Facile conversion of lactols to lactones using IBX

Article abstract of DOI:10.1016/j.tetlet.2003.10.174

Lactols, which are insoluble or only sparingly soluble in most of the organic solvents that are generally employed for oxidation, are converted to lactones using o-iodoxybenzoic acid (IBX) in a facile manner under modified experimental conditions [EtOAc-DMSO (9:1) mixture at reflux] in good to excellent isolated yields (66-91%).

Full text of DOI:10.1016/j.tetlet.2003.10.174

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 309–312
Facile conversion of lactols to lactones using IBX
Jarugu Narasimha Moorthy,* Nidhi Singhal and Prasenjit Mal
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India
Received 8 August 2003;revised 21 October 2003;accepted 29 October 2003
Abstract—Lactols, which are insoluble or only sparingly soluble in most of the organic solvents that are generally employed for
oxidation, are converted to lactones using o-iodoxybenzoic acid (IBX) in a facile manner under modified experimental conditions
[EtOAc–DMSO (9:1) mixture at reflux] in good to excellent isolated yields (66–91%).
ꢀ 2003 Elsevier Ltd. All rights reserved.
In continuation of our recent studies on photocycliza-
tion of o-alkylaromatic aldehydes to benzocyclobutenols
H
OH
hν
in the solid-state,1 we wished to elaborate the latter
intermediates into biologically important and structur-
ally diverse dihydroisocoumarins and isocoumarins
following the reaction sequence in Scheme 1. While the
lactols were readily prepared from the precursor
cyclobutenols by deprotonation using LDA followed by
ring opening and subsequent condensation with electro-
philic aldehydes,2 their further oxidation to dihydro-
isocoumarins proved unfruitful with a variety of
oxidation reagents, viz., PCC, PDC, Jones, Swern,
Dess–Martin periodinane (DMP), etc. It was realized
that the failure to oxidize lactols to lactones was due to
poor solubility of lactols in the solvents (dichloro-
methane and acetone) employed for conducting the
oxidation reactions. This led us to explore the use of the
hypervalent o-iodoxybenzoic acid (IBX) in DMSO.3 We
were particularly encouraged by a recent report involv-
ing the use of IBX as a suspended solid for oxidation of
alcohols in a variety of solvents.4 Herein we report our
results on the facile conversion of a variety of sparingly/
difficultly soluble lactols into lactones using IBX under
modified conditions. The results described herein are of
particular significance in view of the fact that the oxi-
dation of lactols to lactones using IBX in DMSO has
previously been reported not to proceed to an appreciable
degree.5 Further, it is noteworthy that the oxidation
of lactols has been accomplished in three instances6
with modified-IBX, viz., 1-hydroxy-1,3-dihydro-3,3-
R1
O
R1
solid state
CH3
R2
R2
i) LDA, -78 ºC, THF
ii) RCHO, 30 min
iii) -78 ºC to rt, H30+
OH
O
O
(O)
O
R
R1
R1
R
R2
R2
O
O
R1
R
R2
Scheme 1.
bis(trifluoromethyl)-1,2-benziodoxole-1-oxide (GDMP,
Grieco Dess–Martin periodinane), and not with IBX.
As mentioned earlier, the diastereomeric mixtures of
lactols 1–8 were prepared starting from benzocyclo-
butenols,2 which in turn were available from solid-state
photolysis of the precursor aldehydes.1 In agreement
with the previous report,5 oxidation of lactols 1–8 with
IBX in DMSO at room temperature was found to occur
only sluggishly, despite the clear solubility of the lactols.
However, the conversion was found to be complete with
1.2 equiv of IBX at elevated temperatures, i.e., at 80 ꢁC in
Keywords: Lactols;Lactones;IBX;Oxidation.
* Corresponding author. Tel.: +91-512-2597438;fax: +91-512-25974-
36;e-mail: moorthy@iitk.ac.in
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.174

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J. N. Moorthy et al. / Tetrahedron Letters 45 (2004) 309–312
Table 1. The results of conversion of lactols 1–9 to the corresponding lactones using IBX
Lactol
Lactone
Solvent
Yield (%)a
OH
O
Me
NC
Me
NC
Me
Me
Me
O
O
b
74
CN
CN
CN
1
Me
Me
O
OH
Me
Me
Me
O
O
b
90
CN
CN
CN
Me
Me
2
Me
Br
Me
Br
OH
O
b
O
O
80
76
77
82
66
Me
Br
C
H
3
Me
Br
C H
Me OH
Me
Br
O
Br
O
O
b
4
Me
C H
Me
Br
C H
Br
Me OH
Me
Me
O
O
O
O
Me
Br
O
O
O
O
O
b
5
6
7
Br
C H
C H
Me
Me
Me OH
Me
Me
Me
Br
O
b
b
b
C
C
H
H
Br
C H
Me
Me
Me OH
Me
Me
Me
NC
O
NC
Me
C
C
H
H
Me
Me OH
Me
Me
Me
NC
O
91
8
C H
NC
Me
Me
Me
Me
20c
b
9
O
OH
O
O
DMSOd
––
80
80
60
e
C6H6
CHCl3
e
EtOAce
a Isolated yield.
b EtOAc–DMSO (9:1) mixture, reflux, 2.5–3.0 h.
c The remainder was an intractable material.
d At room temperature (ca. 30 ꢁC) for 0.5 h. Several intractable products were revealed by TLC analysis.
e Reflux, ca. 10 h.
a mixed solvent system consisting of ethyl acetate–
DMSO in a 9:1 ratio;the latter was employed to avoid
obvious complications with the use of DMSO. In this
solvent system, all the lactols 1–8 were clearly soluble at
the ethyl acetate reflux temperature, although IBX
remained as a suspended material.7 In all cases, the
reaction was complete (as monitored by TLC analysis) in
2.5–3 h, and the lactones were isolated in 66–91% yields
(Table 1).8 Thus, the reason for the failure to observe
oxidation of lactols to lactones at room temperature in
the present instance and in the previous attempts5 must
be attributable to the experimental conditions that pre-
cluded the activation barriers for bimolecular reactions
from being overcome. Notably, the lactols 3–8 undergo

J. N. Moorthy et al. / Tetrahedron Letters 45 (2004) 309–312
311
oxidation in the same amount of time as that required for
lactols 1 and 2, in spite of the fact that the latter are more
congested.
poor solubility except in a solvent such as DMSO is
singularly remarkable. We believe that the facile lactol
to lactone conversion described herein will constitute an
invaluable addition to the repertoire of transformations
mediated by the inexpensive IBX, which is fast becom-
ing indispensable in organic oxidations.
To test the generality, the oxidation of lactol 9, which
does not contain the hydroxy group at the benzylic
position, was examined. While the oxidation with
1.2 equiv of IBX in DMSO at room temperature led to
an intractable mixture as revealed by TLC analysis, the
oxidation in a heterogeneous phase in chloroform, ethyl
acetate or benzene at reflux yielded the lactone in
respectable isolated yields, albeit in longer reaction
times. The best results were observed with benzene and
chloroform as the solvents (Table 1). While the advan-
tage of heterogeneous reaction conditions is clearly
evident, the intriguing solvent dependence cannot be
readily explained.
Acknowledgements
We thank the Department of Science and Technology
for financial support. N.S. and P.M. are grateful to
C.S.I.R. for junior and senior research fellowships,
respectively.
The mechanism of formation of the lactones may be
described in a manner analogous to that described for
the conversion of alcohols to aldehydes or ketones.9
Accordingly, the attack of the lactol should furnish the
intermediate in Scheme 2, which may decompose to the
lactone and IBA (iodosobenzoic acid), the reduction
product of IBX. Given the same mechanistic scenario
for the oxidation of alcohols and lactols, what then is
the cause of the higher activation barrier in the latter
that necessitates comparatively higher temperatures for
oxidation? We believe that the presumed steric factors5
cannot be entirely responsible, as lactol 9 also requires
higher temperature in a variety of solvents. Further-
more, lactols 1, 2, and 3–8 undergo oxidation without
any perceptible difference in the rates as reflected from
the reaction times for complete conversion. Rather, the
stereoelectronic effects10 emanating from the presence of
an additional oxygen in the intermediate (Scheme 2),
when compared to that resulting from the attack of
simple alcohols on IBX, may be decisive in the decom-
position of the intermediate into IBA and the lactone.
References and Notes
1. (a) Moorthy, J. N.;Mal, P.;Natarajan, R.;Venugopalan,
P. Org. Lett. 2001, 3, 1579;(b) Moorthy, J. N.;Mal, P.;
Natarajan, R.;Venugopalan, P. J. Org. Chem. 2001, 66,
7013;(c) Moorthy, J. N.;Venkatakrishnan, P.;Mal, P.;
Venugopalan, P. J. Org. Chem. 2003, 68, 327.
2. Fitzgerald, J. J.;Pagano, A. R.;Sakoda, V. M.;Olofson,
R. A. J. Org. Chem. 1994, 59, 4117.
3. Frigerio, M.;Santagostino, M. Tetrahedron Lett. 1994, 35,
8019.
4. More, J. D.;Finney, N. S. Org. Lett. 2002, 4, 3001.
5. Corey, E. J.;Palani, A. Tetrahedron Lett. 1995, 36, 3485.
6. (a) VanderRoest, J. M.;Grieco, P. A. J. Am. Chem. Soc.
1993, 115, 5841;(b) Lach, F.;Moody, C. J. Tetrahedron
Lett. 2000, 41, 6893;(c) Grieco, P. A.;Collins, J. L.;
Moher, E. D.;Fleck, T. J.;Gross, R. S. J. Am. Chem. Soc.
1993, 115, 6078.
7. Nicolaou, K. C.;Montagnon, T.;Baran, P. S.
Chem., Int. Ed. 2002, 41, 993.
Angew.
8. In a typical experiment, 0.1 g of the lactol (0.35–0.5 mmol)
and 1.2 equiv of IBX in 10 mL of the ethyl acetate–DMSO
(9:1) mixture were heated at reflux. The progress of the
reaction was monitored by TLC analysis. After 2.5–3.0 h,
the reaction mixture was cooled, the insoluble matter was
filtered, and the resultant product mixture was subjected
to short pad silica-gel column chromatography to isolate
pure lactones.
Although discovered more than a decade ago,11 there
has been renaissance of interest in recent years in
employing IBX for oxidations;9;12 a variety of IBX-
mediated oxidations have been uncovered. Although
several reagents may be employed for the oxidation of
lactols, the advantage offered by IBX for substrates with
The characterization data for representative lactols and
lactones are given below. It should be noted that the
lactols in some cases were diastereomeric mixtures, with
one of the isomers being present only as a minor
constituent (ca. <20%). The data given below are for the
major diastereomers.
1: Colorless crystalline powder, mp 216 ꢁC (dec);IR (KBr)
cmꢀ1 3405, 2923, 2223; 1H NMR (DMSO-d6, 400 MHz)
2.32 (s, 3H), 2.44 (s, 3H), 2.46 (s, 3H), 2.76 (dd, 1H,
J1 ¼ 16:3 Hz, J2 ¼ 11:7 Hz), 2.98 (dd, 1H, J1 ¼ 16:6 Hz,
J2 ¼ 2:4 Hz), 5.27 (dd, 1H, J1 ¼ 11:6 Hz, J2 ¼ 2:7 Hz), 6.00
(d, 1H, J ¼ 6:1 Hz), 7.15 (d, 1H, J ¼ 6:1 Hz), 7.35 (s, 1H),
7.54 (s, 1H), 7.588 (s, 1H), 7.591 (s, 1H); 13C NMR
(DMSO-d6, 100 MHz) 18.0, 19.7, 19.8, 32.8, 64.6, 90.9,
110.8, 111.3, 118.1, 118.2, 127.9, 129.4, 132.67, 132.68,
133.89, 133.93, 139.2, 139.3, 140.8, 145.0;FAB-MS 319
(M+H), 301, 273, 232. Anal. Calcd for C20H18N2O2 (MW
318.38): C, 75.45;H, 5.70;N, 8.80. Found: C, 75.05;H,
6.21;N, 8.52.
O
OH
O
I
H
O
OH
O
IBX
O
O
O
I
O
H2O
O
Intermediate
O
OH
O
I
O
IBA
O
1-Lactone: Colorless crystalline powder, mp 218–220 ꢁC;
Scheme 2.
IR (KBr) cmꢀ1 1724, 2224, 2926; 1H NMR (CDCl3,

312
J. N. Moorthy et al. / Tetrahedron Letters 45 (2004) 309–312
400 MHz) 2.34 (s, 3H), 2.53 (s, 3H), 2.62 (s, 3H), 3.07 (dd,
362.06): C, 43.13;H, 3.90. Found: C, 43.55;H, 3.47.
4: Colorless crystalline powder, mp 225 ꢁC (dec);IR (KBr)
cmꢀ1 3441, 2908; 1H NMR (DMSO-d6+CDCl3, 400 MHz)
2.38 (s, 3H), 2.54–2.60 (m, 1H), 2.57 (s, 3H), 2.97 (dd, 1H,
J1 ¼ 17:2 Hz, J2 ¼ 3:4 Hz), 5.22 (d, 1H, J ¼ 11:7 Hz), 5.99
(d, 1H, J ¼ 5:1 Hz), 7.30–7.40 (m, 5H); 13C NMR
(DMSO-d6 + CDCl3, 100 MHz) 19.2, 25.2, 37.9, 67.1,
89.8, 124.5, 125.9 (·2), 126.6, 127.3, 128.1, 132.8, 134.9,
136.5, 141.7;FAB-MS 413 (M+H), 395, 273, 219. Anal.
Calcd for C17H16Br2O2 (MW 412.12): C, 49.54;H, 3.91.
Found: C, 49.98;H, 4.38.
1H, J1 ¼ 16:6 Hz, J2 ¼ 2:9 Hz), 3.21 (dd, 1H, J1 ¼ 16:3 Hz,
J2 ¼ 12:4 Hz), 5.70 (dd, 1H, J1 ¼ 12:2 Hz, J2 ¼ 2:9 Hz),
7.44 (s, 1H), 7.56 (s, 2H), 8.11 (s, 1H); 13C NMR (CDCl3,
100 MHz) 18.3, 20.1, 20.2, 33.5, 76.5, 112.9, 116.6, 117.6,
117.9, 127.7, 128.0, 131.3, 131.9, 132.6, 134.4, 136.1, 140.2,
140.6, 141.8, 163.5;FAB-MS 317 (M+H), 299, 273. Anal.
Calcd for C20H16N2O2 (MW 316.36): C, 75.93;H, 5.10;N,
8.90. Found: C, 76.25;H, 4.93;N, 9.38.
3: Colorless crystalline powder, mp 178–179 ꢁC;IR
(KBr) cmꢀ1 3320, 2915; 1H NMR (DMSO-d6+CDCl3,
400 MHz) 1.00 (t, 3H, J ¼ 7:6 Hz), 1.60–1.66 (m, 2H), 2.27
(dd, 1H, J1 ¼ 16:4 Hz, J2 ¼ 11:6 Hz), 2.36 (s, 3H), 2.58 (s,
3H), 2.72 (dd, 1H, J1 ¼ 16:4 Hz, J2 ¼ 3:4 Hz), 4.07–4.09
(m, 1H), 5.83 (d, 1H, J ¼ 5:6 Hz); 13C NMR (DMSO-
d6+CDCl3, 100 MHz) 9.6, 19.2, 25.1, 28.1, 35.4, 66.1, 89.2,
124.7, 126.3, 132.3, 133.1, 134.8, 136.3;FAB-MS 365
(M+H), 347, 267, 219, 149. Anal. Calcd for C13H16Br2O2
(MW 364.08): C, 42.90;H, 4.43. Found: C, 43.05;H, 4.07.
3-Lactone: Colorless crystalline powder, mp 98–99 ꢁC;IR
(KBr) cmꢀ1 2970, 1715; 1H NMR (CDCl3, 400 MHz) 1.09
(t, 3H, J ¼ 7:3 Hz), 1.77–1.82 (m, 1H), 1.86–1.91 (m, 1H),
2.73 (s, 3H), 2.75 (s, 3H), 2.70–2.80 (m, 1H), 3.22 (dd, 1H,
J1 ¼ 16:8 Hz, J2 ¼ 2:4 Hz), 4.25–4.31 (m, 1H); 13C NMR
(CDCl3, 100 MHz) 9.4, 22.4, 26.5, 27.6, 35.5, 78.5, 123.0,
125.3, 129.5, 138.9, 141.4, 143.1, 164.0;FAB-MS 363
(M+H), 319, 283, 227. Anal. Calcd for C13H14Br2O2 (MW
4-Lactone: Colorless crystalline powder, mp 175–177 ꢁC;
1
IR (KBr) cmꢀ1 2922, 1716; H NMR (CDCl3, 400 MHz)
2.76 (s, 3H), 2.79 (s, 3H), 3.15 (dd, 1H, J1 ¼ 17:0 Hz,
J2 ¼ 12:0 Hz), 3.47 (dd, 1H, J1 ¼ 17:0 Hz, J2 ¼ 2:7 Hz),
5.39 (d, 1H, J ¼ 11:7 Hz), 7.39–7.49 (m, 5H); 13C NMR
(CDCl3, 100 MHz) 22.5, 26.6, 38.1, 78.5, 123.0, 125.2,
126.2, 128.7, 128.8, 129.8, 137.9, 138.6, 141.7, 143.5, 163.5;
FAB-MS 411 (M+H), 393, 273, 219. Anal. Calcd for
C17H14Br2O2 (MW 410.11): C, 49.80;H, 3.41. Found: C,
50.22;H, 3.96.
9. (a) Nicolaou, K. C.;Baran, P. S. Angew. Chem., Int. Ed. 2002,
41, 2678;(b) Wirth, T. Angew. Chem., Int. Ed. 2001, 40, 2812.
10. Deslongchamps, P. Stereoelectronic Effects in Organic
Chemistry;Pergamon: Oxford, 1983.
11. Hartmann, C.;Meyer, V. Chem. Ber. 1893, 26, 1727.
12. Zhdankin, V. V.;Stang, P. J. Chem. Rev. 2002, 102, 2523.