Organocatalytic aerobic oxidative cleavage of cyclic 1,2-diketones

Article abstract of DOI:10.1055/s-0033-1338494

The first organocatalytic aerobic oxidative cleavage of cyclic 1,2-diketones is reported. The reaction occurs in either aqueous or alcoholic media and is promoted by a simple N-heterocyclic carbene catalyst derived from a 1,2,4-triazolium ion. No strong oxidants are required. The application of the process in a one-pot synthesis of a cyclic anhydride is also possible. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1338494

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Organocatalytic Aerobic Oxidative Cleavage of Cyclic 1,2-Diketones
Oxidative Cleavage of Cyclic 1,2-Diketones
Sivaji Gundala, Claire-Louise Fagan, Eoghan G. Delany, Stephen J. Connon*
Trinity Biomedical Sciences Institute, School of Chemistry, The University of Dublin, Trinity College, Dublin 2, Ireland
Fax +353(1)6712826; E-mail: connons@tcd.ie
Received: 03.05.2013; Accepted after revision: 27.05.2013
N
A
Abstract: The first organocatalytic aerobic oxidative cleavage of
N
N
Me
cyclic 1,2-diketones is reported. The reaction occurs in either aque-
ous or alcoholic media and is promoted by a simple N-heterocyclic
carbene catalyst derived from a 1,2,4-triazolium ion. No strong ox-
idants are required. The application of the process in a one-pot syn-
thesis of a cyclic anhydride is also possible.
4
I
O
O
O
O
(15 mol%)
OMe
DBU (110 mol%)
THF–MeOH (1:1)
r.t., air
1
2
3 94%
Key words: oxidation, biaryls, carboxylic acids, catalysis, esters
B
O
O
O
O
NHC catalysis
oxidative
cleavage
products
The oxidative cleavage of 1,2-diols is a time-honoured
synthetic tool of enormous importance. By contrast, the
corresponding oxidative cleavage of 1,2-diketones to
yield carboxylic acids has received considerably less at-
tention. There are a number of methods available for this
transformation involving the use of stoichiometric oxi-
dants such as Oxone,1 calcium perchlorate,2 CuCl/pyri-
dine/O2,3 and sodium percarbonate/alkaline H2O2.4,5 The
photochemical aerobic oxidation of phenanthrene on sili-
ca gel is possible, but yields multiple products.6
RO
OR
ROH–THF
base, air
5
6a R = H
6b R = Me
R = H, Me
Scheme 1 A: A previously observed oxidative esterification reaction
of benzaldehyde involving the intermediacy of benzyl. B: The pro-
posed organocatalytic oxidative cleavage of α-diones.
ble 1, entry 1). Increasing the reaction concentration to ei-
ther 0.5 M or 1.0 M had only marginal influence on
efficiency (Table 1, entries 2 and 3), and thus for opera-
tional convenience 0.2 M was selected as the concentra-
tion of choice for further studies. Increasing the loading of
base improved the product yield to 41% (Table 1, entry 4),
however, the use of elevated reaction temperatures had no
effect (Table 1, entries 5 and 6). It appears that diacid for-
To the best of our knowledge, no catalytic version of this
reaction is known, although a single example of the oxi-
dative esterification of a 1,2-diketone catalysed by dichlo-
roethoxyoxyvanadium in ethanol (under an O2
atmosphere) has been reported.7,8
Very recently, we9,10 (among others11,12) have been en- mation (these reactions are carried out in air, so the inter-
gaged in the development of N-heterocyclic carbene vention of adventitious water is difficult to prevent) is
(NHC)-catalysed oxidative esterification processes in- problematic in these experiments.
volving aldehyde substrates. In the course of these studies,
We next investigated the corresponding transformations
we detected (and confirmed the intermediacy of) benzil
involving water as the nucleophile. Speculating that reac-
(1) in the aerobic oxidative esterification of benzaldehyde
tions involving THF–H2O in a 1:1 ratio would not be op-
timal from both carbene-generation and substrate-
solubility standpoints, we began by retaining the condi-
tions previously used in the methanolysis experiments in
a 5:1 THF–H2O mixture. Under these conditions the diac-
id 9 was generated in low yield (Table 1, entry 7). Further
reduction in the contribution of the protic solvent allowed
the eventual preparation of the cleaved diacid in 83%
(2) to methylbenzoate (3) catalysed by the carbene de-
rived from the triazolium ion 4 in the presence of stoichio-
metric DBU and methanol (Scheme 1, A).10,13 This led us
to propose that if one exposed a cyclic 1,2-diketone 5 (in-
stead of an aldehyde) to similar conditions it could bring
about an organocatalytic oxidative cleavage reaction to
give either dicarboxylic acids (i.e., 6a) or diesters (i.e.,
6b), depending on the protic nucleophile used (Scheme 1,
B).
yield in a 20:1 THF–H2O solvent mixture (Table 1, entries
8 and 9). The use of 2.2 equivalents of DBU is critical for
To test this hypothesis, phenanthrene-9,10-dione (7) was the success of the organocatalytic cleavage reaction: A re-
reacted with either methanol or water in air in the presence peat of the reaction with less base resulted in lower prod-
of precatalyst 4 and DBU (Table 1). In a 1:1 mixture of uct yield (Table 1, entry 10). It would seem likely that the
THF and MeOH at ambient temperature we were pleased requirement for elevated base loadings is related to the
to obtain the ring-opened diester 8, albeit in low yield (Ta- need to prevent protonation of the carbene catalyst by the
dicarboxylic acid product.14
With an efficient protocol in hand, our attention turned to
substrate scope (Table 2). While the aqueous protocol
leading to carboxylic acids proved the most effective in
SYNLETT 2013, 24, 1225–1228
Advanced online publication: 04.06.2013
DOI: 10.1055/s-0033-1338494; Art ID: ST-2013-R0416-C
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

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S. Gundala et al.
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Table 2 Substrate Scope
Table 1 NHC-Mediated Oxidative Cleavage of 7: Preliminary
Experiments
N
N
N
N
1.
Me
4
I
N
N
Me
O
O
O
O
O
O
O
O
O
4
I
(15 mol%)
RO
(15 mol%)
Me
Me
DBU (2.2 equiv)
THF–H2O (20:1)
r.t., air
DBU (X equiv)
THF–ROH
r.t., air
2. MgSO4
MeI (5.0 equiv)
OR
7
8 R = Me
9 R = H
O
Entry Product
X
Temp Concn (M) THF/ROH Yield
(%)a
Entry 1,2-Diketone
Product
Yield
(%)a
Me
O
1
2
8
8
8
8
8
8
9
9
9
9
1.1
1.1
1.1
2.2
2.2
2.2
2.2
2.2
2.2
1.1
r.t.
r.t.
0.2
0.5
1.0
0.2
0.2
0.2
0.2
0.2
0.2
0.2
1:1
1:1
26
28
31
41
41
41
12
24
83
41
O
O
O
3
r.t.
1:1
1
2
3
82
80
83
O
O
4
r.t.
1:1
Me
5
30 °C
40 °C
r.t.
1:1
7
8
6
1:1
O2N
Me
O
7
5:1
O
O2N
O
8
r.t.
10:1
20:1
20:1
O
9
r.t.
NO2
O
O
10
r.t.
Me
NO2
a Determined by 1H NMR spectroscopy using styrene as an internal
standard.
16
10
11
Me
O
O
O
O
our preliminary studies, we were also interested in extend-
ing the methodology to oxidative cleavage to produce di-
esters. Thus, in these reactions MgSO4 was added to
sequester the water from the solvent after the C–C bond-
breaking processes involving 7 and 10–15 were complete,
and the dicarboxylate products were then esterified via the
addition of MeI.
O
O
Me
17
Me
O
O
N
O
N
O
N
Under these conditions, 7 could be converted into the bi-
aryldiester 8 in high yield (Table 2, entry 1). The dinitro
substrate analogue 10 also underwent smooth transforma-
tion to 16 (Table 2, entry 2). Unsymmetrical quinones also
undergo the reaction: oxidative cleavage of the chrysene
derivative 11 provided 17 with comparable efficiency
(Table 2, entry 3). Gratifyingly, the phenanthroline-de-
rived dione 12 produced the bipyridyl diester 18 (of syn-
thetic potential as a starting material for transition-metal
ligand synthesis) in 70% yield (Table 2, entry 4). In this
instance esterification with an electrophile introduces a
chemoselectivity problem, which is readily circumvented
through Fischer esterification with MeOH.
4b
70
66
N
O
O
Me
12
18
Me
Me
O
O
O
O
O
O
5
13
19
Me
Me
O
O
O
O
O
O
Exposure of the tricyclic quinone 13 to the reaction con-
ditions resulted in the isolation of the relatively strained
1,8-naphthalene dicarboxylic acid dimethyl ester (19) in
slightly reduced yield (Table 2, entry 5), while the corre-
sponding anthrancene derivative 20 could be similarly
prepared from 14 in almost identical yield (Table 2, entry
6). Perhaps unsurprisingly (under these basic conditions),
oxidative cleavage of the enolisable 1,2-dione 15 proved
more challenging: this reaction was not clean, however,
the acyclic diester 21 could be isolated in low (yet appre-
ciable) yield (Table 2, entry 7).
6
7
68
18
14
O
20
O
O
O
O
Me
O
Me
21
15
a Isolated yield.
b Alkylative esterification replaced with an in situ Fischer esterifica-
tion with MeOH and H2SO4 (see Supporting Information for details).
Synlett 2013, 24, 1225–1228
© Georg Thieme Verlag Stuttgart · New York

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Oxidative Cleavage of Cyclic 1,2-Diketones
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We were also able to exploit this organocatalytic process
in the one-pot synthesis of an anhydride from a 1,2-dione
(Scheme 2). The α-dione 7 was first oxidatively cleaved in
the presence of the carbene derived from 4 in an aqueous
medium. When this reaction was complete, addition of
magnesium sulfate and trifluoroacetic anhydride led to the
cyclisation of the in situ formed diacid 9 to afford the an-
hydride 22 in good isolated yield. To the best of our
knowledge, such a one-pot sequence starting from a 1,2-
diketone is unprecedented in the literature.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
References and Notes
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(7) This work was concerned with the oxidative cleavage of
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Soc., Perkin Trans. 1 1998, 7.
N
N
1.
Me
O
O
O
O
4
I
O
(15 mol%)
DBU (2.2 equiv)
THF–H2O (20:1)
r.t., air
22 73%
7
2. MgSO4
(CF3CO)2O
(8) Recently, the organocatalytic (TEMPO-mediated in the
presence of NaClO2) oxidative cleavage of diols has been
accomplished, see: Shibuya, M.; Doi, R.; Shibuta, T.;
Uesugi, S.-I.; Iwabuchi, Y. Org. Lett. 2012, 14, 5006.
(9) Noonan, C.; Baragwanath, L.; Connon, S. J. Tetrahedron
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Scheme 2 A novel one-pot oxidative cleavage–cyclisation se-
quence: chemoselective conversion of a 1,2-diketone into an anhy-
dride
In our previous work in the oxidative esterification of
benzaldehyde,10 we proposed a complex mechanism (sup-
ported by, inter alia, both the spectroscopic observation of
intermediates and the results of competition experiments)
whereby benzil (formed from the aerobic oxidation of
benzoin in basic media) can be attacked by both the car-
bene and the alcohol nucleophile to give an adduct which
collapses to form the Breslow intermediate and the car-
boxylic acid ester. In the absence of evidence to the con-
trary, these distinct but related oxidative cleavage
transformations could be potentially rationalised in a sim-
ilar fashion. An investigation to probe the mechanism of
the oxidative cleavage is under way.
(10) (a) Delany, E. G.; Fagan, C.-L.; Gundala, S.; Mari, A.;
Broja, T.; Zeitler, K.; Connon, S. J. Chem. Commun. 2013,
49, in press. (b) Delany, E. G.; Fagan, C.-L.; Gundala, S.;
Zeitler, K.; Connon, S. J. Chem. Commun. 2013, 49, in press.
(11) Reviews concerning oxidative NHC-catalysed processes:
(a) Knappke, C. E. I.; Imami, A.; Jacobi von Wangelin, A.
ChemCatChem 2012, 4, 937. (b) DeSarkar, S.; Biswas, A.;
Samanta, R. C.; Studer, A. Chem. Eur. J. 2013, 19, 4664.
(12) Representative examples of NHC-mediated oxidative
esterification and related reactions, for nitrobenzene as
oxidant, see: (a) Miyashita, A.; Suzuki, Y.; Kobayshi, M.;
Kuriyama, N.; Higashino, T. Heterocycles 1996, 43, 509.
(b) Castells, J.; Pujol, F.; Llitjós, H.; Moreno-Mañas, M.
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E.; Scheidt, K. A. Org. Lett. 2008, 10, 4331. (d) Maki, B.;
Chan, A.; Scheidt, K. A. Synthesis 2008, 1306. (e) Kim, H.;
Park, Y.; Hong, J. Angew. Chem. Int. Ed. 2009, 48, 7577.
(f) Maki, B.; Chan, A.; Philips, E. M.; Scheidt, K. A.
Tetrahedron 2009, 65, 3102. (g) Lee, K.; Kim, H.; Hong, J.
Angew. Chem. Int. Ed. 2012, 51, 5735. TEMPO as oxidant:
(h) Guin, J.; De Sarkar, S.; Grimme, S.; Studer, A. Angew.
Chem. Int. Ed. 2008, 47, 8727. Diphenoquinone as oxidant:
(i) Guin, J.; De Sarkar, S.; Grimme, S.; Studer, A. J. Am.
Chem. Soc. 2010, 132, 1190. Azobenzene as oxidant:
(j) Inoue, H.; Higashiura, K. J. Chem. Soc. Chem. Commun.
1980, 549. (k) Rose, C. A.; Zeitler, K. Org. Lett. 2010, 12,
4552. Riboflavin as oxidant: (l) Tam, S.-W.; Jimenez, L.;
Diederich, F. J. Am. Chem. Soc. 1992, 114, 1503. (m) Uno,
T.; Inokuma, T.; Takemoto, Y. Chem. Commun. 2012, 48,
1901. (n) Zhao, X.; Ruhl, K. E.; Rovis, T. Angew. Chem. Int.
Ed. 2012, 51, 12330. Related reactions involving quenching
with an electrophile: (o) Lin, L.; Li, Y.; Du, W.; Deng, W.-
P. Tetrahedron Lett. 2010, 51, 3571. (p) Maji, B.;
Vedachalan, S.; Ge, X.; Cai, S.; Liu, X.-W. J. Org. Chem.
2011, 76, 3016. (q) Xin, Y.-C.; Shi, S.-H.; Xie, D.-D.; Hui,
X.-P.; Xu, P.-F. Eur. J. Org. Chem. 2011, 6527. (r) Park, J.
H.; Bhilare, S. V.; Youn, S. W. Org. Lett. 2011, 13, 2228.
(s) Gu, L.; Zhang, Y. J. Am. Chem. Soc. 2010, 132, 914.
In summary, a new, organocatalytic oxidative cleavage
reaction of cyclic 1,2-diones has been developed. The use
of water as the nucleophile allows the generation of a di-
acid in high yield under mild conditions. While the corre-
sponding methanolytic transformation occurs, it is less
productive. Coupling an in situ esterification with the
more efficient acid-generating reaction allows the forma-
tion of esters in good yields from a variety of cyclic dike-
tones. The process is promoted by an NHC derived from
a readily prepared, simple triazolium ion precursor, and
no strong stoichiometric oxidants are required. If trifluo-
roacetic acid and a drying agent are added to the reaction
mixture after formation oxidative cleavage, cyclisation to
form the cyclic anhydride occurs in good overall yield.15
Acknowledgment
We thank Science Foundation Ireland, The Irish Research Council
and the European Research Council for financial support.
© Georg Thieme Verlag Stuttgart · New York
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S. Gundala et al.
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(t) Nair, V.; Varghese, V.; Paul, R. R.; Jose, A.; Sinu, C. R.;
Menon, R. S. Org. Lett. 2010, 12, 2653. (u) Chiang, P.-C.;
Bode, J. W. Org. Lett. 2011, 13, 2422. Cooperative
transition-metal-ion catalysis with air as the oxidant
(v) Zhao, J.; Mück-Lichtenfeld, C.; Studer, A. Adv. Synth.
Catal. 2013, 355, 1098.
Dimethyl Biphenyl-2,2′-dicarboxylate (8)
Prepared according to the general procedure using
phenanthrene-9,10-dione (7, 104.11 mg, 0.50 mmol).
Purified via flash chromatography (n-hexane–EtOAc, 9:1),
110 mg (82%) as a pale yellow solid; mp 73–75 °C (lit.16 74–
75 °C). 1H NMR (400 MHz, CDCl3): δ = 7.98 (d, J = 7.6 Hz,
2 H), 7.51 (app. t, 2 H), 7.40 (app. t, 2 H), 7.18 (d, J = 7.6 Hz,
2 H), 3.59 (s, 6 H). HRMS: (ESI+): m/z calcd for C16H15O4:
271.0970; found: 271.0984.
Dimethyl 4,4′-Dinitrobiphenyl-2,2′-dicarboxylate (16)
Prepared according to the general procedure using 2,7-
dinitro-9,10-phenanthrenequinone (10, 149.10 mg, 0.50
mmol). Purified via flash chromatography (n-hexane–
EtOAc, 9:1), 144 mg (80%) as a white solid; mp 178–180 °C
(lit.17 182–183 °C). 1H NMR (400 MHz, CDCl3): δ = 8.94 (d,
J = 2.3 Hz, 2 H), 8.45 (dd, J = 2.3, 8.5 Hz, 2 H), 7.37 (d,
J = 8.5 Hz, 2 H), 3.76 (s, 6 H).
(13) For a recent example of the use of 1,2-dicarbonyl
compounds as reaction components in the NHC-mediated
acyloin condensation, see: Rose, C. A.; Gundala, S.; Fagan,
C.-L.; Franz, J. F.; Connon, S. J.; Zeitler, K. Chem. Sci.
2012, 3, 73.
(14) It is unclear at this juncture why the reactions involving
MeOH are reproducibly less efficient than their variants in
aqueous media. Investigations into this phenomenon are
under way.
(15) General Procedure for the Esterification of Cyclic
Diketones
To a 25 mL vial equipped with a magnetic stirring bar was
charged the triazolium precatalyst 4 (18 mg, 0.07 mmol, 15
mol%). Dry THF (1.25 mL) and deionised H2O (62.5 μL)
were added. DBU (170.0 μL, 1.10 mmol, 220 mol%) was
added, and the solution was stirred for 2 min. The aromatic
diketone (0.50 mmol) was then added. The vessel was sealed
with a plastic lid perforated by 4 holes (ca. 2 mm in
diameter). After stirring for 20 h at r.t., MgSO4 (1.40 mmol,
170 mg) and 5.0 equiv of MeI were added, and the resulting
mixture was stirred for 12 h. The solvent was then removed
in vacuo, and the resulting residue was subjected to flash
chromatography to yield the diester product.
Dimethyl Naphthalene-1,8-dicarboxylate (19)
Prepared according to the general procedure using 13 (91.02
mg, 0.50 mmol). Purified via flash chromatography (n-
hexane–EtOAc, 9:1), 80 mg (66%) as a pale yellow solid;
mp 100–104 °C (lit.18 102–103 °C). 1H NMR (400 MHz,
CDCl3): δ = 8.00–7.97 (m, 4 H), 7.53 (app t, 2 H), 3.90 (s, 6
H). HRMS: (ESI+): m/z calcd for C14H13O4: 245.0814;
found: 245.0817.
(16) Martinek, M.; Korf, M.; Srogl, J. Chem. Commun. 2010, 46,
4387.
(17) Leung, M.-K.; Yang, C.-C.; Lee, J.-H.; Tsai, H.-H.; Lin, C.-
F.; Huang, C.-Y.; Su, Y. O.; Chiu, C.-F. Org. Lett. 2007, 9,
235.
(18) Van Dorp, B. Justus Liebigs Ann. Chem. 1874, 172, 270.
Synlett 2013, 24, 1225–1228
© Georg Thieme Verlag Stuttgart · New York