Cyclobutenedione-based method for the synthesis of substituted 2- pyridinones and dihydro-2-pyridinones

Article abstract of DOI:10.1021/jo990069t

1,2-Addition of N-Boc-protected α-amino carbanions to cyclobutenediones followed by methylation of the resulting alkoxides generated 4-(1-N-Boc- aminoalkyl)-4-methoxy-3-cyclobutenones. Removal of the Boc protecting group and thermal ring expansion gave dihydro-2-pyridinones in good yields. Treatment of the dihydro-2-pyridinones with NBS/pyridine led to the formation of the corresponding 2-pyridinones. This methodology proved general with regard to both the cyclobutenediones and α-amino carbanions.

Full text of DOI:10.1021/jo990069t

4042
J . Org. Chem. 1999, 64, 4042-4049
Cyclobu ten ed ion e-Ba sed Meth od for th e Syn th esis of Su bstitu ted
2-P yr id in on es a n d Dih yd r o-2-p yr id in on es
Shijie Zhang and Lanny S. Liebeskind*
Sanford S. Atwood Chemistry Center, Emory University, 1515 Pierce Drive, Atlanta, Georgia 30322
Received J anuary 14, 1999
1,2-Addition of N-Boc-protected R-amino carbanions to cyclobutenediones followed by methylation
of the resulting alkoxides generated 4-(1-N-Boc-aminoalkyl)-4-methoxy-3-cyclobutenones. Removal
of the Boc protecting group and thermal ring expansion gave dihydro-2-pyridinones in good yields.
Treatment of the dihydro-2-pyridinones with NBS/pyridine led to the formation of the corresponding
2-pyridinones. This methodology proved general with regard to both the cyclobutenediones and
R-amino carbanions.
In tr od u ction
A century ago, Decker investigated the oxidation of
pyridinium salts to the corresponding 2-pyridinones with
ferricyanide under basic conditions.14 This method pro-
vides easy access to a variety of 2-pyridinones as long as
the starting pyridinium salts are available. Other oxi-
dants such as H2O2, KMnO4, and Ag(I) salts have also
been used in the transformation of pyridinium salts to
the corresponding 2-pyridinones.15
Substituted 2-pyridinones are commonly synthesized
from acyclic starting materials. Chung’s synthesis of
2-pyridinones involves an intramolecular Dieckmann-like
condensation,16 and many 2-pyridinone synthetic meth-
odologies incorporate the Michael addition as a key step
in the formation of the six-membered rings. Representa-
tive synthetic routes have been developed by J un-
jappa,17,18 Chuit,19 and Cainelli.20 2-Pyridinones have also
been synthesized through a variety of cycloaddition
procedures.13,21-24 Although a variety of methods for the
preparation of substituted 2-pyridinones have been re-
ported, new, concise, regioselective, and functional-group-
tolerant methods are continuously being sought.
The 2-pyridinone substructure is found in many bio-
logically active natural and synthetic compounds that
possess medicinal properties. These range from anti-
bacterial1-3 and antifungal4 agents to free radical scav-
engers,5 the latter of which play a role in a variety of
diseases including cardiovascular disease, connective
tissue damage, inflammatory disorder, and CNS injury.6
Huperzine A, isolated from the Chinese drug Huperzia
serrata, is a potent inhibitor of acetylcholinesterase and
is effective in the treatment of memory impairment,
myasthenia gravis, and multi-infarct dementia, with
minimal side effects. It is also a promising drug candidate
for senile dementia diseases, including Alzheimer’s.7
N-Substituted 2-pyridinones have been employed as
active ingredients in drugs for the therapy of fibrotic
disease8 and have been evaluated as inhibitors of human
leukocyte elastase.9 Some synthetic 2-pyridinones have
also demonstrated high hypotensive activity10 or cardio-
tropic activity.11 For these reasons, the synthesis of
compounds containing a 2-pyridinone substructure has
become increasingly important in a variety of medical
applications.
Ba ck gr ou n d
Numerous methods for the preparation of substituted
In 1994, a route to ring-fused 2-pyridinones by an
intramolecular regioselective vinylketene cyclization was
reported (Scheme 1).25 The precursors of the key vi-
nylketene intermediates are 4-heteroaromatic substi-
tuted cyclobutenones, which are obtained either through
2-pyridinones have been reported in the literature.12,13
* Tel: (404) 727-6604. FAX: (404) 727-0845. E-mail: CHEMLL1@
emory.edu.
(1) Casinovi, C. G.; Grandolini, G.; Mercantini, R.; Oddo, N.; Olivieri,
R.; Tonolo, A. Tetrahedron Lett. 1968, 3175.
(2) Dolle, R. E.; Nicolaou, K. C. J . Am. Chem. Soc. 1985, 107, 1691.
(3) Rigby, J .; Balasubramanian, N. J . Org. Chem. 1989, 54, 224.
(4) Cox, R. J .; O’Hagan, D. J . Chem. Soc., Perkin Trans. 1 1991,
2537.
(5) Teshima, Y.; Shin-ya, K.; Shimazu, A.; Furihata, K.; Chul, H.
S.; Furihata, K.; Hayakawa, Y.; Nagai, K.; Seto, H. J . Antibiot. 1991,
44, 685.
(13) Mckillop, A.; Boulton, A. J . In Comprehensive Heterocyclic
Chemistry; Boulton, A. J ., Mckillop, A., Eds.; Pergamon: Oxford, 1984;
Vol. 2, p 67.
(14) Decker, H. Chem. Ber. 1892, 25, 443.
(15) Mohrle, H.; Weber, H. Tetrahedron 1970, 26, 2953.
(16) Chung, K. H.; Cho, K. Y.; Asami, Y.; Takahashi, N.; Yoshida,
S. Heterocycles 1991, 32, 99.
(17) Aggarwab, V.; Singh, G.; Ila, H.; J unjappa, H. Synthesis 1982,
214.
(18) Datta, A.; Ila, H.; J unjappa, H. J . J . Org. Chem. 1990, 55, 5589.
(19) Chuit, C.; Corriu, R. J . P.; Perz, R.; Reye, C. Tetrahedron 1986,
42, 2293.
(20) Cainelli, G.; Panunzio, M.; Giacomini, D.; Simone, B. D.;
Camerini, R. Synthesis 1994, 805.
(21) Kappe, T.; Pocivalnik, D. Heterocycles 1983, 20, 1367.
(22) Gotthardt, H.; Flosbach, C. Chem. Ber. 1988, 121, 951.
(23) Tutonda, M. G.; Vandenberghe, S. M.; Van Aken, K. J .;
Hoornaert, G. J . J . Org. Chem. 1992, 57, 2935.
(24) Sheehan, S. M.; Padwa, A. J . Org. Chem. 1997, 62, 438.
(25) Gurski-Birchler, A.; Liu, F.; Liebeskind, L. S. J . Org. Chem.
1994, 59, 7737.
(6) Free Radical Damage and its Control; Rice-Evans, C. A., Burdon,
R. H., Eds.; Elsevier: Amsterdam, 1994.
(7) He, X. C.; Wang, Z. Y.; Li, Y. L.; Bai, D. L. Zhongguo Yaowu
Huaxue Zazhi (J . Med. Chem., China) 1994, 4, 257.
(8) Margolin, S. B. U.S. Patent 59214, 07 May 1993.
(9) Grontas, W. C.; Stanga, M. A.; Brobaker, M. J .; Huang, T. L.;
Moi, M. L.; Carroll, R. T. J . Med. Chem. 1985, 28, 1106.
(10) Matyus, P.; Kasztreiner, E.; Diesler, E.; Behr, A.; Varga, I.;
Kosary, J .; Rabloczky, G.; J aszlits, L. Arch. Pharm. (Weinheim, Ger.)
1994, 327, 543.
(11) Narusevicius, E.; Garaliene, V.; Krauze, A.; Duburs, G. Khim.-
Farm. Zh. 1989, 23, 1459.
(12) Tieckelmann, H. In Heterocyclic Compounds, Pyridine and Its
Derivatives, Supplement Part Three; Abramovitch, R. A., Ed.; Wiley-
Interscience: New York, 1974; p 597.
10.1021/jo990069t CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/04/1999

Substituted 2-Pyridinones and Dihydro-2-pyridinones
J . Org. Chem., Vol. 64, No. 11, 1999 4043
Sch em e 1a
Sch em e 4
a
Z ) CHdCH, C(OMe)dCH, S, N-Me, N-MOM; R1 ) aryl,
alkyl; R2 ) alkyl, aryl, alkoxy, amino; R3 ) H, OH, OAc; R4, R5
H or benzo.
)
Sch em e 5
Sch em e 2
Sch em e 3
the 1,2-addition product in 51% yield (Scheme 4). Un-
fortunately, under a variety of thermolytic reaction con-
ditions, complicated mixtures were obtained, from which
the desired dihydropyridinone could not be isolated.
To eliminate the possible interference of the hydroxyl
group during the thermal ring-expansion process, which
proceeds through a vinylketene intermediate, protection
of the 4-hydroxyl group of the cyclobutenone product was
carried out (Scheme 5). This tactic was successful. The
O-methylated product 3a was produced quantitatively by
following a literature procedure.30 Removal of the Boc
protecting group followed by thermolysis of the crude
product generated the 3,6-dihydro-2-pyridinone 4a in
75% yield after chromatographic purification (Scheme 5).
Spectroscopic data are consistent with the proposed
structure. The assignment of the CdC bond at the
indicated γ,δ-position for 4a is based upon the chemical
shifts of the C3 methyl group and the C3-H (δ 1.50 and
3.08 ppm) and the magnitude of the coupling constant
between them (J ) 7.2 Hz).
The MeI-based protection of the 4-hydroxyl group of
other 4-hydroxycyclobutenones was problematic, but
direct methylation of the alkoxide intermediate, produced
upon the addition of the R-amino carbanion to a cy-
clobutenedione, with MeOSO2CF3 was effective in most
cases. This allowed the generality of the cyclobutenedi-
one-based approach to dihydropyridinones to be assayed.
The results are summarized in Table 1. The regiochem-
istry of nucleophilic attack on the unsymmetrically
substituted cyclobutenediones, which is well established
to occur at the nonvinylogous ester or amide carbonyl
group, dictates the substitution pattern in the resulting
dihydropyridinone. Treatment of the reaction mixture
generated from the addition of the R-amino carbanions
2 to cyclobutenediones 1 with 2.5 equiv of MeOTf at -78
°C for 20 min, followed by quenching of the reaction
mixture with aqueous NaHCO3 at -78 °C, gave the
methylated products 3 in the indicated yields after
chromatography. The low-temperature quench was es-
sential; a complicated mixture was obtained when a
Stille cross-coupling of 4-chlorocyclobutenones with 2-het-
eroaromatic stannanes or through nucleophilic addition
of 2-lithiated heteroaromatics to substituted cyclobutene-
diones. This methodology proved quite general and
allowed the construction of 2-pyridinone-based aza-
heteroaromatics bearing various substituents in moder-
ate to good yields.
In an effort to extend the cyclobutenone-based method
for the synthesis of 2-pyridinones to nonfused heteroaro-
matic systems, lithiated imines were added to substituted
cyclobutenediones.26 However, the ring-expansion process
did not provide the expected 2-pyridinones through
cyclization of vinylketene intermediates; rather, a 1,2-
shift led to the formation of substituted 2-amino-4-
cyclopentene-1,3-diones (Scheme 2).
To circumvent this process, a dihydropyridinone syn-
thesis was attempted through ring expansion of cy-
clobutenones bearing an aminoalkyl substituent at the
4-position, as shown in Scheme 3. Oxidation of the
resulting dihydropyridinones would then generate the
corresponding pyridinones. The results of that study are
described herein.
Resu lts a n d Discu ssion
In contrast to the inefficient direct deprotonation of
N-tert-butoxycarbonyl dimethylamine (sec-BuLi in Et2O
at -78 °C for 10 h),27 the readily available tri-n-butyl-
stannylated N-Boc-dimethylamine effectively produced
the corresponding lithiate 2a by tin-lithium exchange.28
Low-temperature reaction of this R-amino anion with
3-isopropoxy-4-methylcyclobutene-1,2-dione 1a followed
by aqueous NaHCO3 quench and deprotection of the
amine with anhydrous TFA at room temperature29 gave
(26) Sun, L.; Liebeskind, L. S. J . Org. Chem. 1994, 59, 6856.
(27) Beak, P.; Lee, W. K. Tetrahedron Lett. 1989, 30, 1197.
(28) Chong, J . M.; Park, S. B. J . Org. Chem. 1992, 57, 2220.
(29) Grehn, L.; Ragnarsson, U. J . Org. Chem. 1981, 46, 3492.
(30) Liebeskind, L. S.; Granberg, K. L.; Zhang, J . J . Org. Chem.
1992, 57, 4345.

4044 J . Org. Chem., Vol. 64, No. 11, 1999
Ta ble 1. Dih yd r o-2-p yr id in on e Syn th esis
Zhang and Liebeskind
cyclobutenedione, 1
R-amino anion, 2
R3 R4
entry
R1
R2
3
yld %
4
yld %
1
2
3
4
5
6
7
8
9
Me
t-Bu
Ph
Et
Ph
Et
Ph
Et
Ph
i-PrO
i-PrO
i-PrO
Et
i-PrO
Et
i-PrO
Et
NMe2
H
H
H
H
Me
Me
Me
Me
3a
3b
3c
3d
3e
3f
3g
3h
3i
53
73
68
55
a
42
74c
64c
85
4a
4b
4c
4d
4e
4f
4g
4h
4i
75
87
86
71
68b
80
73
32
89
-(CH2)4-
-(CH2)3-
EtO2C
EtO2C
H
Me
Me
Me
10
11
Ph
Ph
NMe2
NMe2
3j
a
4j
40b
Ph
Bn
3k
88
4k
83
a
b
The crude products 3e and 3j displayed complex spectroscopic data due to diastereomers and rotamers and were not purified. Overall
yields for 4e and 4j were calculated from the corresponding cyclobutenedione 1. c 3g and 3h were isolated as the 4-hydroxycyclobutenone,
not the methyl ethers. The 4-methoxycyclobutenone was subsequently generated by using the Ag2O/MeI protocol and was used without
purification.
Ta ble 2. Oxid a tion of Dih yd r o-2-p yr id in on es to
room-temperature quench was applied. The R-amino-
2-P yr id in on es
carbanions used in entries 1-6 and 9 were generated by
Sn-Li exchange, starting from the corresponding tri-n-
butylstannyl derivatives.31 The R-amino carbanions in
entries 10 and 11 were generated directly from the Boc-
protected amines by deprotonation with sec-BuLi; LDA
was used to deprotonate N-tert-butoxycarbonyl-N-methyl
glycine ethyl ester for entries 7 and 8.
The alkoxide produced by reaction of the LDA-gener-
entry
R1
R2
R3
R4
product
yld %
ated enolate of N-tert-butoxycarbonyl-N-methyl glycine
ethyl ester with a cyclobutenedione gave complicated
mixtures when treated with MeOTf (entries 7 and 8). In
these cases, methylation of the free alcohol was success-
fully achieved by using the MeI/Ag2O protocol shown in
Scheme 5.30 Because mixtures of diastereomers were
generated with the N-tert-butoxycarbonyl-N-methyl gly-
cine ethyl ester system, the crude products were sub-
jected to deprotection and thermal ring expansion with-
out purification of the intermediates.
1
2
3
4
5
6
7
8
9
Me
t-Bu
Ph
Et
Ph
Et
Ph
Et
Ph
i-PrO
i-PrO
i-PrO
Et
i-PrO
Et
i-PrO
Et
NMe2
H
H
H
H
Me
Me
Me
Me
5a
5b
5c
5d
5e
5f
5g
5h
5i
86
77
88
85
82
60
66
85
99
-(CH2)4-
-(CH2)3-
EtO2C
EtO2C
H
Me
Me
Me
10
11
Ph
Ph
NMe2
NMe2
5j
41
71
After N-Boc deprotection of 3b-k , thermolysis gave
dihydropyridones 4b-k , whose structures were assigned
by analogy to 4a as described above. The structure
assignments of 4b-h in entries 2-8 were based upon
the IR spectral data similar to those obtained for 4a (Cd
O stretch 1635-1643 cm-1) and, inter alia, the enol ether-
Ph
Bn
5k
absorption for the carbonyl groups of 4i-k (1618 cm-1),
the downfield 13C NMR absorptions for the ring CHOMe
carbons (δ > 70 ppm), and the simple methyl ether-
1
1
like H NMR chemical shift of the OMe group (δ 3.01-
like H NMR chemical shift of the OMe group (δ 3.44-
3.80) and the 13C NMR spectroscopic data for the ring
CHR1 carbons (δ 37.9-53.9 ppm). The position of the
double bond of 4i-k in entries 9-11 is different from that
in 4a -h , perhaps a consequence of the greater double
bond delocalization achievable in these three cases (â-
(dimethylamino)-R,â-unsaturated amide). The structure
assignment was based upon the exceptionally low IR
3.18).
Oxidation of some of the dihydro-2-pyridinones (4a -
d ) to 2-pyridinones 5 could be carried out with DDQ in
refluxing benzene;32 however, NBS/pyridine (1:3) in THF
gave good to excellent yields of 2-pyridinones 5 from all
of the dihydropyridinones prepared in this study. The
results are summarized in Table 2. The oxidation was
generally complete within 12 h, but longer reaction times
were required for highly congested substrates.
(31) Beak, P.; Lee, W. K. J . Org. Chem. 1993, 58, 1109.

Substituted 2-Pyridinones and Dihydro-2-pyridinones
J . Org. Chem., Vol. 64, No. 11, 1999 4045
temperature over 30 min. Hexane (2 mL) was added to the
solution, and the aqueous layer was diluted with 10 mL of H2O
and extracted with 3 × 20 mL of Et2O. The combined organic
layers were dried over MgSO4, concentrated, and purified by
flash chromatography using the solvents shown below. In the
cases of 3a -f and 3i, the residue before chromatography was
dissolved in 50 mL of CH3CN and washed with 3 × 10 mL
hexane to remove most of the n-Bu4Sn byproduct. Collection
of the CH3CN layer and removal of the solvent gave the crude
product, which was then purified by flash chromatography.
For 3e and 3j, the crude products were carried on directly to
the next step without chromatographic purification.
Con clu sion s
A new method for the synthesis of dihydro-2-pyridi-
nones, starting from substituted cyclobutenediones and
R-aminoanions, has been established. The combination
of NBS/pyridine was a versatile oxidizing reagent for
transforming the dihydro-2-pyridinones into the corre-
sponding 2-pyridinones. This methodology allows the
synthesis of highly substituted 2-pyridinones, which
would be difficult to obtain through other methods.
4-(N-Boc-N-m eth ylam in om eth yl)-3-isopr opoxy-4-m eth -
oxy-2-m eth yl-2-cyclobu ten -1-on e, 3a . N-Boc-(tri-n-butyl-
stannyl)dimethylamine (1.433 g, 3.300 mmol, 1.10 equiv),
n-butyllithium (3.00 mL, 1.10 M, 3.30 mmol, 1.10 equiv),
3-isopropoxy-4-methyl-3-cyclobutene-1,2-dione (0.462 g, 3.000
mmol, 1.00 equiv), and methyl triflate (1.230 g, 7.500 mmol,
2.50 equiv) yielded 0.500 g (1.600 mmol, 53%) of 3a as a yellow
oil after chromatography; TLC (silica gel, 30% EtOAc in
hexane, Rf ) 0.10); chromatographic purification (flash column,
silica gel, 2 × 15 mm, 20% EtOAc in hexane). IR (CH2Cl2, KCl,
cm-1): 1758 (s), 1691 (s), 1612 (s). 1H NMR (CDCl3, 300
MHz): δ 4.82 (sept, J ) 6.0 Hz, 1 H), 3.79 (d, J ) 14.7 Hz, 1
H), 3.36 (d, J ) 14.7 Hz, 1 H), 3.29 (s, 3 H), 2.85 (s, 3 H), 1.77
(s, 3 H), 1.42 (s, 9 H), 1.42 (d, J ) 6.0 Hz, 6 H). 13C NMR
(CDCl3, 75.5 MHz): δ190.6 (190.1), 179.8 (178.7), 155.2 (154.9),
122.4 (123.0), 95.9, 78.6 (79.1), 76.3 (76.1), 51.7, 49.2 (49.6),
35.9 (35.4), 27.8, 22.4, 6.4 (6.7) (absorptions due to rotamers
are indicated in brackets). Anal. Calcd for C16H27NO5: C, 61.32;
H, 8.68; N, 4.47; O, 25.53. Found: C, 61.18; H, 8.71; N, 4.42.
4-(N-Boc-N-m eth yla m in om eth yl)-2-tert-bu tyl-3-isop r o-
p oxy-4-m eth oxy-2-cyclobu ten -1-on e, 3b. N-Boc-(tri-n-bu-
tylstannyl)dimethylamine (1.433 g, 3.300 mmol, 1.10 equiv),
n-butyllithium (3.00 mL, 1.10 M, 3.30 mmol, 1.10 equiv), 4-tert-
butyl-3-isopropoxy-3-cyclobutene-1,2-dione (0.589 g, 3.000 mmol,
1.00 equiv), and methyl triflate (1.230 g, 7.500 mmol, 2.50
equiv) yielded 0.780 g (2.190 mmol, 73%) of 3b as a white solid
after chromatography; TLC (silica gel, 30% EtOAc in hexane,
Rf ) 0.44); chromatographic purification (flash column, silica
gel, 2 × 15 mm, 10% EtOAc in hexane); mp 81.2-83.0 °C. IR
(CH2Cl2, KCl, cm-1): 1749 (s), 1690 (s), 1603 (s). 1H NMR
(CDCl3, 300 MHz): δ 4.92 (sept, J ) 6.0 Hz, 1 H), 4.02 (d, J )
14.7 Hz, 1 H), 3.27 (s, 3 H), 3.06 (d, J ) 14.7 Hz, 1 H), 2.73 (s,
3 H), 1.35 (s, 9 H), 1.26 (d, J ) 6.0 Hz, 6 H), 1.10 (s, 9 H). 13C
NMR (CDCl3, 75.5 MHz): δ 188.5, 178.6, 155.6, 138.0, 96.9,
79.2, 77.4, 51.8, 50.1, 36.4, 30.9, 28.2, 27.9, 22.8, 22.6. Anal.
Calcd for C19H33NO5: C, 64.20; H, 9.36; N, 3.94; O, 22.50.
Found: C, 64.28; H, 9.43; N, 3.92.
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. Flash chromatographic purifica-
tion was performed using 32-63 mm SiO2 with compressed
air as a source of positive pressure. All thin-layer chromatog-
raphy was carried out using Merck Kieselgel 60 F254 plates
with visualization by UV and phosphomolybdic acid or iodine
stain. Melting points are uncorrected and were taken on a
Thomas-Hoover melting point apparatus in open capillary
tubes, using either recrystallized samples or samples that
crystallized during concentration of the chromatography elu-
ents. 1H NMR spectra were recorded at 300 MHz and were
internally referenced to CHCl3 (7.26 ppm), C6H6 (7.15 ppm),
or CH2Cl2 (5.32 ppm). 13C NMR spectra were recorded at 75
MHz and were referenced to CDCl3 (77.0 ppm) or C6D6 (128.0
ppm). IR spectra were recorded in CH2Cl2 solution using a KCl
cell.
THF and CH3CN were dried with 4 Å molecular sieves and
then titrated for water content with a Fisher Coulomatic K-F
Titrimeter. n-Butyllithium and sec-butyllithium solutions were
obtained from Aldrich in Sure-Seal bottles and were titrated
using diphenylacetic acid as titrant and indicator. MeI,
TMEDA, and i-Pr2NH were obtained from Aldrich and freshly
distilled before use. Trifluoroacetic acid, tri-n-butyltin chloride,
N-bromosuccinimide, and silver(I) oxide were purchased from
Aldrich and used without purification. Lithium diisopropyla-
mide (LDA) was freshly made from i-Pr2NH (1.0 equiv) and
n-butyllithium (1.0 equiv) in THF (0.5 M) under N2 at 0 °C
for 10 min.
The following compounds were prepared by literature
methods: 3-isopropoxy-4-methyl-3-cyclobutene-1,2-dione,33 3-iso-
propoxy-4-phenyl-3-cyclobutene-1,2-dione,33 4-tert-butyl-3-iso-
propoxy-3-cyclobutene-1,2-dione,33 3,4-diethyl-3-cyclobutene-
1,2-dione,25 N-Boc-dimethylamine,31 N-Boc-piperidine,31 N-Boc-
pyrrolidine,31 N-Boc-dibenzylamine,31 N-Boc-isoquinoline,31
N-Boc-sarcosine ethyl ester,31 N-Boc-(tri-n-butylstannyl)dim-
ethylamine,31 N-Boc-2-(tri-n-butylstannyl)piperidine,31 and
N-Boc-2-(tri-n-butylstannyl)pyrrolidine.31 3-(N,N-Dimethy-
lamino)-4-phenyl-3-cyclobutene-1,2-dione was prepared by a
procedure similar to that described in the literature for the
preparation of 3-methyl-4-(N,N-dibenzylamino)-3-cyclobutene-
1,2-dione.34
Gen er a l P r oced u r e for Ma k in g 3a -f a n d 3i-k . A 0.25
M THF solution (1.10 molar equiv) of R-tri-n-butylstannyl-N-
Boc-dialkylamine, N-Boc-isoquinoline, or N-Boc-dibenzylamine
in a flame-dried round-bottomed flask was cooled to -78 °C
under N2, and 1.10 molar equiv of n-butyllithium (for 3a -f
and 3i) or sec-butyllithium (for 3j,k ) was added dropwise via
syringe. The reaction mixture was kept at -78 °C for 20 min
and then transferred slowly to a 0.4 M THF solution of the
cyclobutenedione 1, which was precooled to -78 °C under N2.
The solution of the R-amino anion was kept at -78 °C during
the transfer process to avoid decomposition. After 30 min of
stirring at -78 °C, 2.50 molar equiv of MeOTf was added
slowly, and stirring was continued at -78 °C for 15 min. The
reaction mixture was then quenched with 10 mL of a saturated
aqueous solution of NaHCO3 and then warmed to room
4-(N-Boc-N-m eth ylam in om eth yl)-3-isopr opoxy-4-m eth -
oxy-2-p h en yl-2-cyclobu ten -1-on e, 3c. N-Boc-(tri-n-butyl-
stannyl)dimethylamine (1.433 g, 3.300 mmol, 1.10 equiv),
n-butyllithium (3.00 mL, 1.10 M, 3.30 mmol, 1.10 equiv),
3-isopropoxy-4-phenyl-3-cyclobutene-1,2-dione (0.649 g, 3.000
mmol, 1.00 equiv), and methyl triflate (1.230 g, 7.500 mmol,
2.50 equiv) yielded 0.770 g (2.050 mmol, 68%) of 3c as a white
solid after chromatography; TLC (silica gel, 30% EtOAc in
hexane, Rf ) 0.40); chromatographic purification (flash column,
silica gel, 2 × 15 mm, 5% EtOAc in hexane); mp 83.0-84.6 °C
(CH2Cl2/hexane). IR (CH2Cl2, KCl, cm-1): 1749 (s), 1691 (s),
1
1623 (s). H NMR (CDCl3, 300 MHz): δ 7.77 (d, J ) 7.2 Hz, 2
H), 7.35 (dd, J ) 7.2, 7.2 Hz, 2 H), 7.26 (t, J ) 7.2 Hz, 1 H),
5.16 (sept, J ) 5.7 Hz, 1 H), 4.17 (d, J ) 14.7 Hz, 1 H), 3.43 (s,
3 H), 3.30 (d, J ) 14.7 Hz, 1 H), 2.84 (s, 3 H), 1.55 (d, J ) 5.7
Hz, 3 H), 1.45 (d, J ) 5.7 Hz, 3 H), 1.31 (s, 9 H). 13C NMR
(CDCl3, 75.5 MHz): δ 187.1, 179.1, 155.7, 128.4, 128.1, 127.6,
126.6, 125.7, 98.0, 79.3, 78.7, 52.4, 50.3, 36.3, 27.9, 22.8, 22.6.
Anal. Calcd for C21H29NO5: C, 67.18; H, 7.79; N, 3.73; O, 21.31.
Found: C, 67.26; H, 7.86; N, 3.67.
4-(N-Boc-N-m eth ylam in om eth yl)-2,3-dieth yl-4-m eth oxy-
2-cyclobu ten -1-on e, 3d . N-Boc-(tri-n-butylstannyl)dimethy-
lamine (1.433 g, 3.300 mmol, 1.10 equiv), n-butyllithium (3.00
mL, 1.10 M, 3.30 mmol, 1.10 equiv), 3,4-diethyl-3-cyclobutene-
1,2-dione (0.415 g, 3.00 mmol, 1.00 equiv), and methyl triflate
(1.230 g, 7.500 mmol, 2.50 equiv) yielded 0.492 g (1.650 mmol,
(32) Davis, B. R.; Halsall, T. G. J . Chem. Soc. (C) 1962, 29, 1833.
(33) Liebeskind, L. S.; Fengl, R. W.; Wirtz, K. R.; Shawe, T. T. J .
Org. Chem. 1988, 53, 2482.
(34) Krysan, D. J .; Gurski, A.; Liebeskind, L. S. J . Am. Chem. Soc.
1992, 114, 1412.

4046 J . Org. Chem., Vol. 64, No. 11, 1999
Zhang and Liebeskind
55%) of 3d as a light yellow oil after chromatography; TLC
(silica gel, 30% EtOAc in hexane, Rf ) 0.41); chromatographic
purification (flash column, silica gel, 2 × 15 mm, 10% EtOAc
in hexane). IR (CH2Cl2, KCl, cm-1): 1752 (s), 1689 (s), 1624
gel, 2 × 15 mm; 1st, 200 mL of 10% EtOAc in hexane; 2nd,
20% EtOAc in hexane). IR (CH2Cl2, KCl, cm-1): 3500 (br, m),
1756 (s), 1691 (s), 1628 (w). 1H NMR (CDCl3, 300 MHz: δ 5.00
(s, diastereomer 1, δ 4.93 s, diastereomer 2, 1 H), 4.28-4.08
(m, 3 H), 2.91 (s, diastereomer 1, δ 2.68 s, diastereomer 2, 3
H), 2.65-2.53 (m, 2 H), 2.23-2.12 (m, 2 H), 1.40 (s, diastere-
omer 1, δ 1.37 s, diastereomer 2, 9 H), 1.28-1.17 (m, 6 H),
1.09-1.02 (m, 3 H). Anal. Calcd for C18H29NO6: C, 60.83; H,
8.22; N, 3.94; O, 27.01. Found: C, 60.72; H, 8.23; N, 3.85.
4-(N-Boc-N-m eth yla m in om eth yl)-3-(N, N-d im eth yla m i-
n o)-4-m eth oxy-2-p h en yl-2-cyclobu ten -1-on e, 3i. N-Boc-
(tri-n-butylstannyl)dimethylamine (0.945 g, 2.180 mmol, 1.09
equiv), n-butyllithium (2.00 mL, 1.10 M, 2.200 mmol, 1.10
equiv), 3-N,N-(dimethylamino)-4-phenyl-3-cyclobutene-1,2-di-
one (0.403 g, 2.000 mmol, 1.00 equiv), and methyl triflate
(0.820 g, 5.000 mmol, 2.50 equiv) yielded 0.614 g (1.700 mmol,
85%) of 3i as a pale yellow solid after chromatography; TLC
(silica gel, 60% EtOAc in hexane, Rf ) 0.22); chromatographic
purification (flash column, silica gel, 2 × 15 mm; 1st, 200 mL
of 20% EtOAc in hexane; 2nd, 2% MeOH/CHCl3); mp 118.0-
120.0 °C (CH2Cl2/hexane). IR (CH2Cl2, KCl, cm-1): 1741 (s),
1690 (s), 1614 (s), 1595 (s). 1H NMR (CDCl3, 300 MHz): δ
7.38-7.20 (m, 5 H), 4.12 (d, J ) 14.7 Hz, 1 H), 3.41 (s, 3 H),
3.26 (s, 3 H), 3.22 (d, J ) 14.7 Hz, 1 H), 3.03 (s, 3 H), 2.83 (s,
3 H), 1.43 (s, 9 H). 13C NMR (CDCl3, 75.5 MHz): δ 184.2, 166.9,
155.8, 129.7, 128.2, 128.0, 126.5, 119.3, 95.2, 79.0, 51.9, 50.0,
41.1, 39.9, 36.6, 28.1. HRMS (EI) calcd for C20H29N2O4 (M +
H)+: 361.2627, found 361.2141. Anal. Calcd for C20H28N2O4:
C, 66.64; H, 7.83; N, 7.77; O, 17.75. Found: C, 65.92; H, 7.62;
N, 7.70.
1
(w). H NMR (C6D6, 300 MHz): δ 4.10 (d, J ) 14.4 Hz, 1 H),
3.18 (d, J ) 14.4 Hz, 1 H), 3.11 (s, 3 H), 2.72 (s, 3 H), 2.60 (m,
2 H), 1.97 (m, 2 H), 1.35 (s, 9 H), 1.09 (t, J ) 7.5 Hz, 3 H), 0.99
(t, J ) 7.5 Hz, 3 H). 13C NMR (CDCl3, 75.5 MHz): δ 193.9,
180.6, 155.3, 154.0, 99.0, 78.8, 51.5, 49.6, 36.0, 27.8, 20.8, 16.3,
11.5, 10.4. Anal. Calcd for C16H27NO4: C, 64.62; H, 9.15; N,
4.71; O, 21.52. Found: C, 64.62; H, 9.19; N, 4.65.
4-(N-Boc-2-piper idin yl)-3-isopr opoxy-4-m eth oxy-2-ph en -
yl-2-cyclobu ten -1-on e, 3e. N-Boc-2-(tri-n-butylstannyl)pip-
eridine (0.996 g, 2.100 mmol, 1.05 equiv), n-butyllithium (2.00
mL, 1.10 M, 2.20 mmol, 1.10 equiv), 3-isopropoxy-4-phenyl-3-
cyclobutene-1,2-dione (0.433 g, 2.00 mmol, 1.00 equiv), and
methyl triflate (0.820 g, 5.00 mmol, 2.50 equiv) yielded 3e as
a light yellow solid that displayed complex spectroscopic data
due to diastereomers and rotamers. The crude product was
carried on to the next step without purification.
4-(N-Boc-2-p yr r olid in yl)-2,3-d iet h yl-4-m et h oxy-2-cy-
clobu t en -1-on e, 3f. N-Boc-2-(tri-n-butylstannyl)pyrrolidine
(2.030 g, 4.41 mmol, 1.10 equiv), n-butyllithium (4.00 mL, 1.10
M, 4.40 mmol, 1.10 equiv), 3,4-diethyl-3-cyclobutene-1,2-dione
(0.553 g, 4.00 mmol, 1.00 equiv), and methyl triflate (1.640 g,
10.00 mmol, 2.50 equiv) yielded 3f (0.540 g, 1.670 mmol, 42%)
as a pale yellow oil after chromatography. The NMR spectra
of the crude product depict a mixture of two diastereomers in
a 3:4 ratio; TLC (silica gel, 20% EtOAc in hexane, Rf ) 0.46,
0.52); chromatographic purification (flash column, silica gel,
2 × 15 mm, 1st, 400 mL of 5% EtOAc in hexane; 2nd, 10%
EtOAc in hexane). IR (CH2Cl2, KCl, cm-1): 1748 (s), 1688 (s),
4-(N-Boc-isoqu in olin o)-3-(N,N-dim eth ylam in o)-4-m eth -
oxy-2-p h en yl-2-cyclobu ten -1-on e, 3j. N-Boc-isoquinoline
(0.770 g, 3.300 mmol, 1.10 equiv), sec-butyllithium (3.00 mL,
1.10 M, 3.300 mmol, 1.10 equiv), 3-N,N-(dimethylamino)-4-
phenyl-3-cyclobutene-1,2-dione (0.604 g, 3.00 mmol, 1.00 equiv),
and methyl triflate (1.230 g, 7.50 mmol, 2.50 equiv) yielded a
yellow solid that displayed complex spectroscopic data due to
diastereomers and rotamers. The crude product was carried
on to the next step without purification.
1
1623 (m). H NMR (CDCl3, 300 MHz): δ 4.21-4.14 (m, 1 H),
3.46-3.02 (m, 2 H), 3.23 (s, major, δ 3.20, s, minor, 3 H), 2.92-
1.68 (m, 8 H), 1.44 (s, 2 H), 1.39 (s, 9 H), 1.29 (t, J ) 7.8 Hz,
major, δ 1.20, t, J ) 7.8 Hz, minor, 3 H), 1.10 (t, J ) 7.8 Hz,
major, δ 1.13, t, J ) 7.8 Hz, minor, 3 H). Anal. Calcd for C18H29
-
NO4: C, 66.84; H, 9.04; N, 4.33; O, 19.79. Found: C, 66.97; H,
8.99; N, 4.22.
(N-Boc-N-m et h yla m in o)-(1-h yd r oxy-2-isop r op oxy-4-
oxo-3-p h en yl-cyclobu t-2-en yl)-a cetic a cid eth yl ester , 3g.
N-Boc-sarcosine ethyl ester (0.913 g, 4.200 mmol, 1.05 equiv)
in 5 mL of THF was added slowly to a THF solution of LDA
(4.400 mmol, 1.10 equiv) at -78 °C under nitrogen. After 30
min of stirring at -78 °C, the solution was transferred slowly
to a solution of 3-isopropoxy-4-phenyl-3-cyclobutene-1,2-dione
(0.865 g, 4.000 mmol, 1.00 equiv) in 5 mL of THF, which was
precooled to -78 °C. After 30 min at -78 °C, the reaction was
quenched with 10 mL of saturated aqueous NaHCO3 and then
warmed slowly to room temperature. H2O (10 mL) was used
to dilute the mixture, which was extracted with 3 × 20 mL of
Et2O. The combined Et2O layers were dried over MgSO4,
concentrated, and purified by chromatography to yield 3g
(1.274 g, 2.940 mmol, 74%) as a light yellow viscous oil (NMR
spectra of the crude product show a 1:3 ratio of two diaster-
eomers); TLC (silica gel, 20% EtOAc in hexane, Rf ) 0.11-
0.15); chromatographic purification (flash column, silica gel,
2 × 15 mm, 10% EtOAc in hexane). IR (CH2Cl2, KCl, cm-1):
4-(N-Boc-N-ben zyla m in oben zyl)-3-(N,N-d im eth yla m i-
n o)-4-m eth oxy-2-p h en yl-2-cyclobu ten -1-on e, 3k . N-Boc-
dibenzylamine (0.654 g, 2.200 mmol, 1.10 equiv), sec-butyl-
lithium (2.00 mL, 1.10 M, 2.200 mmol, 1.10 equiv), 3-N,N-
(dimethylamino)-4-phenyl-3-cyclobutene-1,2-dione (0.402 g,
2.00 mmol, 1.00 equiv), and methyl triflate (0.820 g, 5.00 mmol,
2.50 equiv) yielded 0.911 g (1.780 mmol, 88%) of 3k as a
mixture of two diastereomers (major diastereomer, 0.580 g,
white solid; minor diastereomer, 0.331 g, light yellow foam)
after chromatography; TLC (silica gel, 60% EtOAc in hexane,
Rf ) 0.48 for the major diastereomer; Rf ) 0.37 for the minor
diastereomer); chromatographic purification (flash column,
silica gel, 2 × 15 mm; 1st, 500 mL of 15% EtOAc in hexane;
2nd, 30% EtOAc in hexane). Data for the major diastereomer:
mp 186-188 °C (CH2Cl2/hexane). IR (CH2Cl2, KCl, cm-1): 1741
1
(m), 1683 (s), 1612 (s), 1596 (s). H NMR (CDCl3, 300 MHz):
δ 7.95 (d, J ) 7.5 Hz, 2 H), 7.48 (d, J ) 7.5 Hz, 2 H), 7.39 (t,
J ) 7.5 Hz, 2 H), 7.32-7.25 (m, 3 H), 7.18 (t, J ) 7.5 Hz, 1 H),
6.96-6.92 (m, 3 H), 6.56-6.53 (m, 2 H), 6.19 (s, 1 H), 4.19 (d,
J ) 15.9 Hz, 1 H), 4.07 (d, J ) 15.9 Hz, 1 H), 3.41 (s, 3 H),
3.35 (s, 3 H), 3.04 (s, 3 H), 1.21 (s, 9 H). 13C NMR (CDCl3, 75.5
MHz): δ 182.8, 166.8, 156.0, 139.7, 136.1, 131.5, 130.1, 128.5,
128.3, 128.1, 127.5, 127.2, 127.0, 126.4, 125.7, 120.8, 98.6, 79.8,
62.4, 52.1, 47.5, 41.6, 39.6, 28.0. Anal. Calcd for C32H36N2O4:
C, 74.97; H, 7.08; N, 5.46; O, 12.48. Found: C, 74.88; H, 7.08;
N, 5.53. Data for the minor diastereomer. IR (CH2Cl2, KCl,
1
3446 (br, s), 1755 (s), 1693 (s), 1628 (s). H NMR (CDCl3, 300
MHz): δ 7.75-7.71 (m, 2 H), 7.40-7.26 (m, 3 H), 5.22 (sept, J
) 6.0 Hz, major, δ 5.10, sept, J ) 6.0 Hz, minor, 1 H), 4.84 (br
s, major, δ 5.06, br s, minor, 1 H), 4.53 (s, major, δ 5.54, s,
minor, 1 H), 4.38-4.12 (m, 2 H), 3.01 (s, major, δ 2.69, s, minor,
1 H), 1.50-1.36 (m, 15 H), 1.23 (t, J ) 7.2 Hz, 3 H). Anal.
Calcd for C23H31NO7: C, 63.73; H, 7.21; N, 3.23; O, 25.83.
Found: C, 63.63; H, 7.27; N, 3.18.
1
cm-1): 1743 (m), 1682 (s), 1614 (s), 1596 (s). H NMR (CDCl3,
(N-Boc-N-m eth yla m in o)-(2,3-d ieth yl-1-h yd r oxy-4-oxo-
cyclobu t-2-en yl)-a cetic a cid eth yl ester , 3h . N-Boc-sar-
cosine ethyl ester (0.913 g, 4.200 mmol, 1.05 equiv), LDA (4.400
mmol, 1.10 equiv), and 2,3-diethyl-3-cyclobutene-1,2-dione
(0.553 g, 4.000 mmol, 1.00 equiv) yielded after purification by
chromatography 3h (0.912 g, 2.570 mmol, 64%) as a light
yellow viscous oil (1:1 ratio of two diastereomers) following the
procedure for 3g; TLC (silica gel, 20% EtOAc in hexane, Rf )
0.10-0.14); chromatographic purification (flash column, silica
300 MHz): δ 7.28-6.83 (m, 15 H), 6.06 (br s, 1 H), 5.04 (br s,
2 H), 3.36 (s, 3 H), 3.33 (s, 3 H), 2.82 (s, 3 H), 1.25-1.19 (m, 9
H). 13C NMR (CDCl3, 75.5 MHz): δ 182.9, 166.4, 156.6, 140.8,
137.9, 129.2, 128.6, 128.3, 128.1, 127.9, 127.6, 127.3, 126.8,
126.3, 125.3, 121.2, 98.6, 79.7, 52.3, 49.7, 41.2, 39.6, 31.4, 28.0.
Anal. Calcd for C32H36N2O4: C, 74.97; H, 7.08; N, 5.46; O,
12.48. Found: C, 75.05; H, 7.14; N, 5.48.
Gen er a l P r oced u r e for 4a -k . Compound 3 in 10 mL of
CH2Cl2 was treated with 1-2 mL of TFA under N2 at room

Substituted 2-Pyridinones and Dihydro-2-pyridinones
J . Org. Chem., Vol. 64, No. 11, 1999 4047
temperature for 2 h. The reaction mixture was neutralized
with 2 M NaOH solution with stirring and then diluted with
20 mL of Et2O. The aqueous layer was extracted with 3 × 20
mL of Et2O, and the combined organic layers were dried over
K2CO3. Removal of solvent gave the crude amine, which was
directly subjected to thermolysis at 155-160 °C under N2 for
2.5 h. The resulting compound was purified by chromatogra-
phy.
1 H), 0.97 (br t, J ) 7.5 Hz, 3 H), 0.76 (br t, J ) 7.5 Hz, 3 H).
13C NMR (CDCl3, 75.5 MHz): δ 170.0, 141.8, 119.4, 57.6, 48.2,
42.7, 33.3, 23.8, 18.7, 11.7, 8.5. Anal. Calcd for C11H19NO2: C,
66.97; H, 9.71; N, 7.10; O, 16.22. Found: C, 67.08; H, 9.69; N,
7.01.
3,6,7,8,9,9a -Hexah ydr o-2-isopr opoxy-1-m eth oxy-3-ph en -
yl-qu in olizin -4-on e, 4e. 4-(N-Boc-2-piperidino)-3-isopropoxy-
4-methoxy-2-phenyl-2-cyclobuten-1-one 3e (crude product) in
2.0 mL of TFA and thermolysis yielded 0.430 g (1.360 mmol,
68% from 1e) of 4e as a light brown viscous oil after chroma-
tography. The product was a mixture of two diastereomers in
a 0.6:1 ratio. TLC (silica gel, 60% EtOAc in hexane, Rf ) 0.35-
0.40); chromatographic purification (flash column, silica gel,
2 × 15 mm, 20% EtOAc in hexane). IR (CH2Cl2, KCl, cm-1):
1760 (w), 1711 (w), 1643 (s). 1H NMR (CDCl3, 300 MHz): δ
7.37-7.14 (m, 5 H), 4.58-4.52 (m, 1 H), 4.16-3.84 (m, 3 H),
3.72 (s, major, δ 3.69, s, minor, 3 H), 3.67-3.65 (m, 1 H), 2.45-
1.15 (m, 6 H), 1.05-0.98 (m, 6 H). Anal. Calcd for C19H25NO3:
C, 72.35; H, 7.99; N, 4.44; O, 15.22. Found: C, 72.18; H, 7.98;
N, 4.37.
6,7-Dieth yl-8-m eth oxy-2,3,6,8a -tetr ah ydr o-1H-in dolizin -
5-on e, 4f. 4-(N-Boc-2-pyrrolidino)-2,3-diethyl-4-methoxy-2-cy-
clobuten-1-one 3f (0.362 g, 1.120 mmol, 1.00 equiv) in 1.5 mL
of TFA and thermolysis yielded 0.200 g (0.900 mmol, 80%) of
4f as a light yellow oil after chromatography. The product was
a mixture of two diastereomers in a 2:3 ratio; TLC (silica gel,
60% EtOAc in hexane, Rf ) 0.08); chromatographic purification
(flash column, silica gel, 2 × 15 mm, 60% EtOAc in hexane).
IR (CH2Cl2, KCl, cm-1): 1635 (s). 1H NMR (CDCl3, 300 MHz):
δ 4.19-3.69 (m, 2 H), 3.60 (s, major, δ 3.61, s, minor, 3 H),
3.44-2.93 (m, 2 H), 2.63-2.38 (m, 1 H), 2.24-1.40 (m, 7 H),
0.98 (t, J ) 7.8 Hz, major, δ 0.99, t, J ) 7.8 Hz, minor, 3 H),
0.88 (t, J ) 7.5 Hz major, δ 0.63, t, J ) 7.5 Hz, minor, 3 H).
HRMS (EI) calcd for C13H21NO2Li (M+Li)+: 230.1732, found
230.1735.
6-Ca r b oet h oxy-4-isop r op oxy-5-m et h oxy-1-m et h yl-3-
ph en yl-3,6-dih ydr o-2-pyr idon e, 4g. (N-Boc-N-methylamino)-
(1-hydroxy-2-isopropoxy-4-oxo-3-phenyl-cyclobut-2-enyl)-ace-
tic acid ethyl ester 3g (1.185 g, 2.730 mmol, 1.00 equiv), methyl
iodide (1.552 g, 10.930 mmol, 4.00 equiv), silver(I) oxide (1.267
g, 5.470 mmol, 2.00 equiv), and potassium carbonate (1.889 g,
13.670 mmol, 5.01 equiv) followed by deprotection with 2.0 mL
of TFA and thermolysis yielded 0.690 g (1.990 mmol, 73%) of
4g as a light brown viscous oil after chromatography. The
product was a mixture of two diastereomers in a 1:3 ratio: TLC
(silica gel, 30% EtOAc in hexane, Rf ) 0.10-0.14); chromato-
graphic purification (flash column, silica gel, 2 × 15 mm; 1st,
400 mL of 20% EtOAc in hexane; 2nd, 30% EtOAc in hexane).
IR (CH2Cl2, KCl, cm-1): 1742 (s), 1655 (s). 1H NMR (CDCl3,
300 MHz): δ 7.34-7.24 (m, 3 H), 7.49 (app d, J ) 6.9 Hz, 2
H), 4.48 (d, J ) 2.1 Hz, major, δ 4.64, d, J ) 3.3 Hz, minor, 1
H), 4.28-4.17 (m, 4 H), 3.80 (s, major, δ 3.79 s, minor, 3 H),
2.95 (s, major, δ 2.88, s, minor, 3 H), 1.26 (t, J ) 7.2 Hz, major,
δ 1.31, t, J ) 7.2 Hz, minor, 1 H), 1.13-1.04 (m, 6 H). Anal.
Calcd for C19H25NO5: C, 65.69; H, 7.25; N, 4.03; O, 23.03.
Found: C, 65.56; H, 7.18; N, 3.97.
Before thermolysis to generate 4g and 4h , 1.00 equiv of the
4-hydroxycyclobutenones 3g and 3h were methylated following
a literature procedure,29 using 2.00 equiv of Ag2O, 4.00 equiv
of MeI, and 5.00 equiv of K2CO3 in 10 mL of CH3CN for 3 days.
The crude methyl ethers 3g and 3h were then subjected to
thermolysis after removal of the Boc protecting group.
4-Isop r op oxy-5-m et h oxy-1,3-d im et h yl-3,6-d ih yd r o-2-
p yr id on e, 4a . 4-(N-Boc-N-methylaminomethyl)-3-isopropoxy-
4-methoxy-2-methyl-2-cyclobuten-1-one 3a (0.470 g, 1.500
mmol, 1.00 equiv) in 2.0 mL of TFA and thermolysis yielded
0.240 g (1.130 mmol, 75%) of 4a as a light yellow oil after
chromatography; TLC (silica gel, EtOAc, Rf ) 0.32); chromato-
graphic purification (flash column, silica gel, 2 × 15 mm, 50%
EtOAc in hexane). IR (CH2Cl2, KCl, cm-1): 1715 (w), 1642 (s).
1H NMR (C6D6, 300 MHz): δ 4.02 (sept, J ) 6.0 Hz, 1 H), 3.36
(s, 3 H), 3.29 (dd, J ) 15.6, 3.9 Hz, 1 H), 3.17 (dd, J ) 15.6,
3.0 Hz, 1 H), 3.08 (ddq, J ) 7.2, 3.9, 3.0 Hz, 1 H), 2.59 (s, 3 H),
1.50 (d, J ) 7.2 Hz, 3 H), 1.04 (d, J ) 6.0 Hz, 3 H), 1.02 (d, J
) 6.0 Hz, 3 H). 13C NMR (CDCl3, 75.5 MHz): δ 170.4, 134.8,
131.7, 70.5, 58.5, 48.3, 37.9, 33.5, 22.6, 22.0, 17.4. Anal. Calcd
for C11H19NO3: C, 61.95; H, 8.98; N, 6.57; O, 22.50. Found:
C, 61.65; H, 8.92; N, 6.41.
3-ter t-Bu t yl-4-isop r op oxy-5-m et h oxy-1-m et h yl-3,6-d i-
h yd r o-2-p yr id on e, 4b. 2-tert-Butyl-4-(N-Boc-N-methylami-
nomethyl)-3-isopropoxy-4-methoxy-2-cyclobuten-1-one (0.640
g, 1.800 mmol, 1.00 equiv) 3b in 1.5 mL of TFA and thermoly-
sis yielded 0.400 g (1.570 mmol, 87%) of 4b as a light yellow
oil after chromatography; TLC (silica gel, EtOAc, Rf ) 0.46);
chromatographic purification (flash column, silica gel, 2 × 15
mm, 40% EtOAc in hexane). IR (CH2Cl2, KCl, cm-1): 1704 (m),
1642 (s). 1H NMR (CDCl3, 300 MHz): δ 4.13 (sept, J ) 6.0
Hz, 1 H), 3.92 (dd, J ) 16.5, 2.1 Hz, 1 H), 3.76 (s, 3 H), 3.47
(d, J ) 16.5 Hz, 1 H), 2.95 (s, 3 H), 2.70 (d, J ) 2.1 Hz, 1 H),
1.19 (d, J ) 6.0 Hz, 3 H), 1.17 (d, J ) 6.0 Hz, 3 H), 1.01 (s, 9
H). 13C NMR (CDCl3, 75.5 MHz): δ 169.1, 136.8, 132.9, 70.9,
59.0, 53.9, 49.4, 37.9, 33.4, 28.1, 22.4, 21.9. Anal. Calcd for
C
14H25NO3: C, 65.85; H, 9.87; N, 5.49; O, 18.80. Found: C,
65.71; H, 9.83; N, 5.41.
4-Isopr opoxy-5-m eth oxy-1-m eth yl-3-ph en yl-3,6-dih ydr o-
2-p yr id on e, 4c. 4-(N-Boc-N-methylaminomethyl)-3-isopro-
poxy-4-methoxy-2-phenyl-2-cyclobuten-1-one 3c (0.720 g, 1.920
mmol, 1.00 equiv) in 2.0 mL of TFA and thermolysis yielded
0.453 g (1.650 mmol, 86%) of 4c as a yellow solid after
chromatography; TLC (silica gel, EtOAc, Rf ) 0.45); chromato-
graphic purification (flash column, silica gel, 2 × 15 mm, 50%
EtOAc in hexane); mp 58.5-60.1 °C (hexane). IR (CH2Cl2, KCl,
1
cm-1): 1714 (w), 1650 (s). H NMR (C6D6, 300 MHz): δ 7.47
(br d, J ) 7.5 Hz, 2 H), 7.12 (dd, J ) 7.5, 7.5 Hz, 2 H), 7.03 (br
t, J ) 7.5 Hz, 1 H), 4.29 (br d, J ) 2.1 Hz, 1 H), 3.97 (sept, J
) 6.0 Hz, 1 H), 3.48 (dd, J ) 16.2, 3.6 Hz, 1 H), 3.44 (s, 3 H),
3.16 (dd, J ) 16.2, 2.1 Hz, 1 H), 2.46 (s, 3 H), 0.87 (d, J ) 6.0
Hz, 3 H), 0.86 (d, J ) 6.0 Hz, 3 H). 13C NMR (CDCl3, 75.5
MHz): δ 167.5, 138.3, 133.2, 132.6, 128.0, 127.5, 126.7, 70.4,
58.4, 49.7, 48.3, 33.3, 22.2, 21.6. Anal. Calcd for C16H21NO3:
C, 69.79; H, 7.69; N, 5.09; O, 17.43. Found: C, 69.89; H, 7.66;
N, 5.10.
6-Ca r boeth oxy-3,4-d ieth yl-5-m eth oxy-1-m eth yl-3,6-d i-
h yd r o-2-p yr id on e, 4h . (N-Boc-N-methylamino)-(2,3-diethyl-
1-hydroxy-4-oxo-cyclobut-2-enyl)-acetic acid ethyl ester 3h
(0.853 g, 2.400 mmol, 1.00 equiv), methyl iodide (1.363 g, 9.600
mmol, 4.00 equiv), silver(I) oxide (1.112 g, 4.800 mmol, 2.00
equiv), and potassium carbonate (1.659 g, 12.000 mmol, 5.00
equiv) and followed by deprotection with 2.0 mL of TFA and
thermolysis yielded 0.211 g (0.780 mmol, 32%) of 4h as a light
brown viscous oil after chromatography. The product was a
mixture of two diastereomers in a 1:4 ratio; TLC (silica gel,
60% EtOAc in hexane, Rf ) 0.30-0.36); chromatographic
purification (flash column, silica gel, 2 × 15 mm, 30% EtOAc
in hexane). IR (CH2Cl2, KCl, cm-1): 1740 (s), 1648 (s). 1H NMR
(CDCl3, 300 MHz): δ 4.50 (br s, major, δ 4.63, br s, minor, 1
H), 3.64 (s, major, δ 3.62 s, minor, 3 H), 2.98-2.90 (m, 4 H),
3,4-Die t h yl-5-m e t h oxy-1-m e t h yl-3,6-d ih yd r o-2-p yr i-
don e, 4d. 4-(N-Boc-N-methylaminomethyl)-2,3-diethyl-4-meth-
oxy-2-cyclobuten-1-one 3d (0.745 g, 2.500 mmol, 1.00 equiv)
in 2.0 mL of TFA and thermolysis yielded 0.350 g (1.770 mmol,
71%) of 4d as a light brown oil after chromatography; TLC
(silica gel, EtOAc, Rf ) 0.27); chromatographic purification
(flash column, silica gel, 2 × 15 mm, 50% EtOAc in hexane).
1
IR (CH2Cl2, KCl, cm-1): 1710 (w), 1642 (s). H NMR (CDCl3,
300 MHz): δ 3.97 (br d, J ) 16.2 Hz, 1 H), 3.72 (br d, J ) 16.2
Hz, 1 H), 3.56 (s, 3 H), 3.03 (br m, 1 H), 2.97 (s, 3 H), 2.47 (dq,
J ) 13.8, 7.5 Hz, 1 H), 2.02 (m, 1 H), 1.78 (m, 1 H), 1.65 (m,
2.58-1.62 (m, 6 H), 1.42-0.68 (m, 9 H). Anal. Calcd for C14H23-
NO4: C, 62.43; H, 8.61; N, 5.20; O, 23.76. Found: C, 62.21; H,
8.51; N, 5.08.

4048 J . Org. Chem., Vol. 64, No. 11, 1999
Zhang and Liebeskind
4-(N,N-Dim eth yla m in o)-5-m eth oxy-1-m eth yl-3-p h en yl-
5,6-dih ydr o-2-pyr idon e, 4i. 4-(N-Boc-N-methylaminomethyl)-
3-(N,N-dimethylamino)-4-methoxy-2-phenyl-2-cyclobuten-1-
one 3i (0.600 g, 1.660 mmol, 1.00 equiv) in 1.5 mL of TFA and
thermolysis yielded 0.382 g (1.470 mmol, 89%) of 4i as a light
brown solid after chromatography; TLC (silica gel, EtOAc, Rf
) 0.07); chromatographic purification (flash column, silica gel,
2 × 15 mm, EtOAc); mp 116-118 °C (CH2Cl2/hexane). IR (CH2-
Cl2, KCl, cm-1): 1618 (s). 1H NMR (CDCl3, 300 MHz): δ 7.21-
7.14 (m, 4 H), 7.09-7.03 (m, 1 H), 4.10 (app t, J ) 3.0 Hz, 1
H), 3.58 (app t, J ) 3.0 Hz, 2 H), 3.44 (s, 3 H), 3.02 (s, 3 H),
2.59 (s, 6 H). 13C NMR (CDCl3, 75.5 MHz): δ 166.4, 151.2,
137.8, 131.4, 126.8, 125.3, 107.7, 71.3, 54.9, 48.3, 41.2, 34.3.
Anal. Calcd for C15H20N2O2: C, 69.20; H, 7.74; N, 10.76; O,
12.29. Found: C, 68.96; H, 7.72; N, 10.71.
for C11H17NO3: C, 62.54; H, 8.11; N, 6.63; O, 22.72. Found:
C, 62.61; H, 8.13; N, 6.60.
3-ter t-Bu tyl-4-isop r op oxy-5-m eth oxy-1-m eth yl-2-p yr i-
d on e, 5b. 3-tert-Butyl-4-isopropoxy-5-methoxy-1-methyl-3,6-
dihydropyridone 4b (0.383 g, 1.50 mmol, 1.00 equiv), NBS
(0.294 g, 1.65 mmol, 1.10 equiv), and pyridine (0.356 g, 4.500
mmol, 3.00 equiv) yielded 0.295 g (1.160 mmol, 77%) of 5b as
a white solid after recrystallization; TLC (silica gel, EtOAc,
Rf ) 0.32); mp 119-121 °C (CH2Cl2/hexane). IR (CH2Cl2, KCl,
1
cm-1): 1658 (s), 1589 (s). H NMR (CDCl3, 300 MHz): δ 6.71
(s, 1 H), 4.74 (sept, J ) 6.0 Hz, 1 H), 3.68 (s, 3 H), 3.44 (s, 3
H), 1.46 (s, 9 H), 1.27 (d, J ) 6.0 Hz, 6 H). 13C NMR (CDCl3,
75.5 MHz): δ 161.6, 155.8, 139.1, 128.9, 118.4, 74.6, 57.3, 37.3,
36.3, 30.5, 22.1. Anal. Calcd for C14H23NO3: C, 66.37; H, 9.15;
N, 5.53; O, 18.95. Found: C, 66.45; H, 9.14; N, 5.51.
8,9-Ben zo-2-(N,N-d im eth yla m in o)-1-m eth oxy-3-p h en -
yl-1,6,7,9a -tetr a h yd r o-qu in olizin -4-on e, 4j. 4-(N-Boc-iso-
quinolino)-3-(N,N-dimethylamino)-4-methoxy-2-phenyl-2-cy-
clobuten-1-one 3j (crude product) in 2.0 mL of TFA and
thermolysis yielded 0.420 g (1.210 mmol, 40% from 1j) of 4j
as a yellow solid after chromatography. Only one diastereomer
was formed. TLC (silica gel, 60% EtOAc in hexane, Rf ) 0.25);
chromatographic purification (flash column, silica gel, 2 × 15
mm, 30% EtOAc in hexane); mp 175-177 °C (CH2Cl2/hexane).
IR (CH2Cl2, KCl, cm-1): 1616 (s). 1H NMR (CDCl3, 300 MHz):
δ 7.37-7.16 (m, 9 H), 4.94 (br d, J ) 2.7 Hz, 1 H), 4.85 (ddd,
J ) 12.3, 4.2, 2.1 Hz, 1 H), 4.50 (d, J ) 2.7 Hz, 1 H), 3.05-
2.99 (m, 1 H), 3.01 (s, 3 H), 2.91 (dd, J ) 12.3, 2.1 Hz, 1 H),
2.82-2.77 (m, 1 H), 2.67 (s, 6 H). 13C NMR (CDCl3, 75.5
MHz): δ 166.6, 152.5, 137.9, 137.2, 133.0, 131.5, 128.7, 127.0,
126.6, 126.2, 126.1, 125.6, 108.2, 76.8, 58.0, 57.2, 41.7, 38.0,
29.4. Anal. Calcd for C22H24N2O2: C, 75.83; H, 6.94; N, 8.04;
O, 9.18. Found: C, 75.71; H, 6.94; N, 7.99.
1-Ben zyl-4-(N,N-d im eth yla m in o)-5-m eth oxy-1-m eth yl-
3,6-d ip h en yl-5,6-d ih yd r o-2-p yr id on e, 4k . 4-(N-Boc-N-ben-
zylaminobenzyl)-3-(N,N-dimethylamino)-4-methoxy-2-phenyl-
2-cyclobuten-1-one 3k (0.677 g, 1.320 mmol, 1.00 equiv) in 1.5
mL of TFA and thermolysis yielded 0.455 g (1.100 mmol, 83%)
of 4k as a light yellow solid after chromatography. Only one
diastereomer was formed. TLC (silica gel, 60% EtOAc in
hexane, Rf ) 0.45); chromatographic purification (flash column,
silica gel, 2 × 15 mm, 20% EtOAc in hexane); mp 222-224 °C
(CH2Cl2/hexane). IR (CH2Cl2, KCl, cm-1): 1615 (s). 1H NMR
(CDCl3, 300 MHz): δ 7.38-7.20 (m, 15 H), 5.77 (d, J ) 15.0
Hz, 1 H), 4.64 (br d, J ) 1.5 Hz, 1 H), 3.90 (d, J ) 2.1 Hz, 1
H), 3.51 (d, J ) 15.0 Hz, 1 H), 3.18 (s, 3 H), 2.42 (s, 6 H). 13C
NMR (CDCl3, 75.5 MHz): δ 166.2, 149.1, 138.2, 137.9, 137.2,
131.6, 128.7, 128.4, 128.3, 127.8, 127.2, 127.0, 126.8, 125.9,
108.1, 78.4, 57.4, 55.2, 47.6, 41.2. Anal. Calcd for C27H28N2O2:
C, 78.61; H, 6.84; N, 6.79; O, 7.76. Found: C, 78.50; H, 6.87;
N, 6.81.
4-Isop r op oxy-5-m e t h oxy-1-m e t h yl-3-p h e n yl-2-p yr i-
d on e, 5c. 4-Isopropoxy-5-methoxy-1-methyl-3-phenyl-3,6-di-
hydropyridone 4c (0.248 g, 0.900 mmol, 1.00 equiv), NBS
(0.176 g, 0.990 mmol, 1.10 equiv), and pyridine (0.214 g, 2.71
mmol, 3.01 equiv) yielded 0.215 g (0.790 mmol, 88%) of 5c as
a white solid after recrystallization; TLC (silica gel, EtOAc,
Rf ) 0.17); mp 173-175 °C (CH2Cl2/hexane). IR (CH2Cl2, KCl,
1
cm-1): 1655 (s), 1593 (s). H NMR (CDCl3, 300 MHz): δ 7.37
(d, J ) 6.9 Hz, 2 H), 7.27 (dd, J ) 6.9, 6.9 Hz, 2 H), 7.18 (t, J
) 6.9 Hz, 1 H), 6.17 (s, 1 H), 4.12 (sept, J ) 6.0 Hz, 1 H), 3.63
(s, 3 H), 3.42 (s, 3 H), 0.92 (d, J ) 6.0 Hz, 6 H). 13C NMR
(CDCl3, 75.5 MHz): δ 160.8, 156.2, 139.3, 133.4, 130.4, 127.2,
126.8, 122.6, 119.7, 75.5, 57.2, 37.1, 21.9. Anal. Calcd for
C
16H19NO3: C, 70.31; H, 7.01; N, 5.12; O, 17.56. Found: C,
70.31; H, 7.05; N, 5.18.
3,4-Diet h yl-5-m et h oxy-1-m et h yl-2-p yr id on e, 5d . 3,4-
Diethyl-5-methoxy-1-methyl-3,6-dihydro-2-pyridone 4d (0.160
g, 0.810 mmol, 1.00 equiv), NBS (0.159 g, 0.890 mmol, 1.10
equiv), and pyridine (0.192 g, 2.430 mmol, 3.00 equiv) yielded
0.135 g (0.690 mmol, 85%) of 5d as a light brown solid after
recrystallization; TLC (silica gel, EtOAc, Rf ) 0.08); mp 86-
87 °C (CH2Cl2/hexane). IR (CH2Cl2, KCl, cm-1): 1657 (s), 1590
1
(s). H NMR (CDCl3, 300 MHz): δ 6.55 (s, 1 H), 3.66 (s, 3 H),
3.50 (s, 3 H), 2.60 (q, J ) 7.5 Hz, 2 H), 2.54 (q, J ) 7.5 Hz, 2
H), 1.10 (t, J ) 7.5 Hz, 3 H), 1.08 (t, J ) 7.5 Hz, 3 H). 13C
NMR (CDCl3, 75.5 MHz): δ 160.2, 145.0, 142.0, 131.9, 114.6,
55.7, 37.2, 20.1, 19.9, 13.5, 13.3. Anal. Calcd for C11H17NO2:
C, 67.66; H, 8.78; N, 7.17; O, 16.39. Found: C, 67.63; H, 8.75;
N, 7.18.
2-Isop r op oxy-1-m eth oxy-3-p h en yl-6,7,8,9-tetr a h yd r o-
qu in olizin -4-on e, 5e. 3,6,7,8,9,9a-Hexahydro-2-isopropoxy-
1-methoxy-3-phenyl-quinolizin-4-one 4e (0.315 g, 1.000 mmol,
1.00 equiv), NBS (0.196 g, 1.100 mmol, 1.10 equiv), and
pyridine (0.237 g, 3.00 mmol, 3.00 equiv) yielded 0.256 g (0.820
mmol, 82%) of 5e as a light yellow semisolid after chromatog-
raphy; TLC (silica gel, 60% EtOAc in hexane, Rf ) 0.19);
chromatographic purification (flash column, silica gel, 2 × 15
mm, 24% EtOAc/56% hexane/20% CH2Cl2). IR (CH2Cl2, KCl,
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-P yr id i-
n on e 5a -k . Compound 4 in 10 mL of THF was treated with
1.10 molar equiv of NBS and 3.00 molar equiv of pyridine at
room temperature in the dark for 3 days. The reaction mixture
was then diluted with 20 mL of Et2O and washed with 3 × 5
mL of 2 M NaOH solution to remove the succinimide formed
during the reaction. The NaOH wash was not used for the
more sensitive pyridones 5g,h and 5j,k . The aqueous layer was
extracted with 3 × 20 mL of Et2O, and the combined extracts
were washed once with 5 mL of 2 M NaOH. The combined
organic layers were dried over MgSO4. Removal of solvent gave
crude pyridinone 5, which was purified by chromatography or
recrystallization.
1
cm-1): 1636 (s), 1575 (s). H NMR (CDCl3, 300 MHz): δ 7.34
(app d, J ) 7.2 Hz, 2 H), 7.23 (app t, J ) 7.2 Hz, 2 H), 7.13
(app t, J ) 7.2 Hz, 1 H), 4.11 (sept, J ) 6.0 Hz, 1 H), 3.85 (t,
J ) 6.3 Hz, 2 H), 3.64 (s, 3 H), 2.76 (t, J ) 6.6 Hz, 2 H), 1.81
(m, 2 H), 1.68 (m, 2 H), 0.90 (d, J ) 6.0 Hz, 6 H). 13C NMR
(CDCl3, 75.5 MHz): δ 161.3, 158.0, 138.3, 135.1, 133.7, 130.5,
127.1, 126.4, 118.7, 75.1, 60.5, 42.4, 22.4, 22.0, 21.8, 18.2.
HRMS (EI) calcd for C19H24NO3 (M + H)+ 314.1757, found
314.1769.
6,7-Die t h yl-2,3-d ih yd r o-8-m e t h oxy-1H -in d olizin -5-
on e, 5f. 6,7-Diethyl-8-methoxy-2,3,6,8a-tetrahydro-1H-indolizin-
5-one 4f (0.200 g, 0.900 mmol, 1.00 equiv), NBS (0.175 g, 0.980
mmol, 1.09 equiv), and pyridine (0.214 g, 2.71 mmol, 3.01
equiv) yielded 0.12 g (0.540 mmol, 60%) of 5f as a deep blue
viscous oil after chromatography; TLC (silica gel, EtOAc, Rf
) 0.06); chromatographic purification (flash column, silica gel,
2 × 15 mm, 1% Et3N in EtOAc). IR (CH2Cl2, KCl, cm-1): 1653
(s), 1575 (s). 1H NMR (CDCl3, 300 MHz): δ 4.12 (t, J ) 7.5
Hz, 2 H), 3.69 (s, 3 H), 3.10 (t, J ) 7.5 Hz, 2 H), 2.54 (pent, J
) 7.5 Hz, 4 H), 2.16 (pent, J ) 7.5 Hz, 2 H), 1.14 (t, J ) 7.5
Hz, 3 H), 1.12 (t, J ) 7.5 Hz, 3 H). 13C NMR (CDCl3, 75.5
MHz): δ 160.0, 148.3, 137.6, 136.9, 129.2, 61.2, 48.8, 28.7, 21.5,
4-Isop r op oxy-5-m eth oxy-1,3-d im eth yl-2-p yr id on e, 5a .
4-Isopropoxy-5-methoxy-1,3-dimethyl-3,6-dihydropyridone 4a
(0.180 g, 0.840 mmol, 1.00 equiv), NBS (0.165 g, 0.930 mmol,
1.11 equiv), and pyridine (0.199 g, 2.52 mmol, 3.00 equiv)
yielded 0.152 g (0.720 mmol, 86%) of 5a as a white solid after
recrystallization; TLC (silica gel, EtOAc, Rf ) 0.07); mp 93-
95 °C (CH2Cl2/hexane). IR (CH2Cl2, KCl, cm-1): 1659 (s), 1590
1
(s). H NMR (CDCl3, 300 MHz): δ 6.63 (s, 1 H), 4.50 (sept, J
) Hz, 1 H), 3.62 (s, 3 H), 3.42 (s, 3 H), 1.98 (s, 3 H), 1.20 (d, J
) 6.0 Hz, 6 H). 13C NMR (CDCl3, 75.5 MHz): δ 162.0, 155.6,
139.3, 119.7, 117.7, 75.3, 57.1, 37.0, 22.4, 10.7. Anal. Calcd

Substituted 2-Pyridinones and Dihydro-2-pyridinones
J . Org. Chem., Vol. 64, No. 11, 1999 4049
20.2, 20.1, 14.5, 13.5. Anal. Calcd for C13H19NO2: C, 70.56; H,
8.65; N, 6.33; O, 14.46. Found: C, 70.62; H, 8.74; N, 6.32. The
deep blue color of compound 5f was caused by an impurity
that formed during column separation and the subsequent
concentration process. A second chromatographic purification
left a blue band at the top of the column, but the final
compound was still deeply colored with no obvious improve-
ment. Nevertheless, clean NMR spectra were obtained, and
the compound passed elemental analysis.
6-Ca r b oet h oxy-4-isop r op oxy-5-m et h oxy-1-m et h yl-3-
p h en yl-2-p yr id on e, 5g. 6-Carboethoxy-4-isopropoxy-5-meth-
oxy-1-methyl-3-phenyl-3,6-dihydro-2-pyridone 4g (0.539 g,
1.550 mmol, 1.00 equiv), NBS (0.303 g, 1.700 mmol, 1.10
equiv), and pyridine (0.368 g, 4.650 mmol, 3.00 equiv) yielded
0.352 g (1.020 mmol, 66%) of 5g as a light brown viscous oil
after chromatography; TLC (silica gel, 60% EtOAc in hexane,
Rf ) 0.36); chromatographic purification (flash column, silica
gel, 2 × 15 mm, 30% EtOAc in hexane). IR (CH2Cl2, KCl, cm-1):
1768 (w), 1736 (s), 1644 (s), 1596 (s). 1H NMR (CDCl3, 300
MHz): δ 7.39-7.19 (m, 5 H), 4.39 (q, J ) 7.2 Hz, 2 H), 4.13
(sept, J ) 6.0 Hz, 1 H), 3.76 (s, 3 H), 3.39 (s, 3 H), 1.35 (t, J )
7.2 Hz, 3 H), 0.94 (d, J ) 6.0 Hz, 6 H). 13C NMR (CDCl3, 75.5
MHz): δ 161.8, 160.9, 158.1, 136.4, 132.9, 132.4, 130.3, 127.4,
127.3, 123.8, 75.9, 62.4, 62.1, 33.0, 22.1, 13.9. Anal. Calcd for
3-phenyl-5,6-dihydro-2-pyridone 4i (0.182 g, 0.700 mmol, 1.00
equiv), NBS (0.137 g, 0.770 mmol, 1.10 equiv), and pyridine
(0.166 g, 2.100 mmol, 3.00 equiv) yielded 0.178 g (0.690 mmol,
99%) of 5i as a light yellow solid after recrystallization; TLC
(silica gel, 2% MeOH in CHCl3, Rf ) 0.04); mp 148-150 °C
(CH2Cl2/hexane). IR (CH2Cl2, KCl, cm-1): 1650 (s), 1602 (s),
1
1585 (s). H NMR (CDCl3, 300 MHz): δ 7.33-7.17 (m, 5 H),
6.69 (s, 1 H), 3.66 (s, 3 H), 3.42 (s, 3 H), 2.48 (s, 6 H). 13C
NMR (CDCl3, 75.5 MHz): δ 161.1, 151.5, 140.2, 136.8, 130.7,
127.5, 126.3, 119.4, 119.3, 57.2, 42.7, 36.8. Anal. Calcd for
C
15H18N2O2: C, 69.74; H, 7.02; N, 10.84; O, 12.39. Found: C,
69.65; H, 7.00; N, 10.92.
8,9-Ben zo-6,7-d ih yd r o-2-(N,N-d im eth yla m in o)-1-m eth -
oxy-3-p h en yl-qu in olizin -4-on e, 5j. 8,9-Benzo-2-(N,N-dim-
ethylamino)-1-methoxy-3-phenyl-1,6,7,9a-tetrahydro-quinolizin-
4-one 4j (0.296 g, 0.850 mmol, 1.00 equiv), NBS (0.166 g, 0.930
mmol, 1.09 equiv), and pyridine (0.202 g, 2.550 mmol, 3.00
equiv) yielded 0.120 g (0.350 mmol, 41%) of 5j as a yellow solid
after chromatography; TLC (silica gel, EtOAc, Rf ) 0.36);
chromatographic purification (flash column, silica gel, 2 × 15
mm, 30% EtOAc in hexane); mp 215-216 °C (CH2Cl2/hexane).
1
IR (CH2Cl2, KCl, cm-1): 1620 (s), 1600 (m). H NMR (CDCl3,
300 MHz): δ 8.41-8.38 (m, 1 H), 7.39-7.20 (m, 8 H), 4.20 (br
t, J ) 6.0 Hz, 2 H), 3.43 (s, 3 H), 2.90 (t, J ) 6.0 Hz, 2 H), 2.59
(s, 6 H). 13C NMR (CDCl3, 75.5 MHz): δ 160.8, 153.8, 138.3,
137.1, 133.3, 130.7, 129.6, 129.0, 128.0, 127.8, 127.3, 126.7,
126.4, 118.4, 60.0, 42.8, 39.6, 29.1. HRMS (EI) calcd for
C
19H23NO5: C, 66.07; H, 6.71; N, 4.06; O, 23.16. Found: C,
65.90; H, 6.74; N, 4.02.
6-Ca r boeth oxy-3,4-d ieth yl-5-m eth oxy-1-m eth yl-2-p yr i-
d on e, 5h . 6-Carboethoxy-3,4-diethyl-5-methoxy-1-methyl-3,6-
dihydro-2-pyridone 4h (0.090 g, 0.330 mmol, 1.00 equiv), NBS
(0.065 g, 0.370 mmol, 1.12 equiv), and pyridine (0.079 g, 1.000
mmol, 3.03 equiv) yielded 0.075 g (0.280 mmol, 85%) of 5h as
a light yellow viscous oil after chromatography; TLC (silica
gel, 60% EtOAc in hexane, Rf ) 0.32); chromatographic
purification (flash column, silica gel, 2 × 15 mm, 30% EtOAc
in hexane). IR (CH2Cl2, KCl, cm-1): 1734 (s), 1646 (s), 1591
C
22H23N2O2 (M + H)+: 347.1760, found 347.1750.
1-Ben zyl-4-(N,N-d im eth yla m in o)-5-m eth oxy-1-m eth yl-
3,6-d ip h en yl-2-p yr id on e, 5k . 1-Benzyl-4-(N,N-dimethylami-
no)-5-methoxy-1-methyl-3,6-diphenyl-5,6-dihydro-2-pyridone
4k (0.256 g, 0.620 mmol, 1.00 equiv), NBS (0.121 g, 0.680
mmol, 1.10 equiv), and pyridine (0.147 g, 1.860 mmol, 3.00
equiv) yielded 0.182 g (0.440 mmol, 71%) of 5k as a light yellow
foam after chromatography; TLC (silica gel, 60% EtOAc in
hexane, Rf ) 0.50); chromatographic purification (flash column,
silica gel, 2 × 15 mm, 25% EtOAc in hexane). IR (CH2Cl2, KCl,
cm-1): 1626 (s), 1600 (m). 1H NMR (CDCl3, 300 MHz): δ 7.50-
7.15 (m, 13 H), 6.91 (t, J ) 3.6 Hz, 2 H), 5.08 (br s, 2 H), 3.31
(s, 3 H), 2.63 (s, 6 H). 13C NMR (CDCl3, 75.5 MHz): δ 161.9,
153.0, 140.2, 137.8, 137.0, 131.7, 130.8, 129.5, 128.6, 127.9,
127.8, 127.6, 127.1, 126.5, 126.3, 117.8, 60.0, 48.4, 42.4. HRMS
(EI) calcd for C27H27N2O2 (M + H)+: 411.2073, found 411.2072.
1
(s). H NMR (CDCl3, 300 MHz): δ 4.40 (q, J ) 7.2 Hz, 2 H),
3.69 (s, 3 H), 3.40 (s, 3 H), 2.58 (q, J ) 7.2 Hz, 2 H), 2.52 (q,
J ) 7.2 Hz, 2 H), 1.38 (t, J ) 7.2 Hz, 3 H), 1.14 (t, J ) 7.2 Hz,
3 H), 1.09 (H). 13C NMR (CDCl3, 75.5 MHz): δ 162.4, 160.3,
147.6, 139.8, 134.4, 130.6, 63.5, 62.4, 33.2, 20.9, 20.3, 14.3, 14.0,
13.2. HRMS (EI) calcd for C14H22NO4 (M + H)+: 268.1549,
found: 268.1559. Anal. Calcd for C14H21NO4: C, 62.90; H, 7.92;
N, 5.24; O, 23.94. Found: C, 62.27; H, 7.95; N, 5.24.
4-(N,N-Dim eth yla m in o)-5-m eth oxy-1-m eth yl-3-p h en yl-
2-p yr id on e, 5i. 4-(N,N-Dimethylamino)-5-methoxy-1-methyl-
J O990069T