Application of sulfuryl chloride for the quick construction of β-chlorotetrahydrofuran derivatives from homoallylic alcohols under mild conditions

Article abstract of DOI:10.1055/s-0033-1339351

An efficient and mild method is reported for the construction of β-chlorotetrahydrofuran derivatives by 5-endo chlorocycloetherification of homoallylic alcohols. The system employs sulfuryl chloride as the chlorinating agent under catalyst-free conditions. A variety of homoallylic alcohols with aryl or alkyl substituents were smoothly converted into β- chlorotetrahydrofurans in yields up to 98%.

Full text of DOI:10.1055/s-0033-1339351

PAPER
▌2391
paper
Application of Sulfuryl Chloride for the Quick Construction of β-Chlorotetra-
hydrofuran Derivatives from Homoallylic Alcohols under Mild Conditions
5-endo Chlorocycloetherification of Homoallylic Alcohols
Xianghua Zeng,a,b Chengxia Miao,a Shoufeng Wang,a Chungu Xia,a Wei Sun*a
a
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences,
Lanzhou, 730000, P. R. of China
Fax +86(931)8277088; E-mail: wsun@licp.cas.cn
b
University of Chinese Academy of Sciences, Beijing, 100049, P. R. of China
Received: 28.03.2013; Accepted after revision: 13.06.2013
Based on these literature reports, we speculated that sulfu-
Abstract: An efficient and mild method is reported for the con-
ryl chloride is a potentially promising chlorinating reagent
struction of β-chlorotetrahydrofuran derivatives by 5-endo chloro-
for the preparation of β-chlorotetrahydrofurans. Herein,
we discuss the rapid construction of β-chlorotetrahydrofu-
cycloetherification of homoallylic alcohols. The system employs
sulfuryl chloride as the chlorinating agent under catalyst-free con-
ditions. A variety of homoallylic alcohols with aryl or alkyl substit- ran derivatives by intramolecular electrophilic 5-endo cy-
uents were smoothly converted into β-chlorotetrahydrofurans in
yields up to 98%.
clization of homoallylic alcohols employing sulfuryl
chloride as the chlorinating agent under mild conditions.
Key words: homoallylic alcohols, sulfuryl chloride, 5-endo cycli-
zation, tetrahydrofuran
Importantly, this method is straightforward and does not
use additives or catalysts, in comparison to both our pre-
vious and literature reports,10–12 and it also tolerates sub-
strates containing heteroatoms.
Substituted tetrahydrofurans are useful intermediates and
important structural motifs in biologically active com-
pounds.1 The development of efficient methods for the
synthesis of tetrahydrofuran derivatives, by the intramo-
lecular hydroalkoxylation of allenes,2 intramolecular oxi-
dative C–O bond formation,3 Prins,4 anodic,5 [3+2],6
radical,7 or Heck and reductive-type8 cyclization, among
others, has received considerable attention. Notably,
among the many available methods, electrophilic halocy-
clizations of olefins, in which electrophilic halonium ions
are generated from olefins and opened intramolecularly
by nucleophilic functional groups, are valuable synthetic
transformations for the synthesis of biologically relevant
molecules; β-chlorotetrahydrofuran derivatives are com-
mon structural motifs found in many natural products
(Figure 1).9 Additionally, the method not only realizes
ring formation, but also introduces a new functional group
that favors further transformations. Denmark and co-
workers have reported Lewis base catalyzed bromo- and
iodocycloetherification reactions of unsaturated alcohols
to obtain tetrahydropyran and tetrahydrofuran derivatives
using N-iodosuccinimide or N-bromosuccinimide as a ha-
logenating reagent.10,11 To date, few reaction systems for
chlorocycloetherification have been developed,12 al-
though bromo- and iodocycloetherification reactions of
unsaturated substrates have made significant progress.13–16
Sulfuryl chloride can be used for the acylation of alcohols
and amines, the conversion of carboxylic acid salts to acid
chlorides or anhydrides, and various condensation reac-
tions. On the other hand, it is also used as chlorinating and
sulfonating agent for aromatic or aliphatic compounds.17–20
Br
Cl
Cl
H
H
Br
H
O
O
O
Br
H
H
O
notoryne
obtusallene II
Cl
H
H
Br
Br
H
O
O
obtusallene IV
Figure 1 Biologically active β-chlorotetrahydrofurans
In our previous report, chlorocycloetherification was per-
formed using N-chlorosuccinimide as the chlorinating re-
agent together with 4-toluenesulfonamide as an additive.
N-Chloro-4-toluenesulfonamide (TsNHCl) derived from
exchange of chlorine from N-chlorosuccinimide to 4-tolu-
enesulfonamide was observed by 1H NMR (CDCl3).12,21–23
However, 1a as the model substrate showed low reactivity
with solely N-chlorosuccinimide as the chlorine source
under catalyst- or additive-free conditions in the synthesis
of β-chlorotetrahydrofuran derivative 2a; prolonging the
reaction time to 48 hours gave 2a in only 11% yield (Table
1, entries 1 and 2). In order to develop a practicable, rapid
method, various chlorinating agents such as thionyl chlo-
ride, chloramine T, and phosphorus pentachloride were
examined in place of N-chlorosuccinimide (entries 3–7).
Thionyl chloride and chloramine T were inert in the chlo-
rocycloetherification reaction (entries 3 and 4). However,
using sulfuryl chloride as the chlorinating gave β-chloro-
SYNTHESIS 2013, 45, 2391–2396
Advanced online publication: 22.07.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
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DOI: 10.1055/s-0033-1339351; Art ID: SS-2013-H0246-OP
© Georg Thieme Verlag Stuttgart · New York

2392
X. Zeng et al.
PAPER
tetrahydrofuran derivative 2a in up to 96% yield within 10 and 2p were obtained in 88% and 81% yields, respectively
minutes (entry 6). 1,3,5-Trichloroisocyanuric acid (TCICA) (entries 15 and 16). Additionally, the effect of the substi-
also resulted in a comparable yield (entry 7). Different tuted group on the C=C or C–O bond was examined. Grat-
solvents were examined for the reaction using sulfuryl ifyingly, chlorocyclization products 2q,r were obtained in
chloride as the chlorine source (entries 6, 8–10), and the good yields from the substrates containing a substituted
best result was obtained in dichloromethane. The 5-endo group on the C–O bond (entries 17 and 18). However, re-
chloroetherification of (E)-homoallylic alcohols will usu- action of substrate 1s with a substituent on the C=C bond
ally result in the trans isomer, and this was identified by under identical reaction conditions was unsuccessful (en-
comparison with previous reports.10,12,24
try 19). To further explore the substrate scope, a longer-
chain alcohol 5-phenylpent-4-en-1-ol (1t) was utilized for
the construction of a larger-ring system via 6-endo chlo-
roetherification, both 6-endo- 2t1 and 5-exo-cyclization
products 2t2 were isolated as a 1.3:1 mixture (entry 20).
Finally, the activity of aliphatic homoallylic alcohol 1u
was examined and the product 2u was obtained in 73%
yield (entry 21). To further evaluate the preparative utility
of this methodology, the Z-configured olefin 1v was also
investigated. Encouragingly, the yield of the cyclization
of 1v was nearly the same as that of E-configured olefin
1a (entry 1 vs 22); however, the product 2v should be cis
configuration.12
Table 1 Screening of Chlorinating Agents for the Chlorocycloether-
ification of 1aa
O
chlorine source
solvent, r.t.
OH
Cl
1a
2a
Entry Chlorine source
(equiv)
Solvent
Time
(min)
Yieldb
(%) of 2a
1
2
NCS (1.05)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
THF
10
48 h
10
10
10
10
10
10
10
10
trace
11
0
Table 2 Synthesis of β-Chlorotetrahydrofuran Derivativesa
NCS (1.05)
3
SOCl2 (0.51)
chloramine T (1.1)
PCl5 (0.21)
R2 .
R2
4
0
SO2Cl2
R1
Cl
R4
R3
O
OH
R4
R1
5
85
96
93
91
86
35
CH2Cl2, r.t., 10 min
R3
6
SO2Cl2 (0.51)
TCICA (0.34)
SO2Cl2 (0.51)
SO2Cl2 (0.51)
SO2Cl2 (0.51)
2a–v
1a–v
7
Entry Substrate
Product
Yieldb
(%)
8
9
O
OH
10
EtOAc
R
R
a Reaction conditions: 1a (0.2 mmol), chlorinating agent, anhyd sol-
Cl
vent (1.0 mL), r.t.
1
2
1a, R = Ph
2a
2b
2c
2d
2e
2f
96
97
96
90
94
92
97
91
98
89
91
94
85
95
88
b Isolated yield.
1b, R = 4-MeC6H4
1c, R = 3-MeC6H4
1d, R = 2-MeC6H4
1e, R = 4-ClC6H4
1f, R = 3-ClC6H4
1g, R = 2-ClC6H4
1h, R = 2,6-ClC6H43
1i, R = 4-BrC6H4
1j, R = 3-BrC6H4
1k, R = 2-BrC6H4
1l, R = 4-FC6H4
With the optimized conditions in hand, we next investi-
gated various substituted homoallylic alcohols to explore
the application and the substrate scope of the reaction; the
results are summarized in Table 2. To explore the influ-
ence of steric and electronic properties of the substituent
on the aryl group, we first examined a series of substrates
with substituted phenyl groups in the chlorocycloetherifi-
cation reaction (entries 1–14). The reactivities of the ho-
moallylic alcohols 1a–n were not significantly affected by
the electronic properties and steric hindrance of the sub-
stituents on the benzene ring and the corresponding prod-
ucts 2a–n were obtained in up to 98% yield. Even a
substrate such as 1m with a strong electron-donating
group in the para position provided the chlorocycloether-
ification product 2m in 85% yield (entry 13). Similarly,
substrate 1n containing the strong electron-withdrawing
naphthalene group gave the product 2n in 95% yield (en-
try 14). The system was also applicable to intramolecular
electrophilic chlorocyclizations of substrates with hetero-
aromatic rings, such as 1o,p, and the desired products 2o
3
4
5
6
7
2g
2h
2i
8
9
10
11
12
13
14
15
2j
2k
2l
1m, R = 4-Me2NC6H4
1n, R = 1-naphthyl
1o, R = 2-thienyl
2m
2n
2o
Synthesis 2013, 45, 2391–2396
© Georg Thieme Verlag Stuttgart · New York

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5-endo Chlorocycloetherification of Homoallylic Alcohols
2393
Table 2 Synthesis of β-Chlorotetrahydrofuran Derivativesa
(continued)
action occurred as shown by GC/MS using sulfuryl chlo-
ride as the chlorinating reagent and employing N-
iodosuccinimide as the halogen source led to 2w and 2x in
90% and 87% yields, respectively (Scheme 1); the relative
configuration of these compounds can not be determined.
R2 .
R2
SO2Cl2
R1
Cl
R4
R3
O
OH
R4
R1
CH2Cl2, r.t., 10 min
R3
O
2a–v
1a–v
OH
Entry Substrate
Product
Yieldb
(%)
X
1w
2w
halogen source
16
17
1p, R = 4-pyridyl
2p
2q
81
r.t., CH2Cl2
OH
O
O
OH
OH
OH
X
1x
2x
87
Cl
ClSO2Cl: X = Cl, no product
NBS: X = Br, trace
NIS: X = I, 2w: 90%; 2x: 87%
1q
1r
Scheme 1 Construction of polycyclic compounds
O
O
In summary, we have developed an efficient and mild
method for the construction of β-chlorotetrahydrofuran
derivatives by 5-endo chlorocycloetherification of
homoallylic alcohols using sulfuryl chloride as the chlori-
nating reagent under catalyst-free conditions. Trans-
formation of the thus formed C–Cl bond may serve as
convenient strategy for synthesis of more potent and se-
lective tetrahydrofuran derivatives; the construction poly-
cyclic compounds is under investigation.
18
91
Cl
Cl
2r
2s
c
19
20
–
1s
1t
O
OH
92d
(2t1/2t2
1.3:1)
All chemicals were purchased as reagent grade and used without
further purification, unless otherwise noted. CH2Cl2 was distilled
over CaH2. Nuclear magnetic resonance (1H NMR and 13C NMR)
spectra were obtained on a Bruker Avance III 400 MHz spectrome-
ter; reported downfield from internal TMS. HRMS (ESI) was deter-
mined on a Bruker Daltonics micrOTOF-QII or a Bruker Daltonics
APEX II 47e FT-ICR mass spectrometer. GC-MS was measured on
Agilent 7890A/5975C spectrometer. Silica gel (200–300 mesh) was
used for column chromatography and TLC inspection was on silica
gel GF254 plates.
Cl
2t1
2t2
2u
2v
Cl
O
O
O
β-Chloroetherification; General Procedure
OH
To a soln of homoallylic alcohols (0.2 mmol) in anhyd CH2Cl2 un-
der an argon atmosphere, the corresponding chlorine source (0.51 or
1.05 equiv) was added, and the mixture was stirred for 10 min or the
given time at r.t. Then the reaction was quenched by addition of sat.
aq Na2S2O3 (1.0 mL) and extracted with CH2Cl2 (3 × 5 mL). The
combined organic layers were dried (Na2SO4) and the solvents were
removed under reduced pressure. Finally, the residue was purified
with flash chromatography (EtOAc–petroleum ether, 1:20) to give
the desired product.
21
22
73
94
Cl
Cl
1u
1v
OH
trans-3-Chloro-2-phenyltetrahydrofuran (2a)12
Colorless oil; yield: 34.9 mg (96%).
1H NMR (400 MHz, CDCl3): δ = 7.33–7.38 (m, 5 H), 5.01 (d,
J = 4.0 Hz, 1 H), 4.25–4.30 (m, 1 H), 4.17–4.23 (m, 2 H), 2.43–2.52
(m, 1 H), 2.18–2.25 (m, 1 H).
a Reaction conditions: 1a–v (0.20 mmol), SO2Cl2 (0.21 mmol),
CH2Cl2 (1.0 mL), r.t., 10 min.
b Isolated yield.
c No reaction.
d The total yield of 6-endo and 5-exo.
13C NMR (100 MHz, CDCl3): δ = 139.9, 128.6, 128.1, 125.6, 88.3,
67.3, 63.2, 35.6.
trans-3-Chloro-2-p-tolyltetrahydrofuran (2b)12
Colorless oil; yield: 38.0 mg (97%).
Meanwhile, 1w and 1x were also employed as substrates
to construct polycyclic compounds. Unfortunately, no re-
© Georg Thieme Verlag Stuttgart · New York
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2394
X. Zeng et al.
PAPER
1H NMR (400 MHz, CDCl3): δ = 7.26 (d, J = 8.0 Hz, 2 H), 7.17 (d,
J = 8.0 Hz, 2 H), 4.98 (d, J = 4.0 Hz, 1 H), 4.24–4.29 (m, 1 H),
4.15–4.21 (m, 2 H), 2.42–2.52 (m, 1 H), 2.35 (s, 3 H), 2.17–2.24 (m,
1 H).
13C NMR (100 MHz, CDCl3): δ = 136.7, 135.9, 128.2, 124.5, 87.2,
66.2, 62.2, 34.6, 20.1.
13C NMR (100 MHz, CDCl3): δ = 138.9, 131.6, 127.3, 121.9, 87.5,
67.3, 62.8, 35.6.
trans-2-(3-Bromophenyl)-3-chlorotetrahydrofuran (2j)
Colorless oil; yield: 46.5 mg (89%).
1H NMR (400 MHz, CDCl3): δ = 7.53 (s, 1 H), 7.43 (d, J = 3.6 Hz,
1 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.21–7.25 (m, 1 H), 4.95 (d, J = 4.4
Hz, 1 H), 4.23–4.29 (m, 1 H), 4.13–4.21 (m, 2 H), 2.41–2.51 (m, 1
H), 2.19–2.26 (m, 1 H).
trans-3-Chloro-2-m-tolyltetrahydrofuran (2c)12
Colorless oil; yield: 37.6 mg (96%).
1H NMR (400 MHz, CDCl3): δ = 7.24 (s, 1 H), 7.11–7.18 (m, 3 H),
4.99 (d, J = 4.4 Hz, 1 H), 4.25–4.30 (m, 1 H), 4.16–4.24 (m, 2 H),
2.47–2.52 (m, 1 H), 2.36 (s, 3 H), 2.17–2.24 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 141.3, 135.4, 130.1, 129.1, 127.6,
123.2, 86.4, 66.4, 61.8, 34.6.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C10H10ClBrONa:
282.9496; found: 282.9508.
13C NMR (100 MHz, CDCl3): δ = 139.9, 138.3, 128.8, 128.5, 126.2,
122.7, 88.3, 67.3, 63.3, 35.6, 21.5.
trans-2-(2-Bromophenyl)-3-chlorotetrahydrofuran (2k)
trans-3-Chloro-2-o-tolyltetrahydrofuran (2d)12
Colorless oil; yield: 35.3 mg (90%).
1H NMR (400 MHz, CDCl3): δ = 7.33–7.35 (m, 1 H), 7.17–7.22 (m,
3 H), 5.31 (d, J = 2.4 Hz, 1 H), 4.36–4.41 (m, 1 H), 4.23–4.30 (m, 2
H), 2.36–2.40 (m, 4 H), 2.16–2.22 (m, 1 H).
Colorless oil; yield: 47.5 mg (91%).
1H NMR (400 MHz, CDCl3): δ = 7.54–7.57 (m, 1 H), 7.30–7.40 (m,
2 H), 7.14–7.18 (m, 1 H), 5.42 (s, 1 H), 4.41–4.45 (m, 2 H), 4.30–
4.37 (m, 1 H), 2.23–2.33 (m, 1 H), 2.14–2.19 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 139.1, 131.9, 128.4, 126.5, 126.1,
120.7, 87.2, 67.2, 62.2, 33.2.
13C NMR (100 MHz, CDCl3): δ = 138.9, 134.9, 130.5, 127.8, 126.1,
124.9, 86.5, 67.7, 63.2, 35.1, 19.5.
GC/MS (EI): m/z = 260.0.
trans-3-Chloro-2-(4-chlorophenyl)tetrahydrofuran (2e)12
trans-3-Chloro-2-(4-fluorophenyl)tetrahydrofuran (2l)12
Colorless oil; yield: 40.7 mg (94%).
Colorless oil; yield: 37.6 mg (94%).
1H NMR (400 MHz, CDCl3): δ = 7.30–7.37 (m, 4 H), 4.94 (d,
J = 4.4 Hz, 1 H), 4.22–4.28 (m, 1 H), 4.10–4.21 (m, 2 H), 2.41–2.50
(m, 1 H), 2.18–2.25 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 138.4, 133.8, 128.7, 126.9, 87.5,
67.3, 62.9, 35.6.
1H NMR (400 MHz, CDCl3): δ = 7.33–7.37 (m, 2 H), 7.03–7.08 (m,
2 H), 4.93 (d, J = 4.8 Hz, 1 H), 4.11–4.28 (m, 3 H), 2.43–2.53 (m, 1
H), 2.19–2.26 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 162.5 (d, J = 245 Hz), 135.6 (d,
J = 3 Hz), 127.3 (d, J = 9 Hz), 115.4 (d, J = 21 Hz), 87.6, 67.2, 62.9,
35.6.
trans-3-Chloro-2-(3-chlorophenyl)tetrahydrofuran (2f)12
Colorless oil; yield: 39.7 mg (92%).
1H NMR (400 MHz, CDCl3): δ = 7.15–7.18 (m, 4 H), 4.85 (d,
J = 4.4 Hz, 1 H), 4.12–4.18 (m, 1 H), 4.03–4.10 (m, 2 H), 2.30–2.39
(m, 1 H), 2.07–2.14 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 142.1, 134.6, 129.8, 128.2, 125.7,
123.8, 87.5, 67.4, 62.9, 35.6.
trans-4-(3-Chlorotetrahydrofuran-2-yl)-N,N-dimethylaniline
(2m)
Colorless oil; yield: 38.4 mg (85%).
1H NMR (400 MHz, CDCl3): δ = 7.22 (d, J = 8.4 Hz, 2 H), 6.75 (br,
2 H), 4.91 (d, J = 4.4 Hz, 1 H), 4.20–4.26 (m, 1 H), 4.12–4.19 (m, 2
H), 2.96 (s, 6 H), 2.44–2.53 (m, 1 H), 2.16–2.23 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 143.8, 125.7, 125.2, 111.7, 87.2,
66.0, 62.2, 41.1, 34.6.
trans-3-Chloro-2-(2-chlorophenyl)tetrahydrofuran (2g)12
Colorless oil; yield: 42.0 mg (97%).
GC/MS (EI): m/z = 225.1.
1H NMR (400 MHz, CDCl3): δ = 7.35–7.41 (m, 3 H), 7.27–7.33 (m,
1 H), 5.46 (s, 1 H), 4.38–4.45 (m, 2 H), 4.29–4.36 (m, 1 H), 2.24–
2.29 (m, 1 H), 2.15–2.23 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 138.5, 131.9, 129.6, 129.1, 126.9,
126.9, 86.4, 68.1, 63.0, 34.4.
trans-3-Chloro-2-(naphthalen-1-yl)tetrahydrofuran (2n)
Colorless oil; yield: 44.1 mg (95%).
1H NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 7.6 Hz, 1 H), 7.88 (d,
J = 7.6 Hz, 1 H), 7.80 (d, J = 8.0 Hz, 1 H), 7.51–7.61 (m, 3 H),
7.45–7.49 (m, 1 H), 5.89 (s, 1 H), 4.46–4.51 (m, 2 H), 4.36–4.42 (m,
1 H), 2.33–2.42 (m, 1 H), 2.19–2.24 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 136.3, 133.7, 130.1, 128.9, 128.4,
126.6, 125.8, 125.3, 123.1, 122.7, 86.8, 67.8, 63.7, 35.0.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C14H13ClONa:
255.0547; found: 255.0554.
trans-3-Chloro-2-(2,6-dichlorophenyl)tetrahydrofuran (2h)
Colorless oil; yield: 45.7 mg (91%).
1H NMR (400 MHz, CDCl3): δ = 7.33 (d, J = 8.0 Hz, 2 H), 7.17–
7.21 (m, 1 H), 5.67 (d, J = 7.2Hz, 1 H), 4.75–4.80 (m, 1 H), 4.26–
4.30 (m, 1 H), 4.10–4.15 (m, 1 H), 2.73–2.82 (m, 1 H), 2.30–2.38
(m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 167.7, 135.8, 130.9, 129.9, 129.5,
128.9, 84.6, 67.9, 59.1, 37.5.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C10H9Cl3ONa:
272.9611; found: 272.9616.
trans-3-Chloro-2-(thiophen-2-yl)tetrahydrofuran (2o)
Colorless oil; yield: 33.3 mg (88%).
1H NMR (400 MHz, CDCl3): δ = 7.27 (d, J = 1.2 Hz, 1 H), 7.03 (d,
J = 3.6 Hz, 1 H), 6.98–7.00 (m, 1 H), 5.22 (d, J = 4.0 Hz, 1 H),
4.25–4.32 (m, 1 H), 4.13–4.24 (m, 2 H), 2.52–2.61 (m, 1 H), 2.21–
2.28 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 143.3, 127.0, 125.1, 124.4, 84.8,
67.2, 62.9, 35.7.
trans-2-(4-Bromophenyl)-3-chlorotetrahydrofuran (2i)12
Colorless oil; yield: 51.0 mg (98%).
1H NMR (400 MHz, CDCl3): δ = 7.48 (d, J = 8.8 Hz, 2 H), 7.25 (d,
J = 8.4 Hz, 2 H), 4.92 (d, J = 4.8 Hz, 1 H), 4.22–4.27 (m, 1 H),
4.16–4.20 (m, 1 H), 4.10–4.14 (m, 1 H), 2.41–2.50 (m, 1 H), 2.18–
2.25 (m, 1 H).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C8H9ClSONa:
210.9955; found: 211.9953.
Synthesis 2013, 45, 2391–2396
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5-endo Chlorocycloetherification of Homoallylic Alcohols
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trans-4-(3-Chlorotetrahydrofuran-2-yl)pyridine (2p)
Colorless oil; yield: 29.8 mg (81%).
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C11H13ClONa:
219.0547; found: 219.0549.
1H NMR (400 MHz, CDCl3): δ = 8.62 (d, J = 6.0 Hz, 2 H), 7.48 (d,
J = 6.0 Hz, 2 H), 4.99 (d, J = 4.8 Hz, 1 H), 4.20–4.27 (m, 2 H),
4.12–4.19 (m, 1 H), 2.42–2.51 (m, 1 H), 2.23–2.30 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 151.5, 147.7, 121.2, 86.3, 67.6,
61.9, 35.8.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C9H11ClNO: 184.0524;
found: 184.0521.
trans-3-Chloro-2-cyclohexyltetrahydrofuran (2u)12
Colorless oil; yield: 27.5 mg (73%).
1H NMR (400 MHz, CDCl3): δ = 4.12–4.16 (m, 1 H), 3.87–3.99 (m,
2 H), 3.69–3.72 (m, 1 H), 2.28–2.34 (m, 1 H), 2.10–2.15 (m, 1 H),
1.68–1.79 (m, 7 H), 1.17–1.25 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 91.8, 66.4, 58.7, 41.3, 37.1, 29.3,
28.6, 26.4, 26.0, 25.9.
3-Chloro-5-methyl-2-phenyltetrahydrofuran (2q)
cis-3-chloro-2-phenyltetrahydrofuran (2v)12
Colorless oil; yield: 34.3 mg (87%); ratio cis/trans 2.5:1.
Colorless oil; yield: 34.3 mg (94%).
1H NMR (400 MHz, CDCl3): δ (cis) = 7.35–7.43 (m, 5 H), 4.98 (d,
J = 6.8 Hz, 1 H), 4.23–4.51 (m, 1 H), 4.12–4.20 (m, 1 H), 2.67–2.73
(m, 1 H), 1.96–2.05 (m, 1 H), 1.44 (d, J = 6.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ (cis) = 139.7, 128.5, 128.1, 125.9,
86.5, 74.8, 62.3, 43.8, 22.0.
1H NMR (400 MHz, CDCl3): δ (trans) = 7.29–7.33 (m, 5 H), 5.00
(d, J = 4.4 Hz, 1 H), 4.23–4.51 (m, 1 H), 4.12–4.20 (m, 1 H), 2.25–
2.31 (m, 1 H), 2.05–2.12 (m, 1 H), 1.45 (d, J = 6.0 Hz, 3 H).
1H NMR (400 MHz, CDCl3): δ = 7.33–7.39 (m, 4 H), 7.29–7.32 (m,
1 H), 5.01 (d, J = 4.4 Hz, 1 H), 4.25–4.30 (m, 1 H), 4.17–4.23 (m, 2
H), 2.42–2.52 (m, 1 H), 2.18–2.25 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 140.0, 128.6, 128.1, 125.6, 88.3,
67.3, 63.2, 35.6.
3a-Iodooctahydrobenzofuran (2w)
Colorless oil; yield: 45.4 mg (90%).
1H NMR (400 MHz, CDCl3): δ = 4.04–4.06 (m, 1 H), 3.97 (q,
J = 8.0 Hz, 1 H), 3.86–3.92 (m, 1 H), 2.60–2.67 (m, 1 H), 2.39–2.45
(m, 1 H), 1.98–2.07 (m, 2 H), 1.83–1.89 (m, 2 H), 1.62–1.70 (m, 2
H), 1.49–1.54 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ (trans) = 140.0, 128.5, 128.1,
125.8, 89.0, 77.2, 63.8, 43.3, 20.3.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C11H13ClONa:
219.0547; found: 219.0543.
13C NMR (100 MHz, CDCl3): δ = 84.4, 65.5, 45.5, 39.3, 30.4, 24.7,
23.5, 20.0.
trans-4-Chloro-2,2-dimethyl-5-phenyltetrahydrofuran (2r)
Colorless oil; yield: 38.4 mg (91%).
GC/MS (EI): m/z = 252.0.
1H NMR (400 MHz, CDCl3): δ = 7.43–7.45 (m, 2 H), 7.31–7.39 (m,
3 H), 4.87 (d, J = 8.0 Hz, 1 H), 4.03–4.09 (m, 1 H), 2.47–4.52 (m, 1
H), 2.16–2.21 (m, 1 H), 1.47 (s, 3 H), 1.43 (s, 3 H).
3a-Iodohexahydro-2H-cyclopenta[b]furan (2x)
Colorless oil; yield: 41.4 mg (87%).
1H NMR (400 MHz, CDCl3): δ = 4.78 (d, J = 6.0 Hz, 1 H), 3.90–
3.94 (m, 1 H), 3.72–3.78 (m, 1 H), 2.58–2.63 (m, 1 H), 2.18–2.27
(m, 3 H), 1.87–1.90 (m, 2 H), 1.72–1.74 (m, 1 H), 1.57–1.72 (m, 1
H).
13C NMR (100 MHz, CDCl3): δ = 139.0, 128.5, 126.3, 121.7, 86.5,
80.5, 61.9, 48.9, 29.5, 28.7.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C12H15ClONa:
233.0704; found: 233.0714.
13C NMR (100 MHz, CDCl3): δ = 96.2, 67.3, 47.8, 47.6, 47.2, 32.0,
24.6.
3-Chloro-2-phenyltetrahydro-2H-pyran (2t1)
Colorless oil; yield: 22.4 mg (52%); ratio cis/trans 1:1.
GC/MS (EI): m/z = 238.0.
1H NMR (400 MHz, CDCl3): δ (cis) = 7.32–7.42 (m, 5 H), 4.66 (d,
J = 0.8 Hz, 1 H), 4.18–4.24 (m, 1 H), 3.51–3.61 (m, 2 H), 2.04–2.48
(m, 4 H).
Acknowledgment
13C NMR (100 MHz, CDCl3): δ (cis) = 138.5, 128.6, 128.0, 125.7,
80.5, 69.1, 61.0, 35.2, 27.2.
This work was supported by the National Natural Science Founda-
tion of China (21073210, 21133011 and 21103207).
1H NMR (400 MHz, CDCl3): δ (trans) = 7.32–7.42 (m, 5 H), 4.35
(s, 1 H), 4.07–4.11 (m, 1 H), 3.51–3.61 (m, 2 H), 2.04–2.48 (m, 4
H).
13C NMR (100 MHz, CDCl3): δ (trans) = 138.5, 128.5, 127.6,
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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127.5, 80.5, 69.1, 59.6, 32.3, 19.7.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C11H13ClONa:
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219.0547; found: 219.0549.
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