A novel synthesis of trifluoromethylated multi-substituted alkenes via regio- and stereoselective Heck reaction of (E)-4,4,4-trifluoro-1-phenyl-2- buten-1-one

Article abstract of DOI:10.1055/s-2006-951496

Treatment of (E)-4,4,4-trifluoro-1-phenyl-2-buten-1-one with various aryldiazonium salts in the presence of a palladium catalyst led to a smooth Heck reaction, furnishing α-arylated adducts in good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-951496

LETTER
3025
A Novel Synthesis of Trifluoromethylated Multi-Substituted Alkenes via
Regio- and Stereoselective Heck Reaction of (E)-4,4,4-Trifluoro-1-phenyl-
2-buten-1-one
A
N
ovel Synthe
s
sis of Trif
u
luoromethyl
t
ated
M
o
ulti-Substitut
m
ed Alkenes u Konno,* Shigeyuki Yamada, Akinori Tani, Tomotsugu Miyabe, Takashi Ishihara
Department of Chemistry and Materials Technology, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan
Fax +81(75)7247580; E-mail: konno@chem.kit.ac.jp
Received 18 May 2006
lated-a-aryl-a,b-unsaturated carbonyl compounds via a
Abstract: Treatment of (E)-4,4,4-trifluoro-1-phenyl-2-buten-1-one
regio- and stereoselective Heck reaction of b-fluoroalky-
with various aryldiazonium salts in the presence of a palladium cat-
lated-a,b-unsaturated carbonyl compounds with various
alyst led to a smooth Heck reaction, furnishing a-arylated adducts
types of aryldiazonium salts.8
in good yields.
Key words: Heck reaction, aryldiazonium salts, fluoroorganic Our initial studies were focused on the Heck reaction
compounds
of (E)-4,4,4-trifluoro-1-phenyl-2-buten-1-one (1a) with
phenyldiazonium salt 2a (Scheme 1, Table 1, Ar = Ph).
Much attention has been paid to fluorine-containing com-
pounds as agrochemical and pharmaceutical agents due to
the unique properties exerted by fluorine atom(s).1 Fluo-
roalkyl groups increase lipophilicity allowing for easier
drug transportation, cellular absorption, and improve
binding within hydrophobic pockets of receptors.2 Conse-
quently, the development of novel synthetic methods for
the preparation of fluorine-containing materials continues
to be an important field of research in agricultural, medic-
inal, and organic chemistry.3
ArN2BF4 (2, X equiv)
O
catalyst (Y mol%)
F3C
CF3
Ph
solvent, 40 °C, 2 h
1
O
O
CF3
O
+
+
Ph
F3C
Ph
Ar
Ph
Ar
Ar
3
4
5
Scheme 1
Among various types of fluoroorganic molecules, alkenes
bearing a fluoroalkyl group, A, are one of the most valu-
able synthetic targets because they are found in the frame-
work of biologically active materials, such as
panomifnene (Figure 1).4
Thus, treatment of 1a with 1.2 equivalents of 2a in the
presence of 2.5 mol% Pd2(dba)3·CHCl3 in THF at 40 °C
for 2 hours gave the corresponding adduct 3a in 4% yield,
together with 90% of recovered starting material (Table 1,
entry 1); only the Z-isomer was detected.9 Various sol-
vents, such as toluene, 1,4-dioxane, diethyl ether, and
methanol, did not give satisfactory results (no reaction or
low regioselectivity; Table 1, entries 2–5), however, the
use of ethanol resulted in the formation of 3a in 9% yield,
as the sole product (Table 1, entry 6). Therefore, we fur-
ther examined the reaction conditions in THF or EtOH.
The addition of various types of phosphine ligands did not
lead to an improvement in the yield of the reaction in THF
(Table 1, entries 7–10). On the other hand, the reaction in
refluxing THF afforded the Heck adducts 3 and 4 in a ratio
of 92:8 in 24% combined yield (Table 1, entry 11).
Though a prolonged reaction time as well as the use of 2.2
equivalents of 2a did not bring about a significant change
(Table 1, entries 12 and 13), the reaction with 2.2 equiva-
lents of 2a in the presence of 20 mol% palladium catalyst
gave 3a and 4a in 61% yield (Table 1, entry 14). Addi-
tionally, the reaction with 4.4 equivalents of 2a at reflux
caused a significant improvement in the yield; 3a and 4a
were obtained in 79% yield in a 90:10 ratio (Table 1, entry
16). We also investigated the reaction in ethanol as shown
(Table 1, entries 17–21). In sharp contrast to the reaction
in THF, the ligand effect was significant. Thus, when
R4
O
Rf
R1
R2
R3
Rf
R6
R5
A
B
Rf = CF3, CHF2, etc.
Figure 1
Although several synthetic methods for the preparation of
such compounds have been developed by several groups5
and us,6 little is known on the stereoselective synthesis of
multi-substituted b-fluoroalkylated-a,b-unsaturated car-
bonyl compounds B, which have been widely used as po-
tent synthetic blocks, particularly as Michael acceptors for
conjugate additions, or dienophiles and dipolarophiles for
cycloaddition reactions.7 In this communication, we wish
to describe the first convenient synthesis of b-fluoroalky-
SYNLETT 2006, No. 18, pp 3025–3028
0
3
.1
1
.2
0
0
6
Advanced online publication: 25.10.2006
DOI: 10.1055/s-2006-951496; Art ID: S11106ST
© Georg Thieme Verlag Stuttgart · New York

3026
T. Konno et al.
LETTER
Table 1 Investigation of the Reaction Conditions
Entry
X
Catalyst
Y
Solvent
Yielda
Ratioa
Yielda (%) Recoverya
(equiv)
(mol%)
3a + 4a (%) 3a/4a
5a
(%) of 1a
1
2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
2.2
2.2
3.3
4.4
2.2
2.2
2.2
2.2
2.2
0.5 [Pd2(dba)3·CHCl3]
5
5
THF
4
0
100:0
–
0
90
0.5 [Pd2(dba)3·CHCl3]
Toluene
1,4-Dioxane
Et2O
0
97
3
0.5 [Pd2(dba)3·CHCl3]
5
10
0
80:20
–
2
67
4
0.5 [Pd2(dba)3·CHCl3]
5
0
89
5
0.5 [Pd2(dba)3·CHCl3]
5
MeOH
EtOH
THF
10
9
80:20
100:20
–
0
35
6
0.5 [Pd2(dba)3·CHCl3]
5
3
90
7
0.5 [Pd2(dba)3·CHCl3] + 2 PPh3
0.5 [Pd2(dba)3·CHCl3] + 2 P(o-Tol)3
0.5 [Pd2(dba)3·CHCl3] + 2 P(c-hex)3
0.5 [Pd2(dba)3·CHCl3] + dppe
0.5 [Pd2(dba)3·CHCl3]
5
0
0
quant.
93
8
5
THF
0
–
0
9
5
THF
2
100:20
–
0
85
10
11b
12b,c
13b
14b
15b
16
17
18
19
20
21
5
THF
0
0
quant.
59
5
THF
24
28
8
92:8
75:25
88:12
82:18
83:17
90:10
92:8
93:7
94:6
89:11
88:12
4
0.5 [Pd2(dba)3·CHCl3]
5
THF
9
71
0.5 [Pd2(dba)3·CHCl3]
5
THF
2
90
0.5 [Pd2(dba)3·CHCl3]
20
20
20
20
20
20
20
20
THF
61
63
79
51
45
82 (69)
47
17
12
12
11
3
17
0.5 [Pd2(dba)3·CHCl3]
THF
22
0.5 [Pd2(dba)3·CHCl3]
THF
2
0.5 [Pd2(dba)3·CHCl3]
EtOH
EtOH
EtOH
EtOH
EtOH
32
0.5 [Pd2(dba)3·CHCl3] + 2 PPh3
[Pd2(dba)3·CHCl3]+ 2 P(o-Tol)3
0.5 [Pd2(dba)3·CHCl3] + 2 P(c-Hex)3
0.5 [Pd2(dba)3·CHCl3] + dppe
7
36
11
4
0
33
0
76
a Determined by 19F NMR spectroscopy. Isolated yield in parentheses.
b Carried out at reflux.
c Reaction time, 12 h.
P(o-Tol)3 was used the starting material was completely place smoothly to afford the corresponding Heck adducts
consumed and the corresponding arylated adducts 3a and in 75% or 71% yield, respectively (Table 2, entries 8 and
4a were obtained in 82% yield in a ratio of 94:6 (Table 1, 10), whereas the reactions in ethanol at 40 °C resulted in
entry 18), though the Michael adduct 5a also formed as very low yields of the products (Table 2, entries 7 and 9).
a by-product. Additionally, bulky or bidentate ligands Various halogen-substituted aryldiazonium salts success-
resulted in a significant decrease in the yield (Table 1, en- fully gave the desired materials in 62–74% yield with high
tries 20 and 21). With the optimum reaction conditions de- Z-stereoselectivity, though the Michael adducts 5 formed
termined (Table 1, entries 16 and 19),10 we conducted the in 10–20% yield (Table 2, entries 11–16). However, aryl-
Heck reaction with various types of aryldiazonium salts diazonium salts substituted by stronger electron-with-
(Table 2).
drawing groups, such as cyano, ethoxycarbonyl, and nitro
groups on the benzene ring, did not lead to satisfactory re-
sults when the reaction was performed in ethanol at 40 °C;
the starting diazonium salt 2 was almost completely re-
covered (Table 2, entries 17, 19, and 21). Interestingly,
the reaction with ethoxycarbonyl-substituted aryldiazoni-
um salt in THF at reflux gave the Heck adducts 3 and 4 in
64% yield in a ratio of 80:20 (Table 1, entry 20). On the
other hand, the reaction with the cyano- or nitro-substitut-
Both para- and meta-substituted aryldiazonium salts par-
ticipated well in the Heck reaction to give the correspond-
ing adducts in good yields with a high Z-stereoselectivity
(Tables 2, entries 3 and 5). When the reaction was carried
out in THF at reflux, a slight decrease in the yield as well
as the stereoselectivity was detected (Table 2, entries 4
and 6). Very interestingly, the Heck reaction with ortho-
tolyl or para-anisyldiazonium salt in THF at reflux took
Synlett 2006, No. 18, 3025–3028 © Thieme Stuttgart · New York

LETTER
A Novel Synthesis of Trifluoromethylated Multi-Substituted Alkenes
3027
withdrawing group or bulky salts did not give satisfactory
results.
Table 2 The Heck Reaction with Various Aryldiazonium Salts
Entry Diazonium salt
Methoda Yieldb
Ratiob
Yieldb
Further investigations of the Heck reaction of various flu-
oroalkylated alkenes are currently underway in our labo-
ratory.
3 + 4 (%) 3/4
5 (%)
1
2
A
B
82 (69)
79
94:6
90:10 11
11
N2BF4
3
4
A
B
57 (48)
35
93:7
86:14
10
9
References and Notes
Me
N2BF4
(1) (a) Hiyama, T.; Kanie, K.; Kusumoto, T.; Morizawa, Y.;
Shimizu, M. Organofluorine Compounds; Springer-Verlag:
Berlin-Heidelberg, 2000. (b) Enantiocontrolled Synthesis of
Fluoro-Organic Compounds; Soloshonok, V. A., Ed.;
Wiley: Chichester, 1999. (c) Organofluorine Chemistry;
Chambers, R. D., Ed.; Springer: Berlin, 1997.
5
6
A
B
73 (57)
48
95:5
88:12 10
9
N2BF4
Me
7
8
A
B
9
44:56
48:52
0
6
N2BF4
75 (63)
(d) Biomedical Frontiers of Fluorine Chemistry; Ojima, I.;
McCarthy, J. R.; Welch, J. T., Eds.; American Chemical
Society: Washington D. C., 1996. (e) Organofluorine
Chemistry: Principles and Commercial Applications;
Banks, R. E.; Smart, B. E.; Tatlow, J. C., Eds.; Plenum Press:
New York, 1994.
Me
9
10
A
B
5
100:0
92:8
4
17
MeO
F
N2BF4
71 (55)
11
12
A
B
74 (58)
69
89:11 15
8:20 13
(2) (a) O’Hagen, D.; Rzepa, H. Chem. Commun. 1997, 645.
(b) Mann, J. Chem. Soc. Rev. 1987, 16, 381. (c) Welch, J. T.
Tetrahedron 1987, 43, 3123.
N2BF4
13
14
A
B
67 (50)
68
89:11 10
79:21 19
(3) For reviews see: (a) Dave, R.; Badet, B.; Meffre, P. Amino
Acids 2003, 24, 245. (b) Qiu, X.-L.; Meng, W.-D.; Qing, F.-
L. Tetrahedron 2004, 60, 6711. (c) Mikami, K.; Itoh, Y.;
Yamanaka, M. Chem. Rev. 2003, 104, 1. (d) van Steenis, J.
H.; van der Gen, A. J. Chem. Soc., Perkin Trans. 1 2002,
2117. (e) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56,
7613. (f) Christie, S. D. R. J. Chem. Soc., Perkin Trans. 1
1998, 1577. (g) Ojima, I. Chem. Rev. 1988, 88, 1011.
(h) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97,
757. (i) McClinton, M. A.; McClinton, D. A. Tetrahedron
1992, 48, 6555.
Cl
N2BF4
N2BF4
15
16
A
B
65 (74)
62
88:12 12
79:21 19
Br
17
18
A
B
0
0
–
–
0
trace
NC
N2BF4
N2BF4
19
20
A
B
28
64 (63)
86:16
80:20 15
6
EtO2C
O2N
(4) (a) Kim, M.-S.; Jeong, I.-H. Tetrahedron Lett. 2005, 46,
3545. (b) Liu, X.; Shimizu, M.; Hiyama, T. Angew. Chem.
Int. Ed. 2004, 43, 879.
21
22
23
A
B
C
11
38
41
100:0
69:31 11
73:27 10
0
N2BF4
(5) (a) Radix-Large, S.; Kucharski, S.; Langlois, B. R. Synthesis
2004, 456. (b) Shimizu, M.; Fujimoto, T.; Liu, X.; Minezaki,
H.; Hata, T.; Hiyama, T. Tetrahedron 2003, 59, 9811.
(c) Jennings, M. P.; Cork, E. A.; Ramachanfran, V. J. Org.
Chem. 2000, 65, 8763. (d) Pan, R.-Q.; Liu, X.-X.; Deng, M.
Z. J. Fluorine Chem. 1999, 95, 167. (e) Prié, G.; Thibonnet,
J.; Abarbri, M.; Duchêne, A.; Parrain, J. Synlett 1998, 839.
(f) Shen, Y.; Gao, S. J. Fluorine Chem. 1996, 76, 37.
(6) (a) Konno, T.; Chae, J.; Tanaka, T.; Ishihara, T.; Yamanaka,
H. J. Fluorine Chem. 2006, 127, 36. (b) Konno, T.; Daitoh,
T.; Noiri, A.; Chae, J.; Ishihara, T.; Yamanaka, H.
Tetrahedron 2005, 61, 9391. (c) Konno, T.; Chae, J.;
Tanaka, T.; Ishihara, T.; Yamanaka, H. Chem. Commun.
2004, 690. (d) Konno, T.; Daitoh, T.; Noiri, A.; Chae, J.;
Ishihara, T.; Yamanaka, H. Org. Lett. 2004, 6, 933.
(e) Konno, T.; Takehana, T.; Chae, J.; Ishihara, T.;
Yamanaka, H. J. Org. Chem. 2004, 69, 2188. (f) Chae, J.;
Konno, T.; Kanda, M.; Ishihara, T.; Yamanaka, H. J.
Fluorine Chem. 2003, 120, 185.
(7) (a) Billard, T. Chem. Eur. J. 2006, 12, 974. (b) Yamazaki,
T.; Shinohara, N.; Kitazume, T.; Sato, S. J. Fluorine Chem.
1999, 97, 91. (c) Shinohara, N.; Haga, J.; Yamazaki, T.;
Kitazume, T.; Nakamura, S. J. Org. Chem. 1995, 60, 4363.
(d) Tanaka, K.; Imase, T.; Iwata, S. Bull. Chem. Soc. Jpn.
1996, 69, 2243. (e) Bonnet-Delpon, D.; Chennoufi, A.;
Rock, M. H. Bull. Soc. Chim. Fr. 1995, 132, 402.
(f) Bonnet-Delpon, D.; Bégué, J.-P.; Lequeux, T.;
Ourevitch, M. Tetrahedron 1996, 52, 59.
24
25
B
B
23
36
83:17
58:42
0
9
N2BF4
a Method A: 2 (2.2 equiv), EtOH, 40 °C, 2 h; Method B: 2 (4.4 equiv),
THF, reflux, 2 h; Method C: 2 (4.4 equiv), THF, reflux, 10 h.
b Determined by 19F NMR spectroscopy. Isolated yields are in paren-
theses.
ed aryldiazonium salts in THF did not lead to dramatic
changes (Table 2, entries 18, 22, and 23). Additionally,
the 1-naphthyldiazonium salt gave very poor results
(Table 2, entries 24 and 25).
In summary, we have developed an easy access to a vari-
ety of b-fluoroalkylated-a-aryl-a,b-unsaturated carbonyl
compounds via a regio- and stereoselective Heck reaction
with readily available aryldiazonium salts. Various aryl-
diazonium salts bearing an electron-donating group and
halogens at the para-, meta-, or ortho-position of the ben-
zene ring could participate nicely in the Heck reaction, the
corresponding Z-isomer was formed preferentially. On
the other hand, aryldiazonium salts having an electron-
Synlett 2006, No. 18, 3025–3028 © Thieme Stuttgart · New York

3028
T. Konno et al.
LETTER
(8) Several Heck reactions of fluorine-containing alkenes were
reported, see: (a) Darses, S.; Pucheault, M.; Genêt, J.-P. Eur.
J. Org. Chem. 2001, 1121. (b) Peng, S.; Qing, F.-L.; Guo,
Y. Synlett 1998, 859. (c) The Heck reaction of b-fluoro-
alkylated a,b-unsaturated carbonyl compounds with aryl
halide in the presence of a palladium catalyst has been
reported, however, neither high regioselectivity nor high
yields have been achieved (yield: <48%, regioselectivity
<29:71), see: (d) Gong, Y.; Kato, K.; Kimoto, H. J. Fluorine
Chem. 2000, 105, 169.
(9) The stereochemistry was determined on the basis of the
chemical shifts in the 1H NMR spectra according to the
literature; see ref. 8.
(10) Method A; Typical Procedure: To a solution of
Pd2(dba)3·CHCl3 (10 mol%) and P(o-Tol)3 (40 mol%) in
EtOH was added (E)-4,4,4-trifluoro-1-phenyl-2-buten-1-
one (50 mg, 0.25 mmol) and p-fluorophenyldiazonium
tetrafluoro-borate (115 mg, 0.55 mmol) at r.t., and the
resulting mixture was stirred at 40 °C for 2 h. After cooling
to r.t., the mixture was poured into a sat. aq solution of
NH4Cl, and the resulting mixture was extracted three times
with Et2O. The combined organic layers were washed with
a sat. solution of NaCl, dried over anhyd Na2SO4, filtered,
and concentrated in vacuo. The residue was purified by silica
gel column chromatography to give the corresponding Heck
adduct (43 mg, 0.45 mmol; Z/E, 89:11; 58% yield).
Z-Isomer: 1H NMR (CDCl3) d = 6.15 (q, J = 7.1 Hz, 1 H),
7.02–7.07 (m, 2 H), 7.38–7.47 (m, 4 H), 7.50–7.60 (m, 1 H),
7.86–7.92 (m, 2 H). 19F NMR (CDCl3): d = –59.1 (d, J = 7.1
Hz, 3 F), –110.2 to –110.3 (m, 1 F).
E-Isomer: 1H NMR (CDCl3): d = 6.09 (q, J = 7.1 Hz, 1 H).
19F NMR (CDCl3): d = –57.3 (d, J = 7.1 Hz, 3 F), –111.78 to
–111.84 (m, 1 F).
Method B: The reaction was carried out in the presence of
Pd2(dba)3·CHCl3 in THF at reflux. The workup was the same
as Method A.
Synlett 2006, No. 18, 3025–3028 © Thieme Stuttgart · New York