Intramolecular cyclization of β,β-difluorostyrenes bearing an iminomethyl or a diazenyl group at the ortho position: Synthesis of 3-fluorinated isoquinoline and cinnoline derivatives

Article abstract of DOI:10.1039/b712965c

o-Formyl-substituted β,β-difluorostyrenes readily react with NH₂OH·HCl or NH₄OAc to afford 3-fluoroisoquinoline derivatives in good yield via (i) the formation of the corresponding oximes or imines and (ii) subsequent intramolecular

Full text of DOI:10.1039/b712965c

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Intramolecular cyclization of b,b-difluorostyrenes bearing an iminomethyl or
a diazenyl group at the ortho position: synthesis of 3-fluorinated isoquinoline
and cinnoline derivatives
Junji Ichikawa,*a Yukinori Wada,b Hiroyuki Kuroki,c Jun Miharab and Ryo Nadanob
Received 22nd August 2007, Accepted 2nd October 2007
First published as an Advance Article on the web 23rd October 2007
DOI: 10.1039/b712965c
o-Formyl-substituted b,b-difluorostyrenes readily react with NH2OH·HCl or NH4OAc to afford
3-fluoroisoquinoline derivatives in good yield via (i) the formation of the corresponding oximes or
imines and (ii) subsequent intramolecular replacement of a vinylic fluorine by the sp2 nitrogen of the
=
=
iminomethyl group (HON CH– or HN CH–). b,b-Difluorostyrenes bearing an o-diazenyl group
=
(HN N–), generated by reduction of the corresponding diazonium ions, undergo a similar substitution
to afford 3-fluorinated cinnolines.
Introduction
Isoquinolines and related derivatives including cinnolines are
found in many bioactive natural products. They constitute key
structural components in pharmaceuticals and agrochemicals, as
well as materials such as dyestuffs and liquid crystals.1,2 As a
consequence, their synthesis has been a topic of much research
over the past years.3,4
Scheme 1 Construction of isoquinoline frameworks via substitution and
elimination.
The introduction of fluorine into the original molecules has
come into wide use as one of the most efficient methods for
modification of their biological activities as well as their physical
and chemical properties. Thus, fluorine-containing isoquinoline
derivatives have attracted considerable attention.5 Despite the
great utility and immense potential of ring-fluorinated isoquino-
line frameworks, both as components and intermediates,6 there
still remain problems in their synthesis.†7–9
In our recent publications, we have reported the construction
of isoquinoline frameworks via the intramolecular substitution
of tosylamidate anions, nitrogen nucleophiles bearing an N–
C single bond (sp3-type nucleophiles), for vinylic fluorines in
ortho-functionalized b,b-difluorostyrenes 1 (Scheme 1).8a This ring
formation is promoted by the unique reactivity of 1,1-difluoro-1-
alkenes toward nucleophilic substitution of their vinylic fluorines
via addition–elimination processes,5c followed by aromatization
via elimination of a sulfinic acid to provide the heteroaromatic
system 2.
we wish to report a facile synthesis of 3-fluorinated isoquinolines
and their N-oxides8 or cinnolines9 starting from o-formyl- or o-
amino-substituted b,b-difluorostyrenes, respectively.
Results and discussion
Synthesis of 3-fluoroisoquinoline N-oxides and
3-fluoroisoquinolines
For the purpose of preparing the starting b,b-difluorostyrenes
4 with an oxime moiety at the ortho position, b,b-difluoro-o-
formylstyrenes 3 were treated with hydroxyamine hydrochloride
(NH2OH·HCl) in the presence of Et3N. Unexpectedly, the reaction
directly produced 3-fluoroquinoline N-oxide 5a in 67% yield,
instead of the expected oxime 4a (Scheme 2). This result suggests
that b,b-difluoro-o-formylstyrene 3a was initially converted into
oxime 4a, which in turn readily underwent the intramolecular
=
On the other hand, nitrogen nucleophiles with an N Y double
bond (sp2 nucleophiles) would give rise to the direct construction of
heteroaromatic rings.8b Thus, we investigated a replacement of the
vinylic fluorines by nitrogen nucleophiles such as oxime, imine, and
diimide nitrogens to synthesize isoquinoline derivatives. Herein,
aDepartment of Chemistry, Graduate School of Pure and Applied Sciences,
University of Tsukuba, Tsukuba, Ibaraki 305-8571, Japan. E-mail: junji@
chem.tsukuba.ac.jp; Fax: +81 29 853 4237; Tel: +81 29 853 4237
bDepartment of Chemistry, Graduate School of Science, The University of
Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
cDepartment of Applied Chemistry, Kyushu Institute of Technology, Sensui-
cho, Tobata, Kitakyushu 804-8550, Japan
† Classical Balz–Schiemann (fluorodediazotization) and Halex (halogen
exchange) approaches are still extensively used. See ref. 7.
Scheme 2 Construction of isoquinoline frameworks via substitution
from 4.
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Table 1 Introduction of substituents at the 3-position of 5a
Entry NuM/eq. Solvent Conditions
vinylic substitution, followed by deprotonation on the oxygen,
leading to the final product, isoquinoline N-oxide 5a.‡
Yield (%) (7)
72 (7a)
Although this cyclization successfully proceeded, there was a
drawback in the thermal instability of the starting material, b,b-
difluoro-o-formylstyrenes 3. The coupling reaction of an in situ
generated 2,2-difluorovinylborane with o-iodobenzaldehyde10 af-
forded 3a in 84% yield, as determined by 19F NMR, while
the isolated yield was reduced to 62% after silica gel column
chromatography. Then, we tried to combine the coupling reac-
tion and the cyclization without purification of unstable 3, the
process of which could improve the synthesis of 5. After the
generation of difluorovinylboranes from 2,2,2-trifluoroethyl 4-
methylbenzenesulfonate (CF3CH2OTs) and their coupling reac-
tion with o-iodobenzaldehyde, the crude products were treated
with NH2OH·HCl, leading to the isoquinoline N-oxides 5a and
5b (R = n-Bu and sec-Bu) in 71% and 69% yields from the starting
o-iodobenzaldehyde, respectively (Scheme 3).
1
2
3
t-BuOK (1.5)
PhSLi (1.5)
Pyrrolidine (4.1) Toluene Reflux, 23 h
THF
THF
−78 ◦C, 0.5 h
−78 ◦C to 0 ◦C, 5 h 85 (7b)
74 (7c)
THF, the expected substitution of the fluorine proceeded to give
the corresponding isoquinoline N-oxides 7a or 7b bearing an
oxygen or a sulfur functional group at the 3-position (Scheme 4;
Table 1, entries 1 and 2). A nitrogen nucleophile, pyrrolidine, also
brought about a similar substitution under less basic conditions
to yield 7c (Table 1, entry 3). Thus, the reaction of 5a with
nucleophiles occurred regioselectively at the 3-position via ipso-
attack, whereas it is known that isoquinolines are highly reactive
toward nucleophiles at their 1-position.8e
As further examples of this type of cyclization, we examined
a similar in situ preparation of imine nitrogen nucleophiles
=
(HN CH–). When the crude formylstyrenes 3 were treated with
NH4OAc as an ammonia source, dehydration and subsequent
cyclization were smoothly induced to give isoquinolines 6a and
6b (R = n-Bu and sec-Bu) in 70% and 71% yields based on o-
iodobenzaldehyde, respectively (Scheme 3).‡
Scheme 4 Introduction of substituents at the 3-position of 5a via
substitution.
In addition, the cycloaddition of 5a was attempted by em-
ploying phenylisocyanate (PhNCO) as a dipolarophile, because
isoquinoline N-oxides are well-known to act as 1,3-dipoles. On
treatment of 5a with PhNCO in DMF, the expected reaction
proceeded with accompanying decarboxylation to give 1-anilino-
3-fluoroisoquinoline 8a. In contrast to the above-mentioned
introduction of a substituent at the 3-position, the amino group
11
was exclusively introduced at the 1-position (Scheme 5).§ Thus,
these sequences of processes provide a versatile method for the
synthesis of 3,4-disubstituted and 1,3,4-trisubstituted isoquinoline
derivatives starting from CF3CH2OTs and o-iodobenzaldehyde.
Scheme 3 Synthesis of 3-fluoroisoquinoline N-oxides 5 and 3-fluoroiso-
quinolines 6.
Reactions of 3-fluoroisoquinoline N-oxides
The remaining fluorines in isoquinoline N-oxides 5 were expected
to be quite reactive toward replacement by nucleophiles via similar
addition–elimination processes, which allow the introduction of
another substituent into the isoquinoline frameworks. Initially, we
attempted the reaction of 5a with oxygen and sulfur nucleophiles.
On treatment of 5a with KOt-Bu or LiSPh as a nucleophile in
Scheme 5 Introduction of a substituent at the 1-position of 5a via
1,3-dipolar addition.
‡ The possibility of 6p-electrocyclization in the formation of 5, 6, and 10
cannot be ruled out.
§ Recently, a site-selective (C-1) direct arylation of isoquinoline N-oxides
has been reported, see ref. 11.
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Synthesis of 3-fluorocinnolines
(dF) are given in ppm downfield from C6F6. IR spectra were
recorded on a Shimadzu IR-408 spectrometer or a JEOL JIR-
WINSPEC50 spectrometer. Elemental analyses were performed
with a YANAKO MT-6 CHN Corder apparatus. Mass spectra
were taken with a JEOL MS-700M spectrometer.
As shown in Scheme 3, the direct construction of isoquinoline
frameworks has been successfully achieved by the intramolecular
substitution of the oxime and imine sp nitrogen (HON CH–
2
=
=
and HN CH–). Using these tactics, we next investigated the
All reactions were carried out under nitrogen. Tetrahydrofuran
(THF) was distilled from sodium benzophenone ketyl prior to
use. N,N-Dimethylformamide (DMF) was distilled under reduced
2
=
intramolecular substitution of a diimide sp nitrogen (HN N–),
where the imino carbon was replaced by a nitrogen atom. This
reaction would result in the construction of the cinnoline ring
structure.
o-Amino-b,b-difluorostyrenes 9, prepared from CF3CH2OTs
and o-iodoaniline,12 were treated with isoamyl nitrite (i-AmONO)
for diazotization, and then subsequently reduced with n-
Bu3SnH. The expected intramolecular substitution of the terminal
˚
pressure from CaH2 and stored over 4A molecular sieves. Acetoni-
trile (CH3CN) was distilled under reduced pressure from CaH2 and
˚
stored over 3A molecular sieves. Hexamethylphosphoric triamide
(HMPA) was distilled under reduced pressure from CaH2 and
˚
stored over 4A molecular sieves. Toluene was distilled and stored
over sodium. Column chromatography and preparative thin layer
chromatography were performed on silica gel (Kanto Chemical
Co. Inc., Silica Gel 60 and Wako Pure Chemical Industries, Ltd.,
B5-F), respectively.
=
diazenyl nitrogen (HN N–) proceeded smoothly, to give 3-
fluorocinnoline 10a in 58% yield.‡ Then we tried several other
reducing reagents, and found that benzenethiol raised the yield of
10a and 10b (R = n-Bu and sec-Bu) to 88% and 87%, respectively
(Scheme 6). In the reaction of 9a, diphenyl disulfide (PhSSPh) was
obtained in 90% yield based on PhSH, which implies that PhSH
definitely acted as a reducing agent.
Synthesis of 3-fluoroisoquinoline N-oxides and
3-fluoroisoquinolines
o-(1,1-Difluorohex-1-en-2-yl)benzaldehyde (3a). Butyllithium
(5.0 mL, 1.7 M in hexane, 8.4 mmol) was added to a solution
of CF3CH2OTs (1.0 g, 4.0 mmol) in THF (20 mL) at −78 ◦C over
◦
10 min. 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 allowed to warm up to room temperature and
stirred for an additional 3 h. The solution was treated with
HMPA (5.0 mL), triphenylphosphine (30 mg, 0.11 mmol), and
tris(dibenzylideneacetone)dipalladium–chloroform (1 : 1) (29 mg,
0.028 mmol) and stirred for 15 min. To the resulting solution
were added o-iodobenzaldehyde (738 mg, 3.2 mmol) and copper(I)
iodide (757 mg, 4.0 mmol). After the mixture was stirred for 20 min
at room temperature, the reaction was quenched with phosphate
buffer (pH 7). The mixture was filtered through a Celite pad, 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 pressure,
the residue was purified by column chromatography on silica gel
(Et2O–hexane, 1 : 20) to give 3a (441 mg, 62%) as a pale yellow
liquid. 1H NMR (500 MHz, CDCl3) dH 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, d, J = 1.5 Hz).
13C NMR (126 MHz, CDCl3) dC 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) dF 70.0 (1F, dt, JFF = 43 Hz,
JFH = 3 Hz), 72.8 (1F, dd, JFF = 43 Hz, JFH = 2 Hz). IR (neat) mmax
2970, 2950, 2890, 1840, 1745, 1705, 1600, 1470, 1465, 1245 cm−1.
MS (EI, 70 eV) m/z 224 (M+, 20%), 205 (44), 131 (100), 91 (44).
HRMS m/z calcd for C13H14F2O 224.1013 (M+); found 224.1000.
Scheme 6 Synthesis of 3-fluoroccinnolines 10.
Conclusion
We have accomplished the construction of isoquinoline and
cinnoline frameworks via intramolecular cyclization of b,b-
difluorostyrenes bearing a hydroxyiminomethyl (HON CH–),
=
=
=
an iminomethyl (HN CH–) or a diazenyl (HN N–) group
at the ortho position. The b,b-difluorostyrenes, prepared
from CF3CH2OTs, trialkylboranes and o-formyl- or o-amino-
substituted aryl iodides, readily undergo six-membered ring
closure via dehydration or diazotization under mild conditions
compatible with a variety of functional groups. Thus, this sequence
provides a facile method for the synthesis of selectively ring-
fluorinated nitrogen heterocycles.
Experimental
4-Butyl-3-fluoroisoquinoline
N-oxide
(5a). Butyllithium
1H NMR, 13C NMR, and 19F NMR spectra were recorded on a
JEOL JNM-A-500 or a Bruker DRX 500 spectrometer. 1H NMR
chemical shifts (dH) are given in ppm downfield from Me4Si. 13C
NMR chemical shifts (dC) are given in ppm downfield from Me4Si,
relative to chloroform-d (d = 77.0). 19F NMR chemical shifts
(1.1 mL, 1.49 M in hexane, 1.7 mmol) was added to a THF
(4.5 mL) solution of CF3CH2OTs (203 mg, 0.80 mmol) at −78 ◦C
over 10 min. The reaction mixture was stirred for 20 min at
−78 ◦C, and then tributylborane (0.88 mL, 1.0 M in THF,
0.88 mmol) was added at −78 ◦C. After being stirred for 1 h, the
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reaction mixture was allowed to warm up to room temperature
and stirred for an additional 3 h. The solution was treated with
HMPA (1.5 mL), triphenylphosphine (17 mg, 0.065 mmol) and
tris(dibenzylideneacetone)dipalladium–chloroform (1 : 1) (25 mg,
0.024 mmol) and stirred for 15 min. To the resulting solution was
added o-iodobenzaldehyde (167 mg, 0.72 mmol) and copper(I)
iodide (153 mg, 0.80 mmol). After the mixture was stirred for
15 min at room temperature, the reaction was quenched with
phosphate buffer (pH 7). The mixture was filtered through a
Celite pad, and then organic materials were extracted with Et2O
three times. The combined extracts were washed with brine and
dried over Na2SO4. After removal of the solvent under reduced
pressure, the residue, crude aldehyde 3a, was dissolved in DMF
(3.0 mL). The resulting mixture was treated with NH2OH·HCl
(160 mg, 0.96 mmol) and Et3N (0.22 mL, 1.8 mmol) and
stirred for 12 h. The reaction was quenched with phosphate
buffer (pH 7), and organic materials were extracted with CHCl3
three times. After removal of the solvent under reduced pressure,
the residue was purified by thin layer chromatography on silica gel
(MeOH–AcOEt, 1 : 20) to give 5a (112 mg, 71%) as a pale yellow
liquid. 1H NMR (500 MHz, CDCl3) dH 0.98 (3H, t, J = 7.5 Hz),
1.47 (2H, tq, J = 7.5, 7.5 Hz), 1.69 (2H, tt, J = 7.5, 7.5 Hz), 3.06
(2H, dt, J = 7.5 Hz, JHF = 2.0 Hz), 7.59 (1H, t, J = 7.8 Hz), 7.66
(1H, t, J = 7.8 Hz), 7.74 (1H, d, J = 7.8 Hz), 7.90 (1H, d, J =
7.8 Hz), 8.75 (1H, d, JHF = 6.4 Hz). 13C NMR (126 MHz, CDCl3)
4-Butyl-3-fluoroisoquinoline (6a). Butyllithium (0.65 mL,
1.62 M in hexane, 1.05 mmol) was added to a THF (2.5 mL)
solution of CF3CH2OTs (127 mg, 0.50 mmol) at −78 ◦C over
◦
10 min. The reaction mixture was stirred for 20 min at −78 C,
and then tributylborane (0.55 mL, 1.0 M in THF, 0.55 mmol)
was added at −78 ◦C. After being stirred for 1 h, the reaction
mixture was allowed to warm up to room temperature and
stirred for an additional 3 h. The solution was treated with
HMPA (0.63 mL), triphenylphosphine (11 mg, 0.040 mmol), and
tris(dibenzylideneacetone)dipalladium–chloroform (1 : 1) (10 mg,
0.010 mmol) and stirred for 15 min. To the resulting solution were
added o-iodobenzaldehyde (104 mg, 0.45 mmol) and copper(I)
iodide (95 mg, 0.50 mmol). After the mixture had been stirred
for 20 min at room temperature, the reaction was quenched
with phosphate buffer (pH 7). The mixture was filtered through
a Celite pad, and then organic materials were extracted with
Et2O three times. The combined extracts were washed with water
and brine, and then dried over MgSO4. After removal of the
solvent under reduced pressure, the residue was dissolved in DMF
(4.5 mL). The resulting mixture was treated with H2O (0.45 mL)
and NH4OAc (173 mg, 2.2 mmol) and then stirred for 1 h at
room temperature. The reaction mixture was diluted with H2O,
and organic materials were extracted with AcOEt three times. The
combined extracts were washed with water and brine, and then
dried over Na2SO4. After removal of the solvent under reduced
pressure, the residue was purified by thin layer chromatography
on silica gel (AcOEt–hexane, 1 : 10, and then benzene–hexane, 2 :
1) to give 6a (64 mg, 70%). 1H NMR (500 MHz, CDCl3) dH 0.97
(3H, t, J = 7.5 Hz), 1.46 (2H, tq, J = 7.5, 7.5 Hz), 1.63–1.71 (2H,
m), 3.03 (2H, dt, J = 7.5 Hz, JHF = 0.9 Hz), 7.52 (1H, ddd, J =
8.0, 8.0 Hz, JHF = 0.8 Hz), 7.71 (1H, dd, J = 8.0, 8.0 Hz), 7.97
(1H, d, J = 8.0 Hz), 7.99 (1H, d, J = 8.0 Hz), 8.80 (1H, s). 13C
dC 13.8, 22.6, 24.3, 31.5, 119.0 (d, JCF = 17 Hz), 123.2 (d, JCF
=
6 Hz), 125.6 (d, JCF = 2 Hz), 126.1 (d, JCF = 3 Hz), 128.2, 128.2,
129.5, 135.6 (d, JCF = 7 Hz), 153.5 (d, JCF = 252 Hz). 19F NMR
(470 MHz, CDCl3) dF 46.7 (d, JFH = 6 Hz). IR (KBr disk) mmax
1630, 1605, 1500, 1485, 1440, 1390, 1325, 1240, 1190, 1120 cm−1.
MS (EI, 70 eV) m/z 219 (M+, 100%), 160 (72), 149 (47), 101 (17).
Anal. found: C, 71.15; H, 6.43; N, 6.24, calcd for C13H14FNO: C,
71.21; H, 6.44; N, 6.39%.
NMR (126 MHz, CDCl3) dC 13.9, 22.8, 24.1, 32.1, 115.0 (d, JCF
=
30 Hz), 122.9 (d, JCF = 7 Hz), 125.6 (d, JCF = 2 Hz), 127.6 (d,
4-(Butan-2-yl)-3-fluoroisoqunoline N-oxide (5b). Compound
5b was prepared by the method described for 5a using butyl-
lithium (1.1 mL, 1.49 M in hexane, 1.7 mmol), CF3CH2OTs
(203 mg, 0.80 mmol), tri(butan-2-yl)borane (0.88 mL, 1.0 M in
THF, 0.88 mmol), HMPA (1.5 mL), triphenylphosphine (17 mg,
0.065 mmol), tris(dibenzylideneacetone)dipalladium–chloroform
(1 : 1) (25 mg, 0.024 mmol), o-iodobenzaldehyde (167 mg,
0.72 mmol) and copper(I) iodide (153 mg, 0.80 mmol) in THF
(4.5 mL). Then, crude aldehyde 3b was treated with NH2OH·HCl
(160 mg, 0.96 mmol) and Et3N (0.22 mL, 1.8 mmol) in DMF
(3.0 mL). Purification by thin layer chromatography on silica gel
(MeOH–AcOEt, 1 : 20) gave 5b (109 mg, 69%) as a pale yellow
liquid. 1H NMR (500 MHz, CDCl3) dH 0.90 (3H, t, J = 7.2 Hz),
1.48 (3H, dd, J = 7.2Hz, JHF = 1.4 Hz), 1.84–2.04 (2H, m), 3.50
(1H, tq, J = 7.2, 7.2 Hz), 7.58 (1H, dd, J = 7.8, 7.8 Hz), 7.65 (1H,
dd, J = 7.8, 7.8 Hz), 7.74 (1H, d, J = 7.8 Hz), 8.05 (1H, d, J =
7.8 Hz), 8.77 (1H, d, JHF = 6.4 Hz). 13C NMR (126 MHz, CDCl3)
dC 12.7, 18.9 (d, JCF = 4 Hz), 28.2 (d, JCF = 3 Hz), 33.6, 123.2
(d, JCF = 15 Hz), 123.3 (d, JCF = 4 Hz), 125.8 (d, JCF = 2 Hz),
JCF = 2 Hz), 128.4, 130.7, 138.4 (d, JCF = 6 Hz), 148.6 (d, JCF =
16 Hz), 159.1 (d, JCF = 232 Hz). 19F NMR (470 MHz, CDCl3) dF
79.3 (br s). IR (neat) mmax 2960, 2930, 2870, 1620, 1590, 1440, 1425,
1250, 1220, 750 cm−1. MS (EI, 20 eV) m/z 203 (M+, 67%), 160
(100). Anal. found: C, 76.54; H, 6.95; N, 6.76, calcd for C13H14FN:
C, 76.82; H, 6.94; N, 6.89%.
4-(Butan-2-yl)-3-fluoroisoquinoline (6b). Compound 6b was
prepared by the method described for 6a using butyllithium
(0.65 mL, 1.62 M in hexane, 1.05 mmol), CF3CH2OTs (127 mg,
0.50 mmol), tri(butan-2-yl)butylborane (0.55 mL, 1.0 M in THF,
0.55 mmol), HMPA (0.63 mL), triphenylphosphine (11 mg,
0.040 mmol), tris(dibenzylideneacetone)dipalladium–chloroform
(1 : 1) (10 mg, 0.010 mmol), o-iodobenzaldehyde (104 mg,
0.45 mmol) and copper(I) iodide (95 mg, 0.50 mmol) in THF
(2.5 mL). Then, crude aldehyde 3b was treated with NH4OAc
(173 mg, 2.2 mmol) and H2O (0.22 mL, 1.8 mmol) in DMF
(4.5 mL). Purification by thin layer chromatography on silica
gel (AcOEt–hexane, 1 : 10, and then benzene–AcOEt–hexane 1 :
1
126.2 (d, JCF = 3 Hz), 128.0 (d, JCF = 3 Hz), 129.5, 129.6 (d, JCF
=
10 : 10) to give 6b (65 mg, 71%). H NMR (500 MHz, CDCl3)
8 Hz), 135.7 (d, JCF = 8 Hz), 153.9 (d, JCF = 256 Hz). 19F NMR
(470 MHz, CDCl3) dF 50.9 (br s). IR (KBr disk) mmax 2960, 2940,
2870, 1480, 1435, 1315, 1230, 1215, 1190, 1120, 920 cm−1. MS (EI,
70 eV) m/z 219 (M+, 100%), 174 (50), 115 (47). HRMS m/z calcd
for C13H14FNO 219.1059 (M+); found 219.1082.
dH 0.86 (3H, t, J = 7.3 Hz), 1.46 (3H, dd, J = 7.3 Hz, JHF =
1.5 Hz), 1.82–2.14 (2H, m), 3.49 (1H, tq, J = 7.3, 7.3 Hz), 7.52
(1H, dd, J = 7.9, 7.9 Hz), 7.70 (1H, dd, J = 7.9, 7.9 Hz), 7.98
(1H, d, J = 7.9 Hz), 8.14 (1H, d, J = 7.9 Hz), 8.81 (1H, s). 13C
NMR (126 MHz, CDCl3) dC 12.8, 19.3 (d, JCF = 3 Hz), 28.5
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(d, JCF = 3 Hz), 33.0 (d, JCF = 4 Hz), 119.1 (d, JCF = 26 Hz),
123.1 (d, JCF = 6 Hz), 125.5 (d, JCF = 2 Hz), 127.6 (d, JCF = 2 Hz),
128.5, 130.6, 138.5 (d, JCF = 7 Hz), 148.8 (d, JCF = 17 Hz), 159.3
(d, JCF = 235 Hz). 19F NMR (470 MHz, CDCl3) dF 86.1 (br s). IR
(neat) mmax 2964, 2873, 1623, 1585, 1567, 1500, 1442, 1423, 1380,
1268, 1247, 1153, 933, 752 cm−1. MS (EI, 70 eV) m/z 203 (M+,
37%), 174 (100), 154 (17), 149 (14). Anal. found: C, 76.58; H, 7.00;
N, 6.80, calcd for C13H14FN: C, 76.82; H, 6.94; N, 6.89%.
were removed by evaporation under reduced pressure. The residue
was purified by thin layer chromatography on silica gel (MeOH–
AcOEt, 1 : 20) to give 7c (69 mg, 74%) as a pale brown solid.
1H NMR (500 MHz, CDCl3) dH 1.00 (3H, t, J = 7.4 Hz), 1.50
(2H, tq, J = 7.4, 7.4 Hz), 1.59–1.67 (2H, m), 2.06–2.10 (4H, m),
3.11–3.15 (2H, m), 3.35 (4H, br s), 7.48–7.53 (2H, m), 7.64 (1H,
dd, J = 7.3, 1.2 Hz), 7.86 (1H, d, J = 8.5 Hz), 8.67 (1H, s). 13C
NMR (126 MHz, CDCl3) dC 13.9, 23.2, 26.7, 27.9, 33.0, 49.5,
124.2, 125.1, 127.7, 127.8, 128.0, 129.5, 135.3, 135.9, 148.6. IR
(KBr disk) mmax 3286, 2954, 2925, 1473, 1430, 1321, 1226, 1168,
1122, 759 cm−1. MS (EI, 20 eV) m/z 270 (M+, 12%), 254 (100).
HRMS m/z calcd for C17H22N2O 270.1732 (M+); found 270.1764.
Reactions of 3-fluoroisoquinoline N-oxides
3-tert-Butoxy-4-butylisoquinoline N-oxide (7a). To a solution
of potassium tert-butoxide (63 mg, 0.56 mmol) in THF (2.5 mL)
was added a solution of 5a (82 mg, 0.37 mmol) in THF (2.0 mL)
at −78 ◦C. After the mixture was stirred for 30 min at −78 ◦C, the
reaction was quenched with H2O–THF. 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 (MeOH–AcOEt, 1 : 20) to give
7a (74 mg, 72%) as colorless crystals. 1H NMR (500 MHz, CDCl3)
dH 0.99 (3H, t, J = 7.5 Hz), 1.49 (2H, tq, J = 7.5, 7.5 Hz), 1.62
(9H, s), 1.61–1.68 (2H, m), 3.07 (2H, t, J = 7.5 Hz), 7.47 (1H,
dd, J = 7.8, 7.8 Hz), 7.54 (1H, ddd, J = 7.8, 7.8, 1.2 Hz), 7.64
(1H, d, J = 7.8 Hz), 7.82 (1H, d, J = 7.8 Hz), 8.67 (1H, s). 13C
NMR (126 MHz, CDCl3) dC 13.9, 23.0, 26.6, 29.1, 31.9, 87.2,
123.5, 125.1, 126.1, 127.2, 127.4, 128.2, 129.6, 135.0, 152.1. IR
(KBr disk) mmax 2960, 2920, 1590, 1465, 1360, 1320, 1230, 1180,
1150, 750 cm−1. MS (EI, 20 eV) m/z 273 (M+, 2%), 217 (100), 201
(15), 158 (12). HRMS m/z calcd for C17H23NO2 273.1729 (M+);
found 273.1752.
4-Butyl-3-fluoro-1-anilinoisoquinoline (8a). To a solution of 5a
(73 mg, 0.32 mmol) in DMF (4.0 mL) was added phenyl isocyanate
(0.074 mL, 0.68 mmol). After the reaction mixture was stirred at
100 ◦C for 21 h, phosphate buffer (pH 7) was added. 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 (AcOEt–
hexane, 1 : 3) to give 8a (55 mg, 57%) as a pale yellow solid.
1H NMR (500 MHz, CDCl3) dH 0.95 (3H, t, J = 7.5 Hz), 1.43
(2H, tq, J = 7.5, 7.5 Hz), 1.61 (2H, tt, J = 7.5, 7.5 Hz), 2.89
(2H, t, J = 7.5 Hz), 7.05 (1H, tt, J = 7.5, 1.1 Hz), 7.15 (1H,
br s), 7.34 (2H, dd, J = 8.6, 7.5 Hz), 7.42 (1H, dd, J = 7.8,
7.8 Hz), 7.64 (1H, dd, J = 7.8, 7.8 Hz), 7.68 (2H, dd, J = 8.6,
1.1 Hz), 7.88 (1H, d, J = 7.8 Hz), 7.89 (1H, d, J = 7.8 Hz). 13C
NMR (126 MHz, CDCl3) dC 14.0, 22.6, 23.6, 32.2, 104.4 (d, JCF
31 Hz), 117.0 (d, JCF = 2 Hz), 120.0, 122.0, 122.9, 123.9 (d, JCF
=
=
7 Hz), 124.5 (d, JCF = 2 Hz), 129.0, 130.3, 139.7 (d, JCF = 7 Hz),
139.7, 149.8 (d, JCF = 20 Hz), 157.2 (d, JCF = 230 Hz). 19F NMR
(470 MHz, CDCl3) dF 79.4 (br s). IR (neat) mmax 3450, 2950, 2870,
1620, 1540, 1440, 1415, 1340, 1120, 755 cm−1. MS (EI, 70 eV) m/z
294 (M+, 45%), 251 (100), 204 (7), 128 (7), 77 (19). Anal. found: C,
77.22; H, 6.64; N, 9.31, calcd for C19H19FN2: C, 77.52; H, 6.51; N,
9.52%.
4-Butyl-3-phenylthioisoquinoline N-oxide (7b). To a solution
of thiophenol (54 mL, 0.53 mmol) in THF (1.0 mL) was
added butyllithium (0.35 mL, 1.51 M in hexane, 0.53 mmol) at
◦
◦
−78 C. The reaction mixture was stirred for 30 min at −78 C,
and then a solution of 5a (96 mg, 0.44 mmol) in THF (2.0 mL)
was added at −78 ◦C. After being stirred for 3 h, the mixture
was allowed to warm up to 0 ◦C and stirred for an additional 2 h.
The reaction was quenched with phosphate buffer (pH 7). Organic
materials were extracted with MeOH–AcOEt (1 : 20) 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
(MeOH–AcOEt, 1 : 20) to give 7b (115 mg, 85%) as colorless
crystals. 1H NMR (500 MHz, CDCl3) dH 0.97 (3H, t, J = 7.6 Hz),
1.51 (2H, tq, J = 7.6, 7.6 Hz), 1.63 (2H, tt, J = 7.6, 7.6 Hz),
3.43 (2H, t, J = 7.6 Hz), 7.14–7.19 (1H, m), 7.21–7.24 (4H, m),
7.58–7.63 (2H, m), 7.67–7.70 (1H, m), 7.93–7.96 (1H, m), 8.81
(1H, s). 13C NMR (126 MHz, CDCl3) dC 13.8, 23.0, 31.4, 32.8,
124.5, 125.3, 126.5, 127.8, 127.9, 128.8, 129.1, 129.4, 129.6, 134.5,
135.0, 141.8, 144.1. IR (KBr disk) mmax 3050, 2950, 2920, 1580,
1565, 1480, 1320, 1185, 1135, 740 cm−1. MS (EI, 70 eV) m/z 309
(M+, 9%), 292 (100), 250 (75), 174 (75), 115 (22), 77 (12). HRMS
m/z calcd for C19H19NOS 309.1187 (M+); found 309.1216.
Synthesis of 3-fluorocinnolines
o-(1,1-Difluorohex-1-en-2-yl)aniline
(9a). Butyllithium
(1.56 mL, 1.63 M in hexane, 2.5 mmol) was added to a solution
of CF3CH2OTs (308 mg, 1.21 mmol) in THF (10 mL) at −78 ◦C
over 10 min. The reaction mixture was stirred for 20 min at
−78 ◦C, and then tributylborane (1.33 mL, 1.0 M in THF,
1.33 mmol) was added at −78 ◦C. After being stirred for 1 h, the
reaction mixture was allowed to warm up to room temperature
and stirred for an additional 3 h. The solution was treated
with HMPA (3.0 mL), triphenylphosphine (25 mg, 0.10 mmol)
and tris(dibenzylideneacetone)dipalladium–chloroform (1 : 1)
(25 mg, 0.024 mmol) and stirred for 15 min. To the solution
was added the magnesium salt [generated from o-iodoaniline
(238 mg, 1.09 mmol) and dibutylmagnesium (2.47 mL, 0.44 M in
Et2O, 1.09 mmol) in THF (3.0 mL) at 0 ◦C] and copper(I) iodide
(230 mg, 1.21 mmol). After the mixture had been stirred for 1 h
at room temperature, the reaction was quenched with phosphate
buffer (pH 7). The mixture was filtered through a Celite pad, 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 pressure,
4-Butyl-3-(pyrrolidin-1-yl)isoquinoline N-oxide (7c). To a so-
lution of 5a (77 mg, 0.35 mmol) in toluene (2.0 mL) was added
pyrrolidine (0.12 mL, 1.4 mmol) at room temperature. After the
reaction mixture was heated at reflux for 23 h, volatile components
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the residue was purified by column chromatography on silica gel
(AcOEt–hexane, 1 : 10) to give 9a (176 mg, 77%) as a yellow
liquid. 1H NMR (500 MHz, CDCl3) dH 0.87 (3H, t, J = 7.1 Hz),
1.30–1.35 (4H, m), 2.29 (2H, tdd, J = 7.0 Hz, JHF = 2.3, 2.3 Hz),
3.66 (2H, br s), 6.70–6.77 (2H, m), 7.00 (1H, dd, J = 7.6, 1.5 Hz),
7.12 (1H, ddd, J = 7.6, 7.6, 1.5 Hz). 13C NMR (126 MHz, CDCl3)
dC 13.8, 22.4, 27.7, 29.8 (dd, JCF = 3, 3 Hz), 89.1 (dd, JCF = 22,
Anal. found: C, 70.32; H, 6.28; N, 13.34, calcd for C12H13FN2: C,
70.57; H, 6.42; N, 13.72%.
4-(Butan-2-yl)-3-fluorocinnoline (10b). Compound 10b was
prepared by the method described for 10a using CH3CN
(3.0 mL), CF3CO2H (0.053 mL, 0.72 mmol), i-AmONO (0.10 mL,
0.72 mmol), 9b (76 mg, 0.36 mmol) and thiophenol (0.11 mL,
1.1 mmol). Purification by thin layer chromatography on silica gel
(AcOEt–hexane 1 : 5) gave 10b (64 mg, 87%) as a yellow liquid.
1H NMR (500 MHz, CDCl3) dH 0.87 (3H, t, J = 7.2 Hz), 1.49 (3H,
dd, J = 7.2 Hz, JHF = 1.5 Hz), 1.87–2.03 (2H, m), 3.57 (1H, tq, J =
7.2, 7.2 Hz), 7.75–7.80 (2H, m), 8.14–8.20 (1H, m), 8.48–8.54 (1H,
m). 13C NMR (126 MHz, CDCl3) dC 12.7, 18.9 (d, JCF = 3 Hz),
28.2 (d, JCF = 4 Hz), 33.0 (d, JCF = 3 Hz), 122.9 (d, JCF = 6 Hz),
125.8 (d, JCF = 22 Hz), 129.1 (d, JCF = 2 Hz), 129.4 (d, JCF = 7 Hz),
130.7, 131.5, 150.6, 162.4 (d, JCF = 238 Hz). 19F NMR (470 MHz,
CDCl3) dF 74.1 (br s). IR (neat) mmax 2960, 2940, 2860, 1565, 1525,
1435, 1315, 1235, 1130, 760 cm−1. MS (EI, 20 eV) m/z 204 (M+,
100%), 146 (34). Anal. found: C, 70.32; H, 6.54; N, 13.50, calcd
for C12H13FN2: C, 70.57; H, 6.42; N, 13.72%.
17 Hz), 115.6, 118.4, 119.0 (d, JCF = 3 Hz), 128.9, 130.6, (d, JCF
=
2 Hz), 144.3, 152.8 (dd, JCF = 290, 288 Hz). 19F NMR (470 MHz,
CDCl3) dF 68.7 (1F, d, JFF = 43 Hz), 72.7 (1F, d, JFF = 43 Hz).
IR (neat) mmax 3475, 3375, 2960, 2930, 2860, 1740, 1620, 1495,
1230 cm−1. MS (EI, 70 eV) m/z 211 (M+, 100%), 168 (59), 148
(43). Anal. found: C, 68.14; H, 7.07, N; 6.52, calcd for C12H15F2N:
C, 68.23; H, 7.16; N, 6.63%.
o-(1,1-Difluoro-3-methylpent-1-en-2-yl)aniline
(9b). Com-
pound 9b was prepared by the method described for 9a using
butyllithium (1.56 mL, 1.63 M in hexane, 2.5 mmol), CF3CH2OTs
(308 mg, 1.21 mmol), THF (10 mL), tri(butan-2-yl)borane
(1.33 mL, 1.0 M in THF, 1.33 mmol), HMPA (3.0 mL), triph-
enylphosphine (25 mg, 0.10 mmol), tris(dibenzylideneacetone)-
dipalladium–chloroform (1 : 1) (25 mg, 0.024 mmol), o-iodoaniline
(238 mg, 1.09 mmol), dibutylmagnesium (2.47 mL, 0.44 M in
Et2O, 1.09 mmol), THF (3.0 mL) and copper(I) iodide (230 mg,
1.21 mmol). Purification by thin layer chromatography on silica
gel (AcOEt–hexane, 1 : 5) gave 9b (157 mg, 68%) as a pale yellow
Acknowledgements
The present work is dedicated to Professor Kenji Uneyama, the
2007 recipient of the ACS Award for Creative Work in Fluorine
Chemistry.
We are grateful to Bayer CropScience K.K. for financial
support.
liquid. H NMR (500 MHz, (CD3)2SO, 100 ◦C) dH 0.99 (3H, t,
1
J = 7.3 Hz), 1.03–1.15 (3H, m), 1.31–1.45 (1H, m), 1.54–1.66 (1H,
m), 2.44–2.58 (1H, m), 4.58 (2H, br s), 6.62 (1H, ddd, J = 7.4, 7.4,
1.4 Hz), 6.79 (1H, d, J = 7.4 Hz), 6.92 (1H, d, J = 7.4 Hz), 7.07
(1H, ddd, J = 7.4, 7.4, 1.4 Hz). 13C NMR (126 MHz, (CD3)2SO,
100 ◦C) dC 10.1, 17.2, 26.9, 34.5, 92.4 (dd, JCF = 16, 16 Hz), 114.5,
115.4, 116.1, 127.8, 129.6, 145.8, 151.7 (dd, JCF = 290, 288 Hz).
References
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19F NMR (470 MHz, (CD3)2SO, 100 ◦C) dF 71.2 (1F, br d, JFF
=
49 Hz), 74.1 (1F, br d, JFF = 49 Hz). IR (neat) mmax 3390, 2960,
1730, 1615, 1495, 1455, 1300, 1215, 935, 750 cm−1. MS (EI, 70
eV) m/z 211 (M+, 100%), 182 (57), 162 (82). HRMS m/z calcd
for C12H15F2N 211.1173 (M+); found 211.1184.
4-Butyl-3-fluorocinnoline (10a). To a solution of 9a (65 mg,
0.31 mmol) in CH3CN (3.0 mL) were added CF3CO2H (0.045 mL,
0.61 mmol) and i-AmONO (0.081 mL, 0.61 mmol) at 0 ◦C, and the
reaction mixture was stirred for 30 min. The mixture was treated
with thiophenol (0.10 mL, 0.92 mmol) and then stirred for 30 min
at 0 ◦C. The reaction was quenched with phosphate buffer (pH 7),
and 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 (AcOEt–
hexane 1 : 5) to give 10a (55 mg, 88%) as a yellow liquid. 1H NMR
(500 MHz, CDCl3) dH 0.98 (3H, t, J = 7.6 Hz), 1.47 (2H, tq,
J = 7.6, 7.6 Hz), 1.71 (2H, tt, J = 7.6, 7.6 Hz), 3.09 (2H, t, J =
7.6 Hz), 7.76–7.80 (2H, m), 8.00–8.05 (1H, m), 8.48–8.52 (1H, m).
13C NMR (126 MHz, CDCl3) dC 13.8, 22.8, 23.7, 31.7, 122.0 (d,
JCF = 25 Hz), 122.8 (d, JCF = 7 Hz), 129.2 (d, JCF = 2 Hz), 129.4
(d, JCF = 5 Hz), 130.5, 131.5, 150.5 (d, JCF = 2 Hz), 162.4 (d, JCF
=
236 Hz). 19F NMR (470 MHz, CDCl3) dF 67.6 (br s). IR (neat) mmax
2960, 2870, 1620, 1580, 1535, 1440, 1320, 1235, 1135, 1080, 965,
760 cm−1. MS (EI, 70 eV) m/z 204 (M+, 100%), 162 (43), 133 (47).
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