ORGANIC

LETTERS

Oxidative Cleavage of Alkenes Using an 2010

Vol. 12, No. 24
In Situ Generated Iodonium Ion with 5640-5643
Oxone as a Terminal Oxidant
Prem P. Thottumkara and Thottumkara K. Vinod*

Department of Chemistry, Western Illinois UniVersity, Macomb,

Illinois 61455, United States
[email protected]

Received October 2, 2010

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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 concerns of ozonolysis5 and the toxicity of OsO4. During
represents a broad class of fundamental transformations in the last few decades several attempts have been made by
organic chemistry frequently employed both in academic and different groups to devise safer alternatives for these useful
industrial settings for the synthesis and production of valuable reactions. Prominent among these are the use of high-valent
intermediates and chemical commodities.1 Scission of olefins metal-oxo catalysts, including complexes bearing Mn,6 Mo,7
to aldehydes, ketones, and carboxylic acids is often carried Ru,8 Pd,9 Re,10 and Os.11 In these cases, a co-oxidant is
out using ozonolyis, accompanied by the appropriate employed to regenerate the active catalyst.
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 (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.
olefins.1c,d,4 The utility of these popular methods for oxidative Soc. 1977, 99, 3120.
transformation of alkenes is often hampered by the safety (5) Serious accidents due to explosions during ozonolysis have been
reported. See: Koike, K.; Inoue, G.; Fukada, T. J. Chem. Eng. Jpn. 1999,
(1) (a) Sheldon, R. A.; Kochi, J. K. Metal Catalyzed Oxidations of 32, 295.
Organic Compounds; Academic Press: New York, 1981. (b) Stewart, R. (6) (a) Boer, J. W.; Brinksma, J.; Browne, W. R.; Meetsma, A.; Alsters,
Oxidation in Organic Chemistry; Wiberg, K., Ed.; Academic Press: New P. L.; Hage, R.; Feringa, B. L. J. Am. Chem. Soc. 2005, 127, 7990.
York, 1965. (c) Hudlický, M. Oxidations in Organic Chemistry; American (7) Biradar, A. V.; Sathe, B. R.; Umbarkar, S. B.; Dongare, M. K. J.
Chemical Society Monograph 186; American Chemical Society: Washington Mol. Catal. A: Chem. 2008, 285, 111.
D.C., 1990. (d) Larock, R. C. ComprehensiVe Organic Transformations, (8) (a) Griffith, W. P.; Shoair, A. G.; Suriaatmaja, M. Synth. Commun.
2nd ed.; Wiley-VCH: New York, 1999; p 1234. (e) Lee, D. G.; Chen, T. 2000, 30, 3091. (b) Kogan, V.; Quintal, M. M.; Neumann, R. Org. Lett.
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon 2005, 7, 5039. (e) Plietker, B. J. Org. Chem. 2003, 68, 7123.
Press: Oxford, 1991; Vol. 7, p 541. (9) Wang, A.; Jiang, H. J. Org. Chem. 2010, 75, 2321.
(2) (a) Bailey, P. S. Ozonation In Organic Chemistry; Academic Press: (10) (a) Shing, T. K. M.; Tam, E. K. W. V.; Tai, W. -F.; Chung, I. H. F.;
New York, 1982. (b) Criegee, R. Angew. Chem., Int. Ed. Engl. 1975, 14, Jiang, Q. Chem.sEur. J. 1996, 2, 50. (b) Neisius, N. M.; Plietker, B. J.
745. Org. Chem. 2008, 73, 3218.
(3) (a) Pappo, R.; Allen, D. S., Jr.; Lemieux, R. U.; Johnson, W. S. J. (11) Travis, B. R.; Narayan, R. S.; Borhan, B. J. J. Am. Chem. Soc.
Org. Chem. 1956, 21, 478. 2002, 124, 3824.

10.1021/ol1023807  2010 American Chemical Society

Published on Web 11/16/2010
 Despite the popularity of these transition metal catalyzed protonation of iodosyl benzene) is known to be readily soluble
reactions, the toxicity associated with these metals and the in H2O at pH <2.3.18 Thus, it is not surprising that in the acidic
inability to recover 100% of the spent reagent raises concerns oxidation medium, 2 is more soluble in solvent mixtures with
and obstructs their use in industrial processes. Attempts have higher concentration of D2O. Having established that 2 can
been made to recover osmium catalysts after oxidation by readily be formed from the oxidation of 1 we set out to
immobilization12 or microencapsulation13 of the catalysts on investigate the utility of 2 as an in situ generated reagent for
polymers. In keeping with green trends in organic synthesis, oxidative cleavage of alkenes. Commerically available 1-phenyl-
Ochiai et al. introduced environmentally benign organoiodine 1- cyclohexene 3 was chosen as the test substrate upon which
reagents14 [PhIO, 48%HBF4, 18-Crown-614a and ArI (cat), optimization studies were performed.
48% HBF4, mCPBA14b] for the oxidative cleavage of In this study, we chose to focus our initial attention on
alkenes. More recently, Nicolaou reported a one-pot com- determining whether Oxone alone promoted alkene cleavage.
bination of hydroxylation (Upjohn conditions15) followed by Entries 1 and 2 of Table 1 demonstrate that while Oxone
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- Table 1. Optimization Studies with 1-Phenyl-1-Cyclohexene, 3a
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 equiv % yieldb
entry 1 oxone (4 + 5) 6 7
1 - c
0.5 95 - -
2 - 1.0c 100 - -
Scheme 1. Oxidation of 4-IBAcid by Oxone 3 1.0 0.5 95 5 -
4 1.0 0.75 69 7 24
5 1.0 1.0 45 15 40
6 1.0 1.2 25 10 65
7 1.0 1.5 8d - 92
8 1.0 1.63 3d 5 92
9 1.0 2.0 - - 100
and operationally convenient protocol for the oxidative 10 0.5 2.0 - - 100
cleavage of alkenes and vicinal diols in aqueous acetonitrile 11 0.25 2.0 - - 100
using catalytic amounts of 4-IBAcid in the presence of Oxone 12 0.05 2.0 - - 100
as a terminal oxidant. a
Reactions were carried out on 0.2 g scale in H2O:CH3CN (1:1 v/v, 20
Our initial efforts were directed at establishing the easy mL) at 60 °C for 3 h. b 1H NMR yield. c No 4-IBAcid present. d Exclusively
5 with no 4 present.
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
does convert alkene 3 to the diol products19 4 and 5, no
v/v) readily provided 2. However, we also noted that the
oxidative cleavage is observed. However, in the presence of
oxidation of 1 carried out in 2:1 and 1:1 v/v D2O and CD3CN
4-IBAcid, alkene 3 is cleaved to the corresponding oxidized
were incomplete as evident from the presence of the deshielded
products 6 and 7. The yield of keto-aldehyde 6 and keto-
AA′BB′ signals due to 2 along with the upfield signals of 1 in
acid 7 is dependent on the ratio of 4-IBAcid to Oxone.
the corresponding 1H NMR spectra. The apparent difference
Entries 3-9 demonstrate that in the presence of 1.0 equiv
in the extent of oxidation in the three solvent mixtures may be
of 1, varying equivalents of Oxone results in changes in
a reflection of the solubility differences of 1 and 2 in the
product distribution; an increase in Oxone concentration is
respective media. [Hydroxy(phenyl)iodonium] ion (obtained by
met with a parallel increase in formation of cleaved products
6 and 7. The yield of 6 is never high due to rapid aldehyde
(12) Kobayashi, S.; Endo, M.; Eagayama, S. J. Am. Chem. Soc. 1999,
121, 11229. oxidation to 7 by Oxone.20 We identified that 1.5-2.0 equiv
(13) (a) Kobayashi, S.; Endo, M.; Nagayama, S. J. Org. Chem. 1998, of Oxone proved sufficient for complete conversion of 3 (a
63, 6094. (b) Ho, C. -M.; Yu, W. -Y.; Che, C. -M. Angew. Chem. Int. Ed
2004, 43, 3303. trisubstituted alkene) to 7 (a keto-acid).21 The isolated
(14) (a) Miyamoto, K.; Tada, N.; Ochiai, M. J. Am. Chem. Soc. 2007, product mixture from this optimization study contained small
129, 2772. (b) Miyamoto, K.; Sei, Y.; Yamaguchi, K.; Ochiai, M. J. Am. (<20%) amounts of 1 (see Supporting Information) indicating
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.
(16) Nicolaou, K. C.; Adsool, V. A.; Hale, C. R. H. Org. Lett. 2010, Chem. Soc. 1997, 119, 9614.
12, 1552. (19) Doan, L.; Bradley, K.; Gerdes, S.; Whalen, D. L. J. Org. Chem.
(17) (a) Thottumkara, A. P.; Bowsher, M. S.; Vinod, T. K. Org. Lett. 1999, 64, 6227.
2005, 7, 2933. (b) Ohja, L. R.; Kudugunti, S.; Maddukuri, P. P.; (20) (a) Travis, B. R.; Sivakumar, M.; Hollist, G. O.; Borhan, B. Org.
Kommareddy, A.; Gunna, M. R.; Dokuparthi, P.; Gottam, H. B.; Botha, Lett. 2003, 5, 1031. (b) Gandhari, R.; Maddukuri, P. P.; Vinod, T. K.
K. K.; Parapati, D. R.; Vinod, T. K. SynLett 2009, 1, 117. 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 products was occasionally difficult. To circumvent this
employed in these reaction was lost during the workup either problem, we found that iodobenzene can also be employed
as the water-soluble iodonium ion, 2, or through the as a precatalyst without noticeable detriment to reaction
polymerization of the iodosyl derivative. Irrespective of how performance. Left over iodobenzene after the reaction can
the loss of 1 occurred, the observed quantitative cleavage of then be easily removed under vacuum, simplifying product
3 with only substoichiometric amounts of 1 indicated the purification.
feasibility of a catalytic protocol which we verified by using Phenyl conjugated cyclic alkenes are smoothly cleaved to
substoichiometric quantities of 1 along with 2.0 equiv of the corresponding keto-acids. Electron deficient alkenes
Oxone to obtain near quantitative cleavage of 3 (entries required prolonged reaction times (entries 7-10) for cleav-
10-12). age. To highlight the utility of the reaction it should also be
These optimization studies with stoichiometric 1 served noted that cleavage of 3 and other phenyl conjuagted
as a proof of principle that our in situ generated oxidant 2 cycloalkenes (entries 1-5) were carried out on multigram
effectively cleaves alkenes in the presence of Oxone. The sccale (2-5 g) with no loss in yield. Cleavage of trans-
ability to use 1 catalytically, in concert with the operational chalcone gave only benzoic acid as the product as initially
simplicity of this reaction, prompted us to investigate the formed phenylglyoxalic acid is presumably further oxidized
scope of this transformation. Table 2 shows a selection of 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
Table 2. Substrate Scope of Alkene Oxidative Cleavage
cyclic alkenes were considerably faster than phenyl conju-
gated acylic alkenes.
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
of discernible 1H NMR peaks from the products from the
two substrates (see Supporting Information). Monitoring
these competitive reactions clearly showed that 3 was cleaved
a
Method A: 0.2 equiv of 1 and Oxone in H2O-CH3CN (1:1, v/v). significantly faster than 8 and the rate of cleavage of both 4
Method B: 0.2 equiv of iodobenzene and Oxone in H2O-CH3CN (1:1, v/v). and 5 were faster than that of 11, evidently indicating the
Method C: 1.0 equiv of Iodobenzene and Oxone in H2O-CH3CN (1:1,
v/v). b Isolated yield. c 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.
alkenes cleaved under the newly developed conditions. It (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.
should be noted that in the course of our studies we found (24) Full competition experiment data is provided in the Supporting
that chromatographic separation of 4-IBAcid from desired Information.

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 Scheme 2. Suggested Mechanism for Cleavage of Alkenes
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 Oxone.20 The sterically demanding ring puckering that would
incipient carbocation. Additionally, competition experiments occur if a trans fused dialkoxy-λ3-iodane were to form from
between 4/5 and 13 showed that 4 (and 5) cleaved faster 17 forces the conversion of 17f16 via the benzylic car-
than 13, suggesting that conformationally rigid cis diols are bocation 18. The role of the phenyl group in stabilizing the
better substrates than open chain vicinal diols. No discernible carbocation intermediate in 18 explains the ease of oxidation
rate differences in the cleavage of 11 and 13 were noted. of 5 over 11. The proposed mechanism clearly shows that
This latter observation suggests that the conformational 1.5 equiv of Oxone is required for the conversion of 3f7.
rigidity of the cyclic cis diols offsets the favorable role of a Experimentally it was noted that 1.5-2.0 equiv of Oxone is
phenyl group on the bond cleaved in acylic substrates. required for quantitative cleavage and conversion of 3f7
Unconjugated acylic alkenes (10) and 1,2-alkanediols (14) and we believe that this slight discrepancy stems from the
cleaved only slowly, often requiring 24-36 h for completion decomposition or polymerization of the iodonium ion 2
under the catlaytic conditions (20 mol % 1 with requisite during the reaction accounting for the excess consumption
Oxone) tried. Cleavage of these sluggish substrates were, of Oxone as noted.
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 Figure 1. Substrates Used in Head-to-Head Competitive Oxidative
with its intensity increasing with a corresponding decrease Cleavage Reactions with 3 and 4/5.24
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. In summary we have developed an operationally simple
On the basis of these studies, the following tentative and catalytic procedure for oxidative cleavage of alkenes
mechanism for the oxidative cleavage of alkenes is proposed, using benign and cheap reagents. The new method is versatile
using the cleavage of 3 as an example. The salient features and a safer alternative to existing alkene cleavage procedures.
of the mechanism shown in Scheme 2 are the following. The
rapidly formed 1,2 diols 4 and 5 intercept the iodonium ion Acknowledgment. The authors gratefully acknowledge the
2 to form intermediates 15 and 17 respectively. Cyclic National Science Foundation (CHE-0910565) and the Donors
dialkoxy-λ3-iodane 16, readily formed from 15, cleaves to of the American Chemical Society Petroleum Research Funds
give 6, regenerating 1 ready to re-enter the reaction under (50086-URI) for support of this research.
catalytic conditions with enough Oxone present. Further
oxidation of 6f7 consumes an additional 0.5 equiv of Supporting Information Available: Experimental details
and the spectral data of the isolated compounds. This material
(25) Spiking the 1H NMR sample with terephthalic acid increases the is available free of charge via the Internet at http://pubs.acs.org.
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