Synthesis of 1,3,5-tricarbonyl derivatives by condensation of 1,3-bis(silyl enol ethers) with acid chlorides

Article abstract of DOI:10.1021/jo062153w

A variety of 1,3,5-tricarbonyl derivatives were prepared by reaction of 1,3-bis(silyl enol ethers) with acid chlorides under mild conditions. This includes reactions of both aromatic and aliphatic acid chlorides and bis(acid chlorides). The yields vary de

Full text of DOI:10.1021/jo062153w

Synthesis of 1,3,5-Tricarbonyl Derivatives by Condensation of
1,3-Bis(silyl enol ethers) with Acid Chlorides
Thomas Rahn,†,‡ Van T. H. Nguyen,† T. H. Tam Dang,†,‡ Zafar Ahmed,†,‡ Karen Methling,§
Michael Lalk,§ Christine Fischer,‡ Anke Spannenberg,‡ and Peter Langer*,†,‡
Institut fu¨r Chemie, UniVersita¨t Rostock, Albert-Einstein-Strasse 3a, 18059 Rostock, Germany,
Leibniz-Institut fu¨r Katalyse e. V. an der UniVersita¨t Rostock, Albert-Einstein-Strasse 29a,
18059 Rostock, Germany, and Institut fu¨r Pharmazie, UniVersita¨t Greifswald,
Friedrich-Ludwig-Jahn-Strasse 17, 17487 Greifswald, Germany
peter.langer@uni-rostock.de
ReceiVed October 17, 2006
A variety of 1,3,5-tricarbonyl derivatives were prepared by reaction of 1,3-bis(silyl enol ethers) with
acid chlorides under mild conditions. This includes reactions of both aromatic and aliphatic acid chlorides
and bis(acid chlorides). The yields vary depending on the type of acid chloride employed.
1,3,5-Tricarbonyl derivatives and their higher homologues
occur in a variety of pharmacologically important natural
products (polyketides) and represent important starting materials
for stereoselective syntheses of polyols.1 1,3-Dicarbonyl di-
anions2 represent versatile building blocks for the synthesis of
polyketides. In their pioneering work, Hauser3 and Weiler4
reported the reaction of 1,3-dicarbonyl dianions with esters and
nitriles. These reactions have been successfully applied to the
synthesis of pyran-2-ones.5 However, reactions of dianions with
esters may suffer from proton transfer and O-acylation. In
addition, the preparative scope is limited to substrates which
tolerate the presence of strong nucleophiles and bases. The
reaction of 1,3-dicarbonyl dianions with acid chlorides has been
reported to give complex mixtures.4 In contrast, the condensation
of dianions with N-acyl-2-methylaziridines6 and Weinreb amides7
proved to be very efficient. Harris and co-workers developed
elegant biomimetic syntheses of 1,3,5-tricarbonyl compounds,
1,3,5,7-tetracarbonyl compounds, and higher homologues by
condensation of 1,3-dicarbonyl dianions or 1,3,5-tricarbonyl
trianions with esters and diesters, Weinreb amides, and salts of
â-keto esters.8 Yamaguchi et al. reported the condensation of
1,3-dicarbonyl dianions with ethyl chloroacetate and other
acylating agents.9 3,5-Diketo esters have been prepared also by
other methodssfor example, methyl 3,5-dioxohexanoate is
available by ring-opening of 3-acetyl-4-hydroxy-6-methylpyran-
2-one10sand have found various applications in organic syn-
thesis.11
* To whom correspondence should be addressed. Fax: +381 4986412.
† Institut fu¨r Chemie, Universita¨t Rostock.
(6) Lygo, B. Tetrahedron 1995, 51, 12859.
‡ Leibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock.
§ Institut fu¨r Pharmazie, Universita¨t Greifswald.
(7) Hanamoto, T.; Hiyama, T. Tetrahedron Lett. 1988, 29, 6467.
(8) For a review, see: (a) Harris, T. M.; Harris, C. M. Tetrahedron 1977,
33, 2159. See also: (b) Murray, T. P.; Harris, T. M. J. Am. Chem. Soc.
1972, 94, 8253. (c) Harris, C. M.; Roberson, J. S.; Harris, T. M. J. Am.
Chem. Soc. 1976, 98, 5380; (d) Harris, T. M.; Hay, J. V. J. Am. Chem.
Soc. 1977, 99, 1631. (e) Hubbard, J. S.; Harris, T. M. Tetrahedron Lett.
1978, 47, 4601. (f) Sandifer, R. M.; Bhattacharya, A. K.; Harris, T. M. J.
Org. Chem. 1981, 46, 2260. (g) Gilbreath, S. G.; Harris, C. M.; Harris, T.
M. J. Am. Chem. Soc. 1988, 110, 6172.
(9) Yamaguchi, M.; Shibato, K. Tetrahedron 1988, 44, 4767.
(10) Crombie, L.; Games, D. E.; James, A. W. G. J. Chem. Soc., Perkin
Trans. 1 1996, 2715.
(11) For ethyl 3,5-dioxohexanoate, see: (a) Barrett, A. G. M.; Carr, R.
A. E.; Finch, M. A. W.; Florent, J.-C.; Richardson, G.; Walshe, N. D. A.
J. Org. Chem. 1986, 51, 4254. (b) Barrett, A. G. M.; Morris, T. M.; Barton,
D. H. R. J. Chem. Soc., Perkin Trans. 1 1980, 2272. For 5-aryl-3,5-
dioxopentanoates, see: (c) Narasimhan, N. S.; Ammanamanchi, R. K. J.
Org. Chem. 1983, 48, 3945; see also ref 5.
(1) (a) Staunton, J.; Weissman, K. J. Nat. Prod. Rep. 2001, 18, 380. (b)
Koskinen, A. M. P.; Karisalmi, K. Chem. Soc. ReV. 2005, 34, 677. (c)
Fugmann, B. (Hrsg.) Ro¨mpp-Lexikon Naturstoffe; Georg Thieme Verlag:
Stuttgart, New York, 1997.
(2) Reviews of dianions: (a) Kaiser, E. M.; Petty, J. D.; Knutson, P. L.
A. Synthesis 1977, 509. (b) Thompson, C. M.; Green, D. Tetrahedron 1991,
47, 4223. (c) Thompson, C. M. Dianion chemistry in organic synthesis;
CRC Press: Boca Raton, 1994. (d) Langer, P.; Freiberg, W. Chem. ReV.
2004, 104, 4125.
(3) Harris, T. M.; Boatman, S.; Hauser, C. R. J. Am. Chem. Soc. 1965,
87, 3186.
(4) Huckin, S. N.; Weiler, L. Can. J. Chem. 1974, 52, 1343.
(5) Douglas, C. J.; Sklenicka, H. M.; Shen, H. C.; Mathias, D. S.;
Degen, S. J.; Golding, G. M.; Morgan, C. D.; Shih, R. A.; Mu¨ller, K.
L.; Seurer, L. M.; Johnson, E. W.; Hsung, R. P. Tetrahedron 1999, 55,
13683.
10.1021/jo062153w CCC: $37.00 © 2007 American Chemical Society
Published on Web 02/08/2007
J. Org. Chem. 2007, 72, 1957-1961
1957

Rahn et al.
SCHEME 1. Reaction of 1,3-Bis(silyl enol ethers) with Acid
Chloridesa
1,3-Bis(silyl enol ethers) can be regarded as electroneutral
equivalents of 1,3-dicarbonyl dianions (masked dianions).12,13
Reactions of 1,3-bis(silyl enol ethers) with acid chlorides have
been reported. Chan and co-workers reported the synthesis of
methyl 3,5-dioxohexanoate by reaction of 1-methoxy-1,3-bis-
(trimethylsiloxy)-1,3-butadiene with acetyl chloride.14 Chan and
Chaly reported15 the [3 + 3] cyclization of a 1,3-bis(silyl enol
ether) with a protected 3-oxooctanoyl chloride. The TiCl4-
mediated reaction of a 1,3,5-tris(silyl enol ether) with acid
chlorides and imidazolides resulted in the formation of salicy-
lates by attack of the triene onto the acid derivative and
subsequent Mukaiyama aldol reaction ([5 + 1] cyclization).16
We reported the synthesis of 3(2H)-furanones by condensation
of 1,3-bis(silyl enol ethers) with chloroacetyl chloride and
subsequent cyclization.17 γ-Alkylidenebutenolides are available
by cyclization of 1,3-bis(silyl enol ethers) with oxalyl chlo-
ride18,19 or phthaloyl chloride.20 Recently, we reported the
synthesis of 1,3,5-tricarbonyl compounds by condensation of
1,3-bis(silyl enol ethers) with acid chlorides.21 Herein, we report
full details of these reactions which proceed under mild
conditions. With regard to our preliminary communication,21
the preparative scope was considerably extended. Notably, a
number of products are not directly available from the corre-
sponding 1,3-dicarbonyl dianions, due to competing side reac-
tions of the highly reactive dianions (metal-halide exchange,
competing nucleophilic attack, ring opening, etc.).
a Key: (i) (1) CH2Cl2, -78 f +20 °C, 8-12 h, (2) NaHCO3 (saturated
aqueous solution).
TABLE 1. Synthesis of 1,3,5-Tricarbonyl Compounds 3a-aa
keto/enol
ratio
1
2
3
R1
R2
2-ClC6H4
yielda (%)
a
a
a
a
a
a
a
a
a
a
a
b
a
a
a
a
a
a
a
a
a
a
b
a
b
c
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
0:100
0:100
0:100
14:86
0:100
29:71
20:80
9:91
0:100
0:100
0:100
0:100
0:100
0:100
13:87
11:89
0:100
13:87
0:100
17:83
17:83
17:83
20:80
29:71
33:67
33:67
40:60
59
48
54
45
74
6
2-MeC6H4
4-ClC6H4
2-(MeO)C6H4
4-(ClCH2)C6H4
2,6-(MeO)2C6H3
2,4-(MeO)2C6H3
3,4,5-(MeO)3C6H2
4-(O2N)C6H4
C6F5
2-IC6H4
Ph
1-Naph
2-Naph
PhCH2
(Ph)2CH
1-Ad
H2CdCH(CH2)8
t-Bu
MeOCH2
c-Pr
n-Pr
Et
Me
Me
Me
24
68
65
55
87
66
40
62
87
78
17
67
40
41
91
69
48
34
40
32
50
Results and Discussion
Optimal yields for the reaction of 1,3-bis(silyl enol ethers)
with acid chlorides were obtained in the absence of any Lewis
acid; notably, the use of Me3SiOTf resulted in decomposition.
In addition, the stoichiometry played an important role: the
reactions were carried out using 1.0 equiv of the 1,3-bis(silyl
enol ethers) and 1.5 equiv of the acid chloride. The yields
decreased when 2.0 equiv of the 1,3-bis(silyl enol ethers) and
1.0 equiv. of the acid chloride were employed. The temperature
(-78 f +20 °C), the addition procedure (the acid chloride was
slowly added to a CH2Cl2 solution of the silyl enol ether), and
the workup procedure (use of an aqueous solution of NaHCO3)
also played an important role.
s
t
s
t
u
v
w
x
x
x
x
u
v
w
x
y
z
Me
Et
i-Bu
d
aa (CH2)2OMe Me
a Yields of isolated products.
The reaction of 1,3-bis(silyl enol ethers) 1a and 1b, prepared
from the respective acetoacetates, with various aromatic acid
chlorides afforded the 5-aryl-3,5-dioxopentanoates 3a-n (Scheme
1, Table 1). The condensation of 1a with phenylacetyl chloride
and 1,1-diphenylacetyl chloride afforded the 6-aryl-3,5-dioxo-
hexanoates 3o,p. The reaction of 1a and 1b with a variety of
aliphatic acid chlorides gave the 3,5-dioxoalkanoates 3q-y. The
methoxyethyl and isobutyl 3,5-dioxohexanoates 3z and 3aa were
prepared from 1,3-bis(silyl enol ethers) 1c,d and acetyl chloride.
Surprisingly, all attempts to prepare 3,5-dioxoalkanoates from
4-alkyl-1,3-bis(silyl enol ethers) failed, presumably for steric
reasons. Notably, functionalized 3,5-dioxoalkanoates 3e,i-k are
not directly available from the corresponding 1,3-dicarbonyl
dianions due to formation of complex mixtures. In fact, reactions
of dianions are often limited by competing side reactions, such
as metal-halide exchange, SET processes, elimination, or
polymerization.22 It was previously noted that reactions of
(12) For a review of 1,3-bis(silyl enol ethers), see: Langer, P. Synthesis
2002, 441.
(13) For a review of formal [3 + 3] cyclizations of 1,3-bis(silyl enol
ethers), see: Feist, H.; Langer, P. Synthesis 2007, 327.
(14) Chan, T.-H.; Brownbridge, P. J. Chem. Soc., Chem. Commun. 1979,
578.
(15) Chan, T. H.; Chaly, T. Tetrahedron Lett. 1982, 23, 2935.
(16) (a) Chan, T.-H.; Sto¨ssel, D. J. Org. Chem. 1988, 53, 4901. (b) Chan,
T.-H.; Sto¨ssel, D. J. Org. Chem. 1986, 51, 2423.
(17) Langer, P.; Krummel, T. Chem.sEur. J. 2001, 7, 1720.
(18) (a) Langer, P.; Schneider, T.; Stoll, M. Chem.sEur. J. 2000, 6,
3204. (b) Langer, P.; Eckardt, T.; Schneider, T.; Go¨bel, C.; Herbst-Irmer,
R. J. Org. Chem. 2001, 66, 2222. (c) Ahmed, Z.; Langer, P. J. Org. Chem.
2004, 69, 3753.
(19) For a review of cyclizations of silyl enol ethers with oxalyl chloride,
see: Langer, P. Synlett 2006, 3369.
(20) Albrecht, U.; Nguyen, V. T. H.; Langer, P. Synthesis 2006, 1111.
(21) Reim, S.; Nguyen, V. T. H.; Albrecht, U.; Langer, P. Tetrahedron
Lett. 2005, 46, 8423.
(22) (a) Maercker, A. Methoden Org. Chem. (Houben-Weyl) 4. Aufl.,
Bd. E19d, 1993, 448. (b) Saalfrank, R. W. Methoden Org. Chem. (Houben-
Weyl) 4. Aufl., Bd. E19d, 1993, 567. (c) Thompson, C. M.; Green, D.
Tetrahedron 1991, 47, 4223. (d) Kaiser, E. M.; Petty, J. D.; Knutson, P. L.
A. Synthesis 1977, 509. (e) Bates, R. B.; Buncel, E.; Durst, T. Dianions
and Polyanions, ComprehensiVe Carbanion Chemistry; Elsevier: Amster-
dam, 1980; Part A, pp 1-53. (f) Petragnani, N.; Yonashiro, M. Synthesis
1982, 521. (g) Schleyer, P. v. R. Pure Appl. Chem. 1983, 55, 355. (h)
Thompson, C. M. Dianion chemistry in organic synthesis; CRC Press: Boca
Raton, 1994.
1958 J. Org. Chem., Vol. 72, No. 6, 2007

Synthesis of 1,3,5-Tricarbonyl DeriVatiVes
SCHEME 2. Acylation of 1,3-Bis(silyl enol ethers) 1e,fa
SCHEME 3. Synthesis of 6aa
a Key: (i) (1) CH2Cl2, -78 f +20 °C, (2) NaHCO3 (saturated aqueous
solution).
TABLE 2. Synthesis of Triacylmethanes 4a,b
1
4
R1
yielda (%)
a Key: (i) (1) CH2Cl2, -78 f +20 °C, (2) NaHCO3 (saturated aqueous
solution).
e
f
a
b
Me
Ph
28
36
SCHEME 4. Synthesis of 6b and 6ca
a Yields of isolated products.
dilithiated arylacetonitriles and oximes were not compatible with
the presence of bromo- or nitroaryl groups in the substrates.23,24
The yields of compounds 3a-aa vary from excellent to poor,
depending on the type of acid chloride. Low yields were
obtained for products 3f and 3q, which are derived from
sterically hindered acid chlorides. On the other hand, the reaction
of 1a with sterically hindered pivaloyl chloride afforded 3s in
40% yield. There seems to be a trend toward poorer yields for
more electron-rich (and thus less reactive) acid chlorides (used
for the synthesis of 3d,f,g).
All products were characterized by spectroscopic methods
and exist (in CDCl3 solution) as mixtures of keto/enol tautomers
or exclusively as enol tautomers. Most of the 5-aryl-3,5-
dioxopentanoates exclusively exist in their enol tautomeric form.
This can be explained by conjugation of the enolic double bond
with the arene moiety. In case of 2d,f,g, all containing an
o-methoxy group, some amount of keto tautomer could be
detected. This might be explained by orthogonal twisting of the
arene moiety (due to steric reasons) which results in a decreased
extent of conjugation.
1,3-Bis(silyl enol ethers) 1e and 1f are available from
acetylacetone and benzoylacetone, respectively. Unexpectedly,
the reaction of 1e and 1f with benzoyl chloride (2l) resulted in
acylation of the central rather than the terminal carbon atom of
the 1,3-bis(silyl enol ether) to give products 4a and 4b,
respectively (Scheme 2, Table 2). The yields are relatively low,
due to substantial losses of material during chromatographic
purification. The formation of the regioisomer, which was
formed by attack of the terminal carbon atom of the bis(silyl
enol ether) onto the acid chloride, was not observed. A related
unusual regiochemical behavior was recently observed for the
reaction of 1e and 1f with phthaloyl dichloride.18 On the other
hand, the reactions of 1e and 1f with oxalyl chloride, 1,1-
dimethoxy-2-azidoethane, and 1-chloro-2,2-dimethoxyethane
take a regular path and proceed by attack of the terminal carbon
atom of the 1,3-bis(silyl enol ether) onto the electrophile. The
reaction of 1e and 1f with chloroacetyl chloride proved to be
unsuccessful.17 The formation of 4a,b can be explained by the
lower reactivity of 1e,f compared to â-ketoester-derived 1,3-
bis(silyl enol ethers) which are more electron rich, due to the
influence of the π-donating effect of the ester alkoxy group.
The regioselectivity of 1e,f strongly depends on the type of
electrophile employed. The configurations of the double bonds
of 1,3-bis(silyl enol ethers) are, in many cases, known and vary
depending on the substituents.25 On the basis of the literature,
a Key: (i) (1) CH2Cl2, -78 f +20 °C, (2) NaHCO3 (saturated aqueous
solution).
a relationship between configuration and regioselectivity would
not be expected and is indeed not seen.
The reaction of 1,3-bis(silyl enol ether) 1a with 1,4-ben-
zenedicarboxylic dichloride (5a) proceeded with 2:1 stoich-
iometry and afforded condensation product 6a in 50% yield
(Scheme 3). The structure of 6a was independently confirmed
by crystal structure analysis (see the Supporting Information).
It completely exists in the enol tautomeric form (both in a CDCl3
solution and in the solid state). The reaction of 1a with 1,3-
benzenedicarboxylic dichloride (5b) afforded 6b, which also
completely exists in its enol tautomeric form (Scheme 4).
Pyridine derivative 6c was prepared from 1,3-pyridinedicar-
boxylic dichloride (5c). Recently, we reported20 the synthesis
of benzo-annulated γ-(2,4-dioxobut-1-ylidene)butenolide 6d by
reaction of 1,3-bis(silyl enol ether) 1b with phthaloyl dichloride
(5d) (Scheme 5). The formation of 6d can be explained by
formation of isophthaloyl dichloride and subsequent attack of
the terminal carbon atom of 1b onto the dichloride moiety. The
reaction of 1,3-bis(silyl enol ether) 1e with 1,3-benzenedicar-
boxylic dichloride (5b) afforded 6e by acylation of the central
rather than the terminal carbon atom of the 1,3-bis(silyl enol
ether) (Scheme 6). As noted above, a related unusual regio-
chemical behavior was previously observed for the reaction of
1e and 1f with phthaloyl dichloride (5d).20
The reaction of 1,3-bis(silyl enol ether) 1a with bis(acid
chlorides) 7a-c afforded the tetraoxodioates 8a-c which mainly
(23) Langer, P.; Anders, J. T.; Ja¨hnchen, J.; Weisz, K. Chem.sEur. J.
2003, 9, 3951.
(24) Dang, T. T.; Albrecht, U.; Langer, P. Synthesis 2006, 2515.
(25) (a) Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980, 102,
3534. (b) Brownbridge, P.; Chan, T.-H.; Brook, M. A.; Kang, G. J. Can. J.
Chem. 1983, 61, 688. (c) Molander, G. A.; Cameron, K. O. J. Am. Chem.
Soc. 1993, 115, 830. (d) Hagiwara, H.; Kimura, K.; Uda, H. J. Chem. Soc.,
Chem. Commun. 1986, 860. (e) Cameron, D. W.; Feutrill, G. I.; Perlmutter,
P. Aust. J. Chem. 1982, 35, 1469. (f) Kra¨geloh, K.; Simchen, G. Synthesis
1981, 30.
J. Org. Chem, Vol. 72, No. 6, 2007 1959

Rahn et al.
TABLE 3. Antibacterial Properties of Selected Compoundsa
B. subtilis
E. coli
C. maltosa
S. aureus
P. aeruginosa
3
ATCC 6051
ATCC 11229
ATCC 200
ATCC 6538
ATCC 27853
a
b
c
d
e
f
10
14
17
r
12
r
10
16
19
r
12
r
12
20
22
r
14
r
10
R
14
r
11
r
r
r
r
r
r
r
g
h
i
r
r
r
r
r
r
r
r
r
r
r
r
r
r
r
j
14
33
n.t.
10
25
n.t.
r
n.t.
35
14
35
n.t.
r
20
n.t.
ampicillin
gentamicin
a Key: diameter of inhibition zones in mm; including test plate 6 mm, all test plates were soaked with 0.1 µmol of test substance; r ) resistant; n.t. )
not tested.
SCHEME 5. Reaction of 1,3-Bis(silyl enol ether) 1b with
Phthaloyl Dichloridea
bacteria Bacillus subtilis and Staphylococcus aureus. Growth
inhibition was observed also for the Gram-negative bacteria
Escherichia coli and for the yeast Candida maltosa. However,
no growth inhibition was observed for the Gram-negative
bacteria Pseudomonas aeruginosa. The results of the screenings
are summarized in Table 3. The antimicrobial activity of the
test compounds was only moderate (compared to ampicillin and
gentamicin which are antibiotics in clinical use and were
included for reasons of comparison). In our tests, similar
concentrations of compounds 3, ampicillin, and gentamicin were
applied. The activity clearly depends on the substitution pattern
of the aromatic residue R1. The presence of halide substituents
improved the activity (compounds 3a, 3c, and 3e). The presence
of methoxy groups attached to the arene moiety completely
removed any activity. This observation is in agreement with
our previous work (using a different type of molecule) and may
depend on the mode of action of the tested compounds.26 The
level of antibiotic activity is below the activity of common
antibiotics.
a Key: (i) CH2Cl2, -78 f 20 °C (ref 20).
SCHEME 6. Synthesis of 6ea
Conclusions
a Key: (i) (1) CH2Cl2, -78 f +20 °C, (2) NaHCO3 (saturated aqueous
solution).
In conclusion, we have reported the condensation of 1,3-bis-
(silyl enol ethers) with acid chlorides. These reactions allow
for a convenient synthetic approach to a variety of 1,3,5-
tricarbonyl compounds under mild conditions. The best results
were obtained for reactions of 1,3-bis(silyl enol ethers) derived
from methyl acetoacetate. The use of 1,3-diketone-derived 1,3-
bis(silyl enol ethers) resulted in functionalization of the central
rather than the terminal carbon atom of the bis(silyl enol ethers).
A variety of acid chlorides were successfully employed which
include aromatic, aliphatic, and difunctional substrates. The
yields vary depending on the type of acid chloride employed.
SCHEME 7. Reaction of 1,3-Bis(silyl enol ether) 1a with
Bis(acid chlorides) 7a-ca
Experimental Section
General Procedure A for Synthesis of 3,5-Dioxoalkanoates
3a-k,m-v,x, 6a-c, and 8a-c. To a CH2Cl2 solution of 1,3-bis-
(silyl enol ether) 1 (1.0 equiv) was slowly added the acid chloride
2 (1.5 equiv) at -78 °C. The reaction mixture was slowly warmed
to 20 °C during 6 h, and the solution was stirred at 20 °C for a
further 6-8 h. To the solution was added a saturated aqueous
solution of NaHCO3 (50 mL). The organic layer and the aqueous
layer were separated, and the latter was extracted with CH2Cl2 (3
a Key: (i) (1) CH2Cl2, -78 f +20 °C, 8-12 h; (2) NaHCO3 (saturated
aqueous solution).
exist in their enol tautomeric form (Scheme 7). Notably, the
reactions of 1a with the dichlorides of malonic and succinic
acid were unsuccessful and resulted in the formation of complex
mixtures.
Biological Evaluation. A number of 3,5-dioxoalkanoates 3
were tested for their antibiotic properties. Some of the tested
compounds showed antibiotic activity against the Gram-positive
(26) (a) Albrecht, U.; Lalk, M.; Langer, P. Biorg. Med. Chem. 2005, 13,
1531. (b) Albrecht, U.; Go¨rdes, D.; Schmidt, E.; Thurow, K.; Lalk, M.;
Langer, P. Biorg. Med. Chem. 2005, 13, 4402.
1960 J. Org. Chem., Vol. 72, No. 6, 2007

Synthesis of 1,3,5-Tricarbonyl DeriVatiVes
× 20 mL). The combined organic layers were dried (Na2SO4) and
filtered, and the filtrate was concentrated in vacuo. The residue
was purified by column chromatography (silica gel, n-heptane/
EtOAc ) 10:1) to give the respective products.
General Procedure B for the Synthesis of 3,5-Dioxoalkanoates
3l,w,y-aa and 6e. To a CH2Cl2 solution of 1,3-bis(silyl enol ether)
1 (1.0 equiv) was slowly added the acid chloride 2 (1.5 equiv) at
-78 °C. The reaction mixture was slowly warmed to 20 °C during
8-12 h. To the solution was added a saturated aqueous solution of
NaHCO3. The organic and the aqueous layer were separated, and
the latter was extracted with CH2Cl2 (3 × 100 mL). The combined
organic layers were dried (Na2SO4) and filtered, and the filtrate
was concentrated in vacuo. The residue was purified by column
chromatography (silica gel, n-hexane/EtOAc).
1438 (s), 1402 (s), 1338 (s), 1275 (br, s), 1185 (m), 1141 (s), 1121
(s), 1082 (s), 1016 (m), 1004 (s), 949 (m), 897 (m), 873 (m), 858
(w), 834 (m), 816 (s), 782 (m). MS (EI, 70 eV): m/z ) 362 (M+,
11), 330 (14), 289 (29), 271 (13), 257 (15), 247 (42), 215 (44),
173 (100), 147 (12), 69 (22). HRMS (EI, 70 eV): calcd for
C18H18O8 (M+) 362.0996, found 362.0984.
Dimethyl 3,5,9,11-Tetraoxotridecanedioate (8a). Following
procedure A and starting with 7a (0.47 g, 2.40 mmol) and 1a (2.50
g, 9.60 mmol), dissolved in CH2Cl2 (8 mL), 8a was isolated as a
yellow oil (0.49 g, 57%). 1H NMR (300 MHz, CDCl3, keto/enol )
25:75): (keto) δ ) 1.35 (m, 6H, CH2), 2.52 (t,3J ) 5.5 Hz, 4H,
COCH2CH2), 3.56 (s, 4H, COCH2CO), 3.71 (s, 4H, CH2), 3.72 (s,
6H, CH3); (enol) 1.61 (m, 6H, CH2), 2.30 (t,3J ) 5.5 Hz, 4H,
COCH2CH2), 3.34 (s, 4H, COCH2CO), 3.73 (s, 6H, CH3), 5.58 (s,
2H, CH), 15.10 (s, 2H, OH). 13C NMR (75 MHz, CDCl3): enol:
δ ) 25.5, 28.9, 37.9, 45.2, 52.8, 100.2, 168.3, 187.3, 193.4. IR
(neat, cm-1): ν˜ ) 3466 (w), 2953 (m), 2863 (w), 1743 (s), 1616
(s), 1559 (m), 1541 (w), 1507 (w), 1437 (m), 1409 (w), 1329 (m),
1263 (s), 1202 (m), 1156 (m), 1016 (m), 920 (m), 777 (w). MS
(EI, 70 eV): m/z ) 356 (M+, 4), 293 (41), 292 (15), 223 (38),
222(24), 209 (27), 199 (44), 180 (21), 171 (21) 167 (48), 163 (23),
158 (81), 143 (95), 139 (100), 126 (80), 125 (62), 121 (24), 116
(22), 111 (50), 101 (98), 97 (49), 84 (40), 69 (97). Anal. Calcd for
C17H24O8 (356.37): C, 57.30; H, 6.79. Found: C, 57.30; H, 6.66.
Biological Studies. Bacterial cultures were obtained from the
ATCC (American Type Culture Collection, 10801 University Blvd.,
Manassas, VA 20110-2209).
Assay for Antimicrobial and Antifungal Activity. A modified
disk diffusion method was used to determine the antimicrobial
activity of the compounds. Nutrient agar was used for bacteria and
malt agar for C. maltosa. A sterile filter disk of 6 mm (B&D
research) diameter impregnated with test compound was used for
the assay. The paper disk was placed on the agar plate seeded with
the respective microorganisms. The plates were kept in the
refrigerator at 4 °C for 4 h. Then the plates were turned over to
incubate overnight at 37 °C in an inverted position. In contrast, C.
maltosa was incubated at 28 °C for 72 h. At the end of the
incubation period, the clear zones of inhibition around the paper
disk were measured. Negative control experiments were performed
by using paper disks loaded with an equivalent volume of solvent,
and positive control experiments were performed by use of an
equivalent amount of ampicillin, and gentamicin in case of C.
maltosa. The amount of substance of the compounds tested during
the experiments was 1000 nmol per paper disk.
Methyl 5-(o-Chlorophenyl)-3,5-dioxopentanoate (3a). Follow-
ing procedure A and starting with 2a (1.01 g, 5.76 mmol) and 1a
(3.00 g, 11.52 mmol), dissolved in CH2Cl2 (10 mL), 3a was isolated
1
as a yellow oil (0.86 g, 59%). H NMR (300 MHz, CDCl3, keto/
enol ) 0:100): δ ) 3.31 (s, 2H, CH2), 3.59 (s, 3H, OCH3), 6.02
(s, 1H, CH), 7.13 - 7.28 (m, 3H, Ar), 7.43 (dd, 3J ) 7.4 Hz, 4J )
1.9 Hz, 1H, Ar), 15.19 (s, 1H, OH). 13C NMR (75 MHz, CDCl3):
δ ) 45.7, 52.9, 102.4, 127.3, 130.5, 131.1, 132.3, 132.3, 134.8,
168.1, 183.6, 188.6. IR (neat, cm-1): ν˜ ) 2954 (w), 1744 (s), 1605
(s), 1472 (m), 1437 (s), 1264 (br, s), 1160 (m), 1098 (m) 1045
(m), 1015 (m), 954 (w), 766 (m), 743 (m). MS (EI, 70 eV): m/z )
256 (M+, 37Cl, 1), 254 (M+, 35Cl, 4), 222 (19), 220 (43), 219 (99),
194 (21), 187 (80), 183 (39), 181 (89), 141 (76) 139 (100), 131
(11), 113 (18), 111 (65), 101 (22), 89 (16), 77 (12), 75 (31), 69
(71). Anal. Calcd for C12H11ClO4 (254.67): C, 56.59; H, 4.35.
Found: C, 56.30; H, 4.31.
Ethyl 5-Phenyl-3,5-dioxopentanoate (3l). Following procedure
B and starting with 1b (6.0 mmol, 1.646 g) and benzoyl chloride
(7.2 mmol, 0.807 g), dissolved in 15 mL of CH2Cl2, 3l was isolated
by column chromatography (n-hexane/EtOAc ) 20:1 f 10:1 f
1
5:1) as a yellow oil (0.920 g, 66%). H NMR (300 MHz, CDCl3,
keto/enol ) 0:100): δ ) 1.28 (t, J ) 7.2 Hz, 3 H, OCH2CH3),
3.48 (s, 2 H, CH2), 4.24 (q, J ) 7.1 Hz, 2 H, OCH2CH3), 6.29 (s,
1 H, CH), 7.43-7.56 (m, 3 H, Ar), 7.87-7.89 (m, 1 H, Ar), 15.79
(s, 1 H, OH). 13C NMR (75 MHz, CDCl3): δ ) 14.0, 45.8, 61.4,
96.7, 127.0, 128.6, 132.6, 134.0, 167.5, 182.5, 189.2. MS (EI, 70
eV): m/z ) 234 (M+, 0.4), 160 (1), 146.5 (2), 105 (3), 85 (2), 58
(3), 32 (25), 28 (100). IR (KBr, cm-1): ν˜ ) 2984 (m), 1739 (s),
1607 (s), 1460 (m), 1268 (s), 1180 (m), 1150 (m), 1030 (m), 765
(m), 696 (m). UV-vis (CH3CN, nm): λmax (log ꢀ) ) 247.6 (3.73),
312.5 (4.12). Anal. Calcd for C13H14O4: C, 66.65; H, 6.02. Found:
C, 66.93; H, 6.65.
1,4-Bis(6-methoxy-2,4,6-trioxohex-1-yl)benzene (6a). Follow-
ing procedure A and starting with 5a (0.22 g, 1.10 mmol) and 1a
(1.15 g, 4.42 mmol), dissolved in CH2Cl2 (3 mL), 6a was isolated
as a yellow solid (0.20 g, 50%). Mp: 120-121 °C. 1H NMR (300
MHz, CDCl3, keto/enol ) 0:100): δ ) 3.53 (s, 2H, CH2), 3.79 (s,
3H, OCH3), 6.34 (s, 1H, CH), 7.95 (s, 2H, Ar), 15.60 (s, 1H, OH).
13C NMR (75 MHz, CDCl3): δ ) 45.3, 51.9, 96.8, 126.6, 136.8,
167.1, 179.5, 189.8. IR (KBr, cm-1): ν˜ ) 3447 (br, m), 3112 (m),
3023 (w), 2964 (w), 2938 (m), 1736 (s), 1618 (br, s), 1507 (s),
Acknowledgment. Financial support from the Ministry of
Education of Vietnam (scholarship for V.T.H.N.) and from the
state of Mecklenburg-Vorpommern (Landesgraduiertenstipen-
dium for Z.A.) is gratefully acknowledged.
Supporting Information Available: Data for the crystal
structure analysis, experimental procedures, spectroscopic data, and
copies of NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO062153W
J. Org. Chem, Vol. 72, No. 6, 2007 1961