Complex base-induced generation of 3,4-dehydroquinoline: A new access to quinoline derivatives

Article abstract of DOI:10.1016/S0040-4039(01)01339-9

3,4-Dehydroquinoline was easily generated from 3-bromoquinoline and a complex base NaNH₂-tBuONa. Nucleophilic condensation of amines and thiolates were performed in good yields.

Full text of DOI:10.1016/S0040-4039(01)01339-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7037–7039
Complex base-induced generation of 3,4-dehydroquinoline:
a new access to quinoline derivatives
Ste´phanie Blanchard, Ge´rald Guillaumet* and Paul Caube`re
Institut de Chimie Organique et Analytique, UMR-CNRS 6005, Universite´ d’Orle´ans, rue de Chartres, BP 6759,
45067 Orleans cedex 2, France
Received 8 June 2001; accepted 23 July 2001
Abstract—3,4-Dehydroquinoline was easily generated from 3-bromoquinoline and a complex base NaNH2–tBuONa. Nucleophilic
condensation of amines and thiolates were performed in good yields. © 2001 Elsevier Science Ltd. All rights reserved.
As part of a program of medicinal chemistry under-
taken a few years ago,1 we are pursuing investigations
on the synthesis and reactivity of heterocycles contain-
ing nitrogen. Recently we were confronted with the
preparation of quinoline derivatives. Our experience in
arynic chemistry1a,b,2 led us to consider the use of
didehydroquinolines as intermediates. Taking account
of the results previously obtained in the pyridine series,2
we anticipated that these transient reactive species
ought to be easily generated from appropriate
halogenoquinolines and a complex base.2 The major
interest of this procedure, compared to the existing
ones,3,4 is that it can be conducted on a large scale and
can use inexpensive reagents. Moreover, under our
conditions anionic as well as neutral nucleophiles may
react with the intermediates with low competition from
the base used to generate them.
These results deserve some comment. Overall yields
vary from acceptable to very good. In fact the apparent
lower yields obtained from primary amines are due to
the formation of disubstituted products.5
Interestingly, the ratios 3/4 were always close to 1. This
result is explained by a balance between electronic and
steric effects. Indeed the electron-withdrawing effect of
the nitrogen favors attack on C4, while steric hindrance
of the hydrogen on C5 favors attack on the C3
position.
With these results in hand, we studied the condensation
of thiolates as representative charged nucleophiles
(Table 2).
The formation of isomers 6 and 7 in equivalent
amounts supports the hetarynic intermediate and shows
that no SNAr takes place. It is noteworthy that two
equivalents of NaNH2 were sufficient to perform the
reaction. In fact an increase in the amount of this
reagent (4 equivalents) allowed shorter reaction times,
but led to the formation of appreciable amounts of
4-aminoquinoline.
In the present paper, we report our first successful
results obtained in this area. Firstly we tried to
react primary and secondary amines with the com-
mercially available 3-bromoquinoline 1 in the presence
of the complex base NaNH2–tBuONa in tetra-
hydrofuran. The reactions observed are summarized in
Table 1.
The derivatives 4a and 7a were synthesized directly
from 4-chloroquinoline by an SNAr reaction with very
good yields.6,7 This method could be used for the
synthesis of compounds 4 and 7.
In conclusion, quinoline derivatives 3, 4, 6 and 7 may
be easily obtained by elimination–addition under our
conditions.8,9 The application to the synthesis of new
heterocycles is actively pursued.
Keywords: dehydroquinoline; complex base NaNH2–tBuONa; arynic
chemistry.
* Corresponding author. Tel.: +33 (0)2 38 41 70 73; fax: +33 (0)2 38
41 70 78; e-mail: gerald.guillaumet@univ-orleans.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01339-9

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S. Blanchard et al. / Tetrahedron Letters 42 (2001) 7037–7039
Table 1.
Amines 2
Time (h)
3b (%)
4b (%)
3+4b,d (%)
Piperidine 2a
Morpholine 2b
1
1
1
1
1
3
3
3
3a 42
3b 40
3c 37
3d 36c
3e 38
3f 25
3g 24
3h 25
4a 40
4b 40
4c 37
4d 36c
4e 37
4f 20
4g 23
4h 25
82
80
74
72
75
45
47
50
Dipropylamine 2c
1-Methylpiperazine 2d
1-Benzylpiperazine 2e
Isopropylamine 2f
tert-Butylamine 2g
4-Phenylbutylamine 2h
a 1:2:NaNH2:tBuONa=1:2:4:2.
b Isolated yields calculated from 3-bromoquinoline.
c Measured by NMR.
d Compounds 3 and 4 are easily separated by flash chromatography on silica gel.
Table 2.
Thiolates 5
Time (h)
6b (%)
7b (%)
6+7b,d (%)
C6H5SNa 5a
2
3
4
6a 40
6b 39
6c 28
7a 39
7b 38
7c 25
79
77
53
3-MeOC6H4SNa 5b
C2H5SNac 5c
a 1:5:NaNH2:tBuONa=1:2:2:2.
b Isolated yields calculated from 3-bromoquinoline.
c HMPT (2.5×10−3 mol 2%) was added to solubilize the formed salt.
d Compounds 6 and 7 are easily separated by flash chromatography on silica gel.
Acknowledgements
Heterocycles 1997, 45, 2113; (b) Rodriguez, I.; Kuehm-
Caube`re, C.; Vinter-Pasquier, K.; Renard, P.; Pfeiffer, B.;
Caube`re, P. Tetrahedron Lett. 1998, 39, 7283.
We are grateful to A.D.I.R. Company (Servier,
Courbevoie, France) for financial support.
3. (a) Caube`re, P. Rev. Heteroatom Chem. 1991, 4, 78; (b)
Caube`re, P. Chem. Rev. 1993, 93, 2317; (c) Gilbert, J. C.;
Hou, D.-R.; Grimme, J. W. J. Org. Chem. 1999, 64, 1529;
(d) Connon, S. J.; Hegarty, A. F. J. Chem. Soc., Perkin
Trans. 1 2000, 1245.
References
1. (a) Graf-Christophe, S.; Kuehm-Caube`re, C.; Renard, P.;
Pfeiffer, B.; Pierre´, A.; Le´once, S.; Caube`re, P. Bioorg.
Med. Chem. Lett. 2000, 10, 2589; (b) Kuehm-Caube`re, C.;
Caube`re, P.; Jamart-Gre´goire, B.; Pfeiffer, B.; Guardiola-
Lemaitre, B.; Manechez, D.; Renard, P. Eur. J. Med.
Chem. 1999, 34, 51; (c) Lamazzi, C.; Le´once, S.; Pfeiffer,
B.; Renard, P.; Guillaumet, G.; Rees, C. W.; Besson, T.
Bioorg. Med. Chem. Lett. 2000, 10, 2183; (d) Maze´as, D.;
Guillaumet, G.; Viaud, M.-C. Heterocycles 1999, 50, 1065;
(e) Bourlot, A.-S.; Sanchez, I.; Dureng, G.; Guillaumet,
G.; Massingham, R.; Monteil, A.; Wilson, E.; Pujol, M.
D.; Me´rour, J.-Y. J. Med. Chem. 1998, 41, 3142.
4. (a) Gros, P.; Fort, Y.; Caube`re, P. J. Chem. Soc., Perkin
Trans. 1 1997, 3597; (b) Reinecke, M. G. Tetrahedron
1982, 38, 427.
5. The presence of disubstituted products was detected by
mass spectrometry.
6. Brooker, L. G. S.; Keyes, G. H.; Sprague, R. H.;
VanDyke, R. H.; VanLare, E.; VanZandt, G.; White, F. L.
J. Am. Chem. Soc. 1951, 73, 5326.
7. Brower, K. R.; Samuels, W. P.; Way, J. W.; Amstutz, E.
D. J. Org. Chem. 1953, 18, 1648.
1
8. All new compounds were fully characterized by H NMR,
13C NMR, MS and IR spectra and gave correct elemental
analysis.
2. (a) Vinter-Pasquier, K.; Jamart-Gre´goire, B.; Caube`re, P.

S. Blanchard et al. / Tetrahedron Letters 42 (2001) 7037–7039
7039
9. General procedure: To the complex base prepared accord-
ing to Ref. 1b was added, at 40°C, the amine (2 equiv.) or
the thiolate (2 equiv.) (generated in situ with 2 equiv. of
NaNH2). The mixture was stirred for 2 h at 40°C. After
cooling at 0°C, a solution of 3-bromoquinoline in THF
was added. The mixture was stirred at rt. The reaction was
monitored by TLC and stopped when the 3-bromoquino-
line had disappeared. The mixture was then hydrolyzed at
0°C and extracted with CH2Cl2. The combined extracts
were dried with MgSO4 and the solvent was removed
under reduced pressure. The product was purified by flash
chromatography on silica gel using as eluent ethyl acetate–
hexane (5–30%).
J=4.8 Hz), 2.73 (4H, t, J=4.8 Hz); 13C NMR (CDCl3,
62.9 MHz): l ppm 156.5 (C), 150.3 (CH), 149.0 (C), 137.4,
129.4, 128.8 (CH), 128.6 (C), 127.9, 126.8, 124.7, 123.3
(CH), 123.0 (C), 108.2 (CH), 62.6 (CH2), 52.6 (2×CH2),
51.7 (2×CH2); MS (IS)=304.5 (M+H)+. Anal. calcd for
C20H21N3: C, 79.17; H, 6.98; N, 13.85. Found: C, 78.94;
1
H, 7.04; N, 13.61. 6b: mp: 171–172°C; H NMR (CDCl3,
250 MHz): l ppm 8.51 (1H, d, J=2.1 Hz), 8.36 (1H, d,
J=8.5 Hz), 7.84 (1H, J=8.2 Hz), 7.69–7.76 (1H, m),
7.51–7.57 (2H, m), 7.40–7.52 (2H, m), 6.99 (1H, d, J=7.9
Hz), 4.19 (3H, s) 13C NMR (CDCl3, 62.9 MHz): l ppm
158.5, 146.5, 143.1, 130.9 (C), 130.6, 130.1 (CH), 128.4
(3×CH), 126.7, 126.1 (3×CH), 125.4 (C), 115.4, 106.9
(CH), 56.2 (CH3); MS (IS)=268 (M+H)+. Anal. calcd for
C16H13NOS: C, 71.88; H, 4.90; N, 5.24. Found: C, 71.63;
Data for selected compounds 3e–4e and 6b–7b; 3e: mp:
104–105°C; 1H NMR (CDCl3, 250 MHz): l ppm 8.79 (1H,
d, J=2.7 Hz), 7.98 (1H, dd, J=7.3 Hz, J=1.8 Hz),
7.63–7.67 (1H, m), 7.40–7.49 (2H, m), 7.33–7.36 (4H, m),
3.30–3.31 (2H, m), 3.59 (2H, s, 2H), 3.30 (4H, t, J=5.0
Hz), 2.66 (4H, t, J=5.0 Hz); 13C NMR (CDCl3, 62.9
MHz): l ppm 145.6 (CH), 141.8, 139.9 (C), 129.0 (C),
128.8, 126.7, 126.0, 124.9 (CH), 113.8 (CH), 51.5 (CH2),
29.3 (4×CH2); MS (IS)=304.5 (M+H)+. Anal. calcd for
C20H21N3: C, 79.17; H, 6.98; N, 13.85. Found: C, 78.87;
1
H, 4.62; N, 5.15 7b: mp: 78–79°C; H NMR (CDCl3, 250
MHz): l ppm 8.58 (1H, d, J=4.8 Hz), 8.20 (1H, d, J=8.2
Hz ), 8.09 (1H, J=8.2 Hz), 7.69–7.76 (1H, m), 7.53–7.60
(1H, m), 7.37 (1H, t, J=7.9 Hz), 7.10–7.18 (2H, m),
6.97–7.02 (1H, m), 6.83 (1H, d, J=4.8 Hz), 3.22 (3H, s),
13C NMR (CDCl3, 62.9 MHz): l ppm 160.5, 149.4 (CH),
148.3, 147.5 (C), 130.7 (CH), 130.6 (C), 129.9, 129.8, 127.2,
126.5 (CH), 125.9 (C), 123.4, 119.9, 118.0, 115.6 (CH),
55.4 (CH3); MS (IS)=268 (M+H)+. Anal. calcd for
C16H13NOS: C, 71.88; H, 4.90; N, 5.24. Found: C, 71.97;
H, 4.75; N, 5.37.
1
H, 7.13; N, 13.55. 4e: oil; H NMR (CDCl3, 250 MHz): l
ppm 8.70 (1H, d, J=4.8 Hz), 8.00–8.06 (2H, m), 7.60–7.66
(1H, m), 7.41–7.48 (1H, m), 7.35–7.37 (3H, m), 7.35 (1H,
d, J=4.8 Hz), 7.25–7.31 (1H, m), 3.63 (2H, s), 3.24 (4H, t,