An effective contribution to functionalized pyridines synthesis by way of an unusual rearrangement of amidines

Article abstract of DOI:10.1016/S0040-4020(01)01197-8

A new synthesis of 2-pyridineacetamides was developed starting from pyran-2-one N-functionalized amidines 4. Secondary amines reacted in a sealed tube with amidines 4 and, by nucleophilic attack on pyran-2-one nucleus and thermal rearrangement, afforded exclusively the 2-pyridineacetamide derivatives 6 or a mixture of amide compounds 6 and 7 depending on the substituents linked to C-α of the starting amidine 4.

Full text of DOI:10.1016/S0040-4020(01)01197-8

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 1213±1221
An effective contribution to functionalized pyridines synthesis by
way of an unusual rearrangement of amidines
Egle M. Beccalli, Alessandro Contini and Pasqualina Trimarcop
Á
Istituto di Chimica Organica, Facolta di Farmacia e Centro Interuniversitario di Ricerca sulle Reazioni Pericicliche e Sintesi di Sistemi
Á
Etero e Carbociclici, Universita degli Studi di Milano, Via Venezian 21, 20133 Milano, Italy
Received 21 September 2001; revised 2 November 2001; accepted 29 November 2001
AbstractÐA new synthesis of 2-pyridineacetamides was developed starting from pyran-2-one N-functionalized amidines 4. Secondary
amines reacted in a sealed tube with amidines 4 and, by nucleophilic attack on pyran-2-one nucleus and thermal rearrangement, afforded
exclusively the 2-pyridineacetamide derivatives 6 or a mixture of amide compounds 6 and 7 depending on the substituents linked to C-a of
the starting amidine 4. q 2002 Elsevier Science Ltd. All rights reserved.
Amidines ®nd widespread applications in organic chemistry
as starting materials for preparation of many different
nitrogen-containing heterocycles.1
In particular we decided to synthesize some 4,5-dihydro-n-
triazoles bearing on C-4 an useful substituent which shifted
the reaction to achieve the amidines with the purpose to
study in detail the reactivity of these substrates. We further-
more point out the presence of the pyran-2-one nucleus on
the N-1 position.
For some years we have been interested in developing
syntheses of nitrogen heterocycles through intramolecular
rearrangements
and/or
condensations
involving
functionalized acetamidines. We recently reported that
the thermal rearrangement of the 5-amino-4,5-dihydro-n-
triazoles bearing a 2-H-pyran-2-one group at N-1 gave a
mixture of nitrogen functionalized tertiary amidines and
1H-pyrano[4,3-b]pyrrol-4-ones. The amidine yield depends
strongly on selected reaction conditions and on C-4
substitution of dihydro-n-triazoles2 (Scheme 1).
It is well known that several kinds of nucleophiles can react
with pyran-2-one at C-2 and C-6 causing initial ring
opening, followed by
a recyclization into a new
heterocyclic system.3 As well, the methylene group linked
to amidine tertiary function is easily transformed into
carbanion able to react in intramolecular nucleophilic
condensations.4
Scheme 1. Reagents and conditions: toluene, re¯ux; or n.PrOH, re¯ux, or toluene, BF3.Et2O, re¯ux
Keywords: amidines; 2H-pyran-2-one; 2-pyridineacetamide; thermal rearrangement.
Corresponding author. Tel.: 139-2-58354483; fax: 139-2-58354476; e-mail: trimarco@mailserver.unimi.it
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)0 1197-8

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E. M. Beccalli et al. / Tetrahedron 58 (2002) 1213±1221
Scheme 2. aReagents and conditions: toluene, re¯ux or n.propanol, re¯ux. p2h not isolated, but obtained in situ: see Experimental.
For this reason we decided to exploit either pyran-2-one
nucleus reactivity and nucleophilic carbon atom on C-a to
amidine group, with the purpose to ®nd a satisfactory route
to synthesize 2-pyridineacetamides. These substituted
pyridines are of general interest owing to the presence of
similar structures in several compounds with antiarrhytmic,5
anti HIV6 and enzymatic inhibitory activity.7
and pyran-2-one nitrogen-functionalized amidines offers a
new effective route to highly substituted 2-pyridine-
acetamides with the advantage to avoid a multi-step
synthesis, through an unusual rearrangement.
1. Results and discussion
We now report that the reaction between secondary amines
The preparation of 4,5-dihydro-n-triazoles 3a±h from
Scheme 3.

E. M. Beccalli et al. / Tetrahedron 58 (2002) 1213±1221
1215
cycloaddition of azide 1 and appropriate enamines 2a±h
in benzene solution has already been described.2
Compounds 3a±e, g are known and have trans con®gura-
tion. The same con®guration was also assigned to new
products 3f and 3h which show a NMR coupling constant
of about 3 Hz.
achieved by these reaction conditions. Just in 5 h at 1708C
the major isomer was shown to be the 2-pyridineacetamide
6a (88%) beside the 4,6-dimethylpyridine 5 in 12% yield.
The ratio of 5 and 6a in the mixture was determined by 1H
NMR analysis. In fact the different hydrogen shift on C-3
for 5 and 6a (6.70and 6.87 d, respectively) allowed a clear
difference between the two pyridines obtained. Performing
the reaction at 2008C, the amide derivative 6a was only
obtained.
Compounds 3a±h when heated in boiling n-propanol or in
toluene gave the corresponding amidines 4a±h (Scheme 2).
It is well known the cleavage of the N(1)±N(2) bond in the
4,5-dihydro-n-triazole nucleus is made easier by electron-
withdrawing groups on N-1.8
These results point out that under mild conditions the
nucleophylic addition on the C-6 (path b) prevails, but at
higher temperatures the addition product to C-2 position
(path a) is favored.11
During our preliminary experiment the 6-methyl-4-(1-
morpholino-2-phenylethylideneamino)-2H-pyran-2-one 4a
was re¯uxed in piperidine as solvent and after 17 h turned
into a mixture of substituted pyridines 5 and 6a in the ratio
of 1:2 (Scheme 3).
In order to verify that 5 does not arise from hydrolysis of
amide 6a, this product was reacted 35 h at 608C under the
most favorable conditions to 5 formation. The H NMR
1
spectrum of the crude mixture showed only the signals of
amide derivative 6a, thus con®rming the independence of
paths leading to 5 and 6, respectively.
Their spectral data were in agreement with the proposed
structures and with available data in literature for similar
substitution pattern.9 13C NMR spectrum of 2-pyridine-
acetamide 6a showed the signals related to CH-3 at about
119 ppm and to amide carbonyl group at 169 ppm, the latter
was validated also by IR stretching at 1630cm 21. 1H NMR
was characterized by three singlets (2.06, 3.80 and 6.87 d)
associated with CH3 on C-4, CH2 linked to amide carbonyl
group on C-2 and H-3 on C-3, respectively.
We thought therefore to extend the reaction to amidines
4b±h and perform the reaction at 2008C. Amidines 4b±h
were mixed with an excess of secondary amines in a sealed
tube and put in preheated oil bath at 2008C. The transforma-
tion required a reaction time within 2±4 h. The expected
amides 6 are listed in Table 1.
1
In H NMR spectrum of 4,6-dimethylpyridine derivative 5
three singlets at 2.05, 2.44 and 6.70 d associated, respec-
tively, with the methyl groups linked to C-4 and C-2 and
H-3 of the pyridine ring appeared diagnostic.
Moreover the high temperature of the reaction mixture was
responsible in some cases of low yields besides the
formation of polymerised material.
The best results were achieved from the amidines 4a±f and
suggest that the yields of the amide derivatives 6a±l, o are
depending on easy deprotonation of methylene group bound
to aryl substituents.
It can be quite reasonable to assume that 5 and 6a come
from two different pathways, which seem competitive in
these reaction conditions (Scheme 4).
According to path a the pyridine amide derivative 6a
resulted from the nucleophilic attack of the amino group
on the C-2 position of 2-pyranone nucleus followed by
ring opening and intramolecular cyclization, by way of the
C-a amidinic carbanion intermediate.
Under these reaction conditions the amidines 4b±f were
converted into the expected pyridineacetamides 6a±l and
6o, whereas the compounds 4g, h gave a mixture of two
amide derivatives 6m and 7a, 6n and 7b, 6p and 7c, respec-
tively. Con®rmation of the structures was obtained from
1
both H and 13C NMR of the puri®ed materials obtained
According to path b the formation of 4,6-dimethylpyridine
derivative 5 is rationalized as follows: addition of the amino
group on the C-6 position of the pyran-2-one nucleus, ring
opening, followed by ring closure of the C-a amidinic
carbanion intermediate. The ®nal product 5 was achieved
after decarboxylation step, as it is well known on the
pyridine nucleus,10 and amino group elimination favored
by aromatization to give pyridine ring.
in a ratio of about 2:1, respectively.
It can be reasonably assumed that 7a±c arise from a trans-
amidation reaction of the amidines 4g, h or of their
intermediate compounds (Scheme 4). Amine exchange
reaction has already been studied12 on formamidines.
Considering that the key synthetic step in the formation of
pyridine nucleus was the ®nal cyclization of the C-a
amidinic carbanion intermediate, the dif®cult formation of
ethyl or methylsulfanylethyl carbanion could explain the
low yield of the desired amides 6m, 6n and 6p and the
concomitant formation of the amides 7a±c.
To con®rm the proposed mechanism and to determine the
best conditions to enhance the yield of amide derivatives 6
we decided to investigate the reaction closely.
The reaction of the amidine 4a in piperidine as solvent at
608C for 35 h afforded a reaction mixture containing 15% of
amide 6a and pyridine 5 in 85% yield. During subsequent
experiments the piperidine and the amidine 4a were mixed
in a sealed tube and put in a preheated oil bath at 170and
then at 2008C. Signi®cant improvements in yields were
In order to verify that the amides 7a±c do not arise from
nucleophilic attack on C-a of the pyridine nucleus,13 the
amide 6m was treated with a large amount of piperidine
and heated in a sealed tube for 4 h, under the same
1
previously adopted conditions. H NMR analysis of the

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E. M. Beccalli et al. / Tetrahedron 58 (2002) 1213±1221
Scheme 4.
Table 1. Preparation of 2-pyridineacetamides 6 and 7 from amidines 4
Starting compounds
Amine
Reaction time (h)
Amide 6 yield (%)
Amide 7 yield (%)
4a
4a
4a
4b
4c
4c
4d
4d
4d
4e
4e
4f
Piperidine
4
3
2.5
4
2.5
2.5
2.5
2.5
4
2.5
2.5
4
6a (70)
6b (72)
6c (75)
6d (67)
6e (70)
6f (73)
6g (60)
6h (60)
6i (53)
6j (70)
6k (65)
6l (65)
6m (40)
6n (57)
6o (65)
6p (42)
N-Methylpiperazine
Morpholine
Piperidine
Piperidine
N-Methylpiperazine
piperidine
N-Methylpiperazine
N-Carbethoxypiperazine
Piperidine
N-Methylpiperazine
N-Methylpiperazine
Piperidine
4g
4g
4a
4h
4
3
2
2
7a (20)
7b (26)
N-Methylpiperazine
Diethylamine
N-Methylpiperazine
7c (23)

E. M. Beccalli et al. / Tetrahedron 58 (2002) 1213±1221
1217
crude reaction mixture showed only the amide 6m peaks
and con®rmed transamidation hypothesis.
Jˆ8.4 Hz, ArH-60); 7.25 (1H, dd, Jˆ8.4 and 2.2 Hz, ArH-
50); 7.52 (1H, d, Jˆ2.2 Hz, ArH-30). Anal. calcd for
C18H18Cl2N4O3: C, 52.83; H, 4.43; N, 13.69; found: C,
52.94; H, 4.51; N, 13.42.
2. Conclusion
3.1.3. 4-(4,5-Dihydro-4-methylsulfanylmethyl-5-morpho-
lino-1H-1,2,3-triazol-1-yl)-6-methyl-2H-pyran-2-one 3h.
A benzene solution (20ml) of morpholine (1.74 g,
20mmol) was added dropwise to a stirred solution of
azide 1 (3 g, 20mmol) and 3-methylsulfanylpropionalde-
hyde (2.08 g, 20 mmol) in benzene (30 ml). The mixture
was stirred at rt until the starting azide disappeared (about
3 h) (TLC cyclohexane/EtOAc, 1:9). The solution was dried
with Na2SO4, ®ltered and the ®ltrate evaporated under
reduced pressure. The residue was dissolved in CH2Cl2
and by adding iPr2O afforded pure 3h (4.8 g, 74%) as
These results demonstrated the double reactivity of the
amidines functionalized at iminic nitrogen with pyran-2-
one nucleus and the synthetic potentiality of the substrate.
In this case the amidines became part of a wide chapter of the
synthetic methodology to obtain functionalized pyridines.
3. Experimental
3.1. General
cream needles; mp 998C (decomp.); IR (Nujol) nmax 1727
1
(CvO) cm21; H NMR d 2.20(3H, s, CH S), 2.29 (3H, s,
3
Melting points were determined using a Buchi 510
(capillary) or an Electrothermal 9100 apparatus and are
uncorrected. IR spectra were measured using a JASCO IR
CH3), 2.21±2.45 (5H, m, CH2NCH2 and 1H of CH2S linked
to C-4), 2.99 (1H, dd, Jˆ4.3 Hz and Jgemˆ13.8 Hz, H of
CH2S linked to C-4), 3.60±3.70 (4H, m, CH2OCH2), 4.65
(1H, d, Jtransˆ3.0Hz, H-5), 4.75 (1H, ddd, Jtransˆ3.0Hz,
Jˆ4.3 and 7.3 Hz, H-4), 5.77 (1H, s, H-3 pyranone), 6.71
(1H, s, H-5 pyranone). Anal. calcd for C14H20N4O3S: C,
51.84; H, 6.21; N, 17.27; found C, 51.89; H, 6.27; N, 16.98.
1
Report 100 instrument. H and 13C NMR spectra (tetra-
methylsilane as internal standard) were recorded with EM
Varian Gemini 200, Bruker AC 200 and Bruker Avance 300
Spectrometers. J values are given in Hz for solutions in
CDCl3. Column chromatography was performed on
Kieselgel 60 (Merck) 0.063±0.200 mm with eluents and
ratios indicated.
3.1.4. 4-[2-(2,4-Dichlorophenyl)-1-morpholino-ethylide-
neamino]-6-methyl-2H-pyran-2-one 4f. Dihydrotriazole
3f (4.1 g, 10mmol) was dissolved in n-propanol (70ml)
and heated under re¯ux until the starting compound dis-
appeared (2 h), progress of the reaction being followed by
TLC (cyclohexane/EtOAc 4:6). The solvent was removed in
vacuo. The crude residue was taken up with CH2Cl2 and
insoluble precipitate was ®ltered off. The ®ltrate was evapo-
rated under reduced pressure to give a residue, which was
crystallized from n-PrOH to afford the amidine 4f (2.67 g,
70%) as orange plates; mp 1378C; IR (Nujol) nmax 1715
Materials. 2,4-Dichlorophenylacetaldehyde,14 azide 115 and
enamines 2a, b, d,16 2c,17 2e18 have already been described.
4,5-Dihydrotriazoles 3a±e and 3g and amidines 4a±e and
4g are known compounds.2
3.1.1. (E) 4-[2-(2,4-Dichlorophenyl)-ethenyl]-morpholine
2f. 2,4-Dichlorophenylacetaldehyde (5.9 g, 30mmol) and
morpholine (2.7 ml, 30mmol) were dissolved in anhydrous
toluene (60ml) and heated at re¯ux with azeotropic removal
of water. The reaction progress was checked by IR spectro-
scopy until aldehyde absorption disappeared. The toluene
solution was dried with Na2SO4, ®ltered and the solvent
1
(CvO) cm21; H NMR d 2.18 (3H, s, CH3); 3.41±3.65
(8H, m, morpholine); 3.78 (2H, s, CH2); 5.23 (1H, s,
H±3), 5.63 (1H, s, H-5); 7.10(1H, d, Jˆ8.4 Hz, ArH-60),
7.29 (1H, dd, Jˆ8.4 and 1.8 Hz, ArH-50), 7.44 (1H, d,
Jˆ1.8 Hz, ArH-30). Anal. calcd for C18H18Cl2N2O3: C,
56.71; H, 4.76; N, 7.35. Found: C, 56.68; H, 4.74; N, 7.41.
1
removed under reduced pressure. After IR and H NMR
analysis and without further puri®cation, the pale yellow
oily residue (7 g, 90%) was reacted with azide. IR (liquid
®lm) nmax 1633 cm21 1H NMR d 3.05±3.15 (4H, m,
;
CH2NCH2), 3.72±3.80(4H, m, CH OCH2), 5.63 (1H, d,
3.1.5. 6-Methyl-4-(3-methylsulfanyl-1-morpholino-propyl-
ideneamino)-2H-pyran-2-one 4h. A solution of dihydro-
triazole 3h (3.2 g, 10mmol) was re¯uxed in toluene
(60ml), progress of the reaction being followed by TLC
(cyclohexane/EtOAc, 1:9). After disappearance of the start-
ing material (3 h) the solvent was removed in vacuo and the
oily residue crystallized by adding of Et2O to give 4h
(2.46 g, 83%) as cream needles; mp 1118C; IR (Nujol)
2
Jˆ13.9 Hz, vinylic H), 6.60(1H, d, Jˆ13.9 Hz, vinylic
H), 7.07±7.34 (3H, m, ArH). Anal. calcd for
C12H13Cl2NO: C, 55.83; H, 5.08; N, 5.43; found: C, 55.64;
H, 4.96; N, 5.31.
3.1.2. 4-[4-(2,4-Dichlorophenyl)-4,5-dihydro-5-morpho-
lino-1H-1,2,3-triazol-1-yl]-6-methyl-2H-pyran-2-one 3f.
Azide 1 (3.0g, 20mmol) was dissolved in benzene
(20ml) and an equimolar amount of enamine 2f, dissolved
in benzene (20ml), was added dropwise. The mixture was
stirred overnight at room temperature. (TLC cyclohexane/
EtOAc, 1:9) The white precipitate was ®ltered off and
recrystallized from benzene to give pure 3f as white crystals
(5.97 g, 73%); mp 1548C (decomp.); IR (Nujol) nmax 1716
(CvO) cm21; 1H NMR d 2.33 (3H, s, CH3); 2.43±2.52 (4H,
m, CH2NCH2); 3.65±3.75 (4H, m, CH2OCH2); 4.57 (1H, d,
Jˆ3.3 Hz, H-5); 5.98 (1H, d, Jˆ3.3 Hz, H-4); 5.73 (1H, s,
H-3 pyranone); 6.77 (1H, s, H-5 pyranone); 6.57 (1H, d,
1
nmax 1690(C vO) cm21; H NMR d 2.08 (3H, s, CH3);
2.22 (3H, s, SCH3), 2.56±2.70(4H, m, 2 £CH2), 3.45±
3.53 (4H, m, CH2NCH2); 3.70±3.78 (4H, m, CH2OCH2);
5.28 (1H, s, H-3), 5.67 (1H, s, H-5). Anal. calcd for
C14H20N2O3S: C, 56.74; H, 6.80; N, 9.45; found: C, 56.65;
H, 6.73; N, 9.30.
3.1.6. Reaction of the amidine 4a with piperidine at
re¯ux. Synthesis of 4-(4,6-dimethyl-3-phenyl-pyridin-2-
yl)-morpholine 5 and 2-(4-methyl-6-morpholino-5-phen-
yl-pyridin-2-yl)-1-piperidin-1-yl-ethanone 6a. Amidine

1218
E. M. Beccalli et al. / Tetrahedron 58 (2002) 1213±1221
4a (1.56 g, 5 mmol) was suspended in piperidine (15 ml).
The reaction mixture was re¯uxed until disappearance (TLC
monitoring) of the starting compound (17 h). The amine
excess was removed in vacuo and the crude residue
chromatographed on a silica gel column, eluent EtOAc/
cyclohexane (4:6). Two fractions were collected: a ®rst
minor fraction containing the pyridine derivative 5 and a
second fraction containing the pyridine amide 6a
(CH2OCH2); 119.3 (C-3); 127.5, 128.9, 130.4 (ArCH);
126.2, 138.3, 147.9 (ArCqu); 152.3 (C-2); 160.1 (C-6);
169.5 (CvO). Anal. calcd for C23H30N4O2: C, 70.02; H,
7.66; N, 14.20; found: C, 69.87; H, 7.54; N, 13.99.
3.2.3. 2-(4-Methyl-6-morpholino-5-phenyl-pyridin-2-yl)-
1-morpholin-4-yl-ethanone 6c. (EtOAc); orange plates
from iPr2O; mp 1348C; IR (Nujol) nmax 1634 (CvO)
1
cm21; H NMR d 2.06 (3H, s, p-CH3); 2.90±2.98 (4H, m,
Compound 5: White crystals from iPr2O, 0.39 g, yield 29%,
mp 878C; H NMR d 2.05 (3H, s, p-CH3); 2.44 (3H, s,
CH2NCH2); 3.42±3.50(4H, m, CH 2OCH2); 3.60±3.77 (8H,
1
m, OvCN(CH2)2 and CH2OCH2); 3.80(2H, s, CH ); 6.87
2
o-CH3); 2.92±3.02 (4H, m, CH2NCH2); 3.43±3.50(4H,
m, CH2OCH2); 6.70(1H, s, H-3); 7.2±7.44 (5H, m, ArH);
13C NMR d 20.8 (p-CH3); 24.5 (o-CH3); 50.1 (CH2NCH2);
67.4 (CH2OCH2); 119.1 (m-CH); 127.3, 128.8, 130.6,
(ArCH); 125.0, 138.8, 147.2 (ArCqu); 155.2 (C bound to
o-CH3); 160.0 (C bound to morpholino group). Anal. calcd
for C17H20N2O: C, 76.09; H, 7.51; N, 10.44; found: C,76.01;
H, 7.62; N, 10.33.
(1H, s, H-3); 7.26±7.45 (5H, m, ArH). 13C NMR d 20.6
(p-CH3) 42.3 and 43.3 (OvC±N(CH2)2); 47.0( CH2±
CvO); 49.7 (CH2NCH2); 66.9 (2£CH2OCH2), 119.0(C-
3); 127.2, 128.5, 130.0 (ArCH); 125.9, 137.8, 147.6
(ArCqu), 151.7 (C-2); 159.7 (C-6); 169.4 (CvO). Anal.
calcd for C22H27N3O3: C, 69.27; H, 7.13; N, 11.02; found:
C, 69.02; H, 7.16; N, 10.81.
3.2.4. 2-(4-Methyl-6-morpholino-5-p-tolyl-pyridin-2-yl)-
1-piperidin-1-yl-ethanone 6d. (EtOAc/cyclohexane, 7:3);
cream needles from iPr2O; mp 908C; IR (Nujol) nmax 1644
(CvO) cm21; 1H NMR d 1.42±1.65 (6H, m, CH2CH2CH2);
2.05 (3H, s, p-CH3); 2.39 (3H, s, CH3-tolyl); 2.84±2.98 (4H,
Compound 6a: cream crystals from petroleum ether, 1.14 g,
yield 60%, mp 1128C; IR (Nujol) nmax 1630(C vO) cm21
;
1H NMR d 1.45±1.70(6H, m, CH CH2CH2); 2.06 (3H, s,
2
p-CH3); 2.90±3.00 (4H, m, CH 2NCH2); 3.42±3.50(4H, m,
CH2OCH2); 3.54±3.69 (4H, m, OvC±N(CH2)2); 3.80(2H,
s, CH2); 6.87 (1H, s, H-3); 7.29±7.47 (5H, m, ArH); 13C
NMR d 20.6 (p-CH3); 24.6, 25.6, 26.5 (CH2CH2CH2);
43.0, 43.6 (OvC±N(CH2)2); 47.7 (CH2±CvO); 49.7
(CH2NCH2); 66.9 (CH2OCH2), 118.9 (C-3); 127.1, 128.5,
130.1 (ArCH); 125.6, 138.0, 147.4 (ArCqu), 152.2 (C-2);
159.6 (C-6); 169.0(C vO). Anal. calcd for C23H29N3O2: C,
72.79; H, 7.70; N, 11.07; found: C, 72.67; H, 7.63; N, 11.09.
m, CH2NCH2); 3.43±3.50(4H, m, CH OCH2); 3.56±3.68
2
(4H, m, OvCN(CH2)2); 3.79 (2H, s, CH2); 6.85 (1H, s,
H-3); 7.11±7.24 (4H, m, ArH); 13C NMR d 20.6 (p-CH3);
21.3 (CH3-tolyl); 24.6, 25.6, 26.5 (CH2CH2CH2); 43.0and
43.7 (OvC±N(CH2)2); 47.6 (CH2±CvO); 49.6
(CH2NCH2); 66.9 (CH2OCH2), 118.8 (C-3); 129.2, 129.9,
(ArCH); 125.5, 134.9, 136.6, 147.4 (ArCqu); 152.0(C-2);
159.6 (C-6); 168.9 (CvO). Anal. calcd for C24H31N3O2: C,
73.25; H, 7.94; N, 10.68; found: C, 73.17; H, 7.85; N, 10.89.
3.2. General procedure for the preparation of amide
derivatives 6 and 7
3.2.5.
2-[5-(4-Chlorophenyl)-4-methyl-6-morpholino-
pyridin-2-yl]-1-piperidin-1-yl-ethanone 6e. (EtOAc/
cyclohexane, 6:4); cream plates from iPr2O; mp 868C; IR
(Nujol) nmax 1620(C vO) cm21; 1H NMR d 1.38±1.70(6H,
m, CH2CH2CH2); 2.04 (3H, s, p-CH3); 2.90±3.00 (4H, m,
CH2NCH2); 3.43±3.54 (4H, m, CH2OCH2); 3.53±3.68 (4H,
m, OvC±N(CH2)2); 3.79 (2H, s, CH2); 6.87 (1H, s, H-3);
7.23 and 7.40(4H, 2 x d, AB system, Jˆ8.5 Hz, ArH); 13C
NMR d 20.9 (p-CH3); 25.0, 26.0, 26.9 (CH2CH2CH2); 43.4
and 43.9 (OvC±N(CH2)2); 48.0( CH2±CvO); 50.2
(CH2NCH2); 67.2 (CH2OCH2); 119.5 (C-3); 129.2, 131.9
(ArCH); 124.9, 133.3, 136.9, 147.7 (ArCqu); 153.1 (C-2);
160.0 (C-6); 169.1 (CvO). Anal. calcd for C23H28ClN3O2:
C, 66.74, H, 6.82, N, 10.15; found: C, 66.63; H, 6.77; N,
10.21.
Amidines 4a±h (5 mmol) mixed with a large amount of the
appropriate amine (100 mmol) in a sealed tube were put in a
preheated oil bath at 2008C and heated for at least 2 h. After-
wards, the progress of the reaction was monitored by TLC
every 30min, until disappearance of the starting amidine 4.
The amine excess was removed in vacuo and the residue
was chromatographed on silica gel affording compound 6
and in some cases minor amounts of compound 7 (eluent
described later). The yields of isolated and puri®ed products
6 and 7 are listed in Table 1.
3.2.1. 2-(4-Methyl-6-morpholino-5-phenyl-pyridin-2-yl)-
1-piperidin-1-yl-ethanone 6a. (EtOAc/cyclohexane, 4:6).
Analytical data are described earlier.
3.2.6.
2-[5-(4-Chlorophenyl)-4-methyl-6-morpholino-
pyridin-2-yl]-1-(4-methyl-piperazin-1-yl)-ethanone 6f.
(MeOH/EtOAc, 7:3); cream plates from iPr2O; mp 1158C;
IR (Nujol) nmax 1630(C vO) cm21; 1H NMR d 2.06 (3H, s,
p-CH3); 2.31 (3H, s, CH3±N); 2.30±2.50 (4H, m,
(CH2)2NCH3); 2.93±3.00 (4H, m, CH2NCH2); 3.45±3.57
(4H, m, CH2OCH2); 3.65±3.80(4H, m, O vC±N(CH2)2);
3.81 (2H, s, CH2); 6.88 (1H, s, H-3); 7.25 and 7.41 (4H, 2 x
d, AB system, Jˆ8.4 Hz, ArH); 13C NMR d 20.4 (p-CH3);
41.8 and 43.3 (H3C±N(CH2)2); 46.1 (H3C±N); 46.5 (CH2±
CvO); 49.8 (CH2NCH2); 54.7 and 55.3 (OvCN(CH2)2);
66.8 (CH2OCH2); 119.2 (C-3); 128.8, 131.5 (ArCH);
124.6, 133.0, 136.4, 147.5 (ArCqu); 152.4 (C-2,); 159.6
3.2.2. 2-(4-Methyl-6-morpholino-5-phenyl-pyridin-2-yl)-
1-(4-methyl-pyperazin-1-yl)-ethanone
EtOAc, 7:3); cream plates from iPr2O; mp 1108C; IR
6b.
(MeOH/
1
(Nujol) nmax 1620(C vO) cm21; H NMR d 2.05 (3H, s,
p-CH3); 2.33 (3H, s, H3C±N); 2.35±2.47 (4H, m, H3C±
N(CH2)2); 2.87±2.96 (4H, m, CH2NCH2); 3.38±3.48 (4H,
m, CH2OCH2); 3.67±3.82 (4H, m, OvCN(CH2)2); 3.80
(2H, s, CH2); 6.85 (1H, s, H-3); 7.20±7.42 (5H, m,
ArH).13C NMR d 20.9 (p-CH3); 42.0and 43.8 (H 3C±
N(CH2)2); 46.3 (H3C±N); 46.6 (CH2±CvO); 50.1
(CH2NCH2); 55.0and 55.6 (O vC±N(CH2)2); 67.2

E. M. Beccalli et al. / Tetrahedron 58 (2002) 1213±1221
1219
(C-6); 169.0(C vO). Anal. calcd for C23H29ClN4O2: C,
66.46; H, 6.83; N, 13.08; found: C, 66.39; H, 6.81; N, 13.09.
42.9 and 43.5 (OvC±N±(CH2)2); 47.6 (CH2±CvO); 49.7
(CH2NCH2); 66.8 (CH2OCH2); 115.3 and 115.7 (ArCH.
ortho to F, Jˆ21.5 Hz); 119.0(C-3); 124.7 (C-5); 131.6
and 131.8 (ArCH meta to F, Jˆ7.7 Hz); 133.7 and 133.8
(ArCqu para to F, Jˆ3 Hz); 147.4 (C-4); 152.5 (C-2); 159.7
(C-6); 159.3 and 164.2 (C linked to F, JCFˆ247.0Hz); 168.8
(CvO). Anal. calcd for C23H28FN3O2: C, 69.48; H, 7.10; N,
10.58; found: C, 69.39; H, 7.03; N, 10.46.
3.2.7. 2-[5-(4-Bromophenyl)-4-methyl-6-morpholino-pyri-
din-2-yl]-1-piperidin-1-yl-ethanone 6g. (EtOAc/cyclo-
hexane, 7:3); orange plates from iPr2O; mp 938C; IR
1
(Nujol) nmax 1633 (CvO) cm21; H NMR (200 MHz,) d
1.40±1.78 (6H, m, CH2CH2CH2), 2.06 (3H, s, p-CH3),
2.92±3.00 (4H, m, CH2NCH2), 3.48±3.56 (4H, m,
CH2OCH2); 3.58±3.71 (4H, m, OvC±N(CH2)2); 3.81
(2H, s, CH2); 6.89 (1H, s, H-3) 7.20and 7.56 (4H, 2 £d,
AB system, Jˆ8.4 Hz, ArH); 13C NMR d 20.5 (p-CH3);
24.6, 25.6, 26.6 (CH2CH2CH2); 43.0and 43.6 (O vC±
N(CH2)2); 47.6 (CH2±CvO); 49.8 (CH2NCH2); 66.9
(CH2OCH2); 119.2 (C-3); 121.5 (C-5);131.7 and 131.8
(ArCH) 124.5 and 137 (2 ArCqu) 147.3 (C-4); 152.8
(C-2); 159.5 (C-6); 168.8 (CvO). Anal. calcd for
C23H28BrN3O2: C, 60.26; H, 6.16; N, 9.17; found: C,
59.94; H, 6.15; N, 8.98.
3.2.11. 2-[5-(4-Fluorophenyl)-4-methyl-6-morpholino-
pyridin-2-yl]-1-(4-methyl-piperazin-1-yl)-ethanone 6k.
(MeOH/EtOAc, 7:3); cream plates from iPr2O; mp 508C;
1
IR (Nujol) nmax 1632 (CvO) cm21; H NMR d 2.04 (3H,
s, p-CH3), 2.27 (3H, s, CH3±N); 2.30±2.43 (4H, m,
(CH2)2NCH3); 2.85±2.97 (4H, m, CH2NCH2); 3.35±3.47
(4H, m, CH2OCH2); 3.60±3.75 (4H, m, OvC±N(CH2)2);
3.78 (2H, s, CH2); 6.87 (1H, s, H-3); 7.10and 7.29 (4H, 2 £d,
AB system Jˆ8.8 Hz, ArH). 13C NMR d 20.4 (p-CH3); 41.8
and 43.3 (H3C±N(CH2)2); 46.1 (H3C±N); 46.4 (CH2±
CvO); 49.8 (CH2NCH2); 54.7 and 55.3 (OvC±N
(CH2)2); 66.8 (CH2OCH2); 115.3 and 115.8 (ArCH ortho
to F, Jˆ21.5 Hz); 119.1 (C-3); 124.8 (C-5); 131.6 and
131.8 (ArCH meta to F Jˆ7.8 Hz); 133.7 and 133.8
(ArCqu para to F, Jˆ2.9 Hz); 147.5 (C-4); 152.2 (C-2);
159.80(C-6); 159.4 and 164.3 ( C linked to F, JCFˆ
247.0Hz); 169.1 (C vO). Anal. calcd for C23H29FN4O2:
C, 66.95; H, 7.09; N, 13.59; found: C, 66.75; H, 6.99; N,
13.51.
3.2.8.
2-[5-(4-Bromophenyl)-4-methyl-6-morpholino-
pyridin-2-yl]-1-(4-methyl-piperazin-1-yl)-ethanone 6h.
(MeOH/EtOAc, 7:3); ochre plates from iPr2O; mp 1128C;
IR (Nujol) nmax 1650(C vO) cm21; 1H NMR d 2.06 (3H, s,
3H, p-CH3); 2.32 (3H, s, N±CH3); 2.36±2.44 (4H, m,
(CH2)2NCH3); 2.92±2.97 (4H, m, CH2NCH2); 3.47±3.52
(4H, m, CH2OCH2); 3.68±3.79 (4H, m, OvC±N(CH2)2);
3.81 (2H, s, CH2); 6.88 (1H, s, H-3); 7.19 and 7.57 (4H, 2£d,
AB system, Jˆ8.1 Hz, ArH); 13C NMR d 20.5 (p-CH3);
41.8 and 43.3 (H3C±N(CH2)2); 46.1 (H3C±N); 46.5
(CH2±CvO); 49.8 (CH2NCH2); 54.7 and 55.3 (OvC±
N(CH2)2); 66.8 (CH2OCH2); 119.2 (C-3); 131.8 (ArCH);
121.1, 124.6, 136.9, 147.4 (ArCqu); 152.4 (C-2); 159.6
(C-6); 169.0(C vO). Anal. calcd for C23H29BrN4O2: C,
58.35, H, 6.17, N, 11.83; found: C, 58.50; H, 6.17; N, 11.71.
3.2.12. 2-[5-(2,4-Dichlorophenyl)-4-methyl-6-morpho-
lino-pyridin-2-yl]-1-(4-methyl-piperazin-1-yl)-ethanone
6l. (MeOH/EtOAc, 7:3); yellow oil; IR (liquid ®lm) nmax
1
1643 (CvO) cm21; H NMR d 2.00 (3H, s, p-CH3); 2.30
(3H, s, CH3±N); 2.32±2.40(4H, m, (CH ) NCH3); 2.95±
2 2
3.00 (4H, m, CH2NCH2); 3.47±3.55 (4H, m, CH2OCH2);
3.66±3.78 (4H, m, OvC±N (CH2)2); 3.83 (2H, s, CH2);
6.90(1H, s, H-3); 7.18 (1H, d, Jˆ8.1 Hz, H-60); 7.34 (1H,
dd, Jˆ8.1 and 2.2 Hz, H-50), 7.53 (1H, d, Jˆ2.2 Hz, H-30);
13C NMR d 19.6 (p-CH3); 41.8 and 43.5 (H3C±N(CH2)2);
46.0(H 3C±N); 46.4 (CH2±CvO); 49.73 (CH2NCH2); 54.7
and 55.2 (OvC±N(CH2)2); 66.8 (CH2OCH2); 118.9 (C-3);
127.5, 129.7, 132.8 (ArCH); 122.9, 134.0, 135.1, 135.7,
148.5 (ArCqu); 153.3 (C-2); 159.7 (C-6); 169.0(C vO).
Anal. calcd for C23H28Cl2N4O2: C, 59.72; H, 6.11; N,
12.12; found: C, 59.57; H, 6.04; N, 11.96.
3.2.9. 4-{2-[5-(4-Bromophenyl)-4-methyl-6-morpholino-
pyridin-2-yl]-acetyl}-piperazine-1-carboxylic acid ethyl
ester 6i. (EtOAc/cyclohexane, 9:1); white crystals from
iPr2O; mp 1428C; IR (Nujol) nmax 1632 (CvO), 1680
1
(N±C±OO) cm21; H NMR d 1.29 (3H, t, Jˆ7 Hz, CH3±
CH2); 2.07 (3H, s, p-CH3), 2.92±2.97 (4H, m, CH2NCH2);
3.40±3.60 (8H, m, CH2OCH2 and (CH2)2NCOOEt); 3.64±
3.77 (4H, m, OvC±N(CH2)2); 3.83 (2H, s, CH2); 4.17 (2H,
dd, Jˆ7 Hz, CH2±CH3); 6.89 (1H, s, H-3); 7.19 and 7.58
(4H, 2£d, AB system, Jˆ8.4 Hz, ArH); 13C NMR d 14.7
(CH3±CH2); 20.5 (p-CH3); 41.7 (C2H5OCO±N(CH2)2);
43.5 and 43.9 (OvC±N(CH2)2); 46.3 (CH2±CvO); 49.8
(CH2NCH2); 61.8 (CH2OCvO); 66.8 (CH2OCH2); 119.2
(C-3); 132.0and 132.1 (ArCH); 121.2, 124.8, 136.7, 147.6
(ArCqu); 152.1 (C-2); 155.8 (COOC2H5); 160.0 (C-6);
169.2 (CvO). Anal. calcd for C25H31BrN4O4: C, 56.59; H,
5.89; N, 10.57; found: C, 56.36; H, 5.72; N, 10.34.
3.2.13. 2-(4,5-Dimethyl-6-morpholino-pyridin-2-yl)-1-
piperidin-1-yl-ethanone 6m. (EtOAc/cyclohexane, 7:3);
white needles from iPr2O; mp 818C; IR (Nujol) nmax 1630
(CvO) cm21; 1H NMR d 1.30±1.65 (6H, m, CH2CH2CH2);
2.17 (3H, s, m-CH3); 2.23 (3H, s, p-CH3); 2.98±3.10(4H, m,
CH2NCH2); 3.50±3.68 (4H, m, OvC±N(CH2)2); 3.78 (2H,
s, CH2); 3.80±3.87 (4H, m, CH2OCH2); 6.87 (1H, s, H-3);
13C NMR d 14.2 (m-CH3); 20.2 (p-CH3); 24.9, 25.9, 26.9
(CH2CH2CH2); 43.3 and 44.1 (OvC±N±(CH2)2); 47.9
(CH2±CvO); 51.1 (CH2NCH2); 67.6 (CH2OCH2); 120.1
(C-3); 121.7 (C-5); 148.4 (C-4); 151.1 (C-2); 161.4 (C-6);
169.3 (CvO). Anal. calcd for C18H27N3O2: C, 68.09; H,
8.58; N, 13.24; found: C, 68.36; H, 8.65; N, 13.19.
3.2.10. 2-[5-(4-Fluorophenyl)-4-methyl-6-morpholino-
pyridin-2-yl]-1-piperidin-1-yl-ethanone 6j. (EtOAc/
cyclohexane, 7:3); pale yellow oil; IR (liquid ®lm) nmax
1640(C vO) cm21 1H NMR d 1.42±1.63 (6H, m,
;
CH2CH2CH2); 2.04 (3H, s, p-CH3); 2.95±2.99 (4H, m,
CH2NCH2); 3.45±3.51 (4H, m, CH2OCH2); 3.54±3.67
(4H, m, OvC±N(CH2)2); 3.79 (2H, s, CH2); 6.87 (1H, s,
H-3); 7.10and 7.29 (4H, 2 £d, AB system, Jˆ8.8 Hz, ArH);
13C NMR d 20.4 (p-CH3); 24.5, 25.6, 26.5 (CH2CH2CH2);
3.2.14. 2-(4,5-Dimethyl-6-piperidino-pyridin-2-yl)-1-
piperidin-1-yl-ethanone 7a. White needles from iPr2O;
1
mp 728C; IR (Nujol) nmax 1630(C vO) cm21; H NMR d

1220
E. M. Beccalli et al. / Tetrahedron 58 (2002) 1213±1221
1.30±1.80 (12H, m, 2£CH2CH2CH2); 2.15 (3H, s, m-CH3);
2.19 (3H, s, p-CH3); 2.92±3.06 (4H, m, CH2NCH2); 3.50±
3.68 (4H, m, OvC±N(CH2)2); 3.76 (2H, s, CH2); 6.80(1H,
s, 1H, H-3); 13C NMR d 14.3 (m-CH3); 20.3 (p-CH3); 25.0,
25.1, 26.0, 26.7, 26.8 (CH2 of piperidines); 43.3, 44.4
s, CH2S); 3.77 (2H, s, CH2CO); 3.80±3.86 (4H, m,
CH2OCH2); 6.87 (1H, s, H-3); 13C NMR d 16.3 (CH3S);
19.2 (p-CH3); 31.3 (CH2S); 41.8 and 43.5 ((CH2)2NCH3);
46.0(NCH 3); 46.3 (CH2CvO); 51.8 (CH2NCH2); 54.7 and
55.2 (OvC±N(CH2)2); 67.3 (CH2OCH2); 121.3 (C-3);
123.0(C-5); 149.5 (C-4); 152.2 (C-2); 161.9 (C-6); 168.9
(CvO). Anal. calcd for C19H30N4O2S: C, 60.28; H, 7.99; N,
14.81; found: C, 60.35; H, 8.13; N, 14.76.
(OvC±N±(CH2)2); 47.9 (CH2±CvO); 52.0(CH NCH2);
2
119.3 (C-3); 121.9 (C-5); 148.0(C-4); 150.8 (C-2); 162.9
(C-6); 169.6 (CvO). Anal. calcd for C19H29N3O: C, 72.33,
H, 9.27, N, 13.33; found: C, 72.28; H, 9.19; N, 13.25.
3.2.19. 2-[4-Methyl-6-(4-methyl-piperazin-1-yl)-5-methyl-
sulfanylmethyl-pyridin-2-yl]-1-(4-methyl-piperazin-1-yl)-
ethanone 7c. Yellow oil; IR (liquid ®lm) nmax 1644 (CvO)
cm21; 1H NMR d 2.13 (3H, s, CH3S); 2.27 (3H, s, p-CH3);
2.30±2.42 (4H, m, (CH2)2NCH3); 2.39 (3H, s, CH3±N);
2.41 (3H, s, CH3±N); 2.58±2.67 (4H, m, (CH2)2NCH3);
3.18±3.24 (4H, m, CH2NCH2); 3.58±3.72 (4H, m, OvC±
N(CH2)2); 3.77 (2H, s, CH2S); 3.78 (2H, s, CH2CO); 6.89
(1H, s, H-3); 13C NMR d 16.3 (CH3S); 19.3 (p-CH3); 31.3
(CH2S); 41.8 and 43.6 (CH2)2NCH3); 46.1 (NCH3); 46.3
(NCH3); 46.4 (CH2CvO); 51.3 (CH2NCH2); 54.7 and
55.0(O vC±N(CH2)2); 55.2 and 55.5 ((CH2)2NCH3);
121.0(C-3); 122.9 (C-5); 149.3 (C-4); 152.0(C-2); 161.9
(C-6); 169.1 (CvO). Anal. calcd for C20H33N5OS: C,
61.34; H, 8.50; N, 17.90; found: C, 61.39; H, 8.65; N,
17.81.
3.2.15. 2-(4,5-Dimethyl-6-morpholino-pyridin-2-yl)-1-(4-
methyl-piperazin-1-yl)-ethanone 6n. (MeOH/EtOAc,
7:3); pale yellow oil; IR (liquid ®lm) nmax 1644 (CvO)
cm21 1H NMR d 2.18 (3H, s, m-CH3); 2.23 (3H, s,
;
p-CH3) 2.31 (3H, s, CH3±N); 2.33±2.43 (4H, m,
(CH2)2NCH3); 3.02±3.10 (4H, m, CH2NCH2); 3.62±3.76
(4H, m, OvC±N(CH2)2); 3.77 (2H, s, CH2); 3.82±3.88
(4H, m, CH2OCH2); 6.85 (1H, s, H-3); 13C NMR d 14.0
(m-CH3); 20.0 (p-CH3); 41.7 and 43.5 ((CH2)2NCH3); 46.1
(NCH3); 46.3 (CH2CvO); 50.8 (CH2NCH2); 54.7 and 55.3
(OvC±N(CH2)2); 67.2 (CH2OCH2); 119.9 (C-3); 121.6 (C-
5); 148.3 (C-4); 150.4 (C-2); 161.1 (C-6); 169.3 (CvO).
Anal. calcd for C18H28N4O2: C, 65.02, H, 8.48, N, 16.86;
found: C, 64.83; H, 8.42; N, 16.68.
3.2.16. 2-[4,5-Dimethyl-6-(4-methyl-piperazin-1-yl)-pyri-
din-2-yl]-1-(4-methyl-piperazin-1-yl)-ethanone 7b. Pale
1
yellow oil; IR (liquid ®lm) nmax 1643 (CvO) cm21; H
Acknowledgements
NMR d 2.15 (3H, s, m-CH3); 2.21 (3H, s, p-CH3); 2.27
(3H, s, CH3±N); 2.33±2.38 (4H, m, (CH2)2NCH3); 2.44
(3H, s, CH3±N); 2.64±2.74 (4H, m, (CH2)2NCH3); 3.12±
3.22 (4H, m, CH2NCH2); 3.61±3.73 (4H, m, OvC±N±
(CH2)2); 3.76 (2H, s, CH2); 6.83 (1H, s, H-3); 13C NMR d
14.1 (m-CH3); 20.0 (p-CH3); 41.7 and 43.6 ((CH2)2NCH3);
46.0(NCH 3); 46.2 (NCH3); 46.4 (CH2CvO); 50.0
(CH2NCH2); 54.7 and 55.3 (OvC±N(CH2)2 and
CH2NCH2); 119.5 (C-3); 121.5 (C-5); 148.1 (C-4); 150.2
(C-2); 161.1 (C-6); 169.4 (CvO). Anal. calcd for
C19H31N5O: C, 66.04, H, 9.05, N, 20.28; found: C, 66.31;
H, 9.13; N, 20.07.
The authors are grateful to the M.U.R.S.T. (Italian Ministry
of University, Science and Technology) for ®nancial
support.
References
1. Boyd, G. V. The Chemistry of Amidines and Imidates; Patai,
S., Rappoport, Z., Eds.; Interscience: London, 1991; Vol. 2,
pp 367±426.
2. Erba, E.; Pocar, D.; Trimarco, P. J. Chem. Soc., Perkin Trans.
1 2001, 1723±1728.
3.2.17. N,N-Diethyl-2-(4-methyl-6-morpholino-5-phenyl-
pyridin-2-yl)-acetamide 6o. (EtOAc/cyclohexane, 7:3);
chestnut plates from iPr2O; mp 778C; IR (Nujol) nmax
3. (a) Ellis, G. P. Comprehensive Heterocyclic Chemistry;
Boulton, A. J., McKillop, A., Eds.; Pergamon: Oxford,
1984; Vol. 3,
p 681 and references cited therein.
1631 (CvO) cm21 1H NMR d 1.13±1.25 (6H, m,
;
(b) Moreno-ManÄas, M.; Pleixats, R. Adv. Heterocycl. Chem.
1992, 53, 59 and following.
2£CH3CH2); 2.08 (3H, s, p-CH3); 2.93±3.01 (4H, m,
CH2NCH2); 3.43±3.50(4H, m, CH 2OCH2); 3.52±3.63
(4H, m, 2£CH2CH3); 3.79 (2H, s, CH2CvO); 6.88 (s; 1H,
H-3); 7.27±7.43 (5H, m, ArH); 13C NMR d 13.1 (CH3); 14.4
(CH3); 20.5 (p-CH3); 40.3 (CH2); 42.6 (CH2); 43.2
(CH2CvO); 49.7 (CH2NCH2); 66.9 (CH2OCH2); 119.0
(C-3); 127.0, 128.5, 130.1 (ArCH); 125.6, 138.1, 147.3
(ArCqu); 152.5 (C-2); 159.6 (C-6.); 169.9 (CvO). Anal.
calcd for C22H29N3O2: C, 71.89; H, 7.96; N, 11.44; found:
C, 71.75; H, 7.83; N, 11.29.
4. (a) Beccalli, E. M.; Erba, E.; Gelmi, M. L.; Pocar, D. J. Chem.
Soc., Perkin Trans. 1 1996, 1359±1364. (b) Erba, E.;
Sporchia, D. J. Chem. Soc., Perkin Trans. 1 1997, 3021±3024.
5. Bernhart, C. A.; Condamine, C.; Damarne, H.; Roncucci, R.;
Gagnol, J. P.; Gautier, J. P.; Serre, M. A. J. Med. Chem. 1983,
26, 451±455.
6. Humber, D. C.; Bamford, M. J.; Berthell, R. C.; Cammack, N.;
Cobley, K.; Evans, D. N.; Gray, N. M.; Hann, M. M.; Orr,
D. C.; Saunders, J.; Shenoy, B. E. V.; Storer, R.; Weingarten,
G. G.; Wyatt, P. G. J. Med. Chem. 1993, 36, 3120±3128.
7. Sliskovic, D. R.; Picard, J. A.; O'Brien, P. M.; Liao, P.; Roark,
W. H.; Roth, D. B.; Anderson, M. A.; Bak Mueller, S.; Bocan,
T. M. A.; Bousley, R. F.; Hamelehle, K. L.; Homan, R.;
Reindel, J. F.; Stan®eld, R. L.; Turluck, D.; Krause, B. R.
J. Med. Chem. 1998, 41, 682±690.
3.2.18. 2-(4-Methyl-5-methylsulfanylmethyl-6-morpho-
lino-pyridin-2-yl)-1-(4-methyl-piperazin-1-yl)-ethanone
6p. (MeOH/EtOAc, 7:3); chestnut plates from iPr2O; mp
1
728C; IR (Nujol) nmax 1643 (CvO) cm21; H NMR d
2.11 (3H, s, CH3S); 2.25 (3H, s, p-CH3); 2.20±2.34 (4H,
m, (CH2)2NCH3); 2.37 (3H, s, CH3±N); 3.08±3.14 (4H, m,
CH2NCH2); 3.40±3.72 (4H, m, OvC±N(CH2)2); 3.75 (2H,
Ï
8. Kadaba, P. K. B.; Stanovnik, B.; Tisler, M. Adv. Heterocycl.
Chem. 1984, 37, 339 and references cited therein.

E. M. Beccalli et al. / Tetrahedron 58 (2002) 1213±1221
1221
9. (a) Johnson, C. D. Comprehensive Heterocyclic Chemistry;
Boulton, A. J., McKillop, A., Eds.; Pergamon: Oxford,
1984; Vol. 2, pp 117±124 and references cited therein.
(b) Grasselli, J. G., Ritchey, W. M., Eds.; 2nd ed, Atlas of
Spectral Data and Physical Constants for Organic
Compounds; CRC: Cleveland, 1975; Vol. 4, pp 373±408.
(c) Pourchert, C. J.; Behnke, J. The Aldrich Library of 13C
and 1H FT NMR Spectra; 1st ed; Aldrich Chemical Co:
Milwaukee, 1993. (d) Pretsch, E.; Seibl, J.; Clerc, T.;
Simon, W. Tables of Spectral Data for Structure Determina-
tion of Organic Compounds; 2nd ed; Springer: New York,
1989.
A. J., Mc Killop, A., Eds.; Pergamon: Oxford, 1984; pp 684±
685 and references cited therein.
12. Furth, P. S.; Reitmann, M. S.; Cook, A. F. Tetrahedron Lett.
1997, 38, 5403±5406.
13. VorbruÈggen, H. Adv. Heterocycl. Chem. 1990, 49, 142.
14. Kugita, H.; Inoue, H.; Ikezaki, M.; Takeo, S. Chem. Pharm.
Bull. 1970, 18, 2028±2037.
15. Cervera, M.; Moreno-ManÄas, M.; Pleixats, R. Tetrahedron
1990, 46, 7885±7892.
16. Broekhof, N. L. J. M.; Jonkers, F. L.; van der Gen, A.
Tetrahedron Lett. 1979, 26, 2433±2436.
17. Stamos, I. K. Tetrahedron Lett. 1982, 23, 459±462.
18. Crispi, G.; Giacconi, P.; Rossi, E.; Stradi, R. Synthesis 1982,
787±788.
10. Naito, T.; Dohmori, R.; Kotake, T. Chem. Pharm. Bull. 1964,
12, 588±590.
11. Ellis, G. P. Comprehensive Heterocyclic Chemistry; Boulton,