Selenium-catalyzed iodohydrin formation from alkenes

Article abstract of DOI:10.1016/j.tetlet.2006.09.024

A new simple method for catalyzed iodohydroxylation of alkenes using stoichiometric amounts of water is described. The iodohydrins were prepared in good yields from the corresponding alkenes using N-iodosuccinimide, 2 equiv of H₂O, and catalytic amounts of diphenyl diselenide in MeCN.

Full text of DOI:10.1016/j.tetlet.2006.09.024

Tetrahedron Letters 47 (2006) 7849–7852
Selenium-catalyzed iodohydrin formation from alkenes
Ignacio Carrera, Margarita C. Brovetto and Gustavo A. Seoane*
Departamento de Quı´mica Orga´nica, Facultad de Quı´mica, Universidad de la Repu´blica, C.C. 1157, Montevideo, Uruguay
Received 17 August 2006; revised 2 September 2006; accepted 6 September 2006
Abstract—A new simple method for catalyzed iodohydroxylation of alkenes using stoichiometric amounts of water is described. The
iodohydrins were prepared in good yields from the corresponding alkenes using N-iodosuccinimide, 2 equiv of H2O, and catalytic
amounts of diphenyl diselenide in MeCN.
Ó 2006 Elsevier Ltd. All rights reserved.
Halohydrin formation is a versatile reaction in organic
synthesis, allowing the stereoselective functionalization
of carbon–carbon double bonds.1 In particular, bromo-
and iodohydrins have been repeatedly used in total syn-
thesis. However, although the direct preparation of
bromohydrins from the reaction of dilute aqueous
solutions of halogens with alkenes is a well-established
methodology,2 the preparation of iodohydrins using
the same procedure is hampered by the ready reversibil-
ity of the addition of hypoiodous acid. In this case an
iodide ion scavenger is generally used to obtain satisfac-
tory yields.3
the rate, allowing the reaction to proceed in reasonably
short times. Considering its high polarity, water is
almost always used in a large excess for halohydrin
formation, acting both as a reagent and as a solvent.
Exceptions to this procedure are given by Dalton meth-
od, which uses DMSO as the sole solvent,18 and some
special cases of halohydrin formation involving an
anchimeric assistance from an oxygenated functional
group already present in the molecule, such as a sulfox-
ide, followed by a subsequent attack by water.19
In connection with our ongoing effort to prepare marine
natural products from cyclohexadienediols of microbial
origin, several oxygen-labeled halohydrins were
needed.20 We thus began by investigating procedures
to prepare them using water in stoichiometric amounts.
Dalton’s method is not adequate in this instance, since
the oxygen atom in the resulting iodohydrin is supplied
by the DMSO used as solvent. Other reported methods
utilize water in very large excesses,21 and even a proce-
dure to produce labeled epoxides via iodohydrins uses
10 equiv of water-18O.3d
Other methodologies of the formation of iodohydrins
from alkenes include the use of H5IO6/NaHSO3,4 N-
iodoimides,5 N-iodosaccharin,6 bis(pyridine)iodine(I)
salts,7 dimethyldioxirane/MeI,8 triodide ion,9 and the
reaction with iodine mediated by clays in aqueous
media.10 Alternatively, iodohydrins are derived from
the epoxides using different reagents, such as hydroiodic
acid,11 iodine, and crown ethers as catalyst,12 the
Ti(O-i-Pr)4/I2 complex,13 metal iodides,14 or a ionic
liquid.15 Iodohydrins could also be prepared from other
halohydrins by halogen exchange,16 or from carbonyl
compounds by iodomethylation with CH2I2 in the
presence of SmI2.17
Preliminary studies using standard methods5 showed
that the reaction rate is highly dependent on the amount
of water present (vide infra). The use of a few equiva-
lents of water resulted in excessively long reaction times,
which makes the reaction unsuitable for preparative
purposes. For instance, more than 160 h were needed
for the complete conversion of 2 mmol of diene 2 using
20 equiv of water, and no reaction was observed after
72 h using 2 equiv of water. In this context a catalyst
seems to be necessary in order to accelerate the reaction.
There are reports of catalyzed halohydrin formation
from alkenes. When using N-haloimides as the electro-
philic species, the reaction can be accelerated by adding
The iodohydrin formation from alkenes is usually
carried out in polar media, which help to stabilize the
formation of charged intermediates and thus increase
Keywords: Alkenes; Selenium; Iodohydroxylation; Stereoselectivity;
Halohydrins.
*
Corresponding author. Tel.: +598 2 924 4066; fax: +598 2 924
1906; e-mail: gseoane@fq.edu.uy
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.024

7850
I. Carrera et al. / Tetrahedron Letters 47 (2006) 7849–7852
Bronsted or Lewis acids in stoichiometric or catalytic
amounts, since acids enhance the heterolytic cleavage
of N-haloimides.22 Unfortunately, this method lacks
generality since it cannot be used on acid labile sub-
strates, such as diols 1 and 2.23
integration of the corresponding NMR signals of the
products, the spectra being taken upon disappearance
of the starting material. In all cases, the reaction showed
a complete regioselectivity toward the less hindered
disubstituted double bond and obeyed the generalized
Markownikoff’s rule, regardless of the solvent system
used (Scheme 1).
Recently, Tunge and Mellegaard24 reported on the sele-
nium-catalyzed bromolactonization of unsaturated
acids. The neutral conditions used and the resemblance
between both mechanisms attracted our attention and
thus we decided to study the ability of selenium reagents
to catalyze halohydrin formation. Herein, we report on
the catalyzed formation of iodohydrins from alkenes
using stoichiometric amounts of water, under neutral
conditions.
The stereoselectivity was good, giving a higher than 5:1
ratio for the electrophilic attack anti to the bulky
protecting group, 1a. The modest enhancement of stereo-
selectivity observed with decreasing amounts of water
could be ascribed to the diminished polarity of the
solvent system (vide infra).
Next, the catalytic reaction was investigated using
diphenyl diselenide as the catalyst. Specifically, diene 1
was treated with 5 mol % of PhSeSePh, 1.1 equiv of
NIS and variable amounts of water in different solvent
systems, from 0 °C to ambient temperature (Table 2).
(1S,2R)-1,2-O-Isopropylidene-3-methylcyclohexa-3,5-
diene-1,2-diol, 1,25 was used as a model alkene (Scheme
1). This chiral diene, readily available in our laboratory
by the biotransformation of toluene,26 presents interest-
ing features for this study. The protected cis-diol func-
tionality and the presence of di- and trisubstituted
conjugated double bonds allow for taking into account
both the stereo- and regioselectivity of the reaction,
respectively.
The addition of PhSeSePh significantly improved the
reaction rate, since the time needed for the complete
consumption of the starting 1 mmol of olefin diminished
in all conditions tried. However, the effect of the catalyst
on the selectivity was not significant. The selectivities
afforded by the catalyzed and uncatalyzed reactions in
otherwise similar conditions (see Tables 1 and 2) were
nearly the same, considering the experimental error
(integration of NMR signals).
In our preliminary efforts the iodohydroxylations were
carried out following a slight modification of a reported
procedure,5 using 1.1 equiv of N-iodosuccinimide (NIS)
in mixtures of DME and decreasing amounts of water,
from 0 °C to ambient temperature. In addition, acetoni-
trile was also used in order to address the effect of
changing the polarity of the solvent mixture (Table 1).
The selectivity of the reaction was determined by the
The amount of water used has a profound effect on the
kinetics and a much smaller effect on the selectivity of
iodohydrin formation. Given its high dielectric constant
(for water, eT = 78.30; for DME, eT = 7.20; for MeCN,
eT = 35.94),27 the amount of water in the mixture dra-
matically affects the polarity of the system, which influ-
ences the kinetics of this reaction. An inspection of
Tables 1 and 2 shows that for large amounts of water
the reaction rate is almost independent of the co-solvent
used (Table 1, entries 1 and 4, and Table 2, entries 1 and
3). However, if water is used in small amounts the polar-
ity of the system is mainly determined for the organic
solvent and, therefore, significant differences in reaction
X
X
X
NIS, H2O-solvent
0 ºC to rt; (catalyst)
O
O
O
O
O
O
+
HO
HO
I
I
1, X = Me
2, X = Br
a
b
Scheme 1. Iodohydroxylations of model alkenes.
Table 1. Iodohydroxylation of diene 1 in different solvent systemsa
Entry Solvent/H2O
equiv Timeb Selectivityc Yieldd
Table 2. Catalyzed iodohydroxylation of diene 1 in different solvent
systemsa
Entry Solvent/H2O
equiv Timeb Selectivityc Yieldd
H2O/ (h)
equiv
(%)
H2O/ (h)
equiv
(%)
Olefin
Olefin
1
2
3
4
5
1:1 DME/H2O
140
10
2
140
2
1
9
40
0.7
15
84:16
92:8
97:3
86:14
95:5
94
60
75
60
72
1
2
3
4
1:1 DME/H2O
140
2
140
2
0.5
7
0.5
4
82:18
96:4
80:20
95:5
72
50
60
81
25:1 DME/H2O
140:1 DME/H2O
1:1 MeCN/H2O
140:1 MeCN/H2O
140:1 DME/H2O
1:1 MeCN/H2O
140:1 MeCN/H2O
a Reaction conditions: 1 mmol of olefin, 5 mol % of PhSeSePh and
1.1 equiv of NIS in 5 mL of H2O-solvent as specified, from 0 °C to rt.
b Time for the disappearance of 1 mmol of olefin. Conversion data
points were determined by TLC, every 10 min during the first 2 h of
reaction; and every 30 min over that time.
a Reaction conditions: 1 mmol of olefin and 1.1 equiv of NIS in 5 mL
of H2O-solvent as specified, from 0 °C to rt.
b Time for the disappearance of 1 mmol of olefin. Conversion data
points were determined by TLC, every 10 min during the first 2 h of
reaction; and every 30 min over that time.
c 1a:1b.
c 1a:1b.
d Combined yields.
d Combined yields.

I. Carrera et al. / Tetrahedron Letters 47 (2006) 7849–7852
7851
Table 3. Selenium catalyzed iodohydroxylation of representative
rates are observed in both solvent systems, favoring the
reactions run in the more polar acetonitrile (Table 1
entries 3 and 5 and Table 2 entries 2 and 4). In addition,
the difference is more pronounced for the uncatalyzed
reaction, in agreement with the suggested role of the
selenium catalyst assisting the heterolytic cleavage of
N-haloimides24,28 and thus making it less dependent
on the polarity of the system. Regarding the stereoselec-
tivity the effect of water is smaller, although noticeable
when used in small amounts. In this case, the lower
polarity of the reaction medium increases the selectivity
for an electrophilic attack anti to the protecting group
(entries 1–3, and 4–5 of Table 1 and entries 1–2 and
3–4 of Table 2). This observation agrees with the pres-
ence of a less dissociated and thus more hindered elec-
trophilic species in less polar media. The effective size
of the electrophile is dependent on the polarity of the
medium, which governs its dissociation, and thus a less
polar system favors the electrophilic attack from the less
hindered face. Since the best selectivity is obtained with
either solvent system when using 2 equiv of water, we
chose to carry out the reaction in acetonitrile because
of the higher yield and reaction rate (Table 2, entry 4).
alkenesa
Entry Substrate
Products
Time Yieldb
(h)
(%)
1a:1b
95:5
2a:2b
94:6
OH
1
1
2
4
81
2
3
30
1
78c
77d
Ph
I
Ph
OH
4
5
5
3
65
81
I
OH
COOH
7
COOH
7
7
7
I
I
6
7
3
70f
0e
O
OH
O
O
—
—
OMe
O
8
9
—
—
10
0e
OBn
Once the optimal conditions for the catalyzed iodohydr-
oxylation of diene 1 were defined, an array of represen-
tative olefins was submitted to them. In most cases the
corresponding iodohydrins were obtained in good yields
(Table 3).
HO
I
40g
a Reactions were run with 1.1 equiv of NIS, 2 equiv of H2O, 5 mol % of
PhSeSePh, MeCN at 0 °C to rt.
As expected, the iodohydroxylation of diene 229 took
place with total regioselectivity. The stereoselectivity
was excellent, similar to the one obtained for model
diene 1, giving a 94:6 ratio of iodohydrins in a good
yield (78%, entry 2). Some b-epoxide, resulting from
iodide intramolecular displacement on the major isomer,
was also isolated (6%). The reactions on styrene and
cyclohexene proceeded cleanly in good isolated yields,
even though small amounts of styrene oxide were iso-
lated in the reaction of styrene. For oleic acid a single
iodohydrin is obtained in a high yield. This remarkable
regioselectivity during iodohydrin formation was
reported previously by Song et al.30
b Isolated yields.
c Plus 6% of b-epoxide.
d Plus 4% of epoxide.
e No reaction, 100% of recovered starting material.
f Carried out at À20 °C. 1:1 mixture of epimers.
g Losses due to volatility.
decomposition. The low reactivity of these systems to-
ward iodohydrin formation is known.3d,5
Trisubstituted alkenes, such as 2-methyl-2-butene, took
longer to react but still gave the desired iodohydrin.
The reaction was clean, showing a complete conversion
to the desired product when monitored by NMR. The
modest yield reported in entry 9 was due to the difficul-
ties during the isolation of the very volatile halohydrin.
According to entries 1 and 9, it is possible to achieve a
complete regioselectivity toward the reaction of a disub-
stituted alkene when both di- and trisubstituted double
bonds are present in the same molecule.
Dihydropyran, which contains a very sensitive electron-
rich double bond, decomposes at 0 °C under the reac-
tion conditions. However, when the reaction was carried
out at À20 °C an anomeric 1:1 mixture of iodohydrins
was isolated in a very good yield.
For the conjugated acid derivatives (entries 7 and 8) no
reaction was observed at an ambient temperature and
bringing the reaction to reflux caused an extensive
In summary, this letter describes the use of diphenyl
diselenide as an efficient catalyst for a simple iodohydr-
oxylation of alkenes using stoichiometric amounts of
water. This feature is of interest in synthetic schemes
where the amount of water needs to be controlled, for
example, in the preparation of oxygen-labeled com-
pounds. The results in this area will be reported in due
course. Moreover, the lower polarity associated with
this solvent system allows for a moderate increase in
the stereoselectivity of iodohydrin formation. The addi-
tion of PhSeSePh only affects the time and/or the condi-
tions needed to react, with no effects on the selectivity.
General synthetic procedure: PhSeSePh (5 mol %) was added at 0 °C
to a stirred solution of the alkene in MeCN (5 mL/mmol of alkene).
Next was added NIS (1.1 equiv) and distilled water (2 equiv), and the
reaction was let to warm up to ambient temperature. After the
specified time, it was diluted with saturated solution of NaHSO3 and
extracted with methylene chloride. The combined organic layers were
washed with saturated NaCl, dried over MgSO4 and then the solvent
was removed in vacuo. The crude product was purified by column
chromatography on silica gel using hexanes/ethyl acetate as eluant.

7852
I. Carrera et al. / Tetrahedron Letters 47 (2006) 7849–7852
10. (a) Mahajan, V. A.; Shinde, P. D.; Gajare, A. G.;
Karthikeyan, M.; Wakharkar, R. D. Green Chem. 2002,
4, 325; (b) Villegas, R. A.; de Aguiar, M. R.; de Mattos,
M. C. S.; Guarino, A. W.; Barbosa, L. M.; Assumpc¸ao, L.
C. J. Braz. Chem. Soc. 2004, 15, 150.
Nonetheless, given the diminished polarity of the
reaction medium, the use of the catalyst is imperative
to achieve the desired reaction in acceptable times.
11. Parker, R. E.; Isaacs, N. S. Chem. Rev. 1959, 59, 737.
12. Sharghi, H.; Massah, A. R.; Eshghi, H.; Niknam, K. J.
Org. Chem. 1998, 63, 1455.
Acknowledgments
´
Support of this work from the DINACYT (PDT 054,
13. Alvarez, E.; Nunez, M. T.; Martın, V. S. J. Org. Chem.
˜
1990, 55, 3429.
´
Ministerio de Educacion y Cultura, Uruguay) is grate-
14. (a) Otsubo, K.; Inagana, J.; Yamaguchi, M. Tetrahedron
Lett. 1987, 28, 4435; (b) Sarmah, P.; Barua, N. C.
Tetrahedron Lett. 1988, 29, 5815; (c) Yadav, J. S.; Reddy,
B. V. S.; Reddy, Ch. S.; Rajasekhar, K. Chem. Lett. 2004,
33, 476.
fully acknowledged. The authors thank Professor T.
Hudlicky for providing the cultures of P. putida F39/
D.I.C. thanks PEDECIBA (Project URU/97/016) for
a scholarship.
15. Ranu, B. C.; Banerjee, S. J. Org. Chem. 2005, 70, 4517.
16. Cambie, R. C.; Noall, W. I.; Potter, G. J.; Rutledge, P. S.;
Woodgate, P. D. J. Chem. Soc., Perkin Trans. 1 1977, 226.
17. (a) Imamoto, T.; Takeyama, T.; Koto, H. Tetrahedron
Lett. 1986, 27, 3243; (b) Tabuchi, T.; Yamaguchi, M.
Tetrahedron Lett. 1986, 27, 3891.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.09.024.
18. Dalton, D. R.; Hendrickson, J. B.; Jones, D. G. J. Chem.
Soc., Chem. Commun. 1966, 17, 591.
19. Raghavan, S.; Reddy, S. J. Org. Chem. 2003, 68, 5754.
20. Carrera, I.; Brovetto, M.; Seoane, G. In 11th Brazilian
Meeting on Organic Synthesis, Canela, Brazil, August
2005.
References and notes
1. Rodriguez, J.; Dulcere, J.-P. Synthesis 1993, 1177, and
references cited therein.
21. To our knowledge the lowest reported percentage of water
in the solvent mixture used in standard methods is 6%,
corresponding to 30–40 equiv, see Ref. 7.
22. (a) Lambert, F. L.; Ellis, W. D.; Parry, R. J. J. Org. Chem.
1965, 30, 304; (b) Konradsson, P.; Mootoo, D. R.;
McDevitt, R. E.; Fraser-Reid, B. J. Chem. Soc., Chem.
Commun. 1990, 270.
23. Madsen, R.; Fraser-Reid, B. J. Org. Chem. 1995, 60,
772.
24. Mellegaard, S. R.; Tunge, J. A. J. Org. Chem. 2004, 69,
8979.
2. See, for example: Larock, R. C. Comprehensive Organic
Transformations; VCH: New York, 1989; pp 325–327.
3. (a) Conforth, J. W.; Green, D. T. J. Chem. Soc. (C) 1970,
846; (b) Parrilli, M.; Barone, G.; Adinolfi, M.; Mangoni,
L. Tetrahedron Lett. 1976, 17, 207; (c) Antonioletti, R.;
´
DAuria, M.; De Mico, A.; Piancatelli, G.; Scettri, A.
Tetrahedron 1983, 39, 1765; (d) Borhan, B.; Nazarian, S.;
Stocking, E. M.; Hammock, B. D.; Kurth, M. J. J. Org.
Chem. 1994, 59, 4316.
4. Masuda, H.; Takase, K.; Nishio, M.; Hasegawa, A.;
Nishiyama, Y.; Ishii, Y. J. Org. Chem. 1994, 59, 5550.
5. Smietana, M.; Gouverneur, V.; Mioskowski, C. Tetra-
hedron Lett. 2000, 41, 193.
25. Hudlicky, T.; Luna, H.; Barbieri, G.; Kwart, L. D. J. Am.
Chem. Soc. 1988, 110, 4735.
26. Brovetto, M.; Schapiro, V.; Cavalli, G.; Padilla, P.; Sierra,
A.; Seoane, G.; Suescun, L.; Mariezcurrena, R. New J.
Chem. 1999, 23, 549.
6. De Mattos, M. C. S.; Sanseverino, A. M. J. Chem. Res.
(S) 1994, 440.
27. Reichardt, C. Solvents and Solvents Effects in Organic
Chemistry; VCH: New York, 1990.
´
´
´
´
7. Barluenga, J.; Alvarez-Perez, M.; Rodrıguez, F.; Fananas,
˜
´
28. (a) Ref. 24; (b) Hori, T.; Sharpless, K. B. J. Org. Chem.
1979, 44, 4208.
F.; Cuesta, J. A.; Garcıa-Granda, S. J. Org. Chem. 2003,
68, 6583.
8. Sanseverino, A. M.; da Silva, F. M.; Jones, Jr.; de Mattos,
M. C. S. Quim. Nova 2001, 24, 637.
29. Hudlicky, T.; Gonzalez, D.; Gibson, D. Aldrichim. Acta
1999, 32, 35.
9. Sanseverino, A. M.; de Mattos, M. C. S. Synthesis 1998,
1584.
30. Song, W.; Suh, D.; Kang, Y.; No, K.; Han, B. Bull.
Korean Chem. Soc. 1998, 19, 59.