Cyclisation/fluorination of nitrogen containing dienes in superacid HF-SbF5: A new route to 3- and 4-fluoropiperidines

Article abstract of DOI:10.1039/b719309b

Various N,N-diallylic amines and amides were rapidly converted to fluorinated piperidines after a novel cyclisation/fluorination reaction in superacid HF-SbF₅. The Royal Society of Chemistry.

Full text of DOI:10.1039/b719309b

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COMMUNICATION
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Cyclisation/fluorination of nitrogen containing dienes in superacid
HF–SbF5: a new route to 3- and 4-fluoropiperidineswz
Emilie Vardelle,a Diego Gamba-Sanchez,a Agnes Martin-Mingot,a
a
a
b
ˆ
´
´
Marie-Paule Jouannetaud, Sebastien Thibaudeau* and Jerome Marrot
Received (in Cambridge, UK) 14th December 2007, Accepted 18th January 2008
First published as an Advance Article on the web 31st January 2008
DOI: 10.1039/b719309b
Various N,N-diallylic amines and amides were rapidly converted
to fluorinated piperidines after a novel cyclisation/fluorination
reaction in superacid HF–SbF5.
nucleophilic substitution of such a dicationic intermediate,
using a double bond as nucleophile (Scheme 1).
The cyclisation/fluorination reaction was firstly attempted
with several amines and amides (Table 1).y
After reaction in HF–SbF5 (molar ratio 8 : 1, 3 min, 0 1C),
amines 1a,b and amides 1f–h (entries 1, 2 and 9–11) afforded
the expected fluorinated products in moderate to good yields.
Selectively (poly)fluorinated analogues of biologically active
compounds have attracted significant interest among synthetic
and medicinal chemists over the years, mainly due to a fluorine
atom’s unique specificities.1 In addition, nitrogen heterocycles
and especially piperidine are ubiquitous structural features of
many alkaloid natural products.2 As a consequence, fluori-
nated piperidines became important synthetic building blocks
in the design of antimetabolite and drug candidates.3 Despite
its importance for application related to life sciences, the
synthesis of fluoropiperidines has not been largely explored.
Such fluorinated heterocycles are usually prepared by using
the common dehydroxyfluorination of hydroxypiperidines
with (diethyl)aminosulfur trifluoride (DAST) but this method
suffers from rearranged4 and dehydrated3,5 side products,
difficulty already encountered by Middleton.6 Other routes
such as the use of N-fluoro-derivatives, ring opening of
aziridines or electrochemical process are also mentioned but
remain very specific.7 In this communication, we demonstrate
a novel reaction of cyclisation/fluorination in superacid
HF–SbF5 as an alternative route to 4-fluoropiperidines from
easily accessible dienes. During the past decades, Jacquesy
et al. extensively studied nitrogen compounds behavior in
superacid HF–SbF5, showing the ability to perform reactions
that cannot occur in conventional media.8 As a part of our
ongoing research in superacid HF–SbF5, we recently reported
that hydrofluorination of unsaturated amines can be per-
formed, as an entry to b-fluoroamines.9 It has been demon-
strated that this novel methodology was based on the
formation of a highly reactive electrophilic intermediate. The
postulated ammonium–carbenium dicationic intermediate can
undergo nucleophilic attack even in the presence of a poor
nucleophilic partner. Based on these promising results, we
decided to explore the ability to perform intramolecular
1
In all cases no other products could be detected by H NMR
of the crude reaction mixture suggesting that compounds 2f,g
might be sensitive to purification. These first attempts showed
the ability to use our methodology from either secondary or
tertiary amines but also from aliphatic amides. Benzylic amine
and aromatic amide reactivity has also been tested (entries 3,
13). Whatever the reaction conditions, substrates 1c and 1i
gave a complex mixture of compounds, probably due to a
possible competition between the double bond and the aro-
matic ring as nucleophilic partner. Indeed, when the aromatic
ring is polysubstituted (entry 4) or deactivated (entries 5, 14)
the desired fluorinated cyclic products are isolated. The sub-
stitution with a nitro group in ortho position (entry 15)
allowed the formation of the desired fluorinated compound
in 53% yield beside a side product 2k0 in 17% yield. The
formation of this non-cyclic compound might be the fact of a
possible steric hindrance between the ortho-nitro group and
the double bond, preventing partially from the intramolecular
trapping of the carbocationic center. At this stage it should be
pointed out that hydroxy analogues can also be obtained from
amides, depending on acidity conditions. When the acidity of
the media is higher (entry 12), fluoro and hydroxy derivatives
were formed in 28 and 31%, respectively. The formation of a
3-fluoropiperidine 2e0 after reaction of amine 1e at ꢀ78 1C,
and the formation of a mixture of 3- and 4-fluoroisomers at
ꢀ50 1C (entries 6, 7) encouraged us to postulate a mechanism
(Scheme 2). Mild conditions are clearly needed to obtain
selectively the 3-fluoropiperidine, which seems to indicate that
this isomer could be an intermediate in the reaction course.
Indeed, the formation of compound 2e starting from the
3-fluoropiperidine 2e0 confirmed this hypothesis (entry 8).
a
´
`
Universite de Poitiers, UMR 6514-Laboratoire ‘‘Synthese et
´
´
Reactivite des Substances Naturelles’’, 40, avenue du Recteur Pineau,
F-86022 Poitiers Cedex, France. E-mail: sebastien.thibaudeau@univ-
poitiers.fr; Fax: 33-549453501; Tel: 33-549453702
´
Institut Lavoisier de Versailles, UMR 8180, Universite de Versailles,
45 Avenue des Etats Unis, 78035 Versailles cedex, France
b
w For crystallographic data in CIF or other electronic format see DOI:
10.1039/b719309b
z Electronic supplementary information (ESI) available: All experi-
mental procedures and spectral data. See DOI: 10.1039/b719309b
Scheme 1 Strategy to obtain fluorinated piperidines.
Chem. Commun., 2008, 1473–1475 | 1473
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Table 1 Cyclisation/fluorination of amines and amidesa
Entry
Substrate
Product
Yieldb (%)
1
2
3
4
R = H
R = Me
R = Bn
R = CH2C6F5
R = p-NO2Bn
R = p-NO2Bn
R = p-NO2Bn
1a
1b
1c
1d
1e
1e
1e
2aꢂHCl
2bꢂHCl
70
85
/
c
—
c
2d
2e
2e0
68
35
52
32
21
100g
34
30
69
28
31
5
6d
7f
e
2e
2e0
e
Scheme 2 Proposed mechanism.
e
8
9
2e0
R = CHO
2e
2f
1f
been studied. Indeed starting from homoallylic substrate 1n
only 28% of pyrrolidine 2l was formed among a large amount
of side products, and whatever reaction conditions, substrate
1o gave only a complex mixture of compounds (entries 4, 5).
All these results seem to comfort our previously proposed
mechanism based on the strong reactivity of the dicationic
superelectrophilic intermediate. It appears that the extension
of the distance between the protonated function and the
carbenium decreases the reactivity of the intermediate and so
the selectivity of the reaction, whereas substitution of the
double bond with a methyl inductive donating group opens
new possibilities toward the formation of new fluorinated
nitrogen containing cyclic products. It has to be pointed out
that the formation of this novel fluorinated pyrrolidine re-
mains unclear. Isomerisation after intramolecular cyclisation
could be postulated, but extended additional work is currently
under progress to propose a reasonable hypothesis for the
formation of compound 2l. The formation of cyclic sulfona-
mide 2p starting from N-tosyl diene (entry 6) confirmed the
possible competition between double bond and aromatic ring
attack, in accordance with previous results.9 At this stage the
10h
11
12i
R = COCH3
R = COCF3
R = COCF3
1g
1h
1h
2g
2h
2h
j
2h0
b
—
b
13
R = Bz
R = p-NO2Bz
R = o-NO2Bz
1i
1j
1k
—
14h
15h
2j
2k
2k0
55
53
17
k
a
Standard conditions: HF–SbF5 molar ratio 8 : 1, 3 min, 0 1C.
Chemical yield after column chromatography. Complex mixture.
b
c
d
e
f
Reaction performed at ꢀ78 1C. 2e0
=
Reaction per-
formed at ꢀ50 1C. Conversion.10 h Reaction performed at ꢀ30 1C.
g
i
j
k
HF–SbF5 molar ratio
4
:
1. 2h0
=
2k0
=
After protonation of the nitrogen atom, the strong acidity of
the medium allows the formation of the ammonium–carbe-
nium dication A. It has been previously showed that such
dication can be considered as a superelectrophilic intermedi-
ate.11 The proximity of the charges strongly activates its
electrophilic character, allowing nucleophilic substitution with
poor nucleophile partners.12 In our case, the non-protonated
double bound can act as a nucleophile, despite its electronic
deactivation by the strong withdrawing effect of the proximal
ammonium ion, and undergoes intramolecular cyclisation to
form B. Such diene intramolecular cyclisation could be com-
pared to previously postulated mechanism for the formation
of azabicyclo[3,2,1]octenes in strong acidic conditions.13 The
formation of the 3-fluoropiperidine 2e0 starting from 1e in
mild conditions, confirmed the possible 1,3-hydride shift,
leading to inductively more stabilized intermediate C precur-
sor of 3-fluoropiperidine. In usual conditions (HF–SbF5 molar
ratio 8 : 1, 0 1C, 3 min) the more stabilized intermediate D
(optimal charges repulsion and inductive stabilization) is
obtained after 1,2-hydride and methyl shifts and then trapped
by fluoride ion to give the precursor of the 4-fluoropiperidine.
To complete the understanding of this novel process, a series
of dienes has been submitted to reaction (Table 2).y
Table 2 Cyclisation/fluorination of various dienes
Entry Substrate
1
Product
Yield (%)a
1j
2j 55
2
3
4
5
6
7
1l
2l 50
2l 86
2l 28
—
1m
1n
1o
1p
1q
1r
b
b
—
2p 81
A preliminary study of the influence of the double bond
substitution on the reaction course was attempted using 1j as
model substrate. Whatever the position of the methyl sub-
stitution a novel cyclic fluorinated pyrrolidine derivative 2l
was obtained in good yield (entries 2, 3). The influence of the
distance between the unsaturation and the function has also
b
—
b
—
b
—
b
—
8
a
b
Chemical yield after column chromatography. Complex mixture.
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concerning the role of fluorine in medicinal chemistry: ; (c) C.
Isanbor and D. O’Hagan, J. Fluorine Chem., 2006, 127, 303; (d) J.
P. Begue and D. Bonnet-Delpon, J. Fluorine Chem., 2006, 127, 992;
´ ´
(e) K. L. Kirk, J. Fluorine Chem., 2006, 127, 1013; (f) S. Purser, P.
R. Moore, S. Swallow and V. Gouverneur, Chem. Soc. Rev., 2008,
37, 320.
2 D. O’Hagan, Nat. Prod. Rep., 2000, 17, 435.
3 (a) J. L. Castro, I. Collins, M. G. N. Russel, A. P. Watt, B. Sohal,
D. Rathbone, M. S. Beer and J. A. Stanton, J. Med. Chem., 1998,
41, 2667; (b) M. B. van Niel, I. Collins, M. S. Beer, H. B.
Broughton, S. K. F. Cheng, S. C. Goodacre, A. Heald, K. L.
Locker, A. M. MacLoed, D. Morrisson, C. R. Moyes, D. O’Con-
nor, A. Pike, M. Rowley, M. G. N. Russel, B. Sohal, J. A. Stanton,
S. Thomas, H. Verrier, A. P. Watt and J. L. Castro, J. Med.
Chem., 1999, 42, 2087; (c) M. Rowley, D. J. Hallet, S. Goodacre,
C. Moyes, J. Crawforth, T. J. Sparey, S. Patel, R. Marwood,
S. Patel, S. Thomas, L. Hitzel, D. O’Connor, N. Szeto, J. L.
Castro, P. H. Hutson and A. M. MacLoed, J. Med. Chem., 2001,
44, 1603.
4 D. J. Hallet, U. Gerhard, S. C. Goodacre, L. Hitzel, T. J.
Sparey, S. Thomas and M. Rowley, J. Org. Chem., 2000, 65,
4984.
5 (a) G. C. B. Harriman, J. Shao and J. R. Luly, Tetrahedron Lett.,
2000, 41, 8853; (b) T. Ladduwahetty, A. L. Boase, A. Mitchinson,
C. Quin, S. Patel, K. Chapman and A. M. MacLoed, Bioorg. Med.
Chem. Lett., 2006, 16, 3201.
Fig. 1 ORTEP drawings of 2e and 2j.15
deallylation process remains unclear and is currently studied.
First attempts to obtain fluorinated cyclic ethers or esters were
unsuccessful (entries 7, 8). Whatever conditions used, the
reaction was not selective leading to a complex mixture of
compounds, showing that this novel process seems not to be
consistent with non-nitrogen containing dienes. For all 4-
fluoropiperidines, similarly to 3-fluoropiperidines,14 a pre-
ferred axial orientation of the fluorine atom in the six-mem-
bered ring chair can be postulated, confirmed by X-ray
analysis of amine 2e and amide 2j (Fig. 1).
6 W. J. Middleton, J. Org. Chem., 1975, 40, 574.
7 (a) L. R. Fish, M. T. Gilligan, A. C. Humphries, M. Ivarsson, T.
Ladduwahetty, K. J. Merchant, D. O’Connor, S. Patel, E. Phi-
lipps, H. M. Vargas, P. H. Hutson and A. M. MacLoed, Bioorg.
Med. Chem. Lett., 2005, 15, 3665; (b) X. E. Hu, Tetrahedron Lett.,
2002, 43, 5315; (c) J. I. Yoshida, Y. Ishichi and S. Isoe, J. Am.
Chem. Soc., 1992, 114, 7594.
8 (a) J. C. Jacquesy, in Stable Carbocation Chemistry, ed.
G. K. S. Prakash and P. R. Schleyer, John Wiley and Sons,
New York, 1997, pp. 549–574; (b) J. C. Jacquesy, in Carbocation
Chemistry, ed. G. A. Olah, Wiley, New York, 2004,
pp. 359–376.
9 S. Thibaudeau, A. Martin-Mingot, M. P. Jouannetaud, O. Karam
and F. Zunino, Chem. Commun., 2007, 3198.
10 The term ‘‘conversion’’ is used here to mean the total percentage of
product detected in the reaction mixture by 1H NMR before
isolation.
11 (a) G. A. Olah, Angew. Chem., Int. Ed. Engl., 1993, 32, 767;
(b) G. A. Olah and D. A. Klumpp, Acc. Chem. Res., 2004, 37,
211.
12 (a) Y. Zhang and D. A. Klumpp, Tetrahedron Lett., 2002, 43,
6841; (b) Y. Zhang, A. McElrea, G. V. Sanchez, Jr, D. Do, A.
Gomez, S. L. Aguirre, R. Rendy and D. A. Klumpp, J. Org.
Chem., 2003, 68, 5119; (c) D. A. Klumpp, P. S. Beauchamp, G. V.
Sanchez, Jr, S. Aguirre and S. De Leon, Tetrahedron Lett., 2001,
42, 5821.
In conclusion, we have developed a novel superacidic
cyclisation/fluorination reaction as a new route to fluorinated
piperidines starting from easily accessible starting materials. In
addition, we have also showed that this novel concept could be
applied to substituted dienes as an entry to more elaborated
fluorinated nitrogen containing cyclic derivatives. The identi-
fication of a product intermediate allowed us to postulate a
mechanism based on the intramolecular nucleophilic trapping
of a superelectrophilic dication. This investigation sets the
stage for the rapid access to high biologically valued fluori-
nated building blocks. Further work is now directed at carry-
ing on the scope and limitations study of this innovative
process and at extending it to more elaborated dienes.
This work was generously supported by the Ministere de
´
rieur et de la Recherche (grant to E. V.)
l’Enseignement Supe
and the CNRS.
13 (a) M. G. Beretta, B. Rindone and C. Scolastico, Synthesis, 1975, 7,
440; (b) M. Kimura, T. Nakajima, S. Inaba and H. Yamamoto,
Chem. Pharm. Bull., 1976, 24, 515.
Notes and references
y Procedure for the production of 2j: To a mixture of HF–SbF5 (6 mL,
8 : 1 molar ratio) maintained at ꢀ30 1C was added 500 mg of 1j (2.03
mmol). The mixture was magnetically stirred at the same temperature
for 5 min. The reaction mixture was then neutralized with water–
ice–Na2CO3 and extracted with dichloromethane. The combined
organic phases were dried (MgSO4) and concentrated in vacuo.
Purification of the residue by silica gel chromatography (70 : 30
petroleum ether–ethyl acetate) gave the product as a colourless powder
(296 mg, 55%). All experimental procedures and spectral data are
reported in ESI.z
1 For general reviews on the physical properties of fluorinated
compounds: (a) B. E. Smart, in Chemistry of Organic Fluorine
Compounds II: A Critical Review, ed. M. Hudlicky and A. E.
Pavlath, ACS Monograph 187, American Chemical Society, Wa-
shington, DC, 1995, pp. 979–1010; (b) B. E. Smart, in Organo-
fluorine Chemistry: Principles and Commercial Applications, ed. R.
E. Banks, B. E. Smart and J. C. Tatlow, Plenum Publishing
Corporation, New York, 1994, pp. 57–88; for recent reviews
14 A. Sun, D. C. Lankin, K. Hardcastle and J. P. Snyder, Chem.–Eur.
J., 2005, 11, 1579.
15 Thermal ellipsoids represent 30% probabilities. Crystal structure
ꢀ
analysis of 2e: C13H17FN2O2, 100 K, triclinic, space group P1; a =
6.3802(11), b = 7.2136(11), c = 14.245(3) A, a = 96.205(7), b =
93.734(8), g = 103.868(7)1, V = 629.95(19) A3; Z = 2; total
reflections collected: 26 662; independent reflections: 3642 (2993 Fo
4 4s(Fo)); data were collected up to a 2ymax value of 60.161
(98.6% coverage). Number of variables: 164; R1 = 0.0380, wR2
= 0.1125, S = 1.075; highest residual electron density 0.454 e Aꢀ3
.
CCDC 670158. Crystal structure analysis of 2j: C13H15FN2O3,
ꢀ
room temperature, triclinic, space group P1; a = 6.6927(3), b =
8.2566(3), c = 12.1565(5) A, a = 79.479(2), b = 80.510(2), g =
78.922(2)1, V = 642.26(5) A3; Z = 2; total reflections collected:
13 438; independent reflections: 2260 (1917 Fo 4 4s(Fo)); data were
collected up to a 2ymax value of 501 (100% coverage). Number of
variables: 173; R1 = 0.0366, wR2 = 0.1177, S = 1.136; highest
residual electron density 0.163 e Aꢀ3. CCDC 670159w.
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Chem. Commun., 2008, 1473–1475 | 1475