Ethyl N-(o-ethynyl)malonanilide as a useful building block for the preparation of 3,4-disubstituted-2(1H)-quinolones, 3,4-disubstituted- and 2,3,4-trisubstituted quinolines

Article abstract of DOI:10.1055/s-1998-1656

3,4-Disubstituted-2(1H)-quinolones have been prepared through a procedure based on the palladium-catalysed reaction of the readily available ethyl N-(o-ethynyl))malonanilide with aryl, heteroaryl and vinyl halides or vinyl triflates followed by the cycliz

Full text of DOI:10.1055/s-1998-1656

446
LETTERS
SYNLETT
Ethyl N-(o-Ethynyl)malonanilide as a Useful Building Block for the Preparation of 3,4-Disubstituted-
2(1H)-quinolones, 3,4-Disubstituted- and 2,3,4-Trisubstituted Quinolines
*a
*b
b
b
b
Antonio Arcadi, Sandro Cacchi, Giancarlo Fabrizi, Fedele Manna, Paola Pace
a
Dipartimento di Chimica, Ing. Chimica e Materiali, Via Vetoio, 67100 L’Aquila, Italy
b
Dipartimento di Studi di Chimica e Tecnologia delle Sostanze Biologicamente Attive, Università “La Sapienza”, P.le A. Moro 5, 00185 Roma, Italy
Fax: + 39 (6) 4991.2780; e-mail: cacchi@axrma.uniroma1.it
Received 5 January 1998
Abstract. 3,4-Disubstituted-2(1H)-quinolones have been prepared
through a procedure based on the palladium-catalysed reaction of the
readily available ethyl N-(o-ethynyl))malonanilide with aryl, heteroaryl
and vinyl halides or vinyl triflates followed by the cyclization of the
resulting coupling derivatives under basic conditions. It is shown that
3,4-disubstituted-2(1H)-quinolones are useful synthetic intermediates
for the preparation of 3,4-disubstituted- and 2,3,4-trisubstituted
quinolines.
Our results are summarized in the Table.
The construction of heterocyclic derivatives based upon the concept of
palladium-catalysed coupling/cyclization of alkyne bearing a proximate
(pro)nucleophile has proved to be a versatile and efficient synthetic
1,2
methodology.
Our continuing interest in this area, and our
involvement in a program designed to identify novel non-nucleoside
2(1H)-quinolone-based anti-AIDS agents, led us to investigate the
utilization of this methodology for the preparation of substituted 2(1H)-
3
quinolones. In particular, we decided to evaluate the employment of
ethyl N-(o-ethynyl)malonanilide 1 as the starting building block. This
compound can be readily prepared in 80% overall yield from o-
4
iodoaniline through a one-pot three-step procedure.
Now we report that compound 1 reacts with aryl, heteroaryl and vinyl
5
halides or triflates 2 to afford the coupling derivatives 3 and that
subsequent treatment of 3 with NaH or KOt-Bu in DMSO leads to the
formation of the 3,4-disubstituted-2(1H)-quinolones 4 through an
6
intramolecular carbocyclization (Scheme 1).
Scheme 1
Most probably the carbocyclization proceeds through a mechanism
similar to that proposed for the carbocyclization of propargyl
ethylmalonates and involves the intramolecular nucleophilic attack of
To keep the methodology as simple as possible, we briefly investigated
the development of an in situ coupling/cyclization procedure starting
from the silyl derivative 5. We used reaction conditions similar to those
employed by us in the palladium-catalysed coupling/cyclization of o-
[(trimethylsilyl)ethynyl]phenyl acetates with aryl halides or vinyl
2
the carbanion, generated from 3, on the carbon-carbon triple bond
affording, after protonation,
a six-membered ring methylidene
intermediate that isomerizes to the quinolone derivative 4. The nature of
the substituent linked to the acetylenic moiety, R, is crucial for the
success of the cyclization step. Best results were obtained in the
presence of aromatic rings bearing electron-withdrawing substituents.
No quinolone derivative was obtained, under our standard conditions, in
the presence of the electron-donating p-methoxyphenyl group or the n-
butyl group.
7
triflates. This protocol, however, provided satisfactory results only
with p-iodoacetophenone (Scheme 2).
The scope of this facile synthesis of 2(1H)-quinolones is tremendously
broadened by the ease of their conversion into a variety of 3,4-
disubstituted- and 2,3,4-trisubstituted quinolines through the
8,9
corresponding triflates 6.
For example, quinoline derivatives

April 1998
SYNLETT
447
F. J. Chem. Research (S) 1985, 135; Terpko, M.O.; Heck, R.F. J.
Am; Chem. Soc. 1979, 101, 5281; Walser, A.; Szente, A.;
Hellerbach, J. J. Org. Chem. 1973, 38, 449; Fryer, R.L.; Brust, B.;
Sternbach, L.H. J. Chem. Soc. 1964, 3097.
4.
Preparation of ethyl N-(o-ethynyl))malonanilide 1: to a solution of
o-iodoaniline (3.0 g, 13.7 mmol) in DMF (6.0 mL) were added
Et NH (10 mL), trimethylsilylacetylene (2.28 mL, 16.4 mmol),
2
Pd(OAc) (PPh ) (0.205 g, 0.27 mmol) and CuI (0.104 g, 0.54
2
3 2
mmol). The reaction mixture was stirred at room temperature
under argon for 2 h. After this time, it was diluted with ethyl
Scheme 2
acetate, washed with a saturated NH Cl solution and a saturated
4
10-17
18
7a-d
were obtained in good to high yields from 6b according to
NaCl solution. The organic layer was separated, dried (Na SO )
2
4
the conditions reported in Scheme 3.
and concentrated at reduced pressure.
To the residue were added MeOH (10 mL) and K CO (0.189 g,
2
3
1.37 mmol) and the mixture was stirred at room temperature for 1
h. Then, MeOH was evaporated under vacuum and the residue
was dissolved in ethyl acetate. The solution was washed with a
saturated NaCl solution, the organic layer was separated, dried
(Na SO ) and concentrated at reduced pressure.
2
4
The residue was dissolved in anhydrous THF and the solution was
cooled at 0 °C. Then, ethyl malonylchloride (4.1 g, 27.4 mmol)
was added at 0 °C and the resulting reaction mixture was stirred at
room temperature for 15 min. After this time, the mixture was
diluted with ethyl acetate, washed with a saturated NaCl solution,
the organic layer was separated, dried (Na SO ) and concentrated
2
4
under vacuum. The residue was purified by chromatography on
silica gel eluting with a n-hexane/ethyl acetate 80/20 (v/v) mixture
to give 1 (2.5 g, 80% yield; mp = 75-7 °C; IR (KBr) 3279, 2150,
-1
1
1728, 1671 cm ; H NMR (CDCl ) δ 1.33 (t , J = 7.1 Hz, 3 H),
3
3.55 (s, 1 H), 3.52 (s, 2 H), 4.26 (q, J = 7.1 Hz, 2 H), 7.07-8.44 (m,
13
4 H), 9.41 (bs, 1 H); C NMR (CDCl ) δ 13.4, 42.1, 52.7, 79.0,
3
84.6, 111.5, 119.9, 123.8, 130.1, 132.3, 139.8, 163.0, 169.5; MS
+
m/e: 231 (M , 24), 186 (3), 117 (100).
5.
A typical procedure for the palladium-catalysed coupling is as
follows: to a solution of 1 (0.200 g, 0.87 mmol) in DMF (2 mL),
Et NH (2 mL), m-nitrophenyl iodide 2c (0.259 g, 1.04 mmol),
2
Pd(OAc) (PPh ) (0.032 g), and CuI (0.017 g, 0.087 mmol) were
2
3 2
added. The reaction mixture is gently purged with argon and
stirred at room temperature for 1.5 h under argon. Then, ethyl
acetate and HCl 0.2 N were added, the organic layer was
Scheme 3
separated, washed with a saturated NaHCO solution, a saturated
3
NaCl solution, dried (Na SO ), and concentrated at reduced
Acknowledgments. The authors are greatly indebted to the Fondazione
Cenci Bolognetti for financial support of this research. The authors are
also indebted to Dr. Luciana Turchetto of the Istituto Superiore di Sanità
for obtaining the mass spectra of new products.
2
4
pressure. The residue was purified by chromatography eluting
with a 95/5 (v/v) n-hexane/EtOAc mixture to give 3c (0.202 g,
66% yield); mp = 112-113 °C; IR (KBr) 2984, 2130, 1720, 1663
-1
1
cm ; H NMR (CDCl ) δ 1.33 (t, J = 7.1 Hz, 3 H), 3.57 (s, 2 H),
3
4.36 (q, J = 7.1 Hz, 2 H), 7.10 (t, J = 7.6 Hz, 1 H), 7.34-7.57 (m, 3
References and Notes
H), 7.95 (d, J = 7.7 Hz, 1 H), 8.16 (d, J = 8.3 Hz, 1 H), 8.48 (d, J =
13
1.
Cacchi, S.; Fabrizi, G.; Carangio, A. Synlett 1997, 959; Cacchi, S.;
Carnicelli, V.; Marinelli, F. J. Organomet. Chem. 1994, 475, 289;
Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron 1993, 49, 4955;
Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron Lett. 1989, 30,
2581.
8.3 Hz, 1 H), 8.76 (s, 1 H), 10.44 (sb, 1 H); C NMR (CDCl ) δ
3
14.2, 41.3, 62.4, 87.3, 94.0, 111.9, 120.1, 123.2, 123.9, 125.0,
126.8, 129.4, 130.5, 132.5, 137.5, 139.6, 148.4, 163.4, 170.5; MS
+
m/e: 352 (M , 1), 293 (15), 277 (13), 262 (31), 208 (11), 149
(100), 144 (28).
2.
3.
Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F. Synlett 1993, 65.
6.
A typical procedure for the carbocyclization is as follows: to a
solution of 3c (0.200 g, 0.57 mmol) in DMSO (5 mL) was added
KOt-Bu (0.159 g, 1.42 mmol). The reaction mixture was stirred at
110 °C for 0.5 h, then poured into a separatory funnel containing
ethyl acetate and a saturated NaCl solution. The organic layer was
For other approaches to substituted 2(1H)-quinolones, see:
Fourquez, J.M.; Godard, A.; Marsais, F.; Quéguiner, G. J.
Heterocyclic Chem. 1995, 32, 1165; Kuroda, T.; Suzuki, F.
Tetrahedron Lett. 1991, 32, 6915; Bell, A.S.; Greenhill, J.V. In
The Chemistry of Heterocycles; Taylor, E.C. Ed.; J. Wiley &
Sons: Chichester, 1990; Vol. 32, part III; Roberts, D.A.; Ruddock,
K.S. Synthesis 1987, 843; Gaston, J.L.; Greer, R.J.; Grundon, M.
separated, washed with water, dried (Na SO ), and concentrated
2
4
at reduced pressure. The residue was purified by chromatography
eluting with a 60/40 (v/v) n-hexane/EtOAc mixture to give 4c

448
LETTERS
SYNLETT
-1
(0.124 g, 62% yield): mp = 223-5 °C; IR (KBr) 1720, 1663 cm
;
62.4 (CH -CH -O), 87.4 (C −C -Ph), 92.9 (C −C -Ph), 161.7
3
2
sp
sp
sp
sp
1
+
H NMR (CDCl ) δ 1.17 (t, J = 6.4 Hz, 3 H), 4.30 (m, 4 H), 7.15
(F-C
, J = 246.0 Hz), 167.0 (-COOEt); MS m/e: 409 (M ,
aromatic
3
(t, J = 7.6 Hz, 1 H), 7.35 (d, J = 7.6 Hz, 1 H), 7.48-7.79 (m, 4 H),
8.07 (d, J = 8.1 Hz, 1 H), 8.23 (s, 1 H), 12.2 (s, 1 H); C NMR
57), 380 (100), 364 (27), 352 (19), 335 (24), 322 (21), 234 (13),
207 (17).
13
(CDCl ) δ 13.9, 34.5, 61.4, 116.0, 117.3, 1221.7, 122.5, 123.0,
3
13. Cacchi, S.; Morera, E.; Ortar, G. Synthesis 1986, 320.
126.0, 128.2, 130.1, 131.5, 135.1, 138.8, 140.1, 144.8, 147.9,
+
14. 7c (prepared according to the conditions described in ref. 15): oil;
158.7, 166.0; MS m/e 352 (M , 32), 306 (100), 276 (15), 260 (40),
-1
1
IR (neat) 2951, 1728, 1605 cm ; H NMR (CDCl ) δ 1.29 (t, J +
3
232 (48), 204 (50), 176 (13).
7.2 Hz, 3 H), 4.09 (s, 3 H), 4.41 (q, J = 7.2 Hz, 2 H), 4.50 (s, 2 H),
6.92 (t, J = 8.6 Hz, 2 H), 7.13 (t, J = 5.5 Hz, 2 H), 7.60 (m, 1 H),
7.
8.
Arcadi, A.; Cacchi, S.; Del Rosario, M.; Fabrizi, G.; Marinelli, F.
J. Org. Chem. 1996, 61, 9280.
7.78 (m, 1 H), 7.98 (d, J = 8.5 Hz, 1 H), 8.28 (d, J = 8.4 Hz, 1 H);
For recent leading works on the synthesis of quinoline derivatives
based on palladium chemistry, see: Arcadi, A.; Cacchi, S.; Fabrizi,
G.; Marinelli, F.; Pace, P. Synlett 1996, 568; Kundu, N.G.;
Mahanty, J.S.; Das, P.; Das, B. Tetrahedron Lett. 1993, 34, 1625;
Godard, A.; Rocca, P.; Fourquez, J.-M.; Rovera, J.-C.; Marsais,
F.; Quéguiner, G. Tetrahedron Lett. 1993, 34, 7919; Tori, S.; Xu,
L.H.; Sadakane, M.; Okumoto, H. Synlett 1992, 514; Larock,
R.C.; Kuo, M.-Y. Tetrahedron Lett. 1991, 32, 569; Crisp, G.T.;
Papadopoulos, S. Aust. J. Chem. 1989, 42, 279.
13
C NMR (CDCl ) δ 13.8 (CH -CH -O), 34.4 (-CH -C H -p-F),
3
3
2
2
6 4
, J = 244.0
60.3 (CH -O), 62.1 (CH CH -O), 161.5 (F-C
3
3-
2
aromatic
+
Hz), 165.6, 167.7 (-COOMe and -COOEt); MS m/e: 367 (M ,
100), 322 (25), 307 (27), 279 (64), 263 (80), 234 (79), 207 (36),
156 (31).
15. Cacchi, S.; Ciattini, P.G.; Morera, E.; Ortar, G. Tetrahedron Lett.
1986, 27, 3931.
16. 7d (prepared according to the conditions described in ref. 17): oil;
-1
1
IR (neat) 3419, 2976, 1721 cm ; H NMR (CDCl ) δ 0.86-1.55
9.
For reviews on the synthesis of quinolines, see: Cheng, C.-C.;
Yan, S.-J. Org. React. 1983, 28, 37; Jones, G. Chem. Heterocycl.
Compd. 1977, 32, 93.
3
(m, 9 H), 3.52 (q, J = 7.0 Hz, 4 H), 4.27 (m, 4 H), 6.91 (t, J = 8.7
Hz, 2 H), 7.05-7.35 (m, 4 H), 7.52 (t, J = 7.1 Hz, 1 H), 7.72 (t, J =
13
8.7 Hz, 1 H); C NMR (CDCl ) δ 13.3 (CH -CH -O), 14.1 (CH -
3
3
2
3
10. 7a (prepared according to the conditions described in ref. 11): mp
CH -N), 34.8 (−CH -C H -p-F), 44.3 (CH -CH -N), 157.3 (F-
-1
1
2
2
6
4
3
2
= 85-7 °C; IR (KBr) 2992, 1720 cm ; H NMR (CDCl ) δ 1.36 (t,
3
+
C
, J = 182.3 Hz), 169.6 (−COOEt); MS m/e: 380 4M , 15),
aromatic
J = 7.1 Hz, 3 H), 4.41 (q, J = 7.1 Hz), 4.85 (s, 2 H), 6.91 (t, J = 8.7
Hz, 2 H), 7.05 (t, J = 3.2 Hz, 2 H), 7.54 (m, 1 H), 7.77 (m, 1 H),
351 (97), 337 (15), 305 (100), 264 (18), 235 (28), 207 (14).
13
8.11 (m, 1 H), 9.34 (s, 1 H); C NMR (CDCl ) δ 14.4 (CH -CH -
17. Cacchi, S.; Carangio, A.; Fabrizi, G.; Moro, L.; Pace, P. Synlett, in
3
3
2
O), 35.6 (-CH -C H -p-F), 61.9 (CH CH -O), 161.5 (F-C ,
aromatic
J = 241.0 Hz), 166.7 (-COOEt); MS m/e: 309 (M , 5), 263 (100),
235 (21), 207 (8), 184 (7).
press.
2
6
4
3-
2
+
18. The triflate 6b was prepared in 93% yield by treating 4b (0.140 g,
0.431 mmol) with PhN(Tf) (0.184 g, 0.517 mmol) in the presence
2
11. Cacchi, S.; Ciattini, P.G.; Morera, E.; Ortar, G. Tetrahedron Lett.
1986, 27, 5541.
of NaH (0.021 g, 0.517 mmol) in DMF (3 mL) at room
-1
1
temperature for 1 h: oil; IR (neat) 3082, 2992, 1737 cm ;
H
12. 7b (prepared according to the conditions described in ref. 13): mp
NMR (CDCl ) δ 1.33 (t, J = 7.1 Hz, 3 H), 4.41 (q, J = 7.1 Hz, 2
H), 4.51 (s, 2 H), 6.94 (t, J = 8.6 Hz, 2 H), 7.12 (t, J = 5.4 Hz, 2 H),
3
-1
1
= 128-130 °C; IR (KBr) 2927, 2212, 1729 cm ; H NMR
(CDCl ) δ 1.30 (t, J = 7.1 Hz, 3 H), 4.43 (m, 4 H), 6.94 (t, J = 8.4
Hz, 1 H), 7.14 (t, J = 8.4 Hz, 2 H), 7.26-7.64 (m, 8 H), 7.72 (t, J =
7.57 (t, J = 7.1 Hz, 1 H), 7.77 (t, 8.3 Hz, 1 H), 8.00 (t, J = 8.3 Hz,
3
13
2 H); C NMR (CDCl ) δ 14.0 (CH -CH O), 34.9 (-CH -C H -
3
3
2
2
6 4
8.2 Hz, 1 H), 7.91 (d, J = 8.3 Hz, 1 H), 8.14 (d, J = 8.3 Hz, 1 H);
p-F), 63.1 (CH -CH -O), 118.6 (CF , J = 320.0 Hz) 161.1 (F-
3 2 3
13
C NMR (CDCl ) δ 14.3 (CH -CH -O), 35.0 (-CH -C H -p-F),
C
, J = 181.1 Hz), 164.5 (-COOEt).
3
3
2
2
6
4
aromatic