Iodination of organic substrates with halide salts and H2O2 using an organotelluride catalyst.

Article abstract of DOI:10.1021/ol0068142

[figure: see text] Organotelluride 1 is a water-soluble catalyst for the oxidation of iodide with hydrogen peroxide in pH 6 phosphate buffer. In two-phase systems, organic substrates are efficiently iodinated using 0.8 mol % of catalyst. Water-soluble substrates are iodinated without an organic cosolvent.

Full text of DOI:10.1021/ol0068142

ORGANIC
LETTERS
2001
Vol. 3, No. 3
349-352
Iodination of Organic Substrates with
Halide Salts and H O Using an
2 2
Organotelluride Catalyst
Donald E. Higgs, Marina I. Nelen, and Michael R. Detty*
Department of Chemistry, DiVision of Medicinal Chemistry, State UniVersity of
New York at Buffalo, Buffalo, New York 14260
mdetty@acsu.buffalo.edu
Received November 1, 2000
ABSTRACT
Organotelluride 1 is a water-soluble catalyst for the oxidation of iodide with hydrogen peroxide in pH 6 phosphate buffer. In two-phase
systems, organic substrates are efficiently iodinated using 0.8 mol % of catalyst. Water-soluble substrates are iodinated without an organic
cosolvent.
The halogenation of organic substrates is an important
reaction for the preparation of specialty, pharmaceutical, and
agricultural chemicals. The general method used to haloge-
nate organic substrates has been the use of bromine, chlorine,
or iodine. However, halogenation reactions have associated
environmental hazards with respect to transport, handling,
and storage of chlorine, bromine, and iodine.1 Halide salts
are safer commodities and can be oxidized to the corre-
sponding positive halogen/hypohalous acid by a variety of
methods. One method is the oxidation of chloride, bromide,
or iodide with H2O2, a powerful and environmentally friendly
oxidant.2 Although the oxidation of these halides with H2O2
is thermodynamically favored, it is kinetically slow.3 At
lower pH, the oxidation is accelerated and the hypohalous
acids generated from hydrochloric or hydrobromic acid and
H2O2 have been used for the successful halogenation of a
variety of organic substrates although acid-sensitive func-
tionality will not tolerate the reaction conditions.4
Nature has evolved the haloperoxidase enzymes to perform
biological halogenations at neutral pH with the available
H2O2 and halide salts found in seawater.5 In recent years,
chemists have sought catalysts to activate H2O2 and other
peroxides (such as tert-butyl hydroperoxide) to mimic the
function of the haloperoxidases and to provide environmen-
tally friendly means for the halogenation of organic sub-
strates.6 We have been interested in the activation of H2O2
using organotellurium compounds as catalysts and have
successfully performed halogenation reactions in the presence
(5) (a) Wever, R.; Kreen, M. B. E. In Vanadium in Biological Systems;
Chasteen, N. D., Ed.; Kluwer Academic Publishers: Dordrecht, The
Netherlands, 1990; pp 81-97. (b) Butler, A. In Bioinorganic Catalysis;
Reedijk, J., Ed.; Marcel Dekker: New York, 1992; pp 425-445. (c) Butler,
A.; Walker, J. V. Chem. ReV. 1993, 93, 1937-1944.
(6) (a) Conte, V.; Di Furia, F.; Moro, S. Tetrahedron Lett. 1994, 35,
7429-7432. (b) Dinesh, C. U.; Kumar, R.; Pandey, B.; Kumar, P. Chem.
Commun. 1995, 611-612. (c) Barhate, N. B.; Gajare, A. S.; Wakharkar,
R. D.; Bedekar, A. V. Tetrahedron Lett. 1998, 39, 6349-6350. (d) Bora,
U.; Bose, G.; Chaudhuri, M. K.; Dhar, S. S.; Gopinath, R.; Khan, A. T.;
Patel, B. K. Org. Lett. 2000, 2, 247-249.
(7) (a) Detty, M. R.; Gibson, S. L. J. Am. Chem. Soc. 1990, 112, 4086-
4088. (b) Detty, M. R.; Gibson, S. L. Organometallics 1992, 11, 2147-
2155. (c) Detty, M. R.; Friedman, A. E.; Oseroff, A. J. Org. Chem. 1994,
59, 8245-8250. (d) Detty, M. R.; Zhou, F.; Friedman, A. E. J. Am. Chem.
Soc. 1996, 118, 313-318.
(1) Clark, J. H.; Ross, J. C.; Macquarrie, D. J.; Barlow, S. J.; Bastock,
T. W. Chem. Commun. 1997, 1203-1204.
(2) Jones, C. W. Applications of Hydrogen Peroxide and DeriVatiVes;
“RSC Clean Technology Monographs”; Clark, J. H., Ed.; The Royal Society
of Chemistry: Cambridge, UK, 1999.
(3) (a) Leulier, A. Bull. Soc. Chim. Fr. 1924, 35, 1325-1330. (b)
Mohammed, A.; Liebhafsky, H. A. J. Am. Chem. Soc. 1934, 56, 1680-
1685.
(4) (a) Lubbecke, P.; Boldt, P. Angew. Chem. 1976, 88, 641-643. (b)
Keegstra, M. A.; Brandsma, L. Synthesis 1988, 890-891.
10.1021/ol0068142 CCC: $20.00 © 2001 American Chemical Society
Published on Web 01/06/2001

of H2O2 and halide salts.7 While these reactions have
demonstrated proof of principle, the positive halogen species
were trapped in the presence of a large excess of substrate,
limiting the synthetic utility of these earlier studies.
The activation of H2O2 with organotellurides is a multistep
process involving oxidative addition, ligand exchange, and
reductive elimination.7c,d The active halogenating species in
the telluride-catalyzed reactions may either be the free
halogen/hypohalous acid or a halotelluronium salt intermedi-
ate as illustrated in Scheme 1.8 The rate-limiting step in these
We report highly efficient iodination reactions employing
the organotelluride catalyst 1 (Figure 1b) for the oxidation
of iodide with H2O2. The catalyst 1 was designed to provide
water solubility and to optimize both oxidation with H2O2
and reductive elimination or halogen transfer. We anticipated
that the amino substituent of 1 would add electron density
to the telluride, which would facilitate oxidation with H2O2.
The oxygen atom of the phenoxypropyl group would chelate
the oxidized tellurium center by donating an electron pair
(via a five-membered ring, Figure 1b) to block addition of
iodide to form the I-Te-I array and to activate nucleophilic
attack at the iodo ligand. The catalyst 1 is readily oxidized
by hydrogen peroxide with a second-order rate constant of
(3.93 ( 0.08) × 102 M-1 s-1 in pH 6 phosphate buffer and
is an effective iodination catalyst at 0.8 mol % of substrate
(see Supporting Information for experimental details). As a
biscarboxylate salt, 1 is water-soluble and remains in solution
at pH 6, where the iodination reactions were run. The near-
neutral pH of these reactions is tolerated by most acid-
sensitive organic functionality. Furthermore, the reactions
can be run without an organic cosolvent if the substrates
have some aqueous solubility.
Scheme 1. Possible Halogenating Agents from the Oxidation
of Halide Salts with Organotelluride Catalysts
Biscarboxylate salt 1 was prepared from 4-N,N-bis-
(carboethoxymethyl)aniline as shown in Scheme 2. The
Scheme 2a
reactions appears to be the rate of reductive elimination or
cleavage of the halogen-tellurium bond.7d,8 The most
effective catalysts have some water solubility,7d and the most
active halogen transfer agents have a chelating heteroatom
as a ligand to the oxidized tellurium center (see Figure 1a).9
addition of TeCl4 to 4-N,N-bis(carboethoxymethyl)aniline
followed the procedure of Engman and Persson10 except that
1 equiv of pyridine was added to give pyridinium salt 2 as
an isolable intermediate,11 which was then reduced with
sodium bisulfite to give the ditelluride 3. Ditelluride 3 was
isolated as the major product in a 2:1 mixture with the
corresponding monotelluride (85% isolated yield of the
mixture). We were not able to separate the ditelluride from
the monotelluride in this mixture. Ditelluride 3 was reduced
with NaBH4 to the corresponding sodium aryltellurolate,
which reacted with 1-bromo-3-phenoxypropane to give the
Figure 1. (a and b) Chelating ligands that activate halo ligand on
tellurium. (c) Catalyst 1.
The chelating ligand prevents the addition of a second halide
to the oxidized tellurium atom while the positive charge
activates the halo ligand to nucleophilic attack.9
(8) (a) Leonard, K. A.; Zhou, F.; Detty, M. R. Organometallics 1996,
15, 4285-4292. (b) Butcher, T. S.; Zhou, F.; Detty, M. R. J. Org. Chem.
1998, 63, 169-176. (c) Butcher, T. S.; Detty, M. R. J. Org. Chem. 1999,
64, 5677-5681.
(9) (a) Detty, M. R.; Friedman, A. E.; McMillan, M. Organometallics
1995, 14, 1442-1449. (b) Detty, M. R.; Williams, A. J.; Hewitt, J. M.;
McMillan, M. Organometallics 1995, 14, 5258-5262.
(10) Engman, L.; Persson, J. Organometallics 1993, 12, 1068-1072.
(11) (a) Logan, M. E.; Decann, C. A.; Oenick, M. D. B.; Snodgrass, G.
L.; Snoke, R. E. Eur. Pat. Appl., 30 pp. CODEN: EP 747704 A2 961211.
Application: EP 96-304211 960606. Chem. Abstr. 1997, 126, 57086. (b)
Logan, M. E. (SUNY College at Brockport), private communication.
350
Org. Lett., Vol. 3, No. 3, 2001

bisester 4 in 74% isolated yield. Compound 4 was saponified
with 4 equiv of sodium hydroxide in aqueous EtOH to give
1 in >95% isolated yields.12
The 1-catalyzed iodinations of organic substrates with NaI
and H2O2 are summarized in Table 1 and used the following
1.12 For entry 8, the sodium salt of 4-pentenoic acid was
iodinated without an organic cosolvent and 5-iodo-γ-vale-
rolactone was isolated in a yield nearly identical to the two-
phase procedure of entry 1. In the absence of catalyst, less
than 10% conversion of substrate was observed after 24 h
for all substrates in Table 1.
The iodination of N,N-dimethylaniline (entry 6) and
N-phenylmorpholine (entry 7) gave the 4-substituted products
with >98% regioselectivity as determined by the H NMR
Table 1. Iodination of Organic Substrates with NaI, Hydrogen
Peroxide, and 0.8 mol % of Organotelluride Catalyst 1a
1
spectra of the crude product mixtures. The lactonizations of
4-pentenoic acid (entries 1 and 8), 2,2-diphenyl-4-pentenoic
acid13 (entry 2), and 2-(1-cyclohexen-1-yl) acetic acid14 (entry
3) as well as the cyclization of 4-pentenol (entry 4) gave
only products containing five-membered rings as determined
1
by H NMR. Unreacted 2-(1-cyclohexen-1-yl)acetic acid
(35%) was recovered from entry 3. The iodination of 1,3,5-
trimethoxybenzene (entry 5) gave 2-3% of the diiodo
product as determined by the 1H NMR spectrum of the crude
product mixture.
As shown for each substrate entry of Table 1, the
1-catalyzed iodinations with iodide and H2O2 gave results
nearly identical to the use of elemental iodine in two-phase
systems. Furthermore, neither the catalyzed iodination nor
the direct iodination with iodine was effective with unacti-
vated aromatic substrates (benzene, toluene) giving less than
10% iodination after 24 h with 5 equiv of H2O2 and 4 equiv
of NaI in the catalyzed reaction and less than 10% iodination
after 24 h with 2.5 equiv of iodine.
We are developing chlorination and bromination reactions
using chalcogenide catalysts with halide salts and H2O2. In
other systems, bromination reactions with organotelluride
reagents have been less efficient than iodination reactions
Table 2. Bromination of Organic Substrates with Sodium
Bromide, Hydrogen Peroxide, and 2.5 mol % of Organotelluride
Catalyst 1
general procedure. The substrate (2.5 mmol) and 1 (10.3 mg,
0.020 mmol) were dissolved in a stirred mixture of 25 mL
of ether and 50 mL of pH 6 phosphate buffer at ambient
temperature. Sodium iodide as a 2 M solution (2.75-5.0 mL)
and 2 M H2O2 (2.1-6.3 mL) were added independently in
small aliquots via syringe every 5 min over a 45-min interval
in the stoichiometry described in Table 1. The reaction
mixtures were stirred until reaction was complete (1-5 h)
as monitored by 1H NMR. The organic phase was separated
and the aqueous layer extracted with two additional aliquots
of ether. The combined ether extracts were washed with brine
and then 3% sodium bisulfite, dried over MgSO4, and
concentrated. The crude product was purified via chroma-
tography on SiO2 or recrystallization for crystalline products.
Isolated yields of purified products are compiled in Table
(12) Experimental details and characterization of products are compiled
in the Supporting Information.
(13) Arnold, R. T.; Lindsay, K. L. J. Am. Chem. Soc. 1953, 75, 1048-
1049.
(14) Klein, J. J. Am. Chem. Soc. 1959, 81, 3611-3614.
Org. Lett., Vol. 3, No. 3, 2001
351

with organotelluride reagents.8a This is presumably due to
the greater bond strength of the Te-Br bond relative to the
bond strength of the Te-I bond. In stoichiometric reactions,
selenium(IV) bromides were found to be better brominating
agents than tellurium(IV) bromides presumably due to the
weaker Se-Br bond strength, which facilitates bromine
transfer.
We are currently preparing the selenide analogue of 1 and
related compounds as catalysts for brominations and chlo-
rinations. Hopefully, the weaker selenium-halogen bonds
in the oxidized catalyst will provide more efficient chlorina-
tion and bromination of organic substrates to complement
the efficient iodinations that we have described here.
Consistent with these earlier observations, the 1-catalyzed
brominations of organic substrates required higher concentra-
tions of bromide, peroxide, and catalyst than the correspond-
ing iodinations as well as longer reaction times. Several
examples are listed in Table 2 using 2.5 mol % of 1 in pH
6 phosphate buffer with a 15-fold excess of H2O2 (3 M) and
a 10-fold excess of NaBr (2 M). These reactions were
stopped after 24 h. It should be noted that in the absence of
catalyst less than 5% conversion of substrate to product
occurred after 24 h. Although the sodium salt of 4-pentenoic
acid was readily brominated under these reaction conditions,
2,2-diphenyl-4-pentenoic gave only trace amounts of prod-
ucts after 24 h. The bromination of 1,3,5-trimethoxybenzene
gave only 45% conversion to 2-bromo-1,3,5-trimethoxyben-
zene after 24 h.
Acknowledgment. We thank the donors of the Petroleum
Research Fund, administered by the American Chemical
Society, for partial support of this work. We also thank Dr.
Margaret E. Logan (SUNY College at Brockport) for sharing
her modified procedure for the addition of tellurium tetra-
chloride to electron-rich aromatic substrates.
Supporting Information Available: Detailed experi-
mental procedures and characterization data for the prepara-
tion of catalyst 1, compounds 2-4, and the products of
entries 1-8 of Table 1, experimental details for the oxidation
of 1 with H2O2. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL0068142
352
Org. Lett., Vol. 3, No. 3, 2001