A Facile Synthesis of 2,4-Disubstituted 3-Fluoroquinolines via Intramolecular Cyclization of o-Cyanomethylamino-β,β-difluorostyrenes

Article abstract of DOI:10.1246/cl.2003.1000

o-Cyanomethylamino-β,β-difluorostyrenes are treated with base (LiTMP, NaH, or K₂CO₃) to generate the corresponding carbanions, which in turn readily undergo intramolecular replacement of the vinylic fluorine and subsequent eliminatio

Full text of DOI:10.1246/cl.2003.1000

1000
Chemistry Letters Vol.32, No.11 (2003)
A Facile Synthesis of 2,4-Disubstituted 3-Fluoroquinolines
via Intramolecular Cyclization of o-Cyanomethylamino-ꢀ,ꢀ-difluorostyrenes
Yukinori Wada, Takashi Mori, and Junji IchikawaÃ
Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033
(Received August 25, 2003;CL-030779)
o-Cyanomethylamino-ꢀ,ꢀ-difluorostyrenes are treated with
base (LiTMP, NaH, or K2CO3) to generate the corresponding
carbanions, which in turn readily undergo intramolecular re-
placement of the vinylic fluorine and subsequent elimination
to afford 2,4-disubstituted 3-fluoroquinolines in good yield.
thesis of 3-fluoroquinolines by cyclization of 1 via carbanions
generated by deprotonation of the cyanomethyl groups11 and
subsequent aromatization of intermediates 2 that can be conduct-
ed in two ways (Scheme 1);(i) elimination of HCN leading to 3-
fluoroquinolines 3 (Route A;X = H), or (ii) elimination of HX
leading to 2-cyano-3-fluoroquinolines 4 (Route B;X = Ts, R 2
=
H).12
The starting materials were easily prepared via the one-pot
synthesis of o-amino-ꢀ,ꢀ-difluorostyrenes 5 (5a: R1= n-Bu,
5b: R1 = s-Bu)9 starting from 2,2,2-trifluoroethyl p-toluenesul-
fonate and o-iodoaniline,13 followed by known transformations.
The Strecker reaction of 5 with aldehydes gave the substrates
1a–e suitable for Route A. Substrates 1f, g for Route B bearing
a p-toluenesulfonyl group (Ts) on the nitrogen were obtained by
tosylation of 5 and subsequent cyanomethylation with bromoa-
cetonitrile.
We then attempted the cyclization of difluorostyrenes 1 ob-
tained above under basic conditions. The reaction of 1a with
NaH (6 molar amounts), LDA (3 molar amounts), or lithium
hexamethyldisilazide (LiHMDS, 6 molar amounts) in THF
was unsuccessful and gave 5a instead, probably through the loss
of HCN and successive hydrolysis of the resulting imine (vide
infra). After many trials, we found that treatment with 6 molar
amounts of lithium tetramethylpiperidide (LiTMP) in THF sur-
prisingly promoted the expected intramolecular substitution
even at À78 ꢀC to afford 3-fluoroquinoline 3a in 64% yield (Ta-
ble 1, Entry 1).14
Quinolines are widespread in the alkaloid family and consti-
tute an important class of compounds in medicinal and agricul-
tural chemistry, and also in material science.1 Since the incorpo-
ration of fluorine into organic molecules has come into wide use
as a means of modifying their biological activities and physical
properties, fluorine-containing quinoline derivatives have been
attracting considerable attention.2,3 3-Fluorinated quinolines
have been reported to exhibit notable biological activities, and
especially to be noted is their apparent lack of genotoxicity that
is often observed in quinolines, which would allow their medic-
inal and agricultural use.4 In spite of the significant potential of
ring-fluorinated quinoline frameworks both as components and
intermediates,5 so far their synthetic methods have been quite
limited.6,7
In our recent publications, we have reported the construction
of six-membered ring-fluorinated heterocyclic compounds, such
as isochromenes, isothiochromenes, isoquinolines, and quino-
lines.8 ꢀ,ꢀ-Difluorostyrene derivatives bearing sp3-O, sp3-S,
sp2-N, and sp2-C nucleophiles undergo intramolecular substitu-
tion of the fluorine in a 6-endo-trig fashion, leading to heterocy-
cle formation.9 The reactions are promoted by the unique reac-
tivity of gem-difluoroalkenes toward nucleophilic vinylic
substitution (SNV) via addition–elimination processes.10
Table 1. Synthesis of 2,4-disubsutituted 3-fluoroquinolines
3a–e
R1
R1
R1
Base
F
F
R1
R1
R1
F2C
NC
F
Base
– F–
NC
N
H
N
H
R2
N
F2C
H2N
F2C
R2
R2
1
3
NC
N
X
N
X
NC
R2
R2
Entry R1
R2
1
Base (ma)a Solv. Conditions Yield%b
5
1
2
1
2
3
4
5
n-Bu
s-Bu
n-Bu
H
H
1a LiTMP (6.0) THF À78 ꢀC, 1 h 64 (3a)
1b LiTMP (6.0) THF À78 ꢀC, 1 h 56 (3b)
1c NaH (2.1) DMF 0 ꢀC, 1.5 h 81 (3c)
R1
F
Route A (X = H)
Ph
– HCN
R2
N
3
4
n-Bu 2-Furyl 1d NaH (2.1) DMF r.t., 1.5 h 81 (3d)
n-Bu 1-c-C6H9 1e NaH (2.1) DMF 70 ꢀC, 0.5 h 27 (3e)
R1
Route B
(X = Ts, R2 = H)
F
ama: molar amount. bIsolated yields.
– HX
NC
N
As further examples of the reaction, difluorostyrenes 1b, c
were subjected to similar conditions. On their treatment with 6
molar amounts of LiTMP, 1b afforded the expected product
3b (Table 1, Entry 2), whereas 1c gave a complex mixture of
products. Screening of base and reaction conditions was con-
ducted again for 1c to reveal the following fact. When 1c was
treated with 2.1 molar amounts of NaH in DMF, the intramolec-
ular replacement by the in situ generated carbon nucleophile suc-
Scheme 1. Synthetic strategy for 3-fluoroquinolines.
In order to synthesize 3-fluoroquinolines bearing substitu-
ents and functional groups, the ‘‘intramolecular substitution’’
concept was applied to o-cyanomethylamino-ꢀ,ꢀ-difluorosty-
renes 1, where CN would function as a leaving group as well
as a transformable group. Herein we wish to report a facile syn-
Copyright Ó 2003 The Chemical Society of Japan

Chemistry Letters Vol.32, No.11 (2003)
1001
nBu
N
cessfully proceeded to give 3c in 81% yield (Entry 3). Substrates
1d, e bearing a heteroaryl or an alkenyl group as R2 also under-
went the cyclization under the latter conditions (Entries 4 and 5).
There was one more plausible reaction pathway other than
substitution–elimination process (path I depicted in Table 1),
namely an HCN-elimination–6ꢁ-electrocyclization–HF-elimi-
nation process (path II). In order to elucidate the reaction mech-
anism, we prepared imine 6 from aminostyrene 5a and benzalde-
hyde and then subjected 6 to the conditions employed above.
The corresponding 3-fluoroquinoline 3c was not observed in this
reaction, which ruled out the possibility of path II, a 6ꢁ-electro-
cyclization process. Consequently, the cyclization of 1 proceeds
through vinylic substitution of fluorine, followed by elimination
of HCN (path I, Table 1).
F
0.06 M NaOH
reflux, 2 h
/ EtOH–H2O
HO2C
7
nBu
94%
81%
39%
nBu
N
F
F
H2, 10% Pd/C
r.t., 24 h
/ MeOH
NC
H2NH2C
N
8
nBu
4a
i) KOH, H2O2
reflux, 7 h
/ EtOH–H2O
F
ii) Pb(OAc)4
40 °C, 24 h
/ t-BuOH
BocHN
N
9
References and Notes
1
a) F. S. Yates, in ‘‘Comprehensive Heterocyclic Chemistry,’’ ed.
by A. R. Katritzky and C. W. Rees, Pergamon, New York
(1984), Vol. 2, Chap. 2.09. b) K. W. Bentley, ‘‘The Isoquinoline
Alkaloids,’’ Harwood Academic, Amsterdam (1998).
For reviews, see: a) M. J. Silvester, Adv. Heterocycl. Chem., 59, 1
(1994). b) M. J. Silvester, Aldrichimica Acta, 24, 31 (1991). c)
‘‘Organofluorine Chemistry, Principles and Commercial Applica-
tions,’’ ed. by R. E. Banks, B. E. Smart, and J. C. Tatlow, Plenum,
New York (1994).
Y. Hirano, M. Uehara, K. Saeki, T. Kato, K. Takahashi, and T.
Mizutani, J. Health Sci., 48, 118 (2002) and references therein.
T. Kato, K. Saeki, Y. Kawazoe, and A. Hakura, Mutat. Res., 439,
149 (1999) and references therein.
nBu
nBu
NaH (2.1 ma)
F
F2C
Ph
0 → 70 °C, 6 h
Ph
N
N
/ DMF
2
6
3c
We next attempted the cyclization of difluorostyrene 1f to
provide 3-fluoroquinoline 4a bearing a cyano group, which is
a versatile substituent that can be readily converted into other
functional groups. We tried to keep the cyano group during
the cyclization and aromatization to allow the synthesis of func-
tionalized 3-fluoroquinolines. A tosyl group in 1f was introduced
on the nitrogen atom to function as a leaving group instead of the
cyano group.12 Treatment of 1f under similar conditions for 1c–e
promoted intramolecular cyclization and successive elimination
of p-toluenesulfinic acid to give the desired cyanoquinoline 4a.
When 1f, g were treated with 2.1 molar amounts of K2CO3 in
DMF at 50 ꢀC, the two processes proceeded smoothly to afford
4a, b in better yield.
3
4
5
´
a) E. Arzel, P. Rocca, F. Marsais, A. Godard, and G. Queguiner,
Tetrahedron, 55, 12149 (1999). b) F. Mongin, L. Mojovic, B.
´
Guillamet, F. Trecourt, and G. Queguiner, J. Org. Chem., 67,
´
8991 (2002).
6
7
For the synthesis of fluoroquinolines, see: a) R. D. Chambers, M.
Parsons, G. Sandford, C. J. Skinner, M. J. Atherton, and J. S.
Moilliet, J. Chem. Soc., Perkin Trans. 1, 1999, 803 and references
therein. b) L. Strekowski, A. S. Kiselyov, and M. Hojjat, J. Org.
Chem., 59, 5886 (1994). c) G.-Q. Shi, S. Takagishi, and M.
Schlosser, Tetrahedron, 50, 1129 (1994).
For recent reports on quinoline synthesis, see: a) K. Kobayashi, K.
Yoneda, T. Mizumoto, H. Umakoshi, O. Morikawa, and H.
Konishi, Tetrahedron Lett., 44, 4733 (2003) and references
therein. b) J. N. Kim, H. J. Lee, K. Y. Lee, and H. S. Kim, Tetra-
hedron Lett., 42, 3737 (2001). c) C. S. Cho, B. H. Oh, J. S. Kim,
T.-J. Kim, and S. C. Shim, Chem. Commun., 2000, 1885 and ref-
erences therein.
a) Y. Wada, J. Ichikawa, T. Katsume, T. Nohiro, T. Okauchi, and
T. Minami, Bull. Chem. Soc. Jpn., 74, 971 (2001). b) J. Ichikawa,
Y. Wada, H. Miyazaki, T. Mori, and H. Kuroki, Org. Lett., 5, 1455
(2003).
For the construction of five-membered ring-fluorinated heterocy-
cles via 5-endo-trig process, see: J. Ichikawa, Y. Wada, M.
Fujiwara, and K. Sakoda, Synthesis, 2002, 1917.
R1
R1
R1
K2CO3
(2.1 ma)
F
F
F2C
NC
50 °C, 7 h
/ DMF
N
Ts
NC
N
Ts
NC
N
1f R1 = n-Bu
1g R1 = s-Bu
4a R1 = n-Bu: 85%
4b R1 = s-Bu: 79%
(ma: molar amount)
After having obtained 4, we examined their transformation
into 2-functionalized 3-fluoroquinolines 7–9 having a carboxy,
an aminomethyl, or an amino group. On treatment of 4a with
aqueous NaOH, hydrolysis of the cyano group selectively occur-
red without the loss of fluorine to afford 2-quinolinecarboxylic
acid 7 in excellent yield. Hydrogenation of 4a in methanol over
palladium on activated carbon successfully reduced the cyano
group to give fluoroquinoline 8 bearing an aminomethyl group
at the 2-position in 81% yield. Moreover, hydrolysis of the cyano
group followed by the Hofmann rearrangement of the corre-
sponding amide led to Boc-protected 2-amino-3-fluoroquinoline
9 in 39% yield. Functionalized 3-fluoroquinolines 7–9 are attrac-
tive compounds as building blocks because their carboxy and
amino groups allow to introduce the fluoroquinoline moiety into
organic molecules.
8
9
10 a) B. E. Smart, in ‘‘Organofluorine Chemistry, Principles and
Commercial Applications,’’ ed. by R. E. Banks, B. E. Smart, and
J. C. Tatlow, Plenum, New York (1994), Chap. 3. b) V. J. Lee,
in ‘‘Comprehensive Organic Synthesis,’’ ed. by B. M. Trost,
Pergamon, Oxford (1991), Vol. 4, Chap. 1.2.
11 D. Enders, J. Kirchhoffa, P. Gerdesa, D. Mannesa, G. Raabea, J.
Runsinka, G. Bocheb, M. Marschb, H. Ahlbrechtc, and H.
Sommerc, Eur. J. Org. Chem., 1998, 63272.
12 H. Tokuyama, M. Sato, T. Ueda, and T. Fukuyama, Heterocycles,
54, 105 (2001).
13 J. Ichikawa, J. Fluorine Chem., 105, 257 (2000).
14 A similar intramolecular substitution with imidoyl anions proceed-
ed at room temperature. See Ref. 8b.
In conclusion, we have accomplished the construction of
quinoline frameworks via intramolecular cyclization of o-cyano-
methylamino-ꢀ,ꢀ-difluorostyrenes. Thus obtained 3-fluorinated
quinolines with sp2-C substituents and functional groups at the
2-position are complementary to the products of our former flu-
oroquinoline synthesis.8b
Published on the web (Advance View) October 6, 2003;DOI 10.1246/cl.2003.1000