Synthesis of Quinolone-Fused Multi-ring-Sized Heterocycles via Combined Claisen Rearrangement/Ring-Closing Metathesis Reactions

Article abstract of DOI:10.1055/s-2003-42041

Synthetic strategy on 4-quinolone nucleus coupling aza-Claisen rearrangement and ring-closing metathesis was developed. Thus, quinolone-fused multiring-sized oxygen heterocycles 5a-c were prepared from 5-hydroxy-7-methoxy- 3-(4-methoxyphenyl)-4(1H)-quinol

Full text of DOI:10.1055/s-2003-42041

LETTER
2089
Synthesis of Quinolone-Fused Multi-ring-Sized Heterocycles via Combined
Claisen Rearrangement/Ring-Closing Metathesis Reactions
Synthesis of
Q
uin
h
olone-Fused
r
Multiri
i
ng-Size
s
d Heteroc
t
ycles ophe Pain,a Sylvain Célanire,a Gérald Guillaumet,a Benoît Joseph*a,b
a
Institut de Chimie Organique et Analytique, UMR-CNRS 6005, Université d’Orléans, B.P. 6759, 45067 Orléans Cedex 2, France
b
Laboratoire de Chimie Organique 1, UMR-CNRS 5622, Université Claude Bernard - Lyon 1, CPE - Bâtiment 308, 43 Boulevard du
11 Novembre 1918, 69622 Villeurbanne Cedex, France
Fax +33(4)72431214; E-mail: benoit.joseph@univ-lyon1.fr
Received 7 July 2003
synthesis of dihydrooxepino-, oxecino-, oxonino[2,3-
f]quinolin-11-one or azepino[2,3-f]quinolin-11-one com-
pounds. A retrosynthetic analysis shows that oxygen or
nitrogen heterocyclic cores can be prepared using a com-
Abstract: Synthetic strategy on 4-quinolone nucleus coupling
aza-Claisen rearrangement and ring-closing metathesis was devel-
oped. Thus, quinolone-fused multiring-sized oxygen heterocycles
5a–c were prepared from 5-hydroxy-7-methoxy-3-(4-methoxyphe-
nyl)-4(1H)-quinolone (1). According to the same strategy, azepi- bined aza-Claisen rearrangement/RCM methodology
(Scheme 1).5
no[2,3-f]quinolone derivative 9 was synthesised from triflate 6.
Key words: quinolone, Claisen rearrangement, olefin, ring-closing
metathesis
Herein, we report the successful synthesis of new quinolo-
ne-fused multiring-sized heterocycles. The RCM oxygen
precursors 4 were prepared from 5-hydroxy-7-methoxy-
3-(4-methoxyphenyl)-4(1H)-quinolone (1)6 as illustrated
The ring-closing metathesis (RCM) reaction has become
a versatile method for constructing cyclic alkenes or
alkynes.1 This method has rapidly evolved into a routine
tool for the synthesis of natural products,2 medium-ring
and macro-ring carbocyclic or heterocyclic motifs.3 The
generalisation into synthetic organic chemistry has been
driven primarily by the discovery of well-defined and
functional-group-tolerant catalysts independently by
Schrock and Grubbs.1e
in Scheme 2. Allylation of 1 in the presence of sodium hy-
dride (2 equivalents) in DMF afforded 2 in 71% optimised
yield. It should be noted that compound 4a was also iso-
lated in 5% yield. Claisen rearrangement7 of allyl com-
pound 2 in xylene was carried out in a sealed tube at
200 °C for 24 hours. 6-Allyl-5-hydroxy-4-quinolone (3)
was obtained in 80% yield. Alkylation of 3 in the presence
of sodium hydride (2 equivalents) and 3-bromopentene, 4-
bromobutene or 5-bromopentene (2 equivalents) in DMF
afforded 4a–c in fair yields.
In our ongoing research of new 4-quinolones with poten-
tial antitumor activity,4 we focused our attention on the
Scheme 1
SYNLETT 2003, No. 13, pp 2089–2091
1
6
.1
0
.2
0
0
3
Advanced online publication: 08.10.2003
DOI: 10.1055/s-2003-42041; Art ID: G16103ST
© Georg Thieme Verlag Stuttgart · New York

2090
C. Pain et al.
LETTER
Scheme 2
the desired compound 710 in 76% optimised yield
(Scheme 3). Without the nitrogen protecting group, the
ring-closure metathesis of 7 failed.1c Compound 7 was
acetylated according to classical method. Finally, RCM
reaction on 8 afforded seven-membered ring derivative
911 in 95% yield. Again, the structure was determined by
NMR experiments.
Table 1 Synthesis of Derivatives 5
Compd
5a
n
1
2
3
Yield (%)
Mp (°C)
81
86
80
175–176 (EtOAc)a
200–202 (EtOAc)a
243–244 (EtOAc)a
5b
5c
a Recrystallisation solvent.
In summary, we have developed an efficient route to qui-
nolone-fused multiring-sized oxygen heterocycles 5 using
combined Claisen rearrangement and ring-closing met-
athesis reactions. The same approach was performed on 5-
triflate 6 to afford azepino[2,3-f]quinolin-11-one (9).
Ring-closing metathesis7 with commercially available
Grubb’s catalyst (10 mol%) in dichloromethane (0.02 M)
at r.t. converted 4a to a single isomer of cyclised com-
pound 5a8 in 81% yield. The structure was established
from 1H NMR coupling constants and 2D NOESY exper-
iments.
References
(1) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
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3012. (e) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001,
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Lamothe, S. Tetrahedron Lett. 2001, 42, 2645.
Similarly, the same reaction was applied to compounds 4b
and 4c to give eight- and nine-membered fused ring deriv-
atives 5b and 5c in good yields (Table 1).9 In our hands,
no E-isomer of cyclised compound was observed. Follow-
ing these results, we considered the preparation of azepi-
no[2,3-f]quinolin-11-one derivative 9 from triflate 6.4 As
previously reported,4 an aromatic nucleophilic substitu-
tion reaction occurred when 6 was heated in the presence
of primary or secondary amine. From this statement, we
planned to treat the same triflate with diallylamine to un-
dergo a SNAr followed by a 3-aza-Claisen rearrangement
of the intermediate. The reaction between 6 and diallyl-
amine in a sealed tube at 120 °C for 24 hours afforded
Synlett 2003, No. 13, 2089–2091 © Thieme Stuttgart · New York

LETTER
Synthesis of Quinolone-Fused Multi-ring-Sized Heterocycles
2091
Scheme 3
(3) (a) Fürstner, A.; Langemann, K. Synthesis 1997, 792.
(b) Goldring, W. P. D.; Hodder, A. S.; Weiler, L.
Tetrahedron Lett. 1998, 39, 4955. (c) Dirat, O.; Vidal, T.;
Langlois, Y. Tetrahedron Lett. 1999, 40, 4801. (d) Hunt, J.
C. A.; Laurent, P.; Moody, C. J. Chem. Commun. 2000,
1771. (e) Crimmins, M. T.; King, B. W.; Zuercher, W. J.;
Choy, A. L. J. Org. Chem. 2000, 65, 8499. (f) Lane, C.;
Snieckus, V. Synlett 2000, 1294. (g) Boyer, F.-D.; Hanna,
I.; Nolan, S. P. J. Org. Chem. 2001, 66, 4094.
(h) Chatterjee, A. K.; Toste, F. D.; Goldberg, S. D.; Grubbs,
R. Pure Appl. Chem. 2003, 75, 421.
(4) (a) Joseph, B.; Darro, F.; Guillaumet, G.; Kiss, R.; Frydman,
A. PCT Int. Appl. WO 0112607, 2001; Chem. Abstr. 2001,
134, 193348. (b) Joseph, B.; Béhard, A.; Lesur, B.;
Guillaumet, G. Synlett 2003, 1542.
128.6 (CH), 128.2 (C), 125.7 (CH), 124.4 (C), 123.1 (C),
115.9 (C), 113.7 (2 CH), 91.7 (CH), 70.2 (CH2), 55.7 (CH3),
55.4 (CH3), 41.4 (CH3), 21.5 (CH2). MS (IS): m/z = 364
(M + H+). Anal. Calcd for C22H21NO4: C, 72.71; H, 5.82; N,
3.85. Found: C, 73.03; H, 5.94; N, 3.77.
(9) All new compounds gave satisfactory spectroscopic (1H-,
13C NMR, MS and IR) and analytical data.
(10) Physical data of compound 7: mp 119–120 °C (EtOAc). IR
(KBr): n = 3460, 1630, 1610, 1570, 1560, 1512 cm–1. 1H
NMR (250 MHz, CDCl3): d = 10.18 (broad s, 1 H, NH), 7.49
(d, 2 H, J = 7.8 Hz, Ar-H), 7.43 (s, 1 H, =CH), 6.93 (d, 2 H,
J = 7.8 Hz, Ar-H), 6.06 (s, 1 H, Ar-H), 6.17–5.89 (m, 2 H,
=CH), 5.34–5.25 (m, 1 H, =CH2), 5.08–4.95 (m, 3 H, =CH2),
3.90–3.82 (m, 5 H, OCH3 + CH2), 3.79 (s, 3 H, OCH3), 3.61
(s, 3 H, NCH3), 3.44–3.42 (m, 2 H, CH2). 13C NMR (62.90
MHz, CDCl3): d = 178.7 (CO), 162.0 (C), 158.6 (C), 154.9
(C), 142.1 (C), 140.2 (C), 137.9 (C), 137.2 (C), 130.1 (2
CH), 128.1 (CH), 121.8 (CH), 115.1 (CH2), 114.4 (CH2),
113.6 (2 CH), 112.0 (CH), 110.7 (C), 86.1 (CH), 55.4 (CH3),
55.3 (CH3), 51.4 (CH2), 41.5 (CH3), 30.2 (CH2). MS (IS):
m/z = 391 (M + H+). Anal. Calcd for C24H26N2O3: C, 73.82;
H, 6.71; N, 7.17. Found: C, 73.95; H, 6.60; N, 7.08.
(11) Physical data of compound 9: mp 245–246 °C (EtOAc). IR
(KBr): n = 1671, 1635, 1612, 1575, 1513 cm–1. 1H NMR
(250 MHz, CDCl3): d = 7.54 (s, 1 H, =CH), 7.50 (d, 2 H,
J = 8.7 Hz, Ar-H), 6.88 (d, 2 H, J = 8.7 Hz, Ar-H), 6.69 (s,
1 H, Ar-H), 5.75–5.68 (m, 1 H, =CH), 5.52–5.40 (m, 2 H,
CH2 + =CH), 3.98 (s, 3 H, OCH3), 3.81 (s, 3 H, OCH3), 3.78
(s, 3 H, NCH3), 3.63–3.43 (m, 3 H, CH2), 1.74 (s, 3 H,
COCH3). 13C NMR (62.90 MHz, CDCl3): d = 174.9 (CO),
169.5 (CO), 158.9 (C), 158.6 (C), 142.9 (C), 141.8 (C),
140.8 (CH), 130.1 (2 CH), 128.2 (C+CH), 127.7 (C), 124.2
(CH), 123.3 (C), 117.0 (C), 113.8 (2 CH), 95.6 (CH), 56.0
(CH3), 55.4 (CH3), 43.6 (CH2), 41.6 (CH3), 21.8 (CH3), 21.5
(CH2). MS (IS): m/z = 405 (M + H+). Anal. Calcd for
C24H24N2O4: C, 71.27; H, 5.98; N, 6.93. Found: C, 70.99; H,
6.12; N, 6.89.
(5) Chattopadhyay, S. K.; Maity, S.; Panja, S. Tetrahedron Lett.
2002, 43, 7781.
(6) (a) Ziegler, F. E. Chem. Rev. 1988, 88, 1423.
(b) Frauenrath, H. In Methods of Organic Chemistry
(Houben–Weyl), Stereoselective Synthesis, Vol. E21d;
Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E.,
Eds.; Thieme: Stuttgart, 1995, 3301–3756.
(7) Typical RCM Procedure: Under argon atmosphere,
Grubb’s reagent (19.6 mg, 0.02 mmol) was added to a
solution of 4a (93 mg, 0.24 mmol) in dry CH2Cl2 (10 mL).
The final solution was stirred at r.t. for 2 h. The solvent was
evaporated. The residue was purified by column
chromatography (petroleum ether–EtOAc, 2:8; then EtOAc)
to give 70 mg (81%) of 5a.
(8) Physical data of compound 5a: mp 175–176 °C (EtOAc). IR
(KBr): n = 1626, 1609, 1584, 1511 cm–1. 1H NMR (250
MHz, CDCl3): d = 7.52 (d, 2 H, J = 8.8 Hz, Ar-H), 7.42 (s,
1 H, =CH), 6.89 (d, 2 H, J = 8.8 Hz, Ar-H), 6.36 (s, 1 H, Ar-
H), 5.89–5.77 (m, 1 H, CH=), 5.51–5.45 (m, 1 H, CH=),
4.80–4.77 (m, 2 H, CH2), 3.90 (s, 3 H, OCH3), 3.80 (s, 3 H,
OCH3), 3.69 (s, 3 H, NCH3), 3.58–3.54 (m, 2 H, CH2). 13
C
NMR (62.90 MHz, CDCl3): d = 175.6 (CO), 159.7 (C),
158.7 (C), 158.6 (C), 141.6 (C), 140.4 (CH), 130.1 (2 CH),
Synlett 2003, No. 13, 2089–2091 © Thieme Stuttgart · New York