Enaminones acylation: Competitive formation of quinolin-4-one and isoquinolin-1-one derivatives

Article abstract of DOI:10.1055/s-2001-18719

The reaction of enaminones with some o-halogenobenzoyl chlorides allows the preparation of 3-acyl-2-alkylquinolin-4-one and/or 4-acyl-3-alkylisoquinolin-1-one derivatives depending on the structure of the starting materials. Due to their easy availability the compounds prepared ar.e attractive precursors for further synthesis of polycondensed heterocycles.

Full text of DOI:10.1055/s-2001-18719

PAPER
2419
Enaminones Acylation: Competitive Formation of Quinolin-4-one and
Isoquinolin-1-one Derivatives
A
cylation of Enaminon
a
es gali Valès, Vladimir Lokshin, Gérard Pèpe, André Samat,* Robert Guglielmetti
Université de la Méditerranée, Faculté des Sciences de Luminy, UMR 6114 CNRS Case 901, 13288 Marseille Cedex 9, France
Fax +33(4)91829301; E-mail: samat@luminy.univ-mrs.fr
Received 27 July 2001; revised 27 September 2001
nones 5 was investigated using experimental conditions
described in reference5 which are very close to those pre-
viously reported by Grohe et al.3,4 By refluxing the enam-
inone with the acid chloride in the presence of
Abstract: The reaction of enaminones with some o-halogenoben-
zoyl chlorides allows the preparation of 3-acyl-2-alkylquinolin-4-
one and/or 4-acyl-3-alkylisoquinolin-1-one derivatives depending
on the structure of the starting materials. Due to their easy availabil-
ity the compounds prepared are attractive precursors for further syn- triethylamine in toluene for 3 hours followed by the addi-
thesis of polycondensed heterocycles.
tion of excess of DBU and further heating, the products
formed are separated and purified by column chromatog-
raphy. Under these conditions, besides the expected 3-
acyl-2-alkylquinolin-4-ones 6 which can be compared to
3 (Scheme 1), the 4-acyl-3-alkylisoquinolin-1-ones 7
originating from N-acylation of the enaminones
(Scheme 2, Table 1) have also been isolated in some cases
depending on the molecular structure of the reagents.
Key words: acylation, enaminones, heterocycles, quinolines, iso-
quinolines
The -enaminones (or -keto enamines) defined by
Greenhill1 as monoenamines of 1,3-diketones or 3-keto
esters are an important class of organic synthetic interme-
diates. These highly reactive compounds usually react as
ambident nucleophiles at the nitrogen or (and) C -atom.
Table 1 Products Formed in the Reaction of 4 with 5
Application of enaminones as synthetic intermediates es-
pecially in heterocyclic chemistry is well documented.2
One illustration is the approach to the pharmacologically
important 4-quinolone-3-carboxylic esters elaborated by
Grohe et al.3,4 (Scheme 1).
Entry
1
2
Products, Yield (%)a
6
7
Others
b
1
2
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
4b
4b
4b
4b
5a
5b
5c
5d
5e
5f
–
8 (68)
6ab (10)
6ac (34)
6ad (36)
6ae (37)
6af (41)
6ag (19)
6ah (32)
–
–
–
In this reaction, the first step is a selective C -acylation of
the enamino ester 2 (for instance the acylated product can
be isolated for R1 = H), followed by the nucleophilic sub-
stitution of the halogen atom which is activated by the
presence of electron-withdrawing groups on the aromatic
ring.3,4 Recently this approach has been used to prepare
heterocyclic compounds such as 3 in which R1 = Ar.5
3
–
–
4
–
–
5
–
–
6
–
–
7
5g
5h
5a
5b
5c
5d
5e
5f
–
9 (17)
We decided to extend the field of application of this reac-
tion, using enaminones obtained from 1,3-diketones. Re-
sults of our study are reported in this paper.
8
–
–
–
–
–
–
–
–
–
–
9
7ba (71)
7bb (68)
7bc (70)
The reaction of 2,4,5-trifluorobenzoyl chloride (4a) or 2-
chloro-5-nitrobenzoyl chloride (4b) with a set of enami-
10
11
12
13
14
15
16
–
–
O
O
O
6bd (26) 7bd (52)
6be (23) 7be (54)
6bf (40) 7bf (14)
COCl
1. NEt3, ∆
OEt
OEt
+
R
R
2. DBU, ∆
Cl (F) HN
R2
R1
N
R2
R1
-2HCl
1
3
2
5g
5h
–
–
7bg (51)
7bh (32)
R1= H, CH3
R2= Alk, Ar, N(CH3)2
R= NO2, F, Cl
a Yield for isolated products.
b Not observed.
Scheme 1
Synthesis 2001, No. 16, 30 11 2001. Article Identifier:
1437-210X,E;2001,0,16,2419,2426,ftx,en;Z08801SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

2420
M. Valès et al.
PAPER
Scheme 2
The molecular structure of compounds 6 and 7 have been
confirmed by 1H and 13C NMR spectroscopy and elemen-
tal analyses (Table 2). Although compounds 6 and 7 have
similar 1H NMR spectra, these two structures can be eas-
ily differentiated on the basis of the 13C NMR chemical
shift of the endocyclic carbonyl group ( = 173.5–175.5
and 161.0–163.3 for 6 and 7, respectively). For one com-
pound of each kind (6bd and 7bc), the molecular structure
has been confirmed by X-ray cristallography (Figures 1
and 2).
In two cases, compounds having a molecular structure dif-
ferent from that of 6 and 7 have been identified. Especial-
ly, the reaction of the acid chloride 4a with the enaminone
5a (Table 1, entry 1) leads to N-acylation of the enamino-
ne, the resulting compound 8 being not able to cyclize to
7aa under the conditions used. This cyclization can be
achieved subsequently with sodium hydride in THF as
solvent (Scheme 3).
Figure1 Molecular structure of compound 6bd
Several remarks can be made about the influence of the
structure of starting reagents on the course of the reaction.
First, the significant influence of the nature of the acid
chloride can be highlighted. For instance, while com-
During the reaction of the same acid chloride 4a, but with
the N,N-dimethylhydrazino derivative of the benzoylace-
tone 5g (Table 1, entry 7), another byproduct has been iso-
1
lated besides the expected quinolone 6ag. H and 13C
NMR data as well as crystallographic analysis (Figure 3)
allowed to identify this compound as the N,N-dimethylhy-
drazine of 3-acetyl-6,7-difluoroflavone 9.
The existence of a tautomeric equilibrium from the C-acy-
lated intermediate A (Scheme 4) can explain the forma-
tion of 9.
Indeed, according to numerous studies devoted to the tau-
tomerism of nitrogenated derivatives of 1,3-diketones,
changing the amino fragment of an enaminone to a N,N-
dimethylhydrazine one, favors unambiguously such an
equilibrium.6,7
The data gathered in Table 1 show moderate yields of 6
and 7. This result is certainly due to the weak reactivity of
enaminones rather than the formation of byproducts. In-
deed variable amounts of starting enaminones have often
been isolated during liquid chromatography purification.
This behavior has been reported by Cecchetti et al.5
Figure 2 Molecular structure of compound 7bc
Synthesis 2001, No. 16, 2419–2426 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Acylation of Enaminones
2421
O
CH3
CH3
O
CH3
CH3
3'
6'
F
F
4'
5'
F
F
2' F
1'
NaH
THF
-HF
4a
+
5a
N
N
Pr
Pr
O
O
8
7aa (52%)
Scheme 3
N(CH3)2
CH3
O
O
N
O
F
F
F
F
Ph
CH3
4a
+
5g
F
HN
F
HO
Ph
N(CH3)2
C
A
-HF
-HF
N(CH3)2
CH3
O
O
O
O
N
F
F
Ph
F
N
CH3
F
Ph
N(CH3)2
6ag
9
Scheme 4
entries 9–16). It clearly appears that the nucleophilic char-
acter of the -carbon atom is weaker for enamino ketones
than for enamino esters. This phenomenon, previously ob-
served, is explained by the decrease of the negative charge
on this carbon atom due to a higher electron-withdrawing
effect of the ketonic carbonyl compared to the carbonyl
group of the ester.8,9
Finally, the effect of the nature of the amino fragment of
enamino ketones has to be taken into account. For in-
stance, the reactivity of the nitrogen atom of compounds
(5b, 5d, 5f), including a N-Ph group is weaker than the re-
activity of the same atom in molecules bearing a N-Pr
group. This lower reactivity allows the C -acylation fol-
lowed by cyclization to quinolones, even for acid chloride
4b which favors generally the N-acylation reaction and
the formation of isoquinolones (Table 1, entries 12,14).
Figure 3 Molecular structure of compound 9
In this context, the very low yield observed for the forma-
tion of compound 6ab (C - and N-positions on the corre-
sponding enaminone 5b are unactivated) and the
formation of compound 8 (the C -position of the enami-
none 5a is unactivated but not the N-position) can be eas-
ily explained.
pound 4a leads exclusively to quinolones 6, acid chloride
4b favors unambiguously the formation of 7. One can
make the assumption that, when 4a is used, even if the N-
acylation reaction is possible (see example of compound
8), the nucleophilic character of the C -atom of the enam-
inone is not sufficient enough to promote (in the chosen
experimental conditions) the substitution of the fluorine
atom, itself weakly activated compared to the chlorine
atom in the case of compound 4b.
Thus the described method allows the preparation of two
different families of functionalized heterocycles depend-
ing on the structure of the starting reagents. Despite the
moderate yield, the simplicity of this method and the easy
accessibility of the precursors make this reaction highly
attractive, especially in the frame of polycondensed het-
erocyclic systems.
Secondly, the structure of the enaminone plays also an im-
portant role. Indeed, using the same acid chloride 4b,
changing amino esters 2 (Scheme 1) by enamino ketones,
modifies completely the direction of the reaction (Table 1,
Synthesis 2001, No. 16, 2419–2426 ISSN 0039-7881 © Thieme Stuttgart · New York

2422
M. Valès et al.
PAPER
Table 2 Physical and Spectroscopic Data of Compounds 6 and 7a
Product
Mp (°C) Rfb
132–133 0.1
1H NMR (CDCl3/TMS)
, J (Hz)
13C NMR (CDCl3/TMS)
, J (Hz)
6ab
2.12 (s, 3 H, CH3), 2.66 (s, 3 H, COCH3), 6,45 19.8 (CH3), 32.4 (COCH3), 107.0 (d, 2JCF = 39.4, C-8),
(dd, 1 H, J = 11.7, 6.5, H-8), 7.33 (m, 2 H,
113.8 (d, 2JCF =18.4, C-5), 123.1 (d, 3JCF = 3.5, C-4a),
NC6H5), 7.70 (m, 3 H, NC6H5), 8.13 (dd, 1 H, 123.7 (C-3), 128.8 (CH), 130.7 (CH), 131.3 (CH), 138.6
J = 9.0, 9.1)
(CN), 139.2 (d, 3JCF = 9.1, C-8a), 148.0 (q, 1JCF = 252.3,
2JCF = 11.3, C-6), 151.6 (C-2), 153.0 (q, 1JCF = 255.0,
2JCF = 15.2, C-7), 174.2 (CO), 203.7(COCH3)
6ac
6ad
6ae
162–163 0.26
163–164 0.3
149–150 0.53
0.93 (t, 3 H, J = 7.2, CH2CH2CH3), 1.67 (m, 2 10.9 (CH2CH2CH3), 18.4 (CH3), 21.9 (CH2CH2CH3),
H, CH2CH2CH3), 2.24 (s, 3 H, CH3), 3.94(t, 2 49.1 (CH2CH2CH3), 105.4 (d, 2JCF = 22.9, C-8), 113.8
H, J = 8.0, CH2CH2CH3), 7.21–7.30 (m, 3 H, (d, 2JCF = 17.9, C-5), 122.5 (C-3), 123.7 (d, 3JCF = 6.3,
H-8 and H of COC6H5), 7.37 (m, 1 H, H of
C-4a), 128.7 (CH), 129.3 (CH), 133.6 (CH), 137.4 (C),
COC6H5), 7.74 (m, 2 H , H of COC6H5), 7.89 137.6 (d, 3JCF = 8.3, C-8a), 147.6 (q, 1JCF = 248.0, 2JCF
=
(dd, 1 H, J = 9.3, 9.2, H-5)
13.5, C-6), 149.6 (C-2), 153.5 (q, 1JCF = 252.8, 2JCF
14.7, C-7), 173.6 (CO), 196.8 (COPh)
=
2.01 (s, 3 H, CH3), 6.53 (dd, 1 H, J = 13.8, 6.5, 19.6 (CH3), 107.0 (d, 2JCF = 22.9, C-8), 113.7 (d, 2JCF
H-8), 7.31 (m, 2 H, NC6H5), 7.44 (m, 2 H,
17.9, C-5), 122.2 (C-3), 122.8 (d, 3JCF = 3.8, C-4a),
=
COC6H5), 7.56 (m, 1 H, COC6H5), 7.69 (m, 3 128.7 (CH), 128.8 (CH), 129.5 (CH), 130.6 (CH), 131.2
H, NC6H5), 7.96 (m, 2 H, COC6H5), 8.11 (dd, (CH), 133.6 (CH), 137.5 (NC), 138.2 (C), 139.5 (d, 3JCF
1 H, J = 10.1, 10.0, H-5)
= 9.4, C-8a), 147.9 (q, 1JCF = 252.7, 2JCF = 16.0, C-6),
150.2 (C-2), 153.2 (q, 1JCF = 254.3, 2JCF = 15.7, C-7),
174.1 (CO), 196.4 (COPh)
0.90 (t, 3 H, J = 7.4, CH2CH2CH3), 1.58 (m, 2 10.8 (CH2CH2CH3), 21.8 (CH2CH2CH3), 37.5 (CH2),
H, CH2CH2CH3), 3.95 (t, 2 H, J = 7.8,
CH2CH2CH3), 4.05 (s, 2 H, CH2), 7.25–7.34
(m, 6 H, H-8 and CH2C6H5), 7.39 (m, 2 H,
49.2 (CH2CH2CH3), 105.1 (d, 2JCF = 23.8, C-8), 114.4
(d, 2JCF = 16.6, C-5), 124.0 (d, 3JCF = 4.9, C-4a), 127.4
(CH), 128.1 (CH), 128.3 (C-3), 128.6 (CH), 129.1 (CH),
COC6H5), 7.51 (m, 1 H, COC6H5), 7.90 (m, 2 129.4 (CH), 133.5 (CH), 135.4 (C), 137.3 (C), 137.8 (d,
H, COC6H5), 8.20 (dd, 1H, J = 9.4, 9.3, H-5) 3JCF = 9.3, C-8a), 147.9 (q, 1JCF = 250.5, 2JCF= 13.0, C-
6), 150.4 (C-2), 153.9 (q, 1JCF= 254.0, 2JCF = 14.5, C-7),
174.2 (CO), 196.2 (COPh)
6af
171–172 0.45
3.79 (s, 2 H, CH2), 6.42 (dd, 1 H, J = 12.0, 6.4, 37.7 (CH2), 106.8 (d, 2JCF = 22.2, C-8), 113.7 (d, 2JCF
H-8), 6.74 (m, 2 H, NC6H5), 6.93 (m, 2 H,
18.5, C-5), 122.8 (d, 3JCF = 4.5, C-4a), 123.6 (C-3),
=
CH2C6H5), 7.05 (m, 3 H, CH2C6H5), 7.37–7.45 126.8 (CH), 128.3 (CH), 128.4 (CH), 128.5 (CH), 129.2
(m, 5 H, NC6H5 and COC6H5), 7.54 (m, 1 H, (CH), 129.5 (CH), 130.1 (CH), 133.4 (CH), 135.7 (C),
COC6H5), 7.96 (m, 2 H, COC6H5),8.19 (dd, 1 137.39 (NC), 137.45 (C), 139.8 (d, 3JCF =9.5, C-8),
H, J = 8.9, 8.8, H-5)
148.1 (q, 1JCF = 250.5, 2JCF = 13.6, C-6), 151.5 (C-2),
153.2 (q, 1JCF = 255.2, 2JCF = 15.6, C-7), 174.6 (CO),
195.8 (COPh)
6ag
6ah
188
0.29
2.27 (s, 3 H, CH3), 3.01 [s, 6 H, N(CH3)2], 7.29 17.1 (CH3), 43.5 [N(CH3)2], 105.5 (d, 2JCF = 23.2, C-8),
(m, 2 H, COC6H5), 7.42 (m, 2 H, H-8 and
114.6 (d, 2JCF = 20.2, C-5), 122.2 (C-3), 123.8 (d, 3JCF
=
COC6H5), 7.79 (m, 2 H, COC6H5), 7.97 (dd, 1 4.1, C-4a), 128.9 (CH), 129.5 (CH), 133.7 (CH), 137.4
H, J = 9.3, 9.2, H-5)
(C), 138.5 (d, 3JCF = 8.7, C-8a), 148.2 (q, 1JCF =246.3,
2JCF = 13.2, C-6), 153.7 (q, 1JCF = 258.6, 2JCF = 16.2, C-
7), 153.8 (C-2), 173.5 (CO), 196.2 (COPh)
161–162 0.33
2.63 [s, 6 H, N(CH3)2], 3.80 (s, 2 H, CH2), 7.06 41.4 (CH2), 43.3 [N(CH3)2], 104.5 (d, 2JCF = 23.0, C-8),
(m, 6 H, H-8 and CH2C6H5), 7.22 (m, 2 H,
115.7 (d, 2JCF = 23.9, C-5), 124.1 (d, 3JCF = 4.7, C-4a),
COC6H5), 7.34 (m, 1 H, COC6H5), 7.69 (m, 2 125.1 (C-3), 127.7 (CH), 128.1 (CH), 128.6 (CH),129.0
H, COC6H5), 8.00 (dd, 1H, J = 9.2, 9.1, H-5) (CH), 130.6 (CH), 133.7 (CH), 135.9 (C), 136.6 (C),
137.3 (d, 3JCF = 8.9, C-8a), 147.6 (q, 1JCF = 214.0, 2JCF
=
12.1, C-6), 151.6 (C-2), 153.0 (q, 1JCF = 254.4, 2JCF
13.7, C-7), 174.6 (CO), 194.1 (COPh)
=
6bd
217–218 0.13
1.93 (s, 3 H, CH3), 6.75 (d, 1 H, J = 9.4, H-8), 19.1 (CH3), 119.6 (C-8), 122.8 (C-7), 123.8 (C-4a),
7.28–7.43 (m, 4 H, NC6H5 and COC6H5), 7.45 125.2 (C-3), 126.2 (C-5), 128.7 (CH), 128.9 (CH), 129.5
(m, 1 H, COC6H5), 7.57 (m, 3 H, NC6H5), 7.84 (CH), 130.8 (CH), 131.3 (CH), 133.9 (CH), 137.1 (C),
(m, 2 H, COC6H5), 8.06 (dd, 1 H, J = 9.4, 2.7, 137.9 (C), 143.5 (C-6), 145.7 (C-8a), 150.8 (C-2), 174.7
H-7), 9.06 (d, 1 H, J = 2.7, H-5)
(CO), 195.7 (COPh)
Synthesis 2001, No. 16, 2419–2426 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Acylation of Enaminones
2423
Table 2 Physical and Spectroscopic Data of Compounds 6 and 7a (continued)
Product
Mp (°C) Rfb
1H NMR (CDCl3/TMS)
, J (Hz)
13C NMR (CDCl3/TMS)
, J (Hz)
6be
141–142 0.4
0.80 (t, 3 H, J = 7.3, CH2CH2CH3), 1.46 (m, 2 11.0 (CH2CH2CH3), 22.2 (CH2CH2CH3), 37.9 (CH2),
H, CH2CH2CH3), 4.02 (m, 4 H, CH2CH2CH3 49.5 (CH2CH2CH3), 118.2 (C-8), 123.6 (C-4a), 125.9
and CH2), 7.17 (m, 5 H, CH2C6H5), 7.25 (m, 2 (C-3), 126.6 (C-7), 126.9 (C-5), 127.8 (CH), 128.4
H, COC6H5), 7.41 (m, 1H, COC6H5), 7.55 (d, (CH), 128.9 (CH), 129.5 (CH), 129.7 (CH), 134.0 (CH),
1 H, J = 9.5, H-8), 7.78 (m, 2H, COC6H5), 8.29 135.2 (C), 137.1 (C), 143.6 (C-6), 144.5 (C-8a), 151.3
(dd, 1 H, J = 9.4, 2.7, H-7), 9.10 (d, 1 H, J =
(C-2), 175.4 (CO), 195.8 (COPh)
2.7, H-5)
6bf
208–209 0.29
101–102 0.28
196–197 0.26
3.82 (s, 2 H, CH2), 6.75 (m, 3 H, H-8 and
NC6H5), 6.95 (m, 2 H, CH2C6H5), 7.06 (m, 3 126.5 (C-7), 127.2 (C-5), 128.7 (CH), 128.9 (CH), 129.4
H, CH2C6H5), 7.42 (m, 4 H, NC6H5 and (CH), 129.7 (CH), 130.5 (CH), 134.0 (CH), 135.5 (C),
COC6H5), 7.53 (m, 2 H, COC6H5), 7.99 (m, 2 137.2 (NC), 137.3 (C), 143.6 (C-6), 146.2 (C-8a), 152.4
H, COC6H5), 8.16 (m, 1 H, H-7), 9.22 (m, 1 H, (C-2), 175.5 (CO), 195.5 (COPh)
38.1 (CH2), 119.8 (C-8), 123.1 (C-4a), 125.5 (C-3),
H-5)
7ba
1.05 (t, 3 H, J = 7.4, CH2CH2CH3), 1.78 (m, 2 11.4 (CH2CH2CH3), 17.9 (CH3), 21.9 (CH2CH2CH3),
H, CH2CH2CH3), 2.49 (s, 3 H, CH3), 2.65 (s, 3 33.2 (COCH3), 46.3 (CH2CH2CH3), 118.8 (C-4), 124.0
H, COCH3), 4.10 (t, 2 H, J = 7.7,
CH2CH2CH3), 7.40 (d, 1 H,J = 9.0, H-5), 8.33 4a), 140.9 (C-7), 145.4 (C-3), 161.0 (CO), 203.3
(dd, 1 H, J = 9.0, 2.2, H-6), 9.10 (d, 1 H, J =
(C-8a), 124.2 (C-8), 124.6 (C-6), 126.4 (C-5), 137.4 (C-
(COCH3)
2.1, H-8)
7bb
7bc
2.04 (s, 3 H, CH3), 2.65 (s, 3 H, COCH3), 7.27 19.5 (CH3), 33.1 (COCH3), 118.6 (C-4), 124.5 (C-8),
(m, 2 H, NC6H5), 7.43–7.60 (m, 4 H, H-5 and 124.6 (C-8a), 124.7 (C-6), 126.9 (C-5), 128.1 (CH),
NC6H5), 8.38 (dd, 1 H, J = 8.9, 2.4, H-6), 9.09 129.4 (CH), 130.1 (CH), 137.6 (C), 138.0 (C-4a),141.5
(d, 1 H, J = 2.4, H-8)
(C-7), 145.6 (C-3), 161.4 (CO), 202.9 (COCH3)
157
0.33
1.08 (t, 3 H, J = 7.3, CH2CH2CH3), 1.80 (m, 2 11.4 (CH2CH2CH3), 18.6 (CH3), 22.0 (CH2CH2CH3),
H, CH2CH2CH3), 2.36 (s, 3 H, CH3), 4.14 (t, 2 46.3 (CH2CH2CH3), 115.7 (C4), 124.1 (C-8a), 124.7 (C-
H, J = 7.3, CH2CH2CH3), 7.28 (d, 1 H, J = 9.0, 8), 125.2 (C-6), 126.4 (C-5), 129.3 (CH), 129.8 (CH),
H-5), 7.51 (m, 2 H, COC6H5), 7.67 (1 H, m,
134.7 (CH), 137.2 (C), 138.8 (C-4a), 142.2 (C-7), 145.6
COC6H5), 7.91 (m, 2 H, COC6H5), 8.23 (dd, 1 (C-3), 161.3 (CO), 195.9 (COPh)
H, J = 9.0, 2.3, H-6), 9.24 (d, 1 H, J = 2.3, H-8)
7bd
7be
120–121 0.3
125–126 0.63
1.92 (s, 3 H, CH3), 7.2 (m, 2 H, NC6H5), 7.32 20.0 (CH3), 115.5 (C-4), 124.6 (C-8a), 124.7 (C-8),
(d, 1 H, J = 9.0, H-5), 7.49–7.58 (m, 5 H,
125.3 (C-6), 126.8 (C-5), 128.1 (CH), 129.3 (CH), 129.4
NC6H5 and COC6H5), 7.67 (m, 1 H, COC6H5), (CH), 129.7 (CH), 130.1 (CH), 134.7 (CH), 137.0 (C),
7.96 (m, 2 H, COC6H5), 8.29 (dd, 1 H, J = 9.0, 137.5 (C), 139.4 (C-4a), 142.7 (C-7), 145.7 (C-3), 161.6
2.4, H-6), 9.21 (d, 1 H, J = 2.4, H-8)
(CO), 195.5 (COPh)
0.76 (t, 3 H, J = 7.2, CH2CH2CH3), 1.43 (m, 2 11.4 (CH2CH2CH3), 22.0 (CH2CH2CH3), 37.5 (CH2),
H, CH2CH2CH3), 3.85 (m, 4-H, CH2CH2CH3 46.8 (CH2CH2CH3), 117.6 (C-4), 124.7 (C-8), 125.7 (C-
and CH2), 7.08 (m, 5 H, CH2C6H5), 7.16 (d, 1 6), 126.5 (C-5), 127.5 (C-8a), 128.1 (CH), 129.2 (CH),
H, J = 8.9, H-5), 7.29 (m, 2 H, COC6H5), 7.45 129.3 (CH), 129.9 (CH), 134.8 (CH), 135.8 (C), 137.1
(m, 1 H, COC6H5), 7.75 (m, 2 H, COC6H5),
(C), 138.9 (C-4a), 143.6 (C-7), 145.9 (C-3), 161.7 (CO),
8.08 (dd, 1 H, J = 8.9, 2.4, H-6), 9.10 (d, 1 H, 195.7 (COPh)
J = 2.3, H-8)
7bf
144–146 0.69
3.52 (s, 2 H, CH2), 6.49 (m, 2 H, NC6H5), 6.72 38.7 (CH2), 118.0 (C-4), 125.6 (C-8), 125.9 (C-6), 126.7
(m, 2 H, CH2C6H5), 6.87 (m, 3 H, CH2C6H5), (C-5), 127.7 (C-8a), 127.8 (CH), 129.0 (CH), 129.1
7.12 (m, 3 H, NC6H5), 7.21 (d, 1 H, J = 9.0, H- (CH), 129.6 (CH), 129.8 (CH), 130.0 (CH), 130.1 (CH),
5), 7.31 (m, 2 H, COC6H5), 7.47 (m, 1 H,
130.7 (CH), 135.6 (CH), 136.2 (C), 137.7 (C), 137.9
COC6H5), 7.75 (m, 2 H, COC6H5), 8.13 (dd, 1 (C), 140.2 (C-4a), 145.1 (C-7), 146.9 (C-3), 162.8(CO),
H, J = 9.0, 2.7, H-6), 9.05 (d, 1 H, J = 2.4, H-8) 196.1 (COPh)
7bg
163–164 0.45
2.31 (s, 3 H, CH3), 3.12 [s, 6 H, N(CH3)2], 7.33 18.3 (CH3), 42.9 [N(CH3)2], 115.2 (C-4), 124.1 (C-8),
(d, 1H, J = 9.0, H-5), 7.52 (m, 2 H, COC6H5), 125.8 (C-6), 126.7 (C-8a), 126.8 (C-5), 129.8 (CH),
7.69 (m, 1 H, COC6H5), 7.99 (m, 2 H,
COC6H5), 8.30 (dd, 1 H, J = 8.9, 2.4, H 6),
9.07 (d 1 H, J = 2.2, H-8)
130.3 (CH), 134.9 (CH), 138.1 (C), 139.6 (C-4a), 145.8
(C-7), 147.3 (C-3), 161.4 (CO), 195.4 (COPh)
Synthesis 2001, No. 16, 2419–2426 ISSN 0039-7881 © Thieme Stuttgart · New York

2424
M. Valès et al.
PAPER
Table 2 Physical and Spectroscopic Data of Compounds 6 and 7a (continued)
Product
Mp (°C) Rfb
161–162 0.63
1H NMR (CDCl3/TMS)
, J (Hz)
13C NMR (CDCl3/TMS)
, J (Hz)
7bh
2.70 [s, 6 H, N(CH3)2], 3.92 (s, 2 H, CH2), 7.24 37.4 (CH2), 42.9 [N(CH3)2], 116.8 (C-4), 124.2 (C-8),
(m, 5 H, CH2C6H5), 7.32 (d, 1 H, J = 8.9, H 5), 125.7 (C-6), 126.4 (C-8a), 126.5 (C-5), 128.4 (CH),
7.50 (m, 2 H, COC6H5), 7.65 (m, 1 H,
128.6 (CH), 129.2 (CH), 129.9 (CH), 134.7 (CH), 137.1
COC6H5), 7.95 (m, 2 H, COC6H5), 8.25 (dd, 1 (C), 137.8 (C), 138.8 (C-4a), 145.6 (C-7), 147.8 (C-3),
H, J = 8.9, 2.3, H-7), 9.19 (d, 1 H, J = 2.1, H-8) 161.4 (CO), 195.1 (COPh)
7aa
104–105 0.33
0.90 (t, 3 H, J = 7.8, CH2CH2CH3), 1.61 (m, 2 11.2 (CH2CH2CH3), 17.5 (CH3), 22.0 (CH2CH2CH3),
H, CH2CH2CH3), 2.32 (s, 3 H, CH3), 2.58 (s, 3 32.9 (COCH3), 45.9 (CH2CH2CH3), 110.7 (d, 2JCF
=
H, COCH3), 3.92 (m, 2 H, CH2CH2CH3), 6.97 19.3, C-5), 116.1 (d, 2JCF = 18.4, C-8), 118.3 (C-4),
(dd, 1 H, J = 11.5, 6.7, H-5), 7.97 (dd, 1 H, J = 121.4 (d, 3JCF = 4.7, C-8a), 137.3 (d, 3JCF = 2.3, C-4a),
9.2, 9.1, H-8)
149.2 (q, 1JCF = 250.7, 2JCF = 14.2, C-7), 153.6 (q, 149.2
(q, 1JCF = 250.7, 2JCF = 14.2, C-7), 153.6 (q, 1JCF = 245.7,
2JCF = 15.0, C-6), 160.5 (C-3), 163.3 (CO), 203.3
(COCH3)
a Satisfactory microanalyses obtained: C 0.12; H 0.11; N 0.08.
b TLC was carried out on Merck 60F254 silica gel sheets, eluent: cyclohexane–EtOAc (8:2).
Acid chlorides 4a (Aldrich), 4b (Lancaster) and tert-butoxy-
Indeed, the ortho-position of alkyl groups and ketonic
groups in compounds 6 and 7 opens the way to various cy-
clization reactions. Two examples of this kind of transfor-
mations (based on known methods10,11) are given on
Schemes 5 and 6.
bis(dimethylamino)methane (Bredereck’s reagent) (Aldrich) are
commercially available. Enaminones 5 were prepared from corre-
sponding 1,3-diketones and primary amines according to a standard
procedure.12 Compounds 5a,13 5b,14 5c,15 5d,12 5f,16 and 5g17 were
previously described.
1,4-Diphenyl-3-propylaminobut-2-en-1-one (5e)
O
Ph
O
O
Yellow oil; yield: 90%.
F
F
F
F
BBr3, CH2Cl2
-H2O
Ph
CH2Ph
1H NMR: = 0.90 (t, 3 H, J = 7.4 Hz, CH2CH2CH3), 1.61 (m, 2 H,
CH2CH2CH3), 3.12 (m, 2 H, CH2CH2CH3), 3.69 (s, 2 H, CH2), 5.69
(s, 1 H, CH), 7.09–7.34 (m, 5 H, CH2C6H5), 7.41 (m, 3 H, COC6H5),
7.84 (m, 2 H, COC6H5), 11.49 (s, 1 H, NH).
N
N
Pr
Pr
10 (90%)
6ae
3-(2,2-Dimethylhydrazino)-1,4-diphenylbut-2-en-1-one (5h)
Yield: 82%; yellow solid; mp 68–69 °C.
Scheme 5
1H NMR: = 2.51 [s, 6 H, N(CH3)2], 3.82 (s, 2 H, CH2), 5.64 (s, 1
H, CH), 7.21–7.35 (m, 5 H, CH2C6H5), 7.43 (m, 3 H, COC6H5), 7.82
(m, 2 H, COC6H5), 11.63 (s, 1 H, NH).
O
Ph
Ph
N
N
CH3
Ph
1. Me3C-O-CH(NMe2)2
2. NH4OAc
3-Acyl-2-alkylquinolin-4-ones (6) and 4-Acyl-3-
alkylisoquinolin-1-ones (7); General Procedure
N
O2N
O2N
Ph
O
O
A solution of the acid chloride 4 (5 mmol) in anhyd toluene (8 mL)
was added to a mixture of enaminone 5 (3.2 mmol) and anhyd Et3N
(10 mmol) in anhyd toluene (7 mL). The resulting mixture was re-
fluxed for 3 h, then DBU (10 mmol) was added and refluxing was
maintained for 3 h more. The solvent was evaporated to dryness and
the residue was dissolved in CH2Cl2 (25 mL). The organic phase
was washed with aq sat. NH4Cl solution and then with brine, dried
(MgSO4) and concentrated in vacuo. The crude product was puri-
fied by column chromatography (silica gel, cyclohexane–EtOAc,
8:2) to afford compounds 6 or (and) 7 (Table 2).
7bd
11 (45%)
Scheme 6
More details concerning different cyclization reactions of
compouds 6 and 7 will be communicated in the near fu-
ture.
All reactions were conducted under argon with magnetic stirring.
All solvents (Carlo Erba Company, France) for the reactions were
purified before use and were dried, if necessary. THF was distilled
under N2 from sodium benzophenone ketyl and used immediately.
Column liquid chromatography were carried out on Merck silica gel
60 (70–230 mesh). Melting points were determined on a Büchi 510
apparatus in open glass capillaries and are uncorrected. The 1H and
13C NMR spectra were recorded on a Bruker AC 250 spectrometer
(250 MHz and 62.5 MHz, respectively) in CDCl3 as solvent with
tetramethylsilane as the internal standard. Chemical shifts ( ) are re-
ported in ppm and coupling constants (J) are in Hz. Elemental anal-
yses were performed using a Perkin-Elmer EA 240 instrument.
4-[N-Propyl-N-(2,4,5-trifluorobenzoyl)amino]pent-3-en-2-one
(8)
Compound 8 was prepared from 4a and 5a using the above general
procedure.
Yellow oil; yield: 68% (650 mg); Rf 0.5 (cyclohexane–EtOAc, 8:2).
1H NMR: = 1.02 (t, 3 H, J = 6.6 Hz, CH2CH2CH3), 1.61 (m, 2 H,
CH2CH2CH3), 2.02 (s, 3 H, CH3), 2.34 (s, 3 H, COCH3), 3.76 (t, 2
H, J = 7.5 Hz, CH2CH2CH3), 5.72 (s, 1 H, H-3), 6.89 (m, 1 H, H-3’),
7.4 (m, 1 H, H-6’).
Synthesis 2001, No. 16, 2419–2426 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Acylation of Enaminones
2425
13C NMR: = 11.4 (CH2CH2CH3), 18.4 (CH3), 21.5 (CH2CH2CH3),
the solution was poured into H2O (5 mL). The red precipitate was
filtered, washed with H2O and dried (170 mg, 39%). This product
was added without purification to a stirred solution of NH4Ac (154
mg, 2 mmol) in DMF (5 mL). The mixture was heated at 95–100 °C
for 5 h. The resulting solution was allowed to cool to r.t. and then
poured into H2O (5 mL). The precipitate formed was filtered,
washed with H2O, and dried to provide 11 (170 mg, 45%); white
solid; mp 244–246 °C.
2
32.0 (COCH3), 47.9 (CH2CH2CH3), 106.2 (d, JCF = 20.0,
2
3
2JCF = 20.0 Hz, C-3’), 118.0 (ddd, JCF = 20.0, JCF1 = 3JCF2 = 4.5
1
2
Hz, C-6’), 120.2 (d, JCF = 257.0 Hz, C-2), 121.6 (dd, JCF = 20.0,
3JCF = 2.7 Hz, C-1’), 124.5 (C-3), 151.4 (dd, JCF = 264.1,
1
2JCF = 24.5 Hz, C-4’), 153.6 (dd, JCF = 242.6, JCF = 23.9 Hz, C-
1
2
5’), 152.5 (C-4), 163.5 (C=O), 197.1 (COCH3).
(6,7-Difluoro-4-oxo-2-phenyl-[4H-1]benzopyran-3-yl)methyl
Ketone Dimethylhydrazone (9)
Compound 9 was prepared from 4a and 5g using the above general
procedure.
1H NMR: = 6.32 (d, 1 H, J = 5.7 Hz, H-4), 7.17 (d, 1 H, J = 8.4
Hz, H-10), 7.37 (m, 5 H, C6H5), 7.41–7.51 (m, 5 H, NC6H5), 7.89
(dd, 1 H, J = 9.0, 2.4 Hz, H 9), 8.26 (d, 1 H, J = 6.0 Hz, H-3), 9.06
(d, 1 H, J = 2.7 Hz, H-7).
Yield: 17% (174 mg); white solid; mp 156–157 °C; Rf 0.25 (cyclo-
hexane–EtOAc, 8:2).
1H NMR: = 2.09 (s, 3 H, CH3), 2.19 [s, 6 H, N(CH3)2], 7.21 (dd, 1
H, J = 9.8, 6.2 Hz, H-8), 7.31 (m, 3 H, C6H5), 7.52 (m, 2 H, C6H5),
7.83 (dd, 1 H, J = 9.6, 9.5 Hz, H-5).
13C NMR: = 110.6 (C-4), 113.1 (C-1a), 125.1 (C-7), 126.2 (C-9),
128.6 (C-6a), 129.4 (CH), 129.6 (CH), 129.7 (C-10), 130.3 (CH),
130.4 (CH), 130.5 (CH), 131.4 (CH), 137.4 (C), 139.1 (C), 142.5
(C-10a), 147.5 (C-4a), 147.7 (C-8), 149.4 (C-3), 160.3 (CO), 161.1
(C-1).
13C NMR: = 19.4 (CH3), 46.5 [N(CH3)2], 107.1 (d, 2JCF = 21.2 Hz,
C-8), 113.0 (d, 2JCF = 21.2 Hz, C-5), 120.6 (d, 3JCF = 4.8 Hz, C-4a),
122.5 (C-3), 128.4 (CH), 128.8 (CH), 131.0 (CH), 148.6 (dd,
Crystallographic Data for Compounds 6bd, 7bc and 918,
Crystals suitable for X-ray analysis were obtained by recrystalliza-
tion from MeOH. For all compounds the probability of the thermal
ellipsoids is 50%.
2
3
1JCF = 250.7, JCF = 13.4 Hz, C-6), 152.2 (d, JCF = 9.8 Hz, C-8a),
1
2
154.0 (dd, JCF = 258.6, JCF = 15.5 Hz, C-7), 160.2 (C-2), 163.1
(C=N), 175.7 (C=O).
Data for 6bd: C23H16N2O4 (384.4). Crystal size 0.4 0.2 0.2 mm;
monoclinic, space group P21/n: a = 12.812(2), b = 8.464(2),
4-Acetyl-6,7-difluoro-3-methyl-2-propyl-2H-isoquinolin-1-one
(7aa)
c = 17.229(3) Å;
= 90.83(2)°; V = 1868.1(6) Å3; Z = 4;
Dc = 1.367 Mg m–3; F(000) = 800; T = 293(2) K; = 0°–27.14°,
–16 < h < 16, 0 <k < 13, 0 < l < 22. Reflections collected 4141, in-
dependent reflections 4141, reflections having I > 2 (I) 2039. Full
matrix least-squares refinement led to the final convergence with
R = 0.0490.
To a stirred suspension of NaH (80 mg, 3.3 mmol) in anhyd THF (5
mL) was added slowly a solution of 8 (900 mg, 3 mmol) in anhyd
THF (5 mL). The mixture was refluxed for 4 h and the solvent was
evaporated in vacuo. The resulting oil was dissolved in cold H2O.
The aqueous phase was acidified with 10% HCl to pH 5–6 and ex-
tracted with CH2Cl2 (2 20 mL). The combined organic phases
were washed with H2O (30 mL) and brine, dried (MgSO4) and con-
centrated in vacuo. The crude product was purified by column chro-
matography (silica gel, cyclohexane–EtOAc, 8:2) to afford
compound 7aa (435 mg, 52%) as a white solid.
Data for 7bc: C20H18N2O4 (350.4). Crystal size 0.6 0.3 0.3 mm;
monoclinic, space group P21/n: a = 11.798(2), b = 7.5320(10),
c = 20.092(4) Å;
= 96.29(5)°; V = 1774.7(5) Å3; Z = 4;
Dc = 1.311 Mg m–3; F(000) = 736; T = 293(2) K; = 0°–27.14°,
–15 < h < 14, 0 <k < 9, 0 < l < 25. Reflections collected 3932, inde-
pendent reflections 3932, reflections having I > 2 (I) 1626. Full
matrix least-squares refinement led to the final convergence with
R = 0.0420.
2,3-Difluoro-11-phenyl-5-propyl-5H-benzo[b]acridin-12-one
(10)
Data for 9: C19H16F2N2O2 (342.3). Crystal size 0.5 0.5 0.2 mm;
monoclinic, space group P21/a: a = 12.161(2), b = 8.799(10),
A 1.0 M solution of BBr3 in CH2Cl2 (3 mL, 3 mmol) was added
slowly to a stirred solution of quinolone 6ae (313 mg, 0.75 mmol)
in CH2Cl2 (30 mL) at –78 °C under dry argon. The solution was al-
lowed to warm to r.t., stirred overnight and poured into H2O (30
mL). The organic phase was washed with H2O (30 mL) and brine
(30 mL), dried (MgSO4) and concentrated in vacuo. The crude prod-
uct was purified by column chromatography (silica gel, CH2Cl2) to
afford compound 10 (270 mg, 90%) as a yellow solid; mp 218–
219 °C.
c = 16.126(3) Å;
= 97.94(2)°; V = 1709.0(5) Å3; Z = 4;
Dc = 1.311 Mg m–3; F(000) = 712; T = 293(2) K; = 0°–27.14°,
–15 < h < 15, 0 <k < 11, 0 < l < 20. Reflections collected 3792, in-
dependent reflections 3792, reflections having I > 2 (I) 1584. Full
matrix least-squares refinement led to the final convergence with
R = 0.0417.
1H NMR: = 1.19 (t, 3 H, J = 7.5 Hz, CH3), 2.03 (m, 2 H, CH2),
4.21 (t, 2 H, J = 7.8 Hz, NCH2), 7.01 (dd, 1 H, J = 12.8, 6.1 Hz, H-
4), 7.23 (m, 3 H, H-7,8,9), 7.39–7.52 (m, 5 H, C6H5), 7.79 (s, 1 H,
H-6), 7.91 (m, 1 H, H-10), 8.1 (dd, 1 H, J = 9.5, 9.6 Hz, H-1).
References
(1) Greenhill, J. V. Chem. Soc. Rev. 1977, 6, 277.
(2) (a) Kucklander, U. In The Chemistry of Enamines;
Rappoport, Z., Ed.; Wiley: Chichester, 1994, Chap. 10, 523.
(b) Stille, J. R.; Barta, N. S. Stud. Nat. Prod. Chem. 1996, 18,
315. (c) Lue, P.; Greenhill, J. V. Adv. Heterocycl. Chem.
1997, 67, 207. (d) Granik, V. G.; Makarov, V. A.; Parkanyi,
C. Adv. Heterocycl. Chem. 1999, 72, 283. (e) Katritzky, A.
R.; Fang, Y.; Donkor, A.; Xu, J. Synthesis 2000, 2029; and
references cited therein..
(3) Grohe, K.; Heitzer, H. Liebigs Ann. Chem. 1987, 29.
(4) Grohe, K.; Heitzer, H. Liebigs Ann. Chem. 1987, 871.
(5) Cecchetti, V.; Fravolini, A.; Sabatini, S.; Tabarrini, O.; Xin,
T. Eur. J. Med. Chem. 1998, 33, 899.
13C NMR: = 11.3 (CH2CH2CH3), 19.9 (CH2CH2CH3), 49.1
2
(CH2CH2CH3), 102.7 (d, JCF = 23.0 Hz, C-4), 110.9 (C-6), 116.0
3
(d, 2JCF = 15.5 Hz, C-1), 118.9 (d, JCF = 3.1 Hz, C-1a), 119.0 (C-
11a), 124.7 (C-9), 126.8 (C-7), 127.0 (C-8), 128.0 (CH), 128.2
(CH), 128.5 (CH), 128.6 (C-10), 128.9 (C-10a), 135.8 (C-6a), 139.4
3
(C), 139.7 (d, JCF = 9.7 Hz, C-4a), 141.2 (C-11), 144.2 (C-5a),
1
2
145.3 (dd, JCF = 242.9, JCF = 16.9 Hz, C-2), 154.7 (dd,
1JCF = 263.2, 2JCF = 15.1 Hz, C-3), 177.8 (C-12).
1,5-Diphenyl-8-nitro-5H-benzo[c][1,6]naphthyridin-6-one (11)
To a stirred solution of 7bd (384 mg, 1 mmol) in 1,4-dioxane (5
mL) was added Bredereck’s reagent (191 mg, 1.1 mmol). The re-
sulting mixture was heated under reflux for 5 h. After cooling to r.t.,
(6) Yakimovich, S. L.; Zelenin, K. N. Russ. J. Gen. Chem. 1995,
65, 637.
Synthesis 2001, No. 16, 2419–2426 ISSN 0039-7881 © Thieme Stuttgart · New York

2426
M. Valès et al.
PAPER
(7) Yakimovich, S. L.; Zerova, I. V. J. Org. Chem. USSR 1991,
27, 1427.
(12) Maroni, P.; Cazaux, L.; Tisnes, P.; Zambetti, M. Bull. Soc.
Chim. Fr. 1980, 2, 179.
(8) Zelenin, A. K.; Ershov, B. A.; Zelenin, K. N. Russ. J. Gen.
Chem. 1991, 64, 636.
(13) Dabrowski, J.; Kamienska-Trela, K. J. Am. Chem. Soc.
1976, 98, 2826.
(9) Wang, M. X.; Miao, W. S.; Cheng, Y.; Huang, Z. T.
Tetrahedron 1999, 55, 14611.
(14) Braibante, M. E. F.; Braibante, H. S.; Missio, L.;
Andricopulo, A. Synthesis 1994, 898.
(10) Singh, B.; Bacon, E. R.; Lesher, G. Y.; Robinson, S.;
Pennock, P. O.; Bode, D. C.; Pagani, E. D.; Bentley, R. G.;
Connell, M. J.; Hamel, L. T.; Silver, P. J. J. Med. Chem.
1995, 38, 2546.
(15) Nishio, T.; Omote, Y. Synthesis 1980, 390.
(16) Bol’shedvorskaya, R. L.; Pavlova, G. A.; Gavrilov, L. D.;
Alekseeva, N. V.; Vereshchagin, L. I. Zh. Org. Chem. 1972,
8, 1879; Chem. Abstr. 1973, 78, 15707.
(11) Wrobel, J.; Sredy, J.; Moxham, C.; Dietrich, A.; Li, Z.;
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Tio, C.; Zhang, Z. J. Med. Chem. 1999, 42, 3199.
(17) Turner, J. A.; Jacks, W. S. J. Org. Chem. 1989, 54, 4229.
(18) The crystallographic data have been deposited at the
Cambrige Crystallographic Data Center. The registration
numbers are: 171351(6bd), 171352(7bc), and 171353(9).
Synthesis 2001, No. 16, 2419–2426 ISSN 0039-7881 © Thieme Stuttgart · New York