Asymmetric addition of alkyllithium to chiral imines: α-Naphthylethyl group as a chiral auxiliary

Article abstract of DOI:10.1021/jo9908602

The diastereoselective nucleophilic addition of alkyllithium to N- alkylidene-α-naphthylethylamine was carried out. In the presence of Lewis acids or Lewis bases, organolithiums reacted smoothly with imines to give the corresponding amines in high stereoselectivity (up to 100% de). Furthermore, the resulting optically active amines were found to be useful for asymmetric reactions as chiral ligands.

Full text of DOI:10.1021/jo9908602

J . Org. Chem. 1999, 64, 8821-8828
8821
Asym m etr ic Ad d ition of Alk yllith iu m to Ch ir a l Im in es:
r-Na p h th yleth yl Gr ou p a s a Ch ir a l Au xilia r y
Hideki Yamada, Tomohiko Kawate, Atsushi Nishida, and Masako Nakagawa*
Faculty of Pharmaceutical Sciences, Chiba University, 1-33, Yayoi-cho, Inage-ku,
Chiba-shi 263-8522, J apan
Received May 26, 1999
The diastereoselective nucleophilic addition of alkyllithium to N-alkylidene-R-naphthylethylamine
was carried out. In the presence of Lewis acids or Lewis bases, organolithiums reacted smoothly
with imines to give the corresponding amines in high stereoselectivity (up to 100% de). Furthermore,
the resulting optically active amines were found to be useful for asymmetric reactions as chiral
ligands.
In tr od u ction
enantiomerically pure amines after removing chiral
auxiliaries. Also, the enantioselective alkylation of achiral
imines has been investigated using various external
chiral ligands.7
Chiral amines are often critical components of biologi-
cally active compounds and pharmaceutical agents. The
nucleophilic addition of organometallic reagents to imines
is one of the key methods for preparing various amines.
A variety of asymmetric alkylations of imines have been
explored to date.1 The diastereoselective addition of
organometallic reagents to the CdN bond of chiral
compounds such as imines,2 hydrazones,3 oxime ethers,4
sulfinimines,5 and chiral acyliminium ions6 with orga-
nometallic reagents is an appealing route to obtain
As part of a project aimed at developing a method for
the synthesis of enantiomerically pure amines, we previ-
ously reported the asymmetric reduction of imines using
newly developed chiral boranes,8 and more recently we
reported the first enantioselective asymmetric Pictet-
Spengler reaction of nitrones (1a ),9 which is considered
an intramolecular addition of an indole ring to imines
(Scheme 1). We also found that the diastereoselective
Pictet-Spengler reaction of 1b proceeded with moderate
stereoselectivity (up to 72% de) using an R-phenylethyl
group as a chiral auxiliary,10 whereas the bulkier R-naph-
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10.1021/jo9908602 CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/09/1999

8822 J . Org. Chem., Vol. 64, No. 24, 1999
Yamada et al.
Sch em e 1
Sch em e 3
Sch em e 2
Ta ble 1. Dia ster eoselective Alk yla tion of Im in e 4
thylethyl group11 gave higher diastereoselectivity (up to
86% de). On the other hand, in the diastereoselective
nucleophilic addition of imines using an R-phenylethyl
group, Yamamoto and co-workers2e reported that Cram
selectivity is remarkably enhanced in the reaction of
imines with allyl-9-BBN. In addition, Savoia and co-
worker2h found that methylcopper-boron trifluoride re-
acted with imines derived from chiral amines in high
stereoselectivity.
These results prompted us to investigate the intermo-
lecular asymmetric addition to imines. In this paper, we
report the details of the highly diastereoselective addition
of organolithium reagents to imines, in which a chiral
R-naphthylethyl group is used as a chiral auxiliary.12
run
additive
time (h) yield (%)
(R,R):(S,R)
% de
1
2
3
4
5
6
7
8
none
3
1
0.7
1
2
1
1.2
4.5
32
76
92
84
80
99
66
41
79:21
93:7
92:8
87:13
79:21
90:10
98:2
71:29
[(S,S):(R,S)]
58
86
84
74
58
80
96
42
a
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
TMEDAc
b
a,d
a,e
l-sparteinec
l-sparteinec,f
a
b
d
1.6 equiv. 3 equiv. c 2 equiv. -45 °C. e -20 °C. f (S)-4 was
used.
(S,R)-12 in 32% yield (run 1). The diastereomeric excess
was determined to be 58% de by 1H NMR analysis of the
amines before and/or after purification. The proton at the
new stereocenter appeared as two clearly separated
signals (R,R: 3.35 ppm; S,R: 3.76 ppm) for the two
diastereoisomers, and there were two well-separated
methine protons at the 1′ position (R,R: 4.36 ppm; S,R:
4.48 ppm). The absolute configuration of the newly
formed chiral center in the adducts was confirmed as
described below. Tomioka and co-workers reported the
asymmetric addition of methyllithium to imine in the
presence of chiral ligands,7a in which a coordinated Li
cation activated the imines as a Lewis acid. In our
reaction, however, the use of excess n-butyllithium (5.0
equiv) did not improve the yield or selectivity.
Therefore, we investigated the effect of Lewis acids on
the addition of alkyllithium. Although the addition of
MgBr2‚OEt2 (no reaction) or Mg(OEt)2 (21% yield, 52%
de) was not effective, the addition of BF3‚OEt2 to the
reaction of (R)-4 with n-butyllithium increased the
chemical yield with a high diastereomeric excess. Thus,
the reaction of (R)-4 with n-butyllithium in the presence
of BF3‚OEt2 (1.6 equiv) proceeded smoothly to give 12
within 1 h in 76% yield with 86% de (run 2), whereas
Resu lts a n d Discu ssion
In preliminary reactions, we carried out the reaction
of methyllithium with a chiral imine, which was prepared
from (R)-R-phenylethylamine with benzaldehyde and
pivalaldehyde, respectively (Scheme 2). However, the
results were not satisfactory. Therefore, we chose a
bulkier R-naphthylethylamine to improve the asymmetric
induction. The requisite chiral N-alkylidenenaphthyl-
ethylamines 4-11 were simply prepared from (R)-R-
naphthylethylamine and the corresponding aldehydes
(Scheme 3). We first focused our attention on the addition
of n-butyllithium to a typical imine substrate 4. The
results are presented in Table 1. The addition of n-
butyllithium (2.0 equiv) to a toluene solution of (R)-4 at
-78 °C gave a mixture of alkylated amines (R,R)-12 and
(10) (a) Soe, T.; Kawate, T.; Fukui, N.; Nakagawa, M. Tetrahedron
Lett. 1995, 36, 1857-1860. (b) Soe, T.; Kawate, T.; Fukui, N.; Hino,
T.; Nakagawa, M. Heterocycles 1996, 42, 347-358.
(11) Kawate, T.; Yamanaka, M.; Nakagawa, M. Heterocycles 1999,
50, 1033-1039.
(12) A part of this work has been published as a preliminary
communication: Kawate, T.; Yamada, H.; Yamaguchi, K.; Nishida, A.;
Nakagawa, M. Chem. Pharm. Bull. 1996, 44, 1776-1778.

R-Naphthylethyl Group as a Chiral Auxiliary
J . Org. Chem., Vol. 64, No. 24, 1999 8823
Ta ble 2. Dia ster eoselective Alk yla tion of Va r iou s Im in es
Ta ble 3. Effect of Ad d itives on th e Dia ster eoselective
Alk yla tion of Va r iou s Im in es
run imine R2Li time (h) amine yield (%) (R,R):(S,R) % de
additive
(equiv)
time
yield (R,R):
1
2
3
4
4
n-Bu
Me
1
2
6
1
12
13
14
14
76
88
5
93:7
92:8
41:59
63:37
86
84
18
26
run imine
(h) amine (%) (S,R) % de
t-Bu
1
2
4
nonea
BF3‚OEt2 (1.6)
3
2
12
13
32 79:21
88 92:8
58
84
t-Bua
99
5
5
6
Me
1
15
98
95:5
90
3
4
5
6
8
BF3‚OEt2 (1.6)
none
TMEDA (2)
I-sparteine (2)
3
3
3
1
20
46 84:16
63 15:85
93 12:88
83 24:76
68
70
76
52
6
7
Me
n-Bu
4
25
16
17
56
26
>99:1
>99:1
∼100
∼100
8
9
7
Me
n-Bu
1.5
1.5
18
19
76
93
>99:1
85:15
∼100
7
8
9
9
BF3‚OEt2 (3.2)
TMEDA (2)
4
3
6
21
52 72:28
96 19:81
56 24:76
44
62
52
70
a
l-sparteineb (2)
THF was used.
10
11
10
11
BF3‚OEt2 (1.6)
3
6
22
23
76 88:12
32 35:65
76
30
when 3.0 equiv of BF3‚OEt2 was used, the yield increased
dramatically up to 92% (run 3). Thus, it appears that BF3‚
OEt2 activated not only the CdN double bonds but also
controlled the conformation of the R-naphthylethyl group.
TMEDA (2)
b
12
BF3‚OEt2 (3.2)
4
NR
a
b
n-BuLi (2 equiv) was used. MeLi (4 equiv) was used.
In the presence of BF3‚OEt2, the diastereoselectivity
decreased with an increase in the reaction temperature
(runs 4 and 5). Changing solvents from toluene to THF,
Et2O, and CH2Cl2 had only a small effect on the chemical
yields and diastereoselectivities.
The addition of a Lewis base such as N,N,N′,N′-
tetramethylethylenediamine (TMEDA) enhanced the re-
action of n-butyllithium with imine (R)-4 to give a nearly
quantitative yield with high diastereomeric excess (80%
de, run 6). Furthermore, the addition of l-sparteine as a
chiral Lewis base gave the best results, with a diaster-
eomeric excess of 96% de (run 7), whereas a similar
reaction with (S)-4 gave 12 in 41% yield with poor
diastereoselectivity (42% de, run 8), indicating a mis-
matched pair. These results suggest that the addition of
Lewis acids or Lewis bases improves the yield and
diastereoselectivity.
or (R)-9, in BF3‚OEt2-mediated conditions, low yields and
modest diastereoselectivities were observed (runs 3 and
7), suggesting that boron trifluoride coordinated to a ring
nitrogen atom. Therefore, we carried out the reaction of
(R)-8 with methyllithium without using BF3‚OEt2 and
found that the yield increased up to 63% (run 4).
Interestingly, in contrast to the BF3‚OEt2-mediated reac-
tion of 8, the opposite diastereomer (S,R)-20 was the
major product in 70% de. Furthermore, the addition of
TMEDA increased the yield and diastereoselectivity
(93%, 76% de, run 5). The addition of l-sparteine showed
similar results and gave the (S,R) isomer as the major
product. The same procedures were applied to quinoline
derivative (R)-9, which also furnished the (S,R) isomer
as the major product, provided TMEDA or l-sparteine
was used. The reaction of methyllithium with imine (R)-
10, derived from 2-methoxybenzaldehyde, also showed a
similar trend. In contrast, methyllithium did not react
with the imine 11, which has an indole ring. The above
results indicated that the reaction of (R)-8-(R)-10 in the
presence of BF3‚OEt2 gave (R,R)-amines predominantly,
whereas when a Lewis base was used, (S,R)-amines were
the major diastereomers.
A range of commercially available alkyllithium com-
pounds was also added to a wide range of imines under
BF3‚OEt2-assisted conditions, and the results were stud-
ied in detail (Table 2). Reaction of (R)-4 with methyl-
lithium gave 13 in 88% yield in a diastereomeric ratio of
92:8 (run 2). A significantly lower yield and selectivity
were observed for the reaction of (R)-4 with tert-butyl-
lithium in toluene. In THF, however, tert-butyllithium
reacted with (R)-4 quantitatively (run 4). The reaction
of (R)-5, derived from 1-naphthaldehyde, with methyl-
lithium gave (R,R)-15 in 90% de. Reaction of the imine
(R)-6, which has R-hydrogens, with either methyllithium
or n-butyllithium resulted in the corresponding amines
in low chemical yield but gave excellent diastereoselec-
tivity. Reaction of imine (R)-7, which has a branched
alkyl group, with methyllithium gave the best result,
with a diastereomeric excess of ∼100% de (run 8).
The absolute configuration of the newly formed chiral
center was determined as follows. The chiral auxiliary
was removed from 18 by hydrogenolysis [H2, Pd(OH)2/
C], and the resulting chiral amine was converted to
known N-tosyl-3,3-dimethyl-2-butylamine 2413 (Scheme
4). Comparison of the specific rotation of 24 ([R]15D +39.3
(c 1.05, EtOH)) with the reported value13 ([R]D -12.85
(EtOH) for 59.6% ee (S)) showed that the absolute
configuration of 24 was (R), and hence the absolute
configuration of 18 was (1R,1′R). The configuration of 24
was confirmed by X-ray analysis.14 Similarly, hydro-
genolysis of 16 followed by tosylation gave sulfonamide
This reaction was extended to other imines bearing an
alkoxyphenyl group or a pyridine or quinoline ring, which
may chelate to alkyllithiums or additives and enhance
the stereoselectivity of organometallic addition to a
carbonyl group (Table 3). When methyllithium was added
to imines with a pyridine or quinoline ring, such as (R)-8
252a ([R]25 +22.1 (c 0.88, EtOH)). The newly formed
D
(13) Raban, M.; Moulin, C. P.; Lauderback, S. K.; Swilley, B.
Tetrahedron Lett. 1984, 25, 3419-3422.
(14) The experimental details of X-ray analysis are provided as
Supporting Information.

8824 J . Org. Chem., Vol. 64, No. 24, 1999
Yamada et al.
Sch em e 4
chiral center was assigned to be (R) on the basis of the
reported specific rotation ([R]23 +28 (c 1.7, EtOH) for
D
(R)-25). The stereochemistry of 15 was determined to be
(1R,1′R) on the basis of a comparison of its 1H NMR
spectrum with published data.15 The crystallographic
structure of (R,R)-13 also confirmed that the absolute
configuration of the new stereogenic center was (R).14 In
1
the H NMR spectra of these diastereomeric mixtures,
the two methine protons of the (R,R) diastereomers gave
signals at fields higher than those of the (S,R) diaster-
eomers.
Although the detail course of stereoselective reaction
pathway is yet unclear, we have tried a semiempirical
molecular orbital calculation of BF3-complexed (R)-416
and the lowest-energy conformation of BF3-complexed
(R)-4 is shown in Figure 1 (transition state A). In this
conformation, the naphthyl group is almost perpendicular
to the π-plane, which consists of CdN double bonds and
the phenyl group, and shields the bottom face of the
π-plane. Therefore, the alkyllithium reagent should at-
tack from the top of the π-plane and give the observed
diastereomer predominantly. This model may be sup-
ported by the poor asymmetric induction obtained by the
reaction using an R-phenylethyl group as a chiral aux-
iliary (4% de, Scheme 2).
F igu r e 1. Transition state models for the diastereoselective
alkylation of imines.
amides and tested in the asymmetric deprotonation of
tert-butylcyclohexanone 26 under the conditions devel-
oped by Simpkins17a (Table 4). When (R,R)-13 or (R,R)-
15 was used, silylenolether (S)-27 was obtained predomi-
nantly (runs 2 and 3). Interestingly, the introduction of
a 2-methoxy group to the phenyl ring of (R,R)-22 gave
the opposite stereoselectivity. While the mechanism of
the asymmetric induction is not yet clear, these finding
may be useful for designing new chiral amines for
asymmetric deprotonation.
In the case of imine (R)-8, which has a pyridine ring,
alkylation proceeded smoothly without BF3‚OEt2 to give
the (S,R) diastereomer predominantly. It seemed that
methyllithium coordinated to two nitrogen atoms to form
a rigid five-membered ring to stabilize the transition
state. When alkylation occurs with methyllithium, with
coordination of the lithium atom in the five-membered
ring, the reagent will attack from the si face to avoid
unfavorable interaction with the R-methyl group (transi-
tion states B and C). A similar approach can be used to
explain why alkylation of imines (R)-8 or (R)-9 gave an
opposite stereoselectivity using BF3‚OEt2 or TMEDA.
Recently, the asymmetric deprotonation of prochiral
ketones using chiral lithium amides has been widely
studied.17 The resulting chiral amines (R,R)-13, (R,R)-
15, and (R,R)-22 were converted into chiral lithium
In summary, high diastereoselectivity was observed in
the reaction of organolithiums and chiral imines that
contain an R-naphthylethyl group as a chiral auxiliary.
Transition state models to explain this diastereoselec-
tivity were presented. The application of the resulting
chiral amines to other asymmetric reactions is in progress.
Exp er im en ta l Section
Syn t h esis of (R)-N-Ben zylid en e-1-p h en ylet h yla m in e
(2a ). Typ ica l P r oced u r e. A mixture of benzaldehyde (3.1 mL,
30.4 mmol) and (R)-R-phenylethylamine (3.8 mL, 29.4 mmol)
in benzene (50 mL) was heated for 2 h at reflux temperature
using a Dean-Stark apparatus. The mixture was concentrated
under reduced pressure to give the imine 2a (5.90 g, 96%) as
(17) (a) Cousins, R. P. C.; Simpkins, N. S. Tetrahedron Lett. 1989,
30, 7241-7244. (b) Cox, P. J .; Simpkins, N. S. Tetrahedron: Asymmetry
1991, 2, 1-26. (c) Koga, K. J . Synth. Org. Chem., J pn. 1990, 48, 463-
475. (d) Koga, K.; Shindo, M. J . Synth. Org. Chem., J pn. 1995, 53,
1021-1032.
(15) Majewski, M.; MacKinnon, J . Can. J . Chem. 1994, 72, 1699-
1704.
(16) The calculation (MOPAC, AM1) was carried out using CAChe
system Version 3.8, CAChe Scientific Inc., 1995.

R-Naphthylethyl Group as a Chiral Auxiliary
J . Org. Chem., Vol. 64, No. 24, 1999 8825
Ta ble 4. Asym m etr ic Dep r oton a tion of
4-ter t-bu tylcycloh exa n on e u sin g Ch ir a l Lith iu m Am id e
(minor isomer) δ 1.35 (6H, d, J ) 6.6 Hz), 1.57 (1H, brs), 3.76
(2H, q, J ) 6.6 Hz), 7.20-7.36 (10H, m); LRFABMS m/z 226
(M+ + H).
(2R ,1′R )-N -(1′-P h e n y le t h y l)-3,3-d im e t h y l-2-b u t y l-
a m in e [(R,R)-3b ] a n d (2S,1′R)-N-(1′-P h en ylet h yl)-3,3-
d im eth yl-2-bu tyla m in e [(S,R)-3b]. 50% yield (76:24, -78 °C,
6 h); colorless oil. (R,R)-3b (major isomer): colorless oil; [R]26
D
-5.5 (c 1.2, CHCl3); IR (neat) 3080, 1600, 1495, 1450 cm-1; 1H
NMR (CDCl3) δ 0.85 (3H, d, J ) 6.6 Hz), 0.89 (9H, s), 1.18
(1H, brs), 1.28 (3H, d, J ) 6.6 Hz), 2.30 (1H, q, J ) 6.5 Hz),
3.77 (1H, q, J ) 6.6 Hz), 7.16 (1H, m), 7.28-7.36 (4H, m); 13
C
NMR (CDCl3) δ 15.95, 23.61, 26.53, 34.74, 57.07, 59.62, 126.67,
126.70, 128.25, 147.49; LRFABMS m/z 206 (M+ + H); HR-
FABMS calcd for C14H24N (M+ + H) 206.1909, found 206.1906.
(S,R)-3b (minor isomer): colorless oil; [R]26 +98.3 (c 1.5,
D
CHCl3); IR (neat) 3060, 1600, 1490, 1470 cm-1
;
1H NMR
(CDCl3) δ 0.81 (9H, s), 0.95 (3H, d, J ) 6.3 Hz), 1.16 (1H, brs),
1.32 (3H, d, J ) 6.6 Hz), 2.00 (1H, q, J ) 6.3 Hz), 3.86 (1H, q,
J ) 6.6 Hz), 7.20-7.32 (5H, m); 13C NMR (CDCl3) δ 14.20,
25.59, 26.47, 34.11, 55.36, 58.04, 126.58, 126.99, 128.09,
146.16; LRFABMS m/z 206 (M+ + H); HRFABMS calcd for
C
14H24N (M+ + H) 206.1909, found 206.1905.
Syn th esis of (R)-N-Ben zylid en e-1-(1-n a p h th yl)eth yl-
a m in e (4). Typ ica l P r oced u r e. A mixture of benzaldehyde
(3.10 mL, 30.5 mmol) and (R)-1-(1-naphthyl)ethylamine (5.14
g, 30.0 mmol) in benzene (50 mL) was heated for 2 h at reflux
temperature using a Dean-Stark apparatus. The mixture was
concentrated under reduced pressure, and the residue was
recrystallized from n-hexane to give the imine 4 (7.42 g, 95%)
as orange prisms: mp 89.5-90.5 °C (n-hexane); [R]15D -250.3
(c 1.04, CHCl3); [R]17D +250.4 (c 1.0, CHCl3) for (S)-4; IR (KBr)
1
3040, 1640, 1590 cm-1; H NMR (CDCl3) δ 1.72 (3H, d, J )
6.6 Hz), 5.33 (1H, q, J ) 6.6 Hz), 7.36-7.52 (6H, m), 7.72-
7.85 (5H, m), 8.24 (1H, d, J ) 8.0 Hz), 8.39 (1H, s); 13C NMR
(CDCl3) δ 24.53, 65.56, 123.59, 124.00, 125.28, 125.66, 125.75,
127.29, 128.24, 128.49, 128.90, 130.53, 130.64, 133.97, 136.49,
141.16, 159.56; LRFABMS m/z 260 (M+ + H). Anal. calcd for
a
Reference 17a.
C
19H17N: C, 87.99; H, 6.61; N, 5.40. Found: C, 88.30; H, 6.69;
N, 5.51.
a yellow oil; 2a was used for the next reaction without further
purification: [R]27D -64.7 (c 1.0, CHCl3); IR (neat) 3060, 1645,
(R)-N-[(1-Na p h t h yl)m et h ylen e]-1-(1-n a p h t h yl)et h yl-
a m in e (5). 98% yield (reflux, 3 h); brown oil; [R]22 -231.6 (c
1
1600, 1580, 1490 cm-1; H NMR (CDCl3) δ 1.59 (3H, d, J )
D
0.98, CHCl3); IR (neat) 3050, 1640, 1620, 1560 cm-1; 1H NMR
(CDCl3) δ 1.82 (3H, d, J ) 6.6 Hz), 5.42 (1H, q, J ) 6.6 Hz),
7.45-7.61 (6H, m), 7.75 (1H, d, J ) 8.0 Hz), 7.83-7.91 (5H,
m), 8.32 (1H, d, J ) 8.6 Hz), 9.00 (1H, d, J ) 8.5 Hz), 9.04
(1H, s); 13C NMR (CDCl3) δ 24.89, 67.00, 123.63, 124.10,
124.55, 125.15, 125.31, 125.71, 125.78, 125.94, 127.05, 127.33,
128.53, 128.94, 129.17, 130.62, 130.92, 131.29, 131.78, 133.79,
134.01, 141.24, 159.50; LRFABMS m/z 310 (M+ + H); HR-
FABMS calcd for C23H20N (M+ + H) 310.1596, found 310.1604.
6.8 Hz), 4.55 (1H, q, J ) 6.6 Hz), 7.22-7.44 (8H, m), 7.78 (2H,
m), 8.37 (1H, s); 13C NMR (CDCl3) δ 24.83, 69.65, 126.57,
126.76, 128.20, 128.35, 128.45, 130.98, 136.36, 145.15, 159.35;
LRFABMS m/z 210 (M+ + H); HRFABMS calcd for C15H16
N
(M+ + H) 210.1283, found 210.1298.
(R )-N -(2,2-D im e t h y lp r o p y lid e n e )-1-p h e n y le t h y l-
a m in e (2b). 98% yield (reflux, 2 h); colorless oil; [R]27 +60.2
D
(c 1.0, CHCl3); IR (neat) 3060, 1665, 1600, 1490 cm-1; 1H NMR
(CDCl3) δ 1.08 (9H, s), 1.45 (3H, d, J ) 6.8 Hz), 4.27 (1H, q,
J ) 6.7 Hz), 7.21 (1H, m), 7.29-7.36 (4H, m), 7.61 (1H, d, J )
0.7 Hz); 13C NMR (CDCl3) δ 24.96, 26.95, 35.97, 68.99, 126.38,
126.45, 128.20, 145.59, 170.18; LRFABMS m/z 190 (M+ + H);
HRFABMS calcd for C13H20N (M+ + H) 190.1596, found
190.1578.
Syn th esis of (R)-N-(3-P h en ylp r op ylid en e)-1-(1-n a p h -
th yl)eth yla m in e (6). A solution of 3-phenylpropionaldehyde
(1.0 mL, 8.0 mmol) in dry CH2Cl2 (10 mL) was added dropwise
to a stirred solution of the amine (1.3 mL, 8.0 mmol) in the
presence of anhydrous MgSO4 (4.0 g) in dry CH2Cl2 (90 mL)
at 0 °C over a period of 20 min. After being stirred at 0 °C for
2 h, the mixture was filtered through a Celite pad. The filtrate
was concentrated under reduced pressure to give the imine 6
Syn th esis of (1R,1′R)-Bis(1-p h en yleth yl)a m in e [(R,R)-
3a] an d (1S,1′R)-Bis(1-ph en yleth yl)am in e [(S,R)-3a]. Typi-
ca l P r oced u r e. Methyllithium (2.64 mL of a 1.14 M solution
of Et2O, 3.0 mmol) was added dropwise to a stirred solution
of the imine 2a (314.4 mg, 1.5 mmol) and BF3‚OEt2 (0.30 mL,
2.4 mmol) in dry toluene (35 mL) at -78 °C under an argon
atmosphere for 2 min. After being stirred at -78 °C for 6 h,
the reaction was quenched with saturated NaHCO3 (20 mL).
The reaction mixture was diluted with AcOEt (20 mL), and
the organic layer was separated, washed with brine (20 mL),
and dried over Na2SO4. After removal of the solvent, the yellow
oil was subjected to column chromatography on silica gel with
AcOEt/n-hexane (1/40) to give a diastereomeric mixture of
(R,R)-3a and (S,R)-3a (298.0 mg, 88%) as a pale yellow oil. 1H
NMR analysis of the product indicated a 52:48 ratio of
diastereomers, which were inseparable by column chromatog-
raphy: IR (neat) 3080, 1600, 1495, 1450 cm-1; 1H NMR (CDCl3)
(R,R)-3a 18 (major isomer) δ 1.27 (6H, d, J ) 6.6 Hz), 1.57 (1H,
brs), 3.50 (2H, q, J ) 6.6 Hz), 7.20-7.36 (10H, m); (S,R)-3a
(2.27 g, 99%) as a yellow oil: IR (neat) 3060, 1665, 1600 cm-1
;
1H NMR (CDCl3) δ 1.68 (3H, d, J ) 6.8 Hz), 2.62 (2H, dt, J )
4.7, 7.8 Hz), 2.87 (2H, t, J ) 7.7 Hz), 5.11 (1H, q, J ) 6.7 Hz),
7.22-7.26 (5H, m), 7.42-7.51 (3H, m), 7.65 (1H, d, J ) 6.8
Hz), 7.73 (1H, d, J ) 8.1 Hz), 7.82-7.86 (2H, m), 8.10 (1H, d,
J ) 6.8 Hz); LRFABMS m/z 288 (M+ + H). This compound
was not stable enough to give a satisfactory HRFABMS and
was used for the next reaction.
(R)-N-(2,2-Dim eth ylp r op ylid en e)-1-(1-n a p h th yl)eth yl-
a m in e (7). 96% yield (reflux, 2 h); orange oil; [R]18 -36.9 (c
D
0.99, CHCl3); IR (neat) 3040, 1670, 1595 cm-1; 1H NMR (CDCl3)
δ 1.08 (9H, s), 1.58 (3H, d, J ) 6.9 Hz), 5.06 (1H, q, J ) 6.6
Hz), 7.35 (1H, d, J ) 0.7 Hz), 7.43-7.54 (3H, m), 7.72 (2H,
(18) Eleveld, M. B.; Hogeveen, H.; Schudde, E. P. J . Org. Chem.
1986, 51, 3635-3642.

8826 J . Org. Chem., Vol. 64, No. 24, 1999
Yamada et al.
m), 7.84 (1H, m), 8.15 (1H, d, J ) 8.5 Hz); 13C NMR (CDCl3)
δ 24.63, 26.87, 36.03, 65.07, 123.56, 123.66, 125.10, 125.49,
125.59, 126.96, 128.77, 130.53, 133.83, 141.47, 170.07; LR-
m), 3.35 (1H, t, J ) 7.1 Hz), 4.36 (1H, q, J ) 6.7 Hz), 7.09-
7.11 (2H, m), 7.21-7.60 (6H, m), 7.69-7.76 (2H, m), 7.81-
7.89 (2H, m); (S,R)-12 (minor isomer) δ 0.82 (3H, t, J ) 7.1
Hz), 1.08-1.28 (4H, m), 1.49 (3H, d, J ) 6.3 Hz), 1.53-2.74
(3H, m), 3.76 (1H, dd, J ) 5.8, 8.0 Hz), 4.48 (1H, q, J ) 6.4
Hz), 7.09-7.11 (2H, m), 7.21-7.60 (6H, m), 7.69-7.76 (2H,
m), 7.81-7.89 (2H, m); LRFABMS m/z 318 (M+ + H); HR-
FABMS calcd for C23H28N (M+ + H) 318.2222, found 318.2218.
(1R ,1′R )-N -[1′-(1-N a p h t h y l)e t h y l]-1-p h e n y le t h y l-
a m in e [(R,R)-13] a n d (1S,1′R)-N-[1′-(1-Na p h th yl)eth yl]-
1-p h en yleth yla m in e [(S,R)-13] (Ta ble 2, r u n 2). 88% yield
(92:8, -78 °C, 2 h); colorless solid. (R,R)-13 (major isomer):
FABMS m/z 240 (M+ + H); HRFABMS calcd for C17H22
N
(M+ + H) 240.1752, found 240.1733.
(R )-N -[(2-P yr id yl)m e t h yle n e ]-1-(1-n a p h t h yl)e t h yl-
a m in e (8). 96% yield (reflux, 3 h); brown oil; [R]26 -196.1 (c
D
1.1, CHCl3); IR (neat) 3050, 1650, 1585 cm-1; 1H NMR (CDCl3)
δ 1.77 (3H, d, J ) 6.6 Hz), 5.47 (1H, q, J ) 6.6 Hz), 7.30 (1H,
ddd, J ) 1.2, 4.9, 7.6 Hz), 7.46-7.55 (3H, m), 7.72-7.81 (3H,
m), 7.87 (1H, dd, J ) 1.5, 8.1 Hz), 8.15 (1H, dt, J ) 1.0, 7.8
Hz), 8.25 (1H, d, J ) 8.6 Hz), 8.51 (1H, s), 8.63 (1H, ddd, J )
1.0, 1.7, 4.9 Hz); 13C NMR (CDCl3) δ 24.07, 65.10, 121.32,
123.44, 123.95, 124.58, 125.28, 125.52, 125.82, 127.45, 128.85,
130.62, 133.93, 136.36, 140.30, 149.22, 154.74, 160.60; LR-
FABMS m/z 261 (M+ + H); HRFABMS calcd for C18H17N2
(M+ + H) 261.1392, found 261.1394.
colorless prisms; mp 95.5-96.0 °C (AcOEt/n-hexane); [R]17
D
+89.3 (c 0.98, CHCl3); IR (KBr) 3320, 3040, 1595, 1510 cm-1
;
1H NMR (CDCl3) δ 1.33 (3H, d, J ) 6.9 Hz), 1.38 (3H, d, J )
6.6 Hz), 1.57 (1H, brs), 3.58 (1H, q, J ) 6.7 Hz), 4.39 (1H, q,
J ) 6.8 Hz), 7.15-7.53 (8H, m), 7.68 (1H, d, J ) 6.6 Hz), 7.76
(1H, d, J ) 8.0 Hz), 7.86-7.90 (2H, m); 13C NMR (DMSO-d6)
δ 24.38, 24.81, 50.34, 54.83, 122.56, 122.74, 125.12, 125.47,
125.68, 126.39, 126.57, 128.09, 128.61, 130.91, 133.48, 141.61,
146.25; LRFABMS m/z 276 (M+ + H). Anal. calcd for
(R)-N -[(2-Qu in olyl)m e t h yle n e ]-1-(1-n a p h t h yl)e t h yl-
a m in e (9). 99% yield (reflux, 3 h); brown oil; [R]27 -130.6 (c
D
0.83, CHCl3); IR (neat) 3040, 1645, 1595 cm-1; 1H NMR (CDCl3)
δ 1.80 (3H, d, J ) 6.5 Hz), 5.54 (1H, q, J ) 6.6 Hz), 7.47-7.67
(4H, m), 7.73 (1H, ddd, J ) 1.4, 7.0, 8.4 Hz), 7.78 (1H, d, J )
8.1 Hz), 7.83-7.89 (3H, m), 8.10 (1H, d, J ) 8.3 Hz), 8.19 (1H,
d, J ) 8.3 Hz), 8.28 (1H, d, J ) 8.5 Hz), 8.32 (1H, d, J ) 8.6
Hz), 8.69 (1H, s); 13C NMR (CDCl3) δ 24.07, 65.19, 118.49,
123.49, 124.03, 125.32, 125.55, 125.86, 127.25, 127.53, 127.59,
128.66, 128.87, 129.42, 129.64, 130.67, 133.97, 136.33, 140.23,
147.63, 155.00, 161.10; LRFABMS m/z 311 (M+ + H); HR-
FABMS calcd for C22H19N2 (M+ + H) 311.1548, found 311.1527.
(R)-N-(2-Met h oxyb en zylid en e)-1-(1-n a p h t h yl)et h yl-
C
20H21N: C, 87.22; H, 7.69; N, 5.09. Found: C, 87.29; H, 7.57;
N, 5.01. (S,R)-13 (minor isomer): 1H NMR (CDCl3) δ 1.39 (3H,
d, J ) 6.9 Hz), 1.49 (3H, d, J ) 6.3 Hz), 1.57 (1H, brs), 3.89
(1H, q, J ) 6.8 Hz), 4.58 (1H, q, J ) 6.4 Hz), 7.15-7.53 (8H,
m), 7.68 (1H, d, J ) 6.6 Hz), 7.76 (1H, d, J ) 8.0 Hz), 7.86-
7.90 (2H, m).
(1R,1′R)-N-[1′-(1-Na p h th yl)eth yl]-2,2-d im eth yl-1-p h en -
yl-1-p r op yla m in e [(R,R)-14] a n d (1S,1′R)-N-[1′-(1-Na p h -
th yl)eth yl]-2,2-d im eth yl-1-p h en yl-1-p r op yla m in e [(S, R)-
14] (Ta ble 2, r u n 4). 99% yield (63:37, THF, -78 °C, 1 h);
brown oil. The diastereomers were partially separated by flash
column chromatography. (R,R)-14 (major isomer): yellow oil;
a m in e (10). 95% yield (reflux, 2 h); brown oil; [R]27 -157.5
D
(c 1.0, CHCl3); IR (neat) 3040, 1635, 1600, 1285, 1245, 1180
1
cm-1; H NMR (CDCl3) δ 1.73 (3H, d, J ) 6.6 Hz), 3.85 (3H,
s), 5.35 (1H, q, J ) 6.6 Hz), 6.90 (1H, d, J ) 8.0 Hz), 7.00 (1H,
t, J ) 7.5 Hz), 7.37 (1H, ddd, J ) 1.7, 7.3, 8.3 Hz), 7.45-7.55
(3H, m), 7.66 (1H, d, J ) 7.4 Hz), 7.83-7.87 (2H, m), 8.12 (1H,
[R]25 +96.9 (c 0.56, CHCl3); IR (neat) 3060, 1595, 1510 cm-1
;
D
1H NMR (CDCl3) δ 0.85 (9H, s), 1.37 (3H, d, J ) 6.8 Hz), 1.85
(1H, brs), 3.07 (1H, s), 4.25 (1H, q, J ) 6.6 Hz), 7.10 (2H, brs),
7.22-7.32 (4H, m), 7.40 (1H, ddd, J ) 1.2, 6.8, 8.0 Hz), 7.46
(1H, t, J ) 7.6 Hz), 7.65 (1H, d, J ) 6.1 Hz), 7.72 (1H, d, J )
8.2 Hz), 7.82 (1H, d, J ) 8.0 Hz); 13C NMR (CDCl3) δ 24.83,
27.23, 34.66, 51.04, 69.37, 123.34, 123.66, 125.10, 125.21,
125.59, 126.54, 126.90, 127.46, 128.64, 128.91, 131.64, 133.84,
141.82, 142.18; LRFABMS m/z 318 (M+ + H); HRFABMS calcd
for C23H28N (M+ + H) 318.2222, found 318.2229. (S,R)-14
dd, J ) 1.9, 7.8 Hz), 8.28 (1H, d, J ) 8.8 Hz), 8.91 (1H, s); 13
C
NMR (CDCl3) δ 24.78, 55.44, 66.09, 110.92, 120.76, 123.63,
123.93, 124.96, 125.19, 125.66, 125.69, 127.11, 127.56, 128.86,
130.62, 131.74, 133.96, 141.67, 155.66, 158.75; LRFABMS m/z
290 (M+ + H); HRFABMS calcd for C20H20NO (M+ + H)
290.1545, found 290.1575.
(R )-N -[(3-In d olyl)m e t h yle n e ]-1-(1-n a p h t h yl)e t h yl-
a m in e (11). 96% yield (reflux, 3 h); brown amorphous solid;
[R]27D -330.9 (c 0.80, CHCl3); IR (KBr) 3400, 3045, 1630, 1620,
(minor isomer): yellow oil; [R]25 -21.0 (c 0.90, CHCl3); IR
D
(neat) 3060, 1595, 1510 cm-1; 1H NMR (CDCl3) δ 0.93 (9H, s),
1.41 (3H, d, J ) 6.3 Hz), 1.71 (1H, brs), 3.61 (1H, s), 4.28 (1H,
q, J ) 6.3 Hz), 7.20-7.43 (8H, m), 7.62 (1H, d, J ) 6.8 Hz),
7.71 (1H, d, J ) 8.3 Hz), 7.81 (1H, d, J ) 8.0 Hz), 7.92 (1H, d,
J ) 8.3 Hz); 13C NMR (CDCl3) δ 21.25, 27.32, 35.01, 50.62,
69.33, 123.43, 123.78, 125.19, 125.40, 125.57, 126.60, 127.09,
127.51, 128.67, 128.91, 130.91, 133.86, 141.71, 142.90; LR-
1
1580 cm-1; H NMR (CDCl3) δ 1.76 (3H, d, J ) 6.8 Hz), 5.27
(1H, q, J ) 6.6 Hz), 7.28-7.36 (3H, m), 7.42 (1H, s), 7.45-
7.56 (3H, m), 7.74 (1H, d, J ) 8.0 Hz), 7.87 (1H, d, J ) 8.0
Hz), 7.92 (1H, d, J ) 6.8 Hz), 8.32-8.35 (2H, m), 8.56 (1H,
m), 8.62 (1H, s); 13C NMR (CDCl3) δ 25.01, 66.16, 111.23,
115.56, 121.25, 121.86, 123.14, 123.80, 124.07, 125.24, 125.42,
125.67, 125.75, 127.10, 128.65, 128.87, 130.70, 133.95, 136.65,
141.93, 154.07; LRFABMS m/z 299 (M+ + H); HRFABMS calcd
for C21H19N2(M+ + H) 299.1548, found 299.1539.
FABMS m/z 318 (M+ + H); HRFABMS calcd for C23H28
N
(M+ + H) 318.2222, found 318.2226.
(1R,1′R)-Bis[1-(1-n a p h th yl)eth yl]a m in e [(R,R)-15] a n d
(1S,1′R)-Bis[1-(1-n a p h th yl)eth yl]a m in e [(S,R)-15] (Ta ble
2, r u n 5). 98% yield (95:5, -78 °C, 1 h); yellow oil. The
diastereomers were separated by column chromatography.
Dia ster eoselective Alk yla tion of Im in es. Syn th esis of
(1R ,1′R )-N -[1′-(1-Na p h t h yl)e t h yl]-1-p h e n yl-1-p e n t yl-
a m in e [(R,R)-12] a n d (1S,1′R)-N-[1′-(1-Na p h th yl)eth yl]-
1-p h en yl-1-p en tyla m in e [(S,R)-12)]. Typ ica l P r oced u r e
(Ta ble 1, r u n 2). n-Butyllithium (0.63 mL of a 1.6 M solution
of n-hexane, 1.0 mmol) was added dropwise to a stirred
solution of the imine 4 (129.5 mg, 0.5 mmol) and BF3‚OEt2
(0.10 mL, 0.8 mmol) in dry toluene (10 mL) at -78 °C under
an argon atmosphere for 2 min. After being stirred at -78 °C
for 1 h, the reaction was quenched with saturated NaHCO3
(10 mL). The reaction mixture was diluted with AcOEt (10
mL), and the organic layer was separated, washed with brine
(10 mL), and dried over Na2SO4. After removal of the solvent,
the yellow oil was subjected to column chromatography on
silica gel with AcOEt/n-hexane (1/30-1/10) to give a diaster-
eomeric mixture of (R,R)-12 and (S,R)-12 (120.1 mg, 76%) as
(R,R)-15 (major isomer): yellow oil; [R]30 -31.5 (c 0.79,
D
CHCl3); [R]25 -81.2 (c 3.9, MeOH) ([R]22 -53.59 (c 3.9,
D
D
MeOH)14); IR (neat) 3340, 3050, 1595, 1510 cm-1 1H NMR
;
(CDCl3) δ 1.44 (6H, d, J ) 6.8 Hz), 1.85 (1H, brs), 4.50 (2H, q,
J ) 6.6 Hz), 7.19 (2H, ddd, J ) 1.4, 6.9, 8.3 Hz), 7.35 (2H,
ddd, J ) 1.2, 6.8, 8.0 Hz), 7.49 (2H, t, J ) 7.7 Hz), 7.70-7.76
(6H, m), 7.81 (2H, m); 13C NMR (CDCl3) δ 24.45, 51.26, 122.67,
123.07, 125.16, 125.39, 125.63, 127.08, 128.65, 131.45, 133.89,
141.94; LRFABMS m/z 326 (M+ + H); HRFABMS calcd for
C
24H24N (M+ + H) 326.1909, found 326.1905. (S,R)-15 (minor
isomer): yellow oil; IR (neat) 3320, 3050, 1595, 1510 cm-1; 1H
NMR (CDCl3) δ 1.25 (1H, brs), 1.53 (6H, d, J ) 6.6 Hz), 4.75
(2H, q, J ) 6.6 Hz), 7.40-7.48 (6H, m), 7.63 (2H, d, J ) 7.1
Hz), 7.76 (2H, d, J ) 8.3 Hz), 7.87 (2H, d, J ) 7.5 Hz), 8.01
(2H, d, J ) 8.3 Hz); 13C NMR (CDCl3) δ 23.34, 50.16, 123.01,
123.10, 125.34, 125.67, 125.74, 127.24, 128.90, 131.16, 133.96,
141.72; LRFABMS m/z 326 (M+ + H); HRFABMS calcd for
1
a pale yellow oil. H NMR analysis of the product indicated a
93:7 ratio of diastereomers, which were inseparable by column
chromatography. IR (neat) 3060, 1600, 1510 cm-1 1H NMR
;
(CDCl3) (R,R)-12 (major isomer) δ 0.79 (3H, t, J ) 7.2 Hz),
1.08-1.28 (4H, m), 1.35 (3H, d, J ) 6.6 Hz), 1.53-2.74 (3H,
C
24H24N (M+ + H) 326.1909, found 326.1933.

R-Naphthylethyl Group as a Chiral Auxiliary
J . Org. Chem., Vol. 64, No. 24, 1999 8827
(2R ,1′R )-N -[1′-(1-Na p h t h yl)e t h yl]-4-p h e n yl-2-b u t yl-
a m in e [(R,R)-16] a n d (2S,1′R)-N-[1′-(1-Na p h th yl)eth yl]-
4-p h en yl-2-bu tyla m in e [(S,R)-16] (Ta ble 2, r u n 6). 56%
yield (>99:1, -78 °C, 4 h); yellow oil, inseparable mixture.
FABMS calcd for C19H21N2 (M+ + H) 277.1705, found 277.1711.
(S,R)-20 (minor isomer): yellow oil; [R]26 -37.0 (c 0.37,
D
CHCl3); IR (neat) 3320, 3050, 1590, 1570 cm-1 1H NMR
;
(CDCl3) δ 1.41 (3H, d, J ) 6.6 Hz), 1.54 (3H, d, J ) 6.6 Hz),
1.96 (1H, brs), 4.00 (1H, q, J ) 6.6 Hz), 4.64 (1H, q, J ) 6.6
Hz), 7.14 (1H, dd, J ) 4.8, 7.3 Hz), 7.20 (1H, d, J ) 7.8 Hz),
7.41-7.45 (3H, m), 7.58 (1H, dt, J ) 5.8, 7.5 Hz), 7.66 (1H, d,
J ) 7.3 Hz), 7.71 (1H, d, J ) 8.1 Hz), 7.84 (1H, m), 8.01 (1H,
m), 8.56 (1H, d, J ) 4.9 Hz); 13C NMR (CDCl3) δ 22.15, 23.01,
50.19, 56.14, 121.28, 121.81, 123.00, 123.17, 125.21, 125.66,
127.12, 128.85, 131.10, 133.90, 136.34, 141.34, 149.24, 164.40;
LRFABMS m/z 277 (M+ + H); HRFABMS calcd for C19H21N2
(M+ + H) 277.1705, found 277.1711.
(R,R)-16 (major isomer): yellow oil; [R]26 +46.8 (c 0.96,
D
1
CHCl3); IR (neat) 3060, 1600, 1510 cm-1; H NMR (CDCl3) δ
1.08 (3H, d, J ) 6.6 Hz), 1.42-1.44 (4H, m), 1.64 (1H, m), 1.83
(1H, m), 2.50-2.72 (3H, m), 4.75 (1H, q, J ) 6.6 Hz), 7.11-
7.23 (5H, m), 7.42-7.50 (3H, m), 7.62 (1H, d, J ) 6.3 Hz), 7.71
(1H, d, J ) 8.1 Hz), 7.85 (1H, m), 8.19 (1H, d, J ) 8.3 Hz); 13
C
NMR (CDCl3) δ 21.13, 23.89, 32.14, 38.44, 50.06, 50.29, 122.83,
122.91, 125.23, 125.58, 125.61, 125.70, 127.01, 128.24, 128.35,
128.92, 131.19, 133.93, 142.04, 142.52; LRFABMS m/z 304
(M+ + H); HRFABMS calcd for C22H26N (M+ + H) 304.2065,
found 304.2049.
(1R,1′R)-N-[1′-(1-Na p h t h y)et h yl]-1-(2-q u in olyl)et h yl-
a m in e [(R,R)-21] a n d (1S,1′R)-N-[1′-(1-Na p h th y)eth yl]-1-
(2-qu in olyl)eth yla m in e [(S,R)-21] (Ta ble 3, r u n 7). 52%
yield (72:28, -78 °C, 4 h); brown oil. The diastereomers were
partially separated by flash chromatography. (R,R)-21 (major
(R ,1′R )-N -[1′-(1-Na p h t h yl)e t h yl]-1-p h e n yl-3-h e p t yl-
a m in e [(R,R)-17] a n d (3S,1′R)-N-[1′-(1-Na p h th yl)eth yl]-
1-p h en yl-3-h ep tyla m in e [(S,R)-17] (Ta ble 2, r u n 7). 26%
yield (>99:1, -78 °C, 25 h); yellow oil, inseparable mixture.
isomer): brown oil; [R]27 +201.0 (c 0.51, CHCl3); IR (neat)
D
(R,R)-17 (major isomer): yellow oil; [R]27 +54.8 (c 1.06,
3320, 3060, 1620, 1600, 1560 cm-1; H NMR (CDCl3) δ 1.43
1
D
1
CHCl3); IR (neat) 3060, 1600, 1510 cm-1; H NMR (CDCl3) δ
(6H, d, J ) 6.6 Hz), 2.43 (1H, brs), 3.91 (1H, q, J ) 6.8 Hz),
4.45 (1H, q, J ) 6.6 Hz), 7.23 (1H, d, J ) 8.3 Hz), 7.32 (1H,
ddd, J ) 1.5, 6.9, 8.4 Hz), 7.41 (1H, m), 7.48-7.52 (2H, m),
7.70 (1H, ddd, J ) 1.5, 6.9, 8.4 Hz), 7.74 (1H, d, J ) 8.1 Hz),
7.78-7.85 (3H, m), 7.90 (1H, d, J ) 8.8 Hz), 8.03 (1H, d, J )
8.6 Hz), 8.08 (1H, d, J ) 8.6 Hz); 13C NMR (CDCl3) δ 23.61,
24.45, 51.81, 57.43, 120.14, 123.05, 123.10, 125.13, 125.41,
125.74, 125.82, 127.06, 127.37, 127.49, 128.77, 129.17, 129.22,
131.44, 133.94, 136.19, 141.43, 147.89, 165.58; LRFABMS m/z
327 (M+ + H); HRFABMS calcd for C23H23N2 (M+ + H)
327.1861, found 327.1848. (S,R)-21 (minor isomer): brown oil,
[R]30D -55.2 (c 0.88, CHCl3); IR (neat) 3320, 3050, 1620, 1600,
0.85 (3H, t, J ) 7.2 Hz), 1.17-1.47 (10H, m), 1.74 (2H, m),
2.49-2.69 (3H, m), 4.75 (1H, q, J ) 6.6 Hz), 7.13-7.16 (3H,
m), 7.21-7.25 (2H, m), 7.44-7.50 (3H, m), 7.64 (1H, d, J )
6.4 Hz), 7.72 (1H, d, J ) 8.3 Hz), 7.85 (1H, m), 8.22 (1H, d,
J ) 8.1 Hz); 13C NMR (CDCl3) δ 14.04, 22.86, 24.26, 27.96,
31.65, 34.36, 35.54, 50.27, 53.98, 122.99, 123.18, 125.18,
125.56, 125.60, 126.98, 128.25, 128.90, 131.30, 133.92, 141.99,
142.78; LRFABMS m/z 346 (M+ + H); HRFABMS calcd for
C
25H32N (M+ + H) 346.2535, found 346.2538.
(2R,1′R)-N-[1′-(1-Na p h th yl)eth yl]-3,3-d im eth yl-2-bu tyl-
a m in e [(R,R)-18] a n d (2S,1′R)-N-[1′-(1-Na p h th yl)eth yl]-
3,3-d im eth yl-2-bu tyla m in e [(S,R)-18] (Ta ble 2, r u n 8). 76%
yield (>99:1, -78 °C, 1.5 h); yellow oil, inseparable mixture.
1
1560 cm-1; H NMR (CDCl3) δ 1.49 (3H, d, J ) 6.9 Hz), 1.58
(3H, d, J ) 6.6 Hz), 2.23 (1H, brs), 4.24 (1H, q, J ) 6.6 Hz),
4.69 (1H, q, J ) 6.6 Hz), 7.35-7.44 (4H, m), 7.50 (1H, m), 7.65
(1H, d, J ) 7.1 Hz), 7.68-7.72 (2H, m), 7.78 (1H, d, J ) 8.0
Hz), 7.82 (1H, m), 8.04-8.10 (3H, m); 13C NMR (CDCl3) δ
22.52, 22.64, 50.29, 56.90, 119.57, 123.15, 123.18, 125.21,
125.63, 125.92, 127.14, 127.31, 127.47, 128.77, 129.18, 129.27,
131.13, 133.87, 136.35, 141.47, 147.66, 164.81; LRFABMS m/z
327 (M+ + H); HRFABMS calcd for C23H23N2 (M+ + H)
327.1861, found 327.1848.
(R,R)-18 (major isomer): yellow oil; [R]15 -17.4 (c 1.06,
D
CHCl3); IR (neat) 3030, 1595, 1510 cm-1; 1H NMR (CDCl3) δ
0.93-0.96 (12H, m), 1.02 (1H, brs), 1.42 (3H, dd, J ) 1.0, 6.6
Hz), 2.44 (1H, q, J ) 6.5 Hz), 4.63 (1H, q, J ) 6.5 Hz), 7.43-
7.51 (3H, m), 7.71-7.72 (2H, m), 7.85 (1H, dd, J ) 1.2, 6.8
Hz), 8.28 (1H, d, J ) 8.3 Hz); 13C NMR (CDCl3) δ 15.65, 23.02,
26.62, 34.71, 52.15, 59.76, 123.41, 125.19, 125.54, 125.63,
126.96, 128.86, 131.02, 133.92, 143.52; LRFABMS m/z 256
(M+ + H); HRFABMS calcd for C18H26N (M+ + H) 256.2065,
found 256.2063. (S,R)-18 (minor isomer): 1H NMR (CDCl3) δ
0.68 (9H, s), 1.02 (1H, brs), 1.37 (3H, d, J ) 6.8 Hz), 1.71 (3H,
d, J ) 7.0 Hz), 3.83 (1H, q, J ) 6.5 Hz), 5.22 (1H, q, J ) 7.1
Hz), 7.43-8.28 (7H, m).
(1R,1′R)-N-[1′-(1-Na p h th y)eth yl]-1-(2-m eth oxyp h en yl)-
eth yla m in e [(R,R)-22] a n d (1S,1′R)-N-[1′-(1-Na p h th y)-
eth yl]-1-(2-m eth oxyp h en yl)eth yla m in e [(S,R)-22] (Ta ble
3, r u n 10). 76% yield (88:12, -78 °C, 3 h); yellow oil. The
distereomers were separated by preparative TLC. (R,R)-22
(3R,1′R)-N-[1′-(1-Na p h t h yl)et h yl]-2,2-d im et h yl-3-h ep -
tyla m in e [(R,R)-19] a n d (3S,1′R)-N-[1′-(1-Na p h th yl)eth yl]-
2,2-d im eth yl-3-h ep tyla m in e [(S,R)-19] (Ta ble 2, r u n 9).
93% yield (85:15, -78 °C, 1.5 h); colorless oil; inseparable
(major isomer): yellow oil; [R]25 +27.7 (c 0.83, CHCl3); IR
D
1
(neat) 3360, 3060, 1595, 1240 cm-1; H NMR (CDCl3) δ 1.35
(3H, d, J ) 6.8 Hz), 1.38 (3H, d, J ) 6.5 Hz), 1.98 (1H, brs),
3.53 (3H, s), 3.87 (1H, q, J ) 6.8 Hz), 4.40 (1H, q, J ) 6.6 Hz),
6.80 (1H, dd, J ) 1.0, 8.1 Hz), 6.90 (1H, dt, J ) 1.0, 7.4 Hz),
7.14 (1H, dd, J ) 1.7, 7.5 Hz), 7.20 (1H, ddd, J ) 1.7, 7.3, 8.0
Hz), 7.34 (1H, ddd, J ) 1.7, 6.8, 8.5 Hz), 7.41 (1H, ddd, J )
1.2, 6.8, 8.0 Hz), 7.50 (1H, dd, J ) 7.4, 8.1 Hz), 7.73 (1H, d,
J ) 8.1 Hz), 7.76 (1H, d, J ) 7.0 Hz), 7.84 (1H, m), 7.89 (1H,
d, J ) 8.5 Hz); 13C NMR (CDCl3) δ 22.71, 24.62, 50.82, 51.05,
54.82, 110.53, 120.53, 122.96, 123.11, 124.97, 125.19, 125,74,
126.79, 127.47, 127.70, 128.67, 131.53, 133.50, 133.87, 141.80,
157.36; LRFABMS m/z 306 (M+ + H); HRFABMS calcd for
C21H24NO (M+ + H) 306.1858, found 306.1870. (S,R)-22 (minor
isomer): yellow oil; [R]26D -37.6 (c 1.0, CHCl3); IR (neat) 3330,
1
mixture. IR (neat) 3040, 1510 cm-1; H NMR (CDCl3) (R,R)-
19 (major isomer) δ 0.66 (9H, s), 0.97 (3H, t, J ) 7.2 Hz), 1.05-
1.85 (10H, m), 3.17 (1H, d, J ) 10.7 Hz), 5.05 (1H, q, J ) 7.1
Hz), 7.40-7.51 (3H, m), 7.58-7.61 (1H, m), 7.69-7.73 (1H,
m), 7.83-7.86 (1H, m), 7.89-8.03 (1H, m); (S,R)-19 (minor
isomer) δ 0.67 (9H, s), 1.00 (3H, t, J ) 7.2 Hz), 1.05-1.85 (10H,
m), 3.64 (1H, dd, J ) 1.6, 10.6 Hz), 5.14 (1H, q, J ) 6.4 Hz),
7.40-8.03 (7H, m); LRFABMS m/z 298 (M+ + H); HRFABMS
calcd for C12H32N (M+ + H) 298.2535, found 298.2523.
(1R ,1′R )-N -[1′-(1-Na p h t h y)e t h yl]-1-(2-p yr id yl)e t h yl-
a m in e [(R,R)-20] a n d (1S,1′R)-N-[1′-(1-Na p h th y)eth yl]-1-
(2-p yr id yl)eth yla m in e [(S,R)-20] (Ta ble 3, r u n 3). 46%
yield (84:16, -78 °C, 3 h); yellow oil. The diastereomers were
separated by preparative TLC. (R,R)-20 (major isomer): yel-
1
3050, 1595, 1240 cm-1; H NMR (CDCl3) δ 1.40 (3H, d, J )
6.6 Hz), 1.50 (3H, d, J ) 6.6 Hz), 1.73 (1H, brs), 3.73 (3H, s),
4.28 (1H, q, J ) 6.6 Hz), 4.53 (1H, q, J ) 6.6 Hz), 6.88 (1H, d,
J ) 8.2 Hz), 6.95 (1H, dt, J ) 1.2, 7.5 Hz), 7.22-7.29 (2H, m),
7.39 (1H, ddd, J ) 1.5, 6.9, 8.4 Hz), 7.42 (1H, dd, J ) 1.6, 7.9
Hz), 7.45 (1H, t, J ) 7.7 Hz), 7.67 (1H, d, J ) 7.1 Hz), 7.72
low oil; [R]27 +114.7 (c 0.46, CHCl3); IR (neat) 3320, 3050,
D
1590, 1570 cm-1; 1H NMR (CDCl3) δ 1.37 (3H, d, J ) 6.8 Hz),
1.40 (3H, d, J ) 6.6 Hz), 2.11 (1H, brs), 3.68 (1H, q, J ) 6.8
Hz), 4.32 (1H, q, J ) 6.6 Hz), 6.93 (1H, d, J ) 7.6 Hz), 7.14
(1H, m), 7.37 (1H, ddd, J ) 1.5, 6.9, 8.4 Hz), 7.42 (1H, m),
7.48-7.54 (2H, m), 7.73-7.79 (2H, m), 7.85 (1H, d, J ) 8.0
Hz), 7.93 (1H, d, J ) 8.5 Hz), 8.61 (1H, m); 13C NMR (CDCl3)
δ 23.33, 24.49, 51.36, 56.42, 121.74, 122.06, 122.94, 123.19,
125.09, 125.36, 125.72, 127.01, 128.78, 131.38, 133.92, 136.08,
141.17, 149.54, 164.78; LRFABMS m/z 277 (M+ + H); HR-
(1H, d, J ) 8.3 Hz), 7.84 (1H, m), 7.87 (1H, d, J ) 8.3 Hz); 13
C
NMR (CDCl3) δ 21.89, 22.26, 49.77, 50.40, 55.07, 110.58,
120.67, 123.03, 123.27, 125.14, 125.52, 125.65, 127.05, 127.64,
127.70, 128.78, 131.04, 133.22, 133.85, 141.83; LRFABMS m/z
306 (M+ + H); HRFABMS calcd for C21H24NO (M+ + H)
306.1858, found 306.1864.

8828 J . Org. Chem., Vol. 64, No. 24, 1999
Yamada et al.
Syn th esis of (R)-N-(p-Tolu en esu lfon yl)-3,3-d im eth yl-
2-bu tyla m in e (24). A mixture of the amine 18 (1.9 g, 7.4
mmol) and 20% Pd(OH)2 on carbon (0.75 g) in methanol (35
n-hexane, 2.4 mmol) was added dropwise to a stirred solution
of the amine (R,R)-13 (716.0 mg, 2.6 mmol) in dry THF (40
mL) at -78 °C under an argon atmosphere. After being stirred
at -78 °C for 5 min, the reaction mixture was warmed to room
temperature for 20 min and stirred for 40 min. After the
mixture was cooled to -78 °C again, TMSCl (1.3 mL, 10.1
mmol) was added. A solution of 4-tert-butylcyclohexanone 26
(308.0 mg, 2.0 mmol) in dry THF (10 mL) was added dropwise
to the mixture over a period of 8 min. After the mixture stirred
at -78 °C for 1 h, Et3N (4 mL) and saturated NaHCO3 (10
mL) were added. The organic layer was separated and ex-
tracted with petroleum ether (15 mL × 2). The combined or-
ganic extracts were washed with saturated NH4Cl (20 mL ×
2) and saturated NaHCO3 (20 mL × 2) and dried over Na2-
SO4. Evaporation of the solvent gave the colorless oil, which
was subjected to column chromatography on silica gel with
n-hexane, AcOEt/n-hexane (1/10), and AcOEt to give the
silylenolether 27 (286.3 mg, 63%) as a colorless oil. For further
purification, the silylenolether 27 was distilled under a reduced
pressure (Kugelrohr, 130 °C/2 mmHg) to give 27 (217.1 mg,
48%) as a colorless oil. The enantiomeric excess of this
compound was determined by measuring the optical rotation,
which indicated 69% ee (S).
mL) was stirred under
a hydrogen atmosphere at room
temperature for 6 h. The catalyst was filtered through a Celite
pad, and the filtrate was concentrated under atmospheric
pressure to give the amine as a colorless oil, which was used
for the next reaction without further purification. A solution
of p-toluenesulfonyl chloride (1.7 g, 8.9 mmol) in dry THF (15
mL) was added dropwise to a stirred solution of the amine
and Et3N (1.24 mL, 8.9 mmol) in dry THF (35 mL) for 7 min
at 0 °C under an argon atmosphere. The reaction mixture was
stirred for at 0 °C 30 min and then at room temperature for
40 h. A solution of 3 N hydrochloric acid was added dropwise
to the mixture (∼pH 3) at 0 °C, and then the organic layer
was separated, washed with H2O (10 mL) and brine (10 mL),
and dried over Na2SO4. After removal of the solvent, the yellow
solid was subjected to column chromatography on silica gel
with AcOEt/n-hexane (1/ 8-1/ 2). The first eluted material was
1-ethylnaphthalene (1.0 g, 87%, from 18), and the second was
the sulfonamide 24 (1.1 g, 59%, from 18) as a colorless solid.
Recrystallization from AcOEt/n-hexane gave the sulfonamide
24 as colorless prisms: mp 130.0-131.0 °C (AcOEt/n-hexane);
[R]15 +39.3 (c 1.05, EtOH) ([R]D -12.85 (EtOH) for 59.6% ee
D
4-ter t-Bu tyl-1-(tr im eth ylsilyloxy)cycloh exen e 27. Col-
orless oil; bp 130 °C/2 mmHg (Kugelrohr) (66-67 °C/0.44
(S)-24);13 1H NMR (CDCl3) δ 0.83 (9H, s), 0.88 (3H, d, J ) 6.6
Hz), 2.42 (3H, s), 3.05 (1H, dq, J ) 6.6, 8.5 Hz), 4.49 (1H, d,
J ) 8.5 Hz), 7.29 (2H, d, J ) 7.8 Hz), 7.77 (2H, dt, J ) 2.0, 8.7
Hz); 13C NMR (DMSO-d6) δ 15.21, 20.90, 26.18, 34.23, 57.53,
126.51, 129.37, 139.24, 142.12; IR (KBr) 3300, 3240, 3060,
1600, 1320, 1170 cm-1; LRFABMS m/z 256 (M+ + H). Anal.
calcd for C13H21NO2S: C, 61.14; H, 8.29; N, 5.48. Found: C,
61.17; H, 8.38; N, 5.42.
mmHg (Kugelrohr));16a [R]26 -54.7 (c 1.5, CHCl3) for 69% ee
D
for (S)-isomer ([R]22D -69.2 (c 1.5, CHCl3) for 88% ee (S)-27);16a
1H NMR (CDCl3) δ 0.18 (9H, s), 0.87 (9H, s), 1.19-1.30 (2H,
m), 1.75-1.84 (2H, m), 1.95-2.12 (3H, m), 4.84 (1H, m).
Ack n ow led gm en t. This study was supported by a
Grant-in-Aid for Scientific Research from the Ministry
of Science, Education, Sports and Culture. The authors
thank Drs. K. Yamaguchi and H. Seki and Ms. R. Hara
of the Chemical Analytical Center of Chiba University
for performing the X-ray analyses and the microanaly-
ses and measuring the mass spectra.
(R)-N-(p-Tolu en esu lfon yl)-4-p h en yl-2-bu tyla m in e (25).
43% yield (2 steps); (hydrogenolysis, rt, 8 h; tosylation, 0 °C,
1 h, then rt, 23 h); pale yellow oil; [R]25 +22.1 (c 0.88, EtOH)
D
([R]23 +28 (c 1.7, EtOH) for (R)-25);2a IR (neat) 3280, 3060,
D
1600, 1320, 1160 cm-1; H NMR (CDCl3) δ 1.05 (3H, d, J )
1
6.5 Hz), 1.67 (2H, m), 2.41 (3H, s), 2.55 (2H, m), 3.34 (1H, m),
4.84 (1H, d, J ) 7.8 Hz), 7.03 (2H, m), 7.13-7.28 (5H, m), 7.76
(2H, m); 13C NMR (CDCl3) δ 21.43, 21.57, 31.75, 39.02, 49.60,
125.80, 127.00, 128.25, 128.29, 129.60, 138.17, 141.30, 143.14;
Su p p or tin g In for m a tion Ava ila ble: 1H NMR and X-ray
analysis data. This material is available free of charge via the
Internet at http://pubs.acs.org.
LRFABMS m/z 304 (M+ + H); HRFABMS calcd for C17H22
-
NO2S (M+ + H) 304.1371, found 304.1353.
Asym m etr ic Dep r oton a tion of 4-ter t-Bu tylcycloh ex-
a n on e (26). n-Butyllithium (1.5 mL of a 1.6 M solution in
J O9908602