Exploring the one-pot C-acylation of cyclic 1,3-diones with unactivated carboxylic acid

Article abstract of DOI:10.1016/j.tetlet.2010.02.111

The use of DCC, triethylamine, and 4-dimethylaminopyridine in dichloromethane provides a general and standard one-pot procedure for the C-acylation of cyclic 1,3-diones with a wide range of carboxylic acids, giving rise to β-triketones in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2010.02.111

Tetrahedron Letters 51 (2010) 2348–2350
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Exploring the one-pot C-acylation of cyclic 1,3-diones with unactivated
carboxylic acid
Sylvie Goncalves a, Marc Nicolas b, Alain Wagner a, Rachid Baati a,
*
a Université de Strasbourg, Faculté de Pharmacie, CNRS/UMR 7199, Laboratoire des Systèmes Chimiques Fonctionnels, 74 route du Rhin BP60024, 67401 Illkirch, France
b Les Laboratoires Pierre Fabre CDCC, 16 rue Jean Rostand 81600 Gaillac, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The use of DCC, triethylamine, and 4-dimethylaminopyridine in dichloromethane provides a general and
standard one-pot procedure for the C-acylation of cyclic 1,3-diones with a wide range of carboxylic acids,
giving rise to b-triketones in good to excellent yields.
Received 1 February 2010
Revised 19 February 2010
Accepted 22 February 2010
Available online 24 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
C-Acylation
Cycloalkane-1,3-dione
b-Triketone
Regioselectivity
The cyclic b-triketone moiety,1 also called 2-acyl-cycloalkane-
1,3-dione, is part of the skeleton of diverse natural compounds,
such as 12 and 2,3 with a wide range of biological activities such
as antibiotic, antibacterial, and anticancer properties (Fig. 1). More-
over, hundreds of patents4 describe herbicides containing the b-tri-
ketone structure like compound 3,5 or deriving from it like
tralkoxydim 4.6 By analogy with 1,3,5-triketonates,7 b-triketones
are also attractive as they can be envisioned as tridentate ligands
for metals. Finally, they can be used as building blocks in the syn-
thesis of various heterocycles.1 The existence of b-triketones in a
completely enolized form explains the possibility of synthesizing
such a wide range of heterocycles.
NH2
OH
O
OH
O
O
O
HO
OH
O
OH OH
O
O
OH
chelocardin : 1
usnic acid : 2
O
O
N
OH
O
O
Cl
OMe
Me
N
OMe
OH
Cl
Me
Me
tralkoxydim : 4
3
Three methods are reported in the literature for the preparation
of 2-acyl-cycloalkane-1,3-dione. The first one consists of exhaus-
tive methylation of phloroglucinol derivatives giving rise to b-trik-
etones moiety.1 In the more general second route, representing the
vast majority of existing protocols, 1,3-diones are initially O-acyl-
ated with acyl chloride, anhydrides or carboxylic acid, and in a sec-
ond step a catalyzed O–C isomerization led to the b-triketone.1
Various catalysts were employed in this two-step process such as
Lewis acids (AlCl3, ZnCl2), bases (imidazole, 4-DMAP), and heat.1
Alternatively, dehydration reagents such as dicyclohexylcarbodi-
imide (DCC),8 chloroamidinium salts,9 and 1,1-carbonyldiimidaz-
ole10 can also be used for the C-acylation of 1,3-diones with
carboxylic acids. The preparation of 2-acyl-cyclohexane-1,3-diones
can also be performed under more drastic conditions by using stoi-
Figure 1. Biologically active compounds and herbicides containing the b-triketone
moiety.
chiometric amount of strong bases, such as barium hydride in tet-
rahydrofuran under reflux, from 1,3-diones and anhydrides.11
Finally, only recently, Zhou developed the first catalytic C-acyla-
tion, of mostly acyclic 1,3-dicarbonyl compounds, however, using
SmCl3 as the catalyst, and acyl chlorides as acyl donors.12
In the course of our studies toward the total synthesis of a nat-
ural product, we were interested in a one-pot C-acylation proce-
dure of cyclic 1,3-diones, with functionalized carboxylic acid as
the acyl donor. However, we found that this reaction performed
with unactivated carboxylic acids has received scant attention,8
and no general standard procedure was known for these sub-
strates. Moreover, some reports have also mentioned the difficul-
ties and failures to perform such transformation that needs most
of the time specific optimization conditions and much more
* Corresponding author. Fax: +33 368 854 306.
E-mail address: baati@bioorga.u-strasbg.fr (R. Baati).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.111

S. Goncalves et al. / Tetrahedron Letters 51 (2010) 2348–2350
2349
activated precursors such as acyl cyanide.13,14 Only few reports,
Table 2
Exploring the scope of the reaction on various cyclic 1,3-diones
most of which are patents, include the acylation of 1,3-diones with
unactivated carboxylic acids using DCC as the coupling agent.5,8,9,15
Moreover, drastic conditions are generally used and the reported
procedures always differ from one to the other. The use of DCC
was also found for C-acylation of tetronic acids, Meldrum’s acids,
and b-keto-d-valerolactones with carboxylic acids,8,10,16 however,
these substrates exhibit reactivities that differ from cycloalkane-
1,3-diones. To the best of our knowledge, a general protocol for
the preparation of 2-acyl-cyclohexane-1,3-diones using unactivat-
ed organic acid as the acyl donor has not been reported so far. As a
consequence, the development of an efficient one-pot standard
procedure to access cyclic b-triketones from 1,3-cyclic diketone
and unactivated carboxylic acid is desirable. In this Letter, we
describe an efficient simple one-pot method for the synthesis of
2-acyl-cyclohexane-1,3-diones with a broad scope of application
under mild conditions.
O
OH
O
O
DCC / 4-DMAP
+
R1
R2
n = 0,1, 2
Et3N / DCM
14h / rt
R1
HO
O
O
n
n
R2
n = 0,1, 2
Entry
1,3-Dione
Product
Yield (%)
O
OH
O
1
2
85
6a
6
O
O
O
OH
O
100
O
O
7a
7
O
OH
O
The standard procedure was first optimized for the C-acylation
of cyclohexane-1,3-dione with phenylacetic acid to obtain 2-(2-
phenylacetyl)cyclohexane-1,3-dione 5 (Table 1). One-pot reactions
were done by using DCC and a catalytic amount of 4-DMAP, the
best catalyst reported for the O–C isomerization. Firstly, we tested
triethylamine and after 3 h of reaction, 5 was obtained in 29% along
with some O-acylated product in 62%, the kinetic product (entry 1).
This result proved that the O–C isomerization was not complete
and performing the reaction during 14 h permitted to increase
the yield to 88% (entry 2). Moreover, a control experiment without
4-DMAP led to the exclusive formation of the O-acylated product,
demonstrating the role of 4-DMAP in the O–C isomerization pro-
cess. Two other bases, diisopropylethylamine and potassium car-
bonate, were also tested without any improvement (entries 3
and 4). Acetonitrile and 1,2-dichloroethane were also tried as po-
tential solvents for the reaction. In MeCN, the yield of 5 was
slightly decreased to 72% (entry 5) compared to DCM (Entry 2).
DCE was relatively equivalent to DCM and 5 was obtained in a
comparable yield (entry 6).
3
4
100
86
O
O
O
8
O
8a
O
OH
O
O
9
O
9a
O
O
5
6
7
37
/
O
10
11
10a
O
OH
O
O
O
O
11a
OH
O
O
O
O
82
O
12
12a
O
OH
Finally, with the aim to get a quantitative yield while shorten-
ing the reaction time, we decided to exploit the benefit of micro-
wave irradiation. Unfortunately, the yield of 5 was not better
(entry 7). The screening of the reaction parameters allowed identi-
fying the optimized conditions for the synthesis of b-triketones:
DCC (1.2 equiv), 4-DMAP (0.2 equiv), and Et3N (1.2 equiv) in DCM
at room temperature for 14 h. We next studied the generality of
the procedure and investigated the scope of the reaction for a panel
of cycloalkane-1,3-dione, which were reacted with 2-meta-tolyl-
acetic acid, as a model unactivated acid, under the optimized
conditions (Table 2). As a general trend, all the C-acylations17
proceeded smoothly and without any complications for the prepa-
ration of C6-membered b-triketones. In most of the cases, they
were obtained in good to excellent yields. 5-dimethyl and 5-fur-
yl-cyclohexan-1,3-diones 7 and 8 behaved similar to 6 (entry 1),
giving quantitatively b-triketones 7a and 8a (entries 2 and 3). 3-
hydroxy-1H-phenalen-1-one 9 led to the formation of 9a in a good
yield of 86% (entry 4). The methodology was next extended to 7-
and 5-membered ring 1,3-diketone. The reaction proceeded mod-
erately with cycloheptan-1,3-dione 10, giving 10a in 37% yield (en-
try 5).
This limitation is ascribed to the low reactivity of 10 in DCM and
increasing the temperature of the reaction did not permit to get a
better yield. No reaction occurred with the cyclopentan-1,3-dione
11 due to a significant lack of reactivity (entry 6), while tetronic
acid 12 provided efficiently 12a in 82% of yield (entry 7). These re-
sults demonstrate that the ring size of the cyclic 1,3-diones has a
significant influence on the C-acylation efficiency. While C6-mem-
bered substrates afforded the b-triketones satisfactorily, C7-mem-
bered 1,3-dione was less reactive and C5-membered 1,3-dione did
not react at all. We were then interested in exploring the reactivity
of different carboxylic acid substrates in the reaction with cyclo-
hexane-1,3-dione (Table 3). Firstly, we studied the influence of
the substitution on the aromatic part of the acidic component. To
our delight, acids 13, 14, and 15 gave the corresponding b-trike-
tones 13a, 14a, and 15a in good yields (84–90%) (entries 1, 2,
and 3), in accordance with the previous result for 6a.
Table 1
Optimization of the conditions on the synthesis of 5
O
DCC (1.2 equiv)
OH
O
O
O
4-DMAP (0.2 equiv)
+
base / solvent
HO
O
5
(1.0 equiv)
(1.0 equiv)
Entry
Base (1.2 equiv)
Solvent
Time
Temperature
Yielda (%)
1
2
3
4
5
6
7
Et3N
Et3N
DIPEA
K2CO3
Et3N
Et3N
Et3N
DCM
DCM
DCM
DCM
MeCN
DCE
1.5 h
14 h
14 h
14 h
14 h
14 h
0.1 h
rt
rt
rt
rt
29
88
69
57
72
83
73
rt
rt
Increasing the number of substituents did not affect the reac-
tion. Indeed, acids 16 and 17 led to b-triketones 16a and 17a,
respectively, in good yields (entries 4 and 5). It is important to note
that the reaction conditions tolerate various functionalities such as
DCM
90 °Cb
a
Isolated yields.
Reaction performed under microwave irradiation.
b

2350
S. Goncalves et al. / Tetrahedron Letters 51 (2010) 2348–2350
Table 3
ylic acid, using DCC and a catalytic amount of 4-DMAP, in DCM
Exploring the scope of the reaction with various acids
at room temperature. Scopes and limitations were explored by
varying the 1,3-dione moiety as well as the carboxylic acid sub-
strate. From these studies, we can conclude that our procedure
has broad scope of application and tolerates many functional
groups. Under this optimal procedure, a series of 2-acyl-1,3-cyclo-
alkan-1,3-diones were prepared in good to excellent yields.
O
OH
O
O
O
DCC / 4-DMAP
R
n
R
+
HO
n
Et3N/DCM
14h / rt
O
Entry
1
Carboxylic acid
Product
Yield (%)
OH
OH
OH
O
O
Acknowledgments
HO
OMe
OMe
85
90
84
74
13
O
O
13a
We acknowledge the Laboratoire Pierre Fabre (Plantes et Indus-
tries) and the CNRS for financial support of S.G.
O
O
HO
HO
NHBoc
NHBoc
2
3
4
14
Supplementary data
O
O
14a
Supplementary data (general methods, general procedure and
data, 1H NMR and 13C NMR spectra of new compounds) associated
with this article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.02.111.
Br
Br
15
O
O
15a
O
O
OH
OH
O
O
O
O
HO
HO
References and notes
16
O
O
16a
1. (a) Rubinov, D.; Rubinova, I.; Akhrem, A. Chem. Rev. 1999, 99, 1047–1065. and
references cited therein; (b) Barceló, M.; Raviña, E.; Masaguer, C. F.; Domíngez,
E.; Areias, F. M.; Brea, J.; Loza, M. I. Bioorg. Med. Chem. Lett. 2007, 17, 4873–
4877.
2. (a) Chabbert, Y.; Scavizzi, M. Antimicrob. Agents Chemother. 1976, 9, 36–41; (b)
Chu, D.; Bernstein, E.; Huckin, S. Can. J. Chem. 1978, 56, 1059–1062; (c) Chopra,
I. Antimicrob. Agents Chemother. 1994, 38, 637–640.
3. Safak, B.; Cfitci, I.; Ozdemir, M.; Kiyildi, N.; Cetinkaya, Z.; Aktepe, O.; Altindis,
M.; Asik, G. Phytother. Res. 2009, 23, 955–957.
4. 176 patents have been published since 1976 (SciFinder Scholar research
conducted in December 2009 with herbicides and 1,3-cyclohexanedione as
keywords).
5. Pontzen, R. et al. (Bayer CropScience AG, Germany; et al.) German Patent
10209645, 2002.
6. Potapovich, M. V.; Eremin, A. N.; Rubinov, D. B.; Metelitza, D. I. Appl. Biochem.
Microbiol. 2008, 44, 19–27.
7. (a) Arimoto, H.; Ohba, S.; Nishiyama, S.; Yamamura, S. Tetrahedron Lett. 1994,
35, 4581–4584; (b) Harada, Y.; Mizobe, Y.; Hidai, M. J. Organomet. Chem. 1999,
574, 24–31; (c) El-Qisairi, A.; Henry, P. M. J. Organomet. Chem. 2000, 603, 50–60.
8. Tabuchi, H.; Hamamoto, T.; Ichiara, A. Synlett 1993, 651–652.
9. Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 6984–6988.
5
6
82
63
OMe
OMe
O
O
17a
17
S
S
OH
OH
O
O
HO
HO
18
O
O
18a
N
N
7
8
/
/
19
O
O
19a
20a
O
O
OH
OH
HO
HO
20
O
O
OMe
OMe
OMe
OMe
10. Khlebnocova, T. S.; Isakova, V. G.; Baranovsky, A. V.; Borisov, E. V.; Lakhvich, F.
A. J. Fluorine Chem. 2006, 127, 1564–1569.
11. Shen, Q.; Huang, W.; Wang, J.; Zhou, X. Org. Lett. 2007, 4491–4494.
12. Lim, S.; Min, Y.; Choi, B.; Kim, D.; Yoon, I.; Lee, S. S.; Lee, I. Tetrahedron Lett.
2001, 42, 7645–7649.
9
22
81
O
OMe
OMe
21
21a
13. Nicolaou, K. C.; Montagnon, T.; Vassilikogiannakis, G.; Mathison, C. J. N. J. Am.
Chem. Soc. 2005, 127, 8872–8888.
O
OH
O
O
14. Vassilikogiannakis, G.; Margaros, I.; Tofi, M. Org. Lett. 2004, 205–208.
15. (a) Huang, K. H.; Eaves, J.; Veal, J.; Barta, T.; Geng, L.; Hinkley, L.; Hanson, G.
(Serenex, Inc., USA) American Patent 656230, 2005.; (b) Pontzen, R. et al. (Bayer
Aktiengesellschaft, Germany) German Patent 19946853, 1999.; (c) Pontzen, R.
et al. (Bayer, A.-G., Germany) German Patent 19962923, 1999.; (d) Pontzen, R.
et al. (Bayer Aktiengesellschaft, Germany) German Patent 10037149, 2000.; (e)
Willms, L.; Van Almsick, A.; Bieringer, H.; Auler, T.; Thurwachter, F. (Aventis
CropScience GmbH, Germany) German Patent 19935218, 1999.; (f) Walter, H.
et al. (BASF A.-G., Germany; et al.) German Patent 19857898, 1998.; (g)
Wetcholowsky, Ingo et al. (Bayer A.-G., Germany) German Patent 19921732,
1999.; (h) Westphalen, K. et al. (BASF A.-G., Germany) German Patent
19700019, 1997.; (i) Morita, K.; Ohno, T.; Shimozono, T.; Watanabe, Y.;
Yoshizawa, H. (Hokko Chemical Industry Co., Ltd, Japan) Japanese Patent
138857, 1997.; (j) Watanabe, S. et al. (Nissan Chemical Industries, Ltd, Japan)
Japanese Patent 258032, 1988.; (k) Watanabe, S. et al. (Nissan Chemical
Industries, Ltd, Japan) Japanese Patent 302981, 1987.
16. (a) Pashkovskii, F. S.; Katok, Y. M.; Khlebnikova, T. S.; Koroleva, E. V.; Lakhvich,
F. A. Russ. J. Org. Chem. 2003, 39, 998–1009; (b) Pashkovskii, F. S.; Shchukina, E.
M.; Gribovskii, M. G.; Lakhvich, F. A. Russ. J. Org. Chem. 2006, 42, 527–540.
17. Typical experimental procedure: The carboxylic acid (2 mmol), DCC (2.40 mmol),
Et3N (2.40 mmol), and 4-DMAP (0.2 mmol) were added to a solution of cyclic
1,3-diones (2 mmol) in dry dichloromethane (2 mL). The reaction mixture was
stirred for 14 h at room temperature. After dilution with DCM (10 mL) and
filtration of the precipitate, aqueous HCl 1 M was added to the filtrate. The
aqueous phase was extracted with diethyl ether (3 Â 10 mL). The combined
organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by column chromatography on silica gel and
characterized by 1H, 13C, IR, and HRMS analyses.
HO
OTBDPS
OTBDPS
10
22
22a
bromoaryl, methylether, protected amine, and acetal. 2-(thiophen-
3-yl)acetic acid 18 gave also 18a in an acceptable yield of 63% (en-
try 6), while 2-(pyridin-3-yl)acetic acid 19 or pent-4-enoic acid 20,
afforded complex reaction mixtures (entries 7 and 8). In general,
we observed that the presence of a nitrogen-containing heterocy-
cle or an olefin moiety on the carboxylic acid led to the formation
of several by-products difficult to identify. Finally, other function-
alized carboxylic acids such as 21 and 22 were tested (entries 9 and
10). The low yield obtained with 3-(3,4,5-trimethoxyphenyl)prop-
anoic acid 21 for the preparation of 21a could be ascribed to its low
solubility in DCM, and increasing the temperature did not improve
the efficiency of the reaction. Interestingly, 3-(tert-butyldiphenyl-
silyloxy)propanoic acid 22 gave expected 22a in 81%, demonstrat-
ing the compatibility of silyl protected alcohol under our mild
optimized conditions.
In summary, we report herein the first general procedure for the
one-pot C-acylation of cyclic 1,3-diones with unactivated carbox-