Synthesis of enantioenriched 2-substituted 4-phenylbutylamines by hydrogenolysis of optically pure 6-alkoxy-5,6-dihydro-4H-1,2-oxazines

Article abstract of DOI:10.1002/1099-0690(200208)2002:16<2838::AID-EJOC2838>3.0.CO;2-O

Lewis acid promoted exchange of the 6-ethoxy group of 6H- 1,2-oxazines 1-3 with (-)-menthol furnished the optically active heterocycles 4-6. Diastereomers 4a and 4b, which could be separated efficiently by chromatography, were excellent substrates for hig

Full text of DOI:10.1002/1099-0690(200208)2002:16<2838::AID-EJOC2838>3.0.CO;2-O

FULL PAPER
Synthesis of Enantioenriched 2-Substituted 4-Phenylbutylamines by
Hydrogenolysis of Optically Pure 6-Alkoxy-5,6-dihydro-4H-1,2-oxazines
Monika Buchholz,[a] Florian Hiller,[b] and Hans-Ulrich Reißig*[a]
Keywords: Amines / Asymmetric synthesis / Chiral auxiliaries / Hydrogenation
Lewis acid promoted exchange of the 6-ethoxy group of 6H-
1,2-oxazines 1−3 with (−)-menthol furnished the optically
active heterocycles 4−6. Diastereomers 4a and 4b, which
could be separated efficiently by chromatography, were ex-
cellent substrates for highly diastereoselective conjugate ad-
ditions of phenyllithium and n-butyllithium, thus providing
the enantiopure trans-substituted 1,2-oxazines 7a, 7b, 8a,
and 8b in good yields. Exhaustive hydrogenolysis of 7a af-
forded the primary amine 9 with an enantiomeric excess of
80%, whereas hydrogenolysis of 8a and 8b gave the corres-
ponding amines (R)-11 and (S)-11, respectively, with an ee of
more than 90%.
( Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany,
2002)
Introduction
is illustrated in Scheme 1 and involves a reductive cleavage
of the NϪO bond, fragmentation of the resulting semiace-
tal C and reduction of the CϭN bond. Recyclization of
D furnishes the cyclic imine E, which is then reduced to
pyrrolidine F. Compounds F can be isolated as products if
the substituent at C-2 of F is not an aryl group[6] or if a
substituent at C-3 hampers the last reduction step sterically
or electronically.[5] However, for starting materials such as
A the reaction proceeds to completion and hydrogenolysis
of the benzylic CϪN bond affords the primary amine B as
the final product usually in good yield.[1Ϫ5]
We have demonstrated in earlier investigations that ex-
haustive hydrogenolysis of 3-phenyl-substituted 6-alkoxy-
5,6-dihydro-4H-1,2-oxazines A in the presence of palladium
transforms these heterocycles into the 4-phenylbutylamines
B (Scheme 1).[1Ϫ5] The mechanism of this cascade reaction
Results and Discussion
In previous publications we reported the synthesis of en-
antioenriched 2-methyl-4-phenylbutylamine (ee up to Ͼ
90%) from this reductive cleavage sequence employing 6-
alkoxy-6H-1,2-oxazine precursors synthesised by an asym-
metric hetero-DielsϪAlder reaction with enantiopure enol
ether auxiliaries.[2] We now want to present our first results
with enantiopure 1,2-oxazines A synthesised by an alternat-
ive route (Scheme 2). This method employs a highly diaster-
eoselective conjugate addition of organolithium compounds
to enantiopure 6H-1,2-oxazines such as 4a and 4b. These
precursor compounds were prepared by a Lewis acid cata-
lysed exchange of the 6-ethoxy group of racemic 1,2-oxaz-
ine 1[7] employing (Ϫ)-menthol as auxiliary. This reaction
involves an azapyrylium ion[8] and provides a 45:55 mixture
of the two diastereomers 4a,b in 89% yield, which can be
separated either by column chromatography or — more ef-
ficiently — by HPLC, furnishing the diastereomerically
pure precursor compounds 4a and 4b in 28% and 52%
yield, respectively. Use of methyl mandelate as the auxiliary
was less efficient.[9] The conversion of 6-ethoxy-substituted
Scheme 1
[a]
Institut für Chemie Ϫ Organische Chemie, Freie Universität
Berlin,
Takustr. 3, 14195 Berlin, Germany
E-mail: hans.reissig@chemie.fu-berlin.de
[b]
Institut für Organische Chemie der Technischen Universität
Dresden,
01062 Dresden, Germany
2838
 WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002 1434Ϫ193X/02/0816Ϫ2838 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2002, 2838Ϫ2843

Synthesis of Enantioenriched 2-Substituted 4-Phenylbutylamines
FULL PAPER
When compound 7a was exhaustively hydrogenated un-
der standard conditions it provided 9 in good yield and
with a specific optical rotation of Ϫ5.85 (c ϭ 0.99, CHCl3;
Scheme 4). Since 9 was not known in an enantiopure form
we prepared a racemic sample of rac-9 from rac-10[12] and
compared the Mosher amides of enantioenriched 9 by
HPLC with those of the diastereomers obtained from rac-
9. Thus, an enantiomeric excess of 80% could be deter-
mined for optically active 9. Since the absolute configura-
tion at C-5 of 7a is R the predominant enantiomer of 9
should also have an R configuration at C-2. It is obvious
that the corresponding S enantiomer is available in an ana-
logous fashion with 7b as the starting material.
Scheme 2
1,2-oxazines was also examined with compounds 2 and 3.
The exchanges were less efficient in these cases (although
not optimized) and resulted in isomers 5a,b and 6a,b.
Again, the diastereomers are separable by chromato-
graphy.[9] The ratios of a:b in all three examples seem to
reflect the thermodynamic equilibria which are, as expected,
not far from 50:50. The absolute configuration of 4a at C-6
is S as unambiguously determined by an X-ray analysis.[10]
With the two enantiopure diastereomers 4a and 4b in
hand we investigated the conjugate addition of organoli-
thium compounds and the hydrogenolysis of the resulting
adducts. Reactions with phenyllithium and n-butyllithium
were executed as described for racemic 6H-1,2-oxaz-
ines,[11,12] and for 4a they furnished products 7a and 8a in
good yields (Scheme 3). As expected, the bulky 6-menthyl-
oxy group of 4a leads to highly selective trans-additions fur-
nishing diastereomerically pure compounds (dr Ն 95:5).
Similarly, reactions of diastereomer 4b with the two organo-
lithium compounds furnished adducts 7b and 8b, again with
excellent trans selectivity. The chirality of the menthyl group
seems to have no dramatic influence on the yields and dia-
stereoselectivities in these addition reactions. However, we
observed a clear effect on the efficiency of the conjugate
addition when a sterically more demanding aryllithium
compound was added to 3-(p-methoxyphenyl)-substituted
6H-1,2-oxazines corresponding to 4a and 4b, thus revealing
an interesting matched/mismatched situation.[5]
Scheme 4
Hydrogenolysis of the 5-butyl-substituted 1,2-oxazines 8a
and 8b afforded the expected primary amine 11 with a negli-
gible optical rotation (Ϫ0.37 starting from 8b). Since we did
not expect almost complete racemization in these experi-
ments, we prepared a sample of rac-11 by conjugate addi-
tion of n-butyllithium to rac-12 followed by hydro-
genolysis.[12] The corresponding diastereomeric Mosher
amides of rac-11 did not show two HPLC signals. However,
a splitting of signals of two carbon atoms was observed
in the 13C NMR spectrum. In contrast, the Mosher amide
derived from the primary amine 11 obtained from 8b did
not show this splitting. Since the signals were relatively
broad an error of approximately 5% must be allowed for
this method of analysis. Nevertheless, these experiments re-
veal that (R)-11 was formed with an enantiomeric excess of
Ն90%. It is likely that (S)-11 has a similar enantiopurity.
The preferential absolute configurations at the stereogenic
centres as depicted in Scheme 5 are derived from the config-
urations of the precursor heterocycles 8a and 8b.
Conclusion
The experiments disclosed here demonstrate that
enantiopure 6H-1,2-oxazines such as 4a and 4b are available
with reasonable efficiency by separation of the diastereo-
mers obtained after 6-alkoxy group exchange with (Ϫ)-
menthol as auxiliary. We have demonstrated again[11,12] that
the conjugate addition of phenyllithium or n-butyllithium
Scheme 3
Eur. J. Org. Chem. 2002, 2838Ϫ2843
2839

M. Buchholz, F. Hiller, H.-U. Reißig
FULL PAPER
12[12] were prepared by literature procedures. All other chemicals
are commercially available and were used as received.
General Procedure for the Preparation of 6-Menthyloxy-6H-1,2-ox-
azines 4؊6: BF3·OEt2 (2 equiv.) was added at Ϫ78 °C to a solution
of the 1,2-oxazine 1, 2 or 3 in CH2Cl2 (20 mL/mmol). After stirring
for 30 min the optically active alcohol (3 equiv.) was added and the
solution was allowed to warm to room temp. The reaction mixture
was stirred for 24 h, then water (5 mL/mmol) was added, the phases
separated, the organic layer dried (Na2SO4) and the solvent evapor-
ated. The crude products were purified by chromatography (neutral
aluminium oxide). The diastereomers were separated by HPLC or
flash chromatography.
6-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyloxy]-3-phenyl-6H-1,2-
oxazine (4): According to the general procedure, BF3·OEt2
(0.75 mL, 5.97 mmol) and (Ϫ)-menthol (1.41 g, 9.00 mmol) were
added to a solution of 1,2-oxazine 1 (0.610 g, 3.00 mmol) in
CH2Cl2. Purification of the crude product [(6R):(6S) ϭ 55:45] by
chromatography (n-hexane/ethyl acetate, 8:1) led to 1,2-oxazine 4
(0.836 g, 89%). The separation of the diastereomers by HPLC (n-
hexane ϩ 5% ethyl acetate) yielded 4a (0.261 g, 28%) as colourless
crystals (m.p. 132Ϫ136 °C) and 4b (0.492 g, 52%) as colourless
crystals (m.p. 98Ϫ103 °C).
Scheme 5
occurs with a very high trans selectivity. Since the stereo-
genic centre generated in this addition step is not directly
involved during hydrogenolysis the slight loss of enantio-
purity on going from 7a to 9 is probably caused at the stage
of the intermediate γ-amino aldehyde (D in Scheme 1). The
phenyl group enhances the C-H acidity in the α-position
and partial racemization by deprotonation/protonation or
via the enol tautomer may lower the optical purity of the
final product. An isomerization at the stage of the cyclic
imine (E in Scheme 1) to an enamine as intermediate is also
possible but seems less probable. The reaction sequence as
illustrated here for the model substrates 7a, 8a, and 8b leads
to 2-substituted 4-phenylbutylamines with good to high
enantiopurity. It should also be applicable to other substitu-
tion patterns since many organolithium compounds can be
used in the first step of the sequence. In the racemic series
we have already combined the conjugate addition of
organolithium compounds with trapping of the interme-
diate with a large variety of electrophiles.[11,12] This method
introduces an additional substituent at C-4 with high trans
selectivity (with respect to the group at C-5). Thus, the
method described here should be extendable to enantioen-
riched primary amines with two stereogenic centres at C-2
and C-3.
(6S)-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyloxy]-3-phenyl-6H-
1,2-oxazine (4a): [α]2D0 ϭ ϩ54.7 (c ϭ 1.0, CHCl3). 1H NMR
(200 MHz): δ ϭ 7.76Ϫ7.66, 7.47Ϫ7.37 (2 m, 2 H, 3 H, Ph), 6.60
(d, J ϭ 10.0 Hz, 1 H, 4-H), 6.42 (dd, J ϭ 4.5, 10 Hz, 1 H, 5-H),
5.64 (d, J ϭ 4.5 Hz, 1 H, 6-H), 3.62 (dt, J ϭ 4.5, 10.5 Hz, 1 H, 1Ј-
H), 2.36Ϫ2.21 (m, 1 H, 2Ј-H), 2.10 [mc, 1 H, CH(CH3)2], 1.70Ϫ0.74
(m*, 7 H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-H), *contains 0.92, 0.83 [2 d, J ϭ
7.0 Hz, 3 H each, CH(CH3)2], 0.90 (d, J ϭ 6.5 Hz, 3 H, 5Ј-CH3)
ppm. 13C NMR (50.3 MHz): δ ϭ 153.9 (s, C-3), 134.2, 129.7, 128.6,
126.1, 126.0 (s, 4 d, C-5, Ph), 116.2 (d, C-4), 93.1 (d, C-6), 79.9 (d,
C-1Ј), 48.5 (d, C-2Ј), 42.3 (t, C-6Ј), 34.3 (t, C-4Ј), 31.8 (d, C-5Ј),
25.7 [d, CH(CH3)2], 23.3 (t, C-3Ј), 22.1, 21.1, 16.3 (3 q, CH3) ppm.
IR (KBr): ν˜ ϭ 3100Ϫ2750 cmϪ1 (CϪH), 1640 (CϭC), 1525 (Cϭ
N). C20H27NO2 (313.4) calcd. C 76.65, H 8.68, N 4.47; found C
76.84, H 8.78, N 4.50.
(6R)-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyloxy]-3-phenyl-6H-
1,2-oxazine (4b): [α]2D0 ϭ Ϫ104.8 (c ϭ 1.0, CHCl3). 1H NMR
(200 MHz): δ ϭ 7.75Ϫ7.61, 7.47Ϫ7.37 (2 m, 2 H, 3 H, Ph), 6.61
(d, J ϭ 10.0 Hz, 1 H, 4-H), 6.37 (dd, J ϭ 4.5, 10 Hz, 1 H, 5-H),
5.76 (d, J ϭ 4.5 Hz, 1 H, 6-H), 3.84 (dt, J ϭ 4, 10.5 Hz, 1 H, 1Ј-
H), 2.23Ϫ2.08 (m, 1 H, 2Ј-H), 1.99 [mc, 1 H, CH(CH3)2], 1.74Ϫ0.77
(m*, 7 H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-H), *contains 0.94 (d, J ϭ 6.5 Hz,
3 H, 5Ј-CH3), 0.83, 0.81 [2 d, J ϭ 7.0 Hz, 3 H each, CH(CH3)2]
ppm. 13C NMR (50.3 MHz): δ ϭ 154.1 (s, C-3), 134.2, 129.6, 128.7,
126.5, 125.9 (s, 4 d, C-5, Ph), 116.1 (d, C-4), 88.2 (d, C-6), 75.0 (d,
C-1Ј), 48.2 (d, C-2Ј), 40.3 (t, C-6Ј), 34.5 (t, C-4Ј), 31.5 (d, C-5Ј),
25.3 [d, CH(CH3)2], 23.5 (t, C-3Ј), 23.3, 20.8, 16.0 (3 q, CH3) ppm.
IR (KBr): ν˜ ϭ 3150Ϫ2825 cmϪ1 (CϪH), 1640 (CϭC), 1550 (Cϭ
N). C20H27NO2 (313.4) calcd. C 76.65, H 8.68, N 4.47; found C
76.82, H 8.91, N 4.48.
Experimental Section
General: Unless otherwise stated all reactions were performed un-
der an argon atmosphere in flame-dried flasks by adding the com-
ponents with a syringe. All solvents were dried using standard pro-
cedures. IR spectra were measured with a PerkinϪElmer FT-IR
spectrometer Nicolet 5 SXC or Nicolet 205. 1H and 13C NMR spec-
tra were recorded on Bruker instruments (AC 300, WH 270, AC
250, AC 200) in CDCl3 solution. The chemical shifts are given rel-
ative to TMS or to the CDCl3 signal (δH ϭ 7.27, δC ϭ 77.0). Higher
order NMR spectra were approximately interpreted as first-order
spectra if possible. Neutral aluminium oxide (activity III, Fluka/
Ethyl 6-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyloxy]-6H-1,2-ox-
azine-3-carboxylate (5): According to the general procedure,
BF3·OEt2 (0.13 mL, 1.04 mmol) and (Ϫ)-menthol (0.235 g,
1.50 mmol) were added to a solution of 1,2-oxazine 2 (0.100 g,
Merck) or silica gel (0.040Ϫ0.063 mm, Fluka) were used for col- 0.500 mmol) in CH2Cl2 (20 mL/mmol). The access of menthol was
umn chromatography. Nucleosil 50Ϫ5 (Macherey & Nagel) was
used for HPLC. Melting points are uncorrected. Optical rotations
were determined with PerkinϪElmer 141 or PerkinϪElmer 241 po-
removed by distillation. Chromatography (n-hexane/ethyl acetate,
8:1) of the crude product yielded 5 [26 mg, 17%, (6R):(6S) 50:50]
as a colourless solid. 1H NMR (300 MHz): δ ϭ 6.70, 6.68 (2 d,
larimeter at 20 °C. The starting materials 1,[7] 2,[7] 3,[7] 10[12] and J ϭ 10.0 Hz, 0.5 H each, 4-H), 6.27, 6.24 (2 dd, J ϭ 4.5, 10 Hz,
2840
Eur. J. Org. Chem. 2002, 2838Ϫ2843

Synthesis of Enantioenriched 2-Substituted 4-Phenylbutylamines
FULL PAPER
0.5 H each, 5-H), 5.80, 5.70 (2 d, J ϭ 4.5 Hz, 0.5 H each, 6-H),
tracts were dried (Na2SO4) and the solvent removed in vacuo. The
4.49Ϫ4.30 (m, 4 H, OCH2), 3.80, 3.60 (dt, J ϭ 4, 10 Hz, 1 H, 1Ј-H), crude product was purified by column chromatography (neutral
2.33Ϫ2.22 (m, 1 H, 2Ј-H), 2.15Ϫ1.85 [m, 3 H, 2Ј-H, CH(CH3)2],
1.72Ϫ0.72 (m, 7 H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-H), 1.38, 1.37 (t, J ϭ
7.0 Hz, 1.5 H each, CH3), 0.94, 0.91 (2 d, J ϭ 6.5 Hz, 1.5 H each,
5Ј-CH3), 0.90, 0.83, 0.80, 0.79 [4 d, J ϭ 7.0 Hz, 1.5 H each,
CH(CH3)2] ppm. 13C NMR (75.5 MHz): δ ϭ 162.4, 162.2 (2 s, Cϭ
O), 148.3, 148.0 (s, C-3), 125.1, 124.4 (2 d, C-5), 114.7 (d, C-4),
94.2, 89.3 (2 d, C-6), 81.4, 75.9 (2 d, C-1Ј), 62.2, 62.1 (2 t, OCH2),
48.3, 47.9 (2 d, C-2Ј), 42.5, 40.3 (2 t, C-6Ј), 34.4, 34.2 (2 t, C-4Ј),
31.7, 31.4 (2 d, C-5Ј), 25.7, 25.2 [2 d, CH(CH3)2], 23.30, 23.27 (2 t,
C-3Ј), 22.2, 22.1, 21.0, 20.9, 16.3, 15.8, 14.14, 14.11 (8 q, CH3)
ppm. IR (KBr): ν˜ ϭ 2960Ϫ2870 cmϪ1 (CϪH), 1725 (CϭO), 1635
(CϭC), 1530 (CϭN). C17H27NO4 (309.4): calcd. C 65.99, H 8.80,
N 4.53; found C 65.92, H 8.85, N 4.32.
aluminium oxide).
(5R,6S)-6-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyloxy]-3,5-
diphenyl-5,6-dihydro-4H-1,2-oxazine (7a): According to the general
procedure, a solution of 1,2-oxazine 4a (223 mg, 0.707 mmol) in
THF (7 mL) was added to a solution of phenyllithium (0.80 mL,
1.60 mmol, 2  solution in cyclohexane/diethyl ether). After addi-
tion of H2O (0.5 mL) the mixture was allowed to warm to room
temp. Chromatography (n-hexane/ethyl acetate 25:1) and HPLC (n-
hexane ϩ 2% ethyl acetate) yielded 7a (184 mg, 67%) as a colour-
less solid, m.p. 139 °C, and 4a (20 mg, 9%). [α]2D0 ϭ ϩ7.7 (c ϭ 1.01,
CHCl3). 1H NMR (270 MHz): δ ϭ 7.76Ϫ7.70 (m, 2 H, Ph),
7.42Ϫ7.22 (m, 8 H, Ph), 5.06 (d, J ϭ 4.4 Hz, 1 H, 6-H), 3.47 (dt,
J ϭ 4.4, 10.7 Hz, 1 H, 1Ј-H), 3.36Ϫ3.29 (m, 1 H, 5-H), 3.08 (dd,
J ϭ 7.4, 18.4 Hz, 1 H, 4-Hax), 2.74 (dd, J ϭ 5.2, 18.4 Hz, 1 H, 4-
Heq), 2.31Ϫ2.23 (m, 1 H, 2Ј-H), 1.84Ϫ1.72 [m, 1 H, CH(CH3)2],
1.63Ϫ0.60 (m*, 7 H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-H), *contains 0.87 (q,
J ϭ 6.6 Hz, 3 H, CH3), 0.79, 0.61 (2 d, J ϭ 7.4 Hz, 3 H each, CH3)
ppm. 13C NMR (62.9 MHz): δ ϭ 155.9 (s, C-3), 140.4, 135.7, 129.7,
128.7, 128.5, 127.7, 127.2, 125.6 (2 s, 6 d, Ph), 101.2 (d, C-6), 80.5
(d, C-1Ј), 48.8 (d, C-2Ј), 42.8 (t, C-6Ј), 40.0 (d, C-5), 34.3 (t, C-4Ј),
31.7 (d, C-5Ј), 26.0 [d, CH(CH3)2], 25.4 (t, C-4), 23.1 (t, C-3Ј),
22.2 (q, 5Ј-CH3), 21.1, 16.1 [2 q, CH(CH3)] ppm. IR (KBr): ν˜ ϭ
3095Ϫ2840 cmϪ1 (CϪH), 1605 (CϭN), 1090, 890, 690. C26H33NO2
(391.6): calcd. C 79.76, H 8.49, N 3.58; found C 79.71, H 8.31,
N 3.74.
6-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyloxy]-3-trifluoro-
methyl-6H-1,2-oxazine (6): According to the general procedure,
BF3·OEt2 (0.13 mL, 1.04 mmol) and (Ϫ)-menthol (0.235 g,
1.50 mmol) were added to a solution of 1,2-oxazine 3 (0.098 g,
0.500 mmol) in CH2Cl2. The access of menthol was removed by
distillation. Chromatography (n-hexane/ethyl acetate, 4:1) of the
crude product yielded
6
[31 mg, 26%, (6R):(6S) 53:47].
C15H22F3NO2 (305.3): calcd. C 59.00, H 7.26, N 4.59; found C
58.93, H 7.29, N 4.95.
A sample of 6 obtained by asymmetric cycloaddition was separated
by flash-chromatography (n-hexane/ethyl acetate 15:1).[9]
(6S)-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyloxy]-3-trifluoro-
methyl-6H-1,2-oxazine (6a): Colourless crystals, m.p. 64Ϫ71 °C.
[α]2D0 ϭ ϩ128 (c ϭ 0.47, CHCl3). 1H NMR (200 MHz): δ ϭ 6.38
(dd, J ϭ 4, 10 Hz, 1 H, 5-H), 6.29 (d, J ϭ 10.0 Hz, 1 H, 4-H), 5.70
(d, J ϭ 4.0 Hz, 1 H, 6-H), 3.60 (dt, J ϭ 4.5, 10.5 Hz, 1 H, 1Ј-H),
2.27Ϫ1.95 [m, 2 H, 2Ј-H, CH(CH3)2], 1.72Ϫ0.75 (m*, 7 H, 3Ј-H,
4Ј-H, 5Ј-H, 6Ј-H), *contains 0.92 (d, J ϭ 6.5 Hz, 3 H, 5Ј-CH3),
0.91, 0.81 [2 d, J ϭ 7.0 Hz, 3 H each, CH(CH3)2] ppm. 13C NMR
(5S,6R)-6-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyloxy]-3,5-
diphenyl-5,6-dihydro-4H-1,2-oxazine (7b): According to the general
procedure, a solution of 1,2-oxazine 4b (115 mg, 0.365 mmol) in
THF (4 mL) was added to a solution of phenyllithium (0.45 mL,
0.90 mmol, 2  solution in cyclohexane/diethyl ether). After addi-
tion of H2O (0.3 mL) the mixture was allowed to warm to room
temp. Chromatography (n-hexane/ethyl acetate 25:1) yielded 7b
(57 mg, 40%) as a colourless solid, m.p. 170Ϫ171 °C, and a mixture
of 7b and 4b (36 mg, 7b:4b ؍ 85:15, calculated yield of 7b: 31 mg,
21%). [α]2D0 ϭ Ϫ46.7 (c ϭ 1.02, CHCl3). 1H NMR (270 MHz): δ ϭ
7.74Ϫ7.70 (m, 2 H, Ph), 7.40Ϫ7.24 (m, 8 H, Ph), 5.27 (d, J ϭ
2.2 Hz, 1 H, 6-H), 3.72 (dt, J ϭ 3.9, 10.7 Hz, 1 H, 1Ј-H), 3.35Ϫ3.30
(m, 1 H, 5-H), 3.05 (dd, J ϭ 8.1, 18.4 Hz, 1 H, 4-Hax), 2.71 (dd,
J ϭ 1.5, 18.4 Hz, 1 H, 4-Heq), 2.18Ϫ2.14 (m, 1 H, 2Ј-H), 2.09Ϫ1.98
[m, 1 H, CH(CH3)2], 1.67Ϫ0.69 (m*, 7 H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-
H), *contains 0.90, 0.80, 0.70 (3 d, J ϭ 6.6 Hz, 3 H each, CH3)
ppm. 13C NMR (62.9 MHz): δ ϭ 156.2 (s, C-3), 140.8, 135.9, 129.6,
128.7, 128.5, 127.6, 127.2, 125.5 (2 s, 6 d, Ph), 94.0 (d, C-6), 74.4
(d, C-1Ј), 48.1 (d, C-2Ј), 39.5 (d, C-5), 39.2 (t, C-6Ј), 34.5 (t, C-4Ј),
31.3 (d, C-5Ј), 25.5 [d, CH(CH3)2], 23.9 (t, C-4), 23.2 (t, C-3Ј),
22.3 (q, 5Ј-CH3), 21.0, 15.8 [2 q, CH(CH3)2] ppm. IR (KBr): ν˜ ϭ
2960Ϫ2865 cmϪ1 (CϪH), 1600 (CϭN), 1090, 1015, 885, 700.
C26H33NO2 (391.6): calcd. C 79.76, H 8.49, N 3.58; found C 79.50,
H 8.29, N 3.35.
2
(50.3 MHz): δ ϭ 147.1 (q, JC,F ϭ 35 Hz, C-3), 126.2 (d, C-5),
1
120.3 (q, JC,F ϭ 274 Hz, CF3), 111.9 (d, C-4), 94.0 (d, C-6), 81.2
(d, C-1Ј), 48.3 (d, C-2Ј), 42.2 (t, C-6Ј), 34.2 (t, C-4Ј), 31.7 (d, C-
5Ј), 25.7 [d, CH(CH3)2], 23.2 (t, C-3Ј), 22.1, 21.0, 16.3 (3 q, CH3)
ppm. IR (KBr): ν˜ ϭ 2980Ϫ2820 cmϪ1 (CϪH), 1630 (CϭC), 1570
(CϭN).
(6R)-[(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyloxy]-3-trifluoro-
methyl-6H-1,2-oxazine (6b): Colourless oil. [α]2D0 ϭ Ϫ174 (c ϭ 0.43,
CHCl3). 1H NMR (200 MHz): δ ϭ 6.35 (dd, J ϭ 3.5, 9.5 Hz, 1 H,
5-H), 6.25 (d, J ϭ 9.5 Hz, 1 H, 4-H), 5.81 (d, J ϭ 3.5 Hz, 1 H, 6-
H), 3.81 (dt, J ϭ 4, 10.5 Hz, 1 H, 1Ј-H), 2.20Ϫ2.08, 1.89 [m, mc, 1
H each, 2Ј-H, CH(CH3)2], 1.72Ϫ0.74 (m*, 7 H, 3Ј-H, 4Ј-H, 5Ј-H,
6Ј-H), *contains 0.94 (d, J ϭ 6.5 Hz, 3 H, 5Ј-CH3), 0.84, 0.77 [2 d,
J ϭ 7.0 Hz, 3 H each, CH(CH3)2] ppm. 13C NMR (50.3 MHz):
δ ϭ 147.6 (q, 2JC,F ϭ 35 Hz, C-3), 126.9 (d, C-5), 120.4 (q, 1JC,F ϭ
274 Hz, CF3), 112.0 (d, C-4), 89.2 (d, C-6), 75.7 (d, C-1Ј), 48.0 (d,
C-2Ј), 40.1 (t, C-6Ј), 34.3 (t, C-4Ј), 31.4 (d, C-5Ј), 25.3 [d,
CH(CH3)2], 23.3 (t, C-3Ј), 22.2, 20.7, 15.7 (3 q, CH3).
(5R,6S)-5-n-Butyl-6-[(1R,2S,5R)-2-isopropyl-5-methylcyclo-
hexyloxy]-3-phenyl-5,6-dihydro-4H-1,2-oxazine (8a): According to
the general procedure, a solution of 1,2-oxazine 4a (470 mg,
1.50 mmol) in THF (15 mL) was added to a solution of n-butylli-
thium (1.32 mL, 3.30 mmol, 2.5  solution in n-hexane). After ad-
dition of methanol (1.00 mL) the mixture was allowed to warm to
room temp. After work-up no further purification was necessary.
1,2-Oxazine 8a (471 mg, 85%) was isolated as colourless solid (m.p.
109Ϫ113 °C, de Ն 94%). [α]2D0 ϭ ϩ40.9 (c ϭ 0.80, CHCl3). 1H
NMR (300 MHz): δ ϭ 7.74Ϫ7.65, 7.41Ϫ7.35 (2 m, 2 H, 3 H, Ph),
4.90 (d, J ϭ 3.0 Hz, 1 H, 6-H), 3.54 (dt, J ϭ 4.5, 10.5 Hz, 1 H, 1Ј-
General Procedure for the Addition of Organolithium Compounds to
4: A solution of 6H-1,2-oxazine 4 (1 equiv.) in THF (10 mL/mmol
of 1,2-oxazine) at Ϫ78 °C was added over a period of 15 min to a
solution of the corresponding organolithium compound (2.2
equiv.) in THF (10 mL/mmol of 1,2-oxazine). Methanol or water
was then added and the mixture was allowed to warm to room
temp. After addition of a sat. aqueous ammonium chloride solu-
tion (10 mL/mmol of 1,2-oxazine) the mixture was extracted with
diethyl ether (2 ϫ 20 mL/mmol of 1,2-oxazine), the combined ex-
Eur. J. Org. Chem. 2002, 2838Ϫ2843
2841

M. Buchholz, F. Hiller, H.-U. Reißig
FULL PAPER
H), 2.79 (dd, J ϭ 7, 18 Hz, 1 H, 4-Hax), 2.29 (dd, J ϭ 2.5, 18 Hz,
A Mosher amide of 9 was prepared according to ref.[14] The diaster-
1 H, 4-Heq), 2.24Ϫ2.00 [m, 3 H, 2Ј-H, CH(CH3)2, 5-H], 1.69Ϫ0.70 eomers show two HPLC peaks (n-hexane ϩ 2% ethyl acetate, 4 ϫ
(m*, 13 H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-H, CH2), *contains 0.92, 0.82 [2 244 mm, flow 1 mL/min, 52 bar; ret. time 42 min/44 min).
d, J ϭ 7.0 Hz, 3 H each, CH(CH3)2], 0.90 (t, J ϭ 7.0 Hz, 3 H,
CH3), 0.87 (d, J ϭ 6.5 Hz, 3 H, 5Ј-H) ppm. 13C NMR (75.5 MHz):
δ ϭ 155.0 (s, C-3), 136.5, 129.4, 128.4, 125.5 (s, 3 d, Ph), 100.3 (d,
C-6), 79.6 (d, C-1Ј), 48.9 (d, C-2Ј), 42.7 (t, C-6Ј), 34.4 (t, C-4Ј),
32.9, 31.7 (2 d, C-5, C-5Ј), 30.7, 29.0 (2 t, CH2), 25.7 [d,
CH(CH3)2], 23.7, 23.3, 22.7 (3 t, CH2, C-4, C-3Ј), 22.2, 21.2, 16.3,
14.0 (4 q, CH3) ppm. IR (KBr): ν˜ ϭ 3100Ϫ2850 cmϪ1 (CϪH),
1625, 1620 (CϭC, CϭN). C24H37NO2 (371.6): calcd. C 77.58, H
10.04, N 3.77; found C 77.45, H 10.42, N 3.49.
(S)-2,4-Diphenylbutylamine [(S)-9]: According to the general pro-
cedure, 1,2-oxazine 7a (136 mg, 0.347 mmol) and Pd/C (36 mg) in
ethanol (5 mL) and ethyl acetate (3 mL) were stirred under hydro-
gen atmosphere for 23 h. Kugelrohr distillation (0.015 mbar, 100
°C) yielded 9 (64 mg, 82%, ee 80%) as a colourless oil. [α]2D0
Ϫ5.85 (c ϭ 0.99, CHCl3).
ϭ
(S)-1-Hexyl-2-(2-phenylethyl)amine [(S)-11]: According to the gen-
eral procedure, 1,2-oxazine 8a (186 mg, 0.500 mmol) and Pd/C
(50 mg) in ethanol (5 mL) were stirred under hydrogen atmosphere
for 22 h. kugelrohr distillation (0.015 mbar, 100 °C) yielded (S)-11
(80 mg, 80%) as a colourless oil. [α]2D0 ϭ 0.00 (c ϭ 0.87, CHCl3).
1H NMR (300 MHz): δ ϭ 7.29Ϫ7.05 (m, 5 H, Ph), 2.59 (d, J ϭ
5.0 Hz, 2 H, 1-H), 2.58 (t, J ϭ 8.0 Hz, 2 H, 2Ј-H), 1.65Ϫ1.10 (m,
11 H, NH2, 1Ј-H, 2-H, 3-H, 4-H, 5-H), 0.91Ϫ0.75 (m, 3 H, CH3)
ppm. 13C NMR (75.5 MHz): δ ϭ 142.8, 128.3*, 125.6 (s, 2 d, Ph),
45.1 (t, C-1), 40.6 (d, C-2), 33.5, 33.2, 31.1, 28.9, 23.1 (5 t, C-1Ј,
C-2Ј, C-3, C-4, C-5), 14.1 (q, CH3) ppm, *higher intensity. IR
(film): ν˜ ϭ 3500Ϫ3100 cmϪ1 (NϪH), 3100Ϫ2860 (CϪH), 1600
(CϭC). C14H23N (205.3): calcd. C 81.89, H 11.29, N 6.82; found
C 81.44, H 11.77, N 6.56.
(5R,6R)-5-n-Butyl-6-[(1R,2S,5R)-2-isopropyl-5-methylcyclo-
hexyloxy]-3-phenyl-5,6-dihydro-4H-1,2-oxazine (8b): According to
the general procedure, a solution of 1,2-oxazine 4b (313 mg,
1.00 mmol) in THF (10 mL) was added to a solution of n-butylli-
thium (0.91 mL, 2.20 mmol, 2.42  solution in n-hexane). After
addition of H2O (0.6 mL) the mixture was allowed to warm to
room temp. After work-up no further purification was necessary.
1,2-Oxazine 8b (368 mg, 99%) was isolated as colourless crystals
(m.p. 78Ϫ80 °C, de Ն 98% by HPLC). [α]2D0 ϭ Ϫ102 (c ϭ 1.13,
1
CHCl3). H NMR (300 MHz): δ ϭ 7.70Ϫ7.61, 7.41Ϫ7.34 (2 m, 2
H, 3 H, Ph), 5.12 (d, J ϭ 3.0 Hz, 1 H, 6-H), 3.70 (dt, J ϭ 4.5,
10.5 Hz, 1 H, 1Ј-H), 2.75 (dd, J ϭ 7, 18 Hz, 1 H, 4-Hax), 2.32 (dd,
J ϭ 2, 18 Hz, 1 H, 4-Heq), 2.25Ϫ2.15 (m, 1 H, 2Ј-H), 1.99 [mc, 2
H, CH(CH3)2, 5-H], 1.71Ϫ0.63 (m*, 13 H, 3Ј-H, 4Ј-H, 5Ј-H, 6Ј-H,
CH2), *contains 0.94 (d, J ϭ 6.5 Hz, 3 H, 5Ј-CH3), 0.93 (t, J ϭ
6.5 Hz, 3 H, CH3), 0.78, 0.68 (2 d, J ϭ 7.0 Hz, 3 H each,
CH(CH3)2] ppm. 13C NMR (75.5 MHz): δ ϭ 155.3 (s, C-3), 136.5,
129.3, 128.4, 125.5 (s, 3 d, Ph), 94.1 (d, C-6), 74.0 (d, C-1Ј), 48.1
(d, C-2Ј), 39.6 (t, C-6Ј), 34.6 (t, C-4Ј), 32.8, 31.3 (2 d, C-5, C-5Ј),
30.9, 29.1 (2 t, CH2), 25.4 [d, CH(CH3)2], 23.2, 23.1, 22.7 (3 t, CH2,
C-4, C-3Ј), 22.4, 21.0, 15.7, 14.0 (4 q, CH3) ppm. IR (KBr): ν˜ ϭ
3100Ϫ2850 cmϪ1 (CϪH), 1625, 1620 (CϭC, CϭN). C24H37NO2
(371.6): calcd. C 77.58, H 10.04, N 3.77; found C 77.67, H 10.24,
N 3.76.
(R)-1-Hexyl-2-(2-phenylethyl)amine [(R)-11]: According to the gen-
eral procedure, 1,2-oxazine 8b (168 mg, 0.452 mmol) and Pd/C
(50 mg) in ethanol (5 mL) and ethyl acetate (5 mL) were stirred
under hydrogen atmosphere for 18 h. Kugelrohr distillation
(0.015 mbar, 100 °C) yielded (R)-11 (57 mg, 61%) as a colourless
oil. [α]2D0 ϭ Ϫ0.37 (c ϭ 1.09, CHCl3).
1-Hexyl-2-(2-phenylethyl)amine (rac-11): According to the general
procedure 1,2-oxazine 12 (219 mg, 0.833 mmol) and Pd/C (85 mg)
in ethanol (10 mL) and ethyl acetate (5 mL) were stirred under hy-
drogen atmosphere for 24 h. Kugelrohr distillation (0.015 mbar, 100
°C) yielded rac-11 (145 mg, 85%) as a colourless oil. A Mosher
amide of 11 was prepared according to ref.[14] The diastereomers
show two signals for two of the carbon atoms in the 13C NMR
spectrum: 13C NMR (62.9 MHz, C6D6): δ ϭ 165.9 (s, CϭO), 142.7,
133.7 (2 s, Ph), 129.5, 128.7, 128.6, 128.4, 127.6, 126.1 (6 d, Ph),
122.3 (s, CF3), 54.8 (q, OCH3), 42.4 (t, CH2), 37.9 (d, CH), 33.9,
33.8*, 33.1, 33.0*, 31.6, 28.9, 23.2 (7 t, CH2), 14.2 (q, CH3).
(*signal of the second diastereomer).
General Procedure for the Hydrogenolysis of 1,2-Oxazines 7a, 8a,
8b, 10 and 12: Ethanol or ethanol/ethyl acetate and Pd (10%)/C
were saturated with hydrogen. Then, the corresponding 1,2-oxazine
was added and the mixture stirred under hydrogen at atmospheric
pressure and room temp for the time indicated below. The suspen-
sion was then filtered through a sintered glass plug which contained
a pad of Celite, eluting with ethyl acetate. The filtrate was concen-
trated in vacuo and the crude product was purified by kugelrohr
distillation.
Acknowledgments
Generous support by the Deutsche Forschungsgemeinschaft (Gra-
duiertenkolleg ‘‘Struktur-Eigenschafts-Beziehungen bei Hetero-
cyclen’’), Fonds der Chemischen Industrie and Schering AG is most
gratefully acknowledged. We thank Dr. R. Zimmer for his help
during preparation of this manuscript.
2,4-Diphenylbutylamine (rac-9):[13] According to the general pro-
cedure, 1,2-oxazine 10 (300 mg, 1.07 mmol) and Pd/C (110 mg) in
ethanol (10 mL) and ethyl acetate (3 mL) were stirred under hydro-
gen atmosphere for 20 h. Kugelrohr distillation (0.015 mbar, 110
°C) yielded rac-9 (195 mg, 81%) as a colourless oil. 1H NMR
(270 MHz): δ ϭ 7.42Ϫ7.02 (m, 10 H, Ph), 3.00Ϫ2.76 (m, 2 H, 1-
H), 2.62Ϫ2.52 (m, 1 H, 2-H), 2.51Ϫ2.43 (m, 2 H, 4-H), 2.05Ϫ1.85
(m, 2 H, 3-H), 1.31 (br. s, 2 H, NH2) ppm. 13C NMR (62.9 MHz):
δ ϭ 142.9, 142.1, 128.5, 128.2, 128.2, 128.0, 126.5, 125.6 (2 s, 6 d,
Ph), 49.0 (d, C-2), 48.1 (t, C-4), 35.4, 33.5 (2 t, C-3, C-1) ppm. IR
(film): ν˜ ϭ 3375 cmϪ1 (NϪH), 3085Ϫ2860 (CϪH), 1600, 1495,
1455, 760, 700. MS (EI, 80 eV): m/z (%) ϭ 225 (100) [Mϩ], 194
(25) [Mϩ Ϫ CH3NH2], 121 (24), 104 (41), 91 (66), 30 (86). HRMS
(EI, 80 eV) C16H19NO: calcd. 225.1518; found 225.1543.
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Eur. J. Org. Chem. 2002, 2838Ϫ2843

Synthesis of Enantioenriched 2-Substituted 4-Phenylbutylamines
FULL PAPER
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2843