A new approach to the synthesis of (Z)-2-fluoro-2-alkenals via Wittig-type carbonyl condensation reactions of 2-(fluoromethyl)-4,4,6-trimethyl-1,3-oxazine phosphonium bromide

Article abstract of DOI:10.1016/j.tetlet.2013.01.017

We report here the transformation of aldehydes to their (Z)-α-fluoro-α,β-unsaturated aldehyde homologs by condensation with the phosphonium salt of the Meyer's oxazine obtained from bromofluoroacetonitrile. After methylation with trimethyloxonium tetrafluoroborate the quaternized oxazine is cleanly reduced to mostly Z 2-fluoro-2-alkenals by sodium borohydride at room temperature. This methodology is compatible with usual protecting groups and affords an efficient access to functionalized mostly Z 2-fluoro-2-alkenals derived from natural products and their corresponding (Z)-2-fluoro-2-alkenols.

Full text of DOI:10.1016/j.tetlet.2013.01.017

Tetrahedron Letters 54 (2013) 1658–1660
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A new approach to the synthesis of (Z)-2-fluoro-2-alkenals via Wittig-type
carbonyl condensation reactions of
2-(fluoromethyl)-4,4,6-trimethyl-1,3-oxazine phosphonium bromide
Mohammed Kajjout a, Michaël Smietana b, Jacques Leroy b, Christian Rolando a,
⇑
a Université de Lille 1, Sciences et Technologies, USR CNRS 3290, Miniaturisation pour la synthèse, l’Analyse & la Protéomique, 59655 Villeneuve d’Ascq Cedex, France
b Ecole Normale Supérieure, UMR CNRS 8640, « PASTEUR », 24 rue Lhomond, 75231 Paris, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We report here the transformation of aldehydes to their (Z)-a-fluoro-a,b-unsaturated aldehyde homologs
Received 4 August 2012
Revised 20 December 2012
Accepted 8 January 2013
Available online 16 January 2013
by condensation with the phosphonium salt of the Meyer’s oxazine obtained from bromofluoroaceto-
nitrile. After methylation with trimethyloxonium tetrafluoroborate the quaternized oxazine is cleanly
reduced to mostly Z 2-fluoro-2-alkenals by sodium borohydride at room temperature. This methodology
is compatible with usual protecting groups and affords an efficient access to functionalized mostly Z
2-fluoro-2-alkenals derived from natural products and their corresponding (Z)-2-fluoro-2-alkenols.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
2-Fluoro-2-alkenals
Oxazine
Phosphonium salt
During the course of our studies devoted to the lignification
process in plants, we were led to synthesize fluorinated analogs
of some of the cinnamic glucoside monomers involved in lignin
biosynthesis, such as b-fluoroconiferin. This compound was pre-
pared via a Horner–Wadsworth–Emmons olefination reaction from
tetra-O-acetylglucoside of vanillin and diethyl (fluorocarboeth-
oxymethyl)phosphonate under phase transfer conditions, affording
of Grignard reagents. They also have been transformed into a con-
jugated chain by reaction with a Wittig–Horner reagent during the
synthesis of retinoid X receptor agonists or RXR selective modula-
tors.4
a-Fluoro-a,b-unsaturated aldehydes are obtained by oxida-
tion of the corresponding alcohol, using the Des-Martin reagent
or tetrapropylammonium perruthenate/N-methylmorpholine-N-
oxide (TPAP/NMO) system. Only few syntheses lead directly to
the aldehyde, and they use even harsher conditions, which are
not compatible with functionalized molecules.5 Indeed, aldehydes
are easily reduced in mild conditions at room temperature by so-
dium borohydride to the corresponding alcohol.6 We recently pre-
sented a strategy for the synthesis of (Z)-b-fluoroallyl alcohols
based on the palladium-catalyzed formylation by carbon monoxide
a E/Z mixture of isomeric
a-fluoro-a,b-unsaturated esters which
was isomerized into a pure (Z)-
a
-fluoro-a,b-unsaturated ester.
The five ester groups were reduced by in situ generated lithium
borohydride (NaBH4, LiCl, glyme, 80 °C) to (Z)-b-fluoroconiferin
whose isolation from glyme proved to be delicate.1 So we looked
for a more convenient route to such b-fluorocinnamyl alcohols
which would proceed via the reduction of the corresponding alde-
hydes with NaBH4. As a result, we are particularly interested in
applying the same strategy we developed for the synthesis of the
natural compound coniferin, which is based on the mild reduction
of the corresponding aldehyde by NaBH4.2
of
a-bromo-a-fluoroolefins obtained by a Wittig–Burton reaction,
to obtain
a
-fluoro conjugated aldehydes which were then reduced
to the corresponding alcohols.6a We present here an alternate ap-
proach to 2-fluoro-2-alkenals based on the condensation of the an-
ion of 2-(fluoromethyl)-4,4,6-trimethyl-1,3-oxazine phosphonium
bromide 5 with the corresponding aldehydes.
2-Fluoropropenal derivatives have attracted much attention
and 2-fluoropropenals are key intermediates for the synthesis of
Oxazines are commonly prepared by the Ritter reaction of
a nitrile with a diol in sulfuric acid and this method was used
to prepare 2-(fluoromethyl)-4,4,6-trimethyl-1,3-oxazine from
fluoroacetonitrile and 2-methyl-1,3-pentanediol.7 Although
bromofluoroacetonitrile 3 has been mentioned in the literature,
neither preparation nor characterization data for this compound
are available to the best of our knowledge.8 We prepared it by
dehydration over phosphorus pentoxide of bromofluoroacetamide
biologically active compounds and complex structures.3 (Z)-
a-flu-
orocinnamic aldehydes have been used as precursors to obtain chi-
ral 2-fluoro-3-phenylpropionic acid or have been transformed into
an imine, which leads to chiral fluorinated allyl amines by addition
⇑
Corresponding author. Tel.: +33 320434977; fax: +33 320336136.
E-mail address: Christian.rolando@univ-lille1.fr (C. Rolando).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.017

M. Kajjout et al. / Tetrahedron Letters 54 (2013) 1658–1660
1659
O
N
O
Br
Br
Br
i
ii
O
R
O
iii
i, ii
NH2
O
+
3
P(C6H5)3
1
2
F
F
F
N
N
H
Br-
F
F
H
O
Scheme 1. Synthesis of bromofluoroacetonitrile 3. Reagents: (i) aqueous ammonia,
0 °C; (ii) phosphorus pentoxide (1.25 equiv).
6a-e
O
R
iv, v
+
H
R
N
H
N
F
-
BF4
Me
F
mostly Z
O
Br
i
ii
8a-e
7a-e
H
3
N
F
Scheme 3. Synthesis of 8a–e. Reagents and conditions: (i) n-BuLi, THF, ꢀ78 °C,
F
Br
30 min; (ii) RCHO, ꢀ78 °C to rt, 3 h, dil HCl; (iii) Me3OþBFꢀ, CH2Cl2, 2 h; (iv) NaBH4,
4
4 (ca. 1:1 mixture)
pH = 7.0, ꢀ35 to ꢀ40 °C; (v) (CO2H)2, H2O, reflux, 2 h.
O
H
+
P(C6H5)3
N
Table 1
Br-
F
Synthesis of aldehydes 8a–e via the oxazines 6a–e
5
Entry Carbonyl compound
Alkene 6
Yieldb,c
Alkenal 8
Yieldb,d
Scheme 2. Synthesis of 5. Reagents and conditions: (i) 2-methyl-1,3-pentanediol,
H2SO4, 0–5 °C; (ii) (C6H5)3P (1 equiv) 80 °C, overnight.
Z/E
Z/E
ratioa
(%)
ratioa
(%)
a
b
c
C6H5CHO
60:40
60:40
65:35
55:45
50
63
70
30
100:0
86:14
94:6
56
40
64
32
p-NO2C6H4CHO
p-CH3OC6H4CHO
o-CH3Op-
2 (76% yield) while the amide was obtained from ethyl bromofluo-
roacetate 1 and aqueous ammonia following the synthesis de-
scribed by Young and Tarrant9 for chlorofluoroacetonitrile (63%
yield) (Scheme 1).10
d
94:6
(OGlu)C6H4CHOe
n-C11H23CHO
e
84:16
77
100:0
51
a
b
c
Once the nitrile was synthesized, 2-(bromofluoromethyl)-4,4,6-
trimethyl-1,3-oxazine 4 was obtained using the Meyers proce-
Ratios determined on the crudes by 19F NMR.
Isolated, preparative TLC.
Yields from 5.
Yields from 6.
OGlu = 2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl.
dure11 as
a ca. 1:1 inseparable mixture of diastereomers
d
e
(Scheme 2).12 The bromofluoro oxazines, though moderately sta-
ble, were not distilled but were used as such (50% yield unoptim-
ized). Treatment of the mixture with
1
equivalent of
triphenylphosphine without a solvent at 80 °C, afforded a ca.
54:46 mixture of the diastereomeric phosphonium salts 5 which
were identified by mass spectrometry and NMR (82% yield).
Wittig condensation of the anions of the diastereoisomeric mix-
ture 5 generated with n-butyllithium in THF at ꢀ78 °C, with some
representative carbonyl compounds, was checked. While the
unsaturated ketone 6-methyl-5-hepten-2-one was found to be
unreactive in these conditions, aldehydes reacted easily. For exam-
ple, with benzaldehyde, a 60:40 mixture of Z and E alkenes 6a was
obtained in a 50% overall yield (preparative thin layer chromatog-
raphy). Comparable results were obtained with some other aro-
matic aldehydes such as vanillin tetra-O-acetylglucoside or
aliphatic aldehydes (Table 1).
isomerization presumably took place during the reduction of oxa-
zines 6 mixtures.
In conclusion, we have shown that
a-fluoro-a,b-unsaturated
aldehydes may be advantageously obtained using the oxazine
derived from bromofluoroacetonitrile. These aldehydes can be
smoothly reduced to the corresponding alcohols by sodium boro-
hydride. This methodology is applied to access highly functional-
ized aldehydes as 8d used as precursor for (Z)-b-fluoroconiferin,
a strong inhibitor of lignin polymerization, for example.6a Other
applications of the reactivity of this new reagent are currently
under investigation. The obtained 2-fluoroalkenals may also be
reduced with a deuterated chiral reagent to afford prochiral
2-fluroalkenols for biosynthetic studies.14
Attempted direct reduction of the oxazine moiety with sodium
borohydride at controlled pH (7.0) and low temperature (ca.
ꢀ40 °C) failed.10 On the other hand, catalytic reduction with hydro-
gen over Pd/BaSO4 led to the selective reduction of the C–C double
bond. Fortunately, the reduction of the carbon–nitrogen double
bond of such conjugated systems could be more easily achieved
after prior quaternization of the nitrogen atom.13 While methyl io-
dide was found to be unreactive, trimethyloxonium tetrafluorobo-
rate led to the N-methyl quaternary salt 7 (19F NMR monitoring)
which was subsequently reduced with sodium borohydride then
hydrolyzed without further purification with aqueous oxalic acid
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
01.017. These data include MOL files and InChiKeys of the most
important compounds described in this article.
References and notes
1. Daubresse, N.; Chupeau, Y.; Francesch, C.; Lapierre, C.; Pollet, B.; Rolando, C.
Chem. Commun. 1997, 1489–1490.
to give a-fluoro-a,b-unsaturated aldehydes 8 (Scheme 3). Starting
2. Daubresse, N.; Francesch, C.; Mhamdi, F.; Rolando, C. Synthesis 1998, 157–161.
3. (a) Lamy, C.; Hofmann, J.; Parrot-Lopez, H.; Goekjian, P. Tetrahedron Lett. 2007,
48, 6177–6180; (b) Tsuchikawa, H.; Matsushita, N.; Matsumori, N.; Murata, M.;
Oishi, T. Tetrahedron Lett. 2006, 47, 6187–6191; (c) Fishkin, N.; Yefidoff, R.;
Gollipalli, D. R.; Rando, R. R. Bioorg. Med. Chem. Lett. 2005, 13, 5189–5194; (d)
Michellys, P.-Y.; Boehm, M. F.; Chen, J.-H.; Grese, T. A.; Karanewsky, D. S.;
Leibowitz, M. D.; Liu, S.; Mais, D. A.; Mapes, C. M.; Reifel-Miller, A.; Ogilvie, K.
M.; Rungta, D.; Thompson, A. W.; Tyhonas, J. S.; Yumibe, N.; Ardecky, R. J.
Bioorg. Med. Chem. Lett. 2003, 13, 4071–4075.
from benzaldehyde (entry a) and dodecanal (entry e) only Z alke-
nals were obtained whereas for the other substituted aromatic
aldehydes examined (entries b–d), mixtures of Z and E alkenes
were formed in which the Z isomer is more abundant (Table 1).
During the reduction of (E,Z)-a-fluorocinnamic thioester mixtures
by NaBH4 at room temperature we obtained previously pure (Z)-
b-fluoroallyl alcohols with double bond isomerization.6i A similar

1660
M. Kajjout et al. / Tetrahedron Letters 54 (2013) 1658–1660
4. (a) Vora, H. U.; Rovis, T. J. Am. Chem. Soc. 2010, 132, 2860–2861; (b) Pierry, C.;
Zoute, L.; Jubault, P.; Pfund, E.; Lequeux, T.; Cahard, D.; Couve-Bonnaire, S.;
Pannecoucke, X. Tetrahedron Lett. 2009, 50, 264–266; (c) Noguchi, T.; Tanaka,
N.; Nishimata, T.; Goto, R.; Hayakawa, M.; Sugidachi, A.; Ogawa, T.; Niitsu, Y.;
Asai, F.; Ishizuka, T.; Fujimoto, K. Chem. Pharm. Bull. 2009, 57, 22–33; (d) Hibi,
S.; Kikuchi, K.; Yoshimura, H.; Nagai, M.; Tai, K.; Hida, T. J. Med. Chem. 1998, 41,
3245–3252.
7. Patrick, T. B.; Hosseini, S.; Bains, S. Tetrahedron Lett. 1990, 31, 179–182.
8. Pews, R. G.; Lysenko, Z. J. Org. Chem. 1985, 50, 5115–5119.
9. Young, J. A.; Tarrant, P. J. Am. Chem. Soc. 1949, 71, 2432–2433.
10. Selected data for bromofluoroacetonitrile 3: bp 90 °C; mmax (CCl4)/cmꢀ1 3002,
2252; 1H NMR (250 MHz, CDCl3, dH) 6.70 (d, J = 48.8 Hz); 19F NMR (235 MHz,
CDCl3, dF) ꢀ148.1 (d, J = 48.8 Hz); 13C NMR (62 MHz, CDCl3, dc) 66.7 (d,
J = 255.5 Hz), 112.3 (d, J = 32.8 Hz).
5. (a) Funabiki, K.; Murata, E.; Fukushima, Y.; Matsui, M.; Shibata, K. Tetrahedron
1999, 55, 4637–4642; (b) Hatanaka, F.; Tsuchiya, M.; Yoshimatsu, M. Synlett
2005, 2191–2194; (c) Sauvetre, R.; Masure, D.; Chuit, C.; Normant, J. F. Synthesis
1978, 128–130.
11. Meyers, A. I.; Nabeya, A.; Adickes, H. W.; Politzer, I. R.; Malone, G. R.; Kovelesky,
A. C.; Nolen, R. L.; Portnoy, R. C. J. Org. Chem. 1973, 38, 36–56.
12. Selected data for oxazine
4
(ca. 1:1 mixture of diastereomers) 1H NMR
(400 MHz, CDCl3, dH) 1.23 (d, 3H, J = 6.2 Hz), 1.42 (br s, 3H), 1.45 (dd, ½H, J
ꢁ10.0, 1.6 Hz), 1.46(6) (s, 1.5H), s 1.46(9) (s, 1.5H), 1.49 (dd, ½H, J = 10.2,
1.5 Hz), 1.75 (dd, ½H, J = 9.8, 9.2 Hz), 1.79 (dd, ½H, J = 9.9, 9.1 Hz), 4.17 (m, 1H),
6.41 (d, ½H, J = 51.0 Hz), 6.42 (d, ½H, J = 51.0 Hz); 19F NMR (235 MHz, CDCl3,
dF) ꢀ145.1 (dd, J = 51.5, 2.1 Hz), ꢀ145.9 (dd, J = 51.2, 2.2 Hz); 13C NMR (62 MHz,
CDCl3, dc) 24.2, 24.5, 25.49, 25.53, 27.6, 28.0, 49.63, 49.73, 54.1 (unresolved),
65.40, 65.45, 85.3 (d, J = 269.6 Hz), 85.4 (d, J = 270.1 Hz), 163.91 (d, J = 19.1 Hz),
163.99 (d, J = 19.5 Hz).
6. (a) Zemmouri, R.; Kajjout, M.; Castanet, Y.; Eddarir, S.; Rolando, C. J. Org. Chem.
2011, 76, 7691–7698; (b) Bowman, W. R.; Bridge, C. F.; Brookes, P.; Cloonan, M.
O.; Leach, D. C. J. Chem. Soc., Perkin Trans. 1 2002, 58–68; (c) Denmark, S. E.;
Harmata, M. A.; White, K. S. J. Am. Chem. Soc. 1989, 111, 8878–8891; (d)
Hackett, A. G.; Kotyk, J. J.; Fujiwara, H.; Logusch, E. W. J. Am. Chem. Soc. 1990,
112, 3669–3671; (e) Jaeger, B.; Lay, H.; Lehmann, J.; Ziser, L. Carbohydr. Res.
1991, 217, 99–106; (f) Okutani, M.; Mori, Y. J. Org. Chem. 2009, 74, 442–444; (g)
Yang, J.; Rallapalli, S. K.; Cook, J. M. Tetrahedron Lett. 2010, 51, 815–817; (h) Yin,
W.; Kabir, M. S.; Wang, Z.; Rallapalli, S. K.; Ma, J.; Cook, J. M. J. Org. Chem. 2010,
75, 3339–3349; (i) Kajjout, M.; Zemmouri, R.; Eddarir, S.; Rolando, C.
Tetrahedron 2012, 68, 3225–3230.
13. Malone, G. R.; Meyers, A. I. J. Org. Chem. 1974, 39, 623–628.
14. Midland, M. M.; Greer, S.; Tramontano, A.; Zderic, S. A. J. Am. Chem. Soc. 1979,
101, 2352–2355.