Asymmetric hydrogenation of 1,4,5,6-tetrahydropyrazine-2-(N-tert- butyl)carboxamide catalyzed by trans-chelating chiral diphosphine-rhodium complexes

Article abstract of DOI:10.1021/jo981939u

Highly enantioselective hydrogenation of 1,4,5,6-tetrahydropyrazine-2- (N-tert-butyl)carboxamide (2) was accomplished by a rhodium complex coordinated with a chiral diphosphine TRAP ligand, which is possible to chelate to a transition metal atom in a trans-manner. Of particular interest is that (R,R)-(S,S)-i-BuTRAP gave 97% ee of the corresponding piperazine-2- carboxylic acid derivative (3) with (S) configuration, while the hydrogenation with (R,R)-(S,S)-MeTRAP-rhodium catalyst provided (R)-3 with up to 85% ee. ³¹P NMR studies of behavior of i-Bu- and MeTRAP-rhodium catalysts during the reaction suggest that the asymmetric hydrogenation of 2 with TRAPs may involve two competitive reaction pathways, giving their respective enantiomeric products 3.

Full text of DOI:10.1021/jo981939u

1232
J . Org. Chem. 1999, 64, 1232-1237
Asym m etr ic Hyd r ogen a tion of
1,4,5,6-Tetr a h yd r op yr a zin e-2-(N-ter t-bu tyl)ca r boxa m id e Ca ta lyzed
by Tr a n s-Ch ela tin g Ch ir a l Dip h osp h in e-Rh od iu m Com p lexes
Ryoichi Kuwano and Yoshihiko Ito*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering,
Kyoto University, Kyoto 606-8501, J apan
Received September 24, 1998
Highly enantioselective hydrogenation of 1,4,5,6-tetrahydropyrazine-2-(N-tert-butyl)carboxamide
(2) was accomplished by a rhodium complex coordinated with a chiral diphosphine TRAP ligand,
which is possible to chelate to a transition metal atom in a trans-manner. Of particular interest is
that (R,R)-(S,S)-i-BuTRAP gave 97% ee of the corresponding piperazine-2-carboxylic acid derivative
(3) with (S) configuration, while the hydrogenation with (R,R)-(S,S)-MeTRAP-rhodium catalyst
provided (R)-3 with up to 85% ee. 31P NMR studies of behavior of i-Bu- and MeTRAP-rhodium
catalysts during the reaction suggest that the asymmetric hydrogenation of 2 with TRAPs may
involve two competitive reaction pathways, giving their respective enantiomeric products 3.
In tr od u ction
Catalytic asymmetric hydrogenation of olefins using
an optically active transition metal complex is one of the
most progressing methodologies for preparation of a wide
range of optically active compounds.1 Especially, asym-
metric hydrogenation of acyclic R-acetamidoacrylates has
met with success, providing efficient preparation of
optically active R-amino acids.2,3 However, successful
asymmetric hydrogenation of olefins has been still lim-
ited. Only a few examples of highly enantioselective
hydrogenation of cyclic olefins have been reported.4,5
Optically active 2-substituted piperazines are impor-
tant pharmacophores that can be found in many drugs.
For example, (S)-4-(tert-butoxycarbonyl)piperazine-2-(N-
tert-butyl)carboxamide (1) is an important synthetic
intermediate of Merck HIV protease inhibitor Indinavir
sulfate (Crixivan) (Figure 1).6 The Merck research group
has reported synthesis of optically active piperazine 1 by
asymmetric hydrogenation of 1,4,5,6-tetrahydropyrazine-
2-carboxamide 2 catalyzed by chiral rhodium complex,
F igu r e 1.
in which high enantioselectivities have been, however,
achieved under high hydrogen pressure (70-100 kg/
cm2)7,8 or extremely low temperature (-40 °C).9
(1) For reviews of catalytic asymmetric hydrogenation, see: (a)
Takaya, H.; Ohta, T.; Noyori, R. In Catalytic Asymmetric Synthesis;
Ojima, I., Ed.; VCH: NewYork, 1993; pp 1-39. (b) Noyori, R.
Asymmetric Catalysis in Organic Synthesis; J ohn Wiley & Sons: New
York, 1994; pp 16-94. (c) Pfaltz, A.; Brown, J . M. In Stereoselective
Synthesis; Helmchen, G., Hofmann, R. W., Mulzer, J ., Schaumann, E.,
Eds.; Theime: Stuttgart, 1996; Vol. 7, pp 4334-4359.
(2) For reviews, see: Ko¨enig, K. E. In Asymmetric Synthesis;
Morrison, J . D., Ed.; Academic Press: New York, 1985; Vol. 5, pp 71-
101.
(3) Recent examples, see: (a) Burk, M. J .; Feaster, J . E.; Nugent,
W. A.; Harlow, R. L. J . Am. Chem. Soc. 1993, 115, 10125-10138. (b)
Zhu, G.; Cao, P.; J iang, Q.; Zhang, X. J . Am. Chem. Soc. 1997, 119,
1799-1780. (c) Chan, A. S. C.; Hu, W.; Pai, C.-C.; Lau, C.-P.; J iang,
Y.; Mi, A.; Yan, M.; Sun, J .; Lou, R.; Deng, J . J . Am. Chem. Soc. 1997,
119, 9570-9571. (c) Imamoto, T.; Watanabe, J .; Wada, Y.; Masuda,
H.; Yamada, H.; Tsuruta, H.; Matsukawa, S.; Yamaguchi, K. J . Am.
Chem. Soc. 1998, 120, 1635-1636.
Previously, we have reported the preparation of trans-
chelating chiral diphosphine TRAPs (Chart 1)10,11 and
(6) (a) Askin, D.; Eng, K. K.; Rossen, K.; Purick, R. M.; Wells, K.
M.; Volante, R. P.; Reider, P. J . Tetrahedron Lett. 1994, 35, 673-676.
(b) Vacca, J . P.; Dorsey, B. D.; Schleif, W. A.; Levin, R. B.; McDaniel,
S. L.; Darke, P. L.; Zugay, J .; Quintero, J . C.; Blahy, O. M.; Roth, E.;
Sardana, V. V.; Schlabach, A. J .; Graham, P. I.; Condra, J . H.; Gotlib,
L.; Holloway, M. K.; Lin, J .; Chen, I.-W.; Vestag, K.; Ostovic, D.;
Anderson, P. S.; Emini, E. A.; Huff, J . R. Proc. Natl. Acad. Sci. U.S.A.
1994, 91, 4096-4100. (c) Klabe, R. M.; Bacheler, L. T.; Ala, P. J .;
Erickson-Viitanen, S.; Meek, J . L. Biochemistry 1988, 27, 8735-8742.
(7) Rossen, K.; Weissman, S. A.; Sager, J .; Reamer, R. A.; Askin,
D.; Volante, R. P.; Reider, P. J . Tetrahedron Lett. 1995, 36, 6419-
6422.
(8) Rossen, K.; Pye, P. J .; DiMichele, L. M.; Volante, R. P.; Reider,
P. J . Tetrahedron Lett. 1998, 39, 6823-6826.
(4) (a) Hayashi, T.; Kawamura, N.; Ito, Y. Tetrahedron Lett. 1988,
29, 5969-5972. (b) Broene, R. D.; Buchwald, S. L. J . Am. Chem. Soc.
1993, 115, 12569-12570. (c) Armstrong, J . D., III.; Eng, K. K.; Keller,
J . L.; Purick, R. M.; Hartner, F. W., J r.; Choi, W.-B.; Askin, D.; Volante,
R. P. Tetrahedron Lett. 1994, 35, 3239-3242. (d) Foti, C. J .; Comins,
D. L. J . Org. Chem. 1995, 60, 2656-2657.
(5) Kinetic resolution of cyclic allyl alcohols by catalytic asymmetric
hydrogenation, see: Kitamura, M.; Kasahara, I.; Manabe, K.; Noyori,
R. J . Org. Chem. 1988, 53, 708-710.
(9) Pye, P. J .; Rossen, K.; Reamer, R. A.; Tsou, N. N.; Volante, R.
P.; Reider, P. J . J . Am. Chem. Soc. 1997, 119, 6207-6208.
(10) (R,R)-(S,S)-TRAP ) (S,S)-2,2′′-bis[(R)-1-(dialkylphosphino)et-
hyl]-1,1′′-biferrocene.
(11) (a) Sawamura, M.; Hamashima, H.; Ito, Y. Tetrahedron: Asym-
metry 1991, 2, 593-596. (b) Sawamura, M.; Hamashima, H.; Sug-
awara, M.; Kuwano, R.; Ito, Y. Organometallics 1995, 14, 4549-4558.
(c) Kuwano, R.; Sawamura, M.; Okuda, S.; Asai, T.; Ito, Y.; Redon, M.;
Krief, A. Bull. Chem. Soc. J pn. 1997, 70, 2807-2822.
10.1021/jo981939u CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/02/1999

Asymmetric Hydrogenation by Chiral Rh Complexes
J . Org. Chem., Vol. 64, No. 4, 1999 1233
Ta ble 1. Asym m etr ic Hyd r ogen etion of 2a Ca ta lyzed by
Ch a r t 1
TRAP -Rh od iu m Com p lexa
ee
convn, (3a ),
c
d
entry
[Rh]
ligandb
solvent
%
%
confign
1
2f
3
4
5
6
7
8
9
10
11
12
13g
1f
[Rh(NBD)2]PF6 PhTRAP
[Rh(NBD)2]PF6 PhTRAP
[Rh(NBD)2]PF6 i-PrTRAP EDC
[Rh(NBD)2]PF6 i-BuTRAP EDC
[Rh(NBD)2]PF6 BuTRAP
[Rh(NBD)2]PF6 EtTRAP
[Rh(NBD)2]PF6 MeTRAP
[Rh(NBD)2]PF6 i-BuTRAP THF
[Rh(NBD)2]PF6 i-BuTRAP C6H6
[Rh(NBD)2]PF6 i-BuTRAP MeOH
[Rh(NBD)2]PF6 i-BuTRAP i-PrOH
EDC
EDC
7
27
5
100
100
100
34
100
88
0
23
0
3
53
4
e
43
e
97
34
35
61
95
95
e
85
e
e
93
e
S
S
S
S
R
S
S
EDC
EDC
EDC
their applications to some asymmetric reactions.12-16
AlkylTRAP ligands bearing flexible linear alkyl groups
on their phosphorus atoms were effective for the asym-
metric hydrogenation of itaconates17 and R-acetami-
doacrylates including â,â-disubstituted ones.18 In this
paper, we report that a trans-chelating chiral diphos-
phine (R,R)-(S,S)-i-BuTRAP is an effective chiral ligand
for rhodium catalyzed asymmetric hydrogenation of 2,
which proceeds under mild condition to give (S)-pipera-
zine-2-carboxamide 3 with up to 97% ee. Of particular
interest is that its (R) enantiomer was prepared in high
enantioselectivity by the rhodium-catalyzed hydrogena-
tion with (R,R)-(S,S)-MeTRAP ligand, whose chiral sense
is the same as that of (R,R)-(S,S)-i-BuTRAP.19
S
S
[RhCl(COD)]2
i-BuTRAP EDC
[Rh(COD)2]OTf i-BuTRAP EDC
[Rh(COD)2]OTf i-BuTRAP EDC
[Rh(COD)2]ClO4 i-BuTRAP EDC
[Rh(COD)2]ClO4 i-BuTRAP EDC
[Rh(COD)2]BF4 i-BuTRAP EDC
[Rh(NBD)2]PF6 i-BuTRAP EDC
[Rh(NBD)2]SbF6 i-BuTRAP EDC
15g
16f
17g
18g
19g
84
36
75
85
100
95
93
95
96
96
S
S
S
S
S
20g,h [Rh(NBD)2]SbF6 i-BuTRAP EDC
a
Reactions were carried out at 50 °C and 1 kg/cm2 of hydrogen
pressure for 24 h in 0.250 M solution of 2a unless otherwise noted.
b
The ratio of 2a /[Rh]/ligand was 100:1:1.1. (R,R)-(S,S)-TRAPs
were used. c Determined by 1H NMR analysis of evaporated
d
reaction mixture. Determined by chiral HPLC analysis with
Resu lts a n d Discu ssion
SUMICHIRAL OA-2000. e Not determined. f 2 mol % of catalyst
was used. g Initial concentration of 2a was 0.125 M. The reaction
h
Asym m etr ic Hyd r ogen a tion of 2a w ith Rh od iu m -
(I)-TRAP Com p lex. Asymmetric hydrogenations of
1-tert-butoxycarbonyl-4-phenoxycarbonyl-1,4,5,6-tetrahy-
dropyrazine-2-(N-tert-butyl)carboxamide (2a ) were car-
ried out in 1,2-dichloroethane (EDC, 0.25 M) at 50 °C
under 1 kg/cm2 of hydrogen for 24 h with 1 mol % of chiral
catalyst prepared in situ from a variety of (R,R)-(S,S)-
TRAP and [Rh(NBD)2]PF6 (eq 1). Enantiomeric excesses
of 3a thus obtained were determined by chiral HPLC
analysis with SUMICHIRAL OA-2000. The results are
was carried out at 2 kg/cm2 of hydrogen pressure.
(12) (a) Sawamura, M.; Hamashima, H.; Ito, Y. J . Am. Chem. Soc.
1992, 114, 8295-8296. (b) Sawamura, M.; Hamashima, H.; Ito, Y.
Tetrahedron 1994, 50, 4439-4454. (c) Sawamura, M.; Hamashima, H.;
Shinoto, H.; Ito, Y. Tetrahedron Lett. 1995, 36, 6479-6482.
(13) (a) Sawamura, M.; Kuwano, R.; Ito, Y. Angew. Chem., Int. Ed.
Engl. 1994, 33, 111-113. (b) Sawamura, M.; Kuwano, R.; Shirai, J .;
Ito, Y. Synlett 1995, 347-348. (c) Kuwano, R.; Sawamura, M.; Shirai,
J .; Takahashi, M.; Ito, Y. Tetrahedron Lett. 1995, 36, 5239-5242.
(14) Goeke, A.; Sawamura, M.; Kuwano, R.; Ito, Y. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 662-663.
summarized in Table 1. Phosphorus substituents of
TRAP ligand remarkably affected not only enantioselec-
tivity but also catalytic activity. Rhodium complex coor-
dinated with Ph- and i-PrTRAP converted 2a into 3a in
only 7 and 5% yields for 24 h, respectively (Table 1,
entries 1 and 3). Bulky phenyl and isopropyl groups on
phosphorus atoms of the chiral ligands might block
coordination of 2a to the rhodium metal center. Use of 2
mol % of PhTRAP-rhodium catalyst gave (S)-rich 3a
with 43% ee in 27% NMR yield (Table 1, entry 2).
i-BuTRAP, bearing â-branched primary alkyl P-substit-
uents, was the most effective chiral diphosphine for the
asymmetric hydrogenation to give 97% ee of (S)-3a
quantitatively (Table 1, entry 4). The â-branched alkyl
group of i-BuTRAP may be important in achievement of
the high enantioselectivity unlike Et- and BuTRAP
bearing nonbranched alkyl P-substituents, which pro-
vided 3a quantitatively but with low enantiomeric excess
(Table 1, entries 5 and 6). To our surprise, MeTRAP-
rhodium catalyst not only presented much lower catalytic
activity but also showed a chiral sense of enantioselection
opposite to that with other TRAP-rhodium catalyst
employed, giving (R)-3a with 61% ee (Table 1, entry 7).
The absolute configuration of 3a was assigned by com-
parison of its retention time in the chiral HPLC analysis
with that of the authentic sample prepared from (S)-
piperazine-2-(N-tert-butyl)carboxamide.
(15) Sawamura, M.; Sudoh, M.; Ito, Y. J . Am. Chem. Soc. 1996, 118,
3309-3310.
(16) Kuwano, R.; Miyazaki, H.; Ito, Y. Chem. Commun. 1998, 71-
72.
(17) Kuwano, R.; Sawamura, M.; Ito, Y. Tetrahedron: Asymmetry
1995, 6, 2521-2526.
(18) (a) Sawamura, M.; Kuwano, R.; Ito, Y. J . Am. Chem. Soc. 1995,
117, 9602-9603. (b) Kuwano, R.; Okuda, S.; Ito, Y. J . Org. Chem. 1998,
63, 3499-3503. (c) Kuwano, R.; Okuda, S.; Ito, Y. Tetrahedron:
Asymmetry 1998, 9, 2773-2775.
(19) For examples of catalytic asymmetric syntheses of both enan-
tiomers from a single chiral source, see: (hydrogenation) (a) Kawano,
H.; Ikariya, T.; Ishii, Y.; Saburi, M.; Yoshikawa, S.; Uchida, Y.;
Kumobayashi, H. J . Chem. Soc., Perkin Trans. 1 1989, 1571-1575.
(b) Kitamura, M.; Hsiao, Y.; Ohta, M.; Tsukamoto, M.; Ohta, T.;
Takaya, H.; Noyori, R. J . Org. Chem. 1994, 59, 297-310. (hydrosily-
lation) (c) Kinting, A.; Kreuzfeld, H.-J .; Abicht, H.-P. J . Organomet.
Chem. 1989, 370, 343-349. (d) Nishibayashi, Y.; Segawa, K.; Ohe, K.;
Uemura, S. Organometallics 1995, 14, 5484-5487. (e) Nishibayashi,
Y.; Segawa, K.; Takada, H.; Ohe, K.; Uemura, S. Chem. Commun. 1996,
847-848. (Heck reaction) (f) Ashimori, A.; Overman, L. E. J . Org.
Chem. 1992, 57, 4571-4572. (Diels-Alder reaction) (g) Kobayashi, S.;
Ishitani, H. J . Am. Chem. Soc. 1994, 116, 4083-4084. (h) Kobayashi,
S.; Ishitani, H.; Hachiya, I.; Araki, M. Tetrahedron 1994, 50, 11623-
11636. (i) Desimoni, G.; Faita, G.; Righetti, P. P. Tetrahedron Lett.
1996, 37, 3027-3030. (j) Desimoni, G.; Faita, G.; Invernizzi, A. G.;
Righetti, P. P. Tetrahedron 1997, 53, 7671-7688. (dihydroxylation)
(k) Vanhessche, K. P. M.; Sharpless, K. B. J . Org. Chem. 1996, 61,
7978-7979.
THF and benzene can be used as solvent for the
asymmetric hydrogenation without significant decrease

1234 J . Org. Chem., Vol. 64, No. 4, 1999
Kuwano and Ito
Ta ble 2. Asym m etr ic Hyd r ogen a tion of 2 Ca ta lyzed by
Ch a r t 2
i-Bu TRAP -Rh od iu m Com p lexa
convn,
%
ee,
%
b
c
entry
R1
R2
substrate
product
confign
1
2
3
4
5d
6
7
8
9
t-BuO PhO
t-BuO BnO
t-BuO MeO
t-BuO t-BuO
t-BuO t-BuO
2a
2b
2c
2d
2d
2e
2f
85
76
89
8
69
75
40
29
18
3a
3b
3c
3d
3d
3e
3f
96
94
93
S
S
S
S
S
S
S
S
S
87
Ta ble 3. Asym m etr ic Hyd r ogen a tion of 2 Ca ta lyzed by
BnO
BnO
PhO
t-BuO
96e
94
MeTRAP -Rh od iu m Com p lexa
convn,
%
ee,
%
t-BuO Me
Me t-BuO
2g
2h
3g
3h
55
b
c
entry
R1
R2
substrate
product
confign
93f
a
Reactions were carried out at 50 °C and 1 kg/cm2 of hydrogen
pressure for 24 h in 0.125 M solution of 2 unless otherwise noted.
The ratio of 2/[Rh(NBD)2]SbF6/(R,R)-(S,S)-i-BuTRAP was 100/1/
1
2
3
4
t-BuO PhO
t-BuO BnO
t-BuO t-BuO
2a
2b
2d
2e
2f
2f
2f
2g
2h
32
21
21
31
60
25
85
16
16
3a
3b
3d
3e
3f
3f
3f
3g
3h
62
69
81
62
81
81
85
51
76
R
R
R
R
R
R
R
R
R
1.1. Determined by 1H NMR analysis of evaporated reaction
b
BnO
BnO
BnO
BnO
PhO
mixture. c Determined by chiral HPLC analysis with SUM-
5
t-BuO
t-BuO
t-BuO
6d
7e
8
d
ICHIRAL OA-2000 unless otherwise noted. The reaction was
carried out with 2 mol % of catalyst in 0.25 M solution of 2d .
e Determined by chiral HPLC analysis with SUMICHIRAL OA-
t-BuO Me
Me t-BuO
f
9
4100. Determined by chial HPLC analysis with SUMICHIRAL
OA-2200.
a
Reactions were carried out at 50 °C and 1 kg/cm2 of hydrogen
pressure for 24 h in 0.250 M solution of 2 unless otherwise noted.
The ratio of 2/[Rh(NBD)2]SbF6/(R,R)-(S,S)-MeTRAP was 100/1/1.1.
of the stereoselectivity (Table 1, entries 8 and 9), but 1,2-
dichloroethane is superior in the solubilities of 2 and 3.
Alcoholic solvents, i-PrOH and MeOH, lowered catalytic
efficiency (Table 1, entries 10 and 11). The neutral
catalyst system generated from i-BuTRAP and [RhCl-
(COD)]2 did not work as catalyst (Table 1, entry 12).
Other i-BuTRAP-rhodium complexes generated from
Rh(OBz)(COD), Rh(acac)(COD), Rh(acac)(CO)2, and Rh-
(BPh4)(COD) have no catalytic activity. Counteranion of
cationic i-BuTRAP-rhodium complex affected the cata-
lytic activity significantly (Table 1, entries 13-19).
Rhodium complex bearing less coordinating counteran-
Determined by 1H NMR analysis of evaporated reaction mixture.
b
c See Table 2. [Rh(COD)2]OTf was used. e The reaction was
d
carried out at 2 kg/cm2 of hydrogen pressure.
2h , which were both protected by acetyl group at either
the 4- or 1-position, proceeded slowly to give the corre-
sponding piperazine-2-carboxamide in 29 and 18% con-
version after 24 h, but the enantioselectivities were
significantly controlled by the position of N-acetyl group
(2g, 55% ee; 2h , 93% ee). This finding may indicate that
the enantioselectivities of the asymmetric hydrogenation
of 2 by means of i-BuTRAP ligand depend on the
alkoxycarbonyl protective group on the 4-N-position
rather than the 1-N-position. 1-N-tert-Butoxycarbonyl-
1,4,5,6-tetrahydropyrazine-2-(N-tert-butyl)carboxamide (4)
(Chart 2) with no protection at the 4-N-position did not
undergo the hydrogenation by i-BuTRAP-rhodium cata-
lyst. The hydrogenation of methyl ester 5 proceeded up
to 52% conversion (2 mol % catalyst, 24 h), giving 6 with
92% ee. Choice of protective groups for the 2-carboxylic
functional group has some influence for the reactivities,
but is not essential for high enantioselectivity.
ion, such as PF6 and SbF6-, revealed higher turnover
-
-
frequency. However, the counteranions TfO- and ClO4
caused remarkable decrease in the catalytic activity.
Even weak interaction of such counteranions with the
rhodium metal center might obstruct coordination of 2
on the catalyst, but the obstruction did not cause signifi-
cant decrease in the enantioselectivity. Slightly higher
hydrogen pressure (2.0 kg/cm2) improved reaction rate
without loss of enantioselectivity (Table 1, entry 20), but
the hydrogenation at 100 kg/cm2 yielded 20% ee of (S)-
3a in only 8% conversion.
As previously mentioned, the asymmetric hydrogena-
tions of 2 with MeTRAP-rhodium catalyst are notewor-
thy (Table 3). The enantioselectivities observed also
depended upon the choice of the 4-N-protective group of
2 like those of the hydrogenation using i-BuTRAP. The
tert-butoxycarbonyl group is the best protective group at
the 4-N-position, giving 81% ee for the hydrogenation
product at 50 °C and 1 kg/cm2 of hydrogen pressure
(Table 3, entries 3 and 5). Alkoxycarbonyl group at the
1-position hardly affected the stereoselectivity but con-
trolled the reactivity. A highest enantioselectivity and a
highest turnover number were attained in the asym-
metric hydrogenation of 2d , which has the 1-N-benzy-
loxycarbonyl and the 4-N-tert-butoxycarbonyl groups,
forming (R)-3d with 85% ee in 87% conversion under 2
kg/cm2 of hydrogen pressure for 24 h (Table 3, entry 7).
In addition, the similar effect of the counteranion on
catalytic activity, mentioned above, was also observed in
the MeTRAP-rhodium-catalyzed asymmetric hydroge-
nation (Table 3, entry 6).
Effects of P r otective Gr ou p s in 2. Prior to the
asymmetric hydrogenation of 1,4,5,6-tetrahydropyrazine-
2-carboxylic acid, the two enamino nitrogens and one
carboxylic group of 2 were modified by common protective
groups. The efficiency of the asymmetric hydrogenation
of 2 was much dependent upon a choice of the protective
groups. The enantioselective hydrogenation of various
1,4,5,6-tetrahydropyrazine-2-carboxamides 2a -h with
the 1- and 4-N-protective groups (0.125 M) was carried
out at 50 °C under 1 kg/cm2 of hydrogen gas in the
presence of i-BuTRAP-rhodium complex, as summarized
in Table 2. Substrate 2a , which has the 1-N-tert-butoxy-
carbonyl and the 4-N-phenoxycarbonyl groups, presented
the highest enantiomeric excess (96% ee) as well as a high
chemical yield (85%) (Table 2, entry 1). The oxycarbonyl
protective groups at the 1-nitrogen as well as the
4-nitrogen generally provided the satisfactory enantio-
meric excesses. However, 1,4-bis(tert-butoxycarbonyl)
derivative 2e was reluctant to hydrogenation with
i-BuTRAP-rhodium catalyst, probably due to its steric
hindrance (Table 2, entry 4). Hydrogenations of 2g and
Mech a n istic Stu d ies. To shed light on the origin for
the reverse enantioselection of MeTRAP to that of i-

Asymmetric Hydrogenation by Chiral Rh Complexes
J . Org. Chem., Vol. 64, No. 4, 1999 1235
F igu r e 2. (a) 31P NMR spectrum of the mixture of [Rh(NBD)2]-
SbF6 and (R,R)-(S,S)-i-BuTRAP after treatment with hydro-
gen. (b) 31P NMR spectrum of the above sample after treatment
with 5 molar equiv of 2c under hydrogen atmosphere.
F igu r e 4. (a) 31P NMR spectrum of the mixture of [Rh(NBD)2]-
SbF6 and (R,R)-(S,S)-MeTRAP after treatment with hydrogen.
(b) 31P NMR spectrum of the above sample after treatment
with 5 molar equiv of 2c. (c) 31P NMR spectrum of the mixture
of [Rh(NBD)2]SbF6, (R,R)-(S,S)-MeTRAP and 2c after treat-
ment with hydrogen. (d) After 24 h.
F igu r e 3. 13C NMR spectrum of the mixture of [Rh(NBD)2]-
SbF6 and (R,R)-(S,S)-i-BuTRAP after treatment with hydro-
gen.
i-BuTRAP-rhodium complex because of the steric repul-
sion between 2 and P-isobutyl groups of the catalyst.
On the other hand, similar experiment with MeTRAP
is remarkably different from that of i-BuTRAP. Treat-
ment of [Rh(NBD)2]SbF6 with MeTRAP under hydrogen
atmosphere gave very broad signals in 31P NMR in
CD2Cl2 (Figure 4a). On addition of 5 equiv of 2c into the
CD2Cl2 solution, a pair of double doublet signals were
observed at δ 25.67 (J P-Rh ) 132 Hz, J P-P ) 31 Hz) and
27.15 (J P-Rh ) 142 Hz, J P-P ) 31 Hz) (resonances A)
(Figure 4b), which was identified as [Rh(2c)(MeTRAP)]+
(9). The MeTRAP-rhodium catalyst may prefer coordi-
nation of 2 to oxidative addition of hydrogen. The small
P-P spin coupling constant of A indicates that MeTRAP
in the complex coordinates to a rhodium atom in cis-
chelating manner. 31P NMR spectrum of a mixture of [Rh-
(NBD)2]SbF6, (R,R)-(S,S)-MeTRAP and 2c (1:1:5) followed
by treatment with hydrogen in CD2Cl2 for 10 min showed
three sets of resonances corresponding to three cis-
chelating MeTRAP-rhodium species including 9 (Figure
4c). The other two sets of double doublet resonances
appear at δ 23.12 (J P-Rh ) 112 Hz, J P-P ) 27 Hz), 46.19
(J P-Rh ) 117 Hz, J P-P ) 27 Hz) (resonances B) and δ 6.10
(J P-Rh ) 106 Hz, J P-P ) 24 Hz), 55.28 (J P-Rh ) 167 Hz,
J P-P ) 24 Hz) (resonances C). After 24 h, resonances B
disappeared, and a small amount of A and C remained
with new unidentified signal D which appears at 34-40
ppm resulting from decomposition of the catalyst (Figure
4d). The enantiomeric excess of 3c isolated from the
mixture was 61% ee (R). These results suggest that
coordination of 2 would take precedence over oxidative
addition of hydrogen in the hydrogenation using Me-
TRAP-rhodium complex.22 The different mechanism and
chelating mode from those with i-BuTRAP are operating
for the reverse asymmetric induction in the hydrogena-
BuTRAP, behavior of i-BuTRAP- and MeTRAP-rhod-
ium complexes during the asymmetric hydrogenation of
2c was monitored by 31P NMR measurement. Reaction
of i-BuTRAP and [Rh(NBD)2]SbF6 in CD2Cl2 followed by
treatment with hydrogen gave a single rhodium complex,
trans-[Rh(i-BuTRAP)]SbF6 (7), which showed a doublet
peak at δ 35.17 ppm with 110 Hz of P-Rh spin coupling
constant in the 31P NMR spectrum (Figure 2a) and no
signals at high magnetic field region (from -40 to 0 ppm)
in the 1H NMR spectrum. The trans-chelation of i-
BuTRAP was also confirmed by the 13C NMR spectra,
where the resonances of the 13-carbons R to the phos-
phorus atoms are split into a virtually coupled triplet,
indicating large virtual coupling constant by two phos-
phorus atoms coordinating to a rhodium atom (Figure
3).20 No observable change of the 31P NMR was detected
after addition of 5 molar equiv of 2c under hydrogen
atmosphere (Figure 2b), while the substrate was con-
verted to (S)-3c with 97% ee. The results may suggest
that 7 is an active and the most thermodynamically
stable catalyst prior to the rate-determining step of the
catalytic hydrogenation. The complex 7 might undergo
an oxidative addition with hydrogen, leading to an
equilibrium with [RhH2(i-BuTRAP)]+ (8) which lies
far to 7. The existing 8 in low concentration might
react with 2,21 which is hard to coordinate to the
(20) Redfield, D. A.; Cary, L. W.; Nelson, J . H. Inorg. Chem. 1975,
14, 50-59.
(21) The mechanism involving an oxidative addition of hydrogen
prior to olefin coordination is accepted for the hydrogenation of
nonchelating olefins catalyzed by RhCl(PPh3)3, and causes deterioration
of enantioselectivity in asymmetric hydrogenation of R-acetamidoacry-
lates: (a) Osborn, J . A.; J ardine, F. H.; Young J . F.; Wilkinson, G. J .
Chem. Soc. A 1966, 1711-1732. (b) Halpern, J . Inorg. Chim. Acta 1981,
50, 11-19 and references therein. (c) Daniel, C.; Koga, N.; Han, J .;
Fu, X. Y.; Morokuma, K. J . Am. Chem. Soc. 1988, 110, 3773-3787.
(d) Ojima, I.; Kogure, T.; Yoda, N. J . Org. Chem. 1980, 45, 4728-4739.
(e) Sinou, D. Tetrahedron Lett. 1981, 22, 2987-2990.
(22) The precedence of olefin coordination to oxidative addition of
hydrogen was observed in mechanistic studies of asymmetric hydro-
genation of R-acetamidoacrylates: (a) Landis, C. R.; Halpern, J . J . Am.
Chem. Soc. 1987, 109, 1746-1754 and references therein. (b) Halpern,
J . In Asymmetric Synthesis; Morrison, J . D., Ed.; Academic Press: New
York, 1985; Vol. 5, pp 41-69.

1236 J . Org. Chem., Vol. 64, No. 4, 1999
Kuwano and Ito
C16H27N3O5: C, 56.29; H, 7.97; N, 12.31. Found: C, 56.31; H,
7.86; N 12.06.
tion of 2. Low enantioselectivity of EtTRAP might arise
from competition for the two mechanisms and the two
chelation modes described above.
1-Ben zyloxyca r b on yl-4-p h en oxyca r b on yl-1,4,5,6-t et -
r a h yd r op yr a zin e-2-(N-ter t-bu tyl)ca r boxa m id e (2e): 95%
1
yield; white powder; mp 130 °C; H NMR (300 MHz, CDCl3,
Con clu sion
TMS) δ 1.24 (s, 9H), 3.68-3.93 (m, 4H), 5.20 (s, 2H), 5.66 (br
s, 1H), 7.11-7.50 (m, 10 H), 7.68 (s, 1H); 13C{1H} NMR (75.5
MHz, CDCl3) δ 28.39, 41.41, 43.20, 51.10, 68.35, 116.93, 120.51,
121.28, 126.03, 128.35, 128.47, 128.58, 129.46, 135.42, 150.56,
We found that trans-chelating chiral diphosphine
TRAPs are effective chiral ligands for the asymmetric
hydrogenation of 2 catalyzed by rhodium complex. The
asymmetric hydrogenation proceeded smoothly under
mild condition (50 °C, 1 kg/cm2 of hydrogen pressure) to
provide optically active 2-piperazinecarboxamide 3 with
up to 97% ee. Of interest is that the two enantiomers of
3 were obtained with high enantiomeric excess by choice
of P-substituents of (R,R)-(S,S)-TRAP ligand, i.e., tet-
rahydropyrazine 2f, bearing 1-N-benzyloxycarbonyl and
4-N-tert-butoxycarbonyl groups, gave (S)- and (R)-3f with
94 and 85% ee by use of the chiral ligands (R,R)-(S,S)-
i-BuTRAP and (R,R)-(S,S)-MeTRAP, respectively. The
reverse of enantioselectivity with the two TRAP ligands
may be caused by the difference in their chelating mode
on rhodium complex.
150.88, 154.92, 162.87; IR (KBr) 3320, 1739, 1714, 1638 cm-1
.
Anal. Calcd for C24H27N3O5: C, 65.89; H, 6.22; N, 9.60.
Found: C, 65.92; H, 6.24; N 9.63.
4-Acetyl-1-ter t-bu toxyca r bon yl-1,4,5,6-tetr a h yd r op yr a -
zin e-2-(N-ter t-bu tyl)ca r boxa m id e (2g): 95% yield; white
1
powder; mp 189 °C; H NMR (300 MHz, CDCl3, TMS) δ 1.41
(s, 9H), 1.49 (s, 9H), 2.31 (s, 3H), 3.53-3.63 (m, 2H), 3.63-
3.73 (m, 2H), 5.78 (br s, 1H), 7.31 (s, 1H); 13C{1H} NMR (75.5
MHz, CDCl3) δ 21.32, 28.02, 28.79, 41.33, 51.21, 82.72, 116.78,
121.46, 154.29, 163.25, 168.75; IR (KBr) 3324, 1706, 1672, 1656
cm-1. Anal. Calcd for C16H27N3O4: C, 59.06; H, 8.36; N, 12.91.
Found: C, 59.32; H, 8.08; N 12.75.
1,4-Bis(ter t-bu toxycar bon yl)-1,4,5,6-tetr ah ydr opyr azin e-
2-(N-ter t-bu tyl)ca r boxa m id e (2d ). The compound was pre-
pared from 4 and (Boc)2O according to literature procedure
1
for 2f in 99% yield: white powder; mp 165 °C; H NMR (300
MHz, CDCl3, TMS) δ 1.40 (s, 9H), 1.48 (s, 9H), 1.51 (s, 9H),
3.51-3.64 (m, 4H), 5.71 (br s, 1H), 7.47 (s, 1H); 13C{1H} NMR
(75.5 MHz, CDCl3) δ 28.06, 28.88, 41.24, 42.44, 51.00, 82.32,
82.70, 115.35, 121.79, 151.36, 154.58, 163.65; IR (KBr) 3340,
1718, 1646 cm-1. Anal. Calcd for C19H33N3O5: C, 59.51; H, 8.67;
N, 10.96. Found: C, 59.39; H, 8.53; N 10.90.
Gen er a l P r oced u r e of Asym m etr ic Hyd r ogen a tion of
2 Ca ta lyzed by TRAP -Rh od iu m Com p lex. A solution of
[Rh(NBD)2]SbF6 (1.3 mg, 2.5 µmol) and (R,R)-(S,S)-TRAP (2.8
µmol) in 1,2-dichloroethane (1.0 mL) was stirred at room
temperature for 10 min under argon atmosphere, and 2 (0.25
mmol) was added. Immediately, the flask was cooled at -78
°C and repeatedly evacuated and filled with hydrogen. The
reaction mixture was stirred at 50 °C for 24 h. After the solvent
was evaporated, the residue was passed through a short silica
gel column (hexane/EtOAc ) 1/3) to give a mixture of 3 and
unreacted 2 in quantitative yield.
Exp er im en ta l Section
Gen er a l Meth od s. 1,2-Dichloroethane was distilled from
CaH2 under nitrogen, and 99.99999% of hydrogen was used.
The (R,R)-(S,S)-TRAPs11c 2f, 2h , 4, and 57 were prepared
according to literature procedures.
1-ter t-Bu toxyca r bon yl-4-p h en oxyca r bon yl-1,4,5,6-tet-
r a h yd r op yr a zin e-2-(N-ter t-bu tyl)ca r boxa m id e (2a ). To a
solution of 1-tert-butoxycarbonyl-1,4,5,6-tetrahydropyrazine-
2-(N-tert-butylcarboxamide) (4) (5.67 g, 20 mmol) and NaHCO3
(1.92 g, 23 mmol) in EtOAc (40 mL) and MeCN (10 mL) was
added phenyl chloroformate (3.30 g, 21 mmol) for 30 min at
50 °C. After 30 min of stirring at this temperature, the mixture
was diluted with 10 mL of H2O and extracted three times with
EtOAc. The organic layer was washed with brine and dried
over Na2SO4, and the solvent was evaporated. The residue was
purified by a flash column chromatography on silica gel
(hexane/EtOAc ) 1/1) to give 2a (6.37 g, 79%): white powder;
1-ter t-Bu toxyca r bon yl-4-p h en oxyca r bon ylp ip er a zin e-
2-(N-ter t-bu tyl)ca r boxa m id e (3a ): 100% yield; 97% ee (S);
white powder; mp 183 °C; [R]20D -53.0 (c 1.03, CHCl3); 1H NMR
(300 MHz, CDCl3, TMS) δ 1.35 (s, 9H), 1.51 (s, 9H), 3.02-
3.43 (br m, 3H), 3.84-4.10 (br m, 2H), 4.32-4.82 (br m, 2H),
5.93 (br s, 1H), 7.04-7.24 (m, 3H), 7.35 (t, J ) 7.8 Hz, 2H);
13C{1H} NMR (75.5 MHz, CDCl3) δ 28.23, 28.63, 40.82 (br s),
42.90, 43.25, 43.76, 51.30, 81.60, 121.92, 125.40, 129.27,
1
mp 174 °C; H NMR (300 MHz, CDCl3, TMS) δ 1.42 (s, 9H),
1.50 (s, 9H), 3.61-3.91 (m, 4H), 5.75 and 5.66 (a pair of br s,
1H), 7.13 (d, J ) 7.5 Hz, 2H), 7.25 (t, J ) 7.5 Hz, 1H), 7.39 (t,
J ) 7.5 Hz, 2H), 7.68 and 7.50 (a pair of s, 1H); 13C{1H} NMR
(75.5 MHz, CDCl3) δ 28.05, 28.82, 41.13 and 40.88 (a pair of
s), 43.28 and 44.06 (a pair of s), 51.20, 82.70, 117.39, 120.17
and 119.57 (a pair of s), 121.42, 126.07, 129.53, 150.65, 151.08,
154.25, 163.31; IR (KBr) 3444, 1740, 1708, 1642 cm-1. Anal.
Calcd for C21H29N3O5: C, 62.51; H, 7.24; N, 10.41. Found: C,
62.41; H, 7.20; N 10.41.
151.45, 154.09, 155.41, 168.23; IR (KBr) 3352, 1732, 1678 cm-1
.
Anal. Calcd for C21H31N3O5: C, 62.20; H, 7.71; N, 10.36.
Found: C, 62.09; H, 7.76; N, 10.09.
4-Ben zyloxycar bon yl-1-ter t-bu toxycar bon ylpiper azin e-
2-(N-ter t-bu tyl)ca r boxa m id e (3b). The compound was ob-
4-Ben zyloxyca r bon yl-1-ter t-bu toxyca r bon yl-1,4,5,6-tet-
r a h yd r op yr a zin e-2-(N-ter t-bu tyl)ca r boxa m id e (2b): 92%
1
tained as a mixture with 2b (3b/2b ) 76/24): 94% ee (S); H
1
yield; white powder; mp 148 °C; H NMR (300 MHz, CDCl3,
NMR (200 MHz, CDCl3, TMS) δ 1.31 (s, 9H), 1.48 (s, 9H),
2.98-3.30 (br m, 3H), 3.80-3.99 (br m, 2H), 4.34-4.65 (br m,
2H), 5.15 (s, 2H), 5.88 (br s, 1H), 7.28-7.43 (m, 5H).
TMS) δ 1.39 (s, 9H), 1.47 (s, 9H), 3.52-3.61 (m, 2H), 3.61-
3.70 (m, 2H), 5.22 (s, 2H), 5.72 and 5.66 (a pair of br s, 1H),
7.29-7.42 (m, 5H), 7.51 (s, 1H); 13C{1H} NMR (75.5 MHz,
CDCl3) δ 27.85, 28.64, 40.93 and 40.58 (a pair of s), 42.84 and
43.36 (a pair of s), 50.91, 68.43 and 68.20 (a pair of s), 82.38,
116.33, 120.58 and 119.82 (a pair of s), 128.26, 128.56, 128.62,
135.21, 152.41, 154.35, 163.37; IR (KBr) 3436, 1734, 1706, 1648
cm-1. Anal. Calcd for C22H31N3O5: C, 63.29; H, 7.48; N, 10.06.
Found: C, 63.21; H, 7.46; N 10.10.
1-ter t-Bu toxyca r bon yl-4-m eth oxyca r bon ylp ip er a zin e-
2-(N-ter t-bu tyl)ca r boxa m id e (3c). The compound was ob-
1
tained as a mixture with 2c (3c/2c ) 89/11): 93% ee (S); H
NMR (200 MHz, CDCl3, TMS) δ 1.33 (s, 9H), 1.49 (s, 9H),
2.93-3.27 (br m, 3H), 3.77-4.01 (br m, 2H), 4.31-4.60 (br m,
2H), 5.91 (br s, 1H).
1,4-Bis(ter t-bu toxycar bon yl)piper azin e-2-(N-ter t-bu tyl)-
ca r boxa m id e (3d ). The compound was obtained as a mixture
with 2d (3d /2d ) 69/31): 87% ee (S); 1H NMR (200 MHz,
CDCl3, TMS) δ 1.33 (s, 9H), 1.46 (s, 9H), 1.48 (s, 9H), 2.92-
3.22 (br m, 3H), 3.72-3.94 (br m, 2H), 4.29-4.56 (br m, 2H),
5.83 (br s, 1H).
1-ter t-Bu toxyca r bon yl-4-m eth oxyca r bon yl-1,4,5,6-tet-
r a h yd r op yr a zin e-2-(N-ter t-bu tyl)ca r boxa m id e (2c): 99%
1
yield; white powder; mp 135 °C; H NMR (300 MHz, CDCl3,
TMS) δ 1.40 (s, 9H), 1.48 (s, 9H), 3.55-3.61 (m, 2H), 3.61-
3.67 (m, 2H), 3.82 (s, 3H), 5.71 (br s, 1H), 7.47 (s, 1H); 13C-
{1H} NMR (75.5 MHz, CDCl3) δ 27.94, 28.73, 40.99 and 40.68
(a pair of s), 42.83 and 42.36 (a pair of s), 50.98, 53.52, 82.36,
116.35, 120.45 and 119.94 (a pair of s), 152.97, 154.25, 163.34;
IR (KBr) 3332, 1738, 1705, 1654 cm-1. Anal. Calcd for
1-Ben zyloxyca r bon yl-4-p h en oxyca r bon ylp ip er a zin e-
2-(N-ter t-bu tyl)ca r boxa m id e (3e). The compound was ob-
1
tained as a mixture with 2e (3e/2e ) 75/25): 96% ee (S); H
NMR (300 MHz, CDCl3, TMS) δ 1.29 (s, 9H), 3.00-3.52 (br

Asymmetric Hydrogenation by Chiral Rh Complexes
J . Org. Chem., Vol. 64, No. 4, 1999 1237
m, 3H), 3.92-4.21 (br m, 2H), 4.36-4.87 (br m, 2H), 5.09-
5.33 (br AB q, 2H), 5.80 (br s, 1H), 7.02-7.55 (m, 10H).
1-Ben zyloxycar bon yl-4-ter t-bu toxycar bon ylpiper azin e-
2-(N-ter t-bu tyl)ca r boxa m id e (3f). The compound was ob-
0.91 (m, 18H), 1.07-1.18 (m, 6H of norbornane × 2), 1.36-
1.68 (m, 12H and 4H of norbornane × 2), 1.63 (dt, J 3
) 7.2
H-H
Hz, |J 3
+ J 5H-P′| ) 11.0 Hz, 6H), 2.13-2.19 (m, 2H of
H-P
norbornane × 2), 3.13 (tq, |J 2
+ J 4H-P′| ) 6.6 Hz, J 3
)
H-H
H-P
1
tained as a mixture with 2f (3f/2f ) 40/60): 94% ee (S); H
7.2 Hz, 2H), 4.19-4.24 (m, 2H), 4.36 (s, 10H), 4.51 (t, J ) 2.6
Hz, 2H), 4.57 (dd, J ) 1.4, 2.6 Hz, 2H); 13C {1H} NMR (75.5
Hz, CD2Cl2) δ 16.05, 24.15, 24.71, 24.92 (2C), 26.54, 26.67,
NMR (300 MHz, CDCl3, TMS) δ 1.29 (s, 9H), 1.46 (s, 9H),
2.83-3.30 (br m, 2H), 3.13 (dd, J ) 4.5, 13.8 Hz, 1H), 3.72-
4.08 (br m, 2H), 4.35-4.70 (br m, 2H), 5.15 (d, J ) 12 Hz,
1H), 5.21 (d, J ) 12 Hz, 1H), 5.69 and 5.97 (a pair of br s, 1H),
7.28-7.41 (m, 5H).
29.69 (t, |J 1
+ J 3C-P| ) 21 Hz), 30.15 (norbornane), 31.04
C-P
(t, |J 1
+ J 3C-P| ) 23 Hz), 35.63 (t, |J 1
+ J 3C-P| ) 21 Hz),
C-P
C-P
36.97 (norbornane), 38.80 (norbornane), 66.07, 68.62, 71.11,
71.80, 82.40, 92.35; 31P {1H} NMR (121.5 MHz, CD2Cl2, 85%
H3PO4) δ 35.17 (d, J P-Rh ) 110 Hz).
4-Acet yl-1-ter t-b u t oxyca r b on ylp ip er a zin e-2-(N-ter t-
bu tyl)ca r boxa m id e (3g). The compound was obtained as a
mixture with 2g (3g/2g ) 29/71): 55% ee (S).
1-Acet yl-4-ter t-b u t oxyca r b on ylp ip er a zin e-2-(N-ter t-
bu tyl)ca r boxa m id e (3h ). The compound was obtained as a
mixture with 2h (3h /2h ) 18/82): 93% ee (S).
No observable change in the 31P NMR spectrum was
detected after addition of 2c (17.5 mg, 54 µmol) in CD2Cl2 (0.2
mL) into the NMR sample.
31P NMR Stu d y of Beh a vior of i-Bu TRAP -Rh Com p lex
d u r in g Asym m etr ic Hyd r ogen a tion of 2c. A mixture of
[Rh(NBD)2]SbF6 (5.3 mg, 10 µmol) and (R,R)-(S,S)-i-BuTRAP
(7.1 mg, 11 µmol) in CD2Cl2 (0.7 mL) was stirred at room
temperature for 5 min under argon atmosphere. After 2c (17.5
mg, 54 µmol) was added, the solution was degassed by three
freeze-pump-thaw cycles, before hydrogen was introduced
into the reaction vessel. The mixture was stirred for 10 min
and transferred into a hydrogen-filled NMR tube via a cannula.
Hydrogenation of 2c proceeded slowly (completed within 7 h)
to give (S)-3c in 97% ee, but the sample gave the same 31P
NMR spectrum as [Rh(i-BuTRAP)]SbF6 during the reaction:
31P {1H} NMR (121.5 MHz, CD2Cl2, 85% H3PO4) δ 35.17 (d,
J P-Rh ) 110 Hz).
Asym m etr ic Hyd r ogen a tion of 2f u sin g (R,R)-(S,S)-
MeTRAP -Rh od iu m Ca ta lyst. A solution of [Rh(NBD)2]SbF6
(1.3 mg, 2.5 µmol) and (R,R)-(S,S)-MeTRAP (1.5 mg, 2.7 µmol)
in 1,2-dichloroethane (1.0 mL) was stirred at room tempera-
ture for 10 min under argon atmosphere. The solution was
transferred by a cannula to an argon-filled glass autoclave, in
which 2f (105 mg, 0.25 mmol) was placed beforehand. Im-
mediately, the autoclave was cooled to -78 °C and repeatedly
evacuated and filled with hydrogen. Hydrogen was introduced
into the vessel until the pressure gauge indicated 1 kg/cm2.
The reaction mixture was stirred at 50 °C for 24 h. After the
solvent was evaporated, the residue was passed through a
short silica gel column (hexane/EtOAc ) 1/3) to give a mixture
of 85% ee of (R)-3f and 2f quantitatively. The mixture was
purified by recrystallization from hexane/EtOAc to give 100%
31P NMR Stu d y for Rea ction of MeTRAP a n d [Rh -
(NBD)2]SbF 6 u n d er Hyd r ogen Atm osp h er e. The experi-
ment was performed according to the procedure described
above. Only very broad peaks were observed in 31P NMR
measurement. After 2c (6.8 mg, 20 µmol) in CD2Cl2 (0.2 mL)
was added to the solution in CD2Cl2, a pair of double doublet
peaks appeared in the 31P NMR spectrum: 31P {1H} NMR
(121.5 MHz, CD2Cl2, 85% H3PO4) δ 25.67 (dd, J P-P ) 31 Hz,
J P-Rh ) 132 Hz), 27.15 (dd, J P-P ) 31 Hz, J P-Rh ) 142 Hz).
31P NMR Stu d y of Beh a vior of MeTRAP -Rh Com p lex
d u r in g Asym m etr ic Hyd r ogen a tion of 2c. The experiment
was performed according to the procedure described above.
Three sets of double doublet signals appeared in 31P NMR
spectrum as shown in Figure 4c. After 24 h, 50% of 2c was
converted into (R)-3c (61% ee).
ee of (R)-3f (17.1 mg, 16%): Colorless crystal; mp 135 °C; [R]20
D
+32.9 (c 0.99, CHCl3); 1H NMR (300 MHz, CDCl3, TMS) δ 1.29
(s, 9H), 1.46 (s, 9H), 2.83-3.30 (br m, 2H), 3.13 (dd, J ) 4.5,
13.8 Hz, 1H), 3.72-4.08 (br m, 2H), 4.35-4.70 (br m, 2H), 5.15
(d, J ) 12.0 Hz, 1H), 5.21 (d, J ) 12.0 Hz, 1H), 5.69 and 5.97
(a pair of br s, 1H), 7.28-7.41 (m, 5H); 13C{1H} NMR (75.5
MHz, CDCl3) δ 28.23, 28.50, 41.16 (br s), 41.96 (br s), 43.02
(br s), 51.44, 55.71 (br s), 67.78, 80.41, 128.07, 128.30, 128.63,
136.22, 154.63, 156.08, 167.69; IR (KBr) 3360, 1704, 1696, 1678
cm-1. Anal. Calcd for C22H33N3O5: C, 62.99; H, 7.93; N, 10.02.
Found: C, 62.78; H, 7.87; N, 10.00.
NMR Stu d y for th e Rea ction of i-Bu TRAP a n d [Rh -
(NBD)2]SbF 6 u n d er Hyd r ogen Atm osp h er e. A mixture of
[Rh(NBD)2]SbF6 (5.2 mg, 10 µmol) and (R,R)-(S,S)-i-BuTRAP
(7.1 mg, 10 µmol) in CD2Cl2 (0.7 mL) was stirred at room
temperature for 5 min under argon atmosphere. The solution
was degassed by three freeze-pump-thaw cycles, before
hydrogen was introduced into the reaction vessel. The mixture
was stirred for 10 min and transferred into a hydrogen-filled
NMR tube via a cannula. The NMR spectra are as follows:
1H NMR (300 MHz, CD2Cl2) δ 0.71 (d, J ) 6.3 Hz, 6H), 0.85-
Ack n ow led gm en t. We are grateful to Nichijun
Chemicals for their kind offering of 1,4,5,6-tetrahydro-
pyrazine-2-(N-tert-butyl)carboxamides and (S)-4-tert-
bu t oxyca r bon ylpiper a zin e-2-(N-ter t-bu t yl)ca r box-
amide.
J O981939U