An expedient synthesis of 6-arylpiperidine-2,4-diones by chain-extension of β-aryl-β-aminoacids

Article abstract of DOI:10.1016/S0040-4039(01)01991-8

The synthesis of novel 6-arylpiperidine-2,4-diones is described in five steps starting from β-aryl-β-aminoacids via the chain extension of the latter into δ-aryl-δ-amino-β-ketoacids. The chemical pathway involves an acylation of Meldrum's acid and yields useful building blocks for heterocyclic chemistry.

Full text of DOI:10.1016/S0040-4039(01)01991-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8997–8999
An expedient synthesis of 6-arylpiperidine-2,4-diones by
chain-extension of b-aryl-b-aminoacids
Nicolas Leflemme, Patrick Dallemagne* and Sylvain Rault
Centre d’Etudes et de Recherche sur le Me´dicament de Normandie, UFR des Sciences Pharmaceutiques,
1, rue Vaube´nard, 14032 Caen cedex, France
Received 10 October 2001; revised 22 October 2001; accepted 24 October 2001
Abstract—The synthesis of novel 6-arylpiperidine-2,4-diones is described in five steps starting from b-aryl-b-aminoacids via the
chain extension of the latter into d-aryl-d-amino-b-ketoacids. The chemical pathway involves an acylation of Meldrum’s acid and
yields useful building blocks for heterocyclic chemistry. © 2001 Elsevier Science Ltd. All rights reserved.
We have recently pointed out the interest of the dihy-
dropyridones of the type 1 as memory enhancers in
relation with their nicotinic acetylcholine receptor
affinity.1 Their synthesis was achieved starting from
b-aryl-b-aminoacids 2, converted in three steps into the
chain-extension of 2, rather than from the corresponding
aldehydes, using Roskamp’s protocol,7 or from aryli-
denetoluenesulfinamides prepared in delicate conditions
with expensive reagents.8 The effectiveness of the
present preparation of 4 designates furthermore 5 and 6
as useful building blocks in pseudopeptide chemistry and
in some alkaloid synthesis.9
N-protected d-aryl-d-amino-b-ketoketones
3 before
being cyclised to 1 (Scheme 1).2
In connection with this study, we required an efficient
preparation for the infrequently reported piperidine-
diones 4, the oxidised analogs of 1. Taking our experi-
ence in the b-aryl-b-aminoacids field into account, we
focused on the improved synthesis of 4, starting from
these readily available, eventually chiral, starting materi-
als.3–6 The chemical pathway involved the cyclisation of
d-aryl-d-amino-b-ketoacids derivatives 5–6, obtained by
We chose to exploit the condensation of 3-trifluoro-
acetylamino-3-arylpropionyl chlorides 7a–d, derived
from aminothienyl, furyl and phenylpropionic acids
2a–d, with Meldrum’s acid in dichloromethane in the
presence of pyridine, followed by refluxing in methanol
or tertbutanol, to afford the corresponding d-aryl-d-trifl-
uoroacetylamino-b-ketoesters 5a–d and 6a–d (Scheme 2).
Scheme 1.
Keywords: 6-arylpiperidine-2,4-diones; d-aryl-d-amino-b-ketoacids; b-aryl-b-aminoacids; Meldrum’s acid; chain-extension.
* Corresponding author. Tel.: 33 2 31 56 59 10; fax: 33 2 31 93 11 88; e-mail: dallemagne@pharmacie.unicaen.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01991-8

8998
N. Leflemme et al. / Tetrahedron Letters 42 (2001) 8997–8999
Yields of this sequence, ranging from 71 to 79%, were
higher than those obtained with treatment of 7a–d by
ethyl malonate magnesium or lithium salts.10,11
Finally, cyclisation of 5a–d or 6a–d was achieved by a
mild alkaline treatment, using a 2N aqueous NaOH
solution in THF, to give in 79–89% yields 4a–d12
among which 4d was the sole hitertho reported 6-
arylpiperidine-2,4-dione.8
The potential interest of d-aryl-d-trifluoroacetylamino-
b-ketoesters 5a–d and 6a–d, as useful building blocks,
prompted us to study the conditions of their O and N
deprotection. Whilst, methyl esters 6a–d did not lend
themselves to hydrolysis, tertbutyl derivatives 5a–d, led
in trifluoroacetic acid at room temperature to the d-
aryl-d-trifluoroacetylamino-b-ketoacids 9a–d, in near-
quantitative yields. Removal of the trifluoroacetic
group of 9a–d occurred in refluxing aqueous hydrochlo-
ric acid solution, but with subsequent decarboxylation,
yielding the aminoaryl-butanone hydrochloric salts
10a–d.
The same general pathway, applied for example to
(R)-(+) 3-amino-3-phenylpropionic acid 2d, issued from
the penicillin acylase-catalysed hydrolysis of the corre-
sponding N-phenylacetyl derivative 11d, according to
the Soloshonok procedure,13 led without racemisation
to (R)-(+) 4d (Scheme 3).14
In summary, this paper describes a very easy, cheap
and versatile preparation of the title compounds. The
biological evaluation of 4a–d and related compounds
Scheme 2. (i) TFA/TFA2O; (ii) (ClCO)2/CH2Cl2; (iii) Meldrum’s acid/pyridine/CH2Cl2; (iv) MeOH or tertBuOH; (v) TFA/
CH2Cl2; (vi) (6N) HCl/H2O; (vii) (2N) NaOH/H2O/THF.
Scheme 3. (i) ClCOCH2C6H5/H2O/Me2CO; (ii) penicillin acylase/NaHCO3/H2O.

N. Leflemme et al. / Tetrahedron Letters 42 (2001) 8997–8999
8999
and the chemical reactivity of 5, 6 are currently under
methylene chloride (50 ml), was added oxalyl chloride
(0.15 mol) and the reaction mixture was refluxed for 3 h.
The solvent was evaporated under reduced pressure to
afford 7a (88%). A mixture of Meldrum’s acid (0.021
mol) and pyridine (0.05 mol) in dry methylene chloride
(50 ml) was stirred for 0.5 h at rt. The reaction mixture
was then cooled at 0°C and 7a (0.02 mol) was added
dropwise. The reaction mixture was quenched after 2 h at
0°C by adding an aqueous HCl (1N) solution and
extracted twice with methylene chloride (50 ml). The
combined organic layers were dried over calcium chloride
and evaporated in vacuo. The Meldrum’s adduct 8a was
refluxed for 4 h in methanol (50 ml) and evaporated to
dryness. The oily residue was dissolved in methylene
chloride (50 ml), washed with a saturated aqueous
NaHCO3 solution, dried over calcium chloride and evap-
orated to dryness to give 6a (79%). To a stirred solution
of 6a (0.02 mol) in THF (20 ml) was added an aqueous
NaOH (2N) solution (20 ml). After 2 h, the solution was
acidified to pH 6.5 with an aqueous HCl (1N) solution
and extracted twice with methylene chloride (25 ml). The
combined organic layers were dried over calcium chloride
and evaporated in vacuo to give 4a (84%) as white
investigation.
References
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12. The experiment is as follows: Synthesis of 4a. To a
solution of 2a (0.03 mol) in trifluoroacetic acid (10 ml),
was added trifluoroacetic anhydride (0.075 mol) and the
reaction mixture was stirred for 1 h at rt. The solvent was
evaporated under reduced pressure and the oily residue
was poured into a saturated aqueous NaHCO3 solution.
The aqueous layer was washed with diethyl ether (50 ml),
acidified to pH 1 with an aqueous HCl (6N) solution and
extracted twice with diethyl ether (50 ml). The combined
organic layers were dried over magnesium sulfate and
evaporated to dryness. To a solution of the residue in dry
1
crystals. Mp: 174°C; IR (KBr) 3183, 1716, 1668 cm−1; H
NMR (400 MHz, CDCl3) l 2.93 (2H, ddd, J=4.5, 8.3
and 16.3 Hz, CH2), 3.34 (2H, dd, J=19.9 and 19.9 Hz,
CH2), 4.95 (1H, m, CH), 6.42 (1H, bs, NH), 7.04 (1H, dd,
J=1.0 and 4.9 Hz, Harom.), 7.23 (1H, dd, J=1.0 and 2.9
Hz, Harom.), 7.40 (1H, dd, J=2.9 and 4.9 Hz, Harom.); 13C
NMR (100 MHz, CDCl3) l 46.0, 47.4, 48.7, 122.1, 125.1,
128.1, 140.2, 168.7, 202.1. Anal. calcd for C9H9NO2S: C,
55.37; H, 4.65; N, 7.17. Found: C, 55.62; H, 4.59; N,
6.88.
13. Soloshonok, V. A.; Fokina, N. A.; Rybakova, A. V.;
Shishkina, I. P.; Galushko, S. V.; Sorochinsky, A. E.;
Kuhkar, V. P. Tetrahedron: Asymmetry 1995, 6, 1601–
1610.
14. (R)-(+) 4d: [h]D20=124.9 (c 0.025 MeOH), [lit.8: [h]D20=
124.3 (c 0.37, CHCl3).