An enantioselective ketene-imine cycloaddition method for synthesis of substituted ring-fused 2-pyridinones

Article abstract of DOI:10.1021/jo015794u

Previously, a method for the stereoselective synthesis of β-lactams, starting from 2H-δ²-thiazolines and Meldrum's acid derivatives, has been reported from our laboratory. We now report a new method for the synthesis of optically active, highly substituted ring-fused 2-pyridinones. This was discovered when 2-alkyl-δ²-thiazolines and Meldrum's acid derivatives were treated with HCl(g) in benzene at 5 → 78 °C. Further refinement of the synthetic protocol revealed that use of 1,2-dichloroethane as solvent at 0 → 64 °C led to the desired 2-pyridinones in good yields and with excellent enantioselectivity. Use of these conditions allowed preparation of 2-pyridinones from several different δ²-thiazolines and Meldrum's acid derivatives and may be a general route to 2-pyridinones.

Full text of DOI:10.1021/jo015794u

6756
J . Org. Chem. 2001, 66, 6756-6761
An En a n tioselective Keten e-Im in e Cycloa d d ition Meth od for
Syn th esis of Su bstitu ted Rin g-F u sed 2-P yr id in on es
Hans Emtena¨s, Lisa Alderin, and Fredrik Almqvist*
Organic Chemistry, Department of Chemistry, Umea˚ University, SE-901 87 Umea˚, Sweden
fredrik.almqvist@chem.umu.se
Received May 25, 2001
Previously, a method for the stereoselective synthesis of â-lactams, starting from 2H-∆2-thiazolines
and Meldrum’s acid derivatives, has been reported from our laboratory. We now report a new method
for the synthesis of optically active, highly substituted ring-fused 2-pyridinones. This was discovered
when 2-alkyl-∆2-thiazolines and Meldrum’s acid derivatives were treated with HCl(g) in benzene
at 5 f 78 °C. Further refinement of the synthetic protocol revealed that use of 1,2-dichloroethane
as solvent at 0 f 64 °C led to the desired 2-pyridinones in good yields and with excellent
enantioselectivity. Use of these conditions allowed preparation of 2-pyridinones from several different
∆2-thiazolines and Meldrum’s acid derivatives and may be a general route to 2-pyridinones.
Sch em e 1a
In tr od u ction
Recently, we reported the stereoselective synthesis of
optically active â-lactams.1 This rigid framework, with
different stereochemistry than that of penicillin, was
designed to be a suitable scaffold for the development of
compounds (termed pilicides) that inhibit pilus formation
in uropathogenic E. coli. The synthesis took use of acyl
Meldrum’s acids and ∆2-thiazolines as key intermediates,
which gave the desired â-lactams in yields as high as 93%
in the best cases. In our design work, however, we saw a
possibility to obtain more potent pilicides if we could
introduce an additional substituent in the â-lactam ring.
To do so, the most direct approach would be to use
2-alkyl- or 2-aryl-substituted ∆2-thiazolines and perform
the same ketene-imine cycloaddition. Although the steric
hindrance in the â-lactam-forming step would be sub-
stantial with a substituent in the ∆2-thiazoline, others
have shown that this approach can be successful.2,3
Therefore, substituted ∆2-thiazolines were synthesized
by the method described by Myers.4,5 This methodology
is very attractive since commercially available nitriles,
via their corresponding imino ethers, can be condensed
with (R)-cysteine methyl ester hydrochloride. Thus, a set
of different substituted ∆2-thiazolines was prepared
(Scheme 1). The other building block, i.e., the Meldrum’s
acid derivatives, was easily made from an activated
carboxylic acid and Meldrum’s acid6 (Scheme 1).
a
Key: (a) HCl(g), EtOH, 0 °C, 4 h; (b) (R)-cysteine methyl ester
hydrochloride, TEA, CH2Cl2, 0 °C f rt, 17 h; (c) DMAP, CH2Cl2,
-12 °C f rt, 4 h.
did not give the desired benzyl-substituted â-lactam.
Instead, a ring-fused 2-pyridinone framework was formed
(Figure 1).
The core structure of these heterocycles can be found
in numerous biologically active compounds with diverse
medicinal properties. These range from antibacterial7-9
and antifungal10 agents to free-radical scavengers11,12 and
angiotensin converting enzyme (ACE) inhibitors (Figure
Surprisingly, when the benzyl-substituted ∆2-thiazo-
line 1c was used, the previously so successful approach
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10.1021/jo015794u CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/13/2001

Synthesis of Substituted Ring-Fused 2-Pyridinones
J . Org. Chem., Vol. 66, No. 20, 2001 6757
procedures have been reported separately by Padwa39,40
and Liebeskind41,42 that cover the preparation of ring-
fused 2-pyridinones.
Resu lts a n d Discu ssion
Although a variety of methods for the synthesis of
substituted 2-pyridinones are available, new direct ap-
proaches that are regioselective and mild enough to allow
preparation of optically active products are continuously
attracting interest. Therefore, we decided to investigate
this novel enantioselective route from acyl Meldrum’s
acids and substituted ∆2-thiazolines further. Sets of
2-alkyl- and 2-aryl-substituted ∆2-thiazolines 1a -e and
Meldrum’s acid derivatives 2a -c (Scheme 1) were there-
fore synthesized. Using the conditions applied in our
previous â-lactam synthesis, i.e., HCl(g) in benzene at 5
f 78 °C, a small library of substituted ring-fused
2-pyridinones 3a -e was then prepared (Table 1). The
yields were moderate to good, and all the products were
optically active. Moreover, the synthesis could easily be
performed on a gram scale without any decrease in the
isolated yields; 2.3 g of 2-pyridinone 3a was prepared
corresponding to an isolated yield of 69% (83% based
upon recovered ∆2-thiazoline 1c).
A tentative mechanistic explanation to the formation
of substituted 2-pyridinones could be as follows (Scheme
2). Instead of an attack back at the activated imine A,
which would give a â-lactam, a [1,5] sigmatropic rear-
rangement results in enamide B. Then, an intramolecu-
lar attack at the â carbonyl group closes the six-
membered ring to give C. After consecutive removal of a
proton and water, the final 2-pyridinone D is thus
formed. According to this mechanism, a ∆2-thiazoline
lacking a methylene group in the R2-substituent adjacent
to the imine carbon would not be able to form a 2-pyri-
dinone. Therefore, attempts to use 2-phenyl- or 2-isopro-
pyl-substituted ∆2-thiazolines (1d and 1e) should not
result in any 2-pyridinones. Indeed, performing the
reaction with these substrates resulted in undefined
products. In these cases, one could expect the â-lactam
“pathway” to be dominating but no substituted â-lactams
could be isolated.
F igu r e 1. â-Lactams or 2-pyridinones can be selectively
prepared by choosing a 2-H-substituted or a 2-alkyl-substituted
∆2-thiazoline.
F igu r e 2. Examples of a natural product and a synthetic
compound of medicinal interest that possess a 2-pyridinone
framework.
2).13-15 2-Pyridinones also serve as inhibitors of Aâ-
peptide aggregation,16,17 which is believed to play an
important role in amyloid formation in Alzheimer’s
disease (Figure 2).
N-Substituted 2-pyridinones have also been used as
active ingredients for the therapy of fibrotic disease,18 and
they have been evaluated as inhibitors of human leuko-
cyte elastase.19 Moreover, this framework can be trans-
formed to piperidine, pyridine, quinolizidine, and indoliz-
idine alkaloids,20,21 which, together with their potential
as conformationally constrained amino acids,22-24 make
them into important intermediates in natural product
synthesis and versatile scaffolds for preparation of pep-
tide mimetics.
Due to the importance of substituted 2-pyridinones,
many preparative methods have been reported in the
literature.25-38 In recent years, attractive cycloaddition
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Kemp, J . A.; Nordstedt, C. J . Biol. Chem. 2000, 275, 1673-1678.
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A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford,
1996; Vol. 5.
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W. D. Tetrahedron 1997, 53, 12789-12854.
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64, 8648-8659.
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4049.

6758 J . Org. Chem., Vol. 66, No. 20, 2001
Emtena¨s et al.
Ta ble 1. In flu en ce of Differ en t Con d ition s for th e
Syn th esis of 2-P yr id in on es Rega r d in g Yield a n d
En a n tiom er ic Excess
Whelk-O1 column gave excellent separation. In this case,
the enantiomers were detected with both UV spectros-
copy and mass spectrometry (Figure 3). Racemic 2-pyri-
dinone (()-3a was also prepared to verify that the peaks
from the UV and MS detection corresponded to the
enantiomers. The reproducibility of the ee determinations
was confirmed by five separate HPLC measurements on
different batches of 2-pyridinone 3b. The major enanti-
omer ((-)-3b) was thus obtained with an enantiomer
ratio of 98.5 ( 0.3% corresponding to 97% ee.
The enantiomeric excess of the key intermediates 1a -c
were 75-100%, and the resulting 2-pyridinones 3a -e
had ee’s of 64-97% (Table 1). Thus, one could conclude
that some racemization occurred on formation of 2-pyri-
dinones when the synthesis was performed in refluxing
benzene for 3 h. In the worst case, for the 2-pyridinone
3c, the ee had decreased as much as 19%. The temper-
ature was an obvious parameter that could affect the
racemization rate, and a decrease in temperature to 69
°C in the synthesis of 2-pyridinone 3a gave an increase
in ee from 77 to 86% without any substantial decrease
in isolated yield.
T
time yielda ee 2-pyridinone ee ∆2-thiazoline ∆ eeb
compd (°C) (h)
(%)
(%)
(%)
(%)
Reactions with Benzene as Solvent
3a
3b
3c
3d
3e
3a
78
78
78
78
78
69
3
3
3
3
3
4
69
29
69
66
36
63
77
97
73
64
84
86
92
100
92
75
100
92
15
3
19
11
16
6
Reactions with 1,2-Dichloroethane as Solvent
3a
3b
3c
3d
3e
3a
64 14
64 14
64 14
64 14
64 14
85
86
66
77
63
32
89
97
92
75
97
92
92
100
92
75
100
92
3
3
0
0
3
0
However, although previously the solvent of choice in
the â-lactam synthesis based upon acyl Meldrum’s ac-
ids,1,6 there are drawbacks with using benzene as a
solvent. Apart from being carcinogenic it also freezes at
4 °C. Since HCl(g) is led through the reaction mixture
just above the freezing point of benzene, precipitation and
thus a stop in the gas flow was occasionally experienced.
Another problem is that the protonated ∆2-thiazolines
easily precipitate if the HCl(g) is passed through the
solution too vigorously or under a prolonged time. Even
though the temperature is raised during the synthesis,
the precipitated ∆2-thiazoline does not dissolve properly,
giving a decrease in yield of the desired 2-pyridinones.
It turned out that 1,2-dichloroethane is superior to
benzene as solvent in this reaction in many aspects. One
does not encounter any problems when introducing the
HCl(g) into the solution, no back flow of HCl(g) and no
precipitation ïf ∆2-thiazoline occur. The reaction can also
be heated to the temperatures required to get the
2-pyridinones. Moreover, when the synthesis was per-
formed at 64 °C overnight only limited racemization
(1.5%) could be detected for 3a , 3b, and 3e while the other
two 2-pyridinones, 3c and 3d , could be synthesized
without any racemization at all (Table 1). Also a signifi-
cant increase in isolated yield was observed with 1,2-
dichloroethane as solvent and the most striking example
was 3b for which the yield increased from 29% (using
benzene) to 86%. It should be noted that also 3a could
be prepared without any racemization, although at a
lower yield, if the synthesis was conducted for only 1 h
at 64 °C.
64
1
a
Yields were determined after purification by flash column
b
chromatography. The difference in enantiomeric excesses be-
tween the ∆2-thiazolines and the 2-pyridinones.
Sch em e 2. Ten ta tive Mech a n ism for th e
F or m a tion of 2-P yr id in on es fr om ∆2-Th ia zolin es
a n d Keten es Gen er a ted fr om Acyl Meld r u m ’s Acid s
Con clu sion s
Mea su r em en t of Op tica l P u r ity a n d Op tim iza tion
of th e 2-P yr id in on e Syn th esis. To establish the enan-
tioselectivity in formation of the 2-pyridinones, the
enantiomeric excess of the ∆2-thiazolines was first mea-
sured by chiral HPLC using a Chiralcel OD-H column.43
The enantiomers were detected by UV spectroscopy and
had identical spectra. The 2-pyridinones were also sub-
jected to a chiral HPLC measurement and the (S,S)
A new enantioselective synthesis of highly substituted
2-pyridinones has been developed. The method is mild
and convergent, which indicates a high potential for
future parallel synthesis of diverse 2-pyridinone libraries.
The methodology is also easy to scale-up, which makes
synthesis of potential leads for further biological testing
in gram quantities straightforward. The synthetic pro-
tocol has been refined to a highly enantioselective 2-py-
ridinone forming step giving the desired 2-pyridinones
in good to excellent yields. Therefore, by choosing the
(43) Raman, P.; Razavi, H.; Kelly, J . W. Org. Lett. 2000, 2, 3289-
3292.

Synthesis of Substituted Ring-Fused 2-Pyridinones
J . Org. Chem., Vol. 66, No. 20, 2001 6759
F igu r e 3. Optical purity of the 2-pyridinones was measured by chiral HPLC ((S,S) Whelk-O1). The enantiomers showed identical
mass spectra as exemplified for 3c synthesized by the original conditions (HCl(g) in benzene, 5 f 78 °C, 3 h, 73% ee).
correct ∆2-thiazolines (substituted or unsubstituted) we
are now allowed to enantioselectively synthesize either
hexane/dichloromethane/2-propanol 48:48:4 as mobile phase
for the 2-pyridinones.
(4R)-2-Meth yl-4,5-d ih yd r oth ia zole-4-ca r boxylic Acid
â-lactams or 2-pyridinones (Figure 1).
Meth yl Ester (1a ). Prepared as described for 1c from aceto-
nitrile to give ∆2-thiazoline 1a as an oil (3.06 g, 73%). Data in
agreement with published procedures:44,45 1H NMR (400 MHz,
Exp er im en ta l Section
CDCl3) δ 4.98-5.07 (m, 1H), 3.77 (s, 3H), 3.46-3.62 (m, 2H),
2.23 (d, J ) 1.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.1,
Gen er a l Meth od s. All reactions were carried out under an
inert atmosphere with dry solvents under anhydrous condi-
tions, unless otherwise stated. 1,2-Dichloroethane and CH2-
Cl2 were distilled from calcium hydride immediately before use.
THF was distilled from potassium, and toluene was distilled
from sodium. HCl(g) was passed through concentrated sulfuric
acid before use. TLC was performed on silica gel 60 F254
(Merck) with detection by UV light and staining with a solution
of anisaldehyde (26 mL), glacial acetic acid (11 mL), and
concentrated sulfuric acid (35 mL) in 95% ethanol (960 mL).
Flash column chromatography (eluents given in brackets) was
performed on silica gel (Matrex, 60 Å, 35-70 µm, Grace
Amicon). Centrifugal preparative TLC was performed using
rotors coated with silica gel 60 PF254 containing CaSO4 (Merck).
The moving bands were visualized using UV light. The 1H and
13C NMR spectra were recorded on a Bruker DRX-400 for
solutions in CDCl3 [residual CHCl3 (δH 7.26 ppm) or CDCl3
(δC 77.0 ppm), as internal standard] at 298 K. First-order
chemical shifts and coupling constants were obtained from one-
dimensional spectra, and proton resonances were assigned
from COSY experiments. IR spectra were recorded on an ATI
Mattson Genesis Series FTIR spectrometer. Optical rotations
were measured with a Perkin-Elmer 343 polarimeter at 20 °C.
High-resolution mass spectra [EI or FAB] were recorded on a
J EOL J MS-SX 102 spectrometer. Analyses of enantiomeric
excess were performed with a HPLC equipped with a Chiralcel
OD-H column with hexane/2-propanol 70:30 as mobile phase
for the ∆2-thiazolines and a (S,S) Whelk-O 1 column with
170.0, 78.0, 52.6, 36.1, 20.2; HRMS (EI+) calcd for C6H9NO2S
159.0354, obsd 159.0355.
(4R)-2-E t h yl-4,5-d ih yd r ot h ia zole-4-ca r b oxylic Acid
Meth yl Ester (1b). Prepared as described for 1c from ethyl
cyanide to give ∆2-thiazoline 1b as an oil (4.19 g, 79%): [R]D
93° (c 1.28, CHCl3); IR 2976, 2953, 1739, 1620, 1437, 1200,
926 cm-1 1H NMR (400 MHz, CDCl3) δ 4.97-5.06 (m, 1H),
;
3.76 (s, 3H), 3.42-3.58 (m, 2H), 2.53 (dq, J ) 7.6, 1.5 Hz, 2H),
1.18 (t, J ) 7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 175.9,
171.3, 77.8, 52.5, 35.2, 27.7, 11.9; HRMS (EI+) calcd for C7H11
NO2S 173.0510, obsd 173.0510.
-
(4R)-2-Ben zyl-4,5-d ih yd r ot h ia zole-4-ca r b oxylic Acid
Meth yl Ester (1c). Dry HCl(g) was passed through a solution
of benzylcyanide (22.6 g, 193 mmol) in dry EtOH (15 mL)
during 4 h at 0 °C. After standing overnight at room temper-
ature, the mixture was concentrated to give ethyl benzylimi-
date hydrochloride as white crystals, which were used in the
next step without further purification. Triethylamine (12 mL,
86.1 mmol) was slowly added to a suspension of (R)-cysteine
methyl ester hydrochloride (15.0 g, 87.4 mmol) in dry CH2Cl2
(100 mL) at 0 °C. After 20 min, a suspension of ethyl
benzylimidate hydrochloride (13 g, 65.1 mmol) in CH2Cl2 (30
(44) Eggleton, G. L.; Bushman, D. R.; Whitlock, D. W.; Pugh, D. K.;
Chance, K. L. J . Chem. Eng. Data 1984, 29, 351-354.
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Chem. Pharm. Bull. 1967, 15, 644-647.

6760 J . Org. Chem., Vol. 66, No. 20, 2001
Emtena¨s et al.
mL) was added, and the mixture was allowed to attain room
temperature overnight. Then, the mixture was diluted with
CH2Cl2 and washed with water, saturated aqueous NaHCO3,
and brine. The aqueous layers were extracted with CH2Cl2,
and the combined organic layers were dried (Na2SO4), filtered,
and concentrated. The residue was purified by flash column
chromatography (heptane/ethyl acetate, 1:1) to give ∆2-thia-
zoline 1c as an oil (12.7 g, 83% from benzylcyanide): [R]D -59°
(c 2.40, CHCl3); IR λ 3027, 2951, 1736, 1616, 1435, 1198, 1174
NMR (100 MHz, CDCl3) δ 168.5, 161.2, 154.3, 146.4, 136.3,
133.9, 133.7, 131.7, 130.2, 129.7, 129.0 (splitted), 128.7, 128.4,
127.9, 127.6, 126.0, 125.6, 125.4, 123.7, 116.1, 115.2, 63.4, 53.2,
36.9, 31.6; HRMS (EI+) calcd for C26H21NO3S 427.1242, obsd
427.1228.
(3R)-7-(Na p h th a len -1-ylm eth yl)-5-oxo-2,3-d ih yd r o-5H-
th ia zolo[3,2-a ]p yr id in e-3-ca r boxylic Acid Meth yl Ester
(3b). By following the procedure described for the preparation
of 3a from 1c and 2c, 1a (312 mg, 1.96 mmol) and 2c (838
mg, 2.68 mmol) gave 3b as a white foam (593 mg, 86%): [R]D
-184° (c 1.63, CHCl3); IR λ 2920, 1747, 1647, 1572, 1504, 1211,
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.24-7.36 (m, 5H), 5.09
(m, 1H), 3.80-3.91 (m, 2H), 3.82 (s, 3H), 3.42-3.61 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 173.8, 171.2, 135.6, 129.1, 128.7,
127.3, 77.9, 52.7, 40.8, 35.7; HRMS (EI+) calcd for C12H13NO2S
235.0667, obsd 235.0669.
4-(R)-2-P h en yl-4,5-d ih yd r o-th ia zole-4-ca r boxylic a cid
m eth yl ester , (1d ). Prepared as described for 1c from phenyl
cyanide to give ∆2-thiazoline 1d as an oil (2.18 g, 91%). Data
in agreement with published procedures.43
1
1018, 779 cm-1; H NMR (400 MHz, CDCl3) δ 7.88-7.85 (m,
2H) 7.79 (d, J ) 8.2 Hz, 1H) 7.48-7.410 (m, 3H) 7.34 (d, J )
6.8 Hz, 1H) 6.10 (d, J ) 1.2 Hz, 1H) 5.97 (d, J ) 1.3 Hz, 1H)
5.52 (dd, J ) 8.3, 2.1 Hz, 1H) 4.20 (s, 2H) 3.78 (s, 3H) 3.67
(dd, J ) 11.7, 8.3 Hz, 1H) 3.50 (dd, J ) 11.7 Hz, 2.1 Hz, 1H),
13C NMR (100 MHz, CDCl3) δ 168.4, 161.9, 155.2, 146.8, 133.9,
133.5, 131.9, 128.8, 127.9, 127.9, 126.3, 125.8, 125.5, 123.9,
114.1, 101.8, 62.5, 53.2, 38.9, 31.8; HRMS (FAB+) calcd for
(4R)-2-Isopr opyl-4,5-dih ydr oth iazole-4-car boxylic Acid
Meth yl Ester (1e). Prepared according to published proce-
dures.46
C
20H18NO3S 352.1005, obsd 352.1007.
(3R)-7-Meth yl-5-oxo-8-p h en yl-2,3-d ih yd r o-5H-th ia zolo-
5-(1-Hyd r oxyeth ylid en e)-2,2-d im eth yl[1,3]d ioxa n e-4,6-
d ion e (2a ). Prepared according to published procedures.6
5-(Hydr oxyph en ylm eth ylen e)-2,2-dim eth yl[1,3]dioxan e-
4,6-d ion e (2b). Prepared according to published procedures.6
5-(1-Hydr oxy-2-n aph th alen -1-yleth yliden e)-2,2-dim eth -
yl[1,3]d ioxa n e-4,6-d ion e (2c). Oxalyl chloride (10 mL, 114
mmol) and DMF (0.1 mL) were added to a solution of
1-naphthylacetic acid (7.56 g, 40.6 mmol) in dry CH2Cl2 (80
mL). After being stirred for 30 min at room temperature, the
solution was refluxed for 1.5 h, cooled to room temperature,
and concentrated. The residue was co-concentrated three times
from dry CH2Cl2 and dissolved in dry CH2Cl2 (40 mL). The
solution was added slowly during 1 h to a stirred solution of
Meldrum’s acid (5.19 g, 36 mmol) and DMAP (8.62 g, 70.3
mmol) in dry CH2Cl2 (80 mL) at -10 °C. The resulting solution
was allowed to attain room temperature and was then stirred
for 3 h before being diluted with CH2Cl2 and washed with
aqueous KHSO4 (2%), water, and brine. The aqueous layers
were extracted with CH2Cl2, and the combined organic layers
were dried (Na2SO4), filtered, and concentrated. The residue
was recrystallized from Et2O to give 2c as white crystals (10.2
g, 91%): mp 104 °C dec; IR λ 3060, 2995, 1728, 1645, 1568,
[3,2-a ]p yr id in e-3-ca r boxylic Acid Meth yl Ester (3c). By
following the procedure described for the preparation of 3a
from 1c and 2c, 1c (565 mg, 2.40 mmol) and 2a (633 mg, 3.40
mmol) gave 3c as a white foam (478 mg, 66% (95% based on
recovered stmrl, ∆2-thiazoline 1c)): [R]D -185° (c 1.47, CHCl3);
IR λ 3053, 2999, 2954, 1753, 1649, 1581, 1483, 1416, 1207,
991, 839, 748, 702, cm-1 1H NMR (400 MHz, CDCl3) δ
;
7.45 7.33 (m, 3H), 7.25-7.21 (m, 2H), 6.24 (d, J ) 0.8 Hz,
1H), 5.65 (dd, J ) 8.6, 2.5 Hz, 1H), 3.83 (s, 3H), 3.64 (dd, J )
11.6, 8.6 Hz, 1H), 3.45 (dd, J ) 11.6, 2.5 Hz, 1H), 1.97 (d, J )
0.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.6, 161.2, 151.9,
146.1, 136.6, 129.8, 128.8, 128.1, 116.6, 115.1, 63.5, 53.3, 31.8,
20.7; HRMS (EI+) calcd for
301.0770.
C16H15NO3S 301.0773, obsd
(3R)-7,8-Dim eth yl-5-oxo-2,3-d ih yd r o-5H-th ia zolo[3,2-a ]-
p yr id in e-3-ca r boxylic Acid Meth yl Ester (3d ). By follow-
ing the procedure described for the preparation of 3a from 1c
and 2c, 1b (285 mg, 1.65 mmol) and 2a (450 mg, 2.42 mmol)
gave 3d as a white foam (302 mg, 77% (97% based on recovered
stmrl, ∆2-thiazoline 1b)): [R]D -205° (c 3.92, CHCl3); IR λ 2889,
2956, 1743, 1651, 1577, 1496, 1425, 1176, 985, 827, 731 cm-1
;
1H NMR (400 MHz, CDCl3) δ 5.93 (s, 1H), 5.41 (d, J ) 8.4 Hz,
1H), 3.65-3,53 (m, 4H), 3.36 (d, J ) 11.8 Hz, 1H), 1.95 (s,
3H), 1.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 168.2, 160.2,
152.2, 143.4, 114.3, 108.8, 62.8, 52.6, 31.3, 19.6, 15.3; HRMS
(EI+) calcd for C11H13NO3S 239.0616, obsd 239.0616.
1
1201, 918, 773 cm-1; H NMR (400 MHz, CDCl3) δ 15.49 (s,
1H), 7.95-8.01 (m, 1H), 7.86-7.92 (m, 1H), 7.83 (d, J ) 7.8
Hz, 1H), 7.41-7.58 (m, 4H), 4.96 (s, 2H), 1.77 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 195.1, 170.5, 160.5, 133.8, 132.1, 130.5,
128.8, 128.3, 128.2, 126.5, 125.8, 125.4, 123.6, 105.0, 91.6, 38.4,
26.8; HRMS (EI+) calcd for C18H16O5 312.0998, obsd 312.0999.
Anal. Calcd for C18H16O5: C, 69.22; H, 5.16; N, 25.61. Found:
C, 69.2; H, 5.2; N, 25.6.
(3R)-5-Oxo-7-p h en yl-2,3-d ih yd r o-5H-th ia zolo[3,2-a ]p y-
r id in e-3-ca r boxylic Acid Meth yl Ester (3e). By following
the procedure described for the preparation of 3a from 1c and
2c, 1a (230 mg, 1.45 mmol) and 2b (480 mg, 1.93 mmol) gave
3e as a white foam (260 mg, 63%): [R]D -68° (c 1.38, CHCl3);
IR λ 2950, 1743, 1645, 1562, 1495, 1207, 1174, 993, 843, 760
cm-1; 1H NMR (400 MHz, CDCl3) δ 7.46-7.55 (m, 2H), 7.34-
7.44 (m, 3H), 6.45 (s, 1H), 6.36 (s, 1H), 5.60 (d, J ) 8.8 Hz,
1H), 3.70-3.82 (m, 4H), 3.54 (d, J ) 11.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 168.3, 161.8, 153.2, 147.3, 137.3, 129.4,
128.8, 126.6, 111.9, 100.0, 62.5, 53.1, 31.8; HRMS (EI+) calcd
for C15H13NO3S 287.0616, obsd 287.0611.
(3RS)-7-(Na p h t h a len -1-ylm et h yl)-5-oxo-8-p h en yl-2,3-
d ih yd r o-5H -t h ia zolo[3,2-a ]p yr id in e-3-ca r b oxylic Acid
Meth yl Ester ((()-3a ). To a solution of diisopropylamine (90
µL, 0.635 mmol) in dry THF (1.2 mL) was added n-butyllithium
(330 µL 1.6 M in hexane, 0.529 mmol) at 0 °C. After being
stirred for 1 h, the solution was cooled to -78 °C and 3a (170
mg, 0.400 mmol) dissolved in dry THF (1.0 mL) was added
dropwise. NH4Cl(aq) (1 mL) was added after stirring at -78
°C for 1 h, and the mixture was allowed to attain room
temperature before being diluted with CH2Cl2. The pH was
adjusted to 4 with 6 N HCl, and the mixture was washed with
water and brine. The aqueous layers were extracted with CH2-
Cl2, and the combined organic layers were dried (Na2SO4),
filtered, and concentrated. Purification by Centrifugal pre-
parative TLC (heptane:ethyl acetate, 30:70) gave 2-pyridinone
(3R)-7-(Na p h th a len -1-ylm eth yl)-5-oxo-8-p h en yl-2,3-d i-
h ydr o-5H-th iazolo[3,2-a ]pyr idin e-3-car boxylic Acid Meth -
yl Ester (3a ). Dry HCl(g) was passed through a solution of
1c (501 mg, 2.13 mmol) and 2c (970 mg, 3.11 mmol) in 1,2-
dichloroethane (28 mL) during 15 min at 0 °C. The solution
was stirred for 11 h at 64 °C, then more 2c (480 mg, 1.53 mmol)
was added. The mixture was then stirred for another 2 h before
it was cooled to room temperature, diluted with CH2Cl2, and
washed with water, saturated aqueous NaHCO3, and brine.
The aqueous layers were extracted with CH2Cl2, and the
combined organic layers were dried (Na2SO4), filtered, and
concentrated. Purification by flash column chromatography
(heptane/ethyl acetate, 1:4) gave 2-pyridinone 3a as a white
foam (771 mg, 85% yield from ∆2-thiazoline 1c): [R]D -152°
(c 1.01, CHCl3); IR λ 3041, 2953, 1753, 1655, 1581, 1485, 793
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.82 (dd, J ) 7.2, 2.1 Hz,
1H), 7.73 (d, J ) 8.3 Hz, 1H), 7.62 (dd, J ) 7.2, 1.8 Hz, 1H),
7.45-7.34 (m, 8H), 7.21 (d, J ) 6.8 Hz, 1H), 5.82 (s, 1H) 5.60
(dd, J ) 8.5, 2.4 Hz, 1H), 3.89-4.06 (m, 2H), 3.80 (s, 3H), 3.65
(dd, J ) 11.8, 8.6 Hz, 1H), 3.45 (dd, J ) 11.8, 2.4 Hz, 1H); 13
C
(46) Pattenden, G.; Thom, S. M. J . Chem. Soc., Perkin Trans. 1 1993,
1629-1636.

Synthesis of Substituted Ring-Fused 2-Pyridinones
J . Org. Chem., Vol. 66, No. 20, 2001 6761
(()-3a as a white foam (54 mg, 32%): [R]D 0° (c 1.00, CHCl3),
NMR and IR data in agreement with 3a .
and the foundation for technology transfer in Umea˚ for
financial support.
Su p p or tin g In for m a tion Ava ila ble: 13C NMR spectra of
1a -c, 2c, and 3a -e. Chiral HPLC chromoatogram of 1a -c
and 3a -e. This material is available free of charge via the
Internet at http://pubs.acs.org.
Ack n ow led gm en t. We thank Professor Torbjo¨rn
Frejd and Ian Sarvary for help with the ee measure-
ments of the ∆2-thiazolines (Chiralcel OD-H). We are
grateful to the Swedish Natural Science Research
Council, the Knut and Alice Wallenberg Foundation,
J O015794U