Tetrapropylammonium perruthenate catalyzed glycol cleavage to carboxylic (Di)acids

Article abstract of DOI:10.1021/ol202354g

A new method to accomplish glycol cleavage to carboxylic (di)acids in one step using catalytic amounts of tetrapropylammonium perruthenate (TPAP) together with N-methylmorpholine N-Oxide (NMO) as the stoichiometric oxidant is presented. In addition to regenerating the active catalyst, the N-oxide stabilizes intermediary carbonyl hydrates and thereby shifts a crucial equilibrium. The mild oxidation protocol is applicable to a broad range of substrates providing the respective acids, diacids, or keto acids in high yields.

Full text of DOI:10.1021/ol202354g

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5788–5791
Tetrapropylammonium Perruthenate
Catalyzed Glycol Cleavage to Carboxylic
(Di)Acids
Andrea-Katharina C. Schmidt† and Christian B. W. Stark*,†,‡
€
€
€
€
Fakultat fur Chemie und Mineralogie, Institut fur Organische Chemie, Universitat
Leipzig, Johannisallee 29, 04103 Leipzig, Germany, and Fachbereich Chemie, Institut fu€r
€
Organische Chemie, Universitat Hamburg, Martin-Luther-King-Platz 6,
20146 Hamburg, Germany
stark@chemie.uni-hamburg.de
Received August 30, 2011
ABSTRACT
A new method to accomplish glycol cleavage to carboxylic (di)acids in one step using catalytic amounts of tetrapropylammonium perruthenate
(TPAP) together with N-methylmorpholine N-Oxide (NMO) as the stoichiometric oxidant is presented. In addition to regenerating the active
catalyst, the N-oxide stabilizes intermediary carbonyl hydrates and thereby shifts a crucial equilibrium. The mild oxidation protocol is applicable to
a broad range of substrates providing the respective acids, diacids, or keto acids in high yields.
The oxidativecleavageofvicinal diolstothe correspond-
ing carbonyl compounds is a frequently used transformation
in synthetic organic chemistry.1 Lead tetraacetate (Criegee
oxidation)2 and, more importantly, periodic acid or its
salts (Malaprade reaction)3 are the reagents of choice and
generally give the corresponding aldehydes or ketones in
good yields. However, if the carboxylic (di)acid is the desired
product (Scheme 1), usually two consecutive oxidation reac-
tions are required. There are only a few methods that
accomplish this transformation in a single step. The reagent
systems used include Co(II)/O2,4 PCC (stoichiometric),5
ruthenium pyrochlore oxides/O2,6 MoO2(acac)2/tBuOOH,7
and WO42ꢀ/PO43ꢀ/H2O2.8 These methods, however, suffer
from serious drawbacks such as toxicity of reagents, harsh-
ness of reaction conditions, lack of selectivity, or limited
compatibility with sensitive functional groups.
Tetrapropylammonium perruthenate (TPAP) in combi-
nation with N-methylmorpholine N-oxide (NMO) is a well-
established mild and efficient catalyst for alcohol oxida-
tions.9 So far, a TPAP-catalyzed oxidative cleavage of
vicinal diols to carbonyl compounds has only been observed
as an unwanted side reaction, particularly with strained
(6) Felthouse, T. R. J. Am. Chem. Soc. 1987, 109, 7566.
(7) Kandeda, K.; Morimoto, K.; Imanaka, T. Chem. Lett. 1988, 17,
1295.
†
€
Universitat Leipzig.
‡
€
Universitat Hamburg.
(1) Shing, T. K. M. In Comprehensive Organic Synthesis; Trost, B. M.,
Flemming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 7, p 703.
(2) Criegee, R. Ber. 1931, 64B, 260.
(3) (a) Malaprade, M. L. Bull. Soc. Chem. Fr. 1928, 43, 683. (b)
Malaprade, M. L. Compt. Rend. 1928, 186, 382.
(4) (a) de Vries, G.; Schors, A. Tetrahedron Lett. 1968, 54, 5689. (b)
Mastrorilli, P.; Surama, G. P.; Nobile, C. F.; Farinola, G.; Lopez, L. J.
Mol. Catal. 2000, 156, 278. (c) Iwahama, T.; Yoshino, Y.; Keitoku, T.;
Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2000, 65, 6502.
(8) Venturello, C.; Ricci, M. J. Org. Chem. 1986, 51, 1599.
(9) (a) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D.
J. Chem. Soc., Chem. Commun. 1987, 1625. (b) Griffith, W. P.; Ley, S. V.
Aldrichimica Acta 1990, 23, 13. (c) Ley, S. V.; Norman, J.; Griffith,
W. P.; Marsden, S. P. Synthesis 1994, 639. (d) Langer, P. J. Prakt. Chem.
2000, 342, 728.
(10) (a) Quenau, Y.; Krol, W.; Bornmann, W. G.; Danishefsky, S. J.
J. Org. Chem. 1992, 57, 4043. (b) Acosta, C. K.; Rao, P. N.; Kim, H. K.
Steroids 1993, 58, 205. (c) Wiberg, K. B.; Snoonian, J. R. J. Org. Chem.
1998, 63, 1402. (d) Williams, D. R.; Heidebrecht, R. W., Jr. J. Am. Chem.
Soc. 2003, 125, 1843.
ꢀ
ꢀ
(5) Cisneros, A.; Fernandez, S.; Hernandez, J. E. Synth. Commun.
1982, 12, 833.
r
10.1021/ol202354g
Published on Web 10/14/2011
2011 American Chemical Society

cyclic substrates.10 In these cases, the corresponding di-
aldehydes or keto aldehydes were obtained as the products
(Scheme 1).
was observed. This prompted us to carry out a systematic
investigation of the reaction conditions.
A solvent screening was conducted using 1,2-dodecane-
diol as the test substrate in the presence of 20 mol %
catalyst and 20 equiv of NMO H2O (Table 1). The screen-
3
ing included solvents that provided good results in the TPAP-
catalyzed oxidation of primary alcohols to carboxylic acids.11
The best results (70 and 69% yield, respectively) were
obtainedwhenthe classic TPAP-solventsdichloromethane
and acetonitrile were used (Table 1, entries 1 and 2).
Reducing the catalyst loading or the amount of co-oxidant/
hydrate stabilizing agent lead to diminished yields.
Scheme 1. Envisaged Glycol Cleavage to the Corresponding
Carboxylic (Di)Acids or Keto Acids vs Stepwise Process
Table 1. Solvent Screening
We have recently developed a protocol for the TPAP-
catalyzed direct oxidation of primary alcohols to car-
boxylic acids.11 With 10 mol % TPAP and 10 equiv of
isolated yield
entry
solvent
of 2 (%)
1
2
3
4
5
CH2Cl2
MeCN
DMF
70
69
64
54
62
NMO H2O in acetonitrile a wide range of substrates can
3
be converted to the corresponding acids.11 The key feature
of our method is the stabilization of the intermediate
aldehyde hydrate which was accomplished by using an excess
of NMO containing 1 equiv of water of crystallization. Hydra-
acetone
THF
tion experiments support our assumption that NMO H2O
3
not only serves as the co-oxidant but also, and uniquely,
stabilizes the aldehyde hydrate.12 This stabilization most
likely occurs through hydrogen-bonding between the geminal
diol and the Lewis basic oxygen of the N-oxide (Figure 1).13
We next applied our optimized conditions (20 mol %
TPAP, 20 equiv of NMO H2O, in CH2Cl2 (0.1 M)) to
3
various 1,2-diols containing different functionalities. As
summarized in Table 2, a range of acyclic vicinal diols gave
the respective cleavage products in good yields (Table 2,
entries 1ꢀ6). Products were isolated either as free acids or,
after treatment with TMS-diazomethane,15 as the resulting
methyl esters (see Table 2 and Supporting Information for
details). In the case of substrate 716 (Table 2, entry 4) the
initially obtained hydroxy acid was cyclized under Brønsted
acid catalysis and isolated as bicyclic lactone 817 (see
Table 2 and Supporting Information for details). Cleavage
of dihydroxyolefin 11 resulted in the corresponding acid
1218 as the major product in 41% yield (Table 2, entry 6).
Figure 1. Possible modes of carbonyl hydrate stabilization by
NMO.
(13) For related hydrogen bond acceptor properties of NMO, see:
Fink, H.-P.; Weigel, P.; Purz, H. J.; Ganster, J. Prog. Polym. Sci. 2001,
26, 1473.
(14) For a related catalytic oxidative cleavage of hydroxy ethers
yielding cyclic esters, see: Roth, S.; Stark, C. B. W. Chem. Commun.
2008, 6411.
(15) Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull. 1981,
29, 1475.
(16) This substrate was prepared by RuO4-catalysed oxidative cycli-
On the basis of these findings we decided to investigate
the potential of TPAP and the hydrate stabilization con-
cept for the direct conversion of vicinal diols to the corres-
ponding (di)acids or keto acids14 (Scheme 1). Indeed, when
simple 1,2-diols were subjected to catalytic amounts of
TPAP in the presence of NMO H2O, along with other
3
€
zation of geranyl acetate followed by deprotection: (a) Roth, S.; Gohler,
oxidation products, the formation of corresponding acids
€
S.; Cheng, H.; Stark, C. B. W. Eur. J. Org. Chem. 2005, 4109. (b) Gohler,
€
S.; Roth, S.; Cheng, H.; Goksel, H.; Rupp, A.; Haustedt, L. O.; Stark,
C. B. W. Synthesis 2007, 2751.
(11) Schmidt, A.-K. C.; Stark, C. B. W. Org. Lett. 2011, 13, 4164.
(12) An investigation of the hydration equilibrium of 4-pyridine
carboxaldehyde by 1H NMR spectroscopy showed that the presence
(17) (a) Klein, E.; Rojahn, W. Tetrahedron 1965, 21, 2353. (b) Herz,
W.; Sharma, R. P. J. Org. Chem. 1975, 40, 192. (c) Volz, F.; Wadman,
S. H.; Hoffmann-Roder, A.; Krause, N. Tetrahedron 2009, 65, 1902.
€
of 10 equiv of NMO H2O leads to a considerable shift towards the
3
(18) (a) Burger, B. V.; Petersen, W. G. B.; Weber, W. G.; Munro,
Z. M. J. Chem. Ecol. 2002, 28, 2527. (b) Flachsbart, B.; Fritzsche, M.;
Weldon, P. J.; Schulz, S. Chem. Biodiversity 2009, 6, 1.
carbonyl hydrate. This effect is largely irrespective of the solvent used;
see ref 11 for details.
Org. Lett., Vol. 13, No. 21, 2011
5789

Table 2. Substrate Scopea
a Reagents and conditions: 0.5ꢀ1.0 mmol scale; diol (1 equiv) in CH2Cl2 (0.1 M), TPAP (20 mol %), NMO H2O (20 equiv), addition of TPAP at 0 °C,
3
and then stirring at rt. b Isolated yield. c Conducted at a higher concentration (0.25 M). d Isolated as methyl ester after esterification of the crude product
with TMSCHN2 (3 equiv). e Isolated after p-TsOH-catalyzed lactonization of the crude product.
However, a number of side products weredetected. Although
double bonds are usually compatible with TPAP oxida-
tions,9 the double bond in this particular distance to the
vicinal diol is likely the reason for the somewhat lower
selectivity.19 We next focused on the conversion of cyclic
substrates. Diols 13 and 15 gave the respective cleavage
products in excellent yields (Table 2, entries 7 and 8). The
release of ring strain is expected to favor the oxidative
scission reaction.10 The more complex oxygen-bridged bicyclic
diols 17 and 1920 were also successfully cleaved to the
corresponding tetrahydropyran diacids and isolated as
diesters 18 and 20 after treatment with TMS-diazome-
thane15 (Table 2, entries 9 and 10). It is worth noting
that the oxidation-sensitive p-methoxybenzyl ether of
diol 17 remained unaffected. (þ)-cis-Pinonic acid (22)
and other substituted cyclobutaneacetic acids were ob-
tained in good to high yields (65ꢀ90%) from the corre-
sponding 2,3-pinanediols (Table 2, entries 11ꢀ14). In
general, a variety of functional groups as well as typical
protecting groups such as ethers, silyl ethers, ketals,
esters, and remote tertiary alcohols proved to be com-
patible with the oxidative cleavage protocol. Moreover,
potentially labile stereocenters were not affected under
the standard reaction conditions (Table 2, entries 5, 6,
and 8ꢀ14).
(19) Cheng, H.; Stark, C. B. W. Angew. Chem. 2010, 122, 1632.
Angew. Chem., Int. Ed. 2010, 45, 1587.
(20) The diols were obtained by dihydroxylation of the respective
olefins which were prepared through a [4 þ 3]-cycloaddition route
according to: (a) Kim, H.; Hoffmann, H. M. R. Eur. J. Org. Chem.
2000, 2195. (b) Hartung, I. V.; Hoffmann, H. M. R. Angew. Chem. 2004,
116, 1968. Angew. Chem., Int. Ed. 2004, 43, 1934. See also: Hoffmann,
H. M. R.; Dunkel, R.; Mentzel, M.; Reuter, H.; Stark, C. B. W. Chem.;
Eur. J. 2001, 7, 4771.
€
(21) Haslinger, E.; Hufner, A. Monatsh. Chem. 1995, 126, 1109.
5790
Org. Lett., Vol. 13, No. 21, 2011

Abietic acid derived diol 29 was cleaved to keto acid 30
with a moderate yield of 40% (Table 2, entry 15).21 Simple
oxidation of the secondary hydroxy group was also ob-
served, resulting in a considerable amount (36%) of un-
cleaved hydroxy ketone. The stability of this side product
against oxidative degradation is expected toresult from the
carbonyl group being in conjugation to the double bond.
Thus, the ketone does not easily form hydrates (vide infra;
cf. also Scheme 2).
tertiary hydroxy ketone 31 and the diketone 32 underwent
smooth conversion to the corresponding acids (Scheme 3).
These control experiments not only provide some mechan-
istic insight but also demonstrate that competing alcohol
oxidations to ketols or dicarbonyls do not necessarily lead
to any loss of material. Apparently, such initial side pro-
ducts can be converted to the same target compounds by
an analogous mechanistic pathway as for the original starting
material (Scheme 2). Moreover, these results (Scheme 3)
imply further applications of our cleavage procedure.
Scheme 2. Proposed Glycol Cleavage Mechanism Involving
Carbonyl Hydrates
Scheme 3. Oxidative Cleavage of a Hydroxy Ketone and a
Diketone
In summary, we have developed a mild protocol for the
direct oxidative glycol cleavage to carboxylic (di)acids.
TPAP serves as the catalyst, and NMO as the stoichio-
metricoxidant. Inaddition, the N-oxide actsasa reagent to
stabilize intermediary aldehyde hydrates and thereby pushes
carboxylic acid formation. The same effect may be opera-
tive in converting initial shunt products such as hydroxy
ketones or diketones to the desired target molecules. The
mild reaction protocol is applicable to a wide range of
substrates providing the respective acids, diacids (or
diesters), or keto acids in good to high yields. Vicinal diols
containing primary, secondary, and tertiary alcohols are
smoothly oxidized to the expected cleavage products.
Under the standard conditions many functional as well
as protecting groups are tolerated and potentially
labile stereocenters remain intact. We therefore believe
that the method presented here is a valuable alternative
to existing procedures.
We propose a mechanism that involves initial formation
of a cyclic perruthenate diester (A in Scheme 2)19 which
then oxidatively collapses under cleavage of the CꢀC bond
to give the corresponding carbonyl compounds (Scheme 2).
Hydration of the latter and subsequent oxidation give the
desired carboxylic acid (or diacid).11 It is also conceivable
that the diol is first oxidized to the hydroxy ketone (or
diketone) which, after hydration, could also form a cyclic
perruthenate diester (B in Scheme 2). The oxidative frag-
mentation of this Ru(VII) diester would result in a car-
boxylic acid (two carboxylic acids in the case of a diketone
precursor) and an aldehyde which could then be oxidized
further.11 In any case, the success of the overall process is
strongly dependent on the efficiency of the hydrate forma-
tion (Scheme 2). We have previously shown that effective
formation of geminal diols from aldehydes can be achieved
Acknowledgment. We are grateful for financial support
from the Studienstiftung des deutschen Volkes (fellowship
to A.-K.C.S.).
by adding an excess of NMO H2O.11 In order to test
3
whether the bottom half of the mechanism depicted in
Scheme 2 is a realistic pathway, we subjected starting
materials (already) containing one or two carbonyl groups
to our standard cleavage procedure (Scheme 3). Both the
Supporting Information Available. Experimental pro-
cedures and analytical data. This material is available free
of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 21, 2011
5791