A novel, facile route to β-fluoroamines by hydrofluorination using superacid HF-SbF5

Article abstract of DOI:10.1039/b703629a

A range of unsaturated amines and sulfonamides were converted to β-fluoro nitrogen analogues after hydrofluorination in superacid HF-SbF₅, based on the formation of highly reactive electrophilic intermediates. The Royal Society of Chemistry.

Full text of DOI:10.1039/b703629a

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COMMUNICATION
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A novel, facile route to b-fluoroamines by hydrofluorination using
superacid HF–SbF5{
Se´bastien Thibaudeau,*a Agne`s Martin-Mingot,a Marie-Paule Jouannetaud,a Omar Karamb and
Fabien Zuninob
Received (in Cambridge, UK) 29th March 2007, Accepted 10th May 2007
First published as an Advance Article on the web 7th June 2007
DOI: 10.1039/b703629a
In this communication, we demonstrate a new and facile
approach for the synthesis of b-fluoro nitrogen building blocks by
a simple hydrofluorination of unsaturated nitrogen compounds in
superacid HF–SbF5, based on the dramatic reactivity of super-
electrophilic ammonium dication intermediates.
A range of unsaturated amines and sulfonamides were
converted to b-fluoro nitrogen analogues after hydrofluorina-
tion in superacid HF–SbF5, based on the formation of highly
reactive electrophilic intermediates.
Introduction of fluorine atom(s) may significantly improve the
pharmacodynamic and pharmacokinetic profiles of a drug
through simultaneous alteration of its electronic, lipophilic and
steric characteristics as well as its metabolic stability,1 mainly due
to a fluorine atom’s unique specificities.2 As a consequence,
selectively (poly)fluorinated analogues, in particular fluorinated
nitrogen analogues,3 of biologically active compounds are
regarded as tools of relevant interest for pharmaceutical
research.4,5 Consequently the discovery of new methods to access
fluoroamines remains a major challenge in synthetic chemistry.
Few methods are reported in the literature to give b-fluoro
nitrogen compounds.6 The most commonly used strategy is the
nucleophilic substitution of an amino alcohol using (diethylami-
no)sulfur trifluoride and derivatives, but this method suffers from
the formation of rearranged and dehydrated products, a difficulty
already encountered by Middleton.7a The ring opening of
aziridines with various fluorine sources provides an alternative
route to b-fluoroamines, but this technology lacks generality and
requires starting materials that are not readily available.7b
Halofluorination or hydrofluorination of unsaturated amines
using a combination of Olah’s reagent and an electrophile source
could be an alternative route. However, to the best of our
knowledge, few examples are mentioned in the literature, probably
due to the strong electronic deactivation of the double bond after
protonation of the amino group.8 During the past decades
Jacquesy et al. performed extensive studies on the reactivity of
nitrogen compounds in superacid media (HF–SbF5) showing the
ability to perform reactions that cannot occur in usual conditions.9
Among these results, bromofluorination of the allylic part of
tabersonine and simple allylamine have been performed using an
NBS–HF–SbF5 system leading to c-bromo-b-fluoroamines10 and
confirming the possibility of performing additions on N-allylic
systems in superacid.
The hydrofluorination reaction was attempted firstly on
N-allylpiperidine as a model substrate, under various conditions.
The reaction of compound 1a in HF–SbF5 (7 : 1 molar ratio) at
220 uC afforded the expected b-fluoroamine 2a as the major
product.{ In order to determine the influence of the acidity on the
conversion, the reaction was carried out with various amounts of
Lewis acid. When substrate 1a was used in pure HF, no reaction
occurred. When the HF–SbF5 molar ratio was lowered to 4 : 1, we
observed the formation of a large amount of undesired products.
A decrease in conversion at lower temperatures and no improve-
ment at higher ones led us to set the reaction temperature to
220 uC. In optimized conditions (HF–SbF5 7 : 1 molar ratio,
220 uC, 60 min) N-allylpiperidine gave 72% of product 2a after
purification using column chromatography. This result prompted
us to submit a series of N-allylic amines to reaction (Table 1).
Expected b-fluoroamines 2b–g were obtained in good yields
(Table 1, entries 2–7), confirming the generality of the reaction to
give fluorinated nitrogen building blocks. It should be pointed out
that N-allylbenzylamine 1h gave only a complex mixture of
compounds, whatever the conditions. In optimized conditions,
compound 1i yielded desired fluorinated product 2i in 45% yield,
but also cyclized product 2i9, issued from intramolecular cycliza-
tion, in 24% yield. These results are in accordance with a Friedel–
Crafts reaction already observed in superacid starting from
amides.11 It is notable that, in our case, a weakly nucleophilic
para-nitro substituted arene could trap the dicationic ammonium
intermediate, confirming its highly electrophilic character.
In all cases, even after prolonged reaction time, a small amount
of starting material remained in the crude reaction mixture. After
submitting fluorinated compound 2c to the reaction conditions, a
mixture of alkene 1c and fluorinated product 2c was obtained in a
1
5 : 95 molar ratio (determined by H NMR spectroscopy of the
crude reaction mixture). These results provided evidence of
equilibrium in the mechanism (Scheme 1). Recently, Klumpp
et al. performed the arylation of unsaturated amines in superacid
CF3SO3H in the presence of benzene12 and showed the ability of
unsaturated piperidine to react with poorly nucleophilic arenes
after formation of a superelectrophilic13 ammonium dication.
Similarly, we postulate that, after protonation of the nitrogen
atom, the strong acidity of the medium allows the formation of
superelectrophilic dication A. The ammonium cation plays a
aUniversite´ de Poitiers, CNRS UMR 6514, Laboratoire ‘‘Synthe`se et
Re´activite´ 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
b@rtMolecule, 40, avenue du Recteur Pineau, F-86022 Poitiers Cedex,
France. E-mail: contact@artmolecule.fr; Fax: +33-549454121;
Tel: +33-549454121
{ Electronic supplementary information (ESI) available: Experimental
procedures and NMR spectra. See DOI: 10.1039/b703629a
3198 | Chem. Commun., 2007, 3198–3200
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Table 1 Hydrofluorination of N-allylic amines
Table 2 Hydrofluorination of N-allylic derivatives
Entry
Substrate
Product
Yield (%)a
Entry Substrate
Product
Yield (%)a
1
2
3
4
5
6
R = CH2
R = NH
R = NBn
R = NAc
R = O
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
72
57
85
69
61
70
1
2
3
R = COOMe
R = Bz
R = p-NO2-Bz
3a
3b
3c
—
4b19
4c
—
86
69
R = CO
4
3d
3d
R = OH
R = OH
R = F
4d20
4d
97
34
31
5b
4d9
7
1g
2g
40
6
3e
3f
4e
4f
64
74
b
b
8
9
R = Bn
R = p-NO2-Bn
1h
1i
—
2i
—
45
24
7
a
b
Chemical yield after column chromatography. Quenching with
HF–pyridine 70 : 30 w/w (24 h, 220 uC) before hydrolysis.
a
b
Chemical yield after column chromatography. Complex mixture.
nucleophilic character of the arene was decreased by the presence
of the electron withdrawing nitro group in the para position, only
hydrofluorination occurred, with 74% yield (Table 2, entry 7). The
observed differences of reactivity between amines, amides and
sulfonamides encouraged us to postulate that reactivities depend
on the electrophilic character of the intermediates. The protonation
of amides occurs on the oxygen atom16 to give the monocation
and a second protonation gives the reactive dication B (Scheme 2).
In the chemistry of dicationic electrophiles, the proximity of the
charge centers may influence the reactivity of the intermediates.17
In the amide case, carboxonium–carbenium dication B seems to be
less electrophilic than the ammonium–carbenium dication A where
charge repulsion is higher. The dication B is insufficiently
electrophilic to react with a fluoride ion in superacid and leads
to hydroxy derivatives after hydrolysis. When fluorinating agent
HF–pyridine is added, the intermediate can be partially fluori-
nated. After N-protonation of a sulfonamide group,18 a second
protonation gives the dicationic intermediate C, which can be
trapped by the arene or fluoride ions, depending on the
nucleophilic character of the aromatic ring, showing a similar
reactivity of dicationic intermediates A and C.
Scheme 1
critical role in activating the nearby electrophilic site12 and the
intermediate can be fluorinated, even in the presence of a poor
nucleophile such as solvated fluorine in the polymeric anion form,
SbnF5n+12, of the superacidic medium.14
To explore the generality of the hydrofluorination, amides,
sulfonamides and carbamates have been submitted to the reaction
conditions (Table 2).
Reaction of carbamate 3a was unsuccessful and no material
could be extracted after hydrolysis of the crude product. This result
could be explained by an alkyl–oxygen cleavage of protonated
carbamate leading to carbamic acids, already observed by Olah in
superacid.15 The behaviour of amides and amines appeared to be
different. After reaction in the usual conditions, amides 3b–c gave
only corresponding hydroxy products 4b–c in good yields. Starting
from phthalimide 3d, when fluorinating agent HF–pyridine was
added to reaction mixture (Table 2, entry 5), we observed the
formation of fluorinated product 4d9 in 31% yield, beside the
hydroxy derivative (34% yield). It should be noticed that no
intramolecular reaction occurs starting from amide 3c, whereas
such a reaction was observed with compound 1i (Table 1, entry 9),
results which further strengthen the hypothesis of the relative
reactivities of dicationic intermediates. Sulfonamide behaviour was
different. Indeed, compound 4e was obtained in 64% yield after
reaction of 3e by intramolecular Friedel–Crafts reaction. When the
We have also found that hydrofluorination presents some
limitations, as only 30% of c-fluorinated product 4g was obtained
after reaction of compound 3g and no fluorinated product was
Scheme 2
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In summary, we have found that N-allylic amines and
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b-fluoro nitrogen-containing compounds in good yields after a
simple hydrofluorination reaction. We have also showed that
b-hydroxy analogues can be obtained starting from corresponding
amides. To reflect these relative reactivities we proposed a
mechanism showing that this new reaction of hydrofluorination
of N-allylic compounds is based on the strong electrophilic
character of the carbenium ion formed in the b-position to the
ammonium ion. The present work opens new possibilities for the
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Notes and references
{ Procedure for the production of 2a: to a mixture of HF–SbF5 (9 ml, 7 : 1
molar ratio), maintained at 220 uC, was added 250 mg of
N-allylpiperidine. The mixture was magnetically stirred at the same
temperature for 1 h. 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 (97 : 2 : 1 CH2Cl2–MeOH–
NH3) gave the product as a colourless oil (209 mg, 72%). All experimental
procedures and spectral data are reported in the ESI.{
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3200 | Chem. Commun., 2007, 3198–3200
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