Ring-opening/recyclization reactions of (dimethylamino)propenoyl- substituted cyclopropanes: Facile synthesis of halogenated pyridin-2(1H)-ones

Article abstract of DOI:10.1055/s-0029-1217391

A facile and efficient synthesis of substituted pyridin-2(1H)-ones has been developed by the reaction of readily available 1-carbamoyl-1-[3-(dimethylamino) propenoyl]cyclopropanes with phosphoryl chloride or phosphorus tribromide in dichloromethane at roo

Full text of DOI:10.1055/s-0029-1217391

PAPER
2497
Ring-Opening/Recyclization Reactions of (Dimethylamino)propenoyl-
Substituted Cyclopropanes: Facile Synthesis of Halogenated Pyridin-2(1H)-
ones
Synthesis of
H
alo
u
genated Pyr
i
idin-2(1
H
)-on
Z
es hang, Yang Zhou, Yongjiu Liang, Zijiang Jiang, Dewen Dong*
Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. of China
E-mail: dwdong@ciac.jl.cn
Received 25 February 2009; revised 17 April 2009
O
O
OHC
Br
Ar
O
Br
O
PBr3/DMF
120 °C
Abstract: A facile and efficient synthesis of substituted pyridin-
2(1H)-ones has been developed by the reaction of readily available
1-carbamoyl-1-[3-(dimethylamino)propenoyl]cyclopropanes with
phosphoryl chloride or phosphorus tribromide in dichloromethane
at room temperature.
N
N
+
NHAr
Br
(CH2)2Br
(CH2)2Br
Scheme 1 Reactions of cyclopropanes with the Vilsmeier reagent
(PBr3/DMF)
Key words: cyclization, cyclopropanes, enaminones, pyridin-
2(1H)-ones, ring opening
phosphorus tribromide/N,N-dimethylformamide, pro-
duced an inseparable mixture even at 120 °C (Scheme 1).
The pyridin-2(1H)-one motif makes up the core structure
of numerous biologically active natural products and syn-
thetic compounds, such as elfamycin and ilicolicin, that
find a wide range of application in the pharmaceutical and
agrochemical industries.1,2 Actually, functionalized pyri-
din-2(1H)-ones and their benzo-/hetero-fused analogues
have become very important in the areas of natural prod-
uct and pharmaceutical chemistry and are widely used as
versatile intermediates in the synthesis of a variety of aza-
heterocycles, such as pyridine, piperidine, quinolizidine,
and indolizidine alkaloids.3,4 Extensive work has generat-
ed many synthetic approaches for pyridin-2(1H)-ones in-
volving pyridinium salt chemistry,5 Guareschi–Thorpe
reaction,6 hetero-Diels–Alder reaction,7 Dieckmann-type
condensation,8 and metal-mediated cycloaddition.9 Other
notable methods starting from polarized ketene S,S- and
N,N-acetals have been reported.10
Very recently, we achieved divergent synthesis of fully
substituted 1H-pyrazoles and isoxazoles from oximes of
1-acyl-1-carbamoylcyclopropanes in the presence of
phosphoryl chloride/N,N-dimethylformamide and phos-
phoryl chloride/dichloromethane, respectively.16 Similar-
ly, substituted cyclophosphamidic chlorides and their
analogues were obtained by subjecting 3-acetyl-2-(aryl-
amino)-5,6-dihydro-4H-pyrans to phosphoryl chloride in
dichloromethane.17 These results suggest that phosphoryl
chloride, as a reagent, showed different reaction behavior
from the Vilsmeier reagent, phosphoryl chloride/N,N-
dimethylformamide.
Inspired by these findings and in continuation with our re-
search on the synthesis of functionalized heterocycles
from b-oxo amide derivatives, we are interested in the
synthetic potential of readily available 1-carbamoyl-1-[3-
(dimethylamino)propenoyl]cyclopropanes 118 and exam-
ined their reactivity toward phosphoryl chloride or phos-
phorus tribromide in dichloromethane. As a result of these
studies, we provided an alternative one-pot synthesis of
halogenated pyridin-2(1H)-ones 2 and 3 from cyclopro-
panes 1. Herein, we report our experimental results and a
proposed mechanism involved in the ring-opening/recy-
clization reactions.
Halogenated pyridin-2(1H)-ones represent an important
subset of pyridin-2(1H)-ones, which have been utilized as
useful intermediates for the synthesis of various aza-het-
erocycles and evaluated as a scaffold in natural product
synthesis.11 Unfortunately, the most available approaches
for accessing pyridin-2(1H)-ones are not general for the
preparation of halogenated pyridin-2(1H)-ones. During
the course of our studies on Vilsmeier–Haack reactions,
we developed an efficient synthesis of halogenated pyri-
din-2(1H)-ones from a range of b-oxo amide derivatives,
such as a-unsubstituted/a-monosubstituted b-oxo
The substrates 1 were prepared from 1-acyl-1-carbamoyl-
cyclopropanes and N,N-dimethylformamide dimethyl
acetal in high yields (up to 91%) according to the proce-
dure described in our previous work.18 With a series of
condensation adducts 1a–f in hand, we selected 1-[3-
(dimethylamino)propenoyl]-N-phenylcyclopropanecar-
boxamide (1a) as a model compound to examine its be-
havior under different conditions. Thus, the reaction of 1a
with phosphoryl chloride (5.0 equiv) in dichloromethane
was first attempted at room temperature. As monitored by
TLC, the reaction proceeded smoothly and furnished a
white solid after workup and purification by column chro-
amides,12
ans,13 1-acyl-1-carbamoylcyclopropanes,14 and a-[(di-
methylamino)methylene]-b-oxo under
amides15
3-acetyl-2-(arylamino)-5,6-dihydro-4H-pyr-
Vilsmeier conditions. However, the reaction of 1-acyl-1-
carbamoylcyclopropanes with the Vilsmeier reagent,
SYNTHESIS 2009, No. 15, pp 2497–2500
x
x.
x
x
.
2
0
0
9
Advanced online publication: 08.06.2009
DOI: 10.1055/s-0029-1217391; Art ID: F04409SS
© Georg Thieme Verlag Stuttgart · New York

2498
R. Zhang et al.
PAPER
matography of the resulting mixture. The product was for ten hours, whereby the yield of 2a reached 71% (Table
characterized as 4-chloro-3-(2-chloroethyl)-1-phenylpy- 1, entry 1).
ridin-2(1H)-one (2a) (68% yield, Scheme 2) on the basis
Under the optimized conditions as for the synthesis of 2a
of its spectral and analytical data, which was in good
(Table 1, entry 1), a range of reactions of 1-carbamoyl-1-
[3-(dimethylamino)propenoyl]cyclopropanes 1b–f was
agreement with that reported in our previous work.14
subjected to phosphoryl chloride in dichloromethane, and
the results are summarized in Table 1. The efficiency of
Ph
O
O
N
POCl3 (5.0 equiv)
the cyclization proved to be suitable for 1b–f affording the
corresponding halogenated pyridin-2(1H)-ones 2b–f in
moderate to good yields (Table 1, entries 2–6). The versa-
tility of this pyridin-2(1H)-one synthesis was further eval-
NHPh
O
Me2N
Cl
CH2Cl2, r.t.
68%
(CH2)2Cl
1a
2a
Scheme 2 Reaction of 1a in the presence of phosphoryl chloride in uated by performing the cyclopropanes 1a–f with another
dichloromethane
halogenated reagent phosphorus tribromide under the oth-
erwise identical conditions (Table 1, entries 7–12). The
results demonstrated the efficiency and synthetic interest
of the ring-opening/recyclization reactions of 1 bearing
variable arylamide groups with respect to both phosphoryl
chloride and phosphorus tribromide in dichloromethane.
Therefore, we provided an alternative approach to haloge-
nated pyridin-2(1H)-ones. In comparison to the synthetic
approach to pyridin-2(1H)-ones of type 2 under Vilsmeier
conditions,14 the present protocol is associated with mild
conditions and easy control of the reaction orientation.
The optimization of the reaction conditions, including the
ratio of phosphoryl chloride to 1a, and reaction tempera-
ture, were then investigated. It seemed that the increase of
temperature had no significant influence on the reaction
rate and conversion. But too lower ratio of phosphoryl
chloride to 1a, 1.0:1.0 for example, resulted in prolonged
reaction times and low yields. A series of experiments re-
vealed that 1.5 equivalents of phosphoryl chloride was ef-
fective for the synthesis of halogenated pyridin-2(1H)-
ones, and the optimal results were obtained when the re-
action of 1a was performed with 2.0 equivalents of phos-
phoryl chloride in dichloromethane at room temperature
On the basis of the obtained results and our previous stud-
ies,15,17 a plausible mechanism for the synthesis of haloge-
nated pyridin-2(1H)-ones 2 is presented in Scheme 3
Table 1 Reactions of 1-Carbamoyl-1-[3-(dimethylamino)propenoyl]cyclopropanes 1 with Phosphoryl Chloride or Phosphorus Tribromide in
Dichloromethanea
Ar
O
O
N
POCl3 or PBr3
CH2Cl2, r.t.
NHAr
O
X
Me2N
(CH2)2X
1
2 X = Cl
3 X = Br
Entry
1
Substrate
1a
Reagent
POCl3
POCl3
POCl3
POCl3
POCl3
POCl3
PBr3
Ar
Ph
X
Product
2a
Yieldb (%)
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
71
70
76
63
55
68
65
59
56
62
53
69
2
1b
4-MeOC6H4
2b
2c
3
1c
4-MeC6H4
4
1d
4-ClC6H4
2d
2e
5
1e
2,4-Me2C6H3
5-Cl-2-MeOC6H3
Ph
6
1f
2f
7
1a
3a
8
1b
PBr3
4-MeOC6H4
4-MeC6H4
3b
3c
9
1c
PBr3
10
11
12
1d
PBr3
4-ClC6H4
3d
3e
1e
PBr3
2,4-Me2C6H3
5-Cl-2-MeOC6H3
1f
PBr3
3f
a Reaction conditions: (i) for entries 1–6: POCl3 (2.0 equiv), CH2Cl2, r.t., 8.0–12.0 h; (ii) for entries 7–12: PBr3 (2.0 equiv), CH2Cl2, r.t., 7.0–
10.0 h.
b Isolated yields.
Synthesis 2009, No. 15, 2497–2500 © Thieme Stuttgart · New York

PAPER
Synthesis of Halogenated Pyridin-2(1H)-ones
2499
13C NMR (125 MHz, CDCl3): d = 31.8, 41.4, 56.2, 108.0, 113.4,
125.6, 127.4, 128.6, 130.3, 136.1, 145.6, 153.0, 160.8.
(with POCl3 as example). Iminium ion A is generated
from the reaction of enaminone 1 with phosphoryl chlo-
ride, which then undergoes ring-opening and halogena- Anal. Calcd for C14H12Cl3NO2: C, 50.55; H, 3.64; N, 4.21. Found:
tion reactions to form intermediate B.18,19 Intramolecular
C, 50.23; H, 3.79; N, 4.27.
cyclization of B gives rise to intermediate C, followed by
4-Bromo-3-(2-bromoethyl)-1-phenylpyridin-2(1H)-one (3a)
the elimination of dimethylamine to afford substituted py-
ridin-2(1H)-one 2.
White solid: mp 108–110 °C.
IR (KBr): 3082, 2969, 1635, 1580, 1535, 959, 759, 700 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.36 (t, J = 8.0 Hz, 2 H), 3.64 (t,
J = 8.0 Hz, 2 H), 6.48 (d, J = 8.0 Hz, 1 H), 7.16 (d, J = 8.0 Hz, 1 H),
7.34–7.36 (m, 2 H), 7.41–7.44 (m, 1 H), 7.45–7.51 (m, 2 H).
OPOCl2
O
O
POCl3
POCl3
Me2N+
NHAr
Me2N
1
A
13C NMR (125 MHz, CDCl3): d = 29.0, 34.7, 110.8, 126.3, 128.7,
129.0, 129.3, 135.4, 136.1, 140.1, 160.3.
O
ArHN
N+Me2
NMe2
Ar
Ar
Anal. Calcd for C13H11Br2NO: C, 43.73; H, 3.11; N, 3.92. Found: C,
44.15; H, 2.92; N, 3.68.
Ar
N
– NHMe2
N
HN
Cl
O–
O
Cl
O–
CH2CH2Cl
Cl
4-Bromo-3-(2-bromoethyl)-1-(4-methoxyphenyl)pyridin-
2(1H)-one (3b)
White solid: mp 115–116 °C.
CH2CH2Cl
CH2CH2Cl
C
B
2
Scheme 3 Tentative mechanism of the reaction of 1-carbamoyl-1-
[3-(dimethylamino)propenoyl]cyclopropanes
chloride
1H NMR (500 MHz, CDCl3): d = 3.35 (t, J = 7.5 Hz, 2 H), 3.63 (t,
J = 7.5 Hz, 2 H), 3.84 (s, 3 H), 6.45 (d, J = 7.5 Hz, 1 H), 6.98–7.00
(m, 2 H), 7.14 (d, J = 7.0 Hz, 1 H), 7.25–7.27 (m, 2 H).
1 with phosphoryl
13C NMR (125 MHz, CDCl3): d = 29.4, 35.1, 55.8, 111.0, 114.8,
127.7, 130.7, 133.3, 136.1, 136.3, 159.8, 160.9.
In summary, we have described a facile and efficient syn-
thesis of substituted pyridin-2(1H)-ones 2 from a series of
1-carbamoyl-1-[3-(dimethylamino)propenoyl]cycloprop-
anes 1 in the presence of phosphoryl chloride or phospho-
rus tribromide in dichloromethane. This protocol is
associated with readily available starting materials, mild
conditions, good yields, and wide range of synthetic po-
tential of the product.
Anal. Calcd for C14H13Br2NO2: C, 43.44; H, 3.39; N, 3.62. Found:
C, 43.18; H, 3.53; N, 3.58.
4-Bromo-3-(2-bromoethyl)-1-(4-methylphenyl)pyridin-2(1H)-
one (3c)
White solid: mp 87–89 °C.
1H NMR (500 MHz, CDCl3): d = 2.40 (s, 3 H), 3.35 (t, J = 8.0 Hz,
2 H), 3.63 (t, J = 7.5 Hz, 2 H), 6.46 (d, J = 7.5 Hz, 1 H), 7.14 (d,
J = 7.5 Hz, 1 H), 7.22 (d, J = 8.0 Hz, 2 H), 7.29 (t, J = 8.5 Hz, 2 H).
All reagents were purchased from commercial sources and used
without treatment, unless otherwise indicated. The products were
13C NMR (125 MHz, CDCl3): d = 21.1, 29.1, 34.8, 110.8, 126.1,
130.0, 130.6, 135.6, 136.2, 137.7, 138.8, 160.5.
1
purified by column chromatography over silica gel. H NMR and
13C NMR spectra were recorded at 500 MHz and 125 MHz, respec-
tively, with TMS as internal standard at 25 °C on a Varian Inova-
500 spectrometer. IR spectra (KBr) were recorded on a Magna-560
FTIR spectrophotometer in the range of 400–4000 cm–1. Petroleum
ether (PE) used was the fraction boiling in the range 30–60 °C.
Anal. Calcd for C14H13Br2NO: C, 45.32; H, 3.53; N, 3.77. Found: C,
45.43; H, 3.57; N, 3.69.
4-Bromo-3-(2-bromoethyl)-1-(4-chlorophenyl)pyridin-2(1H)-
one (3d)
White solid: mp 82–84 °C.
4-Chloro-3-(2-chloroethyl)-1-phenylpyridin-2(1H)-one (2a);
Typical Procedure
1H NMR (500 MHz, CDCl3): d = 3.35 (t, J = 7.5 Hz, 2 H), 3.63 (t,
J = 8.0 Hz, 2 H), 6.49 (d, J = 7.0 Hz, 1 H), 7.11 (d, J = 7.5 Hz, 1 H),
7.31 (d, J = 8.0 Hz, 2 H), 7.47 (d, J = 9.0 Hz, 2 H).
To a soln of 1a (0.52 g, 2.0 mmol) in CH2Cl2 (10 mL) was added
POCl3 (4.0 mmol) at r.t. with stirring. The mixture was stirred 10.0
h and then the reaction was quenched with sat. aq NaHCO3 (30 mL)
and extracted with CH2Cl2 (3 × 20 mL). The organic extracts were
washed with sat. aq NaCl (3 × 20 mL), dried (anhyd MgSO4), fil-
tered, and concentrated in vacuo. Purification was carried out by
flash chromatography (silica gel, PE–EtOAc, 8:1) to give 2a (0.38
g, 71%).
13C NMR (125 MHz, CDCl3): d = 28.9, 34.6, 111.2, 127.6, 129.5,
130.8, 134.6, 134.9, 136.3, 138.5, 160.1.
Anal. Calcd for C13H10Br2ClNO: C, 39.88; H, 2.57; N, 3.58. Found:
C, 39.52; H, 2.46; N, 3.72.
4-Bromo-3-(2-bromoethyl)-1-(2,4-dimethylphenyl)pyridin-
2(1H)-one (3e)
White solid: mp 81–84 °C.
Pyridin-2(1H)-ones 2a–e are known compounds, their analytical
data are in good agreement with those reported in our previous
work.14
1H NMR (500 MHz, CDCl3): d = 2.09 (s, 3 H), 2.37 (s, 3 H), 3.37
(t, J = 7.5 Hz, 2 H), 3.61–3.71 (m, 2 H), 6.47 (d, J = 7.5 Hz, 1 H),
7.01–7.06 (m, 2 H), 7.12 (d, J = 7.5 Hz, 1 H), 7.15 (s, 1 H).
4-Chloro-3-(2-chloroethyl)-1-(5-chloro-2-methoxyphenyl)pyri-
din-2(1H)-one (2f)
White solid: mp 95–97 °C.
13C NMR (100 MHz, CDCl3): d = 17.4, 21.0, 29.2, 34.6, 110.8,
126.6, 127.8, 130.6, 131.8, 134.4, 135.7, 136.2, 136.9, 139.3, 160.2.
IR (KBr): 3073, 2945, 1653, 1605, 1545, 905, 787, 707 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.23 (t, J = 7.5 Hz, 2 H), 3.78 (t,
J = 7.5 Hz, 2 H), 3.80 (s, 3 H), 6.30 (d, J = 7.5 Hz, 1 H), 6.97 (d,
J = 9.0 Hz, 1 H), 7.06 (d, J = 7.0 Hz, 1 H), 7.26 (s, 1 H), 7.38 (d,
J = 9.0 Hz, 1 H).
Anal. Calcd for C15H15Br2NO: C, 46.78; H, 3.93; N, 3.64. Found: C,
47.29; H, 4.11; N, 3.43.
Synthesis 2009, No. 15, 2497–2500 © Thieme Stuttgart · New York

2500
R. Zhang et al.
PAPER
4-Bromo-3-(2-bromoethyl)-1-(5-chloro-2-methoxyphenyl)pyri-
din-2(1H)-one (3f)
White solid: mp 103–104 °C.
(6) (a) Baron, H.; Remfry, F. G. P.; Thorpe, J. F. J. Chem. Soc.
1904, 85, 1726. (b) Aggarwal, V.; Singh, G.; Ila, H.;
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IR (KBr): 3071, 2942, 1650, 1601, 1542, 1495, 1273, 1018, 750,
711 cm–1.
1H NMR (500 MHz, CDCl3): d = 3.35 (t, J = 7.5 Hz, 2 H), 3.61–3.64
(m, 2 H), 3.80 (s, 3 H), 6.45 (dd, J1 = 7.5 Hz, J2 = 2.0 Hz, 1 H),
6.97–6.99 (m, 2 H), 7.26 (d, J = 2.0 Hz, 1 H), 7.38 (dd, J1 = 7.5 Hz,
J2 = 2.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): d = 29.2, 35.0, 56.5, 111.0, 113.7,
125.8, 128.8, 129.8, 130.6, 131.0, 136.2, 136.7, 153.2, 160.3.
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Anal. Calcd for C14H12Br2ClNO2: C, 39.89; H, 2.87; N, 3.32.
Found: C, 40.37; H, 2.98; N, 3.35.
Acknowledgment
Financial support of this research by the National Natural Science
Foundation of China (No: 20872136) is greatly acknowledged.
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Synthesis 2009, No. 15, 2497–2500 © Thieme Stuttgart · New York