One-Pot synthesis of -alkylidene - Butyrolacton-2-ones (Tetronic Acid Derivatives): Polar solvent induces a new type of -lactonization

Article abstract of DOI:10.1055/s-0030-1258113

An efficient, one-pot synthetic protocol toward α-alkylidene γ- butyrolacton-2-ones, a rather unexplored class of heterocyclic scaffolds starting from primary amines, methyl acetoacetate, and chloroacetyl chloride is described. The mixture of MeCN-MeOH as a polar solvent triggers a new cycloaddition of the enaminone intermediate. The reaction is completed within 12 hours under reflux condition to produce the title compounds. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258113

1854
LETTER
One-Pot Synthesis of a-Alkylidene-g-butyrolacton-2-ones (Tetronic Acid
Derivatives): Polar Solvent Induces a New Type of g-Lactonization
O
ne-PotSynthesis
b
of
a
-Alkylid
d
ene-
g
-butyro
o
lacton-2-one
l
s
ali Alizadeh,* Hamideh Sabahnoo, Zohreh Noaparast, Nasrin Zohreh, Azadeh Mikaeili
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
Fax +98(21)88006544; E-mail: aalizadeh@modares.ac.ir
Received 19 March 2010
tive natural products13 [for example, galanolactone (1),
Abstract: An efficient, one-pot synthetic protocol toward a-alky-
lidene-g-butyrolacton-2-ones, a rather unexplored class of hetero-
cyclic scaffolds starting from primary amines, methyl acetoacetate,
and chloroacetyl chloride is described. The mixture of MeCN–
Figure 1], but also as starting materials in various synthet-
ic transformations. They can undergo reduction,14 oxida-
tion,15 aziridination,16 1,3-dipolar,17 and Diels–Alder18
MeOH as a polar solvent triggers a new cycloaddition of the enam- cycloadditions, nucleophilic conjugate additions,18 and
intramolecular Stetter reactions.19
inone intermediate. The reaction is completed within 12 hours un-
der reflux condition to produce the title compounds.
Tetronic acid derivatives and their metabolites are wide-
Key words: g-lactone, a-alkylidene-g-butyrolactone, tetronic acid,
spread in nature, whereof vitamin C and penicillic acid are
enaminone, chloroacetyl chloride, polar solvent, one-pot multicom-
undoubtedly the most important.20 A large array of bio-
ponent reaction
logical properties including antibutic, analgesic, insecti-
cidal, antifungal, and antitumor properties21 have attracted
the interest of many research groups on the synthesis of
Lactones of five, and larger rings, are of interest because
this class of heterocyclic compounds. Recently ester de-
rivatives of nodulisporacid A (2) isolated from a marine-
of their applications in building up biologically active
compounds, which exhibit various pharmacological activ-
derived fungus Nodulisporium sp. CRIF1 have been
ities.1–5 They are commonly known for their cytostatic and
found to show activity against eleven cancer cell lines.22
antimicrobial6,7 activity. Many of them have feeding de-
terrent activity against insects.8–10 Interest in naturally oc-
curring and synthetic a-alkylidene-g-butyrolactones is
surging11 as several of them have been shown to display
anti-inflammatory COX-2 inhibition, as well as phytotox-
ic and cytotoxic activities.12 The a-alkylidene-g-butyro-
lactone substructure has attracted particular attention, not
only for being present in a wide range of biologically ac-
On account of this wide range of activity, a variety of syn-
thetic methods for both tetronic acids23 and a-alkylidene-
g-butyrolactones24 has been developed. Surprisingly, to
our knowledge, there currently exists no efficient proce-
dure for the synthesis of compounds including a combina-
tion of these two characteristic substructures together
directly from readily available building blocks.
O
O
O
H
galanolactone (1)
O
O
O
O
HO
HO
O
O
O
O
O
O
E-isomer
Z-isomer
nodulisporacid A (2)
Figure 1 Natural products, which contain the a-alkylidene-g-butyrolactone substructure
SYNLETT 2010, No. 12, pp 1854–1858
x
x
.x
x
.2
0
1
0
Advanced online publication: 30.06.2010
DOI: 10.1055/s-0030-1258113; Art ID: D07410ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
One-Pot Synthesis of a-Alkylidene-g-butyrolacton-2-ones
1855
Recently, our group reported the synthesis of a novel se-
ries of heterocyclic compounds using the reaction of
enamines or enaminones with various electrophiles via
one-pot MCR.25 In a continuation of this study, we be-
come interested in the application of chloroacetyl chloride
(which display electrophilic property at two sites of its
structure) via multicomponent reaction for synthesis of a-
alkylidene-g-butyrolacton-2-ones as tetronic acid ana-
logues. Our strategy to reach this goal is outlined in
Table 1. Reaction between primary amines 3, methyl ace-
toacetate, and chloroacetyl chloride in a mixture of
MeCN–MeOH as solvent under thermal conditions leads
to the formation of [1-(alkylamino)ethylidene]-
2,4(3H,5H)-furandione 4 after 12 hours in 70–85%
yields.26
Table 1 Reaction between Primary Amines 3, Methyl Acetoacetate
and Chloroacetyl Chloride in a Mixture of MeCN–MeOH as Solvent
under Thermal Conditions
R
RNH2
3
N
Me
H
O
E-isomer
O
+
O
O
O
MeCN–MeOH
reflux, 12 h
Me
Cl
OMe
+
R
N
O
Me
H
O
Cl
Z-isomer
O
O
To show the effect of polar solvent, the reaction of prima-
ry amine 3, methyl acetoacetate, and chloroacetyl chloride
was performed in CH2Cl2 or refluxing toluene. After 24
hours, the H NMR spectrum of the reaction mixture
showed that product 4 has been not formed even in a trace
4
Entry
R
Yield of 4 (%)
4a 71
E/Z
1
1
2
3
4
5
7
8
9
Et
53:47
66:34
60:40
62:38
67:33
60:40
63:37
63:37
n-Pr
n-Bu
t-Bu
i-Pr
i-Bu
All
4b 80
amount (Scheme 1).
4c 75
RNH2
3
4d 77
+
4e 82
O
O
CH2Cl2 or refluxing toluene
24 h
no reaction
4f 70
Me
OMe
4g 78
+
O
Cy
4h 85
Cl
Cl
RNH2
RNH2
+
Scheme 1 The reaction in CH2Cl2 or refluxing toluene
+
R
N
O
O
O
O
To investigate the scope and limitations of the reaction,
and especially to confirm the proposed product structure
4, we first decided to study the effect of using different
alkyl acetoacatate (ethyl acetoacatate) and performed its
reaction with primary amine 3 and chloroacetyl chloride
under the same conditions. It was found that the reaction
was quite general towards the alkyl acetoacatate compo-
nent. In view of the success of the reaction, we then em-
ployed bromoacetyl bromide under these conditions to
form the [1-(alkylamino)ethylidene]-2,4(3H,5H)-furandi-
ones 4, with slightly increased yield. All of our results
were summarized in Scheme 2.
Me
H
O
Me
OMe
Me
OEt
O
+
+
71%
72%
Cl
O
O
Cl
O
E-isomer
Cl
Cl
R
Me
N
H
O
RNH2
+
RNH2
+
O
76%
75%
O
O
O
O
O
Z-isomer
The structures of compounds 4a–h were deduced from
Me
OMe
Me
OEt
1
their, mass, IR, and high field H NMR and 13C NMR
4
+
+
spectra as described for 4a. The mass spectrum of 4a dis-
played a molecular ion peak at m/z = 169. Initial fragmen-
tation for most products involved the loss of H2O with 4a
showing a fragment ion at m/z = 151. In the IR spectrum
of 4a, one absorption band at 3460, three bands at 1728,
1638, and 1615 cm–1, which are, respectively, related to
NH, C=O of ketone, C=O of ester, and C=C stretching fre-
quencies, clearly indicated the most important functional
groups of the product.
Br
O
Br
O
Br
Br
Scheme 2 Evaluation of ethyl acetoacatate and bromoacetyl bromide
in the reaction under similar conditions. Conditions for all reactions:
MeCN–MeOH, reflux, 12 h.
The presence of these two rotational isomers was con-
firmed by the H NMR and 13C NMR spectra of 4a–h
1
Synlett 2010, No. 12, 1854–1858 © Thieme Stuttgart · New York

1856
A. Alizadeh et al.
LETTER
O
R
O
O
NH
O
Cl
Cl
+
RNH2
Me
– HCl
Me
OMe
Me
O
3
5
R
N
Me
H
O
O
R
R
– MeCl
Me
NH
O
O
N
O
O
path B
Cl
Me
8
Me
O
Me
O
4
R
H2O, HCl
path A
O
NH
O
– HCl
Cl
Cl
Me
OH
7
6
O
Cl
9
..
Me
NHR
O
RHN
Me
RHN
O
Me
O
O
O
O
O
O
O
E-isomer
Z-isomer
Scheme 3 The proposed mechanism for the formation of a-alkylidene-g-butyrolacton-2-one (tetronic acid) 4
where two sets of peaks were detected. The 1H NMR spec- sible intermediates 8 or 9 provide the observed product 4
trum of 4a exhibited two triplet signals at 1.32 (3JHH = 7.3 by loss of a molecule of MeCl or HCl, respectively.
Hz) and 1.35 ppm (3JHH = 7.3 Hz) readily recognized as
In conclusion, we have reported a novel and convenient
arising from two CH2CH3 groups. Two sharp singlet sig-
one-pot synthesis of a-alkylidene-g-lacton-2-ones (tetron-
nals at d = 2.54 and 2.58 ppm are related to two methyl
ic acids). This class of compounds is not only prepared by
a multicomponent reaction for the first time but also to our
knowledge, there is no other efficient method for their
groups. Two quartets at d = 3.47 and 3.50 ppm (3JHH = 7.3
Hz for both of them) correspond to the two CH2CH3
groups. The CH2 of the lactone ring appears as two singlet
synthesis. As regards the structural viewpoint, these mate-
signals at d = 4.38 and 4.40 ppm. The signal of the NH for
rials are tetronic acids on one hand and a-alkylidene-g-
the two rotamers appears as two relatively broad signals at
lactones on the other, as well as possessing an enamine
1
d = 10.01 and 10.99 ppm. The H-decoupled 13C NMR
component. Other features of this reaction are that it is
performed under neutral, catalyst-free conditions and con-
spectrum of 4a is in agreement with the product structure.
In the aliphatic region there are 8 signals related to four
stitutes a simple and direct high-yield approach to this
Me and four CH2 groups. Two quaternary carbon of two
class of compounds. The simplicity of this procedure
rotamers which are attached to two C=O groups resonate
makes it an interesting alternative to complex multistep
at d = 90.36 and 91.76 ppm. The most important region of
approaches.
the spectrum is related to carbonyl groups that have 4
C=O signals for two rotamers.
References and Notes
Although no detailed mechanistic studies have been car-
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1 1988, 1823.
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tion of primary amine 3 and methyl acetoacetate would
provide the enaminone intermediate 5. Addition of the
enaminone 5 to chloroacetyl chloride flowed by loss of
HCl gives 2-imino-1,3-dicarbonyl 6 which tautomerizes
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path B, the polar solvent induces intramolecular nucleo-
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LETTER
One-Pot Synthesis of a-Alkylidene-g-butyrolacton-2-ones
1857
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(26) To a magnetically stirred 10 mL flat-bottom flask,
containing ethylamine (0.09 g, 2 mmol) was added methyl
acetoacetate (0.24 g, 2 mmol), and this mixture was stirred
at r.t. under solvent-free conditions for 10 min. A solution of
chloroacetyl chloride (0.22 g, 2 mmol) in MeCN (5 mL) was
added dropwise to the reaction mixture. The progress of the
reaction was followed by TLC. When enaminone 5 was fully
consumed, MeOH (2 mL) was added and the mixture
allowed to stir at 110–120 °C for 11 h. After completion of
the reaction, the solvent was removed under reduced
pressure. The residue was purified by column chromatog-
raphy on silica gel (n-hexane–EtOAc = 1:1) to obtain
product 4a as a white powder (0.12 g, 71%). IR (KBr): 3460
(NH), 1728 (CO2), 1638 (C=O), 1615 (C=C) cm–1. MS (EI,
70 eV): m/z (%) = 169 (93) [M+], 151 (85), 123 (38), 95 (34),
82 (69), 68 (50), 58 (100), 42 (92).
E-Isomer of 4a: 1H NMR (500.13 MHz, CDCl3): d = 1.35 (3
H, t, 3JH,H = 7.3 Hz, CH2CH3), 2.54 (3 H, s, CH3), 3.47 (2 H,
q, 3JH,H = 7.3 Hz, CH2CH3), 4.40 (2 H, s, CH2O), 10.99 (1 H,
s, NH). 13C NMR (125.75 MHz, CDCl3): d = 13.86
(CH2CH3), 14.42 (CH3), 38.43 (CH2CH3), 69.97 (OCH2),
91.76 (C=CCH3), 170.80 (C=CCH3), 172.52 (CO2), 197.10
(C=O).
Z-isomer of 4a: 1H NMR (500.13 MHz, CDCl3): d = 1.32 (3
H, t, 3JH,H = 7.3 Hz, CH2CH3), 2.58 (3 H, s, CH3), 3.50 (2 H,
q, 3JH,H = 7.3 Hz, CH2CH3), 4.38 (2 H, s, CH2O), 10.01 (1 H,
s, NH). 13C NMR (125.75 MHz, CDCl3): d = 14.27
(CH2CH3), 14.62 (CH3), 38.12 (CH2CH3), 72.00 (OCH2),
90.36 (C=CCH3), 169.94 (C=CCH3), 176.35 (CO2), 193.62
(C=O).
Compound 4b: yield 0.28 g (80%); white powder; mp 112–
114 °C. IR (KBr): 3465 (NH), 1734 (CO2), 1661 (C=O),
1604 (C=C) cm–1. MS (EI, 70 eV): m/z (%) = 183 (100)
[M+], 165 (87), 154 (70), 150 (59), 137 (39), 125 (47), 97
(75), 82 (72), 67 (70).
E-isomer of 4b: 1H NMR (500.13 MHz, CDCl3): d = 1.05 (3
H, t, 3JH,H = 7.4 Hz, CH2CH3), 1.75 (2 H, q, 3JH,H = 7.4 Hz,
CH2CH3), 2.55 (3 H, s, CH3), 3.43 (2 H, t, 3JH,H = 6.9 Hz,
CH2N), 4.42 (2 H, s, OCH2), 11.10 (1 H, s, NH). 13C NMR
(125.75 MHz, CDCl3): d = 11.16 (CH2CH3), 13.96 (CH3),
30.87 (CH2CH3), 45.18 (CH2N), 69.97 (CH2O), 91.88
(C=CCH3), 161.90 (C=CCH3), 170.96 (CO2), 197.18 (C=O).
Z-isomer of 4b: 1H NMR (500.13 MHz, CDCl3): d = 1.03 (3
H, t, 3JH,H = 7.4 Hz, CH2CH3), 1.72 (2 H, q, 3JH,H = 7.4 Hz,
CH2CH3), 2.60 (3 H, s, CH3), 3.40 (2 H, t, 3JH,H = 7.0 Hz,
CH2N), 4.40 (2 H, s, OCH2), 10.13 (1 H, s, NH). 13C NMR
(125.75 MHz, CDCl3): d = 11.16 (CH2CH3), 14.37 (CH3),
31.22 (CH2CH3), 44.85 (CH2N), 72.04 (CH2O), 90.44
(C=CCH3), 161.93 (C=CCH3), 170.07 (CO2), 193.61 (C=O).
Compound 4e: yield 0.28 g (82%); white powder; mp 118–
120 °C. IR (KBr): 3230 (NH), 1725 (CO2), 1639 (C=O),
1604 (C=C) cm–1. MS (EI, 70 eV): m/z (%) = 183 (100)
[M+], 165 (78), 137 (24), 110 (39), 96 (94), 83 (47), 67 (35),
55 (16).
E-isomer of 4e: 1H NMR (500.13 MHz, CDCl3): d = 1.30 (6
H, d, 3JH,H = 6.2 Hz, 2 CHCH3), 2.51 (3 H, s, CH3), 3.91–
3.99 (1 H, m, 1 CHCH3), 4.33 (2 H, s, CH2O), 10.94 (1 H, s,
NH). 13C NMR (125.75 MHz, CDCl3): d = 13.85 (2
CHCH3), 22.82 (CH3), 45.75 (CHCH3), 69.89 (CH2O),
Synlett 2010, No. 12, 1854–1858 © Thieme Stuttgart · New York

1858
A. Alizadeh et al.
LETTER
NH). 13C NMR (125.75 MHz, CDCl3): d = 14.31 (2
CHCH3), 22.78 (CH3), 45.41 (CHCH3), 71.84 (CH2O),
90.05 (C=CCH3), 168.61 (C=CCH3), 176.31 (CO2), 193.58
(C=O).
91.43 (C=CCH3), 169.43 (C=CCH3), 172.53 (CO2), 196.96
(C=O).
Z-isomer of 4e: 1H NMR (500.13 MHz, CDCl3): d = 1.28 (6
H, d, 3JH,H = 6.2 Hz, 2 CHCH3), 2.56 (3 H, s, CH3), 3.91–
3.99 (1 H, m, CHCH3), 4.30 (2 H, s, CH2O), 9.94 (1 H, s,
Synlett 2010, No. 12, 1854–1858 © Thieme Stuttgart · New York

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