Oxidative cleavage of alkenes using an in situ generated iodonium ion with oxone as a terminal oxidant

Article abstract of DOI:10.1021/ol1023807

A facile and operationally convenient catalytic procedure for oxidative cleavage of alkenes is described. In situ formed [hydroxy(4-carboxyphenyl) iodonium]ion, 2, from the oxidation of 4-iodobenzoic acid, 1, has been shown to facilitate the cleavage of a variety of alkenes in presence of Oxone as a co-oxidant. Optimization of the reaction conditions using 1-phenyl-1- cyclohexene, 3, and the competitive oxidative cleavage of different substrates using the optimized conditions has uncovered important mechanistic details of the reaction.

Full text of DOI:10.1021/ol1023807

ORGANIC
LETTERS
2010
Vol. 12, No. 24
5640-5643
Oxidative Cleavage of Alkenes Using an
In Situ Generated Iodonium Ion with
Oxone as a Terminal Oxidant
Prem P. Thottumkara and Thottumkara K. Vinod*
Department of Chemistry, Western Illinois UniVersity, Macomb,
Illinois 61455, United States
mftkV@wiu.edu
Received October 2, 2010
ABSTRACT
A facile and operationally convenient catalytic procedure for oxidative cleavage of alkenes is described. In situ formed [hydroxy-
(4-carboxyphenyl)iodonium]ion, 2, from the oxidation of 4-iodobenzoic acid, 1, has been shown to facilitate the cleavage of a variety of alkenes
in presence of Oxone as a co-oxidant. Optimization of the reaction conditions using 1-phenyl-1-cyclohexene, 3, and the competitive oxidative
cleavage of different substrates using the optimized conditions has uncovered important mechanistic details of the reaction.
The oxidative functionalization and cleavage of alkenes
represents a broad class of fundamental transformations in
organic chemistry frequently employed both in academic and
industrial settings for the synthesis and production of valuable
intermediates and chemical commodities.1 Scission of olefins
to aldehydes, ketones, and carboxylic acids is often carried
out using ozonolyis, accompanied by the appropriate
workup.1c,d,2 Alternatively, alkenes can also be cleaved using
the Lemieux-Johnson Protocol (OsO4 followed by NaIO4).3
OsO4 is also the choice reagent for the syn-hydroxylation of
olefins.1c,d,4 The utility of these popular methods for oxidative
transformation of alkenes is often hampered by the safety
concerns of ozonolysis5 and the toxicity of OsO4. During
the last few decades several attempts have been made by
different groups to devise safer alternatives for these useful
reactions. Prominent among these are the use of high-valent
metal-oxo catalysts, including complexes bearing Mn,6 Mo,7
Ru,8 Pd,9 Re,10 and Os.11 In these cases, a co-oxidant is
employed to regenerate the active catalyst.
(4) (a) Criegee, R.; Marchand, B.; Wannowius, H. Annalen 1942, 550,
99. (b) Sharpless, K. B.; Teranishi, A. Y.; Backvall, J. E. J. Am. Chem.
Soc. 1977, 99, 3120.
(5) Serious accidents due to explosions during ozonolysis have been
reported. See: Koike, K.; Inoue, G.; Fukada, T. J. Chem. Eng. Jpn. 1999,
32, 295.
(1) (a) Sheldon, R. A.; Kochi, J. K. Metal Catalyzed Oxidations of
Organic Compounds; Academic Press: New York, 1981. (b) Stewart, R.
Oxidation in Organic Chemistry; Wiberg, K., Ed.; Academic Press: New
York, 1965. (c) Hudlicky´, M. Oxidations in Organic Chemistry; American
Chemical Society Monograph 186; American Chemical Society: Washington
D.C., 1990. (d) Larock, R. C. ComprehensiVe Organic Transformations,
2nd ed.; Wiley-VCH: New York, 1999; p 1234. (e) Lee, D. G.; Chen, T.
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 7, p 541.
(6) (a) Boer, J. W.; Brinksma, J.; Browne, W. R.; Meetsma, A.; Alsters,
P. L.; Hage, R.; Feringa, B. L. J. Am. Chem. Soc. 2005, 127, 7990.
(7) Biradar, A. V.; Sathe, B. R.; Umbarkar, S. B.; Dongare, M. K. J.
Mol. Catal. A: Chem. 2008, 285, 111.
(8) (a) Griffith, W. P.; Shoair, A. G.; Suriaatmaja, M. Synth. Commun.
2000, 30, 3091. (b) Kogan, V.; Quintal, M. M.; Neumann, R. Org. Lett.
2005, 7, 5039. (e) Plietker, B. J. Org. Chem. 2003, 68, 7123.
(9) Wang, A.; Jiang, H. J. Org. Chem. 2010, 75, 2321.
(10) (a) Shing, T. K. M.; Tam, E. K. W. V.; Tai, W. -F.; Chung, I. H. F.;
Jiang, Q. Chem.sEur. J. 1996, 2, 50. (b) Neisius, N. M.; Plietker, B. J.
Org. Chem. 2008, 73, 3218.
(2) (a) Bailey, P. S. Ozonation In Organic Chemistry; Academic Press:
New York, 1982. (b) Criegee, R. Angew. Chem., Int. Ed. Engl. 1975, 14,
745
.
(3) (a) Pappo, R.; Allen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S. J.
Org. Chem. 1956, 21, 478.
(11) Travis, B. R.; Narayan, R. S.; Borhan, B. J. J. Am. Chem. Soc.
2002, 124, 3824.
10.1021/ol1023807  2010 American Chemical Society
Published on Web 11/16/2010

Despite the popularity of these transition metal catalyzed
reactions, the toxicity associated with these metals and the
inability to recover 100% of the spent reagent raises concerns
and obstructs their use in industrial processes. Attempts have
been made to recover osmium catalysts after oxidation by
immobilization12 or microencapsulation13 of the catalysts on
polymers. In keeping with green trends in organic synthesis,
Ochiai et al. introduced environmentally benign organoiodine
reagents14 [PhIO, 48%HBF4, 18-Crown-614a and ArI (cat),
48% HBF4, mCPBA14b] for the oxidative cleavage of
alkenes. More recently, Nicolaou reported a one-pot com-
bination of hydroxylation (Upjohn conditions15) followed by
the addition of stoichiometric Ph(IOAc)2 to effect alkene
cleavage.16 Continuing our interest in developing catalytic
and selective oxidation protocols using water-soluble hy-
pervalent iodine reagents in presence of Oxone as a co-
oxidant,17 we reasoned that the oxidation of 4-iodobenzoic
acid (4-IBAcid, 1) with Oxone would yield [hydroxy(4-
carboxyphenyl)-iodonium]ion, 2, a structural derivative of
the active reagent reported by Ochiai et al. for alkene
functionalization (Scheme 1).14a Herein, we report a facile
protonation of iodosyl benzene) is known to be readily soluble
in H2O at pH <2.3.18 Thus, it is not surprising that in the acidic
oxidation medium, 2 is more soluble in solvent mixtures with
higher concentration of D2O. Having established that 2 can
readily be formed from the oxidation of 1 we set out to
investigate the utility of 2 as an in situ generated reagent for
oxidative cleavage of alkenes. Commerically available 1-phenyl-
1- cyclohexene 3 was chosen as the test substrate upon which
optimization studies were performed.
In this study, we chose to focus our initial attention on
determining whether Oxone alone promoted alkene cleavage.
Entries 1 and 2 of Table 1 demonstrate that while Oxone
Table 1. Optimization Studies with 1-Phenyl-1-Cyclohexene, 3a
equiv
% yieldb
entry
1
oxone
(4 + 5)
6
7
1
2
3
4
5
6
7
8
-
-
0.5c
1.0c
0.5
0.75
1.0
1.2
1.5
1.63
2.0
2.0
95
100
95
69
45
25
8d
3d
-
-
-
5
-
-
-
24
40
65
92
92
100
100
100
100
Scheme 1. Oxidation of 4-IBAcid by Oxone
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
0.25
0.05
7
15
10
-
5
-
-
-
-
9
and operationally convenient protocol for the oxidative
cleavage of alkenes and vicinal diols in aqueous acetonitrile
using catalytic amounts of 4-IBAcid in the presence of Oxone
as a terminal oxidant.
10
11
12
-
-
-
2.0
2.0
a Reactions were carried out on 0.2 g scale in H2O:CH3CN (1:1 v/v, 20
mL) at 60 °C for 3 h. b 1H NMR yield. c No 4-IBAcid present. d Exclusively
5 with no 4 present.
Our initial efforts were directed at establishing the easy
oxidation of 1 with Oxone in aqueous acetonitrile to produce
the corresponding iodonium ion, 2, the desired active reagent.
Treatment of 1 with 0.75 equiv of Oxone in D2O/CD3CN (3:1
v/v) readily provided 2. However, we also noted that the
oxidation of 1 carried out in 2:1 and 1:1 v/v D2O and CD3CN
were incomplete as evident from the presence of the deshielded
AA′BB′ signals due to 2 along with the upfield signals of 1 in
does convert alkene 3 to the diol products19 4 and 5, no
oxidative cleavage is observed. However, in the presence of
4-IBAcid, alkene 3 is cleaved to the corresponding oxidized
products 6 and 7. The yield of keto-aldehyde 6 and keto-
acid 7 is dependent on the ratio of 4-IBAcid to Oxone.
Entries 3-9 demonstrate that in the presence of 1.0 equiv
of 1, varying equivalents of Oxone results in changes in
product distribution; an increase in Oxone concentration is
met with a parallel increase in formation of cleaved products
6 and 7. The yield of 6 is never high due to rapid aldehyde
oxidation to 7 by Oxone.20 We identified that 1.5-2.0 equiv
of Oxone proved sufficient for complete conversion of 3 (a
trisubstituted alkene) to 7 (a keto-acid).21 The isolated
product mixture from this optimization study contained small
(<20%) amounts of 1 (see Supporting Information) indicating
1
the corresponding H NMR spectra. The apparent difference
in the extent of oxidation in the three solvent mixtures may be
a reflection of the solubility differences of 1 and 2 in the
respective media. [Hydroxy(phenyl)iodonium] ion (obtained by
(12) Kobayashi, S.; Endo, M.; Eagayama, S. J. Am. Chem. Soc. 1999,
121, 11229.
(13) (a) Kobayashi, S.; Endo, M.; Nagayama, S. J. Org. Chem. 1998,
63, 6094. (b) Ho, C. -M.; Yu, W. -Y.; Che, C. -M. Angew. Chem. Int. Ed
2004, 43, 3303.
(14) (a) Miyamoto, K.; Tada, N.; Ochiai, M. J. Am. Chem. Soc. 2007,
129, 2772. (b) Miyamoto, K.; Sei, Y.; Yamaguchi, K.; Ochiai, M. J. Am.
Chem. Soc. 2009, 131, 1382.
(15) Van Rheeven, V.; Kelley, R. C.; Cha, D. Y. Tetrahedron Lett. 1976,
23, 1973.
(18) Richter, H. W.; Cherry, B. R.; Zook, T. D.; Koser, G. F. J. Am.
Chem. Soc. 1997, 119, 9614.
(16) Nicolaou, K. C.; Adsool, V. A.; Hale, C. R. H. Org. Lett. 2010,
12, 1552.
(19) Doan, L.; Bradley, K.; Gerdes, S.; Whalen, D. L. J. Org. Chem.
1999, 64, 6227.
(17) (a) Thottumkara, A. P.; Bowsher, M. S.; Vinod, T. K. Org. Lett.
2005, 7, 2933. (b) Ohja, L. R.; Kudugunti, S.; Maddukuri, P. P.;
Kommareddy, A.; Gunna, M. R.; Dokuparthi, P.; Gottam, H. B.; Botha,
K. K.; Parapati, D. R.; Vinod, T. K. SynLett 2009, 1, 117.
(20) (a) Travis, B. R.; Sivakumar, M.; Hollist, G. O.; Borhan, B. Org.
Lett. 2003, 5, 1031. (b) Gandhari, R.; Maddukuri, P. P.; Vinod, T. K.
J. Chem. Educ. 2007, 84, 852.
Org. Lett., Vol. 12, No. 24, 2010
5641

that the major bulk of the stoichiometric amount of 1 initially
employed in these reaction was lost during the workup either
as the water-soluble iodonium ion, 2, or through the
polymerization of the iodosyl derivative. Irrespective of how
the loss of 1 occurred, the observed quantitative cleavage of
3 with only substoichiometric amounts of 1 indicated the
feasibility of a catalytic protocol which we verified by using
substoichiometric quantities of 1 along with 2.0 equiv of
Oxone to obtain near quantitative cleavage of 3 (entries
10-12).
These optimization studies with stoichiometric 1 served
as a proof of principle that our in situ generated oxidant 2
effectively cleaves alkenes in the presence of Oxone. The
ability to use 1 catalytically, in concert with the operational
simplicity of this reaction, prompted us to investigate the
scope of this transformation. Table 2 shows a selection of
products was occasionally difficult. To circumvent this
problem, we found that iodobenzene can also be employed
as a precatalyst without noticeable detriment to reaction
performance. Left over iodobenzene after the reaction can
then be easily removed under vacuum, simplifying product
purification.
Phenyl conjugated cyclic alkenes are smoothly cleaved to
the corresponding keto-acids. Electron deficient alkenes
required prolonged reaction times (entries 7-10) for cleav-
age. To highlight the utility of the reaction it should also be
noted that cleavage of 3 and other phenyl conjuagted
cycloalkenes (entries 1-5) were carried out on multigram
sccale (2-5 g) with no loss in yield. Cleavage of trans-
chalcone gave only benzoic acid as the product as initially
formed phenylglyoxalic acid is presumably further oxidized
by Oxone to benzoic acid.22 While 1-phenyl cyclododecene
(entry 4) was easily oxidized, its des-phenyl counterpart
(entry 12) suffered from slow oxidative cleavage. In general,
we found that the rate of cleavage of phenyl conjugated
cyclic alkenes were considerably faster than phenyl conju-
gated acylic alkenes.
Table 2. Substrate Scope of Alkene Oxidative Cleavage
Nonphenyl conjugated alkenes cleaved the slowest often
requiring 24-36 h for completion. We also observed that
use of stoichiometric iodobenzene along with the required
amount of Oxone21 facilitated quantitative cleavage of these
reluctant alkenes in 6-8 h (entries 11-13). It was also
intresting to observe that oxidative transformation of the
alkenyl sufide (entry 13) to 4-(p-toluylsulfonyl)butyric acid
can be readily accomplished using two additional equiv of
Oxone in the reaction (Method C) for the oxidation of the
sulfur atom.23
We viewed our ability to use vicinal diols as substrates
(entry 14) as an opportunity to gain further insight into
plausible reaction mechanisms. Our earlier optimization
studies had hinted that vicinal diols were intermediates en
route to full oxidized products (Table 1). In order to
rationalize further some of the trends we observed so far
(e.g., relative difficulty in cleaving unconjugated alkenes, the
role of vicinal diols along the reaction pathway, and the easier
and faster cleavage of cis-diols over trans-diols) we decided
to perform a series of competition experiments to more
clearly understand this newly developed reaction.
Competition experiments between 3 and 8 and between
4/5 and 11 were conducted under our catalytic conditions
(20 mol % 1 and required amount of Oxone21 in a 1:1 v/v
solution of D2O/CD3CN) and the relative ease of oxidation
of competing substrates were monitored by the appearance
1
of discernible H NMR peaks from the products from the
two substrates (see Supporting Information). Monitoring
these competitive reactions clearly showed that 3 was cleaved
significantly faster than 8 and the rate of cleavage of both 4
and 5 were faster than that of 11, evidently indicating the
a Method A: 0.2 equiv of 1 and Oxone in H2O-CH3CN (1:1, v/v).
Method B: 0.2 equiv of iodobenzene and Oxone in H2O-CH3CN (1:1, v/v).
Method C: 1.0 equiv of Iodobenzene and Oxone in H2O-CH3CN (1:1,
c
v/v). b Isolated yield. 1H NMR yield.
(21) Oxone required for quantitative cleavage of susbtrates depend on
the nature of the substrates employed and whether the initially formed
cleaved products are further oxidized.
(22) Yan, J.; Travis, B. R.; Borhan, B. J. Org. Chem. 2004, 69, 9299.
(23) Trost, B. M.; Curran, P. P. Tetrahedron Lett. 1981, 22, 1287.
(24) Full competition experiment data is provided in the Supporting
Information.
alkenes cleaved under the newly developed conditions. It
should be noted that in the course of our studies we found
that chromatographic separation of 4-IBAcid from desired
5642
Org. Lett., Vol. 12, No. 24, 2010

favorable effect of having a phenyl group on the bond being
cleaved. We take it that the stability afforded by the phenyl
ring on any build up of positive charge is responsible for
observed rate differences (vide infra). More revealing data
came from our studies of the cleavage of vicinal diols. During
optimization studies we had observed that the cis diol 4 was
cleaved faster than trans diol 5 and were curious whether
such an observation offered us insight into a possible reaction
mechanism. Head-to-head competition experiments between
11 and 12 clearly demonstrated that cis-1,2-cyclohexanediol,
11, was cleaved faster than its trans counterpart, 12. In
comparing rates of cleavage of a mixture of 4/5 and 11 we
noted that even trans alcohol 5 cleaved faster than 11,
underscoring the importance of presumably stabilizing an
incipient carbocation. Additionally, competition experiments
between 4/5 and 13 showed that 4 (and 5) cleaved faster
than 13, suggesting that conformationally rigid cis diols are
better substrates than open chain vicinal diols. No discernible
rate differences in the cleavage of 11 and 13 were noted.
This latter observation suggests that the conformational
rigidity of the cyclic cis diols offsets the favorable role of a
phenyl group on the bond cleaved in acylic substrates.
Unconjugated acylic alkenes (10) and 1,2-alkanediols (14)
cleaved only slowly, often requiring 24-36 h for completion
under the catlaytic conditions (20 mol % 1 with requisite
Oxone) tried. Cleavage of these sluggish substrates were,
however, observed to be complete within 6-8 h when
stoichiometric 1 or iodobenzene was employed. We believe
that the slow rate of cleavage in these cases not only stems
from the lack of favorable structural features in the substrates
(phenyl group on the bond cleaved or conformationally rigid
cis-diols) but also from the decomposition of the active
reagent, 2 over time. Appearance of a singlet at δ 8.1225
with its intensity increasing with a corresponding decrease
in the intensity of the signals from 2 in the 1H NMR spectra
recorded at various intervals during the competitive reactions
suggest such a decomposition.
Scheme 2. Suggested Mechanism for Cleavage of Alkenes
Oxone.20 The sterically demanding ring puckering that would
occur if a trans fused dialkoxy-λ3-iodane were to form from
17 forces the conversion of 17f16 via the benzylic car-
bocation 18. The role of the phenyl group in stabilizing the
carbocation intermediate in 18 explains the ease of oxidation
of 5 over 11. The proposed mechanism clearly shows that
1.5 equiv of Oxone is required for the conversion of 3f7.
Experimentally it was noted that 1.5-2.0 equiv of Oxone is
required for quantitative cleavage and conversion of 3f7
and we believe that this slight discrepancy stems from the
decomposition or polymerization of the iodonium ion 2
during the reaction accounting for the excess consumption
of Oxone as noted.
Figure 1. Substrates Used in Head-to-Head Competitive Oxidative
Cleavage Reactions with 3 and 4/5.24
In summary we have developed an operationally simple
and catalytic procedure for oxidative cleavage of alkenes
using benign and cheap reagents. The new method is versatile
and a safer alternative to existing alkene cleavage procedures.
On the basis of these studies, the following tentative
mechanism for the oxidative cleavage of alkenes is proposed,
using the cleavage of 3 as an example. The salient features
of the mechanism shown in Scheme 2 are the following. The
rapidly formed 1,2 diols 4 and 5 intercept the iodonium ion
2 to form intermediates 15 and 17 respectively. Cyclic
dialkoxy-λ3-iodane 16, readily formed from 15, cleaves to
give 6, regenerating 1 ready to re-enter the reaction under
catalytic conditions with enough Oxone present. Further
oxidation of 6f7 consumes an additional 0.5 equiv of
Acknowledgment. The authors gratefully acknowledge the
National Science Foundation (CHE-0910565) and the Donors
of the American Chemical Society Petroleum Research Funds
(50086-URI) for support of this research.
Supporting Information Available: Experimental details
and the spectral data of the isolated compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
(25) Spiking the H NMR sample with terephthalic acid increases the
intensity of the singlet at δ 8.12; however, formation of terephthalic acid
in the reaction medium is still being debated.
OL1023807
Org. Lett., Vol. 12, No. 24, 2010
5643