Metal-free efficient, general and facile iododecarboxylation method with biodegradable co-products

Article abstract of DOI:10.1002/adsc.201100145

The development of a novel, efficient and robust method for the general conversion of aliphatic and aromatic carboxylic acids to organic iodides without the use of heavy metals or strong oxidizing agents is reported. Commercially available N-iodoamides were used for both initiation and halogen donation under irradiative conditions. Isolation of the product is extremely simple and the major co-product is removed as a water-soluble biodegradable material. Copyright

Full text of DOI:10.1002/adsc.201100145

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DOI: 10.1002/adsc.201100145
Metal-Free Efficient, General and Facile Iododecarboxylation
Method with Biodegradable Co-Products
a
a
a,
Kseniya Kulbitski, Gennady Nisnevich, and Mark Gandelman *
a
Schulich Faculty of Chemistry, Technion – Israel Institute of Technology, Technion City, Haifa 32000 Israel
Fax : (+972)-4-829-3703; phone: (+972)-4-829-5951; e-mail: chmark@tx.technion.ac.il
Received: February 28, 2011; Published online: June 14, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100145.
Abstract: The development of a novel, efficient and
robust method for the general conversion of ali-
phatic and aromatic carboxylic acids to organic io-
dides without the use of heavy metals or strong oxi-
dizing agents is reported. Commercially available
N-iodoamides were used for both initiation and hal-
ogen donation under irradiative conditions. Isola-
tion of the product is extremely simple and the
major co-product is removed as a water-soluble bio-
degradable material.
Keywords: green chemistry; halogenation; iodode-
carboxylation; organic iodides; synthetic methods
Organic iodides are highly versatile and useful re-
agents in organic chemistry. They are commonly used
as substrates for the synthesis of pharmaceutical and
agricultural materials, and also used as contrast
[
1]
agents in medical applications. They have found par-
ticular use in nucleophilic displacement reactions and
in metal-mediated homo- and heterocoupling process-
es due to the relatively weak nature of the CÀI
[2]
bond. The preparation of these compounds by iodo-
decarboxylation of carboxylic acids is a particularly
[
3]]
attractive approach due to the following considera-
tions: carboxylic acids are broadly available and inex-
pensive substrates, and unreacted acid can easily be
separated from the product by basic work-up. Al-
though there are several existing methods in the liter-
ature for iododecarboxylation, each has different limi-
tations hampering their use in industrial or routine
[
3]
laboratory applications. In the classical Hunsdieck-
er–Borodin reaction, the silver salt 1, which should be
separately prepared from the corresponding carboxyl-
ic acid and isolated, is extremely sensitive to water
[
Scheme 1, (a)]. Modified Hunsdiecker reactions uti- Scheme 1. Existing iododecarboxylation methods (a)–(f),
lize direct treatment of the acid with mercury oxide and (g) the approach pursued in this work.
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Adv. Synth. Catal. 2011, 353, 1438 – 1442

Metal-Free Efficient, General and Facile Iododecarboxylation Method
or lead tetraacetate [Scheme 1, (b) and (c)]. The use
of heavy metals in these reactions is not suitable for
pharmaceutical applications. Barton iododecarboxyla-
tion [Scheme 1, (d)] is an attractive metal-free alter-
native; however it is operationally complex and not
an atom economical procedure. Thus, Barton esters 3,
which are prepared from N-hydroxypyridine-2-thione
2
, decompose in the presence of the iodine donor
(
CF CH I or CHI ) to give the desired organic iodide Scheme 2. Hypothesized mechanistic pathway for our ap-
3
2
3
and related organic co-product 4 which should be spe- proach.
cially separated. Prior conversion of carboxylic acids
to acyl chlorides is commonly required for the prepa-
[
4]
ration of the Barton esters 3. Another metal-free io- a wide range of primary, secondary, tertiary alkanoic
dodecarboxylation process, which tolerates a wide and aromatic carboxylic acids. Moreover, the reaction
range of substrates, involves the reaction of a carbox- produces a clean product and the only co-product
ylic acid with (diacetoxyiodo)benzene and molecular formed is both non-toxic, biodegradable, and water-
iodine [the Suꢁrez reaction; Scheme 1, (e)]. However soluble after a simple one-step work-up.
the use of hypervalent iodine
A
H
U
G
R
N
U
G
All known radical iododecarboxylation reactions
relatively strong oxidizing agents, may lead to produc- [Scheme 1, (a)–(e)] involve multicomponent mixtures
tion of unwanted mixtures of side products (vide of reagents. We were interested in pursuing an ap-
infra). Additionally, the excess acetic acid also pro- proach which would use a single metal-free com-
duced during the course of the reaction can compete pound as both initiator and iodinating agent. Towards
[
3]
with poorly reactive carboxylic acid substrates.
this end, we examined simple N-iodoamides possess-
Moreover, formation of at least one equivalent of ing the relatively weak NÀI bonds [bond dissociation
[
5]
À1 [9]
toxic and not biodegradable iodobenzene as a co- energy (BDE) 30–50 kcalmol ]. We hypothesized
product seriously hampers the potential application of that homolytic cleavage of the NÀI bond would result
this method on an industrial scale. A metal-free, pow- in an N-based radical A which could, in turn, reversi-
erful iododecarboxylation can be also achieved with bly abstract the carboxylic acid hydrogen to form
[
3]
[10]
tert-butyl hypoiodite (t-BuOI). However, this re- acyl
ACHTUNGTRENNUNG
agent is unstable and should be stored below 08C or H bonds in carboxylic acids [BDEACHTNUGTRENNUNG
3
[
6]
À1 [2]
freshly prepared in situ. In addition, CÀH bond iodi- 112 kcalmol ] is comparable to that of NÀH bonds
À1
nation in parallel to the desired iododecarboxylation in amides [BDE
A
H
U
G
E
N
N
(CH C(O)NH )=108 kcalmol ;
3
2
[
15]
À1 [11]
was reported for some cases. The existing methods BDE
A
H
U
G
R
N
U
G
Irreversible
2
2
described above are applicable to various alkanoic loss of CO would produce an R-radical which can be
2
acids, however the scope of aromatic acids as sub- iodinated with another molecule of the NÀI contain-
strates is severely limited.
ing compound.
Conversion of a,b-unsaturated alkenoic and alkyn-
In order to check the feasibility of this approach,
ACHTUNGTRENNUNGo ic carboxylic acids to 1-iodoalkenes and 1-iodoal- we examined several N-iodoamides. We were pleased
kynes using N-iodosuccinimide (NIS) and a basic cat- to find that when 5-phenylvaleric acid (7a) was react-
alyst or surfactants has been reported [Scheme 1, ed with either NIS or DIH in refluxing acetonitrile
[7]
(
f)]. This reaction presumably proceeds via an ionic under irradiation with a tungsten lamp, the desired
mechanism and involves formation of iodonium spe- product 7b was formed in 44% and 59% conversion
[
8]
cies 5 as a key intermediates. Therefore, an unsatu- using NIS and DIH, respectively (Table 1).
rated carbon-carbon bond a to the carboxylic unit is In general, we have found that although NIS can be
required and the method is highly limited to a,b-unsa- used for iododecarboxylation of numerous substrates
turated acid substrates. Our attempts to apply the re- (see Supporting Information), DIH usually leads to
ported reaction conditions to both alkanoic and aro- more efficient and clean reactions. Therefore, most of
matic carboxylic acids failed to furnish the corre- the studies presented below are based on the use of
sponding iododecarboxylation products.
DIH. Examination of the influence of solvent and
Here we report a novel, general, efficient and op- ratio of reagents showed that, under optimized condi-
erationally simple method for iododecarboxylation. tions, full conversion of 7a to 7b was observed with
We have found that the robust and commercially 1:1.5 mol ratio of acid:DIH in 1,2-dichloroethane
available 1,3-diiodo-5,5-dimethylhydantoin (DIH, 6) after 1 hour (Table 1, entry 7).
can be used as a sole reagent both as reaction initiator
and iodine source under irradiative conditions while not equivalent in terms of bond energy, are
Scheme 1, (g)]. This reaction does not use heavy both active for iododecarboxylation under the devel-
It should be noted that the two NÀI bonds in DIH,
[
[
12]
metals or strong oxidizing agents and is applicable to oped conditions. For example, when 1:0.5 mol ratio
Adv. Synth. Catal. 2011, 353, 1438 – 1442
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1439

Kseniya Kulbitski et al.
COMMUNICATIONS
[a]
Table 1. Optimization of reaction conditions.
diacid 18. Interestingly, we did not observe overiodi-
nated cubanes or by-products resulting from ring
[
15]
opening.
The iododecarboxylation of aromatic carboxylic
acids by known methods is more challenging than
their aliphatic counterparts, and is feasible with a se-
lected number of approaches on a limited scope of
substrates. Our methodology proved to be applica-
ble to aromatic acids, although longer reaction times
were required in order to achieve good yields
Entry
Solvent
Mol ratio
a:DIH
Conversion
[b]
7
[%]
[
3]
1
2
3
4
5
6
7
8
9
acetonitrile
acetonitrile
carbon tetrachloride
cyclohexane
ethyl acetate
1,2-dichloroethane
1,2-dichloroethane
1,2-dichloroethane
1,2-dichloroethane
1:1
1:1
1:1
1:1
1:1
1:1
A
H
U
G
R
N
U
G
44
59
40
45
62
83
100
(
Table 2, entries 17–20). Notably, we obtained hetero-
and homo-dihaloaromatic compounds in generally
good yields; these compounds are invaluable in se-
1:1.5
1:1
1:0.5
[
16]
[
c]
quential metal-mediated coupling reactions.
7
[
d]
An important facet of this methodology is the
facile work-up of the reaction mixture. At the conclu-
sion of the reaction, the species present include: the
desired organic iodide, unreacted acid (if any), mono-
N-iodo dimethylhydantoins, and 5,5-dimethylhydan-
toin (DMH) 6’. All unreacted N-iodo-containing com-
pounds are reduced to water-soluble DMH 6’ with
aqueous sodium bisulfite [see Scheme 1, (g)]. Treat-
ment with sodium bicarbonate transfers unreacted
60
[
a]
Reaction conditions D: reflux; hn: irradiation with tung-
sten lamp.
[
[
b]
c]
1
Conversion was determined by H NMR.
Reaction was performed without irradiation in refluxing
solvent.
Reaction time 8 h.
[
d]
of acid:DIH is used under standard conditions starting carboxylic acid to the aqueous phase as the
Table 1, entry 9), more than 50% conversion is ob- corresponding salt, and upon extraction and concen-
(
tained after 8 h (see also Table 2 entry 3).
tration the essentially clean product is obtained. Nota-
[17]
With these optimized conditions in hand, we fur- bly, DMH is a non-toxic biodegradable material.
ther examined the scope of this method. A broad
Although the mechanism has not been studied in
range of primary, secondary, and tertiary alkanoic car- depth, several indications point to a radical-type
boxylic acids reacted under these conditions mechanism. The reaction is substantially slower if per-
(
Table 2). Suitable substrates incorporating primary formed without irradiation. When iododecarboxyla-
carboxylic acid functionalities include linear, tion of 5-phenylvaleric acid was performed in the
branched, benzylic, and polyfluorinated derivatives. presence of 0.1 equiv. radical scavenger TEMPO, the
Notably, no erosion of the stereocenters is observed reaction was significantly slowed and conversion to
when the reaction is performed with enantiomerically product was reduced from 83% to 11% after one
pure carboxylic acids (entries 6 and 7).
hour. Further evidence of radical involvement is seen
Secondary carboxylic acids 14a and 15a can easily when acid 27a is subjected to standard reaction condi-
be converted into the corresponding synthetically val- tions. The formation of cyclic product 28 together
[
13]
uable cyclic iodides. While clean conversion of pi- with expected iodide 27b suggests radical transfer
peridine carboxylic acid 14a to the iodide 14b using from the putative acyloxyl species to the adjacent me-
the Suꢁrez reaction protocol proved to be challeng- thoxy group (Scheme 3). Additional studies are re-
[14]
ing, our method directly provided the desired com- quired in order to elucidate mechanistic details of this
pound in 87% yield. Iododecarboxylation of trans- process.
phenylcyclopropylcarboxylic acid 16a results in a mix-
In conclusion, we have developed a novel, efficient,
ture of cis- and trans-phenyliodocyclopropanes with and robust method for conversion of carboxylic acids
the thermodynamically favored trans-isomer as the to useful iodo-organic compounds using commercially
major product (entry 12).
available N-iodoamides. The broad scope of this
The suitability of tertiary carboxylic acids as sub- transformation includes application to primary, secon-
strates was explored by subjecting 4-methoxycarbo- dary, and tertiary alkanoic as well as aromatic carbox-
nylcubanecarboxylic acid 17a to the standard reaction
conditions. The corresponding iodide 17b was formed
in a high yields when either DIH or NIS were used
(
Table 2, entres 13). Compound 17b can then be hy-
drolyzed and the resulting iodo-cubanecarboxylic acid
7’a can then be selectively converted to diiodocu-
1
bane 17’b. This compound can also be obtained di-
rectly in high yield by di-iododecarboxylation of Scheme 3. Evidence for a radical pathway.
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Adv. Synth. Catal. 2011, 353, 1438 – 1442

Metal-Free Efficient, General and Facile Iododecarboxylation Method
Table 2. Representative examples of iododecarboxylation of carboxylic acids.
[a]
[a]
Entry R=
Mol ratio
Time Yield Entry R=
Mol ratio
Time Yield
[%]
RCO H:DIH [h]
[%]
RCO H:DIH [h]
2
2
[c]
1
1:1
6
85
12
1:1.2
2
66
[
d]
2
3
1:1.2
1:0.5
1:1
2
80
84
73
13
14
15
1:1.2
1:1.2
1:2.5
2
2
4
93
93
76
8
17’: Y=I
4
5
CH
CF
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(CH ) - 10
15
3
2 16
[e]
A
C
H
T
U
N
G
T
R
E
N
N
U
N
G
(CF ) - 11
1:1.5
1:1.2
24
2
78
83
16
1:1
1:1
15
15
80
43
3
2 12
1
7
8
6
1
1:1
15
15
52
95
7
8
9
1
12’: Y=HCOO-
1:1.2
1:1.5
1:1.2
1:1.2
2
2
2
2
87
77
19
20
21
22
1:1.5
1:2
15
24
24
82
61
80
[b]
87
80
1:1.5
1:1.5
0
1
14’: Y=BOC
1
1:1.2
3
75
23
1:1.5
15
47
[
[
[
a]
Isolated yield.
b]
75% yield is obtained after 4 h when 1.5 equiv. of NIS were used.
c]
trans-Phenylcyclopropylcarboxylic acid was used as a substrate. 7% of cis-phenyliodocyclopropane was obtained and isolated
from the reaction products.
The same yield is obtained with 1.5 equiv. NIS after 4 h.
[
[
d]
e]
The same yield is obtained with 2 equiv. of NIS after 15 h.
ylic acids. Isolation of the product is extremely simple tions of this methodology to the synthesis of valuable
and the major co-product is removed as a water-solu- materials and mechanistic studies of the process are
ble non-toxic material. Exploration of further applica- underway in our laboratories.
Adv. Synth. Catal. 2011, 353, 1438 – 1442
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1441

Kseniya Kulbitski et al.
COMMUNICATIONS
Experimental Section
[6] a) D. D. Tanner, G. C. Gidley, J. Am. Chem. Soc. 1968,
9
0, 808; b) R. Montoro, T. Wirth, Org. Lett. 2003, 5,
4
729.
General Procedure for Iododecarboxylation
[
7] a) J. P. Das, S. Roy, J. Org. Chem. 2002, 67, 7861; b) D.
Naskar, S. Chowdhury, S. Roy, Tetrahedron Lett. 1998,
A mixture of R-COOH (1 mmol), N-iodoamide (DIH or
NIS) (0.5–2 mmol), and solvent (3–6 mL) was irradiated
3
9, 699; c) K. C. Rajanna, N. M. Reddy, M. R. Reddy,
P. K. Saiprakash, J. Dispersion Sci. Technol. 2007, 28,
13.
8] C. Kuang, Q. Yang, H. Senboku, M. Tokuda, Synthesis
005, 1319.
(
tungsten-filament lamp) for 1–24 h under reflux conditions.
After cooling, the reaction mixture was washed with aque-
6
ous 1M NaHSO . The aqueous phase was extracted with
3
[
[
CHCl and combined organic fractions were washed with a
3
2
saturated solution of NaHCO , dried with Na SO , filtered
3
2
4
9] V. D. Filimonov, E. A. Krasnokutskaya, O. Kh. Pole-
shchuk, Yu. A. Lesina, V. K. Chaikovskii, Russ. Chem.
Bull. Int. Ed. 2006, 55, 1328.
through short silica pad and concentrated under vacuum to
give substantially pure iodide RÀI.
Supporting Information including experimental details,
product characterization and NMR spectra is available.
[
10] For homolytic NÀI bond cleavage, see: R. L. Tlumak,
J. C. Day, J. P. Slanga, P. S. Skell, J. Am. Chem. Soc.
1
982, 104, 7257.
11] F. G. Bordwell, G. Z. Ji, J. Am. Chem. Soc. 1991, 113,
398.
12] BDE(N(1)ÀI)=41 kcalmol ;
9 kcalmol : see ref. We suppose that under reaction
[
[
8
Acknowledgements
À1
BDE(N(3)ÀI)=
À1
[9]
2
We thank Elaine M. Schuster for valuable discussions.
conditions an equilibrium is established between initial-
ly formed NÀH and existing NÀI bonds. When DIH
and hydantoin 6 are mixed even at room temperature a
fast equilibrium was established and the mono-iodo de-
rivatives were observed by the NMR.
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 1438 – 1442