Vilsmeier cyclization of α-acetyl-α-aroyl ketene-N,S-acetals: Direct and efficient synthesis of halogenated pyridin-2(1H)-ones

Article abstract of DOI:10.1039/c4ra14626c

An efficient synthetic route to 3-aroyl-5-formyl-4-halo pyridin-2(1H)-ones has been developed via Vilsmeier cyclization of 2-(ethylthio(arylamino)methylene)-1-alkylbutane-1,3-dione. The synthetic protocol has demonstrated the first example of Vilsmeier cyclization of α-acetyl-α-aroylketene-N,S-acetals, providing a novel route to 4-bromo/chloro pyridin-2(1H)-ones.

Full text of DOI:10.1039/c4ra14626c

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Vilsmeier cyclization of a-acetyl-a-aroyl ketene-
N,S-acetals: direct and efficient synthesis of
halogenated pyridin-2(1H)-ones†
Cite this: RSC Adv., 2015, 5, 11293
a
a
a
b
Haifeng Yu, Yongmei Zhang, Tiechun Li, Peiqiu Liao, Quanping Diao,a
Received 16th November 2014
Accepted 6th January 2015
*
*
Guang Xin,a Qingling Menga and Dongyan Houa
DOI: 10.1039/c4ra14626c
www.rsc.org/advances
An efficient synthetic route to 3-aroyl-5-formyl-4-halo pyridin- 5,6-dihydro-4H-pyrans,10c b-oxo amides10d and 2-((dimethyl-
2(1H)-ones has been developed via Vilsmeier cyclization of amino)methylene)-3-oxo-N-arylbutanamides,10e and a variety of
2-(ethylthio(arylamino)methylene)-1-alkylbutane-1,3-dione. The halogenated pyridine-2(1H)-ones were efficiently synthesized in
synthetic protocol has demonstrated the first example of Vilsmeier good yields (Scheme 1A). Compared with other work,6–8 this
cyclization of a-acetyl-a-aroylketene-N,S-acetals, providing a novel Vilsmeier cyclization efficiently afforded halogenated pyridine-
route to 4-bromo/chloro pyridin-2(1H)-ones.
2(1H)-ones bearing formyl groups, which may render them
extremely versatile as synthons in further synthetic trans-
formations, and was characterized by good generality,
simple execution, readily available substrates, and mild condi-
tions. As a result, these advantages make the Vilsmeier
cyclization of acyclic substrates to yield halogenated pyridine-
2(1H)-ones very attractive.
Readily available ketene-N,S-acetals have emerged as
versatile intermediates in the synthesis of heterocyclic
compounds.11 Over the past decades, great attention was
focused on the investigation of a-aroyl/cyano ketene-N,S-
acetals, because their a-position can act as nucleophile and
react with electrophilic species resulting in their further
functionalization and subsequent transformations to a variety
of heterocycles.12 To date, the investigation on the synthesis
and application of a-acetyl-a-aroyl ketene-N,S-acetals are
not reported. As part of our contributions to the chemistry
of ketene-S,S-acetals,13–15 we recently investigated the
synthesis of a-acetyl-a-aroyl ketene-N,S-acetals and examined
Pyridin-2(1H)-ones are very important heterocycles in medicinal
chemistry and pharmacology due to their diverse pharmaco-
logical and biological activities.1,2 Halogenated pyridin-2(1H)-
ones are an important subset of pyridin-2(1H)-ones and have
been utilized as versatile synthetic intermediates for further
elaboration of the pyridine-2(1H)-one core3 and a wide variety of
potent bioactive heterocycles.4 Although the halogenation of
pyridin-2(1H)-ones occurs very easily, a mixture of mono- and
dihalogenated products is oen obtained.5 Consequently, the
direct preparation of halogenated pyridine-2(1H)-ones from
acyclic substrates is a worthy research challenge. Marcoux and
co-workers investigated the annulation reaction of esters bearing
active methane with vinamidinium hexauorophosphate salts,
and 5-chloro pyridine-2(1H)-ones were successfully obtained.6
Dechoux et al. efficiently prepared 3-bromo pyridine-2(1H)-ones
by bromo-cyclization of the ensuing d-dienaminoester.7 Zhu and
co-workers reported the synthesis of 3-uoro-4-aryl-pyridine-
2(1H)-ones from Michael-adduct of uoronitroacetate and
a,b-unsaturated ketones.8 Recently, Dong, et al. researched in
detail Vilsmeier cyclization of 3-oxo-N-phenylbutanamide deriv-
atives9,10 such as 1-acetyl-N-arylcycl-opropanecarboxamides,10a
a-acetyl-a-carbamoylketene dithioacetals,10b 2-arylamino-3-acetyl-
aSchool of Chemistry and Life Science, Anshan Normal University, Anshan, Liaoning
114007, China. E-mail: yuhf68105@sina.com; Fax: +86-412-2960065
bDepartment of Chemistry, Northeast Normal University, Changchun, Jilin 130024,
China
† Electronic supplementary information (ESI) available: Experimental procedures,
analytical data, and spectra copies of all compounds. CCDC 974611. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c4ra14626c
Scheme 1 Vilsmeier cyclization of acyclic substrates.
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Table 1 Synthesis of a-acetyl-a-aroyl ketene-N,S-acetals 1a–ka
their reactions with Vilsmeier reagents. We found that 2-
(ethylthio(arylamino)methylene)-1-alkylbutane-1,3-dione
1
could stereoselectively be synthesized in excellent yields, fol-
lowed by its efficient Vilsmeier cyclization to afford 3-arolyl-5-
formyl-4-halo pyridin-2(1H)-ones 2 in good yields (Scheme 1B).
Herein, we would like to report our ndings.
Kirsch and co-workers reported the synthesis of symmetric
a,a-dioxoketene-N,S-acetals such as (methylthio(phenylamino)
Entry
Ar
R
1
Yieldb (%)
Z/Ec
methylene)pentane-2,4-dione
and
diethyl
2-(methyl-
1
2
3
4
5
6
7
8
4-MeC6H4
3-MeC6H4
4-MeOC6H4
Ph
4-BrC6H4
2-Thiophenyl
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC6H4
3-MeC6H4
4-FC6H4
4-BnC6H4
2-MeC6H4
1a
1b
1c
1d
1e
1f
1g
1h
1i
85
86
84
88
90
86
83
85
75
87
81
13 : 1
10 : 1
14 : 1
10 : 1
13 : 1
15 : 1
11 : 1
11 : 1
10 : 1
27 : 1
11 : 1
thio(phenylamino)methylene)malonate.16 Therefore, according
to the procedure described by Kirsch, we initially examined the
preparation
of
2-(ethylthio(phenylamino)methylene)-1-p-
tolylbutane-1,3-dione 1a from one-pot reaction of 1-p-
tolylbutane-1,3-dione, isorhodanides and bromoethane in the
presence of K2CO3 at room temperature and found that 1a was
obtained in 85% yield. The reaction showed high stereo-
selectivity and favored the formation of (Z)-1a which is
conrmed by X-ray crystallographic analysis (Fig. 1).17 In a
similar fashion, compounds 1b–k were prepared in excellent
yields and with high stereoselectivity. Results of our ndings are
listed in Table 1. It is noteworthy that compounds 1 are stable at
room temperature and could be stored indenitely without
decomposition.
9
10
11
1j
1k
a
Reaction conditions: 1-arylbutane-1,3-dione (5 mmol), isorhodanides
b
(5 mmol), EtBr (5 mmol) and K2CO3 (10 mmol). Isolated yields.
c
1
Molar ratio of Z/E-1 isomers determined by H NMR.
Next, we used the optimized reaction conditions to dene
With a-acetyl-a-aroyl ketene-N,S-acetals 1 in hand, we started
our investigation on Vilsmeier cyclization of compound 1 resulting
in the formation of halogenated pyridin-2(1H)-ones. The reaction
of 1a with Vilsmeier reagent POCl3/DMF was selected as model
reaction to screen the experimental conditions. It was found that
1a reacted with Vilsmeier reagent POCl3/DMF (4 equiv.) below 70
ꢀC to afford an unstable major product at room temperature
(Table 2, entry 1–3). To our delight, when the reaction was carried
out at 80 ꢀC for 12 h, a stable white solid product was obtained in
35% yield. From the spectral and analytical data, the product was
characterized as desirable product 4-chloro-5-(4-benzoyl)-6-oxo-1-
phenyl-1,6-dihydropyridine-3-methylcarbaldehyde 2a (Table 2,
entry 4). Additionally, the yield of 2a was not markedly improved
by either prolonging reaction time or further elevating reaction
temperature (Table 2, entry 5 and 6). However, the reaction
showed dependence on the amount of Vilsmeier reagent POCl3/
DMF (Table 2, entry 7–9), becoming more efficient with an
increased load of this reagent. Consequently, 2a was obtained in
85% yield when 1a reacted with 6.0 equiv. of Vilsmeier reagent at
80 ꢀC for 4 h (Table 2, entry 8). Accordingly, the optimal reaction
conditions are 6.0 equiv. of Vilsmeier reagent and a temperature of
80 ꢀC.
the scope of this Vilsmeier cyclization for the synthesis of
halogenated pyridin-2(1H)-ones, and the results are summa-
rized in Table 3. The Vilsmeier cyclization of 1a–j and POCl3/
DMF proceeded smoothly under the optimized conditions to
efficiently
afford
corresponding
3-aroyl-4-chloro-5-for-
mylpyridin-2(1H)-ones in high yields (Table 3, entry 1–10). It is
noteworthy that the electronic effects of aromatic substituents
on both aroyl and aryl amino groups are insignicant to the
cyclization reaction. In the case of 2-((ethylthio)-(o-tolylamino)-
Table 2 Screening of conditions for Vilsmeier cyclization of a-acetyl-
a-aroyl ketene-N,S-acetalsa
POCl3/DMF
(equiv.)
Entry
T [ꢀC]
Time [h]
Yield [%] of 2ab
c
1
2
3
4
5
6
7
8
9
4
4
4
4
4
4
5
6
7
25
60
70
80
80
90
80
80
80
12
12
12
12
24
12
7
—
c
—
c
—
35
34
37
63
85
83
4
4
a
Reaction conditions: 1a (0.25 mmol), solvent (1 mL). b Isolated yields.
An unstable product was yielded at room temperature.
c
Fig. 1 Molecular structure of (Z)-1a.
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Table 3 Synthesis of various halogenated pyridin-2(1H)-ones 2a
Scheme 2 Reaction of 1l and POCl3/DMF.
Entry
1
1
Product 2
Yieldb (%)
2a X ¼ Cl
2b X ¼ Br
85
21c
81
82
80
1a
2c X ¼ Cl
2d X ¼ Br
2
3
4
5
6
1b
1c
1d
1e
1f
2e X ¼ Cl
2f X ¼ Br
85
83
2g X ¼ Cl
2h X ¼ Br
84
84
Scheme 3 Plausible Mechanism of Vilsmeier cyclization of a-acetyl-
a-aroyl ketene-N,S-acetals 1.
2i X ¼ Cl
2j X ¼ Br
79
77
when 1a reacted with Vilsmeier reagent POBr3/DMF under the
same conditions, 2b was efficiently produced in 81% yield
(Table 3, entry 1). Similarly, 1b–k underwent the Vilsmeier
cyclization to efficiently afford the corresponding 3-aroyl-4-
bromo-5-formyl pyridin-2(1H)-ones in high yields (Table 3,
entry 2–11).
Junjappa and co-workers investigated Vilsmeier reaction of
a-acetyl ketene-N,S-acetals with POCl3/DMF (1.5 equiv.) at 80 ꢀC
and found that the diketonealdehyde enamine was obtained in
moderate yield.18 In our research, we also checked the Vilsmeier
reaction of a-acetyl ketene-N,S-acetals 1l under the above opti-
mized conditions. Unlike Junjappa's work, the reaction fur-
nished 4-chloro-1-(4-chlorophenyl)-2-oxo-1,2-dihydropyridine-
3-carbaldehyde 2w in 61% yield (Scheme 2).
2k X ¼ Cl
2l X ¼ Br
80
79
2m X ¼ Cl
2n X ¼ Br
85
81
7
1g
1h
1i
2o X ¼ Cl
2p X ¼ Br
82
83
8
2q X ¼ Cl
2r X ¼ Br
79
78
9
2s X ¼ Cl
2t X ¼ Br
85
85
10
1j
On the basis of the results obtained together with the rele-
vant reports,9,10 a possible reaction mechanism is proposed in
Scheme 3. It is clear that the reaction commenced from the
halogenation of 1 in the presence of Vilsmeier reagent to
generate vinyl chloride I. Sequential Vilsmeier reactions of I
lead to the formation of intermediate II, which occurs intra-
molecular aza-cyclization reaction to give the intermediate III.
Upon treatment with water, III is converted into the interme-
diate IV, which sheds dimethylamine to give the intermediate V.
Finally, halogenated pyridine-2(1H)-ones 2 are obtained aer
the removal of H proton.
32
2u X ¼ Cl
2v X ¼ Br
77d
74d
11
1k
a
Reaction conditions: 1 (0.25 mmol), POCl3/DMF or POBr3/DMF (1.5
b
c
mmol), 80 ꢀC, 4–5 h. Isolated yields. The reaction of 1a and PBr3/
d
DMF under the optimized conditions. Reaction conditions: 1k (0.25
mmol), POCl3/DMF or POBr3/DMF (2.5 mmol), 120 ꢀC, 12 h.
methylene)-1-phenylbutane-1,3-dione 1k, 2k was isolated in
32% yield, which might stem from the steric hindered effect of
the ortho-substituted methyl group on the benzene ring of aryl
amine (Table 3, entry 11). However, when 1k reacted with POCl3/
DMF (10 equiv.) at 120 ꢀC for 12 h, the yield of 2k was enhanced
up to 77% (Table 3, entry 11). The reaction was also successfully
extended to the synthesis of 4-bromo pyridin-2(1H)-ones.
According to Dong's work, the reaction of 1a and PBr3/DMF
initially carried out under the optimized conditions afforded 4-
bromo-5-(4-methylbenzoyl)-6-oxo-1-phenyl-1,6-dihydropyridine-
3-carbaldehyde 2b in 21% yield (Table 3, entry 1). To our delight,
Conclusion
In conclusion, we rstly prepared (Z)-a-acetyl-a-aroyl ketene-
N,S-acetals 1 and conrmed their conguration by X-ray crys-
tallographic analysis. Subsequently, a facile and efficient one-
pot synthesis of 3-aroyl-5-formyl-4-halopyridin-2(1H)-ones 2
was successfully developed from Vilsmeier cyclizations of
readily available substrate 1. Further application of synthe-
sized halogenated pyridin-2(1H)-ones 2 is ongoing in our
group.
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We are grateful to the National Nature Science Foundation of
China (20902010) and Science Foundation of Anshan City
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