Iodine(III)-mediated intramolecular sulfeno- and selenofunctionalization of β,γ-unsaturated tosyl hydrazones and oximes

Article abstract of DOI:10.1039/c7ob02892j

A cascade radical cyclization/sulfenylation or selenylation of β,γ-unsaturated hydrazones and oximes was realized under mild conditions with phenyliodine(iii) diacetate (PIDA) as the sole oxidant, leading to the construction of diversely functionalized heteroatom-containing pyrazoline and isoxazoline derivatives. This metal-free radical process is suggested to encompass a sequential C-N/O and C-S/Se bond fomation.

Full text of DOI:10.1039/c7ob02892j

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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Iodine(III)-Mediated Intramolecular Sulfeno- and
Selenofunctionalization of β, γ-unsaturated Tosyl Hydrazones and
Oximes
Received 00th January 20xx,
Accepted 00th January 20xx
Jing-miao Yu,a Chun Cai*a
DOI: 10.1039/x0xx00000x
A cascade radical cyclization/sulfenylation or selenylation of β, γ-unsaturated hydrazones and oximes was realized under
mild conditions with phenyliodine(III) diacetate (PIDA) as the sole oxidant, leading to the construction of various diversely
functionalized heteroatom-containing pyrazoline and isoxazoline derivatives. This metal-free radical process is suggested
to encompass a sequential C-N/O and C-S/Se bond fomation.
www.rsc.org/
Previous work:
NHTs
Introduction
N
(b)
(only)
Pyrazolines1 and isoxazolines2 represent two classes of
privileged heterocycles that widely exist in biologically active
natural products and pharmaceuticals such as anti-amoebic,
hypotensive, analgesic, anti-cancer, anti-bacterial, anti-
depressant and nonsteroidal anti-inflammatory agents.
Consequently, a plethora of novel and elegant methodologies
for construction of these five-membered heteroatom-
containing heterocycles have received extensive attention.
β, γ-unsaturated hydrazones and oximes have recently
emerged as versatile synthons in a variety of transition-metal-
catalyzed and transition-metal-free reactions, affording
pyrazoline and isoxazoline derivatives. Representative
transition-metal-catalyzed(e.g., cobalt3, copper4, palladium5,
etc.) cyclizations of β,γ-unsaturated hydrazones and oximes
are powerful approaches for the synthesis of diversely
functionalized pyrazolines and isoxazolines(Scheme 1a). For
instance, in 2014, Wang et al.4b reported Cu-catalyzed
intramolecular oxytrifluoromethylthiolation of internal alkenes
of unsaturated oximes by using AgSCF3 as the SCF3-souce.
Recently, Huang et al.5c reported Pd-catalyzed tandem
aminomethylation/cyclization/aromatization reaction of β, γ-
unsaturated hydrazones with aminals via C−N bond acꢀvaꢀon.
However, the utility and applicability of the above reactions
were limited by high cost or toxicity of the transition metals
and/or harsh reaction conditions.
R1
PC
XH
XH
N
N
X
Metal
R2
Radical initiator
N
(a)
(c)
R1
R1
R1
This work:
PhI(OAc)2 (1.5 equiv)
DBU (1.5 equiv)
R2
XH
X
N
Y
N
R2
Y
(d)
MeCN, rt
R1
R2
R1
Y
XH = NHTs, OH
Y = S, Se
Scheme 1. Strategies for cyclization of β, γ-unsaturated hydrazones and oximes
demonstrated in 20146, is a considerable elegant approach.
Major progresses6-7 along this line have been mainly achieved
focused on the photocatalytic hydrazonyl radical-mediated
radical cascade reactions(Scheme 1b). Although visible light
photoredox catalysis played very important role in the direct
generation of hydrazonyl radicals from N-H bonds, the β,γ-
unsaturated oximes proved to be not suitable for this strategy,
presumably by the higher redox potential of oximes relative to
that of the photocatalyst. Meanwhile, the development of
metal-free reactions initiated by radical initiators
(e.g.,TEMPO8, TBN9, TBHP10, hypervalent iodine11, etc.) is
crucial for solving this problem(Scheme 1c).
Apart from this,
a visible-light-induced photocatalytic
hydroamination and oxyamination of β,γ-unsaturated
hydrazones, pioneered by the work of Xiao and co-workers
Hypervalent iodine reagents are well-known as
nonexplosive and readily available oxidizing reagents for
mediating organic reactions involving the formation of new
carbon–carbon bond and carbon–heteroatom bond12.
Therefore, hypervalent iodine reagents have been employed
to mediate the difunctionalization of unactivated alkenes13,
which provides an alternative platform for this transformation.
In 2015, Wang et al.11a described the intramolecular oxy-
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fluorination of alkenyl oximes by employing PhI(OPiv)2 as the Table 2. Iodine(III)-mediated intramolecular sulfenofunctionalization of β, γ-
unsaturated tosyl hydrazones with disulfides a, b
mediator and HF-pyridine as the F-source, and Xiao et al.11b
reported the PhI(OAc)2-promoted radical cyclization of β,γ-
unsaturated hydrazones and oximes. However, to our
knowledge, there are no reports of iodine(III)-mediated
intramolecular sulfeno- and selenofunctionalization of β,γ-
unsaturated hydrazones and oximes.
Inspired by these mentioned facts, organosulfur and
organoselenium chemistry14, we envisioned the direct
generation of the N-centered radicals from N-H bonds or the
O-centered radicals from O-H bonds mediated by hypervalent
iodine reagent, followed by radical cyclization/sulfenylation or
selenylation cascade reactions. Herein, we report the
application of β,γ-unsaturated tosyl hydrazones and oximes in
radical cyclization/sulfenylation or selenylation reactions
catalyzed by hypervalent iodine reagent. During this reaction,
benign PIDA(PhI(OAc)2) was used as the oxidant and
disulfides/ diselenides were employed as the S/Se-
sources(Scheme 1d).
Results and discussion
The initial investigation was focused on the reaction of β,γ-
unsaturated tosyl hydrazone 1a with disulfide 2a and various
iodine(III) sources in the presence of DBU(2,3,4,6,7,8,9,10-
octahydropyrimido[1,2-a]azepine) as the base (Table1, entries
1-3). Compare to other iodine(III) sources like PhIO and PIFA,
Table 1. Optimization of the Reaction Conditions a
Entry
1
2
3
4
5
6
7
8
iodine(III)
PhIO
PIDA
PIFA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
PIDA
-
Base
DBU
DBU
DBU
K2CO3
NaOH
TBD
TMG
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
-
Solvent
THF
THF
THF
THF
THF
THF
THF
MeOH
DMF
PhMe
DCM
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
Yield 3ab
45
67
32
21
25
43
34
Trace
11
52
49
82
62
87
73
83
9
10
11
12
13c
14d
15e
16f
17
18
a Reaction conditions: β,γ-unsaturated tosyl hydrazone 1a (0.2 mmol), disulfides 2
(0.15 mmol), PIDA(1.5 equiv), DBU (1.5 equiv) in MeCN (2 mL) under an Ar
atmosphere at room temperature for 6 h. b Isolated yield.
PIDA was approved to be the best choice to generate the
target product 3aa in 67% yield (Table 1, entry 2). Encouraged
by this result, some other inorganic bases such as K2CO3 and
NaOH and organic bases such as TBD and TMG were studied,
which virtually did not lead to any significant improvement
(Table 1, entries 4-7). Further investigation on different
solvents revealed that other solvents such as MeOH, DMF,
toluene and DCM either gave inferior results or completely
hindered the reaction(Table 1, entries 8-11). To our
gratification, an improved yield of target product 3aa was
achieved in MeCN (Table 1, entry 12). Varying the equivalents
0
0
PIDA
a
Reaction conditions: β,γ-unsaturated tosyl hydrazone 1a (0.2 mmol), disulfide
2a (0.15 mmol), iodine(III) (0.3 mmol), base (0.3 mmol) and solvent (2.0 mL), Ar,
at room temperature, stirred for 6h. b Isolated yield. c 1.2 equiv of PIDA. d 2 equiv
of PIDA. e 1.2 equiv of DBU. f 2 equiv of DBU.
2 | J. Name., 2012, 00, 1-3
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of PIDA and DBU, and both 1.5 equivalents of PIDA and DBU Table 3. Iodine(III)-mediated intramolecular sulfenofunctionalization of β, γ-
unsaturated oximes with disulfides a, b
were the best choices for production of the desired product
(Table 1, entries 13-16). In addition, control experiments
showed that no product was obtained in the absence of
oxidant or base (Table 1, entries 17-18).
With the optimized reaction condition in hand, we
proceeded to explore the scope of the reaction. We first
examined the reaction between β,γ-unsaturated tosyl
hydrazone 1a and various disulfides 2. In general, disulfides
with different substituents on the para- or meta-position of
the phenyl ring worked effectively. Substituents on substrates
2
have some effect on the reactions. For example, electron-
donating group at the para-positions of the phenyl ring (1d-1g
)
performed well in the reaction with 1a to furnish the desired
product 3ab in a 87% yield (Table 2, 3ab), while electron-
deficient disulfides (2c-e) resulted in slightly lower yields(Table
2, 3ac-e). However, too strong electron-withdrawing group
such as 4-nitro group led to a quite lower yield(42%) (Table 2,
3af). Substrates bearing methyl at different positions of the
phenyl ring could reacted smoothly with 2a to furnish the
products in fairly good yields(Table 2, 3ac and 3aj). Aliphatic
and heterocyclic disulfides, such as dimethyl disulfide, di-n-
propyl disulfide and were also tolerated, and the yields of
corresponding products ranged from 47% to 68% (Table 2,
3ah–j). Next, the substrate generality with respect to the
a
Reaction conditions: β,γ-unsaturated oximes 1 (0.2 mmol), disulfides 2 (0.15
mmol), PIDA(1.5 equiv), DBU (1.5 equiv) in MeCN (2 mL) under an Ar atmosphere
at room temperature for 6 h. b Isolated yield.
We next found that β, γ-unsaturated oximes
6 could be used
alkenyl tosyl hydrazones
1 was investigated. The reactions
as substrates (to replace hydrazones 1) under the same
proceeded smoothly for β,γ-unsaturated tosyl hydrazones with
either electron-withdrawing or electron-donating substituents
present on the aromatic ring (1b–i) to afford the desired
products in moderate to high yields (Table 2, 3ba–ia). In
general, the substituent groups or substitution patterns of the
aromatic ring have no obvious effect on this reaction. As for a
cyclic aliphatic- or 2-naphthyl-substiuted tosyl hydrazone, the
reaction proceeded fairly well under the optimized condition
either, giving products 3ja–ka in moderate yields (Table 2, 3ja–
ka).
condition, affording suflur-containing isoxazolines as the
products in a similar fashion. In all the studied examples,
disulfides with electron-donating group or electron-
withdrawing one at the phenyl ring could transform to the
corresponding isoindolinones 7ab and 7ad smoothly in good
yields (Table 3, 7ab and 7ad). Besides, dimethyl disulfide 2h
was employed and gave product 7ah in 47% yield (Table 3,
7ah). Similarly, β,γ-unsaturated oximes with electron-
withdrawing or electron-donating substituents on the
aromatic ring could convert to the desired products in good
yields (Table 3, 7ba and 7ca). Alkyl-substiuted oxime 6d was
found to be accommodated, affording the desired product 7la
in 67% yield (Table 3, 7da). Gratifyingly, diselenides also
proceeded well to furnish the corresponding selenium-
containing isoxazolines (Scheme 3).
Scheme 2. Selenofunctionalization of β, γ-unsaturated tosyl hydrazone. Reaction
conditons: 1a (0.2 mmol), diselenides 4 (0.15 mmol) PIDA(1.5 equiv), DBU (1.5 equiv) in
MeCN (2 mL) under an Ar atmosphere at room temperature for 6 h.
To further explore the influence of heteroatom and expand
the scope of structures, we then simply examined the cascade
cyclization/addition reaction of β,γ-unsaturated tosyl
hydrazone 1a with diselenides(as an alternative to
Scheme 3. Selenofunctionalization of β, γ-unsaturated oxime. Reaction conditons: 6a
(0.2 mmol), diselenides 4 (0.15 mmol) PIDA(1.5 equiv), DBU (1.5 equiv) in MeCN (2 mL)
under an Ar atmosphere at room temperature for 6 h.
disulfides)(Scheme 2). In line with our expectation, diselenides
Finally, some control experiments were carried out in order
to reveal the reaction pathway of this transformation (Scheme
also proved to be suitable for this transformation, and the
desired products 5aa-c were obtained in excellent yields,
4
). TEMPO was added as radical scavenger under the standard
highlighting the efficiency of this synthetic methodology
.
reaction conditions, which resulted in the formation of 9a and
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β,γ-unsaturated tosyl hydrazone 1a or oxime 6a affords the anionic
intermediate A under basic conditions. Subsequently, a single-
electron oxidation of A by PIDA gives the N-centered or O-centered
radical B. The formed hyadrazone or oxime radical B would undergo
a radical intramolecular cyclization to produce the C-centered
radical C. The C-centered radical C reacted with diphenyl disulfide
2a to form the desired product 3aa or 7aa via a radical propagation
and regenerate the sulfenyl radical which could recombine to
diphenyl disulfide 2a(Scheme 5, Path I). The C-centered radical C
could also reacted with diphenyl diselenide 4a to form the desired
product 5aa or 8aa in a similar way(Scheme 5, Path II).
10a in 92% and 84% yield respectively (Scheme 4a). This
finding
Conclusions
In conclusion, we have developed a novel and efficient
iodine(III)-mediated
intramolecular
sulfeno-
and
selenofunctionalization of β, γ-unsaturated hydrazones and
oximes using disulfides and diselenides as sulfur and selenium
sources. This reaction provides
straightforward method to prepare
a
a
convenient and
variety of useful
heteroatom-containing pyrazoline and isoxazoline derivatives.
In addition, this method features a broad substrate scope,
wide group tolerance and chemoselectivity.
Scheme 4. Control experiments. (a) Reaction condition: 1b or 6a (0.2 mmol), disulfide
2a (0.15 mmol), PIDA(1.5 equiv), DBU (1.5 equiv), TEMPO (2.0 equiv) in MeCN (2 mL)
under an Ar atmosphere at room temperature for 6 h. (b) Reaction condition: 1a (0.2
mmol), disulfide 2a (0.15 mmol), diselenide 4a (0.15 mmol), PIDA(1.5 equiv), DBU (1.5
equiv), in MeCN (2 mL) under an Ar atmosphere at room temperature for 6 h.
Experimental
General experimental method
All chemical reagents are obtained from commercial suppliers and
used without further purification. All unknown compounds are
characterized by 1H NMR, 13C NMR, MS. Analytical thin-layer
chromatography are performed on glass plates precoated with silica
gel impregnated with a fluorescent indicator (254 nm), and the
suggests that the process does indeed involve C-centered
radical intermediate C. One pot reaction of 1a, 2a and 4a was
tested for the the reactivity of 2a and 4a (Scheme 4b). The
result shows that the ratio of the corresponding product 3aa
and 7aa is 1:19, indicating that the reactivity of 4a is superior
plates are visualized by exposure to ultraviolet light.1H NMR and 13
C
to 2a
.
NMR spectra are recorded on an AVANCE 500 Bruker spectrometer
operating at 500 MHz and 125 MHz in CDCl3, respectively, and
chemical shifts are reported in ppm. Multiplicities are indicated by s
(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br
(broad). Mass spectra are taken on a Waters UPLC H-class LC-MS
instrument in the electrospray ionization (ESI) mode. Only
molecular ions (M + 1) are given for the ESI-MS analysis.
On the basis of previous work and experimental
observations8-11, a plausible mechanism was proposed as
illustrated in Scheme 5. At the beginning, deprotonation of the
A
typical procedure for the synthesis of 3-phenyl-5-
((phenylthio)methyl)-1-tosyl-4,5-dihydro-1H-pyrazole (3aa)
A 10 mL reaction vessel with a magnetic stirring bar was equipped
with β,γ-unsaturated hydrazone (1a) (0.2 mmol), disulfide (2a) (0.15
mmol), PIDA (0.3 mmol), DBU (0.3 mmol) and MeCN (2 mL). The
mixture was stirred under Ar atmosphere at r.t. for 6 h. The
reaction solution was diluted with ethyl acetate, washed with
water, dried over anhydrous Na2SO4. After the solvent had been
removed under reduced pressure, the residue was purified by flash
chromatography using PE-AcOEt (10:1-5:1, v/v) as the eluent to
sulfer- containing pyrazoline (3aa).
The rest products were prepared by a similar procedure.
3-phenyl-5-((phenylthio)methyl)-1-tosyl-4,5-dihydro-1H-
pyrazole (3aa), white solid. Yield: 69 mg, 82%. 1H NMR (500 MHz,
CDCl3) δ 7.74 – 7.63 (m, 4H), 7.57 – 7.50 (m, 2H), 7.49 – 7.38 (m,
5H), 7.35 – 7.31 (m, 1H), 7.24 (d, J = 8.0 Hz, 2H), 4.07 (dd, J = 13.7,
3.2 Hz, 1H), 3.97 (tdd, J = 10.6, 9.2, 3.2 Hz, 1H), 3.27 (dd, J = 17.4,
Scheme 5. Proposed mechanism
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10.8 Hz, 1H), 3.12 – 3.06 (m, 2H), 2.40 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 7.76 – 7.59 (m, 4H), 7.48 – 7.39 (m, 3H), 7.35 – 7.29 (m,
CDCl3) δ 156.68, 143.35, 133.37, 130.64, 129.71, 128.79, 128.55, 3H), 7.24 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 6.7 Hz, 1H), 4.07 (dd, J =
128.25, 127.66, 125.96, 125.72, 60.06, 38.83, 37.62, 20.61. ESI-MS 13.7, 3.2 Hz, 1H), 3.98 (tdd, J = 10.7, 9.2, 3.2 Hz, 1H), 3.27 (dd, J =
+
m/z: 423 [M+1] . HRMS (ESI) Calcd for [C23H22N2O2S2] requires 17.4, 10.8 Hz, 1H), 3.12 – 3.03 (m, 2H), 2.44 (s, 3H), 2.40 (s, 3H). 13C
[M+H]+ 423.1195, found 423.1194.
NMR (125 MHz, CDCl3) δ 156.65, 143.28, 138.09, 130.74, 129.69,
3-phenyl-5-((p-tolylthio)methyl)-1-tosyl-4,5-dihydro-1H-pyrazole 129.08, 128.51, 128.06, 127.63, 126.47, 125.95, 125.57, 60.03,
(3ab), white solid. Yield: 76 mg, 87%. 1H NMR (500 MHz, CDCl3) δ 38.83, 37.44, 20.59. ESI-MS m/z: 437 [M+1] +. HRMS (ESI) Calcd for
7.71 – 7.67 (m, 2H), 7.64 (d, J = 8.1 Hz, 2H), 7.48 – 7.39 (m, 5H), 7.23 [C24H24N2O2S2] requires [M+H]+ 437.1352, found 437.1349.
(dd, J = 8.2, 3.0 Hz, 4H), 4.01 (dd, J = 13.6, 3.2 Hz, 1H), 3.93 (qd, J =
5-((methylthio)methyl)-3-phenyl-1-tosyl-4,5-dihydro-1H-
10.4, 3.2 Hz, 1H), 3.27 (dd, J = 17.4, 10.7 Hz, 1H), 3.11 – 3.02 (m, pyrazole (3ah), white solid. Yield: 48 mg, 67%. 1H NMR (500 MHz,
2H), 2.43 (s, 3H), 2.40 (s, 3H). 13C NMR (125 Hz, CDCl3) δ 156.70, CDCl3) δ 7.84 (d, J = 8.3 Hz, 2H), 7.74 – 7.69 (m, 2H), 7.49 – 7.40 (m,
143.30, 135.92, 130.63, 129.69, 129.51, 128.99, 128.50, 127.65, 3H), 7.33 (d, J = 8.1 Hz, 2H), 4.12 (dtd, J = 10.6, 9.0, 3.2 Hz, 1H), 3.30
125.95, 60.16, 38.76, 38.19, 20.62, 20.13. ESI-MS m/z: 437 [M+1]+. (dd, J = 13.6, 3.2 Hz, 1H), 3.26 – 3.16 (m, 2H), 3.01 (dd, J = 13.5, 8.9
HRMS (ESI) Calcd for [C24H24N2O2S2] requires [M+H]+ 437.1352, Hz, 1H), 2.44 (s, 3H), 2.31 (s, 3H). 13C NMR (125 MHz, CDCl3) δ
found 437.1349.
156.85, 143.40, 131.10, 129.67, 128.63, 127.64, 125.98, 60.44,
5-(((4-fluorophenyl)thio)methyl)-3-phenyl-1-tosyl-4,5-dihydro-
1H-pyrazole (3ac), white solid. Yield: 69 mg, 78%. 1H NMR (500 MHz, Calcd for [C18H20N2O2S2] requires [M+H]+ 361.1039, found 361.1041.
38.46, 38.32, 20.63, 15.24. ESI-MS m/z: 361 [M+1] +. HRMS (ESI)
CDCl3) δ 7.72 – 7.67 (m, 2H), 7.63 (d, J = 8.3 Hz, 2H), 7.57 – 7.47 (m,
3-phenyl-5-((propylthio)methyl)-1-tosyl-4,5-dihydro-1H-pyrazole
2H), 7.47 – 7.40 (m, 3H), 7.25 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 8.7 Hz, (3ai), colorless oil. Yield: 52 mg, 68%. 1H NMR (500 MHz, CDCl3) δ
1H), 3.98 – 3.87 (m, 2H), 3.28 (dd, J = 17.3, 10.7 Hz, 1H), 3.12 – 3.06 7.84 (d, J = 8.4 Hz, 2H), 7.74 – 7.69 (m, 2H), 7.47 – 7.40 (m, 3H), 7.33
(m, 2H), 2.41 (s, 3H). 19F NMR (470 MHz, CDCl3) δ -114.59. 13C NMR (d, J = 8.0 Hz, 2H), 4.08 (dtd, J = 10.7, 9.2, 3.3 Hz, 1H), 3.34 (dd, J =
(125 MHz, CDCl3) δ 156.61, 143.43, 131.74, 131.68, 130.59, 129.74, 13.4, 3.3 Hz, 1H), 3.25 (dd, J = 17.3, 10.7 Hz, 1H), 3.16 (dd, J = 17.3,
128.54, 128.28, 127.67, 127.59, 125.94, 115.44, 115.27, 60.01, 9.1 Hz, 1H), 2.98 (dd, J = 13.4, 9.3 Hz, 1H), 2.69 (t, J = 7.3 Hz, 2H),
38.73, 20.60. ESI-MS m/z: 441 [M+1] +. HRMS (ESI) Calcd for 2.44 (s, 3H), 1.74 (dt, J = 14.6, 7.3 Hz, 2H), 1.07 (t, J = 7.3 Hz, 3H). 13
C
[C23H21FN2O2S2] requires [M+H]+ 441.1101, found 441.1099.
NMR (125 MHz, CDCl3) δ 156.81, 143.37, 131.11, 129.80, 129.65,
128.61, 127.64, 125.98, 60.73, 38.44, 36.30, 33.75, 22.12, 20.63,
5-(((4-chlorophenyl)thio)methyl)-3-phenyl-1-tosyl-4,5-dihydro-
1H-pyrazole (3ad), white solid. Yield: 68 mg, 75%.1H NMR (500 12.43. ESI-MS m/z: 389 [M+1] +. HRMS (ESI) Calcd for [C20H24N2O2S2]
MHz, CDCl3) δ 7.72 – 7.63 (m, 4H), 7.51 – 7.34 (m, 7H), 7.26 (d, J = requires [M+H]+ 389.1352, found 389.1353.
8.1 Hz, 2H), 3.99 (dd, J = 13.7, 3.1 Hz, 1H), 3.92 (qd, J = 10.3, 3.1 Hz,
2-(((3-phenyl-1-tosyl-4,5-dihydro-1H-pyrazol-5-
1H), 3.27 (dd, J = 17.4, 10.8 Hz, 1H), 3.12 – 3.05 (m, 2H), 2.41 (s, yl)methyl)thio)benzo[d]thiazole (3aj), white solid. Yield: 45 mg,
1
3H). 13C NMR (125 MHz, CDCl3) δ 156.62, 143.49, 131.95, 130.60, 47%. H NMR (500 MHz, CDCl3) δ 8.00 – 7.94 (m, 1H), 7.94 – 7.89
130.19, 129.77, 129.61, 128.60, 128.36, 127.68, 127.60, 125.96, (m, 2H), 7.87 – 7.79 (m, 1H), 7.71 – 7.66 (m, 2H), 7.51 (ddd, J = 8.4,
59.84, 38.76, 37.90, 20.63. ESI-MS m/z: 457 [M+1] +. HRMS (ESI) 7.3, 1.2 Hz, 1H), 7.47 – 7.36 (m, 4H), 7.30 (d, J = 8.0 Hz, 2H), 4.50 –
Calcd for [C23H21ClN2O2S2] requires [M+H]+ 457.0806, found 4.39 (m, 2H), 3.72 – 3.65 (m, 1H), 3.28 (dd, J = 9.9, 2.9 Hz, 2H), 2.42
457.0808.
(s, 3H). 13C NMR (125 MHz, CDCl3) δ 164.47, 156.81, 152.06, 143.48,
134.65, 130.79, 129.72, 129.61, 128.61, 127.84, 127.64, 125.99,
5-(((4-bromophenyl)thio)methyl)-3-phenyl-1-tosyl-4,5-dihydro-
1H-pyrazole (3ae), white solid. Yield: 80 mg, 80%. 1H NMR (500 125.23, 123.57, 120.60, 120.17, 60.30, 38.23, 36.65, 20.63. ESI-MS
+
MHz, CDCl3) δ 7.73 – 7.68 (m, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.54 (d, J m/z: 480 [M+1] . HRMS (ESI) Calcd for [C24H21N3O2S3] requires
= 8.5 Hz, 2H), 7.49 – 7.37 (m, 5H), 7.27 (d, J = 8.0 Hz, 2H), 4.00 (dd, J [M+H]+ 480.0869, found 480.0867.
= 13.7, 3.1 Hz, 1H), 3.92 (tdd, J = 10.5, 9.3, 3.1 Hz, 1H), 3.28 (dd, J =
3-(4-methoxyphenyl)-5-((phenylthio)methyl)-1-tosyl-4,5-
17.4, 10.8 Hz, 1H), 3.12 – 3.05 (m, 2H), 2.41 (s, 3H). 13C NMR (125 dihydro-1H-pyrazole (3ba), white solid. Yield: 71 mg, 79%. H NMR
MHz, CDCl3) δ 156.60, 143.50, 132.62, 131.28, 130.55, 130.34, (500 MHz, CDCl3) δ 7.69 – 7.60 (m, 4H), 7.56 – 7.50 (m, 2H), 7.42
129.78, 129.59, 128.62, 127.68, 127.60, 125.95, 119.66, 59.79, (dd, J = 8.4, 7.0 Hz, 2H), 7.35 – 7.30 (m, 1H), 7.23 (d, J = 8.1 Hz, 2H),
38.76, 37.71, 20.63. ESI-MS m/z: 501 [M+1] +. HRMS (ESI) Calcd for 6.95 – 6.90 (m, 2H), 4.06 (dd, J = 13.7, 3.2 Hz, 1H), 3.93 (tdd, J =
1
[C23H21BrN2O2S2] requires [M+H]+ 501.0301, found 501.0299.
10.6, 9.1, 3.2 Hz, 1H), 3.87 (d, J = 0.6 Hz, 3H), 3.23 (dd, J = 17.3, 10.7
Hz, 1H), 3.10 – 3.02 (m, 2H), 2.39 (s, 3H). 13C NMR (125 MHz, CDCl3)
5-(((4-nitrophenyl)thio)methyl)-3-phenyl-1-tosyl-4,5-dihydro-
1H-pyrazole (3af), white solid. Yield: 39 mg, 42%. 1H NMR (500 δ 160.63, 156.45, 143.22, 133.41, 130.57, 128.70, 128.48, 128.22,
MHz, CDCl3) δ 8.19 – 8.15 (m, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.64 – 127.67, 127.60, 125.65, 122.31, 113.05, 59.87, 54.42, 38.90, 37.59,
7.56 (m, 3H), 7.51 (d, J = 8.9 Hz, 2H), 7.42 – 7.32 (m, 3H), 7.21 (s, 20.59. ESI-MS m/z: 453 [M+1] +. HRMS (ESI) Calcd for [C24H24N2O3S2]
1H), 4.09 – 3.96 (m, 2H), 3.27 – 3.15 (m, 2H), 3.04 (dd, J = 17.4, 8.6 requires [M+H]+ 453.1301, found 453.1299.
Hz, 1H), 2.33 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 156.55, 144.11,
3-(4-fluorophenyl)-5-((phenylthio)methyl)-1-tosyl-4,5-dihydro-
1
143.75, 130.77, 129.92, 129.39, 128.74, 127.74, 127.55, 125.95, 1H-pyrazole (3ca), light yellow oil. Yield: 77 mg, 88%. H NMR (500
125.44, 123.48, 123.22, 59.13, 38.78, 36.12, 20.62. ESI-MS m/z: 468 MHz, CDCl3) δ 7.71 – 7.62 (m, 4H), 7.56 – 7.50 (m, 2H), 7.42 (dd, J =
[M+1] +. HRMS (ESI) Calcd for [C23H21N3O4S2] requires [M+H]+ 8.5, 6.9 Hz, 2H), 7.35 – 7.31 (m, 1H), 7.24 (d, J = 8.1 Hz, 2H), 7.15 –
468.1046, found 468.1043.
7.06 (m, 2H), 4.06 (dd, J = 13.7, 3.2 Hz, 1H), 3.97 (tdd, J = 10.6, 9.3,
3.2 Hz, 1H), 3.25 (dd, J = 17.4, 10.8 Hz, 1H), 3.11 – 3.04 (m, 2H), 2.40
3-phenyl-5-((m-tolylthio)methyl)-1-tosyl-4,5-dihydro-1H-
pyrazole (3ag), white solid. Yield: 61 mg, 70%. 1H NMR (500 MHz, (s, 3H). 19F NMR (470 MHz, CDCl3) δ -108.76. 13C NMR (125 MHz,
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CDCl3) δ 164.19, 162.19, 155.62, 143.40, 133.28, 130.60, 128.79, HRMS (ESI) Calcd for [C24H24N2O3S2] requires [M+H]+ 453.1301,
128.54, 128.24, 128.00, 127.93, 127.63, 125.96, 125.75, 114.92, found 453.1299.
114.75, 60.12, 38.85, 37.56, 20.61. ESI-MS m/z: 441 [M+1] +. HRMS
(ESI) Calcd for [C23H21FN2O2S2] requires [M+H]+ 441.1101, found
3-(2-chlorophenyl)-5-((phenylthio)methyl)-1-tosyl-4,5-dihydro-
1H-pyrazole (3ia), light yellow oil. Yield: 45 mg, 49%. H NMR (500
1
MHz, CDCl3) δ 7.71 – 7.60 (m, 2H), 7.56 (dd, J = 7.7, 1.7 Hz, 1H), 7.52
– 7.44 (m, 2H), 7.40 – 7.32 (m, 3H), 7.32 – 7.21 (m, 5H), 4.07 – 3.87
441.1099.
3-(4-chlorophenyl)-5-((phenylthio)methyl)-1-tosyl-4,5-dihydro-
(m, 2H), 3.35 (dd, J = 17.9, 10.4 Hz, 1H), 3.24 (dd, J = 17.9, 9.7 Hz,
1H-pyrazole (3da), yellow oil. Yield: 78 mg, 86%. 1H NMR (500 MHz,
1H), 3.10 (dd, J = 13.7, 10.3 Hz, 1H), 2.40 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ 7.58 (dd, J = 16.2, 8.0 Hz, 4H), 7.47 (d, J = 7.7 Hz, 2H), 7.39
CDCl3) δ 156.83, 143.50, 133.45, 131.88, 130.64, 130.15, 129.61,
– 7.31 (m, 4H), 7.28 (d, J = 7.4 Hz, 1H), 7.19 (d, J = 7.9 Hz, 2H), 4.00
129.53, 129.18, 128.95, 128.56, 128.23, 127.75, 125.89, 125.75,
60.72, 41.81, 37.58, 20.64. ESI-MS m/z: 457 [M+1] +. HRMS (ESI)
(dd, J = 13.7, 3.1 Hz, 1H), 3.92 (qd, J = 10.4, 3.2 Hz, 1H), 3.19 (dd, J =
17.4, 10.8 Hz, 1H), 3.07 – 2.96 (m, 2H), 2.35 (s, 3H). 13C NMR (125
MHz, CDCl3) δ 155.58, 143.47, 135.80, 133.24, 130.55, 128.80,
128.58, 128.26, 127.96, 127.61, 127.16, 125.77, 60.20, 38.70, 37.54,
20.62. ESI-MS (C23H21ClN2O2S2) m/z: 457 [M+1] +. HRMS (ESI) Calcd
for [C23H21ClN2O2S2] requires [M+H]+ 457.0806, found 457.0808.
3-(4-bromophenyl)-5-((phenylthio)methyl)-1-tosyl-4,5-dihydro-
1H-pyrazole (3ea), yellow oil. Yield: 77 mg, 77%. 1H NMR (500 MHz,
CDCl3) δ 7.59 (d, J = 8.2 Hz, 2H), 7.52 – 7.44 (m, 6H), 7.37 (t, J = 7.7
Hz, 2H), 7.29 (d, J = 7.4 Hz, 1H), 7.19 (d, J = 8.1 Hz, 2H), 4.01 (dd, J =
13.8, 3.2 Hz, 1H), 3.92 (tdd, J = 10.7, 9.3, 3.2 Hz, 1H), 3.20 (dd, J =
17.4, 10.8 Hz, 1H), 3.08 – 2.96 (m, 2H), 2.35 (s, 3H). 13C NMR (125
MHz, CDCl3) δ 155.65, 143.48, 133.23, 130.92, 130.55, 128.80,
Calcd for [C23H21ClN2O2S2] requires [M+H]+ 457.0806, found
457.0808.
3-cyclopentyl-5-((phenylthio)methyl)-1-tosyl-4,5-dihydro-1H-
pyrazole (3ja), colorless oil. Yield: 66 mg, 80%. 1H NMR (500 MHz,
CDCl3) δ 7.66 – 7.56 (m, 2H), 7.48 (d, J = 7.6 Hz, 2H), 7.40 (t, J = 7.7
Hz, 2H), 7.33 – 7.29 (m, 1H), 7.26 (d, J = 8.0 Hz, 2H), 3.95 (dd, J =
13.7, 3.2 Hz, 1H), 3.77 (tdd, J = 10.7, 9.0, 3.2 Hz, 1H), 2.98 (dd, J =
13.7, 10.6 Hz, 1H), 2.75 (td, J = 17.1, 16.4, 9.3 Hz, 2H), 2.64 (dd, J =
17.8, 9.1 Hz, 1H), 2.44 (s, 3H), 1.80 (ddd, J = 12.3, 8.1, 5.1 Hz, 2H),
1.71 – 1.60 (m, 4H), 1.50 (dtd, J = 24.7, 7.5, 4.2 Hz, 2H). 13C NMR
(125 MHz, CDCl3) δ 165.34, 143.14, 133.54, 130.35, 128.42, 128.27,
128.17, 127.77, 125.51, 59.28, 39.71, 39.40, 37.50, 29.33, 24.35,
20.62. ESI-MS m/z: 415 [M+1] +. HRMS (ESI) Calcd for [C22H26N2O2S2]
requires [M+H]+ 415.1508, found 415.1507.
128.58, 128.26, 127.60, 127.35, 125.77, 124.20, 60.22, 38.65, 37.54,
+
20.62. ESI-MS m/z: 501 [M+1]
. HRMS (ESI) Calcd for
[C23H21BrN2O2S2] requires [M+H]+ 501.0301, found 501.0299.
5-((phenylthio)methyl)-1-tosyl-3-(4-(trifluoromethyl)phenyl)-
4,5-dihydro-1H-pyrazole (3fa), colorless oil. Yield: 73 mg, 75%. 1H
NMR (500 MHz, CDCl3) δ 7.79 (d, J = 8.3 Hz, 2H), 7.66 (dd, J = 8.1,
5.7 Hz, 4H), 7.58 – 7.49 (m, 2H), 7.42 (t, J = 7.5 Hz, 2H), 7.37 – 7.32
(m, 1H), 7.25 (d, J = 8.0 Hz, 2H), 4.10 – 3.97 (m, 2H), 3.30 (dd, J =
17.5, 10.7 Hz, 1H), 3.15 – 3.06 (m, 2H), 2.40 (s, 3H). 19F NMR (470
MHz, CDCl3) δ -62.92. 13C NMR (125 MHz, CDCl3) δ 155.14, 143.59,
133.18, 130.62, 128.88, 128.64, 128.29, 127.58, 126.16, 125.85,
124.65, 60.40, 38.63, 37.57, 20.62. ESI-MS m/z: 491 [M+1] +. HRMS
(ESI) Calcd for [C24H21F3N2O2S2] requires [M+H]+ 491.1069, found
491.1068.
3-(naphthalen-2-yl)-5-((phenylthio)methyl)-1-tosyl-4,5-dihydro-
1H-pyrazole (3ka), white solid. Yield: 74 mg, 78%. 1H NMR (500
MHz, CDCl3) δ 8.02 (dd, J = 8.6, 1.7 Hz, 1H), 7.91 (d, J = 1.6 Hz, 1H),
7.87 (ddd, J = 8.1, 4.0, 2.0 Hz, 3H), 7.69 (d, J = 8.3 Hz, 2H), 7.60 –
7.53 (m, 4H), 7.44 (t, J = 7.8 Hz, 2H), 7.36 – 7.32 (m, 1H), 7.23 (d, J =
8.1 Hz, 2H), 4.10 (dd, J = 13.7, 3.2 Hz, 1H), 4.01 (tdd, J = 10.6, 9.2,
3.2 Hz, 1H), 3.41 (dd, J = 17.3, 10.8 Hz, 1H), 3.21 (dd, J = 17.3, 9.2
Hz, 1H), 3.12 (dd, J = 13.7, 10.6 Hz, 1H), 2.38 (s, 3H). 13C NMR (125
MHz, CDCl3) δ 156.71, 143.34, 133.36, 131.84, 130.70, 128.80,
128.53, 128.25, 127.66, 127.49, 127.27, 126.86, 126.52, 125.81,
125.72, 122.53, 60.14, 38.78, 37.66, 20.57. ESI-MS m/z: 473 [M+1]+.
HRMS (ESI) Calcd for [C27H24N2O2S2] requires [M+H]+ 473.1352,
found 473.1353.
3-(3,4-dimethoxyphenyl)-5-((phenylthio)methyl)-1-tosyl-4,5-
1
dihydro-1H-pyrazole (3ga), white solid. Yield: 67 mg, 69%. H NMR
3-phenyl-5-((phenylselanyl)methyl)-1-tosyl-4,5-dihydro-1H-
pyrazole (5aa), yellow oil. Yield: 75 mg, 80%. 1H NMR (500 MHz,
CDCl3) δ 7.62 (td, J = 7.2, 6.6, 1.8 Hz, 4H), 7.59 – 7.54 (m, 2H), 7.42 –
7.33 (m, 6H), 7.18 (d, J = 8.1 Hz, 2H), 3.95 – 3.85 (m, 2H), 3.25 (dd, J
= 17.4, 10.7 Hz, 1H), 3.07 (dd, J = 13.0, 11.0 Hz, 1H), 2.98 (dd, J =
17.3, 9.6 Hz, 1H), 2.35 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 156.33,
143.25, 132.11, 130.60, 129.66, 128.49, 128.41, 127.64, 126.49,
125.93, 61.09, 39.43, 31.26, 20.61. ESI-MS m/z: 471 [M+1] +. HRMS
(ESI) Calcd for [C23H22N2O2SSe] requires [M+H]+ 471.0640, found
471.0642.
(500 MHz, CDCl3) δ 7.70 – 7.62 (m, 2H), 7.57 – 7.50 (m, 2H), 7.45 –
7.36 (m, 3H), 7.35 – 7.30 (m, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.07 (dd, J
= 8.3, 2.0 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 4.05 (dd, J = 13.7, 3.2 Hz,
1H), 3.98 (s, 3H), 3.94 (s, 4H), 3.24 (dd, J = 17.3, 10.7 Hz, 1H), 3.10 –
3.01 (m, 2H), 2.39 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 156.61,
150.48, 148.17, 143.28, 133.36, 130.53, 128.71, 128.49, 128.23,
127.65, 125.67, 122.58, 119.86, 109.46, 108.02, 59.91, 55.20, 55.00,
38.86, 37.61, 20.59. ESI-MS m/z: 483 [M+1] +. HRMS (ESI) Calcd for
[C25H26N2O4S2] requires [M+H]+ 483.1407, found 483.1406.
3-(3-methoxyphenyl)-5-((phenylthio)methyl)-1-tosyl-4,5-
5-((benzylselanyl)methyl)-3-phenyl-1-tosyl-4,5-dihydro-1H-
pyrazole (5ab), white solid. Yield: 90 mg, 93%. 1H NMR (500 MHz,
CDCl3) δ 7.79 (d, J = 8.3 Hz, 2H), 7.68 – 7.65 (m, 2H), 7.43 (dddd, J =
14.2, 8.4, 5.9, 2.3 Hz, 5H), 7.37 (dd, J = 8.5, 6.8 Hz, 2H), 7.33 – 7.28
(m, 3H), 4.11 – 4.05 (m, 1H), 3.97 (s, 2H), 3.31 (dd, J = 12.7, 3.3 Hz,
1H), 3.16 – 3.05 (m, 2H), 2.92 (dd, J = 17.3, 8.8 Hz, 1H), 2.43 (s, 3H).
13C NMR (125 MHz, CDCl3) δ 156.67, 143.36, 138.46, 131.17, 129.66,
1
dihydro-1H-pyrazole (3ha), white solid. Yield: 61 mg, 67%. H NMR
(500 MHz, CDCl3) δ 7.62 (d, J = 8.3 Hz, 2H), 7.52 – 7.45 (m, 2H), 7.38
(dd, J = 8.5, 6.9 Hz, 2H), 7.31 – 7.26 (m, 2H), 7.19 (d, J = 8.1 Hz, 2H),
7.16 (dt, J = 7.6, 1.2 Hz, 1H), 6.96 (ddd, J = 8.2, 2.6, 1.0 Hz, 1H), 4.01
(dd, J = 13.7, 3.2 Hz, 1H), 3.95 – 3.88 (m, 1H), 3.83 (s, 3H), 3.21 (dd, J
= 17.4, 10.8 Hz, 1H), 3.06 – 3.00 (m, 2H), 2.35 (s, 3H). 13C NMR (125
MHz, CDCl3) δ 158.72, 156.69, 143.38, 133.33, 130.97, 130.53,
128.78, 128.66, 128.55, 128.24, 127.61, 125.71, 118.64, 115.88,
110.70, 60.06, 54.50, 38.89, 37.60, 20.61. ESI-MS m/z: 453 [M+1] +.
128.61, 128.02, 127.70, 127.62, 125.98, 60.99, 39.18, 28.62, 27.30,
+
20.65. ESI-MS m/z: 485 [M+1]
. HRMS (ESI) Calcd for
[C24H24N2O2SSe] requires [M+H]+ 485.0796, found 485.0797.
6 | J. Name., 2012, 00, 1-3
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2.98 (dd, J = 13.6, 8.9 Hz, 1H). 19F NMR (470 MHz, CDCl3) δ -109.72.
13C NMR (125 MHz, CDCl3) δ 163.84, 161.84, 154.32, 133.71, 129.20,
128.22, 127.74, 127.67, 125.93, 124.70, 115.00, 114.83, 78.72,
38.63, 36.80. ESI-MS m/z: 288 [M+1] +. HRMS (ESI) Calcd for
[C16H14FNOS] requires [M+H]+ 288.0853, found 288.0851.
3-(tert-butyl)-5-((phenylthio)methyl)-4,5-dihydroisoxazole (7da),
colorless oil. Yield: 33 mg, 67%. 1H NMR (500 MHz, CDCl3) δ 7.43 (dt,
J = 8.1, 1.4 Hz, 2H), 7.34 (td, J = 7.7, 1.6 Hz, 2H), 7.26 (td, J = 7.2, 1.4
Hz, 1H), 4.78 – 4.65 (m, 1H), 3.31 (ddd, J = 13.5, 4.5, 1.5 Hz, 1H),
3.10 (ddd, J = 17.0, 10.1, 1.5 Hz, 1H), 2.96 – 2.87 (m, 2H), 1.23 (d, J =
1.6 Hz, 9H). 13C NMR (125 MHz, CDCl3) δ 164.72, 134.03, 128.99,
128.14, 125.72, 77.60, 37.93, 36.64, 32.05, 27.11. ESI-MS m/z: 250
[M+1] +. HRMS (ESI) Calcd for [C14H19NOS] requires [M+H]+ 250.1260,
found 250.1258.
5-((methylselanyl)methyl)-3-phenyl-1-tosyl-4,5-dihydro-1H-
1
pyrazole (5ac), white solid. Yield: 72 mg, 88%. H NMR (500 MHz,
CDCl3) δ 7.84 (d, J = 8.3 Hz, 2H), 7.74 – 7.70 (m, 2H), 7.47 – 7.41 (m,
3H), 7.33 (d, J = 8.1 Hz, 2H), 4.15 (dtd, J = 10.7, 9.1, 3.1 Hz, 1H), 3.33
– 3.25 (m, 2H), 3.14 – 3.04 (m, 2H), 2.44 (s, 3H), 2.20 (s, 3H). 13C
NMR (125 MHz, CDCl3) δ 156.55, 143.38, 131.11, 129.79, 129.65,
128.62, 127.63, 125.95, 61.06, 39.19, 29.69, 20.63, 4.18. ESI-MS m/z:
409 [M+1] +. HRMS (ESI) Calcd for [C18H20N2O2SSe] requires [M+H]+
409.0483, found 409.0481.
3-phenyl-5-((phenylthio)methyl)-4,5-dihydroisoxazole
(7aa),
light yellow solid. Yield: 34 mg, 64%. 1H NMR (500 MHz, CDCl3) δ
7.68 – 7.64 (m, 2H), 7.47 – 7.38 (m, 5H), 7.32 (dd, J = 8.4, 6.8 Hz,
2H), 7.27 – 7.21 (m, 1H), 4.88 (dddd, J = 10.8, 9.1, 6.6, 4.5 Hz, 1H),
3.48 – 3.42 (m, 1H), 3.38 (dd, J = 13.6, 4.5 Hz, 1H), 3.28 (dd, J = 16.8,
6.6 Hz, 1H), 2.99 (dd, J = 13.6, 8.9 Hz, 1H). 13C NMR (125 MHz,
CDCl3) δ 155.30, 133.75, 129.21, 128.40, 128.21, 127.77, 125.90,
125.77, 78.58, 38.59, 36.82. ESI-MS m/z: 270 [M+1] +. HRMS (ESI)
Calcd for [C16H15NOS] requires [M+H]+ 270.0947, found 270.0945.
3-phenyl-5-((phenylselanyl)methyl)-4,5-dihydroisoxazole (8aa),
white solid. Yield: 46 mg, 72%. 1H NMR (500 MHz, CDCl3) δ 7.67 –
7.62 (m, 2H), 7.57 (dd, J = 6.5, 3.1 Hz, 2H), 7.41 (dd, J = 5.3, 2.0 Hz,
3H), 7.33 – 7.27 (m, 3H), 4.91 (dddd, J = 11.0, 9.3, 6.8, 4.5 Hz, 1H),
3.45 (dd, J = 16.8, 10.2 Hz, 1H), 3.32 (dd, J = 12.6, 4.6 Hz, 1H), 3.21
(dd, J = 16.8, 6.8 Hz, 1H), 3.01 (dd, J = 12.6, 9.0 Hz, 1H). 13C NMR
(125 MHz, CDCl3) δ 155.23, 132.30, 129.20, 128.38, 127.76, 126.62,
125.75, 79.43, 39.12, 30.47. ESI-MS m/z: 318 [M+1] +. HRMS (ESI)
Calcd for [C16H15NOSe] requires [M+H]+ 318.0392, found 318.0391.
5-((benzylselanyl)methyl)-3-phenyl-4,5-dihydroisoxazole (8ab),
colorless liquid. Yield: 50 mg, 76%. 1H NMR (500 MHz, CDCl3) δ 7.65
(dd, J = 6.7, 3.0 Hz, 2H), 7.41 (dd, J = 5.1, 2.0 Hz, 3H), 7.36 – 7.25 (m,
4H), 7.25 – 7.18 (m, 1H), 4.88 (dtd, J = 10.3, 7.4, 4.8 Hz, 1H), 3.92 –
3.88 (m, 2H), 3.39 (dd, J = 16.7, 10.3 Hz, 1H), 3.11 (dd, J = 16.7, 7.2
Hz, 1H), 2.84 (dd, J = 12.9, 4.9 Hz, 1H), 2.73 (dd, J = 12.9, 7.6 Hz, 1H).
13C NMR (125 MHz, CDCl3) δ 155.38, 138.03, 129.12, 128.54, 128.03,
127.72, 127.63, 125.98, 125.74, 79.90, 39.38, 26.90, 26.49. ESI-MS
m/z: 332 [M+1] +. HRMS (ESI) Calcd for [C17H17NOSe] requires
[M+H]+ 332.0548, found 332.0547.
3-phenyl-5-((p-tolylthio)methyl)-4,5-dihydroisoxazole
(7ab),
yellow oil. Yield: 42 mg, 75%. 1H NMR (500 MHz, CDCl3) δ 7.70 –
7.65 (m, 2H), 7.41 (dd, J = 5.2, 2.1 Hz, 3H), 7.34 (d, J = 8.2 Hz, 2H),
7.13 (d, J = 7.9 Hz, 2H), 4.85 (dddd, J = 10.8, 9.0, 6.6, 4.6 Hz, 1H),
3.47 – 3.41 (m, 1H), 3.38 – 3.23 (m, 2H), 2.94 (dd, J = 13.5, 8.9 Hz,
1H), 2.34 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 155.29, 136.20,
129.99, 129.21, 129.00, 128.46, 127.76, 125.78, 78.69, 38.55, 37.45,
20.10. ESI-MS m/z: 284 [M+1] +. HRMS (ESI) Calcd for [C17H17NOS]
requires [M+H]+ 284.1104, found 284.1103.
5-(((4-chlorophenyl)thio)methyl)-3-phenyl-4,5-dihydroisoxazole
(7ad), white solid. Yield: 37 mg, 61%. 1H NMR (500 MHz, CDCl3) δ
7.71 – 7.63 (m, 2H), 7.47 – 7.39 (m, 3H), 7.39 – 7.32 (m, 2H), 7.31 –
7.27 (m, 2H), 4.88 (dddd, J = 10.2, 8.4, 6.6, 4.7 Hz, 1H), 3.46 (dd, J =
16.8, 10.3 Hz, 1H), 3.33 (dd, J = 13.7, 4.7 Hz, 1H), 3.27 (dd, J = 16.8,
6.6 Hz, 1H), 3.01 (dd, J = 13.7, 8.4 Hz, 1H). 13C NMR (125 MHz, CDCl3)
δ 155.29, 132.40, 132.00, 130.52, 129.32, 128.35, 127.81, 125.79,
78.41, 38.62, 37.17. ESI-MS m/z: 304 [M+1] +. HRMS (ESI) Calcd for
[C16H14ClNOS] requires [M+H]+ 304.0557, found 304.0558.
Conflicts of interest
There are no conflicts to declare.
5-((methylthio)methyl)-3-phenyl-4,5-dihydroisoxazole
(7ah),
colorless liquid. Yield: 19 mg, 47%. 1H NMR (500 MHz, CDCl3) δ 7.71
– 7.64 (m, 2H), 7.45 – 7.37 (m, 3H), 5.00 – 4.92 (m, 1H), 3.47 (dd, J =
16.7, 10.3 Hz, 1H), 3.29 (dd, J = 16.7, 7.0 Hz, 1H), 2.86 (dd, J = 13.8,
4.9 Hz, 1H), 2.72 (dd, J = 13.7, 7.6 Hz, 1H), 2.22 (s, 3H). 13C NMR
(125 MHz, CDCl3) δ 155.44, 131.23, 129.19, 127.76, 125.76, 79.43,
38.63, 37.09, 15.28. ESI-MS m/z: 208 [M+1] +. HRMS (ESI) Calcd for
[C11H13NOS] requires [M+H]+ 208.0791, found 208.0789.
Notes and references
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3-(4-methoxyphenyl)-5-((phenylthio)methyl)-4,5-
dihydroisoxazole (7ba), white solid. Yield: 47 mg, 78%. 1H NMR
(500 MHz, CDCl3) δ 7.64 – 7.54 (m, 2H), 7.45 – 7.36 (m, 2H), 7.30 (dd,
J = 8.4, 6.8 Hz, 2H), 7.25 – 7.19 (m, 1H), 6.97 – 6.87 (m, 2H), 4.83
(dddd, J = 10.1, 8.9, 6.5, 4.5 Hz, 1H), 3.83 (s, 3H), 3.47 – 3.32 (m, 2H),
3.23 (dd, J = 16.7, 6.5 Hz, 1H), 2.97 (dd, J = 13.5, 8.9 Hz, 1H). 13C
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127.31, 125.84, 120.97, 113.18, 78.29, 54.41, 38.84, 36.79. ESI-MS
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[M+H]+ 300.1053, found 300.1052.
3-(4-fluorophenyl)-5-((phenylthio)methyl)-4,5-dihydroisoxazole
(7ca), white solid. Yield: 40 mg, 70%. 1H NMR (500 MHz, CDCl3) δ
7.68 – 7.56 (m, 2H), 7.48 – 7.36 (m, 2H), 7.31 (dd, J = 8.4, 6.8 Hz, 2H),
7.25 – 7.18 (m, 1H), 7.13 – 7.01 (m, 2H), 4.87 (dddd, J = 10.8, 9.0,
6.6, 4.5 Hz, 1H), 3.46 – 3.33 (m, 2H), 3.24 (dd, J = 16.8, 6.7 Hz, 1H),
This journal is © The Royal Society of Chemistry 20xx
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Organic & Biomolecular Chemistry
Page 8 of 9
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DOI: 10.1039/C7OB02892J
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C7OB02892J
Iodine(III)-Mediated Intramolecular Sulfeno- and Selenofunctionalization of β,
γ-unsaturated Hydrazones and Oximes
Jing-miao Yu,a Chun Cai*a
A cascade radical cyclization/sulfenylation or selenylation of β, γ-unsaturated hydrazones and
oximes was realized under mild conditions with phenyliodine(III) diacetate (PIDA) as the sole
oxidant, leading to the construction of various diversely functionalized heteroatom-containing
pyrazoline and isoxazoline derivatives. This metal-free radical process is suggested to
encompass a sequential C-N/O and C-S/Se bond fomation.