Chemoselective syntheses of various cyanofluoromethylene compounds from organic bromides by use of sodium triethylgermanate(IV) and its mechanistic studies

Article abstract of DOI:10.1055/s-1999-3438

The chemoselective syntheses of various cyanofluoromethylene compounds proceeded through the formation of the cyanofluoromethyl anion from 2- fluoro-2-phenyl-2-phenyl-thioacetonitrile by the use of sodium triethylgermanate(IV) (Et₃GeNa).

Full text of DOI:10.1055/s-1999-3438

676
PAPER
Chemoselective Syntheses of Various Cyanofluoromethylene Compounds
from Organic Bromides by Use of Sodium Triethylgermanate(IV) and Its
Mechanistic Studies
Yasuo Yokoyama, Kunio Mochida
Department of Chemistry, Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588, Japan
Fax +81(3)59921029; E-mail: 940429@gakushuin.ac.jp
Received 1 October 1998; 26 October 1998
od is particularly suitable for the synthesis of the cy-
Abstract: The chemoselective syntheses of various cyanofluoro-
anofluoromethylene compound, because the target
molecule can be formed more straightforwardly. Howev-
methylene compounds proceeded through the formation of the cy-
anofluoromethyl anion from 2-fluoro-2-phenyl-2-phenyl-thioaceto-
er, investigation of the preparative method using direct
cyanofluo-romethylation has been limited.4 In this con-
nection, we have already reported the germanate anion
species promoted synthesis of a cyanofluoromethylene
compound by use of 2-fluoro-2-phenyl-2-phenylthioace-
tonitrile as the cyanofluoromethylene source (Scheme 1).5
This reaction was applied for the first and efficient synthe-
ses of fluorinated homoallylic and homopropargylic cy-
anides.
nitrile by the use of sodium triethylgermanate(IV) (Et3GeNa).
Key words: germanium reagents, fluorine derivatives, carboni-
triles, mechanism
In recent years, the development of synthetic reactions of
various fluorinated compounds has been important in or-
ganic synthesis, because these compounds have useful
chemical and physical properties.1 Particularly, the prepa-
ration of fluorinated compounds containing various func-
tional groups is an attractive method owing to the
potential utility of the fluorinated products as useful syn-
thetic precursors. Among them, the synthesis of a cy-
anofluoromethylene compound is a challenging problem Scheme 1
from the viewpoint of not only its role as a building block,
but also its multifunctional carbon chemistry.2 There are
In continuation of our work, we introduce an effective and
two strategies for the synthesis of cyanofluoromethylene
compounds; the first is a stepwise introduction of cyano
and fluoro groups,3 and the second is the introduction of a
cyanofluoromethylene unit to a substrate. The latter meth-
chemoselective transformation of organic bromides hav-
ing various substituents such as chloro, ester units, and
some protective groups to the desired fluorinated cyanides
Table 1 Cyanofluoromethylation of Organic Halide Under Various Reaction Conditions
Entry
Operation 1
Operation 2
Solvent
X
Yielda (%)
Temp. (°C)
Time (h)
Temp. (°C)
Time (h)
1
2
3
4
5
6
7
8
9
10
11
12
13
0
–30
–60
–80
–60
–60
–60
–60
–60
–60
–60
–60
–60
0.25
0.25
0.25
0.25
0.5
–80
–80
–80
–80
–80
–80
0
–30
–60
–80
–80
–80
–80
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.25
0.5
0.5
0.5
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
Et2O
hexane
THF
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
78
97
97
86
97
97
70
97
97
69
96
7.8
NR
1.0
0.25
0.25
0.25
0.25
0.25
0.25
0.25
a Yield of isolated pure product.
Synthesis 1999, No. 4, 676–682 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Chemoselective Syntheses of Various Cyanofluoromethylene Compounds
677
Table 2 Chemoselective Cyanofluoromethylation of Various
Organic Bromides
by use of the foregoing method. This reaction proceeded
smoothly to give the corresponding compound in excel-
lent yield without decomposition of the substituent. We
also report some mechanistic studies of the foregoing
method.
1-Halooctane was chosen as a model electrophile and
Et3GeNa promoted synthesis of a cyanofluoromethylene
compound was examined under various conditions using
2-fluoro-2-phenyl-2-phenylthioacetonitrile (Table 1).
Entry
1
R-
Yielda (%)
95
Cl-(CH2)3-
As expected, the treatment of 2-fluoro-2-phenyl-2-phe-
nylthioacetonitrile with Et3GeNa at 0 °C for 0.25 h (Oper-
ation 1) followed by the addition of 1-bromooctane at –80
°C for 0.5 h (Operation 2) afforded 2-fluoro-2-phenylde-
canenitrile in 78% yield (entry 1). In this case, many uni-
dentified byproducts were also obtained. The formation of
these byproducts was suppressed by carrying out the Op-
eration 1 at low temperature. The desired compound was
given quantitatively when the first operation took place at
–30 or –60 °C (entries 2 and 3). On the other hand, the
starting fluorinated cyanide was treated at –80 °C and 1-
bromooctane was added to give the target compound in
moderate yield, because 10% of the starting material was
recovered (entry 4). When Operation 1 was carried out
over a prolonged period, the desired product was also ob-
tained quantitatively (entries 5 and 6). These facts re-
vealed that the active species of this reaction was formed
effectively at –30 to –60 °C for 0.25 hours and this species
was stable at the same reaction conditions. The reaction
temperature and the period of Operation 2 are significant
factors in this reaction. When Operation 2 took place at
0 °C, the desired compound was obtained in 70% yield,
while at lower temperatures the corresponding cyanide
was obtained quantitatively (entries 7 vs 3, 8 and 9).
Moreover, when Operation 2 was carried out for 0.25
hours (–80 °C), the target cyanide and 1-fluoro-1-pheny-
lacetonitrile were obtained in 69 and 28% yields, respec-
tively (entry 10). The latter compound probably was
generated by the quenching of an active species of this
method. In this reaction, diethyl ether could be used as a
solvent, but hexane was unfavorable (entries 11 and 12).
Interestingly, 1-chlorooctane could not be transformed to
the product at all and was almost recovered under the
same conditions; nevertheless, allylic or propargylic chlo-
rides were applicable as substrates (entry 13).5 The results
of entry 3 and 13 indicated that an organic bromide was
more suitable for this reaction than an organic chloride
and prompted us to try the chemoselective transformation
of organic bromides having various functional groups to
the desired cyanofluoromethylene compounds.
2
3
4
5
Cl-(CH2)5-
96
96
96
96
AcO-(CH2)5-
BzO-(CH2)5-
6
7
8
9
EtO2C-(CH2)5-
MOMO-(CH2)5-
MEMO-(CH2)5-
98
96
96
96
a Yield of isolated pure product.
Some bromo esters were also employed as substrates of
this reaction. When w-acetoxy, w-benzoyloxy, and w-tri-
methylacetoxy bromides were applied to this reaction, the
corresponding compounds were obtained perfectly with-
out decomposition of their structures (entries 3, 4, and 5).
Ethyl 6-bromohexanoate could be transformed to the flu-
orinated cyano ester quantitatively (entry 6). Moreover,
some cyanofluoromethylene compounds which had pro-
tective groups on the hydroxy unit, such as a methoxyme-
thyl (MOM) and 2-methoxyethoxymethyl (MEM)
substituent, could be formed in excellent yields (entries 7
and 8). Furthermore, a five-membered cyclic acetal which
is a known protective group of a carbonyl substituent was
unaffected under these reaction conditions. The cy-
anofluoromethylene compound having the foregoing
groups could be easily synthesized in excellent yields (en-
try 9). These results suggested that this reaction was fa-
vorable for the chemoselective transformation of organic
bromides containing various substituents to the corre-
sponding cyanofluoromethylene compounds. Fortunately,
hexaethyldigermane (Et3GeGeEt3) was recovered quanti-
tatively from the mixture. This compound could be reused
for the formation of Et3GeNa.6 Generally, the organoger-
manium compound is too expensive to use in organic syn-
thesis, but it can be employed as a useful synthetic reagent
if it is recovered and reused.
Several results of the transformation of organic bromides
to fluorinated cyanides by use of 2-fluoro-2-phenyl-2-
phenylthioacetonitrile/Et3GeNa system are shown in Ta-
ble 2.
When 1-bromo-3-chloropropane or 1-bromo-5-chloro-
pentane was used as the substrate, the desired cyanofluo-
romethylene compounds were obtained in excellent yields
without loss of the chloromethylene unit (entries 1 and 2).
Synthesis 1999, No. 4, 676–682 ISSN 0039-7881 © Thieme Stuttgart · New York

678
Y. Yokoyama, K. Mochida
PAPER
Scheme 2
At the next stage, we tried to clarify the mechanism of this In conclusion, we have reported a chemoselective cy-
reaction. When the reaction of entry 3 (Table 1) was car- anofluoromethylation of various organic bromides using
ried out in the presence of 2.1 equivalents of 1-bromooc- Et3GeNa. This reaction proceeded smoothly under mild
tane, the corresponding cyanofluoromethylene product, conditions to give the desired compound in excellent
and octyl phenyl sulfide (C6H5SC8H17) and Et3GeGeEt3 yield. This method is very attractive not only in the area
were obtained in 97, 99, and 99% yields (based on 2-flu- of organic synthesis, but also in the field of fluorine chem-
oro-2-phenyl-2-phenylthioacetonitrile), respectively. The istry, because the active intermediate is an a-fluorinated
same reaction was unaffected by 1-oxy-2,2,6,6-tetrameth- carbanion which is difficult to form.10 Further investiga-
ylpiperidine (TEMPO) which is well known as a radical tion is now in progress.
scavenger, and the target compound was obtained in 95%
yield. This fact suggested that the active intermediate of
this reaction was not a radical species. On the other hand,
treatment of 2-fluoro-2-phenyl-2-phenylthioacetonitrile
100 MHz (Varian UNITY-INOVA-400). Chemical shifts were re-
Mps are uncorrected. 1H NMR Spectra were recorded at 400 MHz
(Varian UNITY-INOVA-400). 13C NMR Spectra were recorded at
ported as d values (ppm) downfield from TMS. 19F NMR Spectra
were recorded at 376 MHz (Varian UNITY-INOVA-400). Chemi-
cal shifts were reported as d values (ppm) upfield from CFCl3. IR
Spectra were recorded with Shimadzu FTIR-4200. MS and HRMS
were recorded with Jeol JMS DX-303. Et3GeNa was prepared from
Et3GeGeEt3 in HMPA according to the literature.6 2-Phenyl-2-phe-
nylthioacetonitrile, 5-bromopentyl acetate, 5-bromopentyl benzoate
and Et3GeSC6H5 were synthesized according to the literature proce-
dures.11 Commercially available 1-fluoropyridinium trifluo-
romethanesulfonate, 5-bromopentan-1-ol, trimethylacetyl chloride,
DMAP, chloroform, dimethoxymethane, P2O5, 2-methoxy-
ethoxymethyl chloride, iPr2NEt, 1-chlorooctane, 1-bromooctane,
TEMPO, 3-bromo-1-chloropropane, 3-bromo-1-chloropentane,
ethyl 6-bromohexanoate, 2-(2-bromoethyl)-1,3-dioxolane and D2O
(99.9%) were used without further treatment. Silica gel, Wakogel
C-200 was obtained from Wako Pure Chemical Industries, Ltd. and
Silica Gel 60, from Merck. Solvents were purified before use: Et2O
and THF were distilled from sodium benzophenone ketyl; hexane,
HMPA, dichloroethane, benzene and CH2Cl2 were distilled from
CaH2. All reactions were carried out under argon. Reaction temper-
atures were bath temperature (MeOH/liq N2). All reactions were
monitored by TLC on 0.25 mm E. Merck silica gel plates (60F-
254), where materials were detected by a UV lamp and applying the
5% ethanolic solution of phosphomolybdenic acid and heat.
with Et3GeNa followed by D2O (99.9%) trapping of the
active intermediate afforded 98% of the desired deuteride,
64% of thiophenol,7 and 99% (based on the starting cya-
nide) of Et3GeGeEt3 (Scheme 2).
Moreover, when phenyl triethylgermyl sulfide
(Et3GeSC6H5) was treated with a catalytic amount of
Et3GeNa, thiophenol (64%)7 and Et3GeGeEt3 (91%, based
on Et3GeSC6H5 + Et3GeNa) were obtained (Scheme 3).8
Scheme 3
Judging from all these results, the reaction mechanism
was considered as follows. At first, 2-fluoro-2-phenyl-2-
phenylthioacetonitrile was transformed to the correspond-
ing a-cyano-a-fluoro carbanion and Et3GeSC6H5 by
Et3GeNa. This fluorinated carbanion was stable at under
–30 °C, but it was decomposed at 0 °C (Table 1, entries 2,
3, 8, and 9 vs 1 and 7). It was thought that this step pro-
gressed through one-electron transfer from a germanate
anion to the starting sulfide or the nucleophilic attack of a
germyl anion to the sulfur atom of a cyanide. It was clear
that the driving force of this reaction was the thiophilicity
of the germanium atom.5,9 Thus, Et3GeSC6H5 was formed
easily by the thiophilic character of the germanium atom
and a-cyano-a-fluoro carbanion was obtained effectively.
In the second step, the former species (carbanion) reacted
with an organic bromide to form the cyanofluoromethyl-
ene compound, and the latter compound was decomposed
to thiophenol and Et3GeGeEt3 by a catalytic amount of a
germanate anion. Furthermore, a phenyl sulfide was ob-
tained from the reaction of thiophenol with an organic
bromide.
2-Fluoro-2-phenyl-2-phenylthioacetonitrile
To a solution of 2-phenyl-2-phenylthioacetonitrile (6.0 g, 26.6
mmol) in dichloroethane (100 mL) was added 1-fluoropyridinium
trifluoromethanesulfonate (11.8 g, 47.7 mmol). After stirring for 3.5
h at reflux temperature, the mixture was poured on to ice-water and
was extracted with Et2O. The dried, concentrated organic phase was
passed through a short column of silica gel (Wakogel C-200) and
eluted with Et2O. Concentration of this eluate followed by crystal-
lization in hexane afforded the product as white crystals; yield: 5.0
g (77%); mp 73–74 °C.
1H NMR: d = 7.69–7.76 (m, 4 H), 7.44–7.55 (m, 6 H).
13C NMR: d = 136.37 (s), 133.55 (d, JC,F = 23.4 Hz), 130.94 (d, JC,F
= 15.4 Hz), 129.47 (s), 128.95 (s), 128.71 (d, JC,F = 1.5 Hz), 125.28
(d, JC,F = 2.3 Hz), 114.28 (d, JC,F = 43.7 Hz), 97.36 (d, JC,F = 227.5
Hz).
19F NMR: d = –118.37 (s).
Synthesis 1999, No. 4, 676–682 ISSN 0039-7881 © Thieme Stuttgart · New York

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Chemoselective Syntheses of Various Cyanofluoromethylene Compounds
679
IR (KBr): n = 3070, 2235, 1572, 1390, 1457, 1219, 1026, 976, 864,
13C NMR: d = 95.24 (s), 71.59 (s), 67.24 (s), 66.50 (s), 58.80 (s),
33.46 (s), 32.33 (s), 28.63 (s), 24.71 (s).
762, 691 cm–1.
MS (70 eV): m/z (%) = 243 (M+, 100), 224 (M+ – F, 5), 217 (M+ –
CN, 5), 198 (M+ – CN – F, 5), 166 (M+ – Ph, 5), 134 (M+ – SPh,
100), 115 (M+ – F – SPh, 3), 109, (SPh, 100), 108 (M+ – CN – SPh,
55), 77 (Ph, 32).
IR (neat): n = 2940, 1471, 1281, 1244, 1200, 1119, 1046, 1042, 936,
851, 642, 561 cm–1.
MS (70 eV): m/z (%) = 256 (M+81[Br], 1), 254 (M+79[Br], 1), 225
(M+81[Br] – CH3O, 10), 223 (M+79[Br] – CH3O, 11), 181 (M+81[Br]
– C3H7O2, 42), 179 (M+79[Br] – C3H7O2, 43), 151 (M+81[Br] –
C4H9O3, 100), 149 (M+79[Br] – C4H9O3, 100), 105 (C4H9O3, 100).
HRMS: m/z calcd for C14H10FNS: 243.0518; found: 243.0559.
HRMS: m/z calcd for C9H1981BrO3: 256.0497; found: 256.0496 and
5-Bromopentyl Trimethylacetate
calcd for C9H1979BrO3: 254.0518; found: 254.0526.
To a solution of 5-bromopentan-1-ol (2.5 g, 15.0 mmol) in benzene
(30 mL) were added trimethylacetyl chloride (1.9 g, 15.7 mmol), a
catalytic amount of DMAP and pyridine (1.4 g, 17.7 mmol) at r.t.
After stirring for 17 h, the mixture was poured on to ice-water and
was extracted with Et2O. The dried, concentrated organic phase was
purified by column chromatography [silica gel (Silica Gel 60), hex-
ane/Et2O 10:1] to give the product as a clear oil; yield: 1.5 g (40%).
1H NMR: d = 4.07 (t, 2 H, J = 6.4 Hz), 3.42 (t, 2 H, J = 6.8 Hz), 1.90
(tt, 2 H, J = 7.1 and 6.8 Hz), 1.70–1.63 (m, 2 H), 1.56–1.49 (m, 2
H), 1.20 (s, 9 H).
13C NMR: d = 178.32 (s), 63.78 (s), 38.57 (s), 33.32 (s), 32.11 (s),
27.64 (s), 27.06 (s), 24.44 (s).
IR (neat): n = 2967, 1728, 1284, 1153, 1457, 580 cm–1.
MS (70 eV): m/z (%) = 252 (M+81[Br], 28), 250 (M+79[Br], 28), 171
(M+ – Br, 5), 167 (M+81[Br] – C5H9O, 1), 165 (M+79[Br] – C5H9O,
1), 151 (M+81[Br] – C5H9O2, 100), 149 (M+79[Br] – C5H9O2, 100),
101, (C5H9O2, 2), 85 (C5H9O, 100).
2-Fluoro-2-phenyldecanenitrile; Typical Procedure
To a solution of 2-fluoro-2-phenyl-2-phenylthioacetonitrile (37.7
mg, 0.155 mmol) in THF (2 mL) was slowly added 0.42 N Et3GeNa
in HMPA (0.4 mL) at –60 °C. After stirring for 0.25 h at –60 °C, the
temperature was lowered to –80 °C, and 1-bromooctane (44.9 mg,
0.233 mmol) was added to the mixture. The mixture was stirred for
0.5 h at –80 °C and then was passed through a short column of silica
gel (Wakogel C-200) and eluted with Et2O. Concentration of this
eluate followed by column chromatographic purification (Silica Gel
60, hexane/Et2O 15:1) afforded the title compound; yield: 37.1 mg
(97%). Moreover, 16.0 mg (46%) of octyl phenyl sulfide and 24.6
mg (99%, based on 2-fluoro-2-phenyl-2-phenylthioacetonitrile) of
Et3GeGeEt3 were obtained as byproducts.
When this reaction was carried out on a ten-times scale, the desired
compound was obtained in 97% yield (371 mg).
When this reaction was carried out using 2.1 equiv amount of 1-bro-
mooctane (62.8 mg, 0.325 mmol), the corresponding compound,
octyl phenyl sulfide and Et3GeGeEt3 were obtained in 97% (37.0
mg), 99% (34 mg), and 99% (24.6 mg, based on 2-fluoro-2-phenyl-
2-phenylthioacetonitrile) yields, respectively.
HRMS: m/z calcd for C10H1981BrO2: 252.0548; found: 252.0591 and
calcd for C10H1979BrO2: 250.0568; found: 250.0567.
5-Bromopentyl Methoxymethyl Ether
To a solution of 5-bromopentan-1-ol (2.5 g, 15.0 mmol) in CHCl3
(60 mL) were added dimethoxymethane (3.4 g, 44.7 mmol) and a
catalytic amount of P2O5 at r.t. After stirring for 3 h, the mixture was
poured on to ice-water and was extracted with Et2O. The dried, con-
centrated organic phase was purified by column chromatography
[silica gel (Silica Gel 60), hexane/Et2O 7:1] to give the product as a
clear oil; yield: 1.7 g (54%).
1H NMR: d = 4.62 (s, 2 H), 3.54 (t, 2 H, J = 6.2 Hz), 3.42 (t, 2 H, J
= 6.8 Hz), 3.36 (s, 3 H), 1.90 (tt, 2 H, J = 7.1 and 6.8 Hz), 1.66–1.58
(m, 2 H), 1.57–1.49 (m, 2 H).
When this reaction was carried out in the presence of TEMPO (24.2
mg, 0.155 mmol), the corresponding compound was obtained in
95% yield (36.5 mg).
1H NMR: d = 7.51–7.42 (m, 5 H), 2.27–2.07 (m, 2 H), 1.60–1.43 (m,
2 H), 1.35–1.43 (m, 10 H), 0.87 (t, 3 H, J = 6.8 Hz).
13C NMR: d = 136.34 (d, JC,F = 23.0 Hz), 129.78 (d, JC,F = 1.9 Hz),
128.86 (s), 125.59 (d, JC,F = 6.1 Hz), 117.38 (d, JC,F = 34.1 Hz),
92.06 (d, JC,F = 183.8 Hz), 41.68 (d, JC,F = 25.3 Hz), 31.73 (s), 29.17
(s), 29.05 (s), 28.98(s), 23.78 (d, JC,F = 3.5 Hz), 22.58 (s), 14.05 (s).
19F NMR: d = –146.94 (dd, JF,H = 25.2 and 16.6 Hz).
13C NMR: d = 96.26 (s), 67.27 (s), 55.00 (s), 33.53 (s), 32.43 (s),
28.76 (s), 24.81 (s).
IR (neat): n = 2957, 2250, 1495, 1466, 1379, 1334, 1225, 1098,
1001, 931, 764, 714 cm–1.
IR (neat): n = 2984, 1456, 1281, 1252, 1246, 1144, 1111, 1078,
1042, 939, 644, 565 cm–1.
MS (70 eV): m/z (%) = 212 (M+81[Br], 2), 210 (M+79[Br], 2), 181
(M+81[Br] – CH3O, 10), 179 (M+79[Br] – CH3O, 11), 151 (M+81[Br]
– C2H5O2, 100), 149 (M+79[Br] – C2H5O2, 100), 131 (M+ – Br, 2).
MS (70 eV): m/z (%) = 247 (M+, 8), 221 (M+ – CN, 5), 135 (M+ –
C8H16, 100), 134 (M+ – C8H17, 46), 113 (C8H17, 1), 77 (Ph, 13).
HRMS: m/z calcd for C16H22FN: 247.1736; found: 247.1784.
HRMS: m/z calcd for C7H1581BrO2: 212.0235; found: 212.0280 and
5-Chloro-2-fluoro-2-phenylpentanenitrile
calcd for C10H1979BrO2: 210.0255; found: 210.0253.
This compound (clear oil) was synthesized in 95% yield (31.1 mg,
Table 2, entry 1) from 1-bromo-3-chloropropane in a similar man-
ner (column chromatographic purification: hexane/Et2O 30:1) to
that described in the Typical Procedure.
1H NMR: d = 7.53–7.45 (m, 5 H), 3.62–3.57 (m, 2 H), 2.45–2.29 (m,
2 H), 2.13–2.01 (m, 2 H).
13C NMR: d = 135.69 (d, JC,F = 22.6 Hz), 130.11 (d, JC,F = 1.5 Hz),
129.06 (s), 124.54 (d, JC,F = 6.1 Hz), 116.98 (d, JC,F = 34.1 Hz),
91.41 (d, JC,F = 184.5 Hz), 43.69 (s), 39.07 (d, JC,F = 25.3 Hz), 26.91
(d, JC,F = 3.1 Hz).
5-Bromopentyl 2-Methoxyethoxymethyl Ether
To a solution of 5-bromopentan-1-ol (2.5 g, 15.0 mmol) in CH2Cl2
(70 mL) were added 2-methoxyethoxymethyl chloride (4.1 g, 32.9
mmol) and iPr2NEt (4.5 g, 34.8 mmol) at r.t.. After stirring for 2 h,
the mixture was poured on to ice-water and was extracted with
Et2O. The dried, concentrated organic phase was purified by col-
umn chromatography [silica gel (Silica Gel 60), hexane/Et2O 3:1] to
give the product as a clear oil; yield: 1.8 g (47%).
1H NMR: d = 4.72 (s, 2 H), 3.71–3.68 (m, 2 H), 3.58–3.56 (m, 2 H),
3.56 (t, 2 H, J = 6.2 Hz), 3.42 (t, 2 H, J = 6.8 Hz), 3.40 (s, 3 H), 1.89
(tt, 2 H, J = 7.3 and 6.8 Hz), 1.66–1.58 (m, 2 H), 1.57–1.47 (m, 2 H).
19F NMR: d = –148.08 (dd, JF,H = 25.2 and 16.1 Hz).
IR (neat): n = 2946, 2240, 1495, 1451, 1317, 1292, 1234, 1069,
1001, 931, 856, 829, 760, 715, 654 cm–1.
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Y. Yokoyama, K. Mochida
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MS (70 eV): m/z (%) = 213 (M+37[Cl], 33), 211 (M+35[Cl], 100), 194
(M+37[Cl] – F, 0.3), 192 (M+35[Cl] – F, 1), 187 (M+37[Cl] – CN, 1),
185 (M+35[Cl] – F, 3), 176 (M+ – Cl, 75), 157 (M+ – Cl – F, 2), 150
(M+ – Cl – CN, 2), 148 (M+ – Cl – C2H4, 30), 136 (M+37[Cl] – Ph,
66), 134 (M+35[Cl] – Ph, 100), 117 (M+37[Cl] – F – Ph, 6), 115
(M+35[Cl] – F – Ph, 32), 110 (M+37[Cl] – CN – Ph, 30), 108
(M+35[Cl] – CN – Ph, 100), 77 (Ph, 100).
1H NMR: d = 8.05–8.02 (m, 2 H), 7.58–7.37 (m, 8 H), 4.31 (t, 2 H,
J = 6.6 Hz), 2.28–2.12 (m, 2 H), 1.79 (tt, 2 H, J = 14.5 and 6.6 Hz),
1.70–1.50 (m, 4 H).
13C NMR: d = 166.52 (s), 136.10 (d, JC,F = 22.6 Hz), 132.88 (s),
130.26 (s), 129.87 (d, JC,F = 1.9 Hz), 129.50 (s), 128.92 (s), 128.33
(s), 124.53 (d, JC,F = 6.1 Hz), 117.26 (d, JC,F = 34.1 Hz), 91.86 (d,
JC,F = 184.1 Hz), 64.61 (s), 41.57 (d, JC,F = 24.9 Hz), 28.44 (s), 25.63
HRMS: m/z calcd for C11H1137ClFN: 213.0534; found: 213.0491
(s), 23.60 (d, JC,F = 3.5 Hz).
19F NMR: d = –147.31 (dd, JF,H = 24.1 and 14.9 Hz).
and calcd for C11H1135ClFN: 211.0563; found: 211.0576.
IR (neat): n = 2953, 2250, 1719, 1603, 1464, 1387, 1316, 1275,
7-Chloro-2-fluoro-2-phenylheptanenitrile
1115, 1071, 1026, 763, 714 cm–1.
This compound (clear oil) was synthesized in 96% yield (35.6 mg,
Table 2, entry 2) from 1-bromo-5-chloropentane in a similar man-
ner (column chromatographic purification: hexane/Et2O 30:1) to
that described in the Typical Procedure.
1H NMR: d = 7.52–7.44 (m, 5 H), 3.52 (t, 2 H, J = 6.6 Hz), 2.27–
2.10 (m, 2 H), 1.79 (tt, 2 H, J = 13.9 and 6.6 Hz), 1.66–1.43 (m, 4
MS (30 eV): m/z (%) = 325 (M+, 1), 306 (M+ – F, 1), 204 (M+ –
C7H5O2, 2), 203 (M+ – C7H6O2, 15), 178 (M+ – F – C7H5O2, 5), 177
(M+ – F – C7H6O2, 45), 123 (M+ – CN – F – C9H10O2, 46), 105
(C7H5O, 100), 77 (Ph, 3).
HRMS: m/z calcd for C20H20FNO2: 325.1478; found: 325.1470.
H).
13C NMR: d = 136.10 (d, JC,F = 23.1 Hz), 129.91 (d, JC,F = 1.9 Hz),
128.95 (s), 124.54 (d, JC,F = 6.5 Hz), 117.23 (d, JC,F = 34.1 Hz),
91.85 (d, JC,F = 184.1 Hz), 44.61 (s), 41.52 (d, JC,F = 25.3 Hz), 32.12
(s), 26.24 (s), 23.20 (d, JC,F = 3.5 Hz).
2-Fluoro-2-phenyl-7-(trimethylacetoxy)heptanenitrile
This compound (clear oil) was synthesized in 92% yield (43.6 mg,
Table 2, entry 5) from 5-bromopentyl trimethylacetate in a similar
manner (column chromatographic purification: hexane/Et2O 6:1) to
that described in the Typical Procedure.
1H NMR: d = 7.51–7.44 (m, 5 H), 4.03 (t, 2 H, J = 6.6 Hz), 2.23–
2.09 (m, 2 H), 1.68–1.53 (m, 4 H), 1.46–1.34 (m, 2 H), 1.18 (s, 9 H).
13C NMR: d = 178.52 (s), 136.12 (d, JC,F = 22.6 Hz), 129.86 (d, JC,F
= 1.5 Hz), 128.91 (s), 124.53 (d, JC,F = 6.1 Hz), 117.24 (d, JC,F = 34.1
Hz), 91.85 (d, JC,F = 184.1 Hz), 63.97 (s), 41.58 (d, JC,F = 24.9 Hz),
38.69 (s), 28.31 (s), 27.15 (s), 25.52 (s), 23.55 (d, JC,F = 3.5 Hz).
19F NMR: d = –147.37 (dd, JF,H = 25.2 and 16.1 Hz).
IR (neat): n = 3094, 2955, 2240, 1495, 1464, 1317, 1271, 1223,
1094, 1001, 952, 843, 764, 734, 698, 652 cm–1.
MS (70 eV): m/z (%) = 241 (M+37[Cl], 47), 239 (M+35[Cl], 100), 222
(M+37[Cl] – F, 0.3), 220 (M+35[Cl] – F, 1), 215 (M+37[Cl] – CN, 1),
213 (M+35[Cl] – F, 4), 204 (M+ – Cl, 13), 185 (M+ – Cl – F, 1), 178
(M+ – Cl – CN, 1), 164 (M+37[Cl] – Ph, 1), 162 (M+35[Cl] – Ph, 4),
159 (M+ – Cl – CN, 1), 137 (M+37[Cl] – CN – C6H6, 33), 135
(M+35[Cl] – CN – C6H6, 100), 118 (M+37[Cl] – CN – F – C6H6, 2),
116 (M+35[Cl] – CN – F – C6H6, 25), 77 (Ph, 60).
19F NMR: d = –147.33 (dd, JF,H = 24.1 and 14.9 Hz).
IR (neat): n = 2940, 2240, 1726, 1480, 1453, 1398, 1365, 1284,
1159, 1034, 1001, 937, 765, 698 cm–1.
HRMS: m/z calcd for C13H1537ClFN: 241.0847; found: 241.0802
MS (30 eV): m/z (%) = 305 (M+, 4), 286 (M+ – F, 4), 204 (M+ –
C5H9O2, 69), 178 (M+ – CN – C5H9O2, 14), 177 (M+ – CN –
C5H10O2, 100), 158 (M+ – CN – F – C5H10O2, 100), 85 (C5H9O2,
100).
and calcd for C13H1535ClFN: 239.0876; found: 239.0837.
7-Acetoxy-2-fluoro-2-phenylheptanenitrile
This compound (clear oil) was synthesized in 96% yield (39.1 mg
Table 2, entry 3) from 5-bromopentyl acetate in a similar manner
(column chromatographic purification: hexane/Et2O 6:1) to that de-
scribed in the Typical Procedure.
1H NMR: d = 7.51–7.43 (m, 5 H), 4.04 (t, 2 H, J = 6.6 Hz), 2.30–
2.09 (m, 2 H), 2.04 (s, 3 H), 2.03–1.49 (m, 4 H), 1.46–1.38 (m, 2 H).
13C NMR: d = 171.13 (s), 136.13 (d, JC,F = 23.0 Hz), 129.88 (d, JC,F
= 1.9 Hz), 128.93 (s), 124.54 (d, JC,F = 6.1 Hz), 117.25 (d, JC,F = 34.1
Hz), 91.86 (d, JC,F = 183.8 Hz), 64.13 (s), 41.54 (d, JC,F = 24.9 Hz),
28.25 (s), 25.48 (s), 23.54 (d, JC,F = 3.1 Hz), 20.94 (s).
HRMS: m/z calcd for C18H24FNO2: 305.1791; found: 305.1776.
Ethyl 7-Cyano-7-fluoro-7-phenylheptanoate
This compound (clear oil) was synthesized in 98% yield (42.0 mg,
Table 2, entry 6) from ethyl 6-bromohexanoate in a similar manner
(column chromatographic purification: hexane/Et2O 6:1) to that de-
scribed in the Typical Procedure.
1H NMR: d = 7.51–7.44 (m, 5 H), 4.12 (q, 2 H, J = 7.1 Hz), 2.28 (t,
2 H, J = 7.3 Hz), 2.27–2.12 (m, 2 H), 1.67–1.46 (m, 4 H), 1.43–1.37
(m, 2 H), 1.25 (t, 3 H, J = 7.1 Hz).
19F NMR: d = –147.31 (dd, JF,H = 24.1 and 14.9 Hz).
13C NMR: d = 173.42 (s), 136.16 (d, JC,F = 22.6 Hz), 129.85 (d, JC,F
= 1.5 Hz), 128.91 (s), 124.55 (d, JC,F = 6.1 Hz), 117.27 (d, JC,F = 34.1
Hz), 91.90 (d, JC,F = 183.8 Hz), 60.27 (s), 41.46 (d, JC,F = 25.3 Hz),
33.98 (s), 28.42 (s), 24.49(s), 23.50 (d, JC,F = 3.5 Hz), 14.21 (s).
IR (neat): n = 2953, 2250, 1738, 1464, 1367, 1244, 1037, 766, 698
cm–1.
MS (30 eV): m/z (%) = 263 (M+, 1), 244 (M+ – F, 2), 220 (M+ –
C2H3O, 1), 204 (M+ – C2H3O2, 5), 201 (M+ – F – C2H3O, 20), 192
(M+ – CN – C2H3O, 1), 185, (M+ – F – C2H3O2, 2), 178 (M+ – CN –
C2H3O2, 13), 177 (M+ – CN – C2H4O2, 100), 158 (M+ – CN – F –
C2H4O2, 1), 157 (M+ – CN – F – C2H3O2, 10), 129 (C7H13O2, 78).
19F NMR: d = –147.29 (dd, JF,H = 24.1 and 16.1 Hz).
IR (neat): n = 2940, 2250, 1732, 1464, 1375, 1259, 1183, 1115,
1030, 920, 766, 698 cm–1.
MS (30 eV): m/z (%) = 277 (M+, 1), 258 (M+ – F, 10), 249 (M+ –
CN, 3), 248 (M+ – C2H5, 22), 232 (M+ – OC2H5, 5), 230 (M+ – CN
– F, 3), 214 (M+ – F – C2H5O, 14), 204 (M+ – C3H5O2, 6), 185, (M+
– F – C3H5O2, 8), 177 (M+ – CN – C3H4O2, 100), 176 (M+ – CN –
C3H5O2, 13), 171 (M+ – F – C4H7O2, 4), 143 (M+ – CN – F –
C4H7O2, 17), 73 (C3H5O2, 2).
HRMS: m/z calcd for C15H18FNO2: 263.1322; found: 263.1345.
7-Benzoyloxy-2-fluoro-2-phenylheptanenitrile
This compound (clear oil) was synthesized in 96% yield (48.4 mg,
Table 2, entry 4) from 5-bromopentyl benzoate in a similar manner
(column chromatographic purification: hexane/Et2O 5:1) to that de-
scribed in the Typical Procedure.
HRMS: m/z calcd for C16H20FNO2: 277.1478; found: 277.1432.
Synthesis 1999, No. 4, 676–682 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Chemoselective Syntheses of Various Cyanofluoromethylene Compounds
681
2-Fluoro-7-(methoxymethoxy)-2-phenylheptanenitrile
This compound (clear oil) was synthesized in 96% yield (39.5 mg,
Table 2, entry 7) from 5-bromopentyl methoxymethyl ether in a
similar manner (column chromatographic purification: hexane/
Et2O 3:1) to that described in the Typical Procedure.
MS (70 eV): m/z (%) = 235 (M+, 1), 234 (M+ – H, 3), 215 (M+ – HF,
2), 157 (M+ – C6H6, 18), 130 (M+ – HCN – C6H6, 5), 129 (M+ – H
– HCN – C6H6, 36), 77 (Ph, 3), 73 (C3H5O2, 100).
HRMS: m/z calcd for C13H14FNO2: 235.1009; found: 235.0993.
1H NMR: d = 7.51–7.42 (m, 5 H), 4.60 (s, 2 H), 3.50 (t, 2 H, J = 6.4
Hz), 3.34 (s, 3 H), 2.30–2.08 (m, 2 H), 1.69–1.40 (m, 6 H).
Trapping Experiment of an Active Intermediate by Use of D2O
(Scheme 2)
13C NMR: d = 136.21 (d, JC,F = 23.0 Hz), 129.84 (d, JC,F = 1.5 Hz),
128.90 (s), 124.58 (d, JC,F = 5.6 Hz), 117.31 (d, JC,F = 34.1 Hz),
96.37 (s), 91.93 (d, JC,F = 183.8 Hz), 67.30 (s), 55.12 (s), 41.63 (d,
This experiment was carried out by use of D2O in a similar manner
(column chromatographic purification: hexane/Et2O 30:1) to that
described in the Typical Procedure. 2-Deutero-2-fluoro-2-phe-
nylacetonitrile, thiophenol and Et3GeGeEt3 were obtained in 98%
(21.1 mg), 64% (11 mg), and 99% (24.6 mg, based on 2-fluoro-2-
phenyl-2-phenylthioacetonitrile) yields, respectively.
JC,F = 25.3 Hz), 29.33 (s), 25.73 (s), 23.61 (d, JC,F = 3.5 Hz).
19F NMR: d = –147.09 (dd, JF,H = 25.1 and 14.9 Hz).
IR (neat): n = 2957, 2250, 1495, 1466, 1379, 1334, 1225, 1098,
2-Deutero-2-fluoro-2-phenylacetonitrile
1001, 931, 764, 714 cm–1.
1H NMR: d = 7.57–7.54 (m, 5 H).
MS (30 eV): m/z (%) = 265 (M+, 5), 234 (M+ – OCH3, 2), 233 (M+
– CH4O, 5), 220 (M+ – CN – F, 1), 204 (M+ – C2H5O2, 21), 190 (M+
– C3H7O2, 100), 171 (M+ – F – C3H7O2, 6), 169 (M+ – F – Ph, 1),
164 (M+ – CN – C3H7O2, 1), 162 (M+ – CN – Ph, 1), 145 (M+ – CN
– F – C3H7O2, 3), 143 (M+ – CN – F – Ph, 13), 129 (M+ – CN – F –
Ph – CH2, 89), 113 (C8H17, 1), 77 (Ph, 3), 75 (C3H7O2, 25), 61
(C2H5O2, 12).
13C NMR: d = 131.22 (d, JC,F = 3.1 Hz), 129.34 (s), 129.32 (s),
127.51 (d, JC,F = 4.2 Hz), 115.21 (d, JC,F = 33.8 Hz), 79.88 (dt, JC,D
= 24.6 Hz, JC,F = 180.7 Hz).
19F NMR: d = –168.53 (t, JF,D = 6.9 Hz).
IR (neat): n = 3069, 2260, 1497, 1455, 1250, 1092, 1071, 939, 858,
760, 696, 637 cm–1.
MS (70 eV): m/z (%) = 136 (M+, 100), 117 (M+ – F, 45), 110 (M+ –
HRMS: m/z calcd for C15H20FNO2: 265.1478; found: 265.1519.
CN, 100), 91 (M+ – CN – F, 88), 77 (Ph, 34).
2-Fluoro-7-(2-methoxyethoxymethoxy)-2-phenylheptanenitrile
This compound (clear oil) was synthesized in 96% yield (46.0 mg,
Table 2, entry 8) from 5-bromopentyl 2-methoxyethoxymethyl
ether in a similar manner (column chromatographic purification:
hexane/Et2O 3:2) to that described in the Typical Procedure.
1H NMR: d = 7.51–7.44 (m, 5 H), 4.69 (s, 2 H), 3.68–3.66 (m, 2 H),
3.56–3.54 (m, 2 H), 3.53 (t, 2 H, J = 6.4 Hz), 3.39 (s, 3 H), 2.26–
2.09 (m, 2 H), 1.66–1.41 (m, 6 H).
13C NMR: d = 136.18 (d, JC,F = 23.0 Hz), 129.82 (d, JC,F = 1.5 Hz),
128.88 (s), 124.55 (d, JC,F = 6.5 Hz), 117.28 (d, JC,F = 34.1 Hz),
95.42 (s), 91.91 (d, JC,F = 183.8 Hz), 71.75 (s), 67.41 (s), 66.69 (s),
58.99 (s), 41.59 (d, JC,F = 25.3 Hz), 29.27 (s), 25.69 (s), 23.60 (d,
HRMS: m/z calcd for C8H5DFN: 136.0547; found: 136.0529.
Reaction of Et3GeSC6H5 with a Catalytic Amount of Et3GeNa
(Scheme 3)
To a solution of Et3GeSC6H5 (41.7 mg, 0.155 mmol) in THF (2
mL)/HMPA (0.36 mL) was slowly added a solution of Et3GeNa in
HMPA (0.037 mL, 0.43 N) at –60 °C. The mixture was stirred for 1
h at –60 °C and then was passed through a short column of silica gel
(Wakogel C-200), and eluted with Et2O. Concentration of this elu-
ate followed by column chromatographic purification (Silica Gel
60, hexane) afforded 24.8 mg (91%, based on Et3GeSC6H5
Et3GeNa) of Et3GeGeEt3. Moreover, 11.0 mg (64%) of thiophenol
was obtained.
+
JC,F = 3.5 Hz).
19F NMR: d = –147.09 (dd, JF,H = 24.4 and 16.0 Hz).
References
IR (neat): n = 2936, 2240, 1452, 1366, 1242, 1171, 1115, 1053, 934,
766, 698 cm–1.
(1) For selected reviews, see:
MS (30 eV): m/z (%) = 309 (M+, 2), 290 (M+ – F, 1), 289 (M+ – HF,
3), 234 (M+ – C3H7O2, 10), 233 (M+ – C3H8O2, 3), 232 (M+ – Ph,
10), 214 (M+ – F – C3H8O2, 29), 185 (M+ – F – C4H9O3, 30), 184
(M+ – F – C4H10O3, 100), 159 (M+ – CN – F – C4H9O3, 1), 158 (M+
– CN – F – C4H10O3, 7), 105 (C4H9O3, 20), 89 (C4H9O2, 45).
Banks, R. E. Organofluorine Chemicals and Their Industrial
Applications; Soc. Chem. Ind.: London, 1979.
Filler, R.; Kobayashi, Y. Biomedical Aspects of Fluorine
Chemistry; Kodansha Ltd.: Tokyo, 1982.
Liebman, J. K.; Greenberg, A.; Dolbier Jr., W. R. Fluorine-
Containing Molecules, Structure, Reactivity, Synthesis; VCH:
New York, 1988.
HRMS: m/z calcd for C17H24FNO3: 309.1740; found: 309.1727.
Welch, J. T.; Eshwarakrishman, S. Fluorine in Bioorganic
Chemistry; Wiley: New York, 1991.
(2) For a review and some papers, see:
2-(3-Cyano-3-fluoro-3-phenylpropyl)-1,3-dioxolane
This compound (clear oil) was synthesized in 96% yield (35.0 mg,
Table 2, entry 9) from 2-(2-bromoethyl)-1,3-dioxolane in a similar
manner (column chromatographic purification: hexane/Et2O 4:1) to
that described in the Typical Procedure.
1H NMR: d = 7.52–7.43 (m, 5 H), 4.94 (t, 1 H, J = 4.2 Hz), 3.97–
3.91 (m, 2 H), 3.90–3.84 (m, 2 H), 2.45–2.17 (m, 2 H), 1.99–1.86
(m, 2 H).
13C NMR: d = 135.90 (d, JC,F = 22.6 Hz), 129.93 (d, JC,F = 1.5 Hz),
128.95 (s), 124.60 (d, JC,F = 6.1 Hz), 117.10 (d, JC,F = 34.1 Hz),
102.70 (s), 91.55 (d, JC,F = 184.5 Hz), 76.68 (s), 65.06 (d, JC,F = 1.9
Hz), 35.52 (d, JC,F = 25.7 Hz) 28.10 (d, JC,F = 2.7 Hz)
Takeuchi, Y. J. Syn. Org. Chem. Jpn. 1997, 55, 886.
Takeuchi, Y.; Takagi, K.; Yamaba, T.; Nabetani, M.;
Koizumi, T. J. Fluorine Chem. 1994, 68, 149.
Takeuchi, Y.; Kawahara, S.; Suzuki, S.; Koizumi, T. J. Org.
Chem. 1996, 61, 301.
(3) For example, Takeuchi, Y.; Itoh, N.; Satoh, T.; Koizumi, T.;
Yamaguchi, K. J. Org. Chem. 1993, 58, 1812 and references
cited therein.
(4) Pews, R. G.; Lysenko, Z. J. Org. Chem. 1985, 50, 5115.
(5) Yokoyama, Y.; Mochida, K. J. Chem Soc., Chem. Commun.
1998, 1093.
19F NMR: d = –148.22 (dd, JF,H = 24.1 and 17.2 Hz).
(6) Bulten, E. J.; Noltes, J. G. Tetrahedron Lett. 1966, 4389.
Bulten, E. J.; Noltes, J. G. Tetrahedron Lett. 1967, 1443.
IR (neat): n = 3545, 2973, 2250, 1736, 1668, 1495, 1412, 1217,
1143, 1032, 976, 947, 883, 763, 698 cm–1.
Synthesis 1999, No. 4, 676–682 ISSN 0039-7881 © Thieme Stuttgart · New York

682
Y. Yokoyama, K. Mochida
PAPER
(7) In this reaction, thiophenol was probably obtained
quantitatively, but we could not isolate it perfectly because of
its volatility. In contrast, diphenyl disulfide which was formed
by the aerobic oxidation of thiophenol or the radical coupling
reaction was not detected at all.
intermediate in the present method was stable, because two
electron-withdrawing groups (phenyl and cyano substituents)
were attached to the anion center. For a review, see Chambers,
R. D. Fluorine in Organic Chemistry; Wiley: New York,
1973.
(8) It was thought that 0.1 equiv of Et3GeNa acted as initiator of
this reaction, but we could not make clear its reaction
mechanism. Further investigation is in progress.
(9) Yokoyama, Y.; Mochida, K. Synlett 1996, 1191.
Yokoyama, Y.; Mochida, K. Tetrahedron Lett. 1997, 38,
3443.
(11) 2-Phenyl-2-phenylthioacetonitrile: Fortes, C. C.; Okino, E. A.
Synth. Commun. 1990, 20, 1943.
5-Bromopentyl acetate: Manchand, P. S.; Micheli, R. A.;
Saposnik, S. J. Tetrahedron 1992, 48, 9391.
5-Bromopentyl benzoate: Kabalka, G. W.; Sastry, K. A. R.;
Hsu, H. C.; Hylarides, M. D. J. Org. Chem. 1981, 46, 3113.
Et3GeSC6H5: Kobayashi, M.; Kobayashi, M.; Yoshida, M.
Bull. Chem. Soc. Jpn. 1985, 58, 473.
Yokoyama, Y.; Mochida, K. Synlett 1997, 907.
Yokoyama, Y.; Mochida, K. Synlett 1998, 37.
(10) The a-fluorinated carbanion was unstable owing to its p–p
repulsion. On the other hand, it was thought that the active
Synthesis 1999, No. 4, 676–682 ISSN 0039-7881 © Thieme Stuttgart · New York