Convenient synthesis of 5-methylene-4-substituted-2(5H)-furanones

Article abstract of DOI:10.1016/j.tetlet.2004.12.040

A synthesis of novel 4-(substituted)benzyl-5-methylene-2(5H)-furanones involving Stobbe condensation of substituted aldehydes with ethyl levulinate followed by treatment with acetic anhydride in the presence of sodium acetate, has been developed.

Full text of DOI:10.1016/j.tetlet.2004.12.040

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1009–1012
Convenient synthesis of 5-methylene-4-substituted-2(5H)-furanones
Vishal A. Mahajan, Popat D. Shinde, Hanumant B. Borate and Radhika D. Wakharkar*
Division of Organic Chemistry: Technology, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune 411 008, India
Received 1October 2004; revised 30 November 2004; accepted 8 December 2004
Available online 22 December 2004
Abstract—A synthesis of novel 4-(substituted)benzyl-5-methylene-2(5H)-furanones involving Stobbe condensation of substituted
aldehydes with ethyl levulinate followed by treatment with acetic anhydride in the presence of sodium acetate, has been developed.
Ó 2004 Elsevier Ltd. All rights reserved.
The furanone moiety is present in a number of natural
products and can be an important platform for the total
synthesis of various natural products as well as for the
development of new asymmetric methodologies.1
Recently, increasing attention has been given to devel-
oping new synthetic routes for polysubstituted fura-
nones, 5-alkylidenefuranones in particular, due to their
widespread occurrence and biological activity.2
furanones, it was found that the exomethylene moiety
is responsible for the biological activity of these mole-
cules.4a Very few methods are available for the synthesis
of substituted 5-alkylidenefuranones and the utility of
these methods suffers from certain drawbacks such as re-
stricted generality,5a multistep sequences5b and the use
of expensive chemicals.5c,d We disclose here a synthesis
of novel 4-(substituted)benzyl-5-methylene-2(5H)-fura-
nones, involving Stobbe condensation6 of substituted
arylaldehydes with ethyl levulinate to give the key inter-
mediate 7 followed by cyclization (Scheme 1).
Protoanemonin3 1 is the simplest representative of this
class, which forms the core of several naturally occur-
ring molecules4a–e (Fig. 1). In the class of 5-alkylidene
The regioselectivity of the condensation was greatly
dependent upon the temperature of the reaction and
the substitution pattern of the aromatic aldehyde. The
reaction was conducted at different temperatures for
optimization of conditions to achieve a maximum yield
of the desired product 7. At room temperature the prod-
uct was a mixture of 7 and 8 in equal ratio, whereas the
yield of 7 could be increased when the reaction was
performed at lower temperature (À10 °C). Acid 8
was obtained exclusively using DBU in refluxing dry
THF.
R
MeO
O
O
O
O
2-(1-Methoxy-11-dodecyl)
-penta-2,4-dien-4-olide 2
R= (CH2)8CH=CH2
Protoanemonin 1
H
O
O
HO
H
H
H
O
O
O
OMe
H
H
H
H
The acid 7 was further treated with anhydrous sodium
acetate and acetic anhydride to give furanone 9. The
quantity of acetic anhydride used and the reaction tem-
perature controlled the nature of product. Formation of
substituted naphthalene derivative 11 predominated
(85–95%) at 110–120 °C, whereas the reaction proceeded
to give furanone 9 as the major product at 80–90 °C.
More than 5 equiv of acetic anhydride and high temper-
ature resulted in a decrease in the proportion of fura-
none. The competing formation of E mixed anhydride
10 and the naphthalene derivative 11 could not be to-
tally avoided. A plausible mechanism for the formation
H
O
OH
OH
O
OH
O
O
Tetrodecamycin 4
Figure 1.
Tetronomycin 3
Keywords: 5-Methylene-2(5H)-furanones; Arylaldehydes; Ethyl levuli-
nate; Acetic anhydride; Sodium acetate.
*
Corresponding author. Tel./fax: +9120 25893641; e-mail:
dalton.ncl.res.in
rdw@
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.040

1010
V. A. Mahajan et al. / Tetrahedron Letters 46 (2005) 1009–1012
O
O
O
O
CHO
a
CH3
OH
OH
+
+
CH3
OEt
R
R
R
O
O
8
5
7
6
b
c
O
O
AcO
O
+
+
R
O
R
R
OAc
11
R = as shown in Table 1
O
9
10
Scheme 1. Reagents and conditions: (a) aq NaOH, ethanol, À10 °C, 4–5 h, (7, 80–95%); or Ref. 6; (b) anhydr NaOAc, Ac2O, 80 °C, 3 h; (c) aq
NaOH, ethanol, rt, 2–3 h.
O
ble bond from aryl conjugation to carbonyl conjugation
followed by enolization and lactonization. We believe
a
CHO
n
that the double bond isomerization proceeds to give a
mixture of Z and E products and then the Z isomer of
compound 10 favors the formation of furanone 9, while
its E isomer remains unreacted at 80–90 °C. On the
other hand, a higher temperature 110–120 °C favors
the formation of the more stable E isomer which readily
cyclizes to the naphthalene derivatives 11.
n
OH
O
n = 9
12
13
O
b
n
n
+
O
O
AcO
The intermediate 7 could be recovered by hydrolysis of
mixed anhydride 10 using aqueous sodium hydroxide.
It was noteworthy that during hydrolysis the isomerized
double bond regained its original orientation as shown
in Scheme 1. This simple protocol7 proved to be general
for the synthesis of furanones 9 starting from a variety
of aromatic aldehydes and dodecyl aldehyde (an exam-
ple of an aliphatic aldehyde to show the versatility of
the protocol Scheme 2).
15
14
O
Scheme 2. (a) Reagents and conditions: 6, aq NaOH, ethanol, À10 °C,
4–5 h, (13, 82%); (b) anhydr NaOAc, Ac2O, 80 °C, 3 h, (14, 51%; 15,
24%).
of furanone 9 in a single step from the corresponding
intermediate 7 involves firstly isomerization of the dou-
Table 1. Ratio of compounds 9:10:11 in % yield
Entry
Product 9
Yielda (%)
Entry
11
Product 9
Yielda (%)
9
10
11
9
10
11
I
MeO
O
O
O
O
1
52
27
32
11
57
33
34
8
2
MeO
MeO
MeO
OMe
OAc
O
O
O
2
50
13
12
57
O
O
OAc
MeO
OMe
O
3
4
64
56
18
24
8
13
14
60
67
23
15
—
18
O
O
MeO
MeO
O
O
O
18
O
O
OMe

V. A. Mahajan et al. / Tetrahedron Letters 46 (2005) 1009–1012
1011
Table 1 (continued)
Entry
Product 9
Yielda (%)
Entry
Product 9
Yielda (%)
9
10
11
9
10
11
MeO
MeO
O
O
5
6
72
17
9
15
6120
—
O
O
OMe
OMe
O
O
67
55
2156
1
62
58
18
15
—
O
O
O
MeO
OMe
O
O
O
7
30
12
17
32
O
O
O
O
OMe
OMe
O
O
O
8
9
75
63
10
22
6
18
19
57
64
12
17
20
13
MeO
Cl
O
OMe
OMe
O
10
O
S
O
O
OMe
OMe
O
MeO
O
O
10
48
20
15
20
52
29
6
O
O
MeO
a Isolated yield.
The novel 5-methylene-4-substituted-2(5H)-furanones8
described in the present communication and depicted
in Table 1 were found to be more stable as compared
to protoanemonin. The furanones showed characteristic
IR carbonyl absorptions9 and the 1H NMR spectra were
in full agreement with 5-methylenelactone moiety. The
13C assignments of the furanones were made by 1H
decoupled and DEPT experiments. Signals obtained by
1H–1H COSY and NOESY spectra confirmed the struc-
tures of the corresponding furanones 9 and mixed anhy-
drides 10.
References and notes
1. Carter, N. B.; Nadany, A. E.; Sweeny, J. B. J. Chem. Soc.,
Perkin. Trans. 1 2002, 2324–2342.
2. (a) Manny, A. J.; Kjelleberg, S.; Kumar, N.; Nys, R. D.;
Read, R. W.; Steinberg, P. Tetrahedron 1997, 53, 15813–
15826; (b) Bruckner, R. Chem. Commun. 2001, 141–152.
3. (a) Shaw, E. J. Am. Chem. Soc. 1946, 68, 2510–2511; (b)
Gruxdmann, C.; Kober, E. J. Am. Chem. Soc. 1955, 77,
2332–2333.
4. (a) Painter, F. F.; Bauscke, G.; Kestel, M. Tetrahedron Lett.
2000, 41, 9977–9980; (b) Hori, K.; Hikage, N.; Inagaki, A.;
Mori, S.; Nomura, K.; Yoshii, E. J. Org. Chem. 1992, 57,
2888–2992; (c) Lee, S.; Chang, S.; Chen, C. J. Nat. Prod.
2001, 64, 1548–1551; (d) Kwon, H. C.; Baek, N. I.; Choi, S.
U.; Lee, K. R. Chem. Pharm. Bull. 2000, 48, 614–616; (e)
Jacobi, P. A.; Yongkai, L. Org. Lett. 2003, 5, 701–704.
5. (a) Sorg, A.; Siegel, K.; Bruckner, R. Synlett 2004, 321–325;
(b) Grigg, R.; Savic, V.; Thornton-Pett, M. Tetrahedron
1997, 53, 10633–10642; (c) Tanabe, Y.; Ohino, N. J. Org.
Chem. 1988, 53, 1560–1563; (d) Krafft, M. E.; Pankowski, J.
Synlett 1991, 865–866.
In summary, we have developed an efficient two-step
and conceptually novel strategy for the synthesis of 4-
(substituted)benzyl/naphthylmethylene-5-methylene-2(5H)-
furanones. Our method has the advantages of simplicity
and good yields from commercially available starting
materials.
6. Swaminathan, B. V. Ind. J. Chem. 1976, 14B, 620.
7. Typical procedure for the synthesis of 5-methylene-4-benzyl
(substituted)-2(5H)-furanones 9. The carboxylic acid 7
(102 mmol) was mixed with anhydrous sodium acetate
(204 mmol) and acetic anhydride (510 mmol) and allowed
to stir at 85 °C under nitrogen for 3 h. The mixture was
allowed to cool to rt when crystals of sodium acetate
precipitated. The reaction mixture was poured on ice,
Acknowledgements
The authors are thankful to the Department of Science
and Technology (DST) and Dabur Research Founda-
tion, Ghaziabad, India for financial support. V.A.M.
and S.P.D. thank CSIR, New Delhi for the award of
Senior Research Fellowships.

1012
V. A. Mahajan et al. / Tetrahedron Letters 46 (2005) 1009–1012
stirred vigorously for 30 min and extracted with ethyl
3.80 (s, 9H), 4.93 (d, J = 2.9 Hz, 1H), 5.15 (m, 1H), 5.81 (br
s, 1H), 6.36 (s, 2H); 13C NMR (50 MHz, CDCl3) d 33.06,
56.29 (2C), 60.89, 94.67, 106.25 (2C), 118.60, 131.50,
137.68, 153.81 (2C), 155.76, 157.89, 168.44; MS (FAB) m/z
(% relative intensity) 276 (M+, 100), 261 (9), 245 (10), 217
(21), 181 (81), 166 (22). Anal. Calcd for C15H16O5: C, 65.21;
H, 5.79%. Found: C, 65.33; H, 5.84%.
acetate. The organic layer was washed repeatedly with fresh
portions of water, followed by dilute sodium bicarbonate
solution, then with brine, dried over anhydrous sodium
sulfate and concentrated under reduced pressure. Purifica-
tion by column chromatography (silica gel) using petroleum
ether–ethyl acetate as eluent provided the desired furanones
9 (yields 48–75%).
8. Our disclosure: Gurjar, M. K.; Wakharkar, R. D.; Borate,
H. B.; Mahajan, V. A.; Shinde, P. D.; Bhure, M. H.;
Mahajan, D. C. Indian Patent 1559/DEL/2003.
5-Methylene-4-(3,4,5-trimethoxybenzyl)furan-2 (5H)-one.
Yield 72%; mp 115 °C; IR (CHCl3) m 3018, 1787, 1765,
1212 cmÀ1
;
1H NMR (200 MHz, CDCl3) d 3.71(s, 2H),
9. Winston, A.; Kemp, R. N. Tetrahedron 1971, 27, 543–548.