Convenient approach to chiral 4-monosubstituted 1,3-oxazolidine-2-thiones

Article abstract of DOI:10.1080/00397911.2017.1368083

Chiral 4-monosubstituted 1,3-oxazolidine-2-thiones are regarded as one of the modified version of Evans auxiliaries in asymmetric aldol condensation, which can generate two adjacent chiral carbon centers in one time They have advantages over Evans auxiliaries in some aspects, however, their application is highly limited by their preparation approaches as toxic or flammable chemicals are involved. Here, a mild and applicable procedure for preparing the chiral oxazolidine-2-thione auxiliaries has been developed in this article. Potassium ethylxanthate and the corresponding chiral amino alcohols as the starting material in absolute ethanol are mixed and the mixture are heated under reflux for 1 h in open air to provide 1,3-oxazolidine-2-thiones chiral auxiliaries in moderate to excellent yields.

Full text of DOI:10.1080/00397911.2017.1368083

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
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ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
A convenient approach to chiral 4-
monosubstituted 1,3-oxazolidine-2-thiones
Zheng Lu, Yong-Qing Yang, Jiu-Hui Li, Jun-Nan Wei & Yi-Zhu Wang
To cite this article: Zheng Lu, Yong-Qing Yang, Jiu-Hui Li, Jun-Nan Wei & Yi-Zhu Wang
(2017): A convenient approach to chiral 4-monosubstituted 1,3-oxazolidine-2-thiones, Synthetic
Communications, DOI: 10.1080/00397911.2017.1368083
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1368083
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Date: 02 September 2017, At: 07:29

A convenient approach to chiral 4-monosubstituted
1,3-oxazolidine-2-thiones
Zheng Lu
School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu, China
Yong-Qing Yang*
School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu, China
Jiu-Hui Li
School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu, China
Jun-Nan Wei
School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu, China
Yi-Zhu Wang
School of Pharmacy, Jiangsu University, Zhenjiang, Jiangsu, China
*Address correspondence to Yong-Qing Yang, School of Pharmacy, Jiangsu University,
Zhenjiang, Jiangsu, 212013, China. E-mail: yqy@ujs.edu.cn
ABSTRACT
1

Chiral 4-monosubstitued 1,3-oxazolidine-2-thiones are regarded as one of the modified
version of Evans auxiliaries in asymmetric aldol condensation, which can generate two adjacent
chiral carbon centres in one time They have advantages over Evans auxiliaries in some aspects,
however their application is highly limited by their preparation approaches as toxic or flammable
chemicals are involved. Here, a mild and applicable procedure for preparing the chiral
oxazolidine-2-thione auxiliaries has been developed in this article. Potassium ethylxanthate and
the corresponding chiral amino alcohols as the starting material in absolute ethanol are mixed and
the mixture are heated under reflux for one hour in open air to provide 1,3-oxazolidine-2-thiones
chiral auxiliaries in moderate to excellent yields.
GRAPHICAL ABSTRACT
KEYWORDS: 1,3-oxazolidine-2-thione, chiral auxiliaries, environmentally-benign, xanthates
Subject classification codes: include these here if the journal requires them
Introduction
Homochiral 4-monosubstituted 1,3-oxalidine-2-thiones are chiral auxiliaries applied in the
enantioselective syntheses,[1] compared to classical chiral 1,3-oxazolidinones (Evans
auxiliaries[2]), 1,3-oxalidine-2-thiones show advantage of easier cleavage[3] and better selectivity
in the acetate-like aldol reaction.[4] Recent studies have shown that oxalidine-2-thiones could also
2

act as convenient sulfur suppliers[5] and Michael donors[6] as well. Approaches to preparation of
1,3-oxazolidine-2-thiones have been developed by several research groups.[1e,7,8] The source of
[1e]
sulfur contains three types, CS2,[7] CSCl2
and 1,1-thiocarbonyldiimidazole.[8] In the
preparations of 4-monosubstituted 1,3-oxalidine-2-thiones starting from corresponding amino
[7]
alcohols, which are commercially available are especially studied broadly.[1c,7a–c] CS2 and
[1e]
CSCl2
are currently employed as the sulfur source(Figure 1). Carbon disulfide (CS2) is
employed as the major source of sulfur by many groups,[7] as it is inexpensive and easily
accessible. Under basic conditions,[4,7a] amino alcohols react with CS2 under refluxing to form
1,3-oxalidine-2-thiones in good to excellent yields. However, regarding low boiling point (46oC)
and low flash point (-30oC) of CS2,[9] refluxing condition would inevitably be potential danger to
researchers. Although addition of hydrogen peroxide (H2O2) to this basic system could shorten the
reaction duration and improve the reaction yield remarkably,[7c] usage and storage of CS2inꢀ the
laboratory is still a serious safety concern.
Thiophosgene (CSCl2) was once reported by Crimmins group[1e] as source of sulfur leading
to excellent yield of (S)-4-benzyl-1,3-oxalidine-2-thione. However, the application of this reaction
is restricted by the high toxicity of CSCl2.[10] Therefore, the need for an environmentally-benigh
access to 1,3-oxalidine-2-thiones still remains. Interestingly, it was reported that xanthates
(potassium ethylxanthate (KSCSOEt)[11a–d] or potassium isopropylxanthate (KSCSOiPr)[11e] could
convert 2-aminophenol to 3H-benzooxazole-2-thione in moderate to excellent yields.
3

Furthermore, KSCSOEt has even been applied in the preparation of indene-based
thiazolidinethione chiral auxiliary.[12] However, to the best of our knowledge, their applications to
forming chiral oxalidine-2-thiones auxiliaries have not been reported yet. Here we are keen to
explore xanthates as safer and milder surrogates of CS2 to the preparation of homochiral
4-monosubstituted 1,3-oxazolidien-2-thione.
Results and Discussion
With (R)-2-phenylglycinol as our model substrate, investigation on search for optimal
conditions for the formation of (R)-4-phenyl-1,3-oxazolidine-2-thione has been conducted. Our
experimental results are summarized in Table 1. Initially the amino alcohol was dissolved in
ethanol and KSCSOEt was added to the solution, the reaction was performed at room temperature,
it turned out that no cyclization compound was obtained at all within one hour (entry 1), no change
was observed even after 12 hours. To our delight, when the reaction temperature was raised to
50oC, desired product was isolated with 31% yield (entry 2). Further heating the oil bath to 100oC
(the reaction mixture was heated at reflux) lead to an outcome of 88% yield (entry 3). Prolonged
reaction time ( > 1 hr, up to 18 hrs) caused deteriorating yield (entries 4-6). Polar solvents (e.g.
THF, MeCN&DMF) have been tested in this system, however none of them showed superiority
over ethanol (entries 11-13). Then the amount of KSCSOEt was tested, and 2.5 eq. of xanthate
seems to be necessary. Increasing the amount of xanthate did not improve the yield, while lower
4

the amount of xanthate lead to drop of the yield (entries 3, 7, 8&9). If the reaction proceeded under
N2 instead of open air, the yield decreased by 13% (entry 10).
The optimal condition is that (R)-2-Phenylglycinol was mixed with KSCSOEt with the
molar ratios as 1:2.5 in ethanol and reacted at 100oC (oil bath) for one hour in open air. We were
satisfied with this result and the application of this reaction in preparation of chiral auxiliaries from
commercial amino alcohols was explored.
In general, homochiral 4-monosubstituted 1,3-oxazolidine-2-thiones (R = Ph, Bn, iPr and
tBu) could be prepared in good to excellent yield. The steric hindrance of the substituent at the
4-position shows some effect on the outcome of the reaction. When R = Bn, which is more flexible
i
t
compared to Ph, Pr and Bu, the corresponding product 2b was isolated only in moderate yield.
The bulkiest one (R = tBu) gives excellent yield in the meanwhile. It shows the more steric
hindrance 4-substitute bears, the better turnout the reaction gives.
In conclusion, a mild and safe procedure to prepare homochiral 4-monosubstituted
1,3-oxazolidine-2-thione auxiliaries has been developed by employment of KSCSOEt in place of
CS2 (or CSCl2). It has been successfully applied to preparation of widely used chiral auxiliaries
(4-Ph, 4-Bn, 4-iPr&4-tBu 1,3-oxazolidine-2-thiones) from corresponding amino alcohols. This
protocol will contribute to wider application of this type of chiral auxiliary in asymmetric
synthesis.
Experimental
5

The starting materials used were purchased from Energy Chemical. All chemicals were
analytical reagent and used as purchased. The reactions described in this manuscript were
performed in standard laboratory glassware. Melting points were recorded on a WRS-1B digital
melting point recorder from Shanghai Precision Scientific Instrument Corporation. Optical
rotations were measured on an Automatic Polarimeter WZZ-2Aꢀ from Shanghai Precision
Scientific Instrument Corporation. Infrared spectra were recorded on a Nicolet Avatar 370 DTGS
machine. 1H NMR and 13Cꢀ NMR spectra were obtained on a Bruker AV400 equipment. ESI-MS
data were recorded on a Shimadzu LCMS-2010EV mass spectrometer. Column chromatography
was performed on silica gel (300–400 mesh) under slightly positive pressure. PE = petroleum ether
(b.p. 60–90oC).
General procedure for preparation of homochiral 4-monosubstituted
1,3-oxzlidine-2-thiones
Potassium ethylxanthate (400mgꢀ, 2.5 mmol) was added to the solution of
(R)-D-phenylglycinol (1a, 137mgꢀ, 1.0 mmol) in ethanol (2.0mLꢀ), then the resulting suspension
was heated to reflux (oil bath at 100oC). The reaction was completed in one hour, which was
monitored by TLC. Then it was cooled to r.t. and diluted with EtOAc (40 mL), and washed with
H2O (10mLꢀ*3) and brine (10 mL). The organic phase was dried over anhydrous Na2SO4. After
concentration under reduced pressure, the crude product was obtained, which was purified through
6

flash
chromatography
(rinsed
with
PE/EtOAc
=
5:1)
to
afford
(R)-4-phenyl-1,3-oxazolidine-2-thione[7a] (1b) as white solid (158mgꢀ, 0.88 mmol), yield 88%.
o
[7a]
o
[7a]
20
Mp 120.0-120.4 C (lit.
Mp 121-122 C); []D27-70.0 (c 0.70, CHCl3) (lit.
[]D
-79.3 (c 0.21, CHCl3)); Rf = 0.3 (PE-EtOAc, 3:1). 1H NMR (400MHzꢀ, CDCl3)  7.45-7.36 (m, 3H,
Ar-H), 7.33-7.29 (m, 2H, Ar-H), 5.12 (dd, J = 8.4, 6.8Hzꢀ, 1H, OCH2), 5.00 (t, J = 9.2Hzꢀ, 1H,
OCH2), 4.48 (dd, J = 8.8, 6.8Hzꢀ, 1H, NCH). 13Cꢀ NMR (100MHzꢀ, CDCl3) 189.6, 137.9, 129.2,
129.0, 126.2, 77.6, 60.1. IR (KBr, solid) vmax 3436, 2922, 1525, 1268, 1170, 763cmꢀ-1. MS (ESI)
m/z 178.0 ([M-H]-).
Supplemental material
Full experimental details, IR, 1H NMR, and 13C NMR data for this article can be accessed
on the publisher’s website.
Funding
This project is supported by the National Natural Science Foundation of China (No.
21572118 & No. 21572080) and Jiangsu University (No. 10JDG042 & No. 14JDG018).
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9

Table 1. Investigation of synthesis of 1b from the corresponding amino alcohol 1a.
Entrya
1
Solvent
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
THF
Reagent/eq.b
2.5
Time/h
Yield/%c
0
1d
1e
1
2
2.5
31
88
73
72
24
87
70
64
75
7
3
2.5
4
2.5
3
5
2.5
7
6
2.5
18
1
7
3.0
8
2.0
1
9
1.5
1
10
11
12
13
14
2.5
1f
1
2.5
ACN
2.5
1
2
DMF
EtOH
2.5
1
12
41
1.1
1
10

aReactions were performed in oil bath at 100oC if there’s no other indication. bThe quantity of the reagent is given in molar equiv.
with respect to 1a. cIsolated yield. dRoom temperature. eOil bath at 50oC. fThe reaction is carried out under N2.
11

Table 2. Scope of synthesizing 1,3-oxazolidine-2-thiones from corresponding amino alcohols
12

Figure 1. Accesses to 1,3-oxazolidine-2-thiones from corresponding amino alcohols.
13