; H 6.97; N 4.53.
Procedure
B using 4-iodo-N,N-dimethylaniline (100 mg,
0.40 mmol), K2CO3 (56 mg, 0.40 mmol), Pd(OAc)2 (0.5 mL of THF
solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.5 mg
4.10. tert-Butyl (4-(1-cyanoprop-1-en-2-yl)phenyl)carbamate
(7h)
Pd(OAc)2), CEPU (0.8 mg), and trans-cinnamaldehyde (25
mL,
0.20 mmol), and chromatography with 10% ether in hexanes gave
7e as yellow solid (48 mg, 96%) as a 2.3:1 (E/Z) mixture. Procedure C
using 4-iodo-N,N-dimethylaniline (100 mg, 0.40 mmol), K2CO3
(56 mg, 0.40 mmol), Pd(OAc)2 (0.5 mL of THF solution containing
1 mg/mL Pd(OAc)2, equivalent to 0.5 mg Pd(OAc)2), MPU (0.7 mg),
Procedure B using tert-butyl (4-iodophenyl)carbamate (100 mg,
0.31 mmol), K2CO3 (43 mg, 0.31 mmol), Pd(OAc)2 (0.4 mL of THF
solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.4 mg
Pd(OAc)2), CEPU (0.7 mg), and crotononitrile (13 mL, 0.16 mmol),
and chromatography with 10% ether in hexanes give 7h as a yellow
oil (41 mg, 100%) as a 2.7:1 (E/Z) mixture. Procedure C using tert-
butyl (4-iodophenyl)carbamate (100 mg, 0.31 mmol), K2CO3
(43 mg, 0.31 mmol), Pd(OAc)2 (0.4 mL of THF solution containing
1 mg/mL Pd(OAc)2, equivalent to 0.4 mg Pd(OAc)2), MPU (0.5 mg),
and trans-cinnamaldehyde (25
mL, 0.20 mmol). Chromatography
with 10% ether in hexanes gave 7e as yellow solid (49 mg, 98%) in
a 5.7:1 (E/Z) mixture; mp 121e124 ꢀC (lit.,37 141e142 ꢀC). 1H: 9.61
(d, J¼8.0, min.) and 9.38 (d, J¼8.2, maj.; 1H), 7.46e7.20 (m, 7H), 6.72
(d, J¼8.9, min.) and 6.65 (d, J¼9.0, maj.; 2H), 6.58 (d, J¼8.2, maj.)
and 6.42 (d, J¼8.0, min.; 1H), 3.06 (s, min.) and 3.03 (s, maj.; 6H).
13C: 193.8, 193.7, 163.3, 162.7, 152.0, 151.5, 141.1, 137.4, 132.9, 130.6,
130.2, 130.1, 129.3,128.3,128.4,128.1, 126.2, 126.0,123.3,111.5, 111.2,
40.2, 40.1. IR: 2897, 2838, 1646, 1603, 1570, 1546, 1522, 1485, 1443,
1367, 1341, 1232, 1198, 1134, 1120, 1029. ESI-MS: 274.4 (MþNa,
100%), 252.4 (MþH, 10%).
and crotononitrile (13
mL, 0.16 mmol). Chromatography with
10/50% ether in hexanes gave 7h as a yellow oil (39 mg, 95%) in
a 2.6:1 (E/Z) mixture; 1H: 7.54 (d, J¼8.7, maj.) and 7.46 (d, J¼8.7,
min.; 2H), 7.41 (m, 2H), 6.70 (br s, 1H), 5.58 (q, J¼0.8, maj.) and 5.33
(q, J¼1.4, min.; 1H), 2.44 (d, J¼0.8, maj.) and 2.25 (d, J¼1.4, min.;
3H), 1.53 (s, 9H). 13C: 159.9, 158.7, 152.4 (two peaks), 140.5, 140.0,
132.3, 132.0, 128.1, 127.2, 126.7, 118.1, 118.0, 94.0, 93.8, 81.1, 80.1,
28.3, 24.5, 20.0. IR: 3357, 2208, 1721, 1581, 1522, 1411, 1364, 1322,
1261, 1225, 1151, 1051, 1024. ESI-MS: 281.4 (MþNa, 100%).
ESIeHRMS: calcd for C15H18N2O2Na [MþNa]þ: 281.1266; found
281.1262.
4.8. 3-(4-(Dimethylamino)phenyl)-1,3-diphenylprop-2-en-1-
one (7f)38
Procedure
B using 4-iodo-N,N-dimethylaniline (100 mg,
0.40 mmol), K2CO3 (56 mg, 0.40 mmol), Pd(OAc)2 (0.5 mL of THF
solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.5 mg
Pd(OAc)2), CEPU (0.8 mg), and trans-chalcone (42 mg, 0.20 mmol),
and chromatography with 10% ether in hexanes gave 7f as an or-
ange solid (65 mg, 100%) as a 2:1 (E/Z) mixture. Procedure C using
4-iodo-N,N-dimethylaniline (100 mg, 0.40 mmol), K2CO3 (56 mg,
0.40 mmol), Pd(OAc)2 (0.5 mL of THF solution containing 1 mg/mL
Pd(OAc)2, equivalent to 0.5 mg Pd(OAc)2), MPU (0.7 mg), and
chalcone (42 mg, 0.20 mmol). Chromatography with 10% ether in
hexanes gave 7f as orange solid (51 mg, 77%) in a 2:1 (E/Z) mixture
mp 52e55 ꢀC (lit.38 mp not given). 1H: 7.96e7.91 (m, 2H), 7.50e7.09
(m, 10H), 7.18 (s, maj.) and 6.89 (s, min.; 1H), 6.68 (d, J¼8.9, maj.)
and 6.57 (d, J¼8.8, min.; 2H), 3.03 (s, maj.) and 2.96 (s, min.; 6H).
13C: 192.9, 191.7, 156.5, 151.4, 150.7, 142.7, 139.9, 139.4, 138.8, 132.3,
132.1, 131.8, 130.0, 129.7, 129.2, 129.1, 128.7, 128.5, 128.4, 128.2,
128.0, 127.9, 126.2, 121.9, 119.0, 111.5, 111.2, 40.2. IR: 2887, 1650,
1602, 1578, 1557, 1542, 1520, 1490, 1444, 1357, 1267, 1197, 1172, 1149,
1017. ESI-MS: 350.4 (MþNa, 60%), 328.4 (MþH, 100%).
4.11. tert-Butyl (4-(4-oxobut-2-en-2-yl)phenyl)carbamate (7i)
Procedure B using tert-butyl (4-iodophenyl)carbamate (100 mg,
0.31 mmol), K2CO3 (43 mg, 0.31 mmol), Pd(OAc)2 (0.4 mL of THF
solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.4 mg
Pd(OAc)2), CEPU (0.7 mg), and trans-crotonaldehyde (13
mL,
0.16 mmol), and chromatography with a gradient of 20/50% ether
in hexanes gave 7i as a yellow solid (21 mg, 50%) as a 92:8 (E/Z)
mixture. Procedure C using tert-butyl (4-iodophenyl)carbamate
(100 mg, 0.31 mmol), K2CO3 (43 mg, 0.31 mmol), Pd(OAc)2 (0.4 mL
of THF solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.4 mg
Pd(OAc)2), MPU (0.5 mg), and trans-crotonaldehyde (13
mL,
0.16 mmol). Chromatography with 20/50% ether in hexanes gave
7i as a yellow solid (23 mg, 55%) in 92:8 (E/Z) mixture; mp
135e137 ꢀC. 1H: 10.16 (d, J¼7.9, maj.) and 9.51 (d, J¼8.1,min.; 1H),
7.52 (d, J¼8.8, 2H), 7.43 (d, J¼8.8, 2H), 6.68 (br s, maj.) and 6.56 (br s,
min.; 1H), 6.41 (d, J¼7.9, maj.) and 6.12 (d, J¼8.1,min.; 1H), 2.55 (s,
maj.) and 2.30 (s,min.; 3H), 1.53 (s, 9H). 13C: 191.3, 156.8, 152.4,
140.4, 134.4, 127.2, 125.9, 118.1, 81.1, 28.3, 16.0. IR: 2979, 1717, 1582,
1521, 1415, 1367, 1328, 1235, 1192, 1150, 1027. APCI-MS: 260.1 (M-H,
100%). ESIeHRMS: calcd for C15H20NO3 [MþH]þ: 262.1443; found
262.1445. EA: calcd for C15H19NO3: C 68.94, H 7.33, N 5.36; found:
68.66, H 7.27, N 5.27.
4.9. (E)-Methyl 3-(4-((tert-butoxycarbonyl)amino)phenyl)
but-2-enoate (7g)
Procedure B using tert-butyl (4-iodophenyl)carbamate (100 mg,
0.31 mmol), K2CO3 (43 mg, 0.31 mmol), Pd(OAc)2 (0.4 mL of THF
solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.4 mg
4.12. tert-Butyl (4-(3-oxo-1-phenylprop-1-en-1-yl)phenyl)
Pd(OAc)2), CEPU (0.7 mg), and methyl crotonate (17
mL, 0.16 mmol),
carbamate (7j)
and chromatography with 10% ether in hexanes gave 7g as a yellow
solid (24 mg, 51%). Procedure C using tert-butyl (4-iodophenyl)
carbamate (100 mg, 0.31 mmol), K2CO3 (43 mg, 0.31 mmol),
Pd(OAc)2 (0.4 mL of THF solution containing 1 mg/mL Pd(OAc)2,
equivalent to 0.4 mg Pd(OAc)2), MPU (0.5 mg), and methyl croto-
Procedure
B
using tert-butyl (4-iodophenyl)-carbamate
(100 mg, 0.31 mmol), K2CO3 (43 mg, 0.31 mmol), Pd(OAc)2 (0.4 mL
of THF solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.4 mg
Pd(OAc)2), CEPU (0.7 mg), and trans-cinnamaldehyde (20
mL,
nate (17
m
L, 0.16 mmol). Chromatography with 10% ether in hexanes
0.16 mmol), and chromatography with 20% ether in hexanes give 7j
as a yellow solid (52 mg, 100%) as a 3:1 (E/Z) mixture. Procedure C
using tert-butyl (4-iodophenyl)-carbamate (100 mg, 0.31 mmol),
gave 7g as a yellow solid (26 mg, 55%); mp 83e85 ꢀC. 1H: 7.44 (d,
J¼8.8, 2H), 7.38 (d, J¼8.8, 2H), 6.60 (br s,1H), 6.13 (q, J¼1.0, 1H), 3.75

M.R. Smith et al. / Tetrahedron 69 (2013) 10139e10151
10145
K2CO3 (43 mg, 0.31 mmol), Pd(OAc)2 (0.4 mL of THF solution con-
taining 1 mg/mL Pd(OAc)2, equivalent to 0.4 mg Pd(OAc)2), MPU
(0.5 mg), and trans-cinnamaldehyde (20 L, 0.16 mmol). Chroma-
4.15. Ethyl 3-(4-methoxyphenyl)-3-phenylacrylate (7m)39
m
Procedure A using 4-iodoanisole (100 mg, 0.43 mmol), K2CO3
(59 mg, 0.43 mmol), Pd(OAc)2 (0.5 mL of THF solution containing
1 mg/mL Pd(OAc)2, equivalent to 0.5 mg Pd(OAc)2), phenylurea
tography with 20% ether in hexanes gave 7j as a yellow solid
(44 mg, 85%) in a 2.5:1 (E/Z) mixture; mp 102e105 ꢀC. 1H: 9.57 (d,
J¼8.0, min.) and 9.46 (d, J¼8.0, maj.; 1H), 7.48e7.23 (m, 9H), 6.68
(br s) and 6.66 (br s; 1H), 6.58 (d, J¼8.0, maj.) and 6.55 (d, J¼8.0,
min.; 1H), 1.54 (s, min.) and 1.52 (s, maj.; 9H). 13C: 193.6, 193.5,
162.0, 161.8, 152.3, 140.7, 140.0, 139.0, 136.7, 133.9, 131.9, 131.1, 130.7,
130.5, 129.7, 129.4, 128.9, 128.6, 128.3, 127.2, 126.0, 118.0, 117.9, 81.1
(two peaks), 28.30 (two peaks). IR: 3297, 2978, 1727, 1649, 1589,
1519, 1449, 1391, 1366, 1343, 1316, 1231, 1150, 1128, 1050, 1026.
APCI-MS: 322.2 (MꢁH, 100%). ESIeHRMS: calcd for C20H22NO3
(0.6 mg), and ethyl cinnamate (33
tography with 5% ether in hexanes gave 7m as a colorless oil
(19 mg, 35%) as 2.6:1 (E/Z) mixture. Procedure using
mL, 0.21 mmol), and chroma-
a
B
4-iodoanisole (100 mg, 0.43 mmol), K2CO3 (59 mg, 0.43 mmol),
Pd(OAc)2 (0.5 mL of THF solution containing 1 mg/mL Pd(OAc)2,
equivalent to 0.5 mg Pd(OAc)2), CEPU (0.8 mg), and ethyl cinnamate
(33 mL, 0.21 mmol), and chromatography with 5% ether in hexanes
gave 7m as a colorless oil (40 mg, 75%) as a 2.1:1 (E/Z) mixture.
Procedure C using 4-iodoanisole (100 mg, 0.43 mmol), K2CO3
(59 mg, 0.43 mmol), palladium acetate (0.5 mL of THF solution
containing 1 mg/mL Pd(OAc)2, equivalent to 0.5 mg Pd(OAc)2), MPU
[MþH]þ: 324.1600; found: 324.1602. EA calcd for C20H21NO3
C
74.28; H 6.55; N 4.33; found C 74.42; H 6.37; N 4.25.
(0.7 mg), and ethyl cinnamate (33 mL, 0.21 mmol). Chromatography
4.13. Ethyl 3-(4-((tert-butoxycarbonyl)amino)phenyl)-3-
with 10% ether in hexanes gave 7m as a colorless oil (17 mg, 29%) as
a 2.1:1 (E/Z) mixture 1H: 7.40e7.16 (m, 7H), 6.91 (d, J¼8.7, min.) and
6.85 (d, J¼8.9, maj.; 2H), 6.32 (s, maj.) and 6.29 (s, min.; 1H), 4.1 (q,
J¼7.1, min.) and 4.05 (q, J¼7.1, maj.; 2H), 3.85 (s, min.) and 3.82 (s,
maj.; 3H), 1.18 (t, J¼7.1, min.) and 1.11 (t, J¼7.1, maj.; 3H). 13C: 166.3,
160.8, 159.7, 156.6, 156.3, 141.5, 139.3, 138.3, 133.1, 130.9, 129.8,
129.3, 129.1, 128.6, 128.3, 128.0, 127.8, 117.9, 116.9, 115.3, 113.8, 113.2,
60.0, 59.9, 55.3, 55.2, 14.1, 14.0. IR: 2974, 1716, 1599, 1573, 1510,
1443, 1463, 1368, 1248, 1147, 1031. ESI-MS: 301.2 (MþNa, 100%).
phenylacrylate (7k)
Procedure B using tert-butyl (4-iodophenyl)carbamate (100 mg,
0.31 mmol), K2CO3 (43 mg, 0.31 mmol), Pd(OAc)2 (0.4 mL of THF
solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.4 mg
Pd(OAc)2), CEPU (0.7 mg), and ethyl cinnamate (27 mL, 0.16 mmol),
and chromatography with 20% ether in hexanes gave 7k as a pale
yellow oil (42 mg, 71%) as a 3:1 (E/Z) mixture. Procedure C using
tert-butyl (4-iodophenyl)carbamate (100 mg, 0.31 mmol), K2CO3
(43 mg, 0.31 mmol), Pd(OAc)2 (0.4 mL of THF solution containing
1 mg/mL Pd(OAc)2, equivalent to 0.4 mg Pd(OAc)2), MPU (0.5 mg),
4.16. (E)-Methyl 3-(4-methoxyphenyl)but-2-enoate (7n)40
and ethyl cinnamate (27 mL, 0.16 mmol). Chromatography with 20%
Procedure A using 4-iodoanisole (100 mg, 0.43 mmol), K2CO3
(59 mg, 0.43 mmol), Pd(OAc)2 (0.5 mL of THF solution containing
1 mg/mL Pd(OAc)2, equivalent to 0.5 mg Pd(OAc)2), phenylurea
ether in hexanes gave 7k as pale yellow oil (45 mg, 77%) in a 3:1 (E/
Z) mixture; 1H: 7.39e7.14 (m, 9H), 6.57 (br s, 1H), 6.33 (s, maj.) and
6.30 (s, min.; 1H), 4.12e4.01 (m, 2H), 1.53 (s, min.) and 1.52 (s, maj.;
9H), 1.17 (t, J¼7.1, min.) and 1.11 (t, J¼7.1, maj.; 3H). 13C: 166.2, 156.0,
152.4 (two peaks), 141.1, 139.6, 139.0, 138.5, 135.2, 133.4, 130.3,
129.4, 129.2, 129.1, 128.5, 128.3, 128.1, 127.8, 127.2, 117.9, 117.6, 117.4,
115.9, 80.9, 60.1, 59.1, 29.3 (two peaks), 14.1, 14.0. IR: 3330, 2979,
1699, 1588, 1519, 1409, 1367, 1316, 1231, 1149, 1051. ESI-MS: 390.3
(MþNa, 100%). ESIeHRMS: calcd for C22H25NO4Na [MþNa]þ:
390.168; found 390.1689.
(0.6 mg), and methyl crotonate (23
tography with 5% ether in hexanes gave 7n as a colorless solid
(23 mg, 53%). Procedure using 4-iodoanisole (100 mg,
mL, 0.21 mmol), and chroma-
B
0.43 mmol), K2CO3 (59 mg, 0.43 mmol) Pd(OAc)2 (0.5 mL of THF
solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.5 mg
Pd(OAc)2), CEPU (0.8 mg), and methyl crotonate (23 mL, 0.21 mmol),
and chromatography with 5% ether in hexanes gave 7n as a color-
less solid (38 mg, 97%). Procedure C using 4-iodoanisole (100 mg,
0.43 mmol), K2CO3 (59 mg, 0.43 mmol), palladium acetate (0.5 mL
of THF solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.5 mg
4.14. tert-Butyl (4-(3-oxo-1,3-diphenylprop-1-en-1-yl)phenyl)
carbamate (7l)
Pd(OAc)2), MPU (0.7 mg), and methyl crotonate (23 mL, 0.21 mmol).
Chromatography with 5% ether in hexanes gave 7n as a colorless
solid (29 mg, 67%), mp 50e51 ꢀC (lit.40 52e53 ꢀC). 1H: 7.46 (d, J¼8.9,
2H), 6.91 (d, J¼8.9, 2H), 6.12 (q, J¼1.2, 1H), 3.84 (s, 3H), 3.75 (s, 3H),
2.58 (d, J¼1.2, 3H). 13C: 167.5, 160.5, 155.3, 134.2, 127.7, 114.8 (two
peaks), 55.3, 51.0, 17.7. IR: 2950, 2844, 1707, 1621, 1600, 1570, 1512,
1439, 1349, 1296, 1275, 1249, 1162, 1021. APCI-MS 175.3 (MꢁOMe,
100%).
Procedure B using tert-butyl (4-iodophenyl)carbamate (100 mg,
0.31 mmol), K2CO3 (43 mg, 0.31 mmol), Pd(OAc)2 (0.4 mL of THF
solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.4 mg
Pd(OAc)2), CEPU (0.7 mg), and chalcone (33 mg, 0.16 mmol), and
chromatography with 20% ether in hexanes gave 7l as a yellow
foam (49 mg, 77%) as a 3:1 (E/Z) mixture. Procedure C using tert-
butyl (4-iodophenyl)carbamate (100 mg, 0.31 mmol), K2CO3
(43 mg, 0.31 mmol), Pd(OAc)2 (0.4 mL of THF solution containing
1 mg/mL Pd(OAc)2, equivalent to 0.4 mg Pd(OAc)2), MPU (0.5 mg),
and chalcone (33 mg, 0.16 mmol). Chromatography with 20% ether
in hexanes gave 7l as a yellow foam (53 mg, 83%) in a 3:1 (E/Z)
mixture; mp 50e53 ꢀC. 1H: 7.93e7.88 (m, 2H), 7.49e7.13 (m, 12H),
7.11 (s, maj.) and 7.04 (s, min.; 1H), 6.58 (br s, maj.) and 6.47 (br s,
min.; 1H), 1.54 (s, maj.) and 1.51 (s, min.; 9H). 13C: 192.9, 192.5,
154.7, 154.5, 152.5 (2 peaks), 141.6, 139.7, 139.1, 138.7, 138.5, 138.3,
135.8, 133.5, 132.7, 132.5, 130.9, 130.7, 129.8, 129.5, 128.8, 128.7,
128.40 (three peaks), 128.3, 128.0, 123.6, 122.5, 118.0, 117.8, 80.9,
80.7, 28.3. IR: 3321, 2978, 1724, 1649, 1584, 1518, 1448, 1409, 1365,
1316, 1231, 1151, 1052, 1016. APCI-MS: 398.0 (MꢁH, 100%), 298.0
4.17. 3-(4-Methoxyphenyl)but-2-enal (7o)23
Procedure A using 4-iodoanisole (100 mg, 0.43 mmol), K2CO3
(59 mg, 0.43 mmol), Pd(OAc)2 (0.5 mL of THF solution containing
1 mg/mL Pd(OAc)2, equivalent to 0.5 mg Pd(OAc)2), phenylurea
(0.6 mg), and trans-crotonaldehyde (18 mL, 0.21 mmol), and chro-
matography with 5% ether in hexanes gave 7o as a pale yellow oil
(28 mg, 76%) as a 3:1 (E/Z) mixture. Procedure B using 4-iodoanisole
(100 mg, 0.43 mmol), K2CO3 (59 mg, 0.43 mmol), Pd(OAc)2 (0.5 mL
of THF solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.5 mg
Pd(OAc)2), CEPU (0.8 mg), and trans-crotonaldehyde (18
mL,
0.21 mmol), and chromatography with 5% ether in hexanes gave 7o
as a pale yellow oil (25 mg, 74%) as a 3:1 (E/Z) mixture. Procedure C
using 4-iodoanisole (100 mg, 0.43 mmol), K2CO3 (59 mg,
0.43 mmol), palladium acetate (0.5 mL of THF solution containing
(MꢁBoc, 100%). ESIeHRMS: calcd for
C
26H26NO3 [MþH]þ:
400.1913; found [MþH] 400.1918. EA: calcd for C26H25NO3 C 78.47;
H 6.31; N 3.51; found C 78.70; H 6.14; N 3.61.

10146
M.R. Smith et al. / Tetrahedron 69 (2013) 10139e10151
1 mg/mL Pd(OAc)2, equivalent to 0.5 mg Pd(OAc)2), MPU (0.7 mg),
and trans-crotonaldehyde (18 L, 0.21 mmol). Chromatography
4.20. 3-(4-Methoxyphenyl)-1,3-diphenylprop-2-en-1-one
(7r)25b
m
with 10% ether in hexanes gave 7o as a pale yellow oil (20 mg, 54%)
in a 3.2:1 (E/Z) mixture 1H: 10.16 (d, J¼7.9, maj.) and 9.51 (d, J¼8.1,
min.; 1H), 7.55 (d, J¼8.9, maj.) and 7.27 (d, J¼8.7, min.; 2H), 6.94 (d,
J¼8.9, 2H), 6.41 (d, J¼7.9, maj.) and 6.12 (d, J¼8.1, min.; 1H), 3.86 (s,
3H), 2.56 (s, maj.) and 2.31 (s, min.; 3H). 13C: 193.5, 191.3, 161.6,
161.4, 160.6,157.0, 132.4,130.6, 130.0, 128.6, 127.8, 125.6,114.1, 113.8,
55.4 (two peaks), 26.2, 16.1. IR: 2934, 2839, 1654, 1596, 1510, 1440,
1376, 1291, 1243, 1181, 1147, 1060, 1027. APCI-MS: 177.3 (MþH,
100%).
Procedure A using 4-iodoanisole (100 mg, 0.43 mmol), K2CO3
(59 mg, 0.43 mmol), Pd(OAc)2 (0.5 mL of THF solution containing
1 mg/mL Pd(OAc)2, equivalent to 0.5 mg Pd(OAc)2), phenylurea
(0.6 mg), and trans-chalcone (45 mg, 0.21 mmol), and chromatog-
raphy with 5% ether in hexanes gave 7r as a yellow oil (13 mg, 20%)
as a 1.7:1 (E/Z) mixture. Procedure B using 4-iodoanisole (100 mg,
0.43 mmol), K2CO3 (59 mg, 0.43 mmol), Pd(OAc)2 (0.5 mL of THF
solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.5 mg
Pd(OAc)2), CEPU (0.8 mg), and chalcone (45 mg, 0.21 mmol), and
chromatography with 5% ether in hexanes gave 7r as a yellow oil
4.18. 3-(4-Methoxyphenyl)but-2-enenitrile (7p)41
(44 mg, 66%) as
a 2.2:1 (E/Z) mixture. Procedure C using
4-iodoanisole (100 mg, 0.43 mmol), K2CO3 (59 mg, 0.43 mmol),
Pd(OAc)2 (0.5 mL of THF solution containing 1 mg/mL Pd(OAc)2,
equivalent to 0.5 mg Pd(OAc)2), MPU (0.7 mg), and chalcone
(44 mg, 0.21 mmol). Chromatography with 10% ether in hexanes
gave 7r as a yellow oil (35 mg, 53%) in a 2.3:1 (E/Z) mixture; 1H:
7.94e7.91 (m, 2H) 7.51e7.14 (m, 10H), 7.13 (s, maj.) and 7.03 (s, min.;
1H), 6.91 (d, J¼8.7, maj.) and 6.90 (d, J¼8.7, min.; 2H), 3.86 (s, maj.)
and 3.79 (s, min.; 3H). 13C: 193.0, 192.4, 160.8, 159.9, 155.1, 154.9,
139.3,138.6,138.4,138.2,133.7,132.6,132.5,131.5,131.2,130.1,129.7,
129.3, 128.9, 128.8, 128.7, 128.4 (two peaks), 128.3, 128.0, 123.4,
121.9, 118.0, 113.9, 113.5, 55.4, 55.2. IR: 3056, 2837, 1656, 1598, 1580,
1563, 1509, 1489, 1445, 1353, 1249, 1211, 1176, 1033, 1017. ESI-MS:
337.4 (MþNa, 100%).
Procedure A using 4-iodoanisole (100 mg, 0.43 mmol), K2CO3
(59 mg, 0.43 mmol), Pd(OAc)2 (0.5 mL of THF solution containing
1 mg/mL Pd(OAc)2, equivalent to 0.5 mg Pd(OAc)2), phenylurea
(0.6 mg), and cis/trans-crotononitrile (17
mL, 0.21 mmol), and
chromatography with 5% ether in hexanes gave 7p as a pale yellow
oil (14 mg, 39%) as a 1.6:1 (E/Z) mixture. Procedure B using 4-
iodoanisole (100 mg, 0.43 mmol), K2CO3 (59 mg, 0.43 mmol),
Pd(OAc)2 (0.5 mL of THF solution containing 1 mg/mL Pd(OAc)2,
equivalent to 0.5 mg Pd(OAc)2), CEPU (0.8 mg), and cis/trans-cro-
tononitrile (17 mL, 0.21 mmol), and chromatography with 5% ether
in hexanes gave 7p as a pale yellow oil (33 mg, 92%) in a 1.6:1 (E/Z)
mixture. Procedure C using 4-iodoanisole (100 mg, 0.43 mmol),
K2CO3 (59 mg, 0.43 mmol), palladium acetate (0.5 mL of THF so-
lution containing
Pd(OAc)2), MPU (0.7 mg), and (E/Z)-crotononitrile (17
1
mg/mL Pd(OAc)2, equivalent to 0.5 mg
L,
4.21. (E)-Methyl 3-phenylbut-2-enoate (8a)42
m
0.21 mmol). Chromatography with 5% ether in hexanes gave 7p as
a pale yellow oil (30 mg, 83%) in a 3.45:1 (E/Z) mixture; 1H: 7.58 (d,
J¼8.9, min.) and 7.44 (d, J¼8.9, maj.; 2H), 6.95 (d, J¼8.9, min.) and
6.92 (d, J¼8.9 maj.; 2H), 5.56 (q, J¼0.9, maj.) and 5.31 (q, J¼1.4, min.;
1H), 3.85 (s, 3H), 2.45 (d, J¼0.9, maj.) and 2.27 (d, J¼1.4, min.; 3H).
13C: 161.3, 160.9, 159.9, 158.8, 130.4, 130.0, 128.7, 127.4, 118.2, 118.1,
114.1, 113.9, 93.6, 93.2, 55.4 (two peaks), 24.5, 20.0. IR: 2937, 2836,
2203, 1600, 1573, 1512, 1441, 1419, 1375, 1297, 1247, 1182, 1119, 1024.
APCI-MS: 174.5 (MþH, 100%).
Procedure B using iodobenzene (55
(68 mg, 0.49 mmol), Pd(OAc)2 (0.6 mL of THF solution containing
1 mg/mL Pd(OAc)2, equivalent to 0.6 mg Pd(OAc)2), CEPU (1 mg),
mL, 0.49 mmol), K2CO3
and methyl crotonate (25 mL, 0.24 mmol). Chromatography using
5% ether in hexanes gave 8a as a colorless oil (24 mg, 57%). 1H:
7.50e7.47 (m, 2H), 7.39e7.37 (m, 3H), 6.15 (q, J¼1.0, 1H), 3.77 (s,
3H), 2.60 (d, J¼1.0, 3H). 13C: 167.2, 155.9, 142.2, 129.0, 128.5, 126.3,
116.7, 51.1, 18.0. IR: 2949, 1712, 1628, 1437, 1347, 1272, 1162, 1031.
APCI-MS: 177.4 (MþH, 20%), 145.3 (MꢁOMe, 100%).
4.19. 3-(4-Methoxyphenyl)-3-phenylacrylaldehyde (7q)39
4.22. Ethyl 3,3-diphenylacrylate (8b/c)43
Procedure A using 4-iodoanisole (100 mg, 0.43 mmol), K2CO3
(59 mg, 0.43 mmol), Pd(OAc)2 (0.5 mL of THF solution containing
1 mg/mL Pd(OAc)2, equivalent to 0.5 mg Pd(OAc)2), phenylurea
Procedure B using iodobenzene (55
(68 mg, 0.49 mmol), Pd(OAc)2 (0.6 mL of THF solution containing
1 mg/mL Pd(OAc)2, equivalent to 0.6 mg Pd(OAc)2), CEPU (1 mg),
mL, 0.49 mmol), K2CO3
(0.6 mg), and trans-cinnamaldehyde (27 mL, 0.21 mmol), and chro-
and ethyl cinnamate (41
ether in hexanes gave 8b as a colorless oil (44 mg, 72%). Procedure C
using iodobenzene (55 L, 0.49 mmol), K2CO3 (68 mg, 0.49 mmol),
mL, 0.24 mmol). Chromatography using 5%
matography with 5% ether in hexanes gave 7q as a yellow oil (17 mg,
34%) as a 2.6:1 (E/Z) mixture. Procedure B using 4-iodoanisole
(100 mg, 0.43 mmol), K2CO3 (59 mg, 0.43 mmol), Pd(OAc)2 (0.5 mL
of THF solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.5 mg
m
Pd(OAc)2 (0.6 mL of THF solution containing 1 mg/mL Pd(OAc)2,
equivalent to 0.6 mg Pd(OAc)2), 4-methoxyphenyl urea (0.8 mg),
and ethyl cinnamate (41 mL, 0.24 mmol). Chromatography using 5%
Pd(OAc)2), CEPU (0.8 mg), and trans-cinnamaldehyde (27
mL,
0.21 mmol), and chromatography with 5% ether in hexanes gave 7q
as a yellow oil (42 mg, 84%) as a 2.6:1 (E/Z) mixture. Procedure C
using 4-iodoanisole (100 mg, 0.43 mmol), K2CO3 (59 mg, 0.43 mmol),
Pd(OAc)2 (0.5 mL of THF solution containing 1 mg/mL Pd(OAc)2,
equivalent to 0.5 mg Pd(OAc)2), MPU (0.7 mg), and trans-cinna-
ether in hexanes gave 8c as a colorless oil (33 mg, 55%); 1H:
7.40e7.31 (m, 8H), 7.24e7.21 (m, 2H), 6.38 (s,1H), 4.06 (q, J¼7.1, 2H),
1.13 (t, J¼7.1, 3H). 13C: 166.1, 156.4, 140.8, 139.0, 129.4, 129.1, 128.3,
128.1, 127.9, 117.5, 60.0, 14.0. IR: 2981, 1708, 1615, 1446, 1365, 1261,
1154, 1032. APCI-MS: 253.4 (MþH, 60%), 207.4 (MꢁOEt, 100%).
maldehyde (27 mL, 0.21 mmol). Chromatography with 10% ether in
hexanes gave 7q as a yellow oil (50 mg, 100%) in a 2.6:1 (E/Z) mix-
ture; 1H: 9.57 (d, J¼7.9, min.) and 9.46 (d, J¼8.1, maj.; 1H), 7.52e7.24
(m, 7H), 6.97 (d, J¼8.7, min.) and 6.90 (d, J¼8.9, maj.; 2H), 6.58 (d,
J¼8.1, maj.) and 6.53 (d, J¼7.9, min.; 1H), 3.89 (s, min.) and 3.85 (s,
maj.; 3H). 13C: 193.7, 193.6, 162.4, 162.1, 161.7, 160.9, 140.3, 138.3,
136.9, 132.6, 131.9, 130.7, 130.4, 130.3, 129.3, 129.0, 128.6, 128.3, 127.0,
125.6, 114.0, 113.8, 55.4. IR: 2839, 1656, 1601, 1584, 1510, 1488, 1462,
1443, 1422, 1387, 1343, 1296, 1244, 1178, 1126, 1029. ESI-MS: 261.4
(MþNa, 100%), 239.4 (MþH, 10%).
4.23. (E)-3-Phenylbut-2-enenitrile (8d)44
Procedure B using iodobenzene (55
mL, 0.49 mmol), K2CO3
(68 mg, 0.49 mmol), Pd(OAc)2 (0.6 mL of THF solution containing
1 mg/mL Pd(OAc)2, equivalent to 0.6 mg Pd(OAc)2), CEPU (1 mg),
and cis/trans-crotononitrile (20 mL, 0.24 mmol). Chromatography
using 5% ether in hexanes gave 8d as a colorless oil (18 mg, 58%). 1H:
7.49e4.41 (m, 5H), 5.63 (br s, 1H), 2.48 (br s, 3H). 13C: 159.8, 138.4,

M.R. Smith et al. / Tetrahedron 69 (2013) 10139e10151
10147
130.2, 128. 8, 125.9, 117.6, 95.6, 20.2. IR: 3062, 2213, 1608, 1573,
1495, 1443, 1382, 1260, 1078, 1024. APCI-MS 144.3 (MþH, 100%).
10% ether in hexanes gave 10f as an orange solid (22 mg, 50%); mp
135e137 ꢀC. 1H: 7.21 (d, J¼8.9, 2H), 7.11 (d, J¼8.8, 2H), 6.70 (d, J¼8.8,
2H), 6.62 (d, J¼8.9, 2H), 6.03 (s, 1H), 2.99 (s, 6H), 2.98 (s, 6H), 1.37 (s,
9H). 13C: 166.7, 156.1, 150.9, 150.3, 131.0, 130.0, 129.7, 127.4, 114.1,
111.4, 111.3, 79.3, 40.5, 40.3, 28.0. IR: 2969, 2802, 1702, 1583, 1519,
1447, 1353, 1263, 1226, 1192, 1115, 945. ESI-MS: 367.4 (MþH, 100%),
4.24. (E)-3-Phenylbut-2-enal (8e/f)45
Procedure B using iodobenzene (55
mL, 0.49 mmol), K2CO3
t
(68 mg, 0.49 mmol), Pd(OAc)2 (0.6 mL of THF solution containing
1 mg/mL Pd(OAc)2, equivalent to 0.6 mg Pd(OAc)2), CEPU (1 mg,
311.4 (Mꢁ BuþH, 100%). ESIeHRMS: calcd for C23H31N2O2 [MþH]þ:
367.2386; found 367.2391.
2 mol %), and crotonaldehyde (20
using 5% ether in hexanes gave 8e as a colorless oil (12 mg, 34%).
Procedure C using iodobenzene (55 L, 0.49 mmol), K2CO3 (68 mg,
mL, 0.24 mmol). Chromatography
4.29. (E)-3-(4-Methoxyphenyl)-2-methylacrylaldehyde (12a)48
m
0.49 mmol), Pd(OAc)2 (0.6 mL of THF solution containing 1 mg/mL
Pd(OAc)2, equivalent to 0.6 mg Pd(OAc)2), 4-methoxyphenyl urea
(0.8 mg), and crotononitrile (20 mL, 0.24 mmol). Chromatography
Procedure B using 4-iodoanisole (100 mg, 0.43 mmol), K2CO3
(59 mg, 0.43 mmol), Pd(OAc)2 (0.5 mL of THF solution containing
1 mg/mL Pd(OAc)2, equivalent to 0.5 mg Pd(OAc)2), CEPU (0.9 mg),
using 5% ether in hexanes gave 8f as a colorless oil (10 mg, 29%). 1H:
10.20 (d, J¼7.8, 1H), 7.57e7.54 (m, 2H), 7.44e7.42 (m, 3H), 6.40 (d,
J¼7.8, 1H), 2.59 (s, 3H). 13C: 191.2, 157.6, 140.6, 130.1, 128.8, 127.3,
126.3, 16.4. IR: 2925, 2853, 1659, 1611, 1444, 1377, 1255, 1141, 1010.
APCI-MS: 147.3 (MþH, 100%).
and methacrolein (17 mL, 0.21 mmol). Chromatography using 20%
ether in hexanes gave 12a as a yellow oil (26 mg, 70%). 1H: 9.55 (s,
1H), 7.54 (d, J¼8.7, 2H), 7.20 (s, 1H), 6.98 (d, J¼8.7, 2H), 3.87 (s, 3H),
2.09 (s, 3H). 13C: 195.6, 160.7, 149.9, 136.2, 132.1, 128.0, 114.2, 55.4,
10.9. IR: 2957, 2838, 2712, 1669, 1621, 1598, 1570, 1509, 1441, 1406,
1305, 1252, 1173, 1115, 1030, 1014. APCI-MS; 177.3 (MþH, 100%).
4.25. 3,3-Diphenylacrylaldehyde (8g)46
4.30. (E)-3-(4-(Dimethylamino)phenyl)-2-
Procedure B using iodobenzene (55
(68 mg, 0.49 mmol), Pd(OAc)2 (0.6 mL of THF solution containing
1 mg/mL Pd(OAc)2, equivalent to 0.6 mg Pd(OAc)2), CEPU (1 mg),
mL, 0.49 mmol), K2CO3
methylacrylaldehyde (12b)49
Procedure
B using 4-iodo-N,N-dimethylaniline (106 mg,
and trans-cinnamaldehyde (30
mL, 0.24 mmol). Chromatography
0.43 mmol), K2CO3 (59 mg, 0.43 mmol), Pd(OAc)2 (0.5 mL of THF
solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.5 mg
Pd(OAc)2), CEPU (0.9 mg), and methacrolein (17 mL, 0.21 mmol).
Chromatography using 20% ether in hexanes gave 12b as a yellow
solid (27 mg, 68%); mp 112e115 ꢀC (lit.49 112 ꢀC). 1H: 9.49 (s, 1H),
7.52 (d, J¼8.9, 2H), 7.13 (s, 1H), 6.73 (d, J¼8.9, 2H), 3.05 (s, 6H), 2.10
(s, 3H). 13C: 195.5, 151.2, 133.6,132.4, 123.2, 111.7, 40.1, 11.0. IR: 2904,
8223, 2718, 1666, 1587, 1523, 1445, 1408, 1356, 1317, 1232, 1192,
1065, 1015. APCI-MS: 190.3 (MþH, 100%).
using 5% ether in hexanes gave 8g as a yellow oil (40 mg, 80%); 1H
9.54 (d, J¼8.0, 1H), 7.48e7.30 (m, 10H), 6.61 (d, J¼8.0, 1H). 13C:
193.5, 162.3, 139.7, 136.7, 130.7, 130.5, 129.5, 128.7, 128.6, 128.4,
127.3. IR: 3057, 2840, 1660, 1591, 1569, 1445, 1389, 1341, 1122. APCI-
MS: 209.4 (MþH, 100%).
4.26. 1,3,3-Triphenylprop-2-en-1-one (8h)47
Procedure B using iodobenzene (55
mL, 0.49 mmol), K2CO3
(68 mg, 0.49 mmol), Pd(OAc)2 (0.6 mL of THF solution containing
1 mg/mL Pd(OAc)2, equivalent to 0.6 mg Pd(OAc)2), CEPU (1 mg),
and chalcone (50 mg, 0.24 mmol). Chromatography using 5% ether
in hexanes gave 8h as a yellow oil (40 mg, 59%); 1H 7.92 (d, J¼7.1,
2H), 7.48e7.39 (m, 8H), 7.30e7.27 (m, 3H), 7.21e7.18 (m, 2H), 7.13 (s,
1H). 13C: 192.7, 154.7, 141.4, 139.0, 138.2, 132.7, 129.8, 129.4, 128.8,
128.6, 128.5, 128.4, 128.1, 124.0. IR: 3058, 2926, 1657, 1571, 1446,
1356, 1265, 1211, 1017. APCI-MS 285.4 (MþH, 100%).
4.31. (E)-tert-Butyl (4-(2-methyl-3-oxoprop-1-en-1-yl)phenyl)
carbamate (12c)
Procedure B using tert-butyl (4-iodophenyl)carbamate (137 mg,
0.43 mmol), K2CO3 (59 mg, 0.43 mmol), Pd(OAc)2 (0.5 mL of THF
solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.5 mg
Pd(OAc)2), CEPU (0.9 mg), and methacrolein (17 mL, 0.21 mmol).
Chromatography using 20% ether in hexanes gave 12c as a pale
yellow solid (31 mg, 56%); mp 105e108 ꢀC. 1H: 9.55 (s, 1H), 7.51 (d,
J¼8.9, 2H), 7.47 (d, J¼8.9, 2H), 7.19 (s, 1H), 6.75 (br s, 1H), 2.08 (s,
3H), 1.53 (s, 9H). 13C: 195.6, 152.4, 149.7, 139.9, 136.8, 131.3, 129.8,
118.1, 81.1, 28.3, 11.0. IR: 3271, 2980, 2920, 1727, 1652, 1587, 1519,
1450, 1393, 1367, 1318, 1232, 1153, 1050, 1027, 1012. APCI-MS: 260.1
4.27. tert-Butyl 3,3-bis(4-methoxyphenyl)acrylate (10a)13
Procedure B using 4-iodoanisole (57 mg, 0.24 mmol) K2CO3
(34 mg, 0.24 mmol), Pd(OAc)2 (0.3 mL of THF solution containing
1 mg/mL Pd(OAc)2, equivalent to 0.3 mg Pd(OAc)2), CEPU (0.5 mg),
and (E)-tert-butyl 3-(4-methoxyphenyl)acrylate (9b, 28 mg,
0.12 mmol), and chromatography with 10% ether in hexanes gave
10b as a colorless oil (22 mg, 54%). 1H: 7.22 (d, J¼8.9, 2H), 7.14 (d,
J¼8.8, 2H), 6.91 (d, J¼8.8, 2H), 6.83 (d, J¼8.9, 2H), 6.15 (s, 1H), 3.85
(s, 3H), 3.82 (s, 3H), 1.34 (s, 9H). 13C: 166.1, 160.5, 159.5, 154.3, 134.0,
131.8, 130.9, 129.9, 117.4, 113.6, 113.2, 80.0, 55.3, 55.2, 27.9. IR: 2973,
1690, 1600, 1509, 1459, 1365, 1287, 1245, 1171, 1137, 1032. ESI-MS:
363.4 (MþNa, 100%).
t
(MꢁH, 100%), 206.3 (Mꢁ Bu, 70%), 188.3 (MꢁBocþNa, 100%).
ESIeHRMS: calcd for
262.1443.
C
15H20NO3 [MþH]þ: 262.1443; found
4.32. (E)-3-Cyclohexyl-3-(4-methoxyphenyl)acrylaldehyde
(12d)50
Procedure B using 4-iodoanisole (68 mg, 0.29 mmol), K2CO3
(0.29 mmol, 40 mg), Pd(OAc)2 (0.3 mL of THF solution containing
1 mg/mL Pd(OAc)2, equivalent to 0.3 mg Pd(OAc)2), CEPU (0.6 mg),
and 3-cyclohexylacrylaldehyde (20 mg, 0.14 mmol). Chromatogra-
phy using 10% ether in hexanes gave 12d as a pale yellow oil (13 mg,
38%). 1H: 9.41 (d, J¼7.9, 1H), 7.17 (d, J¼8.4, 2H), 6.92 (d, J¼8.4, 2H),
6.04 (d, J¼7.9, 1H), 3.85 (s, 3H), 2.38 (m, 1H), 1.82e1.69 (m, 5H),
1.32e1.18 (m, 5H). 13C: 194.5, 171.4, 160.0, 138.4, 130.1, 126.4, 113.6,
55.3, 49.9, 31.8, 26.5, 26.0. IR: 2927, 2852, 1666, 1605, 1510, 1448,
1289, 1247, 1177, 1122, 1030. APCI-MS: 245.3 (MþH, 100%).
4.28. tert-Butyl 3,3-bis(4-(dimethylamino)phenyl)acrylate
(10b)
Procedure
B using 4-iodo N,N-dimethylaniline (60 mg,
0.24 mmol), K2CO3 (34 mg, 0.24 mmol), Pd(OAc)2 (0.3 mL of THF
solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.3 mg
Pd(OAc)2), CEPU (0.5 mg), and (E)-tert-butyl 3-(4-(dimethylamino)
phenyl)acrylate (9c, 30 mg, 0.12 mmol), and chromatography with

10148
M.R. Smith et al. / Tetrahedron 69 (2013) 10139e10151
4.33. (E)-3-Cyclohexyl-3-(4-(dimethylamino)phenyl)acryl-
4.37. (Z)-Methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(dime-
aldehyde (12e)
thylamino)phenyl)acrylate (14b)
Procedure
B
using 4-iodo-N,N-dimethylaniline (72 mg,
Procedure
B
using 4-iodo-N,N-dimethylaniline (300 mg,
0.29 mmol), K2CO3 (0.29 mmol, 40 mg), Pd(OAc)2 (0.3 mL of THF so-
lution containing 1 mg/mL Pd(OAc)2, equivalent to 0.3 mg Pd(OAc)2),
CEPU (0.6 mg), and 3-cyclohexylacrylaldehyde (20 mg, 0.14 mmol).
Chromatography using 10% ether in hexanes gave 12e as a yellow oil
(15 mg, 42%). 1H: 9.46 (d, J¼7.9,1H), 7.14 (d, J¼8.6, 2H), 6.70 (d, J¼8.6,
2H), 6.00 (d, J¼7.9, 1H), 3.01 (s, 6H), 2.42 (m, 1H), 1.83e1.69 (m, 5H),
1.37e1.13 (m, 5H). 13C: 194.9, 172.1, 150.8, 130.2, 125.6, 125.4, 111.4,
46.6, 40.3, 32.2, 26.6, 26.1. IR: 2926, 2852,1659,1604,1521,1446,1394,
1356,1195,1168,1122,1063. APCI-MS:258.4 (MþH,100%) ESIeHRMS:
calcd for C17H24NO [MþH]þ: 258.1858; found 258.1863.
1.20 mmol), K2CO3 (168 mg, 1.20 mmol), Pd(OAc)2 (1.35 mL of THF
solution containing 1 mg/mL Pd(OAc)2, equivalent to 1.35 mg
Pd(OAc)2), CEPU (2.5 mg), and methyl 2-((tert-butoxycarbonyl)
amino)acrylate (123 mg, 0.60 mmol). Chromatography using 40%
ether in hexanes gave 14b as an orange solid (85 mg, 44%); mp
118e120 ꢀC. 1H: 7.51 (d, J¼8.9, 2H), 7.30 (s, 1H), 6.66 (d, J¼8.9, 2H),
5.99 (br s, 1H), 3.82 (s, 3H), 3.01 (s, 6H), 1.46 (s, 9H). 13C: 166.7, 153.5,
151.0, 133.3, 132.0, 121.5, 120.0, 111.6, 80.4, 52.2, 40.1, 28.2. IR: 3332,
2955, 1695, 1601, 1483, 1437, 1366, 1280,1239, 1155, 1124, 1054,1028.
t
APCI-MS: 321.4 (MþH, 100%), 265.4 (Mꢁ Bu, 60%). ESIeHRMS: calcd
for C17H25N2O4 [MþH]þ 321.1814; found; 321.1815.
4.34. 3-(4-Methoxyphenyl)oct-2-enal (12f)50
4.38. (Z)-Methyl-2-((tert-butoxycarbonyl)amino)-3-(4-((tert-
butoxycarbonyl)amino)phenyl)-acrylate (14c)
Procedure B using 4-iodoanisole (78 mg, 0.33 mmol), K2CO3
(46 mg, 0.33 mmol), Pd(OAc)2 (0.4 mL of THF solution containing
1 mg/mL Pd(OAc)2, equivalent to 0.4 mg Pd(OAc)2), CEPU (0.7 mg),
and oct-2-enal (21 mg, 0.17 mmol). Chromatography using 10%
ether in hexanes gave 12f as a pale yellow oil (12 mg, 30%) as a 1.1:1
(E/Z) mixture. 1H: 10.12 (d, J¼8.1, min.) and 9.48 (d, J¼8.0, maj.; 1H),
7.49 (d, J¼8.7, min.) and 7.22 (d, J¼8.5, maj.; 2H), 6.94 (d, J¼8.6, 2H),
6.29 (d, J¼8.1, min.) and 6.08 (d, J¼8.0, maj.; 1H), 3.86 (s, 6H), 3.00
(t, J¼7.8, min.) and 2.55 (t, J¼7.4, maj.; 2H), 1.44e1.26 (m, 6H),
0.89e0.85 (br t, 3H). 13C: 193.9,191.1,166.4,162.8,161.2,160.3,131.6,
131.3, 130.2, 128.2, 128.0, 126.1, 114.2, 113.8, 55.4, 55.3, 31.6, 31.3,
30.0, 29.7, 29.6, 27.4, 22.4, 13.9. IR: 2927, 2855, 1662, 1603, 1510,
1461, 1394, 1291, 1249, 1179, 1143, 1030. APCI-MS: 233.4 (MþH,
100%).
Procedure B using tert-butyl (4-iodophenyl)carbamate (102 mg,
0.32 mmol), K2CO3 (44 mg, 0.32 mmol), Pd(OAc)2 (0.4 mL of THF
solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.4 mg
Pd(OAc)2), CEPU (0.9 mg), and methyl 2-((tert-butoxycarbonyl)
amino) acrylate (32 mg, 0.16 mmol). Chromatography using 40%
ether in hexanes gave 14c as a pale yellow solid (36 mg, 57%); mp
138e141 ꢀC. 1H: 7.50 (d, J¼8.6, 2H), 7.37 (d, J¼8.6, 2H), 7.24 (s, 1H),
6.63 (br s, 1H), 6.13 (br s, 1H), 3.84 (s, 3H), 1.52 (s, 9H), 1.42 (s, 9H).
13C: 166.2, 152.4, 139.4, 131.0, 130.7, 128.6, 117.9, 80.9, 52.5, 28.3,
28.1. IR: 3295, 2980, 1696, 1592, 1524, 1366, 1322, 1241, 1154, 1051.
APCI-MS: 391.0 (MꢁH, 100%). ESIeHRMS: calcd for C20H28N2O6Na
[MþNa]þ 415.1845; found: 415.1839.
4.39. (Z)-Methyl 2-((tert-butoxycarbonyl)amino)-3-phenyl-
acrylate (14d)52
4.35. 3-(4-(Dimethylamino)phenyl)oct-2-enal (12g)
Procedure
B
using 4-iodo-N,N-dimethylaniline (82 mg,
Procedure B using iodobenzene (36
mL, 0.32 mmol), K2CO3
0.33 mmol), K2CO3 (46 mg, 0.33 mmol), Pd(OAc)2 (0.4 mL of THF
solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.4 mg
Pd(OAc)2), CEPU (0.7 mg), and oct-2-enal (21 mg, 0.17 mmol).
Chromatography using 10% ether in hexanes gave 12g as a yellow
oil (13 mg, 30%) in a 1.35:1 (E/Z) mixture. 1H: 10.1 (d, J¼8.3, maj.)
and 9.53 (d, J¼8.0, min.; 1H), 7.50 (d, J¼8.9, maj.) and 7.20 (d, J¼8.6,
min.; 2H), 6.71 (d, J¼8.7, min.þmaj.; 2H), 6.34 (d, J¼8.3, maj.) and
6.04 (1H, d, J¼8.0, min.; 1H), 3.04 (s, maj.) and 3.02 (s, min.; 6H),
2.57 (t, J¼7.6, 2H), 1.44e1.26 (m, 6H), 0.90e0.86 (m, 3H). 13C: 194.2,
191.0, 167.0, 163.1, 151.7, 151.1, 130.4, 128.7, 128.1, 127.0, 125.6, 123.6,
111.8, 111.4, 40.2, 40.1, 31.8, 31.3, 30.5, 29.7, 29.1, 27.9, 22.41, 22.37,
14.0, 13.9. IR: 2656, 2927, 2860, 1733, 1657, 1597, 1521, 1364, 1196,
1168, 1063. APCI-MS: 246.4 (MþH, 100%) ESIeHRMS: calcd for
(44 mg, 0.32 mmol), Pd(OAc)2 (0.4 mL of THF solution containing
1 mg/mL Pd(OAc)2, equivalent to 0.4 mg Pd(OAc)2), CEPU (0.9 mg),
and methyl 2-((tert-butoxy- carbonyl)amino)acrylate (32 mg,
0.16 mmol). Chromatography using 20% ether in hexanes gave 14d
as a colorless oil (22 mg, 50%). 1H: 7.54 (d, J¼6.8, 2H), 7.39e7.31 (m,
3H), 7.25 (s, 1H), 6.18 (br s, 1H), 3.86 (s, 3H), 1.40 (s, 9H). 13C: 166.1,
159.6, 134.12, 130.0, 129.7, 129.2, 128.5, 124.6, 81.0, 52.6, 28.1. IR:
3323, 2979, 1705, 1644, 1483, 1442, 1363, 1257, 1157, 1048, 1026.
APCI-MS: 276.2 (MꢁH, 100%), 178.4 (MꢁBoc, 60%).
4.40. (Z)-Methyl 2-((tert-butoxycarbonyl)amino)-3-(4-
methoxyphenyl)but-2-enoate (14e)
C
16H24NO [MþH]þ: 246.1858; found 246.1855.
Procedure B using 4-iodoanisole (100 mg, 0.43 mmol), K2CO3
(59 mg, 0.43 mmol), Pd(OAc)2 (0.5 mL of THF solution containing
1 mg/mL Pd(OAc)2, equivalent to 0.5 mg Pd(OAc)2), CEPU (0.9 mg),
methyl 2-((tert-butoxycarbonyl)amino)but-2-enoate (46 mg,
0.63 mmol). Chromatography using 40% ether in hexanes gave 14e as
a yellow oil, which crystallized on standing (15 mg, 22%). 1H: 7.12 (d,
J¼7.7, 2H), 6.85 (d, J¼7.7, 2H), 6.02 (br s, 1H), 3.81 (s, 3H), 3.50 (s, 3H),
2.11 (s, 3H), 1.48 (s, 9H). 13C: 166.3, 159.1, 153.3, 133.3, 131.5, 129.0,
128.5,113.5, 80.8, 55.2, 51.7, 28.2, 21.4. IR: 3335, 2977,1704,1607,1503,
1366,1331,1243,1159,1024.ESI-MS:344.3(MþNa,100%). ESIeHRMS:
calcd for C17H23NO5Na [MþNa]þ 344.1474; found 344.1477.
4.36. (Z)-Methyl 2-((tert-butoxycarbonyl)amino)-3-(4-
methoxy phenyl)acrylate (14a)51
Procedure B using 4-iodoanisole (300 mg, 1.29 mmol), K2CO3
(177 mg, 1.29 mmol), Pd(OAc)2 (1.4 mL of THF solution containing
1 mg/mL Pd(OAc)2, equivalent to 1.4 mg Pd(OAc)2), CEPU (2.6 mg),
and methyl 2-((tert-butoxycarbonyl)amino)acrylate (129 mg,
0.63 mmol). Chromatography using 40% ether in hexanes gave 14a
as a pale yellow oil, which crystallized upon standing (132 mg,
68%). Mp 103e106 ꢀC (lit.51 107e108 ꢀC). 1H (acetone-d6): 7.67 (d,
J¼8.8; 2H), 7.47 (br s, 1H), 7.23 (s, 1H), 6.97 (d, J¼8.8, 2H), 3.83 (s,
3H), 3.76 (s, 3H), 1.42 (s, 9H). 13C (acetone-d6): 166.1, 160.6, 153.7,
131.8, 126.6, 124.1, 113.9, 79.1, 54.8, 51.5, 27.6. IR: 3205, 3098, 2974,
2930, 1698, 1637, 1603, 1514, 1443, 1356, 1255, 1163, 1054, 1029. ESI-
MS: 330.3 (MþNa, 100%).
4.41. (Z)-Methyl 2-((tert-butoxycarbonyl)amino)-3-(4-(dime-
thylamino)phenyl)but-2-enoate (14f)
Procedure
B
using 4-iodo-N,N-dimethylaniline (100 mg,
0.40 mmol), K2CO3 (56 mg, 0.40 mmol), Pd(OAc)2 (0.45 mL of THF

M.R. Smith et al. / Tetrahedron 69 (2013) 10139e10151
10149
solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.45 mg
Pd(OAc)2), CEPU (0.8 mg), and methyl 2-((tert-butoxycarbonyl)
amino)but-2-enoate (43 mg, 0.20 mmol). Chromatography using 40%
ether in hexanes gave 17f as an orange oil (19 mg, 28%). 1H: 7.08 (d,
J¼8.8, 2H), 6.66 (d, J¼8.8, 2H), 5.99 (br s,1H), 3.53 (s, 3H), 2.96 (s, 6H),
2.11 (s, 3H), 1.48 (s, 9H). 13C: 166.8, 153.5, 150.0, 138.7, 131.5, 128.4,
122.6,111.8, 80.6, 51.7, 40.4, 28.2, 21.1. IR: 3322, 2977,1703,1608,1487,
1357, 1330, 1244, 1158, 1046, 1019. APCI-MS: 335.4 (MþH, 100%).
ESIeHRMS: calcd for C18H27N2O4 [MþH]þ 335.1971; found 335.1967.
141.3, 139.2, 133.1, 131.3, 131.1, 129.9,129.6, 129.4, 128.7, 128.6, 128.4,
128.3, 127.4, 126.0, 113.83, 113.79, 55.4, 55.3, 30.29, 30.28. IR: 3065,
3000, 2934, 2838, 1683, 1650, 1601, 1585, 1509, 1461, 1433, 1352,
1292, 1245, 1177, 1028. APCI-MS: 253.2 (MþH, 100%).
4.46. 4-(4-(Dimethylamino)phenyl)-4-phenylbut-3-en-2-one
(15e)
Procedure
B using 4-iodo-N,N-dimethylaniline (106 mg,
0.43 mmol), K2CO3 (59 mg, 0.43 mmol), Pd(OAc)2 (0.5 mL of THF
solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.5 mg
Pd(OAc)2), CEPU (0.9 mg), and benzylideneacetone (31 mg,
0.21 mmol). Chromatography using 10e20% ether in hexanes gave
15e as a yellow crystalline solid (57 mg, 100%) in a 2.5:1 (E/Z)
mixture; mp 100e102 ꢀC. 1H: 7.43e7.19 (m) and 7.09 (d, J¼8.7, min.;
7H), 6.70 (d, J¼8.7, min.) and 6.63 (d, J¼8.9, maj.; 2H), 6.58 (s, maj.)
and 6.39 (s, min.; 1H), 3.03 (s, min.) and 3.00 (s, maj.; 6H), 1.93 (s,
min.) and 1.81 (s, maj.; 3H). 13C: 202.3, 199.9, 155.3, 154.9, 151.3,
151.0, 139.9, 139.7, 131.6, 129.7, 129.6, 129.2, 129.0, 128.4, 128.3,
128.2, 127.7, 126.7, 126.1, 123.7, 111.5, 111.4, 40.2, 40.1, 30.2, 30.0. IR:
2895, 2812, 1675, 1631, 1611, 1573, 1553, 1538, 1442, 1357, 1258,
1201, 1172, 1143, 1070, 1012. APCI-MS 266.4 (MþH, 100%)
ESIeHRMS: calcd for C18H20NO [MþH]þ: 266.1545; found 266.1551.
4.42. 40-Methoxy-5,6-dihydro-[1,10-biphenyl]-3(4H)-one
(15a)53
Procedure B using 4-iodoanisole (100 mg, 0.43 mmol), K2CO3
(59 mg, 0.43 mmol), Pd(OAc)2 (0.5 mL of THF solution containing
1 mg/mL Pd(OAc)2, equivalent to 0.5 mg Pd(OAc)2), CEPU (0.9 mg),
and cyclohexenone (21 mL, 0.21 mmol). Chromatography using 40%
ether in hexanes gave 15a as a pale yellow oil (22 mg, 52%). 1H: 7.53
(d, J¼8.9, 2H), 6.93 (d, J¼8.9, 2H), 6.40 (s, 1H), 3.85 (s, 3H), 2.76 (app
t, J¼5.7, 2H), 2.47 (app t, J¼7.0, 2H), 2.19e2.10 (m, 2H). 13C: 199.9,
161.2, 159.1, 130.8, 127.6, 123.7, 114.1, 55.4, 37.2, 27.9, 22.8. IR: 2939,
1645, 1594, 1570, 1511, 1424, 1354, 1329, 1284, 1255, 1231, 1184,
1033. APCI-MS: 203.3 (MþH, 100%).
4.43. 40-(Dimethylamino)-5,6-dihydro-[1,10-biphenyl]-3(4H)-
4.47. tert-Butyl (4-(3-oxo-1-phenylbut-1-en-1-yl)phenyl)car-
bamate (15f)
one (15b)54
Procedure
B
using 4-iodo-N,N-dimethylaniline (106 mg,
Procedure B using tert-butyl (4-iodophenyl)carbamate (137 mg,
0.43 mmol), K2CO3 (59 mg, 0.43 mmol), Pd(OAc)2 (0.5 mL of THF
solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.5 mg
Pd(OAc)2), CEPU (0.9 mg), and benzylideneacetone (31 mg,
0.21 mmol). Chromatography using 20% ether in hexanes gave 15f
as a yellow oil (53 mg, 75%) in a 2.7:1 (E/Z) mixture. 1H: 7.44e7.13
(9H, m), 6.70 (1H, br s), 6.56. (s, maj.) and 6.52 (s, min.; 1H), 1.92 (s,
min.) and 1.85 (s, maj.; 3H), 1.53 (s, min.) and 1.51 (s, maj.; 9H). 13C:
200.5, 200.1, 153.8, 153.7, 152.6, 152.5, 141.0, 139.8, 139.3, 139.0,
135.1, 133.2, 130.7, 129.6, 129.5, 129.3, 128.8, 128.6, 128.4, 127.6,
126.3, 118.0, 80.9, 80.8, 30.3, 30.3, 28.3, 28.3. IR: 3329, 2978, 2896,
2813, 1726, 1675, 1632, 1610, 1573, 1554, 1522, 1492, 1442, 1356,
1318,1257,1167,1144,1070,1053,1013. APCI-MS: 336.1 (MꢁH, 60%),
0.43 mmol), K2CO3 (59 mg, 0.43 mmol), Pd(OAc)2 (0.5 mL of THF
solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.5 mg
Pd(OAc)2), CEPU (0.9 mg), and cyclohexenone (21 mL, 0.21 mmol).
Chromatography using 40% ether in hexanes gave 15b as a yellow
solid (34 mg, 76%); mp 133e135 ꢀC (lit.54 136e137 ꢀC). 1H: 7.51 (d,
J¼8.7; 2H), 6.69 (d, J¼8.7; 2H), 6.42 (s, 1H), 3.02 (s, 6H), 2.75 (app t,
J¼5.6, 2H), 2.45 (app t, J¼6.6, 2H), 2.14e2.10 (m, 2H). 13C: 200.0,
159.5, 151.7, 127.5, 125.1, 121.3, 111.7, 40.1, 37.2, 27.4, 22.9. IR: 2890,
2818,1647,1606,1577,1523,1428,1411,1369,1346,1323,1232,1170,
1064. APCI-MS 216.4 (MþH, 100%).
4.44. tert-Butyl (50-oxo-20,30,40,50-tetrahydro-[1,10-biphenyl]-
4-yl)carbamate (15c)
t
282.4 (Mꢁ Bu, 100%). ESIeHRMS: calcd for C21H24NO3 [MþH]þ:
338.1756; found 338.1759.
Procedure B using tert-butyl (4-iodophenyl)carbamate (137 mg,
0.43 mmol), K2CO3 (59 mg, 0.43 mmol), Pd(OAc)2 (0.5 mL of THF
solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.5 mg
4.48. 1-(4-Methoxyphenyl)-1,5-diphenylpenta-1,4-dien-3-one
(15g)
Pd(OAc)2), CEPU (0.9 mg), and cyclohexeneone (21 mL, 0.21 mmol).
Chromatography using 40% ether in hexanes gave 15c as a pale
yellow solid (36 mg, 62%); mp 147e149 ꢀC. 1H: 7.51e7.41 (4H, m),
6.83 (1H, br s), 6.40 (1H, s), 2.74 (app t, J¼5.5, 2H), 2.47 (app t, J¼6.4,
2H), 2.15e2.09 (m, 2H), 1.52 (s, 9H). 13C: 200.0, 159.1, 152.5, 140.3,
132.7, 127.0, 124.0, 118.2, 80.1, 37.2, 28.3, 27.8, 22.7. IR: 3292, 2949,
1727, 1650, 1580, 1530, 1412, 1351, 1322, 1228, 1158, 1050. APCI-MS:
Procedure B using 4-iodoanisole (100 mg, 0.43 mmol), K2CO3
(59 mg, 0.43 mmol), Pd(OAc)2 (0.5 mL of THF solution containing
1 mg/mL Pd(OAc)2, equivalent to 0.5 mg Pd(OAc)2), CEPU (0.9 mg),
and dibenzylideneacetone (49 mg, 0.21 mmol). Chromatography
using 10% ether in hexanes gave 15g as a yellow oil (29 mg, 41%) in
a 2.3:1 (E/Z) mixture. 1H: 7.54e7.21 (m, 13H), 6.93e6.88 (m, 2H),
6.75 (s, maj.) and 6.69 (s, min.; 1H), 6.44 (d, J¼15.8, min.) and 6.40
(d, J¼15.8, maj.; 1H), 3.85 (s maj.) and 3.81 (s, min.; 3H). 13C: 191.6,
191.2, 160.9, 160.5, 154.4, 154.3, 141.5, 141.34, 141.31, 139.4, 135.1,
135.0, 133.4, 132.0, 131.3, 130.18, 130.15, 130.0, 129.9, 129.5, 128.89,
128.88, 128.70, 128.68, 128.4, 128.1, 127.2, 126.7, 126.6, 125.9, 113.9,
113.8, 55.4, 55.3. IR: 3026, 2933, 2837, 1645, 1588, 1509, 1445, 1330,
1294, 1245, 1179, 1142, 1088, 1030. APCI-MS 341.3 (MþH, 100%); and
also symmetrical bis-arylated product as a yellow oil (19 mg, 21%).
t
288.4 (MþH, 60%), 232.4 (Mꢁ Bu, 100%), 188.4 (MꢁBoc, 100%).
ESIeHRMS: calcd for C17H22NO3 [MþH]þ: 288.1600; found 288.1601.
4.45. 4-(4-Methoxyphenyl)-4-phenylbut-3-en-2-one (15d)55
Procedure B using 4-iodoanisole (100 mg, 0.43 mmol), K2CO3
(59 mg, 0.43 mmol), Pd(OAc)2 (0.5 mL of THF solution containing
1 mg/mL Pd(OAc)2, equivalent to 0.5 mg Pd(OAc)2), CEPU (0.9 mg),
and benzylideneacetone (31 mg, 0.21 mmol). Chromatography
using 10% ether in hexanes gave 15d as a yellow oil (44 mg, 83%) as
a 3:1 (E/Z) mixture. 1H: 7.43e7.20 (m) and 7.16 (d, J¼8.7, min.; 7H),
6.94 (d, J¼8.7, min.) and 6.86 (d, J¼8.9, maj.; 2H), 6.56 (s, maj.) and
6.51 (s, min.; 1H), 3.86 (s, min.) and 3.82 (s, maj.; 3H), 1.92 (s, min.)
and 1.85 (s, maj.; 3H). 13C: 200.5, 200.0, 160.9, 160.3, 154.0, 153.9,
4.49. 1-(4-(Dimethylamino)phenyl)-1,5-diphenylpenta-1,4-
dien-3-one (15h)
Procedure
B using 4-iodo-N,N-dimethylaniline (106 mg,
0.43 mmol), K2CO3 (59 mg, 0.43 mmol), Pd(OAc)2 (0.5 mL of THF

10150
M.R. Smith et al. / Tetrahedron 69 (2013) 10139e10151
7. (a) Colacino, E.; Martinez, J.; Lamaty, F. In Modern Tools for the Synthesis of
Complex Bioactive Molecules; Cossy, J., Arseniyadis, S., Eds.; John Wiley & Sons:
Hoboken, NJ, 2012; p 33; (b) de Vries, J. G. Top. Organomet. Chem. 2012, 42,
1e34.
solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.5 mg
Pd(OAc)2), CEPU (0.9 mg), and dibenzylideneacetone (49 mg,
0.21 mmol). Chromatography using 20% ether in hexanes gave 15h
as a yellow solid (37 mg, 50%) in a 2:1 (E/Z) mixture; mp
125e127 ꢀC.56 1H: 7.50 (d, J¼15.8, min.) and 7.46 (d, J¼15.8, maj.;
1H), 7.44e7.39 (m, 4H) 7.32e7.15 (m, 8H), 6.77 (s, maj.) and 6.58 (s,
min.; 1H), 6.68 (d, J¼8.7, min.) and 6.66 (d, J¼8.9, maj.; 2H), 6.42 (d,
J¼15.8, min.) and 6.39 (d, J¼15.8, maj.; 1H), 3.02 (s, maj.) and 2.98
(s, min.; 6H). 13C: 191.8, 190.8, 155.8, 155.4, 151.4, 151.3, 142.0, 140.5,
140.1, 139.9, 135.5, 135.3, 132.3, 130.2, 130.0, 129.7, 129.6, 129.3,
129.2, 128.6, 128.5, 128.3, 128.0, 127.9, 127.0, 126.9, 126.6, 126.4,
123.7, 111.5, 40.3, 40.2. IR: 2913, 1638, 1610, 1567, 1524, 1445, 1369,
1333, 1286, 1230, 1140, 1061, APCI-MS: 376.3 (MþNa, 100%), 354.3
(MþH, 40%). ESIeHRMS: calcd for C25H24NO [MþH]þ: 354.1858;
found 354.1860.
8. Interest of 3,3-diarylalanines in peptide research and medicinal chemistry: (a)
Gomez-Catalan, J.; Perez, J. J.; Jimenez, A. I.; Cativiela, C. J. Pept. Sci. 1999, 5,
251e262; (b) Haug, B. E.; Skar, M. L.; Svendsen, J. S. J. Pept. Sci. 2001, 7,
425e432; (c) Cho, B.-K.; Seo, J.-H.; Kang, T.-J.; Kim, J.; Park, H.-Y.; Lee, B.-S.;
Kim, B.-G. Biotechnol. Bioeng. 2006, 94, 842e850; (d) Josien, H.; Lavielle, S.;
Brunissen, A.; Saffroy, M.; Torrens, Y.; Beaujouan, J.-C.; Glowinski, J.; Chassaing,
G. J. Med. Chem. 1994, 37, 1586e1601; (e) Augelli-Szafran, C. E.; Roth, B. D.;
Essenburg, A.; Hamelehle, K. L.; Krause, B. R.; Stanfield, R. L. Bioorg. Med. Chem.
Lett. 1994, 4, 1095e1100; (f) Williams, B. J.; Teall, M.; Kenna, J.; Harrison, T.;
Swain, C. J.; Cascieri, M. A.; Sadowski, S.; Strader, C.; Baker, R. Bioorg. Med.
Chem. Lett. 1994, 16, 1903e1908; (g) Pavar, M. C.; Hanif, K.; Azam, A.; Lata, S.;
Qadar Pasha, M. A.; Pasha, S. Bioorg. Med. Chem. Lett. 2006, 16, 2117e2121; (h)
Stranix, B. R.; Lavallee, J.-F.; Sevigny, G.; Yelle, J.; Perron, V.; LeBerre, N.; Her-
bart, D.; Wu, J. J. Bioorg. Med. Chem. Lett. 2006, 16, 3459e3562; (i) Pippel, M.;
Allison, B. D.; Phuong, V. K.; Li, L.; Morton, M. F.; Prendergast, C.; Wu, X.;
Shankley, N. P.; Rabinowitz, M. H. Bioorg. Med. Chem. Lett. 2009, 19, 6373e6375;
(j) Murza, A.; Parent, A.; Besserer-Offroy, E.; Tremblay, H.; Karadereye, F.;
Beaudet, N.; Leduc, R.; Sarret, P.; Marsault, E. Chem. Med. Chem. 2012, 7,
318e325.
9. Preparation of 3,3-diarylalanines: (a) Patterson, D. E.; Xie, S.; Jones, L. A.; Os-
terhout, M. H.; Henry, C. G.; Roper, T. D. Org. Process Res. Dev. 2007, 11, 624e627;
(b) Patterson, D. E.; Powers, J. D.; LeBlanc, M.; Sharkey, T.; Boehler, E.; Irdam, E.;
Osterhout, M. H. Org. Process Res. Dev. 2009, 13, 900e906; (c) Patterson, D. E.;
Xie, S.; Jones, L. A.; Osterhout, M. H.; Henry, C. G.; Roper, T. D. In Asymmetric
Catalysis on Industrial Scale, 2nd ed.; Blaser, H. U., Federsel, H. J., Eds.; Wiley-
VCH: Weinheim, Germany, 2010; pp 473e484; (d) Deng, G.; Ye, D.; Li, Y.; He, L.;
Zhou, Y.; Wang, J.; Li, J.; Jiang, H.; Liu, H. Tetrahedron 2008, 64, 10512e10516; (e)
Soloshonok, V. A.; Ono, T. J. Fluorine Chem. 2009, 130, 547e549.
4.50. tert-Butyl (4-(-3-oxo-1,5-diphenylpenta-1,4-dien-1-yl)
phenyl)carbamate (15i)
Procedure B using tert-butyl (4-iodophenyl)carbamate (137 mg,
0.43 mmol), K2CO3 (59 mg, 0.43 mmol), Pd(OAc)2 (0.5 mL of THF
solution containing 1 mg/mL Pd(OAc)2, equivalent to 0.5 mg
Pd(OAc)2), CEPU (0.9 mg), and dibenzylideneacetone (49 mg,
0.21 mmol). Chromatography using 20% ether in hexanes gave 15i
as a yellow oil (54 mg, 61%) in a 2:1 (E/Z) mixture. 1H: 7.51 (d,
J¼15.9, min.) and 7.48 (d, J¼15.9, maj.; 1H), 7.41e7.20 (14H, m), 6.74
(s, maj.) and 6.70 (s, min.; 1H), 6.66 (br s) and 6.60 (bs; 1H), 6.46 (d,
J¼15.9, min.) and 6.40 (d, J¼15.9, maj.; 1H), 1.53 (s, maj.) and 1.52 (s,
min.; 9H). 13C: 191.6, 191.3, 154.1, 154.0, 152.5, 152.4, 141.6, 141.5,
141.2, 139.8, 139.3, 139.2, 135.4, 135.0, 133.5, 131.3, 130.2, 130.0,
129.9, 129.6, 129.5, 129.0, 128.9, 128.8, 128.7, 128.6, 128.4, 128.3,
128.2, 128.1, 127.2, 126.6, 126.5, 126.3, 118.0, 81.0, 80.8, 28.3. IR:
3309, 2978, 1705, 1642, 1572, 1519, 1447, 1408, 1316, 1232, 1152,
1090, 1052. APCI-MS: 448.3 (MþNa, 40%), 426.3 (MþH, 80%), 370.3
10. (a) Evans, D. A.; Britton, T. C.; Dorow, R. L.; Dellaria, J. F., Jr. Tetrahedron 1988, 44,
5525e5540; (b) Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. J. Am. Chem.
Soc. 1990, 112, 4011e4030.
11. (a) Lin, J.; Liao, S.; Hruby, V. J. Tetrahedron Lett. 1998, 39, 3117e3120; (b) Lin, J.;
Liao, S.; Hruby, V. J. J. Peptide Res. 2005, 65, 105e112.
12. E.g.: Moreno-Manas, M.; Perez, M.; Pleixat, R. Tetrahedron Lett. 1996, 37,
7449e7452; (b) Ikemoto, T.; Nagata, T.; Yamano, M.; Ito, T.; Mizuno, Y.; Tomi-
matsu, K. Tetrahedron Lett. 2004, 45, 7757e7760.
13. Botella, L.; Najera, C. J. Org. Chem. 2005, 70, 4360e4369.
14. Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989e7000.
15. Kondolff, I.; Doucet, H.; Santelli, M. Tetrahedron Lett. 2003, 44, 8487e8491.
16. Allam, B. H.; Singh, K. N. Synthesis 2011, 1125e1131.
17. Mieczynska, E.; Gniewek, A.; Pryjomska-Ray, I.; Trzeciak, A. M.; Grabowska, H.;
Zawadski, M. Appl. Cat. A: Gen. 2011, 393, 195e205.
t
(Mꢁ Bu, 100%). ESIeHRMS: calcd for C28H28NO3 [MþH]þ:
18. Guertler, C.; Buchwald, S. L. Chem.dEur. J. 1999, 5, 3107e3112.
19. As detailed in Ref. 1, an electron-rich iodide that behaved poorly was
4-iodophenol, which afforded none of the expected products, even though it
was largely consumed in the course of the reaction. Protection of the OH group
as an ester or a carbonate resulted in mediocre yields of Heck products, which
moreover were retrieved as the free phenols, due to loss of the O-blocking
group. The poor efficiency of these reactions is thus attributable to premature
release of the phenolic protection in the starting halide and consumption of
now free 4-iodophenol through a variety of side processes. Marginally satis-
factory results were obtained with the sturdier 4-iodophenyl pivalate. In this
case as well, the products emerged as free phenols, purification of which was
problematic. The crude phenols were thus re-pivaloylated prior to flash
chromatography.
20. (a) Cacchi, S.; Gasparrini, F.; Pace, P.; Villani, C. Synlett 2000, 650e652; (b)
Naito, H.; Ohsuki, S.; Sugimori, M.; Atsumi, R.; Minami, M.; Nakamura, Y.; Ishii,
M.; Hirotani, K.; Kumazawa, E.; Ejima, A. Chem. Pharm. Bull. 2002, 50, 453e462;
(c) Sorensen, U. S.; Bleisch, T. J.; Kingston, A. E.; Wright, R. A.; Johnson, B. G.;
Schoepp, D. D.; Ornstein, P. L. Bioorg. Med. Chem. 2003,11,197e205; (d) Minatti, A.;
Zheng, X.; Buchwald, S. L. J. Org. Chem. 2007, 72, 9253e9258; (e) Fall, Y.; Doucet, H.;
Santelli, M. Tetrahedron 2009, 65, 489e495 and literature cited therein.
21. The inertness of aryl chlorides was not unexpected, since it is documented that
bulky electron-rich ligands are necessary for efficient oxidative addition of
Pd(0) to the stronger CeCl bonds (Ref. 13).
426.2069; found 426.2075; and symmetrical bis-arylated product
as a yellow oil (21 mg, 13%).
Acknowledgements
We thank the University of British Columbia, the Canada Re-
search Chair Program, NSERC, CIHR, CFI, and BCKDF for financial
support.
Supplementary data
Proton and 13C NMR spectra of compounds 7, 8, 10, 12, 14, and 15
(99 pages) and three TEM images (3 pages) of Pd nanoparticles
detected in reaction mixtures containing Pd(OAc)2eCEPU catalyst
(102 pages total). Supplementary data related to this article can be
found at http://dx.doi.org/10.1016/j.tet.2013.09.019.
22. Cf. (a) Nejjar, A.; Pinel, C.; Djakovitch, L. Adv. Synth. Catal. 2003, 345, 612e619;
(b) Aggarwal, V. K.; Staubitz, A. C.; Owen, M. Org. Process Res. Dev. 2006, 10,
64e69.
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56. Some symmetrical bis-arylated product (yellow oil, 12 mg, 12%) was also
obtained. However, this material was not fully characterized.