A Facile Synthesis of β-Iodonitro Alkenes via Iodonitration of Alkynes with tert -Butyl Nitrite and Iodine

Article abstract of DOI:10.1055/s-0036-1588794

A convenient synthetic approach to β-iodonitro alkenes based on the iodonitration of alkynes with ^t BuONO and I ₂ is described. No acid or oxidant is required in this reaction.

Full text of DOI:10.1055/s-0036-1588794

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–C
letter
A
en
Y. Fan et al.
Letter
Synlett
A Facile Synthesis of β-Iodonitro Alkenes via Iodonitration of
Alkynes with tert-Butyl Nitrite and Iodine
Yuanyuan Fana
Bei Zhoua
Kun Chena
Bingtao Wangb
Xiaoqing Li*a
Xiangsheng Xu*a
tBuONO (2.6 equiv)
I2 (0.5 equiv)
I
NO2
Ar
Ar
THF, 50 °C
19 examples
30–84% yield
(E/Z = 5.7:1 to >99:1)
a College of Chemical Engineering, Zhejiang University of
Technology, Hangzhou 310014, P. R. China
b Ningbo Institute of Technology, Zhejiang University,
Ningbo 315100, P. R. China
xqli@zjut.edu.cn
future@zjut.edu.cn
Received: 19.03.2017
Accepted after revision: 26.03.2017
Published online: 27.04.2017
Previous work
Ph
I
I
HNO3, KI, Mg(NO3)2
r.t.
(a)
+
DOI: 10.1055/s-0036-1588794; Art ID: st-2017-w0005-l
Ph
Ph
I
NO2
65%
34%
Abstract A convenient synthetic approach to β-iodonitro alkenes
based on the iodonitration of alkynes with tBuONO and I2 is described.
No acid or oxidant is required in this reaction.
I
(b)
NaNO2, Oxone, KI
R1
R
R1
R
CH2Cl2/H2O (2:1 v:v)
r.t.
NO2
Key words β-iodonitro alkenes, iodonitration, alkynes, free radical, di-
functionalization
yield 20–70%
(E/Z = 3.4:1 to 9.1:1)
The free-radical-mediated difunctionalization of
alkynes represents one of the most powerful methodolo-
gies for the construction of polysubstituted alkenes,1 which
are widely present in natural products,2 pharmaceuticals,3
and functional materials.4 In this context, the iodonitration
of alkynes is a particularly useful reaction, because both the
iodo and nitro group in the resulting β-iodonitro alkenes
offer rich possibilities for synthetic manipulations. Despite
significant advances in the free-radical-mediated difunc-
tionalization of alkynes, convenient and selective methods
for the formation of β-iodonitro alkenes via the iodonitra-
tion of alkynes have been little explored. Yusubov and co-
workers developed a KI–HNO3–Mg(NO3)2 system for the io-
donitration of phenylacetylene (Scheme 1, a).5 Kuhakarn
and co-workers developed the iodonitration with NaNO2
and KI using Oxone as the oxidant (Scheme 1, b).6 However,
these methods suffered from poor selectivity or the use of
an acid, an additive or an oxidant.
N
(c)
N
O
NO2
O
R
NO2
R
tBuONO
NO
R
plausible
intermediate
air
NO2
This work
I
(d)
tBuONO (2.6 equiv)
I2 (0.5 equiv)
NO2
yield 30–84%
R
I
R
(E/Z = 5.7:1 to 99:1)
THF, 50 °C
1
2
NO2
NO
tBuONO
air
I2
R
NO2
Scheme 1 Difunctionalization of alkynes with a nitro radical
Recently, the application of tBuONO as a green nitro rad-
ical precursor for the construction of various nitro com-
pounds has attracted much attention, because only air is
needed to initiate the formation of nitro radicals.7 In 2015,
Maiti reported the aerobic oxynitration of alkynes with
tBuONO and TEMPO (Scheme 1, c).8 In this reaction, a vinyl
radical formed by the addition of a nitro radical to the
alkyne was thought to be the plausible intermediate, which
was trapped by TEMPO to form the nitro product. We hy-
pothesized that the vinyl radical may also be trapped by io-
dine to allow the iodonitration of alkynes (Scheme 1, d). As
part of the continuing efforts in our laboratory toward the
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–C

B
Y. Fan et al.
Letter
Synlett
development of a novel free-radical-mediated difunctional-
ization of alkynes,9 herein we disclose an efficient and se-
lective method to construct β-iodonitro alkenes by a metal-
free iodonitration of alkynes with tBuONO and I2.
Products turn out to be the main products at higher tem-
peratures. Notably, reducing the iodine to 0.5 equivalent
has no effect on the reaction outcome (Table 1, entry 15).
With the optimized reaction conditions in hand, we
next investigated the alkyne scope (Scheme 2).10 In general,
the reaction tolerated a wide variety of substrates, includ-
ing not only aryl acetylenes bearing an electron-donating
group (products 2b–e, 2j and 2n), but also one bearing a
strong electron-withdrawing NO2-substituent (product 2i).
It is worth noting that halogen-substituted substrates (F, Cl,
Br) were also tolerated in this reaction (products 2c–h, 2k–
m, 2o), with these halogen atoms enabling further elabora-
tion of the products into more complex molecules. The ap-
plication of a polysubstituted aryl acetylene provided the
desired product 2p as well. Moreover, the iodonitration of
heterocyclic acetylenes delivered the desired products 2q–s
in moderate yields. Notably, compared with the iodonitra-
tion reported by Kuhakarn6 our method provided both bet-
ter yields and higher stereoselectivities of the products.
We commenced our studies by investigating the iodo-
nitration of phenylacetylene (1a) with tBuONO. In an initial
attempt, no product 2a was obtained by using KI or NaI as
the iodine source in THF at 60 °C (Table 1, entries 1 and 2).
To our delight, replacement of the iodine salts by I2 gave the
desired product 2a in 78% yield as a mixture of E and Z iso-
mers in a ratio of 9:1 (Table 1, entry 3). The regiochemistry
1
and stereochemistry was confirmed by comparing the H
NMR spectrum with the reported data.6 Inspired by this re-
sult, we first tested different solvents. We found that the io-
donitration occurs in MeCN, acetone and DCE as well, to
give a good yield of product 2a with the E-isomer as the
main product (Table 1, entries 4–6), while DMF, DMSO,
i
MeOH and PrOH proved to be ineffective (Table 1, entries
7–10). The reaction was also tested at different tempera-
tures (Table 1, entries 11–14), and 50 °C was the best condi-
tion giving the product in 81% yield. Interestingly, the ste-
reochemistry of the reaction is temperature-dependent. Z-
tBuONO (2.6 equiv)
I
I2 (0.5 equiv)
NO2
Ar
Ar
THF, 50 °C
I
I
I
Table 1 Optimization of the Reaction Conditionsa
R
NO2
F3C
NO2
NO2
I
R
NO2
tBuONO
CF3
2a R = H, 80%, E/Z = 9:1
2b R = Me, 80%, E/Z = 32.3:1
2c R = Pr, 78%, E/Z = 7.3:1
2j R = Me, 74%, E/Z = 6.1:1
2k R = F, 79%, E/Z = 11.5:1
2l R = Cl, 84%, E/Z = 11.5:1
conditions
2p 65%, E/Z = 13.3:1
2d R = C5H11, 68%, E/Z = 9.0:1 2m R = Br, 78%, E/Z = 15.7:1
2e R = OMe, 39%, E/Z = 9.0:1
1a
2a
R
I
I
2f R = F, 71%, E/Z = 6.7:1
2g R = Cl, 79%, E/Z = 11.5:1
2h R = Br, 77%, E/Z = 11.5:1
2i R = NO2, 46%
NO2
Temp (°C) Yield (%)b E/Z ratioc
NO2
Entry
Iodine source
Solvent
1
2
KI (2 equiv)
THF
60
60
60
60
60
60
60
60
60
60
r.t.
50
70
80
50
NR
N
2n R = Me, 46%, E/Z = 11.5:1
2o R = Cl, 78%, E/Z = 10.1:1
NaI (2 equiv)
THF
NR
2q 41%, E/Z = 6.7:1
3
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
I2
THF
78
9:1
9:1
I
I
NO2
4
MeCN
acetone
DCE
77
NO2
5
65
10:1
5:1
N
S
6
73
2r 39%, E/Z = 99:1
2s 30%, E/Z = 5.7:1
7
DMF
DMSO
MeOH
iPrOH
THF
trace
trace
trace
trace
65
Scheme 2 Substrate scope for the synthesis of β-hydroxy ketones. Re-
agents and conditions: alkyne (0.5 mmol), tBuONO (1.3 mmol), I2 (0.25
mmol), THF (2 mL), 50 °C, 4 h. Regioisomeric ratios were determined by
1H NMR.
8
9
10
11
12
13
14
15d
7:1
4:1
1:4
1:3
9:1
As mentioned above, β-iodonitro alkenes are versatile
intermediates and building blocks in organic synthesis.
When 2a was treated with N-methylaniline in the presence
of N,N-diisopropylethylamine, 3a was produced in 69%
yield, which can further undergo a photoinduced cycliza-
tion to form 1-methyl-2-phenylindole 4.11 Similarly, substi-
tution reactions with other nucleophiles, such as
thiourea,12 sodium benzenesulfinate13 and dimethyl
malonate14 gave 3b–d, respectively (Scheme 3).
THF
81
THF
78
THF
76
THF
80
a Reaction conditions: 1 (0.5 mmol), I2 (0.5 mmol), tBuONO(1.3 mmol) in
solvent (2.0 mL) for 4 h.
b Isolated yield; NR = no reaction.
c The isomeric ratio was determined by 1H NMR.
d 0.25 mmol of I2 was used.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–C

C
Y. Fan et al.
Letter
Synlett
O2N
O
O
O
O
3d, 35%
O
O
ref. 14
O
O
Ph
S
O
O
I
NO2
PhNHMe
PhSO2Na, AcOH
N
EtNiPr2
PhMe, 60 °C
EtOH, rt, 30 min
ref. 13
NO2
NO2
2a
ref. 11
3c, 90%
EtOH, rt
30 min
H2N
NH2
3a, 69%
S
ref. 12
hv (370 nm)
K3PO4 (2 equiv)
air, MeCN, rt, 48 h
NH
H2N
S
N
NO2
4, 35%
3b, 72%
Scheme 3 Transformations of β-iodonitro alkenes
In summary, we have demonstrated a facile and
efficient radical-mediated iodonitration of alkynes using
tBuONO and I2 as the nitro and iodine sources, respectively.
No acid, additive or additional oxidant is needed in this re-
action. This methodology provides a simple and selective
way to construct synthetically useful β-iodonitro alkenes.
(6) Hlekhlai, S.; Samakkanad, N.; Sawangphon, T.; Pahmakotr, M.;
Reutrakul, V.; Soorukram, D.; Jaipetch, T.; Kuhakarn, C. Eur. J.
Org. Chem. 2014, 7433.
(7) (a) Liu, Y.; Zhang, J.-L.; Song, R.-J.; Qian, P.-C.; Li, J.-H. Angew.
Chem. Int. Ed. 2014, 53, 9017. (b) Shen, T.; Yuan, Y.; Jiao, N.
Chem. Commun. 2014, 50, 554. (c) Koley, D.; Colón, O. C.;
Savinov, S. N. Org. Lett. 2009, 11, 4172. (d) Taniguchi, T.; Sugiura,
Y.; Hatta, T.; Yajima, A.; Ishibashi, H. Chem. Commun. 2013, 49,
2198. (e) Hu, M.; Liu, B.; Ouyang, X.-H.; Song, R.-J.; Li, J.-H. Adv.
Synth. Catal. 2015, 357, 3332. (f) Hirose, D.; Taniguchi, T. Beil-
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Funding Information
Natural Science Foundation of China (51503181)
(8) Dutta, U.; Maity, S.; Kancherla, R.; Maiti, D. Org. Lett. 2014, 16,
6302.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588794.
(9) (a) Li, X.; Shi, X.; Fang, M.; Xu, X. J. Org. Chem. 2013, 78, 9499.
(b) Li, X.; Xu, X.; Shi, X. Tetrahedron Lett. 2013, 54, 3071.
(10) (1-Iodo-2-nitrovinyl)benzene: Typical Procedure
To a stirred solution of phenylacetylene (0.5 mmol), and I2 (0.25
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–C