Enantioselective hydrogenation of enamides catalyzed by chiral rhodium-monodentate phosphite complexes

Article abstract of DOI:10.1016/S0040-4039(02)01838-5

Chiral monophosphites derived from BINOL are cheap and efficient ligands in the Rh-catalyzed hydrogenation of N-acyl enamides, providing amines with high degrees of enantioselectivity (up to 97.0% ee).

Full text of DOI:10.1016/S0040-4039(02)01838-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7941–7943
Enantioselective hydrogenation of enamides catalyzed by chiral
rhodium–monodentate phosphite complexes
Manfred T. Reetz,* Gerlinde Mehler, Andreas Meiswinkel and Thorsten Sell
Max-Planck-Institut fu¨r Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mu¨lheim/Ruhr, Germany
Received 20 August 2002; accepted 30 August 2002
Abstract—Chiral monophosphites derived from BINOL are cheap and efficient ligands in the Rh-catalyzed hydrogenation of
N-acyl enamides, providing amines with high degrees of enantioselectivity (up to 97.0% ee). © 2002 Elsevier Science Ltd. All
rights reserved.
Recently, we reported the surprising finding that chiral
monodentate phosphites 1 are highly efficient ligands in
the Rh-catalyzed hydrogenation of prochiral olefins
such as itaconic acid ester and 2-acetamido acrylic acid
esters (ee=95–99%).1 In an independent study Feringa,
de Vries and co-workers described similar results using
the monophosphoramidite 2.2 Moreover, Pringle3 and
our group4 independently reported on the use of chiral
phosphonites 3 as ligands in Rh-catalyzed olefin hydro-
genation, reactions in which the degree of enantioselec-
tivity is somewhat lower than in the case of 1 and 2.
Taken together the results clearly demonstrate that the
traditional use of chelating ligands is not necessary in
order to obtain high enantioselectivities in a general
manner.5 The fact that ligands 1–3 are readily available
accounts for their industrial interest.6
In a further development of this chemistry Chan
recently described the use of 2 as a ligand in the
Rh-catalyzed hydrogenation of enamides 4,7 the ee
values ranging between 55% and 87% at room tempera-
ture (up to 96% ee at −20°C).8 Zhou independently
* Corresponding author. Fax: +49 208 306 2985; e-mail: reetz@mpi-muelheim.mpg.de
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01838-5

7942
M. T. Reetz et al. / Tetrahedron Letters 43 (2002) 7941–7943
Table 1. Rhodium-catalyzed asymmetric hydrogenation of
enamide 4a using chiral phosphites 1 (solvent: CH2Cl2;
Rh:substrate=1:500; ligand:Rh=2:1; 60 bar H2; 20 h;
30°C)
varies considerably as a function of the nature of the R
group in the ligand. Among the best ligands are those
derived from cyclopentanol (entry 3), benzyl alcohol
(entry 4) and neopentyl alcohol (entry 7). Chiral alco-
hols such as 2-butanol or 1-phenylethanol also lead to
high enantioselectivities, whereby the absolute configu-
ration seems to play only a small role (cf. entries 8–10).
Amino moieties in the phosphites shut down the reac-
tion, possibly due to chelation (entry 11), and strongly
electron-withdrawing groups also lower the hydrogena-
tion rate (entry 14).
Entry
Ligand
Conversion (%)
% ee (configuration of
product)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
100
100
100
100
100
100
100
100
100
100
20
76.0 (R)
89.4 (R)
93.7 (R)
94.2 (R)
93.1 (S)
93.7 (S)
95.3 (R)
92.0 (R)
94.1 (S)
94.9 (R)
0 (–)
The results of experiments using monophosphonites 3
turned out to be less encouraging (solvent: CH2Cl2;
ligand:Rh=2:1; substrate:catalyst=250:1; 60 bar H2;
30°C; 1 h; 100% conversion): 3a (ee=74% S); 3b (ee=
67.2% S); 3c (ee <1%); 3d (ee=58% S). Interestingly, at
1.5 bar H2 similar results were obtained. Catalysts
based on phosphonites 3 appear to be more active than
those based on phosphites 1, although enantioselectivi-
ties are usually considerably lower.
9
10
11
12
13
14
100
100
B5
86.0 (R)
92.7 (S)
n.d.
substantiated this result, and also reported on a novel
monophosphoramidite having a spiro-type structure
which leads to higher enantioselectivities (ee typically
95–99%).9 These two publications prompt us to report
our preliminary results concerning the Rh-catalyzed
hydrogenation of substrates 4 using ligands 1 and 3.
Following these results we started to hydrogenate other
N-acyl enamides 4 using selected phosphite ligands 1.
Although this study has not been completed, the pre-
liminary results summarized in Table 2 demonstrate the
generality of the method. Thus, each substrate can be
matched with the best ligand in a simple process of
screening (which has not yet been performed for all
substrates). This possibility constitutes a major advan-
tage of the method.
One of the advantages of phosphites 1 as ligands in
Rh-catalyzed hydrogenation is their modular nature
which allows for easy variation of the R group in the
alcohol portion (ROH) of the compounds.1,10,11 This
makes simple ligand tuning possible. We have therefore
started to evaluate some of the ligands 1 available in
our laboratory, specifically in a test reaction involving
substrate 4a. In all cases Rh(COD)2BF4 (COD=
cyclooctadiene) was used as the precursor, which leads
to the displacement of one COD by two monophos-
phites. Although only 14 of the 60 in our laboratory
currently available ligands were tested so far, the results
summarized in Table 1 show that, as expected, the ee
In summary, we have developed a simple and efficient
method for the Rh-catalyzed asymmetric hydrogena-
tion of N-acyl enamides which provides chiral amines
with high enantioselectivities.12 Since the BINOL-
derived monophosphites are cheap (e.g. only 2% of the
cost of BINAP), the method is likely to be of industrial
interest.6 Moreover, catalyst optimization for a given
substrate is possible by simple variation of the alcohol
ROH which is incorporated in the synthesis of the
modular ligands 1.
Table 2. Rhodium-catalyzed asymmetric hydrogenation of enamides 4b–e (solvent: CH2Cl2; Rh:substrate=1:500; ligand:Rh=
2:1; 60 bar H2; 20 h; 30°C)
Entry
Enamide
Ligand
Conversion (%)
% ee (configuration of product)
1
2
3
4
5
6
7
8
9
4b
4c
4c
4c
4c
4c
4c
4d
4e
1j
100
100
100
100
100
99.0
99.5
100
69
95.8 (R)
94.3 (R)
\92.0 (S)
\93.0 (S)
93.7 (R)
90.6 (R)
\93.4 (S)
97.0 (R)
1d
1e
1f
1g
1h
1i
1j
1j
76.2 (R)

M. T. Reetz et al. / Tetrahedron Letters 43 (2002) 7941–7943
7943
References
10. The synthesis of BINOL-derived monophosphites is well
known:1,11 (a) Ovchinnikov, V. V.; Cherkasova, O. A.;
Verizhnikov, L. V. Zh. Obshch. Khim. 1982, 52, 707–708;
J. Gen. Chem. 1982, 52, 615–616; (b) Bartik, T.; Gerdes,
I.; Heimbach, P.; Schulte, H.-G. J. Organomet. Chem.
1989, 367, 359–370; (c) Heimbach, P.; Bartik, T.;
Drescher, U.; Gerdes, I.; Knott, W.; Riena¨cker, R.;
Schulte, H.-G.; Tani, K. Kontakte (Darmstadt) 1988, 3,
19–31; (d) Fuji, K.; Kinoshita, N.; Tanaka, K.; Kawa-
bata, T. Chem. Commun. (Cambridge) 1999, 2289–2290;
(e) Chen, W.; Xiao, J. Tetrahedron Lett. 2001, 42, 2897–
2899.
1. Reetz, M. T.; Mehler, G. Angew. Chem. 2000, 112,
4047–4049; Angew. Chem., Int. Ed. 2000, 39, 3889–3890.
2. van den Berg, M.; Minnaard, A. J.; Schudde, E. P.; van
Esch, J.; de Vries, A. H. M.; de Vries, J. G.; Feringa, B.
L. J. Am. Chem. Soc. 2000, 122, 11539–11540.
3. Claver, C.; Fernandez, E.; Gillon, A.; Heslop, K.; Hyett,
D. J.; Martorell, A.; Orpen, A. G.; Pringle, P. G. Chem.
Commun. (Cambridge) 2000, 961–962.
4. Reetz, M. T.; Sell, T. Tetrahedron Lett. 2000, 41, 6333–
6336.
5. (a) Knowles, W. S. Angew. Chem. 2002, 114, 2096–2107;
Angew. Chem., Int. Ed. 2002, 41, 1998–2007; (b) Noyori,
R. Angew. Chem. 2002, 114, 2108–2123; Angew. Chem.,
Int. Ed. 2002, 41, 2008–2022.
11. Reetz, M. T.; Mehler, G.; Meiswinkel, A. Patent Applica-
tion DE-A 100 27 505.2, 06.06.2000.
12. Typical procedure for Rh-catalyzed hydrogenation of
N-acyl enamides 4 using chiral phosphites: A mixture
6. Komarov, I. V.; Bo¨rner, A. Angew. Chem. 2001, 113,
1237–1240; Angew. Chem., Int. Ed. 2001, 40, 1197–1200.
7. For the synthesis and hydrogenation of N-acyl enamides,
see: Burk, M. J.; Casy, G.; Johnson, N. B. J. Org. Chem.
1998, 63, 6084–6085.
consisting of 0.5 mL of
a 2 mM solution of
Rh(COD)2BF4 in dry CH2Cl2 and 0.5 mL of a 4 mM
solution of a phosphite 1 in CH2Cl2 is prepared, which
causes a color change from orange to yellow. Following
addition of substrate 4a (80.6 mg, 0.5 mmol) in 1 mL of
CH2Cl2, the reaction flask is brought into an autoclave. A
H2 pressure of 60 bar is applied and the contents is
stirred at 30°C for 20 h. GC analysis provides the ee
values and degree of conversion.
8. Jia, X.; Guo, R.; Li, X.; Yao, X.; Chan, A. S. C.
Tetrahedron Lett. 2002, 43, 5541–5544.
9. Hu, A.-G.; Fu, Y.; Xie, J.-H.; Zhou, H.; Wang, L.-X.;
Zhou, Q.-L. Angew. Chem. 2002, 114, 2454–2456; Angew.
Chem., Int. Ed. 2002, 41, 2348–2350.