Synthesis of chiral nonracemic 1-(2-pyridinyl)ethylamines: Stereospecific introduction of amino function onto the 2-pyridinylmethyl carbon center

Article abstract of DOI:10.1021/jo0491758

Stereospecific substitutions of optically pure 1-(pyridinyl)ethyl methanesulfonates with various amines are described. The reaction of (R)- or (S)-1-(2-pyridinyl)ethyl methanesulfonate with primary amines, including amino acid esters, gives N-substituted

Full text of DOI:10.1021/jo0491758

Syn th esis of Ch ir a l Non r a cem ic 1-(2-P yr id in yl)eth yla m in es:
Ster eosp ecific In tr od u ction of Am in o F u n ction on to th e
2-P yr id in ylm eth yl Ca r bon Cen ter
J un’ichi Uenishi,*,† Masahiro Hamada,† Sachiko Aburatani,† Katsuya Matsui,‡
Osamu Yonemitsu,‡ and Hiroshi Tsukube§
Kyoto Pharmaceutical University, Misasagi, Yamashina, Kyoto 607-8412, J apan, Department of
Chemistry, Okayama University of Science, Ridaicho, Okayama 700-0005, J apan, and Department of
Chemistry, Graduate School of Science, Osaka City University, Sugimoto, Sumiyoshi-ku,
Osaka 558-8585, J apan
juenishi@mb.kyoto-phu.ac.jp
Received May 16, 2004
Stereospecific substitutions of optically pure 1-(pyridinyl)ethyl methanesulfonates with various
amines are described. The reaction of (R)- or (S)-1-(2-pyridinyl)ethyl methanesulfonate with primary
amines, including amino acid esters, gives N-substituted (S)- or (R)-1-(2-pyridinyl)ethylamines (4)
with inversion of the configuration. Secondary cyclic amines are also reacted with (R)-2 to give the
corresponding substituted amines (5) in excellent yields. Optically pure and meso triamine ligands
having two pyridine rings, (S,S)-4f and meso-4f, (S,S)-9e, (S,R)-9e, and (S,S)-9f, have been prepared
in stereochemically pure form by this method. Not only the substitution reaction of optically active
2 but also that of 1-(4-pyridinyl)ethyl and 1-(3-pyridinyl)ethyl methanesulfonates 11 and 14 take
place stereospecifcally with inversion of the chiral center.
SCHEME 1
In tr od u ction
Although nucleophilic substitution reaction on the
benzylic position has been extensively investigated in
aromatic systems,1 there have been few studies of that
on the pyridinylmethyl position.2 The nucleophilic sub-
stitution reaction of 1-(phenyl)ethyl halide occurs mostly
through an SN1 process along with a partial SN2 process.1a,b
Therefore, this substitution does not take place ste-
reospecifically except in limited cases in which a strong
electron-withdrawing group is attached on the aromatic
ring.1e On the other hand, we have recently reported that
perfect stereospecific substitution occurred in the case
of 1-(2-pyridinyl)ethyl methanesulfonate with an inver-
sion of the configuration through an SN2 process. Opti-
cally pure 1-(2-pyridinyl)ethylamines were obtained when
chiral nonracemic methanesulfonate derivatives were
used for the reaction (Scheme 1).3 Since chiral nonracemic
pyridine derivatives have become important as ligands
in modern asymmetric synthesis as well as molecular
recognition chemistry,4 it will be valuable to synthesize
pure chiral nonracemic pyridine derivatives. In this
paper, we report in detail substitution reactions at the
pyridinylmethyl position with amine nucleophiles, in-
† Kyoto Pharmaceutical University.
‡ Okayama University of Science.
§ Osaka City University.
(1) (a) Allen, A. D.; Kanagasabapathy, V. M.; Tidwell, T. T. J . Am.
Chem. Soc. 1985, 107, 4513-4519. (b) Richard, J . P.; J encks, W. P. J .
Am. Chem. Soc. 1984, 106, 1383-1396 and references therein. (c)
Zieger, H. E.; Bright, D. A.; Haubenstock, H. J . Org. Chem. 1986, 51,
1180-1184. (d) Kinoshita, T.; Ueno, T.; Ikai, K.; Fujiwara, M.;
Okamoto, K. Bull. Chem. Soc. J pn. 1988, 61, 3273-3282. (e) Lim, C.;
Kim, S.-H.; Yoh, S.-D.; Fujio, M. Tsuno, Y. Tetrahedron Lett. 1997,
38, 3243-3246.
(3) (a) Uenishi, J .; Takagi, T.; Ueno, T.; Hiraoka, T.; Yonemitsu, O.;
Tsukube, H. Synlett 1999, 41-44. (b) Uenishi, J .; Hiraoka, T.; Yuyama,
K.; Yonemitsu, O. Heterocycles 2000, 52, 719-732. (c) Uenishi, J .;
Hamada.; Takagi, T.; Yonemitsu, O. Heterocycles 2001, 53, 735-746.
(d) Uenishi, J .; Hamada, M. Tetrahedron: Asymmetry 2001, 21, 2999-
3006.
(2) (a) Chelucci, G.; Cabras, M. A.; Saba, A. Tetrahedron: Asymmetry
1994, 5, 1973-1978. (b) J iang, Q.; Plew, D. V.; Murtuza, S.; Zhang, X.
Tetrahedron Lett. 1996, 37, 797-800. (c) Haviv, F.; DeNet, R. W.;
Michaels, R. J .; Ratajczyk, J . D.; Carter, G. W.; Young, P. R. J . Med.
Chem. 1983, 26, 218-222. (d) Kostik, E. L.; Abiko, A.; Oku, A. J . Org.
Chem. 2001, 66, 1638-1646. (e) J iang, Q.; Plew, D. V.; Murtuza, S.;
Zhang, X. Tetrahedron Lett. 1996, 37, 797-800.
(4) (a) Chelucci, G.; Orru, G.; Pinna, G. A. Tetrahedron 2003, 59,
9471-9515. (b) Fletcher, N. C. J . Chem. Soc., Perkin Trans. 1 2002,
19831-1842. (c) Soai, K.; Sato, I. Viva Origino 2002, 30, 186-198. (d)
Vancheesan, S.; J esudurai, D. Catalysis 2002, 311-337. (e) Chelucci,
G.; Thummel, R. P. Chem. Rev. 2002, 102, 3129-3170. (f) Nishiyama,
H. Enantiomer 1999, 4, 569-574. (g) Mamula, O.; von Zelewsky, A.
Coord. Chem. Rev. 2003, 242, 87-95.
10.1021/jo0491758 CCC: $27.50 © 2004 American Chemical Society
Published on Web 09/01/2004
J . Org. Chem. 2004, 69, 6781-6789
6781

Uenishi et al.
SCHEME 2
SCHEME 3
cluding amino acid esters and preparation of a variety
of chiral nonracemic 1-(pyridinyl)ethylamines.
ment. Since the ee value of 4a or 4b was equal to that of
the original starting material, (R)-2 or (S)-2, the reaction
was proved to occur stereospecifically via an SN2 process.
However, it is noted that the mesylate should not be
used without purification, because the chloride is par-
tially formed in some cases as a secondary product by
substitution of the mesylate with the resulted triethyl-
amine hydrochloride and contaminates the crude product.
Since the chloride has a stereochemistry opposite to that
of the mesylate, the substitution reaction using the crude
mesylate results in a decrease in the overall enantiomeric
purity of the desired enantiomer. In fact, a lower ee value
was observed in the same substitution reaction in some
cases when crude mesylate was used.7 Although the
chloride was produced in a longer reaction time, very
little chloride was formed when the mesylation was
completed in a short time by the use of an excess of
reagents at 0 °C.
DMSO was found to be the best solvent for this
substitution reaction. When the reaction of (R)-2 with
benzylamine was carried out in other solvents such as
HMPA, EtOH, acetonitrile, and DMF at 60 °C for 3 h,
the reactions were clean but yields of (S)-4a did not
exceed 50-60%. In comparison, when the reaction was
conducted in benzene or THF, the yield was poor.
Although the reaction proceeded very well in DMSO,
removal of DMSO from the amine product was sometimes
troublesome. It requires high-vacuum conditions or gel
permeation HPLC separation. In such cases, acetonitrile
is an alternative solvent. Although the reaction in ac-
etonitrile was 3-6 times slower than that in DMSO,
purification of the product was much easier than in the
case of using DMSO. In addition, the reaction proceeded
cleanly even at a temperature over 60 °C, and, more
importantly, the chiral center was not racemized at all
in DMSO and acetonitrile. Therefore, acetonitrile is a
solvent suitable for obtaining polar amine products.
The mesylate (R)-2 reacted with primary as well as
secondary amines as shown in Scheme 4. The results
obtained by using various primary amines, including
Resu lts a n d Discu ssion
We previously reported that lipase-catalyzed kinetic
acetylation of racemic 1-(2-pyridinyl)ethanols by vinyl
acetate gave optically pure (R)-1-(2-pyridinyl)ethyl ac-
etates and recovery of (S)-1-(2-pyridinyl)ethanols.5 (R)-
1-(2-Pyridinyl)ethanols were derived by methanolysis of
the resulting acetates quantitatively. Mesylation of the
optically pure alcohols (R)-1 (R ) H) and (S)-1 (R ) H)
with methanesulfonyl chloride in the presence of either
triethylamine or DMAP gave the corresponding meth-
anesulfonates (R)-2 (R ) H) and (S)-2 (R ) H) in
quantitative yields with retention of the configuration
(Scheme 2).3b These mesylates could be purified by silica
gel column chromatography. Although they become red
in color after 1 day, they can be used for the next reaction.
The red-colored substance increases gradually upon
storage for long periods of time and is assumed to be a
dimer of pyridinium salt due to its solubility in water. If
that is the case, the mesylate can be purified easily by
silica gel chromatography.
Treatment of compound (R)-2 with an excess of ben-
zylamine in DMSO at 60 °C for 3 h gave (S)-N-benzyl-
N-1-(2-pyridinyl)ethylamine (S)-4a in 93% yield. The
reaction with cyclohexylamine gave (S)-4b in 76% yield.
The stereochemistry of the products was confirmed to be
of the (S)-configuration by subsequent independent syn-
theses shown in Scheme 3. Thus, reductive amination of
benzaldehyde with the known (S)-1-(2-pyridinyl)ethyl-
amine (S)-3a ,6 which was also derived by the substitution
reaction of (R)-2 with sodium azide and successive
reduction of the resulted azide,3b gave (S)-4a in 75% yield.
In the same manner, the reaction of (S)-3a with cyclo-
hexanone afforded (S)-4b in 84% yield. On the other
hand, starting from (S)-2, the same sequence of the
reactions gave their enantiomers, (R)-3a , (R)-4a , and (R)-
4b, respectively. The optical purity of the products was
determined to be over 95% ee by a chiral HPLC experi-
(5) Uenishi, J .; Hiraoka, T.; Hata, S.; Nishiwaki, K.; Yonemitsu, O.;
Nakamura, K.; Tsukube, H. J . Org. Chem. 1998, 63, 2481-2487.
(6) Previous reports for the synthesis of nonracemic 1-(2-pyridinyl-
ethyl)amine: (a) Brunner, H.; Fisch, H. J . Organomet. Chem. 1987,
335, 1-14. (b) Michelsen, K. Acta Chem. Scand. 1974, A 28, 428-434..
(c) Cervinka, O.; Belovsky, O.; Rejmanova, P. Coll. Czech. Chem.
Comm. 1973, 38, 1358-1363. (d) Mi, A.; Xiao, X.; Wu, L.; J iang, Y.
Synth. Commun. 1991, 21, 2207-2212.
(7) When the crude mesylate was used for the substitution with
azide anion, the ee values were reported to be 66-92% in ref 2a and
also were confirmed by our hands. However, the reaction gave the
product with excellent ee (>95%) as long as we used the purified
mesylate.
6782 J . Org. Chem., Vol. 69, No. 20, 2004

Synthesis of Chiral Nonracemic 1-(2-Pyridinyl)ethylamines
TABLE 1. Ster eosp ecific Su bstitu tion of (R)- a n d (S)-2
w ith Non ch ir a l a n d Ch ir a l Non r a cem ic P r im a r y Am in es
SCHEME 4
amino acid esters, are summarized in Table 1. The
reaction with primary amines was fast and was complete
within 1 h. The reaction with aniline gave (S)-4c in 79%
yield, and that with bulky adamantylamine gave (S)-4d
in 83% yield (entries 3 and 4). Chiral nonracemic amines
such as (S)- and (R)-1-(phenyl)ethylamines reacted with-
out epimerization to give (S,S)-4e and (S,R)-4e in 82 and
90% yields, respectively (entries 5 and 6). Since the
proton NMR spectrum of the crude product indicated a
single diastereomer, the reaction was confirmed to pro-
ceed stereospecifically. Similarly, the reaction of (R)-2
with (S)-1-(2-pyridinyl)ethylamine ((S)-3a ) gave (S,S)-
N,N-bis[1-(2-pyridinyl)ethyl]amine ((S,S)-4f) in 86% yield
(entry 7). However, that with (R)-3a gave meso-N,N-bis-
1-(2-pyridinyl)ethylamine (meso-4f) in 87% yield (entry
8). The reaction with 2-furylmethylamines efficiently
gave the corresponding amines, (S,S)-4g and (S,R)-4g,
in 62 and 64% yields, respectively (entries 9 and 10).
The reaction of (S)-2 with amino acid ester gave N-1-
(2-pyridinyl)ethyl-substituted amino acid ester. The re-
sults obtained by using seven amino acid esters are listed
in entries 11-17. The reaction with glycine ethyl ester
gave (R)-4h in 77% yield. Although other L-amino acid
esters are good substrates, the reactions caused partial
racemization of the amino acid ester unit. For example,
the reaction with L-alanine ethyl ester at 90 °C gave N-[1-
(2-pyridinyl)ethyl]alanine ester (R)-4i containing 20% of
the other diastereomer due to the epimerization of the
chiral center in the amino acid ester unit. This minor
diastereomer was identified with the major product
yielded by the reaction of (R)-2 with L-alanine ethyl ester.
Better diastereomeric ratios were obtained at 60 °C with
longer reaction times (entries 14-17).
As shown in Table 2, cyclic secondary amines also
reacted with (R)-2 to give (aminoethyl)pyridines (S)-5a -i
in excellent yields. The reaction with (R)- and (S)-
prolinols gave (S,S)-5h and (S,R)-5i as single stereoiso-
mers in 86 and 87% yields, respectively (entries 8 and
9). However, acyclic secondary amines reacted poorly. For
example, the reaction of (R)-2 with diethylamine gave
only 35% yield even with a prolonged reaction time or at
an elevated temperature.8
a
b
Isolated yield. DMSO was used as a solvent. c i-Pr2NEt was
used as a base. CH3CN was used as a solvent at 60 °C. e CH3CN
d
was used as a solvent at 90 °C. f Dr (diastereomeric ratio) ) 4:1.
g
h
i
j
Dr ) 4.4:1. Dr ) 12:1. Dr ) 13:1. Dr ) 14:1.
2,2′-Bipyridine and 2,2′:6′,2′′-terpyridine are important
ligands in coordination chemistry as well as organome-
tallic chemistry.4d,e However, optically pure 1-(2,2′-bipy-
ridinyl)ethylamine derivatives have not been synthesized
so far. Optically pure 6-[1-(N-benzylamino)ethyl]-2,2′-
bipyridine (S)-7 was prepared in 57% yield from optically
pure 6-(1-hydroxyethyl)-2,2′-bipyridinyl methanesulfonate
(8) New optically pure (R,R)- and (R,S)-N-2-pyridinylmethyl-N,N-
bis-[1-(2-pyridinyl)ethyl]amines for luminescent lanthanide complexes
were prepared by this method, see: Yamada, T.; Shinoda, S.; Sugimoto,
H.; Uenishi, J .; Tsukube, H. Inorg. Chem.. 2003, 42, 7932-7937.
J . Org. Chem, Vol. 69, No. 20, 2004 6783

Uenishi et al.
TABLE 2. Ster eosp ecific Su bstitu tion of (R)-2 w ith
Non ch ir a l a n d Ch ir a l Non ch ir a l Secon d a r y Am in es
SCHEME 6
having two pyridine units beside the chiral secondary
ethylamine, they are expected to behave as host mol-
ecules.9
All the results suggest that the substitution reaction
proceeded via the SN2 process. That is, the product was
obtained with perfect inversion of the stereocenter.
However, it is known that SN1 and SN2 reactions compete
in the case of 1-(phenyl)ethyl halide due to the stability
of the benzylic cation.1 An electron-withdrawing group
substituted on the aromatic ring enhances the SN2
process, while an electron-donating group stabilizes the
benzylic cation to suppress it. In the case of a 2-pyridinyl
or 4-pyridinylmethyl group, the corresponding benzylic
cation was destabilized by not only the electron-with-
drawing property but also the reverse resonance effect
of the pyridine ring. Since the SN1 process is unfavorable
in these cases, the SN2 reaction occurs in the reactions
of 1-(2-pyridinyl)ethyl methanesulfonate and 1-(4-pyridi-
nyl)ethyl methanesulfonate. In fact, displacement of (R)-
1-(4-pyridinyl)ethanol (R)-1010 with piperidine took place
via its methanesulfonate (R)-11 stereospecifically to give
optically pure N-1-(4-pyridinyl)ethylpiperidine (S)-12 in
84% yield with an inversion of the stereochemistry
(Scheme 7).
Since the 1-(3-pyridinyl)ethyl cation generated from
1-(3-pyridinyl)ethyl methanesulfonate (R)-14 is stabilized
by the resonance effect of the pyridine ring, it is hydro-
lyzed quite easily on a silica gel column.11 Therefore, 1-(3-
pyridinyl)ethyl methanesulfonate (R)-14 was obtained
with difficulty in pure form12 and substituted amines
were obtained in poor yields with some loss of enantio-
meric purity. However, after the mesylation, the resulting
ammonium chloride salt was removed by filtration, and
the quickly condensed filtrate was subjected to substitu-
a
b
Isolated yield. DMSO was used as a solvent. c CH3CN was
d
used as a solvent. i-Pr2NEt was used as a base.
SCHEME 5
(R)-63b in the same manner as described for the substitu-
tion reaction of (R)-2 (Scheme 6).
More complex chiral pyridines have been prepared by
the same method. Syntheses of 6-phenyl-substituted
pyridines 9a -f are shown in Scheme 6. When mesylate
(R)-8, which was prepared from 1-[2-(6-phenylpyridinyl)]-
ethanol,3d was treated with pyrrolidine, piperidine, and
benzylamine, (S)-9a , (S)-9b, and (S)-9c were obtained in
65, 71, and 90% yields, respectively. Similarly, the
reaction of (R)-8 with (S)- and (R)-1-(phenyl)ethylamines
gave (S,S)-9d and (S,R)-9d in 48 and 61% yields, respec-
tively. No diastereoisomer was detected in the NMR
spectra of the crude products of (S,S)-9d . Triamines (S,S)-
9e and (S,R)-9e were obtained by substitution reaction
with (S)- and (R)-1-(2-pyridinyl)ethylamines in 60 and
69% yields, respectively. Since they are not separable by
chromatographic techniques, including HPLC, the ste-
reospecific synthesis of (S,S)-9e and (S,R)-9e is valuable.
Substitution with (S)-1-[2-(6-phenylpyridinyl)]ethylamine
gave an optically active C2-symmetric triamine ligand
(S,S)-9f in 37% yield. Since they are triamine ligands
(9) Complex formations with some metals are in progress in our
laboratory.
(10) Literature for the synthesis of nonracemic 1-(3- and 4-pyridi-
nyl)ethanols: (a) Ziffer, H.; Kawai, K.-i.; Kasai, M.; Imura, M.;
Froussios, C. J . Org. Chem. 1983, 48, 3017-3021. (b) Laumen, K.;
Schneider, M. P. J . Chem. Soc., Chem. Commun. 1988, 598-600.
(11) Since the hydrolyzed product (R)-1-(3-pyridinyl)ethanol was
found to be 60% ee, SN2 and SN1 processes were in competition.
(12) Aqueous workup or purification by silica gel chromatography
gave a mixture of mesylate and hydrolyzed product.
6784 J . Org. Chem., Vol. 69, No. 20, 2004

Synthesis of Chiral Nonracemic 1-(2-Pyridinyl)ethylamines
SCHEME 7
3.64 (ABq, J ) 7.9, 14.4 Hz, 2H), 3.92 (q, J ) 6.7 Hz, 1H),
7.16 (ddd, J ) 7.6, 4.9, 1.2 Hz, 1H), 7.20-7.30 (m, 5H), 7.34
(d, J ) 8.0 Hz, 1H), 7.65 (td, J ) 7.6, 1.8 Hz, 1H), 8.58 (dm, J
) 5.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 22.6, 51.5, 58.4,
121.1, 121.8, 126.7, 128.0 (2C), 128.1 (2C), 136.4, 140.0, 149.1,
164.1; LRMS (FAB) 213 (M+ + H); HRMS (FAB) calcd for
tion reaction with piperidine to give N-1-(3-pyridinyl)-
ethylpiperidine (S)-15 in 69% yield from (R)-13. As long
as these processes were handled quickly, the ee value
could be maintained over 90%. As an additional example,
the reaction with optically pure (S)-1-(phenyl)ethylamine
gave (S,S)-16 in 40% yield using this recipe. The stereo-
chemical results were confirmed by chiral HPLC and also
by the fact that the formation of a diastereomer of (S,S)-
16 was found to be less than 5% in the NMR spectrum.
These results clearly indicated that the substitution took
place mostly via the SN2 process, even with (3-pyridinyl)-
ethyl methanesulfonate.
C
14H17N2 213.1392 (M+ + H), found 213.1408.
(S)-N-Cycloh exyl-N-[1-(2-p yr id in yl)eth yl]a m in e ((S)-
4b): oil; Rf ) 0.13 (EtOAc); [R]27 -75 (c 1.0, CHCl3); 1H NMR
D
(300 MHz, CDCl3) δ 1.00-1.23 (m, 5H), 1.37 (d, J ) 6.7 Hz,
3H), 1.58-1.80 (m, 3H), 1.90-2.05 (br, 1H), 2.10-2.30 (m, 3H),
4.05 (q, J ) 6.7 Hz, 1H), 7.14 (dd, J ) 7.2, 4.8 Hz, 1H), 7.30
(d, J ) 7.7 Hz, 1H), 7.64 (td, J ) 6.7 and 1.7 Hz, 1H), 8.55 (d,
J ) 5.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 23.4, 24.9, 25.2,
26.1, 33.2, 34.3, 54.1, 55.7, 121.2, 121.7, 136.4, 149.2, 165.2;
LRMS (FAB) 205 (M+ + H); HRMS (FAB) calcd for C13H21N2
205.1705 (M+ + H), found 205.1686.
Con clu sion
In conclusion, stereospecific substitutions of 1-(pyridin-
yl)ethyl methanesulfonates with amines were achieved.
When chiral nonracemic 1-(pyridinyl)ethanol was used,
the corresponding chiral nonracemic 1-(pyridinyl)ethyl-
amine was obtained with inversion of the chiral center.
This methodology is general and useful for the prepara-
tion of not only simple 1-(2-pyridinyl)ethylamines but also
of more complex 1-(2-pyridinyl)ethylamines such as 9.
Construction of multiple chiral complexity of pyridine
containing triamine ligands will be reported in due
course.
(S)-N-P h en yl-N-[1-(2-p yr id in yl)et h yl]a m in e ((S)-4c):
needles; mp 76-77 °C (hexane); Rf ) 0.42 (20% EtOAc in
1
hexane); [R]27 +4 (c 0.9, CHCl3); H NMR (300 MHz, CDCl3)
D
δ 1.54 (d, J ) 6.6 Hz, 3H), 4.45 (br s, 1H), 4.61 (q, J ) 6.6 Hz,
1H), 6.55 (d, J ) 7.7 Hz, 2H), 6.65 (t, J ) 7.3 Hz, 1H), 7.07-
7.14 (m, 3H), 7.33 (d, J ) 7.7 Hz, 1H), 7.58 (td, J ) 7.7 and
1.8 Hz, 1H), 8.56 (dm, J ) 4.8 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 23.1, 54.7, 113.3 (2C), 117.3, 120.2, 121.9 (2C), 129.1,
136.8, 147.0, 149.2, 163.8; LRMS (EI, rel intensity %) 198 (M+,
28), 183 (base), 167 (6), 120 (41); HRMS (EI) calcd for C13H14N2
198.1157 (M+), found 198.1159.
(S)-N-Ad a m a n tyl-N-[1-(2-p yr id in yl)eth yl]a m in e ((S)-
4d ): oil; Rf ) 0.18 (EtOAc); [R]25D -34 (c 1.9, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 1.32 (d, J ) 6.8 Hz, 3H), 1.40-1.70 (m,
13H), 1.93-2.10 (m, 3H), 4.15 (q, J ) 6.8 Hz, 1H), 7.09 (ddd,
J ) 7.2, 4.3, 1.3 Hz, 1H), 7.46 (d, J ) 7.9 Hz, 1H), 7.61 (dd, J
) 7.6, 1.8 Hz, 1H), 8.49 (d, J ) 4.8 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 26.1, 29.5 (3C), 36.6 (3C), 43.6 (3C), 51.3, 51.7, 120.9,
121.3, 136.2, 148.5, 163.0; LRMS (FAB) 257 (M+ + H); HRMS
(FAB) calcd for C17H25N2 257.2018 (M+ + H), found 257.2001.
(S ,S )-N -[1-(P h e n yl)e t h yl]-N -[1-(2-p yr id in yl)e t h yl]-
Exp er im en ta l Section
Gen er a l Su bstitu tion Rea ction of (R)-2 w ith Va r iou s
P r im a r y Am in es. A mixture of (R)-2 (201 mg, 1 mmol), the
corresponding primary amine (1.5-2.5 mmol) listed in Table
1, and diisopropylethylamine (5 mmol) was heated at 60 °C
in DMSO or acetonitrile (2-5 mL). The reaction mixture was
quenched with water and extracted with EtOAc or with
CH2Cl2. If necessary, the mixture was made basic by aq
Na2CO3 and extracted. The organic extract was washed with
brine and dried over MgSO4. The crude product was purified
by silica gel column chromatography eluted with a mixture of
EtOAc and hexane or EtOAc containing 1-5% Et3N. Note for
the experiment: When the product is less polar and easily
separable from DMSO, DMSO is recommended. When the
primary amine is cheap, an excess of the amine can be used
instead of diisopropylethylamine. DMAP can be used instead
of diisopropylethylamine when the product amine is less polar
and easily separable from DMAP.
a m in e ((S,S)-4e): oil; Rf ) 0.20 (EtOAc); [R]25 -167 (c 2.0,
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.27 (d, J ) 6.6 Hz, 3H),
1.30 (d, J ) 6.7 Hz, 3H), 2.10-2.50 (br, 1H), 3.43 (q, J ) 6.6
Hz, 1H), 3.45 (q, J ) 6.7 Hz, 1H), 7.05 (d, J ) 7.7 Hz, 1H),
7.15 (dd, J ) 7.5, 4.8 Hz, 1H), 7.20-7.35 (m, 5H), 7.63 (td, J
) 7.7, 1.6 Hz, 1H), 8.60 (d, J ) 4.9 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 23.4, 25.1, 55.6, 56.1, 121.8, 121.9, 126.8 (2C), 128.3
and 128.3 (2C), 136.2, 145.6, 149.6, 164.7; LRMS (FAB) 227
(M+ + H); HRMS (FAB) calcd for C15H19N2 227.1548 (M+
H), found 227.1538.
+
N-[(R)-1-(P h en yl)et h yl]-N-[(S)-1-(2-p yr id in yl)et h yl]-
(S)-N-Ben zyl-N-[1-(2-pyr idin yl)eth yl]am in e ((S)-4a): oil;
a m in e ((S,R)-4e): oil; Rf ) 0.20 (EtOAc); [R]25 -7 (c 2.0,
D
Rf ) 0.45 (EtOAc); [R]27 -45 (c 1.2, CHCl3); 1H NMR (300
CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.37 (d, J ) 6.6 Hz, 3H),
D
MHz, CDCl3) δ 1.41 (d, J ) 6.7 Hz, 3H), 2.10-2.26 (br, 1H),
1.39 (d, J ) 6.6 Hz, 3H), 2.21 (br s, 1H), 3.80 (q, J ) 6.6 Hz,
J . Org. Chem, Vol. 69, No. 20, 2004 6785

Uenishi et al.
1H), 3.86 (q, J ) 6.6 Hz, 1H), 7.05 (dd, J ) 7.5, 4.8 Hz, 1H),
7.17 (d, J ) 7.5 Hz, 1H), 7.18-7.30 (m, 5H), 7.56 (td, J ) 7.7,
1.6 Hz, 1H), 8.54 (dm, J ) 5.0 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 21.8, 23.5, 55.0, 56.0, 121.1, 121.6, 126.6 (2C), 126.7,
128.2 (2C), 136.2, 145.5, 149.1, 164.4; LRMS (FAB) 227 (M+
+ H); HRMS (FAB) calcd for C15H19N2 227.1548 (M+ + H),
found 227.1545.
Hz, 3H), 2.06 (br s, 1H), 3.13 (q, J ) 7.0 Hz, 1H), 3.85 (q, J )
6.7 Hz, 1H), 4.16 (q, J ) 7.0 Hz, 1H), 4.17 (q, J ) 7.0 Hz, 1H),
7.15 (ddd, J ) 7.7, 4.9, 1.2 Hz, 1H), 7.40 (d, J ) 7.7 Hz, 1H),
7.66 (td, J ) 7.7, 1.8 Hz, 1H), 8.54 (d, J ) 4.9 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 14.0, 18.7, 22.1, 54.0, 56.7, 60.5,
120.8, 121.9, 136.4, 149.1, 163.7, 175.1, minor D-isomer δ 14.1,
19.6, 23.8, 54.6, 58.1, 60.5, 120.7, 121.9, 136.5, 149.1, 164.2,
175.9; IR (neat) 1735, 3325 cm-1; LRMS (FAB) 223 (M+ + H);
HRMS (FAB) calcd for C12H19N2O2 223.1446 (M+ + H), found
223.1464.
(S,S)-N,N-Bis[1-(2-p yr id in yl)eth yl]a m in e ((S,S)-4f): oil;
1
Rf ) 0.30 (5% Et3N in EtOAc); [R]24 -178 (c 2.0, MeOH); H
D
NMR (300 MHz, CDCl3) δ 1.32 (d, J ) 6.7 Hz, 6H), 2.20-2.30
(br, 1H), 3.61 (q, J ) 6.7 Hz, 2H), 7.13 (ddd, J ) 7.4, 5.4, 1.1
Hz, 2H), 7.28 (d, J ) 8.2 Hz, 2H), 7.64 (td, J ) 7.7, 1.8 Hz,
2H), 8.55 (d, J ) 4.9 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ
23.4 (2C), 56.9 (2C), 121.2 (2C), 121.8 (2C), 136.4 (2C), 149.2
(2C), 164.5 (2C); LRMS (FAB) 228 (M+ + H); HRMS (FAB)
calcd for C14H18N3 228.1501 (M+ + H), found 228.1518.
(R)-N-[1-(2-P yr id in yl)eth yl]-L-p h en yla la n in e Eth yl Es-
ter ((R)-4j): dr 81.5% (4.4:1); yellow oil; Rf ) 0.47 (60% EtOAc
in hexane); [R]26 -37 (c 3.8, MeOH); 1H NMR (300 MHz,
D
CDCl3) δ 1.05 (t, J ) 7.1 Hz, 3H), 1.36 (d, J ) 6.6 Hz, 3H),
2.10 (br s, 1H), 2.94 (dd, J ) 13.0, 7.4 Hz, 1H), 3.03 (dd, J )
13, 6.3 Hz, 1H), 3.56 (dd, J ) 7.4, 6.3 Hz, 1H), 3.90 (q, J ) 6.6
Hz, 1H), 3.91 (dq, J ) 7.1, 1.3 Hz, 2H), 6.19 (td, J ) 7.7, 1.7
Hz, 1H), 7.11-7.30 (m, 7H), 8.53 (d, J ) 5.0 Hz, 1H), minor
D-isomer δ 1.17 (t, J ) 7.10 Hz, 3H), 1.33 (d, J ) 6.7 Hz, 3H),
2.05 (br s, 1H), 2.88 (dd, J ) 13.3, 8.1 Hz, 1H), 2.93 (dd, J )
13.3, 6.0 Hz, 1H), 3.81 (q, J ) 6.7 Hz, 1H), 4.12 (q, J ) 7.1 Hz,
2H), 7.02-7.29 (m, 7H), 7.48 (td, J ) 7.7, 1.8 Hz, 1H), 8.45 (d,
J ) 5.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 13.9, 21.9, 39.5,
57.5, 60.3, 60.8, 120.9, 121.9, 126.4, 128.2 (2C), 129.2 (2C),
136.4, 137.3, 148.9, 163.8, 174.1, minor D-isomer δ 13.9, 23.5,
39.9, 58.1, 60.4, 60.8, 1203, 121.6, 128.0 (2C), 129.2 (2C), 136.3,
137.3, 148.8, 164.1, 174.6; IR (neat) 1730, 3320 cm-1; LRMS
(FAB) 299 (M+ + H); HRMS (FAB) calcd for C18H23N2O2
299.1759 (M+ + H), found 299.1776.
m eso-N,N-Bis[1-(2-p yr id in yl)eth yl]a m in e (m eso-4f): oil;
Rf ) 0.30 (5% Et3N in EtOAc); [R]25 (0 (c 2.0, MeOH); 1H
D
NMR (300 MHz, CDCl3) δ 1.38 (d, J ) 6.7 Hz, 6H), 2.65-2.75
(br, 1H), 3.87 (q, J ) 6.7 Hz, 2H), 7.05 (ddd, J ) 7.7, 5.1, 1.2
Hz, 2H), 7.19 (d, J ) 7.7 Hz, 2H), 7.51 (td, J ) 7.7, 1.8 Hz,
2H), 8.46 (dm, J ) 5.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ
22.1 (2C), 56.4 (2C), 120.9 (2C), 121.6 (2C), 138.6 (2C), 148.8
(2C), 164.3 (2C); LRMS (FAB) 228 (M+ + H); HRMS (FAB)
calcd for C14H18N3 228.1501 (M+ + H), found 228.1486.
N-[(S)-1-(2-P yr id in yl)eth yl]-N-[(S)-tetr a h yd r ofu r fu r yl]-
a m in e ((S,S)-4g): oil; Rf ) 0.59 (10% Et3N in EtOAc); [R]27
D
-12 (c 2.5, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.39 (d, J )
6.6 Hz, 3H), 1.49 (m, 1H), 1.81-1.99 (m, 3H), 2.47 (dd, J )
11.7 and 4.0 Hz, 1H), 2.59 (dd, J ) 11.7 and 7.9 Hz, 1H), 3.74
(dt, J ) 8.6, 6.8 Hz, 1H), 3.84 (dt, J ) 8.2, 6.6 Hz, 1H), 3.89
(ABq, J ) 11.6, 6.6 Hz, 1H), 3.95 (qd, J ) 7.0, 4.0 Hz, 1H),
7.14 (ddd, J ) 7.7, 4.8, 1.2 Hz, 1H), 7.38 (d, J ) 7.9 Hz, 1H),
7.65 (td, J ) 7.7, 1.8 Hz, 1H), 8.57 (dm, J ) 4.0 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 22.9, 25.6, 29.3, 52.5, 59.8, 67.8, 78.7,
120.8, 121.7, 136.4, 149.0, 164.8; LRMS (EI, rel intensity %)
206 (M+, 2), 135 (base), 107 (93); HRMS (EI) calcd for
(R)-N-[1-(2-P yr id in yl)eth yl]-L-m eth ion in e Eth yl Ester
((R)-4k ): dr 92.3% (12:1); yellow oil; Rf ) 0.38 (60% EtOAc in
hexane); [R]27 -10.5 (c 1.8, MeOH); 1H NMR (300 MHz,
D
CDCl3) δ 1.20 (t, J ) 7.1 Hz, 3H), 1.40 (d, J ) 6.7 Hz, 3H),
1.86-1.97 (m, 2H), 2.00-2.30 (br, 1H), 2.10 (s, 3H), 2.58-2.64
(m, 2H), 3.44 (t, J ) 5.7 Hz, 1H), 3.88 (q, J ) 6.7 Hz, 1H),
4.04 (qd, J ) 7.1, 1.6 Hz, 2H), 7.15 (dd, J ) 7.1, 4.9 Hz, 1H),
7.29 (d, J ) 7.7 Hz, 1H), 7.64 (td, J ) 7.7, 1.7 Hz, 1H), 8.55 (d,
J ) 4.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 14.1, 15.3, 21.9,
30.3, 32.6, 57.5, 58.0, 60.7, 120.9, 121.9, 136.4, 149.1, 163.8,
174.7; IR (neat) 1730, 3320 cm-1; LRMS (FAB) 283 (M+ + H);
HRMS (FAB) calcd for C14H23N2O2S 283.1480 (M+ + H), found
283.1468.
C
12H18N2O 206.1419 (M+), found 206.1416.
N-[(S)-1-(2-P yr id in yl)eth yl]-N-[(R)-tetr a h yd r ofu r fu r yl]-
a m in e ((S,R)-4g): oil; Rf ) 0.59 (10% Et3N in EtOAc); [R]24
D
-34 (c 1.8, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.39 (d, J )
6.6 Hz, 3H), 1.53 (m, 1H), 1.80-1.96 (m, 3H), 2.19 (br s, 1H),
2.46 (dd, J ) 12.1, 7.7 Hz, 1H), 2.62 (dd, J ) 12.1, 4.0 Hz,
1H), 3.73 (dt, J ) 8.4, 6.6 Hz, 1H), 3.81 (dt, J ) 8.1, 6.6 Hz,
1H), 3.90 (q, J ) 6.6 Hz, 1H), 4.01 (ABq d, J AB ) 12.2 Hz, J A
) 7.3, 3.7 Hz, J B ) 7.0, 3.7 Hz, 1H), 7.13 (ddd, J ) 7.3, 4.8,
1.1 Hz, 1H), 7.34 (d, J ) 7.7 Hz, 1H), 7.64 (td, J ) 7.7 and 1.8
Hz, 1H), 8.55 (dm, J ) 4.8 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 22.9, 25.7, 29.1, 52.0, 59.4, 67.8, 78.3, 120.7, 121.8, 136.5,
149.2, 164.8; LRMS (EI, rel intensity %) 206 (M+, 2), 135
(base), 107 (56); HRMS (EI) calcd for C12H18N2O 206.1419 (M+),
found 206.1408.
(R)-N-[1-(2-P yr id in yl)eth yl]-L-leu cin e Eth yl Ester ((R)-
4l): dr 92.9% (13:1); yellow oil; Rf ) 0.46 (50% EtOAc in
hexane); [R]27D -13 (c 1.1, MeOH); 1H NMR (300 MHz, CDCl3)
δ 0.90 (d, J ) 6.6 Hz, 3H), 0.91 (d, J ) 6.5 Hz, 3H), 1.39 (d, J
) 6.6 Hz, 3H), 1.51 (dd, J ) 7.1, 7.0 Hz, 2H), 1.72 (ddq, J )
13.0, 6.6, 6.5 Hz, 1H), 1.90-2.30 (br, 1H), 3.40 (dd, J ) 7.2,
7.1 Hz, 1H), 3.55 (s, 3H), 3.87 (q, J ) 6.6 Hz, 1H), 7.14 (dd, J
) 7.1, 4.9 Hz, 1H), 7.45 (d, J ) 7.7 Hz, 1H), 7.68 (td, J ) 7.7,
1.7 Hz, 1H), 8.53 (d, J ) 4.9 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 21.7, 22.4, 22.5, 24.7, 42.8, 51.4, 57.7, 57.8, 120.9,
121.9, 136.4, 149.0, 163.9, 176.0; IR (neat) 1738, 3320 cm-1
;
(R)-N-[1-(2-P yr id in yl)eth yl]glycin e Eth yl Ester ((R)-
LRMS (FAB) 251 (M+ + H); HRMS (FAB) calcd for C14H23N2O2
4h ): yellow oil; Rf ) 0.23 (EtOAc); [R]26 -59 (c 1.8, MeOH);
D
251.1759 (M+ + H), found 251.1751.
1H NMR (300 MHz, CDCl3) δ 1.25 (t, J ) 7.1 Hz, 3H), 1.43 (d,
J ) 6.6 Hz, 3H), 2.05 (br s, 1H,), 3.30 (ABq, J ) 17 Hz, 2H),
3.91 (q, J ) 6,6 Hz, 1H), 4.16 (q, J ) 7.1 Hz, 2H), 7.16 (dd, J
) 7.7, 4.8 Hz, 1H), 7.35 (d, J ) 7.7 Hz, 1H), 7.66 (td, J ) 7.7,
1.7 Hz, 1H), 8.55 (d, J ) 4.8 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 13.9, 22.5, 48.7, 58.7, 60.5, 120.8, 121.9, 136.4, 149.0,
163.4, 172.0; IR (neat) 1740 cm-1, 3325 cm-1; LRMS (FAB)
209 (M+ + H); HRMS (FAB) calcd for C11H17N2O2 209.1290
(M+ + H), found 209.1293.
(R)-N-[1-(2-P yr id in yl)et h yl]-L-t yr osin e Met h yl E st er
((R)-4m ): dr 92.3% (12:1); yellow oil; Rf ) 0.3 (80% EtOAc in
hexane); [R]24D -36 (c 3.2, CHCl3); 1H NMR (300 MHz, CDCl3)
δ 1.34 (d, J ) 6.6 Hz, 3H), 2.90 (d, J ) 6.7 Hz, 2H), 3.46 (s,
3H), 3.52 (t, J ) 6.7 Hz, 1H), 3.95 (q, J ) 6.6 Hz, 1H), 6.71 (d,
J ) 8.4 Hz, 2H), 6.94 (d, J ) 8.4 Hz, 2H), 7.18 (dd, J ) 7.3,
4.9 Hz, 1H), 7.47 (d, J ) 7.7 Hz, 1H), 7.67 (td, J ) 7.7, 1.7 Hz,
1H), 8.50 (d, J ) 4.9 Hz, 1H). Two protons for NH and OH
were not observed. 13C NMR (75 MHz, CDCl3) δ 22.0, 38.4,
51.5, 57.5, 61.0, 115.5 (2C), 121.4, 122.4, 127.8, 130.1 (2C),
(R)-[N-1-(2-P yr id in yl)eth yl]-L-a la n in e Eth yl Ester ((R)-
4i): dr (diastereomeric ratio) 80% (4:1); yellow oil; Rf ) 0.27
(EtOAc); [R]26D +4.5 (c 2.8, MeOH); 1H NMR (300 MHz, CDCl3)
δ 1.21 (t, J ) 7.1 Hz, 3H), 1.33 (d, J ) 6.9 Hz, 3H), 1.41 (d, J
) 6.7 Hz, 3H), 2.00-2.30 (br, 1H), 3.36 (q, J ) 6,9 Hz, 1H),
3.94 (q, J ) 6.7 Hz, 1H,), 4.07 (q, J ) 7.1 Hz, 2H), 7.16 (dd, J
) 7.7, 4.9 Hz, 1H), 7.31 (d, J ) 7.7 Hz, 1H), 7.65 (td, J ) 7.7,
1.8 Hz, 1H), 8.56 (d, J ) 4.9 Hz, 1H), minor D-isomer δ 1.26
(d, J ) 7.0 Hz, 3H), 1.27 (t, J ) 7.0 Hz, 3H), 1.38 (d, J ) 6.7
137.2, 148.4, 155.6, 163.6, 174.7; IR (neat) 1735, 3320 cm-1
;
LRMS (FAB) 301 (M+ + H); HRMS (FAB) calcd for C17H21N2O3
301.1552 (M+ + H), found 301.1566.
(R)-N-[1-(2-P yr id in yl)eth yl]-l-tr yp top h a n Meth yl Ester
((R)-4n ): dr 93.3% (14:1); yellow oil; Rf ) 0.30 (80% EtOAc in
hexane); [R]25D -39 (c 2.9, MeOH); 1H NMR (300 MHz, CDCl3)
δ 1.35 (d, J ) 6.7 Hz, 3H), 2.30-2.50 (br s, 1H), 3.18 (d, J )
6786 J . Org. Chem., Vol. 69, No. 20, 2004

Synthesis of Chiral Nonracemic 1-(2-Pyridinyl)ethylamines
6.6 Hz, 2H), 3.45 (s, 3H), 3.68 (t, J ) 6.6 Hz, 1H), 3.94 (q, J )
6.7 Hz, 1H), 7.05-7.20 (m, 4H), 7.28 (d, J ) 8.1 Hz, 1H), 7.34
(d, J ) 7.7 Hz, 1H), 7.57 (d, J ) 8.1 Hz, 1H), 7.61 (td, J ) 7.7,
1.8 Hz, 1H,), 8.11 (br, 1H), 8.52 (d, J ) 4.9 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 21.9, 28.9, 51.5, 57.6, 59.9, 110.7, 111.1,
118.5, 119.1, 121.1, 121.7, 120.0, 122.9, 127.4, 136.1, 136.5,
148.9, 163.7, 175.0; IR (neat) 1730, 3400 cm-1; LRMS (FAB)
324 (M+ + H); HRMS (FAB) calcd for C19H22N3O2 324.1730
(M+ + H), found 324.1695.
Rea ction s w ith Secon d a r y Am in e. The reaction was
carried out under conditions similar to those described for the
synthesis of (S)-4 except that 4-6 equiv of amine should be
used in the absence of diisopropylethylamine.
LRMS (FAB) 239 (M+ + H); HRMS (FAB) calcd for C16H19N2
239.1542 (M+ + H), found 239.1558.
(S)-N-[1-(2-P yr id in yl)eth yl]-1,2,3,4-tetr a h yd r oisoqu in -
olin e ((S)-5g): oil; Rf ) 0.42 (70% EtOAc in hexane); [R]25
D
1
-4 (c 2.0, CHCl3); H NMR (300 MHz, CDCl3) δ 1.48 (d, J )
6.7 Hz, 3H), 2.66-2.87 (m, 4H), 3.60 (d, J ) 14.8 Hz, 1H), 3.76
(q, J ) 6.7 Hz, 1H), 3.85 (d, J ) 14.8 Hz, 1H), 6.96-7.10 (m,
4H), 7.14 (ddd, J ) 7.4, 4.9, 1.3 Hz, 1H), 7.45 (dd, J ) 7.8, 1.1
Hz, 1H), 7.62 (td, J ) 7.7, 1.8 Hz, 1H), 8.54 (ddd, J ) 5.5, 1.6,
0.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 18.3, 29.3, 47.9, 53.3,
65.8, 121.7, 121.9, 125.4, 125.9, 126.6, 128.5, 134.4, 135.0,
136.4, 148.8, 163.6; LRMS (FAB) 239 (M+ + H); HRMS (FAB)
calcd for C16H19N2 239.1542 (M+ + H), found 239.1559.
(S)-2-(Hyd r oxym eth yl)-N-[(S)-1-(2-p yr id in yl)eth yl]p yr -
(S)-N-[1-(2-P yr id in yl)eth yl]p yr r olid in e ((S)-5a ): oil; Rf
) 0.47 (5% Et3N in EtOAc); [R]25D -62 (c 2.0, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 1.43 (d, J ) 6.6 Hz, 3H), 1.73-1.83 (m,
4H), 2.35-2.48 (m, 2H), 2.57-2.68 (m, 2H), 3.40 (q, J ) 6.6
Hz, 1H), 7.14 (ddd, J ) 7.2, 4.9, 1.2 Hz, 1H), 7.39 (d, J ) 7.8
Hz, 1H), 7.64 (td, J ) 7.7, 1.8 Hz, 1H), 8.53 (dm, J ) 5.1 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 21.7, 23.4 (2C), 52.6 (2C),
67.2, 121.5, 121.9, 136.5, 148.9, 164.4; LRMS (FAB) 177 (M+
+ H); HRMS (FAB) calcd for C11H17N2 177.1392 (M+ + H),
found 177.1381.
r olid in e ((S,S)-5h ): oil; Rf ) 0.20 (EtOAc); [R]25 -17 (c 1.9,
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.49 (d, J ) 6.8 Hz, 3H),
1.60-1.83 (m, 4H), 2.50 (m, 1H), 2.92-3.05 (m, 2H), 3.46 (dd,
J ) 10.0, 4.0 Hz, 1H), 3.62 (dd, J ) 10.0, 4.0 Hz, 1H), 3.95-
4.05 (br, 1H), 4.10 (q, J ) 6.8 Hz, 1H), 7.16 (ddd, J ) 7.6, 5.1,
1.1 Hz, 1H), 7.30 (d, J ) 7.7 Hz, 1H), 7.66 (t, J ) 7.7 Hz, 1H),
8.55 (dm, J ) 5.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 19.8,
23.4, 28.7, 50.4, 60.4, 61.5, 64.2, 121.9, 122.0, 136.2, 148.6,
162.0; LRMS (FAB) 207 (M+ + H); HRMS (FAB) calcd for
C
12H19N2O 207.1497 (M+ + H), found 207.1481.
(S)-N-[1-(2-P yr id in yl)eth yl]p ip er id in e ((S)-5b): oil; Rf )
(R)-2-(Hyd r oxym eth yl)-N-[(S)-1-(2-pyr idin yl)eth yl]p yr -
1
0.41 (5% Et3N in EtOAc); [R]25 -34 (c 2.1, CHCl3); H NMR
D
r olid in e ((S,R)-5h ): oil; Rf ) 0.20 (EtOAc); [R]25 -20 (c 2.0,
D
(300 MHz, CDCl3) δ 1.38 (d, J ) 6.7 Hz, 3H), 1.35-1.42 (m,
2H), 1.52-1.61 (m, 4H), 2.30-2.39 (m, 2H), 2.42-2.54 (m, 2H),
3.55 (q, J ) 6.7 Hz, 1H), 7.10 (ddd, J ) 6.7 4.9 1.2 Hz, 1H),
7.40 (dd, J ) 7.3, 1.1 Hz, 1H), 7.62 (td, J ) 7.7, 1.8 Hz, 1H),
8.54 (d, J ) 5.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 17.9,
24.5, 26.1 (2C), 51.4 (2C), 66.1, 121.6, 121.8, 136.0, 148.7, 163.7;
LRMS (FAB) 191 (M+ + H); HRMS (FAB) calcd for C12H19N2
191.1548 (M+ + H), found 191.1522.
CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.45 (d, J ) 6.8 Hz, 3H),
1.68-1.95 (m, 4H), 2.65 (m, 1H), 2.90-3.00 (m, 2H), 3.16 (dd,
J ) 10.0, 4.2 Hz, 1H), 3.20 (dd, 10.0, 4.2 Hz, 1H), 3.40-3.52
(br, 1H), 3.95 (q, J ) 6.8 Hz, 1H), 7.16 (ddd, J ) 6.8, 5.4, 1.1
Hz, 1H), 7.34 (d, J ) 7.7 Hz, 1H), 7.65 (t, J ) 7.7 Hz, 1H),
8.54 (dm, J ) 5.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 16.6,
24.0, 28.7, 48.7, 61.9, 62.4, 63.5, 121.7, 122.0, 136.4, 148.8,
163.7; LRMS (FAB) 207 (M+ + H); HRMS (FAB) calcd for
(S)-N-[1-(2-P yr id in yl)eth yl]m or p h olin e ((S)-5c): oil; Rf
) 0.30 (EtOAc); [R]25D -54 (c 2.0, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 1.42 (d, J ) 6.8 Hz, 3H), 2.40-2.45 (m, 2H), 2.60-
2.65 (m, 2H), 3.51 (q, J ) 6.8 Hz, 1H), 3.73 (t, J ) 4.8 Hz,
4H), 7.15 (ddd, J ) 7.7, 4.8, 1.8 Hz, 1H), 7.38 (d, J ) 7.7 Hz,
1H), 7.65 (td, J ) 7.7, 1.8 Hz, 1H), 8.55 (d, J ) 4.8 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 18.1, 51.0 (2C), 66.7, 66.9 (2C),
C
12H19N2O 207.1497 (M+ + H), found 207.1509.
(S)-N-Ben zyl-N-{1-[6-(2,2′bipyr idin yl)]eth yl}am in e ((S)-
7): oil; Rf ) 0.44 (5% Et3N in EtOAc); [R]22D -71 (c 1.1, CHCl3);
1H NMR (300 MHz, CDCl3) δ 1.46 (d, J ) 6.6 Hz, 3H), 2.09
(br, 1H), 3.69 (s, 2H), 3.99 (q, J ) 6.6 Hz, 1H), 7.20-7.38 (m,
7H), 7.79 (t, J ) 7.7 Hz, 1H), 7.81 (td, J ) 7.1, 1.8 Hz, 1H),
8.28 (d, J ) 7.7 Hz, 1H), 8.48 (d, J ) 7.9 Hz, 1H), 8.68 (dm, J
) 4.8 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 23.1, 51.8, 58.6,
119.1, 121.2, 121.4, 123.6, 126.8, 128.2 (2C), 128.3 (2C), 136.8,
137.3, 140.6 149.1, 155.5, 156.4, 163.8; LRMS (FAB) 290 (M+
+ H); HRMS (FAB) calcd for C19H20N3 290.1657 (M+ + H),
found 290.1654.
122.0 and 122.0, 136.4, 149.0, 162.3; LRMS (FAB) 193 (M+
+
H); HRMS (FAB) calcd for C11H17N2O 193.1341 (M+ + H),
found 193.1371.
(S)-N-[1-(2-P yr idin yl)eth yl]th iom or ph olin e ((S)-5d): oil;
Rf ) 0.20 (EtOAc); [R]25 -18 (c 2.0, CHCl3); 1H NMR (300
D
MHz, CDCl3) δ 1.40 (d, J ) 6.8 Hz, 3H), 2.64-2.70 (m, 4H),
2.71-2.82 (m, 4H), 3.71 (q, J ) 6.8 Hz, 1H), 7.14 (ddd, J )
7.3, 4.9, 1.2 Hz, 1H), 7.38 (d, J ) 7.7 Hz, 1H), 7.63 (td, J )
7.7, 1.8 Hz, 1H), 8.55 (d, J ) 3.8 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 16.2, 28.2 (2C), 52.0 (2C), 66.1, 121.8, 122.1, 136.1,
148.9, 162.5; LRMS (FAB) 209 (M+ + H); HRMS (FAB) calcd
for C11H17N2S 209.1112 (M+ + H), found 209.1128.
P r ep a r a tion of (R)-[2-(6-P h en ylp yr id in yl)]eth yl Meth -
a n esu lfon a te ((R)-8): To a mixture of (R)-[2-(6-phenylpyridin-
yl)]ethanol (199 mg, 1 mmol), Et3N (506 mg, 5 mmol), and
DMAP (24 mg, 0.2 mmol) in CH2Cl2 (5 mL) was added
methanesulfonyl chloride (229 mg, 2 mmol) dropwise at 0 °C.
After the mixture was stirred for 30 min at the same temper-
ature, water was added and the mixture was extracted with
EtOAc. The extract was washed with brine and dried over
MgSO4. Solvent was removed, and the residual oil was
chromatographed on silica gel eluted with 15% EtOAc in
hexane to give mesylate (R)-8 (247 mg) in 89% yield: oil; Rf )
(S)-N-Meth yl-N′-[1-(2-p yr id in yl)eth yl]p ip er a d in e ((S)-
5e): oil; Rf ) 0.50 (50% MeOH in EtOAc); [R]25 -39 (c 2.0,
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.40 (d, J ) 6.9 Hz, 3H),
2.21 (s, 3H), 2.30-2.50 (m, 8H), 3.54 (q, J ) 6.7 Hz, 1H), 7.14
(ddd, J ) 7.6, 5.0, 1.8 Hz, 1H), 7.36 (d, J ) 7.8 Hz, 1H), 7.61
(td, J ) 7.6, 1.6 Hz, 1H), 8.54 (dm, J ) 5.1 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 18.3 45.9 (2C), 50.3, 55.2 (2C), 66.2, 121.8,
121.9, 136.2, 148.9, 163.2; LRMS (FAB) 206 (M+ + H); HRMS
(FAB) calcd for C12H20N3 206.1657 (M+ + H), found 206.1681.
0.20 (EtOAc); [R]25 +52.0 (c 2.0, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 1.47 (d, J ) 6.7 Hz, 3H), 1.74-1.81 (m, 4H), 2.42-
2.52 (m, 2H), 2.61-2.70 (m, 2H), 3.55 (q, J ) 6.7 Hz, 1H), 7.35-
7.48 (m, 4H), 7.40-7.51 (m, 4H), 7.72 (d, J ) 7.7 Hz, 1H), 7.81
(t, J ) 7.7 Hz, 1H), 8.01-8.05 (m, 2H);
13C NMR (75 MHz,
CDCl3) δ 21.7, 38.8, 81.1, 118.9, 120.0, 126.9 (2C), 128.8 (2C),
129.3, 137.9, 138.6, 156.9, 158.0; LRMS (EI) 277 (M+); HRMS
(EI) calcd for C14H15NO3 277.0772 (M+), found 277.0773.
(S)-N-[1-(2-P yr id in yl)et h yl]-1,2,3,4-t et r a h yd r oq u in o-
lin e ((S)-5f): oil; Rf ) 0.40 (20% EtOAc in hexane); [R]25D -71
1
(c 2.0, CHCl3); H NMR (300 MHz, CDCl3) δ 1.66 (d, J ) 6.8
Hz, 3H), 1.80-2.00 (m, 2H), 2.76-2.81 (m, 2H), 3.10-3.20 (m,
1H), 3.30-3.40 (m, 1H), 5.09 (q, J ) 6.8 Hz, 1H), 6.56 (t, J )
7.5 Hz, 1H), 6.58 (t, J ) 7.6 Hz, 1H), 7.00 (d, J ) 7.4 Hz, 2H),
7.14 (dd, J ) 7.5, 4.8 Hz, 1H), 7.28 (d, J ) 7.7 Hz, 1H), 7.59
(td, J ) 7.7, 1.7 Hz, 1H), 8.60 (dm, J ) 4.9 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 16.1, 22.4, 28.4, 43.2, 57.5, 110.9, 115.7,
121.2, 121.7, 122.9, 127.1, 129.2, 136.5, 145.3, 149.2, 162.5;
(S)-N-{1-[2-(6-P h en ylp yr id in yl)]eth yl}p yr r olid in e ((S)-
9a ): oil; Rf ) 0.20 (EtOAc); [R]25D +52.0 (c 2.0, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 1.47 (d, J ) 6.7 Hz, 3H), 1.74-1.81 (m,
4H), 2.42-2.52 (m, 2H), 2.61-2.70 (m, 2H), 3.55 (q, J ) 6.7
Hz, 1H), 7.35-7.48 (m, 4H), 7.56 (dd, J ) 7.2, 1.1 Hz, 1H),
7.70 (t, J ) 7.7 Hz, 1H), 8.01 (dm, J ) 6.9 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 21.7, 23.3 (2C), 52.4 (2C), 67.2, 118.6, 119.6,
J . Org. Chem, Vol. 69, No. 20, 2004 6787

Uenishi et al.
126.9 (2C), 128.5 (2C), 137.0, 139.6, 156.2, 164.5; LRMS (FAB)
253 (M+ + H); HRMS (FAB) calcd for C17H20N2 253.1705 (M+
+ H), found 253.1730.
(c 1.4, CHCl3); Rf ) 0.4 (80% EtOAc in hexane); 1H NMR (300
MHz, CDCl3) δ 1.42 (d, J ) 6.8 Hz, 6H), 2.35-2.60 (br, 1H),
3.80 (q, J ) 6.7 Hz, 2H), 7.29 (d, J ) 7.7 Hz, 2H), 7.35-7.50
(m, 6H), 7.58 (dd, J ) 7.7 and 1.1 Hz, 2H), 7.71 (t, J ) 7.7 Hz,
2H), 8.00 (dm, J ) 8.4 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ
23.9 (2C), 57.2 (2C), 118.5 (2C), 119.7 (2C), 126.9 (4C), 128.6
(4C), 128.7 (2C), 137.0 (2C), 139.7 (2C), 156.6 (2C), 164.7 (2C);
LRMS (FAB) 380 (M+ + H); HRMS (FAB) calcd for C26H26N3
380.2212 (M+ + H), found 380.2104.
(S)-N-{1-[2-(6-P h en ylp yr id in yl)]eth yl}m or p h olin e ((S)-
9b): oil; Rf ) 0.32 (EtOAc); [R]25D +48.3 (c 1.8, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 1.42 (d, J ) 6.8 Hz, 3H), 2.40-2.52 (m,
2H), 2.55-2.66 (m, 2H), 3.70 (q, J ) 6.8 Hz, 1H), 3.73 (t, J )
4.7 Hz), 7.33-7.48 (m, 4H), 7.55 (dd, J ) 7.7, 1.1 Hz, 1H), 7.63
(t, J ) 7.7 Hz, 1H), 8.01 (dm, J ) 7.8 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 18.0, 50.8 (2C), 66.5, 67.2 (2C), 118.5, 120.0,
126.8 (2C), 128.5 (2C), 128.6, 136.9, 139.5, 156.3, 162.8; LRMS
(FAB) 269 (M+ + H); HRMS (FAB) calcd for C18H22N2 269.1654
(M+ + H), found 269.1653.
(R)-1-(4-P yr id in yl)eth yl Meth a n esu lfon a te ((R)-11). To
an ice-cooled solution of 1-(4-pyridinyl)ethanol10 (1.7 g, 13.8
mmol) and triethylamine (6.98 g, 69 mmol) in CH2Cl2 (100 mL)
was added MsCl (4.74 g, 41 mmol) dropwise. After the mixture
was stirred for 20 min at the same temperature, the mixture
was quenched with aq NaHCO3 and extracted with CH2Cl2.
The extract was washed with water and brine and dried over
MgSO4. The crude product was purified by silica gel column
chromatography eluted with 60% EtOAc in hexane to give (R)-
(S )-N -B e n zy l-N -{1-[2-(6-p h e n y lp y r id in y l)]e t h y l}-
a m in e ((S)-9c): oil; Rf ) 0.30 (EtOAc); [R]25 -70 (c 1.7,
D
CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.46 (d, J ) 6.7 Hz, 3H),
2.05-2.45 (br, 1H), 3.70 (dd, J ) 5.7, 3.0 Hz, 2H), 3.98 (q, J )
6.7 Hz, 1H), 7.30-7.52 (m, 10H), 7.62 (dd, J ) 7.2, 1.1 Hz,
1H), 7.72 (t, J ) 7.7 Hz, 1H), 8.04 (dm, J ) 6.9 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 23.0, 51.8, 58.6, 118.5, 119.7, 126.8,
126.9, 128.2 (2C), 128.3 (2C), 128.6 (2C), 128.8 (2C), 137.1,
139.5, 140.5, 156.7, 164.2; LRMS (FAB) 289 (M+ + H); HRMS
(FAB) calcd for C20H21N2 289.1747 (M+ + H), found 289.1713.
(S,S)-N-1-(P h en yl)et h yl-N-{1-[2-(6-p h en ylp yr id in yl)]-
11 (2.16 g) in 78% yield: oil; Rf ) 0.38 (EtOAc); [R]22 -2 (c
D
0.9, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.71 (d, J ) 6.6 Hz,
3H), 2.93 (s, 3H), 5.71 (q, J ) 6.6 Hz, 1H), 7.31 (d, J ) 5.7 Hz,
2H), 8.65 (d, J ) 5.7 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ
23.2, 38.9, 78.0, 120.5 (2C), 150.4 (2C); IR (neat) 1359, 1192
cm-1; LRMS (EI, rel intensity %) 201 (M+, 24), 122 (57), 106
(base); HRMS (EI) calcd for C8H11N3 201.0459 (M+), found
201.0455.
eth yl}a m in e ((S,S)-9d ): oil; Rf ) 0.30 (40% EtOAc in hexane);
1
[R]25 -181 (c 0.7, CHCl3); H NMR (300 MHz, CDCl3) δ 1.31
D
(d, J ) 6.6 Hz, 3H), 1.35 (d, J ) 6.8 Hz, 3H), 3.54 (q, J ) 6.6
Hz, 1H), 3.65 (q, J ) 6.8 Hz, 3H), 7.01 (d, J ) 7.2 Hz, 1H),
7.23-7.38 (m, 5H), 7.42-7.54 (m, 3H), 7.61 (d, J ) 7.7 Hz,
1H), 7.69 (t, J ) 7.7 Hz, 1H), 8.06 (dm, J ) 7.0 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 23.6, 25.3, 55.6, 56.2, 118.3, 120.2,
126.7, 126.8 and 126.8, 126.9, 128.3 and 128.3, 128.6 and 128.6,
128.8 and 128.8, 136.8, 139.5, 145.7, 156.7, 164.2; LRMS (FAB)
303 (M+ + H); HRMS (FAB) calcd for C21H23N2 303.1861 (M+
+ H), found 303.1855.
(S)-N-[1-(4-P yr id in yl)eth yl]p ip er id in e ((S)-12). A mix-
ture of (R)-11 (40 mg, 0.2 mmol) and piperidine (2 mmol) in
acetonitrile (1 mL) was heated at 60 °C for 2.5 h. Aqueous
NaHCO3 and EtOAc were added to the mixture. The organic
layer was washed with water and brine and dried over MgSO4.
The crude product was purified by silica gel column chroma-
tography eluted with EtOAc and EtOAc containing 10% Et3N
to give (S)-12 (32 mg) in 84% yield: oil; Rf ) 0.43 (EtOAc);
1
[R]27 -16 (c 0.4, CHCl3); H NMR (300 MHz, CDCl3) δ 1.33
D
N-[(R)-1-(P h en yl)eth yl]-N-{(S)-1-[2-(6-ph en ylpyr idin yl)]-
(d, J ) 6.8 Hz, 3H), 1.40 (quint, J ) 5.3 Hz, 2H), 1.56 (quint,
J ) 5.3 Hz, 4H), 2.27-2.43 (m, 4H), 3.41 (q, J ) 6.8 Hz, 1H),
7.25 (d, J ) 5.7 Hz, 2H), 8.52 (d, J ) 5.7 Hz, 2H); 13C NMR
(75 MHz, CDCl3) δ 18.3, 24.5, 26.2 (2C), 51.4 (2C), 64.1, 122.9
(2C), 149.7 (2C), 153.3; LRMS (EI, rel intensity %) 190 (M+,
eth yl}a m in e ((S,R)-9d ): oil; Rf ) 0.31 (40% EtOAc); [R]25
D
-71 (c 0.7, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.40 (d, J )
6.5 Hz, 3H), 1.41 (d, J ) 6.6 Hz, 3H), 3.80 (q, J ) 6.5 Hz, 1H),
3.91 (q, J ) 6.6 Hz, 3H), 7.12 (d, J ) 7.3 Hz, 1H), 7.20-7.32
(m, 5H), 7.38-7.48 (m, 3H), 7.55 (d, J ) 7.7 Hz, 1H), 7.69 (t,
J ) 7.7 Hz, 1H), 8.06 (dm, J ) 7.0 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 22.0, 23.3, 55.1, 56.0, 118.2, 119.6, 126.7 and 126.7
(2C), 126.8, 128.3 (2C), 128.6 (2C), 128.7 (2C), 137.0, 139.5,
145.8, 156.4, 164.1; LRMS (FAB) 303 (M+ + H); HRMS (FAB)
calcd for C21H23N2 303.1861 (M+ + H), found 303.1833.
N-{(S)-1-[2-(6-P h en ylp yr id in yl)]}-N-[(S)-1-(2-p yr id in yl-
)eth yl]a m in e ((S,S)-9e): oil; Rf ) 0.38 (2% Et3N in AcOEt);
[R]23D -163 (c 1.45, CHCl3); 1H NMR (300 MHz, CDCl3) δ 1.35
(d J ) 7.0 Hz, 3H), 1.38 (d, J ) 7.3 Hz, 3H), 2.55 (br s, 1H),
3.70 (quint, J ) 7.0 Hz, 2H), 7.14 (ddd, J ) 7.3, 4.8, 1.1 Hz,
1H), 7.19 (d, J ) 7.3 Hz, 1H), 7.34-7.48 (m, 4H), 7.56-7.71
(m, 3H), 8.02 (dm, J ) 7.0 Hz, 2H), 8.55 (dt, J ) 4.8, 0.7 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 23.7 (2C), 57.1, 57.2, 118.5,
119.8, 121.3, 121.8, 126.9, 128.6 (2C), 128.7 (2C), 136.4, 137.0,
139.7, 149.2, 156.6, 164.5, 165.1; LRMS (FAB) 304 (M+ + H);
HRMS (FAB) calcd for C20H22N3 304.1814 (M+ + H), found
304.1808.
11), 175 (base), 112 (66), 106 (21); HRMS (EI) calcd C12H18
-
NO3S 190.1470 (M+), found 190.1471.
Mesyla tion a n d Su bstitu tion Rea ction for th e Syn -
th esis of (S)-15 a n d (S,R)-16. To an ice-cooled solution of
1-(3-pyridinyl)ethanol10 (100 mg, 0.8 mmol) and triethylamine
(404 mg, 4 mmol) in CH2Cl2 was added MsCl (275 mg, 2.4
mmol) dropwise. After the mixture was stirred for 40 min at
the same temperature, a 1:1 mixture of anhydrous ether and
pentane (12 mL) was added. The forming salts were removed
by suction under an Ar atmosphere. The filtrate was con-
densed, and the residual oil was subjected to use for the next
reaction directly. The oily mesylate (R)-14 was dissolved in
acetonitrile (4 mL), to which solution piperidine (8 mmol) was
added for the synthesis of (S)-15 or diisopropylethylamine (1.03
g, 8 mmol) and (R)-1-phenethylamine (2 mmol) were added
for that of (S,R)-16. The whole mixture was heated at 60 °C
for 1 or 21 h, respectively. Aqueous NaHCO3 was added to the
mixture, and the mixture was extracted with EtOAc for (S)-
15 and CH2Cl2 for (S,R)-16. Organic extract was washed with
water and brine and dried over MgSO4. Solvent was removed,
and the residual oil was purified by chromatography on silica
gel eluted with EtOAc and 10% Et3N in EtOAc for (S)-15 and
50% EtOAc in hexane for (S,R)-16. (S)-15 and (S,R)-16 were
obtained in 69 and 40% yields, respectively.
N-{(S)-1-[2-(6-P h en ylp yr id in yl)]}-N-[(R)-1-(2-p yr id in yl-
)eth yl]a m in e ((S,R)-9e): oil; Rf ) 0.38 (2% Et3N in AcOEt);
1
[R]25 -23 (c 1.75, CHCl3); H NMR (300 MHz, CDCl3) δ 1.45
D
(d, J ) 6.6 Hz, 3H), 1.48 (d, J ) 6.6 Hz, 3H), 2.62 (br s, 1H),
3.96 (q, J ) 6.6 Hz, 1H), 4.00 (q, J ) 6.6 Hz, 1H), 7.05 (ddd,
J ) 7.3, 4.8 and 1.1 Hz, 1H), 7.16 (d, J ) 7.3 Hz, 1H), 7.24 (d,
J ) 7.7 Hz, 1H), 7.36-7.54 (m, 5H), 7.60 (t, J ) 7.3 Hz, 1H),
7.99 (dm, J ) 6.6 Hz, 2H), 8.50 (dm, J ) 4.8 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 22.3 (2C), 56.7 (2C), 118.3, 119.2, 120.9,
121.6, 126.9, 128.5 (2C), 128.6 (2C), 136.2, 136.9, 139.5, 149.0,
156.3, 164.2, 164.7; LRMS (FAB) 304 (M+ + H); HRMS (FAB)
calcd for C20H21N3 303.1735 (M+), found 303.1741.
(S)-N-[1-(3-P yr id in yl)eth yl]p ip er id in e ((S)-15): oil; Rf )
1
0.43 (5% Et3N in EtOAc); [R]26 +14 (c 0.6, CHCl3); H NMR
D
(300 MHz, CDCl3) δ 1.39 (d, J ) 6.6 Hz, 3H), 1.37-1.43 (m,
2H), 2.32-2.43 (m, 4H), 3.48 (q, J ) 6.6 Hz, 1H), 7.25 (dd, J
) 7.7, 4.4 Hz, 1H), 7.66 (d, J ) 7.7 Hz, 1H), 8.48 (d, J ) 4.4
Hz, 1H), 8.53 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 18.6, 24.5,
26.1 (2C), 51.2 (2C), 62.5, 123.2, 135.1, 139.1, 148.2, 149.5.
(S,S)-N,N′-Bis[1-(6-p h en yl-2-p yr id in yl)et h yl]a m in e-
((S,S)-9f): oil, Rf ) 0.37 (40% EtOAc in hexane); [R]25D -198.0
6788 J . Org. Chem., Vol. 69, No. 20, 2004

Synthesis of Chiral Nonracemic 1-(2-Pyridinyl)ethylamines
LRMS (FAB) 191 (M+ + H); HRMS (FAB) calcd C12H19N2
191.1548 (M+ + H), found 191.1542.
(A) from the Ministry of Education, Culture, Sports,
Science and Technology, J apan. Financial support from
the Ho-ansha Foundation is gratefully acknowledged
(S)-N-[1-(3-P yr id in yl)eth yl]-N-[(S)-1-p h en eth y]a m in e
((S,R)-16): oil; Rf ) 0.47 (EtOAc); [R]24 -167 (c 0.2, CHCl3);
D
1H NMR (300 MHz, CDCl3) δ 1.28 (d, J ) 6.6 Hz, 3H), 1.28 (d,
J ) 6.6 Hz, 3H), 1.67 (br s, 1H), 3.45 (q, J ) 6.6 Hz, 1H), 3.54
(q, J ) 6.6 Hz, 1H), 7.17-7.36 (m, 6H), 7.61 (d, J ) 7.7 Hz,
1H), 8.41 (d, J ) 1.6 Hz, 1H), 8.50 (dd, J ) 4.8, 1.6 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 24.7 (2C), 52.7, 55.2, 123.5, 126.4
(2C), 126.9, 128.5 (2C), 134.2, 140.7, 145.2, 148.4, 148.9; MS
(FAB) 227 (M+ + H); HRMS (FAB) calcd C15H19N2 227.1548
(M+ + H), found 227.1541.
Su p p or tin g In for m a tion Ava ila ble: Copies of the 1H
and/or 13C NMR spectra for compounds (S)-4a , (S)-4b, (S)-4c,
(S)-4d , (S,S)-4e, (S,R)-4e, (S,S)-4f, meso-4f, (S,S)-4g, (S,R)-
4g, (R)-4h , (R)-4i, (R)-4j, (R)-4k , (R)-4l, (R)-4m , (R)-4n , (S)-
5a , (S)-5b, (S)-5c, (S)-5d , (S)-5e, (S)-5f, (S)-5g, (S,S)-5h , (S,R)-
5h , (R)-7, (S)-9a , (S)-9b, (S)-9c, (S,S)-9d , (S,R)-9d , (S,S)-9e,
(S,R)-9e, (S,S)-9f, (R)-11, (S)-12, (S)-15, and (S)-16. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Ack n ow led gm en t. This work was supported by
Grant-in-Aids for Scientific Research on Priority Areas
J O0491758
J . Org. Chem, Vol. 69, No. 20, 2004 6789