Intramolecular cyclizations of o-substituted β,β-difluorostyrenes: Synthesis of 3-fluorinated isochromenes and isothiochromenes

Article abstract of DOI:10.1246/bcsj.74.971

β,β-Difluorostyrenes bearing an oxygen (OH) or a sulfur (SH, SCOCH₃) nucleophile linked by a methylene unit to the ortho carbon are prepared from 2,2,2-trifluoroethyl p-toluenesulfonate via the in situ generation of 2,2-difluorovinylboranes and their palladium-catalyzed cross-coupling reaction with aryl iodides. These styrene derivatives readily undergo intramolecular nucleophilic substitution of the oxygen and sulfur with loss of fluorine under basic conditions, leading to 3-fluoroisochromenes and 3-fluoroisothiochromenes in high yields.

Full text of DOI:10.1246/bcsj.74.971

c. Jpn.
© 2001 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 74, 971—977 (2001)
971
e Chemical
ciety of Ja-
n
e Chemical
ciety of Ja-
n
β β
Intramolecular Cyclizations of o-Substituted , -Difluorostyrenes:
Synthesis of 3-Fluorinated Isochromenes and Isothiochromenes
Synthesis of 3-Fluoroiso(thio)chromenes
Y. Wada et al.
Yukinori Wada, Junji Ichikawa,* Tadayuki Katsume,† Tomoko Nohiro,† Tatsuo Okauchi,† and
Toru Minami†,*
01
1
7
Department of Chemistry, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033
†Department of Applied Chemistry, Kyushu Institute of Technology, Sensui-cho, Tobata, Kitakyushu 804-8550
SJA8
09-2673
384
(Received November 7, 2000)
vember
00
00
β,β-Difluorostyrenes bearing an oxygen (OH) or a sulfur (SH, SCOCH3) nucleophile linked by a methylene unit to
the ortho carbon are prepared from 2,2,2-trifluoroethyl p-toluenesulfonate via the in situ generation of 2,2-difluorovi-
nylboranes and their palladium-catalyzed cross-coupling reaction with aryl iodides. These styrene derivatives readily
undergo intramolecular nucleophilic substitution of the oxygen and sulfur with loss of fluorine under basic conditions,
leading to 3-fluoroisochromenes and 3-fluoroisothiochromenes in high yields.
.3
3.2
gem-Difluoroolefins are susceptible to nucleophilic attack,
which occurs exclusively at the difluoromethylene carbon.1
The orientation of attack is governed so that the fluorines are
placed at the position β to the electron-rich carbon in the tran-
sition state to avoid electron-pair repulsion. In our recent pub-
lications,2 we have reported the application of this unique reac-
tivity to the nucleophilic 5-endo-trig cyclizations of gem-
difluoroolefins bearing functional groups such as NHTs, OH,
and SH, a cyclization process that is disfavored according to
Baldwin’s rules.3 This 5-membered ring formation proceeds
via intramolecular substitution of vinylic fluorine (addition–
elimination processes)1 to provide ring-fluorinated heterocy-
cles such as indoles, benzo[b]furans, benzo[b]thiophenes, 2-
pyrrolines, 2,3-dihydrofurans, and 2,3-dihydrothiophenes in
high yields. The properties of gem-difluoroolefins: (i) the
highly polarized C–C double bond which allows initial ring
closure and (ii) the successive elimination of fluoride ion
which suppresses the reverse ring opening, play an important
role in this “anti-Baldwin” cyclization.
In continuation of our research on the cyclizations of gem-
difluoroolefins,2,4 we sought to apply the intramolecular substi-
tution concept to the construction of 6-membered heterocyclic
compounds. Our attention was focused on selectively ring-flu-
orinated isochromenes (1H-2-benzopyran derivatives)5 and
isothiochromenes (1H-2-benzothiopyran derivatives)6 as syn-
thetic targets, compounds which could be employed as inter-
mediates in the synthesis of medicinal and agrochemical
agents.7–9 For that purpose β,β-difluorostyrene derivatives
with an oxygen (OH) or a sulfur (SH) nucleophile linked by a
methylene unit to the ortho carbon were designed and subject-
ed to the ring-forming reaction under basic conditions. Herein
we wish to report the results of our studies on the synthesis of
3-fluoroisochromenes and 3-fluoroisothiochromenes.
or a Sulfur Nucleophile. The starting materials, o-substitut-
ed β,β-difluorostyrenes, were easily prepared from 2,2,2-triflu-
oroethyl p-toluenesulfonate (1) using the one-pot method
which we have previously established: the in situ generation of
2,2-difluorovinylboranes 2 and their palladium-catalyzed
cross-coupling reaction with aryl iodides (Scheme 1).10 Diflu-
orostyrenes 3 bearing a hydroxymethyl group at the ortho po-
sition, precursors of 3-fluoroisochromenes, were successfully
obtained by the direct coupling of 2 with the corresponding
aryl iodides (Scheme 1, route A). Thus, o-iodobenzyl alcohols
were pretreated with equimolar amounts of dibutylmagnesium
or methylmagnesium iodide to generate the magnesium alkox-
ides, which in turn coupled with 2 in the presence of a palladi-
um catalyst to afford the desired styrenes 3a–c (55–69%) from
1. The butylmagnesium alkoxides gave slightly better results,
probably due to their solubility.
Alcohols 3 were also obtained via another route, which al-
lows the introduction of a substituent (R2) on the benzylic car-
bon (Scheme 1, route B). The coupling of 2a with o-iodoben-
zaldehyde afforded difluorostyrene 4a bearing an o-formyl
group in an 84% yield determined by 19F NMR, while the iso-
lated yield was 62% because of its instability. The addition of
nucleophiles such as Grignard reagents and diisobutylalumi-
num hydride to 4 regioselectively occurred at the formyl car-
bon in toluene to give 3a,d–f.
As sulfur-containing substrates for the synthesis of 3-fluor-
oisothiochromenes, thioacetates 6 were readily prepared from
1 via mesylates 5 in a one-pot operation by (i) the coupling re-
action of 2 with o-iodobenzyl methanesulfonate and (ii) the
successive introduction of an acetylthio group at the benzylic
position on treatment with sodium thioacetate (Scheme 1,
route C). Thioacetate 6a was transformed into thiol 7a via
transesterification with K2CO3 in methanol.
β β
Cyclization of , -Difluorostyrenes Bearing an Oxygen
or a Sulfur Nucleophile. We next attempted the cyclization
Results and Discussion
β β
Preparation of , -Difluorostyrenes Bearing an Oxygen
of the difluorostyrenes obtained above under basic conditions.

972 Bull. Chem. Soc. Jpn., 74, No. 5 (2001)
Synthesis of 3-Fluoroiso(thio)chromenes
Scheme 1.
Preparation of β,β-difluorostyrenes functionalized at the ortho position.
i, nBuLi (2.1 mol. amt.), THF, ꢀ78 ˚C, 0.5 h; ii, BR13 (1.1 mol. amt.), THF, ꢀ78 ˚C, 1 h then r.t., 3 h; iii, ArI (0.9 mol. amt.), CuI
(1.0–1.1 mol. amt.), Pd2(dba)3•CHCl3 (0.02 mol. amt.), PPh3 (0.08 mol. amt.), r.t., 3a: 17 h; 3b: 5 h; 3c: 4 h; 4a: 0.3 h; 5a: 5 h; 5b:
4 h; iv, 3a: DIBAL (1.5 mol. amt.), toluene, 0 ˚C, 0.5 h; 3d: MeMgI (1.5 mol. amt.), toluene, 0 ˚C, 0.3 h; 3e: nBuMgBr (1.2 mol.
amt.), toluene, 0 ˚C, 0.3 h; 3f: PhMgBr (1.5 mol. amt.), toluene, ꢀ78 ˚C, 0.5 h; v, AcSNa (1.5 mol. amt.), THF, r.t., 10 h; vi,
K2CO3 (2.4 mol. amt.), MeOH, r.t., 1.5 h.
a) Determined by 19F NMR. b) Isolated yield.
Although treatment of 3a with 1.0 molar amount of butyllithi-
um in tetrahydrofuran (THF) resulted in a complex mixture of
products, the expected intramolecular substitution was effected
by the use of NaH (1.1 molar amount) or KH (1.2 molar
amount) in dimethylformamide (DMF) at room temperature,
where the cyclized product, 3-fluoroisochromene 8a, was ob-
tained in 78% or 72% yields, respectively (Table 1, Entries 1
and 2). Furthermore, adding 2 molar amounts of NaH im-
proved the yield of 8a to 84% (Entry 3). This cyclization in 6-
endo-trig fashion smoothly proceeded under milder conditions,
compared to the 5-endo-trig process, affording 2-fluoroben-
zo[b]furan at 60 ˚C.2a
In a similar manner, several other 3-fluoroisochromenes 8
were synthesized from o-(hydroxymethyl)styrenes 3. The ring
closure of 3b bearing a secondary alkyl group (R1) at the vinyl-
ic position successfully proceeded to afford 8b in an 84% yield
(Entry 4). Even in the case of secondary alcohols 3c–f, the cy-
clization of the corresponding alkoxides occurred under simi-
lar conditions, leading to 8c–f including fused tricyclic com-
pound 8c in 50–71% yields, which are lower than those of
Table 1.
Synthesis of 3-Fluoroisochromenes 8
Entry
R1
R2
R3
Substrate
Base (mol. amt.)
Conditions
Yield/%
1
2
3
4
5
6
7
8
nBu
nBu
nBu
sBu
nBu
nBu
nBu
nBu
H
H
H
H
H
H
H
H
3a
3a
3a
3b
3c
3d
3e
3f
NaH (1.1)
KH (1.2)
r.t., 1.5 h
r.t., 2.0 h
r.t., 1.2 h
r.t., 1.7 h
r.t., 2.2 h
r.t., 2.0 h
r.t., 2.0 h
r.t., 2.0 h
78 (8a)
72 (8a)
84 (8a)
84 (8b)
66 (8c)
60 (8d)
71 (8e)
50 (8f)
NaH (2.0)
NaH (2.0)
NaH (1.9)
NaH (2.0)
NaH (2.0)
NaH (2.0)
–(CH2)3–
Me
H
H
H
nBu
Ph

Y. Wada et al.
Bull. Chem. Soc. Jpn., 74, No. 5 (2001) 973
Synthesis of 3-Fluoroisothiochromenes 9
Table 2.
Entry
Y
R1
Substrate
Base (mol. amt.)
Solvent
Conditions
Yield/%
1
2
3
4
H
nBu
nBu
nBu
sBu
7a
6a
6a
6b
KH (1.2)
THF
MeOH
DMF
DMF
r.t., 2.5 h
60 ˚C, 8.5 h
r.t., 0.3 h
90 (9a)
61 (9a)
94 (9a)
90 (9b)
Ac
Ac
Ac
K2CO3 (1.2)
NaOMe (2.0)
NaOMe (2.0)
r.t., 0.3 h
spectra were obtained on a JEOL JNM-A-500 spectrometer.
Chemical shift values were given in ppm relative to internal Me4Si
primary alcohols 8a,b, probably due to their steric hindrance
(Entries 5–8).
1
(for H and 13C NMR: δ-value) or internal C6F6 (for 19F NMR).
In addition, we tried this intramolecular substitution with
sulfur nucleophiles. On treatment of thiol 7a with KH (1.2
molar amount) in DMF, the corresponding 3-fluoroisothio-
chromene 9a was obtained in a 90% yield (Table 2, Entry 1).
Having found the cyclization of the potassium thiolate, we ex-
amined the combination of the two processes of deacetylation
(6 → 7) and cyclization (7 → 9) into a one-pot operation, so as
to refine the synthesis of 9 to make it more efficient. After the
deacetylation of 6a with K2CO3 (1.2 molar amount) in MeOH,
the reaction mixture was heated at 60 ˚C to drive the in situ
generated thiolate to undergo the cyclization, and 9a was ob-
tained in a 61% yield (Entry 2). Screening of the reaction con-
ditions such as base and solvent revealed that treatment of 6a,b
with sodium methoxide (2.0 molar amount) in DMF succes-
sively promoted the two processes to proceed without heating,
leading to 9a,b in excellent yields (Entries 3 and 4).
Mass spectra were taken with a JEOL JMS-DX-300 or a JEOL
JMS-SX-102A spectrometer. Elemental analyses were performed
with aYANAKO MT-3 CHN Corder apparatus. THF was distilled
from sodium diphenylketyl prior to use. Methanol was distilled
from magnesium methoxide and stored over molecular sieves 3A.
DMF was dried over P2O5, then distilled under reduced pressure
from CaH2 and stored over molecular sieves 4A. Commercial
NaH and KH were used without further purification. Sodium
methoxide was prepared from sodium and excess methanol, and
then dried under vacuum at 100 ˚C.
o-(1-Butyl-2,2-difluorovinyl)benzyl Alcohol (3a):
Butyl-
lithium (1.9 mL, 1.6 M in hexane (1 M ꢁ 1 mol dmꢀ3), 3.1 mmol)
was added to a solution of 2,2,2-trifluoroethyl p-toluenesulfonate
(368 mg, 1.5 mmol) in THF (7.5 mL) at ꢀ78 ˚C over 10 min un-
der a nitrogen atmosphere. The reaction mixture was stirred for
20 min at ꢀ78 ˚C, and then tributylborane (1.7 mL, 1.0 M in THF,
1.7 mmol) was added at ꢀ78 ˚C. After being stirred for 1 h, the
reaction mixture was warmed to room temperature and stirred for
an additional 3 h. The solution was treated with hexamethylphos-
phoric triamide (HMPA, 1.5 mL), triphenylphosphine (30 mg,
0.12 mmol), and tris(dibenzylideneacetone)dipalladium–chloro-
form (1/1) (30 mg, 0.029 mmol) and this mixture was stirred for
15 min. To the solution was added the magnesium salt (generated
from o-iodobenzyl alcohol (307 mg, 1.3 mmol) and dibutylmag-
nesium (1.3 mL, 1.0 M in Et2O, 1.3 mmol) in THF (3 mL) at 0 ˚C
for 30 min) and copper(I) iodide (304 mg, 1.6 mmol). After the
mixture had been stirred for 17 h at room temperature, the reaction
was quenched with phosphate buffer (pH 7). The mixture was fil-
tered, and then organic materials were extracted with ethyl acetate
(AcOEt) three times. The combined extracts were washed with
brine and dried over Na2SO4. After removal of the solvent under
reduced pressure, the residue was purified by thin layer chroma-
tography on silica gel (hexane–AcOEt 5:1) to give 3a (205 mg,
69%) as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ 0.86
(3H, t, J ꢁ 7.0 Hz), 1.25–1.35 (4H, m), 1.97 (1H, br s), 2.25–2.31
(2H, m), 4.62 (2H, s), 7.14 (1H, dd, J ꢁ 7.6, 1.4 Hz), 7.28 (1H,
ddd, J ꢁ 7.6, 7.6, 1.4 Hz), 7.34 (1H, ddd, J ꢁ 7.6, 7.6, 1.4 Hz),
7.53 (1H, d, J ꢁ 7.6 Hz). 13C NMR (126 MHz, CDCl3) δ 13.8,
22.4, 29.1, 29.6 (d, JCF ꢁ 2 Hz), 62.6 (d, JCF ꢁ 2 Hz), 90.5 (dd,
JCF ꢁ 22, 17 Hz), 127.6, 127.9, 128.3, 129.9 (d, JCF ꢁ 5 Hz),
132.2 (d, JCF ꢁ 5 Hz), 139.5, 152.6 (dd, JCF ꢁ 289, 284 Hz). 19F
NMR (470 MHz, CDCl3) 67.8 (1F, dt, JFF ꢁ 47, JFH ꢁ 3 Hz), 72.2
(1F, d, JFF ꢁ 47 Hz) ppm. IR (neat) 3300, 2960, 2880, 1740,
1240, 1135, 1045, 790, 765, 735 cmꢀ1. MS (70 eV) m/z (rel inten-
The remaining fluorines in the cyclized products 9 were ex-
pected to be replaced by nucleophiles via similar addition–
elimination processes.1 On treatment of 9a with potassium
benzenethiolate as a nucleophile, the desired 10a was obtained
as shown in Scheme 2.
Scheme 2.
Introduction of substituent at the 3-position.
In conclusion, we have disclosed that our concept of in-
tramolecular nucleophilic substitution of vinylic fluorines can
be successfully applied to the construction of 6-membered
rings as well as 5-membered rings. o-Substituted β,β-difluo-
rostyrenes, prepared from CF3CH2OTs, trialkylboranes, and
aryl iodides, readily undergo 6-membered ring closure, provid-
ing a facile method for the construction of a selectively ring-
fluorinated benzo(thio)pyran framework.
Experimental
General. IR spectra were recorded on a Shimadzu IR-408
spectrometer or a JEOL JIR-WINSPEC50 spectrometer. NMR

974 Bull. Chem. Soc. Jpn., 74, No. 5 (2001)
Synthesis of 3-Fluoroiso(thio)chromenes
sity) 226 (Mꢂ; 38), 159 (87), 117 (100). HRMS Found: m/z
226.1176. Calcd for C13H16OF2: M, 226.1170.
mL), triphenylphosphine (30 mg, 0.11 mmol), and tris(diben-
zylideneacetone)dipalladium–chloroform (1/1) (29 mg, 0.028
mmol) and this mixture was stirred for 15 min. To the solution
was added o-iodobezaldehyde (738 mg, 3.2 mmol) and copper(I)
iodide (757 mg, 4.0 mmol). After the mixture was stirred for 0.3 h
at room temperature, the reaction was quenched with phosphate
buffer (pH 7). The mixture was filtered, and then organic materi-
als were extracted with AcOEt three times. The combined extracts
were washed with brine and dried over Na2SO4. After removal of
the solvent under reduced pressure, the residue was purified by
thin layer chromatography on silica gel (Et2O–hexane 1:20) to
give 4a (441 mg, 62%) as a pale yellow liquid. 1H NMR (500
MHz, CDCl3) δ 0.86 (3H, t, J ꢁ 7.2 Hz), 1.29–1.35 (4H, m),
2.37–2.43 (2H, m), 7.31 (1H, dd, J ꢁ 7.6, 0.6 Hz), 7.47 (1H, dd, J
ꢁ 7.6, 7.6 Hz), 7.61 (1H, ddd, J ꢁ 7.6, 7.6, 1.5 Hz), 7.96 (1H, dd,
J ꢁ 7.6, 1.5 Hz), 10.16 (1H, m). 13C NMR (126 MHz, CDCl3) δ
13.6, 22.2, 29.5 (d, JCF ꢁ 3 Hz), 29.5, 89.1 (dd, JCF ꢁ 24, 17 Hz),
128.3, 128.6, 130.6 (d, JCF ꢁ 2 Hz), 133.9, 134.1, 137.3 (d, JCF ꢁ
4 Hz), 152.7 (dd, JCF ꢁ 290, 287 Hz), 191.1. 19F NMR (470 MHz,
CDCl3) 70.0 (1F, dt, JFF ꢁ 43, JFH ꢁ 3 Hz), 72.8 (1F, dd, JFF ꢁ 43,
o-(1-s-Butyl-2,2-difluorovinyl)benzyl Alcohol (3b): Com-
pound 3b was prepared by the method described for 3a using
2,2,2-trifluoroethyl p-toluenesulfonate (254 mg, 1.0 mmol), butyl-
lithium (1.4 mL, 1.5 M in hexane, 2.1 mmol), tri-s-butylborane
(1.1 mL, 1.0 M in THF, 1.1 mmol), hexamethylphosphoric tria-
mide (1.4 mL), triphenylphosphine (21 mg, 0.080 mmol),
tris(dibenzylideneacetone)dipalladium–chloroform (1/1) (21 mg,
0.020 mmol), o-iodobenzyl alcohol (213 mg, 0.90 mmol) and me-
thylmagnesium iodide (1.0 mL, 0.89 M in THF, 0.90 mmol), and
copper(I) iodide (209 mg, 1.1 mmol) in THF (8 mL). Purification
by thin layer chromatography on silica gel (chloroform–AcOEt
20:1) gave 3b (123 mg, 61%) as a pale yellow liquid. 1H NMR
(500 MHz, (CD3)2SO, 100 ˚C) δ 0.92 (3H, t, J ꢁ 7.0 Hz), 1.02
(3H, d, J ꢁ 7.0 Hz), 1.26–1.40 (1H, m), 1.55 (1H, dqd, J ꢁ 14.0,
7.0, 7.0 Hz), 2.41 (1H, tq, J ꢁ 7.0, 7.0 Hz), 3.00 (1H, br s), 4.47
(2H, s), 7.08 (1H, d, J ꢁ 7.5 Hz), 7.23 (1H, ddd, J ꢁ 7.5, 7.5, 1.2
Hz), 7.32 (1H, ddd, J ꢁ 7.5, 7.5, 1.2 Hz), 7.56 (1H, d, J ꢁ 7.5
Hz). 13C NMR (126 MHz, (CD3)2SO, 100 ˚C) δ 11.1, 17.3, 27.0,
35.1, 60.1, 94.0 (dd, JCF ꢁ 24, 16 Hz), 125.8, 127.0, 127.2, 129.0
J
FH ꢁ 2 Hz) ppm. IR (neat) 2970, 2950, 2890, 1840, 1745, 1705,
(d, JCF ꢁ 2 Hz), 130.3 (d, JCF ꢁ 4 Hz), 140.7, 151.4 (dd, JCF
ꢁ
1600, 1470, 1465, 1245 cmꢀ1. MS (70 eV) m/z (rel intensity) 224
(Mꢂ; 20), 205 (44), 131 (100), 91 (44). HRMS Found: m/z
224.1000. Calcd for C13H14OF2: M, 224.1012.
290, 284 Hz). 19F NMR (470 MHz, (CD3)2SO, 100 ˚C) 70.2 (1F,
br s), 74.9 (1F, d, JFF ꢁ 47 Hz) ppm. IR (neat) 3330, 2990, 1735,
1460, 1290, 1235, 1200, 1065, 1020, 935, 760, 670 cmꢀ1. MS (70
eV) m/z (rel intensity) 226 (Mꢂ; 60), 159 (99), 129 (100). HRMS
Found: m/z 226.1171. Calcd for C13H16OF2: M, 226.1170.
o-(1-Butyl-2,2-difluorovinyl)benzyl Alcohol (3a): To a so-
lution of 4a (204 mg, 0.91 mmol) in toluene (6 mL) was added
DIBAL (1.4 mL, 0.95 M in hexane, 1.4 mmol) at 0 ˚C under a ni-
trogen atmosphere. After the reaction mixture was stirred for 30
min, phosphate buffer (pH 7) was added to quench the reaction.
Organic materials were extracted with AcOEt three times. The
combined extracts were washed with brine and dried over Na2SO4.
After removal of the solvent under reduced pressure, the residue
was purified by thin layer chromatography on silica gel (hexane–
AcOEt 5:1) to give 3a (90 mg, 44%) as a colorless liquid.
1-[o-(1-Butyl-2,2-difluorovinyl)phenyl]ethanol (3d): Com-
pound 3d was prepared by the method described for 3a using 4a
(210 mg, 0.93 mmol) and methylmagnesium iodide (1.4 mL, 1.0
M in Et2O, 1.4 mmol) in toluene (6 mL). Purification by thin layer
chromatography on silica gel (hexane–AcOEt 5:1) gave 3d (124
mg, 55%) as a pale yellow liquid. 1H NMR (500 MHz, CDCl3) δ
0.88 (3H, t, J ꢁ 7.0 Hz), 1.30–1.32 (4H, m), 1.44 (3H, d, J ꢁ 6.3
Hz), 1.89 (1H, br s), 2.16–2.36 (2H, m), 5.00 (1H, q, J ꢁ 6.3 Hz),
7.09 (1H, d, J ꢁ 7.7 Hz), 7.26 (1H, ddd, J ꢁ 7.7, 7.7, 1.2 Hz),
7.37 (1H, ddd, J ꢁ 7.7, 7.7, 1.2 Hz), 7.61 (1H, dd, J ꢁ 7.7, 1.2
Hz). 13C NMR (126 MHz, CDCl3) δ 13.8, 22.4, 24.8, 29.4, 29.6,
66.8, 90.6 (dd, JCF ꢁ 22, 17 Hz), 125.8, 127.5, 128.6, 129.9,
131.3, 144.5, 152.7 (dd, JCF ꢁ 285, 285 Hz). 19F NMR (470 MHz,
CDCl3) 72.2 (1F, br s), 67.7 (1F, br s) ppm. IR (neat) 3369, 2960,
2861, 1741, 1456, 1232, 1132, 1076, 966, 762 cmꢀ1. MS (20 eV)
m/z (rel intensity) 240 (Mꢂ; 41), 220 (93). HRMS Found: m/z
249.1333. Calcd for C14H18OF2: M, 240.1326.
8-(1-Butyl-2,2-difluorovinyl)-1,2,3,4-tetrahydro-1-naphthol
(3c): Compound 3c was prepared by the method described for
3a using 2,2,2-trifluoroethyl p-toluenesulfonate (165 mg, 0.65
mmol), butyllithium (0.82 mL, 1.7 M in hexane, 1.4 mmol), tribu-
tylborane (0.71 mL, 1.0 M in THF, 0.71 mmol), hexamethylphos-
phoric triamide (1 mL), triphenylphosphine (14 mg, 0.053 mmol),
tris(dibenzylideneacetone)dipalladium–chloroform (1/1) (13 mg,
0.013 mmol), 8-iodo-1,2,3,4-tetrahydro-1-naphthol (156 mg, 0.57
mmol) and dibutylmagnesium (1.1 mL, 0.51 M in Et2O, 0.57
mmol) and copper(I) iodide (136 mg, 0.71 mmol) in THF (4 mL).
Purification by thin layer chromatography on silica gel (hexane–
AcOEt 4:1) gave 3c (84 mg, 55%) as a pale yellow liquid. 1H
NMR (500 MHz, (CD3)2SO, 120 ˚C) δ 0.85 (3H, t, J ꢁ 7.0 Hz),
1.24–1.37 (4H, m), 1.58–1.70 (2H, m), 1.90–2.07 (2H, m), 2.21–
2.30 (1H, m), 2.37–2.45 (1H, m), 2.62–2.70 (1H, m), 2.80 (1H, t,
J ꢁ 4.6 Hz), 4.18 (1H, br s), 4.66 (1H, br s), 6.91 (1H, d, J ꢁ 7.6
Hz), 7.04 (1H, d, J ꢁ 7.6 Hz), 7.14 (1H, dd, J ꢁ 7.6, 7.6 Hz). 13C
NMR (126 MHz, (CD3)2SO, 120 ˚C) δ 13.4, 16.8, 21.7, 28.8, 29.0,
29.1 (dd, JCF ꢁ 3, 3 Hz), 32.0, 63.3, 91.9 (dd, JCF ꢁ 21, 17 Hz),
126.8, 127.6 (d, JCF ꢁ 2 Hz), 128.7, 134.1 (d, JCF ꢁ 5 Hz), 137.8
(d, JCF ꢁ 3 Hz), 138.0, 152.2 (dd, JCF ꢁ 284, 281 Hz). 19F NMR
(470 MHz, (CD3)2SO, 120 ˚C) 67.2 (1F, br d, JFF ꢁ 49 Hz), 73.0
(1F, br s) ppm. IR (neat) 3350, 2950, 1745, 1470, 1240, 1135,
1075, 1035, 1005, 785 cmꢀ1. MS (70 eV) m/z (rel intensity) 266
(Mꢂ; 6), 246 (43), 175 (54), 155 (100). HRMS Found: m/z
266.1461. Calcd for C16H20OF2: M, 266.1483.
1-[o-(1-Butyl-2,2-difluorovinyl)phenyl]pentan-1-ol
(3e):
Compound 3e was prepared by the method described for 3a using
4a (141 mg, 0.63 mmol) and butylmagnesium bromide (0.69 mL,
1.1 M in THF, 0.76 mmol) in toluene (4 mL). Purification by thin
layer chromatography on silica gel (hexane–AcOEt 5:1) gave 3e
(137 mg, 77%) as a pale yellow liquid. 1H NMR (500 MHz,
(CD3)2SO, 120 ˚C) δ 0.84 (3H, t, J ꢁ 7.2 Hz), 0.84 (3H, t, J ꢁ 7.0
Hz), 1.22–1.42 (8H, m), 1.46–1.55 (1H, m), 1.58–1.68 (1H, m),
2.21–2.32 (2H, m), 4.50 (1H, br d, J ꢁ 4.6 Hz), 4.54–4.60 (1H,
m), 7.05 (1H, d, J = 7.6 Hz), 7.20 (1H, dd, J ꢁ 7.6, 7.6 Hz), 7.31
(1H, dd, J ꢁ 7.6, 7.6 Hz), 7.53 (1H, d, J ꢁ 7.6 Hz). 13C NMR
o-(1-Butyl-2,2-difluorovinyl)benzaldehyde (4a): Butyllithi-
um (5.0 mL, 1.7 M in hexane, 8.4 mmol) was added to a solution
of 2,2,2-trifluoroethyl p-toluenesulfonate (1.0 g, 4.0 mmol) in
THF (20 mL) at ꢀ78 ˚C over 10 min under a nitrogen atmosphere.
The reaction mixture was stirred for 20 min at ꢀ78 ˚C, and then
tributylborane (4.4 mL, 1.0 M in THF, 4.4 mmol) was added at
ꢀ78 ˚C. After being stirred for 1 h, the reaction mixture was
warmed to room temperature and stirred for an additional 3 h.
The solution was treated with hexamethylphosphoric triamide (5

Y. Wada et al.
Bull. Chem. Soc. Jpn., 74, No. 5 (2001) 975
(126 MHz, (CD3)2SO, 120 ˚C) δ 12.5, 12.8, 21.0, 21.2, 27.1, 28.0,
28.3 (dd, JCF ꢁ 5, 3 Hz), 37.8, 68.6, 91.0 (dd, JCF ꢁ 22, 17 Hz),
125.8, 125.8, 127.3, 128.9, 130.3 (d, JCF ꢁ 5 Hz), 144.4, 151.6
(dd, JCF ꢁ 287, 283 Hz). 19F NMR (470 MHz, (CD3)2SO, 120 ˚C)
67.9 (1F, d, JFF ꢁ 50 Hz), 73.1 (1F, d, JFF ꢁ 50 Hz) ppm. IR
(neat) 3379, 2958, 2862, 1741, 1468, 1234, 1132, 1045, 972, 760
cmꢀ1. MS (20 eV) m/z (rel intensity) 282 (Mꢂ; 38), 145 (23), 88
(100). HRMS Found: m/z 282.1802. Calcd for C17H24OF2: M,
282.1795.
tris(dibenzylideneacetone)dipalladium–chloroform (1/1) (21 mg,
0.020 mmol), 2-iodobenzyl methanesulfonate (282 mg, 0.90
mmol), copper(I) iodide (191 mg, 1.0 mmol), and thioacetic S-
acid (0.11 mL, 1.5 mmol) and sodium hydride (58 mg, 62% dis-
persion in mineral oil, 1.5 mmol) in THF (5 mL). Purification by
thin layer chromatography on silica gel (hexane–AcOEt 50:1)
gave 6b (128 mg, 50%) as a pale yellow liquid. 1H NMR (500
MHz, CDCl3, 50 ˚C) δ 0.90–1.64 (8H, m), 2.33 (3H, s), 2.32–2.38
(1H, m), 4.16 (2H, s), 7.08 (1H, br s), 7.20 (1H, ddd, J ꢁ 7.4, 7.4,
1.2 Hz), 7.26 (1H, dd, J ꢁ 7.4, 7.4 Hz), 7.37 (1H, d, J ꢁ 7.4 Hz).
IR (neat) 2970, 2940, 1735, 1695, 1235, 1135, 1105, 760, 670,
630 cmꢀ1. Found: C, 63.35; H, 6.44%. Calcd for C15H18OF2S: C,
63.36; H, 6.38%.
1-[o-(1-Butyl-2,2-difluorovinyl)phenyl]-1-phenylmethanol
(3f): Compound 3f was prepared by the method described for 3a
using 4a (114 mg, 0.51 mmol) and phenylmagnesium bromide
(0.81 mL, 0.94 M in THF, 0.76 mmol) in toluene (3 mL). Purifi-
cation by thin layer chromatography on silica gel (hexane–AcOEt
o-(1-Butyl-2,2-difluorovinyl)phenylmethanethiol
(7a):
1
5:1) gave 3f (83 mg, 54%) as a pale yellow liquid. H NMR (500
K2CO3 (168 mg, 1.2 mmol) was added to a solution of 6a (299
mg, 1.0 mmol) in methanol (3.5 mL) at 0 ˚C. After the reaction
mixture was stirred for 2 h, phosphate buffer (pH 7) was added to
quench the reaction. Organic materials were extracted with AcO-
Et three times. The combined extracts were washed with brine,
and then dried over Na2SO4. After removal of the solvent under
reduced pressure, the residue was purified by thin layer chroma-
tography on silica gel (hexane–AcOEt 20:1) to give 7a (207 mg,
86%) as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ 0.88
(3H, t, J ꢁ 6.9 Hz), 1.28–1.37 (4H, m), 1.73 (1H, t, J ꢁ 7.5 Hz),
2.26–2.36 (2H, m), 3.70 (2H, d, J ꢁ 7.5 Hz), 7.11 (1H, d, J ꢁ 7.3
Hz), 7.22 (1H, ddd, J ꢁ 7.3, 7.3, 1.2 Hz), 7.30 (1H, ddd, J ꢁ 7.3,
7.3, 1.2 Hz), 7.45 (1H, d, J ꢁ 7.3 Hz). 13C NMR (126 MHz,
CDCl3) δ 13.8, 22.4, 26.0, 29.0, 29.7, 90.7 (dd, JCF ꢁ 22, 17 Hz),
127.1, 128.5, 129.5, 130.3 (dd, JCF ꢁ 3, 3 Hz), 132.5 (d, JCF ꢁ 5
Hz), 139.9, 152.8 (dd, JCF ꢁ 289, 286 Hz). 19F NMR (470 MHz,
CDCl3) 67.9 (1F, d, JFF ꢁ 45 Hz), 73.1 (1F, d, JFF ꢁ 45 Hz) ppm.
IR (neat) 2960, 2940, 1750, 1315, 1290, 1240, 1135, 970, 765,
MHz, CDCl3) δ 0.84 (3H, br s), 1.28 (4H, br), 2.17–2.24 (2H, m),
2.30 (1H, br s), 5.92 (1H, s), 7.12 (1H, d, J ꢁ 7.3 Hz), 7.22–7.35
(7H, m), 7.49 (1H, dd, J ꢁ 7.9, 1.2 Hz). 13C NMR (126 MHz,
CDCl3) δ 13.7, 22.3, 29.0, 29.5, 72.6, 90.7 (dd, JCF ꢁ 23, 15 Hz),
126.6, 127.4, 127.5, 127.6, 128.3, 128.4, 130.2, 132.5 (d, JCF ꢁ 4
Hz), 142.3, 143.3, 152.7 (dd, JCF ꢁ 287, 287 Hz). 19F NMR (470
MHz, CDCl3) 73.1 (1F, br s), 67.9 (1F, d, JFF ꢁ 46 Hz) ppm. IR
(neat) 3381, 2958, 1741, 1452, 1236, 1132, 1018, 764, 700 cmꢀ1
.
MS (20 eV) m/z (rel intensity) 302 (Mꢂ; 21), 235 (94), 179 (100).
HRMS Found: m/z 302.1469. Calcd for C19H20OF2: M, 302.1482.
S-o-(1-Butyl-2,2-difluorovinyl)benzyl Thioacetate (6a):
Compound 6a was prepared by the method described for 4a using
2,2,2-trifluoroethyl p-toluenesulfonate (766 mg, 3.0 mmol), butyl-
lithium (3.8 mL, 1.7 M in hexane, 6.3 mmol), tributylborane (3.3
mL, 1.0 M in THF, 3.3 mmol), hexamethylphosphoric triamide
(3.5 mL), triphenylphosphine (189 mg, 0.72 mmol), tris(diben-
zylideneacetone)dipalladium–chloroform (1/1) (62 mg, 0.060
mmol), o-iodobenzyl methanesulfonate (846 mg, 2.7 mmol), and
copper(I) iodode (573 mg, 3.0 mmol) in THF (15 mL). To the re-
sulting solution of 5a was added a sodium thioacetate generated
from thioacetic S-acid (0.32 mL, 4.5 mmol) and sodium hydride
(175 mg, 62% dispersion in mineral oil, 4.5 mmol). After the
mixture had been stirred for 10 h at room temperature, the reaction
was quenched with phosphate buffer (pH 7). The mixture was fil-
tered, and then organic materials were extracted with AcOEt three
times. The combined extracts were washed with brine and dried
over Na2SO4. After removal of the solvent under reduced pres-
sure, the residue was purified by thin layer chromatography on sil-
ica gel (hexane–AcOEt 50:1) to give 6a (428 mg, 56%) as a pale
yellow liquid. 1H NMR (500 MHz, C6D5CD3, 90 ˚C) δ 0.81 (3H,
t, J ꢁ 7.3 Hz), 1.22 (2H, tq, J ꢁ 7.3, 7.3 Hz), 1.31 (2H, tt, J ꢁ 7.3,
7.3 Hz), 1.93 (3H, s), 2.23 (2H, tdd, J ꢁ 7.3 Hz, JHF ꢁ 2.3, 2.3
Hz), 4.12 (2H, s), 6.97–7.02 (3H, m), 7.23 (1H, d, J ꢁ 7.0 Hz).
13C NMR (126 MHz, C6D5CD3, 90 ˚C) δ 13.7, 22.7, 29.4, 29.6,
30.1 (dd, JCF ꢁ 3, 3 Hz), 31.3, 91.5 (dd, JCF ꢁ 39, 18 Hz), 127.6,
128.6, 130.6, 134.1 (d, JCF ꢁ 4 Hz), 137.2, 137.6, 153.7 (dd, JCF
ꢁ 289, 286 Hz), 193.1. 19F NMR (471 MHz, C6D5CD3, 90 ˚C)
69.1 (1F, d, JFF ꢁ 45 Hz), 74.7 (1F, d, JFF ꢁ 45 Hz) ppm. IR
670 cmꢀ1
.
MS (70 eV) m/z (rel intensity) 242 (Mꢂ; 51), 166
(100), 179 (44). HRMS Found: m/z 242.0912. Calcd for
C13H16F2S: M, 242.0941.
4-Butyl-3-fluoro-1H-2-benzopyran (8a): To a DMF suspen-
sion (0.5 mL) of sodium hydride (28 mg, 60% dispersion in min-
eral oil, 0.69 mmol) was added 3a (78 mg, 0.35 mmol) in DMF (1
mL) at 0 ˚C under a nitrogen atmosphere. After the reaction mix-
ture was stirred at room temperature for 1.2 h, phosphate buffer
(pH 7) was added to quench the reaction. Organic materials were
extracted with AcOEt three times. The combined extracts were
washed with brine and dried over Na2SO4. After removal of the
solvent under reduced pressure, the residue was purified by thin
layer chromatography on silica gel (hexane–AcOEt 5:1) to give
8a (60 mg, 84%) as a colorless liquid. 1H NMR (500 MHz,
CDCl3) δ 0.93 (3H, t, J ꢁ 7.4 Hz), 1.40 (2H, tq, J ꢁ 7.4, 7.4 Hz),
1.46–1.56 (2H, m), 2.42 (2H, td, J ꢁ 7.4, JHF ꢁ 1.4 Hz), 5.22 (2H,
s), 7.00 (1H, d, J ꢁ 7.5 Hz), 7.08–7.14 (2H, m), 7.25 (1H, dd, J ꢁ
7.5, 0.9 Hz). 13C NMR (126 MHz, CDCl3) δ 13.9, 22.4, 22.5,
30.7, 71.4, 89.0 (d, JCF ꢁ 23 Hz), 120.9 (d, JCF ꢁ 7 Hz), 123.7,
125.2, 126.6, 128.4, 133.3 (d, JCF ꢁ 6 Hz), 158.0 (d, JCF ꢁ 264
Hz). 19F NMR (471 MHz, CDCl3) 68.0 (1F, s) ppm. IR (neat)
(neat) 2950, 2925, 2850, 1740, 1690, 1240, 1130, 970, 760 cmꢀ1
.
2960, 2870, 1680, 1490, 1460, 1390, 1245, 1195, 760, 670 cmꢀ1
.
Found: C, 63.21; H, 6.44%. Calcd for C15H18OF2S: C, 63.36; H,
6.38%.
MS (70 eV) m/z (rel intensity) 206 (Mꢂ; 100), 164 (79), 135 (88),
115 (96). Found: C, 75.43; H, 7.45%. Calcd for C13H15OF: C,
75.70; H, 7.33%.
S-o-[1-s-Butyl-2,2-difluorovinyl]benzyl Thioacetate (6b):
Compound 6b was prepared by the method described for 6a using
2,2,2-trifluoroethyl p-toluenesulfonate (255 mg, 1.0 mmol), butyl-
lithium (1.3 mL, 1.7 M in hexane, 2.1 mmol), tri-s-butylborane
(1.1 mL, 1.0 M in THF, 1.1 mmol), hexamethylphosphoric tria-
mide (1.5 mL), triphenylphosphine (21 mg, 0.080 mmol),
4-s-Butyl-3-fluoro-1H-2-benzopyran (8b): Compound 8b
was prepared by the method described for 8a using sodium hy-
dride (16 mg, 60% dispersion in mineral oil, 0.40 mmol) and 3b
(45 mg, 0.20 mmol) in DMF (1 mL). Purification by thin layer
chromatography on silica gel (hexane–AcOEt 5:1) gave 8b (35

976 Bull. Chem. Soc. Jpn., 74, No. 5 (2001)
Synthesis of 3-Fluoroiso(thio)chromenes
mg, 84%) as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ
0.93 (3H, t, J ꢁ 7.4 Hz), 1.28 (3H, dd, J ꢁ 7.4, JHF ꢁ 1.2 Hz),
1.62 (1H, dqdd, J ꢁ 21.6, 7.4, 7.4, JHF ꢁ 1.2 Hz), 1.73 (1H, dqdd,
J ꢁ 21.6, 7.4, 7.4, JHF ꢁ 1.5 Hz), 2.67 (1H, tq, J ꢁ 7.4, 7.4 Hz),
5.17 (2H, s), 7.02 (1H, d, J ꢁ 7.3 Hz), 7.07–7.13 (1H, m), 7.21–
7.27 (2H, m). 13C NMR (126 MHz, CDCl3) δ 12.7, 19.3 (d, JCF ꢁ
3 Hz), 28.3 (d, JCF ꢁ 3 Hz), 32.0 (d, JCF ꢁ 2 Hz), 71.4, 93.8 (d, JCF
ꢁ 28 Hz), 121.4 (d, JCF = 6 Hz), 123.9, 125.1, 126.9, 128.3, 133.9
(d, JCF ꢁ 7 Hz), 158.2 (d, JCF ꢁ 268 Hz). 19F NMR (471 MHz,
CDCl3) 72.2 (1F, s) ppm. IR (neat) 2860, 1660, 1605, 1450, 1385,
1240, 1190, 1060, 930, 760 cmꢀ1. MS (70 eV) m/z (rel intensity)
206 (Mꢂ; 9), 167 (37), 149 (100). Found: C, 75.63; H, 7.36%.
Calcd for C13H15OF: C, 75.70; H, 7.33%.
3-Butyl-2-fluoro-7,8,9,9a-tetrahydro-1-oxaphenalene (8c):
Compound 8c was prepared by the method described for 8a using
sodium hydride (11 mg, 60% dispersion in mineral oil, 0.27
mmol) and 3c (36 mg, 0.14 mmol) in DMF (1.7 mL). Purification
by thin layer chromatography on silica gel (hexane–AcOEt 5:1)
gave 8c (22 mg, 66%) as a pale yellow liquid. 1H NMR (500
MHz, CDCl3) δ 0.93 (3H, t, J ꢁ 7.3 Hz), 1.33–1.57 (4H, m),
1.67–1.78 (1H, m), 1.93–2.10 (2H, m), 2.36–2.45 (3H, m), 2.69–
2.84 (2H, m), 5.26 (1H, dd, J ꢁ 10.1, 6.1 Hz), 6.91 (1H, d, J ꢁ 7.6
Hz), 6.95 (1H, d, J ꢁ 7.6 Hz), 7.16 (1H, dd, J ꢁ 7.6, 7.6 Hz). 13C
NMR (126 MHz, CDCl3) δ 13.9, 20.8, 22.4, 22.5, 28.3, 28.6, 30.8,
78.1, 89.6 (d, JCF ꢁ 23 Hz), 118.5 (d, JCF ꢁ 7 Hz), 125.8 (d, JCF ꢁ
2 Hz), 126.0, 128.0, 133.6 (d, JCF ꢁ 6 Hz), 135.4, 158.0 (d, JCF ꢁ
266 Hz). 19F NMR (471 MHz, CDCl3) 67.9 (1F, s) ppm. IR (neat)
2950, 2880, 1685, 1595, 1465, 1245, 1180, 1020, 810, 780, 755
cmꢀ1. MS (70 eV) m/z (rel intensity) 246 (Mꢂ; 78), 203 (58), 155
(100). HRMS Found: m/z 246.1418. Calcd for C16H19OF: M,
246.1421.
(d, JCF ꢁ 23 Hz), 121.2 (d, JCF ꢁ 7 Hz), 123.8, 125.0, 128.0,
130.5, 132.4 (d, JCF ꢁ 6 Hz), 156.2 (d, JCF ꢁ 264 Hz). 19F NMR
(471 MHz, CDCl3) 68.2 (1F, s) ppm. IR (neat) 2955, 2930, 2860,
1685, 1490, 1455, 1375, 1235, 1155, 965, 760 cmꢀ1. MS (70 eV)
m/z (rel intensity) 262 (Mꢂ; 89), 205 (89), 88 (100). HRMS
Found: m/z 262.1740. Calcd for C17H23OF: M, 262.1733.
4-Butyl-3-fluoro-1-phenyl-1H-2-benzopyran (8f):
Com-
pound 8f was prepared by the method described for 8a using sodi-
um hydride (36 mg, 60% dispersion in mineral oil, 0.91 mmol)
and 3f (137 mg, 0.45 mmol) in DMF (4 mL). Purification by thin
layer chromatography on silica gel (hexane–AcOEt 5:1) gave 8f
(64 mg, 50%) as a pale yellow liquid. 1H NMR (500 MHz,
CDCl3) δ 0.88 (3H, t, J ꢁ 7.3 Hz), 1.23–1.52 (4H, m), 2.38–2.45
(2H, m), 6.28 (1H, s), 6.77 (1H, d, J ꢁ 7.3 Hz), 7.08 (1H, ddd, J ꢁ
8.5, 8.5, 1.2 Hz), 7.28–7.39 (7H, m). 13C NMR (126 MHz,
CDCl3) δ 13.9, 22.3, 22.3, 30.5, 83.0, 89.2 (d, JCF ꢁ 23 Hz), 121.2
(d, JCF ꢁ 6 Hz), 125.2 (d, JCF ꢁ 2 Hz), 125.5, 128.0, 128.4, 128.6
(d, JCF ꢁ 3 Hz), 128.8, 129.3, 133.1 (d, JCF ꢁ 6 Hz), 138.1, 156.5
(d, JCF ꢁ 266 Hz). 19F NMR (471 MHz, CDCl3) 68.3 (1F, s) ppm.
IR (neat) 2929, 2872, 1726, 1680, 1493, 1454, 1387, 1232, 1151,
1093 cmꢀ1. MS (20 eV) m/z (rel intensity) 282 (Mꢂ; 41), 225
(100). HRMS Found: m/z 282.1429. Calcd for C19H19OF: M,
282.1420.
4-Butyl-3-fluoro-1H-2-benzothiopyran (9a): To a THF sus-
pension (6.5 mL) of potassium hydride (KH, 41 mg, 35% disper-
sion in mineral oil, 0.36 mmol) was added 7a (72 mg, 0.30 mmol)
in THF (1.5 mL) at 0 ˚C under a nitrogen atmosphere. After the
reaction mixture was stirred at room temperature for 2.5 h, phos-
phate buffer (pH 7) was added to quench the reaction. Organic
materials were extracted with AcOEt three times. The combined
extracts were washed with brine and dried over Na2SO4. After re-
moval of the solvent under reduced pressure, the residue was puri-
fied by thin layer chromatography on silica gel (hexane–AcOEt
20:1) to give 9a (61 mg, 90%) as a colorless liquid. 1H NMR
(500 MHz, CDCl3) δ 0.92 (3H, t, J ꢁ 7.3 Hz), 1.38 (2H, tq, J ꢁ
7.3, 7.3 Hz), 1.45–1.53 (2H, m), 2.66 (2H, td, J ꢁ 7.6, JHF ꢁ 3.4
Hz), 3.92 (2H, d, JHF ꢁ 4.9 Hz), 7.13 (1H, d, J ꢁ 7.6 Hz), 7.17
(1H, ddd, J ꢁ 7.5, 7.5, 1.5 Hz), 7.25 (1H, dd, J ꢁ 7.5, 7.5 Hz),
7.28 (1H, d, J ꢁ 7.5 Hz). 13C NMR (126 MHz, CDCl3) δ 13.9,
22.5, 24.8 (d, JCF ꢁ 4 Hz), 30.8 (d, JCF ꢁ 2 Hz), 33.6, 116.8 (d,
JCF ꢁ 14 Hz), 124.1 (d, JCF ꢁ 6 Hz), 126.6, 126.9, 127.6, 128.6,
134.6 (d, JCF ꢁ 4 Hz), 153.9 (d, JCF ꢁ 282 Hz). 19F NMR (471
MHz, CDCl3) 64.7 (1F, tt, JFH ꢁ 4, 4 Hz) ppm. IR (neat) 2960,
2890, 1620, 1570, 1490, 1450, 1155, 1100, 765 cmꢀ1. MS (70
eV) m/z (rel intensity) 222 (Mꢂ; 82), 179 (100), 146 (73), 135
(45). Found: C, 70.37; H, 6.85%. Calcd for C13H15FS: C, 70.23;
H, 6.80%.
4-Butyl-3-fluoro-1-methyl-1H-2-benzopyran (8d):
Com-
pound 8d was prepared by the method described for 8a using sodi-
um hydride (35 mg, 60% dispersion in mineral oil, 0.86 mmol)
and 3d (104 mg, 0.43 mmol) in DMF (3 mL). Purification by thin
layer chromatography on silica gel (hexane–AcOEt 5:1) gave 8d
(57 mg, 60%) as a pale yellow liquid. 1H NMR (500 MHz,
CDCl3) δ 0.93 (3H, t, J ꢁ 7.3 Hz), 1.39 (2H, tq, J ꢁ 7.3, 7.3 Hz),
1.50 (2H, tt, J ꢁ 7.3, 7.3 Hz), 1.63 (3H, d, J ꢁ 6.4 Hz), 2.42 (2H,
td, J ꢁ 7.3 Hz, JHF ꢁ 1.7 Hz), 5.42 (1H, q, J ꢁ 6.4 Hz), 7.00 (1H,
dd, J ꢁ 7.6, 0.6 Hz), 7.12 (1H, ddd, J ꢁ 7.6, 7.6, 0.6 Hz), 7.13
(1H, d, J ꢁ 7.6 Hz), 7.25 (1H, ddd, J ꢁ 7.6, 7.6, 0.6 Hz). 13C
NMR (126 MHz, CDCl3) δ 13.9, 19.4, 22.3, 22.4, 30.7, 77.8, 88.0
(d, JCF ꢁ 23 Hz), 121.1 (d, JCF ꢁ 7 Hz), 123.2, 125.2 (d, JCF ꢁ 2
Hz), 128.0, 131.2, 132.5 (d, JCF ꢁ 7 Hz), 156.5 (d, JCF ꢁ 264 Hz).
19F NMR (471 MHz, CDCl3) 68.2 (1F, s) ppm. IR (neat) 2960,
2930, 2860, 1685, 1560, 1490, 1460, 1375, 1360, 1240, 760 cmꢀ1
.
MS (70 eV) m/z (rel intensity) 220 (Mꢂ; 100), 163 (24), 149 (48),
129 (60). HRMS Found: m/z 220.1287. Calcd for C14H17OF: M,
220.1263.
4-Butyl-3-fluoro-1H-2-benzothiopyran (9a): To
a
DMF
suspension (4 mL) of sodium methoxide (33 mg, 0.61 mmol) was
added 6a (87 mg, 0.31 mmol) in DMF (1 mL). After the mixture
was stirred at room temperature for 15 min, the reaction was
quenched with phosphate buffer (pH 7). Organic materials were
extracted with AcOEt three times. The combined extracts were
washed with brine and dried over Na2SO4. After removal of the
solvent under reduced pressure, the residue was purified by col-
umn chromatography on silica gel (hexane–AcOEt 30:1) to give
9a (64 mg, 94%) as a colorless liquid.
4-s-Butyl-3-fluoro-1H-2-benzothiopyran (9b): Compound
9b was prepared by the method described for 9a using sodium
methoxide (28 mg, 0.52 mmol) and 6b (70 mg, 0.25 mmol) in
DMF (6 mL). Purification by column chromatography on silica
gel (hexane–AcOEt 30:1) gave 9b (49 mg, 90%) as a colorless
1,4-Dibutyl-3-fluoro-1H-2-benzopyran (8e): Compound 8e
was prepared by the method described for 8a using sodium hy-
dride (48 mg, 60% dispersion in mineral oil, 1.2 mmol) and 3e
(171 mg, 0.61 mmol) in DMF (6 mL). Purification by thin layer
chromatography on silica gel (hexane–AcOEt 5:1) gave 8e (113
mg, 71%) as a pale yellow liquid. 1H NMR (500 MHz, CDCl3) δ
0.92 (3H, t, J ꢁ 7.3 Hz), 0.93 (3H, t, J ꢁ 7.3 Hz), 1.32–1.58 (8H,
m), 1.69–1.77 (1H, m), 2.02–2.10 (1H, m), 2.36–2.46 (2H, m),
5.24 (1H, ddd, J ꢁ 8.2, 4.8, JHF ꢁ 2.3 Hz), 6.96 (1H, d, J ꢁ 7.6
Hz), 7.09 (1H, ddd, J ꢁ 7.5, 7.5, 1.2 Hz), 7.12 (1H, dd, J ꢁ 7.5,
0.9 Hz), 7.23 (1H, dd, J ꢁ 7.5, 7.5 Hz). 13C NMR (126 MHz,
CDCl3) δ 13.9, 14.0, 22.3, 22.5, 27.2, 30.7, 30.7, 33.5, 81.8, 87.7

Y. Wada et al.
Bull. Chem. Soc. Jpn., 74, No. 5 (2001) 977
liquid. 1H NMR (500 MHz, CDCl3) δ 0.93 (3H, t, J ꢁ 7.3 Hz),
1.34 (3H, dd, J ꢁ 7.3 Hz, JHF ꢁ 1.2 Hz), 1.69 (1H, dqdd, J ꢁ
14.6, 7.3, 7.3 Hz, JHF ꢁ 1.4 Hz), 1.83 (1H, dqdd, J ꢁ 14.6, 7.3,
7.3 Hz, JHF ꢁ 1.4 Hz), 2.84 (1H, tq, J ꢁ 7.3, 7.3 Hz), 3.84 (1H,
dd, J ꢁ 13.7, JHF ꢁ 5.2 Hz), 3.93 (1H, dd, J ꢁ 13.7, JHF ꢁ 4.6
Hz), 7.14 (1H, dd, J ꢁ 7.3, 1.3 Hz), 7.17 (1H, tq, J ꢁ 7.3, 1.3 Hz),
7.24 (1H, tq, J ꢁ 7.3, 1.3 Hz), 7.37 (1H, d, J ꢁ 7.3 Hz). 13C NMR
(126 MHz, CDCl3) δ 12.9, 19.6 (d, JCF ꢁ 3 Hz), 28.5 (d, JCF ꢁ 4
Hz), 34.1, 36.4, 121.3 (d, JCF ꢁ 12 Hz), 124.4 (d, JCF ꢁ 5 Hz),
126.4, 126.7, 127.4, 129.2, 136.0 (d, JCF ꢁ 7 Hz), 155.3 (d, JCF ꢁ
287 Hz). 19F NMR (471 MHz, CDCl3) 68.3 (1F, br s) ppm. IR
(neat) 2960, 2890, 1615, 1490, 1455, 1175, 1145, 1100, 890, 760
cmꢀ1. MS (70 eV) m/z (rel intensity) 222 (Mꢂ; 70), 193 (100),
160 (59). HRMS Found: m/z 222.0861. Calcd for C13H15FS: M,
222.0878.
Sellers, and R. A. DuBoisson, “Additions: Linear Additions across
Double Bonds,” in “Chemistry of Organic Fluorine Compounds
II,” ed by M. Hudlicky and A. E. Pavlath, ACS Monograph 187,
American Chemical Society, Washington, DC (1995), p. 729; V. J.
Lee, “Conjugate Additions of Reactive Carbanions to Activated
Alkenes and Alkynes,” in “Comprehensive Organic Synthesis,” ed
by B. M. Trost, Pergamon Press, Oxford (1991), Vol. 4, p. 69.
2
a) J. Ichikawa, Y. Wada, T. Okauchi, and T. Minami, Chem.
Commun., 1997, 1537. b) J. Ichikawa, M. Fujiwara, Y. Wada, T.
Okauchi, and T. Minami, Chem. Commun., 2000, 1887.
3
J. E. Baldwin, J. Chem. Soc., Chem. Commun., 1976, 734;
J. E. Baldwin, J. Cutting, W. Dupont, L. Kruse, L. Silberman, and
R. C. Thomas, J. Chem. Soc., Chem. Commun., 1976, 736; J. E.
Baldwin, R. C. Thomas, L. I. Krus, and L. Silberman, J. Org.
Chem., 42, 3846 (1977).
4-Butyl-3-phenylthio-1H-2-benzothiopyran (10a):
To a
4
J. Ichikawa, S. Miyazaki, M. Fujiwara, and T. Minami, J.
dimethyl sulfoxide (DMSO) suspension (3 mL) of potassium hy-
dride (156 mg, 35% dispersion in mineral oil, 0.85 mmol) was
added benzenethiol (0.14 mL, 1.4 mmol) at room temperature un-
der a nitrogen atmosphere, and the mixture was stirred for 0.5 h.
To the resulting solution was added 9a (76 mg, 0.34 mmol) in
DMSO (1 mL), and the mixture was stirred at 100 ˚C for 22 h.
The reaction was quenched with phosphate buffer (pH 7), and or-
ganic materials were extracted with AcOEt three times. The com-
bined extracts were washed with brine and dried over Na2SO4.
After removal of the solvent under reduced pressure, the residue
was purified by thin layer chromatography on silica gel (hexane–
AcOEt 30:1) to give 10a (76 mg, 71%) as a yellow liquid. 1H
NMR (500 MHz, CDCl3) δ 0.91 (3H, t, J ꢁ 7.5 Hz), 1.40 (2H, tq,
J ꢁ 7.5, 7.5 Hz), 1.55 (2H, tt, J ꢁ 7.5, 7.5 Hz), 3.01 (2H, t, J ꢁ
7.5 Hz), 3.70 (2H, s), 7.11–7.15 (1H, m), 7.19–7.32 (5H, m),
7.33–7.37 (2H, m), 7.40 (1H, d, J ꢁ 7.6 Hz). 13C NMR (126
MHz, CDCl3) δ 13.9, 22.6, 30.9, 32.2, 33.9, 124.8, 126.2, 126.4,
126.5, 127.2, 128.1, 128.9, 128.9, 130.9, 134.8, 136.6, 141.0. IR
(neat) 3050, 2950, 2930, 2860, 1580, 1470, 1440, 760, 740, 685
cmꢀ1. MS (70 eV) m/z (rel intensity) 312 (Mꢂ; 45), 269 (32), 123
(100). Found: C, 72.92; H, 6.44%. Calcd for C19H20S2: C, 73.03;
H, 6.45%.
Org. Chem., 60, 2320 (1995); J. Ichikawa, M. Kobayashi, Y. Noda,
N. Yokota, K. Amano, and T. Minami, J. Org. Chem., 61, 2763
(1996).
5
For the synthesis of isochromenes, see: R. Mutter, E. M.
M. de la Neva, and M. Wills, Chem. Commun., 2000, 1675; T. Ito,
T. Aoyama, and T. Shioiri, Tetrahedron Lett., 34, 6583 (1993); F.
Cottet, L. Cottier, and G. Descotes, Synthesis, 1987, 497 and refer-
ences cited therein.; L. G. French and T. P. Charlton, Heterocycles,
35, 305 (1993).
6
For the synthesis of isothiochromenes, see: T. R. Klein, M.
Bergemann, N. A. M. Yehia, and E. Fanghänel, J. Org. Chem., 63,
4626 (1998) and references cited therein.
7
“Organofluorine Chemistry, Principles and Commercial
Applications,” ed by R. E. Banks, B. E. Smart, and J. C. Tatlow,
Plenum Press, New York (1994); “Biomedicinal Aspects of Fluo-
rine Chemistry,” ed by R. Filler and Y. Kobayashi, Kodansha and
Elsevier Biomedical, Tokyo (1982); Welch, J. T.; Eswarakrishnan,
S. “Fluorine in Bioorganic Chemistry,” John Wily & Sons, New
York (1991).
8
For reviews on fluorinated heterocycles, see: M. J. Silvest-
er, Adv. Heterocyclic Chem., 59, 1 (1994); M. J. Silvester, Ald-
richimica Acta, 24, 31 (1991).
9
For the synthesis of ring-fluorinated chromenes, see: T.
Hanamoto, K. Shindo, M. Matsuoka, Y. Kiguchi, and M. Kondo,
J. Chem. Soc., Perkin Trans. 1, 2000, 103; F. Camps, J. Coll, A.
Messeguer, and M. A. Pericás, J. Heterocycl. Chem., 17, 1377
(1980).
10 For a review on the synthesis of gem-difluoroolefins, see: J.
Ichikawa, J. Fluorine Chem., 105, 257 (2000).
References
1
B. E. Smart, “Characteristics of C–F Systems,” in “Orga-
nofluorine Chemistry, Principles and Commercial Applications,”
ed by R. E. Banks, B. E. Smart, and J. C. Tatlow, Plenum Press,
New York (1994), p. 57; L. G. Sprague, K. B. Baucom, S. F.