Substitution effect on the hydrofluorination reaction of unsaturated amines in superacid HF/SbF5

Article abstract of DOI:10.1039/b915077c

This paper describes the scope and limitations of the hydrofluorination reaction in superacid HF/SbF₅. On the basis of experimental studies of polyfunctional substrates' behaviour, the dramatic effect of substitution on the superelectrophilic c

Full text of DOI:10.1039/b915077c

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Substitution effect on the hydrofluorination reaction of unsaturated amines
in superacid HF/SbF5†
Fei Liu,a Agne`s Martin-Mingot,a Marie-Paule Jouannetaud,a Omar Karamb and Se´bastien Thibaudeau*a
Received 24th July 2009, Accepted 26th August 2009
First published as an Advance Article on the web 22nd September 2009
DOI: 10.1039/b915077c
This paper describes the scope and limitations of the hydrofluorination reaction in superacid HF/SbF5.
On the basis of experimental studies of polyfunctional substrates’ behaviour, the dramatic effect of
substitution on the superelectrophilic character of ammonium–carbenium dications was emphasized.
This reaction was applied to the synthesis of novel fluorinated key building blocks. Furthermore, the
hydrofluorination reaction and the discovered homodimerization/fluorination reaction were applied to
the synthesis of highly valued fluorinated diamines.
lack of regioselectivity and the poor reactivity of the double bond
Introduction
after protonation of the amino group17 could explain the difficulty
Introducing fluorine atom(s) commonly alters the physical and/or
in performing such reactions with simple unsaturated amines. In
chemical properties of a molecule,1 with dramatic effects on its
our ongoing project toward the synthesis of fluorinated nitrogen
biological activity.2 As a consequence, drug candidates with one or
more fluorine atoms have became commonplace.3 Among fluorine
substitution’s consequences, the strong inductive withdrawing
effect of fluorine on the acidity or basicity of neighbouring
functional groups is especially evident.4 The changes in pKa
can have effects on different parameters in lead optimization
including physicochemical properties, binding, absorption, dis-
tribution, metabolism, excretion (ADME) and safety issues. Even
if fluorine substitution’s effects on oral bioavailability could not
always be accurately predicted,5 the incorporation of nitrogen-
containing organofluorine cores in medicinal chemistry became
very popular.6 Despite the importance of (mono)fluorinated
amines, few synthetic methods are reported in the literature for
their preparation.7 One common method is the ring opening
of aziridines with nucleophilic fluoride sources,8 but it lacks
generality, substrate scope and requires starting materials that
are not readily available. A widely used alternative is the nucle-
ophilic substitution of aminoalcohol with DAST and derivatives,9
but this method suffers from rearranged and dehydrated
product formation.10 Other routes via reductive amination of
a-fluoroenones11 or ketones12 or via Grignard or organolithium
reagents’ addition to a-fluoroenimines have also recently been
reported.13 The simplest route to fluoroamines would appear
to be the halofluorination or hydrofluorination of unsaturated
amines using a combination of HF-base, Olah’s reagents and an
electrophilic source.14 However, to the best of our knowledge, few
successful examples are reported in the literature starting from
either protected vinylimidazole15 or from N-allylic imines.16 The
containing compounds in superacid HF/SbF5,18 we recently
developed a novel route to b-fluoroamines via a hydrofluorination
reaction.19 After successive protonations, the allylic amines gave
dicationic ammonium–carbenium intermediates A in superacid
HF/SbF5. The dicationic intermediates then reacted in good yields
to give b-fluoroamines after fluorination (Scheme 1).
Scheme 1 Hydrofluorination in superacid HF/SbF5.
The ability to be fluorinated, even in the presence of a poor
nucleophile such as solvated fluorine in the polymeric anion form
-
SbnF5n+1
,
20 suggested that the dicationic intermediates A could be
considered as superelectrophiles.
In the following report, we describe further studies to evaluate
the scope and limitations of this original process. We report a dra-
matic effect of both nitrogen- and double bond-substitutions on
the hydrofluorination reaction. We also show that the ammonium–
carbenium dicationic intermediates can be involved in a homod-
imerization/fluorination process, which provides further advances
toward the synthesis of fluorinated highly valued diamine building
blocks.
Results and discussion
Nitrogen substitution effect on the hydrofluorination reaction
A series of N-allylic amines were subjected to reaction in superacid
HF/SbF5 (HF/SbF5 molar ratio 7/1, -20 C, 10 min). Starting
aLaboratoire “Synthe`se et Re´activite´ des Substances Naturelles”, UMR
6514, 40, avenue du Recteur Pineau, F-86022, Poitiers Cedex, France.
E-mail: sebastien.thibaudeau@univ-poitiers.fr; Fax: +33-549453501;
Tel: +33-549453702
◦
from amines, hydrofluorination occurred to give the corresponding
b-fluoroamines with reasonable yields (Table 1, entries 2–10).
During the course of this preliminary study, we also assessed
the difference in reactivity of allylic amines and amides toward
the hydrofluorination reaction (Table 1, entries 1–3).19 Whereas
amines led to the desired fluorinated products, amide 1a underwent
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: Copies of NMR
spectra. See DOI: 10.1039/b915077c
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Table 1 Hydrofluorination of N-substituted allylic substratesa
Entry
1
Substrate
Product
Yield (%)b
69
1a
2¢a
2
3
1b
1c
2b
2c
72
45
2¢c
24
4
5
6
7
1d
1e
1f
2d
2e
2f
31c
22c
35d
60c
1g
2g
8
1h
2h
55c
9
1i
1j
2i
2j
61c
46d
10
a Standard conditions: HF/SbF5 molar ratio 7/1, -20 ◦C, 10 min. b Chemical yield after column chromatography. c 100% conversion. d Side product
formation
hydration in the same conditions. Particularly noteworthy is
also the formation of tetrahydroisoquinoline 2¢c, besides fluo-
roproduct 2c, after reaction of p-NO2-benzylamine 1c. These
results strengthen the hypothesis that the electrophilic character
of the dicationic intermediates strongly influences the reaction
course. The ammonium–carbenium dications A or A¢ (Scheme 2)
obtained after protonation of allylic amines can be considered as
superelectrophiles.21 Indeed, the dications can be quenched by a
poor nucleophile such as solvated fluorine in superacid,20 or by a
strongly deactivated aromatic ring in an intramolecular Friedel–
Crafts process. However, the carboxonium–carbenium dication
B formed after protonation of N-allylic amide was insufficiently
electrophilic to react with fluoride ions of the media and led to the
corresponding alcohol after hydrolysis.
This behaviour of amino alcohols in superacid led to the synthesis
of a novel chiral heterocyclic system starting from quinine in
superacid.22 No similar effect was observed on the hydrofluori-
nation reaction. Amino alcohol 1d and amino ether 1e yielded
corresponding fluoroamines (Table 1, entries 4 and 5), and no
other products resulting from intramolecular nucleophilic attack
were detected in the crude mixture. The low yields obtained after
purification were probably due to the volatility of the fluorinated
products. Amino esters and amino nitriles were also found to be
compatible with the hydrofluorination reaction (Table 1, entries
6–10). However, the absence of selectivity starting from amino
ester 1f showed that the hydrofluorination reaction could present
some limitations. As mentioned previously,23 the intramolecular
participation of the carbonyl group could be postulated. After
formation of a six-membered ring carboxonium ion, the reactivity
of the intermediate could be modified, leading to the formation
In a previous study, we reported that ammonium–carbenium
dications can be trapped by an intramolecular hydroxyl group.
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Scheme 2 Influence of dicationic superelectrophiles on the hydrofluorination reaction.
of undesired side products (entry 6). In a similar way, the for-
mation of a seven-membered ring ammonium–nitrilium dication
could explain why the formation of fluorinated product 2j was
not exclusive (entry 10). To conclude, the hydrofluorination of
N-substituted allylic amines presents few limits and was applied to
the synthesis of novel fluorinated key building blocks in moderate
to good yields.
substrate from undergoing the hydrofluorination reaction. Based
on this hypothesis, the amine function was protected by a p-NO2-
benzoyl group (substrate 4f). In this case, the hydrofluorination
reaction occurred after 10 min reaction at -20 ◦C with starting
material remaining. Under optimized conditions (-20 ◦C, 4h), the
desired product 5f was obtained in 62% yield (Table 2, entry 6).
The protonation on both functions, on the nitrogen atom of the
amine and on the oxygen atom of the amide, let the double bond
sufficiently reactive toward protonation (less withdrawing effects
by increasing the distance) and hydrofluorination took place. In
addition, methyl- and phenyl-substitution of the terminal position
of the allylic chain in the substrates (compounds 4g and 4h) led to
complex mixtures of compounds, even under milder conditions.
To summarize, it appears that the electronic deactivation of
the double bond with inductive and/or mesomeric withdrawing
groups such as an ester function (in neutral or protonated form)
or an ammonium group, strongly deactivates the double bond
toward the electrophilic addition and prevents substrates from
undergoing the hydrofluorination reaction. An alternative toward
the synthesis of fluorinated diamines has been found to be
protection of one amino group as the amide form (formation of
product 5f). In addition, phenyl substitution allows substrates to
react through the ammonium–carbenium dication, but a strong
effect of aromatic substituent on the selectivity of the reaction is
observed. Methyl substituted substrates seemed to be compatible
with the reaction. Among the systems studied, compound 4b was
found to give product 5b as a major product, along with an
unidentified minor product (eqn 1).
Double bond substitution effect on the hydrofluorination reaction
On the basis of these preliminary results, the superelectrophilic
dicationic ammonium–carbenium intermediates were expected
to be reactive toward fluoride ions and should allow, via the
introduction of substituents on the double bond, the synthesis of
various fluorinated amines. With N-acetyl piperazine 4a as a model
substrate,19 substituted starting materials (4b–i) were subjected to
superacid under standard conditions (Table 2).
Initially the reaction was attempted with methyl substituted
substrate 4b. Using an inductive donating methyl substituent,
hydrofluorination still occurred and led to the formation of the
fluorinated amine 5b in 85% yield. Hydrofluorination was also
compatible with phenyl substituted substrate, as shown by the
formation of the fluorinated amine 5c starting from amine 4c
(Table 2, entry 3). However, a large amount of side products
could be detected in the crude mixture, products which could
probably come from an intermolecular Friedel–Crafts reaction.
Unfortunately, substitution with carbonyl containing groups, like
an ester function, completely deactivated the substrate and no
reaction occurred (Table 2, entries 4 and 9). To verify if a hydroflu-
orination process could be used to form fluorinated diamines,
the reactivity of the diamine 4e was tested. Unfortunately the
reaction did not occur, even after a longer reaction time (1 day)
at 0 ◦C (Table 2, entry 5). It appears that after protonation
of the nitrogen atoms, the double bond is too deactivated by
the proximal ammonium ions to be protonated, preventing the
Isolation and characterization of this minor product revealed its
identity to be that of structure 6b. This product could only arise
from a homodimerization process. To the best of our knowledge,
no similar process observed from unsaturated nitrogen derivatives
has been reported yet in superacid. Despite the fact that superacid
was known to catalyse polymerisation (styrene polymerisation
for example),24 Klumpp et al. had previously reported that no
(1)
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Table 2 Hydrofluorination of double bond substituted substratesa
Entry
1
Substrate
Product
Yield (%)b
69
4a
5a
2
3
4
5
4b
4c
4d
4e
5b
5c
85
41c
d
d
/
/
d
d
/
/
6e
4f
5f
62
f
f
7
8
9
4g
4h
4i
/
/
f
f
/
/
d
d
/
/
a Standard conditions: HF/SbF5 molar ratio 7/1, -20 ◦C, 10 min. b Chemical yield after column chromatography. c Side product formation. d No reaction.
e 4 h reaction time. f Complex mixture.
polymerisation or oligomerization of olefinic amines occurred
in superacid.25 This unusual homodimerization of unsaturated
amines in superacid could open up novel alternatives for the
synthesis of highly valued fluorinated diamines. For example, in
the last few years, medicinal chemistry strategies largely used
the concept of immolative linkers, applied toward the synthesis
of biologically active compounds, such as anticancer agents.26
Diamino linkers became interesting targets and got a primordial
place in this strategy. As a fluorine substituent could modify
the chemical and biological properties of diamines linkers by
strongly changing the basicity of the proximal nitrogen functions,
fluorinated diamine building blocks could become of great interest
in SAR studies.27 These considerations prompted us to examine
this dimerization process, and the effect of the reaction param-
eters (HF/SbF5 molar ratio, concentration,. . .) on the reaction
course.
Homodimerization/fluorination reaction in superacid
The first attempt starting from amine 4b using standard conditions
confirmed the formation of the fluorinated dimer 6b in very low
yield beside fluoroamine 5b (Table 3, entry 1). An isomerisation
step was probably involved in the formation of 6b, and thus the
effect of the acidity on its formation was first evaluated. While
strong acidic conditions were not appropriate for the dimerization
process (Table 3, entry 2), using an HF/SbF5 molar ratio of 2/1
value was found to improve the yield of desired dimer 6b (Table 3,
entry 3).
A dilution effect on oligomerization processes is well known
and could also occur in this case. Thus, we therefore investigated
the effect of substrate concentration in the superacid HF/SbF5
medium, on the reaction course. With increasing dilution of the
solution, product 6b formation gradually increased until 36%.
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Table 3 Homodimerization/fluorination in superacida
Concentration
Entry Substrate
(mol L-1)b
HF/SbF5 molar ratio
Products (Yield %)c
1
2
3
4
5
6
4b
4b
4b
4b
4b
4b
0.3
0.3
0.3
0.6
0.17
0.06
7/1
1/1
2/1
2/1
2/1
2/1
5b (85)
6b (<5%)
d
/
5b (44)
5b (36)
5b (39)
5b (10)
6b (12)
6b (<5%)
6b (20)
6b (36)
7
8
4g
4g
0.3
0.17
7/1
2/1
6b (38)
6b (66)
9
4j
0.3
2/1
6b (42)
a Standard conditions : -20 ◦C, 10 min. b Molar concentration of substrate in HF/SbF5 media. c Chemical yield after column chromatography. d Complex
mixture.
It has to be noted that even under these conditions, the usual
hydrofluorination process still occurred in 10% yield (Table 3,
entries 4–6). Based on these promising results, a mechanism was
postulated (Scheme 3).
E (less repulsion of charges, inductive stabilizing effect), pre-
cursor of the fluorinated dimer 6b. The postulated mechanism
emphasizes two points. First, as already reported for an intra-
molecular way by our group,29 despite the strong deactivation
of the double bond, due to the inductive withdrawing effect of
the proximal ammonium ion, the intermediate A can play the
role of nucleophilic partner. Then, repulsive electrostatic effects,
usually mentioned to explain the absence of polymerisation of
polycationic species, do not occur during the process. Since
the formation of the intermediate E, precursor of the desired
fluorinated product 6b, seems to be fully dependant on the
inter-molecular trapping of intermediate C, we postulated that
the methyl substituted substrate 4g or the homoallylic substrate
4j could undergo a similar process. As predicted, the desired
fluorinated dimer could be formed in 66% yield using optimized
conditions starting from substrate 4g (Table 3, entries 7 and 8) and
in 42% yield from substrate 4j (Table 3, entry 9). Increasing dilution
had no positive effect in the latter case, and the yield could not
be improved. The ability to form tricationic species (Scheme 4)
such as intermediates F (by protonation of substrate 4f) or E
(precursor of product 6b), further advances HF/SbF5 superacid
chemistry, toward the synthesis of highly valued fluorinated di-
amines, via both hydrofluorination and dimerization/fluorination
reactions.
Scheme 3 Postulated mechanism for the homodimerization/fluorination
reaction in superacid.
Starting from methyl substituted substrate, N-protonation
(formation of A), followed by double bond protonation allows
the formation of the superelectrophilic ammonium–carbenium
dication B. Based on the carbenium ion’s behaviour in superacid,
an equilibrium between B and protonated cyclopropane C can
be postulated.28 The intermolecular attack of A on intermediate
C could be the key step for the dimerization process, allowing
the formation of trication D. By repulsion of charges, D could
isomerize toward the formation of the more stable intermediate
Scheme 4 Tricationic species in superacid.
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[M]+ (100). HRMS (ESI): Calc for C10H10N2O3: 206.06914, found
206.0692. Mp: 136 ◦C (CH2Cl2/hexane (20/80, v/v)).
Conclusion
In summary, we have showed that the hydrofluorination reaction in
superacid HF/SbF5 can be extended to polyfunctional substrates
to form novel fluorinated key building blocks. In addition, the
dramatic effect of substitution on the superelectrophilic character
of the ammonium–carbenium dications, and thus on the hydroflu-
orination reaction, has been emphasized. Interestingly, an original
homodimerization/fluorination reaction occurred starting from
methyl substituted unsaturated substrates, leading to fluorinated
symmetrical diamine synthesis. Similar intermolecular reactions
between polycationic superelectrophiles and unsaturated partners
could be exploited in synthetic methodologies to access to
fluorinated highly valued products.
Compound 2b: 1-(2-fluoropropyl)piperidine. Optimized proce-
dure (60 min reaction time) was followed, starting from 250 mg
of 1b (2 mmol). Purification by flash column chromatography
(97/2/1: dichloromethane/methanol/NH3 aq.) afforded 209 mg
of the title compound as a colourless oil (72%). 1H NMR
3
(300 MHz, CDCl3, ppm): d 1.23 (3H, dd, JHF = 23.6 Hz,
J=6.4 Hz, CH3CHF), 1.36 (2H, m, CH2CH2CH2), 1.52 (4H,
3
m, CH2CH2CH2), 2.29 (1H, ddd, JHF = 31.2 Hz, J=13.9 Hz,
J=3.0 Hz, CHaHbCHF), 2.37 (4H, m, CH2NCH2), 2.50 (1H,
3
ddd, JHF = 21.6 Hz, J=13.9 Hz, J=7.7 Hz, CHaHbCHF), 4.77
2
(1H, m incl. app. d, JHF = 49.8 Hz, CH3CHF). 13C NMR
2
(75 MHz, CDCl3, ppm): d 19.9 (d, JC-F = 22 Hz, CH3CHF),
24.5 (CH2CH2CH2), 26.3 (CH2CH2CH2), 55.4 (CH2NCH2), 65.0
(d, 2JC-F = 21 Hz, CH2CHF), 89.2 (d, 1JC-F = 167 Hz, CH3CHF).
Experimental details
1
19F{ H} NMR (282 MHz, CDCl3, ppm): d -173.7. MS (EI, 70 ev):
General method
m/z (relative intensity%) 146 [M + H]+ (100). HRMS (ESI): Calc
for C8H16NF: 145.12668, found 145.1269.
The authors draw the reader’s attention to the dangerous features
of superacidic chemistry. Handling of hydrogen fluoride and
antimony pentafluoride must be done by experienced chemists
with all the necessary safety arrangements in place.
Compound 2c and 2¢c. Optimized procedure (10 min re-
action time) was followed, starting from 324 mg of 1c
(1.68 mmol). Purification by flash column chromatography
(99/1: dichloromethane/methanol) afforded 160 mg of the title
compound as a colourless oil (45%). The second compound
1,2,3,4-tetrahydro-4-methyl-6-nitroisoquinoline 2¢c (80 mg, 24%)
was then eluted (95/4/1: dichloromethane/methanol/NH3 aq.).
Compound 2c: N-(4-nitrobenzyl)-2-fluoropropan-1-amine 1H NMR
Reactions performed in superacid were carried out in a sealed
R
Teflonꢀ flask with a magnetic stirrer. No further precautions have
to be taken to prevent the mixture from moisture (test reaction
worked out in anhydrous conditions leads to the same results as
expected). Yields refer to isolated pure products. 1H, 13C and 19
F
NMR were recorded on a 300 MHz Bru¨ker spectrometer using
CDCl3 as solvent. Melting points were determined in a capillary
tube and are uncorrected. High-resolution mass spectra were
performed on a Micromass ZABSpec TOF by the Centre Regional
de Mesures Physiques de l’Ouest, Universite´ Rennes (France). All
separations were done under flash-chromatography conditions on
silica gel (15–40 mm).
3
(300 MHz, CDCl3, ppm): d 1.27 (3H, dd, JHF = 23.9 Hz,
J=6.4 Hz, CH3CHF), 1.66 (1H, broad s, NH), 2.70 (2H, m,
CH2CHF), 3.87 (2H, s, Ph-CH2-NH), 4.75 (1H, m incl. app. d,
2JHF = 49.3 Hz, CH3CHF), 7.45 (2H, d, J=8.8 Hz, CHarom), 8.11
(2H, d, J=8.8 Hz, CHarom). 13C NMR (75 MHz, CDCl3, ppm):
d 17.7 (d, 2JC-F = 22 Hz, CH3CHF), 51.8 (Ph-CH2-NH), 53.5 (d,
2JC-F = 20 Hz, CH2CHF), 89.3 (d, 1JC-F = 165 Hz, CH3CHF), 122.6
(CHarom), 127.5 (CHarom), 146.0 (Carom), 146.9 (Carom).19F{ H} NMR
1
(282 MHz, CDCl3, ppm): d -179.6. MS (GCT, CI+): m/z (relative
intensity%) 212 [M]+ (100). HRMS (ESI): Calc for C10H13N2O2F:
212.09611, found 212.0967. Compound 2¢c: 1,2,3,4-tetrahydro-4-
methyl-6-nitroisoquinoline 1H NMR (300 MHz, CDCl3, ppm):
d 1.27 (3H, d, J=7.0 Hz, CH3CH), 1.97 (1H, broad s, NH),
2.76 (1H, dd, J=12.6 Hz, J=6.3 Hz, NHCHaHbCH), 2.89
(1H, m, NHCH2CH), 3.16 (1H, dd, J=12.6 Hz, J=5.0 Hz,
NHCHaHbCH), 4.01 (2H, s, Ph-CH2-NH), 7.08 (1H, d, J=8.5 Hz,
CHarom), 7.88 (1H, dd, J=8.4 Hz, J=2.3 Hz, CHarom), 8.02 (1H,
d, J=2.3 Hz, CHarom). 13C NMR (75 MHz, CDCl3, ppm): d
19.2 (CH3CH), 31.4 (NHCH2CH), 48.4 (Ph-CH2-NH), 50.1
(NHCH2CH), 120.3 (CHarom), 122.8 (CHarom), 126.6 (CHarom),
141.4 (Carom), 142.8 (Carom), 146.2 (Carom). MS (GCT, CI+): m/z
(relative intensity%) 192 [M]+ (100). HRMS (ESI): Calc for
C10H12N2O2: 192.08988, found 192.0907.
Optimized procedure in superacidic media
To a mi◦xture of HF/SbF5 (3 or 6 mL, 7/1 molar ratio) maintained
at -20 C was added the nitrogen derivative (1 or 2 mmol). The
mixture was magnetically stirred at the same temperature for the
reaction time. The reaction mixture was then neutralized with
water–ice–Na2CO3, and extracted with dichloromethane (¥ 3). The
combined organic phases were dried (MgSO4) and concentrated
in vacuo. Products were isolated by column chromatography over
silica gel.
Compound 2¢a: N-(2-hydroxypropyl)-4-nitrobenzamide. Opti-
mized procedure (10 min reaction time) was followed, starting
from 412 mg of 1a (2 mmol). Purification by flash column chro-
matography (99/1, dichloromethane/methanol) afforded 310 mg
of the title compound as a white solid (69%). 1H NMR (300 MHz,
CDCl3, ppm): d 1.46 (3H, d, J=6.3 Hz, CH3CHOH), 3.67 (1H, dd,
J=14.9 Hz, J=7.5 Hz, CHaHbCHOH), 4.21 (1H, dd, J=14.9 Hz,
J=9.5 Hz, CHaHbCHOH), 4.94 (1H, m, CHOH), 8.10 (2H, d,
J=9.0 Hz, CHarom), 8.27 (2H, d, J=9.0 Hz, CHarom). 13C NMR
(75 MHz, CDCl3, ppm): d 21.5 (CH3CHOH), 62.2 (CH2CHOH),
77.4 (CHOH), 123.8 (CHarom), 129.5 (CHarom), 134.2 (Carom), 149.8
(Carom), 162.5 (CO). MS (GCT, CI+): m/z (relative intensity%) 206
Compound 2d: 2-(N-(2-fluoropropyl)-N-methylamino)ethanol.
Optimized procedure (10 min reaction time) was followed, starting
from 115 mg of 1d (1 mmol). Purification by flash column chro-
matography (94/6: dichloromethane/methanol) afforded 43 mg of
the title compound as a colourless oil (31%). 1H NMR (300 MHz,
CDCl3, ppm): 1.31 (3H, dd, 3JHF = 23.6 Hz, J=6.3Hz, CH3CHF),
2.35 (3H, s, NCH3), 2.59 (5H, m, HOCH2CH2N, NCH2CHF and
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OH), 3.58 (2H, t, J=5.3Hz, HOCH2CH2N), 4.82 (1H, m incl. app.
d, 2JHF = 48.9 Hz, CH3CHF). 13C NMR (75 MHz, CDCl3, ppm):
18.2 (d, 2JC-F = 22 Hz, CH3CHF), 41.5 (d, 4JC-F = 1 Hz, NCH3),
57.4 (HOCH2CH2N), 58.3 (HOCH2CH2N), 61.7 (d, 2JC-F = 21 Hz,
followed, starting from 171 mg of 1h (1 mmol). Purification by
flash column chromatography (99/1: dichloromethane/methanol)
afforded 105 mg of the title compound as a colourless oil
(55%). 1H NMR (300 MHz, CDCl3, ppm): 1.23 (3H, t,
1
3
NCH2CHF), 88.0 (d, 1JC-F = 166 Hz, CH3CHF). 19F { H} NMR
J=6.9Hz, CH3CH2O), 1.27 (3H, dd, JHF = 22.9 Hz, J=6.3Hz,
(282 MHz, CDCl3, ppm): -175.7. MS (GCT, CI+): m/z (relative
intensity%) 106(100). HRMS (ESI): Calc for C5H11NF: 104.08755,
found 104.0873.
CH3CHF), 2.29 (3H, s, NCH3), 2.44 (2H, t, J=7.1Hz,
NCH2CH2COOEt), 2.51 (2H, m, CH2CHF), 2.75 (2H, t,
J=7.3Hz, NCH2CH2COOEt), 4.11 (2H, q, J=7.1Hz, CH3CH2O),
2
4.77 (1H, m incl. app. d, JHF = 50.9 Hz, CH3CHF). 13C NMR
Compound 2e: 2-fluoro-N-(2-methoxyethyl)-N-methylpropan-1-
amine. Optimized procedure (10 min reaction time) was fol-
lowed, starting from 129 mg of 1e (1 mmol). Purification by
flash column chromatography (96/4: dichloromethane/methanol)
afforded 33 mg of the title compound as a colourless oil
(22%). 1H NMR (300 MHz, CDCl3, ppm): 1.27 (3H, dd,
3JHF =23,6Hz, J=6,3Hz, CH3CHF), 2.32 (3H, s, NCH3), 2.55
(2H, m, NCH2CHF), 2.62 (2H, t, J=5.6Hz, MeOCH2CH2N),
3.31 (3H, s, OCH3), 3.44 (2H, t, J=5.6Hz, MeOCH2CH2N),
2
(75 MHz, CDCl3, ppm): 14.5 (CH3CH2O), 19.6 (d, JC-F
=
=
4
22 Hz, CH3CHF), 33.1 (NCH2CH2COOEt), 43.1 (d, JC-F
1 Hz, NCH3), 53.8 (NCH2CH2COOEt), 60.7 (CH3CH2O), 62.9
(d, 2JC-F = 21.2 Hz, CH2CHF), 89.5 (d, 1JC-F = 165 Hz, CH3CHF),
172.9 (s, CO). 19F { H} NMR (282 MHz, CDCl3, ppm): -175.6.
1
MS (GCT, CI+): m/z (relative intensity%) 193(15), 146(100).
HRMS (ESI): Calc for C9H19NO2F: 192.1400, found 192.1398.
Compound 2i: 2-(N-(2-fluoropropyl)-N-methylamino)aceto-
nitrile. Optimized procedure (10 min reaction time) was
followed, starting from 111 mg of 1i (1 mmol). Purification by
flash column chromatography (100%: dichloromethane) afforded
81 mg of the title compound as a colourless oil (61%). 1H NMR
(300 MHz, CDCl3, ppm) : 1.26 (3H, dd, 3JHF = 23.7 Hz, J=6.3Hz,
2
4.79 (1H, m incl. app. d, JHF = 49.7 Hz, CH3CHF). 13C NMR
(75 MHz, CDCl3, ppm): 19.7 (d, 2JC-F = 22 Hz, CH3CHF), 43.8 (d,
4JC-F = 1 Hz, NCH3), 57.6 (MeOCH2CH2N), 59.2 (OCH3), 63.5 (d,
2JC-F = 21 Hz, NCH2CHF), 71.1 (MeOCH2CH2N), 89.6 (d, 1JC-F
=
1
166 Hz, CH3CHF). 19F { H} NMR (282 MHz, CDCl3, ppm):
-174.9. MS (GCT, CI+): m/z (relative intensity%) HRMS (ESI):
Calc for C7H17NOF: 150.1294, found 150.1287.
CH3CHF), 2.36 (3H, s, NCH3), 2.53 (2H, m, CH2CHF), 3.53
2
(2H, broad s, NCCH2N), 4.76 (1H, m incl. app. d, JHF
=
50.2 Hz, CH3CHF). 13C NMR (75 MHz, CDCl3, ppm): 19.2 (d,
2JC-F = 22 Hz, CH3CHF), 43.3 (NCH3), 46.2 (d, JC-F = 2.7 Hz,
4
Compound 2f: methyl 2-(N-(2-fluoropropyl)-N-methylamino)-
acetate
2
1
NCCH2N), 60.9 (d, JC-F = 20 Hz, CH2CHF), 89.6 (d, JC-F
=
166 Hz, CH3CHF), 115.2 (CN). 19F { H} NMR (282 MHz,
CDCl3, ppm): -176.5. MS (GCT, CI+): m/z (relative intensity%)
132(20), 85(100). HRMS (ESI): Calc for C6H11N2F: 130.09063,
found 130.0905.
1
Optimized procedure (10 min reaction time) was followed, starting
from 143 mg of 1f (1 mmol). Purification by flash column chro-
matography (99/1: dichloromethane/methanol) afforded 57 mg of
the title compound as a colourless oil (35%). 1H NMR (300 MHz,
CDCl3, ppm): 1.25 (3H, dd, 3JHF = 23.6 Hz, J=6.3Hz, CH3CHF),
2.41 (3H, s, NCH3), 2.64 (2H, m, CH2CHF), 3.33 (2H, broad s,
MeOOCCH2N), 3.64 (3H, s, COOCH3), 4.77 (1H, m incl. app.
d, 2JHF = 49.7 Hz, CH3CHF). 13C NMR (75 MHz, CDCl3, ppm):
19.5 (d, 2JC-F = 22 Hz, CH3CHF), 43.3 (d, 4JC-F = 1 Hz, NCH3),
Compound
2j:
3-(N-(2-fluoropropyl)-N-methylamino)pro-
panitrile. Optimized procedure (10 min reaction time) was
followed, starting from 124 mg of 1j (1 mmol). Purification
by flash column chromatography (100%: dichloromethane)
afforded 67 mg of the title compound as a colourless oil
4
51.8 (COOCH3), 58.8 (d, JC-F = 2 Hz, MeOOCCH2N), 62.1 (d,
1
3
(46%). H NMR (300 MHz, CDCl3, ppm): 1.28 (3H, dd, JHF
=
1
2JC-F = 20 Hz, CH2CHF), 89.9 (d, JC-F = 166 Hz, CH3CHF),
23.8 Hz, J=6.3Hz, CH3CHF), 2.33 (3H, s, NCH3), 2.44 (2H,
1
171.8 (CO). 19F { H} NMR (282 MHz, CDCl3, ppm): -175.7. MS
t, J=6.9Hz, NCCH2CH2N), 2.61 (2H, m, CH2CHF), 2.77 (2H,
(GCT, CI+): m/z (relative intensity%) 165(20), 106(100).
2
t, J=6.9Hz, NCCH2CH2N), 4.76 (1H, m incl. app. d, JHF
=
49.4 Hz, CH3CHF). 13C NMR (75 MHz, CDCl3, ppm): 16.7
(NCCH2CH2N), 19.4 (d, 2JC-F = 22 Hz, CH3CHF), 42.8 (NCH3),
Compound 2g: methyl 2-(N-(2-fluoropropyl)-N-methylacetate)-
acetate. Optimized procedure (10 min reaction time) was fol-
lowed, starting from 201 mg of 1g (1 mmol). Purification by flash
column chromatography (dichloromethane) afforded 132 mg of
the title compound as a colourless oil (60%). 1H NMR (300 MHz,
CDCl3, ppm): 1.21 (3H, dd, 3JHF = 23.7 Hz, J=6.2 Hz, CH3CHF),
2.85 (2H, m, CH2CHF), 3.56 (4H, d, J=4.2 Hz, MeOOCCH2N),
2
53.6 (NCCH2CH2N), 62.5 (d, JC-F = 21 Hz, CH2CHF), 89.7
(d, JC-F = 166 Hz, CH3CHF), 119.2 (CN). 19F { H} NMR
(282 MHz, CDCl3, ppm): -175.5. MS (GCT, CI+): m/z (relative
intensity%) 106(38), 99(100). HRMS (ESI): Calc for C7H13N2F:
145.1141, found 145.1135.
1
1
2
3.63 (6H, s, COOCH3), 4.79 (1H, m incl. app. d, JHF = 49.6 Hz,
Compound 5a: 1-(4-(2-fluoropropyl)piperazin-1-yl)ethanone.
Optimized procedure (10 min reaction time) was followed, starting
from 168 mg of 4a (1 mmol). Purification by flash column
chromatography (97/2/1: dichloromethane/methanol/NH3 aq.)
afforded 130 mg of the title compound as a colourless oil
2
CH3CHF). 13C NMR (75 MHz, CDCl3, ppm): 19.1 (d, JCF
=
23 Hz, CH3CHF), 51.9 (COOCH3), 56.2 (MeOOCCH2N), 59.8
(d, JCF = 20 Hz, CH2CHF), 91.1 (d,1JCF = 165 Hz, CH3CHF),
2
172.0 (CO). 19F { H} NMR (282 MHz, CDCl3, ppm): -176.0. MS
1
(GCT, CI+): m/z (relative intensity%) 221(15), 201(15), 174(50),
162(100). HRMS (ESI): Calc for C20H38N4O2F: 385.29788, found
385.2975.
1
3
(69%). H NMR (300 MHz, CDCl3, ppm): 1.34 (3H, dd, JHF
=
23.7 Hz, J=6.4 Hz, CH3CHF), 2.09 (3H, s, CH3CO), 2.53
(6H, m, CH2NCH2 and CH2CHF), 3.48 (2H, t, J=5.1 Hz,
CHaHbNCHaHb), 3.64 (2H, m, CHaHbNCHaHb), 4.87 (1H, m
Compound 2h: ethyl 3-(N-(2-fluoropropyl)-N-methylamino)
propanoate. Optimized procedure (10 min reaction time) was
incl. app. d, JHF = 49.6 Hz, CH3CHF). 13C NMR (75 MHz,
2
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CDCl3, ppm): 19.3 (d, J = 22 Hz, CH3CHF), 21.3 (CH3CO),
41.4 (CH2NCH2), 46.2 (CH2NCH2), 53.3 (CH2NCH2), 53.7
(CH2NCH2), 63.5 (d, J = 20 Hz, CH2CHF), 88.9 (d, J = 167 Hz,
20 Hz, CH2CF), 97.2 (d,1JC-F = 172 Hz, CF), 124.3 (CHarom), 128.6
(CHarom), 140.3 (Carom), 150.1 (Carom), 166.1 (CO), 169.3 (CO). 19
F
1
{ H} NMR (282 MHz, CDCl3, ppm): -154.2. HRMS (ESI): Calc
CH3CHF), 168.9 (CO). 19F { H} NMR (282 MHz, CDCl3, ppm):
for [M - HF]+ (C17H22N4O4) : 346.16411, found 346.1625.
1
-174.3. MS (EI, 70 ev): m/z (relative intensity%) 189 [M +
H+]+ (20). HRMS (ESI): Calc for C9H16N2O: 168.12626, found
168.1263.
Compound 6b: 1-(4-(7-(4-acetyl-piperazin-1-yl)-4-fluoro-4-
methyl-heptyl)-piperazin-1-yl)ethanone. Optimized procedure
(10 min reaction time) was followed, starting from 182 mg of
4g (1 mmol). Purification by flash column chromatography
(89.5/10/0.5: dichloromethane/methanol/NH3 aq) afforded
126 mg of the title compound as a colourless oil (66%). 1H
Compound 5b: 1-(4-(2-fluoro-2-methyl-propyl)-piperazin-1-yl)-
ethanone. Optimized procedure (10 min reaction time)
was followed, starting from 182 mg of 4b (1 mmol).
Purification by flash column chromatography (98.5/1/0.5:
dichloromethane/methanol/NH3 aq) afforded 171 mg of the
3
NMR (300 MHz, CDCl3, ppm): 1.28 (3H, d, JHF =21.7 Hz,
CH3CF), 1.59 (8H, m, NCH2CH2CH2), 2.05 (6H, s, CH3CO),
2.32 (12H, m, CH2NCH2); 3,43 (4H, t, J=4.8 Hz, CH2NCH2),
3,58 (4H, t, J=4.8 Hz, CH2NCH2). 13C NMR (75 MHz,
CDCl3, ppm): 21.4 (d,3JC-F =5 Hz, NCH2CH2CH2CF), 21.7
(CH3CO), 24.5 (d,2JC-F = 25 Hz, CH3CF), 37.5 (d,2JC-F = 23 Hz,
NCH2CH2CH2CF), 41.7 (CH2NCH2), 46.6 (CH2NCH2), 53.1
(CH2NCH2), 53.7 (CH2NCH2), 58.8 (NCH2CH2CH2CF), 97.3
1
title compound as a colourless oil (85%). H NMR (300 MHz,
3
CDCl3, ppm): 1.34 (6H, d, JHF =21.4 Hz, CH3CFCH3), 2.05
(3H, s, CH3CO), 2.42 (2H, d, 3JHF =22.8 Hz, CH2CF), 2.52 (2H,
2t, J=5.1 Hz, CH2NCH2), 2.56 (2H, 2t, J=5.1 Hz, CH2NCH2),
3.45 (2H, t, J=5.1 Hz, CH2NCH2), 3.61 (2H, t, J=5.1 Hz,
CH2NCH2). 13C NMR (75 MHz, CDCl3, ppm): 21.7 (s, CH3,
CH3CO), 25.5 (d,2JC-F = 24 Hz, CH3CFCH3), 41.9 (CH2NCH2),
1
(d,1JC-F = 166 Hz, NCH2CH2CH2CF), 169.3 (CO). 19F { H}
4
46.8 (CH2NCH2), 54.6 (d, JC-F = 3.1 Hz, CH2NCH2), 54.8 (d,
NMR (282 MHz, CDCl3, ppm): -145.5. HRMS (ESI): Calc for
2
4JC-F = 3.1 Hz, CH2NCH2), 66.5 (d, JC-F = 21 Hz, CH2CF),
C20H38N4O2F: 385.29788, found 385.2975.
1
96.9 (d,1JC-F = 240 Hz, CH3CFCH3), 169.3 (CO). 19F { H} NMR
(282 MHz, CDCl3, ppm): -139.6. MS (GCT, CI+): m/z (relative
intensity%) 202(50), 182(60), 141(100). HRMS (ESI): Calc for
C10H19N2OF: 202.14814, found 202.1461.
Acknowledgements
We thank the region Poitou-Charentes (grant to F.L.), the CNRS
and the University of Poitiers for financial support.
Compound 5c: 1-(4-(2-fluoro-2-phenyl-propyl)-piperazin-1-yl)-
ethanone. Optimized procedure (10 min reaction time)
was followed, starting from 244 mg of 4c (1 mmol).
Purification by flash column chromatography (96.5/3/0.5:
dichloromethane/methanol/NH3 aq) afforded 108 mg of the
Notes and references
1 (a) D. O’Hagan, Chem. Soc. Rev., 2008, 308; B. E. Smart, J. Fluorine
Chem., 2001, 3; (b) B. E. Smart, in Chemistry of Organic Fluorine
Compounds II: A Critical Review, M. Hudlicky, A. E. Pavlath, Eds.,
ACS Monograph 187, American Chemical Society, Washington, DC,
1995, pp. 979–1010; (c) B. E. Smart, in Organofluorine Chemistry:
Principles and Commercial Applications, R. E. Banks, B. E. Smart,
J. C. Tatlow, Eds., Plenum Publishing Corporation, New York, 1994,
pp. 57–88.
1
title compound as a colourless oil (41%). H NMR (300 MHz,
3
CDCl3, ppm): 1.72 (3H, d, JHF =22.7 Hz, CH3CFPh), 2.05
(3H, s, CH3CO), 2.57 (6H, m, CH2NCH2 and CH2CFPh), 3.37
(2H, m, CH2NCH2), 3.55 (2H, m, CH2NCH2), 7.32 (5H, m,
Harom). 13C NMR (75 MHz, CDCl3, ppm): 19.8 (CH3CO), 23.0
(d,2JC-F = 24 Hz, CH3CFPh), 40.0 (CH2NCH2), 44.8 (CH2NCH2),
2 J-P. Be´gue´ and D. Bonnet-Delpon, in Chimie Bioorganique et me´dicinale
du fluor, CNRS Edition, Paris, 2005.
2
52.6 (CH2NCH2), 52.8 (CH2NCH2), 65.7 (d, JC-F = 23 Hz,
3 (a) S. Purser, P. M. Moore, S. Swallow and V. Gouverneur, Chem. Soc.
Rev., 2008, 37, 320; (b) J-P. Be´gue´ and D. Bonnet-Delpon, J. Fluorine
Chem., 2006, 127, 992; (c) K. L. Kirk, J. Fluorine Chem., 2006, 127,
1013.
4 M. Morgenthaler, E. Schweiser, F. Hoffman-Roder, F. Benini, R. E.
Martin, G. Jaeschke, B. Wagner, H. Fisher, S. Bendels, D. Zimmerili,
J. Schneider, F. Hiedrich, M. Kansy and K. Muller, ChemMedChem.,
2007, 2, 1100.
CH2, CH2CFPh), 96.8 (d,1JC-F = 173 Hz, CH2CFPh), 122.8
(CHarom), 122.9 (CHarom), 125.9 (CHarom), 126.5 (CHarom), 142.0
1
(d,2JC-F = 22 Hz, Carom), 167.3 (CO). 19F { H} NMR (282 MHz,
CDCl3, ppm): -148.5. MS (GCT, CI+): m/z (relative intensity%)
244 (25), 172(40), 141(100). HRMS (ESI): Calc for C15H21N2OF:
264.16379, found 264.1656.
5 M. Rowley, D. J. Hallett, S. Goodacre, C. Moyes, J. Crawforth, T. J.
Sparey, S. Patel, R. Marwood, S. Thomas, L. Hitzel, D. O’Connor, N.
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Compound 5f: N-(3-(4-acetylpiperazin-1-yl)-2-fluoro-2-methyl-
propyl)-4-nitrobenzamide. Optimized procedure (10 min re-
action time) was followed, starting from 374 mg of 4f
(1 mmol). Purification by flash column chromatography (98/2:
dichloromethane/methanol) afforded 226 mg of the title com-
6 W. H. Hagmann, J. Med. Chem., 2008, 51, 4359.
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J. F. Sanz-Cervera, J. L. Acena and M. Sanchez-Rosello, Synlett, 2009,
(4), 525.
pound as
a
colourless oil (62%). 1H NMR (300 MHz,
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3
CDCl3, ppm): 1.34 (3H, d, JHF =21.8 Hz, CH3CF), 2.01 (3H, s,
CH3CO); 2,60 (6H, m, CH2NCH2 and CH2CF), 3.39 (2H, t, J
=4.7 Hz, CHaHbNCHaHb), 3.70 (4H, m, CHaHbNCHaHb and
CH2CF), 7.63 (1H, t, J =4.9 Hz; NH), 7.96 (2H, d, J =8.6 Hz;
H
arom), 8.23 (2H, d, J=8.6 Hz; Harom). 13C NMR (75 MHz,
CDCl3, ppm): 21.7 (CH3CO), 22.4 (d,2JC-F = 23 Hz, CH3CF),
2
41.9 (CH2NCH2), 46.7 (CH2NCH2), 47.3 (d, JC-F = 22 Hz,
2
CH2CF), 54.8 (CH2NCH2), 55.2 (CH2NCH2), 64.7 (d, JC-F
=
4796 | Org. Biomol. Chem., 2009, 7, 4789–4797
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©

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