4-(Dimethylamino)pyridine-catalysed iodolactonisation of γ,δ-unsaturated carboxylic acids

Article abstract of DOI:10.1039/c5ob00806a

4-(Dimethylamino)pyridine functioned as an excellent catalyst for iodolactonisation reactions of γ,δ-unsaturated carboxylic acids, affording γ-lactones, δ-lactones, or both under neutral conditions at room temperature. The effects of substrate structures

Full text of DOI:10.1039/c5ob00806a

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DOI: 10.1039/C5OB00806A
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4‐(Dimethylamino)pyridine‐Catalysed Iodolactonisation of γ,δ‐
Unsaturated Carboxylic Acids
Received 00th January 20xx,
Accepted 00th January 20xx
Chuisong Meng, Zhihui Liu, Yuxiu Liu*, and Qingmin Wang*
4‐(Dimethylamino)pyridine functioned as an excellent catalyst for iodolactonisation reactions of γ,δ‐unsaturated carboxylic
acids, affording γ‐lactones, δ‐lactones, or both under neutral conditions at room temperature. The effects of substrate
structure on the iodolactonisation were investigated, and a catalytic mechanism is proposed.
DOI: 10.1039/x0xx00000x
www.rsc.org/
lower.5
He
also
developed
some
asymmetric
Introduction
bromolactonisation system by using amino‐thiocarbamate
catalysts.6
Five or six‐membered lactones (γ‐ or δ‐lactones) are present in
a wide variety of natural products, and they also serve as
building blocks and intermediates for the synthesis of natural
products and pharmaceuticals. 1 Several strategies have been
developed for the formation of lactones; among them,
halolactonisation of unactivated olefins is a powerful, widely
used method, since the resultant halogens on the lactones can
provide flexible handles for further functionalisation. The
reaction usually adopts olefinic acids as substrates and N‐
halosuccinimide as the halogen source, but the need for low
temperature and the narrow substrate scope hinder the
practical applications of this method.2 Fortunately the
combination of proper catalyst and halogen source have been
found to accelerate the reaction, allow wider substrate scopes,
or provide higher enantiomeric excesses. For example,
DMAP has frequently been used to catalyse chemical
reactions such as acylations,7 esterifications,8 Baylis–Hillman
reactions,9 and some other reactions.10 Recently, as part of our
ongoing investigation of the applications of DMAP in organic
chemistry,7e we discovered that DMAP could act as an
excellent catalyst for the iodolactonisation of γ,δ‐unsaturated
carboxylic acids with NIS as the iodonium source to form γ‐
and δ‐lactones in high yields at room temperature, with
reaction times ranging from 10 min to 2.5 h. Herein, we report
the optimisation of the DMAP‐catalysed iodolactonisation and
the detailed investigation of the substrate scope, and a
reasonable mechanism based on the results of preliminary
NMR spectroscopy studies is proposed.
Rousseau and co‐workers adopted
collidine)iodine(I) hexafluorophosphate as the iodonium
a reactive bis(sym‐
Results and Discussion
The reaction conditions (solvent and catalyst concentration)
were optimised with 4‐pentenoic acid (1a) as a model
substrate (Table 1). In dichloromethane in the absence of
catalyst, 1a was completely consumed within 2 h at room
temperature, and the reaction proceeded via a 5‐exo
cyclisation to generate γ‐lactone 2a in 74% yield (entry 1).
When 10 mol % DMAP was added to the reaction mixture, the
reaction time was markedly shorter (10 min), and the yield
increased to 99% (entry 2). A survey of other solvents (entries
3–8) revealed that the best results were obtained in
dichloromethane. When the catalyst loading was reduced to 5
mol %, the reaction time increased to 30 min and the yield
decreased slightly (entry 9). Therefore, all subsequent
reactions were performed with 10 mol % DMAP at room
temperature in dichloromethane.
source to accomplish the medium‐sized iodolactone
formation;3
Gao
accomplished
enantioselective
iodolactonisations of trans‐5‐aryl‐4‐pentenoic acids with
moderate enantiomeric excesses by using noncommercial
chiral quaternary ammonium salts as chiral phase‐transfer
catalysts and N‐iodosuccinimide (NIS) as iodonium source;4
Yeung found the zwitterion formed from 3,5‐
(bistrifluoromethyl)phenyl
isothiocyanate
and
N,N‐
dimethylaminopyridine (DMAP) could be used in the formation
of seven‐ to nine‐membered ring size lactones; however, when
using N‐chlorosuccinimide (NCS) and NIS instead of N‐
bromosuccinimide (NBS), the reaction yields were much
State Key Laboratory of Elemento‐Organic Chemistry, Research Institute of
Elemento‐Organic Chemistry, Collaborative Innovation Center of Chemical Science
and Engineering (Tianjin)
Nankai University
Tianjin 300071, People’s Republic of China
Under the optimised conditions (Table 1, entry 2), the
substrate scope of the reaction was investigated with various
5‐alkyl‐ and 5‐aryl‐4(E)‐pentenoic acids (Table 2). All the tested
substrates smoothly underwent iodolactonisation in the
presence of 10 mol % DMAP and 1.2 equiv of NIS at room
E‐mail: liuyuxiu@nankai.edu.cn, wangqm@nankai.edu.cn, wang98h@263.net
Electronic Supplementary Information (ESI) available: [GC spectra for Table 1, 1H
and 13C NMR spectra for compounds
1 and 2]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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temperature, although a longer reaction time was required for
substrates with 5‐aryl substituents. This increase in reaction
time was likely due to both steric and electronic effects. It has
previously been reported4 that the products of
iodolactonisation reactions of 4(E)‐pentenoic acids depend on
the electronic nature of the substituent at the 5‐position. In
our study, 5‐alkyl‐4(E)‐pentenoic acid substrates mainly
afforded to γ‐lactones, the structures of which were
determined by H,H‐COSY or by comparison with literature data
(entries 1 and 2). Iodolactonisation of 5‐phenyl‐4(E)‐pentenoic
acid (1d) generated both γ‐lactone 2d and δ‐lactone 3d, that is,
products arising from 5‐exo and 6‐endo cyclisation,
respectively, in a 25:75 ratio, as indicated by analysis of the 1H
NMR spectrum of the crude reaction mixture (entry 3).
Iodolactonisation of substrates with electron‐rich aromatic
rings, such as p‐methoxyphenyl (1e), 3,4‐dimethoxyphenyl (1f),
and thienyl (1g), generated only δ‐lactones (entries 4–6).
Substrates with electron‐deficient aromatic rings were well
tolerated, but they preferentially afforded γ‐lactones:
specifically, mixtures of γ‐ and δ‐lactones in ratios ranging
from 25:1 to 100:1 were generated by the iodolactonisation
reaction of 5‐(4‐chlorophenyl)‐4(E)‐pentenoic acid (1h) and the
Table 2. Iodolactonisation of 1b–m in the presence of DMAPa
DOI: 10.1039/C5OB00806A
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entry
1
substrate
time
yield
(%)b
92
product
10 min
2b
:3b
10:1
(1b)
(1c)
2
3
10 min
2 h
93
86
2c
:3c
10:1
2d:3d
1:3
(1d)
(1e)
(1f)
(1g)
O
4
5
6
7
1 h
1 h
2 h
2 h
90
92
87
84
3e
3f
OH
O
reactions of 1i
reaction conditions,
,
1j, and 1k (entries 7–10). Under the standard
substrate bearing an electron‐
a
withdrawing CF3 group at the ortho position of the aromatic
ring (1l) gave only γ‐lactone 2l (entry 11).
3g
Table 1. DMAP‐Catalysed Iodolactonisation of 1aa
2h:3h
50:1
(1h)
entry
DMAP
(mol %)
none
time
solvent
conversion
(%)b
yield (%)b
8
2.5 h
79
2i:3i
100:1
1
2
3
4
5
6
7
8
9
2 h
CH2Cl2
CH2Cl2
CH3CN
acetone
MeOH
H2O
100
74
99
90
88
96
94
95
92
95
(1i)
(1j)
9
2.5 h
2.5 h
73
76
2j:3j
20:1
10
10
10
10
10
10
10
5
10 min
10 min
10 min
10 min
10 min
10 min
10 min
30 min
100
100
100
100
100
100
100
100
10
2k:3k
50:1
(1k)
(1l)
11
12
2.5 h
2.5 h
70
75
2l
toluene
THF
2m:epimer
CH2Cl2
1:1
aReaction conditions: 1a (2.5 mmol), NIS (3 mmol, 1.2 equiv), and DMAP in 10 mL
(1m cis:trans 1:1)
of solvent. bConversion and yield determined by GC.
aReaction conditions: 1b–m (2.5 mmol), NIS (3 mmol, 1.2 equiv), and DMAP in 10
mL of CH2Cl2. bIsolated yield.
It should be mentioned that although various trans‐5‐
substituted‐4‐pentenoic acids afforded products arising from
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5‐exo or 6‐endo cyclisation, all the products had high
diastereomeric ratios because the iodolactonisation Next, we investigated the iodolactonisation reactions of 4‐
proceeded stereospecifically via trans nucleophilic addition to pentenoic acids with an aliphatic or aryl substituent at the 4‐
a cyclic iodonium intermediate.1c The relative configuration of position (Table 3). We were delighted to find that all the tested
the products is shown in Table 2. Furthermore, the fact that a substrates underwent iodolactonisation via 5‐exo cyclisation in
ARTICLE
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DOI: 10.1039/C5OB00806A
1:1 mixture of (E)‐ and (Z)‐1m afforded a pair of the presence of DMAP (10 mol %) to furnish γ‐lactones in high
diastereoisomers of 5‐exo lactone 2m in a 1:1 ratio (entry 12) yields as the only isolable products, although the 4‐aryl‐4‐
indicated that the reaction had a very high stereospecificity.
pentonic acids required slightly longer reaction times (entries 3
to 10). A substrate with a naphthyl group also underwent the
DMAP‐catalysed iodolactonisation smoothly (entry 11).
Table 3. Iodolactonisation of 1n–x in the presence of DMAPa
The good catalytic performance of DMAP in the above‐
described iodolactonisation reactions aroused our interest in
its role in the reaction. We speculated that the electron‐
donating effect of the dimethylamino substituent increased
the electron density of the pyridine ring, thus strengthening
the nucleophilicity of the pyridine nitrogen atom, which was
entry
1
substrate
time
10 min
yield (%)b
94
product
2n
1
likely to have activated NIS to some extent. We used H NMR
OH
spectroscopy to verify this speculation. The chemical shift of
the methylene hydrogen atoms of NIS was at 3.04 ppm in
deuterated chloroform, whereas the signal shifted upfield to
2.75 ppm in the presence of equimolar DMAP (Figure 1). This
result illustrates that the electron density of the dicarboximide
ring was increased by the addition of DMAP. In contrast, DMAP
and NBS could not form into a complex because no changes in
the chemical shifts were found.5 The nucleophilic nitrogen
atom of the pyridine ring of DMAP can interact with the iodine
atom of NIS, leading to an increase in the distance between
the iodine atom and the nitrogen atom of NIS and movement
of the electrons in the I–N bond toward the dicarboximide ring.
O
(1n)
2
3
4
5
6
7
10 min
2 h
94
87
89
87
86
81
2o
2p
2q
2r
(1o)
(1p)
(1q)
(1r)
(1s)
1 h
2 h
2 h
2s
2t
2.5 h
(1t)
8
2.5 h
85
2u
(1u)
(1v)
9
2.5 h
2.5 h
83
70
2v
10
2w
Figure 1. 1H NMR spectra of NIS alone (lower panel) and an equimolar mixture of DMAP
and NIS (upper panel) in deuterated chloroform 10 min after mixing.
(1w)
(1x)
With this evidence in hand, we propose the following
mechanism for the DMAP‐catalysed iodolactonisation
reactions (Scheme 1). NIS is initially activated by DMAP to form
11
2 h
84
2x
complex I, then the positively‐charged iodonium atom adds to
aReaction conditions: 1n–x (2.5 mmol), NIS (3 mmol, 1.2 equiv), and DMAP in 10
the double bond of the γ,δ‐unsaturated carboxylic acid
substrate to give iodonium intermediate II. Deprotonation of
the carboxyl group by the succinimide anion and subsequent
mL of CH2Cl2. bIsolated yield.
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nucleophilic addition of the carbonyl oxygen to cyclic iodonium binocular microscope melting point apparatus and are
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intermediate II afford the target γ‐ or δ‐lactone with uncorrected. High‐Resolution Mass SDpOecI:t1r0a.10(3H9/RCM5OSB)00w80e6reA
simultaneous release of DMAP. The 6‐endo selectivity of the obtained with an FT‐ICR MS spectrometer (Ionspec, 7.0 T).
reactions of substrates with electron‐rich aromatic rings may
Synthesis of olefinic acids.
be due to the fact that these substrates can stabilise the
developing positive charge at the benzylic position;1c,11
(E)‐5‐Alkyl‐4‐pentenoic acids (1b
–
c
), (E)‐5‐aryl‐4‐pentenoic
whereas this circumstance is unfavorable in substrates with
electron‐poor aromatic rings, so they undergo the 5‐exo mode
of ring closure. Unlike aromatic rings, alkyl substituents cannot
stabilise the developing positive charge, so alkyl‐substituted
substrates preferentially undergo the exo mode of ring closure,
which is consistent with Baldwin’s rules.12 Substrates with
substituents at the 4‐position have no choice but to undergo 5‐
exo cyclisation, owing to the instability of the primary alkyl
carbenium ions.
acids (1d
–
m
), 4‐alkyl‐4‐pentenoic acids (1n ) and 4‐aryl‐4‐
–o
pentenoic acids (1p–x) were made according to literature
procedures;6,13,14 characterisation data for new compounds is
reported in Supporting information.
General procedure for the DMAP‐catalysed iodolactonisations.
To a solution of γ‐unsaturated carboxylic acids (2 mmol, 1.0
eq), catalyst DMAP (0.2 mmol, 0.1 eq) in CH2Cl2 (10 mL) in the
dark was added NIS (2.4 mmol, 1.2 eq). The resulting mixture
was stirred at room temperature and monitored by TLC. After
the reaction was complete, reaction mixture was quenched
with saturated Na2SO3 (20 mL), diluted with water (30 mL), and
extracted with CH2Cl2 (3×10 mL). The combined extracts were
washed with brine (20 mL), dried over MgSO4, filtered, and
concentrated in vacuo. The residue was purified by flash
column chromatography to give the corresponding product.
5‐(iodomethyl)dihydrofuran‐2(3H)‐one
(2a). Colourless oil,
1
yield: 94%; H NMR (400 MHz, CDCl3): δ 4.61–4.55 (m, 1H),
3.45–3.36 (m, 2H), 2.71–2.57 (m, 2H), 2.55–2.45 (m, 1H), 2.05–
1.96 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 176.4, 78.5, 28.9,
28.1, 8.4. HRMS (ESI): calcd for C5H8IO2 [M+H]+: 226.9563;
found: 226.9561.
1‐iodoethyl)dihydrofuran‐2(3H)‐one
(
2b
)
and 5‐iodo‐6‐
methyltetrahydro‐2H‐pyran‐2‐one (3b). Colourless oil; yield:
1
92%; H NMR (400 MHz, CDCl3) for 2b: δ 4.19–4.30 (m, 2H),
2.51–2.67 (m, 2H), 2.45–2.51 (m, 1H), 1.99–2.05 (m, 1H), 1.97
(d, J = 6.2 Hz, 3H); for 3b: δ 4.60‐4.70 (m, 1H), 4.00‐4.10 (m,
1H), 2.38‐2.60 (m, 3H), 1.99–2.05 (m, 1H), 1.59 (d, J = 6.2 Hz,
3H); 13C NMR (100 MHz, CDCl3) for 2b: δ 176.4, 83.4, 29.5, 29.0,
27.9, 24.2; for 3b: 169.8, 81.7, 32.1, 30.9, 24.3, 21.5; HRMS
(ESI): calcd for C6H10IO2 [M+H]+: 240.9719; found: 240.9715.
The ratio of integrals for H‐6 of 2b and 3b was 10:1 observed
by 1H NMR spectroscopy.
Scheme 1. Proposed Mechanism of DMAP‐Catalysed Iodolactonisation.
Conclusions
In summary, we used DMAP as a unique catalyst for
iodolactonisation reactions in which DMAP served two
purposes in the catalytic cycle: it activated NIS and stabilised
the iodonium intermediate. 1H NMR spectroscopy was used to
support a proposed mechanism. With catalysis by DMAP, γ,δ‐
unsaturated carboxylic acids could be efficiently and
regioselectively converted to γ‐ or δ‐lactones under mild
conditions.
1‐iodopropyl)dihydrofuran‐2(3H)‐one
(
2c)
and 6‐ethyl‐5‐
iodotetrahydro‐2H‐pyran‐2‐one (3c). Colourless oil; yield: 93%;
1H NMR (400 MHz, CDCl3) for 2c: δ 4.41 (q, J = 7.2 Hz, 1H ),
4.11 (td, J = 7.2 Hz, J = 3.6 Hz, 2H), 2.63–2.48 (m, 3H), 2.09–
1.92 (m, 2H), 1.85–1.78 (m, 1H), 1.08 (t, J = 7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3) for 2c: δ 176.5, 81.8, 41.9, 29.1, 29.0,
28.5, 13.7; for 3c: 170.0, 85.9, 31.8, 30.8, 27.7, 22.4, 8.71;
HRMS (ESI): calcd for C7H12IO2 [M+H]+: 254.9876; found:
254.9875. The ratio of integrals for methyl of 2c and 3c was
10:1 observed by 1H NMR spectroscopy.
Experimental Section
1H NMR and 13C NMR spectra were obtained at 400 MHz using
a Bruker AV400 spectrometer in CDCl3 or DMSO‐d6 with
tetramethylsilane as the internal standard. Chemical shift
values (δ) are given in parts per million (ppm). Gas
chromatograms were obtained at SHIMADZU GC‐2014 FID
detector. The melting points were determined on an X‐4
5‐(iodo(phenyl)methyl)dihydrofuran‐2(3H)‐one (2d) and 5‐iodo‐
6‐phenyltetrahydro‐2H‐pyran‐2‐one (3d). White solid; mp:
95 °C (decomposition); yield: 86%; 1H NMR (400 MHz, CDCl3) δ
7.39–7.30 (m, 5H), 5.55 (d, J = 8.0 Hz, 0.75H), 5.13 (d, J = 8.0 Hz,
0.25H), 4.88 (q, J = 8.0 Hz, 0.25H), 4.42 (q, J = 8.0 Hz, 0.75H),
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2.89–2.81 (m, 0.75H), 2.73–2.67 (m, 0.75H), 2.60–2.53 (m, 8.0 Hz, 1H), 5.11 (d, J = 8.0 Hz, 1H), 5.03 (dd, J = 16.0 Hz, J = 8.0
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0.75H), 2.48–2.33 (m, 1.50H), 2.19–2.12 (m, 0.25H); HRMS Hz, 1H), 2.75 (dd, J = 12.0 Hz, J = 8.0 Hz, D1OHI):,120..160339(/tC, 5JO=B80.0080H6zA,
(ESI): calcd for C12H12IO2 [M+H]+: 302.9876; found: 302.9872. 2H), 2.15 (t, J = 8.0 Hz, 1H); 13C NMR (100MHz, CDCl3): δ 175.8,
The ratio of integrals for H‐6 of 2d and 3d was 1:3 observed by 148.3, 141.9, 134.2, 130.1, 123.5, 122.9, 82.0, 30.7, 29.4, 29.2;
1H NMR spectroscopy.
HRMS (ESI): calcd for C11H10INO4Na [M+Na]+: 369.9535; found:
369.9536.
5‐iodo‐6‐(4‐methoxyphenyl)tetrahydro‐2H‐pyran‐2‐one
White solid; mp: 65 °C (decomposition); yield: 90%; H NMR 5‐(iodo(2‐nitrophenyl)methyl)dihydrofuran‐2(3H)‐one (2m) and
(400 MHz, CDCl3): δ 7.25 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 8.0 Hz, its epimer. White solid; mp: 128–129 °C; yield: 75%; H NMR
(3e).
1
1
2H), 5.49 (d, J = 8.0 Hz, 1H), 4.41–4.36 (m, 1H), 3.82 (s, 3H), (400 MHz, CDCl3): 8.05 (dd, J = 8.0 Hz, J = 1.2 Hz, 0.5H), 7.92
2.87–2.79 (m, 1H), 2.74–2.66 (m, 1H), 2.55–2.47 (m, 1H), 2.46– (dd, J = 8.0 Hz, J = 1.2 Hz, 0.5H), 7.86 (ddd, J = 8.0 Hz, J = 1.2 Hz,
2.38 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 169.4, 160.2, 129.8, 1H), 7.65 (td, J = 8.0 Hz, J = 1.2 Hz, 1H), 7.47 (td, J = 8.0 Hz, J
128.2, 114.0, 86.9, 55.3, 31.0, 30.7, 24.8; HRMS (ESI): calcd for =1.2 Hz, 1H), 5.89 (d, J = 4.0 Hz, 0.73H), 5.86 (s, 0.27H), 5.17–
C12H14IO3 [M+H]+: 332.9982; found: 332.9985.
5.12 (m, 0.5H), 4.37–4.33 (m, 0.5H), 2.85–2.71 (m, 1H), 2.70–
2.62 (m, 1.44H), 2.62–2.44 (m, 0.56H), 2.26–2.05 (m, 1H).
HRMS (ESI): calcd for C11H10INO4Na [M+Na]+: 369.9535; found:
369.9536. The ratio of integrals for H‐5 of diastereoisomers of
2m was 1:1.
6‐(3,4‐dimethoxyphenyl)‐5‐iodotetrahydro‐2H‐pyran‐2‐one (3f).
White solid; mp: 50 °C (decomposition); yield: 92%; H NMR
(400 MHz, CDCl3): δ 6.90 (dd, J = 8.0 Hz, J = 2.0 Hz ,1H), 6.86 (d,
J = 8.0 Hz, 1H), 6.81 (d, J = 2.0 Hz, 1H), 5.48 (d, J = 8.0 Hz, 1H),
1
4.41 (td, J = 8.0 Hz, J = 4.0 Hz, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 4‐(iodo(5‐oxotetrahydrofuran‐2‐yl)methyl)benzonitrile (2k) and
2.87–2.79 (m, 1H), 2.75–2.67 (m, 1H), 2.54–2.39 (m, 2H). 13C 4‐(3‐iodo‐6‐oxotetrahydro‐2H‐pyran‐2‐yl)benzonitrile (3k). The
NMR (100 MHz, CDCl3): δ 169.4, 149.7, 149.1, 130.1, 119.8, ratio of integrals for H‐6 of 2k and 3k was 50:1. White solid;
1
110.8, 109.6, 87.0, 56.0, 55.9, 31.0, 30.6, 24.7; HRMS (ESI): mp: 159 °C (decomposition); yield: 76%; H NMR (400 MHz,
calcd for C13H16IO4 [M+H]+: 363.0093; found: 363.0085.
CDCl3): 7.62 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 5.05 (d, J
= 12.0 Hz, 1H), 4.97 (dd, J = 16.0 Hz, J = 8.0 Hz, 1H), 2.73–2.67
(m, 1H), 2.65–2.59 (m, 2H), 2.17–2.07 (m, 1H); 13C NMR (100
MHz, CDCl3): δ 175.8, 144.8, 132.7, 128.9, 118.3, 112.3, 81.9,
31.2, 29.3, 29.1; HRMS (ESI): calcd for C13H11INO4 [M+COOH]‐:
371.9739; found: 371.9736.
5‐iodo‐6‐(thiophen‐2‐yl)tetrahydro‐2H‐pyran‐2‐one (3g). White
1
solid; mp: 60 °C (decomposition); yield: 87%; H NMR (400
MHz, CDCl3): δ 7.38 (d , J = 8.0 Hz, 1H), 7.13 (d , J = 8.0 Hz, 1H),
7.03 (t , J = 8.0 Hz, 1H), 5.82 (t , J = 8.0 Hz, 1H), 4.49 (d , J = 4.0
Hz, 1H), 2.87–2.79 (m, 1H), 2.73–2.67 (m, 1H), 2.54–2.48 (m,
1H), 2.42–2.35 (m, 1H); 13C NMR (100 MHz, CDCl3): δ 168.5, 5‐(iodo(2‐(trifluoromethyl)phenyl)methyl)dihydrofuran‐2(3H)‐
140.6, 127.2, 126.9, 126.5, 83.1, 30.8, 30.4, 24.2; HRMS (ESI): one (2l). White solid; mp: 78–79 °C; yield: 70%; 1H NMR (400
calcd for C9H10IO2S [M+H]+: 308.9446; found: 308.9438.
MHz, CDCl3): δ 7.83 (d, J = 8.0 Hz, 1H), 7.60–7.54 (m, 2H), 7.38
(t, J = 9.2 Hz, 1H), 5.40 (d, J = 13.2 Hz, 1H), 5.06 (dd, J = 15.0 Hz,
J = 7.2 Hz, 2H), 2.72–2.58 (m, 3H), 2.22–2.17 (m, 1H); 13C NMR
(100 MHz, CDCl3): δ 175.8, 138.5, 132.7, 131.2, 128.4, 126.9 (q,
5‐((4‐chlorophenyl)iodomethyl)dihydrofuran‐2(3H)‐one
(2h)
and 6‐(4‐chlorophenyl)‐5‐iodotetrahydro‐2H‐pyran‐2‐one (3h).
The ratio of integrals for H‐6 of 2h and 3h was 50:1. Semi‐solid;
yield: 84%; 1H NMR (400 MHz, CDCl3): δ 7.36 (d, J = 8.0 Hz, 2H),
7.29 (d, J = 8.0 Hz, 2H), 5.06 (d, J = 8.0 Hz, 1H), 4.89 (q, J = 8.0
Hz, 1H), 2.68–2.51 (m, 3H), 2.15–2.05 (m, 1 H); 13C NMR (100
J
C,F = 29.7 Hz), 126.0 (q, J C,F = 5.8 Hz), 124.2 (q, J C,F = 272.4 Hz),
82.8, 29.0, 28.5, 25.7; HRMS (ESI): calcd for C13H11F3IO4
[M+HCOO]‐: 414.9660; found: 414.9655.
MHz, CDCl3): δ 176.0, 138.0, 134.4, 129.5, 129.1, 82.4, 32.7, 5‐(iodomethyl)‐5‐methyldihydrofuran‐2(3H)‐one
(
2n).
1
29.3, 29.0; HRMS (ESI): calcd for C11H10ClIO2Na [M+Na]+: Colourless oil; yield: 94%; H NMR (400 MHz, CDCl3): δ 3.45–
358.9300; found: 358.9307.
3.38 (m, 2H), 2.76–2.61 (m, 2H), 2.37–2.29 (m, 1H), 2.19–2.12
(m, 1H), 1.63 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 175.8, 83.8,
32.8, 29.5, 26.0, 14.6; HRMS (ESI): calcd for C6H10IO2 [M+H]+:
240.9719; found: 240.9715.
5‐(iodo(4‐nitrophenyl)methyl)dihydrofuran‐2(3H)‐one (2i) and
5‐iodo‐6‐(4‐nitrophenyl)tetrahydro‐2H‐pyran‐2‐one
ratio of integrals for H‐6 of 2i and 3i was 100:1. White solid;
(3i). The
mp: 120–121 °C; yield: 79%; 1H NMR (400 MHz, CDCl3): δ 8.19 5‐ethyl‐5‐(iodomethyl)dihydrofuran‐2(3H)‐one (2o). Colourless
(d, J = 8.8 Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H), 5.09 (d, J = 9.2 Hz, oil; yield: 94%; 1H NMR (400 MHz, CDCl3): δ 3.40–3.30 (m, 2H),
1H), 5.01 (dd, J = 16.0 Hz, J = 8.0 Hz, 1H), 2.78–2.69 (m, 1H), 2.64–2.54 (m, 2H), 2.19–2.13 (m, 2H), 1.89–1.82 (m, 2H), 0.97–
2.65–2.60 (m, 2H), 2.19–2.09 (m, 1H); 13C NMR (100 MHz, 0.88 (m, 3H); 13C NMR (100 MHz, CDCl3): δ 176.0, 86.1, 31.6,
CDCl3): δ 175.7, 147.6, 146.8, 129.1, 124.1, 81.9, 30.5, 29.3, 30.7, 29.4, 13.3, 8.0; HRMS (ESI): calcd for C7H12IO2 [M+H]+:
29.2; HRMS (ESI): calcd for C11H10INO4Na [M+Na]+: 369.9535; 254.9876; found: 254.9875.
found: 369.9536.
5‐ethyl‐5‐(iodomethyl)dihydrofuran‐2(3H)‐one (2p). Colourless
5‐(iodo(3‐nitrophenyl)methyl)dihydrofuran‐2(3H)‐one (2j) and oil; yield: 87%; 1H NMR (400 MHz, CDCl3): δ 7.39 (s, 5H), 3.63 (s,
5‐iodo‐6‐(3‐nitrophenyl)tetrahydro‐2H‐pyran‐2‐one
(
3j). The 2H), 2.77–2.48 (m, 4H); 13C NMR (400 MHz, CDCl3): δ 175.3,
ratio of integrals for H‐6 of 2j and 3j was 25:1. White solid; mp: 140.7, 128.8, 128.5, 124.9, 86.0, 33.9, 29.2, 16.5; HRMS (ESI):
1
143–144 °C; yield: 73%; H NMR (400 MHz, CDCl3): δ 8.28 (s, calcd for C11H12IO2 [M+H]+: 302.9876; found: 302.9868.
1H), 8.14 (d, J = 8.0 Hz, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.52 (t, J =
This journal is © The Royal Society of Chemistry 20xx
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Organic & Biomolecular Chemistry
Page 6 of 7
ARTICLE
5‐(iodomethyl)‐5‐(4‐methoxyphenyl)dihydrofuran‐2(3H)‐one
Journal Name
5‐(iodomethyl)‐5‐(naphthalen‐1‐yl)dihydrofuran‐2(3H)‐one (2x).
View Article Online
1
1
DOI: 10.1039/C5OB00806A
(
2q). Colourless oil; yield: 89%; H NMR (400 MHz, CDCl3): δ Semi solid; yield: 84%; H NMR (400 MHz, CDCl3): δ 7.92–7.78
7.24 (d, J =8.0 Hz, 2H), 6.83 (d, J = 8.0 Hz, 2H), 3.74 (s, 3H), 3.52 (m, 4H), 7.58–7.43 (m, 3H), 4.15 (d, J = 8.0 Hz, 1H), 3.81 (d, J =
(s, 2H), 2.71–2.60 (m, 2H), 2.59–2.54 (m, 1H), 2.52–2.41 (m, 11.6 Hz, 1H), 3.09–3.01 (m, 1H), 2.98–2.83 (m, 2H), 2.57–2.48
1H); 13C NMR (100 MHz, CDCl3): δ 175.5, 159.7, 132.4, 126.3 (m, 1H); 13C NMR (400 MHz, CDCl3): δ 175.2, 136.0, 134.7,
114.1, 86.0, 55.4, 33.8, 29.3, 16.8; HRMS (ESI): calcd for 130.0, 129.9, 128.7, 126.6, 125.8, 125.3, 123.9, 123.8, 86.9,
C12H14IO3 [M+H]+: 332.9982; found: 332.9985.
34.2, 29.2, 16.8; HRMS (ESI): calcd for C15H14IO2 [M+H]+:
353.0032; found: 353.0022.
5‐(4‐chlorophenyl)‐5‐(iodomethyl)dihydrofuran‐2(3H)‐one (2r).
Colourless oil; yield: 87%; 1H NMR (400 MHz, CDCl3): δ 7.37 (s,
2H), 7.36 (s, 2H), 3.59 (s, 2H), 2.81–2.68 (m, 2H), 2.60–2.50 (m,
2H); 13C NMR (100 MHz, CDCl3): δ 175.0, 139.2, 134.6, 129.0,
126.4, 85.6, 33.9, 29.2, 15.7; HRMS (ESI): calcd for C11H11ClO2
[M+H]+: 336.9486; found: 336.9481.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (21132003, 21421062, 21372131) and the Specialised
Research Fund for the Doctoral Program of Higher Education
(20120031110010) and "111" Project of Ministry of Education
5‐(4‐fluorophenyl)‐5‐(iodomethyl)dihydrofuran‐2(3H)‐one (2s).
Colourless oil; yield: 86%; 1H NMR (400 MHz, CDCl3): δ 7.39 (dd,
J = 8.0 Hz, J = 4.0 Hz, 2H), 7.09 (t, J = 8.0 Hz, 2H), 3.60 (s, 2H),
2.82–2.50 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 175.0, 162.6
(d, JC,F = 247.0 Hz), 136.5 (d, JC,F = 3.0 Hz), 126.9 (d, JC,F = 9.0 Hz),
115.8 (d, JC,F = 9.0 Hz), 85.7, 33.9, 29.2, 16.0; HRMS (ESI): calcd
for C11H11FIO2 [M+H]+: 320.9782; found: 320.9779.
of China (Project No. B06005
research programs.
）for financial support for our
Notes and references
1
2
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,
,
5‐(iodomethyl)‐5‐(4‐(trifluoromethyl)phenyl)dihydrofuran‐
2(3H)‐one (2t). Colourless oil; yield: 81%; H NMR (400 MHz,
1
4
2763; c) S. Ranganathan, K. M. Muraleedharan, N. K. Vaish
and N. Jayaraman, Tetrahedron, 2004, 60, 5273; d) T.
Janecki, E. Błaszczyk, K. Studzian, A. Janecka, U. Krajewska
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Laya, A. K. Banerjee and E. V. Cabrera, Curr. Org. Chem.,
CDCl3): δ 7.68 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.0 Hz, 2H), 3.62 (s,
2H), 2.83–2.73 (m, 2H), 2.65–2.53 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ 174.8, 144.71, 130.9 (q, J = 32.0 Hz ), 125.9 (q, J = 4.0
Hz ), 125.5, 123.8 (q, J = 270.0 Hz ), 85.6, 34.0, 29.1, 15.2;
HRMS (ESI): calcd for C13H11F3IO4 [M+HCOO]‐: 414.9660; found:
414.9655.
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4‐(2‐(iodomethyl)‐5‐oxotetrahydrofuran‐2‐yl)benzonitrile (2u).
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1
White solid; mp: 138–139 °C; yield: 85%; H NMR (400 MHz,
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CDCl3): δ 7.72 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 3.60 (s,
2H), 2.86–2.72 (m, 2H), 2.65–2.51 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ 174.5, 146.0, 132.7, 125.9, 118.1, 112.7, 85.4, 33.9,
29.0, 14.7; HRMS (ESI): calcd for C13H11INO4 [M+HCOO]‐:
371.9739; found: 371.9736.
3
4
5‐(iodomethyl)‐5‐(3‐nitrophenyl)dihydrofuran‐2(3H)‐one
(2v).
Colourless oil; yield: 83%; 1H NMR (400 MHz, CDCl3): δ 8.28 (s,
1H), 8.24 (d, J = 8.0 Hz, 1H), 8.21 (d, J = 8.0 Hz, 1H), 7.64 (t, J =
8.0 Hz, 1H), 3.67 (s, 2H), 2.91–2.81 (s, 2H), 2.76–2.68 (s, 1H),
2.63–2.54 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 174.5, 148.4,
143.2, 131.2, 130.1, 123.6, 120.2, 85.3, 33.8, 29.1, 15.0; HRMS
(ESI): calcd for C12H11INO6 [M+HCOO]‐: 391.9637; found:
391.9635.
,
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5‐(3,5‐difluorophenyl)‐5‐(iodomethyl)dihydrofuran‐2(3H)‐one
(
2w). White solid; mp: 61–62 °C; yield: 70%; 1H NMR (400 MHz,
CDCl3): δ 6.98 (d, J = 2.0 Hz, 1H), 6.96 (d, J = 2.0 Hz, 1H), 6.83
(tt, J = 8.0 Hz, J =2.0 Hz, 1H), 3.60 (s, 2H), 2.85–2.71 (m, 2H),
2.64–2.54 (m, 2H); 13C NMR (100 MHz, CDCl3) : δ 174.5, 163.1
(dd, JC,F = 249.0, 13.0 Hz), 144.8 (t, JC,F = 9.0 Hz), 108.5 (dd, JC,F
= 19.0, 8.0 Hz), 104.2 (t, JC,F = 25.0 Hz), 85.1, 33.9, 29.0, 14.6;
HRMS (ESI): calcd for C11H10F2IO2 [M+H]+: 338.9688; found:
338.9677.
8
9
,
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Organic & Biomolecular Chemistry
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