Homogeneous catalytic aminocarbonylation of iodoalkenes and iodobenzene with amino acid esters under conventional conditions and in ionic liquids

Article abstract of DOI:10.1016/j.tet.2004.11.064

Amino acid methyl esters were used as amine nucleophiles in palladium catalysed aminocarbonylation of iodobenzene and iodoalkenes (1-iodo-cyclohexene and 17-iodo-androst-16-ene). 2-Oxo-carboxamide type derivatives can be isolated as a result of double CO insertion by using iodobenzene as a substrate at elevated carbon monoxide pressure. On the contrary, carboxamides of expected structure were obtained exclusively in excellent yields in the whole pressure range by using iodoalkenes. The aminocarbonylation of 17-iodo-androst-16-ene in [bmim][PF₆] or [bmim][BF₄] (where bmim=1-butyl-3-methyl- imidazolium cation) ionic liquids was also carried out and the ionic liquid-catalyst mixtures have been reused several times with only a small loss of activity.

Full text of DOI:10.1016/j.tet.2004.11.064

Tetrahedron 61 (2005) 797–802
Homogeneous catalytic aminocarbonylation of iodoalkenes and
iodobenzene with amino acid esters under conventional conditions
and in ionic liquids
a
a
b,c
b,c
Erno Mu¨ller, Gabor Peczely, Rita Skoda-Foldes, Eszter Takacs, George Kokotos,d
˝
´
´
´
*
¨
Evagelos Bellis and Laszlo Kollar
d
a,e,
´
´
´
a
´ ´
Department of Inorganic Chemistry, University of Pecs, PO Box 266, H-7624 Pecs, Hungary
b
´ ´
Department of Organic Chemistry, University of Veszprem, H-8200 Veszprem, Hungary
c
´
Research Group for Petrochemistry of the Hungarian Academy of Sciences, PO Box 158, H-8201 Veszprem, Hungary
dLaboratory of Organic Chemistry, University of Athens, 15771 Athens, Greece
e
´
Research Group for Chemical Sensors of the Hungarian Academy of Sciences, H-7624 Pecs, Hungary
Received 22 September 2004; revised 2 November 2004; accepted 25 November 2004
Available online 8 December 2004
Abstract—Amino acid methyl esters were used as amine nucleophiles in palladium catalysed aminocarbonylation of iodobenzene and
iodoalkenes (1-iodo-cyclohexene and 17-iodo-androst-16-ene). 2-Oxo-carboxamide type derivatives can be isolated as a result of double CO
insertion by using iodobenzene as a substrate at elevated carbon monoxide pressure. On the contrary, carboxamides of expected structure
were obtained exclusively in excellent yields in the whole pressure range by using iodoalkenes. The aminocarbonylation of 17-iodo-androst-
16-ene in [bmim][PF6] or [bmim][BF4] (where bmimZ1-butyl-3-methyl-imidazolium cation) ionic liquids was also carried out and the ionic
liquid–catalyst mixtures have been reused several times with only a small loss of activity.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
reasons: (i) amino acid derivatives or (oligo)peptides can be
marked at the N-termini by the desired aromatic (or alkenyl)
groups and (ii) skeletons of practical importance can be
functionalized by amino acids protected at the carboxyl
termini.
Palladium-catalysed carbonylation reactions including
amino- and alkoxycarbonylation and carbonylative
coupling reactions are widely used in synthetic chemistry.1
There are a number of applications concerning the synthesis
of simple building blocks and the functionalization of
biologically important skeletons.2 Aminocarbonylation
plays a special role among these reactions, since those
carboxamides which are hardly available via the carboxylic
acid–carboxylic halide–carboxamide route (e.g., with bulky
substituents at the amide nitrogen) can be synthesised from
easily available starting materials. The synthesis of
unsaturated carboxamides or aryl carboxamides with
various structures has been published using enol-triflates/
iodo-alkenes or aryl triflates/aryl halides as substrates in
aminocarbonylation, respectively.3
Although homogeneous carbonylation reactions may serve
as an attractive tool in organic synthesis, there are serious
difficulties in product separation and catalyst recovery.
Among the methods (the use of various two-phase systems,4
supported catalysts,5 aqueous/organic media,6 and alterna-
tive solvents like supercritical fluids,7 fluorous solvents8)
aiming at the reduction of these problems, ionic liquid
catalysis plays an important role.9 Homogeneous catalysis
carried out in ionic liquids drew particular attention in the
last few years and several examples for various palladium
catalysed reactions carried out in ionic liquids have been
published. However, there are only some sporadic results
for the palladium catalysed aminocarbonylation of organic
halides in ionic liquids.10
The application of amino acid esters as N-nucleophiles in
aminocarbonylation could be of great importance for two
Keywords: Aminocarbonylation; Carbon monoxide; Amino acid; Palla-
dium; Ionic liquid.
* Corresponding author. Tel.: C36 72503600; fax: C36 72501518;
e-mail: kollar@ttk.pte.hu
Although the N-acylation of amino acids is widely used in
synthetic chemistry, to the best of our knowledge, there is
only one example for the use of homogeneous
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.11.064

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E. Muller et al. / Tetrahedron 61 (2005) 797–802
798
aminocarbonylation of enol triflates by aminoacid deriva-
tives as a tool for the introduction of a carboxamide
moiety.11 (This reaction was carried out using a slight
excess of the C-protected amino acid as nucleophile, at 3 bar
CO pressure (40 psi) at room temperature resulting in the
products in 45–78% yields after 2 days). We found
recently,12 that homogeneous catalytic aminocarbonylation
of steroidal substrates can be effectively carried out in ionic
liquids as solvents even at atmospheric CO pressure using
various palladium–phosphine catalytic systems.
86% yields after column chromatography (see Section 4).
However, iodobenzene (1) shows a rather poor reactivity
towards amino acid derivatives under the same reaction
conditions. (Carbonylation products have only been
obtained in traces (!1%) except for 1a which was formed
in 20% yield). The isolation of the corresponding N-benzoyl
amino acids (1a–1f) as pure compounds failed.
Under increased carbon monoxide pressure (10–40 bar) 2-
oxo-carboxamides (1a0–1d0) have been obtained in
excellent yields from iodobenzene (1). The formation of
2-oxo-carboxamides is accompanied by the formation of
simple carboxamides (1a–1f) in surprisingly low amounts
(less than 5%, if any detectable amount). It should be noted
that 2-oxoamides present very interesting biological proper-
ties. For example, various lipophilic 2-oxoamides are potent
inhibitors of digestive lipases14–16 and phospholipases A2.17
Most recently it has been reported that 2-oxoamides based
on g-aminoacids inhibit Group VIA phospholipase A2 and
exhibit interesting in vivo anti-inflammatory and analgesic
activity.18 Carrying out the carbonylation reaction with the
iodovinyl substrates (2 and 3) under same reaction
conditions, the corresponding double-carbonylation
products (2a0–2d0) were absent even at 40 bar carbon
monoxide pressure.
Encouraged by the increasing importance of the selective
synthesis of amino acid derivatives, we decided to
investigate the possibility of extending the scope of this
method to iodo-aryl/iodo-alkenyl substrates. Accordingly,
the high-yielding aminocarbonylation of iodo-benzene,
1-iodo-cyclohexene and 17-iodo-androst-16-ene with
amino acid methyl esters of different types is published in
the present paper.
2. Results and discussion
2.1. Aminocarbonylation in conventional organic
solvents
Although the formation of 2-oxo-carboxamide can be
explained in two ways, namely both the ‘glyoxyl-route’
and the ‘acyl-aminocarbonyl-route’ can be operative,
detailed mechanistic studies revealed that the latter is
responsible for the formation of double-carbonylation.19,20
This way, the iodo-substrates are oxidatively added to in situ
formed palladium(0) complexes. Carbon monoxide is
coordinated to palladium and its insertion to Pd–C bond
takes place. While benzoyl-palladium complexes might
form the corresponding benzoyl-aminocarbonyl complex
which leads to keto-carboxamides (1a0–f0) by reductive
elimination, the alkenoyl-palladium species react directly
with the amine nucleophile providing the corresponding
carboxamide (2a–2f and 3a–3f).
Iodo-benzene (1), 1-iodo-cyclohexene (2) and 17-iodo-
androst-16-ene (3) were reacted with methyl glycinate (a),
methyl alaninate (b), methyl phenylalaninate (c), methyl
valinate (d), methyl 4-amino-4-benzyl-butanoate (e) and
methyl N-alaninoyl-prolinate (f) under atmospheric carbon
monoxide in the presence of in situ generated palladium(0)-
triphenylphosphine catalysts (Scheme 1). Palladium(II)
acetate was used as catalytic precursor. (The formation of
Pd(0) species from the generally used Pd(OAc)2–PPh3
system has been proved by cyclic voltammetry and 31P
NMR.13 The reduction of Pd(II) to Pd(0) is due to PPh3,
which is itself oxidised to triphenylphosphine oxide).
The reactivities of the two types of substrates, that of
iodobenzene (1) and iodo-alkenes (1-iodo-cyclohexene (2)
and 17-iodo-androst-16-ene (3)) are markedly different. The
formation of the expected amides was observed both with 2
and 3 under atmospheric carbon monoxide at 50 8C in DMF.
The resulting amides (2a–2f, 3a–3f) have been obtained
with practically complete conversion and isolated in 70–
It is worth noting, that the good reactivity of the substrates
with iodo-alkene functionality and the easy work-up of the
reaction mixtures make these derivatives suitable for any
functionalization. The use of iodo-alkenes as synthetic
substitutes for the corresponding enol-triflates is supported
Scheme 1. Reaction of iodo-benzene (1) and iodo-alkenes (2 and 3) with amino acid derivatives under carbonylation conditions.

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E. Muller et al. / Tetrahedron 61 (2005) 797–802
799
not only by green chemistry principles but also their
advantageous synthetic properties as substrates in homo-
geneous catalytic reactions. The advantageous use of
steroidal substrates with 17-iodo-16-ene functionality has
been proved in a variety of palladium-catalysed homo-
geneous reactions.21
be mentioned that using this phosphine no leaching of the
ligand into the extract was observed.
3. Conclusions
Palladium catalysed aminocarbonylation proved to be an
efficient method for the functionalization of iodobenzene
and iodoalkenes using amino acid methyl esters as amine
nucleophiles. The reactivity of the two types of substrates
differs substantially. 2-Oxo-carboxamide type derivatives
have been isolated as a result of double CO insertion by
using iodobenzene, while carboxamides were obtained
exclusively in excellent yields in the whole pressure range
using iodoalkenes. 17-Iodo-androst-16-ene was success-
fully carbonylated in [bmim][PF6] or [bmim][BF4] ionic
liquids and the ionic liquid–catalyst mixtures have been
reused several times with only a small loss of activity.
2.2. Aminocarbonylation of 3 in ionic liquids
As products obtained with homogeneous catalytic trans-
formations of steroidal substrates cannot be separated by
distillation, several repetitive chromatographic separations
are needed for the complete removal of the catalyst, which is
essential for compounds of pharmaceutical interest.
Recently, we have found12 that the palladium-content of the
crude steroidal product could be decreased by the use of
ionic liquids as solvents during aminocarbonylation of
steroidal 17-iodo-16-ene derivatives with morpholine as the
nucleophile. The ionic liquid–catalyst mixture could be
reused several times with only a small loss of activity.
4. Experimental
4.1. General procedures
A similar method was effectively used for the model
aminocarbonylation of 3 with methyl glycinate as the
nucleophile (Table 1). The steroidal substrate was reacted
with methyl glycinate in the presence of a palladium catalyst
and Et3N in carbon monoxide atmosphere at 100 8C. The
product could be extracted with toluene together with the
unreacted starting material.
1H and 13C NMR spectra were recorded in CDCl3 on a
Varian Inova 400 spectrometer at 400.13 and 100.62 MHz,
respectively. Chemical shifts d are reported in ppm relative
to CHCl3 (7.26 and 77.00 ppm for 1H and 13C, respectively).
Elemental analyses were measured on a 1108 Carlo Erba
apparatus.
Based on our previous results, [bmim]C[PF6]K and
[bmim]C[BF4]K ionic liquids were used as solvents and
in situ formed palladium complexes as catalysts derived
from Pd(OAc)2CnPPh3 or Pd(OAc)2CnDPPBA (DPPBA:
4-(diphenylphosphino)benzoic acid) precursors. A rela-
tively high phosphine/palladium ratio was essential for the
efficient re-circulation of the catalyst, so the reactions were
carried out at 6, 8 or 10 P/Pd ratios.
Samples of the catalytic reactions were analysed with a
Hewlett Packard 5830A gas chromatograph fitted with a
capillary column coated with OV-1.
4.2. 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
substrate (1, 2 or 3), 0.65 mmol amino acid methyl ester (a,
b, c, d, e or f) were dissolved in 10 ml DMF (10 ml) under
argon. Triethylamine (0.5 ml) was added to the homo-
geneous yellow solution and the atmosphere was changed to
carbon monoxide. The colour changed to dark red. The
reaction was conducted for 6 h at 50 8C. Some metallic
palladium was formed at the end of the reaction which was
filtered. (A sample of this solution was immediately
analysed by GC–MS.) The mixture was then concentrated
Although the reuse of the ionic liquid–catalyst mixture
seems to be less effective here compared to the amino-
carbonylation with morpholine, the same effects of the
modification of the reaction conditions on the conversion
were observed. The ionic liquid [bmim]C[BF4]K was found
to be superior to [bmim]C[PF6]K. The increase in the ratio
of PPh3 to palladium led to lower conversion (compare
entries 1, 3, 4 in Table 1). The best results were obtained
with the Pd(OAc)2C10DPPBA catalytic system. It should
Table 1. Carbonylation of 17-iodo-5a-androst-16-ene in the presence of methyl glycinate using Pd(OAc)2Cphosphine in situ catalysts in ionic liquidsa
Entry
Solvent
Phosphine
P/Pd
Conversion (%)
Run 3
Run 1
Run 2
Run 4
Run 5
1
2
3
4
5
6
7
8
[bmim]C[PF6]K
[bmim]C[BF4]K
[bmim]C[PF6]K
[bmim]C[PF6]K
[bmim]C[PF6]K
[bmim]C[BF4]K
[bmim]C[PF6]K
[bmim]C[BF4]K
PPh3
PPh3
PPh3
PPh3
DPPBA
DPPBA
DPPBA
DPPBA
6
6
8
10
6
6
10
10
99
100
93
98
100
90
83
76
88
92
98
78
62
58
87
86
98
70
74
57
54
—
83
55
88
52
55
—
—
—
64
85
100
100
100
100
100
100
70
a Reaction conditions: ionic liquid (600 mg), 1 (0.2 mmol), Pd(OAc)2 (0.01 mmol), the phosphine (as indicated), Et3N (0.15 ml) and methyl glycinate
hydrochloride (0.4 mmol) were heated in CO atmosphere for 8 h at 100 8C.

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E. Muller et al. / Tetrahedron 61 (2005) 797–802
800
and evaporated to dryness. The residue was dissolved in
chloroform (20 ml) and washed with water (20 ml). The
organic 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, than
chloroform/ethanolZ1/1) yielded the desired compounds
as yellow solids.
C12H13NO4 (235.24): C, 61.27; H, 5.57; N, 5.95; Found:
C, 61.42, H, 5.79; N, 5.68. Yield: 74%.
4.5.5. Methyl N-(phenylglyoxyl)-phenylalaninate (1c0).
1H NMR (CDCl3) d: 8.23 (d, JZ7.6 Hz, 2H, Ph); 7.58 (t,
JZ8.0 Hz, 1H, Ph); 7.44 (t, JZ8.0 Hz; 2H, Ph); 7.27 (m,
4H, Ph); 7.15 (d, JZ6.8 Hz, 2H, Ph); 4.93 (dq; JZ6.4,
2.4 Hz, 1H, NHCH); 3.74 (s, 3H, OCH3); 3.23 (dd, JZ11.5;
5.2 Hz, 1H, CHaHb); 3.15 (dd, JZ11.5, 5.6 Hz, 1H,
CHaHb). 13C NMR (CDCl3) d: 186.9; 171.0; 161.2; 135.4;
134.5; 133.1; 131.1; 129.2; 128.7; 128.5; 127.3; 53.3; 52.5;
38.0. MS m/z (rel. int. %): 311 (2) (MC), 206 (8), 178 (12),
162 (22), 146 (19), 105 (100), 81 (33), 51 (28). Anal. calcd
for C18H17NO4 (311.34): C, 69.44; H, 5.50; N, 4.50; Found:
C, 69.65, H, 5.67; N, 4.31. Yield: 82%.
4.3. Aminocarbonylation experiments at high pressure
The DMF solution of the catalyst precursor and reactants
(amounts given in Section 4.2) was transferred under argon
into a 100 ml stainless steel autoclave. The reaction vessel
was pressurised up to 40 bar total pressure with carbon
monoxide and the magnetically stirred mixture was heated
in an oil bath at 50 8C for 6 h. The work-up procedure is
identical with that given above.
1
4.5.6. Methyl N-(phenylglyoxyl)-valinate (1d0). H NMR
(CDCl3) d: 8.30 (d, JZ8.0 Hz, 2H, Ph); 7.60 (m, 1H, Ph);
7.4 (m, 3H, Ph CNH); 4.59 (dd, JZ5.2, 9.2 Hz, 1H, CH);
2.27 (dh, JZ6.4; 5.2 Hz; 1H, CH(CH3)2); 0.99 (d, JZ
6.4 Hz, 3H, CH3); 0.96 (d, JZ6.4 Hz; 3H, CH3). 13C NMR
(CDCl3) d: 187.0; 171.4; 161.5; 134.4; 133.2; 131.2; 128.5;
57.3; 52.3; 31.4; 19.0; 17.8. IR (KBr, (cmK1)): 3390 (NH);
1745 (COO); 1684 (amide-I), 1668 (n (CO). MS m/z (rel. int.
%): 263 (10) (MC), 204 (8), 158 (18), 130 (57), 105 (100),
77 (45). Anal. calcd for C14H17NO4 (263.29): C, 63.87; H,
6.51; N, 5.32; Found: C, 63.71, H, 6.68; N, 5.10. Yield:
74%.
4.4. Aminocarbonylation in ionic liquid
In
a typical procedure, 17-iodo-5a-androst-16-ene
(0.2 mmol), Pd(OAc)2 (0.01 mmol), PPh3 (0.02 mmol),
methyl glycinate (0.4 mmol) and [bmim]C[PF6]K or
[bmim]C[BF4]K (600 mg) were placed in a Schlenk-tube
equipped with a magnetic stirrer, a septum inlet and a reflux
condenser with a balloon on the top. This was placed under
carbon monoxide, and Et3N (0.15 ml) was added. The
reaction mixture was heated at 100 8C for 8 h. The mixture
was extracted twice with 0.4 ml toluene. The extracts were
analysed by GC. Any volatiles were removed from the ionic
liquid in vacuo and new load of starting materials (steroid,
Et3N and methyl glycinate) for the next catalytic run were
added to the ionic liquid/catalyst mixture and the atmos-
phere was changed to carbon monoxide. The consecutive
runs were conducted for the same reaction time.
4.5.7. Methyl N-(phenylglyoxyl)-4-amino-4-benzyl-
butanoate (1e0). 1H NMR (CDCl3) d: 8.2 (d, JZ8 Hz,
2H, Ph(ortho)); 7.60 (t, 1H, Ph(para)); 7.4 (t, 2H, Ph(meta));
7.15–7.30 (m, 5H, Ph); 6.9 (brs, 1H, NH); 4.30 (m, 1H, CH);
3.63 (s, 3H, OCH3); 2.87 (d, JZ6.8 Hz; CH2); 2.40 (m, 2H,
CH2); 2.00 (m, 1H, CHaHb); 1.80 (m, 1H, CHaHb). 13C
NMR (CDCl3) d: 183.0; 173.6; 161.6; 137.1; 134.4; 133.3;
131.1; 129.4; 128.6; 128.5; 126.8; 51.8; 50.4; 41.3; 30.9;
29.1. IR (KBr, (cmK1)): 3380 (NH); 1720 (COO); 1688
(CON), 1660 (CO). MS m/z (rel. int. %): 339 (3) (MC), 248
(22), 117 (27), 105 (100), 91 (31), 77 (43). Anal. calcd for
C20H21NO4 (339.39): C, 70.78; H, 6.24; N, 4.13; Found: C,
70.94, H, 6.50; N, 3.88. Yield: 77%.
4.5. Characterization of the products
4.5.1. Methyl N-(benzoyl)-glycinate (1a). MS m/z (rel. int.
%): 193 (9) (MC), 161 (5), 134 (18), 105 (100), 77 (35).
4.5.2. Methyl N-(phenylglyoxyl)-glycinate (1a0). 1H NMR
(CDCl3) d: 8.31 (d, JZ8.4 Hz, 2H; Ph); 7.61 (t, JZ7.6 Hz,
1H, Ph); 7.46 (m, 2H, Ph); 4.16 (d, JZ5.6 Hz, 2H); 3.78 (s,
3H, OCH3). 13C NMR (CDCl3) d: 186.8; 169.3; 161.8;
134.5; 133.1; 131.2; 128.5; 52.5; 41.1. IR (KBr, (cmK1)):
3370 (NH); 1753 (COO); 1670 (CON). MS m/z (rel. int. %):
221 (7), 207 (6), 116 (18), 105 (100), 77 (42). Anal. calcd
for C11H11NO4 (221.21): C, 59.73; H, 5.01; N, 6.33; Found:
C, 59.92, H, 5.12; N, 6.50. Yield: 79%.
4.5.8. Methyl N-(1-cyclohexenoyl)glycinate (2a). 1H NMR
(CDCl3) d: 6.67 (brs, 1H; ]CH); 6.18 (brs, 1H, NH); 4.07
(d, JZ5.2 Hz, 1H, NHCH2); 3.74 (s, 3H, OCH3); 2.24 (m,
2H, CH2); 2.14 (m, 2H, CH2); 1.68 (m, 2H, CH2); 1.58 (m,
2H, CH2). 13C NMR (CDCl3) d: 170.7; 168.5; 134.5; 132.5;
52.3; 41.3; 25.4; 24.1; 22.1; 21.5. IR (KBr, (cmK1)): 3435
(NH); 1742 (COO); 1670 (CON); 1625 (C]C). MS m/z
(rel. int. %): 197 (30) (MC), 165 (4), 138 (11), 109 (100), 81
(61), 53 (13). Anal. calcd for C10H15NO3 (197.23): C,
60.90; H, 7.67; N, 7.10; Found: C, 61.05, H, 7.86; N, 7.35.
Yield: 75%.
4.5.3. Methyl N-(benzoyl)-alaninate (1b). MS m/z (rel. int.
%): 207 (3) (MC), 148 (45), 105 (100), 77/25.
4.5.4. Methyl N-(phenylglyoxyl)-alaninate (1b0). 1H NMR
(CDCl3) d: 7.3–7.7 (m, 5H); 6.27 (brs, 1H, NH); 4.59
(quint., 1H, 7.2 Hz, CHCH3); 3.70 (s, 3H, OCH3); 1.31 (d,
JZ7.2 Hz, 3H, CHCH3). 13C NMR (CDCl3) d: 187.0;
172.4; 161.2; 134.4; 132.1; 131.1; 128.5; 52.6; 48.1; 18.0.
IR (KBr, (cmK1)): 3380 (NH); 1725 (COO); 1645 (CON).
MS m/z (rel. int. %): 235 (1) (MC), 204 (1), 176 (4), 130
(44), 105 (100), 102 (25), 77 (32). Anal. calcd for
4.5.9. Methyl N-(1-cyclohexenoyl)-alaninate (2b). 1H
NMR (CDCl3) d: 6.60 (brs, 1H; ]CH); 6.27 (brs, 1H,
NH); 4.57 (quint., 1H, JZ7.2 Hz, CHCH3); 3.68 (s, 3H,
OCH3); 2.18 (brs, 2H, CH2); 2.09 (m, 2H, CH2); 1.62 (m,
2H, CH2); 1.58 (m, 2H, CH2); 1.35 (d, JZ7.2 Hz, 3H,
CHCH3). 13C NMR (CDCl3) d: 173.7; 167.8; 134.0; 132.6;
52.2; 47.9; 25.2; 24.0; 21.9; 21.4; 18.3. IR (KBr, (cmK1)):
3405,3425 (NH); 1738 (COO); 1672 (CON); 1628 (C]C).

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E. Muller et al. / Tetrahedron 61 (2005) 797–802
801
MS m/z (rel. int. %): 211 (12) (MC), 152 (35), 109 (100), 81
(36), 79 (23). Anal. calcd for C11H17NO3 (211.26): C,
62.54; H, 8.11; N, 6.63; Found: C, 62.76, H, 8.34; N, 6.47.
Yield: 78%.
1.95 (dd, JZ12.0, 8.0 Hz, 1H, 15-CHaHb); 0.69–1.67 (m,
19H, ring protons); 0.96 (s, 3H, 18-CH3); 0.79 (m, 3H, 19-
CH3). 13C NMR (CDCl3) d: 170.7; 165.8; 149.9; 137.1;
56.8; 55.1; 52.3; 47.2; 46.5; 41.0; 8.4; 36.4; 35.0; 33.8; 31.9;
31.6; 29.0; 28.9; 26.8; 22.1; 20.7; 16.5; 12.1. MS m/z (rel.
int. %): 373 (18) (MC), 358 (25), 285 (12), 257 (100), 161
(26), 147 (28), 121 (32), 105 (39), 91 (39), 67 (35), 55 (26).
IR: 3325 (NH); 1736 (CO); 1642 (CO). Anal. calcd for
C23H35NO3 (373.54): C, 73.96; H, 9.44; N, 3.75; Found: C,
74.05, H, 9.63; N, 3.92. Yield: 88%.
4.5.10. Methyl N-(1-cyclohexenoyl)-phenylalaninate (2c).
1H NMR (CDCl3) d: 7.2 (m, 5H, Ph); 6.54 (brs, 1H, ]CH);
6.17 (d, JZ7.2 Hz, 1H, NH); 4.86 (dt, JZ7.2 Hz, 1H,
CHCH2); 3.64 (s, 3H, OCH3); 3.09 (m, 2H, CH2Ph); 2.07
(m, 4H, CH2CH2); 1.58 (m, 2H, CH2); 1.51 (m, 2H, CH2).
13C NMR (CDCl3) d: 172.0; 167.7; 135.9; 134.0; 132.5;
129.1; 128.3; 126.8; 52.9; 51.9; 37.6; 25.1; 23.8; 21.8; 21.2.
IR (KBr, (cmK1)): 3431 (NH); 1754 (COO); 1681 (CON);
1638 (C]C). MS m/z (rel. int. %): 287 (4) (MC), 228 (4),
162 (38), 109 (100), 91 (18), 81 (35), 79 (23). Anal. calcd
for C17H21NO3 (287.36): C, 71.06; H, 7.37; N, 4.87; Found:
C, 71.28, H, 7.25; N, 4.59. Yield: 81%.
4.5.15. Methyl N-(17-androst-16-enoyl)-alaninate (3b).
1H NMR (CDCl3) d: 6.30 (brs, 2H; 16-HCNH); 4.52
(quint., 1H, JZ7.1 Hz, CHCH3); 3.63 (s, 3H, OCH3); 2.05
(m, 1H, 15-CHaHb); 1.85 (m, 1H, 15-CHaHb); 1.35 (d, JZ
7.1 Hz, 3H, CHCH3); 0.8–1.60 (m, 22H, steroidal skeleton);
0.86 (s. 3H, 18-CH3); 0.70 (s. 3H, 19-CH3). 13C NMR
(CDCl3) d: 173.6; 165.1; 149.8; 136.6; 56.6; 55.0; 52.2;
47.5; 47.0; 46.3; 38.3; 36.3; 34.8; 33.6; 31.7; 31.4; 28.8;
28.7; 26.6; 21.9; 20.5; 18.3; 16.3; 12.0. IR (KBr, (cmK1)):
3445 (NH); 1753 (COO); 1680 (CON); 1602 (C]C). MS
m/z (rel. int. %): 387 (80) (MC), 355 (92), 254 (90), 192
(100), 161 (41), 126 (92). Anal. calcd for C24H37NO3
(387.56): C, 74.38; H, 9.62; N, 3.61; Found: C, 74.56, H,
9.40; N, 3.39. Yield: 78%.
4.5.11. Methyl N-(1-cyclohexenoyl)-valinate (2d). 1H
NMR (CDCl3) d: 6.59 (brs, 1H, ]CH); 6.13 (d, JZ
8.4 Hz, 1H, NH); 4.54 (dd, JZ8.4, 5.2 Hz, NHCH); 3.66 (s,
3H, OCH3); 2.20 (m, 1H, CH(CH3)2); 0.88 (d, JZ6.8 Hz,
3H, CH3); 0.85 (d, JZ6.8 Hz; 3H, CH3); 13C NMR (CDCl3)
d: 172.6; 168.2; 133.8; 132.9; 56.8; 51.9; 31.3; 25.2; 24.1;
21.9; 21.4; 18.8; 17.8. IR (KBr, (cmK1)): 3425 (NH); 1742
(COO); 1670 (CON); 1621 (C]C). MS m/z (rel. int. %):
239 (3) (MC), 180 (14), 109 (100), 81 (40), 79 (36). Anal.
calcd for C13H21NO3 (239.31): C, 65.25; H, 8.84; N, 5.85;
Found: C, 65.47, H, 9.05; N, 5.70. Yield: 79%.
4.5.16. Methyl N-(17-androst-16-enoyl)-phenylalaninate
(3c). H NMR (CDCl3) d: 7.40 (m, 1H, Ph); 7.23 (m, 1H,
1
Ph); 7.10 (m, 1H, Ph); 6.31 (brs, 1H, 16-H); 6.05 (d, JZ
7.8 Hz, 1H, NH); 4.92 (q, JZ7.0 Hz, 1H, NHCH); 3.70 (s,
3H, OCH3); 3.1 (m, 2H, CH2Ph); 2.2 (m, 1H, 15-CHaHb);
1.95 (m, 1H, 15-CHaHb); 0.8–1.65 (m, 22H, steroidal
skeleton); 0.94 (s. 3H, 18-CH3); 0.80 (s. 3H, 19-CH3). 13C
NMR (CDCl3) d: 171.9; 165.0; 149.8; 136.8; 135.8; 129.1;
128.1; 126.8; 56.5; 54.9; 52.6; 52.0; 47.0; 46.2; 38.2; 37.6;
36.2; 34.7; 33.5; 31.7; 31.4; 28.8; 28.7; 26.5; 21.9; 20.4;
16.2; 11.9. IR (KBr, (cmK1)): 3420 (NH); 1748 (COO);
1667 (CON); 1601 (C]C). Anal. calcd for C30H41NO3
(463.66): C, 77.71; H, 8.91; N, 3.02; Found: C, 77.93, H,
8.70; N, 3.27. Yield: 83%.
4.5.12. Methyl N-(1-cyclohexenoyl)-4-amino-4-benzyl-
1
butanoate (2e). H NMR (CDCl3) d: 7.27 (d, JZ7.2 Hz;
2H, Ph); 7.2 (m, 3H, Ph); 6.52 (brs, 1H, ]CH); 5.6 (br d,
JZ7.0 Hz; 1H, NH); 4.22 (m, 1H, CHCH2); 3.63 (s, 3H,
OCH3); 2.9 (m, 1H, CHaHb); 2.7 (m, 1H, CHaHb); 2.35 (m,
4H, 2!CH2); 2.13 (m, 4H, CH2CH2); 1.65 (m, 2H, CH2);
1.57 (m, 2H, CH2). 13C NMR (CDCl3) d: 174.1; 168.0;
138.0, 133.2, 132.9, 129.3, 128.2, 126.3, 51.4; 49.9, 41.0;
30.8; 28.5; 25.1; 24.0; 21.9; 21.3. IR (KBr, (cmK1)): 3423
(NH); 1734 (COO); 1672 (CON); 1625 (C]C). MS m/z
(rel. int. %): 315 (1) (MC), 224 (25), 109 (100), 98 (37), 247
(29), 91 (12), 81 (26). Anal. calcd for C19H25NO3 (315.41):
C, 72.35; H, 7.99; N, 4.44; Found: C, 72.62; H, 8.20; N,
4.24. Yield: 69%.
4.5.17. Methyl N-(17-androst-16-enoyl)-valinate (3d). 1H
NMR (CDCl3) d: 6.4 (brs, 1H, 16-H); 6.14 (d, JZ8.4 Hz,
1H, NH); 4.55 (m, 1H, NHCH); 3.65 (s, 3H, OCH3); 2.02–
2.15 (m, 2H, 15-CHaHbCCH (CH3)2); 1.95 (dd, JZ11.0,
8.2 Hz, 1H, 15-CHaHb); 0.7–1.6 (m, 22H, steroidal
skeleton); 0.91 (s, 3H, 18-CH3); 0.84 (d, JZ6.4 Hz, 3H,
CH3); 0.83 (d, JZ6.4 Hz; 3H, CH3); 0.74 (s, 3H, 19-CH3).
13C NMR (CDCl3) d: 172.5; 165.5; 150.0; 136.9; 56.6; 56.4;
51.9; 47.1; 46.2; 38.3; 36.3; 34.9; 33.6; 31.7; 31.4; 31.3;
28.8; 28.7; 26.6; 21.9; 20.5; 18.8; 17.7; 16.3; 12.0. IR (KBr,
(cmK1)): 3430 (NH); 1740 (COO); 1676 (CON); 1605
(C]C)). MS m/z (rel. int. %): 415 (12) (MC), 400 (19), 356
(24), 285 (84), 269 (30), 257 (60), 161 (23), 147 (25), 121
(39), 105 (53), 95 (68), 67 (74), 55 (100). Anal. calcd for
C26H41NO3 (415.62): C, 75.14; H, 9.94; N, 3.37; Found: C,
75.29, H, 10.11; N, 3.21. Yield: 80%.
4.5.13. Methyl N-(1-cyclohexenoyl)-N0-alaninoyl-pro-
linate (2f). H NMR (CDCl3) d: 6.70 (brs, 1H, NH); 6.65
1
(brs, 1H, ]CH); 4.80 (qi, JZ6.4 Hz, 1H, CHCH3); 4.52
(dd, JZ8.6, 4.8 Hz, 1H, CHCOO); 3.71 (s, 3H, OCH3); 3.60
(m, 2H, NCH2); 1.95–2.25 (m, 8H, 4!CH2); 1.50–1.70 (m,
4H, 2!CH2); 1.41 (d, JZ6.4 Hz, 3H, CHCH3). 13C NMR
(CDCl3) d: 172.3; 171.7; 167.4; 149.7; 134.3; 58.8; 52.3;
46.9; 46.6; 29.0; 25.4; 25.0; 24.1; 22.1; 21.5; 18.1. IR (KBr,
(cmK1)): 3420 (NH); 1751 (COO); 1665 (CON); 1645
(CON); 1614 (C]C). MS m/z (rel. int. %): 308 (2) (MC),
180 (10), 152 (21), 128 (15), 109 (100), 81 (14). Anal. calcd
for C16H24N2O4 (308.38): C, 62.32; H, 7.84; N, 9.08;
Found: C, 62.45, H, 7.59; N, 9.31. Yield: 80%.
4.5.18. Methyl N-(17-androst-16-enoyl)-4-amino-4-
benzyl-butanoate (3e). H NMR (CDCl3) d: 7.2–7.4 (m,
5H, Ph); 6.18 (brs, 1H, 16-H); 5.50 (brs, 1H, NH); 4.22 (m,
1H, CHCH2Ph); 3.62 (s, 3H, OCH3); 2.8–2.9 (m, 2H, CH2);
2.7 (m, 2H, CH2); 2.16 (m, 1H, 15-CHaHb); 1.92 (m, 1H,
1
4.5.14. Methyl N-(17-androst-16-enoyl)-glycinate (3a).
1H NMR: 6.44 (m, 1H, 16-H); 6.13 (m, 1H, NH); 4.08 (d,
JZ4.9 Hz, 2H, CH2); 3.75 (s, 3H, OCH3); 2.20 (ddd, JZ
12.0, 4.2, 2.8 Hz, 1H, 15-CHaHb); 2.15–2.20 (m, 1H, 5-CH);

¨
E. Muller et al. / Tetrahedron 61 (2005) 797–802
802
Ed.; Encyclopedia of Catalysis; Wiley: London, 2002; Vol. I,
pp 737–805.
15-CHaHb); 0.8–1.65 (m, 22H, steroidal skeleton C
CHCH2); 0.92 (s. 3H, 18-CH3); 0.80 (s. 3H, 19-CH3). 13C
NMR (CDCl3) d: 174.1; 165.9; 150.9; 136.5; 136.1; 135.3;
132.8; 129.5; 128.5; 126.9; 56.5; 55.1; 51.7; 50.3; 47.3;
46.6; 41.1; 38.5; 36.5; 34.9; 33.8; 31.9; 31.6; 28.9; 28.8;
26.8; 22.1; 20.6; 16.5; 12.1. IR (KBr, (cmK1)): 3422 (NH);
1720 (COO); 1665 (CON); 1598 (C]C). Anal. calcd for
C32H45NO3 (491.71): C, 78.17; H, 9.22; N, 2.85; Found: C,
78.26, H, 9.35; N, 2.60. Yield: 67%.
5. Panster, P.; Wieland, S. In Applied Homogeneous Catalysis
with Organometallic Compounds; Cornils, B., Herrmann,
W. A., Eds.; Wiley-VCH: Weinheim, 1996; pp 605–623.
6. Aqueous-Phase Organometallic Catalysis. Concepts and
Applications; Cornils, B., Herrmann, W. A., Eds.; Wiley-
VCH: Weinheim, 1998.
7. Jessop, P. G.; Ikariya, T.; Noyori, R. Chem. Rev. 1999, 99,
475–493.
4.5.19. Methyl N-(17-androst-16-enoyl)-N0-alaninoyl-
prolinate (3f). H NMR (CDCl3) d: 6.71 (d, JZ7.0 Hz,
´
8. (a) Horvath, I. T. Acc. Chem. Res. 1998, 31, 641–650.
Barthel-Rosa, L. P.; Gladysz, J. A. Coord. Chem. Rev. 1999,
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1
NH); 6.40 (s, 1H, 16-H); 4.78 (qi, JZ6.4 Hz, 1H, CH); 4.52
(dd, JZ8.6, 4.8 Hz, 1H, CH); 3.68 (s, 3H, OCH3); 3.60 (m,
2H, CH2); 1.9–2.3 (m, 8H); 1.38 (d, JZ6.4 Hz, CH3); 0.8–
1.65 (m, 20H, steroidal skeleton); 0.92 (s. 3H, 18-CH3); 0.80
(s. 3H, 19-CH3). 13C NMR (CDCl3) d: 172.4; 171.7; 165.0;
150.1; 145.3; 58.7; 56.8; 55.1; 52.2; 47.2; 46.8; 46.4; 38.4;
36.4; 35.0; 33.8; 31.9; 31.5; 29.0; 28.9; 26.8; 24.9; 22.1;
20.7; 18.1; 16.5; 12.1. Anal. calcd for C29H44N2O4 (484.68):
C, 71.87; H, 9.15; N, 5.78; Found: C, 71.67, H, 9.27; N,
5.88. Yield: 77%.
9. (a) Welton, T. Chem. Rev. 1999, 99, 2071–2083. (b) Gordon,
C. M. Appl. Catal. A: Gen. 2001, 222, 101–117. (c)
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Catal. Today 2002, 74, 157–189. (e) Keim, W. Green Chem.
2003, 5, 105–111.
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76–79.
11. Freskos, J. N.; Ripin, D. H.; Reilly, M. L. Tetrahedron Lett.
1993, 34, 255–256.
´ ´ ´
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Acknowledgements
The authors thank the Hungarian Research Fund (OTKA
035047, TS044800), the Hungarian-Greek Intergovern-
mental Cooperation in Science and Technology (TeT GR-
5/2001) and Johnson Matthey for the loan of palladium(II)
acetate.
´ ´
¨
therein. Csakai, Z.; Skoda-Foldes, R.; Kollar, L. Inorg. Chim.
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