Ring-fluorinated isoquinoline and quinoline synthesis: Intramolecular cyclization of o-cyano- and o-isocyano-β,β-difluorostyrenes

Article abstract of DOI:10.1021/ol034192p

(Matrix presented) o-Cyano-β,β-difluorostyrenes react with organolithiums selectively at the cyano carbon to generate the corresponding sp² nitrogen anions, which in turn undergo intramolecular replacement of the vinylic fluorine to afford 3-fl

Full text of DOI:10.1021/ol034192p

ORGANIC
LETTERS
2003
Vol. 5, No. 9
1455-1458
Ring-Fluorinated Isoquinoline and
Quinoline Synthesis: Intramolecular
Cyclization of o-Cyano- and
o-Isocyano-â,â-difluorostyrenes
,†
Junji Ichikawa,* Yukinori Wada,† Hiroyuki Miyazaki,‡ Takashi Mori,† and
Hiroyuki Kuroki‡
Department of Chemistry, Graduate School of Science, The UniVersity of Tokyo,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, and Department of Applied Chemistry,
Kyushu Institute of Technology, Sensui-cho, Tobata, Kitakyushu 804-8550, Japan
junji@chem.s.u-tokyo.ac.jp
Received February 4, 2003
ABSTRACT
o-Cyano-â,â-difluorostyrenes react with organolithiums selectively at the cyano carbon to generate the corresponding sp2 nitrogen anions,
which in turn undergo intramolecular replacement of the vinylic fluorine to afford 3-fluoroisoquinolines. Similarly, the reaction of â,â-difluoro-
o-isocyanostyrenes with organomagnesiums or -lithiums generates the corresponding sp2 carbanions on the isocyano carbon. Subsequent
cyclization via substitution of the fluorine leads to 3-fluoroquinolines.
The quinoline and isoquinoline nuclei are regioisomers of
benzene-annulated pyridines (benzo[b]pyridine and benzo-
[c]pyridine). They are widespread in the alkaloid family and
constitute an important class of compounds in pharmaceu-
ticals, agrochemicals, and dyestuffs.1 Due to their substantial
applicability, the syntheses of quinolines and isoquinolines
are extensively studied topics.2,3 However, despite their
common properties and much research on their preparation,
a synthetic methodology based on a single concept that can
be applied to both ring systems remains to be developed.
In our recent publications, we have reported the construc-
tion of five- and six-membered ring-fluorinated heterocyclic
compounds such as indoles, benzo[b]furans, benzo[b]thio-
phenes, 2-pyrrolines, 2,3-dihydrofurans, 2,3-dihydrothiophenes,
isochromenes, and isothiochromenes (Scheme 1a).4 gem-
Difluoroalkenes bearing functional groups such as NHTs,
OH, and SH undergo nucleophilic 5- and 6-endo-trig cy-
clizations via deprotonation of these functional groups that
generates sp3 nitrogen, oxygen, and sulfur nucleophiles. The
reactions are promoted by the unique reactivity of gem-
difluoroalkenes toward nucleophilic substitution of their
(3) For recent reports on isoquinoline synthesis, see: (a) Dai, G.; Larock,
R. C. J. Org. Chem. 2002, 67, 7042. (b) Huang, Q.; Hunter, J. A.; Larock,
R. C. J. Org. Chem. 2002, 67, 3437 and references therein. For recent reports
on quinoline synthesis, see: (c) Kim, J. N.; Lee, H. J.; Lee, K. Y.; Kim, H.
S. Tetrahedron Lett. 2001, 42, 3737 and references therein. (d) Amii, H.;
Kishikawa, Y.; Uneyama, K. Org. Lett. 2001, 3, 1109. (e) Cho, C. S.; Oh,
B. H.; Kim, J. S.; Shim, S. C. Chem. Commun. 2000, 1885 and references
therein.
(4) (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) Wada, Y.; Ichikawa, J.; Katsume, T.;
Nohiro, T.; Okauchi, T.; Minami, T. Bull. Chem. Soc. Jpn. 2001, 74, 971.
(d) Ichikawa, J.; Wada, Y.; Fujiwara, M.; Sakoda, K. Synthesis 2002, 1917.
† The University of Tokyo.
‡ Kyushu Institute of Technology.
(1) (a) Yates, F. S. In ComprehensiVe Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Eds.; Pergamon: New York, 1984; Vol. 2, Chapter
2.09. (b) Bentley, K. W. The Isoquinoline Alkaloids; Harwood Academic:
Amsterdam, 1998.
(2) Coffey, D. S.; Kolis, S. P.; May, S. A. In Progress in Heterocyclic
Chemistry; Gribble, G. W., Gilchrist, T. L., Eds.; Pergamon: Amsterdam,
2002; Vol. 14, Chapter 6.1.
10.1021/ol034192p CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/04/2003

expected that addition of external nucleophiles (Nu) to C-N
multiple bonds (XY) such as those of cyano and isocyano
groups would generate sp2 nitrogen and carbon nucleophiles,
respectively, as shown in Scheme 1b.10 These in situ-
generated nucleophilic groups located at the ortho position
of â,â-difluorostyrenes would then promote similar cycliza-
tions, leading directly to the construction of ring-fluorinated
aromatics, both isoquinolines and quinolines with incorpora-
tion of a substituent (Nu) on the heterocyclic rings.11
The starting materials were easily prepared as outlined in
Scheme 2 by using the one-pot sequence that we have
Scheme 1. Intramolecular Substitution of in Situ-Generated
Nucleophiles (Y-)
Scheme 2. Preparation of Ortho-Substituted
â,â-Difluorostyrenes 3 and 6a
vinylic fluorines via addition-elimination processes.5 Their
reactivity is due to (i) the electrophilic activation of the C-C
double bond by the two fluorine atoms, (ii) the stabilization
of the intermediary carbanion by the â-anion stabilizing effect
of fluorine, and (iii) the leaving-group ability of the fluoride
ion. This “intramolecular substitution” concept for ring
formation prompted us to explore its application to the
construction of quinoline and isoquinoline frameworks.
Herein we wish to report a facile, common methodology
for the syntheses of 3-fluorinated isoquinolines and quino-
lines starting from ortho-substituted â,â-difluorostyrenes.
Although these selectively ring-fluorinated heterocycles have
significant potential as components6a and synthetic inter-
mediates6b of biologically active substances and advanced
materials,7 their synthetic methods are still quite limited.8,9
The introduction of fluorine atoms especially onto hetero-
cyclic ring carbons is even more difficult than the fluorine
introduction onto the carbons of fused benzene rings.
To accomplish direct construction of six-membered aro-
matic nuclei, we chose to examine sp2 nucleophiles for the
intramolecular substitution of gem-difluoroalkenes. It was
a Reagents and conditions: (i) n-BuLi (2.1 equiv), THF, -78
°C, 0.5 h; (ii) BR3 (1.1 equiv), THF, -78 °C, 1 h, and then rt, 3 h;
(iii) o-IC6H4CN or o-IC6H4NHMgn-Bu (0.9 equiv), CuI (1.0 equiv),
Pd2(dba)3‚CHCl3 (0.02 equiv), PPh3 (0.08 equiv), THF-HMPA (4:
1), rt, 1 h; (iv) HCO2H (1.2 equiv), Ac2O (1.2 equiv), pyridine, rt,
1 h; (v) POCl3 (1.2 equiv), Et3N (2.2 equiv), CH2Cl2, 0 °C, 0.5 h.
previously developed for the preparation of â,â-difluorosty-
renes.12 The coupling reactions of 2,2-difluorovinylboranes
2 [generated in situ from 2,2,2-trifluoroethyl p-toluene-
sulfonate (1)] with o-iodobenzonitrile or N-butylmagnesio-
o-iodoaniline (generated from o-iodoaniline and dibutylmag-
nesium) were carried out in the presence of CuI and a
palladium catalyst to give o-cyano-â,â-difluorostyrenes 3 and
o-amino-â,â-difluorostyrenes 4. Aminostyrenes 4 were sub-
jected to formylation of the nitrogen followed by dehydration
of the resulting formamides 5, leading to the desired â,â-
difluoro-o-isocyanostyrenes 6.
(5) (a) Smart, B. E. In Organofluorine Chemistry, Principles and
Commercial Applications; Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.;
Plenum: New York, 1994; Chapter 3. (b) Lee, V. J. In ComprehensiVe
Organic Synthesis; Trost, B. M., Ed.; Pergamon: Oxford, 1991; Vol. 4,
Chapter 1.2.
(6) For example, see: (a) Kato, T.; Saeki, K.; Kawazoe, Y.; Hakura, A.
Mutat. Res. 1999, 439, 149 and references therein. (b) Arzel, E.; Rocca,
P.; Marsais, F.; Godard, A.; Queguiner, G. Tetrahedron 1999, 55, 12149.
(7) (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: New York, 1994.
We first attempted the generation of intramolecular nu-
cleophiles in difluorostyrenes 3 by the addition of external
(8) Classical Balz-Shiemann (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.
(10) Wakefield, B. J. In ComprehensiVe Organic Chemistry; Jones, D.
N., Ed.; Pergamon: Oxford, 1979; Vol. 3, pp 951-953.
(9) For the synthesis of fluoroisoquinolines, see: (a) Bellas, M.;
Suschitzky, H. J. Chem. Soc. 1964, 4561. For the synthesis of fluoroquino-
lines, see: (b) 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 therein. (c) Strekowski, L.; Kiselyov, A. S.; Hojjat, M. J.
Org. Chem. 1994, 59, 5886. (d) Shi, G.-q.; Takagishi, S.; Schlosser, M.
Tetrahedron 1994, 50, 1129.
(11) For the synthesis of isoquinolines from aryl cyanides, see: (a) Lyse´n,
M.; Kristensen, J. L.; Vedsø, P.; Begtrup, M. Org. Lett. 2002, 4, 257. For
the synthesis of quinolines from aryl isocyanides, see: (b) Curran, D. P.;
Du, W. Org. Lett. 2002, 4, 3215. (c) Kobayashi, K.; Nakashima, T.; Mano,
M.; Morikawa, O.; Konishi, H. Chem. Lett. 2001, 602. (d) Suginome, M.;
Fukuda, T.; Ito, Y. Org. Lett. 1999, 1, 1977 and references therein.
(12) Ichikawa, J. J. Fluorine Chem. 2000, 105, 257 and references therein.
1456
Org. Lett., Vol. 5, No. 9, 2003

nucleophiles to the cyano group. In this scheme, the external
nucleophile should exclusively attack the cyano carbon
without adding to the difluoromethylene carbon. When 3a
was treated with n-BuMgCl, its nucleophilic attack took place
on the cyano carbon to generate the corresponding imino
nitrogen anions, which in turn underwent intramolecular
substitution of the fluorine to give the expected 3-fluoroiso-
quinoline 7a in 65% yield (Table 1, entry 1). While treatment
via the corresponding sp2 carbanion, providing 3-fluoro-
quinolines with a substituent at the 2-position.
Treatment of isocyanostyrene 6a with n-BuLi in THF gave
a complex mixture, probably due to its high nucleophilicity.
After the reactions of 6a with a Grignard reagent were
conducted in several solvents, the choice of solvent was
found to be crucial in controlling the reaction site. When 6a
was treated with n-BuMgBr in THF and toluene, o-(1-butyl-
2,2-difluorovinyl)-N-pentylideneaniline was obtained in 10
and 73% yields, respectively. These results indicated that
the addition of Grignard reagent in toluene selectively
occurred on the isocyano carbon, but subsequent cyclization
did not take place. To raise the reactivity of the intermediary
carbanion, HMPA was added to the reaction mixture after
generation of the carbanion, leading to the desired 3-fluo-
roquinoline 8a in 69% yield (Table 2, entry 1). Several other
Table 1. Synthesis of 1,4-Disubstituted 3-Fluoroisoquinolines
7 from 3
Table 2. Synthesis of 2,4-Disubstituted 3-Fluoroquinolines 8
from 6a
entry
3
R′M (equiv)
solvent
THF
temp, time
% yield
1
2
3
4
5
6
7
8
9
3a n-BuMgCl (4.0)
3a n-BuLi/CeCl3 (3.0) THF
reflux, 10 h
-78 °C, 3 h
-78 °C, 4 h
65 (7a )
62 (7a )
74 (7a )
3a n-BuLi (1.2)
3a n-BuLi (1.2)
3a n-BuLi (1.2)
3b n-BuLi (1.2)
3a MeLi (1.2)
3a t-BuLi (1.2)
3a PhLi (1.2)
THF
Et2O
-78 °C, 0.5 h 86 (7a )
toluene -78 °C, 1 h
Et2O -78 °C, 7 h
toluene 0 °C, 0.5 h
Et2O
toluene -78 °C, 1 h
toluene 90 °C, 7 h
82 (7a )
82 (7b)
81 (7c)
-78 °C, 0.5 h 88 (7d )
entry
6
R′M (equiv)
% yield
85 (7e)
84 (7f)
1
2
3
4
5b
6c
6a
6b
6a
6a
6a
6a
n-BuMgBr (1.2)
n-BuMgBr (1.2)
EtMgBr (1.2)
i-PrMgCl (1.2)
t-BuLi (1.2)
69 (8a )
60 (8b)
59 (8c)
64 (8d )
78 (8e)
61 (8f)
10
3a HAli-Bu2 (1.1)
of 3a with n-BuLi/CeCl3, an effective reagent for 1,2-additon
to R,â-unsaturated ketones,13 afforded 7a in 62% yield (entry
2), the reaction of 3a with n-BuLi gave an even better result
(74% yield, entry 3). Screening of solvents in this reaction
revealed that in Et2O or toluene, the addition of n-BuLi
occurred regioselectively at the cyano carbon of 3a to afford
7a in 86 and 82% yields (entries 4 and 5).
Et3GeLi (1.5)
a Reagents and conditions: (i) R′M, toluene, rt, 15 min; (ii) toluene-
HMPA (5:1), 0 °C, 1 h, and then rt, 1 h. b Conditions: -78 °C, 1 h, and
then rt, 1 h. HMPA was not added. c Solvent: toluene-THF (6:1).
Conditions: -78 °C, 1 h, and then rt, 4 h.
Under the reaction conditions obtained above, we exam-
ined the reaction of other nucleophiles such as methyllithium,
tert-butyllithium, phenyllithium, and diisobutylaluminum
hydride. As summarized in Table 1, treatment of 3 with these
nucleophiles successfully led to cyclization to afford high
yields of 3-fluoroisoquinolines 7a-f bearing a butyl, methyl,
tert-butyl, or phenyl group or hydrogen at the 1-position and
a butyl or sec-butyl group at the 4-position (entries 4-10).
Thus, this sequence provides a facile entry to 1,4-disubsti-
tuted 3-fluoroisoquinolines.
After having accomplished the synthesis of isoquinolines
as described above, we next tried to construct the quinoline
framework by means of the same strategy with the reversed
order of the carbon and nitrogen in the ortho substituent.
For this purpose, â,â-difluorostyrenes bearing an isocyano
group instead of a cyano group should be employed as
starting materials. The reaction of o-isocyanostyrenes with
nucleophiles was expected to proceed in a similar manner
2,4-disubstituted 3-fluoroquinolines 8b-e were successfully
obtained on treatment of 6 with primary, secondary, or
tertiary alkylmetals such as n-BuMgBr, EtMgBr, i-PrMgCl,
and t-BuLi (entries 2-5).
In the attempted synthesis of 2-silylated 3-fluoroquinolines
by the reaction of 6a with triphenylsilyllithium or dimeth-
ylphenylsilyllithium as the external nucleophile, 4-butyl-3-
fluoroquinoline was obtained instead in 50 or 46% yield,
respectively, probably due to the instability of 2-silyl-3-
fluoroquinolines. We also examined a similar reaction of 6a
with triethylgermyllithium, prepared in situ from triethylger-
manium hydride, N,N,N′,N′-tetramethylethylenediamine, and
t-BuLi.14 The expected addition to the isocyano group and
the subsequent cyclization occurred, leading to 3-fluoro-
quinoline 8f with a germyl group at the 2-position (entry
6).15 As shown in Table 2, diverse 2,4-disubstituted 3-fluo-
roquinolines can be synthesized by this method.
(14) Yamaguchi, J.; Tamada, Y.; Takeda, T. Bull. Chem. Soc. Jpn. 1993,
66, 607.
(13) Imamoto, T.; Sugiura, Y. J. Phys. Org. Chem. 1989, 2, 93.
Org. Lett., Vol. 5, No. 9, 2003
1457

In conclusion, we have accomplished the efficient con-
struction of ring-fluorinated isoquinoline and quinoline
frameworks starting from ortho-substituted â,â-difluorosty-
renes via (i) the addition of nucleophiles to generate intra-
molecular sp2 nucleophiles and (ii) their cyclization by sub-
stitution of the vinylic fluorine. Both 3-fluoroisoquinolines
and 3-fluoroquinolines with a variety of substituents are
readily synthesized by this methodology on the basis of the
same concept. Thus, we have disclosed a new aspect of
fluorine as a synthetic tool for heteroaromatic ring-forming
reactions.
Acknowledgment. This work was financially supported
by a grant from TOSOH F-TECH, INC., to J.I.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data of compounds 3-8. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL034192P
(15) Reaction of 6a with tributylstannyllithium afforded 4-butyl-3-
fluoroquinoline or the corresponding biquinoline, and these results will be
reported in detail elsewhere.
1458
Org. Lett., Vol. 5, No. 9, 2003