High-yielding synthesis of 2-arylacrylamides via homogeneous catalytic aminocarbonylation of α-iodostyrene and α,α′-diiodo-1,4-divinylbenzene

Article abstract of DOI:10.1016/j.tet.2007.10.102

Highly reactive iodoalkenes (α-iodostyrene and α,α′-diiodo-1,4-divinylbenzene) were prepared and used as substrates in palladium-catalysed aminocarbonylation reaction. Regardless of the type of amine nucleophile the corresponding N-substituted phenylacryl

Full text of DOI:10.1016/j.tet.2007.10.102

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Tetrahedron 64 (2008) 61e66
www.elsevier.com/locate/tet
High-yielding synthesis of 2-arylacrylamides via homogeneous catalytic
aminocarbonylation of a-iodostyrene and a,a0-diiodo-1,4-divinylbenzene
*
´
´
Attila Takacs, Roland Farkas, Laszlo Kollar
´
´
Department of Inorganic Chemistry, University of Pe´cs, H-7624 Pe´cs, PO Box 266, Hungary
Received 22 June 2007; received in revised form 8 October 2007; accepted 26 October 2007
Available online 1 November 2007
Abstract
Highly reactive iodoalkenes (a-iodostyrene and a,a0-diiodo-1,4-divinylbenzene) were prepared and used as substrates in palladium-catalysed
aminocarbonylation reaction. Regardless of the type of amine nucleophile the corresponding N-substituted phenylacrylamides have been formed
chemoselectively in nearly quantitative yields. High isolated yields (up to 83%) have been achieved both with unfunctionalised simple amines
and amino acid methyl esters under mild reaction conditions.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Aminocarbonylation; Carbon monoxide; Amino acid; Palladium; a-Iodostyrene
1. Introduction
in homogeneous cross-coupling (Stille-coupling).9 Several appli-
cations are known for the application of iodostyrene possessing
the iodo substituent in the unsaturated side chain. (E )-b-
Iodostyrene as an iodoalkene coupling partner has been reacted
in copper-mediated Stille cross-coupling with 1,3,5-tris[(E )-
2-(tributylstannyl)vinyl]benzene.10 a-Iodostyryl group can be
introduced by the application of a-iodostyrene in Heck-11 and
Stille-coupling12 reactions, inanalogousreactionusing2-pyridyl-
silanes,13 as well as its addition to aldehydes.14,15
The bromo analogue, (E )-b-bromostyrene, however, has
been used more frequently in various transition metal-catalysed
reactions. Its electrochemical carboxylation was carried out in
the presence of nickel(II) catalysts.16 It was also used as a sub-
strate in palladium-catalysed asymmetric KumadaeCorriu
coupling,17 in multiple coupling reactions with norbornane
and dicyclopentadiene,18 in the reaction with chlorovinylsilanes
resulting in b-substituted vinylsilanes19 and in the functionalisa-
tion of cephem skeleton.20
Palladium-catalysed carbonylation reactions, carried out in
the presence of various nucleophiles like amines and alcohols,
belong to the most widely used homogeneous catalytic reactions
in synthetic chemistry.1 There are a number of applications
concerning the synthesis of simple building blocks and the func-
tionalisation of biologically important skeletons.2 Aminocarbo-
nylation plays a special role among these reactions, since those
carboxamides which are difficult to preparevia the conventional
carboxylic acidecarboxylic halideecarboxamide route (e.g.,
with bulky substituents at the amide nitrogen) can be synthes-
ised from easily available starting materials.3 In addition to
the enol-triflates and aryl triflates the corresponding iodo
analogues, iodoalkenes and iodoaromatics have been used for
aminocarbonylation reaction. The homogeneous catalytic syn-
thesis of unsaturated carboxamides or aryl carboxamides with
various structures has been published also by our group.4,5
The application of styrene-derived iodoaromatics (2-iodo-
and 4-iodostyrene) is well known in polymer chemistry 6e8 and
The a-bromostyrene, the close analogue of our title sub-
strates, has also been applied in several homogeneous catalytic
reactions, such as in palladium-catalysed cross-coupling and
consecutive [4þ4] cycloaddition sequence,21 in sequential ami-
nation/Heck cyclisation,22 in direct amination with secondary
and primary amines resulting in enamines and imines,
* Corresponding author.
E-mail address: kollar@ttk.pte.hu (L. Kollar).
´
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.10.102

62
A. Taka´cs et al. / Tetrahedron 64 (2008) 61e66
respectively.23 The three-component coupling reaction involv-
ing allene brought about allylic silanes.24 Several cyanoate
complexes of iron, cobalt or nickel act as efficient catalyst in
cross-coupling with organic halides.25
palladium(0)-triphenylphosphine catalysts (Scheme 2). Palla-
dium(II) acetate was used as catalytic precursor and reduced
to Pd(0) as described previously in detail.27,28
O
Encouraged by the increasing importance of the selective
synthesis of unsaturated carboxamides, especially that of 2-
arylacrylamides, as potential building blocks and their
applicability as substrate in asymmetric synthesis, we decided
to investigate the possibility of extending the scope of aminocar-
bonylation to a-iodostyrene derivatives expected to be highly
reactive substrates. Accordingly, the clean and nearly quantita-
tive aminocarbonylation of a-iodostyrene and a,a0-diiodo-1,4-
divinylbenzene with simple primary and secondary amines, as
well as with amino acid methyl esters is reported in the present
paper.
I
NR'R'
CO,HNR'R''
Pd(OAc)2 / PPh3
5
5a-5i
O
I
NR'R'
CO,HNR'R''
Pd(OAc)2 / PPh3
R"R'N
I
O
6a-6h
6
2. Results and discussion
R'
R''
a
b
H
H
t-Bu
Ph
2.1. Synthesis of a-iodostyrene (5) and a,a0-diiodo-1,4-
divinylbenzene (6)
c
d
e
f
-(CH2)5-
-(CH2)2O(CH2)2-
H
H
CH2COOCH3
CH(CH3)COOCH3
The above two iodoalkenes have been synthesised by the
26
known methodology of Barton et al.
with some modifica-
g
h
i
H
CH(CH(CH3)2)COOCH3
tions (See Section 4). The conventional ketoneehydrazonee
iodoalkene route has been used. Accordingly, acetophenone
(1) and 1,4-diacetylbenzene (2) have been converted to the
corresponding hydrazones (3 and 4) using barium oxide or
triethylamine, respectively. Compounds 3 and 4 were reacted
with iodine in the presence of a base (TMG¼N,N,N0,N0-tetra-
methylguanidine) resulting in a-iodostyrene (5) and a,a0-
diiodo-1,4-divinylbenzene (6), respectively (Scheme 1). The
‘iodovinyl’ product-forming step has been carried out under
argon providing strictly moisture- and oxygen-free conditions.
-CH(COOCH3)(CH2)3-
-CH(COOCH2Ph)(CH2)3-
Scheme 2. Palladium-catalysed aminocarbonylation of 5 and 6.
The reactivity of 5, compared to several types of iodoal-
kenes, proved to be exceptionally high. All of the resulting
N-substituted 2-phenylacrylamides (5ae5i) have been ob-
tained with practically complete conversion and isolated in
63e83% yields after column chromatography (Section 4).
Even those amines which have shown decreased reactivity in
aminocarbonylation of various iodoalkenes, i.e., arylamine
(b) and sterically hindered secondary amines (h and i), pro-
vided excellent isolated yields (Table 1).
I
X
I2, TMG
5
X = O
X = NNH2
1
3
N2H4, BaO
By carrying out the aminocarbonylation of 5 under in-
creased carbon monoxide pressure (40 bar), the expected car-
boxamides (5ae5i) have been obtained in yields similar to
those obtained under normal carbon monoxide pressure (Table
1). It is worth noting that double carbonylation resulting in
keto-carboxamides was not observed using GCeMS neither
at atmospheric pressure nor at elevated carbon monoxide pres-
sure, so the reaction is said to be completely chemoselective.
The ‘bis-iodovinyl’ type substrate 6 has been reacted with
the same amines of various structures aeh as in case of 5
(Scheme 2). The bis-carboxamides (6ae6h) have been ob-
tained in excellent yields except for 6b. (The lower reactivity
of the aniline nucleophile resulted in complex mixtures includ-
ing some carboxylic acids formed from hydroxycarbonylation
of 6 in the presence of traces of water. The isolation of the ex-
pected amide 6b failed.) Due to the excellent reactivity of the
‘iodovinyl’ functionality, substrate 6 was practically com-
pletely converted almost in all cases even under atmospheric
carbon monoxide pressure (Table 2).
X
I
I2, TMG
I
X
6
X = O
2
4
N2H4, Et3N
X = NNH2
Scheme 1. Synthesis of the iodoalkenes (5 and 6) from the corresponding
ketones via their hydrazones.
2.2. Aminocarbonylation of 5 and 6
a-Iodostyrene (5) was reacted with tert-butylamine (a), an-
iline (b), piperidine (c), morpholine (d), methyl glycinate (e),
methyl alaninate (f), methyl valinate (g), methyl prolinate (h)
and benzyl prolinate (i) under atmospheric and high pressure
(40 bar) carbon monoxide in the presence of in situ generated

A. Taka´cs et al. / Tetrahedron 64 (2008) 61e66
63
Table 1
Palladium-catalysed aminocarbonylation of 5a
The advantage of this methodology has been illustrated
by several types of skeletons of biological importance, like
tropane-alkaloids29 and steroids.30
Amine
Reaction time [h] p(CO) [bar] Isolated yieldb (amide) [%]
t-BuNH2 (a)
t-BuNH2 (a)
Aniline (b)
Aniline (b)
22
22
22
22
1
40
1
83 (5a)
82 (5a)
70 (5b)
68 (5b)
79 (5c)
77 (5c)
74 (5d)
73 (5d)
76 (5e)
73 (5e)
72 (5f)
71 (5f)
69 (5g)
67 (5g)
67 (5h)
65 (5h)
63 (5i)
4. Experimental
40
1
4.1. General procedures
Piperidine (c) 22
Piperidine (c) 22
Morpholine (d) 22
Morpholine (d) 22
40
1
1H and 13C NMR spectra were recorded in CDCl3 on a Varian
Inova 400 spectrometer at 400.13 MHz and 100.62 MHz,
respectively. Chemical shifts d are reported in ppm relative
40
1
GlyOMe (e)
GlyOMe (e)
AlaOMe (f)
AlaOMe (f)
ValOMe (g)
ValOMe (g)
ProOMe (h)
ProOMe (h)
ProOBz (i)
a
22
22
22
22
22
22
66
66
66
40
1
to residual CHCl3 (7.26 ppm and 77.00 ppm for H and 13C,
1
respectively). Elemental analyses were measured on a 1108
Carlo Erba apparatus. Samples of the catalytic reactions were
analysed with a Hewlett Packard 5830A gas chromatograph
fitted with a capillary column coated with OV-1.
40
1
40
1
40
40
4.2. Synthesis of a-iodostyrene (5)
Reaction conditions: 0.025 mmol Pd(OAc)2; 0.05 mmol PPh3, 1 mmol
a-iodostyrene (5); 3 mmol nonfunctionalised amine (or 1.1 mmol amino acid
methyl ester hydrochloride); 10 mL DMF.
Acetophenone (1) (40 g, 0.33 mol), freshly distilled hydra-
zine hydrate (98%, 18.36 g, 0.36 mol) and barium oxide
(12.60 g) in absolute ethanol (50 mL) were heated for 5 h at
90 ꢀC. After completion of the reaction, ether (100 mL) was
added and filtered and the mixture was dried over sodium
hydroxide for a day. At last it was evaporated to give the hydra-
zone (3) derivative. The product was used in the next step
without further purification.
To a stirred solution of iodine (58.73 g, 0.231 mol) in di-
chloromethane (150 mL) the mixture of 1,1,3,3-tetramethyl-
guanidine (TMG, 115.88 g, 1.006 mol) and acetophenone
hydrazone (3) (15 g, 0.112 mol) in dichloromethane (30 mL)
was added dropwise at room temperature. After the addition
was complete, the mixture was stirred for half an hour. Then
the solvent was evaporated and the residue was heated at
90 ꢀC under argon atmosphere for 2 h. The mixture was poured
into water (400 mL) and extracted with ether (three times
100 mL). The combined organic layer was washed with 1 N
aqueous HCl (three times 50 mL), water (50 mL), 5% aqueous
NaHCO3 (twice 50 mL), water (50 mL), saturated aqueous
Na2S2O3 (10 mL) and water (twice 50 mL) again, dried over
sodium sulfate and evaporated. Purification by column chroma-
tography (silicagel, petroleum ether) gave pure 5 as a yellow
viscous material. Yield: 8.51 g; 33%.
b
Practically complete conversion (>98%) has been obtained in all cases.
Table 2
Palladium-catalysed aminocarbonylation of 6a
Amine
Isolated yieldb (amide) [%]
t-BuNH2 (a)c
Piperidine (c)
Morpholine (d)
GlyOMe (e)
AlaOMe (f)
ValOMe (g)
ProOMe (h)
a
80 (6a)
75 (6c)
73 (6d)
70 (6e)
70 (6f)
66 (6g)
62 (6h)
Reaction conditions (unless otherwise stated): 0.025 mmol Pd(OAc)2;
0.05 mmol PPh3, 1 mmol a,a0-diiodo-1,4-divinylbenzene (6); 3 mmol non-
functionalised amine (or 1.1 mmol amino acid methyl ester); p(CO)¼1 bar;
10 mL DMF, 22 h.
b
Practically complete conversion (>98%) has been obtained in all cases.
p(CO)¼40 bar.
c
3. Conclusions
Palladium-catalysed aminocarbonylation proved to be an
efficient method for the functionalisation of a-iodovinyl
substituted aromatics, a-iodostyrene and a,a0-diiodo-1,4-di-
vinylbenzene using the great variety of amine nucleophiles.
It could be stated that the exceptional reactivity of the iodo-
styrene substrates compared to cyclic and open-chain iodo-
alkenes, the clean and nearly quantitative aminocarbonylation
enabled the facile synthesis of 2-arylacrylamide type synthetic
building blocks. These could also serve as intermediates of
chiral building blocks, which are available via asymmetric
hydrogenation.
Furthermore, the easy work-up of the reaction mixtures ob-
tained with these substrates makes these reactions of synthetic
importance. The use of iodoalkenes as synthetic substitutes for
the corresponding enol-triflates is supported not only by green
chemistry principles but also by their advantageous synthetic
properties as substrates in homogeneous catalytic reactions.
a-Iodostyrene31e33 (5): dH (400 MHz, CDCl3) 7.52 (d,
7.2 Hz, 2H, Ph); 7.30e7.41 (m, 3H, Ph); 6.48 (br s, 1H,
]CH); 6.07 (br s, 1H, ]CH). dC (100.6 MHz, CDCl3)
141.7; 133.7; 128.8; 128.4; 127.3; 107.5. MS m/z (rel int. %):
230 (21), 103 (100), 77 (42). Analysis calculated for C8H7I
(230.05): C, 41.77; H, 3.07; found: C, 41.51; H, 3.16. The
spectral data above are in accordance with the literature data.
4.3. Synthesis of a,a0-diiodo-1,4-divinylbenzene (6)
1,4-Diacetylbenzene (2) (10 g, 0.062 mol), triethylamine
(31.19 g, 0.308 mol) and freshly distilled hydrazine hydrate
(98%, 7.41 g, 0.148 mmol) in absolute ethanol (30 mL) were
heated for 5 h at 90 ꢀC. After completion of the reaction the

64
A. Taka´cs et al. / Tetrahedron 64 (2008) 61e66
mixture was evaporated, dichloromethane was added and
the solution dried over sodium sulfate for a day. The organic
phase was then evaporated to give the hydrazone (4) deriva-
tive. The product was used in the next step without further
purification.
4.5. Aminocarbonylation experiments at high pressure
The DMF solution of the catalyst precursor and reactants
(amounts given in Section 4.4) was transferred under argon
into a 100 mL stainless steel autoclave. The reaction vessel
was pressurised up to 40 bar total pressure with carbon mon-
oxide and the magnetically stirred mixture was heated in an
oil bath at 50 ꢀC for 22 h. The work-up procedure is identical
with that given above.
To a stirred solution of iodine (75.12 g, 0.296 mol) in
dichloromethane (150 mL), 1,1,3,3-tetramethylguanidine (TMG,
71.02 g, 0.617 mmol) and 1,4-diacetylbenzene dihydrazone
(4) (11.73 g, 0.062 mol) in dichloromethane (50 mL) were
added dropwise at room temperature. After the addition was
completed, the mixture was stirred for half an hour. Then
the solvent was evaporated and the residue was heated at
90 ꢀC under argon atmosphere for 2 h. The mixture was
poured into water (450 mL) and extracted with ether (three
times 150 mL). The combined organic layer was washed
with 1 N aqueous HCl (three times 50 mL), water (50 mL),
5% aqueous NaHCO3 (twice 50 mL), water (50 mL), saturated
aqueous Na2S2O3 (10 mL) and water (twice 50 mL) again,
dried over sodium sulfate and evaporated. Purification by col-
umn chromatography (silicagel, petroleum ether) gave pure 6
as a yellow solid material. Yield: 5.06 g; 22%.
4.6. Characterisation of the products
N-tert-Butyl-2-phenylacrylamide (5a): dH (400 MHz, CDCl3)
7.30e7.42 (m, 5H, Ph); 6.00 (br s, 1H, ]CH); 5.54 (br s, 1H,
NH); 5.52 (br s, 1H, ]CH). dC (100.6 MHz, CDCl3) 166.8;
146.0; 137.3; 128.5; 128.3; 127.9; 120.7; 51.5; 28.6. IR (KBr
(cmꢁ1)): 3259 (NH); 1646 (CON). MS m/z (rel int. %): 203
(38), 188 (32), 146 (24), 131 (45), 103 (100), 77 (23). Analysis
calculated for C13H17NO (203.28): C, 76.81; H, 8.43; N,
6.89; found: C, 76.65; H, 8.52; N, 6.60; Rf (10% EtOAc/
CHCl3) 0.76; Rf (5% EtOAc/CHCl3) 0.69; yellow solid, mp
70e72 ꢀC.
a,a0-Diiodo-1,4-divinylbenzene (6): dH (400 MHz, CDCl3)
7.45 (s, 4H, C6H4); 6.50 (br s, 1H, ]CH); 6.09 (br s, 1H,
]CH). dC (100.6 MHz, CDCl3) 142.0; 127.9; 127.8; 106.0.
MS m/z (rel int. %): 382 (11), 255 (100), 128 (62), 102 (9),
76 (5). Analysis calculated for C10H8I2 (381.98): C, 31.44;
H, 2.11; found: C, 31.29, H, 2.31. Mp 65 ꢀC.
N-Phenyl-2-phenylacrylamide (5b):34e37 dH (400 MHz,
CDCl3) 7.58 (br s, 1H, NH); 7.10e7.55 (m, 10H, 2ꢂPh); 6.22
(br s, 1H, ]CH); 5.70 (br s, 1H, ]CH). dC (100.6 MHz,
CDCl3) 165.5; 145.2; 137.7; 136.6; 128.9; 128.6; 128.4;
128.1; 124.6; 122.7; 120.0. IR (KBr (cmꢁ1)): 3230 (NH);
1651 (CON). MS m/z (rel int. %): 223 (46), 146 (3), 103
(100), 77 (30). Analysis calculated for C15H13NO (223.27): C,
80.69; H, 5.87; N, 6.27; found: C, 80.49; H, 5.96; N, 6.02; Rf
(10% EtOAc/CHCl3) 0.82; yellow solid, mp 138e140 ꢀC. The
spectral data were in accordance with the literature data.
2-Phenyl-1-piperidin-1-yl-propenone (5c):38 dH (400 MHz,
CDCl3) 7.20e7.42 (m, 5H, Ph); 5.65 (br s, 1H, ]CH); 5.29
(br s, 1H, ]CH); 3.60e3.70 (m, 2H, NCH2); 3.25e3.31 (m,
2H, NCH2); 1.60 (br s, 4H, (CH2)2); 1.32 (br s, 2H, CH2). dC
(100.6 MHz, CDCl3) 169.1; 145.2; 135.7; 129.8; 128.5; 125.6;
113.2; 47.9; 42.3; 26.2; 25.3; 24.4. IR (KBr (cmꢁ1)): 1634
(CON). MS m/z (rel int. %): 215 (100), 214 (80), 103 (90), 77
(33). Analysis calculated for C14H17NO (215.30): C, 78.10; H,
7.96; N, 6.51; found: C, 77.89; H, 8.11; N, 6.40; Rf (10%
EtOAc/CHCl3) 0.55; yellow solid, mp 170e173 ꢀC. The
spectral data were in accordance with the literature data.
1-Morpholin-4-yl-2-phenyl-propenone (5d): dH (400 MHz,
CDCl3) 7.24e7.42 (m, 5H, Ph); 5.70 (br s, 1H, ]CH); 5.33
(br s, 1H, ]CH); 3.55e3.80 (m, 4H, 2ꢂOCH2); 3.42 (br s,
2H, CH2); 3.32 (br s, 2H, CH2). dC (100.6 MHz, CDCl3)
169.3; 144.4; 135.3; 128.8; 128.5; 125.6; 114.4; 66.7 (double in-
tensity); 47.3; 41.9. IR (KBr (cmꢁ1)): 1639 (CON). MS m/z (rel
int. %): 217 (52), 132 (22), 103 (100), 77 (36). Analysis calcu-
lated for C13H15NO2 (217.27): C, 71.87; H, 6.96; N, 6.45; found:
C, 71.73; H, 7.08; N, 6.38; Rf (10% EtOAc/CHCl3) 0.40; Rf
(50% EtOAc/CHCl3) 0.61; golden highly viscous material.
(2-Phenyl-acryloylamino)-acetic acid methyl ester (5e): dH
(400 MHz, CDCl3) 7.3e7.45 (m, 5H, Ph); 6.34 (br s, 1H,
NH); 6.12 (br s, 1H, ]CH); 5.63 (br s, 1H, ]CH); 4.08 (d,
9 Hz, 2H, CH2); 3.70 (s, 3H, OCH3). dC (100.6 MHz,
4.4. Aminocarbonylation experiments at normal pressure
In a typical experiment a solution of Pd(OAc)2 (5.6 mg,
0.025 mmol), PPh3 (13.1 mg, 0.05 mmol), 0.5 mmol iodo sub-
strate (5), 1.5 mmol nonfunctionalised amine (aed) (or
0.55 mmol amino acid methyl ester (eeh) hydrochloride)
were dissolved in 10 mL of DMF under argon. Triethylamine
(0.5 mL) was added to the homogeneous yellow solution and
the atmosphere was changed to carbon monoxide. The colour
changed to dark red. The reaction was conducted for 22 h at
50 ꢀC. Some metallic palladium was formed at the end of the
reaction which was filtered off. (A sample of this solution was
immediately analysed by GCeMS.) The mixture was then con-
centrated and evaporated to dryness. The residue was dissolved
in chloroform (20 mL) and washed with water (20 mL). The or-
ganic phase was thoroughly washed twice with 5% HCl
(20 mL), saturated NaHCO3 (20 mL), brine (20 mL), dried
over Na2SO4 and concentrated to a yellow waxy material or
a thick oil. Chromatography (silica, chloroform, then chloro-
form/ethanol¼4/1) yielded the desired compounds as yellow
solids.
By carrying out the reaction with 6, a solution of Pd(OAc)2
(5.6 mg, 0.025 mmol), PPh3 (13.1 mg, 0.05 mmol), 0.5 mmol
iodo substrate (6), 3.0 mmol nonfunctionalised amine (aed)
(or 1.1 mmol amino acid methyl ester (eeh) hydrochloride)
were dissolved in 10 mL of DMF under argon. Triethylamine
(1.0 mL) was added to the homogeneous yellow solution and
further steps were carried out as above.

A. Taka´cs et al. / Tetrahedron 64 (2008) 61e66
65
CDCl3) 170.1; 167.5; 144.2; 136.6; 128.6; 128.5; 128.0;
122.4; 52.2; 41.4. IR (KBr (cmꢁ1)): 3332 (NH); 1752
(COO); 1665 (CON). MS m/z (rel int. %): 219 (22), 160
(12), 146 (18), 131 (35), 103 (100), 77 (29). Analysis calcu-
lated for C12H13NO3 (219.24): C, 65.74; H, 5.98; N, 6.39;
found: C, 65.64; H, 5.81; N, 6.23; Rf (10% EtOAc/CHCl3)
0.46; Rf (20% EtOAc/CHCl3) 0.60; yellow solid, mp 68e
70 ꢀC.
2-(2-Phenyl-acryloylamino)-propionic acid methyl ester (5f):
dH (400 MHz, CDCl3) 7.30e7.50 (m, 5H, Ph); 6.38 (br s, 1H,
NH); 6.07 (br s, 1H, ]CH); 5.60 (br s, 1H, ]CH); 4.64 (quin-
tet, 7.2 Hz, 1H, CHCH3); 3.70 (s, 3H, OCH3); 1.4 (d, 7.2 Hz,
3H, CHCH3). dC (100.6 MHz, CDCl3) 173.2; 166.9; 144.4;
136.6; 128.6; 128.5; 128.0; 122.1; 52.4; 48.3; 18.1. IR (KBr
(cmꢁ1)): 3327 (NH); 1744 (COO); 1662 (CON). MS m/z
(rel int. %): 233 (4), 174 (56), 131 (42), 103 (100), 77 (24).
Analysis calculated for C13H15NO3 (233.27): C, 66.94; H,
6.48; N, 6.00; found: C, 66.78; H, 6.62; N, 5.76; Rf (10%
EtOAc/CHCl3) 0.60; Rf (20% EtOAc/CHCl3) 0.75; golden
highly viscous material.
N-tert-Butyl-2-[4-(1-tert-butylcarbamoyl-vinyl)-phenyl]acryl
amide (6a): dH (400 MHz, CDCl3) 7.38 (s, 4H, C6H4); 5.91 (br s,
2H, ]CH); 5.60 (br s, 2H, NH); 5.57 (br s, 2H, ]CH); 1.36 (s,
18H, 2ꢂC(CH3)3). dC (100.6 MHz, CDCl3) 166.9; 145.6; 137.1;
127.9; 120.1; 51.6; 28.6. IR (KBr (cmꢁ1)): 3328 (NH); 1644
(CON). MS m/z (rel int. %): 328 (70), 313 (30), 272 (21), 228
(100), 172 (47), 128 (45), 57 (43). Analysis calculated for
C20H28N2O2 (328.45): C, 73.14; H, 8.59; N, 8.53; found: C,
73.01, H, 8.73; N, 8.29; Rf (4% EtOH/CHCl3) 0.79; Rf (50%
EtOAc/CHCl3) 0.70; off-white solid, mp 180e183 ꢀC.
2-{4-[1-(Piperidine-carbonyl)-vinyl]-phenyl}-1-piperidin-1-
yl-propenone (6c): dH (400 MHz, CDCl3) 7.38 (s, 4H, C6H4);
5.67 (br s, 2H, ]CH); 5.28 (br s, 2H, ]CH); 3.60 (br s, 4H,
NCH2); 3.23 (br s, 4H, NCH2); 1.55 (br s, 8H, 4ꢂCH2); 1.30
(br s, 4H, 2ꢂCH2). dC (100.6 MHz, CDCl3) 168.8; 144.6;
135.7; 126.0; 113.5; 47.9; 42.3; 26.2; 25.5; 24.4. IR (KBr
(cmꢁ1)): 1628 (CON). MS m/z (rel int. %): 352 (100), 323
(4), 269 (26), 241 (34), 207 (10), 186 (17), 128 (37), 98 (77).
Analysis calculated for C22H28N2O2 (352.48): C, 74.97; H,
8.01; N, 7.95; found: C, 74.85, H, 8.11; N, 7.76; Rf (4%
EtOH/CHCl3) 0.53; Rf (50% EtOAc/CHCl3) 0.43; off-white
solid, mp 171e172 ꢀC.
3-Methyl-2-(2-phenyl-acryloylamino)-butyric acid methyl
ester (5g): dH (400 MHz, CDCl3) 7.30e7.50 (m, 5H, Ph);
6.20 (br s, 1H, NH); 6.09 (s, 1H, ]CH); 5.62 (br s, 1H,
]CH); 4.60 (m, 1H, CHNH); 2.15 (m, 1H, CH(CH3)2; 0.91
(d, 7.2 Hz, 3H, CHCH3); 0.8 (d, 7.2 Hz, 3H, CHCH3). dC
(100.6 MHz, CDCl3) 173.8; 167.2; 144.5; 136.6; 132.4;
128.6; 128.0; 122.1; 57.4; 52.1; 31.1; 18.9; 17.7. IR (KBr
(cmꢁ1)): 3352 (NH); 1743 (COO); 1666 (CON). MS m/z (rel
int. %): 261 (6), 202 (43), 131 (29), 103 (100), 77 (20). Anal-
ysis calculated for C15H19NO3 (261.32): C, 68.94; H, 7.33; N,
5.36; found: C, 68.70; H, 7.12; N, 5.06; Rf (10% EtOAc/
CHCl3) 0.64; dark yellow bright highly viscous material.
1-(2-Phenyl-acryloyl)-pyrrolidine-2-carboxylic acid methyl
ester (5h): dH (400 MHz, CDCl3) 7.25e7.50 (m, 5H, Ph);
5.71 (br s, 1H, ]CH); 5.41 (br s, 1H, ]CH); 4.58 (m, 1H,
NCH); 3.72 (s, 3H, OCH3); 3.30 (t, 7.4 Hz, 2H, NCH2);
1.7e2.22 (m, 4H, (CH2)2). dC (100.6 MHz, CDCl3) 172.5;
169.2; 145.4; 135.3; 128.7; 128.4; 126.0; 115.0; 58.4; 52.1;
48.5; 29.3; 24.8. IR (KBr (cmꢁ1)): 1744 (COO); 1639
(CON). MS m/z (rel int. %): 259 (14), 200 (67), 131 (40),
103 (100), 77 (22). Analysis calculated for C15H17NO3
(259.30): C, 69.48; H, 6.61; N, 5.40; found: C, 69.30; H,
6.52; N, 5.26; Rf (10% EtOAc/CHCl3) 0.31; Rf (20% EtOAc/
CHCl3) 0.53; dark yellow bright highly viscous material.
1-(2-Phenyl-acryloyl)-pyrrolidine-2-carboxylic acid benzyl
ester (5i): dH (400 MHz, CDCl3) 7.25e7.50 (m, 5H, Ph);
5.74 (br s, 1H, ]CH); 5.43 (br s, 1H, ]CH); 5.20 (AB-dd,
2H, CH2Ph); 4.65 (m, 1H, NCH); 3.30 (t, 7.4 Hz, 2H,
NCH2); 1.7e2.25 (m, 4H, (CH2)2). dC (100.6 MHz, CDCl3)
171.9; 169.3; 145.5; 135.7; 135.3; 128.7; 128.6; 128.5;
128.3; 128.1; 126.0; 115.2; 66.9; 58.6; 48.5; 29.4; 24.8. IR
(KBr (cmꢁ1)): 1743 (COO); 1640 (CON). MS m/z (rel int.
%): 335 (6), 200 (87), 131 (44), 103 (100), 77 (22). Analysis
calculated for C21H21NO3 (335.40): C, 75.20; H, 6.31; N,
4.18; found: C, 75.02; H, 6.42; N, 4.01; Rf (10% EtOAc/
CHCl3) 0.50; Rf (20% EtOAc/CHCl3) 0.65; dark yellow bright
highly viscous material.
2-{4-[1-(Morpholin-4-yl-carbonyl)-vinyl]-phenyl}-1-morpho-
lin-4-yl-propenone (6d): dH (400 MHz, CDCl3) 7.42 (s, 4H,
C6H4); 5.78 (br s, 2H, ]CH); 5.37 (br s, 2H, ]CH); 3.60e
3.80 (m, 8H, 4ꢂCH2); 3.30e3.50 (m, 8H, 4ꢂCH2). dC
(100.6 MHz, CDCl3) 169.0; 143.6; 135.6; 126.1; 114.9; 66.7;
47.3; 41.9. IR (KBr (cmꢁ1)): 1632 (CON). MS m/z (rel int.
%): 356 (83), 328 (10), 271 (26), 207 (43), 128 (40), 100
(100). Analysis calculated for C20H24N2O4 (356.42): C, 67.40;
H, 6.79; N, 7.86; found: C, 67.57, H, 6.92; N, 7.58; Rf (4%
EtOH/CHCl3) 0.50; Rf (50% EtOAc/CHCl3) 0.61; pale brown
solid, mp 185e190 ꢀC.
(2-{4-[1-(Methoxycarbonylmethyl-carbamoyl)-vinyl]-phenyl}-
acryloylamino)-acetic acid methyl ester (6e): dH (400 MHz,
CDCl3) 7.45 (s, 4H, C6H4); 6.25 (br s, 2H, NH); 6.14 (br s, 2H,
]CH); 5.70 (br s, 2H, ]CH); 4.14 (d, 7.5 Hz, 2H, NHCH2);
3.75 (s, 3H, OCH3). dC (100.6 MHz, CDCl3) 163.9; 161.2;
137.5; 130.6; 122.0; 116.1; 46.1 35.2. IR (KBr (cmꢁ1)): 3310
(NH); 1748 (COO); 1652 (CON). Analysis calculated for
C18H20N2O6 (360.37): C, 59.99; H, 5.59; N, 7.77; found: C,
60.11, H, 5.75; N, 7.53; Rf (4% EtOH/CHCl3) 0.42; Rf (50%
EtOAc/CHCl3) 0.15; white solid, mp 130e133 ꢀC.
(2-{4-[1-(1-Methoxycarbonyl-ethyl-carbamoyl)-vinyl]-phenyl}-
acryloylamino)-propionic acid methyl ester (6f): dH (400 MHz,
CDCl3) 7.45 (s, 4H, C6H4); 6.28 (br s, 2H, NH); 6.10 (br s,
2H, ]CH); 5.72 (br s, 2H, ]CH); 4.70 (quintet, 7.1 Hz, 2H,
NHCH ); 3.75 (s, 6H, OCH3); 1.42 (d, 7.1 Hz, 6H, CHCH3).
dC (100.6 MHz, CDCl3) 167.0; 160.6; 137.6; 130.5; 122.0;
115.9; 46.2; 42.1; 11.9. IR (KBr (cmꢁ1)): 3284 (NH); 1747
(COO); 1647 (CON). MS m/z (rel int. %): 388 (10), 329 (52),
258 (100), 198 (18), 128 (30). Analysis calculated for
C20H24N2O6 (388.42): C, 61.85; H, 6.23; N, 7.21; found: C,
61.75, H, 6.43; N, 7.07; Rf (4% EtOH/CHCl3) 0.56; Rf (50%
EtOAc/CHCl3) 0.44; white solid, mp 111 ꢀC.
(2-{4-[1-(1-Methoxycarbonyl-2-methyl-propyl-carbamoyl)-
vinyl]-phenyl}-acryloylamino)-3-methyl-butyric acid methyl

66
A. Taka´cs et al. / Tetrahedron 64 (2008) 61e66
ꢀ
4. Acs, P.; Muller, E.; Rangits, G.; Lorand, T.; Kollar, L. Tetrahedron 2006,
´ ´
´
¨
62, 12051e12056.
ester (6g): dH (400 MHz, CDCl3) 7.43 (s, 4H, C6H4); 6.21 (br
s, 2H, NH); 6.10 (br s, 2H, ]CH); 5.72 (br s, 2H, ]CH);
4.65 (m, 2H, NHCH ); 3.72 (s, 6H, OCH3); 2.20 (m, 2H,
CH(CH3)2); 1.90 (d, 7.0 Hz, 3H, CH(CH3)); 1.95 (d,
7.0 Hz, 3H, CH(CH3). dC (100.6 MHz, CDCl3) 166.0;
161.0; 137.8; 125.8; 122.0; 115.9; 51.2; 45.9; 24.9; 12.8;
11.6. IR (KBr (cmꢁ1)): 3376 (NH); 1742 (COO); 1655
(CON). MS m/z (rel int. %): 444 (58), 385 (67), 286 (100),
128 (65). Analysis calculated for C24H32N2O6 (444.53): C,
64.85; H, 7.26; N, 6.30; found: C, 64.97, H, 7.41; N, 6.08;
Rf (4% EtOH/CHCl3) 0.58; Rf (50% EtOAc/CHCl3) 0.69;
pale yellow solid, mp 100e102 ꢀC.
1-(2-{4-[1-(2-Methoxycarbonyl-pyrrolidine-1-carbonyl)-vinyl]-
phenyl}-acryloyl)-pyrrolidine-2-carboxylic acid methyl ester (6h):
dH (400 MHz, CDCl3) 7.50 (s, 4H, C6H4); 5.79 (br s, 2H,
]CH); 5.46 (br s, 2H, ]CH); 4.60 (m, 2H, NCH); 3.78 (s,
6H, OCH3); 3.30e3.40 (m, 4H, CH2); 1.80e2.30 (m, 8H,
CH2). dC (100.6 MHz, CDCl3) 166.3; 162.8; 138.6; 129.1;
120.2; 109.0; 52.2; 46.0; 42.3; 23.1; 18.5. IR (KBr (cmꢁ1)):
1744 (COO); 1638 (CON). MS m/z (rel int. %): 440 (1), 253
(17), 128 (100). Analysis calculated for C24H28N2O6
(440.50): C, 65.44; H, 6.41; N, 6.36; found: C, 65.35, H,
6.62; N, 6.16; Rf (4% EtOH/CHCl3) 0.44; yellow solid, mp
147e150 ꢀC.
´
5. Muller, E.; Peczely, G.; Skoda-Foldes, R.; Takacs, E.; Kokotos, G.; Bellis,
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¨
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