A new method for stereoselective oxidation of chiral 2-pyrrolidino-1- ethanol derivatives to oxazolopyrrolidines using trimethylamine-N-oxide in the presence of iron carbonyls

Article abstract of DOI:10.1016/j.tetlet.2005.03.101

Chiral 2-pyrrolidino-1-ethanol derivatives were oxidatively cyclized to the corresponding oxazolopyrrolidines, with excellent stereoselectivity by treatment with excess Me₃NO in the presence of 20% of an iron carbonyl complex.

Full text of DOI:10.1016/j.tetlet.2005.03.101

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3407–3410
A new method for stereoselective oxidation of chiral
2-pyrrolidino-1-ethanol derivatives to oxazolopyrrolidines
using trimethylamine-N-oxide in the presence of iron carbonyls
Anthony J. Pearson* and Yoonhyun Kwak
Department of Chemistry, Case Western Reserve University, Cleveland, OH 44106, USA
Received 25 January 2005; revised 28 February 2005; accepted 11 March 2005
Available online 2 April 2005
Abstract—Chiral 2-pyrrolidino-1-ethanol derivatives were oxidatively cyclized to the corresponding oxazolopyrrolidines, with excel-
lent stereoselectivity by treatment with excess Me3NO in the presence of 20% of an iron carbonyl complex.
Ó 2005 Elsevier Ltd. All rights reserved.
Pyrrolidine ring systems are of considerable interest in
organic chemistry because they are present in the struc-
tures of numerous biologically important compounds
and natural products.1 In addition, this heterocyclic
moiety can be used as a structural component of chiral
auxiliaries and chiral ligands for asymmetric synthesis.2
So it is not surprising that various approaches have been
developed for the stereoselective functionalization of
these heterocycles.3 Oxazolopyrrolidines occupy an
important place as intermediates for the construction
of substituted pyrrolidines,4 since they undergo stereo-
controlled ring-opening reactions with organometallic
reagents such as Grignard and Reformatsky reagents.5
Moreover, chiral oxazolidines have themselves been
widely exploited as chiral templates in asymmetric syn-
thesis.6 However, most of the practical syntheses of
oxazolidines have been carried out by condensation of
amino alcohols with an aldehyde or its equiva-
lent,4a,c,6a–c and even though other methods have been
reported, they are less practical because of harsh reac-
tion conditions or low yields.7
In this letter we report a new method for oxidative cycliz-
ation of chiral 2-pyrrolidino-1-ethanol derivatives that
promises to be a valuable approach for functionaliz-
ation of the pyrrolidine ring. The oxidation uses trimeth-
ylamine-N-oxide in the presence of sub-stoichiometric
amounts of an iron carbonyl. Various reaction condi-
tions were examined for this transformation, using com-
pound 1a as the test system (Eq. 1), and these are
summarized in Table 1, along with the results for other
pyrrolidines using the optimized conditions. While benz-
ene was used as solvent for the reactions listed here,
acetonitrile can also be used. A single diastereomer,
thermodynamically more stable according to MM2 cal-
culations, was formed in each case except 1c, which gave
a 7:1 mixture in favor of 2c, and the structures were con-
firmed by NMR NOESY experiments and comparison
with similar known compounds.4 As far as we are
aware, this is the first reported example of an oxidation
reaction promoted by this reagent combination.
Trimethylamine-N-oxide is generally used to remove
CO ligands from metal carbonyls, and to demetallate
R
R
R
a R = PhCH2
OH
OH
Me3NO, catalyst
PhH, rt, 8h
NH2
b R = Ph
N
N
Br
Br
O
ð1Þ
c R = i-Pr
d R = CO2But
78-89%
1
2
*
Corresponding author. Tel.: +1 216 3685920; fax: +1 216 3683006; e-mail: ajp4@po.cwru.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.101

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A.J.Pearson, Y.Kwak / Tetrahedron Letters 46 (2005) 3407–3410
Table 1. Reaction conditions for oxidation of chiral 2-pyrrolidino-1-
ethanol derivatives to oxazolopyrrolidines
CHDFe(CO)3, even for prolonged reaction time gave
no oxidation products, and starting material was recov-
ered quantitatively. This is not surprising in view of the
known role of hydroxyl groups in a variety of transition
metal catalyzed oxidation reactions.12 Presumably the
actual oxidant becomes coordinated to the OH group
and the amine oxidation reaction occurs intramolecu-
larly. While the exact details of this process are not
known, we believe that an iminium intermediate is
formed, and the hydroxyl reacts with this moiety to
form the oxazolidine ring. This is suggested by the
observation that 1b gave a low yield of 2b, and the only
other product that we observed is N-benzoylpyrrolidine
(3, Eq. 2). A plausible mechanism that accounts for the
formation of 3 is outlined in the Scheme 1.
Substrate Catalyst (mol %)
Me3NO, equiv Product (% yield)
1a
1a
1a
1a
1b
1c
1d
CHDFe(CO)3 (20) 6.0
CHDFe(CO)3 (20) 2.0
Fe(CO)4PPh3 (20) 6.0
Fe(CO)5 (20) 6.0
2a (91)
2a (40)a
2a (90)
2a (ca. 10)a
2b (28)
CHDFe(CO)3 (20) 6.0
CHDFe(CO)3 (20) 6.0
CHDFe(CO)3 (20) 6.0
2c (83)b
2d (76)
a Unreacted starting material was recovered.
b Inseparable 7:1 mixture of diastereomers.
diene–Fe(CO)3 complexes,8 though the mechanisms of
these processes are still unclear,9 and we do not presently
have any information on the nature of the actual oxidant.
Both amine oxide and iron carbonyl are essential for this
reaction. When either was omitted starting material
was recovered quantitatively. An excess of Me3NO is re-
quired for high yield conversion, 2 equiv leading to only
40% yield over a reaction time of 8 h. Generally we have
used 6 equiv to ensure complete oxidation in a reason-
able time. The reaction uses sub-stoichiometric amount
of the iron carbonyl, but since these complexes are
slowly destroyed by the amine oxide, 20 mol % was
generally used to ensure completion of reaction before
the catalyst is lost.
Ph
Ph
Ph
O
OH
Me3NO, CHDFe(CO)3
PhH, rt, 8h
N
N
O
N
+
1b
2b
3
ð2Þ
For most substrates, intermediate 4 is the preferred
iminium cation (with an endocyclic double bond), and
cyclization of the pendant OH group affords 2. How-
ever, when R = Ph, resonance stabilization of the alter-
native iminium 5 promotes its formation in addition to
4. Since the hydroxyl cannot cyclize onto the iminium
cation of 5, this intermediate instead reacts with the
amine oxide to generate 6, fragmentation of which gene-
rates 3 in addition to formaldehyde and trimethylamine
(as its ammonium salt). This type of reaction of amine
oxides is known to account for the conversion of alkyl
bromides to carbonyl compounds when treated with
Me3NO,13 a reaction that is closely related to the
Kornblum oxidation.14
Pentacarbonyliron is more reactive toward Me3NO, and
is completely destroyed before the pyrrolidine oxidation
has proceeded to the extent of 10%. The phosphine
derivative, Fe(CO)4PPh3, is a stable and inexpensive
solid that has excellent shelf life,10 but for the present
applications it was difficult to separate residual iron
complex from the products. The 1,3-cyclohexadiene
complex, CHDFe(CO)3, is readily prepared,11 affords
comparable yields to those obtained using Fe(CO)4
PPh3, and is easier to separate from the oxidation prod-
uct, so we used this material for all subsequent reactions.
Iron carbonyls appear to be uniquely suited for this
transformation, as attempts to convert 1a to 2a under
similar conditions by using FeCl3, FeSO4, or Fe(OAc)2
as catalysts were completely unsuccessful, and 1a was
recovered unchanged in each case.
The mechanism shown here is supported by the obser-
vation that 1 (R = 4-methoxyphenyl) gives a poorer
yield (12%) of the cyclization product 2, with a greater
amount of the corresponding benzamide, while 1
(R = 2-nitrophenyl) gives a higher yield (35%) of 2
(R = 2-nitrophenyl), with a smaller amount of the benz-
amide. These results are consistent with the expected
The oxidation requires a neighboring hydroxyl group—
treatment of the methyl ether of 1a with Me3NO/
R
OH
N
2
path A
R
OH
4
N
NMe3
N
R
O
O
NMe3
OH
5
OH
R
3 + HCHO + Me3NH+
path B
N
6
Scheme 1.

A.J.Pearson, Y.Kwak / Tetrahedron Letters 46 (2005) 3407–3410
3409
Ph
Ph
OH
Ph
OH
O
H
N
N
N
no reaction
ð3Þ
90%
7
8
9 (1.6:1)
Wiley and Sons: New York; (b) Attygalle, A. B.;
Morgan, E. D. Chem.Soc.Rev.
Michael, J. P. Nat.Prod.Rep.
stabilities of the cations 5, though we were not able to
completely suppress the undesired pathway.
1984, 13, 245; (c)
2001, 18, 520–542; (d)
Garraffo, H. M.; Jain, P.; Spande, T. F.; Daly, J. W.;
Jones, T. H.; Smith, L. J.; Zottig, V. E. J.Nat.Prod.
2001, 64, 421–427.
Further evidence for the intermediacy of an iminium
intermediate comes from studies on the cyclization of re-
lated piperidine and azacycloheptane derivatives (Eq. 3).
Thus, the six-membered ring derivative 7 was completely
resistant to oxidation under the normal conditions,
while 8 was converted to 9 in excellent yield (as a 1.6:1
mixture of diastereomers, which are calculated to have
similar MM2 energies). Both mechanistic studies and
synthetic applications for oxidative functionalization
of tertiary amines have been described in the literature,15
and it is known that the rate constant for oxidation of a
five- or seven-membered ring amine is 5 and 13 times
greater, respectively, than that of the six-membered ring
system.16 This has been attributed to the energy differ-
ence associated with planarization of the nitrogen in
these ring systems during conversion of the amine to
an iminium cation. Our results are therefore consistent
with this mechanism.
2. (a) Huryn, D. M. In Comprehensive Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 1, p64; (b) Whitesell, J. K. Chem.Rev. 1989, 89,
1581–1590; (c) Whitesell, J. K. Acc.Chem.Res. 1985, 18,
280–284; (d) Sprott, K. T.; Corey, E. J. Org.Lett. 2003, 5,
2465–2467.
3. (a) Lutete, L. M.; Kadota, I.; Yamamoto, Y. J.Am.
Chem.Soc. 2004, 126, 1622–1623; (b) Jahn, U.; Muller,
¨
M.; Aussieker, S. J.Am.Chem.Soc. 2000, 122, 5212–5213;
(c) Trost, B. M.; Pinkerton, A. B.; Kremzow, D. J.Am.
Chem.Soc. 2000, 122, 12007–12008; (d) Marks, T. J.;
Hong, S. J.Am.Chem.Soc.
2002, 124, 7886–7887; (e)
Burgess, L. E.; Meyers, A. I. J.Am.Chem.Soc. 1991, 113,
9858–9859.
4. (a) Husson, H.-P.; Royer, J. Chem.Soc.Rev. 1999, 28,
383–394; (b) Katritzky, A. R.; Cui, X.-L.; Yang, B.; Steel,
´
P. J. J.Org.Chem. 1999, 64, 1979–1985; (c) Andres, J. M.;
Herraiz-Sierra, I.; Pedrosa, R.; Perez-Encabo, A. Eur.
´
´
J.Org.Chem. 2000, 1719–1726.
5. (a) Takahashi, H.; Niwa, H.; Higashiyama, K. Heterocy-
cles 1988, 27, 2099–2102; (b) Wu, M.-J.; Pridgen, L. N. J.
In summary, we have discovered a novel oxidizing
system that allows the stereoselective conversion of N-
hydroxyethylpyrrolidines to oxazolopyrrolidines. These
products are known to have useful chemistry that allows
their applications in synthesis of substituted pyrrolidine
derivatives. Future efforts in our laboratory will be
focused on exploring the chemistry of these systems, as
well as other oxidation reactions promoted by the
Me3NO/iron carbonyl system.17
Org.Chem.
Alvarez, M. A.; Andres, C.; Gonzalez, A.; Pedrosa, R.
1991, 56, 1340–1344; (c) Alberola, A.;
´
Synthesis 1990, 1057–1058; (d) Andres, C.; Gonzalez, A.;
´
´
Pedrosa, R.; Perez-Encabo, A. Tetrahedron Lett. 1992,
´
´
33(20), 2895–2898; (e) Muralidharan, K. R.; Mokhal-
lalati, M. K.; Pridgen, L. N. Tetrahedron Lett. 1994, 35,
7489–7492.
6. (a) Hoppe, I.; Hoppe, D.; Wolff, C.; Egert, E.; Herbst, R.
1989, 28, 67–69; (b)
Angew.Chem, . Int.Ed.Engl.
Scolastico, C. Pure Appl.Chem. 1988, 60(11), 1689–1698;
(c) Adam, W.; Peters, K.; Peters, E.-M.; Schambony, S. B.
J.Am.Chem.Soc. 2000, 122, 7610–7611; (d) Adam, W.;
Schambony, S. B. Org.Lett. 2001, 3, 79–82.
Acknowledgements
We are grateful to the National Science Foundation for
financial support of this research.
7. (a) Mo¨hrle, H.; Kamper, C. Die Pharm. 1983, 38, 512–520;
(b) Leonard, N. J.; Musker, W. K. J.Am.Chem.Soc.
1960, 82, 5148–5155; (c) Pandey, G.; Kumaraswamy, G.
Tetrahedron Lett. 1988, 29, 4153–4156.
Supplementary data
8. Shvo, Y.; Hazum, E. Chem.Commun.
337.
9. (a) Eekhof, J. H.; Hogeveen, H.; Kellogg, R. M. Chem.
Commun. 1976, 657; (b) Elzinga, J.; Hogeveen, H. Chem.
Commun. 1977, 705–706.
10. Clifford, A. F.; Mukherjee, A. K. Inorg.Chem. 1963, 2,
151–153.
11. (a) Pearson, A. J. Iron Compounds in Organic Synthesis;
Academic: San Diego, 1994, Chapter 4; (b) Kno¨lker, H.-J.;
Ahrens, B.; Gonser, P.; Heininger, M.; Jones, P. G.
Tetrahedron 2000, 56, 2259–2271.
1974, 336–
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.03.101. Experimental procedures for the prepara-
tion of compounds 1, as well as the oxidation of 1 to
2, and spectroscopic data of all new compounds. The
supplementary data is available online with the paper
in ScienceDirect.
References and notes
12. Katsuki, T.; Sharpless, K. B. J.Am.Chem.Soc. 1980, 102,
5974–5976.
1. (a) Elbein, A. D.; Molyneux, R. In Alkaloids; Chemical
and Biological Perspectives; Pelletier, S. W., Ed.; John
13. Franzen, V.; Otto, S. Chem.Ber.
1363.
1961, 94, 1360–

3410
A.J.Pearson, Y.Kwak / Tetrahedron Letters 46 (2005) 3407–3410
14. Kornblum, N.; Powers, J. W.; Anderson, G. J.; Jones, W.
J.; Larson, H. O.; Levand, O.; Weaver, W. M. J.Am.
Chem.Soc. 1957, 79, 6562.
C.; Rool, P.; Santamaria, J. Tetrahedron Lett. 1998, 39,
9423–9426; (d) Burka, L. T. J.Am.Chem.Soc. 1985, 107,
2549–2551.
15. (a) North, M. Angew.Chem., Int.Ed. 2004, 43, 4126–4128;
(b) Murahashi, S.-I.; Komiya, N.; Terai, H.; Nakae, T.
16. Wang, F.; Sayre, L. M. J.Am.Chem.Soc. 1992, 114, 248–255.
17. Dasgupta, B.; Donaldson, W. A. Tetrahedron Lett. 1998,
39, 343–346.
J.Am.Chem.Soc.
2003, 125, 15312–15313; (c) Ferroud,