Reaction of 3-methylamino-1,2-diols with dihalomethanes. Synthesis of chiral 4-substituted 3-methyltetrahydro-1,3-oxazin-5-ols

Article abstract of DOI:10.1016/S0040-4020(00)00744-4

Enantiomerically pure 4,5-disubstituted 3-methyltetrahydro-1,3-oxazines have been obtained by reaction of 3-methylamino-1,2-diols with dichloromethane by regioselective differentiation of hydroxyl groups. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00744-4

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 8173±8177
Reaction of 3-Methylamino-1,2-diols with Dihalomethanes.
Synthesis of Chiral 4-Substituted
3-Methyltetrahydro-1,3-oxazin-5-ols
a
a
a
Chakib Hajji, M Luisa Testa, Roberto de la Salud-Bea, Elena Zaballos-Garcõa,
a
a
Â
a,
Âb
Â
Â
Juan Server-Carrio and Jose Sepulveda-Arques
*
a
Â
Â
Departamento de Quõmica Organica, Facultad de Farmacia, Universidad de Valencia, E-46100, Burjassot, Valencia, Spain
 Â
Departamento de Quõmica Inorganica, Facultad de Farmacia, Universidad de Valencia, E-46100, Burjassot, Valencia, Spain
b
Received 25 May 2000; revised 31 July 2000; accepted 18 August 2000
AbstractÐEnantiomerically pure 4,5-disubstituted 3-methyltetrahydro-1,3-oxazines have been obtained by reaction of 3-methylamino-1,2-
diols with dichloromethane by regioselective differentiation of hydroxyl groups. q 2000 Published by Elsevier Science Ltd.
It has been established that although dichloromethane is a
good solvent for organic reactions because of its low cost
and solvating ability, it is not unreactive and with amines
and diamines undergoes reactions leading to salts, aminals
and Mannich adducts.1 There are no reports in the literature
concerning the formation of tetrahydro-1,3-oxazines or
oxazolidines by reaction of dichloromethane with 1,3 or
1,2-amino alcohols. Here, as a continuation of our interest
in the synthesis of amino alcohols,2 we report some
examples of reactions of 2,3-epoxyalcohols and 1,3 or
1,2-amino alcohols, where dichloromethane or dibromo-
methane can be used as C-1 synthon unit, for the preparation
of tetrahydro-1,3-oxazines or oxazolidines with good yields.
with secondary and primary amines in the presence of
titanium tetraisopropoxide occurs with high regioselectivity
affording regioisomers from C-3 attack.3,4 When we studied
the reaction of the primary amines, methyl, ethyl and
propylamine with the epoxyalcohol 1A (room temperature,
THF, titanium tetraisopropoxide) we found that the alkyla-
minodiols 2Aa±c were obtained as single regioisomers as a
result of C-3 attack (Scheme 1, Table 1).
It is worth noting that it has been established3,4 that in the
absence of titanium(IV) the ring opening reactions of
epoxyalcohols with primary amines at room temperature,
proceed at slow rate and with low regioselectivity. However,
we found that in the case of epoxyalcohol 1A, the reac-
tion with aqueous methylamine, aqueous ethylamine and
It is known that ring opening of chiral 2,3-epoxyalcohols
Scheme 1. A RˆPh, B RˆC3H7; a R0ˆCH3, b R0ˆCH3, b R0ˆEt, c R0ˆPr.
Keywords: heterocycles; oxazines; oxazolidines; dichloromethane; amino alcohols.
* Corresponding author. Tel.: 196-3864938, fax: 196-3864939; e-mail: jose.sepulveda@uv.es
0040±4020/00/$ - see front matter q 2000 Published by Elsevier Science Ltd.
PII: S0040-4020(00)00744-4

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C. Hajji et al. / Tetrahedron 56 (2000) 8173±8177
Table 1. Reaction of epoxyalcohols 1A and 1B with MeNH2, EtNH2 and PrNH2
Epoxyalcohol 1A
Epoxyalcohol 1B
R0NH2
MeNH2
EtNH2
PrNH2
THF±Ti(IV)
(258C)
Cl2CH2±Ti(IV)
(258C)
Cl2CH2±Ti(IV)
(608C)
CH3OH
(1008C)
THF±Ti(IV)
(258C)
Cl2CH2±Ti(IV)
(258C)
6 h
2Aa 72%
17 h
48 h
3Aa 78%
14 h
2Aa 98%
168 h
28 h
3Ba 67% 1
3Aa 18%1
2Aa 55%
24 h
3Ab 6% 1
2Ab 70%
48 h
2120Ba (75:25)
79%
168 h
2120Ba (60:40) 17%
168 h
20 h
2Ab 75%
48 h
3Ab 50%
14 h
2Ab 95%
2120Bb (75:25)
78%
168 h
2120Bc (77:23)
76%
2120Bb (89:11) 78%
24 h
2Ac 64%
48 h
2Ac 64%
14 h
2Ac 90%
168 h
2120Bc (97:3) 76%
2Ac 65%
Table 2. Reaction of aminodiols 2 with dichloromethane
2Aa
2Ab
108 h 3Ab 70%
2Ac
2Ba
24 h 3Ba 98%
2Bb
2Bc
a
a
a
Cl2CH2 (1008C)
28 h 3Aa 100%
a Tetrahydro-1,3-oxazines were not formed under similar reaction conditions.
propylamine took place in methanol at 1008C without
catalyst, affording the single regioisomers 2Aa±c, with
similar rates and regioselectivity to reactions carried out
in THF and with titanium tetraisopropoxide. However, the
yields were higher because there was no need of the workup
procedure for the removal of the catalyst.
reactor (3Aa 100%, 3Ab 70%). With the aminodiol 2Ac the
formation of an oxazine was not detected (Table 2).
When the mixture of aminodiols 2Ba and 20Ba was heated
in dichloromethane (1008C, 24 h) the aminodiol 2Ba was
converted into the tetrahydro-1,3-oxazine 3Ba (98% yield
based on reacted 2Ba) which was easily separated from the
unreacted aminodiol 20Ba. Products from reaction with
dichloromethane were not detected when the mixtures of
aminodiols 2Bb, 20Bb and 2Bc, 20Bc were heated with
this solvent (Table 2).
When we studied the ring opening reactions of the epoxy-
alcohol 1B with these primary amines (room temperature,
THF, titanium tetraisopropoxide), we obtained different
results. In contrast with the epoxyalcohol 1A which afforded
single regioisomers 2Aa±c, the epoxyalcohol 1B did not
react with the amines with complete regioselectivity and
mixtures of regioisomers from C3/C2 attack, 2Ba±c and
20Ba±c were obtained.
These results indicate that the reaction of the aminodiols 2
with dichloromethane affording the (4R,5R)-4-substituted
tetrahydro-1,3-oxazin-5-ols 3, takes place with excellent
yields only in the case of the N-methyl derivatives. Agami
et al.5,6 have reported examples of cyclization reactions
where the presence of a N-methyl substituent enhances the
cyclization rate in N-Boc aminoalcohols.
The results were completely different when the solvent of
the reaction was dichloromethane. The epoxyalcohol 1A in
the reaction with methyl and ethylamine (room temperature,
titanium tetraisopropoxide), afforded the aminodiols 2Aa
and 2Ab, but in addition the (4R,5R) 4-substituted tetra-
hydro-1,3-oxazin-5-ols 3Aa and 3Ab, were also obtained
in low yields. In the reaction with propylamine no traces
of the corresponding tetrahydro-1,3-oxazine was detected.
The experiments were then attempted at 608C in a pressure
reactor and the tetrahydro-1,3-oxazines were obtained with
better yields (3Aa 78%, 3Ab 50%). In the reaction with
propylamine at 608C, the tetrahydro-1,3-oxazine was not
detected.
An X-ray crystallographic analysis of 3Aa con®rmed
unequivocally the structure and stereochemistry. The
X-ray study was made with a single crystal of 3Aa, obtained
In the reaction of 1B with the mentioned primary amines, in
dichloromethane, the alkylaminodiols 2Ba±c and 20Ba±c
were obtained with similar rates, but regioselectivities
were much better than in experiments carried out in THF.
With this epoxyalcohol 1B, the tetrahydro-1,3-oxazine 3Ba
(67%) was obtained only in the case of the reaction with
methylamine.
The best results in the preparation of the oxazines 3Aa and
3Ab occurred when the aminodiols 2Aa and 2Ab, were
directly heated with dichloromethane at 1008C in a pressure
Figure 1.

C. Hajji et al. / Tetrahedron 56 (2000) 8173±8177
8175
trometer and chemical shifts are recorded relative to
Me4Si. High-resolution mass spectral data were obtained
with a VG Autospec spectrometer.
Synthesis of aminodiols 2
Figure 2.
Procedure a. Titanium tetraisopropoxide (3.5 mmol) was
added to a solution of 2,3-epoxyalcohols (1A, 1B)10
(1.73 mmol) and the corresponding alkylamine (2 mmol)
in dry tetrahydrofuran (20 mL). The mixture was heated
in a pressure reactor at the temperature and time indicated.
Then a solution of 10% NaOH in saturated brine (10 mL)
was added and the suspension stirred for an additional
period of 12 h. The solution was ®ltered through a short
pad of celite. The organic layer was separated and the
aqueous layer was extracted with dichloromethane
(3£10 mL). The combined organic layers were dried over
MgSO4 and evaporated in vacuo and chromatographed on
silica gel NEt3 pre-treated (2.5% v/v). Eluting with hexane/
ethyl acetate mixtures provided the amino alcohols 2Aa±c
and 2120Ba±c.
from an experiment with racemic phenylglycidol as starting
material and revealed the presence of two molecules in the
asymmetric unit, one of each enantiomer. Fig. 1, shows one
molecule of the 4R,5R-enantiomer with the numbering
scheme used in the crystal study.
The most similar example to the selective differentiation of
hydroxyl groups here described, has been reported for chiral
3-amino-4-phenyl-1,2-butanediol.7 In this work the reaction
of the 3-amino-1,2-diols with trichloromethylchloroformate
affords oxazolidinones or oxazinones under kinetic or
thermodinamic control respectively. 1,3-Oxazolidines,
tetrahydro-1,3-oxazines and their derivatives are in equi-
librium8 and in the case of compounds 3 the equilibrium
appears to be completely shifted to the six-membered ring.
Procedure b. A solution of the 2,3-epoxyalcohol 1A
(6.6 mmol) in methanol (20 mL) and a solution of aqueous
methylamine (40%), aqueous ethylamine (70%) or propyl-
amine (17.4 mmol) was heated in a pressure reactor at
1008C for 14 h. After cooling, the mixture was concentrated
in vacuo affording the amino alcohols 2Aa±c.
The cyclization reaction involving the methylamino and the
primary hydroxyl groups in the case of methyl aminodiols 2
suggested we attempt a similar cyclization with natural
methylamino alcohols. Ephedrine and pseudoephedrine,
which contain a methylamino group and a vecinal secondary
alcohol, would afford with dichloromethane the formation
of ®ve membered rings by similar cyclization reactions.
When (2)-ephedrine and (1)-pseudoephedrine were heated
in dichloromethane at 1008C for 12 h the corresponding 1,3-
oxazolidines 4, (4S,5R)-3,4-dimethyl-5-phenyl-1,3-oxazo-
lidine and 5, (4S,5S)-3,4-dimethyl-5-phenyl-1,3-oxazo-
lidine, were obtained with 37 and 41% yields, respec-
tively. When we used dibromomethane, lower temperatures
(508C) were needed and the 1,3-oxazolidines were obtained
with better yields (4, 49%, 5, 51%)9 (Fig. 2).
(2R,3R)-3-Methylamino-3-phenyl-1,2-propanediol
(2Aa). a. 72% (258C, 6 h), b. 98%. White solid. Mp 105±
1068C. [a]2D0ˆ271 (c 0.52, CHCl3). nmax (Nujol) 3335 (br),
1
1659, 1485, 1308, 1224, 1107, 894. H NMR (CDCl3):
dˆ2.26 (s, 3H), 3.17 (br, 3H), 3.53 (d, Jˆ4.7 Hz, 2H),
3.70 (d, Jˆ5.5 Hz, 1H), 3.84 (m, 1H), 7.32 (m, 5H). 13C
NMR (CDCl3): dˆ34.2 (q), 64.5 (d), 68.4 (t), 73.3 (d),
127.7 (d), 128.2 (d), 128.6 (d), 138.9 (s). m/z (CI) 182 (1,
MH1), 164 (1), 150 (2), 134 (1), 120 (100), 107 (4), 91 (5).
HRMS (CI): MH1, found 182.1188. C10H16NO2 requires
182.1181.
In conclusion, we have demonstrated the synthetic utility of
dichloromethane and dibromomethane as very useful C-1
synthon units for the preparation of tetrahydro-1,3-oxazines
and 1,3-oxazolidines with 1,3 and 1,2-methylamino
alcohols as starting materials.
(2R,3R)-3-Ethylamino-3-phenyl-1,2-propanediol (2Ab).
a. 75% (258C, 20 h), b. 95%. White solid. Mp 98±998C.
[a]2D0ˆ247 (c 0.03, CHCl3). nmax (Nujol) 3415 (br), 1636,
1
1495, 1425, 1329, 1098. H NMR (CDCl3): dˆ0.98 (t,
Jˆ7.0 Hz, 3H), 2.40 (dq, Jˆ17.5, 7.0 Hz, 2H), 3.41 (m,
2H), 3.73 (d, Jˆ4.7 Hz, 1H), 3.86 (m, 1H), 7.25 (m, 5H).
13C NMR (CDCl3): dˆ14.5 (q), 41.2 (t), 64.2 (t), 65.3 (d),
73.4 (d), 127.4 (d), 127.9 (d), 128.3 (d), 138.7 (s). m/z (FAB)
196 (100, MH1), 177 (11), 165 (4), 154 (70), 134 (50).
HRMS (FAB) MH1, found 196.1331. C11H18NO2 requires
196.1337.
Experimental
Unless otherwise speci®ed, materials were purchased from
commercial suppliers and used without further puri®cation.
THF was distilled from Na/benzophenone immediately
prior to use. CH2Cl2 was distilled from calcium hydride
under argon. Analytical thin layer chromatography was
performed on Merck pre-coated silica gel (60 F254) plates
and ¯ash column chromatography was accomplished on
Merck Kieselgel 60 (230±240 mesh). Melting points were
determined with a Ko¯er hot-stage apparatus and are uncor-
rected. Optical rotations were measured at room tempera-
(2R,3R)-3-Propylamino-3-phenyl-1,2-propanediol (2Ac).
a. 64% (258C, 24 h), b. 90%. White solid. Mp 107±1088C.
[a]2D0ˆ263 (c 0.12, CHCl3). nmax (Nujol) 3402 (br), 1642,
1
1495, 1408, 1358, 1092, 1034. H NMR (CDCl3): dˆ0.78
(t, Jˆ7.0 Hz, 3H), 1.36 (m, 2H), 2.27 (m, 2H), 3.37 (m, 2H),
3.70 (d, Jˆ5.0 Hz, 1H), 3.82 (m, 1H), 7.22 (m, 5H). 13C
NMR (CDCl3): dˆ11.4 (q), 22.5 (t), 48.8 (t), 63.9 (t),
65.5 (d), 73.3 (d), 127.1 (d), 127.7 (d), 128.1 (d), 139.0
(s). m/z (FAB) 210 (100, MH1), 195 (5), 177 (3), 165 (2).
1
ture in a Perkin±Elmer 241 polarimeter. H and 13C NMR
spectra were measured for CDCl3 solutions at 250 and
62.9 MHz, respectively, using a Bruker AC-250 spec-

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C. Hajji et al. / Tetrahedron 56 (2000) 8173±8177
HRMS (FAB): MH1, found 210.1503. C12H20NO2 requires
210.1494.
(Nujol) 3472 (br), 1642, 1418, 1354, 1041. 1H NMR
(CDCl3): dˆ1.92 (s, 3H), 2.25 (br, 1H), 2.85 (d, Jˆ
8.7 Hz, 1H, H-4), 3.31 (t, Jˆ10.6 Hz, 1H, H-6), 3.71 (d,
Jˆ8.0 Hz, 1H, H-2), 3.75 (m, 1H, H-5), 4.17 (dd, Jˆ10.6,
5.1 Hz, 1H, H-60), 4.41 (d, Jˆ8.0 Hz, 1H, H-20), 7.35 (m,
5H). 13C NMR (CDCl3): dˆ36.7 (q), 68.0 (d), 71.6 (t), 75.3
(d), 87.0 (t), 128.1 (d), 128.5 (d), 128.7 (d), 138.4 (s). m/z
(CI) 193 (M1, 100), 176 (75), 149 (90), 133 (84), 118 (47),
91 (24). HRMS (CI): MH1, found 194.1187. C11H16NO2
requires 194.1181.
(2R,3R)-3-Methylamino-1,2-hexanediol (2Ba). a. 2120Ba
79% (C3/C2, 75:25, 258C, 168 h). White solid. nmax (Nujol)
3415 (br), 1655, 1470, 1273, 1073. 1H NMR (CDCl3):
dˆ0.87 (t, Jˆ6.5 Hz, 3H), 1.33 (m, 2H), 1.47 (m, 2H),
2.41 (s, 3H), 2.86 (m, 1H), 3.72 (m, 3H). 13C NMR
(CDCl3): dˆ14.2 (q), 19.4 (t), 31.8 (t), 34.7 (q), 63.1 (d),
63.9 (t), 71.1(d). m/z (EI) 148 (4, MH1), 116 (16), 86 (100),
74 (42). HRMS (EI): MH1, found 148.1334. C7H18NO2
requires148.1337.
(4R,5R)-3-Ethyl-4-phenyltetrahydro-1,3-oxazin-5-ol (3Ab).
a. 50% (608C, 48 h). b. 70% (1008C, 108 h). Colourless oil.
nmax (Nujol) 3427 (br), 1655, 1448, 1169, 1073, 1048. H
1
(2R,3R)-3-Ethylamino-1,2-hexanediol (2Bb). a. 2120Bb
78% (C3/C2, 75:25, 258C, 168 h). White solid. nmax
(Nujol) 3421 (br), 1655, 1463, 1293, 1078. 1H NMR
(CDCl3): dˆ0.86 (t, Jˆ6.5 Hz, 3H), 1.01 (t, Jˆ7.0 Hz,
3H), 1.33 (m, 2H), 1.42 (m, 2H), 2.56 (m, 1H), 2.64 (m,
2H), 3.56 (m, 2H), 3.64 (m, 1H). 13C NMR (CDCl3): dˆ
13.8 (q), 15.5 (t), 19.3 (t), 32.9 (t), 42.8 (t), 61.1 (d), 64.2 (t),
71.3 (d). m/z (EI) 162 (1, MH1), 144 (1), 130 (10), 118 (4),
100 (100), 88 (13). HRMS (EI): MH1, found 162.1497.
C8H20NO2 requires162.1494.
NMR (CDCl3): dˆ0.70 (t, Jˆ7.3 Hz, 3H), 2.37 (m, 2H),
3.01 (d, Jˆ8.7 Hz, 1H, H-4), 3.21 (t, Jˆ10.6 Hz, 1H,
H-6), 3.65 (m, 1H, H-5), 3.72 (d, Jˆ8.0 Hz, 1H, H-2),
4.05 (dd, Jˆ10.6, 4.7 Hz, 1H, H-60), 4.51 (d, Jˆ8.0 Hz,
1H, H-20), 7.24 (m, 5H). 13C NMR (CDCl3): dˆ11.7 (q),
42.7 (t), 68.1 (d), 71.6 (t), 73.1 (d), 84.1 (t), 127.9 (d), 128.6
(d), 128.7 (d), 138.6 (s). m/z (EI) 207 (32, M1), 192 (8), 164
(14), 162 (100), 149 (16), 146 (52), 132 (37), 118 (47), 107
(30), 91 (50). HRMS (EI): M1, found 207.1262. C12H17NO2
requires 207.1259.
(2R,3R)-3-Propylamino-1,2-hexanediol (2Bc). a. 2120Bc
76% (C3/C2, 77:23, 258C, 168 h). White solid. nmax (Nujol)
3351 (br), 1655, 1469, 1308, 1073. 1H NMR (CDCl3):
dˆ0.87 (m, 6H), 1.36 (m, 6H), 2.48 (m, 1H), 2.61 (m,
2H), 3.53 (m, 1H), 3.55 (m, 2H), 3.67 (m, 1H). 13C NMR
(CDCl3): dˆ11.7 (q), 14.2 (q), 19.4 (t), 23.6 (t), 33.4 (t),
50.8 (t), 61.6 (d), 64.3 (t), 71.4 (d). m/z (EI) 176 (1, MH1),
158 (1), 144 (10), 132 (4), 115 (8), 114 (100), 102 (4), 72
(10). HRMS (EI): MH1, found 176.1642. C9H22NO2
requires 176.1650.
(4R,5R)-3-Methyl-4-propyltetrahydro-1,3-oxazin-5-ol
(3Ba). a. 67% (258C, 28 h). b. 98% calculated on reacted
2Ba (1008C, 24 h). White crystals. Mp 778C. nmax (Nujol)
1
3402 (br), 1655, 1558, 1470, 1194, 1066, 1015. H NMR
(CDCl3): dˆ0.90 (t, Jˆ7.0 Hz, 3H), 1.40 (m, 3H), 1.51 (m,
1H), 2.32 (s, 3H), 2.40 (dt, Jˆ8.7, 4.4 Hz, 1H, H-4), 3.31
(dd, Jˆ10.6, 8.9 Hz, 1H, H-6), 3.50 (ddd, Jˆ8.7, 8.9,
4.6 Hz, 1H, H-5), 3.95 (dd, Jˆ10.6, 4.6 Hz, 1H, H-60),
4.10 (d, Jˆ10.0 Hz, 1H, H-2), 4.34 (d, Jˆ10.0 Hz, 1H,
H-20). 13C NMR (CDCl3): dˆ14.0 (q), 18.5 (t), 29.9 (t),
34.6 (q), 63.4 (d), 64.3 (d), 71.6 (t), 85.7 (t). m/z(EI) 159
(75, M1), 128 (8), 116 (100), 114 (79), 100 (45), 70 (54).
HRMS (EI): M1, found 159.1253. C8H17NO2 requires
159.1259.
Synthesis of tetrahydro-1,3-oxazines 3
Procedure a. The corresponding alkylamine (3.9 mmol)
was added to a solution of the 2,3-epoxyalcohols 1A, 1B
(3.3 mmol) and titanium tetraisopropoxide (6.6 mmol) in
dichloromethane (40 mL). The mixture was heated in the
pressure reactor at the temperature and times indicated.
Then a solution of 10% NaOH in saturated brine (30 mL)
was added and the suspension stirred for an additional
period of 12 h. The solution was ®ltered through a short
pad of celite. The organic layer was separated and the
aqueous layer was extracted with dichloromethane
(3£10 mL). The combined organic layers were dried over
MgSO4 and evaporated in vacuo. The crude product was
puri®ed by chromatography on silica gel eluting with
hexane/ethyl acetate mixtures affording the oxazines 3Aa,
3Ab and 3Ba.
Synthesis of 1,3-oxazolidines (4, 5)
A solution of (2)ephedrine o-(1)pseudoephedrine (3 mmol)
in (a) CH2Cl2 (20 mL) or (b) CH2Br2 (4 mL) was heated to
temperature and the time indicated. After cooling, the crys-
talline precipitate (the corresponding salt hydrochloride or
hydrobromide) was ®ltered off and washed with dichloro-
methane. The ®ltrate was evaporated in vacuo and the resi-
due was puri®ed by chromatography on silica gel eluting
with hexane/ethyl acetate mixtures affording the corre-
sponding oxazolidines 4 and 5.
(4S,5R)-3,4-Dimethyl-5-phenyl-1,3-oxazolidine (4). a.
37% (1008C, 4 h). b. 49% (508C, 7 h). Colourless oil.
[a]2D0ˆ112.13 (c 1.04, CHCl3). nmax (Nujol) 3427 (br),
Procedure b. The aminodiols 2Aa, 2Ab and a mixture of
2Ba and 20Ba (6 mmol) in CH2Cl2 (50 mL) were heated to
temperature and the time indicated. The solvent was evapo-
rated in vacuo and the residue was puri®ed by chroma-
tography on silica gel eluting with hexane/ethyl acetate
mixtures affording the oxazines 3Aa, 3Ab and 3Ba.
1
1661, 1502, 1457, 1386, 1239, 1054. H NMR (CDCl3):
dˆ0.55 (d, Jˆ6.6 Hz, 3H), 2.23 (s, 3H), 2.73 (dq, Jˆ6.9,
6.6 Hz, 1H, H-4), 3.93 (d, Jˆ3.3 Hz, 1H, H-2), 4.74 (d,
Jˆ3.3 Hz, 1H, H-20), 4.97 (d, Jˆ6.9 Hz, 1H, H-5), 7.19
(m, 5H). 13C NMR (CDCl3): dˆ14.0 (q), 37.4 (q), 63.1
(d), 81.7 (d), 87.9 (t), 126.6 (d), 127.0 (d), 127.6 (d),139.7
(s). m/z (CI) 178 (11, MH1), 176 (100), 162 (11), 148 (78),
(4R,5R)-3-Methyl-4-phenyltetrahydro-1,3-oxazin-5-ol
(3Aa). a. 78% (608C, 48 h). b. 100%. (1008C, 28 h). White
crystals. Mp 1428C. [a]2D0ˆ243.75 (c 0.032, CHCl3). nmax

C. Hajji et al. / Tetrahedron 56 (2000) 8173±8177
8177
146 (13), 132 (6), 118 (14), 105 (14), 91 (16). HRMS (CI):
M1, found 178.1225. C11H16NO requires 178.1231.
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469±477; Mills, J. E.; Maryanoff, C. A.; McComsey, D. F.;
Stanzione, R. C.; Scott, L. J. Org. Chem. 1987, 52, 1857±1859;
(4S,5S)-3,4-Dimethyl-5-phenyl-1,3-oxazolidine (5). a.
41% (1008C, 14 h). b. 49%, (508C, 14 h). Colourless oil.
[a]2D0ˆ159.37 (c0.48, CHCl3). nmax (Nujol) 3434 (br),
1
1636, 1493, 1470, 1386, 1239, 1066. H NMR (CDCl3):
dˆ1.15 (d, Jˆ6.2 Hz, 3H), 2.39 (s, 3H), 2.53 (dq, Jˆ8.7,
6.2 Hz, 1H, H-4), 4.33 (d, Jˆ3.6 Hz, 1H, H-2), 4.46 (d,
Jˆ8.7 Hz, 1H, H-5), 4.75 (d, Jˆ3.6 Hz, 1H, H-20), 7.24
(m, 5H). 13C NMR (CDCl3): dˆ13.0 (q), 37.0 (q), 67.8
(d), 85.8 (d), 87.4 (t), 126.0 (d), 128.1 (d), 128.4 (d),138.3
(s). m/z (EI) 177 (1, M1), 148 (7), 132 (5), 117 (5), 105 (7),
91 (10), 86 (19), 71 (90), 58 (100). HRMS (EI): M1, found
177.1145. C11H15NO requires 177.1153.
È
Federsel, H. J.; Konberg, E.; Lilljequist, L.; Swahm, B. M. J. Org.
Chem. 1990, 55, 2254±2256; Souquet, F.; Martens, T.; Fleury,
M. B. Synth. Commun. 1993, 23, 817±828; Matsumoto, K.;
Uchida, T.; Hashimoto, S.; Yonezawa, Y.; Iida, H.; Kakehi, A.;
Otani, S. Heterocycles 1993, 36, 2215±2219; Hon, Y. S.; Chang,
F. J.; Lu, L. J. Chem. Soc., Chem. Commun. 1994, 2041±2042;
Gonzalez, C.; Greenhouse, R. Heterocycles 1985, 23, 1127±1130.
Â
Â
2. Sepulveda-Arques, J.; Armero-Alarte, T.; Acero-Alarcon, A.;
Â
Zaballos-Garcõa, E.; Yruretagoyena±Solesio, B.; Ezquerra-
X-Ray crystal data
Carrera, J. Tetrahedron 1996, 52, 2097±2102.
3. Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 1557±
1560.
ꢀ
C11H15NO2, Mˆ193.245, triclinic P1; aˆ6.5003(4), bˆ
Ê
Ê 3
10.230(2), cˆ16.108(1) A, aˆ72.86(1), bˆ78.35(1), gˆ
Â
4. Canas, M.; Poch, M.; Verdaguer, X.; Moyano, A.; Pericas, A.;
-3
89.98(1)8, Uˆ1000.5(2) A , Dcˆ1.28 g cm , Zˆ4, MoKa
Riera, A. Tetrahedron Lett. 1991, 32, 6931±6934.
5. Agami, C.; Couty, F.; Hamon, L.; Venier, O. Tetrahedron Lett.
1993, 34, 4509±4512.
(lˆ0.7107 A), mˆ0.88 cm21. Data reduction with xray 76
Ê
System.11 From the 3508 independent re¯ections 1923 were
considered observed with the I . 2sꢀI† criterion. The struc-
ture was solved by direct methods using the program sir
92.10.12 Re®nement by least-squares on F2 with shelxl
97.13 (256 parameters). All non-hydrogen atoms were aniso-
tropically re®ned. Hydrogens bonded to C atoms were
placed at calculated positions. Fourier difference maps
detected the hydrogens of the hydroxyl groups that were
treated with a riding model in which the torsion angle of
hydrogen atom was re®ned. Extinction coef®cientˆ
0.014(7). Weighting scheme wˆ1/[s2(Fo2)1(0.1359P)2]
were Pˆ(F2o12Fc2)/3. Final values: R1ˆ0.062, wR2ˆ0.143,
6. Agami, C.; Couty, F.; Hamon, L.; Venier, O. Bull. Chem. Soc.
Fr. 1995, 132, 808±814.
7. Melon, C.; Gravier-Pelletier, C.; Merrer, Y. L.; Depezay, J. C.
Bull. Chem. Soc. Fr. 1992, 129, 585±593.
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8. Laszlo, L.; Lakatos, A. G.; FuÈlop, F.; Bernath, G.; Riddell, F. G.
Tetrahedron 1997, 53, 1081±1088.
9. Gelbcke, M.; Baudet, M.; Hoyois, J.; Van De Vliedt, G.;
Deleers, M. Nov. J. Chim. 1983, 7, 41±47.
10. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune,
H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765±5780.
11. Stewart, J. M.; Machin, P. A.; Dickinson, C. W.; Ammon,
H. L.; Heck, H.; Flack, H. The X-RAY76 System, Technical report
TR-446; Computer Science Center, University of Maryland,
College Park, Maryland, 1976.
Ê ±3
Sˆ1.032 and Drmaxˆ0.25, Drminˆ20.30e A . Molecular
graphics were done with ortep3 for Windows.14
12. Altomare, A.; Burla, M. C.; Camalli, M.; Cascarano, G.;
Giacovazzo, G.; Guagliardi, A.; Polidori, G. J. Appl. Crystallogr.
1994, 27, 435.
Acknowledgements
Â
We are indebted to Direccion General de Investigacion
Cientõ®co y Tecnica, for project PB98-1451. M Luisa
Testa thanks Generalitat Valenciana for a grant.
Â
13. Sheldrick, G.M., shelxl 97, Programme for the re®nement of
È
crystal structures. University of Gottingen, Germany, 1997.
14. Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565.
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