A practical and straightforward access to fluorinated homoallylic alcohols in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2013.03.082

Herein, a practical and straightforward access to fluorinated homoallylic alcohols is reported. The corresponding products were obtained in good to excellent yield in brine or THF as a solvent using indium(0) and the readily available 3-chloro-2-fluoroprop-1-ene to promote the allylation reaction. This methodology affords an easy access to valuable fluorinated products under mild conditions.

Full text of DOI:10.1016/j.tetlet.2013.03.082

Tetrahedron Letters 54 (2013) 2821–2824
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A practical and straightforward access to fluorinated homoallylic alcohols
in aqueous media
⇑
⇑
Gérald Lemonnier, Thomas Poisson , Samuel Couve-Bonnaire, Xavier Pannecoucke
Normandie Univ., COBRA, UMR 6014 et FR 3038, Univ. Rouen, INSA Rouen, CNRS, 1 rue Tesnière, 76821 Mont Saint-Aignan Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein, a practical and straightforward access to fluorinated homoallylic alcohols is reported. The corre-
sponding products were obtained in good to excellent yield in brine or THF as a solvent using indium(0)
and the readily available 3-chloro-2-fluoroprop-1-ene to promote the allylation reaction. This methodol-
ogy affords an easy access to valuable fluorinated products under mild conditions.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 22 February 2013
Revised 15 March 2013
Accepted 18 March 2013
Available online 26 March 2013
Keywords:
Fluorine
Fluoroolefins
Water
Molecules containing fluorine atoms are of great interest due to
the remarkable properties of this intriguing atom.1 The ability of
the fluorine atom to modify the physical and chemical properties
of a molecule pushes it at the forefront of the agrochemical and
drug discovery.1 As a result, molecules containing fluorine are
found in around 20% of pharmaceuticals and more than 40% of
agrochemicals, contrasting with the lack of fluorinated molecules
in nature.2 Therefore, since the discovery of the pioneering Balz–
Schiemann reaction3 the organic chemist community developed
several approaches to introduce fluorine in an efficient and practi-
cal way.4 Recently, lots of efforts were devoted to develop and de-
sign new and efficient access to fluorinated molecules.5 These
methodologies basically focused on two strategies: (1) the forma-
tion of the C–F bond4 and (2) the functionalization of the readily
available fluorinated building blocks.5,6 Among all these fluori-
nated molecules, fluoroolefins7 are pretty interesting and appeal-
ing by their use in material science8 or as a template toward the
design of peptidomimetics (Fig. 1).9
dehydrogenative C–C forming bond12a or an Hosomi–Sakurai reac-
tion with fluorinated allylsilane12b have been reported to date.
Thus, we report herein a simple, mild, and straightforward access
to these new compounds using 3-chloro-2-fluoroprop-1-ene and
indium13 in aqueous media (Fig. 2).
Initially, the first set of reactions was performed in water at
room temperature using 1.2 equiv of indium and 1.1 equiv of 3-
chloro-2-fluoroprop-1-ene. Pleasingly, the desired product 2a
was obtained in good yield, 72% (entry 1, Table 1). Then 2 equiv
of In(0) was used, furnishing a slight improvement of the conver-
sion into 2a (entry 2). The use of 1.5 equiv of indium along with
1.5 equiv of 3-chloro-2-fluoroprop-1-ene gave
a significant
enhancement of the conversion, the desired alcohol was obtained
in 90% yield (entry 3), while the use of 2 equiv of indium and
On the other hand, homoallylic alcohols are considered as a key
building block in organic synthesis allowing a huge range of post-
functionalization.10 Thus, taking into account these points and as
part of our current research program dealing with the develop-
ment of valuable fluorinated building blocks,11 we were interested
in the synthesis of secondary and tertiary fluorinated homoallylic
alcohols. Surprisingly, only two reports dealing with an access to
secondary fluorinated alcohols using either an iridium-catalyzed
Figure 1. Examples of relevant fluorinated olefins.
⇑
Corresponding authors. Tel.: +33 2 35 52 24 11; fax: +33 2 35 52 29 59 (T.P.);
tel.: +33 2 35 52 24 20; fax: +33 2 35 52 29 59 (X.P.).
E-mail addresses: thomas.poisson@insa-rouen.fr (T. Poisson), xavier.panne-
coucke@insa-rouen.fr (X. Pannecoucke).
Figure 2. Present work.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.082

2822
G. Lemonnier et al. / Tetrahedron Letters 54 (2013) 2821–2824
Table 1
bearing an electron-withdrawing group were investigated. Pleas-
Optimization of the reaction conditions
ingly, an ester moiety was well tolerated under our reaction condi-
tions giving the corresponding homoallylic alcohols 2b in 88%
yield, while benzaldehyde afforded the allylated adduct 2c in 66%
yield (entries 1–3). Electron-rich aromatic aldehyde such as para-
anisaldehyde 1d was used giving the fluorinated alcohol 2d in
99% yield (entry 4). Unprotected phenol 1e was also suitable for
this process affording the desired product 2e in 73% yield (entry
Entry
Solvent
x equiv
y equiv
Yielda (%)
5), as well as
a-substituted-a,b-unsaturated aldehyde 1f which
1
2
3
4
5
6
H2O
H2O
H2O
H2O
H2O
Brine
1.2
2
1.5
2
2
2
1.1
1.1
1.5
1.5
2
72
76
90
89
gave the allylic alcohol 2f in very good yield (entry 6). Interest-
ingly, valuable heteroaromatic backbones such as thiophene 1g
and pyridine 1h were also compatible for the allylation reaction
(entries 7 and 8). Then, we turned our attention to the aliphatic
aldehydes. Hydrocinnamaldehyde 1i gave the corresponding fluo-
rinated allylic alcohol 2i in quantitative yield (entry 9), while non-
anal 1j and citronellal 1k gave lower yield, 60% and 57%,
respectively, probably due to their higher volatility (entries 10
and 11). Aldehyde 1l was used, affording the corresponding fluori-
nated alcohol 2l in excellent yield (entry 12). With both citronellal
1k and aldehyde 1l as substrates, no significant diastereoselectivi-
ties were observed (entries 11 and 12). This methodology was suc-
cessfully applied to both racemic trans- and cis-fluoro-
cyclopropane bearing an aldehyde moiety.11c The trans isomer
1m furnishes the corresponding difluorinated cyclopropane deriv-
ative 2m in 63% and good 80:20 diastereoisomeric ratio (entry 13),
while the cis isomer 1n gave the allylated alcohol 2n as a single
diastereoisomer in 83% yield (entry 14).16 Finally, ketones were
98 (91)b
100 (99)b
2
a
Determined by 19F NMR and 1H NMR of the crude product using an internal
standard.
b
Isolated yield.
1.5 equiv of the fluorinated starting material did not afford any
improvement (entry 4). Finally the use of 2 equiv of In(0) with
2 equiv of fluorinated chloro-allyl species gave the product in
91% isolated yield (entry 5), and the replacement of water by
brine14 gave a complete conversion of the aldehyde and the desired
product in quantitative isolated yield (entry 6).
Having these optimized conditions in hands,15 we next move on
to the scope of the reaction (Table 2). First, aromatic aldehydes
Table 2
Scope of the reactiona
Entry
1
Starting material
Product
Yieldb (%)
1a
2a
2b
99
88
2
1b
3
4d
5
1c
1d
1e
2c
2d
2e
66
99
73
6c
7
1f
2f
87
83
1g
2g
8c
1h
2h
77

G. Lemonnier et al. / Tetrahedron Letters 54 (2013) 2821–2824
2823
Table 2 (continued)
Entry
Starting material
Product
Yieldb (%)
9d
1i
2i
99
10e
11e
12e
1j
2j
60
1k
1l
2k
2l
57 (53:47)g
97 (50:50)g
13d
14d
1m
1n
2m
2n
63 (80:20)g
83 (100:0)g
15d
1o
1p
2o
2p
13
99
16f
17f
1q
1r
2q
2r
57
73
18f
a
Conditions: 1 (1 equiv), 3-chlorofluoropropene (2 equiv), In(0) (2 equiv), brine (1.5 mL), rt, 16 h.
Isolated yield.
72 h reaction time.
Reaction performed at 40 °C for 72 h.
Reaction performed at 60 °C for 24 h.
b
c
d
e
f
Reaction was performed at 60 °C in THF for 24 h.
g
Diastereoisomeric ratio determined by 19F NMR on the crude reaction mixture.
investigated as substrates in the course of this fluoro-allylation
process. Unfortunately, under standard conditions ketone 1o re-
acted poorly and gave the desired product 2o with only 13% yield
(entry 15). A survey of temperature and solvents revealed that an
increase of temperature from room temperature to 60 °C and the
use of THF as a solvent afford quantitatively the desired product
2p from the highly activated ketone 1p (entry 16). These reaction
conditions were applied to the less activated acetophenone 1o,
unfortunately without any improvement. Then, trifluoroketone
1q was engaged under these experimental conditions furnishing
the corresponding product 2q in good yield (entry 17). Finally,
the unactivated cyclohexanone 1r was successfully used as a start-
ing material and the corresponding allylated products 2r were iso-
lated in 73% (entry 18).
Acknowledgments
This work has been partially supported by INSA Rouen, Rouen
University, CNRS, EFRD and Labex SynOrg (ANR-11-LABX-0029).
G.L. thanks the EFRD for a postdoctoral fellowship (EFRD 32819).
Gaëlle Milanole is acknowledged for generous gift of aldehydes
1m and 1n.
References and notes
1. (a) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308–319; (b) Bégué, J.-P.; Bonnet-
Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine; John Wiley & Sons,
Inc.: Hoboken, NJ, 2008; (c) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-
VCH: Weinheim, 2004; (d) Mikami, K.; Itoh, Y.; Yamanaka, M. Chem. Rev. 2004,
104, 1–16.
2. (a) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881–1886; (b) Purser,
S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320–330.
3. Balz, G.; Schiemann, G. Ber. 1927, 60B, 1186–1190.
4. For review on fluorine introduction see: (a) Furuya, T.; Kuttruff, C. A.; Ritter, T.
Curr. Opin. Drug Discov. Dev. 2008, 11, 803–819; (b) Furuya, T.; Kamlet, A. S.;
Ritter, T. Nature 2011, 473, 470–477; (c) Hollingworth, C.; Gouverneur, V. Chem.
Commun. 2012, 48, 2929–2942; Selected examples: (d) McMurtrey, K. B.;
Racowski, J. M.; Sanford, M. S. Org. Lett. 2012, 14, 4094–4097; (e) Rauniyar, V.;
Lackner, A. D.; Hamilton, G. L.; Toste, F. D. Science 2011, 334, 1681–1684.
5. For recent reviews see: (a) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011,
111, 4475–4520; (b) Leclerc, E.; Pannecoucke, X.; Ethève-Quelquejeu, M.;
Sollogoub, M. Chem. Soc. Rev. 2013. http://dx.doi.org/10.1039/c2cs35403a; (c)
Zhu, R.; Buchwald, S. L. J. Am. Chem. Soc. 2012, 134, 12462–12465; (d) Fuchibe,
K.; Takahashi, M.; Ichikawa, J. Angew. Chem., Int. Ed. 2012, 51, 12059–12062.
6. (a) Special Issue on Fluorinated Synthons, J. Fluorine Chem. 2004, 125, 477–645.;
(b) Fluorine-Containing Synthons; Soloshonok, V. A., Ed.; American Chemical
In summary, we report herein the first access to fluorinated
homoallylic alcohols using a mild and ecofriendly process. This
process using indium(0), the readily available 3-chloro-2-fluoro-
prop-1-ene and brine as a reaction solvent was successfully ap-
plied to
a broad range of highly functionalized aldehydes.
Activated ketones were also successfully converted into the de-
sired tertiary allylic alcohols using THF as a solvent. This approach
offers a straightforward access to this new class of compounds.
Further studies toward the reactivity and the functionalization of
these promising products are currently underway in our
laboratory.

2824
G. Lemonnier et al. / Tetrahedron Letters 54 (2013) 2821–2824
Society: Washington, DC, 2005; (c) Current Fluoroorganic Chemistry: New
4131; (f) David, E.; Milanole, G.; Ivashkin, P.; Couve-Bonnaire, S.; Jubault, P.;
Pannecoucke, X. Chem. Eur. J. 2012, 18, 14904–14917.
12. (a) Hassan, A.; Montgomery, T. P.; Krische, M. J. Chem. Commun. 2012, 48,
4692–4694; (b) Hayashi, T.; Usuki, Y.; Iio, H. J. Fluorine Chem. 2010, 131, 709–
713.
13. For reviews dealing with the use of indium(0) in allylation reaction see: (a)
Bowyer, W. J.; Singaram, B.; Sessler, A. M. Tetrahedron 2011, 67, 7449–7460; (b)
Augé, J.; Lubin-Germain, N.; Uziel, J. Synthesis 2007, 1739–1764; (c) Shen, Z.-L.;
Wang, S.-Y.; Chok, Y.-K.; Xu, Y.-H.; Loh, T.-P. Chem. Rev. 2013, 113, 271–401.
14. For the beneficial effect of brine or saturated aqueous solution in indium
promoted allylation reaction see: Sun, X.-W.; Liu, M.; Xu, M.-H.; Lin, G.-Q. Org.
Lett. 2008, 10, 1259–1262.
Synthetic Directions, Technologies, Materials, and Biological Applications;
Soloshonok, V. A., Mikami, K., Yamazaki, T., Welch, J. T., Hoenk, J. F., Eds.;
American Chemical Society: Washington, DC, 2007.
7. (a) Landelle, G.; Bergeron, M.; Turcotte-Savard, M.-O.; Paquin, J.-F. Chem. Soc.
Rev. 2011, 40, 2867–2908; (b) Yanai, H.; Taguchi, T. Eur. J. Org. Chem. 2011,
5939–5954; (c) Hara, S. Top. Curr. Chem. 2012, 327, 59–86.
8. (a) Babudri, F.; Farinola, G. M.; Naso, F.; Ragni, R. Chem. Commun. 2007, 1003–
1022; (b) Babudri, F.; Cardone, A.; Farinola, G. M.; Martinelli, C.; Mendichi, R.;
Naso, F.; Striccoli, M. Eur. J. Org. Chem. 2008, 1977–1982.
9. Selected examples: (a) Dutheuil, G.; Couve-Bonnaire, S.; Pannecoucke, X.
Angew. Chem., Int. Ed. 2007, 46, 1290–1292; (b) Van der Veken, P.; Senten, K.;
Kertèsz, I.; De Meester, I.; Lambeir, A.-M.; Maes, M.-B.; Scharpé, S.; Haemers, A.;
Augustyns, K. J. Med. Chem. 2005, 48, 1768–1780; (c) Zhao, K.; Lim, D. S.;
Funaki, T.; Welch, J. T. Bioorg. Med. Chem. 2003, 11, 207–215; For reviews see:
(d) Couve-Bonnaire, S.; Cahard, D.; Pannecoucke, X. Org. Biomol. Chem. 2007, 5,
1151–1157; (e) Taguchi, T.; Yanai, H. In Fluorine in Medicinal Chemistry and
Chemical Biology; Ojima, I., Ed.; Blackwell Publishing Inc., Chichester, 2009; p
257.
10. Selected examples: (a) Makita, N.; Hoshino, Y.; Yamamoto, H. Angew. Chem., Int.
Ed. 2003, 42, 941–9434; (b) Blanc, A.; Toste, F. D. Angew. Chem., Int. Ed. 2006, 45,
2096–2099; (c) Malkov, A. V.; Barlóg, M.; Miller-Potuckà; Kabeshov, L. M. A.;
Farrugia, L. J.; Kocovsky, P. Chem. Eur. J. 2012, 18, 6873–6884.
15. Representative procedure: In
(14 mg, 0.1 mmol), and brine (1 mL) were added. Then, 3-chloro-2-fluoroprop-
1-ene (18 L, 0.2 mmol) was added and the vial was sealed (screwed cap). The
a 1.5 mL vial, indium (23 mg, 0.2 mmol), 1a
l
resulting mixture was stirred at rt for 16 h, then DCM was added and the
aqueous phase was extracted 2 times. Organic layer was dried over MgSO4 and
the residue was purified by flash chromatography (petroleum ether/ethyl
acetate mixture) to afford the corresponding fluorinated alcohol 2a (20 mg,
99% yield). Physical data: Colorless oil. 1H NMR (300 MHz, CDCl3, 25 °C):
3
3
3
d = 7.23 (d, JH,H = 8.7 Hz, 2H), 7.19 (d, JH,H = 8.7 Hz, 2H), 4.82 (dd, JH,H = 5.8,
3
3
3
7.4 Hz, 1H), 4.55 (dd, JH,H = 2.8, JH,F = 17.3, 1H), 4.23 (dd, JH,H = 2.8,
3JH,F = 50.0, 1H), 2.58–2.38 (m, 2H), 2.34 (br s, 1H). 13C NMR (75 MHz, CDCl3,
25 °C): d = 162.8 (d, 1JC,F = 257 Hz), 141.5, 133.5, 128.6 (2C), 127.0 (2C), 93.0 (d,
11. (a) Poisson, T.; Belhomme, M.-C.; Pannecoucke, X. J. Org. Chem. 2012, 77, 9277–
9285; (b) Ivashkin, P.; Couve-Bonnaire, S.; Jubault, P.; Pannecoucke, X. Org. Lett.
2012, 14, 5130–5133; (c) Milanole, G.; Couve-Bonnaire, S.; Bonfanti, J.-F.;
Jubault, P.; Pannecoucke, X. J. Org. Chem. 2013, 78, 212–223; (d) Lemonnier, G.;
Zoute, L.; Quirion, J.-C.; Jubault, P. Org. Lett. 2010, 12, 844–846; (e) Lemonnier,
G.; Zoute, L.; Dupas, G.; Quirion, J.-C.; Jubault, P. J. Org. Chem. 2009, 74, 4124–
2JC,F = 19 Hz), 70.2, 42.3 (d, JC,F = 26 Hz) ppm. 19F NMR (282 MHz, CDCl3,
2
3
25 °C): d = ꢀ95.9 (dddd, JF,H = 15, 17, 22, 50 Hz) ppm. IR (neat):
mmax ¼ 3385; 1675; 1493; 1013; 818 cmꢀ1
.
Elementary Anal. Calcd for
~
C10H10ClFO (200.64): C, 59.86; H, 5.02. Found: C, 59.90; H, 4.67.
16. So far, we have not been able to determine the stereochemistry of the product.