Rhodium/MonoPhos-Catalysed Asymmetric Hydrogenation of Enamides

Article abstract of DOI:10.1002/1615-4169(200210)344:9<1003::AID-ADSC1003>3.0.CO;2-M

The monodentate phosphoramidite MonoPhos has been used in the rhodium-catalysed asymmetric hydrogenation of N-acetyl-α-arylenamides. This ligand is readily available via a one-step procedure and is air stable. Its Rh(I) complex, which is an effective catalyst precursor for the hydrogenation of dehydroamino acids, also gives high enantioselectivities for this class of substrates. Because of the facile synthesis and stability of MonoPhos, its complex provides a general solution in preparing chiral amine derivatives through asymmetric hydrogenation.

Full text of DOI:10.1002/1615-4169(200210)344:9<1003::AID-ADSC1003>3.0.CO;2-M

FULL PAPERS
Rhodium/MonoPhos-Catalysed Asymmetric Hydrogenation of
Enamides
a
a
a,
¬
Michel van den Berg, Robert M. Haak, Adriaan J. Minnaard, * Andre H. M. de
Vries,b Johannes G. de Vries,b,* Ben L. Feringaa,*
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute, University of Groningen,
a
9747 AG Nijenborgh 4, The Netherlands
Fax: ( ‡ 31)-50-3634296, e-mail: Feringa@chem.rug.nl, Minnaard@chem.rug.nl
b
DSM Fine Chemicals Advanced Synthesis & Catalysis, P.O. Box 18, 6160 MD Geleen, The Netherlands
Fax: ( ‡ 31)-46-4767604, e-mail: Hans-JG.Vries-de@dsm.com
Received: May 23, 2002; Accepted: July 9, 2002
Dedicated to Professor Roger Sheldon on the occasion of his 60th birthday.
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de or from the author.
Abstract: The monodentate phosphoramidite Mono- facile synthesis and stability of MonoPhos, its
Phos has been used in the rhodium-catalysed asym- complex provides a general solution in preparing
metric hydrogenation of N-acetyl-a-arylenamides. chiral amine derivatives through asymmetric hydro-
This ligand is readily available via a one-step genation.
procedure and is air stable. Its Rh(I) complex, which
is an effective catalyst precursor for the hydrogena- Keywords: asymmetric catalysis; chiral amines; enam-
tion of dehydroamino acids, also gives high enantio- ides; enantioselective hydrogenation; homogeneous;
selectivities for this class of substrates. Because of the phosphoramidites; rhodium
Introduction
rhodium were used in all these studies with the majority
being chiral diphosphines. The limited number of stud-
Transition metal-catalysed asymmetric hydrogenation is ies on the asymmetric hydrogenation of a-arylenamides
a highly efficient and practical way of introducing suggests that this is a class of substrates which is more
chirality.[1,2,3,4] The introduction of this new asymmetric difficult to hydrogenate with high enantioselectivity.
hydrogenation methodology for the industrial prepara- Recently, we and others have shown that bidentate
tion of homochiral building blocks and intermediates is ligands are not a prerequisite to obtain high enantiose-
seen to proceed at a steady pace. Extensive research has lectivities in the hydrogenation of dehydroamino acids.
been performed since the first publications in 1968 by Monodentate phosphonites,[25] phosphites[26] and phos-
Knowles and Horner.[5,6] In olefin hydrogenation the phoramidites[27] can also be used to achieve excellent
emphasis has been on the development of new chiral levels of chiral induction. Major advantages of, for
ligands and catalysts for the reduction of functionalised instance, monodentate phosphoramidites are that these
prochiral olefins, in particular to afford optically active ligands are easy to prepare in 1 ~ 2 chemical steps and
amino acids. For recent examples of highly enantiose- that they are stable towards air, unlike most phosphines,
lective reduction of non-functionalised olefins see the which adds to the practicality of catalysts based on these
work of Pfaltz[7,8] and Buchwald.[9] The asymmetric ligands. Herein we report the use of a monodentate
hydrogenation of enamides has been studied to a limited phosphoramidite ligand, MonoPhos 1, in the asymmet-
extent although it would provide a highly attractive ric hydrogenation of a-arylenamides. This study dem-
means to produce chiral amines. One of the first onstrates for the first time that primary amine deriva-
examples of the asymmetric hydrogenation of an a- tives can be obtained with high enantioselectivities
arylenamide was reported by Kagan et al. employing a using chiral hydrogenation catalysts based on cheapand
complex of rhodium, with DIOP as a bidentate ligand, to readily accessible monodentate ligands.
[10]
afford ee×s upto 92%.
Higher enantioselectivities
were obtained with chiral phosphine ligands like
DuPHOS, BPE,[11,12,13] CDP,[14] BICP,[15] Binaphane,[16]
,
Results and Discussion
DIOP analogues,[17,18] bdpmi,[19] PennPhos,[20] amino-
phosphine BDPAB,[21] bisphosphinite spirOP[22] and The rhodium-catalysed asymmetric hydrogenation of
TangPhos.[23,24] Bidentate ligands which can chelate enamides (Scheme 1) was examined using the phos-
Adv. Synth. Catal. 2002, 344, No. 9
¹ 2002 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 1615-4150/02/34409-1003 1007 $ 17.50+.50/0
1003

Michel van den Berg et al.
FULL PAPERS
compared to ethyl acetate as a solvent (Table 1,
entries 1, 2 vs. 3, 4). To investigate the scope of this
asymmetric hydrogenation various enamides were
studied (Figure 2). The results of hydrogenation both
in ethyl acetate and dichloromethane are summarised in
Table 1. The complex of rhodium and MonoPhos is
capable of hydrogenating a variety of a-arylenamides
with modest to high levels of enantioselectivity. Heter-
oaromatic a-enamides 8 and 9 (entries 20 27) are
hydrogenated with comparable results as seen in the
hydrogenation of 3. The highest enantioselectivity is
À
Figure 1. Monodentate phosphoramidite ligand MonoPhos
1.[27,30]
phoramidite ligand (S)-MonoPhos 1, previously shown found for substrate 9 in dichloromethane at 5 8C
to be highly effective in asymmetric hydrogenation of providing the corresponding N-acetylamine with 94%
dehydroamino acids.
ee (Table 1, entry 25). Halogen substitution at the
The enamide substrates 3 7 and 10 (Figure 2) aromatic ring (substrate 4) affords similar results when
were prepared following literature procedures compared with 3, but the additional chloride substituent
(Scheme 2).[13,20,28] The stereochemistry of 5 and there- provides a means to subsequently functionalise the
fore of 6 was determined by X-ray diffraction analysis.[29] product via a palladium catalysed cross-coupling reac-
The heteroaromatic enamides 8 and 9 were synthesised tion. From entries 9 and 13 it becomes evident that the
using a modified literature procedure[11] starting from introduction of an ethyl substituent at the olefinic
the corresponding aryl nitriles (Scheme 2). (S)-Mono- moiety has a large influence on the enantioselectivity in
Phos 1 was prepared as described earlier from (S)-bis-b- the hydrogenation.
naphthol and HMPA.[27,30] The actual catalyst was
Substrate 5, having a Z configuration at the alkene,
prepared in situ from the precursor Rh(COD)2BF4 and affords the product in high enantioselectivity but
two equivalents of MonoPhos 1 as the chiral ligand in substrate 6, with an E configuration, yields a substan-
ethyl acetate or dichloromethane.
tially lower ee in the hydrogenation product. Besides the
The hydrogenation reactions were performed in an lower selectivity the conversion of E-6 is also much
autoclave with magnetic stirring under a H2 pressure of slower when compared to substrate Z-5; a finding which
15 bar. We were pleased to see that the parent substrate contrasts with examples reported in the literature,[13,31]
3 could be hydrogenated at room temperature to for which high levels of ee were observed in the
provide the corresponding N-acetylamine in 100% hydrogenation of mixtures of E and Z enamides.
yield with an enantioselectivity of 86%. The enantiose- Furthermore it was found that the hydrogenation of E-
lectivity improved to 90% by lowering the temperature isomer 6 in dichloromethane at 25 8C was accompanied
À
to 5 8C. Furthermore it is noted that using dichloro- by isomerisation of the olefinic double bond during the
methane as a solvent, slightly higher ee×s are obtained reaction yielding Z-5. This isomerisation was not
Scheme 2. Synthesis of substrates;[11,13,20,28] 1: H2NOH HCl,
EtOH, pyridine; 2: Ac2O, AcOH, Fe, TMSCl, toluene; 3:
MeMgBr, Et2O; 4: Ac2O, Et2O.
Figure 2. N-Acetyl-a-arylenamide substrates.
Scheme 1. Hydrogenation using monodentate phophoramidite MonoPhos 1.
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Adv. Synth. Catal. 2002, 344, 1003 1007

Rhodium/MonoPhos-Catalysed Asymmetric Hydrogenation of Enamide
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Table 1. Rh-catalysed asymmetric hydrogenation of various N-acetyl-a-arylenamides.[a]
Entry
Substrate
Solvent
T [8C]
Conversion [%][b]
ee [%][c]
Configuration[d]
1
2
3
4
5
6
7
8
3
3
3
3
4
4
4
4
5
5
5
5
6
6
6
7
7
7
7
8
8
8
8
9
9
9
9
4
10
DCM
DCM
EtOAc
EtOAc
DCM
25
5
25
100
100
100
100
100
100
100
100
100
47
100
52
11
58
86
90
74
87
89
92
73
93
84
89
63
87
24
15
26
43
43
24
36
85
92
69
72
90
94
81
93
89
35
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
À
À
5
25
À
DCM
5
EtOAc
EtOAc
DCM
25
À
5
9
25
À
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
DCM
5
EtOAc
EtOAc
DCM
EtOAc
EtOAc
DCM
25
À
5
25
25
À
5
24
80
45
63
25
S[e]
S[e]
S[e]
S[e]
S
S
S
S
S
À
DCM
5
EtOAc
EtOAc
DCM
25
À
5
62
25
100
100
100
23
100
100
100
22
À
DCM
5
EtOAc
EtOAc
DCM
25
À
5
25
À
DCM
5
S
S
EtOAc
EtOAc
DCM
25
À
5
S
25
25
100
52
S[f]
[g]
À
DCM
[a]
The reaction conditions were Rh(COD)2BF:MonoPhos:substrate ˆ 0.02:0.042:1, H2 pressure 15 bar, reaction time 20 h,
although most reactions gave full conversion in within 4 h.
[b]
[c]
[d]
1
Conversion to product determined by H NMR and GC analysis.
Determined by chiral GC, see experimental section.
Absolute configurations were assigned by analogy, through chiral GC elution order with an enantiopure sample of N-
acetylphenylethylamine.
[e]
[f]
[g]
Absolute configurations were assigned by analogy, through chiral GC elution order according to literature.[13]
Reaction time of one hour.
Not determined.
observed in ethyl acetate or at lower reaction temper- selectivity were found (entry 29). Compared to 6, the
atures. Enamide 7 with a t-Bu groupcould be hydro- incorporation of the olefinic double bond in a six-
genated in moderate to good yield, although with membered ring does not seem to have a major influence
disappointing ee. Further research is needed to eluci- on the asymmetric hydrogenation reaction.
date if the low ee is due to steric hindrance of the bulky t-
Bu group or due to the presence of an aliphatic group
instead of an aromatic one which changes the electronic Conclusion
properties of the enamide. After the hydrogenation of 7,
NMR revealed acetamide present in the reaction Catalytic hydrogenation of N-acetyl-a-arylenamides
mixture. When a substrate was used with the double using Rh(COD)2BF4 and MonoPhos results in full
bond in a six-membered ring (dehydronaphthalene conversions and high ee×s. Halogen substituents on the
derivative 10) a slow reaction rate and moderate phenyl ring do not give any problems when compared to
Adv. Synth. Catal. 2002, 344, 1003 1007
1005

Michel van den Berg et al.
FULL PAPERS
and the solvent evaporated under reduced pressure. The
products were purified by recrystallisation from ethyl acetate.
Spectral data of 3 - 7 and 10 were in agreement with those
reported in literature.[13,20]
the unsubstituted substrate neither are there any
problems when the phenyl is replaced by a heteroar-
omatic ring. The substitution pattern and the configu-
ration at the olefinic double bond on the other hand
have an influence on the hydrogenation. Whereas the Z-
isomer gives similar results to substrate 3, the E-isomer
has a lower conversion and enantioselectivity. The
hydrogenation of t-Bu-substituted enamides poses a
problem for this catalytic system as lower enantioselec-
tivities are obtained. Although some diphosphines
clearly result in higher ee×s in the hydrogenation of N-
acetyl-a-arylenamides, we have shown that bidentate
ligands are not a prerequisite for the hydrogenation of
N-acetyl-a-arylenamides as well. Most notable the
readily accessible monodentate phosphoramidite
MonoPhos can also be used to obtain full conversions
and high ee×s.
General Procedure for the Synthesis of N-Acetyl-a-
arylenamides 8 and 9[11]
To a stirred solution of MeMgBr (6 mL, 3 M solution in Et2O)
diluted with Et2O (20 mL) was added dropwise a solution of
ArCN (17 mmol) in Et2O (10 mL). The mixture was heated at
reflux overnight until all the starting material was converted
(as indicated by TLC). Subsequently, a solution of acetic
anhydride (1.60 mL, 17 mmol) in Et2O (20 mL) was added
dropwise and the mixture was heated at reflux overnight. After
cooling to room temperature, methanol was added until all
salts were dissolved (35 mL). Water (50 mL) was added and the
reaction mixture was extracted with EtOAc (3 Â 50 mL). The
combined extracts were washed with brine, dried over MgSO4,
and the solvent evaporated under reduced pressure. The
products were purified by column chromatography using silica
gel and a mixture of ethyl acetate and hexane as the eluent.
Spectral data of 8 and 9 were in agreement with those reported
in literature.[11]
Experimental Section
General Remarks
All reactions were performed in a dry nitrogen atmosphere
using standard Schlenk techniques. Solvents were reagent
grade and dried and distilled before use following standard
procedures. NMR spectra were recorded at room temperature
in CDCl3 on Varian Gemini 200 (200 MHz) or Varian VXR 300
(300 MHz) spectrometers. Chemical shifts were determined
relative to the residual solvent peak. Enantiomeric excesses
were determined by capillary GC analysis on an HP 5890 with a
Supelco b-Dex 120 column (30.0 m  250 mm  0.25 mm) and
on an HP 6890 with Chrompack Chirasil-L-Val (25.0 m Â
250 mm  0.25 mm) or Chirasil-Dex CB column (25.0 m Â
General Procedure for the Asymmetric
Hydrogenation of N-Acetyl-a-arylenamides 3 10
In an autoclave with seven small glass tubes equipped with
magnetic stirrers, the glass tubes were charged with substrate
(120 mmol), Rh(COD)2BF4 (0.97 mg, 2.40 mmol), MonoPhos
(1.81 mg, 5.04 mmol) and CH2Cl2 (3 mL). The autoclave was
purged three times with nitrogen and two times with hydrogen
before being pressurised with H2 to 15 bar. The solution was
stirred (20 h) at room temperature. The resulting solution was
passed through a small plug of silica gel using ethyl acetate as
the eluent. The conversion of the reaction and the ee of the
product were determined by GC or HPLC.
250 mm
Â
0.25 mm), with helium as carrier gas. HPLC
analyses were performed using a Chiralcel-OD column
(250 mm  4.6 mm), with n-heptane/2-propanol as mobile
phase (98:2, 1 mL/min) and detection by a diode array UV/Vis
detector.
Acknowledgements
General Procedure for the Synthesis of N-Acetyl-a-
arylenamides 3 7 and 10[13,20,28]
We thank Ing. M. van Gelder for assistance with the GC and
HPLC analyses. Financial support from the Dutch Ministry of
Economic Affairs, grant EETK97107 and EETK99104,
administered through the EET program for the development
of clean technology is gratefully acknowledged.
Acetophenone (11.7 mL, 100 mmol) and hydroxylamine
hydrochloride salt (14.8 g, 213 mmol) were dissolved in
ethanol (150 mL) and pyridine (15 mL). After refluxing for
5 h the solvent was evaporated and water (150 mL) was added
before the solution was cooled while stirring in an ice bath. The
precipitate was filtered and washed with ice/water (50 mL)
before being dissolved in ethyl acetate, dried over MgSO4, and
the solvent evaporated under reduced pressure. No further
purification was required for the next step.
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1006
Adv. Synth. Catal. 2002, 344, 1003 1007

Rhodium/MonoPhos-Catalysed Asymmetric Hydrogenation of Enamide
FULL PAPERS
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