A Multicomponent Approach to Oxazolidinone Synthesis Catalyzed by Rare-Earth Metal Amides

Article abstract of DOI:10.1002/cctc.201900221

Three-component reaction of epoxides, amines, and dimethyl carbonate catalyzed by rare-earth metal amides has been developed to synthesize oxazolidinones. 47 examples of 3,5-disubstituted oxazolidinones were prepared in 13–97 % yields. This is a simple and most practical method which employs easily available substrates and catalysts, and is applicable to a wide range of aromatic and aliphatic amines, as well as mono-substituted epoxides. Scope of disubstituted epoxides is rather limited, which requires further study. Preliminary mechanistic study reveals two possible reaction pathways through intermediates of β-amino alcohols or amides.

Full text of DOI:10.1002/cctc.201900221

Accepted Article
Title: A Multicomponent Approach to Oxazolidinone Synthesis
Catalyzed by Rare-Earth Metal Amides
Authors: Meixia Zhou, Xizhou Zheng, Yaorong Wang, Dan Yuan, and
Yingming Yao
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10.1002/cctc.201900221
ChemCatChem
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A Multicomponent Approach to Oxazolidinone Synthesis
Catalyzed by Rare-Earth Metal Amides
Meixia Zhou,[a] Xizhou Zheng,[a] Yaorong Wang,[a] Dan Yuan,*[a] and Yingming Yao*[a]
Three-component reaction of epoxides, amines, and dimethyl
carbonate catalyzed by rare-earth metal amides has been developed
to synthesize oxazolidinones. 47 examples of 3,5-disubstituted
oxazolidinones were prepared in 13-97% yields. This is a simple and
most practical method which employs easily available substrates
and catalysts, and is applicable to a wide range of aromatic and
aliphatic amines, as well as mono-substituted epoxides. Scope of
disubstituted epoxides is rather limited, which requires further study.
Preliminary mechanistic study reveals two possible reaction
pathways through intermediates of β-amino alcohols or amides.
practical approach to a broad range of oxazolidinone synthesis
is highly desirable.
Our group has reported rare-earth metal complexes that
catalyzed oxazolidinone synthesis, through reaction of epoxides
and isocyanates,[4f] as well as three-component reaction of CO2,
epoxides and anilines.[7d] As part of our ongoing studies on
efficient synthesis of oxazolidinones, we studied three-
component reaction of epoxides, amines and dialkyl carbonates
catalyzed by readily available rare-earth metal amides RE(μ-
Cl)Li[(Me3Si)2N]3(THF)3. A wide range of anilines and aliphatic
amines reacted with epoxides and dialkyl carbonates, and
generated 47 oxazolidinones in 13-97% yields, which is a most
practical and widely applicable method to synthesize
oxazolidinones.
Introduction
Oxazolidinones are important intermediates in organic
synthesis,[1] which also find potential application as HIV-1
protease inhibitors, antibiotics, and antidepressant drugs.[2]
Many methods have been developed to produce oxazolidinones,
including carbonylation reaction of β-amino alcohols with CO2 or
dialkyl carbonates,[3] cycloaddition reaction of epoxides with
isocyanates,[4] and reaction of CO2 with propargylamines or
ethyleneimines.[5] Among them, starting materials are either of
limited availability (e.g., isocyanates, propargylamines, and
ethyleneimines), or highly toxic (e.g., isocyanates). Kleij, Gao
and others reported reactions of epoxides and carbamates,
which generated 3-H and 3-aryloxazolidinones, whereas 3-
alkyloxazolidinones were not accessible.[6] In recent years, a
three-component reaction of amines, epoxides, and CO2, has
received increasing interests, as it employs easily available
starting materials, and transforms CO2 into value added
compounds.[7] A modified version of the three-component
reaction involves 1,2-dihaloethanes, amines and CO2.[8] However,
limitations such as addition of one or more equivalents of bases
and largely excessive epoxides or dihaloethanes, and low
activity of aliphatic amines have hindered their application.
Results and Discussion
A
series
of
rare-earth
metal
amides
RE(μ-
Cl)Li[(Me3Si)2N]3(THF)3 [RE = La (1), Nd (2), Sm (3), Y (4), Yb
(5)] were tested in catalyzing three-component reaction of
aniline (1a), 2-(phenoxymethyl)oxirane (2a), and dimethyl
carbonate
(DMC)
(Table
1).
5-(Phenoxymethyl)-3-
phenyloxazolidin-2-one (3a) was obtained in 73-97% yields after
12 h reaction at 80 ºC under neat conditions (Table 1, entries 2-
6). In comparison, trace amount of product was detected without
any catalyst (Table 1, entry 1). Catalytic activity of rare-earth
metal amides decreased as ionic radii of metal ions decreased.
Almost quantitative yield of 97% was obtained in the presence of
La(μ-Cl)Li[(Me3Si)2N]3(THF)3 (1) (Table 1, entry 2). It is
noteworthy that La[(Me3Si)2N]3 (6) showed inferior activity
comparing to that of complex 1 incorporating LiCl, suggesting
that the presence of LiCl improves catalytic activity (Table 1,
entry 7). Indeed, addition of LiCl into La[(Me3Si)2N]3-catalyzed
reaction led to an improved yield of 92% (Table 1, entry 8). LiCl-
enhanced catalytic activity has been reported in rare-earth metal
Recently, Jamieson et al. developed
a modified three-
amide-catalyzed aldol reaction[10] and alkene epoxidation[11]
,
component reaction replacing CO2 with dialkyl carbonates. This
reaction was mediated by phosphazene base BEMP,[9] which
worked well with aliphatic amines, while reactions of aniline
derivatives remain to be explored. Therefore, developing a more
attributing to cooperation of Ln and Li cations. Different reaction
conditions, including substrate ratios, catalyst loadings, solvents
and reaction time were then screened (Table S1), and the
optimal condition is confirmed as follows: 2 mol% of complex 1,
80 ºC, 12 h reaction time, substrate ratio of 2:1:2 (1a: 2a: DMC),
neat (Table 1, entry 2). Different dialkyl carbonates were also
studied (Table 1, entries 9 and 10), and DMC is selected for
further study as the reaction has the advantages of high-yielding,
high atom economy, and easy purification due to low boiling
point of DMC. Moreover, DMC is of low toxicity, which finds
potential application in green and sustainable manufacturing.
[a]
M. Zhou, X. Zheng, Prof. Y. Wang, Dr. D. Yuan, Prof. Y. Yao
Laboratory of Organic Synthesis of Jiangsu Province
College of Chemistry, Chemical Engineering and Materials Science
Dushu Lake Campus, Soochow University
Suzhou 215123 (P.R. China)
E-mail: yuandan@suda.edu.cn (D. Y.)
yaoym@suda.edu.cn (Y. Y.)
Supporting information for this article is given via a link at the end of
the document.
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Table 1. Condition Screening for the Reaction of Aniline, 2-
(Phenoxymethyl)oxirane, and Dimethyl Carbonate.[a]
Table 2. Substrate Scope of Anilines[a]
Entry
Catalyst
Yield(%)[b]
1
-
Trace
97
2
La(μ-Cl)Li[(Me3Si)2N]3(THF)3 (1)
Nd(μ-Cl)Li[(Me3Si)2N]3(THF)3 (2)
Sm(μ-Cl)Li[(Me3Si)2N]3(THF)3 (3)
Y(μ-Cl)Li[(Me3Si)2N]3(THF)3 (4)
Yb(μ-Cl)Li[(Me3Si)2N]3(THF)3 (5)
La[(Me3Si)2N]3 (6)
3
93
4
89
5
88
[a] Reaction conditions: aniline (2 mmol), 2-(phenoxymethyl)oxirane 2a (1
mmol), dimethyl carbonate (2 mmol), complex 1 (0.02 mmol, 2 mol%), 80 ºC,
12 h, isolated yield.
6
73
7
81
8
La[(Me3Si)2N]3 (6) + LiCl
La(μ-Cl)Li[(Me3Si)2N]3(THF)3 (1)
La(μ-Cl)Li[(Me3Si)2N]3(THF)3 (1)
92
Although three-component reaction of amines, CO2 and
epoxides also produces oxazolidinones, low to no activities of
aliphatic amines is a common limitation of this method (vide
supra).[7a-e,g,h] It is thus important to study the performance of
rare-earth metal amides in catalyzing reaction of aliphatic
amines, epoxides, and DMC. Under afore-established condition,
the reaction of benzyl amine with 2-(phenoxymethyl)oxirane and
DMC gave product 3m in a moderate yield of 76% (Table S2,
entry 1). Further optimization of reaction conditions revealed that
4 mol% catalyst loading gave rise to significantly improved yield
of 95% (Table S2, entries 2-5).
Various aliphatic amines were studied and results are
summarized in Table 3. Substituted benzyl amines reacted
straightforwardly, which yielded desired products 3n and 3o in
95% and 87% yields, respectively. Bulkier α-substituted benzyl
amines, i.e., 1-phenylethan-1-amine and 2-phenylpropan-2-
amine, reacted sluggishly, and generated oxazolidinones 3p and
3q in yields of 54% and 19%, respectively. The latter yield was
improved to 60% through increasing catalyst loading to 8 mol%,
whereas the BEMP-based system did not show any activity.[9c]
Reactions of 2-phenylethan-1-amine and 3-phenylpropan-1-
amine gave comparable yields of 92% (3r) and 84% (3s),
respectively. Cyclic and linear aliphatic amines, including
heteroatom-containing substrates, were studied and yields of
desired oxazolidinones 3t-z fell in the range of 70-94%. For
sterically hindered 2-methylpropan-2-amine, the corresponding
oxazolidinone 3za was isolated in a good yield of 87%. Pyridin-
2-ylmethanamine and pyridin-3-ylmethanamine were converted
into oxazolidinones 3zb and 3zc in 78% and 65% yields,
respectively. These results reveal that this rare-earth metal
amide-catalyzed DMC-involved three component reaction is
applicable to both aromatic and aliphatic amines, which is
superior to that of CO2-participated three-component reaction.
9[c]
10[d]
95
82
[a] Reaction conditions: aniline 1a (2 mmol), 2-(phenoxymethyl)oxirane 2a (1
mmol), dimethyl carbonate (2 mmol), catalyst (2 mol%), 80 ºC, 12 h, neat. [b]
Determined by 1H NMR spectroscopy based on 2-(phenoxymethyl)oxirane
with 1,3,5-trimethoxybenzene as an internal standard. [c] Diethyl carbonate.
[d] Diphenyl carbonate.
Under optimal conditions, the scope of the three-component
reaction was studied (Table 2). Anilines bearing either electron-
donating or withdrawing groups in para or meta positions were
converted straightforwardly into corresponding oxazolidinones
(products 3b-f, 3h-k) in 86-92% yields. The only low yield of
57% was obtained from reaction of p-nitroaniline (1g), because
the strong electron-withdrawing substituent weakens its
nucleophilicity. In addition, the reaction of aniline with ortho-
substituents (e.g., chloro group in 1l) resulted in a poor yield of
13%, as a result of increased steric hindrance. This is the first
example of 3-aryloxazolidinone preparation from three
component reaction of epoxide, aniline, and dialkyl carbonate,
proving a simple approach to synthesize oxazolidinones from
easily available starting materials and catalysts. In addition, the
reaction works under neat conditions, and produces MeOH as
the only byproduct.
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infra). Increasing the catalyst loading to 8 mol% led to improved
yield of 67%. Reaction of 2,2-dimethyloxirane did not form
oxazolidinone, but generated β-amino alcohol 4l1 almost
exclusively. Al-aminotriphenolate complex-catalyzed reactions of
disubstituted epoxides and phenyl carbamate gave better results
(48-77% yields) under mild conditions (50 ºC, 2 mol% cat.).[6c]
Table 3. Scope of Aliphatic Amines[a]
Table 4. Scope of Epoxides[a]
[a] Reaction conditions: amine (2 mmol), 2-(phenoxymethyl)oxirane 2a (1
mmol), dimethyl carbonate (2 mmol), complex 1 (0.04 mmol, 4 mol%), 80 ºC,
12 h, isolated yield. [b] 8 mol% catalyst loading.
On the basis of amine scope study, different epoxides were
investigated (Table 4). Monosubstituted epoxides bearing ether,
alkyl, alkenyl, phenyl, or hydroxyl groups were converted into
various oxazolidinones in 32-94% yields. Reactions of ether-
containing epoxides yielded 3,5-disubstituted oxazolidinones in
80-94% yields (products 4b-d and 5b-e), without deactivating
the catalyst. Reaction of methyl glycidyl ether produced
oxazolidinone 4e in 67% yield, along with β-amino alcohol 4e1 in
28% yield. Improved yield of 91% was obtained by increasing
the catalyst loading to 4 mol%. Besides, epoxides bearing alkyl
or alkenyl groups were also tolerated and generated
corresponding oxazolidinones in yields of 70-80% (products 4f-h
and 5f-h). Different regioselectivity was observed in reactions of
styrene oxide, due to favorable ring-opening at benzylic
positions. Mixtures of 4- and 5- substituted oxazolidinones were
obtained in overall 66% and 72% yields, respectively. In addition,
the reaction of epoxide bearing a hydroxyl group (i.e., oxiran-2-
ylmethanol) yielded oxazolidinone 4j in 32% yield,[12a] along with
β-amino alcohol 4j1 (14% yield),[12b] and oxazinanone 4j2 (23%
yield),[12c] which was attributed to a reduced chemo-selectivity
caused by the OH group.
[a] Reaction conditions: amine (2 mmol), epoxide (1 mmol), dimethyl
carbonate (2 mmol). R1 = Ph: complex 1 (2 mol%); R1 = Bn: complex 1 (4
mol%). 80 ºC, 12 h, isolated yield. [b] 4 mol% catalyst. [c] 8 mol% catalyst.
Control experiments were conducted to further understand the
reaction mechanism (Scheme 1). 2-(phenoxymethyl)oxirane 2a
was treated with 1 equivalent of aniline in the absence of
complex 1, which generated amino alcohols A and B in 48% and
20% yields, respectively. The same results were obtained in the
presence of 2 mol% complex 1 as well. Formation of B should
Reactions of disubstituted epoxides proceeded sluggishly due
to steric hindrance. Cyclohexene oxide was converted to trans-
3-phenylhexahydrobenzooxazolidin-2-one 4k as
a
single
diastereomer in 36% yield, along with trans-configured β-amino
alcohol 4k1 (48% yield),[13] and carbamate 4k2 (8% yield) (vide
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be suppressed under template catalytic conditions due to
presence of excess aniline. β-amino alcohols analogous to A
(i.e., compounds 4e1, 4j1, 4k1, and 4l1) were detected in
reactions of other epoxides (vide supra), suggesting that they
are intermediates of oxazolidinone formation.
oxazolidinones.[6a-e] This might be a minor route that is only
applicable to aliphatic amines (vide supra).
Scheme 2. Possible Pathway for the Three-Component Reaction.
With the multicomponent method in hand, we attempted to
synthesize linezolid, which is a oxazolidinone-based antibiotic,
from easily available starting materials (S)-N-(oxiran-2-
ylmethyl)acetamide (2m) and 3-fluoro-4-(4-morpholinyl)aniline
(1k).[15] Although under template conditions, 1k reacted
straightforwardly with 2-(phenoxymethyl)oxirane (2a) and
generated oxazolidinone 3k in 91% yield (Table 2), reaction with
(S)-N-(oxiran-2-ylmethyl)acetamide (2m) did not yield linezolid,
but generated oxazolidinones 4m1 and 4m2 (Scheme 3). Both
compounds are characterized by NMR and MS techniques, and
the identity of 4m1 is further confirmed by X-ray diffraction
analysis. Apparently, C-N bond of amide group was cleaved,
and ring-closure occurred preferentially to the NH side instead of
aniline side.
Scheme 1. Control Experiments to Produce Oxazolidinones.
At 30 ºC, β-amino-alcohol A reacted with excess amount of
DMC in the presence of complex 1, and formed compound 3a in
85% yield, along with 13% carbamate C. Intramolecular
transesterification of C leads to quantitative formation of 3a
under template condition, suggesting C as an intermediate for
3a.[6a-e]
This route is further proved by the stereochemistry of
cyclohexene oxide reaction. Starting from cis-configured
cyclohexene oxide, ring-opening of epoxides caused by
nucleophilic aniline led to configuration inversion, forming trans-
4k1. Subsequent amidation of 4k1 with DMC led to carbamate
4k2 formation, which underwent ring-closing to form
oxazolidinone 4k.
Another control reaction of aniline and DMC catalyzed by
complex 1 afforded urea D in 12% yield, which did not react with
2-(phenoxymethyl)oxirane 2a. On the other hand, benzyl amine
was converted into carbamate
E in 89% yield, which
subsequently reacted with 2-(phenoxymethyl)oxirane 2a and
produced oxazolidinone 3m in 15% yield determined by 1H NMR
spectroscopy.[6a-e]
Based on above-discussed findings, two plausible pathways
are proposed. The formation of amino alcohol followed by
reaction with DMC through amidation generating carbamate and
subsequent
intramolecular
transesterification
leads
to
oxazolidinone formation (Scheme 2).[3c-h] This procedure
resembles the reaction of epoxides and carbamates.[6] The other
pathway starts from formation of amides,[14] which generate
carbamates that further react with epoxides to yield
Scheme 3. Attempt to Synthesize Linezolid through Multicomponent Reaction.
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In summary, we have developed a simple and highly practical
rare-earth-metal-catalyzed multicomponent approach for the
synthesis of oxazolidinones. Starting materials, i.e., epoxides,
carbonate, and amines, are all easily available, and substrate
scope includes a wide range of aromatic and aliphatic amines,
as well as mono-substituted epoxides. 47 examples of variously
substituted oxazolidinones were obtained in 13-97% yields,
demonstrating wide applicability of this method. Scope of
disubstituted epoxides is limited, which requires further study.
Preliminary mechanistic studies reveal that two possible
pathways, i.e., through reaction of β-amino-alcohols and DMC,
or through reaction of amides with epoxides, give access to
oxazolidinones. Study on rare-earth metal catalyzed atom-
economic transformations is on-going in our laboratory.
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Complex 1 (R1 = Ph: 17.6 mg, 0.02 mmol; R1 = Bn: 35.2 mg, 0.04 mmol),
amines (2 mmol), epoxides (1 mmol), and DMC (0.17 mL, 2 mmol) were
introduced into a 5 mL glass vial equipped with a stir bar in a glovebox,
and heated at 80 ºC after 12 h reaction. The reaction mixture was purified
by column chromatography using ethyl acetate/petroleum ether = 1/3-1/0,
and the resulting oxazolidinone was characterized by 1H and 13C NMR
spectroscopy and HR MS.
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We gratefully acknowledge financial support from the National
Natural Science Foundation of China (Grant 21871198), the
Project of Scientific and Technologic Infrastructure of Suzhou
(SZS201708), and PAPD.
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Keywords: oxazolidinones • rare earth amides •
multicomponent reactions
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10.1002/cctc.201900221
ChemCatChem
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M. Zhou, X. Zheng, Y. Wang, D. Yuan,*
Y. Yao*
Page No. – Page No.
A Multicomponent Approach to
Oxazolidinone Synthesis Catalyzed
by Rare-Earth Metal Amides
A simple rare-earth-metal-catalyzed multicomponent approach to oxazolidinone
synthesis is developed from easily available materials, i.e., epoxides, carbonate,
and amines. Substrate scope includes a wide range of aromatic and aliphatic
amines, as well as mono- and di-substituted epoxides. Preliminary mechanistic
studies suggest β-amino alcohols or amides as intermediates.
This article is protected by copyright. All rights reserved.