The Heck reaction of polymer-supported allylamine with aryl iodides

Article abstract of DOI:10.1016/j.tet.2012.10.092

The Heck reaction of Wang resin-bound allylamine with aryl iodides produces various, substituted cinnamylamines. The catalyst and additive system consisting of palladium(II) acetate, n-Bu₄NOAc and potassium chloride, in addition to potassium carbonate in N,N-dimethylformamide, accomplishes a regioselective γ-arylation. By utilising the easily formed and stable carbamate linker on Wang resin, the incompatibility of free amines with the palladium catalyst is avoided. The cinnamylamine products are cleaved from the resin with trifluoroacetic acid under mild conditions and are converted into chromatographically separable acetamides. Our solid-phase method offers a new alternative for the synthesis of cinnamylamine derivatives, as biologically interesting compounds and useful synthetic intermediates.

Full text of DOI:10.1016/j.tet.2012.10.092

Tetrahedron 69 (2013) 839e843
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The Heck reaction of polymer-supported allylamine with aryl iodides
,
a
a
a
a
Tuomo Leikoski a , Pauli Wrigstedt , Jussi Helminen , Jorma Matikainen , Jussi Sipila ,
*
€
Jari Yli-Kauhaluoma b
a Department of Chemistry, Laboratory of Organic Chemistry, PO Box 55 (A. I. Virtasen aukio 1), University of Helsinki, FI-00014 Helsinki, Finland
b Faculty of Pharmacy, Division of Pharmaceutical Chemistry, PO Box 56 (Viikinkaari 5 E), University of Helsinki, FI-00014 Helsinki, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
The Heck reaction of Wang resin-bound allylamine with aryl iodides produces various, substituted
cinnamylamines. The catalyst and additive system consisting of palladium(II) acetate, n-Bu4NOAc and
potassium chloride, in addition to potassium carbonate in N,N-dimethylformamide, accomplishes a re-
Received 22 June 2012
Received in revised form 23 September
2012
Accepted 15 October 2012
Available online 8 November 2012
gioselective g-arylation. By utilising the easily formed and stable carbamate linker on Wang resin, the
incompatibility of free amines with the palladium catalyst is avoided. The cinnamylamine products are
cleaved from the resin with trifluoroacetic acid under mild conditions and are converted into chro-
matographically separable acetamides. Our solid-phase method offers a new alternative for the synthesis
of cinnamylamine derivatives, as biologically interesting compounds and useful synthetic intermediates.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Heck
Solid-phase
Polymer
Palladium
Allylamine
Cinnamylamine
1. Introduction
alkenes as substrates has been shown to be particularly challenging
and allylamine derivatives are representative examples of such
Arylated allylamines, such as cinnamylamines, are important
synthetic intermediates and key structural units in many bi-
ologically active compounds. Conn and co-workers discovered
a modified cinnamylamine that acts as an inhibitor of bovine
plasma semicarbazide-sensitive amine oxidase.1 Lermer and co-
workers studied the use of synthetic oligonucleotides in the cata-
lytic cleavage of RNA, where uracil was substituted in its 5-position,
compounds.10e22 In addition, an extra concern in the preparation of
such compounds, by Heck coupling, is caused by the strong in-
teraction between amine nitrogens and palladium atoms.10,11,18,23,24
As such, in most trials amines have to be protected as less co-
ordinating derivatives.
Compared to the vast amount of research conducted on the Heck
reaction, the number of publications about its solid-phase version are
relatively limited. There are however examples where either the
olefin or the halide component has been attached to a polymeric
support.25e35 In addition, solid-phase methods have been utilised in
intramolecular Heck reactions.36e42 Even the palladium catalyst
complexes have been bound covalently to polystyrene, while keeping
all the other reactants in solution.43,44 Frei and Blackwell attached the
olefinic component covalently to cellulose, with the help of a Rink-
amide linker, to produce stilbenes, which were cleaved from cellu-
lose with trifluoroacetic acid (TFA) vapour.45 Kopylovich and co-
workers absorbed reaction mixtures onto silica gel and performed
microwave-assisted Heck reactions in the absence of solvent.46
The incompatibility of free amines with palladium catalysis was
established in the early years of the Heck reaction. As an example,
the unsubstituted allylamine yielded only mixtures of unidentified
products, instead of the desired aryl amine.13,18,21,22 However, some
exceptions exist. A very typical example is the intramolecular Heck
reaction of N-allyl-o-haloaniline derivatives, which has been utilised
with the
g
carbon atom of allylamine.2 Robin and Rousseau used
arylated allylamines as precursors in 4-endo trig cyclisations to
form azetidines.3
The Heck reaction is a powerful and modern palladium-
catalysed method for generation of carbonecarbon bonds be-
tween unsaturated entities, and it has been extensively utilised in
arylation and vinylation of olefins.4e7 Though widely studied since
its independent introduction by Heck and Mizoroki, in the early
70’s,8,9 there are no straightforward rules to assess reaction con-
ditions for a particular type of coupling reaction. As a result, finding
satisfactory conditions for an individual reaction typically requires
thorough screening and optimisation. For example, in terms of
general reactivity and regioselectivity, the use of electron-rich
* Corresponding author. Tel.: þ358 50 554 3682; fax: þ358 9 191 50366; e-mail
address: tuomo.leikoski@helsinki.fi (T. Leikoski).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.092

840
T. Leikoski et al. / Tetrahedron 69 (2013) 839e843
in syntheses of indoles.24,47 The suitability of anilines, as reactants, is
obviously associated with conjugation of the lone pair on the ni-
trogen with the aromatic p-electron system, whereas the effective
compounds, we also wanted to synthesise intermediates that could
be hydrogenated to the corresponding 1,3-arylaminopropanes.
We attached allylamine, like propargylamine in our Sonogashira
studies,49 through a carbamate linker onto the polymeric support.
This polymer-supported amine is easily prepared by a two-step
procedure, starting from the commercially available Wang resin
via the 4-nitrophenyl carbonate resin intermediate (Scheme 2).
Previously, the carbamate method has been used successfully in the
syntheses of low molecular-mass compounds, such as 1,2,3-
triazoles,50 and in the solid-phase synthesis of oligomeric pep-
tides.51 In addition to the easy attachment, with the simultaneous
protection of amines and to the stability of the linker in neutral and
basic conditions, this method enables fast and quantitative cleavage
of the amine product, with 50% trifluoroacetic acid in dichloro-
methane. Herein, we report our results on the Heck reaction of
Wang resin-bound allylamine with aryl iodides, the cleavage and
isolation of the cinnamylamine products, and their purification as
chromatographically separable acetamides.
reactions observed with some tertiary allylamines15,17,19 might be
explained by steric hindrance on the nitrogen atom. A general
strategy in the Heck reactions of allylamine derivatives is protection
of the amino group, for example, as phthalimides,11,18,21,22 tri-
fluoroacetamides11,13,14 or carbamates,10e13,16,18,20,21 which simul-
taneously renders the olefin less electron-rich and therefore more
reactive. Noteworthysuccessful reactions havebeenperformed with
N,N-diprotected
allylamines
containing
a
carbamate
moiety.10e13,16,20,21 Very recently Jiang and co-workers utilised N,N-
(t-BOC)2-allylamine, as an efficient substrate in a regioselective and
stereoselective reaction with various aryl bromides.10
An additional challenge with the Heck reaction of allylamine
derivatives is regioselectivity. It is possible to obtain
b as well as g
arylated allylamines, depending on the direction of migratory in-
sertion, of the arylpalladium halide, into the C]C bond. There are
examples in the literature where the Heck reaction of allylamine
derivatives has been performed with excellent regioselectivity, in
respect to either b17e19 or g10e13 arylation. In the Heck reaction of
three-carbon units in general, rearrangement of the double bond is
possible as well, as there are hydrogen atoms in two distinct po-
sitions available in the organopalladium intermediate, during the
2. Results and discussion
Finding satisfactory Heck conditions, for our test reaction sys-
tem with Wang resin-bound allylamine and iodobenzene, was
much more difficult than originally anticipated. We tested palla-
dium acetate, Pd2(dba)3 and Herrmann’s palladacycle,52e54 as
catalysts and triethylamine, sodium acetate, caesium acetate, po-
tassium carbonate, sodium hydrogen carbonate, caesium carbon-
ate, pyrrolidine and 1,1,3,3-tetramethylguanidine, as bases. We
performed experiments with or without tri-o-tolylphosphine, ad-
ditives, e.g., potassium chloride and caesium chloride,55 and ionic
mediators, such as n-Bu4NCl, n-Bu4NBr and n-Bu4NOAc. For sol-
vents we tested N,N-dimethylformamide (DMF), N,N-dimethyla-
cetamide, N-methylpyrrolidone and even oxygen-free water, as co-
solvent. The temperature range of our reactions was 50e130 ꢀC.
In most of our experiments the yields were very low, or the
cinnamylamine product was not formed at all. However, we applied
successfully the solution phase method of Battistuzzi and co-
workers, with palladium(II) acetate (5 mol %), potassium carbon-
ate, n-Bu4NOAc and potassium chloride in DMF.48 The reaction of
Wang resin-bound allylamine, with iodobenzene at 85 ꢀC for 22 h,
gave a 44% yield of N-cinnamylacetamide, after cleavage with 50%
TFA in dichloromethane, liberation of the amine product from its
TFA salt with triethylamine, acetylation with acetic anhydride,
triethylamine and N,N-dimethylaminopyridine (DMAP) (Scheme 2)
and purification by flash chromatography. This Heck procedure was
b
hydride elimination step.12,48 Formation of regioisomers is shown
as a simplified cascade of reactions, in Scheme 1.
Scheme 1. Regiochemistry in the Heck reaction of three-carbon units.
originally developed to control the
b hydride elimination of the
organopalladium intermediate (see Scheme 1), in the synthesis of
cinnamaldehydes from acrolein diethyl acetal and aryl halides.48
Because allylamine is similarly a relatively electron-rich olefin,
Based on our previous results on the Sonogashira coupling of
polymer-bound propargylamine, with aryl iodides,49 we decided to
study whether cinnamylamines could similarly be synthesised, by
the Heck reaction of polymer-bound allylamine. In addition to de-
veloping new methods for the synthesis of this interesting group of
having two
hydride elimination for its part might well be responsible for the
success of our reaction.
b hydrogens prone to elimination, the selectivity of the
b
Scheme 2. Loading of allylamine to Wang resin, the Heck reaction, cleavage and acetylation.

T. Leikoski et al. / Tetrahedron 69 (2013) 839e843
841
We achieved almost as good a result when we replaced palla-
3. Conclusion
dium(II) acetate with Herrmann’s palladacycle catalyst, using the
above-mentioned method. After the test reaction of iodobenzene
with 1 mol % of the catalyst, a 40% yield of the product was ob-
tained. Keeping in mind the high performance of this catalyst, even
at ppm levels, its use in solid-phase Heck reactions might be worth
more detailed studies. On the other hand, replacement of potas-
sium carbonate or potassium chloride, with caesium carbonate or
caesium chloride, respectively, decreased the yield significantly.
We noticed that the time and temperature window of our Heck
procedure is relatively narrow. When the duration of the reaction at
85 ꢀC was increased from 22 to 74 h, the yield decreased from 44 to
29%. The yield dropped below 5% when the three-day reaction was
performed at 100 ꢀC. The stoichiometryof the substrates is essential. A
mixture ofdiarylated isomers dominated, besides thedesired product,
if iodobenzene was applied in excess into the reaction mixture.
Therefore, we introduced only 1 M equivalent of the aryl iodide, with
respect to polymer-bound allylamine, throughout the whole series of
reactions.
Though there is some deviation in the yields of N-cinnamylace-
tamides (Table 1), no clear relationship between the structures of the
aryl iodides and the yields can be stated. For example, all the three
isomers of chloroiodobenzene gave reasonable yields but with 40-
iodoacetophenone and 4-iodobenzonitrile, significantly higher yields
would have been expected. Interestingly, 2-iodothiophene and 4-
iodonitrobenzene did not give even a trace of the coupling prod-
ucts, although the former has been used successfully in the Heck re-
action,56 and the latter was used in Battistuzzi’s original procedure.48
These unexpected features may be due to slow reaction rates of the
polymer-supported allylamine. The arylpalladium iodide species is
undoubtedly formed efficiently from each of these substrates, by
oxidative addition of zero-valent palladium. However, these highly
reactive intermediates can be consumed by fast, unwanted side re-
actions in solution, without reaching the polymer-bound allylamine.
We have developed a new solid-phase synthesis method where
the applicability of the Heck reaction, with its high performance
and wide functional group tolerance, is combined with the benefits
of solid-phase synthesis. The Heck reaction of allylamine, 30 ꢀC
above its boiling point, with aryl iodides is enabled, without the
inhibiting effect of palladium-nitrogen coordination. The carba-
mate linker, conveniently formed on Wang resin, which is stable
under the reaction conditions and rapidly cleaved, serves as a pro-
tective group for the amino functionality and renders the carbon-
ecarbon double bond less electron-rich, and more reactive towards
palladium coupling. Due to relatively few alternatives available for
g-arylation of allylamine, our solid-phase method offers new pos-
sibilities for the synthesis of biologically interesting cinnamylamine
derivatives with diverse aryl substitution.
4. Experimental
4.1. General
Reagents were obtained from Aldrich, Fluka, Acros and Merck.
Wang resin (polymer-bound 4-(benzyloxy)benzyl alcohol, loading
1.1 mmol/g; 100e200 mesh; cross-linked with 1% divinylbenzene)
was commerciallyavailable from NovaBiochem. Theyields are based
on the actual loading of the commercial resin. DMF was dried by
distillation from anhydrous CaSO4 under reduced pressure. Trie-
thylamine was dried by distillation from P2O5. Unless otherwise
stated, commercial-grade reagents and solvents were used without
further purification or drying. Merck aluminium sheets coated with
silica gel 60 F254 were used for thin layer chromatography and they
were visualised by UV light at 254 nm. Column chromatography was
performed with Fluka silica gel 60; 230e400 mesh. 1H and 13C NMR
spectra were recorded at 300 and 75 MHz, respectively, on a Varian
Mercury 300 Plus spectrometer. Chemical shifts are relative to the
residual solvent resonance of 7.26 ppm for CDCl3, in the proton
spectra, and to the resonance of 77.2 ppm for CDCl3 or 29.8 ppm for
acetone-d6, in the carbon spectra. FT-IR spectra were recorded on
a Perkin Elmer Spectrum One FT-IR Spectrometer, equipped with
a one reflection ATR unit. Melting points were obtained using an
Electrothermal Melting Point Apparatus Cat. No. IA6301 and theyare
uncorrected. Normal and high resolution EI-MS analyses were per-
formed with a Jeol JMS-700 mass spectrometer at 700 eV.
Table 1
Yields of N-cinnamylacetamides obtained from various aryl iodides
Entry
Aryl group
Yield (%)a
1
2
3
4
5
6
7
8
9
10
Ph
44
54
4-CleC6H4
3-CleC6H4
2-CleC6H4
4-CH3COeC6H4
Naphthalen-1-yl
4-CNeC6H4
3-MeOeC6H4
4-NO2eC6H4
Thiophen-2-yl
49
61b
35
39b
25
23b
n.r.
n.r.
4.2. Loading of allylamine to Wang resin through a carba-
mate linker
a
Based on an actual loading of 1.1 mmol/g of the commercial Wang resin.
As an inseparable mixture of E and Z isomers with an approximate ratio of 4:1 as
Allylamine was attached to Wang resin according to the re-
ported procedure,50 suitable for primary and secondary amines
with slight modifications. Wang resin, polymer-bound 4-
benzyloxybenzyl alcohol, (loading 1.1 mmol/g) was swollen in
CH2Cl2 (10 mL/g resin). Pyridine (1.8 mL/g resin) was added fol-
lowed by 4-nitrophenyl chloroformate (5.1 equiv) in CH2Cl2
(10.7 mL/g). The mixture was stirred at room temperature for 25 h,
filtered and washed with CH2Cl2 (5ꢁ6 mL/g resin). The resulting
carbonate resin was swollen immediately with DMF (10 mL/g
resin), and allylamine (10 equiv) was added at 0 ꢀC. The mixture
was stirred at room temperature for 21 h. After filtering, the resin
was washed (2ꢁ6 mL/g resin) with each of DMF, MeOH, THF,
diethyl ether and CH2Cl2, and dried in vacuo. IR (C]O, cmꢂ1): 1722.
b
determined by 1H NMR spectroscopy.
In the reactions with 2-chloroiodobenzene, 1-iodonaphthalene
and 3-iodoanisole, an inseparable mixture of E and Z isomers, with
an approximate ratio of 4:1 according to 1H NMR spectroscopy, was
obtained (See Experimental). The unusually high yield of the Z iso-
mer, with respect to the E isomer, commonly obtained in the Heck
reaction has been associated with additional steric hindrance.56
The reaction conditions we applied possess characteristics,
which enhance their usability in solid-phase synthesis. DMF, as
a polar aprotic solvent, swells the resin very effectively and si-
multaneously assists in the separation of various ionic species, thus
increasing their solubilities. Suitable concentrations of halide (KCl)
and acetate (n-Bu4NOAc) ligands in the reaction medium are likely
to increase the stability, reactivity and selectivity of the cata-
lyst.57e59 The stabilisation effect is very evident, as black metallic
palladium precipitates, typical for Heck reactions with palladiu-
m(II) acetate, were not observed at all in most of our trials.
4.3. General procedure for the Heck reaction of polymer-
bound allylamine with aryl iodides in solution
Polymer-bound allylamine (0.80 g, 1.1 mmol/g), aryl iodide
(1.0 equiv), palladium(II) acetate (0.05 equiv), n-Bu4NOAc

842
T. Leikoski et al. / Tetrahedron 69 (2013) 839e843
(2.0 equiv), potassium chloride (1.0 equiv) and potassium carbonate
(1.5 equiv), in dry DMF (5.0 mL), were stirred under argon at 85 ꢀC
for 18e26 h. After filtering, the resin was washed (2ꢁ10 mL) with
each of DMF, MeOH, THF, diethyl ether and CH2Cl2, and subjected to
the cleavage step.
7.31e7.33 (m, 1H). 13C NMR (CDCl3): 23.4, 41.6, 124.7, 126.4, 127.4,
127.8, 129.9, 130.8, 134.7, 138.5, 170.1. HRMS [Mþ$]; calcd for
C
11H1235ClNO: 209.0609; found: 209.0616.
4.5.4. (E,Z)-N-[3-(2-Chlorophenyl)allyl]acetamide
(4). Polymer-
bound allylamine (0.80 g, 1.1 mmol/g) was treated with 2-
iodochlorobenzene (224 mg, 0.939 mmol), palladium(II) acetate
(10.2 mg, 0.0454 mmol), n-Bu4NOAc (553 mg, 1.83 mmol), potas-
sium chloride (76.6 mg, 1.03 mmol) and potassium carbonate
(196 mg, 1.42 mmol) for 26 h, according to the general procedure.
Cleavage and acetylation (general procedure) followed by column
chromatography on SiO2 (acetone/EtOAc 1:8) gave the product 4
(113 mg, 61%), as a mixture of E and Z isomers with an approximate
ratio of 4.3:1.0 according to 1H NMR spectroscopy. Yellow oil. Rf
(acetone/EtOAc 1:4) 0.34. IR (cmꢂ1): 695, 752, 966, 1544, 1634,
3299. 1H NMR (CDCl3): 1.96 (s, 3H, Z); 2.02 (s, 3H, E); 4.02 (dt, J¼1.6,
6.5, 2H, Z); 4.06 (dt, J¼1.5, 6.2, 2H, E); 5.70 (br s, 1H, Z); 5.84 (br s,
1H, E); 5.78 (td, J¼6.5, 11.5, 1H, Z); 6.18 (td, J¼6.2, 15.8, 1H, E); 6.66
(td, J¼1.6, 11.5, 1H, Z); 6.88 (td, J¼1.5, 15.8, 1H, E); 7.08e7.52 (m, 4H,
E, 4H, Z). 13C NMR (acetone-d6): 22.8 (E, Z), 38.1 (Z), 41.6 (E), 127.1,
127.8, 128.1, 129.6, 130.4, 131.2, 133.1, 135.8, 169.9 (E, Z). HRMS
[Mþ$]; calcd for C11H1235ClNO: 209.0609; found: 209.0605.
4.4. General procedure for the cleavage and acetylation of the
coupling product
The polymer-bound coupling product was stirred in TFA/CH2Cl2
(1:1 v/v, 5 mL) at room temperature for 2 h. After filtering, the resin
was washed successively with CH2Cl2 and methanol. The filtrate
was evaporated with toluene (10 mL) under reduced pressure to
give the crude product, which was dissolved in triethylamine
(2 mL) and acetic anhydride (1 mL). A catalytic amount of DMAP
was added and the mixture was stirred at room temperature for 2 h.
The solvents were evaporated twice with ethanol (10 mL), under
reduced pressure, to give the crude acetylated product, which was
subjected to SiO2 column chromatography.
4.5. Syntheses of N-cinnamylacetamides 1e8
4.5.1. N-Cinnamylacetamide (1). Polymer-bound allylamine (0.80 g,
1.1 mmol/g) was treated with iodobenzene (183 mg, 0.897 mmol),
palladium(II) acetate (12.7 mg, 0.0566 mmol), n-Bu4NOAc (552 mg,
1.83 mmol), potassium chloride (70.0 mg, 0.939 mmol) and po-
tassium carbonate (207 mg, 1.50 mmol) for 22 h, according to the
general procedure. Cleavage and acetylation (general procedure)
followed by column chromatography on SiO2 (EtOAc to acetone/
EtOAc 1:3) gave the known60 compound 1 (69.8 mg, 44%). Col-
ourless crystals (EtOAc), mp 80e82 ꢀC (mp lit.60 88e90 ꢀC). Rf
(acetone/EtOAc 1:4) 0.32. IR (cmꢂ1): 692, 750, 963,1557,1641, 3283.
1H NMR (CDCl3): 2.01 (s, 3H); 4.00 (dt, J¼1.2, 6.2, 2H); 5.89 (br s,
1H); 6.17 (td, J¼6.2, 15.9, 1H); 6.50 (d, J¼15.9, 1H); 7.18e7.36 (m,
5H). 13C NMR (CDCl3): 23.4, 41.8, 125.7, 126.4, 127.8, 128.7, 132.2,
136.6, 170.1. MS (m/z): 175, 132, 116, 115, 84, 44 (100%). 1H NMR data
are in accordance with those reported in the literature.61
4.5.5. (E)-N-[3-(4-Acetylphenyl)allyl]acetamide (5). Polymer-bound
allylamine (0.80 g, 1.1 mmol/g) was treated with 40-iodoacetophe-
none (222 mg, 0.902 mmol), palladium(II) acetate (11.4 mg,
0.0508 mmol), n-Bu4NOAc (599 mg, 1.99 mmol), potassium chlo-
ride (72.5 mg, 0.972 mmol) and potassium carbonate (151 mg,
1.09 mmol) for 21 h, according to the general procedure. Cleavage
and acetylation (general procedure) followed by column chroma-
tography on SiO2 (acetone/EtOAc 1:2 to 1:6) gave the product 5
(67.5 mg, 35%). Colourless crystals (EtOAc), mp 101e102 ꢀC. Rf (ac-
etone/EtOAc 1:4) 0.23. IR (m/z): 753, 962, 1267, 1360, 1551, 1628,
1678, 3292. 1H NMR (CDCl3): 2.03 (s, 3H); 2.57 (s, 3H); 4.05 (dt,
J¼1.5, 6.0, 2H); 5.86 (br s, 1H), 6.30 (td, J¼6.0, 16.0, 1H); 6.53 (d,
J¼16.0, 1H); 7.39 (d, J¼8.5, 2H); 7.87 (d, J¼8.5, 2H). 13C NMR (ace-
tone-d6): 22.9, 26.6, 41.7,127.1,129.5,130.4,131.0,137.0,142.5,169.9,
197.3. HRMS [Mþ$]; calcd for C13H15NO2: 217.1103; found: 217.1111.
4.5.2. (E)-N-[3-(4-Chlorophenyl)allyl]acetamide
(2). Polymer-
bound allylamine (0.80 g, 1.1 mmol/g) was treated with 4-
iodochlorobenzene (214 mg, 0.897 mmol), palladium(II) acetate
(9.8 mg, 0.044 mmol), n-Bu4NOAc (531 mg, 1.76 mmol), potassium
chloride (72.6 mg, 0.974 mmol) and potassium carbonate (196 mg,
1.40 mmol) for 21 h, according to the general procedure. Cleavage
and acetylation (general procedure) followed by column chroma-
tography on SiO2 (acetone/EtOAc 1:6 to 1:5) gave the product 2
(100 mg, 54%). Colourless crystals (EtOAc), mp 94e97 ꢀC. Rf (ace-
tone/EtOAc 1:4) 0.29. IR (cmꢂ1): 719, 1091, 1538, 1627, 3288. 1H
NMR (CDCl3): 2.02 (s, 3H); 4.01 (dt, J¼1.5, 6.0, 2H); 5.77 (br s, 1H);
6.15 (td, J¼6.0,15.9,1H); 6.45 (td, J¼1.5, 15.9,1H), 7.23e7.34 (m, 4H).
13C NMR (CDCl3): 23.4, 41.7, 126.4, 127.7, 128.9, 131.0, 133.5, 135.1,
170.1. HRMS [Mþ$]; calcd for C11H1235ClNO: 209.0609; found:
209.0600.
4.5.6. (E,Z)-N-[3-(Naphthalen-1-yl)allyl]acetamide
(6). Polymer-
bound allylamine (0.80 g, 1.1 mmol/g) was treated with 1-
iodonaphthalene (240 mg, 0.945 mmol), palladium(II) acetate
(15.9 mg, 0.0708 mmol), n-Bu4NOAc (549 mg, 1.82 mmol), potas-
sium chloride (71.6 mg, 0.960 mmol) and potassium carbonate
(203 mg, 1.47 mmol) for 22 h, according to the general procedure.
Cleavage and acetylation (general procedure) followed by column
chromatography on SiO2 (acetone/EtOAc 1:8 to 1:6) gave the
product 6 (76.8 mg, 39%), as a mixture of E and Z isomers with an
approximate ratio of 3.3:1.0 according to 1H NMR spectroscopy.
Pale yellow wax. Rf (acetone/EtOAc 1:4) 0.31. IR (cmꢂ1): 729, 777,
1545, 1646, 3278. 1H NMR (CDCl3): 1.89 (s, 3H, Z); 2.03 (s, 3H, E);
3.98 (dt, J¼1.7, 6.4, 2H, Z); 4.13 (dt, J¼1.5, 6.2, 2H, E); 5.57 (br s, 1H,
Z); 5.86 (br s, 1H, E); 5.94 (td, J¼6.4, 11.3, 1H, Z); 6.19 (td, J¼6.2, 15.7,
1H, E); 7.06 (d, J¼11.3, 1H, Z); 7.26 (d, J¼15.7, 1H, E); 7.39e8.12 (m,
7H, E, 7H, Z). 13C NMR (acetone-d6): 20.4 (Z), 22.2 (E), 37.6 (Z), 41.2
(E), 123.8, 123.9, 125.9, 126.0, 126.2, 127.9, 128.7, 130.4, 131.1, 131.4,
134.0, 134.9, 169.2 (E, Z). HRMS [Mþ$]; calcd for C15H15NO:
225.1154; found: 225.1155.
4.5.3. (E)-N-[3-(3-Chlorophenyl)allyl]acetamide
(3). Polymer-
bound allylamine (0.80 g, 1.1 mmol/g) was treated with 3-
iodochlorobenzene (217 mg, 0.910 mmol), palladium(II) acetate
(15.7 mg, 0.0699 mmol), n-Bu4NOAc (533 mg, 1.77 mmol), potas-
sium chloride (80.8 mg,1.08 mg) and potassium carbonate (207 mg,
1.50 mmol) for 19 h, according to the general procedure. Cleavage
and acetylation (general procedure) followed by column chroma-
tography on SiO2 (acetone/EtOAc 1:7 to 1:4) gave the product 3
(89.9 mg, 49%). Colourless crystals (EtOAc), mp 72e74 ꢀC. Rf (ace-
tone/EtOAc 1:4) 0.31. IR (cmꢂ1): 684, 778, 964, 1557, 1633, 3285. 1H
NMR (CDCl3): 2.02 (s, 3H); 4.01 (dt, J¼1.3, 6.1, 2H); 5.78 (br s, 1H),
6.18 (td, J¼6.1,15.9,1H); 6.44 (td, J¼1.3,15.9,1H); 7.18e7.22 (m, 3H);
4.5.7. (E)-N-[3-(4-Cyanophenyl)allyl]acetamide
(7). Polymer-
bound allylamine (0.80 g, 1.1 mmol/g) was treated with 4-
iodobenzonitrile (205 mg, 0.895 mmol), palladium(II) acetate
(14.3 mg, 0.0637 mmol), n-Bu4NOAc (576 mg, 1.91 mmol), potas-
sium chloride (68.5 mg, 0.919 mmol) and potassium carbonate
(187 mg, 1.35 mmol) for 22 h, according to the general procedure.
Cleavage and acetylation (general procedure) followed by column

T. Leikoski et al. / Tetrahedron 69 (2013) 839e843
843
13. Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Sferrazza, A. Org. Biomol. Chem. 2011, 9,
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14. Reddington, M. V.; Cunninghan-Bryant, D. Tetrahedron Lett. 2011, 52, 181e183.
15. Jiang, T.-S.; Li, J.-H. Chem. Commun. 2009, 7236e7238.
16. Brown Ripin, D. H.; Bourassa, D. E.; Brandt, T.; Castaldi, M. J.; Frost, H. N.;
Hawkins, J.; Johnson, P. J.; Massett, S. S.; Neumann, K.; Phillips, J.; Raggon, J. W.;
Rose, P. R.; Rutherford, J. L.; Sitter, B.; Stewart, A. M., III; Vetelino, M. G.; Wei, L.
Org. Process Res. Dev. 2005, 9, 440e450.
17. Wu, J.; Marcoux, J.-F.; Davies, I. W.; Reider, P. J. Tetrahedron Lett. 2001, 42,
159e162.
chromatography on SiO2 (acetone-EtOAc 1:4 to 1:2) gave the
product (43.7 mg, 25%). Colourless crystals (EtOAc), mp
7
129e131 ꢀC. Rf (acetone-EtOAc 1:4) 0.23. IR (cmꢂ1): 727, 801, 971,
1534, 1628, 2221, 3286. 1H NMR (CDCl3): 2.03 (s, 3H); 4.06 (dt,
J¼1.5, 6.0, 2H); 5.75 (br s, 1H), 6.32 (td, J¼6.0, 16.0, 1H); 6.51 (d,
J¼16.0, 1H); 7.41 (d, J¼8.2, 2H); 7.57 (d, J¼8.2, 2H). 13C NMR (CDCl3):
23.4, 41.6, 111.1, 119.0, 127.0, 130.1, 130.3, 132.6, 141.2, 170.1. HRMS
[Mþ$]; calcd for C12H12N2O: 200.0950; found: 200.0944.
18. Olofsson, K.; Sahlin, H.; Larhed, M.; Hallberg, A. J. Org. Chem. 2001, 66, 544e549.
19. Olofsson, K.; Larhed, M.; Hallberg, A. J. Org. Chem. 2000, 65, 7235e7239.
20. Dong, Y.; Busacca, C. A. J. Org. Chem. 1997, 62, 6464e6465.
21. Busacca, C. A.; Dong, Y. Tetrahedron Lett. 1996, 37, 3947e3950.
22. Malek, N. J.; Moormann, A. E. J. Org. Chem. 1982, 47, 5395e5397.
23. Phuan, P.-W.; Kozlowski, M. C. Tetrahedron Lett. 2001, 42, 3963e3965.
24. Larock, R. C.; Babu, S. Tetrahedron Lett. 1987, 5291e5294.
4.5.8. (E,Z)-N-[3-(3-Methoxyphenyl)allyl]acetamide (8). Polymer-
bound allylamine (0.80 g, 1.1 mmol/g) was treated with 3-iodoa-
nisole (221 mg, 0.944 mmol), palladium(II) acetate (10.3 mg,
0.0459 mmol), n-Bu4NOAc (534 mg, 1.77 mmol), potassium chlo-
ride (67.0 mg, 0.899 mmol) and potassium carbonate (183 mg,
1.32 mmol) for 18 h, according to the general procedure. Cleavage
and acetylation (general procedure) followed by column chroma-
tography on SiO2 (acetone/EtOAc 1:8 to 1:6) gave the product 8
(42.3 mg, 23%), as a mixture of E and Z isomers with an approximate
ratio of 3.8:1.0 according to 1H NMR spectroscopy. Pale yellow oil. Rf
(acetone/EtOAc 1:4) 0.28. IR (cmꢂ1): 689, 774, 1038, 1156, 1194,
1264, 1545, 1647, 3283. 1H NMR (CDCl3): 1.95 (s, 3H, Z); 2.00 (s, 3H,
E); 3.79 (s, 3H, E, 3H, Z); 3.89 (dt, J¼1.2, 6.0, 2H, Z); 4.00 (dt, J¼1.2,
6.2, 2H, E); 5.77 (br s, 1H, Z); 5.83 (br s, 1H, E); 5.93 (td, J¼6.0, 15.7,
1H, Z); 6.16 (td, J¼6.2, 15.7, 1H, E); 6.46 (d, J¼15.7, 1H, E, 1H, Z);
6.73e7.28 (m, 4H, E, 4H, Z). 13C NMR (CDCl3): 23.2 (Z), 23.3 (E), 38.2
(Z), 41.7 (E), 55.3, 111.8, 113.5, 119.1, 126.0, 129.7, 132.2, 138.1, 159.9,
170.2 (E, Z). HRMS [Mþ$]; calcd for C12H15NO2: 205.1103; found:
205.1095.
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Acknowledgements
€
44. Schwarz, J.; Bohm, V. P. W.; Gardiner, M. G.; Grosche, M.; Herrmann, W. A.;
This research has been supported by TEKES (The Finnish Fund-
ing Agency for Technology and Innovation), Juvantia Pharma Ltd,
Orion Corporation, Hormos Medical, The Academy of Finland, The
DDTC Research Programme of the University of Helsinki, The
Finnish Work Environment Fund and Alfred Kordelin Foundation.
We thank Dr. Alistair W.T. King for reviewing the language.
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