CH2Cl2 as reagent in the synthesis of methylene-bridged 3,3′-bis(oxazolidin-2-one) derivatives under ambient conditions

Article abstract of DOI:10.1039/c4ra03248a

This paper describes a highly efficient and facile transformation of substituted oxazolidin-2-ones to methylene-bridged 3,3′-bis(oxazolidin-2- one) derivatives in a mixture solvent of CH₂Cl₂ (DCM) and N,N-dimethylformamide (DMF) in the presence of NaH at ambient temperature. Isotopic labeling experiments indicated that the C of the bridged methylene group was derived from CH₂Cl₂ instead of DMF and other unknown substances in the NaH reagent (60% dispersion in mineral oil). the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra03248a

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CH2Cl2 as reagent in the synthesis of methylene-
bridged 3,30-bis(oxazolidin-2-one) derivatives
under ambient conditions†
Cite this: RSC Adv., 2014, 4, 25933
Received 10th April 2014
Accepted 21st May 2014
*
Qingfeng Liu, Yansen Zhang, Zhiguo Zhang, Tongxin Liu, Lei Shi and Guisheng Zhang
DOI: 10.1039/c4ra03248a
www.rsc.org/advances
This paper describes a highly efficient and facile transformation of functionality.20 Recently, we designed
a series of chiral
substituted oxazolidin-2-ones to methylene-bridged 3,30-bis(ox- compounds that can be prepared from the intermediate
azolidin-2-one) derivatives in a mixture solvent of CH2Cl2 (DCM) and methylene-bridged 3,30-bis((S)-4-benzyloxazolidin-2-one) (2a,
N,N-dimethylformamide (DMF) in the presence of NaH at ambient Table 1) to evaluate their antitumor activity. For the preparation
temperature. Isotopic labeling experiments indicated that the C of the of the key intermediate 2a, we rst attempted to follow the
bridged methylene group was derived from CH2Cl2 instead of DMF reported methods,7–12 which were successfully applied to
and other unknown substances in the NaH reagent (60% dispersion in prepare other methylene-bridged bis(N-heterocycle)s via the
mineral oil).
reactions of DCM with imidazole,2,7 pyrrolidine,8 pyrrole,9 pyr-
azole,10 pyridine,11 and 1,2,3-triazole.12 To our disappointment,
these methods did not work to prepare 2a. A few synthetic
examples of methylene-bridged 3,30-bis(oxazolidin-2-one)
derivatives have been reported to date. Ingleby21 reported an
efficient approach to 3,30-bis(oxazolidin-2-one) methanes via
the reaction of oxazolidin-2-ones with paraformaldehyde in the
presence of p-MeC6H4SO3H at 100 ꢀC; Zinner22 demonstrated
two procedures to prepare bis(benzoxazolidinon-3-yl)methane
by treating benzoxazolidinone with benzoxazolon-3-ylchloro-
methane and metal sodium in EtOH under reuxing, and with
CH2Br2 catalyzed by KOH in EtOH in a water bath in yields of
60%, and 9%, respectively. Seebach23 treated 4-isopropyl-5,5-
diphenyloxazolidinone with BuLi, NaI and chloromethyl methyl
sulde in DME at 0 ꢀC to obtain the dimer 3,30-bis((S)-4-iso-
Typically, inert DCM is chosen as a solvent for its versatility in
a variety of organic applications. The activation of DCM has been
studied because of an interest in the construction of methylene-
bridged bisamines, which are usually used as various ligands,1
N-heterocyclic carbenes.2 DCM has been reported to react with
aliphatic amines,3–6 i.e. the nitrogen-containing heterocyclic
compounds, such as imidazole,2,7 pyrrolidine,8 pyrrole,9 pyr-
azole,10 pyridine,11 and 1,2,3-triazole,12 to form the correspond-
ing methylene-bridged compounds withmoderateto highyields.
However, due to their low reactivity, the reaction of oxazolidin-
2-ones with DCM to form methylene-bridged bis(2-oxazolidi-
none) derivatives has not been realized yet.
2-Oxazolidinones have been widely utilized in asymmetric
reactions, such as aldol condensation,13 alkylation,14 haloge-
nation,15 amination,16 radical addition,17 and Diels–Alder reac-
tions,18 and as intermediates for the asymmetric synthesis of
bioactive compounds.13c,19 Moreover, a relatively large number
of naturally occurring and synthetic molecules with antibacte-
rial, antiallergenic, immunosuppressants, or monoamine
oxidase inhibition activities contain the amino alcohol
propyl-5,5-diphenyl-2-oxazolidinon-3-yl)methane as
a
side
product in a yield of 13%. To the best of our knowledge, there is
no detailed investigation on the synthesis of bis(2-oxazolidinon-
3-yl) methanes, particularly under mild conditions. Herein, we
report a mild and efficient approach to bis(2-oxazolidinon-3-yl)
methanes by treating 2-oxazolones with NaH in mixture
solvents of DCM and DMF under ambient temperature, in
which DCM is disclosed as a C source.
During the course of our ongoing work on the synthesis of
oxazolidinone derivatives, we performed a reaction of (S)-4-
benzyloxazolidin-2-one (1a) with an alkynyl bromide mediated
by NaH in DMF. The reaction was conducted by stirring
a mixture of (S)-4-benzyloxazolidin-2-one and NaH in DMF for
a certain time. Subsequently, the alkynyl bromide, which was
dissolved in a small amount of DCM, was added to the mixture,
and the resulting reaction mixture was then stirred for a certain
Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine
Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of
Education, School of Chemistry and Chemical Engineering, Henan Normal
University, Xinxiang, Henan 453007, P.R. China. E-mail: zgs6668@yahoo.com; Fax:
+86 373-3325250
† Electronic supplementary information (ESI) available. CCDC [997065]. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c4ra03248a
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Table 1 Survey of reaction conditionsa
Entry
Solvent
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
DCM
DMF
48
48
33
33
48
48
48
27
9
0
0
46
28
0
DCM/DMF (1 : 5)
DCM/DMF (1 : 2)
DCM/EtOAc (1 : 5)
DCM/THF (1 : 5)
DCM/Et2O (1 : 5)
DCM/DMF (1 : 5)
DCM/DMF (1 : 5)
0
0
61c
98d
a
Unless otherwise indicated, all the reactions were carried out with 1a (1 mmol) and NaH (1 equiv.) in a solvent (3 mL) at ambient temperature (25–
30 ꢀC). b Isolated yield of 2a. 1.5 equiv. of NaH was used. 1.8 equiv. of NaH was used.
c
d
time under ambient temperature. During the work-up of the 2-one 1i, was similar to oxazolidinones 1a-g and gave the cor-
reaction mixture, a small amount of an unexpected byproduct responding methylene-bridged products 2h and 2i in 89% and
was accidentally separated, which was subsequently character- 84% yields, respectively. Note that the reactions could not
ized as a methylene-bridged 3,30-bis(oxazolidin-2-one) derivate proceed when acyclic carbamates 1j–l were employed.
2a by 1H NMR, 13C NMR, HRMS and X-ray diffraction (XRD)
Considering that both the DCM and DMF can act as single
analysis. Because of the mild and basic condition, this unex- carbon source,2–12,24 a labeling experiment was performed
pected nding is worthy of further evaluation as an alternative (Scheme 1) to elucidate the carbon source of the bridged
and efficient approach to 3,30-bis(oxazolidin-2-one)methanes 2. methylene. The result of the reaction with 13C-labeled DCM
This nding suggested that DCM should be a reagent to form indicated that the bridged methylene of compound 2 originated
2a. Therefore, to optimize this reaction, a reaction of 1a in pure entirely from CH2Cl2 (99.1% incorporation) instead of DMF and
DCM was rst performed (Table 1, entry 1), to our surprise, no other unknown substances from the NaH reagent (60%
reaction occurred. This result raises doubt as to whether DMF dispersion in mineral oil).25
would provide the bridged carbon of 2a because DMF can also
Because DCM serves as a reagent in the transformation of 1
serve as a carbon source.24 However, the reaction of 1a in pure to 2, we propose that the ability of DMF, a strong polar aprotic
DMF also did not work (Table 1, entry 2). Subsequently, some solvent, in playing important role in the transformation is
mixed solvents, such as DCM/DMF, DCM/THF, and DCM/Et2O, a result of the polar solvent's solvating certain reactant inter-
were screened (Table 1, entries 3–7), and the results indicated mediate species, thereby decreasing the intermediate energy
that both DCM and DMF are necessary for the reaction. Using relative to the starting material. A series of control experiments
this result, a detailed screening of the reaction conditions was supported this proposal to some extent (Table 3). It was found
conducted using the model compound of 1a. Aer several that the reactions proceeded smoothly to afford the desired
attempts, the optimal condensation condition was developed, product 2a in good to excellent yields, when different polar
which is listed in Table 1 (entry 8): the reaction of 1a (1.0 mmol) solvents, including strong polar DMSO, and other amides, such
and NaH (1.8 equiv.) in DCM/DMF (v/v 1 : 5, 3 mL) under as N,N-diethylformamide, N,N-dimethylbutyramide, N,N-dieth-
ambient conditions gave the desired product 2a with an excel- ylbutyramide, and N,N-diethylbenzamide were employed. In
lent yield of 98%.
DMSO (Table 3, entry 1), 1a reacted with DCM in the presence of
Under the optimized conditions, we explored the scope of NaH at ambient conditions to give 2a in a yield of 95%,
the NaH-mediated reaction of DCM with various 2-oxazolidi- although it took a longer time than in DMF (Table 2, entry 1).
nones 1, and the results are shown in Table 2. It was found that
To our delight, a reactant intermediate was detected by LC-
the reactions of 2-oxazolidinones (including 2-oxazolidinone 1f, MS in small amounts in the control experiment, in which
4-substituted 2-oxazolidinones 1a–e, and benzoxazolidinone 1g) N,N-diethylformamide was employed as a solvent (Table 3, entry
proceeded smoothly to afford the desired products in excellent 2). The presence of a 3-methylene-4-benzyl-2-oxazolidinonium
yields. The reactivity of six-numbered cyclic carbamates, such as nucleus was strongly indicated by observing the peak at m/z 190.
1,3-oxazinan-2-one 1h and 1,4-dihydro-2H-benzo[d][1,3]oxazin- Aer enrichment and purication, the intermediate was
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Table 2 Synthesis of bis(oxazolidin-2-one) methane derivatives catalyzed by NaHa
No.
1
Substance
Time (h)
Product
Yieldb (%)
9
98
2
3
16
13
89
95
4
17
91
5
6
13
16
90
83
7
16
87
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Table 2 (Contd.)
No.
8
Substance
Time (h)
Product
Yieldb (%)
19
89
9
19
24
84
c
10
11
—
—
c
24
24
—
—
—
c
12
—
a
All the reactions were carried out with 1 (1 mmol) and NaH (1.8 equiv.) in DCM/solvent (1 : 5, 3 mL) at ambient temperature (25–30 ꢀC). b Isolated
yield of 2. c The desired product was not observed.
characterized as 3-chloromethyl-4-benzyl-2-oxazolidinone
A
On the basis of the abovementioned results and literature,26
(Scheme 2) by 1H NMR and 13C NMR. 1H NMR in CDCl3 of the a plausible mechanism for the reaction is illustrated in Scheme
intermediate showed a doublet at 4.86 ppm and 4.70 ppm, and 2. Although the detailed mechanism of the present reaction is
13C NMR showed a resonance at 56.1 ppm. Both the sets of NMR still not very clear, the following speculation is reasonable.
data are consistent with A as the major species in the reaction Cyclic carbamate 1 undergoes N-alkylation with dichloro-
solvent. Added 2-oxazolidinone 1a to pure intermediate A which methane in the presence of NaH to chloromethyl analogue A.
was obtained from the experiment (Table 3, entry 2), under Then, the transient acyliminium intermediate B (from the
standard condition showed that intermediate A fast loss the balance between species A and B) rapidly undergoes a fast
resonances at 4.86 ppm and 4.70 ppm with the formation of reaction with another nucleophile 1 present in the reaction to
a broad singlet at 4.98 ppm in the 1H NMR. This result indicated form the product 2. The condensation of DCM with 1 is the rate-
that the formation step of aminal 2 from the reaction inter- determining step. The strong polar solvent DMF probably plays
mediates is rapid.
an important role by stabilizing the formation of the
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group was derived from DCM instead of DMF and other
unknown substances in NaH reagent (60% dispersion in
mineral oil). This protocol not only extends the application of
DCM in organic synthesis but also provides an alternative
method for preparing methylene-bridged bis(oxazolidin-2-one)
derivatives. However, it is currently limited in scope to acyclic
carbamates. Further studies to discover synthetic applications
are ongoing.
Scheme 1 Isotope incorporation experiment.
Experimental section
Table 3 Transformations using other polar aprotic solventsa
General information
All the reagents were obtained from commercial sources and
used without further purication. NaH (60% dispersion in
mineral oil) was purchased from Aladdin Industrial Corpora-
tion. The reactions were monitored by TLC on silica gel 60 F254
.
Column chromatography was performed on silica gel 60
(200–300 mesh). The 1H and 13C NMR spectra were recorded at
400 MHz and 100 MHz, respectively. Chemical shis were
reported in ppm using tetramethylsilane (TMS) as an internal
standard in CDCl3 solutions, and coupling constants (J) are
given in Hz. High-resolution mass spectra were measured on
a MicroTOF mass spectrometer.
Entry
1
Solvent
DMSO
Time (h)
24
Yieldb (%)
95
2
3
4
11
24
10
80
General procedure for the preparation of compound 2
81c
85c
A mixture of carbamate 1 (1.0 mmol) and NaH (1.8 equiv., 60%
dispersion in mineral oil) in DMF/DCM (5/1, 3 mL) was stirred
at room temperature for an appropriate duration, and the
reaction was monitored by TLC. Aer completion of the reac-
tion, the reaction mixture was quenched with brine. The
organic layer was separated and evaporated, the residue was
added to H2O (10 mL) and washed with CH2Cl2, and the
combined organics were then concentrated in vacuo. The crude
product was puried by silica-gel column chromatography and
characterized.
5
8d
68c
a
Unless otherwise indicated, all the reactions were carried out with 1a
(1 mmol) and NaH (1.8 equiv.) in DCM/solvent (1 : 5, 3 mL) at ambient
b
c
temperature (25–30 ꢀC). Isolated yield of 2a. Yield is determined by
LC-MS. d The reaction was performed at 45 ꢀC.
3,30-Bis((S)-4-benzyl-2-oxazolidinon-3-yl)methane (2a)
1H NMR (CDCl3, 400 MHz) d 7.31–7.19 (m, 10H), 4.99 (s, 2H),
4.20–4.08 (m, 6H), 3.56–3.55 (d, J ¼ 3.2 Hz, 2H), 2.67–2.61 (dd, J
¼ 9.6 Hz, 2H). 13C{1H} NMR (CDCl3, 100 MHz) d 158.7, 135.0,
129.2, 129.0, 127.2, 67.7, 55.3, 48.4, 37.8. HRMS (ESI), m/z calcd.
for C21H22N2NaO4 ([M + Na]+) 389.1472, found: 389.1474.
3,30-Bis((S)-4-methyl-2-oxazolidinon-3-yl)methane (2b)
Scheme 2 The plausible mechanism.
1H NMR (CDCl3, 400 MHz) d 4.78 (s, 2H), 4.35 (t, J ¼ 8.0 Hz, 2H),
3.94–3.84 (m, 4H), 1.39 (d, J ¼ 6.0 Hz, 6H). 13C{1H} NMR (CDCl3,
100 MHz) d 158.4, 69.4, 50.0, 47.7, 17.7. HRMS (ESI), m/z calcd.
for C9H14N2NaO4 ([M + Na]+) 237.0846, found: 237.0842.
acyliminium ion intermediate B, which makes DCM more
available to react with the nucleophile 1. However, why the
reaction of acyclic carbamate does not work is not yet clear.
In conclusion, we have demonstrated a highly efficient and
3,30-Bis((S)-4-isopropyl-2-oxazolidinon-3-yl)methane (2c)
facile NaH-catalyzed condensation of DCM with cyclic carba- 1H NMR (CDCl3, 400 MHz) d 4.77 (s, 2H), 4.26 (t, J ¼ 9.2 Hz, 2H),
mates to form corresponding aminal derivatives in a mixture 4.11 (dd, J ¼ 6.0 Hz, J ¼ 9.2 Hz, 2H), 3.85–3.81 (m, 2H), 2.46–2.39
solvent of DCM and DMF under ambient temperature. Isotopic (m, 2H), 0.89 (d, J ¼ 7.2 Hz, 6H), 0.85 (d, J ¼ 7.2 Hz, 6H). 13C{1H}
labeling experiments indicated that the bridged methylene NMR (CDCl3, 100 MHz) d 158.9, 63.3, 57.8, 48.1, 26.4, 17.8, 13.9.
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HRMS (ESI), m/z calcd. for C13H22N2NaO4 ([M + Na]+) 293.1472,
found: 293.1475.
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Acknowledgements
We thank the NSFC (21002051, 21172056, 21272057 and
21372065), PCSIRT (IRT1061), China Postdoctoral Science
Foundation funded project (2012M521397, 2013T60701 and
2013M530339), and Key Project of Henan Educational
Committee (13A150546) for the nancial support for this
research.
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