New synthesis of trifluorinated amines from 1-bromopropargylic amines in superacid

Article abstract of DOI:10.1016/j.tetlet.2006.05.123

Treatment of 1-bromopropargylic amines affords the corresponding 1,1,1-trifluoro in one step in HF-SbF₅ medium. 1-Bromo-1,1-difluoro or 2-bromo-1,1,1-trifluoro derivatives could also be prepared, depending on the reaction conditions.

Full text of DOI:10.1016/j.tetlet.2006.05.123

Tetrahedron Letters 47 (2006) 5547–5551
New synthesis of trifluorinated amines from
1-bromopropargylic amines in superacid
´
´ `
Anne-Celine Cantet, Helene Carreyre, Jean-Pierre Gesson,
Brigitte Renoux* and Marie-Paule Jouannetaud*
`
´ ´
Laboratoire ‘Synthese et Reactivite des Substances Naturelles’, UMR CNRS 6514, 40, Avenue du Recteur Pineau,
F-86022 Poitiers Cedex, France
Received 13 April 2006; revised 15 May 2006; accepted 22 May 2006
Available online 19 June 2006
Abstract—Treatment of 1-bromopropargylic amines affords the corresponding 1,1,1-trifluoro in one step in HF–SbF5 medium.
1-Bromo-1,1-difluoro or 2-bromo-1,1,1-trifluoro derivatives could also be prepared, depending on the reaction conditions.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
respectively. In the piperidine and isoquinoline series,
direct alkylation6 with 1,3-dibromopropyne afforded
the corresponding bromopropargylic amines 2 and 3
in moderate yields (41% and 36%, respectively).
Considerable attention has been given to fluorinated
organic compounds due to their potential use in medicinal
and agricultural chemistry.1 Interest in these fluorinated
substances is continuously increasing because introduc-
tionofoneormorefluorineatoms2 maysignificantlymod-
ifythechemical,physical,andbiologicalpropertiesofsuch
substances. These modifications are associated with
increasedstabilityandlipophilicity, whilethestericdistor-
tion, compared to the parent compound, is relatively
small. Among these fluorinated compounds, trifluori-
nated ones play an important role, in particular in the de-
sign of bioactive products. Nevertheless, despite this
growing interest, methods to synthesize such products
are still scarce and new methodologies are required. We
would like to report a novel access to trifluorinated com-
pounds from 1-bromopropargylic amines 1–4 in one step.
These bromopropargylic amine derivatives were then
submitted to acidic conditions. Preliminary experiments
were performed using HF alone (0 °C, 5 h). In all cases,
starting material was recovered. The use of more acidic
conditions (HF–SbF5) was then considered.
2.2. Results
In the present study, the reactions were carried out in
7
HF–SbF5 at low temperature (ꢀ40 °C to ꢀ60 °C).
Starting materials (2 mmol) were fully transformed
within 2–15 min of reaction time. In some cases, subse-
quent treatment with HF–pyridine 70/30 (v/v 1 mL)
was required (entries 2, 4, and 5, Table 1) at ꢀ78 °C.
Then, the resulting mixture was quenched with iced
water (150 mL) and sodium carbonate (80 g). After
extraction with dichloromethane and usual work-up,
the products were isolated by column chromatography
over SiO2.
2. Reaction of compounds 1–4 in HF–SbF5
2.1. Starting materials
Amine derivatives 1, 4 were prepared as indicated in
The results are summarized in Table 1. In HF–SbF5
alone, 1 yielded a gem-bromodifluorinated compound
1a8 as major product (entry 1, Table 1) and only minor
amounts of the trifluoro derivative 1b (ratio 1a/1b
11/1, entry 1, Table 2). Addition of a more nucleo-
philic fluorinating agent (HF–pyridine) allowed
total bromide–fluoride exchange to give trifluorinated
Scheme 1 using Hofmeister3,4 and Jeon’s conditions,5
Keywords: Trifluoro amines; Bromo-difluoro amines; Bromo-trifluoro
amines; Bromopropargylic amines; Superacid.
*
Corresponding authors. E-mail: brigitte.renoux@univ-poitiers.fr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.123

5548
A.-C. Cantet et al. / Tetrahedron Letters 47 (2006) 5547–5551
O
O
N
O
N
Br
H
Br
H
H
(b)
(a)
(c)
NH
N
O
O
O
4
1
Br
R
R
(d)
NH
N
R'
R'
1,2,3,4-tetrahydro-isoquinoline
4-phenyl-piperidine
2
3
Scheme 1. Synthesis of 1-bromoalkynes 1–4. Reagents and conditions: (a) K2CO3, propargyl bromide, crown ether 18-C-6, benzene, (b) NBS,
AgNO3, acetone, (c) (i) H2N–NH2, MeOH; (ii) HCl/MeOH, (d) 1,3-dibromopropyne, NaH, THF.
Table 1. Reactivity of 1-bromopropargylic amine derivatives in HF–SbF5
Entry
Compound
HF–SbF5
Molar ratio
HF–pyridine
Temperature (°C)
Products (yield %)
Time (min)
1
2
3
4
5
1
1
2
3
4
15/1
7/1
7/1
7/1
7/1
10
10
5
15
2
ꢀ60
ꢀ40
ꢀ40
ꢀ40
ꢀ60
1a/1b (77)
1b (88)
12 h
2 h
2b (60)a
3b (96)a
4a (27)b + 4b (16)b
2 h
a Isolated after hydrogenolysis.
b Separated after acylation.9
Table 2. Ratio of fluoro compounds in HF–SbF5
dine treatment), a 1,2-dibromo-1,1-difluoro derivative
4a11 (entry 5, Table 1) was also formed. Halide exchange
was not observed in the case of 4a at ꢀ60 °C after 2 h.
Entry
Compound
Time (min)
CF2Br/CF3
1
2
3
4
Phthalimide 1
Isoquinoline 2
Piperidine 3
10
5
1
11/1
1/1
3/1
4/1
2.3. Reaction mechanism
Primary amine 4
2
Taking into account these data, the postulated mecha-
nism is outlined in Scheme 2. In HF–SbF5, amines are
N-protonated (in the case of 2 and 3, aromatic rings
are also protonated). Further protonation gives a vinylic
carbenium ion B, trapped by a complex fluoride ion
ðSbF6ꢀ; Sb2F11ꢀ; . . .Þ to afford a bromofluoro intermedi-
ate C. Starting from the latter, two mechanisms can be
considered. The first one (reaction pathway a) implies
a protonation of the bromofluoroalkene C to afford D
which is trapped by a fluoride ion to give ion E, precur-
sor of the bromodifluoro compound. At this stage, E
may also undergo protonation followed by elimination
of HBr to yield ion F which can react as previously de-
scribed to afford the trifluorinated compounds 1b–4b
(entries 2–5, Table 1). This exchange is observed in
HF–SbF5 alone but generally necessitates a more fluori-
nating reagent (HF–pyridine) to reach completion. An
analogous exchange has been previously observed in
electrophilic trifluoromethylation of substituted anilines,
indolines, oxindoles, and indoles in superacid.13,14
product 1b10 in good yield (entry 2, Table 1). Double
addition of HF followed by bromide–fluoride exchange
was also observed for amines 2 and 3, albeit at different
rates (Fig. 1).
Since bromodifluoro and trifluoro compounds turned
out to be inseparable by chromatography, 19F NMR
was used to determine their ratio at different reaction
times (Table 2). Starting from isoquinoline 2, a mixture
of CF2Br/CF3 derivatives was observed after 5 min at
ꢀ40 °C (entry 2, Table 2). Complete exchange to afford
2b required the use of HF–pyridine (entry 3, Table 1).
Addition of HF to piperidine 3 as well as halide
exchange was faster leading to 3b in high yield in
HF–SbF5 alone (entry 4, Table 1 and entry 3, Table
2). In both cases, partial aromatic ring bromination
(vide infra) was also observed and the reaction mixture
was treated with H2–Pd/C before separation.
The unexpected formation of the 2-bromoderivative 4a
(entry 5, Table 1) can be explained following pathway
b (Scheme 2). The bromofluoro alkene C can react with
electrophilic bromine to give cyclic bromonium ion G15
Particular behavior was observed for primary amine 4.
In addition to the expected CF2Br/CF3 derivatives
(entry 4, Table 2) or CF3 product (4b12 after HF–pyri-

A.-C. Cantet et al. / Tetrahedron Letters 47 (2006) 5547–5551
5549
O
O
O
N
N
N
CF3
CF2Br
O
O
O
1a
1b
1
Br
N
N
Br
CF3
2b
2
N
N
CF3
3b
3
Br
CF3
Br
Ac
H
CF3
Ac
CF2Br
Br
Ac
N
H
N
H
N
H
N
H
Br
4b
4
4a
4c
Figure 1. Starting materials and fluorinated amines.
H+
Br
Br
H+
F-
R1
N
H
R1
N
H
R1
N
H
Br
N
R1
Br
+
Br
+
+
+
N
R2
R2
R2
R2
R2
F
B
A
C
R1
R1
R1
R1
+ H+
F-
F
F-
+
Br
F
+
F
+
+
+
+
F
N
N
N
F
F
R2
R2
R2
F
H
F
-HBr
H
H
H
F
D
E
F
pathway a
H2O
H2O
H+
R1
N
Br
F
F
R1
N
R1
N
H
F
Br
+
R2
R2
R2
F
F
Br+
C
+
Br
R1 Br
R1 Br
pathway b
R1
+
exchange
F-
Br
+
Br
F
F
+
N
H
N
N
R2
R2
R2
R2
F
F
Br-F
H
H
H
F
F
G
H2O
H2O
R1 Br
N
R1 Br
N
F
Br
R2
F
F
F
F
Scheme 2. Proposed mechanism for the formation of fluorinated compounds.
which adds a fluoride ion to afford H, precursor of 4a
(Table 1, entry 5). Electrophilic bromine ‘Br+’ results
from the oxidation of HBr (generated in situ, pathway
a), a process which has been previously observed in
meta-bromination of phenols16 and gem-difluoration of
bromoamines in superacid.9

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A.-C. Cantet et al. / Tetrahedron Letters 47 (2006) 5547–5551
Table 3. Reactivity of 1–4 in HF–SbF5 with NBS (20 h)
Acknowledgments
Entries
Compound
Conditionsa
CHBrCF3/CF3
We thank CNRS (France) for financial support and the
1
2
3
4
Phthalimide 1
Piperidine 2
Isoquinoline 3
Amine 4
10 min/ꢀ50 °C
15 min/ꢀ40 °C
5 min/ꢀ40 °C
2 min/ꢀ50 °C
2/1
1/4
1/4
49/1
´
Region Poitou-Charentes for a grant (to A.C.C.).
a Followed by treatment with HF–pyridine.
References and notes
1. Dolbier, W. R., Jr. J. Fluorine Chem. 2005, 126, 157–163.
2. (a) Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2005,
44, 214–231; (b) Smart, B. E. J. Fluorine Chem. 2001, 109,
3–11.
3. Reaction of compounds 1–4 in HF–SbF5 with NBS
To confirm the mechanism for the formation of com-
pound 4a, derivatives 1–4 were treated with the electro-
philic bromide donor NBS in superacid medium. Under
these conditions, bromination of the aromatic substrate
is also expected and as a consequence an excess of NBS
(3 or 4 equiv) was used to perform this study.
3. Gesson, J. P.; Jacquesy, J. C.; Rambaud, D. Bull. Soc.
Chim. Fr. 1992, 129, 227–231.
4. Hofmeister, H.; Annen, C.; Laurent, H.; Wiechert, R.
Angew Chem. 1984, 9, 720–721.
5. Jeon, H. B.; Sayre, L. M. Biochem. Biophys. Res. Commun.
2003, 304, 788–794.
6. Casaschi, A.; Grigg, R.; Sano, J. M. Tetrahedron 2001, 57,
607–615.
In all cases, subsequent treatment with HF–pyridine was
carried out for 20 h to complete bromine–fluorine
exchange. 19F NMR was then used to determine the
ratio of 2-bromo-1,1,1-trifluoro and 1,1,1-trifluoro com-
pounds (Table 3). Almost selective bromination was
only observed for primary amine 4 (4c,17 27%), while tri-
fluoro compounds were still the major ones for amines 2
and 3 (entries 2, 3, Table 3).
7. 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 arrange-
ment in place.
8. Compound 1a: 1H NMR (300 MHz, CDCl3, TMS as
internal standard): d 7.91–7.84 (m, 2H, H-4, and H-7), 7.78–
7.72 (m, 2H, H-5, and H-6), 4.00 (t, J = 7.0 Hz, 2H, H-10),
2.83 (m, 2H, H-20). 13C NMR (75 MHz, CDCl3): d 167.7 (C-
1 and C-3), 134.2 (C-5 and C-6), 131.8 (C-3a and C-7a),
123.5 (C-4 and C-7), 120.2 (t, 1JCF = 305 Hz, C-30), 42.1 (t,
These results can be accounted for by considering the
equilibrium between N-protonated form C and diproto-
nated ion D. The reaction course may be governed by
the relative stability of these two entities, depending
on the amine substitution (Scheme 2).
3
2JCF = 22 Hz, C-20), 32.8 (t, JCF = 4.2 Hz, C-10). 19F
NMR (external standard C6F6 (dF = ꢀ162.90), CDCl3): d
ꢀ45.9 (t, J = 11.3 Hz). HRMS (C11H8NO2F279Br): Calcd
302.97065, Found 302.9701.
9. (a) Specific work-up was used in the case of volatile amine
4: compounds 4a and 4b were isolated after acylation was
carried out by treatment of the aqueous phase with acetic
anhydride (4 mL, 3 h; then additional 2 mL for 24 h) and
extraction as usual; (b) Moine, A.; Thibaudeau, S.;
Martin, A.; Jouannetaud, M. P.; Jacquesy, J. C. Tetra-
hedron Lett. 2002, 43, 4119–4122.
In case of amines 2 and 3, electron-donating effects of
alkyl substituents stabilize ion C. Easy protonation
occurs to give ion D, a precursor of trifluoroderivatives
(Scheme 2).
10. Compound 1b: 1H NMR (300 MHz, CDCl3, TMS as
internal standard): d 7.90–7.85 (m, 2H, H-4, and H-7),
7.78–7.74 (m, 2H, H-5, and H-6), 3.97 (t, J = 7.2 Hz, 2H,
H-10), 2.63–2.48 (m, 2H, H-20). 13C NMR (75 MHz,
CDCl3): d 167.7 (C-1 and C-3), 134.2 (C-5 and C-6), 131.8
In contrast, N-protonated form C in free amine appears
destabilized. In this case, protonation is disfavored and
irreversible addition of electrophilic bromide ‘Br+’
occurs leading to cyclic bromonium ion G, a precursor
of a-bromotrifluoro products (Scheme 2). For amide
series, an equilibrium between these two pathways is ob-
served in favor of predominant addition of electrophilic
bromide (entry 1, Table 3).
(C-3a and C-7a), 125.7 (q, 1JCF = 277 Hz, C-30), 123.5 (C-
2
4
and C-7), 32.3 (q, JCF = 29 Hz, C-20), 31.2 (q,
3JCF = 4.1 Hz, C-10). 19F NMR (external standard C6F6
(dF = ꢀ162.90), CDCl3): d ꢀ66.9 (t, J = 8.5 Hz). HRMS
(C11H8NO2F3): Calcd 243.05071, Found 243.0495.
11. Compound 4a: 1H NMR (300 MHz, CDCl3, TMS as
internal standard): d 6.32 (sl, 1H, H-1), 4.53–4.46 (m, 1H,
H-20), 4.18–4.10 (m, 1H, H-10), 3.44–3.34 (m, 1H, H-10),
1.98 (s, 3H, H-3). 13C NMR (75 MHz, CDCl3): d 171.0 (C-
2), 119.6 (t, 1JCF = 307 Hz, C-30), 54.5 (t, 2JCF = 23 Hz, C-
20), 42.9 (C-10), 23.3 (C-3). 19F NMR (external standard
C6F6 (dF = ꢀ162.90), CDCl3): d ꢀ47.0 (dd, J = 164 Hz,
J = 5.6 Hz), ꢀ52.4 (dd, J = 164 Hz, J = 11 Hz). HRMS
(C3H3F279Br81Br: [MꢀÅNHCOCH3]+): Calcd 236.85491,
Found 236.8558.
4. Conclusion
In HF–SbF5, the reaction of 1-bromopropargylic
amines affords trifluorinated amine derivatives in good
yields. 1-Bromodifluoroamines or 2-bromo-1,1,1-triflu-
oro products could also be isolated depending on the
reaction conditions and amine substitution. Further
modification of these compounds may be of interest
for the synthesis of fluorinated bioactive compounds.
Nucleophilic18,19 and radical induced20 substitution of
bromine have been described in the literature on bro-
mo-difluoro or trifluoro derivatives. Such applications21
as well as studies of other haloalkynes are underway in
our laboratory.
12. Compound 4b: 1H NMR (300 MHz, CDCl3, TMS as
internal standard): d 5.81 (sl, 1H, H-1), 3.43 (m, 2H, H-10),
2.36–2.10 (m, 2H, H-20), 1.92 (s, 3H, H-3). 13C NMR
(75 MHz, CDCl3): d 170.7 (C-2), 126.8 (q, 1JCF = 277 Hz,
C-30), 34.0 (q, 2JCF = 28 Hz, C-20), 33,4 (q, 3JCF = 4.4 Hz,
C-10), 23.5 (C-3). 19F NMR (external standard C6F6

A.-C. Cantet et al. / Tetrahedron Letters 47 (2006) 5547–5551
5551
(dF = ꢀ162.90), CDCl3): d ꢀ66.3 (t, J = 9.9 Hz). HRMS
(C5H8NOF3): Calcd 155.05580, Found 155.0563.
13. Debarge, S.; Violeau, B.; Bendaoud, N.; Jouannetaud, M.
P.; Jacquesy, J. C. Tetrahedron Lett. 2003, 44, 1747–1750.
14. Debarge, S.; Kassou, K.; Carreyre, H.; Violeau, B.;
Jouannetaud, M. P.; Jacquesy, J. C. Tetrahedron Lett.
2004, 45, 21–23.
C-20), 41.1 (C-10), 23.5 (C-3). 19F NMR (external standard
C6F6 (dF = ꢀ162.90), CDCl3): d ꢀ72.0 (d, J = 8.5 Hz).
HRMS (C5H7NOF379Br): Calcd 232.96631, Found
232.9680.
18. (a) Wang, Y.; Zhu, S. Synthesis 2002, 13, 1813–1818; (b)
Marcotte, S.; Gerard, B.; Pannecoucke, X.; Feasson, C.;
Quirion, J. C. Synthesis 2001, 6, 929–933.
15. Olah, G. A.; Bollinger, J. M. J. Am. Chem. Soc. 1967, 89,
4744–4752.
19. (a) Magueur, G.; Crousse, B.; Charneau, S.; Grellier, P.;
´
Begue, J. P.; Bonnet-Delpon, D. J. Med. Chem. 2004, 10,
16. Jacquesy, J. C.; Jouannetaud, M. P.; Makani, S. J. Chem.
Soc. Chem. Comm. 1980, 110, 747–750.
2694–2699; (b) Richard, J. P. J. Am. Chem. Soc. 1989,
111(17), 6735–6744.
20. Suzuki, A.; Mae, M.; Amii, H.; Nneyama, K. J. Org.
Chem. 2004, 69, 5132–5139.
21. As an example, substitution of 1a using allyltributyltin
and a catalytic amount of AIBN affords the corresponding
allyldifluoro compound in good yield (93%).
17. Compound 4c: 1H NMR (300 MHz, CDCl3, TMS as
internal standard): d 6.29 (sl, 1H, H-1), 4.50–4.35 (m, 1H,
H-20), 4.05–3.97 (m, 1H, H-10), 3.60–3.47 (m, 1H, H-10),
1.98 (s, 3H, H-3). 13C NMR (75 MHz, CDCl3): d 171.0 (C-
1
2
2), 123.7 (q, JCF = 278 Hz, C-30), 45.7 (q, JCF = 31 Hz,