Nucleophilic trifluoromethylation of conjugate acceptors via phenyl trifluoromethyl sulfone

Article abstract of DOI:10.1016/j.tetlet.2013.08.132

A mild procedure for the conjugate addition of the trifluoromethyl anion to activated Michael acceptors such as arylidenemalononitriles (15 examples) and arylidene Meldrum's acids (9 examples) using phenyl trifluoromethyl sulfone through a reductive magnesium metal mediated procedure is described. The new methodology is used to prepare befloxatone, a reversible and selective monoamine oxidase A inhibitor.

Full text of DOI:10.1016/j.tetlet.2013.08.132

Tetrahedron Letters 54 (2013) 6129–6132
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Nucleophilic trifluoromethylation of conjugate acceptors via phenyl
trifluoromethyl sulfone
⇑
Kaumba Sakavuyi, Kimberly S. Petersen
Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC 27402, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A mild procedure for the conjugate addition of the trifluoromethyl anion to activated Michael acceptors
such as arylidenemalononitriles (15 examples) and arylidene Meldrum’s acids (9 examples) using phenyl
trifluoromethyl sulfone through a reductive magnesium metal mediated procedure is described. The new
methodology is used to prepare befloxatone, a reversible and selective monoamine oxidase A inhibitor.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 16 August 2013
Revised 26 August 2013
Accepted 30 August 2013
Available online 7 September 2013
Keywords:
Trifluoromethylation
Conjugate addition
Befloxatone
Phenyl trifluoromethyl sulfone
As a result of the increasing importance of fluorine containing
molecules in the pharmaceutical, agrochemical, and materials
industries considerable effort has been devoted to the development
of selective fluorination methodologies.1 Replacement of hydrogen
by fluorine, the most electronegative element, changes the proper-
ties of a molecule. In particular, the CF3 group can substantially alter
electronics, chemical reactivity, lipophilicity, bioavailability, and
metabolic stability of a compound. Currently, approximately 20%
of pharmaceuticals and 30–40% of agrochemicals contain fluorine2
and numerous materials including the highly utilized Teflon (poly-
tetrafluoroethyene polymer) are perfluorinated.3
Incorporation of a trifluoromethyl group typically begins with a
trifluoromethyl containing building block. However, utilization of
pre-functionalized systems severely limits late stage incorporation.
Thus, the direct introduction of a trifluoromethyl group is desirable
and this is traditionally promoted via either electrophilic, radical,
or nucleophilic addition (Fig. 1).4
Electrophilic Sources
F3C
Radical Sources
I
O
F3C
I
S
CF3
1
2
3
Umemoto's reagent
Togni's reagent
trifluoroiodomethane
Nucleophilic Sources
O
S
O
F3C TMS
Ph
CF3
4
5
phenyl
trifluoromethyl
sulfone
Ruppert−Prakash
reagent
Nucleophilic trifluoromethylations are attractive reactions be-
cause of the wide array of electrophilic partners and the potential
to develop stereoselective variants. Due to the inherent instability
of the trifluoromethyl anion (CF3À), a variety of methods for its
in situ generation have been developed, the most common being
use of the Ruppert–Prakash reagent (4).5 While this reagent is
highly versatile, the most utilized method of preparation involves
the use of ozone-depleting CF3Br6 (although recently Prakash
et al. have shown that fluoroform can be used as a precursor to
4).7 In contrast, the increasingly attractive reagent, phenyl trifluo-
Figure 1. Sources of ‘CF3’.
romethyl sulfone (5), is readily available from methyl phenyl
sulfide8 and is a precursor in a more environmentally friendly syn-
thesis of silane 4.9 Thus, the use of sulfone 5 is a more economical
and green choice of reagent.
Sulfone 5 has been shown to be an efficient trifluoromethyl
group precursor. Reductive conditions with magnesium metal
alone facilitated the reaction of the proposed trifluoromethyl anion
intermediate with chlorosilane electrophiles to geneÀrate trifluo-
romethylsilanes.9 Alkoxide induced generation of CF3 led to the
generation of
a
-trifluoromethyl alcohols through direct addition
magnesium
⇑
Corresponding author.
E-mail address: kspeters@uncg.edu (K.S. Petersen).
to non-enolizable aldehydes.10 More recently,
a
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.132

6130
K. Sakavuyi, K. S. Petersen / Tetrahedron Letters 54 (2013) 6129–6132
metal-mediated method for the direct trifluoromethylation of
Previous work (1,2-additions):
aldehydes activated by mercury(II) chloride was developed.11
While direct additions of the trifluoromethyl anion to a carbonyl
are well studied using a variety of sources,12 conjugate additions are
rare.13 Ourinterestin developing mild, inexpensive, andselective tri-
fluoromethylation procedures led us to investigate the use of readily
available sulfone 5 in conjugate addition reactions (Scheme 1).
Our initial efforts were directed toward the nucleophilic trifluo-
romethylation of previously examined highly electrophilic alkenes
such as benzylidenemalononitrile (10)13b (Table 1). Our attempts
to use Prakash, Hu, and Olah’s alkoxide induced method to gener-
ate a transient trifluoromethyl anion10 were unsuccessful with 10
and lead to recovery of the sulfone while the malononitrile was
consumed (entries 1 and 2), suggesting the alkoxide reacts sponta-
neously with the highly electrophilic malononitrile over the sul-
fone. Our next attempts were focused on a reductive, magnesium
metal mediated procedure (entries 3–6). Previous work by Hu
O
O
Ar
H
CF3
OH
Mg or tBuOK
6
–CF3
Ph
S
O
5
CF3
Ar
7
EWG
R
This work (1,4-additions):
EWG
8
CF3
R
EWG
EWG
9
Scheme 1. 1,2- versus 1,4-additions.
and co-workers demonstrated that an additive was necessary to
À 11
activate the metal for desulfonylation and generation of CF3
.
Rewardingly, our results followed previous experiments, with mer-
cury(II) chloride (3 mol % relative to amount of magnesium) in DMF
acting as an effective additive and leading to 64% of trifluoromethy-
lated malononitrile 11. We expect the procedure to follow the same
mechanism as proposed by Hu where a single electron transfer
from magnesium metal to sulfone 5 enables a reductive cleavage
Table 1
Reaction Development
CF3
O
S
reagent/additive
CN
CN
Ph
+
Ph
Ph
CF3
À
of the C–S bond to form the CF3 species, followed by addition to
DMF
CN
O
CN
11
the highly electrophilic arylidenemalononitriles.11
5
10
With conditions in hand for the nucleophilic trifluoromethyla-
tion of benzylidenemalononitrile with sulfone 5, we set out to ex-
plore the scope of the reaction (Table 2). Both electron
withdrawing and electron donating substitutents on the benzene
ring are tolerated and gave yields ranging from 52–82% (entries 1–
12). Entries with electron withdrawing groups gave lower yield
agreeing with Hu and co-workers suggestion of rapid reduction of
these substrates due to the reaction condition (entries 6–10).11
Naphthalene (entry 13) and heteroaromatic based malononitriles
(entries 14 and 15) also perform well under the reaction conditions.
Entry
Reagent/additive
T (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
tBuOK/none
tBuOK/none
Mg/none
Mg/ZnCl2
Mg/CuCl2
Mg/HgCl2
0 to rt
12
12
12
24
24
3.5
0
0
0
0
0
À50 to rt
À50 to rt
À50 to rt
À50 to rt
À50 to rt
64
Table 2
Trifluoromethylation of arylidenemalononitrilesa
CF3
Mg, HgCl2 (3 mol%)b
CN
O
S
CN
CN
+
Ph
CF3
Ar
Ar
O
5
CN
11
DMF, –50 °C to rt
10
Entry
Substrate
Product
Yieldc (%)
CN
CN
CF3
CN
1
2
3
4
5
6
7
8
9
10
11
11a R = H
11b R = 4-OMe
65
77
R
11c R = 2-Me
11d R = 3-Me
11e R = 4-Me
11f R = 3-CF3
11g R = 2-F
11h R = 3-F
11i R = 4-F
11j R = 4-NO2
11k R = 2,6-Me2
73
76
70
60
57
58
63
52
60
R
CN
11a–l
CN
CN
CF3
CN
12
13
78
82
CN
11l
CN
CN

K. Sakavuyi, K. S. Petersen / Tetrahedron Letters 54 (2013) 6129–6132
6131
Table 2 (continued)
Entry
Substrate
Product
Yieldc (%)
CF3
CN
CN
11m
CN
CN
CF3
O
S
CN
O
S
14
59
60
CN
11n
CF3
CN
CN
CN
15
CN
11o
a
Reactions carried out using 5 (2 mmol), 10 (1 mmol), Mg (2 mmol) and HgCl2 (0.06 mmol) in DMF (3 mL).
bRelative to the amount of Mg metal used.
c
Isolated yield.
Table 3
Trifluoromethylation of arylidene Meldrum’s acidsa
O
CF3
O
O
O
Mg, HgCl2 (2.4 mol%)b
O
S
O
1. aq HCl, 110 °C
CF3
O
Ar
O
Ar
O
+
Ph
CF3
Ar
OMe
2. MeI, K2CO3
DMF, 75 °C
O
O
5
12
13
14
Entry
Substrate
Product
Yieldc (%)
O
O
CF3 O
1
2
14a R = H
63
69
14b R = 4-OMe
14c R = 2-Me
14d R = 4-Me
14e R = 4-NO2
14f R = 4-F
O
OMe
3
4
5
6
7
65
68
32
45
53
R
R
O
14a–g
14g R = 2,6-Me2
O
CF3
O
O
O
S
O
OMe
8
9
52
54
14h
CF3
O
O
O
O
S
O
OMe
14i
O
O
a
Reactions carried out 5 (2.5 mmol), 12 (1 mmol), Mg (2.5 mmol) and HgCl2 (0.06 mmol) in DMF (3 mL).
bRelative to the amount of Mg metal used.
c
Isolated yield.
Following the successful trifluoromethylation of various arylid-
enemalononitriles, we sought to determine if other Michael accep-
tors would be suitable as electrophiles. Arylidene derivatives of
Meldrum’s acid 12 are highly electrophilic and have previously
undergone nucleophilic trifluoromethylation with trifluoromethyl-
trimethylsilane (4).13a Modification of the above procedure to
include elevated temperatures (75 °C) led to intermediate trifluo-
romethylated compounds 13 which were immediately hydrolyzed
and decarboxylated to avoid decomposition and esterified for ease
of handling (Table 3). Overall yields of transformation of
Meldrum’s acid derivatives 12 to b-trifluoromethyl esters 14 were
between 32% (R = 4-NO2, entry 5) and 69% (R = 4-OMe, entry 2).
Heteroaromatic derivatives of Meldrum’s acid (entries 8 and 9)
were also viable substrates in the process.
O
O
1. Mg, HgCl2 (3 mol%)
CF3
O
O
S
O
DMF, 75 °C
MeO
O
Ph
CF3
+
HO
OBn
2. aq HCl, 110 °C
3. BnBr, K2CO3
O
15
(
)-16: 53%
5
CF3
CF3
TsCl
LiAlH4
THF
HO
OH
)-17: 68%
HO
OTs
pyridine
(
(
)-18: 40%
OH
O
CF3
OH
K2CO3, Δ
DMF
+
( )-18
N
O
N
MeO
MeO
O
O
Befloxatone ((R,R)-20) is a reversible and selective monoamine
oxidase A (MAO-A) inhibitor containing a trifluoromethyl group
at a chiral center (Scheme 2).14 Previous syntheses of befloxatone
have involved the etherification of phenol 19 with trifluoromethyl
O
19
20: 63%, 1:1 (R,R)/(R,S)
Befloxatone
Scheme 2. Synthesis of Befloxatone.

6132
K. Sakavuyi, K. S. Petersen / Tetrahedron Letters 54 (2013) 6129–6132
containing tosylate 18.14c,15 We have developed a synthesis of tos-
ylate 18 using the described conjugate addition of a trifluoro-
methyl group to Meldrum’s acid derivatives. Trifluoromethylation
of compound 15 using our standard trifluoromethylation condi-
tions was followed by hydrolyzation and decarboxylation and
esterification to give product ( )-16 in 53% overall yield. Reduction
of the benzyl ester followed by tosylation of the primary alcohol
gave ( )-18. Finally, etherification of (R)-1915 with ( )-18 yielded
desired compound 20 in a 63% yield and with 1:1 diastereomeric
ratio of the inseparable (R,R) (befloxatone) and (R,S) diasteromers.
Development of an asymmetric variant of the conjugate trifluo-
romethylation is currently underway in our laboratories and would
lead to an asymmetric synthesis of (+)-18 and thus befloxatone
((R,R)-20).
In summary, we have developed a mild procedure for the
conjugate addition of the trifluoromethyl anion to activated
acceptors such as arylidenemalononitriles and arylidene Me-
drum’s acids using readily available phenyl trifluoromethyl sul-
fone (5) through a magnesium metal reductive procedure. This
methodology has been applied to a total synthesis of the MAO-
A inhibitor befloxatone. Future work will be to expand the pro-
cess to other conjugate acceptors and the development of an
asymmetric variant.
References and notes
1. (a) Thayer, A. M. Chem. Eng. News 2006, 84, 15–24; (b) Kirsh, P. Mordern
Fluoroorganic Chemistry; Wiley-VCH: Weinheim, 2004; (c) Banks, R. E.; Smart,
B. E.; Tatlow, J. C. Organofluorine Chemistry: Principles and Commercial
Applications; Plenum Press: New York, 1994; (d) Filler, R.; Kobayashi, Y.;
Yagupolskii, Y. L. Organofluorine Compounds in Medicinal Chemistry and
Biological Applications; Elsevier: Amsterdam, 1993.
2. Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881–1886.
3. Hird, M. Chem. Soc. Rev. 2007, 36, 2070–2095.
4. Ma, J.-A.; Cahard, D. J. Fluorine Chem. 2007, 128, 975–996.
5. (a) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc. 1989, 111,
393–395; (b) Ruppert, I.; Schlich, K.; Volbach, W. Tetrahedron Lett. 1984, 25,
2195–2198.
6. Ramaiah, P.; Krishnamurti, R.; Prakash, G. K. S. Org. Synth. 1995, 72, 232.
7. Prakash, G. K. S.; Jog, P. V.; Batamack, P. T. D.; Olah, G. A. Science 2012, 338,
1324–1327.
8. (a) Kremsner, J. M.; Rack, M.; Pilger, C.; Kappe, C. O. Tetrahedron Lett. 2009, 50,
3665–3668; (b) Chen, Q.-Y.; Duan, J.-X. J. Chem. Soc., Chem. Commun. 1993,
918–919.
9. Prakash, G. K. S.; Hu, J.; Olah, G. A. J. Org. Chem. 2003, 68, 4457–4463.
10. Prakash, G. K. S.; Hu, J.; Olah, G. A. Org. Lett. 2003, 5, 3253–3256.
11. Zhao, Y.; Zhu, J.; Ni, C.; Hu, J. Synthesis 2010, 1899–1904.
12. (a) Wu, S.; Zeng, W.; Wang, Q.; Chen, F.-X. Org. Biomol. Chem. 2012, 10, 9334–
9337; (b) Kawai, H.; Kitayama, T.; Tokunaga, E.; Shibata, N. Eur. J. Org. Chem.
2011, 5959–5961; (c) Kawai, H.; Kusuda, A.; Nakamura, S.; Shiro, M.; Shibata,
N. Angew. Chem., Int. Ed. 2009, 48, 6324–6327; (d) Prakash, G. K. S.; Panja, C.;
Vaghoo, H.; Surampudi, V.; Kultyshev, R.; Mandal, M.; Rasul, G.; Mathew, T.;
Olah, G. A. J. Org. Chem. 2006, 71, 6806–6813; (e) Kawano, Y.; Kaneko, N.;
Mukaiyama, T. Bull. Chem. Soc. Jpn. 2006, 79, 1133–1145; (f) Caron, S.; Do, N.
M.; Arpin, P.; Larivée, A. Synthesis 2003, 1693–1698; (g) Iseki, K.; Nagai, T.;
Kobayashi, Y. Tetrahedron Lett. 1994, 35, 3137–3138.
13. (a) Zemtsov, A. A.; Levin, V. V.; Dilman, A. D.; Struchkova, M. I.; Belyakov, P. A.;
Tartakovsky, V. A. Tetrahedron Lett. 2009, 50, 2998–3000; (b) Dilman, A. D.;
Levin, V. V.; Belyakov, P. A.; Struchkova, M. I.; Tartakovsky, V. A. Tetrahedron
Lett. 2008, 49, 4352–4354; (c) Sosnovskikh, V. Y.; Usachev, B. I.; Sevenard, D. V.;
Röschenthaler, G.-V. J. Org. Chem. 2003, 68, 7747–7754; (d) Sevenard, D. V.;
Sosnovskikh, V. Y.; Kolomeitsev, A. A.; Königsmann, M. H.; Röschenthaler, G.-V.
Tetrahedron Lett. 2003, 44, 7623–7627.
14. (a) Dolle, F.; Valette, H.; Bramoulle, Y.; Guenther, I.; Fuseau, C.; Coulon, C.;
Lartizien, C.; Jegham, S.; George, P.; Curet, O.; Pinquier, J. L.; Bottlaender, M.
Bioorg. Med. Chem. Lett. 2003, 13, 1771–1775; (b) Dolle, F.; Bramouelle, Y.;
Hinnen, F.; Demphel, S.; George, P.; Bottlaender, M. J. Labelled Compd.
Radiopharm. 2003, 46, 783–792; (c) Rabasseda, X.; Sorbera, L. A.; Castañer, J.
Drugs Future 1999, 24, 1057–1067; (d) Curet, O.; Damoiseau, G.; Aubin, N.;
Sontag, N.; Rovei, V.; Jarreau, F. X. J. Pharm. Exp. Ther. 1996, 277, 253–264; (e)
Caille, D.; Bergis, O. E.; Fankhauser, C.; Gardes, A.; Adam, R.; Charieras, T.;
Grosset, A.; Rovei, V.; Jarreau, F. X. J. Pharm. Exp. Ther. 1996, 277, 265–277.
15. Shibatomi, K.; Narayama, A.; Abe, Y.; Iwasa, S. Chem. Commun. 2012, 7380–
7382.
Acknowledgments
We thank the University of North Carolina at Greensboro for
financial support and Dr. Franklin J. Moy and Dr. Brandie M. Ehr-
man for assistance with NMR and mass spectrometry data analysis.
This work was supported by the University of North Carolina at
Greensboro.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2013.08.132.