Microwave-accelerated Claisen rearrangements of allyl tetronates and tetramates

Article abstract of DOI:10.1016/j.tetlet.2003.12.024

[3,3]-Sigmatropic rearrangements of allyl tetronates and allyl tetramates to give 3-allyltetronic or -tetramic acids, respectively, proceed within 20-60min under microwave irradiation (300W, 130-190°C). Consecutive (homo)sigmatropic [1,5] H-shifts such as oxa-ene reactions are promoted less effectively, which allows the isolation of Claisen intermediates of sigmatropic domino sequences, in contrast to conventional heating.

Full text of DOI:10.1016/j.tetlet.2003.12.024

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1121–1124
Microwave-accelerated Claisen rearrangements of allyl
tetronates and tetramates
Rainer Schobert,* Gary J. Gordon, Gillian Mullen and Ralf Stehle
Organisch-chemisches Laboratorium der Universit€at, 95440 Bayreuth, Germany
Received 20 October 2003; revised 1 December 2003; accepted 5 December 2003
Abstract—[3,3]-Sigmatropic rearrangements of allyl tetronates and allyl tetramates to give 3-allyltetronic or -tetramic acids,
respectively, proceed within 20–60 min under microwave irradiation (300 W, 130–190 °C). Consecutive (homo)sigmatropic [1,5] H-
shifts such as oxa-ene reactions are promoted less effectively, which allows the isolation of Claisen intermediates of sigmatropic
domino sequences, in contrast to conventional heating.
Ó 2003 Elsevier Ltd. All rights reserved.
Functionalized 3-alkyltetronic acids 4, which are of
medical interest as potential antibiotic, antiviral and
antineoplastic agents,1 have been recently obtained from
a thermal domino Claisen/Conia/ring-opening reaction
of the corresponding allyl tetronates 1.2 These, in turn,
were readily available from a domino addition/intra-
molecular Wittig alkenation between the corresponding
a-hydroxy allyl esters and the phosphorus ylide
Ph3P@C@C@O.3 By proper choice of conditions either
the Claisen products 2 or the oxa-ene (Conia) rear-
ranged products, the 3-(spirocyclopropyl)dihydrofuran-
2,4-diones 3, were formed as main products in cases
where the allyl tetronates 1 bore an alkyl or a phenyl
residue R3 (Scheme 1). Herein we report on the
dramatically shortened reaction times required for the
formation of 2 under microwave irradiation4 conditions
and on the synthesis of analogous Claisen products from
allyl tetronates bearing chloroaryl residues R3, which is
impossible under classical thermal conditions.
The conventional thermal synthesis of 2 (alongside some
follow-up Conia product 3) from the tetronates 1 in
refluxing acetonitrile normally requires long reaction
times, typically 24–48 h. A selective synthesis of 3 could
X
R3
X
O
O
O
O
Nu
OH
[3s,3s] Claisen
(R3 = C6H4X)
Nu
oxa-ene reaction
(Conia)
O
O
O
O
O
OH
O
X
R2
R2
R2
R2
R1
R1
R1
R1
1
2
3
4
X
R1
R2
-(CH2)5-
-(CH2)5-
-(CH2)5-
2-Cl
3-Cl
4-Cl
1-3 a
b
c
d
e
f
3-NO2 -(CH2)5-
4-NO2 -(CH2)5-
H
H
Ph
Scheme 1. Domino [3s,3s] Claisen/Conia/ring-opening reaction of allyl tetronates 1.
Keywords: Tetronic acid; Claisen rearrangement; Microwave; Tetramates.
* Corresponding author. Tel.: +49-921-552680; fax: +49-921-552671; e-mail: rainer.schobert@uni-bayreuth.de
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.024

1122
R. Schobert et al. / Tetrahedron Letters 45 (2004) 1121–1124
Table 1. Thermal versus microwave syntheses5 of tetronic acids 2 and spirocyclopropyl furandiones 3
Starting compound
Yields 2:3 (%) from the thermal
reaction in CH3CN
Yields 2:3 (%) from the microwave
reaction in CH3CN
Yields 2:3 (%) from the thermal
reaction in toluene/sealed tube
1a
1b
1c
1d
1e
1f
0:0a
0:0a
42:58b
55:45b
43:52b
44:16b
26:37b
61:16g
0:64c
0:63c
0:89c
0:68e
0:42f
0:70e
0:0a
56:8d
32:0d
42:12d
a CH3CN, reflux, 84 h.
b CH3CN, 300 W microwave, 150 °C, 1 h.
c Toluene, 160 °C, 48 h, sealed tube.
d CH3CN, reflux, 48 h.
e Toluene, 170 °C, 35 h, sealed tube.
f Toluene, 180 °C, 48 h, sealed tube.
g CH3CN, 300 W microwave, 130 °C, 1 h.
be achieved by heating solutions of 1 in toluene in a
sealed glass tube at 160–190 °C for 24–48 h.2c
accordingly by microwave-accelerated Claisen rear-
rangement of the corresponding allyl tetramates. For
instance, the simple derivative 5a, synthesized from
ketenylidenetriphenylphosphorane and allyl a-amino-
cyclohexylcarboxylate,3 furnished the tetramic acid 6a in
90% yield and virtually devoid of by-products and of
spirolactam 7a, when irradiated at 110 °C for only
25 min (Scheme 2). Shorter exposure to microwaves at
higher temperatures gave rise to mixtures of 6a and 7a,
whereas conventional heating in acetonitrile gave poor
yields of 6a (at reflux) or again mixtures of Claisen and
Conia products (in the bomb tube).7
While tetronates 1a–c with an o-, m-, or p-chlorophenyl
substituent R3 could be converted into the correspond-
ing 1-(chlorophenyl)-2-methyl-11-oxadispiro[2.1.5.2]do-
deca-4,12-diones
3
under these conditions, the
corresponding tetronic acids 2 were not accessible by
refluxing in acetonitrile. Even prolonged reaction times
(up to 84 h) still resulted in 100% of the starting tetro-
nate being recovered from the reaction mixture. How-
ever, heating of acetonitrile solutions of these tetronates
in a sealed vessel placed in a 300 W focused single-mode
microwave reactor (CEM) at 150 °C for 1 h gave easily
separable mixtures of compounds 2 and 3 in almost
quantitative yields (Table 1). Although allyl tetronates
containing a nitrophenyl group can be rearranged to
tetronic acids 2 by conventional heating in acetonitrile,
we found that microwave irradiation gave similar yields
in much shorter time with less solvent being required.
Only for the preparation of pure tetronic acid 2e was the
thermal process superior to the microwave protocol.
Difficulties were encountered with the o-nitrophenyl
derivative both under conventional thermal and micro-
wave conditions, which led to complicated mixtures of
inseparable products. In general, microwave irradiation
represents a highly efficient means for the Claisen rear-
rangement of differently substituted allyl tetronates. It
reduces reaction times from days to a single hour while
at the same time increasing the overall yields consider-
ably.
Tetronic acids 4 (with R3 ¼ H, alkyl, Ph) have been
synthesized earlier by nucleophilic cleavage of the
cyclopropane ring of 3-(spirocyclopropyl)-dihydro-
furan-2,4-diones 3 with alcohols, amines, thiols and
carbon nucleophiles, in some cases as the final step of an
extended one-pot domino reaction starting with
tetronates 1.2a Derivatives of 3 bearing strongly elec-
tron-withdrawing aryl substituents X are markedly less
reactive. For instance, the nitrophenyl-substi-
tuted 3-(spirocyclopropyl)dihydrofuran-2,4-diones 3d–e
proved inert to refluxing methanol/chloroform and
could only be converted to tetronic acids 4 by initial
Å
treatment with 1 equiv of HBF4 Et2O to increase the
electrophilicity of the cyclopropyl ring by protonation of
the keto oxygen and finally with methanol (Scheme 3).8
Allyl tetronates with a trisalkylsubstituted alkene moiety
such as 8 undergo a formal [2,3]-sigmatropic rear-
rangement under thermal conditions2a leading to 3-alk-
ylidenefurandiones such as 10 as the end products of a
Claisen/Conia/retro-Conia cascade inevitably termi-
3-Substituted tetramic acids, possessing an even greater
biological potential6 than tetronic acids, were obtained
Conditions
Yields 6a:7a (%)
16:0
O
O
O
CH3CN, reflux, 16 h
CH3CN, sealed tube,
130 °C, 38 h
toluene, sealed tube,
69:26
Claisen
Conia
HN
HN
HN
O
OH
O
23:75
180 °C, 48 h
CH3CN, 110 °C, 25 min 90:3
300 W microwave
toluene, 150 °C, 15 min 41:47
300 W microwave
5a
6a
7a
Scheme 2. [3s,3s]-Claisen and Claisen–Conia reactions of allyl tetramate 5a.

R. Schobert et al. / Tetrahedron Letters 45 (2004) 1121–1124
1123
Yield
(%)
Starting
X
Conditions
material
O
O
(i)
(i)
(i)
(ii)
(ii)
(i)
3a
3b
4 a
b
63
OCH3
OH
(i) or (ii)
56
89
92
80
64
O
O
c
3c
3d
3e
O
X
d
e
f
R2
R2
R1
R1
3f
3
4
Å
Scheme 3. Reagents and conditions: (i) 3 (1.0 mmol), CH3OH (5 mL), CHCl3 (20 mL), reflux, 24 h; (ii) 3 (1.0 mmol), CHCl3 (20 mL), HBF4 Et2O
(7.5 M, 0.15 mL), rt, 1 h, then CH3OH (8 mL), reflux, 16 h.
3’
O
O
O
2’
3
[1,3] H-shift
[1,5] H-shift
1’
O
Claisen/Conia/retro-Conia
O
O
O
OH
O
Starting
material
9:10 (%)a 9:10 (%)b
n
n
n
0:87
0:91
8 a
b
57:0
58:0
8a: n = 1
b: n = 2
9
10
Scheme 4. (a) Thermal conditions: toluene, 200 °C, 42 h, sealed tube; (b) microwave conditions: toluene, 190 °C, 20 min, 300 W.
(c) Schobert, R.; Siegfried, S.; Gordon, G. J.; Nieu-
wenhuyzen, M.; Allenmark, S. Eur. J. Org. Chem. 2001,
nated by two H-shift steps. Carrying out the reaction
under microwave irradiation not only cut down the
required reaction times from 42 h to 20 min but also
gave rise exclusively to the [2,3]-rearranged 3-allyl-
tetronic acids 9 (Scheme 4).9
1951–1958.
€
3. (a) Loffler, J.; Schobert, R. J. Chem. Soc., Perkin Trans. 1
1996, 2799–2802; (b) Schobert, R.; Gordon, G. J. Current
Org. Chem. 2002, 6, 1181–1196.
4. For recent examples of Claisen rearrangements under
microwave conditions see: (a) Barriault, L.; Denissova, I.
Org. Lett. 2002, 4, 1371–1374; (b) Durand-Reville, T.;
Gobbi, L. B.; Gray, B. L.; Ley, S. V.; Scott, J. S. Org. Lett.
2002, 4, 3847–3850; (c) Mali, R. S.; Massey, A. P. J. Chem.
Res. (S) 1998, 230–231; (d) Srikrishna, A.; Nagaraju, S.;
Kondaiah, P. Tetrahedron 1995, 51, 1809–1816; (e) Davies,
C. J.; Moody, C. J. Synlett 2002, 1874–1876; (f) Kumar,
H. M. S.; Anjaneyulu, S.; Subba Reddy, B. V.; Ydav, J. S.
Synlett 2000, 1129–1130.
In conclusion, we have demonstrated that microwave
irradiation is a valuable tool for speeding up the Claisen
rearrangement of allyl tetramates and tetronates, with a
lesser effect on other consecutive sigmatropic processes
such as oxa-ene and H-shift reactions. Contrary to
conventional thermal processing, this allows for the
isolation of Claisen intermediates from cascade
sequences in most cases.
5. Typical procedure for the generation of compounds 2 and
3 from 1 using microwave heating: Tetronate 1a (550 mg,
1.73 mmol) was placed in a glass vial with a magnetic
stirrer and acetonitrile (5 mL). The vial was sealed and
placed inside a CEM Discovere single-mode microwave
synthesizer where it was exposed to microwaves at 150 °C
for 1 h. The cap was then removed and the solvent
evaporated in vacuo. The residue was purified by column
chromatography (silica gel 60; diethyl ether/hexane, 1:1,
v/v) to give 1-(20-chlorophenyl)-2-methyl-11-oxadi-
spiro[2.1.5.2]dodecane-4, 12-dione 3a (320 mg, 58%) mp
175 °C (found: C, 67.91; H, 5.98. C18H19ClO3 requires C,
67.82; H, 6.01%) and 3-[10-(200 -chlorophenyl)prop-20-enyl]-
4-hydroxy-1-oxaspiro-[4.5]dec-3-en-2-one 2a (230 mg,
42%) mp 158–159 °C (found: C, 67.77; H, 5.92). 2a: mmax
(KBr)/cmꢀ1 3415, 1750, 1625; 1H NMR (300 MHz,
CDCl3): d 1.60–1.77 (10H, m), 4.65 (1H, dd, 3J 6.1, 4J
Acknowledgements
This work was supported by the British Engineering and
Physical Sciences Research Council (Grant GR/
M97961), the Deutsche Forschungsgemeinschaft (Grant
Scho 402/7-2) and BAYER, plc, Leverkusen who are
also acknowledged for supplying starting materials and
for carrying out biological testing.
References and notes
1. (a) Pattenden, G. Fortsch. Chem. Org. Naturst. 1978, 35,
133–198; (b) Rehse, K.; Wagenknecht, J. Arch. Pharm.
1979, 312, 164–168; (c) Arai, K. Chem. Pharm. Bull. 1989,
37, 3229–3235; (d) Roggo, B. E.; Petersen, F.; Delmendo,
R.; Jenny, H.-B.; Peter, H. H.; Roesel, J. J. Antibiot. 1994,
47, 143–147; (e) Lang, M.; Roesel, J. Arch. Pharm. 1993,
326, 921–924; (f) Sodeoka, M.; Sampe, R.; Kagamizono,
T.; Osada, H. Tetrahedron Lett. 1996, 37, 8775–8778.
2. (a) Schobert, R.; Gordon, G. J.; Bieser, A.; Milius, W.
Eur. J. Org. Chem. 2003, 3637–3647; (b) Schobert, R.;
Siegfried, S.; Gordon, G. J.; Mulholland, D.; Nieu-
wenhuyzen, M. Tetrahedron Lett. 2001, 42, 4561–4564;
1.5 Hz, 10-H), 5.00 (1H, dt, J 17.3, J 1.5 Hz, @CHtrans),
5.27 (1H, dt, 3J 10.2, 4J 1.5 Hz, @CHcis), 6.14–6.26 (1H, m,
@CH), 7.02–7.49 (4H, m, Ph); 13C NMR (75.5 MHz,
CDCl3): d 21.7, 24.4, 32.8, 32.9, 40.1, 82.5, 99.1, 117.8,
128.5, 129.6, 129.9, 130.1, 134.1, 136.3, 137.3, 179.0, 185.0;
m=z (EI) 321 (Mþ+1, 0.4%), 320 (0.8), 319 (0.7), 318 (1.6),
302 (0.1), 301 (0.2), 300 (0.3), 283 (78), 194 (4), 193 (3), 192
(8), 191 (6), 153 (44), 151 (100). 3a: mmax (KBr)/cmꢀ1 2939,
1773, 1732, 1309, 1120; 1H NMR (270 MHz, CDCl3): d
1.16–1.89 (m, 10H), 1.50 (3H, d, 3J 6.2 Hz, CH3), 2.90
3
4
3
3
(1H, dq, J 6.2, 9.2 Hz, 1-H) 3.27 (1H, d, J 9.2 Hz, 2-H),

1124
R. Schobert et al. / Tetrahedron Letters 45 (2004) 1121–1124
7.24–7.40 (4H, m, Ph); 13C NMR (125.7 MHz, CDCl3): d
(75.5 MHz, CDCl3): d 11.6, 21.8, 22.0, 24.6, 32.7, 32.9,
33.3, 57.4, 81.9, 84.3, 102.8, 126.6, 127.8, 129.2, 130.2,
133.3, 135.1, 173.0, 179.3; m=z (EI) 352 (Mþ, 0.2%), 351
(0.1), 350 (0.9), 320 (0.1), 318 (0.7), 302 (0.1), 300 (0.3), 265
(0.7), 157 (39), 155 (100).
11.4, 21.0, 21.1, 32.2, 32.4, 37.8, 38.0, 47.3, 89.2, 126.8,
129.3, 129.6, 130.6, 131.4, 135.4, 171.3, 208.4; m=z (EI) 321
(Mþ+1, 4%), 320 (38), 319 (14), 318 (91), 305 (6), 303 (32),
302 (6), 300 (19), 287 (6), 285 (18), 283 (66), 265 (23), 219
(18), 178 (17), 152 (85), 129 (100).
Acid-catalyzed methanolysis (ii) of 3d: 3d (520 mg,
1.46 mmol) was placed in a round-bottomed flask with a
side arm. Under a constant stream of nitrogen dry
chloroform (20 mL) was added followed by the slow
addition of HBF4 in diethyl ether (7.5 M, 0.2 mL). The
solution was stirred for 1 h, then methanol (10 mL) was
added and the solution was refluxed for 16 h. The solvent
was removed in vacuo and the residue was purified by
column chromatography (silica gel 60; diethyl ether/
hexane, 1:1, v/v) to give 4-hydroxy-3-[syn-20-methoxy-10-
methyl-20-(m-nitrophenyl)ethyl]-1-oxaspiro[4.5]dec-3-en-2-
one 4d (485 mg, 92%) as a white solid of mp 163 °C;
(found: C, 63.11; H, 6.46. C19H23NO6 requires C, 63.15;
H, 6.41%); mmax (KBr)/cmꢀ1 3433, 2937, 1701, 1660, 1602,
1536, 1353; 1H NMR (300 MHz, CDCl3): d 0.96 (3H, d, 3J
6. (a) Royles, B. J. L. Chem. Rev. 1995, 95, 1981–2001; (b)
Fischer, R.; Dumas, J.; Bretschneider, T.; Erdelen, C.;
Wachendorff-Neumann, U.; Santel, H.-J.; Dollinger, M.;
Mencke, N.; Turberg, A.; DE Patent 19518962, 1996;
Chem. Abstr. 1996, 124, 231916g.
7. 6a: mp 166 °C; mmax (KBr)/cmꢀ1 3191, 3081, 1745, 1686; 1H
NMR (300 MHz, CDCl3): d 1.37–1.67 (10H, m), 2.52 (2H,
dd, 3J 6.9, 5.5 Hz, 10-H), 2.94 (1H, t, 3J 5.5 Hz, 3-H), 4.94–
4.98 (1H, m, @CHcis), 5.03 (1H, ddt, 3J 17.1, 2J ¼ 4J
1.5 Hz, @CHtrans), 5.57–5.71 (1H, m, 20-H), 8.78 (1H, s,
NH); 13C NMR (75.5 MHz, CDCl3): d 21.2, 21.3, 24.8,
30.3, 32.7, 49.0 (C-3), 66.8, 118.6, 133.0, 173.4, 212.2. 7a:
mp 156 °C, Rf ¼ 0:75 (ethyl acetate); mmax (KBr)/cmꢀ1
3185, 1748, 1683; 1H NMR (300 MHz, CDCl3): d 1.23–
1.67 (10H, m), 1.34 (3H, d, 3J 6.2 Hz, CH3), 1.45 (1H, dd,
3J 8.3, 2J 3.4 Hz, 1-H) 1.73 (1H, dd, 3J 8.8, 2J 3.4 Hz,
1-H0), 1.85–1.95 (1H, m, 2-H), 8.45 (1H, s, NH); 13C NMR
(75.5 MHz, CDCl3): d 12.0, 21.4, 21.5, 24.8, 26.3, 32.7,
33.2, 34.1, 34.7, 65.9, 173.5, 212.4. 7a0 (diastereomer): mp
156 °C, Rf ¼ 0:66 (ethyl acetate); 1H NMR (300 MHz,
3
7.3 Hz, 10-CH3), 1.13–1.84 (10H, m), 2.83 (1H, dq, J 7.3,
3
2.8 Hz, 10-H), 3.41 (3H, s, OCH3), 4.66 (1H, d, J 2.8 Hz,
20-H), 7.43–7.61 and 8.10–8.17 (4H, m, Ph), 10.00 (1H, s,
OH); 13C NMR (75.5 MHz, CDCl3): d 14.6, 21.6, 21.8,
24.4, 32.6, 33.1, 35.5, 57.6, 82.1, 86.4, 102.0, 121.4, 123.0,
129.6, 132.9, 140.6, 148.4, 173.0, 179.7; m=z (EI) 361 (Mþ,
0.5%), 344 (1), 331 (2), 329 (17), 311 (3), 299 (8), 167 (47),
166 (100).
3
CDCl3): d 1.15 (3H, d, J 6.2 Hz, CH3), 1.23–1.67 (10H,
3
2
3
m), 1.37 (1H, dd, J 8.3, J 3.5 Hz, 1-H) 1.77 (1H, dd, J
8.6, J 3.5 Hz, 1-H0), 2.00–2.08 (1H, m, 2-H), 8.61 (1H, s,
9. Typical procedure for the [2,3]-sigmatropic rearrangement
of allyl tetronates 8: a tightly sealed vial charged with a
solution of 8b (500 mg, 2.12 mmol) in dry toluene (6 mL)
was placed in a CEM Discovere single-mode microwave
synthesizer and irradiated at 190 °C and 3.5 bar for 20 min.
The resulting mixture was left overnight in a refrigerator
for crystallization of product 9b. Colorless crystals
(290 mg, 58%) were obtained after washing the crude
three times with toluene; mp 132 °C; mmax (KBr)/cmꢀ1
2
NH); 13C NMR (75.5 MHz, CDCl3): d 11.2, 21.2, 21.3,
24.7, 25.9, 31.5, 33.0, 33.7, 34.5, 66.0, 174.5, 211.0.
8. Typical procedure (i) for the methanolysis of 3: 3a
(400 mg, 1.26 mmol) was dissolved in dry chloroform
(20 mL) and methanol (5 mL). The solution was heated to
reflux for 24 h after which the solvent was removed in
vacuo. The residue was purified by column chromatogra-
phy (silica gel 60; diethyl ether/hexane: 1:1, v/v) to give
3-[syn-20-(o-chlorophenyl)-20-methoxy-10-methylethyl]-4-
hydroxy-1-oxaspiro[4.5]dec-3-en-2-one 4a as a white solid
(278 mg, 63%) mp 180 °C; (found: C, 64.91; H, 6.56.
C19H23ClO4 requires C, 65.05; H, 6.61%); mmax (KBr)/cmꢀ1
3416, 2936, 1705, 1632; 1H NMR (300 MHz, CDCl3):
d 0.92 (3H, d, 3J 7.3 Hz, 10-CH3), 1.16–1.84 (10H, m), 2.98
(1H, dq, 3J 7.3, 1.9 Hz, 10-H), 3.39 (3H, s, OCH3), 4.93
(1H, d, 3J 1.9 Hz, 20-H), 7.23–7.40 (4H, m, Ph); 13C NMR
1
3413, 3072, 2937, 1702, 1643, 1384; H NMR (300 MHz,
3
CDCl3): d 1.20–1.81 (10H, m), 1.27 (3H, d, J 7.0 Hz, 10-
3
CH3), 1.76 (3H, s, 20-CH3), 3.12 (1H, q, J 7.0 Hz, 10-H),
5.05 (2H, d, 2J 2.7 Hz, @CH2), 7.64 (1H, br, OH); 13C
NMR (75.5 MHz, CDCl3): d 16.9, 21.6, 21.7, 22.3, 24.3,
32.6, 32.7, 34.5, 82.4, 101.6, 110.9, 148.4, 173.8, 178.2;
Accurate mass m=z (EI): calculated 236.14123; found
236.14156.