A facile synthesis of multigram quantity of ethyl 3-ethylmorpholine-3- carboxylate

Article abstract of DOI:10.1016/j.tetlet.2011.03.003

A five-step synthesis of ethyl 3-ethylmorpholine-3-carboxylate proceeding from readily available 2-aminobutyric acid is detailed herein.

Full text of DOI:10.1016/j.tetlet.2011.03.003

Tetrahedron Letters 52 (2011) 2471–2472
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Tetrahedron Letters
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A facile synthesis of multigram quantity of ethyl
3-ethylmorpholine-3-carboxylate
Jacek J. Jagodzinski b, Danielle L. Aubele a, , David A. Quincy b, Michael S. Dappen b, Lee H. Latimer b,
⇑
Roy K. Hom a, Robert A. Galemmo Jr. a, Andrei W. Konradi a, Hing L. Sham a
a Department of Medicinal Chemistry, Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, United States
b Department of Process and Analytical Chemistry, Elan Pharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A five-step synthesis of ethyl 3-ethylmorpholine-3-carboxylate proceeding from readily available 2-ami-
nobutyric acid is detailed herein.
Received 10 February 2011
Accepted 1 March 2011
Available online 12 March 2011
Ó 2011 Elsevier Ltd. All rights reserved.
The morpholine ring structure is a moiety found in a wide vari-
ety of natural products and many pharmaceutically relevant com-
pounds.1 Despite its increasing prevalence in molecules that
display interesting biological and pharmacological properties, the
synthetic utility of the morpholine ring is quite limited due to
the combination of a lack of commercially available C-substituted
morpholines as starting materials, as well as the fact that new syn-
thetic approaches to C-functionalized morpholines remains a rela-
tively unexplored synthetic area.2 Recently, several methods
detailing the preparation of 3-substituted morpholines have been
described.3 However, to our knowledge, few reports of 3,3-disub-
stituted morpholines have been described.3c,4
Recently, in connection with one of our research projects, mul-
tigram quantities of racemic ethyl 3-ethylmorpholine-3-carboxyl-
ate (1) were required. Surprisingly, no reports related to the
preparation of this or similar 3,3-disubstituted morpholines were
found in the literature. Reviews of possible synthetic approaches
to 1 led to the selection of the route displayed in Scheme 1.
Proceeding from the readily available racemic 2-aminobutyric
acid 2, morpholine 1 can be obtained in a straightforward manner.
Esterification of 2, followed by condensation with 4-chlorobenzal-
dehyde provided imine 3 in 85% yield over two steps. Protection of
the carboxylic acid 2 as an ethyl ester gave a significantly better
yield than the methyl ester. This was attributed to the increased
stability of the ethyl ester toward bases used during the synthesis.
Additionally, imine 3 proved quite stable and could be stored at
4 °C for weeks. Alkylation of imine 3 proved to be the key interme-
diate reaction, and was achieved by reaction with 2-chloroethyl-
chloromethyl ether in the presence of potassium tert-butoxide.
The best results were obtained when deprotonation occurred at
À78 °C in the presence of 2-chloroethyl-chloromethyl ether, and
the reaction mixture was allowed to slowly warm to ambient tem-
perature. The 4-chlorobenzyl group was removed by an aqueous
hydrochloride acid work-up to provide amine 4 in 74% yield. Cycli-
zation of amine 4 in the presence of sodium iodide and a catalytic
amount of tetrabutylammonium iodide provided morpholine 1 in
65% yield.
The sequence proved easily reproducible and easy to carry out,
even on a large scale, starting from 100 g of 2-aminobutyric acid. A
single purification step for the entire five-step sequence was re-
quired. Neither imine 3 nor compound 4 required purification.
However, purification of the final morpholine ester 1 was neces-
sary to remove the low-level impurities that interfered with the
subsequent chemistry. We speculate that there may have been
present some carryover amounts of tetrabutylammonium salts
and/or residual 2-chloroethyl-chloromethyl ether. The final prod-
uct, 1, is obtained as a viscous, pale-cream to colorless liquid in five
steps in a 40% overall yield.
The Maruoka catalytic phase-transfer asymmetric alkylation5 of
imine 3 was briefly examined (Scheme 2).
The crude product of the reaction (4a, non-optimized condi-
tions) was in turn subjected to cyclization to morpholine 1a. Its
optical purity was evaluated after preparation of respective N-ben-
zoyl derivative (1b). It was found that the N-benzoyl-morpholine
1b was ꢀ40% ee, indicating that the opportunity exists for further
optimization of imine alkylation conditions and eventually the
Cl
NH2
Et
NH2
OH
Et
CO2Et
CO2Et
O
e
a,b
c,d
O
HN
Et
O
N
Cl
Et CO2Et
2
4
1
3
Scheme 1. Reagents and conditions: (a) EtOH/HCl, reflux; (b) 4-Cl-benzaldehyde,
MgSO4, Et3N, CH2Cl2; (c) 2-chloroethyl–chloromethyl ether, KOtBu, THF, À78 °C to
rt; (d) aq 1 N HCl, ambient, 2 h; (e) NaI, TBAI, K2CO3, CH3CN, rt to 50 °C, 18 h.
⇑
Corresponding author.
E-mail address: danielle.aubele@elan.com (D.L. Aubele).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.003

2472
J. J. Jagodzinski et al. / Tetrahedron Letters 52 (2011) 2471–2472
Cl
Supplementary data
NH2
Et
CO2Et
Et
CO2Et
O
a,b
c,d
Supplementary data (synthesis and characterization of the final
product and intermediates) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2011.03.003.
O
RN
N
Cl
Et CO2Et
4a
1a, R=H
1b, R=Bz
3
References and notes
1. Wijtmans, R.; Vink, M. K. S.; Schoemaker, H. E.; van Delft, F. L.; Blaauw, R. H.;
Rutjes, F. P. J. T. Synthesis 2004, 5, 641.
2. Ghorai, M. K.; Shukla, D.; Das, K. J. Org. Chem. 2009, 74, 7013.
Scheme 2. Reagents and conditions: (a) 2-chloroethyl–chloromethyl ether, CsOH–
H2O, (R)-catalyst, toluene, 0 °C to rt, 24 h; (b) aq 1 N HCl, ambient, 2 h; (c) NaI, TBAI,
K2CO3, CH3CN, rt, 30 h; (d) benzoyl chloride, triethylamine, CH2Cl2, rt, 18 h.
3. (a) Bornholdt, J.; Felding, J.; Kristensen, J. L. J. Org. Chem. 2010, 75, 7454; (b) Yar,
M.; McGarrigle, E. M.; Aggarwal, V. K. Org. Lett. 2009, 11, 257; (c) Yar, M.;
McGarrigle, E. M.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2008, 47, 3784.
4. Cottle, D. L.; Jeltsch, A. E.; Stoudt, T. H.; Walters, D. R. J. Org. Chem. 1948, 11, 286.
5. Wang, Y.-G.; Mii, H.; Kano, T.; Maruoka, K. Bioorg. Med. Chem. Lett. 2009, 19,
morpholine 1 could be prepared as a non-racemic compound as
well.
3795. Maruoka catalyst (both
R and S isomers) is available from Strem
In conclusion, an efficient and scalable route to ethyl
3-ethylmorpholine-3-carboxylate, 1 was developed. The synthesis
proceeds in five steps and 40% overall yield from readily available
2-aminobutyric acid, 2, and requires only a single column chroma-
tography purification of the final product.
Chemicals. Samples of R-catalyst [CAS# 887938-70-7] and S-isomer [CAS#
851942-89-7] were obtained as a gift from Nagase America Corp.
Acknowledgements
We thank Donald Walker and John Maynard for their contribu-
tions to this work.