Syntheses of ring-fluorinated isoquinolines and quinolines via intramolecular substitution: Cyclization of 1,1-difluoro-1-alkenes bearing a sulfonamide moiety

Article abstract of DOI:10.1055/s-2006-926458

On treatment of a base such as NaH, KH, or Et₃N, N-[o-(2,2-difluorovinyl)benzyl]- and N-[o-(3,3-difluoroallyl)phenyl]-substituted p-toluenesulfonamides readily undergo intramolecular substitution of sulfonamide nitrogens for vinylic fluorines i

Full text of DOI:10.1055/s-2006-926458

1590
PAPER
Syntheses of Ring-Fluorinated Isoquinolines and Quinolines via Intramolecu-
lar Substitution: Cyclization of 1,1-Difluoro-1-alkenes Bearing a Sulfonamide
Moiety
S
ynthese
s
u
of Ring-Fluo
n
rinated Isoq
j
uinolin
i
es and Quino
I
lines chikawa,*a Kotaro Sakoda,a Hiroko Moriyama,b Yukinori Wadaa
a
Department of Chemistry, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax +81(3)58414345; E-mail: junji@chem.s.u-tokyo.ac.jp
b
Department of Applied Chemistry, Kyushu Institute of Technology, Sensui-cho, Tobata, Kitakyushu 804-8550, Japan
Received 29 November 2005; revised 10 January 2006
R
R
X
Abstract: On treatment of a base such as NaH, KH, or Et3N, N-[o-
(2,2-difluorovinyl)benzyl]- and N-[o-(3,3-difluoroallyl)phenyl]-
substituted p-toluenesulfonamides readily undergo intramolecular
substitution of sulfonamide nitrogens for vinylic fluorines in a 6-
endo-trig fashion, leading to 3-fluoroisoquinoline and 2-fluoro-
quinoline derivatives, respectively, in high yields.
Nu–
F2C
F2C
–Y
YX
Nu
2
1a X = C, Y = N
1b X = N, Y = C
R
R
N
Key words: fluoroisoquinoline, fluoroquinoline, fluoroalkene, in-
tramolecular substitution, desulfonylation
– F –
F
F
or
N
Nu
Nu
Quinolines and isoquinolines are widespread in the alka-
loid family and constitute an important class of com-
pounds in medicinal and agricultural chemistry, and also
in material science.1 Due to their substantial applicability,
the syntheses of quinolines and isoquinolines are exten-
sively studied topics.2–4 Despite their common properties
and much research on their preparation, little attention has
hitherto been paid to synthetic methodology based on a
single concept that can be applied to both ring systems.5
3a
3b
Scheme 1 Syntheses of 3-fluorinated isoquinolines 3a and quino-
lines 3b from b,b-difluorostyrenes 1
During the study, we found that both N-aryl and N-alkyl
tosylamides were good nucleophiles for the cyclization.
These facts prompted us to investigate both isoquinoline
and quinoline syntheses via similar ring-forming reac-
tions by just changing the position of the benzene ring in
the substrates. Thus, N-[o-(2,2-difluorovinyl)benzyl]- and
As an example embodying such a concept, we have devel-
oped a method for the construction of isoquinoline and
quinoline frameworks on the basis of nucleophilic substi-
tution of vinylic fluorines via addition–elimination pro-
cesses (SNV: nucleophilic vinylic substitution,
Scheme 1):5b o-Cyano-substituted b,b-difluorostyrenes
1a react with organolithiums selectively at the cyano car-
bon to generate the corresponding sp2 nitrogen anions 2a,
which in turn undergo intramolecular replacement of the
vinylic fluorine to afford 3-fluoroisoquinolines 3a. Simi-
larly, the reaction of o-isocyano-substituted b,b-difluo-
rostyrenes 1b with organomagnesiums or organolithiums
proceeds via the corresponding sp2 carbanions 2b, which
substitute the intramolecular fluorine to afford 3-fluoro-
quinolines 3b. In these reactions, the choice of a cyano or
an isocyano group at the ortho position is the key to iso-
quinoline or quinoline synthesis.
N-[o-(3,3-difluoroallyl)phenyl]-substituted
p-toluene-
sulfonamides 6 and 7 were designed as starting materials
for 6-endo-trig cyclization to provide 3-fluoroisoquino-
lines 8, 9 and 2-fluoroquinolines 10, 11, respectively
(Scheme 3).
These selectively ring-fluorinated heterocycles have sig-
nificant potential as components7 and synthetic
intermediates8 of biologically active substances and ad-
vanced materials.9 However, their synthetic methods are
still quite limited and remain to be developed.4e,5b,10–12
Herein we report a facile, common method for the synthe-
ses of ring-fluorinated isoquinolines and quinolines
starting from ortho-functionalized (2,2-difluoro-
vinyl)benzenes and (3,3-difluoroallyl)benzenes.
Previously, we reported the nucleophilic 5-endo-trig cy-
clization of 1,1-difluoro-1-alkenes bearing a sulfonamide
moiety 4.6 The intramolecular substitution of nitrogen nu-
cleophiles for the vinylic fluorines successfully afforded
2-fluoroindoles and 2-fluoropyrrolines 5 (Scheme 2).
R
R
NaH, DMF
F2C
F
N
Ts
HN
Ts
4 R = Alkyl, H
5 73−84%
SYNTHESIS 2006, No. 10, pp 1590–1598
Advanced online publication: 27.04.2006
DOI: 10.1055/s-2006-926458; Art ID: F20405SS
x
x.
x
x
.
2
0
0
6
Scheme 2 Syntheses of 2-fluorinated indoles and pyrrolines via in-
tramolecular substitution of tosylamide nitrogens
© Georg Thieme Verlag Stuttgart · New York

PAPER
Syntheses of Ring-Fluorinated Isoquinolines and Quinolines
1591
R
R
We examined the cyclization of difluorovinylbenzene
substrates 6 via deprotonation on the sulfonamide nitro-
gen. When 6a (R = n-Bu) was treated with 1.1 equivalents
of NaH in DMF, intramolecular cyclization readily pro-
ceeded at room temperature to afford 3-fluoro-1,2-dihy-
droisoquinoline 8a in 89% yield (Table 1, entry 1).
F
F
TsN
N
R
m
8
9
F2C
HN
Ts
n
R
R
When an excess amount (1.2 equiv) of a base was used, ar-
omatized 3-fluoroisoquinoline 9a was formed along with
8a (entries 2 and 3). KH was more suitable for the forma-
tion of 9a, which seemed to be effected via the cyclization
followed by elimination of a sulfinic acid.12c,16 This route
to 9a via 8a was supported by the following experiment:
Treatment of 8a with 1.2 equivalents of KH in DMF
readily promoted the elimination of p-toluenesulfinic acid
to give isoquinoline 9a in almost quantitative yield
(Scheme 5). The desulfonylative aromatization of 8 pro-
ceeded at room temperature, under mild conditions com-
pared to the reported ones.16
6 (m = 0, n = 1)
7 (m = 1, n = 0)
F
N
Ts
F
N
10
11
Scheme 3 Construction of isoquinoline and quinoline frameworks
from (2,2-difluorovinyl)benzenes 6 and (3,3-difluoroallyl)benzenes 7
Synthesis of 3-Fluorinated Isoquinoline Derivatives
The starting materials for isoquinolines, o-substituted
(2,2-difluorovinyl)benzenes 6 were easily prepared from
2,2,2-trifluoroethyl p-toluenesulfonate (12) by the method
which we have previously established: (i) the in situ gen-
eration of (2,2-difluorovinyl)boranes 13 and (ii) their pal-
ladium-catalyzed cross-coupling reaction with aryl
iodides (Scheme 4).13
n-Bu
n-Bu
F
F
KH (1.2 equiv), DMF
0 °C → r.t., 11 h
TsN
N
8a
9a 97%
Scheme 5 Desulfonylative aromatization of dihydroisoquinoline 8a
R
with KH
R
iii
i, ii
F2C
CF3CH2OTs
CF2
C
HO
BR2
These results suggested that employing more than two
equivalents of a base should promote the cyclization and
the successive elimination of the sulfinic acid in a one-pot
operation, leading to a direct synthesis of isoquinolines 9
from 6. Thus, 6a was treated with 2.1 equivalents of KH
to afford 9a in 81% yield without detectable formation of
8a as expected. The use of 2.5 equivalents of KH im-
proved the yields of 9a up to 95% (Table 1, entry 4).
12
13
14a 69% R = n-Bu
14b 61% R = s-Bu
R
R
iv
v
F2C
HN
F2C
BocN
Ts
Ts
15a 83% R = n-Bu
15b 74% R = s-Bu
6a quant. R = n-Bu
6b 98% R = s-Bu
Ring closure of 6b (R = s-Bu) successfully proceeded
similarly to 6a to give dihydroisoquinoline 8b or isoquin-
oline 9b with a secondary alkyl group at the 4-position,
depending on the basic conditions: NaH (1.1 equiv) or KH
(2.6 equiv) (entries 5 and 6).
Scheme 4 Preparation of o-substituted (2,2-difluorovinyl)benzenes
6. Reagents and conditions: (i) n-BuLi (2.1 equiv), THF, –78 °C, 0.5
h; (ii) BR3 (1.1 equiv), THF, –78 °C → r.t., 4 h; (iii) o-I-
C6H4CH2OMgBu (0.9 equiv), CuI (1.0 equiv), Pd2(dba)3·CHCl3 (0.02
equiv), Ph3P (0.08 equiv), THF–HMPA (4:1), r.t., 17 h; (iv) BocN-
HTs (1.5 equiv), Ph3P (3.0 equiv), DEAD (2.5 equiv), THF, r.t., 1 or
10 h; (v) CF3CO2H (10 or 15 equiv), CH2Cl2, r.t., 11 h.
Synthesis of 2-Fluorinated Quinoline Derivatives
Difluorovinylbenzenes 14 bearing a hydroxymethyl
group at the ortho position were obtained by the coupling
of vinylboranes 13 with the corresponding aryl iodide.14
o-Iodobenzyl alcohol was pretreated with equimolecular
amounts of dibutylmagnesium to generate the metal
alkoxide, which in turn coupled with 13 in the presence of
a palladium catalyst to afford 14. Thus, alcohols 14 were
prepared in good yield from 12 in a one-pot operation.
The Mitsunobu reaction15 of 14 with BocNHTs allowed
the introduction of a nitrogen atom to give carbamates 15,
whose deprotection of the Boc group led to the desired
sulfonamides 6 (Scheme 4).
For quinoline synthesis, o-substituted (3,3-difluoroal-
lyl)benzenes 7 were adopted as precursors.17 Their difluo-
roallylbenzene structure could be constructed by SN2¢
reaction of 1-(trifluoromethyl)vinyl compounds18 with o-
functionalized aryllithiums, which were readily available
via directed ortho-lithiation.19 N-Protected anilines 16
were treated with more than 2 equivalents of butyllithium
to generate dilithiated species 17, whose reaction with 1-
(trifluoromethyl)vinyl compounds 18 proceeded with ac-
companying elimination of an allylic fluorine. The SN2¢
adducts, difluoroallyl compounds 19, thus obtained were
subjected to deprotection followed by tosylation of the
Synthesis 2006, No. 10, 1590–1598 © Thieme Stuttgart · New York

1592
J. Ichikawa et al.
PAPER
Table 1 Synthesis of 3-Fluoro-1,2-dihydroisoquinolines 8 and 3-Fluoroisoquinolines 9
R
R
R
R
F
F
– F –, TolSO2H
Base, DMF
F2C
F2C
–
TsN
+
TsN
N
HN
Ts
6
8
9
Entry
R
Base (equiv)
Conditions
Yield (%)a of 8
Yield (%)a of 9
1
2
3
4
5
6
a: n-Bu
NaH (1.1)
NaH (1.2)
KH (1.2)
KH (2.5)
NaH (1.1)
KH (2.6)
0 °C → r.t., 5 h
0 °C → r.t., 4 h
0 °C → r.t., 4 h
0 °C → r.t., 4 h
0 °C → r.t., 9 h
0 °C → r.t., 9 h
89 (94)
-
a: n-Bu
a: n-Bu
a: n-Bu
b: s-Bu
b: s-Bu
80 (89)
10
45
95
-
33
-
89
-
90
a Isolated yield. 19F NMR yield relative to internal C6H5CF3 standard is given in parentheses.
aniline nitrogen to afford the desired sulfonamides 7 11a, the yield was quite low (11% yield) in contrast to the
(Scheme 6). cyclization of 6.
Intramolecular substitution of the amide nitrogen in di- The cyclization of 7b (R = SiMe2Ph) was examined under
fluoroallylbenzene substrates 7 was attempted to provide similar reaction conditions as above. Treatment with 2.2
2-fluorinated quinoline derivatives. When 7a (R = Ph) equivalents of NaH in DMF at 80 °C gave no cyclized
was treated with 1.1 equivalents of NaH in DMF, the ex- products but a desilylated product, N-[o-(3,3-difluoroal-
pected cyclization proceeded at 80 °C, leading not to 2- lyl)phenyl]-p-toluenesulfonamide 7c (R = H) in 81%
fluoro-1,4-dihydroquinoline 10a but directly to the corre- yield. After screening different bases, we found that the
sponding aromatized 2-fluoroquinoline 11a in 47% yield cyclization was effected by triethylamine (Et3N, 3.0
(Table 2, entry 1). Then, we conducted the reaction with equiv) to afford the desired 2-fluoro-1-tosyl-1,4-dihydro-
2.2 equivalents of NaH, which afforded 2-fluoroquinoline quinoline (10b) in 75% yield with accompanying forma-
11a in 79% yield via cyclization followed by elimination tion of the desilylated product 7c (R = H) in 19% yield
of a sulfinic acid (entry 2). While KH also gave compound (Table 2, entry 3). Addition of 1,8-diazabicyclo[5.4.0]un-
dec-7-ene (DBU, 2.0 equiv) after the cyclization with
Et3N (3.0 equiv) gave an aromatized product, 2-fluoro-
quinoline 11b, in 53% yield along with 7c (R = H, 20%
R
yield) and the desilylated dihydroquinoline 10c (R = H,
Li
Li
N
i or ii
iii or iv
R
O
14% yield) (entry 4).20 Since desilylation giving rise to 7c
(R = H) and 10c (R = H) seemed to be caused by a fluoride
ion generated during the cyclization, we tried to capture
the fluoride ion with trimethyl borate [B(OMe)3]. On
treatment of 7b with Et3N (6.0 equiv) and B(OMe)3 (2.0
equiv), 10b was successfully obtained in 85% yield (entry
5).21
F2C
HN
HN
R'
R'
O
R'
O
CF3
16a R' = t-Bu
17a R' = t-Bu
18
19a
R = Ph, R' = t-Bu
16b R' = O-t-Bu
17b R' = O-t-Bu
19b 34%
R = SiMe2Ph,
R' = O-t-Bu
R
R
v or vi
vii
For conversion of 10b into 2-fluoroquinoline 11b, we ex-
amined several conditions. While a base such as NaH or
DBU in DMF gave a complex mixture of products, oxida-
tive treatment with 2,3-dichloro-5,6-dicyano-p-benzo-
quinone (DDQ) was quite effective. The reaction
conducted in refluxing benzene gave rise to aromatization
via cleavage of the tosyl group22 to provide 2-fluoroquin-
oline 11b in 92% yield without affecting the silyl group
(Scheme 7).21 The aromatization via desulfonylation nor-
mally requires harsh conditions with a base or an acid,
such as KOH in DMSO at 140 °C for 30 minutes or 6 M
aqueous HCl in refluxing dioxane for 24 hours,12c,16 with
F2C
F2C
HN
Ts
H2N
7a 85% R = Ph
20a 58% from 18a R = Ph
20b 54% R = SiMe2Ph
7b 94% R = SiMe2Ph
Scheme 6 Preparation of o-substituted (3,3-difluoroallyl)benzenes
7. Reagents and conditions: (i) (for 16a) n-BuLi (2.5 equiv), THF,
0 °C, 2 h → r.t., 20 h; (ii) (for 16b) t-BuLi (2.5 equiv), tetrahydropy-
ran, 0 °C → r.t., 1 h; (iii) (for 17a) 18a (R = Ph, 0.8 equiv), TMEDA
(1.0 equiv), –78 °C → reflux, 5 h; (iv) (for 17b) 18b (R = SiMe2Ph,
1.5 equiv), 0 °C → r.t., 20 h; (v) (for 19a) HCl (20 equiv), H2O–EtOH
(1:1), reflux, 16 h; (vi) (for 19b) Me3SiI (2.0 equiv), CHCl3, 0 °C, 2 h
→ r.t., 1 h; (vii) TsCl (1.5 equiv), pyridine, 0 °C → r.t., 10–16 h.
Synthesis 2006, No. 10, 1590–1598 © Thieme Stuttgart · New York

PAPER
Syntheses of Ring-Fluorinated Isoquinolines and Quinolines
1593
Table 2 Synthesis of 2-Fluoro-1,4-dihydroquinoline 10 and 2-Fluoroquinolines 11
R
R
R
Reagents, DMF
80 °C
+
F2C
HN
Ts
F
N
Ts
F
N
11a R = Ph
7a R = Ph
10a R = Ph
11b R = SiMe2Ph
7b R = SiMe2Ph
10b R = SiMe2Ph
Entry
R
Reagents (equiv)
NaH (1.1)
Time (h)
Yield (%) of 10
Yield (%) of 11
1
a: Ph
2
3
5
-
-
75
9
47
79
0
2
a: Ph
NaH (2.2)
3a
4b
b: SiMe2Ph
b: SiMe2Ph
Et3N (3.0)
i) Et3N (3.0)
ii) DBU (2.0)
i) 5
ii) 1
53
5
b: SiMe2Ph
i) Et3N (3.0),
B(OMe)3 (2.0)
ii) Et3N (3.0)
i) 5
ii) 3
85
0
a Anilide 7c (R = H) was obtained in 19% yield.
b Anilide 7c (R = H) and dihydroquinoline 10c (R = H) were obtained in 20 and 14% yield, respectively.
mental analyses were performed with a YANAKO MT-3 CHN
Corder apparatus. THF was distilled from sodium benzophenone
ketyl prior to use. Tetrahydropyran was distilled from CaH2 prior to
use. HMPA and pyridine were distilled from CaH2 and stored over
molecular sieves (4 Å). CH2Cl2 was distilled from P2O5 and then
from CaH2, and stored over molecular sieves (4 Å). DMF was dried
over P2O5, then distilled under reduced pressure from CaH2, and
stored over molecular sieves (4 Å). Benzene was dried over CaCl2,
then distilled, and stored over molecular sieves (4 Å). CHCl3 (spe-
cial grade, Kokusan Chemical Co., Ltd.) was passed through an alu-
mina column prior to use. Commercial NaH and KH were used
without further purification. Column chromatography and prepara-
tive thin-layer chromatography (PTLC) were performed on silica
gel (Kanto Chemical Co., Inc., Silica Gel 60 and Wako Pure Chem-
ical Industries, Ltd., B5-F, respectively).
one exception: reductive desulfonylation of a benzyl-
sulfonamido group with Raney nickel.16b We have found
that DDQ oxidation readily promotes the desulfonylative
aromatization process under mild and neutral conditions,
which offers a complementary method to Raney nickel re-
duction.
PhMe2Si
DDQ (1.1 equiv)
benzene
PhMe2Si
reflux, 3 h
F
N
Ts
F
N
10b
11b 92%
Scheme 7 Desulfonylative aromatization of dihydroquinoline 10b
via DDQ oxidation
N-tert-Butoxycarbonyl-N-[o-(1,1-difluorohex-1-en-2-yl)ben-
zyl]-p-toluenesulfonamide (15a)
To a solution of N-tert-butoxycarbonyl-p-toluenesulfonamide (314
mg, 1.16 mmol) in THF (5 mL) were added Ph3P (624 mg, 2.32
mmol), alcohol 14a (175 mg, 0.77 mmol)13 in THF (2 mL), and di-
ethyl azodicarboxylate (0.30 mL, 1.65 mmol) at r.t. under N2. After
stirring for 1 h, the mixture was concentrated under reduced pres-
sure. The residue was purified by PTLC on silica gel (hexane–
EtOAc, 3:1) to give 15a (306 mg, 83%) as a pale-yellow liquid.
Thus, 2-fluoroquinoline synthesis has been accomplished
by combining two processes: (i) SN2¢ reaction of trifluo-
romethylalkenes for the preparation of cyclization precur-
sors and (ii) SNV reaction of difluoroalkenes for the ring
formation.
In conclusion, we have demonstrated the construction of
both isoquinoline and quinoline frameworks by a com- IR (neat): 2958, 1739, 1367, 1286, 1236, 1155, 1089, 790, 765, 676,
592, 545 cm–1.
mon strategy: the intramolecular substitution of tosyl-
1H NMR (500 MHz, CDCl3): d = 0.89 (3 H, t, J = 7.0 Hz), 1.36–
1.40 (13 H, m), 2.30 (2 H, br s), 2.43 (3 H, s), 5.04 (2 H, s), 7.15 (1
H, d, J = 7.0 Hz), 7.24–7.35 (5 H, m), 7.70 (2 H, d, J = 8.2 Hz).
13C NMR (126 MHz, CDCl3): d = 13.8, 21.6, 22.4, 27.8, 28.7, 29.6
(dd, JC,F = 3, 3 Hz), 47.9 (d, JC,F = 2 Hz), 84.5, 90.3 (dd, JC,F = 22,
17 Hz), 126.2, 127.0, 128.1, 128.3, 129.2, 130.0 (d, JC,F = 2 Hz),
131.8 (d, JC,F = 5 Hz), 136.0, 137.0, 144.3, 151.1, 152.6 (dd,
JC,F = 287, 287 Hz).
19F NMR (471 MHz, CDCl3): d = 68.5 (1 F, d, JF,F = 44 Hz), 73.0
(1 F, d, JF,F = 44 Hz).
HRMS: m/z calcd for C25H31F2NO4S: 479.1942 (M+); found:
amide nitrogens for vinylic fluorines in 1,1-difluoro-1-
alkenes. The scope of this intramolecular substitution
methodology has been expanded to the synthesis of 2-
fluorinated quinolines starting from (3,3-difluoroal-
lyl)benzene substrates, as well as 3-fluorinated quinolines
from (2,2-difluorovinyl)benzene substrates.23
IR spectra were recorded on a JEOL JIR-WINSPEC50 or a Horiba
FT-300S spectrometer. NMR spectra were obtained on a JEOL
JNM-A-500 or a Bruker DRX500 spectrometer. Chemical shifts
were given in ppm relative to internal Me4Si (for 1H and 13C NMR)
or internal C6F6 (for 19F NMR). Mass spectra were taken with a
JEOL JMS-DX-300 or a JEOL JMS-SX-102A spectrometer. Ele-
479.1972.
Synthesis 2006, No. 10, 1590–1598 © Thieme Stuttgart · New York

1594
J. Ichikawa et al.
PAPER
N-tert-Butoxycarbonyl-N-[o-(1,1-difluoro-3-methylpent-1-en-
2-yl)benzyl]-p-toluenesulfonamide (15b)
7.32 (2 H, d, J = 8.1 Hz), 7.39 (1 H, dd, J = 7.0, 1.1 Hz), 7.77 (2 H,
d, J = 8.1 Hz).
Compound 15b was prepared by the method described for 15a us-
ing N-tert-butoxycarbonyl-p-toluenesulfonamide (173 mg, 0.64
mmol), THF (3 mL), Ph3P (343 mg, 1.28 mmol), alcohol 14b (96
mg, 0.43 mmol)13 in THF (2 mL), and diethyl azodicarboxylate
(0.17 mL, 0.94 mmol). The mixture was stirred at r.t. for 10 h. Pu-
rification by PTLC on silica gel (CHCl3–EtOAc, 20:1) gave 15b
(151 mg, 74%) as a pale-yellow liquid.
13C NMR (126 MHz, CDCl3): d = 12.0, 17.9, 21.5, 28.0, 35.2, 44.5,
93.1 (dd, JC,F = 20, 14 Hz), 127.1, 127.7, 128.4, 129.0, 129.7, 130.6,
131.3, 135.4, 136.4, 143.6, 152.4 (dd, JC,F = 291, 280 Hz).
19F NMR (471 MHz, CDCl3): d = 69.6 (1 F, d, JF,F = 44 Hz), 74.6
(1 F, d, JF,F = 44 Hz).
HRMS: m/z calcd for C20H23F2NO2S: 379.1418 (M+); found:
379.1421.
IR (neat): 2969, 1727, 1367, 1286, 1249, 1232, 1187, 1170, 1089,
676 cm–1.
4-Butyl-3-fluoro-2-p-toluensulfonyl-1,2-dihydroisoquinoline
(8a)
1H NMR (500 MHz, DMSO-d6, 90 °C): d = 0.89–1.68 (8 H, m),
1.25 (9 H, s), 2.42 (3 H, s), 2.38–2.44 (1 H, m), 5.00 (2 H, s), 7.18
(1 H, br s), 7.25 (1 H, d, J = 7.4 Hz), 7.30 (1 H, dd, J = 7.4, 7.4 Hz),
7.35 (1 H, dd, J = 7.4, 7.4 Hz), 7.42 (2 H, d, J = 8.2 Hz), 7.77 (2 H,
d, J = 8.2 Hz).
13C NMR (126 MHz, CDCl3): d = 12.3, 14.0, 18.1, 21.9, 27.6, 39.8,
48.4, 84.7, 91.9 (dd, JC,F = 20, 14 Hz), 124.6, 126.6, 128.2, 129.0 (d,
JC,F = 5 Hz), 129.2, 129.3, 130.1, 135.6 (d, JC,F = 5 Hz), 136.1,
144.7, 150.8, 151.8 (dd, JC,F = 290, 290 Hz).
To a suspension of NaH (9 mg, 60% dispersion in mineral oil, 0.22
mmol) in DMF (0.5 mL) was added 6a (75 mg, 0.20 mmol) in DMF
(1.5 mL) at 0 °C under N2. The reaction mixture was stirred at r.t.
for 4.5 h, and then phosphate buffer (pH 7) was added to quench the
reaction. Organic materials were extracted with Et2O (3 ×), and the
combined extracts were washed with brine and dried (Na2SO4). Af-
ter removal of the solvent under reduced pressure, the residue was
purified by column chromatography on silica gel (pentane–Et2O,
5:1 containing 1% Et3N) to give 8a (63 mg, 89%) as a pale-yellow
liquid.
19F NMR (471 MHz, CDCl3): d = 70.1 (1 F, d, JF,F = 44 Hz), 74.2
(1 F, d, JF,F = 44 Hz).
IR (neat): 2964, 1670, 1359, 1243, 1168, 1085, 1054, 817, 759, 680,
566, 545 cm–1.
HRMS: m/z calcd for C25H31F2NO4S: 479.1942 (M+); found:
479.1905.
1H NMR (500 MHz, CDCl3): d = 0.91 (3 H, t, J = 7.5 Hz), 1.29–
1.43 (4 H, m), 2.23 (3 H, s), 2.45 (2 H, td, J = 7.5 Hz, JH,F = 2.5 Hz),
4.79 (2 H, d, JH,F = 3.7 Hz), 6.88 (1 H, dd, J = 7.3, 1.5 Hz), 6.91–
6.95 (1 H, m), 6.92 (2 H, dd, J = 7.9, 0.6 Hz), 7.00–7.07 (2 H, m),
7.42–7.46 (2 H, m).
13C NMR (126 MHz, CDCl3): d = 13.8, 21.4, 22.5, 23.9, 30.6 (d,
JC,F = 2 Hz), 51.6, 109.8 (d, JC,F = 23 Hz), 122.5 (d, JC,F = 6 Hz),
125.1, 126.7 (d, JC,F = 2 Hz), 127.4, 127.6, 128.7, 128.9, 131.6 (d,
JC,F = 4 Hz), 133.9, 144.1, 147.7 (d, JC,F = 267 Hz).
N-[o-(1,1-Difluorohex-1-en-2-yl)benzyl]-p-toluenesulfonamide
(6a)
To a solution of 15a (69 mg, 0.15 mmol) in CH2Cl2 (1.5 mL) was
added trifluoroacetic acid (0.17 mL, 2.2 mmol) at r.t. The mixture
was stirred at r.t. for 11 h, and then aq NaHCO3 was added. Organic
materials were extracted with EtOAc (3 ×), and the combined ex-
tracts were washed with brine and dried (Na2SO4). After removal of
the solvent under reduced pressure, the residue was purified by
PTLC on silica gel (hexane–EtOAc, 3:1) to give 6a (55 mg, ca.
100%) as a pale-yellow liquid.
19F NMR (471 MHz, CDCl3): d = 65.0 (t, JF,H = 3 Hz).
HRMS: m/z calcd for C20H22FNO2S: 359.1355 (M+); found:
IR (neat): 3280, 2958, 2929, 1739, 1328, 1236, 1162, 1093, 813,
765 cm–1.
359.1367.
1H NMR (500 MHz, CDCl3): d = 0.83 (3 H, t, J = 7.2 Hz), 1.14–
1.28 (4 H, m), 2.13 (2 H, br s), 2.43 (3 H, s), 4.05 (2 H, d, J = 5.9
Hz), 4.79 (1 H, t, J = 5.9 Hz), 7.07–7.15 (1 H, m), 7.23–7.27 (2 H,
m), 7.31 (2 H, d, J = 8.1 Hz), 7.33–7.37 (1 H, m), 7.76 (2 H, d,
J = 8.1 Hz).
13C NMR (126 MHz, CDCl3): d = 13.7, 21.5, 22.3, 28.9, 29.4 (dd,
JC,F = 3, 3 Hz), 44.5, 90.3 (dd, JC,F = 22, 17 Hz), 127.2, 128.0,
128.4, 129.1, 129.8, 130.1 (d, JC,F = 2 Hz), 133.0 (d, JC,F = 5 Hz),
134.8 (d, JC,F = 2 Hz), 136.6, 143.6, 152.5 (dd, JC,F = 287, 287 Hz).
4-(sec-Butyl)-3-fluoro-2-p-toluenesulfonyl-1,2-dihydroisoquin-
oline (8b)
Compound 8b was prepared by the method described for 8a using
NaH (10 mg, 60% dispersion in mineral oil, 0.24 mmol) in DMF (1
mL) and 6b (82 mg, 0.22 mmol) in DMF (1.5 mL). The mixture was
stirred at r.t. for 9 h. Purification by column chromatography on sil-
ica gel (pentane–Et2O, 10:1 containing 1% Et3N) gave 8b (69 mg,
89%) as a pale-yellow solid.
IR (neat): 2969, 1654, 1452, 1357, 1234, 1164, 927, 765, 678, 578
cm–1.
19F NMR (471 MHz, CDCl3): d = 68.3 (1 F, d, JF,F = 46 Hz), 72.7
(1 F, d, JF,F = 46 Hz).
HRMS: m/z calcd for C20H23F2NO2S: 379.1418 (M+); found:
1H NMR (500 MHz, CDCl3): d = 0.84 (3 H, t, J = 7.3 Hz), 1.23 (3
H, dd, J = 7.3 Hz, JH,F = 1.1 Hz), 1.56–1.74 (2 H, m), 2.22 (3 H, s),
2.61 (1 H, tq, J = 7.3, 7.3 Hz), 4.74 (1 H, dd, J = 16.5 Hz, JH,F = 3.6
Hz), 4.80 (1 H, dd, J = 16.5 Hz, JH,F = 3.6 Hz), 6.90 (2 H, d, J = 8.2
Hz), 6.93–6.98 (2 H, m), 6.99–7.05 (2 H, m), 7.40 (2 H, d, J = 8.2
Hz).
379.1413.
N-[o-(1,1-Difluoro-3-methylpent-1-en-2-yl)benzyl]-p-toluene-
sulfonamide (6b)
Compound 6b was prepared by the method described for 6a using
15b (103 mg, 0.22 mmol), CH2Cl2 (2 mL), and trifluoroacetic acid
(0.17 mL, 2.2 mmol). Purification by PTLC on silica gel (hexane–
EtOAc, 3:1) gave 6b (76 mg, 98%) as a pale-yellow liquid.
13C NMR (126 MHz, CDCl3): d = 12.6, 18.9 (d, JC,F = 3 Hz), 21.3,
27.9 (d, JC,F = 4 Hz), 34.0 (d, JC,F = 3 Hz), 51.7, 114.2 (d, JC,F = 20
Hz), 122.8 (d, JC,F = 7 Hz), 125.2, 126.5 (d, JC,F = 2 Hz), 127.2,
127.5, 128.6, 129.0, 132.2 (d, JC,F = 5 Hz), 133.7, 144.0, 147.9 (d,
JC,F = 271 Hz).
19F NMR (471 MHz, CDCl3): d = 69.3 (s).
HRMS: m/z calcd for C20H22FNO2S: 359.1355 (M+); found:
IR (neat): 3282, 2966, 1729, 1450, 1328, 1288, 1232, 1160, 1093,
1060 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.78 (3 H, d, J = 7.2 Hz), 0.93 (3
H, t, J = 7.1 Hz), 1.27–1.38 (2 H, m), 2.28–2.46 (1 H, m), 2.44 (3 H,
s), 3.97–4.18 (2 H, m), 4.70 (1 H, br s), 7.04 (1 H, d, J = 7.0 Hz),
7.24 (1 H, ddd, J = 7.0, 7.0, 1.1 Hz), 7.28 (1 H, dd, J = 7.0, 7.0 Hz),
359.1347.
Synthesis 2006, No. 10, 1590–1598 © Thieme Stuttgart · New York

PAPER
Syntheses of Ring-Fluorinated Isoquinolines and Quinolines
1595
4-Butyl-3-fluoroisoquinoline (9a)
(Na2SO4). After removal of the solvent under reduced pressure, the
residue was purified by PTLC on silica gel (hexane–EtOAc, 3:1) to
give 20a (100 mg, 58%) as a pale-yellow oil.
To a suspension of KH (85 mg, 33% dispersion in mineral oil, 0.70
mmol) in DMF (1 mL) was added 6a (104 mg, 0.27 mmol) in DMF
(2 mL) at 0 °C under N2. The mixture was stirred at r.t. for 4 h, and
then phosphate buffer (pH 7) was added to quench the reaction. Or-
ganic materials were extracted with EtOAc (3 ×), and the combined
extracts were washed with brine and dried (Na2SO4). After removal
of the solvent under reduced pressure, the residue was purified by
PTLC on silica gel (hexane–EtOAc, 3:1) to give 9a (53 mg, 95%)
as a pale-yellow liquid.
IR (neat): 1716, 1622, 1495, 1456, 1234, 1101, 985, 744, 694, 603,
576 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.46 (2 H, br s), 3.51 (2 H, dd,
JH,F = 2.0, 2.0 Hz), 6.57 (1 H, dd, J = 7.6, 0.9 Hz), 6.62 (1 H, ddd,
J = 7.6, 7.6, 0.9 Hz), 6.93 (1 H, d, J = 7.6 Hz), 6.98 (1 H, ddd,
J = 7.6, 7.6, 0.9 Hz), 7.16–7.20 (2 H, m), 7.22–7.25 (3 H, m).
13C NMR (126 MHz, CDCl3): d = 29.6, 90.4 (dd, JC,F = 21, 14 Hz),
115.6, 118.6, 122.2 (dd, JC,F = 3, 3 Hz), 127.4, 127.4, 128.1 (dd,
JC,F = 3, 3 Hz), 128.3, 129.3, 133.3 (dd, JC,F = 3, 3 Hz), 144.2, 154.0
(dd, JC,F = 292, 287 Hz).
19F NMR (471 MHz, CDCl3): d = 71.4 (1 F, d, JF,F = 41 Hz), 72.2 (1
F, d, JF,F = 41 Hz).
IR (neat): 2960, 2930, 2870, 1620, 1590, 1440, 1425, 1250, 1220,
750 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.97 (3 H, t, J = 7.5 Hz), 1.46 (2
H, tq, J = 7.5, 7.5 Hz), 1.63–1.71 (2 H, m), 3.03 (2 H, td, J = 7.5 Hz,
JH,F = 0.9 Hz), 7.52 (1 H, ddd, J = 7.9, 7.9, 0.8 Hz), 7.71 (1 H, dd,
J = 7.9, 7.9 Hz), 7.97 (1 H, d, J = 7.9 Hz), 7.99 (1 H, d, J = 7.9 Hz),
8.80 (1 H, s).
13C NMR (126 MHz, CDCl3): d = 13.9, 22.8, 24.1, 32.1, 115.0 (d,
JC,F = 30 Hz), 122.9 (d, JC,F = 7 Hz), 125.6 (d, JC,F = 2 Hz), 127.6 (d,
JC,F = 2 Hz), 128.4, 130.7, 138.4 (d, JC,F = 6 Hz), 148.6 (d, JC,F = 16
Hz), 159.1 (d, JC,F = 232 Hz).
Anal. Calcd for C15H13F2N: C, 73.45; H, 5.34; N, 5.71. Found: C,
73.64; H, 5.50; N, 5.67.
tert-Butyl N-{o-[3,3-Difluoro-2-(dimethylphenylsilyl)prop-2-
en-1-yl]phenyl}carbamate (19b)
To a solution of carbamate 16b (196 mg, 1.01 mmol) in tetrahydro-
pyran (0.50 mL) was added dropwise t-BuLi (1.76 mL, 1.4 M in
pentane, 2.5 mmol) at 0 °C under argon. After stirring at r.t. for 1 h,
dimethylphenyl(3,3,3-trifluoroprop-1-en-2-yl)silane (18b; 350 mg,
1.52 mmol) was added at 0 °C. After stirring at r.t. for 20 h, the re-
action was quenched with phosphate buffer (pH 7). The mixture
was filtered through a pad of Celite, and then organic materials were
extracted with EtOAc (3 ×). The combined extracts were washed
with brine and dried (Na2SO4). After removal of the solvent under
reduced pressure, the residue was purified by PTLC on silica gel
(hexane–EtOAc, 3:1) to give 19b (139 mg, 34%) as a pale-yellow
oil.
19F NMR (471 MHz, CDCl3): d = 79.3 (s).
Anal. Calcd for C13H14FN: C, 76.82; H, 6.94; N, 6.89. Found: C,
76.54; H, 6.95; N, 6.76.
4-(sec-Butyl)-3-fluoroisoquinoline (9b)
Compound 9b was prepared by the method described for 9a using
KH (70 mg, 33% dispersion in mineral oil, 0.57 mmol) in DMF (1
mL) and 6b (83 mg, 0.22 mmol) in DMF (2.5 mL). The mixture was
stirred at r.t. for 9 h. Purification by PTLC on silica gel (hexane–
EtOAc, 5:1) gave 9b (40 mg, 90%) as a pale-yellow solid.
IR (neat): 2969, 2873, 1623, 1585, 1567, 1500, 1442, 1423, 1380,
1268, 1247, 1153, 933, 752 cm–1.
IR (neat): 2978, 1732, 1687, 1518, 1452, 1367, 1225, 1153, 1111,
1047, 1024, 835, 814, 779, 733, 700 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.32 (6 H, d, J = 1.3 Hz), 1.48 (9
H, s), 3.22 (2 H, s), 5.90 (1 H, br s), 6.93 (1 H, d, J = 7.5 Hz), 6.98
(1 H, dd, J = 7.5, 7.5 Hz), 7.17 (1 H, dd, J = 7.5, 7.5 Hz), 7.31 (2 H,
dd, J = 7.2, 7.2 Hz), 7.34–7.39 (3 H, m), 7.54 (1 H, br s).
1H NMR (500 MHz, CDCl3): d = 0.86 (3 H, t, J = 7.3 Hz), 1.46 (3
H, d, J = 7.2 Hz, JH,F = 1.5 Hz), 1.82–2.01 (2 H, m), 3.49 (1 H, tq,
J = 7.3, 7.3 Hz), 7.52 (1 H, dd, J = 7.9, 7.9 Hz), 7.70 (1 H, dd,
J = 7.9, 7.9 Hz), 7.98 (1 H, d, J = 7.9 Hz), 8.14 (1 H, d, J = 7.9 Hz),
8.81 (1 H, s).
13C NMR (126 MHz, CDCl3): d = 12.8, 19.3 (d, JC,F = 3 Hz), 28.5
(d, JC,F = 3 Hz), 33.0 (d, JC,F = 4 Hz), 119.1 (d, JC,F = 26 Hz), 123.1
(d, JC,F = 6 Hz), 125.5 (d, JC,F = 2 Hz), 127.6 (d, JC,F = 2 Hz), 128.5,
130.6, 138.5, (d, JC,F = 7 Hz), 148.8 (d, JC,F = 17 Hz), 159.3 (d,
JC,F = 235 Hz).
13C NMR (126 MHz, CDCl3): d = –2.6, 27.4 (dd, JC,F = 6, 6 Hz),
28.3, 68.7, 79.7 (dd, JC,F = 28, 5 Hz), 123.0 (dd, JC,F = 20, 13 Hz),
124.2, 127.1, 127.8, 129.3, 129.4, 133.8, 135.8, 136.4, 138.7 (dd,
JC,F = 15, 4 Hz), 153.2, 156.9 (dd, JC,F = 305, 283 Hz).
19F NMR (471 MHz, CDCl3): d = 86.7 (1 F, d, JF,F = 31 Hz), 90.1 (1
F, d, JF,F = 31 Hz).
19F NMR (470 MHz, CDCl3): d = 86.1 (br s).
Anal. Calcd for C13H14FN: C, 76.82; H, 6.94; N, 6.89. Found: C,
76.58; H, 7.00; N, 6.80.
Anal. Calcd for C22H27F2NO2Si: C, 65.48; H, 6.74; N, 3.47. Found:
C, 65.57; H, 6.89; N, 3.29.
o-(3,3-Difluoro-2-phenylprop-2-en-1-yl)aniline (20a)
3,3-Difluoro-[o-(2-dimethylphenylsilyl)]prop-2-en-1-yl]aniline
(20b)
To a solution of amide 16a (165 mg, 1.00 mmol) in THF (2.5 mL)
was added dropwise n-BuLi (1.6 mL, 1.6 M in hexane, 2.5 mmol)
at 0 °C under argon. After stirring at 0 °C for 2 h and at r.t. for 20 h,
(3,3,3-trifluoroprop-1-en-2-yl)benzene (18a; 121 mg, 0.70 mmol)
and N,N,N,N-tetramethylethylenediamine (116 mg, 1.0 mmol) were
added, and the mixture was refluxed for 5 h. The reaction was
quenched with phosphate buffer (pH 7) at r.t. The mixture was fil-
tered through a pad of Celite, and then organic materials were ex-
tracted with EtOAc (3 ×), and the combined extracts were washed
with brine. After removal of the solvent under reduced pressure, the
residue was treated with aq HCl (2.5 mL, 12 M, 30 mmol) in EtOH
(2.5 mL) and the mixture was refluxed for 16 h. The reaction was
quenched with CaCO3 (2.5 g, 25 mmol) and then phosphate buffer
(pH 7) at 0 °C. Organic materials were extracted with EtOAc (3 ×),
and the combined extracts were washed with brine and dried
To a solution of carbamate 19b (261 mg, 0.65 mmol) in CHCl3 (8
mL) was added trimethylsilyl iodide (184 mL, 1.3 mmol) at 0 °C un-
der argon. The mixture was stirred at 0 °C for 2 h and then at r.t. for
an additional 1 h. The reaction was quenched with sat. aq NaHCO3
at 0 °C. Organic materials were extracted with CH2Cl2 (3 ×), and the
combined extracts were washed with brine and dried (Na2SO4). Af-
ter removal of the solvent under reduced pressure, the residue was
purified by PTLC on silica gel (hexane–EtOAc, 2:1) to give 20b
(105 mg, 54%) as a pale-yellow oil.
IR (neat): 3381, 3068, 1684, 1622, 1495, 1456, 1427, 1250, 1215,
1111, 835, 812, 783, 733, 698 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.32 (6 H, s), 3.14 (2 H, s), 3.41
(2 H, br s), 6.58 (1 H, d, J = 7.8 Hz), 6.66 (1 H, dd, J = 7.5, 7.5 Hz),
Synthesis 2006, No. 10, 1590–1598 © Thieme Stuttgart · New York

1596
J. Ichikawa et al.
PAPER
6.84 (1 H, d, J = 7.5 Hz), 7.01 (1 H, dd, J = 7.8, 7.5 Hz), 7.30–7.39
(3 H, m), 7.42 (2 H, d, J = 7.4 Hz).
13C NMR (126 MHz, CDCl3): d = –2.6, 27.1 (dd, JC,F = 6, 6 Hz),
79.2 (dd, JC,F = 27, 5 Hz), 115.5, 118.5, 123.2 (dd, JC,F = 2, 2 Hz),
127.3, 127.8, 129.1, 129.3, 133.8, 136.8, 144.3, 159.1 (dd,
JC,F = 282, 282 Hz).
2-Fluoro-3-phenylquinoline (11a)
To a suspension of NaH (23 mg, 60% dispersion in mineral oil, 0.57
mmol) in DMF (2 mL) was added 7a (103 mg, 0.46 mmol) in DMF
(2 mL) at 0 °C under argon. The mixture was heated at 80 °C for 3
h. The reaction was quenched with phosphate buffer (pH 7) at r.t.
Organic materials were extracted with EtOAc (3 ×), and the com-
bined extracts were washed with brine and dried (Na2SO4). After re-
moval of the solvent under reduced pressure, the residue was
purified by PTLC on silica gel (hexane–EtOAc, 5:1) to give 11a (45
mg, 79%) as a white solid.
19F NMR (471 MHz, CDCl3): d = 86.8 (1 F, d, JF,F = 33 Hz), 90.0 (1
F, d, JF,F = 33 Hz).
Anal. Calcd for C17H19F2NSi: C, 67.29; H, 6.31; N, 4.62. Found: C,
67.32; H, 6.49; N, 4.40.
IR (neat): 3057, 1570, 1496, 1414, 1377, 1252, 1205, 777, 746,
696, 586, 515 cm–1.
N-[o-(3,3-Difluoro-2-phenylprop-2-en-1-yl)phenyl]-p-toluene-
sulfonamide (7a)
1H NMR (500 MHz, CDCl3): d = 7.44 (1 H, tt, J = 7.4, 1.7 Hz), 7.50
(2 H, dd, J = 7.4, 7.4 Hz), 7.55 (1 H, dd, J = 8.0, 8.0 Hz), 7.66 (2 H,
dd, J = 7.4, 1.7 Hz), 7.73 (1 H, ddd, J = 8.0, 8.0, 1.8 Hz), 7.88 (1 H,
d, J = 8.0 Hz), 7.98 (1 H, d, J = 8.0 Hz), 8.27 (1 H, d, JH,F = 9.8
Hz).
13C NMR (126 MHz, CDCl3): d = 124.2, 124.4, 126.4 (d, JC,F = 2
Hz), 127.5, 127.8, 128.5, 128.7, 129.0 (d, JC,F = 3 Hz), 130.4, 134.1
(d, JC,F = 5 Hz), 140.5 (d, JC,F = 6 Hz), 144.9 (d, JC,F = 17 Hz), 158.4
(d, JC,F = 244 Hz).
To a solution of aniline 20a (0.41 mg, 1.7 mmol) in pyridine (8 mL)
was added p-toluenesulfonyl chloride (0.47 g, 2.5 mmol) at 0 °C.
The mixture was stirred at r.t. for 16 h and then treated with H2O.
Organic materials were extracted with Et2O (3 ×), and the combined
extracts were washed with 2 M aq HCl (5 ×) and brine, and then
dried (Na2SO4). After removal of the solvent under reduced pres-
sure, the residue was purified by column chromatography on silica
gel (benzene–CH2Cl2, 2:1) to give 7a (0.56 g, 85%) as a white solid.
IR (neat): 3253, 1728, 1489, 1404, 1333, 1248, 1163, 906, 729, 654
cm–1.
1H NMR (500 MHz, CDCl3): d = 2.37 (3 H, s), 3.51 (2 H, dd,
JH,F = 2.1, 2.1 Hz), 6.54 (1 H, s), 7.05–7.12 (5 H, m), 7.13–7.17
(1 H, m), 7.18–7.27 (5 H, m), 7.59 (2 H, d, J = 8.3, 1.4 Hz).
13C NMR (126 MHz, CDCl3): d = 21.4, 29.5, 90.5 (dd, JC,F = 21, 15
Hz), 126.0, 126.9, 127.1, 127.4, 127.5, 128.1 (dd, JC,F = 3, 3 Hz),
128.5, 129.4, 129.6, 132.8 (dd, JC,F = 3, 3 Hz), 133.4 (dd, JC,F = 2, 2
Hz), 134.0, 136.7, 143.8, 154.1 (dd, JC,F = 293, 288 Hz).
19F NMR (471 MHz, CDCl3): d = 72.3 (1 F, d, JF,F = 38 Hz), 72.6 (1
F, d, JF,F = 38 Hz).
19F NMR (471 MHz, CDCl3): d = 96.8 (d, JF,H = 10 Hz).
HRMS: m/z calcd for C15H10FN: 223.0798 (M+); found: 223.0787.
N-[2-(3,3-Difluoroallyl)phenyl]-p-toluenesulfonamide (7c)
To a suspension of NaH (6.7 mg, 60% dispersion in mineral oil,
0.17 mmol) in DMF (2 mL) was added 7b (35 mg, 0.076 mmol) in
DMF (2 mL) at 0 °C under argon. The mixture was heated at 80 °C
for 2 h. The reaction was quenched with phosphate buffer (pH 7) at
r.t. Organic materials were extracted with EtOAc (3 ×), and the
combined extracts were washed with brine and dried (Na2SO4). Af-
ter removal of the solvent under reduced pressure, the residue was
purified by PTLC on silica gel (hexane–EtOAc, 2:1) to give 7c (20
mg, 81%) as a colorless oil.
HRMS: m/z calcd for C22H19F2NO2S: 399.1106 (M+); found
399.1123.
IR (neat): 1689, 1331, 1215, 1157, 1111, 1090, 908, 810, 729, 698,
656, 552 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.44 (3 H, s), 3.12 (2 H, ddd,
J = 7.9 Hz, JH,F = 1.6, 1.6 Hz), 4.13 (1 H, dtd, JH,F = 24.9 Hz,
J = 7.9 Hz, JH,F = 2.0 Hz), 6.42 (1 H, s), 7.13–7.21 (4 H, m), 7.24 (2
H, d, J = 8.7 Hz), 7.59 (2 H, d, J = 8.7 Hz).
13C NMR (126 MHz, CDCl3): d = 21.5, 24.0 (d, JC,F = 5 Hz), 76.4
(dd, JC,F = 23, 20 Hz), 126.2, 127.2, 127.2, 127.6, 129.6, 129.6,
133.8, 134.5, 136.4, 144.0, 156.5 (dd, JC,F = 287, 287 Hz).
19F NMR (471 MHz, CDCl3): d = 71.5 (1 F, dd, JF,F = 43 Hz,
JF,H = 25 Hz), 74.4 (1 F, d, JF,F = 43 Hz).
N-{o-[3,3-Difluoro-2-(dimethylphenylsilyl)prop-2-en-1-yl]phe-
nyl}-p-toluenesulfonamide (7b)
To a solution of aniline 20b (105 mg, 0.35 mmol) in pyridine (5 mL)
was added p-toluenesulfonyl chloride (99 mg, 0.54 mmol) at 0 °C.
The mixture was stirred at r.t. for 10 h, and then treated with H2O.
Organic materials were extracted with Et2O (3 ×), and the combined
extracts were washed with 0.5 M aq HCl (5 ×) and brine, and then
dried (Na2SO4). After removal of the solvent under reduced pres-
sure, the residue was purified by column chromatography on silica
gel (benzene–CH2Cl2, 2:1) to give 7b (149 mg, 94%) as a pale-yel-
low solid.
HRMS: m/z calcd for C16H15F2NO2S: 323.0792 (M+); found
323.0821.
IR (neat): 3268, 1738, 1689, 1333, 1219, 1159, 1111, 1092, 1045,
811, 702, 660, 542 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.23 (6 H, s), 2.37 (3 H, s), 2.98
(2 H, s), 5.71 (1 H, s), 6.94 (1 H, dd, J = 4.6, 4.6 Hz), 7.04 (1 H, dd,
J = 4.6, 4.6 Hz), 7.08 (1 H, d, J = 4.6 Hz), 7.09 (1 H, d, J = 4.6 Hz),
7.17 (2 H, d, J = 8.1 Hz), 7.28–7.33 (4 H, m), 7.38–7.41 (1 H, m),
7.49 (2 H, d, J = 8.1 Hz).
13C NMR (126 MHz, CDCl3): d = –2.7, 21.5, 26.8 (dd, JC,F = 6, 5
Hz), 79.7 (dd, JC,F = 28, 5 Hz), 126.2, 126.8, 127.1, 127.2, 127.9,
129.5, 129.5, 129.6, 133.8, 133.8, 134.6 (dd, JC,F = 3, 2 Hz), 136.2
(d, JC,F = 2 Hz), 136.5, 143.7, 157.1 (dd, JC,F = 307, 285 Hz).
2-Fluoro-3-(dimethylphenylsilyl)-1-(p-toluenesulfonyl)-1,4-di-
hydroquinoline (10b)
To a solution of sulfonamide 7b (18.9 mg, 0.041 mmol) in DMF (3
mL) were added Et3N (0.017 mL, 0.13 mmol) and B(OMe)3 (9.3
mL, 0.083 mmol) under argon. The mixture was heated at 80 °C for
5 h. Another portion of Et3N (0.017 mL, 0.13 mmol) was added, and
the mixture was heated at 80 °C for an additional 3 h. The reaction
was quenched with phosphate buffer (pH 7) at r.t. Organic materials
were extracted with EtOAc (3 ×), and the combined extracts were
washed with brine and dried (Na2SO4). After removal of the solvent
under reduced pressure, the residue was purified by PTLC on silica
gel (hexane–EtOAc, 3:1) to give 10b (15 mg, 85%) as a colorless
oil.
19F NMR (471 MHz, CDCl3): d = 86.9 (1 F, d, JF,F = 32 Hz), 90.0 (1
F, d, JF,F = 32 Hz).
Anal. Calcd for C24H25F2NO2SSi: C, 62.99; H, 5.51; N, 3.06.
Found: C, 62.76; H, 5.69; N, 2.83.
IR (neat): 1653, 1371, 1244, 1205, 1165, 1111, 1088, 816, 768, 727,
700, 652, 571 cm–1.
Synthesis 2006, No. 10, 1590–1598 © Thieme Stuttgart · New York

PAPER
Syntheses of Ring-Fluorinated Isoquinolines and Quinolines
19F NMR (471 MHz, CDCl3): d = 69.2 (t, JF,H = 7 Hz).
1597
1H NMR (500 MHz, CDCl3): d = 0.44 (6 H, s), 2.16 (2 H, d,
H,F = 6.4 Hz), 2.37 (3 H, s), 6.82 (1 H, d, J = 7.5 Hz), 7.04 (2 H, d,
J
HRMS: m/z calcd for C16H14FNO2S (M+): 303.0729; found:
303.0723.
J = 8.4 Hz), 7.16 (1 H, ddd, J = 7.7, 7.5, 1.2 Hz), 7.29 (1 H, dd,
J = 7.9, 7.7 Hz), 7.29 (2 H, d, J = 8.4 Hz), 7.34–7.42 (3 H, m), 7.43
(2 H, ddd, J = 7.7, 1.6, 1.6 Hz), 7.65 (1 H, d, J = 7.9 Hz).
13C NMR (126 MHz, CDCl3): d = –3.0 (d, JC,F = 3 Hz), 21.6, 28.6
(d, JC,F = 7 Hz), 103.6 (d, JC,F = 34 Hz), 126.7, 126.8, 127.1, 127.3,
127.9, 128.0, 129.3, 129.4, 133.1, 133.7, 133.9, 136.6, 136.9, 144.8,
153.0 (d, JC,F = 261 Hz).
Acknowledgment
We are grateful to TOSOH F-TECH, Inc. for a generous gift of 2-
bromo-3,3,3-trifluoropropene.
19F NMR (471 MHz, CDCl3): dF = 83.2 (d, JF,H = 6 Hz).
HRMS: m/z calcd for C24H24FNO2SSi: 437.1281 (M+); found
References
437.1288.
(1) (a) Yates, F. S. In Comprehensive Heterocyclic Chemistry,
Vol. 2; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon: New
York, 1984, Chap. 2.09. (b) Bentley, K. W. The
Isoquinoline Alkaloids; Harwood Academic: Amsterdam,
1998.
(2) Fraser, H. L.; Floyd, M. B. In Progress in Heterocyclic
Chemistry, Vol. 17; Gribble, G. W.; Joule, J. A., Eds.;
Elsevier: Amsterdam, 2005, Chap. 6.1.
(3) For recent reports on isoquinoline synthesis, see: (a) Mori,
T.; Ichikawa, J. Chem. Lett. 2005, 34, 778. (b) Kobayashi,
K.; Shiokawa, T.; Morikawa, O.; Konishi, H. Chem. Lett.
2004, 33, 236; and references cited therein. (c) Huang, Q.;
Larock, R. C. J. Org. Chem. 2003, 68, 980; and references
cited therein.
(4) For recent reports on quinoline synthesis, see:
(a) Duvelleroy, D.; Perrio, C.; Parisel, O.; Lasne, M.-C. Org.
Biomol. Chem. 2005, 3, 3794. (b) Yadav, J. S.;
3-(Dimethylphenylsilyl)-2-fluoroquinoline (11b)
Dihydroquinoline 10b (20 mg, 0.045 mmol) and DDQ (11 mg,
0.049 mmol) were dissolved in benzene (3 mL) and refluxed for 3
h under argon. The reaction was quenched with phosphate buffer
(pH 7) at r.t. Organic materials were extracted with EtOAc (3 ×),
and the combined extracts were washed with brine and dried
(Na2SO4). After removal of the solvent under reduced pressure, the
residue was purified by PTLC on silica gel (hexane–EtOAc, 5:1) to
give 11b (12 mg, 92%) as a colorless oil.
IR (neat): 3070, 2960, 1593, 1493, 1392, 1369, 1225, 1043, 912,
822, 785, 756, 702 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.70 (6 H, s), 7.39–7.47 (3 H, m),
7.50 (1 H, dd, J = 7.8, 7.6 Hz), 7.61 (2 H, dd, J = 7.6, 1.5 Hz), 7.71
(1 H, ddd, J = 8.1, 7.6, 1.5 Hz), 7.76 (1 H, d, J = 7.8 Hz), 7.92 (1 H,
d, J = 8.1 Hz), 8.16 (1 H, d, JH,F = 8.2 Hz).
13C NMR (126 MHz, CDCl3): d = –2.7, 120.8 (d, JC,F = 51 Hz),
125.9 (d, JC,F = 3 Hz), 126.8, 127.6, 127.8, 128.1, 129.7, 130.9,
134.1, 135.9, 146.7 (d, JC,F = 17 Hz), 149.6 (d, JC,F = 12 Hz), 164.4
(d, JC,F = 239 Hz).
Purushothama, R. P.; Sreenu, D.; Srinivasa, R. R.; Kumar,
V. N.; Nagaiah, K.; Prasad, A. R. Tetrahedron Lett. 2005,
46, 7249. (c) Motokura, K.; Mizugaki, T.; Ebitani, K.;
Kaneda, K. Tetrahedron Lett. 2004, 45, 6029.
(d) Kobayashi, K.; Takagoshi, K.; Kondo, S.; Morikawa, O.;
Konishi, H. Bull. Chem. Soc. Jpn. 2004, 77, 553; and
references cited therein. (e) Ichikawa, J.; Mori, T.;
Miyazaki, H.; Wada, Y. Synlett 2004, 1219. (f) Panda, K.;
Siddiqui, I.; Mahata, P. K.; Ila, H.; Junjappa, H. Synlett
2004, 449.
19F NMR (471 MHz, CDCl3): d = 111.3 (d, JF,H = 8 Hz).
HRMS: m/z calcd for C17H16NFSi (M+): 281.1036; found:
281.1030.
2-Fluoro-1-(p-toluenesulfonyl)-1,4-dihydroquinoline (10c)
(And A One-Pot Procedure for 11b)
(5) For recent examples, see: (a) Ishikawa, T.; Manabe, S.;
Aikawa, T.; Kudo, T.; Saito, S. Org. Lett. 2004, 6, 2361.
(b) Ichikawa, J.; Wada, Y.; Miyazaki, H.; Mori, T.; Kuroki,
H. Org. Lett. 2003, 5, 1455.
(6) (a) Ichikawa, J.; Wada, Y.; Okauchi, T.; Minami, T. Chem.
Commun. 1997, 1537. (b) Ichikawa, J.; Fujiwara, M.; Wada,
Y.; Okauchi, T.; Minami, T. Chem. Commun. 2000, 1887.
(c) Ichikawa, J.; Wada, Y.; Fujiwara, M.; Sakoda, K.
Synthesis 2002, 1917.
(7) For example, see: Kato, T.; Saeki, K.; Kawazoe, Y.; Hakura,
A. Mutat. Res. 1999, 439, 149; and references cited therein.
(8) For cross-coupling and nucleophilic replacement of aryl
fluorides, see: (a) Saeki, T.; Takashima, Y.; Tamao, K.
Synlett 2005, 1771; and references cited therein.
(b) Ackermann, L.; Born, R.; Spatz, J. H.; Meyer, D. Angew.
Chem. Int. Ed. 2005, 44, 7216. (c) Mongin, F.; Mojovic, L.;
Guillamet, B.; Trécourt, F.; Quéguiner, G. J. Org. Chem.
2002, 67, 8991. (d) Braun, T.; Perutz, R. N. Chem. Commun.
2002, 2749. (e) Arzel, E.; Rocca, P.; Grellier, P.; Labaeïd,
M.; Frappier, F.; Guéritte, F.; Gaspard, C.; Marsais, F.;
Godard, A.; Quéguiner, G. J. Med. Chem. 2001, 44, 949.
(9) (a) Silvester, M. J. Adv. Heterocycl. Chem. 1994, 59, 1.
(b) Silvester, M. J. Aldrichimica Acta 1991, 24, 31.
(c) Organofluorine Chemistry, Principles and Commercial
Applications; Banks, R. E.; Smart, B. E.; Tatlow, J. C., Eds.;
Plenum Press: New York, 1994.
To a solution of sulfonamide 7b (34 mg, 0.073 mmol) in DMF (3
mL) was added Et3N (0.031 mL, 0.22 mmol), and the mixture was
heated at 80 °C for 5 h under argon. After DBU (0.022 mL, 0.15
mmol) was added, the mixture was heated at 80 °C for an additional
1 h. The reaction was quenched with phosphate buffer (pH 7) at r.t.
Organic materials were extracted with EtOAc (3 ×), and the com-
bined extracts were washed with brine and dried (Na2SO4). After re-
moval of the solvent under reduced pressure, the residue was
purified by PTLC on silica gel (hexane–EtOAc, 3:1) to give quino-
line 11b (11 mg, 53%) along with 10c (4.4 mg, 20%) as a colorless
oil.
10c
IR (neat): 1699, 1369, 1309, 1205, 1174, 1088, 1043, 787, 764, 696,
652, 600 cm–1.
1H NMR (500 MHz, CDCl3): d = 2.36 (2 H, dd, J = 5.0 Hz,
JH,F = 6.7 Hz), 2.41 (3 H, s), 5.24 (1 H, td, J = 5.0 Hz, JH,F = 1.7
Hz), 6.91 (1 H, d, J = 7.5 Hz), 7.15 (2 H, d, J = 8.3 Hz), 7.20 (1 H,
ddd, J = 7.7, 7.4, 1.1 Hz), 7.31 (1 H, ddd, J = 7.5, 7.4, 1.1 Hz), 7.35
(2 H, d, J = 8.3 Hz), 7.70 (1 H, d, J = 7.7 Hz).
13C NMR (126 MHz, CDCl3): d = 21.7, 25.5 (d, JC,F = 4 Hz), 77.7
(d, JC,F = 34 Hz), 96.5 (d, JC,F = 27 Hz), 126.9, 127.4, 127.4, 128.3,
129.4, 132.6, 133.6, 136.8, 145.0, 150.3 (d, JC,F = 266 Hz).
Synthesis 2006, No. 10, 1590–1598 © Thieme Stuttgart · New York

1598
J. Ichikawa et al.
PAPER
(17) Ichikawa, J.; Miyazaki, H.; Sakoda, K.; Wada, Y. J.
(10) Classical Baltz–Schiemann (fluorodediazotization) and
Halex (halogen exchange) approaches are still extensively
used: Chemistry of Organic Fluorine Compounds II;
Hudlicky, M.; Pavlath, A. E., Eds.; American Chemical
Society: Washington, DC, 1995.
(11) For the synthesis of isoquinolines selectively fluorinated on
their heterocyclic ring, see: (a) Kolechkina, V. G.;
Maksimov, A. M.; Platonov, V. E.; Osina, O. I. Russ. Chem.
Bull. 2001, 50, 322. (b) Bellas, M.; Suschitzky, H. J. Chem.
Soc. 1964, 4561.
(12) For the synthesis of quinolines selectively fluorinated on
their heterocyclic ring, see: (a) Ondi, L.; Volle, J.-N.;
Schlosser, M. Tetrahedron 2005, 61, 717. (b) Mori, T.;
Ichikawa, J. Chem. Lett. 2004, 33, 590. (c) Wada, Y.; Mori,
T.; Ichikawa, J. Chem. Lett. 2003, 32, 1000. (d) Chambers,
R. D.; Parsons, M.; Sandford, G.; Skinner, C. J.; Atherton,
M. J.; Moilliet, J. S. J. Chem. Soc., Perkin Trans. 1 1999,
803; and references cited therein. (e) Strekowski, L.;
Kiselyov, A. S.; Hojjat, M. J. Org. Chem. 1994, 59, 5886.
(13) Ichikawa, J. J. Fluorine Chem. 2000, 105, 257.
(14) Wada, Y.; Ichikawa, J.; Katsume, T.; Nohiro, T.; Okauchi,
T.; Minami, T. Bull. Chem. Soc. Jpn. 2001, 74, 971.
(15) Mitsunobu, O. Synthesis 1981, 1.
(16) For desulfonylation on nitrogens to isoquinolines, see:
(a) Silveira, C. C.; Bernardi, C. R.; Braga, A. L.; Kaufman,
T. S. Synlett 2002, 907; and references cited therein.
(b) Larghi, E. L.; Kaufman, T. S. Tetrahedron Lett. 1997, 38,
3159; and references cited therein . For desulfonylation on
nitrogens to quinolines, see: (c) Kim, J. N.; Chunh, Y. M.;
Im, Y. J. Tetrahedron Lett. 2002, 43, 6209; and references
cited therein. (d) Tokuyama, H.; Sato, M.; Ueda, T.;
Fukuyama, T. Heterocycles 2001, 54, 105.
Fluorine Chem. 2004, 125, 585.
(18) (Trifluoromethyl)vinyl compounds 18 are reactive toward
SN2¢ reaction, when the vinylic substituent R is a silyl or an
aryl group. See: (a) Ichikawa, J.; Fukui, H.; Ishibashi, Y. J.
Org. Chem. 2003, 68, 7800. (b) Bégué, J.-P.; Bonnet-
Delpon, D.; Rock, M. H. J. Chem. Soc., Perkin Trans. 1
1996, 1409.
(19) (a) Fuhrer, W.; Gschwend, H. W. J. Org. Chem. 1979, 44,
1133. (b) Muchowski, J. M.; Venuti, M. C. J. Org. Chem.
1980, 45, 4798.
(20) Anilide 7c (R = H) hardly gave dihydroquinoline 10c
(R = H) on teatment with NaH, which suggests that 10c was
formed via desilylation of 10b.
(21) For transformation of vinylsilanes and arylsilanes, see:
Weber, W. P. Silicon Reagents for Organic Synthesis;
Springer: Berlin, 1983, Chap. 7 and Chap. 8.
(22) Tosyl radical can be used as a leaving group, see:
(a) Timokhin, V. I.; Gastaldi, S.; Bertrand, M. P.;
Chatgilialoglu, C. J. Org. Chem. 2003, 68, 3532. (b)Ouvry,
G.; Zard, S. Z. Chem. Commun. 2003, 778; and the
references cited therein.
(23) For the synthesis of 3-fluoroquinolines starting from (2,2-
difluorovinyl)benzene substrates on the basis of the
intramolecular substitution concept, see: Refs. 4e, 5b, 12b,
and 12c.
Synthesis 2006, No. 10, 1590–1598 © Thieme Stuttgart · New York