Regiospecific azidoiodination of alkenes with sodium periodate, potassium iodide, and sodium azide: A high-yield synthesis of β-Iodoazides

Article abstract of DOI:10.1055/s-0030-1258250

The combination of sodium periodate, potassium iodide, and sodium azide has been found to be an efficient, simple, and inexpensive reagent system for azidoiodination of alkenes. The regiospecific 1,2-azidoiodination proceeds in an anti-Markovnikov fashion to produce -iodoazides in excellent yields. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1258250

PAPER
3879
Regiospecific Azidoiodination of Alkenes with Sodium Periodate, Potassium
Iodide, and Sodium Azide: A High-Yield Synthesis of b-Iodoazides
A
zidoiodinatio
a
n
of
A
lkennes with 4
N
aIO
d
/KI/NaN3 urang V. Chouthaiwale, Pratibha U. Karabal, Gurunath Suryavanshi, Arumugam Sudalai*
Chemical Engineering and Process Development Division, National Chemical Laboratory, Pashan Road, Pune 411 008, India
Fax +91(20)25902676; E-mail: a.sudalai@ncl.res.in
Received 19 July 2010; revised 17 August 2010
Abstract: The combination of sodium periodate, potassium iodide,
I
NaIO4, KI
R2
R2
and sodium azide has been found to be an efficient, simple, and in-
expensive reagent system for azidoiodination of alkenes. The re-
giospecific 1,2-azidoiodination proceeds in an anti-Markovnikov
fashion to produce b-iodoazides in excellent yields.
R1
R1
NaN3, AcOH
25 °C, 2 h
1a–l
R1 = aryl, alkyl
R2 = H, alkyl, CH2OH, CH2OAc
N3
2a–l
70–95%
Key words: azides, alkenes, azidoiodination, b-iodoazides, regio-
specific
Scheme 1 Sodium periodate mediated azidoiodination of alkenes
we reasoned that the sodium periodate, potassium iodide,
and sodium azide combination can be an effective, simple
reagent system for the regiospecific 1,2-azidoiodination
of styrene. Thus, when styrene was treated initially with
sodium periodate, potassium iodide, and sodium azide (all
equimolar) in acetic acid at 25 °C, the corresponding 1-(2-
azido-1-iodoethyl)benzene was isolated in 33% yield.
However, this yield was increased to 95% when the sto-
ichiometry of sodium azide was increased to three equiv-
alents (Scheme 1).15 This prompted us to explore the
effectiveness of the sodium periodate, potassium iodide,
and sodium azide system in the 1,2-azidoiodination of
several alkenes. This new azidoiodination procedure was
indeed found to be quite general for a variety of olefins
and the results of this study are summarized in Table 1.
The 1,2-functionalizations of olefins by the selective ad-
dition of azide and iodo groups (azidoiodination) that pro-
ceeds in a highly regio- and stereoselective manner are of
current interest in organic synthesis. The resulting b-io-
doazides can readily be transformed into versatile inter-
mediates such as vinyl azides,1 amines,2 aziridines,3
tetrazoles,4 etc., which display antituberculosis,5a antibiot-
ic,5b anticancer,5c immunostimulating,5d and anti-HIV5e
activities. The general methods of synthesis for b-io-
doazides consist among others, reaction of alkenes with
IN3, which was prepared in situ by the reaction of either I2
with AgN3 or NaN3 and ICl in polar solvents.6 However,
a considerable drawback associated with IN3 as a reagent,
is its potentially explosive nature, which inhibits its wide-
spread use. Although other reagent systems like I2/NaN3,7
IPy2BF4/TMSN3,8 PhI(OAc)2/TMSN3/Et4NI,9a and poly-
As can be seen from Table 1, a variety of alkenes 1a–l
(aliphatic, styrenic, allylic, and disubstituted) underwent
azidoiodinations to give the corresponding b-iodoazides
2a–l in excellent yields. It is interesting to note that the
regiochemistry of the addition, for all the cases examined,
proceeded in an anti-Markovnikov fashion, indicating a
possible radical pathway.16 Internal olefins such as b-
methylstyrene, cyclohexene, and cinnamyl alcohol gave
products in excellent yields with diastereoselectivities
reaching up to 1:4 (Table 1, entries c, f, and k) as con-
firmed by their 1H NMR spectra. Terminal functionalized
olefin such as allyl acetate also underwent regiospecific
azidoiodination in 92% yield. However, no reactions took
place in the case of conjugated alkenes with electron-
withdrawing groups, which may be a limitation of this
method. Mechanistically, NaIO4 oxidizes both KI and
9b
mer-bound IN3 can serve as azidoiodination reagents,
they all preferentially produce Markovnikov products.
Only a couple of protocols like NaN3/NaI/CAN10 and
11
NaN3/KI/oxone/wet Al2O3 proceed to give anti-Mark-
ovnikov addition products when carried out with olefins.
However, these methods too suffer from certain draw-
backs such as use of expensive reagents and large excess
of oxidants and halide sources. Hence, a practical method
that involves less toxic yet readily available reagents is of
paramount importance. This paper describes one such
process, in which an excellent regiospecific azidoiodina-
tion of alkenes takes place using sodium periodate as the
stoichiometric oxidizing agent and sodium azide and po-
tassium iodide as the azide and iodine sources, respective-
ly, in acetic acid as solvent (Scheme 1).
12
NaN3 simultaneously to liberate I2 and an azide radi-
In continuation of our studies on sodium periodate medi-
ated oxidative halogenation of aromatics,12 halohydroxy-
lation of alkenes,13 and C–H activation of hydrocarbons,14
cal,17 respectively; combination of which probably results
in the formation of IN3 (Scheme 2).18
Homolysis of IN319 provides an azide radical, which then
adds onto alkenes to produce a more stable alkyl radical
species A, thus controlling the regiochemistry of the pro-
cess. The combination of alkyl radical with either I2 or io-
dine radical results in the formation of b-iodoazides 2a–l.
SYNTHESIS 2010, No. 22, pp 3879–3882
x
x.
x
x
.
2
0
1
0
Advanced online publication: 14.09.2010
DOI: 10.1055/s-0030-1258250; Art ID: Z18410SS
© Georg Thieme Verlag Stuttgart · New York

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P. V. Chouthaiwale et al.
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Table 1 NaIO4-Mediated Regiospecific Azidoiodination of Alke-
I2
N3
KI
nesa
NaIO4
I
N3
+
N3
NaN3
A
Entry Alkenes 1
Products 2
Yield (%)b
95
1a
I
I2 or I
a
b
c
styrene
I
N3
I
N3
4-methylstyrene
b-methylstyrene
70
2a
N3
Scheme 2 Proposed mechanistic pathway for the azidoiodination
I
95c
N3
All reactions were carried out under an inert atmosphere. All the
chemicals (AR grade) were obtained from commercial sources and
used without further purification. Petroleum ether (PE) refers to the
fraction with bp 60–80 °C. Reaction progress was monitored by
TLC using aluminum plates precoated with silica gel 60 F254 (0.25
mm, Merck). Column chromatography was performed on silica gel
(60–120 mesh) using PE–EtOAc mixtures as the eluent. IR spectra
were recorded on a Perkin-Elmer FT-IR spectrophotometer. 1H and
13C NMR spectra were recorded in CDCl3 on Bruker AC 200, AV
400 and DRX 500 spectrometers (1H at 200 or 500 MHz; 13C at 50,
100 or 125 MHz) with SiMe4 as internal standard.
I
d
e
4-chlorostyrene
92
85
N3
Cl
Cl
I
4-chloromethylstyrene
N3
N3
f
cyclohexene
93d
88
Azidoiodination of Alkenes; General Procedure
I
I
To a suspension of NaN3 (0.975 g, 15 mmol) and KI (0.830 g, 5
mmol) in AcOH (20 mL) at 25 °C was added NaIO4 (1.069 g, 5
mmol) and the reaction mixture was stirred for 5 min when a dark
brown color was observed. This was followed by the addition of
alkene 1a–l (5 mmol) and the entire reaction mixture was stirred at
the same temperature for 2 h. After the reaction was complete as
monitored by TLC, the mixture was poured into H2O (100 mL) and
extracted with CH2Cl2 (3 × 50 mL). The combined organic layers
were washed with sat. aq NaHCO3 (50 mL), aq 5% Na2S2O3 (50
mL), dried (Na2SO4), and concentrated under reduced pressure. The
crude product was purified by column chromatography (packed
with silica gel 60–120 mesh) using petroleum ether as eluent to af-
ford the pure product 2a–l (Table 1).
g
vinylcyclohexane
N3
I
h
i
hex-1-ene
93
94
90
90c
92
N3
I
hept-1-ene
N3
I
j
dec-1-ene
1-(2-Azido-1-iodoethyl)benzene (2a)
Yield: 95%; pale yellow oil.
IR (CHCl3): 693, 1257, 1446, 1605, 2100, 2921, 3027 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.94 (d, J = 7.7 Hz, 2 H), 5.14 (t,
J = 7.7 Hz, 1 H), 7.30–7.45 (m, 5 H).
5
N3
I
k
l
trans-cinnamyl alcohol
allyl acetate
OH
N3
13C NMR (50 MHz, CDCl3): d = 27.8, 58.5, 127.4, 128.7, 128.9,
140.1.
I
OAc
N3
Anal. Calcd for C8H8IN3: C, 35.19; H, 2.95; N, 15.39. Found: C,
35.10; H, 2.90; N, 15.44.
a Reaction conditions: alkene (5 mmol), KI (5 mmol), NaIO4 (5
mmol), NaN3 (15 mmol), glacial AcOH (15 mL), 25 °C, 2 h.
b Isolated yield.
1-(2-Azido-1-iodoethyl)-4-methylbenzene (2b)
Yield: 70%; pale yellow oil.
IR (CHCl3): 1257, 1446, 2101, 2920, 3027 cm–1.
c Ratio syn/anti = 1:1.
d Ratio syn/anti = 1:4.
1H NMR (200 MHz, CDCl3): d = 2.30 (s, 3 H), 3.87 (d, J = 7.7 Hz,
2 H), 5.09 (t, J = 7.7 Hz, 1 H), 7.10 (d, J = 7.8 Hz, 2 H), 7.27 (d,
J = 7.8 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 21.2, 28.1, 58.6, 127.3, 129.5,
137.2, 138.5.
In conclusion, we have developed a simple procedure
with NaIO4/KI/NaN3 as a new combination for the 1,2-
azidoiodination of alkenes that provides a mild, efficient
entry to vicinal azidoiodoalkanes in high yields under am-
bient conditions. The azidoiodination reaction proceeds to
give b-iodoazides 2a–l in a regiospecific manner.
Anal. Calcd for C9H10IN3: C, 37.65; H, 3.51; N, 14.64. Found: C,
37.70; H, 3.48; N, 14.60.
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PAPER
Azidoiodination of Alkenes with NaIO4/KI/NaN3
3881
1-(2-Azido-1-iodopropyl)benzene (2c)
Yield: 95%; pale yellow oil; mixture of anti/syn (1:1).
IR (CHCl3): 1258, 1605, 1458, 2101, 2990 cm–1.
13C NMR (50 MHz, CDCl3): d = 13.8, 22.3, 28.4, 31.5, 37.1, 58.9.
Anal. Calcd for C6H12IN3: C, 28.47; H, 4.78; N, 16.60. Found: C,
28.50; H, 4.69; N, 16.65.
1H NMR (200 MHz, CDCl3): d = 1.23 (d, J = 6.4 Hz, 3 H), 1.52 (d,
J = 6.4 Hz, 3 H), 3.74–3.99 (m, 2 H), 4.91 (d, J = 7.0 Hz, 1 H), 4.96
(d, J = 8.0 Hz, 1 H), 7.26–7.40 (m, 10 H).
13C NMR (50 MHz, CDCl3): d = 21.2, 28.1, 58.6, 127.3, 129.5,
137.2, 138.5.
1-Azido-2-iodoheptane (2i)
Yield 94%; pale yellow oil.
IR (CHCl3): 669, 769, 923, 1257, 1448, 2102, 2939 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.9 (t, J = 6.6 Hz, 3 H), 1.27–1.50
(m, 6 H), 1.69–1.84 (m, 2 H), 3.57–3.80 (m, 2 H), 4.04–4.17 (m, 1
H).
13C NMR (50 MHz, CDCl3): d = 13.9, 22.3, 28.8, 30.7, 32.2, 37.0,
58.9.
Anal. Calcd for C9H10IN3: C, 37.65; H, 3.51; N, 14.64. Found: C,
37.70; H, 3.48; N, 14.62.
1-(2-Azido-1-iodoethyl)-4-chlorobenzene (2d)
Yield: 92%; pale yellow oil.
IR (CHCl3): 693, 1257, 1489, 1589, 2100 cm–1.
Anal. Calcd for: C7H14IN3: C, 31.48; H, 5.28; N, 15.73. Found: C,
31.40; H, 5.33; N, 15.65.
1H NMR (200 MHz, CDCl3): d = 3.88–3.94 (m, 2 H), 5.10 (dd,
J = 8.2, 7.0 Hz, 1 H), 7.30–7.40 (m, 4 H).
13C NMR (50 MHz, CDCl3): d = 26.0, 58.5, 128.8, 129.1, 134.4,
138.7.
1-Azido-2-iododecane (2j)
Yield: 90%; pale yellow oil.
IR (CHCl3): 668, 770, 923, 1257, 1448, 2103, 2939 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.9 (t, J = 6.1 Hz, 3 H), 1.28–1.51
(m, 12 H), 1.72–1.82 (m, 2 H), 3.59–3.80 (m, 2 H), 4.01–4.11 (m, 1
H).
Anal. Calcd for C8H7ClIN3: C, 31.25; H, 2.29; N, 13.66. Found: C,
31.30; H, 2.25; N, 13.68.
1-(2-Azido-1-iodoethyl)-4-chloromethylbenzene (2e)
Yield: 85%; pale yellow oil.
13C NMR (50 MHz, CDCl3): d = 14.1, 22.6, 25.8, 28.7, 29.2, 29.3,
31.8, 32.0, 37.1, 59.0.
IR (CHCl3): 1257, 1489, 2101, 2920, 3027 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.92 (d, J = 6.9 Hz, 2 H), 4.55 (s,
2 H), 5.12 (t, J = 7.2 Hz, 1 H), 7.32–7.43 (m, 4 H).
13C NMR (50 MHz, CDCl3): d = 26.8, 45.3, 58.5, 127.9, 129.0,
137.9, 140.4.
Anal. Calcd for C10H20IN3: C, 38.85; H, 6.52; N, 13.59. Found: C,
38.75; H, 6.60; N, 13.65.
2-Azido-3-iodo-3-phenylpropan-1-ol (2k)
Yield: 90%; pale yellow oil; mixture of anti/syn (1:1).
IR (CHCl3): 757, 1153, 1217, 1258, 1458, 2096, 2927, 3004, 3330
cm–1.
1H NMR (200 MHz, CDCl3): d = 2.36 (br s, 2 H), 3.40–3.49 (m, 1
H), 3.59–3.66 (m, 1 H), 3.75–3.94 (m, 2 H), 4.02–4.17 (m, 2 H),
5.13 (d, J = 8.5 Hz, 1 H), 5.16 (d, J = 9.2 Hz, 1 H), 7.28–7.48 (m,
10 H).
Anal. Calcd for C9H9ClIN3: C, 33.62; H, 2.82; N, 13.07. Found: C,
33.55; H, 2.85; N, 13.01.
1-Azido-2-iodocyclohexane (2f)
Yield; 93%; pale yellow oil; mixture of anti/syn (4:1).
IR (CHCl3): 669, 769, 923, 1217, 1257, 1448, 2100, 2860, 2939
cm–1.
1H NMR (200 MHz, CDCl3): d = 1.31–1.57 (m, 4 H), 1.99–2.50 (m,
4 H), 3.46–3.58 (m, 1 H), 3.90–4.03 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 28.9, 32.1, 63.1, 64.8, 68.6, 70.0,
127.8, 128.2, 128.6, 128.9, 129.0, 140.1, 140.2.
Anal. Calcd for C9H10IN3O: C, 35.66; H, 3.33; N, 13.86. Found: C,
35.70; H, 3.30; N, 13.85.
13C NMR (50 MHz, CDCl3): d = 23.7, 26.9, 31.8, 33.2, 38.3, 67.1.
3-Azido-2-iodopropyl Acetate (2l)
Yield: 92%; pale yellow oil.
Anal. Calcd for C6H10IN3: C, 28.70; H, 4.01; N, 16.74. Found: C,
28.64; H, 4.10; N, 16.78.
IR (CHCl3): 669, 769, 923, 1257, 1448, 1735, 2101, 2940 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.10 (s, 3 H), 3.74–3.82 (m, 2 H),
4.15–4.37 (m, 3 H).
1-(2-Azido-1-iodoethyl)cyclohexane (2g)
Yield 88%; pale yellow oil.
IR (CHCl3): 669, 769, 923, 1217, 1257, 1448, 2102, 2860, 2939
cm–1.
13C NMR (50 MHz, CDCl3): d = 20.5, 23.8, 55.3, 65.9, 169.3.
Anal. Calcd for C5H8IN3O2: C, 22.32; H, 3.00; N, 15.62. Found: C,
22.38; H, 2.98; N, 15.73.
1H NMR (200 MHz, CDCl3): d = 1.02–1.45 (m, 6 H), 1.63–1.93 (m,
5 H), 3.63–3.82 (m, 2 H), 4.07–4.15 (m, 1 H).
13C NMR (50 MHz, CDCl3): d = 25.6, 25.8, 26.0, 30.5, 32.8, 41.0,
42.1, 56.5.
Acknowledgment
Anal. Calcd for C6H14IN3: C, 34.42; H, 5.06; N, 15.05. Found: C,
34.50; H, 5.01; N, 14.98.
The author P.V.C. thanks CSIR for the award of a fellowship and
DST, New Delhi (sanction no.SR/S1/OC-72/2006) for financial
support. The authors also thank Dr. B. D. Kulkarni, Head, CE-PD
for his constant encouragement and support.
1-Azido-2-iodohexane (2h)
Yield 93%; pale yellow oil.
IR (CHCl3): 667, 769, 925, 1258, 1446, 2103, 2939 cm–1.
References
1H NMR (200 MHz, CDCl3): d = 0.9 (t, J = 6.9 Hz, 3 H), 1.27–1.52
(m, 4 H), 1.73–1.84 (m, 2 H), 3.60–3.83 (m, 2 H), 4.04–4.17 (m, 1
H).
(1) Hassner, A.; Fowler, F. W. J. Org. Chem. 1968, 33, 2686.
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(2) Wasserman, H. H.; Brunner, R. K.; Buynak, J. D.; Carter, C.
G.; Oku, T.; Robinson, R. P. J. Am. Chem. Soc. 1985, 107,
519.
(3) (a) Van Ende, D.; Krief, A. Angew. Chem., Int. Ed. Engl.
1974, 13, 279. (b) Denis, J. N.; Krief, A. Tetrahedron 1979,
35, 2901.
(9) (a) Kirschning, A.; Hashem, M. A.; Monenschein, H.; Rose,
L.; Schoning, K.-U. J. Org. Chem. 1999, 64, 6522.
(b) Kirschning, A.; Monenschein, H.; Schmeck, C. Angew.
Chem. Int. Ed. 1999, 38, 2594.
(10) Nair, V.; George, T. G.; Sheeba, V.; Augustine, A.;
Balagopal, L.; Nair, L. G. Synlett 2000, 1597.
(11) Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O.
Tetrahedron Lett. 2002, 43, 1201.
(12) Emmanuvel, L.; Shukla, R. K.; Sudalai, A.; Suryavanshi, G.;
Sivaram, S. Tetrahedron Lett. 2006, 47, 4793.
(13) Dewkar, G. K.; Narina, S. V.; Sudalai, A. Org. Lett. 2003, 5,
4501.
(14) (a) Shaikh, T. M.; Sudalai, A. Tetrahedron Lett. 2005, 46,
5587. (b) Chouthaiwale, P. V.; Suryavanshi, G.; Sudalai, A.
Tetrahedron Lett. 2008, 49, 6401.
(15) Cambie, R. C.; Hayward, R. C.; Rutledge, P. S.; Smith-
Plalmer, T.; Swelland, B. E.; Woodgate, P. D. J. Chem. Soc.,
Perkin Trans. 1 1979, 180.
(16) (a) L’abbe, G.; Hassner, A. Angew. Chem., Int. Ed. Engl.
1971, 10, 98. (b) Workentin, M. S.; Wagner, B. D.; Lusztyk,
J.; Wayner, D. D. M. J. Am. Chem. Soc. 1995, 117, 119.
(17) (a) Tingoli, M.; Tiecco, M.; Chianelli, D.; Balducci, R.;
Temperini, A. J. Org. Chem. 1991, 56, 6809. (b) Fontana,
F.; Minisci, F.; Yan, Y. M.; Zhao, L. Tetrahedron Lett. 1993,
34, 2517.
(18) Barluenga, J.; Campos-Gomez, E.; Rodriguez, D.;
Gonzalez-Bobes, F.; Gonzalez, J. M. Angew. Chem. Int. Ed.
2005, 44, 5851.
(19) Marinescu, L. G.; Pedersen, C. M.; Bols, M. Tetrahedron
2005, 61, 123.
(4) (a) Ranganathan, S.; Ranganathan, D.; Mehrotra, A. K.
Tetrahedron Lett. 1973, 2265. (b) Moorthy, S. N.;
Devaprabhakara, D. Tetrahedron Lett. 1975, 257.
(5) (a) Gallardo, H.; Conte, G.; Bryk, F.; Cristina, M.; Lourenco,
S.; Costa, M. S.; Ferreira, V. F. J. Braz. Chem. Soc. 2007, 18,
1285. (b) Aufort, M.; Herscovici, J.; Bouhours, P.; Moreau,
N.; Girard, C. Bioorg. Med. Chem. Lett. 2008, 18, 1195.
(c) Tullis, J. S.; VanRens, J. C.; Natchus, M. G.; Clark, M.
P.; De, B.; Hsieh, L. C.; Janusz, M. J. Bioorg. Med. Chem.
Lett. 2003, 13, 1665. (d) Lee, T.; Cho, M.; Ko, S.-Y.; Youn,
H.-J.; Baek, D. J.; Cho, W.-J.; Kang, C.-Y.; Kim, S. J. Med.
Chem. 2007, 50, 585. (e) Whiting, M.; Tripp, J. C.; Lin,
Y.-C.; Lindstrom, W.; Olson, A. J.; Elder, J. H.; Sharpless,
K. B.; Fokin, V. V. J. Med. Chem. 2006, 49, 7697.
(6) (a) Hantzsch, A.; Schumann, M. Ber. Dtsch. Chem. Ges.
1900, 33, 522. (b) Hassner, A.; Levy, L. J. Am. Chem. Soc.
1965, 87, 4203. (c) Hassner, A. Acc. Chem. Res. 1971, 4, 9.
(7) (a) Woodgate, P. D.; Lee, H. H.; Rutledge, P. S.; Cambie, R.
C. Synthesis 1977, 462. (b) Terent’ev, A. O.; Krylov, I. B.;
Kokorekin, V. A.; Nikishin, G. I. Synth. Commun. 2008, 38,
3797.
(8) Barluenga, J.; Alvarez-Perez, M.; Fananas, F. J.; Gonzalez,
J. M. Adv. Synth. Catal. 2001, 343, 335.
Synthesis 2010, No. 22, 3879–3882 © Thieme Stuttgart · New York