Sodium nitrite (NaNO2) catalysed iodo-cyclisation of alkenes and alkynes using molecular oxygen

Article abstract of DOI:10.1016/j.tetlet.2008.05.013

We have developed a convenient iodo-cyclisation reaction using NaNO₂ as catalyst and molecular oxygen as the terminal oxidant. The reactive species, acetyl hypoiodite (IOAc), was generated in situ from TBAI and AcOH. The iodo-cyclisation reaction with a range of alkenes and alkynes gave good to excellent yields. Iodo-amination products can also be obtained using carbamates prepared from commercially available allylic alcohols and alkynic alcohols.

Full text of DOI:10.1016/j.tetlet.2008.05.013

Tetrahedron Letters 49 (2008) 4424–4426
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Tetrahedron Letters
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Sodium nitrite (NaNO2) catalysed iodo-cyclisation of alkenes and alkynes
using molecular oxygen
*
Hongjun Liu, Yuanhang Pan, Choon-Hong Tan
Department of Chemistry, 3 Science Drive 3, National University of Singapore, Singapore 117543, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed a convenient iodo-cyclisation reaction using NaNO2 as catalyst and molecular oxygen
as the terminal oxidant. The reactive species, acetyl hypoiodite (IOAc), was generated in situ from TBAI
and AcOH. The iodo-cyclisation reaction with a range of alkenes and alkynes gave good to excellent
yields. Iodo-amination products can also be obtained using carbamates prepared from commercially
available allylic alcohols and alkynic alcohols.
Received 3 April 2008
Revised 23 April 2008
Accepted 2 May 2008
Available online 9 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
The environmental and economic benefits of using molecular
oxygen for the oxidation of organic molecules are clear. This
oxidant is available at almost no cost and produces no environ-
mentally hazardous by-products.1 Catalysts such as N-hydroxyph-
thalimide (NHPI) were developed to carry the reactive oxygen.1a
Alkanes were successfully oxidised with NHPI/O2 to valuable
oxygen-containing compounds such as alcohols and ketones.
Nitrogen monoxide (NO) is a highly reactive and unstable radi-
cal and can be oxidised easily to nitrogen dioxide (NO2) by mole-
cular oxygen (O2). The unique redox property of NaNO2 has
allowed it to be exploited as a carrier for O2. The NaNO2/O2 system
has been reported recently for the oxidation of both primary and
secondary alcohols.2–5 These conditions were used in combination
with catalytic amounts of 2,2,6,6-tetramethyl-1-piperidinyloxyl
(TEMPO) and molecular bromine.2a Alternatively, the oxidation
can also be carried out under a high pressure–air atmosphere with
catalytic amounts of TEMPO and 1,3-dibromo-5,5-dimethylhydan-
toin.2b A catalytic amount of [bis(acetoxy)iodo]benzene (PIDA) and
TEMPO/KNO2 can be used for alcohol oxidation.3 Solid supported
PIDA is also useful in this reaction. The hypervalent iodine reagent,
iodoxybenzene (PhIO2), was exploited for the oxidation of alcohols
in water and in combination with Br2/NaNO2.4 Transition metals
can also be included to promote the reaction. The FeCl3–TEMPO–
NaNO2 system has been shown to be efficient for aerobic oxidation
of a broad range of alcohols.5
conversion rate. This system has displayed considerable promise
for practical application in industry.7
A number of methods have been reported for the construction
of lactones from olefinic carboxylic acids through halolactonisa-
tion.8 We reported a new method for iodolactonisation based on
diacetyloxyiodate(I). This hypervalent iodine reagent was gener-
ated in situ with tetra-n-butylammonium iodide (TBAI) and PIDA.
PIDA, in turn, was generated in situ using a catalytic amount of
iodobenzene with sodium perborate as the stoichiometric
oxidant.9 We are keen to develop a more efficient method for this
iodolactonisation and in this Letter, we report the use of the
NaNO2/O2 system for the cyclisation of alkenes and alkynes.
The iodolactonisation reaction of 2,2-dimethylpent-4-enoic acid
1a was catalysed with NaNO2 (20 mol %), TBAI (1.1 equiv) and
acetic acid (1 equiv). Molecular oxygen was supplied through a
balloon. Only a small amount of lactone 2a (31%) was isolated
(Table 1, entry 3). Acetic acid played an important role in this reac-
tion. With only 0.5 equiv of acetic acid, the yield of 2a was a disap-
pointing 21% (entry 2) and no reaction was observed in the absence
of acetic acid (entry 1). When 5 equiv of acetic acid were employed,
the reaction was complete within 13 h in excellent yield. If oxygen
was bubbled directly into the solvent, the reaction was complete
within 7 h and the isolated yield was improved to 92% (entry 5).
When 1% water (v/v) was added in CH2Cl2, only a 54% yield of 2a
was obtained after 36 h. The yield of the reaction was not affected
when the amount of NaNO2 was reduced to 10 mol % (entry 6).
However, the efficiency of the reaction was greatly reduced when
the catalyst loading was reduced to 5 or 2 mol % (entries 7 and 8).
No reaction was observed in the absence of the catalyst. This reac-
tion gives better yields and is complete within a shorter time com-
pared to the more classical reaction conditions using I2–Na2CO3–KI
(64% yield after 25 h).8h
Aerobic oxidative iodination activated by NaNO2 has been
shown to occur effectively and selectively with full iodine atom
economy using air as the oxidant.6 The NaNO2/O2 system can be
modulated for environmental problems. For example, it can be
used to efficiently oxidise persistent pollutants such as trichloro-
phenol into CO2, CO and biodegradable organic products with high
A series of d-pentenoic acids 1b–g (Fig. 1) were subjected to the
optimised conditions for iodolactonisation using 10 mol % of
NaNO2 and 5 equiv of acetic acid (Table 2, entries 1–6). The
* Corresponding author. Tel.: +65 68742845; fax: +65 67791691.
E-mail address: chmtanch@nus.edu.sg (C.-H. Tan).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.013

H. Liu et al. / Tetrahedron Letters 49 (2008) 4424–4426
4425
Table 1
O
Iodolactonisation of 2,2-dimethylpent-4-enoic acid 1a
CO2H
NaNO2 10 mol%, O2,
O
O
CO2H
NaI 2 equiv.,
AcOH, rt, 8 h
NaNO2, O2, AcOH
O
I
1a
2a
n
Bu4NI 1.1 equiv.
Yield: 74%
I
CH2Cl2, rt
1a
2a
Scheme 1. Iodolactonisation using sodium iodide.
Entry
NaNO2 (equiv)
AcOH (equiv)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
0.2
0.2
0.2
0.2
0.2
0.1
0.05
0.02
0
0
0.5
1
2
5
5
5
5
5
36
36
36
36
7
15
36
36
36
0
21
31
43
92b
90
48
36
0
O
NaNO2 10 mol%,
AcOH 5 equiv., O2
Ts
I
OCONHTs
O
N
n
Bu4NI 1.1 equiv.,
3
CH2Cl2, rt, 24 h
4a
Yield: 52%
a
Isolated yield.
Oxygen was bubbled directly into the reaction.
Scheme 2. Iodo-amination of O-allylic carbamates.
b
O
R1
2b: R1=H; R2=H
2c: R1=Bn; R2=H
1b: R1=H; R2=H
R2
O
Ts
R1
I
N
N
O
1c: R1=Bn; R2=H
OH
R2
R3
4a: R1=R2=R3=H
CO2H
CO2H
R1
R1
5a: R1=R2=R3=H
1
2
1
2
O
2d
: R =Et; R =H
1d
: R =Et; R =H
R3
R
4b: R1=H; R2=R3=Me
4c: R1=Me; R2=R3=H
5b: R1=H; R2=R3=Me
5c: R1=Me; R2=R3=H
1
2
1
2
2e
: R =Me; R =H
2f
1e
: R =Me; R =H
O
R2
I
1
2
1
2
1f
: R =H; R =Me
: R =H; R =Me
R2
O
Ts
H
2g: R1=H; R2=Et
1g: R1=H; R2=Et
O
5d: R=H
5e: R=Me
4d: R=H
4e: R=Me
OH
2h: R1=H; R2=H
2i: R1=Et; R2=H
1h: R1=H; R2=H
1i: R1=Et; R2=H
95
R1
R
R1
O
I
1
2
R2
1
2
2j
: R =H; R =Me
1j
: R =H; R =Me
R2
Figure 2. Substrates and products of the iodo-amination reaction.
I
Figure 1. Substrates and products of iodolactonisation.
products is highly dependent on the reaction conditions. To test
the substrate scope of the NaNO2/O2 system, O-allylic carbamate
3 was subjected to our optimised conditions affording the iodo-
amination product 4a in 52% isolated yield (Scheme 2). The O-cyc-
lised product and the 6-endo product were not observed. It is note-
worthy that this iodo-amination reaction can be carried out in one
pot. Allylic alcohols 5a–c (Fig. 2) can be converted to the corre-
sponding carbamates in situ (Table 3), however, only moderate
yields were obtained (Table 3, entries 1–3). Further optimisations
to improve the isolated yields were not successful which included
the reaction time and the ratio of reagents. We also found that the
alkynic alcohols 5d–e could give interesting amino-alkenes 4d–e.
However, they were obtained in relatively low yields. NOE experi-
ments showed that only E olefins 4d–e were formed.
Table 2
Iodolactonisation of various alkenes and alkynes
Entry
Substrate
Time (h)
Product
Yielda (%)
1
2
3
4
5
6
7
8
9
1b
1c
1d
1e
1f
1g
1h
1i
24
16
13
16
18
20
18
22
22
2b
2c
2d
2e
2f
2g
2h
2i
87
84 (dr = 1.7:1)
61 (dr = 1.7:1)
84 (dr = 2:1)
80 (dr = 5:1)
94 (dr = 2.3:1)
64
84
74
1j
2j
a
Isolated yield, no side products observed for all the substrates.
Based on these preliminary data, we have proposed a possible
pathway for the reaction (Scheme 3). NO acts as a catalyst to carry
O2 by conversion into NO2. NO2 oxidises iodide from TBAI in the
reactions were complete within 24 h and good yields were
obtained. Only the 5-exo-trig ring-closed lactones 2b–g were
isolated. NMR studies of the lactones 2c–g showed that the syn
isomers were the major products.
Table 3
Iodo-amination of various alkenes and alkynes
This protocol was also employed with alkynes 1h–j to prepare
iodoenol lactones 2h–j (Table 2, entries 7–9) which were reported
as potential inhibitors of serine proteases and glutathione S-trans-
ferases.10 The reaction was highly diastereoselective and only the E
olefins were formed.
We replaced TBAI with the more common iodide source, so-
dium iodide (NaI). We found that acetic acid was required as sol-
vent for the reaction to proceed well. Lactone 2a was isolated in
74% yield (Scheme 1).
NaNO2 10 mol%,
AcOH 5 equiv., O2,
product
4
+
alcohol
TsNCO
nBu4NI 1.1 equiv.,
CH2Cl2, rt
5
Entry
5
Time (h)
4
Yielda (%)
1
2
3
4
5
5a
5b
5c
5d
5e
24
24
24
28
28
4a
4b
4c
4d
4e
70
42
78
36
40
The halocyclisation reaction of olefinic compounds has been
shown to work with ambident nucleophiles such as carbamates,
ureas and amides.11 Preference for the O-cyclised or N-cyclised
a
Isolated yield.

4426
H. Liu et al. / Tetrahedron Letters 49 (2008) 4424–4426
References and notes
n
Bu4NI + AcOH
NO2
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yields of products. Iodo-amination products can also be obtained
using carbamates prepared from commercially available allylic
alcohols and alkynic alcohols.
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This work is supported by grants (R-143-000-342-112) and a
scholarship (to L.H.J.) from the National University of Singapore.
We thank the Medicinal Chemistry Program for their financial
support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.05.013.