Stereoselective synthesis of iodofluoroalkenes by iodofluorination of alkynes using IF5-pyridine-HF

Article abstract of DOI:10.1016/j.tetlet.2016.02.063

The iodofluorination of alkynes was carried out using IF₅-pyridine-HF and hydroquinone. The iodofluorination of an internal alkyne and a terminal alkyne proceeded stereoselectively to give the corresponding iodofluoroalkenes. An unsymmetrically

Full text of DOI:10.1016/j.tetlet.2016.02.063

Tetrahedron Letters 57 (2016) 1379–1381
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of iodofluoroalkenes by iodofluorination
of alkynes using IF5-pyridine-HF
⇑
Hitoshi Ukigai, Shoji Hara
Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The iodofluorination of alkynes was carried out using IF5-pyridine-HF and hydroquinone. The iodofluori-
nation of an internal alkyne and a terminal alkyne proceeded stereoselectively to give the corresponding
iodofluoroalkenes. An unsymmetrically substituted internal alkyne and electron deficient alkyne also
afforded the corresponding iodofluoroalkenes stereoselectively. The iodofluoroalkenes thus obtained
were used in the stereoselective synthesis of di- and trisubstituted fluoroalkenes.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 8 January 2016
Revised 12 February 2016
Accepted 16 February 2016
Available online 16 February 2016
Keywords:
Iodofluorination
Iodofluoroalkene
Fluoroalkene
Stereoselective synthesis
IF5-pyridine-HF
Introduction
R1
F
I
IF5-pyridine-HF
reductant
R1C CR2
The iodofluorination reaction of alkynes has been conveniently
used for the stereoselective synthesis of iodofluoroalkenes,1 key
intermediates for the synthesis of di- or trisubstituted fluo-
roalkenes.2 Generally, iodofluorination reaction is performed using
the ‘IF’ species generated in situ from I+ and FÀ sources, and various
types of I+ and FÀ sources have been used. The conventional iod-
ofluorination reaction has been successfully applied to internal
alkyne, however, terminal alkynes afforded the expected iodofluo-
rination products in low yields, because of the formation of by-
products such as 1-iodo-1-alkyne.1i Therefore, more convenient
and effective reagents are required for iodofluorination of
R2
1
2
Scheme 1.
(Table 1). When KI was used as the reductant, 1,2-diiododo-1-
dodecene (3a) and 1-iodo-1-dodecyne (4a) were formed instead
of the desired trans-1-iodo-2-fluoro-1-dodecene (2a). When I2
was used as the reductant, 2a was formed in 48% yield, however,
3a and 4a were also formed. On the other hand, when catechol
was used as the reductant, 2a was formed selectively in 75% yield.
The best result was obtained when hydroquinone was used, and 2a
was obtained in 82% yield.
The iodofluorination of the various alkynes was carried out
using IF5-pyridine-HF and hydroquinone (Table 2). From terminal
alkynes, the desired (E)-1-iodo-2-fluoro-1-alkenes were obtained
stereo- and regioselectively (entries 1, 2, 4, 7, and 8). In the reac-
tion with internal alkynes, both symmetrically substituted alkynes
(1c, e) and unsymmetrically substituted alkynes (1f, i–k), gave the
corresponding iodofluoroalkenes stereo- and regioselectively
(entries 3, 5, 6, and 9–11). The iodofluorination of electron
deficient alkynes such as 1j and 1k was previously unknown.
Nevertheless, their iodofluorination using IF5-pyridine-HF and
hydroquinone successfully afforded the corresponding iodofluo-
roalkenes (2j) and (2k) stereo- and regioselectively5 (entries 10
and 11).
alkynes. Recently, we reported
a stable hypervalent iodine
reagent, IF5-pyridine-HF, and its application to fluorination
reactions.3 We also reported the iodofluorination of alkenes using
the ‘IF’ species generated from IF5-pyridine-HF and a reductant.4
In this study, the iodofluorination of alkynes was investigated
using IF5-pyridine-HF and a reductant to develop a more conve-
nient and effective method for the synthesis of iodofluoroalkenes
(Scheme 1).
Results and discussion
Initially, the iodofluorination of 1-dodecyne (1a) with IF5-pyri-
dine-HF was carried out in the presence of various reductants
⇑
Corresponding author. Tel./fax: +81 11 7066556.
E-mail address: shara@eng.hokudai.ac.jp (S. Hara).
http://dx.doi.org/10.1016/j.tetlet.2016.02.063
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

1380
H. Ukigai, S. Hara / Tetrahedron Letters 57 (2016) 1379–1381
Table 1
OH
OH
Iodofluorination of 1a using IF5-pyridine-HF and various reductantsa
-pyridine-HF
- 4 HF
IF -pyridine-HF
+ 2
5
IF5-pyridine-HF
C10H21C CH
reductant, CH2Cl2
1a
O
R1C CR2
R1
F
I
C
10H21
C
10H21
I
I
+
+
C
10H21C C-I
1
"IF"
+
2
R2
F
2a
H
I
H
4a
O
3a
2
Yield of 2ab (%)
Yield of 3ac (%)
Yield of 4ac (%)
Scheme 2.
Reductant
KI
I2
0
30
31
0
70
12
0
48
75
82
The iodofluoroalkenes thus obtained can be used for the stere-
oselective synthesis of di- and trisubstituted fluoroalkenes. The
Suzuki–Miyaura coupling reaction of (E)-1-iodo-2-fluorododec-1-
ene 2a with organoboranes afforded disubstituted fluoroalkenes
(5) and (6) stereoselectively8 (Scheme 3).
Next, we attempted to synthesize trisubstituted fluoroalkene
(7) by the cross-coupling reaction of ethyl (E)-2-iodo-1-fluoro-1-
phenylpent-1-ene (2f) with phenylboronic acid.9 However, the
cross-coupling reaction of 2f with phenylboronic acid was sluggish,
and 2f decomposed during the reaction without the formation of 7.
This problem could be overcome using phenyltriolborate (8)10
instead of phenylboronic acid, and the desired 7 was obtained in
92% yield. Moreover, trisubstituted fluoroalkenes having three dif-
ferent substituents were also synthesized. Thus, the Sonogashira
reaction of 2f with 1-hexyne, and Suzuki–Miyaura coupling of 2j
with 8 afforded the corresponding trisubstituted fluoroalkenes
(9) and (10) stereoselectively (Scheme 4).
Catechol
Hydroquinone
0
0
a
The reaction was carried out at room temperature for 12 h using 2.0 equiv of
IF5-pyridine-HF and reductant to 1a.
b
19F NMR yield.
GC yield.
c
In the present reaction, IF5-pyridine-HF was reduced by hydro-
quinone to give IF species which added to alkyne as shown in
Scheme 2. Formation of p-quinone was confirmed in the reaction
mixture. As the IF species is unstable in solution, it is difficult to
decide the real active species which caused the selectivity of the
present reaction. However, it was reported that the reactivity of
the IF species is dependent on the reagents used.7 Therefore, choice
of the reducing reagent is important to realize the desired
selectivity.
Table 2
Iodofluorination reaction of alkynes using IF5-pyridine-HF and hydroquinonea
Entry
1
Alkyne
Reaction time (h)
Product
Yieldb (%)
65 (82)
C10H21C CH
C10H21
I
12
2a
1a
F
H
I
CH2C CH
1b
2
20
(67)
2b
F
H
PrC CPr
Pr
I
2c
3
15
11
15
12
19
20
14
24
17
71 (87)
(68)
1c
F
Ph
Pr
I
PhC CH
2d
2e
4
1d
F
Ph
H
I
PhC CPh
5
72 (90)
71 (99)
60 (73)
60 (72)
(65)
1e
F
Ph
Ph
I
PhC CMe
2f
6
1f
F
Me
AcO (CH2)9C CH
AcO-(CH2)9
I
H
7
2g
1g
F
i-PrOOC (CH2)8C CH
i-PrOOC(CH2)8
I
2h
8
1h
F
H
PhSC CMe
PhS
I
9c
10d
11
2i
1i
Me
F
MeC C-COOEt
Me
I
2j
67 (78)
81 (87)
1j
F
Ph
COOEt
I
PhC C-C-Me
2k
1k
O
F
COMe
a
b
c
If otherwise not mentioned, the reaction was carried out at room temperature in CH2Cl2 using 2 equiv of IF5-pyridine-HF and hydroquinone.
Isolated yield based on alkyne used. In parentheses, 19F NMR yield.
1.2 equiv of IF5-pyridine-HF and hydroquinone were used.
d
The reaction was carried out in (CH2Cl)2 at 60 °C using 4 equiv of IF5-pyridine-HF and hydroquinone.

H. Ukigai, S. Hara / Tetrahedron Letters 57 (2016) 1379–1381
1381
References and notes
C
10H21
I
PhB(OH)2, Pd cat.,KOH
benzene, 80 °C 1h
C10
H
21 Ph
H
F
H
1. (a) Olah, G. A.; Nojima, M.; Kerekes, I. Synthesis 1973, 780; (b) Zupan, M.
Synthesis 1976, 473; (c) Olah, G. A.; Welch, J. T.; Vankar, Y. D.; Nojima, M.;
Kerekes, I.; Olah, J. A. J. Org. Chem. 1979, 44, 3872; (d) Barluenga, J.; Rodríguez,
M. A.; González, J. M.; Campos, P. J.; Asensio, G. Tetrahedron Lett. 1986, 27,
3303; (e) Gregorcic, A.; Zupan, M. Bull. Chem. Soc. Jpn. 1987, 60, 3083; (f)
Eddarir, S.; Francesch, C.; Mestdagh, H.; Rolando, C. Bull. Soc. Chim. Fr. 1997,
134, 741; (g) Shelhamer, D. F.; Jones, B. C.; Pettus, B. J.; Pettus, T. L.; Stringer, J.
M.; Heasley, V. L. J. Fluorine Chem. 1998, 88, 37; (h) Kobayashi, S.; Sawaguchi,
M.; Ayuba, S.; Fukuhara, T.; Hara, S. Synlett 2001, 1938; (i) Conte, P.; Panunzi,
B.; Tingoli, M. Tetrahedron Lett. 2006, 47, 273.
2. As for the review and book, see: (a) Hara, S. In Fluorine-Containing Synthons;
Soloshonok, V. A., Ed.; American Chemical Society: Washington, DC, 2005; pp
120–134; (b) Yanai, H.; Taguchi, T. Eur. J. Org. Chem. 2011, 5939; (c) Landelle,
G.; Bergeron, M.; Turcotte-Savard, M.-O.; Paquin, J.-F. Chem. Soc. Rev. 2011, 40,
2867; (d) Hara, S. In Top. Curr. Chem.; Wang, J., Ed.; Springer: Berlin, Heidelberg,
2012; Vol. 327, pp 59–86.
F
2a
67%
5
Bu
Bu
Pd cat.,KOH
C10H21
F
BPin
2a
benzene, 80 °C 1h
H
73%
6
Scheme 3.
O
K
3. (a) Hara, S.; Monoi, M.; Umemura, R.; Fuse, C. Tetrahedron 2012, 68, 10145; (b)
Kunigami, M.; Hara, S. J. Fluorine Chem. 2014, 167, 101; (c) Kunigami, M.; Hara,
S. Carbohydr. Res. 2015, 417, 78; (d) Inoue, T.; Fuse, C.; Hara, S. J. Fluorine Chem.
2015, 179, 48.
PhB
O
O
Ph
F
Ph
Me
8
Ph
Pd(OAc)2
I
DMF-H2O, 60 °C, 6 h
4. Yano, S.; Hara, S. Synthesis 2015, 47, 2839.
F
Me
5. Typical procedure: To a CH2Cl2 solution (5 mL) of IF5-pyridine-HF (321 mg,
1 mmol) and 1-dodecyne (83 mg, 0.5 mmol) in a TeflonTM vessel was added
hydroquinone (110 mg, 1 mmol) at 0 °C, and the mixture was stirred at 0 °C for
30 min and at room temperature overnight. The solid materials was removed
2f
7
92%
by filtration through
a celite, and the filtrate was washed with aqueous
Ph
C
C-Bu
Pd(PPh3)4
HC C-Bu
CuI, Et3N, THF
rt, 24 h
NaHCO3, and aqueous Na2S2O3, successively. The organic layer was dried over
MgSO4 and concentrated under reduced pressure. Purification by column
chromatography (silica gel, hexane) gave 2a in 65% yield (101 mg, 0.33 mmol).
19F NMR yield was obtained using fluorobenzene as an internal standard. IR
2f
F
Me
77%
9
(neat) 2925, 1651, 1086 cmÀ1 1H NMR (400 MHz) d 5.66 (d, J = 17.6 Hz, 1H),
;
2.54–2.45 (m, 2H), 1.57–1.54 (m, 2H), 1.27 (br s, 14H), 0.88 (t, J = 6.4 Hz, 3H);
19F NMR (376 MHz) d À82.15 to 82.32 (m, 1F) [lit.6 À82.25 (dt, J = 23.0,
1
2
J = 17.7 Hz, 1F)]; 13C NMR (100 MHz) d 164.6 (d, JC–F = 265.4 Hz), 55.0 (d, JC–
F = 40.2 Hz), 32.2, 31.3 (d, 2JC–F = 25.8 Hz), 30.0, 29.9, 29.7, 29.6, 29.1, 26.1, 23.0,
14.5.
Me
Me
F
8
Pd(OAc)2
I
Ph
DMF-H2O, rt, 22 h
F
COOEt
COOEt
10
2j
6. Yoshida, M.; Ota, D.; Fukuhara, T.; Yoneda, N.; Hara, S. J. Chem. Soc., Perkin Trans.
1 2002, 384.
70%
7. Shellhamer, D. F.; Jones, B. C.; Pettus, B. J.; Pettus, T. L.; Stringer, J. M.; Heasley,
V. L. J. Fluorine Chem. 1988, 88, 37.
Scheme 4.
8. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
9. As for the synthesis of trisubstituted fluoroalkenes, see: (a) Chen, C.; Wilcoxen,
K.; Zhu, Y.-F.; Kim, K.; McCarthy, J. R. J. Org. Chem. 1999, 64, 3476; (b) Tsai, H.-J.;
Lin, K.-W.; Ting, T.; Burton, D. J. Helv. Chem. 1999, 82, 2231; (c) Landelle, G.;
Champagne, P. A.; Barbeau, X.; Paquin, J.-F. Org. Lett. 2009, 11, 681; (d) Cao, C.-
R.; Ou, S.; Jiang, M.; Liu, J.-T. Org. Biomol. Chem. 2014, 12, 467.
10. (a) Yamamoto, Y.; Takizawa, M.; Yu, X.-Q.; Miyaura, N. Angew. Chem., Int. Ed.
2008, 47, 928; (b) Li, G.-Q.; Yamamoto, Y.; Miyaura, N. Tetrahedron 2011, 67,
6804; (c) Li, G.-Q.; Yamamoto, Y.; Miyaura, N. Synlett 2011, 1769; (d)
Yamamoto, Y. Heterocycles 2012, 85, 799; (e) Sakashita, S.; Takizawa, M.;
Sugai, J.; Ito, H.; Yamamoto, Y. Org. Lett. 2013, 15, 4308.
Acknowledgments
We are grateful to prof. Yasunori Yamamoto (Hokkaido Univer-
sity) for his helpful advice on the Suzuki–Miyaura coupling using
triolborate, and Daikin industries, Ltd for their donation of IF5.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.02.
063.