A convenient synthesis of 2-methyl-3-oxoheptane-1,7-dicarboxylic esters and amides

Article abstract of DOI:10.1016/j.tetlet.2004.02.067

A range of simple derivatives of 2-methyl-3-oxoheptane-1,7-dicarboxylic acid have been prepared by Birch reduction/methylation of 2,6-dimethoxybenzoic acid derivatives followed by solvolysis.

Full text of DOI:10.1016/j.tetlet.2004.02.067

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2899–2901
A convenient synthesis of 2-methyl-3-oxoheptane-1,7-
dicarboxylic esters and amides
Mark C. Elliott,a,* Matthew J. Gist,a Falmai Binnsb and Richard G. Jonesb
aSchool of Chemistry, Cardiff University, PO Box 912, Cardiff CF10 3TB, UK
bBaxenden Chemicals Ltd, Paragon Works, Baxenden, Accrington BB5 2SL, Lancashire, UK
Received 4 January 2004; revised 4 February 2004; accepted 13 February 2004
Abstract—A range of simple derivatives of 2-methyl-3-oxoheptane-1,7-dicarboxylic acid have been prepared by Birch reduction/
methylation of 2,6-dimethoxybenzoic acid derivatives followed by solvolysis.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
O
X
O
X
Na, NH3
then R-I
R
MeO
OMe
MeO
OMe
Derivatives of 3-oxoheptane-1,7-dioic acid have been
prepared a number of times, mostly using Claisen or
dianion chemistry.1 These compounds are of interest as
synthetic intermediates,2 and the corresponding amides
have been shown to have activity as inhibitors of human
dihydrorotate dehydrogenase.3
R1OH
O
O
O
R1O
X
The formation of differentiated dicarbonyl compounds
is of general synthetic interest, especially in the case of
similar carbonyls such as the carboxylic acids in the
present case.4 We now report a convenient synthesis of
the title compounds based on the hydrolytic and sol-
volytic ring-opening of Birch reduction products as
shown in the general Scheme 1.
R
Scheme 1.
O
O
OMe
OMe
OMe
i
Me
MeO
The Birch reduction/alkylation of benzoic acid deriva-
tives, largely developed by Mander5 and Schultz6 and
their respective co-workers, has been used numerous
times over the last 30 years.7
MeO
OMe
1, 81%
In our hands, the reductive alkylation of methyl
2,6-dimethoxybenzoate initially proved problematic,
and it was only when we first distilled the supposedly
anhydrous liquid ammonia from sodium that we were
able to isolate compound 1 in good yield (Scheme 2).
The preparation of the corresponding amides by this
method failed, although we were able to carry out nor-
Scheme 2. Reagents and conditions: (i) K, NH3, THF, t-BuOH then
MeI.
mal Birch reductions to give 2 and 3 with no problems
(Scheme 3). In the attempted reductive alkylations,
variable amounts of the same compounds were formed.
With ester 1 in hand, the simplest way to access the
required amides was by reaction with the corresponding
lithium amides. This worked well for the anilide 4
but was less effective for n-propylamide 5 (Scheme 4).
Keywords: Birch reduction.
* Corresponding author. Tel.: +44-29-20874686; fax: +44-29-208740-
30; e-mail: elliottmc@cardiff.ac.uk
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.067

2900
M. C. Elliott et al. / Tetrahedron Letters 45 (2004) 2899–2901
O
O
O
O
NHR
OMe
NHR
OMe
NHR
OMe
NHR
O
i
i
Me
MeO
Me
MeO
H
MeO
MeO
4, R = Ph
7, R = Ph
2, R = Ph, 99%
5, R = n-Pr
8, R = n-Pr
3, R = n-Pr, 83%
Scheme 5. Reagents and conditions: (i) THF, H2O, 2 M HCl, 2 h.
Scheme 3. Reagents and conditions: (i) K, NH3, THF, t-BuOH then
NH4Cl.
catalyst. Reactions were generally complete within 2 h,
although for convenience the reaction could be left
longer with no loss in isolated yield. In most cases the
crude products were essentially pure, and satisfactory
spectroscopic data were obtained directly.
O
O
OMe
OMe
NHR
OMe
i
Me
MeO
Me
MeO
Various modified protocols were investigated with the
aim of forming more hindered esters, particularly
t-butyl. These were unsuccessful, with the acids 6a–c
being obtained in these cases as sole products. Similarly,
use of ammonium chloride failed to give the corre-
sponding unsymmetrical amides. However, these reac-
tions were only briefly investigated.
4, R = Ph, 75%
1
5, R = n-Pr, 22%
Scheme 4. Reagents and conditions: (i) RNH2, n-BuLi, THF, 0 ꢁC
then 1, 0–25 ꢁC.
Nevertheless, we were able to prepare sufficient quanti-
ties of the amides to carry out hydrolysis studies.
We considered the possibility that hydrolysis of com-
pounds 1, 4 and 5 might give rise to the cyclic 1,3-di-
carbonyl compounds under suitably mild conditions.
Although this proved not to be the case, we were able to
accomplish the partial hydrolysis of compounds 4 and 5
by addition of dilute hydrochloric acid (2 M) to give
compounds 7 and 8 in aqueous THF solution (Scheme
5). After stirring for 2 h, monitoring the disappearance
of starting material by TLC analysis, the desired com-
pounds were obtained in good yields (Scheme 5).
Compounds 1, 4 and 5 were subjected to solvolysis
under a range of conditions. The results are summarised
in Table 1. Stirring compounds 1, 4 or 5 in THF with
concentrated hydrochloric acid gave compounds 6a–c in
variable yields (entries 1–3). The lower yields in entries 2
and 5 are probably not representative. For example,
compound 6b was prepared in 80% yield by addition of
a dichloromethane solution of boron tribromide to
compound 4 in the same solvent. After 48 h the product
was isolated by normal aqueous work-up. Reaction of
the same substrates with methanol and ethanol were
also straightforward (entries 4–9). In these cases the
alcohol was used as solvent, again with the addition of a
small amount of concentrated hydrochloric acid as
Typical experimental procedures and selected data are
as follows.8
2. Methyl-7-anilino-6-methyl-5,7-dioxoheptanoate 6e
Table 1. Solvolysis reactions of compounds 1, 4 and 5
2,6-Dimethoxy-1-methyl-N-phenylcyclohexa-2,5-diene-
1-carboxamide (0.1 g, 0.37 mmol) was dissolved in
MeOH (3 mL). To this was added concentrated hydro-
chloric acid (0.5 mL). The flask contents were then
stirred for 2 h. Following the addition of water (10 mL),
the organic materials were extracted with ethyl acetate
(3 · 20 mL). The combined organic phases were dried
over sodium sulfate and concentrated in vacuo. Purifi-
cation by flash column chromatography (1:1 hexane/
ether) gave the title compound (0.41 g, 42%) as a col-
ourless solid, mp 62–64 ꢁC (Found: C, 65.28; H, 7.22; N,
5.15%. C15H19NO4 requires C, 64.97; H, 6.91; N,
5.05%.) mmax (Nujol mull)/cmÀ1 1728 and 1680; dH
(400 MHz; d6-DMSO) 8.32 (1H, br s, NH) 7.53 (2H, d, J
7.9, phenyl 2-H and 6-H), 7.33 (2H, apparent t, J 7.9,
phenyl 3-H and 5-H), 7.12 (1H, t, J 7.4, phenyl 4-H),
3.66 (3H, s, OCH3), 3.57 (1H, q, J 7.2, HCCH3), 2.71
(2H, t, J 7.0, OCCH2), 2.36 (2H, t, J 7.1, MeO2CCH2),
1.93 (2H, apparent quintet, J 7.1, CH2CH2CH2) and
1.51 (3H, d, J 7.2, H3C).
O
X
O
O
O
ROH/H+
Me
MeO
OMe
RO
X
Me
1, 4, 5
6a - 6i
Product Time (h)
Entry
X
R
Yield (%)a
1
2
3b
4
5
6
7
8
9
OMe
NHPh
H
6a
6b
6c
6d
6e
6f
2
2
84
31 (80)b
83
H
NHn-Pr
OMe
H
3
Me
Me
Me
Et
Et
Et
6
98
42
NHPh
NHn-Pr
OMe
2
15
36
5
88
94
6g
6h
6i
NHPh
NHn-Pr
92
92
15
a Refers to isolated yield. Most experiments were conducted only once,
so these results are not optimised.
b Yield in parentheses refers to hydrolysis using BBr3/H2O.

M. C. Elliott et al. / Tetrahedron Letters 45 (2004) 2899–2901
2901
Bestmann, H. J.; Graf, G.; Hartung, H. Angew. Chem.,
Int. Ed. Engl. 1965, 4, 596–597; For related compounds see
Stritzke, K.; Schulz, S.; Nishida, R. Eur. J. Org. Chem.
2002, 3884–3892.
3. 2-Methoxy-1-methyl-6-oxo-N-phenylcyclohex-
2-ene-1-carboxamide 7
2,6-Dimethoxy-1-methyl-N-phenylcyclohexa-2,5-diene-
1-carboxamide (0.17 g, 0.62 mmol) was dissolved in
THF (10 mL). Water (15 mL) was added followed by
2 M hydrochloric acid (3 mL). The reaction was allowed
to stir for 2 h after which the reaction was seen to be
complete by TLC analysis (Et2O solvent system). Fol-
lowing the addition of saturated aqueous sodium
bicarbonate solution, the product was extracted into
ethyl acetate and the organic layer separated and dried
over sodium sulfate. Following filtration the solvent was
removed in vacuo. The product was recrystallised from
2:1 hexane/Et2O to yield the pure title compound,
(0.11 g, 68%) as a colourless solid, mp 90–92 ꢁC. mmax :
(Nujol mull)/cmÀ1 3380, 1731 and 1684; dH (400 MHz;
CDCl3) 8.00 (1H, br s, N-H), 7.47 (2H, d, J 7.7, phenyl
2-H and 6-H), 7.31 (2H, apparent t, J 8.0, phenyl 3-H
and 5-H), 7.10 (1H, t, J 7.5, phenyl 4-H), 5.10 (1H, dd,
J1 5.2, J2 3.2, CH), 3.71 (3H, s, CH3O), 2.78 (1H, m,
OCHCH) 2.52 (2H, m, HCCH2), 2.36 (1H, m, OCHCH)
and 1.59 (3H, s, CH3).
2. Hunter, J. H.; Hogg, J. A. J. Am. Chem. Soc. 1949, 71,
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J. Chem. Soc. 1960, 1571–1575; Nasipuri, D.; Guha, M.
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4. For example see Schwarz, K.-H.; Kleiner, K.; Ludwig, R.;
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1263–1271.
In summary, we have developed a convenient approach
to the title compounds by Birch reduction/alkylation of
2,6-dimethoxybenzoic acid derivatives followed by sol-
volysis. The approach appears to be reasonably general,
although some limitations have been highlighted.
7. House, H. O.; Strickland, R. C.; Zaiko, E. J. J. Org. Chem.
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Acknowledgements
We are extremely grateful to Baxenden Chemicals Ltd
for financial support.
References and notes
8. All new compounds were characterised by a combination of
proton and 13C NMR spectroscopy, infrared spectroscopy
and mass spectrometry.
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