Iodination of enol acetates and 1,3-diones using N-iodosaccharin

Article abstract of DOI:10.1081/SCC-120022182

Iodination of enol acetates and 1,3-diones with N-iodosaccharin yielding the corresponding α-iodoketones and 2-iodo-1,3-diones is presented. Reactions are carried out at room temperature under neutral conditions and in short reaction times.

Full text of DOI:10.1081/SCC-120022182

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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 16, pp. 2917–2924, 2003
Iodination of Enol Acetates and 1,3-Diones
Using N-Iodosaccharin
*
Darko Dolenc
University of Ljubljana, Faculty of Chemistry and
Chemical Technology, Ljubljana, Slovenia
ABSTRACT
Iodination of enol acetates and 1,3-diones with N-iodosaccharin
yielding the corresponding a-iodoketones and 2-iodo-1,3-diones is
presented. Reactions are carried out at room temperature under
neutral conditions and in short reaction times.
Key Words: Halogenation; Iodine; N-Haloamides; Enol esters.
*Correspondence: Darko Dolenc, University of Ljubljana, Faculty of
Chemistry and Chemical Technology, Askerceva 5, 1000 Ljubljana, Slovenia;
Fax: þ3861 2419 220; E-mail: darko.dolenc@uni-lj.si.
2917
DOI: 10.1081/SCC-120022182
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2918
Dolenc
INTRODUCTION
Organic iodine compounds are interesting as such or as synthetic
intermediates since iodine is an excellent leaving group and can be
replaced with other groups in numerous reactions. A variety of iodina-
tion reagents has been introduced in last decades.[1] Introduction of an
iodine atom into an organic molecule is sometimes difficult due to the
weakness of the carbon–iodine bond. For electrophilic iodination, more
reactive reagents are those in which the iodine atom is made more elec-
tropositive. The electrophilicity of iodine can be enhanced by binding it
to a strong electron-attracting group or atom or by the use of Brønsted or
Lewis acids as catalysts. N-Haloamides represent moderately electro-
philic reagents, suitable for work in neutral media, best known among
these are N-halosuccinimides. Substitution of carbonyl group in cyclic
amide by a sulfonic group enhances the electrophilicity of the reagent.
Representative examples of such compounds include derivatives of
saccharin, of which all four halo derivatives are known. N-Chloro- and
N-bromosaccharin can be prepared very easily, and chlorosaccharin is
now even commercially available.[2,3] N-Iodosaccharin is a new reagent
of this class, but it has already proven as a reagent for electrophilic
iodination and other applications.[4,5]
Halogenation of the a-position in ketones can be readily accom-
plished only in ketones, enolized to a great extent, e.g., 1,3-diketones
and similar compounds. Therefore, in most cases it is necessary to trans-
form carbonyl compound into a stable enol derivative, such as enol ester.
However, even with stable enol or its derivative, iodination with elemen-
tal iodine is often sluggish and incomplete and, for that reason, more
reactive iodination reagents are required. In this article the results of
iodination of ketone enol acetates and 1,3-dicarbonyl compounds with
N-iodosaccharin are presented (Sch. 1).
RESULTS AND DISCUSSION
Iodination of enol acetates with N-iodosaccharin proceeds fast,
usually in a few minutes at room temperature. The most suitable solvents
proved to be aqueous (5–10% of water) acetonitrile or acetone, as the
reactions in these solvents were fast and clean. Dichloromethane also
worked well, but with some substrates a substantial amount of a by-
product, N-acetylsaccharin, was formed. Nucleophilic solvents, such as
alcohols, tend to incorporate into the product and mixtures of a-iodoke-
tones and their dialkylacetals are formed. The reaction of cyclohexen-1-yl

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Iodination of Enol Acetates and 1,3-Diones
2919
Scheme 1.
acetate (1a) with dried NISac in dry methanol yielded a mixture of 65%
1,1-dimethoxy-2-iodocyclohexane (1c) and 35% of 2-iodocyclohexanone
(1b). Unfortunately, we did not succeed to prepare pure acetal even with
strictly dried solvent (methanol) and NISac. Also these acetals seem to be
very unstable and do not survive chromatographic purification on silica.
Iodination of 4-tert-butylcyclohexen-1-yl acetate led to a mixture of
28% cis and 72% trans 4-tert-butyl-2-iodocyclohexanone,[6] which we
could not separate by column chromatography. Similarly, iodination of
camphor enol acetate also yielded a mixture of endo and exo isomers (40
and 60%, respectively).[7] The reactions are not stereospecific, resembling
the addition of iodine to the corresponding enolate.[6,7]
1,3-Diones react fast, yielding monoiodo derivatives with an equimo-
lar quantity of the reagent. The isolation of 2-iodo-1,3-diones raised some
problems, as these compounds are relatively unstable and rather acidic.
Washing with sodium sulfite to reduce excess reagent or iodine, caused
reduction of the 2-iodo-1,3-dione to the starting ketone. Sodium thiosul-
fate proved to be a substantially better, though not a completely inert
reducing agent.

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2920
Dolenc
Solid 2-iodo-5,5-dimethylcyclohexane-1,3-dione (7b) exhibits
a
strong and broad band in theregion 2500–3200 cm ꢀ1 in its IR spectrum,
1
the H and 13C NMR spectra in acetone d6 also contain several peaks,
indicating an enol structure of the compound. However, spectra taken in
themorepolar DMSO
d6, show only thedikteoneform. Although
spectroscopically pure, the compound does not exhibit a sharp melting
point, but melts in a range of about 10ꢁC.
The presented results indicate the greater reactivity of N-iodosac-
charin compared to the commercially available reagent of the same
class, N-iodosuccinimide. The former appears to be a few 100 times
more reactive, as established by our measurements. This shortens the
reaction times to a few minutes at room temperature, which is a substan-
tial improvement, as the reaction with N-iodosuccinimidetakes 0.5–1 h
in refluxing tetrachloromethane or dioxane.[8] Iodinations with N-iodo-
saccharin can be carried out in neutral or slightly acidic medium, which is
beneficial for compounds containing sensitive functional groups. The
reaction by-product, saccharin, can be easily removed by washing with
sodium hydrogen carbonate or other, even milder bases.
The above results suggest that N-iodosaccharin could bea promising
reagent for introducing iodine into organic molecules.
EXPERIMENTAL
Melting points were determined by a hotstage microscope and are
1
uncorrected. H and 13C NMR spectra are measured on Bruker Avance
DPX-300 instrument with tetramethylsilane as internal standard. Mass
spectra were measured on VG-Analytical AutospecQ instrument. Solvents
and reagents were used as received (Fluka, Aldrich). N-Iodosaccharin was
prepared from Ag salt of saccharin and iodine in acetone.[4]
Enol acetates. Enol acetates 1a–5a were prepared from ketones and
2-propenyl acetate in the presence of p-toluenesulfonic acid with a con-
tinuous distillation of acetone formed.[9] 6a was prepared by the action of
(1) butyllithium and (2) acetic anhydride on camphor.[10]
Iodination of enol acetates and b-diketones 8a and 9a. Typical pro-
cedure. One point zero millimole of enol acetate was dissolved in 1–2 mL
of solvent (see Table 1) and 1.05 mmol of N-iodosaccharin was added.
The reaction mixture was stirred at room temperature until the conver-
sion of the starting enol acetate was complete. The mixture was diluted
with diethyl ether, washed with aqueous solution of sodium hydrogen
carbonate and sodium thiosulfate, with water again and dried over
anhydrous sodium sulfate. The solvent was evaporated under reduced

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Iodination of Enol Acetates and 1,3-Diones
2921
Table 1. Iodination of enol acetates and b-diketones with N-iodosaccharin.
Yielda
(%)
Starting compd.
Product
Solvent
Time
MeCN–H2O,
4:1
15 min
90
CH2Cl2
CH2Cl2
1 h
90 (54)
93 (56)
1.5 h
MeCN–H2O,
4:1
15 min
15 min
94 (65)
88 (64)
MeCN–H2O,
4:1
CH2Cl2
6 h
70
Acetone–H2O,
4:1
10 min
88 (65)
CH2Cl2
HOAc
1.5 h
90
82
10 min
aIsolated yield (after purification by recrystallization or chromatography).
pressure and the crude product, if neccesary, purified by chromatography
or recrystallization.
Iodination of 5,5-Dimethylcyclohexane-1,3-dione (7a). Onepoint zero
millimoleof 7a was dissolved in 1 mL of acetone–water 2:1 and
1.05 mmol of N-iodosaccharin was added under stirring. After 10 min,
the reaction mixture was diluted with 2 mL of 1 M sodium dihydrogen
citrate, the product was filtered with suction and washed with water. Two
hundred and thirty five milligrams (88%) of practically pure 5,5-
dimethyl-3-hydroxycyclohex-2-ene-1-one (7b) was obtained, with a

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2922
Dolenc
melting range 155–165ꢁC. After crystallization from acetone–petroleum
ether, melting range did not narrow considerably.
Spectroscopic and Other Data
2-Iodocyclohexanone (1b).[11] Oil. 1H NMR (CDCl3, ꢀ/ppm):
1.56–1.78 (m, 2H), 1.95–2.17 (m, 4H), 2.33 (m, 1H), 3.27 (t, J ¼ 4.3 Hz,
1H). 13C NMR (CDCl3, ꢀ/ppm): 22.4, 26.6, 32.3, 36.3, 37.2, 204.7. MS
(m/z (%)): 224 (Mþ, 80), 180 (17), 127 (18), 97 (58), 69 (65), 55 (79),
41 (100).
4-tert-Butyl-2-iodocyclohexanone (2b, mixture of cis and trans iso-
mers).[6] Oil. 1H NMR (CDCl3, ꢀ/ppm): 0.93 (s), 1.3–1.8 (m), 1.9–2.4
(m), 3.32 (dt, J ¼ 6.1, 14.6 Hz, H3a, trans-isomer), 4.69 (m, 1H, H2
trans-isomer), 4.91 (dd, J ¼ 6.0, 13.4 Hz, 1H, H2, cis-isomer).
1
2-Iodo-1-phenylethanone (3b).[11] Oil. H NMR (CDCl3, ꢀ/ppm): 4.36
(s, 2H), 7.5 (m, 2H), 7.6 (m, 1H), 8.0 (m, 2H). 13C NMR (CDCl3, ꢀ/ppm):
1.8, 128.7, 128.9, 133.4, 133.7, 192.7.
2-Iodoindan-1-one (4b).[12] M.p. 67–69ꢁC (Lit.[12] 68–70ꢁC). 1H NMR
(CDCl3, ꢀ/ppm): 3.48 (dd, J ¼ 18.4, 2.6 Hz, 1H), 3.89 (dd, J ¼ 18.4,
7.4 Hz, 1H), 4.96 (dd, J ¼ 7.4, 2.6 Hz, 1H), 7.43 (m, 2H), 7.66 (td,
J ¼ 7.5, 1.2 Hz, 1H), 7.87 (d, J ¼ 8.0 Hz, 1H). 13C NMR (CDCl3,
ꢀ/ppm): 19.3, 39.5, 125.0, 126.4, 128.1, 132.8, 135.5, 151.2, 201.4.
2-Iodo-1,2,3,4-tetrahydronaphthalene-1-one (5b).[12] M.p. 76–78ꢁC
(Lit.[12] 76–78ꢁC). 1H NMR (CDCl3, ꢀ/ppm): 2.09–2.20 (m, 1H),
2.25–2.34 (m, 1H), 2.88 (dt, J ¼ 17.0, 3.8 Hz, 1H), 3.15 (ddd, 17.0, 11.1,
4.7 Hz, 1H), 5.03 (td, J ¼ 3.8, 0.7 Hz, 1H), 7.29 (m, 1H), 7.35 (m, 1H),
7.51 (td, J ¼ 7.5, 1.3 Hz, 1H), 8.09 (dd, J ¼ 7.8, 1.3 Hz, 1H). 13C NMR
(CDCl3, ꢀ/ppm): 27.8, 30.7, 32.7, 127.0, 128.6, 128.7, 129.3, 133.9,
142.7, 191.8.
2-Iodo-3-hydroxy-5,5-dimethylcyclohex-2-ene-1-one (7b).[13] M.p.
157–165ꢁC (Lit.[13] 165ꢁC). H NMR (acetone d6, ꢀ/ppm): 1.07 (s, 6H),
1
2.5 (m, 4H), 9.94 (s, OH). 13C NMR (acetone d6, ꢀ/ppm): 27.4 (CH3), 32.5
(C5), 44.1 and 49.7 (C4 and C6), 77.9 (C2), 174.9 (C3), 191.6 (C1). IR
(KBr pellet, cmꢀ1): 2500 (broad, OH), 1550. MS (m/z (%)): 266 (Mþ, 90),
210 (100), 195 (20), 168 (16), 127 (10), 111 (23), 83 (97).
2-Iodo-1,3-diphenylpropane-1,3-dione (8b).[14] M.p. 104–106 (Lit.[14]
104–105ꢁC). H NMR (CDCl3, ꢀ/ppm): 6.93 (s, 1H), 7.45 (m, 4H), 7.57
1
(m, 2H), 7.98 (m, 4H). 13C NMR (CDCl3, ꢀ/ppm): 93.1, 127.1, 128.6,
132.4, 135.5, 185.7. MS (m/z (%)): 224 (89), 223 (93), 147 (62), 105
(100), 77 (75), 69 (58).

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Iodination of Enol Acetates and 1,3-Diones
2923
Ethyl 2-Iodo-3-oxo-3-phenylpropanoate (9b).[15] Oil. 1H NMR
(CDCl3, ꢀ/ppm): 1.22 (t, J ¼ 7.2 Hz, 3H), 4.25 (q, J ¼ 7.2 Hz, 2H), 5.95
(s, 1H), 7.49 (m, 2H), 7.51 (m, 1H), 7.99 (m, 2H). 13C NMR (CDCl3,
ꢀ/ppm): 13.7, 23.9, 63.2, 128.8, 129.0, 132.9, 133.9. IR (NaCl disc, cmꢀ1):
1730, 1675.
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Received in the UK October 25, 2002

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