Asymmetric enamide hydrogenation using planar-chiral cyrhetrenes

Article abstract of DOI:10.1016/j.tetlet.2007.06.113

The catalytic asymmetric hydrogenation of α-arylenamides using catalysts prepared in situ from [Rh(cod)₂]BF₄ and cyrhetrenyldiphosphines was effective with a range of enamides. The corresponding acetamides were obtained with up to 93

Full text of DOI:10.1016/j.tetlet.2007.06.113

Tetrahedron Letters 48 (2007) 6189–6191
Asymmetric enamide hydrogenation using planar-chiral cyrhetrenes
Ren e´ T. Stemmler and Carsten Bolm*
Institut f u¨ r Organische Chemie der RWTH Aachen, Landoltweg 1, D-52074 Aachen, Germany
Received 20 May 2007; revised 19 June 2007; accepted 22 June 2007
Available online 24 June 2007
Abstract—The catalytic asymmetric hydrogenation of a-arylenamides using catalysts prepared in situ from [Rh(cod)
cyrhetrenyldiphosphines was effective with a range of enamides. The corresponding acetamides were obtained with up to 93% ee.
2007 Elsevier Ltd. All rights reserved.
2 4
]BF and
ꢀ
Asymmetric hydrogenations catalyzed by transition
metals continue to find widespread applications not only
An initial screening with N-(1-phenylvinyl)acetamide
(6a) as substrate revealed that the optimal conditions
involved a catalyst formed in situ from 1 mol % of
[Rh(cod) ]BF and 1.1 mol % of diphosphine 1, ethyl
1
,2
in academia but also in industry. Considerable efforts
have been devoted to the development of new, effective
ligands, since enantioselective hydrogenation reactions
are highly atom economic and give products which are
important building blocks for the synthesis of biologi-
cally active compounds.
2
4
acetate as solvent and a hydrogen pressure of 10 bar
(Scheme 2). Use of bis(diphenylphosphino)-substituted
cyrethrene 1b led to the most enantioselective catalyst
affording 7a with 93% ee at room temperature (Table
5
,7
1
, entry 1).
As part of our continuing studies of cyrhetrene-contain-
3
ing ligands for asymmetric catalysis, we recently
In order to examine the substrate scope, conversions of
several substituted a-arylenamides were investigated
8
reported the synthesis of novel planar-chiral phosphines
1
(AaPhos-type), 2 and 3 bearing cyrhetrene backbones
using [Rh(cod) ]BF and cyrhetrene 1b as catalyst sys-
2
4
4
9
(
Fig. 1). Their palladium(II) and rhodium(I) complexes
tem in ethyl acetate at room temperature. Enamides
6b–e bearing either electron withdrawing substituents
or electron donating ones on the aromatic ring were
reduced to the corresponding acetamides 7b–e having
85–91% ee within 24 h (Table 1, entries 2–5). Generally,
a hydrogen pressure of 10 bar was applied and only in
the case of (4-methoxyphenyl)enamide (6d) a pressure
of 20 bar was necessary to achieve full conversion.
ortho-Substitution on the aromatic ring slowed down
are highly effective catalysts for asymmetric allylic alkyl-
ation, the hydrogenation of various olefins and the
Hayashi-Miyaura reaction. Herein, we describe the
application of cyrhetrenes 1 in the rhodium-catalyzed
5
asymmetric hydrogenation of a-arylenamides.
Cyrhetrenes 1 were synthesized in a five-step procedure
from acetylcyrhetrene (4) as reported earlier (Scheme
1
4
,6
10
).
the reaction significantly, presumably due to steric
congestion. Application of (2-bromophenyl)enamide
(
6f) in the hydrogenation reaction at a hydrogen pres-
sure of 50 bar led to only 20% conversion, furnishing
product 7f with low ee (entry 6). Additional substitution
on the olefin moiety was tolerated, although an in-
creased hydrogen pressure was necessary in these cases
as well. Both enamides 6g and 6h were applied as a mix-
ture of E/Z-isomers in a 2:1 ratio. (4-Methylphenyl)ena-
mide (6g) was hydrogenated to the corresponding
acetamide 7g with high enantioselectivity (91% ee; entry
Me
Me
PR'2
OR'
PR2
CO
PR2
CO
PPh2
CO
Re
Re
Re
OC
OC
OC
CO
CO
CO
1
2
3
Figure 1. Planar-chiral cyrhetrenyl phosphines.
7). In contrast, acetamide 7h was isolated with only 68%
*
Corresponding author. Fax: +49 241 809 2391; e-mail: carsten.bolm@
oc.rwth-aachen.de
ee (entry 8). It is known that some catalyst systems
hydrogenate isomeric mixtures of E/Z-enamides with
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.06.113

6190
R. T. Stemmler, C. Bolm / Tetrahedron Letters 48 (2007) 6189–6191
O
1) CBS reduction
Me
1) ClCO2CH(Cl)Me,
HPR'2, TlPF6,
BH3 •THF
Me
2
3
) NaI, TMSCl, Me NH
2
Me
NMe2
PR'2
) nBuLi, ClPR2
PR2
CO
PR2
CO
Re
CO
4
Re
CO
(
Re
CO
OC
CO
OC
2) HBF , NaHCO
OC
4
3
R
,
S
p)-5
(R,Sp)-1
1
a R = Ph, R' = Cy (AaPhos)
1
1
1
b R = Ph, R' = Ph
c R = 3,5-Me Ph, R' = Ph
2
d R = Ph, R' = 3,5-Me Ph
2
Scheme 1. Synthesis of diphosphines 1.
O
O
O
[Rh(cod) ]BF (1.0 mol%),
O
2
4
[
Rh(cod) ]BF (1 mol%),
2 4
cyrhetrene (1.1 mol%)
1
b (1.1 mol%),
H (20 bar)
2
Me
NH
Ph
Me
NH
Ph
Me
NH
Me
Me
NH
Me
Me
Me
Me
Me
Me
H2 (10 bar), EtOAc, rt
Me
7a
EtOAc, rt, 27 h
6
a
6i
7i
Scheme 2. Asymmetric hydrogenation of a-arylenamide 6a.
33%, 5% ee
O
O
[
Rh(cod) ]BF (1.0 mol%),
2 4
high enantioselectivity, while others are sensitive to the
NH
1b (1.1 mol%),
H (50 bar)
2
NH
1
1,12
configuration of the double bond.
The current sys-
Me
Me
tem appears to be substrate dependent in this respect.
EtOAc, rt, 36 h
7
j
Additionally, the aliphatic enamide 6i and the cyclic
enamide 6j were subjected to the hydrogenation (Scheme
6j
4
1%, 6% ee
3
). Unfortunately, in both cases the enantioselectivity
was low and the conversion was incomplete, even at
0 and 50 bar of hydrogen pressure, respectively. While
Scheme 3. Additional enamides examined in the asymmetric hydro-
genation reaction.
2
in the former case steric bulk probably inhibited proper
coordination of the substrate and therefore led to lower
turnover, in the latter case the E-configured double
bond of enamide 6i might be the cause of the observed
could be applied, which expands the utility of the
methodology. However, in some cases a Z-configured
double bond seems to be necessary for high
enantioselectivity.
1
4
lack of enantioselectivity.
In conclusion, AaPhos derivatives 1a–d have been suc-
cessfully applied in the rhodium-catalyzed asymmetric
hydrogenation of various a-arylenamides 6, which
provided the corresponding acetamides 7 with up to
Acknowledgements
The authors are grateful to the Deutsche Forschungs-
gemeinschaft (SFB 380) and the Fonds der Chemischen
Industrie for financial support. Experimental assistance
9
3% ee. Furthermore, b-substituted a-arylenamides
Table 1. Substrate scope of the asymmetric hydrogenation of a-arylenamides 6
O
O
[
Rh(cod) ]BF (1.0 mol%),
2 4
Me
R
NH
Me
R
NH
cyrhetrene 1b (1.1 mol%)
H , EtOAc, rt
2
R'
R'
6
a−h
7a−h
0
a,b
ee (%)
Entry
R
R
H
Time (h)
p(H
2
) (bar)
Product
Conversion (%)
1
2
3
4
5
6
H
H
H
H
H
H
Me
Me
16
22
24
20
22
72
20
22
10
10
10
20
10
50
20
20
7a
7b
7c
7d
7e
7f
100
100
100
100
100
20
93 (R)
91 (R)
89 (R)
85 (R)
88 (R)
3
4-Cl
4-CF
3
4-MeO
4-Me
2-Br
4-Me
H
c
7
c
7g
7h
100
100
91 (R)
68 (R)
8
a
The enantiomeric ratios were determined by HPLC using a chiral stationary phase. See Ref. 13 for details.
Absolute configurations of the products were either assigned by comparison of their optical rotation with literature data or are based on the
assumption of an identical reaction pathway.
b
c
An isomeric mixture of the enamide (E/Z 2:1) was employed.

R. T. Stemmler, C. Bolm / Tetrahedron Letters 48 (2007) 6189–6191
6191
by K. Deckers is appreciated, and R.T.S. thanks DFG
Casy, G.; Johnson, N. B. J. Org. Chem. 1998, 63, 6084–
085.
. Typical procedure for the hydrogenation of enamides 6:
Rh(cod) ]BF (2.0 mg, 5.0 lmol, 1.0 mol %) and cyrhet-
6
(
GRK 440) for a predoctoral stipend.
9
[
2
4
rene 1b (4.0 mg, 5.5 lmol, 1.1 mol %) were placed in a vial
under argon, dissolved in ethyl acetate (0.4 mL) and
stirred at room temperature for 20 min. A solution of
enamide 6a (81 mg, 0.50 mmol) in ethyl acetate (0.4 mL)
was added, and the vial was placed into an argon-filled
100 mL autoclave. The autoclave was sealed, purged with
hydrogen (3 · 10 bar) and finally pressurized to 10 bar.
The reaction mixture was stirred for 16 h, after which full
conversion of the starting material was achieved as
indicated by TLC analysis (pentane/ethyl acetate 1:3).
The solution was filtered through a short plug of silica gel
(elution with ethyl acetate) and concentrated. N-(1-Phen-
References and notes
1
. For overviews of industrial aspects see: (a) J a¨ kel, C.;
Paciello, R. Chem. Rev. 2006, 106, 2912–2942; (b) Feder-
sel, H.-J. Nat. Rev. Drug Disc. 2005, 4, 685–697; (c)
Hawkins, J. M.; Watson, T. J. N. Angew. Chem., Int. Ed.
004, 43, 3224–3228; Angew. Chem. 2004, 116, 3286–3290;
d)Asymmetric Catalysis on Industrial Scale; Blaser, H.-U.,
Schmidt, E., Eds.; Wiley-VCH: Weinheim, Germany,
004; (e) Blaser, H.-U. Chem. Commun. 2003, 293–296;
f) Blaser, H.-U.; Spindler, F.; Studer, M. Appl. Catal. A:
2
(
2
(
Gen. 2001, 221, 119–143.
. For overviews of phosphorous ligands for asymmetric
hydrogenation, see: (a) Tang, W.; Zhang, X. Chem. Rev.
ylethyl)acetamide (7a) was isolated as pale yellow solid
1
2
(81 mg, 99%). H NMR (400 MHz, CDCl
3
) d 1.49 (d,
J = 6.9 Hz, 3H), 1.99 (s, 3H), 5.13 (dq, J = 7.4, 6.9 Hz,
1H), 5.64 (br s, 1H, NH), 7.25–7.37 (m, 5H). The
enantiomeric ratio was determined by chiral GC using
a FS Cyclodex b-I/P capillary column (25 m · 0.2 mm),
2
003, 103, 3029–3070; (b) Blaser, H.-U.; Malan, C.; Pugin,
B.; Spindler, F.; Steiner, H.; Studer, M. Adv. Synth. Catal.
003, 345, 103–151.
2
5
3
4
. Cyrhetrene is an abbreviation for g -cyclopentadienyl-
rhenium(I) tricarbonyl complexes.
with H
2
as the carrier gas; 49.4 min (minor), 50.7 min
(major).
. (a) Bolm, C.; Xiao, L.; Hintermann, L.; Focken, T.;
Raabe, G. Organometallics 2004, 23, 2362–2369; (b)
Stemmler, R. T.; Bolm, C. J. Org. Chem. 2005, 70,
10. ortho-Substituted a-arylenamides are generally challeng-
ing substrates in the hydrogenation reaction, and they
often lead to low enantiomeric excesses of the correspond-
ing acetamides. The influence of ortho-substitutents has
been studied, and alternative modes of coordination of the
enamide, which are competitive in the case of ortho-
substituted a-arylenamides, were suggested by Imamoto:
Gridnev, I. D.; Yasutake, M.; Higashi, N.; Imamoto, T.
J. Am. Chem. Soc. 2001, 123, 5268–5276.
11. For examples of insensitive catalyst systems see: (a) Burk,
M. J.; Wang, Y. M.; Lee, J. R. J. Am. Chem. Soc. 1996,
118, 5142–5143; (b) Zhu, G.; Zhang, X. J. Org. Chem.
1998, 63, 9590–9593; (c) Li, W.; Zhang, X. J. Org. Chem.
2000, 65, 5871–5874; (d) Zeng, Q.-H.; Hu, X.-P.; Duan,
Z.-C.; Liang, X.-M.; Zheng, Z. J. Org. Chem. 2006, 71,
393–396.
12. For an example of a catalyst system sensitive to the
configuration of the enamide-double bond see: Imamoto,
T.; Oohara, N.; Takahashi, H. Synthesis 2004, 1353–1358.
13. The enantiomeric ratios were determined by HPLC or GC
using a chiral stationary phase [HPLC: Daicel Chiralcel
columns, GC: FS-Cyclodex b I/P (25 m · 0.2 mm)]. The
separation conditions for compounds 7b–j are as follows:
Acetamide 7b: AS, heptane/2-PrOH 90:10, 1.0 mL/min,
220 nm, 22.6 min (minor), 25.9 min (major); 7c: AS,
heptane/2-PrOH 90:10, 1.0 mL/min, 205 nm, 15.5 min
(minor), 17.8 min (major); 7d: OD, heptane/2-PrOH
90:10, 1.0 mL/min, 220 nm, 9.7 min (major), 11.4 min
(minor); 7e: AD-H, heptane/2-PrOH 95:5, 0.6 mL/min,
220 nm, 16.9 min (major), 22.4 min (minor); 7f: AD-H,
heptane/2-PrOH 90:10, 0.6 mL/min, 220 nm, 9.4 min
(major), 11.1 min (minor); 7g: OD-H, heptane/2-PrOH
95:5, 0.55 mL/min, 220 nm, 16.6 min (major), 19.7 min
(minor); 7h: OD-H, heptane/2-PrOH 90:10, 0.55 mL/min,
220 nm, 17.9 min (major), 20.6 min (minor); 7i: FS-
9
1
925–9931; (c) Stemmler, R. T.; Bolm, C. Synlett 2007,
365–1370.
5
6
. Preliminary results of the hydrogenation of enamide 6a
have been reported earlier, see Ref. 4b.
. Analytical data for new cyrhetrene 1d: mp: 139–142 ꢁC
2
D
3
1
(
C
2
dec); ½aꢀ ꢁ143 (c 1.1, CHCl
3
); H NMR (300 MHz,
6
D
6
) d 1.37 (dd, J = 6.7, 6.2 Hz, 3H, CH
3
), 1.92 (s, 6H,
· ArCH ), 2.07 (s, 6H, 2 · ArCH ), 4.29–4.43 (m, 2H,
3
3
Cp-CH, CH), 4.64–4.73 (m, 1H, Cp-CH), 5.01 (dd,
J = 2.7, 1.6 Hz, 1H, Cp-CH), 6.56 (s, 1H, Ar-CH), 6.79
(
s, 1H, Ar-CH), 6.97–7.23 (m, 10H, Ar-CH), 7.41 (dt,
J = 8.0, 1.3 Hz, 2H, Ar-CH), 7.57 (dt, J = 8.1, 1.7 Hz, 2H,
1
3
Ar-CH); C NMR (75 MHz, C
6
D
6
) d 19.1 (CH
), 29.7 (dd, J = 21.0, 10.3 Hz, CH), 79.6
Cp-CH), 86.8 (d, J = 3.9 Hz, Cp-CH), 93.6 (d,
3
), 21.2
(
(
6C, 4 · ArCH
3
J = 5.0 Hz, Cp-CH), 96.9 (dd, J = 17.5, 15.4 Hz, Cp-C),
22.0 (d, J = 22.5 Hz, Cp-C), 127.9 (Ar-CH), 128.7 (d,
1
J = 10.8 Hz, 2C, Ar-CH), 128.9 (d, J = 7.9 Hz, 2C, Ar-
CH), 129.8 (2C, Ar-CH), 130.0 (2C, Ar-CH), 130.2 (Ar-
CH), 131.6 (Ar-CH), 133.2 (Ar-CH), 133.5 (Ar-CH), 133.7
(
d, J = 21.6 Hz, 2C, Ar-CH), 134.9 (J = 21.7 Hz, 2C, Ar-
CH), 136.9 (d, J = 18.5 Hz, 2C, Ar-C), 137.6 (d,
J = 7.8 Hz, 2C, Ar-C), 138.0 (d, J = 5.2 Hz, 2C, Ar-C),
3
1
1
38.5 (d, J = 7.3 Hz, 2C, Ar-C); P NMR (121 MHz,
) d ꢁ29.61 (d, J = 25.4 Hz), +11.68 (d, J = 25.4 Hz);
6 6
C D
ꢁ1
IR (KBr, cm ) m 2019, 1921, 1435, 1038, 845, 744, 695,
+
+
6
7
[
[
5
(
10, 505; MS (EI) m/z (%) 788 (M , 18), 786 [(Mꢁ2) , 10],
+
+
60 [(MꢁCO) , 100], 758 [(Mꢁ2ꢁCO) , 64], 732
+
+
(Mꢁ2CO) , 25], 730 [(Mꢁ2ꢁ2CO) , 15], 575
2 2
+
+
(MꢁCOꢁPPh ) , 60], 573 [(Mꢁ2ꢁCOꢁPPh ) , 38],
+
47 [(MꢁPXyl ) , 16], 546 (16), 518 (14), 461 (17), 459
2
11). Anal. Calcd for C38H O P Re: C, 57.93; H, 4.48.
35 3 2
Found: C, 57.65; H, 4.81.
2
Cyclodex b I/P, 80 kPa H , 80.4 min (minor), 81.0 min
7
8
. The following enantioselectivities have been achieved: 1a
in DCM): 87% ee; 1b (in EtOAc): 93% ee; 1c (in EtOAc):
7% ee; 1d (in EtOAc): 78% ee.
. All enamides were prepared according to reported proce-
dures by Burk: (a) Burk, M. J.; Wang, Y. M.; Lee, J. R. J.
Am. Chem. Soc. 1996, 118, 5142–5143; (b) Burk, M. J.;
(major); 7j: OD-H, Heptan/2-PrOH 90:10, 0.55 mL/min,
210 nm, 28.2 min (minor), 33.3 min (major).
(
7
14. Presumably, the Z-isomer of a-arylenamides is hydroge-
nated more selectively, which was also observed by
*
Imamoto using the DiSquareP /Rh(I) catalyst system,
see Ref. 12.