Bromination/desilicobromination of silylated monofluoroalkenes using tetrabutylammonium tribromide under microwave conditions

Article abstract of DOI:10.1016/j.jfluchem.2012.10.008

New conditions for the bromination/desilicobromination of silylated monofluoroalkenes using tetrabutylammonium tribromide under microwave conditions are presented. The reaction is fast (20 min) and provide, after the desilicobromination step, the bromoflu

Full text of DOI:10.1016/j.jfluchem.2012.10.008

Journal of Fluorine Chemistry 145 (2013) 77–80
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Bromination/desilicobromination of silylated monofluoroalkenes using
tetrabutylammonium tribromide under microwave conditions
*
Bianca Malo-Forest, Jessye-Ann Roy, Jean-Franc¸ois Paquin
Canada Research Chair in Organic and Medicinal Chemistry, De´partement de chimie, Universite´ Laval, Que´bec, QC G1V 0A6, Canada
A R T I C L E I N F O
A B S T R A C T
Article history:
New conditions for the bromination/desilicobromination of silylated monofluoroalkenes using
tetrabutylammonium tribromide under microwave conditions are presented. The reaction is fast
(20 min) and provide, after the desilicobromination step, the bromofluoroalkene where the replacement
of the silyl group is done with retention of configuration with little or no stereochemical erosion.
Isomeric enrichment is even observed in one case. Optimization of the reactions conditions and
applications to various substrates are reported.
Received 22 June 2012
Received in revised form 15 October 2012
Accepted 16 October 2012
Available online 23 October 2012
Keywords:
ß 2012 Elsevier B.V. All rights reserved.
Bromination
Desilicobromination
Monofluoroalkene
Bromofluoroalkene
Tetrabutylammonium tribromide
Microwave conditions
1. Introduction
configuration with little or no stereochemical erosion. Isomeric
enrichment is even observed in one case.
We recently reported a 5-step sequence for the stereoselective
synthesis of tetrasubstituted monofluoroalkenes (4) starting from
commercially available 2,2,2-trifluoro-1-iodoethane (Fig. 1) [1,2].
One of the key steps of the sequence was the bromination/
desilicobromination reaction (2 ! 3) where the silyl group was
replaced by a bromine atom with retention of configuration and a
simultaneous isomeric enrichment [1].
Recognizing the importance of the monofluoroalkene motif [3]
in medicinal chemistry [4,5], we decided to apply this sequence for
the synthesis of fluorinated analogues of bioactive compounds. In
that sense, we needed access to compound 6a that was going to be
used as a versatile and key intermediate for our syntheses.
Bromination/desilicobromination of 5a to produce 6a had been
performed previously with success (Fig. 2) [1].
Unfortunately, problems at the bromination step were some-
time encountered while repeating this transformation forcing us to
investigate novel and more reliable conditions. Herein, we report
the use of tetrabutylammonium tribromide (n-Bu4NBr3) under
microwave conditions for the bromination of silylated mono-
fluoroalkenes. The reaction is fast (20 min) and provide, after the
desilicobromination step, the bromofluoroalkene where the
replacement of the silyl group is done with retention of
2. Results and discussion
Bromination/desilicobromination of silylated monofluoroalk-
ene 5a under the original conditions [1,6] gave full conversion with
the major product being the desired bromofluoroalkene 6a (55%
isolated yield) along with an unidentified side-product (ca. 31%
estimated by 19F NMR of the crude product) (Table 1, entry 1). In
addition, no isomeric enrichment was observed. The results varied
slightly using different bottles of bromine but in all cases, the side-
product was present in significant amounts and the Z/E ratio of the
bromofluoroalkene was moderate. Slight variations of the original
conditions were also explored. For instance, adding a base (K2CO3)
in the bromination step led to a cleaner reaction (i.e. side-product
free) although the isolated yield was low and the Z/E was nearly
identical to the starting silylated alkene (entry 2). Alternatively,
using tetrabutylammonium fluoride (TBAF) as the base in the
desilicobromination step [7] led to complete decomposition (entry
3). Based on those results, we decided to screen for other reaction
conditions that would not rely on using bromine. Directly
replacing Br2 by n-Bu4NBr3, a reagent reported as an alternative
to Br2 for various bromination reactions [8], led to no reaction
(entry 4). Performing the bromination under microwave heating
under solvent-free condition gave a low conversion with an
excellent selectivity (entry 5). Since no side-product was
detected and the Z/E ratio for the bromofluoroalkene was excellent
* Corresponding author. Tel.: +1 418 656 2131x11430; fax: +1 418 656 7916.
E-mail address: jean-francois.paquin@chm.ulaval.ca (J.-F. Paquin).
0022-1139/$ – see front matter ß 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2012.10.008

78
B. Malo-Forest et al. / Journal of Fluorine Chemistry 145 (2013) 77–80
Table 1
Initial screening.
Entry
1
Conditions
Results
(i) Br2, CH2Cl2, ꢀ78 8C to rt
(ii) CH3ONa, CH3OH, 0 8C to rt
(i) Br2, K2CO3, CH2Cl2, ꢀ78 8C to rt
(ii) CH3ONa, CH3OH, 0 8C to rt
(i) Br2, CH2Cl2, ꢀ78 8C to rt
(ii) TBAF, THF, 0 8C to rt
(i) n-Bu4NBr3, CH2Cl2, 50 8C
(ii) CH3ONa, CH3OH, 0 8C to rt
(i) n-Bu4NBr3, MW, 100 8C, 2 min
(ii) CH3ONa, CH3OH, 0 8C to rt
55% yielda (Z/E = 63/37)b
Fig. 1. Synthetic approach to tetrasubstituted monofluoroalkenes.
2
3
4
5
46% yield (Z/E = 71/29)b
Decompositionc,d
No reactionc
2% conv.c (Z/E > 97/3)c
a
The crude product was contaminated by ca. 31%, as estimated by 19F NMR, of an
Fig. 2. Bromination/desilicobromination of silylated monofluoroalkene 5a.
unidentified side-product.
b
Determined by 19F NMR analysis of the isolated product after purification by
flash chromatography.
c
Determined by 19F and/or 1H NMR analysis of the crude mixture.
Absence of 19F NMR signals in the crude mixture.
d
(Z/E > 97/3), further optimization was undertaken and selected
results are shown in Table 2.
Under solvent-free conditions, heating for 10 min the reaction
mixture in the microwave either at 80 or 125 8C provided low
conversion (<5%). Running the reaction at 150 8C completely shuts
down the reaction. We hypothesized that adding a solvent would
help the reaction to proceed however still no reaction was
observed using CH3CN at 160 8C. Fortunately, running the reaction
at 100 8C in water provided a promising 48% conversion with only
one isomer present in the crude mixture as detected by 19F NMR
analysis. A slight improvement was obtained when using CH3OH, a
preferred solvent according to Pfizer solvent selection guide [9]
(entry 6) and further optimization were performed using that
solvent. Initially, the effect of reaction time was then evaluated and
the best conversions were observed when the reaction was
allowed to run for 15 min (compared to 10 and 25 min). Increasing
the amount of n-Bu4NBr3 from 1 to 1.4 equivalents led to full
conversion (entry 9). It is worth noting that in all cases, 19F NMR
analysis of the crude product showed a Z/E > 97/3 for 6a indicating
an isomeric enrichment similarly to what had been observed with
the original conditions [1]. Finally, some fine-tuning of the reaction
conditions was performed (results not shown) and led to the use of
1.5 equiv. of n-Bu4NBr3 with heating at 80 8C for 20 min. These
conditions provided cleaner crude products with fewer impurities
and were used for the examination of other substrates (Table 3).
Performing the bromination/desilicobromination using the opti-
mized conditions on 5a, the bromofluoroalkene 6a was isolated in
60% yield with a Z/E > 97/3 (entry 1). Using silylated monofluor-
oalkene 5b bearing a 2-(tert-butyldimethylsilyloxy)ethoxy side-
chain gave the alcohol 6b in 84% yield with a slight stereochemical
erosion (entry 2). The deprotection of the silylated alcohol under
those conditions indicates a limitation in term of functional group
tolerance. Finally, silylated monofluoroalkene bearing different 2-
(dialkylamino)ethoxy side-chain were submitted to the bromina-
tion/desilicobromination reaction. The desired bromofluoroalkenes
were isolated in low to moderate yield with little or no
stereochemical erosion (entries 3–5). In all these cases, complete
separation by flash chromatography of the desired products from n-
Bu4NBr3 related residues (various tetrabutylammonium salts as
Table 2
Optimization of the bromination/desilicobromination using n-Bu4NBr3.
Entry
Solvent
Temp. (8C)
Time (min)
n-Bu4NBr3 equiv.
Conv. (%)a
1
2
3
4
5
6
7
8
9
–
80
125
150
160
100
80
10
10
10
10
10
10
15
25
15
1
3
5
–
1
–
1
0
CH3CN
H2O
1
0
1
48
51
70
63
100
CH3OH
CH3OH
CH3OH
CH3OH
1
80
1
80
1
80
1.4
a
Determined by 19F and/or 1H NMR analysis of the crude mixture.

B. Malo-Forest et al. / Journal of Fluorine Chemistry 145 (2013) 77–80
79
Table 3
Selected bromination/desilicobromination of silylated monofluoroalkenes using n-Bu4NBr3.
Entry
1
Substrate
Product
Yield (%)a
60
Z/Eb
6a
>97/3
85/15
>97/3
2
84
3
35
4
25
>97/3
5
39
88/12
a
Isolated yield.
b
Determined by 19F and/or 1H NMR analysis of the crude mixture.
detected by 1H NMR) proved to be somewhat challenging due to
similarpolaritiesand partly explainsthe low isolated yields since the
crude 19F NMR showed mostly the desired product.
300 MHz in CDCl3 at ambient temperature using tetramethylsi-
lane (1H NMR) or residual CHCl3 (1H and 13C NMR) as the internal
standard, or CFCl3 (
19F NMR) as the external standard. Infrared
In conclusion, we have reported the use of tetrabutylammo-
nium tribromide under microwave conditions for the bromina-
tion of silylated monofluoroalkenes. The reaction is fast, reliable
and provides, after the elimination of the silyl group under basic
condition, the bromofluoroalkene where the replacement of the
silyl group is done with retention of configuration with little or
no stereochemical erosion. Isomeric enrichment is even
observed in one case. The bromofluoroalkenes generated will
be used for the synthesis of fluorinated bioactive compounds
and these results will be reported in due course.
spectra were recorded on a Bomem FT-IR MB-Series or a Thermo
Scientific Nicolet 380 FT-IR spectrometer. High-resolution mass
spectra were obtained on a LC/MS-TOF Agilent 6210 using
electrospray ionization (ESI). Reactions performed under micro-
wave heating were conducted in a Biotage1 Initiator using a
sealed vessel.
3.1. General procedure for the bromination/desilicobromination
reaction
To a stirred solution of the silylated compounds (1 mmol) in
MeOH (9 mL) was added n-Bu4NBr3 (1.5 mmol). The mixture was
heated for 20 min at 80 8C under microwave irradiation. After
cooling the reaction mixture back to rt, it was treated with 1.5 M
solution of CH3ONa in CH3OH (4 mmol) at 0 8C, stirred for 30 min at
this temperature and allowed to warm to rt over 1 h. Water was
3. Experimental
All reactions were carried out under an argon atmosphere with
dry solvents under anhydrous conditions. 1H, 13C and 19F spectra
were recorded on a VARIAN Inova 400 MHz or a BRUKER Avance

80
B. Malo-Forest et al. / Journal of Fluorine Chemistry 145 (2013) 77–80
added and the layers were separated. The aqueous layer was
extracted with EtOAc (3ꢁ). The combined organic extracts were
washed with brine, dried over anhydrous MgSO4 and concentrated.
The crude material was purified by flash chromatography to give
the desired product.
2.80 (t, 2H, J = 6.0 Hz) 2.53 (m, 4H), 1.63 (m, 4H), 1.46 (m, 2H); 13
NMR (100 MHz, CDCl3) 159.4, 154.7 (d, JC–F = 249 Hz), 131.8 (d,
C
d
JC–F = 3 Hz), 131.0, 129.3, 129.1, 129.0, 128.3, 128.1 (d, JC–F = 5 Hz),
159.4, 115.0, 114.3, 66.1, 58.0, 55.2, 26.0, 24.3; 19F NMR (376 MHz,
CDCl3)
d
ꢀ84.6 (s, 1F); HRMS-ESI calcd for C21H23BrFNO [M+H]+
407.1033, found 407.1033.
3.1.1. (Z)-1-(1-bromo-2-fluoro-2-phenylvinyl)-4-methoxybenzene
(6a)
Acknowledgments
Following the general procedure on a 0.375 mmol scale of 5a,
the desired product (69 mg, 60%, Z/E > 95/5) was isolated as a
yellow oil by flash chromatography using 1% Et2O/petroleum
ether. The spectroscopic data were in agreement with the
literature [1].
This work was supported by the Canada Research Chair
Program, the Natural Sciences and Engineering Research Council
of Canada, the Canada Foundation for Innovation, the Fonds de
recherche sur la nature et les technologies (FQRNT), FQRNT Centre
in Green Chemistry and Catalysis, FQRNT Research Network on
Protein Function, Structure and Engineering (PROTEO) and the
3.1.2. (Z)-2-(4-(1-bromo-2-fluoro-2-phenylvinyl)phenoxy)ethanol
(6b)
Following the general procedure on a 0.135 mmol scale of 5b,
the desired product (38 mg, 84%, Z/E = 85/15) was isolated as white
crystals by flash chromatography using 15% EtOAc/hexanes. IR
´
Universite Laval.
References
(neat)
913, 694 cmꢀ1; 1H NMR (300 MHz, CDCl3)
7.22 (m, 3H), 6.79 (m, 4H), 4.03 (m, 4H), 3.94 (m, 4H), 2.12 (s, 1H);
13C NMR (75 MHz, CDCl3)
159.0, 154.8 (d, JC–F = 250 Hz), 131.9 (d,
JC–F = 3 Hz), 129.5, 128.4, 128.1 (d, JC–F = 5 Hz), 114.8, 114.2, 113.3,
n
= 3375, 2933, 2875, 1604, 1507, 1488, 1289, 1247, 1066,
[1] G. Landelle, P.A. Champagne, X. Barbeau, J.-F. Paquin, Organic Letters 11 (2009)
d
7.34 (d, 2H, J = 8.8 Hz),
681–684.
[2] For other synthetic approaches to monofluoroalkenes developed in our laboratory,
see:
d
(a) G. Landelle, M.-O. Turcotte-Savard, J. Marterer, P.A. Champagne, J.-F. Paquin,
Organic Letters 11 (2009) 5406–5409;
104.2 (d, JC–F = 30 Hz), 69.4, 61.5; 19F NMR (282 MHz, CDCl3)
d
´
´
(b) X. Pigeon, M. Bergeron, F. Barabe, P. Dube, H.N. Frost, J.-F. Paquin, Angewandte
ꢀ85.3 (s, 1F); HRMS-ESI calcd for C16H15BrFO2 [M+H]+ 337.0236,
Chemie International Edition 49 (2010) 1123–1127;
(c) J.-F. Paquin, Synlett (2011) 289–293;
(d) G. Landelle, M.-O. Turcotte-Savard, L. Angers, J.-F. Paquin, Organic Letters 13
(2011) 1568–1571;
found 337.0234.
(e) M. Bergeron, T. Johnson, J.-F. Paquin, Angewandte Chemie International Edition
50 (2011) 11112–11116.
[3] G. Landelle, M. Bergeron, M.-O. Turcotte-Savard, J.-F. Paquin, Chemical Society
Reviews 40 (2011) 2867–2908.
3.1.3. (Z)-2-(4-(1-bromo-2-fluoro-2-phenylvinyl)phenoxy)-N,N-
dimethylethanamine (6c)
Following the general procedure on a 0.22 mmol scale of 5c, the
desired product (20.1 mg, 25%, Z/E > 95/5) was isolated as a yellow
oil by flash chromatography using 2% MeOH/CH2Cl2. IR (neat)
[4] For selected examples, see:
(a) M.C. Pirrung, H.J. Ha, C.P. Holmes, Journal of Organic Chemistry 54 (1989)
1543–1548;
(b) M.C. Pirrung, C.P. Holmes, D.M. Horowitz, D.S. Nunn, Journal of the American
Chemical Society 113 (1991) 1020–1025;
(c) M.C. Pirrung, J. Chen, E.G. Rowley, A.T. McPhail, Journal of the American
Chemical Society 115 (1993) 7103–7110;
(d) X. Li, S.M. Singh, V. Luu-The, J. Coˆte´, S. Laplante, F. Labrie, Bioorganic &
Medicinal Chemistry 4 (1996) 55–60;
n
= 2943, 2820, 2771, 1603, 1508, 1248, 1174, 1032, 695 cmꢀ1; 1H
7.26 (m, 5H), 7.20 (d, 2H, J = 4.2 Hz), 6.83
(d, 2H, J = 8.7 Hz), 4.05 (t, 2H, J = 5.6 Hz), 2.73 (t, 2H, J = 5.7 Hz), 2.33
(s, 6H); 13C NMR (75 MHz, CDCl3)
167.8, 158.6 (d, JC–F = 245 Hz),
NMR (400 MHz, CDCl3)
d
d
131.6 (d, JC–F = 3 Hz), 130.8, 129.9, 129.8, 129.4, 127.9 (d, JC–
F = 5 Hz), 114.8, 114.0, 65.1, 57.7, 50.3, 45.2, 29.7, 21.9; 19F NMR
(e) J.P. Burkhart, P.M. Weintraub, C.A. Gates, R.J. Resvick, R.J. Vaz, D. Friedrich, M.R.
Angelastro, P. Bey, N.P. Peet, Bioorganic & Medicinal Chemistry 10 (2002) 929–934;
(f) P.M. Weintraub, A.K. Holland, C.A. Gates, W.R. Moore, R.J. Resvick, P. Bey, N.P.
Peet, Bioorganic & Medicinal Chemistry 11 (2003) 427–431.
[5] For, selected examples, see:
(376 MHz, CDCl3)
d
ꢀ85.7 (s, 1F); HRMS-ESI calcd for C18H20BrFNO
[M+H]+ 364.0707, found 364.0713.
(a) R.J. Abraham, S.L.R. Ellison, P. Schonholzer, W.A. Thomas, Tetrahedron 42
(1986) 2101–2110;
3.1.4. (Z)-1-(2-(4-(1-bromo-2-fluoro-2-
(b) T. Allmendiger, P. Furet, E. Hungerbu¨ hler, Tetrahedron Letters 31 (1990) 7297–
7300;
(c) J.T. Welch, J. Lin, Tetrahedron 52 (1996) 291–304;
(d) P. Wipf, T.C. Henninger, S.J.J. Geib, Journal of Organic Chemistry 63 (1998)
6088–6089;
phenylvinyl)phenoxy)ethyl)pyrrolidine (6d)
Following the general procedure on a 0.16 mmol scale of 5d, the
desired product (13.5 mg, 35%, Z/E > 95/5) was isolated as a
yellow-orange oil by flash chromatography using 2% MeOH/
(e) C. Dugave, L. Demange, Chemical Reviews 103 (2003) 2475–2532;
(f) A. Niida, K. Tomita, M. Mizumoto, H. Tanigaki, T. Terada, S. Oishi, A. Otaka, K.-i.
Inui, N. Fujii, Organic Letters 8 (2006) 613–616;
(g) G. Dutheuil, S. Couve-Bonnaire, X. Pannecoucke, Angewandte Chemie Interna-
tional Edition 46 (2007) 1290–1292;
CH2Cl2. IR (neat)
693 cmꢀ1 1H NMR (300 MHz, CDCl3)
J = 8.6 Hz), 4.11 (t, 2H, J = 5.8 Hz), 2.92 (t, 2H, J = 5.7 Hz), 2.65 (m,
4H), 1.82 (m, 4H); 13C NMR (100 MHz, CDCl3)
174.6, 158.9, 154.8
(d, JC-F = 250 Hz), 131.9 (d, JC–F = 3 Hz), 129.5, 128.3, 128.1 (d, JC–
F = 5 Hz), 114.9, 114.4, 54.8, 34.4, 32.2, 25.2, 23.6, 22.9, 14.4; 19F
n
= 2924, 2851, 1603, 1508, 1249, 1227, 1174,
;
d
7.21 (m, 7H), 6.83 (d, 2H,
d
(h) S. Couve-Bonnaire, D. Cahard, X. Pannecoucke, Organic & Biomolecular Chem-
istry 5 (2007) 1151–1157;
(i) T. Taguchi, H. Yanai, in: I. Ojima (Ed.), Fluorine in Medicinal Chemistry and
Chemical Biology, Blackwell Publishing Inc., 2009, pp. 257–290.
[6] R.P. Fisher, H.P. On, J.T. Snow, G. Zweifel, Synthesis (1982) 127–129.
[7] R.B. Miller, G. McGarbey, Journal of Organic Chemistry 43 (1978) 4424–4431.
NMR (282 MHz, CDCl3)
C
d
ꢀ85.6 (s, 1F); HRMS-ESI calcd for
20H22BrFNO [M+H]+ 390.0863, found 390.0877.
´
´
[8] (a) M. Fournier, F. Fournier, J. Berthelot, Bulletin de la Societe Chimique de
Belgique 93 (1984) 157–158;
3.1.5. (Z)-1-(2-(4-(1-bromo-2-fluoro-2-
(b) J. Berthelot, M. Fournier, Canadian Journal of Chemistry 64 (1986) 603–607;
(c) J. Berthelot, C. Guette, M. Essayegh, P.L. Desbene, Journal of Synthetic Com-
munications 16 (1986) 1641–1645;
(d) J. Berthelot, Y. Benammar, B. Desmazieres, Canadian Journal of Chemistry 73
(1995) 1526–1530.
phenylvinyl)phenoxy)ethyl)piperidine (6e)
Following the general procedure on a 0.97 mmol scale of 5e, the
desired product (118 mg, 39%, Z/E = 88/12) was isolated as a brown
oil by flash chromatography using 2% MeOH/CH2Cl2. IR (neat)
[9] K. Alfonsi, J. Colberg, P.J. Dunn, T. Fevig, S. Jennings, T.A. Johnson, H.P. Kleine, C.
Knight, M.A. Nagy, D.A. Perry, M. Stefaniak, Journal of Fluorine Chemistry 10 (2008)
31–36.
n
= 2933, 1603, 1508, 1247, 1174, 693 cmꢀ1
;
1H NMR (400 MHz,
7.20 (m, 7H), 6.81 (d, 2H, J = 8.7 Hz, 4.11 (t, 2H, J = 5.9 Hz),
CDCl3)
d