Synthesis and characterization of permethylated 1,3,5-tri- and 1,3,5,7-tetracarbonyl compounds

Article abstract of DOI:10.1016/j.tet.2011.08.065

Permethylated 1,3,5-tri- and 1,3,5,7-tetracarbonyl compounds were prepared and structurally characterized. 2,2,4,4-Tetramethyl-3,5-dioxoesters were prepared by condensation of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with acid chlorides and subsequent re

Full text of DOI:10.1016/j.tet.2011.08.065

Tetrahedron 67 (2011) 8780e8789
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and characterization of permethylated 1,3,5-tri- and 1,3,5,7-
tetracarbonyl compounds
,
,
,
Silke Erfle a b, Thomas Rahn a b, Franziska Bendrath a, Wolfgang Baumann b, Dirk Michalik a b, Haijun Jiao b,
Anke Spannenberg , Armin Borner b, Peter Langer a
Institut fur Chemie, Universitat Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
b
a,
,b,
*
€
a
€
€
b
€
€
Leibniz-Institut fur Katalyse an der Universitat Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 July 2011
Received in revised form 22 August 2011
Accepted 23 August 2011
Available online 27 August 2011
Permethylated 1,3,5-tri- and 1,3,5,7-tetracarbonyl compounds were prepared and structurally character-
ized. 2,2,4,4-Tetramethyl-3,5-dioxoesters were prepared bycondensation of 1,3-bis(trimethylsilyloxy)-1,3-
butadienes with acid chlorides and subsequent reaction with methyl iodide. 2,2,4,4,6,6-Hexa-substituted
3,5-dioxopimelates were prepared by condensation of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with
methyl 3-chloro-3-oxopropanoate and subsequent methylation. The use of caesium carbonate as the base
for the methylation proved to be important to achieve good yields. The conformation of the products was
studied by experimental and theoretical methods (DFT calculations).
Keywords:
Tetracarbonyl compounds
Ketones
Ó 2011 Elsevier Ltd. All rights reserved.
Conformation
Polyketides
1. Introduction
detailed spectroscopic characterization of 3,5-dioxopimelates by
condensation of 1,3-bis(silyloxy)-1,3-butadienes with methyl 3-
1,3-Dicarbonyl compounds constitute one of the most important
building blocks in organic chemistry and have found widespread
applications. 1,3,5-Tricarbonyl compounds have also found several
applications in organic and medicinal chemistry. A great variety of
pharmacologically important natural products are biosynthetically
chloro-3-oxopropanoate.5 Cyclopropanated and peralkylated poly-
carbonyl compounds cannot undergo intramolecular aldol con-
densations because they lack CH-acidic methylene groups. Recently,
we have reported the synthesis of cyclopropanated 1,3,5-tricarbonyl
compounds based on a combination of Claisen condensations and
cyclopropanations.6
derived from poly(b
-oxo)carboxylic acids (polyketides).1 This in-
cludes various anticancer drugs and antibiotics, which are clinically
used.1 Polyketides and related 1,3-oligocarbonyl derivatives repre-
sent important synthetic building blocks (e.g., for the synthesis of
polyols by stereoselective reduction).2 1,3,5,7-Tetracarbonyl com-
pounds and their higher homologues are mostly unstable and rap-
idly undergo an intramolecular aldol condensation to give
polyhydroxylated arenes. Harris and co-workers reported the bio-
mimetic synthesis of various polyketides, which rapidly undergo
intramolecular aldol condensations, based on condensations of 1,3-
dicarbonyl dianions or 1,3,5-tricarbonyl trianions with carboxylic
acid derivatives.3 We have reported the synthesis of various 3,5-
dioxopentanoates based on condensation reactions of 1,3-
bis(silyloxy)-1,3-butadienes with acid chlorides.4 3,5-Dioxopime-
lates are stable 1,3,5,7-tetracarbonyl compounds containing two
terminal ester groups, which cannot undergo an intramolecular al-
dol condensation. Recently, we have reported the synthesis and first
The dialkylation of 1,3-dicarbonyl compounds is frequently
carried out in undergraduate student courses and often used in
organic synthesis.7 The first synthesis of a peralkylated 1,3,5-
tricarbonyl compound, i.e., diethyl 2,2,4,4-tetraethylacetonedi-
carboxylate, has been reported in 1891 by von Pechmann and
Dunschmann.8a Ried and co-workers reported the first synthesis of
€
dimethyl 2,2,4,4-tetramethylacetonedicarboxylate (A) by reaction
of dimethyl acetonedicarboxylate with methyl iodide in the pres-
ence of sodium methanolate (Fig. 1).8b However, all these products
were not characterized by spectroscopic methods. Despite their
structural simplicity and aesthetic attraction, peralkylated 1,3,5,7-
tetracarbonyl compounds, such as B (Fig. 1) have, to the best of
our knowledge, not been described in the literature so far.
Herein, we report the synthesis and characterization of a great
variety of permethylated 1,3,5-tricarbonyl- and 1,3,5,7-tetracarbonyl
compounds based on a new and convenient synthetic protocol. In
addition, we report studies related to the conformation of the
products by experimental and theoretical methods (DFT calcula-
tions). To our opinion, the molecules reported herein combine the
* Corresponding author. E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.08.065

S. Erfle et al. / Tetrahedron 67 (2011) 8780e8789
8781
out at elevated temperature (55 ꢀC, entry 2). A dramatic improve-
ment of the yield (57%) was observed when caesium carbonate
(Cs2CO3) instead of K2CO3 was employed (entry 4). While the
concentration had no major influence on the yield (entry 6), the
yield again dropped when the reaction was carried out at 55 in-
stead of 20 ꢀC (entry 5). The advantageous effect of the use of
Cs2CO3 might be explained by its higher basicity. The low yields in
case of K2CO3 can be explained by incomplete methylation and
decomposition under the reaction conditions.
A
O
O
O
Me
Me
Me
Me
MeO
OMe
B
O
O
O
O
Me
Me
Me
Me
Me
Me
Table 1
MeO
OMe
Optimization of the synthesis of 2a
Entry
c (1a) [M]
Base
T [ꢀC]
Yielda [%] (2a)
1
2
3
4
5
6
1.0
1.0
0.85
1.0
1.0
0.5
K2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
20
55
20
20
55
20
12
0
12
57
30
56
Fig. 1. Symmetrical permethylated diesters.
features of structural simplicity, aesthetic attraction, structural in-
terest and novelty and are, therefore, of fundamental chemical and
theoretical interest. In addition, polyketides are of interest as po-
tential anticancer drugs and antibiotics as outlined above.
a
Yields of isolated products.
The preparative scope was next studied (Scheme 1, Table 2). All
reactions were carried out following the optimized conditions
discussed above (Table 1, entry 4). The reaction of unsymmetrical
3,5-dioxopimelates 1beg afforded the desired 1,3,5,7-tetracarbonyl
compounds 2beg in good yields. The reaction of 3,5-
dioxopimelates 1hej, containing a substituent R1 located at the
central carbon atom, afforded the corresponding permethylated
products 2a and 2h,i. All products were isolated in good yields
(45e77%) and are stable at ꢁ20 ꢀC under an argon atmosphere.
2. Results and discussion
Our original plan was to prepare permethylated 1,3,5-
tricarbonyl and 1,3,5,7-tetracarbonyl compounds by base-
mediated Claisen condensations. All attempts to realize this con-
cept failed, due to fragmentation of the products by retro-Claisen
reactions under the reaction conditions employed. The employ-
ment of silyl enol ethers instead of enolates also proved to be un-
successful. Therefore, we changed our strategy and envisaged the
direct base-mediated methylation of 1,3,5-tricarbonyl and 1,3,5,7-
tetracarbonyl compounds. 1,3,5,7-Tetracarbonyl compounds 1aej
were prepared, following our recently published procedure,5 by
reaction of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with methyl
3-chloro-3-oxopropanoate (Scheme 1). The synthesis of derivatives
1a,b,hej has been previously reported.5 All derivatives exist, as
previously studied,5 as mixtures of ketoeenol tautomers (mainly in
the form of the enolized central 1,3-diketone unit).
Table 2
Synthesis of 2aei
1
2
R1
R2
Yielda [%] (1)
Yielda [%] (2)
a
b
c
d
e
f
g
h
i
a
b
c
d
e
f
g
a
h
i
H
H
H
H
H
H
H
Me
Me
Et
86b
77b
58
69
62
57
74
47
64
55
74
77
62
66
45
i-Pr
i-Bu
i-Pent
n-Oct
Bn
Me
Et
Et
57
70
84b
46b
62b
Et
Me3SiO
R1
OSiMe3
OR2
j
4-(MeO)C6H4
O
O
O
O
a
Yields of isolated products.
Ref. 5.
Me3SiOTf
Ref. 5
b
MeO
OR2
O
O
R1
1a-j
1,3,5-Tricarbonyl compounds 3aeh and 3j are available by con-
densation of 1-methoxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene
with various acid chlorides ROCl (Scheme 2). Dimethyl acetone-
MeO
Cl
MeI
i
O
O
O
O
Me
Me
Me
Me
Me3SiO
OSiMe3
OMe
MeO
OR2
Me 3SiOTf
Ref. 4a
O
O
O
R1
2a-i
Me
O
R
OMe
Scheme 1. Synthesis of 2aei. Conditions: i: MeI (7.0 equiv), Cs2CO3 (7.0 equiv), DMSO,
12 h (see Table 1); for products 1aej only the keto-form is depicted for clarity.
3a-n
R
Cl
i
As a test reaction, we studied the transformation of dimethyl
3,5-dioxopimelate (1a) into hitherto unknown dimethyl 2,2,4,4,6,6-
hexamethyl-3,5-dioxopimelate (2a) (Scheme 1, Table 1). The re-
action of a DMSO solution of 1a with methyl iodide (7.0 equiv), in
the presence of potassium carbonate (K2CO3, 7.0 equiv), afforded
the desired product 2a, however, in only 12% yield (14 h, 20 ꢀC,
Table 1, entry 1). The low yield is a result of the formation of
a complex mixture. Extension of the reaction time did not result in
an improvement. An even more complex mixture was formed and
no product at all could be isolated when the reaction was carried
MeI
O
O
O
Me Me
R
OMe
Me Me
4a-n
Scheme 2. Synthesis of 4aen. Conditions: i: procedure A: MeI (7.0 equiv), Cs2CO3
(7.0 equiv), DMSO, 20 ꢀC, 12 h; procedure B: MeI (5.0 equiv), K2CO3 (5.0 equiv), DMSO,
20 ꢀC, 8 h.

8782
S. Erfle et al. / Tetrahedron 67 (2011) 8780e8789
1,3-dicarboxylate (3i) is commercially available. The methylation of
3aed and 3fej, in the presence of Cs2CO3 (7.0 equiv), afforded the
2,2,4,4-tetramethyl-3,5-dioxoesters of 4aed and 4fej in 20e73%
yields (Scheme 2, Table 3). Interestingly, the employment of K2CO3
(5.0 equiv) instead of Cs2CO3 resulted in a significant decrease of the
yields. An exception is the synthesis of cyclopropyl-substituted de-
rivative 4e, which completely failed when Cs2CO3 was used. In
contrast, product 4e could be isolated, albeit in only 22% yield, when
K2CO3 was employed. Products 4m,n were prepared using K2CO3
because the new protocol was not available at that time when the
experiments were carried out. The low yields in case of K2CO3 can be
explained by incomplete methylation and decomposition under the
reaction conditions. All products are stable at ꢁ20 ꢀC under an argon
atmosphere.
So we again conducted such experiments with the esters 4e, 4a and
4h, and got indeed similar results. Despite averaged mirror sym-
metry for the molecules (Cs, planar zigezag chain as in the draw-
ings), we find NOE cross peaks incompatible with such
a conformation. In both 4a and 4h, the aryl ortho protons exhibit
contact with the adjacent (
surprising) as well as with the remote Me groups (
Furthermore, weak, positive NOE cross peaks occur between the
methoxy singlet and the Me groups in position and the ortho aryl
g
position) CMe2 group (which is not
a
position).
g
protons. These observations could not be made for 4e because of
insufficient signal separation (<0.01 ppm) of the methyl singlets.
These results can only be explained by contribution of a distorted,
probably syn/anti-like conformation (as described above) that al-
lows the ends of the chain to approach each other.
Several conformations are possible for tetraketides 2. In the 1H
and 13C NMR spectra at ambient temperature only sharp signals are
displayed, which indicate, that either one conformer is pre-
dominantly present or the interconversion of possible conformers
is too fast for separate NMR detection. Temperature lowering to
ꢁ80 ꢀC for 2h resulted only in minor line broadening of signals.
Therefore, we have carried out 1H NOESY experiments with 2h and
2i, respectively. These measurements gave hints for the existence of
at least two conformers in the equilibria for both 2h and 2i. For
example, in the NOESY spectrum of 2h cross peaks were obtained
between the CH2 protons of the ethyl group at C-4 and both the
OCH3 and the OCH2 protons. This points out a conformation where
the substituents at both ends of the chain can approach the ethyl
group at 4-position (picture A of compound 2h in Fig. 3). Further-
more, we found also cross peaks between the protons of OCH3 and
CH3-6 groups as well as between the protons of OCH2CH3 and CH3-
2. Such NOEs could only be expected for a conformation with
a neighbourhood of the dimethyl groups in 2- or 6-position with
the ethoxy, and methoxy groups, respectively (picture B of com-
pound 2h in Fig. 3). A statement concerning the conformations at
the C-2,C-3 and C-5,C-6 bonds is not possible for 2h, since the
resonances of the methyl groups were not sufficiently separated.
Similarly, the spectra of 2i showed NOEs, which also prove the
existence of at least two species in the conformational equilibrium.
For example, cross peaks between the protons of o-Ph, m-Ph and
CH3-4 with OCH3 and OCH2 indicate to exist as well a conformer
corresponding to A in Fig. 3. Furthermore, it was found that the
CH3-4 signal correlates with both the signals of CH3-2 and CH3-6
protons. The signals of both CH3-2 groups also show cross peaks
with OCH2 and the signals for the CH3-6 groups with OCH3. These
cross peaks point out as well a conformation which is represented
by picture B (Fig. 3).
Table 3
Synthesis of 4aen
3, 4
R
Yielda [%] (3) Yielda [%] (4, A) Yielda [%] (4, B)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
4-(NO2)C6H4
4-MeC6H4
3-ClC6H4
2-ClC6H4
c-Pr
65b
55c
61c
59b
91b
67
20
58
55
65
0
73
73
62
65
33
82
31
dg
dg
24
12
7
de
22
17
16
32
dg
dg
dg
dg
17
11
2-Furyl
2-Thienyl
2-Naphthyl
MeO
4-(MeO)C6H4
c-Hex
61d
62b
de
42c
62
2,6-F2C6H3
48
2-(NO2)e3-MeC6H3 86f
2-(NO2)e5-FC6H3
86f
a
Yields of isolated products using procedure A or B (see legend of Scheme 2).
See Ref. 4a.
See Ref. 6b.
See Ref. 4b.
Commercially available.
See Ref. 12.
Experiment was not carried out.
b
c
d
e
f
g
The structure of 4a was independently confirmed by X-ray
crystal structure analysis (Fig. 2).9
Fig. 2. The molecular structure of compound 4a. Displacement ellipsoids are drawn at
the 30% probability level. Hydrogen atoms are omitted for clarity.
In a preceding paper6 we had shown by DFTcalculations10,11 that
bis-cyclopropanated 1,3,5-triketones are able to adopt conforma-
tions that can be designated syn/anti (with respect to the central
carbonyl group). In such an arrangement, the substituents at both
ends of the chain should be able to approach each other, which was
proven by NMR spectroscopy (1H NOESY measurements at
dichloromethane solutions). These compounds are closely related
to those investigated in the present paper by formally ‘clipping’ the
three-membered rings and thus converting them into CMe2 units.
Fig. 3. Relevant NOE cross peaks found for compounds 2h and 2i.

S. Erfle et al. / Tetrahedron 67 (2011) 8780e8789
8783
ꢀ
Since the X-ray structural data of ester 4a are available (Fig. 2,
vide supra), we carried B3LYP/6-311þG** DFT calculations10,11 on
the conformational changes for reasons of comparison (see com-
putational part and Supplementary data for details). On the basis of
our analysis discussed above, we have found two stable conformers
(Fig. 4). One conformer agrees well with the data reported by X-ray
analysis (Fig. 2), which is also the more stable one; and the
O2eC3eC2eC1 torsional angle is 115.1ꢀ (106.7ꢀ from X-ray analy-
sis). The second conformer has the O2eC3eC2eC1 torsional angle
of ꢁ22.7ꢀ and is less stable by 3.02 kcal/mol. The approximated
equilibrium ratio should be more than 99 to 1 at room temperature.
For analyzing the dynamic process, we have also computed the
rotational barrier of the para-nitrophenyl around C1eC11 bond. For
searching the potential energy surface, we have rotated the tor-
sional angle O1eC1eC11eC16 by 360ꢀ for relaxed scan at the HF/6-
31G* level. Two identical energy minimum structures and two
identical energy maximum structures have been located. Further
optimization of the maximum structures results in a transition
state; the O1eC1eC11eC16 torsional angle is 117.4ꢀ, while that of
the minimum structure is 11.0ꢀ; indicating a rotation of about 106ꢀ.
As expected, the computed rotational barrier of 3.83 kcal/mol is
rather small, in dictating the free rotation in solution.
for 4i. The conformer with longer O1eO2 distance (4.529 A) is
2.06 kcal/mol more stable than that one with shorter O1eO2 dis-
ꢀ
tance (3.320 A). On the basis of our results, we have built the iso-
mers of 2a with the distances of the carbonyl groups as long as
possible and two conformers of 2a were obtained. The more stable
a longer O1eO2 distance
(4.315 A) than the less stable conformer (3.042 A); the O1eO3
conformer possesses, as expected,
ꢀ
ꢀ
ꢀ
distance of the more stable isomer is 4.551 A, which is close to that
ꢀ
of the less stable conformer (4.656 A).
Triketide 4k was transformed by hydrogenation (H2, Pd/C
10 mol %, MeOH), using our recently reported procedure,12 into 4-
quinolone 5 (Scheme 3). The formation of the product can be
explained by transformation of the nitro to an amino group, attack
of the latter to the carbonyl group to give an imine and subsequent
hydrogenation of the latter.
O
Me
NO2 O
O
O
Me
Me Me
O
Me
i
OMe
N
H
58%
OMe
Me Me
Me Me
Me
4k
5
Scheme 3. Synthesis of 5. Conditions: i, Pd/C (10 mol %), H2, MeOH, 12 h, 20 ꢀC.
Surprisingly, the reaction of 3m with 5.0 equiv of iodomethane,
in the presence of potassium carbonate, resulted only in threefold
methylation and formation of methyl 2,4,4-trimethyl-3,5-
dioxopentanoate (6) (Scheme 4). The exact structure of 6 could be
O
O
O
O
O
O
Me
OMe
i
OMe
Me Me
NO 2
NO 2
33%
3m
6
ii
O
O
N
Me
Me
Me
Me
Me
Me
N
H
A
7
53%
Scheme 4. Synthesis of 7. Conditions: i, MeI (5.0 equiv), K2CO3 (5.0 equiv), DMSO, 8 h,
20 ꢀC; ii, Pd/C 10%, H2, MeOH, 12 h, 20 ꢀC.
clarified by its transformation into product 7 by hydrogenation (H2,
Pd/C 10 mol %, MeOH). The structure of 7 was independently con-
firmed by X-ray crystal structure analysis (Fig. 5).8 The formation of
7 can be explained by reduction of the nitro to an amino group,
attack of the latter to the carbonyl group to give imine A and sub-
sequent hydrogenation of the imine.
Fig. 4. Calculated relative energies and the O1eO2 distances at the B3LYP/6-311þG**
level of theory of dimethyl dimethylmalonate (top), 4i (middle) and 2a (bottom).
Hydrogen atoms are omitted for clarity.
In conclusion, we have reported the synthesis of permethylated
1,3,5-tri- and 1,3,5,7-tetracarbonyl compounds. 2,2,4,4-Tetra-
methyl-3,5-dioxoesters were prepared by condensation of 1,3-
bis(trimethylsilyloxy)-1,3-butadienes with acid chlorides and sub-
sequent reaction with methyl iodide. 2,2,4,4,6,6-Hexa-substituted
3,5-dioxopimelates were prepared by condensation of 1,3-
bis(trimethylsilyloxy)-1,3-butadienes with methyl 3-chloro-3-
oxopropanoate and subsequent methylation. The use of caesium
carbonate as the base for the methylation proved to be important to
achieve good yields. The structure and the conformation of the
products were studied by combined experimental and computa-
tional methods.
On the basis of our above discussion, conformations of tetra-
ketide 2a were also calculated. Since no crystal structure exists as
a reference, the conformations of dimethyl dimethylmalonate as
benchmark were calculated first. As shown in Fig. 4, two con-
formers were calculated for dimethyl dimethylmalonate. The en-
ergy difference at B3LYP/6-311þG** is 2.27 kcal/mol; the more
ꢀ
stable conformer has a longer O1eO2 distance (4.642 A) than the
ꢀ
less stable conformer (3.276 A). This indicates that the longer the
distance of the two C]O groups, the more stable the isomer. On the
basis of these results and also of the results obtained for cyclo-
propyl-polyketides,6 two stable conformers have also been found

8784
S. Erfle et al. / Tetrahedron 67 (2011) 8780e8789
(0.14 mL, 0.8 mmol) in CH2Cl2 (24 mL), the product was isolated as
a yellow oil (0.713 g, 69%). 1H NMR (300 MHz, CDCl3): enol:
d
¼0.95
(d, 3J¼6.7 Hz, 6H, CH3), 1.86e1.99 (m, 1H, CH), 2.92 (s, 2H, CH2), 3.68
(s, 3H, OCH3), 3.86 (d, 3J¼6.6 Hz, 2H, CH2), 3.90 (s, 2H, CH2), 6.33 (s,
1H, CH), 12.02 (br, 1H, OH). 13C NMR (75 MHz, CDCl3): enol:
d
¼19.4,
19.4 (CH3), 27.6 (CH), 41.5 (C-7), 45.2 (C-3), 51.6 (OCH3), 70.8 (CH2),
100.3 (C-5), 168.9 (C-2,8), 190.1 (C-6), 198.9 (C-4). IR (ATR, cmꢁ1):
~
n
¼ 2991 (w), 2942 (w), 2891 (w), 1740 (s), 1600 (m), 1437 (m),
1409 (w), 1244 (s), 1150 (s), 1016 (s). HRMS (ESI): calcd for C12H18O6
([MþH]þ) 259.08403, found 259.08438.
3.2.3. 1-Isopentyl 7-methyl 3,5-dioxoheptanedioate (1e). Starting with
1-isopentyloxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene (2.53 g, 8 m
mol), methyl malonyl chloride (0.43 mL, 4 mmol) and Me3SiOTf
(0.14 mL, 0.8 mmol) in CH2Cl2 (24 mL), the product was isolated as
a yellow oil (0.675 g, 62%). 1H NMR (300 MHz, CDCl3): enol:
d
¼0.92
(d, 3J¼6.3 Hz, 6H, CH3), 1.48e1.56 (m, 2H, CH2), 1.58e1.74 (m, 1H,
CH), 2.92 (s, 2H, CH2), 3.68 (s, 3H, OCH3), 3.90 (s, 2H, CH2), 4.13 (t,
3J¼6.9 Hz, 2H, CH2), 6.33 (s, 1H, CH), 12.04 (br, 1H, OH). 13C NMR
Fig. 5. The molecular structure of compound 7. Displacement ellipsoids are drawn at
the 30% probability level.
(75 MHz, CDCl3): enol:
d
¼22.9, 22.9 (CH3), 24.3 (CH), 38.7 (CH2),
41.5 (C-7), 45.2 (C-3), 51.6 (OCH3), 62.5 (CH2), 100.3 (C-5), 168.1 (C-
3. Experimental section
3.1. General
2,8), 190.1 (C-6), 198.9 (C-4). IR (ATR, cmꢁ1): ¼ 2990 (w), 2929
~
n
(w), 2878 (w), 1730 (s), 1610 (m), 1443 (m), 1399 (w), 1241 (s), 1155
(s), 1014 (s). HRMS (ESI): calcd for C13H20O6 ([MþH]þ) 273.05273,
found 273.05296.
1H NMR (300.13 MHz, 400.13 MHz and 500.13 MHz) and 13C
NMR spectra (75.5 MHz, 100.6 MHz and 125.8 MHz) were recorded
on Bruker spectrometers AVANCE 300, AVANCE 400 and AVANCE
500. The chemical shifts are referenced to solvent signals (CDCl3:
3.2.4. 1-Methyl 7-ocytl 3,5-dioxoheptanedioate (1f). Starting with
1-octyloxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene (2.51 g, 8 mmol),
methyl malonyl chloride (0.43 mL, 4 mmol) and Me3SiOTf (0.14 mL,
0.8 mmol) in CH2Cl2 (24 mL), the product was isolated as a yellow oil
d
1H¼7.26,
d
13C¼77.0). The melting points are uncorrected.
(0.717 g, 57%). 1H NMR (300 MHz, CDCl3): enol:
d
¼0,86 (t, 3J¼6.6 Hz,
3.2. Typical procedure for the synthesis of 3,5-dioxopimelates
(1ceg)
3H, CH3), 1.25e1.40 (m, 28H, 5CH2, 6CH3), 1.61 (m, 2H, CH2), 2.92 (s,
2H, CH2), 3.68 (s, 3H, OCH3), 3.90 (s, 2H, CH2), 4.07 (t, 3J¼6.7 Hz, 2H,
OCH2), 6.33 (s, 1H, CH), 12.01 (br, 1H, OH). 13C NMR (75 MHz, CDCl3):
To a CH2Cl2 solution (70 mL) of the 1,3-bis(trimethylsilyloxy)-
1,3-butadiene (18.0 mmol) were added methyl malonyl chloride
(0.819 g, 6.0 mmol, 0.64 mL) and TMSOTf (0.267 g, 1.2 mmol,
0.22 mL) at ꢁ78 ꢀC under argon atmosphere. The solution was
allowed to warm to 20 ꢀC within 6 h and was stirred at this tem-
perature for 12 h. To the solution was added a saturated aqueous
solution of NH4Cl (30 mL), the organic and the aqueous layer were
separated and the latter was extracted with diethyl ether
(3ꢂ30 mL). The combined organic layers were extracted with
a saturated aqueous solution of NaCl, dried (Na2SO4), filtered and
the filtrate was concentrated in vacuo. The residue was purified by
chromatography (silica gel, n-heptane/EtOAc¼3:1). The products
reside as mixtures of ketoeenol tautomers. Only the enol signals
(main tautomer) are listed. Products 1a,b,hej were prepared as
previously reported.5
enol:
d
¼14.1 (CH3), 22.6, 25.8, 28.3, 29.1, 29.1, 31.7 (CH2), 41.5 (C-7),
45.2 (C-3), 51.6 (OCH3), 65.3 (OCH2), 100.3 (C-5), 168.1 (C-2,8), 190.1
(C-6), 198.9 (C-4). IR (ATR, cmꢁ1):
n
¼ 2989 (w), 2936 (w), 2881 (w),
~
1739 (s), 1611 (m), 1437 (m), 1399 (w), 1253 (s), 1148 (s), 1015 (s).
HRMS (ESI): calcd for C16H26O6 ([MþH]þ) 315.11533, found 315.11567.
3.2.5. 1-Benzyl 7-methyl 3,5-dioxoheptanedioate (1g). Starting with
1-benzyloxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene (2.69 g, 8 m
mol), methyl malonyl chloride (0.43 mL, 4 mmol) and Me3SiOTf
(0.14 mL, 0.8 mmol) in CH2Cl2 (24 mL), the product was isolated as
a yellow oil (0.818 g, 70%). 1H NMR (400 MHz, CDCl3): enol:
d¼2.92
(s, 2H, CH2), 3.69 (s, 3H, OCH3), 3.90 (s, 2H, CH2), 5.20 (s, 2H, CH2Ph),
6.33 (s, 1H, CH), 7.32e7.35 (m, 5H, Ph), 12.05 (br, 1H, OH). 13C NMR
(100 MHz, CDCl3): enol:
d¼41.5 (C-7), 45.2 (C-3), 51.6 (OCH3), 66.5
(CH2Ph), 100.3 (C-5), 128.3, 128.4, 128.6, 135.1 (Ph), 168.1 (C-2,8),
190.1 (C-6), 198.9 (C-4). IR (ATR, cmꢁ1):
n
¼ 2996 (w), 2933 (w),
~
3.2.1. 1-Isopropyl 7-methyl 3,5-dioxoheptanedioate (1c). Starting
with 1-isopropyloxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene (2.31 g,
8 mmol), methyl malonyl chloride (0.43 mL, 4 mmol) and Me3SiOTf
(0.14 mL, 0.8 mmol) in CH2Cl2 (24 mL), the product was isolated as
2885 (w), 1732 (s), 1601 (m), 1429 (m), 1407 (w), 1254 (s), 1148 (s),
1010 (s). HRMS (ESI): calcd for C15H16O6 ([MþH]þ) 293.16228,
found 293.16231.
a yellow oil (0.567 g, 58%). 1H NMR (300 MHz, CDCl3): enol:
d
¼1.22 (d,
3J¼6.3 Hz, 6H, CH3), 2.92 (s, 2H, CH2), 3.69 (s, 3H, OCH3), 3.90 (s, 2H,
3.3. Procedure A for the synthesis of 2,2,4,4,6,6-hexamethyl-
3,5-dioxopimelates 2aei
CH2), 5.00 (m, 1H, CH), 6.33 (s, 1H, CH), 12.05 (br, 1H, OH). 13C NMR
(75 MHz, CDCl3):enol:
d
¼21.7(CH3), 41.8 (C-7), 45.2(C-3), 51.6(OCH3),
69.6 (CH), 100.3 (C-5), 168.1 (C-2,8) (CO), 190.1 (C-6), 198.9 (C-4). IR
To a DMSO solution (1 mL/1.0 mmol of 1) of 1 (1 equiv)
was added dry Cs2CO3 (7 equiv). Subsequently, MeI (7 equiv)
was added at 0 ꢀC. After 30 min the cooling was removed and
the solution was stirred for 12 h. Brine (10 mL) and diethyl
ether (10 mL) were added to the solution and the aqueous and
organic layers were separated. The latter was extracted again
with brine (3ꢂ10 mL). The organic layers were dried (Na2SO4),
filtered and the filtrate was concentrated in vacuo. The
(ATR, cmꢁ1):
n
¼ 2995 (w), 2934 (w), 2886 (w), 1736 (s), 1606 (m),
~
1434 (m), 1403 (w), 1248 (s), 1152 (s), 1017 (s). HRMS (ESI): calcd for
C11H16O6 ([MþH]þ) 245.03708, found 245.03722.
3.2.2. 1-Isobutyl 7-methyl 3,5-dioxoheptanedioate (1d). Starting
with 1-isobutoxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene (2.42 g,
8 mmol), methyl malonyl chloride (0.43 mL, 4 mmol) and Me3SiOTf

S. Erfle et al. / Tetrahedron 67 (2011) 8780e8789
8785
residue was purified by column chromatography (silica gel,
heptanes/EtOAc).
(Mþ, 1), 269 (23), 255 (14), 237 (24), 199 (38), 185 (38), 171 (50), 157
(13), 143 (13), 139 (18), 129 (94), 115 (76), 111 (13), 101 (100), 87
(23), 73 (90), 71 (24), 70 (63), 69 (36), 59 (46), 57 (52), 43 (16), 42
(27), 41 (56), 39 (11). Anal. Calcd for C18H30O6 (342.43): C, 63.14; H,
8.83. Found: C, 63.10; H, 8.86.
3.3.1. Dimethyl 2,2,4,4,6,6-hexamethyl-3,5-dioxoheptanedioate
(2a). Starting with dimethyl 3,5-dioxoheptanedioate (1a) (0.500 g,
2.3 mmol), Cs2CO3 (5.24 g, 16.2 mmol) and iodomethane (1.02 mL,
16.2 mmol) in DMSO (2.3 mL), 2a was isolated as a colourless oil
3.3.5. 1-iso-Pentyl 7-methyl 2,2,4,4,6,6-hexamethyl-3,5-dioxoheptane-
dioate (2e). Starting with 1-isopentyl 7-methyl 3,5-dioxoheptane-
dioate (1e) (0.500 g, 1.8 mmol), Cs2CO3 (4.19 g, 12.8 mmol) and
iodomethane (0.81 mL,12.8 mmol) in DMSO (1.8 mL), product 2e was
isolated as a slight yellow oil (0.360 g, 55%). 1H NMR (300 MHz,
(0.395 g, 57%).1H NMR (300 MHz, CDCl3):
d
¼1.40 (s, 6H, CH3),1.42 (s,
12H, CH3), 3.71 (s, 6H, OCH3). 13C NMR (75 MHz, CDCl3):
d
¼23.6, 24.2
(CH3), 52.3 (OCH3), 55.4, 64.1 (C), 174.0, 206.8 (CO). IR (ATR, cmꢁ1):
~
n
¼ 2988 (w), 2952 (w), 1738 (m), 1687 (s), 1459 (w), 1435 (w), 1387
(w), 1369 (w), 1254 (m), 1193 (m), 1142 (s), 1023 (m), 993 (m), 975
(m), 921 (w), 902 (w), 844 (w), 777 (w). GCeMS (EI, 70 eV): m/z (%):
300 (Mþ, 0.4), 199 (22), 171 (11), 129 (86), 101 (100), 73 (95), 70 (26),
69 (22), 59 (11), 42 (14), 41 (25). Anal. Calcd for C15H24O6 (300.35): C,
59.98; H, 8.05. Found: C, 59.81; H, 8.04.
CDCl3):
d
¼0.92 (d, 3J¼6.3 Hz, 6H, CH3), 1.42 (s, 12H, CH3), 1.43 (s, 6H,
CH3), 1.48e1.56 (m, 2H, CH2), 1.58e1.74 (m, 1H, CH), 3.71 (s, 3H,
OCH3), 4.13 (t, 3J¼6.9 Hz, 2H, CH2). 13C NMR (75 MHz, CDCl3):
¼22.4,
d
23.6, 24.1, 24.2 (CH3), 25.0 (CH), 36.9 (CH2), 52.3 (OCH3), 55.4, 55.6 (C-
2,6), 64.0 (C-4), 64.1 (CH2), 173.6, 174.0, 206.9, 207.0 (C]O). IR (ATR,
cmꢁ1):
n
¼ 2955 (m), 2929 (m), 2871 (w),1737 (s),1711 (m),1689 (s),
~
3.3.2. 1-Ethyl 7-methyl 2,2,4,4,6,6-hexamethyl-3,5-dioxoheptanedioate
(2b). Starting with 1-ethyl 7-methyl 3,5-dioxoheptanedioate (1b)
(0.500 g, 2.2 mmol), Cs2CO3 (4.95 g, 15.2 mmol) and iodomethane
(0.95 mL, 15.2 mmol) in DMSO (2.2 mL), product 2b was isolated as
1466 (m), 1386 (m), 1368 (w), 1253 (m), 1142 (s), 1022 (m), 991 (m),
921 (w), 842 (w), 773 (w). GCeMS (EI, 70 eV): m/z (%): 356 (Mþ, 0.4),
237 (11), 199 (22), 185 (31), 129 (100), 101 (56), 73 (48), 71 (52), 70
(34), 69 (24), 59 (13), 43 (27), 42 (13), 41 (24). Anal. Calcd for C19H32O6
(356.45): C, 64.02; H, 9.05. Found: C, 63.77; H, 9.32.
a colourless oil (0.508 g, 74%). 1H NMR (500 MHz, CDCl3):
d
¼1.21 (t,
3J¼7.3 Hz, 3H, CH2CH3),1.34 (s, 6H, CH3-4),1.35 (s,12H, CH3-2,6), 3.65
(s, 3H, OCH3), 4.10 (q, 3J¼7.3 Hz, 2H, CH2). 13C NMR (125.8 MHz,
3.3.6. 1-Methyl 7-octyl 2,2,4,4,6,6-hexamethyl-3,5-dioxoheptane-
dioate (2f). Starting with 1-methyl 7-octyl 3,5-dioxoheptanedioate
(1f) (0.500 g, 1.6 mmol), Cs2CO3 (3.63 g, 11.1 mmol) and iodo-
methane (0.70 mL, 11.1 mmol) in DMSO (1.6 mL), product 2f was
isolated as a colourless oil (0.470 g, 74%). 1H NMR (300 MHz, CDCl3):
CDCl3):
d
¼13.8 (CH2CH3), 23.6, 24.0, 24.1 (CH3-2,4,6), 52.2 (OCH3),
55.3, 55.5 (C-2,6), 61.3 (OCH2), 63.9 (C-4), 173.9 (C-7), 173.4 (C-1),
206.89, 206.92 (C-3,5). IR (ATR, cmꢁ1):
n
¼ 2985 (w), 2949 (w), 1737
~
(m), 1709 (m), 1687 (s), 1468 (m), 1386 (m), 1367 (w), 1253 (m), 1142
(s), 1023 (m), 990 (m), 954 (w), 902 (w), 859 (w), 842 (w), 776 (w),
427 (w). GCeMS (EI, 70 eV): m/z (%): 314 (Mþ, 0.7), 269 (13), 237 (18),
213 (20), 199 (22), 185 (10), 143 (64), 129 (70), 115 (48), 111 (10), 101
(79), 87 (100), 73 (74), 70 (45), 69 (32), 59 (34), 43 (10), 42 (22), 41
(35), 29 (10). Anal. Calcd for C16H26O6 (314.37): C, 61.13; H, 8.34.
Found: C, 61.29; H, 8.56.
d
¼0.86 (t, 3J¼6.6 Hz, 3H, CH3), 1.25e1.40 (m, 28H, 5CH2, 6CH3), 1.61
(m, 2H, CH2), 3.69 (s, 3H, OCH3), 4.07 (t, 3J¼6.7 Hz, 2H, OCH2). 13
C
NMR (75 MHz, CDCl3):
(CH3), 25.8, 28.3, 29.1, 29.1, 31.7 (CH2), 52.3 (OCH3), 55.4, 55.6 (C-2,6),
d¼14.1 (CH3), 22.6 (CH2), 23.6, 24.1, 24.2
64.0 (C-4), 65.6 (OCH2), 173.6, 174.0, 206.9, 207.0 (CO). IR (ATR,
cmꢁ1):
n
¼ 2984 (w), 2928 (m), 2856 (w), 1738 (m), 1710 (m), 1688
~
(s), 1467 (m), 1386 (m), 1368 (w), 1253 (m), 1144 (s), 1022 (m), 991
(m), 903 (w), 842 (w), 775 (w), 723 (w), 429 (w). GCeMS (EI, 70 eV):
m/z (%): 398 (Mþ, 0.9), 269 (16), 237 (14), 227 (27),199 (48),185 (42),
171 (21), 157 (13), 139 (13), 129 (100), 115 (16), 111 (40), 101 (81), 87
(12), 73 (45), 71 (39),70 (40), 69 (37), 59 (26), 57 (18), 55 (10), 43
(19), 42 (13), 41 (24). Anal. Calcd for C22H38O6 (398.53): C, 66.30; H,
9.61. Found: C, 66.18; H, 9.56.
3.3.3. 1-iso-Propyl 7-methyl 2,2,4,4,6,6-hexamethyl-3,5-dioxoheptane-
dioate (2c). Starting with 1-isopropyl 7-methyl 3,5-dioxoheptane-
dioate (1c) (0.500 g, 2.0 mmol), Cs2CO3 (4.67 g, 14.3 mmol) and
iodomethane (0.90 mL, 14.3 mmol) in DMSO (2.0 mL), 2c was isolated
as a colourless oil (0.310 g, 47%). 1H NMR (300 MHz, CDCl3):
d
¼1.22 (d,
3J¼6.3 Hz, 6H, CH3), 1.38 (s, 6H, CH3), 1.40 (s, 6H, CH3), 1.41 (s, 6H,
CH3), 3.69 (s, 3H, OCH3), 5.00 (m, 1H, CH). 13C NMR (75 MHz, CDCl3):
d
¼21.5, 23.7, 23.9, 24.3 (CH3), 52.3 (OCH3), 55.4, 55.8 (C-2,6), 63.9 (C-
3.3.7. 1-Benzyl 7-methyl 2,2,4,4,6,6-hexamethyl-3,5-dioxoheptane-
dioate (2g). Starting with 1-benzyl 7-methyl 3,5-dioxoheptane-
dioate (1g) (0.500 g, 1.7 mmol), Cs2CO3 (3.90 g, 11.9 mmol) and
iodomethane (0.75 mL, 11.9 mmol) in DMSO (1.7 mL), product 2g
was isolated as a slight yellow oil (0.494 g, 77%). 1H NMR (400 MHz,
4), 69.1 (CH), 173.0, 174.0, 207.1, 207.2 (CO). IR (ATR, cmꢁ1):
n
¼ 2983
~
(w), 2942 (w), 2876 (w), 1734 (m), 1708 (m), 1687 (s), 1468 (m), 1386
(m), 1373 (w), 1254 (m), 1144 (s), 1103 (s), 1022 (m), 990 (m), 954 (w),
902 (m), 864 (w), 842 (w), 777 (w), 425 (m). GCeMS (EI, 70 eV): m/z
(%): 328 (Mþ, 0.7), 269 (23), 255 (14), 237 (24), 199 (30), 185 (48), 157
(47), 140 (22), 139 (15), 129 (77), 115 (70), 111 (12), 102 (12), 101 (100),
87 (42), 73 (73), 71 (18), 70 (57), 69 (31), 59 (37), 43 (34), 42 (22), 41
(41). HRMS (ESI): calcd for C17H29O6 ([MþH]þ) 329.1959, found
329.1963.
CDCl3):
(s, 3H, OCH3), 5.14 (s, 2H, CH2), 7.32e7.35 (m, 5H, Ph). 13C NMR
(100 MHz, CDCl3):
¼23.6, 24.1, 24.2 (CH3), 52.3, 55.4 (C-2,6), 55.7
(OCH3), 64.0 (C-4), 67.1 (CH2Ph), 128.3, 128.4,128.6,135.1 (Ph), 173.3,
d¼1.35 (s, 6H, CH3), 1.39 (s, 6H, CH3), 1.43 (s, 6H, CH3), 3.69
d
174.0, 206.7, 207.1 (C]O). IR (ATR, cmꢁ1):
n
¼ 3090 (w), 3065 (w),
~
2987 (w), 2949 (w), 1736 (m), 1709 (m), 1687 (s), 1498 (w), 1456 (m),
1387 (m), 1368 (w), 1254 (m), 1132 (s), 989 (m), 737 (m), 697 (m),
602 (w), 424 (w). GCeMS (EI, 70 eV): m/z (%): 376 (Mþ, 0.1), 129 (15),
101 (18), 91 (100), 73 (17), 70 (10). Anal. Calcd for C21H28O6 (376.44):
C, 67.00; H, 7.50. Found: C, 67.25; H, 7.41.
3.3.4. 1-iso-Butyl 7-methyl 2,2,4,4,6,6-hexamethyl-3,5-dioxoheptane-
dioate (2d). Starting with 1-isobutyl 7-methyl 3,5-dioxoheptane-
dioate (1d) (0.500 g, 1.9 mmol), Cs2CO3 (4.42 g, 13.5 mmol) and
iodomethane (0.85 mL, 13.5 mmol) in DMSO (1.9 mL), product 2d
was isolated as a colourless oil (0.425 g, 64%). 1H NMR (300 MHz,
CDCl3):
d
¼0.91 (d, 3J¼6.7 Hz, 6H, CH3), 1.39 (s, 6H, CH3), 1.40 (s, 6H,
3.3.8. Dimethyl 2,2,4,4,6,6-hexamethyl-3,5-dioxoheptanedioate (2a)
prepared from 1h. Starting with dimethyl 4-methyl-3,5-dioxo-
heptanedioate (1h) (0.500 g, 2.1 mmol), Cs2CO3 (4.95 g, 15.2 mmol)
and iodomethane (0.96 mL, 15.2 mmol) in DMSO (2.1 mL), product
2a was isolated as a colourless oil (0.404 g, 62%).
CH3), 1.41 (s, 6H, CH3), 1.86e1.99 (m, 1H, CH), 3.69 (s, 3H, OCH3),
3.86 (d, 3J¼6.6 Hz, 2H, CH2). 13C NMR (75 MHz, CDCl3):
¼19.0,
d
23.6, 24.1, 24.3 (CH3), 27.6 (CH), 52.3 (OCH3), 55.4, 55.7 (C-2,6), 64.0
(C-4), 71.4 (CH2), 173.5, 174.0, 206.7, 207.0 (CO). IR (ATR, cmꢁ1):
n
¼
~
2957 (w), 2876 (w), 1736 (m), 1710 (m), 1688 (s), 1469 (m), 1386
(m), 1368 (w), 1253 (m), 1142 (s), 1022 (m), 989 (m), 952 (w), 922
(w), 842 (w), 776 (w), 430 (w). GCeMS (EI, 70 eV): m/z (%): 342
3.3.9. 1-Ethyl 7-methyl 4-ethyl-2,2,4,6,6-pentamethyl-3,5-
dioxoheptanedioate (2h). Starting with 1-ethyl 7-methyl 4-ethyl

8786
S. Erfle et al. / Tetrahedron 67 (2011) 8780e8789
3,5-dioxoheptanedioate (1i) (0.600 g, 2.3 mmol), Cs2CO3 (5.30 g,
16.3 mmol) and iodomethane (1.0 mL, 16.3 mmol) in DMSO
(2.3 mL), product 2h was isolated as a slight yellow oil (0.506 g,
(54.1),150(17.2),137 (90.9),110 (19.5), 95(100), 69(26.7). Anal. Calcd
for C10H10O5 (210.18): C, 57.14; H, 4.80. Found: C, 57.15; H, 4.90.
66%). 1H NMR (500 MHz, CDCl3):
d
¼0.72 (t, 3J¼7.3 Hz, 3H, CCH2CH3),
3.4.2. Methyl 5-cyclohexyl-3,5-dioxovalerate (3k). Starting with
1-cyclohexanecarboxylic acid chloride (844 mg, 5.56 mmol) dis-
solved in CH2Cl2 (10 mL) and 1,3-bis(silyl enol ether) (3.00 g,
11.52 mmol), 3k was isolated as a colourless oil (0.81 g, 62%). 1H
1.25 (t, 3J¼7.3 Hz, 3H, OCH2CH3), 1.37 (s, 3H, CH3-4), 1.390 (s, 3H,
CH3-6), 1.394, 1.40 (2s, 2ꢂ 3H, CH3-2,6), 1.41 (s, 3H, CH3-2), 1.93 (m,
AB part of ABX3, 2H, CCH2CH3), 3.68 (s, 3H, OCH3), 4.14 (q, 3J¼7.3 Hz,
2H, OCH2). 13C NMR (125.8 MHz, CDCl3):
d¼9.2 (CCH2CH3), 13.8
NMR (300 MHz, CDCl3, keto/enol¼0:100):
d
¼1.26e1.43 (m, 4H,
(OCH2CH3), 19.3 (CH3-4), 24.0, 24.3, 24.7, 24.8 (CH3-2,6), 30.0
(CCH2CH3), 52.2 (OCH3), 55.8, 56.0 (C-2,6), 61.3 (OCH2), 68.3 (C-4),
CH2), 1.67e1.96 (m, 6H, CH2), 2.13e2.22 (m, 1H, CH), 3.35 (s, 2H,
CH2), 3.74 (s, 3H, OCH3), 5.59 (s, 1H, CH), 15.22 (br s, 1H, OH). IR
173.4 (C-1), 173.9 (C-7), 205.6, 205.7 (C-3,5). IR (ATR, cmꢁ1):
(neat, cmꢁ1):
n
¼ 2929 (s), 2854 (s), 1744 (s), 1597 (s). HRMS (ESI):
~
n
¼ 2984 (w), 2948 (w), 2884 (w),1731 (m),1686 (s),1461 (m),1385
calcd for C12H19NaO4 ([MþNa]þ) 249.10973, found 249.10989.
~
(m), 1365 (w), 1251 (m), 1141 (s), 1062 (w), 1023 (m), 983 (m), 927
(w), 859 (m), 814 (w), 772 (w), 733 (w), 427 (w). HRMS (ESI): calcd
for C17H29O6 ([MþH]þ) 329.1959, found 329.1962. Anal. Calcd for
C17H28O6 (328.40): C, 62.17; H, 8.59. Found: C, 62.31; H, 8.55.
3.4.3. Methyl 5-(2,6-Difluorophenyl)-3,5-dioxovalerate (3l). Starting
with 2,6-difluorobenzoyl chloride (1.02 g, 5.76 mmol) dissolved in
CH2Cl2 (10 mL) and 1,3-bis(silyl enol ether) (3.00 g, 11.52 mmol), 3l
was isolated as an orange oil (0.79 g, 48%). 1H NMR (300 MHz,
3.3.10. 1-Ethyl 7-methyl 4-(4-methoxyphenyl)-2,2,4,6,6-penta-
methyl-3,5-dioxoheptanedioate (2i). Starting with 1-ethyl 7-methyl
4-(4-methoxyphenyl)-3,5-dioxoheptanedioate (1j) (0.260 g, 0.8 mm
ol), Cs2CO3 (1.76 g, 5.4 mmol) and iodomethane (0.34 mL, 5.4 mmol)
inDMSO(0.77 mL),product 2iwasisolatedasa colourless oil(0.140 g,
CDCl3, keto/enol¼0:100): ¼3.47 (s, 2H, CH2), 3.77 (s, 3H, CH3), 6.02
d
5
(t, 1H, JH,F¼1.51 Hz, CH), 6.94e6.99 (m, 2H, Ph), 7.36e7.45 (m, 1H,
Ph), 15.13 (s, 1H, OH). 19F NMR (282 MHz, CDCl3):
d
¼ꢁ110.29. 13C
NMR (75 MHz, CDCl3):
d
¼45.0 (CH2), 52.5 (OCH3), 103.7 (t,
2
4JC,F¼3.30 Hz, CH), 112.16 (d, JC,F¼23.11 Hz, CHeAr), 112.2 (d,
3
45%). 1H NMR (500 MHz, CDCl3):
d
¼1.15 (s, 3H, CH3-6), 1.18 (s, 3H,
2JC,F¼23.11 Hz, CHeAr), 132.6 (t, JC,F¼11.00 Hz, CHeAr), 160.3 (d,
CH3-2),1.18 (t, 3J¼7.3 Hz, 3H, OCH2CH3),1.33 (s, 3H, CH3-6),1.34 (s, 3H,
CH3-2), 1.94 (s, 3H, CH3-4), 3.55 (s, 3H, OCH3), 3.80 (s, 3H, p-OCH3),
1JC,F¼256.39 Hz, CF), 160.4 (d, JC,F¼256.39 Hz, CF), 167.6 (COH),
1
177.7 (CO2Me), 187.7 (CO). MS (EI, 70 eV) m/z¼241 (MꢁMeþ, 4), 224
4.00 (m, 2H, OCH2), 6.85 (m, 2H, m-C6H4), 7.17 (m, 2H, o-C6H4). 13
C
(30), 196 (24), 183 (86), 141 (100), 113 (19), 69.
NMR (125.8 MHz, CDCl3):
23.65, 24.88, 24.93 (CH3-2,6), 52.1 (OCH3), 55.2 (p-OCH3), 55.8, 55.9
(C-2,6), 61.2 (OCH2), 70.6 (C-4), 113.5 (m-C6H4), 127.7 (i-C6H4), 130.0
d
¼13.8 (OCH2CH3), 19.9 (CH3-4), 23.63,
3.5. General procedure A for the synthesis of 2,2,4,4-
tetramethyl-3,5-dioxopentanoates 4
(o-C6H4),159.3 (p-C6H4),173.2 (C-1),173.7 (C-7), 206.3, 206.4 (C-3,5).
IR(ATR, cmꢁ1):
n
¼ 2984 (m), 2941 (w), 2839(w),1735 (m),1709(m),
To a DMSO solution (1 mL/1.0 mmol of 3) of 3 (1 equiv) was
added dry Cs2CO3 (7 equiv). Subsequently, MeI (7 equiv) was
added at 0 ꢀC. After 30 min, the cooling bath was removed and
the solution was stirred for 12 h. Brine (10 mL) and diethyl
ether (10 mL) were added to the solution and the aqueous and
organic layers were separated. The latter was extracted again
with brine (3ꢂ10 mL). The organic layers were dried (Na2SO4),
filtered and the filtrate was concentrated in vacuo. The residue
was purified by column chromatography (silica gel, heptane/
ethyl acetate).
~
1688 (m),1608 (m),1579 (w),1512 (m),1463 (m),1385 (m),1296 (m),
1252 (s),1187 (m),1142 (s),1062 (w),1025 (m), 989 (m), 928 (w), 836
(m), 797 (m), 731 (w), 682 (w), 632 (m), 593 (m), 533 (m). GCeMS (EI,
70 eV): m/z (%): 406 (Mþ, 13), 278 (11), 277 (70), 264 (13), 263 (87),
231 (58), 203 (45), 175 (24), 162 (35), 161 (49), 135 (14), 134 (51), 133
(100), 119 (19), 115 (16), 101 (21), 91 (18), 87 (38), 73 (30), 59 (18), 41
(10). Anal. Calcd for C22H30O7 (406.47): C, 65.01; H, 7.44. Found: C,
65.18; H, 7.44.
3.4. General procedure for the synthesis of 1,3,5-tricarbonyl
compounds 3
3.5.1. Methyl 2,2,4,4-tetramethyl-5-(4-nitrophenyl)-3,5-dioxopen-
tanoate (4a). Starting with methyl 5-(4-nitrophenyl)-3,5-dioxope-
ntanoate (3a) (0.500 g, 1.9 mmol), Cs2CO3 (4.3 g, 13.2 mmol) and
iodomethane (0.83 mL, 13.2 mmol) in DMSO (1.9 mL), product 4a
was isolated as a colourless solid (0.123 g, 20%); mp 67 ꢀC. 1H NMR
To a suspension of the 1,3-bis(silyl enol ether) (2.0 equiv) in
CH2Cl2 (2 mL/mmol) was added the acid chloride (1.0 equiv) at
ꢁ78 ꢀC. The reaction mixture was allowed to warm to 20 ꢀC and
stirred for 12 h. After aqueous work-up using a saturated NaHCO3
solution, the aqueous layer was extracted with CH2Cl2. The com-
bined organic layers were dried (Na2SO4) and concentrated in
vacuo. The residue was purified by column chromatography (hex-
ane/EtOAc¼2:1) to give product 3. The synthesis of 3a,d,e,h,4a 3g,4b
3b,c,j6b and 3m,n12 has been previously reported.
(300 MHz, CDCl3):
OCH3), 8.00 (AA0XX0, 2H, Ar), 8.27 (AA0XX0, 2H, Ar). 13C NMR
(75 MHz, CDCl3):
¼24.0, 25.0, 52.1 (CH3), 55.7, 62.4 (C), 123.6 (CH
meta), 130.0 (CH ortho), 141.2 (C ipso), 149.8 (C para), 173.7, 196.2,
d¼1.38 (s, 6H, CH3), 1.52 (s, 6H, CH3), 3.57 (s, 3H,
d
208.7 (CO). IR (ATR, cmꢁ1):
n
¼ 3118 (w), 3003 (w), 2983 (w), 2959
~
(w), 2945 (w), 1742 (m), 1698 (m), 1671 (s), 1605 (w), 1520 (s), 1457
(w), 1441 (w), 1428 (w), 1393 (m), 1387 (m), 1346 (s), 1271 (m), 1241
(m),1189 (m),1167 (m),1134 (s), 1042 (s),1003 (m), 965 (s), 910 (m),
887 (m). MS (EI, 70 eV) m/z¼321 (Mþ, 0.2), 150 (100), 129 (10), 104
(15), 101 (14), 76 (10), 73 (18). Anal. Calcd for C16H19NO6 (321.33): C,
59.81; H, 5.96; N, 4.36. Found: C, 60.10; H, 6.079; N, 4.39.
3.4.1. Methyl 5-(2-furyl)-3,5-dioxopentanoate (3f). Starting with
1-furoylchloride (0.75 mL, 5.76 mmol) dissolved in CH2Cl2 (10 mL)
and 1,3-bis(silyl enol ether) (3.00 g, 11.52 mmol), 3f was isolated as
an orange oil (0.88 g, 73%). 1H NMR (300 MHz, CDCl3, keto/
enol¼0:100):
d
¼3.44 (s, 2H, CH2), 3.77 (s, 3H, CH3), 6.19 (s, 1H, CH),
3.5.2. Methyl
2,2,4,4-tetramethyl-3,5-dioxo-5-p-tolylpentanoate
6.56 (dd, 3J¼3.59, 1.73 Hz, 1H, CH), 7.19 (dd, 3J¼3.57 Hz, 4J¼0.75 Hz,
1H, CH), 7.59 (dd, 3J¼1.73 Hz, 4J¼0.77 Hz, 1H, CH), 15.22 (s, 1H, OH).
(4b). Starting with methyl 3,5-dioxo-5-p-tolylpentanoate (3b)
(0.641 g, 2.7 mmol), Cs2CO3 (6.2 g, 19.1 mmol) and iodomethane
(1.2 mL, 19.1 mmol) in DMSO (2.7 mL), product 4b was isolated as
13C NMR (75 MHz, CDCl3):
d¼44.4 (CH2), 52.5 (CH3), 96.5, 112.7,
116.4, 146.5 (CH), 149.8 (C), 168.0, 175.0, 185.1 (CO). IR (neat, cmꢁ1):
a colourless oil (0.459 g, 58%); 1H NMR (300 MHz, CDCl3):
d
¼1.32 (s,
6H, CH3), 1.49 (s, 6H, CH3), 2.38 (s, 3H, CH3), 3.54 (s, 3H, OCH3), 7.20
(m, 2H, Ar), 7.76 (m, 2H, Ar). 13C NMR (75 MHz, CDCl3):
¼21.6, 24.4,
24.6 (CH3), 52.0 (OCH3), 56.0, 62.1 (C),129.2,129.3 (CHAr),133.7,143.7
~
n
¼ 3133 (w, br), 2955 (w), 1738 (s), 1598 (s, br), 1466 (s), 1436 (s),
1387 (m), 1255 (s, br), 1227 (s), 1154 (s), 1090 (m), 1011 (s), 927 (m),
d
883 (s), 835 (m), 758 (s, br). MS (EI, 70 eV) m/z¼210 (Mþ, 31.2), 178

S. Erfle et al. / Tetrahedron 67 (2011) 8780e8789
8787
(CAr), 173.6, 196.6, 209.2 (CO). IR (ATR, cmꢁ1):
n
¼ 3017 (w), 3000
n
¼ 3138 (w), 2986 (w), 2949 (w), 1736 (m), 1703 (m), 1664 (s),
~
~
(w), 2978 (w), 2958 (w), 2942 (w), 2870 (w),1733 (m),1697 (m),1661
(s), 1603 (m), 1570 (w), 1467 (m), 1438 (m), 1408 (w), 1382 (m), 1369
(w), 1271 (m), 1247 (m), 1196 (m), 1172 (m), 1142 (s), 1123 (m), 996
(m), 957 (m), 915 (m), 883 (w), 837 (s). MS (EI, 70 eV) m/z¼290 (Mþ,
0.6), 119 (100), 91 (15), 73 (5). Anal. Calcd for C17H22O4 (290.35): C,
70.32; H, 7.64. Found: C, 70.48; H, 7.63.
1566 (w), 1462 (s), 1384 (m), 1367 (w), 1275 (s), 1229 (m), 1194 (m),
1144 (s), 1082 (w), 1045 (m), 1012 (m), 971 (s), 898 (m), 885 (m),
865 (m), 838 (m). MS (EI, 70 eV) m/z¼266 (Mþ, 20), 165 (43), 137
(43), 129 (14), 123 (10), 109 (78), 101 (33), 95 (100), 73 (44), 41 (16),
39 (14). Anal. Calcd for C14H18O5 (266.29): C, 63.15; H, 6.81. Found:
C, 63.21; H, 6.82.
3.5.3. Methyl 5-(3-chlorophenyl)-2,2,4,4-tetramethyl-3,5-dioxope-
ntanoate (4c). Starting with methyl 5-(3-chlorophenyl)-3,5-dioxo-
pentanoate (3c) (0.500 g, 1.9 mmol), Cs2CO3 (4.5 g, 13.7 mmol) and
iodomethane(0.86 mL,13.7 mmol)inDMSO(1.9 mL), product 4cwas
isolated as a colourless oil (0.338 g, 55%). 1H NMR (300 MHz, CDCl3):
3.5.7. Methyl
2,2,4,4-tetramethyl-3,5-dioxo-5-(thien-2-yl)penta-
noate (4g). Starting with methyl 3,5-dioxo-5-(thien-2-yl)penta-
noate (3g) (0.500 g, 2.2 mmol), Cs2CO3 (5.0 g, 15.5 mmol) and
iodomethane (0.97 mL, 15.5 mmol) in DMSO (2.2 mL), product 4g
was isolated as a colourless oil (0.460 g, 73%). 1H NMR (300 MHz,
d
¼1.35 (s, 6H, CH3), 1.49 (s, 6H, CH3), 3.56 (s, 3H, OCH3), 7.36 (dd,
CDCl3):
d
¼1.32 (s, 6H, CH3), 1.51 (s, 6H, CH3), 3.59 (s, 3H, OCH3), 7.06
3J¼8.0, 8.0 Hz, 1H, Ar), 7.50 (ddd, 3J¼8.0 Hz, 4J¼2.0, 2.0 Hz, 1H, Ar),
(dd, 3J¼5.0, 3.9 Hz, 1H, CH), 7.56 (dd, 3J¼3.9 Hz, 4J¼1.0 Hz, 1H, CH),
7.70 (ddd, 3J¼8.0 Hz, 4J¼2.0, 2.0 Hz, 1H, Ar), 7.85 (dd, 4J¼2.0, 2.0 Hz,
7.61 (dd, 3J¼5.0 Hz, 4J¼1.0 Hz, 1H, CH). 13C NMR (75 MHz, CDCl3):
1H, Ar). 13C NMR (75 MHz, CDCl3):
d¼24.2, 24.8 (CH3), 52.1 (OCH3),
d
¼24.1, 24.4 (CH3), 52.2 (OCH3), 55.9, 61.8 (C), 128.3, 132.9, 134.0
(CH), 143.4 (C), 173.6, 190.0, 208.2 (CO). IR (ATR, cmꢁ1):
n
¼ 3104
~
56.0, 62.2 (C),127.1,129.2,129.7,132.7 (CHAr),134.8,137.8 (CAr),173.6,
196.1, 208.9 (CO). IR (ATR, cmꢁ1):
n
¼ 3071 (w), 2998 (w), 2986 (w),
(w), 2986 (w), 2949 (w), 1737 (m), 1699 (m), 1647 (s), 1515 (w), 1467
(m), 1410 (s), 1386 (m), 1368 (w), 1354 (m), 1255 (s), 1192 (m), 1139
(m),1082 (w),1062 (m),1033 (s), 996 (m), 951 (m), 927 (m), 901 (m),
875 (w), 848 (m), 831 (m), 724 (s). MS (EI, 70 eV) m/z¼282 (Mþ, 6),
181 (8),125 (6),111 (100),101 (11), 73 (17). Anal. Calcd for C14H18O4S
(282.36): C, 59.55; H, 6.43; S,11.36. Found: C, 59.81; H, 6.45; S,11.35.
~
2875 (w), 2950 (w), 1740 (m), 1699 (m), 1674 (s), 1570 (w), 1469 (m),
1434 (w),1386(m),1368 (w),1254 (m),1142 (s),1040(m), 971 (s), 903
(w), 841 (w). MS (EI, 70 eV) m/z¼312 (Mþ, 37Cl, 0.3), 310 (Mþ, 35Cl,
0.8), 209 (4), 141 (33), 140 (7), 139 (100), 129 (5), 111 (17), 101 (9), 73
(11). Anal. Calcd for C16H19ClO4 (310.77): C, 61.84; H, 6.16; Cl, 11.41.
Found: C, 62.14; H, 6.167; Cl, 11.22.
3.5.8. Methyl 2,2,4,4-tetramethyl-5-(naphth-2-yl)-3,5-dioxopentanoate
(4h). Starting with methyl 5-(naphth-2-yl)-3,5-dioxopentanoate
(3h) (0.500 g, 1.8 mmol), Cs2CO3 (4.2 g, 12.9 mmol) and iodo-
methane (0.81 mL, 12.9 mmol) in DMSO (1.8 mL), product 4h was
isolated as a colourless oil (0.367 g, 62%). 1H NMR (300 MHz, CDCl3):
3.5.4. Methyl 5-(2-chlorophenyl)-2,2,4,4-tetramethyl-3,5-diox-
opentanoate (4d). Starting with methyl 5-(2-chlorophenyl)-3,5-
dioxopentanoate (3d) (0.450 g, 1.7 mmol), Cs2CO3 (4.0 g, 12.3 mmol)
and iodomethane (0.78 mL, 12.3 mmol) in DMSO (1.9 mL), product 4d
was isolated as a colourless oil (0.354 g, 65%). 1H NMR (400 MHz,
d
¼1.35 (s, 6H, CH3), 1.58 (s, 6H, CH3), 3.52 (s, 3H, OCH3), 7.51e7.62
(m, 2H, Ar), 7.84e7.98 (m, 4H, Ar), 8.36e8.38 (m, 1H, Ar). 13C NMR
(75 MHz, CDCl3):
¼24.6, 24.7, 52.1 (CH3), 56.2, 62.3 (C), 124.9,126.8,
127.7, 128.4, 128.7, 129.8, 130.9 (CHAr), 132.3, 133.6, 135.2 (CAr), 173.7,
CDCl3):
7.17e7.34 (m, 4H, Ar). 13C NMR (100 MHz, CDCl3):
52.2 (OCH3), 55.4, 63.5 (C), 126.0, 127.4, 130.1 (CHAr), 130.4 (CAr), 130.4
d
¼1.39 (s, 6H, CH3), 1.42 (s, 6H, CH3), 3.56 (s, 3H, OCH3),
d
¼23.4, 24.0 (CH3),
d
(CHAr), 138.6 (CAr), 174.0, 203.0, 207.4 (CO). IR (ATR, cmꢁ1):
n
¼ 2988
197.0, 209.4 (CO). IR (ATR, cmꢁ1):
¼ 3059 (w), 2985 (w), 2948 (w),
~
~
n
(w), 2940 (w), 1742 (m), 1707 (s), 1682 (m), 1589 (w), 1456 (m), 1442
(m), 1431 (m), 1391 (w), 1367 (w), 1264 (m), 1235 (w), 1186 (w), 1155
(m), 999 (m), 969 (m), 894 (w), 772 (m), 744 (m), 703 (m), 469 (m),
399 (w). MS (EI, 70 eV) m/z¼312 (Mþ, 37Cl, 0.1), 310 (Mþ, 35Cl, 0.3),
209 (1),141 (34),139 (100),111 (14), 73 (12). Anal. Calcd for C16H19ClO4
(310.77): C, 61.84; H, 6.16; Cl, 11.41. Found: C, 61.52; H, 6.27; Cl, 11.29.
2873 (w), 1736 (m), 1697 (m), 1666 (s), 1626 (m), 1596 (w), 1466 (m),
1434 (m), 1386 (m), 1368 (w), 1264 (m), 1226 (m), 1193 (m), 1145
(m), 1120 (m), 1038 (m), 1021 (m), 972 (m), 937 (m), 909 (m), 865
(m), 854 (m), 826 (m), 779 (m), 760 (m), 634 (w), 601 (w), 586 (w),
560 (w), 476 (m). MS (EI, 70 eV) m/z¼326 (Mþ, 4), 155 (100), 141 (6),
128 (14),127 (83),126 (11),101 (15), 73 (14). Anal. Calcd for C20H22O4
(326.39): C, 73.60; H, 6.79. Found: C, 73.39; H, 6.80.
3.5.5. Methyl 5-cyclopropyl-3,5-dioxo-2,2,4,4-tetramethylpentanoate
(4e). Starting with 3e (0.55 g, 3.0 mmol), K2CO3 (2.06 g, 14.9 mmol),
DMSO (1.8 mL) and iodomethane (0.93 mL, 14.9 mmol), 4e was iso-
lated as a colourless oil (0.16 g, 22%). 1H NMR (300 MHz, CDCl3):
3.5.9. Dimethyl 2,2,4,4-tetramethyl-3-oxopentanedioate (4i). Starting
with dimethyl 3-oxopentanedioate (3i) (0.600 g, 3.4 mmol), Cs2CO3
(7.86 g, 24.1 mmol) and iodomethane (1.5 mL, 24.1 mmol) in DMSO
(3.4 mL), product 4i was isolated as a colourless oil (0.508 g, 65%). 1H
d
¼0.91 (m, 2H, CH2), 1.02 (m, 2H, CH2), 1.38 (s, 6H, CH3), 1.39 (s, 6H,
CH3), 2.01 (m, 1H, CH), 3.67 (s, 3H, OCH3). 13C NMR (75 MHz, CDCl3):
¼12.4 (CH2), 16.9 (CH), 22.4, 23.7, 52.3 (CH3), 55.4, 63.3 (C), 173.9,
NMR (300 MHz, CDCl3):
NMR (75 MHz, CDCl3):
d
¼1.39 (s, 12H, CH3), 3.68 (s, 6H, OCH3). 13
C
d
d¼23.8 (CH3), 52.3 (OCH3), 55.2 (C), 173.8,
207.6, 207.9 (CO). IR (ATR, cmꢁ1):
n
¼ 2999 (w), 2986 (w), 2951 (w),
205.9 (CO). IR (ATR, cmꢁ1):
n
¼ 2990 (w), 2953 (w), 1732 (m), 1699
~
~
1744 (m), 1707 (w), 1686 (s), 1469 (w), 1386 (m), 1258 (m), 1194 (m),
1141 (s), 1100 (w), 1061 (m), 1034 (m), 1020 (m), 992 (s), 953 (w), 917
(w), 861 (w). HRMS (ESI): calcd for NaC13H20O4 ([MþNa]þ) 263.1254,
found 263.1254. Anal. Calcd for C13H20O4 (240.30): C, 64.98; H, 8.39.
Found: C, 65.02; H, 8.30.
(s), 1434 (m), 1385 (w), 1367 (m), 1260 (m), 1192 (m), 1035 (m), 1000
(m), 980 (m), 935 (w), 923 (w), 901 (w), 852 (w), 827 (w), 772 (w),
693 (w), 655 (w), 415 (w). MS (EI, 70 eV) m/z¼230 (Mþ, 0.6), 199
(12), 129 (55), 102 (10),101 (76), 73 (100), 70 (11), 69 (11), 59 (13), 42
(10), 41 (20). Anal. Calcd for C11H18O5 (230.26): C, 57.38; H, 7.88.
Found: C, 57.57; H, 7.90.
3.5.6. Methyl 5-(furan-2-yl)-2,2,4,4-tetramethyl-3,5-dioxopentanoate
(4f). Starting with methyl 5-(furan-2-yl)-3,5-dioxopentanoate
(3f) (0.400 g, 1.9 mmol), Cs2CO3 (4.4 g, 13.4 mmol) and iodo-
methane (0.84 mL, 13.4 mmol) in DMSO (1.9 mL), product 4f was
isolated as a colourless oil (0.377 g, 73%). 1H NMR (300 MHz,
3.5.10. Methyl 5-(4-methoxyphenyl)-2,2,4,4-tetramethyl-3,5-
dioxopentanoate (4j). Starting with methyl 5-(4-methoxyphenyl)-
3,5-dioxopentanoate (3j) (0.400 g, 1.6 mmol), Cs2CO3 (3.64 g,
11.2 mmol) and iodomethane (0.70 mL, 11.2 mmol) in DMSO
(1.9 mL), product 4j was isolated as a colourless oil (0.160 g, 33%). 1H
CDCl3):
d
¼1.33 (s, 6H, CH3), 1.45 (s, 6H, CH3), 3.58 (s, 3H, OCH3),
6.51 (dd, 3J¼3.6, 1.7 Hz, 1H, CH), 7.17 (dd, 3J¼3.6 Hz, 4J¼0.7 Hz, 1H,
NMR (300 MHz, CDCl3):
3H, OCH3), 3.81 (s, 3H, OCH3), 6.84 (m, 2H, Ar), 7.82 (m, 2H, Ar). 13
NMR (75 MHz, CDCl3):
¼24.3, 24.5 (CH3), 51.9 (OCH3), 55.3 (OCH3),
56.0, 61.8 (C), 113.5 (CHAr), 129.0 (CAr), 131.5 (CHAr), 163.1 (CAr), 173.5,
d
¼1.28 (s, 6H, CH3), 1.44 (s, 6H, CH3), 3.51 (s,
CH), 7.53 (dd, 3J¼1.7 Hz, 4J¼0.7 Hz, 1H, CH). 13C NMR (75 MHz,
C
CDCl3):
d
¼23.0, 24.5 (CH3), 52.1 (OCH3), 55.7, 60.8 (C), 112.4, 118.4,
d
146.0 (CH), 151.5 (C), 173.7, 186.5, 207.0 (CO). IR (ATR, cmꢁ1):

8788
S. Erfle et al. / Tetrahedron 67 (2011) 8780e8789
195.2, 209.3 (CO). IR (ATR, cmꢁ1):
n
¼ 2984 (w), 2947 (w), 2841 (w),
in a suspension of K2CO3 (1.46 g, 10.59 mmol) in DMSO (1.3 mL) and
iodomethane (0.7 mL, 10.59 mmol), 4n was isolated as a colourless
~
1736 (m), 1697 (m), 1664 (s), 1598 (s), 1573 (m), 11,510 (m), 1460 (m),
1385 (m),1367 (w),1312 (m),1153 (s),1028 (m), 996 (m), 952 (m), 912
(w), 840(m), 803 (w), 771(m), 694(w), 635(w), 613(m), 520(m), 423
(w). MS (EI, 70 eV) m/z¼306 (Mþ, 0.8),136 (12),135 (100). Anal. Calcd
for C17H22O5 (306.35): C, 66.65; H, 7.24. Found: C, 66.57; H, 7.32.
solid (0.08 g,11%);mp 74 ꢀC.1H NMR (300 MHz, CDCl3):
CH3), 1.58 (s, 6H, CH3), 3.73 (s, 3H, OCH3), 7.21e7.41 (m, 2H, Ar),
d
¼1.47 (s, 6H,
8.19e8.23 (m, 1H, Ar). 13C NMR (75 MHz, CDCl3):
d
¼23.4, 23.7 (CH3),
52.4 (OCH3), 55.6, 63.1 (C), 115.6 (d, 2J¼26.2 Hz, CHAr), 116.8 (d,
2J¼23.5 Hz, CHAr), 127.3 (d, 3J¼9.9 Hz, CHAr), 140.1 (d, 3J¼8.4 Hz, CAr),
3.5.11. Methyl 5-cyclohexyl-2,2,4,4-tetramethyl-3,5-dioxopentanoate
(4k). Starting with methyl 5-cyclohexyl-3,5-dioxopentanoate (3k)
(0.226 g, 1.0 mmol), Cs2CO3 (2.281 g, 7.0 mmol) and iodomethane
(0.44 mL, 7.0 mmol) in DMSO (1.0 mL), product 4k was isolated as
141.8 (CAr), 165.3 (d, 1J¼261 Hz, CF), 173.6, 201.7, 208.7 (CO). 19F NMR
(282 MHz, CDCl3):
d
¼ꢁ99.97 (CF). IR (ATR, cmꢁ1):
n
¼ 3114 (w),
~
3082 (w), 2993 (w), 2952 (w), 1744 (m), 1719 (m), 1688 (s), 1621 (w),
1585 (m), 1529 (s), 1474 (m), 1437 (m), 1406 (w), 1388 (w), 1346 (s),
1314 (w),1272 (s),1215 (m),1194(m),1150(s),1086 (w),1034 (m), 979
(m), 901 (w), 870 (s), 840 (s), 760 (m). HRMS (ESI): calcd for
NaC16H18FNO6 ([MþNa]þ) 362.10104, found 362.10084. Anal. Calcd
for C16H18FNO6 (339.32): C, 56.63; H, 5.35; N, 4.13. Found: C, 56.55; H,
5.25; N, 4.07.
a
d
colourless oil (0.231 g, 82%). 1H NMR (300 MHz, CDCl3)
¼1.20e1.26 (m, 4H, CH2), 1.37 (s, 6H, CH3), 1.37 (s, 6H, CH3),
1.61e1.77 (m, 6H, CH2), 2.74e2.84 (m, 1H, CH), 3.69 (s, 3H, OCH3).
13C NMR (75 MHz, CDCl3)
¼22.6, 23.8 (CH3), 25.6, 25.6, 30.3 (CH2),
45.9 (CH), 52.1 (OCH3), 55.0, 63.4 (Cq), 174.1 (COOCH3), 207.4, 211.9
d
(CO). IR (ATR, cmꢁ1):
n
¼ 2984 (w), 2930 (s), 2854 (m), 1746 (s),
~
1715 (s),1687 (s). MS (EI, 70 eV): m/z¼282 (Mþ,1),172 (11),140 (10),
111 (35), 83 (100), 55 (21), 41 (16). Anal. Calcd for C16H26O4
(282.375): C, 68.06; H, 9.28. Found: C, 67.593; H, 9.252.
3.6.3. Methyl 5-(2-nitrophenyl)-2,4,4-trimethyl-3,5-dioxopentanoate
(6). Starting with 3m (0.34 g, 1.28 mmol) dissolved in a suspension
of K2CO3 (0.89 g, 6.41 mmol) in DMSO (0.8 mL) and iodomethane
(0.40 mL, 6.41 mmol), 6 was isolated as a colourless oil (0.13 g, 33%).
3.5.12. Methyl 5-(2,6-difluorophenyl)-2,2,4,4-tetramethyl-3,5-dioxo-
pentanoate (4l). Starting with methyl 5-(2,6-difluorophenyl)-3,5-
dioxopentanoate (3l) (0.256 g, 1.0 mmol), Cs2CO3 (2.281 g,
7.0 mmol) and iodomethane (0.44 mL, 7.0 mmol) in DMSO (1.0 mL),
product 4l was isolated as a colourless oil (0.095 g, 31%). 1H NMR
1H NMR (300 MHz, CDCl3):
d
¼1.40 (d, 3J¼7.0 Hz, 3H, CH3), 1.56 (s,
3H, CH3), 1.57 (s, 3H, CH3), 3.70 (s, 3H, OCH3), 4.35 (q, 3J¼7.0 Hz, 1H,
CH), 7.37 (dd, 3J¼7.6 Hz, 4J¼1.5 Hz, 1H, Ar), 7.60 (ddd, 3J¼8.3, 7.5 Hz,
4J¼1.5 Hz, 1H, Ar), 7.73 (ddd, 3J¼7.6, 7.5 Hz, 4J¼1.2 Hz, 1H, Ar), 8.18
(dd, 3J¼8.3 Hz, 4J¼1.2 Hz, 1H, Ar). 13C NMR (75 MHz, CDCl3):
¼15.1,
d
(300 MHz, CDCl3)
d
¼1.44 (s, 6H, CH3), 1.49 (s, 6H, CH3), 3.70 (s, 3H,
21.9, 23.2 (CH3), 46.9 (CH), 52.5 (CH3), 63.4 (C), 124.5, 127.0, 130.1,
OCH3), 6.90e6.95 (m, 2H, Ar), 7.36e7.41 (m, 1H, Ar). 19F NMR
134.4 (CHAr), 136.8, 145.3 (CAr), 170.9, 203.0, 205.9 (CO). IR (ATR,
(282 MHz, CDCl3)
d
¼ꢁ109.7 (s, CArF). 13C NMR (75 MHz, CDCl3)
cmꢁ1):
n
¼ 2990 (w), 2950 (w), 1744 (m), 1716 (m), 1693 (s), 1573
~
d
¼22.7, 23.3 (CH3), 52.3 (OCH3), 55.4, 64.0 (Cq), 111.7 (m, CHAr), 116.8
(w), 1527 (s), 1458 (m), 1346 (s), 1304 (m), 1208 (m), 1081 (m), 1031
(m), 994 (m), 952 (s), 915 (w), 954 (m), 791 (m). HRMS (ESI): calcd
for NaC15H17NO6 ([MþNa]þ) 330.0948, found 330.0946. Anal. Calcd
for C15H17NO6 (307.30): C, 58.63; H, 5.58, N, 4.56. Found: C, 58.71;
H, 5.64, N, 4.52.
2
3
(t, JC,F¼24.0 Hz, CAr), 131.3 (t, JC,F¼9.9 Hz, CHAr), 158.4 (dd,
1JC,F¼249 Hz, 3JC,F¼8.3 Hz, CF), 174.0 (COOCH3), 199.1, 204.6 (CO). IR
(ATR, cmꢁ1):
n
¼ 3102 (w), 3065 (w), 2989 (m), 2952 (m), 2845 (w),
~
1745 (m), 1716 (s), 1693 (s), 1622 (s), 1588 (m). MS (EI, 70 eV): m/
z¼312 (Mþ,1), 211 (9),141 (100),129(16),101(17), 73 (21). Anal. Calcd
for C16H18F2O4 (312.309): C, 61.53; H, 5.81. Found: C, 61.523; H, 698.
3.7. General procedure for the synthesis of quinolines 5 and 7
3.6. General procedure for the synthesis of 4m,n
A MeOH solution of starting material and of Pd/C was stirred
under a hydrogen atmosphere for 24 h at 20 ꢀC. The catalyst was
filtered off and the filtrate was concentrated in vacuo. The residue
was purified by crystallization of EtOAc/heptanes-mixtures.
To a suspension of K2CO3 (5.0 equiv) in DMSO (0.3e0.5 mL/
mmol) was added 3 (1.0 equiv). To the reaction mixture was
dropwise added iodomethane (5.0 equiv) at 20 ꢀC with vigorous
stirring. After stirring at 20 ꢀC for 8 h, K2CO3 was removed by fil-
tration. The solid was thoroughly washed with diethyl ether. The
filtrate was washed with water until the yellow colour disappears,
dried (Na2SO4) and concentrated in vacuo. The residue was purified
by column chromatography (hexane/EtOAc¼2:1) to give product 4.
3.7.1. Methyl 2-methyl-2-(3,3,8-trimethyl-4-oxo-1,2,3,4-tetrahydr-
oquinolin-2-yl)propanoate (5). Starting with 4k (0.10 g, 0.30
mmol) dissolved in a suspension of Pd/C (10%) in MeOH (1.2 mL)
under H2-atmosphere, 5 was isolated as a yellow solid (0.05 g,
58%); mp 144 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼1.01 (s, 3H, CH3),
1.17 (s, 3H, CH3), 1.25 (s, 3H, CH3), 1.32 (s, 3H, CH3), 1.57 (d,
3J¼3.3 Hz, 1H, CH), 2.17 (s, 3H, CH3), 4.56 (d, 3J¼3.9 Hz, 1H, NH),
6.59 (m, 1H, Ar), 7.15 (m, 1H, Ar), 7.66 (m, 1H, Ar) (one signal not
3.6.1. Methyl 5-(3-methyl-2-nitrophenyl)-2,2,4,4-tetramethyl-3,5-
dioxopentanoate (4m). Starting with 3k (1.00 g, 3.58 mmol) dis-
solved in a suspension of K2CO3 (2.48 g, 17.91 mmol) in DMSO
(2.1 mL) and iodomethane (1.11 mL, 17.91 mmol), 4m was isolated
found). 13C NMR (75 MHz, CDCl3):
(CH3), 44.6, 47.5 (C), 52.7 (CH), 66.2 (OCH3), 116.3 (CHAr), 120.8
d
¼16.7, 19.3, 19.8, 26.2, 28.3
as a yellow oil (0.21 g, 17%). 1H NMR (300 MHz, CDCl3):
d¼1.46 (s,
(CAr), 125.5, 135.6 (CHAr), 146.9 (CAr), 177.8, 198.7 (CO) (one signal
not found). IR (ATR, cmꢁ1):
n
¼ 3385 (m), 2981 (m), 2951 (w),
~
6H, CH3), 1.51 (s, 6H, CH3), 2.40 (s, 3H, CH3), 3.64 (s, 3H, OCH3),
7.40e7.42 (m, 2H, Ar), 7.47e7.49 (m, 1H, Ar). 13C NMR (75 MHz,
1730 (s), 1655 (s), 1605 (s), 1587 (m), 1524 (m), 1469 (m), 1455
(m), 1436 (m), 1367 (w), 1357 (w), 1330 (m), 1265 (m), 1232 (m),
1203 (m), 1190 (m), 1139 (s), 1116 (m), 1097 (m), 1037 (m), 989
(m), 971 (m), 945 (w), 927 (w), 882 (w), 854 (m), 830 (m), 803
(w), 786 (w), 764 (w), 752 (s). MS (EI, 70 eV) m/z¼289 (Mþ, 22.9),
271 (21.1), 256 (60.4), 212 (100), 188 (86.9), 172 (23.7), 160 (74.6),
146 (27.7), 128 (10.9), 115 (10.4), 91 (21.9), 77 (8.6). Anal. Calcd for
C17H23NO3 (289.37): C, 70.56; H, 8.01, N, 4.84. Found: C, 70.44; H,
7.93, N, 4.69.
CDCl3):
d
¼18.1, 23.9, 24.3, 52.3 (CH3), 55.8, 63.0 (C), 125.7, 129.9
(CHAr), 131.9, 132.7 (CAr), 134.1 (CHAr), 173.6, 199.1, 208.0 (CO) (one
signal not found). IR (ATR, cmꢁ1):
n
¼ 2988 (w), 2951 (w),1744 (m),
~
1707 (m), 1683 (s), 1601 (w), 1533 (s), 1463 (m), 1387 (m), 1363 (m),
1262 (s), 1193 (m), 1141 (s), 1067 (w), 1029 (m), 978 (s), 902 (w), 856
(m), 826 (w). HRMS (ESI): calcd for NaC17H21NO6 ([MþNa]þ)
358.12611, found 358.12581. Anal. Calcd for C17H21NO6 (335.35): C,
60.89; H, 6.31; N, 4.18. Found: C, 60.76; H, 6.45; N, 3.95.
3.6.2. Methyl 5-(5-fluoro-2-nitrophenyl)-2,2,4,4-tetramethyl-3,5-di-
oxopentanoate (4n). Starting with 3k (0.6 g, 2.12 mmol) dissolved
3.7.2. 2-Ethyl-3,3-dimethyl-2,3-dihydroquinolin-4(1H)-one (7). Sta-
rting with 6 (0.23 g, 0.75 mmol) dissolved in a suspension of Pd/C

S. Erfle et al. / Tetrahedron 67 (2011) 8780e8789
8789
(10%) in MeOH (3.0 mL) under H2-atmosphere, 7 was isolated as
a yellow solid (0.08 g, 53%); mp 94 ꢀC. 1H NMR (300 MHz, CDCl3):
¼1.00e1.05 (m, 6H, CH3), 1.23 (s, 3H, CH3), 1.48e1.73 (m, 2H, CH2),
3.10 (m, 1H, CH), 4.52 (s, 1H, NH), 6.66 (m, 1H, Ar), 6.71 (m, 1H, Ar),
7.29 (m, 1H, Ar), 7.83 (m, 1H, Ar). 13C NMR (75 MHz, CDCl3):
References and notes
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.
2. For ethyl 3,5-dioxohexanoate, see for example: (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.
3. For a review, see: (a) Harris, T. M.; Harris, C. M. Tetrahedron 1977, 33, 2159; (b)
See also: Gilbreath, S. G.; Harris, C. M.; Harris, T. M. J. Am. Chem. Soc. 1988, 110,
6172.
4. (a) Rahn, T.; Nguyen, V. T. H.; Dang, T. H. T.; Ahmed, Z.; Lalk, M.; Fischer, C.;
Spannenberg, A.; Langer, P. J. Org. Chem. 2007, 72, 1957; (b) Rahn, T.; Dang,
T. H. T.; Spannenberg, A.; Fischer, C.; Langer, P. Org. Biomol. Chem. 2008, 6,
3366.
d
d
¼11.2,
18.1, 21.2 (CH3), 21.6 (CH2), 45.1 (C), 63.0 (CH), 115.4 (CHAr), 117.l
(CAr), 117.6, 128.3, 134.7 (CHAr), 149.7 (CAr), 199.2 (CO). IR (ATR,
cmꢁ1):
n
¼ 3381 (w), 3337 (m), 2968 (w), 2928 (w), 1646 (s), 1607
~
(s), 1581 (m), 1505 (s), 1482 (s), 1438 (m), 1378 (m), 1335 (s), 1307
(m), 1281 (m), 1262 (m), 1247 (m), 1230 (m), 1174 (m), 1155 (m),
1118 (m), 1094 (m), 1030 (m), 1006 (m), 976 (s), 952 (m), 908 (w),
883 (w), 857 (w), 837 (w), 789 (m). MS (EI, 70 eV) m/z¼203 (Mþ,
27.5), 174 (100), 160 (7.6), 146 (11.3), 132 (17.5). Anal. Calcd for
C13H17NO (203.28): C, 76.81; H, 8.43, N, 6.89. Found: C, 76.88; H,
8.37, N, 6.87.
5. Reim, S.; Michalik, D.; Weisz, K.; Xiao, Z.; Langer, P. Org. Biomol. Chem. 2008, 6,
3079.
6. (a) Rahn, T.; Jiao, H.; Baumann, W.; Spannenberg, A.; Langer, P. Eur. J. Org. Chem.
€
2008, 971; (b) Rahn, T.; Bendrath, F.; Hein, M.; Baumann, W.; Jiao, H.; Borner, A.;
Villinger, A.; Langer, P. Org. Biomol. Chem. 2011, 9, 5172.
7. See for example: (a) Kim, H. R.; Shin, S. I.; Park, H. J.; Jeon, D. J.; Ryu, E. K. Synlett
1998, 789; (b) Freskos, J. N.; Laneman, S. A.; Reilly, M. L.; Ripin, D. H. Tetrahedron
Lett. 1994, 35, 835.
3.8. Computational part
8. (a) Murin, B.; Riedl, W.; Risse, K. H.; Scheublein, M. Chem. Ber. 1959, 2033; (b)
Dunschmann, M.; von Pechmann, H. Liebigs Ann. Chem. 1891, 261, 173.
9. CCDC-812646 and 812647 contain all crystallographic details of this publica-
tion and is available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.
html or can be ordered from the following address: Cambridge Crystallographic
Data Centre, 12 Union Road, GB-Cambridge CB21EZ; fax: (þ44) 1223 336 033;
or deposit@ccdc.cam.ac.uk.
All calculations were carried out by using the Gaussian 03
program on the B3LYP/6-311þG** level of theory. All structures
were first optimized at the B3LYP/6-31G* level of theory and
characterized as either energy minimum without imaginary fre-
quencies or transition state with only one imaginary frequency on
the potential energy surface. The optimized structures were refined
at the B3LYP/6-311þG** level. For discussion and comparison, the
structural and energetic parameters at B3LYP/6-311þG** were
used. See also Supplementary data.
€
10. (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648; (b) Stevens, P. J.; Devlin, F. J.;
Chablowski, C. F.; Frisch, M. J. J. Phys. Chem. 1994, 98, 11623.
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Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Ki-
tao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev,
O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Moro-
kuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.;
Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A.
D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
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Wallingford CT, 2004.
Acknowledgements
Financial support by the DFG and by the State of Mecklenburg-
Vorpommern (scholarship for F.B.) is gratefully acknowledged.
Supplementary data
Details of the computational studies. Supplementary data as-
sociated with this article can be found, in the online version, at
doi:10.1016/j.tet.2011.08.065.
€
12. Rahn, T.; Appel, B.; Baumann, W.; Jiao, H.; Borner, A.; Fischer, C.; Langer, P. Org.
Biomol. Chem. 2009, 9, 1931.