Reusable Palladium/Phosphine/Ionic Liquid Systems in Aminocarbonylation
Letters in Organic Chemistry, 2009, Vol. 6, No. 6
451
R
greater in this ionic liquid upon the reuse of the catalyst/ionic
liquid mixture than at optimal P/Pd ratios in [bmim]+[PF6]-.
H2N
COOMe
HCl.
1 + CO +
The results show that the catalyst/ionic liquid systems
should be fine-tuned for each particular aminocarbonylation
reaction when using nucleophiles of diverse structures.
O
H
N
COOMe
EXPERIMENTAL
Pd(OAc)2/phosphine
Et3N, ionic liquid
The ionic liquid [bmim]+[PF6]- was prepared as described
previously [12]. Pd(OAc)2, phosphine ligands, amino acid
esters and [bmim]+[BF4]- were good quality commercial
products and were used as received without further
purification.
R
5 R=Me
6 R=CH2Ph
7 R=(CH2)2SCH3
Catalytic Experiments
Scheme 4. Aminocarbonylation of 17-iodo-5ꢀ-androst-16-ene (1)
In a typical procedure, 17-iodo-5ꢀ-androst-16-ene (0.2
mmol), Pd(OAc)2 (0.01 mmol), the ligand (PPh3 or DPPBA
as indicated in Tables 2 and 3), glycine methyl ester or L-
proline benzyl ester (0.4 mmol) and the ionic liquid (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 100oC 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 amino acid ester) for the
next catalytic run were added to the ionic liquid/catalyst
mixture and the atmosphere was changed to carbon
monoxide. The consecutive runs were conducted for the
same reaction time.
with L-alanine-, L-phenylalanine- and L-methionine methyl esters.
the Pd(OAc)2 + 10 DPPBA catalyst (entry 13) that gives the
best results in this solvent again.
The optimal reaction conditions, the Pd(OAc)2 + 4 PPh3
catalyst precursor and [bmim]+[PF6]- solvent, were applied
successfully in the aminocarbonylation of 1 with methyl
esters of L-alanine, L-phenylalanine and L-methionine
(Scheme 4, Table 4) leading to the steroid-amino acid
conjugates 5, 6 and 7, respectively. The results turned out to
be slightly better in most cases than those obtained before
with either the Pd(OAc)2 + 6 PPh3 /[bmim]+[PF6]- (A) or the
Pd(OAc)2 + 10 DPPBA / [bmim]+[BF4]- (B) systems [11],
where conversions dropped to 92%, 87%, 70% (system A)
and 94%, 88%, 79% (system B) in the third runs of the
reactions of L-Ala-OMe, L-Phe-OMe and L-Met-OMe,
respectively. However, the differences are less marked here
than in the reaction of the secondary amine L-proline benzyl
ester (see Table 3).
Toluene extracts were analysed by gas chromatography
(Hewlett Packard 5890) and occasionally by GC-MS
1
(Hewlett Packard 5971A GC-MSD, HP-1 column) and H
NMR spectroscopy (BRUKER AVANCE 400 spectrometer,
CDCl3 solutions).
CONCLUSIONS
The analytical data of the products corresponded well to
authentic samples of the same compounds [5, 11].
In aminocarbonylation reactions using amino acid esters
as nucleophiles, [bmim]+[PF6]- was proved to be a superior
solvent to [bmim]+[BF4]- in contrast to a similar reaction of
the secondary amine morpholine. In the first ionic liquid,
optimal phosphine/palladium ratio is 4 irrespective of the use
of either PPh3 or the more polar ligand DPPBA. In
[bmim]+[BF4]- the best results can be obtained with the
Pd(OAc)2 + 10 DPPBA system, though the loss of activity is
ACKNOWLEDGEMENTS
The authors thank the Hungarian National Science
Foundation for financial support (OTKA T048391, and
NK71906) R. S.-F. thanks the Hungarian Academy of
Sciences for J. Bolyai fellowship.
Table 4. Carbonylation of 1 with L-alanine-, L-phenylalanine- and L-methionine Methyl Esters Using the Pd(OAc)2 + 4 PPh3
/[bmim]+[PF6]- Systema
Yieldb (%)
Nucleophile
Product
Run 1
100
Run 2
100
100
98
Run 3
97
Run 4
68
Run 5
66
L-Ala-OMe
L-Phe-OMe
L-Met-OMe
5
6
7
100
99
78
76
100
76
65
61
aReaction conditions: [bmim]+[PF6]- (600mg), 1 (0.2mmol), Pd(OAc)2 (0.01mmol), PPh3 (0.04mmol), Et3N (0.15ml), and amino acid ester hydrochloride (0.4 mmol) were heated in
CO atmosphere for 8h at 100°C.
bDetermined by GC as an average of three experiments.