Chemistry Letters Vol.33, No.9 (2004)
1207
compounds to difluoromethylated compounds, see: a) L. R.
Cox, G. A. DeBoos, J. J. Fullbrook, J. M. Percy, N. S. Spencer,
and M. Tolley, Org. Lett., 5, 337 (2003). b) G. K. S. Prakash,
M. Mandal, S. Schweizer, N. A. Petasis, and G. A. Olah, J.
Org. Chem., 67, 3718 (2002). c) M. Mae, M. Matsuura, H.
Amii, and K. Uneyama, Tetrahedron Lett., 43, 2069 (2002).
See also Ref. 1b.
a) R. Sasson, A. Hagooly, and S. Rozen, Org. Lett., 5, 769
(2003) and references therein. b) R. Bujok and M. Makosza,
Synlett, 2002, 1285 and references therein.
Under the reaction conditions obtained above, we conducted
the reaction of several other substrates. Consequently, 2-substi-
tuted 4-(difluoromethyl)quinolines 9a, 9d–9f, 9i, 9j and 2,7-di-
substituted 4-(difluoromethyl)quinolines 9b, 9c, 9g, 9h were
synthesized on treatment of trifluoromethylstyrenes 4a–4j with
20 mol % of KCN and 110 mol % of DBU (Table 1).12 The scope
of this reaction was found to be extended to substrates 4d–4h
bearing aryl groups with electron-donating groups (Entry 4)
and electron-withdrawing groups (Entries 5–8). In addition, sub-
strates 4i, 4j bearing carbonyl groups at the imino carbon were
also applicable to this KCN-catalyzed cyclization (Entries 9
and 10).
5
6
7
J. Gonzales, C. J. Foti, and S. Elsheimer, J. Org. Chem., 56,
4322 (1991) and references therein.
´
´
a) J.-P. Begue, D. Bonnet-Delpon, and M. H. Rock, J. Chem.
Soc., Perkin Trans. 1, 1996, 1409. b) J. Ichikawa, H. Fukui,
and Y. Ishibashi, J. Org. Chem., 68, 7800 (2003) and refer-
ences therein.
Table 1. Synthesis of 2-substituted 4-(difluoromethyl)quin-
olines 9
CF3
CF2H
KCN (20 mol%)
DBU (110 mol%)
8
9
T. Mori and J. Ichikawa, Chem. Lett., 33, 590 (2004).
B. Jiang, Q.-F. Wang, C.-G. Tang, and M. Xu, Tetrahedron
Lett., 42, 4083 (2001).
80 °C / DMF
N
R2
R1
N
R2
R1
10 1-(Trifluoromethyl)vinylboronic acid: To a suspension of
magnesium turnings (1.41 g, 58 mmol) and trimethoxyborane
(16.2 mL, 145 mmol) in THF (100 mL) was added 2-bromo-
3,3,3-trifluoropropene (5.00 mL, 48.3 mmol) in THF (5 mL)
over 1 h at 0 ꢂC under argon. The reaction mixture was stirred
at 0 ꢂC for 3 h. The reaction was quenched with aq HCl (6 M),
and organic materials were extracted three times each with
100 mL of Et2O. The combined extracts were washed with
brine and then dried over MgSO4. After removal of the sol-
vent under reduced pressure, the residue was immediately
used without purification in the following palladium-cata-
lyzed coupling reaction with o-iodoanilines.9
11 4-(Difluoromethyl)-2-(4-trifluoromethylphenyl)quinoline
(9f): To a solution of 4f (112 mg, 0.33 mmol) in DMF (3 mL)
was added KCN (4.2 mg, 0.065 mmol) and DBU (0.053 mL ,
0.36 mmol). After the reaction mixture was heated at 80 ꢂC for
3 h, phosphate buffer (pH 7) was added to quench the reaction.
Organic materials were extracted three times each with 30 mL
of EtOAc. The combined extracts were washed with brine and
dried over MgSO4. After removal of the solvent under re-
duced pressure, the residue was purified by PTLC on silica
gel (hexane–EtOAc, 10:1) to give 9f (75 mg, 72%) as a color-
less oil. 1H NMR (500 MHz, CDCl3) ꢁ 7.19 (1H, t,
JHF ¼ 54:7 Hz), 7.63 (1H, ddd, J ¼ 8:3, 8.3, 1.2 Hz), 7.76
(2H, d, J ¼ 8:1 Hz), 7.79 (1H, ddd, J ¼ 8:3, 8.3, 1.2 Hz),
8.03 (1H, s), 8.05 (1H, dd, J ¼ 8:3, 1.2 Hz), 8.23 (1H, dd,
J ¼ 8:3, 1.2 Hz), 8.27 (2H, d, J ¼ 8:1 Hz). 13C NMR (126
4
9
Entry
R1
R2
4
Time/h Yield/%
1
2
3
4
5
6
7
8
9
10
Ph
Ph
Ph
H
Cl
4a
4b
12
9
14
12
1
3
2
3
1
76 (9a)
56 (9b)
61 (9c)b
51 (9d)
70 (9e)
72 (9f)
44 (9g)
73 (9h)b
30 (9i)b
27 (9j)b
OMe 4ca
p-MeC6H4
p-BrC6H4
p-CF3C6H4
p-CF3C6H4
p-CF3C6H4
PhCO
H
H
H
Cl
4d
4e
4f
4g
OMe 4ha
H
H
4ia
4ja
EtO2C
1
aSubstrates 4c, 4h–4j were prepared by the reaction of the
corresponding anilines 5 with benzaldehyde (120 mol %), 4-
(trifluoromethyl)benzaldehyde (120 mol %), phenylglyoxal
hydrate (130 mol %), or ethyl glyoxylate (150 mol %) in re-
fluxing benzene (12, 12, 3, or 2 h), respectively, and used
without purification.
bYield based on o-amino-ꢀ-trifluoromethylstyrene 5.
In conclusion, we have accomplished an efficient construc-
tion of CF2H-substituted quinoline frameworks via intramolecu-
lar SN20 reaction of o-methyleneamino-substituted ꢀ-trifluoro-
methylstyrenes. Furthermore, this process is effected under
KCN catalysis to allow carbon–carbon bond formation at the
imino carbon with electrophiles, which provides another rare
example of benzoin-type condensation of imines.8,13
MHz, CDCl3) ꢁ 113.2 (t, JCF ¼ 241 Hz), 115.5 (t, JCF
¼
8 Hz), 123.0, 123.3 (t, JCF ¼ 3 Hz), 124.1 (q, JCF ¼ 272 Hz),
125.8 (q, JCF ¼ 4 Hz), 127.7, 128.0, 130.4, 130.7, 131.5 (q,
JCF ¼ 33 Hz), 138.8 (t, JCF ¼ 22 Hz), 141.9, 148.7, 155.2.
19F NMR (470 MHz, CDCl3/C6F6) ꢁF 46.4 (2F, d, JHF
¼
We are grateful to TOSOH F-TECH, INC. for a generous
gift of 2-bromo-3,3,3-trifluoropropene.
55 Hz), 99.1 (3F, s). IR (neat) 3070, 2974, 2252, 1716,
1610, 1323, 1169, 1113, 904 cmꢁ1. Anal. Found: C, 63.20;
H, 3.30; N, 4.15%. Calcd for C17H10NF5: C, 63.16; H, 3.12;
N, 4.33%.
References and Notes
1
a) For a review, see: J. T. Welch, Tetrahedron, 43, 3123
(1987). b) S. Kaneko, T. Yamazaki, and T. Kitazume, J.
Org. Chem., 58, 2302 (1993) and references therein.
J. A. Erickson and J. I. McLoughlin, J. Org. Chem., 60, 1626
(1995).
For recent reports, see: a) S. Marcotte, B. Gerard, X.
Pannecoucke, C. Feasson, and J.-C. Quirion, Synthesis,
2001, 929 and references therein. b) X.-L. Qui and F.-L. Qing,
J. Org. Chem., 67, 7162 (2002).
12 For related reports on the synthesis of 4-(trifluoromethyl)quin-
olines, see: a) O. Lefebvre, M. Marull, and M. Schlosser, Eur.
J. Org. Chem., 2003, 2115. b) B. Jiang and Y.-G. Si, J. Org.
Chem., 67, 9449 (2002). See also for the synthesis of
4-(heptafluoropropyl)quinoline: c) L. Strekowski, S.-Y Lin,
H. Lee, and J. C. Mason, Tetrahedron Lett., 37, 4655 (1996).
13 B. J. E. Reich, A. K. Justice, B. T. Beckstread, J. H.
Reibenspies, and S. A. Miller, J. Org. Chem., 69, 1357
(2004) and references therein.
2
3
4
For recent reports on the conversion of fluorine-containing
Published on the web (Advance View) August 21, 2004; DOI 10.1246/cl.2004.1206