An efficient synthesis of polysubstituted 3-halo-2(1H)-pyridinones

Article abstract of DOI:10.1055/s-2002-19310

A series of 3-halo-2(1H)-pyridinones 4 have been synthesized by treatment of δ-dienaminoesters 1 with N-halosuccinimide in basic medium. The chemoselectivity of the reaction is discussed.

Full text of DOI:10.1055/s-2002-19310

PAPER
79
An Efficient Synthesis of Polysubstituted 3-Halo-2(1H)-Pyridinones
An
E
fficient Syn
l
o
a
f
Polysubst
u
ituted 3-Halo
d
-2(1
H
)-Pyri
e
dinones Agami, Luc Dechoux,* Séverine Hebbe, Julien Moulinas
Laboratoire de Synthèse Asymétrique associé au CNRS, Université Pierre et Marie Curie, 4 Place Jussieu, 75005 Paris, France
Fax +(33)0144272620; E-mail: dechoux@ccr.jussieu.fr
Received 27 July 2001; revised 15 October 2001
In this reaction, the bromo- -dienaminoesters 3, were
formed as by-products in moderate yields. In order to
study scope and limitations we checked the reaction under
different experimental conditions. We found that adding
1.2 equivalents of NBS to a solution of substrates 1 in
methanol containing 1 equivalent of sodium methoxide
led to an inversion of the chemoselectivity. The bromo- -
dienaminoesters 3 were formed within 5 minutes and
cyclized9 to give the substituted 3-bromo-2(1H)-pyridino-
nes 4 in good yields after being refluxed 1–6 hours
(Scheme 2, Table).
Abstract: A series of 3-halo-2(1H)-pyridinones 4 have been syn-
thesized by treatment of -dienaminoesters 1 with N-halosuccinim-
ide in basic medium. The chemoselectivity of the reaction is
discussed.
Key words: pyridinones, pyrroles -dienaminoesters
The 2(1H)-pyridinone system is a common intermediate
for the synthesis of a wide variety of nitrogen heterocycles
such as pyridine, piperidine, quinolizidine, and indolizi-
dine alkaloids.1 Compounds containing the 2(1H)-pyridi-
none moiety are crucial structural components of
numerous biologically active natural products. In particu-
lar, they constitute the skeleton of elfamycin antibiotics2
and the antifungal compound ilicolicin.3 Simple 2(1H)-
pyridinones find applications in pharmacology due to
their antimicrobial activity.4 Although many methods for
synthesizing 2(1H)-pyridinones have been reported,5 ha-
logenated 2(1H)-pyridinones starting from acyclic sub-
strates to our knowledge, have not been described.
Moreover, halogenated 2(1H)-pyridinones are essential
since they allow a means of introducing an alkyl substitu-
ent through transition metal catalysis6 or halogen-metal
exchange.7 It has been found that -dienaminoesters 1 can
readily be cyclized to 3-halo-2(1H)-pyridinones 4 when
the reagent, N-halosuccinimide is used. This paper reports
a complete description of this reaction. In the course of
studying the reactivity of -dienaminoesters with haloge-
nating reagent, we have recently found that when -die-
naminoesters 1 are treated with 1.2 equiv of NBS in
dichloromethane, pyrroles 2 are formed in good yields
(Scheme 1).8
CO2Me
O
O
O
X
NXS/MeONa/
MeOH
R3
R1
R3
R3
+
reflux
HN
R2
O
N
R2
R2
MeO2C
N
R1
Ph
Ph
R1
Ph
1
4
2
Scheme 2
Examination of the results in the Table shows that this
method gives satisfactory results when R2 is hydrogen
(Table, entries 1–3).10 The 3-bromo-2-(1H)-pyridinones
4a–c were formed in good yields. In these cases, the sub-
stituent R1 does not influence the selectivity but only the
rate of the reaction. Indeed substitution to the phenyl
group decreases the rate of cyclization (1 hour when
R1 = H and 6 hours when R1 = Me). The moderate yield
obtained with substrate 1c (Table, entry 3) is due to prob-
lems in purification.
In contrast, when R2 is a methyl group (Table, entries 4,
5), the yields decreased due to the concurrent formation of
pyrroles 2d,e. Nevertheless, the ratio of 4:2 is still in favor
of the expected 3-bromo-2(1H)-pyridinones 4d,e. Al-
though the origin of the decrease of selectivity is not clear,
it seems that the methyl group stabilizes a carbocation in-
termediate and facilitates the formation of pyrroles 2. It
should also be noted that a cisoid conformation for the cy-
clization of compounds 5 into pyrroles 2 is necessary. It is
likely that this conformation is more favorable when
R2 = Me (Scheme 3). The -enaminoketone 1d (Table,
entry 4) showed similar reactivity. The method was ex-
tended to the synthesis of 3-iodo- and 3-chloro-2(1H)-py-
ridinones 4f,g (Table, entries 6,7). It is noteworthy that 3
equivalents of NCS and a large excess of sodium methox-
ide were necessary to complete the reaction.
CO2Me
Br
CO2Me
O
O
HN
1
O
HN
3
R3
NBS/CH2Cl2
MeO2C
R3
R1
R3
R1
+
R2
R2
R2
N
R1
Ph
Ph
Ph
2
Scheme 1
Synthesis 2002, No. 1, 28 12 2001. Article Identifier:
1437-210X,E;2002,0,01,0079,0082,ftx,en;Z09101SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

80
C. Agami et al.
PAPER
Table Synthesis of 3-Halo-2-(1H)-pyridinones 4
1H and 13C spectra (CDCl3) were recorded on a Bruker ARX 250
spectrometer at 250 MHz and 63 MHz, respectively. Chemical
shifts are reported in ppm from TMS. Optical rotations were reas-
sured with a Perkin-Elmer 141 instrument. Column chromatogra-
phy was performed on silica gel, 230-400 Mesch (Merck). Melting
points were uncorrected and determined with a IA9100 Electrother-
mal instrument. IR spectra were determined with a Nicolet Avatar
320 FT instrument. Elemental analysis were carried out at the “Ser-
vice des microanalyse de l’Université Paris VI” at Paris.
En- Sub- R1
try strate
R2
R3
X
Prod- Ratio
uct 4:2
Yield
(%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1a
1a
H
H
H
H
OCH3
OCH3
OCH3
Br 4a >95:5 82
Br 4b >95:5 83
CH3
CH2OH
Br 4c
Br 4d
Br 4e
>95:5 41
63:37 47
84:16 64
>95:5 84
H
H
H
H
CH3 CH3
-Dienaminoesters 1a–c; Typical procedure
CH3 OCH3
To a solution of benzylamine (2 mL, 18.7 mmol) in MeOH (62 mL)
was added of methyl propiolate (6.6 mL, 74 mmol). The reaction
mixture was refluxed for 2 d and then the solvent evaporated under
vacuum. The residue was recrystallized in MeOH to furnish com-
pound 1a as a white solid (3.08 g; 60%).
H
H
OCH3
OCH3
I
4f
Cl 4g >95:5 37
-Dienaminoester 1a
Mp: 107 °C.
The selectivity of the reaction (formation of pyridinones 4
versus pyrroles 2) is dependent not only on the nature of
the radical R2 but also on the basicity of the reaction me-
dium. Under neutral conditions, formation of pyrroles 2 is
favoured. In contrast, in basic medium 3-halo-2-(1H)-py-
1
IR (cm ): 1708, 1666.
1H NMR (250 MHz, CDCl3): = 3.63 (s, 3 H, CO2CH3), 3.69 (s, 3
H, CO2CH3), 4.39 (s, 2 H, CH2), 5.97 (d, 1 H, J = 15.7 Hz, CH),
ridinones 4 are synthesized in good yields. The mechanis- 7.14 7.33 (m, 7 H, Ar, 2 CH), 9.10 (m, 1 H, NH).
13C NMR (63 MHz, CDCl3): = 50.9, 51.0 (CO2CH3), 52.9 (CH2),
95.2 (Cq), 108.0 (CH); 127.2 (Ar), 128.1 (Ar), 128,9 (Ar), 136.7
(Arq), 143.2 (CH), 157.0 (CH), 169.1 (CO), 169.4 (CO).
tic pathway for these transformations involves imines 5 as
intermediates (Scheme 3). The reactive intermediates
may evolve by processes A (intramolecular displacement
of halogen) or B (deprotonation with sodium methoxide)
to form pyrroles 2 and halo- -dienaminoesters 3 respec-
tively which afford finally the 3-halo-2-(1H)-pyridinones
4.
Anal. Calcd for C15H17NO4: C, 65.44; H, 6.22; N, 5.09. Found: C,
65.45; H, 6.38; N, 4.99.
-Dienaminoester 1b
(56%), mp: 63 °C.
In conclusion, it appears that this synthetic two or three-
step sequence starting from commercially available pri-
mary amines is straightforward for the preparation of 3-
halo-2(1H)-pyridinones 4. This procedure does not re-
quire harsh reaction conditions or sensitive reagents and
gives high yields. We are currently investigating the use
of 3-bromo-2-(1H)-pyridinones 4b,c in asymmetric syn-
thesis in order to prepare polysubstituted enantiopure pip-
eridines.
[ ]D20 +17 (c 0.65, CHCl3).
1
IR (cm ): 1703, 1666, 1599.
1H NMR (250 MHz, CDCl3): = 1.55 (d, 3 H, J = 7 Hz, CH3), 3.64
(s, 3 H, CO2CH3), 3.73 (s, 3 H, CO2CH3), 4.48 (quint, 1 H, J = 7 Hz,
CH), 5.94 (d, 1 H, J = 15.5 Hz, CH), 7.12 7.35 (m, 7 H, Ar, 2
CH), 9.17 (m, 1 H, NH).
13C NMR (63 MHz, CDCl3): = 23.2 (CH3), 50.8, 51.0 (CO2CH3),
57.9 (CH), 95.0 (CH), 107.8 (Cq), 126.0 (Ar), 127.9 (Ar), 128.9
(Ar), 142.1 (Arq), 143.2 (CH), 155.7 (CH), 169.1 (CO), 169.4 (CO).
O
R3
R2
MeO2C
N
MeONa
CO2Me
A
O
HN
1
R1
Ph
B
O
CH2Cl2
R3
R1
H
NXS
R3
CO2Me
2
X
R2
X
CO2Me
O
MeONa/MeOH
B
A
R2
N
O
X
R3
Ph
R1
Ph
R3
R1
5
O
N
R2
HN
R2
R1
Ph
Ph
4
3
Scheme 3
Synthesis 2002, No. 1, 79–82 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
An Efficient Synthesis of Polysubstituted 3-Halo-2(1H)-Pyridinones
81
Anal. Calcd for C16H19NO4: C, 66.42; H, 6.62; N, 4.84. Found: C,
66.36; H, 6.64; N, 4.79.
graphed on silica gel (hexane–EtOAc, 80:20) to furnish 4a (128 mg,
82%) as a white solid.
-Dienaminoester 1c
3-Bromo-2(1H)-pyridinone 4a
(49%), mp: 126 °C.
Mp: 139 °C.
1
1H NMR (250 MHz, CDCl3): = 2.20 (s, 1 H, OH), 3.63 (s, 3 H,
CO2CH3), 3.73 (s, 3 H, CO2CH3), 3.79 (dd, 1 H, J = 11.5, 7.5 Hz,
CH2), 3.88 (dd, 1 H, J = 11.5, 4.5 Hz, CH2), 4.45 (ddd, 1 H, J = 4.5,
7.5, 6.5 Hz, CH), 5.99 (d, 1 H, J = 15.5 Hz, CH), 7.23 7.41 (m, 7
H, Ar, 2 CH), 9.47 (m, 1 H, NH).
13C NMR (63 MHz, CDCl3): = 50.9, 51.1 (CO2CH3), 64.5 (CH),
66.2 (CH2), 95.4 (Cq), 107.1 (CH), 126.8 (Ar), 128.4 (Ar), 129.0
(Ar), 137.5 (Cq), 143.5 (CH), 156.7 (CH), 169.4 (CO), 169.5 (CO).
IR (cm ): 1725, 1664.
1H NMR (250 MHz, CDCl3): = 3.84 (s, 3 H, CO2CH3), 5.20 (s, 2
H, CH2), 7.35 (s, 5 H, HAr), 8.18 (d, 1 H, J = 2.5 Hz, CH), 8.24 (d,
1 H, J = 2.5 Hz, CH).
13C NMR (63 MHz, CDCl3): = 52.3 (CO2CH3), 54.3 (CH2), 110.1
(Cq), 115.9 (Cq), 128.5 (Ar, 2 C), 128.7 (Ar), 129.1 (Ar, 2 C),
134.8 (Ar), 140.3 (CH), 141.5 (CH), 159.3 (CO), 163.6 (CO).
Anal. Calcd for C14H12BrNO3: C, 52.20, H, 3.75, N, 4.35. Found: C,
51.40, H, 3.92, N, 4.17.
[ ]D20 +20 (c 0.15, CHCl3).
Anal. Calcd for C16H19NO5: C, 62.94, H, 6.27, N, 4.59. Found: C,
63.23, H, 6.73, N, 4.22.
3-Bromo-2(1H)-pyridinone 4b
IR (cm ): 1725, 1666.
1
-Dienaminoester 1d
1H NMR (250 MHz, CDCl3): = 1.78 (d, 3 H, J = 7 Hz, CH3), 3.81
(s, 3 H, CO2CH3), 6.41 (q, 1 H, J = 7 Hz, CHAr), 7.27 7.43 (m, 5
H, Ar), 8.04 (d, 1 H, J = 2.5 Hz, CH), 8.22 (d, 1 H, J = 2.5 Hz, CH).
13C NMR (63 MHz, CDCl3): = 19.2 (CH3), 52.2 (CO2CH3), 55.4
(CH), 110.2 (Cq), 115.5 (Cq), 127.3 (Ar, 2 C), 128.6 (Ar, C), 129.1
(Ar, 2 C), 138.7 (CH and Ar), 139.7 (CH), 158.7 (CO), 163.6
(CO).
To a solution of benzylamine (1.06 mL, 10 mmol) in MeOH (50
mL) was added of 2,4-pentanedione (1.53 mL, 15 mmol). The reac-
tion mixture was refluxed for 2 h and methyl propiolate (2.5 mL, 28
mmol) was added at r.t. After refluxing for 2 d, the solvent was
evaporated under vacuum. The residual oil was chromatographed
on silica gel (hexane–EtOAc, 80:20) to furnish 1d (2.02 g, 74%) as
a white solid.
Mp: 60 °C.
3-Bromo-2(1H)-pyridinone 4c
IR (cm ): 3445, 1737, 1665.
1H NMR (250 MHz, CDCl3): = 2.21 (s, 3 H, CH3), 2.31 (s, 3 H,
CH3), 3.74 (s, 3 H, CO2CH3), 4.56 (d, 2 H, J = 5.7 Hz, CH2), 5.59
(d, 1 H, J = 15.7 Hz, CH), 7.80 (d, 1 H, J = 15.7 Hz, CH), 7.24
7.36 (m, 5 H, Ar), 11.20 (m, 1 H, NH).
13C NMR (63 MHz, CDCl3): = 16.9 (CH3), 29.4 (COCH3), 47.6
(CO2CH3), 51.3 (CH2), 95.9 (Cq), 104.9 (Cq), 113.5 (CH), 126.9
(Ar), 127.8 (Ar), 129.0 (Ar), 136.6 (Arq), 143.6 (CH), 166.4 (CO),
196.3 (CO).
1
1H NMR (250 MHz, CDCl3): = 2.70 (s, 1 H, OH), 3.81 (s, 3 H,
CO2CH3), 4.31 (d, 2 H, J = 6 Hz, CH2), 6.31 (t, 1 H, J = 6 Hz,
CHAr), 7.34 7.39 (m, 5 H, Ar), 8.24 (s, 2 H, 2 CH).
13C NMR (63 MHz, CDCl3): = 52.8 (CO2CH3), 61.7 (CH), 62.6
(CH2), 110.2 (Cq), 115.3 (Cq), 128.0 (Ar, 2 C), 128.9 (Ar, C),
129.2 (Ar, 2 C), 135.5 (CAr), 140.1 (CH), 140.3 (CH), 159.6 (CO),
163.8 (CO).
-Dienaminoester 1e
3-Bromo-2(1H)-pyridinone 4d
To a solution of benzylamine (2 mL, 18.7 mmol) in MeOH (62 mL)
was added methyl acetoacetate (2.4 mL, 22.4 mmol). The reaction
mixture was refluxed for 2 h and then methyl propiolate (2.5 mL, 28
mmol) was added at r.t. After 2 d at reflux, the solvent was evapo-
rated under vacuum. The residue was recrystallized in MeOH to fur-
nish compound 1e as a white solid (4.10 g, 76%). Mp:106 °C.
1H NMR (250 MHz, CDCl3): = 2.50 (s, 3 H, CH3), 2.61 (s, 3 H,
COCH3), 5.49 (s, 2 H, CH2), 7.13 7.16 (m, 2 H, Ar), 7.24 7.36 (m,
3 H, Ar), 8.15 (s, 1 H, CH).
13C NMR (63 MHz, CDCl3): = 17.9 (CH3), 29.5 (COCH3), 49.2
(CH2), 111.8 (Cq), 118.0 (Cq), 126.4 (Ar, 2 C), 127.8 (Ar), 128.9
(Ar), 134.9 (Ar), 141.1 (CH), 152.4 (Cq), 159.3 (CO), 196.0 (CO).
1
IR (cm ): 1693, 1646, 1572.
1H NMR (250 MHz, CDCl3): = 2.28 (s, 3 H, CH3), 3.75 (s, 3 H,
CO2CH3), 3.79 (s, 3 H, CO2CH3), 4.58 (d, 2 H, J = 5.7 Hz, CH2),
6.12 (d, 1 H, J = 15.2 Hz, CH), 7.26 7.42 (m, 5 H, Ar), 7.78 (d, 1
H, J = 15.2 Hz, CH), 11.02 (m, 1 H, NH).
3-Bromo-2(1H)-pyridinone 4e
1H NMR (250 MHz, CDCl3): = 2.71 (s, 3 H, CH3), 3.85 (s, 3 H,
CO2CH3), 5.49 (s, 2 H, CH2), 7.13 7.33 (m, 5 H, Ar), 8.35 (s, 1 H,
CH).
13C NMR (63 MHz, CDCl3): = 16.0 (CH3), 47.7 (CH2), 50.8
(CO2CH3), 51.0 (CO2CH3), 93.8 (CIV), 110.1 (CH), 126.8 (Ar),
127.8 (Ar), 129,0 (Ar), 136.9 (ArCIV), 140.6 (CH), 166.6 (CIV),
169.8 (CO), 170.8 (CO).
13C NMR (63 MHz, CDCl3): = 17.6 (CH3), 49.1 (CH2), 52.2
(CO2CH3), 109.6 (Cq), 112.0 (Cq), 126.4 (Ar, 2 C), 127.7 (Ar, C),
128.9 (Ar, 2 C), 135.0 (Ar), 141.7 (CH), 153.4 (CIV), 159.6 (CO),
164.9 (CO).
Anal. Calcd for C16H19NO4: C, 66.42, H, 6.62, N, 4.84. Found: C,
65.89, H, 6.63, N, 4.84.
3-Iodo-2(1H)-pyridinone 4f
To a solution of NaOMe (20.5 mg, 0.38 mmol) and -dienami-
noester 1a (105 mg, 0.38 mmol) in MeOH (3.8 mL) at r.t. was added
NIS (104 mg, 0.46 mmol) in portions. The reaction was then re-
fluxed for 4 h and then the solvent was evaporated under vacuum.
The residue was quenched with an aq solution of NH4Cl and ex-
tracted with CH2Cl2 (3 10 mL). The combined organic layers were
dried (MgSO4) and chromatographed on silica gel (hexane–EtOAc,
80:20) to yield 4f (99 mg, 84%) as a colorless oil.
3-Bromo-2(1H)-pyridinones 4a e; Typical Procedure
To a solution of NaOMe (21.5 mg, 0.40 mmol) and -dienami-
noester 1a (110 mg, 0.40 mmol) in MeOH (4 mL) at r.t. was added
NBS (85 mg, 0.48 mmol) in small quantities. The reaction was re-
fluxed for 1 h and solvent evaporated under vacuum. The residue
was quenched with an aq solution of NH4Cl and extracted with
CH2Cl2 (3 10 mL). The combined organic layers were dried
(MgSO4) and concentrated. The residual solid was chromato-
Synthesis 2002, No. 1, 79–82 ISSN 0039-7881 © Thieme Stuttgart · New York

82
C. Agami et al.
PAPER
1H NMR (250 MHz, CDCl3): = 3.77 (s, 3 H, CO2CH3), 5.12 (s, 2
H, CH2), 7.19 7.37 (m, 5 H, Ar), 8.13 (d, 1 H, J = 2 Hz, CH), 8.40
(d, 1 H, J = 2 Hz, CH).
13C NMR (63 MHz, CDCl3): = 52.3 (CO2CH3), 54.7 (CH2), 91.5
(Cq), 111.2 (Cq), 128.5 (Ar, 2 C), 128.6 (Ar), 129.1 (Ar, 2 C),
134.9 (Ar), 142.6 (CH), 147.4 (CH), 159.6 (CO), 163.4 (CO).
References
(1) Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V. In
Comprehensive Heterocyclic Chemistry, Vol. 5; Pergamon
Press: Oxford, 1996.
(2) Dolle, R. E.; Nicolaou, K. C. J. Am. Chem. Soc. 1985, 107,
1691.
(3) Cox, R. J.; O’Hagan, D. J. Chem. Soc., Perkin Trans 1 1991,
2537.
(4) Pierce, J. B.; Ariyan, Z. S.; Ovenden, G. S. J. Med. Chem.
1982, 25, 131.
3-Chloro-2(1H)-pyridinone 4g
To a solution of NaOMe (21.5 mg, 0,40 mmol) and -dienami-
noester 1a (110 mg, 0.40 mmol) in MeOH (3.8 mL) at r.t. was added
NCS (163 mg, 1.20 mmol) in portions. After 1 h, NaOMe (100 mg,
1.85 mmol) was added and the reaction mixture was then refluxed
for 4 h and the solvent was evaporated under vacuum. The residue
was quenched with an aq solution of NH4Cl and extracted with
CH2Cl2 (3 10 mL). The combined organic layers were dried
(MgSO4) and chromatographed on silica gel (hexane–EtOAc,
80:20) to yield 4g (42 mg, 37%) as a colorless oil.
1H NMR (250 MHz, CDCl3): = 3.78 (s, 3 H, CO2CH3), 5.14 (s, 2
H, CH2), 7.20 7.33 (m, 5 H, Ar), 7.96 (d, 1 H, J = 2.3 Hz, CH), 8.07
(d, 1 H, J = 2.3 Hz, CH).
13C NMR (63 MHz, CDCl3): = 51.6 (CO2CH3), 51.9 (CH2), 105.9
(Cq), 109.3 (Cq), 128.3 (Ar, 2 C), 128.5 (Ar), 128.9 (Ar, 2 C),
136.2 (Ar), 139.5 (CH), 140.6 (CH), 158.6 (CO), 163.6 (CO).
(5) (a) Marcoux, J. F.; Marcotte, F. A.; Wu, J.; Dormer, P. G.;
Davies, I. W.; Hughes, D.; Reider, P. J. J. Org. Chem. 2001,
66, 4194. (b) Sieburth, S. M.; Hiel, G.; Lin, C. H.; Kuan, D.
P. J. Org. Chem. 1994, 59, 80. (c) Sieburth, S. M.; Chen, J.
J. Am. Chem. Soc. 1991, 113, 8163. (d) Cainelli, G.;
Panunzio, M.; Giacomini, D.; Di Simone, B.; Camerini, R.
Synthesis 1994, 805. (e) Tutonda, M. G.; Vandenberghe, S.
M.; Van Aken, K. J.; Hoornaert, G. J. J. Org. Chem. 1992,
57, 2935. (f) Zhang, S.; Liebeskind, L. S. J. Org. Chem.
1999, 64, 4042. (g) Padwa, A.; Sheehan, S. M.; Straub, C. S.
J. Org. Chem. 1999, 64, 8648.
(6) (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
(b) Choi, W. B.; Houpis, I. N.; Churchill, H.; Molina, O.;
Lynch, J. E.; Volante, R. P.; Reider, P. J.; King, A. O.
Tetrahedron Lett. 1995, 36, 4571. (c) Houpis, I. N.; Choi,
W. B.; Reider, P. J.; Molina, O.; Churchill, H.; Lynch, J.;
Volante, R. P. Tetrahedron Lett. 1994, 35, 9355.
(7) Domagala, J. M. J. Heterocyclic Chem. 1984, 21, 1705.
(8) Agami, C.; Dechoux, L.; Hebbe, S. Synlett 2001, 1440.
(9) For cyclizations of dehalogenated -dienaminoesters see
(a) Anghelide, N.; Draghici, C.; Raileanu, D. Tetrahedron
1974, 30, 623. (b) Palacios, F.; Garcia, J.; Ochoa de Retana,
A.; Oyarzabal, J. Heterocycles 1995, 41, 1915. (c) Cocco,
M. T.; Congiu, C.; Maccioni, A.; Onnis, V. Synthesis 1992,
371. (d) Lee, C. H.; Kohn, H. J. Heterocycl. Chem. 1990, 27,
2107. (e) Khan, M. A.; Adams, H. Tetrahedron Lett. 1999,
40, 5389.
Bromo- -dienaminoester 3a
To a solution of -dienaminoester 1a (276 mg, 1 mmol) in THF at
r.t. was added NBS (214 mg, 1.20 mmol) in portions. After 10 min
the reaction was quenched with an aq solution of NH4Cl and ex-
tracted with CH2Cl2 (3 10 mL). The combined organic layers were
dried (MgSO4), evaporated under vacuum and chromatographed on
silica gel (hexane–EtOAc, 70:30) to yield 3a (267 mg, 75%) as a
colorless oil.
1H NMR (250 MHz, CDCl3): = 3.75 (s, 3 H, CO2CH3), 3.82 (s, 3
H, CO2CH3), 4.52 (d, 2 H, J = 6 Hz, CH2), 7.27 7.45 (m, 5 H, Ar),
8.30 (s, 1 H, CH), 8.61 (d, 1 H, J = 13.5 Hz, CH), 9.53 (t, 1 H, J = 6
Hz, NH).
13C NMR (63 MHz, CDCl3): = 51.2 (CO2CH3), 53.0 (CO2CH3),
53.4 (CH2), 92.6 (Cq), 100.7 (Cq), 127.5 (Ar, 2 C), 128.2 (Ar),
129.0 (Ar, 2 C), 136.4 (Ar), 137.4 (CH), 155.6 (CH), 164.5 (CO),
169.2 (CO).
(10) 3-Bromo-2(1H)-pyridinone(4a) has been correlated with
methyl-6-hydroxynicotinate. By hydrogenolysis compound
4a under atmospheric pressure using Pd/C as catalyst
methyl-6-hydroxynicotinate was obtained. See: (a) Shiao,
M. J.; Ku, W. S.; Hwu, J. R. Heterocycles 1993, 36, 323.
(b) Torrado, A.; Imperiali, A. J. Org. Chem. 1996, 61, 8940.
Synthesis 2002, No. 1, 79–82 ISSN 0039-7881 © Thieme Stuttgart · New York