Boron-catalyzed arylthiooxygenation of n -allylamides: Synthesis of (arylsulfanyl)oxazolines

Article abstract of DOI:10.1055/s-0034-1378948

Oxazoles and aryl sulfides are chemical entities that are found in many natural products and biologically and pharmaceutically active molecules. It is therefore highly desirable to develop an efficient and practical approach to the synthesis of arylsulfanyl-substituted oxazolines. We developed a simple and efficient method for boron-catalyzed sequential arylsulfanylation and oxygenation of N-allylamides. The protocol uses readily available 1-(arylsulfanyl)pyrrolidine-2,5-diones as the arylsulfanylation reagents and inexpensive boron trifluoride etherate as the catalyst; no ligands or additives are required, and it is not necessary to purge the reaction vessel of air. The method therefore provides an efficient and practical strategy for the synthesis of arylsulfanyl-substituted heterocycles.

Full text of DOI:10.1055/s-0034-1378948

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 676–680
letter
676
J. Yu et al.
Letter
Synlett
Boron-Catalyzed Arylthiooxygenation of N-Allylamides: Synthesis
of (Arylsulfanyl)oxazolines
Jipan Yua
Hua Tiana
Chang Gaoa
Haijun Yanga
Yuyang Jiangb
Hua Fu*a,b
R3
O
R4
R2
BF3•OEt2, DCE
105 °C, 24 or 36 h
O
O
R1
+
N
SAr
SAr
R1
N
R4
N
R2
H
R3
O
a Key Laboratory of Bioorganic Phosphorus Chemistry and
Chemical Biology (Ministry of Education), Department of
Chemistry, Tsinghua University, Beijing 100084, P. R. of China
b Key Laboratory of Chemical Biology (Guangdong Province),
Graduate School of Shenzhen, Tsinghua University, Shenzhen
518057, P. R. of China
fuhua@mail.tsinghua.edu.cn
Received: 26.10.2014
Accepted after revision: 24.11.2014
Published online: 08.01.2015
tion,11 aminohalogenation,12 azidooxygenation,13 amino-
and oxotrifluoromethylation,14 carbo- and heterofunction-
alization,15 and dicarbofunctionalization reactions.16 In-
spired by the excellent results that have been achieved, we
examined the boron-catalyzed sequential arylsulfanylation
and oxygenation of N-allylamides to give arylsulfanyl-sub-
stituted oxazolines.
DOI: 10.1055/s-0034-1378948; Art ID: st-2014-w0886-l
Abstract Oxazoles and aryl sulfides are chemical entities that are
found in many natural products and biologically and pharmaceutically
active molecules. It is therefore highly desirable to develop an efficient
and practical approach to the synthesis of arylsulfanyl-substituted oxaz-
olines. We developed a simple and efficient method for boron-cata-
lyzed sequential arylsulfanylation and oxygenation of N-allylamides.
The protocol uses readily available 1-(arylsulfanyl)pyrrolidine-2,5-di-
ones as the arylsulfanylation reagents and inexpensive boron trifluoride
etherate as the catalyst; no ligands or additives are required, and it is
not necessary to purge the reaction vessel of air. The method therefore
provides an efficient and practical strategy for the synthesis of arylsulfa-
nyl-substituted heterocycles.
We began our search for optimal conditions for such
transformations by examining the reaction of N-(2-phenyl-
prop-2-en-1-yl)benzamide (1a) with 1-(phenylsulfanyl)-
pyrrolidine-2,5-dione (2a) to give 2,5-diphenyl-5-[(phenyl-
sulfanyl)methyl]-4,5-dihydro-1,3-oxazole (3a) in the pres-
ence of various catalysts in 1,2-dichloroethane at room
temperature under air (Table 1, entries 1–5). Boron trifluo-
ride etherate as catalyst (entry 2) gave oxazole 3a in 12%
yield after 24 hours. Increasing the amount of catalyst gave
higher yields (entries 6 and 7). Good to excellent yields
were obtained by using 0.2 equivalents of boron trifluoride
etherate catalyst at higher temperatures (60 or 105 °C) (en-
tries 8 and 9). The yield decreased when the reaction time
was reduced (entry 10), whereas increasing the reaction
time to 30 hours had little effect on the yield (entry 11).
Next, we examined the effects of various solvents (entries 9
and 12–14), and we confirmed that 1,2-dichloroethane is a
suitable solvent (entry 9). In the absence of the catalyst, the
product 3a was obtained in 52% yield (entry 15). Perform-
ing the reaction under an atmosphere of nitrogen (entry
16) gave a yield similar to that obtained under air (entry 9).
Having determined the optimal conditions for the
transformation, we investigated the scope of the boron-cat-
alyzed arylthiooxygenation of various substituted N-allyl-
amides 1 with 1-(arylsulfanyl)pyrrolidine-2,5-diones 2 (Ta-
ble 2).17 All the substrates examined gave reasonable yields
of the corresponding (arylsulfanyl)oxazolines 3. N-Allyl-
arylamides 1 (R1 = aryl) gave higher yields than N-allylalkyl-
Key words oxazoles, sulfurizations, sulfides, oxygenations
Oxazole moieties are found in many natural products
and in many biologically and pharmaceutically active mole-
cules;1 oxazoles are also useful as building blocks and inter-
mediates in organic synthesis.1a,2 Similarly, aryl sulfides are
indispensable in materials science and in biology, especially
the pharmaceutical area,3 and the formation of C–S bonds is
a key step in the synthesis of a broad range of functional
molecules.4 Conventional approaches to aryl sulfides in-
volve transition metal-catalyzed coupling reactions of thi-
ols or disulfides with aryl halides or pseudohalides.5 Struc-
tures that contain both oxazole and aryl sulfide moieties
might, therefore, be very useful. Mellor and co-workers re-
ported synthesis of compounds of this type through the re-
action of N-allylamides with organic disulfides in the pres-
ence of manganese(III) acetate.6 Difunctionalization of
alkenes is a promising strategy for the synthesis of various
molecules under either transition-metal-mediated or met-
al-free conditions;7 this strategy has been used in dioxy-
genation,8 aminooxygenation,9 diamination,10 fluoroamina-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 676–680

677
J. Yu et al.
Letter
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Table 1 Optimization of Conditions for the Reaction of N-(2-Phenyl-
prop-2-en-1-yl)benzamide (1a) with 1-(Phenylsulfanyl)pyrrolidine-
2,5-dione (2a) to give 2,5-Diphenyl-5-[(phenylsulfanyl)methyl]-4,5-di-
hydro-1,3-oxazole (3a)a
Table 2 Arylthiooxygenation of Substituted N-Allylamides 1a
O
R2
R1
N
H
R4
R3
R3
R4
S
O
BF3•OEt2, DCE
105 °C, 24 or 36 h
1
O
O
R1
N
H
+
N
R2
Ph
Ph
N
S
R5
1a
O
3
R5
+
SPh
O
2
N
O
Entry R1
R2 R3
R4 R5
Time Prod- Yieldb
3a
N
S
(h)
uct
(%)
O
1
2
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
24
3a
3b
3c
82
2a
4-Tol
3-Tol
2-Tol
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-Tol
4-ClC6H4
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
24
24
24
24
36
36
24
24
24
24
24
24
24
24
24
24
24
24
36
24
24
24
24
24
24
24
24
77
67
92
70
63
67
71
63
74
36
55
56
62
85
38
65
53
51
53
64
67
65
75
67
90
77
72
72
78
54
Entry Catalyst (equiv)
Solvent
Temp (°C)
Time (h) Yieldb (%)
3
4
3d
3e
3f
1
2
FeCl3 (0.2)
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
toluene
THF
r.t.
24
24
24
24
24
24
24
24
24
12
30
24
24
24
24
24
0
12
0
5
3,5-Me2C6H3
4-t-BuC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-O2NC6H4
3-O2NC6H4
2-thienyl
Ph
BF3·OEt2 (0.2)
CuI (0.2)
r.t.
6
3
r.t.
7
3g
3h
3i
4
CuCl2 (0.2)
r.t.
0
8
5
Pd(OAc)2 (0.2)
BF3·OEt2 (1.0)
BF3·OEt2 (1.5)
BF3·OEt2 (0.2)
BF3·OEt2 (0.2)
BF3·OEt2 (0.2)
BF3·OEt2 (0.2)
BF3·OEt2 (0.2)
BF3·OEt2 (0.2)
BF3·OEt2 (0.2)
–
r.t.
0
9
6
r.t.
57
79
55
82
59
82
23
47
69
52
80
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
3j
7
r.t.
3k
3l
8
60
9
105
105
105
105
105
105
105
105
3m
3n
3o
3p
3q
3r
10
11
12
13
14
15
16c
Ph
t-Bu
Ph
MeCN
DCE
DCE
4-Tol
H
3,5-Me2C6H3
2-naphthyl
3-O2NC6H4
2-thienyl
4-Tol
H
3s
BF3·OEt2 (0.2)
H
3t
a Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), catalyst, anhyd solvent
(2 mL), sealed Schlenk tube, under air.
H
3u
3v
3w
3x
3y
3z
b Isolated yield.
c Under N2.
H
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-Me
3-Me
4-Cl
amides 1 (R1 = alkyl) (entry 16). The 1-methyl-2-phenyl-
prop-2-enyl amide 1 (R2 = Me) also gave a good yield of the
corresponding product 3ae (entry 30). The reaction gave a
slightly lower yield when R3 was hydrogen (entries 17–22)
or methyl (entry 23), possibly because intermediate IV (see
below) is more stable for substrates 1 (R3 = aryl). Substrates
1 (R4 = H) were more reactive than 1 (R4 = Me) (entry 31).
The reactivities of the 1-(arylsulfanyl)pyrrolidine-2,5-di-
ones (2) were not obviously affected by electronic effects of
substituents on the aromatic rings. The arylthiooxygen-
ation of N-allylamides 1 with 1-(arylsulfanyl)pyrrolidine-
2,5-diones 2 tolerates various functional groups, including
Ph
Ph
4-ClC6H4
Ph
4-Cl
3aa
3ab
3ac
3ad
3ae
2-Cl
Ph
4-NO2 24
4-Tol
Me Ph
H Ph
H
H
24
24
4-Tol
a Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), BF3·OEt2 (0.04 mmol),
anhyd DCE (2 mL), 105 °C, sealed Schlenk tube, under air.
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 676–680

678
J. Yu et al.
Letter
Synlett
ether (entry 7), fluoro (entry 8), chloro (entries 9, 15, and
26–28), bromo (entry 10), nitro (entries 11, 12, 21, and 29),
or 2-thienyl groups (entries 13 and 22).
Electrophilic reaction of III with allylic amide 1 gives inter-
mediate IV, which isomerizes to give imidic acid V. Intra-
molecular cyclization of V in the presence of complex II
gives the product 3, with release of succinimide and the
catalyst.
We also examined some reactions of the synthesized
products. For example, oxidation of oxazole 3z with 3-chlo-
roperoxybenzoic acid in dichloromethane at room tem-
perature for 12 hours gave the corresponding sulfone 4 in
73% yield (Scheme 3). Sulfone groups are present in many
biologically active molecules19 and are also valuable as syn-
thetic intermediates in organic synthesis;20 for example,
analogues of 4 can be halogenated or alkylated.21
When the arylthiooxygenation of chiral N-[(1R)-1-
phenylprop-2-en-1-yl]benzamide (1z) was investigated in
the presence of 1.5 equivalents of boron trifluoride etherate
at room temperature for 24 hours, the reaction showed
high diastereoselectivity giving (4S,5S)-2,4-diphenyl-5-
[(phenylsulfanyl)methyl]-4,5-dihydro-1,3-oxazole (3af) in
47% yield, with only traces of the corresponding (4S,5R)-
isomer 3af′ (Scheme 1).
A possible mechanism on the arylthiooxygenation of
substituted N-allylamides (Scheme 2) is proposed on the
basis of the results described above and references from the
literature.18 Treatment of sulfide 2 with boron trifluoride
etherate gives complex I, which undergoes heterolysis of
the N–S bond to form the anionic complex II and cation III.
In conclusion, we have developed a simple, efficient,
and practical method for the arylthiooxygenation of substi-
tuted N-allylamides to give arylsulfanyl-substituted oxaz-
oles in good yields. The protocol uses readily available 1-
O
O
Ph
BF3•OEt2 (1.5 equiv)
DCE, r.t., 24 h
O
O
SPh
SPh
N
+
+
N
S
Ph
H
N
N
Ph
Ph
1z
2a
O
3af' (trace)
3af (47% yield)
Scheme 1 Synthesis of the chiral (phenylsulfanyl)oxazoline 3af
O
R2
BF3
R1
N
R4
O
H
O
R3
BF3•OEt2
1
+SAr
N
SAr
N
SAr
III
–
BF3
O
O
O
2
I
N
O
II
R3
R3
R4
O
R2
R4
R4
O
OH
+
II
R1
+
SAr
R1
R1
N
SAr
SAr
N
R2
H
N
O
R2
R3
IV
3
V
+
NH
BF3
O
Scheme 2 A possible mechanism for the boron-catalyzed arylthiooxygenation of substituted N-allylamides
Cl
MCPBA (3.0 equiv)
CH2Cl2, r.t., 12 h
Ph
Ph
O
S
O
S
O
O
N
N
Cl
4 (73% yield)
3z
Scheme 3 Oxidation of (arylsulfanyl)oxazole 3z to the corresponding sulfone 4
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 676–680

679
J. Yu et al.
Letter
Synlett
(arylsulfanyl)pyrrolidine-2,5-diones as the arylsulfanylat-
ing reagents and inexpensive boron trifluoride etherate as
the catalyst; it requires no ligand or additive, and it is not
necessary to expel air from the reaction vessel. The reaction
also shows a wide tolerance towards various functional
groups. The strategy should therefore have a wide range of
applications in synthesis of arylsulfanyl-substituted hetero-
cycles.
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Acknowledgment
The authors wish to thank the National Natural Science Foundation of
China (Grant Nos. 20972083 and 21172128), and the Ministry of Sci-
ence and Technology of China (Grant No. 2012CB722605) for financial
support.
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Synlett
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5-[(Phenylsulfanyl)methyl]-2-(2-thienyl)-4,5-dihydro-1,3-
oxazole (3v)
Eluent: PE–EtOAc (5:1); colorless film; yield: 37 mg (67%).
1H NMR (600 MHz, CDCl3): δ = 7.49 (d, J = 3.3 Hz, 1 H), 7.40 (d, J
= 7.4 Hz, 3 H), 7.27 (t, J = 7.7 Hz, 2 H), 7.20 (t, J = 7.4 Hz, 1 H),
7.03 (t, J = 4.3 Hz, 1 H), 4.84–4.79 (m, 1 H), 4.11 (dd, J = 14.8, 9.4
Hz, 1 H), 3.85 (dd, J = 14.8, 6.7 Hz, 1 H), 3.31 (dd, J = 13.8, 5.4 Hz,
1 H), 3.05 (dd, J = 13.8, 7.2 Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ = 159.7, 134.9, 130.5, 130.4, 130.2,
130.0, 129.2, 127.6, 126.9, 78.9, 59.7, 38.4.
ESI-MS: m/z = 298.3 [M + Na]+.
4-Methyl-5-phenyl-5-[(phenylsulfanyl)methyl]-2-(4-tolyl)-
4,5-dihydro-1,3-oxazole (3ad)
Eluent: PE–EtOAc (5:1); light-yellow film; yield: 58 mg (78%).
1H NMR (600 MHz, CDCl3): δ = 7.78 (d, J = 8.1 Hz, 2 H), 7.36 (t, J =
7.4 Hz, 2 H), 7.33–7.28 (m, 5 H), 7.19 (d, J = 8.0 Hz, 2 H), 7.15 (d,
J = 7.3 Hz, 2 H), 7.11 (t, J = 7.2 Hz, 1 H), 4.46 (q, J = 6.9 Hz, 1 H),
3.67 (s, 2 H), 2.40 (s, 3 H), 0.84 (d, J = 6.9 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.1, 142.1, 139.0, 136.8, 130.4,
129.1, 128.9, 128.5, 128.3, 127.7, 126.4, 125.9, 124.6, 91.4, 70.4,
45.4, 21.7, 19.4.
ESI-MS: m/z = 374.1 [M + H]+.
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(17) 5-(Arylsulfanyl)-4,5-dihydro-1,3-oxazoles 3a–af; General
Procedure
A 25-mL Schlenk tube containing a magnetic stirrer was
charged with allylamide 1 (0.2 mmol), 1-(arylthio)pyrrolidine-
2,5-dione 2 (0.3 mmol), and anhyd DCE (2.0 mL). BF3·OEt2 (0.04
mmol) was added, the tube was sealed, and the mixture was
stirred at 105 °C until the reaction was complete (TLC). The
solution was concentrated in a rotary evaporator and the
residue was purified by column chromatography (silica gel, PE–
EtOAc). Data for three representative products are given below.
5-Phenyl-5-[(phenylsulfanyl)methyl]-2-(4-tolyl)-4,5-
dihydro-1,3-oxazole (3b)
Eluent: PE–EtOAc (5:1); colorless film; yield: 55 mg (77%).
1H NMR (400 MHz, CDCl3): δ = 7.79 (d, J = 7.4 Hz, 2 H), 7.42–7.29
(m, 7 H), 7.21–7.13 (m, 5 H), 4.47 (d, J = 14.7 Hz, 1 H), 4.22 (d, J =
14.7 Hz, 1 H), 3.62 (d, J = 13.9 Hz, 1 H), 3.51 (d, J = 13.9 Hz, 1 H),
2.40 (s, 3 H).
(20) (a) Tetrahedron Organic Chemistry Series; Vol. 10; Simpkins, N.
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4115.
13C NMR (100 MHz, CDCl3): δ = 163.2, 143.7, 141.9, 136.5, 130.4,
129.1, 128.9, 128.7, 128.3, 127.9, 126.5, 124.9, 124.8, 88.6, 66.5,
46.1, 21.7.
ESI-MS: m/z = 360.4 [M + H]+.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 676–680

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