New iodination reactions of saturated hydrocarbons

Article abstract of DOI:10.1002/anie.200501195

Unactivated C-H bonds react with iodine when exposed to trimethylsilyl azide in the presence of a hypervalent iodine reagent or, alternatively, to aqueous H₂O₂, acetic anhydride, and sodium azide (see scheme). (Chemical Equation Presented).

Full text of DOI:10.1002/anie.200501195

Angewandte
Chemie
À
C H Activation
DOI: 10.1002/anie.200501195
New Iodination Reactions of Saturated
Hydrocarbons**
JosØ Barluenga,* Esther Campos-Gómez,
David Rodríguez, Francisco Gonzµlez-Bobes, and
JosØ M. Gonzµlez
Selective processes that afford functionalized derivatives
À
from the reaction of nonactivated C H bonds are of current
interest.[1] Bromination and chlorination reactions are val-
uable tools for this purpose with saturated hydrocarbons.[2]
[3]
However,the related iodination is not so well developed.
Herein,we report on new iodination reactions of alkanes
under mild thermal conditions. The process relies on the use
of the combination of hypervalent iodine,I ,and trimethyl-
2
silyl azide (TMSN3). Furthermore,a related and efficient
iodination in water,using H 2O2 as a convenient source for the
oxidant,has also been established.
Hydrocarbons can be iodinated under photochemical
conditions by employing PhI(OAc)2/I2/tBuOH,a process that
likely involves the formation of intermediate alkoxyl radi-
cals.[3e] Alternative processes that lead to the development of
[*] Prof. Dr. J. Barluenga, E. Campos-Gómez, Dr. D. Rodríguez,
Dr. F. Gonzµlez-Bobes, Dr. J. M. Gonzµlez
Instituto Universitario de Química Organometµlica “Enrique
Moles”
Unidad Asociada al C.S.I.C.
Universidad de Oviedo
33071 Oviedo (Spain)
Fax: (+34)98-510-3450
E-mail: barluenga@uniovi.es
[**] This research was partially supported by the Spanish DGI (MCT-01-
BQU-3853). E.C.-G. is grateful to the Spanish M.E.C. for an FPU
Fellowship. F.G.-B. thanks the Principado of Asturias for a pre-
doctoral fellowship. Generous support from Merck Sharp & Dohme
(UK) is gratefully acknowledged.
Supporting information for this article (13C NMR spectra of
compounds 2a–k) is available on the WWW under http://www.an-
gewandte.org or from the author.
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new methodology and involve different types of intermedi-
À
ates as the species responsible for the C H activation step are
of great significance and,overall,might result in new and
distinctive synthetic features. Being interested in employing
more convenient thermal conditions,we decided to inves-
tigate reactions using azide to activate the hypervalent iodine
reagent.[4] 1-Acetoxy-1,2-benziodoxole-3(1H)-one[5] was
chosen as the hypervalent iodine reagent. We expected that
a catalytic amount of azide would be able to promote the
desired iodination. This assumption was initially validated
Scheme 1. Synthesis of iodocyclohexane 2a from the thermal reaction
of cyclohexane (1a) with I2 promoted by a cyclic l3-iodane and catalytic
amounts of TMSN3 (Method A, Table 1).
with cyclohexane (1a) as model compound,using TMSN as
3
the azide donor (Scheme 1).
The concentration of the azide
Table 1: Thermal iodination of hydrocarbons 1 to give alkyl iodides 2.
is crucial to accomplish the reported
iodination. Routinely,to investigate
the scope of the iodination (meth-
od A),[6] 4 ” 10À3
m of azide was
Entry
1
1
Method
t [h]
2
Yield[a]
used. The results are summarized
in Table 1. This novel iodination can
be applied to different alkanes,
either cyclic or acyclic. Interest-
ingly,for the latter,an improved
selectivity is noted.[3e] Now,only
secondary positions are iodinated,
without significant evidence for
related functionalization of the pri-
mary ones. Benzylic positions are
equally cleanly iodinated. This new
reaction provides useful indicators.
It relies on a thermal process;
moreover,the use of a catalytic
amount of azide and the observed
selectivity for the iodination of
linear hydrocarbons are also signifi-
cant. Furthermore,this new process
is very convenient with regard to
the isolation of 2,as well as the
recovery of the reaction by-product.
o-Iodobenzoic acid can be easily
removed and recycled by simple
aqueous extraction at proper pH.
For the iodination of xylenes,an
additional feature is noted. These
are very efficient processes,which
give rise to an increase in the
incorporation of iodine atoms into
the organic structure. Now,under
proper conditions,most of the I 2 can
be successfully used to functionalize
the hydrocarbon.[7] On the basis of
the formed products,the well-docu-
mented chemistry of azidobenzio-
doxoles,and taking into consider-
ation the above-mentioned fea-
tures,we propose that the sequence
in Scheme 2 offers a feasible mech-
anistic rationalization for the
reported iodinations.
A[b]
B[c]
15
19
0.91
1.31 (1.43)[d]
A
B
18
13
0.89
2
3
1.88 (1.99)[d]
A
B
18
8
0.71[e,f]
1.03[e] (1.33)[d]
A
B
18
6
0.38 (0.90)[f]
1.33 (1.42)[d]
4
5
[g]
A
B
30
13
–
1.27
A
B
56
13
0.58 (0.90)[h]
1.08
6
7
A
B
18
19
1.59
1.18
A
B
18
19
1.54
1.68
8
9
A
B
18
9
1.58
0.57
A
B
17
20
0.79
1.46
10
11
A
B
15
18
0.43[i]
[j]
–
[a] Given as the ratio between mmol of isolated iodinated compound 2 per mmol of added iodine (mmol
of 2 per mmol of I2). [b] See Scheme 1 and reference [6]. [c] See Scheme 3 and reference [15]. [d] In
1
parentheses, yield obtained by integration from the H NMR spectra of the crude reaction mixture (1-
phenylethanol or anisole were used as an externally added standard to record the NMR spectra).
[e] Ratio 2c:2c’ꢀ2.3:1, by 1H NMR spectroscopy (300 MHz) and GC. [f] Using one equivalent of
TMSN3 with respect to the iodane. Iodination of 1c was not observed when 10 mol% of TMSN3 was
used. [g] 0.62 mmol of trans-1-acetoxy-1-methyl-2-iodocyclohexane were formed. See reference [3e].
[h] Reaction time 20 h, one equivalent of TMSN3 was used. [i] Ratio 2k:2k’ꢀ1:1.1 by GC. [j] Only traces
of iodinated derivatives were detected.
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Angewandte
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noted differences for the adsorption of n-
alkanes on the surface of water might
account well for the trend in terms of
reactivity in a qualitative sense.[16] This
approach offers a convenient method to
conduct the iodination of a varied and
representative set of hydrocarbons in the
presence of water.[17] At the same time,
this is a very efficient protocol for directly
iodinating alkanes,particularly,consider-
ing the high percentage of iodine that is
typically incorporated into the structure
of the hydrocarbon.
Overall,new reactions and significant
experimental advances have been ach-
ieved for the iodination of hydrocarbons,
which is a notoriously difficult reaction.
At the same time,new perspectives for
the use of well-established cyclic azidoio-
danes have been offered by the present
study. The examination of the possible
reaction paths followed by using different
hypervalent iodine reagents is also of
interest with regard to investigating alter-
Scheme 2. Proposed mechanism for the conversion of 1 into 2 (Method A, Table 1).
First,the starting acetoxyiodane leads to the formation of
the known[5b,c] azidoiodane A. Next,interaction with I 2 should
render active species,such as the iodanyl radical B,[8] a process
in which a fraction of iodine acts as an efficient scavenger of
azido radicals. The radical B would be responsible for the
activation of the alkane[9] giving rise to o-iodobenzoic acid
and a C-centered radical C,which then furnishes 2[10] by
trapping iodine.[11]
In an attempt to perform related reactions using simpler
reagents we have explored the reaction of alkanes with iodine,
aqueous solutions of NaN3,[12] and H2O2 as oxidant.[13] We
found that,in the presence of acetic anhydride,an efficient
iodination reaction takes place,as depicted in Scheme 3 for
native reactive combinations based on simpler reagents.
Further studies on the scope and implications of the herein
reported chemistry are underway in our laboratories.
Experimental Section
Warning: We have not experienced any explosions while conducting
our experiments,either using method A or B (so far,we carried out
reactions that lead to about 5 mmol of compounds 2); however,much
care should be taken when working with azides,especially when
heating them,as they are potentially explosive compounds.
Method A: All reactions were carried out under a positive
pressure of nitrogen. In a typical experiment,I 2 (1.1 mmol,0.28 g) and
TMSN3 (10%,13 mL) were sequentially added to a suspension of 1-
acetoxy-1,2-benziodoxol-3(1H)-one (1 mmol,0.31 g) in cyclohexane
(25 mL). The resulting mixture was stirred at 608C (bath temper-
ature) for 15 h. The mixture was allowed to cool and then quenched
with aqueous NaOH (5%,25 mL). The organic layer was distilled
under reduced pressure,and excess cyclohexane was recovered. The
distillation residue was diluted with diethyl ether (20 mL) and washed
with aqueous Na2S2O3 (5%,30 mL),brine (30 mL),and dried over
anhydrous Na2SO4. The solvent was removed at reduced pressure and
the resulting oil was further purified by column chromatography,by
using a mixture of hexanes as eluent,to afford cyclohexyl iodide 2a
(0.21 g,0.91 mmol) as an irritating colorless oil.
À
Scheme 3. Synthesis of a-iodotoluene (2b) by a C H functionalization
reaction in water (Method B, Table 1).
Method B: In
a typical experiment,Ac 2O (1.2 mL),H 2O
the functionalization of the benzylic position of toluene. The
addition of small amounts of water adjusts the concentration
of H2O2 and minimizes the formation of by-products (alcohol,
(0.5 mL),and NaN (0.20 g,3 mmol) were sequentially added to a
3
cooled solution (water/ice bath) of I2 (0.25 g,1 mmol) in toluene
(5 mL). H2O2 (30% in water,0.3 mL) was added and the mixture was
vigorously stirred at 408C for 13 h. The reaction mixture was poured
into a saturated solution of NaHCO3 (20 mL) and washed with
aqueous Na2S2O3 (5%,15 mL). The organic layer was dried over
anhydrous Na2SO4,and the excess toluene was recovered by
distillation. The yellowish residue was purified by column chroma-
tography,by using a mixture of hexanes as eluent,to afford benzyl
iodide 2b (0.41 g,1.88 mmol) as a lachrymatory pale yellow oil.
acetate).[14]
[15]
This new reaction (see Table 1,method B
for data
concerning the scope),on average,shows improved efficiency
with respect to iodine incorporation into the organic pre-
cursor,allows an easy isolation of compounds 2,and retains
the selectivity for the iodination of secondary versus primary
positions. Accordingly,linear pentane ( 1c) is nicely iodinated;
however,the related n-hexane (1k) fails to react to appreci-
able extension. Though yet very preliminary,the previously
Received: April 5,2005
Published online: August 10,2005
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5853

Communications
À
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Keywords: alkanes · azides · C H activation ·
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at 608C for 24 h,furnished 2a (99%,with respect to A). No
reaction was observed when 1a and A were mixed and heated at
608C for 24 h.
[11] For functionalization reactions that incorporate more than
1 mmol of atomic iodine for each mmol of added I2,the
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ruled out,at present.
[2] R. H. Crabtree,A. Habib in Comprehensive OrganicSynthesis,
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dramatic decrease of the efficiency of the iodination reaction.
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H2O (0.5 mL),I 2 (1 mmol),NaN 3 (3 mmol),H 2O2 (30% aqueous
solution,0.3 mL). Reagents were mixed at 0 8C and vigorously
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À
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3281.
2
3
mol% referred to the benziodoxole).
[7] Previously,only one method has been reported incorporating
more than one atom of iodine into the alkane for each molecule
of the iodine source (CI4),see reference [3b].
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