Facile synthesis of 1,2,3-tricarbonyls from 1,3-dicarbonyls mediated by cerium(IV) ammonium nitrate

Article abstract of DOI:10.1016/j.tetlet.2014.01.145

A mild and efficient protocol for the synthesis of vicinal tricarbonyl compounds from β-dicarbonyls in a single step using cerium(IV) ammonium nitrate as a catalytic oxidant is described. Ease of execution, wide substrate scope and the suitability for the synthesis of commercially important compounds like ninhydrin, alloxan and oxoline make this reaction particularly noteworthy.

Full text of DOI:10.1016/j.tetlet.2014.01.145

Tetrahedron Letters 55 (2014) 1890–1893
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Tetrahedron Letters
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Facile synthesis of 1,2,3-tricarbonyls from 1,3-dicarbonyls mediated
by cerium(IV) ammonium nitrate
Akhil Sivan a, Ani Deepthi b,
⇑
a Department of Chemistry, Amrita Vishwa Vidyapeetham, Kollam 690 525, Kerala, India
b Department of Chemistry, University of Kerala, Thiruvananthapuram 695 581, Kerala, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild and efficient protocol for the synthesis of vicinal tricarbonyl compounds from b-dicarbonyls in a
single step using cerium(IV) ammonium nitrate as a catalytic oxidant is described. Ease of execution,
wide substrate scope and the suitability for the synthesis of commercially important compounds like nin-
hydrin, alloxan and oxoline make this reaction particularly noteworthy.
Received 20 November 2013
Revised 27 January 2014
Accepted 28 January 2014
Available online 6 February 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Vicinal tricarbonyl compounds
Cerium(IV) ammonium nitrate
b-Dicarbonyl compounds
Ninhydrin
Catalyst
1,2,3-Tricarbonyls or vicinal tricarbonyl compounds (VTCs)
have gained attention among the organic chemists ever since the
first synthesis of diphenyl triketone in 1890 by von Pechmann
and de Neufville.1 Their importance stems from the challenges in-
volved in the synthesis and their inherent reactivity. The chemistry
of these compounds has been widely studied by Rubin, Wasserman
and their co-workers.2 Numerous biological targets such as FK-
506,3 rapamycin and protease inhibitor molecules have been suc-
cessfully synthesized from VTCs.2 In addition, these compounds
have also been used for the construction of heterocycles having
unusual substitution patterns.4 Of the various methods currently
available for the synthesis of VTCs, those from b-dicarbonyl com-
pounds constitute an important route. This involves a two-step
procedure consisting of functionalizing the central carbon followed
by oxidation with suitable reagents such as Dess–Martin period-
inane,5a selenium dioxide,5b singlet oxygen,5c,6,7 ozone7,8 and
DMSO5b,9 (Scheme 1). Very recently, the synthesis of 2-oxo-1,3-
propanedial, the smallest VTC, by the oxidation of acetone10 and
that of substituted VTCs by the oxidation of Morita–Baylis–Hillman
(MBH) adducts11 formed from substituted benzaldehydes and
acrylate have been reported.
O
O
R1
R2
O
O
O
O
NAr
R1
R2
t
R1
O3
R2
B
H+
N2
u
O
H2O
O
o
r
Cl
or 1O2
NMe2
DM
D
Dess-Martin
or SeO2 or
O
O
O
O
O
DMSO
R1
R2
R1
R2
R1
R2
Bu4N+F-, 1O2
Br
O
Et
D
M
3
N
2
O
D
O
O
3
O
1
r
r
O
O
o
R1
o
R2
R1
R2
X
O
O
ONs
X = Ph3P, Me2S,
R1
R2
Pyridine, IPh
Br
Br
Scheme 1. Various routes for VTC synthesis from 1,3-diones.
investigation on the addition of radical cations, generated from
b-dicarbonyls to terminal acetylenes13 and that of a recent report
on the dimerization of b-dicarbonyls14 in the presence of stoichi-
ometric amounts of cerium(IV) ammonium nitrate (CAN),15 we
were quite curious to explore the fate of radical cations derived
from b-dicarbonyls in the presence of catalytic amounts of CAN
(Scheme 2). Our studies in this direction have now led to the facile
synthesis of VTCs, in moderate to good yields, and the results are
presented in this Letter.
Apart from an isolated report,12 there has not been any system-
atic investigation on the use of single electron oxidants for the syn-
thesis of VTCs from b-dicarbonyl compounds. In light of our recent
⇑
Corresponding author. Tel.: +91 9447151002.
E-mail address: anideepthi@gmail.com (A. Deepthi).
http://dx.doi.org/10.1016/j.tetlet.2014.01.145
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

A. Sivan, A. Deepthi / Tetrahedron Letters 55 (2014) 1890–1893
1891
shown in Scheme 2)14 in 56% yield and the desired product 2a in
37% yield (entry 4). Passing oxygen gas through the reaction mix-
ture (entry 5) resulted in a decrease of the product yield to 60%
along with formation of other oxidation products. The use of ceriu-
m(IV) ammonium sulfate (CAS) in place of CAN did not yield any
product (entry 7) while use of other single electron oxidants such
as FeCl3 and Mn(OAc)3 resulted in lower product yields (entries 8
and 9) compared to that shown in entry 2. From these results the
optimized condition for the formation of VTC was found to
be usage of 10 mol % CAN in dry CH3CN under N2 atmosphere
(entry 2).
The generality of the reaction was studied and the results are
presented in Table 2. Moderate to good yields of VTCs were ob-
tained by using various b-ketoesters (entries 1–5), 1,3-diketones
(entries 6–8) and b-diesters (entries 9 and 10). It was observed that
the reaction of 1,3-dicarbonyls containing aromatic and electron-
donating aromatic substituents resulted in higher product yields
(entries 1, 4, 6, 7) while those with alkyl and electron-withdrawing
substituents furnished the VTCs in lower yields (entries 2, 3, 5, 8).
O
O
O
O
O
O
O
O
Earlier report
Present study
R1
R1
R2
R2
. H2O
R1
R2
R1
R2
O
CAN (1.1 equiv)
CAN (10 mol %)
Scheme 2. Reaction of 1,3-diones with CAN.
As an exploratory experiment, ethyl benzoylacetate 1a was
treated with CAN (10 mol %) in dry acetonitrile. Work-up followed
by column chromatography afforded the product 2a in 86% yield.
The structure of the product was established by spectroscopic
analysis and the data were compared with those available in the
literature.11 In the IR spectrum of 2a, the appearance of a broad
absorption peak at 3443 cmÀ1 clearly indicated the presence of
an OH group while the carbonyl groups showed stretching fre-
quencies at 1744, 1691 and 1639 cmÀ1, respectively. In the 1H
NMR spectrum, the OH protons were seen as a broad singlet cen-
tred at d 5.39. The quaternary carbon appeared at d 91.7 in the
13C NMR spectrum while the three carbonyl carbons were recorded
at d 193.3, 191.5 and 191.0. The mass spectrum data also agreed
with the proposed structure.16 All the above spectral evidence in
conjunction with literature reports11,17 confirmed that the VTCs
were formed as a mixture of the dihydroxy and keto forms as ex-
pected (Scheme 3).
The reaction was then studied thoroughly and the exact amount
of CAN required was investigated. It was observed that usage of
5 mol % CAN as catalyst resulted in longer reaction time and lower
product yield indicating the insufficient amount of the catalyst
(Table 1, entry 1). Increasing the amount of CAN to 10 mol %
resulted in 86% product yield (entry 2), whereas when the catalyst
loading was increased to 15 mol % (entry 3) the yield of the VTC
was found to decrease proportionately. The use of stoichiometric
amounts of CAN resulted in the formation of dimer (structure
Table 2
Reaction of various acyclic 1,3-diones with catalytic amounts of CAN
O
O
O
O
O
O
CAN (10 mol %)
R1
R2
R1
R2
R1
R2
. H2O
dry CH3CN
0°C to RT, 4 h
HO OH
O
Entry
1
Substrate
Product
Yielda (%)
86
O
O
O
O
Ph
OEt
Ph
OEt
O
1a
2a
O
O
O
O
2
3
71
62
OEt
OEt
2b
O
O
1b
O
O
O
O
O
O
O
CAN (10 mol %)
O
O
. H O
OEt
Ph
OEt
Ph
2
Ph
OEt
Cl
Cl
dry CH3CN
0°C to RT, 4h
86%
HO OH
OEt
OEt
2c
O
2a
1c
O
1a
O
O
O
O
MeO
MeO
MeO
MeO
Scheme 3. Synthesis of ethyl 2,3-dioxo-3-phenylpropanoate.
OEt
OEt
2d
4
5
88
43
O
1d
OMe
OMe
Table 1
Optimization of reaction conditions
O
O
O
O
OMe
OMe
O
2e
1e
O
O
O
O
N
N
O
O
Oxidant
O
O
O
O
. H O
OEt
Ph
OEt
Ph
2
Ph
OEt
Solvent
Temperature
Time
HO OH
6
7
82
65
O
2a
Ph
Ph
Ph
Ph
Ph
Ph
4a
O
1a
3a
O
O
O
O
O
Entry Oxidant
mol % Solvent
Temperature Time
(h)
Yielda
(%)
4b
3b
O
O
O
O
1
2
3
4
5
6
7
8
9
CAN
CAN
CAN
CAN
CAN
CAN
CASc
FeCl3
5
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3OH
CH3CN
CH2Cl2
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
RT-reflux
RT-reflux
12
4
3.5
4
35
86
51
37
60b
54
0
8
52
69
72
10
15
100
10
10
10
10
3c
4c
O
O
O
O
O
4
9
EtO
OEt
EtO
OEt
12
12
24
12
6a
O
O
O
5a
O
10
51
O
Mn(OAc)3 10
CH3CO2H RT-reflux
10
i-PrO
Oi-Pr
i-PrO
Oi-Pr
6b
a
b
c
Reactions performed in an inert atmosphere (N2 gas).
Reaction performed in the presence of oxygen.
CAS-cerium(IV) ammonium sulfate.
O
5b
a
Isolated yield.

1892
A. Sivan, A. Deepthi / Tetrahedron Letters 55 (2014) 1890–1893
This is probably due to the greater ease of formation of the
intermediate radical cation (formed by the initial oxidation of the
1,3-diketone by CAN) owing to its higher stability when the substi-
tuent is aromatic and electron-donating. A pronounced variation in
the yield of the product was not observed in the case of b-diesters
possibly due to the comparable stability of the radical cations
formed in these cases.
A probable reaction pathway for the formation of VTC, involving
the participation of the nitrate ligand is described along the follow-
ing lines (Scheme 4). The electrophilic radical cation I generated
from 1a by oxidation using CAN, probably gets attacked by NO3À
anion to form intermediate II14 which in turn gets converted to
the N-oxide IV by the concomitant re-oxidation of Ce(III) to Ce(IV).
The N-oxide IV then transforms to the oxy-anion V by the extru-
sion of nitrite anion.18 The resultant monohydroxylated compound
VI can further undergo the above processes to finally yield the
dihydroxylated product 2a. The higher experimental yields
obtained for the product in addition to what is predicted by the
above mechanism may be attributed to the trace amounts of dis-
solved oxygen present in the acetonitrile solvent.19 More details
regarding the exact mechanism are under study.
The reaction was further extended to various cyclic 1,3-dicar-
bonyl compounds and the results are presented in Table 3. The cyc-
lic diones exhibited varied reactivity and moderate yields of
products were obtained in all cases. It is noteworthy that industri-
ally important compounds like ninhydrin 12, oxoline 14 and allox-
an 16 can be synthesized through this novel methodology.
In conclusion, we have developed a mild protocol for the syn-
thesis of VTCs from b-dicarbonyl compounds. It is to be noted that
among the various literature reports on the synthesis of VTCs from
1,3-dicarbonyls, the present method is simple to execute and can
be accomplished in a single step in high yields. Further studies to-
wards the synthesis of vicinal tetra and pentacarbonyl compounds
are underway.
Ce(IV) Ce(III)
OH
O
OH
O
OH
Ph
O
NO3
Ph
OEt
Ph
OEt
II
OEt
O
N
O
1a
I
O
H
O
O
Ce(IV)
Ce(III)
O
O
O
OEt
HO
Ph
OEt
Ph
Ph
Ph
OEt
O
O
O
O
N
O
N
H
N
O
O
O
IV
III
O
V
Acknowledgments
H
The authors thank SERB, Department of Science and Technology
(DST), New Delhi for financial assistance. The authors are also
extremely grateful to all members of the organic section of NIIST,
Trivandrum for their support in the analysis of the compounds.
The authors also thank Dr. Rajeev S. Menon for the useful discus-
sions regarding the mechanism of this reaction.
O
O
O
O
O
O
above process
repeats
OEt
Ph
OEt
Ph
OEt . H2O
HO OH
OH
O
VI
2a
Scheme 4. Mechanistic rationale.
Supplementary data
Table 3
Reaction of various cyclic 1,3-diones with catalytic amounts of CAN
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
01.145.
Entrya
Substrate
Product
Yieldb (%)
O
O
References and notes
O
O
1
72
1. de Neufville, R.; von Pechmann, H. Berichte 1890, 23, 3375.
2. (a) Rubin, M. B. Chem. Rev. 1975, 75, 177; (b) Rubin, M. B.; Gleiter, R. Chem. Rev.
2000, 100, 1121; (c) Wasserman, H. H.; Parr, J. Acc. Chem. Res. 2004, 37, 687.
3. (a) Jones, T. K.; Mills, S. G.; Reamer, R. A.; Askin, D.; Desmond, R.; Volante, R. P.;
Shinkai, I. J. Am. Chem. Soc. 1989, 111, 1157; (b) Jones, T. K.; Reamer, R. A.;
Desmond, R.; Mills, S. G. J. Am. Chem. Soc. 1990, 112, 2998.
4. (a) Nair, V.; Deepthi, A. Tetrahedron Lett. 2006, 47, 2037; (b) Adlington, R. M.;
Baldwin, J. E.; Catterick, D.; Pritchard, G. J. J. Chem. Soc., Perkin Trans. 1 2001,
668.
5. (a) Batchelor, M. J.; Gillespie, R. J.; Golec, J. M. C.; Hedgecock, C. J. R. Tetrahedron
Lett. 1993, 34, 167; (b) Dayer, F.; Dao, H. L.; Gold, H.; Rodé Gowal, H.; Dahn, H.
Helv. Chim. Acta 1974, 57, 2201; (c) Wasserman, H. H.; Pickett, J. E. J. Am. Chem.
Soc. 1982, 104, 4695.
O
7
8
O
O
O
2
3
70
66
O
O
9
10
O
O
O
6. (a) Mahran, M. R.; Abdou, W. M.; Sidky, M. M.; Wamhoff, H. Synthesis 1987,
506; (b) Faust, J.; Mayer, R. Synthesis 1976, 411; (c) Pardo, S. N.; Salomon, R. G. J.
Org. Chem. 1981, 46, 2598.
7. (a) Schank, K.; Schuhknecht, C. Chem. Ber. 1982, 115, 3032; (b) Schank, K.; Lick,
C. Chem. Ber. 1982, 115, 3890; (c) Schank, K.; Lick, C. Synthesis 1983, 392.
8. (a) Wasserman, H. H.; Ennis, D. S.; Power, P. L.; Ross, M. J.; Gomes, B. J. Org.
Chem. 1993, 58, 4785; (b) Wasserman, H. H.; Chen, J. H.; Xia, M. J. Am. Chem. Soc.
1999, 121, 1401; (c) Wasserman, H. H.; Chen, J. H.; Xia, M. Helv. Chim. Acta
2000, 83, 2607.
9. (a) Wolfe, S.; Berry, J. E.; Petersen, M. R. Can. J. Chem. 1976, 54, 210; (b) Tatsugi,
J.; Izawa, Y. J. Chem. Res. (S) 1988, 356; (c) Heffner, R. J.; Joullié, M. M. Synth.
Commun. 1991, 21, 2231; (d) Heffner, R.; Safaryn, J. E.; Joullié, M. M. Tetrahedron
Lett. 1987, 28, 6539.
10. Goswami, S.; Maity, A. C.; Fun, H. K.; Chantrapromma, S. Eur. J. Org. Chem. 2009,
1417.
O
O
11
12
O
O
OH
O
O
4
5
61
56
O
O
13
O
14
O
O
O
HN
HN
O
N
H
O
O
N
H
11. Santos, M. S.; Coelho, F. RSC Adv. 2012, 2, 3237.
12. Tugaut, V.; Pellegrini, S.; Castanet, Y.; Mortreux, A. J. Mol. Catal. A: Chem. 1997,
127, 25.
15
16
a
Reaction conditions: CAN (10 mol %), dry CH3CN, 0 °C to rt, 4 h.
b
13. Sivan, A.; Deepthi, A.; Nandialath, V. Synthesis 2011, 15, 2466.
Isolated yield.

A. Sivan, A. Deepthi / Tetrahedron Letters 55 (2014) 1890–1893
1893
14. Song, J.; Zhang, H.; Chen, X.; Li, X.; Xu, D. Synth. Commun. 2010, 40, 1847.
15. For reviews on CAN see (a) Nair, V.; Deepthi, A. Chem. Rev. 2007, 107, 1862; (b)
Nair, V.; Deepthi, A. Tetrahedron 2009, 65, 10745; (c) Sridharan, V.; Menndez, J.
C. Chem. Rev. 2010, 110, 3805.
(75 MHz, CDCl3): (Tricarbonyl compound) dC 193.3, 191.0, 170.8, 135.3, 133.6,
131.7, 130.1, 129.1, 128.4, 64.1, 13.9; (Hydrate) dC 191.5, 169.9, 134.4, 131.7,
130.2, 129.4, 128.7, 91.7, 62.9, 13.7. HRMS (EI): m/z [M]+ Calcd. for C11H10O4
206.1947; Found: 206.1950.
16. General experimental procedure: To an ice cold, de-oxygenated solution of b-
dicarbonyl compound 1a in dry CH3CN (4 mL), 10 mol % of CAN was added. The
solution was allowed to stir and the temperature was gradually raised to rt.
After completion of the reaction as indicated by TLC, the solvent was rotary
evaporated and the crude residue was extracted with CH2Cl2. The organic layer
was washed with brine solution (3 Â 10 mL) and dried over anhydrous Na2SO4.
The residue was subjected to column chromatography using silica gel 100–200
mesh and hexane–EtOAc as solvent system to yield 2a. Spectral data of a
representative compound: Ethyl 2,3-dioxo-3-phenylpropanoate (2a): Yellow oil;
Yield: 86%; Mixture of vicinal tricarbonyl compound and its hydrated form; IR
17. Dei, K.; Morino, K.; Sudo, A.; Endo, T. J. Polym. Sci., Part A: Polym. Chem. 2011, 49,
2245.
18. (a) The presence of nitrite anion was determined both qualitatively and
quantitatively. See: Svehla, G. Vogel’s Textbook of Macro and Semimicro
Qualitative Inorganic Analysis, 5th ed.; Longman, 1979; Chapter 4, p 310.; (b)
Ahmed, M. J.; Stalikas, C. D.; Tzouwara-Karayanni, S. M.; Karayannis, M. I.
Talanta 1996, 43, 1009.
19. When the model reaction (Scheme 3) was done with rigorously dry and
degassed CH3CN solvent (the solvent was dried thrice using standard
procedures), the yield of the VTC 2a was found to reduce to 75%. This
probably indicates that the trace amounts of water present in the solvent act as
a source of dissolved oxygen, catalyzing the reaction and this explains the
higher than predicted yields obtained for the product.
(film m .
max): 3443, 2924, 1744, 1691, 1639, 1452, 1236, 1128, 1014, 921 cm–1
1H NMR (300 MHz, CDCl3): dH 7.98–8.12 (m, 2H), 7.60–7.83 (m, 1H), 7.43–7.58
(m, 2H), 5.39 (bs, 2H), 4.19 (q, J = 7.2 Hz, 2H), 1.08 (t, J = 7.2 Hz, 3H). 13C NMR