Selective functionalizations of 2-phenylpyridine: lactones upon organic versus organometallic activations

Article abstract of DOI:10.1016/j.tetlet.2006.05.006

2-Phenylpyridine activated by chromium tricarbonyl reacts with bis(TMS) ketene acetals to give pyridine-substituted bicyclic γ-lactones. On the other hand, its reaction with the same acetals leads, upon activation with methylchloroformate, to dihydropyrid

Full text of DOI:10.1016/j.tetlet.2006.05.006

Tetrahedron Letters 47 (2006) 4553–4556
Selective functionalizations of 2-phenylpyridine: lactones
upon organic versus organometallic activations
a
b
a,
a
b
*
´
´
Yiming Xu, Eugenia Aldeco-Perez, Henri Rudler, Andree Parlier and Cecilio Alvarez
aLaboratoire de Chimie Organique, UMR-CNRS 7611, Institut de Chimie Mole´culaire, Universite´ Paris VI,
T 44-45 4 place Jussieu, 75252 Paris Cedex 5, France
bInstituto de Qu´ımica UNAM, Circuito Exterior, Ciudad Universitaria Coyoacan, CP 04510 Mexico DF, Mexico
Received 23 March 2006; revised 26 April 2006; accepted 2 May 2006
Available online 22 May 2006
Abstract—2-Phenylpyridine activated by chromium tricarbonyl reacts with bis(TMS) ketene acetals to give pyridine-substituted
bicyclic c-lactones. On the other hand, its reaction with the same acetals leads, upon activation with methylchloroformate, to dihy-
dropyridines which can be oxidized to highly substituted, lactone-containing piperidines.
Ó 2006 Elsevier Ltd. All rights reserved.
The lactone function is the pharmacophore of many nat-
R1
R2
O
O
SiMe3
SiMe3
B
ural and nonnatural molecules possessing important
biological properties: lactones fused to heterocycles are
part of this class of compounds.1–5 During our ongoing
research in this area, we were faced with the problem of
the selective functionalization of 2-phenylpyridine 1 and
more precisely with the introduction of a lactone func-
tion on each of the two aromatic rings. Although, both
substituted benzene and pyridine rings had already been
submitted separately to such modifications,6–13 the easy
introduction of such functions in this substrate was not
obvious for steric and electronic reasons.
A
N
1
Scheme 1.
mium tricarbonyl complex 2 in 63% yield as a yellow
solid mp 120 °C.
The goal of this communication is to show that this can
nevertheless be achieved by first activating the phenyl
ring with a metal, in this case chromiumtricarbonyl
(route A), and second, by activating the pyridine ring
with an acylium ion (route B), both intermediate ‘com-
plexes’ undergoing a double nucleophilic addition of a
1,3-C,O-dinucleophile originating from a bis(TMS) ke-
tene acetal14–16 (Scheme 1). As far as the first attempt
is considered, in contrast to the two other isomers of
phenylpyridine which gave only the nitrogen coordi-
nated chromiumpentacarbonyl complexes,17 2-phenyl-
The addition of the ketene acetal 3a to complex 2 in
THF/DMF, in the presence of a twofold excess of a
molar solution of t-BuOK in THF, at ꢀ76 °C and stirring
for 4 h, was followed by the addition of an excess of
iodine in THF (4 equiv) at the same temperature. The
solution was kept at room temperature overnight and
iodine in excess eliminated. Work up led to a mixture
of two compounds which were separated by silica gel
chromatography (Scheme 2). As a consequence of the
NMR data,19 structure 4a was given to the less polar
product, isolated in 18% yield as white crystals mp
162 °C, an acid resulting from the ortho addition of
the ketene acetal acting as a C-nucleophile to the phenyl
ring of phenylpyridine, followed by a iodine-induced
rearomatization.20,21
pyridine
1
reacts with chromium hexacarbonyl,
according to the literature,18 to give the expected chro-
Keywords: Phenylpyridine; Bis(TMS) ketene acetals; Nucleophilic
additions; c- and d-Lactones.
According to its physical properties,22 the more polar
*
Corresponding author. Tel.: +33 01442 75092; fax: +33 01442
75504; e-mail: rudler@ccr.jussieu.fr
product 5a (13%) is not an acid but a lactone (dCO,
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.006

4554
Y. Xu et al. / Tetrahedron Letters 47 (2006) 4553–4556
observed, the yield of the acid, 49%, was much better,
O
R1
R2
OSiMe3
OSiMe3
R1
R2
the yield of the lactone (11%) being roughly the same.
In spite of the fact that the yields of lactones are much
lower than for other substituted aromatic ring systems,
this approach allows for the desired functionalization
of the phenyl ring in 2-phenylpyridine. Lets now con-
sider the transformation of the pyridine moiety.
1)
OH
3
+
N
N
2) tBuOK
3) I2
Cr(CO)3
2
4
In a previous paper,12 we already described the sluggish
reactivity of 2-phenylpyridine activated by methylchlo-
roformate towards ketene acetals 3. Under the usual
conditions (1.5 equiv of acetal, 3 equiv of methylchloro-
formate, 2 h at room temperature), this substrate led to
a low 15% yield of the expected 1,4-dihydropyridine 6
(Scheme 3). The yield could however be substantially in-
creased by leaving the reaction for 12 h (70% yield
according to the NMR, 35% isolated product). When
dihydropyridine 6 was reacted with a twofold excess of
m-chloroperbenzoic acid in diethylether at room tem-
perature,13 for two days, a slow reaction took place
leading to a polar, poorly soluble crystalline compound,
mp 206 °C, in 35% yield23 (Scheme 4). According to its
NMR data,24 this compound neither is an acid, nor con-
tains a carbon–carbon double bond, thus is not the ex-
pected hydroxylactone 7 (Scheme 5).
R1
4'
O
3'
5'
6'
R2
3a
2
a R1R2=(CH2)5
b R1=R2=Me
3
2'
O
7a
N
4
7
5
6
5
Scheme 2.
1
182.2 ppm) showing in the H NMR spectrum besides
the signals for the protons of the pyridine ring, signals
for three adjacent vinylic protons, and a highly de-
shielded signal at d 5.61 ppm typical for the protons
on the carbon bearing the oxygen function of the lac-
tones.8 1H,1H and 1H,13C correlation spectra clearly
indicated that this compound had structure 5a. An X-
ray analysis (Fig. 1) confirmed the ortho, meta addition
of the dinucleophile, leading to a c-lactone, the ring
junction being cis.
The mass spectrum confirmed that an extra oxygen had
been introduced in the hypothetical 7.
This is the first example of the double nucleophilic addi-
tion of such a ketene acetal to a substituted phenyl ring
in which the addition of the C-nucleophile takes place at
the ortho position. Indeed, both in aromatic rings bear-
ing electron-attracting or electron-releasing substituents,
this addition occurred either at the meta or at the para
positions.8 This special selectivity can be inferred to an
ortho directing effect of the nitrogen atom of the pyri-
dine nucleus. Complex 2 reacted similarly with ketene
acetal 3b to give a mixture of acid 4b (6%) and lactone
5b (7%). When instead the enolate was prepared from
the TMS ester (R1R2@(CH2)5) and LDA, although a
mixture of the corresponding acids and lactones was
Crystals suitable for an X-ray analysis (Fig. 2) could be
grown from dichloromethane solutions.25 Fig. 2 shows
that indeed the expected d-lactone is present as it should
be in 7, but that an intramolecular interaction of the hy-
droxyl group of 7 with the carbon–carbon double bond
took place, giving a new lactone fused to a hydroxy-
tetrahydrofurane. Surprisingly, the oxygen bridge and
the hydroxyl group are cis, a geometry which is not in
agreement with an intramolecular ring-opening of a pre-
sumed intermediate epoxide. The transformation of 7
O
Me
Me
Me
OSiMe3
OSiMe3
OH
Ph
Me
3
N
Ph
N
CH3OCOCl
O
OMe
1
6
Scheme 3.
O
Me
Me
Me
6
Me
OH
O
7
OH
10
5
8
ArCO3H
O
O
3
1
N
Ph
OMe
N
Ph
O
O
OMe
6
9
Figure 1. Diamond view of lactone 5b.
Scheme 4.

Y. Xu et al. / Tetrahedron Letters 47 (2006) 4553–4556
4555
O
Me
Me
Me
Me
Me
Me
HO
Me
HO
Me
O
OH
Ph
O
O
HO+
HO+
OH
Ph
OH
Ph
OMe
O
O
O
O
N
N
Ph
OMe
N
N
+
O
O
O
O
OMe
OMe
6
7
8
9
Scheme 5.
6. Bellassoued, M.; Chelain, E.; Collot, J.; Rudler, H.;
Vaissermann, J. Chem. Commun. 1999, 187–188.
7. Rudler, H.; Parlier, A.; Cantagrel, F.; Bellassoued, M.
Chem. Commun. 2000, 771–772.
8. Rudler, H.; Comte, V.; Garrier, E.; Bellassoued, M.;
Chelain, E.; Vaissermann, J. J. Organomet. Chem. 2001,
621, 284–298.
9. Rudler, H.; Harris, P.; Parlier, A.; Cantagrel, F.; Denise,
B.; Bellasssoued, M.; Vaissermann, J. J. Organomet.
Chem. 2001, 624, 186–202.
10. Rudler, H.; Alvarez, C.; Parlier, A.; Aldeco-Perez, E.;
Denise, B.; Xu, Y.; Vaissermann, J. Tetrahedron Lett.
2004, 45, 2409–2411.
11. Rudler, H.; Denise, B.; Parlier, A.; Daran, J. C. Chem.
Commun. 2002, 940–941.
12. Rudler, H.; Denise, B.; Xu, Y.; Parlier, A.; Vaissermann,
J. Eur. J. Org. Chem. 2005, 3724–3749.
13. Rudler, H.; Denise, B.; Xu, Y.; Vaissermann, J. Tetra-
hedron Lett. 2005, 46, 3449–3451.
Figure 2. Diamond view of lactone 9.
14. For the synthesis of bis(TMS) ketene acetals see: Ains-
worth, C.; Kuo, Y.-N. J. Organomet. Chem. 1972, 46, 73–
87.
15. For recent applications of this methodology see: Ullah, E.;
Rotzoll, S.; Schmidt, A.; Michalik, D.; Langer, P. Tetra-
hedron Lett. 2005, 8997–8999.
into 9 would rather involve the formation of an epoxide
trans to the lactone ring which opens-up to give an imin-
ium 8. An intramolecular addition of the hydroxyl
group to C-1 might then give 9 (Scheme 5).
16. Ullah, E.; Langer, P. Synlett 2004, 15, 2782–2784.
17. Unpublished results.
Thus, up to five stereogenic centers can be formed in two
steps from 2-phenylpyridine 1 in a high stereoselective
way leading to a polysubstituted piperidine.26–31
18. Djukic, J. P.; Maisse, A.; Pfeffer, M. J. Organomet. Chem.
1998, 567, 65–74.
19. 1H NMR of 4b (200 MHz, CDCl3): d 1.54 (s, 6H,
(CH3)2CH); 7.16 (dd, 1H, J = 4 Hz); 7.38 (m, 2H); 7.51
(m, 1H); 7.62 (m, 3H); 8.60 (d, 1H), 11.00 (s, 1H, CO2H);
13C NMR (50 MHz, CDCl3): d 180.18 (CO); 157.21, 148.8,
146.42, 138.0, 136.67, 127.46, 126.39, 122.47, 121.90,
46.50, 26.62.
A further goal of these transformations will thus be the
preparation in an enantioselective way of these types of
polycyclic lactones.
20. For the addition of nucleophiles to arenetricarbonylchro-
mium complexes see for example: McQuillin, F. J.; Parker,
D. G.; Stephenson, G. R. In Transition Metal Organo-
metallics for Organic Synthesis; Cambridge University
Press: Cambridge, UK, 1991; pp 182–231.
Acknowledgments
ECOS-NORD, ANUIES/CONACYT (Contract M02P04
France-Mexico) are acknowledged for financial support.
21. For transition metal mediated dearomatization reactions
see: Pape, A. R.; Kaliappan, K. P.; Kundig, E. P. Chem.
¨
References and notes
Rev. 2000, 100, 2917–2940.
1
22. Lactones 5b H NMR (400 MHz, CDCl3): d 8.53 (d, 1H,
0
0
J = 8 Hz, H6 ), 7.63 (m, 1H, H4 ), 7.42 (d, 1H, J = 8 Hz,
1. Hoffmann, H. M. R.; Rabe, J. Angew. Chem., Int. Ed.
Engl. 1985, 24, 94–110.
2. Koch, S. S. C.; Chamberlain, A. R. In Studies in Natural
Products Chemistry; Atta-ur-Rahman, Ed.; Elsevier Sci-
ence B.V.: Amsterdam, The Netherlands, 1995; Vol. 16, pp
687–725.
3. Han, G.; LaPorte, M. G.; Folmer, J. J.; Werner, K. M.;
Weinreb, S. M. J. Org. Chem. 2000, 65, 6293–6306.
4. Alibes, R.; Ballbe, M.; Busque, F.; de March, P.; Elias, L.;
Figueredo, M.; Font, J. Org. Lett. 2004, 6, 1813–1816.
5. Sibi, M. P.; Subramanian, T. Synlett 2004, 7, 1211–1214.
0
0
H3 ), 7.13 (dd, 1H, J = 2 and 8 Hz, H5 ), 6.46 (d, 1H,
J = 10 Hz, H5), 6.00 (m, 1H, H6), 5.78 (dd, J = 2 and
10 Hz, H7), 5.61 (m, 1H, H7a), 4.23 (d, 1H, J = 12 Hz,
H3a), 1.01 and 1.07 (s, 6H, 2 CH3). 13C NMR (CDCl3,
100 MHz): d 21.2, 26.4 (CH3), 42.0 (C3), 42.5 (C3a), 76.9
0
0
(C7a), 120.6 ðC3 Þ, 122.7 ðC5 Þ, 123.15 (C5), 125.1 (C7),
0
0
0
136.3 (C4), 136.7 ðC4 Þ, 149.13 ðC6 Þ, 156.5 ðC2 ), 182.2
(CO). Compound 5a 1H NMR (CDCl3, 200 MHz): d 8.50
0
0
(d,0 1H, J = 8 Hz, H6 Þ, 7.65 (m, 1H, H4 ), 7.43 (m, 1H,
0
H3 ), 7.20 (m, 1H, H5 ), 6.40 (d, 1H, J = 6 Hz, H5), 5.98

4556
Y. Xu et al. / Tetrahedron Letters 47 (2006) 4553–4556
(m, 1H, H6), 5.80 (dd, 1H, J = 2 and 10 Hz, H7), 5.56 (m,
128.23–129.78 (C6H5), 100.49 (C1), 87.06 (C3), 76.46
(C10), 70.27 (C8), 58.45 (C7), 52.87 (OCH3), 39.64 (C6),
24.14 and 29.61 ((CH3)2C).
1H, H7a), 4.10 (d, 1H, J = 12 Hz, H3a), 1.07–1.67 (m, 10H,
(CH2)5). 13C NMR (CDCl3, 50 MHz): d 179.96 (CO),
0
0
0
157.17 ðC2 ), 149.20 ðC6 Þ, 136.86 ðC4 Þ, 136.08 (C4), 126.42
25. Crystal data for 5b and 9, CCDC 232997 and 298171, can
be obtained free of charge from the Cambridge Data
Centre via www.ccdc.ac.uk/data.report/cif.
0
0
(C7), 125.01 (C6), 124.49 (C5), 122.74 ðC5 Þ, 120.99 ðC3 Þ,
77.16 (C7a), 43.77 (C3,3a), 21.10–29.24 ((CH2)5).
23. For a general review on non-biomimetic reactions of
dihydropyridines and applications see: Lavilla, R. J.
Chem. Soc., Perkin Trans.1 2002, 1141–1156; See also:
Lavilla, R.; Baron, X.; Coll, O.; Gullon, F.; Masdeu, C.;
Bosch, J. J. Org. Chem. 1998, 63, 10001–10005; Zhao, G.;
Deo, U. C.; Ganem, B. Org. Lett. 2001, 3, 201–203.
26. For the synthesis of piperidines see for example: Laschat,
S.; Dickner, T. Synthesis 2000, 1781–1813.
27. For the biological properties of piperidines see: Beak, P.;
Stehle, N. W.; Wilkinson, T. J. Org. Lett. 2000, 2, 155–158.
28. O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435–446.
29. Elliot, R. L.; Kopecka, H.; Lin, N.-H. Y.; He, H.; Garvey,
D. S. Synthesis 1995, 772–774.
30. Basha, F. Z.; Debernadis, J. F. Pure Appl. Chem. 1994, 66,
2201–2204.
31. Li, N.-H.; Carrera, G. M., Jr.; Anderson, D. J. J. Med.
Chem. 1994, 37, 3542–3553.
1
24. Lactone 9 H NMR (200 MHz, CDCl3): d 7.37–7.54 (m,
5H, C6H5), 5.95 (d, 1H, J = 4 Hz, H3), 4.94 (dd, 1H, J = 4
and 5 Hz, H8), 4.43 (m, 1H, H10), 3.42 (s, 3H, OCH3), 3.32
(m, 1H, H7), 1.43 and 1.45 (s, 6H, (CH3)2C); 13C NMR
(CDCl3, 50 MHz): d 173.71 (CO), 151.76 (CO2Me),