Synthesis and transformations of 2-(phenylhydroxymethyl)cyclohexylamines

Article abstract of DOI:10.1016/S0040-4020(01)00176-4

Diastereomeric 2-(phenylhydroxymethyl)cyclohexylamines were synthesised by reduction of 2-benzoylcyclohexylamines. (1S*,2R*)-2-Benzoylcyclohexylamine can be reduced diastereoselectively to the corresponding γ-amino alcohol with sodium borohydride; for the trans counterpart (1R*,2R*)-2-benzoylcyclohexylamine, lithium aluminium hydride was found to be a selective reducing agent. In both cases, high syn selectivities were observed. The amino alcohols were transformed to the corresponding cyclohexane-fused tetrahydro-1,3-oxazin-2-ones and -2-thiones. The γ-amino alcohols reacted with arylimidates to afford 4,5-dihydro-6H-1,3-oxazines. Their cyclization with phenyl isothiocyanate yielded 2-phenyliminotetrahydro-1,3-oxazines.

Full text of DOI:10.1016/S0040-4020(01)00176-4

TETRAHEDRON
Pergamon
Tetrahedron 57 )2001) 3175±3183
Synthesis and transformations of
2-ꢀphenylhydroxymethyl)cyclohexylamines
a
a,b
c
c
Peter Csomos, Gabor Bernath, Pal Sohar, Antal Csampai, Norbert De Kimpe
d
Â
Â
Â
Â
Â
and Ferenc Fulop
Â
Â
a,p
È È
aInstitute of Pharmaceutical Chemistry, University of Szeged, P.O. Box 121, H-6720 Szeged, Hungary
bResearch Group for Heterocyclic Chemistry of the Hungarian Academy of Sciences, P.O. Box 121, H-6720 Szeged, Hungary
c
È
È
Â
Department of General and Inorganic Chemistry, Eotvos Lorand University, P.O. Box 32, H-1518 Budapest, Hungary
dDepartment of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Gent University, Coupure Links 653,
B-9000 Gent, Belgium
Received 15 November 2000; revised 15 January 2001; accepted 1 February 2001
AbstractÐDiastereomeric 2-)phenylhydroxymethyl)cyclohexylamines were synthesised by reduction of 2-benzoylcyclohexylamines.
)1Sp,2Rp)-2-Benzoylcyclohexylamine can be reduced diastereoselectively to the corresponding g-amino alcohol with sodium borohydride;
for the trans counterpart )1Rp,2Rp)-2-benzoylcyclohexylamine, lithium aluminium hydride was found to be a selective reducing agent. In
both cases, high syn selectivities were observed. The amino alcohols were transformed to the corresponding cyclohexane-fused tetrahydro-
1,3-oxazin-2-ones and -2-thiones. The g-amino alcohols reacted with arylimidates to afford 4,5-dihydro-6H-1,3-oxazines. Their cyclization
with phenyl isothiocyanate yielded 2-phenyliminotetrahydro-1,3-oxazines. q 2001Elsevier Science Ltd. All rights reserved.
1. Introduction
stereoselectivity. The literature syntheses of alicyclic
amino alcohols containing three stereogenic centres
commonly involve the reductions of b-amino ketones,13±15
enaminones16±18 or isoxazolines.19,20
The stereocontrolled synthesis of 1,3-amino alcohols has
attracted much attention recently because of their
pharmacological properties and their utility as building
blocks for the preparation of potential pharmacons.1±6
Alicyclic amino alcohol derivatives have also been intro-
duced into therapy. For example, ciramadol and tramadol
are used as analgesics.7
In recent years, the synthesis of cycloalkane-fused hetero-
cycles has been one of our main research topics. A number
of alicycle-condensed oxazines, thiazines and pyrimidines
have been prepared by ring closure of the corresponding
1,3-difunctional compounds. The chemistry and stereo-
chemistry of the partially saturated heterocycles obtained
has been widely investigated.21 As a continuation of our
earlier investigations, our present aim was the diastereo-
selective synthesis of hydroxymethylcyclohexylamines
containing a phenyl substituent on the carbon atom adjacent
to the anellation. The synthesised amino alcohols were
transformed to different alicycle-condensed 1,3-oxazines
for further conformational studies.
The methods most generally applied for the preparation of
stereoisomeric 1,3-amino alcohols involve reduction reac-
tions.8 These include mainly the reductions of the corre-
sponding b-amino carbonyl derivatives or the cleavage of
N,O-heterocycles.9 The alicyclic amino alcohols can also be
obtained via these two procedures. However, various
methods can be used for the stereoselective preparation of
alicyclic 1,2-disubstituted 1,3-amino alcohols possessing
two stereogenic centres.10±12 The preparation of the corre-
sponding stereohomogeneous alicyclic amino alcohols
possessing three stereogenic centres is more dif®cult and
is dependent on the selectivity of the reduction reaction.
On the other hand, as the number of possible stereoisomers
increases, only some of them can be prepared with good
2. Synthesis
For the preparation of amino alcohols 3 and 6, amino
ketones 2 and 5 were chosen as key intermediates. N-Substi-
tuted derivatives of 2 and 5 were earlier prepared for
pharmacological studies of their analgesic activity.17 The
partially unsaturated derivative of 2, )1Rp,2Sp)-N-)tert-
butoxycarbonyl)-2-[)30,40-methylenedioxy)benzyl]-4-cyclo-
hexenylamide was used as a building block in the synthesis
of montanine-type Amaryllidaceae alkaloids.22,23 To obtain
Keywords: amino alcohols; 1,3-oxazines; 1,3-benzoxazines.
Corresponding author. Tel.: 136-62-545-564; fax: 136-62-545-705;
e-mail: fulop@pharma.szote.u-szeged.hu
p
0040±4020/01/$ - see front matter q 2001Elsevier Science Ltd. All rights reserved.
PII: S0040-4020)01)00176-4

Â
P. Csomos et al. / Tetrahedron 57 92001) 3175±3183
3176
Scheme 1. )a) 1equiv. PCl 5, CH2Cl2, 08C±rt, 2 h; )b) 3 equiv. AlCl3, benzene, 608C, 4 h; )c) 4 equiv. NaHB4, EtOH, 2108C±rt, 3 h )d) conc. HCl, 708C;
)e) recrystallization from EtOH; )f) LiAlH4, Et2O, 08C, 1h±rt, 3 h.
the amino ketones 2 and 5 with known stereochemistry,
b-amino acids 1 and 4 were employed as starting materials
)Scheme 1).
amino alcohol 3a as the major product. The cis amino
ketone 2 could be reduced diastereoselectively with
NaBH4 in ethanol at 2108C )Table 1). For the trans
amino ketone 5, lithium aluminium hydride proved to be a
selective reducing agent. The H NMR spectrum of the
crude product of the reduction of 5 revealed a 9:1mixture
of 6a and b.
1
Treatment of cis-2-aminocyclohexanecarboxylic acid 1
with phosphorus)V) chloride, and subsequent Friedel±
Crafts acylation in the presence of AlCl3, gave amino ketone
2 in relatively good yield )51%). The trans amino ketone 5
was prepared similarly, starting from amino acid 4, but in
only moderate yield )24%). Epimerisation of the cis amino
ketone 2 in concentrated hydrochloric acid at 708C for three
days resulted in a 1:9 mixture of 2 and 5. From this mixture,
the trans amino ketone 5 was obtained in 48% yield by
recrystallization from ethanol. By this method, 5 can be
prepared directly from the readily available cis-2-amino-
cyclohexanecarboxylic acid 1.
An alternative synthesis of 3a is shown in Scheme 2.
b-Imino ketone 8 was prepared from b-diketone 7 and
benzylamine. The catalytic reduction of 8 with 5% Pt/C at
room temperature afforded 9 diastereoselectively. After
recrystallization from diisopropyl ether, the Pd)OH)2/C-
catalysed hydrogenolysis of 9 provided amino alcohol 3a
in a yield of 88% )Scheme 2). For the preparation of amino
alcohols possessing structures similar to that of 3a, selective
reductions were performed with PtO2, starting from the
corresponding enamino ketones.16,18
The reduction of b-amino ketones with metal hydrides
a preference
usually occurs with syn selectivity,24
consistent with a b-chelated transition state.25 The different
reductions of the cis amino ketone 2 also provided syn
Alternatively, the addition of thiocyanic acid, generated
from potassium thiocyanate in 50% sulfuric acid, to
Table 1. Selectivity of the reduction of cis-amino ketone 2
Reducing agent
Reaction conditions
3a )%)
3b )%)
HCl salt
HCl salt
Base
Base
Base
NaBH4 )4 equiv.)
NaBH4 )4 equiv.)
LiAlH4 )2 equiv.)
l-Selectridea )3 equiv.)
Na )10 equiv.)
EtOH, rt )3 h)
89
98
71
42
43
70
92
11
2
29
58
57
30
8
EtOH, 2108C±rt )3h)
Et2O, 08C )1h)±rt )3 h)
THF, 2788C )6 h)±rt )4 h)
i-PrOH/THF, rt )4 h)
EtOH, rt )6 days)
Base
Base
10% Pd/Cb
Raney-Nic
EtOH, rt )5 days)
a
Traces of trans isomers 6a and b were also detected.
0.1g/1g 2.
0.2 g/1g 2.
b
c
Scheme 2. )a) 1.04 equiv. benzylamine, toluene, re¯ux, Dean±Stark trap, 3 h; )b) 5% Pt/C, H2 )60 bar), EtOH, rt, six days; )c) 20% Pd)OH)2/C, H2 )60 bar),
MeOH, rt, 48 h.

Â
P. Csomos et al. / Tetrahedron 57 92001) 3175±3183
3177
1-benzoylcyclohexene 11 afforded the isothiocyanate inter-
mediate 12, which was converted to amino ketone 5 via
acidic hydrolysis )Scheme 3). A similar addition to 1-acetyl-
cyclohexene was earlier performed for the preparation of
)1Rp,2Rp)-2-acetylcyclohexylamine.26
by ethyl chloroformate treatment.27 In these cases, only
moderate yields were obtained. The cyclizations of 3a and
6a with ethyl benzimidate in ethanol, under acid catalysis,
resulted in 4,5-dihydro-6H-1,3-oxazines 15 and 20. Treat-
ment of 3a and 6a with phenyl isothiocyanate provided the
thiourea derivatives 16 and 21. With methyl iodide, 16 and
21 gave thioethers, which were transformed in alkaline
medium to 2-phenyliminotetrahydro-1,3-oxazines 17 and
22.
Amino alcohols 3a and 6a were transformed to different
alicycle-condensed 1,3-oxazines )Schemes 4 and 5).
The reactions of 3a and 6a with ethyl chloroformate
provided urethane intermediates, which were converted
with sodium methoxide to tetrahydro-1,3-oxazin-2-ones
13 and 18 in good yields. The corresponding 2-thiones 14
and 19 were prepared from 3a and 6a by reaction with
carbon disul®de in the presence of triethylamine. The
triethylammonium dithiocarbamate intermediates formed
were transformed without isolation to 2-thioxo-1,3-oxazines
3. Spectroscopic studies
The IR, 1H and 13C NMR spectral data on compounds 2, 3,
5, 6, 8, 9 and 13±22 are given in Tables 2 and 3 and prove
the structures unambiguously. The numbering of the
chemical names )compounds 2, 3, 5, 6, 8 and 9) according
Scheme 3. )a) 1.2 equiv. PhMgBr, Et2O, re¯ux, 6 h; )b) 1equiv. KSCN, 0.5 equiv. 50% H 2SO4, 508C, 6 h; )c) conc. HCl, 708C, three days.
Scheme 4. )a) 1.1 equiv. ClCOOEt, 4.4 equiv. 10% NaOH in H2O/toluene, 30 min; )b) 0.11 equiv. NaOMe, 1308C, 1h; )c) 11equiv. CS 2, 1.1 equiv. Et3N,
CHCl3, 08C±rt, four days; )d) 1.1 equiv. ClCOOEt, 1.1 equiv. Et3N, CHCl3, 08C, 5 min rt, 30 min re¯ux, 3 h; )e) 1equiv. ethyl benzimidate, cat. CH 3COOH,
ethanol, re¯ux, 36 h; )f) 1 equiv. PhSCN, toluene, 8 h; )g) 10 equiv. MeI, methanol, rt, 3 h; )h) 38 equiv. 15% KOH in methanol, rt, two days.
Scheme 5. )a) 1.1 equiv. ClCOOEt, 4.4 equiv. 10% NaOH in H2O/toluene, 30 min; )b) 0.11 equiv. NaOMe, 1308C, 1h; )c) 1.1equiv. CS 2, 1.1 equiv. Et3N,
CHCl3, 08C±rt, four days; )d) 1.1 equiv. ClCOOEt, 1.1 equiv. Et3N, CHCl3, 08C, 5 min rt, 30 min re¯ux, 3 h; )e) 1equiv. ethyl benzimidate, cat. CH 3COOH,
ethanol, re¯ux, 36 h; )f) 1 equiv. PhSCN, toluene, 8 h; )g) 10 equiv. MeI, methanol, rt, 3 h; )h) 38 equiv. 15% KOH in methanol, rt, two days.

Table 2. Characteristic IR frequencies )in KBr discs, cm21) and 1H NMR data )in CDCl3 solution, for 2, 3b and 5 in D2O, at 500 MHz. Chemical shifts in ppm, dTMSˆ0 ppm, coupling constants in Hz) on compounds 2,
3, 5, 6, 8, 9 and 13±22 )assignments were supported by 2D-HSC )HMQC) and for 13, 14, 17, 19, 20 and 22 also by DNOE measurements)
Compound
H-2 d )1H)a
H-4a m )1H)b
H-8a )1H)c
CH2 )Pos. 5±8) 4-8 m's )8H)
H-2,6, H-3,5, H-4
Phenyl in pos. 2
H-2,6, H-3,5, H-4
Phenyl in side-chain
nOH &nNH band
nCvN bandd
2
±
3.84
,1.6e
2.07
3.55
1.61
±
1.65
1.99
2.09
2.07
1.81
,2.0e
,1.95e
,2.0e
1.85
,1.3e
1.86
3.65
3.35
3.62
1.0±2.1
2.40
±
3.23
3.95
3.97
4.02
,4.6h
3.92
2.93
2.96
2.99
4.50
2.92
1.4±2.0
1.0±1.6e
1.2±1.9
7.89
7.82, 7.44, 7.58
7.20f, ,7.3
7.25±7.40e
±
±
±
±
3200±2800
3400±2800
3400±2700
3200±2800
3400±2700
±
3300±2600
3235
3185
1675
±
±
1674
±
±
3a
3bg
5
6a
8
4.99
4.67
±
4.70
±
5.02
5.42
5.46
5.45
4.72
5.36
5.34
5.47
5.40
4.98
5.28
7.46, 7.60
0.7±1.7
1.4±2.5
1.0±2.1
1.0±1.9
1.1±2.0
1.0±2.25
1.1±2.25
1.1±2.0e
0.6±2.0e
0.6±2.0e
0.6±2.3
0.9±2.1e
0.6±2.1
7.1±7.3e
±
7.26
7.40, ,7.33e, ,7.33e
7.20f, 7.25±7.40 e
7.25f, 7.3±7.4
,7.3e
9
7.25±7.40e
±
13
14
15
16
17
18
19
20
21
22
±
±
1721
1543
1651
1234
1669
1698
1550
1641
1238
1662
7.30f, 7.35±7.5
,7.25e
8.09, 7.3±7.4e
7.25, 7.42, 7.20
7.25±7.40e, 6.95
±
±
3500±3000
3250±2700
3215, 3115
3160
7.25±7.4e
7.16, ,7.35e
7.12, ,7.35e
7.16, ,7.28e
,7.28e
±
8.04, 7.40, 7.44
7.22, 7.46, 7.18
7.35, 7.23, 6.93
±
3500±2700
3200±2700
7.23, ,7.35e
Further signals, N1H3, br s )3H): 4.65 )2, 5), OH, br s )1H): , 3.3 )3a), ,2.2 )16), CH2, d )2H): 4.48, J: 6.0 )8), 2£d )2£1H): 3.78 and 3.96, J: 12.5 )9), NH, sharp s)1H): 12. 4 )8), br s )1H): 6.6 )13), 8.1and 8.3 ) 16 and
21, vicinal to phenyl), 7.4 )17), 6.65 )18), 8.3 )19), 5.8 )22), d 6.80, J: 7.3 )16), 5.92, J: 9.3 )21).
J: 1.5 )3a, 9), 3.5 )6a, 16), 2.0 )13), 5.3 )18, 20), 2.5 )15), 4.5 )19, 22), 3.0 )21); singlet for 13 and 17, triplet for 16.
a
b
Broad multiplet. Lines are resolved for 2 )td, J: 8.5, 4.2), 6a, )tt, J: 12, 3.3) and 13 )d, J: 12.5).
Lines are coalesced to broad signals for 14, 16 and 17. The multiplicity is identi®able for 6a and 22 )dt) and 21 )qa), respectively. Lines are separated to td, J: 7.0 and 3.5, )2); d, J: 2.8 )3a, 9), J: 4.9 )3), t, J: 3.0 )3b),
c
qa, J: 3.5 )15), dt, J: 11.0 and 4.0 )18±20).
nCvO band for 2, 5, 13 and 18; group frequency of the thiourethane/thiourea of b-NH or nCvS character for 14, 16, 19 and 21.
Overlapping signals.
The separated signal )1H) of one of the ortho-hydrogens.
Hydrochloride.
Broad signal.
d
e
f
g
h

Â
P. Csomos et al. / Tetrahedron 57 92001) 3175±3183
3179
to the IUPAC nomenclature is not identical with that used in
the text, or in Tables 2 and 3, in order to facilitate the com-
parison of spectroscopically analogous data. As concerns the
stereostructures )the con®gurations and conformations), only
the following remarks are necessary. Compound 8 is
stabilized by chelation: via tautomeric rearrangement, 8
assumes a six-membered conjugated ring structure involving
an intramolecular hydrogen bond. Such an association is very
common for b-imino-oxo compounds.28
the cyclohexane-fused oxazines: of the two stable chair±
chair conformers of 3,1-oxazines containing NH)1) or sp2
N-1vicinal to the anellated carbon, the N)1)- in form is
preferred. In compounds 13±15 and 17, this situation is
more probable, in consequence of the bulkier CHPh group
in position 4 bonded to the other anellated carbon instead of
the methylene group in the same position in the molecules
investigated earlier.
The relative con®guration of C-4 was determined by means
of DNOE measurements )Table 3). For the trans-anellated
isomers, the interactions between H-8aax and the ortho
hydrogens of the 4-phenyl ring and the similar interactions
of the latter with H-5ax and between H-4 and H-5eq con®rm
the axial position of the 4-phenyl substituent trans to H-4a
and cis to H-8a.
Compounds 2 and 5, containing two asymmetric centres,
can exist in cis or trans con®gurations. In accordance with
expectations, compound 2 is the cis and 5 the trans isomer.
The sum of the shifts of the carbons of the cyclohexane ring
is 192.7 ppm for 2, and 209.4 ppm for 5. The sterically less
favourable structure of the cis isomer 2 is revealed in the
up®eld shifts of the 13C NMR lines, due to the steric
compression shift.29,30a The 16.7 ppm difference in the
sum of the shifts is unambiguous proof of the con®gura-
tions. The heterobicycles 13±15, 17±20 and 22 containing
three asymmetric centres may exist as four stereoisomers
and, in the case of the cis-anellated skeleton, as two stable
)chair±chair) conformations each.
The DNOE results on the cis-anellated isomers 13, 15 and
17 prove the equatorial orientation of the 4-phenyl group
trans to both H-4a and H-8a. The most relevant NOE in this
respect was observed between H-4a and H-8a in the 1,3-
diaxial position.
The analogous stereostructures of 15 and 18 with those of
the other cis and trans-anellated compounds follow directly
from the very similar chemical shifts of the relevant H/C
atoms.
Compounds 18±20 and 22 are trans-anellated. This follows
from )i) the double triplet ®ne structure of the H-8a signal
due to two diaxial vicinal couplings of ca. 11 Hz, and )ii) the
down®eld shifts of the C-4a lines in comparison with those
for the cis counterparts, in accordance with the expected
up®eld shifts of these signals in the more crowded cis
isomers )®eld effect). While the C-4a shifts are
41.4^0.8 ppm for 18±20 and 22, they are 37.6^0.5 ppm
for the isomers 13±15 and 17. The smaller and opposite
difference in the C-8a shifts suggests conformationally
homogeneous, quasi-rigid structures for the cis isomers
with N)1) in a quasi-axial position. This is in accordance
with our earlier ®nding31±34 concerning the conformation of
For the monocyclic compounds, it is easy to determine the
relative con®gurations of the substituted ring carbons and
the substituents, respectively, but this is not possible for the
third asymmetric carbon in the side-chain )position 4). The
tt and dt multiplicities of the H-4a and H-8a signals of 6a
)two large couplings of about 12 Hz), characteristic of
diaxial vicinal interactions,35 are proof of the trans-
diequatorial position of the substituents. The up®eld shift
)®eld effect) of the C-4a line )by 2.2 ppm) and the down®eld
Table 3. 13C NMR chemical shifts )in ppm, dTMSˆ0 ppm), at 125.7 MHz. Solvent: CDCl3 )for 2, 3b and 5: D2O) of compounds 2, 3, 5, 6, 8, 9 and 13±22
)assignments were supported by DEPT and 2D-HSC )HMQC), and for 8 and 9 also by 2D-COLOC )HMBC) measurements)
Compound
C-2a
C-4
C-4a
C-5
C-6
C-7
C-8
C-8a
Phenyl in position 4
C-1C-2,6 C-3,5
129.5
Phenyl in side-chain
C-4
C-1C-2,6
C-3,5
C-4
2
±
±
±
±
±
±
±
206.5
78.3
74.7
204.4
78.3
194.4 100.7
77.9
81.8
83.9
79.5
75.9
81.1
82.5
84.8
80.0
70.2
81.6
44.7
47.3
43.7
26.3 23.0
26.1 18.3
24.6 21.1
21.0
19.9
23.0
27.9
35.8
28.0
49.8
52.2
50.3
135.5 128.9
144.1 126.3
142.7 129.2
135.1 129.0
143.1 127.1
138.2 126.6
139.5 125.8
137.8 125.8
136.6 125.9
139.1 125.4
134.8
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
±
3a
3bb
5
6a
8d
128.2
128.7
129.5
127.6
127.8
127.8
128.6
128.8
126.8
127.0
135.0
126.6
128.4
126.4
128.1
128.4
49.3c 30.9 24.124.7
29.7
39.5
26.2 164.2
50.7
c
49.5
28.3 25.0
27.9 23.4
25.4 20.0
24.9 18.8
19.4 24.6
25.0 19.6
25.6
22.0
18.4
19.7
19.9
20.7
51.1
±
±
143.0 127.0
143.6 128.5
128.8
128.7
±
127.4
127.4
±
9
47.1
38.1
37.1
37.6
47.1
38.6
41.5
40.7
41.1
51.3
42.2
28.1
31.0
30.5
33.1
58.0
50.8
52.7
53.1
54.3
52.3
49.2
50.8
50.1
56.0
50.2
13
14
15
16
17
18
19
20
21
22
155.4
187.5
154.8
179.4
148.5
154.0
186.4
154.3
180.1
148.3
±
±
±
±
±
±
127.2c 127.3
133.9 128.0c 128.2c 130.3
25.1 21.1c 21.0c 30.5
136.3 125.8c 128.2
127.0c 143.4 124.9c 130.0
127.3c
121.9
±
±
25.4 20.6
26.1 23.3
26.5 25.4
27.7 25.7
25.3 25.1
27.7 26.2
19.5
25.3
23.7
25.1
22.8
25.1
33.0
32.3
31.6
34.5
33.5
35.1
138.8 125.8
137.1 126.5
136.3 126.8
139.1 126.6
135.7 125.8
138.9 127.1
128.7
128.2e 128.2e
129.0 128.9
127.3c 127.8
127.8
128.6
129.2
141.9 119.8
127.9
±
±
±
±
±
±
134.0 128.0c 128.1c 130.3
127.6c 142.4 125.2
129.2 141.8 119.8
130.4
128.4
126.3c
121.9
a
Urethane )13, 17, 18 and 22), thiourethane )14 and 19), thiocarbamide )16 and 21) or ±O±CvN± group )15 and 20).
b
c
d
e
Chlorohydrate, the major component in the 97:3 mixture.
Interchangeable assignments.
NCH2: 46.3.
Overlapping lines.

Â
P. Csomos et al. / Tetrahedron 57 92001) 3175±3183
3180
shift of the H-8a signal )by 0.95 ppm) for 3a in comparison
with 6a suggest an equatorial!axial change in the position
of the NH2 group and thus the cis arrangement of the sub-
stituents )H-8a is more shielded in the axial position, in
accordance with the literature). In the salt of 3b, the main
component is cis-anellated, as indicated by the small t
splitting of the H-8a signal.
ethyl acetate and dried. After recrystallization from ethanol,
the crystals were ®ltered off. The mother liquor was evapo-
rated and the residue was recrystallized from ethanol. The
two crystalline fractions were combined, and dissolved in
100 mL of cold water. The solution was made alkaline with
potassium carbonate and extracted with ethyl acetate
)3£80 mL). After drying )Na2SO4) and evaporation of the
organic solvent, a pale-yellow oil was obtained, which was
puri®ed by recrystallization as the hydrochloride )white
powder).
In the thioureas 16 and 21, this group is cis-axial and trans-
equatorial, as proved by the small splitting and down®eld
shift of the H-8a signal in 16 and the up®eld shifts of the
C-4a and C-8a lines )®eld effect).
4.1.2.
ꢀ1Sp,2Rp)-2-[ꢀRp)-a-Hydroxybenzyl]cyclohexyl-
amine ꢀ3a). Method A. The hydrochloride salt of amino
ketone 2 )5.56 g, 23.19 mmol) was suspended in 60 mL of
ethanol. The suspension was stirred and cooled in salt±ice±
water. Sodium hydrogen carbonate )1.97 g, 23.45 mmol)
and then sodium borohydride )3.48 g, 92 mmol) were
added, the temperature of the mixture being maintained
below 2108C, and stirring was continued until the mixture
warmed up to room temperature. It was then stirred for a
4. Experimental
4.1. General
Melting points were determined on a Ko¯er apparatus and
are uncorrected. The physical and analytical data on the
compounds prepared are listed in Table 2. Amino acids 1
and 4 were prepared from the corresponding alicyclic 1,2-
dicarboxylic anhydrides by ammonolysis, followed by
Hoffmann degradation and ion-exchange chromatography.45
For the preparation of b-diketone 7, 4-cyclohex-1-enyl-
morpholine was reacted with benzoyl chloride and the
intermediate 4-)2-benzoylcyclohex-1-enyl)morpholine was
hydrolysed.46 The synthesis of 10 started from cyclohexa-
none and sodium cyanide; the cyanohydrin formed was
treated with phosphorus oxychloride in pyridine.47 The
Grignard reaction of 1-cyanocyclohexene with phenyl-
magnesium bromide afforded 11.48
1
further 3 h and processed in the usual way. The H NMR
spectrum of the crude product revealed a 98:2 mixture of 3a
and b. Trituration of the oily residue with diisopropyl ether
gave 3a as white crystalline powder.
Method B. A solution of diketone 7 )10.12 g, 50 mmol) and
benzylamine )5.57 g, 52 mmol) was re¯uxed for 3 h in
75 mL of abs. toluene, using a Dean±Stark trap. After
evaporation of the solvent, the red±brown oily residue
was triturated with diisopropyl ether to give 8 as white
crystalline powder.
b-Imino ketone 8 )5.00 g, 17.16 mmol) was dissolved in
50 mL of ethanol and hydrogenated for six days in the
presence of 5% platinum on carbon )0.50 g) at room
temperature and 60 bar. The catalyst was ®ltered off and
the solvent was evaporated off, to afford a white crystalline
powder. The 1H NMR spectrum of the crude product
revealed the presence of homogeneous 9.
IR spectra were run in KBr discs on a Bruker IFS-S 5 FT
spectrometer, controlled by opus 2.0 software. The H and
1
13C NMR spectra were recorded in CDCl3 solution in 5 mm
tubes, at room temperature, on a Bruker DRX-500
spectrometer at 500.13 )1H) and 125.76 )13C) MHz, with
the deuterium signal of the solvent as the lock and TMS
as internal standard. For DNOE measurements,30b,36 the
standard Bruker microprogram DNOEMULT.AU to gener-
ate NOE37 was used with a selective pre-irradiation time.
DEPT spectra38 were run in a standard manner,39 using only
the uˆ1358 pulse to separate the CH/CH3 and CH2 lines
phased up and down.
The recrystallized benzylamino alcohol
9
)2.43 g,
8.20 mmol) was dissolved in 50 mL of methanol and the
solution was stirred for 48 h in the presence of 20%
palladium hydroxide on carbon )0.12 g) at room tempera-
ture and 60 bar. After ®ltration and evaporation, the result-
ing crystalline product was triturated with diisopropyl ether
to give 3a as white crystalline powder.
The 2D-COSY,40 2D-HMQC41,42 and 2D-HMBC43,44
spectra were obtained by using the standard Bruker pulse
programs cosygssw, hxco.au )INV4GSSW) and
hxxco.au )INV4GSLRNDSW), respectively.
4.1.3. ꢀ1Rp,2Rp)-2-Benzoylcyclohexylamine hydrochlo-
ride ꢀ5). Method A. The same method was used as for the
cis counterpart 2, but starting from the trans amino acid 4.
However, the work-up was performed as follows. After
the reaction mixture was poured into 200 g of ice±water,
the aqueous phase was separated, washed with ethyl
acetate, and then neutralized with sodium carbonate. The
precipitate was ®ltered off )suction), washed with ethyl
acetate )2£200 mL), then stirred with chloroform
)200 mL) and decanted. After ®ltration, the two phases
were separated and the aqueous phase was extracted with
chloroform )200 mL). The combined organic phases were
dried )Na2SO4) and the organic solvents were evaporated
off. A pale-yellow oil was obtained, which was puri®ed as
the hydrochloride )white crystalline powder).
4.1.1. ꢀ1Sp,2Rp)-2-Benzoylcyclohexylamine hydrochlo-
ride ꢀ2). To a suspension of phosphorus)V) chloride )21g,
0.1mol) in 300 mL of dichloromethane at 0 8C, cis-2-amino-
cyclohexanecarboxylic acid 1)14.32 g, 0.1mol) was added
and the mixture was stirred for 2 h. After evaporation of the
solvent, the residue was dried in a vacuum desiccator at
room temperature for 3 h. To the residue, 300 mL of dry
benzene and anhydrous aluminium chloride )40 g, 0.3 mol)
were added. The mixture was heated at 608C for 4 h, cooled
to room temperature, and then poured into 200 g of ice±
water. The mixture was shaken in an ice-bath, and the
precipitate formed was ®ltered off, washed twice with

Â
P. Csomos et al. / Tetrahedron 57 92001) 3175±3183
3181
Method B. To a stirred mixture of 1-benzoylcyclohexene 11
)2.80 g, 15 mmol), a 50% aqueous solution of potassium
thiocyanate )1.48 g, 15 mmol) and 50% aqueous sulfuric
acid )0.8 mL, 7.5 mmol sulfuric acid) were added simul-
taneously dropwise at 558C. After the addition of the
reagents was complete, the reaction mixture was stirred at
558C for 6 h. It was next cooled to room temperature and
extracted with diethyl ether )3£30 mL). The combined
organic phases were extracted with 5% sodium hydrogen-
carbonate solution )2£20 mL) and water )20 mL), and the
ether phase was dried )Na2SO4) and evaporated. To the
2.93 g of yellow oily residue obtained, 20 mL of concen-
trated hydrochloric acid was added and the reaction mixture
was stirred at 708C until it became homogeneous )three
days). It was then allowed to cool down to room temperature
and was extracted with diethyl ether )2£10 mL). After
evaporation of the aqueous phase, a white crystalline
powder was obtained, which was ®ltered off and washed
with diethyl ether and acetone.
To this solution, sodium hydroxide )0.62 g, 15.40 mmol)
dissolved in 10 mL of water was added. After the addition
of ethyl chloroformate )0.42 g, 3.85 mmol), the reaction
mixture was shaken intensely for 30 min. The phases were
separated and the aqueous phase was extracted with toluene
)10 mL). The combined organic phases were extracted with
water )10 mL), dried )Na2SO4) and evaporated, to give
0.92 g of oily residue. Trituration with petroleum ether
afforded the white crystalline urethane derivative, which
was recrystallized from diisopropyl ether )mp: 117±
1188C, 0.82 g, 85%, white powder).
This urethane derivative of 6a )0.20 g, 0.72 mmol) was
thoroughly mixed with sodium methoxide )0.02 g,
0.38 mmol), and the mixture was maintained at 1308C for
1h. The melt was extracted with 10 mL of hot ethyl acetate,
and the extract was ®ltered, dried )Na2SO4) and evaporated.
The oily residue crystallized on trituration with diisopropyl
ether )white crystalline powder).
Method C. Amino ketone 2 )3.5 g, 17.22 mmol) was
dissolved in 50 mL of concentrated hydrochloric acid and
the reaction mixture was stirred at 708C for three days.
Evaporation in vacuo led to a white crystalline powder,
which was ®ltered off and washed successively with diethyl
4.1.7. ꢀ4Rp,4aRp,3aSp)-4-Phenyl-4a,5,6,7,8,8a-hexahydro-
4H-3,1-benzoxazine-2ꢀ1H)-thione ꢀ14) and ꢀ4Rp,4aRp,
3aRp)-4-Phenyl-4a,5,6,7,8,8a-hexahydro-4H-3,1-benz-
oxazine-2ꢀ1H)-thione ꢀ19). To a stirred solution of the
amino alcohol 3a or 6a )0.30 g, 1.46 mmol) in chloroform
)10 mL), triethylamine )0.16 g, 1.6 mmol) dissolved in
5 mL of chloroform was added dropwise. Carbon disul®de
)0.12 g, 1.6 mmol) was then added under ice cooling and
the mixture was kept at room temperature for four days.
The solution was next evaporated to dryness, the
residual oil was dissolved in 10 mL of chloroform, and
triethylamine )0.16 g, 1.6 mmol) and ethyl chloroformate
)0.17 g, 1.60 mmol) were added dropwise under ice
cooling. The mixture was sirred for 30 min, then re¯uxed
for 3 h and evaporated. The residual oil was dissolved
in chloroform )15 mL) and washed with 1% aqueous
HCl solution )10 mL). The organic phase was dried
)Na2SO4) and evaporated. To the yellow oil obtained, diiso-
propyl ether was added to give white crystalline powder 14
or 19.
1
ether and acetone. The H NMR spectrum of the crude
product revealed a 9:1mixture of 5 and 2.
4.1.4.
ꢀ1Rp,2Rp)-2-[ꢀRp)-a-Hydroxybenzyl]cyclohexyl-
amine ꢀ6a). To an ice-cooled, stirred suspension of lithium
aluminium hydride )1.68 g, 44.26 mmol) in 100 mL of
diethyl ether, the amino ketone base of 5 )4.50 g,
22.13 mmol) in 20 mL of diethyl ether was added dropwise
during 1h. Stirring was continued until the mixture warmed
up to room temperature. It was then stirred for a further 3 h
and processed in the usual way. Trituration of the oily
residue with diisopropyl ether gave 6a as white crystalline
powder. The 1H NMR spectrum of the crude product
revealed a 9:1mixture of 6a and b.
4.1.5. ꢀ4Rp,4aRp,3aSp)-4-Phenyl-4a,5,6,7,8,8a-hexahydro-
4H-3,1-benzoxazin-2ꢀ1H)-one ꢀ13). Amino alcohol 3a
)0.52 g, 2.53 mmol) was dissolved in 20 mL of toluene.
To this solution, sodium hydroxide )0.50 g, 11.12 mmol)
dissolved in 5 mL of water was added. After the addition
of ethyl chloroformate )0.30 g, 2.78 mmol), the reaction
mixture was shaken intensely for 30 min. The phases were
next separated and the aqueous phase was extracted with
toluene )10 mL). The combined organic phases were
extracted with water )10 mL), dried )Na2SO4) and evapo-
rated, to give 0.62 g of an oily residue. This urethane
derivative was thoroughly mixed with sodium methoxide
)0.02 g, 0.38 mmol), and the mixture was maintained at
1308C for 1h. The melt was dissolved in 10 mL of chloro-
form and was extracted with water )10 mL). The aqueous
phase was extracted with chloroform )2£5 mL). The
combined organic phases were dried )Na2SO4) and evapo-
rated. Trituration of the oily residue with diisopropyl ether
gave 13 as a white crystalline powder.
4.1.8. ꢀ4Rp,4aRp,3aSp)-2,4-Diphenyl-1,2,4a,5,6,7,8,8a-octa-
hydro-4H-3,1-benzoxazine ꢀ15) and ꢀ4Rp,4aRp,3aRp)-2,4-
Diphenyl-1,2,4a,5,6,7,8,8a-octahydro-4H-3,1-benzoxazine
ꢀ20). To a solution of amino alcohol 3a or 6a )0.30 g,
1.5 mmol) in dry ethanol )10 mL), ethyl benzimidate
)0.22 g, 1.5 mmol) and two drops of glacial acetic acid in
1mL of dry ethanol was added. The reaction mixture was
re¯uxed for 12 h. Then, two drops of ethyl benzimidate
were added and the solution was re¯uxed for a further
24 h. After evaporation, white crystalline powder of 15 or
20 was obtained.
4.1.9. Thiourea derivatives 16 and 21. Phenyl isothio-
cyanate )0.30 mL, 2.5 mmol) was added to amino alcohol
3a or 6a )0.50 g, 2.5 mmol) dissolved in 20 mL of dry
toluene. The reaction mixture was stirred at room tempera-
ture for 8 h and evaporated. The white crystalline powder
obtained was taken up in diisopropyl ether and the solution
was ®ltered.
4.1.6. ꢀ4Rp,4aRp,3aRp)-4-Phenyl-4a,5,6,7,8,8a-hexahydro-
4H-3,1-benzoxazin-2ꢀ1H)-one ꢀ18). Amino alcohol 6a
)0.72 g, 3.50 mmol) was dissolved in 25 mL of toluene.
4.1.10. ꢀ4Rp,4aRp,3aSp)-4-Phenyl-2ꢀ1H)-phenylimino-4a,
5,6,7,8,8a-hexahydro-4H-3,1-benzoxazine ꢀ17) and ꢀ4Rp,

Â
P. Csomos et al. / Tetrahedron 57 92001) 3175±3183
3182
Table 4. Analytical data on the compounds prepared
Compound
Yield )%)
Mp )8C)
Formula
Analysis
C )%)
H )%)
N )%)
Calcd
Found
Calcd
Found
Calcd
Found
2
3a
5
6a
8
9
13
14
15
16
17
18
19
20
21
22
51
77 )A)b 88 )B)b,c
213±215a
119±121d
209±211a,e
121±122d
75±77d
C13H18ClNO
C13H19NO
C13H18ClNO
C13H19NO
C20H21ClNO
C20H24NO
C14H17NO2
C14H17NOS
C20H21NO
C20H24N2OS
C18H22N2O
C14H17NO2
C14H17NOS
C20H21NO
65.13
76.06
65.13
76.06
82.44
81.31
72.70
67.98
82.44
70.55
76.56
72.70
67.98
82.44
70.55
76.56
65.35
75.77
64.89
75.83
82.32
81.47
72.30
68.43
82.37
70.14
76.62
73.02
68.32
82.32
70.43
76.73
7.57
9.33
7.57
9.33
7.26
8.53
7.417.32
6.93
7.26
8.23
9.92
7.417.58
6.93
7.26
7.68
9.14
7.82
9.27
6.97
8.40
6.06
7.23
7.43
8.35
10.11
6.06
6.70
7.45
5.84
6.82
5.84
6.82
54.815.1
4.74
6.1
6.01
6.72
6.12
6.84
24 )A)b 50 )B)b 48 )C)b
70
78
91f
78
47
86
87
63
74
43
88
80
72
118±120d
240±241g
228±229d
106±109e
155±157h
163±165d
199±201i
217±219h
171±172e
166±168i
144±146d
4.78
5.50
6
5.66
24.815.1
7.10
9.92
6.34
5.66
4.814.84
7.10
9.92
6.89
9.89
5.47
C20H24N2OS
C18H22N2O
8.23
9.92
8.14
10.27
7.05
9.62
a
Ethanol-diethyl ether )solvent for recrystallization).
Corresponding methods in Section 4.
Yield starting from 9.
Diisopropyl ether )solvent for recrystallization).
Ethanol )solvent for recrystallization).
b
c
d
e
f
Yield starting from 8 )solvent for recrystallization).
Ethyl acetate-ethanol )solvent for recrystallization).
Diisopropyl ether-ethyl acetate )solvent for recrystallization).
Ethyl acetate )solvent for recrystallization).
g
h
i
4aRp,3aRp)-4-Phenyl-2ꢀ1H)-phenylimino-4a,5,6,7,8,8a-
hexahydro-4H-3,1-benzoxazine ꢀ22). Thiourea derivative
16 or 21 )0.23 g, 0.69 mmol) was dissolved in methanol
)10 mL), methyl iodide )0.44 mL, 6.9 mmol) was added
and the solution was stirred for 3 h at room temperature.
After evaporation of the solvent, the residue was stirred in
10 mL of 15% methanolic potassium hydroxide for two
days. After evaporation, ice±water )10 mL) and chloroform
)15 mL) were added, and the phases were separated. The
aqueous phase was extracted with chloroform )10 mL). The
combined organic phases were dried )Na2SO4) and evapo-
rated. The oxazines 17 and 22 were obtained as white
crystalline powders )Table 4).
7. Wuensch, B.; Hoefner, G.; Bauschke, G. Arch. Pharm. 1993,
326, 101.
8. Bartoli, G.; Cimarelli, C.; Palmieri, G. J. Chem. Soc., Perkin
Trans. 1 1994, 537.
Â
9. Barluenga, J.; Tomas, M.; Ballesteros, A.; Kong, J.-S.
Tetrahedron 1996, 52, 3095.
   Â
10. Stajer, G.; Szabo, A. E.; FuÈlop, F.; Bernath, G.; Sohar, P.
È
J. Heterocycl. Chem. 1984, 21, 1373.
Â
11. Szakonyi, Z.; FuÈlop, F.; Bernath, G.; Evanics, F.; Riddell, F. G.
È
Tetrahedron 1998, 54, 1013.
Â
12. FuÈlop, F.; Simon, L.; Simon-Talpas, G.; Bernath, G. Synth.
È
Commun. 1998, 28, 2303.
Â
13. Oszbach, G.; Neszmelyi, A. Liebigs Ann. Chem. 1990, 211.
Â
Â
14. Neszmelyi, A.; Lotter, H.; Kiss, A.; Pelczer, I.; Oszbach, G.
Liebigs Ann. Chem. 1991, 917.
15. Hardley, J. P.; Fletcher III, H.; Russel, P. B. Experientia 1978,
34, 1124.
Acknowledgements
16. Szmuszkovicz, J.; Skaletzky, L. L. J. Org. Chem. 1967, 32,
3300.
We express thanks to the Hungarian Scienti®c Research
Foundation for grant OTKA T030452.
17. Letton, J. C.; Maher, E.; Gearien, J. E. J. Med. Chem. 1972,
15, 1328.
18. Szmuszkovicz, J.; Chidester, C. G.; Laurian, L. G.; Scahill,
T. A. J. Org. Chem. 1986, 51, 5002.
References
È
Â
19. Jager, V.; Buss, V.; Schwab, W. Liebigs Ann. Chem. 1980,
122.
  Â
20. Stajer, G.; Szabo, A. E.; Frimpong-Manso, S.; Bernath, G.;
È
1 . FÈluop, F.; Huber, I.; Bernath, G. Sci. Pharm. 1996, 64, 367.
2. Chang, B. L.; Ganesan, A. Bioorg. Med. Chem. Lett. 1997, 7,
1511.
Â
Sohar, P. Tetrahedron 1990, 46, 6859.
3. Trentman, W.; Mehler, T.; Martens, J. Tetrahedron: Asymmetry
1997, 8, 2033.
Â
21. FuÈlop, F.; Bernath, G.; Pihlaja, K. Adv. Heterocycl. Chem.
È
1998, 69, 349.
4. Merino, P.; Castillo, E.; Merchan, F. L.; Tejero, T. Tetrahedron:
Asymmetry 1997, 8, 1725.
22. Ishizaki, M.; Hoshino, O.; Iitaka, Y. Tetrahedron Lett. 1991,
32, 7079.
5. Musso, D. L.; Mehta, N. B.; Soroko, F. E. Bioorg. Med. Chem.
Lett. 1997, 7, 1 .
23. Ishizaki, M.; Hoshino, O.; Iitaka, Y. J. Org. Chem. 1992, 57,
7285.
24. Tramontini, M. Synthesis 1982, 605.
Â
6. FuÈlop, F.; Huber, I.; Bernath, G.; Honig, H.; Seufer-
È
Wasserthal, P. Synthesis 1991, 43.
È

Â
P. Csomos et al. / Tetrahedron 57 92001) 3175±3183
3183
25. Houben-Weil, Stereoselective Synthesis. Thieme: Stuttgart,
1996; Vol. 7, pp 4046.
37. Noggle, J. H.; Schirmer, R. E. The Nuclear Overhauser Effect;
Academic: New York, 1971.
26. Boiko, I. P.; Malina, U. F.; Zuk, O. I.; Samutov, U. U.;
Unkovskij, B. V. Zh. Org. Khim. 1975, 11, 605 )J. Org.
Chem. )Eng. Transl.), 1975, 11, 602).
38. Pegg, D. T.; Doddrel, D. M.; Bendall, M. R. J. J. Chem. Phys.
1982, 77, 2745.
39. Bendall, M. R.; Doddrell, D. M.; Pegg, D. T.; Hull, W. E. High
Resolution Multipulse NMR Spectrum Editing and DEPT;
Bruker: Karlsruhe, 1982.
Â
27. FuÈlop, F.; Csirinyi, G.; Bernath, G. Synthesis 1985, 1149.
È
28. Holly, S.; Sohar, P. In Theoretical and Technical Introduction
to the Series Absorption Spectra in the Infrared Region;
Â
40. Ernst, R. R.; Bodenhauser, G.; Wokaun, A. Principles of
Nuclear Magnetic Resonance in One and Two Dimensions;
Two Dimensional Correlation Methods Based on Coherence
Transfer; Clarendon: Oxford, UK, 1989; pp 400±440.
41. Sanders, J. K. M.; Hunter, B. K. Modern NMR Spectroscopy.
A Guide for Chemists; Oxford University: Oxford, 1987.
42. Ernst, R. R.; Bodenhauser, G.; Wokaun, A. Principles of
Nuclear Magnetic Resonance in One and Two Dimensions;
Heteronuclear Two Dimensional Correlation Spectroscopy
in Isotropic Phase; Clarendon: Oxford, UK, 1987; pp 471±
479.
 Â
Akademiai Kiado: Budapest, 1975; p 87.
29. Grant, D. M.; Cheney, E. V. J. Am. Chem. Soc. 1967, 89, 5315.
Â
30. )a) Sohar, P. Nuclear Magnetic Resonance Spectroscopy;
Field Effect 9Steric Compression Shift); Vol. 2; CRC: Boca
Â
Raton, FL, 1983; p 154±155. )b) Sohar, P. Nuclear Magnetic
Resonance Spectroscopy; Gated Decoupling. Determination
of NOE and the Absorption Intensities; Vol. 1; CRC, 1983;
p 196±197.
Â
Â
31. Sohar, P.; Bernath, G. Org. Magn. Reson. 1973, 5, 159.
Â
32. Sohar, P.; Gera, L.; Bernath, G. Org. Magn. Reson. 1980, 14,
Â
204.
43. Bax, A.; Morris, G. J. Magn. Reson. 1981, 42, 501.
44. Kessler, H.; Griesinger, C.; Zarboch, I.; Loosli, H. J. Magn.
Reson. 1984, 57, 331.
Â
33. Sohar, P.; FuÈlop, F.; Bernath, G. Org. Magn. Reson. 1984, 22,
Â
È
527.
  Â
34. Stajer, G.; Frimpong-Manso, S.; Bernath, G.; Sohar, P.
45. Plieninger, H.; Schneider, K. Chem. Ber. 1959, 92, 1594.
Á Â
46. Fos, E.; Borras, L.; Gasull, M.; Mauleon, D.; Cargnico, G.
Heterocycl. Chem. 1991, 28, 753.
35. )a) Karplus, M. J. Chem. Phys. 1959, 30, 1115. )b) Karplus, M.
J. Chem. Phys. 1960, 33, 1842±1849.
J. Heterocycl. Chem. 1992, 29, 203.
47. Wheeler, O. H.; Lerner, I. J. Am. Chem. Soc. 1956, 78, 63.
48. Bergmann, E. D. Bull. Res. Counc. Israel 1956, 5A, 150.
36. Sanders, J. K. M.; Mersh, I. D. Prog. Nucl. Magn. Reson.
1982, 15, 353.