Stereo- and regio-selective addition of iodotoluene difluoride to alk-1-ynes.
Selective synthesis of 2-fluoro-1-iodoalk-1-enes
Shoji Hara,*† Masaki Yoshida, Tsuyoshi Fukuhara and Norihiko Yoneda*
Division of Molecular Chemistry, Graduate School of Engineering, Hokkaido University, Sapporo 060, Japan
Table 1 Synthesis of (E)-1-iodo-2-fluoroalk-1-enesa
p-Iodotoluene difluoride reacted with 1-alkynes to give trans
adducts which could be converted to 2-fluoro-1-iodoalk-
Alkyne
R
Yield of 3 (%)b
1-enes without isolation.
80c
65d
Me(CH2)9–
HO(CH2)9–
a
b
c
The introduction of a fluorine atom into the double bond of
natural products, such as terpenes,1 nucleosides,2 retinal,3 fatty
acids,4 prostaglandins5 and peptides6 has been of great interest
because the fluorinated analogues of natural compounds are
expected to have different pharmacological properties from the
original ones. The fluoroalkenyl parts of such compounds have
been synthesized by the condensation of a-fluorocarbanions
with carbonyl compounds3,5,6a,b,7 or the b-elimination reaction
from fluorohaloalkanes2,4b,6c but the stereoselectivities are
generally low. A cross-coupling reaction using fluoroalkenyl
halides or fluoroalkenylmetals would be a versatile method for
the stereoselective synthesis of fluoroalkenes.8 However, the
cross-coupling method has not been adequately developed for
fluoroalkene synthesis because stereoselective synthesis of the
fluoroalkenyl halides is difficult. Recently, we reported that
p-iodotoluene difluoride (1) can be directly prepared from
p-iodotoluene by an electrochemical method and used for the
fluorination of b-dicarbonyl compounds.9 During our continu-
ing study of the organic synthesis using 1, we found that 1 adds
to alk-1-ynes to give (E)-(2-fluoroalk-1-enyl)(4-methyl-
phenyl)iodonium fluorides (2)10,11 which could be converted to
(E)-2-fluoro-1-iodoalk-1-enes stereo- and regio-selectively
(Scheme 1).
77d
80
Cl(CH2)9–
MeO2C(CH2)8–
d
e
65
55
CH2–
f
O
H
O
(CH2)8–
O
g
72
But
(CH2)8–
a If not mentioned elsewhere, the reaction was carried out as described in the
notes. b Isolated yields based on alkynes used. c After the reaction of alkyne
with 1, 1 equiv. of CuI and KI in DMF (2 ml) was added. d After the reaction
of alkynes with 1, the reaction mixture was added to 10 equiv. of CuI and
KI in CH2Cl2 (30 ml).
p-Tol-IF2, Et3N–5HF
R
F
IF-Tol-p
R
F
I
ml) were introduced into a reaction vessel made of TeflonTM PFA and
p-iodotoluene difluoride (3 mmol) in Et3N–5HF (22 ml) was added at 0 °C.
After stirring for 1 h, the mixture was extracted with CH2Cl2, dried over
MgSO4, and concentrated under reduced pressure. The residue was
dissolved in CH2Cl2 (5 ml) and added to CuI (3.8 g, 20 mmol) and KI (3.32
g, 20 mmol) in CH2Cl2 (25 ml). The reaction mixture was stirred at room
temperature for 3 h and extracted with CH2Cl2. The product was isolated by
column chromatography (silica gel/hexane–diethyl ether) in 80% yield.
CuI, KI, DMF
1
RC CH
CH2Cl2
H
H
2
3
Scheme 1
p-Iodotoluene difluoride 1 was electrochemically prepared
from p-iodototoluene in Et3N–5HF9 and used for further
reaction without isolation. (E)-(2-Fluoroalk-1-enyl)(4-methyl-
phenyl)iodonium fluoride (2), which was stable and could be
isolated and characterized, was used for the further trans-
formation without isolation. The iodonation of 2 by modifica-
tion of the reported procedure12 provided (E)-2-fluoro-1-io-
doalk-1-enes (3) in good yields (Table 1).‡ The reaction can be
carried out without the protection of functionalities such as
ketones, esters, and even hydroxy groups in alkynes. Further
application of this method to the stereoselective synthesis of
fluoroalkenes is under investigation.
3
CNC Stereochemistry of 3a–g was determined from JH–F data. Stereo-
specificities of > 98% are indicated by GC, and 1H and 19F NMR
spectroscopy. Spectral data for 2a: dH(400 MHz, CDCl3) 7.866 (d, J 8.3, 2
H), 7.2015 (d, J 8.3, 2 H), 6.725 (d, J 15.125, 1 H), 2.662–2.754 (m, 2 H),
2.361 (s, 3 H). 1.167–1.576 (m, 14 H), 0.881 (t, 7.1, 3 H); dF(84.67 MHz,
CDCl3)(C6F6 as an internal standard) 269.131 to 269.834 (m, 1 F). For 3d:
dH(400 MHz, CDCl3) 5.67 (d, J 17.81, 1 H), 3.67 (s, 3 H), 2.50 (dt, J 7.32,
22.4 Hz, 2 H), 2.31 (t, J 7.56, 2 H), 1.64–1.51 (m, 4 H), 1.35–1.31 (m, 8 H);
dF(84.67 MHz, CDCl3)(C6F6 as an internal standard) 281.969 to 282.721
(m, 1 F); n(neat)/cm21 1735 and 1650.
1 M. Schlosser, Tetrahedron, 1978, 34, 3 and references cited therein.
2 J. R. McCarthy, E. T. Jarvi, D. P. Matthews, M. L. Edwards,
N. J. Prakash, T. L. Bowlin, S. Mehdi, P. S. Sunkara and P. Bey, J. Am.
Chem. Soc., 1989, 111, 1127.
Notes and References
† E-mail: Hara@org-mc.eng.hokudai.ac.jp
‡ Typical experimental procedure: p-iodotoluene difluoride was electro-
chemically prepared in a divided cell made of TeflonTM PFA with a
NafionTM 117 film using two smooth Pt Sheets (20 3 20 mm) for the anode
and cathode. p-Iodotoluene (3 mmol) and Et3N–5HF (22 ml) were
introduced into the anodic cell and Et3N–5HF (22 ml) was introduced into
the cathodic cell. The electrolysis was carried out under constant electricity
(50 mA h21) until 2 F mol21 of electricity was passed. The resulting Et3N–
5HF solution of p-iodotoluene difluoride in the anodic cell was used for
further reaction. Methyl undec-10-ynoate (293 mg, 2 mmol) and CH2Cl2 (6
3 A. Francesch, R. Alvarez, S. Lo´pez and A. R. de Lera, J. Org. Chem.,
1997, 62, 310.
4 (a) P.-Y. Kwork, F. W. Muellner and J. Fried, J. Am. Chem. Soc., 1987,
109, 3692; (b) D. Michel and M. Schlosser, Synthesis, 1996, 1007; (c)
P. H. Buist, B. Behrouzian, K. A. Alexopoulos, B. Dawson and
B. Black, Chem. Commun., 1996, 2671.
5 M. L. Boys, E. W. Collington, H. Finch, S. Swanson and J. F.
Whitehead, Tetrahedron Lett., 1988, 29, 3365; H. Nakai, N. Hamanaka,
H. Miyake and M. Hayashi, Chem. Lett., 1979, 1499.
Chem. Commun., 1998
965
Hara, Shoji
