Synthesis of 4-hydroxy-2-oxazolidinones catalyzed by tin alkoxides

Article abstract of DOI:10.1002/ejoc.201101465

Synthesis of 4-hydroxy-2-oxazolidinone derivatives was accomplished from the reaction of α-hydroxy ketones with isocyanates in the presence of a catalytic amount of a tin alkoxide. The reactions proceeded under mild conditions and are highly atom economic

Full text of DOI:10.1002/ejoc.201101465

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101465
Synthesis of 4-Hydroxy-2-oxazolidinones Catalyzed by Tin Alkoxides
Ryota Kojima,[a] Satoshi Sawamoto,[a] Aritomo Okamura,[a] Hiroki Takahashi,[a]
Shinji Tsunoi,[a] and Ikuya Shibata*[a]
Keywords: Heterocycles / Tin / Ketones / Isocyanates / Diastereoselectivity
Synthesis of 4-hydroxy-2-oxazolidinone derivatives was ac-
complished from the reaction of α-hydroxy ketones with iso-
cyanates in the presence of a catalytic amount of a tin alk-
oxide. The reactions proceeded under mild conditions and
are highly atom economical.
Table 1. Effects of catalysts.[a]
Introduction
2-Oxazolidinones[1] are important heterocyclic com-
pounds that are useful as intermediates in organic synthesis
and as biologically active compounds.[2] The reaction of α-
hydroxy ketones with isocyanates to give 2-oxazolidi-
nonones is highly atom economical. Recently, reactions un-
der microwave irradiation have been reported by Tamariz
et al.,[3] in which exo-methylene-type oxazolidinones were
produced. We present here the tin-catalyzed reaction of α-
hydroxy ketones with isocyanates under mild conditions to
produce 4-hydroxy-2-oxazolidinones. In the catalytic reac-
tion, the nucleophilic Sn–O and Sn–N bonds work very well
as active catalytic species.[4]
Entry
Catalyst
Conditions
Yield / %
1
2
3
4
5
6
7
none
Bu2Sn=O
Bu3SnOMe
Bu2Sn(OMe)2
Bu3SnOMe
Bu2Sn(OMe)2
Bu2Sn(OMe)2
80 °C, 3 h
80 °C, 3 h
80 °C, 3 h
80 °C, 3 h
trace
62
68
72
81
87
61
MW, 110 °C, 5 min[b]
MW, 110 °C, 5 min[b]
MW, 110 °C, 5 min[b,c]
[a] The reaction was carried out with 1a (1 mmol), BuN=C=O
(1 mmol), and the catalyst (0.1 mmol) in MeCN (1 mL). [b] 30 W.
[c] THF (1 mL) was used as the solvent.
Results and Discussion
Initially, the reaction involving acetoin (1a) and n-butyl
isocyanate was examined, as shown in Table 1. Without a
catalyst, no reaction proceeded at 80 °C for 3 h (Table 1,
Entry 1). In the presence of the tin catalyst (10 mol-%), 4-
hydroxy-4-methyl-1,3-oxazolidin-2-one (2a) was obtained
(Table 1, Entries 2–4). Although heating conditions caused
effective reactions, microwave irradiation also gave desired
2a in only 5 min (Table 1, Entries 5 and 6). THF solvent
was also useful (Table 1, Entry 7).
Next, the reactions were performed by using various α-
hydroxy ketones 1 and isocyanates and were catalyzed by
Bu2Sn(OMe)2 under microwave irradiation (Table 2). In the
reaction of 1a, 4-hydroxy-1,3-oxazolidin-2-one (2b) was ob-
tained (Table 2, Entry 2). Thus, aliphatic and aromatic iso-
cyanates were applicable. Secondary alcohol 1b also reacted
with isocyanate to give the corresponding oxazolidinones
2c–2e, in which trans-dimethyl-substituted ones predomi-
nated (Table 2, Entries 3–5). Sterically hindered tertiary
alcohol 1c was also reactive under the conditions and gave
tetrasubstituted oxazolidinone 2f (Table 2, Entry 6). Thus,
from these reactions, products possessing labile α-aminal
functionalities were obtained. In almost cases, the desired
products were obtained in only 5 min.
A plausible catalytic cycle is described in Scheme 1. The
Sn–O and Sn–N bonds bear high nucleophilicity.[5] Initially,
tin methoxide reacts with α-hydroxy ketone 1 to give α-stan-
noxy ketone A. The Sn–O bond of A adds to an isocyanate
to form stannyl carbamate B.[6] The resulting Sn–N bond
adds to the remaining carbonyl moiety intramolecularly.
The Sn–O bond of cyclized product C reacts with starting
α-hydroxy ketone 1. As a result, 4-hydroxy-4-methyl-1,3-ox-
azolidin-2-one (2) is obtained with the regeneration of cata-
lytic species A.[7]
[a] Research Center for Environmental Preservation,
Osaka University,
2-4 Yamadaoka, Suita, Osaka, 565-0871, Japan
Fax: +81-(6)6879-8978
When benzoin (3) was used as a starting material, trans-
4,5-diphenyl-substituted oxazolidinone 4 was obtained un-
der heating conditions in 76% yield with high diastereo-
E-mail: shibata@epc.osaka-u.ac.jp
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101465.
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I. Shibata et al.
SHORT COMMUNICATION
Table 2. Reaction with α-hydroxy ketones 1 and isocyanates.[a]
steric repulsion between the two phenyl groups in the cycli-
zation step and further by the formation of the thermody-
namically stable 4,5-diphenyl-substituted structure.
Scheme 2. Reaction with the use of benzoin (3).
When an excess amount of isocyanate was treated with
3, a cyclized product involving internal tetrasubstituted alk-
ene 5 was obtained selectively (Scheme 3). This is because
of β-elimination from aminal product 4.[9]
Scheme 3. Reaction with the use of benzoin (3).
The reaction using allyldiphenyl-substituted substrate 6
afforded product 7. In contrast to the formation of 4, the
4,5-diphenyl substituents were oriented cis in product 7
(Scheme 4). The stereochemistry of 7 was determined by an
NOE study. This stereoselective reaction is explained in
terms of steric repulsion between the allyl and vic-phenyl
group in the cyclization step.[10]
[a] The reaction was carried out with 1 (1 mmol), BuN=C=O
(1 mmol), and Bu2Sn(OMe)2 (0.1 mmol) in MeCN (1 mL).
[b] Major stereoisomer was confirmed by X-ray crystallography.[8]
Scheme 1. Plausible cyclization mechanism.
Scheme 4. Reaction with the use of allyl-substituted benzoin 6.
The reaction of methyldiphenyl-substituted 8 proceeded
selectivity (Scheme 2). The stereochemistry of the main
product was determined by X-ray crystallography.[8] This effectively under MW irradiation, and cis-4,5-diphenyl-sub-
high diastereoselectivity can be explained in terms of the stituted product 9 was also obtained (Scheme 5).[8]
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Synthesis of 4-Hydroxy-2-oxazolidinones Catalyzed by Tin Alkoxides
Scheme 7. Reaction with isothiocyanate.
Scheme 5. Reaction with the use of methyl-substituted benzoin 8.
Conclusions
In summary, various nitrogen heterocyclic compounds
were obtained from α-hydroxy ketones 1. The advantage of
the presented reactions is that they are highly atom eco-
nomical where no side product was obtained at all.
In contrast to the reaction for diphenyl-substituted sub-
strates 3, 6, and 8 (Schemes 2, 4, and 5), the diastereoselec-
tivity of the reaction by using dimethyl-substituted sub-
strate 1b was dependent on the conditions (Table 3). Thus,
under microwave irradiation in polar solvent (Table 2, En-
try 3) or heating conditions (Table 3, Entry 1), trans-di-
methyl-substituted oxazolidinone 2c-trans was obtained
predominantly. On the other hand, heating for a short time
in THF (Table 3, Entry 2) afforded cis-4,5-dimethyl-substi-
tuted isomer 2c-cis as a major product. Prolonged reaction
time increased the ratio of 2c-trans (Table 3, Entry 3). Thus,
it was assumed that a reversible reaction occurred in the
reaction of 1b (Scheme 6).[11] At the initial stage, 2c-cis is
formed as a kinetically controlled product. Heating condi-
tions or prolonged reaction time results in the formation of
thermodynamically stable 2c-trans.[12]
Experimental Section
Representative Procedure for the Preparation of 2-Oxazolidinones
under Heating: A 10-mL round-bottomed flask was flame dried
under reduced pressure. Under an atmosphere of nitrogen, Bu2-
Sn(OMe)2 (0.0295 g, 0.1 mmol), MeCN (1.0 mL), α-hydroxy
ketone 1 (1.0 mmol), and the isocyanate (1.0 mmol) were added.
The mixture was heated at reflux (80 °C) and stirred for 3 h. The
reaction was quenched with H2O (0.5 mL), and the layers were
quickly separated. The aqueous phase was further extracted with
diethyl ether, and the combined extracts were dried with sodium
sulfate and concentrated. The crude product was then purified by
flash column chromatography (hexane/EtOAc, 9:1 to 3:7). The de-
sired product was obtained with an eluent mixture of hexane/
EtOAc = 7:3.
Table 3. Effect of the conditions in the reaction of 1b.[a]
Representative Procedure for the Preparation of 2-Oxazolidinones
under Microwave Irradiation: A 5-mL vial was flame dried under
reduced pressure. Under an atmosphere of nitrogen, Bu2Sn-
(OMe)2 (0.0295 g, 0.1 mmol), MeCN (1.0 mL), α-hydroxy ketone 1
(1.0 mmol), and the isocyanate (1.0 mmol) were added. The vial
was sealed with a septum and was set in the microwave reactor.
The mixture was stirred under microwave irradiation at 30 W for
5 min. The reaction temperature was measured by an IR sensor.
A representative temperature profile is shown in the Supporting
Information. After the reaction, the mixture was quenched with
H2O (0.5 mL), and the layers were quickly separated. The aqueous
phase was further extracted with diethyl ether, and the combined
extracts were dried with sodium sulfate and concentrated. The
crude product was then purified by flash column chromatography
(hexane/EtOAc, 9:1 to 3:7). The desired product was obtained with
an eluent mixture of hexane/EtOAc = 7:3.
Entry
Conditions
Yield / %
Ratio trans/cis
1
2
3
MeCN, 80 °C, 3 h
THF, 60 °C, 15 min
THF, 60 °C, 60 min
81
87
89
76:24
8:92
26:74
[a] The reaction was carried out with 1b (1 mmol), BuN=C=O
(1 mmol), and Bu2Sn(OMe)2 (0.1 mmol), in solvent (1 mL).
Recrystallization of 2e, 4, and 9 was performed from hexane with
the addition of a small amount of Et2O.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental and characterization data of all new compounds.
Acknowledgments
Scheme 6. Reversible reaction of acetoin 1b.
This research was supported by the Ministry of Education, Science,
Sports, and Culture, Japan, the Japan Securities Scholarship Foun-
dation and the Naito Foundation.
Other than isocyanates, isothiocyanate (RN=C=S) could
be used as an electrophile (Scheme 7). The addition oc-
curred across the C=N group of the isothiocyanate.[13]
Thus, oxazolidin-2-thione 10 was obtained selectively. Sim-
ilar to the case of isocyanates, the α-aminal moiety was in-
volved.
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Eur. J. Org. Chem. 2011, 7255–7258
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I. Shibata et al.
SHORT COMMUNICATION
[2] a) G. Cardillo, M. Orena, S. Sandri, C. Tomashini, Tetrahedron
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[7]
[8]
Tin-catalyzed cycloadditions with the use of epoxides has been
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Chem. 1986, 51, 2177–2184.
CCDC-822458 (for 2e), -840180 (for 4), and -822457 (for 9)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_r-
equest/cif.
[3] Dehydrated cyclic products were obtained under MW irradia-
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[4] For examples of the synthetic uses of organotin compounds,
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[5] Sn–O and Sn–N bonds bear high nucleophilicity. In some
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[9]
In the reaction of Scheme 2, product 5 was not formed during
isolation. Although the exact reason for the formation of 5 is
not clear, we suppose that, for example, by using an excess
amount of isocyanate, formation of the carbamate of the cy-
clized product would accelerate the elimination to give 5.
In the cyclization of allyldiphenyl-substituted tin adducts, we
have already reported that diphenyl substituents prefer to ori-
ent in a cis fashion. I. Shibata, R. Kojima, S. Tsunoi, T. No-
zaki, T. Watanabe, A. Ninomiya, M. Yasuda, A. Baba, Org.
Biomol. Chem. 2010, 8, 2009–2011.
[10]
[11] Tamariz et al. also propose a similar equilibrium: R. Martinez,
H. A. Jiménez-Vázquez, J. Tamariz, Tetrahedron 2000, 56,
3857–3866.
[12] For the reaction of diphenyl-substituted substrates 3, 6, and
8, the diastereoselectivity was not changed by the conditions.
Because the Ph group is bulkier than the Me group, the use of
3, 6, and 8 would not cause a reversible reaction in contrast to
the case of 1b.
[13] In the cycloaddition of epoxides, the addition occurred across
the C=S group of the isothiocyanate.[7]
Received: October 8, 2011
Published Online: November 8, 2011
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Eur. J. Org. Chem. 2011, 7255–7258