Julia-Kocienski approach to trifluoromethyl-substituted alkenes

Article abstract of DOI:10.1016/j.tetlet.2013.08.069

A Julia-Kocienski approach to trifluoromethyl-substituted alkenes was evaluated in the reactions of 1,3-benzothiazol-2-yl, 1-phenyl-1H-tetrazol-5-yl, and 1-tbutyl-1H-tetrazol-5-yl 2,2,2-trifluoroethyl sulfones with aldehydes. Among the various conditions tested, the best yields were obtained with 1-phenyl-1H-tetrazol-5-yl 2,2,2-trifluoroethyl sulfone, in CsF-mediated, room temperature olefinations in DMSO. Aromatic aldehydes gave (trifluoromethyl)vinyl derivatives in 23-86% yields, with generally moderate stereoselectivity. Straightforward synthesis of the Julia-Kocienski reagent, and conversion to trifluoromethyl-substituted alkenes under mild reaction conditions, are the advantages of this approach.

Full text of DOI:10.1016/j.tetlet.2013.08.069

Accepted Manuscript
Julia-Kocienski Approach to Trifluoromethyl-Substituted Alkenes
Deborah O. Ayeni, Samir K. Mandal, Barbara Zajc
PII:
S0040-4039(13)01455-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.08.069
TETL 43432
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
26 July 2013
15 August 2013
19 August 2013
Please cite this article as: Ayeni, D.O., Mandal, S.K., Zajc, B., Julia-Kocienski Approach to Trifluoromethyl-
Substituted Alkenes, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.08.069
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Julia-Kocienski Approach to Trifluoromethyl-Substituted Alkenes1
Deborah O. Ayeni,2 Samir K. Mandal, and Barbara Zajc*
Department of Chemistry, The City College and The City University of New York, 160 Convent
Avenue, New York, NY 10031-9198
barbaraz@sci.ccny.cuny.edu
* Corresponding author
ABSTRACT
A Julia-Kocienski approach to trifluoromethyl-substituted alkenes was evaluated in the reactions
of 1,3-benzothiazol-2-yl, 1-phenyl-1H-tetrazol-5-yl, and 1-tbutyl-1H-tetrazol-5-yl 2,2,2-
trifluoroethyl sulfones with aldehydes. Among the various conditions tested, the best yields
were obtained with 1-phenyl-1H-tetrazol-5-yl 2,2,2-trifluoroethyl sulfone, in CsF-mediated,
room temperature olefinations in DMSO. Aromatic aldehydes gave (trifluoromethyl)vinyl
derivatives in 23-86% yields, with generally moderate stereoselectivity. Straightforward
synthesis of the Julia-Kocienski reagent, and conversion to trifluoromethyl-substituted alkenes
under mild reaction conditions, are the advantages of this approach.

Selective fluorination of organic molecules is highly important for pharmaceuticals and
agrochemicals, due to the remarkable influence fluorine can have on bioactivity.3 In these
contexts, trifluoromethyl-substituted alkenes are of synthetic value as intermediates, or as
biologically active end products (e.g. bifenthrin, an insecticidal pyrethroid). However, synthetic
approaches to (trifluoromethyl)vinyl derivatives are relatively under-explored. Among the
various methods, metal-mediated approaches to vinyl trifluoromethylation include: (a) Pd-
catalyzed reactions of vinyl sulfonates with TMS- or TES-CF3,4 (b) Cu-catalyzed reactions of
vinyl bromides with TMS-CF3,5 (c) Fe- and Cu-catalyzed reactions of vinyltrifluoroborates and
vinylboronic acids with Togni’s reagent,6,7 (d) Cu-catalyzed reaction of vinyl boronic acid with
Umemoto’s reagent,8 (e) Cu-catalyzed decarboxylative trifluoromethylation with Togni’s
reagent,9 (f) Cu- and Fe-catalyzed decarboxylative trifluoromethylation with Langlois
reagent,10,11 (g) Heck-like reaction on in situ formed 3,3,3-trifluoropropene,12 (h) Hiyama
reaction of aryl iodides with (E)-trimethyl-(3,3,3-trifluoroprop-1-enyl)silane,13 (i) redox-
chemical methods involving Ir14 and Ru15,16 catalysts. Wittig- and Horner-type reactions have
also been evaluated as approaches to vinyl trifluoromethylated compounds. For example, the
17
TBAF-mediated condensation of aldehydes with Ph2P(O)CH2CF3 as well as synthesis of
Ph3P+CH2CH3•OTf– and its reaction with aldehydes promoted by CsF,18 have been reported in
the literature.
Interestingly, the Julia-Kocienski approach19 to trifluoromethyl-substituted alkenes has not
been reported to date, although its potential for the preparation of various types of fluoroalkenes
has been demonstrated.20 Herein, we report our results on the synthesis of (trifluoromethyl)vinyl
compounds via such an approach.
In order to evaluate the use of Julia-Kocienski olefination reactions, synthesis of a series of
heteroaryl sulfones, i.e. 1-phenyl-1H-tetrazol-5-yl 2,2,2-trifluoroethyl sulfone (PT-sulfone), 1,3-
benzothiazol-2-yl 2,2,2-trifluoroethyl sulfone (BT-sulfone), and 1-tert-butyl-1H-tetrazol-5-yl
2,2,2-trifluoroethyl sulfone TBT sulfone, was undertaken (Table 1).
Table 1
Synthesis of 2,2,2-trifluoroethyl heteroaryl sulfones

Entry
Yield of 1a Oxidation Conditions
Yield of 2b
2a: 83%
2b: 90%
2c: 69%
1
2
3
1a: 90%
1b: 87%
1c: quant
cat CrO3, H5IO6, CH3CN, rt
m-CPBA, CHCl3, rt
cat. Mo4O24(NH4)6•4H2O, H2O2, EtOH, rt
a Yield of the crude product. The crude sulfide was used in the oxidation.
b Yield is of isolated and purified products.
Next, condensation conditions were screened in reactions of heteroaryl sulfones 2a–c, with 2-
naphthaldehyde (Table 2). Reaction of PT-sulfone 2a in the presence of DBU gave a low 7%
yield of 3 (entry 1). Under basic conditions, elimination of fluoride from heteroaryl sulfones 2a–
c is possible (vide infra Scheme 1 and discussion) leading to difluoro olefin 4, which represents a
dead end intermediate. Therefore, addition of a source of F– was considered in order to reverse
this elimination. This has previously been demonstrated in Wittig- and Horner-type syntheses of
(trifluoromethyl)vinyl compounds, mediated by TBAF or by CsF.17,18 Indeed, TBAF-mediated
condensation of 2a in acetonitrile at room temperature increased the yield to 34%, but a lower
selectivity was observed (entry 2). Changing the solvent to THF increased the yield and
selectivity (entry 3). BT-sulfone 2b gave a comparatively lower yield in the TBAF-mediated
reaction in THF at room temperature, and a marginally better selectivity (entry 4). Lowering of
the reaction temperature to 0 ˚C marginally increased the yield and selectivity (compare entries 4
and 5).
Reaction of 2b mediated by TASF (tris(dimethylamino)sulfonium
difluorotrimethylsilicate) in CH2Cl2 gave both a lower yield and selectivity (entry 6). Next, CsF
was tested (entries 7-9) in the reactions of sulfones 2a–c. Condensations were performed in
DMSO at room temperature, and among the three sulfones 2a gave the highest yield (entry 7).
Olefination with BT-sulfone 2b gave a lower yield and selectivity (entry 8), whereas reaction
with TBT-sulfone 2c proceeded with best selectivity, but in a much lower yield (entry 9). The

yield and selectivity in the TBAF-mediated reaction of 2a in DMSO were similar to those
obtained in CsF-mediated reaction (compare entries 7 and 10).
Table 2
Screening of Olefination Conditions of Heteroaryl Sulfones with 2-Naphthaldehyde
O
O
CHO
Conditions
S
CF3
Het
CF3
2a–2c
3
Entry
Sulfone
2a
Conditions
Yield of 3 (%)a % E/Zb
1
2
3
4
5
6
DBU, CH2Cl2, rt
7
28:72
37:63
31:69
27:73
20:80
35:65
TBAF,c CH3CN, rt
TBAF,c THF, rt
TBAF, THF, rt
34
47
27
29
23
2a
2a
2b
TBAF, THF, 0 ˚C
TASF, CH2Cl2, rt
2b
2b
7
CsF, DMSO, rt
CsF, DMSO, rt
CsF, DMSO, rt
TBAF, DMSO, rt
86
58
40
85
41:59
44:56
30:70
40:60
2a
2b
2c
2a
8
9
10
a Yield is of isolated and purified products.
b Determined by 19F NMR.
c Dried for 4 h under vacuum.
There was one other problem in these fluoride-mediated condensations. In the presence of
adventitious water, 2-vinylnaphthalene (7) was formed, plausibly via the Julia intermediate 6.
As shown in Scheme 1, initial conjugate addition of water to vinyl sulfone 4, produced by loss of
fluoride, can result in difluorohydrin 5. Multiple pathways are available for the formation of
intermediate 6 from compound 5. In one pathway, expulsion of HF can result in an acyl fluoride
that can undergo hydrolysis, followed by decarboxylation. Alternatively, difluorohydrin 5 could

fragment by loss of carbonyl fluoride (COF2), and reaction of the latter with H2O leads to CO2
and HF. Formation of both acyl fluoride and carbonyl fluoride upon reaction of nucleophiles
with difluorovinyl compounds has been reported.21,22 Condensation of 6, generated by such
pathways, with 2-naphthaldehyde would then produce 2-vinylnaphthalene (7). This problem was
more pronounced under TBAF-mediated reactions, than when CsF was employed as the base.
This is not surprising due to the lower hygroscopic nature of CsF as compared to TBAF. We
therefore decided to pursue olefinations using CsF in DMSO.
Scheme 1
Two problems to contend with in the olefination reaction
F
F
O O
S
–F–
O O
S
O O
S
H2O
OH
F
Base
CF2
CF2
2a
Het
Het
Het
+F–
4
5
F–, H2O
Hc
O O
+
CHO
S
CO2 + 2 HF
Hb
JHa-Hb = 11.0 Hz
JHa-Hc = 17.7 Hz
JHb-Hc = 0.9 Hz
Het
CH2
Ha
7
6
With the optimization reactions completed, a series of aldehydes were reacted with PT-
sulfone 2a, under CsF-mediated conditions in DMSO at room temperature. The scope of these
olefinations is shown in Table 3. Condensation reactions seem to be highly substrate dependent.
Use of 1-naphthaldehyde instead of 2-naphthaldehyde gave a lower yield, with no E/Z selectivity
(compare entries 1 and 2). Extending the aromatic core to the phenanthrene system resulted in a
slight lowering of yield (entry 3) but the product yield with the isomeric 9-anthraldehyde was
better (entry 4). The E/Z ratio in the case of the latter was significantly in favor of the E-isomer.
This could possibly be due to unique substrate structure, that could favor formation of highly
stabilized zwitterionic intermediates leading to the trans alkene via an E1 elimination path.20
The reaction of pyren-1-carboxaldehyde proceeded in a better yield and the E/Z ratio paralleled
the phenanthrene carboxaldehyde reaction (entry 5). Electron-withdrawing groups on the
aromatic ring produced acceptable product yields (entries 6–8) but low yield was obtained with
3-methoxybenzaldehyde (entry 9). The highly electron-rich 4-methoxybenzaldehyde did not
afford any product. Interestingly, 6-methoxy-2-naphthaldehyde produced an acceptable product

yield (entry 10). Most surprisingly, 4-phenylbenzaldehyde gave the lowest yield in the series
(entry 11). Ring electronics appear to play little role, if any, in the stereoselection because the
electron-rich and electron-deficient aldehydes gave comparable E/Z product ratios. Reactions
with an alkyl aldehyde (n-octanal) and a cinnamaldehyde were unsuccessful.
Table 3
Reactions of PT-sulfone 2a with various aldehydes.a
H
O O
S
CF3
N
Ar
O
H
N
CF3
N
N
CsF, DMSO
rt
Ar
3, 8–17
Ph
2a
Entry Aldehyde
Product
Yieldb (%) %E/Zc 19F NMRd
 ppm
1
3: 86
8: 57
9: 42
10: 50
41:59 E: –63.7
Z: –57.8
CHO
CF3
2
52:48 E: –63.9
Z: –58.3
CHO
CF3
3
4
56:44 E: –63.9
Z: –58.2
CHO
CF3
92:8
E: –64.4
Z: –61.7
CF3
CHO

5
6
11: 62
12: 50
61:39 E: –63.6
Z: –58.3
CF3
CHO
O
O
38:62 E: –64.2
Z: –58.2
MeO
NC
MeO
NC
CHO
CF3
7
13: 42
14: 52
15: 37
39:61 E: –64.4
Z: –58.2
CHO
CF3
8e
9
37:63 E: –64.4
Z: –58.2
O2N
O2N
CHO
CF3
OMe
OMe
39:61 E: –63.9
Z: –57.9
CHO
CF3
MeO
MeO
10
11
16: 51
17: 23
44:56 E: –63.4
Z: –57.8
CHO
CF3
40:60 E: –63.7
Z: –58.0
CHO
CF3
a For a representative procedure, please see ref 23.
b Yields are of isolated and purified products.
c Determined by 19F NMR of the crude reaction mixtures.
d Referenced to CFCl3 as an internal standard.
e Sulfone 2a was used as the limiting reactant, see the Supporting Information for details.
An initial attempt at isomerization of the E/Z-3 alkene mixture under I2-catalyzed conditions
did not produce a change in the ratio.24

In summary, we have demonstrated that the Julia-Kocienski olefination offers a relatively
straightforward route to (trifluoromethyl)vinyl compounds despite the problem of fluoride
expulsion as well as the formation of protio vinyl products. Yields are substrate-dependent,
whereas stereoselectivities generally are not. Facile synthesis of reagent and mild olefination
conditions are clear advantages of such an approach.
Acknowledgment: This work was supported by NSF Grant CHE-1058618 and by PSC
CUNY awards. Infrastructural support was provided by NIH Grants 2G12RR03060-26A1 from
the NCRR and by 8G12MD007603-27 from the NIMHD.
References:
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the Synthesis of Trifluoromethyl-Substituted Olefins, Annual Biomedical Research
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2. Undergraduate research participant, supported through the NIH RISE and MARC programs.
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23. Condensation
of
2a
with
6-methoxynaphthalene-2-carboxaldehyde:
To
6-
methoxynaphthalene-2-carboxaldehyde (93.1 mg, 0.500 mmol, 1.0 molar equiv), PT-sulfone
2a (73.0 mg, 0.25 mmol, 0.5 molar equiv), and anhydrous CsF (190 mg, 1.25 mmol, 2.5
molar equiv), was added anhydrous DMSO (10.0 mL), and the reaction mixture was stirred
at room temperature. After 1 h, 2a (73.0 mg, 0.25 mmol, 0.5 molar equiv) and CsF (190 mg,
1.25 mmol, 2.5 molar equiv) were added, and this step was repeated two more times, until a
total of 292 mg (1.00 mmol, 2.0 molar equiv) of 2a and 760 mg (5.00 mmol, 10.0 molar

equiv) of CsF were used in the reaction. After 19 h, water (5.0 mL) was added to the reaction
mixture, and the mixture was extracted with EtOAc (3 x 20.0 mL). The combined organic
layer was washed with water (3 x 15.0 mL), followed by brine, dried over anhydrous
Na2SO4, and the solvent was evaporated under reduced pressure. Purification by column
chromatography (SiO2, 12% EtOAc in hexanes) yielded E/Z-16 (64.3 mg, 51%) as an off-
white solid.
24. Gaukroger, K.; Hadfield, J. A.; Hepworth, L. A.; Lawrence, N. J.; McGown, A. T. J. Org.
Chem. 2001, 66, 8135-8138, and references therein.

Graphical Abstract