One pot synthesis of nitrogen-containing polycyclic δ-lactones by double nucleophilic addition of bis(trimethylsilyl)ketene acetals to pyridines

Article abstract of DOI:10.1039/b201780f

Pyridine and bis(TMS)ketene acetals (TMS = trimethylsilyl) react successively with methylchloroformate and iodine (or peracids) to give, via functionalized dihydropyridines, bicyclic nitrogen-containing lactones which have been characterized by X-ray crys

Full text of DOI:10.1039/b201780f

One pot synthesis of nitrogen-containing polycyclic d-lactones by double
nucleophilic addition of bis(trimethylsilyl)ketene acetals to pyridines†
Henri Rudler,*a Bernard Denise,a Andrée Parliera and Jean-Claude Daranb
a Laboratoire de Synthèse Organique et Organométallique, UMR 7611, Université Pierre et Marie Curie, 4,
place Jussieu, 75252 Paris cedex 05, France. E-mail: rudler@ccr.jussieu.fr; Fax: +330144275504;
Tel: +330144275092
b Laboratoire de Chimie de Coordination, Université Paul Sabatier, 205 Route de Narbonne, 31077
Toulouse cedex 04, France
Received (in Cambridge, UK) 18th February 2002, Accepted 13th March 2002
First published as an Advance Article on the web 28th March 2002
Pyridine and bis(TMS)ketene acetals (TMS = trimethylsi-
lyl) react successively with methylchloroformate and iodine
(or peracids) to give, via functionalized dihydropyridines,
bicyclic nitrogen-containing lactones which have been char-
acterized by X-ray crystallography.
In a series of recent papers,1–4 we described the direct synthesis
of functionalised g-lactones upon interaction of bis(TMS)ke-
tene acetals with transition metal activated double bonds and
involving an original addition–oxidation–addition sequence.
This led, in the case of aromatic systems, to a dearomatization
reaction with formation of dihydrobenzofuran-2-ones (Scheme
1).
for H-2, and only one signal for H-3, at d 4.79 as a multiplet, for
H-4, at d 3.36 as a singlet, and for the three methyl groups at d
3.78 (1Me) and 1.13 (2Me). The 13C NMR spectrum also
exhibited separated signals for some of the carbons of the two
rotamers, for C-2 at d 124.9 and 124.6, and for C-3, at d 106.0
and 105.7. A similar behaviour was observed for various other
bis(trimethylsilyl) ketene acetals 2b–f which gave selectively
the expected dihydropyridyl carboxylic acids 5b–f.
An excess of iodine (2 equiv.) was then added to a
Scheme 1
dichloromethane solution of the acid 5a together with a
saturated aqueous solution of sodium bicarbonate and stirred for
These results and our current interest in the synthesis and uses
12 h. TLC confirmed the disappearance of the starting material
of dihydropyridines5–7 prompted us to extend a similar
and the formation of a single, less polar compound. Removal of
methodology for the transformation of pyridines. Three reasons
iodine in excess, followed by extraction, evaporation of the
guided this choice: first, the double bonds of pyridine, in
solvent, and chromatography gave a single product, as an oil, in
contrast to those of the above unsaturated systems, are very
78% yield. Its NMR data§ agreed with structure 6a and
readily activated towards nucleophilic additions via pyridinium
confirmed again the presence of two rotamers giving signals, for
the two carbonyl groups at d 173.8 and 152.6 (152.5 for the
derivatives, e.g. 1-acylpyridinium salts, reacting with a large
variety of nucleophiles among which are silyl enol ethers;8–10
second rotamer). The 13C NMR spectrum confirmed the
second, the monoaddition of bis(TMS)ketene acetals to pyr-
presence of a single double bond, of a deshielded methine group
idine would lead in one step to new a-dihydropyridinyl
at d 83.1 (82.7), and of a shielded methine group at d 13.6
carboxylic acids of direct interest as reducing agents for carbene
characteristic for a carbon bearing iodine.
complexes and for their pharmacological properties;11 and
third, the diaddition reaction might be the source of new,
bicyclic, nitrogen-containing lactones, as valuable new inter-
mediates for the synthesis of heterocyclic systems.
The purpose of this communication is to describe our
successful attempts in the preparation of both types of
compound, in the absence of any metal.
Thus, a dichloromethane solution (5 ml) of methylchlor-
oformate (1.55 mmol) was added to a solution of bis(TMS)ke-
tene acetal 2a (R1 = R2 = Me, 2.8 mmol) and pyridine 4 (1.5
mmol), at room temperature. Stirring for 1 h followed by
hydrolysis, extraction and evaporation of the solvent in vacuo
left an oil.
Chromatography on silica gel gave an oil, which, according
to TLC, appeared to be a single isomer. Its NMR data‡ agreed
with structure 5a, and indicated the presence of two rotamers at
room temperature, giving signals at d 6.93 and 6.79 as doublets
The acid 5b behaved similarly and led to the corresponding
lactone 6b (R1 = Ph, R2 = H), which was isolated as a
crystalline material, mp 134 °C. Tiny crystals, yet suitable for
an X-ray structure analysis, could be grown from dichloro-
methane–hexane.
A molecular projection of this compound appears in Fig. 1.¶
It confirms the bicyclic nature of the new product and thus the
formation of a d-lactone upon iodination of the enecarbamates
of the type 5 probably to give an N-acyliminium ion which is
trapped intramolecularly by the carboxylate, leading to a trans
† All new compounds described in this paper were fully characterized by
200 and 400 MHz 1H NMR, 50 or 100 MHz 13C NMR, mass spectrometry
and/or elemental analyses.
940
CHEM. COMMUN., 2002, 940–941
This journal is © The Royal Society of Chemistry 2002

Finally it is worthy to note that the O-silyl ketene N,O acetal
8 reacted under the same conditions as 2a–f to give in 75% yield
the corresponding homodihydronicotinamide 9. However, in
contrast to 5a, no lactonisation took place upon its treatment
with iodine.
This new method is being applied to the synthesis of chiral
dihydropyridines for the enantioselective reduction of carbene
complexes and further functionalizations of the lactones are in
progress.
Notes and references
‡ Spectral data for 5a; dH (200 MHz) 10.65 (s, br, 1H), 6.93 and 6.79 (d, J
7.4, 2H), 4.79 (s, br, 2H), 3.78 (s, 3H), 3.36 (s, br, 1H), 1.13 (s, 6H); dC (50
MHz) 183.62 (CO2H), 151.92 (COOMe), 124.94, 124.62, 106.00, 105.70
(CNC), 53.56 (OMe), 47.17 (CMe2), 40.18 (CH), 21.33 (2 Me).
§ For 6a; dH (400 MHz) 7.28, 6.92 (d, J 6, 1H), 6.40, 6.25 (s, 1H), 5.16 (t,
J 6.8, 1H), 5.06, 5.04 (s, 1H), 3.85 (s, 3H), 2.41, 2.39 (s, 1H), 1.45 (s, 3H),
1.35 (s, 3H), dC (100 MHz) 173.88 (CO), 152.67, 152.50 (CO), 121.79
(CNC), 105.42, 104.99 (CNC), 83.18, 82.69 (C(N)O), 54.08 (OCH3), 46.66
(Cq), 44.51, 44.37 (CH), 27.26, 26.12 (Me), 13.64 (C-I).
Fig. 1 Molecular view (ORTEP3)15 with the atom labelling scheme.
Ellipsoids are drawn at 50% probability. Selected bond distances (Å) and
bond angles (°): C(1)–I(1) 2.148(7), C(1)–C(4) 1.511(10), C(4)–C(3)
1.493(10), C(3)–C(2) 1.317(11), C(2)–N(1) 1.438(9), N(1)–C(7) 1.441(9),
C(7)–O(1) 1.457(10), C(7)–C(1) 1.510(10), O(1)–C(6) 1.360(9), C(6)–
O(61) 1.181(10), C(6)–C(5) 1.530(9), C(5)–C(4) 1.558(10), N(1)–C(11)
1.370(9), C(11)–O(11) 1.184(9), C(11)–O(12) 1.365(9), O(12)–C(12)
1.439(9); C(4)–C(1)–C(7) 108.4(6), C(4)–C(1)–I(1) 114.1(5), C(7)–C(1)–
I(1) 109.3(5), C(1)–C(4)–C(3) 110.2(6), C(4)–C(3)–C(2) 122.4(7), C(3)–
C(2)–N(1) 122.1, N(1)–C(11)–O(11) 125.3(7), N(1)–C(11)–O(12)
109.8(6), O(11)–C(11)–O(12) 125.0(7).
¶ Crystal data for 6b: [C15H14INO4]; Mr = 399.17; monoclinic; space
group P21/n; a = 6.1448(5), b
92.97(1)°, V = 1455.3(2) Å3, Z = 4, rcalcd. = 1.822 Mg m23, m = 2.216
mm21, numerical absorption correction applied, Tmin = 0.5938, Tmax
= 12.505(1), c = 18.965(1) Å, b =
=
0.6860; MoKa radiation; T
= 180 K; w/o scans (Oxford-Diffraction
orientation of the carbon–iodine bond with respect to the new
carbon-oxygen bond.
Xcalibur);12 2qmax = 50.04°; reflections collected/unique used, 7143/2514
(Rint = 0.0889) 2119 [I > 2s(I)]; parameters refined, 191; R/wR2[(I >
This easy two-step diaddition reaction prompted us to attempt
the one pot transformation of pyridine into the lactone 6a. Thus,
treatment of the mixture of pyridine and bis(TMS)ketene acetals
2a first with methylchloroformate, at room temperature for one
hour, then with an excess of iodine, followed by stirring
overnight, led to the expected lactones 6a in a 90% yield.
A further possibility existed for the transformation of the
acids 5 into lactones: the oxidative cyclization via the
epoxidation of one of the double bonds of the dihydropyridines
5.4,5
2s(I)] = 0.0660/0.1593; GOF = 1.123; D/smax = 0.006; [Dr]min/[Dr]max
,
21.31/1.72. Structure solution and refinement with the programs SIR9713
and SHELXL97.14 CCDC 178733. See http://www.rsc.org/suppdata/cc/b2/
b201780f/ for electronic files in .cif or other electronic format.
∑ For 7a; dH 6.94 (d, J 8.2, 1H), 6.81 (d, J 8.2, 1H), 6.34, 6.18 (s, br, 1H),
5.10, 5.02 (d, J 8.2), 4.79 (s, br, 1H), 3.84 (s, 3H), 2.36, 2.38 (s, 1H), 1.42
(s, 3H), 1.37 (s, 3H); dC 152.83, 152.70 (CO), 121.84 (CNC), 103.93, 103.52
(CNC), 81.21, 80.83 (C(N)O), 51.04 (OCH3), 46.17 (CMe2), 45.60 (COH),
42.60, 42.52 (CH), 27.17 (Me), 26.02( Me).
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