A facile and efficient synthesis of 3,5-disubstituted tetronic acids in aqueous media involving acid-catalyzed intramolecular oxa-pyridylethylation

Article abstract of DOI:10.1055/s-2004-836034

A facile and efficient one-pot synthesis of 3-[bis(alkylthio/alkylamino) methylene]-5-(pyridyl/quinoylmethyl) furan-2,4(3H,5H)-diones 3 and 10, based on a sequential aldol condensation and lactonization reaction between α-oxo ketene-S,S-acetals 1 and pyridine/qinoline-carboxaldehydes 2 in aqueous media, has been developed. A mechanism involving an acid-catalyzed intramolecular oxa-pyridylethylation reaction is proposed for the formation of the lactone ring.

Full text of DOI:10.1055/s-2004-836034

LETTER
49
A Facile and Efficient Synthesis of 3,5-Disubstituted Tetronic Acids in Aque-
ous Media Involving Acid-Catalyzed Intramolecular Oxa-Pyridylethylation
S
ynthesis of 3,5-D
i
isubstit
h
uted
T
etroni
e
c
Acids in Aqueo
Bus Media i, Qun Liu,* Shaoguang Sun, Jun Liu, Wei Pan, Lei Zhao, Dewen Dong*
Department of Chemistry, Northeast Normal University, Changchun, 130024, P. R. China
E-mail: dongdw663@nenu.edu.cn
Received 25 August 2004
O
S
O
O
O
Abstract: A facile and efficient one-pot synthesis of 3-[bis(alkyl-
thio/alkylamino)methylene]-5-(pyridyl/quinoylmethyl) furan-
S
S
OEt
( )n
( )n
i
S
S
Ar
Ar
ArCHO
2,4(3H,5H)-diones 3 and 10, based on a sequential aldol condensa-
tion and lactonization reaction between a-oxo ketene-S,S-acetals 1
and pyridine/qinoline-carboxaldehydes 2 in aqueous media, has
been developed. A mechanism involving an acid-catalyzed in-
tramolecular oxa-pyridylethylation reaction is proposed for the
formation of the lactone ring.
O
ii
S
( )n
HO
O
O
3
(Ar = 4-Pyridyl,
2-Pyridyl, 2-Quinoyl)
4
1 (n = 1, 2)
2
Scheme 1 Reagents and conditions: (i) NaOH, EtOH–H2O (2:1,
v/v), r.t., 0.5–1.0 h; (ii) HCl aq (1 N), r.t., 0.5–2.0 h.
Key words: aqueous media, tetronic acid derivatives, a-oxo
ketene-S,S-acetals, oxa-pyridylethylation, a-oxo ketene-N,N-ace-
The initial study was performed on the aldol condensation
between a-oxo ketene-S,S-acetal 1a (n = 1) and 4-pyridi-
necarboxaldehyde 2a in the presence of NaOH according
to the procedure described in literature (Scheme 1).8
The only product was obtained from the resulting
reaction mixture in excellent yield and identified as 3-
(1,3-dithiolan-2-ylidene)-5-(pyridin-4-ylmethyl)furan-2,
4(3H,5H)-dione (3a) on the basis of its elemental analysis,
1H NMR and 13C NMR spectra and single crystal X-ray
analysis. The product is thus a tetronic acid derivative
instead of an alkenoyl ketene dithioacetal 4.
tals
Tetronic acid derivatives (TADs), e.g. vitamin C and pen-
icillic acid, have attracted much attention for their pres-
ence in many natural products along with a large array of
useful biological and pharmacological activities.1,2 To
date, extensive work has been reported on the synthetic
methodology for this kind of compounds and their practi-
cal applications. Generally, TADs can be principally syn-
thesized either by the modification of the pre-constructed
core scaffold of a TAD3 or through the construction of 3-
oxo-g-lactone ring from appropriately substituted open
chain precursors.4 Nevertheless, to match the increasingly
scientific and practical demands for TADs, it is still of
continued interest and great importance to explore novel
and efficient synthetic approaches for such compounds.
On the other hand, a-oxo ketene-S,S-acetals are emerging
as a kind of versatile intermediate5 in the construction of
heterocyclic6 and carbocyclic7 compounds over the last
several decades. Pak and co-workers reported the aldol
condensation of a-oxo ketene-S,S-acetals 1 with aryl alde-
hydes which was followed by ester hydrolysis and decar-
boxylation to give alkenoyl ketene dithoacetals 4.8 In our
previous work,9,10 we found that halodecarboxylation
could further take place after the aldol condensation of a-
oxo ketene-S,S-acetals 1 with some aryl aldehydes. As a
part of further investigation of this kind of a-oxo ketene-
S,S-acetals, we here wish to report a novel synthetic meth-
od for 3,5-disubstituted TADs 3 involving tandem aldol
condensation and acid-catalyzed lactonization reaction of
a-oxo ketene-S,S-acetals 1 with the selected heteroaryl al-
dehydes, as well as the further transformation to TADs 10
by the displacement reaction with various amines.
In an attempt to extend the scope of this novel reaction, a-
oxo ketene-S,S-acetal 1b and some other aryl aldehydes
were selected and examined in this protocol. Consequent-
ly, a range of TADs 3b–f were successfully synthesized in
very high yields following the same one-pot procedure.
Some of the results are summarized in Table 1.11 How-
ever, when the protocol was applied to 3-pyridine-
carboxaldehyde 2d, 4-nitrobenzaldehyde 2e and 2-
nitrobenzaldehyde 2f, only the corresponding a-carboxyl-
a-alkenoyl ketene dithioacetals 4g–i were obtained in ex-
cellent yields, and no lactonization product was detected.
The results reveal that the chemical structures of the aryl
aldehydes strongly affect the orientation of the final aldol
condensation products.
To collect more information, some supporting experi-
ments were conducted on the reaction of 1a and 2a. In one
experiment, the condensation reaction of 1a with 2a was
carried out in the presence of NaOH in absolute ethanol at
room temperature for 0.5 hour. The sodium carboxylate
5a (Scheme 2) was formed and isolated from the reaction
mixture in 98% yield. It is worth noting that 5a is quite
stable under ambient atmosphere. In another experiment,
where the aqueous solution of 5a was acidified with dilute
acetic acid at 0 °C, the mixture of 4a and 3a was obtained
1
in 95% total yield (4a:3a = 1:4, according to H NMR
SYNLETT 2005, No. 1, pp 0049–0054
0
5.
0
1.
2
0
0
5
spectra). The results reveal that a-carboxyl-a-alkenoyl
ketene dithioacetal 4a was very labile under acidic condi-
Advanced online publication: 29.11.2004
DOI: 10.1055/s-2004-836034; Art ID: U23704ST
© Georg Thieme Verlag Stuttgart · New York

50
X. Bi et al.
LETTER
Table 1 Reactions between a-Oxo Ketene-S,S-acetals 1a,b and Aryl Aldehydes 2a–f
Entry
Substrates
n
Ar
Product
Time (h)
Yield (%)a
1
2
1
1a
1b
1a
1b
1a
1b
1a
1a
1a
2a
2a
2b
2b
2c
2c
2d
2e
2f
1
2
1
2
1
2
1
1
1
4-Pyridyl
4-Pyridyl
2-Pyridyl
2-Pyridyl
2-Quinoyl
2-Quinoyl
3-Pyridyl
4-O2NC6H4
2-O2NC6H4
3a
3b
3c
3d
3e
3f
1.0
1.0
2.5
2.5
1.0
1.0
3.0
3.0
3.0
95
93
88
91
90
94
95
93
93
2
3
4
5
6
7
4g
4h
4i
8
9
a Isolated yields.
tions. Apparently, the one-pot reaction to the tetronic acid
derivatives 3 involves a sequential aldol condensation and
acid induced cyclization of intermediate 4. Considering
both carbonyl and pyridyl group as electron-withdrawing
groups, the lactonization seems to be a regioselective
Michael-type addition.12 As a matter of fact, the novel lac-
tonization should be classified as a pyridinium-directed
intramolecular oxa-pyridylethylation reaction.
O
S
O
S
Figure 1 1H NMR spectra of the methylene of (a) 3a and (b) 3a-D.
i
ii
S
S
1a
2a
3a
N
N
O
ONa
O
OH
deuterated tetronic acid derivative 3a-D was obtained in
89% yield. Comparing the 1H NMR spectra of 3a and 3a-
D, it is observed that there are obvious changes occurring
at the range of d = 3.0–3.3 ppm (Figure 1). The disappear-
ance of the 2J coupling in the 1H NMR spectrum of 3a-D
indicates that the methylene group is deuterated during the
lactonization process. However, the fact that 4g, 4h and 4i
are inert to lactonization under the same reaction condi-
tions suggests that the deuteration might commence from
the protonation of the pyridyl ring instead of the direct ad-
dition of D+ to the double bond.22
4a
5a
Scheme 2 Reagents and conditions: (i) NaOH, EtOH, 0.5 h; (ii)
HOAc (20%, aq), 0 °C, 10 min.
Pyridylethylation has been extensively studied over the
last several decades.13–21 Various nucleophiles including
sulfur,14 nitrogen,15 carbon,16 phosphorus,17 selenium,18
and silicon19 have proven to be effective in this pyridyl-
ethylation reaction. However, there are few reports on the
oxygen nucleophiles employed in the pyridylethylation.
Doering et al. gave an example of oxa-pyridylethylation
of 2-vinylpyridine with ethanol catalyzed by sodium
ethoxide.13 The reaction was carried out under strongly
basic condition and its yield was very low (20%). Their at-
tempts, together with that from other research groups, to
develop oxa-pyridylethylation under acidic conditions
were unsuccessful.20,21 To the best of our knowledge, the
lactonization of 4 to give tetronic acid derivatives 3 is the
first example of acid-catalyzed intramolecular oxa-py-
ridylethylation reaction.
As has been widely known, the electronegative nitrogen
imposes the electron deficiency on the a- and g-positions
of pyridine, and the electron deficiency can be extended to
a double bond conjugated in the a- and g-positions but im-
possible in the b-position due to the resonance interac-
tions of the double bonds.13,18,23 Therefore, a plausible
mechanism is proposed for the lactonization (Scheme 3,
3a-D as an example). The lactonization is initiated by the
protonation of 4a-D at the basic nitrogen of pyridyl ring
and leads to the formation of a strong electrophilic site at
the a-position of intermediate 7 through the resonance of
the pyridinium ring. An intramolecular pyridylethylation
then takes place while the attack of the nucleophilic
oxygen atom of carboxyl group to the electrophilic site
and give a lactonized intermediate 8. Through a quick
To gain the much more clear insight into the mechanism
of this novel oxa-pyridylethylation reaction, the deuteri-
um labeling experiment was then carried out. After the
treatment of sodium salt 5a with 1.5 equivalents
CF3CO2D in D2O for one hour at ambient temperature, the
Synlett 2005, No. 1, 49–54 © Thieme Stuttgart · New York

LETTER
Synthesis of 3,5-Disubstituted Tetronic Acids in Aqueous Media
51
O
O
S
O
S
O
S
β
D+
α
S
S
S
N+
N
N
D
O D
D
O
O D
O
O D
CF3COO-
CF3COO-
6
4a–D
7
O
O
O
D
S
S
S
S
S
–
S
O
N+
O
O
N
N
D
O
D
O
O
CF3COO-
CF3COO-
3a–D
8
9
Scheme 3 A proposed mechanism for the lactonization.
resonance recovery to the pyridinium ring, intermediate 8 2,4-diones, was achieved by addition of the selected
is transformed into intermediate 9 bearing a negative amines directly to the reaction mixture of 1a and 2a,b
charge carbon. Accompanied with the protonation of this when the lactonization reaction was completed (moni-
carbon anion and a subsequent deprotonation of the pyri- tored by TLC), as shown in Scheme 4.26 A range of TADs
dinium ring in the presence of NaHCO3, the intermediate 10a–i was obtained in moderate to high yields, some of
9 affords the final product 3a-D. From the mechanism, it the results are listed in Table 2.
is not difficult to understand why the deuteration occurs
In summary, we have presented here a facile, one-pot syn-
on the methylene group and no deuterated evidence on the
thetic route to a range of tetronic acid derivatives, 3-
pyridyl ring is detected.
[bis(alkylthio/alkylamino)methylene]-5-(pyridyl/quinoyl
In the present work, we combined ketene dithioacetal methyl)furan-2,4(3H,5H)-diones 3 and 10, and proposed
group and tetronic acid ring in the same molecules, which a mechanism for the lactonization. Associated with readi-
makes compounds 3 having the potential to become high- ly available starting materials, mild conditions and high
ly valuable organic intermediates. It is reported by some yields, this novel approach is actually involved in sequen-
researchers that the selective 1,4-reduction of a-oxo tial aldol condensation and acid-catalyzed intramolecular
ketene-S,S-acetals has been achieved in Mg/MeOH or Zn/ oxa-pyridylethylation reaction.
HOAc systems.24 In these cases, the carbonyl groups are
leaving intact. These results suggest that there might exist
the feasibility to convert compounds 3 to protected b-keto
Acknowledgment
Financial support of this work by the NNSFC (20272008) and the
Key Project of Chinese Ministry of Education (03059) are grateful-
ly acknowledged.
aldehydes, which is very useful for organic synthesis as
most natural TADs bears 3-acyl substituent. The investi-
gation aimed at this is ongoing in our laboratory.
O
O
References
O
NHR
NHR
OEt
i, ii, iii
(1) (a) Haynes, L. J.; Plimmer, J. R. Q. Rev. Chem. Soc. 1960,
14, 292. (b) Pilli, R. A.; Ferreira de Oliveira, M. C. Nat.
Prod. Rep. 2000, 17, 117.
Ar
ArCHO
S
S
O
O
1a
2
10
(2) (a) Ishida, K.; Teruya, T.; Simizu, S.; Osada, H. J. Antibiot.
2004, 57, 136. (b) Liu, Y.; Hong, J.; Lee, C.; Im, K.; Kim,
N.; Choi, J.; Jung, J. J. Nat. Prod. 2002, 65, 1307.
(c) Sodeoka, M.; Sampe, R.; Kojima, S.; Baba, Y.; Usui, T.;
Ueda, K.; Osada, H. J. Med. Chem. 2001, 44, 3216.
(d) Usui, T.; Kojima, S.; Kidokoro, S.; Ueda, K.; Osada, H.;
Sodeoka, M. Chem. Biol. 2001, 8, 1209. (e) Buhler, H.;
Bayer, A.; Effenberger, F. Chem.–Eur. J. 2000, 6, 2564.
(f) Hegde, V. R.; Patel, M. G.; Das, P. R.; Pramanik, B.;
Puar, M. S. J. Antibiot. 1997, 50, 126. (g) Roggo, B. E.;
Petersen, F.; Delmendo, R.; Jenny, H. B.; Peter, H. H.;
Roesel, J. J. Antibiot. 1994, 47, 136.
(3) (a) Schobert, R.; Gordon, G. J.; Mullen, G.; Stehle, R.
Tetrahedron Lett. 2004, 45, 1121. (b) Kemmler, M.; Bach,
T. Angew. Chem. Int. Ed. 2003, 42, 4824. (c) Paintner, F.
F.; Allmendinger, L.; Bauschke, G. Synlett 2003, 83.
(d) Paintner, F. F.; Allmendinger, L.; Bauschke, G.; Polborn,
K. Synlett 2002, 1308. (e) Velázquez, F.; Olivo, H. F. Org.
Lett. 2002, 4, 3175.
Ar = 4-Pyridyl
2-Pyridyl
Scheme 4 Reagents and conditions: (i) NaOH, EtOH–H2O (2:1,
v/v), r.t., 0.5–1.0 h; (ii) HCl (1 N), r.t., 0.5–2.0 h; (iii) RNH2, r.t.,
0.5–2.5 h.
On the other hand, a-oxoketene-S,S-acetals can be used as
1,3-electrophilic 3-carbon equivalents due to the push–
pull character of the ketene dithioacetal group. Indeed, nu-
merous works on the displacement of the bisalkylthio
groups of a-oxo ketene-S,S-acetals with varied amines to
give a-oxo ketene-N,N-acetals have been reported.5,25
These researches encourage us to envisage the protocol to
combine the lactonization with the displacement reaction
together. In the present work, one-pot synthesis of TADs
10, 5-pyridinemethyl-3-bis(alkylamino)methylenefuran-
Synlett 2005, No. 1, 49–54 © Thieme Stuttgart · New York

52
X. Bi et al.
LETTER
Table 2 One-Pot Synthesis of Tetronic Acid Derivatives 10
Product
R
R
Substrate 2
Temp (°C)
Time (h)
2.0
Yield (%)a
10a
-(CH2)2-
-(CH2)3-
-(CH2)4-
2a
2a
2a
2a
2a
2a
2b
2b
2b
r.t.
r.t.
r.t.
r.t.
80
r.t.
r.t.
80
r.t.
90
92
89
85
71
90
83
67
85
10b
2.0
10c
2.5
10db
Me
H
Me
3.0
10ec
H
4.0
10f
HO(CH2)2-
-(CH2)2-
HO(CH2)2-
1.5
10g
3.5
10hc
H
H
5.0
10i
HO(CH2)2-
HO(CH2)2-
3.0
a Isolated yields.
b Methylamine (aq, 30%) was used.
c NH3 (aq, 27%) was employed and the reaction mixture was heated to 80 °C after ammonia was added.
(4) (a) Schobert, R.; Jagusch, C. Tetrahedron Lett. 2003, 44,
6449. (b) Pévet, I.; Meyer, C.; Cossy, J. Tetrahedron Lett.
2001, 42, 5215. (c) Langer, P.; Eckardt, T.; Schneider, T.;
Göbel, C.; Herbst-Irmer, R. J. Org. Chem. 2001, 66, 2222.
(d) Schobert, R.; Siegfried, S.; Gordon, G.; Mulholland, D.;
Nieuwenhuyzen, M. Tetrahedron Lett. 2001, 42, 4561.
(e) Langer, P.; Eckardt, T. Synlett 2000, 844. (f) Paleta, O.;
Volkov, A.; Hetflejs, J. J. Fluorine Chem. 2000, 102, 147.
(g) Mitsos, C. A.; Zografos, A. L.; Igglessi-Markopoulou, O.
J. Org. Chem. 2000, 65, 5852. (h) Effenberger, F.; Syed, J.
Tetrahedron: Asymmetry 1998, 9, 817; and references
therein.
(5) For reviews, see: (a) Dieter, R. K. Tetrahedron 1986, 42,
3029. (b) Junjappa, H.; Ila, H.; Asokan, C. V. Tetrahedron
1990, 46, 5423. (c) Kolb, M. Synthesis 1990, 171. (d) Ila,
H.; Junjappa, H.; Barun, O. J. Organomet. Chem. 2001, 624,
34.
(6) Ila, H.; Junjappa, H.; Mohanta, P. K. In Progress in
Heterocyclic Chemistry, Vol. 13; Gribble, G. H.; Gilchrist,
L. T., Eds.; Pergamon Press: Oxford, 2001, Chap. 1, 1–24.
(7) (a) Kocienski, P. J.; Alessandro, P.; Liu, Q. J. Chem. Soc.,
Perkin Trans. 1 2001, 2356. (b) Gill, S.; Kocienski, P.;
Kohler, A.; Pontiroli, A.; Liu, Q. Chem. Commun. 1996,
1743. (c) Barun, O.; Nandi, S.; Panda, K.; Ila, H.; Junjappa,
H. J. Org. Chem. 2002, 67, 5398. (d) Nandi, S.; Syam
Kumar, U. K.; Ila, H.; Junjappa, H. J. Org. Chem. 2002, 67,
14. (e) Joseph, B. K.; Verghese, B.; Sudarsanakumar, C.;
Deepa, S.; Viswam, D.; Chandran, P.; Asokan, C. V. Chem.
Commun. 2002, 736.
and was stirred for 10 min. A yellowish solid was filtered
and washed with H2O (3 × 30 mL). The crude product was
purified by column chromatography over silica gel using
acetone–Et2O (2:1, v/v) as eluent to give product 3a (2.80 g,
95%) as a white crystal.
3-(1,3-Dithiolan-2-ylidene)-5-(pyridin-4-ylmethyl)furan-
2,4(3H,5H)-dione (3a): white crystal; mp 195–197 °C. 1H
NMR (400 MHz, CDCl3): d = 3.04 (dd, J = 8.0, 16.0 Hz, 1
H), 3.29 (dd, J = 4.0, 16.0 Hz, 1 H), 3.57–3.65 (m, 4 H), 4.89
(dd, J = 4.0, 8.0 Hz, 1 H), 7.20 (d, J = 8.0 Hz, 2 H), 8.50 (d,
J = 4.0 Hz, 2 H). 13C NMR (125 MHz, CDCl3): d = 192.5,
186.1, 168.0, 149.9 (2 C), 144.5, 124.9 (2 C), 106.3, 82.2,
38.7, 37.9, 36.8. IR (KBr): 1739, 1680, 1601, 1486, 1195,
1074, 828 cm–1. Anal. Calcd for C13H11NO3S2: C, 53.22; H,
3.78; N, 4.77; found: C, 53.46; H, 3.95; N, 4.98. Selected
crystal data for 3a: colorless plate orthorhombic space group
P2 (1)2(1)2(1), a = 4.9141 (3), b = 10.8597 (6), c = 24.4537
(15) Å, V = 1304.99 (13) Å3, b = 90°, Z = 4, Dc = 1.493 g
cm–3, m (Cu-Ka) = 1.40 cm–1.
3-(1,3-Dithiolan-2-ylidene)-5-(pyridin-4-yl-mono-
deuterated methyl) Furan-2,4(3H,5H)-dione (3a-D):
white solid; mp 194–196 °C. 1H NMR (500 MHz, CDCl3):
d = 3.03 (d, J = 7.0 Hz, 0.5 H), 3.27 (d, J = 3.5 Hz, 0.5 H),
3.57–3.66 (m, 4 H), 4.88 (dd, J = 3.5, 7.0 Hz, 1 H), 7.20 (d,
J = 4.5 Hz, 2 H), 8.51 (d, J = 4.5 Hz, 2 H). 13C NMR (125
MHz, CDCl3): d = 192.9, 186.0, 168.2, 150.1 (2 C), 144.8,
125.0 (2 C), 106.9, 82.4, 38.5, 38.1. IR (KBr): 1741, 1679,
1601, 1488, 1191, 1074, 1029, 791 cm–1. MS (ESI):
m/z (%) = 295 (100) [M + 1]+.
(8) Choi, E. B.; Youn, I. K.; Pak, C. S. Synthesis 1991, 15.
(9) Zhao, Y.; Liu, Q.; Sun, R.; Zhang, Q.; Xu, X. Synth.
Commun. 2004, 34, 463.
3-(1,3-Dithian-2-ylidene)-5-(pyridin-4-ylmethyl)furan-
2,4(3H,5H)-dione (3b): white solid; mp 199–201 °C. 1H
NMR (300 MHz, CDCl3): d = 2.32–2.36 (m, 2 H), 2.97 (dd,
J = 7.2, 14.7 Hz, 1 H), 3.11–3.13 (m, 4 H), 3.24 (dd, J = 3.6,
14.7 Hz, 1 H), 4.75 (dd, J = 3.6, 7.2 Hz, 1 H), 7.18 (d, J = 5.7
Hz, 2 H), 8.49 (d, J = 5.7 Hz, 2 H). 13C NMR (75 MHz,
CDCl3): d = 192.5, 184.0, 167.5, 149.8 (2 C), 144.3, 124.8 (2
C), 108.7, 81.0, 36.7, 30.9, 28.5, 28.4, 21.1. IR (KBr): 1733,
1669, 1433, 1173, 1074, 818 cm–1. Anal. Calcd for
C14H13NO3S2: C, 54.70; H, 4.26; N, 4.56. Found: C, 54.48;
H, 4.38; N, 4.75.
(10) Wang, M.; Xu, X.; Liu, Q.; Xiong, L.; Yang, B.; Gao, L.
Synth. Commun. 2002, 32, 3437.
(11) General Procedure for the Preparation of 3 (3a as
example).
To a solution of a-acetyl-a-ethoxylcarbonyl ketene cyclic
dithioacetal 1a (2.32 g, 10 mmol) and 4-pyridine
carboxaldehyde 2a (1.28 g, 12 mmol) in 30 mL EtOH–H2O
(2:1, v/v), NaOH (0.8 g, 20 mmol) was added. After stirring
at r.t. for 0.5 h, the mixture was acidified with aq HCl (1 N)
to adjust the pH value to 5 and was stirred for another 0.5 h.
The resulting mixture was poured into cold sat. aq NaHCO3
3-(1,3-Dithiolan-2-ylidene)-5-(pyridin-2-ylmethyl)furan-
2,4(3H,5H)-dione (3c): white solid; mp 182–184 ºC.
1H NMR (400 MHz, CDCl3): d = 3.14 (dd, J = 8.0, 16.0 Hz,
Synlett 2005, No. 1, 49–54 © Thieme Stuttgart · New York

LETTER
Synthesis of 3,5-Disubstituted Tetronic Acids in Aqueous Media
53
1 H), 3.50 (dd, J = 4.0, 16.0 Hz, 1 H), 3.59–3.65 (m, 4 H),
5.20 (dd, J = 4.0, 8.0 Hz, 1 H), 7.14–7.17 (m, 1 H), 7.22 (d,
(15) (a) Shapiro, S.; Rose, I.; Freedman, L. J. Am. Chem. Soc.
1957, 79, 2811. (b) Safak, C.; Erdojjan, H.; Palaska, E.;
Sunal, R.; Durd, S. J. Med. Chem. 1992, 35, 1296.
J = 8.0 Hz, 1 H), 7.59–7.64 (m, 1 H), 8.52 (d, J = 4.4 Hz, 1
H). IR (KBr): 1736, 1678, 1591, 1492, 1436, 1196, 1071,
779 cm–1. MS (ESI): m/z (%) = 294 (100) [M + 1]+. Anal.
Calcd for C13H11NO3S2: C, 53.22; H, 3.78; N, 4.77. Found:
C, 53.41; H, 3.94; N, 4.96.
3-(1,3-Dithian-2-ylidene)-5-(pyridin-2-ylmethyl)furan-
2,4(3H,5H)-dione (3d): white solid; mp 171–173 °C. 1H
NMR (600 MHz, CHCl3): d = 2.36–2.40 (m, 2 H), 3.09 (dd,
J = 9.0, 14.4 Hz, 1 H), 3.13–3.16 (m, 4 H), 3.46 (dd, J = 3.6,
14.4 Hz, 1 H), 5.08 (dd, J = 3.6, 9.0 Hz, 1 H), 7.14–7.16 (m,
1 H), 7.23 (d, J = 7.8 Hz, 1 H), 7.60–7.63 (m, 1 H), 8.53 (d,
J = 4.8 Hz, 1 H). IR (KBr): 1727, 1664, 1433, 1421, 1175,
1079 cm–1. Anal. Calcd for C14H13NO3S2: C, 54.70; H, 4.26;
N, 4.56. Found: C, 54.85; H, 4.06; N, 4.78.
3-(1,3-Dithiolan-2-ylidene)-5-(quinolin-2-ylmethyl)fu-
ran-2,4(3H,5H)-dione (3e): white solid; mp 152–154 °C.
1H NMR (300 MHz, CDCl3): d = 3.42 (dd, J = 7.8, 15.6 Hz,
1 H), 3.57–3.66 (m, 4 H), 3.68 (dd, J = 3.9, 15.6 Hz, 1 H),
5.28 (dd, J = 3.9, 7.8 Hz, 1 H), 7.33 (d, J = 8.4 Hz, 1 H),
7.45–7.50 (m, 1 H), 7.62–7.67 (m, 1 H), 7.77 (d, J = 8.4 Hz,
1 H), 7.90 (d, J = 8.4 Hz, 1 H), 8.08 (d, J = 8.4 Hz, 1 H). IR
(KBr): 1740, 1675, 1501, 1428, 1197, 1074, 1008 cm–1.
Anal. Calcd for C17H13NO3S2: C, 59.46; H, 3.82; N, 4.08.
Found: C, 59.71; H, 4.08; N, 3.82.
3-(1,3-Dithian-2-ylidene)-5-(quinolin-2-ylmethyl)furan-
2,4(3H,5H)-dione (3f): white solid; mp 194–196 °C. 1H
NMR (500 MHz, CDCl3): d = 2.34–2.36 (m, 2 H), 3.10–3.13
(m, 4 H), 3.37 (dd, J = 8.0, 15.5 Hz, 1 H), 3.64 (dd, J = 4.0,
15.5 Hz, 1 H), 5.15 (dd, J = 4.0, 8.0 Hz, 1 H), 7.31–7.33 (m,
1 H), 7.46–7.49 (m, 1 H), 7.64–7.67 (m, 1 H), 7.76 (d,
J = 8.0 Hz, 1 H), 7.92 (d, J = 8.5 Hz, 1 H), 8.06 (d, J = 8.0
Hz, 1 H). IR (KBr): 1733, 1670, 1599, 1436, 1173, 1079
cm–1. Anal. Calcd for C18H15NO3S2: C, 60.48; H, 4.23; N,
3.92. Found: C, 60.69; H, 4.05; N, 4.08.
(E)-2-(1,3-Dithiolan-2-ylidene)-3-oxo-5-(pyridin-3-yl)-
pent-4-enoic Acid (4g): yellowish solid; mp 186–188 °C.
1H NMR (500 MHz, DMSO): d = 3.38–3.41 (m, 4 H), 7.42–
7.45 (m, 1 H), 7.46 (d, J = 16.0 Hz, 1 H), 7.52 (d, J = 16.0
Hz, 1 H), 8.11 (d, J = 8.0 Hz, 1 H), 8.56 (d, J = 4.5 Hz, 1 H),
8.83 (s, 1 H). IR (KBr): 3419, 1683, 1642, 1586, 1419, 1206,
733 cm–1. Anal. Calcd for C13H11NO3S2: C, 53.22; H, 3.78;
N, 4.77. Found: C, 53.02; H, 3.91; N, 4.58.
(E)-2-(1,3-Dithiolan-2-ylidene)-5-(4-nitrophenyl)-3-oxo-
pent-4-enoic Acid (4h): yellowish solid; mp 188–189 °C.
1H NMR (500 MHz, DMSO): d = 3.44–3.60 (m, 4 H), 7.52
(d, J = 16.0 Hz, 1 H), 7.58 (d, J = 16.0 Hz, 1 H), 7.94 (d,
J = 8.0 Hz, 2 H), 8.25 (d, J = 8.0 Hz, 2 H). IR (KBr): 3445,
1634, 1599, 1510, 1416, 1343, 1205, 731 cm–1; known
compound, see ref.10
(c) Babaev, E. V.; Tsisevich, A. A. J. Chem. Soc., Perkin
Trans. 1 1999, 399. (d) Kuzmich, D.; Mulrooney, C.
Synthesis 2003, 1671. (e) Cliffe, I. A.; Ifill, A. D.; Mansell,
H. L.; Todd, R. S.; White, A. C. Tetrahedron Lett. 1991, 32,
6789; and references therein.
(16) (a) Levine, R.; Wilt, M. H. J. Am. Chem. Soc. 1952, 74, 342.
(b) Wilt, M. H.; Levine, R. J. Am. Chem. Soc. 1953, 75,
1368. (c) Houpis, I. N.; Lee, J.; Dorziotis, I.; Molina, A.;
Reamer, B.; Volante, R. P.; Reider, P. J. Tetrahedron 1998,
54, 1185.
(17) Hersman, M. F.; Audrieth, L. F. J. Org. Chem. 1958, 23,
1889.
(18) Holler, M.; Sin, H. S.; James, A.; Burger, A.; Trisch, D.;
Biellmann, J. F. Chem.–Eur. J. 2000, 6, 2053.
(19) Nozakura, S. Bull. Chem. Soc. Jpn. 1956, 29, 784.
(20) (a) Paquette, L. A. J. Org. Chem. 1962, 27, 2780.
(b) Bissot, T. C.; Parry, R. W.; Campbell, D. H. J. Am.
Chem. Soc. 1957, 79, 796.
(21) Salamone, J. C.; Snider, B.; Fitch, W. L. Macromolecules
1970, 3, 707.
(22) Teller, F.; Audouin, M.; Sauvetre, R. J. Fluorine Chem.
2002, 113, 167.
(23) For a related report ‘protonated pyridylazo moiety activated
the phenyl ring to nucleophilic attack in aqueous sulfuric
acid’, see: Miura, Y.; Momoki, M. J. Chem. Soc., Perkin
Trans. 2 1998, 1185.
(24) (a) Choi, E. B.; Youn, I. K.; Pak, C. S. Synthesis 1988, 792.
(b) Mellor, J. M.; Schofield, R. S.; Korn, S. R. Tetrahedron
1997, 53, 17151. (c) Hu, Y.; Liu, Q.; Dong, D. Chin. Chem.
Lett. 1992, 3, 417.
(25) For a review, see: Huang, Z.; Wang, M. Heterocycles 1994,
37, 1233.
(26) General Procedure for the Preparation of 10 (10e as
example).
To a solution of 1a (2.32 g, 10 mmol) and 2a (1.28 g, 12
mmol) in 30 mL EtOH–H2O (2:1, v/v), NaOH (0.8 g, 20
mmol) was added. After stirring at r.t. for 0.5 h, the mixture
was acidified with aq HCl (1 N) to adjust the pH value to 5
and was stirred for another 0.5 h till the lactonization
reaction was completed (monitored by TLC). Then, aq
NH4OH (6 mL, 27%) was added and the reaction mixture
was heated to 80 ºC. After stirring for 3 h, the mixture was
allowed to cool down to r.t. and poured into cold aq NH4Cl.
A yellowish solid precipitated from the system, which was
filtered and washed with H2O (3 × 30 mL). The crude
product was purified by column chromatography over silica
gel using acetone–Et2O (5:1, v/v) as eluent to give product
10e as a white solid (1.65 g, 71%).
(E)-2-(1,3-Dithiolan-2-ylidene)-5-(2-nitrophenyl)-3-oxo-
pent-4-enoic Acid (4i): yellowish solid; mp 191–193 °C. 1H
NMR (500 MHz, DMSO): d = 3.39–3.45 (m, 4 H), 7.34 (d,
J = 15.0 Hz, 1 H), 7.64–7.67 (m, 1 H), 7.74 (d, J = 15.0 Hz,
1 H), 7.77–7.86 (m, 1 H), 7.87 (d, J = 7.5 Hz, 1 H), 8.07 (d,
J = 8.0 Hz, 1 H). IR (KBr): 2929, 1654, 1628, 1578, 1525,
1428, 1391, 1342, 1274, 1207, 727 cm–1. Anal. Calcd for
C14H11NO5S2: C, 49.84; H, 3.29; N, 4.15. Found: C, 50.11;
H, 3.34; N, 4.28.
3-(Imidazolidin-2-ylidene)-5-(pyridin-4-ylmethyl)furan-
2,4(3H,5H)-dione (10a): white solid; decomposition point
241–243 °C.1H NMR (400 MHz, DMSO): d = 2.80 (dd,
J = 8.0, 14.4 Hz, 1 H), 2.33 (dd, J = 4.0, 14.4 Hz, 1 H), 3.57
(br s, 4 H), 4.74 (dd, J = 4.0, 8.0 Hz, 1 H), 7.26 (d, J = 6.0
Hz, 2 H), 8.45 (d, J = 6.0 Hz, 2 H). IR (KBr): 3334, 1734,
1647, 1601, 1447, 1058, 1000 cm–1. Anal. Calcd for
C13H13N3O3: C, 60.22; H, 5.05; N, 16.21. Found: C, 60.47;
H, 4.82; N, 16.43.
(12) Perlmutter, P. Conjugate Addition Reaction in Organic
Synthesis; Pergamon Press: Oxford, 1992.
(13) Doering, W. E.; Weil, R. A. N. J. Am. Chem. Soc. 1947, 69,
5-(Pyridin-4-ylmethyl)-3-(tetrahydropyrimidin-2(1H)-
ylidene)furan-2,4(3H,5H)-dione (10b): white solid; mp
112–113 °C. 1H NMR (400 MHz, CDCl3): d = 2.01–2.07 (m,
2 H), 2.95 (dd, J = 8.0, 16.0 Hz, 1 H), 3.25 (dd, J = 4.0, 16.0
Hz, 1 H), 3.42 (br s, 4 H), 4.70 (dd, J = 4.0, 8.0 Hz, 1 H), 7.22
(d, J = 4.0 Hz, 2 H), 7.87 (br s, 1 H), 8.50 (d, J = 4.0 Hz, 2
H), 8.60 (br s, 1 H). 13C NMR (100 MHz, DMSO): d = 192.8,
2461.
(14) For a review see: Friedman, M. J. Protein Chem. 2001, 20,
431.
Synlett 2005, No. 1, 49–54 © Thieme Stuttgart · New York

54
X. Bi et al.
LETTER
173.1, 154.7, 149.2 (2 C), 145.9, 124.7 (2 C), 79.7, 37.6 (2
C), 36.2, 19.0. IR (KBr): 3325, 3279, 1710, 1634, 1602,
1464, 1417, 1151, 1007 cm–1. Anal. Calcd for C14H13NO3S2:
C, 54.70; H, 4.26; N, 4.56. Found: C, 54.77; H, 4.38; N, 4.55.
MS (ESI): m/z (%) = 569 (100) [2 M + 23]+.
3.56 (m, 8 H), 4.75 (dd, J = 2.5, 8.5 Hz, 1 H), 5.07 (br s, 2
H), 7.26 (d, J = 5.0 Hz, 2 H), 8.45 (d, J = 5.0 Hz, 2 H), 8.55
(br s, 2 H). IR (KBr): 3334, 1709, 1648, 1560, 1466, 1210,
1009 cm–1. Anal. Calcd for C15H19N3O5: C, 56.07; H, 5.96;
N, 13.08. Found: C, 56.17; H, 6.01; N, 13.05.
3-(1,3-Diazepan-2-ylidene)-5-(pyridin-4-ylmethyl)furan-
2,4(3H,5H)-dione (10c): white solid; mp 193–194 °C. 1H
NMR (400 MHz, CDCl3): d = 1.91 (br s, 4 H), 2.93 (dd,
J = 7.2, 14.4 Hz, 1 H), 3.25 (dd, J = 3.6, 14.4 Hz, 1 H), 3.47
(br s, 4 H), 4.69 (dd, J = 3.6, 7.2 Hz, 1 H), 7.23 (d, J = 5.6
Hz, 2 H), 8.27 (br s, 1 H), 8.50 (d, J = 5.6 Hz, 2 H), 9.05 (br
s, 1 H). 13C NMR (100 MHz, DMSO): d = 193.9, 174.5,
163.1, 149.6 (2 C), 145.1, 124.8 (2 C), 82.2, 80.08, 44.4 (2
C), 36.6, 27.0 (2 C). IR (KBr): 3269, 1709, 1635, 1467,
1062, 993 cm–1. Anal. Calcd for C15H15NO3S2: C, 56.05; H,
4.70; N, 4.36. Found: C, 56.25; H, 4.81; N, 4.33. MS (ESI):
m/z (%) = 596 (100) [2 M + 23]+.
3-(Imidazolidin-2-ylidene)-5-(pyridin-2-ylmethyl)furan-
2,4(3H,5H)-dione (10g): white solid; decomposition point
240–241 °C. 1H NMR (400 MHz, DMSO): d = 2.85 (dd,
J = 9.6, 14.4 Hz, 1 H), 3.25 (dd, J = 3.2, 14.4 Hz, 1 H), 3.59
(br s, 4 H), 4.85 (dd, J = 3.2, 9.6 Hz, 1 H), 7.26–7.29 (m, 1
H), 7.34 (d, J = 7.6 Hz, 1 H), 7.73–7.78 (m, 1 H), 8.29 (br s,
2 H), 8.52 (d, J = 4.4 Hz, 1 H). IR (KBr): 3316, 1716, 1646,
1615, 1448, 1061, 785, 630 cm–1. Anal. Calcd for
C13H13N3O3: C, 60.22; H, 5.05; N, 16.21. Found: C, 60.55;
H, 4.79; N, 16.34. Selected crystal data: monoclinic, P2
(1)/c, a = 5.1342 (2), b = 25.5679 (14), c = 11.3206 (9) Å,
V = 1478.32 (15) Å3, b = 95.853 (3)°, Z = 4, Dc = 1.435 g
cm–3, m (Cu-Ka) = 1.40 cm–1.
3-[Bis(methylamino)methylene]-5-(pyridin-4-
ylmethyl)furan-2,4-(3H,5H)-dione (10d): white solid; mp
151–153 °C. 1H NMR (500 MHz, DMSO): d = 2.79 (dd,
J = 7.5, 14.0 Hz, 1 H), 3.12 (dd, J = 3.5, 14.0 Hz, 1 H), 3.00
(br s, 6 H), 4.70 (br s, 1 H), 7.25 (d, J = 6.0 Hz, 2 H), 8.26
(br s, 2 H), 8.44 (d, J = 6.0 Hz, 2 H). IR (KBr): 3252, 1713,
1641, 1601, 1465, 1070, 811, 787 cm–1. Anal. Calcd for
C13H15N3O3: C, 59.76; H, 5.79; N, 16.08. Found: C, 59.91;
H, 5.98; N, 16.29.
3-(Diaminomethylene)-5-(pyridin-4-ylmethyl)furan-2,4-
(3H,5H)-dione (10e): white solid; mp 196–198 °C. 1H NMR
(500 MHz, DMSO): d = 2.74 (dd, J = 3.5, 14.5 Hz, 1 H),
3.10 (dd, J = 7.5, 14.5 Hz, 1 H), 4.43 (dd, J = 3.5, 7.5 Hz, 1
H), 7.08 (br s, 1 H), 7.17 (br s, 1 H), 7.27 (d, J = 5.5 Hz, 2
H), 7.90 (d, J = 5.0 Hz, 1 H), 8.45 (d, J = 5.5 Hz, 2 H), 9.66
(d, J = 5.0 Hz, 1 H). 13C NMR (100 MHz, DMSO): 192.3,
189.7, 173.4, 149.0 (2 C), 146.9, 124.8 (2 C), 93.6, 77.5,
37.0. IR (KBr): 3268, 3132, 1700, 1592, 1463, 1049, 834
cm–1. Anal. Calcd for C11H11N3O3: C, 56.65; H, 4.75; N,
18.02. Found: C, 56.42; H, 4.90; N, 18.23.
3-(Diaminomethylene)-5-(pyridin-2-ylmethyl)furan-2,4-
(3H,5H)-dione (10h): white solid; mp 198–200 °C. 1H
NMR (400 MHz, DMSO): d = 2.84 (dd, J = 9.6, 14.8 Hz, 1
H), 3.24 (dd, J = 3.2, 14.8 Hz, 1 H), 4.86 (dd, J = 3.2, 9.6 Hz,
1 H), 7.22–7.25 (m, 1 H), 7.30 (d, J = 7.6 Hz, 1 H), 7.60 (s,
2 H), 7.71–7.73 (m, 1 H), 7.74 (br s, 2 H), 8.50 (d, J = 4.4
Hz, 1 H). 13C NMR (100 MHz, DMSO): d = 193.1, 189.6,
174.0, 157.8, 148.7, 136.6, 123.7, 93.3, 78.1, 40.5. IR (KBr):
3282, 3140, 1699, 1631, 1596, 1456, 1061, 1012, 759 cm–1.
MS (ESI): m/z (%) = 234 (100) [M + 1]+. Anal. Calcd for
C11H11N3O3: C, 56.65; H, 4.75; N, 18.02. Found: C, 56.39;
H, 4.89; N, 18.25.
3-[Bis(2-hydroxyethylamino)methylene]-5-(pyridin-2-
ylmethyl)furan-2,4(3H,5H)-dione (10i): white solid; mp
158–159 °C. 1H NMR (400 MHz, DMSO): d = 2.82 (dd,
J = 10.0, 14.8 Hz, 1 H), 3.25 (dd, J = 2.4, 14.8 Hz, 1 H), 3.57
(br s, 8 H), 4.86 (dd, J = 2.4, 10.0 Hz, 1 H), 5.07 (br s, 2 H),
7.23–7.26 (m, 1 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.70–7.74 (m,
1 H), 8.51 (d, J = 4.0 Hz, 1 H), 8.62 (br s, 2 H). IR (KBr):
3340, 1710, 1655, 1559, 1465, 1196, 1070 cm–1. MS (ESI):
m/z (%) = 322 (100) [M + 1]+. Anal. Calcd for C15H19N3O5:
C, 56.07; H, 5.96; N, 13.08. Found: C, 56.20; H, 6.07; N,
13.13.
3-[Bis(2-hydroxyethylamino)methylene]-5-(pyridin-4-
ylmethyl)furan-2,4(3H,5H)-dione (10f): white solid; mp
157–158 °C. 1H NMR (500 MHz, DMSO): d = 2.78 (dd,
J = 8.5, 14.5 Hz, 1 H), 3.14 (dd, J = 2.5, 14.5 Hz, 1 H), 3.54–
Synlett 2005, No. 1, 49–54 © Thieme Stuttgart · New York