Efficient one-pot synthesis of enantiomerically pure 2-(hydroxymethyl)- morpholines

Article abstract of DOI:10.1002/ejoc.200601006

An efficient and convenient one-pot procedure for the synthesis of enantiomerically pure 2-(hydroxymethyl)morpholines with a widely variable substitution pattern was developed. Addition of chiral β-amino alcohols to (S)- or (R)-epichlorohydrin in the pres

Full text of DOI:10.1002/ejoc.200601006

FULL PAPER
DOI: 10.1002/ejoc.200601006
Efficient One-Pot Synthesis of Enantiomerically Pure 2-(Hydroxymethyl)-
morpholines
[a]
[a]
[a]
Matthias Breuning,* Malte Winnacker, and Melanie Steiner
Keywords: Asymmetric synthesis / Nitrogen heterocycles / Cyclization / Morpholines / Epichlorohydrin
An efficient and convenient one-pot procedure for the syn-
thesis of enantiomerically pure 2-(hydroxymethyl)morph-
olines with a widely variable substitution pattern was devel-
oped. Addition of chiral β-amino alcohols to (S)- or (R)-epi-
sponding chloro alcohols, which were treated with NaOMe
to give the epoxides and, by subsequent intramolecular cycli-
zation, the target compounds in good yields (57–77%).
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
4
chlorohydrin in the presence of LiClO afforded the corre- Germany, 2007)
Introduction
Mono- and disubstituted morpholines are the chiral
cores of a wide variety of pharmacologically highly active
[
1]
substances. A selection of such compounds, with the clini-
[2]
cally used antidepressant reboxetine (1) as the prime ex-
ample, is shown in Figure 1.[ Characteristic of these
morpholines are side chains in the 2-position of various
complexity, which are synthetically accessible from a func-
tionalized C1 unit. In particular, enantiomerically pure
morpholines of type 6, possessing a 2-(hydroxymethyl) sub-
stituent, provide excellent precursors for the stereoselective
preparation of heterocycles, as already demonstrated in sev-
3]
[
4]
eral syntheses. Despite their importance, only a few ster-
[
5,6]
eoselective approaches have so far been developed,
which are based on the condensation of chiral β-amino
[
7]
[8]
alcohols with activated glycerols, glycidols, chloroacetyl
[
9]
[10]
chloride, methyl 4-bromo-2-butenoate,
or 1,3-difunc-
tionalized 2-butenes.[ However, all of these procedures re-
quire two or more steps for the construction of the morph-
oline system.
11]
Herein we present a straightforward one-pot procedure
that allows fast and efficient access to enantiomerically pure
2
-(hydroxymethyl)morpholines 6 with a widely variable
Figure 1. Pharmacologically active compounds possessing a chiral
morpholine subunit and the target morpholines 6.
substitution pattern. The key step is the Lewis acid assisted
addition of chiral β-amino alcohols to (S)- and (R)-epichlo-
rohydrin, followed by intramolecular cyclization in the pres-
ence of a base.
tiomerically pure epichlorohydrin 8 [e.g. (S)-8] to give the
chloro alcohol 9, (2) its base-induced cyclization to the ep-
oxide 10, and (3) the final ring closure, delivering the de-
sired morpholine 6. In addition to the necessity to find reac-
tion conditions compatible with all three steps, there are
two major problems to be solved concerning the regioselec-
tivity. Firstly, the initial addition of 7 to (S)-8 has to pro-
ceed highly selectively at the epoxide group. Any competing
attack of 7 at the chlorine-bearing terminal carbon atom of
(S)-8 would lead to the enantiomeric or, in the case of chiral
Results and Discussion
The desired one-pot approach comprises three steps
(Scheme 1): (1) the addition of an amino alcohol 7 to enan-
[
a] Institute of Organic Chemistry, University of Würzburg,
Am Hubland, 97074 Würzburg, Germany
Fax: +49-931-888-4755
E-mail: breuning@chemie.uni-wuerzburg.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
2100
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2100–2106

Enantiomerically Pure 2-(Hydroxymethyl)morpholines
FULL PAPER
amino alcohols, to the diastereomeric epoxide and, thus, to Table 1. Lewis acid mediated addition of the amino alcohol 7a to
rac-8.
a reduced optical purity in the product 6. Secondly, the final
ring closure of 10 has to occur in a 6-exo-tet fashion in
order to give 6, which requires an attack of the OH group
at the inner position of the epoxide 10. A competing reac-
tion at the terminal site of the epoxide would deliver an
oxazepane as a byproduct (7-endo-tet ring closure).
Lewis acid[a] (equiv.)
Solvent
T
°C]
t
[h]
Conversion
(Yield[ ) [%]
[b]
Entry
c]
[
1
2
3
4
5
6
7
8
9
–
(CH
(CH
(CH
(CH
(CH
toluene
toluene
MeOH
2
2
2
2
2
Cl)
Cl)
Cl)
Cl)
Cl)
2
2
2
2
2
20
20
20
20
20
20
60
20
20
20
72
72
72
72
14
14
4
14
72
72
trace
50
50
LiX[d] (1.3)
CsClO
4
(1.3)
Mg(ClO
4
)
2
(1.3)
50
LiClO
LiClO
LiClO
LiClO
LiClO
LiClO
4
(1.3)
100 (86)
100 (89)
100 (84)
50
70
70 (61)
4
(1.3)
(1.3)
(1.3)
(0.1)
(0.1)
4
4
4
4
(CH
2
Cl)
2
1
0
toluene
[
a] Low conversion or decomposition with NaI, CsI, ZnBr
SnCl , ZrCl , CuI, MgSO , and BF ·OEt as the Lewis acids. [b]
Judged by TLC. [c] Isolated yields. [d] LiCl, LiBr, or LiI·2H O.
2 3
, BiBr ,
4
4
4
3
2
2
Scheme 1. Concept for the intended one-pot synthesis of enantio-
merically pure 2-(hydroxymethyl)morpholines 6.
Initial studies to establish the stepwise route and, sub-
sequently, the one-pot procedure, were performed on the
condensation of 2-(benzylamino)ethanol (7a) and racemic
epichlorohydrin (rac-8) as the model reaction.
screened, the reaction could not be stopped selectively at
this stage but delivered instead mixtures of unreacted start-
ing material rac-9, the desired product rac-10, and ring-clo-
sure products like rac-6a. Good yields of the epoxide rac-
10 (61%) were obtained with KOtBu in dichloroethane. The
direct preparation of rac-10 from 7a is also possible; the
addition of 7a to rac-8 in dichloroethane (see Table 1, En-
try 5) and subsequent treatment with KOtBu afforded rac-
10 in 63% isolated yield.
Optimization of the Stepwise Route
It is known that the ring opening of epichlorohydrin (8)
[
12]
with nucleophiles proceeds smoothly and highly regiose-
lectively at C-3 in the presence of many Lewis acids such as
[13]
MgSO , BF ·OEt , or LiClO .
In our case, quantitative
4
3
2
4
conversion of 7a into the chloro alcohol rac-9 only occurred
with LiClO in toluene or dichloroethane (Table 1); the in-
4
termediate rac-9 was obtained in high isolated yield (84–
8
9%) within 14 h at 20 °C or 4 h at 60 °C (Table 1, En-
Scheme 2. Base-induced cyclization of the chloro alcohol rac-9 to
the epoxide rac-10.
tries 5–7). The Lewis acid LiClO had to be applied in a
slight excess, since the reaction rate in the presence of cata-
4
lytic amounts was too low for the efficient formation of rac-
9
1
(ca. 70% conversion within 72 h, Table 1, Entries 9 and
0).
It is important to mention that, in the reactions with a reaction at the more highly substituted inner position of
The intramolecular cyclization of the epoxide rac-10 to
[
14]
the morpholine rac-6a
requires a 6-exo ring closure (i.e.
LiClO as the Lewis acid, the epoxide rac-10 was not de- the epoxide, Table 2). Since this attack should be favored
4
1
tected in the H NMR spectra of the crude reaction mix- under protic or Lewis acidic conditions, camphorsulfonic
[
15]
tures. Since rac-10 would be the product of the unwanted acid in CH Cl2 and LiClO in toluene or dichloroethane
2
4
SN2 reaction at the terminal chlorine-bearing carbon atom were screened; however, only traces of rac-6a were detected.
of rac-8, this proves a highly regioselective attack of 7a at In contrast, basic conditions, which bear the risk of a com-
the epoxide function of rac-8 and also suggests that high peting 7-endo cyclization at the less-substituted terminal
regiocontrol (and, therefore, also potentially high ste- carbon atom of rac-10 to afford the oxazepane rac-11,
reocontrol) would be obtained in the intended morpholine proved to be successful. With NaOMe in MeOH, KOtBu
syntheses with enantiomerically pure epichlorohydrin (vide in tBuOH, or LiOH in Et O (Table 2), the desired morph-
2
infra).
oline rac-6a was obtained in 42–50% yield, albeit ac-
The second step, the cyclization of the chloro alcohol companied by 10–22% of rac-11. Weaker bases like NaOH
[
16]
rac-9 to the epoxide rac-10, proved to be difficult in H O/MeOH or DBU in EtOH
delivered inseparable
2
(Scheme 2). With most of the base/solvent systems mixtures of unidentified compounds.
Eur. J. Org. Chem. 2007, 2100–2106
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2101

M. Breuning, M. Winnacker, M. Steiner
Table 2. Cyclization of the epoxide rac-10 to the morpholine rac- Stereoselective One-Pot Synthesis of 2-(Hydroxymethyl)-
FULL PAPER
6a and the oxazepane rac-11.
morpholines
Finally, the scope of this one-pot procedure was evalu-
ated in the stereoselective synthesis of several morpholines
6
(Table 4). Condensation of commercially available (S)-epi-
chlorohydrin [(S)-8, 97% ee] with a selection of achiral and
chiral β-amino alcohols 7 delivered the target molecules 6
in good yields of 57–77%. The structures of all products 6
were unambiguously proven by extensive two-dimensional
NMR experiments. Alkyl, dialkyl, and phenyl groups are
tolerated in the α-position to the nitrogen atom of 7
Entry
1
Base (equiv.) Solvent
T
°C]
t
[h]
rac-6a[a]
Yield [%] Yield [%]
rac-11[a]
[
[
17]
NaOMe
1.3)
KOtBu (1.4) tBuOH
LiOH (3.2) Et
MeOH
20
14
49
16
(
2
3
20
35
72
72
50
42
22
10
(Table 4, Entries 2–6). The N-benzyl group, which will allow
2
O
further manipulations at the nitrogen atom after hydro-
[
a] Isolated yields.
[18]
genolytic deprotection, is not essential; the N-methyl de-
rivative 7f also underwent the cyclization to give 6f in 61%
yield (Table 4, Entry 6). With the secondary o-hydroxyani-
line 7g as the substrate, the benzoxazine 6g was formed in
Optimization of the One-Pot Procedure
6
7% yield (Table 4, Entry 7). Primary amines like 2-amino-
ethanol (6h), however, failed to give a defined product
Table 4, Entry 8). An N-Boc protecting group as in 7i,
With these results in hand we turned our attention to the
one-pot procedure (Table 3). A mixture of 7a, rac-8, and
(
LiClO was stirred in a given solvent until TLC indicated
4
which significantly reduces the nucleophilicity of the nitro-
gen atom, inhibits the reaction with (S)-8, even at elevated
temperatures (Table 4, Entry 9). Finally, it is noteworthy to
mention that a significant amount (18% yield) of an ox-
azepane byproduct of type 11 was found only in the cycliza-
tion of the unsubstituted amino alcohol 7a with (S)-8, but
not in the analogous reactions of the substituted amino
quantitative conversion into the intermediate rac-9. After
the addition of base, continued stirring for 14–72 h, and
workup, the products rac-6a and rac-11 were separated by
column chromatography, and their yields were determined.
The best results were obtained at 20 and 60 °C in toluene
with NaOMe as the base and MeOH as a cosolvent
(Table 3, Entries 1 and 2). Under these conditions, the
[19]
alcohols 7b–g.
morpholine rac-6a was isolated in 55 and 62% yield, respec-
tively, which is by far better than the overall yield of the
single-step reactions (ca. 23%). Other base/solvent combi- (S)-8 and a selection of β-amino alcohols 7.
Table 4. Enantioselective preparation of the morpholines 6 from
nations afforded rac-6a in significantly lower yields, even at
elevated temperatures or prolonged reaction times (Table 3,
Entries 3–6). The oxazepane rac-11 was formed as a minor
side product in all reactions. Cyclizations with LiOtBu or
LiOH as the bases afforded complex product mixtures.
Entry
6, 7
R
R1
R2
R3
Yield of 6[a] ee/de [%]
%]
[
Table 3. Conditions for the one-pot synthesis of rac-6a.
1[b]
59[c]
94[d]
a
b
c
d
e
f
Bn
Bn
Bn tBu
Bn
Bn
Me
Bn
H
iPr
H
H
H
H
H
H
H
H
H
[
e]
[f]
2
3
63
60
77
57
61
67
Ͼ97
Ͼ97
Ͼ97
[
e]
[f]
[f]
[
[
[
b]
b]
b]
4
5
6
H
Ph
[d]
Me Me
H
–
97
Ͼ97
[f]
Ph
7[e]
2
3
[d]
g
R –R =
benzo
H
97
Entry
Base (equiv.) Solvent[a]
T
t[a]
rac-6a[b]
rac-11[b]
8[
9
b]
h
i
H
Boc
H
H
H
–[g]
–
–
[°C]
[h]
Yield [%] Yield [%]
[
e]
[h]
Bn
H
–
1
2
NaOMe
2.5)
NaOMe
2.5)
toluene[c] 20
14/14
4/4
55
62
14
24
[
a] Isolated yields. [b] 20 °C. [c] 14% of the oxazepane 11 was iso-
lated. [d] Enantiomeric excess (ee) was determined by F NMR
spectroscopy of the corresponding Mosher esters. [e] 50 °C. [f] Ac-
cording to H NMR spectroscopy, diastereomerically pure com-
pounds after column chromatography. [g] Complex product mix-
(
19
toluene[c] 60
(
1
3
4
5
6
NaOH (1.4) toluene
KOtBu (2.0) tBuOH
20
90
60
60
14/72
72/6
14/72
14/72
37
35
31
45[e]
8
20
8
[20]
ture. [h] No reaction.
[
d]
KOtBu (2.0) (CH
2
Cl)
2
KOtBu (2.0) toluene
12
The enantiomeric purities of 6a, 6e, and 6g were analyzed
by 19F NMR spectroscopy of the corresponding Mosher
esters. A slightly diminished ee of 94%, as compared to the
97% ee of the chiral reactant [(S)-8] used, was found for the
[
a] Reaction time prior to/after the addition of base. [b] Isolated
yields. [c] Methanol was added as a cosolvent prior to treatment
with base. [d] 47% of the epoxide rac-10 was isolated. [e] 14% of
the epoxide rac-10 was isolated.
2102
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Eur. J. Org. Chem. 2007, 2100–2106

Enantiomerically Pure 2-(Hydroxymethyl)morpholines
FULL PAPER
morpholine 6a; thus, a slight erosion of the optical purity pounds rac-, (S)- and (R)-epichlorohydrin [rac-8, (S)-8 (97% ee),
and (R)-8 (97% ee)], and 2-(benzylamino)ethanol (7a) are commer-
cially available and were used as received. The enantiomerically
had occurred, probably a consequence of an interfering SN2
reaction in the first step, which is the addition of 7a to (S)-
pure benzylamino alcohols 7b,[ 7d, 7e, and 7g are known
compounds, which were prepared by reductive amination of benz-
aldehyde in analogy to 7c; the methylamino alcohol 7f was pre-
21]
[22]
[23]
[24]
8
(vide supra). However, no such erosions of the ee were
observed for the dimethyl derivative 6e (97% ee) and the
oxazepane 6g (97% ee). Furthermore, no diastereomeric
products were detected in the reactions of the chiral amino
[25]
pared according to a literature procedure.
alcohols 7b–d and 7f with (S)-8.[
20]
(S)-2-(Benzylamino)-3,3-dimethylbutan-1-ol (7c): A solution of (S)-
The morpholines 6b–d
2
-amino-3,3-dimethylbutan-1-ol (318 mg, 2.71 mmol) and benzal-
dehyde (277 µL, 287 mg, 2.71 mmol) in absolute MeOH (5 mL) was
stirred at 20 °C for 2 h. NaBH (102 mg, 271 mmol) was added at
°C, and stirring was continued for 1 h. CH Cl (50 mL) and satu-
Cl (30 mL) were added, and the layers were sepa-
Cl (20 mL),
the combined organic layers were washed with brine (20 mL), dried
and 6f were obtained in enantio- and diastereomerically
pure form after column chromatography.
With this one-pot procedure, both, cis- (7b,c) and trans-
disubstituted morpholines (7d,f) are accessible in stereo-
chemically homogeneous form and good yields. Therefore,
the relative configuration of the two chiral reactants 7 and
4
0
2
2
rated aq. NH
4
rated. After extraction of the aqueous layer with CH
2
2
8
to each other is not critical. All possible stereoisomers of with MgSO , and the solvent was removed in vacuo. The residue
4
a given disubstituted morpholine can be synthesized, as was chromatographed (silica gel; EtOAc) to afford 7c (471 mg,
= 0.40
). H NMR
], 1.50–3.00 (br. s, 2
also shown in the condensation of 7d with the enantiomeric 2.27 mmol, 84% yield) as a highly viscous colorless oil. R
f
2
3
1
(CH
2
Cl
2
/MeOH, 95:5). [α]
D 3
= +9.85 (c = 0.56, CHCl
epichlorohydrin (R)-8 giving the morpholine 6k, the cis-
configured diastereomer of 6d, in 72% yield (Scheme 3).
(
400 MHz, CDCl
3
): δ = 0.97 [s, 9 H, C(CH )
3 3
H, NH, OH), 2.40 (dd, J = 6.4, 4.7 Hz, 1 H, CHN), 3.41 (dd, J =
0.6, 6.4 Hz, 1 H, CHHOH), 3.66 (dd, J = 10.6, 4.7 Hz, 1 H,
CHHOH), 3.84 (d, J = 12.8 Hz, 1 H, CHHPh), 3.91 (d, J =
1
1
3
12.8 Hz, 1 H, CHHPh), 7.24–7.39 (m, 5 H, Ph) ppm. C NMR
(100 MHz, CDCl
3
3 3 3 3
): δ = 27.5 [C(CH ) ], 34.6 [C(CH ) ], 54.5
(
CH
2
Ph), 60.2 (CH
2
OH), 67.3 (CHN), 127.3 (Ph), 128.3 (Ph), 128.7
(
1
Ph), 140.7 (Ph) ppm. IR (KBr): ν˜ = 3170, 2952, 2863, 1483, 1453,
–
1
053, 748, 697 cm . HRMS (ESI; MeCN/CHCl
3
, 1:1): calcd. for
Scheme 3. Condensation of 7d with (R)-8 to give the morpholine
[C
13
H
21NO + H]+ 208.1696; found 208.1696.
6k.
1-[Benzyl(2-hydroxyethyl)amino]-3-chloropropan-2-ol (rac-9): Race-
mic epichlorohydrin (rac-8, 2.15 g, 1.83 mL, 23.3 mmol) and
LiClO (2.49 g, 23.3 mmol) were added to a solution of 7a (3.20 g,
1.2 mmol) in toluene (40 mL). After 14 h at 20 °C, EtOAc
100 mL) was added, and the reaction mixture was washed with
water (2ϫ50 mL). The combined aqueous layers were extracted
with EtOAc (2ϫ50 mL). The combined organic layers were washed
4
Conclusions
2
(
An efficient and convenient one-pot procedure for the
preparation of enantiomerically pure 2-(hydroxymethyl)-
morpholines, which are versatile synthetic building blocks,
was developed. Treatment of chiral β-amino alcohols with
4
with brine (50 mL), dried with MgSO , and the solvent was re-
moved in vacuo. Purification by column chromatography (silica gel;
(S)-epichlorohydrin and LiClO4 in toluene and, sub-
EtOAc/Et N, 100:1) delivered rac-9 (4.60 g, 18.9 mmol, 89% yield)
3
1
sequently, with NaOMe in MeOH delivered the desired tar- as a slightly yellow oil. R = 0.25 (CH Cl /MeOH, 95:5). H NMR
f
2
2
get molecules in 57–77% yield. The scope of this reaction (400 MHz, CDCl ): δ = 2.27 (br. s, 1 H, OH), 2.67 (dd, J = 13.4,
3
was demonstrated in the stereoselective synthesis of seven 2- 8.3 Hz, 1 H, 1-H), 2.70 (ddd, J = 13.4, 5.3, 4.4 Hz, 1 H, 1-HЈ), 2.74
(
dd, J = 13.4, 4.2 Hz, 1 H, 1Ј-H), 2.79 (ddd, J = 13.4, 6.8, 4.8 Hz,
(
hydroxymethyl)morpholines and of one benzoxazine. The
1
3
2
1
H, 1Ј-HЈ), 3.25 (br. s, 1 H, OH), 3.50 (dd, J = 11.1, 5.6 Hz, 1 H,
-H), 3.54 (dd, J = 11.1, 4.8 Hz, 1 H, 3-HЈ), 3.64 (m, 2 H, 2Ј-H,
Ј-HЈ), 3.67 (d, J = 13.9 Hz, 1 H, CHHPh), 3.79 (d, J = 13.6 Hz,
H, CHHPh), 3.88 (m, 1 H, 2-H), 7.20–7.40 (m, 5 H, Ph) ppm.
epimeric products are likewise accessible from (R)-epichlo-
rohydrin and the respective amino alcohols. Further investi-
gations like the extension of this method to the stereoselec-
tive synthesis of chiral 3-(hydroxymethyl)morpholines, 2-
1
3
C NMR (100 MHz, CDCl
3
): δ = 47.5 (C-3), 56.7 (C-1Ј), 57.7 (C-
(hydroxymethyl)piperazines, and -dioxanes are in progress.
2
Ј, CH Ph), 68.9 (C-2), 127.6 (Ph), 128.7 (Ph), 129.1 (Ph), 138.5
2
(
1
Ph) ppm. IR (film): ν˜ = 3348, 2952, 2885, 2834, 1638, 1495, 1453,
–
1
3
049, 738, 702 cm . HRMS (ESI; MeCN/CHCl , 1:1): calcd. for
+
Experimental Section
12 18 2
[C H ClNO + H] 244.1099; found 244.1097.
General: Optical rotations (25 °C, 10 cm cell) were measured with
a Jasco P-1020 polarimeter. All NMR spectra were acquired at
2-[Benzyl(oxiranylmethyl)amino]ethanol (rac-10) from rac-9: A solu-
tion of rac-9 (800 mg, 3.28 mmol) in (CH Cl) (15 mL) was treated
with KOtBu (438 mg, 3.92 mmol) and stirred at 20 °C for 8 h.
CH Cl (50 mL) was added, and the reaction mixture was washed
with saturated aq. NH Cl (50 mL) and brine (50 mL), dried with
MgSO , and the solvent was removed in vacuo. The residue was
chromatographed (silica gel; CH Cl /MeOH, 95:5) to give rac-10
(415 mg, 2.00 mmol, 61% yield) as a slightly yellow oil. R = 0.30
): δ = 2.48 (dd,
J = 4.8, 2.7 Hz, 1 H, 3Ј-H), 2.51 (dd, J = 14.0, 6.3 Hz, 1 H, 1Ј-H),
2
2
3
20 °C with a Bruker AV 400 instrument with CDCl as the internal
reference. IR spectra were recorded with a Jasco FT-IR-410 spec-
trometer. High resolution mass spectra were measured with a
2
2
4
Bruker Daltonics micrOTOF focus spectrometer. R
f
values refer to
4
TLC on aluminum foil backed silica gel plates. Column chromatog-
raphy was performed on silica gel (63–200 mesh). For the detection
of compounds, the extinction of fluorescence at 254 nm was used.
All reactions were performed under argon in dry solvents. Com-
2
2
f
1
2 2 3
(CH Cl /MeOH, 95:5). H NMR (400 MHz, CDCl
Eur. J. Org. Chem. 2007, 2100–2106
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2103

M. Breuning, M. Winnacker, M. Steiner
FULL PAPER
1
2
2
6
3
1
5
.55–2.80 (br. s, 1 H, OH), 2.72 (ddd, J = 13.1, 5.6, 4.4 Hz, 1 H,
-H), 2.74 (dd, J = 4.8, 4.1 Hz, 1 H, 3Ј-HЈ), 2.85 (ddd, J = 13.1,
CHCl
5.1 Hz, 1 H, 3-H), 2.83 (m, 2 H, 3-HЈ, 5-H), 2.97 (ddd, J = 12.6,
Ph), 3.79 (m,
.07 (m, 1 H, 2Ј-H), 3.62 (m, 2 H, 1-H, 1-HЈ), 3.68 (d, J = 13.6 Hz, 2 H, 7-H, 7-HЈ), 3.83 (m, 1 H, 6-H), 3.96 (m, 1 H, OH), 7.20–7.40
3 3
). H NMR (400 MHz, CDCl ): δ = 2.51 (ddd, J = 12.4, 7.3,
.6, 4.8 Hz, 1 H, 2-HЈ), 2.89 (dd, J = 14.1, 3.3 Hz, 1 H, 1Ј-HЈ), 5.8, 1.5 Hz, 1 H, 5-HЈ), 3.73 (m, 4 H, 2-H, 2-HЈ, CH
2
1
3
H, CHHPh), 3.83 (d, J = 13.5 Hz, 1 H, CHHPh), 7.20–7.40 (m, (m, 5 H, Ph) ppm. C NMR (100 MHz, CDCl
H, Ph) ppm. 13C NMR (100 MHz, CDCl
): δ = 45.1 (C-3Ј), 50.9 57.8 (C-3), 63.5 (CH Ph), 69.1 (C-6), 70.2 (C-2), 76.4 (C-7), 127.6
Ph), 127.5 (Ph), (Ph), 128.6 (Ph), 129.1 (Ph), 138.6 (Ph) ppm. IR (film): ν˜ = 3408,
28.6 (Ph), 129.1 (Ph), 138.7 (Ph) ppm. IR (film): ν˜ = 3409, 2943,
3
): δ = 57.2 (C-5),
3
2
(C-2Ј), 56.0 (C-1Ј), 56.1 (C-2), 59.0 (C-1), 59.4 (CH
2
–
1
1
2
2937, 2861, 1455, 1103, 1058, 742, 700 cm . HRMS (ESI; MeOH):
calcd. for [C12
+ H]+ 208.1332; found 208.1335.
–1
833, 1602, 1453, 1051, 739 cm . HRMS (ESI; MeOH): calcd. for
H17NO
2
[C
12
H17NO
2
+ H]+ 208.1332; found 208.1324.
(
2R,5S)-N-Benzyl-2-(hydroxymethyl)-5-isopropylmorpholine (6b):
2
-[Benzyl(oxiranylmethyl)amino]ethanol (rac-10) from 7a and rac-8:
Cl)
(800 mg,
.50 mmol) were added. The reaction mixture was stirred at 20 °C
157 mg, 631 µmol, 63% yield; R = 0.60 (CH Cl /MeOH, 95:5).
f
2
2
2
3
1
To a solution of 7a (1.00 g, 940 µL, 6.60 mmol) in (CH
10 mL), rac-8 (670 mg, 570 µL, 7.30 mmol) and LiClO
2
2
D 3 3
[α] = +19.2 (c = 1.0 in CHCl ). H NMR (400 MHz, CDCl ): δ
(
7
4
3 2
= 0.95 [d, J = 6.8 Hz, 3 H, CH(CH ) ], 0.99 [d, J = 6.8 Hz, 3 H,
CH(CH ) ], 2.15 (m, 1 H, 5-H), 2.30 [oct, J = 6.9 Hz, 1 H,
3 2
for 14 h, cooled to 0 °C, treated with KOtBu (2.96 g, 26.4 mmol),
and stirred at 20 °C for a further 6 h. Workup and chromatography
as described above afforded rac-10 (862 mg, 4.16 mmol, 63% yield)
as a slightly yellow oil.
3 2
CH(CH ) ], 2.37 (dd, J = 13.1, 3.2 Hz, 1 H, 3-H), 2.45 (br. s, 1 H,
OH), 2.82 (dd, J = 13.1, 7.8 Hz, 1 H, 3-HЈ), 3.57 (dd, J = 11.5,
3.3 Hz, 1 H, CHHOH), 3.59 (d, J = 13.5 Hz, 1 H, CHHPh), 3.67
(dd, J = 11.5, 6.6 Hz, 1 H, CHHOH), 3.76 (m, 1 H, 2-H), 3.82 (dd,
J = 11.8, 3.3 Hz, 1 H, 6-H), 3.90 (dd, J = 11.8, 4.4 Hz, 1 H, 6-HЈ),
N-Benzyl-2-(hydroxymethyl)morpholine (rac-6a) and N-Benzyl-1,4-
oxazepan-6-ol (rac-11): NaOMe (42.0 mg, 780 µmol) was added to
a solution of rac-10 (125 mg, 600 µmol) in MeOH (3 mL). The re-
action mixture was stirred at 20 °C for 14 h, and the solvent was
4
.02 (d, J = 13.5 Hz, 1 H, CHHPh), 7.20–7.40 (m, 5 H, Ph) ppm.
1
3
C
NMR (100 MHz, CDCl
CH(CH ], 26.1 [CH(CH ], 48.7 (C-3), 58.2 (CH
), 63.9 (C-5), 64.7 (CH OH), 71.6 (C-2), 127.2 (Ph), 128.5 (Ph),
28.8 (Ph), 139.4 (Ph) ppm. IR (KBr): ν˜ = 3423, 2958, 2869, 1452,
3
):
δ
=
3 2
19.0 [CH(CH ) ], 20.4
[
3
)
2
3
)
2
2
Ph), 62.3 (C-
6
1
1
2
removed in vacuo. The residue was dissolved in Et
washed with saturated aq. NH Cl (5 mL) and brine (5 mL). The
organic layer was dried with MgSO , and the solvent removed in
vacuo. Column chromatography (silica gel, CH Cl /MeOH, 98:2)
afforded, in the order of elution, rac-11 (20.0 mg, 96.5 µmol, 16%
2
O (5 mL) and
4
–
1
093, 1072, 1045, 742, 698 cm . HRMS (ESI; MeCN/CHCl
3
, 1:1):
4
calcd. for [C15H23NO
2
+ H]+ 250.1802; found 250.1806.
2
2
(
2R,5S)-N-Benzyl-5-tert-butyl-2-(hydroxymethyl)morpholine (6c):
[
26]
yield) and rac-6a (61 mg, 290 µmol, 49% yield) as slightly yellow
oils. For the characterization, see the enantiomerically pure com-
pounds below.
Colorless solid, 158 mg, 599 µmol, 60% yield; R = 0.60 (CH Cl /
f
2
2
23
1
MeOH, 95:5); m.p. 92–93 °C. [α]
NMR (400 MHz, CDCl ): δ = 0.98 [s, 9 H, C(CH
7.1, 5.0 Hz, 1 H, OH), 2.34 (t, J = 5.6 Hz, 1 H, 5-H), 2.46 (dd,
J = 14.6, 3.9 Hz, 1 H, 3-H), 2.87 (dd, J = 14.6, 11.5 Hz, 1 H, 3-
HЈ), 3.45 (m, 2 H, CH OH), 3.83 (dd, J = 12.2, 5.6 Hz, 1 H, 6-H),
.85 (d, J = 13.7 Hz, 1 H, CHHPh), 3.88 (dd, J = 12.1, 5.8 Hz, 1
H, 6-HЈ), 3.94 (m, 1 H, 2-H), 4.05 (d, J = 13.7 Hz, 1 H, CHHPh),
D
= –6.79 (c = 1.0 in CHCl
3
). H
], 1.89 (dd, J
3
3 3
)
=
General Procedure for the One-Pot Synthesis of the 2-(Hy-
droxymethyl)morpholines 6: A solution of the amino alcohol 7
(1.00 mmol) in absolute toluene (5 mL) was treated with (S)-epi-
2
3
chlorohydrin [(S)-8, 102 µL, 120 mg, 1.30 mmol] and LiClO
4
(
(
138 mg, 1.30 mmol). After 14–48 h at 20 °C or 50 °C, MeOH
1.3 mL) and NaOMe (135 mg, 2.50 mmol) were added, and stir-
1
3
7
.25 (m, 1 H, Ph), 7.31 (m, 2 H, Ph), 7.36 (m, 2 H, Ph) ppm.
NMR (100 MHz, CDCl ): δ = 28.1 [C(CH ], 36.1 [C(CH ], 45.2
C-3), 60.6 (C-6), 61.2 (CH Ph), 64.1 (CH OH), 66.7 (C-5), 69.7
C-2), 127.2 (Ph), 128.4 (Ph), 128.8 (Ph), 140.2 (Ph) ppm. IR (KBr):
C
3
3
)
3
3 3
)
ring was continued for 14–72 h. The reaction mixture was quenched
with saturated aq. NH Cl (30 mL), and the aqueous layer was ex-
tracted with EtOAc (3ϫ30 mL). The combined organic layers were
extracted with brine (20 mL), dried with MgSO , and the solvent
was removed in vacuo. Chromatographic purification (silica gel;
Et O/hexanes, 50:50 or CH Cl /MeOH, 98:2 Ǟ 90:10) delivered
(
(
2
2
4
ν˜ = 3474, 2955, 2926, 2862, 2808, 1351, 1260, 1112, 1021, 805,
4
–
1
7
+
3 2
38 cm . HRMS (ESI; MeCN/CHCl , 1:1): calcd. for [C16H25NO
+
H] 264.1958; found 264.1958.
2R,5R)-N-Benzyl-2-(hydroxymethyl)-5-phenylmorpholine
18 mg, 770 µmol, 77% yield; R = 0.65 (n-pentane/Et
2
2
2
2
the desired 2-(hydroxymethyl)morpholine 6. In the case of 7a, the
oxazepane 11 was formed as a byproduct.
(
2
(6d):
O, 25:75).
). H NMR (400 MHz, CDCl ): δ
= 1.83 (dd, J = 7.1, 5.4 Hz, 1 H, OH), 2.06 (dd, J = 11.5, 10.7 Hz,
): δ = 1.93 (br. s, 1 1 H, 3-H), 2.78 (dd, J = 11.5, 2.3 Hz, 1 H, 3-HЈ), 2.88 (d, J =
H, OH), 2.01 (dd, J = 12.4, 9.9 Hz, 1 H, 3-H), 2.19 (td, J = 11.4, 13.3 Hz, 1 H, CHHPh), 3.38 (dd, J = 10.4, 3.4 Hz, 1 H, 5-H), 3.54
f
2
3
1
(
R)-N-Benzyl-2-(hydroxymethyl)morpholine (6a): 123 mg, 593 µmol, [α]
D
= –69.7 (c = 1.0 in CHCl
3
3
2 2 D
Cl = –23.2
/MeOH, 95:5). [α]2
2
5
9% yield; 94% ee; R
f
= 0.19 (CH
1
(
c = 1.0, CHCl
3
). H NMR (400 MHz, CDCl
3
3
1
1
.3 Hz, 1 H, 5-H), 2.67 (m, 2 H, 3-HЈ, 5-HЈ), 3.48 (d, J = 12.7 Hz,
(ddd, J = 11.5, 6.3, 5.3 Hz, 1 H, CHHOH), 3.56 (dd, J = 11.4,
H, CHHPh), 3.53 (d, J = 12.6 Hz, 1 H, CHHPh), 3.56 (dd, J = 10.5 Hz, 1 H, 6-H), 3.62 (ddd, J = 11.6, 7.1, 3.4 Hz, 1 H, CHHOH),
1.4, 6.4 Hz, 1 H, CHHOH), 3.62 (dd, J = 11.4, 3.5 Hz, 1 H,
3.75 (m, 1 H, 2-H), 3.84 (d, J = 13.4 Hz, 1 H, CHHPh), 3.86 (dd,
J = 11.4, 3.5 Hz, 1 H, 6-HЈ), 7.20–7.32 (m, 6 H, Ph), 7.37 (t, J =
CHHOH), 3.66 (m, 1 H, 2-H), 3.71 (td, J = 11.3, 2.5 Hz, 1 H, 6-
1
3
H), 3.90 (ddd, J = 11.4, 3.3, 1.9 Hz, 1 H, 6-HЈ), 7.20–7.37 (m, 5 H,
8.0 Hz, 2 H, Ph), 7.49 (d, 7.2 Hz, 2 H, Ph) ppm. C NMR
): δ = 53.1 (C-3), 59.4 (CH Ph), 64.3 (CH OH),
Ph) ppm. 13C NMR (100 MHz, CDCl
): δ = 53.2 (C-5), 54.7 (C- (100 MHz, CDCl
3
2
2
3
3
1
2
), 63.5 (CH
2
Ph), 64.5 (CH
2
OH), 66.8 (C-6), 76.1 (C-2), 127.4 (Ph),
67.3 (C-5), 73.5 (C-6), 76.8 (C-2), 127.1 (Ph), 128.1 (Ph), 128.4 (Ph),
128.87 (Ph), 128.94 (Ph), 138.5 (Ph), 139.5 (Ph) ppm. IR (film): ν˜
28.5 (Ph), 129.3 (Ph), 137.7 (Ph) ppm. IR (film): ν˜ = 3408, 2927,
868, 2815, 1454, 1117, 1052, 748, 700 cm . HRMS (ESI; MeCN):
–1
= 3440, 2953, 2854, 2808, 1738, 1494, 1452, 1266, 1119, 1045, 738,
+
–1
calcd. for [C12
a was determined by F NMR spectroscopy of the corresponding
R)-Mosher ester, as shown below.
H17NO
2
1
+ H] 208.1332; found 208.1329. The ee of
702 cm . HRMS (ESI; MeCN/CHCl
3 2
, 1:1): calcd. for [C18H21NO
9
+ H]+ 284.1645; found 284.1642.
6
(
(
R)-N-Benzyl-2-(hydroxymethyl)-5,5-dimethylmorpholine
(6e):
O,
D 3
25:75). [α] = –68.5 (c = 1.0 in CHCl ). H NMR (400 MHz,
(
S)-N-Benzyl-1,4-oxazepan-6-ol (11): 37.1 mg, 179 µmol, 18% 135 mg, 574 µmol, 57% yield; 97% ee; R = 0.65 (n-pentane/Et
f
2
/MeOH, 95:5). [α]2
2
= +12.6 (c = 1.0,
23
1
yield; R
f
= 0.30 (CH
2
Cl
2
D
2104
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2100–2106

Enantiomerically Pure 2-(Hydroxymethyl)morpholines
FULL PAPER
CDCl
3
): δ = 1.05 (s, 6 H, 2ϫ5-CH
3
), 1.88 (br. s, 1 H, OH), 2.26
propionyl chloride, 99% ee, 2.0 equiv.] in CH
was added to a solution of the morpholine 6 (1.0 equiv.), Et
(2.0 equiv.), and a catalytic amount of DMAP in CH Cl (20
.6 Hz, 1 H, 6-H), 3.52 (d, J = 10.9 Hz, 1 H, 6-HЈ), 3.57 (m, 3 H, mL/mmol 6). After 2 h at 25 °C, water (200 mL/mmol 6) was
OH, 2-H), 4.01 (d, J = 13.8 Hz, 1 H, CHHPh), 7.20–7.40 (m, added, and the reaction mixture was extracted with Et
H, Ph) ppm. 13C NMR (100 MHz, CDCl
): δ = 14.7 (5-CH ), (3ϫ300 mL/mmol 6). The combined organic layers were washed
4.4 (5-CH ), 47.5 (C-3), 52.9 (C-5), 53.8 (CH Ph), 64.3 (CH OH), with brine (300 mL/mmol 6), dried with MgSO , and the solvent
7.3 (C-2), 77.7 (C-6), 126.9 (Ph), 128.4 (Ph), 128.7 (Ph), 140.1 (Ph) was removed in vacuo. Purification by column chromatography (sil-
2 2
Cl (20 mL/mmol 6)
(dd, J = 11.8, 9.9 Hz, 1 H, 3-H), 2.34 (dd, J = 11.8, 2.9 Hz, 1 H,
3
N
3
0
-HЈ), 3.02 (d, J = 13.8 Hz, 1 H, CHHPh), 3.45 (dd, J = 10.9,
2
2
CH
2
2
O
5
2
7
3
3
3
2
2
4
ppm. IR (film): ν˜ = 3432, 2964, 2852, 1454, 1362, 1070, 1055, 731,
2
ica gel; n-pentane/Et O, 1:1) gave the Mosher esters as slightly yel-
low oils.
–1
6
98 cm . HRMS (ESI; MeCN/CHCl
H] 236.1645; found 236.1639. The ee of 6e was determined by
3
, 1:1): calcd. for [C14
H
21NO
2
+
+
(
R)-Mosher Ester of rac-6a: 16.0 mg, 37.8 µmol, 71% yield. 19F
NMR (376 MHz, CDCl ): δ = –71.70 (s, CF ), –71.73 (s, CF ) ppm.
19
F NMR spectroscopy of the corresponding (S)- and (R)-Mosher
esters, as shown below.
3
3
3
(
(
R)-Mosher Ester of 6a: 17.2 mg, 40.6 µmol, 76% yield. 19F NMR
376 MHz, CDCl ): δ = –71.73 (s, CF ) ppm. Calculated dia-
(
1
2R,5R)-2-(Hydroxymethyl)-N-methyl-5-phenylmorpholine
(6f):
3
3
27 mg, 612 µmol, 61% yield; R = 0.20 (n-pentane/Et
f
2
O, 50:50).
23
1
stereomeric excess: 94%.
[α]
D
= –129.5 (c = 1.0 in CHCl
3
). H NMR (400 MHz, CDCl
3
): δ
=
1.92 (br. s, 1 H, OH), 2.07 (s, 3 H, NCH
3
), 2.21 (dd, J = 11.4,
Mosher Esters of 6e: (S)-Mosher ester: 12.6 mg, 27.9 µmol, 57%
1
(
6
0.9 Hz, 1 H, 3-H), 2.87 (dd, J = 11.5, 2.3 Hz, 1 H, 3-HЈ), 3.04
dd, J = 10.4, 3.4 Hz, 1 H, 5-H), 3.51 (dd, J = 11.5, 10.4 Hz, 1 H,
-H), 3.63 (br. dd, J = 11.4, 6.5 Hz, 1 H, CHHOH), 3.72 (br. d, J
11.4 Hz, 1 H, CHHOH), 3.80 (dd, J = 11.5, 3.5 Hz, 1 H, 6-HЈ),
19
yield. F NMR (376 MHz, CDCl
Mosher ester: 17.9 mg, 38.0 µmol, 96% yield. F NMR (376 MHz,
CDCl ): δ = –71.80 (s, CF ) ppm. Calculated diastereomeric excess:
7%.
3 3
): δ = –71.78 (s, CF ) ppm. (R)-
19
3
3
=
3
(
6
9
.86 (m, 1 H, 2-H), 7.25–7.40 (m, 5 H, Ph) ppm. 1 C NMR
100 MHz, CDCl ): δ = 43.8 (NCH ), 56.9 (C-3), 64.3 (CH OH),
9.0 (C-5), 73.1 (C-6), 76.6 (C-2), 128.0 (Ph), 128.6 (Ph), 128.7
3
Mosher Esters of 6g: (S)-Mosher ester: 16.3 mg, 34.5 µmol, 87%
3
3
2
1
9
yield. F NMR (376 MHz, CDCl
3 3
): δ = –71.65 (s, CF ) ppm. (R)-
1
9
Mosher ester: 16.1 mg, 34.1 µmol, 86% yield. F NMR (376 MHz,
(Ph), 139.0 (Ph) ppm. IR (KBr): ν˜ = 3404, 2949, 2850, 2792, 1451,
–1
CDCl ): δ = –71.69 (s, CF ) ppm. Calculated diastereomeric excess:
1121, 1056, 759, 702 cm . HRMS (ESI; MeCN/CHCl
3
, 1:1): calcd.
3
3
+
97%.
for [C12
H17NO
2
+ H] 208.1332; found 208.1336.
R)-N-Benzyl-2-(hydroxymethyl)-3,4-dihydro-2H-1,4-benzoxazine
6g): 178 mg, 697 µmol, 70% yield; 97% ee; R
(
(
f
= 0.20 (n-pentane/ Acknowledgments
O, 75:25). [α]2
): δ = 1.91 (t, J = 6.4 Hz, 1 H, OH), 3.28 (m, 2
OH), 4.29 (m, 1 H, 2-H), 4.44 (s,
3
= –14.3 (c = 0.10 in MeOH). 1H NMR
Et
400 MHz, CDCl
H, 3-H, 3-HЈ), 3.82 (m, 2 H, CH
H, CH Ph), 6.66 (m, 1 H, H-7), 6.71 (dd, J = 8.1, 1.5 Hz, 1 H,
H-8), 6.81 (m, 1 H, 6-H), 6.87 (dd, J = 7.9, 1.5 Hz, 1 H, 5-H),
2
D
(
3
This work was supported by the Deutsche Forschungsgemeinschaft
2
(
DFG) (Emmy Noether fellowship to M. B.) and the Fonds der
2
2
Chemischen Industrie. The technical assistance of Reiner Beringer
is acknowledged.
7
4
1
.23–7.34 (m, 5 H, Ph) ppm. 13C NMR (100 MHz, CDCl
8.4 (C-3), 55.1 (CH Ph), 63.6 (CH OH), 73.9 (C-2), 112.7 (C-8),
18.2 (C-7), 116.6 (C-5), 121.9 (C-6), 127.3 (Ph), 127.4 (Ph), 128.9
3
): δ =
2
2
[
1] R. Wijtmans, M. K. S. Vink, H. E. Schoemaker, F. L.
van Delft, R. H. Blaauw, F. P. J. T. Rutjes, Synthesis 2004, 641–
662.
(Ph), 135.3 (C-4a), 138.0 (Ph), 143.6 (C-8a) ppm. IR (KBr): ν˜ =
–
1
3393, 3031, 2923, 2852, 1605, 1504, 1245, 1221, 1049, 741 cm .
[
2] a) E. H. F. Wong, M. S. Sonders, S. G. Amara, P. M. Tinholt,
M. F. P. Piercey, W. P. Hoffmann, D. K. Hyslop, S. Franklin,
R. D. Porsolt, A. Bonsignori, N. Carfagna, R. A. McArthur,
Biol. Psychiatry 2000, 47, 818–829; b) H. Berzewski, M.
Van Moffaert, C. A. Gagiano, Eur. Neuropsychopharmacol.
+
HRMS (ESI; MeCN/CHCl
3 2
, 1:1): calcd. for [C16H17NO + H]
56.1332; found 256.1332. The ee of 6g was determined by 9F
1
2
NMR spectroscopy of the corresponding (S)- and (R)-Mosher es-
ters, as shown below.
1
997, 7, S37–S47.
(
2S,5R)-N-Benzyl-2-(hydroxymethyl)-5-phenylmorpholine (6k): Col-
orless solid, 205 mg, 723 µmol, 72% yield; R = 0.45 (n-pentane/
= –30.8 (c = 1.0 in CHCl ).
): δ = 2.49 (dd, J = 12.1, 4.0 Hz, 1 H,
-H), 2.83 (dd, J = 12.1, 2.7 Hz, 1 H, 3-HЈ), 2.91 (d, J = 13.4 Hz,
H, CHHPh), 2.99 (br. s, 1 H, OH), 3.51 (dd, J = 9.3, 3.8 Hz, 1
[
3] 2: a) J. Ong, D. I. B. Kerr, H. Bittiger, P. C. Waldmeier, P. A.
Baumann, N. G. Cooke, S. J. Mickel, W. Froestl, Eur. J. Pharm-
acol. 1998, 362, 27–34; 3: b) S. Kawashima, T. Matsuno, S.
Yaguchi, H. Sasahara, T. Watanabe, T. PCT Int. Appl.
WO 02088112, 2002; 4: c) R. A. Ancliff, C. M. Cook, C. D.
Eldred, P. M. Gore, L. A. Harrison, M. A. Hayes, S. T. Hodg-
son, D. B. Judd, S. E. Keeling, X. Q. Lewell, G. Mills, G. M.
Robertson, S. Swanson, A. J. Walker, M. Wilkinson, PCT Int.
Appl. WO 03082861, 2003; 5: d) S. Kato, T. Morie, T. Kon, N.
Yoshida, T. Karasawa, J. Matsumoto, J. Med. Chem. 1991, 34,
f
O, 25:75); m.p. 104–105 °C. [α]2
H NMR (400 MHz, CDCl
3
Et
2
D
3
1
3
3
1
H, 5-H), 3.73 (m, 2 H, 6-H, CHHOH), 3.75 (d, J = 13.4 Hz, 1 H,
CHHPh), 3.87 (m, 1 H, 2-H), 4.02 (dd, J = 11.6, 7.4 Hz, 1 H, 6-
HЈ), 4.20 (dd, J = 11.6, 7.4 Hz, 1 H, CHHOH), 7.20–7.40 (m, 8 H,
Ph), 7.46 (m, 2 H, Ph) ppm. 13C NMR (100 MHz, CDCl
): δ =
OH), 66.8 (C-5), 68.3 (C-6),
3.4 (C-2), 127.3 (Ph), 128.1 (Ph), 128.52 (Ph), 128.54 (Ph), 128.76
3
6
16–624.
5
7
(
2
1
+
2 2
1.7 (C-3), 59.3 (CH Ph), 63.7 (CH
[
[
4] For modifications of the 2-(hydroxymethyl) group in morph-
[5a,5b,9,11a]
olines of type 6, see refs.
Ph), 128.81 (Ph), 138.1 (Ph), 139.0 (Ph) ppm. IR (KBr): ν˜ = 3487,
5] For non-stereoselective syntheses of morpholines of type 6, see:
a) J. A. H. Lainton, M. C. Allen, M. Burton, S. Cameron,
T. R. G. Edwards, G. Harden, R. Hogg, W. Leung, S. Miller,
J. J. Morrish, S. M. Rooke, B. Wendt, J. Comb. Chem. 2003, 5,
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4
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www.eurjoc.org
2105

M. Breuning, M. Winnacker, M. Steiner
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Received: November 21, 2006
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Published Online: March 9, 2007
2106
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Eur. J. Org. Chem. 2007, 2100–2106