Asymmetric synthesis. 39. Synthesis of 2-(1-aminoalkyl)piperidines via 2-cyano-6-phenyl oxazolopiperidine

Article abstract of DOI:10.1021/jo960910s

The asymmetric synthesis of a series of 2-(1-aminoalkyl) piperidines using (-)-2-cyano-6-phenyloxazolopiperidine 1 is described. LiAlH₄ reduction of 1 followed by hydrogenolysis led to the diamine 3. The same strategy applied to C-2-methylated

Full text of DOI:10.1021/jo960910s

6700
J . Org. Chem. 1996, 61, 6700-6705
Asym m etr ic Syn th esis. 39.1 Syn th esis of
2-(1-Am in oa lk yl)p ip er id in es via 2-Cya n o-6-p h en yl
Oxa zolop ip er id in e
Olivier Froelich, Patrice Desos, Martine Bonin, J ean-Charles Quirion,* and
Henri-Philippe Husson*
Laboratoire de Chimie The´rapeutique associe´ au C.N.R.S., Faculte´ des Sciences Pharmaceutiques et
Biologiques, Universite´ Rene´ Descartes, 4, Avenue de l'Observatoire, 75270 Paris Cedex 06, France
J ieping Zhu
Institut de Chimie des Substances Naturelles du CNRS 91198, Gif-sur-Yvette Cedex, France
Received May 17, 1996X
The asymmetric synthesis of a series of 2-(1-aminoalkyl) piperidines using (-)-2-cyano-6-
phenyloxazolopiperidine 1 is described. LiAlH4 reduction of 1 followed by hydrogenolysis led to
the diamine 3. The same strategy applied to C-2-methylated compound 7 afforded [(2S)-2-
methylpiperidin-2-yl]methanamine (9). Addition of lithium derivatives to the cyano group of 1
resulted in the formation of an intermediate imino bicyclic system (11a -c) which could be
diastereoselectively reduced to substituted diamino alcohols 13a -c. The addition of an excess of
PhLi to 1 in the presence of LiBr furnished disubstituted amine 19, the precursor of diphenyl-
[(2S)-piperidin-2-yl]methanamine (22).
In tr od u ction
An ever growing interest in 1,2-diamine compounds
exists since this system is an integral feature in many
compounds of pharmaceutical value and in chiral ligands
for asymmetric synthesis.2 Among this family 2-(ami-
nomethyl)pyrrolidine and -piperidine derivatives are of
particular interest.3,4 These compounds are generally
prepared in optically pure form from the corresponding
amino acids5 or amino esters;3a neither of these methods
allows the diastereoselective preparation of derivatives
substituted on the carbons bearing the amine functions.
Furthermore, the preparation of (aminomethyl)piperidine
derivatives requires not easily available enantiomerically
pure pipecolic acid as a starting material, in contrast with
proline which is available in its enantiomeric forms.6
F igu r e 1.
a primary amine with a remarkable stereoselectivity.8
This reactivity has been used for the preparation of
spiropiperidines related to histionicotoxin.9,10 We also
observed that the aminonitrile function of alkylated
derivatives of 1 could be reduced without elimination to
give intermediate imines which can in turn be reduced
to 1,2-diamines or react with electrophiles.9
We decided to investigate these reactivities in order
to prepare unsubstituted and substituted aminomethyl
piperidine derivatives (Figure 1).
In a continuation of our studies on 2-cyano-6-phenyl-
oxazolopiperidine 1,7 , we were interested in the reactivity
of nucleophiles toward the cyano group. Our first results
showed that the reaction of organolithium or cuprate
derivatives with 1 gave an imine which was reduced to
Resu lts a n d Discu ssion
Syn th esis of (-)-[(2S)-piper idin -2-yl]m eth an am in e
(3). It was felt that synthon 1 was a good candidate for
a short asymmetric synthesis of 2-(aminomethyl)piperi-
dine, provided that the cyano group could be reduced
cleanly without competitive elimination. It is known that
R-aminonitriles can be reduced with LiAlH4 either to
diamines by reduction of the cyano group or into mono-
amines by a decyanation process. The results depend
greatly on the substitution pattern.11 Generally, mono-
substituted R-aminonitriles yield diamines. Recently an
example of reduction of 2-cyanopiperidine leading to a
diamine has been published.12
X Abstract published in Advance ACS Abstracts, August 15, 1996.
(1) For part 38, see: Micouin, L.; Bonin, M.; Cherrier, M.-P.; Tomas,
A.; Quirion, J .-C.; Husson, H.-P. Tetrahedron 1996, 52, 7719.
(2) Togni, A.; Venanzi, L. M. Angew. Chem. Int. Ed. Engl. 1994, 33,
497.
(3) For recent exemples of synthesis of biologically active compounds,
see: (a) Naylor, A.; J udd, D. B.; Scopes, D. I. C.; Hayes, A. G.; Birch,
P. J . J . Med. Chem. 1994, 37, 2138. (b) Giardina, G.; Clarke, G. D.;
Dondio, G.; Petrone, G.; Sbacchi, M.; Vecchietti, V. J . Med. Chem. 1994,
37, 3482. (c) Morikawa, K.; Honda, M.; Endoh, K.; Matsumoto, T.;
Akamatsu, K.; Mitsui, H.; Koizumi, M. Chem. Pharm. Bull. 1990, 38,
930.
(4) For recent examples of use of 2-(aminomethyl)pyrrolidine and
-piperidine derivatives in asymmetric synthesis, see: (a) Froelich, O.;
Bonin, M.; Quirion, J .-C.; Husson, H.-P. Tetrahedron: Asymmetry 1993,
4, 2335. (b) Kobayashi, S.; Hayashi, T. J . Org. Chem. 1995, 60, 1098.
(c) Asami, M.; Usui, K.; Higuchi, S.; Inoue, S. Chem. Lett. 1994, 297.
(5) (a) Perumattam, J .; Shearer, B. G.; Confer, W. L.; Mathew, R.
M. Tetrahedron Lett. 1991, 32, 7183. (b) Mukaiyama, T. Tetrahedron
1981, 37, 4111.
(8) Zhu, J .; Quirion, J .-C.; Husson, H.-P. Tetrahedron Lett. 1989,
30, 5137.
(9) Zhu, J .; Quirion, J .-C.; Husson, H.-P. J . Org. Chem. 1993, 58,
6451.
(10) Zhu, J .; Quirion, J .-C.; Husson, H.-P. Tetrahedron Lett. 1989,
30, 6323.
(11) (a) Morris, G. F.; Hauser, C. R. J . Org. Chem. 1962, 27, 465.
(b) Leonard, N. J .; Hauck, F. P. J . Am. Chem. Soc. 1957, 79, 5279.
(6) Vecchietti, V.; Giordani, A.; Giardina, G.; Colle, R.; Clarke, G.
D. J . Med. Chem. 1991, 34, 397.
(7) (a) Bonin, M.; Grierson, D. S.; Royer, J .; Husson, H.-P. Org.
Synth. 1991, 70, 54 and references cited herein. (b) Guerrier, L.; Royer,
J .; Grierson, D. S.; Husson, H.-P. J . Am. Chem. Soc. 1983, 105, 7754.
S0022-3263(96)00910-3 CCC: $12.00 © 1996 American Chemical Society

Synthesis of 2-(1-Aminoalkyl)piperidines
J . Org. Chem., Vol. 61, No. 19, 1996 6701
Sch em e 1
F igu r e 2.
Sch em e 2
2-Cyano-6-phenyloxazolopiperidine (1) was easily pre-
pared from (R)-(-)-phenylglycinol and glutaraldehyde in
the presence of KCN.7 When (-)-1 was treated with
LiAlH4 in Et2O at rt, diamino alcohol 2 (Scheme 1) was
obtained in 97% yield. As observed by Hoornaert,12 the
aminomethyl chain adopted a mixed axial-equatorial
position (∑J 2,3 ) 11.5 Hz)13 ascribed to a strong gauche
interaction between aminomethyl group and the N-
(phenylethanol) substituent. Hydrogenolysis of the chiral
appendage led easily to the 1,2-diamine 3 in 91% yield
isolated as its dihydrochloride salt. Examination of the
1H NMR spectrum indicated that an equatorial position
was adopted by the aminomethyl chain (∑J 2,3 > 14 Hz).
To demonstrate the versatility of our strategy for
preparing chiral ligands used in asymmetric synthesis,
we decided to study the selective N-alkylation of the
primary amine. For this purpose, diamino alcohol 2 was
treated with methyl chloroformate followed by reduction
of the resulting carbamate 4 with LiAlH4 then hydro-
genolysis of N-methyl intermediate 5. Under these
conditions N-methyl diamine 6 was obtained as an
optically pure compound in 66% overall yield from
synthon 1.
Syn th esis of [(2S)-2-m eth ylp ip er id in -2-yl]m eth a n -
a m in e (9). In order to prepare C-2-substituted deriva-
tives of (aminomethyl)piperidine, we first examined the
reduction of C-2-methylated compound 7 obtained as a
pure isomer by a deprotonation-alkylation sequence
from synthon 1.7 At rt in Et2O, compound 7 was quan-
titatively reduced to diamino alcohol 8. Reduction of the
nitrile function was confirmed by the appearance of an
AB spin system (δ 2.87) in the 1H NMR spectrum
assigned to H-7 protons. This result was unexpected as
it is known that disubstituted aminonitriles are generally
reduced to monoamines by elimination of the cyano
group, especially when the cyano group and nitrogen lone
pair are in an antiperiplanar disposition.14 In the 2-cy-
ano-6-phenyloxazolopiperidine series, it is known15 that
the cyano group adopts an axial position antiperiplanar
to the nitrogen lone pair (Figure 2). It is likely that the
oxazolidine function is reduced, leading first to a five-
membered chelating intermediate via the participation
of the ring nitrogen. As a consequence, elimination of
the nitrile cannot be assisted by the N-lone pair electron
and an alternative mechanism; i.e reduction to the amino
function prevails. Hydrogenolysis of 8 under standard
conditions furnished C-2-methylated (aminomethyl)pip-
eridine 9 in 90% yield.
Syn th esis of (1-p ip er id in -2-yl)a lk yla m in es 14a ,b
a n d 16b a n d (R)-p h en yl[(2S)-p ip er id in -2-yl]m et h -
a n a m in e (14c). The next target was the preparation
of diamines substituted on the side chain (Scheme 2). A
reinvestigation of the reaction of organolithium deriva-
tives (MeLi, BuLi, or PhLi) with 1 indicated that the
expected imines 10 were isolated in the cyclized form 1116
as indicated by spectral analyses. All attempts to purify
crude 11a led to decomposition products. A structural
study was conducted on compound 11b. In MS (EI), the
base peak was observed at m/z 255 (M - 31, M - CH2-
OH), indicating a product with a phenylethanol opened
1
chain substituent on the nitrogen. In the H NMR two
narrow triplets were observed at δ 3.34 (J ) 4.1 Hz) and
5.2 ppm (J ) 2.5 Hz); they were attributed to bridgehead
H-2 and H-6, respectively, by 1H-13C COSY and are
indicative of diaxial substituents at C-2 and C-6. The
formation of these imines can be easily explained by the
attack of an intermediate imine salt on the potential
iminium ion at C-6.
(12) Compernolle, F.; Saleh, M. A.; Toppet, S.; Hoornaert, G. J . Org.
Chem. 1991, 56, 5192.
(13) In order to make easier comparison of NMR data, the products
are described with the numbering indicated for 2 in Scheme 1.
(14) (a) Leonard, N. J .; Sauers, R. P. J . Am. Chem. Soc. 1957, 79,
6210. (b) Miyano, S.; Yamashita, O.; Sumoto, K.; Shima, K.; Hayashi-
matsu, M.; Satoh, F. J . Heterocycl. Chem. 1987, 24, 47.
(15) Bonin, M., The`se de Doctorat, Universite´ de Paris-Sud, Orsay,
1986.
(16) The imino-oxazolidine structure was first proposed: Delgado,
A.; Mauleon, D. Synth. Commun. 1988, 18, 823. We reported the same
type of structure in our first communication (ref 8).

6702 J . Org. Chem., Vol. 61, No. 19, 1996
Froelich et al.
Sch em e 3
Sch em e 4
Complete reduction of 11b with NaBH4 in CH3OH
occurred with a remarkable stereoselectivity, giving the
amino alcohol 13b. However, in the case of 11a and 11c
the reaction was not diastereoselective. The problem was
circumvented using a two-step route: (i) NaBH3CN
reduction of 11a -c at pH 3 affording 12a -c (ii) LiAlH4
reduction of 12a -c leading stereoselectively to com-
pounds 13a -c. Morpholines 12 were obtained as single
isomers for R ) Bu (12b) and R ) Ph (12c) and as a 9/1
mixture of two isomers at C-7 for R ) Me (12a ). For 12b,
12c, and the major isomer of 12a , an axial position for
H-2 and H-8 was indicated by similar chemical shifts and
coupling constant values in their 1H NMR spectra. A
NOE experiment conducted on 12a (major) indicated a
cis relationship for H-2, H-8, and the C-7 methyl group.
Thus it was possible to assign the (2S,7S,8R) absolute
configuration for compound 12a (major) and consequently
the same for compounds 12b and 12c.
Sch em e 5
Syn t h esis of d ip h en yl[(2S)-p ip er id in -2-yl]m et h -
a n a m in e (22). When compound 1 was treated with an
excess of PhLi, concomitant formation of 11c and diphen-
yl aminal 19 was observed (Scheme 4). Selective forma-
tion of 19 (75% yield) could be obtained using 5 equiv of
PhLi and LiBr. This product was characterized by the
absence of the imine absorption in the IR spectra. In the
13C NMR spectra a quaternary carbon was observed (δ
This configuration is explained by a preferential in-
tramolecular attack of the primary alcohol of 11 on the
accessible si face of the protonated imine, followed by the
reduction of the aminal function of the intermediate,
which could not be isolated (Scheme 3).
1
72.8 ppm), and in the H NMR spectra, H-2 and H-6 ap-
peared as broad singlets (δ 4.10 and 4.35). The mecha-
nism of the reaction probably involves initial formation
of imine salt 23 (Scheme 5), followed by association of
LiBr, acting as a Lewis acid, allowing opening of the oxa-
zolidine ring. Addition of PhLi on the intermediate imi-
nium ion 24 gives the observed diphenyl aminal product
19. This hypothesis is supported by the non-reactivity
of the unactivated monophenyl derivative 11c toward Ph-
Li, even in the presence of LiBr. All attempts to introduce
two different substituents during this reaction failed.
Generally the reaction of nitriles with organometallic
species (RLi, RMgX), gives the corresponding imines.20
Recently, Ciganek21 reported a double addition of alky-
lcerium dichlorides to nitriles to give tertiary carbi-
namines, while Wemple22 described the first example of
double addition with the retention of chiral integrity of
the asymmetric center R to the nitrile. However, to the
best of our knowledge, this reaction has never been
applied to R-aminonitrile in order to prepare 1,1-disub-
stituted 1,2-diamines.
Stereoselective opening of the amino ether function of
12a -c with LiAlH4 afforded exclusively 1,2-diamines
13a -c. The H-2, H-7 coupling constant values indicated
an erythro stereochemistry.17 This configuration has
been previously confirmed by the preparation of a rigid
intermediate derived from diamine 14b.8 It is interesting
to notice that the major products of the direct reduction
of 11b with NaBH4 furnished compounds 13b with the
same configuration. This result indicates that reduction
of morpholines 12 occurred via a retention mechanism
as proposed for ketals18 and oxazolidines.19 Reduction
with LiAlH4 of the mixture of epimeric methylated
derivatives 12a furnished exclusively erythro compound
13a . This observation could indicate a mechanism
involving a transient iminium form with an intramolecu-
lar delivery of hydride. However, it might be possible
that the major diastereomer of 12a is reduced much
faster than the minor diastereomer.
Finally 1,2-diamines 14a and 14b were obtained by
hydrogenolysis of the chiral appendage, in 59 and 50%
overall yields, respectively, from 1.
The synthesis of diamine 14c containing a benzylamine
function necessitated protection of 13c as a benzamide
17c before hydrogenolysis of the chiral phenylethanol
moiety to give 18c. Acid hydrolysis of the amide function
of 18c led finally to 14c.
NaBH4 reduction of aminal 19 afforded diamino alcohol
20. An examination of the 1H NMR spectrum of 20
indicated that the piperidine ring of this compound
adopts a boat conformation (J 2,3
) J 2,3
) 7.5 Hz)
ax
eq
which may be attributed to a strong gauche interaction
between the C-2 substituent and the N-1 benzyl chain.
Elimination of the chiral appendage of 20 required prior
protection of the primary amine as a trifluoroacetamide
21, followed by hydrogenolysis and then deprotection by
acid treatment leading to 22 (34% yield from 1).
Compounds 13 represent useful intermediates allowing
selective N-methylation via a two-step process involving
an intermediate carbamate which was directly reduced
(LiAlH4) to compound 15b. Hydrogenolysis of the chiral
appendage afforded N-methyl diamine 16b. Thus chemo-
selective substitution can be envisaged on each amino
group.
Con clu sion
We have achieved the enantiospecific synthesis of a
series of piperidines bearing a 2-aminomethyl group
which can be substituted at N and/or C atoms.
(17) (a) Stork, G.; J acobson, R. M.; Levitz, R. Tetrahedron Lett. 1979,
771. (b) Pornet, J .; Miginiac, L. Bull. Soc. Chim. Fr. 1975, 841. (c)
Alvernhe, G.; Laurent, A. Tetrahedron Lett. 1973, 1057.
(20) Schaeffer, F. C. in Chemistry of the Cyano Group; Rappoport,
Z., Ed.; Interscience: New York, 1971; p 239.
(18) Brewster, J . H. in Comprehensive Organic Synthesis. Trost, B.
M.; Fleming, I. Eds; Pergamon Press: New York, 1991; Vol. 8, p 211.
(19) Munchhof, M. J .; Meyers, A. I. J . Org. Chem. 1995, 60, 7084.
(21) Ciganek, E. J . Org. Chem. 1992, 57, 4521.
(22) Fedij, V.; Lenoir III, E. A.; Suto, M. J .; Zeller, J . R.; Wemple, J .
Tetrahedron: Asymmetry 1994, 5, 1131.

Synthesis of 2-(1-Aminoalkyl)piperidines
J . Org. Chem., Vol. 61, No. 19, 1996 6703
127.4, 128.1, 128.7, 137.5; HRMS calcd for C15H25N2O (MH+)
249.1966, found 249.1963.
These diamines constitute precursors for the elabora-
tion of more sophisticated biologically interesting com-
pounds. Furthermore the selective functionalization of
the side chain allows the modulation of the catalytic
properties of this series of chiral ligands.
[(2S)-P ip er id in -2-yl]-N-m eth ylm eth a n a m in e (6). Hy-
drogenolysis of a solution of diamino alcohol 5 (0.85 g, 3.42
mmol) in MeOH (20 mL) in the presence of palladium on
charcoal (0.15 g) afforded after filtration and evaporation of
the solvent 0.84 g of an oily residue. 2-Phenylethanol was
eliminated by trituration of the residue with Et2O. Diamine
6 was obtained as an oil (0.394 g, 3.08 mmol) in 90% yield:
[R]D -12 (c 0.8, MeOH); IR 3425, 2933, 1647, 1450 cm-1; MS
Exp er im en ta l Section
Infrared spectra were recorded as solution in CHCl3. 1H
NMR (300 MHz) and 13C NMR (75 MHz) were recorded in
CDCl3 or CD3OD solution; chemical shifts were measured as
ppm downfield of internal tetramethylsilane. Mass spectral
data were recorded either in the electron-impact (EI) or
chemical-ionization (CI) mode. Analytical TLC was performed
on glass plates coated with silica gel 60 F254 (Merck). Optical
rotations of CHCl3 or MeOH solutions were measured at 20 (
3 °C. Tetrahydrofuran (THF) and ether were distilled from
sodium/benzophenone immediately prior to use. All reactions
were performed under an atmosphere of dry N2.
(2R)-2-[(2S)-2-(Am in om et h yl)p ip er id in -1-yl]-2-p h en -
yleth a n ol (2). To a stirred suspension of LiAlH4 (0.5 g, 13.14
mmol) in Et2O (25 mL) at -10 °C under N2 atmosphere was
slowly added a solution of 2-cyanopiperidine 1 (1 g, 4.38 mmol)
in Et2O (5 mL). After 2 h at rt the mixture was treated with
0.5 mL of H2O, 0.5 mL of 15% aqueous NaOH, and 1.5 mL of
H2O. The white precipitate was filtered and washed several
times with Et2O. After removal of the solvent under reduced
pressure, the compound 2 was isolated pure as a pale yellow
oil in 97% yield (1.0 g, 4.25 mmol): [R]D -70 (c 0.87, CHCl3);
MS (EI) m/ z (rel intensity) 234 (M+, 1), 204 (80), 121 (10), 84
(80); 1H NMR (CDCl3) δ 1.0-1.65 (m, 6 H), 1.80 (ddd, J ) 11.6,
11.0, 2.8 Hz), 2.46 (m), 2.82 (dd, J ) 13.5, 2.8 Hz), 2.90 (dt, J
) 11.6, 3.2 Hz), 3.30 (dd, J ) 13.5, 5.0 Hz), 3.63 (dd, J ) 10.5,
4.8 Hz), 4.02 (t, J ) 10.5 Hz), 4.27 (dd, J ) 10.5, 4.8 Hz), 7.12-
7.35 (m, 5 H); 13C NMR δ 23.1, 25.2, 28.8, 42.7, 44.7, 57.6,
60.4, 61.5, 126.7, 127.5, 128.2, 136.5; dihydrochloride (recryst
MeOH/ Et2O). Anal. Calcd for C14H24N2OCl2: C, 54.72; H,
7.87; N, 9.12. Found: C, 54.41; H, 7.64; N, 8.80.
1
(CI) 129 (M + 1), 98, 84; H NMR (CDCl3) δ 1.1-1.8 (m, 6H),
2.4 (s), 2.5-2.7 (m, 4 H), 3.10 (br d, J ) 11.9 Hz); 13C NMR δ
24.6, 26.4, 30.7, 36.7, 46.7, 56.2, 57.8. Anal. Calcd for
C7N2H16: C, 65.57; H, 12.58; N, 21.84. Found: C, 65.40; H,
12.67, N, 21.74.
(2R)-2-[(2S)-2-(Am in om eth yl)-2-m eth ylp ip er id in -1-yl]-
2-p h en yleth a n ol (8). To a suspension of LiAlH4 (1.0 g, 26.2
mmol) in ether (50 mL) was added a solution of compound 77
(1.0 g, 4.15 mmol) in ether. After stirring of the mixture for
3h, H2O (0.5 mL) was carefully added, followed by NaOH (10%)
(0.5 mL) and then water (1.5 mL). After filtration, concentra-
tion of the organic phases gave a solid which was crystallized
from methanol (1.01 g, 98%): mp 252 °C; [R]D +166 (c 1.0,
MeOH); IR 3394, 2946, 1405, 1027 cm-1; MS (EI) m/ z (rel
intensity) 249 (MH+, 10), 218 (50), 121 (25), 98 (100); 1H NMR
δ 0.70 (s), 1.05-1.80 (m, 6H), 2.48 (td, J ) 11.2, 3.0 Hz), 2.72
(br s OH), 2.87 (AB system, 2 H), 2.95 (dt, J ) 11.2, 3.6 Hz),
3.45 (dd, J ) 10.6, 4.7 Hz), 3.85 (t, J ) 10.6 Hz), 4.27 (dd, J )
10.6, 4.7 Hz), 7.1-7.4 (m, 5 H); 13C NMR δ 18.7, 20.7, 27.1,
36.8, 40.8, 49.6, 57.2, 61.1, 62.1, 127.3, 129.3, 139.6. Anal.
Calcd for C15H24N2O: C, 72.54; H, 9.74; N, 11.28. Found C,
72.83, H, 9.86, N, 10.99.
[(2S)-2-Meth ylp ip er id in -2-yl]m eth a n a m in e (9). Hydro-
genolysis of 180 mg of 8 in the manner described in the
preparation of 3 afforded 9 as hygroscopic crystals in 90%
yield: [R]D -4.5 (c 1.0, MeOH); IR 3421, 2923 cm-1; MS (CI)
129 (MH+), 112, 102, 98; 1H NMR (CD3OD) δ 1.65 (s), 1.8-2.0
(m, 6H), 3.34 (br t, J ) 5.9 Hz, 2H), 3.48 (br s, 2H); 13C NMR
(CD3OD) δ 18.6, 19.7, 22.6, 32.3, 41.2, 46.0, 57.1.
(2R)-2-[(1S,5S)-7-Met h yl-6,8-d ia za b icyclo[3.2.1]oct -6-
en -8-yl]-2-p h en yleth a n ol (11b). A solution of 1 (2 g, 8.77
mmol) in freshly distilled Et2O (30 mL) was cooled to -10 °C
under a N2 atmosphere. After addition of n-BuLi (6.4 mL, 9.6
mmol), the resulting solution was stirred for 2 h at rt and then
quenched with saturated aqueous NH4Cl. The general workup
procedure gave an orange oil which was purified by flash
chromatography (SiO2, cyclohexane/AcOEt 1:1) to give n-
butylimine 11b (yellow oil, 2.1 g, 7.39 mmol, 85% yield): [R]D
-57 (c 1.5, CHCl3); IR 3400, 1650, 1510 cm-1; MS (EI) m/ z
(rel intensity) 286 (M+, 10), 255 (100), 203 (80); 1H NMR
(CDCl3) δ 0.90 (t, J ) 7 Hz), 1.2-1.9, 2.0, 2.3 (m, 12 H), 3.34
(t, J ) 4.1 Hz), 3.42 (dd, J ) 5.5, 4.1 Hz), 3.75 (dd, J ) 11.0,
4.1 Hz), 3.82 (dd, J ) 11.0, 5.5 Hz), 5.2 (t, J ) 2.5 Hz), 7.2-
7.4 (m, 5 H); 13C NMR (CDCl3) δ 13.8, 16.8, 22.7, 24.4, 25.3,
27.8, 30.6, 64.5, 66.1, 67.0, 85.6, 127.7, 128.4, 128.5, 140.5,
177.3.
[(2S)-P ip er id in -2-yl]m eth a n a m in e (3). To a solution of
amino alcohol 2 (0.9 g, 3.85 mmol) and 10% palladium on
charcoal (150 mg) in MeOH (8 mL) was added 4 mL of
MeOH-2 N HCl. The mixture was hydrogenated with stirring
for 6 h. After filtration on Celite with MeOH, the solvent was
removed under reduced pressure. The residue was washed
several times with Et2O to eliminate 2-phenylethanol. Crys-
tallization of the dihydrochloride salt in MeOH/Et2O gave 3
as white crystals in 91% yield (655 mg, 3.51 mmol): mp 240-
242 °C; [R]D -5.7 (c 0.42, MeOH); MS (CI) 115 (M + 1, 100),
1
84 (20); H NMR (D2O) δ 1.65, 1.95, 2.15 (3m, 6 H), 3.10 (td),
3.28 (dd, J ) 13.6, 7.0 Hz), 3.40 (dd, J ) 13.6, 5.8 Hz), 3.55
(m, 2H); 13C NMR (D2O) δ 23.3, 23.8, 28.4, 43.5, 47.6, 56.2.
Anal. Calcd for C6H16N2Cl2: C, 38.51; H, 8.61; N, 14.97.
Found: C, 38.48; H, 8.71; N, 14.78.
(2R)-2-[(2S)-2-[(Meth yla m in o)m eth yl]p ip er id in -1-yl]-2-
p h en yleth a n ol (5). A solution of amino alcohol 2 (1.15 g,
4.91 mmol) and methyl chloroformate (417 µL, 5.40 mmol) in
CHCl3 (15 mL) and 15% aqueous NaOH solution (3 mL) was
stirred for 3 h at rt. The resulting mixture was washed with
saturated aqueous NH4Cl and extracted with CHCl3. The
combined organic layers were washed with water, dried over
MgSO4, and then evaporated to furnish the corresponding
carbamate 4 as an oil which was dissolved in Et2O (25 mL)
and added to a stirred suspension of LiAlH4 (0.38 g, 10 mmol)
in anhydrous Et2O (20 mL) at 0 °C. After stirring for 3 h at
rt, the mixture was treated with H2O (0.38 mL), 15% NaOH
(0.38 mL), and then H2O (1.14 mL). The resulting precipitate
was filtered off and washed with Et2O. After removal of the
solvent under reduced pressure, methyl amine 5 was isolated
as a colorless oil in 76% (0.914 g, 3.68 mmol): [R]D +15 (c 1.2,
CHCl3); IR 3415, 2936, 1686, 1543, 1109 cm-1; MS (EI) m/ z
(rel intensity) 249 (MH+, 100), 218 (12), 204 (20), 141 (8), 121
(10), 105 (25), 91 (35), 84 (95). 1H NMR (CDCl3) δ 1.1-1.7
(m, 6H), 1.82 (ddd, J ) 11.8, 10.5, 3.0 Hz), 2.47 (s), 2.62 (m),
2.71 (dd, J ) 12.3, 3.5 Hz), 2.81 (dt, J ) 11.8, 4.0 Hz), 3.00
(dd, J ) 12.3, 4.8 Hz), 3.62 (dd, J ) 10.3, 4.4 Hz), 3.95 (t, J )
10.3 Hz), 4.22 (dd, J ) 10.3, 4.4 Hz), 7.1-7.4 (m, 5H); 13C NMR
(CDCl3) δ 23.8, 25.9, 30.9, 37.0, 45.2, 54.3, 57.2, 61.0, 62.1,
(2R)-2-P h en yl-2-[(1S,5S)-7-ph en yl-6,8-diazabicyclo[3.2.1]-
oct-6-en -8-yl]eth a n ol (11c). A solution of 1 (2 g, 8.77 mmol)
in freshly distilled Et2O (40 mL) was cooled to -78 °C. After
addition of PhLi (5 mL, 10 mmol), the resulting solution was
stirred for 1.5 h at rt and then quenched with saturated
aqueous NH4Cl. The general workup procedure gave an oily
residue which was purified by flash chromatography (SiO2,
CH2Cl2/MeOH 95:5) to give imine 11c as a yellow oil in 93%
yield, (2.5 g, 8.15 mmol): [R]D -43 (c 2.0, CHCl3); IR 3350,
3027, 1640, 1520, 1428 cm-1; MS (EI) m/ z (rel intensity) 306
1
(M+, 14), 275 (100), 203 (45); H NMR (CDCl3) δ 1.1-1.9 (m,
6 H), 3.45 (dd, J ) 5.3, 4.7 Hz), 3.81 (dd, J ) 11.2, 4.7 Hz),
3.88 (dd, J ) 11.2, 5.3 Hz), 3.95 (t, J ) 2.9 Hz), 5.50 (t, J )
2.4 Hz), 7.3-7.6 (m, 10 H); 13C NMR (CDCl3) δ 16.8, 25.0, 25.2,
64.8, 65.7, 66.2, 86.2, 127.6, 127.9, 128.4, 128.5, 128.6, 131.0,
131.9, 140.4, 171.9; HRMS calcd for C20H22N2O 306.1732, found
306.1725.
(1S,4R,9a S)-1-Meth yl-4-p h en ylocta h yd r op yr id o[2,1-c]-
[1,4]oxa zin -1-a m in e (12a ). A solution of 1 (2 g, 8.77 mmol)
in freshly distilled Et2O (30 mL) was cooled to -10 °C. After
addition of MeLi (6 mL, 9.60 mmol), the yellow solution was

6704 J . Org. Chem., Vol. 61, No. 19, 1996
Froelich et al.
stirred for 2 h at rt and then quenched with saturated aqueous
NH4Cl. The general workup procedure gave an orange oil
which decomposed rapidly at room temperature. Direct solu-
bilization with MeOH and THF (20 mL of each) gave a yellow
solution which was acidified with 1 N aqueous HCl (pH 3).
After addition of NaBH3CN (580 mg, 9.23 mmol), the mixture
was maintained at pH 3, refluxed for 1.5 h, and then neutral-
ized at pH 7 with saturated aqueous NaHCO3 and extracted
with CH2Cl2. The organic layer was dried on MgSO4, concen-
trated, and purified by flash chromatography on silica gel
(hexane/diethyl ether 1:1) to give a mixture of two epimeric
compounds in 74% yield and in a 90/10 ratio. An analytical
sample of 12a was obtained by preparative TLC: [R]D -108
(c 0.46, CHCl3 ); MS (EI) m/ z (rel intensity) 246 (1), 245 (16),
231 (42), 212 (37), 187 (100), 186 (86), 104 (89); 1H NMR
(CDCl3) δ 1.35 (s, 3H), 1.4-1.8 (m, 7H), 2.1 (s, 2H, NH2), 2.18
(dd, J ) 10.8, 2.5 Hz), 2.72 (dt, J ) 11.6, 3.6 Hz), 3.20 (dd, J
) 11.0, 4.0 Hz), 3.48 (dd, J ) 12.1, 4.0 Hz), 3.68 (dd, J ) 12.1,
11.0 Hz), 7.2-7.4 (m, 5 H); 13C NMR (CDCl3) δ 24.5, 25.5, 27.7,
26.4, 53.5, 65.3, 68.5, 69.1, 84.5, 127.5, 127.9, 128.5, 140.0.
Anal. Calcd for C15H22N2O: C, 73.13; H, 9.00; N, 11.37.
Found: C, 72.97; H, 8.94, N, 11.18.
δ 20.5, 23.3, 24.0, 26.0, 44.6, 45.9, 59.7, 60.4, 61.9, 127.3, 128.0,
128.8, 136.1; HRMS calcd for C15H24N2O 249.1966, found
249.1964.
(2R)-2-[(2S)-2-[(1R)-1-Am in op en t yl]p ip er id in -1-yl]-2-
p h en yleth a n ol (13b). Aminoalcohol 13b (1.21 g, 4.15 mmol)
was prepared from butylmorpholine 12b (1.3 g, 4.51 mmol) in
92% yield as described for 13a to give pale yellow crystals:
mp 212-214 °C (Et2O/hexane); [R]D -80 (c 1.0, CHCl3); IR
3400, 1510 cm-1; MS (EI) m/ z (rel intensity) 290 (M+, 20), 204
1
(100); H NMR (CDCl3) δ 0.95 (t, J ) 7 Hz), 1.3-1.6 (m, 12
H), 1.8 (br t, J ) 11.2 Hz), 2.35 (br d, J ) 10.7 Hz), 2.75 (br s,
NH2, OH), 2.98 (br d, J ) 11.2 Hz), 3.62 (m, 2 H), 4.10 (t, J )
10.4 Hz), 4.48 (dd, J ) 10.4, 4.5 Hz), 7.1-7.4 (m, 5 H); 13C
NMR (CDCl3) δ 14.1, 22.9, 23.8, 24.2, 26.2, 29.2, 34.7, 46.2,
49.5, 59.8, 60.5, 60.9, 127.4, 128.0, 128.9, 136.4; HRMS calcd
for C18H31N2O 291.2434, found 291.2434.
(2R)-2-[(2S)-2-[(R)-(1-Am in op h en yl)m eth yl]p ip er id in -
1-yl]-2-p h en yleth a n ol (13c). Aminoalcohol 13c (1.27 g, 4.12
mmol) was prepared from phenylmorpholine 12c (1.35 g, 4.38
mmol) in 94% yield as described for 13a to yield an oil: [R]D
-40 (c 1.0, CHCl3); IR 3015, 2895, 1550, 1520 cm-1; MS (EI)
m/ z (rel intensity) 310 (M+, 15), 279 (100), 204 (100); 1H NMR
(CDCl3) δ 0.8-1.9 (m, 7 H), 2.68 (dt, J ) 10.7, 3.8 Hz), 3.0 (dt,
11.5, 2.5 Hz), 3.65 (dd, J ) 10.8, 4.4 Hz), 3.9 (br s, NH2, OH),
4.10 (dd, J ) 10.8, 10.4), 4.5 (dd, J ) 10.4, 4.4 Hz), 5.00 (d, J
) 3.8 Hz), 7.1-7.5 (m, 10 H); 13C NMR (CDCl3) δ 23.6, 23.9,
25.6, 45.7, 53.8, 60.8, 61.8, 62.4, 126.7, 127.2, 127.9, 128.4,
128.5, 129.0, 136.5; HRMS calcd for C20H26N2O 310.2044, found
310.2042.
(1S,4R,9a S)-1-Bu t yl-4-p h en yloct a h yd r op yr id o[2,1-c]-
[1,4]oxa zin -1-a m in e (12b). A solution of n-butylimine 11b
(2 g, 6.99 mmol) in MeOH/THF (25 mL of each) was acidified
with 1 N aq HCl (pH 3). After addition of NaBH3CN (0.48 g,
7.69 mmol), the reaction mixture was maintained at pH 3,
refluxed for 1.5 h, and then neutralized at pH 7 with saturated
aq NaHCO3 and extracted three times with CH2Cl2. The
organic layers were dried over MgSO4, concentrated, and
purified by flash chromatography on silica gel (cyclohexane/
AcOEt 3:1) to give the butylmorpholine 12b in 72% yield (1.4
g, 4.86 mmol) as a pale yellow oil: [R]D -97 (c 1.2, CHCl3); IR
3400, 3020, 2938, 1480, 1224 cm-1; MS (EI) m/ z 288 (M+, 1),
(1R)-1-[(2S)-P ip er id in -2-yl]eth a n a m in e (14a ). A solu-
tion of amino alcohol 13a (0.95 g, 3.83 mmol) and 10%
palladium on charcoal (0.15 g) in MeOH (10 mL) was acidified
with 4 mL of MeOH/2 N HCl. The reaction mixture was
stirred for 5 h under an H2 atmosphere and then filtered over
a Celite bed with MeOH and concentrated. After trituration
with Et2O, the resulting precipitate was washed several times
(Et2O, 20 mL) to eliminate 2-phenylethanol. Recrystallization
in MeOH/Et2O led to white crystals of diamine 14a as a
dihydrochloride salt (0.677 g, 3.37 mmol) in 88% yield: [R]D
+43 (c 0.56, MeOH); MS (CI) 201 (M + 1, 100), 112 (10), 84
1
272 (3), 231 (5), 187 (100); H NMR (CDCl3) δ 0.92 (t, J ) 7
Hz), 1.2-1.8 (m, 13 H), 2.10 (br s, NH2), 2.20 (dd, J ) 11, 2.1
Hz), 2.70 (dt, J ) 11.5, 2.5 Hz), 3.18 (dd, J ) 11.1, 4.0 Hz),
3.46 (dd, J ) 12, 4.0 Hz), 3.75 (dd, J ) 12, 11.1 Hz), 7.2-7.4
(m, 5 H); 13C NMR (CDCl3) δ 14.2, 23.3, 24.5, 24.7, 25.5, 27.3,
39.0, 53.6, 65.3, 67.2, 69.2, 85.6, 127.5, 127.9, 128.5, 140.2.
Anal. Calcd for C18H28N2O: C, 74.95; H, 9.78; N, 9.71.
Found: C, 75.01; H, 9.89; N, 9.76.
1
(25); H NMR (CD3OD) δ 1.55 (d, J ) 6.9 Hz), 1.7-2.2 (m, 6
H), 3.20 (td, J ) 12.8, 3.8 Hz), 3.52 (ddd, J ) 11.8, 5.1, 3.1),
3.60 (dt, J ) 12.8, 1.6 Hz), 3.73 (qd, J ) 6.9, 5.1 Hz); 13C NMR
(CD3OD) δ 15.7, 22.8, 25.6, 25.6, 46.8, 50.6, 60.0. Anal. Calcd
for C7H18N2Cl2: C, 41.79; H, 9.02; N, 13.92. Found: C, 42.04;
H, 8.72; N, 13.85.
(1S,4R,9a S)-1,4-Dip h en ylocta h yd r op yr id o[2,1-c][1,4]-
oxa zin -1-a m in e (12c). Following the same procedure as for
product 12a , phenylimine 11c (2 g, 6.53 mmol) was reduced
with NaBH3CN (0.45 g, 7.18 mmol) in 1.5 h at reflux under
acidic conditions (MeOH/THF 1:1, 50 mL; 1 N HCl, pH 3).
Identical workup and flash chromatography purification (SiO2,
hexane/ether 1:1) gave a white solid (12c) in 75% yield (1.5 g,
4.89 mmol): mp 155 °C (ether/heptane); [R]D -50 (c 0.92,
CHCl3); IR 3400, 3090, 2950, 1510 cm-1; MS (CI) 309 (M + 1,
(1R)-1-[(2S)-P ip er id in -2-yl]p en ta n -1-a m in e (14b).
A
solution of amino alcohol 13b (0.9 g, 3.10 mmol) and palladium
hydroxide (20% on charcoal, 0.15 g) in MeOH (10 mL) was
stirred for 6 h under an H2 atmosphere and then filtered over
Celite and concentrated under vacuo. The oily residue was
purified by chromatography on alumina. The first elution with
CH2Cl2/MeOH 98:2 gave the 2-phenylethanol byproduct, then
CH2Cl2/MeOH/NH4OH 85:10:5 led to butylamine 14b (0.44 g,
2.63 mmol) as a pale yellow oil (85% yield): [R]D +6.3 (c 1.56,
CHCl3); IR 3288, 2930, 1590 cm-1; MS (EI) m/ z (rel intensity)
170 (M+, 100), 84 (35); 1H NMR (CDCl3) δ 0.90 (t), 1.2-1.6
(m, 12 H), 2.40 (ddd, J ) 11.1, 4.0, 2.3 Hz), 2.62 (m), 2.65 (td,
J ) 11.9, 2.9 Hz), 3.10 (br d, J ) 11.9 Hz); 13C NMR (CDCl3)
δ 14.1, 22.8, 24.8, 26.4, 26.7, 28.9, 33.4, 47.4, 55.7, 61.7. Anal.
Calcd for C10H22N2: C, 70.52; H, 13.02; N, 16.45. Found: C,
70.37; H, 13.17; N, 16.35.
1
100), 292 (35); H NMR (CDCl3) δ 1.0-1.8 (m, 7 H), 2.45 (dd,
J ) 11.0 and 2.4 Hz), 2.55 (br s, NH2) 2.78 (br d, J ) 11.2 Hz),
3.40 (dd, J ) 11.2, 4.1 Hz), 3.68 (dd, J ) 12.1, 4.1 Hz), 3.98
(dd, J ) 12.1, 11.2 Hz), 7.3, 7.8 (m, 10 H); 13C NMR (CDCl3) δ
24.6, 25.6, 26.9, 53.8, 65.6, 69.6, 69.8, 87.9, 127.3-128.7, 140.1,
143.6. Anal. Calcd for C20H24N2O: C, 77.88; H, 7.84; N, 9.08.
Found: C, 77.55; H, 7.78; N, 8.88.
(2R )-2-[(2S )-2-[(1R )-1-Am in oe t h yl]p ip e r id in -1-yl]-2-
p h en yleth a n ol (13a ). To a stirred suspension of LiAlH4 (0.25
g, 6.57 mmol) in anhydrous Et2O (25 mL) at -5 °C was added
slowly a solution of methyl morpholine 12a as a mixture of
isomers (1.4 g, 5.69 mmol) in ether (5 mL). After 1.5 h at rt,
the mixture was treated with H2O (0.25 mL), 15% aqueous
NaOH (0.25 mL), and H2O (0.75 mL). The resulting white
precipitate was filtered and washed several times with Et2O.
After removal of the solvent under reduced pressure, com-
pound 13a was isolated pure as a pale yellow oil in 95% yield
(1.34 g, 5.4 mmol): [R]D -68 (c 2.3, CHCl3); IR 3010, 2890,
1600 cm-1; MS (EI) m/ z (rel intensity) 248 (M+, 2), 204 (100);
(CI) 249, 1H NMR (CDCl3) δ 1.1 (d, J ) 6.6 Hz), 1.2-1.6 (m, 6
H), 1.7 (td, J ) 11.5, 2.5 Hz), 2.25 (dt, J ) 10.8, 2.8 Hz), 2.6-
2.7 (br s, NH2, OH), 2.92 (br d, J ) 11.5 Hz), 3.65 (dd, J )
10.5, 4.8 Hz), 3.85 (qd, J ) 6.6, 2.8 Hz), 4.08 (t, J ) 10.5 Hz),
4.45 (dd, J ) 10.5, 4.8 Hz), 7.1-7.4 (m, 5H); 13C NMR (CDCl3)
(2R)-2-[(2S)-2-[(1R)-1-(N-Meth ylam in o)pen tyl]piper idin -
1-yl]-2-p h en yleth a n ol (15b). A solution of amino alcohol
13b (1.4 g, 4.82 mmol) in CHCl3 (40 mL) was heated for 2 h
under reflux with methyl chloroformate (0.41 mL, 5.31 mmol).
The resulting mixture was quenched with saturated aqueous
NH4Cl and extracted following a general workup procedure
to give a pale yellow oil which was dissolved in Et2O (10 mL)
and added to a stirred suspension of LiAlH4 (0.16 g, 4.2 mmol)
in anhydrous Et2O (30 mL) at -5 °C. After 3 h at rt, the
mixture was treated with H2O (0.16 mL), 15% aqueous NaOH
(0.16 mL), and H2O (0.48 mL). The resulting white precipitate
was filtered and washed several times with Et2O. After
removal of the solvent under reduced pressure, methyl amine
15b was isolated as a colorless oil in 78% yield (1.14 g, 3.76
mmol): [R]D -105 (c 1.0, CHCl3); IR 3250, 2930, 1450 cm-1
;

Synthesis of 2-(1-Aminoalkyl)piperidines
J . Org. Chem., Vol. 61, No. 19, 1996 6705
MS (EI) m/ z (rel intensity) 304 (M+, 12), 274 (10), 204 (100);
1H NMR (CDCl3) δ 0.95 (t), 1.35-1.7 (m, 13 H), 2.45 (dt, J )
11.1, 2.7 Hz), 2.50 (s), 2.97 (br d, J ) 11.6 Hz), 3.14 (m), 3.62
(dd, J ) 10.4, 4.9 Hz), 4.05 (dd, J ) 10.9, 10.4 Hz), 4.28 (dd,
J ) 10.9, 4.9 Hz), 7.2, 7.35 (m, 5 H); 13C NMR (CDCl3) δ 14.1,
23.2, 24.5, 24.8, 26.2, 28.6, 30.4, 35.0, 46.3, 58.6, 59.2, 59.7,
60.4, 127.5, 128.0, 128.9, 136.1; HRMS calcd for C19H32N2O
304.2512, found 304.2515.
was stirred for 10 min at rt and then cooled to -20 °C before
addition of phenyl lithium (3.4 mL, 6.8 mmol). The solution
was slowly warmed to rt over 1.5 h and then quenched with
saturated aq NH4Cl. The combined organic layers were
washed with H2O, dried over MgSO4, and concentrated.
Purification by flash chromatography (SiO2, CH2Cl2/MeOH 98:
2) led to compound 19 (0.380 g, 0.98 mmol) as a viscous oil in
75% yield: [R]D -142 (c 1.7, MeOH); IR 3455, 3248, 2944, 2831,
1443, 1423 cm-1; MS (EI) m/ z (rel intensity) 384 (M+, 8), 367
(5), 353 (11), 307 (6), 289 (6), 265 (100); 1H NMR (CDCl3) δ
1.4-2.1 (m, 6 H), 3.80, 3.95 (2 m, 3 H), 4.10 (br s); 4.35 (br s),
7.2-7.6 (15 H); 13C NMR (CDCl3) δ 15.6, 20.4, 25.6, 60.1, 62.0,
65.5, 71.8, 72.8, 125.7-128-4, 140.3, 140.9, 154.2. Anal.
Calcd for C26H28N2O: C, 80.21; H, 7.34; N, 7.29. Found: C,
80.21; H, 7.34; N, 7.03.
(1R)-N-Met h yl-1-[(2S)-p ip er id in -2-yl]p en t a n -1-a m in e
(16b). A solution of diamino alcohol 15b (0.5 g, 1.65 mmol)
and 20% palladium hydroxide on charcoal (80 mg) in MeOH
(10 mL) was stirred for 3 h under a hydrogen atmosphere and
then filtered over a Celite pad and concentrated under vacuo.
The oily residue was purified by flash chromatography (SiO2).
First elution gave the 2-phenylethanol byproduct (CH2Cl2/
MeOH, 95:5), then other solvent mixture (CH2Cl2/MeOH, 90:
10) led to the title compound 16b (0.26 g, 1.43 mmol) as a
colorless oil in 87% yield: [R]D -12 (c 1.0, CHCl3); IR 3420,
2950, 2700, 1592, 1467 cm-1; MS (EI) m/ z (rel intensity) 185
(2R)-2-[(2S)-2-(Am in od ip h en ylm eth yl)p ip er id in -1-yl]-
2-p h en yleth a n ol. (20). A methanolic solution (15 mL) of 19
(0.3 g, 0.78 mmol) and NaBH4 (61 mg, 1.6 mmol) was stirred
for 2.5 h at rt and then quenched with saturated aq NH4Cl
and extracted with CH2Cl2. The organic layer was washed
with H2O, dried over MgSO4, and concentrated to yield 96%
of pure amino alcohol 20 (0.291 g, 0.75 mmol) as an oil: [R]D
1
(M + 1, 18), 151 (10), 137 (15), 123 (15); H NMR (CDCl3) δ
0.85 (t), 1.20-2.0 (m, 12 H), 2.60 (s), 2.90 (td, J ) 12.4, 4.0
Hz), 3.12 (dt, J ) 12.0, 2.0 Hz), 3.20 (m), 3.45 (brd, J ) 12.4
Hz); 13C NMR (CDCl3) δ 13.9, 22.6, 22.6, 22.7, 22.9, 28.4, 28.4,
33.7, 45.4, 58.0, 61.3; HRMS calcd for C11H24N2 184.1938,
found 184.1929.
-101 (c 1.4, MeOH); IR 3521, 3196, 2366, 2333, 1428 cm-1
;
MS (EI) m/ z (rel intensity) 386 (M+, 17), 355 (3), 265 (17),
1
N-[(R)-[(2S)-1-[(1R)-2-Hydr oxy-1-ph en yleth yl]piper idin -
2-yl]p h en ylm et h yl]ben za m id e (17c). To a solution of
amino alcohol 13c (1.24 g, 4 mmol) in CH2Cl2 (60 mL) was
added diluted aqueous NaOH (15%, 4 mL) and benzoyl chloride
(0.62 g, 4.4 mmol). The reaction mixture was stirred for 2.5 h
at rt and then diluted with saturated aqueous NH4Cl and
extracted with CH2Cl2. The organic layers were concentrated
and purified by chromatography (Al2O3, CH2Cl2/MeOH 99:1)
to give compound 17c as a yellow oil (1.37 g, 3.32 mmol, 83%
204 (100); H NMR (CDCl3) δ 0.65-1.15 (4 H), 1.6 (m), 1.80
(m), 2.0 (ddd, J ) 14.4, 9.6, 7.2 Hz), 2.53 (ddd, J ) 14.4, 4.3,
3.3 Hz), 3.72 (dd, J ) 15.6, 8.2 Hz), 4.0 (m, 2 H), 4.22 (t, J )
7.5 Hz), 7.2-7.5 (m, 15 H); 13C NMR (CDCl3) δ 19.7, 21.0, 23.7,
40.7, 63.5, 63.7, 66.8, 71.1, 126.0-129.0, 141.4, 144.1, 147.7;
HRMS calcd for C26H30N2O 386.2356, found: 386.2355.
N-[[(2S)-1-[(1R)-2-Hyd r oxy-1-p h en yleth yl]p ip er id in -2-
yl]d ip h en ylm eth yl]-2,2,2-tr iflu or oa ceta m id e (21). A solu-
tion of amino alcohol 20 (1 g, 2.59 mmol) in CH2Cl2 (30 mL)
was stirred for 4 h at 20 °C with trifluoroacetic anhydride (0.43
mL, 3.10 mmol) and triethylamine (0.73 mL, 5.18 mmol) and
then quenched with saturated aq NH4Cl. The general workup
procedure gave an oily residue which was purified by flash
chromatography (SiO2, CH2Cl2). Pure compound 21 was
isolated in 79% yield as a colorless oil (0.99 g, 2.04 mmol): [R]D
-18.4 (c 1, CHCl3); IR 3420, 3250, 3100, 1750 cm-1; MS (EI)
m/ z (rel intensity) 483 (M + 1, 25), 345 (20), 297 (30), 204
(100); 1H NMR (CDCl3) δ 1.2-1.7 (m, 7 H), 2.11 (br d, J )
14.7 Hz), 3.87, 4.21 (2 br d, J ) 12.0 Hz), 4.10 (dd, J ) 4.0, 3.8
Hz), 4.42 (dd, J ) 6.7, 6.0 Hz), 7.1-7.5, 7.6 (m, 15 H); 13C NMR
(CDCl3) δ 18.3, 19.1, 21.3, 42.1, 60.8, 64.2, 67.6, 68.0, 127.4-
129.8, 141.0, 141.2.
yield): [R]D -38.4 (c 1.0, CHCl3); IR 3332, 2931, 1637 cm-1
;
MS (EI) m/ z (rel intensity) 414 (M+, 15), 383 (100), 309 (25),
1
293 (15); H NMR (CDCl3) δ 0.9-1.8 (m, 6 H), 2.11 (td, J )
11.4, 2.8 Hz), 2.75 (ddd, J ) 8.6, 5.2, 4.8 Hz), 3.08 (dt, J )
11.4, 3.6 Hz), 3.52 (dd, J ) 10.8, 5.3 Hz), 3.97 (dd, J ) 10.8,
10.1 Hz), 4.40 (dd, J ) 10.1, 5.3 Hz), 6.08 (dd, J ) 7.1, 5.2
Hz), 6.82 (d, J ) 7.1 Hz), 7.3-7.9 (m, 15 H); 13C NMR (CDCl3)
δ 23.5, 25.4, 25.6, 45.1, 52.7, 60.5, 61.7, 62.2, 126.2-131.6,
135.6, 135.9, 140.2, 167.7; HRMS calcd for C26H27N2O (M -
CH2OH) 383.2122, found 383.2116.
N-[(R)-P h en yl[(2S)-p ip er id in -2-yl]m et h yl]b en za m id e
(18c). A solution of amino alcohol 17c (1.2 g, 2.91 mmol) and
activated 10% palladium on charcoal (180 mg) in MeOH (10
mL) was stirred for 3 h under an H2 atmosphere and then
filtered over Celite and concentrated. 2-Phenylethanol was
eliminated by trituration of the oily residue with Et2O. Pure
compound 18c was thus obtained in 81% yield as a colorless
viscous oil (0.69 g, 2.35 mmol): [R]D +14 (c 1, CHCl3); IR 3340,
2940, 1638 cm-1; MS (EI) m/ z (rel intensity) 295 (M + 1, 10),
Dip h en yl[(2S)-p ip er id in -2-yl]m eth a n a m in e (22). A so-
lution of trifluoroacetamide 21 (0.85 g, 1.76 mmol) in MeOH
(12 mL) was acidified with concentrated HCl (4 mL) and
stirred for 1 h under hydrogene atmosphere with 10% acti-
vated palladium on charcoal (100 mg). After filtration over
Celite, the mixture was heated directly under reflux in diluted
aqueous HCl (6 N, 20 mL) for 12 h. 2-Phenylethanol and
trifluoroacetic acid byproducts were extracted of the crude
mixture with CH2Cl2. Aqueous layer was concentrated under
vacuo (up to 5 mL), then neutralized (pH 7) and extracted
following the usual work-up procedure. Pure diphenylamine
22 was then isolated as a colorless oil in 60% yield (0.28 g,
1.05 mmol): [R]D -28.6 (c 0.5, CHCl3); IR 3317, 3057, 2932,
2852, 1596 cm-1; MS (EI) m/ z (rel intensity) 267 (M + 1, 20),
250 (25), 182 (26), 165 (12), 104 (54), 85 (67), 84 (100); 1H NMR
(CDCl3) δ 1.20-1.80 (m, 6 H), 1.95 (br s, NH, NH2), 2.68 (td,
J ) 11.5, 2.7 Hz), 3.05 (br d, J ) 11.5 Hz), 3.49 (dd, J ) 10.5,
2.0 Hz), 7.35, 7.5 (m, 10 H); 13C NMR (CDCl3) δ 25.4, 26.8,
27.1, 47.8, 63.5, 63.8, 126.8-129.2, 146.0, 146.8; HRMS calcd
for C18H23N2 267.1860, found 267.1854.
1
174 (50), 122 (50), 105 (100); H NMR (CDCl3) δ 0.9-1.9 (m,
6 H), 2.51 (td, J ) 13.0, 2.4 Hz), 2.84 (ddd, J ) 10.7, 6.1, 1.8),
2.97 (br d, J ) 13.0 Hz), 5.0 (dd, J ) 7.8, 6.1 Hz), 7.1-7.9 (m,
10 H), 7.62 (d, J ) 7.8 Hz); 13C NMR (CDCl3) δ 24.6, 26.8,
30.1, 47.0, 57.8, 60.4, 126.5-131.3, 134.6, 139.2, 166.6; HRMS
calcd for C19H22N2O 294.1732, found 294.1748.
(R)-P h en yl[(2S)-p ip er id in -2-yl]m eth a n a m in e (14c). A
solution of benzamide 18c (0.6 g, 2.04 mmol) in 6 N HCl (12
mL) was heated for 24 h under reflux and then diluted at rt
and washed three times with Et2O to eliminate benzoic acid.
The aqueous layers were concentrated up to 5 mL, basified
with NaOH (30%, pH 7), and extracted with CH2Cl2. The
general workup procedure gave 14c as a pale yellow oil in 79%
yield (0.3 g, 1.61 mmol): [R]D +0.7 (c 1, MeOH); MS (EI) m/ z
(rel intensity) 191 (M + 1, 15), 172 (10), 153 (25), 106 (25), 84
(100); IR 3600, 2900, 1600, 1510 cm-1; 1H NMR (CDCl3) δ 1.3-
1.9 (m, 6 H), 2.62 (td, J ) 12.1, 3.1 Hz), 2.80 (ddd, J ) 10.9,
6.7, 2.2 Hz), 3.05 (dt, J ) 12.1, 2.0 Hz), 3.9 (d, J ) 6.7 Hz), 7.3
(m, 5 H); 13C NMR (CDCl3) δ 24.4, 25.7, 28.0, 46.9, 60.4, 62.8,
127.2, 127.4, 128.5, 149.1; HRMS calcd for C12H19N2 (M + 1)
191.1548; found 191.1559.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for compounds 5, 9, 11c, 13a -c, 14c, 15b, 16b, 18c,
and 20-22 (26 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead for ordering information.
(2R)-2-[(1S,5R)-7,7-Dip h en yl-6,8-d ia za bicyclo[3.2.1]oct-
8-yl]-2-p h en yleth a n ol (19). A solution of 1 (0.3 g, 1.31 mmol)
and LiBr (0.592 g, 6.81 mmol) in freshly distilled Et2O (20 mL)
J O960910S