SmCl3-catalyzed C-acylation of 1,3-dicarbonyl compounds and malononitrile

Article abstract of DOI:10.1021/ol701961z

(Chemical Equation Presented) A recyclable, convenient, and efficient catalytic system for C-acylation of 1,3-dicarbonyl compounds and malononitrile with acid chlorides has been developed, giving moderate to excellent yields under mild conditions. This is the first catalytic example of such reactions. In addition, by applying this protocol as the key step, 3,5-disubstituted-1H- pyrazole-4-carboxylate can easily be synthesized in high yields in a one-pot procedure.

Full text of DOI:10.1021/ol701961z

ORGANIC
LETTERS
2007
Vol. 9, No. 22
4491-4494
SmCl3-Catalyzed C-Acylation of
1,3-Dicarbonyl Compounds and
Malononitrile
Quansheng Shen,† Wen Huang,† Jialiang Wang,† and Xigeng Zhou*,†,‡
Department of Chemistry, Shanghai Key Laboratory of Molecular Catalysis and
InnoVatiVe Materials, Fudan UniVersity, Shanghai 200433, People’s Republic of
China, and State Key Laboratory of Organometallic Chemistry, Shanghai 200032,
People’s Republic of China
xgzhou@fudan.edu.cn
Received August 10, 2007
ABSTRACT
A recyclable, convenient, and efficient catalytic system for C-acylation of 1,3-dicarbonyl compounds and malononitrile with acid chlorides has
been developed, giving moderate to excellent yields under mild conditions. This is the first catalytic example of such reactions. In addition,
by applying this protocol as the key step, 3,5-disubstituted-1H-pyrazole-4-carboxylate can easily be synthesized in high yields in a one-pot
procedure.
1,3,3′-Triketones are useful intermediates in organic syn-
thesis, especially for the preparation of some biologically
active compounds such as SR141716, phloroglucinols, and
5-deazaaminopterin.1,2 Surprisingly, only a limited number
of procedures for the synthesis of 1,3,3′-triketones have been
developed. In most cases, 1,3,3′-triketones are prepared by
C-acylation of 1,3-dicarbonyl compounds.3-8 Nevertheless,
these methods usually require the use of stoichiometric
amounts of strong bases such as EtONa,4 BaH2,5 EtMgBr,6
n-BuLi,7 or powerful reductive metals like Na,8 which are
not suitable for sensitive substrates. Notably, Rathke and
Cowan developed a MgCl2-promoted C-acylation of 1,3-
dicarbonyl compounds.9 Although these possess many po-
tential advantages, the main limitation of this strategy is that
a stoichiometric amount of Lewis acid and 2 equiv of tertiary
amine additive are required. This is because an acylation
product 3 is always a stronger acid than the corresponding
dicarbonyl precursor 2 and thus may neutralize a portion of
the â-diketonate intermediate (Scheme 1, route c). Therefore,
the development of an alternative catalytic method for
obtaining 1,3,3′-triketones represents a challenging but
attractive subject from the viewpoints of operational simplic-
ity, economy, and environmental impact.
† Fudan University.
‡ State Key Laboratory of Organometallic Chemistry.
(1) (a) Francisco, M. E.; Seltzman, H. H.; Gilliam, A. F.; Mitchell, R.
A.; Rider, S. L.; Pertwee, R. G.; Stevenson, L. A.; Thomas, B. F. J. Med.
Chem. 2002, 45, 2708. (b) Su, T. L.; Huang, J. T.; Chou, T. C.; Otter, G.
M.; Sirotnak, F. M.; Watanabe, K. A. J. Med. Chem. 1988, 31, 1209.
(2) (a) Terada, M.; Nakano, M.; Ube, H. J. Am. Chem. Soc. 2006, 128,
16044. (b) Jung, M. E.; Min, S. J.; Houk, K. N.; Ess, D. J. Org. Chem.
2004, 69, 9085. (c) Lin, C. T.; Shih, J. H.; Chen, C. L.; Yang, D. Y.
Tetrahedron Lett. 2005, 46, 5033.
(3) (a) Miyashita, A.; Suzuki, Y.; Nagasaki, I.; Ishiguro, C.; Iwamoto,
K. I.; Higashino, T. Chem. Pharm. Bull. 1997, 45, 1254. (b) Sekine, M.;
Kume, A.; Nakajima, M.; Hata, T. Chem. Lett. 1981, 1087. (c) Tarbell, D.
S.; Price, J. R. J. Org. Chem. 1956, 21, 144.
(7) Jung, J. C.; Watkins, E. B.; Avery, M. A. Synth. Commun. 2002, 32,
3767.
(8) Peter, M.; Christo, I.; Marin, A. Chem. Ber. 1964, 97, 2987.
(9) (a) Rathke, M. W.; Cowan, P. J. J. Org. Chem. 1985, 50, 2622. (b)
Little, R. D.; Russu, W. A. J. Org. Chem. 2000, 65, 8096.
(4) Lawesson, S. O.; Busch, T. Acta Chem. Scand. 1989, 8, 1717.
(5) Lim, S.; Min, Y.; Choi, B.; Kim, D.; Lee, S. S.; Lee, I. M.
Tetrahedron Lett. 2001, 42, 7645.
(6) Skarzewski, J. Tetrahedron 1989, 14, 4593.
10.1021/ol701961z CCC: $37.00
© 2007 American Chemical Society
Published on Web 09/29/2007

Scheme 1. Mechanistic Hypothesis
Table 1. Optimization of the Reaction Conditions for
Acylation of Diethyl Malonate with Benzoyl Chloridea
entry
catalysts
solvent
toluene
time (h)
yieldb (%)
1
2
3
4
5
6
7
8
9
10
11c
12
13
14
15
16
17
18
19
20
21d
MgCl2
AlCl3
FeCl3
BiCl3
InCl3
12
10
10
12
12
12
10
5
5
4
4
5
5
5
12
12
4
4
4
4
5
20
24
20
18
32
21
16
52
56
87
84
78
65
50
55
0
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
H3BO3
FeCl3‚6H2O
LaCl3
NdCl3
SmCl3
SmCl3
DyCl3
ErCl3
YbCl3
Yb(OTf)3
none
SmCl3
SmCl3
SmCl3
SmCl3
SmCl3
Taking into account those results, we considered that one
way to avoid the competitive deprotonation of the acylation
product would be to make the coordination between metal
and â-diketonate more stable than that of the tricarbonyl
counterpart. Lanthanide trichlorides are known to activate
â-diketone in the presence of bases, forming lanthanide
â-diketonate complexes.10 Given the facts that the lan-
thanide-ligand bond strength predominantly depends on the
electrostatic interaction and the degree of steric saturation,
and that the introduction of an electron-withdrawning sub-
stituent could lead to decreased stabilization of lanthanide
tri(â-diketonates),11 we reasoned that it should be possible
to control the preferential deprotonation of dicarbonyl
compounds and intercept the resulting enolate intermediate
with acyl chloride as an electrophile (Scheme 1, routes a
and b). Herein, we wish to report a general, highly efficient,
and catalytic method for C-acylation of 1,3-dicarbonyl
compounds and malononitrile with acid chlorides.
Initially, we sought an effective catalytic system for the
C-acylation of active methylene compounds, guided by the
template reaction between benzoyl chloride 1a and diethyl
malonate 2a. A range of reaction conditions were tested, and
some of the results are listed in Table 1. As expected,
lanthanide trichlorides proved to be efficient catalysts for
the C-acylation of 1a with 2a. However, under the same
conditions, for the other Lewis acids only very low yields
of 3aa were obtained even with longer reaction time (Table
1, entries 1-7). Among lanthanide trichlorides employed
(Table 1, entries 8-14), the medium-sized SmCl3 catalyzed
the formation of 3aa most efficiently. This is consistent with
57
68
trace
58
62
n-C6H14
CH3CN
ClCH2CH2Cl
toluene
a Reaction conditions: diethyl malonate (1.0 mmol), benzoyl chloride
(1.1 mmol), catalyst (10 mol %), solvent (4 mL), Et3N (1.2 mmol), rt. b LC
yield based on 1,3-dicarbonyl compound. c Catalyst (5 mol %). d Pyridine
as base (1.2 mmol).
the upward trend of the stability of lanthanide â-diketonate
complexes,11 demonstrating that the coordination of the
diketonate to lanthanide may play a key role in the equilib-
rium of the deprotonation of the acylation product and the
substrate. No C-acylation reaction occurred in the absence
of any catalyst (Table 1, entry 16).
A screening of solvents for the SmCl3 system revealed
that toluene is a suitable solvent, and triketone 3aa was
formed in 87% yield (Table 1, entry 10). Less activity in
CH3CN and with pyridine as a base indicate that increased
basicity of solvent or base may lead to preferential coordina-
tion of these reagents over â-diketonates, which resulted in
lower yields (entries 19 and 21). In the MgCl2 catalytic
system,9 where a stoichiometric amount of MgCl2 and 2
equiv of tertiary amine additive were required, it was
observed in the present case that 1 equiv of Et3N was enough
to effect complete conversion of the substrate in the presence
of a catalytic amount of SmCl3.
Having determined the optimum reaction conditions, we
investigated the generality of this process. As can be seen
from Table 2, a variety of 1,3-dicarbonyl compounds can
be C-acylated by 1a to give the corresponding products in
moderate to excellent yields, depending on the steric
hindrance at the methylene carbon and the nature of carbonyl
functional groups (Table 2, entries 1-8). Interestingly, cyclic
1,3-diketones can also be employed in this SmCl3-catalyzed
(10) Xu, G.; Wang, Z. M.; He, Z.; Lue, Z.; Liao, C. S.; Yan, C. H. Inorg.
Chem. 2002, 41, 6802.
(11) (a) Tsukube, H.; Shinoda, S. Chem. ReV. 2002, 102, 2389. (b)
Tsukube, H.; Shinoda, S.; Tamiaki, H. Coord. Chem. ReV. 2002, 226, 227.
(c) Marks, T. J.; Ernst, R. D. In ComprehensiVe Organometallic Chemistry;
Wilkinson, G., Stone, F. G., Abel, A. E. W., Eds.; Pergamon Press: Oxford,
UK, 1982; Vol. 3, pp 173-270. (d) Evans, W. J. AdV. Organomet. Chem.
1985, 24, 77. (e) Chen, Y. L.; Li, X. S.; Zhang, H.; Ou, Y. M. J. Rare
Earth 2004, 25, 87.
4492
Org. Lett., Vol. 9, No. 22, 2007

extend this method to application for the intramolecular
C-acylation. Treatment of 4 with 5 mol % of SmCl3 afforded
the intramolecular acylation product 5 in 86% yield (Scheme
2).
Table 2. SmCl3-Catalyzed Acylation of Various
1,3-Dicarbonyl Compoundsa
Scheme 2. SmCl3-Catalyzed Cyclization of
2-(3-Oxo-3-phenylpropanoyl)benzoyl Chloride
Next, we set out to study the scope and limitation of the
electrophilic coupling partner in more detail. As shown in
Table 2, a number of different acid chlorides have been
reacted with 1,3-dicarbony1 compounds. 4-Chlorophenyl acid
chloride 1b reacted comparably to 2a-c providing the
desirable products in 81-87% yields (Table 2, entries 9-11).
The aromatic acid chloride 1c, which has an electron-
withdrawing substituent at the para-position, reacted more
quickly and the triketone 3cc was obtained in 88% yield
(Table 2, entry 12). However, the aromatic acid chloride 1e,
bearing an electron-donating substituent at the para-position,
reacted sluggishly and gave the corresponding triketone 3ea
in 72% yield (Table 2, entry 16). A nitro substituent in the
meta-position of the aryl acid chloride 1d had only a slight
influence on the reactivity, as compared to the p-nitrophenyl
acid chloride 1c (Table 2, entries 12 and 13). Furthermore,
we examined the reactions of aliphatic acid chlorides like
2-phenyl acetyl chloride 1f. The reactions of 1f with 2b and
2c proceeded smoothly to give 3fb and 3fc, respectively, in
moderate yields (Table 2, entries 18 and 19). Importantly,
this protocol can tolerate heteroatoms as found in isonico-
tinoyl chloride (Table 2, entry 20).
The development of new methods for the efficient and
selective preparation of highly substituted coumarins is of
great interest in organic chemistry because of the frequent
existence of such structures in biologically active compounds
and their role as valuable synthetic intermediates for
potentially new pharmaceuticals.12 Encouraged by the above
results, we subsequently explored the reaction of 4-hydroxy-
coumarin (2i) with 1a. However, only the O-acylation rather
than C-acylation product (3ai) was obtained in 85% yield
(Scheme 3).
a Conditions: acyl choloride (1.1 mmol), 1,3-dicarbonyl compound (1.0
mmol), SmCl3 (5 mol %), toluene (4 mL), Et3N (1.2 mmol), rt. b Isolated
yield. c 10 mol % of SmCl3. d 10 mol % of SmCl3.
acylation (Table 2, entries 4, 7, and 8). To our delight
sterically hindered 2-substituted 1,3-dicarbonyl compounds
can be acylated to a reasonable extent in the presence of
SmCl3 (Table 2, entries 5, 7, and 8). It is noted that diethyl
malonate 2a, which has a low acidity, also displayed high
reactivity and reacted quickly with 1a and 1e to give the
desired products in 80% and 72% yields, respectively (Table
2, entries 1 and 16), despite the need to extend the reaction
time to 4 h, and using a higher catalyst loading of 10 mol %
to increase the yield.
Scheme 3. SmCl3-Catalyzed C-Acylation of
4-Hydroxycoumarins with Benzoyl Chloride
To the best of our knowledge, this is the first acylation of
1,3-dicarbonyl compounds promoted by a catalytic amount
of Lewis acids. These successful results encouraged us to
Org. Lett., Vol. 9, No. 22, 2007
4493

Until now, no example of the Lewis acid-catalyzed
coupling of malononitrile with acid chlorides has been
reported. After having established that SmCl3 is an efficient
catalyst for the inter- and intramolecular acylations of 1,3-
dicarbonyl compounds, we were keen to explore the reaction
of malononitrile with benzoyl chloride. SmCl3 indeed led to
the desired product 7 in good yield (Scheme 4), indicating
yields. This provides a mild and straightforward route to
pyrazole-4-carboxylate derivatives (Scheme 5).
Scheme 5. SmCl3-Catalyzed One-Pot Synthesis of
Pyrazole-4-carboxylate
Scheme 4. SmCl3-Catalyzed Acylation of Malononitrile with
Benzoyl Chloride
Finally, we checked the reusability of the SmCl3 catalyst
in the reaction of 8.8 mmo ofl 1a with 8 mmo of l 2c in
toluene at room temperature. After the first experiment, the
insoluble catalyst was readily recovered by filtrating the
reaction mixture and then removing amine salt washed by
acetonitrile for the next use. The results of seven runs showed
that the recovered catalyst retains its activity in terms of
yields (86%, 82%, 83%, 85%, 84%, 85%, and 82%,
respectively) and rates.
In summary, a general and highly efficient LnCl3-catalyzed
intra- and intermolecular C-acylation of 1,3-dicarbonyl
compounds and malononitrile with acid chlorides has been
developed. This method provides significant advantages in
cost, tolerance of functional groups, and simplicity of
operation by obviating the use of strong bases and stoichio-
metric amounts of Lewis acids. Furthermore, the present
catalyst is readily recovered and reused at least seven times
for such reaction without visible loss of catalytic activity.
Further investigations on the mechanism details and synthetic
applications of this method are underway in our lab.
that SmCl3 is also highly effective in the catalytic acylation
of malononitrile with acid chlorides as substrates.
Pyrazole-4-carboxylate derivatives possess important phar-
macological properties including analgesic, antipyretic, and
antiinflammatory properties.13 Several methods to synthesize
these compounds from 1,3-diketones have been reported in
the literature.14 However, they usually involve multistep
processes and give the products only in poor to moderate
yields. Having successfully developed an efficient acylation
of 1,3-dicarbonyl compounds with acid chlorides, we finally
turned our attention to the application of this method to the
one-pot synthesis of highly substituted pyrazole-4-carbox-
ylate building blocks, which can be further functionalized.
Treatment of 1,3-dicarbonyl compounds 2 with acid chlorides
1 in the presence of 5 mol % of SmCl3 and 1.2 equiv of
Et3N followed by reacting with hydrazine allowed the
isolation of multisubstituted pyrazoles 8-11 in 72-81%
(12) (a) Liao, Y. X.; Kuo, P. Y.; Yang, D. Y. Tetrahedron Lett. 2003,
44, 1599. (b) Mao, P. C. M.; Mouscadet, J. F.; Leh, H.; Auclair, C.; Hsu,
L. Y. Chem. Pharm. Bull. 2002, 50, 1634. (c) Staunton, J. In ComprehensiVe
Organic Chemistry; Sammes, P. G., Ed.; Pergamon: Oxford, UK, 1979;
Vol. 4.
Acknowledgment. We thank the National Natural Sci-
ence Foundation of China and the Natural Science Founda-
tion of Shanghai.
(13) Moro, S.; Varanob, F.; Cozzac, G.; Paganoc, M. A.; Zagottoa, G.;
Chilina, A.; Guiottoa, A.; Catarzib, D.; Calottab, V.; Pinnac, L. A.; Meggioc,
F. Lett. Drug. Des. DiscoVery 2006, 3, 281.
(14) (a) Morelli, C. F.; Saladino, A.; Speranza, G.; Manitto, P. Eur. J.
Org. Chem. 2005, 21, 4621. (b) Vanier, C.; Wagner, A.; Mioskowski, C. J.
Comb. Chem. 2004, 6, 846.
Supporting Information Available: Experimental details
and characterization of the compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL701961Z
4494
Org. Lett., Vol. 9, No. 22, 2007