Asymmetric Rh-catalyzed hydrogenation of enamides with a chiral 1,4- bisphosphine bearing diphenylphosphino groups

Full text of DOI:10.1021/jo981612t

9590
J . Org. Chem. 1998, 63, 9590-9593
Asym m etr ic Rh -Ca ta lyzed Hyd r ogen a tion
of En a m id es w ith a Ch ir a l
1,4-Bisp h osp h in e Bea r in g
Dip h en ylp h osp h in o Gr ou p s
F igu r e 1. (R,R)-BICP.
Guoxin Zhu and Xumu Zhang*
Department of Chemistry, The Pennsylvania State
University, University Park, Pennsylvania 16802
electron-rich DuPhos- and BPE-type ligands were ef-
ficient catalysts for the asymmetric hydrogenation of
enamides8 and enolates.9 They reported that analogous
Rh-chiral bisphosphines bearing diphenylphosphino groups
(e.g., BINAP, DIOP, and CHIRAPHOS) led to signifi-
cantly lower enantioselectivities in the reduction of
enamides (<60% ee).8
Received August 7, 1998
In tr od u ction
Much effort has been devoted to the development of
efficient asymmetric synthetic methods for the prepara-
tion of enantiomerically enriched compounds.1,2 Among
various methods for the enantiomerically selective syn-
thesis of chiral organic compounds from prochiral precur-
sors, enantioselective catalytic hydrogenation of dehydro
precursors has been extensively developed.3 In fact,
asymmetric hydrogenation is one of the most practical
methods in asymmetric synthesis, accounting for 70% of
all procedures used on a commercial scale.4 However,
most asymmetric catalytic hydrogenation systems only
hydrogenate electron-deficient olefins with high enanti-
oselectivity and high reactivity. In contrast, electron-
rich olefins, such as simple enamides5 and enolates,6 are
generally poor substrates for asymmetric hydrogenation
with most known systems. Since enamides and enolates
upon asymmetric hydrogenation can be converted to
enantiomerically pure amines and alcohols,7 it would be
extremely desirable to have a general and efficient
method for this transformation. Recently, Burk and co-
workers have reported that Rh complexes bearing the
We have been interested in elucidating the steric and
electronic effects10 of various diphenylphosphino-bearing
chiral ligands in asymmetric hydrogenation processes.
Recently a new chiral 1,4-bisphosphine, 2(R),2′(R)-bis-
(diphenylphosphino)-1(R),1′(R)-dicyclopentane ((R,R)-
BICP, Figure 1), was reported from our laboratory as an
excellent ligand for the Rh-catalyzed asymmetric hydro-
genation of dehydroamino acids.11 The key feature of this
new ligand is that four stereogenic centers are introduced
in a conformationally rigid bicyclic backbone, which is
fundamentally different from either axially dissymmetric
BINAP or bisphosphines with two stereogenic centers.
Herein, we describe the highly enantioselective Rh-
catalyzed hydrogenation of enamides using the BICP
ligand. Among the known chiral bisphosphines with
diphenylphosphino groups, the BICP ligand gives the
highest enantioselectivity for the rhodium-catalyzed
asymmetric hydrogenation of simple enamides.
Resu lts a n d Discu ssion
The active catalyst employed in our study was gener-
ated in situ from a cationic Rh complex, [Rh(COD)2]BF4
or [Rh(COD)2]OTf, and bisphosphine BICP (1:1.2). Ena-
mide 1a was chosen as a model substrate to screen
various reaction conditions. As shown in Table 1, the
solvent had little effect on the enantioselectivities for this
reaction. Under 40 psi H2 at room temperature, reaction
in nonpolar solvents such as benzene (85.2% ee, entry 1)
and toluene (86.3% ee, entry 2) gave better enantiose-
lectivities than in polar solvents (entry 3, CH2Cl2, 75.7%
ee; entry 4, MeOH, 80.8% ee; entry 5, acetone, 77.3% ee,
entry 6, DMF, 77.4% ee, entry 7, THF, 80.6% ee). A small
hydrogen pressure effect was found for this asymmetric
catalytic system. Higher pressure gave slightly better
enantioselectivities and reactivities (e.g., 86.3% ee under
40 psi of hydrogen (entry 2) vs 80.2% ee under 14.7 psi
(entry 9)). However, increasing hydrogen pressure fur-
ther did not provide any improvement in the enantiose-
lectivity. A neutral rhodium catalyst formed in situ from
(1) (a) Catalytic Asymmetric Synthesis; Ojima, I., ed.; VCH: New
York, 1993. (b) Sheldon, R. A. Chirotechnology; Marcel Dekker: New
York, 1993. (c) Noyori, R. Asymmetric Catalysis In Organic Synthesis;
Wiley: New York, 1994.
(2) (a) Kotha, S. Tetrahedron 1994, 50, 3639. (b) Brunner, H. In
Topics in Stereochemistry; Interscience: New York, 1988; Vol. 18, p
129. (c) Handbook of Enantioselective Catalysis; Brunner, H., Zet-
tlmeier, W., Eds.; VCH: New York, 1993; Vol. 2.
(3) (a) Knowles, W. S. Acc. Chem. Res. 1983, 16, 106. (b) Noyori, R.
Science 1990, 248, 1194. (c) Noyori, R.; Takaya, H. Acc. Chem. Res.
1990, 23, 345. (d) Vineyard, B. D.; Knowles, W. S.; Sabacky, M. J .;
Bachman, D. l.; Weinkauff, D. J . J . Am. Chem. Soc. 1977, 99, 5946.
(e) Ojima, I.; Clos, N.; Bastos, C. Tetrahedron 1989, 45, 6901. (f)
Benincori, T.; Brenna, E.; Sannicolo, F.; Trimarco, L.; Antognazza, P.;
Cesarotti, E.; Demartin, F.; Pilati, T. J . Org. Chem. 1996, 61, 6244.
(g) Uemura, T.; Zhang, X.; Matsumura, K.; Sayo, N.; Kumobayashi,
H.; Ohta, T.; Nozaki, K.; Takaya, H. J . Org. Chem. 1996, 61, 5510.
(4) Cannarsa, M. J . Proceeding of the Chiral USA’97 and a related
report of Technol. Catal. Int.
(5) (a) Morimoto, T.; Chiba, M.; Achiwa, K. Chem. Pharm. Bull.
1992, 40, 2894. (b) Kagan, H. B.; Langlois, N.; Dang, T. P. J .
Organomet. Chem. 1975, 90, 353. (c) Sinou, D.; Kagan, H. B. J .
Organomet. Chem. 1976, 114, 325. (d) highly enantioselective hydro-
genation of enamines was achieved using a chiral titanocene catalyst:
Lee, N. E.; Buchwald, S. L. J . Am. Chem. Soc. 1994, 116, 5985.
(6) (a) Brown, J . M.; Murrer, B. A. J . Chem. Soc., Perkin Trans. 2
1982, 489. (b) Koenig, K. E.; Bachman, G. L.; Vineyard, B. D. J . Org.
Chem. 1980, 45, 2362. (c) Selke, R.; Pracejus, H. J . Mol. Catal. 1986,
37, 213. (d) Fryzuk, M. D.; Bosnich, B. J . Am. Chem. Soc. 1978, 100,
5491. (e) Koenig, K. E. In Asymmetric Synthesis; Morrison, J . D., Ed.;
Academic Press: New York, 1985; Vol. 5, Chapter 3.
(8) Burk, M. J .; Wang, Y. M.; Lee, J . R. J . Am. Chem. Soc. 1996,
118, 5142.
(9) Burk, M. J . J . Am. Chem. Soc. 1991, 113, 8518.
(10) For electronic effect of chiral phosphines, see: (a) Inoguchi, K.;
Achiwa, K. Synlett 1991, 49. (b) RajanBabu, T. V.; Casalnuovo, A. L.
J . Am. Chem. Soc. 1992, 114, 6265. (c) RajanBabu, T. V.; Ayers, T. A.;
Halliday, G. A.; You, K. K.; Calabrese, J . C. J . Org. Chem. 1997, 62,
6012 and references therein.
(7) (a) J acques, J .; Collect, A.; Wilen, S. H. Enantiomers, Racemates,
and Resolutions; J ohn Wiley and Sons: New York, 1981. (b) Nogradi,
M. Stereoselective Synthesis, 2nd ed.; VCH: Weinheim, Germany, 1995.
(c) J uaristi, E.; Escalante, J .; Leon-Romo, J . L.; Reyes, A. Tetrahe-
dron: Asymmetry 1998, 9, 715 and references therein.
(11) Zhu, G.; Cao, P.; J iang, Q.; Zhang, X. J . Am. Chem. Soc. 1997,
119, 1799.
10.1021/jo981612t CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/18/1998

Notes
J . Org. Chem., Vol. 63, No. 25, 1998 9591
Ta ble 1. Rh od iu m Ca ta lyzed Asym m etr ic
Hyd r ogen a tion of En a m id e 1a a
Ta ble 2. Asym m etr ic Hyd r ogen a tion of En a m id es by a
Ca tion ic Rh od iu m -(R,R)-BICP Com p lexa
entry
solvent
pressure (psi)
eec (%)
entry
1c
Ar
R
eed (%)
1
2
3
4
5
6
7
8d
9
benzene
toluene
CH2Cl2
MeOH
acetone
DMF
40
40
40
40
40
40
40
40
85.2
86.3
75.7
80.8
77.3
77.4
80.6
86.3
80.2
84.9
11.4
1
2
3
4
5
6
7
8
9
10
11
12
13
1a
1b
1c
1d
1e
1f
1g
1h
1i
C6H5
H
H
H
H
H
H
H
CH3
86.3
86.1
85.7
86.4
93.0
91.6
85.2
95.0
93.5
90.5
95.2
95.1
93.6
4-Me-C6H4
3-Me-C6H4
4-CF3-C6H4
4-Ph-C6H4
4-MeO-C6H4
2-Np
THF
toluene
toluene
benzene
toluene
C6H5
C6H5
C6H5
14.7
14.7
40
CH(CH3)2
CH2Ph
CH3
10
1j
1k
1l
11e
4-MeO-C6H4
4-CF3-C6H4
2-Np
a
The reaction was carried out at rt for 24 h. The catalyst was
made in situ by stirring a solution of [Rh(COD)2]BF4 and the ligand
in toluene [[substrate (0.5 mmol, 0.125 M)/[Rh]/(R,R)-BICP )
1:0.01:0.011]]. The reaction was in quantitative yield. The R
CH3
CH3
1m
a
The reaction was carried out at rt under an initial hydrogen
pressure of 40 psi for 24-36 h. The catalyst was made in situ by
stirring a solution of [Rh(COD)2]OTf and (R,R)-BICP in toluene
[[substrate (0.5 mmol, 0.125 M)/][Rh]/(R,R)-BICP ) 1:0.01:0.011]].
b
configuration was assigned by comparison of optical rotation with
reported data.8 c Enantiomeric excesses were determined by chiral
GC using a Supelco Chiral Select 1000 column at 130 °C.
b
The reaction went in quantitative yield. The R configuration was
[Rh(COD)2]OTf was used as catalyst precursor. e [Rh(COD)Cl]2
d
assigned by comparison of optical rotation with reported data.8
c Enamides 1 were prepared according to literature methods5a-c,12
or by reduction of corresponding oximes by iron powder in the
was used as catalyst precursor.
BICP and [Rh(COD)Cl]2 was much less effective than the
cationic Rh species (entry 11, 11.4% ee vs entry 8, 86.3%
ee). Under similar conditions, hydrogenation of enamide
1a proceeded with low conversion, giving only 11.4%
enantiomeric excess (entry 11). Overall, the optimized
conditions use the catalyst generated in situ from [Rh-
(COD)2]BF4 or [Rh(COD)2]OTf (1.0 mol %) and BICP (1.2
mol %), and the reaction is carried out at room temper-
ature in toluene under 40 psi H2.
The scope of the asymmetric hydrogenation reaction
with different substrates is shown in Table 2. A series
of R-aryl enamides were reduced to give the enantiomeri-
cally enriched R-arylethylamine derivatives with good
enantioselectivities using the optimal reaction conditions.
Only a small electronic effect of the aryl ring was
observed on the enantioselectivity. For example, 4′-
methylphenyl-substituted and 4′-(trifluoromethyl)phenyl-
substituted enamides 1b (entry 2) and 1d (entry 4) gave
similar results with enamide 1a (entry 1), while 4′-
methoxyphenyl-substituted enamide 1f gave better enan-
tioselectivity (entry 6). Increasing the steric bulk of the
group on the 4′-position on the phenyl ring of the enamide
gave slightly better enantioselectivities. For example, 4′-
phenylphenyl-substituted enamide 1e (entry 5) was
hydrogenated in high yield with 93.0% ee compared to
phenyl enamide 1a (86.3% ee, entry 1).
An important feature of the Rh-BICP catalyst was
found when we extended this hydrogenation reaction to
an R-aryl enamide with a â-methyl group, 1h . The
catalyst system can hydrogenate this â-substituted ena-
mide effectively and gave higher enantioselectivity than
the corresponding terminal enamide substrate 1a . The
hydrogenation reaction was not sensitive to the geometry
of the substrates, as an isomeric mixture of (Z)- and (E)-
enamides with a ratio of 1:2 was reduced smoothly in 95%
ee under the standard reaction conditions. The ability
to reduce such â-substituted enamides greatly expands
the utility of this hydrogenation methodology for the
synthesis of various chiral amine derivatives. These
d
presence of acetic anhydride in DMF. Enantiomeric excesses
were determined by chiral GC using a Supelco Chiral Select 1000
column or by Chiral HPLC with a Regis (R,R)-Whelk-O1 column.
amine derivatives are useful building blocks for biologi-
cally active compounds. Because it is currently difficult
to synthesize isomerically pure enamides using existing
methods,5a-c,12 this insensitivity to the isomeric composi-
tion of enamides should be critical for the practical
synthesis of chiral amines. Further study showed that
a series of different â-substituted isomeric enamide
mixtures (1h -j) and â-methyl-substituted enamides with
various substituents on the 1-aryl group (1k -l) can be
reduced in high yield with high enantioselectivities. The
reaction is not sensitive to electronic effects of a sub-
stituent on the 1-aryl group. For example, the 4-meth-
oxyphenyl-substituted species 1k and the 4-(trifluoro-
methyl)phenyl analogue 1l showed almost the same
reactivities and enantioselectivities under identical hy-
drogenation conditions (entries 11 and 12). The enanti-
oselectivities achieved in the Rh-BICP system are com-
parable to the results obtained with Burk’s Rh-DuPhos
catalysts, the only previously reported system that can
tolerate Z and E mixtures of simple enamides.
To further expand the utility of this asymmetric
enamide hydrogenation, we have examined our catalytic
system with some cyclic enamides (Figure 2). The
successful reduction of these cyclic enamide substrates
can lead to important chiral cyclic amines12b,13 (e.g.,
(12) (a) Lenz, G. R. Synthesis 1978, 489. (b) Tschen, D. M.;
Abramson, L.; Cai, D.; Desmond, R.; Dolling, U. H.; Frey, L.; Karady,
S.; Shi, Y. J .; Verhoeven, T. R. J . Org. Chem. 1995, 50, 4321. (c) Boar,
R. B.; McGhie, J . F.; Robonson, M.; Barton, D. H. R.; Horwell, D. C.;
Stick, R. V. J . Chem. Soc., Perkin Trans. 1 1975, 1237. (d) Laso, N.
M.; Quiclet-Sire, B.; Zard, S. Z. Tetrahedron Lett. 1996, 37, 1605. (d)
Reduction of an oxime in the presence of acetic anhydride in DMF by
iron powder provided an alternative way to synthesize enamides from
ketones (Casalnuovo, A. L. Personal communication). (e) Conversion
of oximes to enamides with iron powder in acetic anhydride was also
reported: Burk, M. J . Proc. ChiraTech’ 97 Symp.

9592 J . Org. Chem., Vol. 63, No. 25, 1998
Notes
chiral capillary column: Chiral Select 1000 column [dimensions,
15 m × 0.25 mm (i.d.); Carrier gas, He (1 mL/min)]. HPLC
analysis was carried out on a Waters 600 chromatograph with
an (R,R)-Poly Whelk-01 column from Regis Technologies, Inc.
[particle size, 5.0 mm; column dimensions, 25 cm (length) × 0.46
cm (i.d.); column temperature, 25 °C].
Gen er a l P r oced u r e for Asym m etr ic Hyd r ogen a tion . To
a solution of [Rh(COD)2]BF4 (5.0 mg, 0.012 mmol) in toluene
(10 mL) in a glovebox was added (R,R)-BICP (0.15 mL of 0.1 M
solution in toluene, 0.015 mmol). After the mixture was stirred
for 30 min, substrate enamide (1.2 mmol) was added. The
hydrogenation was performed at room temperature under 40 psi
of hydrogen for 24 h. After the hydrogen was released, the
reaction mixture was passed through a short silica gel column
to remove the catalyst. The enantiomeric excess was measured
by capillary GC or HPLC directly without any further purifica-
tion. The absolute configuration of the products was determined
by comparing the observed rotation with the reported value.8
Ch a r a cter iza tion of Su bstr a tes. N-Acetyl-1-p h en ylen -
th en a m in e (1a ):8 1H NMR (360 MHz, CDCl3) δ 2.13 (br, 3H),
5.09 (s, 1H), 5.88 (s, 1H), 6.85 (br, 1H), 7.43-7.21 (m, 5H).
N-Acet yl-1-(4-m et h ylp h en yl)en t h en a m in e (1b ):8 1H NMR
(360 MHz, CDCl3) δ 2.13 (s, 3H), 2.36 (s, 3H), 5.05 (s, 1H), 5.83
(s, 1H), 6.80 (br, 1H), 7.17 (d, J ) 8.1 Hz, 2H), 7.31 (d, J ) 7.53
Hz, 2H). N-Acetyl-1-(3-m eth ylp h en yl)en th en a m in e (1c):8
1H NMR (360 MHz, CDCl3) δ 2.12 (s, 3H), 2.37 (s, 3H), 5.06 (s,
1H), 5.85 (s, 1H), 6.89 (br, 1H), 7.27-7.15 (m, 4H). N-Acetyl-
1-[4-(tr iflu or om eth yl)p h en yl]en th en a m in e (1d ):8 1H NMR
(200 MHz, CDCl3) δ 2.11 (s, 3H), 5.16 (s, 1H), 5.82 (s, 1H), 6.98
(br, 1H), 7.50-7.64 (m, 4H). N-Acetyl-1-(4-p h en ylp h en yl)-
en th en a m in e (1e): 1H NMR (360 MHz, acetone-d6) δ 2.35 (s,
3H), 5.27 (s, 1H), 6.09 (s, 1H), 7.60-7.91 (m, 9 H), 8.80 (br, 1H);
13C NMR (75 MHz, acetone-d6) δ 24.6, 101.9, 128.05, 128.1,
128.8, 130.2, 139.0, 141.6, 142.2, 142.9, 170.1; MS m/z 237, 221,
180, 152, 78, 63, 43; HRMS calcd for C16H15NO (M+) 237.1154,
found 237.1143. N-Acetyl-1-(4-m eth oxyph en yl)en th en am in e
(1f):8 1H NMR (360 MHz, CDCl3) δ 2.13 (s, 3H), 3.82 (s, 3H),
5.01 (s, 1H), 5.77 (s, 1H), 6.75 (br, 1H), 6.89 (d, J ) 8.80 Hz,
2H), 7.35 (d, J ) 8.50 Hz, 2H); 1H NMR (200 MHz, CDCl3) δ
2.11 (s, 3H), 5.16 (s, 1H), 5.82 (s, 1H), 6.98 (br, 1H), 7.50-7.64
(m, 4H). N-Acetyl-1-(2-n a p h th yl)eth en a m in e (1g):8 1H NMR
(360 MHz, CDCl3) δ 2.15 (s, 3H), 5.24 (s, 1H), 5.94 (s, 1H), 7.03
(br, 1H), 7.49-7.55 (m, 3H), 7.80-7.87 (m, 4H). N-Acetyl-1-
p h en ylp r op en a m in e (1h ):8 Z-E isomers (1:2.05), 1H NMR
(360 MHz, CDCl3) δ (major isomer) 1.70 (d, J ) 7.34 Hz, 3H),
2.18 (s, 3H), 5.95 (q, J ) 6.94 Hz, 1 H), 6.59 (br, 1H), 7.25-7.45
(m, 5H); δ (minor isomer) 1.86 (d, J ) 7.02 Hz, 3H), 2.05 (s, 3H),
6.05 (q, J ) 7.00 Hz, 1 H), 6.65 (br, 1H). N-Acetyl-1-p h en yl-
3-m eth ylbu ten a m in e (1i):8 Z-E isomers (1.53:1), 1H NMR
(360 MHz, CDCl3) δ (major isomer) 1.08 (d, J ) 6.63 Hz, 6H),
2.17 (s, 3H), 2.53-2.65 (m, 1H), 5.71 (d, J ) 9.64 Hz, 1H), 6.58
(br, 1H), 7.25-7.45 (m, 5H); δ (minor isomer) 1.70 (s, 3H), 2.80
(m, 1H), 5.77 (d, J ) 9.70 Hz, 1H), 5.65 (br, 1H). N-Acetyl-
1,3-d ip h en ylp r op en a m in e (1j):8 Z-E isomer (2.61:1): 1H
NMR (360 MHz, CDCl3) δ (major isomer) 1.81 (s, 6H), 3.52 (d, J
) 7.06 Hz, 2H), 6.00 (t, J ) 7.07 Hz, 1H), 6.69 (br, 1H), 7.21-
7.48 (m, 10H); δ (minor isomer) 1.81 (s, 3H), 3.60 (d, J ) 7.33
Hz, 2H), 6.16 (m, 1H).
F igu r e 2.
tetrahydroisoquinolines14). Under the standard reaction
conditions used for acyclic enamide substrates, hydroge-
nation of cyclic enamides 3 and 4 showed high reactivity,
giving the corresponding N-acetylamine with moderate
enantioselectivity (60.3% ee for 3 and 64.5% ee for 4).
Asymmetric hydrogenation of N-acetyl-1-methylene-
1,2,3,4-tetrahydroisoquinoline 5 proceeded smoothly, af-
fording (R)-(-)-N-acetylsalsolidine15 in quantitative yield
in 77.8% ee.
In summary, the BICP ligand is one of the best chiral
diphenylphosphino ligands for the rhodium-catalyzed
asymmetric hydrogenation of electron-rich olefin sub-
strates.16 This method provides an efficient approach to
a wide range of enantiomerically enriched arylalky-
lamines. The key feature of this catalytic system is that
the enantioselectivity of the hydrogenation reaction is not
sensitive to the geometry of the starting enamides. Thus,
a series of Z- and E-â-substituted amide isomers can be
reduced in high yield and with high enantioselectivity.
The mechanistic details for this reaction are not yet clear.
Further study will focus on this aspect of the chemistry
as well as further modification of the new ligand system
to accommodate a broader range of enamide substrates.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions and manipulations were
performed in
a nitrogen-filled glovebox or using standard
Schlenk techniques. Toluene, benzene and tetrahydrofuran
(THF) were distilled from sodium benzophenone ketyl under
nitrogen. Methylene chloride was distilled from CaH2. Metha-
nol was distilled from Mg under nitrogen. The chiral BICP
ligand was prepared as previously described.11 All the enamide
substrates were prepared following reported procedures or by
reduction of the corresponding oxime by iron in the presence of
acetic anhydride in DMF.5a-c,12 GC analysis was carried out on
Helwett-Packard 5890 and 6890 gas chromatographs using a
N-Acetyl-1-(3-m eth oxyph en yl)pr open am in e(1k): Z-E iso-
mer (1.8:1), 1H NMR (360 MHz, CDCl3) δ (major isomer) 1.69
(d, J ) 7.43 Hz, 3H), 2.18 (s, 3H), 3.80 (s, 1H), 5.84 (q, J ) 7.00
Hz, 1H), 6.56 (br, 1H), 6.83-6.94 (m, 2H), 7.26-7.37 (m, 2H); δ
(minor isomer) 1.75 (d, 3H), 1.74 (s, 3H), 3.82 (s, 3H), 5.91 (q,
1H), 6.60 (br, 1H); 13C NMR (75 MHz, CDCl3) δ (major isomer)
14.0, 23.1, 55.3, 113.7, 119.1, 126.6, 130.1, 130.9, 133.9, 159.2,
169.1; δ (minor isomer) 13.6, 20.5, 55.4, 114.2, 120.3, 126.7,
130.3, 130.8, 135.3, 159.7, 173.8; MS m/z 205, 190, 162, 134, 119,
91, 77, 43; HRMS calcd for C12H15NO2 (M+) 205.1103, found
205.1095.
(13) Kohmura, Y.; Kawasaki, K.-I.; Katsuki, T. Synlett 1997, 1456.
(14) (a) Noyori, R.; Ohta, M.; Hsiao, Y.; Kitamura, M.; Ohta, T.;
Takaya, H. J . Am. Chem. Soc. 1986, 108, 7117. (b) M. Kitamura,
Tsukamoto, M.; Takaya, H.; Noyori, R. Bull. Chem. Soc. J pn. 1996,
69, 1695. (c) Kitamura, M.; Hsiao, Y.; Ohta, M.; Tsukamoto, M.; Ohta,
T.; Takaya, H.; Noyori, R. J . Org. Chem. 1994, 59, 297.
(15) (a) Morimoto, T.; Nakajima, N.; Achiwa, K. Tetrahedron:
Asymmetry 1995, 6, 75. (b) Czarnocki, Z.; MacLean, D. B.; Szarek, W.
A. Heterocycles 1992, 34, 943. (c) Munchhof, M. J .; Meyers, A. I. J .
Org. Chem. 1995, 60, 7086.
(16) The enantioselectivity achieved in the Rh-BICP-catalyzed
hydrogenation of â-substituted isomeric enamides is comparable to that
obtained with Rh-DuPhos catalysts (ref 8). For enamides without
â-substitutions, Rh-DuPhos catalysts give better enantioselectivities
than those with the Rh-BICP catalytic system. An efficient chiral
aminodiphenylphosphine for asymmetric hydrogenation of enamides
without â-substitutions was disclosed during the course of our inves-
tigation: Zhang, F.-Y.; Chan, A. S. C. Abstract. Symposium on
Frontiers of Chemistry, Hong Kong, 1997. Zhang, F.-Y.; Pai, C.-C.;
Chan, A. S. C. J . Am. Chem. Soc. 1998, 120, 5808.
N -Ace t yl-1-[4-(t r iflu or om e t h yl)p h e n yl]p r op e n a m in e
1
(1l): Z-E isomer (3.28:1), H NMR (360 MHz, CDCl3) δ (major
isomer) 1.80 (d, J ) 6.92 Hz, 3H), 2.18 (s, 3H), 6.00 (q, J ) 7.00
Hz, 1H), 6.70 (br, 1H), 7.45-7.60 (m, 4H); δ (minor isomer) 1.89
(d, J ) 6.79 Hz, 3H), 1.80 (s, 3H), 6.18 (m, 1H), 6.70 (br, 1H);
13C NMR (75 MHz, CDCl3) δ (major isomer) 14.0, 23.1, 55.3,
113.7, 119.1, 126.6, 130.1, 130.9, 133.9, 159.2, 169.1; δ (minor
isomer) 13.6, 20.5, 55.4, 114.2, 120.3, 126.7, 130.3, 130.8, 135.3,

Notes
J . Org. Chem., Vol. 63, No. 25, 1998 9593
159.7, 173.8; MS m/z 243, 200, 172, 132, 56, 43; HRMS calcd for
C12H12F3NO (M+) 243.0871, found 243.0864.
) 7.43 Hz, 3H), 1.73 (m, 2H), 1.93 (s, 3 H), 4.83 (m, 1H), 6.75
(d, J ) 7.92 Hz, 1H), 7.34 (d, J ) 8.26 Hz, 2H), 7.52 (d, J ) 8.11
Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 10.6, 23.0, 29.0, 54.8,
119.6-129.8 (m), 146.7, 169.8; HRMS calcd for C12H14F3NO (M+)
245.1027, found 245.1025. 1-(N-Acet yla m id o)in d a n e: 1H
NMR (360 MHz, CDCl3) δ 1.82 (m, 1H), 2.03 (s, 3H), 2.59 (m,
1H), 2.86-2.98 (m, 2 H), 5.47 (m, 1H), 5.70 (br, 1H), 7.22-7.30
(m, 4H). N-(1,2,3,4-Tetr a h yd r o-1-n a p h th yl)a ceta m id e: 1H
NMR (360 MHz, CDCl3) δ 1.81 (s, 3H), 1.90-2.05 (m, 4H), 2.75-
2.79 (m, 2H), 5.17 (m, 1H), 5.71 (br, 1H), 7.08-7.29 (m, 4H).
Deter m in a tion of En a n tiom er ic Excesses. Chiral capil-
lary GC column: â-DEX-390 column. Dimensions: 15 m × 0.25
mm (i.d.). Carrier gas: He (1 mL/min). The racemic products
were obtained by hydrogenation of substrates with an achiral
catalyst. The following is the retention time for the racemic
products. N-Acetyl-1-p h en yleth yla m in e (capillary GC, 130
°C, isothermal) (S) t1 ) 27.6 min, (R) t2 ) 29.3 min. N-Acetyl-
1-[4-(tr iflu or om eth yl)p h en yl]eth yla m in e (capillary GC, 150
°C, isothermal) (S) t1 ) 14.0 min, (R) t2 ) 14.8 min. N-Acetyl-
N-Acetyl-1-(2-n a p h th yl)p r op en a m in e (1m ):8 Z-E isomers,
1H NMR (360 MHz, CDCl3) δ (major isomer) 1.82 (d, J ) 6.97
Hz, 3H), 2.23 (s, 3H), 6.11 (q, J ) 6.95 Hz, 1 H), 6.92 (br, 1H),
7.46-7.86 (m, 7H); δ (minor isomer) 1.92 (d, J ) 6.96 Hz, 3H),
1.86 (s, 3H), 6.23 (q, J ) 6.99 Hz, 1 H), 6.80 (br, 1H).
1-(N-Acetyla m id o)in d en e (3). To a solution of oxime of
1-indanone (2.64 g 20 mmol) and acetic anhydride (15 mL) in
DMF (50 mL) was added iron powder (10.0 g), and then the
reaction was initiated by adding few drops of chlorotrimethyl-
silane under nitrogen. After the reaction mixture was stirred
at room temperature for 4 h, TLC showed that the reaction was
complete. The reaction mixture was diluted with ether, and solid
was filtered off through a short column of Celite. The filtrate
was concentrated, and the residue was purified by flash chro-
matography on silica gel. Recrystallization from CH2Cl2-
hexanes afforded pure enamide 3: 2.5 g, 72.2% yield. 1H NMR
(360 MHz, acetone-d6) δ 2.13 (s, 3H), 3.37 (m, 2H), 6.85 (m, 1H),
7.21-7.27 (m, 2H), 7.45-7.47 (m, 1H), 7.60 (d, J ) 7.36 Hz, 1H),
9.10 (br, 1H); 13C NMR (75 MHz, acetone-d6) δ 23.7, 36.8, 114.5,
118.1, 124.7, 125.9, 126.7, 137.6, 141.1, 143.6, 169.2; MS m/z
173, 132, 103, 77, 43; HRMS calcd for C11H11NO (M+) 173.0841,
found 173.0832.
1-tolyleth yla m in e (capillary GC, 140 °C, isothermal) (S) t1
)
27.8 min, (R) t2 ) 28.9 min. N-Acetyl-1-(3-m eth ylp h en yl)-
eth yla m in e (capillary GC, 140 °C, isothermal) (S) t1 ) 23.4 min,
(R) t2 ) 24.6 min. N-Acetyl-1-(4-m eth oxyp h en yl)eth yla m in e
(capillary GC, 140 °C for 60 min then 20 °C/min to 180 °C,
gradient) (S) t1 ) 62.8 min, (R) t2 ) 63.2 min. N-Acetyl-1-
p h en ylp r op yla m in e (capillary GC, 135 °C, isothermal) S) t1
) 26.0 min, (R) t2 ) 27.1 min. N-Acetyl-1-p h en yl-3-m eth yl-
bu tyla m in e (capillary GC, 145 °C, isothermal) (S) t1 ) 26.2 min,
(R) t2 ) 27.1 min. N-Acetyl-1-[4-(tr iflu or om eth yl)p h en yl]-
p r op yla m in e (capillary GC, 150 °C, isothermal) (S) t1 ) 17.7
min, (R) t2 ) 18.5 min. 1-(N-Acetyla m id o)in d a n e (capillary
GC, 160 °C, isothermal) (S) t1 ) 17.9 min, (R) t2 ) 18.7 min.
N-(1,2,3,4-Tetr a h yd r o-1-n a p h th yl)a ceta m id e (capillary GC,
180 °C, isothermal) (S) t1 ) 10.1 min, (R) t2 ) 11.4 min.
N-Acetyl-1-p h en ylbu tyla m in e (capillary GC, 150 °C isother-
mal) (S) t1 ) 14.8 min, (R) t2 ) 15.4 min. N-Acetyl-1-(2-fu r yl)-
eth yla m in e (capillary GC, 140 °C, isothermal) (S) t1 ) 5.7 min,
(R) t2 ) 5.9 min. N-Acetyl-1-(2-th ien yl)eth yla m in e (capillary
GC, 140 °C, isothermal) (S) t1 ) 16.0 min, (R) t2 ) 16.7 min.
Chiral HPLC Column: (R,R)-Poly Whelk-0 from Regis Tech-
nologies, Inc. Particle size: 5.0 µm. Column dimensions: 25
cm (length) × 0.46 cm (i.d.). Column temperature: 25 °C.
N-Acet yl-1-(2-Na p h t h yl)et h yla m in e (HPLC, 1.0 mL/min,
2-PrOH/hexane ) 1), (S) t1 ) 10.2 min, (R) t2 ) 60.7 min.
N-Acet yl-1-(1-n a p h t h yl)et h yla m in e (HPLC, 1.0 mL/min,
2-PrOH/hexane ) 1), (S) t1 ) 9.4 min, (R) t2 ) 29.9 min.
N-Acetyl-1-(4-p h en ylp h en yl)eth yla m in e (HPLC, 1.0 mL/min,
2-PrOH/hexane ) 1), (S) t1 ) 8.6 min, (R) t2 ) 18.5 min.
N-Acetyl-1-(2-n a p h th yl)p r op yla m in e (HPLC, 1.0 mL/min,
2-PrOH/hexane ) 1), (S) t1 ) 9.6 min, (R) t2 ) 39.8 min.
N-Acet yl-1,3-d ip h en ylp r op yla m in e (HPLC, 1.0 mL/min,
2-PrOH/hexane ) 7:3), (S) t1 ) 9.2 min, (R) t2 ) 13.5 min.
N-Acetyl-1-(4-m eth oxyp h en yl)p r op yla m in e (HPLC, 1.0 mL/
min, 2-PrOH/hexane ) 7:3), (S) t1 ) 10.7 min, (R) t2 ) 22.8 min.
1
N-(3,4-Dih yd r o-1-n a p h th yl)a ceta m id e (4): H NMR (360
MHz, acetone-d6) δ 1.98 (s, 3H), 2.20 (m, 2H), 2.64 (m, 2H), 6.32
(m, 1H), 7.07 (m, 3H), 7.22 (m, 1H), 8.53 (br, 1H); 13C NMR (75
MHz, acetone-d6) δ 22.9, 23.8, 28.4, 118.7, 122.6, 127.1, 128.1,
128.4, 133.6, 137.6, 169.6. HRMS calcd for C12H13NO (M+)
187.0997, found 187.0993.
Ch a r a cter iza tion of P r od u cts. N-Acetyl-1-p h en yleth y-
la m in e:8 1H NMR (360 MHz, CDCl3) δ 1.47 (d, J ) 6.93 Hz,
3H), 1.95 (s, 3H), 5.08 (m, 1H), 6.05 (br, 1H), 7.21-7.33 (m, 5H).
N-Acetyl-1-(2-n a p h th yl)eth yla m in e:8 1H NMR (200 MHz,
CDCl3) δ 1.57 (d, J ) 6.90 Hz, 3H), 2.00 (s, 3H), 5.26-5.33 (m,
1H), 6.00 (br, 1H), 7.40-7.51 (m, 3H), 7.75-7.83 (m, 4H).
N-Acetyl-1-[4-(tr iflu or om eth yl)ph en yl]eth ylam in e:8 1H NMR
(200 MHz, CDCl3) δ 1.49 (d, J ) 6.98 Hz, 3H), 2.00 (s, 3H), 5.16
(m, 1H), 5.76 (br, 1H), 7.42 (d, J ) 8.16 Hz, 2H), 7.59 (d, J ) 8.4
Hz, 2H). N-Acetyl-1-(4-p h en ylp h en yl)eth yla m in e: 1H NMR
(360 MHz, CDCl3) δ 1.53 (d, J ) 6.90 Hz, 3H), 2.01 (s, 3H), 5.18
(m, 1H), 5.67 (br, 1H), 7.32-7.46 (m, 5H), 7.55-7.58 (m, 4H);
13C NMR (75 MHz, CDCl3) δ 21.7, 23.5, 48.5, 126.6, 127.1, 127.3,
127.4, 128.8, 140.4, 140.7, 142.1, 169.1; MS m/z: 239, 224, 196,
182, 165, 155, 120, 77, 43; HRMS calcd for C16H17NO (M+)
239.1310, found 239.1303. N-Acetyl-1-tolyleth yla m in e:8 1H
NMR (360 MHz, CDCl3) δ 1.45 (d, J ) 6.94 Hz, 3H), 1.94 (s,
3H), 2.34 (s, 3H), 5.04 (m, 1H), 6.06 (br, 1H), 7.12 (d, J ) 8.08
Hz, 2H), 7.23 (d, J ) 8.10 Hz, 2H). N-Acetyl-1-(3-m eth ylp h e-
n yl)eth yla m in e:8 1H NMR (360 MHz, CDCl3) δ 1.47 (d, J )
6.88 Hz, 3H), 1.97 (s, 3H), 2.35 (s, 3H), 5.08 (m, 1H), 5.77 (br,
1H), 7.0.07-7.11 (m, 3H), 7.23-7.26 (m, 1H). N-Acetyl-1-(4-
m eth oxyp h en yl)eth yla m in e:8 1H NMR (360 MHz, CDCl3) δ
1.47 (m, 3H), 1.96 (s, 3H), 2.03 (s, 3H), 5.08 (m, 1H), 5.07 (br,
1H), 6.84-6.88 (m, 2H), 7.22-7.26 (m, 2H). N-Acetyl-1-
p h en ylp r op yla m in e:8 1H NMR (360 MHz, CDCl3) δ 0.88 (t, J
) 7.41 Hz, 3H), 1.84 (m, 2H), 1.98 (s, 3H), 4.88 (m, 1H), 5.68
(br, 1H), 7.23-7.36 (m, 5H). N-Acetyl-1-(2-n a p h th yl)p r op y-
la m in e:8 1H NMR (300 MHz, CDCl3) δ 0.92 (t, J ) 7.41 hz, 3H),
1.87-1.97 (m, 2H), 2.00 (s, 3H), 5.04 (m, 1H), 5.84 (br, 1H), 7.26-
7.47 (m, 3H), 7.73 (s, 1H), 7.80-7.83 (m, 3H). N-Acetyl-1-
p h en yl-3-m eth ylbu tyla m in e:8 1H NMR (360 MHz, CDCl3) δ
0.91-0.95 (m, 6 H), 1.50-1.71 (m, 3H), 2.04 (s, 3H), 5.04 (m,
1H), 5.63 (br, 1H), 7.23-7.35 (m, 5H). N-Acetyl-1,3-d ip h en yl-
p r op yla m in e:8 1H NMR (360 MHz, CDCl3) δ 1.95 (s, 3 H), 2.13-
2.19 (m, 2H), 2.57-2.60 (m, 2H), 5.03 (m, 1H), 5.80 (br, 1H),
7.14-7.35 (m, 10 H). N-Acetyl-1-(4-m eth oxyp h en yl)p r op y-
la m in e: 1H NMR (360 MHz, CDCl3) δ 0.85 (t, J ) 7.40 Hz, 3H),
1.73-1.88 (m, 2H), 2.04 (s, 3 H), 3.78 (s, 3H), 4.82 (m, 1H), 5.95
(d, J ) 8.08 Hz, 1H), 6.83-6.87 (m, 2 H), 7.17-7.26 (m, 2H);
13C NMR (75 MHz, CDCl3) δ 10.7, 23.4, 28.9, 54.4, 55.2, 114.0,
127.8, 134.2, 158.7, 169.1; HRMS calcd for C12H17NO2 (M+)
207.1259, found 207.1249. N-Acetyl-1-[4-(tr iflu or om eth yl)-
p h en yl]p r op yla m in e: 1H NMR (360 MHz, CDCl3) δ 0.86 (t, J
Ack n ow led gm en t. This work was supported by a
Camille and Henry Dreyfus New Faculty Award and
Teaching-Scholar Award, an ONR Young Investigator
Award, a DuPont Young Faculty Award, Catalytica
Pharmacuticals, and DuPont Agricultural Products. We
acknowledge a generous loan of precious metals from
J ohnson Matthey, Inc., and a gift of chiral GC columns
from Supelco and thank Dr. Albert L. Casalnuovo of
DuPont Agrochemical Products for useful suggestions
of enamide synthesis.
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data
of new compounds (16 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
J O981612T