Improved Synthetic Method for 5-[(Phenylthio)methyl]oxazoline Derivatives: Electrophilic Cyclization of Allylic Amide Using a Bronsted Acid and Tetrabutylammonium Chloride under Mild Conditions

Article abstract of DOI:10.1055/s-0039-1690836

The synthesis of oxazolines using electrophilic cyclization of allylic amide is a simple and powerful method. However, cyclization involving arylsulfenylation requires harsh reaction conditions. We found that the reaction proceeds under mild heating conditions with the combination of a Bronsted acid and tetrabutylammonium chloride. This method enabled the synthesis of 5-[(arylsulfenyl)methyl]oxazoline derivatives under mild conditions and demonstrated high tolerance for various functional groups.

Full text of DOI:10.1055/s-0039-1690836

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© Georg Thieme Verlag Stuttgart · New York
2020, 31, A–E
letter
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Y. Nagao, K. Hiroya
Letter
Synlett
Improved Synthetic Method for 5-[(Phenylthio)methyl]oxazoline
Derivatives: Electrophilic Cyclization of Allylic Amide Using a Brønsted
Acid and Tetrabutylammonium Chloride under Mild Conditions
Yoshihiro Nagao*
Kou Hiroya
O
O
SPh
tetrabutylammonium chloride (20 mol%)
10-camphorsulfonic acid (20 mol%)
Ar1
O
Ar2
+
PhS
N
Ar1
N
Ar2
N
H
DMF, 40 °C, 24 h
Faculty of Pharmacy, Musashino University, 1-1-20 Shin-machi,
Nishitokyo-shi, Tokyo, Japan
O
19 examples
up to 97% yield
yo_nagao@musashino-u.ac.jp
Received: 08.01.2020
Accepted: 04.02.2020
Table 1 Conditions Screenings
Published online: 26.02.2020
DOI: 10.1055/s-0039-1690836; Art ID: st-2020-l0016-l
PhS-succinimide (2; 1.2 equiv)
PhS
H
Ph
activator (0.1 equiv)
O
N
Ph
Ph
solvent, 40 °C, 24 h
yielda
N
Abstract The synthesis of oxazolines using electrophilic cyclization of
allylic amide is a simple and powerful method. However, cyclization in-
volving arylsulfenylation requires harsh reaction conditions. We found
that the reaction proceeds under mild heating conditions with the com-
bination of a Brønsted acid and tetrabutylammonium chloride. This
method enabled the synthesis of 5-[(arylsulfenyl)methyl]oxazoline de-
rivatives under mild conditions and demonstrated high tolerance for
various functional groups.
Ph
O
1a
3a
Entry
Activator
Solvent
Yield (%)a
1b
2b
3b
4b
5b
6
MgCl2
FeCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
MeCN
N.R.
N.R.
N.R.
N.R.
23
Ce(OTf)3
B(C6F5)3
AlCl3
Key words oxazoline, oxazine, thioether, sulfide, electrophilic cycliza-
tion
HCl aq.
TsOH
20
Oxazolines are important compounds frequently found
in natural products1 and biologically active molecules;2
some of their derivatives are often used as ligands3 or di-
recting groups.4 Since the development of a facile synthetic
method, oxazoline derivatives have been recognized as an
important research field and various strategies have been
reported.5 An electrophilic cyclization reaction using allylic
amide and a cationic reagent is currently one of the most
reliable approaches; this reaction is also a convenient
method for introducing a heteroatom into the carbon–car-
bon double bond under mild reaction conditions (Scheme 1).
7
N.R.
56
8
TsOH, TBAC
TBAC
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
THF
9
N.R.
59
10
11
12
13
14
15
16
17
18
19c
CSA, TBAC
PPTS, TBAC
BzOH, TBAC
TsOH, TBAB
TsOH, TBAI
CSA, TBAC
CSA, TBAC
CSA, TBAC
CSA, TBAC
CSA, TBAC
25
9
57
2
33
AcOEt
CH2Cl2
DMF
51
O
O
[E]+
R
52
[E]
O
N
R
N
R
88
N
H
[E]
H
DMF
>99
[E]+ = electrophilic reagent (halogen, O, S, Se, CF3 etc.)
a Yields were determined by 1H NMR spectroscopy.
b 1.0 equiv of activator was used.
Scheme 1 Electrophilic cyclization of allylic amide
c 0.2 equiv of activator were used.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Y. Nagao, K. Hiroya
Letter
Synlett
However, most previous research has focused on an
halocyclization reaction with cationic halogen species,6a–h
while there are only a few reports on the use of other elec-
trophiles (e.g., selenium,6i,j sulfur,7 oxygen,6k,l CF3 cation,6m
and hypervalent iodine compounds.6n,o In particular, there
are insufficient studies on electrophilic cyclization reac-
tions involving carbon–sulfur bond formation.
acid, the reaction was carried out under anhydrous condi-
tions to avoid hydrolysis, but it did not proceed (entry 7).
Considering that hydrochloric acid releases chloride anions
as well as protons, we added chloride ions to this reaction.
The desired product was obtained in moderate yield
through the addition of 10 mol% of tetrabutylammonium
chloride (TBAC; entry 8), while no reaction occurred in the
absence of a Brønsted acid (entry 9). These entries suggest-
ed that a combination of protons and halide anions plays an
important role in this reaction. In addition, while camphor-
sulfonic acid could have been used instead of p-toluenesul-
fonic acid, other acids tended to decrease the yield accord-
ing to acidity (entries 10–12). Tetrabutylammonium bro-
mide (TBAB) produced the desired product in the same
yield as TBAC,10 but tetrabutylammonium iodide (TBAI) was
not applicable (entries 13 and 14). Finally, examining sol-
vent effects, we confirmed that DMF is a suitable solvent
(entries 15–18). Increasing the amount of catalyst from 10
mol% to 20 mol% gave quantitative yields (entry 19). There-
fore, we decided that entry 19 had the optimal conditions
for this reaction.
Recently, Fu et al.7d reported a synthetic method for
5-[(arylsulfenyl)methyl]oxazolinederivativesusingactivated
(phenylsulfenyl)succinimide with BF3·OEt2. Although their
method was successful, it required temperatures greater
than 100 °C. Therefore, improving their method under
milder reaction conditions is essential for the synthesis of
oxazolines that have sensitive functional groups. Herein,
we report that a catalytic amount of a Brønsted acid and
tetrabutylammonium salt as an activator are the most suit-
able conditions for this reaction.
We investigated the initial conditions for the electro-
philic cyclization reaction of N-2-phenylallyl)benzamide
(1a) with N-(phenylsulfenyl)succinimide (2) in the pres-
ence of activators (Table 1). We used various metal reagents
(entries 1–5). The desired oxazoline 3a was obtained in low
yield only when using a stoichiometric amount of alumi-
num chloride(III) after 24 h. Referring to Hostier et al.,8 we
tried using a Brønsted acid as an activator. When a catalytic
amount of diluted hydrochloric acid was added, the reac-
tion underwent moderate conversion, but 3a was obtained
in low yield due to the acid-catalyzed hydrolysis of 3a (en-
try 6). Using p-toluenesulfonic acid instead of hydrochloric
Next, we investigated the substrate scopes (Scheme 2).
The aromatic ring in the benzamide moiety gave the corre-
sponding oxazolines in good yield regardless of electron
density and substituent position (3a–h). Although het-
eroaryl amide required an extension of the reaction time,
the reaction proceeded smoothly (3i,j). A ferrocene deriva-
tive, which is an easily oxidizable moiety, gave a moderate
yield by improving the reaction conditions and shortening
PhS-succinimide (1.2 equiv)
TBAC (20 mol%), CSA (20 mol%)
SPh
O
Ar1
O
Ar2
Ar1
N
H
Ar2
N
DMF, 40 °C, 24 h
yielda
1a–o
3a–o
OMe
NO2
CHO
SPh
Ph
SPh
SPh
SPh
O
SPh
O
O
O
O
Ph
N
Me
Ph
N
Ph
N
Ph
N
Ph
N
3a, 96%
3b, 88%
3c, 89%
3d, 97%
3e, 62%
Me
SPh
SPh
SPh
Me
SPh
SPh
O
O
O
S
O
Me
O
O
Ph
N
Ph
N
Ph
N
Ph
N
Ph
N
3i,b 78%
3j,b 93%
3f, 93%
3g, 90%
3h, 68%
O
SPh
SPh
SPh
Ph
Ph
Ph
SPh
O
O
O
O
O
N
Fe
SPh
N
N
N
O
Ph
MeO
Cl
Ph
N
3k,c 70%
3l, 93%
3m, 86%
3n, 85%
3o,d 78%
Scheme 2 Substrate scope for allylic amides. a Isolated yield. b Reaction time was 48 h. c 100 mol% of TBAC and CSA were used, reaction time was 1 h.
d Reaction time was 72 h.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

C
Y. Nagao, K. Hiroya
Letter
Synlett
B from nucleophilic attack of the chloride ion. The olefin of
1 interacted with B to form a thiiranium ion C, and the cor-
responding oxazoline 3 was obtained by subsequent intra-
molecular cyclization. Although phenylsulfenyl chloride B is
known to be a highly reactive sulfenylating reagent, it has
been reported to spontaneously explode during storage,
even in a refrigerator.13 Thus, B presents problems for large-
scale preparation and storage. In this reaction, B could be
prepared catalytically; therefore, the reaction was safer
than the conventional method.
O
O
PhS
Ph
Ph
Me
O
optimal conditions
Ph
Ph
N
H
a)
b)
Me
N
3p, 73%
PhS
O
H
N
H
N
1t
3q, 72%
Ph
O
O
Ph
c)
Ph
N
Ph
Ph
PhS
N
H
1r
4r, 86%
O
H O
H+
Cl–
S
O
Ph
O
Ph
S
N
S N
Ph
Cl
d)
e)
Ph
Ph
Ph
N
H
N
succinimide
PhS
O
O
1s
4s, 58%
2
A
B
O
Ph
PhS
O
O
SPh
O
Ph
N
H
Ar
N
B
O
Ar
Ph
Ar
N
1t
3t, 0%
Ph
N
Ar
N
H
H
S-Ph
H+
Cl–
1
C
3
Scheme 3 Substrate scope for miscellaneous unsaturated benzamides
Scheme 4 Plausible reaction mechanism
the reaction time (3k). A substrate with cyclic acetal moiety
proceeded smoothly without the loss of acetal (3l). Substit-
uent studies of the olefin part, which could be applied to
both electron-rich and electron-poor olefins, also proceed
well with a bulky structure, such as 1-naphthyl moiety
(3m–o).
This reaction can be applied to not only the N-(2-aro-
matic)allylic amide but also methallylic amide (Ar2 = Me) or
unsubstituted allylic amide (Ar2 = H, Scheme 3, eq. a and b).
The 1,3-oxazine derivative 4r was obtained as a result of
6-exo cyclization when using homoallylamide 1r (Scheme 3,
eq. c). In trans-cinnamic amide, which is a 1,2-disubstituted
olefin, 6-endo cyclization was preferred to 5-exo cyclization
to obtain oxazine 4s (Scheme 3, eq. d). However, these reac-
tion conditions could not be applied to the alkynyl amide 1t
(Scheme 3, eq. e).
Finally, the transformations of the oxazoline are pre-
sented in Scheme 5. This reaction proceeded with good
yield even with 1.0 g of 1n. Oxazoline 3n was easily opened
by an acid-catalyzed hydrolysis reaction and converted into
1,2-aminoalcohol derivative 5 with good yield. The oxida-
tion of 3n using an aqueous sodium hypochlorite solution
could be converted into sulfoxides 6a and 6b without the
loss of the oxazoline moiety. Moreover, sulfoxides are also
important chemical compound groups.14
We found that the combination of a Brønsted acid and
TBAC proceeded at 40 °C in an electrophilic cyclization re-
action involving sulfide formation. The substrate scope of
this reaction was wide, and the desired oxazolines were ob-
tained in good yields.15–17 In addition, this reaction gave the
desired product without loss of yield even on the gram
scale, and the product could be easily converted into 1,2-
aminoalcohol or sulfoxide, which is important for synthetic
compounds, which can be useful building blocks.
We deduced a plausible mechanism for this reaction
from the results of our examination and previous literature
(Scheme 4).11,12 The sulfenylating reagent 2 became A
through protonation and generated phenylsulfenyl chloride
OH
HCl aq.
H
PhS
N
Ph
THF
rt, 24 h
83%
Ar
SPh
O
Ph
PhS-succinimide
Cl
O
TBAC/CSA (20 mol%)
O
5
Ar
N
DMF, 40 °C, 24 h
91%
Ph
N
H
(Ar = 4-chlorophenyl)
O
O
PhS
PhS
Ar
1n
1.069 g (3.93 mmol)
3n
NaOCl
Ph
Ph
O
+
O
MeCN, rt, 5 h
89%, dr = 1:1
Ar
N
N
6a
6b
Scheme 5 Transformation of oxazoline derivative
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

D
Y. Nagao, K. Hiroya
Letter
Synlett
Acknowledgment
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Ashmawy. M. I.; Mellor, J. M. J. Chem. Soc., Perkin Trans. 1 1988,
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Chem. 1992, 57, 4025. (d) Yu, J.; Tian, H.; Gao, C.; Yang, H.; Jiang,
Y.; Fu, H. Synlett 2015, 26, 676. (e) Senadi, G. C.; Guo, B.-C.; Hub,
W.-P.; Wang, J.-J. Chem. Commun. 2016, 52, 11410.
(f) Miyamoto, Y.; Mitani, N.; Yanagi, R.; Kashimura, S.; Suga, S.;
Yoshida, J.; Matsumoto, K. Heterocycles 2018, 96, 1373.
(8) Hostier, T.; Ferey, V.; Ricci, G.; Pardo, D. G.; Cossy, J. Chem.
Commun. 2015, 51, 13898.
The authors would like to thank MARUZEN-YUSHODO Co., Ltd.
(https://kw.maruzen.co.jp/kousei-honyaku/) for the English language
editing.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690836.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
(9) When TBAB was used, small amount of the 5-(bro-
momethyl)oxazoline derivative was produced as a byproduct
(Scheme 6).
References and Notes
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Zia, M. F.; Wencel-Delord, J.; Besset, T.; Maesa, B. U. W.;
Schnürch, M. Chem. Soc. Rev. 2018, 47, 6603. (b) Sammakia, T.;
Latham, H. A. J. Org. Chem. 1996, 61, 1629.
O
H O
H+
Cl–
S
S
N
S N
Ph
Cl
Ph
Ph
succinimide
O
O
2
A
B
O
SPh
O
Ar
B
O
Ar
Ph
Ar
N
Ph
N
Ar
N
H
H
S-Ph
H+
Cl–
1
C
3
Scheme 6
(10) (a) Behforouz, M.; Kerwood, J. E. J. Org. Chem. 1969, 34, 51.
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C. G.; Kehr, G.; Gilmour, R. Beilstein J. Org. Chem. 2018, 14, 1021.
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J. Am. Chem. Soc. 2000, 122, 11031. (k) Godfrey, J. D.; Gordon, E.
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(m) Kawamura, S.; Sekine, D.; Sodeoka, M. J. Fluorine Chem.
2017, 203, 115. (n) Alhalib, A.; Kamouka, S.; Moran, W. J. Org.
Lett. 2015, 17, 1453. (o) Moon, N. G.; Harned, A. M. Tetrahedron
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(13) (a) Epstein, W. W.; Sweat, F. W. Chem. Rev. 1967, 67, 247.
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(14) Experimental Procedure for Substrate Scopes (Scheme 2)
A 15 mL test tube equipped with a three-way cock was charged
with a magnetic stirrer, N-(2-phenylprop-2-en-1-yl)benzamide
(1a, 47.5 mg, 0.20 mmol), N-(phenylthio)pyrrolidine-2,5-dione
(2, 49.7 mg, 0.24 mmol, 1.2 equiv), and tetrabutylammonium
chloride (11.1 mg, 0.04 mmol, 20 mol%). The test tube was evac-
uated and refilled with dry argon gas three times. Dry DMF (2.0
mL) was added to give a clear solution. (+)-10-Camphorsulfonic
acid (9.2 mg, 0.40 mmol, 20 mol%) was added under a slow
stream of argon gas. The reaction mixture was heated to 40 °C
for 24 h. After being cooled to room temperature, the reaction
mixture was quenched by adding of saturated aqueous Na2S2O3
(1.0 mL) and saturated aqueous NaHCO3 (1.0 mL). The separated
aqueous layer was extracted with EtOAc three times, and the
combined organic layers were washed with brine, dried over
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E

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Y. Nagao, K. Hiroya
Letter
Synlett
anhydrous Na2SO4, and concentrated under reduced pressure.
The residue was purified by flash column chromatography
(hexane/EtOAc, 7:3) as eluent to give to 3a (66.4 mg, 0.192
mmol, 96%) as a colorless oil.1H NMR (500 MHz, CDCl3):  = 7.85
(d, J = 8.0 Hz, 2 H), 7.48 (t, J = 7.4 Hz, 1 H), 7.39 (t, J = 7.7 Hz, 2 H),
7.33 (s, 4 H), 7.31–7.27 (m, 2 H), 7.20–7.11 (m, 3 H), 4.45 (d, J =
14.6 Hz, 1 H), 4.17 (d, J = 14.6 Hz, 1 H), 3.57 (d, J = 14.0 Hz, 1 H),
3.49 (d, J = 14.0 Hz, 1 H). 13C NMR (125 MHz, CDCl3):  = 162.8,
141.8, 135.9, 133.7, 131.4, 130.4, 128.8, 128.7, 128.3, 128.2,
127.3, 126.5, 126.3, 88.2, 66.5, 45.9.
3.58 (d, J = 13.5 Hz, 1 H), 3.39 (d, J = 13.5 Hz, 1 H). 13C NMR (125
MHz, CDCl3):  = 168.4, 141.1, 135.5, 133.8, 133.5, 131.8, 130.5,
129.0, 128.6, 128.5, 127.0, 126.9, 126.8, 76.4, 49.0, 45.9.
(16) Experimental Procedure for the Synthesis of Compound 6
To
a
solution of 5-(4-chlorophenyl)-2-phenyl-5-[(phen-
ylthio)methyl]-4,5-dihydrooxazole (3n, 50.4 mg, 0.127 mmol)
in MeCN (2.7 mL), sodium hypochloride solution (10.5%, 0.21
mL, 1.1 equiv) was added. The reaction mixture stirred at room
temperature. After completion of the reaction, the reaction
mixture was quenched by saturated aqueous Na2S2O3. The
organic phase was separated, and the aqueous phase was
extracted with EtOAc three times. The combined organic layers
were washed with brine, dried over anhydrous Na2SO4, and con-
centrated under reduced pressure. The residue was purified by
flash column chromatography (hexane/EtOAc 4:6) as eluent to
give an inseparable mixture of diastereoisomers 6a and 6b (46.7
mg, 0.113 mmol, 89%) as a colorless oil.1H NMR (500 MHz,
CDCl3):  = 8.08 (d, J = 8.0 Hz, 2 H, diastereomer A),  = 7.92 (d,
J = 8.0 Hz, 2 H, diastereomer B), 7.68–7.40 (m, 8 H, A), 7.68–7.40
(m, 12 H, B), 7.38–7.30 (m, 4 H, A), 4.80 (d, J = 14.9 Hz, 1 H, A),
4.55 (d, J = 14.9 Hz, 1 H, B), 4.28 (d, J = 14.9 Hz, 1 H, B), 4.22 (d,
J = 14.9 Hz, 1 H, A), 3.60 (d, J = 13.7 Hz, 1 H, B), 3.51 (d, J = 14.3
Hz, 1 H, A), 3.40 (d, J = 14.3 Hz, 1 H, A), 3.33 (d, J = 13.7 Hz, 1 H,
B). 13C NMR (125 MHz, CDCl3):  = 162.8, 162.6, 144.5, 144.3,
141.6, 140.1, 134.4, 134.1, 131.8, 131.8, 131.3, 131.2, 129.4,
129.4, 129.2, 129.1, 128.5, 128.5, 128.4, 128.2, 127.0, 127.0,
126.5, 125.9, 124.1, 123.9, 86.1, 85.9, 70.1, 69.1, 67.6, 66.8.
(15) Experimental Procedure for the Synthesis of Compound 5
To a solution of 5-(4-chlorophenyl)-2-phenyl-5-[(phenylthio)-
methyl]-4,5-dihydrooxazole (3n, 51.3 mg, 0.135 mmol) in THF
(1.3 mL), dilute hydrochloric acid (1.0 mol/L, 1.3 mL) was added.
The reaction mixture stirred at room temperature. After being
stirred for 24 h, the reaction mixture was quenched by satu-
rated aqueous NaHCO3. The organic phase was separated, and
the aqueous phase was extracted with EtOAc three times. The
combined organic layers were washed with brine, dried over
anhydrous Na2SO4, and concentrated under reduced pressure.
The residue was purified by flash column chromatography
(hexane/EtOAc, 6:4) as eluent to give to 5 (44.8 mg, 0.113 mmol,
83%) as a white solid.1H NMR (500 MHz, CDCl3):  = 7.64 (d, J =
7.4 Hz, 2 H), 7.48 (t, J = 7.4 Hz, 1 H), 7.43–7.36 (m, 4 H), 7.29–
7.23 (m, 4 H), 7.22–7.14 (m, 3 H), 6.48 (br s, 1 H), 4.02 (dd, J =
13.9, 6.3 Hz, 1 H), 4.03 (br s, 1 H), 3.68 (dd, J = 13.9, 6.3 Hz, 1 H),
© 2020. Thieme. All rights reserved. Synlett 2020, 31, A–E