New enantioselective synthesis of monofluorinated pyridines designed for the preparation of chemical libraries

Article abstract of DOI:10.1002/adsc.200700488

Chiral pyridines with a fluorine atom in the benzylic position are easily accessible from optically active propargylic fluorides by using the Bohlmann-Rahtz reaction. Such pyridines, possessing four points of molecular diversity, are useful scaffolds for

Full text of DOI:10.1002/adsc.200700488

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DOI: 10.1002/adsc.200700488
New Enantioselective Synthesis of Monofluorinated Pyridines
Designed for the Preparation of Chemical Libraries
Anne-Laure Blayo,a StØphanie Le Meur,b Danielle GrØe,a,* and RenØ GrØea
a
UniversitØ de Rennes 1, Laboratoire de Synth›se et Electrosynth›se Organiques, CNRS UMR 6510, Avenue du GØnØral
Leclerc, 35042 Rennes Cedex, France
Fax : (+33)-(0)2-2323-6978; e-mail: danielle.gree@univ-rennes1.fr
Bioprojet Biotech, 4 rue du Chesnay Beauregard, BP 96205, 35762 Saint GrØgoire, France
b
Received: October 8, 2007; Published online: February 8, 2008
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Chiral pyridines with a fluorine atom in four points of molecular diversity, are useful scaf-
the benzylic position are easily accessible from opti- folds for the preparation of chemical libraries.
cally active propargylic fluorides by using the Bohl-
mann–Rahtz reaction. Such pyridines, possessing Keywords: chemical libraries; fluorides; fluorination;
pyridines
Introduction
The pyridine nucleus has been recognized from long
time ago as an important component for biological ac-
tivity in various types of natural products and for
their synthetic analogues. Therefore, this skeleton is
widely represented as a privileged scaffold in bioor-
ganic and medicinal chemistry and several thousands
Scheme 1. Retrosynthetic analysis for the preparation of
type I pyridines.
of pyridine-containing molecules are found in drugs
and in agrochemicals.[1] On the other hand, it is well
known that the introduction of fluorine in organic
molecules strongly modifies their physical, chemical (Scheme 1).[6] This approach used, as the key inter-
and biological activities and this has been also of mediates, optically active propargylic fluorides which
much use in fluorobiorganic chemistry.[2] Therefore are easily accessible by the routes we have reported
pyridines bearing one or several fluorine atom(s), recently.[7,8] The goal of this publication is to describe
either on the heteroaromatic nucleus or on the side our preliminary results in this area with (i) an efficient
chains, appear particularly attractive and many exam- preparation of the key pyridine (À)-7, selected as a
ples of such molecules have been already described in model and (ii) the use of this intermediate in several
medicinal chemistry.[1,2] As part of our research pro- organic and Pd-catalyzed coupling reactions. We will
gramme on the design of new strategies for the enan- demonstrate also that all these molecules have been
tioselective synthesis of monofluorinated molecules,[3] obtained in high ees (>94%).
we became interested in the preparation of optically
active pyridines with a fluorine in benzylic position.
To date, very few molecules of this sort have been Results and Discussion
synthesized and there is no general strategy to pre-
pare them.[4] Of particular interest to us were the type The synthesis of the first key intermediate, the prop-
I pyridines which possess four points of molecular di- argylic fluoride (À)-6, is indicated in Scheme 2. Start-
versity and therefore would be suitable for the prepa- ing from commercially available (S)-butynol 1, the
ration of chemical libraries.
propargylic alcohol (À)-5 was obtained in four
The strategy we have designed towards these target straightforward steps: protection as THP ether,[9] fol-
molecules, involved the Bohlman–Rahtz reaction[5] lowed by condensation of corresponding anion with
under the conditions described by Bagley p-bromobenzaldehyde, oxidation and THP deprotec-
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Scheme 2. Synthesis of pyridine (À)-7.
tion. Analysis by HPLC on a chiral stationary phase cohol 5 did not afford the desired pyridine 8 but in-
demonstrated that the intermediate (À)-5 had a very stead the furan 11, albeit in low yield (22%), very
high ee (>98%).
likely by cyclization of intermediate 9 followed by
The dehydroxyfluorination step was performed loss of NH3 (Scheme 3).
using diethylaminosulfur trifluoride (DAST),[10] and
The propargylic alcohol function was responsible
after optimization of the reaction conditions (CH2Cl2 for this undesired process, therefore the correspond-
at À108C), the propargylic fluoride (À)-6 was ob- ing silyl ether 12 was prepared in 95% yield. Starting
tained in 68% yield. It was not possible to establish from this intermediate the Bohlman–Ratz condensa-
the enantiomeric purity of this fluoride either by tion was found to be difficult, affording a complex
chiral HPLC or by NMR in the presence of Eu(hfc)3, mixture of products from which the pyridine 13 was
A
a common problem in this series of compounds.[11] isolated in 26% yield only. Finally the deprotection of
However, since it will be demonstrated in the next 13 did not give the desired pyridine 8 but the rear-
part that the pyridines obtained from (À)-6 have very ranged compound 14 which was isolated in 50% yield
high ees (>94%), it is clear that this dehydroxyfluori- (Scheme 4). The structure of this unexpected product
nation step occurs with inversion of configuration[12] was clearly established from its spectral data. In par-
and very little racemization, if any.
ticular, the NMR data were in excellent agreement
The next step was the synthesis of the pyridine (À)-7 with those of similar compounds.[13] Therefore, the
through the Bohlmann–Rahtz condensation.[5] This re- route through the propargylic fluorides appears really
action, performed under the reaction conditions de- advantageous.
scribed by Bagley,[6] gave the desired pyridine in 71%
The bromine on the aromatic ring in key intermedi-
yield. Once again, it was not possible to measure the ate (À)-7 was a first handle to introduce the molecu-
ee on this intermediate by chiral HPLC since no sepa- lar diversity on this pyridine, as indicated on
ration of the peaks was observed on the correspond- Scheme 5. After a careful selection and optimization
ing racemic compound (Æ)-7 by using five different of the reaction conditions, it was found that the Sono-
columns. However, measurements by 19F NMR in the gashira coupling was best performed in aqueous
presence of the chiral shift reagent Eu
demonstrated that this key pyridine intermediate had was done under argon, the desired pyridine (À)-15
ee >94%. was obtained in 97% yield. The Suzuki–Miyaura cou-
(hfc)3 clearly medium, as reported recently.[14] When the reaction
It is noteworthy that the reverse order of reactions, pling was also performed under aqueous reaction con-
synthesis of the pyridine with the alcohol function fol- ditions in the presence of a phase transfer catalyst af-
lowed by dehydroxyfluorination, could not be per- fording the desired pyridine (À)-16 in 84% yield.[15]
formed until now. Using the Bohlmann–Rahtz reac- Finally, the Heck coupling was best performed by
tion under the previous conditions, the propargylic al- using triethylamine as solvent and the target pyridine
472
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New Enantioselective Synthesis of Monofluorinated Pyridines
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Scheme 3. Synthesis of furan 11.
Scheme 4. Synthesis of pyridine lactol 14.
(À)-17 was isolated in 85% yield. For all these mole- was obtained in 84% yield by MnO2 oxidation of
cules the analysis of the enantiomeric excess could be (À)-18.
performed only by 19F NMR in the presence of
Both compounds are very attractive intermediates
A
N
signals were observed for the corresponding racemic sition of the pyridine nucleus.
derivatives. This method allowed us to establish ees
>94% for pyridines (À)-15 to (À)-17.
The ester function was a second place to be used Conclusions
for the development of the molecular diversity in
these molecules. Saponification of the hindered ester This study confirms the versatility of propargylic fluo-
in pyridine (À)-7 was found to be difficult and could rides in the synthesis of useful building blocks for fur-
not be performed satisfactorily until now. However, ther applications in organic and medicinal chemistry.
reduction by LiAlH4 afforded the alcohol (À)-18 in These fluorides are easily accessible in high enantio-
83% yield (Scheme 6). For this more polar compound meric purity and the Bohlmann–Rahtz reaction af-
analysis by chiral HPLC could be performed, afford- fords, under the conditions proposed by Bagley, inter-
ing a 97.3% ee. This result unambiguously confirms esting pyridines with several points of molecular di-
the previous data obtained by NMR in the presence versity. Development of this chemistry, as well as
of chiral shift reagents. Finally, the aldehyde (+)-19 preparation of other heterocycles starting from prop-
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as a mixture of diastereoisomers; colourless oil; yield: 4.09 g
(93%); Rf (pentane/EtOAc, 9/1)=0.58 (major), Rf (pentane/
EtOAc, 9/1)=0.42 (minor).
Synthesis of Propargylic Alcohol 3
To a solution of the above ether 2 (2 g, 13.0 mmol) in anhy-
drous THF (50 mL) was added, dropwise under argon at
À788C, n-BuLi (10.1 mL of a 1.6 N solution in hexane,
16.2 mmol). The reaction mixture was stirred during 1 h at
this temperature and a solution of p-bromobenzaldehyde
(3.12 g, 16.9 mmol) in anhydrous THF (15 mL) was added.
The reaction mixture was stirred during 3 h with the temper-
ature raising slowly to room temperature before addition of
a saturated ammonium chloride solution. The aqueous
phase was extracted with ethyl acetate. The combined or-
ganic phases were washed with water, dried (MgSO4) and
concentrated under vacuum. The colorless oily residue was
purified by chromatography on silica gel (eluent: pentane/
EtOAc, 9/1 then 7/3) affording alcohol 3 as a colourless oil;
yield: 3.91 g (89%). This complex mixture of four diastereo-
isomers was used directly for the next reaction.
Synthesis of Propargylic Ketone 4
To a solution of alcohol 3 (3.91 g, 11.5 mmol) in CH2Cl2
(50 mL) was added freshly prepared MnO2 (5.01 g,
57.6 mmol). The black suspension was magnetically stirred
during 1.5 h at room temperature. After filtration on silica
gel and distillation under vacuum of the solvents, the crude
product was pure enough to be used directly in the next
step of the synthesis; yellow oil, mixture of two diastereoiso-
mers; yield: 3.46 g (89%); Rf (pentane/EtOAc, 9/1)=0.44
(major), Rf (pentane/EtOAc, 9/1)=0.34 (minor).
Scheme 5. Synthesis of pyridines (À)-15 to (À)-17.
argylic fluorides, are under active study in our group
and will be reported in due course.
Experimental Section
Synthesis of Propargylic Alcohol (À)-5
The characterization data for all compounds are available in
the Supporting Information.
To a solution of the above ketone 4 (3.18 g, 9.4 mmol) in ab-
solute ethanol (100 mL) PPTS (474 mg, 1.9 mmol) was
added and the solution was stirred at 558C during 4 h. After
removal of the solvents under vacuum, the resulting yellow-
orange oil was purified by chromatography on silica gel
(eluent: pentane/EtOAc, 9/1 then 7/3) affording alcohol
(À)-5 as yellow crystals; yield: 2.06 g (86%); Rf (pentane/
EtOAc, 7/3)=0.39 Rf (pentane/EtOAc, 9/1)=0.14. Chiral
HPLC data: column Chiralcel OD, eluent hexane/2-propa-
nol, 90/10, 1 mLminÀ1, detection at 272 nm: retention times
for (+)-5: 9.1 min, for (À)-5: 10.7 min. Using these condi-
tions, a 98.6% ee was calculated for the above (À)-5 sample.
Synthesis of THP Ether 2
To a solution of but-3-yn-2-ol (2 g, 28.5 mmol) in anhydrous
CH2Cl2 (50 mL) were added at 08C and under argon, first
para-toluenesulfonic acid (27 mg, 0.1 mmol) and then drop-
wise 3,4-dihydro-2H-pyran (2.9 mL, 2.64 g, 31.4 mmol). The
reaction mixture was magnetically stirred during 2.5 h at
08C. After removal of the solvent under reduced pressure,
the yellow crude oil was purified by chromatography on
silica gel (eluent: pentane/EtOAc, 9/1) to afford the ether 2
Scheme 6. Synthesis of pyridines (À)-18 and (À)-19.
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Synthesis of Propargylic Fluoride (À)-6
Synthesis of Pyridine 13
To a solution of alcohol 5 (1.5 g, 5.9 mmol) in CH2Cl2
(150 mL) maintained at À108C was added dropwise DAST
(1.55 mL, 11.8 mmol). After stirring at À108C during 0.5 h,
the reaction mixture was washed with water (4”50 mL).
The organic phase was dried (MgSO4) and concentrated
under vacuum. The yellow oil was purified by chromatogra-
phy on silica gel (eluent: pentane/Et2O, 95/5) affording fluo-
ride (À)-6 as pale yellow crystals; yield: 1.03 g (68%); Rf
(pentane/EtOAc, 9/1)=0.41.
Starting from ether 12 (184 mg, 0.37 mmol), the same proce-
dure as for the preparation of pyridine 7 was followed with
a reaction time of 14 h. After purification by chromatogra-
phy on silica gel (eluent: pentane/Et2O, 9/1 and then 8/2),
the pyridine 13 was obtained as a colourless oil; yield:
58 mg (26%).
Synthesis of Lactol 14
To a solution of pyridine 13 (58 mg, 0.1 mmol) in THF
(3 mL) was added, under argon, TBAF (300 mL of a 1M so-
lution in THF). The reaction mixture was stirred at room
temperature for 2 h. After addition of water the product
was extracted with CH2Cl2 and the organic phases washed,
dried (MgSO4) and concentrated under vacuum. The crude
oil was purified by chromatography on silica gel (eluent:
pentane/Et2O, 1/1) to afford lactol 14 as a colourless oil;
yield: 17 mg (50%).
Synthesis of Pyridine (À)-7
To a solution of ammonium acetate (5.28 g, 68.5 mmol) in
absolute ethanol (50 mL) was added ethyl acetoacetate
(866 mL, 6.9 mmol) and this colourless solution was magneti-
cally stirred during 2.5 h at room temperature. Then a solu-
tion of propargylic fluoride (À)-6 (1.03 g; 4.0 mmol) in etha-
nol (20 mL) was added. The solution became yellow and it
was stirred for further 2.5 h at room temperature before ad-
dition of iodine (205 mg, 0.8 mmol). After 1 h stirring,
excess iodine was removed by addition of a 10% Na2S2O3
aqueous solution (100 mL). Then the aqueous phase was ex-
tracted twice with CH2Cl2. The combined organic phases
were washed, dried (MgSO4) and concentrated under
vacuum. The crude oil was purified by chromatography on
silica gel (eluent: pentane/Et2O, 9/1) to afford pyridine (À)-7
as a yellow oil; yield: 1.05 g (71%); Rf (pentane/Et2O,
8/2)=0.43.
Synthesis of Pyridine (À)-15
A suspension of pyridine (À)-7 (160 mg, 0.4 mmol) in dis-
tilled water (1.6 mL) was degassed by bubbling argon for
10 min to eliminate oxygen. Then are successively added:
pyrrolidine (76 mL, 0.9 mmol), Pd(PPh3)4 (25 mg, 5 mol%),
R
CuI (8 mg, 10 mol%) and oct-1-yne (129 mL, 0.9 mmol). The
reaction mixture was heated at 708C under argon during
5 h. After cooling down to room temperature the reaction
mixture was extracted with ether. The combined organic
phases were washed with water, dried (MgSO4) and concen-
trated under vacuum. The oily crude product was purified
by chromatography on silica gel (eluent: pentane/Et2O, 9/1)
affording the target pyridine (À)-15 as a yellow oil; yield:
167 mg (97%); Rf (pentane/Et2O, 8/2)=0.41.
Synthesis of Furan 11
To a solution of ammonium acetate (1.035 g, 13.4 mmol) in
absolute ethanol (10 mL) was added ethyl acetoacetate
(170 mL, 1.34 mmol) and this colourless solution was mag-
netically stirred during 3.5 h at room temperature. Then a
solution of propargylic alcohol 5 (200 mg, 0.79 mmol) in eth-
anol (4 mL) was added. The solution became yellow and it
was stirred for further 2.5 h at room temperature before ad-
dition of iodine (205 mg, 0.8 mmol). After 1 h stirring,
excess iodine was removed by addition of a 10% Na2S2O3
aqueous solution (100 mL). Then the aqueous phase was ex-
tracted twice with CH2Cl2. The combined organic phases
were washed, dried (MgSO4) and concentrated under
vacuum. The crude oil was purified by chromatography on
silica gel (eluent: pentane/Et2O, 9/1) to afford furan 11 as a
colourless oil; yield: 64 mg (22%).
Synthesis of Pyridine (À)-16
Distilled water (800 mL) was degassed by bubbling argon for
10 min to eliminate oxygen. Then were added successively:
pyridine (À)-7 (100 mg, 0.3 mmol), phenylboronic acid
(67 mg, 0.6 mmol), potassium carbonate (75 mg, 0.6 mmol),
CTAB (100 mg, 0.3 mmol) and palladium acetate (3 mg, 5
mol%). The reaction mixture was heated overnight to
1008C under argon. After cooling down to room tempera-
ture the reaction mixture was extracted with ether. The
combined organic phases were washed with water, filtered
on celite, dried (MgSO4) and concentrated under vacuum.
The crude product was purified by chromatography on silica
gel (eluent: pentane/Et2O, 9/1) affording the target pyridine
(À)-16 as a white powder; yield: 83 mg (84%); Rf (pentane/
Et2O, 8/2)=0.42.
Synthesis of Ether 12
To a solution of alcohol 5 (100 mg, 0.39 mmol) in CH2Cl2
(2.5 mL) was added t-BuPh2SiCl (163 mg, 0.59 mmol) and
imidazole (40 mg, 0.59 mmol). The reaction mixture was
stirred at room temperature for 15 h. After addition of
water the product was extracted with CH2Cl2 and the organ-
ic phases washed, dried (MgSO4) and concentrated under
vacuum. The crude oil was purified by chromatography on
silica gel (eluent: pentane/EtOAc, 7/3) to afford ether 12 as
a colourless oil; yield: 184 mg (95%).
Synthesis of Pyridine (À)-17
The pyridine (À)-7 (200 mg, 0.6 mmol) was dissolved in tri-
ethylamine (2.7 mL) and this solution was degassed by bub-
bling argon for 10 min to eliminate oxygen. To this solution
were successively added: tri-o-tolylphosphine (17 mg, 20
mol%), palladium acetate (3 mg, 5 mol%) and methylacry-
late (80 mL, 0.9 mmol). The reaction mixture was heated
overnight to 1008C under argon. After cooling down to
room temperature the reaction mixture was extracted with
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Anne-Laure Blayo et al.
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ethyl acetate. The combined organic phases were washed
with water, dried (MgSO4) and concentrated under vacuum.
The crude product (yellow oil) was purified by chromatogra-
phy on silica gel (eluent: pentane/Et2O, 8/2) affording the
target pyridine (À)-17 as a pale yellow oil; yield: 173 mg
(85%). The corresponding racemic derivative (Æ)-17 crystal-
lized slowly in the fridge. Rf (pentane/Et2O, 8/2)=0.21.
Series 639, Washington, DC, 1996; b) J. T. Welch, S. Es-
warakrishnan, Fluorine in BioorganicChemistry , Wiley
Interscience, New York, 1991; c) J. T. Welch, Tetrahe-
dron 1987, 43, 3123; d) C. Isanbor, D. OꢁHagan, J. Flu-
orine Chem. 2006, 127, 303; e) J-P. BØguØ, D. Bonnet-
Delpon, J. Fluorine Chem. 2006, 127, 992; f) K. L. Kirk,
J. Fluorine Chem. 2006, 127, 1013, and references cited
therein.
Synthesis of Pyridine (À)-18
[3] For a new synthesis of chiral, non-racemic, benzylic flu-
orides see: D. GrØe, R. GrØe, Tetrahedron Lett. 2007,
48, 5435.
To a suspension of LiAlH4 (52 mg, 1.37 mmol) in anhydrous
THF (1 mL) was added, at 08C under argon and dropwise, a
solution of pyridine (À)-17 (100 mg, 0.27 mmol) in anhy-
drous THF (2 mL). The reaction mixture was stirred at 08C
for 0.5 h and then during 3 h at room temperature. After
cooling to 08C, a saturated aqueous solution of potassium
sodium tartrate (3 mL) was first added and then CH2Cl2
(5 mL). After stirring for a few minutes a clear solution was
obtained and the aqueous solution was extracted with
CH2Cl2. The combined organic layers were washed, dried
(MgSO4) and concentrated under vacuum. The crude prod-
uct (yellow oil) was purified by chromatography on silica gel
(eluent: pentane/EtOAc, 6/4) affording the target pyridine
(À)-18 as a white solid; yield: 74 mg (83%); Chiral HPLC
data (column Chiralpak AD-H, eluent heptane/2-propanol,
90/10, 0.6 mLminÀ1, detection at 205 nm): retention times
for (+)-18: 15.1 min, for (À)-18: 18.2 min. Using these con-
ditions, a 97.3% ee was derived for the above (À)-18
sample.
[4] For recent examples of such pyridines see: H. Paulsen,
C. Schmeck, A. Brandes, G. Schmidt, J. Stoltefuss, S. N.
Wirtz, N. Lçgers, P. Naab, K-D. Bremm, H. Bischoff, D.
Schmidt, S. Zaiss, S. Antons, Chimia, 2004, 58, 490.
[5] F. Bohlmann, D. Rahtz, Chem. Ber. 1957, 90, 2265.
[6] a) M. C. Bagley, C. Glover, E. D. Chevis, Synlett 2005,
649; b) M. C. Bagley, C. Glover, E. A. Merritt, Synlett
2007, 2459, and references cited therein.
[7] a) M. Prakesch, D. GrØe, R. GrØe, Acc. Chem. Res.
2002, 35, 175; b) J. Filmon, D. GrØe, R. GrØe, J. Fluo-
rine Chem. 2001, 107, 271; c) E. Kerouredan, M. Pra-
kesch, D. GrØe, R. GrØe, Lett. Org. Chem. 2004, 1, 87;
d) V. Manthati, D. GrØe, R. GrØe, Eur. J. Org. Chem.
2005, 3825, and references cited therein.
[8] For other recent syntheses and uses of mono- and gem-
difluorinated propargylic derivatives see: a) L. Carroll,
Ma. C. Pacheco, L. Garcia, V. Gouverneur, Chem.
Commun. 2006, 4113; b) S. Arimitsu, G. B. Hammond,
J. Org. Chem. 2007, 72, 8559; c) S. Fustero, B. Fernan-
dez, S. Arimitsu, G. B. Hammond, Org. Lett. 2007, 9,
4251; d) S. Arimitsu, J. M. Jacobsen, G. B. Hammond,
Tetrahedron Lett. 2007, 48, 1625, and references cited
therein.
[9] D. Obrecht, Helv. Chim. Acta 1989, 72, 447.
[10] a) W. J. Middleton, J. Org. Chem. 1975, 40, 574; b) M.
Hudlicky, Org. React. 1988, 35, 513; c) R. P. Singh, J. M.
Shreeve, Synthesis 2002, 2561.
Synthesis of Pyridine (+)-19
To a solution of alcohol (À)-18 (50 mg, 0.15 mmol) in anhy-
drous CH2Cl2 was added, portionwise, freshly prepared
MnO2 (300 mg, 30 equiv.). The reaction mixture was stirred
during 4 h at room temperature and filtered over Celite.
After removal of the solvent under vacuum, the crude prod-
uct was purified by chromatography on silica gel (eluent:
pentane/Et2O, 2/1) affording the target pyridine (+)-19 as a
colourless oil; yield: 42 mg (84%).
[11] See, for instance: V. Madiot, P. Lesot, D. GrØe, J. Cour-
tieu, R. GrØe, Chem. Commun. 2000, 169.
[12] For discussions on the stereoselectivity during the de-
hydroxyfluorination of propargylic alcohols and corre-
sponding cobalt-carbonyl complexes see: a) M. Pra-
kesch, E. Kerouredan, D. GrØe, R. GrØe, J. DeChancie,
K. N. Houk, J. Fluorine Chem. 2004, 125, 537; b) V. L.
Manthati, A. S. K. Murthy, F. Caijo, D. Drouin, P.
Lesot, D. GrØe, R. GrØe, Tetrahedron: Asymmetry
2006, 17, 2306, and references cited therein.
Acknowledgements
We thank Dr. Said Gmouh for his advices in using chiral
HPLC and Ronan Marion for preliminary studies in these
series.
[13] L. Santos, A. Vargas, M. Moreno, B. R. Manzano, J. M.
Lluch, A. Douhal, J. Phys. Chem. A 2004, 108, 9331.
[14] S. Bhattacharya, S. Sengupta, Tetrahedron Lett. 2004,
45, 8733.
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Adv. Synth. Catal. 2008, 350, 471 – 476