Stereoselective synthesis of 4-fluoro-1,3-alkadienylboronates and their application in the stereoselective synthesis of fluoropolyenes

Article abstract of DOI:10.1016/j.jfluchem.2007.07.009

(1E,3E)- and (1E,3Z)-4-fluoro-1,3-alkadienylboronates were stereoselectively prepared by the Heck-reaction of a vinylboronate with (E)- or (Z)-2-fluoro-1-alkenyliodonium salts, and applied to the Suzuki-Miyaura coupling reaction for the synthesis of fluor

Full text of DOI:10.1016/j.jfluchem.2007.07.009

Journal of Fluorine Chemistry 128 (2007) 1444–1448
www.elsevier.com/locate/fluor
Stereoselective synthesis of 4-fluoro-1,3-alkadienylboronates
and their application in the stereoselective
synthesis of fluoropolyenes
*
Miho Sakai, Tong Guan, Shoji Hara
Division of Chemical Process Engineering, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
Received 23 June 2007; received in revised form 16 July 2007; accepted 24 July 2007
Available online 31 July 2007
Abstract
(1E,3E)- and (1E,3Z)-4-fluoro-1,3-alkadienylboronates were stereoselectively prepared by the Heck-reaction of a vinylboronate with (E)- or
(Z)-2-fluoro-1-alkenyliodonium salts, and applied to the Suzuki–Miyaura coupling reaction for the synthesis of fluoropolyenes.
# 2007 Elsevier B.V. All rights reserved.
Keywords: Heck-reaction; Fluoroalkadienylboronates; Suzuki–Miyaura coupling; Fluoropolyene; Fluoroalkenyliodonium salts
1. Introduction
2. Result and discussion
Polyene natural products that exhibit significant bioactiv-
ities are widely known in nature [1,2]. The fluorinated
analogs of the polyene are of great interest for studying their
actions in vivo and the modification of their activities [3–8].
Fluorodienylmetals (1) are effective as building blocks for the
synthesis of polyene analogs with fluorine attached to the
double bonds [5,8]. Although fluorodienylboronates (1,
M = B in Scheme 1) can be used as building blocks for
the synthesis of various fluoropolyenes by the Suzuki–
Miyaura coupling reaction [9], they have not yet been
synthesized.
In the Heck-reaction of the vinylboronates with haloalkenes,
the Suzuki–Miyaura coupling reaction competes to give dienes
and the yield of the desired dienylboronates decreases [10].
Recently, Whiting co-workers successfully depressed the
undesired Suzuki–Miyaura coupling using 4,4,6-trimethyl-2-
vinyl-1,3,2-dioxaborinane as the vinylboronate and performing
the reaction at a high temperature [11]. However, under the same
conditions, the Heck-reaction of (E)-2-fluoro-1-iodoalkenes (2)
with vinylboronates such as 4,4,6-trimethyl-2-vinyl-1,3,2-
dioxaborinane or 4,4,5,5-tetramethyl-2-vinyl-[1,3,2]-dioxabor-
olane (7) proceeded non-selectively to give a mixture of
products, e.g. (E)- and (Z)-fluorodienylboronates, and the
Suzuki–Miyaura coupling product. Alkenyliodonium salts are
more reactive than the corresponding iodides in the cross-
coupling reaction [15,16], and therefore, the Heck-reaction of
(E)-2-fluoro-1-dodecenyl iodonium salt (3a) with 4,4,5,5-
tetramethyl-2-vinyl-[1,3,2]-dioxaborolane (7) was examined
(Table 1). As expected, the reaction proceeded at room
temperature and the desired (1E,3E)-4-fluoro-1,3-tetradecadie-
nylboronate (5a) was obtained stereoselectively (>95%). Under
those conditions, (2-tolylvinyl)boronate (9), the Heck-reaction
product with a tolyl group on 3a, and 4-fluoro-1,3-tetradecadiene
(8), the Suzuki–Miyaura coupling product, were also formed as
by-products [17]. As reported previously, amine is superior to
K2CO3 as a base to selectively obtain the Heck product (entries 2
Alkadienylboronates are synthesized by the Heck-reaction
of vinylboronates (4) with haloalkenes and used for
polyene synthesis [10,11]. Recently, we succeeded in the
stereoselective synthesis of (E)- and (Z)-2-fluoro-1-iodoalk-
enes (2) and 2-fluoroalkenyliodonium salts (3) [12–14]. For
the synthesis of fluoroalkadienylboronates (5) and their
application in the synthesis of fluoropolyenes (6), we
examined the Heck-reaction of vinylboronates (4) with 2-
fluoro-1-iodoalkenes 2 and 2-fluoroalkenyliodonium salts 3
(Scheme 2).
* Corresponding author. Fax: +81 11 706 6556.
E-mail address: hara@org-mc.eng.hokudai.ac.jp (S. Hara).
0022-1139/$ – see front matter # 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2007.07.009

M. Sakai et al. / Journal of Fluorine Chemistry 128 (2007) 1444–1448
1445
Table 1
Synthesis of fluoroalkadienylboronate by Heck-reaction using fluoroalkenyliodonium salta
Entry
Solvent
Base
Yield of 5a (%)b
Yield of 8 and 9 (%)c
8
9
1
2
3
4
5
Toluene
DMF
THF
Bu3N
Bu3N
Bu3N
K2CO3
Bu3N
40 (97)
60 (96)
60 (97)
19 (96)
65 (96)d
2
10
10
6
3
4
3
2
3
DMF
DMF
5
a
lf otherwise not mentioned, the reaction was carried out using 1.2 eq of 7, 1.2 eq of base, and 5 mol% of Pd(OAc)2.
Isolated yield base on 3a. In parentheses, stereoselectivity, and a (1E,3Z)-isomer was formed as by-product.
Determined by GC.
b
c
d
2.4 eq of 7 was used.
Table 2
Synthesis of fluoroalkadienylboronates by Heck-reaction using various fluoroalkenyliodonium salta
Entry
1
Fluoroalkenyliodonium salt 3
Products
Yield of 5(%)b
65 (96)
2
57 (95)
3
4
60 (97)
60 (98)
5
55 (95)
46 (94)
6
a
lf otherwise not mentioned, the reaction was carried out using 2.4 eq of 7, 1.2 eq of Bu3N, and 5 mol% of Pd(OAc)2.
lsolated yield base on 3. In parentheses, stereoselectivity determined by 19F NMR.
b

1446
M. Sakai et al. / Journal of Fluorine Chemistry 128 (2007) 1444–1448
3. Conclusion
In conclusion, various (1E,3E)- and (1E,3Z)-4-fluoro-1,3-
alkadienylboronates were stereoselectively prepared by the
Heck-reaction of 4,4,5,5-tetramethyl-2-vinyl-[1,3,2]-dioxabor-
olane with (E)- or (Z)-2-fluoro-1-alkenyliodonium salts. The
reaction proceeded at room temperature and the pure
fluoroalkadienylboronates were isolated by column chromato-
graphy. The resulting fluoroalkadienylboronates can be used for
the synthesis of fluoropolyenes by the Suzuki–Miyaura
coupling reaction with aryl or alkenyl halides.
Scheme 1.
4. Experimental
4.1. General methods
The IR spectra were recorded using a JASCO FT/IR-410
spectrophotometer. The 1H NMR (400 MHz) spectra, 19F NMR
(376 MHz) spectra and 13C NMR (100 MHz) spectra were
recorded in CDCl3 on a JEOL JNM-A400II FT NMR spectro-
meter and the chemical shift, d, are referred to TMS (1H, 13C) and
CFCl3 (19F), respectively. The EI-high-resolution mass spectra
were measured on a JEOL JMS-700TZ spectrometer.
Scheme 2.
and 4) [18]. When the reaction was carried out using Bu3N as a
base and 2.4 eq of 7 to 3a, 5awas obtained in 65% yield (entry 5).
Under these conditions, 8 (5% yield) and 9 (3% yield), which can
be separated from 5a by silica gel column chromatography, were
also formed.
(E)-2-Fluoroalkenyliodonium salts 3a–e was prepared from
the corresponding alkynes and iodotoluene difluoride according
to a literature [13]. (Z)-2-Fluoroalkenyliodonium salt 3f was
prepared from the corresponding 1-alkyne in two steps
according to the literatures [14]. 4,4,5,5-Tetramethyl-2-vinyl-
[1,3,2]-dioxaborolane 7 was purchased from Aldrich or
prepared according to the literature [19].
Various 2-fluoroalkenyliodonium salts (3a–f) were used in
the synthesis of 4-fluoro-1,3-alkadienylboronates 5a–f
(Table 2). When (E)-fluoroalkenyliodonium salts (3a–e) were
used, the corresponding (1E,3E)-4-fluoro-1,3-alkadienylbor-
onates (5a–e) were obtained in 55-65% yield with good
stereoselectivity (94–98%). Functional groups such as
ketone and ester can tolerate these reaction conditions,
and functionalized fluoroalkadienylboronates (5c–e) were
obtained (entries 3–5). On the other hand, the reaction with
(Z)-fluoroalkenyliodonium salt (3f) proceeded less selec-
tively, and the desired (1E, 3Z)-4-fluoro-1,3-alkadienylbor-
onate (5f) was obtained in lower yield (46%) with a significant
amount of the Suzuki–Miyaura coupling product (20%) (entry
6) [17].
4.2. Synthesis of fluoroalkadienylboronates
4.2.1. (1E,3E)-2-(4-Fluoro-1,3-tetradecadienyl)-4,4,5,5-
tetramethyl-[1,3,2]-dioxaborolane (5a)
A mixture of Pd(OAc)2 (11 mg, 0.05 mmol), Bu3N (110 mg,
0.6 mmol), 3a (238 mg, 0.5 mmol), and 7 (185 mg, 1.2 mmol)
in DMF (1.5 ml) was stirred under N2 atmosphere at room
temperature for 2 h. Then, the mixture was poured into water
and extracted with ether three times. The combined organic
layers were dried over MgSO4 and concentrated under reduced
pressure. Purification by column chromatography (silica gel/
hexane–ether) gave 5a (110 mg, 0.33 mmol) in 65% yield. IR
The resulting fluoroalkadienylboronates 5 can be used for
fluoropolyene synthesis by the Suzuki–Miyaura coupling
reaction. When 5a was subjected to the coupling reaction
with ethyl 4-iodobenzoate (10), arylated (1E,3E)-4-fluorote-
tradecadiene (12) was obtained in good yield. Simi-
larly, (1E,3E,5E)-1-phenyl-6-fluorohexadecatriene (13) was
obtained by the coupling reaction with b-bromostyrene (11)
(Scheme 3).
1
(neat) 2927, 1665, 1145 cmÀ1. H NMR d 0.88 (t, J = 6.8 Hz,
3H), 1.27 (s, 12H), 1.27–1.31 (m, 14H), 1.52–1.54 (m, 2H),
2.42 (dt, J = 23.4, 7.3 Hz, 2H), 5.48 (d, J = 17.5 Hz, 1H), 5,82
(dd, J = 19.8, 11.2 Hz, 1H), 6.97 (dd, J = 17.5, 11.3 Hz, 1H).
19F NMR d À95.64 (dt, J = 19.6, 23.3 Hz, 1F). 13C NMR d
14.10, 22.67, 24.73 (4C), 26,32, 28.64 (d, J = 25.9 Hz), 28.98,
29.29, 29.31, 29.46, 29.55, 31.88, 83.15 (2C), 110.62 (d,
J = 26.5 Hz), 142.99 (d, J = 12.4 Hz), 166.10 (d, J = 261.2 Hz).
HRMS (EI): calc. for C20H36O2FB: 338.2792, found 338.2794.
4.2.2. (1E,3E)-2-(5-Cyclohexyl-4-fluoro-1,3-pentadienyl)-
4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane (5b)
IR (neat) 2926, 1663, 1608, 1331, 1146 cmÀ1. H NMR d
1.16–1.26 (m, 10H), 1.28 (s, 12H), 1.64–1.72 (m, 1H), 2.31 (dd,
1
Scheme 3.

M. Sakai et al. / Journal of Fluorine Chemistry 128 (2007) 1444–1448
1447
J = 24.5, 7.1 Hz, 2H), 5.47 (d, J = 17.5 Hz, 1H), 5.87 (dd,
J = 20.1, 11.2 Hz, 1H), 6.93 (dd, J = 17.5, 11.2 Hz, 1H). 19F
NMR d À93.15 (dt, J = 20.2, 24.4 Hz, 1F). 13C NMR d 24.73
(4C), 26.13 (2C), 26.25, 32.86 (2C), 35.40, 36.33 (d,
J = 26.0 Hz), 83.13 (2C), 111.73 (d, J = 26.6 Hz), 143.00 (d,
J = 12.1 Hz), 164.99 (d, J = 261.2 Hz). HRMS (EI): calc. for
C17H28O2FB: 294.2166, found 294.2149.
(2C), 83.11, 108.72 (d, J = 11.4 Hz), 141.42 (d, J = 5.7 Hz),
163.14 (d, J = 269.9 Hz), 171.19.
4.3. Suzuki–Miyaura reaction using 5a
4.3.1. Ethyl 4-{(1E,3E)-4-fluoro-1,3-
tetradecadienyl}benzoate (12)
4.2.3. (1E,3E)-2-(13-Acetoxy-4-fluoro-1,3-tridecadienyl)-
4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane (5c)
A mixture of Pd(PPh3)4 (28.8 mg, 0.025 mmol), ethyl p-
iodobenzoate (166 mg, 0.6 mmol), 5a (169 mg, 0.5 mmol), aq
K2CO3 (0.6 ml of 2 M solution), and EtOH (0.6 ml) in toluene
(5 ml) was stirred under N2 atmosphere at 80 8C for 20 h. The
mixture was poured into water and extracted with ether three
times. Combined organic layers were dried over MgSO4 and
concentrated under reduced pressure. Purification by column
chromatography (silica gel/hexane-ether) gave 12 (153 mg,
0.43 mmol) in 85% yield. IR (neat) 2926, 2855, 1718, 1665,
IR (neat) 2931, 1741, 1664, 1608, 1335, 1240, 1146 cmÀ1
.
1H NMR d 1.27 (s, 12H), 1.27–1.30 (m, 10H), 1.55–1.62 (m,
4H), 2.05 (s, 3H), 2.42 (dt, J = 23.4, 7.6 Hz, 2H), 4.05 (t,
J = 6.7 Hz, 2H), 5.48 (d, J = 17.5 Hz, 1H), 5.82 (dd, J = 19.8,
11.3 Hz, 1H), 6.96 (dd, J = 17.6, 11.4 Hz, 1H). 19F NMR d
À95.70 (dt, J = 19.5, 23.2 Hz, 1F). 13C NMR d 20.81, 24.59
(4C), 25.73, 26.14, 28.43. 28.50 (d, J = 26.2 Hz), 28.75, 29.03,
29.09, 29.17, 64.45, 83.01 (2C), 110.53 (d, J = 26.2 Hz), 142.79
(d, J = 12.4 Hz), 165.84 (d, J = 261.3 Hz), 171.04. HRMS (EI):
calc. for C21H36O4FB: 382.2690, found 382.2681.
1
1604, 1276 cmÀ1. H NMR d 0.87 (t, J = 7.1 Hz, 3H), 1.26–
1.43 (m, 14H), 1.40 (t, J = 7.1 Hz, 3H), 1.55–1.61 (m, 2H),
2.46 (dt, J = 23.4, 7.4 Hz, 2H), 4.37 (q, J = 7.1 Hz, 2H), 5.93
(dd, J = 19.5, 11.3 Hz, 1H), 6.49 (d, J = 15.5 Hz, 1H), 6.78 (dd,
J = 15.1, 11.5 Hz, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.98 (d,
J = 8.3 Hz, 2H). 19F NMR d À96.81 (dt, J = 19.9, 23.1 Hz, 1F).
13C NMR d 14.01, 14.22, 22.59, 26.30, 28.62 (d, J = 26.8 Hz),
28.87, 29.24, 29.26, 29.44, 29.52, 31.81, 60.72, 108.56 (d,
J = 28.4 Hz), 124.53 (d, J = 11.2 Hz), 125.66 (2C), 128.79,
129.58(d, J = 10.1 Hz), 129.82 (2C), 141.72, 164.80 (d,
J = 259.4 Hz), 166.20. HRMS(EI) calc. for C23H33FO2:
360.2464, found: 360.2470.
4.2.4. Methyl (10E,12E)-10-fluoro-13-(4,4,5,5-tetramethyl-
[1,3,2]-dioxaborolan-2-yl)-10, 12-tridecadienoate (5d)
1
IR (neat) 2932, 1740, 1664, 1608, 1335 cmÀ1. H NMR d
1.27 (s, 12H), 1.27–1.31 (m, 8H), 1.43–1.62 (m, 4H), 2.30 (t,
J = 7.6 Hz, 2H), 2.42 (dt, J = 23.4, 7.6 Hz, 2H), 3.67 (s, 3H),
5.48 (d, J = 17.6 Hz, 1H), 5.82 (dd, J = 19.7, 11.2 Hz, 1H), 6.96
(dd, J = 17.6, 11.2 Hz, 1H). 19F NMR d À95.71 (dt, J = 20.2,
23.2 Hz, 1F). 13C NMR d 24.63 (4C), 24.77, 26.16, 28.54 (d,
J = 26.5 Hz), 28.75, 28.94 (2C), 29.01, 33.92, 51.28, 83.03
(2C), 110.56 (d, J = 26.5 Hz), 142.80 (d, J = 12.4 Hz), 165.86
(d, J = 261.3 Hz), 174.10. HRMS (EI): calc. for C20H34O4FB:
368.2534, found 368.2526.
4.3.2. (1E,3E,5E)-6-Fluoro-1-phenyl-1,3,5-hexadecatriene
(13)
A mixture of Pd(PPh3)4 (28.8 mg, 0.025 mmol), (E)-b-
bromostyrene (165 mg, 0.9 mmol), 5a (169 mg, 0.5 mmol), aq
KOH (0.6 ml of 2M solution), and EtOH (0.6 ml) in toluene
(5 ml) was stirred under N2 atmosphere at 50 8C for 2 h. The
mixture was poured into water and extracted with ether three
times. Combined organic layers were dried over MgSO4 and
concentrated under reduced pressure. Purification by column
chromatography (silica gel/hexane-ether) gave 13 (110 mg,
0.35 mmol) in 70% yield. IR (neat) 2926, 2854, 1663, 1604,
984 cmÀ1. 1H NMR d 0.87 (t, J = 6.5 Hz, 3H), 1.26 (brs, 14H),
1.31–1.58 (m, 2H), 2.39 (dt, J = 23.4, 7.3 Hz, 2H), 5.84 (dd,
J = 19.6, 10.1 Hz, 1H), 6.22–6.35 (m, 2H), 6.51 (d, J = 15.6 Hz,
1H), 6.83 (dd, J = 15.4, 9.5 Hz, 1H), 7.21–7.40 (m, 5H). 19F
NMR d À98.91 (dt, J = 19.9, 23.1 Hz, 1F). 13C NMR d 14.11,
22.68, 26.41, 28.65 (d, J = 27.1 Hz), 28.98, 29.32, 29.33, 29.51,
29.58, 31.89, 108.69 (d, J = 28.2 Hz), 126.21 (2C), 126.35 (d,
J = 10.8 Hz), 127.34, 128.60 (2C), 129.06, 131.44, 131.50 (d,
J = 7.2 Hz), 137.39, 163.81 (d, J = 258.0 Hz). HRMS (EI):
calc. for C22H31F: 314.2410, found: 314.2415.
4.2.5. (12E,14E)-12-Fluoro-2,2-dimethyl-15-(4,4,5,5-
tetramethyl-[1,3,2]-dioxaborolan-2-yl)-12, 14-
pentadecadien-3-one (5e)
1
IR (neat) 2931, 1705, 1664, 1608, 1334 cmÀ1. H NMR d
1.13 (s, 9H), 1.27 (s, 12H), 1.27–1.30 (m, 8H), 1.54–1.55 (m,
4H), 2.37–2.48 (m, 4H), 5.48 (d, J = 17.5 Hz, 1H), 5.82 (dd,
J = 19.8, 11.2 Hz, 1H), 6.96 (dd, J = 17.6, 11.4 Hz, 1H). 19F
NMR d À95.67 (dt, J = 19.9, 23.5 Hz, 1F). 13C NMR d 23.85,
24.72 (4C), 26.28, 26.37 (3C), 28.66 (d, J = 26.5 Hz), 28.91,
29.20, 29.22, 29.31, 36.35, 44.05, 83.13 (2C), 110.62 (d,
J = 26.6 Hz), 142.93 (d, J = 12.4 Hz), 166.02 (d, J = 261.5 Hz),
216.08. HRMS (EI) calc. for C23H40O3FB: 394.3054, found
394.3056.
4.2.6. (1E,3Z)-2-(13-Acetoxy-4-fluoro-1,3-tridecadienyl)-
4,4,5,5-tetramethyl-[1,3,2]-dioxaborolane (5f)
1
IR (neat) 2930, 1740, 1360 cmÀ1. H NMR d 1.24–1.32
(m, 10H), 1.27 (s, 12H), 1.51–1.63 (m, 4H), 2.05 (s, 3H), 2.21
(dt, J = 17.6, 7.4 Hz, 2H), 4.05 (t, J = 6.7 Hz, 2H), 5.35 (dd,
J = 35.0, 10.9 Hz, 1H), 5.42 (d, J = 18.1 Hz, 1H), 7.29 (dd,
J = 17.9, 10.9 Hz, 1H). 19F NMR d À98.26 (dt, J = 36.4,
17.7 Hz, 1F). 13C NMR d 20.98, 24.72 (4C), 25.85, 25.95,
28.55, 28.81, 29.15, 29.29 (2C), 32.21(d, J = 25.7 Hz), 64.58
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