Lactonizations of carboxylic acid-substituted 3-fluorodihydropyridines with electrophiles: Peculiar behaviour of F+

Article abstract of DOI:10.1039/b807092j

Whereas for 3-fluorodihydropyridine-substituted carboxylic acids electrophiles such as HCl, iodine, bromine and peracids discriminate the double bond lacking and that bearing fluorine, no such differentiation took place in the case of electrophilic fluori

Full text of DOI:10.1039/b807092j

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Lactonizations of carboxylic acid-substituted 3-fluorodihydropyridines
with electrophiles: peculiar behaviour of F+w
a
a
a
a
´
Henri Rudler,* Andree Parlier, Louis Hamon, Patrick Herson and
Jean-Claude Daranb
Received (in Cambridge, UK) 28th April 2008, Accepted 23rd May 2008
First published as an Advance Article on the web 8th July 2008
DOI: 10.1039/b807092j
Whereas for 3-fluorodihydropyridine-substituted carboxylic
acids electrophiles such as HCl, iodine, bromine and peracids
discriminate the double bond lacking and that bearing fluorine,
no such differentiation took place in the case of electrophilic
fluorine since the formation of both mono and gem-difluorolac-
tones took place.
The use of bis(TMS)ketene acetals 1 as dinucleophiles for the
transformation of carbon–carbon double bonds either into
g- or d-lactones has provided access to a large class of new
polyheterocycles.1 In the case of pyridines, these cycloaddi-
Scheme 1
prepared according to the published method and isolated in 85
to 90% yields.1 The presence of fluorine in 4b was confirmed
by the 19F NMR spectrum which disclosed two broad signals,
at d ꢀ131.8 and ꢀ132.4 ppm, whereas the 13C NMR spectrum
agreed with the suggested structure, C-3 giving rise to two
doublets at d 147.7 and 148.2 ppm (J = 249 Hz).7 Treatment
of 4b with anhydrous HCl in diethyl ether led to a new
compound the physical properties of which were consistent
with those of the lactone 6b. The 13C NMR spectrum con-
firmed indeed the presence of a fluorine-substituted double
bond as in 4b, with two doublets at d 149.65 and 148.81 ppm
for C-6 (J = 250 Hz), at d 107.44 ppm (d, J = 41 Hz) for C-7
and the typical signals for C-1 at d 77.62 and 77.85 ppm
(Scheme 2).
tions evolved via the formation of isolable 4-(1-carboxyalkyl)-
dihydropyridines 2 which led very easily to stable d-lactones 3
fused to tetrahydropyridines (Scheme 1).2
These ring-closure reactions were not only induced by protic
acids but occurred also with electrophiles such as Br+, I+,
HO+, allowing thus to introduce various functionalities in b
to the oxygen atom of the lactones. These results prompted us
to consider the addition of electrophilic fluorine by the same
means to get access to new fluorinated lactones.3 It is indeed
well established that the introduction of fluorine in organic
compounds might not only lead to biologically active com-
pounds but could possibly, in the case of biologically active
compounds, deeply modify their activity.4
As far as other electrophiles are concerned,1 we first examined
the interaction of dihydropyridine 4b with CuBr2 on alumina, a
selective source of electrophilic bromine.1,7 This led indeed to an
almost quantitative yield of a single compound 7b (98%, mp
154 1C). Similarly, when the classical iodolactonization was
applied to 4b, a single lactone 8b was obtained in 82% yield
(white solid, mp 145 1C), the NMR data of which were in all
respect comparable to those of 7b, the signal for C-9 being highly
shielded and appearing now at d 10.73 and 11.04 ppm for the two
Several electrophilic fluorinating agents have been used in
the literature for that purpose among which 1-chloromethyl
4-fluoro-1,4-diazoniabicyclo(2.2.2)octane bis(tetrafluorobo-
rate) or Selectfluort 5 is now one of the most popular.5 In
the case of dihydropyridines, precedents for their oxidation
with
N-fluoropyridinium triflate and N-fluorodibenzenesulfonimide
in the presence of external nucleophiles can be found in the
literature: Lavilla et al. observed indeed the formation, in a
stereocontrolled manner, of 3-fluorinated tetrahydropyri-
dines.6 We have therefore carried out such reactions both on
N-carbomethoxy dihydropyridines 2 and on the 3-fluoro
analogs 4 (R1 = R2 = Me; R1 R2 = (CH2)5) which were
a
´
Laboratoire de Chimie Organique, Universite Pierre et Marie Curie,
UMR CNRS 7611, CC 47, 4 place jussieu, 75252 Paris cedex 5,
France. E-mail: henri.rudler@upmc.fr; Fax: (+)33(0)144273787;
Tel: (+)33(0)144275092
b Laboratoire de Chimie de Coordination, 205 route de Narbonne,
31077 Toulouse Cedex 4, France
w Electronic supplementary information (ESI) available: Experimental
section and physical data for 4a,b, 6a,b, 7b, 8b, 9b, 10a,b. CCDC
reference numbers 668553 and 673543. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/b807092j
Scheme 2
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Scheme 3
Fig. 2 X-Ray crystal structure of compound 12b. Ellipsoids are
drawn at the 30% probability level.
nonequivalent fluorine signals (two doublets) at ꢀ117.2 and
2
ꢀ112.1 ppm, JFF = 248 Hz.z
All of these data were secured by a single-crystal X-ray
structure determinationy (Fig. 1).
To the second more polar product (mp 140 1C, 32%) was
assigned structure 12b on the basis of its NMR data. The
presence of two types of fluorine atoms was confirmed by
the 19F NMR spectrum which disclosed indeed four signals for
the two rotamers, at d ꢀ134.8 and ꢀ134.2 ppm, as singlets (for
F-6), and at d ꢀ198.4 and ꢀ198.7 ppm, as doublets of
doublets, J = 47 and 7 Hz, for F-9.z A crystal structure
determination (Fig. 2) confirmed the regio- and stereo-
chemistry of the reaction, the introduced fluorine being
trans, axial with respect to the lactone bridge.y
Two points warrant therefore a comment: (a) the stereo-
chemical outcome of the lactonization reaction of the dihydro-
pyridines is the same whatever the nature of the halogen: all of
the reactions led to trans, diaxial halolactones.8a,c Since fluor-
ine decreases the electron density at the double bond, electro-
philic additions are in general more difficult: it seems thus not
surprising to observe only one of the two possible regioisomers
with HCl and typical other electrophiles.8d,e This result agrees
also with the calculated charge distributions (Scheme 5 (I)).9
Moreover, if one considers the relative enthalpies of the
transition states, it appears that protonation of the fluorine-free
double bond is favoured by 7.1 (for the trans-H) and by 5.5 kcal
molꢀ1 (for the cis-H) over the fluorine-substituted double bond.
(Scheme 5 (II)). Similarly, the addition of F+ to dihydropyridine
Scheme 4
rotamers, as two doublets, 3JCF = 7 Hz. Finally, the interaction of
4b with a slight excess of m-chloroperbenzoic acid led in a modest
27% yield to a crystalline compound, mp 197 1C, the physical data
of which were in agreement with those of the expected hydro-
xylactone 9b. Thus, all of these electrophiles reacted with the
double bond lacking fluorine. However, the course of the reaction
was different in the case of electrophilic fluorine. Thus, the
reaction of 2a in acetonitrile with a slight excess of Selectfluort
in the presence of sodium hydrogen carbonate led to a single, new
compound 10a (white crystals, 69%, mp 116 1C), dCO,
174.16 ppm, containing a secondary fluorine atom according to
its H and 19F NMR spectra with signals corresponding to two
1
rotamers, at d 5.40 and 5.37 ppm and at d ꢀ198.10 and
ꢀ199.3 ppm (J = 48 Hz) typical for axially oriented fluorines.
Similarly, 2b led to 10b in 77% yield (white crystals, mp141 1C)
(Scheme 3).
When however the same reaction was carried out on 4b, two
products were obtained (Scheme 4). To the less polar product
(mp 110 1C, 40%) was assigned structure 11b on the basis of its
NMR data. Its 13C NMR spectrum confirmed the existence of
the lactone function, dCO, 172.67 ppm, of a disubstituted
double bond C(6)QC(7) as in 10b, and of a deshielded signal
at d 115.97 ppm as a triplet (J = 248 Hz), consistent with the
presence of a geminal difluorinated carbon. This was also
assessed by the 19F NMR spectrum which disclosed two
Fig. 1 X-Ray crystal structure of compound 11b. Ellipsoids are
drawn at the 30% probability level.
Scheme 5
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Scheme 6
54.13 (OMe), 47.77 (C4), 38.35 and 37.98 (d, J = 17 Hz, C5), 33.98,
33.90, 33.07, 25.15, 21.26, 20.52 (5CH2). 19F NMR (376 MHz, CDCl3)
d ꢀ134.2 and ꢀ134.8 (br s, F6), ꢀ198.4 and 198.7 (dd, J = 47 and
J = 7 Hz, F9). Analysis. Calc. for C14H18FNO4: C, 55.81; H, 5.69; N,
4.65. Found: C, 55.69; H, 5.75; N, 4.51%.
2 should also lead to the trans fluorolactone. Let’s now examine
the interaction of Selectfluort with 4. It has been established
that polarized double bonds react with Selectfluort, according
to a two stage process.8b Accordingly, a nucleophilic addition of
the double bond to fluorine with cleavage of the fluorine–nitro-
gen bond, neutralization of the developing positive charge on the
a-carbon in A by NR3 (NR3 = TEDA–CH2Cl+BF4ꢀ), would
first give syn addition products B. In the second step, an
intramolecular substitution might lead to the observed lactones
(Scheme 6).
y Crystal data for 11b: C14H17F2NO4, M = 301.29, orthorhombic,
space group Pbca, a = 13.566(3), b = 10.620(2), c = 18.434(4) A,
V = 2655.9(9) A3, Z = 8, Dc = 1.507 g cmꢀ3, m = 0.128 mmꢀ1
(Mo-Ka, l = 0.71073) T = 180 K, 5889 reflections collected; 1597
unique reflections (Rint = 0.149), R1, wR2 [I 4 2s(I)] = 0.0690,
0.1490, R1, wR2 (all data) = 0.1648, 0.2136. CCDC 668553. Crystal
ꢀ
data for 12b: C14H17F2NO4, M = 301.29, triclinic, space group P1,
a = 8.0326(8), b = 8.7779(11), c = 10.5283(10) A, V = 693.44(14) A3,
Z = 2, Dc = 1.443 g cmꢀ3, m = 0.122 mmꢀ1 (Mo-Ka, l = 0.71073)
T = 250 K, 12 253 reflections collected, 3300 unique reflections
(Rint = 0.0493), R1, wR2 [I 4 2s(I)] = 0.0394, 0.0486 R1, wR2
(all data) = 0.0672, 0.0709. CCDC 673543.
The formation of the gem-difluoro lactone 11 is reminiscent of
the transformation of 2-fluoro enol ethers into gem-difluoro
compounds.10,11 Therefore, competition between the formation
of 11 and 12 might indeed exist. According to calculations
(Scheme 5 (III)) the enthalpies of formation of the 3-gem
difluoro cation and the 3,5-difluoro-substituted intermediate
carbocationic species are roughly the same. Therefore, the ratio
of 11 to 12 should depend on the relative rates of transformation
of the last intermediate B. Since in both intermediates (X = F,
X = H) the introduced fluorine is axial, cis with respect to
NR3+, a similar stabilizing effect might be observed,12 and thus
a similar rate of the intramolecular lactonization of both inter-
mediates B (X = H and X = F), the influence of either one or
two fluorine atoms on the a-carbon being almost the same.
Our current efforts include expanding the scope of these
reactions to polyfluorinated dihydropyridines, getting a deeper
insight into the mechanism of these transformations, and
achieving enantioselective lactonizations.
1 (a) H. Rudler, B. Denise, Y. Xu, A. Parlier and J. Vaissermann,
Eur. J. Org. Chem., 2005, 3724–3744; (b) Y. Xu, H. Rudler, B.
Denise, A. Parlier, P. Chaquin and P. Herson, Tetrahedron Lett.,
2006, 47, 4541–4544.
2 For related transformations see, P. Langer, Eur. J. Org. Chem.,
2007, 2233–2238, and references therein.
3 L. F. Lourie, Y. A. Serguchev, G. V. Shevchenko, M. V. Ponomenko,
A. N. Chernega, E. B. Rusanov and J. A. K. Howard,
J. Fluorine Chem., 2006, 127, 377–385.
4 (a) W.-D. Meng and F.-L. Qing, Curr. Top. Med. Chem., 2006, 6,
1499–1528; (b) B. E. Smart, J. Fluorine Chem., 2001, 109, 3–11;
(c) J. P. Begue and D. Bonnet-Delpon, Chimie Bioorganique
´ ´
´
et Medicinale du Fluor, EDP Sciences/CNRS Eds, Paris,
France, 2005; (d) R. P. Singh and J. M. Shree, Acc. Chem. Res.,
2004, 37, 31–34; (e) D. O’Hagan, Chem. Soc. Rev., 2008, 37,
308–319.
5 R. E. Banks, V. Murtagh and E. Tsiliopoulous, J. Fluorine Chem.,
1991, 52, 389–401.
6 R. Lavilla, O. Coll, R. Kumar and J. Bosch, J. Org. Chem., 1998,
63, 2728–2730.
7 G. A. Rood, J. M. DeHaan and R. Zibuck, Tetrahedron Lett.,
1996, 37, 157–158.
Notes and references
1
8 (a) R. D. Bach and H. F. Henneike, J. Am. Chem. Soc., 1970, 92,
5589–5602; (b) S. P. Vincent, M. D. Burkart, C.-Y. Tsai, Z. Zhang
and C.-H. Wong, J. Org. Chem., 1999, 64, 5264–5279; (c) M.
Albert, K. Dax and J. Ortner, Tetrahedron, 1998, 54, 4839–4848;
(d) R. N. Haszeldine, I-ud-D. Mir and A. E. Tipping, J. Chem.
Soc., Perkin Trans. 1, 1976, 2349–2353; (e) T. Tidwell, Angew.
Chem., Int. Ed. Engl., 1984, 23, 20–32.
9 M. W. Schmidt, K. K. Baldridge, J. A. Boatz, S. T. Elbert, M. S.
Gordon, J. J. Jensen, S. Koseki, N. Matsunaya, K. A. Nguyen, S.
Su, T. L. Windus, M. Dupuis and J. A. Montgomery, J. Comput.
Chem., 1993, 14, 1337–1363.
10 C. G. Francisco, C. C. Gonzalez, N. R. Paz and E. Suarez, Org.
Lett., 2003, 5, 4171–4173.
11 M. J. Tozer and T. F. Herpin, Tetrahedron, 1996, 52, 8619–8683.
12 N. E. J. Gooseman, D. O’Hagan, M. J. G. Peach, A. M. Z. Slawin,
D. J. Tozer and R. J. Young, Angew. Chem., Int. Ed., 2007, 46,
5904–5908.
z 11b: White solid, mp 110 1C, 40%. H NMR (400 MHz, CDCl3) d
6.88 and 6.75 (d, J = 8 Hz, 1H, H7), 6.20 and 6.03 (d, J = 4 Hz, 1H,
H1), 5.04 (m, 1H, H6), 3.84 (s, 3H, OMe), 3.00 (m, 1H, H5), 2.20–1.00
(m, 10H, 5CH2). 13C NMR (100 MHz, CDCl3) d 172.67 (C3), 152.23
and 151.98 (NCO), 122.64 and 122.46 (C7), 115.97 (t, J = 248 Hz, C9),
103.22 (C6), 79.02 and 78.31 (d, J = 34 Hz, C1), 54.16 (OMe), 48.44
(C4), 36.10 (m, C5), 35.98, 35.79, 35.60, 34.89, 34.78, 34.28, 24.98,
20.90, 20.79 (5CH2). 19F NMR (376 MHz, CDCl3) d ꢀ112.1 (d, JFF
=
251 Hz, F19), ꢀ117.2 (d, J = 251 Hz, F29). Analysis. Calc. for
C14H17F2NO4: C, 55.81; H, 5.69; N, 4.65. Found: C, 55.78; H, 5.71;
N, 4.59%. 12b: White solid, mp 140 1C, 32%. 1H NMR (400 MHz,
CDCl3) d 7.03 and 6.90 (d, J = 9 Hz, 1H, H7), 6.33 and 6.17 (br s, 1H,
H1), 5.31 (d, J = 47 Hz, 1H, H9), 3.83 (s, 3H, OMe), 3.18 (t, J = 9 Hz,
1H, H5), 2.10–1.35 (m, 10H, 5CH2). 13C NMR (100 MHz, CDCl3) d
172.62 (C3), 152.59 and 152.19 (NCO), 146.09 and 145.39 (d, J = 247
Hz, C6), 107.61 and 107.28 (d, J = 40 Hz, C7), 78.32 and 77.95 (dd, J
= 200 and J = 6 Hz, C9), 76.70 and 76.44 (t, J = 26 Hz, C1) 54.18 and
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This journal is The Royal Society of Chemistry 2008
4152 | Chem. Commun., 2008, 4150–4152