Highly efficient synthesis of 3-amino-/alkylthio-cyclobut-2-en-1-ones based on the cyclization of acyl ketene dithioacetals

Article abstract of DOI:10.1039/c0cc02470h

A new strategy for the highly efficient one-pot synthesis of 3-amino-/alkylthio-cyclobut-2-en-1-ones based on the cyclization of acyl ketene dithioacetals is disclosed. In addition, the rearrangement of 3-amino-cyclobut-2-en-1-ones to 4-quinolone derivatives is described.

Full text of DOI:10.1039/c0cc02470h

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Highly efficient synthesis of 3-amino-/alkylthio-cyclobut-2-en-1-ones
based on the cyclization of acyl ketene dithioacetalsw
Yu-Long Zhao,* Shao-Chun Yang, Chong-Hui Di, Xiao-Dan Han and Qun Liu*
Received 9th July 2010, Accepted 23rd August 2010
DOI: 10.1039/c0cc02470h
A new strategy for the highly efficient one-pot synthesis of
3-amino-/alkylthio-cyclobut-2-en-1-ones based on the cyclization
of acyl ketene dithioacetals is disclosed. In addition, the
rearrangement of 3-amino-cyclobut-2-en-1-ones to 4-quinolone
derivatives is described.
(Scheme 1). Furthermore, reaction of 3a with 4-methylaniline
was carried out, which resulted in the formation of 2a1 in 72%
yield (Scheme 1).
On the basis of the above experimental results and related
reports,4,6,7a,7b a mechanism for the formation of 2 is proposed
in Scheme 2. In the presence of ButOK, a vinyl enolate anion
intermediate A is formed by deprotonation of the methylene
group of acyl ketene dithioacetals 1 (Scheme 2). Subsequently,
a 4-electron electrocyclic ring closure of the vinyl enolate A to
cyclobutanone B may occur. Under basic conditions, the
elimination of an alkylthiol from B gives 3-alkylthiocyclobut-
2-en-1-ones 3.6a Whereas, in the presence of an amine,
3-aminocyclobut-2-en-1-ones 2 are thought to be produced
via the nucleophilic amine addition and alkylthiol elimination
processes.6b
In recent research on the VLA-4 (very late activating antigen-4)
antagonists,1 3-aminocyclobut-2-en-1-one derivatives have
been described as potent VLA-4 antagonists.2 However, to
date synthesis of 3-amino-cyclobut-2-en-1-ones is limited to
the following: condensation of cyclobutane-1,3-diones with
primary amines;2 [2+2] cycloaddition of ketenes with ynamides;3
and the reaction of 3-ethoxycyclobut-2-enones with amino
acids.4 We report in this communication a novel and efficient
synthesis of 3-aminocyclobut-2-en-1-ones 2 from the easily
available acyl ketene dithioacetals 1.5
An alternative mechanism that can be considered for the
formation of 3-alkylthiocyclobut-2-en-1-ones 3 from the vinyl
enolate A is the involvement of intramolecular Michael
addition (Scheme 2). Although this 4-endo-trig cyclization is
disfavored according to Baldwin’s rules, the validity of this
assumption is open to question. For example, 5-endo-trig
‘‘anti-Baldwin’’ ring closure occurred in the cyclization of
gem-difluoroolefins9 or ketene dithioacetals (gem-dithioolefins)10
bearing a homoallylic heteroatom nucleophile. In addition,
the 3-exo-dig cyclization of propargylic halides possessing
In continuation of our studies on the application of
ketene dithioacetals,6,7 we found that the reaction of
4-(bis(methylthio)methylene)heptane-3,5-dione (1a) with
4-methylaniline under basic conditions afforded a cyclobutenone
derivative,8 4-methyl-2-propionyl-3-(p-tolylamino)cyclobut-2-
enone (2a1). Under optimal conditions, (i.e., 1a (1.0 mmol),
4-methylaniline (1.0 mmol) and ButOK (2.0 equiv.) in DMSO
(2.0 mL) at room temperature for 0.5 h), 2a1 was obtained in
76% yield (Table 1, entry 1).z Under the conditions described
in Table 1, entry 1, a range of reactions of 1a (R2 = COEt)
with amines were carried out (Table 1). As a result, various
amines such as arylamines with either electron-rich (entry 1),
electron-neutral (entry 2), or electron-deficient (entry 3)
groups, heteroaromatic amine (entry 4), primary and secondary
aliphatic amines (entries 5 and 6), reacted smoothly with 1a to
give the corresponding 3-aminocyclobut-2-en-1-ones 2a1–6 in
good to high yields. In addition, 3-dimethylaminocyclobut-
2-en-1-one 2a7 was obtained in 73% yield from the reaction of
1a in DMF (entry 7, DMF as a dimethylamine equivalent).
Similarly, reactions of acyl ketene dithioacetals 1b (R2 = CO2Me)
and 1c (R2 = Ph) in DMF gave the corresponding 3-dimethyl-
aminocyclobut-2-en-1-ones 2b7 and 2c7 in 74% and 70%
yields, respectively (entries 8 and 9).
a
suitably placed active methine was also observed.11
Nevertheless, the preparation of 3-amino-/alkylthio-cyclobut-
2-en-1-ones from the cyclization of acyl ketene dithioacetals
provides a very convenient route to cyclobut-2-enones.2–4,8
It is well known that functionalized cyclobut-2-enones easily
undergo thermal ring-expansion reaction to offer efficient
access to functionalized monocyclic or ring-annelated carbo-
and heterocycles.8,12 To explore the synthetic potential of
cyclobut-2-enones 2, the ring-expansion reaction of 2 was
examined (Scheme 3). As expected, the reaction of 3-arylamino-
cyclobut-2-en-1-one 2a1 could proceed smoothly to give
4-quinolone derivative 4a1 in 56% yield in toluene at 110 1C
for 16 h (Fig. 1).13 To our satisfaction, the yield of 4a1 was
increased to 72% under identical conditions with the addition
of catalytic amounts of p-toluenesulfonamide (PTSA, 10%;
Scheme 3). Similarly, 4-quinolones 4a2 and 4a3 were obtained
in 70% yield from the reaction of 3-arylaminocyclobut-2-en-1-
ones 2a2 and 2a3, respectively (Scheme 3). Thus, the above
thermal ring-expansion reaction of 3-arylaminocyclobut-2-
en-1-ones provides an efficient approach to functionalized
quinolin-4(1H)-ones.14
In order to gain insight into the mechanism, the reaction of
1a was investigated. Under conditions identical to those
in Table 1, entry 1 but in the absence of an amine, 3-methyl-
thiocyclobut-2-en-1-one 3a was afforded in 82% yield
Department of Chemistry, Northeast Normal University,
Changchun 130024, China. E-mail: zhaoyl351@nenu.edu.cn;
Fax: +86 43 185099759; Tel: +86 43 185099759
w Electronic supplementary information (ESI) available: Detailed
experimental procedures and analytical data. CCDC 781521 (4a1).
For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c0cc02470h
On the basis of the above experimental results together with
the related reports,8,12 a mechanism for the formation of
4-quinolones 4 is proposed and depicted in Scheme 4. Under
thermal conditions, the 3-arylaminocyclobut-2-en-1-one 2
c
7614 Chem. Commun., 2010, 46, 7614–7616
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Table 1 Synthesis of 3-aminocyclobut-2-en-1-ones 2 from the reaction of 1 and aminesa
Entry
Substrate
R, R
R1
R2
R3
R4
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1b
1c
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
Me
Me
C6H5
COEt
COEt
COEt
COEt
COEt
COEt
COEt
CO2Me
C6H5
H
H
H
H
H
4-MeC6H4
C6H5
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
2a1 (76)
2a2 (70)
2a3 (66)
2a4 (69)
2a5 (75)
2a6 (70)
2a7 (73)
2b7 (74)
2c7 (70)
4-ClC6H4
2-Pyridyl
CH3(CH2)3
(CH2)5
Me
Me
Me
Me
Me
Me
DMF
DMF
Et
a
b
Reaction conditions: 1 (1.0 mmol), amine (1.0 mmol), ButOK (2.0 mmol), DMSO/DMF (2.0 mL), room temperature. Isolated yield.
Scheme 4 Proposed mechanism for the formation of 4.
Scheme 1 Synthesis of 3-methylthiocyclobutenone 3a and its reaction
with 4-methylaniline.
4-quinolones 4 (Scheme 4). As to the role of PTSA in increasing
the yield of 4-quinolones 4, it may be due to a weak base effect
to accelerate the formation of vinylketene intermediate A.
In conclusion, we have developed a new strategy for the
highly efficient one-pot synthesis of 3-amino-/alkylthio-cyclobut-
2-en-1-ones 2 and 3 via a base-promoted cyclization of acyl
ketene dithioacetals 1. The simplicity of execution, readily
available substrates, mild reaction conditions, short reaction
time make this synthetic strategy most attractive for practical
applications. As a synthetic application, 4-quinolones 4 were
prepared in high yields through a tandem ring-opening/
recyclization of 2. Further studies to expand the synthetic
utility of these functionalized cyclobutenones are in progress.
Scheme 2 Proposed mechanism for the formation of 2 and 3.
Financial support from the NNSFC (20972026), the
Department of Science and Technology of Jilin Province
(20080548), the Training Fund of NENU’s Scientific Innovation
Project (NENU-STC07017), the Fundamental Research
Funds for the Central Universities (NENU-STB07007), and
the Analysis and Testing Foundation of Northeast Normal
University is acknowledged.
Scheme 3 Synthesis of 4-quinolones 4a1–3 from 2a1–3.
Notes and references
z General procedure for the synthesis of cyclobutenones 2 (taking
2a1 as an example): To a solution of 4-(bis(methylthio)methylene)-
heptane-3,5-dione 1a (1.0 mmol, 232 mg) and 4-methylaniline
(1.0 mmol, 107 mg) in DMSO (2.0 mL) was added ButOK (2.0 mmol,
224 mg) in one portion. The reaction mixture was stirred for 0.5 h at
room temperature. After 1a was consumed (monitored by TLC), the
reaction mixture was poured into saturated aqueous NaCl (25 mL),
neutralized with aqueous HCl and extracted with CH2Cl2 (10 mL ꢀ 3).
Fig. 1 ORTEP drawing of 4a1.
The combined organic extracts were dried over anhydrous MgSO4,
filtered and concentrated under reduced pressure to yield the
undergoes a 4p electrocyclic cleavage to generate vinylketene
intermediate A, which rapidly cyclizes via 6p electrocyclic ring
closure, followed by tautomerization to give the coresponding
corresponding crude product, which was purified by silica gel
chromatography (ethyl acetate–hexane = 1/9, v/v) to give 2a1
(185 mg, 76%) as a white solid.
c
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Chem. Commun., 2010, 46, 7614–7616 7615

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c
7616 Chem. Commun., 2010, 46, 7614–7616
This journal is The Royal Society of Chemistry 2010