A new and efficient route for 1,3,3′-triketones

Article abstract of DOI:10.1016/S0040-4039(01)01654-9

Cyclic and acyclic 1,3,3′-triketones were prepared by the reactions adopting β-diketones and anhydrides in the presence of barium or strontium hydrides in high yields. Crystal structure of 4-acetyl-2,2,6,6-tetramethyl-3,5-heptanedione (3a) represented the

Full text of DOI:10.1016/S0040-4039(01)01654-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7645–7649
A new and efficient route for 1,3,3%-triketones
Sunkwon Lim,a Yosep Min,b Bohyun Choi,a Daesig Kim,b Il Yoon,c Shim Sung Leec and
Ik-Mo Leea,*
aDepartment of Chemistry, Inha University, 253 Yonghyundong, Namku, Inchon 402-751, South Korea
bMicroelectronics Lab, Samsung Advanced Institute of Technology, San c24, Nongseo-Ri, Kiheung-Eup, Yongin-City,
Kyungki-Do 449-900, South Korea
cDepartment of Chemistry, Gyeongsang National University, Chinju 660-701, South Korea
Received 3 August 2001; accepted 31 August 2001
Abstract—Cyclic and acyclic 1,3,3%-triketones were prepared by the reactions adopting b-diketones and anhydrides in the presence
of barium or strontium hydrides in high yields. Crystal structure of 4-acetyl-2,2,6,6-tetramethyl-3,5-heptanedione (3a) represented
,
the dorminant keto form and provided evidence for intermolecular CꢀH···O hydrogen bonds (average C···O distance; 3.437 A,
average CꢀH···O angle; 169.25°). © 2001 Elsevier Science Ltd. All rights reserved.
1,3,3%-Triketones, first prepared by reactions between
b-diketones and acid anhydrides in the presence of
carboxylate anions in as early as 1955,1 have attracted
interest due to application of active herbicides in which
the treatment of tyrosinaemia, a disorder involving
increased concentrations of tyrosine in the blood, was
found.4
1,3,3%-triketone
derivatives
inhibit
p-hydroxy-
Also, keto-enol tautomerism in these compounds has
been extensively studied by novel methods such as the
deuterium isotope effect.5 Recently, multidentate lig-
ands have attracted much interest due to enhanced
stability and possible formation of multinuclear com-
plexes. Tetraketones and Schiff bases have been utilized
to take advantage of these properties.6 When we con-
sider the rich chemistry of b-diketonates7 and 1,3,5-
phenylpyruvate dioxygenase (HPPD).2 Zeneca Agro-
chemicals first reported that herbicidal 2-benzoyl-
1,3-cyclohexanediones, referred to as the triketones,
effectively inhibit the action of HPPD in 1982.3 Since
then, most major agrochemical companies are reported
to have or have had research projects in this area.
Another pharmaceutical activity of these compounds in
R4
O
R3
R3
R1
R2
R4
O
R4
MH2
R1
R2
O
O
O
O
(M=Ba, Sr)
O
O
Toluene, reflux
1a R1, R2 = t-Bu, R3=H
1b R1, R2 = t-Bu, R3=H
2a R4 = Me
2b R4 = t-Bu
3a R1, R2 = t-Bu, R3=H, R4= Me
3b R1, R2 = t-Bu, R3=H, R4 =t-Bu
3c R1, R2 = -(CH2)2-, R3=H, R4 =Me
3d R1, R2 = -(CH2)3-, R3=H, R4 = Me
3e R1, R3 = -(CH2)3-, R2, R4 = Me
3f R1, R3 = -(CH2)4-, R2, R4 =Me
1c R1, R2 = -(CH2)2-, R3=H 2a R4 = Me
1d R1, R2 = -(CH2)3-, R3=H 2a R4 = Me
1e R1, R3 = -(CH2)3-, R2=Me 2a R4 = Me
1f R1, R3 = -(CH2)4-, R2=Me 2a R4 =Me
Scheme 1.
Keywords: 1,3,3%-triketones; b-diketones; anhydrides; barium (strontium) b-diketonates; intermolecular CꢀH···O hydrogen bonds.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01654-9

7646
S. Lim et al. / Tetrahedron Letters 42 (2001) 7645–7649
triketonates,8 1,3,3%-triketones can be used as possible
tridentate ligands commanding facial geometry and
new class of chemistry can be examined.
reported by the reaction of cyclohexane-1,3-diones with
benzoylcyanide.3 However, no general preparative
methods for cyclic or acyclic 1,3,3%-triketones have been
reported.
Several preparative methods have been adopted. Con-
ventional acylation of b-dicarbonyl compounds aided
by bases suffers low yields due to undesired products
resulting from O-acylation and other side reactions.
Taylor et al. claimed that treatment of thallous salts of
b-dicarbonyl compounds, formed by the reaction
between thallium ethoxide and b-dicarbonyl com-
pounds, with acyl fluorides produced 1,3,3%-triketones
in high yields even though only one example was
reported.9 However, treatment of thallous salts of b-
dicarbonyl compounds with other acyl halides pro-
duced O-acylated products. Improved synthesis of
In this paper, a new and efficient pathway for 1,3,3%-
triketones will be addressed. This method can be appli-
cable to the synthesis of both cyclic and acyclic
1,3,3%-triketones with even bulky substituents such as
t-butyl group and high yield is another advantage.
As shown in Scheme 1, various types of b-diketones
reacted with anhydrides in the presence of BaH2 or
SrH2 (0.5 equivalent) to produce 1,3,3%-triketones with
metal acetates almost quantitatively except acetylcy-
cloalkanone cases.10 Table 1 summarizes the reaction
2-benzoylcyclohexane-1,3-dione
derivatives
was
Table 1. Summary of reaction conditions and results

S. Lim et al. / Tetrahedron Letters 42 (2001) 7645–7649
7647
conditions and product data. A typical triketone was
crystallographically characterized and shown in Fig. 1.
However, reaction with acetylacetone (acac) cannot avoid
side reactions (eight spots in TLC) possibly due to the
presence of several a protons next to the car-bonyl groups.
It was observed that the reaction rates increased in the
order of acetylcycloalkanone, cyclo-b-diketones, and
alkyl-b-diketones. In the case of cyclo-b-diketones, selec-
tivity towards 1,3,3%-triketones was found to be dependent
on the solvents. In toluene, crude products resulted in
three or four spots in TLC, while 1,3,3%-triketones were
the only isolated organic product in THF. It appears that
higher reaction temperatures in refluxing toluene may
induce further reaction such as decomposition, but other
organic compounds could not be characterized due to
failure in isolation. However, it cannot be completely
excluded that the solubility of b-diketones or polarity of
solvents may be the reasons for these different behaviors.
Also, it was observed that cyclohexa-b-dione made the
reaction proceed faster than cyclopenta-b-dione.
tetramethyl-3,5-heptanedione) instead of BaH2 and tmhd
causes the reaction to proceed to completion within 1 h
even in room temperature. However, no reaction pro-
ceeded with Ba(tmhd)2 hydrates.
On the other hand, Ba(NO3)2 with NEt3, Ba(Oi-Pr)2, and
Sr(acetate)2 failed to make the reaction proceed. Cyclic
anhydrides such as succinic anhydride and glutaric
anhydride and diimides also failed to produce corre-
sponding triketones.
From these results, a plausible pathway is proposed, as
shown in Scheme 2.
Much faster reaction rates with anhydrous Ba(tmhd)2
strongly supports the metal b-diketonate intermediate
and that the formation of metal b-diketonates is the rate
determining step. The proposed pathway is a kind of
replacement reaction as reported in the reactions of metal
b-diketonates with acyl halides,11 where similar interme-
diates were proposed. Nucleophilic attack of coordinated
b-diketonates onto anhydrides is another possibility as
reported in the interaction of b-diketonates with diene
complexes of Pd(II) and Pt(II).12 No reaction with
Ba(tmhd)2 hydrates effectively excluded this possibility.
Coordinated H2O prevented anhydrides from coordina-
tion and joining the reaction. Also, no reactions adopting
other barium or strontium compounds where other
coordinating ligands are present support this proposition.
Barium (or strontium) b-diketonates appear to be inter-
mediates because adoption of Ba(tmhd)2 (tmhd=2,2,6,6-
Since the predominant interatomic interactions in Group
II b-diketonate complexes are electrostatic (i.e. ionic) in
nature and the average coordination numbers observed
for Sr and Ba complexes are 6–8,7b Lewis bases such as
anhydrides are expected to fill the coordination sites. An
ethereal oxygen atom coordinates over a carbonyl one
because many examples with coordinated ethers are
reported, while complexes with coordinated ketones are
rare.11 Also, model analysis shows coordination through
carbonyls places the substituents in a position to block
the nucleophilic attack of b-diketonates onto the carbonyl
group. In the same manner, inertness of cyclic anhydrides
towards nucleophilic attack can be explained. In the cases
of diimides, the presence of hydrogen on a nitrogen atom
may retard the coordination, which results in no reaction.
Figure 1. 20% thermal ellipsoid diagram for the X-ray crystal-
lographic geometry of 4-acetyl-2,2,6,6-tetramethyl-3,5-heptane-
Adoption of cyclo-b-diketones requires the deviation
from planar nature of coordinated b-diketonates, which
retards the nucleophilic attack. The larger ring of cyclo-
hexane-1,3-dione in comparison to cyclopentane-1,3-
dione induces less deviation of planarity, which results
in a faster reaction rate. In the case of acetylcycloalka-
,
dione. Selected bond lengths (A) and angles (°): C6ꢀC5, 1.529(4);
C6ꢀC7, 1.513(4); C6ꢀC9, 1.523(4); C5ꢀO1, 1.219(4); C7ꢀO2,
1.222(4); C9ꢀO3, 1.207(3), C5ꢀC6ꢀC7, 107.1(2); C5ꢀC6ꢀC9,
110.6(2); C7ꢀC6ꢀC9, 110.5(2).
R2
R1
R1
R2
O
O
M(OCOR2)2 +
R1
R1
O
O
O
2
O
O
O
M
R2
M = Ba, Sr
Scheme 2.

7648
S. Lim et al. / Tetrahedron Letters 42 (2001) 7645–7649
Crystallographic data (excluding structure factors) for
the structures in this paper have been deposited with
the Cambridge Crystallographic Data Centre as supple-
mentary publication numbers CCDC 163331. Copies of
the data can be obtained, free of charge, on application
to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
[fax:+44(0)1223-3336033 or e-mail: deposit@ccdc.cam.
ac.uk].
Acknowledgements
This research was supported by the Korea Research
Foundation for the 21st Century (2000) and Samsung
Advanced Institute of Technology (1999–2000).
Figure 2. Packing structure of the molecules of 4-acetyl-
2,2,6,6-tetramethyl-3,5-heptanedione stabilized by CꢀH···O
hydrogen bonds. Non-hydrogen bonding H atoms are omit-
ted for clarity.
References
none, the slowest reaction rate appears to originate
from the fact that formation of enol and coordination
to a metal are effectively suppressed because methines
of b-diketonates locate on the bridge-head of the ring.
1. Rogers, N. A. J.; Smith, H. J. Chem. Soc. 1955, 341.
2. Lee, D. L.; Knudsen, C. G.; Michaely, W. J.; Chin,
H.-L.; Nguyen, N. H.; Carter, C. G.; Cromartie, T. H.;
Lake, B. H.; Shribbs, J. M.; Fraser, T. Pestic. Sci. 1998,
54, 377 and references cited therein.
3. Michaely, W. J.; Kratz, G. W. EP 0135191, 1986.
4. Ellis, M. K.; Lindestedt, S. T.; Lock, E. A.; Markstedt,
M. E. H.; Mutter, L. C.; Prisbylla, M. P. WO 93/00080,
1992.
NaH also produced triketones but at a much slower
rate. In the preparation of triketones with alkyl sub-
stituents, it took at least 3 or 4 days to complete the
reaction even in refluxing toluene. This may result from
the fact that Na is smaller than Sr and Ba and simulta-
neous coordination of both b-diketonates and anhy-
drides is not easy. Actually, sodium b-diketonates are
reported to have a 4–6 coordination number, which is
less than Sr and Ba analogues.
5. Bolvig, S.; Duus, F.; Hansen, P. E. Magn. Reson. Chem.
1998, 36, 315.
6. (a) Garnovskii, A. D.; Nivorozhkin, A. L.; Minkin, V. I.
Coord. Chem. Rev. 1993, 126, 1; (b) Fenton, D. E.;
Regan, C. M. Inorg. Chim. Acta 1982, 58, 83; (c) Fenton,
D. E.; Tate, J. R.; Casellato, U.; Tamburini, S.; Vigato,
P. A.; Vidali, M. Inorg. Chem. Acta 1984, 83, 23; (d)
Lintvedt, R. L.; Schoenfelner, B. A.; Ceccarelli, C.; Glick,
M. D. Inorg. Chem. 1982, 21, 2114.
7. (a) Metrotra, R. C.; Bohra, R.; Gaur, D. P. Metal
i-Diketonates and Allied Derivatives; Academic Press:
London, UK, 1978; (b) Otway, D. J.; Rees, Jr., W. S.
Coord. Chem. Rev. 2000, 210, 279; (c) Nikonov, M. V.;
Chizhov, D. L.; Ratner, V. G.; Pashkevich, K. I. J.
Fluorine Chem. 2000, 106, 115.
8. (a) Harada, Y.; Mizobe, Y.; Hidai, M. J. Organomet.
Chem. 1999, 574, 24; (b) El-Qisairi, A.; Henry, P. M. J.
Organomet. Chem. 2000, 603, 50; (c) Arimoto, H.; Ohba,
S.; Nishiyama, S.; Yamamura, S. Tetrahedron Lett. 1994,
35, 4581.
9. Taylor, E. C.; Alexander, M. US Patent 3,947,488, 1974.
10. Detailed reaction procedures and spectroscopic data
including crystallographic data can be found in the sup-
porting information sheet.
The presence of acid such as formic acid makes the
triketone decompose to the corresponding b-diketones.
Bubbling H2 into the reaction mixture induced no
reaction, possibly due to blocking the coordination of
anhydrides by preoccupying the coordination sites
around metal ions.
The crystal structure shown in Fig. 1 represented the
dominant keto form, as evidenced in the 1H NMR
spectrum where the methine peaks appears at 5.63 ppm,
which is quite unusual. 2-Acyl-1,3-cycloalkanediones13
are only observed in the enolic form, whereas
triacetylmethane14 is reported to exist in both the enolic
and keto forms. Three carbonyl groups are located in
syn manner, which will address facial conformation if
this is coordinated to an appropriate metal ion. In Fig.
2, intermolecular hydrogen bonds in this crystalline
compound were illustrated. Although H atoms have
been included in their idealized positions, some methyl
H atoms of t-butyl groups are located close to the
carbonyl O atoms of the neighboring molecules, provid-
ing evidence for intermolecular CꢀH···O hydrogen
A representative experimental procedure is as follows. A
solution containing 2.95 g (15.71 mmol) of 2,2,6,6-tetra-
methyl-3,5-heptanedione (tmhd) in toluene (20 ml) was
added to a suspended solution of BaH2 (1.0 g, 7.14
mmol) in toluene (15 ml). After stirring for 10 min at
room temperature, a solution of acetic anhydride (1.46 g,
14.28 mmol) in toluene (10 ml) was added to the mixture.
The reaction mixture was refluxed for 8 h and then was
cooled down to room temperature. The resulted solution
was filtered to remove insoluble barium acetate and the
,
bonds (average C···O distance; 3.437 A, average
CꢀH···O angle; 169.25°).15
Further studies to clarify the reaction mechanism and
to prepare the new metal complexes with facial geome-
try are in progress.

S. Lim et al. / Tetrahedron Letters 42 (2001) 7645–7649
7649
filtrate was evaporated under reduced pressure. The
residue was recrystallized in hexane (20 ml) at −20°C to
obtain a colorless crystal (3.10 g, 95.98%). 1H NMR
(199.976 MHz, CDCl3): 5.63 (s, 1H, ((CH3)3CC(O))2-
CH(C(O)CH3), 2.21 (s, 3H, ((CH3)3CC(O))2CH(C(O)-
CH3), 1.16 (s, 18H, ((CH3)3CC(O))2CH(C(O)CH3); 13C
NMR (50.289 MHz, CDCl3): 203.11 (s, ((CH3)3CC-
(O))2CH(C(O)CH3), 197.12 (s, ((CH3)3CC(O))2CH(C(O)-
CH3), 68.96 (s, ((CH3)3CC(O))2CH(C(O)CH3), 44.11 (s,
((CH3)3CC(O))2CH(C(O)CH3), 27.34 (s, ((CH3)3CC(O))2-
CH(C(O)CH3), 24.93 (s, ((CH3)3CC(O))2CH(C(O)CH3);
anal. calcd for C13H22O3: C, 68.99; H, 9.80; found: C,
68.57; H, 10.23.
Nonhebel, D. C. J. Chem. Soc. 1962, 4628; (d) Nojiri, T.;
Motoi, M.; Hashimoto, I. Bull. Chem. Soc. Jpn. 1971, 44,
850.
12. Johnson, B. F. G.; Lewis, J.; Subramaniam, M. S. J.
Chem. Soc. (C) 1968, 1993.
13. (a) Liepins, E.; Petrova, M. V.; Gudrimiece, E.; Paulins,
I. Magn. Reson. Chem. 1989, 27, 907; (b) Forsen, S.;
Merenyi, F.; Nilsson, M. Acta Chem. Scand. 1964, 18,
1208.
14. (a) Dreyfus, M.; Garnier, F. Tetrahedron 1974, 30, 133;
(b) Yoshida, Z.; Ogoshi, H.; Tokumitsu, T. Tetrahedron
1970, 26, 5691.
15. (a) Taylor, R.; Kennard, O. J. Am. Chem. Soc. 1982,
104, 5063; (b) Desiraju, G. R. Acc. Chem. Res. 1991, 24,
290.
11. (a) Barry, W. J. J. Chem. Soc. 1960, 670; (b) Murdoch,
H. D.; Nonhebel, D. C. J. Chem. Soc. 1962, 2153; (c)