Synthetic organic chemistry with 2-ethoxy-2-(phenylselenenyl)perfluoroalk-2-enenitrile: Application to α-cyanoperfluoroacylation of aldehydes

Article abstract of DOI:10.1021/jo0201880

(Z)- and (E)-2-Ethoxyperfluoro-2-(phenylselenenyl)alk-2-enenitriles 2-4 prepared by our original method underwent transmetalation on treatment with n-BuLi or EtMgBr, and the successive reaction with aldehyde and ketones afforded the corresponding allylic alcohols 10a-f, 9a, and 11a,b in good to high yields. Hydrolysis of the alcohols gave α-cyano-α,β-unsaturated perfluoroalkyl ketones 13a-c, 13e, 12a, and 15a. (α-Cyanoperfluoroalkyl ketones were easily converted to (α,β-unsaturated 3-aryl-2-cyanoallylic alcohols 18-22 having interesting biological activities and chemical reactivities.

Full text of DOI:10.1021/jo0201880

Syn th etic Or ga n ic Ch em istr y w ith
2-Eth oxy-2-(p h en ylselen en yl)p er flu or oa lk -2-en en itr ile: Ap p lica tion
to r-Cya n op er flu or oa cyla tion of Ald eh yd es
Mitsuhiro Yoshimatsu* and Yoshie Timura
Department of Chemistry, Faculty of Education, Gifu University, Yanagido, 1-1, Gifu 501-1193, J apan
yoshimae@cc.gifu-u.ac.jp
Received March 18, 2002
(Z)- and (E)-2-Ethoxyperfluoro-2-(phenylselenenyl)alk-2-enenitriles 2-4 prepared by our original
method underwent transmetalation on treatment with n-BuLi or EtMgBr, and the successive
reaction with aldehyde and ketones afforded the corresponding allylic alcohols 10a -f, 9a , and 11a ,b
in good to high yields. Hydrolysis of the alcohols gave R-cyano-R,â-unsaturated perfluoroalkyl
ketones 13a -c, 13e, 12a , and 15a . R-Cyanoperfluoroalkyl ketones were easily converted to R,â-
unsaturated 3-aryl-2-cyanoallylic alcohols 18-22 having interesting biological activities and
chemical reactivities.
While Knoevenagel reactions are well-known as a
useful synthetic procedure for the preparation of R,â-
unsaturated ketones and esters,1 application of this
method to the preparation of the R,â-unsaturated per-
fluoroalkyl ketones is difficult.2 These compounds have
been widely utilized as novel starting materials to obtain
fluorine-containing biologically active compounds3 via
other multistep routes.4 Therefore, intensive efforts have
been made by organic and fluorine chemists to find new
methodology for praparation of R,â-unsaturated perfluo-
roalkyl ketones. Recently, we have reported both per-
fluoroacylation5 and R-cyano formylation6 of aldehydes
and ketones based on a Wittig-type olefination using
â-alkoxy alkenyllithium. A simple two-step process is
shown in Figure 1: electrophilic addition of the â-alkoxy
alkenyllithium with aldehydes or ketones, followed by
hydrolysis of the allylic alcohols obtained from the first
step. R-Cyano-R,â-unsaturated perfluoroalkyl ketones are
also an almost unknown chemical species for the same
above reasons. If a novel R-cyano perfluoroacylation of
aldehydes and ketones is achieved, it will provide a novel
and convenient method for R,â-unsaturated R-cyano
perfluoroalkyl ketones as shown in Figure 1. We selected
F IGURE 1.
SCHEME 1. Tr a n sm eta la tion of â-Eth oxy-â-
p er flu or oa lk yl-r-(p h en ylselen en yl)a cr ylon itr ile
SCHEME 2a
a
Reagents: (i) lithium 2,2,6,6-tetramethylpiperidide (LTMP)/
-78 °C/RfCO2Et/MsCl.
(1) Tietze, L.; Beifuss, U. Comprehensive Organic Synthesis; Trost,
B. M.,; Fleming, I., Paquette, L. A., Eds.; Pergamon: New York, 1991;
Vol. 2, p 341.
new vinylic selenides as a precursor for the â-alkoxy
alkenyllithiums. R-Cyano vinylic selenides would provide
two kinds of alkenylmetals via transmetalation of the
â-ethoxy-â-perfluoroalkyl-R-(phenylselenenyl)acryloni-
triles as shown in Scheme 1. Here we report a novel
preparation of R-cyano-R,â-unsaturated perfluoroalkyl
ketones via a Wittig-type olefination and its convenient
conversion to 2-cyanoallylic alcohols.
We first examined the preparation of vinylic selenides
2-4 by our original method using (phenylselenenyl)-
acetonitrile 1 as shown in Scheme 2. Acetonitrile 1 was
treated with lithium 2,2,6,6-tetramethylpiperidide (LTMP)
(2) Katsuyama, I.; Funabiki, K.; Matsui, M.; Muramatsu, H.;
Shibata, K. Chem. Lett. 1996, 179.
(3) Filler, R.; Kobayashi, Y. Biomedicinal Aspects of Fluorine
Chemistry; Kodansha: Tokyo, J apan, 1982. Ishikawa, N. Biologically
Active Organofluorine Compounds; CMC: Tokyo, J apan, 1990.
(4) Aldol condensation of trifluoroacetone and the succesive oxida-
tion: Mead, D.; Loh, R.; Asato, A. E.; Lin, R. S. H. Tetrahedron Lett.
1985, 26, 2873. Iminophosphonate route: Ishihara, T.; Maekawa, T.;
Ando, T. Tetrahedron Lett. 1983, 24, 4229. Boronate ester route:
Takada, E.; Hara, S.; Suzuki, A. Heteroat. Chem. 1992, 3, 483.
(5) Perfluoroacylation: Yoshimatsu, M.; Sugimoto, T.; Okada, N.;
Kinoshita, S. J . Org. Chem. 1999, 64, 5162. Matsubara, Y.; Yoshimatsu,
M. J . Org. Chem. 2000, 65, 4456.
(6) R-Cyanoformylation: Yoshimatsu, M.; Yamaguchi, S.; Matsub-
ara, Y. J . Chem. Soc., Perkin Trans. 1 2001, 2560.
10.1021/jo0201880 CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/12/2002
5678
J . Org. Chem. 2002, 67, 5678-5682

2-Ethoxy-2-(phenylselenenyl)perfluoroalk-2-enenitrile
TABLE 1. r-Cya n op er flu or oa cyla tion of Ald eh yd es a n d Keton es w ith â-Eth oxy Alk en yllith iu m
entry
vinyl selenide (Rf)
conditionsa
R1
R2
alcohol (% yield)
product (% yield)
1
2
3
4
5
6
7
8
9
10
11
12
13
3 (CF2CF3)
A
B
A
A
A
B
A
A
A
B
A
B
A
mesityl
mesityl
p-methoxyphenyl
p-bromophenyl
(CH2)5
H
H
H
H
10a (67)
10a (47)
10b (54)
10c (54)
10d (31)
10d (57)
10e (46)
10f (60)
9a (17)
13a (54)
13b (46)
13c (10)
14 (43)b
(CH2)5
styryl
phenylethynyl
mesityl
mesityl
mesityl
H
H
H
H
H
H
13e (55)
12a (78)
15a (59)
16 (40)b
2 (CF3)
9a (51)
4 (CF2CF2CF3)
11a (50)
11a (78)
11b (49)
mesityl
(CH2)5
a
b
Condition A: n-BuLi/THF/-78 °C. Condition B: EtMgBr/Et2O/-78 °C. Structure for 14 and 16:
SCHEME 3
F IGURE 2.
at -78 °C, and the successive addition of RfCO2Et and
then MsCl gave the corresponding vinylic selenides 2-4,
respectively. The mechanism of the new preparative
method for the vinylic selenides is shown in Scheme 3.
Deprotonation of 1 with LTMP gives R-seleno carbanion
5, which is treated with ethyl perfluoroalkanoate to give
the intermediate 6. Since perfluoroalkyl ketone 7 could
not be detected in the reaction products, the rate of the
de-ethoxylation of 6 would be very slow. Methanesulfo-
nylation of 6 affords 8, which undergoes demethanesulfo-
nylation to give the desired selenides 2-4.
The transmetalation of 3 with n-BuLi (condition A)
easily proceeded, and successive treatment with mesityl
aldehyde afforded the allylic alcohol (E)-10a in good yield.
The structure of 10a was determined by the IR spectral
data, showing the absorption in both hydroxy and cyano
groups at ν 3750-3150 and 2220 cm-1 by 1H NMR
spectral data and the hydroxy and its R-proton at δ 2.97
(br s, OH) and 5.93 (br s, CHOH). Mass and elemental
analyses show the molecular formula as C17H18F5NO2.
The stereochemistry of 10a was determined as E by NOE
enhancement as shown in Figure 2. Irradiation of the
ethoxy methylene protons of 10a increased the intensity
of the R-proton of the hydroxy group. The reaction of 3
with EtMgBr (condition B)/mesityl aldehyde gave 10a in
almost the same yield. However, trifluoromethyl vinylic
selenide 2 resulted in a low yield of alcohol 9a by
condition A. We observed the changes in the reaction
mixture after the addition of n-BuLi to a THF solution
of 2. The color of the reaction mixture quickly changed
to red and then to a dark-brown suspension. Neverthe-
less, the addition of aldehyde to the mixture gave rise to
low yields of the products. On the other hand, condition
B succeeded in providing allylic alcohol 9a in moderate
yield (entry 10). The reactions with various aldehydes
and ketones were examined and the results are shown
in Table 1. Next, we performed the hydrolysis of 10a
using protic or Lewis acids and found that p-toluene-
sulfonic acid was effective for the R-cyano perfluoro-
acylation. The hydrolysis of 10a -c, 9a , and 11a afforded
the corresponding R,â-unsaturated perfluoroalkyl ketones
13a -c, 13e, and 12a , respectively. The representative
structure of R,â-unsaturated perfluoroalkyl ketone 13a
is shown as follows. The IR spectrum shows two char-
acteristic absorptions of both cyano and carbonyl groups
1
at ν 2220 (CN) and 1720 (CO) cm-1. Furthermore, H
NMR exhibits an olefinic proton at δ 6.98 ppm as a
singlet. 19F NMR also exhibits a single isomer of the
pentafluoroethyl absorptions at δ -46.87 and -3.67 ppm.
Mass and elemental analyses show the corresponding
molecular formula as C15H12F5NO. The stereochemistry
of 13a was determined after leading to allylic alcohol 18
by the reduction of 13a as shown below. NOE enhance-
ment between the olefinic and the methine protons of 18
was observed as 10%. The elimination of allylic alcohols
10d and 11b gave the dienes 14 and 16, not the
R,â-unsaturated ketones. Next, we attempted a tandem
J . Org. Chem, Vol. 67, No. 16, 2002 5679

Yoshimatsu and Timura
SCHEME 4a
SCHEME 6a
a
Reagents: (i) n-BuLi/PhSe(NC)CdC(OEt)CF2CF3/-78 °C; (ii)
p-TosOH/ClCH2CH2Cl/83 °C.
SCHEME 5a
a
Reagents: (i) MeONa/0 °C; (ii) BnNH2/ClCH2CH2Cl/83 °C; (iii)
PhSNa/THF/0 °C.
companied by diphenyl diselenide. Surprisingly, the
reaction with sodium benzenethiolate underwent reduc-
tion of the selenenyl function of the vinylic selenide 4 to
give the acrylonitrile in 33% yield.
a
Exp er im en ta l Section 5
Reagent: (i) NaBH4/EtOH/0 °C.
The elemental analysis were measured by the Yanako CHN
corder (MT-6) by the autosampling system at the Center of
Instrumentation of Gifu University. The stereochemistries of
the vinylic selenides 2-4 were determined by the NOE
enhancements between the ethoxy methylene protons and the
ortho-aromatic protons. High-resolution mass was obtained by
using a J EOL Gcmate spectrometer with a direct-insertion
probe at an ionization voltage of 70 eV.
R-cyano perfluoroacylation; however, the hydroysis of the
penta-1,4-dien-3-ol 17 afforded a complex mixture (Scheme
4).
On the other hand, 3-substituted 2-cyanoallylic alco-
hols have been an important raw material in food
chemistry,7 in the synthesis of nuciferol precursors8 and
naturally occurring derivatives which have been used for
fragnance enhancement. A few multistep routes are
known in the literature. One strategy is based on the use
of epoxide functionalization of 2-cyanoacrylic acid esters
involving epoxidation-reduction-de-epoxidation.9 An-
other pathway to the 2-cyanoallylic alcohols is based on
rearrangement of the Baylis-Hillman products involving
a bromination-formylation-hydrolysis process.10 It is not
possible to reduce the 2-cyanoacrylic acid ester or its
derivatives even under mild conditions by using NaBH4/
EtOH to provide the saturated alcohols, exclusively. A
simple and general synthetic method for the preparation
of 2-cyanoallylic alcohols has not been reported. The
products we obtained here are novel precursors for the
fluorine-containing 2-cyanoallylic alcohol by a convenient
method. The trifluoromethyl ketone 12a was reduced
under the conditions (NaBH4/EtOH/0 °C) to give 2-cy-
anoallylic alcohol 18 in 76% yield (Scheme 5). The further
reduced product 19 was not observed. Pentafluoroethyl
and heptafluoropropyl ketone 13a and 15a provided the
corresponding alcohols 20 and 21, respectively.
P r ep a r a tion of (Z)- a n d (E)-3-Eth oxy-4,4,5,5,5-p en ta -
flu or o-2-(ph en ylselen o)-2-pen ten en itr ile (3), Typical P r o-
ced u r e. Under an Ar atmosphere, a THF (5.00 mL) solution
of phenylselenoacetonitrile (2.89 g, 14.7 mmol) was added
dropwise to a THF (20.0 mL) solution of 2,2,6,6-tetramethyl-
piperidide (prepared from 2,2,6,6-tetramethylpiperidine (4.16
g, 29.5 mmol) and n-BuLi (14.7 mL, 22.1 mmol)) at -78 °C.
After the mixture was stirred for 10 min, ethyl pentafluoro-
propionate (3.36 mL, 22.1 mmol) and then a THF (5.00 mL)
solution of methanesulfonyl chloride (2.53 g, 22.1 mmol) were
added dropwise. The whole solution was stirred for 10 min
and poured into water (150 mL). The organic solvent was
removed and the aqueous layer was extracted with ether. The
combined organic layer was dried over MgSO4. The solvent
was removed under reduced pressure. The residue was purified
by column chromatography on silica gel eluting with EtOAc-
n-hexane (1:20) to give (Z)- and (E)-3-ethoxy-4,4,5,5,5-penta-
fluoro-2-(phenylseleno)-2-pentenenitrile (3) as a yellow oil. The
stereochemistries of (E)- and (Z)-3, 2, and 4 were determined
by the NOE enhacements of (Z)-isomers. Irradiation of the
ethoxy methylene protons increased the intensities of the
ortho-aromatic protons as follows ((Z)-3 (1%), (Z)-2 (1%), (Z)-4
(7%)).
(Z)- a n d (E)-3-Eth oxy-4,4,5,5,5-p en ta flu or o-2-(p h en yl-
Furthermore, we examined the transformation of the
new R-cyanovinylic selenides as shown in Scheme 6. The
nucleophilc reaction with sodium methoxide to 4 occurred
at the â-position of the cyano group and afforded â-meth-
oxy vinylic selenide 22 and acetal 23. The reaction with
benzylamine gave the â-amino vinylic selenide 24, ac-
selen o)-2-p en ten en itr ile (3): Z:E ) 71:29; IR (film, cm-1
)
1
2210 (CN); H NMR δ 1.39 (t, J ) 7 Hz, Z-Me), 1.45 (t, J ) 7
Hz, E-Me), 4.25 (q, J ) 7 Hz, E-CH2), 4.45 (q, J ) 7 Hz, Z-CH2),
7.38-7.50 (m, E- and Z-ArH), 7.65-7.69 (m, E- and Z-ArH);
19F NMR δ -36.20 (d, J ) 3 Hz, E-CF2), -34.25 (d, J ) 2 Hz,
Z-CF2), -34.24 (d, J ) 2 Hz, Z-CF2), -5.13 (t, J ) 2 Hz, E-CF3),
-4.39 (t, J ) 2 Hz, Z-CF3); MS m/z 371 (M+). Anal. Calcd for
(7) Nishimura, O.; Masuda, H.; Mihara, S. J . Agric. Food. Chem.
1987, 35, 338. Nishimura, O.; Mihara, S. Der. Food Sci. 1988, 18
(Flavor, Fragrances) 375; Chem. Abstr. 1989, 110, 6350a.
(8) Basavaiah, D.; Sarma, P. K. S. J . Chem. Soc., Chem. Commun.
1992, 955.
(9) Trost, B. M.; Balkovec, J . M.; Mao, M. K. T. J . Am. Chem. Soc.
1983, 105, 6755.
(10) Aiai, M.; Baudy-Floc’h, M.; Robert, A.; Grel, P. L. Synthesis
1996, 403.
(11) Hbaieb, S.; Ayed, T. B.; Amri, H. Synth. Commun. 1997, 27,
2825. Beltraief, I.; Hbraieb, S.; Besbes, R.; Amri, H.; Villieras, M.;
Villieras, J . Synthesis 1998, 1765. Basavaiah, D.; Kumaragurubaran,
N.; Padmaja, K. Synlett 1999, 1630.
C
13H10F5NOSe: C, 42.18; H, 2.72; N, 3.78. Found: C, 42.55;
H, 2.84; N, 3.75.
(Z)- a n d (E)-3-Eth oxy-4,4,4-tr iflu or o-2-(p h en ylselen o)-
2-bu ten en itr ile (2): a yellow oil; Z:E ) 80:20; IR (film, cm-1
)
2200 (CN); 1H NMR (400 MHz, CDCl3) δ 1.40 (t, J ) 7 Hz,
Z-Me), 1.45 (t, J ) 7 Hz, E-Me), 7.36-7.49 (m, ArH), 7.60-
7.72 (m, ArH); MS m/z 241 (M+). Anal. Calcd for C12H10F3-
NOSe: C, 45.02; H, 3.15; N, 4.37. Found: C, 44.72; H, 3.21;
N, 3.54.
(Z)- a n d (E)-3-Eth oxy-4,4,5,5,6,6,6-h ep ta flu or o-2-(p h en -
ylselen o)-2-h exen en itr ile (4): a yellow oil; Z:E ) 75:15; IR
5680 J . Org. Chem., Vol. 67, No. 16, 2002

2-Ethoxy-2-(phenylselenenyl)perfluoroalk-2-enenitrile
1
(film, cm-1) 2210 (CN); H NMR (400 MHz, CDCl3) δ 1.38 (t,
Anal. Calcd for C16H14F5NO2: C, 55.33; H, 4.06; N, 4.03.
Found: C, 55.61; H, 4.23; N, 3.63.
J ) 7 Hz, Z-Me), 1.46 (t, J ) 7 Hz, E-Me), 4.25 (q, J ) 7 Hz,
E-OCH2), 4.42 (q, J ) 7 Hz, Z-OCH2), 7.25-7.48 (m, ArH),
7.64-7.68 (m, ArH); 19F NMR δ -48.42 (s, E-CF2), -47.93 (t,
J ) 12 Hz, Z-CF2), -33.97 (d, J ) 9 Hz, E-CF2), -32.67 (br d,
J ) 9, Z-CF2), -2.77 (t, J ) 9 Hz, E-CF3), -2.73 (t, J ) 9 Hz,
Z-CF3); MS m/z 421 (M+). Anal. Calcd for C14H10F7NOSe: C,
40.01; H, 2.39; N, 3.33. Found: C, 39.65; H, 2.56; N, 3.32.
Rea ction s of 2-Lith io-3-eth oxy-3-p er flu or oa lk yl-2-a lk -
en en itr ile w ith Ald eh yd es a n d Keton es, Typ ica l P r oce-
d u r e. Under an Ar atmosphere, n-BuLi (0.50 mL, 0.75 mmol)
was added dropwise to a THF (3.00 mL) solution of 3 (0.18 g,
0.50 mmol) at -78 °C and the mixture was stirred for 10 min.
Then a THF (1.00 mL) solution of mesityl aldehyde (0.11 g,
0.73 mmol) was added to the mixture. The whole solution was
stirred for 10 min and poured into water (100 mL). The organic
layer was separated and the aqueous layer was extracted with
ether. The combined organic layer was dried over MgSO4. The
solvent was removed under reduced pressure. The residue was
purified by preparative TLC on silica gel eluting with AcOEt-
hexane (1:3). (E)-2-Cyano-3-ethoxy-4,4,5,5,5-pentafluoro-1-
mesitylpent-2-en-1-ol (10a ) (0.12 g, 67%) was obtained as
colorless prisms (mp 60-63 °C).
(E)-4-Cya n o-5-et h oxy-6,6,7,7,7-p en t a flu or o-1-p h en yl-
h ep t-4-en -1-yn -3-ol (10f): a yellow oil; IR (film, cm-1) 3600-
3300 (OH), 2230 (CN); 1H NMR (400 MHz, CDCl3) δ 1.40 (3H,
t, J ) 7 Hz, Me), 3.50 (1H, br s, OH), 4.20 (2H, q, J ) 7 Hz,
OCH2), 5.65 (1H, br s, CHO), 7.24-7.38 (3H, m, ArH), 7.43-
7.81 (2H, m, ArH); 19F NMR δ -37.61 (2F, t, J ) 3 Hz, CF2),
-5.05 (3F, br s, CF3); MS m/z 345 (M+). Anal. Calcd for
C
16H12F5NO2: C, 56.66; H, 3.58; N, 4.05. Found: C, 56.32; H,
3.76; N, 3.88.
(E)-2-Cya n o-3-eth oxy-4,4,4-tr iflu or o-1-m esitylbu t-2-en -
1-ol (9a ): a yellow oil; IR (film, cm-1) 3650-3000 (OH), 2250
(CN); 1H NMR (400 MHz, CDCl3) δ 0.97 (3H, t, J ) 7 Hz, Me),
2.25 (3H, s, Me), 2.41 (6H, s, Mex2), 2.62 (1H, br s, OH), 3.21-
3.30 (1H, m, OCH2), 3.85-3.94 (1H, m, OCH2), 5.91 (1H, br d,
J ) 2 Hz, CHO), 6.85 (2H, br s, ArH); 19F NMR δ -14.25 (3F,
s, CF3); MS m/z 313 (M+). Anal. Calcd for C16H18F3NO2: C,
61.34; H, 5.79; N, 4.47. Found: C, 60.94; H, 5.69; N, 4.38.
(E)-2-Cya n o-3-eth oxy-4,4,5,5,6,6,6-h ep ta flu or o-1-m esi-
tylh ex-2-en -1-ol (11a ): white powders, mp 56-58 °C; IR
(film, cm-1) 3600-3300 (OH), 2230 (CN); 1H NMR (400 MHz,
CDCl3) δ 1.05 (3H, t, J ) 7 Hz, Me), 2.26 (3H, s, Me), 2.40
(1H, br s, OH), 2.43 (6H, s, Mex2), 3.20-3.26 (1H, m, OCH2),
3.89-3.95 (1H, m, OCH2), 6.02 (1H, br d, J ) 2 Hz, CHO),
6.87 (2H, br s, ArH); 19F NMR δ -48.56 (1F, d, J ) 290 Hz,
CF2), -47.43 (1F, d, J ) 290 Hz, CF2), -33.97 (1F, dd, J )
293 and 7 Hz, CF2), -32.76 (1F, dd, J ) 293 and 7 Hz, CF2),
-2.75 (3F, t, J ) 9 Hz, CF3); MS m/z 413 (M+). Anal. Calcd
for C18H18F7NO2: C, 52.30; H, 4.39; N, 3.38. Found: C, 52.09;
H, 4.42; N, 3.41.
10a : IR (film, cm-1) 3750-3160 (OH), 2220 (CN); 1H NMR
(400 MHz, CDCl3) δ 0.96 (3H, t, J ) 7 Hz, Me), 2.25 (3H, s,
Me), 2.40 (6H, s, Mex2), 2.97 (1H, br s, OH), 3.14-3.19 (1H,
m, OCH2), 3.84-3.92 (1H, m, OCH2), 5.93 (1H, br s, CHO),
6.84 (2H, br s, ArH); 19F NMR δ -36.62 (1F, d, J ) 282 Hz,
CF2), -34.87 (1F, d, J ) 282 Hz, CF2), -5.02 (3F, t, J ) 2 Hz,
CF3); MS m/z 363 (M+). Anal. Calcd for C17H18F5NO2: C, 56.20;
H, 4.99; N, 3.85. Found: C, 56.09; H, 5.01; N, 3.79.
Rea ction of 3-Eth oxy-3-p er flu or oa lk yl-2-a lk en en itr il-
2-yl Ma gn esiu m Br om id e w ith Ald eh yd es a n d Keton es,
Typ ica l P r oced u r e. An Et2O solution of EtMgBr (1.00 mL,
1.00 mmol) was added dropwise to a THF (2.00 mL) solution
of 3 (0.10 g, 0.27 mmol) under an Ar atmosphere. The reaction
mixture was stirred for 10 min. Then the electrophile was
added to the mixture at the same temperature. The workup
procedure afforded the results as shown in Table 1.
(E)-1-[2-(3-Eth oxy-4,4,5,5,6,6,6-h ep ta flu or o-2-h exen en i-
tr ilyl)cycloh exa n ol (11b): a yellow oil; IR (film, cm-1) 3600-
3200 (OH), 2210 (CN); 1H NMR (400 MHz, CDCl3) δ 1.24-
1.30 (1H, m, CH2), 1.41 (3H, t, J ) 7 Hz, Me), 1.58-1.93 (9H,
m, CH2), 2.35 (1H, br s, OH), 4.19 (2H, q, J ) 7 Hz, OCH2);
19F NMR δ -48.42 (2F, s, CF2), -33.29 (2F, q, J ) 9 Hz, CF2),
-2.97 (3F, t, J ) 9 Hz, CF3); MS m/z 149.
(1Z,4E)-2,4-Dicya n o-5-et h oxy-6,6,7,7,7-p en t a flu or o-1-
m esityl-3-p en ta flu or oeth ylh ep t-1,4-d ien -3-ol (17): color-
less prisms, mp 126-128 °C; IR 3500-3200 (OH), 2250 (CN);
1H NMR (400 MHz, CDCl3) δ 1.46 (3H, t, J ) 7 Hz, Me), 2.21
(6H, s, Mex2), 2.28 (3H, s, Me), 4.31-4.43 (2H, m, OCH2), 5.69
(1H, br s, OH), 6.91 (2H, s, ArH), 7.77 (1H, s, olefinic H); 19F
NMR δ -41.16 (2F, s, CF2), -35.38 (2F, s, CF2), -6.12 (3F, s,
CF3), -5.39 (3F, s, CF3); MS m/z 532 (M+). Anal. Calcd for
C22H18F10N2O2: C, 49.63; H, 3.41; N, 5.26. Found: C, 49.61;
H, 3.56; N, 5.19.
(E)-2-Cya n o-3-eth oxy-4,4,5,5,5-p en ta flu or o-1-(4-m eth -
oxyp h en yl)p en t-2-en -1-ol (10b): IR (film, cm-1) 3800-3160
1
(OH), 2300 (CN); H NMR (400 MHz, CDCl3) δ 1.24 (3H, t, J
) 7 Hz, Me), 3.48 (1H, br s, OH), 3.79 (3H, s, OMe), 4.02-
4.15 (2H, m, OCH2), 5.79 (1H, s, CHO), 6.94 (2H, d, J ) 9 Hz,
ArH), 7.28 (2H, d, J ) 9 Hz, ArH); 19F NMR δ -37.20 (2F, d,
J ) 3 Hz, CF2), -5.22 (3F, t, J ) 2 Hz, CF3); MS m/z 351 (M+).
Anal. Calcd for C15H14F5NO3: C, 51.29; H, 4.02; N, 3.99.
Found: C, 51.69; H, 4.31; N, 3.70.
(E)-2-Cya n o-3-eth oxy-4,4,5,5,5-p en ta flu or o-1-(4-br om o-
p h en yl)p en t-2-en -1-ol (10c): IR (film, cm-1) 3600-3300
Hyd r a tion of Allylic Alcoh ols 9-11, Typ ica l P r oce-
d u r e. A ClCH2CH2Cl (2.00 mL) solution of (E)-2-cyano-3-
ethoxy-4,4,5,5,5-pentafluoro-1-mesitylpent-2-en-1-ol (10a ) (0.17
g, 0.47 mmol) and p-toluenesulfonic acid (89 mg, 0.47 mmol)
was refluxed for 10 min. A cooled mixture was poured into
saturated NaHCO3 (50 mL) and the organic layer was sepa-
rated. The aqueous layer was extracted with CHCl3. The
combined organic layer was dried over MgSO4. The solvent
was removed under reduced pressure. The residue was purified
by preparative TLC on silica gel eluting with AcOEt-hexane
(1:3). (E)-2-Cyano-1-mesityl-4,4,5,5,5-pentafluoro-1-penten-3-
1
(OH), 2250 (CN); H NMR (400 MHz, CDCl3) δ 1.38 (3H, t, J
) 7 Hz, Me), 3.69 (1H, br s, OH), 4.13 (2H, q, J ) 7 Hz, OCH2),
5.80 (1H, s, CHO), 7.26 (2H, br d, J ) 8 Hz, ArH), 7.49 (2H,
br d, J ) 8 Hz, ArH); 19F NMR δ -37.12 (2F, d, J ) 10 Hz,
CF2), -5.23 (3F, t, J ) 2 Hz, CF3); MS m/z 399 (M+). Anal.
Calcd for C14H11BrF5NO2: C, 42.02; H, 2.77; N, 3.50. Found:
C, 42.34; H, 3.03; N, 3.23.
(E)-1-[2-(3-Eth oxy-4,4,5,5,5-p en ta flu or o-2-p en ten en itr i-
lyl)]cycloh exa n ol (10d ): IR (film, cm-1) 3600-3300 (OH),
1
2200 (CN); H NMR (400 MHz, CDCl3) δ 1.22-1.32 (1H, m,
one (13a ) was obtained as a brown oil. 13a : IR (film, cm-1
)
CH2), 1.41 (3H, t, J ) 7 Hz, Me), 1.57-1.92 (10H, m, CH2),
3.01 (1H, br s, OH), 4.18 (2H, q, J ) 7 Hz, OCH2); 19F NMR δ
-35.29 (2F, s, CF2), -5.15 (3F, t, J ) 1 Hz, CF3); MS m/z 320
(M+).
2200 (CN), 1720 (CO); 1H NMR (400 MHz, CDCl3) δ 2.32 (6H,
s, Mex2), 2.33 (3H, s, Me), 6.98 (2H, s, ArH), 8.71 (1H, s,
olefinic H); 19F NMR δ -46.87 (2F, s, CF2), -3.67 (3F, s, CF3);
MS m/z 317 (M+). Anal. Calcd for C15H12F5NO: C, 56.79; H,
3.81; N, 4.42. Found: C, 56.47; H, 4.18; N, 3.99.
(1E,4E)-4-Cya n o-5-eth oxy-6,6,7,7,7-p en ta flu or o-1-p h en -
ylh ep ta -1,4-d ien -3-ol (10e): a yellow oil; IR (film, cm-1
)
3600-3300 (OH), 2220 (CN); 1H NMR (400 MHz, CDCl3) δ 1.39
(3H, t, J ) 7 Hz, Me), 3.41 (1H, br s, OH), 4.07-4.18 (2H, m,
OCH2), 5.40 (1H, d, J ) 6 Hz, CHO), 6.28 (1H, dd, J ) 16 and
7 Hz, olefinic H), 6.74 (1H, d, J ) 16 Hz, olefinic H), 7.24-
7.34 (3H, m, ArH), 7.36-7.40 (2H, m, ArH); 19F NMR δ -37.29
(2F, s, CF2), -5.13 (3F, d, J ) 2 Hz, CF3); MS m/z 347 (M+).
(E)-2-Cyan o-1-(4-m eth oxyph en yl)-4,4,5,5,5-pen taflu or o-
1-p en ten -3-on e (13b): yellow plates, mp 66-73 °C; IR (film,
cm-1) 2200 (CN), 1700 (CO); 1H NMR (400 MHz, CDCl3) δ 3.95
(3H, s, OMe), 7.05 (2H, d, J ) 7 Hz, ArH), 8.16 (2H, d, J ) 7
Hz, ArH), 8.32 (1H, s, olefinic H); 19F NMR δ -39.78 (2F, d, J
) 1 Hz, CF2), -3.74 (3F, d, J ) 1 Hz, CF3); MS m/z 305 (M+).
J . Org. Chem, Vol. 67, No. 16, 2002 5681

Yoshimatsu and Timura
Anal. Calcd for C13H8F5NO2: C, 51.16; H, 2.64; N, 4.59.
Found: C, 51.18; H, 2.78; N, 4.61.
CF2), -3.40 (3F, dd, J ) 8 and 11 Hz, CF3); MS m/z 369 (M+).
Anal. Calcd for C16H14F7NO: C, 52.04; H, 3.82; N, 3.79.
Found: C, 51.79; H, 3.95; N, 3.61.
(E)-2-Cya n o-1-(4-br om op h en yl)-4,4,5,5,5-p en t a flu or o-
1-p en ten -3-on e (13c): yellow needles, mp 33 °C; IR (film,
cm-1) 2210 (CN), 1710 (CO); 1H NMR (400 MHz, CDCl3) δ 7.72
(2H, d, J ) 7 Hz, ArH), 7.98 (2H, d, J ) 7 Hz, ArH), 8.33 (1H,
s, olefinic H); 19F NMR δ -39.84 (2F, d, J ) 1 Hz, CF2), -3.72
(3F, s, CF3); MS m/z 353 (M+). Anal. Calcd for C12H5BrF5NO:
C, 40.71; H, 1.42; N, 3.96. Found: C, 40.53; H, 1.85; N, 3.25.
(E)-2-(1-Cycloh exen yl)-3-eth oxy-4,4,5,5,5-p en ta flu or o-
p en t-2-en en itr ile (14): a yellow oil; IR (film, cm-1) 2260
(CN); 1H NMR (400 MHz, CDCl3) δ 1.31 (3H, t, J ) 7 Hz, Me),
1.61-1.74 (4H, m, CH2), 2.21-2,23 (4H, m, CH2), 4.00 (2H, q,
J ) 7 Hz, OCH2), 6.12 (1H, br s, olefinic H); 19F NMR δ -37.84
(2F, s, CF2), -4.85 (3F, s, CF3); MS m/z 295 (M+).
Rea ction of (Z)- a n d (E)-3-Eth oxy-4,4,5,5,6,6,6-h ep -
t a flu or o-2-(p h en ylselen en yl)-2-h exen en it r ile (4) w it h
Na OMe. NaOMe (1.00 mL, 1.00 mmol) in MeOH was added
to a dry MeOH (1.00 mL) solution of 4 (0.20 g, 0.48 mmol) at
0 °C. The reaction mixture was stirred for 10 min and poured
into water (100 mL). The organic layer was separated and the
aqueous layer was extracted with ether. The combined organic
layer was dried over MgSO4. The solvent was removed under
reduced pressure. The residue was purified by TLC on silica
gel eluting with AcOEt-n-hexane (1:40) to give (E)-4,4,5,5,6,6,6-
heptafluoro-2-(phenylselenenyl)-2-hexenenitrile (22) (0.06 g,
29%) and 4,4,5,5,6,6,6-heptafluoro-3,3-dimethoxy-2-(phenyl-
selenenyl)hexanenitrile (23) (0.12 g, 56%) as a yellow oil,
accompanied by diphenyl diselenide (0.01 g, 12%).
22: E:Z ) 18:82; IR (cm-1) 2250 (CN); 1H NMR (400 MHz,
CDCl3) δ 4.00 (3H, s, OMe), 7.39-7.52 (3H, m, ArH), 7.66-
7.70 (2H, m, ArH); (E)-22 could not be detected by the 1H NMR
spectrum. 19F NMR δ -48.99 (s, E-CF2), -48.42 (s, Z-CF2),
-34.11 (q, J ) 9 Hz, E-CF2), -33.98 (2F, q, J ) 9 Hz, Z-CF2),
-3.08 to -2.76 (m, E- and Z-CF3); MS m/z 407 (M+). Anal.
Calcd for C13H8NOSe: C, 38.44; H, 1.98; N, 3.45. Found: C,
38.51; H, 2.31; N, 2.99.
23: IR (cm-1) 2250 (CN); 1H NMR (400 MHz, CDCl3) δ 3.61
(3H, s, OMe), 3.66 (3H, s, OMe), 4.31 (1H, br s, CH), 7.35-
7.47 (3H, m, ArH), 7.72-7.78 (2H, m, ArH); 19F NMR δ -46.67
to -46.41 (2F, m, CF2), -36.62 to -36.44 (2F, m, CF2), -2.91
to -2.84 (3F, m, CF3); MS m/z 392, 352, 312, 157 (PhSe). Anal.
Calcd for C14H12F7O2Se: C, 38.37; H, 2.76; N, 3.20. Found: C,
38.63; H, 2.29; N, 3.02.
Rea ction of 4 w ith Ben zyla m in e. A benzene (2.00 mL)
solution of 4 (0.20 g, 0.48 mmol) and benzylamine (0.10 g, 0.95
mmol) was refluxed for 10 h. The solvent was evaporated and
the residue was purified by TLC on silica gel eluting with
AcOEt-n-hexane (1:10) to give (Z)-3-benzylamino-4,4,5,5,6,6,6-
heptafluoro-2-(phenylselenenyl)-2-hexenenitrile (24) (0.04 g,
54%) as a brown oil.
24: IR (cm-1) 2220 (CN); 1H NMR (400 MHz, CDCl3) δ 4.52
(2H, d, CH2), 7.00 (1H, s, NH), 7.30-7.42 (8H, m, ArH), 7.67-
7.69 (2H, m, ArH); 19F NMR δ -49.20 (2F, s, CF2), -42.95 (2F,
q, J ) 8 Hz, CF2), -2.86 (3F, t, J ) 8 Hz, CF3); MS m/z 180,
165, 152, 89, 76. Anal. Calcd for C19H13F7N2Se: C, 47.42; H,
2.72; N, 5.82. Found: C, 45.56; H, 3.13; N, 5.95.
Rea ction of 4 w ith P h SNa . A THF (1.50 mL) solution of
4 (0.20 g, 0.48 mmol) was added to a THF (2.00 mL) solution
of PhSNa (prepared from thiophenol (0.06 g, 0.57 mmol) and
NaH (0.03 g, 0.71 mmol)) at 0 °C. The reaction mixture was
stirred for 1 h and poured into water (50.0 mL). The organic
layer was separated and the aqueous layer was extracted with
ether. The combined organic layer was dried over MgSO4. The
solvent was removed under reduced pressure. The residue was
purified by preparative TLC on silica gel eluting with AcOEt-
n-hexane (1:10) to give (E)-3-ethoxy-4,4,5,5,6,6,6-heptafluoro-
2-hexenenitrile (25) (0.03 g, 33%) as a pale yellow oil, accom-
panied by diphenyl diselenide (0.10 g, 55%).
(1E,4E)-4-Cya n o-6,6,7,7,7-p en ta flu or o-1-p h en ylh ep ta -
1,3-d ien en itr ile (13e): orange needles, mp 67-69 °C; IR 2210
1
(CN); H NMR (400 MHz, CDCl3) δ 7.41-7.68 (5H, m, ArH),
7.75-7.82 (2H, m, olefinic H), 8.32 (1H, d, J ) 8 Hz, olefinic
H); 19F NMR δ -39.80 (2F, s, CF2), -3.97 (3F, d, J ) 1 Hz,
CF3); MS m/z 301 (M+). Anal. Calcd for C14H8F5NO: C, 55.83;
H, 2.68; N, 4.65. Found: C, 55.46; H, 2.80; N, 4.57.
(E )-2-Cya n o-4,4,4-t r iflu or o-1-m e sit yl-1-b u t e n -3-on e
1
(12a ): a yellow oil; IR 2250 (CN), 1620 (CO); H NMR (400
MHz, CDCl3) δ 2.20 (6H, s, Mex2), 2.27 (3H, s, Me), 6.92 (2H,
s, ArH), 7.84 (1H, s, olefinic H); 19F NMR δ - 5.12 (3F, s, CF3);
MS m/z 267 (M+).
(E)-2-Cya n o-4,4,5,5,6,6,6-h ep t a flu or o-1-m esit ylh ex-1-
en -3-on e (15a ): IR 2230 (CN), 1720 (CO); 1H NMR (400 MHz,
CDCl3) δ 2.31 (6H, s, Mex2), 2.32 (3H, s, Me), 6.98 (2H, s, ArH),
8.70 (1H, s, olefinic H); 19F NMR δ -48.05 (2F, t, J ) 7 Hz,
CF2), -38.00 (2F, q, J ) 10 Hz, CF2), -2.78 (3F, t, J ) 10 Hz,
CF3); MS m/z 367 (M+). Anal. Calcd for C16H12F7NO: C, 53.80;
H, 3.28; N, 3.92. Found: C, 53.52; H, 3.27; N, 3.78.
(E)-2-(1-Cycloh exen yl)-3-eth oxy-4,4,5,5,6,6,6-h eptaflu or o-
1
2-h exen en itr ile (16): a yellow oil; IR 2220 (CN); H NMR
(400 MHz, CDCl3) δ 1.31 (3H, t, J ) 7 Hz, Me), 1.62-1.68 (2H,
m, CH2), 1.70-1.76 (2H, m, CH2), 2.20-2.25 (4H, m, CH2), 4.00
(2H, q, J ) 7 Hz, OCH2), 6.12 (1H, d, J ) 2 Hz, olefinic H); 19
F
NMR δ -48.35 (2F, t, J ) 12 Hz, CF2), -35.84 (2F, q, J ) 9
Hz, CF2), -2.89 (3H, t, J ) 9 Hz, CF3); MS m/z 318 (M+ - Et).
R ed u ct ion of (E)-2-Cya n o-4,4,4-t r iflu or o-1-m esit yl-1-
bu ten -3-on e (13a ), Typ ica l P r oced u r e. NaBH4 (28.0 mg,
0.74 mmol) was added to a EtOH (2.00 mL) solution of the
titled compound 13a (0.10 g, 0.37 mmol) at 0 °C. The reaction
mixture was stirred for 30 min. The workup procedure afforded
(E)-2-cyano-4,4,4-trifluoro-1-mesityl-1-buten-3-ol (18) (76.0 mg,
76%) as colorless prisms.
18: mp 110-112 °C; IR 3441 (OH), 2260 (CN); 1H NMR
(400 MHz, CDCl3) δ 2.19 (6H, s, Mex2), 2.27 (3H, s, Me), 4.12
(1H, q, J ) 6 Hz, OH), 4.68 (1H, q, J ) 6 Hz, CHO), 6.89 (2H,
s, ArH), 7.57 (1H, s, olefinic H); 19F NMR δ -0.30 (3F, d, J )
6 Hz, CF3); MS m/z 269 (M+). Anal. Calcd C14H14F3NO: C,
62.45; H, 5.24; N, 5.20. Found: C, 62.29; H, 5.24; N, 5.05.
(E)-2-Cya n o-4,4,5,5,5-p en ta flu or o-1-m esityl-1-p en ten -
3-ol (20): mp 102-103 °C; IR 3392 (OH), 2245 (CN); 1H NMR
(400 MHz, CDCl3) δ 2.18 (6H, s, Mex2), 2.27 (3H, s, Me), 4.02
(1H, br s, OH), 4.80 (1H, dd, J ) 5 and 17 Hz, CHO), 6.89
(2H, s, ArH), 7.53 (1H, s, olefinic H); 19F NMR δ -52.19 (2F,
dd, J ) 17 and 278 Hz, CF2), -42.02 (2F, dd, J ) 5 and 278
Hz, CF2), -3.74 (3F, s, CF3); MS m/z 302 (M+ - OH). Anal.
Calcd for C14H14F5NO: C, 56.43; H, 4.42; N, 4.39. Found: C,
56.15; H, 4.45; N, 4.30.
25: IR (cm-1) 2230 (CN); 1H NMR (400 MHz, CDCl3) δ 1.48
(3H, t, J ) 7 Hz, Me), 3.98 (2H, q, J ) 7 Hz, CH2), 4.99 (1H,
s, olefinic H); 19F NMR δ -49.48 (2F, s, CF2), -38.65 (2F, q, J
) 9 Hz, CF2), -3.36 (3F, t, J ) 9 Hz, CF3); MS m/z 259 (small
M+).
(E)-2-Cyan o-4,4,5,5,6,6,6-h eptaflu or o-1-m esityl-1-h exen -
1
3-ol (21): mp 94-96 °C; IR 3395 (OH), 2246 (CN); H NMR
Ack n ow led gm en t. The support of a part of this
work by the Ministry of Education, Science and Culture,
J apan, is gratefully acknowledged.
(400 MHz, CDCl3) δ 2.19 (6H, s, Mex2), 2.27 (3H, s, Me), 4.13
(1H, br s, OH), 4.88 (1H, br d, J ) 17 Hz, CHO), 6.89 (2H, s,
ArH), 7.55 (1H, s, olefinic H); 19F NMR δ -47.31 (2F, ddd, J
) 5 and 11 and 293 Hz, CF2), -39.53 (2F, br d, J ) 287 Hz,
J O0201880
5682 J . Org. Chem., Vol. 67, No. 16, 2002