Enantioselective Rh-catalyzed hydrogenation of enol acetates and enol carbamates with monodentate phosphoramidites

Article abstract of DOI:10.1021/ol051559c

(Chemical Equation Presented) Monodentate phosphoramidites, in particular PipPhos and its octahydro analogue, are excellent ligands for the rhodium-catalyzed asymmetric hydrogenation of aromatic enol acetates, enol carbamates, and 2-dienol carbamates up to 98% ee. These latter substrates were hydrogenated selectively to the carbamates of the allyl alcohol.

Full text of DOI:10.1021/ol051559c

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4177-4180
Enantioselective Rh-Catalyzed
Hydrogenation of Enol Acetates and
Enol Carbamates with Monodentate
Phosphoramidites
Lavinia Panella,† Ben L. Feringa,*,† Johannes G. de Vries,*,†,‡ and
Adriaan J. Minnaard*,†
Department of Organic and Molecular Inorganic Chemistry, Stratingh Institute,
UniVersity of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands, and
DSM Research, Life Sciences-AdVanced Synthesis, Catalysis & DeVelopment,
P.O. Box 18, 6160 MD Geleen, The Netherlands
b.l.feringa@rug.nl; hans-jg.Vries-de@dsm.com; a.j.minnaard@rug.nl
Received July 2, 2005
ABSTRACT
Monodentate phosphoramidites, in particular PipPhos and its octahydro analogue, are excellent ligands for the rhodium-catalyzed asymmetric
hydrogenation of aromatic enol acetates, enol carbamates, and 2-dienol carbamates up to 98% ee. These latter substrates were hydrogenated
selectively to the carbamates of the allyl alcohol.
In the rhodium-catalyzed asymmetric hydrogenation of
prochiral olefins,1 bidentate phosphine ligands were long
considered to be essential for high enantioselectivities.2
However, in the past few years, monodentate phosphines,3a
phosphonites,3b phosphites,3c,e and phosphoramidites3d were
shown to be excellent and sometimes superior alternatives
to bidentate ligands,4 in terms of enantioselectivity, simplicity
of synthesis, and ease of structural variation. The use of a
monodentate phosphoramidite in a large-scale production of
an R-alkyl cinnamate was recently announced by DSM.5
The asymmetric hydrogenation of enol acetates gives
access to chiral esters, which makes this method an interest-
ing alternative to the enantioselective hydrogenation of
prochiral ketones for the preparation of chiral alcohols. Very
few ligands have been reported to be successful for this
transformation despite the structural similarity with enamides,
the majority of which can be hydrogenated with high
enantioselectivity.2,4 In one of the most recent examples,
enantioselectivities up to 99% ee were achieved using Rh-
† University of Groningen.
‡ DSM Research.
(1) For reviews, see: (a) Knowles, W. S. Angew. Chem., Int. Ed. 2002,
41, 1998. (b) Noyori, R. Angew. Chem., Int. Ed. 2002, 41, 2008. (c)
Chaloner, P. A.; Esteruelas, M. A.; Joo´, F.; Oro, L. A. Homogeneous
Hydrogenation; Kluwer: Dordrecht, 1994. (d) Brown, J. M. In Compre-
hensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer: Berlin, 1999; Vol. 1, Chapter 5.1.
(4) For reviews, see: (a) Komarov, I. V.; Bo¨rner, A. Angew. Chem.,
Int. Ed. 2001, 40, 1197. (b) Jerphagnon, T.; Renaud, J.-L.; Bruneau, C.
Tetrahedron: Asymmetry 2004, 15, 2101. (c) Lagasse, F.; Kagan, H. B.
Chem. Pharm. Bull. 2000, 48, 315.
(5) (a) de Vries, A. H. M.; Lefort, L.; Boogers, J. A. F.; de Vries, J. G.;
Ager, D. J. Chim. Oggi 2005, 23 (2), Supplement on Chiral Technologies,
18. (b) Hoen, R.; Boogers, J. A. F.; Bernsmann, H.; Minnaard, A. J.;
Meetsma, A.; Tiemersma-Wegman, T. D.; de Vries, A. H. M.; de Vries, J.
G.; Feringa, B. L. Angew. Chem., Int. Ed. 2005, 44, 4209.
(2) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029.
(3) (a) Guillen, F.; Fiaud, J.-C. Tetrahedron Lett. 1999, 40, 2939. (b)
Claver, C.; Fernandez, E.; Gillon, A.; Heslop, K.; Hyett, D. J.; Martorell,
A.; Orpen, A. G.; Pringle, P. G. Chem. Commun. 2000, 961. (c) Reetz, M.
T.; Mehler, G. Angew. Chem., Int. Ed. 2000, 39, 3889. (d) 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. (e) Hua,
Z.; Vassar, V. C.; Ojima, I. Org. Lett. 2003, 5, 3831.
10.1021/ol051559c CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/17/2005

TangPhos for the hydrogenation of aromatic acyclic enol
acetates.6b Catalysts such as Ru-Tunaphos and Rh-PennPhos
were found to be more efficient for cyclic enol acetates (up
to 99% ee).6c,f The only example of a successful use of
monodentate ligands was recently reported by Reetz, who
found enantioselectivities up to 94% ee for the more difficult
alkenyl carboxylates, using a Rh-monophosphite catalyst.7
Previously, using bidentate Duphos, 64% ee was obtained
in the hydrogenation of a comparable enol acetate.6g In most
cases, reaction times between 12 and 14 h have been
reported.8
A possible explanation for the slow development in this
area might be the weaker coordination of the acyl group of
the enol ester to the metal as compared to the enamides
(Figure 1). It is well-known that this secondary coordination
is important in the enantiodiscrimination.9
Figure 2. Monodentate phosphoramidites used in this study.
To our surprise MonoPhos (A1, Table 1, entry 1) induced
a very low ee in the hydrogenation of 1. On the contrary, a
high 90% ee was obtained by using ligand A4 (entries 2
Table 1. Asymmetric Hydrogenation of Enol Acetatesa
Figure 1. Substrates with bidentate structural features.
In view of the excellent results we have previously
obtained with BINOL-derived monodentate phosphoramid-
ites in the Rh-catalyzed hydrogenation of a variety of
olefins,3d,5,10 we became intrigued with the idea of applying
these ligands for the more challenging enol acetates. We also
envisioned the use of enol carbamates, in the hope that the
increased electron density would improve the binding
capabilities of the substrate to the metal center and make it
more akin to an enamide (Figure 1). To establish the activity
and selectivity of phosphoramidite-based catalysts, we
performed initial hydrogenation experiments on aromatic enol
acetates11 using a selection of phosphoramidite ligands
(Figure 2).
entry substrate product ligand conversionb (%) eec,d (%)
1
2
3
4
5
6
7
8
1
4
4
4
4
5
5
5
6
A1
A4
A4
A5
A4
A4
A5
A4
89
97
10 (R)
90 (R)
90 (R)
66 (R)
78 (R)
90 (R)
29 (R)
98 (R)
1
1e
1
100
90
2
74
2f
2
92
32
3
100
a Reactions were performed in 4 mL of solvent with 0.2 mmol of substrate
and 1 mol % catalyst at room temperature for 16 h. b Conversions
(6) (a) Liu, D.; Zhang, X. Eur. J. Org. Chem. 2005, 646. (b) Tang, W.;
Liu, D.; Zhang, X. Org. Lett. 2003, 5, 205. (c) Wu, S.; Wang, W.; Tang,
W.; Lin, M.; Zhang, X. Org. Lett. 2002, 4, 4495. (d) Chi, Y.; Zhang, X.
Tetrahedron Lett. 2002, 43, 4849. (e) Li, W.; Zhang, Z.; Xiao, D.; Zhang,
X. J. Org. Chem. 2000, 65, 3489. (f) Jiang, Q.; Xiao, D.; Zhang, Z.; Cao,
P.; Zhang, X. Angew. Chem., Int. Ed. 1999, 38, 516. (g) Boaz, N. W.
Tetrahedron Lett. 1998, 39, 5505. (h) Le Gendre, P.; Braun, T.; Bruneau,
C.; Dixneuf, P. H. J. Org. Chem. 1996, 61, 8453. (i) Ohta, T.; Miyake, T.;
Seido, N.; Kumobayashi, H.; Takaya, H. J. Org. Chem. 1995, 60, 357. (j)
Burk, M. J. J. Am. Chem. Soc. 1991, 113, 8518.
1
determined by H NMR and GC. c ee’s determined by chiral GC. d In all
cases, the (S)-enantiomer of the ligand was used. e Reaction carried out at
10 bar H2. f Reaction carried out at 20 bar H2.
and 3), while ligand A5 gave again a modest result (entry
4). Solvent screening indicated that CH2Cl2 was the best in
terms of enantioselectivity, similar to most phosphoramidite-
based hydrogenations.12 Using MeOH as solvent, the opposite
enantiomer (26% ee) was obtained. Good selectivity but
somewhat lower reactivity was observed by using ligand A4
on 1-p-Cl-phenyl-vinyl acetate (entries 5 and 6),13 whereas
an excellent 98% ee, with higher reactivity (entry 8), was
obtained with 1-p-NO2-phenyl-vinyl acetate. Small structural
(7) Reetz, M. T.; Goossen, L. J.; Meiswinkel, A.; Paetzold, J.; Jensen,
J. F. Org. Lett. 2003, 5, 3099.
(8) The only exception was reported by Boaz: 2 h reaction time for
1-alkyl-enol acetates and dienyl esters.6g
(9) Vineyard, B. D.; Knowles, W. S.; Sabacky, M. J. J. Mol. Catal. 1983,
19, 159.
(10) For some recent examples, see: (a) Bernsmann, H.; van den Berg,
M.; Hoen, R.; Minnaard, A. J.; Mehler, G.; Reetz, M. T.; de Vries, J. G.;
Feringa, B. L. J. Org. Chem. 2005, 70, 943. (b) Hoen, R.; van den Berg,
M.; Bernsmann, H.; Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. Org.
Lett. 2004, 6, 1433. (c) Pen˜a, D.; Minnaard, A. J.; de Vries, J. G.; Feringa,
B. L. J. Am. Chem. Soc. 2002, 124, 14552.
(11) For the preparation of enol acetates, see: (a) House, H. O.; Crumrine,
D. S.; Teranishi, A. Y.; Olmstead, H. D. J. Am. Chem. Soc. 1973, 95, 3310.
(b) Noyce, D. S.; Pollack R. M. J. Am. Chem. Soc. 1969, 91, 119.
(12) van den Berg, M.; Minnaard, A. J.; Haak R.; Leeman, M.; Schudde,
E. P.; Meetsma, A.; Feringa, B. L.; de Vries, A. H. M.; Maljaars, C. E. P.;
Willans, C. E.; Hyett, D.; Boogers, J. A. F.; Henderickx, H. J. W.; de Vries,
J. G. AdV. Synth. Catal. 2003, 345, 308.
4178
Org. Lett., Vol. 7, No. 19, 2005

changes (ligands A4 and A5) induced remarkably different
results (entries 2 vs 4, 5 vs 7). The outcome of this
preliminary investigation showed that monodentate phos-
phoramidites are indeed suitable ligands for the Rh-catalyzed
asymmetric hydrogenation of vinyl carboxylates. At this point
we decided to test our assumptions regarding the superiority
of vinyl carbamates with the same catalysts.
Simple 1-phenylvinyl N,N-dialkylcarbamates are accessible
from ketones by reacting the corresponding enolates with
carbamoyl chlorides (Scheme 1).14,15
obtained demonstrates the influence of the ligand structural
features. Other heterocyclic ring sizes in the ligand (A3 and
A7) resulted in poorer enantioselectivities compared to A4.
Changing the backbone of the ligand from BINOL to
octahydro-BINOL (B4) produced no change in the enantio-
selectivity, as 94% ee was achieved in both cases. In view
of the superior performance of ligands A4 and B4, they were
selected as the ligands of choice for further studies.
Table 3 shows the results obtained in the hydrogenation
Table 3. Asymmetric Hydrogenation of 1-Phenylvinyl
N,N-Dialkylcarbamatesa
Scheme 1. Synthesis of 1-Phenylvinyl N,N-Dialkylcarbamates
entry
substrate
product
ligand
eeb-d (%)
1
2
3
4
5
7e
8e
8f
8g
9
10
11
11
11
12
A4
A4
A4
B4
A4
94 (R)
96 (R)
98 (R)
96 (R)
95 (R)
In this way N,N-dimethyl (7), N,N-diethyl (8), and N,N-
diisopropyl (9) substituted vinyl carbamates were prepared.
Hydrogenation of 7 confirmed our assumptions, as evidenced
by an increase of enantioselectivity from 90% for 4 to 94%
ee for 10 using ligand A4 (Table 2, entry 4). Very good
a Reactions were performed in 4 mL of solvent with 0.2 mmol of substrate
and 1 mol % catalyst at room temperature for 16 h. b All reactions went to
full conversion. c ee’s were determined by chiral GC. d In all cases, the (S)-
enantiomer of the ligand was used. e Reaction completed after 4 h. f Reaction
carried out at -20 °C and 20 bar H2. g Reaction completed after 2 h.
of 1-phenylvinyl N,N-dialkylcarbamates, varying the sub-
stitution pattern on the nitrogen. A small increase in ee from
94% to 96% was noted in the hydrogenation of the N,N-
diethyl carbamate 8, with both ligands A4 and B4 (entries 2
and 4). An excellent 98% ee (entry 3) was also obtained by
decreasing the temperature to -20 °C. On the other hand,
no further improvement was achieved using substrate 9. It
should be emphasized that the catalyst loading for this set
of reactions was reduced to 1 mol %, without effecting
reactivity or enantioselectivities (entry 1). A closer look at
the reaction rate revealed a very efficient catalytic system
and a substantial difference between ligands A4 and B4, as
the reactions were found to be finished in around 4 and 2 h,
respectively.16 In view of these excellent results, we decided
to expand the substrate scope further (Figure 3).
Table 2. Asymmetric Hydrogenation of 1-Phenylvinyl
N,N-Dimethylcarbamate 7a
entry
ligand
conversionb (%)
eec,d (%)
1
2
A1
A2
A3
A4
A5
A6
A7
A8
B4
C4
100
100
100
100
100
6
19 (R)
64 (R)
14 (R)
94 (R)
93 (R)
22 (R)
76 (R)
92 (R)
94 (R)
15 (R)
3
4
5
6
7
100
3
8
Modifications of literature procedures, based on the
multigram-scale synthesis and R-lithiation of the simple vinyl
carbamate 19 (Scheme 2),17 allowed the preparation of
substrates 14-17 with perfect control over the regioselec-
tivity in good yields.18
9
100
77
10
a Reactions were performed in 4 mL of solvent with 0.2 mmol of substrate
and 2 mol % catalyst at room temperature for 16 h. b Conversions
determined by 1H NMR or GC. c ee’s determined by chiral GC. d In all
cases, the (S)-enantiomer of the ligand was used.
It should be noted that the preparation of substrate 13 was
not possible using the conditions described in Scheme 1. The
activities were obtained in almost all cases, except when a
sterically demanding amine (A8, entry 8) or BINOL moiety
(C4, entry 10) were used. The variety of enantioselectivities
(15) For an alternative synthesis, see also: Peters, J. G.; Seppi, M.;
Fro¨hlich, R.; Wibbeling, B.; Hoppe D. Synthesis 2002, 3, 381.
(16) The use of an Endeavor allows one to follow the uptake of H2 during
the reaction: Pen˜a, D.; Minnaard, A. J.; de Vries, A. H. M.; de Vries, J.
G.; Feringa, B. L. Org. Lett. 2003, 5, 475.
(13) Lower reactivity for this substrate was also observed using a Ru-
Tunaphos catalyst (48 h).6c
(14) (a) Olofson, R. A.; Cuomo, J.; Bauman, B. A. J. Org. Chem. 1978,
43, 2073. (b) Jiang, X.; van den Berg, M.; Minnaard, A. J.; Feringa, B. L.;
de Vries, J. G. Tetrahedron: Asymmetry 2004, 15, 2223.
(17) (a) Jung, M. E.; Blum, R. B. Tetrahedron Lett. 1977, 43, 3791. (b)
Bates, R. B.; Kroposki, L. M.; Potter, D. E. J. Org. Chem. 1972, 37, 560.
(18) (a) Sengupta, S.; Snieckus, V. J. Org. Chem. 1990, 55, 5680. (b)
Superchi, S.; Sotomayor, N.; Miao, G.; Joseph, B.; Snieckus, V. Tetrahedron
Lett. 1996, 37, 6057.
Org. Lett., Vol. 7, No. 19, 2005
4179

Table 4. Asymmetric Hydrogenation of Enol
N,N-Diethylcarbamates 13-18a
entry substrate productb ligand pressure H2 (bar) eec,d (%)
1
2
3
4
5
6
7
8
13
14
14
15
16
17
18
18
20
21
21
22e
23e
24
25
25
A4
A4
B4
A4
A4
A4
A4
B4
5
25
10
5
98 (R)
63 (S)
69 (S)
73
5
43
10
15
10
97 (R)
76 (R)
77 (R)
a Reactions were performed in 4 mL of solvent with 0.2 mmol of substrate
and 1 mol % catalyst at room temperature for 16 h. b Conversions
determined by 1H NMR or GC; all reactions went to completion. c ee’s
were determined by chiral GC. d In all cases, the (S)-enantiomer of the ligand
was used. e The absolute configuration has not been established.
Figure 3. Enol carbamate hydrogenation substrates.
same conditions would prevent the selective preparation of
substrates such as 14 or 15, since a mixture of the internal
(E/Z) and the desired terminal double bond would be
obtained. Hence, the method presented in Scheme 2 is very
versatile. Substrate 18 was instead synthesized following
Scheme 1.11a
(only 10 bar H2 were used) for this substrate when using
ligand B4 (entry 3).20 Interestingly the sterically hindered
substrate 16 could also be hydrogenated to full conversion
(entry 5), although the enantioselectivity was modest. To our
surprise, an excellent 97% ee was achieved for the dienyl
substrate 17 (entry 6), and only 10 bar H2 was necessary to
achieve complete conversion to the product.21 On the other
side, lower enantioselectivity was observed for the dienyl
carbamate 18 (entries 7 and 8). It should be mentioned that
in both cases the catalytic system showed very good
selectivity as the hydrogenation proceeded leaving the extra
internal double bond intact.
Scheme 2. Regiocontrolled Synthesis of Enol
N,N-Diethylcarbamates19
In conclusion, we have shown that monodentate phos-
phoramidites, in particular PipPhos (A4) and its octahydro
analogue (B4), are excellent ligands for the rhodium-
catalyzed asymmetric hydrogenation of aromatic enol ac-
etates, aromatic enol carbamates, and 2-dienyl carbamates
with excellent enantioselectivities up to 98%. Fast reactions
were achieved, making the combination of enol carbamates
and monodentate phosphoramidites very competitive com-
pared to the existing systems.
The results of the asymmetric hydrogenation of substrates
13-18 are depicted in Table 4. An excellent 98% ee (entry
1) was obtained for substrate 13, confirming also for enol
carbamates the importance of an electron-withdrawing group
on the aromatic moiety. Moreover, this substituent had a
beneficial influence also on the activity, as the reaction was
finished after around 1 h. According to Burk, the presence
of electron-withdrawing groups enhances metal olefin bind-
ing, resulting in higher rates and enantioselectivities.6j As
shown for substrate 15 (entry 4), the presence of a benzyl
group causes a decrease in enantioselectivity (73% ee),
although full conversion was achieved with 5 bar H2 using
A4. When the substituent is an alkyl group (substrate 14), a
further decrease in enantioselectivity (63% ee, entry 2) was
observed and a higher pressure was necessary in order to
reach full conversion. We were pleased to see an increase
both in terms of enantioselectivity (69% ee) and reactivity
Acknowledgment. We thank Dr. H. Bernsmann for a
donation of ligands, T. D. Tiemersma-Wegman and E. P.
Schudde for technical support, and A. Kiewiet for mass
spectrometry. Financial support from CW/STW is gratefully
acknowledged.
Supporting Information Available: Experimental data,
spectral data for new or not described substrates and products,
and methods for enantiomeric excess determination. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL051559C
(19) See Supporting Information for more details.
(20) The results on substrates 14 and 15 are comparable with those
obtained by using Duphos on similar enol acetates; see ref 6g.
(21) A similar phenomenon was previously observed by using Duphos
on a similar enol acetate; see ref 6g.
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Org. Lett., Vol. 7, No. 19, 2005