Polysubstituted quinolines from 2-alkynylanilines and α,β-ynones through a sequential conjugate addition-cyclization process

Article abstract of DOI:10.1055/s-0029-1216734

Polysubstituted quinolines have been prepared, usually in good to high yields, from readily available 2-alkynylanilines and α,β-ynones through a sequential process that omits the isolation of the enaminone intermediates. The reaction tolerates several use

Full text of DOI:10.1055/s-0029-1216734

LETTER
1245
Polysubstituted Quinolines from 2-Alkynylanilines and a,b-Ynones through a
Sequential Conjugate Addition–Cyclization Process
P
a
olysubstituted
Q
o
uinolines fro
b
m
2-Alkyny
e
lanilines an
r
d
a
,
b
-Y
t
Dipartimento A.B.A.C., Università degli Studi della Tuscia e Consorzio Universitario ‘La Chimica per l’Ambiente’, Via S. Camillo
De Lellis, 01100 Viterbo, Italy
b
Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi ‘La Sapienza’, P. le A. Moro 5, 00185 Rome, Italy
Fax +39(06)49912780; E-mail: sandro.cacchi@uniroma1.it
Received 3 February 2009
Enaminones 3 contain two nucleophilic centers: the nitro-
gen atom and the a-carbon of the a,b-unsaturated system.
Potentially, they might undergo the desired 6-exo dig
C-cyclization to quinolines or/and a 5-endo-dig N-cycli-
Abstract: Polysubstituted quinolines have been prepared, usually
in good to high yields, from readily available 2-alkynylanilines and
a,b-ynones through a sequential process that omits the isolation of
the enaminone intermediates. The reaction tolerates several useful
functionalities including ether, cyano, ester, and chloro substitu- zation to N-vinylic indoles (Scheme 2).
ents.
R1
Key words: enaminones, cyclization, quinolines, a,b-ynones, 2-
alkynylanilines
COR3
R2
6-exo dig
C-cyclization
R1
N
R2
Because of their multifunctional character, 3-enaminones
4
are useful synthetic intermediates and a wide range of
N
synthetic procedures rely on their chemistry.1 As part of
5-endo dig
H
R1
COR3
N-cyclization
3
our program on the development of new efficient ap-
N
COR3
proaches to polysubstituted heterocycles we recently de-
scribed the utilization of 3-enaminone derivatives in the
5
R2
synthesis of pyrroles,2 pyridines,2 quinolones,3 and in-
Scheme 2
doles.4 Herein we report on the utilization of 3-enamin-
ones in the construction of the polysubstituted quinoline
We started our study by examining the conversion of 3a
(R1 = R2 = R3 = Ph) into the corresponding quinoline de-
rivative 4a.
skeleton, a structural motif that is prevalent in a variety of
biologically active compounds.5 In particular, we decided
to investigate the feasibility of a process based on the con-
jugate addition6 of 2-alkynylanilines 1 to a,b-ynones 27
followed by the cyclization of the resultant enaminones 3
to the quinoline products 4 (Scheme 1).
The enaminone 3a was prepared in 90% isolated yield via
conjugate addition of one equivalent of 2-(phenylethy-
nyl)aniline to one equivalent of 1,3-diphenylpropynone in
MeOH at 120 °C (48 h).8,9 Its stereochemistry was as-
signed on the basis of NMR analysis and on our previous
studies on related compounds.2–4 Using i-PrOH as the sol-
vent under the same conditions gave the conjugate addi-
tion product in moderate yield (45%) and only trace
amounts, if any, of 3a were detected when the reaction
was carried out in DMSO, MeCN, and NMP at 120 °C for
24 hours.
R3
O
R1
R1
R2
N
NH2
R2
H
COR3
1
2
3
R1
In the presence of copper, palladium, and gold catalysts
3a was found to undergo preferentially a 5-endo-dig N-
cyclization process. The main reaction product was al-
ways the N-vinylic indole derivative 5a under a variety of
conditions (using NaAuCl4 5a was isolated in almost
quantitative yield; Table 1, entry 4) and no evidence of 4a
formation was attained. This behavior is in agreement
with the general reactivity of ‘simple’ 2-(alkynyl)anilines
and -anilides in the presence of transition metals,10 al-
though 2-(alkynyl)trifluoroacetanilides have been shown
to afford palladium-catalyzed 6-exo-dig cyclization pro-
cesses via intramolecular nucleophilic attack of the amide
oxygen across the activated carbon–carbon triple bond.11
COR3
R2
N
4
Scheme 1
SYNLETT 2009, No. 8, pp 1245–1250
Advanced online publication: 17.04.2009
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x.
x
x.
2
0
0
9
DOI: 10.1055/s-0029-1216734; Art ID: G02909ST
© Georg Thieme Verlag Stuttgart · New York

1246
R. Bernini et al.
LETTER
We then decided to omit transition metals and to investi- and base to the crude mixture derived from the conjugate
gate the cyclization of 3a in the presence of bases. The addition of 2-(alkynyl)anilines to a,b-ynones in MeOH
cyclization of alkynes containing proximate carbon pro- after evaporation of the volatile materials. Using 1a and
nucleophiles in the presence of bases has been used by us 2a as the model system, excellent results in terms of yield,
for the synthesis of indoles,12 butenolides,13 and quino- temperature, and reaction time were obtained when the
lones.14 Solvents were found to play a key role in the cyclization step was carried out in NMP (Table 2, entry 2)
cyclization of 3a in the presence of bases. For example, 3a and MeCN (Table 2, entry 5) using Cs2CO3 as the base at
was recovered in almost quantitative yield upon treatment 60 °C. Utilization of DMSO, which gave the highest yield
with Cs2CO3 in MeOH (Table 1, entry 5). Pleasingly, the in the cyclization of 3a (Table 1, entry 7), is flawed by the
quinoline product was obtained in high yield subjecting formation of significant amounts of 6a (Figure 1, Table 2,
3a to Cs2CO3 in NMP (Table 1, entry 6) and switching to entry 1). The carbonyl derivative 6a was also isolated in
DMSO allowed for the isolation of 4a in 92% yield15 27% yield using DMA (Table 2, entry 4). Most probably
(Table 1, entry 7).
it is formed via oxidation of 4a. We have not investigated
the details of this reaction.
Table 1 Optimization of Cyclization Conditionsa
Ph
O
Ph
Ph
COPh
Ph
COPh
Ph
COPh
Ph
N
+
N
N
N
Ph
H
Ph
5a
COPh
6a
3a
4a
Figure 1
Entry Catalyst
Solvent Base
Temp Time Yield Yield
(°C) (h)
of 4a of 5a
(%) b (%)b
Table 2 Preparation of 4a from 1a and 2a Omitting the Isolation of
the Enaminone Intermediatea,b
1
2
3
4
5
6
7
CuBr
PdCl2
dioxane Cs2CO3 80
4
–
35c
50c
90c
98c
Entry Solvent Base
Temp (°C) Time (h) Yield of 4a (%)c
d
MeCN
MeOH
MeOH
MeOH
NMP
–
80
Cs2CO3 60
60
8
–
1
2
3
4
5
DMSO Cs2CO3
r.t.
60
60
60
60
1
60d
81
NaAuCl4
4
–
NMP
NMP
DMA
Cs2CO3
K2CO3
Cs2CO3
1
NaAuCl4
–
1
–
24
0.5
1.5
82
e
–
–
–
Cs2CO3 35
Cs2CO3 35
Cs2CO3 35
12
3
–
–
65e
83f
82
92
–
–
MeCN Cs2CO3
DMSO
2
a Reactions were carried out on a 0.2 mmol scale using 1 equiv of 1a
and 1 equiv of 2a.
a Unless otherwise stated, reactions were carried out on a 0.2 mmol
scale using 0.1 equiv of transition-metal catalyst (when used), 1 equiv
of base (when used) in 1.5 mL of solvent.
b The conjugate addition step was carried out in 0.5 mL of MeOH at
120 °C for 48 h.
b Yields are given for isolated products.
c Yields are given for isolated products.
c Compound 5a was isolated as a single stereoisomer. Its configura-
tion was not assigned.
d The benzoyl derivative 6a was isolated in 29% yield.
e The benzoyl derivative 6a was isolated in 27% yield.
f The benzoyl derivative 6a was isolated in 10% yield.
d In the presence of 0.05 equiv of PdCl2.
e Compound 3a was recovered in almost quantitative yield.
Using the optimized conditions, we next explored the
scope and generality of the sequential process.16 As shown
in Table 3, a wide variety of quinolines can be prepared in
good to high yields and several useful functionalities are
tolerated, including ether, cyano, ester, and chloro substit-
uents. Bromo-containing quinolines can also be prepared
although the bromoquinoline 4e was isolated in moderate
yield. In this case, formation of 4e was accompanied by
the formation of the quinolone product 7e (11%), most
probably formed via a base-catalyzed cyclization pro-
cess,17 and by a 34% yield of the oxidation derivative 6e
(Scheme 3).
Having established the best conditions for the cyclization
of 3a, we explored the formation of quinolines from 2-
(alkynyl)anilines and a,b-ynones through a sequential
process that would omit the isolation of the enaminone
intermediates.
We realized very soon that the two steps (conjugate addi-
tion and cyclization) could not be carried out using the
same reaction medium. Indeed, the base-catalyzed
cyclization does not occur in MeOH (Table 1, entry 5;
MeOH is the best solvent for the conjugate addition step,
see above) and the conjugate addition does not occur in
NMP or DMSO (the best solvents for the cyclization step;
Table 1, entries 6 and 7). Therefore, we investigated a
procedure based on the addition of the appropriate solvent
As for the substitution patterns, this method appears to
have some limitations with 2-alkynylanilines bearing
electron-withdrawing substituents para to the nitrogen or
Synlett 2009, No. 8, 1245–1250 © Thieme Stuttgart · New York

LETTER
Polysubstituted Quinolines from 2-Alkynylanilines and a,b-Ynones
1247
Br
substituents ortho to the nitrogen. In both cases a detri-
mental effect was observed on the first step of the process
most probably because the electronic and steric effects of
these substituents tend to decrease the nucleophilicity of
the nitrogen atom. For example, no conjugate addition
products were isolated when 1m and 1n (Figure 2) were
subjected to standard reaction conditions.
Ar
O
1. MeOH, 120 °C, 24 h
2. Cs2CO3, MeCN, 60 °C, 1 h
+
NH2
Ph
Ar
Ar
O
Ph
O
Br
Ph
Me
MeO2C
N
4e (43%)
+
NH2
Ph
O
N
Ph
NH2
Me
6e (34%)
7e (11%)
1m
1n
Ar = 4-MeOC6H4
Figure 2
Scheme 3
Table 3 Synthesis of Multisubstituted Quinolines from 2-(Alkynyl)anilines and a,b-Ynonesa–c
Entry 2-(Alkynyl)aniline
a,b-Ynone
Conjugate addi- Cyclization Quinoline 4
Yield (%)d
tion time (h)
time (h)
COPh
Ph
Ph
1
2
48
1.5
4a
83
COPh
Ph
NH2
Ph
N
2a
1a
1b
48
48
1.5
4b
76
Cl
Cl
O
OMe
O
NH2
Ph
N
Ph
2b
OMe
3
0.5e
4c
74
Ph
Cl
Cl
O
O
F
F
NH2
Ph
2c
N
Ph
Ph
1c
4
5
48
24
4
1
4d
4e
51
Cl
COPh
Cl
Me
C5H11
Me
COPh
C5H11
2d
NH2
N
1d
43f
OMe
MeO
Br
O
O
Br
NH2
N
Ph
Ph
1e
2e
Synlett 2009, No. 8, 1245–1250 © Thieme Stuttgart · New York

1248
R. Bernini et al.
LETTER
Table 3 Synthesis of Multisubstituted Quinolines from 2-(Alkynyl)anilines and a,b-Ynonesa–c (continued)
Entry 2-(Alkynyl)aniline
a,b-Ynone
Conjugate addi- Cyclization Quinoline 4
Yield (%)d
tion time (h)
time (h)
Me
OMe
Me
6
48
24
4f
42
O
O
Ph
NH2
2f
N
Ph
OMe
1f
7
8
48
48
2
4g
4h
64
83
Cl
Cl
O
Me
O
Me
Me
NH2
Ph
N
Ph
1d
2g
Me
0.75
Cl
OMe
O
OMe
O
NH2
Ph
1g
2h
N
Ph
Cl
9
48
48
0.5
4i
4j
65
77
Ph
CN
Ph
O
F
O
F
F
NH2
N
Ph
CN
1h
Ph
2i
10
1
F
O
OMe
O
NH2
Ph
N
Ph
1i
2b
OMe
11
24
1.5
4k
70
Me
Me
O
CF3
O
Ph
NH2
2j
N
N
Ph
O
1f
CF3
12
48
4.5
4l
43
Ph
Ph
O
Me
Me
NH2
Ph
Ph
1a
2k
Synlett 2009, No. 8, 1245–1250 © Thieme Stuttgart · New York

LETTER
Polysubstituted Quinolines from 2-Alkynylanilines and a,b-Ynones
1249
Table 3 Synthesis of Multisubstituted Quinolines from 2-(Alkynyl)anilines and a,b-Ynonesa–c (continued)
Entry 2-(Alkynyl)aniline
a,b-Ynone
Conjugate addi- Cyclization Quinoline 4
Yield (%)d
tion time (h)
time (h)
72g
1
4m 70
CF3
COPh
CF3
13
Ph
2a
COPh
NH2
N
Ph
F
1j
14
69
0.5
4n
80
F
CO2Me
O
CO2Me
NH2
O
1k
OMe
CF3
N
OMe
2l
15
16
48
24
1
2
4o
4p
75
70
Ph
Cl
O
Ph
CF3
NH2
Cl
O
1l
Ph
N
Ph
2j
Cl
OMe
Cl
MeO
O
NH2
O
Ph
1e
2h
N
Ph
a Reactions were carried out on a 0.2 mmol scale using 1 equiv of 1 and 1 equiv of 2.
b Unless otherwise stated, the conjugate addition step was carried out in 0.5 mL of MeOH at 120 °C.
c Unless otherwise stated, the cyclization step was carried out adding 1.5 mL of MeCN and 1 equiv of Cs2CO3 to the crude mixture derived
from the conjugate addition after evaporation of the volatile material.
d Yields are given for isolated products.
e The cyclization step was carried out in NMP.
f Compounds 6e and 7e were isolated in 34% and 11% yield, respectively.
g The conjugate addition step was carried out in 1 mL of MeOH.
In conclusion, we have developed an efficient and simple References and Notes
approach to the synthesis of polysubstituted quinolines
from readily available 2-alkynylanilines and a,b-ynones
A. A. Tetrahedron 2003, 59, 8463. (b) Stanovnik, B.; Svete,
(1) For recent reviews, see: (a) Elassar, A.-Z. A.; El-Khair,
through a sequential process that omits the isolation of
enaminone intermediates. Using this protocol, a wide va-
riety of functionalized quinolines can be prepared in good
to high yields.
J. Chem. Rev. 2004, 104, 2433.
(2) Cacchi, S.; Fabrizi, G.; Filisti, E. Org. Lett. 2008, 10, 2629.
(3) Bernini R., Cacchi S., Fabrizi G., Sferrazza A.; Synthesis;
2009, in press
(4) Bernini, R.; Cacchi, S.; Fabrizi, G.; Filisti, E.; Sferrazza, A.
Synlett 2009, submitted.
(5) For some recent reviews, see: (a) Sikorski, J. A. J. Med.
Chem. 2006, 49, 1. (b) White, N. J. Lancet Infect. Dis. 2007,
7, 549. (c) Bradbury, B. J.; Pucci, M. J. Curr. Opin. Pharm.
2008, 8, 574. (d) Michael, J. P. Nat. Prod. Rep. 2008, 25,
166.
(6) Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka, H.
Synthesis 1990, 215.
Acknowledgment
Work was carried out in the framework of the National Project
‘Stereoselezione in Sintesi Organica. Metodologie ed Applicazioni’
supported by the Ministero dell’Università e della Ricerca Scienti-
fica e Tecnologica and by the University ‘La Sapienza’.
(7) Karpov, A. S.; Muller, T. J. J. Org. Lett. 2003, 5, 3451.
Synlett 2009, No. 8, 1245–1250 © Thieme Stuttgart · New York

1250
R. Bernini et al.
LETTER
(8) Conjugate additions of 2-(alkynyl)anilines to 1,3-diphenyl-
propynones (MeOH, 120 °C) were carried out using a
Carousel Tube Reaction (Radley Discovery).
SiO2 [n-hexane–EtOAc, 85:15] to afford 64 mg (92% yield)
of 4a.
Light brown solid; mp 137–139 °C. IR (KBr): 3059, 2924,
1662 cm–1. 1H NMR (400 MHz, CDCl3): d = 8.31–8.29 (m,
1 H), 8.11–8.08 (m, 1 H), 7.80–7.78 (m, 1 H), 7.63–7.54 (m,
5 H), 7.38–7.36 (m, 1 H), 7.29–7.13 (m, 10 H), 4.49–4.41
(m, 2 H). 13C NMR (100.6 MHz, CDCl3): d = 198.0, 156.4,
148.1, 144.4, 140.0, 138.6, 137.4, 133.3, 133.2, 130.4,
130.1, 129.3, 128.6, 128.5, 128.4, 128.21, 128.17, 127.2,
126.3, 126.0, 125.0, 35.3. Anal. Calcd for C29H21NO: C,
87.19; H, 5.30. Found: C, 87.25; H, 5.36.
(9) Enaminones 3 can also be prepared by treating the conjugate
addition products derived from 2-iodonilines and 1,3-diaryl-
propynones with terminal alkynes. Using this procedure, 3a,
3q, and 3r were isolated in 77%, 74%, and 70% overall
yields, respectively. This protocol, however, appeared less
suited for the development of a sequential process that would
omit the isolation of the enaminone intermediates
(Scheme 4).
(16) Typical Procedure for the Preparation of Quinolines 4
from 2-(Alkynyl)anilines 1 and a,b-Ynones 2
COPh
I
I
MeOH, 120 °C
48 h
Ph
To a stirred solution of 1b (45.5 mg, 0.2 mmol) in anhyd
MeOH (0.5 mL), 2b (47.3 mg, 0.2 mmol) was added at r.t.
The reaction mixture was warmed at 120 °C and stirred for
48 h. After that period the volatile materials were evaporated
at reduced pressure, Cs2CO3 (65.2 mg, 0.2 mmol) and anhyd
MeCN (1.5 mL) were added. The resulting reaction mixture
was warmed at 60 °C and stirred for 1.5 h. After cooling, the
reaction mixture was diluted with EtOAc, washed with 2 N
HCl and brine. The organic layer was dried over Na2SO4 and
concentrated under reduced pressure. The residue was
purified by chromatography on SiO2 [n-hexane–EtOAc,
85:15] to afford 71.0 mg (76% yield) of 4b.
NH2
N
H
Ph
1.5 equiv
COPh
1 equiv
86%
Ar
(1.2 equiv)
PdCl2(PPh3)2 (2 mol%)
CuI (4 mol%)
Ar
(i-Pr)2NH
Ph
DMF, r.t.
N
H
COPh
White solid; mp 167–169 °C. IR (KBr): 3072, 2943, 1664
cm–1. 1H NMR (400 MHz, CDCl3): d = 8.30–8.28 (m, 1 H),
8.02–8.00 (m, 1 H), 7.82–7.78 (m, 1 H), 7.63–7.56 (m, 3 H),
7.29–7.28 (m, 3 H), 7.17–7.09 (m, 6 H), 7.03–7.01 (m, 1 H),
Ar = Ph (3a; 90%); 4-MeOC6H4 (3q; 86%), ClC6H4 (3r; 81%)
Scheme 4
6.96–6.94 (m, 1 H), 4.43–4.32 (m, 2 H), 3.73 (s, 3 H). 13
C
(10) For some selected references on the transition-metal-
catalyzed cyclization of 2-(alkynyl)anilines and -anilides,
see: (a) (Pd and Au) Iritani, K.; Matsubara, S.; Utimoto, K.
Tetrahedron Lett. 1988, 29, 1799. (b) (Cu) Cacchi, S.;
Fabrizi, G.; Parisi, L. M. Org. Lett. 2003, 5, 3843. While
the manuscript was in preparation, an indium-catalyzed
cyclization of b-enamino esters [prepared from b-keto esters
and 2-(alkynyl)anilines] to N-vinylic indoles was described:
(c) Murai, K.; Hayashi, S.; Takaichi, N.; Kita, Y.; Fujioka,
H. J. Org. Chem. 2009, 74, 1418.
(11) (a) Cacchi, S.; Fabrizi, G.; Marinelli, F.; Moro, L.; Pace, P.
Synlett 1997, 1363. (b) Cacchi, S.; Fabrizi, G.; Marinelli, F.
Synlett 1999, 401.
(12) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F. Synlett
2000, 647.
NMR (100.6 MHz, CDCl3): d = 197.8, 159.5, 156.4, 148.1,
143.7, 139.9, 138.7, 137.1, 133.2, 132.2, 130.6, 130.2,
129.8, 129.31, 129.28, 128.7, 128.6, 128.2, 127.4, 125.7,
124.7, 122.5, 120.1, 113.0, 55.3, 34.7. Anal. Calcd for
C30H22ClNO2: C, 77.66; H, 4.78. Found: C, 77.52; H, 4.70.
(17) For a recent review, see: (a) Kouznetsov, V. V.; Méndez,
L. Y. V.; Gómez, M. M. Curr. Org. Chem. 2005, 9, 141.
For other selected references, see: (b)Mitscher, L. A. Chem.
Rev. 2005, 105, 559. (c) Glushkov, R. G.; Marchenko,
N. B.; Padeiskaya, E. N.; Shipilova, L. D. Khim.-Farm. Zh.
1990, 24, 24. (d) White, L. A.; Storr, R. C. Tetrahedron
1996, 52, 3117. (e) Clemencin-Le Guillou, C.; Remuzon,
P.; Bouzard, D.; Quirion, J.-C.; Giorgi-Renault, S.; Husson,
H.-P. Tetrahedron 1998, 54, 83. (f) Liu, Y.; Yu, C.-Y.;
Wang, M.-X. ARKIVOC 2003, (ii), 146. (g) Ding, D.; Li,
X.; Wang, X.; Du, Y.; Shen, J. Tetrahedron Lett. 2006, 47,
6997. (h) Park, C.-H.; Lee, J.; Jung, H. Y.; Kim, M. J.; Lim,
S. H.; Yeo, H. T.; Choi, E. C.; Yoon, E. J.; Kim, K. W.; Cha,
J. H.; Kim, S.-H.; Chang, D.-J.; Kwon, D.-Y.; Li, F.; Suh,
Y.-G. Bioorg. Med. Chem. 2007, 15, 6517. (i) Al-Hiari,
Y. M.; Al-Mazari, I. S.; Shakya, A. K.; Darwish, R. M.;
Abu-Dahab, R. Molecules 2007, 12, 1240. (j) Zewge, D.;
Chen, C.-y.; Deer, C.; Dormer, P. G.; Hughes, D. L. J. Org.
Chem. 2007, 72, 4276. (k) Jones, C. P.; Anderson, K. W.;
Buchwald, S. L. J. Org. Chem. 2007, 72, 7968.
(13) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F. Synlett
1993, 65.
(14) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Manna, F.; Pace, P.
Synlett 1998, 446.
(15) Typical Procedure for the Cyclization of Enaminones 3
to Quinolines 4
To a stirred solution of 3a (80 mg, 0.2 mmol) in anhyd
DMSO (1.5 mL), Cs2CO3 (66 mg, 0.2 mmol) was added at
r.t. The reaction mixture was warmed at 35 °C and stirred for
2 h. After cooling, the reaction mixture was diluted with
EtOAc, washed with 2 N HCl and brine. The organic layer
was dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified by chromatography on
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