Asymmetric hydrogenation of methyl (Z)-2-acetamido-3-(3,4-dimethoxyphenyl) acrylate catalyzed by Rh complexes with available amidophosphite ligands

Article abstract of DOI:10.1007/s11172-010-0309-7

A convenient express procedure for the preparation of methyl (Z)-2-acetamido-3-(3,4-dimethoxyphenyl)acrylate was developed. Asymmetric hydrogenation of this substrate in the presence of rhodium catalysts involving synthetically available amidophosphite li

Full text of DOI:10.1007/s11172-010-0309-7

Russian Chemical Bulletin, International Edition, Vol. 59, No. 9, pp. 1761—1764, September, 2010
1761
Asymmetric hydrogenation of methyl (Z )ꢀ2ꢀacetamidoꢀ
3ꢀ(3,4ꢀdimethoxyphenyl)acrylate catalyzed by Rh complexes
with available amidophosphite ligands
S. E. Lyubimov, P. V. Petrovskii, E. A. Rastorguev, and V. A. Davankov
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 6471. Eꢀmail: lssp452@mail.ru
A convenient express procedure for the preparation of methyl (Z )ꢀ2ꢀacetamidoꢀ3ꢀ(3,4ꢀ
dimethoxyphenyl)acrylate was developed. Asymmetric hydrogenation of this substrate in the
presence of rhodium catalysts involving synthetically available amidophosphite ligands was
carried out, which is characterized by high enantioselectivity (to 99.5% ee) and complete
conversion. An approach to the selective formation of cationic complexes containing two
ligands of different nature in one coordination sphere of rhodium was suggested.
Key words: amidophosphites, hydrogenation, rhodium, methyl (Z)ꢀ2ꢀacetamidoꢀ3ꢀ(3,4ꢀ
dimethoxyphenyl)acrylate.
Optically active unnatural amino acids are valuable
objects for the use in medicinal chemistry, as well as inꢀ
termediates for the synthesis of a whole series of bioꢀ
logically active compounds.1—6 Reactions of asymmetꢀ
ric metalꢀcomplex hydrogenation is a convenient apꢀ
proach to the preparation of chiral amino acid derivatives,
which is characterized by low loading of catalysts
and using hydrogen as the least expensive reducing agent.7
Further treatment of the obtained products containing
protecting groups, viz., hydrolysis, leads to the target chiral
unnatural amino acids.1,7—11 Interesting objects also
are methoxyꢀsubstituted phenylalanines used as key interꢀ
mediates in the synthesis of proteinase inhibitors, that
opens access to the new agents for cancer therapy.12
In addition, (S)ꢀ3,4ꢀdimethoxyphenylalanine deriꢀ
vative 1 found its application in the synthesis of berꢀ
berine alkaloid, viz., (S)ꢀxylopinine (2),13 it can be also
used for the preparation of antiparkinsonian drug LꢀDOPA
(3, Scheme 1).8,11,14
The most efficient ligands used nowadays in asymmetꢀ
ric hydrogenation are bidentate phosphines.15,16 Comparꢀ
atively recent studies showed that the use of synthetically
available phosphiteꢀtype ligands in asymmetric hydrogeꢀ
nation also allows one to reach high degree of conversion
and enantioselectivity (>99% ee).17,18 Monodentate ligand
L1 is of special interest because of simplicity of its syntheꢀ
sis, availability of starting components, and efficiency in
hydrogenation (see Refs 19—22).
To develop efficient and inexpensive process for the
asymmetric hydrogenation of methyl (Z)ꢀ2ꢀacetamidoꢀ
3ꢀ(3,4ꢀdimethoxyphenyl)acrylate (4) and synthesis of
(S)ꢀ3,4ꢀdimethoxyphenylalanine derivative 1, we have
Scheme 1
i. Four steps.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1714—1717, September, 2010.
1066ꢀ5285/10/5909ꢀ1761 © 2010 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 59, No. 9, September, 2010
Lyubimov et al.
entry 1). Ethyl acetate and acetone lead to the higher
conversion within 2 h, with the enantiomeric excess valꢀ
ues being 60 and 68% ee, respectively. The use of CH2Cl2
as the solvent allowed us to reach 99.5% ee at 50% converꢀ
sion within 2 h. The elevation of temperature from 50 to
70 °C promotes an increase in the rate of the process, with
a small loss in enantioselectivity (see Table 1, entries 4
and 5). An increase in the pressure of H2 to 50 atm allowed
us to quantitatively obtain the product within 140 min and
with 99.3% ee at 50 °C.
To reach the optimum activity of the catalyst, we synꢀ
thesized a cationic rhodium complex 6 (Scheme 3), which
contains amidophosphite ligand L1 and triphenylꢀ
phosphine in the rhodium coordination sphere. The
31Р{H} NMR spectrum of compound 6 exhibits the correꢀ
1
sponding spinꢀspin coupling constants JPPh ,L = 33.5,
3
1
JRhP,L = 243.0, JRhP,PPh = 145.8 Hz and chemical shifts
3
δ 137.0 and 30.5 corresponding to the amidophosphite
and phosphine ligands. The elemental analysis data are in
good agreement with the structure suggested. The use of
Rh "mixed" complexes with one chiral and another achiral
ligand in asymmetric hydrogenation was demonstrated
in a number of works, nevertheless all these complexꢀ
es were formed in situ starting from [Rh(COD)2]BF4
and the corresponding ligands.23—26 In such a method
of preparation, formation of both heterocombination
[(COD)RhL1L2]BF4 and two variants of homocombinaꢀ
tion ([(COD)RhL1L1]BF4 and [(COD)RhL2L2]BF4) is
possible, with the homocombination from achiral ligand
exclusively leading to the racemic product of the asymꢀ
metric reaction.23 Our approach implies formation of only
heterocomplex containing two different ligands. The study
of activity of complex 6 in hydrogenation of substrate 4
showed that in the presence of complex 6, the reaction
rate is higher (see Table 1, entries 7—11) than in the presꢀ
ence of the catalytic system containing two amidophosꢀ
phite ligands (see Table 1, entries 1—6), however, lower
enantioselectivity values were observed when the "mixed"
complex 6 was used. Complex 6 turned out to be rather
sensitive to the reaction conditions. For instance, when
hydrogenation was carried out in acetone at 25 atm of H2
the product was formed with enantiomeric excess 66% ee.
An increase in the pressure of H2 to 50 atm leads to
studied catalytic properties of ligand L1 and its diamiꢀ
dophosphite analog L2.
Results and Discussion
For obtaining methyl (Z)ꢀ2ꢀacetamidoꢀ3ꢀ(3,4ꢀdiꢀ
methoxyphenyl)acrylate (4) (Scheme 2), we developed an
express procedure, which includes reflux of azlactone 5
(see Ref. 8) in methanol. In this case, addition of metallic
sodium in catalytic amount, which forms an active methylꢀ
ate, leads to the instantaneous dissolution of substrate 5
and further spontaneous precipitation of the reaction prodꢀ
uct 4. Subsequent purification leads to the target enamide
4 in 90% yield.
An initial study of the catalytic system, obtained from
[Rh(COD)2]BF4 (COD is the 1,5ꢀcyclooctadiene) and
amidophosphite ligand L1, in the hydrogenation of methꢀ
yl (Z)ꢀ2ꢀacetamidoꢀ3ꢀ(3,4ꢀdimethoxyphenyl)acrylate (4)
was performed in a number of organic solvents (Table 1)
at 50 °C because of poor solubility of the starting enamide 4
at room temperature. When the pressure of H2 was 25 atm,
it was found that in the presence of THF both conversion
and enantioselectivity were rather low (see Table 1,
Scheme 2

2ꢀAcetamidoꢀ3ꢀ(3,4ꢀdimethoxyphenyl)acrylate
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 9, September, 2010
1763
Table 1. Hydrogenation of methyl (Z)ꢀ2ꢀacetamidoꢀ3ꢀ(3,4ꢀdimethoxyphenyl)acrylate (4)
Entry
Catalyst
Solvent
PH /atm
T/°C
t/min
Conversion (%)
ee (%)*
2
1
2
3
4
5
6
7
8
[Rh(COD)2]BF4/2L1
THF
EtOAc
25
25
25
25
25
50
25
25
50
25
50
25
50
50
50
50
50
70
50
50
50
50
50
50
50
50
120
120
120
120
120
140
60
60
50
60
50
18
70
100
50
78
100
98
100
100
80
100
80
11
60
68
99.5
98.5
99.3
40
66
47
50
65
98
98.5
[Rh(COD)2]BF4/2L1
[Rh(COD)2]BF4/2L1
Acetone
CH2Cl2
CH2Cl2
CH2Cl2
EtOAc
Acetone
Acetone
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
[Rh(COD)2]BF4/2L1
[Rh(COD)2]BF4/2L1
[Rh(COD)2]BF4/2L1
6
6
6
6
9
10
11
12
13
6
[Rh(COD)2]BF4/L2
[Rh(COD)2]BF4/L2
120
130
100
* (S)ꢀConfiguration in all the cases.
a decrease in enantioselectivity (see Table 1, entries 8 and
9), with other reaction conditions remaining constant.
Conversely, in CH2Cl2 an increase in the pressure of H2
leads to the increase in the rate of the process, with enanꢀ
tioselectivity being also increased (see Table 1, entries 10
and 11).
two ligands of different nature in one coordination sphere
of rhodium. The studies of "mixed" complex obtained on
the activity in hydrogenation of methyl (Z)ꢀ2ꢀacetamidoꢀ
3ꢀ(3,4ꢀdimethoxyphenyl)acrylate (4) showed that this catꢀ
alyst is able to significantly accelerate the reaction. Alꢀ
though, a very high enantioselectivity was not observed in
the presence of this catalyst, the introduction of achiral
ligands with increased steric requirements, as well as difꢀ
ferent electronic characteristics, can be promising for the
development of optimum catalysts for asymmetric metal
complex catalysis.
Scheme 3
Experimental
31
Р and 1H NMR spectra (161.98, 400.13 MHz) were reꢀ
corded on an Avance 400 spectrometer. Elemental analysis was
performed in the Laboratory of Organic Microanalysis of A. N.
Nesmeyanov Institute of Organoelement Compounds, Russian
Academy of Sciences. Ligands (Rax)ꢀ2ꢀ(8ꢀpiperidinꢀ1ꢀyl)ꢀ(diꢀ
naphtho[2,1ꢀd:1´,2´ꢀf][1,3,2]dioxaphosphepane) (L1) and (Rax)ꢀ
bis[(dinaphtho[2,1ꢀd:1´,2´ꢀf][1,3,2]dioxaphosphepanyl)]ꢀ1,4ꢀ
piperazine (L2), as well as [Rh(COD)2]BF4, were synthesized
according to the known procedures.20,31,32
Synthesis of methyl (Z)ꢀ2ꢀacetamidoꢀ3ꢀ(3,4ꢀdimethoxyꢀ
phenyl)acrylate (4). Metallic sodium (30 mg) was added to
a boiling solution of 4ꢀ(3,4ꢀdimethoxybenzylidene)ꢀ2ꢀmethylꢀ4Hꢀ
oxazolꢀ5ꢀone (5) (5 g) in methanol (70 mL), an immediate disꢀ
solution of azlactone 5 was observed. The solution was refluxed
for 5—10 min resulting in spontaneous precipitation of the reacꢀ
tion product. The mixture obtained was cooled (–10 °C), the
product was filtered off, washed with methanol (15 mL) and
CH2Cl2 (10 mL). Further recrystallization from ethyl acetate
leads to compound 4 as a white powder. The yield was 5.08 g
(90%). Spectral characteristics of 4 agree with the literature data.8
Synthesis of [{1,2:5,6ꢀηꢀ(1,5ꢀcyclooctadiene)}{(Ra)ꢀ2ꢀ(3ꢀpiꢀ
peridinꢀ1ꢀyl)ꢀ(dinaphtho[2,1ꢀd:1´,2´ꢀf][1,3,2]dioxaphospheꢀ
pane}triphenylphosphine]rhodium tetrafluoroborate (6). Ligand
L1 (78 mg, 0.2 mmol) in CH2Cl2 (2 mL) was added to a solution
of [1,2:5,6ꢀηꢀ(1,5ꢀcyclooctadiene)]triphenylphosphinechloroꢀ
We also studied catalytic properties of diamidophosꢀ
phite ligand L2 in CH2Cl2. An increase in the pressure of
hydrogen from 25 to 50 atm favors both the hydrogenation
rate of 4 and enantiomeric excess values for the reaction
product 1 (see Table 1, entries 12 and 13). Since the strucꢀ
ture of ligands L1 and L2 are similar, the enantiomeric
excess values are also similar under the same reaction conꢀ
ditions (Table 1, entries 4, 6 and 12, 13). However, the
hydrogenation rate on diamidophosphite ligand L2 is
somewhat higher.
In conclusion, we have offered a convenient express
procedure for the preparation of methyl (Z)ꢀ2ꢀacetamidoꢀ
3ꢀ(3,4ꢀdimethoxyphenyl)acrylate (4). Using synthetically
available diamidophosphite ligands, a quantitative conꢀ
version and high enantioselectivity (to 99.5% ee) were
reached in the preparation of the compoundꢀprecursor of
valuable biologically active compounds. The known phosꢀ
phine, phosphonite, and amidophosphite ligands used in
this reaction are available by multiꢀstep synthesis.8,27—30
We have also for the first time developed an approach to
the selective formation of cationic complexes containing

1764
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Lyubimov et al.
rhodium33 (100 mg, 0.2 mmol) in CH2Cl2 (5 mL). The mixture
was stirred for 3 min, followed by addition of AgBF4 (38 mg,
0.2 mmol) in THF (4 mL). The solution was additionally stirred
for 40 min, a precipitate of AgCl was filtered off, the solvent was
evaporated in vacuo. The product was purified on silica gel
(chloroform). The yield of compound 6 was 141 mg (75%), an
orange powder m.p. 205—210 °C (with decomp.). Found (%):
C, 63.91; H, 5.24; N, 1.34. C51H49BF4NO2P2Rh. Calculatꢀ
ed (%): C, 63.83; H, 5.15; N, 1.46.
Asymmetric hydrogenation of methyl (Z)ꢀ2ꢀacetamidoꢀ3ꢀ(3,4ꢀ
dimethoxyphenyl)acrylate (general procedure). The compound
[Rh(COD)2]BF4 (2 mg, 0.005 mmol) and ligand (0.005 or
0.01 mmol) or complex 6 (0.005 mmol) were added to the correꢀ
sponding solvent (6 mL). The solution was stirred for 5 min,
followed by addition of methyl (Z)ꢀ2ꢀacetamidoꢀ3ꢀ(3,4ꢀdiꢀ
methoxyphenyl)acrylate 4 (138 mg, 0.5 mmol). An autoclave
was purged with argon, filled with hydrogen to the required presꢀ
sure. The reactor was heated to the corresponding temperature
(10 min), and the experiments were performed by stirring the
reaction mixture. After the reaction was completed, the hydroꢀ
gen was slowly released, the reaction mixture was concentrated.
Conversion of 4 was measured using 1H NMR. Optical yields
were determined by HPLC on a Agilent HPꢀ1100 chromatoꢀ
graph using Chiralcel OJꢀH columns (UV 219 nm, hexane/isoꢀ
propanol = 7/3, 1 mL min–1) according to the recommendaꢀ
tions in the work.28 The retention times for enantiomers of meꢀ
thyl 2ꢀacetamidoꢀ3ꢀ(3,4ꢀdimethoxyphenyl)propionate (1) were
9.3 (R) and 13.5 min (S), for enamide 4, 16.4 min.
11. W. S. Knowles, M. J. Sabacky, B. O. Vineyard, LꢀDopa proꢀ
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Received March 31, 2010;
in revised form June 29, 2010