Microwave-assisted synthesis of highly substituted aminomethylated 2-pyridones

Article abstract of DOI:10.1021/jo048554y

By employing microwave-assisted organic synthesis (MAOS) efficient conditions to introduce aminomethylene substituents in highly substituted bicyclic 2-pyridones have been established. Primary amino methylene substituents were introduced via a cyanodehalo

Full text of DOI:10.1021/jo048554y

Microwave-Assisted Synthesis of Highly Substituted
Aminomethylated 2-Pyridones
Nils Pemberton, Veronica A° berg, Hanna Almstedt, Andreas Westermark, and
Fredrik Almqvist*
Organic Chemistry, Department of Chemistry, Umeå University, SE-90187 Umeå, Sweden
fredrik.almqvist@chem.umu.se
Received August 18, 2004
By employing microwave-assisted organic synthesis (MAOS) efficient conditions to introduce
aminomethylene substituents in highly substituted bicyclic 2-pyridones have been established.
Primary amino methylene substituents were introduced via a cyanodehalogenation followed by a
borane dimethyl sulfide reduction of the afforded nitrile. In both of these transformations, microwave
irradiation proved to be superior to traditional conditions and the primary amines were obtained
in good overall yields (55-58% over three steps). To incorporate tertiary aminomethylene
substituents in the 2-pyridone framework, a microwave-assisted Mannich reaction using preformed
iminium salts proved to be effective. Thus highly substituted 2-pyridones were obtained in 48-
93% yields.
Introduction
This alternative microwave-assisted method allows simple
and fast preparation of highly substituted 2-pyridones
in good yields and with limited racemization.
The core structure of 2-pyridinones, or more commonly
referred to as 2-pyridones, is present in a wide range of
compounds with diverse biological application areas
(Figure 1). Besides showing, e.g., antibacterial,1 anti-
fungal,2 and antitumor activity,3,4 members of these
heterocycles also act as inhibitors of Aâ-peptide aggrega-
tion thought to play an important role in Alzheimers’
disease.5,6
An enantioselective acyl-ketene imine cycloaddition
reaction to synthesize ring-fused substituted 2-pyridones
has previously been reported from our laboratory (Figure
2).7,8 Starting from commercially available nitriles and
carboxylic acids, this synthetic pathway rendered a first
generation of 2-pyridones that were designed to target
periplasmic escort proteins, chaperones, in uropathogenic
Escherichia coli. Recently, efficient improvements of the
original synthetic procedure were reported (Figure 2).9
Chaperones are essential for the assembly of adhesive
protein organelles known as pili or fimbriae present on
the surface of the bacteria. In the absence of these
organelles the bacteria become noninfectious.10 Thus,
compounds interfering with pili/fimbriae formation,
pilicides, would represent a novel class of antibacterial
agents directed against bacterial virulence.11 Encourag-
ing affinity predictions of substituted 2-pyridones binding
to the chaperones PapD and FimC have previously been
confirmed in vitro by direct binding assays using both
surface plasmon resonance techniques and NMR spec-
troscopy, where the corresponding acid of 4a (Scheme 1)
was found to be a potent binder.12 Still, position six
(Figure 2) is available for further substitution and thus
provides an opportunity to introduce hydrophilic func-
tionalities targeting increased bioavailability and en-
hanced chaperone affinity in the pilicide project. For
example, in the case of ampicillin and amoxycillin, the
introduction of an amine substituent led to a broad
spectrum antibiotic also affecting Gram-negatives.13 In
addition, introducing amine substituents in the 2-pyri-
done framework would result in highly substituted rigid
amino acids, which could serve as versatile scaffolds and
peptide mimetics (compare with compound 3 in Figure
1).14
(1) Li, Q.; Mitscher, L. A.; Shen, L. L. Med. Res. Rev. 2000, 20, 231-
293.
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Y.; Cushman, M. J. Med. Chem. 2003, 46, 5712-5724.
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(10) Mulvey, M. A. Cell. Microbiol. 2002, 4, 257-271.
(11) Lee, Y. M.; Almqvist, F.; Hultgren, S. J. Curr. Opin. Pharmacol.
2003, 3, 513-519.
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T.; Hultgren, S. J.; Pinkner, J. S.; Almqvist, F.; Kihlberg, J. Chem-
BioChem 2001, 2, 915-918.
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(14) Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-G.; Lubell,
W. D. Tetrahedron 1997, 53, 12789-12854.
10.1021/jo048554y CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/15/2004
7830
J. Org. Chem. 2004, 69, 7830-7835

Synthesis of Highly Substituted Aminomethylated 2-Pyridones
FIGURE 1. Examples of 2-pyridones (1 and 2) and a tetrahydro derivative 3 with different biological effects.1,4,14
FIGURE 2. Synthetic methods toward substituted bicyclic 2-pyridones based upon the acyl-ketene imine cycloaddition.7-9
Aromatic cyanodehalogenation and subsequent reduc-
tion of the cyano functionality was considered a well
investigated and straightforward pathway toward pri-
mary aminomethylated 2-pyridones.15,16 As a complement
to the primary amines, and to expand the chemical
diversity of these structures, tertiary amines were also
desired. A few scattered examples where 2-pyridones
react with imines in a Mannich reaction in the corre-
sponding position have previously been described,17,18 and
recently, microwave-mediated Mannich reactions per-
formed with electron-rich aromatic substrates have also
been published.19,20 Nevertheless, applications on more
complex structures such as functionalized 2-pyridones
with a challenging substitution pattern have previously
not been reported. In this paper, we describe two efficient
microwave-assisted synthetic pathways to primary and
tertiary aminomethylated 2-pyridones. Primary amines
were obtained via a cyanodehalogenation followed by
reduction of the resulting nitrile, and a modified Mannich
reaction furnished the corresponding tertiary amines.
Results and Discussion
To obtain the nitriles to be used as amine precursors,
brominated 2-pyridones 5a-c were prepared in excellent
yields using bromine in acetic acid (Scheme 1).21 Various
cyanodehalogenation procedures employing transition-
metal catalysts, e.g., palladium-catalyzed reactions utiliz-
ing zinc cyanide as the cyanide source, have worked well
with aryl halides.22,23 Unfortunately, the brominated
2-pyridone 5a was not consumed in these reactions, a fact
that might be due to poisoning of the catalyst by the
sulfur containing starting material. As a consequence,
the attention was turned to the original Rosenmund von
Braun cyanation employing CuCN in refluxing DMF, and
this time the desired cyanosubstituted 2-pyridones were
obtained. Still, the long reaction times and the rather
harsh workup procedure were not ideal resulting in low
and irreproducible yields. Recent reports of alternative
cyanodehalogenation reactions performed on aryl halides
have shown that microwave-assisted organic synthesis,
MAOS, can improve this reaction significantly.23-26 There-
fore, it was investigated if this technology would be
(15) Ellis, G. P.; Romney-Alexander, T. M. Chem. Rev. 1987, 87,
779-794.
(21) Padwa, A.; Sheehan, S. M.; Straub, C. S. J. Org. Chem. 1999,
64, 8648-8659.
(16) Sundermeier, M.; Zapf, A.; Beller, M. Eur. J. Inorg. Chem. 2003,
3513-3526.
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3273.
(17) Patel, A. K.; Mayadeo, M. S.; Deodhar, K. D. Ind. J. Chem.,
Sect. B: Org. Chem. Incl. Med. Chem. 1987, 26, 1099-1101.
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1980, 2, 512-528.
(19) Sharifi, A.; Mirzaei, M.; Nairni-Jamal, M. R. Monatsh. Chem.
2001, 132, 875-880.
(20) Mojtahedi, M. M.; Sharifi, A.; Mohsenzadeh, F.; Saidi, M. R.
Synth. Commun. 2000, 30, 69-72.
(23) Alterman, M.; Hallberg, A. J. Org. Chem. 2000, 65, 7984-7989.
(24) Arvela, R. K.; Leadbeater, N. E.; Torenius, H. M.; Tye, H. Org.
Biomol. Chem. 2003, 1, 1119-1121.
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9125.
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59, 2253-2258.
J. Org. Chem, Vol. 69, No. 23, 2004 7831

Pemberton et al.
SCHEME 1a
a Reagents and conditions: (i) Br2, AcOH, rt gave 5a-c; (ii) N-iodosuccinimide, AcOH/TFA, rt gave 5d; (iii) CuCN, NMP, MW 220 °C,
20 min; (iv) BH3‚Me2S, THF, MW 100 °C, 1 min.
beneficial also for the Rosenmund von Braun cyano-
dehalogenation. In the first attempts, 2-pyridone 5a and
CuCN were heated in DMF at 200 °C for 10 min using
microwave irradiation. Although product was formed, the
yields were still low (<30%) and a lot of unconsumed
starting material remained. Extending the reaction time
to 20 min gave more product but also significant amounts
of byproducts. Fortunately by increasing the temperature
to 220 °C and switching the solvent to N-methyl-2-
pyrrolidinone, NMP, the cyano-substituted 2-pyridone 6a
was obtained without detecting any competing side
reaction. However, the isolated yields did not reflect the
encouraging TLC and LC-MS data. The commonly
applied workup procedures for the Rosenmund von Braun
reaction are often harsh, e.g., heating with HCl and
FeCl3,15 which clearly affected the total yield and also
was a concern regarding the risk of racemization. There-
fore, after trying different extraction procedures with
unsatisfactory outcomes, most of the NMP was lyophi-
lized from water. This was followed by thorough extrac-
tion of the remaining solid with CH2Cl2, which proved
critical to obtain good overall yields. Final purification
with column chromatography resulted in cyano-substi-
tuted 2-pyridones 6a-c (Scheme 1) in very good yields
taking into account the presence of the sterically de-
manding naphthyl substituent in 5a and 5b. Although
still optically active, a substantial loss in enantiomeric
purity was observed in the cyanation step, and the
enantiomeric excess (ee) went down from 79% for 4b and
5b, respectively, to a moderate ee of 36% for the cyanated
derivative 6b.
The remaining step to the desired primary amines was
the reduction of the nitrile. To accomplish this transfor-
mation, some constrains had to be considered. First,
sulfur-assisted NaBH4 reduction of carboxylic acid esters
has been reported27 indicating that one might experience
selectivity problems and over-reduction to the corre-
sponding alcohol. Second, Padwa and co-workers have
shown that transition-metal-catalyzed hydrogenation
reactions at high pressure (90 psi) saturates the 2-pyri-
done skeleton.21 Encouraged by previous successful use
of PdO in a selective dehalogenation of iodopyridone 5d
at atmospheric pressure, hydrogenation was utilized in
the initial attempts to reduce the nitrile. Unfortunately,
hydrogenations at atmospheric pressure using various
catalysts, e.g., PdO, Pd/C,28 and PtO2,29 as well as dif-
ferent sources of hydrogen (hydrogen gas or ammonium
formate) or elevated pressure at 50 psi all proved
unsuccessful. Pd-S/C30 and Rh/C were also applied to
investigate whether the low reactivity could be explained
by poisoning of the catalyst, but without success. Several
electrophilic reducing agents that had been reported as
suitable reducing agents for nitriles such as N-ethyl-N-
isopropylaniline-borane (BACH-EI),31,32 AlH3‚NMe2Et,33
and BH3‚Me2S (BMS)34 were tested. Again, the cyano
group remained intact using both BACH-EI and AlH3‚
NMe2Et, yet in the latter case the methyl ester was
reduced to the corresponding alcohol according to LC-
MS. The most promising result was achieved with the
BMS complex in THF, where traces of the desired amine
could be detected after several hours at room tempera-
ture. Refluxing overnight gave a substantial increase of
product formation, although this also yielded consider-
able amounts of byproducts. With the intention to
improve the unsatisfactory yields and reaction times,
microwave irradiation was studied as an alternative
heating source. This gave complete conversion of the
hitherto almost inert cyano functionality in 60 s at 100
°C, and primary amines 7a-c were obtained in good
yields (Scheme 1). The optical purity, however, continued
to deteriorate also during this transformation and the
enantiomeric excess for primary amine 7b was only 8%.
To introduce symmetrical dialkylamines, the renowned
Mannich reaction was employed; a classical method
known since the early 1900s,35 often mentioned as one
of the most important C-C bond-forming reactions in
organic chemistry.36 Initial efforts using aqueous form-
aldehyde and protic solvents proved unfruitful as no
aminomethylated product could be detected. However,
switching to paraformaldehyde and dried aprotic solvents
gave some product; still, the yields were poor and a lot
of unidentified byproducts were formed. These well-
known limitations of the Mannich reaction could possibly
(29) Clive, D. L. J.; Hisaindee, S. J. Org. Chem. 2000, 65, 4923-
4929.
(30) Aggarwal, V. K.; Alonso, E.; Hynd, G.; Lydon, K. M.; Palmer,
M. J.; Porcelloni, M.; Studley, J. R. Angew. Chem., Int. Ed. 2001, 40,
1430-1433.
(31) Brown, H. C.; Kanth, J. V. B.; Zaidlewicz, M. Tetrahedron 1999,
55, 5991-6000.
(32) Brown, H. C.; Kanth, J. V. B.; Zaidlewicz, M. J. Org. Chem.
1998, 63, 5154-5163.
(33) Marlett, E. M.; Park, W. S. J. Org. Chem. 1990, 55, 2968-2969.
(34) Brown, H. C.; Choi, Y. M.; Narasimhan, S. J. Org. Chem. 1982,
47, 3153-3163.
(27) Khanapure, S. P.; Saha, G.; Sivendran, S.; Powell, W. S.;
Rokach, J. Tetrahedron Lett. 2000, 41, 5653-5657.
(28) Brana, M. F.; Rodriguez, M. L. J. Heterocycl. Chem. 1982, 19,
1297-1300.
(35) Mannich, C. K.; Kro¨sche, W. Arch. Pharm. 1913, 250, 647-
667.
(36) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed.
1998, 37, 1044-1070.
7832 J. Org. Chem., Vol. 69, No. 23, 2004

Synthesis of Highly Substituted Aminomethylated 2-Pyridones
TABLE 1. Microwave-Assisted Mannich Reaction on Substituted 2-Pyridones
entry
R1
R2
R3
NMe2
morpholine
NMe2
morpholine
NMe2
morpholine
time (s)
product
yielda (%)
1
2
3
4
5
6
phenyl
methyl
methyl
CH2-1-naphthyl
CH2-1-naphthyl
CH2-1-naphthyl
CH2-1-naphthyl
400
400
8a
8b
8c
8d
8e
8fc
92
93
48
64
55
66
phenyl
phenyl
400 × 2b
400 × 2b
400 × 2b
400 × 2b
phenyl
cyclopropyl
cyclopropyl
a Yield of the purified product. b An additional amount of 1.1 equiv of iminium salt was added. c The enantiomeric excess was 75%
(compared to 79% ee for the starting material 4b) as determined by chiral HPLC.
be diminished by shortening the reaction times, and
encouraged by the results from both the cyanodehalo-
genation and the BMS reduction of the nitriles, micro-
wave irradiation was applied also in this reaction. Initial
studies resulted in poor yields, at the best 28%. This could
be due to slow formation of the in situ generated iminium
salt, allowing competing side reactions to occur. To avoid
these problems, preformed methylene iminium salts were
used, giving a higher concentration of the reactive
species. Thus, commercially available Eschenmoser’s salt
(I- Me2N+ ) CH2) and pyridone 4c were irradiated for 9
min in 1,2-dichloroethane at 160 °C. This improved the
result substantially as 8a could be isolated in 78% yield.
The use of preformed iminiumsalts is a well-proven
strategy in the Mannich reaction often known to shorten
reaction times and increase yields.36 Several methods for
their preparation are available,37 and N,N-morpholine-
and N,N-dimethylmethyleneammonium chloride were
prepared according to published procedures by cleavage
of aminals with acetyl chloride.38 The aminals were
conveniently synthesized by condensing the amine of
choice with formaldehyde under aqueous conditions.39
The methyleneammonium chloride salts proved effective
and compounds 8a and 8b were isolated in 92 and 93%,
respectively (Table 1, entries 1 and 2). With these
excellent results in hand, the microwave-assisted Man-
nich reaction was now applied on the sterically more
challenging 2-pyridones 4a and 4b, which required
another portion of reactant and heating for an additional
400s to be completed. Bearing in mind the pronounced
steric impact of the CH2-naphthyl substituent R2 in 4a
and 4b (Table 1), the isolated yields for 8c-f (48-66%)
were satisfying. It has previously been observed that the
dimethylmethyleneammonium salt is less reactive than
the corresponding morpholineammonium salt.37 This was
also confirmed by the results obtained in this study
(Table 1, entries 3 and 4). Besides resulting in good to
excellent yields, this microwave-assisted method offers
a much faster reaction, 7-14 min compared to >22 h for
earlier published procedures.17,18 Moreover, in contradic-
tion to what was observed for the previously described
microwave-assisted cyanation and reduction step, the
optical purity was not affected as much during this
transformation and tertiary amine 8f was obtained with
an ee of 75% (compared to 79% ee for the starting
material 4b).
Conclusions
To accomplish the incorporation of aminomethylene
substituents in highly substituted and functionalized
2-pyridones, microwave-assisted chemistry has been
utilized. New conditions to efficiently cyanodehalogenate
2-pyridones were established followed by a microwave-
assisted borane dimethyl sulfide reduction of the afforded
nitrile. Finally, microwave irradiation in combination
with the use of preformed iminium salts proved to be
effective for the synthesis of 2-pyridones substituted with
tertiary amines. For all these reactions, the common
theme was that, despite substantial steric hindrance,
satisfying yields and short reaction times were achieved.
Experimental Section
2-Pyridonecarboxylic Acid Methyl Esters (4a-c). Pre-
pared according to previously published procedures.7,9
(3R)-6-Bromo-7-naphthalen-1-ylmethyl-5-oxo-8-phen-
yl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic
Acid Methyl Ester (5a). Br2 (110 µL, 2.1 mmol) was added
dropwise to a stirred solution of 4a (1.0 g, 2.3 mmol) in AcOH
(40 mL) at rt. After being stirred for 10 min, the reaction
mixture was concentrated. Purification by silica gel chroma-
tography (heptane/EtOAc, 1:1) gave 5b as a white foam (1.1
g, 93%): [R]D -140 (c 1.0, CHCl3); IR λ 2921, 2850, 1747, 1654,
1581, 1467, 1357, 1224 cm-1 1H NMR (400 MHz, CDCl3) δ
;
7.83 (dd, J ) 7.8, 1.6 Hz, 1H), 7.76-7.69 (m, 2H), 7.48-7.32
(m, 3H), 7.20-6.94 (m, 6H), 5.78 (dd, J ) 8.6, 2.6 Hz, 1H),
4.38-4.24 (m, 2H), 3.89 (s, 3H), 3.73 (dd, J ) 11.8, 8.6 Hz,
1H), 3.50 (dd, J ) 11.8, 2.6, 1H); 13C NMR (100 MHz, CDCl3)
δ 168.1, 157.7, 152.2, 146.2, 136.1, 133.6, 132.5, 131.5, 129.7,
129.2, 128.7, 128.6 (broad and splitted), 128.5, 127.0, 125.9,
125.5, 125.4, 124.4, 122.8, 117.0, 114.4, 64.9, 53.5, 37.2, 31.7;
HRMS (FAB) calcd for [M + H]+ C26H21BrNO3S 506.0426, obsd
506.0427.
6-Bromo-7-(naphthalen-1-ylmethyl)-5-oxo-8-cyclopro-
pyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxyl-
ic Acid Methyl Ester (5b). Br2 (28 µL, 0.54 mmol) was added
dropwise to a stirred solution of 4b (200 mg, 0.51 mmol) in
AcOH (6 mL) at rt. After being stirred for 30 min, the reaction
was quenched with 10% aqueous Na2S2O5 and the solution was
extracted with CH2Cl2. The organic layers were washed with
10% aqueous NaHCO3 and brine, and the resulting aqueous
(37) Bo¨hme, H.; Haake, M. Adv. Org. Chem. 1976, 9, 107-223.
(38) Bo¨hme, H.; Hartke, K. Chem. Ber. 1960, 93, 1305-1309.
(39) Heaney, H.; Papageorgiou, G.; Wilkins, R. F. Tetrahedron 1997,
53, 2941-2958.
J. Org. Chem, Vol. 69, No. 23, 2004 7833

Pemberton et al.
layers were combined and re-extracted with CH2Cl2. The
combined organic layers were dried (Na2SO4), filtered, and
concentrated. Purification by silica gel chromatography (hep-
tane/EtOAc, 1:4) gave 5b as a white foam (217 mg, 90%): [R]D
-177 (c 1.0, CHCl3); IR λ 2996, 2950, 2356, 1752, 1639, 1209,
mmol) gave 6b as a white foam (78 mg, 88%): [R]D -44 (c 1.0,
CHCl3); IR λ 3004, 2954, 2360, 2213, 1747, 1644, 1481, 1213,
1
1164, 792; H NMR (400 MHz, CDCl3) δ 8.12 (d, J ) 8.2 Hz,
1H), 7.89 (d, J ) 7.9 Hz, 1H), 7.75 (d, J ) 8.7 Hz, 1H), 7.62-
7.51 (m, 2H), 7.34 (t, 1H), 6,89 (d, J ) 7.1 Hz, 1H) 5.74 (dd, J
) 8.9, 2.2 Hz, 1H), 4.83-4.70 (m, 2H), 3.86 (s, 3H), 3.76 (dd,
J ) 11.9, 9.0 Hz, 1H), 3.58 (dd, J ) 11.9, 2.2 Hz, 1H), 1.27-
1.21 (m, 1H), 0.69-0.65 (m, 2H); 0.55-0.53 (m, 2H): 13C NMR
(100 MHz, CDCl3) δ 167.7, 162.9, 158.6, 155.6, 133.8, 132.4,
131.7, 128.9, 127.6, 126.4, 125.9, 125.5, 124.1, 122.8, 115.2,
114.5, 101.7, 63.5, 53.6, 34.8, 31.7, 11.3, 7.7, 7.2; HRMS (FAB)
calcd for [M + H]+ C24H21N2O3S 417.1273, obsd 417.1289.
(3R)-6-Cyano-7-methyl-5-oxo-8-phenyl-2,3-dihydro-5H-
thiazolo[3,2-a]pyridine-3-carboxylic Acid Methyl Ester
(6c). By following the procedure described for the preparation
of 6a from 5a, 5c (150 mg, 0.39 mmol) gave 6c as a pale yellow
foam (110 mg, 86%): [R]D -161 (c 1.0, CHCl3); IR λ 3012, 2956,
2215, 1749, 1648, 1440, 1365, 1257, 1216 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.50-7.39 (m, 3H), 7.25-7.18 (m, 2H), 5.72
(dd, J ) 8.8, 2.3 Hz, 1H), 3.85 (s, 3H), 3.72 (dd, J ) 11.9, 8.8
Hz, 1H), 3.51 (dd, J ) 11.9, 2.3 Hz, 1H), 2.21 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 167.6, 158.8, 158.4, 154.3, 135.0, 129.7,
129.5, 129.1 (splitted), 128.9, 116.5, 115.4, 99.5, 64.1, 53.5,
31.7, 20.0; HRMS (FAB) calcd for [M + H]+ C17H15N2O3S
327.0803, obsd 327.0805.
1
790; H NMR (400 MHz, CDCl3) δ 8.16 (d, J ) 8.2 Hz, 1H),
7.90 (d, J ) 8.1 Hz, 1H), 7.74 (d, J ) 8.4 Hz, 1H), 7.64-7.51
(m, 2H), 7.31 (t, 1H), 6.86 (d, J ) 6.9 Hz, 1H), 5.72 (dd, J )
8.7, 2.5 Hz, 1H), 4.88-4.74 (m, 2H), 3.85 (s, 3H), 3.72 (dd, J )
11.8, 8.7 Hz, 1H), 3.57-3.51 (dd, J ) 11.8, 2.4 Hz, 1H), 1.44-
1.36 (m, 1H), 0.73-0.63 (m, 2H); 0.59-0.50 (m, 2H); 13C NMR
(100 MHz, CDCl3) 168.3, 157.6, 154.4, 146.6, 133.8, 132.4,
131.8, 128.9, 127.1, 126.2, 125.7, 125.6, 123.8, 122.9, 114.7,
114.4, 64.0, 53.4, 36.6, 31.6, 12.2, 7.7, 7.3; HRMS (FAB) calcd
for [M + H]+ C23H21BrNO3S 470.0426, obsd 470.0439.
(3R)-6-Bromo-7-methyl-5-oxo-8-phenyl-2,3-dihydro-5H-
thiazolo[3,2-a]pyridine-3-carboxylic Acid Methyl Ester
(5c). By following the procedure described for the preparation
of 5a from 4a, 4c (400 mg, 1.3 mmol) gave 5c as a white foam
(500 mg, 98%): [R]D -213 (c 1.0, CHCl3); IR λ 2998, 2950, 1745,
1639, 1579, 1471, 1429, 1211 cm-1; 1H NMR (400 MHz, CDCl3)
δ 7.46-7.32 (m, 3H), 7.24-7.15 (m, 2H), 5.67 (dd, J ) 8.6, 2.4
Hz, 1H), 3.80 (s, 3H), 3.67 (dd, J ) 11.7, 8.6 Hz, 1H), 3.42 (dd,
J ) 11.8, 2.4 Hz, 1H), 2.10 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 168.1, 157.2, 150.4, 145.1, 136.7, 129.9, 129.6, 128.9, 128.8,
128.4, 116.2, 112.5, 64.6, 53.3, 31.6, 22.1; HRMS (FAB) calcd
for [M + H]+ C16H15BrNO3S 379.9956, obsd 379.9947.
(3R)-6-Iodo-7-naphthalen-1-ylmethyl-5-oxo-8-phenyl-
2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic Acid
Methyl Ester (5d). N-Iodosuccinimide (125 mg, 0.56 mmol)
was added to a stirred solution of 4a (100 mg, 0.23 mmol) in
AcOH (1 mL) and TFA (50 µL) at rt. After being stirred for 24
h, the reaction mixture was poured on ice-water and neutral-
ized with aqueous saturated NaHCO3. The precipitate was
filtered off and purified by silica gel chromatography (heptane/
EtOAc, 1:1) giving 5d as a pale orange solid (97 mg, 78%):
[R]D 176 (c 0.65, CHCl3); IR λ 2360, 2344, 1747, 1635, 1570,
1458, 1211, 1151, 993 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.82
(d, J ) 7.8 Hz, 1H), 7.71 (m, 2H), 7.48-7.31 (m, 3H), 7.21-
7.01 (m, 5H), 6.97 (d, J ) 7.5 Hz, 1H), 5.77 (dd, J ) 8.7, 2.4
Hz, 1H), 4.42-4.28 (m, 2H), 3.87 (s, 3H), 3.71 (dd, J ) 11.8,
8.7 Hz, 1H), 3.43 (dd, J ) 11.8, 2.4 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 168.1, 158.7, 156.5, 147.6, 136.3, 133.5, 132.5,
131.5, 129.6, 129.1, 128.6, 128.5 (broad and splitted), 128.3,
127.0, 125.8, 125.5, 125.3, 124.5, 122.7, 117.1, 94.3, 65.2, 53.4,
42.0, 31.7; HRMS (FAB) calcd for [M + H]+ C26H21INO3S
554.0287, obsd 554.0303.
(3R)-6-Aminomethyl-7-naphthalen-1-ylmethyl-5-oxo-8-
phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carbox-
ylic Acid Methyl Ester (7a). BH3‚Me2S (250 µL, 2 M in THF,
0.5 mmol) was added dropwise to a solution of 6a (50 mg, 0.11
mmol) in dry THF (4 mL) at rt. The reaction vessel was sealed
and heated for 60 s at 100 °C using microwave irradiation.
The reaction mixture was cooled to room temperature, diluted
with CH2Cl2, poured onto ice-cold aqueous HCl (1 M), and
agitated. The pH was then adjusted to ∼10 with 2 M aqueous
NaOH, and the aqueous layer was extracted with CH2Cl2. The
combined organic layers were dried and concentrated. The
crude product was dissolved in MeOH and swirled with
Amberlyst 15. The solid phase was transferred to a filtration
funnel and washed with MeOH. The product was released by
addition of 10% NH3 in MeOH and eluted with MeOH.
Concentration of the filtrate gave 7a as a yellow oil (36 mg,
72%): [R]D -44 (c 0.25, CHCl3); IR λ 2958, 2854, 1747, 1631,
1492, 1440, 1259, 1214 cm-1 1H NMR (400 MHz, CDCl3) δ
;
7.83 (d, J ) 8.2 Hz, 1H), 7.78 (d, J ) 8.1 Hz, 1H), 7.71 (d, J )
8.7 Hz, 1H), 7.54-7.00 (m, 9H), 5.74 (dd, J ) 8.6, 2.7 Hz, 1H),
4.25-4.11 (m, 2H), 3.96-3.51 (m, 8H), 3.48 (dd, J ) 11.8, 2.7
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 168.1, 161.3, 153.5,
148.9, 135.8, 133.8, 133.6, 131.2, 129.7, 129.3, 128.7 (split),
128.5 (split), 127.3, 126.3, 125.9, 125.5, 124.4, 123.2, 118.4,
116.6, 64.2, 53.6, 38.0, 33.2, 31.7; HRMS (FAB) calcd for [M +
Na]+ C27H24N2NaO3S 479.1405, obsd 479.1405.
(3R)-6-Cyano-7-naphthalen-1-ylmethyl-5-oxo-8-phenyl-
2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic Acid
Methyl Ester (6a). CuCN (120 mg, 1.3 mmol) was added to
a stirred solution of 5a (150 mg, 0.30 mmol) in NMP (1.0 mL)
at rt. The reaction mixture was heated at 220 °C for 20 min
using microwave irradiation, and the solvent was then re-
moved by lyophilization from deionized water. The residue was
thoroughly extracted with CH2Cl2, dried, and concentrated.
Purification by silica gel chromatography (heptane/EtOAc, 1:1)
gave 6a as a white foam (110 mg, 82%): [R]D -83 (c 1.0,
CHCl3); IR λ 3012, 2956, 2217, 1751, 1654, 1486, 1442, 1369
(3R)-6-Aminomethyl-8-cyclopropyl-7-naphthalen-1-yl-
methyl-5-oxo-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-
carboxylic Acid Methyl Ester (7b). By following the pro-
cedure described for the preparation of 7a from 6a, 6b (46 mg,
0.11 mmol) gave 7b as a yellow oil (33 mg, 73%): [R]D -64 (c
0.25, CHCl3); IR λ 2952, 1747, 1631, 1569, 1504, 1259, 1214
1
cm-1; H NMR (400 MHz, CDCl3) δ 8.18 (d, J ) 8.2 Hz, 1H),
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.79 (d, J ) 7.8 Hz, 1H),
7.94-7.27 (m, 5H), 6.81 (d, J ) 6.8 Hz, 1H), 5.67 (d, J ) 7.3
Hz, 1H), 4.77-4.56 (m, 2H), 3.96-3.31 (m, 9H), 1.40 (m, 1H),
0.76-0.31 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 168.3, 161.1,
155.6 149.5, 133.7 (splitted), 131.6, 128.7, 127.3, 126.4, 126.0,
125.5, 123.8, 123.4, 116.9, 115.7, 63.4, 53.5, 37.6, 32.6, 31.6,
11.8, 7.2, 7.1; HRMS (FAB) calcd for [M + H]+ C24H25N2O3S
421.1586, obsd 421.1593.
7.70 (d, J ) 8.1 Hz, 1H), 7.62 (d, J ) 8.2 Hz, 1H), 7.47-7.29
(m, 3H), 7.19-6.92 (m, 5H), 6.87 (d, J ) 7.3 Hz, 1H), 5.79 (dd,
J ) 8.9, 2.3 Hz, 1H), 4.41-4.27 (m, 2H), 3.89 (s, 3H), 3.75 (dd,
J ) 11.9, 8.9 Hz, 1H), 3.52 (dd, J ) 11.9, 2.3 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 167.6, 160.7, 158.7, 155.2, 134.4, 133.6,
132.4, 131.4, 129.7, 129.2, 128.8 (broad and splitted), 128.6,
127.6, 126.1, 125.7, 125.3, 125.2, 122.7, 117.1, 115.2, 101.3,
64.4, 53.7, 35.3, 31.8; HRMS (EI) calcd for [M]+ C27H20N2O3S
452.1195, obsd 452.1193.
(3R)-6-Aminomethyl-7-methyl-5-oxo-8-phenyl-2,3-dihy-
dro-5H-thiazolo[3,2-a]pyridine-3-carboxylic Acid Methyl
Ester (7c). By following the procedure described for the
preparation of 7a from 6a, 6c (36 mg, 0.11 mmol) gave 7c as
a yellow oil (27 mg, 67%): [R]D -110 (c 0.13, CHCl3); IR λ 2956,
1747, 1631, 1575, 1490, 1442, 1216 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.49-7.30 (m, 3H), 7.25-7.15 (m, 2H), 5.64 (dd, J )
6-Cyano-7-(naphthalen-1-ylmethyl)-5-oxo-8-cyclopro-
pyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxyl-
ic Acid Methyl Ester (6b). By following the procedure
described for the preparation of 6a from 5a, 5b (100 mg, 0.21
7834 J. Org. Chem., Vol. 69, No. 23, 2004

Synthesis of Highly Substituted Aminomethylated 2-Pyridones
8.5, 2.4, 1H), 3.92-3.69 (m, 7H), 3.62 (dd, J ) 11.5, 8.6, 1H),
3.41 (dd, J ) 11.6, 2.3, 1H), 2.02 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 168.8, 161.1, 152.0, 147.8, 136.4, 130.0, 129.9, 129.0,
128.9, 128.5, 118.0, 115.3, 64.0, 53.6, 37.9, 31.7, 18.0; MS (ESI)
calcd [M + H]+ for C17H19N2O3S 331, obsd 331.
(3.2 mL) at rt. The reaction vessel was sealed and heated for
400 s at 140 °C using microwave irradiation, more N,N-
morpholinemethyleneammonium chloride (105 mg, 0.77 mmol)
was added, and the reaction mixture was heated for another
400 s at 140 °C. The reaction mixture was then diluted with
CH2Cl2 and MeOH and concentrated. Purification by silica gel
chromatography (EtOAc f EtOAc, 2.5% triethylamine) gave
8d as a yellow foam (237 mg, 64%): [R]D -98 (c 1.0, CHCl3);
6-Dimethylamino-7-methyl-5-oxo-8-phenyl-2,3-dihydro-
5H-thiazolo[3,2-a]pyridine-3-carboxylic Acid Methyl Es-
ter (8a). N,N-Dimethylmethyleneammonium chloride (140
mg, 1.50 mmol) was added to a stirred solution of 4c (200 mg,
0.66 mmol) in dry 1,2-dichloroethane (3 mL) at rt. The reaction
vessel was sealed and heated for 400 s at 140 °C using
microwave irradiation. The reaction mixture was then diluted
with CH2Cl2 and MeOH and concentrated. Purification by
silica gel chromatography (EtOAc f EtOAc, 2.5% triethyl-
amine) gave 8a as a white foam (219 mg, 92%): [R]D -163 (c
1.0, CHCl3); IR λ 2939, 2817, 1747, 1631, 1490, 1209, 703; 1H
NMR (400 MHz, CDCl3) δ 7.43-7.30 (m, 3H) 7.24-7.16 (m,
2H) 5.64 (dd, J ) 8.6, 2.5 Hz, 1H) 3.78 (s, 3H) 3.59 (dd, J )
11.7, 8.7 Hz, 1H) 3.47 (d, J ) 12.2 Hz, 1H) 3.38 (dd, J ) 11.7,
2.5 Hz, 1H) 3.31 (d, J ) 12.2 Hz, 1H) 2.25 (s, 6H) 2.0 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 168.6, 161.5, 150.7, 144.2, 137.3
130.0, 129.7, 128.7, 128.6, 127.9, 122.2, 116.7, 64.0, 54.2, 53.1,
45.4, 31.3; 17.5; HRMS (FAB) calcd for [M + H]+ C19H23N2O3S
359.1429, obsd 359.1426.
1
IR λ 2952, 2846, 1749, 1633, 1490, 1112, 701 cm-1; H NMR
(400 MHz, CDCl3) δ 7.84-7.79 (m, 2H) 7.68 (d, J ) 8.2 Hz,
1H) 7.46-7.38 (m, 2H) 7.34 (t, 1H) 7.17-7.04 (m, 6H) 5.75
(dd, J ) 8.6, 2.7 Hz, 1H) 4.49 (d, J ) 15.9, 1H) 4.34 (d, J )
15.9 Hz, 1H) 3.87 (s, 3H) 3.69 (dd, J ) 11.8, 8.7 Hz, 1H) 3.56-
3.50 (m, 4H) 3.46 (dd, J ) 11.8, 2.7 Hz, 1H) 3.32 (m, 2H) 2.40-
2.30 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 168.5, 161.9, 153.1,
145.7, 136.5, 134.8, 133.4, 131.7, 129.9, 129.3, 128.6, 128.4,
128.4, 128.0, 126.7, 125.8, 125.5, 125.4, 124.4, 122.8, 122.3
117.5, 66.9, 64.3, 53.5, 53.2, 53.2, 32.0, 31.3; HRMS (FAB) calcd
for [M + H]+ C31H31N2O4S 527.2005, obsd 527.2008.
6-Dimethylamino-7-(naphthalen-1-ylmethyl)-5-oxo-8-
cyclopropyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-
carboxylic Acid Methyl Ester (8e). By following the pro-
cedure described for the preparation of 8c from 4a, 4b (200
mg, 0.51 mmol) gave 8e as a white foam (125 mg, 55%): [R]D
-177 (c 1.0, CHCl3); IR λ 2939 2948, 2817, 2767, 1747, 1633,
1579, 1498, 1211, 792, 773; 1H NMR (400 MHz, CDCl3) δ 8.23
(d, J ) 8.4 Hz, 1H), 7.86 (d, J ) 7.8 Hz, 1H) 7.69 (d, J ) 8.2
Hz, 1H) 7.60-7.48 (m, 2H) 7.31-27 (m, 1H) 6.82 (d, J ) 6.8
Hz, 1H) 5.69 (dd, J ) 8.7, 2.5 Hz, 1H) 4.83-4.80 (m, 2H) 3.81
(s, 3H) 3.67 (dd, J ) 11.8, 8.7 Hz, 1H) 3.48 (dd, J ) 11.7, 2.6
Hz, 1H) 3.30-3.19 (m, 2H) 2.19 (s, 6H) 1.34-1.24 (m, 1H)
0.63-0.53 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 168.8, 161.9,
155.1, 146.0, 134.6, 133.7, 132.1, 128.8, 126.8, 126.1, 125.7,
125.6, 123.7, 123.2, 114.4, 63.5, 53.8, 53.2, 45.6, 31.4 (split),
11.7, 7.4, 7.1; HRMS (FAB) calcd for [M + H]+ C26H29N2O3S
449.1899, obsd 449.1887.
6-Morpholino-7-methyl-5-oxo-8-phenyl-2,3-dihydro-5H-
thiazolo[3,2-a]pyridine-3-carboxylic Acid Methyl Ester
(8b). By following the procedure described for the preparation
of 8a from N,N-Dimethylmethyleneammonium chloride and
4c, N,N-morpholinemethyleneammonium chloride and 4c (200
mg, 0.66 mmol) gave 8b as a white foam (249 mg, 93%): [R]D
-161 (c 1.0, CHCl3); IR λ 2955, 2850, 2360, 1749, 1631, 1490,
1
1112, 703; H NMR (400 MHz, CDCl3) δ 7.45-7.34 (m, 3H),
7.26-7.20 (m, 2H), 5.67 (dd, J ) 8.6, 2.6 Hz, 1H), 3.82 (s, 3H),
3.70-3.64 (m, 4H), 3.63-3.53 (m, 2H), 3.46-3.38 (m, 2H),
2.53-2.48 (m, 4H), 2.07 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
168.6, 161.5, 151.3, 144.5, 137.2, 130.0, 129.8, 128.7, 128.6,
128.0, 121.0, 116.8, 67.1, 64.1, 53.4, 53.1, 31.2, 17.5; HRMS
(FAB) calcd for [M + H]+ C21H25N2O4S 401.1535, obsd 401.1536.
6-Dimethylamine-7-(naphthalen-1-ylmethyl)-5-oxo-8-
phenyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carbox-
ylic Acid Methyl Ester (8c). N,N-Dimethylmethylene-
ammonium chloride (144 mg, 1.54 mmol) was added to a
stirred solution of 4a (300 mg, 0.70 mmol) in dry 1,2-
dichloroethane (3 mL) at rt. The reaction vessel was sealed
and heated for 140 °C for 400 s using microwave irradiation,
more N,N-dimethylmethyleneammonium chloride (72 mg, 0.77
mmol) was added, and the reaction mixture was heated for
another 400 s at 140 °C. The reaction mixture was then diluted
with CH2Cl2 and MeOH and concentrated. Purification by
silica gel chromatography (EtOAc f EtOAc 2.5% triethyl-
amine) gave 8c as a white foam (148 mg, 48%): [R]D -151 (c
1.0, CHCl3); IR λ 3048, 2940, 2817, 2767, 1747, 1633, 1490,
790, 701; 1H NMR (400 MHz, CDCl3) δ 7.83-7.77 (m, 2H), 7.67
(d, J ) 8.2 Hz, 1H), 7.45-7.30 (m, 3H), 7.12-6.99 (m, 6H),
5.76 (dd, J ) 8.6, 2.6 Hz, 1H), 4.44 (d, J ) 16 Hz, 1H), 4.32 (d,
J ) 16 Hz, 1H), 3.85 (s, 3H), 3.66 (dd, J ) 11.8, 8.7 Hz, 1H),
3.44 (dd, J ) 11.8, 2.6 Hz, 1H), 3.30-3.20 (m, 2H), 2.21 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 168.5, 161.8 152.2, 145.5,
136.5, 134.5, 133.3, 131.6, 129.8, 129.2, 128.4, 128.3, 128.2,
127.9, 126.7, 125.8, 125.4, 125.3, 124.2, 123.4, 122.8, 117.2,
64.2, 53.9, 53.1, 45.6, 31.8, 31.3; HRMS (FAB) calcd for [M +
H]+ C29H29N2O3S 485.1899, obsd 485.1866.
6-Morpholino-7-(naphthalen-1-ylmethyl)-5-oxo-8-
cyclopropyl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-
3-carboxylic Acid Methyl Ester (8f). By following the
procedure described for the preparation of 8d from 4a, 4b (400
mg, 1.02 mmol) gave 8f as a yellow foam (331 mg, 66%): [R]D
-110 (c 1.0, CHCl3); IR λ 2956, 2844, 1749, 1631, 1496, 1110,
1
792, 773, 728; H NMR (400 MHz, CDCl3) δ 8.20 (d, J ) 8.4
Hz, 1H), 7.87 (d, J ) 7.5 Hz, 1H) 7.70 (d, J ) 8.2 Hz, 1H)
7.61-7.48 (m, 2H) 7.29 (t, 1H) 6.84 (d, J ) 7.1 Hz, 1H) 5.68
(dd, J ) 8.7, 2.6 Hz, 1H) 4.87-4.78 (m, 2H) 3.82 (s, 3H) 3.69
(dd, J ) 11.8, 8.7 Hz, 1H) 3.52-3.45 (m, 5H) 3.32 (m, 2H) 2.34
(m, 4H) 1.40-1.32 (m, 1H) 0.68-0.53 (m, 4H); 13C NMR (100
MHz, CDCl3) δ 168.6, 161.8, 155.5, 146.1, 134.7, 133.5, 131.9,
128.7, 126.6, 126.0, 125.6, 125.4, 123.6, 122.9, 122.4, 114.5,
66.9, 63.4 53.3, 53.1, 52.9, 31.4, 31.2, 11.5, 7.3, 7.0; HRMS
(FAB) calcd for [M + H]+ C28H31N2O4S 491.2005, obsd 491.1998.
Acknowledgment. We thank Linda Thunberg at
AstraZeneca Mo¨lndal for help with the ee measure-
ments. We are also grateful to the Swedish Natural
Science Research Council, the Knut and Alice Wallen-
berg Foundation, and the Foundation for Technology
Transfer in Umeå for financial support.
Supporting Information Available: 13C NMR spectra of
5a-d, 6a-c, 7a-c, and 8a-f. HPLC chromatogram for ee
determinations of compounds 4b, 5b, 6b, 7b, and 8f. General
Experimental Section. This material is available free of charge
via the Internet at http://pubs.acs.org.
6-Morpholino-7-(naphthalen-1-ylmethyl)-5-oxo-8-phen-
yl-2,3-dihydro-5H-thiazolo[3,2-a]pyridine-3-carboxylic
Acid Methyl Ester (8d). N,N-Morpholinemethyleneammo-
nium chloride (209 mg, 1.54 mmol) was added to a stirred
solution of 4a (300 mg, 0.70 mmol) in dry 1,2-dichloroethane
JO048554Y
J. Org. Chem, Vol. 69, No. 23, 2004 7835