Synthesis of morpholin-2-ones by chemoselective intramolecular rhodium-catalyzed reductive ring expansion of oxazolidines

Article abstract of DOI:10.1021/ol703135w

(Chemical Equation Presented) The rhodium-catalyzed reductive intramolecular ring expansion of N-(ethoxycarboxymethyl)oxazolidines was carried out under an atmosphere of carbon monoxide and hydrogen to afford N-methylmorpholin-2-ones in good to excellent

Full text of DOI:10.1021/ol703135w

ORGANIC
LETTERS
2008
Vol. 10, No. 7
1357-1359
Synthesis of Morpholin-2-ones by
Chemoselective Intramolecular
Rhodium-Catalyzed Reductive Ring
Expansion of Oxazolidines
Maksym Vasylyev and Howard Alper*
Centre for Catalysis Research and InnoVation, Department of Chemistry, UniVersity of
Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
howard.alper@uottawa.ca
Received December 31, 2007
ABSTRACT
The rhodium-catalyzed reductive intramolecular ring expansion of N-(ethoxycarboxymethyl)oxazolidines was carried out under an atmosphere
of carbon monoxide and hydrogen to afford N-methylmorpholin-2-ones in good to excellent yields.
The traditional approach to the synthesis of the majority of
heterocyclic compounds involves the use of appropriate
alicyclic precursor(s) that lead to the formation of the
desirable heterocycle upon cyclization reaction. Although this
approach is widely applied, an alternative strategy, which
takes advantage of the fact that some heterocyclic compounds
can be prepared from smaller heterocyclic substrates by the
transition metal-catalyzed ring expansion process, has at-
tracted a great deal of attention in the last 20 years.1
reaction, thus significantly broadening the scope of the target
products.3
The carbonylative ring expansion of five-membered ring
heterocycles usually proceeds under more drastic conditions
(higher temperatures and pressures of CO) than those
required for smaller heterocycles.1a In some instances, as was
demonstrated by one of us earlier in the case of thiazolidines,
the reaction product was not the expected thiomorpholinone,
but instead, was a thiazolidinone, formed as a result of a
sequential carbonylation-ketene extrusion-carbonylation
process.4 The ring expansion-contraction of thiazolidines
The most extensively investigated example of the ring
expansion strategy is the insertion of carbon monoxide into
a carbon-heteroatom bond of a heterocyclic compound.1 The
reaction proceeds well for three- and four-membered het-
erocycles since the ring-opening and expansion can be
facilitated by relief of ring strain during the transformation.
As a result, the synthesis of â-lactams, â-lactones, γ-lactones,
and their thio analogues by the ring-expansion carbonylation
reaction has been extensively studied.2 Electrophiles other
than carbon monoxide such as isocyanates, isothiocyanates
and carbodiimides were also used for the ring-expansion
(2) (a) Heck, R. F. J. Am. Chem. Soc. 1963, 85, 1460-1463. (b) Calet,
S.; Urso, F.; Alper, H. J. Am. Chem. Soc. 1989, 111, 931-934. (c) Kamiya,
Y.; Kawato, K.; Ota, H. Chem. Lett. 1980, 1549-52. (d) Lee, J. T.; Thomas,
P. J.; Alper, H. J. Org. Chem. 2001, 66, 5424-5426. (e) Lu, S.; Alper, H.
J. Org. Chem. 2004, 69, 3558-3561. (f) Mahadevan, V.; Getzler, Y. D. Y.
L.; Coates, G. W. Angew. Chem., Int. Ed. 2002, 41, 2781-2784. (g) Rowley,
J. M.; Lobkovsky, E. B.; Coates, J. W. J. Am. Chem. Soc. 2007, 129, 4948-
4960. (h) Piotti, M. E.; Alper, H. J. Am. Chem. Soc. 1996, 118, 111-116.
(i) Shimizu, I.; Maruyama, T.; Makuta, T.; Yamamoto, A. Tetrahedron Lett.
1993, 34, 2135-2138. (j) Tanner, D.; Somfai, P. Bioorg. Med. Chem. Lett.
1993, 3, 2415-2418. (k) Wang, M. D.; Calet, S.; Alper, H. J. Org. Chem.
1989, 54, 20-21.
(3) (a) Butler, D. C. D.; Inman, G. A.; Alper, H. J. Org. Chem. 2000,
65, 5887-5890. (b) Inman, G. A.; Butler, D. C. D.; Alper, H Synlett 2001,
914-919. (c) Larksarp, C.; Sellier, O.; Alper, H. J. Org. Chem. 2001, 66,
3502-3506. (d) Church, T. L.; Byrne, C. M.; Lobkovsky, E. B.; Coates,
G. W. J. Am. Chem. Soc. 2007, 129, 8156-8162.
(1) Khumtaveeporn, K.; Alper, H. Acc. Chem. Res. 1995, 28, 414-422.
(b) Church, T. L.; Getzler, Y. D. Y. L.; Bryne C. M.; Coates G. W. Chem.
Commun. 2007, 657-674.
10.1021/ol703135w CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/01/2008

led us to investigate the reactivity of the structurally related
N-(ethoxycarboxymethyl)oxazolidines under similar reaction
conditions.
Isolation of (5R)-4-N-methyl-5-phenylmorpholin-2-one 3a
suggested that the ring expansion did take place. However,
spectroscopic evidence indicated the absence of the ethoxy-
carboxymethyl fragment and the presence of the methyl
group attached to the nitrogen atom, thus leading us to
conclude that the ring expansion did not happen through the
ring expansion-carbonylation sequence. Rather, it may have
proceeded through an intramolecular nucleophilic attack of
the oxygen atom of the oxazolidine at the carbon of the ester
functional group, resulting in the formation of iminium
intermediate 2 as illustrated in Scheme 2.
We now describe the synthesis of new N-(ethoxycar-
boxymethyl)oxazolidines and their reaction with the [Rh-
(COD)Cl]2/KI catalytic system under carbonylative condi-
tions. We further show that the reactivity of the N-(ethoxycar-
boxymethyl)oxazolidines differs significantly from their thio-
analog in that instead of ring expansion-contraction, it
undergoes intramolecular reductive ring expansion with the
formation of morpholin-2-ones. This approach constitutes a
new route to these particular types of heterocycles.5
Substituted N-(ethoxycarboxymethyl)oxazolidines were
synthesized starting from the corresponding enantiomerically
pure amino alcohols6 by alkylation with ethyl bromoacetate
and subsequent cyclization with paraformaldehyde,7 attaining
the desired oxazolidines as depicted in Scheme 1.
Scheme 2. Proposed Mechanism for the Intramolecular Ring
Expansion of 1a via the Intermediate Iminium Ion 2
Scheme 1. Synthesis of N-(Ethoxycarboxymethyl)oxazolidines
The next step in the reaction is most likely a two-electron
one-proton reduction (formal hydride addition) of 2. Al-
though it is not clear how this step occurred since there was
no source of hydride in the reaction media, we rationalized
that the conversion could be improved by the use of a mixture
of carbon monoxide and hydrogen instead of pure carbon
monoxide to satisfy the need for the rhodium hydride species
in the reaction. As illustrated in Table 1 (entry 2), the use of
CO/H2 mixture dramatically improves the conversion of 1a
into (5R)-4-N-methyl-5-phenylmorpholin-2-one 3a affording
the product in nearly quantitative yield. Additional evidence
for our mechanistic hypothesis was obtained by carrying the
reaction out under an atmosphere of deuterium gas and
carbon monoxide. The 13C NMR spectrum of the isolated
compound shows a signal for the carbon nucleus of the
N-methyl functional group as a triplet due to carbon-
deuterium coupling.8 The use of pure hydrogen gas (no CO),
however, results in a reduction of the rhodium catalyst and
deposition of rhodium metal in the form of “rhodium mirror”
(Table 1, entry 5). It is evident, therefore, that although
carbon monoxide does not participate in the reaction directly,
its presence is necessary to stabilize the catalyst.
An initial attempt employing 1a as a model substrate and
5 mol % of [Rh(COD)Cl]2 and 10 mol % of KI as the
catalyst, in toluene at 180 °C under 65 atm of carbon
monoxide, gave only 11% of the reaction product which
appeared to be (5R)-4-N-methyl-5-phenylmorpholin-2-one 3a
(Table 1, entry 1). In the absence of the catalyst, or using
Table 1. Catalytic Reductive Ring Expansion of 1aa
entry
catalystb
CO, atm H2, atm t, °C yield,c %
1
2
3
4
5
6
7
[Rh(COD)Cl]2/KI
[Rh(COD)Cl]2/KI
65
30
65
50
180
180
180
180
100
100
100
11
95
d
d
e
30
Further optimization showed that the reaction temperature
could be decreased from 180 to 100 °C (Table 1, entry 6),
Co2(CO)8/Ru3(CO)12
[Rh(COD)Cl]2/KI
[Rh(COD)Cl]2/KI
[Rh(COD)Cl]2/KI
30
30
5
(4) Khumtaveeporn, K.; Alper, H. J. Am. Chem. Soc. 1994, 116, 5662-
6.
30
5
97
97
(5) Alternative routes to (5R)-4-N-methyl-5-phenylmorpholin-2-one 3a
were described in following articles: (a) Alker, D.; Harwood, L. M.;
Williams, C. E. Tetrahedron 1997, 53, 12671-12678. (b) Agami, C.; Couty,
F.; Hamon, L.; Prince, B.; Puchot, C. Tetrahedron 1990, 46, 7003-7010.
(c) Agami, C.; Couty, F.; Daran, J. C.; Prince, B.; Puchot, C. Tetrahedron
Lett. 1990, 31, 2889-2892.
a All experiments were carried out in anhydrous toluene for 15 h. b Entries
1, 2, 5-7: [Rh(COD)Cl]2, 5 mol %, KI, 10 mol %; entry 4: Co2(CO)8, 30
mol %, Ru3(CO)12, 14 mol %. c Isolated yield after purification by column
chromatography. d Starting material was decomposed. e Rhodium metal
deposition was observed.
(6) McKennon, J. M.; Meyers A. I. J. Org. Chem. 1993, 58, 3568-
3571.
(7) Compounds 1a and N-(cyanomethyl)-4-phenyloxazolidine: Deprez,
P.; Royer, J.; Husson, H.-P. Tetrahedron 1993, 49, 3781-3792.
(8) The fact that only 63% of the compound has N-CH2D structural
fragment (calculated according to the integral values of the NMR spectrum,
(S11 (inset), Supporting Information) may be due to hydrogen-deuterium
exchange which occurs in rhodium hydride bonded to 1,5-cyclooctadiene.
Co2(CO)8/Ru3(CO)12 as the catalytic system, reaction resulted
in the formation of decomposition products (Table 1, entries
3 and 4).
1358
Org. Lett., Vol. 10, No. 7, 2008

and the pressure of hydrogen and carbon monoxide could
be reduced to 5 atm (Table 1, entry 7).
substituent at position 4 of the oxazolidine ring, has a
significant influence on the performance of the reaction.
To probe whether the reductive ring expansion reaction
could be extended to substrates containing an N-cyanomethyl
substituent, N-(cyanomethyl)-4-phenyloxazolidine7 was syn-
thesized. Unfortunately, no morpholin-2-imine was formed
during the reaction conducted using conditions suitable for
ring expansion of N-(ethoxycarboxymethyl)oxazolidines.
In conclusion, we have developed a rhodium-catalyzed
method for the novel reductive ring expansion of N-
(ethoxycarboxymethyl)oxazolidines to N-methylmorpholin-
2-ones. The reaction may proceed through an intermediate
iminium ion, which undergoes further reduction by a rhodium
hydride species.
With these optimized conditions in hand, the scope of the
rhodium-catalyzed reductive intramolecular ring expansion
of N-(ethoxycarboxymethyl)oxazolidines was examined. The
results summarized in Table 2 demonstrate that the catalytic
Table 2. Catalytic Reductive Intramolecular Ring Expansion of
N-(Ethoxycarboxymethyl)oxazolidinesa,9
Acknowledgment. We are grateful to the National
Science and Energy Research Council of Canada for support
of the research.
entry
compd
R
yield,b %
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
(R)-Ph
(S)-Ph
97
80
95
81
97
81
76
Supporting Information Available: Experimental pro-
cedures and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
(R)-i-Bu
(S)-i-Bu
(R)-Bn
(S)-Bn
(S)-i-Pr
OL703135W
3g
(9) General procedure for the catalytic ring expansion reaction: In a
typical procedure, 1 mmol of N-(ethoxycarboxymethyl)oxazolidine and 0.05
mmol of [Rh(COD)Cl]2 were dissolved in 10 mL of anhydrous toluene in
a glass liner equipped with a magnetic stirring bar. To this solution was
added 0.1 mmol of KI, and the liner was inserted into a 45 mL autoclave,
which was then sealed. Carbon monoxide, 5 atm, was introduced to the
autoclave by the two consecutive pump-release cycles. Finally, hydrogen
gas was introduced into the autoclave bringing the overall pressure to 10
atm. The autoclave was placed in a thermostated oil bath at 100 °C and the
reaction was carried out for 15 h. The autoclave was then cooled, and
pressure was released. The reaction mixture was concentrated, and the
residue was subjected to flash chromatography.
a Reaction conditions: [Rh(COD)Cl]2, 5 mol %, KI, 10 mol %, CO, 5
atm, H2, 5 atm, toluene, 10 mL, 100 °C, 15 h. b Isolated yield after
purification by column chromatography.
reductive ring expansion of oxazolidines 1a-g provides
N-methylmorpholin-2-ones 3a-g in good to excellent yields.
Neither the nature, nor the stereo configuration of the
Org. Lett., Vol. 10, No. 7, 2008
1359