NaIO4-KI-NaN3 as a new reagent system for C-H functionalization in hydrocarbons

Article abstract of DOI:10.1016/j.tetlet.2008.08.071

The NaIO₄-KI-NaN₃ combination has been found to be an efficient, reliable, and inexpensive reagent system for mono- and 1,2-difunctionalization of hydrocarbons via C-H bond activation to afford vicinal azido- and acetoxy iodinations of cyclic hydrocarbons.

Full text of DOI:10.1016/j.tetlet.2008.08.071

Tetrahedron Letters 49 (2008) 6401–6403
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
NaIO4–KI–NaN3 as a new reagent system for C–H
functionalization in hydrocarbons
*
Pandurang V. Chouthaiwale, Gurunath Suryavanshi, Arumugam Sudalai
Chemical Engineering and Process Development Division, National Chemical Laboratory, Pashan Road, Pune 411 008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The NaIO4–KI–NaN3 combination has been found to be an efficient, reliable, and inexpensive reagent
system for mono- and 1,2-difunctionalization of hydrocarbons via C–H bond activation to afford vicinal
azido- and acetoxy iodinations of cyclic hydrocarbons.
Received 18 June 2008
Revised 18 August 2008
Accepted 21 August 2008
Available online 25 August 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Azides
C–H activation
Iodination
NaIO4
Direct and selective replacement of C–H bonds in hydrocarbons
with C–C, C–O, C–N, and C–X groups is an important and long-
standing goal in chemistry.1 Generally, for monofunctionalization
of unactivated C–H bonds, catalytic systems such as organometal-
lic compounds,2a metallo-porphyrin complexes,2b superacids,2c Gif
and Gif-Orsay systems,2d MeReO3/H2O2,2e OsO4,2f polyoxometal-
lates,2g and other systems1 have been reported. In particular, a
new, effective method for 1,2-functionalization of unactivated
C–H bonds in a single step, which represents a major challenge
for chemists, has been developed by Barluenga’s group.3 In addi-
tion, free-radical iodinations of hydrocarbons with iodine, despite
its endothermic nature, have emerged as a useful route for the
activation of C–H bonds in hydrocarbons.4
During the course of our study on NaIO4-mediated oxidative
halogenations,5 we noticed that regiospecific addition of I–N3,6
generated in situ, onto styrenes took place in an anti-Markovnikov
fashion, suggesting a probable radical pathway.7 This prompted us
to explore the effectiveness of the NaIO4–KI–NaN3 combination in
the C–H activation of alkanes. We report here the use of NaIO4–KI–
NaN3 to selectively functionalize the C–H bonds of hydrocarbons to
produce iodoalkanes 2a–g, 1-acetoxy- or 1-azido-2-iodocycloalk-
anes 3a–d (Scheme 1) or benzyl azides 5, in excellent yields upon
reaction with the respective hydrocarbons.
I
I
i
i
25 oC
X
99%
i = NaIO4, KI, NaN3, AcOH
at 45 oC, X = N3, 65%
at 75 oC, X = OAc, 94%
Scheme 1. NaIO4-mediated C–H activation of cyclohexane.
a variety of alkanes including cyclic and acyclic, and its completion
is readily ascertained by a distinct color change in the reaction
from dark brown to colorless. The presence of both NaIO4 and
NaN3 was essential for obtaining high yields of iodoalkanes 2a–g.
Interestingly, for linear alkanes, an improved selectivity was ob-
served as only the methylene positions were iodinated (Table 1,
entries e–g).
Surprisingly, for cyclooctane under the same reaction condi-
tions, the reaction took a different course to furnish 3a in 60% yield
along with 2d in 15% yield (Table 2).
However, with 6 molar equiv of NaN3, 3a was obtained in 85%
yield with syn:anti ratio of 2:1. In contrast, vigorous stirring of
2 equiv each of NaIO4 and NaN3 along with KI (1 equiv) gave only
2d in 99% yield (Table 1). It was also found that both NaIO4 and
NaN3, in appropriate concentrations, were critical in determining
product selectivities. Thus, for cyclohexane, at 45 °C, with 3 molar
equiv of NaN3, 2a (81%) was obtained along with 3b (10%) and 3c
(5%), while use of 6 molar equiv of NaN3 resulted in improved
product selectivity: 3b (62%) and 3c (35%). At 75 °C, an excellent
yield of 3c (94%) was realized with NaIO4 (2 equiv; 10 mmol). For
cyclopentane, at 45 °C, only cyclopentyl monoacetate (5f) was
When cyclohexane was treated with NaIO4, KI, and NaN3 (all
1 equiv) in acetic acid at 25 °C, iodocyclohexane (2a) was isolated
in 32% yield; however, the yield was increased to 99% when
3 equiv of NaN3 was used. This novel iodination8 is successful for
* Corresponding author. Tel.: +91 20 25902174; fax: +91 20 25902676.
E-mail address: a.sudalai@ncl.res.in (A. Sudalai).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.071

6402
P. V. Chouthaiwale et al. / Tetrahedron Letters 49 (2008) 6401–6403
Table 1
Table 3
NaIO4-mediated azidation at the benzylic C–H bond of alkyl arenesa
a
NaIO4-mediated iodination of alkanes with KI and NaN3
NaIO4, KI
NaIO4, KI
Ar-CH2N3
R-I
Ar-CH3
4
R-H
NaN3, AcOH, 25 oC
NaN3, AcOH, 25 oC
2a-g
1
5a-e
Entry
Arene (4)
t (h)
Benzyl azide (5)
Benzyl azide
2-Methylbenzyl azide
3-Methylbenzyl azide
4-Methylbenzyl azide
3,5-Dimethylbenzyl azide
Yieldb (%)
Entry
R–H (1)
t (h)
Yield of 2b (%)
a
b
c
d
e
Toluene
8
8
7
8
7
95
85
90
93
89
a
b
c
d
e
f
Cyclohexane
Cyclopentane
Cycloheptane
Cyclooctane
n-Pentane
8
6
8
4
9
6
8
99
98
o-Xylene
m-Xylene
p-Xylene
Mesitylene
99
99c
99 (2:1)d
98 (1.1:1)e
97 (2.5:2.2:1)f
n-Hexane
n-Heptane
a
Reaction conditions: arene (5 mL), NaIO4 (5 mmol), KI (5 mmol), NaN3
g
(30 mmol), glacial AcOH (20 mL), 25 °C.
b
a
Yield was calculated based on KI.
Reaction conditions: alkane (5 mL), NaIO4 (5 mmol), KI (5 mmol), NaN3
(15 mmol), glacial AcOH (15 mL), 25 °C.
b
Yield was calculated based on KI.
2 equiv each of NaIO4 and NaN3 used.
2-I:3-I pentane.
c
heptane and cyclopentane, nucleophilic substitution becomes a
favorable process.10
d
e
2-I:3-I hexane.
f
2-I:3-I:4-I heptane; (ratios determined by 1H NMR and GC).
Direct azidation via functionalization at Ar–C–H bonds is an
atom economical route in organic synthesis.11 A recent report on
direct azidation of activated arenes using polymer-supported
iodine azide has established that a certain electron-donating
capacity is needed at the benzylic position for the reaction to
occur.12 With the NaIO4–KI–NaN3 system (1:1:3 molar ratio), we
found that toluene was functionalized smoothly at the benzylic
position to give benzyl azide (85%) along with benzyl acetate
(10%). Further, on increasing the concentration of azide (6 equiv),
exclusive formation of monobenzyl azide 5a (95%) was realized.13
Notably, no polyazidation took place for other alkylarenes even if
greater equivalents of NaN3 were used (Table 3).
Table 2
a
NaIO4-mediated 1,2-difunctionalization of cycloalkanes with KI and NaN3
Entry
R–H (1)
NaN3
(equiv)
t (h)
T (°C)
Yield of 3b (%)
I
I
+
1
N3
3a
2d
Mechanistically, NaIO4 oxidizes KI as well as NaN3 simulta-
5
neously, to liberate I2 and an azide radical,14 respectively, combi-
3
6
4
4
25
25
60
15
—
85c
nation of which results in the formation of I–N3. To confirm the
formation of I2, the alkane was treated with molecular iodine
I
I
instead of KI and we found that similar results were indeed obtained.
+
N3
2
12c
Homolysis of I–N3
provides an azide radical, which abstracts a
OAc
proton from alkanes to produce alkyl radical A. Combination of
radical A with I2 followed by oxidative elimination of the resulting
alkyl iodide15 generates alkene 6 (confirmed by GC analysis). Addi-
tion of either I–N3 or I–OAc across the double bond of 6 produces
3b and 3c, respectively (Scheme 2). Evidence for the radical path-
way is deduced from the following experiments: (i) no reaction
3c
3b
3
6
3
3
24
24
10
10
45
45
75
75
10
62
—
5d
35
70e
94f
—
OH
O
O
I
took place in the presence of N-tert-butyl-a-phenylnitrone, a radi-
cal scavenger;12c (ii) regioselective azidoiodination of styrene
under the reaction conditions led to the isolation of 2-azido-1-
iodo-ethylbenzene.6 In the case of direct azidation of alkyl arenes,
the involvement of a benzyl radical followed by a benzyl cation12a
is similarly proposed.
3
3d
g
3
6
10
30
45
45
—
50h,i
a
Reaction conditions: cycloalkane (5 mL), NaIO4 (5 mmol), KI (5 mmol), glacial
In conclusion, we have described NaIO4–KI–NaN3 as a new effi-
cient system suitable for mono and 1,2-difunctionalization of
hydrocarbons via C–H bond activation. In particular, vicinal azido-
AcOH (15 mL).
b
c
d
e
f
Yield was calculated based on KI.
syn:anti = 2:1 by 1H NMR.
2a was formed in 81% yield.
2a was also formed in 25% yield.
2 equiv of NaIO4 was used.
cyclopentyl acetate 5f was formed in 95% yield.
Cyclopentyl acetate 5f was also formed in 46% yield.
Stereochemistry was not assigned.
g
h
i
.
.
I
I or I2
I
N3
-HN3
A
obtained in 95% yield, whereas an increase of azide concentration
(6 molar equiv) gave an unusual 1, 2-dihydroxyiodo derivative9
3d in 50% yield along with 5f (46%) (Table 2). In the case of cyclo-
heptane, an increase of either the temperature or the azide concen-
tration resulted in only cycloheptyl monoacetate in 96% yield.
Overall, increasing the temperature facilitates oxidative elimina-
tion of the iodoalkane to furnish an alkene, thereby giving higher
yields of difunctionalized products. However, in the case of cyclo-
I-OAc
or
I-N3
I
O
X
6
3b X =N3
3c X = OAc
Scheme 2. Proposed mechanism.

P. V. Chouthaiwale et al. / Tetrahedron Letters 49 (2008) 6401–6403
6403
8. General experimental procedure for iodination of alkanes: To a suspension of
NaN3 (0.975 g, 15 mmol) and KI (0.830 g, 5 mmol) in glacial acetic acid (20 ml)
at 25 °C was added NaIO4 (1.069 g, 5 mmol), and the reaction mixture was
stirred for 5 min during which time the reaction turned dark brown in color.
Alkane (5 ml) was then added, and the reaction mixture was stirred at the same
temperature for 8 h until the mixture became colorless. The reaction mixture
was poured into water (100 ml) and extracted with CH2Cl2 (3 Â 50 ml)). The
combined organic layers were washed with a saturated solution of NaHCO3
(50 ml) and aqueous Na2S2O3 (5%, 50 ml), dried over an hyd. Na2SO4, and
concentrated. Unreacted alkanes were recovered by simple distillation under
reduced pressure to give the crude product, which was purified by column
chromatography (silica gel 60-120 mesh) using petroleum ether as eluent to
afford the pure product 2a–g.
and acetoxy iodinations of cyclic hydrocarbons in high yield and
selectivity are unique and unprecedented. A high yield direct azi-
dation at the benzylic position in less activated alkyl arenes has
been demonstrated under ambient conditions.
Acknowledgments
The author PVC thanks CSIR and DST, New Delhi (Sanction No.
SR/S1/OC-22/2002) for financial support. The authors also thank
Dr. B.D. Kulkarni, Head, CE-PD for his encouragement and support.
Spectral data for compound 2a: Colorless oil; Yield: 99%; IR (CHCl3)
m 2933,
2854, 1448, 1215, 1172, 1095, 987, 759, 669, cmÀ1 1H NMR (200 MHz, CDCl3) d
;
References and notes
1.37–1.49 (m, 3H), 1.64–1.74 (m, 3H), 1.93–2.05 (m, 2H), 2.13–2.20 (m, 2H),
4.30–4.43 (m, 1H); 13C NMR (50 MHz, CDCl3): d 25.14, 27.22, 32.66, 39.51;
Anal. calcd. for C6H11I: C, 34.31; H, 5.28. Found C, 34.30; H, 5.30.
9. Presumably formed by displacement of the corresponding 2-iodocyclopentyl
acetate with water.
10. Liu, B.; Shine, H. J. J. Phys. Org. Chem. 2001, 14, 81.
11. Eric, F. V.; Turnbull, K. Chem. Rev. 1988, 88, 297.
12. (a) Viuf, C.; Bols, M. Angew. Chem., Int. Ed. 2001, 40, 623; (b) Baruah, M.; Bols, M.
Synlett 2002, 1111;; (c) Marinescu, L. G.; Pedersen, C. M.; Bols, M. Tetrahedron
2005, 61, 123.
13. General experimental procedure for azidation of alkyl arenes: To a suspension of
NaN3 (1.950 g, 30 mmol) and KI (0.830 g, 5 mmol) in glacial acetic acid (20 ml)
at 25 °C was added NaIO4 (1.069 g, 5 mmol), and the reaction mixture was
stirred for 5 min during which time the reaction turned dark brown in color.
Alkyl arene (5 ml) was added and the reaction mixture was stirred at the same
temperature for 8 h. The reaction mixture was poured into water (100 ml) and
extracted with CH2Cl2 (3 Â 50 ml)). The combined organic layers were washed
with a saturated solution of NaHCO3 (50 ml) and aqueous Na2S2O3 (5%, 50 ml),
dried over anhyd. Na2SO4, and concentrated. Unreacted alkyl arene was
recovered by simple distillation under reduced pressure to give the crude
product, which was purified by column chromatography (silica gel 60–120
mesh) using petroleum ether as eluent to afford the pure product 5a–e.
1. (a) Activation and Functionalization of C–H Bonds, ACS Symposium Series 885;
Goldberg, K. I., Goldman, A. S., Eds.; American Chemical Society: Washington,
DC, 2004; (b) Curci, R.; D’Accolti, L.; Fusco, C. Acc. Chem. Res. 2006, 39, 1; (c)
Godula, K.; Sames, D. Science 2006, 312, 67; (d) Labinger, J. A.; Bercaw, J. E.
Nature 2002, 417, 507.
2. (a) Crabtree, R. H. Chem. Rev. 1995, 95, 987;; (b) Mansuy, D. Pure Appl. Chem.
1987, 59, 759; (c) Sommer, J.; Bukala, J. Acc. Chem. Res. 1993, 26, 370; (d) Barton,
D. H. R. NATO ASI Ser., Ser. E: Appl. Sci. 1996, 320, 589; (e) Murray, R. W.; Iyanar,
K.; Chen, J.; Wearing, J. T. Tetrahedron Lett. 1995, 36, 6415; (f) Bales, B. C.;
Brown, P.; Dehestani, A.; Mayer, J. M. J. Am. Chem. Soc. 2005, 127, 2832; (g) Hill,
C. L. Catal. Met. Complexes 1992, 9, 253.
3. (a) Barluenga, J.; Gonzalez-Bobes, F.; Gonzalez, J. M. Angew. Chem., Int. Ed. 2002,
41, 2556; (b) Davies, H. M. L.; Jin, Q. Org. Lett. 2005, 7, 2293.
4. (a) Tanner, D. D.; Gidley, G. C. J. Am. Chem. Soc. 1968, 90, 808; (b) Schreiner, P.
R.; Lauenstein, O.; Butova, E. D.; Fokin, A. A. Angew. Chem., Int. Ed. 1999, 38,
2786; (c) Fokin, A. A.; Lauenstein, O.; Gunchenko, P. A.; Schreiner, P. R. J. Am.
Chem. Soc 2001, 123, 1842; (d) Schreiner, P. R.; Lauenstein, O.; Butova, E. D.;
Gunchenko, P. A.; Kolomitsin, I. V.; Wittkopp, A.; Feder, G.; Fokin, A. A. Chem.
Eur. J. 2001, 7, 4997; (e) Monotoro, R.; Wirth, T. Org. Lett. 2003, 5, 4729; (f) Giri,
R.; Chen, X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2005, 44, 2112; (g) Barluenga, J.;
Campos-Gomez, E.; Rodriguez, D.; Gonzalez-Bobes, F.; Gonzalez, J. M. Angew.
Chem., Int. Ed. 2005, 44, 5851.
5. (a) Dewkar, G. K.; Narina, S. V.; Sudalai, A. Org. Lett. 2003, 5, 4501; (b)
Emmanuvel, L.; Shaikh, T. M. A.; Sudalai, A. Org. Lett. 2005, 7, 5071; (c) Shaikh,
T. M.; Sudalai, A. Tetrahedron Lett. 2005, 46, 5587; (d) Emmanuvel, L.; Shukla, R.
K.; Sudalai, A.; Suryavanshi, G.; Sivaram, S. Tetrahedron Lett. 2006, 47, 4793.
6. We have observed that styrene was converted cleanly into 2-azido-1-iodo-
ethylbenzene under similar reaction conditions.
Spectral data for compound 5a: Colorless liquid; Yield: 95%; IR (CHCl3)
3015, 2930, 2877, 2097, 1605, 1586, 1496, 1455, 1255, 1217, 758, 699,
668 cmÀ1 1H NMR (200 MHz, CDCl3) d 4.33 (s, 2H), 7.34–7.43 (m 5H); 13C NMR
m 3032,
;
(50 MHz, CDCl3): d 54.70, 128.15, 128.23, 128.76, 135.30; Anal. calcd. for
C7H7N3: C, 63.14; H, 5.30; N, 31.56. Found C, 63.00; H, 5.40; N, 31.20.
14. (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.
15. Patai, S.; Rappoport, Z. The Chemistry of Functional Group; John Wiley & Son,
1983. Chapter 18, p 744.
7. (a) Abbe, L.; Hassner, A. Angew. Chem., Int. Ed. 1971, 10, 98; (b) Workentin, M.
S.; Wagner, B. D.; Lusztyk, J.; Wayner, D. D. M. J. Am. Chem. Soc. 1995, 117, 119.