Practical asymmetric synthesis of 1,2-diamines in the 3-aminoazepane series

Article abstract of DOI:10.1021/jo026711s

A simple and versatile method for the enantio- and diastereoselective synthesis of mono- or disubstituted 3-aminoazepanes is described. The key step involves a highly regio- and diastereoselective tandem ring-enlargement/alkylation or reduction process. T

Full text of DOI:10.1021/jo026711s

P r a ctica l Asym m etr ic Syn th esis of 1,2-Dia m in es in th e
3-Am in oa zep a n e Ser ies
S. Cutri, M. Bonin,* L. Micouin,* and H.-P. Husson
Laboratoire de Chimie The´rapeutique, UMR 8638 associe´e au CNRS et a` l’Universite´ Rene´ Descartes,
Faculte´ des Sciences Pharmaceutiques et Biologiques, 4, av de l’Observatoire,
75270 Paris Cedex 06, France
A. Chiaroni
Institut de Chimie des Substances Naturelles, Avenue de la Terrasse, F-91198 Gif-sur-Yvette, France
micouin@pharmacie.univ-paris5.fr; bonin@pharmacie.univ-paris5.fr
Received November 14, 2002
A simple and versatile method for the enantio- and diastereoselective synthesis of mono- or
disubstituted 3-aminoazepanes is described. The key step involves a highly regio- and diastereo-
selective tandem ring-enlargement/alkylation or reduction process. This novel synthetic route
provides enantiomerically pure constrained diamines interesting as scaffolds for medicinal
chemistry.
SCHEME 1
In tr od u ction
Vicinal diamines and their derivatives have been
shown to play key roles in medicinal chemistry, coordina-
tion chemistry, and asymmetric catalysis.1 Among this
family, constrained diamine systems continue to attract
synthetic interest due to their wide potential as medicinal
agents. Novel polyamino derivatives recently reported as
potential contrast enhancement agents in MRI have
displayed considerable improvement of in vivo stability
and biodistribution relative to nonrigid gadolinium(III)
complexes.2 Various CNS receptor ligands3 and antitumor
chiral cis-platin analogues4 have been developed in the
3-aminoazepane series. Although various synthetic path-
ways have been devised for the preparation of function-
alized azepanes,5 a straightforward access to enantiopure
polysubstituted 3-aminoazepanes, as general scaffolds for
the elaboration of bioactive compounds, would be desir-
able.
phenyl- and 2-furyl-3-aminoazepanes 3a ,c from 2-cyano-
6-oxazolopiperidine 1.6 The key step involved a one-pot
reduction and ring-enlargement process of intermediates
2 occurring in a totally regio- and diastereoselective
manner (Scheme 1).
We report in this article our full investigations in this
field, as well as the generalization of this original ring-
enlargement reaction for the diastereo- and enantio-
selective preparation of 2,7-disubstituted 3-aminoazepanes
4.
In previous preliminary synthetic studies, we reported
the asymmetric synthesis of optically pure trans-2-
(1) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed.
1998, 37, 2581.
(2) Chong, H.-S.; Garmestani, K.; Bryant, L. H.; Brechbiel, M. W.
J . Org. Chem. 2001, 66, 7745.
Resu lts a n d Discu ssion
(3) (a) Matecka, D.; Rothman, R. B.; Radesca, L.; De Costa, B. R.;
Dersch, C. M.; Partilla, J . S.; Pert, A.; Glowa, J . R.; Wojnicki, H. E.;
Rice, K. C. J . Med. Chem. 1996, 39, 4704. (b) Hirokawa, Y.; Morie, T.;
Yamazaki, H.; Yoshida, N.; Kato, S. Bioorg. Med. Chem. Lett. 1998, 8,
619. (c) Zhao, S.; Freeman, J . P.; Bacon, C. L.; Fox, G. B.; O’Driscoll,
E.; Foley, A. G.; Kelly, J .; Farrell, U.; Regan, C.; Mizsak, S. A.;
Szmuszkovicz, J . Bioorg. Med. Chem. 1999, 7, 1647.
Syn th esis of 2-Su bstitu ted 3-Am in oazepan es. Mul-
tigram quantities of bicyclic imines 2 can be prepared in
one step from 2-cyano 6-oxazolopiperidine 17 in yields
ranging from 74% to 97% (Scheme 2).
These stable compounds are key intermediates for the
ring-enlargement strategy. Under protic conditions, reac-
(4) Rezler, E. M.; Fenton, R. R.; Esdale, W. J .; McKeage, M. J .;
Russell, P. J .; Hambley, T. W. J . Med. Chem. 1997, 40, 3508.
(5) (a) Meyers, A. I.; Downing, S. V.; Weiser, M. J . J . Org. Chem.
2001, 66, 1413. (b) Chong, H.-S.; Ganguly, B.; Broker, G. A.; Rogers,
R. D.; Brechbiel, M. W. J . Chem. Soc., Perkin Trans. 1 2002, 2080 and
references therein. (c) Kantorowski, E. J .; Kurth, M. J . Tetrahedron
2000, 56, 4317. (d) Evans, A. P.; Robinson, J . E. Org. Lett. 1999, 1,
1929.
(6) Cutri, S.; Bonin, M.; Micouin, L.; Froelich, O.; Quirion, J .-C.;
Husson, H.-P. Tetrahedron Lett. 2000, 41, 1179.
(7) Bonin, M.; Grierson, D. S.; Royer, J .; Husson, H.-P. Org. Synth.
1992, 70, 54.
10.1021/jo026711s CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/20/2003
J . Org. Chem. 2003, 68, 2645-2651
2645

Cutri et al.
SCHEME 2a
SCHEME 4a
a
Reagents and conditions: (a) NaH, TBDMSCl, 94% (R ) Ph),
86% (R ) nBu), 81% (R) 2-OMe-Ph), 95% (R ) 2-Py); (b) see Table
a
Reagents and conditions: R1 ) Ph, nBu, 2-Py/R1Li, Et2O, -78
°C; R1 ) 2-OMe-Ph, 2-furyl/R1Li, TMEDA, THF, -78 °C.
1.
SCHEME 3a
TABLE 1. Dia ster eoselective Access to Am in a ls 10 or 11
producta
R1
conditions
10:11
yield (%)b
11a
11b
11d
10e
Ph
Li/NH3
LAH
LAH
19:81
<5:95
<5:95
98:2
64
65
74
68
nBu
2-MeOPh
2-Py
H2, Pd/C
a
b
Major diastereomer. Yield of diastereomerically pure com-
pound.
prepared and protected as O-silylated compounds 10a -e
in 70-90% yield (Scheme 4).
Selective imine reductions proved to be particularly
troublesome and highly dependent on their substitution
patterns. Our first attempts to reduce 9a using LAH
under various experimental conditions led to either
irreproducible results or the known desilylated azepane
derivative 8a . More encouraging results were obtained
using dissolving-metal conditions.9 Treatment of 9a with
lithium in liquid ammonia afforded, in a first experiment,
a mixture of aminals 10a and 11a in a 1/1 ratio. Careful
optimization of the reprotonation conditions improved
this ratio significantly in favor of the 11a isomer, leading
to pure material in 64% yield (Table 1). The presence of
a bicyclic aminal could be ascertained by typical NMR
chemical shifts (a doublet at 4.58 ppm and a peak at 60.5
a
Reagents and conditions: (a) NaBH3CN, H+, THF, MeOH; (b)
LAH, Et2O; (c) NaBH4, MeOH.
tion of butyl or phenyl derivatives 2a ,b with NaBH4 or
NaBH3CN have been reported to give piperidines 5 or
morpholines 6, respectively, in a high diastereoselective
manner (Scheme 3).8
Treatment of the same imines with LAH led to a
completely different 1,2-diamine system. No trace of six-
membered ring derivatives could be observed starting
from aromatic conjugated imines 2a ,c. However, in the
butyl series an inseparable mixture of compounds 8b and
5b was obtained. The best conditions were found by
adding LAH carefully to an ether solution of the imine
(20 °C, 3 h; 8b/5b ) 9/1). The different issues of
reductions can be explained by chemoselective nitrogen
activation. On the one hand, activation of the secondary
aminal nitrogen under protic conditions leads to a six-
membered ring; on the other hand, activation of the
piperidine nitrogen under Lewis acidic conditions leads
to the ring enlargement. The lack of selectivity observed
in the aliphatic series probably relies on the formation
of a transient morpholine 6b, known to be reduced into
piperidine systems by LAH. This morpholine was indeed
isolated when LAH reduction of 2b was performed at low
temperature (-78 °C).
Since the ring enlargement proceeds by a two-step
reduction, isolation of the transient aminal should allow
selective functionalization at the C-7 azepane position
by a nucleophilic opening with a suitable organometallic
nucleophile instead of a hydride. Before selective reduc-
tions trials, the alcohol function was first protected in
order to avoid the formation of morpholine-type inter-
mediates. Various aryl and alkyl imines 2a -e were thus
1
ppm observed, respectively, in the H and the 13C NMR
spectra were attributed to the C-7 reduced position, two
broad deshielded proton signals consistent with the
searched bicyclic aminal system). Absolute configuration
of the newly created asymmetric center was determined
unambiguously by chemical transformation of 11a into
O-silylated piperidine derivative 12a by acidic NaBH3-
CN reduction.7 In the 2-methoxyphenyl series, simple
LAH reduction afforded the corresponding aminal 11d
with reasonable yield and high diastereoselectivity,
without over-reduction into the corresponding azepane.
Both methods failed when applied to the pyridinyl imine
9e reduction. LAH reduction led only to desilylation or
degradation material, whereas lithium or sodium in
liquid ammonia gave an inseparable mixture of aminals
10e and 11e (60:40 ratio, 95% yield). Pd-catalyzed
hydrogenation in various solvents was therefore inves-
tigated. The hydrogenation of the imine in ethyl acetate
afforded the corresponding aminals 10e and 11e as an
equimolar mixture, whereas in methanol, the major
derivative 10e could be isolated in a diastereomerically
pure form. Finally, 11b could be obtained as a single
diastereomer after LAH reduction.
In each case, 1H and 13C NMR spectra revealed
characteristic signals of bridged bicyclic structures as
(8) Froelich, O.; Desos, P.; Bonin, M.; Quirion, J .-C.; Husson, H.-P.
J . Org. Chem. 1996, 61, 6700.
(9) Corey, E. J .; Imwinkelried, R.; Pikul S.; Xiang, Y. B. J . Am.
Chem. Soc. 1989, 111, 5493.
2646 J . Org. Chem., Vol. 68, No. 7, 2003

Mono- or Disubstituted 3-Aminoazepanes
SCHEME 5
SCHEME 7
TABLE 2. Dia ster eoselective Access to P olysu bstitu ted
Azep a n es 14
product
R1
R2
yield (%)a
de (%)b
SCHEME 6a
14a
14b
14c
14d
14e
14f
Ph (2R)
Ph (2R)
Ph (2R)
2-Py (2R)
2-Py (2R)
2-Py (2R)
Me
iBu
Bn
Me
iBu
Bn
57
84
95
69
70
65
>95
>95
>95
>95
>95
>95
a
b
Yield of diastereomerically pure compound. Determined by
1H NMR of the crude reaction mixture.
reactive species from bicyclic aminals 10 or 11 and enable
further functionalizations of the azepane at the C-7
position. Although the reactivity of such aminals is
unknown, the related reaction of nucleophilic reagents,
especially organomagnesium compounds, with oxazo-
lidines is well-documented.11 Initial experiments were
performed on phenylaminal 11a , using methylmagne-
sium bromide as a nucleophile and a Lewis acid (Table
2). The best results were obtained via refluxing 11a in
ether with an excess of organomagnesium reagent (3.5
equiv), leading to compound 14a in 57% yield as a single
diastereomer. The formation of a ring-enlarged derivative
could be ascertained by typical NMR data: 13C NMR
spectrum displayed the three CH peaks at 49.5, 62.2, 62.8
ppm and one methyl signal at 23.4 ppm as expected from
a
i
Reagents and conditions: (a) LAH, Pr2O or Et2O, reflux; (b)
H2, Pd/C, MeOH-HCl for 8a ,b,d ,f or H5IO6 (2.6 equiv), MeNH2,
H2O, MeOH, then MeOH-HCl for 8c. bFrom 2a ,c via one-step
reduction (Scheme 3).
shown above. However, the relative configuration of the
newly created stereogenic center (C-7) could not be
determined directly from the NMR data. This was
achieved by correlation with the corresponding erythro
(J ) 3.9-4.3 Hz) or threo (J ) 10.1-11.2 Hz) O-silylated
aminoalkyl piperidines 12 after acidic NaBH3CN aminal
reduction of analytical samples (Scheme 5).
1
Since bicyclic aminals are believed to be intermediates
in the one-step ring enlargement process, their reduction
with LAH should lead to the known azepanes 8. This was
indeed the case, although this transformation required
harsher reaction conditions than with the direct imine
reduction. LAH treatment of aminal 11d in refluxing
diisopropyl ether afforded in a diastereoselective manner
the desilylated and demethylated azepane 8f with the
desired azepane cyclic core 8d as a minor side product
(8d /8f ) 25/75).10Using milder conditions (refluxing in
diethyl ether), the desired product 8d was obtained as
the major product (8d /8f ) 80/20). Unfortunately, pres-
ence of a pyridine ring seemed to inhibit the ring-
enlargement process. Finally, unprotected 2-substituted
3-amino azepanes were obtained in good yield after
hydrogenolysis or oxidative cleavage. Interestingly, using
this two-step process, diamine 8b could be obtained in
good yield and total diastereoselectivity, without any six-
membered ring contaminants. Once again, the trans
relative configuration of such azepanes could be ascertain
by the typical H-2/H-3 coupling constant of 9 Hz.
the alkylation process. The H NMR spectrum showed a
multiplet at 2.90 ppm for the C-7 proton and a doublet
at δ 3.82 ppm for the C-2 proton.
The use of iso-butyl as well as benzyl Grignards as
nucleophiles afforded exclusively ring-enlarged deriva-
tives 14b,c in diastereomerically pure form. Interestingly,
no reduction product arising from an hydride transfer
with the branched organomagnesium reagent could be
detected. Unlike the LAH reduction of aminals 11b,d ,
the ring enlargement occurred without any O-desilyla-
tion. Final compounds 4a ,b,c could be obtained after
desilylation and hydrogenolysis. Following standard
procedure, benzylazepane 4c was finally converted to
crystalline benzamide 15, and its relative configuration
was determined by X-ray crystallography analysis. The
3,7-cis configuration could be attributed to derivatives
4a ,b by comparisons of their 1H and 13C NMR spectra.
The same ring-enlargement reactions were then per-
formed starting from pyridyl aminal 10e, to study the
Syn th esis of 2,7-Disu bstitu ted 3-Am in oa zep a n es.
During the ring-enlargement process, a transient seven-
membered imine was reduced by a hydride. However, the
use of a Lewis acidic nucleophile should lead to the same
(11) (a) For a general review on aminals preparation, see: Pawlenko,
S.; Lang-Fugmann, S. In Houben-Weyl Methoden der Organische
Chemie; Hageman, H., Klaman, D., Eds.; Georg Thieme Verlag:
Stuttgart, 1992, E14a/3. Aminals as chiral auxiliary: (b) Alexakis, A.;
Mangeney, P.; Nelsen, N.; Tranchier, J . P.; Gosmini, R.; Raussou, S.
Pure Appl. Chem. 1996, 68, 531. (c) J ung, M. E.; Huang, A. Org. Lett.
2000, 2, 2659. Nucleophilic opening of oxazolidines: (d) Bloch, R. Chem.
Rev. 1998, 98, 1407. (e) Enders, D.; Reinhold: U. Tetrahedron:
Asymmetry 1997, 8, 1895. (f) Steinig, A. G.; Spero, D. M. Org. Prep.
Proc. Int. 2000, 32, 205.
(10) Such reductive demethylation has been previously described
on ortho-substituted methoxyphenols: Kimura, K.; Tanaka, M.; Iketani
S.-I.; Shono, T. J . Org. Chem. 1987, 52, 836.
J . Org. Chem, Vol. 68, No. 7, 2003 2647

Cutri et al.
IR spectra were recorded as thin film unless otherwise stated.
Mass spectral data were recorded in chemical-ionization (CI)
i
mode. Tetrahydrofuran (THF) and ether (Et2O or Pr2O) were
distilled from sodium/benzophenone immediately prior to use;
CH2Cl2, TMEDA, Et3N, MeOH, CHCl3 were distilled from
CaH2. Compounds 1, 2a , 2b, 3a , 3c were prepared according
to previously reported procedures.6-8
(1S,5S)-2-[7-(2-Meth oxyp h en yl)-6,8-d ia za bicyclo[3.2.1]-
oct-6-en -8-yl]-(2R)-p h en yl-eth a n ol 2d . Anisole (4.28 mL,
39.5 mmol) was added to a cold (0 °C) mixture of n-butyl-
lithium (1.6 M in hexanes, 16.4 mL, 26 mmol) and TMEDA
(3.96 mL, 26.3 mmol) in THF (20 mL) under an atmosphere
of Ar. The reaction mixture was maintained at 20 °C for 45
min and then cooled to -78 °C. A solution of 2-cyano-6-
phenyloxazolopiperidine (1) (2.0 g, 8.8 mmol) in THF (20 mL)
was added, and the reaction mixture was allowed to warm to
room temperature and maintained overnight. The reaction
mixture was cautiously diluted with a saturated, aqueous
solution of NH4Cl, extracted with CH2Cl2 (2 ×), and the
combined organic layers were dried (MgSO4). The solvent was
evaporated to give an oily residue. The residue was purified
by chromatography (CH2Cl2/MeOH 95/5) to provide imine 2d
(yellow oil, 2.18 g, 74%). [R]D ) +46 (c 1.4, CH2Cl2); IR (neat)
3326, 2940, 1656, 1599 cm-1; MS m/z 337 (MH+); 1H NMR
(CDCl3) δ 1.20-1.80 (m, 6H), 3.52 (t, J ) 4.8 Hz, 1H), 3.53 (s,
3H), 3.77 (dd, J ) 11.1, 4.3 Hz, 1H), 3.87 (dd, J ) 11.1, 5.2
Hz, 1H), 4.22 (t, J ) 2.9 Hz, 1H), 5.45 (t, J ) 2.6 Hz, 1H), 6.83
(d, J ) 7.4 Hz, 1H), 6.94 (td, J ) 7.7, 0.9 Hz, 1H), 7.21-7.33
(m, 5H), 7.37 (td, J ) 7.7, 1.7 Hz, 1H), 7.79 (dd, J ) 7.7, 1.8
Hz, 1H); 13C NMR (CDCl3) δ 17.0, 24.4, 26.0, 55.0, 65.1, 65.9,
68.0, 84.3, 111.2, 120.7, 121.6, 127.4, 128.3, 128.5, 130.6, 132.1,
141.1, 158.6, 172.2.
F IGURE 1. X-ray structure of derivative 15.
F IGURE 2. Origin of the relative configuration of disubsti-
tuted aminoazepanes.
SCHEME 8
(1S,5S)-2-(7-F u r a n -2-yl-6,8-d ia za bicyclo[3.2.1]oct-6-en -
8-yl)-(2R)-p h en yl-eth a n ol 2c. Yellow oil, 2.47 g, 95%; [R]D
) -11 (c 1.1, CH2Cl2); IR (neat) 3320, 2947, 1622 cm-1; MS
m/z 297 (MH+); 1H NMR (CDCl3) δ 1.20-1.85 (m, 6H), 3.47 (t,
J ) 4.7 Hz, 1H), 3.78 (dd, J ) 11.1, 4.2 Hz, 1H), 3.85 (t, J )
2.9 Hz, 1H), 3.92 (dd, J ) 11.1, 5.2 Hz, 1H), 5.50 (t, J ) 2.9
Hz, 1H), 6.46 (dd, J ) 3.4, 1.5 Hz, 1H), 6.67 (d, J ) 3.4 Hz,
1H), 7.25-7.35 (m, 5H), 7.51 (t, J ) 1.5 Hz, 1H); 13C NMR
(CDCl3) δ 16.7, 25.3, 25.4, 64.6, 65.8, 66.3, 86.2, 111.9, 114.4,
127.8, 128.4, 128.6, 140.2, 145.4, 162.4.
(1S,5S)-2R-P h en yl-2-(7-p yr id in -2-yl-6,8-d ia za b icyclo-
[3.2.1]oct-6-en -8-yl)-eth a n ol 2e. nBuLi (21.9 mL, 1.6 M in
hexanes, 35.1 mmol) was added to a stirred solution of
2-bromopyridine (4.48 mL, 46.8 mmol) in anhydrous Et2O (30
mL) at -70 °C under argon. After 30 min a solution of 2-cyano-
6-phenyl-oxazolopiperidine 1 (2 g, 8.77 mmol) in Et2O (10 mL)
was added. The mixture was stirred at -70 °C for 5 h. The
reaction mixture was cautiously diluted with a saturated,
aqueous solution of NH4Cl and extracted with CH2Cl2 (2 ×),
and the combined organic layers were dried (MgSO4). The
residue was purified by chromatography (CH2Cl2/MeOH 95/
influence of each stereogenic center on the stereochemical
outcome of this reaction. Compounds 14d ,e,f were ob-
tained in good yields as single diastereomers. Once again,
a 3,7-cis configuration could be established for compound
14f by NOE experiments on its desilylated derivative and
attributed to the other compounds by comparisons of
1
their H and 13C NMR spectra.
Alkylations are therefore totally diastereoselective.
Surprisingly, the stereochemical outcome is independent
of the C-2 stereogenic center configuration, unlike previ-
ous examples in the piperidine series.12 The 3,7-cis
configuration could be explained by a mechanism involv-
ing an intramolecular delivery of nucleophile in an early
transition state (Figure 2).
In summary, we have developed a simple and versatile
method for the rapid elaboration of 2-mono- or 2,7-
disubstituted 3-aminoazepanes. We have shown that
bicyclic aminals are powerful synthetic intermediates in
allowing a tandem ring-enlargement/alkylation process
in a highly regio- and diastereoselective manner. This
novel synthetic route leads to various enantiomerically
constrained diamines interesting as scaffolds for medici-
nal chemistry. Application of this method to the prepara-
tion of biologically active compounds is currently under-
way in our laboratory.
5) to provide 2c (amorphous yellow solid, 2.61 g, 97%). [R]D
)
-44 (c 1.1, CH2Cl2); IR (neat) 3330, 2945, 2871, 1609, 1586
1
cm-1; MS m/z 308 (MH+); H NMR (CDCl3) δ 1.13-1.92 (m,
6H), 3.57 (t, J ) 5.4 Hz, 1H), 3.85 (d, J ) 5.4 Hz, 1H), 4.38 (t,
J ) 2.9 Hz, 1H), 5.49 (t, J ) 2.5 Hz, 1H), 7.13-7.24 (m, 5H),
7.29 (ddd, J ) 7.7, 4.8, 1.5 Hz, 1H), 7.68 (td, J ) 7.7, 1.5 Hz,
1H), 7.96 (br. d, J ) 7.7 Hz, 1H), 8.53 (br. d, J ) 4.8 Hz, 1H);
13C NMR (CDCl3) δ 17.0, 24.7, 25.1, 64.0, 65.1, 66.4, 87.2, 122.1,
124.9, 127.6, 128.2, 128.4, 136.3, 139.8, 149.2, 151.3, 173.2.
Gen er a l P r oced u r e for th e P r ep a r a tion of O-Silyla ted
Im in es 9. The preparation of imine 9a is representative. NaH
(60% suspension in mineral oil, 614 mg, 15.4 mmol) was added
at 0 °C under argon to a stirred solution of imine 2a (2.36 g,
7.71 mmol) in THF (94 mL). After 30 min at room temperature,
tert-butyldimethylsilyl chloride (2.33 g, 15.4 mmol) was added.
The resulting mixture was stirred for an additional 16 h at
20 °C. The reaction mixture was cautiously diluted with a
saturated, aqueous solution of NH4Cl and extracted with CH2-
Cl2 (2 ×), and the combined organic layers were dried (MgSO4).
Exp er im en ta l Section
Gen er a l Meth od s. 1H NMR (300 or 400 MHz) and 13C
NMR (75 MHz) were recorded in CDCl3 or CD3OD solution.
(12) Stevens, R. V. Acc. Chem. Res. 1984, 17, 289.
2648 J . Org. Chem., Vol. 68, No. 7, 2003

Mono- or Disubstituted 3-Aminoazepanes
The residue was purified by flash chromatography (cyclohex-
ane/AcOEt 1/1, then 2/8, then AcOEt) to provide 9a as a yellow
oil (3.04 g, 94%).
(1S,5S)-8-[2-(ter t-Bu tyl-dim eth yl-silan yloxy)-(1R)-ph en -
yl-eth yl]-7-p h en yl-6,8-d ia za bicyclo[3.2.1]oct-6-en e 9a . Oil,
P r ep a r a tion of Am in a l 11b,d . The preparation of aminal
11d is representative. To a solution of imine 9d (500 mg, 1.11
mmol) in Et2O (25 mL) under argon was carefully added
LiAlH4 (329 mg, 8.67 mmol). The reaction mixture was stirred
3 h at room temperature and then treated successively with
aqueous NaOH (1 N, 658 mL) and H2O (987 µL). After
filtration through Celite, the organic phase was concentrated
in vacuo. The residue was purified by flash chromatography
(AcOEt/MeCN/NH4OH, 237/12/1) to provide 11d as a colorless
oil (371 mg, 74%).
[R]D ) +10 (c 0.9, CH2Cl2); IR (neat) 2951, 2858, 1605 cm-1
;
MS m/z 421 (MH+); H NMR (CDCl3) δ -0.22 (s, 3H), -0.17
(s, 3H), 0.71 (s, 9H), 1.11-1.78 (m, 6H), 3.32 (t, J ) 5.6 Hz,
1H), 3.63 (dd, J ) 10.3, 5.6 Hz, 1H), 3.82 (t, J ) 2.9 Hz, 1H),
3.88 (dd, J ) 10.3, 5.6 Hz, 1H), 5.54 (t, J ) 2.7 Hz, 1H), 7.14-
7.37 (m, 8H), 7.61 (m, 2H); 13C NMR (CDCl3) δ -1.5, -0.5,
16.9, 24.8, 18.2, 25.9, 66.5, 68.0, 86.0, 127.4, 128.0, 128.4, 128.7,
130.9, 132.5, 142.8, 150.2, 171.8.
1
(1S,5S)-8-[2-(ter t-Bu tyl-dim eth yl-silan yloxy)-(1R)-ph en -
yl-eth yl]-(7R)-(2-m eth oxy p h en yl)-6,8-d ia za bicyclo[3.2.1]-
octa n e 11d . Oil; [R]D ) +12 (c 0.8, CH2Cl2); IR (neat) 3320,
1
2952, 2926, 1492 cm-1; MS m/z 453 (MH+); H NMR (CDCl3)
(1S,5S)7-Bu t yl-8-[2-(ter t-b u t yl-d im et h yl-sila n yloxy)-
(1R)-p h en yl-eth yl]-6,8-d ia za bicyclo [3.2.1]oct-6-en e 9b.
Yellow oil, 2.65 g, 86%; [R]D ) -18 (c 1.8, CH2Cl2); IR (neat)
δ -0.17 (s, 3H), -0.12 (s, 3H), 0.74 (s, 9H), 0.80-1.78 (m, 6H),
2.43 (s, 1H), 3.43 (br. s, 3H), 3.36-3.47 (m, 1H), 3.60-3.73
(m, 2H), 3.93 (br. s, 1H), 4.58 (d, J ) 4.1 Hz, 1H), 4.67 (br. s,
1H), 6.63 (d, J ) 7.3 Hz, 1H), 6.86 (t, J ) 7.3 Hz, 1H), 7.08
(td, J ) 7.6, 1.4 Hz, 1H), 7.17-7.38 (m, 5H), 7.97 (d, J ) 7.9
Hz, 1H); 13C NMR (CDCl3) δ -1.4, -1.5, 16.3, 18.3, 25.9, 29.8,
33.4, 54.9, 57.8, 60.3, 66.6, 69.1, 74.3, 109.5, 120.0, 127.0, 127.3,
128.1, 128.5, 128.8, 130.2, 141.7, 156.6.
(1S,5S)-7R-Bu tyl-8-[2-(ter t-bu tyl-d im eth yl-sila n yloxy)-
(1R)-p h en yl-eth yl]-6,8-d ia za bicyclo[3.2.1]octa n e 11b. Col-
orless oil, 290 mg, 65%; [R]D ) +6 (c 1.0, CH2Cl2); IR (neat)
2954, 2929, 2857, 1463 cm-1; MS m/z 403 (MH+); 1H NMR
(CDCl3) δ -0.22 (s, 3H), -0.17 (s, 3H), 0.72 (s, 9H), 0.81 (t, J )
7.1 Hz, 1H), 0.96-1.91 (m, 12H), 2.76 (br. s, 1H), 2.80 (br. s,
1H), 3.22 (dt, J ) 8.7, 5.3 Hz, 1H), 3.55 (m, 2H), 3.82 (dd, J )
12.2, 7.7 Hz, 1H), 4.56 (br. s, 1H), 7.11-7.37 (m, 5H); 13C NMR
(CDCl3) δ -1.6, -1.5, 14.1, 17.3, 18.2, 23.0, 25.9, 26.1, 30.4,
31.0, 32.4, 58.0, 59.6, 65.9, 69.0, 73.8, 127.2, 128.2, 128.5, 141.7.
P r ep a r a tion of Am in a l 10e. A solution of 9e (929 mg, 2.20
mmol) in dry methanol (36 mL) containing palladium catalyst
(10% Pd/C, 186 mg) was stirred at room temperature under
hydrogen atmosphere. After 48 h, catalyst was removed by
filtration through Celite, and the solvent removed in vacuo.
The residue was purified by flash chromatography (AcOEt/
MeCN/NH4OH, 237/12/1) to provide 10e as a pale yellow
amorphous solid (633 mg, 68%).
(1S ,5S )-8-[2-(t er t -Bu t yl-d im e t h yl-sila n yloxy)-(1R )-
p h en yl-et h yl]-(7R)-p yr id in -2-yl-6,8-d ia za b icyclo[3.2.1]-
octa n e 10e. Amorphous; [R]D ) -31 (c 1.4, CH2Cl2); IR (neat)
3299, 2929, 2857, 1592 cm-1; MS m/z 424 (MH+); 1H NMR
(CDCl3) δ -0.15 (s, 3H), -0.13 (s, 3H), 0.78 (s, 9H), 1.51-1.94
(m, 7H), 3.21 (br. s, 1H), 3.38 (t, J ) 5.5 Hz, 1H), 3.44 (dd, J
) 10.2, 5.2 Hz, 1H), 3.80 (dd, J ) 10.2, 5.7 Hz, 1H), 4.15 (br.
s, 1H), 4.98 (br. s, 1H), 6.61 (d, J ) 6.8 Hz, 1H), 6.92-7.06 (m,
4H), 7.10 (dd, J ) 7.5, 4.9, 1H), 7.46 (td, J ) 7.5, 1.8 Hz, 1H),
8.51 (d, J ) 4.9 Hz, 1H); 13C NMR (CDCl3) δ -1.5, -1.4, 17.7,
18.1, 25.8, 31.9, 33.0, 65.1, 65.2, 66.2, 69.2, 76.0, 121.4, 121.8,
126.7, 127.7, 128.2, 136.0, 141.5, 147.8, 162.3.
1
2954, 2856, 1636 cm-1; MS m/z 401 (MH+); H NMR (CDCl3)
δ -0.26 (s, 3H), 0.20, (s, 3H), 0.70 (s, 9H), 0.83 (t, J ) 7.3 Hz,
1H), 1.10-1.80 (m, 10H), 2.13 (m, 1H), 2.27 (m, 1H), 3.24 (m,
2H), 3.57 (dd, J ) 10.2, 6.0 Hz, 1H), 3.84 (dd, J ) 10.2, 5.4
Hz, 1H), 5.27 (br. s, 1H), 7.02-7.36 (m, 5H); 13C NMR (CDCl3)
δ -5.3, 14.1, 18.3, 18.5, 23.0, 24.4, 25.2, 26.1, 28.4, 31.2, 66.8,
68.2, 68.5, 85.4, 127.5, 128.5, 128.8, 128.9, 142.1, 177.2.
(1S,5S)-8-[2-(ter t-Bu tyl-dim eth yl-silan yloxy)-(1R)-ph en -
yl-eth yl]-7-(2-m eth oxy-p h en yl)-6,8-dia za bicyclo[3.2.1]oct-
6-en e 9d . Yellow oil, 2.81 g, 81%; [R]D ) +72 (c 1.0, CH2Cl2);
IR (neat) 2951, 2855, 1600 cm-1; MS m/z 451 (MH+); 1H NMR
(CDCl3) δ -0.17 (s, 3H), -0.10 (s, 3H), 0.77 (s, 9H), 1.20-1.90
(m, 6H), 3.47 (t, J ) 5.6 Hz, 1H), 3.53 (s, 3H), 3.68 (dd, J )
10.2, 5.8 Hz, 1H), 3.94 (dd, J ) 10.2, 5.4 Hz, 1H), 4.13 (t, J )
3.5 Hz, 1H), 5.56 (t, J ) 2.6 Hz, 1H), 6.81 (d, J ) 8.0 Hz, 1H),
6.96 (td, J ) 7.5, 0.9 Hz, 1H), 7.16-7.37 (m, 5H), 7.86 (dd, J
) 7.7, 1.8 Hz, 1H); 13C NMR (CDCl3) δ -1.5, 17.0, 18.3, 24.3,
25.9, 54.9, 66.4, 68.3, 68.8, 84.5, 111.3, 120.7, 122.4, 127.0,
128.0, 128.8, 130.4, 131.8, 142.4, 158.8, 171.9.
(1S,5S)-8-[2-(ter t-Bu tyl-d im eth yl-sila n yloxy)-1R-p h en -
yl-eth yl]-7-pyr idin -2-yl-6,8-diazabicyclo[3.2.1]oct-6-en e 9e.
Yellow oil, 3.08 g, 95%; [R]D ) -1 (c 1.4, CH2Cl2); IR (neat)
2950, 2927, 2855, 1607 cm-1; MS m/z 422 (MH+); 1H NMR
(CDCl3) δ -0.19 (s, 3H), -0.16 (s, 3H), 0.75 (s, 9H), 1.06-1.85
(m, 6H), 3.37 (t, J ) 5.6 Hz, 1H), 3.64 (dd, J ) 10.3, 5.6 Hz,
1H), 3.90 (dd, J ) 10.3, 5.6 Hz, 1H), 4.13 (t, J ) 2.9 Hz, 1H),
5.67 (t, J ) 2.5 Hz, 1H), 7.12-7.26 (m, 6H), 7.88 (td, J ) 7.8,
1.7 Hz, 1H), 8.10 (d, J ) 7.8 Hz, 1H), 8.48 (dt, J ) 4.8, 0.9 Hz,
1H); 13C NMR (CDCl3) δ -1.5, 17.0, 18.2, 24.4, 24.6, 25.9, 66.4,
66.9, 68.1, 86.3, 122.3, 124.9, 127.2, 128.3, 128.5, 136.4, 140.6,
149.4, 152.0, 173.3.
P r ep a r a tion of Am in a l 11a . NH3 (3.5 mL) was condensed
at -78 °C under argon onto a stirred solution of 9a (500 mg,
1.19 mmol) in THF (2.5 mL). After addition of small pieces of
lithium (25 mg, 3.56 mmol), stirring was continued for 3 h. A
solution of anhydrous tert-butyl alcohol (527 mg, 7.13 mmol)
in THF (10 mL) was then added dropwise at -40 °C. The
reaction mixture was allowed to warm gradually to ambient
temperature with stirring for the slow evaporation of NH3.
After addition of solid NH4Cl (763 mg, 14.3 mmol), the reaction
mixture was filtered through a Celite bed, and the organic
layers were dried over MgSO4 and concentrated to give a
mixture of diastereomers (11a /10a , 81/19). The residue was
purified by chromatography (AcOEt/MeCN/NH4OH, 246/3/1)
to provide the major compound 11a as a yellow oil (321 mg,
64%).
Gen er a l P r oced u r e for th e P r ep a r a tion of Dia m in es
8b, 8d , 8f. The preparation of diamine 8d is representative.
LiAlH4 (445 mg, 11.7 mmol) was carefully added at room
temperature to a solution of aminal 11d (1.32 g, 2.93 mmol)
in Et2O (50 mL) under argon. The reaction mixture was stirred
for 24 h at reflux, allowed to cool, and treated at room
temperature successively with aqueous NaOH (1 N, 2.64 mL)
and H2O (3.96 mL). After filtration through Celite, the residue
was washed several times with Et2O, and the organic layer
was concentrated in vacuo. The residue was purified by flash
chromatography (AcOEt/MeCN/NH4OH, 237:12:1) to provide
8d as a colorless oil (488 mg, 49%).
(1S,5S)-8-[2-(ter t-Bu tyl-dim eth yl-silan yloxy)-(1R)-ph en -
yl-eth yl]-(7R)-p h en yl-6,8-d ia za bicyclo[3.2.1]octa n e 11a .
Oil; [R]D ) -5 (c 1.0, CH2Cl2); IR (neat) 3427, 2928, 2855, 1493
(2R)-[(2R)-(2-Meth oxy-p h en yl)-a zep a n -3S-yla m in o]-2-
p h en yl-eth a n ol 8d . Oil; [R]D ) -62 (c 1.4, CH2Cl2); IR (neat)
1
cm-1; MS m/z 423 (MH+); H NMR (CDCl3) δ -0.20 (s, 3H),
1
-0.16 (s, 3H), 0.72 (s, 9H), 0.98-1.79 (m, 6H), 2.53 (br. s, 1H),
3.19 (br. s, 1H), 3.59 (m, 2H), 3.88 (dd, J ) 11.7, 7.6 Hz, 1H),
4.58 (d, J ) 5.8 Hz, 1H), 4.74 (br. s, 1H), 7.0-7.34 (m, 10H);
13C NMR (CDCl3) δ -1.4, -1.5, 16.4, 18.3, 26.0, 26.8, 33.5, 60.7,
62.0, 65.9, 69.2, 74.7, 125.8, 127.1, 127.5, 127.8, 128.4, 128.6,
141.6, 142.1.
3407, 2928, 1600 cm-1; MS m/z 341 (MH+); H NMR (CDCl3)
δ 1.42-1.92 (m, 9H), 2.79 (m, 1H), 2.95 (m, 1H), 3.15 (m, 1H),
3.33 (dd, J ) 11.6, 4.2 Hz, 1H), 3.84 (d, J ) 7.6 Hz, 1H), 3.86
(s, 3H), 6.91 (d, J ) 7.8 Hz, 1H), 6.98 (td, J ) 7.8-1.4 Hz,
1H), 7.08-7.30 (m, 6H), 7.34 (dd, J ) 7.5, 1.4 Hz, 1H); 13C
NMR (CDCl3) δ 21.9, 31.0, 34.5, 49.8, 55.5, 63.2, 63.6, 66.0,
J . Org. Chem, Vol. 68, No. 7, 2003 2649

Cutri et al.
110.9, 121.1, 127.0, 127.3, 128.1, 128.3, 128.5, 133.6, 142.5,
156.7; HRMS calcd for C21H29N2O2 (MH+) 341.2229, found
341.2231.
bromide (3 M/Et2O, 2.71 mL, 8.12 mmol) was added at room
temperature to a solution of aminal 11a (976 mg, 2.31 mmol)
in ether (40 mL) under argon. The reaction mixture was stirred
for 3 h at reflux. The reaction mixture was cautiously diluted
with a saturated, aqueous solution of NH4Cl and extracted
with CH2Cl2 (2 ×), and the combined organic layers were dried
(MgSO4). The residue was purified by flash chromatography
(AcOEt/MeCN/NH4OH, 237/12/1) to afford 14a as a yellow oil
(577 mg, 57%).
[2-(ter t-Bu tyl-d im eth yl-sila n yloxy)-(1R)-p h en yl-eth yl]-
(7R)-m eth yl-(2R)-p h en yl-a zep a n -(3S)-yl)-a m in e 14a . Oil;
[R]D ) -16 (c 0.6, CH2Cl2); IR (neat) 3362, 2927 cm-1; MS m/z
439 (MH+); 1H NMR (CDCl3) δ -0.21 (s, 6H), 0.70 (s, 9H), 0.97
(d, J ) 6.4 Hz, 3H), 1.10-1.85 (m, 8H), 2.90 (m, 1H), 3.01 (m,
1H), 3.23-3.38 (m, 3H), 3.82 (d, J ) 8.6 Hz, 1H), 7.10-7.35
(m, 10H); 13C NMR (CDCl3) δ -1.4, 18.4, 23.3, 23.4, 26.0, 36.6,
37.6, 49.5, 62.2, 62.8, 63.6, 68.0, 127.0, 127.1, 127.5, 127.8,
128.1, 128.8, 142.8, 145.1.
2-[(2R)-Bu tyl-a zep a n -(3S)-yla m in o]-(2R)-p h en yl-eth a -
n ol 8b. The compound was prepared from compound 11b
according to the previous procedure, although Et2O was
replaced by iPr2O. Pure 8b was obtained without any purifica-
tion, as a colorless oil (833 mg, 98%). [R]D ) -17 (c 1.0, MeOH);
IR (neat) 3425, 1636 cm-1; MS m/z 291 (MH+); 1H NMR
(CDCl3) δ 0.84 (t, J ) 6.4 Hz, 3H), 1.12-1.63 (m, 12H), 2.14
(br. s, 3H), 2.34 (m, 1H), 2.47 (m, 1H), 2.54 (m, 1H), 2.97 (dt,
J ) 13.2, 4.0 Hz, 1H), 3.40 (dd, J ) 10.6, 7.6 Hz, 1H), 3.58
(dd, J ) 10.6, 4.7 Hz, 1H), 3.70 (dd, J ) 7.6, 4.8 Hz, 1H), 7.05-
7.33 (m, 5H); 13C NMR (CDCl3) δ 14.5, 22.1, 23.2, 29.4, 32.0,
32.3, 34.4, 49.0, 62.2, 63.3, 66.6, 127.4, 127.8, 128.9, 142.8.
(2R)-[(3S)-(2-Hydr oxy-(1R)-ph en yl-eth ylam in o)-azepan -
2-yl]-p h en ol 8f. The compound was prepared from compound
11d according to previous procedure, although Et2O was
i
replaced by Pr2O. The residue was purified by flash chroma-
[2-(ter t-Bu tyl-d im eth yl-sila n yloxy)-(1R)-p h en yl-eth yl]-
(7S)-isobu tyl-(2R)-p h en yl-a zep a n -(3S)-yl)-a m in e 14b. Oil,
931 mg, 84%; [R]D ) -16 (c 0.8, CH2Cl2); IR (neat) 3356, 2928,
tography (AcOEt/MeCN/NH4OH, 237:12:1) to provide com-
pound 8f as a colorless oil (478 mg, 50%). [R]D ) -17 (c 1.1,
CH2Cl2); IR (neat) 3301, 2928, 1732 cm-1; MS m/z 327 (MH+);
1H NMR (CDCl3) δ 1.50-1.92 (m, 9H), 2.78 (m, 1H), 2.94 (m,
1H), 3.12 (dt, J ) 13.7, 4.3 Hz, 1H), 3.33 (dd, J ) 10.5, 6.7 Hz,
1H), 3.41-3.52 (m, 2H), 3.72 (d, J ) 7.9 Hz, 1H), 6.85 (td, J )
7.8, 1.2 Hz, 1H), 6.92 (dd, J ) 7.8, 1.1 Hz, 1H), 7.11-7.35 (m,
7H); 13C NMR (CDCl3) δ 21.9, 31.0, 34.6, 49.8, 55.5, 63.2, 63.6,
66.0, 110.9, 121.1, 127.0, 127.3, 128.0, 128.2, 128.5, 133.7,
142.6, 156.8.
Gen er a l P r oced u r e for th e Syn th esis of 2,3-Dia m in es
3a ,b,d ,f. The preparation of diamine 3d is representative.
Stirring under hydrogen atmosphere of compound 8d (645 mg,
1.90 mmol) in methanol (30 mL) in the presence of aqueous
HCl (pH 2) and 10% Pd/C (129 mg) for 48 h at room
temperature afforded a compound, which after filtration and
concentration, was dissolved in ether and extracted three times
with an aqueous 2 N HCl solution. Aqueous layers were made
basic (NaOH 6 N) and then extracted with AcOEt. The organic
layer were dried (Na2SO4) and concentrated to provide 3d as
a colorless oil (397 mg, 95%).
1
1600 cm-1; MS m/z 481 (MH+); H NMR (CDCl3) δ -0.12 (s,
6H), 0.72 (d, J ) 6.2 Hz, 6H), 0.80 (s, 9H), 1.00-1.90 (m, 9H),
2.89 (m, 1H), 3.0 (td, J ) 8.7, 3.6 Hz, 1H), 3.30-3.46 (m, 3H),
3.75 (d, J ) 8.7 Hz, 1H), 7.18-7.40 (m, 10H); 13C NMR (CDCl3)
δ -1.5, 18.4, 22.3, 23.2, 23.5, 24.6, 26.0, 36.3, 36.6, 46.4, 51.7,
62.4, 63.0, 63.7, 68.0, 127.0, 127.2, 127.7, 127.8, 128.1, 128.7,
142.8, 144.8.
[(7S)-Ben zyl-(2R)-p h en yl-a zep a n -(3S)-yl]-[2-(ter t-bu tyl-
d im eth yl-sila n yloxy)-(1R)-p h en yl-eth yl]-a m in e 14c. Oil,
1.13 g, 95%; [R]D ) +15 (c 1.1, CH2Cl2); IR (neat) 3415, 2926
1
cm-1; MS m/z 515 (MH+); H NMR (CDCl3) δ -0.20 (s, 6H),
0.75 (s, 9H), 1.20-1.90 (m, 8H), 2.53 (dd, J ) 13.3, 8.2 Hz,
1H), 2.62 (dd, J ) 13.3, 5.6 Hz, 1H), 2.90 (m, 1H), 3.03 (m,
1H), 3.27 (dd, J ) 13.1, 7.5 Hz, 1H), 3.38 (dd, J ) 13.1, 7.5
Hz, 1H), 3.76 (d, J ) 8.5 Hz, 1H), 6.87-7.40 (m, 15H); 13C
NMR (CDCl3) δ -1.4, 18.4, 23.2, 26.0, 35.5, 36.9, 43.4, 56.3,
62.7, 62.8, 63.5, 68.0, 127.0, 127.1, 127.6, 127.8, 128.1, 128.3,
128.7, 129.3, 139.5, 142.8, 144.2.
[2-(ter t-Bu tyl-d im eth yl-sila n yloxy)-(1R)-p h en yl-eth yl]-
((7R)-m eth yl-2-pyr idin -(2R)-yl-azepan -(3S)-yl)-am in e 14d.
Oil, 739 mg, 69%; [R]D ) -15 (c 0.8, CH2Cl2); IR (neat) 3424,
(2R)-(2-Meth oxyp h en yl)-a zep a n -(3S)-yla m in e 3d . Oil;
[R]D ) -42 (c 1.1, CH2Cl2); IR (neat) 3355, 2928, 1640 cm-1
;
MS m/z 221 (MH+); 1H NMR (CDCl3) δ 1.42-2.08 (m, 8H), 2.86
(m, 2H), 3.14 (m, 1H), 3.72 (d, J ) 9.4 Hz, 1H), 3.83 (s, 3H),
6.88 (d, J ) 7.5 Hz, 1H), 6.95 (td, J ) 7.5, 1.4 Hz, 1H), 7.22
(td, J ) 7.5, 1.5 Hz, 1H), 7.34 (dd, J ) 7.5, 1.4 Hz, 1H); 13C
NMR (CDCl3) δ 22.0, 30.1, 36.3, 49.1, 55.5, 58.0, 66.1, 110.8,
121.1, 127.9, 128.9, 132.5, 156.9; HRMS calcd for C13H21N2O
(MH+) 221.1654, found 221.1654.
1
2929, cm-1; MS m/z 440 (MH+); H NMR (CDCl3) δ -0.15 (s,
3H), -0.13 (s, 3H), 0.80 (s, 9H), 1.10-1.50 (m, 6H), 1.30 (d, J
) 6.7 Hz, 3H), 2.05 (br. s, 2H), 2.75 (m, 2H), 3.54 (m, 1H),
3.54 (d, J ) 5.0 Hz, 1H), 3.67 (dd, J ) 7.6, 4.3 Hz, 1H), 3.78
(dd, J ) 13.5, 7.6 Hz, 1H), 7.01 (dd, J ) 6.6, 5.0 Hz, 1H), 7.10-
7.33 (m, 6H), 7.51 (td, J ) 8.2, 1.7 Hz, 1H), 8.42 (br.d, J ) 5.0
Hz, 1H); 13C NMR (CDCl3) δ -1.3, 18.7, 20.1, 23.5, 26.1, 30.3,
30.7, 58.7, 58.9, 59.7, 64.9, 68.9, 121.2, 121.8, 127.2, 127.9,
128.2, 128.4, 136.4, 142.7, 149.1, 167.8.
(2R)-Bu tyl-a zep a n -(3S)-yla m in e 3b. The compound was
prepared from compound 8b (663 mg, 95%). It proved to be
air-sensitive and was characterized in its bis hydrochloride
form (prepared after standing in an HCl atmosphere for 0.5
h). [R]D ) +3 (c 1.0, MeOH); IR (neat) 3418 cm-1; MS (base)
[2-(ter t-Bu tyl-d im eth yl-sila n yloxy)-(1R)-p h en yl-eth yl]-
((7S)-isobu tyl-2-pyr idin -(2R)-yl-azepan -(3S)-yl)-am in e 14e.
Oil, 822 mg, 70%; [R]D ) -12 (c 0.8, CH2Cl2); IR (neat) 3412,
1
m/z 171 (MH+); H NMR (D2O, hydrochloride) δ 0.72 (t, J )
1
2928, 1468, 1434 cm-1; MS m/z 482 (MH+); H NMR (CDCl3)
6.9 Hz, 3H), 1.03-2.00 (m, 15H), 3.08 (m 1H), 3.24 (m, 1H),
3.35 (dt, J ) 11.9, 3.8 Hz, 1H), 3.48 (dt, J ) 11.9, 4.1 Hz, 1H);
13C NMR (CDCl3) δ 14.5, 22.3, 22.7, 26.3, 27.4, 31.4, 31.8, 47.9,
54.0, 61.8; HRMS calcd for C10H23N2 (MH+) 171.1861, found
170.1863.
δ -0.15 (s, 3H), -0.13 (s, 3H), 0.75 (s, 9H), 0.82 (m, 7H), 0.90-
1.60 (m, 6H), 1.51 (t, J ) 6.5 Hz, 2H), 2.17 (br. s, 2H), 2.73
(m, 2H), 3.55 (m, 1H), 3.55 (d, J ) 5.8 Hz, 1H), 3.67 (m, 2H),
6.99 (ddd, J ) 7.5, 4.5, 1.3 Hz, 1H), 7.10-7.30 (m, 6H), 7.49
(td, J ) 7.5, 1.3 Hz, 1H), 8.41 (d, J ) 4.5 Hz, 1H); 13C NMR
(CDCl3) δ 1.3, 18.5, 20.0, 23.0, 25.0, 26.1, 30.4, 30.6, 47.2, 59.6,
59.7, 62.6, 64.0, 68.8, 121.7, 122.0, 127.2, 127.9, 128.1, 136.1,
142.6, 149.0, 166.3.
2-[(3S)-Am in o-a zep a n -(2R)-yl]-p h en ol 3f. Oil, 272 mg,
90%; [R]D ) -85 (c 1.0, CH2Cl2); IR (neat): 3352, 2929, 1588
1
cm-1; MS m/z 207 (MH+); H NMR (CDCl3) δ 1.60-1.90 (m,
6H), 2.80 (td, J ) 13.4, 3.4 Hz, 1H), 3.03-3.19 (m, 2H), 3.50
(d, J ) 8.7 Hz, 1H), 3.60 (br. s, 2H), 6.81 (td, J ) 7.8, 1.1 Hz,
1H), 6.87 (dd, J ) 8.8, 1.0 Hz, 1H), 7.07-7.20 (m, 2H); 13C
NMR (CDCl3) δ 22.2, 28.4, 34.5, 47.6, 56.5, 71.5, 117.5, 119.2,
128.1, 128.8, 156.4; HRMS calcd for C12H19N2O (MH+) 207.1497,
found 207.1499.
Gen er a l P r oced u r e for th e P r ep a r a tion of Tr isu bsti-
tu ted Azep a n es 14a -c. The preparation of diamine 14a is
representative. An ethereal solution of methylmagnesium
[(7S)-Ben zyl-2-p yr id in -(2R)-yl-a zep a n -(3S)-yl]-[2-(ter t-
bu tyl-d im eth yl-sila n yloxy)-(1R)-p h en yl-eth yl]-a m in e 14f.
Oil, 817 mg, 65%; [R]D ) -11 (c 1.1, CH2Cl2); IR (neat) 3390,
3028, 2952 cm-1; MS m/z 516 (MH+); 1H NMR (CDCl3) δ -0.20
(s, 3H), -0.15 (s, 3H), 0.75 (s, 9H), 1.00-1.40 (m, 8H), 2.60
(m, 2H), 2.79 (dd, J ) 13.6, 8.6 Hz, 1H), 2.99 (dd, J ) 13.6,
5.7 Hz, 1H), 3.24 (dd, J ) 6.6, 4.5 Hz, 1H), 3.30 (m, 2H), 3.89
(dd, J ) 8.6, 5.7 Hz, 1H), 6.97 (ddd, J ) 7.6, 4.8, 1.5 Hz, 1H),
7.04-7.27 (m, 11H), 7.44 (td, J ) 7.6, 1.5 Hz, 1H), 8.34 (ddd,
2650 J . Org. Chem., Vol. 68, No. 7, 2003

Mono- or Disubstituted 3-Aminoazepanes
J ) 4.8, 1.7, 0.7 Hz, 1H); 13C NMR (CDCl3) δ - 1.2, 18.4, 20.0,
26.0, 30.2, 30.5, 44.1, 59.3, 59.6, 63.7, 65.6, 68.4, 121.1, 121.9,
126.3, 127.0, 127.5, 127.9, 128.0, 128.4, 128.5, 129.5, 136.3,
139.0, 142.7, 148.8, 164.9.
(7S)-Isobu tyl-(2R)-p h en yl-a zep a n -(3S)-yla m in e 4b. Oil,
77%; [R]D ) -20 (c 0.9, CHCl3); IR (neat) 3367, 2951, 1666,
1
1602 cm-1; MS m/z 247 (MH+); H NMR (CDCl3) δ 0.78 (d, J
) 6.3 Hz, 3H), 0.82 (d, J ) 6.3 Hz, 3H), 1.12-1.80 (m, 10H),
1.95 (m, 1H), 2.12 (m, 1H), 2.99 (m, 1H), 3.10 (td, J ) 9.5, 4.4
Hz, 1H), 3.49 (d, J ) 9.5 Hz, 1H), 7.20-7.38 (m, 5H); 13C NMR
(CDCl3) δ 22.3, 23.0, 23.1, 24.7, 35.6, 39.3, 46.1, 52.7, 57.8,
63.1, 127.3, 128.9, 144.7; HRMS (CI, MH+) calcd for C16H27N2
247.2174, found 247.2174.
(7S)-Ben zyl-(2R)-p h en yl-a zep a n -(3S)-yla m in e 4c. Oil,
81%; [R]D ) +67 (c 1.0, CHCl3); IR (neat) 3359, 3025, 2926,
1673, 1601 cm-1; MS m/z 281 (MH+); 1H NMR (CDCl3) δ 1.17-
2.17 (m, 9H), 2.63 (dd, J ) 13.6, 8.3 Hz, 1H), 2.70 (dd, J )
13.6, 6.0 Hz, 1H), 3.06 (td, J ) 9.5, 4.5 Hz, 1H), 3.18 (m, 1H),
3.59 (d, J ) 9.5 Hz, 1H), 6.91-7.38 (m, 10H); 13C NMR (CDCl3)
δ 23.0, 35.2, 39.5, 43.3, 57.5, 58.3, 63.1, 126.0, 127.4, 128.3,
128.6, 128.9, 129.3, 139.6, 144.3; HRMS (CI, MH+) calcd for
Gen er a l P r oced u r e for th e P r ep a r a tion of Tr isu bsti-
tu ted Azep a n es 4a -c. The preparation of diamine 4a is
representative. BF3.Et2O (809 µL, 6.6 mmol) was added to a
solution of azepane 14a (577 mg, 1.3 mmol) in CHCl3 (15 mL)
under argon. The reaction mixture was stirred 15 h at reflux,
allowed to cool, and treated with an aqueous saturated
NaHCO3 solution. The organic layer were separated and dried
on MgSO4, and the solvent was evaporated. The crude product
was then submitted to hydrogenolysis in methanol (15 mL)
under H2 atmosphere in the presence of HCl (pH 2) and 10%
Pd/C (76 mg) for 48 h, to afford a compound, which after
filtration and concentration, was dissolved in ether and
extracted three times with aqueous HCl solution. Aqueous
layers were made basic (6 N NaOH) and then extracted with
AcOEt. The organic layer was dried (Na2SO4) and concentrated
to give 4a as a colorless oil (224 mg, 70%).
C
19H25N2 281.2018, found 281.2015.
Ack n ow led gm en t. S.C. wishes to thank the “Ligue
Nationale contre le Cancer” for a grant.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of all new compounds. X-ray structure determination
and crystal data for compound 15. This material is available
free of charge via the Internet at http://pubs.acs.org.
(7R)-Meth yl-(2R)-p h en yl-a zep a n -(3S)-yla m in e 4a . Oil;
[R]D ) -18 (c 0.8, CH2Cl2); IR (neat) 3363, 2924, 1644, 1600
1
cm-1; MS m/z 205 (MH+); H NMR (CDCl3) δ 1.08 (d, J ) 6.3
Hz, 3H), 1.17-2.15 (m, 9H), 3.05-3.10 (m, 2H), 3.55 (d, J )
9.5 Hz, 1H), 7.17-7.40 (m, 5H); 13C NMR (CDCl3) δ 23.5, 37.2,
39.2, 50.6, 58.0, 63.5, 127.3, 129.0, 145.1; HRMS (CI, MH+)
calcd for C13H21N2 205.1705, found 205.1707.
J O026711S
J . Org. Chem, Vol. 68, No. 7, 2003 2651