BF3·OEt2-mediated C-C bond-forming reaction of α-hydroxyketene-(S,S)-acetals with active methylene compounds and its application in the synthesis of substituted 3,4-dihydro-2-pyridones

Article abstract of DOI:10.1055/s-2006-958412

The C-C bond-forming reaction between α-hydroxyketene-(S,S)-acetals 2 and active methylene compounds is described. Mediated by boron trifluoride etherate (BF₃·OEt₂), a series of C-C bond coupling products, 2-(2-acetyl-1-methyl-3-oxob

Full text of DOI:10.1055/s-2006-958412

156
LETTER
BF3·OEt2-Mediated C–C Bond-Forming Reaction of a-Hydroxyketene-(S,S)-
acetals with Active Methylene Compounds and Its Application in the Synthesis
of Substituted 3,4-Dihydro-2-pyridones
B
F
·
O
Et
-
2 uMediatedC–
n
C
Bond-Forming
R
L
eaction of
a
-
H
i
ydroxy
u
ketene-(
S
,
S
)-
,
acetals Fushun Liang,* Qun Liu,* Bing Li
3
Department of Chemistry, Northeast Normal University, Changchun 130024, P. R. of China
Fax +86(431)5099759; E-mail: liangfs112@nenu.edu.cn
Received 24 July 2006
been recognized.5 In our recent research, a-alkenoyl
ketene-(S,S)-acetals, as five-carbon 1,5-bielectrophilic
synthons, have been utilized to construct six-membered
carbocycles and/or heterocycles including highly substi-
Abstract: The C–C bond-forming reaction between a-hydroxy-
ketene-(S,S)-acetals 2 and active methylene compounds is de-
scribed. Mediated by boron trifluoride etherate (BF3·OEt2), a series
of C–C bond coupling products, 2-(2-acetyl-1-methyl-3-oxobutyl)-
N-aryl-3,3-bis(ethylthio)acrylamides 3 was obtained in high to ex- tuted phenols, functionalized 2,3-dihydro-4-pyridones,
cellent yields by the reaction of 2a–e (R1 = Ar) with acetylacetone.
pyrido[2,3-d]pyrimidines and 2,3-dihydrothiopyran-4-
ones based on [5C+1C],6a [5C+1N],6b,c and [5C+1S]6d
Various N-aryl-substituted 3,4-dihydropyridones 5 were prepared
in high yields from 3 via a two-step procedure. Upon the reaction of
annulation strategies, respectively. On the other hand, as
2f (R1 = H) with active methylene compounds, 3,4-dihydropyri-
dones 6 and/or 7, were obtained in a one-pot reaction with moderate
to good yields.
part of the synthetic applications of a-oxoketene-(S,S)-
acetals,7 a series of a-hydroxyketene-(S,S)-acetals was
obtained based on the Morita–Baylis–Hillman (MBH) re-
actions of a-acetylketene-(S,S)-acetals (used as activated
Keywords: C–C bond-forming reaction, a-hydroxyketene-(S,S)-
acetals, active methylene compounds, substituted 3,4-dihydro-2-
alkenes) with carbonyl compounds in the presence of
titanium tetrachloride catalyst.8 It was found that the re-
sulting a-hydroxyketene-(S,S)-acetals, as a special type of
allylic alcohol, may further react with a-acetylketene-
(S,S)-acetals (activated alkene), furnishing the double
MBH adducts.8 This procedure provides a new entry to
chemoselective Csp2–Csp3 bond formation starting from
the corresponding a-hydroxyketene-(S,S)-acetals. Asokan
and co-workers also presented the utility of a-hydroxy-
ketene dithioacetals in organic synthesis. For example,
they reported the synthesis of substituted pyridines from
Vilsmeier–Haack reactions of a-hydroxyketene-(S,S)-
acetals9 and the synthesis of a,b-unsaturated dithioesters
from the reaction of a-hydroxyketene-(S,S)-acetals with
Lawesson’s reagent.10 Inspired by the abovementioned
MBH reactions, in our continuing research on the synthet-
ic applications of a-oxoketene-(S,S)-acetals, we focused
our attention on the construction of a Csp3–Csp3 bond from
a-hydroxyketene-(S,S)-acetals and active methylene com-
pounds. The application of this methodology led to the
formation of a C–C coupling product, which in turn could
be used for the synthesis of 3,4-dihydro-2-pyridones,
which serve as valuable building blocks in the construc-
tion of piperidines, perhydroquinolones, indolizidines,
quinolizidines and other alkaloid ring systems and have a
wide range of biological and pharmacological activities.11
The general and common methods towards 3,4-dihydro-
2-pyridones require multistep synthesis,12–14 usually via a
combination of three steps: (1) a condensation, (2) a con-
jugate addition, and (3) an N-acylation.14a Therefore, de-
velopment of simple and convenient synthetic procedures
for such nitrogen-containing heterocycles represents an
attractive and interesting area of research in synthetic or-
ganic and medicinal chemistry. Herein, we wish to report
our experimental results.
pyridones, one-pot synthesis
The carbon–carbon bond-forming reaction is one of the
most fundamental approaches for the construction of
molecular framework in organic chemistry.1 In carbon–
carbon bond-forming reactions, the direct displacement of
the hydroxyl group of an allylic or benzylic alcohol by a
carbon nucleophile would be quite useful since it would
be both atom-efficient and environmentally benign be-
cause preparation of the reactive materials would not be
required (alcohols are generally transformed into the cor-
responding halides or esters prior to reactions with nu-
cleophiles due to the fact that the hydroxyl group is a poor
leaving group) and only water would be generated as a
side product.2 In this context, expansion of substrates for
this type of reaction to a wide range of active methylene
compounds and other types of alcohols is desired and has
stimulated much interest in organic chemists. Recently,
Baba and co-workers described the direct carbon–carbon
bond forming from alcohols and active methylenes,
alkoxyketones, and indoles catalyzed by indium trichlo-
ride.3 Kaneda et al. reported a Brønsted acid mediated
heterogeneous addition reaction of 1,3-dicarbonyl com-
pounds to alkenes and alcohols.4 Hence, the selection of
suitable substrates, especially the alcohol component, for
the carbon–carbon bond-forming reaction is of great
significance in achieving the synthetic applications.2,3
Over the past decades, the utility of a-oxoketene-(S,S)-
acetals as versatile intermediates in organic synthesis has
SYNLETT 2007, No. 1, pp 0156–0160
Advanced online publication: 20.12.2006
DOI: 10.1055/s-2006-958412; Art ID: W15306ST
© Georg Thieme Verlag Stuttgart · New York
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4.
0
1.
2
0
0
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LETTER
BF3·OEt2-Mediated C–C Bond-Forming Reaction of a-Hydroxyketene-(S,S)-acetals
157
Initially, a variety of a-hydroxyketene-(S,S)-acetals 2 Table 3 Reactions of a-Hydroxyketene-(S,S)-acetals 2 with
Acetylacetone
were prepared in excellent yields by reduction with sodi-
um borohydride of the corresponding a-acetylketene-
Entry Substrate R1
Time
(min)
Product Yield of 3
(S,S)-acetals 1.15 For example, upon treatment of 1a with
sodium borohydride (1.1 equiv) in methanol at 0 °C for
about 55 minutes, alcohol 2a was obtained in 96% isolat-
ed yield after workup (Table 1). Similarly, alcohols 2b–f
were obtained in 93–97% yields under the identical
conditions.
(%)a
1
2
3
4
2b
2c
2d
2e
4-ClC6H4
30
45
50
50
3b
3c
3d
3e
90
82
84
82
2-MeC6H4
2,4-Me2C6H3
2-MeOC6H4
Table 1 Reduction Reactions of a-Acetylketene-(S,S)-acetals 1
a Isolated yields after silica gel chromatography.
O
O
OH
O
NHR1
NaBH4
MeOH
NHR1
acetylacetone was first examined to optimize the reaction
conditions. Thus, the variation of solvents (THF, DMF,
CH2Cl2 and MeCN) and temperature (0 °C to r.t.) were
investigated (Table 2). It was found that either in dichlo-
romethane or in N,N-dimethylformamide, no C–C cross-
coupling products were detected when the reaction of 2a
with acetylacetone (1.2 equiv) proceeded at 0 °C for three
hours in the presence of BF3·OEt2 (1.2 equiv) (Table 2,
entries 1 and 2). When tetrahydrofuran or acetonitrile was
used as the solvent (entries 3 and 4, respectively), the re-
action afforded 3a in low to moderate yields. However,
when the reaction was carried out with neat acetylacetone
(2a–acetylacetone = 1.0:15.0, molar ratio) and was cata-
lyzed by BF3·OEt2 (1.2 equiv) at 0 °C for 40 minutes, the
product 3a was obtained in 87% yield (Table 2, entry 5).
When the reaction was performed at room temperature, 3a
was produced in relatively low yield (70%, Table 2, entry
6). Under the optimized conditions as described above
(Table 2, entry 5), the corresponding C–C coupling prod-
ucts 3b–e (R1 = Ar) were obtained in high to excellent
yields (82–90%, Table 3, entries 1–4).16
EtS
SEt
1a–f
EtS
SEt
2a–f
Entry
Substrate R1
Product Time
(min)
Yield
(%)a
1
2
3
4
5
6
1a
1b
1c
1d
1e
1f
C6H5
2a
2b
2c
2d
2e
2f
55
45
45
60
50
30
96
97
95
93
93
95
4-ClC6H4
2-MeC6H4
2,4-Me2C6H3
2-MeOC6H4
H
a Isolated yields after silica gel chromatography.
With the readily available alcohols 2 in hand, we next
turned to the study of the C–C cross-coupling reaction of
2 with active methylene compounds (Table 2 and
Table 3). A model reaction between 2a (R1 = Ph) with
Once products 3a–e were obtained, their transformation
into pyridones was studied. However, direct transforma-
tion of 3 into pyridones with either BF3·OEt2 or titanium
tetrachloride–triethylamine was unsuccessful after
several attempts. Looking for an alternative route, com-
pounds 3a–e were then deacetylated by treatment with
sodium hydroxide (1.2 equiv) in ethanol at 60 °C, afford-
ing products 4a–e in 80–89% yields (Table 4). The aza-
annulation of 4a–e was tried in the presence of BF3·OEt2
(1.2 equiv) at 0 °C, but the desired products were not
obtained. To our delight, by replacing BF3·OEt2 with
titanium tetrachloride–triethylamine, the cyclization
products N-aryl-substituted 3,4-dihydro-2-pyridones
5a–e were generated in 81–88% yields (Table 4).17
Meanwhile, the reactions of alcohol 2f (R1 = H) with ac-
tive methylene compounds were investigated under iden-
tical conditions as mentioned above. Interestingly, the
formation of a pyridone ring was achieved by a one-pot
process (Table 5). Thus, when 2f was treated with acetyl-
acetone (15.0 equiv) and boron trifluoride, pyridone 6a
was obtained as the sole product (Table 5, entry 1). To ex-
tend this interesting one-pot reaction, other active methyl-
ene compounds such as b-ketoesters, b-diesters and
Table 2 Reaction of 2a with Acetylacetone under Different Condi-
tions
O
O
O
O
SEt
OH
O
SEt
CONHPh
NHPh
SEt
BF3·OEt2
EtS
2a
3a
Entrya
2a
Acetylacetone Solvent
Time
(h)
Yield of
(mmol) (mmol)
3a (%)b
1
2
3
4
5
6
1.0
1.0
1.0
1.0
1.0
1.0
1.2
1.2
CH2Cl2
DMF
THF
MeCN
–
3.0
3.0
2.0
2.0
0.7
0.5
0c
0c
1.2
12
1.2
45
15.0
15.0
87
–
70
a BF3 (1.2 equiv) was used in all the reactions.
b Isolated yields after silica gel chromatography.
c Complex product mixture was obtained.
Synlett 2007, No. 1, 156–160 © Thieme Stuttgart · New York

158
J. Liu et al.
LETTER
benzoylacetone were subjected to the reaction sequences. acid character (pKa = 16.4, while for acetylacetone, pKa =
When the reaction was performed with ethyl acetylacetate 13.3; for ethyl acetylacetate, pKa = 14.2).19 Accordingly,
(Table 5, entry 2), the structure of the resulting product a series of 5-substituted 3-[bis(ethylthio)methylene]-4,6-
could not be easily determined from the corresponding 1H dimethyl-3,4-dihydropyridones 6 and/or 3-[(difluoro-
and 13C NMR spectra and mass spectrum. Fortunately, boryloxy)(ethylthio)methylene]-4,6-dimethyl-3,4-dihydro-
single-crystals could be grown in a mixture of petroleum pyridones 7 were successfully prepared in moderate to
ether and dichloromethane and the structure was estab- good yields.20 Indeed, this protocol provides a convenient
lished by X-ray diffraction analysis as 7b (Figure 1).18 In and efficient one-pot synthesis of polysubstituted 3,4-di-
the case of using methyl acetylacetate as the carbon nu- hydro-2-pyridones.
cleophile, the reaction furnished two products, 6c and 7c,
with respective yields of 23% and 35% (Table 5, entry 3).
The possible mechanism for the formation of pyridones 6
and/or 7 from substrate 2f is proposed, as depicted in
For benzoylacetone substrate, 5-benzoyl-3-[(difluoro-
Scheme 1.21,22 The carbon–carbon coupling depends on
boryloxy)(ethylthio)methylene]-4,6-dimethyl-3,4-dihydro-
the formation of the allylic carbocation generated from 2f.
This is then followed by the azaannulation to give pyri-
pyridone (7d) was the main product (66% yield, Table 5,
entry 4). The diesters, such as ethyl malonate were found
to be inert to the C–C bond coupling reaction under the
identical conditions, probably due to its relatively weak
and subsequent formation of the BF3 complex.23
done 6. Clearly, the formation of 7 would involve the
hydrolysis of 6 (SNV, nucleophilic vinylic substitution)22
Table 4 Synthesis of N-Aryl-Substituted 3,4-Dihydro-2-pyridones from 3
SEt
O
O
SEt
O
SEt
TiCl4, Et3N
CH2Cl2
SEt
NaOH
EtOH
SEt
CONHAr
SEt
CONHAr
N
O
Ar
3a–e
4a–e
5a–e
Entry
Substrate
Ar
Ph
Product 4
Yield of 4 (%)
Product 5a
Yield of 5 (%)b
1
2
3
4
5
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
87
89
85
83
80
5a
5b
5c
5d
5e
85
88
85
81
82
4-ClC6H4
2-MeC6H4
2,4-Me2C6H3
2-MeOC6H4
a The cyclization reactions were carried out in the presence of TiCl4–Et3N at 0 °C.
b Isolated yields.
Table 5 Reactions of a-Hydroxyketene-(S,S)-acetals 2f with Active Methylenes
OH
O
O
SEt
O
SEt
O
O
R2
SEt
R2
O
R2
NH2
SEt
F
+
B
EtS
BF3·OEt2
N
H
O
N
H
O
F
2f
6
7
Entry
Substrate
R2
Time (h)
Product 6
Yield (%)a
Product 7
Yield (%)a
6
7
b
1
2
3
4
2f
2f
2f
2f
Me
2.0
5.0
4.5
6.0
6a
6b
6c
6d
89
7a
7b
7c
–
b
EtO
MeO
Ph
–
54
35
66
23
b
–
7dc
a Isolated yields after silica gel chromatography.
b Not detected.
c MeCN was used as the solvent.
Synlett 2007, No. 1, 156–160 © Thieme Stuttgart · New York

LETTER
BF3·OEt2-Mediated C–C Bond-Forming Reaction of a-Hydroxyketene-(S,S)-acetals
159
References and Notes
(1) (a) March, J. Advanced Organic Chemistry, 4th ed.; Wiley:
New York, 1992. (b) Current Trends in Organic Synthesis;
Scolastico, C.; Nicotra, F., Eds.; Plenum: New York, 1999.
(2) (a) Trost, B. M. Science 1991, 254, 1471. (b) Kabalka, G.
W.; Yao, M.-L.; Borella, S.; Wu, Z.-Z. Org. Lett. 2005, 7,
2865; and references therein.
(3) Yasuda, M.; Somyo, T.; Baba, A. Angew. Chem. Int. Ed.
2006, 45, 793.
(4) Motokura, K.; Fujita, N.; Mori, K.; Mizugaki, T.; Ebitani,
K.; Kaneda, K. Angew. Chem. Int. Ed. 2006, 45, 2605.
(5) For reviews on the synthesis and application of a-oxoketene-
(S,S)-acetals, see: (a) Dieter, R. K. Tetrahedron 1986, 42,
3029. (b) Tominaga, Y. J. Heterocycl. Chem. 1989, 26,
1167. (c) Junjappa, H.; Ila, H.; Asokan, C. V. Tetrahedron
1990, 46, 5423. (d) Kolb, M. Synthesis 1990, 171.
(e) Junjappa, H.; Ila, H. Phosphorus, Sulfur Silicon 1994, 35,
95. (f) Junjappa, H.; Ila, H.; Mohanta, P. K. In Progress in
Heterocyclic Chemistry, Vol. 13; Gribble, G. H.; Gilchrist,
L. T., Eds.; Pergamon Press: Oxford, 2001, Chap. 1, 1–24.
(6) (a) Bi, X.; Dong, D.; Liu, Q.; Pan, W.; Zhao, L.; Li, B. J. Am.
Chem. Soc. 2005, 127, 4578. (b) Dong, D.; Bi, X.; Liu, Q.;
Cong, F. Chem. Commun. 2005, 28, 3580. (c) Zhao, L.;
Liang, F.; Bi, X.; Sun, S.; Liu, Q. J. Org. Chem. 2006, 71,
1094. (d) Bi, X.; Dong, D.; Li, Y.; Liu, Q. J. Org. Chem.
2005, 70, 10886.
Figure 1 ORTEP drawing of compound 7b
OH
O
O
CONH2
CONH2
BF3·OEt2
R2
HOBF3
– H2OBF3
EtS
SEt
EtS
SEt
2f
(7) (a) Liu, Q.; Che, G.; Yu, H.; Liu, Y.; Zhang, J.; Zhang, Q.;
Dong, D. J. Org. Chem. 2003, 68, 9148. (b) Yu, H.; Liu, Q.;
Yin, Y.; Fang, Q.; Zhang, J.; Dong, D. Synlett 2004, 999.
(c) Bi, X.; Liu, Q.; Sun, S.; Liu, J.; Pan, W.; Zhao, L.; Dong,
D. Synlett 2005, 49. (d) Zhao, Y.; Liu, Q.; Zhang, J.; Liu, Z.
J. Org. Chem. 2005, 70, 6913.
(8) (a) Yin, Y.; Wang, M.; Liu, Q.; Hu, J.; Sun, S.; Kang, J.
Tetrahedron Lett. 2005, 46, 4399. (b) Pan, W.; Dong, D.;
Sun, S.; Liu, Q. Synlett 2006, 1090.
O
SEt
SEt
O
SEt
SEt
BF3
– H2O
H2O
– HSEt
R2
R2
CONH2
N
O
O
H
6
O
SEt
O
SEt
BF3
R2
O
(9) Thomas, A. D.; Asokan, C. V. Tetrahedron Lett. 2002, 43,
2273.
R2
OH
F
B
N
H
O
(10) Nair, S. K.; Jose, A. M.; Asokan, C. V. Synthesis 2005, 1281.
(11) Selected examples: (a) Kuethe, J. T.; Comins, D. L. J. Org.
Chem. 2004, 69, 5219. (b) Huang, S.; Comins, D. L. Chem.
Commun. 2000, 569. (c) Kuethe, J. T.; Comins, D. L. Org.
Lett. 2000, 2, 855. (d) Avenoza, A.; Busto, J. H.; Cativiela,
C.; Corzana, F.; Peregrina, J. M.; Zurbano, M. M. J. Org.
Chem. 2002, 67, 598.
(12) Reviews on the synthesis of pyridones: (a) McKillop, A.;
Boulton, A. In Comprehensive Heterocyclic Chemistry, Vol.
2, Part 2A; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon
Press: New York, 1984, 67ff. (b) Jones, G. In
N
H
O
F
7
Scheme 1 Possible mechanism for the formation of 6 and/or 7
In summary, the C–C bond-forming reaction of a-hy-
droxyketene-(S,S)-acetals and active methylene com-
pounds has been described. The utility of the C–C bond
formation products has been demonstrated in the syn-
thesis of N-aryl-substituted 3-[bis(ethylthio)methylene]-
4,6-dimethyl-3,4-dihydropyridones 5 and substituted
2,3-dihydro-3-[bis(ethylthio)methylene]-4,6-dimethyl-
3,4-dihydropyridones 6 and/or 3-[(difluoroboryloxy)(eth-
ylthio)methylene]-4,6-dimethyl-3,4-dihydropyridones 7
in concise steps and good to high yields. The protocol
provides a simple, straightforward, and efficient synthesis
of polysubstituted 3,4-dihydro-2-pyridones. Further
studies on the extension on the scope of this C–C bond-
forming reaction, as well as synthetic applications, are
ongoing.
Comprehensive Heterocyclic Chemistry, Vol. 5; Katritzky,
A. R.; Rees, C. W.; Scriven, E. F. V., Eds.; Pergamon Press:
Oxford, 1996, 167–243. (c) Torres, M.; Gil, S.; Parra, M.
Curr. Org. Chem. 2005, 9, 1757.
(13) Review on synthetic methods for 2-pyridones: Torres, M.;
Gil, S.; Parra, M. Curr. Org. Chem. 2005, 9, 1757; and
references cited therein.
(14) Selected examples: (a) Wagman, A. S.; Wang, L.; Nuss, J.
M. J. Org. Chem. 2000, 65, 9103. (b) Carles, L.; Narkunan,
K.; Penlou, S.; Rousset, L.; Bouchu, D.; Ciufolini, M. A. J.
Org. Chem. 2002, 67, 4304. (c) Itami, K.; Yamazaki, D.;
Yoshida, J. Org. Lett. 2003, 5, 2161. (d) Ferraccioli, R.;
Carenzi, D.; Motti, E.; Catellani, M. J. Am. Chem. Soc. 2006,
128, 722.
(15) (a) Ouyang, Y.; Dong, D.; Yu, H.; Liang, Y.; Liu, Q. Adv.
Synth. Catal. 2006, 348, 206. (b) Pak, C. S.; Choi, E. B.
Synthesis 1992, 1291.
(16) Preparation of 3 (3a as an example); Typical Procedure:
To a well-stirred suspension of 2a (1.0 mmol, 0.31 g) in
Acknowledgment
Financial supports from the Key Grant Project of Chinese Ministry
of Education (10412) and the National Natural Sciences Foundation
of China (20272008) are gratefully acknowledged.
Synlett 2007, No. 1, 156–160 © Thieme Stuttgart · New York

160
J. Liu et al.
LETTER
anhyd acetylacetone (15 mmol, 1.55 mL) was added
BF3·OEt2 (1.2 mmol, 0.15 mL). The mixture was stirred for
40 min at 0 °C until the reaction was complete (as indicated
by TLC) and neutralized with aq NaHCO3 (10%). After
workup, the crude product was purified by column
chromatography (eluent: PE–EtOAc, 5:1) to give 3a in 87%
yield.
(d, J = 6.5 Hz, 3 H), 1.23–1.32 (m, 6 H), 1.55 (s, 3 H), 2.81–
2.95 (m, 4 H), 3.99–4.02 (q, J = 6.5 Hz, 1 H), 5.22 (d, J = 7.5
Hz, 1 H), 7.10 (t, J = 8.5 Hz, 2 H), 7.37 (d, J = 8.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3): d = 162.4, 142.2, 136.7, 136.2,
132.9, 132.4, 129.4, 128.2 (2 × C), 109.5 (2 × C), 33.4, 28.2,
27.7, 19.3, 19.0, 14.2, 13.4. IR (KBr): 3070, 2964, 2927,
2865, 1644, 1487, 1454, 1085, 775 cm–1. MS: m/z = 368.1
[M + H]+. Anal. Calcd for C18H22ClNOS2: C, 58.75; H, 6.03;
N, 3.81. Found: C, 58.58; H, 5.96; N, 3.70.
Selected data for compounds 3:
2-(2-Acetyl-1-methyl-3-oxobutyl)-N-phenyl-3,3-
bis(ethylthio)acrylamide (3a): white solid; mp 88–91 °C.
1H NMR (500 MHz, CDCl3): d = 1.15 (d, J = 6.5 Hz, 3 H),
1.17–1.21 (m, 3 H), 1.25–1.66 (m, 3 H), 2.23 (s, 3 H), 2.24
(s, 3 H), 2.61–2.92 (m, 4 H), 4.06 (d, J = 11.5 Hz, 1 H), 4.21
(m, 1 H), 7.12–7.15 (m, 1 H), 7.34 (t, J = 7.5 Hz, 2 H), 7.58
(t, J = 7.5 Hz, 2 H), 7.75 (s, 1 H). 13C NMR (125 MHz,
CDCl3): d = 204.0, 202.6, 164.7, 146.6, 136.7, 132.8, 128.1
(2 × C), 123.6, 118.8 (2 × C), 71.8, 37.4, 30.1, 28.5, 26.8,
26.5, 17.0, 14.3, 13.8. IR (KBr): 3340, 2968, 2360, 1732,
1698, 1653, 1529, 760 cm–1. MS: m/z = 394.1 [M + H]+.
Anal. Calcd for C20H27NO3S2: C, 61.04; H, 6.91; N, 3.56.
Found: C, 60.90; H, 6.75; N, 3.44.
2-(2-Acetyl-1-methyl-3-oxobutyl)-N-o-tolyl-3,3-
bis(ethylthio)acrylamide (3c): white solid; mp 97–99 °C.
1H NMR (500 MHz, CDCl3): d = 1.17 (d, J = 7.0 Hz, 3 H),
1.18–1.21 (m, 3 H), 1.29–1.31 (m, 3 H), 2.25 (s, 3 H), 2.26
(s, 3 H), 2.35 (s, 3 H), 2.63–2.92 (m, 4 H), 4.10 (d, J = 11.0
Hz, 1 H), 4.24–4.27 (m, 1 H), 7.08 (t, J = 7.5 Hz, 1 H), 7.21
(t, J = 7.5 Hz, 2 H), 7.62 (s, 1 H), 7.98 (d, J = 7.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 203.6, 202.7, 164.9, 146.8,
134.6, 132.6, 129.6, 128.0, 125.8, 124.2, 121.6, 71.7, 37.3,
30.0, 28.6, 26.9, 26.5, 17.2, 17.0, 14.1, 13.7. IR (KBr): 3364,
2975, 2924, 2360, 2170, 1694, 1668, 1517, 1456, 769 cm–1.
MS: m/z [M + H]+ calcd for C21H29NO3S2: 407.2; found:
408.6. Anal. Calcd for C21H29NO3S2: C, 61.88; H, 7.17; N,
3.44. Found: C, 61.57; H, 6.81; N, 3.23.
(18) X-ray diffraction data for 7b has been deposited at the
Cambridge Crystallographic Data Centre with
supplementary publication number CCDC 611469.
(19) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
(20) Preparation of 6 and 7 (6a as an example); Typical
Procedure: To a well-stirred suspension of 2f (1.0 mmol,
0.235g) in acetylacetone (15 mmol, 1.55 mL) was added
BF3·OEt2 (1.2 mmol, 0.2 mL). The mixture was stirred at
0 °C for 2 h until the reaction was complete (as indicated by
TLC) and neutralized with aq NaHCO3 (10%). After
workup, the crude product was purified by column
chromatography (eluent: PE–EtOAc = 5:1) to give 6a in
89% yield.
Selected data for compounds 6 and 7:
5-Acetyl-3-[bis(ethylthio)methylene]-4,6-dimethyl-3,4-
dihydropyridin-2(1H)-one (6a): yellow solid; mp 66–68
°C. 1H NMR (500 MHz, CDCl3): d = 1.15 (d, J = 7.0 Hz, 3
H), 1.17–1.34 (m, 6 H), 2.28 (s, 3 H), 2.34 (s, 3 H), 2.81–3.03
(m, 4 H), 4.60 (q, J = 7.0 Hz, 1 H), 7.98 (s, 1 H). 13C NMR
(125 MHz, CDCl3): d = 195.9, 162.7, 146.7, 142.6, 132.8,
117.1, 35.8, 29.0, 28.7, 28.1, 18.7, 18.5, 14.3, 13.6. IR
(KBr): 3246, 3093, 2963, 2924, 2865, 2360, 2342, 1673,
1617, 1577, 1230, 786 cm–1. MS: m/z = 300.0 [M + H]+.
Anal. Calcd for C14H21NO2S2: C, 56.15; H, 7.07; N, 4.68.
Found: C, 56.08; H, 6.95; N, 4.43.
3-[Bis(ethylthio)methylene]-4,6-dimethyl-5-
(17) Preparation of 5 (5a as an example); Typical Procedure:
To a well-stirred suspension of 3a (1.0 mmol, 0.43 g) in
EtOH (10 mL) was added NaOH (1.2 mmol, 0.05 g). The
mixture was stirred at 60 °C for 1.0 h, and then poured into
H2O (80 mL) under stirring. The precipitated solid was
collected by filtration, washed with H2O (3 × 30 mL) and
then dried in vacuo to afford the product 4a (0.31 g, 87%) as
a white solid. To a well-stirred suspension of 4a (1.0 mmol,
0.35 g) in anhyd CH2Cl2 (10 mL) were added TiCl4 (1.2
mmol, 0.14 mL) and Et3N (1.4 mmol, 0.20 mL). The mixture
was stirred for about 2 h until the reaction was complete (as
indicated by TLC) and neutralized with aq NaHCO3 (10%).
After workup, the crude product was purified by column
chromatography (eluent: PE–EtOAc = 15:1) to give 5a in
85% yield.
methyloxycarbonyl-3,4-dihydropyridin-2(1H)-one (6c):
yellow solid; mp 115–116 °C. 1H NMR (500 MHz, CDCl3):
d = 1.12 (d, J = 7.5 Hz, 3 H), 1.24–1.31 (m, 6 H), 2.30 (s, 3
H), 2.83–3.01 (m, 4 H), 3.77 (s, 3 H), 4.59–4.60 (q, J = 7.5
Hz, 1 H), 7.46 (s, 1 H). 13C NMR (125 MHz, CDCl3): d =
167.1, 163.3, 148.0, 143.8, 133.6, 109.1, 51.4, 36.2, 30.1,
29.2, 19.8, 18.8, 15.1, 14.5. IR (KBr): 3187, 3090, 2943,
2927, 1709, 1673, 1629, 1525, 1486, 1345, 1217, 1182, 772
cm–1. MS: m/z = 316.1 [M + H]+. Anal. Calcd for
C14H21NO3S2: C, 53.30; H, 6.71; N, 4.44. Found: C, 53.13;
H, 6.63; N, 4.29.
3-[(Difluoroboryloxy)(ethylthio)methylene]-4,6-
dimethyl-5-methyloxycarbonyl-3,4-dihydropyridin-
2(1H)-one (7c): yellow solid; mp 98–100 °C. 1H NMR (500
MHz, CDCl3): d = 1.16 (d, J = 6.5 Hz, 3 H), 1.37 (t, J = 7.5
Hz, 3 H), 2.32 (s, 3 H), 3.12–3.17 (q, J = 7.5 Hz, 2 H), 3.78
Selected data for compounds 5:
3-[Bis(ethylthio)methylene]-4,6-dimethyl-1-phenyl-3,4-
dihydropyridin-2(1H)-one (5a): yellow solid; mp 87–89
°C. 1H NMR (500 MHz, CDCl3): d = 1.16 (d, J = 6.5 Hz, 3
H), 1.25–1.30 (m, 6 H), 1.55 (s, 3 H), 2.82–2.94 (m, 4 H),
4.00–4.02 (q, J = 6.5 Hz, 1 H), 5.21 (d, J = 6.5 Hz, 1 H), 7.19
(d, J = 7.5 Hz, 2 H), 7.31 (t, J = 7.5 Hz, 1 H), 7.40 (t, J = 7.5
Hz, 2 H). 13C NMR (125 MHz, CDCl3): d = 162.4, 141.4,
137.6, 137.3, 133.4, 128.4, 128.0 (2 × C), 126.6, 109.0 (2 ×
C), 33.5, 28.1, 27.8, 19.3, 19.1, 14.2, 13.4. IR (KBr): 3063,
2962, 2921, 2867, 2360, 2170, 1648, 1595, 1539, 1489, 699
cm–1. MS: m/z = 334.3 [M + H]+. Anal. Calcd for
C18H23NOS2: C, 64.82; H, 6.95; N, 4.20. Found: C, 64.64; H,
6.79; N, 4.04.
3-[Bis(ethylthio)methylene]-1-(4-chlorophenyl)-4,6-
dimethyl-3,4-dihydropyridin-2(1H)-one (5b): yellow
solid; mp 136–137 °C. 1H NMR (500 MHz, CDCl3): d = 1.14
(s, 3 H), 3.79–3.81 (q, J = 6.5 Hz, 1 H), 6.84 (s, 1 H). 13
C
NMR (125 MHz, CDCl3): d =185.6, 166.5, 160.8, 141.2,
110.6, 95.4, 51.8, 28.9, 24.4, 21.7, 19.0, 14.7. IR (KBr):
2927, 2284, 1786, 1758, 1731, 1592, 1491, 1383, 1028
cm–1. MS: m/z = 320.1 [M + H]+. Anal. Calcd for
C12H16BF2NO4S: C, 45.16; H, 5.05; N, 4.39. Found: C,
45.05; H, 4.99; N, 4.15.
(21) Bisaro, F.; Prestat, G.; Vitale, M.; Poli, G. Synlett 2002,
1823.
(22) (a) Bernasconi, C. F. Tetrahedron 1989, 45, 4017.
(b) Bernasconi, C. F.; Brown, S. D.; Ali, M.; Rappoport, Z.;
Yamataka, H.; Salim, H. J. Org. Chem. 2006, 71, 4795.
(23) (a) Jones, R. C. F.; Begley, M. J.; Peterson, G. E.; Sumaria,
S. J. Chem. Soc., Perkin Trans. 1 1990, 1959.
(b) Balasubramanian, S.; Ward, D. L.; Nair, M. G. J. Chem.
Soc., Perkin Trans. 1 2000, 567.
Synlett 2007, No. 1, 156–160 © Thieme Stuttgart · New York

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