Synthesis of hydroxylated 3,4-dihydropyridine-2-ones from intramolecular nucleophilic addition reaction of oxirane-containing tertiary enamides

Article abstract of DOI:10.1055/s-0030-1259703

Catalyzed by p-toluenesulfonic acid in dry acetonitrile, oxirane-containing tertiary enamides underwent efficient cyclization via intramolecular addition to produce 3-hydroxy-3,4-dihydropyridin-2(1H)-one derivatives in moderate to good yields. Georg Thiem

Full text of DOI:10.1055/s-0030-1259703

LETTER
927
Synthesis of Hydroxylated 3,4-Dihydropyridine-2-ones from Intramolecular
Nucleophilic Addition Reaction of Oxirane-Containing Tertiary Enamides
Synthesis of
H
y
u
droxylated
3
o
,4-Dihydropyridine
Y
-2-one
s
ang,a Shuo Tong,a De-Xian Wang,a Zhi-Tang Huang,a Jieping Zhu,b,c Mei-Xiang Wang*a,b
a
Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. of China
b
The Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, P. R. of China
Fax +86(10)62796761; E-mail: wangmx@mail.tsinghua.edu.cn
Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne,
EPFL-SB-ISIC-LSPN, 1015, Lausanne, Switzerland
c
Received 1 December 2010
Dedicated to Professors Xiyan Lu and Lixin Dai for their great contributions to organic chemistry
as a unique nucleophile to react intramolecularly with an
Abstract: Catalyzed by p-toluenesulfonic acid in dry acetonitrile,
oxirane-containing tertiary enamides underwent efficient cycliza-
tion via intramolecular addition to produce 3-hydroxy-3,4-dihydro-
pyridin-2(1H)-one derivatives in moderate to good yields.
oxirane moiety to give homoclausenamide.10c Very re-
cently, tertiary enamides have been shown to undergo
Lewis acid catalyzed intramolecular enaminic addition re-
action to carbonyl groups, yielding quaternary carbon-
containing hydroxylated pyrrol-2-one derivatives.11 In or-
der to continue our study in the exploration of reactivity
of tertiary enamides and to synthesize 3-hydroxy-3,4-di-
hydropyridin-2-one derivatives, the analogues of natural-
ly occurring homoclausenamide, we undertook the
current investigation.
Key words: enamides, oxiranes, nucleophilic addition, cyclization,
3,4-dihydropyridin-2-ones
Pyridin-2-one derivatives and their partially reduced 3,4-
dihydropyridin-2(1H)-one derivatives are important or-
ganic compounds. For example, while the former class of
compounds finds wide applications in medicinal chemis-
try because of their diverse biological activities,1 the latter
occurs as natural products such as homoclausenamide.2
3,4-Dihydropyridin-2(1H)-ones also constitute useful
scaffolds for the constrained amino acids.3 In comparison
with well-documented synthetic methods for pyridine-2-
one derivatives,4 the synthesis of 3,4-dihydropyridin-2-
one compounds has remained largely unexplored.4,5
We started our study with the intramolecular cyclization
reaction of oxiranecarboxamide-derived enamide 4a
(Table 1). When reaction of 4a was conducted in boiling
water, no cyclization product 5a was obtained at all. In-
stead, 2-hydroxy-N-methyl-5-oxo-3,5-diphenylpentan-
amide (6)12 was isolated in 68% yield (entry 1, Table 1).
In the presence of two equivalents of p-toluenesulfonic
acid, the reaction of 4a at ambient temperature in acetoni-
trile (entry 2, Table 1) or at a lower temperature (from 0
°C to r.t.) in a mixture of acetonitrile and water (1:1, entry
3, Table 1) gave compound 6 in a lower yield. In the
former case, a trace amount of the desired cyclization
product 5a was observed (entry 2, Table 1). Interestingly,
when reaction was carried out in acetonitrile with a cata-
lytic amount of p-toluenesulfonic acid (20 mol%), 3-hy-
droxy-1-methyl-4,6-diphenyl-3,4-dihydropyridin-2(1H)-
one (5a) was produced efficiently as the major product in
78% yield (entry 4, Table 1). When dry acetonitrile was
used as the solvent, the formation of 6 was prohibited and
the desired N-heterocyclic compound 5a13 was yielded as
the sole product (entry 5, Table 1). The employment of 4
Å MS, however, decreased the reaction rate (entry 6,
Table 1). It should be noted that trifluoroacetic acid did
not effect the intramolecular transformation of 4a in near-
ly two days (entry 7, Table 1).
Enamines are very powerful intermediates in synthetic or-
ganic chemistry.6 As the enamine variant, enamides are,
however, stable and show diminished nucleophilic reac-
tivity because of the electron-withdrawing effect of the N-
acyl group which alleviates the delocalization of nitrogen
lone-pair electrons to carbon–carbon double bond.7 It has
been shown in recent years that secondary enamides, the
enamide species bear an N–H moiety, are able to react
with different electron-deficient reactants in the presence
of a Lewis acid catalyst.8 These secondary enamides act
actually as the aza-ene components to undergo the aza-ene
reactions.8a The nucleophilic reactions of tertiary enam-
ides have been rarely reported. Only very strong electro-
philes such as acid chlorides, acid anhydrides, and
Vilsmeier reagents are reported to react with tertiary en-
amides and enecarbamates.7,9
In the study of biomimetic synthesis of clausena alka-
loids,10 we have discovered that tertiary enamide behaves
To examine the scope of the synthesis of 3,4-dihydropyri-
din-2(1H)-ones, a number of oxirane-containing enam-
ides were prepared from the CuI-catalyzed cross-coupling
reaction of 3-aryl-2-carboxamides with vinyl iodide 2 fol-
lowed by N-alkylation reaction with alkyl halides in the
presence of sodium hydride at 0 °C (Scheme 1). In all
SYNLETT 2011, No. 7, pp 0927–0930
x
x.
x
x.
2
0
1
1
Advanced online publication: 08.03.2011
DOI: 10.1055/s-0030-1259703; Art ID: W32710ST
© Georg Thieme Verlag Stuttgart · New York

928
L. Yang et al.
LETTER
Table 1 Reaction of Tertiary Enamide 4a under Different Reaction Conditionsa
Ph
N
O
Ph
OH
O
OH
O
O
Ph
conditions
Ph
O
+
Ph
N
Ph
HN
Me
Me
Me
4a
5a
6
Entry
Catalyst (mmol)
–
Solvent
H2O
Additive
Temp (°C)
reflux
Time (h)
Yield of 5a (%)b Yield of 6 (%)b
1
2
3
4
5
6
7
–
4
22
10
5
–
68
43
33
trace
–
TsOH (200)
TsOH (200)
TsOH (20)
TsOH (20)
TsOH (20)
TFA (20)
MeCN
–
r.t.
trace
–
MeCN–H2Oc
MeCN
–
0 °C to r.t.
0 °C to r.t.
0 °C to r.t.
0 °C to r.t.
0 °C to r.t.
–
78
MeCN (dry)
MeCN (dry)
MeCN (dry)
–
5
78
4 Å MSd
–
24
40
78
–
trace
–
a In the presence or absence of an acid, 4a (0.4 mmol) was reacted in reaction media (12 mL) at different temperature.
b Isolated yield.
c Ratio of MeCN over H2O was 1:1 in volume.
d 4 Å MS (100 mg) was used.
cases, the cross-coupling reaction gave moderate yields of
3 while N-alkylation generally afforded good to excellent
yields of enamides 4 (Table 2).
O
CuI, DMGC, Cs2CO3
1,4-dioxane, reflux
O
Ar1
NH2
+
Ar2
I
1
2
Under the optimized catalytic conditions, all enamides 4
tested underwent efficient intramolecular nucleophilic ad-
dition to epoxide moiety. For example, enamides 4a–e,
bearing either an electron-withdrawing group or an elec-
tron-donating group at both benzene rings, were convert-
ed into the corresponding 3,4-dihydropyridin-2(1H)-one
derivatives 5a–e in moderate to good chemical yields (41–
84%, entries 1–5, Table 2). Substituents including an allyl
(4f) and benzyl (4g) other than a methyl group (4a–f) on
nitrogen atom led to equally efficient intramolecular cy-
clization reaction to afford the six-membered heterocyclic
compounds 5f and 5g in 78% and 61%, respectively (en-
tries 6 and 7, Table 2). When an enantiopure amide
(2R,3S)-1a (ee >99.5%) was used, enantiopure product
O
O
O
RX, NaH
O
DMF, 0 °C
Ar1
N
Ar2
Ar1
N
R
Ar2
H
4
3
Ar1
N
TsOH (0.2 equiv)
MeCN, 0 °C to r.t., 5 h
OH
O
Ar2
R
5
Scheme 1 Synthesis of 3,4-dihydropyridin-2(1H)-ones 5 from ter-
tiary enamides 4
Table 2 Chemical Yields of Compounds 3–5
Entry Product 3 (%)
Product 4 (%)
Product 5 (%)
1
2
3
4
5
6
7
8
3a Ar1 = Ar2 = Ph (68)
4a Ar1 = Ar2 = Ph, R = Me (100)
5a Ar1 = Ar2 = Ph, R = Me (78)
3b Ar1 = 4-ClC6H4, Ar2 = Ph (48)
3c Ar1 = 4-MeC6H4, Ar2 = Ph (47)
3d Ar1 = Ph, Ar2 = 4-BrC6H4 (50)
3e Ar1 = Ph, Ar2 = 4-FC6H4 (49)
4b Ar1 = 4-ClC6H4, Ar2 = Ph, R = Me (90)
4c Ar1 = 4-MeC6H4, Ar2 = Ph, R = Me (83)
4d Ar1 = Ph, Ar2 = 4-BrC6H4, R = Me (78)
4e Ar1 = Ph, Ar2 = 4-FC6H4, R = Me (100)
4f Ar1 = Ar2 = Ph, R = All (100)
5b Ar1 = 4-ClC6H4, Ar2 = Ph, R = Me (41)
5c Ar1 = 4-MeC6H4, Ar2 = Ph, R = Me (77)
5d Ar1 = Ph, Ar2 = 4-BrC6H4, R = Me (67)
5e Ar1 = Ph, Ar2 = 4-FC6H4, R = Me (84)
5f Ar1 = Ar2 = Ph, R = All (78)
4g Ar1 = Ar2 = Ph, R = Bn (100)
5g Ar1 = Ar2 = Ph, R = Bn (61)
2R,3S-3a Ar1 = Ar2 = Ph (33)
2R,3S-4a Ar1 = Ar2 = Ph, R = Me (79)
3S,4S-5a Ar1 = Ar2 = Ph, R = Me (62)
Synlett 2011, No. 7, 927–930 © Thieme Stuttgart · New York

LETTER
Synthesis of Hydroxylated 3,4-Dihydropyridine-2-ones
929
spectrum of isolated 8a in CDCl3 exhibited two sets of
proton signals corresponding to 8a and 8b in a 2:1 ratio.
1. 1-iodocyclohexene,
CuI, DMGC, Cs2CO3
1,4-dioxane, reflux
O
O
O
O
2. MeI, NaH, DMF, 0 °C
The formation of 3-hydroxy-3,4-dihydropyridin-2(1H)-
one derivatives from oxirane-containing enamides is best
explained by the regioselective intramolecular enaminic
attack of an enamide to the C-3 position of the epoxide ox-
onium A. The resulting iminium intermediate B under-
goes deprotonation to afford heterocyclic product 5. In the
presence of water, however, iminium intermediate B was
trapped by a water molecule, yielding an N,O-ketal inter-
mediate. Ring-chain transformation leads to the formation
of product 6 (Scheme 3)
Ph
N
Ph
NH2
1
Me
7
Ph
Ph
TsOH (0.2 equiv)
OH
OH
O
MeCN, 0 °C, 10 min
+
N
O
N
Me
Me
8a (42%)
8b (40%)
Scheme 2 Synthesis of hexahydroquinolin-2(1H)-one derivatives 8
In conclusion, we have provided a new method for the
synthesis of 3-hydroxy-3,4-dihydropyridin-2(1H)-one de-
rivatives from p-toluenesulfonic acid catalyzed intramo-
lecular cyclization of oxirane-containing tertiary
enamides.
(3S,4S)-5a (ee >99.5%) was obtained without racemiza-
tion (entry 8, Table 2).
The reaction was readily extended to alkyl-substituted
enamide substrates. Scheme 2 illustrates, for example, the
construction of a hexahydroquinolin-2(1H)-one skeleton.
Under the identical p-toluenesulfonic acid catalyzed con-
ditions, intramolecular cyclization of enamide 7, which
was derived from the cross-coupling reaction between ox-
iranecarboxamide 1 and 1-iodocyclohexene followed by
N-methylation, proceeded very rapidly to furnish fused
bicyclic product 8a. In addition, compound 8b with car-
bon–carbon double bond shifted to exo position of d-lac-
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Included are
experimental procedures and spectroscopic data for compounds 3–8.
Copies of 1H NMR and 13C NMR spectra of compounds 3–8.
Acknowledgment
This work is supported by the National Natural Science Foundation
of China (20820102034), Ministry of Science and Technology
(2009CB724704), Ministry of Health (2009ZX09501), and the Chi-
nese Academy of Sciences.
1
tam ring was also isolated. Evidenced by the H NMR
spectra, compounds 8a and 8b, which were separated us-
ing silica gel column chromatography, were able to under-
go slow interconversions to yield a mixture of 8a and 8b
1
in equilibrium in solution. For example, the H NMR
References and Notes
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O+
Ar1
Ar1
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H
OH
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+ H+
27, 445.
4
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John Wiley and Sons: Chichester, 1994.
Ar2
N
O
Ar2
N+
R
R
B
A
– H+
H2O
– H+
Ar1
Ar1
N
OH
O
OH
O
Ar2
N
R
Ar2
OH
R
(7) Carbery, D. R. Org. Biomol. Chem. 2008, 6, 3455.
(8) (a) Matsubara, R.; Kobayashi, S. Acc. Chem. Res. 2008, 41,
292; and references cited therein. (b) Brønsted acid
catalyzed reaction of secondary enamides with imines is also
known. See: Terada, M.; Machioka, K.; Sorimachi, K.
Angew. Chem. Int. Ed. 2006, 45, 2254. (c) Terada, K.;
Machioka, K.; Sorimachi, K. J. Am. Chem. Soc. 2007, 129,
10336.
(9) For examples of enaminic reactions of tertiary enamides,
see: (a) Shono, T.; Matsumura, Y.; Tsubata, K.; Sugihara,
Y.; Yamane, S.-i.; Kanazawa, T.; Aoki, T. J. Am. Chem. Soc.
1982, 104, 6697. (b) Eberson, L.; Malmberg, M.; Nyberg,
K. Acta Chem. Scand. 1984, 38, 391. (c) Meth-Cohn, O.;
5
C
+ H+
Ar1
Ar1
H
H
O
Ar2
OH
OH
O
– H+
Ar2
N+
HN
O
OH
H
R
R
6
D
Scheme 3 Proposed reaction pathways of oxirane-containing tertia-
ry enamides
Synlett 2011, No. 7, 927–930 © Thieme Stuttgart · New York

930
L. Yang et al.
LETTER
Hz, 3 H). 13C NMR (75 MHz, CDCl3, 300 K): d = 199.5,
172.8, 139.2, 136.8, 133.4, 128.76, 128.7, 128.4, 128.2,
127.3, 73.6, 44.8, 40.7, 25.7. ESI-MS: 298 (52) [M + 1]+,
320 (100) [M + Na]+. Anal. Calcd for C18H19NO3: C, 72.71;
H, 6.44; N, 4.71. Found: C, 72.94; H, 6.59; N, 4.86.
(13) General Procedure for the Synthesis of Compounds 5
and 8
Westwood, K. T. J. Chem. Soc., Perkin Trans. 1 1984, 1173.
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Zheng, Q.-Y.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X.
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To a solution of 4 or 7 (0.4 mmol) in dry MeCN (12 mL) was
added PTSA (0.08 mmol, 14 mg) while stirring at 0 °C. The
mixture was then kept stirring until the starting material was
completely consumed. Water (100 mL) was added, and the
mixture was extracted with EtOAc (3 × 50 mL). The organic
layer was dried with anhyd MgSO4 and concentrated. The
residue was subjected to a silica gel (200–300 mesh) column
eluted with a mixture of PE and EtOAc (3:1) to afford pure
5 or 8.
(12) Typical Procedure for the Conversion of 4a into
Compound 6
Refluxing a suspension of enamide 4a (0.4 mmol, 111 mg)
in deionized H2O (12 mL) for 4 h under argon protection
gave rise to a homogeneous solution. After addition of brine
(30 mL), the mixture was extracted with EtOAc (3 × 20 mL).
The organic layer was dried with anhyd Na2SO4, filtered,
and concentrated under vacuum. The residue was subjected
to chromatography using a silica gel (200–300 mesh)
column eluting with a mixture of PE and EtOAc (1:1) as
mobile phase to give product 6.
Selected Data for Compound 5a
Mp 143–145 °C. IR (KBr): n = 3442, 1668 cm–1. 1H NMR
(300 MHz, CDCl3, 300 K): d = 7.25–7.40 (m, 10 H), 5.35 (d,
J = 2.4 Hz, 1 H), 4.38 (dd, J = 1.0, 13.7 Hz, 1 H), 3.88 (d,
J = 1.8 Hz, 1 H), 3.78 (dd, J = 2.4, 13.7 Hz, 1 H), 3.04 (s, 3 H).
13C NMR (75 MHz, CDCl3, 300 K): d = 172.9, 141.6, 140.6,
135.0, 128.9, 128.7, 128.66, 128.0, 127.7, 127.3, 113.3,
71.3, 45.8, 32.7. ESI-MS: m/z = 280 (26) [M + 1]+, 302 (100)
[M + Na]+. Anal. Calcd for C18H17NO2: C, 77.40; H, 6.13; N,
5.01. Found: C, 77.25; H, 6.39; N, 4.94.
Mp 130–132 °C. IR (KBr): n = 3307, 1637 cm–1. 1H NMR
(300 MHz, CDCl3, 300 K): d = 7.23–7.98 (m, 10 H), 6.26 (s,
1 H), 4.38 (dd, J = 3.9, 5.2 Hz, 1 H), 3.73–3.85 (m, 2 H),
3.41–3.47 (m, 1 H), 3.29 (d, J = 5.6 Hz, 1 H), 2.71 (d, J = 2.7
Synlett 2011, No. 7, 927–930 © Thieme Stuttgart · New York

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