From dicarbonylallene to 1-aryl-3,6-dimethyl-4-aminoaryl-2-pyridones: a one-pot versatile and uncatalyzed synthesis

Article abstract of DOI:10.1016/j.tet.2007.07.079

Reaction of amines with an allenic precursor leads to new 1-aryl-3,6-dimethyl-4-aminoaryl-2-pyridones in good yields. These syntheses can be performed in two distinct steps, allowing the possibility to introduce different substituents in the positions 1 a

Full text of DOI:10.1016/j.tet.2007.07.079

Tetrahedron 63 (2007) 10511–10520
From dicarbonylallene to 1-aryl-3,6-dimethyl-4-aminoaryl-2-
pyridones: a one-pot versatile and uncatalyzed synthesis
a,c
Thomas Boisse, Beno ˆı t Rigo,
a,c,*
b,c
R ꢀe gis Millet and Jean-Pierre H ꢀe nichart
b,c
a
Laboratoire de Synth eꢁ ses Organiques, Hautes Etudes d’Inge´nieur, 13 rue de Toul, 59046 Lille, France
b
Institut de Chimie Pharmaceutique Albert Lespagnol, Universite´ de Lille 2, 3 rue du Professeur Laguesse, 59006 Lille, France
c
EA 2692 (IFR INSERM 114)
Received 11 April 2007; revised 20 July 2007; accepted 23 July 2007
Available online 31 July 2007
Abstract—Reaction of amines with an allenic precursor leads to new 1-aryl-3,6-dimethyl-4-aminoaryl-2-pyridones in good yields. These
syntheses can be performed in two distinct steps, allowing the possibility to introduce different substituents in the positions 1 and 4. By using
o-aminopyridine, a new pyridopyrimidone is easily obtained.
Ó 2007 Elsevier Ltd. All rights reserved.
1
. Introduction
We have chosen to start our study with 3,6-dimethyl com-
pounds. The strategy is based on the retrosynthetic analysis
described in Figure 2, allene 3 being the precursor of the
The 2-pyridone unit is a key structural feature in a number of
biologically active compounds.
1
–3
28
For instance, it can be
key dicarbonyl intermediate. To the best of our knowledge,
this type of allene has never been involved in 2-pyridone
4
5
found in the toxin ricinine, the psychoactive huperzine A,
or in the lead anticancer alkaloid camptothecin (Fig. 1).
Other pyridones act as HIV-1 reverse transcriptase inhibi-
6
29
synthesis. In the same way as for acetylenic precursors,
the allene group should provide the unsaturation necessary
for aromatization.
7
8
9
10–12
tors, or as herbicides, pesticides, and fungicides.
Ar
HN
Ar
O
O
O
HN
O
O
O
H
N
N
OMe
N
O
N
NH
Ar
N
Ar
1
O
O
N
O
H2N
Huperzine A
2
3
OH O
Ricinine
Figure 1.
Camptothecin
O
O
O
+
O
O
OMe
Cl
5
4
1
3–17
In connection with ongoing projects in these fields,
we
PPh3
Br
became interested in developing a versatile and efficient
route to 1-aryl-3,6-dimethyl-4-aminoaryl-2-pyridones. Re-
cent reviews describe the main strategies of preparation to
OMe
OMe
O
7
O
6
1
8,19
the pyridone ring system.
existing routes for their synthesis, new methods are still
Despite a large number of
Figure 2. Retrosynthetic strategy for the synthesis of substituted 3,6-di-
methylpyridones.
2
0–26
being developed.
A frequently encountered approach
involves condensation of ammonia or amines with an unsat-
urated 1,5-dicarbonyl compound, with one of the carbonyl
groups belonging to a carboxylic acid derivative.
2
7
2. Results and discussion
2.1. Synthesis and reactivity of allene 3
Keywords: 2-Pyridones; Pyridopyrimidone; Allene.
*
Starting point of the synthesis was methyl acetoacetate 5,
whose protection of the ketone function has already been
Corresponding author. Tel.: +33 3 28 38 48 58; fax: +33 3 28 38 48 04;
e-mail: rigo@hei.fr
0
040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.079

10512
T. Boisse et al. / Tetrahedron 63 (2007) 10511–10520
3
0,31
described.
In our hands, ketone protection was accom-
OMe
O
O
OMe
panied by a trans-esterification reaction, giving a mixture
of both esters 8a and 8b. Thus, a back trans-esterification
of glycol ester 8a to methyl ester 8b was realized by reacting
the crude reaction medium with methanol in the presence of
sodium methoxide (Scheme 1). Acid chloride 4 was a known
O
O
i
C6H4-pOMe
N
H
3
12a
3
2
compound, whose reactivity with triphenylphosphoranes
We obtained this chloride
3
3,34
C6H4-pOMe
O
has already been reported.
HN
N
by reacting potassium salt 9 with oxalyl chloride. Since
some difficulties were experienced to obtain a perfectly
dried salt 9, ester 8b was saponified with a solution of potas-
sium silanolate
molecular sieves (Scheme 1).
NH-C6H4-pOMe
O
O
C6H4-pOMe
3
5–38
˚
N
H
in tetrahydrofuran, dried with 3 A
C6H4-pOMe
1a
2a
6 4 2
Scheme 3. Reagents and conditions: (i) p-MeOC H NH , 2 equiv, MeOH,
reflux, 20 h, 20% NMR yield.
O
O
O
O
O
O
O
O
i
iv
OMe
R
Cl
Because of the low stability of enaminoester 12a (see later
for the reactivity of compounds like 2a), we focused our at-
tention on the protected allene 11. To estimate its reactivity,
it was treated with to secondary aliphatic amines such as
dimethylamine, piperidine, and N-methylpiperazine. In the
former case (Scheme 4), using aqueous dimethylamine,
three main products could be identified by NMR: enami-
noester 13 as a couple of both Z and E stereoisomers 13b
5
8a R = O(CH2)2OH
b R = OCH3
4
ii
8
iii
9
R = OK
Scheme 1. Reagents and conditions: (i) HOCH
2
2
CH OH, toluene, pTSA,
reflux, Dean–Stark, 20 h; (ii) MeONa/MeOH, reflux, 24 h, 46% for two
ꢀ
˚
steps; (iii) TMSOK, THF, 3 A MS, 20 C, 12 h; (iv) (ClCO)
2
, CH
2
Cl
2
,
ꢀ
0
C, 12 h, 90% (crude yield).
0
and 13b , and only one isomer of the enamine 14b (only
Synthesis of allenesfrom an acid chloride and the appropriate
phosphorane is a known method. In this way, chloride 4
was reacted with the phosphorane 6 obtained from salt 10,
5
0
3
9–45
traces of amidified 15b can be detected). These compounds
could not be purified because ethylenedioxy protecting group
was cleaved upon chromatography on silica gel, and separa-
tion of compounds could not be obtained. Nevertheless, the
isomers were characterized by NMR according to their rela-
tive proportions in the reaction mixture (Table 1—entry 1).
In other conditions, by bubbling dimethylamine in a solution
of allene 11 in methanol, only amide 15b was obtained.
Purification of this compound by column chromatography on
4
6
˚
again in the presence of 3 A molecular sieves (Scheme 2).
Allene 11 was prepared in an overall 55% yield from com-
pounds 4 and 6 as a brown oil, which can be stocked at
ꢀ
ture. Deprotection of the acetal of an acetylenic aldehyde
ꢁ
40 C for years, but slowly decomposes at room tempera-
ꢀ
This method has been adapted to the deprotection of allenic
47,48
was described by Gorgues using formic acid at 40 C.
ꢀ
rapid decomposition of the product. Unprotected allene 3,
SiO led again to cleavage of the protecting group, and enam-
2
inoketone 2b was isolated in 40% yield (Table 1—entry 2).
acetal 11, by lowering temperature to 30 C in order to avoid
thus obtained with a 60% yield, readily decomposes at
ꢀ
room temperature, but it can be stocked at ꢁ40 C for
O
OMe
months.
OMe
O
R
O
O
O
i
O
O
O
O
O
+
- + PPh3
PPh3
Br
Br
N
N
OMe
i
ii
OMe
OMe
11
13b,b'
14b R = OMe
15b R = NMe2
O
O
O
10
7
6
N
O
N
O
ii
O
iii
iii
O
O
OMe
O
OMe
N
N
O
iv
O
O
15b
2b
Scheme 4. Reagents and conditions: (i) DMA 40%, 1.2 equiv, H
0 h, 80%; (ii) DMA, excess MeOH, rt, 6 h; (iii) SiO
two steps.
2
O, rt,
2
, EtOAc, 40% for
3
11
1
3
Scheme 2. Reagents and conditions: (i) PPh , EtOAc, reflux, 24 h, 80%; (ii)
˚
, 3 A MS, 20 C, 30 min; (iii) 4, 0 C, 1 h, then 20 C, 12 h,
ꢀ
ꢀ
ꢀ
Et
5
3
N, CH
2
Cl
2
ꢀ
5% for three steps; (iv) HCO
2
H, 30 C, 8 h, 60%.
Allene 11 was now reacted with piperidine (Scheme 5).
Synthesis of amide 15c was not observed; both couples
0
0
Reactivity of unprotected allene 3 was then checked by treat-
ing it with p-anisidine (Scheme 3). Mainly mono-addition of
the aromatic amine on the central carbon was observed, giv-
ing the enaminoester 12a in unsatisfactory yield (20%, deter-
mined by NMR of the crude mixture). A strong degradation
of the reaction mixture occurred after prolonged reaction
times, leading to only traces of the expected pyridone 1a.
of isomers 13c and 13c and 14c and 14c were formed at
the beginning of the reaction. Then, enamines 14c and
0
enaminoesters 13c and 13c (Table 1). The appearance of
14c evolved during the heating of the mixture to give only
0
4
9
a vinylic hydrogen at 6.02 ppm indicated that the double
bond slowly isomerized upon smooth treatment of the crude
mixture by formic acid at room temperature. Surprisingly,

T. Boisse et al. / Tetrahedron 63 (2007) 10511–10520
10513
MeOH, reflux
O
OMe
OMe
O
OMe
O
O
O
O
O
O
i
O
+
N
N
11
13c,c'
14c,c'
ii
+
H
N
O
O
O
N
15c
Scheme 5. Reagents and conditions: (i) piperidine, 1 equiv, rt, 8 h, 90%;
ii) piperidine, 2 equiv, rt, 20 h.
(
acetal function was rather stable under these conditions.
Again, as for dimethylamine adducts, these compounds
could not be purified because of their decomposition upon
chromatography on silica gel, but each isomer was charac-
terized by NMR (Table 1—entry 3).
From these preliminary studies, it was learned that:
(i) in its protected dioxolanyl form, the allene is more
stable than in its ketone counterpart;
(
ii) amines react first at room temperature on the allenic
central carbon and then eventually, more slowly, with
the ester function;
(iii) after reaction with an amine, deprotection of the ketone
group is an easy reaction;
(
iv) there is a possibility of interconversion between the
enamine and the enaminoester form of these com-
pounds.
2.2. Synthesis of 1,4-disubstituted-2,5-dimethyl-
pyridones
Taking these results into account, reaction of allene 11
with 1 equiv of N-methylpiperazine in methanol at room
temperature for 5 h was carried out. As in the previous
0
cases, a mixture of enamines 13d and 13d and 14d and
14d was obtained in a near quantitative yield, but now
0
p-anisidine was added at the end of their formation. To our
delight, after 18 h of reflux in methanol, pyridone 17 was
obtained with a 90% reproducible yield. The initial reaction
0
medium evolved to give only enamines 13d and 13d after
prolonged reaction times, allowing their unambiguous
NMR description (Table 1—entry 4). Although compounds
16d and 2d were not characterized in the reaction media,
we thought that a plausible mechanism involved amidi-
fication of the ester moiety of 13 and 14 by the aromatic
amine to give amide 16d. Then, a trace of water in the
reaction mixture led to hydrolysis of the acetal group, and
cyclization of ketone 2d to pyridone 17 released the mole-
cule of water needed for pursuing the reaction (Scheme 6).
This two-step reaction sequence has then been generalized
by using the primary and secondary amines described in
Table 2.

1
0514
T. Boisse et al. / Tetrahedron 63 (2007) 10511–10520
reflux
OMe
In an attempt to introduce a nitrogen in the aromatic ring,
N
allene 11 was reacted with 2-aminopyridine. Instead of
a pyridone 1i, pyridopyrimidone 18 was isolated in 65%
yield (Scheme 8). Its structure was unambiguously deter-
mined by NOESY experiment to discriminate the other
possible product 19 (Scheme 9—path B). Its formation
involves first attack of the pyridine nitrogen on the allenic
system, before cyclization on the ester moiety through the
free amine group (path A).
O
OMe
OMe
O
O
O
O
N
H
O
O
O
O
+
i
1
1
N
N
N
N
1
4d,d'
13d,d'
MeO
H2O
NH2 ii
O
O
O
N
N
NH2
N
HN
N
N
O
O
O
OMe
OMe
2
CO Me
N
+
HN
HN
N
N
O
11
18
+
-
H2O
O
N
O
N
N
O
1i
N
N
O
OMe
7d
O
1
2d
16d
Scheme 8. Reagents and conditions: dried MeOH, reflux, 48 h, 65%.
ꢀ
Scheme 6. Reagents and conditions: (i) dried MeOH, 20 C, 5 h, or neat,
ꢀ
2.3. Important note
2
0 C, 1 h; (ii) MeOH, reflux, 18 h, 90% for two steps.
The first step of all the previous reaction sequences was
˚
realized either neat, or in dried methanol kept on 3 A MS.
Now, allene 11 was reacted with 2 equiv of substituted ani-
lines in refluxing methanol for 3–48 h depending on the
aniline, and pyridones 1a–g were thus formed in 64–92%
yield (Scheme 7). Reaction time decreases with the increase
of electron-donating groups on the aromatic moiety (from
While repeating some of these reactions by using methanol
from an old bottle, the main (sometimes only) product
obtained was a phenol, such as 22e (Scheme 10). This type
of reaction has been observed for piperidine and N-phenyl-
piperazine but only phenol 22e has been isolated and fully
characterized. The mechanism proposed for their formation
involves addition of the amine on central allenic carbon of
3
4
h for two to no reaction for a para nitro: Table 3—entries
and 8).
1
3, followed by deprotection of the acetal group, giving ke-
Ar
HN
tone 12. In that case, where the water contents of methanol
were higher than in the previous syntheses, hydrolysis of
the acetal protection occurs before amidification of the ester
function [as opposed to what was postulated for the synthesis
of the previous pyridones 1a–g (Scheme 6)]. This allows the
amine catalyzed reaction of the methylketone group of 12
with the ester function leading to 20 by intramolecular
O
O
CO2Me
Ar NH2
N
O
11
Ar
a-g
1
Scheme 7. Reagents and conditions: dried MeOH, reflux, 3–48 h, 64–92%.
Table 2. Synthesis of unsymmetrically disubstituted pyridones
a
Yield (%)
Entry
1
Secondary amine
Aniline
Product
Mp (solvent)
O
N
N
NH
H N
2
OMe
17d
17e
17f
86
170–dec (ether)
N
N
OMe
OMe
O
OMe
OMe
OMe
OMe
2
3
O
NH
68
73
202–dec (ether)
196–198 (ether)
O
N
N
OMe
OMe
H2N
H2N
O
N
N
NH
N
N
OMe
O
H2N
4
NH
17g
83
130–132 (ether)
N
N
a
Isolated yield.

T. Boisse et al. / Tetrahedron 63 (2007) 10511–10520
10515
B
O
N
NH2
N
A
O
O
N
O
O
Path B
O
O
CO2Me
O
A
N
N
H
O
19
Path A
NOESY
O
O
O
O
O
O
O
N
N
NH
N
18
Scheme 9. Plausible mechanism for the synthesis of compound 17, and NOESY correlations.
O
OMe
+ R NH
OMe
+ H O
OMe
from 2-aminopyridine. Eventually, formation of substituted
phenols under non-anhydrous conditions confirms function-
alized allene 11 as a key building-block for a variety of struc-
tures of interest. Biological evaluation of compounds
described herein is in progress and will be reported in due
course.
O
O
O
O
O
O
2
O
2
N
N
11
13e,e'
N
N
1
2e,e'
4. Experimental section
4.1. General
N
N
N
+
R2NH
N
N
O
N
Melting points were determined using an Electrothermal ap-
1
13
paratus and are uncorrected. H NMR and C NMR spectra
were obtained on a Varian Gemini 2000 at 200 and 50 MHz,
respectively. 2D NMR spectra were recorded on a Bruker
DRX-300 spectrometer at 300 MHz. IR spectra were ob-
tained in ATR mode on a FTIR Bruker Tensor 27. Thin layer
O
O
21e
20e
chromatographies were performed on precoated Kieselgel
60F254 plates. APCI (atmospheric pressure chemical ioni-
N
N
+
N
N
zation) mass spectrum was obtained on an LC–MS system
Thermo Electron Surveyor MSQ. Microanalyses were
performed by the ‘Service de Microanalyses’ of LSEO,
Universit ꢀe de Bourgogne, Dijon, France.
OH
2e
2
22c
N
4
.1.1. Methyl (2-methyl-1,3-dioxolan-2-yl)acetate (8b).
Scheme 10. Synthesis and mechanism of formation of phenol 22. Reagents
ꢀ
To a solution of methyl acetoacetate 5 (300 g, 2.58 mol)
and ethylene glycol (208.5 g, 3.36 mol) in toluene (2.5 L)
was added p-toluenesulfonic acid (0.22 g, 1.3 mmol). The
reaction medium was equipped with a Dean–Stark apparatus
and then refluxed until no more water was collected (20 h).
The solvent was evaporated, the residue dissolved in di-
chloromethane (300 mL) and neutralized by an aqueous
solution of potassium carbonate. The organic phase was
then washed three times with water (100 mL), dried upon
and conditions: N-phenylpiperazine, MeOH, 20 C, 6 h, 70%.
cyclization. A second molecule of amine finally adds to the
unconjugated carbonyl group, giving 21 then 22.
5
1
3. Conclusion
In summary, we have achieved a one-pot simple and efficient
synthesis of highly substituted 2-pyridones from a dicarbo-
nylallene. Surprisingly, condensation occurred more readily
while reacting the protecting form rather than the depro-
tected one. The yields are generally excellent and two differ-
ent substitutions can be obtained using a two-step procedure.
Especially, alkyl substituents can be introduced in the
MgSO , and evaporated. The remaining solution was then
4
back trans-esterified by adding methanol (1.5 L) and sodium
methylate 40% in methanol (10 mL). The mixture was re-
fluxed for 24 h, neutralized with citric acid, and evaporated.
The resulting solution was distilled under reduced pressure
to give pure 8b (190.1 g, 46%) as a colorless liquid with
3
0
ꢁ1
the same properties as described in literature. IR: n cm
1723, 1180, 1042; H NMR (CDCl , 200 MHz): d ppm
3
1
4-position, widening its substitution pattern. Synthesis of
a new pyridopyrimidone derivative has been achieved
1.49 (s, 3H, CH –C(OCH ) ), 2.67 (s, 2H, CH –CO), 3.68
3 2 2 2

10516
T. Boisse et al. / Tetrahedron 63 (2007) 10511–10520
Table 3. Synthesis of 1,4-diaryl-3,5-dimethylpyrid-2-ones
Ar
HN
N
O
O
CO2Me
Ar NH2
O
Ar
11
1
a-g
a
Yield (%)
Entry
1
No.
ArNH
2
Product
Reaction time (h)
Mp (solvent)
MeO
O
N
1a
H N
OMe
6
95
80
158–160 (ether)
2
N
H
OMe
O
2
3
4
5
1b
1c
1d
1e
2
H N
24
19
3
159–161 (ether)
206–208 (ether)
133–135 (ether)
N
N
H
O
H N
2
88
92
92
N
H
N
MeO
MeO
OMe
OMe
O
OMe
OMe
H2N
N
N
H
O
O
O
O
N
O
O
b
12
134–136
O
H2N
N
H
Cl
O
6
7
1f
H N
Cl
48
20
64
92
190–192 (ether)
2
N
N
Cl
H
CF3
F3C
O2N
O
N
CF3
b
1g
82–84
N
H
H2N
O
N
c
8
1h
2
H N
NO2
96
NR
—
N
H
NO2
a
Isolated yield.
Purified by preparative HPLC.
No reaction.
b
c
1
3
(
NMR (CDCl , 50 MHz): d ppm 23.4 (CH ), 40.1 (CH ),
s, 3H, CO CH ), 3.94–3.98 (m, 4H, O–CH –CH –O);
C
then heated under reflux for 24 h with vigorous stirring. Af-
ter cooling to room temperature, the resulting precipitate
was filtered and rinsed twice with EtOAc (40 mL) to give
2
3
2
2
3
3
2
5
2.4 (CH ), 64.7 (2CH ), 113.3 (C), 171.4 (C).
3 2
10 as a white salt (103.5 g, 80%), which was not analyzed.
Mp (EtOAc) 131–133 C. IR: n cm 2767, 1745, 1439,
ꢀ
1110; H NMR (CDCl , 200 MHz): d ppm 1.70 (dd,
ꢁ1
4
.1.2. (1-Methoxycarbonyl-ethyl)-triphenyl-phospho-
1
nium bromide (10). To a solution of methyl 2-bromopro-
panoate 7 (50 g, 0.3 mol) in EtOAc (200 mL) was added
triphenylphosphine (94.2 g, 0.4 mol). The mixture was
3
J¼18.4, 7.3 Hz, 3H, CH –CH), 3.58 (s, 3H, CO CH ),
3
2
3
6.97 (sext, J¼7.3 Hz, 1H, CH –CH), 7.63–7.86 (m, 9H,
3

T. Boisse et al. / Tetrahedron 63 (2007) 10511–10520
10517
1
3
ArH), 7.93–8.08 (m, 6H, ArH); C NMR (CDCl , 50 MHz):
3
52.7 (CH ), 99.5 (CH), 99.6 (C), 165.6 (C), 196.3 (C),
3
d ppm 12.9 (d, J¼3.1 Hz, CH ), 36.6 (d, J¼51.7 Hz, CH),
219.9 (C).
3
5
3.3 (CH ), 117.7 (d, J¼87.0 Hz, 3C), 130.2 (d,
3
J¼12.7 Hz, 6CH), 134.2 (d, J¼9.7 Hz, 6CH), 134.9 (d,
4.2. General procedure for the synthesis of unsymmet-
rically 1,4-disubstituted 3,6-dimethyl-pyridones 17d–g
J¼3.3 Hz, 3CH), 168.7 (d, J¼2.0 Hz, C).
4.1.3. Methyl 2-methyl-4-(2-methyl-1,3-dioxolan-2-yl)-
buta-2,3-dienoate (11). A stirred solution of potassium tri-
methylsilanolate (11 g, 0.085 mol) in THF (100 mL) was
A mixture of allene 11 (0.25 g, 2.7 mmol) and 1 equiv of
secondary amine (2.7 mmol) was stirred at room tempera-
ture under nitrogen for 1 h. Aniline of 1 equiv in dried meth-
anol (5 mL) was then added and the solution was refluxed for
6 h. Solvent was evaporated under reduced pressure, and the
dark residue was purified by column chromatography on
˚
dried over 3 A molecular sieves (15 g) overnight then filtered
under nitrogen. To this solution compound 8b (12.5 g,
0
.078 mol) was added. The resulting mixture was stirred un-
der inert atmosphere for 4 h, and the resulting white salt was
filtered under nitrogen and rinsed with CH Cl . Potassium
salt 9 was then introduced in a flask containing CH Cl
SiO eluted by a gradient of ethyl acetate in heptane to
2
give unsymmetrically disubstituted pyridones 17d–g.
2
2
2
2
ꢀ
(
70 mL) and then cooled to 0 C. Oxalyl chloride (6.5 mL,
4.2.1. 1-(4-Methoxyphenyl)-3,6-dimethyl-4-(4-methyl-
piperazin-1-yl)pyridin-2(1H)-one (17d). Gray powder
0
reaction medium over a period of 30 min at 0 C, and stirring
.074 mol) in CH Cl (10 mL) was added dropwise to the
2
2
ꢀ
was continued for 12 h to obtain a solution of acyl chloride 4
ꢀ
n cm 1638, 1611, 1589, 1539, 1511, 1250, 1022, 1003,
(86%); mp (ether) 170 C (dec); TLC R (EtOAc): 0.8; IR:
f
ꢁ
1
1
1
in CH Cl . H NMR (CDCl , 200 MHz): d ppm 1.49 (s,
3
807; H NMR (CDCl , 200 MHz): d ppm 1.95 (s, 3H,
3
2
2
3
O–CH –CH –O); C NMR (CDCl , 50 MHz): d ppm
H, CH –C(OCH ) ), 3.26 (s, 2H, CH –CO), 4.01 (s, 4H,
CO–C–CH ), 2.05 (s, 3H, N–C–CH ), 2.39 (s, 3H, N–
3
CH ), 2.60 (br s, 4H, CH N–CH CH ), 3.10 (br s, 4H,
3 3 2 2
3
2 2
1
2
3
3
2
2
3
2
4.3 (CH ), 53.3 (2CH ), 55.5 (CH ), 106.6 (C), 159.0 (C).
2
CH N–CH CH ), 3.85 (s, 3H, OCH ), 5.94 (d, J¼0.8 Hz,
3
2
3
2
2
3
1
H, CH), 6.98 (td, J¼9.4, 2.6 Hz, 2H, ArH), 7.08 (td,
1
3
Meanwhile, to a stirred solution of phosphonium bromide 10
(
J¼9.4, 2.6 Hz, 2H, ArH); C NMR (CDCl , 50 MHz):
3
˚
33.5 g, 0.078 mol) in CH Cl (200 mL) was added 3 A
d ppm 13.0 (CH ), 21.7 (CH ), 46.1 (CH ), 50.0 (2CH ),
3
2
2
3
3
2
molecular sieves (30 g) and dropwise triethylamine
21.7 mL, 0.156 mol). The yellow solution was allowed to
stir at room temperature for 30 min to give phosphorane 6.
55.2 (2CH ), 55.5 (CH ), 100.0 (CH), 113.1 (C), 114.8
2 3
(
(2CH), 129.0 (2CH), 132.9 (C), 143.0 (C), 157.8 (C),
159.3 (C), 165.4 (C). Anal. Calcd for C H N O $
1
9 25 3 2
The spectroscopic data were in agreement with those
described in the literature.
4/3H O: C 64.93, H 7.93, N 11.96. Found: C 65.00, H
2
7.55, N 12.05.
5
2
ꢀ
To this suspension was added at 0 C the acyl chloride 4
solution prepared previously. The resulting mixture was
allowed to warm to room temperature and stirred for 12 h.
The solvent was then partially evaporated, and heptane
was added to obtain two phases. The suspension was kept
cold overnight to precipitate the triphenylphosphine oxide
and filtered. Solvents were evaporated to give protected al-
lene 11 as a brown oil (9.3 g, 55%), which was used directly
4.2.2. 1-(3,4-Dimethoxyphenyl)-3,6-dimethyl-4-(morpho-
lin-4-yl)pyridin-2(1H)-one (17e). Light gray powder
ꢀ
(73%); mp (ether) 202 C (dec); TLC R (EtOAc/MeOH
f
ꢁ
1
80:20): 0.65; IR: n cm 1654, 1590, 1547, 1514, 1206,
1141, 1021; H NMR (CDCl , 200 MHz): d ppm 1.99 (s,
1
3
3H, CO–C–CH ), 2.08 (s, 3H, N–C–CH ), 3.02–3.09 (m,
3
3
4H, N–CH CH –O), 3.80–3.89 (m, 4H, N–CH CH –O),
2
2
2
2
3.86 (s, 3H, OCH ), 3.92 (s, 3H, OCH ), 5.94 (s, 1H, CH),
3
3
ꢁ
1
in the next step. IR: n cm 1963, 1714, 1276, 1177, 1120,
1
6.68 (d, J¼2.3 Hz, 1H, ArH), 6.73 (dd, J¼8.3, 2.3 Hz, 1H,
1
13
102, 1034, 868; H NMR (CDCl , 200 MHz): d ppm 1.58
3
ArH), 6.95 (d, J¼8.3 Hz, 1H, ArH); C NMR (CDCl ,
3
(s, 3H, CH –C(OCH ) ), 1.91 (d, J¼2.9 Hz, 3H, CH –
C]C), 3.75 (s, 3H, CO CH ), 3.98–4.02 (m, 4H, O–CH –
50 MHz): d ppm 12.9 (CH ), 21.4 (CH ), 50.6 (2CH ), 56.0
3
3
2 2
3
3
3
(2CH ), 67.0 (2CH ), 99.6 (CH), 111.1 (CH), 111.4 (CH),
2 2
2
3
2
1
3
CH –O), 5.49 (q, J¼2.9 Hz, 1H, C]CH); C NMR
113.4 (C), 120.0 (CH), 132.1 (C), 143.2 (C), 148.9 (C),
149.6 (C), 157.6 (C), 165.7 (C). Anal. Calcd for
C H N O $H O: C 62.97, H 7.23, N 7.73. Found: C
2
(
(
(
CDCl , 50 MHz): d ppm 14.8 (CH ), 25.1 (CH ), 52.0
3 3 3
CH ), 64.4 (CH ), 64.7 (CH ), 97.4 (CH), 98.2 (C), 106.4
3
2
2
19 25
3
2
2
C), 167.3 (C), 208.6 (C).
63.12, H 7.31, N 7.69.
4
.1.4. Methyl 2-methyl-5-oxohexa-2,3-dienoate (3). A
solution of compound 11 (2 g, 0.011 mol) in formic acid
4.2.3. 1-(3,4-Dimethoxyphenyl)-3,6-dimethyl-4-(4-phe-
nylpiperazin-1-yl)pyridin-2(1H)-one (17f). Gray powder
ꢀ
partitioned between CH Cl (10 mL) and water (10 mL).
ꢀ
0.76; IR: n cm 1649, 1597, 1546, 1514, 1496, 1220, 1141,
(
2.5 g, 0.055 mol) was stirred at 30 C for 8 h, and then
(68%); mp (ether) 196–198 C; TLC R (EtOAc/MeOH):
f
ꢁ
1
2
2
1
The organic phase was washed two times with water
5 mL), once with a saturated solution of sodium hydrogeno-
1023, 771; H NMR (CDCl , 200 MHz): d ppm 2.00 (s, 3H,
3
(
CO–C–CH ), 2.11 (s, 3H, N–C–CH ), 3.18–3.27 (m, 4H, N–
3
3
carbonate, then with water. The resulting solution was dried
over magnesium sulfate, filtered, and evaporated to give 3 as
a light brown oil (1.36 g, 80%). This unstable product was not
CH CH –NPh), 3.30–3.38 (m, 4H, N–CH CH –NPh), 3.86
2 2 2 2
(s, 3H, OCH ), 3.92 (s, 3H, OCH ), 6.02 (s, 1H, CH), 6.69
3
3
(d, J¼2.3 Hz, 1H, ArH), 6.74 (dd, J¼8.3, 2.3 Hz, 1H, ArH),
13
ꢁ
1
analyzed. IR: n cm 1948, 1722, 1686, 1276, 1220, 1160,
1
6.95 (d, J¼8.3 Hz, 1H, ArH), 6.86–7.03 (m, 3H, ArH),
1
119; H NMR (CDCl , 200 MHz): d ppm 2.05 (s, 3H,
3
7.26–7.36 (m, 2H, ArH); C NMR (CDCl , 50 MHz):
d ppm 13.0 (CH ), 21.4 (CH ), 46.2 (2CH ), 50.4 (2CH ),
3
CH –CO), 2.30 (d, J¼3.1 Hz, 3H, CH –C]C), 3.81 (s,
3
3
3
3
2
3
1
3
3
(
H, CO CH ), 6.10 (q, J¼3.1 Hz, 1H, C]CH); C NMR
56.0 (2CH ), 100.4 (CH), 111.2 (CH), 111.4 (CH), 113.1
2
(C), 116.3 (2CH), 120.0 (CH), 120.2 (CH), 129.2 (2CH),
2
3
CDCl , 50 MHz): d ppm 14.4 (CH ), 27.4 (CH ),
3
3
3

10518
T. Boisse et al. / Tetrahedron 63 (2007) 10511–10520
ꢁ
1
1
(
32.0 (C), 143.3 (C), 148.9 (C), 149.6 (C), 151.1 (C), 158.1
C), 164.5 (C). Anal. Calcd for C H N O $1/2H O: C
IR: n cm 3250, 1635, 1611, 1577, 1562, 1511, 1463,
1392, 1307, 817, 725; H NMR (CDCl , 200 MHz): d ppm
1
1
9
25
3
2
2
3
7
0.07, H 7.06, N 9.81. Found: C 69.87, H 7.02, N 9.45.
1.84 (s, 3H, CO–C–CH ), 2.07 (s, 3H, N–C–CH ), 2.36 (s,
3
3
3
H, ArCH ), 2.39 (s, 3H, ArCH ), 5.84 (br s, 1H, NH),
3 3
4
2
1
1
2
2
3
5
3
2
.2.4. 1-Benzyl-3,6-dimethyl-4-piperidin-1-ylpyridin-
(1H)-one (17g). White crystals (83%); mp (ether) 130–
5.97 (d, J¼0.8 Hz, 1H, CH), 7.06 (dq, J¼8.6, 2.6 Hz, 4H,
13
ArH), 7.18 (dtd, J¼8.6, 2.3, 0.6 Hz, 2H, ArH), 7.26 (dtd,
ꢀ
ꢁ1
32 C; TLC R (EtOAc): 0.68; IR: n cm 2935, 1635,
f
J¼8.6, 2.2, 0.6 Hz, 2H, ArH);
C NMR (CDCl ,
3
1
589, 1546, 1220, 1108, 1012; H NMR (CDCl3,
00 MHz): d ppm 1.54–1.75 (m, 6H, N(CH CH ) CH ),
50 MHz): d ppm 9.7 (CH ), 20.9 (CH ), 21.2 (CH ), 21.6
3 3 3
(CH ), 96.8 (CH), 102.2 (C), 123.7 (2CH), 128.0 (2CH),
3
2
2 2
2
.10 (s, 3H, CO–C–CH ), 2.21 (s, 3H, N–C–CH ), 2.89–
3
130.0 (2CH), 130.1 (2CH), 134.2 (C), 136.9 (C), 137.2
(C), 138.0 (C), 143.0 (C), 149.9 (C), 164.4 (C). Anal. Calcd
for C H N O$2/3H O: C 76.33, H 7.12, N 8.48. Found: C
3
.04 (m, 4H, N(CH CH ) CH ), 5.33 (s, 2H, NCH Ph),
2
2
2 2
2
.88 (s, 1H, CH), 7.10–7.17 (m, 2H, ArH), 7.19–7.33 (m,
H, ArH); C NMR (CDCl , 50 MHz): d ppm 13.4 (CH ),
2
1
22
2
2
1
3
76.25, H 6.90, N 8.59.
3
3
0.5 (CH ), 24.2 (CH ), 26.0 (2CH ), 47.1 (CH ), 51.5
2
3
2
2
(
2CH ), 101.1 (CH), 112.1 (C), 126.3 (2CH), 126.8 (CH),
2
28.5 (2CH), 137.2 (C), 142.3 (C), 158.6 (C), 164.8 (C).
4.3.4. 1-(3,4-Dimethoxyphenyl)-4-[(3,4-dimethoxyphe-
nyl)amino]-3,6-dimethylpyridin-2(1H)-one (1d). Light
1
Anal. Calcd for C H N O $1/3H O: C 69.59, H 7.97, N
7
ꢀ
MeOH 9:1): 0.42; IR: n cm 3246, 1638, 1600, 1557,
brown powder; mp (ether) 133–135 C; TLC R (EtOAc/
f
19
25
3
2
2
ꢁ1
.73. Found: C 69.52, H 7.93, N 7.56.
1
1
509, 1234, 1022, 799, 766; H NMR (CDCl , 200 MHz):
3
4
1
.3. General procedure for the synthesis of 3,6-dimethyl-
,4-diarylpyridones 1a–g
d ppm 1.87 (s, 3H, CO–C–CH ), 2.11 (s, 3H, N–C–CH ),
3 3
3.86 (s, 3H, OCH ), 3.90 (s, 3H, OCH ), 3.92 (s, 6H,
3
3
OCH ), 5.73 (br s, 1H, NH), 5.86 (s, 1H, CH), 6.68–6.80
3
To a solution of allene 11 (0.6 g, 3 mmol) in dried methanol
5 mL) was added 6 mmol of substituted aniline. The mix-
(m, 4H, ArH), 6.88 (dd, J¼7.7, 1.0 Hz, 1H, ArH), 6.93 (d,
1
3
(
J¼8.4 Hz, 1H, ArH); C NMR (CDCl , 50 MHz): d ppm
3
ture was then refluxed under nitrogen for the time mentioned
in Table 3, then partitioned between CH Cl (20 mL) and
9.6 (CH ), 21.5 (CH ), 56.0 (CH ), 56.1 (2CH ), 56.2
3
3
3
3
(CH ), 96.5 (CH), 101.3 (C), 109.2 (CH), 111.3 (CH),
3
2
2
water (10 mL). The organic phase was washed once with
a 5% aqueous solution of HCl, twice with water, dried
over MgSO , and evaporated. Crude product was purified
111.5 (CH), 111.6 (CH), 117.1 (CH), 120.4 (CH), 132.5
(C), 132.8 (C), 143.4 (C), 146.8 (2 C), 149.5 (C), 149.6 (C),
150.5 (C), 164.4 (C). Anal. Calcd for C H N O $5/4H O:
4
23 26
2
5
2
either by recrystallization in ether or by preparative HPLC
eluted by EtOAc.
C 63.80, H 6.63, N 6.47. Found: C 63.99, H 6.43, N 6.37.
4.3.5. 1-(1,3-Benzodioxol-5-yl)-4-(1,3-benzodioxol-5-yl-
amino)-3,6-dimethylpyridin-2(1H)-one (1e). Brown pow-
4.3.1. 1-(4-Methoxyphenyl)-4-[(4-methoxyphenyl)-
amino]-3,6-dimethylpyridin-2(1H)-one (1a). Gray pow-
ꢀ
der; mp 134–136 C; TLC R (EtOAc/MeOH 9:1): 0.70;
f
ꢀ
.65; IR: n cm 3250, 1634, 1613, 1577, 1562, 1507,
ꢁ1
der; mp (ether) 158–160 C; TLC R (EtOAc/MeOH 9:1):
f
IR: n cm 3246, 1640, 1559, 1502, 1483, 1460, 1396,
1212, 1190, 1035, 790, 761; H NMR (CDCl , 200 MHz):
ꢁ
1
1
0
1
3
1
459, 1248, 1034, 830; H NMR (CDCl , 200 MHz):
3
d ppm 1.89 (s, 3H, CO–C–CH ), 2.06 (s, 3H, N–C–CH ),
3
3
d ppm 1.83 (s, 3H, CO–C–CH ), 2.09 (s, 3H, N–C–CH ),
3
5.76 (br s, 1H, NH), 5.85 (d, J¼1 Hz, 1H, CH), 6.00 (d,
3
3
6
4
2
.84 (s, 6H, OCH ), 5.70 (br s, 1H, NH), 5.81 (s, 1H, CH),
3
J¼1.4 Hz, 2H, OCH O), 6.01 (d, J¼1.4 Hz, 2H, OCH O),
2
2
.95 (td, J¼8.8, 2.8 Hz, 4H, ArH), 7.11 (td, J¼8.8, 2.8 Hz,
6.59–6.66 (m, 3H, ArH), 6.71 (d, J¼2.1 Hz, 1H, ArH),
1
3
H, ArH); C NMR (CDCl , 50 MHz): d ppm 9.4 (CH ),
3
6.80 (d, J¼8.1 Hz, 1H, ArH), 6.86 (dd, J¼7.7, 0.8 Hz, 1H,
3
1
3
1.5 (CH ), 55.3 (2CH ), 96.3 (CH), 101.0 (C), 114.5
3
ArH); C NMR (CDCl , 50 MHz): d ppm 9.5 (CH ), 21.5
3 3
3
(
1
4CH), 126.2 (4CH), 132.2 (C), 132.5 (C), 143.1 (C),
50.4 (C), 157.0 (C), 159.0 (C), 164.3 (C). Anal. Calcd for
C H N O $1/2H O: C 70.18, H 6.45, N 7.79. Found: C
(CH ), 96.5 (CH), 101.3 (CH), 101.4 (C), 101.6 (CH),
3
106.4 (CH), 108.3 (2CH ), 109.2 (CH), 117.8 (CH), 121.5
2
(CH), 133.1 (C), 133.6 (C), 145.0 (C), 147.3 (C), 148.1
(C), 148.2 (C), 150.2 (C), 164.2 (C). Anal. Calcd for
C H N O $1/2H O: C 65.11, H 4.94, N 7.23. Found: C
2
1
22
2
3
2
6
9.88, H 6.26, N 8.04.
2
1
18
2
5
2
4
.3.2. 4-Anilino-3,6-dimethyl-1-phenylpyridin-2(1H)-one
64.72, H 4.97, N 7.03.
ꢀ
EtOAc): 0.37; IR: n cm 3242, 1641, 1595, 1555, 1495,
(
1b). Light brown powder; mp (ether) 159–161 C; TLC R
f
ꢁ
1
(
1
4.3.6. 1-(4-Chlorophenyl)-4-[(4-chlorophenyl)amino]-
3,6-dimethylpyridin-2(1H)-one (1f). White powder; mp
1
396, 756, 700; H NMR (CDCl , 200 MHz): d ppm 1.85
3
ꢀ
n cm 3288, 1648, 1597, 1558, 1490, 1463, 1090, 822,
(
s, 3H, CO–C–CH ), 2.10 (s, 3H, N–C–CH ), 5.94 (br s,
3
(ether) 190–192 C; TLC R (EtOAc/MeOH 9:1): 0.74; IR:
f
3
ꢁ
1
1
1
7
9
1
H, NH), 6.07 (s, 1H, CH), 7.10–7.22 (m, 5H, ArH), 7.32–
.53 (m, 5H, ArH); C NMR (CDCl , 50 MHz): d ppm
1
3
738; H NMR (CDCl , 200 MHz): d ppm 1.87 (s, 3H, CO–
3
3
.6 (CH ), 21.5 (CH ), 97.0 (CH), 103.1 (C), 122.8 (2CH),
3
C–CH ), 2.09 (s, 3H, N–C–CH ), 5.81 (br s, 1H, NH), 5.98
3
3
3
24.0 (CH), 128.1 (CH), 128.2 (2CH), 129.3 (4CH), 139.4
(s, 1H, CH), 7.1 (td, J¼8.7, 2.1 Hz, 2H, ArH), 7.13 (td,
(C), 139.8 (C), 142.7 (C), 149.3 (C), 164.2 (C). Anal. Calcd
for C H N O$1/4H O: C 77.39, H 6.32, N 9.50. Found: C
J¼8.6, 2.1 Hz, 2H, ArH), 7.34 (td, J¼8.7, 2.1 Hz, 2H,
13
ArH), 7.45 (td, J¼8.6, 2.1 Hz, 2H, ArH); C NMR
1
9
18
2
2
7
7.45, H 6.30, N 9.60.
(CDCl , 50 MHz): d ppm 9.7 (CH ), 21.6 (CH ), 97.2 (CH),
3
3
3
103.6 (C), 124.2 (2CH), 129.5 (2CH), 129.5 (C), 129.8
(4CH), 134.3 (C), 137.9 (C), 138.5 (C), 142.7 (C), 149.1
4.3.3. 3,6-Dimethyl-1-(4-methylphenyl)-4-[(4-methylphe-
nyl)amino]pyridin-2(1H)-one (1c). Light brown powder;
mp (ether) 206–208 C; TLC R (EtOAc/MeOH 9:1): 0.72;
f
(C), 164.2 (C). Anal. Calcd for C H Cl N O$3/4H O: C
1
9
16
2
2
2
ꢀ
61.22, H 4.73, N 7.51. Found: C 61.32, H 4.42, N 7.77.

T. Boisse et al. / Tetrahedron 63 (2007) 10511–10520
10519
+
+
4
.3.7. 3,6-Dimethyl-1-[3-(trifluoromethyl)phenyl]-4-{[3-
trifluoromethyl)phenyl]amino}pyridin-2(1H)-one (1g).
153.1 (C), 155.2 (C); LC–MS (APCI ) m/z 429 (MH ).
Anal. Calcd for C H N O $1/4H O: C 74.88, H 7.56, N
12.94. Found: C 74.81, H 7.52, N 12.86.
(
Yellowish powder; mp 82–84 C; TLC R (EtOA/MeOH
1
9
25
3
2
2
ꢀ
:1): 0.77; IR: n cm 3261, 1644, 1598, 1560, 1328, 1118,
f
ꢁ
1
9
6
1
98; H NMR (CDCl , 200 MHz): d ppm 1.88 (s, 3H, CO–
3
4.6. 2-Methyl-3,5-dipiperidin-1-ylphenol (22c)
C–CH ), 2.09 (s, 3H, N–C–CH ), 6.05 (s, 1H, CH), 6.17
3
3
1
(
ArH); C NMR (CDCl , 50 MHz): d ppm 9.9 (CH ), 21.7
br s, 1H, NH), 7.28–7.53 (m, 6H, ArH), 7.56–7.72 (m, 2H,
Formed by the same procedure as 22e (not isolated). H
NMR (CDCl , 200 MHz): d ppm 1.63–1.77 (m, 12H,
1
3
3
3
3
(
(
CH ), 97.0 (CH), 105.0 (C), 118.8 (q, J¼4 Hz, CH), 120.3
N(CH CH ) CH ), 2.10 (s, 3H, CH ), 2.98–3.12 (m, 8H,
3
3
2
2 2
2
q, J¼4 Hz, CH), 123.6 (q, J¼272 Hz, CF ), 123.8 (q,
N(CH CH ) CH ), 6.16 (d, J¼2.4 Hz, 1H, CH), 6.27 (d,
3
2
2 2
2
J¼272 Hz, CF ), 125.3 (q, J¼2 Hz, CH), 125.4 (q,
J¼2.4 Hz, 1H, CH).
Acknowledgements
3
J¼4 Hz, CH), 125.6 (q, J¼4 Hz, CH), 130.0 (CH), 130.2
(
(
(
CH), 131.9 (q, J¼33 Hz, C), 132.1 (q, J¼33 Hz, C), 132.1
q, J¼2 Hz, CH), 139.9 (C), 140.7 (C), 142.5 (C), 148.7
C), 164.4 (C). Anal. Calcd for C H F N O: C 59.16, H
2
1 16 6 2
3
.78, N 6.57. Found: C 59.48, H 4.17, N 6.40.
The authors would like to thank the Region Nord-Pas-de-
Calais for T.B.’s scholarship.
4
1
.4. 3-Methyl-4-[(2-methyl-1,3-dioxolan-2-yl)methyl]-
,8-dihydro-2H-pyrido[1,2-a]pyrimidin-2-one (18)
References and notes
To a solution of allene 11 (0.6 g, 3 mmol) in methanol
5 mL) was added 2-aminopyridine (0.28 g, 3 mmol). The
(
1. Smith, D. Comprehensive Organic Chemistry; Sammes, P. G.,
Ed.; Pergamon: Oxford, 1979; Vol. 4, p 3.
2. Bailey, T.; Goe, G.; Scriven, E. Heterocyclic Compounds;
Newkome, G. R., Ed.; Wiley: New York, NY, 1984; Vol. 14,
Part 5, p 1.
mixture was refluxed under nitrogen for 20 h, then parti-
tioned between CH Cl (20 mL) and water (10 mL). The
organic phase was washed once with a 5% aqueous solution
2
2
of HCl, twice with water, dried over MgSO , and evaporated.
4
Crude product was recrystallized in ether to afford pure 18 as
a white powder (0.45 g, 65%). Mp (ether) 214–216; TLC R
3. McKillop, A.; Boulton, A. Comprehensive Heterocyclic
Chemistry; McKillop, A., Boulton, A., Eds.; Pergamon:
Oxford, 1984; Vol. 2, p 67.
4. Yuldashev, P. K. Chem. Nat. Compd. 2001, 37, 274–275.
5. Kozikowski, A. P.; Campiani, G.; Sun, L.-Q.; Wang, S.;
Saxena, A.; Doctor, B. P. J. Am. Chem. Soc. 1991, 118,
11357–11362.
f
ꢁ
1
(
EtOAc): 0.23; IR: n cm 1686, 1625, 1591, 1550, 1475,
1
1
2
3
450, 1038, 1028, 1129, 771, 763; H NMR (CDCl3,
00 MHz): d ppm 1.53 (s, 3H, (CH O) –C–CH ), 2.33 (s,
2
2
3
H, ArCH ), 3.46 (br s, 2H, OCH CH O), 3.59 (br s, 2H,
2
3
2
OCH CH O), 3.87 (br s, 2H, CH –C–(CH O) ), 6.77 (ddd,
2
2
2
2
2
J¼7.8, 6.5, 1.7 Hz, 1H, ArH), 7.32 (ddd, J¼9.0, 1.7,
6. Wall, M. E.; Wani, M. C.; Cook, C. E.; Palmer, K. H.; McPhail,
A. T.; Sim, G. A. J. Am. Chem. Soc. 1966, 88, 3888–3890.
7. Saari, W. S.; Hoffman, J. M.; Wai, J. S.; Fisher, T. E.; Rooney,
C. S.; Smith, A. M.; Thomas, C. M.; Goldman, M. E.; O’Brien,
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0
.8 Hz, 1H, ArH), 7.49 (ddd, J¼9.0, 6.5, 1.4 Hz, 1H,
1
3
ArH), 8.28 (ddd, J¼7.8, 1.4, 0.8 Hz, 1H, ArH); C NMR
(
CDCl , 50 MHz): d ppm 14.1 (CH ), 25.8 (CH ), 37.7
3 3 3
(
CH ), 64.8 (2CH ), 109.7 (C), 111.9 (CH), 124.9 (CH),
2 2
1
1
27.3 (C), 130.2 (CH), 134.5 (CH), 139.8 (C), 151.6 (C),
68.3 (C). Anal. Calcd for C H N O $1/3H O: C 63.15,
8. Basf Aktiengesellschaft. PCT Int. Appl. WO 2002006233,
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1
4
16
2
3
2
H 6.31, N 10.52. Found: C 63.27, H 6.23, N 10.82.
1
988; Chem. Abstr. 1988, 109, 73348.
4
(
.5. 2-Methyl-3,5-bis(4-phenylpiperazin-1-yl)phenol
22e)
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1
1. Sumitomo Chemical Co. Eur. Pat. Appl. EP 535980, 1993;
Chem. Abstr. 1993, 119, 117126.
To a solution of allene 11 (0.5 g, 2.5 mmol) in methanol
taken from an opened bottle (5 mL) was added N-phenyl-
piperazine (0.4 g, 2.5 mmol), and the solution was stirred
at room temperature for 6 h. Solvent was evaporated under
reduced pressure, and the resulting oil was purified by chro-
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matography on SiO eluted by EtOAc to afford phenol 22e as
2
ꢀ
colorless needles (370 mg, 70%). Mp (ether) 165–167 C;
TLC R (EtOAc): 0.81; IR: n cm 2835, 1599, 1583,
1
ꢁ
1
f
1
504, 1450, 1271, 1240, 1119, 993, 761, 688; H NMR
CDCl , 200 MHz): d ppm 2.16 (s, 3H, CH ), 3.03–3.10
m, 4H, N–CH CH –N), 3.22–3.38 (m, 12H, N–CH CH –
2
(
(
3
3
2
2
2
N), 4.95 (br s exch., 1H, OH), 6.22 (d, J¼2.5 Hz, 1H,
CH), 6.36 (d, J¼2.5 Hz, 1H, CH), 6.84–6.95 (m, 2H,
ArH), 6.95–7.03 (m, 4H, ArH), 7.25–7.35 (m, 4H, ArH);
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1
3
C NMR (CDCl , 50 MHz): d ppm 9.9 (CH ), 49.3
3
3
(
2CH ), 49.6 (4CH ), 52.0 (2CH ), 99.9 (CH), 100.6 (CH),
2 2 2
1
(
09.6 (C), 116.1 (2CH), 116.3 (2CH), 119.7 (2CH), 129.0
2CH), 129.1 (2CH), 150.5 (C), 151.1 (C), 151.3 (C),
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