Synthesis of enantiopure primary amines by stereoselective ring opening of chiral octahydro-1,3-benzoxazines by Grignard and organoaluminum reagents

Article abstract of DOI:10.1021/jo960047w

Chiral 1,3-perhydrobenzoxazines 1, 2, and 9-14, prepared by condensation of 8-(benzylamino)-menthol with different aldehydes, react with alkylmagnesium bromides and trimethylaluminum leading to the open amino alcohols 3a-d, 4a-d, and 15-20 in excellent chemical yields and good to excellent diastereomeric excess. The sequential elimination of the menthol appendage by heating with P₂O₅ and the benzyl group by hydrogenolysis lead to primary amines 7a-d, 8a-d, and 27-30 in excellent chemical yields and ee. The addition of the alkyl group from the Grignard derivatives and the methyl group from the trimethylaluminum occurs from opposite sides of the heterocycle, yielding the final primary amines with the same stereochemistry.

Full text of DOI:10.1021/jo960047w

4130
J . Org. Chem. 1996, 61, 4130-4135
Syn th esis of En a n tiop u r e P r im a r y Am in es by Ster eoselective Rin g
Op en in g of Ch ir a l Octa h yd r o-1,3-ben zoxa zin es by Gr ign a r d a n d
Or ga n oa lu m in u m Rea gen ts†
Celia Andre´s, J avier Nieto, Rafael Pedrosa,* and Nieves Villaman˜a´n
Departamento de Quı´mica Orga´nica, Facultad de Ciencias, Universidad de Valladolid,
Dr. Mergelina s/ n, 47011 Valladolid, Spain
Received J anuary 4, 1996X
Chiral 1,3-perhydrobenzoxazines 1, 2, and 9-14, prepared by condensation of 8-(benzylamino)-
menthol with different aldehydes, react with alkylmagnesium bromides and trimethylaluminum
leading to the open amino alcohols 3a -d , 4a -d , and 15-20 in excellent chemical yields and good
to excellent diastereomeric excess. The sequential elimination of the menthol appendage by heating
with P2O5 and the benzyl group by hydrogenolysis lead to primary amines 7a -d , 8a -d , and 27-
30 in excellent chemical yields and ee. The addition of the alkyl group from the Grignard derivatives
and the methyl group from the trimethylaluminum occurs from opposite sides of the heterocycle,
yielding the final primary amines with the same stereochemistry.
Sch em e 1
In tr od u ction
Diastereoselective ring opening of chiral 1,3-oxazo-
lidines directed to the synthesis of enantioenriched
secondary amines was first reported more than 20 years
ago.1 The heterocycle, formed by condensation of an
aldehyde with a chiral N-substituted 1,2-amino alcohol,
yields hydroxyamines in moderate to good de when
reacted with organometallics.2 On the other hand, treat-
ment of an aldehyde with chiral unsubstituted 1,2-amino
alcohols leads to equilibrium mixtures of hydroxyimines
and N-unsubstituted 1,3-oxazolidines, which have been
also used as starting material in the synthesis of homo-
chiral amines with good ee.3
In the ring-opening reactions the configuration at the
newly created stereocenter in the final amine depends
on both the configuration of the chiral centers in the
heterocycle and the nature of the organometallic, but the
final ee’s are always limited by the ratio of the C-2
epimers present in the starting mixture of chiral 1,3-
oxazolidine.4
In contrast, condensation of aldehydes with the 5c-
methyl-2t-[1-methyl-1-(benzylamino)ethyl]-cyclohexan-1r-
ol (“(-)-8-benzylaminomenthol”), easily prepared5 from
(+)-pulegone, leads to chiral 2-alkyloctahydro-1,3-ben-
zoxazines 1, 2, and 9-14 as single diastereomers that
we have previously used as chiral adjuvants in the
asymmetric synthesis of primary amines.6 On the other
hand, the enantiomers of compounds 1, 2, and 9-14 could
be obtained by reaction of aldehydes with (+)-8-(benzyl-
amino)menthol, derived from unnatural (-)-pulegone.7
Resu lts a n d Discu ssion
We have now extended our method to the synthesis of
different primary amines with cycloalkyl (7a -d , 8a -d )
or methyl (27-30) substituents at the stereogenic center.
To this end, 2-methyl- (1) and 2-ethylperhydrobenzox-
azine (2) were reacted with Grignard derivatives pre-
pared from magnesium and cyclopropyl, cyclopentyl,
cyclohexyl, and cycloheptyl bromides. In addition, 1,3-
perhydrobenzoxazines 2 and 9-14 bearing different
substituents at C-2 were also tested toward trimethyl-
aluminum.
† Dedicated in memory of Prof. Fe´lix Serratosa.
X Abstract published in Advance ACS Abstracts, May 15, 1996.
(1) Neelakantan, L. J . Org. Chem. 1971, 36, 2256.
(2) For recent references see: (a) Higashiyama, H.; Inoue, H.;
Yamauchi, T.; Takahashi, H. J . Chem. Soc., Perkin Trans. 1 1995, 111.
(b) Higashiyama, K.; Inoue, H.; Takahashi, H. Tetrahedron 1994, 50,
1083. (c) Davidsen, S. K.; Chu-Moyer, M. Y. J . Org. Chem. 1989, 54,
5558.
(3) See, for instance: (a) Takahashi, H.; Niva, H.; Higashiyama, K.
Heterocycles 1988, 27, 2099. (b) Wu, M. J .; Pridgen, L. N. Synlett 1990,
636. (c) Wu, M. J .; Pridgen, L. N. J . Org. Chem. 1991, 56, 1340. (d)
Muralidharan, K. R.; Mokhallalati, M. K.; Pridgen, L. N. Tetrahedron
Lett. 1994, 35, 7489. (e) Scialdone, M. A.; Meyers, A. I. Tetrahedron
Lett. 1994, 35, 7533.
Initially, the reactions with Grignard derivatives
(Scheme 1) were carried out on 1 and 2 with 4 equiv of
(4) (a) Agami, C.; Meynier, F. J . Org. Chem. 1986, 51, 73. (b) Agami,
C.; Rizk, C. Tetrahedron 1985, 41, 537. (c) Mangeney, P.; Alexakis, A.;
Normant, J . F. Tetrahedron 1984, 40, 1803.
(5) He, X.-C.; Eliel, E. Tetrahedron 1987, 43, 4979.
(6) Alberola, A.; Andre´s, C.; Pedrosa, R. Synlett 1990, 763.
(7) Corey, E. J .; Ensley, H. E.; Suggs, J . W. J . Org. Chem. 1976, 41,
380.
S0022-3263(96)00047-3 CCC: $12.00 © 1996 American Chemical Society

Synthesis of Enantiopure Primary Amines
J . Org. Chem., Vol. 61, No. 12, 1996 4131
Ta ble 1. Ster eoselective Rin g Op en in g of P er h yd r oben zoxa zin es 1 a n d 2 by Cycloa lk ylm a gn esiu m Br om id es, F ollow ed
by Tr a n sfor m a tion in to th e Ch ir a l P r im a r y Am in es
3a -d , 4a -d
5a -d , 6a -d
7a -d , 8a -d
entry
oxazine
solvent
R2MgBr
yield (%)
(de)a
yield (%)
(ee)b
yield (%)
(confgn)c
1
2
3
4
5
6
7
8
9
1
1
2
2
1
1
1
1
2
2
2
Et2O
Et2O
Et2O
Et2O
benzene
benzene
benzene
benzene
benzene
benzene
benzene
a (c-C3H5)
d (c-C7H13
a (c-C3H5)
d (c-C7H13
a (c-C3H5)
b (c-C5H9)
(3a ) 88
(3d ) 40
(4a ) 86
(4d ) 28
(3a ) 96
(3b) 81
(3c) 77
(3d ) 67
(4a ) 95
(4b) 79
(4d ) 58
(6)
(60)
(20)
(84)
(18)
(96)
(76)
(80)
(34)
(>99)
(86)
)
)
(5a ) 68
(5b) 98
(5c) 98
(5d ) 97
(6a ) 64
(6b) 96
(6d ) 97
(>99)d
(96)
(7a ) 98
(7b) 98
(7c) 96
(7d ) 95
(8a ) 96
(8b) 96
(8d ) 95
S
S
S
S
S
S
S
c (c-C6H11
d (c-C7H13
a (c-C3H5)
b (c-C5H9)
d (c-C7H13
)
(>99)d
(80)
)
(>99)d
(>99)
(>99)d
10
11
)
a
b
Determined by integration of the H-NMR signals. Measured by HPLC using a Pirkle CSP column. c Assigned by comparison of the
d
sign of the specific rotation with those previously described. After separation of the major diastereoisomers (3a , 3c, 4a , and 4d ) by flash
chromatography.
Sch em e 2
cyclopropyl- or cycloheptylmagnesium bromide at reflux
for 2 h in diethyl ether as solvent (entries 1-4 in Table
1). The effect of temperature was studied by repeating
these experiments at room temperature. In this case it
was necessary to increase the reaction time to 12 h to
force the reactions to completion, but the effect on the
stereochemical outcome was negligible.
Because of the low stereoselectivity observed, the
experimental conditions were changed by using benzene
as solvent at 78 °C. In this solvent, not only the
diastereomeric excess but also the chemical yields were
improved (compare entries 1-4 versus 5, 8, 9, and 11 in
Table 1). These improved conditions were used for the
reactions of perhydrobenzoxazines 1 and 2 with cyclo-
pentyl- and cyclohexylmagnesium bromide.
As shown in Table 1, the efficiency and the stereose-
lectivity in the ring-opening reactions were found to be
dependent on both the solvent used and the magnesium
derivative. Thus, cyclopentylmagnesium bromide yields
the best diastereomeric excess (96-100%), whereas the
reactions with cyclopropylmagnesium bromide gave a low
stereochemical discrimination (de 6-34%). Cyclohexyl-
magnesium bromide behaves differently because it is the
only reagent that shows a better face discrimination in
diethyl ether6 than in benzene. Compounds 3a , 3c, 4a ,
and 4d were isolated as pure diastereomers from the
reaction mixtures by flash column chromatography using
and 20) could be isolated from the reaction mixtures by
flash chromatography.
a 3/1 mixture of hexane/ethyl acetate as eluent.
In order to test the generality of the ring opening of
It is interesting to note that the single diastereomer
these heterocycles, we explored the behavior of these
3c, obtained by reaction of 2-cyclohexylperhydrobenzox-
azine 14 (entry 7 in Table 2) with trimethylaluminum
compounds toward a different organometallic compound.
To this end, perhydrobenzoxazines 2 and 9-14 were
has physical and spectral characteristics identical to
reacted with 4 equiv of trimethylaluminum in toluene
those of the major diastereomer prepared from 2-meth-
at 20 °C (Scheme 2). In striking contrast with the
ylperhydrobenzoxazine 1 and cyclohexylmagnesium bro-
mide (entry 7 in Table 1), indicating that they are the
same compound and not the expected epimer.
In order to determine the configuration of the new
reported8 nonstereoselective reactions of chiral acetals
with trimethylaluminum, compounds 2 and 9-14 were
completely transformed in these experimental conditions
into the open amino alcohols 3c and 15-19, with excel-
stereocenter as well as to establish the synthetic potential
lent chemical yields and good to complete stereochemical
of the reaction, the open amino alcohols were transformed
differentiation (Table 2).
into the primary amines 7, 8, and 27-30. A previously
The stereodiferentiation is better, in general, for reac-
described6 two-step procedure, consisting of dehydration-
tions with trimethylaluminum than for magnesium
deamination and subsequent hydrogenolytic debenzyla-
derivatives (compare the data from Table 2 and Table
tion, yielded the primary amines. The transformation
1). An exception to this behavior was the 4-pyridyl
of amino alcohols 3, 4, and 15-20 into benzylamines 5,
derivative 13, which gave a diastereomeric mixture of 20
6, and 21-26 was carried out in good chemical yields by
in only 33% de. However, the major diastereomers (19
refluxing in toluene with phosphorus pentoxide for 2 h.
The stereochemical integrity at the stereocenter was
(8) Mori, A.; Fugiwara, J .; Maruoka, K.; Yamamoto, M. J . Orga-
nomet. Chem. 1985, 285, 83.
maintained as demonstrated by analytical HPLC through

4132 J . Org. Chem., Vol. 61, No. 12, 1996
Andre´s et al.
Ta ble 2. Ster eoselective Rin g Op en in g of P er h yd r oben zoxa zin es 2 a n d 9-14 by Tr im eth yla lu m in u m in Tolu en e a t
20 °C, F ollow ed by Tr a n sfor m a tion in to th e Ch ir a l P r im a r y Am in es
3c, 15-20
yield (%)
5c, 21-26
yield (%)
7c, 27-30
entry
oxazine
time (min)
(ee)a
(ee)b
yield (%)
(confgn)c
1
2
3
4
5
6
7
2
9
10
60
10
10
10
60
60
(15) 95
(16) 95
(17) 93
(18) 97
(19) 97
(20) 90
(3c) 94
(89)
(>99)
(61)
(90)
(74)
(33)
(>99)
(21) 96
(22) 82
(23) 95
(24) 97
(25) 85
(26) 50
(5c) 98
(89)
(>99)
(61)
(27) 98
(28) 96
(29) 95
(30) 94
S
S
S
S
S
S
S
10
11
12
13
14
(90)
(>99)d
(>99)d
(>99)
(7c) 98
a
b
Determined by integration of the H-NMR signals. Measured by HPLC using a Pirkle CSP column. c Assigned by comparison of the
d
sign of the specific rotation with those previously described. After separation of the major diastereoisomers (19 and 20) by flash
chromatography.
a column packed with a CSP of the R-naphthamides9 for
compounds 5b, 5d , 21, 23, and 24. Debenzylation by
hydrogenolysis using 10% palladium on carbon as cata-
lyst led to the final amines in nearly quantitative yields.
It is important to note that, contrary to our expecta-
tions, all the primary amines prepared from the magne-
sium or aluminum reagents were of the S configuration,
as determined by comparison of the sign of specific
rotation with those previously reported. This indicates
that the sense of asymmetric induction in the ring
opening of the perhydrobenzoxazines is profoundly af-
fected by the nature of the organometallic: the trimethyl-
aluminum opens the heterocycle from the oxygen face,
whereas the magnesium derivatives predominantly at-
tack from the nitrogen side. Similar reactions have been
previously observed in the opening of chiral oxazolidine10-12
and acetals.13 As previously noted for the ring opening
of chiral acetals,14-16 an increase in the nucleophilicity
of the alkylating reagent increases the stereoselectivity
of the reactions.17 A similar increase in the stereoselec-
tivity has been observed in relation to the chelating
ability of Lewis acids in additions of Grignard reagents
to chiral oxazolidines.18
The stereochemical results of the reactions can be
rationalized by an initial complexation of the organome-
tallics to the oxygen atom in the heterocycle leading to
the complex A or B (Figure 1); the timing of bond
breaking and bond making in A or B, depending on the
nucleophilicity of the reagent, could explain the differ-
ences in both the degree and the sense of diastereose-
lection. Thus, the observed SN2-like alkylation (inver-
sion) with alkylmagnesium bromide occurs, after breaking
the C-O bond, in a late iminium-type transition state
(A′). The magnesium reagent then attacks the less
hindered Re face of C-2. A similar chelated transition
state has been proposed for the addition of Grignard
reagents to oxazolidine-hydroxyimine tautomers.18
On the contrary, although the opposite stereochemical
outcome of the reactions with trimethylaluminum could
F igu r e 1.
be explained as an internal alkylation on (A′), the faster
reaction and the better discrimination with an excess of
this organometallic implies a syncronous retentive alkyl-
ation (SNi-like) in the early transition state (B), when the
heterocycle is still essentially intact.
In summary, this paper describes a new methodology
for the enantioselective synthesis of primary amines. The
reported results reflect the unusual diastereofacial dis-
crimination in the heterocycle, depending on the nature
of the organometallic acting as nucleophile. Further
work is in progress on this matter.
(9) Pirkle, W. H.; Welch, C. J . J . Org. Chem. 1984, 49, 138.
(10) Fuganti, C.; Ghiringhelli, D.; Grasselli, D. Tetrahedron Lett.
1974, 15, 2264.
(11) Takahashi, H.; Suzuki, Y.; Kametani, T. Heterocycles 1983, 20,
607.
(12) Takahashi, H.; Niwa, H.; Higashiyama, K. Heterocycles 1988,
27, 2099.
(13) Ishihara, K.; Hanaki, N.; Yamamoto, H. J . Am. Chem. Soc.
1991, 113, 7074.
Exp er im en ta l Section
Gen er a l. The 1H NMR and 13C NMR spectra were recorded
at 80 and 20 MHz, respectively, in CDCl3 with SiMe4 as
internal standard. J values are given in Hz. Optical rotations
were measured on a digital polarimeter in a 1 dm cell. Melting
points were determined in a capillary tube and are uncor-
rected.
(14) Yamamoto, Y.; Nishii, S.; Yamada, J . J . Am. Chem. Soc. 1986,
108, 7116.
(15) Sato, T.; Otera, J .; Nozaki, M. J . Org. Chem. 1990, 55, 6116.
(16) (a) Denmark, S. E.; Almstead, N. G. J . Org. Chem. 1991, 56,
6458. (b) Denmark, S. E.; Almstead, N. G. J . Org. Chem. 1991, 56,
6485. ( c) Denmark, S. E.; Almstead, N. G. J . Am. Chem. Soc. 1991,
113, 8089.
(17) Hagen, G.; Mayr, H. J . Am. Chem. Soc. 1991, 113, 4954.
(18) Wu, M. J .; Pridgen, L. N. J . Org. Chem. 1991, 56, 1340.
Chromatographic separations were done by flash chroma-
tography using 240-400 mesh silica gel. The enantiomeric
purity was determined by chiral HPLC using a Pirkle (0.46 ×
25 cm) column on the amines derivatized as R-naphthamides.9
For this purpose, the corresponding racemic amines were
prepared, derivatized, and coinjected with our samples.

Synthesis of Enantiopure Primary Amines
J . Org. Chem., Vol. 61, No. 12, 1996 4133
Anhydrous solvents were distilled prior to use from ben-
zophenone ketyl. All the reactions were carried out in oven-
dried glassware under a nitrogen atmosphere. The experi-
mental methods for the reactions with Grignard derivatives
(20 mmol scale), elimination of the menthol appendage, and
debenzylation have been previously described.6
25.1, 22.4, 21.0; IR (Nujol) 3060, 3020, 1025 cm-1. Anal. Calcd
for C24H31NO: C, 82.48; H, 8.94; N, 4.01. Found: C, 82.29;
H, 8.76; N, 4.14.
(-)-N-Ben zyl-2r-p yr idyl-4,4,7r-tr im eth yl-tr a n s-octa h y-
d r o-1,3-ben zoxa zin e (13): yield 90%; colorless solid; mp 101-
102 °C (from EtOH); [R]25 ) -44.3 (c 1.3, EtOAc); 1H NMR δ
D
Syn th esis of P er h yd r oben zoxa cin es 1, 2, a n d 9-14. A
mixture of 8-(benzylamino)menthol5 (5.22 g, 20 mmol) and the
appropriate aldehyde (25 mmol), in toluene (100 mL) was
refluxed under nitrogen until the reaction was completed
(TLC). The mixture was filtered trough a pad of Celite, and
the Celite was washed with toluene. The solvent was evapo-
rated, and the residue was purified by recrystallization from
the solvent given below.
8.42-8.35 (m, 2H), 7.41-7.09 (m, 7H), 5.76 (s, 1H), 3.71 (s,
2H), 3.63 (m, 1H), 1.39 (s, 3H), 1.01 (s, 3H), 0.98 (d, 3H, J )
5.7); 13C NMR δ 149.2, 143.2, 127.7, 126.6, 125.7, 121.9, 86.8,
76.6, 57.5, 47.5, 44.9, 41.3, 35.1, 31.4, 27.4, 25.0, 22.3, 21.6;
IR (Nujol) 3080, 3020, 1180, 1050,1030 cm-1. Anal. Calcd for
C23H30N2O: C, 78.82; H, 8.63; N, 7.99. Found: C, 78.98; H,
8.78; N, 8.11.
(-)-N-Ben zyl-2r-cycloh exyl-4,4,7r-tr im eth yl-tr a n s-oc-
ta h yd r o-1,3-ben zoxa zin e (14): yield 84%; colorless oil; bp
143-145 °C/0.5 mmHg; [R]25D ) -38.8 (c 2.0, EtOAc); 1H NMR
δ 7.46-7.07 (m, 5H), 4.27 (d, 1H, J ) 8.1), 4.08 (d, 1H, J )
17.8), 3.76 (d, 1H, J ) 17.8), 3.41 (dt, 1H, J ) 10.2, 3.7), 1.24
(s, 3H), 1.01 (s, 3H), 0.93 (d, 3H, J ) 5.7); 13C NMR δ 144.0,
127.7, 127.0, 125.6, 92.2, 76.7, 57.0, 46.6, 44.9, 41.4, 40.0, 35.1,
31.4, 29.8, 29.2, 27.5, 26.4, 25.7, 25.5, 25.0, 22.2; IR (Nujol)
(-)-N-Ben zyl-2r,4,4,7r-t et r a m et h yl-tr a n s-oct a h yd r o-
1,3-ben zoxa zin e (1): yield 86%; colorless solid; mp 43-44 °C
1
(from EtOH); [R]25 ) -37.8 (c 3.0, EtOAc); H NMR δ 7.45-
D
7.05 (m, 5H), 4.84 (q, 1H, J ) 6.0), 4.06 (d, 1H, J ) 17.7), 3.67
(d, 1H, J ) 17.7), 3.46 (dt, 1H, J ) 10.1, 3.9), 1.21 (s, 3H,),
1.09 (d, 3H, J ) 6.0), 1.05 (s, 3H), 0.93 (d, 3H, J ) 5.6); 13C
NMR δ 144.3, 127.9, 126.6, 125.6, 83.4, 75.6, 56.7, 46.4, 46.0,
41.4, 34.9, 31.3, 27.1, 24.9, 22.2, 20.9, 19.7; IR (Nujol) 3060,
3020, 1020 cm-1; MS m/z 287 (M+, 1), 272 (52), 146 (15), 134
(14), 91 (100), 41 (13). Anal. Calcd for C19H29NO: C, 79.39;
H, 10.17; N, 4.87. Found: C, 79.27; H, 10.39; N, 4.71.
(-)-N-Ben zyl-2r-eth yl-4,4,7r-tr im eth yl-tr a n s-octah ydr o-
3060, 3020 cm-1
. Anal. Calcd for C24H37NO: C, 81.07; H,
10.49; N, 3.94. Found: C, 80.91; H, 10.32; N, 4.07.
8-[N -Be n zyl-N -[(S )-1-cyclop r op yle t h yl]a m in o]m e n -
th ol (3a ). Major diastereomer: colorless solid; mp 69-70 °C
(from pentane); [R]25D ) +15.3 (c 0.7, hexane); 1H NMR δ 7.81
(s, 1H), 7.50-7.14 (m, 5H), 3.91 (d, 1H, J ) 15.1), 3.83 (d, 1H,
J ) 15.1), 3.54 (dt, 1H, J ) 9.7, 3.6), 2.64 (m, 1H), 1.13 (s,
3H), 1.12 (d, 3H, J ) 6.4), 1.08 (s, 3H), 0.89 (d, 3H, J ) 5.7);
13C NMR δ 142.2, 128.4, 128.2, 126.4, 72.5, 62.7, 56.7, 48.4,
47.7, 44.8, 35.2, 30.8, 26.1, 22.8, 22.0, 17.5, 5.8, 4.2; IR (Nujol)
3160, 3050, 1160, 1010 cm-1. Anal. Calcd for C22H35NO: C,
80.19; H, 10.71; N, 4.25. Found: C, 80.27; H, 10.60; N, 4.12.
8-[N -Be n zyl-N -[(R )-1-cyclop r op yle t h yl]a m in o]m e n -
th ol. Minor diastereomer: 1H NMR δ 8.23 (s, 1H), 7.57-7.15
(m, 5H), 4.13 (d, 1H, J ) 15.5), 3.18 (d, 1H, J ) 15.5), 3.59
(dt, 1H, J ) 10.2, 3.8), 2.66 (m, 1H), 1.21 (d, 3H, J ) 5.9), 1.18
(s, 6H), 0.88 (d, 3H, J ) 5.8); 13C NMR δ 141.9, 128.6, 128.2,
126.6, 72.8, 62.6, 57.7, 48.0, 47.2, 44.9, 35.3, 31.0, 26.1, 23.5,
22.1, 17.1, 17.3, 5.6. Anal. Calcd for C22H35NO: C, 80.19; H,
10.71; N, 4.25. Found: C, 80.08; H, 10.62; N, 4.14.
1,3-ben zoxa zin e (2): yield 94%; colorless solid; mp 34-35 °C
1
(from EtOH); [R]25 ) -51.6 (c 4.4, EtOAc); H NMR δ 7.48-
D
7.12 (m, 5H), 4.55 (t, 1H, J ) 5.7), 3.71 (d, 1H, J ) 17.8), 4.04
(d, 1H, J ) 17.8), 3.45 (dt, 1H, J ) 10.1, 3.7), 1.27 (s, 3H),
1.05 (s, 3H), 0.93 (d, 3H, J ) 5.7), 0.81 (t, 3H, J ) 7.6); 13C
NMR δ 144.5, 127.9, 126.9, 125.7, 89.5, 76.3, 57.0, 46.4, 46.2,
41.7, 35.3, 31.6, 27.4, 27.2, 25.3, 22.3, 21.0, 10.6; IR (Nujol)
3060, 3020, 1020 cm-1; MS m/z 301 (M+, 1), 272 (68), 148 (13),
136 (14), 91 (100), 81 (16), 41 (22). Anal. Calcd for C20H31
-
NO: C, 79.68; H, 10.36; N, 4.65. Found: C, 79.57; H, 10.25;
N, 4.58.
(-)-N-Ben zyl-2r-isop r op yl-4,4,7r-t r im et h yl-tr a n s-oc-
ta h yd r o-1,3-ben zoxa zin e (9): yield 80%; colorless solid; mp
47-48 °C (from EtOH); [R]25D ) -40.7 (c 3.0, EtOAc); 1H NMR
δ 7.46-7.08 (m, 5H), 4.17 (d, 1H, J ) 8.4), 4.07 (d, 1H, J )
18.1), 3.76 (d, 1H, J ) 18.1), 3.43 (dt, 1H, J ) 10.1, 3.6), 1.26
(s, 3H), 1.00 (s, 3H), 0.93 (d, 3H, J ) 5.6), 0.89 (d, 3H, J )
6.4), 0.73 (d, 3H, J ) 6.5); 13C NMR δ 144.1, 127.8, 127.0, 125.6,
93.7, 77.0, 57.1, 46.5, 44.7, 41.5, 35.2, 31.4, 30.7, 27.3, 25.0,
22.2, 20.0, 19.4; IR (Nujol) 3080, 3060, 1090, 1025 cm-1. Anal.
Calcd for C21H33NO: C, 79.95; H, 10.54; N, 4.44. Found: C,
80.07; H, 10.68; N, 4.32.
(-)-N-Ben zyl-2r-bu tyl-4,4,7r-tr im eth yl-tr a n s-octah ydr o-
1,3-ben zoxa zin e (10): yield 75%; colorless solid; mp 51-52
°C (from EtOH); [R]25D ) -46.1 (c 3.0, EtOAc); 1H NMR δ 7.45-
7.12 (m, 5H), 4.66 (t, 1H, J ) 5.1), 4.09 (d, 1H, J ) 18.0), 3.76
(d, 1H, J ) 18.0), 3.49 (dt, 1H, J ) 9.9, 3.8), 1.27 (s, 3H), 1.03
(s, 3H), 0.93 (d, 3H, J ) 5.6); 13C NMR δ 144.4, 127.9, 126.8,
125.6, 87.9, 76.2, 56.9, 46.1, 45.6, 41.6, 35.1, 34.0, 31.4, 28.4,
27.3, 25.0, 22.5, 22.3, 21.4, 13.9; IR (Nujol) 3060, 3020, 1260,
1025 cm-1. Anal. Calcd for C22H35NO: C, 80.19; H, 10.71; N,
4.25. Found: C, 80.32; H, 10.59; N, 4.38.
8-[N -Be n zyl-N -[(S )-1-cyclop e n t yle t h yl]a m in o]m e n -
th ol (3b): colorless solid; mp 83-84 °C (from pentane); [R]25
D
) -6.6 (c 0.7, hexane); 1H NMR δ 7.60 (s, 1H), 7.39-7.13 (m,
5H), 3.83 (d, 1H, J ) 15.4), 3.72 (d, 1H, J ) 15.4), 3.63-3.19
(m, 2H), 1.09 (d, 3H, J ) 6.6), 1.08 (s, 3H), 1.05 (s, 3H), 0.89
(d, 3H, J ) 5.7); 13C NMR δ 142.5, 128.2, 126.3, 125, 63.6, 55.7,
48.8, 47.8, 46.7, 44.7, 35.3, 32.0, 30.8, 28.5, 26.2, 25.4, 24.5,
23.2, 22.5, 22.0, 14.7; IR (Nujol) 3140, 1160, 1130 cm-1. Anal.
Calcd for C24H39NO: C, 80.62; H, 10.99; N, 3.92. Found: C,
80.53; H, 10.88; N, 4.04.
8-[N-Ben zyl-N-[(S)-1-cycloh exyleth yl]a m in o]m en th ol
(3c): colorless solid; mp 88-89 °C (from hexane); [R]25D ) -12.9
(c 0.7, hexane); 1H NMR δ 7.77 (s, 1H), 7.42-7.17 (m, 5H),
3.90 (d, 1H, J ) 15.1), 3.75 (d, 1H, J ) 15.1), 3.40 (dt, J ) 9.8,
3.7), 3.17 (m, 1H), 1.08 (s, 3H), 1.07 (d, 3H, J ) 6.8), 0.97 (s,
3H), 0.88 (d, 3H, J ) 5.6); 13C NMR δ 142.9, 128.3, 127.8, 126.3,
72.4, 64.1, 56.7, 49.8, 47.9, 44.7, 44.3, 35.2, 32.2, 30.8, 27.5,
26.9, 26.6, 26.3,23.2, 22.1, 21.1, 13.1; IR (Nujol) 3150, 1140,
(-)-N-Ben zyl-2r-isobu tyl-4,4,7a-tr im eth yl-tr a n s-octah y-
1080, 1020 cm-1
. Anal. Calcd for C25H41NO: C, 80.81; H,
d r o-1,3-ben zoxa zin e (11): yield 78%; colorless oil; bp 157-
160 °C/2 mmHg; [R]25 ) -45.4 (c 3.2, EtOAc); 1H NMR δ
11.12; N, 3.77. Found: C, 80.73; H, 11.19; N, 3.66.
8-[N -Be n zyl-N -[(S )-1-cycloh e p t yle t h yl]a m in o]m e n -
th ol (3d ): colorless oil; 1H NMR δ 7.68 (s, 1H), 7.37-7.21 (m,
5H), 3.98 (d, 1H, J ) 16.0), 3.67 (d, 1H, J ) 16.0), 3.64-3.15
(m, 2H), 1.05 (s, 3H), 0.93 (s, 3H); 13C NMR δ 142.9, 128.1,
127.4, 126.0, 72.2, 64.1, 57.3, 49.5, 47.6, 45.1, 44.6, 35.1, 34.1,
30.6, 29.5, 28.1, 27.6, 27.2, 26.9, 25.9, 22.9, 21.9, 20.5, 12.3;
IR (neat) 3180, 1220, 1185, 1075, 1030 cm-1. Anal. Calcd for
C26H43NO: C, 80.98; H, 11.24; N, 3.63. Found: C, 80.89; H,
11.12; N, 3.74.
D
7.43-7.12 (m, 5H), 4.76 (t, 1H, J ) 5.8), 3.69 (d, 1H, J ) 17.9),
3.77 (d, 1H, J ) 17.9), 3.49 (dt, 1H, J ) 10.0, 3.6), 1.28 (s,
3H), 1.00 (s, 3H), 0.98 (d, 3H, J ) 6.6), 0.84 (d, 3H, J ) 6.5),
0.74 (d, 3H, J ) 6.4); 13C NMR δ 144.4, 127.8, 126.7, 125.6,
86.1, 76.3, 57.0, 46.0, 45.2, 42.9, 41.5, 35.1, 31.4, 27.2, 24.9,
22.8, 22.5, 22.2, 21.7; IR (neat) 3060, 3020, 1180, 1050, 1025
cm-1. Anal. Calcd for C22H35NO: C, 80.19; H, 10.71; N 4.25.
Found: C, 80.41; H, 10.52; N, 4.39.
(-)-N-Ben zyl-2r-p h en yl-4,4,7r-tr im eth yl-tr a n s-octa h y-
d r o-1,3-ben zoxa zin e (12): yield 66%; colorless solid; mp 90-
8-[N-Ben zyl-N-[(S)-1-cyclop r op ylp r op yl]a m in o]m en -
1
91 °C (from EtOH); [R]25 ) -40.0 (c 3.0, EtOAc); H NMR δ
th ol (4a ). Major diastereomer: colorless oil; [R]25 ) +11.9
D
D
7.52-7.07 (m, 10H), 5.77 (s, 1H), 3.86 (d, 1H, J ) 17.2), 3.62
(d, 1H, J ) 17.2), 3.58 (m, 1H), 1.37 (s, 3H), 0.99 (s, 3H), 0.96
(d, 3H, J ) 5.5); 13C NMR δ 144.1, 140.4, 127.6, 127.5, 127.3,
126.9, 125.4, 88.2, 76.5, 57.4, 47.4, 45.3, 41.5, 35.2, 31.5, 27.7,
(c 0.7, hexane); 1H NMR δ 8.23 (s, 1H), 7.60-7.16 (m, 5H),
4.15 (d, 1H, J ) 14.7), 3.80 (d, 1H, J ) 14.7), 3.59 (dt, 1H, J
) 10.0, 3.8), 1.20 (s, 6H), 0.95 (t, 3H, J ) 7.2), 0.88 (d, 3H, J
) 5.7); 13C NMR δ 141.5, 128.3, 127.8, 126.2, 72.1, 63.6, 62.1,

4134 J . Org. Chem., Vol. 61, No. 12, 1996
Andre´s et al.
1
48.7, 47.5, 44.6, 34.9, 30.5, 27.3, 25.8, 22.2, 21.7, 15.6, 12.8,
5.7, 3.8; IR (Nujol) 3170, 3090, 1160, 1030 cm-1. Anal. Calcd
for C23H37NO: C, 80.41; H, 10.86; N, 4.08. Found: C, 80.29;
H, 10.97; N, 3.93.
[R]25 ) -17.0 (c 0.7, hexane); H NMR δ 7.98 (s, 1H), 7.35-
D
7.21 (m, 5H), 3.77 (s, 2H), 3.70-3.29 (m, 2H); 13C NMR δ 142.5,
128.3, 126.5, 72.5, 63.5, 49.7, 47.9, 46.6, 44.8, 35.4, 30.9, 26.1,
25.4, 24.3, 22.9, 22.5, 22.1, 21.1, 17.5; IR (Nujol) 3080, 1160,
1030 cm-1. Anal. Calcd for C23H39NO: C, 79.94; H, 11.38; N
4.05. Found: C, 79.76; H, 11.26; N, 4.22.
8-[N-Ben zyl-N-[(R)-1-cyclop r op ylp r op yl]a m in o]m en -
th ol. Minor diastereomer: colorless oil; [R]25D ) -31.1 (c 0.8,
1
hexane); H NMR δ 7.93 (s, 1H), 7.48-7.10 (m, 5H), 3.93 (s,
8-[N-Ben zyl-N-[(S)-1-p h en yleth yl]a m in o]m en th ol (19).
2H), 3.60 (m, 1H), 1.25 (s, 3H), 1.11 (s, 3H), 0.89 (d, 3H, J )
5.8); 13C NMR δ 141.5, 128.8, 127.8, 126.3, 72.5, 65.1, 61.9,
48.4, 48.0, 44.9, 35.1, 30.7, 26.5, 26.0, 23.7, 21.9, 16.6, 12.2,
8.3, 3.3. Anal. Calcd for C23H37NO: C, 80.41; H, 10.86; N,
4.08. Found: C, 80.21; H, 10.62; N, 4.26.
Major diastereomer: colorless solid; mp 66-67 °C (from
hexane); [R]25 ) -18.3 (c 0.7, hexane); H NMR δ 7.42-7.17
1
D
(m, 11H), 4.64 (q, 1H, J ) 7.0), 4.15 (d, 1H, J ) 15.3), 3.72 (d,
1H, J ) 15.3), 3.51 (dt, 1H, J ) 10.0, 3.8), 1.44 (d, 3H, J )
7.0), 1.15 (s, 3H), 1.09 (s, 3H), 0.90 (d, 3H, J ) 5.6); 13C NMR
δ 143.4, 141.9, 128.8, 128.2, 126.9, 126.5, 72.6, 63.7, 55.3, 48.5,
48.3, 44.8, 35.3, 30.9, 26.2, 23.1, 22.1, 18.5; IR (Nujol) 3210,
1160, 1030 cm-1. Anal. Calcd for C25H35NO: C, 82.14; H, 9.65;
N, 3.83. Found: C, 82.27; H, 9.51; N, 4.01.
8-[N-Ben zyl-N-[(S)-1-cyclop en t ylp r op yl]a m in o]m en -
th ol (4b): colorless solid; mp 81-82 °C; [R]25D ) -18.6 (c 0.7,
1
hexane); H NMR δ 7.51 (s, 1H), 7.38-7.15 (m, 5H), 3.81 (s,
2H), 3.47 (dt, 1H, J ) 9.8, 3.5), 3.00 (m, 1H), 1.13 (s, 3H), 1.07
(s, 3H), 0.88 (d, 3H, J ) 5.6); 13C NMR δ 142.5, 128.3, 126.4,
72.7, 63.3, 62.8, 49.7, 48.0, 46.5, 44.8, 35.3, 32.5, 30.9, 28.3,
26.3, 25.5, 24.1, 23.3, 22.9, 22.0, 22.1, 13.9; IR (Nujol) 3150,
8-[N-Ben zyl-N-[(R)-1-p h en yleth yl]a m in o]m en th ol. Mi-
nor diastereoisomer: 1H NMR δ 7.86 (s, 1H), 7.35-7.09 (m,
5H), 4.75 (q, 1H, J ) 6.8), 4.15 (d, 1H, J ) 15.4), 3.84 (d, 1H,
J ) 15.4), 3.59 (dt, 1H, J ) 10.2, 3.9), 1.54 (d, 3H, J ) 6.8),
1.29 (s, 3H), 1.07 (s, 3H), 0.83 (d, 3H, J ) 5.9). Anal. Calcd
for C25H35NO: C, 82.14; H, 9.65; N, 3.83. Found: C, 82.02;
H, 9.73; N, 3.71.
1160, 1030 cm-1
. Anal. Calcd for C25H41NO: C, 80.81; H,
11.12; N, 3.77. Found: C, 80.98; H, 10.97; N, 3.96.
8-[N-Ben zyl-N-[(S)-1-cycloh ep t ylp r op yl]a m in o]m en -
th ol (4d ). Major diastereomer: colorless solid; mp 102-104
1
°C (hexane); [R]25 ) -5.4 (c 0.7, hexane); H NMR δ 7.63 (s,
8-[N-Ben zyl-N-[(S)-1-(4-p yr id yl)eth yl]a m in o]m en th ol
(20). Major diastereoisomer: colorless solid; mp 88-89 °C
D
1H), 7.40-7.26 (m, 5H), 3.90 (d, 1H, J ) 17.1), 3.78 (d, 1H, J
) 15.8), 3.50 (dt, 1H, J ) 9.9, 3.6), 2.94 (m, 1H), 1.11 (s, 3H),
1.06 (s, 3H), 0.87 (d, 3H, J ) 5.8); 13C NMR δ 142.7, 128.2,
128.0, 126.3, 72.7, 65.7, 63.7, 49.9, 48.0, 44.8, 44.3, 35.5, 35.3,
30.8, 29.0, 28.1, 27.8, 27.5, 27.3, 26.2, 22.8, 22.3, 22.0, 13.7;
IR (Nujol) 3140, 1160, 1030 cm-1. Anal. Calcd for C27H45NO:
C, 81.14; H, 11.35; N 3.51. Found: C, 81.26; H, 11.22; N, 3.64.
8-[N-Ben zyl-N-[(R)-1-cyclop r op ylp r op yl]a m in o]m en -
th ol. Minor diastereomer: colorless oil; [R]25D ) -16.0 (c 0.6,
(from hexane); [R]25 ) +5.5 (c 0.7, hexane); 1H NMR δ 8.53-
D
8.45 (m, 2H), 7.29-7.05 (m, 8H), 4.55 (q, 1H, J ) 7.0), 4.08 (d,
1H, J ) 15.1), 3.75 (d, 1H, J ) 15.1), 3.53 (dt, 1H, J ) 10.0,
3.8), 1.49 (d, 3H, J ) 7.0), 1.15 (s, 3H), 1.12 (s, 3H), 0.91 (d,
3H, J ) 5.7); 13C NMR δ 152.3, 149.5, 140.7, 128.2, 126.7,
123.5, 72.4, 63.9, 54.2, 48.8, 48.3, 44.5, 35.0, 30.7, 26.0, 23.0,
21.9, 16.7; IR (Nujol) 3220, 1160, 1030 cm-1. Anal. Calcd for
C24H34NO: C, 81.77; H, 9.72; N 3.97. Found: C, 81.62; H, 9.89;
N, 3.83.
1
hexane); H NMR δ 7.55 (s, 1H), 7.39-7.22 (m, 5H), 3.94 (d,
1H, J ) 15.5), 3.69 (d, 1H, J ) 15.5), 3.52 (dt, 1H, J ) 9.5,
3.6), 2.95 (m, 1H), 1.10 (s, 6H), 0.88 (d, 3H, J ) 5.7); 13C NMR
δ 142.5, 128.4, 128.2, 126.4, 72.6, 65.0, 63.5, 48.5, 47.9, 44.6,
43.0, 36.6, 35.2, 30.8, 28.7, 27.6, 26.6, 26.3, 24.6, 22.9, 22.0,
13.8. Anal. Calcd for C27H45NO: C, 81.14; H, 11.35; N, 3.51.
Found: C, 81.28; H, 11.21; N, 3.67.
8-[N -Be n zyl-N -[(R )-1-(4-p yr id yl)e t h yl]a m in o]m e n -
th ol. Minor diastereoisomer: colorless solid; mp 102-103 °C
(from hexane); [R]25D ) -32.8 (c 0.7, hexane); 1H NMR δ 8.40-
8.32 (m, 2H), 7.69 (s, 1H), 7.18-7.08 (m, 7H), 4.68 (q, 1H, J )
7.0), 4.21 (d, 1H, J ) 15.1), 3.78 (d, 1H, J ) 15.1), 3.66 (dt,
1H), 1.56 (d, 3H, J ) 7.0), 1.35 (s, 3H), 1.14 (s, 3H), 0.87 (d,
3H, J ) 5.9). Anal. Calcd for C24H34NO: C, 81.77; H, 9.72;
N, 3.97. Found: C, 81.59; H, 9.83; N, 4.10.
Gen er a l Meth od for th e Rea ction of 2 a n d 9-14 w ith
Tr im eth yla lu m in u m . To a stirred solution of trimethyl-
aluminum in toluene (10 mL; 20 mmol) was added dropwise a
solution of the corresponding perhydrobenzoxazine (5 mmol)
in anhydrous toluene (20 mL). The mixture was stirred at
room temperature until the reaction was finished (TLC) and
then was treated with a saturated solution of NH4Cl and
crushed ice and filtered to eliminate the aluminum hydroxides.
The aqueous solution was extracted with EtOAc (3 × 25 mL).
The combined organic layers were dried over anhydrous Na2-
SO4, filtered, and concentrated in vacuo to yield a crystalline
mass that was recrystallized from hexane or chromatographed
on silica gel using hexane-ether as eluent.
(S)-N-Ben zyl-1-cyclop r op yleth yla m in e h yd r och lor id e
(5a ): colorless solid; mp 153-155 °C (from EtOH-ether);
[R]25 ) -9.3 (c 1.0, MeOH); 1H NMR δ 9.87 (s, 2H), 7.73-
D
7.27 (m, 5H), 4.08 (t, 2H, J ) 5.7), 2.29 (m, 1H), 1.48 (d, 3H,
J ) 6.6), 1.39-0.12 (m, 5H); IR (Nujol) 2720, 1570, 1130, 1030
cm-1
.
(S)-N-Ben zyl-1-cyclop en tyleth yla m in e h yd r och lor id e
(5b): colorless solid; mp 163-165 °C (from EtOH-ether);
1
[R]25 ) +8.0 (c 1.5, MeOH); H NMR δ 9.91 (s, 1H), 9.19 (s,
D
1H), 7.76-7.27 (m, 5H), 4.13 (m, 2H), 2.80 (m, 1H), 1.38 (d,
3H, J ) 6.5); IR (Nujol) 2550, 2420, 1585 cm-1; chiral HPLC
analysis of R-naphthamide ee 96% (UV detector 254 nm, tR
12.41 min, 0.6 mL/min, 85:15 hexane/2-propanol).
8-[N -Be n zyl-N -[(S )-1-m e t h ylp r op yl]a m in o]m e n t h ol
1
(15): colorless solid; mp 97-98 °C (from hexane); H NMR δ
8.04 (s, 1H), 7.37-7.21 (m, 5H), 3.79 (s, 2H), 3.55-3.12 (m,
2H), 1.09 (s, 6H); 13C NMR δ 142.2, 128.2, 126.4, 72.4, 63.2,
53.7, 47.7, 44.6, 35.2, 30.8, 30.2, 26.0, 22.5, 22.0, 16.7, 11.7;
IR (Nujol) 3100, 1160, 1135 cm-1. Anal. Calcd for C21H35NO:
C, 79.44; H, 11.11; N, 4.41. Found: C, 79.23; H, 11.27; N, 4.28.
8-[N-Ben zyl-N-[(S)-1-m et h yl-2-m et h ylp r op yl]a m in o]-
(S)-N-Ben zyl-1-cycloh exyleth yla m in e (5c): colorless oil;
1
bp 112-113 °C/0.25 mmHg; [R]25 ) +16.6 (c 2.0, EtOH); H
D
NMR δ 7.53-7.05 (m, 5H), 3.87 (d, 1H, J ) 13.1), 3.66 (d, 1H,
J ) 13.1), 2.45 (m, 1H), 1.02 (d, 3H, J ) 6.4); IR (Nujol) 3300,
3020 cm-1
.
(S)-N-Ben zyl-1-cycloh ep tyleth yla m in e h yd r och lor id e
m en th ol (16): colorless solid; mp 86-87 °C (from hexane);
(5d ): colorless solid; mp 179-181 °C (from EtOH-ether);
1
1
[R]25 ) -5.4 (c 0.7, hexane); H NMR δ 7.81 (s, 1H), 7.42-
[R]25 ) -6.13 (c 1.4, MeOH); H NMR δ 9.56 (m, 2H), 7.75-
D
D
7.19 (m, 5H), 3.90 (d, 1H, J ) 16.0), 3.71 (d, 1H, J ) 16.0),
3.58-3.18 (m, 2H), 2.30 (m, 1H); 13C NMR δ 142.9, 128.3,
127.7, 126.3, 72.4, 64.2, 56.4, 49.5, 47.8, 44.6, 35.2, 33.6, 30.8,
26.1, 23.1, 22.1, 21.0, 16.2, 11.4; IR (Nujol) 3090, 1160, 1095,
1080 cm-1. Anal. Calcd for C22H37NO: C, 79.70; H, 11.25; N,
4.23. Found: C, 79.62; H, 11.39; N, 4.41.
7.27 (m, 5H), 4.23 (d, 1H, J ) 13.8), 3.99 (d, 1H, J ) 13.8),
2.85 (m, 1H), 1.30 (d, 3H, J ) 6.8); IR (Nujol) 2680, 2480, 1585,
1145 cm-1; chiral HPLC analysis of R-naphthamide ee 80%
(UV detector 254 nm, tR 15.62 min, 0.9 mL/min, 95:5 hexane/
2-propanol).
(S)-N-Ben zyl-1-cyclop r op ylp r op yla m in e h yd r och lo-
r id e (6a ): colorless solid; mp 134-136 °C (from EtOH-ether);
8-[N-Ben zyl-N-[(S)-1-m eth ylpen tyl]am in o]m en th ol (17):
1
colorless oil; H NMR δ 8.05 (s, 1H), 731-7.21 (m, 5H), 3.79
[R]25 ) +7.1 (c 0.7, MeOH); 1H NMR δ 9.6 (s, 2H), 7.67-7.23
D
(s, 2H), 3.68-3.08 (m, 2H), 1.09 (s, 6H); IR (neat) 3170, 1160,
1030 cm-1. Anal. Calcd for C23H39NO: C, 79.94; H, 11.38; N,
4.05. Found: C, 80.16; H, 11.20; N, 4.26.
(m, 5H), 4.19 (s, 2H), 1.06 (t, 3H, J ) 6.9); IR (Nujol) 2720,
2430, 2370, 1565, 1020 cm-1
.
(S)-N-Ben zyl-1-cyclop en t ylp r op yla m in e h yd r och lo-
8-[N-Be n zyl-N-[(S)-1-m e t h yl-3-m e t h ylb u t yl]a m in o]-
m en th ol (18): colorless solid; mp 94-95 °C (from hexane);
r id e (6b): colorless solid; mp 115-117 °C (from EtOH-ether);
1
[R]25 ) +3.4 (c 1.5, MeOH); H NMR δ 9.71 (s, 1H), 9.38 (s,
D

Synthesis of Enantiopure Primary Amines
J . Org. Chem., Vol. 61, No. 12, 1996 4135
1H), 7.79-7.27 (m, 5H), 4.20 (m, 2H), 2.65 (m, 1H), 1.07 (t,
(S)-1-Cycloh exyleth yla m in e h yd r och lor id e (7c): color-
25
3H, J ) 7.2); IR (Nujol) 2390, 1585, 1205 cm-1
.
less solid; mp 221-223 °C (from EtOH-ether); [R]D ) -6.0
1
(S)-N-Ben zyl-1-cycloh ep t ylp r op yla m in e h yd r och lo-
(c 0.7, MeOH); H NMR δ 8.33 (s, 3H), 3.14 (m, 1H), 1.16 (d,
r id e (6d ): colorless solid; mp 179-181 °C (from EtOH-ether);
3H, J ) 6.7); IR (Nujol) 2720, 2560, 2010, 1510, 1065 cm-1
;
1
[R]25 ) -7.8 (c 1.0, MeOH); H NMR δ 9.40 (m, 2H), 7.78-
chiral HPLC analysis of R-naphthamide ee >99% (UV detector
254 nm, tR 12.28 min, 2.0 mL/min, 95:5 hexane/2-propanol).
(S)-1-Cycloh ep tyleth yla m in e h yd r och lor id e (7d ): col-
orless solid; mp 229-231 °C (from EtOH-ether); [R]25D ) -4.4
D
7.30 (m, 5H), 4.40 (d, 1H, J ) 13.6), 4.12 (d, 1H, J ) 13.6),
2.56 (m, 1H), 0.96 (t, 3H, J ) 7.3 Hz); IR (Nujol) 2650, 2330,
1580, 1205 cm-1
.
1
(c 2.2, MeOH); H NMR δ 8.30 (s, 3H), 3.24 (m, 1H), 1.34 (d,
(S)-N-Ben zyl-2-bu tyla m in e h yd r och lor id e (21): color-
3H, J ) 6.7); IR (Nujol) 2880, 2705, 2515 cm-1
.
less solid; mp 142-143 °C (from EtOH-ether); [R]25 ) +2.1
D
(c 2.5, EtOH); 1H NMR δ 9.77 (s, 2H), 7.72-7.21 (m, 5H), 4.01
(s, 2H), 2.86 (m, 1H), 1.38 (d, 3H, J ) 6.5), 0.92 (t, 3H, J )
7.4); IR (Nujol) 2580, 2485, 1590 cm-1; chiral HPLC analysis
of R-naphthamide ee >99% (UV detector 254 nm, tR 19.88 min,
1.0 mL/min, 98:2 hexane/2-propanol).
(S)-1-Cyclop r op ylp r op yla m in e h yd r och lor id e (8a ): col-
orless solid; mp 253-255 °C (from EtOH-ether); [R]25D ) +5.2
1
(c 1.5, MeOH); H NMR δ 8.48 (s, 3H), 2.34 (m, 1H), 1.93 (m,
2H, J ) 7.1), 1.11 (t, 3H, J ) 7.1); IR (Nujol) 2710, 2560, 1510,
1020 cm-1
.
(S)-1-Cyclop en tylp r op yla m in e h yd r och lor id e (8b): col-
(S)-N-Ben zyl-3-m et h yl-2-b u t yla m in e h yd r och lor id e
(22): colorless solid; mp 169-170 °C (from EtOH-ether);
[R]25D ) +2.4 (c 1.7, EtOH); 1H NMR δ 7.75-7.29 (m, 5H), 4.25
(d, 1H, J ) 13.8), 3.98 (d, 1H, J ) 13.8), 2.79 (m, 1H), 2.17 (m,
1H), 1.29 (d, 3H, J ) 6.7), 1.09 (d, 3H, J ) 6.7), 0.95 (d, 3H, J
1
orless solid; mp 238-239 °C (from EtOH-ether); H NMR δ
8.36 (s, 3H), 3.01 (m, 1H), 1.12 (t, 3H, J ) 7.2); IR (Nujol) 2600,
2520, 1510 cm-1
.
(S)-1-Cycloh ep tylp r op yla m in e h yd r och lor id e (8d ): col-
orless solid; mp 243-245 °C (from EtOH-ether); [R]25D ) -6.1
) 6.8); IR (Nujol) 2690, 2550, 2490, 1585 cm-1
.
1
(S)-N-Ben zyl-2-h exyla m in e (23): colorless oil; [R]25
)
(c 0.4, MeOH); H NMR δ 8.32 (s, 3H), 3.00 (m, 1H), 0.98 (t,
D
3H, J ) 6.8); IR (Nujol) 2620, 2540, 1520 cm-1
.
+0.6 (c 3.0, EtOH); 1H NMR δ 7.38-7.24 (m, 5H), 3.81 (d, 1H,
J ) 13.8), 3.75 (d, 1H, J ) 13.8), 2.66 (m, 1H), 1.08 (d, 3H, J
) 6.2); IR (neat) 3300, 3060, 3020, 1450, 1370 cm-1; chiral
HPLC analysis of R-naphthamide ee 61% (UV detector 254 nm,
tR 30.86 min, 0.5 mL/min, 98.5:1.5 hexane/2-propanol).
(S)-N-Ben zyl-4-m et h yl-2-p en t yla m in e h yd r och lor id e
(24): colorless solid; mp 182-183 °C (from EtOH-ether);
[R]25D ) -7.3 (c 0.6, EtOH); 1H NMR δ 9.73 (s, 2H), 7.73-7.28
(m, 5H), 4.02 (t, 2H, J ) 5.2), 3.01 (m, 1H), 1.40 (d, 3H, J )
6.5), 0.88 (d, 3H, J ) 5.8), 0.74 (d, 3H, J ) 5.9); IR (Nujol)
2650, 1575 cm-1; chiral HPLC analysis of R-naphthamide ee
90% (UV detector 254 nm, tR 43.44 min, 0.4 mL/min, 98.8:0.2
hexane/2-propanol).
(S)-2-Bu tyla m in e h yd r och lor id e (27): colorless solid; mp
149-150 °C (from EtOH-ether); [R]25 ) -2.3 (c 4.0, MeOH)
D
1
(lit.21 [R]23 ) -2.64 (c 4.0, MeOH)); H NMR δ 8.28 (s, 3H),
D
3.29 (m, 1H), 1.74 (m, 2H), 1.41 (d, 3H, J ) 6.6), 1.04 (t, 3H,
J ) 7.3); IR (Nujol) 2790, 2620, 2540, 1510, 1010 cm-1
.
(S)-3-Meth yl-2-bu tyla m in e h yd r och lor id e (28): color-
less solid; mp 198-199 °C (from EtOH-ether); [R]25 ) -2.1
D
(c 4.0, MeOH) (lit.21 [R]23 ) -2.19 (c 4.0, MeOH)); 1H NMR δ
D
8.36 (s, 3H), 3.26 (m, 1H, J ) 6.7), 1.97 (m, 1H), 1.36 (d, 3H,
J ) 6.7), 1.07 (d, 3H, J ) 6.8), 1.04 (d, 3H, J ) 6.8); IR (Nujol)
2630, 2530, 1500, 1190 cm-1
.
(S)-2-Hexyla m in e h yd r och lor id e (29): colorless solid; mp
102-103 °C (from EtOH-ether); [R]25 ) -3.4 (c 0.7, EtOH)
(S)-N-Ben zyl-1-p h en yleth yla m in e (25): colorless oil; bp
D
(lit.22 [R]D ) -5.68 (MeOH)); H NMR δ 8.3 (s, 3H), 3.29 (m,
1
82-85 °C/0.25 mmHg; [R]D25 ) -59.9 (c 2.4, EtOH) (lit.19 [R]25
D
1H), 1.40 (d, 3H, J ) 6.4); IR (Nujol) 2580, 2510, 1510 cm-1
.
) -56.1 (c 3.1, EtOH)); 1H NMR δ 7.41-7.19 (m, 5H), 3.81 (q,
(S)-4-Meth yl-2-p en tyla m in e (30): colorless oil; bp 42-43
1H, J ) 6.6), 3.62 (s, 2H), 1.61 (s, 1H), 1.36 (d, 3H, J ) 6.6);
°C; [R]25 ) +3.7 (c 1.0, MeOH) (lit.23 [R]D ) +4.2 (MeOH)).
IR (neat) 3310, 3060, 3020, 1595, 1485 cm-1
.
D
Hydrochloride: colorless solid; mp 219-22 °C (from EtOH-
(S)-N-Ben zyl-1-(4-p yr id yl)eth yla m in e (26): colorless oil;
1
ether); [R]25 ) -7.3 (c 0.3, MeOH); H NMR δ 8.32 (s, 3H),
1
[R]25 ) -60.4 (c 1.1, EtOH); H NMR δ 8.59-8.51 (m, 2H),
D
D
3.40 (m, 1H), 1.41 (d, 3H, J ) 6.5), 0.96 (d, 3H, J ) 6.0), 0.92
7.33-7.18 (m, 7H), 3.80 (q, 1H, J ) 6.6), 3.61 (s, 2H), 1.93 (s,
1H), 1.34 (d, 3H, J ) 6.6); IR (neat) 3280, 3060, 3020, 1450,
(d, 3H, J ) 5.9); IR (Nujol) 2700, 2580, 2490, 1510, 1160 cm-1
.
1410 cm-1
.
Ack n ow led gm en t. We thank to the Spanish DGI-
CYT for the financial support of this work (Project
PB92-0262). One of us (J .N.) also thanks the Ministerio
de Educacio´n y Ciencia of Spain for a Predoctoral
fellowship (F.P.I.).
(S)-1-Cyclop r op yleth yla m in e h yd r och lor id e (7a ): color-
less solid; mp 173-175 °C (from EtOH-ether); [R]25 ) -3.6
D
(c 1.5, MeOH) (lit.20 free base [R]23 ) -21.3 (neat)); 1H NMR
D
δ 8.39 (s, 3H), 2.65 (m, 1H), 1.46 (d, 3H, J ) 6.6), 1.40-0.13
(m, 5H); IR (Nujol) 2600, 2540, 2050, 1120, 1050 cm-1
.
(S)-1-Cyclop en tyleth yla m in e h yd r och lor id e (7b): col-
orless solid; mp 210-211 °C (from EtOH-ether); [R]25D ) +4.8
J O960047W
1
(c 2.0, MeOH); H NMR δ 8.32 (s, 3H), 3.14 (m, 1H), 1.42 (d,
(21) Brown, H. C.; Kim, K. W.; Cole, T. E.; Singaran, B. J . Am.
Chem. Soc. 1986, 108, 6764.
3H, J ) 6.6); IR (Nujol) 2705, 2580, 2020, 1510 cm-1
.
(22) Dictionary of Organic Compounds; Eyre and Spottiswood
Pub.: London, 1965; Vol. 1, p 135.
(23) Dictionary of Organic Compounds; Eyre and Spottiswood
Pub.: London, 1965; Vol. 1, p 160.
(19) Terashima, S.; Wagatsuma, M.; Yamada, S. Chem. Pharm. Bull.
1970, 18, 1137.
(20) Vogel, M.; Roberts, J . D. J . Am. Chem. Soc. 1966, 88, 2262.