Iron-Catalyzed Diastereoselective Synthesis of Disubstituted Morpholines via C-O or C-N Bond Formation

Article abstract of DOI:10.1055/s-0040-1707902

The diastereoselective synthesis of 2,6- and 3,5-disubstituted morpholines was achieved from 1,2-amino ethers and 1,2-hydroxy amines substituted by an allylic alcohol using an iron(III) catalyst. The morpholines were obtained either by C-O or C-N bond formation. A plausible mechanism is suggested, involving a thermodynamic equilibrium to explain the formation of the cis diastereoisomer as the major product.

Full text of DOI:10.1055/s-0040-1707902

SYNLETT
0
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6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2020, 31, A–G
cluster
A
en
Synlett
T. Aubineau et al.
Cluster
Iron-Catalyzed Diastereoselective Synthesis of Disubstituted
Morpholines via C–O or C–N Bond Formation
Thomas Aubineau
Alexandre Dupas
Tian Zeng
0
0
0
0-0
0
0
1-8
4
4
3-
8
0
5
8
Ts
N
Ts
N
Fe(III) cat.
R2
R2
HO
OH
O
Janine Cossy*
0
0
0
0-0
0
0
1-8
7
4
6-9
2
3
9
R1
R1
(
60–97%)
cis/trans up to 95:5
Molecular, Macromolecular Chemistry and Materials, ESPCI Paris,
PSL University, CNRS, 10 Rue Vauquelin, 75005 Paris, France
janine.cossy@espci.fr
Ph
OH
Ph
Ts
Ts
HN
R3
Fe(III) cat.
N
R3
In expression of our deepest gratitude to Prof. Barry M. Trost.
O
O
Published as part of the Cluster The Power of Transition Metals: An
Unending Well-Spring of New Reactivity
cis/trans up to 93:7
(60–81%)
R1 = Ph, Me, H; R2 = H, alkyl, vinyl, CF3, Het(Ar)
R3 = H, alkyl, aryl
Received: 28.04.2020
Accepted after revision: 23.06.2020
Published online: 23.07.2020
In the context of our studies concerning the use of iron
salts for the diastereoselective synthesis of disubstituted
heterocycles by activation of allylic alcohols, we have envi-
9
DOI: 10.1055/s-0040-1707902; Art ID: St-2020-b0236-c
sioned that iron salts like iron trichloride could also induce
the formation of disubstituted morpholines F and H from
the corresponding substituted amino alcohols E and G
Abstract The diastereoselective synthesis of 2,6- and 3,5-disubstitut-
ed morpholines was achieved from 1,2-amino ethers and 1,2-hydroxy
amines substituted by an allylic alcohol using an iron(III) catalyst. The
morpholines were obtained either by C–O or C–N bond formation. A
plausible mechanism is suggested, involving a thermodynamic equilib-
rium to explain the formation of the cis diastereoisomer as the major
product.
(Scheme 1)
Previous work:
Ts
N
Ts
N
Key words morpholine, iron, diastereoselective, thermodynamic
equilibrium
OH
OH
PdCl2(PPh3)2 (5 mol%)
R
R
toluene, 90 °C
Saikia et al.7
(70–90%)
HO
O
A
B
Nitrogen- and oxygen-containing heterocycles are pres-
ent in a great diversity of compounds. Morpholine, which
contains these two heteroatoms, has a high industrial im-
portance and a wide range of applications from rubber ad-
Ts
N
Ts
N
R
R
[(Au2Cl2)dppf]/AgOTf (2.5 mol%)
toluene/CH2Cl2, rt
Bandini et al.8
HO
O
1
ditives to optical brighteners. Moreover, the morpholine
(55–98%)
C
D
scaffold is frequently encountered in biologically active
2
This work:
Ts
compounds. Therefore, a variety of methods has been de-
3
Ts
N
veloped to access this heterocycle, such as the use of vinyl
N
4
sulfonium salts along with amino alcohols, the ring-open-
[Fe] cat.
5
ing of epoxides or aziridines, or the electrochemical activa-
HO
R2
O
R2
6
tion of C=C double bonds. In the field of metal-catalyzed
R1
R1
OH
3f
synthesis of morpholines, several strategies have been de-
veloped depending on which bond is constructed (i.e. C–N,
C–O, or C–C bond). In particular, the formation of the C–O
bond by activation of allylic alcohols have attracted our in-
terest. For example, Saikia et al. have described the diaste-
reoselective synthesis of cis-2,6-disubstituted morpholines
B via the activation of (Z)-allylic alcohols A using a Pd(II)
catalyst, followed by the intramolecular addition of an alco-
E
F
R3 OH
R3
Ts
N
Ts
HN
R4
[Fe] cat.
R4
O
O
G
H
Scheme 1 Metal-catalyzed activation of allylic alcohols to access
disubstituted morpholines
7
hol. Bandini et al. reported a similar transformation, with
8
the help of a cationic gold catalyst, starting from C.
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–G
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synlett
T. Aubineau et al.
Cluster
The synthesis of the amino allylic alcohols 6a–i, precur-
sors of 2,6-disubtituted morpholines F, was achieved from
the commercially available amino acetaldehyde dimethyl
acetal 1 according to the sequence depicted in Scheme 2.
After protection of the amine with a tosyl group, the sulfon-
amide 2 was transformed into the propargyl amine 3 in 95%
yield (propargyl bromide, K CO , acetone, reflux), which
Ts
HN
R4
R4
propargyl alcohol (1.5 equiv)
Ts
N
t-BuOK (1.5 equiv)
DMSO, rt
(39% to quant.)
O
7a–d
8a–d
1
) n-BuLi (2.1 equiv)
THF, 0 °C, 1 h
) PhCHO, THF, rt, 1 h
2
2
3
(63–93%)
was then used as a platform to access a diversity of amino
Ph
OH
Ts
OH
Ph
allylic alcohols 6. Deprotonation of the acetylenic moiety
Ts
HN
1
R4
LiAlH4 (3 equiv)
THF, 0 °C-rt
R4
(
n-BuLi, THF) and addition of an aldehyde (R = Ph, Me, H)
HN
led to the corresponding propargylic alcohols 4a–c. Cleav-
age of the acetal moiety under acidic conditions (PTSA,
O
O
10a–d
9a–d
(40–66%)
100 °C) led to an aldehyde intermediate, which was trans-
R4 = H, n-C6H13, i-Pr, Ph
formed by addition of a nucleophile into different second-
ary alcohols 5a–i. Finally, the partial reduction of the acety-
Scheme 3 Synthesis of the 3,5-disubstituted morpholines precursors
lenic bond (LiAlH , THF, 0 °C to rt) gave the desired allylic
4
alcohols 6a–i. (Scheme 2)
Ts
N
Ts
N
FeCl3·6H2O (5 mol%)
CH Cl , rt, 15 min
Ts
HN
Ts
N
H2N
TsCl (1.2 equiv)
Et3N (3 equiv)
propargyl bromide
(1.8 equiv)
HO
2
2
O
Ph
OH
6a
Ph
MeO
OMe
CH2Cl2
MeO
OMe K2CO3 (3 equiv)
acetone, reflux
O
O
77%
11a
Me Me
1
quant.
2
95%
3
Scheme 4 Iron-catalyzed heterocyclization – formation of the C–O bond
1
) n-BuLi (2.2 equiv)
THF
) R CHO (1.2 equiv)
1
was obtained as a mixture of two diastereoisomers
2
(
cis/trans = 54:46; Table 1, entry 1). The same ratio was ob-
Ts
Ts
N
1) PTSA (1 equiv)
MeCN/H2O
Ts
N
tained with an increased catalyst loading (10 mol%) and an
extended reaction time (48 h), while morpholine 11b was
isolated in good yield (81%; entry 2). The temperature of
the reaction was found to be a critical parameter. Indeed,
heating the reaction mixture up to 50 °C led to a great im-
provement of the diastereoisomeric outcome. After 15 min
at 50 °C, the cis/trans ratio was 60:40 and, after 2 h, the cis
diastereoisomer was obtained as the major product
(cis/trans = 94:6; entries 3 and 4). Under the same condi-
tions, other Lewis or Brønsted acids led to either low diaste-
reoselectivity or the degradation of the products. For exam-
ple, bismuth(III) triflate and indium(III) chloride efficiently
catalyze the cyclization, but, in each case, the morpholine
N
LiAlH4 (3 equiv)
R2 THF, 0 °C to rt
100 °C
HO
O
H
R2
2)
R2 (2.5 equiv)
O
O
THF, rt
15–55%
Me Me
R1 OH
4a–c
R1
OH
a–i
20–61%
R1 OH
6
5a–i
R1 = Ph, Me, H
2
R
= H, n-C6H13, iPr, Ph, vinyl, CF3, 2-furyl
Scheme 2 Synthesis of the 2,6-disubstituted morpholines precursors
A second strategy was employed for the synthesis of
amino allylic alcohols 10a–d precursors of 3,5-disubstitut-
ed morpholines H. Propargyl ethers 8a–d were obtained by
the regioselective opening of monosubstituted aziridines
was formed as
a mixture of two diastereoisomers
7
a–d by the propargylic alcohol in DMSO under basic con-
(cis/trans = 64:36 and 54:46, respectively; entries 5 and 6).
Palladium(II) acetate was, for its part, found to be totally in-
efficient in this transformation (entry 7). Brønsted acids
10
ditions (t-BuOK, DMSO). The terminal triple bond was
then functionalized by addition of the lithium acetylide on
the benzaldehyde. The resultant propargyl alcohols 9a–d
were also tested. While the use of HCl in Et O led to the for-
2
were partially reduced, as previously, by LiAlH to the cor-
responding allylic alcohols 10a–d (Scheme 3).
mation of the 2,6-disubstitued morpholines albeit with no
diastereoselectivity (entry 8), the use of triflic acid (TfOH)
led to the complete degradation of the starting material
(entry 9).
4
In order to test the heterocyclization, 6a was treated
with FeCl ·6H O (5 mol%) in CH Cl at room temperature.
3
2
2
2
After only 15 minutes, full conversion of 6a was observed,
and the monosubstituted morpholine 11a was isolated in
good yield (77%) (Scheme 4).
The optimized conditions were then applied to the pre-
viously synthesized amino alcohols 6 in order to access a
diversity of 2,6-disubstituted morpholines. The isopropyl-
substituted substrate 6c led to the corresponding morpho-
line 11c with a good yield of 77% and a high dr in favor of
the cis diastereoisomer (cis/trans = 94:6). Similarly, the tri-
fluoromethylated morpholine 11d was isolated with a yield
To evaluate the diastereoselectivity, the hexyl-substitut-
ed N-tethered amino alcohol 6b was first chosen for the op-
timization of the reaction conditions. When 6b was treated
with 5 mol% of FeCl ·6H O (CH Cl , 24 h) morpholine 11b
3
2
2
2
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

C
Synlett
T. Aubineau et al.
Cluster
Table 1 Optimization of the Reaction Conditions to Access 2,6-Disub-
stuted Morpholines
substrate 6f led to 11f with
a
high yield of 89%
a
(
cis/trans = 95:5). Interestingly, a furyl-substituted mor-
pholine 11g can also be obtained. As the furyl group tends
to polymerize under the reaction conditions, the reaction
was stopped after only 30 min, which may explain the low
dr of 11g (cis/trans = 60:40) (Scheme 5).
The enantioenriched amino alcohol (R)-6f was also in-
volved in the heterocyclization. After 2 h at 50 °C, the enan-
Ts
N
Ts
N
Lewis acid
x mol%)
(
HO
OH
n-C6H13
CH2Cl2, T, t
O
n-C6H13
Ph
Ph
11
6b
11b
tioenriched morpholine (2S,6R)-11f was obtained with an
Entry Lewis acid
x (mol%) Time (h) Temp ( °C) Yield (%) cis/transb
excellent yield of 89%,
a
high diastereoselectivity
1
2
3
4
5
6
7
8
FeCl
3
·6H
2
O
5
10
10
10
10
10
10
10
10
24
48
rt
n.d.c
81
54:46
54:46
60:40
94:6
64:36
54:46
–
(cis/trans = 95:5) and a high ee of 95% (cis diastereoiso-
mer).12 This result shows that the stereocenter of 6f is re-
covered in 11f and that the configuration of the C2 stereo-
center is induced by the configuration of the C6 center
rt
0.25
50
n.d.
82
2
2
2
2
2
2
(Scheme 6).
Bi(OTf)
InCl
3
50
50
69
Ts
N
Ts
N
3
73
Pd(OAc)
HCle
2
–d
R
R
FeCl3·6H2O (10 mol%)
CH2Cl2, 50 °C, 2 h
S
HO
2
O
6
79
51:49
–
–f
Ph
OH
R)-6f
Ph
9
TfOH
(
89%
(2S,6R)-11f
a
(cis/trans = 95:5)
2 2
Compound 6b was dissolved in CH Cl in a tube. The Lewis acid was added
(ee = 95%)
to the solution, the tube was sealed, and the mixture stirred at rt or 50 °C
during the specified time.
Scheme 6 Formation of an enantioenriched morpholine
b
1
The dr was measured by H NMR spectroscopy of the crude reaction mix-
ture after a short filtration through a plug of silica to remove the iron salts,
and eluted with CH
2
Cl
2
.
c
Not determined.
No conversion.
To evaluate the importance of the substituent of the al-
d
1
1
e
lylic alcohol, 6h (R = Me) and 6i (R = H) were also treated
with FeCl ·6H O. In dichloromethane at 50 °C for 2 h, 6h
HCl in Et
2
O.
f
Degradation of the starting material.
3
2
was transformed to the corresponding morpholine 11h
with a good yield of 80%, however, without any diastereose-
lectivity (cis/trans = 50:50; Table 2, entry 1). The reaction
medium had to be heated up to 100 °C in dichloroethane
(DCE), in a sealed tube, to obtain an excellent yield in 11h
(97%) and a cis/trans ratio of 92:8 in favor of the cis diaste-
reoisomer (entry 2). Compound 6i, incorporating a primary
allylic alcohol, was subjected to similar conditions. At 50 °C
in CH Cl , no cyclization occurred. At 100 °C in DCE the vi-
of 75% and
a
slightly lower dr than for 11c
(
cis/trans = 90:10). The presence of a vinyl moiety has no
influence on the reaction, as 11e was obtained in 80% yield
with a cis/trans ratio of 92:8, while the phenyl-substituted
Ts
N
Ts
N
FeCl3·6H2O (10 mol%)
CH Cl , 50 °C, 2 h
2
2
HO
R2
2
2
O
R2
Ph
OH
c–g
Ph
Table 2 Influence of the Allylic Substitution
6
11c–g
(
yield, cis/trans)
Ts
Ts
N
N
Ts
Ts
N
FeCl3·6H2O (10 mol%)
N
HO
R1 OH
6h, R1 = Me
i, R1 = H
n-C6H13
solvent, T, 2 h
O
n-C6H13
O
O
CF3
R1
11h, R1 = Me
11i, R1 = H
Ph
Ph
1
1c
11d
6
(
77%, cis/trans = 94:6)
(75%, cis/trans = 90:10)
Ts
N
Ts
Ts
Entry
R1
Me
Solvent
CH Cl
Temp ( °C)
Yield (%)
cis/trans
N
N
O
O
1
2
3
50
100
50
80
97
0a
50:50
92:8
–
2
2
O
O
C
2
H
4
Cl
Cl
Cl
2
Ph
Ph
Ph
11e
11f
11g
H
CH
2
2
(
80%, cis/trans = 92:8) (89%, cis/trans = 95:5)
(60%, cis/trans = 60:40)
4
C
2
H
4
2
100
50
50:50
Scheme 5 FeCl ·6H O-catalyzed synthesis of cis-2,6-disubstituted
3
2
a
morpholines
No conversion of 6i.
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

D
Synlett
T. Aubineau et al.
Cluster
nyl-substituted morpholine 11i was isolated with a modest
yield of 50% but without any diastereoselectivity (entries 3
and 4). These results show that a stabilizing electron-do-
nating group favors the heterocyclization and is mandatory
to induce a good diastereoselectivity (vide infra).
Table 3 Optimization of the Reaction Conditions for the Synthesis of
3
,5-Disubstituted Morpholinesa
OH
Ph
Ph
Ts
Ts
N
HN
n-C6H13
Lewis acid
x mol%)
n-C6H13
(
Having demonstrated the efficiency of FeCl as a catalyst
3
O
CH2Cl2, T, t
O
for the formation of 2,6-disubstituted morpholines, we hy-
pothesized that similar conditions could be applied to ade-
quate substrates to lead to 3,5-disubstituted morpholines.
In the same manner as before, the unsubstituted amino
ether 10a was treated with a catalytic amount of FeCl ·6H O
1
0b
12b
Entry Lewis acid
x (mol%) Time (h) Temp ( °C) Yield (%) cis/transb
1
2
3
4
5
6
7
8
9
FeCl
3
·6H
2
O
5
5
2
168
168
30
rt
75
75
76
75
36:64
52:48
83:17
90:10
90:10
90:10
90:10
90:10
36:64
–
3
2
rt
(
5 mol%) in CH Cl , at room temperature. After 15 min, the
2 2
10
10
10
10
10
10
10
10
10
rt
monosubstituted morpholine 12a was isolated with a good
yield of 81% (Scheme 7).
30
40
40
50
40
40
40
40
1
77
OH
Ph
Ph
n.d.c
2.5
Ts
Ts
N
HN
FeCl ·6H O (5 mol%)
n.d.c
3
2
1
2
2
2
2
CH2Cl2, rt, 15 min
81%
O
O
12a
Bi(OTf)
InCl
3
70
10a
3
35
Scheme 7 Iron-catalyzed heterocyclization: formation of the C–N bond
–d
10
PdCl
HCle
2
11
16f
36:64
a
2 2
Compound 10b was dissolved in CH Cl in a tube. The Lewis acid was add-
Compound 10b was chosen for the optimization of the
reaction conditions. The amino ether was first treated with
ed to the solution, the tube was sealed, and the mixture stirred at rt or
5
0 °C during the specified time.
The dr was measured by H NMR spectroscopy of the crude reaction mix-
b
1
5
mol% of FeCl ·H O in CH Cl (rt, 2 h). Although the expect-
ture after a short filtration through a plug of silica plug to remove the iron
3
2
2
2
salts and eluted with CH
2
Cl
2
.
ed morpholine was isolated in 75% yield, analysis of the
c
Not determined.
1
crude reaction mixture by H NMR spectroscopy showed an
d
e
f
No conversion.
HCl in Et O.
Partial degradation of the starting material or of the product.
unexpected cis/trans ratio of 36:64 (Table 3, entry 1). When
the reaction was run for 168 h, the dr slowly evolved to
reach a 1 to 1 ratio of diastereoisomers (cis/trans = 52:48;
entry 2). Increasing the catalyst loading to 10 mol% resulted
in an improvement of the dr, as morpholine 12b was isolat-
ed as an 83:17 mixture of cis and trans diastereoisomers af-
ter 168 h (entry 3). Once again, the temperature was found
to be of importance for the outcome of the cyclization.
When 10b was treated with 10 mol% of FeCl ·6H O, in
2
phenyl group led, for its part, to the corresponding mor-
pholine 12d in 70% yield (cis/trans = 83:17). Finally, the ,-
dimethyl amino ether 10e led to the 3,5,5-trisubstituted
morpholine 12e with a modest yield of 60%, probably be-
cause of the steric hindrance next to the nitrogen (Scheme 8).
3
2
OH
Ph
Ph
CH Cl at 30 °C for 30 h, a similar yield in morpholine was
2
2
Ts
Ts
N
HN
R3
R3
observed (75%) and the dr went up to 90:10 in favor of the
cis compound (entry 4). At 40 °C, it took only 1 h to reach
the full conversion of 10b, and the 3,5-disubstituted morpho-
line 12b was formed with a good yield of 77% and with a
good dr (cis/trans = 90:10; entry 5). It is worth noting that
by further increasing of the temperature, a degradation of
the morpholine was observed, without any change in the dr
FeCl3·6H2O (10 mol%)
CH2Cl2, 40 °C, 2 h
O
O
10c–e
12c–e
Ph
Ph
Ts
Ph
Ts
N
Ts
N
Me
iPr
N
Ph
Me
O
O
O
(
entries 6 and 7).13 Other Lewis or Brønsted acids were also
examined for this heterocyclization, but none of them gave
as good results as iron trichloride (entries 8–11).
1
2c
12d
12e
60%)
(78%, cis/trans = 93:7) (70%, cis/trans = 83:17)
(
Scheme 8 FeCl ·6H O-catalyzed synthesis of cis-3,5-disubstituted
3
2
The optimized conditions were next applied to the pre-
viously synthesized amino ethers 10c–e. When 10c, substi-
tuted by an isopropyl group was subjected to the heterocy-
clization, the corresponding 3,5-disubstituted morpholine
morpholines
During the optimization process, it has been highlighted
that the dr evolves with time, suggesting an equilibration
process (Table 1, entries 3 and 4; Table 3 entries 1 and 2).
The results obtained with substrates 6h and 6i, bearing dif-
ferent substituents at the allylic position, suggest that the
12c was isolated with a good yield (78%) and a good dr
(
cis/trans = 93:7). The amino ether 10d, incorporating a
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

E
Synlett
T. Aubineau et al.
Cluster
Ts
N
O
R2
Ts
N
Ts
N
Ts
N
Ph
trans-F
[Fe]
R2
R2
R2
Ts
N
HO
OH
HO
O
–
H2O
[
Fe]
Ph
Ph
O
H
Ph
[Fe]
O
R2
E
I
J
Ph
Ph
cis-F
Ts
N
R4
[Fe]
H
OH
O
[Fe]
O
Ph
Ph
R4 [Fe]
Ph
Ts
Ts
Ts
R4
N
R4
trans-H
HN
HN
–
H2O
Ph
O
O
O
Ts
N
R4
G
K
L
O
cis-H
Scheme 9 Plausible mechanisms for the iron-catalyzed heterocyclization
presence of an electron-donating group is required to pro-
duce morpholines in good yields and diastereoselectivity
isomer. Indeed, in the trans diastereoisomer, one of the two
substituents has to be axial, thus generating unfavorable
1,3-diaxial interactions with the hydrogen at C6 (Scheme 10).
(Table 2). Thus, it may be hypothesized that the cyclization
process proceeds through a carbocation. From our previous
results in iron-catalyzed heterocycle synthesis, the follow-
ing mechanism could be proposed for both the 2,6- and the
9
R2
O
H 6
R26
6
[Fe]
O
O
Ph
Ph
or
H
N Ts
N Ts
N Ts
2
2
R2
2
3,5-disubstitued morpholines. The activation of the allylic
H
H
H
H
alcohols E and G by FeCl could promote the loss of water
3
cis-F
favored
trans-F
disfavored
Ph
and the formation of a delocalized carbocation (J and L),
stabilized by the substituent of the allylic alcohol. The in-
tramolecular attack of the oxygen or the nitrogen would
lead to the morpholines F and H, respectively, as a mixture
of cis and trans diastereoisomers. At this point, an iron-in-
duced thermodynamic equilibrium could take place, by a
ring-opening/ring-closing process, toward the formation of
the more stable cis diastereoisomer. This equilibrium would
be even easier if the carbocation is stabilized by an elec-
tron-donating group, explaining why a better diastereose-
lectivity is observed when starting from benzylic allylic al-
cohols rather than methyl- or unsubstituted allylic alcohols
1,3-diaxial interactions
Scheme 10 Relative stability of cis and trans diastereoisomers in 2,6-
disubstituted morpholines
Regarding the 3,5-disubtituted morpholine H, a similar
reasoning can be applied. However, the presence of the N-
tosyl group has to be considered (Scheme 11). Indeed, it has
been described that the N–S bond in sulfonamides has a
partial double bond character.1 Crystallographic data pre-
viously obtained for 2,6-disubstituted N-tosyl piperidines
4a
also suggest that the SO moiety is in an equatorial posi-
2
tion.1 Therefore, substituents  to the nitrogen may pro-
mote 1,3-allylic interactions with the N-tolyl group if they
stand in an equatorial position.15 For this reason, a cis diaxi-
al diastereoisomer would be more stable than a trans one,
4b
(Scheme 9).
To explain why the cis diastereoisomer is always pre-
dominant after the thermodynamic equilibrium, the rela-
tive stability of each of the two diastereoisomers has to be
compared, regarding the spatial orientation of their substit-
uents. In the case of the 2,6-disubstituted morpholines F,
the cis diastereoisomer, whose two substituents stand in an
equatorial position, is more stable than the trans diastereo-
3
in spite of diaxial interactions between the R group at C5
and the styrenyl group at C3. Actually, this steric interac-
tion may be the cause of the lower dr observed for 3,5-
compared to 2,6-disubstituted morpholines as the differ-
ence in energy between the two diastereoisomers may be
smaller.
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

F
Synlett
T. Aubineau et al.
Cluster
1,3-diaxial interaction
Ph
H
Mg (10 equiv)
MeOH, ))), 1 h
N
n-C6H13
Ph
Ph
R3
5
R3
5
[Fe]
H
H5
Ph
O
O
O
R3
Ts
N
O
or
66%
15
N
Ts
N
Ts
N
Ts
6 13
n-C H
3
3
3
(cis/trans = 91:9)
cis-H
favored
trans-H
disfavored
Ph
O
1
) OsO4 (20 mol%), NMO
t-BuOH/H2O, then
NaIO4 (5 equiv), H2O/Et2O
1
2b
Ts
(
cis/trans = 90:10)
1,3-allylic interaction
N
n-C6H13
HO
2) NaBH4 (3 equiv), EtOH
Scheme 11 Relative stability of cis and trans diastereoisomers in 3,5-
disubstituted morpholines
O
67%
16
(
cis/trans = 90:10)
Postfunctionalization of the synthesized 2,6-disubsti-
tuted morpholines 11 was then envisaged. The amino moi-
ety in 11b can be deprotected with magnesium powder un-
der ultrasonic activation leading to morpholine 13 in
good yield (88%). It is worth noting that the dr remains in-
tact during this process. The styrenic double bond can also
be transformed to introduce a new substituent on the mor-
pholine ring. Oxidative cleavage under classical conditions
Scheme 13 Synthetic transformations of the 3,5-disubstituted mor-
pholine 12b
16
equilibrium occurring by a ring-opening/ring-closing pro-
cess.19 Post-transformations of the obtained morpholines
were also achieved, showing that they can be used as a plat-
form to access libraries of complex molecules.
(
OsO , NMO then NaIO ) followed by the reduction of the
4
4
Supporting Information
subsequent aldehyde (NaBH , EtOH) led to the primary al-
4
cohol 14 with an excellent yield (82% from 11b; Scheme
Supporting information for this article is available online at
17
12).
https://doi.org/10.1055/s-0036-1707902.
S
u
p
p
orit
n
g Inform ati
o
n
S
u
p
p
orit
n
g Inform ati
o
n
H
N
References and Notes
Mg (10 equiv)
MeOH, ))), 1 h
(
1) Mjos, K. In Kirk-Othmer Encyclopaedia of Chemical Technology,
3rd ed., Vol. 2; Wiley Interscience: New York, 1978, 295–308.
(2) Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014, 57,
0257.
O
n-C6H13
Ts
N
Ph
(
13
88%
cis/trans = 95:5)
1
O
n-C6H13
(3) For reviews on the synthesis of morpholines and derivatives,
see: (a) Pal’chikov, V. A. Russ. J. Org. Chem. 2013, 49, 787.
(b) Wijtmans, R.; Vink, M.. K. S.; Schoemaker, H. E.; van Delft, F.
L.; Blaauw, R. H.; Rutjes, F. P. J. T. Synthesis 2004, 641.
1
) OsO4 (20 mol%), NMO
Ts
N
Ph
(
11b
t-BuOH/H O, then
2
cis/trans = 94:6)
NaIO4 (5 equiv), H2O/Et2O
HO
2
) NaBH4 (3 equiv), EtOH
O
n-C6H13
(
(
c) Trstenjak, U.; Ilaš, J.; Kikelj, D. Synthesis 2012, 44, 3551.
d) Varela, J.; Saá, C. Synthesis 2016, 48, 3470. (e) Palchykov, V.
82%
14
Scheme 12 Synthetic transformations of the 2,6-disubstituted mor-
pholine 11b
A.; Chebanov, V. A. Chem. Heterocycl. Compd. 2019, 55, 324.
f) Aubineau, T.; Cossy, J. Chem. Eur. J. 2019, 46, 7513. (g) Tzara,
A.; Xanthopoulos, D.; Kourounakis, A. P. ChemMedChem 2020,
5, 392.
(
1
Similarly, 3,5-disubstituted morpholines can be post-
functionalized. The amino group in 12b can be deprotected
using the same conditions as before (Mg, MeOH, ultra-
sound) to produce the secondary amine 15 in 66% yield
(
4) Yar, M.; Fritz, S. P.; Gates, P. J.; McGarrigle, E. M.; Aggarwal, V. K.
Eur. J. Org. Chem. 2012, 160.
(5) (a) Jiao, P.-F.; Zhao, B.-X.; Wang, W.-W.; He, Q.-X.; Wan, M.-S.;
Shin, D.-S.; Miao, J.-Y. Bioorg. Med. Chem. Lett. 2006, 16, 2862.
(b) Wang, L.; Liu, Q.-B.; Wang, D.-S.; Li, X.; Han, X.-W.; Xiao, W.-
J.; Zhou, Y.-G. Org. Lett. 2009, 11, 1119.
6) Claraz, A.; Courant, T.; Masson, G. Org. Lett. 2020, 22, 1580.
7) Borah, M.; Borthakur, U.; Saikia, A. K. J. Org. Chem. 2017, 82,
cis/trans = 91:9).18 The styrenyl moiety can also be cleaved
(
under oxidative conditions (OsO , NMO then NaIO ) and the
4
4
(
(
primary alcohol 16 was obtained after reduction of the re-
sulting aldehyde (NaBH , EtOH) with a yield of 67% (from
4
1330.
12b) and with an unchanged cis/trans ratio of 90:10
(
8) Bandini, M.; Monari, M.; Romanello, A.; Tragni, M. Chem. Eur. J.
(
Scheme 13).
2010, 16, 14272.
Iron trichloride has been successfully used for the syn-
(9) Cornil, J.; Gonnard, L.; Bensoussan, C.; Serra-Muns, A.; Gnamm,
C.; Commandeur, C.; Commandeur, M.; Reymond, S.; Guérinot,
A.; Cossy, J. Acc. Chem. Res. 2015, 48, 761.
thesis of both 2,6- and 3,5-disubtituted morpholines by
promoting the formation of either a C–O or a C–N bond.
This catalyst constitutes a cheap and environmentally be-
nign alternative to palladium and gold catalysts. In each
case, the substituted morpholines were isolated mostly as
cis diastereoisomers, as the result of a thermodynamic
(
10) Nyasse, B.; Grehn, L.; Ragnarsson, U. Chem. Commun. 1997, 11,
1
017.
11) See the Supporting Information for the synthesis of substrate
R)-6f.
(
(
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

G
Synlett
T. Aubineau et al.
Cluster
(
12) The ee has been measured by chiral SFC of the 2-hydroxymeth-
the morpholine which was in most cases recovered as a pure
product. Purification by flash chromatography on silica gel was
performed if needed.
ylenic morpholine obtained after oxidative cleavage of the sty-
renic moiety.
(13) Attempts to favor the formation of the trans diastereoisomer at
temperature lower than rt were unsuccessful.
cis-(E)-2-Isopropyl-6-styryl-4-tosylmorpholine (10c)
1
H NMR (400 MHz, CDCl ):  = 7.64 (d, J = 8.1 Hz, 2 H), 7.40–7.18
3
(14) (a) Modaressi-Alam, A. R.; Amirazizi, H. A.; Bagheri, H.;
Bijanzadeh, H.-R.; Kleinpeter, E. J. Org. Chem. 2009, 74, 4740.
(m, 7 H), 6.73–6.59 (m, 1 H), 6.06 (dd, J = 16.1, 5.6 Hz, 1 H),
4.29–4.19 (m, 1 H), 3.68 (dapp, J = 11.3 Hz, 2 H), 3.41–3.29 (m, 1
(
b) Guérinot, A.; Serra-Muns, A.; Gnamm, C.; Bensoussan, C.;
H), 2.43 (s, 3 H), 2.05 (dd , J = 21.7, 10.8 Hz, 2 H), 1.77–1.65 (m,
app
Reymond, S.; Cossy, J. Org. Lett. 2010, 12, 1808; the possibility
to have the SO2 group in an axial position cannot be totally
ruled out.
1 H), 0.98 (d, J = 6.8 Hz, 3 H), 0.93 (d, J = 6.8 Hz, 3 H). 13C NMR
(100 MHz, CDCl ):  = 143.9, 136.3, 132.3, 132.1, 129.8 (2 C),
3
128.6 (2 C), 128.0, 127.8 (2 C), 126.6 (2 C), 126.1, 80.1, 75.6,
(
15) This has been observed on piperidines substrates. See for exam-
50.0, 47.7, 31.6, 21.6, 18.6, 18.4. MS (EI, 70 eV): m/z (abundance)
= 385 (3, M ), 281 (14), 230 (29), 130 (16), 129 (12), 115 (10),
+
•
ple: (a) Cariou, C. A. M.; Snaith, J. S. Org. Biomol. Chem. 2006, 4,
5
1. (b) Toumieux, S.; Compain, P.; Martin, O. R.; Selkti, M. Org.
98 (100), 91 (30), 69 (16), 56 (16). HRMS: m/z calcd for C22H28
-
+
Lett. 2006, 8, 4493. (c) Kishore Vandavasi, J.; Hu, W.-P.; Chandru
Senadi, G.; Chen, H.-T.; Chen, H.-Y.; Hsieh, K.-C.; Wang, J.-J. Adv.
Synth. Catal. 2015, 357, 2788.
NO S [M + H] : 386.1784; found: 386.1789.
3
cis-(E)-3-Isopropyl-5-styryl-4-tosylmorpholine (12c)
1
H NMR (400 MHz, CDCl ):  = 7.76 (d, J = 8.2 Hz, 2 H), 7.38–7.19
3
(
16) Nyasse, B.; Grehn, L.; Ragnarsson, U. Chem. Commun. 1997, 11,
(m, 7 H), 6.67 (dd, J = 16.2, 1 H), 6.56–6.41 (m, 1 H), 4.45–4.35
(m, 1 H), 3.92 (d, J = 11.8 Hz, 1 H), 3.87 (d, J = 12.0 Hz, 1 H), 3.38
(dd, J = 10.9, 3.4 Hz, 1 H), 3.20 (dd, J = 11.9, 4.0 Hz, 1 H), 3.11
(dd, J = 12.0, 3.6 Hz, 1 H), 2.43 (s, 3 H), 2.32–2.23 (m, 1 H), 1.05
1017.
(17) The cis/trans ratio could not be measured because of overlap-
1
ping signals in the H NMR spectrum.
13
(
(
18) Measured by GC/MS analysis of the crude mixture.
19) Experimental Procedure for the Synthesis of 2,6- or 3,5-
Disubstituted Morpholines
(d, J = 6.7 Hz, 3 H), 0.94 (d, J = 6.7 Hz, 3 H). C NMR (100 MHz,
CDCl ):  = 143.4, 138.7, 136.6, 132.8, 130.0 (2 C), 128.7 (2 C),
3
127.9, 127.7, 127.0 (2 C), 126.5 (2 C), 69.1, 66.6, 59.6, 52.9, 28.4,
21.6, 20.6, 20.2. MS (EI, 70 eV): m/z (abundance) = 342 (23), 268
(19), 187 (11), 171 (16), 156 (12), 155 (37), 130 (16), 129 (26),
In a tube was added the amino alcohol in CH Cl . FeCl ·6H 0 was
2
2
3
2
then added to the solution, the tube was sealed, and the
mixture was heated at the specified temperature for 1–2 h.
After cooling, the suspension was filtered through a short plug
of silica gel, and elution was achieved with CH Cl to remove the
128 (11), 117 (33), 115 (27), 91 (100), 69 (14), 65 (15). HRMS:
+
m/z calcd for C22H27NNaO S [M + Na] : 408.1604; found:
3
408.1606.
2
2
iron salts. The filtrate was concentrated under vacuum to afford
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–G