An annulation method for the synthesis of alkyl-substituted 6-carbomethoxy-2-pyridones

Article abstract of DOI:10.1016/j.tet.2009.06.006

A protocol for the synthesis of 5-alkyl and 3,5-dialkyl-6-carbomethoxy-2-pyridones was devised. Key steps include a Mannich reaction, acylation of a tosylamine, and a PPh₃/TiCl₄-promoted intramolecular Reformatsky-type reaction with

Full text of DOI:10.1016/j.tet.2009.06.006

Tetrahedron 65 (2009) 6584–6590
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An annulation method for the synthesis of alkyl-substituted
6-carbomethoxy-2-pyridones
*
Yu Zhang, Brad M. Loertscher, Steven L. Castle
Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A protocol for the synthesis of 5-alkyl and 3,5-dialkyl-6-carbomethoxy-2-pyridones was devised. Key
steps include a Mannich reaction, acylation of a tosylamine, and a PPh3/TiCl4-promoted intramolecular
Reformatsky-type reaction with a thioester as the electrophile. The latter process typically afforded
a vinylogous thiocarbamate via elimination of water rather than the Dieckmann-type product which
would have resulted from elimination of the thiol. However, the Dieckmann-type ketone product was
obtained in one instance. Subsequent elimination of the tosyl group and desulfurization completed the
pyridone synthesis.
Received 27 February 2009
Received in revised form 30 May 2009
Accepted 3 June 2009
Available online 10 June 2009
Dedicated to Professor Larry E. Overman,
an inspiring mentor
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Lyconadin A
Pyridone
Mannich reaction
Reformatsky reaction
Desulfurization
1. Introduction
We have developed a cascade reaction initiated by a 7-exo
acyl radical cyclization which constructs two carbocyclic rings
The 2-pyridone ring system is a component of several archi-
tecturally interesting biologically active natural products.1 As a re-
sult, numerous annulation methods have been designed for its
construction.2,3 In this regard, we were attracted to the structure of
lyconadin A (1, Fig. 1), a Lycopodium alkaloid with a unique penta-
cyclic skeleton that contains a 2-pyridone moiety. Lyconadin A was
isolated by Kobayashi and co-workers from the club moss Lycopo-
dium complanatum, and it was demonstrated to possess modest
anticancer activity.4 Recently, the Smith5 and Sarpong6 groups
reported total syntheses of (þ)-1 and (ꢀ)-1, respectively.
and two stereocenters in a highly selective fashion.7 This method
shows promise for preparing the bicyclo[5.4.0]undecane ring
system imbedded within the framework of 1. Accordingly, we
turned our attention to designing a total synthesis of 1 that in-
corporates the radical cascade process. To streamline the route,
we desired to install the pyridone moiety at an early stage. Thus,
we required a method for preparing a pyridone system with an
alkyl group at C-5 and a carboxy group at C-6. Herein, we detail
our efforts to synthesize such
a compound, which have
culminated in the discovery of a new protocol for pyridone
annulation.
O
H
2. Results and discussion
HN
H
H
H
In 1990, Kozikowski and co-workers developed a 2-pyridone
synthesis which entailed a three-component coupling of ammonia,
methyl propiolate, and a ketone (Scheme 1).8 The simplicity of the
procedure and the fact that it produces 5,6-disubstituted 2-pyr-
idones were appealing. Unfortunately, its utility is restricted to
symmetrical ketones and ketones which can only form a single
N
H
1
Figure 1. Lyconadin A (1).
enamine.9 It occurred to us that
a-keto esters, which fit in the latter
category, would provide 6-carboxy-substituted 2-pyridones if
subjected to the Kozikowski pyridone annulation.
* Corresponding author. Tel.: þ1 801 422 1780; fax: þ1 801 422 0153.
E-mail address: scastle@chem.byu.edu (S.L. Castle).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.06.006

Y. Zhang et al. / Tetrahedron 65 (2009) 6584–6590
6585
H
N
summarized in Scheme 4 and uses ring-closing metathesis to form
a dihydropyridone. Subsequent elimination generates the pyridone
ring. We were intrigued by this approach, as it was demonstrated to
provide a wide variety of substituted pyridones including 5-alkyl-
6-carboxypyridones. However, ring-closing metathesis would not
be a viable cyclization method in our case, as the substrate required
for the total synthesis of lyconadin A would possess additional
double bonds appended to the C-5 alkyl group (i.e., R2 position in
Scheme 4) for use in the key radical cascade reaction.7 Therefore,
we resolved to develop a pyridone annulation method based on the
Donohoe strategy that would employ a different reaction in the
cyclization step.
NH3
CO2Me
O
O
H
O
O
MeOH
100 °C, 10 h
70%
O
O
Scheme 1. Kozikowski pyridone annulation.
To probe the viability of this idea, we employed methyl pyruvate
as the ketone component in this annulation. Reactions with am-
monia failed to give any pyridone products, so we next examined
benzylamines as ammonia surrogates. In these cases, we were able
to obtain pyridones 2a–c (Scheme 2). However, inspection of the
NMR spectra revealed that the carbomethoxy groups were located
on C-5 rather than C-6 in these adducts. A plausible mechanism for
the formation of 2a–c is depicted in Scheme 2 and involves Michael
addition of the amine to methyl propiolate followed by a second
Michael addition of the intermediate allenolate to another mole-
cule of methyl propiolate. Lactamization then provides the 2-pyr-
O
Cl
OBn
R1
R2
Br
HN
R2
BnO
H
R3
N
Zn, THF
R1
idone. Apparently, the
annulation. This supposition was tested by conducting the reaction
in ethanol with ethyl pyruvate as the -keto ester. As expected,
a-keto ester was not participating in the
R3
O
O
R3
R3
OBn
R1
a
DBU
THF
OBn RCM
R1
NH
R1
N
O
N
pyridone 2a bearing a carbomethoxy group was obtained, and none
of the corresponding ethyl ester was observed.
R2
R2
R2
Scheme 4. Donohoe pyridone annulation.
O
Ar
NH2
O
H
CO2Me
We reasoned that an intramolecular Horner–Wadsworth–
Emmons reaction could be substituted for the ring-closing me-
tathesis step. We envisioned employing a thioester as an aldehyde
surrogate, so we attempted the Mannich reaction of silyl ketene
thioacetal 6 and oxime ether 7 (Scheme 5). Lewis acid promoted
Mannich reactions only returned starting material, and a lithium
acetate-catalyzed protocol11 delivered Claisen adduct 8 as the major
N
OMe
MeOH
120 °C, 70 h
R1
O
R2
CO2Me
2a: R1 = R2 = H, 73%
2b: R1 = OMe, R2 = H, 73%
2c: R1 = R2 = OMe, 79%
product in modest yield. Additionally, b-lactam 9 was identified as
Ar
NH
a minor product of this reaction. Fortunately, when tosylimine 10
was substituted for oxime ether 7, Mannich adduct 11 was obtained
in good yield as a ca. 6:1 mixture of diastereomers. The major isomer
was assumed to possess the anti configuration in accordance with
the acyclic transition state proposed by Mukaiyama and co-workers
for the Mannich reaction.11 Although the isomers could be sepa-
rated, in practice the mixture was carried forward since both ster-
eocenters would be destroyed later in the synthesis. Unfortunately,
we were unable to acylate the nitrogen atom of 11 with acid chloride
12 or related reagents that would allow us to pursue the intra-
molecular Horner–Wadsworth–Emmons reaction. Apparently, the
tosylamine is not nucleophilic enough to react with inductively
deactivated acid chlorides such as 12.
Ar
NH2
+
H
CO2Me
OMe
O–
O
H
MeO
NH
Ar
–MeOH
2
CO2Me
CO2Me
Scheme 2. Attempted Kozikowski pyridone annulation with methyl pyruvate. Yields
are based on consumed methyl propiolate.
Since
annulation, we decided to employ a preformed enamine derived
from an -keto ester instead. After some experimentation, we
a-keto esters were unreactive in the Kozikowski pyridone
a
found that annulation of pyrrolidine enamine 3 and propiolamide
(4) proceeded in the presence of toluenesulfonic acid, affording 2-
pyridone 5 (Scheme 3). However, the reaction did not occur with
homologues of enamine 3 that would lead to C-5 substituted pyr-
idones. Apparently, the increased steric hindrance of these sub-
strates prevented the reaction. Thus, the modified Kozikowski
pyridone annulation was unsuitable for construction of 5-alkyl-6-
carboxypyridones.
BnO
N
S
H
OBn
N
O
O
S
LiOAc
DMF
8 (41%)
+
OMe
H
+
OTMS
O
O
OBn
6
N
7
CO2Me
O
9
O
TsOH
N
HN
EtO2C
+
O
P
O
NH2
PhH
80–110 °C
71%
H
CO2Et
Ts
EtO
Cl
O
NHTs
N
EtO 12
LiOAc
OMe
3
4
5
N.R.
6
+
OMe
S
H
DMF
83%
Scheme 3. Modified Kozikowski pyridone annulation.
O
O
10
(6:1 dr)
11
At this point, we became aware of a novel pyridone annulation
strategy developed by Donohoe and co-workers.10 This process is
Scheme 5. Attempted synthesis of Horner–Wadsworth–Emmons cyclization
substrate.

6586
Y. Zhang et al. / Tetrahedron 65 (2009) 6584–6590
This setback prompted us to examine an intramolecular
Reformatsky reaction as a substitute for the Horner–Wadsworth–
Emmons cyclization. To this end, acylation of 11 with bromo-
acetyl chloride was successful, affording a-bromo tosylamide 13
in good yield (Scheme 6). However, we were unable to selectively
reduce the thioester moiety in 13, as exposure to Raney Ni12 or
Lindlar catalyst/Et3SiH13 led to preferential reduction of the
bromide. Similar results were obtained with the chlorinated
analogue of 13.
With a route to the desired 5-alkyl-6-carbomethoxy-2-pyridone
nucleus secured, we briefly explored the scope of the annulation
method. We found that C-5 alkyl groups larger than ethyl are tol-
erated, as shown in Scheme 8. Interestingly, the Mannich reaction
between silyl ketene thioacetal 17 and tosylimine 10 was less se-
lective (1.6:1 anti/syn) than the corresponding reaction between 6
and 10 (Scheme 5). As both diastereomers converge to the same
pyridone, the lack of selectivity is inconsequential. Acylation of the
diastereomeric mixture of tosylamines 18 was sluggish and lower
yielding compared to the acylation of 11; it is likely that optimi-
zation of this transformation would lead to an improved result.
Fortunately, cyclization, elimination, and desulfurization each
proceeded smoothly, affording isopropyl-substituted pyridone 22
in good yield from intermediate 19.
n-BuLi
O
O
O
Br
S
Ts
O
Ts
Ph3P
TiCl4
O
N
N
Br
Cl
OMe
OMe
11
S
THF, –78 °C
79%
DCE/CH2Cl2
–5 °C
O
n-BuLi
13
14
72%
O
10
O
NHTs
OMe
Br
Scheme 6. Intramolecular Reformatsky-type condensation.
S
LiOAc
Cl
S
THF, –78 °C
51%
DMF
74%
TMSO
O
To the best of our knowledge, Reformatsky reactions utilizing
thioesters as acyl electrophiles are unknown.14 However, published
examples of Reformatsky reactions with species such as N-acyl-
oxazolidinones,15 N-acyl pyrazoles,16 and lactones17 encouraged us
to directly attempt the cyclization of 13. SmI2 is typically employed
in intramolecular Reformatsky reactions,14a,18 but treatment of 13
with this reagent merely resulted in debromination. Then, we
discovered the work of Hashimoto and co-workers regarding re-
1.6:1 dr
18
17
O
O
Ph3P
TiCl4
Br
S
Ts
Ts
N
DBU
N
O
OMe
OMe
DMF
96%
DCE/CH2Cl2
–5 °C
S
O
O
82%
19
20
O
O
ductive Claisen-type condensations of
researchers discovered that the combination of PPh3 and TiCl4
promotes the formation of enolates from -bromothioesters. These
species then undergo both self-condensations and crossed-Claisen-
type reactions, affording various types of
-ketothioester adducts.19
a-bromothioesters. These
Lindlar cat.
Et3SiH
NH
NH
a
OMe
OMe
acetone
83%
S
O
O
b
21
22
Fortunately, application of the Hashimoto protocol to substrate 13
resulted in facile cyclization. Interestingly, vinylogous thio-
carbamate 14 was generated rather than the corresponding Die-
ckmann-type product. The reaction was quite moisture-sensitive,
as debrominated starting material predominated when anhydrous
conditions were not employed.
Conversion of compound 14 into the desired 2-pyridone re-
quired elimination of the tosyl group and desulfurization. In prin-
ciple, these two steps could be conducted in either order. In
practice, attempts to cleave the vinyl sulfide from dihydropyridone
14 were unsuccessful. The use of NiCl2/NaBH420and Raney Ni21
resulted in over-reduction to the saturated derivative, whereas Ni-
containing complex reducing agents (NiCRA’s and NiCRA-bpy)22
promoted elimination to the pyridone but not desulfurization.
Moreover, the vinyl sulfide moiety of 14 was quite resistant to acidic
or basic hydrolysis; instead, the methyl ester group was hydrolyzed
preferentially.
Due to the problems encountered in the desulfurization of 14,
we decided to conduct the elimination step first. Thus, treatment
of 14 with DBU afforded pyridone 15 in excellent yield (Scheme 7).
Although Raney Ni caused over-reduction of 15, the combination
of Lindlar catalyst and Et3SiH13 selectively cleaved the vinyl sulfide
without reducing the pyridone. We were pleased to find that the
desired pyridone 16 could be obtained in 95% yield by this
method.
Scheme 8. Synthesis of isopropyl-substituted pyridone 22.
Moreover, a 3,5-dialkyl-substituted pyridone can be fashioned via
this protocol, as outlined in Scheme 9. Acylation of 11 with 2-bro-
mopropanoyl chloride provided tosylamide 23. Then, in contrast to
previous results, cyclization of 23 afforded a separable 1:2.4 mixture
n-BuLi
O
O
Br
Ph3P
TiCl4
Cl
Br
S
Ts
N
O
11
OMe
THF, –78 °C
70%
DCE/CH2Cl2
–5 °C
O
23
O
O
Ts
Ts
N
N
+
OMe
OMe
S
O
O
O
24 (24%)
25 (56%)
1. DBU, DMF
2. Lindlar cat., Et3SiH
acetone
77%
O
O
O
Lindlar cat.
Et3SiH
DBU
NH
NH
NH
14
OMe
OMe
OMe
DMF
97%
acetone
95%
S
O
O
16
O
15
26
Scheme 7. Synthesis of pyridone 16.
Scheme 9. Synthesis of dialkyl-substituted pyridone 26.

Y. Zhang et al. / Tetrahedron 65 (2009) 6584–6590
6587
of vinyl sulfide 24 and ketone 25 in 80% overall yield. Apparently, the
presence of a substituent on the enolate intermediate alters the
product distribution of the cyclization. Vinyl sulfide 24 was processed
in analogous fashion to sulfides 14 and 20, delivering 3,5-dialkyl-
substituted pyridone 26. In principle, it should also be possible to
convert 25 into 26 via a sequence of ketone reduction, mesylation (or
halogenation) of the resultant alcohol, and bis-elimination.
(0.6 mL) was added p-methoxybenzylamine (49.3
m
L, 52.1 mg,
0.380 mmol). The reaction vessel was sealed, and the mixture was
heated at 120 ꢁC for 2 d. After cooling to rt, the mixture was con-
centrated in vacuo. Flash chromatography (SiO2, 25% EtOAc in
hexanes elution) afforded 2b (38.0 mg, 0.139 mmol, 73%) as a col-
orless oil: 1H NMR (CDCl3, 500 MHz)
d
8.17 (d, J¼2.5 Hz, 1H), 7.81
(dd, J¼9.8, 2.8 Hz, 1H), 7.29 (d, J¼9.0 Hz, 2H), 6.88 (d, J¼8.5 Hz, 2H),
6.56 (d, J¼9.5 Hz, 1H), 5.09 (s, 2H), 3.83 (s, 3H), 3.80 (s, 3H); 13C
3. Conclusion
NMR (CDCl3, 125 MHz) d 164.9, 162.7, 159.9, 142.7, 138.6, 130.1 (2C),
127.8, 120.2, 114.6 (2C), 110.1, 55.5, 52.5, 52.3; IR (film) nmax 2953,
2838, 1716, 1612, 1544, 1515, 1396, 1297, 1114 cmꢂ1; HRMS (ESI) m/z
274.10674 (MHþ, C15H15NO4Hþ requires 274.10738).
Prompted by the structure of the alkaloid lyconadin A, we
devised a method for the construction of 5-alkyl and 3,5-dialkyl-
6-carbomethoxy-2-pyridones. Our protocol was inspired by the
metathesis-based pyridone synthesis of Donohoe and co-
workers.10 The annulation substrate is prepared via a Mannich
reaction followed by acylation of the resulting tosylamine. Cycli-
zation is accomplished by means of an intramolecular Reformat-
sky-type reaction employing a thioester as an acyl electrophile.19
Typically, vinylogous thiocarbamates (i.e., 14, 20, and 24) were the
products of this cyclization, but in one case the Dieckmann-type
product (25) was also obtained. Elimination of the tosyl group and
desulfurization complete the pyridone synthesis. We believe that
this new synthetic strategy will have utility in the synthesis of
complex molecules, and attempts to apply our method to the total
synthesis of lyconadin A are in progress.
4.4. Methyl 1-(3,4-dimethoxybenzyl)-6-oxo-1,6-
dihydropyridine-3-carboxylate (2c)
To a solution of methyl pyruvate (17.5
and methyl propiolate (31.8 L, 31.9 mg, 0.380 mmol) in MeOH
(0.6 mL) was added 3,4-dimethoxybenzylamine (56.4 L, 63.5 mg,
mL, 19.4 mg, 0.190 mmol)
m
m
0.380 mmol). The reaction vessel was sealed, and the mixture was
heated at 120 ꢁC for 2 d. After cooling to rt, the mixture was con-
centrated in vacuo. Flash chromatography (SiO2, 25% EtOAc in
hexanes elution) afforded 2c (45.4 mg, 0.150 mmol, 79%) as a col-
orless oil: 1H NMR (CDCl3, 500 MHz)
d
8.17 (d, J¼2.5 Hz, 1H), 7.83
(dd, J¼10.0, 2.5 Hz, 1H), 6.91–6.89 (m, 2H), 6.84 (d, J¼7.5 Hz, 1H),
6.58 (d, J¼9.5 Hz, 1H), 5.10 (s, 2H), 3.88 (s, 3H), 3.87 (s, 3H), 3.84 (s,
4. Experimental
4.1. General
3H); 13C NMR (CDCl3, 125 MHz)
d 164.9, 162.8, 149.6, 149.5, 142.6,
138.7, 128.2, 121.2, 120.2, 111.9, 111.5, 110.2, 56.22, 56.16, 52.7, 52.3;
IR (film) nmax 1718, 1667, 1517, 1446, 1301, 1263, 1239 cmꢂ1; HRMS
(ESI) m/z 304.11635 (MHþ, C16H17NO5Hþ requires 304.11795).
Benzene, dimethylformamide, methylene chloride, and tetra-
hydrofuran were dried by passage through a solvent drying system
containing cylinders of activated alumina. 1,2-Dichloroethane was
dried over activated 4 Å molecular sieves. Flash chromatography
was carried out using 60–230 mesh silica gel. 1H NMR spectra were
acquired on 500 MHz spectrometers with chloroform (7.27 ppm) as
internal reference. Signals are reported as follows: s (singlet),
d (doublet), t (triplet), q (quartet), dd (doublet of doublets), br s
(broad singlet), m (multiplet). Coupling constants are reported in
hertz (Hz). 13C NMR spectra were acquired on spectrometers op-
erating at 125 MHz with chloroform (77.23 ppm) as internal ref-
erence. Infrared spectra were obtained on an FT-IR spectrometer.
Mass spectral data were obtained using ESI techniques.
4.5. Ethyl 6-oxo-1,6-dihydropyridine-2-carboxylate (5)
A mixture of ethyl pyruvate (21
mL, 22 mg, 0.19 mmol), 4 Å MS
(66.2 mg), pyrrolidine (19.5 L, 16.9 mg, 0.238 mmol) and anhy-
m
drous benzene (2.0 mL) was refluxed at 80 ꢁC for 5 h. The mixture
was allowed to cool to rt and was then filtered under Ar. The so-
lution of crude enamine was placed in a sealable tube and treated
with propiolamide23 (33 mg, 0.48 mmol) followed by p-TsOH
(36 mg, 0.21 mmol). The vessel was sealed, and the resulting mix-
ture was stirred at 80 ꢁC for 48 h, then at 110 ꢁC for 12 h. The solvent
was removed in vacuo, and the residue was purified by flash
chromatography (SiO2, 4% MeOH in EtOAc elution), affording 5
(22.5 mg, 0.135 mmol, 71%) as a white solid: 1H NMR (CDCl3,
4.2. Methyl 1-benzyl-6-oxo-1,6-dihydropyridine-3-
carboxylate (2a)
500 MHz)
d
9.73 (br s, 1H), 7.46 (dd, J¼9.2, 6.8 Hz, 1H), 6.98 (dd,
J¼7.0, 1.0 Hz, 1H), 6.81 (dd, J¼9.5, 1.0 Hz, 1H), 4.42 (q, J¼7.0 Hz, 2H),
1.41 (t, J¼7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
d 162.3, 160.1,
To a solution of methyl pyruvate (17.5
and methyl propiolate (32.0 L, 32.2 mg, 0.383 mmol) in MeOH
(0.6 mL) was added benzylamine (41.5 L, 40.7 mg, 0.380 mmol).
mL, 19.4 mg, 0.190 mmol)
140.0, 133.9, 127.3, 109.4, 63.1, 14.4; IR (film) nmax 2979, 1726, 1661,
1610, 1472, 1349, 1284, 1164, 1022 cmꢂ1; HRMS (ESI) m/z 190.04838
(MNaþ, C8H9NO3Naþ requires 190.04746).
m
m
The reaction vessel was sealed, and the mixture was heated at
120 ꢁC for 2 d. After cooling to rt, the mixture was concentrated in
vacuo. Flash chromatography (SiO2, 25% EtOAc in hexanes elution)
afforded 2a (33.9 mg, 0.139 mmol, 73%) as a colorless oil: 1H NMR
4.6. S-Methyl 4-(benzyloxyimino)-2-ethyl-3-
oxobutanethioate (8)
(CDCl3, 500 MHz)
1H), 7.38–7.32 (m, 5H), 6.58 (d, J¼9.5 Hz, 1H), 5.17 (s, 2H), 3.84 (s,
3H); 13C NMR (CDCl3, 125 MHz)
164.9, 162.7, 142.9, 138.7, 135.7,
129.3 (2C), 128.6, 128.4 (2C), 120.3, 110.2, 52.9, 52.3; IR (film) nmax
2951, 1719, 1666, 1612, 1542, 1496, 1446, 1300, 1151 cmꢂ1; HRMS
(ESI) m/z 266.07975 (MNaþ, C14H13NO3Naþ requires 266.07876).
d
8.19 (d, J¼3.0 Hz, 1H), 7.84 (dd, J¼9.2, 2.8 Hz,
n-BuLi (1.6 M in hexane, 567
stirred solution of 1,1,1,3,3,3-hexamethyldisilazane (198
m
L, 0.907 mmol) was added to
a
mL,
d
153 mg, 0.950 mmol) in anhydrous THF (2.0 mL) at ꢂ5 ꢁC under Ar.
The resulting mixture was stirred at ꢂ5 ꢁC for 30 min, cooled to
ꢂ78 ꢁC, and treated with a solution of S-methyl butanethioate
(101 mL, 97.5 mg, 0.825 mmol) in anhydrous THF (590 mL). The
mixture was then stirred at ꢂ78 ꢁC for 30 min, treated with TMSCl
4.3. Methyl 1-(4-methoxybenzyl)-6-oxo-1,6-
dihydropyridine-3-carboxylate (2b)
(121
m
L, 104 mg, 0.953 mmol), stirred at ꢂ78 ꢁC for 1 h, allowed to
warm to rt, and stirred at rt for 15 min. The solvent was removed in
vacuo, the residue was suspended in hexane, and crude silyl ketene
thioacetal 6 was obtained by filtration. Compound 6 was then
To a solution of methyl pyruvate (17.5
mL, 19.4 mg, 0.190 mmol)
and methyl propiolate (31.8 L, 31.9 mg, 0.380 mmol) in MeOH
m
dissolved in anhydrous DMF (650 mL), and this solution was added

6588
Y. Zhang et al. / Tetrahedron 65 (2009) 6584–6590
to a stirred solution of LiOAc (3.9 mg, 0.059 mmol) in anhydrous
DMF (880 L) at rt under Ar. Next, a solution of methyl 2-(benzyl-
oxyimino)acetate (7, 113.8 mg, 0.589 mmol) in anhydrous DMF
(650 L) was added to the mixture, and it was stirred at rt under Ar
(Na2SO4), and concentrated in vacuo. Flash chromatography (SiO2,
8% EtOAc in hexanes elution) afforded 13 (106 mg, 0.221 mmol,
79%) as a colorless oil that was a 6:1 mixture of diastereomers fa-
voring the anti isomer (data for major isomer): 1H NMR (CDCl3,
m
m
for 6 h. The reaction was quenched by the addition of satd aq NH4Cl
(0.2 mL), and the mixture was extracted with EtOAc (3ꢃ1 mL). The
combined organic layers were washed with brine (0.3 mL), dried
(Na2SO4), and concentrated in vacuo. Flash chromatography (SiO2,
20% EtOAc in hexanes elution) afforded 8 (67.4 mg, 0.241 mmol,
500 MHz)
d
7.94 (d, J¼8.5 Hz, 2H), 7.42 (d, J¼8.5 Hz, 2H), 5.46 (d,
J¼10.0 Hz, 1H), 4.56 (d, J¼13.0 Hz, 1H), 4.18 (d, J¼13.5 Hz, 1H), 3.56
(s, 3H), 3.54–3.51 (m, 1H), 2.49 (s, 3H), 2.39 (s, 3H), 1.60–1.54 (m,
2H), 0.99 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
d 201.9, 168.7,
166.5, 146.4, 135.2, 130.3 (2C), 128.8 (2C), 62.5, 53.7, 52.8, 29.2, 23.7,
22.0, 12.1, 11.8; IR (film) nmax 2958, 1747, 1682, 1596, 1436, 1369,
1023 cmꢂ1; HRMS (ESI) m/z 501.99658 (MNaþ, C17H22NO6BrS2Naþ
requires 501.99641).
41%) as a colorless oil: 1H NMR (CDCl3, 500 MHz)
d 7.54 (s, 1H),
7.40–7.36 (m, 5H), 5.31 (s, 2H), 4.47 (t, J¼7.2 Hz, 1H), 2.28 (s, 3H),
1.99–1.92 (m, 2H), 0.92 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
d
195.5, 192.3, 147.6, 142.8, 136.2, 129.0 (2C), 128.8 (2C), 78.6, 63.0,
23.0, 19.5, 12.1; IR (film) nmax 2968, 2932, 1748, 1705, 1678, 1583,
1367,1340,1269,1181,1009 cmꢂ1; HRMS (ESI) m/z 280.10158 (MHþ,
C14H17NO3SHþ requires 280.10019). Additionally, an undetermined
4.9. Methyl 3-ethyl-4-(methylthio)-6-oxo-1-tosyl-1,2,3,6-
tetrahydropyridine-2-carboxylate (14)
amount of
contaminated with recovered 7.
b
-lactam 9 (identified by HRMS) could be obtained
A solution of 13 (28.1 mg, 0.0585 mmol) in anhydrous 1,2-di-
chloroethane (810
m
L) at ꢂ20 ꢁC under Ar was treated with TiCl4
(1.0 M in CH2Cl2, 87
mL, 0.087 mmol) followed by a solution of PPh3
4.7. Methyl 2-(4-methylphenylsulfonamido)-3-
(methylthiocarbonyl)pentanoate (11)
(22 mg, 0.0839 mmol) in anhydrous CH2Cl2 (270 mL). The resultant
mixture was stirred at ꢂ5 ꢁC under Ar for 16 h. The reaction was
quenched by the addition of H2O (100 mL), and the layers were sep-
n-BuLi (1.6 M in hexane, 690
m
L,1.1 mmol) was added to a stirred
L, 186 mg,
arated. The aqueous layer was extracted with EtOAc (3ꢃ1 mL), and
the combined organic layers were washed with brine (0.3 mL), dried
(Na2SO4), and concentrated in vacuo. Flash chromatography (SiO2,
15% EtOAc in hexanes elution) afforded 14 (16.2 mg, 0.0422 mmol,
72%) as a colorless oil that was a 6:1 mixture of diastereomers fa-
voring the anti isomer (data for major isomer): 1H NMR (CDCl3,
solution of 1,1,1,3,3,3-hexamethyldisilazane (240
m
1.15 mmol) in anhydrous THF (4.3 mL) at ꢂ5 ꢁC under Ar. The
resulting mixture was stirred at ꢂ5 ꢁC for 30 min, cooled to ꢂ78 ꢁC,
and treated with a solution of S-methyl butanethioate (120
mL,
118 mg, 0.998 mmol) in anhydrous THF (810
then stirred at ꢂ78 ꢁC for 30 min, treated with TMSCl (146
mL). The mixture was
mL,
500 MHz)
d
7.94 (d, J¼8.0 Hz, 2H), 7.31 (d, J¼8.0 Hz, 2H), 5.46 (d,
125 mg, 1.15 mmol), stirred at ꢂ78 ꢁC for 1 h, allowed to warm to rt,
and stirred at rt for 15 min. The solvent was removed in vacuo, the
residue was suspended in hexane, and crude silyl ketene thioacetal
6 was obtained by filtration. Compound 6 was then dissolved in
anhydrous DMF (1.0 mL), and this solution was added to a stirred
solution of LiOAc (4.2 mg, 0.0643 mmol) in anhydrous DMF
(0.84 mL) at rt under Ar. Next, a solution of methyl 2-(tosylimino)-
acetate (10, 156 mg, 0.647 mmol) in anhydrous DMF (1.0 mL) was
added to the mixture, and the resulting mixture was stirred at rt
under Ar for 6 h. The reaction was quenched by the addition of satd
aq NH4Cl (0.2 mL), and the mixture was extracted with EtOAc
(3ꢃ1 mL). The combined organic layers were washed with brine
(0.3 mL), dried (Na2SO4), and concentrated in vacuo. Flash chro-
matography (SiO2, 20% EtOAc in hexanes elution) afforded 11
(193 mg, 0.537 mmol, 83%) as a white solid that was a 6:1 mixture of
diastereomers favoring the anti isomer (data for major isomer): 1H
J¼2.5 Hz, 1H), 5.39 (d, J¼5.0 Hz, 1H), 3.59 (s, 3H), 3.17–3.13 (m, 1H),
2.43 (s, 3H), 2.24 (s, 3H), 2.14–2.09 (m, 1H), 1.69–1.63 (m, 1H), 1.22 (t,
J¼7.2 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
d 168.6, 161.7, 161.0, 145.0,
135.8,129.6 (2C),129.3 (2C),112.6, 58.5, 52.7, 45.2, 21.9, 21.1,14.9,12.4;
IR (film) nmax 2924, 2853, 1747, 1682, 1532, 1260, 1167, 1087 cmꢂ1
;
HRMS (ESI) m/z 406.07600 (MNaþ, C17H21NO5S2Naþ requires
406.07534).
4.10. Methyl 3-ethyl-4-(methylthio)-6-oxo-1,6-
dihydropyridine-2-carboxylate (15)
A solution of 14 (33 mg, 0.086 mmol) in DMF (3.0 mL) at rt was
treated with DBU (193 mL, 197 mg, 1.29 mmol). The resulting mix-
ture was stirred at rt for 6 h, treated with H2O (0.5 mL) and satd aq
NH4Cl (0.5 mL), and extracted with EtOAc (3ꢃ1 mL). The combined
organic layers were washed with brine (0.3 mL), dried (Na2SO4),
and concentrated in vacuo. Flash chromatography (SiO2, 3% MeOH
in CH2Cl2 elution) afforded 15 (19 mg, 0.084 mmol, 97%) as a white
NMR (CDCl3, 500 MHz)
d
7.71 (d, J¼8.5 Hz, 2H), 7.28 (d, J¼9.0 Hz,
2H), 5.56 (d, J¼11.0 Hz,1H), 4.15 (dd, J¼10.2, 4.8 Hz,1H), 3.46 (s, 3H),
3.00–2.96 (m, 1H), 2.41 (s, 3H), 2.25 (s, 3H), 1.89–1.80 (m, 1H), 1.72–
1.63 (m, 1H), 0.98 (t, J¼7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
solid: 1H NMR (CDCl3, 500 MHz)
d 9.50 (br s, 1H), 6.41 (s, 1H), 3.97
(s, 3H), 2.93 (q, J¼7.3 Hz, 2H), 2.43 (s, 3H), 1.18 (t, J¼7.2 Hz, 3H); 13C
d
201.2, 170.7, 143.8, 137.4, 129.7 (2C), 127.5 (2C), 56.8, 56.5, 52.8,
NMR (CDCl3, 125 MHz) d 161.8, 160.0, 157.9, 128.3, 126.3, 117.2, 53.5,
23.0, 21.8,12.0,11.8; IR (film) nmax 3279, 2966,1744,1674,1598,1435,
1385, 1165 cmꢂ1; HRMS (ESI) m/z 360.09427 (MHþ, C15H21NO5S2Hþ
requires 360.09339).
21.3, 15.0, 14.2; IR (film) nmax 2965, 2930, 1739, 1641, 1527, 1423,
1343, 1280, 1229, 1109, 1055, 927 cmꢂ1; HRMS (ESI) m/z 228.06996
(MHþ, C10H13NO3SHþ requires 228.06889).
4.8. Methyl 2-(2-bromo-N-tosylacetamido)-3-
(methylthiocarbonyl)pentanoate (13)
4.11. Methyl 3-ethyl-6-oxo-1,6-dihydropyridine-
2-carboxylate (16)
A solution of 11 (100 mg, 0.278 mmol) in anhydrous THF
(3.0 mL) at ꢂ78 ꢁC under Ar was treated with n-BuLi (1.6 M in
To a vigorously stirred mixture of 15 (20.6 mg, 0.0906 mmol) and
Lindlar catalyst (606.6 mg) in acetone (4.0 mL) at rt under Ar was
added Et3SiH (214.5 mL, 156 mg, 1.34 mmol) dropwise. The resulting
mixture was stirred at rt for 4 h, filtered through a plug of Celite
(washed with 7ꢃ3.5 mL acetone), and concentrated in vacuo. Flash
chromatography (SiO2, 4% MeOH in CH2Cl2 elution) afforded 16
(15.6 mg, 0.0861 mmol, 95%) as a white solid: 1H NMR (CDCl3,
hexane, 180
m
L, 0.289 mmol), stirred at ꢂ78 ꢁC for 10 min and at rt
for 5 min, then recooled to ꢂ78 ꢁC. Bromoacetyl chloride (25.5
mL,
48.8 mg, 0.310 mmol) was added, and the resulting mixture was
stirred at ꢂ78 ꢁC under Ar for 30 min, warmed to rt, and stirred for
12 h. The reaction was quenched by the addition of satd aq NH4Cl
(0.5 mL), and the mixture was extracted with EtOAc (3ꢃ2 mL). The
combined organic layers were washed with brine (0.5 mL), dried
500 MHz)
d
9.51 (br s, 1H), 7.34 (d, J¼9.0 Hz, 1H), 6.76 (d, J¼9.5 Hz,
1H), 3.97 (s, 3H), 2.84 (q, J¼7.5 Hz, 2H),1.18 (t, J¼7.5 Hz, 3H); 13C NMR

Y. Zhang et al. / Tetrahedron 65 (2009) 6584–6590
6589
(CDCl3, 125 MHz)
d
161.9, 161.4, 144.6, 128.9, 128.1, 127.3, 53.4, 25.0,
1352, 1167 cmꢂ1; HRMS (ESI) m/z 398.10827 (MHþ, C18H23NO5S2Hþ
15.2; IR (film) nmax 2968, 1736, 1662, 1605, 1437, 1324, 1282, 1234,
1099 cmꢂ1; HRMS (ESI) m/z 182.08252 (MHþ, C9H11NO3Hþ requires
182.08117).
requires 398.10904).
4.15. Methyl 3-isopropyl-4-(methylthio)-6-oxo-1,6-
dihydropyridine-2-carboxylate (21)
4.12. Methyl 4-methyl 2-(4-methylphenylsulfonamido)-3-
(methylthiocarbonyl)pentanoate (18)
Following the procedure detailed for the synthesis of 15, but using
20 (26 mg, 0.065 mmol), DMF (2.2 mL), and DBU (147
mL, 149 mg,
0.981 mmol) afforded 21 (15.2 mg, 0.063 mmol, 96%) as a colorless
Following the procedure detailed for the synthesis of 11, but
using n-BuLi (1.6 M in hexane, 3.40 mL, 5.5 mmol), 1,1,1,3,3,3-hexa-
methyldisilazane (1.20 mL, 930 mg, 5.75 mmol), anhydrous THF
(12 mL), S-methyl 3-methylbutanethioate (661.2 mg, 5.00 mmol),
film: 1H NMR (CDCl3, 500 MHz)
d 9.80 (br s, 1H), 6.38 (s, 1H), 3.96 (s,
3H), 2.43 (s, 3H), 2.06–1.99 (m, 1H), 1.35 (d, J¼7.0 Hz, 6H); 13C NMR
(CDCl3, 125 MHz)
d 177.7, 173.0, 159.8, 139.0, 130.2, 116.4, 53.5, 28.2,
20.6 (2C),15.7; IR (film) nmax 2925,1737,1650,1461 cmꢂ1; HRMS (ESI)
m/z 242.08599 (MHþ, C11H15NO3SHþ requires 242.08454).
anhydrous THF (3.5 mL), TMSCl (750 mL, 625 mg, 5.75 mmol), an-
hydrous DMF (4.5 mL), LiOAc (66.0 mg, 1.00 mmol), 10 (1.207 g,
5.00 mmol), and anhydrous DMF (3.5 mL) afforded 18 (1.382 g,
3.70 mmol, 74%) as a white solid that was a 1.6:1 mixture of di-
astereomers favoring the anti isomer. The isomers could be sepa-
rated for characterization purposes. For anti-18: 1H NMR (CDCl3,
4.16. Methyl 3-isopropyl-4-(methylthio)-6-oxo-1,6-
dihydropyridine-2-carboxylate (22)
Following the procedure detailed for the synthesis of 16, but
using 21 (10 mg, 0.041 mmol), Lindlar catalyst (300 mg), acetone
500 MHz)
d
7.70 (d, J¼8.5 Hz, 2H), 7.28 (d, J¼8.5 Hz, 2H), 5.42 (d,
J¼9.0 Hz, 1H), 4.16 (dd, J¼8.8, 5.8 Hz, 1H), 3.48 (s, 3H), 2.71 (dd,
J¼8.0, 6.0 Hz, 1H), 2.40 (s, 3H), 2.25 (s, 3H), 2.24–2.18 (m, 1H), 1.03
(d, J¼7.0 Hz, 3H), 0.90 (d, J¼7.0 Hz, 3H); 13C NMR (CDCl3, 125 MHz)
(2.0 mL), and Et3SiH (98
m
L, 71 mg, 0.61 mmol) afforded 22 (6.7 mg,
0.034 mmol, 83%) as a white solid: 1H NMR (CDCl3, 500 MHz)
d
9.28
(br s, 1H), 7.54 (d, J¼10.0 Hz, 1H), 6.80 (d, J¼9.5 Hz, 1H), 3.97 (s, 3H),
d
199.5, 170.5, 144.1, 136.7, 129.9 (2C), 127.6 (2C), 64.6, 55.5, 52.8,
2.06–1.96 (m, 1H), 1.19 (d, J¼7.0 Hz, 6H); 13C NMR (CDCl3, 125 MHz)
28.0, 21.8, 21.1, 20.0, 12.2; IR (film) nmax 3279, 2957, 1741, 1674, 1455,
1432, 1339, 1312, 1200, 1164, 1093 cmꢂ1; HRMS (ESI) m/z 374.10872
(MHþ, C16H23NO5S2Hþ requires 374.10904).
d
166.1, 159.4, 145.3, 131.2, 128.7, 127.2, 52.9, 27.2, 22.9 (2C); IR (film)
nmax 2973, 1696, 1668,1378 cmꢂ1; HRMS (ESI) m/z 196.09627 (MHþ,
C10H13NO3Hþ requires 196.09682).
For syn-18: 1H NMR (CDCl3, 500 MHz)
d
7.69 (d, J¼8.0 Hz, 2H),
7.26 (d, J¼7.5 Hz, 2H), 5.62 (d, J¼10.5 Hz,1H), 4.27 (dd, J¼10.5, 4.0 Hz,
1H), 3.40 (s, 3H), 2.64 (dd, J¼9.5, 4.0 Hz,1H), 2.40 (s, 3H), 2.24 (s, 3H),
2.22–2.16 (m, 1H), 0.98 (d, J¼7.0 Hz, 3H), 0.94 (d, J¼7.0 Hz, 3H); 13C
4.17. Methyl 2-(2-bromo-N-tosylpropanamido)-3-
(methylthiocarbonyl)pentanoate (23)
NMR (CDCl3, 125 MHz)
d 201.1, 170.5, 143.7, 137.5, 129.7 (2C), 127.4
Following the procedure detailed for the synthesis of 13, but
using 11 (584.5 mg, 1.63 mmol), anhydrous THF (8.0 mL), n-BuLi
(1.6 M in hexane, 1.50 mL, 2.40 mmol), and 2-bromopropanoyl
chloride (1.111 g, 6.50 mmol) afforded 23 (561 mg, 1.13 mmol, 70%)
as a colorless oil that was a mixture of diastereomers at the bromo-
(2C), 61.6, 55.9, 52.6, 28.1, 21.7, 20.9, 19.9, 12.1; IR (film) nmax 3342,
2965, 1745, 1670, 1342, 1168, 1143, 1093 cmꢂ1; HRMS (ESI) m/z
374.10852 (MHþ, C16H23NO5S2Hþ requires 374.10904).
bearing carbon: 1H NMR (CDCl3, 500 MHz)
d
7.68 (d, J¼8.0 Hz, 2H),
4.13. Methyl 2-(2-bromo-N-tosylacetamido)-4-methyl-3-
(methylthiocarbonyl)pentanoate (19)
7.26 (d, J¼8.0 Hz, 2H), 5.77–5.72 (m, 1H), 4.14–4.10 (m, 1H), 3.58 (s,
3H), 2.77–2.72 (m, 1H), 2.40 (s, 3H), 2.08 (s, 3H), 1.63–1.54 (m, 1H),
1.48–1.40 (m, 1H), 1.27–1.19 (m, 3H), 0.88–0.81 (m, 3H); 13C NMR
Following the procedure detailed for the synthesis of 13, but
using 18 (448.2 mg, 1.20 mmol), anhydrous THF (3.0 mL), n-BuLi
(1.6 M in hexane, 1.1 mL, 1.8 mmol), and bromoacetyl chloride
(CDCl3, 125 MHz) d 200.7, 175.7, 172.3, 143.3, 139.2, 129.6 (2C), 127.4
(2C), 60.6, 51.8, 50.4, 31.7, 23.7, 22.3, 21.7, 17.8, 14.0, 11.9; IR (film)
nmax 2960, 1738, 1435, 1336, 1161 cmꢂ1; HRMS (ESI) m/z 494.02870
(MHþ, C18H24BrNO6S2Hþ requires 494.03012).
(400
51%) as a colorless oil that was a 1.6:1 mixture of diastereomers: 1H
NMR (CDCl3, 500 MHz, data for major isomer)
mL, 756 mg, 4.80 mmol) afforded 19 (304.8 mg, 0.616 mmol,
d
7.97 (d, J¼7.0 Hz,
2H), 7.39 (d, J¼8.5 Hz, 2H), 5.34 (d, J¼7.0 Hz, 1H), 4.53 (d, J¼14.5 Hz,
1H), 4.06 (d, J¼13.5 Hz, 1H), 3.59 (s, 3H), 3.56–3.51 (m, 1H), 2.47 (s,
3H), 2.36 (s, 3H), 2.28–2.17 (m, 1H), 1.05 (d, J¼6.5 Hz, 3H), 0.92 (d,
J¼6.5 Hz, 3H); HRMS (ESI) m/z 494.03259 (MHþ, C18H24BrNO6S2Hþ
requires 494.03012).
4.18. Methyl 3-ethyl-5-methyl-4-(methylthio)-6-oxo-1-
tosyl-1,2,3,6-tetrahydropyridine-2-carboxylate (24)
Following the procedure detailed for the synthesis of 14, but
using 23 (43 mg, 0.0870 mmol), anhydrous 1,2-dichloroethane
(1.2 mL), TiCl4 (1.0 M in CH2Cl2, 140
mL, 0.140 mmol), PPh3 (34 mg,
4.14. Methyl 3-isopropyl-4-(methylthio)-6-oxo-1-tosyl-
1,2,3,6-tetrahydropyridine-2-carboxylate (20)
0.13 mmol), and anhydrous CH2Cl2 (400
0.020 mmol, 24%) as a colorless film that was a ca. 1.1:1 mixture of
m
L) afforded 24 (8.1 mg,
diastereomers, and ketone 25 (18 mg, 0.049 mmol, 56%) as a col-
Following the procedure detailed for the synthesis of 14, but
using 19 (19.7 mg, 0.0398 mmol), anhydrous 1,2-dichloroethane
orless film. for 24: 1H NMR (CDCl3, 500 MHz)
d 7.77 and 7.74 (2d,
J¼8.5 Hz, 2H), 7.31–7.27 (m, 2H), 6.00 and 5.57 (2d, J¼9.0 and
10.0 Hz, 1H), 3.65 and 3.66 (2s, 3H), 2.98–2.94 and 2.86–2.82 (2m,
1H), 2.43 and 2.42 (2s, 3H), 2.18 (s, 3H), 1.73–1.64 and 1.85–1.79
(2m, 1H), 1.57 (s, 3H), 1.53–1.46 and 1.43–1.38 (2m, 1H), 0.92 and
0.99 (2t, J¼7.5 Hz, 3H); HRMS (ESI) m/z 398.10839 (MHþ,
C18H23NO5S2Hþ requires 398.10904).
(540
mL), TiCl4 (1.0 M in CH2Cl2, 61
mL, 0.061 mmol), PPh3 (16 mg,
0.061 mmol), and anhydrous CH2Cl2 (180
m
L) afforded 20 (13 mg,
0.033 mmol, 82%) as a colorless oil that was a ca. 3:1 mixture of
diastereomers: 1H NMR (CDCl3, 500 MHz, data for major isomer)
d
8.00 (d, J¼8.5 Hz, 2H), 7.32 (d, J¼9.0 Hz, 2H), 5.43 (s, 1H), 5.41 (d,
J¼2.0 Hz, 1H), 3.68 (s, 3H), 2.73 (dd, J¼7.0, 2.0 Hz, 1H), 2.44 (s, 3H),
2.28 (s, 3H), 2.07–2.00 (m, 1H), 1.14 (d, J¼7.0 Hz, 3H), 1.13 (d,
J¼6.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz, data for major isomer)
For 25: 1H NMR (CDCl3, 500 MHz)
d
7.93 (d, J¼8.5 Hz, 2H), 7.33
(d, J¼8.5 Hz, 2H), 5.45 (s, 1H), 3.80 (s, 3H), 3.16 (q, J¼7.5 Hz, 1H),
2.73 (sextet, J¼7.3 Hz, 1H), 2.47–2.40 (m, 1H), 2.44 (s, 3H), 2.36
(sextet, J¼7.2 Hz, 1H), 1.38 (d, J¼7.0 Hz, 3H), 1.12 (t, J¼7.2 Hz, 3H);
d
170.6, 161.3, 160.2, 145.0, 132.4, 130.0 (2C), 129.1 (2C), 112.2, 58.8,
53.2, 49.7, 31.5, 21.9, 21.3, 20.3, 15.0; IR (film) nmax 2961, 1749, 1683,
13C NMR (CDCl3, 125 MHz)
d 170.9, 169.5, 145.4, 135.4, 132.9, 129.7

6590
Y. Zhang et al. / Tetrahedron 65 (2009) 6584–6590
D.; Wang, K.; Zhang, J.; Wu, R.; Xiang, D.; Liu, Q. Org. Lett. 2007, 9, 2421; (i) Tsai,
T.-H.; Chung, W.-H.; Chang, J.-K.; Hsu, R.-T.; Chang, N.-C. Tetrahedron 2007, 63,
9825; (j) Boisse, T.; Rigo, B.; Millet, R.; He´nichart, J.-P. Tetrahedron 2007, 63,
10511; (k) Pemberton, N.; Jakobsson, L.; Almqvist, F. Org. Lett. 2006, 8, 935; (l)
Kondo, T.; Nomura, M.; Ura, Y.; Wada, K.; Mitsudo, T. Tetrahedron Lett. 2006, 47,
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H. A.; Cross, M. J.; Louie, J. J. Am. Chem. Soc. 2004, 126, 11438.
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(2C), 129.4 (2C), 61.3, 53.3, 42.0, 25.2, 21.9, 18.5, 14.6, 12.5; IR (film)
nmax 2931, 1749, 1708, 1359, 1171, 1087 cmꢂ1; HRMS (ESI) m/z
368.11745 (MHþ, C17H21NO6SHþ requires 368.11623).
4.19. Methyl 3-ethyl-5-methyl-6-oxo-1,6-
dihydropyridine-2-carboxylate (26)
Following the procedure detailed for the synthesis of 15, but
using 24 (3.7 mg, 0.0093 mmol), DMF (1.1 mL), and DBU (71 mL,
72 mg, 0.47 mmol) afforded the vinyl sulfide intermediate, which
was reduced according to the procedure detailed for the synthesis of
16, but using Lindlar catalyst (230 mg), acetone (1.5 mL), and Et3SiH
6. Bisai, A.; West, S. P.; Sarpong, R. J. Am. Chem. Soc. 2008, 130, 7222.
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P.; Kocovsky, P. J. Org. Chem. 2003, 68, 4727; (b) Cappelli, A.; Anzini, M.; Vomero,
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Menziani, M. C.; De Benedetti, P. G.; Langer, T. J. Med. Chem. 1998, 41, 728; (c)
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1998, 1287; (d) Kozikowski, A. P.; Campiani, G.; Sun, L.-Q.; Wang, S.; Saxena, A.;
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Donohoe, T. J.; Fishlock, L. P.; Procopiou, P. A. Synthesis 2008, 2665.
11. Fujisawa, H.; Takahashi, E.; Mukaiyama, T. Chem.dEur. J. 2006, 12, 5082.
12. Rosen, S.; Shahak, I.; Bergmann, E. D. Tetrahedron 1973, 29, 2327.
13. Evans, D. A.; Black, W. C. J. Am. Chem. Soc. 1993, 115, 4497.
14. For reviews of the Reformatsky reaction, see: (a) Ocampo, R.; Dolbier, W. R., Jr.
Tetrahedron 2004, 60, 9325; (b) Fu¨rstner, A. Synthesis 1989, 571; (c) Rathke, M. W.
Org. React. 1975, 22, 423.
(75
m
L, 55 mg, 0.47 mmol), affording 26 (1.4 mg, 0.0072 mmol, 77%)
as a white film: 1H NMR (CDCl3, 500 MHz)
d
9.36 (br s, 1H), 7.20 (s,
1H), 3.95 (s, 3H), 2.82 (q, J¼7.5 Hz, 2H), 2.21 (s, 3H), 1.18 (t, J¼7.2 Hz,
3H); HRMS (ESI) m/z 218.06491 (MNaþ, C10H13NO3Naþ requires
218.07876).
Acknowledgements
We thank the National Science Foundation (CHE-716991) for
financial support.
15. Kashima, C.; Huang, X. C.; Harada, Y.; Hosomi, A. J. Org. Chem. 1993, 58, 793.
16. Kashima, C.; Kita, I.; Takahashi, K.; Hosomi, A. J. Heterocycl. Chem. 1995, 32, 723.
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21. Yoo, K. H.; Choi, E. B.; Lee, H. K.; Yeon, G. H.; Yang, H. C.; Pak, C. S. Synthesis 2006,
1599.
References and notes
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