Microwave-assisted decarboxylation of bicyclic 2-pyridone scaffolds and identification of Aβ-peptide aggregation inhibitors

Article abstract of DOI:10.1039/b503294f

A reagent-free microwave-assisted decarboxylation procedure for carboxylic acid functionalized bicyclic 2-pyridones has been developed. This new method, based on microwave heating at 220°C for 600 seconds in N-methyl pyrrolidone (NMP), proved to be practical and very efficient, resulting in decarboxylated 2-pyridones in near-quantitative yields. The decarboxylated products and the intermediate 2-pyridones in the form of carboxylic acid methyl esters and carboxylic acids were screened for their effect on Aβ-peptide aggregation. Two out of the 21 2-pyridones described in this study inhibited amyloid formation of the Alzheimer Aβ(1-40) peptide. The effect was seen even at a 4: 1 ratio of 2-pyridone and monomeric Aβ-peptide. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b503294f

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A R T I C L E
Microwave-assisted decarboxylation of bicyclic 2-pyridone scaffolds
and identification of Ab-peptide aggregation inhibitors†
a
a
a
a
b
˚
Veronica Aberg, Fredrik Norman, Erik Chorell, Andreas Westermark, Anders Olofsson,
A. Elisabeth Sauer-Erikssonb and Fredrik Almqvist*a
a Organic Chemistry, Department of Chemistry, Umea˚ University, SE-90187, Umea˚, Sweden.
E-mail: fredrik.almqvist@chem.umu.se
b Umea˚ Centre for Molecular Pathogenesis, Umea˚ University, SE-90187, Umea˚, Sweden
Received 7th March 2005, Accepted 3rd May 2005
First published as an Advance Article on the web 29th June 2005
A reagent-free microwave-assisted decarboxylation procedure for carboxylic acid functionalized bicyclic 2-pyridones
has been developed. This new method, based on microwave heating at 220 ◦C for 600 seconds in N-methyl
pyrrolidone (NMP), proved to be practical and very efficient, resulting in decarboxylated 2-pyridones in
near-quantitative yields. The decarboxylated products and the intermediate 2-pyridones in the form of carboxylic
acid methyl esters and carboxylic acids were screened for their effect on Ab-peptide aggregation. Two out of the 21
2-pyridones described in this study inhibited amyloid formation of the Alzheimer Ab(1–40) peptide. The effect was
seen even at a 4 : 1 ratio of 2-pyridone and monomeric Ab-peptide.
Introduction
Alzheimer’s disease (AD) has been correlated to self-assembly
of an endogenic 4 kDa peptide (39–43 residues) denoted Ab-
peptide. The pathological hallmark of AD includes formation
of extra-cellular plaques (amyloid) constituted by depositions of
the Ab-peptide within the brain of affected individuals. However,
the picture is complex and besides the final amyloid, several
other assemblies have been isolated and the toxic effect can
be correlated to both mature amyloid fibrils as well as soluble
diffusible oligomeric assemblies.1–7 Without question, inhibition
of Ab assembly is a major therapeutical challenge, for which an
increased understanding of the mechanism for plaque formation
at both the cellular and the molecular level is needed.
Interfering with protein–protein interactions can be a difficult
task,8–10 nevertheless, small molecules containing a 2-pyridone
core structure have been reported to have both an enhancing and
inhibitory effect on Ab-peptide aggregation (1 and 2, Fig. 1).
Their activity was elucidated by screening libraries of non-
peptidic synthetic molecules.11–13
The earlier reported tricyclic 2-pyridones were synthesized in
seven steps with substitution variations in two positions in the
2-pyridone ring (Fig. 1). The 2-pyridone ring formation step
gave a poor yield (<40%) which significantly contributed to a
low overall yield of ∼10%.11
We have previously developed several procedures, which
provide bicyclic 2-pyridones 3a and 3b in high yields.14–16 These
compounds show structural similarity to those reported to affect
fibril formation e.g. 1 and 2 (Fig. 1), and they also possess
a transformable functional group (R4 = CO2Me in 3a and
R4 = CO2H in 3b, Fig. 1) in a position that has not previously
been studied from a structure–activity relationship (SAR) point
of view. A new decarboxylation procedure, described in this
article, rendered bicyclic 2-pyridones 3c, which to a higher
extent resembles 2-pyridones 1 and 2 (Fig. 1). Besides the
possible biological application of the compounds 3a–c, we
were also encouraged by the novelty of the decarboxylation
reaction. Decarboxylations of aromatic and activated carboxylic
acids, e.g. b-keto acids, are well described in the literature,
while only few examples on other systems have been reported.
Fig. 1 2-Pyridones with activity as both promoters (1: Ro 47–1816/
001) and inhibitors (2: Ro 65–8815/001) of Ab-peptide aggregation.12,13
These molecules show structural resemblance to the substituted 2-pyri-
dones 3a–c (R3 = H, R4 = CO2Me, CO2H, H) described in this paper.
Known methods with limited applicability are, for instance,
thermolysis of peresters,17–19 oxidative decarboxylation with lead
tetraacetate20 and decarboxylation of photolytically induced
acyloxy radicals.21 Two other more general examples that employ
preactivated carboxylic acids are the Barton decarboxylation
of N-carboxythiopyridones22 and the photolytic cleavage of N-
acyloxyphthalimides.23
Here we describe the development of a new efficient
microwave-assisted procedure for the decarboxylation of car-
boxylic acid functionalized 2-pyridones. In addition, the po-
tential of the generated bicyclic 2-pyridones, which include
† Electronic supplementary information (ESI) available: 13C NMR
spectra of 9b–f, 10b–f, and 12a–g. See http://www.rsc.org/suppdata/
ob/b5/b503294f/
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 1 7 – 2 8 2 3
2 8 1 7
©

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carboxylic acid methyl esters, carboxylic acids, and decarboxy-
lated derivatives, to function as inhibitors of Ab(1–40) self-
assembly was evaluated.
the starting material could not be circumvented by a prolonged
reaction time, since this led to decomposition.
Microwave-assisted synthesis has previously been success-
ful in both cyanation and aminomethylation reactions of 2-
pyridones.24 Beneficial use of the microwave technique for
decarboxylation reactions has also been reported25–28 and was
now applied for the decarboxylations of the 2-pyridones 11a–g
(Scheme 1). Thus, after some adjustment of the reaction condi-
tions, it was found that CuCN (10 eq.) in NMP and microwave
heating at 220 ◦C for 600 seconds solved the selectivity issue
and highly favored the saturated 2-pyridones 12a–g (≥36 : 1,
saturated : unsaturated, Scheme 1), as determined by NMR
spectroscopy. In addition, full conversion of the starting material
could be obtained, and a set of seven decarboxylated products
12a–g was isolated in high to excellent yields (Method B: 75–
98%, Scheme 1 and Table 1). The intermediate carboxylic acid
methyl esters 9a–g and their corresponding lithium carboxylates
10a–g were synthesized from D2-thiazolines 7a–g and acyl
Meldrum’s acid 8 according to published procedures (Scheme 1
and Experimental section).14–16
Results and discussion
Identification of a new 2-pyridone decarboxylation procedure
Decarboxylation was first observed under modified
Rosenmund–von Braun conditions, where refluxing a 6-bromo-
2-pyridone carboxylic acid overnight with CuCN in DMF
resulted in a mixture of cyanated and decarboxylated products.
Repeating the procedure with a non-halogenated starting
material 4 gave two decarboxylated products with different
oxidation levels (Fig. 2).
The use of CuCN, however, led to precipitation, and a tedious
and time-consuming work-up procedure, including lyophiliza-
tion, was needed to ensure good overall yields. Therefore, from
a practical point of view, the reaction was again tested without
the CuCN. Now, in contrast to the results with conventional
heating, the reaction proceeded smoothly using the microwave-
assisted method. This demonstrated that the reaction was
thermally induced when conducted with microwave heating in
sealed reaction vessels. Notably, in the absence of the copper
reagent, NMR spectroscopy showed an even greater selectivity.
Only traces of unsaturated product could be detected and the
conversion was so efficient and selective that no additional
purification of the decarboxylated products was needed except
for a washing step to remove the NMP solvent (Method A,
Scheme 1 and Table 1).
Fig. 2 Schematic picture of the initial decarboxylation reaction, which
provides a mixture of saturated and unsaturated products under reflux.
Both the tetrahydro- (5) and the dihydro-derivative (6) were
formed, and the unsaturated 2-pyridone could be isolated as the
major product in ∼30% yield (Fig. 2).
Improvement of reaction conditions
Decarboxylation was not observed in the absence of CuCN
under reflux, and efforts to increase the yield and selectivity by
varying the equivalents of CuCN, reaction time, concentrations
of reacting species, and solvent (DMF, NMP, DMSO) were not
fruitful. The selectivity was at best 1 : 10 (saturated : unsaturated)
and even the predominating species could vary between runs.
Moreover, the problem with low yields due to poor conversion of
By using the microwave technique it was possible to raise the
temperature from the solvent boiling point to 220 ◦C. The choice
of solvent was found to be crucial, as was the total volume used
Table 1 Syntheses of decarboxylated 2-pyridones
Entry
Substrate
R1
Product
Isolated yield (%)a
Isolated yield (%)b
97
1
2
3
4
5
6
7
11a
11b
11c
11d
11e
11f
11g
Ph–
12a
12b
12c
12d
12e
12f
12g
91
94
81
98
87
75
95
c
Ph–CH2–
4-F-Ph–
4-CF3-Ph–
3-CF3-Ph–
Me–
-
99
c
-
99
92
99
Cyclopropyl–
a Method B: CuCN, NMP, MW 220 ◦C, 600 s, purification by column chromatography. b Method A: NMP, MW 220 ◦C, 600 s, no column
chromatography needed. c Not included in the study with Method A.
Scheme 1 Reagents and conditions: 7a–g, 8, and 9a–g were prepared according to published procedures (see Experimental section) (i) HCl(g),
1,2-dichloroethane, MW 140 ◦C, 180 s gave 9a–g (67–99%); (ii) 0.1 M LiOH, THF–MeOH (1 : 4), rt gave 10a–g (85–98%); (iii) Amberlite IR-120
(H+), MeOH gave 11a–g (quant.); (iv) Method A: NMP, MW 220 ◦C, 600 s for 12a,c,e–g (92–99%) or (v) Method B: CuCN, NMP, MW 220 ◦C,
600 s gave 12a–g (75–98%).
2 8 1 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 1 7 – 2 8 2 3

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in the reaction vessel (see Experimental section). The reaction
could be performed in DMF or DMSO, although these did
not lead to full conversion of starting material (220 ◦C, 600 s).
More volatile solvents including toluene, THF, MeOH, MeCN,
acetic acid, water, and different solvent mixtures were also tested
using the new microwave procedure, but only to find NMP to be
the superior solvent. Except for DMF and DMSO, none of the
solvents tested reached the target temperature of 220 ◦C. The
decarboxylation could also be carried out with ionic liquid29 in
dioxane (220 ◦C, 600 s) but in this case unidentified byproducts
were formed, which were not observed with NMP as solvent.
9-carboxylic acid 14 was reported to decarboxylate in MeCN
using a Cu(I)-source, while diphenylacetic acid 16 was inert
under the same conditions (Fig. 4). The reaction is believed
to involve a catalytic cycle with a Cu(I)-stabilized anion
intermediate.30
Substituent effects
The R1 substituent has earlier been shown to have an impact
on the a-position in the 2-pyridone. For example, a greater loss
in enantiomeric excess through racemization of the a-position
was observed for 2-pyridone 9g (R1 = cyclopropyl) than for 2-
pyridone 9a (R1 = phenyl) when heated in 1,2-dichloroethane
under acidic conditions.16 We now wanted to study whether the
properties of the R1 substituent affected the decarboxylation,
since this reaction also involves the a-position. Thus, both aro-
matic substituents with different electronic properties (Table 1,
Entries 1 and 3–5) and aliphatic substituents (Table 1, Entries 2,
6, and 7) were included in position R1. The overall high yields
indicated that the reaction is more or less independent of the
R1 substituent. It is also worth mentioning that the carboxylic
acid 11c and its corresponding lithium carboxylate 10c gave
comparable yields.
Fig. 4 Fluorene 9-carboxylic acid 14 has previously been decarboxy-
lated using a Cu(I) source in MeCN, whereas diphenylacetic acid 16
was inert. Both of these acids were decarboxylated by using microwave
heating in NMP at 220 ◦C for 600 s.
Both of these acids easily underwent decarboxylation to
products 15 and 17, respectively, in high yields (>90%) using our
reagent-free microwave/NMP procedure (Fig. 4). These results
suggest that the method may have a broader applicability than
investigated in this work.
Tentative reaction mechanism
In total, seven carboxylic acid methyl esters 9a–g were
synthesized, hydrolyzed (10a–g and 11a–g) and subjected to
the new decarboxylation method rendering 2-pyridones 12a–g
(Scheme 1).
The derivatives 9a–g and 11a–g contain transformable func-
tional groups in R4 (CO2Me and CO2H) which are not present in
the corresponding position of the previously reported tricyclic
2-pyridones.12,13 These substituents are interesting from a SAR
point of view and, in addition, enable further derivatization.
Thus, the produced compounds 9a–g, 10a–g and 12a–g were
evaluated for their ability to obstruct Ab-peptide aggregation.
The thermally induced decarboxylation could proceed via the
formation of an ylide-stabilized anion intermediate. By perform-
ing the reaction in DMSO-d6 it could be concluded from NMR
spectroscopy that the solvent acts as a proton donor, resulting
in the deuterated decarboxylated product 13 (Fig. 3). This
finding opens up possibilities to react the intermediate anion
with an electrophile, leading to the formation of new interesting
derivatives,28 currently under investigation in our laboratories.
Method applicability
Decarboxylation was successful for both the carboxylic acids
and the lithium carboxylates. In addition, and in agreement with
the mechanistic proposal, neither the corresponding aldehyde
nor the methyl ester was affected by the decarboxylation
procedure.
The use of microwave heating in sealed reaction vessels had
an apparent impact on the decarboxylation reaction of the
2-pyridones. Interestingly, CuCN was only important when
carrying out the reaction in refluxing DMF, however it was
not necessary when using the microwave technique. Altogether,
out of the different procedures described herein, the reagent-free
microwave-assisted decarboxylation Method A proved to be the
most efficient and practical.
Biological significance
Aggregation of the monomeric Ab(1–40) peptide may readily
be observed upon incubation in PBS with slow agitation at
37 ◦C. After 48 hours of incubation, visualization using atomic
force microscopy (AFM) showed that the samples contained
fibrillar structures similar to the ones found in vivo (see
Experimental section and Fig. 5).
The method employed for initiation and following of Ab-
aggregation is highly reproducible and provides a rapid method
to study the effects of added substances. In titration series, where
only the substance of investigation was varied, a concentration-
dependent effect could be monitored. From the initial screening
of the 21 synthesized substances neither the decarboxylated
The method was also applied to two structurally different
carboxylic acids, previously described in the literature. Fluorene
Fig. 3 Thermally induced decarboxylation could proceed via an anion/ylide intermediate that is protonated by the solvent.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 1 7 – 2 8 2 3
2 8 1 9

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for interference of Ab-peptide aggregation. Two carboxylic
acid functionalized 2-pyridones exhibited amyloid inhibitory
activities even at a 4 : 1 ratio of 2-pyridone and monomeric
Ab-peptide. These findings encourage further design and SAR
studies of ring-fused 2-pyridones as inhibitors of Ab-peptide
fibrilization.
Experimental
General synthesis
All reactions were carried out under an inert atmosphere
with dry solvents under anhydrous conditions, unless otherwise
stated. CH2Cl2 and DMF were passed through a column of
Fig. 5 Atomic force microscopy image of Ab(1–40) at 50 lM con-
centration. The sample was incubated in PBS containing 4% DMSO at
37 ◦C for 48 h with slow agitation (130 rpm). Prior to analysis, an aliquot
was withdrawn and diluted 100-fold in double distilled H2O followed by
application to freshly cleaved mica.
˚
Al2O3 and DMF was stored over 3 A molecular sieves. 1,2-
Dichloroethane and TEA were freshly distilled before use. EtOH
˚
was dried over 3 A molecular sieves. HCl(g) was passed through
concentrated H2SO4 prior to use. NMP was not dried before use.
All microwave reactions were carried out in a monomode
reactor (Smith Synthesizer, Biotage AB) using Smith Process
VialsTM sealed with Teflon septa and an aluminum crimp top.
Yield-determining decarboxylation reactions described in the
experimental procedure were carried out in process vials with a
filling volume of 0.5–2.0 ml and with a solvent volume of 1.5 ml.
TLC was performed on Silica Gel 60 F254 (Merck) using UV
light detection. Flash column chromatography (eluents given in
derivatives 12a–g nor the carboxylic acid methyl esters 9a–
g showed any inhibitory effect. Based on earlier results12,13
we expected primarily the decarboxylated products to exhibit
inhibitory activities. It was therefore interesting to find that two
lithium carboxylates 10a and 10e showed clear inhibitory effects.
The corresponding carboxylic acid 11a was also tested, with
comparable results to the lithium carboxylate 10a.
These findings open up new possibilities for future design
and SAR studies. However, at this point we do not know if
the bicyclic 2-pyridones tested in this study and the structurally
related tricyclic compounds12,13 have the same mechanism of
action.
The level of aggregation of the incubated peptides was judged
by polyacrylamide electrophoresis. The results from Ab(1–40)
incubation in the presence of 10a and 10e, respectively, are shown
in Fig. 6.
The current method is qualitative and therefore inhibition
constants cannot be achieved with high accuracy within this
study. A rough estimate, however, suggests a 50% inhibitory
concentration (IC50) of approximately 200 lM for 10e and
800 lM for 10a. Importantly, the estimated IC50 value for 10e
was obtained with only a four-fold excess of 2-pyridone over the
monomeric peptide.
˚
brackets) employed normal phase silica gel (Matrex, 60 A, 35–
70 lm, Grace Amicon). Ion exchange resin (Amberlite IR-120,
H+-form, 20–50 mesh) was washed with MeOH prior to use.
1
The H and 13C NMR spectra were recorded at 298 K with a
Bruker DRX-400 spectrometer in CDCl3 [residual CHCl3 (dH
7.26 ppm) or CDCl3 (dC 77.0 ppm) as internal standard] or
MeOH-d4 [residual CD2HOD (dH 3.30 ppm) or CD3OD (dC
49.0 ppm) as internal standard]. In some cases spectral data
of rotameric mixtures are reported and it should also be noted
that the presence of fluorine substituents leads to reduced peak
intensities. IR spectra were recorded on an ATI Mattson Genesis
Series FTIRTM spectrometer. Optical rotations were measured
with a Perkin–Elmer 343 polarimeter at 20 ◦C.
Assay for evaluation of 2-pyridone effects on Ab(1–40)
oligomerization
Ab(1–40) peptides were obtained from Anaspec (San Jose,
California). The lyophilized peptides could be readily dis-
solved into a monomeric solution using ddH2O containing
30% dimethylsulfoxide (DMSO). The dissolved peptide was
further centrifuged at 20 000g for 30 min to remove potentially
remaining aggregates, followed by freezing in aliquots at −20 ◦C
at a peptide concentration corresponding to 500 lM. This
treatment efficiently conserves the peptide in a monomeric
state and from here fibril formation may be induced in a
highly reproducible manner via a 10× dilution of the stock
solution in PBS (20 mM phosphate buffer pH 7.4 containing
150 mM NaCl) followed by incubation at 37 ◦C with slow
Conclusion
A practical and efficient microwave-assisted decarboxyla-
tion procedure for bicyclic carboxylic acid functionalized 2-
pyridones has been described. This reagent-free method is
fast and convenient and provides decarboxylated 2-pyridones
in near-quantitative yields. It also shows potential use for
decarboxylations of other systems.
The method was used to produce a small set of decarboxylated
2-pyridones, which together with the intermediate carboxylic
acid methyl esters and lithium carboxylates, were screened
Fig. 6 PAGE analysis of Ab(1–40) after incubation at 37 ◦C for 48 h with slow agitation in the presence of various concentrations of 2-pyridone
10a (A) or 10e (B): Lane 1, 0 lM; Lane 2, 200 lM; Lane 3, 400 lM; Lane 4, 600 lM; Lane 5, 800 lM; Lane 6, 1 mM.
2 8 2 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 1 7 – 2 8 2 3

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agitation (130 rpm). Screening for the effects of the substances
upon Ab-oligomerization was performed by addition of the
desired compound (dissolved in 100% DMSO) into the PBS
solution prior to addition of the monomeric Ab(1–40) peptide.
In this investigation the peptide oligomeric propensities were
analyzed at a final DMSO concentration corresponding to
4.0%. Analysis of the aggregation status was performed using
20% tricine polyacrylamide electrophoresis (PAGE) (Amersham
Biosciences, Uppsala, Sweden) according to the manufacturer’s
instructions. Samples were either separated at non-denaturing
conditions or in presence of 0.1% sodium dodecyl sulfate (SDS).
None of the samples were boiled. All gels were stained using
Coomassie brilliant blue staining (Bio-Rad, California).
Compounds 9a–g
These were prepared from 7a–g and 8 according to the published
procedure. Data in agreement with published data for 9a and
9g.14,16
(3R)-8-Benzyl-7-naphthalen-1-ylmethyl-5-oxo-2,3-dihydro-
5H-thiazolo[3,2-a]pyridine-3-carboxylic acid methyl ester (9b).
From 7b (1.1 g, 4.4 mmol) and 8 (4.5 g, 14.4 mmol) was
prepared 9b (1.3 g, 67%): [a]2D0 −10.0 (c 1.0, CHCl3); IR k 3052,
3004, 2954, 1752, 1655, 1580, 1499, 1434, 1213 cm−1; 1H NMR
(400 MHz, CDCl3) d 7.83 (d, J = 8.18 Hz, 1H), 7.75 (d, J =
8.22 Hz, 1H), 7.52–7.10 (m, 10H), 6.13 (s, 1H), 5.65 (dd, J =
8.33, 1.83 Hz, 1H), 4.14–3.96 (m, 2H), 3.91–3.69 (m, 6H), 3.57
(dd, J = 11.71, 1.83 Hz, 1H); 13C NMR (100 MHz, CDCl3) d
168.4, 161, 3, 155.0, 146.1, 138.1, 133.8, 133.1, 131.7, 128.7,
128.6, 127.8, 127.7, 127.4, 126.7, 126.0, 125.6, 125.4, 123.5,
116.1, 111.9, 63.3, 53.2, 36.3, 35.7, 31.7. HRMS (FAB) calcd.
for [M + H]+ C27H24NO3S 442.1477, obsd. 442.1465.
Atomic force microscopy (AFM)
Prior to analysis, the aggregated Ab(1–40) was diluted to 5 lM
with distilled water and applied onto freshly cleaved ruby red
mica (Goodfellow, Cambridge, UK). Samples were allowed to
adsorb for 30 s, washed three times with distilled water, and air
dried. The bound material was imaged with a Nanoscope IIIa
multimode AFM (Digital Instruments Santa Barbara, USA)
using Tapping ModeTM in air. A silicon probe was oscillated
at 280–300 kHz, and images were collected at an optimized
scan rate corresponding to 1 Hz. The image was flattened and
presented in height mode using Nanoscope software (Digital
Instruments).
(3R)-8-(4-Fluorophenyl)-7-naphthalen-1-ylmethyl-5-oxo-2,3-
dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic acid methyl
ester (9c). From 7c (1.1 g, 4.4 mmol) and 8 (4.5 g, 14.4 mmol)
was prepared 9c (1.6 g, 83%): [a]2D0 −8.8 (c 1.0, CHCl3); IR k
3044, 3006, 2955, 2850, 1753, 1655, 1602, 1580, 1490, 1435, 1220,
1
1156 cm−1; H NMR (400 MHz, CDCl3) d 7.81 (m, 1H), 7.73
(d, J = 8.24 Hz, 1H), 7.61 (m, 1H), 7.46–7.23 (m, 5H), 7.19 (d,
J = 6.77 Hz, 1H), 7.11–7.03 (m, 2H), 5.86 (s, 1H), 5.59 (dd, J =
8.58, 2.40 Hz, 1H), 4.03–3.85 (m, 2H), 3.78 (s, 3H), 3.61 (dd, J =
11.80, 8.59 Hz, 1H), 3.42 (dd, J = 11.80, 2.41 Hz, 1H); 13C
NMR (100 MHz, CDCl3) d 168.2 (broad), 162.4 (d, J = 248.13
Hz), 161.0, 154.1, 146.8, 133.7, 133.4, 132.0 (d, J = 3.40 Hz),
131.9 (d, J = 8.10 Hz), 131.5, 131.4 (d, J = 8.08 Hz), 128.6,
127.6, 127.5, 126.0, 125.5, 125.2, 123.4, 115.9 (d, J = 21.74 Hz),
115.8, 115.1, 114.7, 63.3, 53.1, 36.3, 31.4. HRMS (FAB) calcd.
for [M + H]+ C26H21FNO3S 446.1226, obsd. 446.1225.
Thiazolines 7a–g were prepared according to published
procedures
Data in agreement with published data for 7a,f,g.14,16
(4R)-2-Phenylethyl-4,5-dihydrothiazole-4-carboxylic acid
methyl ester (7b). 1H NMR (400 MHz, CDCl3) d 7.31–7.24
(m, 2H), 7.23–7.15 (m, 3H), 5.09–5.02 (m, 1H), 3.79 (s, 3H),
3.62–3.45 (m, 2H), 3.02–2.95 (m, 2H), 2.89–2.81 (m, 2H).
(3R)-7-Naphthalen-1-ylmethyl-5-oxo-8-(4-(trifluoromethyl)-
phenyl)-2,3-dihydro-5H -thiazolo[3,2-a]pyridine-3-carboxylic
acid methyl ester (9d). From 7d (303 mg, 3.3 mmol). and 8
(1.0 g, 3.3 mmol) was prepared 9d (327 mg, 75%): [a]2D0 −38.6
(c 0.4, CHCl3); IR k 3065, 3008, 2957, 1752, 1656, 1583, 1490,
(4R)-2-(4-Fluorobenzyl)-4,5-dihydrothiazole-4-carboxylic acid
methyl ester (7c). 1H NMR (400 MHz, CDCl3) d 7.28–7.20 (m,
2H), 7.03–6.95 (m, 2H), 5.13–5.05 (m, 1H), 3.88–3.82 (m, 2H),
3.81 (s, 3H), 3.60–3.44 (m, 2H).
1
1324, 1214, 1164, 1124 cm−1; H NMR (400 MHz, CDCl3) d
(4R)-2-(4-(Trifluoromethyl)benzyl)-4,5-dihydrothiazole-4-
carboxylic acid methyl ester (7d). 1H NMR (400 MHz, CDCl3)
d 7.58 (d, J = 8.14 Hz, 2H), 7.42 (d, J = 8.14 Hz, 2H), 5.16–5.08
(m, 1H), 3.96–3.91 (m, 2H), 3.82 (s, 3H), 3.64–3.47 (m, 2H).
7.82 (m, 1H), 7.74 (d, J = 8.23 Hz, 1H), 7.67–7.55 (m, 3H),
7.47–7.32 (m, 5H), 7.19 (d, J = 6.95 Hz, 1H), 5.91 (s, 1H), 5.63
(dd, J = 8.51, 2.29 Hz, 1H), 4.03–3.88 (m, 2H), 3.82 (s, 3H),
3.68 (dd, J = 11.76, 8.51 Hz, 1H), 3.48 (dd, J = 11.76, 2.29 Hz,
1H); 13C NMR (100 MHz, CDCl3) d 168.3, 161.1, 153.8, 146.8,
140.0 (broad and split, J = 1.35 Hz, 2C), 133.9, 133.3, 131.6,
130.6, 130.5 (q, J = 32.34 Hz, 2C), 128.8, 127.82, 127.79, 126.2,
125.91 (broad and split, J = 3.71 Hz, 2C), 125.7, 125.4, 123.9
(q, J = 272.16 Hz), 115.8, 114.7, 63.5, 53.3, 36.8, 31.8. HRMS
(FAB) calcd. for [M + H]+ C27H21F3NO3S 496.1194, obsd.
496.1197.
(4R)-2-(3-(Trifluoromethyl)benzyl)-4,5-dihydrothiazole-4-
carboxylic acid methyl ester (7e). 1H NMR (400 MHz, CDCl3)
d 7.58–7.38 (m, 4H), 5.16–5.08 (m, 1H), 3.95–3.89 (m, 2H), 3.80
(s, 3H), 3.63–3.46 (m, 2H).
5-(1-Hydroxy-2-naphthalen-1-ylethylidene)-2,2-
dimethyl[1,3]dioxane-4,6-dione (8)
Meldrum’s acid derivative 8 was prepared as described below
according to a slightly modified published procedure.31 DCC
was dissolved in 100 ml dry CH2Cl2 and stirred for 30 min
at 0 ◦C. Then naphthalen-1-yl-acetic acid (11.7 g, 63 mmol),
Meldrum’s acid (10.0 g, 69 mmol), and DMAP (12.3 g, 101
mmol) was dissolved in 450 ml CH2Cl2 and stirred at −10 ◦C for
45 min. To this solution was added the DCC solution dropwise
over 1.5 h. Thereafter, the solution was allowed to reach room
temperature overnight. KHSO4 (6% aqueous) was added and
the resulting precipitate was filtered off, The filtrate was then
washed 4 times with KHSO4 (6% aqueous) and 2 times with
brine. The combined aqueous phases were re-extracted with
CH2Cl2 and the combined organic phases were dried, filtered
and concentrated. This gave 8 as a pale yellow solid (19.4 g,
99%). Data in agreement with published data.14
(3R)-7-Naphthalen-1-ylmethyl-5-oxo-8-(3-(trifluoromethyl)-
phenyl)-2,3-dihydro-5H -thiazolo[3,2-a]pyridine-3-carboxylic
acid methyl ester (9e). From 7e (1.3 g, 4.4 mmol) and 8 (4.5 g,
14.4 mmol) was prepared 9e (2.1 g, 96%): [a]2D0 −26.0 (c 1.0,
CHCl3); IR k 3044, 3007, 2957, 1752, 1657, 1580, 1485, 1438,
1
1333, 1215, 1165, 1125 cm−1; H NMR (400 MHz, CDCl3) d
7.81 (m, 1H), 7.73 (d, J = 8.22 Hz, 1H), 7.63–7.53 (m, 3H),
7.51–7.32 (m, 5H), 7.18 (m, 1H), 5.94 (bs, 1H), 5.63 (dd, J =
8.53, 2.23 Hz, 1H), 4.05–3.87 (m, 2H), 3.82 (s, 3H), 3.67 (m, 1H),
3.47 (m, 1H); 13C NMR (100 MHz, CDCl3) d 168.3, 161.1, 153.8,
147.0, 137.0, 133.8, 133.7, 133.24, 133.21, 131.5, 129.4, 128.7,
127.8, 127.7, 126.9, 126.1, 125.6, 125.3, 125.1, 123.7 (q, J =
272.84 Hz), 123.4, 115.7, 114.5, 63.5, 53.3, 36.7, 31.7. HRMS
(FAB) calcd. for [M + H]+ C27H21F3NO3S 496.1194, obsd.
496.1192.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 1 7 – 2 8 2 3
2 8 2 1

View Online
(3R)-8-Methyl-7-naphthalen-1-ylmethyl-5-oxo-2,3-dihydro-
5H-thiazolo[3,2-a]pyridine-3-carboxylic acid methyl ester (9f).
From 7f (762 mg, 4.4 mmol) and 8 (4.5 g, 14.4 mmol) was
prepared 9f (1.6 g, 99%): [a]2D0 −13.7 (c 1.0, CHCl3); IR k
3004, 2955, 1752, 1655, 1580, 1502, 1436, 1214 cm−1; 1H NMR
(400 MHz, CDCl3) d 7.87 (m, 1H), 7.84 (m, 2H), 7.51–7.43 (m,
2H), 7.40 (m, 1H), 7.21 (d, J = 6.86 Hz, 1H), 5.82 (s, 1H), 5.60
(dd, J = 8.42, 1.92 Hz, 1H), 4.25–4.09 (m, 2H), 3.79 (s, 3H),
3.69 (dd, J = 11.71, 8.42 Hz, 1H), 3.53 (dd, J = 11.71, 1.92 Hz,
1H), 2.04 (s, 3H); 13C NMR (100 MHz, CDCl3) d 168.5, 161.2,
154.5, 144.2, 133.8, 133.2, 131.7, 128.8, 127.6, 127.0, 126.2,
125.7, 125.5, 123.5, 115.7, 109.0, 63.2, 53.1, 36.2, 31.8, 15.7.
HRMS (FAB) calcd. for [M + H]+ C21H20NO3S 366.1164, obsd.
366.1159.
NMR (400 MHz, MeOH) d 7.80 (m, 1H), 7.72 (d, J = 8.23 Hz,
1H), 7.69–7.62 (m, 2H), 7.61–7.48 (m 3H), 7.44–7.31 (m, 3H),
7.23 (m, 1H), 5.88 (split, 1H), 5.44 (dd, J = 8.69, 1.19 Hz,
1H), 4.09–3.93 (m, 2H), 3.81–3.68 (m, 1H), 3.54 (dd, J =
11.43, 1.46 Hz, 1H); 13C NMR (100 MHz, MeOH) d 173.9,
163.7, 155.5, 150.9, 138.9, 135.50 (and rotamer at 134.97),
135.3, 135.2, 133.0, 132.1 (q, J = 33.01 Hz), 130.7, 129.7, 128.7
(broad), 128.6, 128.48 (and rotamer at 127.95), 127.1, 126.7,
126.4, 125.9 (q, J = 3.37 Hz), 124.6 (q, J = 3.37 Hz), 125.4 (q,
J = 271.8 Hz), 116.6, 115.3 (broad), 68.0, 37.4, 34.2.
Lithium (3R)-8-methyl-7-naphthalen-1-ylmethyl-5-oxo-2,3-
dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylate (10f). [a]D20
1
−10.9 (c 1.0, MeOH); IR k 3408, 1640, 1501, 1390 cm−1; H
NMR (400 MHz, MeOH) d 7.88 (m, 2H), 7.79 (d, J = 8.23 Hz,
1H), 7.51–7.38 (m, 3H), 7.28 (d, J = 6.95 Hz, 1H), 5.67 (s, 1H),
5.38 (dd, J = 8.51, 1.37 Hz, 1H), 4.32–4.21 (m, 2H), 3.77 (dd, J =
11.51, 8.51 Hz, 1H), 3.63 (dd, J = 11.51, 1.37 Hz, 1H), 2.07 (s,
2H); 13C NMR (100 MHz, MeOH) d 173.9, 163.7, 156.5, 148.2,
135.4, 135.2, 133.3, 129.8, 128.6, 128.3, 127.3, 126.8, 126.6,
124.9, 115.2, 111.3, 67.9, 37.0, 34.2, 15.7.
General procedure (slightly modified from the published
procedure15) for the preparation of lithium carboxylates
10a–g from 9a–g
9 (1.6 mmol) was dissolved in THF–MeOH (1 : 4, 56 ml), and
0.1 M aqueous LiOH (1.6 mmol) was added dropwise to the
stirred solution at rt. After stirring overnight, the solution was
concentrated and lyophilized from acetonitrile–water (2 : 3),
giving 10. Data in agreement with published data for 10a and
10g.15
Lithium (3R)-8-cyclopropyl-7-naphthalen-1-ylmethyl-5-oxo-
2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylate (10g).
Data in agreement with published data.15
Lithium
(3R)-7-naphthalen-1-ylmethyl-5-oxo-8-phenyl-2,3-
General procedure for the preparation of 11a–g from 10a–g
dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylate (10a). Data
in agreement with published data.15
10 was dissolved in MeOH or in THF–MeOH. Amberlite IR-120
was added with swirling until the solution reached pH ∼4; the
solid support was then filtered off. The filtrate was concentrated
and the residue was lyophilized from acetonitrile–water (2 : 3)
giving 11.
Lithium
(3R)-8-benzyl-7-naphthalen-1-ylmethyl-5-oxo-2,3-
dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylate (10b). [a]D20
−6.6 (c 1.0, MeOH); IR k 3431, 1640, 1499 cm−1; as a major
rotamer; 1H NMR (400 MHz, MeOH) d 7.81 (d, J = 8.17 Hz,
1H), 7.74 (d, J = 8.24 Hz, 1H), 7.49–7.10 (m, 10H), 5.56 (s,
1H), 5.42 (dd, J = 8.36, 1.31 Hz, 1H), 4.15–4.02 (m, 2H),
3.97–3.71 (m, 3H), 3.66 (dd, J = 11.33, 1.31 Hz, 1H); 13C NMR
(100 MHz, MeOH) d 173.8, 163.8, 156.8, 150.0, 139.8, 135.3,
134.9, 133.1, 129.7, 129.6, 129.2, 128.7, 128.7, 127.6, 127.1,
126.7, 126.5, 124.9, 115.5, 114.2, 68.0, 37.2, 36.6, 34.1.
General procedure for the preparation of 12a–g from 11a–g
Method A. 0.36 mmol of 11 was dissolved in 1.5 ml NMP. The
reaction vessel was sealed and the reaction mixture was heated by
microwave irradiation at 220 ◦C for 600 s with a fixed hold time.
After cooling, EtOAc was added and the solvent was removed by
washing with water. The combined organic phases were dried,
filtered and concentrated, giving 12.
Method B. 0.36 mmol of 11 was dissolved in 1.5 ml NMP,
and 3.6 mmol CuCN was added to the stirred solution at rt. The
reaction vessel was sealed and the reaction mixture was heated by
microwave irradiation at 220 ◦C for 600 s with a fixed hold time.
After cooling, the solvent was removed by lyophilization from
water and the residue was carefully suspended in CH2Cl2 and
the product thoroughly extracted. Filtering and concentration
was followed by purification by flash column chromatography
(heptane–EtOAc–MeOH 1 : 9 : 1) giving 12.
Lithium (3R)-8-(4-fluorophenyl)-7-naphthalen-1-ylmethyl-5-
oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylate (10c).
[a]2D0 −4.3 (c 1.0, CHCl3); IR k 3435, 3154, 3044, 1634, 1489,
1401 cm−1; H NMR (400 MHz, MeOH) d 7.82 (m, 1H), 7.74
1
(d, J = 8.19 Hz, 1H), 7.67 (m, 1H), 7.47–7.30 (m, 5H), 7.19 (d,
J = 6.95 Hz, 1H), 7.16–7.03 (m, 2H), 5.76 (s, 1H), 5.41 (dd, J =
8.57, 1.37 Hz, 1H), 4.10–3.89 (m, 2H), 3.72 (dd, J = 11.35,
8.57 Hz, 1H), 3.53 (dd, J = 11.40, 1.37 Hz, 1H); 13C NMR
(100 MHz, MeOH) d 173.9 (broad), 164.0 (d, J = 246.45 Hz),
163.8, 155.9, 150.7 (d, J = 1.35 Hz), 135.4, 135.3, 134.1 (d, J =
3.37 Hz), 133.7 (d, J = 8.15 Hz), 133.2 (d, J = 8.23 Hz), 133.1,
129.7, 128.9, 128.6, 127.2, 126.7, 126.5, 124.9, 117.1, 116.74 (d,
J = 21.86 Hz), 116.68 (d, J = 21.65 Hz), 114.9, 68.1, 37.5, 34.1.
Lithium (3R)-7-naphthalen-1-ylmethyl-5-oxo-8-(4-trifluoro-
methylphenyl)-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxy-
late (10d). [a]2D0 −22.9 (c 0.3, MeOH); IR k 3394, 1638, 1491,
1401, 1328, 1126 cm−1;1H NMR (400 MHz, MeOH) d 7.81 (m,
1H), 7.74 (d, J = 8.20 Hz, 1H), 7.70–7.58 (m, 3H), 7.57–7.46
(m, 2H), 7.44–7.33 (m, 3H), 7.25 (d, J = 6.97 Hz, 1H), 5.83
(s, 1H), 5.43 (dd, J = 8.78, 1.19 Hz, 1H), 4.10–3.96 (m, 2H),
3.75 (dd, J = 11.53, 8.70 Hz, 1H), 3.54 (dd, J = 11.53, 1.19 Hz,
1H); 13C NMR (100 MHz, MeOH) d 173.8, 163.8, 155.4, 150.6,
142.1 (q, J = 1.35 Hz, 2C), 135.31, 135.28, 133.1, 132.5, 132.0,
131.2 (q, J = 32.34 Hz, 2C), 129.7, 128.9, 128.6, 127.2, 126.7
(broad and split, 2C), 126.5, 125.5 (q, J = 271.49 Hz), 124.8,
116.7, 115.3, 68.0, 37.4, 34.3.
7-Naphthalen-1-ylmethyl-8-phenyl-2,3-dihydrothiazolo[3,2-a]-
pyridin-5-one (12a). Method A. 11a (150 mg, 0.36 mmol) gave
12a as a foam (130 mg, 97%): IR k 3056, 2990, 2957, 1647, 1575,
1488, 1441 cm−1; 1H NMR (400 MHz, CDCl3) d 7.81 (m, 1H),
7.73 (d, J = 8.23 Hz, 1H), 7.61 (m, 1H), 7.47–7.30 (m, 8H),
7.20 (d, J = 6.95 Hz, 1H), 5.81 (s, 1H), 4.50 (m, 2H), 3.96 (s,
2H), 3.26 (m, 2H); 13C NMR (100 MHz, CDCl3) d 161.4, 153.5,
147.1, 136.5, 133.8, 133.7, 131.5, 129.8, 128.9, 128.6, 128.2,
127.8, 127.5, 125.9, 125.5, 125.3, 123.7, 115.8, 114.6, 51.2, 36.7,
28.1. HRMS (FAB) calcd. for [M + H]+ C24H20NOS 366.1266,
obsd. 366.1261.
8-Benzyl-7-naphthalen-1-ylmethyl-2,3-dihydrothiazolo[3,2-a]-
pyridin-5-one (12b). Method B. 11b (155 mg, 0.36 mmol) gave
12b as a foam (130 mg, 94%): IR k 2926, 2853, 1649, 1572, 1498,
1453 cm−1; 1H NMR (400 MHz, CDCl3) d 7.83 (d, J = 8.13 Hz,
1H), 7.75 (d, 8.18 Hz, 1H), 7.51–7.10 (m, 10H), 5.76 (s, 1H),
4.51 (m, 2H), 4.06 (s, 2H), 3.86 (s, 2H), 3.36 (m, 2H); 13C NMR
(100 MHz, CDCl3) d 161.4, 154.1, 146.8, 138.4, 133.7, 133.3,
131.6, 128.58, 128.55, 127.8, 127.6, 127.3, 126.6, 126.0, 125.5
Lithium (3R)-7-naphthalen-1-ylmethyl-5-oxo-8-(3-(trifluoro-
methyl)phenyl)-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxy-
late (10e). [a]2D0 −13.1 (c 1.0, CHCl3); IR k 3365, 3083, 2946,
1629, 1560, 1489, 1334, 1125 cm−1; as a mixture of rotamers; 1H
2 8 2 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 1 7 – 2 8 2 3

View Online
125.3, 123.5, 115.7, 111.7, 51.2, 36.3, 35.6, 28.2. HRMS (FAB)
128.8, 127.6, 127.5, 126.1, 125.6, 125.5, 123.8, 115.1, 113.4,
calcd. for [M + H]+ C25H22NOS 384.1422, obsd. 384.1419.
50.6, 36.1, 28.2, 11.1, 7.67 (2C). HRMS (FAB) calcd. for [M +
H]+ C21H20NOS 334.1266, obsd. 334.1272.
8-(4-Fluorophenyl)-7-naphthalen-1-ylmethyl-2,3-dihydrothi-
azolo[3,2-a]pyridin-5-one (12c). Method A. 11c (157 mg, 0.36
mmol) gave 12c as a foam (140 mg, 99%): IR k 3046, 2988, 2957,
1648, 1489, 1223 cm−1; 1H NMR (400 MHz, CDCl3) d 7.82 (m,
1H), 7.73 (d, J = 8.25 Hz, 1H), 7.59 (m, 1H), 7.46–7.22 (m,
5H), 7.18 (d, J = 6.96 Hz, 1H), 7.13–7.04 (m, 2H), 5.84 (s, 1H),
4.52 (m, 2H), 3.94 (s, 2H), 3.31 (m, 2H); 13C NMR (100 MHz,
CDCl3) d 162.50 (d, J = 123.99 Hz), 161.4, 153.4, 147.5, 133.8,
133.7, 132.4 (d, J = 3.42 Hz), 131.7 (d, J = 8.08 Hz, 2C), 131.6,
128.7, 127.64, 127.58, 126.0, 125.5, 125.3, 123.6, 115.9 (d, J =
21.56 Hz, 2C), 114.9, 114.7, 51.3, 36.6, 28.1. HRMS (FAB)
calcd. for [M + H]+ C24H19FNOS 388.1171, obsd. 388.1173.
Acknowledgements
We thank Dr Anna Linusson at Umea˚ University for helpful
discussions. We are also grateful to the Swedish Natural Science
Research Council, the Knut and Alice Wallenberg Foundation,
Socialstyrelsen, the Medical faculty of Umea˚ University, the
Magnus Bergvalls Foundation, Hja¨rnfonden and Insamlingstif-
telsen for financial support.
References
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24, 219.
2 J. P. Cleary, D. M. Walsh, J. J. Hofmeister, G. M. Shankar, M. A.
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3 D. M. Walsh, I. Klyubin, J. V. Fadeeva, M. J. Rowan and D. J. Selkoe,
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7-Naphthalen-1-ylmethyl-8-(4-(trifluoromethyl)phenyl)-2,3-
dihydrothiazolo[3,2-a]pyridin-5-one (12d). Method B. 11d
(175 mg, 0.36 mmol) gave 12d as a foam (155 mg, 98%): IR k
1
3047, 3000, 2929, 1651, 1580, 1491, 1324, 1164, 1123 cm−1; H
NMR (400 MHz, CDCl3) d 7.81 (m, 1H), 7.73 (d, J = 8.23 Hz,
1H), 7.68 (d, J = 8.13 Hz, 2H), 7.56 (d, J = 8.19 Hz, 1H),
7.46–7.31 (m, 5H), 7.17 (d, J = 6.95 Hz, 1H), 5.90 (s, 1H),
4.53 (m, 2H), 3.94 (s, 2H), 3.32 (m, 2H); 13C NMR (100 MHz,
CDCl3) d 161.4, 153.0, 147.4. 140.3 (q, J = 1.35 Hz, 2C), 133.8,
133.5, 131.6, 130.5, 130.3 (q, J = 32.34 Hz), 128.7, 127.7 (2C),
126.1, 125.9 (q, J = 3.71 Hz, 2C), 125.6, 125.3, 123.9 (q, J =
272.17 Hz), 123.5, 115.3, 114.4, 51.4, 36.7, 28.3. HRMS (FAB)
calcd. for [M + H]+ C25H19F3NOS 438.1139, obsd. 438.1136.
4 A. Lorenzo and B. A. Yankner, Proc. Natl. Acad. Sci. USA, 1994,
91, 12243.
5 C. J. Pike, A. J. Walencewicz, C. G. Glabe and C. W. Cotman, Brain
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12 P. Kuner, B. Bohrmann, L. O. Tjernberg, J. Naslund, G. Huber, S.
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377.
7-Naphthalen-1-ylmethyl-8-(3-(trifluoromethyl)phenyl)-2,3-
dihydrothiazolo[3,2-a]pyridin-5-one (12e). Method A. 11e
(175 mg, 0.36 mmol) gave 12e as a foam (158 mg, 99%): IR k
1
3061, 3002, 1652, 1578, 1487, 1439, 1334, 1165, 1124 cm−1; H
NMR (400 MHz, CDCl3) d 7.80 (m, 1H), 7.72 (d, J = 8.22 Hz,
1H), 7.62–7.29 (m, 8H), 7.16 (m, 1H), 5.90 (s, 1H), 4.50 (m,
2H), 4.00–3.85 (m, 2H), 3.28 (m, 2H); 13C NMR (100 MHz,
CDCl3) d 161.3, 153.0, 147.7, 137.2, 133.7, 133.4, 133.3 (q, J =
1.35 Hz), 131.4, 131.1 (q, J = 32.42 Hz), 129.4, 128.6, 127.6
(2C), 126.8 (q, J = 3.73 Hz), 126.0, 125.5, 125.2, 124.9 (q, J =
3.73 Hz), 123.7 (q, J = 272.50 Hz), 123.4, 115.1, 114.2, 51.3,
36.6, 28.2. HRMS (FAB) calcd. for [M + H]+ C25H19F3NOS
438.1139, obsd. 438.1144.
14 H. Emtenas, L. Alderin and F. Almqvist, J. Org. Chem., 2001, 66,
6756.
15 H. Emtenas, K. Ahlin, J. S. Pinkner, S. J. Hultgren and F. Almqvist,
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62, 2210.
8-Methyl-7-naphthalen-1-ylmethyl-2,3-dihydrothiazolo[3,2-a]-
pyridin-5-one (12f). Method A. 11f (128 mg, 0.36 mmol) gave
12f as a foam (103 mg, 92%): IR k 3044, 2920, 1649, 1571,
1501 cm−1; 1H NMR (400 MHz, CDCl3) d 7.88 (m, 1H),
7.84–7.74 (m, 2H), 7.51–7.44 (m, 2H), 7.40 (m, 1H), 7.20 (d, J =
6.95 Hz, 1H), 5.81 (s, 1H), 4.52 (m, 2H), 4.17 (s, 2H), 3.38 (m,
2H), 2.06 (s, 3H); 13C NMR (100 MHz, CDCl3) d 161.5, 153.7,
145.0, 133.9, 133.4, 131.8, 128.8, 127.7, 127.0, 126.2, 125.7,
125.5, 123.6, 115.5, 108.8, 51.3, 36.2, 28.4, 15.8. HRMS (FAB)
calcd. for [M + H]+ C19H18NOS 308.1109, obsd. 308.1107.
8-Cyclopropyl-7-naphthalen-1-ylmethyl-2,3-dihydrothiazolo[-
3,2-a]pyridin-5-one (12g). Method A. 11g (137 mg, 0.36 mmol)
gave 12g as a foam (120 mg, 99%): IR k 3061, 2999, 1647, 1571,
1491, 1429 cm−1; 1H NMR (400 MHz, CDCl3) d 7.86 (m, 1H),
7.82–7.73 (m, 2H), 7.50–7.37 (m, 3H), 7.26 (d, J = 6.95 Hz,
1H), 5.72 (s, 1H), 4.42 (m, 2H), 4.40 (s, 2H), 3.32 (m, 2H),
1.64 (m, 1H), 0.98–0.89 (m, 2H), 0.75–0.66 (m, 2H); 13C NMR
(100 MHz, CDCl3) d 161.5, 155.9, 147.6, 134.2, 133.9, 131.9,
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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 8 1 7 – 2 8 2 3
2 8 2 3