Practical synthesis of 3-bromo-5,6-dihydropyridin-2-ones via β,γ-unsaturated α-bromo-ketene/imine cycloaddition

Article abstract of DOI:10.1016/j.tet.2004.04.021

An approach to 3-bromo-4-alkyl-6-aryl-5,6-dihydropyridin-2-ones and 3-bromo-5-ethyl-6-aryl-5,6-dihydropyridin-2-ones starting from β,γ-unsaturated α-bromoketenes and imines is reported. The presence of a bromine atom on the double bond allows performing aziridination or bromine displacement with an amine. The reaction gave fused bicyclic N-allyl-aziridines or 3-amino-substituted 5,6-dihydropyridin-2-ones, depending on the substituents on the six-membered ring.

Full text of DOI:10.1016/j.tet.2004.04.021

Tetrahedron 60 (2004) 5031–5040
Practical synthesis of 3-bromo-5,6-dihydropyridin-2-ones via
b,g-unsaturated a-bromo-ketene/imine cycloadditionq;qq
*
Giuliana Cardillo, Serena Fabbroni, Luca Gentilucci, Rossana Perciaccante, Fabio Piccinelli
and Alessandra Tolomelli
`
Dipartimento di Chimica ‘G. Ciamician’, Universita di Bologna, Via Selmi 2, 40126 Bologna, Italy
Received 28 January 2004; revised 15 March 2004; accepted 8 April 2004
Abstract—An approach to 3-bromo-4-alkyl-6-aryl-5,6-dihydropyridin-2-ones and 3-bromo-5-ethyl-6-aryl-5,6-dihydropyridin-2-ones
starting from b,g-unsaturated a-bromoketenes and imines is reported. The presence of a bromine atom on the double bond allows
performing aziridination or bromine displacement with an amine. The reaction gave fused bicyclic N-allyl-aziridines or 3-amino-substituted
5,6-dihydropyridin-2-ones, depending on the substituents on the six-membered ring.
q 2004 Published by Elsevier Ltd.
1. Introduction
Ketenes have long been used in the synthesis of various
heterocyclic compounds.8 In the course of our investigation
on the chemistry of unsaturated bromo-ketenes,9 we have
developed a good approach to the synthesis of 3-bromo-4-
alkyl-5,6-dihydropyridin-2-ones and 3-bromo-5-ethyl-5,6-
dihydropyridin-2-ones.
Nitrogen-containing heterocyclic compounds are important
constituents of biologically active natural products1 and
have attracted considerable attention due to their appli-
cations in many fields such as pharmaceuticals and synthetic
organic chemistry.2 In particular, several representative
pyridin-2-ones possess significant biological activity as
antibacterial, antifungal or free radical scavengers,3 and
may be considered starting materials for the synthesis of
more complex molecules.4 Recently, properly substituted
examples of 5,6-dihydropyridin-2-ones have been regarded to
be useful intermediates for the preparation of spatially defined
scaffolds, constrained counterparts of natural amino acids.5
b,g-Unsaturated a-bromoketenes were prepared starting
from the corresponding acyl halides and triethylamine, and
their reactivity in the ketene-imine cycloaddition was
examined.
2. Results and discussion
Recently, we have been interested in the synthesis of
mimetics of the RGD tripeptide, that is the signaling motif
in a variety of extracellular matrix proteins involved in the
integrin adhesion mechanism.6 In this paper we report on
the synthesis of a new class of 5,6-dihydropyridin-2-ones,
aiming to introduce them as non-peptidic scaffolds in
mimetics of the RGD b-turn topology. Numerous methods
for the preparation of substituted 5,6-dihydropyridin-2-ones
starting from acyclic materials have been reported in the
literature but they usually require forcing conditions and are
non-general.7
2.1. Synthesis of 3-bromo-5,6-dihydropyridin-2-ones
It is known that when an acyl halide is treated with a base,
the corresponding ketene is generated. The labile ketene
readily reacts with the Schiff base 2 to give a six membered
heterocyclic compound. Starting from both 2-bromo-3-
methyl-2-butenoyl chloride 1a and 2-bromo-3-methyl-2-
hexenoyl chloride 1b, deprotonation occurs on the methyl
group, to exclusively give the dehydropyridin-2-one 3 in
high yield (Scheme 1).
The amounts of Schiff base and TEA and the effect of the
temperature were investigated using the reaction of 1a and
2a, and selected results are reported in Table 1.
q CDRI Communication No. 6414.
qq Supplementary data associated with this article can be found in the
online version, at doi: 10.1016/j.tet.2004.04.021
The reaction of 1a with 2 equiv. of the imine 2a, carried out
at 278 8C in CH2Cl2 in the presence of AlMe2Cl, afforded
3a in 54% yield after silica gel chromatography, and the
remaining product was the corresponding benzylamide
Keywords: Imine; Ketene; Cycloaddition; Pyridinone.
*
Corresponding author. Tel.: þ39-51-2099570; fax: þ39-51-2099456;
e-mail address: giuliana.cardillo@unibo.it
0040–4020/$ - see front matter q 2004 Published by Elsevier Ltd.
doi:10.1016/j.tet.2004.04.021

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G. Cardillo et al. / Tetrahedron 60 (2004) 5031–5040
in 64% yield (entry 7). When the reaction was performed
with the allylamino derivative 2f, the corresponding
dihydropyridinone 3f was obtained in 96% yield (entry 8).
Finally, when acyl chloride 1b was reacted with 2a at reflux,
3g was obtained in 94% yield (entry 9). All of the reactions
were monitored by TLC and stopped after disappearance of
the imine.
Good yields and moderate diastereoselectivity were
observed in the reactions of 1a and 1b with the chiral
Schiff base 4, derived by the condensation of benzaldehyde
with (S)-phenylethylamine, in refluxing CH2Cl2. Starting
from 1a, the bromo-dihydropyridin-2-ones 5 and 6 were
obtained in a yield of 98% and 62/38 d.r. (Scheme 2).
Scheme 1. Formation of b,g-unsaturated ketenes and reaction with imines
2.
Table 1. Formation of 3-bromo-4-alkyl-5,6-dihydropyridin-2-one 3 via
ketene–imine cyclization
Scheme 2. Cycloaddition reaction between 1a-b and chiral imine 400.
Entrya
1
(1 equiv.)
2
(equiv.)
TEA
(equiv.)
T
(8C)
3
Yield
(%)b
Under the same conditions, 1b gave 7 and 8 in 55% yield
and 68/32 d.r. The diastereomeric mixtures of 5/6 and 7/8
were easily separated by flash chromatography and
pyridinones were fully characterized by NMR spectroscopy.
The isomer 7 was crystallized from ethanol/water. The (6R)
absolute configuration of the newlycreated stereogenic
center in 7 was established by X-ray diffraction,10 and,
according to this result, the (6S) configuration to 8 could be
assigned (Fig. 1).
1c
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1b
2a (2)
2a (1)
2a (1)
2b (1)
2c (1)
2d (1)
2e (1)
2f (1)
2a (1)
1
1
2
2
2
2
2
2
2
278 to rt
250 to rt
3a
3a
3a
3b
3c
3d
3e
3f
54
65
92
92
94
34
64
96
94
40
40
40
40
40
40
40
3g
a
Reactions were performed in CH2Cl2.
b
c
Yields correspond to the compounds purified by flash chromatography on
silica gel.
Reaction carried out under aluminum-catalyzed conditions.
(entry 1). At 250 8C, in the absence of the Lewis acid, with
1 equiv. of 2a, dihydropyridinone 3a was isolated in 65%
yield (entry 2). Much better results were obtained when 1a
and 2a were refluxed in CH2Cl2 in the presence of 2 equiv.
of TEA (entry 3, 92% yield). These conditions were applied
to the reaction of 1a with imines 2b-f. Excellent results were
obtained in both cases, and 3b and 3c were obtained in
respective yields of 92 and 94% (entries 4 and 5). A lower
yield was observed for 3d, which was obtained from the
cyclization of 1a with the glycine derivative 2d (entry 6).
This result was ascribed to a high degree of autocondensa-
tion of the reactive imine. On the other hand, the
cycloaddition of 1a and b-alanine derivative 2e, gave 3e
Figure 1. X-ray structure of 7.
The structure reported in Figure 1, displays 7 in a boat
conformation, and the hydrogen of the (S)-phenylethyl-
amine group is preferentially in a synperiplanar relationship
with the carbonyl of the cycle.

G. Cardillo et al. / Tetrahedron 60 (2004) 5031–5040
5033
Comparison of the 1H NMR chemical shifts for the pairs of
compounds 5/7 and 6/8 revealed a complete regularity and
allowed us to confidently attribute the (6R) configuration to
5 and the (6S) configuration to 6 (Table 2).
2.2. Reactivity of 3-bromo-4-alkyl-5,6-dihydropyridin-2-
ones and 3-bromo-5-alkyl-5,6-dihydropyridin-2-ones
with allylamine
The presence of the bromine atom on the double bond in the
pyridinones makes possible aziridination via the well-
known Gabriel–Cromwell reaction.11 Aziridines have
recently received great attention, since they can be
considered strained unusual amino acids and they are also
useful precursors for the synthesis of various poly-
functionalized compounds, such as oxazolines, oxazolidi-
nones, hydroxy amino acids, amino alcohols, etc.12
1
Table 2. H NMR data for compounds 5-8
daCHp3
(ppm)
daHp
(ppm)
dH6
(ppm)
dH5
(ppm)
dH5’
(ppm)
J5–6
(Hz)
0
J5 –6
(Hz)
5
6
7
8
1.23
1.65
1.25
1.67
6.19
5.77
6.21
5.80
4.39
4.57
4.42
4.60
2.27
2.37
2.30
2.41
2.83
3.07
2.75
3.00
1.2
1.5
1.8
1.5
7.0
7.2
6.6
6.9
Therefore, we investigated the reactivity of 3-bromo-5,6-
dihydropyridin-2-ones in the presence of allylamine. The
reaction, carried out on several substrates by refluxing the
heterocycle in neat allylamine for 48 h, gave different
results depending on the substituents on the six-membered
ring. Under these conditions, 3-bromo-5-ethyl-5,6-dihydro-
pyridin-2-ones 9 and 10 gave the corresponding fused
bicyclic N-allyl-aziridines 11 and 12 in good yield and
complete diastereoselectivity (Scheme 4).
a
Chemical shifts corresponding to (S)-phenylethylamino group.
Finally we investigated the behavior of 2-bromo-3-
unbranched hexenoyl acyl chloride 1c in the ketene–
imine cyclization with 4. While the reaction was tested
under different conditions, changing the solvent and the
temperature, the six-membered heterocyclic compounds 9
and 10 were obtained in 76% total yield and 78:22 d.r. only
when the reaction was performed in the presence of one
equivalent of AlMe2Cl at 278 8C and 2 equiv. of 4.
The two diastereoisomers were easily separated by flash
chromatography on silica gel and characterized by 1H NMR
analysis, which suggested a 5,6-trans relationship for both
of them (J5,6,0.8 Hz). The major isomer 9 was crystallized
from ethanol and its (10S,5R,6R) absolute configuration was
ascertained by X-ray analysis. (Scheme 3).
Scheme 4. Synthesis of aziridines 11 and 12 via a Gabriel–Cromwell-like
reaction.
The assignment of the stereochemistry of the newly created
stereocenters in 11 was made by analysis of the coupling
constant J4–5 and by means of NOESY-1D13 experiments.
The comparison of the vicinal coupling constant
(J4–5¼1.5 Hz) with literature values14 referring to similar
aziridines, accounted for an anti relationship between the
ethyl substituent on C5 and the aziridine ring. Irradiation of
the proton at C4 and of the proton at C6 resulted in the
enhancement of intensities of the ethyl chain methylene
protons, suggesting that they are cis to each other. The
preferred conformation of (3R,4R,5R,6R)-11, calculated by
means of molecular mechanics energy minimizations of a
set of 103 geometries generated by Monte Carlo pro-
cedure,15 was in complete agreement with the NOESY-1D
signals observed upon irradiation of H4 and H5 (Fig. 2). The
same considerations allowed to attribute the (3S,4S,5S,6S)
stereochemistry to 12.
When the reaction with allylamine was performed on
4-methyl-substituted derivatives, 3-allylamino-4-methyl-
5,6-dihydropyridin-2-ones were obtained instead of the
Scheme 3. Synthesis of 5,6-dihydropyridin-2-ones 9 and 10 and X-ray-
determined structure of 9.

5034
G. Cardillo et al. / Tetrahedron 60 (2004) 5031–5040
The complete chemoselectivity of the reaction between
compounds 3b, 3f, 15 and 16 and allylamine, can be
attributed to the steric hinderance at C3. In accordance with
the nucleophilic substitution of alkyl bromo-2(1H)-pyri-
dones and bromo-uracils,17 a reasonable mechanism could
be suggested for the substitution of the vinyl bromide
(Scheme 6). The allylamine, acting as a base, promoted the
deconjugation of the double bond, so making possible
the substitution of the bromine by allylamine itself. Finally
the more stable double bond in a,b position was restored.
Figure 2. Preferred conformation and NOESY-1D enhancements of 11.
corresponding aziridines. The reaction with 3f and 3b gave
derivatives 13 and 14 in respective yields of 52 and 25%
(Scheme 5).
Finally, deprotection of compound 3b allowed us to
synthesize the dihydropyridin-2-one 15 via cleavage of the
N-(p-methoxybenzyl) group with cerium ammonium
nitrate.16 The reaction carried out in CH3CN/H2O at room
temperature gave 15 in 70% yield. Upon treatment with
TEA, DMAP and di-tert-butyldicarbonate in dry THF, 15
was transformed into the corresponding N-tert-butyloxy-
carbonyl derivative 16 in 90% yield. The reaction of both 15
and 16 with neat allylamine gave the 3-allylamino-
substituted six-membered rings 17 and 18 in quantitative
yield (Scheme 5).
Scheme 6. Suggested mechanism for the substitution of vinyl bromide by
allylamine.
3. Conclusion
A new method for the synthesis of 3-bromo-4-alkyl-5,6-
dihydropyridin-2-ones and 3-bromo-5-ethyl-5,6-dihydro-
pyridin-2-ones starting from 3-methyl-b,g-unsaturated
a-bromoketenes and imines has been developed. This
one-pot ketene formation/cycloaddition was tested on
2-bromo-3-methyl-2-butenoyl chloride 1a and 2-bromo-3-
methyl-2-hexenoyl chloride 1b in the presence of several
different imines. With both substrates, six-membered rings
were obtained in good yield. The same reaction gave
excellent results even with chiral imines and the ketene
derived from 2-bromo-unbranched hexenoyl acyl chloride
1c. Moreover, the presence of the bromine atom on the
double bond makes possible the substitution by allylamine,
leading to the formation of aziridines or 3-allylamino
derivatives. The reaction gave different results depending on
the substituents on the six-membered ring. This class of six
membered polyfunctionalized heterocycles could be
exploited in the preparation of non-peptidic scaffolds
mimicking the b-turn RGD topology.
4. Experimental
4.1. General methods
Unless stated otherwise, solvents and chemicals were
obtained from commercial sources and used without further
purification. Flash chromatography was performed on silica
gel (230–400 mesh). NMR Spectra were recorded with 200,
300, 400 or 600 MHz spectrometers. Chemical shifts were
reported as d values (ppm) relative to the solvent peak of
Scheme 5. Reactions of allylamine with 3-bromo-4-alkyl-dihydropyridin-
2-ones.

G. Cardillo et al. / Tetrahedron 60 (2004) 5031–5040
5035
CDCl3 set at d¼7.27 (1H NMR) or d¼77.0 (13C NMR).
Infrared spectra were recorded with an FT-IR spectrometer.
Melting points are uncorrected. MS analysis were per-
formed on a liquid chromatograph coupled with an
electrospray ionization-mass spectrometer (LC-ESI-MS),
using H2O/CH3CN as solvent at 25 8C (positive scan
100–500 m/z, fragmentor 70 V). Imines 2a-f and 4 were
prepared following a known procedure and characterized by
comparison with literature data.18
under vacuum. 5,6-Dihydro-pyridin-2-one 3a-g were puri-
fied by flash chromatography on silica gel (cyclohexane/
ethyl acetate 95/5 as eluant).
4.3.1. 1-Benzyl-3-bromo-4-methyl-6-phenyl-5,6-
dihydro-pyridin-2-one 3a. Isolated as a pale yellow oil
(327 mg, 92%); IR (film) n 3029, 2930, 1651, 1608,
1
1453 cm21; H NMR (300 MHz, CDCl3) dH 1.95 (3H, s),
2.52 (1H, dd, J¼2.4, 17.2 Hz), 3.03 (1H, dd, J¼7.5,
17.2 Hz), 3.63 (1H, d, J¼14.7 Hz), 4.56 (1H, dd, J¼2.4,
7.5 Hz), 5.63 (1H, d, J¼14.7 Hz), 7.15–7.18 (2H, m), 7.22–
7.40 (8H, m); 13C NMR (50 MHz, CDCl3) dC 24.7 (q), 39.5
(t), 49.5 (t), 56.6 (d), 115.7 (s), 126.4 (d), 127.6 (d), 128.1
(d), 128.2 (d), 128.7 (d), 129.0 (d), 137.5 (s), 139.6 (s),
145.2 (s), 160.7 (s); GC-MS m/z 357 (12), 355 (12), 278
(10), 276 (10), 253 (16), 207 (9), 185 (6), 128 (11), 91 (100).
Anal. Calcd for C19H18BrNO: C, 64.06; H, 5.09; N, 3.93.
Found C, 64.08; H, 5.07; N, 3.92.
4.2. General procedure for the preparation a-bromo-
a,b-unsaturated chlorides 1a-c from a,b-unsaturated
acids
To a stirred solution of a,b-unsaturated acid (10 mmol) in
CH2Cl2 (10 mL), bromine (11 mmol, 0.56 mL) was added
dropwise at 0 8C. The mixture was stirred overnight and
then washed with a saturated solution of Na2S2O3 to remove
unreacted bromine. The organic layer was dried over
Na2SO4 and solvent removed under reduced pressure to
give the dibromo acid as a white powder. The product was
dissolved in THF (10 mL) then piperidine (40 mmol,
3.9 mL) was added in one portion at 0 8C. The solution
was stirred for 24 h at room temperature and then quenched
with HCl 6 M (10 mL). After removing THF under reduced
pressure, the acid aqueous layer was extracted twice with
EtOAc (20 mL). The collected organic layers were dried
over Na2SO4 and concentrated to give the a-bromo acid as a
white powder. SOCl2 (60 mmol, 4.4 mL) was then added to
the neat product at 0 8C and the mixture was refluxed for two
hours. The a-bromo-a,b-unsaturated chlorides 1a-c were
isolated as E/Z unseparable mixtures by distilling under
reduced pressure.
4.3.2. 3-Bromo-1-(4-methoxy-benzyl)-4-methyl-6-
phenyl-5,6-dihydro-pyridin-2-one 3b. Isolated as a pale
yellow oil (356 mg, 92%); IR (film) n 3031, 2932, 1653,
1
1593, 1460 cm21; H NMR (200 MHz, CDCl3) dH 1.90
(3H, s), 2.47 (1H, dd, J¼2.4, 17.4 Hz), 2.96 (1H, dd, J¼7.6,
17.4 Hz), 3.54 (1H, d, J¼14.6 Hz), 3.77 (3H, s), 4.52 (1H,
dd, J¼2.4, 7.6 Hz), 5.49 (1H, d, J¼14.6 Hz), 6.80–6.85
(2H, m), 7.12–7.16 (4H, m), 7.30–7.40 (3H, m); 13C NMR
(50 MHz, CDCl3) dC 24.2 (q), 39.1 (t), 48.4 (t), 55.1 (q),
56.0 (d), 113.8 (d), 115.4 (s), 126.1 (d), 127.7 (d), 128.7 (d),
129.2 (d), 129.4 (s), 139.4 (s), 144.9 (s), 158.9 (s), 160.3 (s);
LC-ESI-MS rt 11.9 min, m/z 386–388 (Mþ1), 408–410
(MþNa). Anal. Calcd for C20H20BrNO2: C, 62.19; H, 5.22;
N, 3.63. Found C, 62.20; H, 5.21; N, 3.65.
4.2.1. 2-Bromo-3-methyl-but-2-enoyl chloride 1a. IR
1
4.3.3. 1-Benzyl-3-bromo-6-(4-methoxy-phenyl)-4-
methyl-5,6-dihydro-pyridin-2-one 3c. Isolated as a white
solid (364 mg, 94%), mp¼105–107 8C; IR (nujol) n 3031,
2928, 1653, 1611, 1449 cm21; 1H NMR (200 MHz, CDCl3)
dH 1.96 (3H, s), 2.47 (1H, dd, J¼2.6, 17.2 Hz), 2.98 (1H,
dd, J¼7.2, 17.2 Hz), 3.62 (1H, d, J¼14.8 Hz), 3.82 (3H, s),
4.49 (1H, dd, J¼2.6, 7.2 Hz), 6.58 (1H, d, J¼14.8 Hz),
6.88 (2H, d, J¼8.8 Hz), 7.07 (2H, d, J¼8.8 Hz), 7.20–7.40
(5H, m); 13C NMR (50 MHz, CDCl3) dC 24.4 (q), 39.4
(t), 49.0 (t), 55.2 (d), 55.8 (q), 114.1 (d), 115.5 (s), 127.3 (d),
128.0 (d), 128.5 (d), 131.3 (s), 137.4 (s), 145.2 (s), 159.0
(s), 160.2 (s); LC-ESI-MS rt 12.8 min, m/z 386–388
(film) n 2950, 1805 cm21; H NMR (300 MHz, CDCl3)
dH 2.11 (s, 3H), 2.13 (s, 3H).
4.2.2. 2-Bromo-3-methyl-hex-2-enoyl chloride 1b. IR
1
(film) n, 2927, 1811 cm21; H NMR (300 MHz, CDCl3)
dH (Major isomer) 0.99 (t, 3H, J¼7.5 Hz), 1.50–1.60 (m,
1
2H), 2.08 (s, 3H), 2.40 (m, 2H). (Minor isomer) H NMR
(CDCl3) d 0.94 (t, 3H, J¼7.2 Hz), 1.50–1.60 (m, 2H), 2.05
(s, 3H) 2.40 (m, 2H).
4.2.3. 2-Bromo-hex-2-enoyl chloride 1c. IR (film) n 2955,
1802 cm21; 1H NMR (300 MHz, CDCl3) dH (Major
isomer)1.02 (t, 3H, J¼7.2 Hz), 1.58–1.68 (m, 2H), 2.47
(Mþ1),
408–410
(MþNa).
Anal.
Calcd
for
C20H20BrNO2: C, 62.19; H, 5.22; N, 3.63. Found C,
62.18; H, 5.22; N, 3.62.
1
(m, 2H), 7.8 (t, 1H, J¼6.9 Hz). (Minor isomer) H NMR
(CDCl3) d 0.95 (t, 3H, J¼7.2 Hz), 1.48–1.57 (m, 2H), 2.40
(m, 2H), 6.68 (t, 1H, J¼7.8 Hz).
4.3.4. (3-Bromo-2-oxo-6-phenyl-4-methyl-5,6-dihydro-
pyridin-1-yl)-acetic acid ethyl ester 3d. Isolated as a
pale yellow oil (120 mg, 34%); IR (film) n 3034, 2926,
4.3. General procedure for the preparation of 5,6-
dihydro-pyridin-2-ones 3a-g and 5-8
1
1741, 1656, 1461 cm21; H NMR (200 MHz, CDCl3) dH
1.22 (t, 3H, J¼7.0 Hz), 2.01 (s, 3H), 2.66 (dd, 1H, J¼6.0,
17.2 Hz), 3.07 (dd, 1H, J¼6.6, 17.2 Hz), 3.37 (d, 1H,
J¼17.6 Hz), 4.15 (q, 2H, J¼7.0 Hz), 4.77 (d, 1H,
J¼17.6 Hz), 4.80 (dd, 1H, J¼6.6, 6.0 Hz), 7.18–7.22 (m,
2H), 7.50–7.62 (m, 3H). 13C NMR (50 MHz, CDCl3) dC
14.3 (q), 29.3 (q), 41.8 (t), 52.0 (t), 60.2 (d), 114.7 (s), 127.1
(d), 127.7 (d), 128.0 (d), 140.2 (s), 145.4 (s), 162.6 (s), 166.9
(s). GC-MS m/z 353 (15), 351 (15), 280 (13), 278 (13), 266
(15), 264 (15), 185 (5), 110 (10), 91 (100). Anal. Calcd for
Acyl chloride 1a-c (1 mmol) was added to a refluxing
solution of imine 2 or 4 (1 mmol, 1 equiv.) and TEA
(0.278 mL, 2 mmol, 2 equiv.) in CH2Cl2 (5 mL). The
reaction was monitored by TLC and quenched with water
after disappearance of the imine reagent. The pH of the
water layer was then adjusted to neutrality with 0.1 M HCl
and diluted with CH2Cl2 (10 mL). The separated organic
layer was dried over Na2SO4 and the solvent was evaporated

5036
G. Cardillo et al. / Tetrahedron 60 (2004) 5031–5040
C16H18BrNO3: C, 54.56; H, 5.15; N, 3.98. Found C, 54.56;
H, 5.18; N, 3.94.
(Mþ1), 392–394 (MþNa). Anal. Calcd for C20H20BrNO:
C, 64.87; H, 5.44; N, 3.78. Found C, 64.90; H, 5.42; N, 3.79.
4.3.5. 3-(3-Bromo-2-oxo-6-phenyl-4-methyl-5,6-dihydro-
pyridin-1-yl)-propionic acid methyl ester 3e. Isolated as a
pale yellow oil (226 mg, 64%); IR (film) n 3029, 2929,
4.3.9. (10S,6S)-3-Bromo-4-methyl-6-phenyl-1-(10-phenyl-
ethyl)-5,6-dihydro-pyridin-2-one 6. Isolated as a white
solid (137 mg, 37%), mp¼105–107 8C; IR (nujol) n 3060,
2976, 1727, 1645, 1494 cm21; 1H NMR (300 MHz, CDCl3)
dH 1.65 (3H, d, J¼7.0 Hz,), 1.84 (3H, s), 2.37 (1H, dd,
J¼1.5, 16.8 Hz), 3.07 (1H, dd, J¼7.2, 16.8 Hz) 4.57 (1H,
dd, J¼1.5, 7.2 Hz), 5.77 (1H, q, J¼7.0 Hz), 6.78–6.82 (2H,
m), 6.95–7.05 (6H, m), 7.15–7.18 (2H, m); 13C NMR
(75 MHz, CDCl3) dC 17.7 (q), 24.1 (q), 40.4 (t), 54.3 (2C,
d), 116.6 (s), 126.0 (d), 126.8 (d), 127.4 (d), 127.7 (d), 127.8
(d), 128.4 (d), 138.5 (s), 140.5 (s), 143.9 (s), 159.9 (s);
[a]1D9¼2109 (c 0.99, CHCl3); LC-ESI-MS rt 13.0 min, m/z
370–372 (Mþ1), 392–394 (MþNa). Anal. Calcd for
C20H20BrNO: C, 64.87; H, 5.44; N, 3.78. Found C, 64.88;
H, 5.45; N, 3.76.
1
1730, 1653,1460 cm21; H NMR (200 MHz, CDCl3) dH
1.92 (s, 3H), 2.56 (dt, 1H, J¼5.7, 16.8 Hz), 2.54 (dd, 1H,
J¼2.2, 17.4 Hz), 2.86 (ddd, 1H, J¼5.7, 8.4, 16.8 Hz), 3.14
(dd, 1H, J¼7.4, 17.4 Hz), 3.16 (ddd, 1H, J¼5.7, 8.4,
13.6 Hz), 3.74 (s, 3H), 4.07 (dt, 2H, J¼5.7, 13.6 Hz), 4.88
(dd, 1H, J¼7.4, 2.2 Hz), 7.00–7.12 (m, 2H), 7.20–7.36 (m,
3H); 13C NMR (50 MHz, CDCl3) dC 24.0 (q), 32.6 (t), 39.1
(t), 43.8 (t), 51.3 (q), 59.0 (d), 115.2 (s), 125.8 (d), 127.6 (d),
128.5 (d), 139.8 (s), 145.2 (s), 160.4 (s), 172.2 (s); LC-ESI-
MS rt 10.7 min, m/z 352–354 (Mþ1), 374–376 (MþNa).
Anal. Calcd for C16H18BrNO3: C, 54.56; H, 5.15; N, 3.98.
Found C, 54.54; H, 5.14; N, 3.97.
4.3.6. 1-Allyl-3-bromo-4-methyl-6-phenyl-5,6-dihydro-
pyridin-2-one 3f. Isolated as a pale yellow oil (295 mg,
4.3.10. (10S,6R)-3-Bromo-6-phenyl-1-(10-phenyl-ethyl)-4-
propyl-5,6-dihydro-pyridin-2-one 7. Isolated as a white
solid (147 mg, 37%), mp¼116–120 8C; IR (nujol) n 3059,
2928, 1646, 1624, 1452 cm21; 1H NMR (300 MHz, CDCl3)
dH 0.67 (3H, t, J¼7.2 Hz,), 1.02–1.15 (2H, m), 1.25 (3H, d,
J¼7.2 Hz), 2.03 (1H, dt, J¼7.0, 13.0 Hz), 2.24–2.31 (1H,
m), 2.30 (1H, dd, J¼1.8, 16.8 Hz), 2.75 (1H, dd, J¼6.6,
16.8 Hz), 4.42 (1H, dd, J¼1.8, 6.6 Hz), 6.21 (1H, q,
J¼7.2 Hz), 7.13–7.17 (2H, m), 7.20–7.40 (8H, m); 13C
NMR (50 MHz, CDCl3) dC 13.4 (q), 16.2 (q), 18.9 (t), 38.6
(t), 38.8 (t), 52.2 (d), 53.2 (d), 115.8 (s), 126.0 (d), 127.2 (d),
127.3 (d), 127.5 (d), 128.3 (d), 128.5(d), 141.3 (s), 141.4 (s),
147.5 (s), 160.4 (s); [a]1D9¼þ34 (c 0.93, CHCl3); LC-ESI-
MS rt 12.4 min, m/z 398–400 (Mþ1), 420–422 (MþNa).
Anal. Calcd for C22H24BrNO: C, 66.33; H, 6.07; N, 3.52.
Found C, 66.32; H, 6.06; N, 3.55.
1
96%); IR (film) n 2967, 2926, 1653, 1457 cm21; H NMR
(200 MHz, CDCl3) dH 1.90 (3H, s), 2.54 (1H, dd, J¼2.6,
17.2 Hz), 3.09 (1H, dd, J¼7.5, 17.2 Hz), 3.19 (1H, dd,
J¼7.2, 15.4 Hz), 4.63 (1H, dd, J¼2.6, 7.5 Hz), 4.74–4.85
(1H, m), 5.05–5.21 (2H, m), 5.68–5.87 (1H, m), 7.12–7.20
(2H, m), 7.25–7.37 (3H, m); 13C NMR (50 MHz, CDCl3)
dC 24.2 (q), 39.1 (t), 48.4 (t), 56.4 (d), 115.5 (s), 117.5 (t),
126.1 (d), 127.7 (d), 128.6 (d), 132.9 (d), 139.5 (s), 145.0
(s), 160.0 (s); LC-ESI-MS rt 11.6 min, m/z 306–308
(Mþ1), 328–330 (MþNa). Anal. Calcd for C15H16BrNO:
C, 58.84; H, 5.27; N, 4.57. Found C, 58.87; H, 5.26; N,
4.55.
4.3.7. 1-Benzyl-3-bromo-6-phenyl-4-propyl-5,6-dihydro-
pyridin-2-one 3g. Isolated as a pale yellow oil (362 mg,
94%); IR (film) n 3029, 2928, 1648, 1611, 1454 cm21; H
4.3.11. (10S,6S)-3-Bromo-6-phenyl-1-(10-phenyl-ethyl)-4-
propyl-5,6-dihydro-pyridin-2-one 8. Isolated as a white
solid (71 mg, 18%), mp¼95–99 8C; IR (nujol) n 3030,
1
NMR (300 MHz, CDCl3) dH 0.75 (3H, t, J¼7.5 Hz,), 1.20–
1.30 (2H, m), 2.16 (1H, dt, J¼7.6, 13.0 Hz), 2.36 (1H, dt,
J¼7.8, 13.0 Hz), 2.53 (1H, dd, J¼2.1, 17.0 Hz), 2.97 (1H,
dd, J¼7.4, 17.0 Hz), 3.65 (1H, d, J¼15.0 Hz), 4.59 (1H, dd,
J¼2.1, 7.4 Hz), 5.64 (1H, d, J¼15 Hz), 7.14–7.17 (2H, m),
7.3–7.39 (8H, m); 13C NMR (75 MHz, CDCl3) dC 13.4 (q),
19.2 (t), 37.5 (t), 39.1 (t), 49.2 (t), 56.3 (d), 115.4 (s), 126.1
(d), 127.4 (d), 127.8 (d), 128.0 (d), 128.5 (d), 128.7 (d),
137.4 (s), 139.1 (s), 148.3 (s), 160.7 (s); LC-ESI-MS rt
14.7 min, m/z 384–386 (Mþ1), 406–408 (MþNa). Anal.
Calcd for C21H22BrNO: C, 65.63; H, 5.77; N, 3.64. Found
C, 65.61; H, 5.79; N, 3.64.
1
2929, 1643, 1453 cm21; H NMR (300 MHz, CDCl3) dH
0.66 (3H, t, J¼7.2 Hz,), 1.03–1.15 (2H, m), 1.67 (3H, d,
J¼7.0 Hz), 2.01–2.11 (1H, m), 2.21–2.30 (1H, m), 2.41
(1H, dd, J¼1.5, 16.8 Hz), 3.00 (1H, dd, J¼6.9, 16.8 Hz),
4.60 (1H, dd, J¼1.5, 6.9 Hz), 5.80 (1H, q, J¼7.0 Hz), 6.78–
6.80 (2H, m), 6.98–7.04 (6H, m), 7.18–7.20 (2H, m); 13C
NMR dC (50 MHz, CDCl3) 13.5 (q), 17.8 (q), 19.0 (t), 38.8
(t), 38.9 (t), 54.2 (2C, d), 116.4 (s), 126.0 (d), 126.8 (d),
127.4 (d), 127.7 (2C, d), 128.4 (d), 138.5 (s), 140.1 (s),
147.3 (s), 160.2 (s); [a]1D9¼281 (c 1.24, CHCl3); LC-ESI-
MS rt 13.6 min, m/z 398–400 (Mþ1), 420–422 (MþNa).
Anal. Calcd for C22H24BrNO: C, 66.33; H, 6.07; N, 3.52.
Found C, 66.35; H, 6.04; N, 3.56.
4.3.8. (10S,6R)-3-Bromo-4-methyl-6-phenyl-1-(10-phenyl-
ethyl)-5,6-dihydro-pyridin-2-one 5. Isolated as a white
solid (226 mg, 61%), mp¼120–122 8C; IR (nujol) n 3028,
2930, 16474, 1630, 1452 cm21
;
1H NMR (300 MHz,
4.4. Reaction of 1c with imines in the presence of
AlMe2Cl
CDCl3) dH 1.23 (3H, d, J¼7.4 Hz,), 1.85 (3H, d,
J1,3¼1.2 Hz), 2.27 (1H, dd,, J1,2¼17.0 Hz, J1,3¼1.2 Hz),
2.83 (1H, ddd, J¼1.2, 7.0, 17.0 Hz) 4.39 (1H, dd,
J1,2¼7.0 Hz, J1,3¼1.2 Hz), 6.19 (1H, q, J¼7.4 Hz), 7.15–
7.18 (2H, m), 7.30–7.42 (8H, m); 13C NMR (50 MHz,
CDCl3) dC 16.3 (q), 24.2 (q), 40.3 (t), 52.4 (d), 53.2 (d),
116.0 (s), 126.1 (d), 127.2 (d), 127.4 (d), 127.5 (d), 128.5
(d), 141.4 (s), 141.8 (s), 144.1 (s), 160.2 (s); [a]1D9¼þ29 (c
1.04, CHCl3); LC-ESI-MS rt 13.4 min, m/z 370–372
To a stirred solution of acyl chloride 1c (0.211 g, 1 mmol) in
CH2Cl2 at 278 8C, AlMe2Cl (1 mL of a 1 M solution in
hexane, 1 equiv.) was added in one portion. After 10 min, a
solution of TEA (0.139 mL, 1 mmol, 1 equiv.) in CH2Cl2
(2 mL) and a solution of the imine (2 equiv.) in CH2Cl2
(2 mL) were added dropwise at the same time. The reaction
was monitored by TLC and quenched, after disappearance

G. Cardillo et al. / Tetrahedron 60 (2004) 5031–5040
5037
of the imine reagent, with a water solution of Seignette salts
(Na/K tartrate). The reaction mixture was filtered through a
celite pad, diluted with CH2Cl2 and washed twice with
water. The organic layer was dried over Na2SO4 and solvent
was removed under reduced pressure. Compounds 9, 10
were purifed by flash chromatography on silica gel
(cyclohexane/Et2O, 95/5 as eluant).
61.2 (d), 115.5 (t), 126.0 (d), 126.8 (d), 127.8 (d), 128.2 (d),
128.3 (d), 128.4 (d), 134.4 (s), 140.6 (s), 145.1 (d), 169.8 (s);
[a]1D9¼2100.0 (c 1.1 CHCl3); LC-ESI-MS rt 15.6 min, m/z
361 (Mþ1), 383 (MþNa). Anal. Calcd for C24H28N2O: C,
79.96; H, 7.83; N, 7.77. Found C, 79.98; H, 7.81; N, 7.75.
4.5.2. (10S,3S,4S,5S,6S)-3,4-[N-(Allyl)-aziridino]-5-ethyl-
6-phenyl-N-(10-phenyl-ethyl)-piperidin-2-one 12. Isolated
as a white solid (144 mg, 40%), mp¼78–80 8C; IR (nujol) n
3052, 2927, 1639, 1450 cm21; 1H NMR (600 MHz, CDCl3)
dH 1.00 (3H, t, J¼7.2 Hz,), 1.27 (1H, m), 1.38 (1H, m), 1.70
(3H, d, J¼7.2 Hz), 1.90 (1H, dd, J¼1.5, 6.0 Hz), 2.18 (1H,
d, J¼6.0 Hz), 2.31 (1H, bt, J¼6.6 Hz), 2.43 (1H, dd,
J¼15.6, 5.4Hz), 3.10 (1H, dd, J¼15.6, 2.4 Hz), 4.35 (1H, s),
4.60 (1H, dd, J¼17.4, 1.5 Hz), 4.80 (1H, dd, J¼10.8,
1.5 Hz), 5.09 (1H, q, J¼7.2 Hz), 5.55 (1H, ddt, J¼17.4,
10.8, 4.8 Hz), 7.01–7.15 (7H, m), 7.20–7.35 (3H, m); 13C
NMR dC (150 MHz, CDCl3) 12.0 (q), 18.2 (q), 25.1 (t), 39.5
(d), 42.9 (d), 46.5 (d), 57.1 (d), 61.1 (t), 62.6 (d), 115.5 (t),
125.6 (d), 126.7 (d), 127.3 (d), 127.8 (d), 128.0 (d), 128.6
(d), 134.4 (s), 140.1 (s), 142.3 (d), 169.6 (s); [a]1D9¼þ11.0
(c0.9 CHCl3); LC-ESI-MS rt 17.0 min, m/z 361 (Mþ1), 383
(MþNa). Anal. Calcd for C24H28N2O: C, 79.96; H, 7.83; N,
7.77. Found C, 79.95; H, 7.83; N, 7.79.
4.4.1. (10S,5R,6R)-3-Bromo-5-ethyl-6-phenyl-1-(10-phe-
nyl-ethyl)-5,6-dihydro-pyridin-2-one 9. Isolated as a
white solid (226 mg, 59%), mp¼150–152 8C; IR (nujol) n
1
3050, 2923, 1666, 1608, 1421 cm21; H NMR (300 MHz,
CDCl3) dH 0.49 (3H, t, J¼7.2 Hz,), 0.82–1.02 (2H, m), 1.21
(3H, d, J¼7.2 Hz), 2.0–2.17 (1H, m), 4.29 (1H, bs), 6.29
(1H, q, J¼7.2 Hz), 6.61 (1H, dd, J1,2¼6.6 Hz, J1,3¼1.2 Hz),
7.13–7.16 (2H, m), 7.30–7.40 (8H, m); 13C NMR (50 MHz,
CDCl3) dC 10.7 (q), 15.9 (q), 25.7 (t), 47.6 (d), 52.2 (d), 56.7
(d), 118.6 (s), 125.9 (d), 127.1 (d), 127.3 (d), 127.9 (d),
128.2 (d), 128.4 (d), 140.0 (s), 140.5 (s), 142.1 (s), 159.0 (s);
[a]1D9¼266 (c 1.14, CHCl3); LC-ESI-MS rt 15.1 min, m/z
384–386 (Mþ1), 406–408 (MþNa). Anal. Calcd for
C21H22BrNO: C, 65.63; H, 5.77; N, 3.64. Found C, 65.61;
H, 5.78; N, 3.63.
4.4.2. (10S,5S,6S)-3-Bromo-5-ethyl-6-phenyl-1-(10-phe-
nyl-ethyl)-5,6-dihydro-pyridin-2-one 10. Isolated as a
dense yellow oil (65 mg, 17%); IR (film) n 3031, 2926,
4.5.3. 1-Allyl-3-allylamino-4-methyl-6-phenyl-5,6-
dihydro-pyridin-2-one 13. Isolated as a pale yellow oil
(146 mg, 52%); IR (film) n 3052, 2925, 1638, 1447 cm21
;
1
1654, 1616, 1452 cm21; H NMR (300 MHz, CDCl3) dH
1.09 (3H, t, J¼7.2 Hz,), 1.58–1.73 (2H, m), 1.63 (3H, d,
J¼7.0 Hz), 2.19 (1H, m), 4.41 (1H, bs), 5.85 (1H, q,
J¼7.0 Hz), 6.61 (1H, dd, J¼6.9 Hz, J1,3¼1.5 Hz), 6.72–
6.78 (2H, m), 6.94–7.06 (6H, m), 7.12–7.18 (2H, m); 13C
NMR (75 MHz, CDCl3) dC 11.5 (q), 16.9 (q), 26.8 (t), 47.2
(d), 53.8 (d), 59.3 (d), 119.4 (s), 125.9 (d), 126.7 (d), 127.5
(d), 127.7 (d), 127.8 (d), 128.6 (d), 138.2 (s), 140.4 (s),140.6
(s), 159.0 (s); [a]1D9¼228 (c 0.97, CHCl3); LC-ESI-MS rt
14.2 min, m/z 384–386 (Mþ1), 406–408 (MþNa). Anal.
Calcd for C21H22BrNO: C, 65.63; H, 5.77; N, 3.64. Found
C, 65.66; H, 5.76; N, 3.62.
1H NMR (300 MHz, CDCl3) dH 1.75 (3H, s), 2.35 (1H, dd,
J¼2.8, 17.2 Hz), 3.05 (1H, dd, J¼7.5, 17.2 Hz), 3.16 (1H,
dd, J¼7.2, 15.3 Hz), 3.42–3.55 (2H, m), 4.58 (1H, dd,
J¼2.8, 7.5 Hz), 4.76–4.83 (1H, m), 5.04–5.22 (4H, m),
5.68–5.75 (2H, m), 7.18–7.19 (2H, m), 7.22–7.40 (3H, m);
13C NMR (50 MHz, CDCl3) dC 18.8 (q), 37.2 (t), 47.7 (t),
51.1 (t), 57.0 (d), 115.5 (t), 117.0 (t), 120.8 (s), 126.4 (d),
127.4 (d), 128.4 (d), 133.3 (s), 133.4 (d), 136.6 (d), 140.7
(s), 164.4 (s); LC-ESI-MS rt 12.1 min, m/z 283 (Mþ1), 305
(MþNa). Anal. Calcd for C18H22N2O: C, 76.56; H, 7.85; N,
9.92. Found C, 76.55; H, 7.84; N, 9.90.
4.5. Reaction of 3-bromo-5,6-dihydro-pyridin-2-ones
with allylamine
4.5.4. 3-Allylamino-1-(4-methoxy-benzyl)-4-methyl-6-
phenyl-5,6-dihydro-pyridin-2-one 14. Isolated as a pale
yellow oil (90 mg, 25%); IR (film) n 3049, 2932, 1644,
1
3-Bromo-5,6-dihydro-pyridin-2-one (1 mmol) was refluxed
in neat allylamine (5 mL) for 2 days. The excess of amine
was then removed by evaporation under reduced pressure.
The products were purified by flash chromatography on
silica gel (eluant: cyclohexane/Et2O 9/1 for 11 and 12,
cyclohexane/ethyl acetate 8/2 for 13 and 14).
1520 cm21; H NMR (300 MHz, CDCl3) dH 1.82 (3H, s),
2.36 (1H, dd, J¼2.7, 17.7 Hz), 3.02 (1H, dd, J¼7.8,
17.7 Hz), 3.59 (3H, m), 3.90 (3H, s), 4.54 (1H, dd, J¼2.7,
7.8 Hz), 5.17 (1H, dq, J¼10.5, 1.5 Hz), 5.19 (1H, bs), 5.28
(1H, dq, J¼17.1, 1.5 Hz), 5.62 (1H, d, J¼15.0 Hz), 6.02
(ddt, J¼17.1, 10.5, 6.0 Hz), 6.95 (2H, m), 7.18–7.24 (4H,
m), 7.36–7.60 (3H, m); 13C NMR (50 MHz, CDCl3) dC 18.9
(q), 37.2 (t), 47.8 (t), 51.2 (t), 55.1 (q), 56.6 (d), 113.9 (s),
115.7 (d), 116.1 (t), 120.9 (s), 126.5 (d), 127.2 (d), 128.8 (d),
129.2 (d), 133.4 (s), 136.7 (d), 140.6 (s), 158.9 (s), 164.8 (s);
GC-MS m/z 362(2), 267 (5), 236 (28), 195 (58), 154 (32),
108 (70), 83 (100), 68 (66), 54 (46). Anal. Calcd for
C23H26N2O2: C, 76.21; H, 7.23; N, 7.73. Found C, 76.21; H,
7.22; N, 7.71.
4.5.1. (10S,3R,4R,5R,6R)-3,4-[N-(Allyl)-aziridino]-5-
ethyl-6-phenyl-N-(10-phenyl-ethyl)-piperidin-2-one 11.
Isolated as a white solid (306 mg, 85%), mp¼73–75 8C;
IR (nujol) n 3050, 2921, 1641, 1452 cm21 1H NMR
;
(300 MHz, CDCl3) dH 0.48 (3H, t, J¼7.5 Hz), 0.58–0.69
(1H, m), 0.99–1.09 (1H, m), 1.21 (3H, d, J¼7.3 Hz), 1.82
(1H, dd, J¼1.5, 6.1 Hz), 2.09–2.17 (1H, m), 2.26 (1H, d,
J¼6.1 Hz), 2.49 (1H, dd, J¼5.2, 14.7 Hz), 3.14 (1H, ddt,
J¼4.2, 14.7, 2.0 Hz), 4.16 (1H, s), 4.69 (1H, dq, J¼17.1,
1.8 Hz), 4.86 (1H, dq, J¼10.5, 1.8 Hz), 5.55–5.68 (1H, ddt,
J¼17.1, 10.5, 4.2 Hz), 6.39 (1H, q, J¼7.3 Hz), 7.27–7.35
(10H, m); 13C NMR dC (100 MHz, CDCl3) 11.5 (q), 17.3
(q), 24.1 (t), 38.9 (d), 43.1 (d), 46.0 (d), 51.2 (d), 58.0 (t),
4.6. N-p-Methoxy-phenyl group removal from dihydro-
pyridin-2-one 3b
A solution of CAN (0.548 g, 1 mmol) in water (5 mL) was
added dropwise at rt to a stirred solution of 3b (0.193 g,

5038
G. Cardillo et al. / Tetrahedron 60 (2004) 5031–5040
0.5 mmol) in CH3CN (5 mL). After three hours the organic
solvent was removed under reduced pressure and the
aqueous residue was diluted with ethyl acetate (20 mL)
and water (10 mL). The organic layer was separated,
dried over Na2SO4 and concentrated under reduced
pressure. Compound 15 was purified by flash chromato-
graphy on silica gel (cyclohexane/ethyl acetate 8/2 as
eluant).
4.7.3. 3-Allylamino-4-methyl-6-phenyl-1-(tert-butyloxy-
carbonyl)-5,6-dihydro-pyridin-2-one 18. Isolated as a
pale yellow oil (340 mg, .99%); IR (film) n 3052, 2924,
1
1710, 1639, 1447 cm21; H NMR (200 MHz, CDCl3) dH
1.49 (9H, s), 1.91 (3H, s), 2.45 (1H, dd, J¼5.0, 17.1 Hz),
2.63 (1H, dd, J¼11.7, 17.1 Hz), 3.55 (1H, ddt, J¼14.7, 6.0,
1.5 Hz), 3.58 (1H, ddt, J¼14.7, 6.0, 1.5 Hz), 4.69 (1H, dd,
J¼5.0, 11.7 Hz), 5.20 (1H, dq, J¼10.5, 1.5 Hz), 5.22 (1H,
dq, J¼17.1, 1.5 Hz), 6.08 (1H, ddt, J¼17.1, 10.2, 6.0 Hz),
7.21–7.48 (5H, m); 13C NMR (75 MHz, CDCl3) dC 24.5
(q), 28.2 (3C, q), 40.1 (t), 49.2 (t), 54.9 (d), 82.9 (s), 112.9
(s), 115.8 (t), 121.2 (s), 125.8 (d), 128.2 (d), 128.9 (d), 137.5
(d), 140.0 (s), 153.5 (s), 162.4 (s); LC-ESI-MS rt 12.6 min,
m/z 343 (Mþ1), 365 (MþNa). Anal. Calcd for C24H28N2O:
C, 79.96; H, 7.83; N, 7.77. Found C, 79.98; H, 7.81; N, 7.75.
Anal. Calcd for C20H26N2O3: C, 70.15; H, 7.65; N, 8.18.
Found C, 70.14; H, 7.65; N, 8.17.
4.6.1. 3-Bromo-4-methyl-6-phenyl-5,6-dihydro-pyridin-
2-one 15. Isolated as a white solid (93 mg, 70%), mp¼134–
136 8C; IR (film) n 3304, 3051, 2923, 1640, 1445 cm21; 1H
NMR (200 MHz, CDCl3) dH 2.10 (3H, s), 2.63–2.72 (2H,
m), 4.74 (1H, t, J¼7.8 Hz), 6.00 (1H, bs), 7.35–7.45 (5H,
m); 13C NMR (50 MHz, CDCl3) dC 24.3 (q), 40.6 (t), 54.6
(d), 115.3 (s), 126.2 (d), 128.4 (d), 129.0 (d), 140.2 (s),
148.9 (s), 162.2 (s); GC-MS m/z 267 (77), 265 (77), 186
(51), 213 (8), 162 (100), 160 (100), 104 (22), 77 (25), 53
(44). Anal. Calcd for C12H12NO: C, 56.16; H, 4.54; N, 5.26.
Found C, 56.17; H, 4.55; N, 5.24.
4.8. X-ray crystallographic determination of compounds
7 and 9
4.7. Preparation of N-tert-butyloxycarbonyl-derivative
16
Data were collected at room temperature on a Bruker AXS
˚
CCD diffractometer (Mo Ka radiation, l¼0.71073 A) for
compound 7 and on an Enraf-Nonius CAD4 diffractometer
˚
To a stirred solution of 15 (0.267 g, 1 mmol) in CH2Cl2
(10 mL) at rt, di-tert-butyl dicarbonate (0.436 g, 2 mmol,
2 equiv.), TEA (0.139 mL, 1 mmol, 1 equiv.) and DMAP
(0.122 g, 1 mmol, 1 equiv.) were added. After 12 h, the
reaction was quenched with water and washed twice with a
saturated solution of NH4Cl (10 mL). The organic layer was
dried over Na2SO4 and solvent was removed under reduced
pressure. Compound 16 was isolated in 90% yield after a
quick purification by chromatography on silica gel (cyclo-
hexane/ethyl ether 6/4 as eluant).
(Mo Ka radiation, l¼0.71073 A) for compound 9. The data
collection, integration and data reduction for 7 were
performed using SMART and SAINT programs19 and an
empirical absorption correction was applied using
SADABS.20 The unit cell parameters for 9 were determined
by a least-squares fitting of 25 randomly selected strong
reflections and an empirical absorption correction was
applied using the azimuthal scan method.21 The structures
were solved by direct methods (SIR97)22 and subsequent
Fourier synthesis and refined by full matrix least-squares on
F 2 (SHELXTL) Ref. 23 for all non-hydrogen atoms for 7
whereas for 9 only the bromine atom was treated
anisotropically because of the poor data/parameter ratio.
Hydrogen atoms were placed in calculated positions except
for the hydrogen bound to C9 in compound 7 and to C8 in
compound 9.
4.7.1. 3-Bromo-4-methyl-6-phenyl-1-(tert-butyloxy-
carbonyl)-5,6-dihydro-pyridin-2-one 16. Isolated as a
pale yellow oil (328 mg, 90%); IR (film) n 3042, 2926,
1
1702, 1644, 1449 cm21; H NMR (200 MHz, CDCl3) dH
1.49 (9H, s), 2.02 (3H, s), 2.73 (1H, dd, J¼2.6, 17.8 Hz),
3.18 (1H, dd, J¼6.6, 17.8 Hz), 5.53 (1H, dd, J¼2.6, 6.6 Hz),
7.15–7.45 (5H, m); 13C NMR (75 MHz, CDCl3) dC 24.7
(q), 27.7 (3C,q), 38.3 (t), 55.5 (d), 83.5 (s), 116.5 (s), 125.4
(d), 128.1 (d), 128.5 (d), 139.9 (s), 149.5 (s), 152.2 (s), 158.8
(s); LC-ESI-MS rt 12.7 min, m/z 366–368 (Mþ1), 388–390
(MþNa). Anal. Calcd for C17H20NO3: C, 55.75; H, 5.50; N,
3.82. Found C, 55.77; H, 5.49; N, 3.79.
4.8.1. Compound 7. C22H23BrNO, M¼397.32, ortho-
˚
rhombic, space group P212121, a¼9.8512(6) A, b¼
3
˚
˚
˚
11.4055(6) A, c¼17.6739(10) A, V¼1985.8(2) A , Z¼4,
F(000)¼820, m¼2.079 mm21
,
Dc¼1.329 g/cm23
. The
reflections collected were 26095, of which 5796 unique
[R(int) ¼0.0996]; 2887 reflections I.2s(I), R1¼0.0448 and
wR2¼0.0984 for 2887 [I.2s(I)] and R1¼0.1048 and
wR2¼0.1170 for all (5796) intensity data. Goodness-of-
fit¼0.867, absolute structure parameter of the model:
x¼0.018 (12), residual electron density in the final Fourier
4.7.2. 3-Allylamino-4-methyl-6-phenyl-5,6-dihydro-
pyridin-2-one 17. Isolated as a pale yellow oil (241 mg,
.99%); IR (film) n 3309, 3050, 2930, 1638, 1441 cm21; 1H
NMR (300 MHz, CDCl3) dH 1.92 (3H, s), 2.46 (1H, dd,
J¼5.4, 16.8 Hz), 2.65 (1H, dd, J¼11.7, 16.8 Hz), 3.53 (1H,
ddt, J¼15.0, 6.0, 1.5 Hz), 3.61 (1H, ddt, J¼15.0, 6.0,
1.5 Hz), 4.69 (1H, dd, J¼5.4, 11.7 Hz), 5.14 (1H, dq,
J¼10.2, 1.5 Hz), 5.25 (1H, dq, J¼17.1, 1.5 Hz), 5.53 (1H,
bs), 5.95 (1H, ddt, J¼17.1, 10.2, 6.0 Hz), 7.24–7.45 (5H,
m); 13C NMR (50 MHz, CDCl3) dC 19.0 (q), 39.6 (t), 51.2
(t), 55.5 (d), 113.4 (s), 115.9 (t), 120.4 (s), 126.5 (d), 128.5
(d), 129.1 (d), 136.6 (d), 141.4 (s), 166.7 (d); GC-MS m/z
242 (50), 227 (9), 280 (13), 213 (8), 137 (14), 106 (100), 68
(63). Anal. Calcd for C15H18N2O: C, 74.35; H, 7.49; N,
11.56. Found C, 74.33; H, 7.50; N, 11.55.
map was 0.392 and 20.406 e A23. CCDC number is
˚
229760.
4.8.2. Compound 9. C21H22BrNO, M¼384.31, ortho-
˚
rhombic, space group P212121, a¼7.659(3) A, b¼
3
˚
˚
˚
12.751(2) A, c¼19.087(4) A, V¼1864.0(9) A , Z¼4,
F(000)¼792, m¼2.212 mm21
,
Dc¼1.369 g/cm23
. The
reflections collected were 2512, of which 2512 unique;
781 reflections [I.2s(I)]. R1¼0.0506 and wR2¼0.1238 for
781 [I.2s(I)] and R1¼0.2501 and wR2¼0.1833 for all
(2512) intensity data. Goodness-of-fit¼0.953, absolute
structure parameter of the model: x¼0.05(3), residual

G. Cardillo et al. / Tetrahedron 60 (2004) 5031–5040
5039
6. (a) Nicolaou, K. C.; Trujillo, J. I.; Jandeleit, B.; Chibale, K.;
Rosenfeld, M.; Diefenbach, B.; Cheresh, D. A.; Goodman,
S. L. Bioorg. Med. Chem. 1998, 6, 1185–1208. (b) Haubner,
R.; Gratias, R.; Diefenbach, B.; Goodman, S. L.; Jonczyk, A.;
Kessler, H. J. Am. Chem. Soc. 1996, 118, 7461–7472.
(c) Ojima, I.; Chakravarty, S.; Dong, Q. Bioorg. Med. Chem.
1995, 3, 337–360.
electron density in the final Fourier map was 0.311 and
20.235 e A23. CCDC number is 229761.
˚
5. Supplementary Material
Crystal data and structure refinement for 7 and 9. Atomic
coordinates (£104) and equivalent isotropic displacement
7. (a) Marson, C. M.; Grabowska, U.; Fallah, A.; Walsgrove, T.;
Eggleston, D. S.; Baures, P. W. J. Org. Chem. 1994, 59,
291–296. (b) Brandstadter, S. M.; Ojima, I.; Hirai, K.
Tetrahedron Lett. 1987, 28, 613–616. (c) Danishefsky, S. J.;
Vogel, C. J. Org. Chem. 1986, 51, 3915–3916. (d) Duran, F.;
Ghosez, L. Tetrahedron Lett. 1970, 3, 245–248.
2
3
˚
parameters (A £10 ) for 7 and 9.
Acknowledgements
8. (a) Tidwell, T. T. Acc. Chem. Res. 1990, 23, 273–279.
(b) Hyatt, J. A.; Raynolds, P. W. Organic Reactions; Paquette,
L. A., Ed.; Wiley: New York, 1994; Vol. 45, pp 159–646.
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We thank MURST (Cofin 2002 and FIRB), ISOF-CNR and
the University of Bologna (funds for selected topics) for
financial support.
9. (a) Cardillo, G.; De Simone, A.; Mingardi, A.; Tomasini, C.
Synlett 1995, 1131–1132. (b) Cardillo, G.; Fabbroni, S.;
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