Synthesis of tetrasubstituted furan derivatives by condensation of 1,3-diketones with cyclic α-hydroxy-β-oxo esters

Article abstract of DOI:10.1002/ejoc.201402388

Tetrasubstituted 3-acylfuran derivatives were obtained by condensation of acetylacetone with alicyclic and heterocyclic α-hydroxy-β-oxo esters under acidic conditions [0.1 equiv. cerium(III) salt in AcOH]. With [b]-annulated 4-acyl-3-hydroxy-5-methylfuran-2-carboxylates as common intermediates, the reaction proceeded along different pathways depending on the starting materials used: Alicyclic α-hydroxy-β-oxo esters gave cycloalkane-annulated furans as products. The ester group was lost after saponification and decarboxylation at elevated temperature. A thiopyrano[3,4-b]-annulated 2H-furan was obtained when starting from a tetrahydrothiopyranone derivative. With piperidones or a tetrahydropyranone as starting materials, the heterocyclic six-membered ring was cleaved in a retro-Mannich type reaction and one carbon atom was lost. 4-Acetyl-5- methylfuran-2-carboxylates with a 2-amino or 2-hydroxyethyl substituent in the 3-position are obtained in these cases. Copyright

Full text of DOI:10.1002/ejoc.201402388

FULL PAPER
DOI: 10.1002/ejoc.201402388
Synthesis of Tetrasubstituted Furan Derivatives by Condensation of
1,3-Diketones with Cyclic α-Hydroxy-β-oxo Esters
Barhiem Schickmous[a] and Jens Christoffers*[a]
Keywords: Synthetic methods / Fused-ring systems / Oxygen heterocycles / Annulation / Cerium
Tetrasubstituted 3-acylfuran derivatives were obtained by
condensation of acetylacetone with alicyclic and heterocyclic
α-hydroxy-β-oxo esters under acidic conditions [0.1 equiv.
cerium(III) salt in AcOH]. With [b]-annulated 4-acyl-3-hy-
droxy-5-methylfuran-2-carboxylates as common intermedi-
ates, the reaction proceeded along different pathways de-
pending on the starting materials used: Alicyclic α-hydroxy-
β-oxo esters gave cycloalkane-annulated furans as products.
The ester group was lost after saponification and decarboxyl-
ation at elevated temperature. A thiopyrano[3,4-b]-annu-
lated 2H-furan was obtained when starting from a tetra-
hydrothiopyranone derivative. With piperidones or a tetra-
hydropyranone as starting materials, the heterocyclic six-
membered ring was cleaved in a retro-Mannich type reaction
and one carbon atom was lost. 4-Acetyl-5-methylfuran-2-
carboxylates with a 2-amino or 2-hydroxyethyl substituent in
the 3-position are obtained in these cases.
pounds usually requires a step with Umpolung reactivity,[4]
e.g. if 1,4-diketones[5] are used as starting materials for
furan-ring closure. Because we had recently discovered a
simple access to acyloins by cerium-catalyzed, aerobic α-
hydroxylation of β-oxo esters,[6] we considered these prod-
ucts as perfect 1,2-dioxy-functionalized building blocks for
the construction of furan rings by cyclo-condensation with
1,3-diketones.
Introduction
The furan ring is one of the leading structural motifs in
heterocyclic chemistry.[1] Several biologically active com-
pounds contain a substituted furan ring. Four examples are
given in Figure 1;[1d] coronary vasodilator Furidarone, two
natural products Wyerone (antifungal from Vicia faba) and
Spongiatriol (antihypertensive from a marine sponge), and
insecticide Bioresmethrin. Several methods have been re-
ported in recent years to access up to fourfold substituted
furan rings by polar condensations[2] as well as metal-cata-
lyzed reactions.[3] However, most of them require elaborate
starting materials such as alkynes with a high degree of
functionalization. With a 1,4-dioxy-functionalized carbon
skeleton, construction of the furan ring from carbonyl com-
Results and Discussion
Our investigations started with reaction of α-hydroxy-β-
oxo ester 1a with acetylacetone (2a) under acidic condi-
tions. After several Brønsted and Lewis acids were investi-
gated, a substoichiometric amount of cerium chloride in
acetic acid turned out to be the optimal reaction medium
for formation of annulated product 3a (Scheme 1). In con-
trast to our earlier results,[5,6] no CeIII/CeIV redox system is
involved here, but CeIII plays simply the role of an oxophilic
Lewis acid.[7] After further optimization of stoichiometry,
reaction time and temperature, a yield of 60% was ob-
tained. Constitution of compound 3a was elucidated by 2D-
NMR spectroscopic techniques, and definitively established
by X-ray crystallography that showed two cis-annulated
five-membered rings (Figure 2).[8] As mechanistically ex-
pected, the dihydrofuran ring was formed by two stepwise
processes: (a) aldol reaction of the nucleophilic α-position
of β-diketone 2a (as the predominant enol-tautomer) with
the endocyclic β-carbonyl group of compound 1a and
(b) nucleophilic addition of the α-hydroxy function of com-
pound 1a into one carbonyl group of β-diketone 2a to fur-
nish the enol ether moiety of the product. The order of
these two steps could also be inverted. Finally, water elimi-
Figure 1. Biologically active furan derivatives.
[a] Institut für Chemie, Carl von Ossietzky Universität Oldenburg,
26111 Oldenburg, Germany
E-mail: jens.christoffers@uni-oldenburg.de
www.christoffers.chemie.uni-oldenburg.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402388.
4410
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Synthesis of Tetrasubstituted Furan Derivatives
nation with formation of the aromatic furan ring is pre-
vented by the quaternary α-carbon atom adjacent to the
ester group.
Scheme 2. Synthesis of cycloalkane annulated furans 4. For condi-
tions and yields see Table 1.
Scheme 1. Annulation of α-hydroxy-β-oxo ester 1a with acetyl-
acetone (2a) under acidic conditions.
Table 1. Conditions and yields of the syntheses of cycloalkane an-
nulated furans 4.
Entry Product (R, n)
Conditions
Yield
42%
1
2
3
4a (R = Me, n = 1) (1) 5 equiv. 2a, 80 °C, 20 h;
(2) KOH, H2O, EtOH,
23 °C, 20 min;
(3) HCl/H2O, 100 °C, 2 h.
4b (R = Me, n = 2) (1) 5 equiv. 2a, 80 °C, 3 h;
27%
62%
9%
(2) KOH, MeOH, 23 °C,
16 h;
(3) HCl/H2O, 50 °C, 2 h.
4c (R = Me, n = 3) (1) 5 equiv. 2a, 120 °C, 1 d;
(2) KOH, H2O, EtOH,
23 °C, 20 min;
(3) HCl/H2O, 100 °C, 4 h.
4
5
6
4d (R = Ph, n = 1) 0.67 equiv. 2b, 40 °C, 7 d.[a]
4e (R = Ph, n = 2) 0.50 equiv. 2b, 120 °C, 2 d.[a] 40%
4f (R = Ph, n = 3) 0.40 equiv. 2b, 120 °C, 1 d.[a] 63%
Figure 2. ORTEP representation of the molecular structure of com-
pound 3a in the solid state.
[a] Steps (2) KOH/H2O and (3) HCl/H2O were not required in these
cases.
To access product 4a with an aromatic furan ring, our
plan was ester saponification of product 3a followed by de-
carboxylation and water elimination. Supported by litera-
ture reports on decarboxylative eliminations of α-quater-
We then turned our interest towards the use of dibenzo-
nary β-hydroxycarboxylates[9] we hoped to achieve this ylmethane (2b) as β-diketone and reacted it with cyclo-
transformation as a consecutive one-flask protocol. Some pentanone derivative 1b under the above mentioned reac-
hydrolysis and decarboxylation of the ethyl ester already tion sequence, but failed to detect any unique furan deriva-
took place under acidic reaction conditions. This process tive in the complex product mixtures. Therefore, we next
could however be facilitated by using more labile methyl investigated the reaction of diketone 2b and ester 1d with a
esters 1b–1d as starting materials in the reaction with seven membered ring, because the latter gave good results
acetylacetone (2a). Nevertheless, incomplete ester saponifi- with diketone 2a. Surprisingly, we found direct formation
cation turned out to be a limiting factor. Completion of of furan 4f under acidic conditions without the need for
the saponification was achieved with KOH. This process ester saponification in alkaline milieu. The driving force for
proceeded smoothly at ambient temperature (which could this facilitated decarboxylative aromatization could be ex-
be followed by TLC or GLC), if the correct solvent mix- tended delocalization of the π-system in the product. How-
tures (H2O/EtOH or MeOH) were applied to ensure homo- ever, prolonged reaction temperature and time (Table 1, En-
geneity of the reaction mixture. Complete decarboxylation– try 6) were required for the formation of product 4f in rea-
dehydratization occurred after acidification and heating sonable yield (63%). The dominating yield-limiting process
with hydrochloric acid. After tedious experimentation, opti- was found to be a retro-Claisen reaction (“Säurespaltung”)
mal reaction conditions were identified for each of products of diketone 2b that gave detectable amounts of benzoic acid
4a–4c (Scheme 2; Table 1, Entries 1–3). The yield of prod- and acetophenone. The laborious separation of these two
uct 4a (42%; Table 1, Entry 1) seems moderate, but it is decomposition products led us to undertake the transfor-
acceptable in view of three transformations performed con- mation with inverted stoichiometry, i.e. with an excess of
secutively without isolation or purification of intermediate oxo ester 1f. Even after further optimization of stoichio-
products. The yield of benzo-annulated homologue 4b metry, reaction time and temperature, the yield of com-
(which was reported before in the literature)[10] is signifi- pound 4e (Table 1, Entry 5) remained unsatisfactory (40%).
cantly lower (Table 1, Entry 2). Product 4c with the seven- Even worse, compound 4d (Table 1, Entry 4) could only be
membered ring gave the best result (62%; Table 1, Entry 3). obtained in very low yields (maximum yield of 9%).
Eur. J. Org. Chem. 2014, 4410–4416
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B. Schickmous, J. Christoffers
FULL PAPER
When reacting tetrahydrothiopyranone derivative 1e with
acetylacetone (2a), water elimination from dihydrofuran in-
termediate 3 took place readily under acidic conditions and
product 5a was obtained in reasonable yield (53%;
Scheme 3). The methoxycarbonyl group was retained in this
product and the new C–C double bond was formed towards
the sulfur atom. It could be speculated that the reason for
this regiochemistry is as follows: As an element of the third
period, sulfur could stabilize a positive charge density in its
β-position by hyperconjugation and thus participate in the
vinylogously extended push-pull-π-system of the acetyl-sub-
stituted enol ether at C2 and C3. However, the thiopyrano-
[3,4-b]furan ring system has only appeared once in the lit-
erature.[11]
Scheme 4. Reaction of piperidones 1f and 1g and tetrahydro-
pyranone 1h. Reaction temperatures and time: 60 °C, 20 h for 6a;
80 °C, 1 d for 6b; and 23 °C, 14 d for 6c.
Scheme 3. Synthesis of thiopyrano[3,4-b]furan derivative 5a.
Investigation of the reactions of piperidone (1f and 1g)
and tetrahydropyran derivative 1h with acetylacetone (2a)
led to the interesting observation that the six-membered
ring was finally cleaved with loss of carbon atom C7 of
intermediate dihydropyran 3b (Scheme 4). As observed for
tetrahydrothiopyran 1e, this transformation took place un-
der acidic conditions. Aromatization of the furan ring was
realized by a retro-Mannich type β-elimination of water and
an acyliminium (X = NAc or NCbz) or carboxonium ion 7
(X = O), respectively. The latter is of course readily solvated
by water under the reaction conditions. Again, reaction
temperatures and times were optimized for each of three
starting materials 1f–1h (see legend of Scheme 4). The yield
of carbamate-protected product 6a was not satisfactory,
presumably because the carbamate function is not of infi-
nite stability under the reaction conditions (60 °C for 20 h).
The acetamide moiety of product 6b was more stable and
this compound was obtained in good yield (86%). Al-
though the NMR spectra supported the constitution with
cleavage of the six-membered ring, the molecular structure
of compound 6b was fully established by X-ray single crys-
tal structure analysis (Figure 3). Tetrahydropyranone 1h,
which was available in our laboratory as the ethyl ester,[12]
underwent the same process, but gave unsatisfactory results
at elevated temperatures. Alternatively, it reacted smoothly
at ambient temperature, although extended reaction times
were required to achieve full conversion. As a further exten-
sion of the multistep reaction cascade, the primary alcohol
was esterified and product 6c with an acetate group was
isolated. The yield was also good (74%).
Figure 3. ORTEP representation of the molecular structure of com-
pound 6b in the solid state.
Scheme 5. Investigation of the reaction with isopropyl acetoacetate
(2c).
When investigating the reaction of α-hydroxy-β-oxo ester
1d with ethyl acetoacetate as β-dicarbonyl component we ing methyl acetoacetate, transesterifications were avoided,
faced complex product mixtures that contained several but the reaction was worse because of the lack of stability
components, which were the result of transesterification of the methoxycarbonyl group. Better results were achieved
processes, as indicated by GC–MS investigations. By choos- when isopropyl ester 2c was used (Scheme 5), because the
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Synthesis of Tetrasubstituted Furan Derivatives
TLC was performed with Merck aluminum plates coated with SiO2
product mixture consisted only of three components, which
could be separated by column chromatography: The aro-
matic target structure 4g was the main product, but the
yield was rather low (33%). Byproduct 5b (6%) is the prod-
uct of dehydratisation without dealkoxycarbonylation, and
compound 8 (10%) resulted from a Knoevenagel intermedi-
ate with (Z)-configuration, which consequently resulted in
lactone ring formation.
1
F254. H and 13C NMR spectra were recorded with a Bruker Av-
ance DRX 500 instrument at 23 °C in CDCl3. Multiplicities of car-
bon signals were determined by DEPT experiments. MS and
HRMS spectra were obtained with a Finnigan MAT 95 (EI) and
a Waters Q-TOF Premier (ESI) spectrometer. IR spectra were re-
corded with a Bruker Tensor 27 spectrometer equipped with a
“GoldenGate” diamond ATR unit. Starting materials 1a–1h were
prepared by cerium-catalyzed α-hydroxylation of respective β-oxo
esters with molecular oxygen, as we have reported before.[6]
Ethyl 3-Acetyl-3a-hydroxy-2-methyl-5,6-dihydro-4H-cyclopenta[b]-
Conclusions
furan-6a-carboxylate (3a):
A mixture of ester 1a (516 mg,
3.00 mmol), acetylacetone (2a; 1.50 g, 15.0 mmol) and CeCl3·7H2O
(112 mg, 0.310 mmol) in AcOH (3 mL) was stirred at 60 °C for 1 d.
After filtration and removal of the solvent under reduced pressure
the crude product was purified by column chromatography (SiO2,
hexane/MTBE, 1:1, Rf = 0.25) to yield title compound 3a (60%,
459 mg, 1.80 mmol) as colorless crystals, m.p. 62 °C. 1H NMR
(500 MHz, CDCl3): δ = 1.30 (t, J = 7.1 Hz, 3 H), 1.45–1.55 (m, 1
H), 1.84–1.90 (m, 1 H), 1.95–2.10 (m, 2 H), 2.28–2.29 (m, 1 H),
Cyclopenta[b]-, tetrahydrobenzo[b]- and cyclohepta[b]-
annulated 3-acetyl-2-methylfurans 4a–4c were obtained up
to 62% yield from cyclocondensation of alicyclic α-hy-
droxy-β-oxo esters 1b–1d with acetyl acetone (2a). The
overall conversion was a multistep reaction sequence start-
ing with a Brønsted- and Lewis-acidic reaction medium
(0.1 equiv. of cerium salt in AcOH), which led to dihy-
drofuran intermediates 3 that involved an aldol reaction 2.31 (s, 3 H), 2.32 (s, 3 H), 2.58 (ddd, J = 6.8, J = 12.0, J = 13.9 Hz,
1 H), 3.41 (s, br., 1 H), 4.26 (q, J = 7.1 Hz, 2 H) ppm. 13C{1H}
NMR (125 MHz, CDCl3): δ = 14.17 (CH3), 15.81 (CH3), 23.61
(CH2), 29.40 (CH3), 36.36 (CH2), 40.78 (CH2), 61.90 (CH2), 93.95
(C), 97.80 (C), 116.67 (C), 169.03 (C), 170.56 (C), 195.12 (C) ppm.
and enol ether formation of both starting materials. For
compound 3a, this intermediate was isolated and structur-
ally characterized (X-ray). Targeting aromatic products 4,
the first steps were followed by ester saponification (in alka-
IR (ATR): ν = 3412 (m), 2987 (w), 2935 (w), 1735 (vs), 1658 (s),
˜
line milieu) and decarboxylation-dehydration with strong
acid and heat. When dibenzoylmethane (2b) was used as
diketone, respective annulated 3-benzoyl-2-phenylfuran de-
rivatives 4d–4f were obtained with up to 63% yield. How-
ever for product 4d the yield was unacceptably low (9%).
The reaction of heterocyclic α-hydroxy-β-oxo esters 1e–
1h with acetyl acetone (2a) did not require basic conditions
for ester saponification and gave a slightly different product
spectrum: Tetrahydrothiopyranone 1e gave thiopyrano[b]-
annulated 2H-furan derivative 5a with an α-quaternary
methoxycarbonyl group. When starting from piperidones 1f
1569 (vs), 1421 (w), 1373 (m), 1308 (m), 1274 (vs), 1197 (m), 1085
(m), 948 (s) cm–1. HRMS (EI, 70 eV): calcd. for C13H18O5 [M+]
254.1154; found 254.1153.
3-Acetyl-2-methyl-5,6-dihydro-4H-cyclopenta[b]furan (4a): A mix-
ture of ester 1b (0.500 g, 3.15 mmol), acetylacetone (2a; 1.58 g,
15.8 mmol) and CeCl3·7H2O (115 mg, 0.310 mmol) in AcOH
(4 mL) was stirred at 80 °C for 20 h. The solvent was removed un-
der reduced pressure and the residue dissolved in a mixture of
EtOH (5 mL) and H2O (2.5 mL). KOH (358 mg, 5.50 mmol) was
added and the mixture stirred at ambient temperature for 20 min.
After acidification with hydrochloric acid (3 molL–1, 2.3 mL) until
and 1g, and tetrahydropyranone 1h, the six-membered pH = 2, the mixture was stirred at 100 °C for 2 h. The solvent was
removed again under reduced pressure and H2O (5 mL) was added
to the residue. The crude product was extracted with MTBE (4ϫ
10 mL) and the organic layer dried with MgSO4, filtered and the
solvent removed under reduced pressure. The crude product was
purified by column chromatography (SiO2, hexane/MTBE, 1:1, Rf
= 0.73) to yield title compound 4a (42%, 217 mg, 1.32 mmol) as a
light yellow solid, m.p. 42 °C. 1H NMR (500 MHz, CDCl3): δ =
2.33 (s, 3 H), 2.44–2.49 (m, 2 H), 2.55 (s, 3 H), 2.66–2.69 (m, 2 H),
2.70–2.73 (m, 2 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ =
15.08 (CH3), 24.63 (CH2), 25.01 (CH2), 27.45 (CH2), 30.01 (CH3),
heterocycle was cleaved after furan-ring formation by a
retro-Mannich type reaction. Iminium/carboxonium species
7 formed intermediately were solvated, thus, one carbon
atom was lost within products 6a–6c (yield up to 86%). For
compound 6b, monocyclic constitution with the hetero-
functionalized side chain was also established by X-ray
crystallography. When starting with acetoacetates instead of
β-diketones, a broad product spectrum was obtained, which
was exemplified with isopropyl ester 2c, which contained at
least three compounds with a furan ring, i.e. tetrasubsti- 120.21 (C), 125.03 (C), 156.83 (C), 162.10 (C), 194.73 (C) ppm. IR
(ATR): ν = 2951 (w), 2862 (w), 1676 (vs), 1546 (s), 1423 (m), 1357
˜
tuted furan 4g, pentasubstituted 2H-furan 5b and annulated
butenolide 8.
In summary, new densely functionalized tetrasubstituted
furan derivatives could be obtained from readily available
cyclic α-hydroxy-β-oxo esters and β-diketones with yields
up to 86%.
(w), 1314 (w), 1313 (w), 1262 (w), 1085 (w), 950 (m), 732 (w), 632
(m) cm–1. HRMS (EI, 70 eV): calcd. for C10H12O2 [M+] 164.0837;
found 164.0835.
3-Acetyl-2-methyl-4,5,6,7-tetrahydrobenzo[b]furan (4b): A mixture
of ester 1c (0.500 g, 2.90 mmol), acetylacetone (2a; 1.45 g,
14.5 mmol) and CeCl3·7H2O (108 mg, 0.290 mmol) in AcOH
(3.7 mL) was stirred at 80 °C for 3 h. The solvent was removed
under reduced pressure and the residue dissolved in MeOH (4 mL).
KOH (731 mg, 13.0 mmol) was added and the mixture stirred at
ambient temperature for 16 h. After acidification with hydrochloric
acid (3 molL–1, 3.8 mL) until pH = 2, the mixture was stirred at
50 °C for 2 h. After filtration and removal of the solvents the crude
Experimental Section
General: Preparative column chromatography was carried out with
Merck SiO2 (35–70 μm, type 60 A) with hexane, tert-butyl methyl
ether (MTBE), acetone, dichloromethane, and methanol as eluents.
Eur. J. Org. Chem. 2014, 4410–4416
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B. Schickmous, J. Christoffers
FULL PAPER
product was purified by column chromatography (SiO2, hexane/
1.86–1.93 (m, 2 H), 2.37 (t, J = 6.1 Hz, 2 H), 2.70 (t, J = 6.1 Hz,
MTBE, 1:1, Rf = 0.60) to yield title compound 4b (27%, 139 mg, 2 H), 7.16–7.20 (m, 3 H), 7.31 (t, J = 7.6 Hz, 2 H), 7.43–7.48 (m,
0.78 mmol) as colorless oil. 1H NMR (500 MHz, CDCl3): δ = 1.72– 3 H), 7.81 (d, J = 7.3 Hz, 2 H) ppm. 13C{1H} NMR (125 MHz,
1.77 (m, 2 H), 1.78–1.83 (m, 2 H), 2.38 (s, 3 H), 2.54 (s, 3 H), 2.52– CDCl3): δ = 21.58 (CH2), 22.65 (CH2), 22.75 (CH2), 23.10 (CH2),
2.55 (m, 2 H), 2.61–2.64 (m, 2 H) ppm. 13C{1H} NMR (125 MHz, 119.41 (C), 120.98 (C), 126.88 (2 CH), 127.98 (CH), 128.16 (2 CH),
CDCl3): δ = 14.87 (CH3), 22.51 (CH2), 22.86 (CH2), 23.05 (CH2), 128.25 (2 CH), 129.73 (2 CH), 130.28 (C), 132.86 (CH), 137.89 (C),
23.08 (CH2), 30.61 (CH3), 116.43 (C), 121.90 (C), 149.28 (C), 150.95 (C), 152.75 (C), 193.48 (C) ppm. IR (ATR): ν = 3061 (w),
˜
156.80 (C), 194.94 (C) ppm. IR (ATR): ν = 2937 (m), 2862 (w), 2938 (m), 2854 (w), 2357 (w), 1626 (vs), 1596 (m), 1578 (w), 1552
˜
1799 (w), 1755 (w), 1714 (m), 1668 (vs), 1555 (w), 1439 (w), 1360 (w), 1489 (m), 1448 (s), 1343 (w), 1448 (m), 1343 (w), 1231 (s), 1024
(w), 1261 (w), 945 (vs), 918 (s), 602 (m) cm–1. MS (EI, 70 eV): m/z
(%) = 178 (81) [M+], 163 (100), 150 (43), 135 (55). HRMS (ESI,
pos. mode): calcd. for C11H15O2 [M + H+] 179.1072; found
179.1068.
(w), 895 (s), 767 (m), 731 (s) cm–1. HRMS (EI, 70 eV): calcd. for
C21H18O2 [M+] 302.1307; found 302.1295.
3-Benzoyl-2-phenyl-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan (4f): A
mixture of dibenzoylmethane (2b; 200 mg, 0.890 mmol), ester 1d
(413 mg, 2.22 mmol) and CeCl3·7H2O (82 mg, 0.22 mmol) in
AcOH (0.9 mL) was stirred at 120 °C for 1 d. After filtration and
3-Acetyl-2-methyl-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan (4c): A
mixture of ester 1d (0.500 g, 2.68 mmol), acetylacetone (2a; 1.34 g,
13.4 mmol) and CeCl3·7H2O (101 mg, 0.270 mmol) in AcOH removal of the solvent under reduced pressure the crude product
(3.4 mL) was stirred at 120 °C for 1 d. The solvent was removed
under reduced pressure and the residue dissolved in a mixture of
EtOH (5 mL) and H2O (2.5 mL). KOH (304 mg, 4.76 mmol) was
was purified by column chromatography (SiO2, hexane/MTBE,
50:1, Rf = 0.18) to yield title compound 4f (63%, 177 mg,
0.560 mmol) as a light yellow solid, m.p. 72 °C. 1H NMR
added and the mixture stirred at ambient temperature for 20 min. (500 MHz, CDCl3): δ = 1.60–1.71 (m, 2 H), 1.71–1.85 (m, 4 H),
After acidification with hydrochloric acid (3 molL–1, 2.3 mL) until
pH = 2, the mixture was stirred at 100 °C for 4 h. The solvent was
removed again under reduced pressure and H2O (5 mL) was added
to the residue. The crude product was extracted with MTBE (4ϫ
10 mL) and the organic layer dried with MgSO4, filtered and the
solvent removed under reduced pressure. The crude product was
purified by column chromatography (SiO2, hexane/MTBE, 1:1, Rf
= 0.76) to yield title compound 4c (62%, 320 mg, 1.65 mmol) as a
2.35–2.39 (m, 2 H), 2.88–2.90 (m, 2 H), 7.14–7.21 (m, 3 H), 7.32–
7.37 (m, 2 H), 7.41–7.50 (m, 3 H), 7.87 (d, J = 8.2 Hz, 2 H) ppm.
13C{1H} NMR (125 MHz, CDCl3): δ = 24.32 (CH2), 26.21 (CH2),
28.20 (CH2), 28.78 (CH2), 30.71 (CH2), 122.47 (C), 122.75 (C),
126.29 (2 CH), 127.69 (CH) 128.23 (2 CH), 128.46 (2 CH), 129.83
(2 CH), 130.14 (C), 133.18 (CH), 137.89 (C), 149.84 (C), 153.80
(C), 194.06 (C) ppm. IR (ATR): ν = 3059 (w), 2926 (m), 2852 (w),
˜
1719 (w), 1655 (vs), 1596 (w), 1490 (w), 1447 (m), 1241 (w), 1174
colorless oil. 1H NMR (500 MHz, CDCl3): δ = 1.63–1.78 (m, 6 H), (w), 899 (s), 768 (m), 730 (m), 689 (vs) cm–1. HRMS (EI, 70 eV):
2.40 (s, 3 H), 2.48 (s, 3 H), 2.67–2.76 (m, 4 H) ppm. 13C{1H} NMR
(125 MHz, CDCl3): δ = 15.14 (CH3), 24.23 (CH2), 26.05 (CH2),
28.11 (CH2), 28.13 (CH2), 30.34 (CH2), 31.11 (CH3), 120.70 (C),
calcd. for C22H20O2 [M+] 316.1463; found 316.1466.
Methyl 3-Acetyl-2-methyl-7,7a-dihydro-5H-thiopyrano[3,4-b]furan-
7a-carboxylate (5a): A mixture of tetrahydrothiopyranone 1e
(100 mg, 0.510 mmol), acetylacetone (2a; 263 mg, 2.63 mmol) and
CeCl3·7H2O (19 mg, 0.052 mmol) in AcOH (0.5 mL) was stirred at
85 °C for 3.5 h. After filtration and removal of the solvent under
reduced pressure the crude product was purified by column
chromatography (SiO2, hexane/acetone, 4:1, Rf = 0.21) to yield title
compound 5a (53%, 70 mg, 0.27 mmol) as a colorless oil, which
slowly decomposed under ambient conditions and must therefore
be stored dark and cold. 1H NMR (300 MHz, CDCl3): δ = 2.34 (s,
3 H), 2.36 (s, 3 H), 2.72 (d, J = 11.1 Hz, 1 H), 3.22 (dd, J = 16.7,
J = 3.5 Hz, 1 H), 3.42 (d, J = 11.3 Hz, 1 H), 3.43 (dd, J = 16.6, J
= 6.0 Hz, 1 H), 3.77 (s, 3 H), 6.32 (dd, J = 5.9, J = 3.4 Hz, 1
H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 16.00 (CH3),
24.46 (CH2), 29.92 (CH2), 30.73 (CH3), 53.08 (CH3), 87.10 (C),
113.77 (CH), 116.07 (C), 138.14 (C), 167.62 (C), 170.74 (C), 193.36
123.45 (C), 152.08 (C), 154.57 (C), 195.60 (C) ppm. IR (ATR): ν =
˜
2932 (m), 2861 (w), 1710 (m), 1662 (s), 1567 (w), 1417 (m), 1359
(m), 1239 (w), 1069 (w), 955 (m), 629 (s), 542 (s) cm–1. HRMS (EI,
70 eV): calcd. for C12H16O2 [M+] 192.1150; found 192.1138.
3-Benzoyl-2-phenyl-5,6-dihydro-4H-cyclopenta[b]furan (4d): A mix-
ture of dibenzoylmethane (2b; 150 mg, 0.670 mmol), ester 1b
(158 mg, 1.00 mmol) and CeCl3·7H2O (37 mg, 0.100 mmol) in
AcOH (0.7 mL) was stirred at 40 °C for 7 d. After filtration and
removal of the solvent under reduced pressure the crude product
was purified by column chromatography (SiO2, hexane/MTBE,
50:1, Rf = 0.16) to yield title product 4d (9%, 18 mg, 0.060 mmol)
1
as a yellow oil. H NMR (500 MHz, CDCl3): δ = 2.43–2.51 (m, 4
H), 2.74–2.86 (m, 2 H), 7.37 (t, J = 7.1 Hz, 3 H), 7.47–7.56 (m, 3
H), 7.83 (d, J = 7.6 Hz, 2 H), 7.99 (d, J = 7.6 Hz, 2 H) ppm.
13C{1H} NMR (125 MHz, CDCl3): δ = 24.05 (CH2), 24.83 (CH2), (C) ppm. IR (ATR): ν = 2952 (w), 2359 (m), 1740 (vs), 1666 (m),
˜
27.61 (CH2), 119.95 (C), 126.94 (2 CH), 128.24 (2 CH), 128.25 (2
1595 (s), 1435 (m), 1394 (m), 1281 (w), 1199 (m), 949 (s) cm–1.
CH), 128.31 (C), 128.33 (CH), 129.59 (2 CH), 130.74 (C), 132.72 HRMS (EI, 70 eV): calcd. for C12H14O4S [M+] 254.0613; found
(CH), 138.13 (C), 158.88 (C), 159.01 (C), 192.49 (C) ppm. IR 254.0603.
(ATR): ν = 2957 (w), 2862 (w), 1654 (s), 1597 (w), 1483 (m), 1448
˜
Methyl
4-Acetyl-3-[2-(benzyloxycarbonylamino)ethyl]-5-methyl-
(w), 1261 (m), 1229 (w), 903 (s) cm–1. MS (EI, 70 eV): m/z (%) =
288 (10) [M+], 141 (4), 115 (5), 105 (100), 77 (69). HRMS (EI,
70 eV): calcd. for C20H16O2 [M+] 288.1150; found 288.1141.
furan-2-carboxylate (6a): A mixture of piperidone 1f (125 mg,
0.407 mmol), acetylacetone (2a; 204 mg, 2.04 mmol) and
CeCl3·7H2O (15 mg, 0.040 mmol) in AcOH (0.5 mL) was stirred at
60 °C for 20 h. After filtration and removal of the solvent under
reduced pressure the crude product was purified by column
3-Benzoyl-2-phenyl-4,5,6,7-tetrahydrobenzo[b]furan (4e): A mixture
of dibenzoylmethane (2b; 0.2 g, 0.9 mmol), ester 1c (307 mg,
1.78 mmol) and CeCl3·7H2O (66 mg, 0.18 mmol) in AcOH chromatography [SiO2, hexane/MTBE, 2:1Ǟ1:1, Rf (hexane/
(0.9 mL) was stirred at 120 °C for 2 d. After filtration and removal
of the solvent under reduced pressure the crude product was puri-
fied by column chromatography (SiO2, n-hexane/MTBE, 50:1, Rf
= 0.16) to yield title compound 4e (40%, 108 mg, 0.360 mmol) as
MTBE, 1:1) = 0.63] to yield title compound 6a (57%, 84 mg,
0.23 mmol) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ =
2.47 (s, 3 H), 2.73 (s, 3 H), 3.21 (t, J = 6.3 Hz, 2 H), 3.45 (q, J =
6.1 Hz, 2 H), 3.86 (s, 3 H), 5.03 (s, 2 H), 5.33 (br. s, 1 H), 7.29–
a yellow oil. 1H NMR (500 MHz, CDCl3): δ = 1.70–1.75 (m, 2 H), 7.38 (m, 5 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 15.85
4414
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 4410–4416

Synthesis of Tetrasubstituted Furan Derivatives
(CH3), 24.35 (CH2), 29.56 (CH3), 41.30 (CH2), 51.95 (CH3), 66.33 2849 (w), 1704 (vs), 1578 (w), 1425 (w), 1281 (m), 1174 (m), 1096
(CH2), 124.17 (C), 127.94 (CH), 128.07 (2 CH), 128.39 (2 CH),
132.87 (C), 136.76 (C), 139.48 (C), 156.46 (C), 159.44 (C), 160.49 236 (33) [M+], 193 (100), 175 (36), 140 (38), 105 (22), 91 (29).
(C), 194.39 (C) ppm. IR (ATR): ν = 3363 (w), 2920 (w), 2851 (w),
HRMS (ESI, pos. mode): calcd. for C14H21O3 [M + H+] 237.1491;
(vs), 1079 (vs), 982 (w), 784 (w) cm–1. MS (EI, 70 eV): m/z (%) =
˜
1706 (vs), 1525 (w), 1412 (w), 1331 (w), 1243 (m), 1160 (w), 903 found 237.1494.
(m), 733 (s) cm–1. HRMS (ESI, pos. mode): calcd. for
3-Isopropyl 8a-Methyl 2-Methyl-5,6,7,8-tetrahydro-8aH-cyclohepta-
[b]furan-3,8a-dicarboxylate (5b): H NMR (500 MHz, CDCl3): δ =
C19H21NNaO6 [M + Na+] 382.1267; found 382.1267.
1
1.23 (d, J = 6.2 Hz, 6 H), 1.37–1.49 (m, 1 H), 1.71–1.83 (m, 3 H),
1.92–2.02 (m, 1 H), 2.19–2.24 (m, 2 H), 2.26 (s, 3 H), 2.29–2.33 (m,
1 H), 3.79 (s, 3 H), 5.11 (sept, J = 6.2 Hz, 1 H), 6.51 (t, J = 7.1 Hz,
1 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 15.43 (CH3),
22.06 (2 CH3), 26.62 (CH2), 27.67 (CH2), 28.04 (CH2), 34.29 (CH2),
52.62 (CH3), 67.15 (CH), 93.26 (C), 107.03 (C), 120.35 (CH),
Methyl 4-Acetyl-3-(2-acetamidoethyl)-5-methylfuran-2-carboxylate
(6b): A mixture of piperidone 1g (250 mg, 1.16 mmol), acetyl-
acetone (2a; 581 mg, 5.81 mmol) and CeCl3·7H2O (43 mg,
0.11 mmol) in AcOH (1.2 mL) was stirred at 80 °C for 1 d. After
filtration and removal of the solvent under reduced pressure the
crude product was purified by column chromatography (SiO2,
CH2Cl2/MeOH, 10:1, Rf = 0.35) to yield title compound 6b (86%,
267 mg, 1.00 mmol) as a colorless resin. 1H NMR (500 MHz,
CDCl3): δ = 1.87 (s, 3 H), 2.51 (s, 3 H), 2.66 (s, 3 H), 3.19 (t, J =
6.0 Hz, 2 H), 3.49 (q, J = 5.4 Hz, 2 H), 3.91 (s, 3 H), 6.45 (br. s, 1
H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ = 15.90 (CH3),
23.15 (CH3), 23.60 (CH2), 31.07 (CH3), 40.41 (CH2), 52.09 (CH3),
124.33 (C), 133.25 (C), 139.44 (C), 159.59 (C), 160.51 (C), 170.26
140.53 (C), 164.16 (C), 169.22 (C), 170.82 (C) ppm. IR (ATR): ν =
˜
2979 (w), 2930 (m), 2852 (w), 1742 (s), 1695 (vs), 1618 (s), 1445
(w), 1395 (m), 1267 (w), 1199 (s), 1141 (m), 1093 (vs), 997 (s) cm–1.
MS (EI, 70 eV): m/z (%) = 294 (13) [M+], 235 (31), 193 (100), 175
(64), 147 (10), 91 (22), 77 (18). HRMS (ESI, pos. mode): calcd. for
C16H23O5 [M + H+] 295.1545; found 295.1555.
Methyl
3-Acetyl-2-oxo-4,5,6,7,8,8a-hexahydrocyclohepta[b]furan-
(C), 194.78 (C) ppm. IR (ATR): ν = 3300 (w), 2952 (w), 2361 (w),
8a-carboxylate (8): 1H NMR (500 MHz, CDCl3): δ = 1.21–1.29 (m,
1 H), 1.50–1.61 (m, 2 H), 1.67–1.77 (m, 2 H), 1.89–1.99 (m, 1 H),
2.12–2.16 (m, 1 H), 2.46–2.51 (m, 2 H), 2.57 (s, 3 H), 3.40–3.45 (m,
1 H), 3.78 (s, 3 H) ppm. 13C{1H} NMR (125 MHz, CDCl3): δ =
23.05 (CH2), 28.01 (CH2), 28.75 (CH2), 29.82 (CH2), 30.20 (CH3),
33.46 (CH2), 53.68 (CH3), 89.98 (C), 124.32 (C), 167.65 (C), 169.90
˜
1715 (s), 1667 (vs), 1601 (w), 1538 (m) 1436 (s), 1412 (m), 1360 (w),
1329 (w), 1245 (m), 1067 (m), 647 (m) cm–1. HRMS (EI, 70 eV):
calcd. for C13H17NO5 [M+] 267.1107; found 267.1101.
Ethyl 4-Acetyl-3-(2-acetoxyethyl)-5-methylfuran-2-carboxylate (6c):
A mixture of pyrancarboxylate 1h (162 mg, 0.860 mmol), acetyl-
acetone (2a; 430 mg, 4.30 mmol) and CeCl3·7H2O (32 mg,
0.086 mmol) in AcOH (0.9 mL) was stirred at ambient temperature
for 14 d. After filtration and removal of the solvent under reduced
pressure the crude product was purified by column chromatog-
raphy (SiO2, hexane/MTBE, 1:2, Rf = 0.37) to yield title compound
6c (74%, 180 mg, 0.640 mmol) as a colorless oil. 1H NMR
(500 MHz, CDCl3): δ = 1.36 (t, J = 7.1 Hz, 3 H), 1.96 (s, 3 H),
2.47 (s, 3 H), 2.63 (s, 3 H), 3.36 (t, J = 6.7 Hz, 2 H), 4.23 (t, J =
6.7 Hz, 2 H), 4.35 (q, J = 7.1 Hz, 2 H) ppm. 13C{1H} NMR
(125 MHz, CDCl3): δ = 14.24 (CH3), 15.68 (CH3), 20.83 (CH3),
24.08 (CH2), 30.96 (CH3), 60.99 (CH2), 63.52 (CH2), 124.19 (C),
131.01 (C), 139.84 (C), 158.88 (C), 160.25 (C), 170.72 (C), 193.93
(C), 179.88 (C), 194.34 (C) ppm. IR (ATR): ν = 2935 (w), 2857
˜
(w), 2935 (w), 1766 (vs), 1739 (vs), 1620 (m), 1446 (w), 1364 (m),
1253 (m), 1241 (s), 1009 (s) cm–1. MS (EI, 70 eV): m/z (%) = 252
(3) [M+], 220 (8), 210 (16), 193 (71), 151 (100), 123 (34), 95 (48).
HRMS (ESI, pos. mode): calcd. for C13H16NaO5 [M + Na+]
275.0895; found 275.0887.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C{1H} NMR spectra of all products.
Acknowledgments
The authors are grateful to Marc Schmidtmann for X-ray crystal-
lography. Miriam Penning is thanked for data processing.
(C) ppm. IR (ATR): ν = 2981 (w), 1737 (vs), 1711 (vs), 1671 (m),
˜
1602 (w), 1413 (m), 1367 (w), 1235 (vs), 1155 (vs), 1099 (w), 1066
(m), 1037 (s), 960 (w), 773 (w) cm–1. HRMS (EI, 70 eV): calcd. for
C14H18O6 [M+] 282.1103; found 282.1093.
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A mixture of cyclic β-oxo ester 1d (186 mg, 1.00 mmol), isopropyl
acetoacetate (2c; 721 mg, 5.00 mmol) and CeCl3·7H2O (37.0 mg,
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4g (33%, 77 mg, 0.33 mmol, Rf = 0.68) as yellow oil. The second
fraction containing compound 5b (6%, 18 mg, 0.060 mmol, Rf =
0.37) was eluted as a colorless liquid. Finally, the last fraction con-
tained compound 8 (10%, 28 mg, 0.10 mmol, Rf = 0.11) as a color-
less oil.
Isopropyl
2-Methyl-5,6,7,8-tetrahydro-4H-cyclohepta[b]furan-3-
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(CH3), 22.09 (2 CH3), 23.88 (CH2), 26.24 (CH2), 28.23 (CH2), 28.34
(CH2), 30.53 (CH2), 66.99 (CH), 114.03 (C), 121.11 (C), 151.83 (C),
155.73 (C), 164.60 (C) ppm. IR (ATR): ν = 2978 (w), 2922 (m),
˜
Eur. J. Org. Chem. 2014, 4410–4416
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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4415

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Published Online: May 22, 2014
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Eur. J. Org. Chem. 2014, 4410–4416