A Radical Smiles Rearrangement Promoted by Neutral Eosin y as a Direct Hydrogen Atom Transfer Photocatalyst

Article abstract of DOI:10.1021/jacs.0c02052

A visible-light-mediated radical Smiles rearrangement has been achieved using neutral eosin Y as a direct hydrogen atom transfer (HAT) photocatalyst. Novel N-heterocycles as single diastereomers featuring an isothiazolidin-3-one 1,1-dioxide moiety are directly accessed by this method. A wide range of functional groups can be incorporated in the products by employing diverse aldehydes and N-(hetero)arylsulfonyl propiolamides. The transformation proceeds through a cascade of visible-light-induced HAT, 1,4-addition, Smiles rearrangement, 5-endo-trig cyclization, and a reverse HAT process. Preliminary biological studies of the highly functionalized heterocyclic compounds suggest potential anticancer activity with some of the synthesized compounds.

Full text of DOI:10.1021/jacs.0c02052

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Communication
A Radical Smiles Rearrangement Promoted by Neutral
Eosin Y as a Direct Hydrogen Atom Transfer Photocatalyst
Jianming Yan, Han Wen Cheo, Wei Kiat Teo, Xiangcheng
Shi, Hui Wu, Shabana Idres, Lih-Wen Deng, and Jie Wu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.0c02052 • Publication Date (Web): 16 Jun 2020
Downloaded from pubs.acs.org on June 16, 2020
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Journal of the American Chemical Society
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A Radical Smiles Rearrangement Promoted by Neutral Eosin Y as a
Direct Hydrogen Atom Transfer Photocatalyst
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Jianming Yan,† Han Wen Cheo,† Wei Kiat Teo,† Xiangcheng Shi,† Hui Wu,‡ Shabana Binte Idres,‡ Lih-
Wen Deng,‡ Jie Wu*,†,#
†
Department of Chemistry, National University of Singapore, 3 Science Drive 3, 117543, Singapore
‡
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, National University
Health System, 8 Medical Drive, 117597, Singapore
#National University of Singapore (Suzhou) Research Institute, No. 377 Lin Quan Street, Suzhou Industrial Park,
Suzhou, Jiangsu, 215123, China
Supporting Information Placeholder
ABSTRACT: A visible light-mediated radical Smiles rearrangement has been achieved using neutral eosin Y as a direct hydrogen
atom transfer (HAT) photocatalyst. Novel N-heterocycles as single diastereomers featuring an isothiazolidin-3-one 1,1-dioxide
moiety are directly accessed by this method. A wide range of functional groups can be incorporated in the products by employing
diverse aldehydes and N-(hetero)arylsulfonyl propiolamides. The transformation proceeds through a cascade of visible-light-
induced HAT, 1,4-addition, Smiles rearrangement, 5-endo-trig cyclization and a reverse HAT process. Preliminary biological studies
of the highly functionalized heterocyclic compounds suggest potential anti-cancer activity with some of the synthesized compounds.
The conventional Smiles rearrangement is an intramolecular
nucleophilic aromatic substitution that occurs at the ipso-
position of arylsulfones.1 The aromatic substrates are typically
activated by electron-withdrawing groups at the ortho or para
positions. Since the seminal work of Speckamp, et al. to
transpose the ionic conditions to radical chemistry,2 the radical
Smiles rearrangement has become a versatile strategy enabling
the formal migration of (hetero)aryl and other unsaturated C–
C bond moieties.3 This radical rearrangement is capable of
breaking various C(sp2)–X (X = S, O, N, C) bonds that are not
limited to sulfones. Distinct from ionic pathways, the presence
of electron-withdrawing groups is not necessary in radical
Smiles rearrangements. Although a stoichiometric amount of a
radical initiator is required to trigger the radical process under
relatively harsh conditions,4 early examples of aryl migration
have benefitted from this rearrangement. Recently, this
entropically favored desulfonylation.4,5 Retention of SO2 to
render a more atom-economic transformation remains rare.8
Scheme 1. Practical Radical Smiles Rearrangement-Based
Transformations
a. Difunctionalization-desulfonylative cyclization of activated alkenes via radical Smiles rearrangement
(Nevado, etc)
O
O
O
R'
O
R
R
R
N
S
R'
R'
various
functionalized
N-heterocyles
- SO2
X
X
N
N
X
O
+
S
X = CF3, SCF3
Ar2P=O, N3
CH(COR'')2, etc
O
precursor
O
Ar
Ar
b. Difunctionalization of unactivated alkenes via radical Smiles rearrangement
(Stephenson, Zhu, etc)
R
O
S
O
O
Y
O
O
- SO2
Y
X
+
R
S
S
R
O
X
Y
X'
S
X
Y
X
Y
R
O
R
O
Stephenson: X = X' = NH(C=O)R; Y = heteroaryl or naphthyl
Zhu: X = CF2Br, X' = CF2I; Y = heteroaryl or X = (CH3)2CBr; X' = (CH3)2CH; Y= heteroaryl
strategy
was
extensively
employed
to
realize
c. This work: SO2-retaining radical Smiles rearrangement promoted by direct HAT photocatalysis
difunctionalization of alkenes or alkynes under both transition-
metal and photoredox catalysis.5 Elegant approaches to access
heterocycles have also been described.6 Notably, the Nevado
group used transition metal-catalyzed radical Smiles
rearrangements to synthesize a series of N-heterocycles.
Reactions of this sort normally employed tailored N-
arylsulfonyl acrylamides as activated alkene substrates
(Scheme 1a).7 Difunctionalization of unactivated alkenes by
photoredox catalysis was nicely illustrated independently by
the Stephenson group5a and the Zhu group.5b,5c In these
reactions, SO2 serves as a traceless linker of two functional
moieties (Scheme 1b). The arylsulfonyl group has been shown
to represent a privileged aryl migrating source in Smiles
rearrangements owing to its excellent reactivity and facile
installation using commercially available arylsulfonyl
chlorides.3d The Smiles rearrangement is followed by an
R'
O
H
N
O
S
O
R
O
P
O
H
O
Ar
S
eosin Y (4 mol%)
H
Ar
+
R
or
Ar'
O
N
R'
CH3CN, 18 W blue LED, 80 o
C
or
O
R'
Ar = aryl or heteroaryl; Ar' = aryl
= aryl or alkyl; R' = alkyl
O
N
O
R
O
S
O
H
Ar'
> 50 exampes; > 30:1 diastereoselectivity
H
P
H
Ar
Ar'
Ar'
O


novel heterocycle scaffolds with potential bioactivity  wide substrate scope  single diastereomer
atom-economic step-economic metal-free additive-free scalable




Our group recently developed a robust and versatile C–H
functionalization protocol using neutral eosin Y as a direct
hydrogen atom transfer (HAT) photocatalyst.9 This efficient
catalytic system enables facile access to a variety of carbon
radicals in an extremely mild and green manner. We envisioned
that radicals generated by this strategy would readily trigger
subsequent cascade radical processes such as the
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aStandard conditions: 1a (0.3 mmol), 2a (0.1 mmol), eosin Y (4 mol%), and
aforementioned Smiles rearrangement to access novel
molecular scaffolds directly. We herein report that subjecting
aldehydes or phosphine oxides and easily accessible N-
arylsulfonyl propiolamides to neutral eosin Y-based direct HAT
CH3CN (1 mL) in a Schlenk tube (20 mL) at 80 oC under blue LED (18 W)
irradiation. Freeze-pump-thaw was repeated 3 times to remove air and fill
argon into the reaction vessel. bConversions and diastereoselectivities
were determined by analysis of the crude 1H NMR using 1,3,5-
trimethoxylbenzene as an internal standard; an isolated yield is shown in
parentheses. cN-methyl-tosylamine was formed. dThe reaction was
performed under 365 nm LED irradiation.
1
2
3
4
5
6
7
8
photocatalytic
conditions
provides
unique
densely
functionalized isothiazolidin-3-one 1,1-dioxides with excellent
diastereoselectivity (Scheme 1c). This approach retains SO2 to
construct potentially bioactive heterocycles, which are
otherwise difficult to prepare. Bioactive compounds containing
an isothiazolidin-3-one 1,1-dioxide moiety are shown in Figure
S1.10
With the optimized conditions in hand, the scope of aldehydes
was examined (Table 2, top). A diverse set of aromatic
aldehydes, regardless of their electronic properties were found
to be compatible with our protocol and produced the
corresponding densely functionalized isothiazolidinones (3b–
3q) as single diastereomers in good yields. Various functional
groups such as hydroxyl (3d), amide (3e), boronic ester (3j),
ester (3c; 3k), halide (3g–3i; 3o–3p) and cyanide (3m–3n)
groups were well tolerated. The aromatic aldehyde substrates
bearing substituents at ortho or meta positions (3n–3q) were
also suitable candidates, indicating the feasibility of further
9
10
11
12
13
14
15
16
17
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27
28
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36
37
38
39
40
41
42
43
44
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46
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Our study was initiated by using benzaldehyde 1a and N-tosyl
propiolamide 2a as model reactants. After extensive
optimization of conditions (Table 1), neutral eosin Y (4 mol%)
o
in CH3CN under 18 W blue LED irradiation at 80 C afforded
heterocyclic product 3a in 87% isolated yield (entry 1). The
configuration of 3a was unambiguously determined by single
crystal X-ray diffraction analysis (Figure S2).11 The elevated
temperature of 80 oC was necessary to ensure an efficient
derivatization. Aliphatic aldehydes containing either
a
branched or linear alkyl chain successfully participated in this
cascade transformation to provide 3r–3v in moderate to good
yields. Decarbonylated product was not observed although a
related study14 indicates that the facile decarbonylation of
branched acyl radical could occur. It is worth noting that
various heterocyclic aldehydes could also be employed and
delivered heterocycle-enriched products (3w–3y) in good
yields. As an initial effort to extend this HAT catalytic system
beyond C–H substrates, we found that phosphine oxides turned
out to be suitable, providing rapid access to phosphine-
containing isothiazolidiones 4a–4e in moderate to good yields
(Table 2, middle). Electron-withdrawing, electron-donating
and sterically demanding substituents in the diaryl phosphine
oxides were well tolerated.
transformation and high diastereoselectivity (>30:1).
A
mixture of diastereomers was obtained in much lower yield at
room temperature (entry 2). The control experiments
indicated that the cis-isomer 3a’ is not stable, which can easily
epimerize to the more stable trans-isomer 3a under heating or
slightly acidic conditions (Scheme S2, Figure S9). Replacing the
eosin Y photocatalyst by combinations of a photoredox catalyst
and a HAT agent12 resulted in little or no desired product
(entries 3 and 4; for evaluation of more photocatalysts, see
Table S1). Use of dianionic Na2eosin Y led to decomposition of
1a with no product detected (entry 5), which is consistent with
our earlier recognition of neutral eosin Y as the active HAT
photocatalyst.9 On the other hand, product 3a could be
obtained in 50% yield using
photocatalyst tetra-n-butylammonium
a
different direct HAT
decatungstate
(TBADT)13 under UV irradiation (entry 6). An excess amount (3
equiv) of aldehyde proved to be essential to obtain products
with high yields (entries 7 and 8). Acetone, tert-butanol and
H2O as solvents also gave the desired product, albeit with lower
yields (entries 9–11). Control experiments in the absence of
blue LED irradiation resulted in no reaction, confirming that
light is essential (entry 12).
The scope with respect to N-arylsulfonyl propiolamides was
subsequently investigated (Table 2, bottom). Systematic
modification of the arylsulfonyl moiety was feasible,
accommodating both electron-rich (5c–5f) and electron-poor
substituents (5g–5i). The reaction also proceeded smoothly
with meta or ortho substituents on the arylsulfonyl groups (5j–
5m). Notably, this cascade protocol is applicable to N-
heteroarylsulfonyl propiolamide, direct joining the pyridine
and thiophene moiety to the isothiazolidione scaffold (5n–5o).
Changing the N-methyl substituent to N-4-pentenyl (5p) or N-
cyclohexyl (5q) was also feasible. The former delivered the
desired isothiazolidinone product (5p) selectively in spite of
the possibility of an alternative cyclization at the terminal
alkene.
Table 1. Selected Optimization Results
H
O
Me
O
S
N
O
O
1a
(3 equiv)
neutral eosin Y (4 mol%)
H
+
H
O
O
blue LED, 18 W
O
Me
S
CH3CN (0.1 M), 80 °C, 48 h
Me
3a
N
Me
standard conditionsa
O
2a
(1 equiv)
b
yield of
(%)
3ab
d.r. of
b
3a
entry
2a
(%)
deviation from standard conditions
none
conv. of
1
2
100
89(87)
37
>30:1
2:1
room temperature instead of 80 o
C
40
70
3
4
Mes-Arc+ClO4- (2 mol%)+HCl (5 mol%)
7
0
-
-
Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (2 mol%)
+ PhCO2Na (5 mol%)
80
5c
6d
Na2eosin Y (4 mol%) as the catalyst
TBADT (4 mol%) as the catalyst
100
100
-
0
50
>30:1
7
8
9
1a
1a
70
40
88
53
>30:1
>30:1
>30:1
>30:1
2 equiv of
4 equiv of
100
100
acetone instead of CH3CN
10
11
12
tert-butanol instead of CH3CN
H2O instead of CH3CN
without blue LED light
100
26
0
80
13
0
-
-
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Table 2. Substrate Scope of Aldehydes, Phosphine Oxides and N-(Hetero)Arylsulfonyl Propiolamides
1
2
3
4
5
6
Me
O
R2
N
O
S
O
O
R1 = (hetero)aryl or alkyl
Ar = aryl
O
N
O
O
O
eosin Y (4 mol%)
N
Ar
O
S
S
Ar
H
H
R2
or
or
O
Ar
P
or
+
H
R2 = alkyl
blue LED, 18 W
P
H
R1
R1
O
O
Me
H
H
Ar
Ar
Ar = (hetero)aryl
CH3CN (0.1 M), 80 °C, 48 h
O
Ar
1
2
3
5
( )
4
(3 equiv)
7
Scope of aldehydesa
8
9
Me
Me
N
Me
N
Me
Me
N
Me
N
O
O
O
O
O
O
O
O
O
O
O
O
N
N
O
O
O
O
O
S
S
S
S
S
O
S
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
H
H
H
H
H
H
H
H
H
H
H
H
O
O
O
O
O
O
Me
Me
Me
Me
Cl
Me
Me
MeO
HO
AcHN
Me
AcO
3b
3c
3d
3e
3f
3g
, 69%
, 77%
, 65%
, 65%
, 64%
, 58%
Me
N
O
O
Me
N
Me
N
Me
N
Me
N
Me
N
O
S
O
O
O
O
O
O
O
O
O
O
S
S
O
O
O
S
S
S
O
O
H
H
O
H
H
H
H
H
H
H
O
O
H
H
H
Me
B
O
O
O
O
Me
Me
NC
Me
Me
Me
MeO2C
F3C
Br
F
O
3h
3i
3j
3k
3l
3m
, 53%
, 60%
, 95%
Me
, 56%
O
, 76%
, 79%
Me
N
Me
Me
N
Me
O
O
O
O
Me
N
O
O
N
O
N
O
O
N
O
S
S
O
O
S
S
O
O
O
S
O
O
S
Me
H
H
H
H
NC
F
H
H
H
H
H
O
H
Me
Me
H
O
O
H
O
O
O
Me
Me
Me
Me
Me
Me
OMe
3q
F
3n
3o
3p
3r
3s
, 47%
, 68%
, 75%
, 72%
, 50%
, 55%
heterocycle-containing aldehyde
Me
Me
N
Me
Me
Me
Me
N
O
O
O
O
S
O
O
O
O
O
N
N
N
N
O
S
O
O
S
O
S
O
O
O
S
O
O
S
Me
H
H
H
H
H
H
O
F
H
H
H
N
O
H
H
Me
H
O
N
N
O
F
O
O
O
Me
O
Me
Me
O
Me
Me
Me
Me
3y
3t
3u
3v
3w
3x
, 60%
, 47%
, 80%
, 80%
, 75%
, 68%
Scope of phosphine oxidesa,b
Me
N
Me
Me
N
Me
N
Me
N
O
O
O
N
O
O
O
O
O
O
S
P
S
S
O
O
O
O
S
P
S
P
O
MeOO
H
H
H
H
H
MeO
F
P
tBu
P
H
H
H
O
O
O
H
H
Me
Me
Me
O
O
Me
Me
OMe
MeO
F
tBu
4a
4b
4c
4d
4e
, 59%
, 70%
, 64%
, 67%
, 44%
Scope of N-(hetero)arylsulfonyl propiolamidesa
Me
N
Me
N
Me
N
Me
N
Me
N
Me
O
O
O
O
O
O
O
O
O
N
O
O
S
S
O
O
O
O
S
S
S
O
S
O
O
H
H
H
H
H
H
H
H
H
H
H
H
O
O
O
O
O
O
OMe
OMe
tBu
NHAc
5a
5b
5c
5d
5e
5f
, 71%
, 54%
, 81%
, 62%
, 90%
, 83%
O
Me
Me
N
Me
N
Me
N
Me
Me
N
O
O
O
O
O
O
O
O
O
N
N
O
O
S
S
O
S
O
O
O
O
S
S
S
O
H
H
F
OMe
H
H
H
H
H
H
O
H
O
H
H
H
O
O
O
O
CO2Me
CF3
F
5g
5h
5i
5j
5k
5l
, 53%
, 68%
, 75%
, 96%
, 52%
, 75%
heteroaryl migration
N-alkyl substituent
Me
Me
N
Me
N
O
O
O
O
N
O
O
N
O
O
O
S
O
S
O
O
S
O
O
N
OMe
S
O
S
H
H
H
S
H
H
H
H
H
H
O
O
O
H
O
Me
N
Cl
O
Me
5m
5p
5q
, 65%
, 46%
, 48%
5n
5o
, 50%
, 88%
aReactions were performed under the standard conditions described in Table 1. Single diastereomers were obtained in all cases and isolated yields are
shown. bReations were performed at room temperature under otherwise the same conditions as the standard conditions described in Table 1.
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(7) was detected by high-resolution electrospray ionization
mass (HR ESI-MS) spectrometric analysis (Figure S4).15 Tert-
butyl group instead of pivaloyl group was incorporated in the
isothiazolidione skeleton of 3z using pivalaldehyde (1z) as the
starting aldehyde, due to facile decarbonylation of pivaloyl
radical to give the more stable tert-butyl radical (eq 3).16
Collectively, these findings support the involvement of acyl
radicals in the present reaction process. We then attempted to
prove the generation of a vinyl radical upon addition of the acyl
radical to the C≡C triple bond (eq 4). Subjection of N-tosyl-N-
isobutyl propiolamide (2r) to the reaction conditions afforded
an isothiazolidinone (5r), together with the γ-lactam 8 in 22%
yield. While the formation of 5r resulted from a Smiles
rearrangement and 5-endo-trig cyclization of the transient
vinyl radical, the generation of 8 could be rationalized by a
competitive pathway involving 1,5-HAT and 5-exo-trig
cyclization,17 which support the presence of the transient vinyl
1
2
3
4
5
6
7
8
Table 3. Incorporation of Complex Molecules
R2
O
O
O
N
O
N
O
O
S
eosin Y (4 mol%)
Me
S
H
R2
H
R1
+
R1
O
blue LED, 18 W
H
O
Me
CH3CN (0.1 M), 80 °C, 48 h
1
(3 equiv)
2
6
Me
O
N
O
Me
O
S
O
Me
O
H
N
H
9
N
5
4
H
H
O
S
O
4
S
O
O
4
5
Me
O
Me
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
H
Me
O
O
O
H
O
O
O
H
H
O
O
H
O
a
a
a
6c
, 61%
6a
6b
, 55%
, 60%
c
b
c
6c
6c
6a
6a
6b
6b
(4R, 5R)- :(4S, 5S)- = 1:1
(4R, 5R)- :(4S, 5S)- = 1:1
(4R, 5R)- :(4S, 5S)- = 1:1
radical intermediate.
A deuterium-labelling study was
H
performed using 4-fluorobenzaldehyde-d (1i-d) in which the
aldehyde C–H was deuterated (eq 5). The reaction gave 3i-d in
which 42% deuteration was found at C-4 of the
isothiazolidinone ring. This deuterium incorporation in the
final product can originate from an initial HAT step from
aldehyde 1i-d. The loss of deuterium is likely due to the trace
amount of water present in the reaction mixture (Figure S5). In
addition, both light on/off experiments and a quantum yield
determination (Ф = 0.17) disfavored a chain mechanism
(Figure S6, eq S14).
Ph
Me
CO2Me
O
CO2Me
O
S
N
O
N
O
N
O
O
S
O
O
S
O
5
4
5
4
5
4
H
H
H
H
H
H
O
O
Me
O
Me
Me
a
a
a
6d
6f
, 32%
, 59%
6e
, 69%
c
c
c
6d
6d
6f
6f
(4R, 5R)- :(4S, 5S)- = 1:1
6e
6e
(4R, 5R)- :(4S, 5S)- = 1:1
(4R, 5R)- :(4S, 5S)- = 1:1
aReactions were performed under the standard conditions in Table 1. A
mixture of two isomers was obtained and overall isolated yields were
shown. Undrawn isomer denotes (4S,5S) configuration at the
isothiazolidione moiety. Configuration of other chiral centers was identical
for the two isomers. bRatio of the two isomers was estimated by chiral HPLC
analysis. cRatio of the two isomers was determined by analysis of the crude
Scheme 3. Mechanistic Investigation
1H NMR spectra.
Reaction with 1 equiv of TEMPO:
Me
eosin Y (4 mol%)
TEMPO
O
O
O
O
N
O
Encouraged by the broad substrate scope of this mild cascade
transformation, we sought to extend the reaction to derivation
of complex molecules (Table 3). Aldehydes derived from
natural products such as epiandrosterone, (-)-menthol, (+)-
fenchol participated in this transformation to afford 6a-6c in
moderate yields. In addition, N-arylsulfonyl propiolamides
prepared from (+)-dehydroabietylamine, D-alanine and D-
phenylalanine also delivered the corresponding products 6d-
6f smoothly. Although four diastereoisomers could be
generated theoretically in each reaction, only two isomers in an
approximate 1:1 ratio determined by 1H NMR or HPLC analysis,
were generated as exclusive trans-configurations obtained
with the isothiazolidinone moiety (4-C vs 5-C). To further
demonstrate the synthetic utility of the established protocol,
the cascade reaction was amenable to scale up to gram-scale
(Scheme 2), illustrating the robustness of this protocol.
H
N
(1.0 equiv)
O
S
Me
S
+
(eq 1)
O
Me
H
blue LED, 18 W
H
F
O
CH3CN (0.1 M), 80 °C, 48 h
Me
F
1i
2a
3i
, 0%
Reaction with 1 equiv of BHT:
tBu
OH
tBu
O
O
N
O
eosin Y (4 mol%)
BHT
(1.0 equiv)
H
O
Me
S
+
O
Me
(eq 2)
blue LED, 18 W
CH3CN (0.1M), 80 °C, 48 h
7
F
F
1i
2a
(HR ESI-MS detected)
Me
O
N
O
O
eosin Y (4 mol%)
H
Me
S
O
S
O
Me
Me
+
(eq 3)
N
Me
O
blue LED, 18 W
CH3CN (0.1 M), 80 °C, 48 h
H
Me
1z
H
Me
Me
Me
O
Me
2a
3z
, 78%
Involvement of vinyl radical
H
O
H
H
O
N
S
O
O
N
O
S
O
O
Scheme 2. Gram Scale Synthesis
H
H
O
F
Me
O
Me
1i
5r
, 66%
F
F
Me
eosin Y (4 mol%)
5-endo-trig
O
O
N
O
+
O
S
(eq 4)
O
O
H
eosin Y (4 mol%)
+
N
blue LED, 18 W
CH3CN (0.1M), 80 °C, 48 h
Me
S
O
S
O
O
O +
Me
blue LED, 18 W
O
Ts
O
H
H
N Ts
N
H
N
CH3CN (0.1 M), 80 °C, 4 d
H
F
O
F
O
Me
Me
O
1i
2a
3i
(83%, 1.5 g)
(15 mmol)
(5 mmol)
F
H
8
, 22%
2r
F
5-exo-trig
Deuterium-labeling study
Control experiments were conducted to probe the reaction
mechanism (Scheme 3). Addition of 2,2,6,6-
tetramethylpiperidin-1-yl)oxyl (TEMPO) or butylated
hydroxytoluene (BHT) completely stopped the reaction (eq 1
and 2), and the adduct of BHT and the 4-fluorobenzoyl radical
Me
O
O
O
O
N
O
eosin Y (4 mol%)
blue LED, 18 W
D
N
O
S
Me
S
+
O
Me
H
(eq 5)
H/D
CH3CN (0.1 M), 80 °C, 48 h
F
O
Me
F
3i-
d, 61%
42% D incorporation
1i-
2a
d
4
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ASSOCIATED CONTENT
Scheme 4. Proposed Mechanism
1
2
3
4
5
6
7
8
O
N
O
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
O
O
Me
N O
S
Ph
O
Me
Ph
Me
S
H
O
O
1a
2a
O
Ph
CO2H
Br
HAT
Br
A
B
Me
HO
O
O
General procedures, analytical data, and NMR spectra (PDF)
X-ray data for compound 3a (CIF)
CO2H
Br
Br
*eosin Y
Br
O
Br
O
Ph
Me
N
Smiles
rearrangement
HO
O
OH
S
O
Br
eosin Y
Br
H
O
blue LED
9
AUTHOR INFORMATION
Me
CO2H
Br
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
RHAT
Br
Me
N
O
S
O
O
Me
Corresponding Author
O
O
Ph
N
O
HO
O
O
Me
5-endo-trig
O
S
O
O
Br
eosin Y
Br
N
*chmjie@nus.edu.sg
Ph
O
S
O
H
Me
Notes
H
Ph
D
Me
O
C
Me
3a
The authors declare no competing financial interests.
Based on all the experimental results and earlier literature
reports,9 a plausible mechanism was proposed as illustrated in
Scheme 4. The excited *eosin Y undergoes a HAT with aldehyde
1a to deliver an acyl radical A. Upon addition of this acyl radical
to N-arylsulfonyl propiolamide 2a, a vinyl radical species B is
generated which initiates the subsequent Smiles
rearrangement to afford a postulated sulfonyl radical C.
Radical C undergoes a 5-endo-trig cyclization to deliver the α-
ACKNOWLEDGMENTS
We are grateful for the financial support provided by the
Ministry of Education (MOE) of Singapore (MOE2017-T2-2-
081), GSK-EDB (R-143-000-687-592), National Natural Science
Foundation of China (Grant No. 21702142, 21871205) and the
National University of Singapore (Suzhou) Research Institute.
carbonyl benzylic radical D. Finally,
D is capable of
REFERENCE
regenerating eosin Y via a reverse HAT (RHAT), simultaneously
furnishing the isothiazolidione product 3a. Even though we
cannot exclude the possibility of a single electron transfer (SET)
between radical D and eosin Y-H, the density functional theory
(DFT) calculations indicated that the SET pathway was unlikely
as the relative free energy barrier was 10 kcal/mol higher than
that of the RHAT pathway (Figure S9).
(a) Levy, A. A.; Rains, H. C.; Smiles, S. The Rearrangement of Hydroxy-
Sulfones. J. Chem. Soc. 1931, 3264–3269. (b) Matsui, K.; Maeno, N.;
Suzuki, S.; Shizuka, H.; Morita, T. Photo-Smiles Rearrangements.
Tetrahedron Lett. 1970, 11, 1467–1469.
2
(a) Loven, R.; Speckamp, W. N.
A Novel 1,4 Arylradical
Rearrangement. Tetrahedron Lett. 1972, 13, 1567–1570. (b) Köhler, J.
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634.
The isothiazolidinone scaffold has been reported to be active
toward PTP1B,10b,18 an important target for the development
of anti-cancer drugs.19 Preliminary evaluation of the anti-
cancer activity of selected synthesized heterocyclic compounds
was conducted in a human breast cancer cell line (MCF7) and a
cervical cancer cell line (HeLa) (Figure S10). It was found that
modification of the isothiazolidinone skeleton can affect the
activity dramatically. The preliminary results (Table S2)
indicated that 3y is active in various cell lines including MCF7
(IC50 = 7.18 M), HeLa (IC50 = 10.08 M), human lung cancer
cell line A549 (IC50 = 20.62 M) and the colon cancer cell line
Caco-2 (IC50 = 32.18 M). Further bioactive investigation of this
unique class of compounds is currently ongoing in our
laboratory.
3
For reviews: (a) Studer, A.; Bossart, M. Radical Aryl Migration
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In conclusion, an efficient radical Smiles rearrangement
initiated by neutral eosin Y-based HAT photocatalysis is
developed. The merits of this transformation include atom- and
step-economic, metal- and additive-free, excellent selectivity,
and generation of otherwise difficultly generated heterocycle
scaffolds. Practical modification of either starting substrate
leads to the direct access to a variety of highly functionalized
isothiazolidinone compounds, which are potentially
biologically interesting molecules. This study highlights the
opportunity of neutral eosin Y-based direct HAT photocatalysis
to access new chemical space via radical rearrangement
transformations.
17650.
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CCDC1921518 (3a) contains the supplementary crystallographic
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(a) Deng, H.-P.; Zhou, Q.; Wu, J. Microtubing-Reactor-Assisted
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Selected recent examples starting from sulfone precursors: (a) Wang,
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Rearrangement Triggered by Visible-Light-Mediated Regioselective
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L.; Wang, F.-L.; Guo, Z.; Cheng, Y.-F.; Wang, N.; Dong, X.-W.; Fang, C.; Liu,
J.; Hou, C.; Tan, B.; Liu, X.-Y. Radical Aryl Migration Enables Diversity-
Oriented Synthesis of Structurally Diverse Medium/Macro- or Bridged-
Rings. Nat. Commun. 2016, 7, 13852.
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Ravelli, D.; Fagnoni, M.; Fukuyama, T.; Nishikawa,T.; Ryu, I. Site-
Selective C–H Functionalization by Decatungstate Anion
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Moteki, S. A.; Usui, A.; Selvakumar, S.; Zhang, T.; Maruoka, K. Metal-
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For the formation of ketone as an adduct of acyl radical and BHT,
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(a) Fan, X.-Z.; Rong, J.-W.; Wu, H.-L.; Zhou, Q.; Deng, H.-P.; Tan, J. D.;
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Unactivated C(sp3)–H Bond via
a C-Centered Radical-Mediated
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18
Combs, A. P.; Zhu, W.; Crawley, M. L.; Glass, B.; Polam, P.; Sparks, R.
Neutral-Eosin-Y-Photocatalyzed
Silane
Chlorination
Using
B.; Modi, D.; Takvorian, A.; McLaughlin, E.; Yue, E. W.; Wasserman, Z.;
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Hollis, G.; Liu, P. C. C.; Metcalf, B. Potent Benzimidazole Sulfonamide
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Kuang, Y.; Wang, K.; Shi, X.; Huang, X.; Meggers, E.; Wu, J. Asymmetric
Synthesis of 1,4-Dicarbonyl Compounds from Aldehydes by Hydrogen
Atom Transfer Photocatalysis and Chiral Lewis Acid Catalysis. Angew.
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Andree, T.; Haskins, J. T. Synthesis and Structure-Activity Relationship
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1,1-dioxides and Thiadiazinones: Potential Anxiolytic Agents. J. Med.
Chem. 1989, 32, 1024−1033 (b) Combs, A. P.; Yue, E. W.; Bower, M.; Ala,
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Zhu, W.; Crawley, M. L.; Pruitt, J.; Sparks, R.; Glass, B.; Modi, D.;
McLaughlin, E.; Bostrom, L.; Li, M.; Galya, L.; Blom, K.; Hillman, M.;
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R.; Li, Y.; Hollis, G.; Burn, T. C.; Wynn, R.; Liu, P.; Metcalf, B. Structure-
Based Design and Discovery of Protein Tyrosine Phosphatase
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Maccari, R.; Ottanà, R. Low Molecular Weight Phosphotyrosine
Protein Phosphatases as Emerging Targets for the Design of Novel
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For Table of Content only
R2
O
O
N
eosin Y
O
O
Ar
S
N
R2
O
S
6
H
R1
CO2H
Br
7
8
9
blue
LED
O
H
Ar
Br
+
O
H
HO
O
O
R1 = (hetero)aryl or alkyl
R2 = alkyl; Ar = (hetero)aryl
Br
Br
R1
O
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46
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HAT photocatalysis & radical Smiles rearrangement
 novel heterocycle scaffolds with potential bioactivity

wide substrate scope
atom- and step-economic
visible-light irradiation


excellent diastereoselectivity
metal- and additive-free


scalable

7
ACS Paragon Plus Environment