A One-Pot Reaction toward the Diastereoselective Synthesis of Substituted Morpholines

Article abstract of DOI:10.1021/acs.orglett.8b03141

The diastereoselective synthesis of various substituted morpholines has been achieved from vinyloxiranes and amino-alcohols under sequential Pd(0)-catalyzed Tsuji-Trost/Fe(III)-catalyzed heterocyclization. Using the same strategy, 2,6-, 2,5-, and 2,3-disubstituted as well as 2,5,6- and 2,3,5-trisubstituted morpholines were obtained in good to excellent yields and diastereoselectivities.

Full text of DOI:10.1021/acs.orglett.8b03141

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A One-Pot Reaction toward the Diastereoselective Synthesis of
Substituted Morpholines
Thomas Aubineau and Janine Cossy*
Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI) - UMR 8231, ESPCI Paris, CNRS, PSL
University, 10 rue Vauquelin, 75231 Paris Cedex 05, France
S
* Supporting Information
ABSTRACT: The diastereoselective synthesis of various substituted
morpholines has been achieved from vinyloxiranes and amino-alcohols
under sequential Pd(0)-catalyzed Tsuji−Trost/Fe(III)-catalyzed het-
erocyclization. Using the same strategy, 2,6-, 2,5-, and 2,3-disubstituted
as well as 2,5,6- and 2,3,5-trisubstituted morpholines were obtained in
good to excellent yields and diastereoselectivities.
eveloping new methods and processes toward polysub-
substrates toward cis-2,5-disubstituted morpholines (Scheme 1,
eq 2).7 In both cases, (Z)-olefins were necessary to have good
yields and good diastereoselectivities. In addition, Bode et al.
have explored the formation of morpholines through a radical
construction of a C−C bond, from a stannylated imine under
copper catalysis.8a The same group showed that the stannyl
group could be replaced by a silyl group provided that the
reaction was activated with an iridium catalyst under light
irradiation (Scheme 1, eq 3).8b−d Another strategy reported by
Saegusa et al. in 1990 consists of the sequential formation of
several bonds in a one-pot reaction.9a Activation of 2-buten-
1,4-diyl diacetate with Pd(0) in the presence of an amino-
alcohol led to the formation of the 2-vinyl morpholine with an
excellent yield through the sequential formation of a C−N and
C−O bond (Scheme 1, eq 4). It is worth mentioning that the
use of a chiral ligand can give access to enantioenriched
morpholines.9b,c,10
D
stituted “privileged”1 scaffolds is a never-ending
challenge for organic chemists. Among heterocycles of interest
in the pharmaceutical and agrochemical areas, morpholines are
widely encountered in biologically active compounds.2 There-
fore, the synthesis of morpholines has been extensively studied
in recent decades and numerous strategies have emerged.3
Particular efforts have been deployed in the field of metal-
mediated reactions. Most of these methods consist of
cyclization of O- or N-tethered substrates with the final
formation of a C−N or a C−O bond respectively (Scheme 1).
Scheme 1. Metal-Catalyzed Syntheses of Morpholines
A wide range of methods is thus available to synthesize
substituted morpholines. However, some of the main draw-
backs associated with these methods are the requirement of
prolonged heating, the use of toxic metals/reagents, or the
need for lengthy syntheses to access the starting materials
generating important wastes. In addition, to the best of our
knowledge, none of them has been applied to the synthesis of
all the possible substitution patterns of the morpholine ring.
Therefore, a flexible approach toward polysubstituted morpho-
lines is still desirable while taking into account the atom
economy principle.
Based on our experience in the environmentally benign
FeCl3-catalyzed diastereoselective formation of various hetero-
cycles,11 we envisioned the construction of the morpholine
core from an ω-hydroxy allylic alcohol intermediate. This
intermediate could result from a Pd-catalyzed Tsuji−Trost
reaction12 between readily available vinyl oxiranes and amino-
alcohols (Scheme 2). We furthermore envisioned that it should
For example, Wolfe et al.4a reported the synthesis of cis-3,5-
disubstituted morpholines with moderate yields and excellent
diastereoselectivities by using a Pd-catalyzed intramolecular
carboamination of a terminal olefin. Later, Michael and co-
workers showed4b that a similar strategy, with a different
palladium catalyst combined with AgBF4, can lead to trans-2,5-
disubstituted morpholines in good yields (Scheme 1, eq 1).
Palladium was also used as a catalyst for the formation of cis-
2,6-disubstituted morpholines by Saikia et al.6a to induce the
cyclization of ω-hydroxy allylic alcohols, while Bandini and co-
workers reported6b a gold-catalyzed cyclization of similar
Received: October 2, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03141
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Letter
not be necessary to control the cis/trans configuration of the
vinyl oxiranes. This method could lead to various substitution
patterns, generating only water as a byproduct (Scheme 2).
85% respectively. A thiophene ring is also compatible with the
conditions, as morpholine 4d was isolated in 82% yield. An
alkyl substituent was not detrimental to the Tsuji−Trost
reaction; however, the cyclization did not occur at rt, but if the
reaction was heated at 50 °C for 1 h, the morpholine 4e was
isolated with an excellent yield of 93%.
Scheme 2. Sequential Pd(0)/Fe(III) Catalysis
Scheme 3. Synthesis of Morpholines from Diverse Vinyl
a
Oxiranes
To validate our hypothesis, phenylvinyl oxirane 1a13 (1.3
equiv) was reacted with N-Ts amino-ethanol 2a. In the
presence of 10 mol % of Pd(PPh3)4 in THF, full conversion of
the amino-alcohol was observed after 1 h with concomitant
formation of the Tsuji−Trost adduct 3 (Table 1, entry 1).
Disappointingly, no conversion of 3 was observed after the
addition of 10 mol % of FeCl3·6H2O to the reaction, while 1
equiv of Fe(III) led to the cyclized product 4a in only 10%
yield (Table 1, entry 2). This result was attributed to the
possible deactivation of the iron catalyst by complexation with
THF. Indeed, switching from THF to CH2Cl2 did not affect
the Tsuji−Trost reaction but improved the cyclization: a
promising 50% conversion of 3 to 4a was observed with 10
mol % of FeCl3·6H2O (Table 1, entry 3). The low conversion
during the iron-catalyzed step was presumably due to a partial
deactivation of the catalyst by triphenylphosphine oxide,
a
Cyclization occurred at 50 °C in a sealed tube.
We next turned our attention to the synthesis of
disubstituted morpholines. Phenyl substituted amino-alcohol
2b was reacted with phenyl vinyl oxirane 1a under the previous
optimized conditions. While the Tsuji−Trost adduct was
formed with full conversion of the amino-alcohol, its
cyclization with 10 mol % of FeCl3·6H2O (1 h, rt) led to
morpholine 5a with a disappointing cis/trans ratio of 55:45, as
proven by NOESY analysis of the crude mixture (Table 2,
Table 1. Optimization of the Conditions
Table 2. Optimization for the Diastereoselective Synthesis
of 2,6-Morpholines
entry solvent
[Pd] cat. (x mol %)
t
2a/3
3/4a
1
2
3
4
THF
THF
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
1 h
1 h
1 h
12 h
0:100 100:0
0:100 90:10
0:100 50:50
0:100 0:100
(81)
a
CH2Cl2 Pd(PPh3)4 (10)
CH2Cl2 Pd(PPh3)4 (1)
b
5
6
CH2Cl2 Pd2(dba)3 (1) + PPh3
(2)
CH2Cl2 PdCl2 (1) + PPh3 (2)
12 h
12 h
8:92
−
100:0
−
cis/
trans
a
b
a
b
entry FeCl3·6H2O (x mol %) temp (°C) t (h)
yield (%)
1 equiv of FeCl3.6H2O was used. Yield of isolated product 4a in
parentheses.
1
2
3
4
5
10
10
15
20
20
rt
1
2
2
2
4
55:45
66:34
79:21
95:5
−
−
−
−
89
c
c
c
c
50
50
50
50
producing the iron complex FeCl3(OPPh3)2 which has a
lower Lewis acidity than FeCl3.14 The Pd catalyst loading was
then decreased to 1 mol %. Under these conditions, 12 h were
necessary to ensure full conversion of the amino-alcohol 2a to
the N-tethered intermediate 3. Subsequent addition of 10 mol
% of FeCl3·6H2O to the medium pleasingly led to a full
conversion of 3, and morpholine 4a was isolated in a good 81%
yield (Table 1, entry 4). Other sources of palladium(0) led to
lower or no conversion of 2a (Table 1, entries 5−6).
With this first set of conditions in hand, we explored the
influence of the vinyl oxirane R1 group (Scheme 3). Different
substituted aromatic rings were tolerated, as the corresponding
morpholines 4b and 4c were isolated with yields of 81% and
95:5
a
Diastereomeric ratio was measured by 1H NMR of the crude
mixture. The major diastereoisomer was identified by NOESY.
Isolated yield. Reactions were run in a sealed tube.
b
c
entry 1). Heating the reaction at 50 °C for 2 h slightly
improved the ratio to 66:34 (Table 2, entry 2). Resubmitting
the isolated morpholine to 10 mol % of FeCl3·6H2O in CH2Cl2
at 50 °C for 2 h led to an increase of the diastereoisomeric
ratio up to 95:5 in favor of the cis compound. These results
highlight, as previously observed,11 that an iron-induced
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equilibration between the cis- and the trans-stereoisomers
occurs, leading to the most stable diastereoisomer as the major
product. With 15 mol % of FeCl3·6H2O, an encouraging 79:21
ratio was obtained, in favor of the cis-morpholine (Table 2,
entry 3). The best result was obtained with 20 mol % of iron
catalyst by heating the reaction for 4 h at 50 °C (Table 2, entry
5). Under these conditions, morpholine 5a was isolated in a
good yield of 89% and an excellent cis/trans ratio of 95:5.
These optimized conditions were next applied to amino
alcohols differing from their R4 substituent (Scheme 4). A vinyl
substituent was tolerated, as morpholine 5b was isolated in
71% yield with a good dr (cis/trans = 93:7). The
6‑cyclopropylmorpholine 5c was obtained in 87% yield with
a dr of 92:8 in favor of the cis-isomer. An alkyl chain has no
influence on the reaction as the corresponding morpholine 5d
was isolated in 83% yield and with similar diastereoselectivity
as previously. It is worth mentioning that the spirocyclic
morpholine 5e was also isolated with an excellent 93% yield.
Scheme 5. Diastereoselective Synthesis of cis-2,5-
Disubstituted Morpholines
Scheme 4. Diastereoselective Synthesis of cis-2,6-
Disubstituted Morpholines
Subsequently, the synthesis of 2,3-disubstitued morpholines
was examined under the optimized conditions (Scheme 6).
Substituted vinyl oxiranes were therefore evaluated, and
pleasingly, the 2-styrenyl-3-methyl morpholine 7a (R2 = Me)
was isolated with a good yield and diastereoselectivity (83%,
cis/trans = 90:10). Unambiguous nuclear Overhauser effect
between the protons of the methyl group and those of the
styrenyl moiety confirmed the relative cis stereochemistry of
the product. Switching to an octanol substituent on the vinyl
oxirane led to the morpholine 7b with a moderate yield of 42%
but with a good diastereoselectivity of 85:15. It is interesting to
note that both the allylation and the cyclization steps tolerate
the presence of a free alcohol. Unfortunately, attempts to use
substituted oxiranes where R2 is Ph− or Bn2NCH2− only led
to the decomposition of the starting material.
Scheme 6. Diastereoselective Synthesis of cis-2,3-
Disubstituted Morpholines
The synthesis of 2,5-disubstituted morpholines was then
examined, and we were pleased to see that the corresponding
products were formed with good to excellent diastereoselectiv-
ities albeit with slightly lower yields than for 2,6-disubstituted
morpholines (Scheme 5). Thus, the phenyl substituted
morpholine 6a was isolated with a yield of 72% and a dr of
85:15 in favor of the cis compound.15 Isopropyl and ethyl
substituted morpholines 6b and 6c were obtained in moderate
yields (60%) but as single cis-diastereoisomers. The methyl-
benzyloxy substituted morpholine 6d was isolated with a
similar yield (cis/trans = 90:10). It is worth noting that a
thiophene moiety was tolerated under these conditions, as the
corresponding thienyl morpholine 6e was isolated in 50% yield
with a good dr of 94:6 still in favor of the cis compound. The
5,5-dimethyl morpholine 6f was, for its part, only observed as
traces. In all these cases, the unreacted starting amino-alcohol
may be partially recovered. Steric hindrance of the nucleophilic
nitrogen caused by the R3 substituent during the Tsuji−Trost
reaction may account for the lower yields obtained in this
series compared with the 2,6-disubstituted morpholines.
The formation of polysubstituted morpholines was next
investigated (Scheme 7). Under the conditions developed
previously, (1R,2S)-N-Ts-1-amino-2-indanol led to the corre-
sponding morpholine 8a (89%) with excellent diastereoselec-
tivity (dr = 94:6). N-Ts-(2R*,3R*)-Dimethylamino-ethanol
gave morpholine 8b with a lower dr (75:25), presumably
because of the low steric hindrance of the methyl groups.
Interestingly the trisubstituted morpholine 8c can be obtained
in a very good yield of 85% as a mixture of four
C
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the cis compound. In the case of 2,5- and 2,3-disubstituted
morpholines additional interactions between the R group and
the N-Ts group have to be taken into consideration. It is
known that ring substituents adjacent to a N-Ts tend to adopt
an axial position to avoid A1,3 strain.17 Therefore, III represents
the most stable 2,5-disubstituted diastereoisomer, where the R
group stands in an axial position to avoid the allylic strain with
the N-Ts group, at the expense of a 1,3-diaxial interaction with
the C3-hydrogen (Scheme 8, eq 2). Similar reasoning can be
applied to 2,3-disubstituted morpholines, with V being the
most stable diastereoisomer (Scheme 8, eq 3).
Scheme 7. Diastereoselective Synthesis of Polysubstituted
Morpholines
a
To demonstrate the utility of the synthesized morpholines,
the deprotection of the amine and the transformation of the
styrenyl group were achieved (Scheme 9). In the presence of
magnesium powder and with ultrasound activation,18 morpho-
line 5d was efficiently detosylated to give morpholine 9 in 82%
yield with retention of the dr. The cinnamyl moiety in 5a was
cleaved by an oxidative cleavage/reduction sequence, to form
morpholinol 10 (72% over three steps).
a
Measured by GC-MS analysis.
a
Scheme 9. Transformation of Synthesized Morpholines
diastereoisomers (dr = 50:30:17:3). Attempts to reach better
diastereoselectivity by increasing the temperature or the
catalyst loading led to decomposition of the product.
From a mechanistic point of view, the diastereoselective
outcome of the reaction may be explained by the formation of
a transient delocalized carbocation upon treatment of the
Tsuji−Trost adduct by iron trichloride. After a 6-exo-trig
cyclization, the morpholine ring is formed as a cis/trans
mixture (see scheme in Supporting Information). Then, an
FeCl3-catalyzed thermodynamic equilibrium may take place
(Table 2, vide supra).11 A ring-opening/ring-closure sequence
then leads to the most stable diastereoisomer as the major
compound (Scheme 8).
a
1
The dr cannot be measured due to overlapping H NMR signals.
Scheme 8. Rational for the Observed Diastereomeric
Outcome
In conclusion, we have developed a versatile method to
access morpholines with different substitution patterns. This
atom-economic method relies on the power of Pd(0)- and
Fe(III)-catalysis and constitutes a unified strategy toward the
synthesis of diversely substituted morpholines from readily
available oxiranes and amino-alcohols, with water as the sole
byproduct. As good to excellent diastereoselectivities were
obtained, this method paves the way to access complex
bioactive molecules or libraries of morpholines that can be
useful to medicinal chemists.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03141.
Experimental procedures, product characterizations, and
1H and 13C NMR spectra for all new compounds (PDF)
It has been reported that N-Ts morpholines adopt a chair
conformation with the sulfonyl group predominantly in an
equatorial position.16 In the case of 2,6-disubstituted morpho-
lines, diastereoisomers I and II differ from the position of the R
substituent, which stands in an equatorial or an axial position
(Scheme 8, eq 1). 1,3-Diaxial interactions make the trans-
diastereoisomer II less stable, thus favoring the formation of
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: janine.cossy@espci.fr
ORCID
Thomas Aubineau: 0000-0001-8443-8058
D
DOI: 10.1021/acs.orglett.8b03141
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Organic Letters
Letter
̌
́
̌
̌
(14) Vancova, V.; Ondrejovic, G.; Gazo, J. Chem. Zvesti 1976, 30,
86−89.
Notes
The authors declare no competing financial interest.
(15) Identification of the major diastereoisomer was done by
derivation to a known N-Bn morpholinol, as no NOE signal was
observed by H NMR on 8a. See SI.
1
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