Visible-Light-Induced Cyclization of Electron-Enriched Phenyl Benzyl Sulfides: Synthesis of Tetrahydrofurans and Tetrahydropyrans

Article abstract of DOI:10.1055/s-0035-1561393

A new approach to the preparation of tetrahydrofurans and tetrahydropyrans through a photoredox catalytic process is described. The introduction of a phenylsulfanyl auxiliary group permits the substrates to be readily oxidized to form cationic intermediates for sequential intramolecular cyclization. The method features mild reaction conditions and operational simplicity.

Full text of DOI:10.1055/s-0035-1561393

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–F
letter
A
W. Li et al.
Letter
Synlett
Visible-Light-Induced Cyclization of Electron-Enriched Phenyl
Benzyl Sulfides: Synthesis of Tetrahydrofurans and Tetrahydropy-
rans
Wei Lia,b
R1
Chao Yanga
Guo-Lin Gaoa
Wujiong Xia*a
R2
Ph
O
S
EDG
photoredox cat.
air, blue light
OX
R2
n
n
EDG
R1
a State Key Laboratory of Urban Water Resource and
Environment, Shenzhen Graduate School. Harbin
Institute of Technology, Harbin 150080, P. R. of China
b Key Laboratory for Food Science and Engineering.
Harbin University of Commerce, Harbin 150076,
P. R. of China
– PhS
n = 1 or 2; X = H, TBS
up to 87%
xiawj@hit.edu.cn
Received: 28.11.2015
Accepted after revision: 23.01.2016
Published online: 04.03.2016
electron-donating substituent. On the basis of recent work
on the electrochemical synthesis of alkoxycarbenium ion
from thioacetals,9 we prepared a series of phenylsulfanyl-
substituted aromatic alkanols for photoredox catalytic reac-
tions, with the idea that the phenylsulfanyl substituent
might act as a leaving group through selective cleavage of
the C–S bond after a single-electron transfer process to give
a carbonium ion as key intermediate for cyclization with
the internal hydroxy group (Scheme 1, c). Here, we present
a novel approach for the preparation of both tetrahydrofu-
rans and tetrahydropyrans through photoredox catalysis;
the method can also give lactams or lactones. The visible-
light-induced C–S bond cleavage of sulfones has been re-
ported previously,10 but visible-light-induced reactions us-
ing a phenylsulfanyl auxiliary group are still rare.11
Our initial investigation began with sulfide 1a as repre-
sentative substrate, air as the oxidative quencher, 5 mol% of
Ru(bpy)3Cl2 as the photoredox catalyst, and MeCN as the
solvent. The reaction mixture was irradiated with blue-
light-emitting diodes (blue LEDs; 6 W) for six hours. To our
pleasure, the tetrahydrofuran product 2a was obtained in
75% yield (Table 1, entry 1). We then screened DMF, DMSO,
DCE, and MeNO2 as solvents, and we found the reaction in
MeNO2 gave the best yield (entries 2–5). In a further exper-
iment, the addition of two equivalents of TFA to the mix-
ture improved the yield to 94% (entry 6). When air was re-
placed with pure O2, the reaction still performed well with-
in same reaction time, but gave a lower yield (entry 7). In a
series of control experiments in the absence of the photo-
DOI: 10.1055/s-0035-1561393; Art ID: st-2015-w0902-l
Abstract A new approach to the preparation of tetrahydrofurans and
tetrahydropyrans through a photoredox catalytic process is described.
The introduction of a phenylsulfanyl auxiliary group permits the sub-
strates to be readily oxidized to form cationic intermediates for sequen-
tial intramolecular cyclization. The method features mild reaction con-
ditions and operational simplicity.
Key words photocatalysis, sulfides, cyclization, tetrahydrofurans, tet-
rahydropyrans
In recent years, the synthesis of tetrahydrofurans and
tetrahydropyrans has attracted considerable research inter-
est, as these moieties are common structural cores in a
broad range of bioactive natural products.1 Diols,2 al-
kanols,2f,3 alkenols,4 and furans5 have been developed as
precursors for constructing the furan skeleton by Lewis acid
or metal-catalyzed reactions. As part of the progress they
have achieved in visible-light photoredox catalysis in or-
ganic synthesis,6 chemists have developed several effective
methods for synthesis of tetrahydrofurans by using visible-
light photoredox catalysts (Scheme 1, a and b).7 In these re-
actions, alkenols are used as the preferred precursors, ow-
ing to their lower oxidation potentials compared with al-
kanols. As part of our continuing investigations on visible-
light-induced organic reactions,8 we were keen to develop a
new approach for the construction of the tetrahydrofuran
moiety from alkanols through prefunctionalization with an
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

B
W. Li et al.
Letter
Synlett
Mes
Previous work
R1
N
R1
(5 mol%)
Me
ClO4
R2
R2
(a)
DCE, 450 nm LED
O
HO
Nicewicz's work
EDG
EDG
CO2Et
CO2Et
photoredox cat.
DMF, blue LEDs
BrCH(CO2Et)2
+
(b)
n
HX
X
n = 1 or 2; X = O, NTs or COOH
Our previous work
R1
This work
R2
Ph
S
O
(c)
EDG
photoredox cat.
air, blue light
OX
R2
n
PhSSPh
+
n
EDG
R1
n = 1 or 2; X = H, TBS
Scheme 1 Previous work and our strategy
catalyst or of blue light, no product was obtained (entries 8
and 9), confirming that the photocatalyst and blue light are
essential for the reaction.
Table 1 Optimization of the Reaction Conditionsa
Ru(bpy)3Cl2
(5 mol%),
solvent
With the optimized reaction conditions in hand, we in-
vestigated the scope of the reaction by preparing a variety
of substrates that were then subjected to the reaction con-
ditions; the results are listed in Table 2. Substrates contain-
ing a phenyl ring bearing an electron-donating methoxy in
the para or ortho position gave the corresponding products
in good yields (Table 2, entries 1 and 2). Substrates substi-
tuted with methyl and/or tert-butyl groups were also toler-
ated under the reaction conditions to give the desired prod-
ucts, albeit in lower yields, possibly due to the higher oxida-
tion potentials of the substrates (entries 3 and 4). Similar
results were obtained in the case of a chloro substituent
(entry 9). When the substrates were di- or trisubstituted
with electron-donating groups, good to high yields were
obtained (entries 5–8 and 10–12). The structure of one of
the products, 2l, was determined by X-ray crystallographic
analysis.12 In addition to the primary alcohol, which gave
product 2a in high yield (entry 13), secondary and tertiary
alcohols also reacted efficiently to afford the corresponding
products in good yields (entries 14–16). Furthermore, this
protocol was suitable for synthesis of a tetrahydropyran
compound (entry 17).
O
S
OTBS
open to air,
blue light
O
O
1a
2a
Entry
Solvent
TFA (equiv)
Time (h)
Yieldb (%)
1
MeCN
DMF
0
0
0
0
0
2
2
2
2
6
8
75
2
57
3
DMSO
DCE
8
56
4
8
trace
85
5
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
3
6
3
94 (85)c
80
7d
8e
9f
3
12
24
0
0
a Reaction conditions: 1a (0.1 mmol), Ru(bpy)3Cl2 (5 mol%), solvent (1.0
mL), blue LEDs (6W).
b Yield determined by GC/MS with biphenyl as internal standard.
c Isolated yield.
d Reaction under O2.
e In darkness.
f No catalyst.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

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Letter
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Table 2 Scope of Phenyl Benzyl Sulfidesa,13,14
Entry
Substrate
Product
Yield(%)b
O
S
R
OTBS
R
1
2
R = 4-MeO
R = 2-MeO
R = 4-Me
2a
2b
2c
2d
2e
2f
85
73
56
60
82
87
80
85
55
71
69
3
4
R = 4-t-Bu
5
R = 2,5-(MeO)2
6
R = 3,4-(MeO)2
7
R = 3,4,5-(MeO)3
R = 3,4-methylenedioxy
R = 2-MeO-5-Cl
2g
2h
2i
8
9
10
11
R = 2-MeO-5-t-Bu
R = 4-MeO-3,5-Me2
2j
2k
12
R = 2-OMe-3,5-(t-Bu)2
72
2l
R2
R1
Ph
S
OTBS
R2
O
R1
O
O
2a
13c
14c
15c
16c
R1 = R2 = H
81
77
72
83
R1 = H, R2 = Me
R1 = H, R2 = Ph
R1 = R2 = Me
2n
2o
2p
O
S
17
82
OTBS
O
2q
O
a Reaction conditions: substrate (0.1 mmol), Ru(bpy)3Cl2 (0.5mol%), MeNO2 (1.0 mL), TFA (2.0 equiv), blue LEDs (6 W).
b Isolated yield.
c Without TFA.
To broaden the synthetic utility of this protocol, lac-
tones and a tetrahydropyrrole were synthesized by replac-
ing the hydroxy group with a carboxy or amine group, re-
spectively, in the absence of TFA. As expected, the corre-
sponding products were obtained in good yields (Scheme
2).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

D
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Letter
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To better understand the reaction mechanism, we ana-
lyzed components of the reaction mixture by GC/MS and
we identified diphenyl disulfide (3a) as a byproduct in the
synthesis of tetrahydrofuran 2a (Scheme 3, a). This result
suggests that 3a is formed through homocoupling of PhS•
radicals and that a benzyl cation is generated in situ after
oxidation through C–S bond cleavage. To confirm this hy-
pothesis, we replaced TFA with K2HPO4, which led to the
formation of styrene 4a after elimination, instead of 2a
(Scheme 3, b).
To map out the reaction mechanism, we measured the
oxidation potential of 1a, as a representative substrate; its
value was 0.72 V versus the standard calomel electrode
(SCE) in MeCN, showing that it can be oxidized by
Ru(bpy)32+ (E1/2II/I = +0.84 V vs. SCE).6a,g On the basis of these
O
Ru(bpy)3Cl2
(0.5 mol%),
MeNO2
Ph
S
O
OH
n
n
open to air,
blue light
O
O
O
1r, n = 1
1s, n = 2
2r, 76%
2s, 72%
Tos
Ru(bpy)3Cl2
(0.5 mol%),
MeNO2
Ph
N
S
H
N
Tos
open to air,
blue light
O
O
1t
2t, 68%
Scheme 2 Syntheses of lactones and a tetrahydropyrrole13,14
results,
a
possible reaction mechanism is proposed
O
Ph
S
Ru(bpy)3Cl2 (0.5 mol%)
S
Ph
OTBS
+
Ph
S
(a)
(b)
CF3COOH (2.0 equiv)
blue LED, MeNO2
O
1a
O
2a
3a
Ph
S
OTBS
Ru(bpy)3Cl2 (0.5 mol%)
OTBS
3a
+
K2HPO4 (2.0 equiv)
blue LED, MeNO2
O
65%
1a
4a
O
Scheme 3 Preliminary mechanistic investigations
O2
O2
Ru2+
Ru+
S
OTBS
blue light
O
1a
– PhS
Ru2+
*
+
+
OH
OTBS
CF3COOH
–TBS
A
B
O
O
– H+
base
O
OTBS
4a
O
2a
O
Scheme 4 The proposed reaction mechanism
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

E
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Letter
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O
S
Ru(bpy)3Cl2 (5 mol%), MeNO2
OTBS
CF3COOH (2 equiv), open to air
Sunlight
O
O
2a
1a
5 h, 74% yield
Scheme 5 Sunlight-driven reaction for synthesis of 2a
(Scheme 4). First, the photocatalyst Ru(bpy)32+ is excited by
blue light to generate the excited species Ru(bpy)32+*, which
is then transformed into Ru(bpy)+ by acceptance of an elec-
tron from 1a to give the cationic intermediate A and a PhS•
References and Notes
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+
radical after C–S bond cleavage. Ru(bpy)3 is then oxidized
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by oxygen to regenerate Ru(bpy)32+. The TBS group is re-
moved in the presence of TFA to give the benzylic cation B,
which undergoes intramolecular cyclization to give the fi-
nal product. In the case of the addition of a base instead of
TFA, the styrene product 4a is formed through an elimina-
tion process. Another possible mechanism in which O2 acts
3+
as an oxidative quencher with oxidation of 1a by Ru(bpy)3
(E1/2III/II = +1.29 V vs. SCE) cannot be excluded (see the Sup-
porting Information).
To demonstrate the operational ease of this visible-
light-driven protocol, we performed the cyclization of 1a
under ambient sunlight (Scheme 5). As expected, this reac-
tion was less efficient than that under light from the blue
LED. Nevertheless, the sunlight-driven reaction reached
completion within five hours and gave 74% yield of desired
product 2a, which indicated a practical strategy for the di-
rect utilization of sunlight in organic synthesis.
In conclusion, we have developed a visible-light-in-
duced cyclization of phenyl benzyl sulfides by using
Ru(bpy)3Cl2 as a photoredox catalyst. This strategy provides
a mild, practical, and environmentally friendly procedure
for the preparation of tetrahydrofurans or tetrahydropy-
rans, as well as lactones or lactams. Studies on visible-light-
induced organic reactions with PhS as an auxiliary group
are ongoing in our laboratory.
Acknowledgment
We are grateful for the financial support from NSFC (Nos. 21272047,
21372055, 21302029, and 21472030), SKLUWRE (No. 2014DX01), the
Fundamental Research Funds for the Central Universities (Grant No.
HIT.BRETIV.201310), and HLJNSF (B201406)
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561393.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

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reaction mixture was allowed to warm to 0 °C and stirred for 5
h. The reaction was quenched with aq NH4Cl (20 mL) and the
mixture was extracted with Et2O (3 × 30 mL). The combined
organic layers were washed with brine (60 mL), dried (MgSO4),
and filtered. The solvent was removed in vacuo to afford a crude
product that was purified by flash chromatography (silica gel)
to give a colorless liquid; yield: 1450 mg (72%). 1H NMR (400
MHz, CDCl3): δ = 7.29–7.11 (m, 7 H), 6.79 (d, J = 7.8 Hz, 2 H),
4.11 (t, J = 6.2 Hz, 1 H), 3.77 (s, 3 H), 3.55 (t, J = 6.2 Hz, 2 H),
2.12–1.81 (m, 2 H), 1.58–1.37 (m, 2 H), 0.86 (s, 9 H), 0.00 (s, 6
H). 13C NMR (150 MHz, CDCl3): δ = 158.51, 135.12, 133.89,
132.39, 128.82, 128.59, 126.90, 113.65, 62.60, 55.19, 52.67,
32.61, 30.68, 25.93, 18.28, –5.35. GC/MS (EI, QMS): m/z (%) =
402 (<1), 345, 293, 235, 161 (100), 73.
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(12) The crystalline material 2l was prepared by a layer-to-layer dif-
fusion method. 2l was dissolved in THF and layered with
hexane. After seven days, a crystal suitable for single-crystal X-
ray diffraction was obtained. CCDC 1431990 contains the sup-
plementary crystallographic data for this paper. The data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/getstructures.
(14) Photocatalytic Cycloetherification of Phenyl Benzyl Sulfides;
General Procedure
A 10 mL round-bottomed flask equipped with a magnetic
stirrer bar was charged with the appropriate phenyl benzyl
sulfide 1 (0.1 mmol), TFA (0.15 mmol), Ru(bpy)3Cl2 (0.005
mmol), and anhyd MeNO2 (1 mL). The mixture was irradiated
with a blue LED (6 W) at r.t. for 4 h. The mixture was the filtered
through a short plug of silica gel that was rinsed with EtOAc.
The filtrate was concentrated and the residue was purified by
flash column chromatography.
2-(4-Methoxyphenyl)tetrahydrofuran (2a)
Colorless liquid; yield: 15.1 mg (85%). 1H NMR (400 MHz, CDCl3)
δ = 7.25 (d, J = 3.6 Hz, 2 H), 6.87 (d, J = 8.6 Hz, 2 H), 4.83 (t,
J = 7.2 Hz, 1 H), 4.08 (dd, J = 14.7, 7.2 Hz, 1 H), 3.91 (dd, J = 14.3,
7.9 Hz, 1 H), 3.80 (s, 3 H), 2.36–2.20 (m, 1 H), 2.11–1.94 (m, 2 H),
1.85–1.71 (m, 1 H). 13C NMR (150 MHz, CDCl3): δ = 158.76,
135.30, 126.94, 113.65, 80.42, 68.47, 55.25, 34.45, 26.05. GC/MS
(EI, QMS): m/z (%) = 178 (46), 177, 147, 136, 135 (100). HRMS
(ESI); m/z [M + H]+ calcd. for C11H15O2: 179.1072; found:
179.1067.
2-(2-Methoxyphenyl)tetrahydrofuran(2b)5f
Colorless liquid; yield: 13.0 mg (73%). 1H NMR (600 MHz, CDCl3)
δ = 7.42 (d, J = 7.5 Hz, 1 H), 7.22 (t, J = 7.7 Hz, 1 H), 6.95 (t, J = 7.4
Hz, 1 H), 6.85 (d, J = 8.1 Hz, 1 H), 5.17 (t, J = 6.9 Hz, 1 H), 4.10
(dd, J = 14.1, 7.1 Hz, 1 H), 3.92 (dd, J = 14.2, 7.4 Hz, 1 H), 2.45–
2.25 (m, 1 H), 2.02–1.86 (m, 2 H), 1.68–1.73 (m, 1 H). 13C NMR
(150 MHz, CDCl3): δ = 156.09, 132.19, 127.73, 125.55, 120.38,
109.99, 75.86, 68.50, 55.22, 33.05, 25.87. GC/MS (EI, QMS): m/z
(%) = 178 (83), 177, 147, 136, 135 (100), 119. HRMS (ESI); m/z
[M + Na]+ calcd. for C11H14NaO2: 201.0891; found: 201.0881.
(15) Smith, A. B. III; Tong, R. Org. Lett. 2010, 12, 1260.
(13) tert-Butyl[4-(4-methoxyphenyl)-4-(phenylsulfa-
nyl)butoxy]dimethylsilane (1a); Typical Procedure15
TMEDA (0.70 g, 6.0 mmol) was added to a 1.6 M solution n-BuLi
in hexane (3.8 mL, 6.0 mmol) in THF (10 mL) at –30 °C, and the
mixture was stirred for 0.5 h. A solution of 1-methoxy-4-[(phe-
nylsulfanyl)methyl]benzene (1.150 g, 5.0 mmol) in THF (5 mL)
was then added dropwise, and the mixture was stirred for a
further 2 h. TBSO(CH2)3Br (1.25 g, 5.0 mmol) was added and
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F