Generation of Oxazolidine-2,4-diones Bearing Sulfur-Substituted Quaternary Carbon Atoms by Oxothiolation/Cyclization of Ynamides

Article abstract of DOI:10.1002/chem.201504356

A novel method for metal-free oxothiolation of ynamides to construct oxazolidine-2,4-diones bearing sulfur-substituted quaternary carbon atoms has been developed. It represents a rare C-O bond cleavage of ynamides, as well as a facile and tandem approach for the formation of C-O, C-S, and C-Cl bonds. This redox-neutral protocol can be applied to the synthesis of multisubstituted oxazolidine-2,4-diones with good chemoselectivity and good yields of isolated products under mild conditions.

Full text of DOI:10.1002/chem.201504356

DOI: 10.1002/chem.201504356
Full Paper
&
Heterocycle Synthesis
Generation of Oxazolidine-2,4-diones Bearing Sulfur-Substituted
Quaternary Carbon Atoms by Oxothiolation/Cyclization of
Ynamides
Hai Huang, Junzhen Fan, Guangke He,* Zhimin Yang, Xiaodong Jin, Qi Liu, and
Hongjun Zhu*[a]
Abstract: A novel method for metal-free oxothiolation of
ynamides to construct oxazolidine-2,4-diones bearing sulfur-
substituted quaternary carbon atoms has been developed. It
represents a rare CÀO bond cleavage of ynamides, as well as
a facile and tandem approach for the formation of CÀO,
CÀS, and CÀCl bonds. This redox-neutral protocol can be ap-
plied to the synthesis of multisubstituted oxazolidine-2,4-
diones with good chemoselectivity and good yields of isolat-
ed products under mild conditions.
Introduction
the possibility of the synthesis of intermediate B by using
DMSO as the sulfoxide;[1a,5] intermediate B could next be
trapped by some external nucleophilic reagent to form a-sub-
stituted amide C (Scheme 2b).
Oxyfunctionalization is an important methodology in the field
of ynamides, and Scheme 1 shows that a series of a-functional-
ized amides can be synthesized by oxidation/functionaliza-
tion.[1] However, most achievements so far have been made
based on gold-catalyzed intermolecular ynamide oxidation.[1c–j]
Thus, further application of the approach mentioned above
has been restricted because of the requirements of high cost
and toxicity of noble-transition-metal catalysts. Recently, to
break through this hurdle, Ye and co-workers[2] have developed
an innovative method for the oxyfunctionalization of ynamides
by using zinc as the catalyst to construct isoquinolones and
b-carbolines. In spite of the existing methods, the further step
to develop a metal-free or even catalyst-free oxyfunctionaliza-
tion of ynamides is of great necessity and yet remains a chal-
lenge.
In 2014, Maulide and co-workers[3] reported a Brønsted acid
catalyzed redox arylation reaction of ynamides and achieved
the goal of metal-free oxyfunctionalization of ynamides. In the
study by Maulide and co-workers, the [3,3] sigmatropic rear-
rangement of intermediate A, generated from an intermolecu-
lar nucleophilic capture of ynamides with aryl sulfoxides, is the
most important step (Scheme 2a).
We started to investigate this original transformation by the
reaction of ynamide 1a with 4-methylbenzenethiol as the nu-
cleophilic reagent and 10 mol% HOTf in DMSO. It is a pity that
almost no 1a was observed to be consumed (Scheme 2c). Un-
expectedly, an interesting product, oxazolidine-2,4-dione 2a,
was formed in 41% yield (Scheme 2d) by using a normal elec-
trophilic reagent,[6] p-tolylsulfenylchloride, instead of 4-methyl-
benzenethiol. In this case, this interesting transformation, fin-
ished by the carbonyl oxygen atom of the oxazolidin-2-one
ring acting as a nucleophilic atom, provided a rare CÀO bond
cleavage and formed new carbon–sulfur, carbon–oxygen, and
carbon–chlorine bonds.
Significantly, oxazolidine-2,4-diones are a class of important
five-membered heterocyclic compounds that constitute an es-
sential structural motif that is found in a variety of biologically
active substances.[7] Thus, the synthesis of oxazolidine-2,4-
diones has attracted considerable attention and many meth-
ods have been established for their synthesis.[8] But it is indicat-
ed that our rare cyclization of ynamides reported herein for
the synthesis of oxazolidine-2,4-diones provides an idealized
efficiency to this structure, and the efficient construction of
quaternary carbon centers is also a very important task in or-
ganic synthesis.[9] To the best of our knowledge, we have also
demonstrated the first metal-free oxyfunctionalization/cycliza-
tion of ynamides involving CÀO bond cleavage/formation for
the construction of sulfur-substituted quaternary carbon
atoms.[10]
Inspired by these reports and our interest in exploring the
metal-free oxyfunctionalization of ynamides,[4] we envisioned
[a] H. Huang, J. Fan, Dr. G. He, Z. Yang, X. Jin, Q. Liu, Prof. Dr. H. Zhu
Department of Applied Chemistry
College of Chemistry and Molecular Engineering
Nanjing Tech University
No. 30 North Puzhu Road, Nanjing, 211816 (P. R. China)
E-mail: hegk@njtech.edu.cn
zhuhj@njtech.edu.cn
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201504356.
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Scheme 1. The oxyfunctionalization of ynamides. EWG: electron-withdrawing group; FG: functional group.
Scheme 2. Intermolecular redox arylation of ynamides and our hypotheses. HOTf: trifluoromethanesulfonic acid; Nu: nucleophile.
Results and Discussion
of 2.5 equivalents of p-tolylsulfenylchloride gave the highest
yield (71%) of 2a (Table 1, entries 5 and 6). In addition, chloro-
thiolation adducts 3a and 4a were not observed by TLC moni-
toring. With anhydrous DMSO employed as the solvent, 2a
was obtained in 76% yield with complete conversion of yna-
mide 1a within 1 h under an N2 atmosphere (Table 1, entry 7).
This transformation gave poor results under oxygen or H2O
conditions, which further reveals that the DMSO probably
plays a role as the oxidant (Table 1, entries 8 and 9).
The above interesting finding exhilarated us and further moti-
vated us to investigate the reaction process. Firstly, the cycliza-
tion conditions were optimized. To our delight, the reaction
gave the corresponding oxazolidine-2,4-dione 2a in 57% yield
in the absence of HOTf (Table 1, entry 1). However, chlorothio-
lation adducts 3a and 4a were also formed in 10 and 13%
yields, respectively, and the stereochemistry was confirmed by
single-crystal X-ray diffraction of product 3a (see the Support-
ing Information for details). To further increase the yield of 2a,
we carried out the reaction under different temperatures from
25 to 1008C (Table 1, entries 2–4). The reaction produced oxa-
zolidine-2,4-dione 2a in 68% yield at 1008C. The employment
With the optimized reaction conditions in hand, we next in-
vestigated the reaction between various ynamides 1 and p-tol-
ylsulfenylchloride 5a (Table 2). It is worth mentioning that this
reaction can be scaled up to 6.0 mmol with high yield and
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electron-donating groups (Me, MeO), halogens (F, Br), and elec-
tron-withdrawing groups (NO2, Ac). In general, ynamides bear-
ing electron-withdrawing groups gave lower yields than those
bearing electron-donating groups on the aromatic ring
(Table 2, entries 2–7). The structure of 2c was confirmed by
X-ray crystallographic analysis (see the Supporting Information
for details). Double-substituted ynamides were also good sub-
strates for this transformation and afforded the corresponding
products 2h and 2i in 61 and 71% yields (Table 2, entries 8
and 9). 3-(Naphthalen-2-ylethynyl)oxazolidin-2-one (1j) also
performed well and furnished 3-(2-chloroethyl)-5-(naphthalen-
2-yl)-5-(p-tolylthio)oxazolidine-2,4-dione (2j) in 67% yield
(Table 2, entry 10). However, the reaction of aryl-substituted
substrate 3-(hex-1-yn-1-yl)oxazolidin-2-one (1k) gave an un-
identified mixture.
Table 1. Optimization of reaction conditions.[a]
Entry
Amount of 5a [equiv] T [8C] Yield [%][b] of 2a/3a/4a
1
2
3
4
5
6
7[c]
8[d]
9[e]
2.0
2.0
2.0
2.0
2.5
3.0
2.5
2.5
2.5
25
50
80
100
100
100
100
100
100
57/10/13
61/7/9
64/6/8
68/7/8
71/–/–
70/–/–
76/–/–
Next, we explored the oxidative cyclization between various
benzenesulfenyl chlorides 5 and ynamide 1a (Table 2, en-
tries 12–21). Notably, different positions of the aryl ring did not
affect the product yields, and various benzenesulfenyl chlor-
ides with a methyl group on the ortho, meta, and para posi-
tions of the aryl ring were converted into the corresponding
products in 79–87% yields (Table 2, entries 12–15). The reac-
tion was compatible with both the electron-donating (tBu and
methoxy) and electron-withdrawing (trifluoromethyl) groups
substituted on benzenesulfenyl chlorides 5 f–5h (Table 2, en-
tries 16 and 17), but a benzenesulfenyl chloride with a strong
electron-withdrawing group afforded a lower yield (Table 2,
entry 18). Benzenesulfenyl chlorides with halogen groups, such
as F, Cl, and Br, were able to be converted into the correspond-
ing oxazolidine-2,4-diones in 69–75% yields (Table 2, en-
tries 19–21).
complex mixture (2a<5%)[f]
complex mixture (2a<10%)[f]
[a] Reaction conditions: Under open air, 1a (0.3 mmol), 5a, and DMSO
(2.0 mL) for 1 h. [b] Yield of isolated product. [c] Under N2 atmosphere.
[d] Under O2 (1 atm) atmosphere. [e] 5.0 equivalents of H2O were added.
[f] Yield was determined by 1H NMR spectroscopy of the crude reaction
mixture with 1,3,5-trimethylbenzene as an internal standard.
Table 2. Oxidative cyclizations of ynamides 1.[a]
To explore the possibility of developing an asymmetric var-
iant,[11] several ynamides containing chiral auxiliaries were ex-
Entry
1
R
Ar
Product
Yield [%]
76
82[b]
76
78
63
72
41
38
61
71
67
–
79
78
80
87
66
71
42
75
73
69
Ph (1a)
4-MePh (5a)
2a
amined (Scheme 3). Satisfyingly,
a diastereoselectivity of
80:20[12] was obtained with an isopropyl-substituted oxazolidi-
none, which reveals the possibility of an asymmetric cycliza-
tion.[13]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
4-MePh (1b)
4-MeOPh (1c)
4-BrPh (1d)
4-FPh (1e)
4-AcPh (1 f)
4-NO2Ph (1g)
3,4-Cl2Ph (1h)
3,5-tBu2Ph (1i)
2-naphthyl (1j)
n-C4H9 (1k)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
4-MePh (5a)
4-MePh (5a)
4-MePh (5a)
4-MePh (5a)
4-MePh (5a)
4-MePh (5a)
4-MePh (5a)
4-MePh (5a)
4-MePh (5a)
4-MePh (5a)
2-MePh (5b)
3-MePh (5c)
2,4-Me2Ph (5d)
2,5-Me2Ph (5e)
4-tBuPh (5 f)
3-MeOPh (5g)
4-CF3Ph (5h)
4-ClPh (5i)
2b
2c
2d
2e
2 f
2g
2h
2i
2j
2k
2ab
2ac
2ad
2ae
2af
2ag
2ah
2ai
2aj
2ak
Scheme 3. Asymmetric oxidative cyclizations of ynamides. Bn: benzyl.
So far, we have developed the process to synthesize 5-sub-
stituted oxazolidine-2,4-diones. Further studies focused on ac-
cessing various oxazolidine-2,4-diones with diverse groups on
the N atom were also carried out. We first examined the effect
of various leaving groups (Et, iPr, tBu, and Bn) on the ester
moiety to determine the ideal structure for producing N-substi-
tuted oxazolidine-2,4-diones (Table 3). Cyclization of ynamides
containing leaving groups such as Et and iPr took place with
poor yields (Table 3, entries 1 and 2). As we reported befor-
4-BrPh (5j)
3-FPh (5k)
Ph (1a)
[a] Reaction conditions:
(2.5 equiv) in DMSO (2.0 mL) at 1008C for 1 h. [b] Scale-up experiment
with 6.0 mmol loading of 1a.
1
(0.3 mmol), benzenesulfenyl chlorides
comparable efficiency (Table 2, entry 1). Gratifyingly, the reac-
tion tolerated a wide range of functional groups including
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4). Presumably because of atropisomerism,[14] ynamides with
groups on the ortho position of the N-aryl ring, such as Me
and Br, generated the corresponding oxazolidine-2,4-diones in
moderate yields with a satisfactory diastereoselectivity (Table 4,
entries 5 and 6).[12] A series of meta-substituted ynamides, in-
cluding some with electron-donating groups (MeO, Me) and
some with electron-withdrawing groups (F, Cl, Br, CF3), were
converted into the corresponding oxazolidine-2,4-diones in
moderate to high yields (Table 4, entries 7–12). The structure of
3aj was further confirmed by single-crystal X-ray diffraction
(see the Supporting Information for details). Meanwhile, the
para effect was not obvious for methyl, bromo, or chloro
groups on the para position of the N-aryl ring in the reaction
(Table 4, entries 13–15). Ynamides possessing benzyl, 2-naph-
thyl, and benzo[d][1,3]-dioxol-5-yl groups on the N atom could
succeed in producing the desired oxazolidine-2,4-diones in 59–
72% yields (Table 4, entries 16–18). Ynamides with an N-butyl
or N-isopropyl group were also good substrates for this reac-
tion and provided the desired products 3as and 3at in moder-
ate yields (Table 4, entries 19 and 20). To our delight, tert-butyl
hex-1-yn-1-yl(phenyl)carbamate (6u) could furnish the 5-aryl-
substituted oxazolidine-2,4-dione 3au in 55% yield (Table 4,
entry 21).
Table 3. Oxidative cyclizations of ynamides containing various leaving
groups.[a]
Entry
R
t [h]
Yield [%][b]
1
2
3
4
Et (6aa)
iPr (6ab)
tBu (6ac)
Bn (6ad)
3
3
1
1
34
36
74
51
[a] Reaction conditions:
6
(0.3 mmol), benzenesulfenyl chlorides
(2.5 equiv) in DMSO (2.0 mL) at 1008C for time t. [b] Yield of isolated
product.
e,[4b,c] N-alkynyl tert-butyloxycarbamates are structures of great
potential for the synthesis of cyclic carbamates, and N-alkynyl
tert-butyloxycarbamate 6ac reacted well to offer the desired
product in good yield (Table 3, entry 3). Furthermore, N-carbo-
benzyloxy-protected ynamide (6ad) furnished the correspond-
ing product in 51% yield, which is relatively lower than that
obtained with 6ac (Table 3, entry 4).
Next, we explored the scope of N-alkynyl tert-butyloxycarba-
mates 6a–6u under the optimized conditions. A variety of
functional groups substituted on the aryl moiety of ynamides
were tolerated and readily gave the corresponding oxazoli-
dine-2,4-diones in moderate to good yields (Table 4, entries 1–
We next synthesized the vinyl alkynyl-substituted substrates
6v–6x to further examine the flexibility of this methodology
(Table 5). The reaction of 3-[(3E)-4-phenyl-3-buten-1-yn-1-yl]ox-
azolidin-2-one (6v) with p-tolylsulfenylchloride gave an un-
identified mixture, and we were unable to isolate the corre-
sponding product. By contrast, vinyl alkynyl-substituted sub-
strate 6w, with a Br atom at the ortho position of the N-aryl
ring, generated the corresponding oxazolidine-2,4-dione in
65% yield with a diastereoselectivity of 85:15, presumably be-
cause of atropisomerism.[12–14] Additionally, ynamide 6x gave
a good yield under the same reaction conditions. The activity
of terminal ynamide 6y was also investigated under the opti-
mized reaction conditions.[15] Interestingly, 3-phenyl-5,5-bis(p-
tolylthio)oxazolidine-2,4-dione (3ay) was obtained in 69%
yield, and its structure was further confirmed by single-crystal
X-ray diffraction (see the Supporting Information for details).
A chlorine atom in the products can be used to introduce
new groups for the synthesis of new bioactive products. For
example, upon reaction with sodium azide, 2a could easily
afford the corresponding azido thiooxazolidine-2,4-dione 2aI
in 80% yield.[16] The copper-catalyzed azide–alkyne cycloaddi-
tion reaction of 2aI with phenylacetylene could produce the
triazole derivative 2aII in 77% yield (Scheme 4).[17] Unsatisfac-
torily, the attempted ring-opening reaction of oxazolidine-2,4-
dione 3aa failed to provide the corresponding thioacrylamide
3aaI and gave 4-methylbenzenethiol and the a-keto amide.[18]
An ynamide without the ester moiety, N-benzyl-4-methyl-N-
(phenylethynyl)benzenesulfonamide (7a), accomplished the
synthesis of a-keto amide 7aa in 89% yield under open air
conditions. In this case, we believe that p-tolylsulfenylchloride
probably plays the role of a Lewis acid like iodine (Scheme 5,
I).[4a,5a] We also confirmed that, in the presence of radical scav-
engers like TEMPO and BHT, the cyclization proceeded smooth-
ly to form oxazolidine-2,4-dione 2a in 65 and 69% yields,
Table 4. Oxidative cyclizations of N-alkynyl tert-butyloxycarbamates 6a–
6u.[a]
Entry R1
R2
Product Yield [%][b]
1
2
3
4
5
6
7
8
Ph (6ac)
Ph
4-MePh (6b) Ph
4-MeOPh (6c) Ph
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3an
3ao
3ap
74
75
78
70
69[c]
62[d]
73
82
80
69
68
80
81
69
74
72
68
59
49
62
55
4-BrPh (6d)
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2-MePh (6e)
2-BrPh (6 f)
3-MePh (6g)
3-FPh (6h)
3-ClPh (6i)
3-BrPh (6j)
3-MeOPh (6k)
3-CF3Ph (6l)
4-MePh (6m)
4-ClPh (6n)
4-BrPh (6o)
Bn (6p)
9
10
11
12
13
14
15
16
17
18
19
20
21
benzo[d][1,3]dioxol-5-yl (6q) 3aq
2-naphthyl (6r)
n-C4H9 (6s)
iPr (6t)
3ar
3as
3at
3au
Ph
n-C4H9 (6u)
Ph
[a] 6 (0.3 mmol), benzenesulfenyl chlorides (2.5 equiv) in DMSO (2.0 mL)
at 1008C for 1 h. Boc: tert-butoxycarbonyl. [b] Yield of isolated product.
[c] d.r.=69:31; ratio assigned by using 1H NMR spectroscopy. [c] d.r.=
1
85:15; ratio assigned by using H NMR spectroscopy.
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a tandem approach of CÀCl formation, CÀO bond
cleavage, and CÀO formation.
Table 5. Scope of the reaction with more ynamides.[a]
Conclusion
Yield [%][b]
In summary, we have demonstrated a new cascade
oxothiolation/cyclization of ynamides for the synthe-
sis of thiooxazolidine-2,4-diones by a benzenesulfenyl
chloride mediated pathway under metal-free condi-
tions. This method tolerated a wide range of func-
tional groups on the ynamide component and was
compatible with different benzenesulfenyl chloride
reagents. This approach revealed the further possibili-
ty of stereoselective synthesis of oxazolidine-2,4-
diones by relying on the use of suitable chiral auxilia-
ries or chiral counteranions. The application of this
protocol toward the synthesis of triazole derivatives
was also demonstrated. Further studies to find more
efficient metal-free oxyfunctionalization systems
based on Brønsted acid catalytic or Lewis acid medi-
ated systems are underway.
Entry Ynamide
Product
complex mixture; no product
isolated
1
(6v)
(3av)
(3aw)
(3ax)
(3ay)
2
65 (d.r.=85:15[c])
(6w)
3
78
69
(6x)
4
Experimental Section
(6y)
Ynamide (0.3 mmol), ArSCl (2.5 equiv), and DMSO
(2.0 mL) were placed in a 10 mL flame-dried Schlenk
tube under nitrogen. The reaction mixture was stirred at
1008C for 1h and was monitored with TLC analysis. The
reaction mixture was quenched by adding EtOAc and
water. The combined organic layers were washed with
[a] Reaction conditions:
6 (0.3 mmol), p-tolylsulfenylchloride (2.5 equiv) in DMSO
(2.0 mL) at 1008C for 1 h. [b] Yield of isolated product. [c] Ratio assigned by using
1H NMR spectroscopy.
which strongly rules out a radical process (Scheme 5, II).[6a] Fur-
brine, dried over Na2SO4, and concentrated under reduced pres-
sure. The residue was purified by silica gel column chromatogra-
phy to give the desired product.
thermore, for the reaction at room temperature, dimethylsul-
fide was detected by GC-MS analysis (m/z 62.1), which indi-
cates that DMSO plays the role of oxidant (Scheme 5, III).[12] Fi-
nally, an experiment with 18O-labeled DMSO was conducted to
give 18O-labeled 2a in 72% yield with greater than 84% 18O-la-
beled product, which also indicates that DMSO acts as the oxi-
dant (Scheme 5, IV).
Acknowledgements
We greatly acknowledge the financial support in part by the
Provincal Natural Science Foundation of Jiangsu, China (no.
BK20140937) and the Postgraduate Innovation Fund of Jiangsu
Province, China (2015, KYLX15_0797).
Based on these facts, a rational mechanism for the formation
of 2 is depicted in Scheme 6. In the presence of benzenesul-
fenyl chlorides, 1 can produce thiirenium ion A.[19] Ketenimini-
um form A’ can increase the electrophilicity and regioselectivi-
ty.[20] Nucleophilic attack of DMSO can generate intermediate
B,[5] which is transformed into complex C through a transfer of
electrons. The corresponding products 2 are generated after
Keywords: cyclization · heterocycles · oxothiolation · synthetic
methods · ynamides
Scheme 4. Synthesis of a triazole derivative and ring opening of an oxazolidine-2,4-dione.
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Scheme 5. Experiments for the mechanistic study. Ts: toluene-4-sulfonyl; TEMPO:2,2,6,6-tetramethyl-1-piperidinoxyl; BHT: 3,5-di-tert-butyl-4-hydroxytoluene.
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Received: October 29, 2015
Published online on January 12, 2016
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ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim