Multicomponent approach in the synthesis of 2,2,6-trisubstituted morpholine derivatives

Article abstract of DOI:10.1021/ol3024105

An efficient synthesis of 2,2,6-trisubstituted morpholine is described which involves a multicomponent process by simply mixing epichlorohydrin, N-bromosuccinimide, nosyl amide, and an olefin. The products contain chloride handles which are suitable for further modification.

Full text of DOI:10.1021/ol3024105

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Multicomponent Approach in the
Synthesis of 2,2,6-Trisubstituted
Morpholine Derivatives
Jing Zhou, Ling Zhou, and Ying-Yeung Yeung*
Department of Chemistry, National University of Singapore, 3 Science Drive 3,
Singapore 117543
chmyyy@nus.edu.sg
Received August 30, 2012
ABSTRACT
An efficient synthesis of 2,2,6-trisubstituted morpholine is described which involves a multicomponent process by simply mixing epichlorohydrin,
N-bromosuccinimide, nosyl amide, and an olefin. The products contain chloride handles which are suitable for further modification.
The increasing demand for new chemical entities urges
synthetic chemists to pursue simple, efficient, selective, high
yielding, and environmentally benign reactions.1 Multi-
component reactions (MCR), which allow the quick as-
sembly of several simple reactants into complex structures
in one pot, certainly provide a possible solution for a green
and efficient synthesis through a diversity-oriented approach.2
These one-pot processes are highly efficient to construct
the scaffold of natural products and diverse drug-like
molecules which make the strategy important in modern
organic synthesis and drug discovery research.3
Among MCRs, electrophilic MCRs were less reported,
partly due to the common incompatibility of electrophiles
with other components.4 Nevertheless, recently, we re-
ported our discovery of electrophilic aminoalkoxylation
reactions. This type of reaction was applied to morpholine
synthesis.5 However, a challenging task was encountered
during the process development: when a monosubstituted
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10.1021/ol3024105
XXXX American Chemical Society

Scheme 1. Aminoalkoxylation Using Monosubstituted Epoxide
Figure 1. Examples of bioactive morpholines.
epoxide was used, the oxonium intermediate could be
opened through the anti-Markovnikov (path A) or the
Markovnikov (path B) pathway (Scheme 1).
Markovnikov product A when using epichlorohydrin as
the partner in the aminoalkoxylation MCR. Subsequent
application tothe synthesisof 2,2,6-trisubstituted morpho-
line A0 is also described.
Product A, the anti-Markovnikov product, is a privi-
leged building block for 2- and 6-substituted morpholines.
In particular, 2,2,6-trisubstituted morpholine A0 is an
important pharmacophore (Figure 1).6 Common strate-
gies, such as the cyclization of amino alcohols (derived
from amino acids which contain R-nitrogen substituents),
can readily achieve 3-substituted morpholine B0.7 In com-
parison, itis not trivial toachieve A0 or related compounds,
particularly when it is optically active.8 Herein we report
an unexpected finding on the formation of the anti-
We initiated the investigation by studying a number of
monosubstituted epoxides using cyclohexene as the model
substrate. Propylene oxide gave no regioselectivity regard-
less of the high reaction yield (Table 1, entry 1). 1,2-Epoxy-
3-methylbutane gave a better regioselectivity, presumably
due the steric hindrance which suppressed the path B nucleo-
philic attack (Table 1, entry 2). Other alkoxy/siloxy sys-
tems were also examined, and some regioselectivities were
observed; up to a 2.5:1 ratio but a relatively low conversion
(56% yield) was detected when using the bulky OTBDPS-
substituted epoxide (Table 1, entries 3ꢀ5). Such steric
effect was not significant, which might be attributed to
the electron-donating ability of the substituents that fa-
vored the Markovnikov-type product 3a. Interestingly, the
electron-deficient epoxides, epibromohydrin and epichlor-
ohydrin, gave good chemical yields and regioselectivity
(Table 1, entries 6 and 7). Optimization of the reaction
temperature led ustoachieve an8:1 ratio of regioselectivity
at ꢀ30 °C (Table 1, entry 9). Other halogen sources were
investigated. The reaction was sluggish when using N-
chlorosuccinimide (NCS) (Table 1, entry 11). Although a
better regioselectivity was observed when using N-iodo-
succinimide (NIS), the chemical conversion was only
moderate (Table 1, entry 12).
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Brands, K. M. J.; Payack, J. F.; Rosen, J. D.; Nelson, T. D.; Candelario,
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D. M.; Hansen, K.; Devine, P. N.; Pye, P. J.; Rossen, K.; Dormer, P. G.;
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Blaauw, R. H.; Rutjes, F. P. J. T. Synthesis 2004, 641.
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Chem.;Eur. J. 2010, 16, 14272–14277. (b) Gharpure, S. J.; Prasad,
J. V. K. J. Org. Chem. 2011, 76, 10325–10331. (c) Kazmierski, W. M.;
Furfine, E.; Spaltenstein, A.; Wright, L. L. Bioorg. Med. Chem. Lett.
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K. S. Bioorg. Med. Chem. 2008, 16, 5157–5163. (e) Albanese, D.; Foschi,
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7871–7875. (g) Albanese, D.; Salsa, M.; Landini, D.; Lupi, V.; Penso, M.
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A.; Yar, M.; McGarrigle, E. M.; Aggarwal, V. K. Eur. J. Org. Chem.
Having identified a suitable system, some 1,1-disubsti-
tuted olefins were examined. A number of exocyclic olefins
gave the desired products with good regioselectivities and
yields (Table 2, entries 1ꢀ3).9 The 4-O-substituted cyclo-
hexyl systems including 1e and 1f also worked well in the
reactions (Table 2, entries 4 and 5). The protected
(9) General procedure: To a solution of N-bromosuccinimide (43 mg,
0.24 mmol) and nosyl amide (40 mg, 0.2 mmol) in epichlorohydrin (0.4 mL)
in dark was added olefin 1 (0.24 mmol) at ꢀ30 °C. After stirring for 16 h
at this temperature, the reaction was quenched with saturated Na2S2O3
(2 mL). The mixture was extracted with EtOAc (3 ꢁ 10 mL). The
combined extracts were washed with brine (15 mL), dried over anhy-
drous Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by flash column chromatography to yield the corresponding
product.
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Investigation of Various Monosubstituted Epoxidesa
Table 3. Base-Mediated Cyclization of 2a
entry
R
temp (°C) time (h) yield (%)b ratio (2a/3a)c
1
2
3
4
5
6
7
8
9
Me
25
25
8
8
80
77
71
64
56
84
86
92
90
81
trace
30
1.0:1
3.5:1
2.0:1
2.3:1
2.5:1
4.3:1
4.5:1
7.1:1
8.0:1
8.0:1
NA
CHMe2
CH2OBn
CH2OTBS
CH2OTBDPS
CH2Br
25
8
25
8
25
8
25
8
CH2Cl
25
8
CH2Cl
CH2Cl
0
8
ꢀ30
ꢀ40
ꢀ30
ꢀ30
16
16
24
24
10 CH2Cl
11d CH2Cl
12e CH2Cl
10:1
a Reactions were carried out with cyclohexene (1a) (0.24 mmol),
NsNH2 (0.2 mmol), and NBS (0.24 mmol) in epoxide (0.4 mL). b Isolated
yield of the mixture of 2a and 3a.c Based on NMR analysis of crude product.
d N-Chlorosuccinimide was used. e N-Iodosuccinimide was used.
Table 2. Aminoalkoxylation of Olefin 1a
a Reactions were carried out with 2 (0.1 mmol) and K2CO3 (0.2
mmol) in MeCN (2 mL) at 25 °C. b Isolated yield.
Scheme 2. One-Pot Synthesis of 4f
a Reactions were carried out with NsNH2 (0.2 mmol), olefin 1 (0.24
mmol), and NBS (0.24 mmol) in epichlorohydrin (0.4 mL) at ꢀ30 °C for
16 h. b Isolated yield of the mixture of 2 and 3 by column chromato-
graphy. c Based on NMR analysis of the crude product.
Org. Lett., Vol. XX, No. XX, XXXX
C

piperidine substrate 1g gave the corresponding product
in 92% yield with a 6:1 ratio of regioselectivity (Table 2,
entry 6). This type of MCR reaction worked equally
smooth for aliphatic 1,1-disubstituted olefins, but the
reaction rate was somewhatdeteriorated whenusingbulkier
substrates (Table 2, entries 7ꢀ10). The stereochemical re-
lationship of 2 was established by X-ray crystallographic
study of 2d.10
Scheme 3. Mechanistic Investigation of the MCR
After performing the aminoalkoxylation, we were inter-
ested to further manipulate product 2 to achieve the
morpholine compounds. In all cases, treatment of 2 with
base in MeCN at room temperature gave the correspond-
ing morpholine products exclusively and no chlorine sub-
stitution (i.e., the four-membered ring formation) was
observed (Table 3). The structures of 4 were further con-
firmed by an X-ray crystallographic study of 4d.10
In fact, the reaction can be conducted in a one-pot
fashion. For instance, after the standard aminoalkoxyla-
tion MCR of 1f under standard conditions, the unused
epichlorohydrin was recovered using distillation. The
crude mixture was then treated with K2CO3 in MeCN to
give the desired morpholine 4f (Scheme 2).
Next, we examined the use of enantiopure (R)-epichloro-
hydrin in the reaction using 1f, and the desired morpholine 4f
was obtained with equal magnitude of enantiomeric excess
(99% ee). The stereochemistry of 4f was established by an
X-ray crystallographic study.10 It is noteworthy that 4f was
isolated exclusively as a single enantiomer; that is, the meso-
substrate 1f, which contains a 4-substituted unit, was de-
symmetrized in the reaction (Scheme 2).
the MCR was proven to be unlikely to happen (Scheme 3,
eq 2). We suspect that the chlorine atom may play a role in
the reaction; this remains unclear and is subjected to more
intensive clarification.
In summary, we have developed an efficient electrophilic
multicomponent reaction using epichlorohydrin, an olefin,
nosyl amide, and N-bromosuccinimide, giving the haloge-
nated products with high regioselectivity. 2,2,6-Trisubsti-
tuted morpholines were achieved by using this protocol.
The morpholines contained methylene chloride handles
that can readily be derivatized to yield other functional
molecules. When enantiopure epichlorohydrin was used,
the corresponding optical pure morpholine was accom-
plished. Interestingly, it was found that the meso-olefinic
substrate 1f was desymmetrized in the reaction.
Acknowledgment. We thank the financial support from
National University of Singapore (Grant No. 143-000-
509-112). Weacknowledgethe receipt ofanNUS Research
Scholarship (to J.Z.).
For this type of MCR, it was surprising to observe that
the electron-deficient epoxide epichlorohydrin gavesimilar
reactivity to the corresponding alkyl or alkoxy/siloxy
epoxides (Table 1). We have performed the MCR using
an electron-deficient OMs epoxide which returned with no
reaction (Scheme 3, eq 1). A preopening of the epoxide in
Supporting Information Available. Experimental pro-
cedures, CIF files, and additional information. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
(10) The details appear in the Supporting Information.
D
Org. Lett., Vol. XX, No. XX, XXXX