Ruthenium-Catalysed Enantioselective Hydrogenation of Trisubstituted Enamides Derived from 2-Tetralone and 3-Chromanone: Influence of Substitution on the Amide Arm and the Aromatic Ring

Article abstract of DOI:10.1002/adsc.200390017

Cyclic enamides were prepared in one step from tetralone and chromanone derivatives and primary amides under acidic conditions. The enantio-selective hydrogenation of these enamides bearing an endocyclic trisubstituted carbon-carbon double bond was perfor

Full text of DOI:10.1002/adsc.200390017

FULL PAPERS
Ruthenium-Catalysed Enantioselective Hydrogenation of
Trisubstituted Enamides Derived from 2-Tetralone and
3-Chromanone: Influence of Substitution on the Amide Arm
and the Aromatic Ring
J. L. Renaud, P. Dupau, A.-E. Hay, M. Guingouain, P. H. Dixneuf, C. Bruneau*
¬
¬
Institut de Chimie, UMR 6509, Organometalliques et Catalyse, Universite de Rennes 1, Campus de Beaulieu-35042
Rennes Cedex, France
Fax: [ ‡ 33]-2-23-23-69-39, e-mail: christian.bruneau@univ-rennes1.fr
Received: July 5, 2002; Accepted: September 20, 2002
Abstract: Cyclic enamides were prepared in one step precatalysts were used. On the other hand, the
from tetralone and chromanone derivatives and presence of a coordinating atom at some specific
primary amides under acidic conditions. The enantio- position on the tetralone and chromanone skeleton
selective hydrogenation of these enamides bearing an led to a dramatic decrease of the enantiomeric
endocyclic trisubstituted carbon-carbon double bond excesses.
was performed at room temperature in the presence
of ruthenium catalysts. On the one hand, the nature of
the amide group had little influence on the enantio- Keywords: asymmetric catalysis; chiral ligand; hydro-
selectivity of the hydrogenation when mononuclear genation; optically active amides; ruthenium
Introduction
rhodium which encourages a high degree of spatial
definition on coordination, this is a model reaction that
Since the pioneering work on cyclopropanation,[1] and cannot be directly transferred to any type of enamide
on hydrogenation,[2,3] enantioselective catalysis has derivatives. By contrast, electron-rich olefins, such as
undergone an explosive growth,[4] especially during the simple enolates or enamines, are generally poor sub-
last decade, due to the synthesis of new chiral ligands strates for asymmetric hydrogenation with most known
and progress in organometallic chemistry.[5] Today, the systems.[9b,11] Recently, some groups have reported that
increasing number of industrial applications clearly rhodium complexes bearing electron-rich phosphine
demonstrates its efficiency and its practicability.[6]
ligands,[12] a spirocyclic phosphite,[13] or a conformation-
One of the still challenging enantioselective processes ally rigid cyclic backbone [14] were efficient catalysts for
is the preparation of optically active amine derivatives, the hydrogenation of enamides.
which constitute a class of key intermediates for human
We focused our interest on the preparation of
and plant health and are efficient ligands in asymmetric optically active 3-aminochromanes and 2-aminotetra-
catalysis.[7] Among the methods allowing the synthesis lines which are presentin biologically active compounds
of such enantiopure compounds,[8] the hydrogenation of such as (‡)-S20499,[15] MK-0499,[16] and SR-58611A.[17]
enamines, ene-amides, ene-carbamates, imines... repre- Our strategy was based on the hydrogenation of the
sents one of the most direct routes.[9]
enamides of 2-tetralone and 3-chromanone catalysed by
Precursors of amines can be classified in two major chiral ruthenium complexes.
groups: those arising from dehydroamino acids and
In this paper, we wish to report the synthesis of
those from protected enamines. Since Knowles×[2] and trisubstituted enamides bearing different functionalities
Kagan×s[3] works, the hydrogenation of dehydroamino linked to the aromatic ring in order to understand the
acids has been extensively and successfully studied.[10] influence of the nature of the amide moiety and the
These intensive efforts have led to the synthesis of
variety of new diphosphine ligands: phospholane,[10a]
H
N
H
N
neutral polyhydroxyphospholane,[10a, b] phosphine,[10c, d]
phosphite,[10d] and supported phosphine.[10e, f] However,
due to the formation of a chelated complex between the
Z
Z
*
Y
Y
O
O
X
X
dehydroamino acid [an electron-deficient olefin] and Scheme 1.
230
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 1615-4150/03/3451+2-230 238 $ 17.50-.50/0
Adv. Synth. Catal. 2003, 345, No. 1+2

Ru-Catalysed Enantioselective Hydrogenation of Trisubstituted Enamides
FULL PAPERS
Table 2. Enantioselective hydrogenation with catalyst A.[a]
substitution pattern on the aromatic ring during the
catalytic hydrogenation process (Scheme 1).
Entry
R
Compound
Yield
[%]
ee [%9
1
2
3
4
Me
Et
Pr
Ph
CH2Cl
CH2OMe
CH2OBn
5a
5b
5c
5d
5e
5f
94
94
95
94
94
95
98
80 (‡)
76 (‡)
80 (‡)
87 (‡)
47 (‡)
56 (‡)
27 (‡)
Results and Discussion
Preparation of the Enamides
5(b]
6
Recently, the preparation of acetamide derivatives from
ketones has been carried out in a two-step procedure
which involved transformation of the ketone into an
oxime followed by treatment with iron metal in the
presence of acetic anhydride and acetic acid.[12e, f] How-
ever, this method based on the use of acetic derivatives
allows only the preparation of N-acetylenamides. A
more direct and general transformation of a ketone into
7
5g
[a]
General conditions : substrate 1a g (0.5 mmol), catalyst
(0.2 mol %), MeOH (5 mL), hydrogen pressure
(10 MPa), r.t., isolated yields.
[b]
At60 8C.
an enamide based on the condensation with a primary fonic acid as catalyst and by using a Dean À Stark
amide has been performed in the presence of Amber- apparatus to remove water (Scheme 2).
lyst 15 as dehydrating agent to prepare trisubstituted
Under similar conditions the enamides of 2-tetralone,
3-chromanone and their methoxy- and bromo-substi-
enamides.[16,17]
Recently, we have also reported an easy and direct tuted derivatives were obtained in good yields (55
route to enamides[18] and ene-carbamates[19] based on 98%, Table 1). It is noteworthy that this method makes
the condensation of primary enamides and carbamates possible the preparation of the enamides 1e h and 4b
with cyclic ketones in the presence of para-toluenesul- bearing an additional chelating group on their amide
arm, and offer the possibility of studying its influence on
the subsequent enantioselective hydrogenation.
All the enamides were obtained by using 2.5 equiv-
alents of primary amides, except for the compound 1e
R1
R1
H
N
which required 5 equivalents of the chloroacetamide.
The necessity of increasing the amount of amide might
be due toan electron-attracting effect, which leads to the
deactivation of the amide moiety. The same effect
probably explains that, under similar conditions, no
conversion into the desired product was obtained with
trichloroacetamide.
This new method opens a general and direct route to
enamides from non-activated cyclic ketones and makes
possible the preparation of a variety of enamides.
R
O
PTSA, toluene, ∆
RCONH2
O
X
X
1a-h: R1 = H, X = CH2
2a-b: R1 = Br, X = CH2
3a-b: R1 = H, X = O
4a-b: R1 = OMe, X = O
Scheme 2.
Table 1. Preparation of the enamides 1a h, 2a, b, 3a, b, 4a, b.
R1
R
Compound
Yield
[%]
Hydrogenation of Enamides 1a g
Entry
X
When the enamides 1a g were hydrogenated in the
presence of 2 mol % of the dimeric catalyst
[NH2Et2][{(S)-BinapRuCl}2(m-Cl)3][20] in methanol at
room temperature, their conversion was completed
within 20 h and the amides 5a g were obtained in
good yields (94 98%, Scheme 3).
With this catalyst, ees are located in the range 27
87%. The nature of the amide moiety plays a role in the
enantioselective process. The introduction of a chelating
heteroatom at the b-position of the amide dramatically
decreased the ees (entries 5 7). These results might be
explained by a competing chelation between the car-
bonyl group and the heteroatom of the amide chain with
the metal during the hydrogenation reaction.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
O
H
H
H
H
H
H
H
H
Br
Br
H
H
OMe
OMe
Me
Et
Pr
Ph
CH2Cl
CH2OMe
CH2OBn
CH2SBn
Me
Ph
Me
Ph
Me
1a
1b
1c
1d
1e
1f
1g
1h
2a
2b
3a
3b
4a
4b
80
98
98
80
75
80
80
90
63
79
55
63
80
50
O
O
O
CH2OMe
Adv. Synth. Catal. 2003, 345, 230 238
231

J. L. Renaud etal.
FULL PAPERS
H
N
H
N
H
N
H
N
R
R
H2 (10 MPa), MeOH, r.t.
*
H2 (10 MPa), MeOH, r.t.
*
O
O
O
O
20 h, catalyst A or B
20 h, catalyst A or B
1a-g
5a-g
7
6
(+)-7: 64% ee with catalyst A
(−)-7: 94% ee with catalyst B
catalyst A: [NH2Et2][{(S)-BinapRuCl}2(µ-Cl)3] 0.2 mol %
catalyst B: ((R)-Binap)Ru(O2CCF3)2 0.5 mol %
Scheme 4.
Scheme 3.
from the sulfide to the sulfone 1i by oxidation with an
excess of H2O2 did not improve the reaction as no
hydrogenation was observed. Further experiments
proved that those sulfur-containing enamides could
interact with the catalyst. Indeed the hydrogenation of
1a which furnished the tetrahydronaphthylacetamide 5a
in 95% yield and 90% ee in the presence of 0.5 mol % of
[(R)-Binap]Ru(O2CCF3)2, was inhibited by addition of
10 mol % of 1h to the starting compound. Only the
starting material 1a was totally recovered. When we
carried out the hydrogenation of 1h in the presence of
0.5 mol % of [Ru(COD)Cl2]n and (S)-MeO-Biphep as a
chiral ligand,[23] the same result was observed.
The better efficiency of the precatalyst B for the
enantioselective hydrogenation of enamides derived
from tetralone has been confirmed by the hydrogena-
tion of the 7-methyltetralone-eneacetamide 6, obtained
in 63% yield from the corresponding ketone under the
conditions described in Table 1 and Scheme 2. Thus,
hydrogenation of 6 in the presence of 0.5 mol % of the
Table 3. Enantioselective hydrogenation with catalyst B.[a]
Entry
R
Compound
Yield [%]
ee [%]
1
Me
Me
Et
Pr
5a
5a
5b
5c
5d
5e
5f
95
95
95
95
95
95
95
98
90 (À)
90 (À)
90 (À)
92 (À)
96 (À)
71 (À)
89 (À)
89 (À)
2[b]
3
4
5
Ph
6[c]
7
CH2Cl
CH2OMe
CH2OBn
CH2SBn
8[d]
9
5g
5h
no reaction
[a]
General conditions: substrate 1a g (0.5 mmol), catalyst
(0.5 mol %), MeOH (5 mL), hydrogen pressure
(10 MPa), r.t., isolated yields.
0.1 mol % of ruthenium complex.
1 mol % of ruthenium complex.
[b]
[c]
[d]
0.2 mol % of ruthenium complex.
Better results in terms of enantioselectivity were catalyst precursor A or B in methanol at room temper-
obtained when [(R)-Binap]Ru(O2CCF3)2 B was used as ature under 10 MPa of hydrogen pressure and after 20 h
catalyst precursor (Scheme 3, Table 3). afforded quantitative yields of the corresponding amide
Starting from the enamides 1a c where R is an alkyl 7 in 64 and 94% ee, respectively (Scheme 4).
group or 1f, g where R is an ether group, ees around 90%
were obtained which indicated that the amide chain in
these examples had no significant influence on the Hydrogenation of Enamides 2, 3 and 4
enantioselectivity of the hydrogenation, even with only
0.1 mol % of catalyst loading (entries 1 and 2). The best From the preceding results, it appeared that the right
enantiomeric excess was obtained from the benzoyl choice of the catalyst precursor was essential to achieve
enamide 1d which led to 5d in 96% ee. This is in high enantioselectivity. The catalytic activity of the
agreement with previous results[17] and mightbe ex-
plained by the rigidity of the enebenzamide system.
dimeric complex was more sensitive to the presence of
an heteroatom on the amide moiety than the monomeric
The chloromethylacetamide 1e led to the hydro- ruthenium complex and the best results for the hydro-
genated derivative 5e in 95% yield butin only 71% ee. genation of this type of enamides were obtained with
This lower enantiomeric excess might arise either from a [(R)-Binap]Ru(O2CCF3)2 as precatalyst.
competing chelation of the chloride atom, or a weaker
To study the influence of a coordinating heteroatom
interaction between the amide moiety and the ruthe- on the enantioselectivity of the hydrogenation, the
nium centre, due to the electron-attracting effect of the eneacetamides 2a (63%), 3a (55%) and enebenzamides
chloride atom. Nevertheless, this result is still better 2b (79%), 3b (63%) were prepared starting from the
than that obtained with the dimeric ruthenium precata- corresponding 8-bromo-2-tetralone 9[24] and the unsub-
lyst(47% ee).
stituted 3-chromanone 10[25] according to our method
By contrast with the good results obtained for the (Figure 1).
hydrogenation of aliphatic sulfides[21] and sulfones,[22] no
This influence of an heteroatom was noticed during
reaction occurred with our substrate 1h in these the hydrogenation of the chromanone derivatives 4a, b
conditions. This suggests that the sulfide derivative (Scheme 5, Table 4, entries 1 4), where the highest
poisons the catalyst and thus inhibits its reactivity. Going enantiomeric excesses were obtained with [(R)-Binap]-
232
Adv. Synth. Catal. 2003, 345, 230 238

Ru-Catalysed Enantioselective Hydrogenation of Trisubstituted Enamides
FULL PAPERS
R1
Br
R1
H
N
H
N
O
O
R
R
H2 (10 MPa), MeOH, r.t.
*
O
O
O
20 h, catalyst C
X
X
9
10
2a, b, 3a, b
11a, b, 12a, b
Figure 1.
Scheme 6.
OMe
OMe
H
N
H
N
stituted chromanone derivative (92% ee for 12b as
compared to 96% ee for the corresponding benzamide
5d derived from 2-tetralone).
R
R
H2 (10 MPa), MeOH, r.t.
*
O
O
20 h, catalyst A or B
O
O
The presence of the coordinating bromide atom in 2a
and 2b has a dramatic negative influence on the
enantioselectivity of this reaction. Whereas the pres-
ence of a neighbouring bromide atom might bring the
greatest benefit in some cases such as in the hydro-
genation of 2'-bromoacetophenone,[27] in this special
case, the competition with the amide group probably
4 a, b
8 a, b
total conversion
8% < ee < 35%
Scheme 5.
Ru(O2CCF3)2 B. However, these ees were much lower induces a mismatch situation which leads to a poor
than those obtained from the enamides 1a and 1f enantiomeric excess.
(Table 3, entries 1and 7), which suggests that the oxygen
atom in the ring or the methoxy group of the chroma-
none plays a crucial role in the discriminating step of the Conclusion
hydrogenation.
The direct hydrogenation of the enamides 2a, b and We have shown that the transformation of unsubstituted
3a, b was attempted in the presence ofa catalytic amount 2-tetralone and 3-chromanone into optically active
of [(S)-Biphemp]Ru(O2CCF3)2 (C) (Schema 6).[26] The amine derivatives could be performed efficiently at
results are reported in Table 4.
room temperature via the enantioselective hydrogena-
Compounds 2a and 2b were hydrogenated at room tion of enamides in the presence of a mononuclear
temperature under our classical conditions without ruthenium catalyst such as [(S)-Biphemp]Ru(O2CCF3)2
cleavage of the C-Br bond and led to the amides 11a or [(R)-Binap]Ru(O2CCF3)2. A detailed study on the
and 11b in good yields (90 and 95%, respectively) but nature of the substructure of the enamide derivative
the enantiomeric excesses were very low (16% and 22%, indicates that in the presence of these mononuclear
respectively). By contrast, the hydrogenation of the ruthenium precursors, the transient coordination to the
enamides 3a and 3b was also very efficientand afforded
metal centre essentially involves the carbonyl group of
the amides 12a and 12b with good enantioselectivities the amide and is not affected by the presence of a
(72 and 92% ee, respectively). Here again, the eneben- heteroatom such as an oxygen on the amide arm, which
zamide appeared to be the most appropriate substrate to is not the case with the binuclear ruthenium catalyst
reach the best enantioselection.
[NH2Et2][{(S)-BinapRuCl}2(m-Cl)3]. On the other hand,
These results clearly indicate that the oxygen atom of the presence of a chloroacetyl group on the amide group
the cyclic ether functionality has little influence on the had a negative effect on the enantioselectivity with both
enantioselectivity of the hydrogenation of the unsub- catalytic systems.
Table 4. Hydrogenation of compounds 2, 3 and 4.[a]
Entry
X
R
R1
Enamide
ProdaulycstCtYaiteld [%]
ee [%]
1
2
3
4
5
6
7
8
O
O
O
O
CH2
CH2
O
Me
CH2OMe
Me
CH2OMe
Me
Ph
OMe
OMe
OMe
OMe
Br
Br
H
H
4a
4b
4a
4b
2a
2b
3a
3b
8a
8b
8a
8b
11a
11b
12a
12b
B
B
A
A
C
C
C
C
97
94
95
95
90
95
95
95
35 (‡)
22 (‡)
8 (À)
20 (À)
16 (‡)
22 (‡)
72 (‡)
92 (‡)
Me
Ph
O
[a]
General conditions: substrate 1a
g (0.5 mmol), catalyst (0.5 mol %), MeOH (5 mL), hydrogen pressure (10 MPa),
isolated yields.
Adv. Synth. Catal. 2003, 345, 230 238
233

J. L. Renaud etal.
FULL PAPERS
Whereas the presence of a bromide at C-6[16] or a
methoxy group at C-7[17] has no effect on the enantio-
selectivity during the hydrogenation of enamides de-
rived from tetralone, we demonstrated that the enan-
tioselectivity is much lower when acoordinating group is
introduced at the C-8 position on the aromatic ring of
this type of substrates.
8.2 Hz, 2H, CH2 ring), 6.58 (broad s, 1H, NH), 6.80 7.20 (m,
5H, 4CH ar. ‡ CH C); 13C NMR (50.3 MHz, CDCl3): d ˆ 13.9
ˆ
(CH3 amide), 19.2 (CH2 amide), 27.5 (CH2 ring), 28.0 (CH2
ˆ
ring), 39.6 (CH2 amide), 111.4 (CH ), 125.8 (CH ar.), 126.0
(CH ar.), 126.7 (CH ar.), 127.1 (CH ar.), 132.8 (C quat. CN),
ˆ
134.9 (C quat. ar.), 135.4 (C quat. ar.), 172.2 (CO amide);
HRMS: calcd. for C14H17NO: 215.13101; found : 215.13260.
N-(3,4-Dihydronaphthalen-2-yl)-benzamide (1d): Isolated
as a white solid in 80% yield after flash chromatography on
silica gel (ether/pentane: 1/2). 1H NMR (200.13 MHz,
CD3OD): d ˆ 2.55 (t, J ˆ 8.0 Hz, 2H, CH2 ring), 2.84 (t, J ˆ
Experimental Section
ˆ
8.0 Hz, 2H, CH2 ring), 6.80 7.20 (m, 5H, 4 H ar.‡CH C),
1H NMR and 13C NMR spectra were taken on 200 MHz
Bruker AC 200 spectrometers. Chemical shifts are reported
in ppm referenced to the residual proton resonances of the
solvents. Mass spectra (MS) were obtained on GC-MS
Hewlett-Packard HP 5971 apparatus. Thin-layer chromatog-
raphy (TLC) was performed on Merck silica gel 60 F 254. Silica
gel Merck Geduran SI (40 63 mm) was used for column
chromatography.
7.30 7.60 (m, 3H ar.), 7.70 7.90 (2H ar.); 13C NMR
(50.3 MHz, CDCl3): d ˆ 27.5 (CH2 ring), 28.1 (CH2 ring),
ˆ
112.4 (CH ), 126.0 (CH ar.), 126.3 (CH ar.), 126.8 (CH ar.),
127.2 (3 CH ar.), 128.7 (2 CH ar.), 131.8 (CH ar.), 133.0 (C quat.
ˆ
CN), 134.8 (C quat. ar.), 134.9 (C quat. ar.), 135.6 (C quat. ar.),
166.4 (CO amide); HRMS: calcd. for C17H15NO: 249.11536;
found : 249.11644.
N-(3',4'-Dihydronaphthalen-2'-yl)-(2-chloroacetamide)
(1e): For compound 1e, 5 equivalents of chloroacetamide were
used and the reflux was maintained for 48 hours. This enamide
was isolated as a beige solid in 75% yield after flash
General Procedure for the Preparation of the
Enamides 1a h, 2a, b, 3a, b, 4a, b
1
chromatography on silica gel (ether/pentane: 1/2). H NMR
(200.13 MHz, CDCl3): d ˆ 2.48 (t, J ˆ 8.0 Hz, 2H, CH2 ring),
In a 250 mL round-bottom flask equipped with a Dean À Stark
apparatus were introduced the ketone (10 mmol, 1 equiv.), the
primary amide (25 mmol, 2.5 equiv.) and para-toluene sulfonic
acid (1 mmol, 0.1 equiv.) in 60 mL of toluene. The mixture was
refluxed for 20 h under an inert atmosphere. After cooling
down to room temperature, 150 mL of a saturated solution of
hydrogen carbonate were added and the mixture was warmed
t o 608C for 30 min. After cooling down to room temperature,
the organic layer was extracted, washed with water (3 Â
100 mL), dried over magnesium sulfate and concentrated.
The enamide was purified by chromatography on silica gel.
N-(3,4-Dihydronaphthalen-2-yl)-acetamide (1a): Isolated
as a white solid in 80% yield after flash chromatography on
silica gel (ether/pentane: 1/2). 1H NMR (200.13 MHz, CDCl3):
d ˆ 2.09 (s, 3H, CH3 amide), 2.42 (t, J ˆ 8.0 Hz, 2H, CH2 ring),
2.85 (t, J ˆ 8.0 Hz, 2H, CH2 ring), 6.87 (broad s, 1H, NH), 6.90
2.90 (t, J ˆ 8.0 Hz, 2H, CH2 ring), 4.10 (s, 2H, CH2Cl), 6.90
13
ˆ
7.20 (m, 5H, 4H ar.‡CH C), 7.61 (broad s, 1H, NH); C NMR
(50.3 MHz, CDCl3): d ˆ 27.2 (CH2 ring), 27.9 (CH2 ring), 43.0
ˆ
(CH2Cl), 112.9 (CH ), 126.4 (CH ar.), 126.4 (CH ar.), 126.8
ˆ
(CH ar.), 127.2 (CH ar.), 132.9 (C quat. CN), 133.98 (C quat.
ar.), 134.2 (C quat. ar.), 164.0 (CO amide); HRMS: calcd. for
C12H12ClNO: 221.06074; found : 221.06002.
N-(3',4'-Dihydronaphthalen-2'-yl)-(2-methoxyacetamide)
(1f): Isolated as a white solid in 80% yield after flash
1
chromatography on silica gel (ether/pentane: 1/2). H NMR
(200.13 MHz, CDCl3): d ˆ 2.46 (t, J ˆ 8.0 Hz, 2H, CH2 ring),
2.87 (t, J ˆ 8.0 Hz, 2H, CH2 ring), 3.44 (s, 3H, OCH3), 3.93 (s,
2H, CH2O), 6.90 7.12 (m, 4H ar.), 7.13 (s, 1H, CH), 7.62
(broad s, 1H, NH); 13C NMR (50.32 MHz, CDCl3): d ˆ 27.36
(CH2 ring), 27.96 (CH2 ring), 59.26 (OCH3), 72.10 (CH2O),
ˆ
111.75 (CH ), 125.92 (CH ar.), 126.17 (CH ar.), 126.73 (CH
ar.), 127.11 (CH ar.), 132.80 (C quat. CN), 134.33 (C quat. ar.),
7.10 (m, 5H, 4 CH ar.‡CH C); 13C NMR (50.3 MHz, CDCl3):
ˆ
ˆ
d ˆ 24.6 (CH3 amide), 27.2 (CH2 ring), 28.1 (CH2 ring), 111.6
134.70 (C quat. ar.), 167.71 (CO amide).
ˆ
(CH ), 125.9 (CH ar.), 126.0 (CH ar.), 126.8 (CH ar.), 127.20
(CH ar.), 132.9 (C quat. CN), 134.9 (C quat. ar.), 135.7 (C
N-(3',4'-Dihydronaphthalen-2'-yl)-(2-benzyloxyacetamide)
ˆ
(1g): Isolated as a white solid in 80% yield after flash
quat. ar.), 169.7 (CO amide).
1
chromatography on silica gel (ether/pentane: 1/2). H NMR
N-(3,4-Dihydronaphthalen-2-yl)-propionamide (1b): Iso-
lated as a white solid in 98% yield after flash chromatography
on silica gel (ether/pentane: 1/2). 1H NMR (200.13 MHz,
CD3OD): d ˆ 1.11 (t, J ˆ 7.0 Hz, 3H, CH3 amide), 2.27 (q,
J ˆ 7.0 Hz, 2H, CH2 amide), 2.38 (t, J ˆ 8.0 Hz, 2H, CH2 ring),
2.78 (t, J ˆ 8.0 Hz, 2H, CH2 ring), 6.80-7.20 (m, 5H, 4CH ar. ‡
(200.13 MHz, CDCl3); d ˆ 2.44 (t, J ˆ 8.2 Hz, 2H, CH2 ring),
2.87 (t, J ˆ 8.2 Hz, 2H, CH2 ring), 4.01 (s, 2H, CH2O), 4.61 (s,
ˆ
2H, OCH2Ph), 6.90 7.11 (m, 4H ar.), 7.13 (s, 1H, CH ), 7.25
7.50 (m, 5H ar.), 7.70 (broad s, 1H, NH); 13C NMR (50.3 MHz,
CDCl3): d ˆ 27.4 (CH2 ring), 28.0 (CH2 ring), 69.7 (OCH2Ph),
ˆ
73.8 (OCH2), 111.9 (CH ), 126.0 (CH ar.), 126.2 (CH ar.), 126.8
CH C); 13C NMR (50.3 MHz, CDCl3): d ˆ 9.8 (CH3 amide),
ˆ
(CH ar.), 127.1 (CH ar.), 128.1 (2 CH ar.), 128.5 (CH ar.), 128.8
27.5 (CH2 ring), 28.0 (CH2 ring), 30.8 (CH2 amide), 111.4
ˆ
(2 CH ar.), 132.8 (C quat. CN), 134.2 (C quat. ar.), 134.7 (C
ˆ
(CH ), 125.8 (CH ar.), 126.0 (CH ar.), 126.7 (CH ar.), 127.1
(CH ar.), 132.7 (C quat. CN), 134.9 (C quat. ar.), 135.3 (C
quat. ar.), 136.6 (C quat. ar.), 167.7 (CO amide).
ˆ
N-(3',4'-Dihydronaphthalen-2'-yl)-[2-(benzyl sulfide)aceta-
quat. ar.), 172.9 (CO amide).
mide] (1h): Isolated as a yellow solid in 90% yield after flash
N-(3,4-Dihydronaphthalen-2-yl)-butyramide (1c): Isolated
as a beige solid in 98% yield after flash chromatography on
silica gel (ether/pentane: 1/2). 1H NMR (200.13 MHz,
CD3OD): d ˆ 0.97 (t, J ˆ 7.4 Hz, 3H, CH3 amide), 1.70
1
chromatography on silica gel (ether/pentane: 1/2). H NMR
(200.13 MHz, CDCl3): d ˆ 2.32 (t, J ˆ 8.1 Hz, 2H, CH2 ring),
2.84 (t, J ˆ 8.1 Hz, 2H, CH2 ring), 3.21 (s, 2H, CH2S), 3.74 (s, 2H,
ˆ
CH2S), 6.90 7.15 (m, 5H, 4H ar. ‡ CH ), 7.17 7.45 (m, 5H
ˆ
(sextuplet, J 7.4 Hz, 2H, CH2 amide), 2.25 (t, J ˆ 7.4 Hz, 2H,
ar.), 7.77 (broad s, 1H, NH); 13C NMR (50.3 MHz, CDCl3): d ˆ
CH2 amide), 2.42 (t, J ˆ 8.2 Hz, 2H, CH2 ring), 2.86 (t, J ˆ
234
Adv. Synth. Catal. 2003, 345, 230 238

Ru-Catalysed Enantioselective Hydrogenation of Trisubstituted Enamides
FULL PAPERS
27.2 (CH2 cycle), 28.0 (CH2 ring), 36.5 (CH2S), 37.5 (CH2S),
111.6 (CH ), 126.0 (CH ar.), 126.2 (CH ar.), 126.8 (CH ar.),
CDCl3): d ˆ 30.8 (CH2 ring), 42.8 (CH ring), 68.3 (OCH2
ˆ
ˆ
ring), 117.0 (CH ), 119.4 (CH ar.), 121.5 (CH ar.), 127.0 (2
127.1 (CH ar.), 127.7 (CH ar.), 128.9 (3 CH ar.), 129.0 (2 CH
CH ar.), 127.9 (CH ar.), 128.6 (2 CH ar.), 130.6 (CH ar.), 131.7
ˆ
ˆ
ar.), 132.8 (C quat. CN), 134.6 (C quat. ar.), 134.6 (C quat. ar.),
(C quat. CN), 134.2 (C quat. ar.), 153.9 (C quat. ar.), 167.3
137.2 (C quat. ar.), 166.9 (CO amide).
(CO amide); HRMS: calcd. for C16H13NO2: 251.09463; found:
251.09367.
N-(3',4'-Dihydronaphthalen-2'-yl)-[2-(benzylsulfonyl)ace-
tamide] (1i): Sulfide 1h was dissolved in methanol before
adding an aqueous solution of H2O2 (10 equiv.) atroom
temperature. A white precipitate appeared quickly. The
mixture was stirred at room temperature for one hour. The
solid was filtered, washed with water and dried under vacuum.
The sulfone derivative was obtained as white solid in 95%
N-(5-Methoxybenzo[b]pyran-3-yl)-acetamide (4a); Isolat-
ed as a white solid in 80% yield after flash chromatography on
silica gel (ether/pentane: 1/1). 1H NMR (200.13 MHz, CDCl3):
d ˆ 2.06 (s, 3H, CH3 amide), 3.78 (s, 3H, OCH3), 4.90 (s, 2H,
OCH2 cycle), 6.43 (d, J ˆ 8.2 Hz, 1H ar.), 6.45 (d, J ˆ 8.2 Hz, 1H
ˆ
ar.), 6.60 (s, 1H, CH ), 6.98 (t, J ˆ 8.2 Hz, 1H ar.), 7.07 (s large,
1
yield. H NMR (200.13 MHz, CDCl3): d ˆ 2.40 (t, J ˆ 8.2 Hz,
1H, NH); 13C NMR (50.3 MHz, CDCl3): d ˆ 23.9 (CH3 amide),
ˆ
ˆ
2H, CH2 ring), 2.84 (t, J 8.4 Hz, 2H, CH2 ring), 3.26 (d, J
14.2 Hz, 1H, CH2SO2), 3.64 (d, J 14.2 Hz, 1H, CH2SO2), 4.14
55.7 (OCH3), 65.3 (OCH2 ring), 102.9 (CH ar.), 104.0 (CH ar.),
ˆ
ˆ
108.5 (CH ), 108.8 (C quat. ar.), 127.6 (CH ar.), 133.9 (C quat.,
CN), 152.9 (C quat. ar.), 155.1 (C quat. ar.), 169.1 (CO
amide).
ˆ
ˆ
ˆ
(d, J
13.0 Hz, 1H, CH2SO2), 4.23 (d, J
13.0 Hz, 1H,
ˆ
CH2SO2), 6.90 7.12 (m, 4H ar.), 7.15 (s, 1H, CH ), 7.28 7.50
(m, 5H ar.), 8.51 (broad s, 1H, NH); 13C NMR (50.3 MHz,
CDCl3): d ˆ 27.0 (CH2 ring), 27.9 (CH2 ring), 53.5 (CH2SO2),
N-(5'-Methoxybenzo[b]pyran-3'-yl)-2-methoxyacetamide
(4b): Isolated as a colourless oil in 50% yield after flash
1
ˆ
57.3 (CH2SO2), 112.5 (CH ), 126.0 (CH ar.), 126.3 (CH ar.),
chromatography on silica gel (ether/pentane: 1/1). H NMR
126.7 (CH ar .), 127.1 (CH ar.), 128.8 (C quat. ar.), 128.9 (CH
(200.13 MHz, CDCl3): d ˆ 3.44 (s, 3H, OCH3 amide), 3.79 (s,
ˆ
ˆ
ar.), 129.2 (2 CH ar.), 130.7 (2 CH ar.), 132.9 (C quat. CN),
3H, OCH3), 3.91 (s, 2H, OCH2 amide), 4.99 (d, J 1.0 Hz, 2H,
134.5 (C quat. ar.), 135.0 (C quat. ar.), 162.1 (CO amide);
HRMS: calcd. for C19H19NO2S: 325.11365; found: 325.11420.
N-(8'-Bromo-3',4'-dihydronaphthalen-2'-yl)-acetamide
(2a): Isolated as a white solid in 80% yield after flash
CH2 ring), 6.43 (d, J ˆ 8.2 Hz, 1H ar.), 6.46 (d, J ˆ 8.2 Hz, 1H
ˆ
ar.), 6.75 (s, 1H, CH ), 6.98 (t, J ˆ 8.2 Hz, 1H ar.), 7,85 (broad s,
1H, NH); 13C NMR (50.3 MHz, CDCl3): d ˆ 55.7 (OCH3),
59.26 (OCH3), 65.3 (OCH2 ring), 72.10 (CH2O), 102.9 (CH ar.),
1
ˆ
chromatography on silica gel (ether/pentane: 1/2). H NMR
104.0 (CH ar.), 108.5 (CH ), 108.8 (C quat. ar.), 127.6 (CH ar.),
133.9 (C quat., CN), 152.9 (C quat. ar.), 155.1 (C quat. ar.),
169.1 (CO amide).
ˆ
(200.13 MHz, CDCl3): d ˆ 2.09 (s, 3H, CH3 amide), 2.42 (t, J ˆ
8.0 Hz, 2H, CH2 ring), 2.85 (t, J ˆ 8.0 Hz, 2H, CH2 ring), 6.87
ˆ
(broad s, 1H, NH), 6.90 7.10 (m, 5H, 4 CH ar. ‡ CH C);
N-(7-Methyl-3,4-dihydronaphthalen-2-yl)-acetamide (6a):
Isolated as a beige solid in 63% yield after flash chromatog-
raphy on silica gel (ether/pentane: 1/2). 1H NMR (200.13 MHz,
CDCl3): d ˆ 2.09 (s, 3H, CH3 amide), 2.25 (s, 3H, CH3), 2.40 (t,
J ˆ 8.1 Hz , 2H, CH2 ring), 2.81 (t, J ˆ 8.1 Hz , 2H, CH2 ring),
13C NMR (50.3 MHz, CDCl3): d ˆ 24.6 (CH3 amide), 27.2 (CH2
ˆ
ring), 28.1 (CH2 ring), 111.6 (CH ), 125.9 (CH ar.), 126.0 (CH
ar.), 126.8 (CH ar.), 127.20 (CH ar.), 132.9 (C quat. CN), 134.9
ˆ
(C quat. ar.), 135.7 (C quat. ar.), 169.7 (CO amide); HRMS:
calcd. for C12H12NOBr: 265.01023; found: 265.01254.
ˆ
6.75 (broad s, 1H, NH), 6.80 7.15 (m, 4H, 3H ar. ‡ CH );
N-(8'-Bromo-3',4'-dihydronaphthalen-2'-yl)-benzamide
13C NMR (50.3 MHz, CDCl3): d ˆ 21.1 (CH3), 24.7 (CH3
ˆ
(2b): Isolated as a white solid in 80% yield after flash
amide), 27.5 (CH2 ring), 27.6 (CH2 ring), 111.7 (CH ), 126.5
(CH ar.), 126.9 (CH ar.), 126.9 (CH ar.), 129.8 (C quat, CN),
1
ˆ
chromatography on silica gel (ether/pentane: 1/2). H NMR
(200.13 MHz, CDCl3): d ˆ 2.09 (s, 3H, CH3 amide), 2.42 (t, J ˆ
134.7 (C quat, ar.), 135.4 (C quat, ar.), 136.2 (C quat, ar.), 169.2
(CO amide).
8.0 Hz, 2H, CH2 ring), 2.85 (t, J ˆ 8.0 Hz, 2H, CH2 ring), 6.87
ˆ
(broad s, 1H, NH), 6.90 7.10 (m, 5H, 4 CH ar. ‡ CH C);
N-(7-Methyl-3,4-dihydronaphthalen-2-yl)-propionamide
13C NMR (50.3 MHz, CDCl3): d ˆ 24.6 (CH3 amide), 27.2 (CH2
(6b): Isolated as a beige solid in 98% yield after flash
1
ˆ
ring), 28.1 (CH2 ring), 111.6 (CH ), 125.9 (CH ar.), 126.0 (CH
ar.), 126.8 (CH ar.), 127.20 (CH ar.), 132.9 (C quat. CN), 134.9
chromatography on silica gel (ether/pentane: 1/1). H NMR
ˆ
(200.13 MHz, CDCl3): d ˆ 1.19 (t, J ˆ 7.5 Hz, 3H, CH3), 2.25 (s,
3H, CH3), 2.26 (q, J ˆ 7.5 Hz , 2H, CH2), 2.40 (t, J ˆ 8.0 Hz, 2H,
CH2 ring), 2.82 (t, J ˆ 8.0 Hz , 2H, CH2 ring), 6.56 (broad s, 1H,
(C quat. ar.), 135.7 (C quat. ar.), 169.7 (CO amide); HRMS:
calcd. for C17H14BrNO: 327.02588; Found: 327.02374.
NH), 6.75 7.15 (m, 4H, 3H ar. ‡ CH ); 13C NMR (50.3 MHz,
ˆ
N-(Benzo[b]pyran-3-yl)-acetamide (3a): Isolated as an oil
in 55% yield after flash chromatography on silica gel (ether/
pentane: 1/1). 1H NMR (200.13 MHz, CDCl3): d ˆ 4.86 (d, J ˆ
1.2 Hz, 2H , CH2), 6.54 (broad s, 1H, NH), 6.78 (d, J ˆ 7.9 Hz,
1H ar.), 6.87 (dd, J ˆ 7.4, 1.2 Hz, 1H ar.), 6.93 7.05 (m, 3H ar.);
13C NMR (50.3 MHz, CDCl3): d ˆ 24.1 (CH3 amide), 65.6
CDCl3): d ˆ 9.8 (CH3 amide), 21.2 (CH3), 27.5 (CH2 cycle), 27.6
ˆ
(CH2 ring), 30.7 (CH2 amide), 111.7 (CH ), 126.5 (CH ar.),
126.9 (CH ar.), 126.9 (CH ar.), 129.8 (C quat, CN), 134.7 (C
ˆ
quat, ar.), 135.4 (C quat, ar.), 136.2 (C quat, ar.), 172.8 (CO
amide).
ˆ
(OCH2 ring), 107.8 (CH ar.), 115.4 (CH ar.), 122.0 (CH ), 122.8
(C quat. ar.), 126.4 (CH ar.), 127.8 (CH ar.), 129.6 (C quat.,
ˆ
CN), 152.0 (C quat. ar.), 169.0 (CO amide); HRMS: calcd. for
C11H11NO2: 189.07898; found: 189.07902.
N-(Benzo[b]pyran-3-yl)-benzamide (3b): Isolated as an oil
in 63% yield after flash chromatography on silica gel (ether/
pentane: 1/1). 1H NMR (200.13 MHz, CDCl3): d ˆ 5.01 (d, J ˆ
1.0 Hz, 2H, CH2), 6.68 (broad s, 1H, NH), 6.82 (d, J ˆ 8.6 Hz,
1H), 6.87 (dd, J ˆ 7.2, 1.3 Hz, 1H), 6.98 7.14 (m, 3H), 7.40
7.55 (m, 3H), 7.68 7.81 (m, 2H); 13C NMR (50.3 MHz,
Catalysts for Enantioselective Hydrogenation
Chiral catalysts [(R)-Binap]Ru(O2CCF3)2,[28] [NH2Et2][{((S)-
Binap)RuCl}2(m-Cl)3],[20] and [(S)-Biphemp]Ru(O2CCF3)2
[28]
were prepared using previously described procedures.
Adv. Synth. Catal. 2003, 345, 230 238
235

J. L. Renaud etal.
FULL PAPERS
N-(1,2,3,4-Tetrahydronaphthalen-2-yl)-benzamide
(5d):
General Procedure for the Hydrogenation of
Enamides
1
White solid. H NMR (200.13 MHz, CDCl3): d ˆ 1.70 2.00
(m, 1H, CH2 ring), 2.05 2.30 (m, 1H, CH2 ring), 2.74 (dd, J ˆ
16.2, 8.2 Hz, 1H, CH2 ring), 2.82 3.05 (m, 2H, CH2 ring), 3.23
(dd, J ˆ 16.2, 5.1 Hz, 1H, CH2 ring), 4.30 4.65 (m, 1H, CHN),
6.08 (broad s, 1H, NH), 7.11 (broad s, 4H ar.), 7.25 7.50 (m, 3H
ar.), 7.60 7.80 (m, 2H ar.); 13C NMR (50.3 MHz, CDCl3): d ˆ
27.5 (CH2 ring), 28.9 (CH2 ring), 35.7 (CH2 ring), 45.9 (CHN),
126.00 (CH ar.), 126.2 (CH ar.), 127.1 (2 CH ar.), 128.6 (2 CH
ar.), 128. 9 (CH ar.), 129.5 (CH ar.), 131.4 (CH ar.), 134.2 (C
quat, ar.), 134.8 (C quat, ar.), 135.6 (C quat, ar.), 167.3 (CO
amide); anal. calcd. for C17H17NO: C 81.11, H 6.77, N 5.50%;
found: C 81.24, H 6.82, N 5.57%; HPLC retention time: (À)
enantiomer: 47 min; (‡) enantiomer: 35 min.
In a 125 mL stainless steel autoclave were placed under an
argon atmosphere the enamide (1 mmol, 1 equiv.), the chiral
precatalyst (0.005 mmol, 0.5% mol.). The mixture was de-
gassed by three vacuum-filling with argon cycles before adding
8 mL of degassed and distilled methanol. Air present in the gas
inlet tube was removed by flushing with a stream of hydrogen.
Then the autoclave was purged three times by hydrogen and
the vessel was pressurised to 100 bar. After 20 h under
mechanical stirring at 20 8C, the autoclave was carefully
opened, the solvent was removed under reduced pressure.
Conversion was determined by 1H NMR analysis of the crude
mixture. Subsequently, the residue was purified by chromatog-
raphy on silica gel, eluted with a 1:1 mixture of heptane and
ether. Enantiomeric excesses was determined by HPLC on
Chiracel OD column (eluent: hexane/i-PrOH: 95/5; flow:
1 mL/min; temperature: 25 8C; detection : 210 nm).
N-(1',2',3',4'-Tetrahydronaphthalen-2'-yl)-(2-chloroacet-
amide) (5e): Beige solid. 1H NMR (200.13 MHz, CDCl3): d ˆ
1.65 1.90 (m, 1H, CH2 ring), 1.95 2.20 (m, 1H, CH2 ring), 2.69
(dd, J ˆ 16.2, 8.5 Hz, 1H, CH2 cycle), 2.80 3.00 (m, 2H, CH2
ring), 3.13 (dd, J ˆ 16.2, 5.5 Hz, 1H, CH2 ring), 4.03 (s, 2H,
ClCH2), 4.15 4.40 (m, 1H, CHN), 6.54 (broad s, 1H, NH),
6.95 7.20 (m, 4H ar.); 13C NMR (50.3 MHz, CDCl3): d ˆ 27.5
(CH2), 28.9 (CH2), 35.7 (CH2), 44.7 (CHN), 59.1 (OCH3), 72.1
(OCH2), 125.9 (CH ar.), 126.2 (CH ar.), 128.8 (CH ar.), 129.4
(CH ar.), 134.1 (C quat, ar.), 135.4 (C quat, ar.), 169.0 (CO
amide); HRMS (FAB): calcd. for C12H15ClNO (MH+):
224.0842; found: 224.0844; HPLC retention time: (À) enan-
tiomer: 17 min; (‡) enantiomer: 14 min.
N-(1,2,3,4-Retrahydronaphthalen-2-yl)-acetamide
(5a):
1
White solid. H NMR (200.13 MHz, CDCl3): d ˆ 1.60 1.86
(m, 1H, CH2 ring), 1.95 (s, 3H, CH3 amide), 1.96 2.10 (m, 1H,
CH2 ring), 2.62 (dd, J ˆ 16.0, 7.8 Hz, 1H, CH2 ring), 2.75 2.95
(m, 2H, CH2 ring), 3.10 (dd, J ˆ 16.0, 4.8 Hz, 1H, CH2 ring),
4.10 4.50 (m, 1H, CHN), 5.50 (broad s, 1H, NH), 7.09 (broad s,
4H ar.); 13C NMR (50.3 MHz, CDCl3): d ˆ 23.5 (CH3 amide),
27.2 (CH2 ring), 28.6 (CH2 ring), 35.7 (CH2 ring), 45.2 (CHN),
126.0 (CH ar.), 126.2 (CH ar.), 128.9 (CH ar.), 129.5 (CH ar.),
134.1 (C quat, ar.), 135.5 (C quat, ar.), 169.8 (CO amide);
HRMS: calcd. for C12H15NO: 189.11536; found: 189.11573;
HPLC retention time: (À) enantiomer: 22 min; (‡) enantiom-
er: 27 min.
N-(1',2',3',4'-Tetrahydronaphthalen-2'-yl)-(2-methoxyacet-
amide) (5f): White solid. 1H NMR (200.13 MHz, CDCl3): d ˆ
1.68 1.88 (m, 1H, CH2 ring), 1.95 2.18 (m, 1H, CH2 ring), 2.66
(dd, J ˆ 16.3, 8.6 Hz, 1H, CH2 ring), 2.80 2.96 (m, 2H, CH2
ring), 3.11 (dd, J ˆ 16.3, 5.4 Hz, 1H, CH2 ring), 3.37 (s, 3H,
OCH3), 3.87 (s, 2H, OCH2), 4.15 4.45 (m, 1H, CHN), 6.51
(broad s, 1H, NH), 6.98 7.16 (m, 4Har.);13C NMR(50.3 MHz,
CDCl3): d ˆ 27.5 (CH2 ring), 28.9 (CH2 ring), 35.7 (CH2 ring),
44.7 (CHN), 59.1 (OCH3), 72.1 (OCH2), 125.9 (CH ar.), 126.2
(CH ar.), 128.8 (CH ar.), 129.4 (CH ar.), 134.1 (C quat, ar.),
135.4 (C quat, ar.), 169.0 (CO amide); HRMS: calcd. for
C13H17NO2: 219.12593; found: 219.12577; HPLC retention
time: (À) enantiomer: 16 min; (‡) enantiomer: 14 min.
N-(1,2,3,4-Tetrahydronaphthalen-2-yl)-propionamide (5b):
1
White solid. H NMR (200.13 MHz, CDCl3): d ˆ 1.08 (t, J ˆ
7.6 Hz, 3H, CH3 amide), 1.50 1.80 (m, 1H, CH2 ring), 1.85
2.13 (m, 1H, CH2 ring), 2.15 (q, J ˆ 7.6 Hz, 2H, CH2 amide),
2.59 (dd, J ˆ 16.2, 9.8 Hz, 1H, CH2 ring), 2.70 2.85 (m, 2H,
CH2 ring), 2.96 (dd, J ˆ 16.2, 4.9 Hz, 1H, CH2 ring), 3.85 4.15
(m, 1H, CHN), 4.84 (broad s, 1H, NH), 7.00 (broad s, 4H ar.);
13C NMR (50.3 MHz, CDCl3): d ˆ 10.1 (CH3 amide), 27.4 (CH2
ring), 28.8 (CH2 ring), 29.8 (CH2 amide), 35.7 (CH2 ring), 45.1
(CHN), 125.9 (CH ar.), 126.2 (CH ar.), 128.9 (CH ar.), 129.5
(CH ar.), 134.3 (C quat, ar.), 135.6 (C quat, ar.), 173.5 (CO
amide); HRMS: calcd. for C13H17NO: 203.13101; found:
203.13123; HPLC retention time: (À) enantiomer: 21 min;
(‡) enantiomer: 24 min.
N-(1',2',3',4'-tetrahydronaphthalen-2'-yl)-(2-benzyloxyacet-
amide) (5g): White solid. 1H NMR (200.13 MHz, CDCl3): d ˆ
1.60 1.90 (m, 1H, CH2 ring), 1.95 2.20 (m, 1H, CH2 ring), 2.65
(dd, J ˆ 16.3, 8.5 Hz, 1H, CH2 ring), 2.75 2.95 (m, 2H, CH2
ring), 3.10 (dd, J ˆ 16.3, 5.2 Hz, 1H, CH2 cycle), 3.97 (s, 2H,
OCH2), 4.15 4.40 (m, 1H, CHN), 4.52 (s, 2H, OCH2), 6.60 (d
large, J ˆ 7.3 Hz, 1H, NH), 6.95 7.15 (m, 4H ar.), 7.16-7.40 (m,
5H ar.); 13C NMR (50.3 MHz, CDCl3): d ˆ 27.3 (CH2 ring), 28.8
(CH2 ring), 35.7 (CH2 ring), 44.7 (CHN), 69.7 (OCH2), 73.7
(OCH2), 126.0 (CH ar.), 126.2 (CH ar.), 128.04 (2 CH ar.), 128.3
(CH ar.), 128.7 (2 CH ar.), 128.9 (CH ar.), 129.5 (CH ar.), 134.1
(C quat, ar.), 135.5 (C quat, ar.), 136.8 (C quat, ar.), 169.1 (CO
amide); anal. calcd. for C19H21NO2: C 76.89, H 7.13, N 4.76%;
found: C 77.26, H 7.17, N 4.74%; HPLC retention time: (À)
enantiomer: 12 min; (‡) enantiomer: 10 min.
N-(1,2,3,4-Tetrahydronaphthalen-2-yl)-butyramide
(5c):
1
Beige solid. H NMR (200.13 MHz, CDCl3): d ˆ 0.92 (t, J ˆ
7.6 Hz, 3H, CH3 amide), 1.64 (sext., J ˆ 7.6 Hz, 2H, CH2
amide), 1.71 1.87 (m, 1H, CH2 ring), 1.92 2.06 (m, 1H, CH2
ring), 2.11 (t, J ˆ 7.6 Hz, 2H, CH2 amide), 2.61 (dd, J ˆ 16.5,
7.9 Hz, 1H, CH2 ring), 2.70 3.00 (m, 2H, CH2 ring), 3.11 (dd,
J ˆ 16.3, 5.2 Hz, 1H, CH2 cycle), 4.10 4.50 (m, 1H, CHN), 5.43
(broad s, 1H, NH), 6.90 7.20 (m, 4Har.);13C NMR(50.3 MHz,
CDCl3): d ˆ 13.8 (CH3 amide), 19.4 (CH2 amide), 27.5 (CH2
ring), 28.9 (CH2 ring), 35.8 (CH2 ring), 38.8 (CH2 amide), 45.2
(CHN), 125.9 (CH ar.), 126.1 (CH ar.), 128.9 (CH ar.), 129.44
(CH ar.), 134.4 (C quat, ar.), 135.6 (C quat, ar.), 172.7 (CO
amide); anal. calcd. for C14H19NO: C 77.10, H 9.18, N 6.27%;
found: C 77.38, H 8.82, N 6.44; HPLC retention time: (À)
enantiomer: 16 min; (‡) enantiomer: 13 min.
N-(7-Methyl-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide
1
(7a): Beige solid. H NMR (200.13 MHz, CDCl3): d ˆ 1.60
1.86 (m, 1H, CH2 ring), 1.96 (s, 3H, CH3 amide), 1.90 2.10 (m,
1H, CH2 ring), 2.27 (s, 3H, CH3), 2.58 (dd, J ˆ 16.2, 7.8 Hz, 1H,
CH2 ring), 2.70 2.90 (m, 2H, CH2 ring), 3.10 (dd, J ˆ 16.2,
4.9 Hz, 1H, CH2 cycle), 4.10 4.40 (m, 1H, CHN), 5.50 (broad s,
1H, NH), 6.75 7.05 (m, 3H ar.); 13C NMR (50.3 MHz, CDCl3):
236
Adv. Synth. Catal. 2003, 345, 230 238

Ru-Catalysed Enantioselective Hydrogenation of Trisubstituted Enamides
FULL PAPERS
d ˆ 21.0 (CH3), 23.5 (CH3 amide), 26.7 (CH2 ring), 28.7 (CH2
ring), 35.7 (CH2 ring), 45.1 (CHN), 127.1 (CH ar.), 128.8 (CH
ar.), 130.0 (CH ar.), 132.5 (C quat, ar.), 133.9 (C quat, ar.), 135.4
(C quat, ar.), 169.9 (CO amide); HPLC retention time: (À)
enantiomer: 19 min; (‡) enantiomer: 13 min.
2.68 (dd, J ˆ 17.4, 4.1 Hz, 1H, CH2 ring), 2.91 (dd, J ˆ 17.5,
6.0 Hz, 1H, CH2 ring), 3.33 (s, 3H, OCH3 amide), 3.77 (s, 3H,
OCH3), 3.85 (s, 2H, OCH2 amide), 4.06 (dd, J ˆ 3.4, 1.1 Hz, 2H,
CH2 cycle), 4.35 4.60 (m, 1H, CHN), 6.43 (dd, J ˆ 8.3, 1.0 Hz,
1H ar.), 6.49 (dd, J ˆ 8.3, 1.0 Hz, 1H ar.), 6.73 (d large, J ˆ
7.3 Hz, 1H, NH), 7.07 (t, J ˆ 8.3 Hz, 1H ar.); 13C NMR
(50.3 MHz, CDCl3): d ˆ 28.2 (CH2 ring), 28.5 (CH2 ring), 36.7
(CH2 ring), 46.1 (CHN), 125.8 (C quat. ar.), 127.0 (2 CH ar.),
127.4 (CH ar.), 128.1 (2 CH ar.), 128.6 (CH ar.), 130.3 (CH ar.),
131.6 (CH ar.), 133.8 (C quat. ar), 134.7 (C quat. ar), 138.3 (C
quat. ar.), 167.1 (CO amide); HRMS: calcd. for C17H16BrNO:
392.04153; found: 329.04398; HPLC retention time: (À)
enantiomer: 21 min; (‡) enantiomer: 24 min.
N-(7-Methyl-1,2,3,4-tetrahydronaphthalen-2-yl)-propion-
1
amide (7b): Beige solid. H NMR (200.13 MHz, CDCl3): d ˆ
1.13 (t, J ˆ 7.7 Hz, 3H, CH3 amide), 1.60 1.85 (m, 1H, CH2
ring), 1.87 2.08 (m, 1H, CH2 ring), 2.16 (q, J ˆ 7.7 Hz, 2H, CH2
amide), 2.26 (s, 3H, CH3), 2.7 (dd, J ˆ 16.2, 8.0 Hz, 1H, CH2
cycle), 2.70 2.90 (m, 2H, CH2 cycle), 3.06 (dd, J ˆ 16.2, 5.3 Hz,
1H, CH2 ring), 4.10 4.40 (m, 1H, CHN), 5.47 (broad s, 1H,
NH), 6.75 7.05 (m, 3H ar.); 13C NMR (50.3 MHz, CDCl3): d ˆ
10.0 (CH3 amide), 21.0 (CH3), 26.7 (CH2 ring), 28.8 (CH2 ring),
29.9 (CH2 amide), 35.7 (CH2 ring), 45.0 (CHN), 127.1 (CH ar.),
128.8 (CH ar.), 130.0 (CH ar.), 132.5 (C quat, ar.), 134.0 (C quat,
ar.), 135.4 (C quat, ar.), 173.4 (CO amide); HRMS: calcd. for
C14H19NO: 217.14666; found: 217.14854; HPLC retention time:
(À) enantiomer: 19 min ; (‡) enantiomer: 11 min.
N-(3,4-Dihydrobenzo[b]pyran-3-yl)-acetamide
(12a):
1
White solid. H NMR (200.13 MHz, CDCl3): d ˆ 1.93 (s, 3H,
CH3 amide), 2.69 (d large, J ˆ 17.5 Hz, 1H, CH2 ring), 2.84 (dd,
J ˆ 17.5, 5.5 Hz, 1H, CH2 ring), 3.77 (s, 3H, OCH3), 4.00 (dd,
J ˆ 10.9, 1.3 Hz, 1H, CH2 ring), 4.11 (ddd, J ˆ 10.9, 3.5, 2 Hz,
1H, CH2 ring), 4.35 4.60 (m, 1H, CHN), 5.79 (broad s, 1H,
NH), 6.43 (d, J ˆ 8.2 Hz, 1H ar.), 6.48 (d, J ˆ 8.2 Hz, 1H ar.),
7.07 (t, J ˆ 8.2 Hz, 1H ar.); 13C NMR (50.3 MHz, CDCl3): d ˆ
23.4 (CH3 amide), 25.6 (CH2 cycle), 41.9 (CHN), 55.5 (OCH3),
67.7 (OCH2 ring), 102.5 (CH ar.), 108.7 (C quat, ar.), 109.5 (CH
ar.), 127.4 (CH ar.), 154.7 (C quat. ar.), 158.4 (C quat. ar.), 170.0
(CO amide); HRMS: calcd. for C11H13NO2: 191.09463; found:
191.09161; HPLC retention time: (À) enantiomer: 16 min; (‡)
enantiomer: 19 min.
N-(5-Methoxy-3,4-dihydrobenzo[b]pyran-3-yl)-acetamide
(8a): White solid. 1H NMR (200.13 MHz, CDCl3): d ˆ 1.93 (s,
3H, CH3 amide), 2.69 (d large, J ˆ 17.5 Hz, 1H, CH2 ring), 2.84
(dd, J ˆ 17.5, 5.5 Hz, 1H, CH2 ring), 3.77 (s, 3H, OCH3), 4.00
(dd, J ˆ 10.9, 1.3 Hz, 1H, CH2 ring), 4.11 (ddd, J ˆ 10.9, 3.5,
2 Hz, 1H, CH2 cycle), 4.35 4.60 (m, 1H, CHN), 5.79 (broad s,
1H, NH), 6.43 (d, J ˆ 8.2 Hz, 1H ar.), 6.48 (d, J ˆ 8.2 Hz, 1H
ar.), 7.07 (t, J ˆ 8.2 Hz, 1H ar.); 13C NMR (50.3 MHz, CDCl3):
d ˆ 23.4 (CH3 amide), 25.6 (CH2 ring), 41.9 (CHN), 55.5
(OCH3), 67.7 (OCH2 ring), 102.5 (CH ar.), 108.7 (C quat, ar.),
109.5 (CH ar.), 127.4 (CH ar.), 154.7 (C quat. ar.), 158.4 (C quat.
ar.), 170.0 (CO amide); anal. calcd. for C12H15NO3: C 65.19, H
6.99, N 6.32%; found: C 65.14, H 6.83, N 6.33%; HPLC
retention time: (À) enantiomer: 16 min; (‡) enantiomer:
19 min.
N-(3,4-Dihydrobenzo[b]pyran-3-yl)-benzamide
(12b):
1
White solid. H NMR (200.13 MHz, CDCl3): d ˆ 1.93 (s, 3H,
CH3 amide), 2.69 (d large, J ˆ 17.5 Hz, 1H, CH2 ring), 2.84 (dd,
J ˆ 17.5, 5.5 Hz, 1H, CH2 ring), 3.77 (s, 3H, OCH3), 4.00 (dd,
J ˆ 10.9, 1.3 Hz, 1H, CH2 ring), 4.11 (ddd, J ˆ 10.9, 3.5, 2 Hz,
1H, CH2 ring), 4.35 4.60 (m, 1H, CHN), 5.79 (broad s, 1H,
NH), 6.43 (d, J ˆ 8.2 Hz, 1H ar.), 6.48 (d, J ˆ 8.2 Hz, 1H ar.),
7.07 (t, J ˆ 8.2 Hz, 1H ar.); 13C NMR (50.3 MHz, CDCl3): d ˆ
30.8 (CH2 ring), 42.8 (CHN), 68.3 (OCH2 ring), 117.0 (CH ar.),
119.4 (C quat. ar.), 109.5 (CH ar.), 127.4 (CH ar.), 154.7 (C quat.
ar.), 158.4 (C quat. ar.), 170.0 (CO amide); HPLC retention
time: (À) enantiomer: 14 min ; (‡) enantiomer: 19 min.
N-(5'-Methoxy-3',4'-dihydrobenzo[b]pyran-3'-yl)-(2-me-
thoxyacetamide) (8b): White solid. 1H NMR (200.13 MHz,
CDCl3): d ˆ 2.68 (dd, J ˆ 17.4, 4.1 Hz, 1H, CH2 ring), 2.91 (dd,
J ˆ 17.5, 6.0 Hz, 1H, CH2 ring), 3.33 (s, 3H, OCH3 amide), 3.77
(s, 3H, OCH3), 3.85 (s, 2H, OCH2 amide), 4.06 (dd, J ˆ 3.4,
1.1 Hz, 2H, CH2 ring), 4.35 4.60 (m, 1H, CHN), 6.43 (dd, J ˆ
8.3, 1.0 Hz, 1H ar), 6.49 (dd, J ˆ 8.3, 1.0 Hz, 1H ar.), 6.73 (d
large, J ˆ 7.3 Hz, 1H, NH), 7.07 (t, J ˆ 8.3 Hz, 1H ar.);
13C NMR (50.3 MHz, CDCl3): d ˆ 25.7 (CH2 ring), 41.5
(CHN), 55.4 (OCH3), 59.0 (OCH3 amide), 67.5 (OCH2 ring),
71.9 (OCH2 amide), 102.5 (CH ar.), 108.6 (C quat, ar.), 109.5
(CH ar.), 127.4 (CH ar.), 154.7 (C quat, ar.), 158.4 (C quat., ar.),
169.4 (CO amide); anal. calcd. for C12H15NO3: C 65.19, H 6.99,
N 6.32%; found: C 65.14, H 6.83, N 6.33%; HPLC retention
time: (À) enantiomer: 14 min; (‡) enantiomer: 15 min.
N-(8'-Bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-acetamide
(11a): White solid. 1H NMR (200.13 MHz, CDCl3):
d ˆ 1.80 1.61 (m, 2H, CH2 ring), 2.00 (s, 3H, CH3), 2.53 (dd,
J ˆ 17.2, 8.4 Hz, 1H, CH2), 2.93 2.80 (m, 2H, CH2), 3.15 (dd,
J ˆ 17.2, 5.4 Hz, 1H, CH2), 4.90 4.65 (m, 1H, CHN), 5.62 (br s,
1H, NH), 7.10 6.97 (m, 2H, ar), 7.40 (d, J ˆ 7.1 Hz, 1H ar);
13C NMR (50.3 MHz, CDCl3): d ˆ 23.6 (CH3), 28.0 (CH2 ring),
28.3 (CH2 ring), 36.6 (CH2 ring), 45.5 (CH), 127.4 (CH ar.),
128.0 (CH ar.), 130.2 (CH ar.), 133.8 (C quat, ar.), 138.3 (C
quat., ar.), 169.6 (CO amide); HPLC retention time: (À)
enantiomer: 14 min; (‡) enantiomer: 22 min.
Acknowledgements
¬
The authors wish to thank Oril Industries and la Region
Bretagne for support.
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