Indium(III) chloride-catalyzed oxidative cleavage of carbon-carbon multiple bonds by tert-butyl hydroperoxide in water-a safer alternative to ozonolysis

Article abstract of DOI:10.1016/j.tetlet.2008.02.089

An efficient and general method for the oxidative cleavage of alkenes and alkynes using tert-butyl hydroperoxide and indium(III) chloride as catalyst in water to give the corresponding carboxylic acids or ketones has been achieved. The reaction conditions are compatible with sensitive moieties such as peptide bonds, tert-butyl carboxylic esters and N-Boc-protected tryptophan. The catalyst could be recycled.

Full text of DOI:10.1016/j.tetlet.2008.02.089

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2588–2591
Indium(III) chloride-catalyzed oxidative cleavage
of carbon–carbon multiple bonds by tert-butyl
hydroperoxide in water—a safer alternative to ozonolysis
Brindaban C. Ranu *, Sukalyan Bhadra, Laksmikanta Adak
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
Received 19 January 2008; revised 13 February 2008; accepted 16 February 2008
Available online 21 February 2008
Abstract
An efficient and general method for the oxidative cleavage of alkenes and alkynes using tert-butyl hydroperoxide and indium(III)
chloride as catalyst in water to give the corresponding carboxylic acids or ketones has been achieved. The reaction conditions are
compatible with sensitive moieties such as peptide bonds, tert-butyl carboxylic esters and N-Boc-protected tryptophan. The catalyst
could be recycled.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Oxidative cleavage; Alkenes; tert-Butyl hydroperoxide; Indium(III) chloride; Water
The oxidative cleavage of alkenes to carboxylic acids
and ketones is a very useful reaction in organic synthesis.1
The commonly used reagents for this transformation
include ozone and several metal oxides such as OsO4 and
RuO4 in combination with a co-oxidant like NaIO4 and
Oxone.1,2 Although ozonolysis is a very reliable method,
a major issue is the concern for safety; serious or fatal acci-
dents may occur.3 In addition, ozone gas is highly toxic and
damaging to human health and its generation requires
supports6b have been reported. However, they lack general
applicability and do not provide satisfactory yields. There-
fore, a simple, efficient and safe procedure for oxidative
cleavage of olefins, which can excel ozonolysis, is highly
desirable. Recently, a gold(I)-catalyzed oxidative cleavage
of alkenes to carbonyl compounds using tert-butyl
hydroperoxide as oxidant and neocuproine as ligand was
reported.6f This has led us to report our results on the
oxidative cleavage of alkenes and alkynes with t-BuOOH
catalyzed by InCl3 in H2O in the absence of any ligand
(Scheme 1).
4
special instrumentation. On the other hand OsO4 because
of its high volatility and toxicity4c is not environmentally
acceptable and thus restricts its use for large-scale applica-
tions in industry. Ruthenium compounds,5 being very
expensive, are also disadvantaged. An efficient and green
protocol for the oxidation of alkenes to the corresponding
carboxylic acids using hydrogen peroxide and Na2WO4 as
a catalyst has been demonstrated by Noyori et al.6e,g Other
procedures involving relatively less toxic reagents6 such as
titanium based catalysts6a and heteropolyacids on oxide
R1
1
2
InCl3 (cat)
RCO H
+R CO2H ( R = H )
2
R
or R2
R1
tBuOOH , H2O
or
2(R2 = alkyl)
1
R
RCO H
90 oC
+
R COR
2
R , R1, R2 = H / alkyl / aryl
InCl3 (cat)
tBuOOH , H2O
90 oC
O
*
Corresponding author. Tel.: +91 33 24734971; fax: +91 33 24732805.
Scheme 1.
E-mail address: ocbcr@iacs.res.in (B. C. Ranu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.089

B. C. Ranu et al. / Tetrahedron Letters 49 (2008) 2588–2591
2589
The experimental procedure is very simple.7 A mixture
Table 2
Oxidative cleavage of alkenes and alkynes
of alkene/alkyne, t-BuOOH and InCl3 in water was heated
at 90 °C for a certain period of time (TLC). Standard work
up provided the product. The aqueous solution of InCl3
and t-BuOH left after work up was recycled for subsequent
reactions without any appreciable loss of efficiency. Several
experiments were carried out using various reagents and
catalysts to optimize the reaction conditions. When t-
BuOOH was replaced by H2O2 the yields of products did
not rise above 25%. InCl3 gave the best results of the sev-
eral Lewis acid catalysts investigated (Table 1).
Entry Substrate
Product
Time Yielda Ref.
(h)
(%)
1
2
PhCO2H
8
88
4c
6e
Ph
CO2H
8.5 78
MeO
MeO
Cl
CO2H
3
4
8.6 75
6e
11
Cl
CO2H
9
8
81
81
Several diversely substituted alkenes underwent clean
cleavage using this procedure to furnish the corresponding
products. The results are summarized in Table 2. The open
chain mono- substituted (Table 2, entries 1–5) and 1,2-
disubstituted (Table 2, entries 6–7) olefins were oxidized
to the corresponding carboxylic acids, while the 1,1-disub-
stituted substrate (Table 2, entry 11) provided the corre-
sponding ketone. The unsubstituted cyclic olefins,
cyclohexene (Table 2, entry 8) and cyclooctene (Table 2,
entry 10) produced adipic and suberic acids, respectively,
in very high yields. These carboxylic acids were obtained
as crystals after work up and did not require any further
purification. These reactions were also scaled up to multi-
gram quantities without any difficulty. Both adipic and
suberic acids are industrially very important6e and this pro-
cedure may serve as an alternative to existing methods.6
The substituted cyclic olefin, 1-methylcyclohexene (Table
2, entry 9), upon oxidative cleavage, furnished the corres-
ponding keto acid. The exocyclic olefins (entries 12 and
13) were cleaved to the corresponding ketones very effi-
ciently. A few complex olefins containing peptide bonds
together with t-butyl ester groups and Boc-protected try-
ptophan moiety (Table 2, entries 14–17) underwent
cleavage to the corresponding carboxylic acids without
affecting these sensitive functionalities. These substituted
peptide carboxylic acids are highly useful compounds and
are not easy to prepare using standard methods.8 The
optically active peptides (Table 2, entries 15–17) retained
their optical purity under the reaction conditions. The aro-
matic as well as aliphatic alkynes (Table 2, entries 18–21)
were also cleaved to produce the corresponding carbox-
ylic acids without the formation of a-diketones9a or a,a0-
dioxygenated derivatives.9b
5
6
CH3(CH2)5CH@CH2 CH3(CH2)5COOH
5d
4c
Ph
PhCO2H
8.5 83
Ph
Ph
7
8
PhCO2H
8
9
85
92
4c
HO2C(CH2)4CO2H
5d
9
10
11
CH3CO(CH2)4CO2H 8.2 84
6b
5d
4c
HOOC(CH2)6CO2H
8
8
94
84
Ph
Ph
O
O
12
13
8
80
11
6e
O
8.2 68
tBu
(CH2)8CONH
tBu
(CH2)8CONH
CO2H
BnO2C
(CH2)2
14
15
16
9
72
—
—
—
(CH2)2
BnO2C
O
(CH3)8
CO2H
O
(CH2)8
CO2Me
N
H
8.5 78
CO2Me
Ph
N
H
Ph
O
(CH3)8
CO2H
O
(CH2)8
t
t
10
68
62
CO2 Bu
N
H
CO2 Bu
N
H
O
O
CO2Me
CO2Me
(CH2)8
(CH3)8
CO2H
N
H
N
H
17
10
—
N
Boc
N
Boc
18
19
20
21
a
Ph–C„CH
CH3(CH2)3C„CH
Ph–C„C–Ph
PhCO2H
CH3(CH2)3CO2H
PhCO2H
9
12
11
12
76
68
71
64
4c
5d
5d
5d
Table 1
Results of the cleavage reaction using different Lewis acids
Et–C„C–Et
EtCO2H
O
Lewis acid
Isolated yields of pure products (1H and 13C NMR).
tBuOOH, H2O
Ph
Ph
9 h, 90 oC
Lewis acid
Yielda (%)
Lewis acid
Yielda (%)
The reactions, are in general very clean and high yield-
ing and no side products were isolated. The majority of
the products were obtained in high purities (>98%) after
work up and a few were purified by crystallization or col-
umn chromatography. When the reaction was carried out
CuCl2
CeCl3
FeCl3
a
38
37
42
ZnCl2
TiCl4
InCl3
39
55
84
Yields calculated from 1H NMR spectra of the crude products.

2590
B. C. Ranu et al. / Tetrahedron Letters 49 (2008) 2588–2591
is cheaper than AuCl. The final products in the present
OH
[O]
CO2H
CO2H
H2O
InCl3
method are carboxylic acids/ketones, whereas in the other
procedure, the products are aldehydes. Thus, this method
is complementary to the Au(I)-catalyzed method.6f
In conclusion, we have developed a very clean, efficient
and general method for the oxidative cleavage of alkenes
and alkynes using tert-butyl hydroperoxide and indium-
(III) chloride as catalysts in water to give the corresponding
carboxylic acids or ketones. The advantages of this method
are the general applicability to a wide variety of alkenes
and alkynes, compatibility with sensitive function-
alities, one-pot cleavage of exocyclic double bonds to
ketones and high yields. The use of water as the reaction
medium, reusability of the aqueous solution of catalyst
and no need for waste disposal, make this procedure
greener, safe and potentially useful for industrial
applications.
O
tBuOOH
OH
Scheme 2.
100
80
60
40
20
0
cyclohexene
cyclohexene oxide
cyclohexane diol
adipic acid
Acknowledgements
6
2
9
4
Time (h)
We are pleased to acknowledge the financial support
from CSIR, New Delhi (Grant No. 01(1936)/04/EMR-II)
for this investigation. S.B. and L.A. are also grateful to
CSIR for their fellowships.
Fig. 1.
with styrene using t-BuOOH alone in the absence of InCl3
for a prolonged period (18 h), only 10% of benzoic acid was
obtained. On the other hand, InCl3 alone without TBHP
did not initiate the reaction at all. We suggest that the oxi-
dative cleavage occurred through a number of steps involv-
ing epoxide formation followed by hydrolysis with H2O to
give a diol which was then cleaved to a carboxylic acid or
ketone (Scheme 2). The isolation of cyclohexene oxide,
1,2-cyclohexanediol and adipic acid at different stages of
the cleavage reaction of cyclohexene established the inter-
mediacy of these compounds as outlined in Scheme 2.
The progress of the reaction through these intermediates
is depicted in Figure 1.
Both pure cyclohexene oxide and 1,2-cyclohexane diol
when treated with TBHP/InCl3 using this procedure pro-
duced adipic acid in nearly quantitative yields. The argu-
ment for hydrolysis of the intermediate epoxide by H2O
gained support by the formation of 1-hydroxy-2-methoxy-
cyclohexane when water was replaced by methanol for the
cleavage of cyclohexene oxide. The formation of an epox-
ide from an olefin by TBHP is also precedent.10
This procedure has advantages to that catalyzed by
AuCl in the presence of neocuproine.6f Our method does
not require any ligand, whereas in other procedures virtu-
ally no oxidation occurred without ligand. The compatibil-
ity of sensitive functionalities such as a peptide bond, a
tert-butyl carboxylic ester and N-Boc-protected tryptophan
and cleavage of exocyclic double bonds were not been
addressed in the Au(I)-catalyzed method. The yields of
products and reaction time in our method are, in general,
much better than those catalyzed by AuCl particularly,
the yield in the cleavage of a-methyl styrene (Table 2, entry
11), 84% (8 h) compared to 39% (36 h). The catalyst, InCl3
References and notes
1. (a) Shing, T. K. M. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 7, pp 703–
716; (b) Hudlicky, M. Oxidations in Organic Chemistry. In ACS
Monograph 186; American Chemical Society: Washington, DC, 1990;
p 77.
2. (a) Bailey, P. S. Chem. Rev. 1958, 58, 925–1010; (b) Larock, R. C. In
Comprehensive Organic Transformations, 2nd ed.; Wiley-VCH: New
York, 1999; pp 1213–1215.
3. (a) Ogle, R. A.; Schumacher, J. L. Process. Saf. Prog. 1998, 17, 127–
133; (b) Koike, K.; Inou, G.; Fukuda, T. J. Chem. Eng. Jpn. 1999, 32,
295–299.
4. (a) Henry, J. R.; Weinreb, S. M. J. Org. Chem. 1993, 58, 4745; (b)
Travis, B. R.; Narayan, R. S.; Borhan, B. J. Am. Chem. Soc. 2002,
124, 3824–3825; (c) Lee, K.; Kim, Y.-H.; Han, S. B.; Kang, H.; Park,
S.; Seo, W. S.; Park, J. T.; Kim, B.; Chang, S. J. Am. Chem. Soc. 2003,
125, 6844–6845; (d) Whitehead, D. C.; Travis, B. R.; Borhan, B. J.
Am. Chem. Soc. 2006, 47, 3797–3800.
5. (a) Cornely, J.; Ham, L. M. S.; Meade, D. E.; Dragojlovic, V. Green
Chem. 2003, 5, 34–37; (b) Zimmermann, F.; Meux, E.; Mieloszynski,
J.-L.; Lecuire, J.-M.; Oget, N. Tetrahedron Lett. 2005, 46, 3201–3203;
(c) Yang, D.; Chen, F.; Dong, Z.-M.; Zhang, D.-W. J. Org. Chem.
2004, 69, 2221–2223; (d) Che, C.-M.; Yip, W.-P.; Yu, W.-Y. Chem.
Asian J. 2006, 1, 453–458.
6. (a) Lee, S.-O.; Raja, R.; Harris, K. D. M.; Thomas, J. M.; Johnson, B.
F. G.; Sankar, G. Angew. Chem., Int. Ed 2003, 42, 1520–1523; (b)
Brooks, C. D.; Huang, L.-C.; McCarron, M.; Johnstone, R. A. W.
Chem. Commun. 1999, 37–38; (c) Freitag, J.; Muchter, M.; Ond-
ruschka, B. Green Chem. 2003, 5, 291–295; (d) Antonelli, E.;
D’Aloisio, R.; Gambaro, M.; Fiorani, T.; Venturello, C. J. Org.
Chem. 1998, 63, 7190–7206; (e) Noyori, R.; Aoki, M.; Sato, K. Chem.
Commun. 2003, 1977–1986; (f) Xing, D.; Guan, B.; Cai, G.; Fang, Z.;
Yang, L.; Shi, Z. Org. Lett. 2006, 8, 693–696; (g) Sato, K.; Aoki, M.;
Noyori, R. Science 1998, 281, 1646–1647.
7. Representative procedure for the oxidative cleavage of cyclohexene to
adipic acid (Table 2, entry 8). A mixture of cyclohexene (82 mg,

B. C. Ranu et al. / Tetrahedron Letters 49 (2008) 2588–2591
2591
1 mmol), indium(III) chloride (44 mg, 20 mol %) and tert-butyl
hydroperoxide (0.5 mL, 70%, 3.8 mmol) in water (2.5 mL) was heated
at 90 °C for 9 h (TLC). The cooled reaction mixture was then
extracted with ethyl acetate (3 ꢀ 10 mL) and the extract was washed
with brine (2 ꢀ 5 mL) and dried (Na2SO4). Evaporation of the solvent
furnished crystals of adipic acid (134 mg, 92%) of more than 98%
purity. (If necessary, the crude products were purified by column
chromatography over silica gel.) The melting point and spectroscopic
data (IR, 1H and 13C NMR) of the products were in good agreement
with those of an authentic sample of adipic acid.11 The aqueous
solution of InCl3 and t-BuOH left after work up, was recycled for six
subsequent reactions without any appreciable loss of efficiency.
This procedure was followed for the oxidative cleavage of all the
alkenes and alkynes listed in Table 2. Although this procedure was
based on mmol scale, the reaction was also carried out on multigram
quantities without any difficulty. All the products except four (Table
2, entries 14–17) are known compounds and were identified by
comparison of their melting points, when applicable, and spectro-
scopic data (IR, 1H and 13C NMR) with those reported (see references
in Table 2). The novel compounds (Table 2, entries 14–17) were
characterized by their spectroscopic data (IR, 1H and 13C NMR,
HRMS) which are provided below.
1H); 13C NMR (75 MHz, CDCl3 + DMSO-d6) d 16.2, 24.2, 27.6, 27.7,
27.8, 27.9, 28.1, 34.3, 34.4, 46.5, 50.7, 171.9, 172.2, 173.5; HRMS m/z
26
calcd for C14H25NO5K [M+K]+ 326.1733; found: 326.1880; ½aꢂD
ꢁ18.9 (c 5.00, CHCl3).
9-(1-tert-Butoxycarbonyl-2-phenyl-ethyl carbamoyl)-nonanoic acid
(Table 2, entry 16): viscous yellow liquid; IR (neat) 3062, 3028,
2927, 2854, 1712, 1643, 1481, 1242, 1193, 1159 cmꢁ1 1H NMR
;
(300 MHz, CDCl3) d 1.18–1.42 (m, 16H), 1.53–1.60 (m, 5H), 1.97–
2.14 (m, 2H), 2.27 (t, J = 7.39 Hz, 2H), 2.96 (d, J = 5.93 Hz, 2H), 4.71
(q, J = 7.07 Hz, 1H), 7.02–7.20 (m, 5H); 13C NMR (75 MHz, CDCl3)
d 25.0, 28.3, 29.3 (2C), 29.4 (3C), 29.5, 29.7, 30.0, 34.4(2C), 53.8, 82.9,
127.3, 128.8 (2C), 129.7 (2C), 135.6, 179.8, 179.9, 180.1; HRMS m/z
26
calcd for C23H35NO5Na [M+Na]+ 428.2413; found: 428.2415; ½aꢂD
+5.1 (c 5.00, CHCl3).
3-[2-(9-Carboxy-nonanoylamino)-2-methoxycarbonyl-ethyl]-indole-1-
carboxylic acid tert-butyl ester (Table 2, entry 17): yellow viscous
liquid; IR (neat) 3435, 3250, 2850, 1720, 1658, 1216, 1053, 1028, 1007,
;
823, 702 cmꢁ1 1H NMR (300 MHz, CDCl3) d 1.23–1.45 (m, 10H),
1.56–1.68 (m, 9H), 1.99–2.04 (m, 4H), 2.15 (t, J = 7.45 Hz, 2H), 3.15–
3.29 (m, 2H), 3.67 (s, 3H), 4.08 (q, J = 7.14 Hz, 1H), 7.17–7.46 (m,
5H), 8.07 (d, J = 7.05 Hz, 1H); 13C NMR (75 MHz, CDCl3) d 25.5,
28.0 (3C), 28.8, 29.0, 29.1, 29.2, 29.3, 33.7, 36.5, 52.3, 52.4, 60.4, 83.7,
114.9, 115.3, 118.8, 122.5, 124.0, 124.5, 130.5, 135.2, 172.2, 173.1,
174.9, 175.8; HRMS m/z calcd for C27H38N2O7K [M+K]+ 541.2316;
9-(2-Benzyloxycarbonyl-ethylcarbamoyl)-nonanoic acid (Table 2,
entry 14): Yellow viscous oil; IR (neat) 3300, 2929, 2856, 1733,
27
1653, 1170 cmꢁ1
;
1H NMR (300 MHz, CDCl3) d 1.02–1.21 (m, 8H),
found: 541.2417; ½aꢂD +37.3 (c 5.00, CHCl3).
1.53–1.55 (m, 4H), 2.11 (t, J = 7.56 Hz, 2H), 2.27–2.41 (m, 2H), 2.57
(t, J = 6.01 Hz, 2H), 3.50 (q, J = 5.91 Hz, 2H), 5.12 (s, 2H), 6.14 (br s,
1H), 7.29–7.38 (m, 5H); 13C NMR (75 MHz, CDCl3) d 23.8, 25.6, 29.0
(2C), 29.1, 29.2, 34.2, 34.9, 36.7, 43.8, 66.6, 128.3 (2C), 128.5, 128.7
(2C), 135.7, 172.6, 173.4, 177.3; HRMS m/z calcd for C20H29NO5Na
[M+Na]+ 386.2046; found: 386.2127.
8. Nielsen, T. E.; Le Quement, S. T.; Meldal, M. Org. Lett. 2007, 9,
2469–2472.
9. (a) Che, C.-M.; Yu, W.-Y.; Chan, P.-M.; Cheng, W.-C.; Peng, S.-M.;
Lau, K.-C.; Li, W.-K. J. Am. Chem. Soc. 2000, 122, 11380–11392; (b)
Chabaud, B.; Sharpless, K. B. J. Org. Chem. 1979, 44, 4202–4204.
10. (a) Yin, G.; Danby, A. M.; Kitko, D.; Carter, J. D.; Scheper, W. M.;
Busch, D. H. Inorg. Chem. 2007, 46, 2173–2180; (b) Choudary, B. M.;
Pal, U.; Kantam, M. L.; Ranganath, K. V. S.; Sreedhar, B. Adv.
Synth. Catal. 2006, 348, 1038–1042.
9-(1-Methoxycarbonyl-ethyl carbamoyl)-nonanoic acid (Table 2, entry
15): yellow viscous liquid; IR (neat) 3388, 3288, 2931, 2856, 1737,
1651, 1546, 1215, 1026, 1004 cmꢁ1
;
1H NMR (300 MHz,
CDCl3 + DMSO-d6) d 1.10–1.23 (m, 12H), 1.30–1.44 (m, 3H), 1.98–
2.12 (m, 4H), 3.56 (s, 3H), 4.22–4.30 (m, 1H), 7.72 (d, J = 5.98 Hz,
11. Pouchert, C. J. In The Aldrich Library of NMR Spectra, 2nd ed.;
Aldrich Chemical: Milwaukee, 1983; Vols. 1–2.