Enantioselective rhodium-catalyzed hydrogenation of enamides in the presence of chiral monodentate phosphanes

Article abstract of DOI:10.1002/ejoc.200600024

The rhodium-catalyzed asymmetric hydrogenation of different acyclic and cyclic N-acyl enamides to give N-acyl-protected optically active amines has been examined for the first time in detail in the presence of chiral monodentate 4,5-dihydro-3H-dinaphthoph

Full text of DOI:10.1002/ejoc.200600024

FULL PAPER
DOI: 10.1002/ejoc.200600024
Enantioselective Rhodium-Catalyzed Hydrogenation of Enamides in the
Presence of Chiral Monodentate Phosphanes
[a]
[a]
[a]
[a]
Stephan Enthaler, Bernhard Hagemann, Kathrin Junge, Giulia Erre, and
Matthias Beller*[
a]
Keywords: Asymmetric catalysis / Homogeneous catalysis / Hydrogenation / Monodentate phosphane ligands / Enamides
The rhodium-catalyzed asymmetric hydrogenation of dif-
phosphorus atom and the enamide substrate. Applying opti-
ferent acyclic and cyclic N-acyl enamides to give N-acyl-pro- mized conditions up to 95% ee and catalyst activity up to
–
1
tected optically active amines has been examined for the first
time in detail in the presence of chiral monodentate 4,5-dihy-
dro-3H-dinaphthophosphepines 5a–i. The enantioselectivity
is largely dependent on the nature of the substituent at the
2000 h (TOF) have been achieved.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
Introduction
workers. Applying diphosphane rhodium catalysts enantio-
[
4]
selectivity up to 90% has been obtained. Over a period of
nearly 30 years the development of new ligands for asym-
metric hydrogenation has focused on the synthesis of biden-
tate ligands. During this time several effective bidentate
phosphanes such as Me-DuPhos, Me-BPE, DIOP, BINAP
and others were developed for the hydrogenation of en-
The importance of chiral amines is demonstrated by their
broad scope of applications as building blocks and syn-
thons for pharmaceuticals and agrochemicals. In addition,
they are of significant use for the synthesis of natural com-
[
1]
pounds, chiral auxiliaries, and optically active ligands.
Hence, the development of new and improved methods for
the preparation of enantiomerically pure amines is an im-
portant target of industrial and academic research. Several
synthetic approaches to optically active amines have been
established in the past. Still one of the most practical ap-
proaches is the separation of enantiomers through resolu-
tion, e.g. in the presence of chiral acids. The main drawback
of this concept is the poor atom efficiency and the negative
environmental impact. A more attractive access is repre-
sented by applying enantiomerically pure starting materials
from the “chiral pool”. Another powerful strategy is the
application of stereoselective syntheses in particular reac-
tions catalyzed by transition-metal complexes.[ Examples
of such transition-metal-catalyzed reactions, which offer a
versatile and elegant approach to enantiomerically pure
amines, are the alkylation or arylation of imines, hydrocy-
anation of carbon–carbon double bonds and aziridina-
[4,5]
th
amides.
At the end of the 20 century the predominant
role of bidentate ligands changed and monodentate ligands
[6,7]
received more attention.
The advantages of mono-
dentate phosphorus ligands are their easier synthesis and
tunability compared to bidentate phosphanes. Scheme 1 il-
lustrates some examples of monodentate phosphorus li-
gands for asymmetric hydrogenation on the basis of the chi-
ral 1,1Ј-binaphthol skeleton. Important contributions in
this area came independently from Feringa and de Vries et
[8]
[9]
al. (phosphoramidites 1), Reetz et al. (phosphites 2),
[10]
and Pringle and Claver et al. (phosphonites 3). Further-
more, excellent enantioselectivity was shown by Zhou and
2]
co-workers applying monodentate spiro phosphoramidites
[11]
(SIPHOS).
[12]
Following the original work of Gladiali
to Zhang,
and parallel
[13]
we have established the synthesis of various
monodentate phosphanes based on a 4,5-dihydro-3H-di-
[
2c]
tion. However, the most popular catalytic reaction with
respect to industrial applications is the asymmetric hydro-
genation of imines or N-protected enamines and en-
naphtho[2,1-c;1Ј,2Ј-e]phosphepine framework (4 and 5a–i),
[14]
which resembles the 1,1Ј-binaphthol core.
Recently, we
have shown that asymmetric hydrogenation of amino acid
precursors, dimethyl itaconate and β-keto esters proceeds
with enantioselectivities up to 95% ee in the presence of
[
3]
amides.
Pioneering work in the field of enantioselective hydro-
genation of enamides has been reported by Kagan and co-
[13]
ligand 5a. Moreover, other groups demonstrated the use-
fulness of these ligands in several catalytic asymmetric reac-
tions.
To the best of our knowledge there exists only one publi-
cation dealing with the hydrogenation of enamides in the
[
15]
[
a] Leibniz-Institut für Katalyse an der Universität Rostock e.V.,
Albert-Einstein-Str. 29A, 18059 Rostock, Germany
Fax: +49-381-12815000
E-mail: matthias.beller@ifok-rostock.de
2912
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2912–2917

Enantioselective Hydrogenation of Enamides in the Presence of Phosphanes
FULL PAPER
substrate and 4-phenyl-4,5-dihydro-3H-dinaphtho[2,1-
c;1Ј,2Ј-e]phosphepine (5a) as our standard ligand. Typically,
we used an in situ pre-catalytic mixture of 1 mol-%
[
Rh(cod) ]BF and 2.1 mol-% of the corresponding ligand.
2 4
All hydrogenation reactions were carried out in an 8fold
[
18]
parallel reactor array with 3.0 mL reactor volume.
At first, we focused our attention on the influence of
different solvents, such as dichloromethane, methanol, ethyl
acetate, toluene, and also variation of the initial pressure
(1.0 bar, 5.0 bar and 10 bar). Selected results are presented
in Figure 1.
Scheme 1. Chiral monodentate ligands with 2,2Ј-binaphthyl frame-
work.
presence of monodentate phosphepines. Here, Reetz et
al.[ described the rhodium-catalyzed hydrogenation of N-
16]
(1-phenylvinyl)acetamide (6a) with ligands 5a [conversion:
5
9
0%; enantiomeric excess: 14% (R)] and 5i [conversion:
4%; enantiomeric excess: 24% (R)] in dichloromethane. To
our surprise the tert-butyl-substituted ligand 5i showed bet-
ter selectivity and yield than the phenyl-substituted ligand
5a. In our benchmark tests, for instance, in the asymmetric
hydrogenation of amino acid precursors, dimethyl itaconate
and β-keto esters, we always observed the opposite behav-
iour.
Figure 1. Solvent and pressure variation. Reactions were carried
2 4
out at 30 °C for 24 h with 0.0024 mmol [Rh(cod) ]BF , 0.005 mmol
ligand 5a and 0.24 mmol substrate in 2.0 mL solvent. Conversion
and ee values were determined by GC [50 m Lipodex E (Macherey–
Nagel), 80 °C, (R)-7a 26.7 min, (S)-7a 28.3 min]. The absolute con-
figuration was determined by comparing the sign of specific rota-
Discussion
The interesting results of Reetz and co-workers[15] stimu-
lated us to study the potential of our ligand library 5a–i in
[
5i]
tion with reported data and the original sample (Aldrich).
the field of asymmetric hydrogenation of enamides in more
For all solvents best enantioselectivity (80–90% ee) is
detail. In general, the ligands are prepared by metallation of achieved at 1.0 bar, but without complete conversion within
,2Ј-dimethylbinaphthyl with two equiv. of n-butyllithium, reasonable time (24 h). Increasing the pressure of hydrogen
2
followed by quenching with diethylamino(dichloro)phos- to 5.0 bar or 10.0 bar accelerated the reaction and full con-
phane. Deprotection with gaseous HCl produced 4-chloro- version is reached, but at somewhat lower selectivity. The
4,5-dihydro-3H-dinaphtho[2,1-c;1Ј,2Ј-e]phosphepine in
a
results also indicated toluene as the solvent of choice for
yield of 80%. This enantiomerically pure chlorophosphane our model reaction (conversion: 96%; enantioselectivity:
is easily coupled with various Grignard reagents to give a 91%).
broad selection of ligands of type 5.
To find the optimum of the enantioselectivity−pressure
Unsubstituted and substituted N-(1-phenylvinyl)acet- dependency we performed a fine tuning of the hydrogen
amides 6a–6e were obtained by reacting the corresponding pressure in toluene. At 2.5 bar hydrogen pressure both good
benzonitrile with a methyl Grignard followed by addition enantioselectivity (93% ee) and acceptable reaction time
of acetic anhydride.[8e] The cyclic N-acyl enamide 6f was (6 h) have been achieved.
synthesized by a standard protocol implying transformation
Next, we investigated the influence of the temperature on
of the ketone to the corresponding oxime and subsequent the selectivity and yield as described in Figure 2. Applying
reductive acylation with iron in the presence of acetic acid our model ligand 5a there is no pronounced effect on the
[
17]
[19]
anhydride.
selectivity between 10 and 30 °C. At higher temperatures
Initial studies on the influence of reaction conditions a decrease of the ee is observed (87% ee at 50 °C and 83%
were carried out with N-(1-phenylvinyl)acetamide (6a) as ee at 70 °C).
Eur. J. Org. Chem. 2006, 2912–2917
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2913

S. Enthaler, B. Hagemann, K. Junge, G. Erre, M. Beller
FULL PAPER
Table 1. Hydrogenation of N-(1-phenylvinyl)acetamide (6a).[a]
Entry
Ligand
Conversion [%][b]
ee [%][b,c]
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
4
93 (R)
72 (R)
88 (R)
87 (R)
93 (R)
63 (R)
90 (R)
30 (R)
16 (S)
19 (S)
10
1
[
a] All reactions were carried out at 30 °C under 2.5 bar pressure
of hydrogen for 6 h with 0.0024 mmol [Rh(cod) ]BF , 0.005 mmol
2
4
Figure 2. Dependency of enantioselectivity vs. temperature. Reac-
tions were carried out at the corresponding temperature for 1–24 h
ligand and 0.24 mmol substrate in toluene (2.0 mL). [b] Conversion
and ee values were determined by GC [50 m Lipodex E (Macherey–
Nagel), 80 °C, (R)-7a 26.7 min, (S)-7a 28.3 min]. [c] The absolute
configuration was determined by comparing the sign of specific
with 0.0024 mmol [Rh(cod)
2 4
]BF , 0.005 mmol ligand 5a and
0.24 mmol substrate in 2.0 mL toluene. Conversion and ee values
were determined by GC [50 m Lipodex E (Macherey–Nagel),
[5i]
rotation with reported data and the original sample (Aldrich).
5i]
8
0 °C, (R)-7a 26.7 min, (S)-7a 28.3 min].[
To estimate the activity of the catalyst in more detail the
To demonstrate the scope and limitations of our ligand
ratio between metal and substrate was varied starting from toolbox we performed the asymmetric hydrogenation of
initially 1:100 to 1:2000. At 50 °C and 2.5 bar of hydrogen four different N-(1-phenylvinyl)acetamides (Table 2). Re-
complete conversion was observed within one hour, which garding the substrates both electron-donating substituents
–1
corresponds to a turnover frequency (TOF) of 2000 h .
at the phenyl group, in particularly a methoxy group in
In order to evaluate the substituent effect at the phos- para- as well as in meta-position and electron-withdrawing
phorus atom of the ligand, we studied the asymmetric hy- substituents such as para-fluoro or para-trifluoromethyl
drogenation of N-(1-phenylvinyl)acetamide (6a) in the pres- have been tested. Enantioselectivity up to 95% ee is ob-
ence of nine different 4,5-dihydro-3H-dinaphtho[2,1-c;1Ј,2Ј- tained with ligands 5a (Table 2, Entry 1) and 5e (Table 2,
e]phosphepines (5a–5i) using the optimized reaction condi- Entry 5) for electron-rich substrates. In general, aryl phos-
tions (2.5 bar hydrogen pressure, toluene, 30 °C, 6 h). These phepines with electron-donating substituents showed better
results are presented in Table 1.
selectivity than phosphepines having electron-withdrawing
In agreement with our previous studies, it appeared groups.
that for obtaining good enantioselectivity aryl-substituted
The introduction of electron-withdrawing substituents in
phosphepine ligands are necessary, while alkyl-substituted N-(1-phenylvinyl)acetamide 6d and 6e decreased the
ligands showed significantly lower selectivity. Substitution enantioselectivity compared to the non-substituted N-(1-
on the phenyl ring at the phosphorus atom with electron- phenylvinyl)acetamide (6a). Here, the best selectivities of
withdrawing (5b, 5c) as well as electron-donating groups 83–86% ee are obtained with ligands 5a, 5e and 5g.
(5d–5g) resulted in decreased selectivity in comparison to
Again for all substrates 6a–6e the alkyl-substituted 4,5-
the phenyl ligand 5a. Here, only ligand 5e represented an dihydro-3H-dinaphtho[2,1-c;1Ј,2Ј-e]phosphepines gave sig-
exception (Table 1, Entry 5), which led to 93% ee.
nificantly lower selectivity.
Interestingly, the behaviour of the tert-butyl ligand 5i is
Next, the hydrogenation of the sterically more hindered
quite different in the hydrogenation of 6a. In contrast to N-(3,4-dihydro-1-naphthyl)acetamide (6f) was tested
the results obtained by Reetz et al., under our reaction con- (Scheme 2). The use of different pre-catalysts including
ditions compound 5i induced a change in the absolute con- [Rh(5a) (cod)]BF , [Rh(5e) (cod)]BF and [Rh(5i) (cod)]
2
4
2
4
2
figuration of the product to the opposite (S)-enantiomer, BF gave an excellent yield (Ͼ99%) of 7f.
4
albeit with significantly lower ee.
However, the observed enantioselectivity is significantly
In addition to the ligands 5, we also tested the commer- lower [5a: 15% (S); 5e: 11% (S); 5i: 35% (R)] when com-
1
2
cially available (S)-MonoPhos ligand (1, R = R = Me), pared to 1,1-disubstituted enamides. These results indicate
which gives excellent enantioselectivity in various hydrogen- a crucial influence of the substitution pattern on the en-
ations of prochiral double bonds.[
8,20]
However, in the pres- amide group.
ent test reaction we obtained only poor yield and enantio-
selectivity (Table 1, Entry 10).
It is important to note that in comparison to bidentate
ligands the application of monodentate ligands offers an
2914
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© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2912–2917

Enantioselective Hydrogenation of Enamides in the Presence of Phosphanes
FULL PAPER
Table 2. Asymmetric hydrogenation of substituted N-(1-phenyl- opportunity to replace one equiv. of the ligand by other chi-
vinyl)acetamides 6b–6e.[
a]
ral or achiral monodentate ligands. This remarkable combi-
[
9d–9f,15,21]
natorial approach was introduced by Reetz et al.,
[
22]
and Feringa et al. for different transition-metal-catalyzed
[
23]
reactions.
We followed this concept and used 4-phenyl-4,5-dihydro-
3H-dinaphtho[2,1-c;1Ј,2Ј-e]phosphepine (5a) with different
achiral phosphanes in a ratio of 1.05 to 1.05 equiv. in the
presence of 1.0 equiv. of [Rh(cod) ]BF . The results ob-
tained for the hydrogenation of N-(1-phenylvinyl)acetamide
6a) under optimized reaction conditions are presented in
7
b
7c
2
2
4
1
2
1
Entry Ligand (R = CH
3 3
O; R = H) (R = H; R = CH O)
[b,c]
[b,d]
ee [%]
ee [%]
(
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
91 (R)
63 (R)
79 (R)
87 (R)
92 (R)
33 (R)
89 (R)
rac
95 (R)
72 (R)
84 (R)
87 (R)
89 (R)
53 (R)
89 (R)
26 (R)
23 (S)
Table 3.
Table 3. Application of ligand mixtures in the asymmetric hydro-
genation of N-(1-phenylvinyl)acetamide (6a).[
a]
21 (S)
1
1
Entry Ligand
7d (R = F)
7e (R = CF
3
)
ee [%][
b,c]
ee [%]
[b,c]
10
11
12
13
14
15
16
17
18
5a
5b
5c
5d
5e
5f
5g
5h
5i
86 (R)
51 (R)
71 (R)
71 (R)
86 (R)
34 (R)
83 (R)
4 (R)
78 (R)
62 (R)
73 (R)
65 (R)
78 (R)
68 (R)
85 (R)
44 (R)
25 (S)
Entry
Ligand B
Conversion [%][b]
ee [%][b,c]
1
2
3
4
5
5a
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
93 (R)
85 (R)
88 (R)
81 (R)
74 (R)
PPh
3
P(p-MeO-C
P(p-Me-C
PCy
6 4 3
H )
H )
4 3
6
3
[
a] All reactions were carried out at 30 °C under 2.5 bar pressure
of hydrogen for 6 h with 0.0024 mmol [Rh(cod) ]BF , 0.0025 mmol
rac
2
4
[
a] All reactions were carried out at 30 °C under 2.5 bar pressure
of hydrogen for 6 h with 0.0024 mmol [Rh(cod) ]BF , 0.005 mmol
ligand and 0.24 mmol substrate in 2.0 mL toluene. [b] Conversion
Ͼ99%) was determined by GC (Agilent Technologies, 30 m, 50–
00 °C), ee values were determined by GC [50 m Lipodex E (Mach-
ligand 5a, 0.0025 mmol achiral ligand and 0.24 mmol substrate in
2.0 mL toluene. [b] Conversion and ee values determined by GC
[50 m Lipodex E (Macherey–Nagel), 80 °C, (R)-7a 26.7 min, (S)-7a
28.3 min]. [c] The absolute configuration was determined by com-
paring the sign of specific rotation with reported data and the origi-
nal sample (Aldrich).[
2
4
(
3
5i]
erey–Nagel), 100–180 °C, (R)-7b 36.1 min, (S)-7b 36.4 min, (R)-7c
3
4.8 min, (S)-7c 35.0 min, (R)-7d 31.0 min, (S)-7d 31.2 min, (R)-
e 32.4 min, (S)-7e 32.7 min]. [c] The absolute configurations were
7
In general, we observed a slight decrease in enantio-
selectivity from that observed when using 2.1 equiv. of li-
gand 5a. On the assumption that probably three different
metal complexes could be formed, in particular, two homo-
determined by comparing the sign of specific rotation with re-
[
5i]
ported data. [d] Absolute configuration of product was assigned
by analogy.
combination products, the chiral [Rh(5a)(5a)(cod)]BF and
4
the achiral [Rh(L)(L)(cod)]BF , and the hetero-combina-
4
tion product [Rh(L)(5a)(cod)]BF , we deduce a significantly
4
lower reaction rate or inactivity for the achiral complex
[
Rh(L)(L)(cod)]BF relative to complex [Rh(5a)(5a)(cod)]-
4
BF4 or [Rh(L)(5a)(cod)]BF4. Tricyclohexylphosphane
Table 3, Entry 5) was found to be the only exception, as
(
we noticed a more pronounced decrease of the enantio-
meric excess.
Scheme 2. Asymmetric hydrogenation of N-(3,4-dihydro-1-naph-
thyl)acetamide (6f). All reactions were carried out at 30 °C under
Conclusions
2
.5 bar pressure of hydrogen for 6 h with 0.0024 mmol [Rh(cod)
2
]-
BF , 0.005 mmol ligand and 0.24 mmol substrate in 2.0 mL tolu-
4
We demonstrated the application of monodentate 4,5-di-
ene. Conversion was determined by GC (Agilent Technologies, hydro-3H-dinaphtho[2,1-c;1Ј,2Ј-e]phosphepines 5 in the
3
0 m, 50–300 °C) and ee values were determined by HPLC [AD-
H Chiralpak (Agilent Technologies), n-hexane/ethanol, 95:5, rate
.0 mL/min, (S)-7f 6.2 min, (R)-7f 7.2 min]. The absolute configu-
rhodium-catalyzed asymmetric hydrogenation of various
enamides. The influences of different reaction parameters
are presented. For the first time high enantioselectivity (up
to 95% ee) for such reactions is obtained in the presence of
1
ration was determined by comparing the sign of specific rotation
with reported data.
Eur. J. Org. Chem. 2006, 2912–2917
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2915

S. Enthaler, B. Hagemann, K. Junge, G. Erre, M. Beller
FULL PAPER
monodentate phosphanes. Best results were observed with ferred via syringe into the autoclave. Then, the autoclave was
charged with hydrogen and the mixture was stirred at the required
aryl-substituted phosphepine ligands for reduction of N-(1-
temperature. After the predetermined time the hydrogen was re-
phenylvinyl)acetamide, while alkyl-substituted phosphepine
leased and the reaction mixture passed through a short plug of
ligands yielded only low selectivity.
silica gel. The enantioselectivity and conversion were measured by
GC or HPLC without further modifications.
Experimental Section
Acknowledgments
All manipulations were performed under argon using standard
Schlenk techniques. Diethyl ether and toluene were distilled from
sodium benzophenone ketyl under argon. Methanol was distilled
We thank M. Heyken, S. Buchholz and Dr. C. Fischer (all Leibniz-
Institut für Katalyse e. V. an der Universität Rostock) for excellent
technical assistance and Prof. Dr. S. Gladiali for general dis-
cussions. Generous financial support from the state of Mecklen-
burg-Western Pomerania and the BMBF is gratefully acknowl-
edged.
from Mg under argon. Dichloromethane was distilled from CaH
under argon. The ligands 5 were synthesized according to our pre-
2
viously published protocols.[
13]
2 4
[Rh(cod) ]BF (purchased from
Fluka) was used without further purification.
General Procedure for the Synthesis of Substituted N-(1-Phenylvinyl)-
acetamides 6a–6e: To a stirred solution of methylmagnesium bro-
mide (17.0 mmol, 3.0 mol/L diethyl ether, 6.0 mL) in diethyl ether
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masino, M. Lemaire, Chem. Rev. 2000, 100, 2159–2231; e) H.-
P. Jacqueline, Chiral Auxiliaries and Ligands in Asymmetric
Synthesis, John Wiley & Sons, New York, 1995; f) M. Nógradi,
(17.0 mmol) in diethyl ether (20 mL) was added dropwise during a
period of 30 minutes. After complete addition the solution was re-
fluxed for eight hours. Within a few hours a yellow precipitate was
formed. After refluxing the reaction mixture was cooled to 0 °C,
and a solution of acetic anhydride (17.0 mmol) in diethyl ether
nd
Stereoselective Synthesis, Wiley-VCH, Weinheim, 2 ed., 1995;
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(20 mL) was added carefully over 30 minutes. The reaction mixture
was refluxed for eight hours. To the resulting suspension methanol
was added at room temperature whilst stirring until all precipitates
were dissolved (approximately 50 mL). The homogeneous solution
was mixed with water/ethyl acetate (1:1, 100 mL). After phase sepa-
ration the aqueous layer was extracted three times with ethyl ace-
1994, 59, 297–310; j) H. P. Buser, B. Pugin, F. Spindler, M.
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Chem. Soc. 1986, 108, 7117–7119.
4
tate (50 mL). The combined organic layers were dried with MgSO .
After removing of the solvents the semi crystalline crude oil was
purified by column chromatography (n-hexane/ethyl acetate, 1:1).
Removal of the solvent yielded the crystalline products. [yields: (6a)
[
[
2] a) R. Noyori, Asymmetric Catalysis in Organic Synthesis, Wiley,
New York, 1994; b) M. Beller, C. Bolm (Eds.), Transition Met-
nd
1.51 g (55%), (6b) 1.66 g (51%), (6c) 1.50 g (46%), (6d) 1.52 g
als for Organic Synthesis, Wiley-VCH, Weinheim, 2 ed., 2004;
(50%), (6e) 1.91 g (49%)]
c) E. N. Jacobsen, A. Pfaltz, H. Yamamoto (Eds.), Comprehen-
sive Asymmetric Catalysis, Springer, Berlin, 1999.
General Procedure for the Synthesis of the Cyclic N-Acyl Enamide
f: A stirred solution of the corresponding ketone (30.3 mmol), hy-
3] H.-U. Blaser, B. Pugin, F. Spindler, J. Mol. Catal. A 2005, 231,
6
1–20.
droxylamine–hydrochloride (73 mmol) and pyridine (62.2 mmol) in
ethanol (40 mL) was heated to 85 °C for a period of 16 hours. The
solvent was removed, and the residue was dissolved in ethyl acetate/
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. After removal of the solvents the product
(
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4
(0.0024 mmol) and the corresponding
2916
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Eur. J. Org. Chem. 2006, 2912–2917

Enantioselective Hydrogenation of Enamides in the Presence of Phosphanes
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Published Online: April 26, 2006
Eur. J. Org. Chem. 2006, 2912–2917
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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