Olefin-metathesis-based synthesis of furans by an RCM/deprotonation/ phosphorylation sequence and their Diels-Alder reactions

Article abstract of DOI:10.1002/ejoc.201101078

Butenolides, obtained by ring-closing metathesis (RCM) of acrylates, undergo quantitative deprotonation with amide bases. Trapping of the resulting anions with electrophiles, for example, chlorophosphates, give furans. Subsequent Diels-Alder reaction and acid-catalysed rearrangement of the resulting oxabicyclonorbornadienes give substituted benzenes.

Full text of DOI:10.1002/ejoc.201101078

FULL PAPER
DOI: 10.1002/ejoc.201101078
Olefin-Metathesis-Based Synthesis of Furans by an RCM/Deprotonation/
Phosphorylation Sequence and Their Diels–Alder Reactions
Bernd Schmidt*[a] and Diana Geißler[a]
Keywords: Lactones / Metathesis / Ruthenium / Oxygen heterocycles / Metalation
Butenolides, obtained by ring-closing metathesis (RCM) of
acrylates, undergo quantitative deprotonation with amide
bases. Trapping of the resulting anions with electrophiles, for
example, chlorophosphates, give furans. Subsequent Diels–
Alder reaction and acid-catalysed rearrangement of the re-
sulting oxabicyclonorbornadienes give substituted benzenes.
Introduction
The synthesis of aromatic and heteroaromatic com-
pounds from acyclic precursors using olefin metathesis is a
rapidly expanding field.[1,2] Reactions previously described
in the literature can be classified as assisted tandem cata-
lytic[3] RCM/aromatization sequences,[4–6] one-flask se-
quences comprising an Ru-catalysed RCM step followed by
an oxidation[7–10] or elimination reaction,[11–13] and two-
step procedures involving isolation of the RCM product,
which is then converted into an aromatic compound.[14,15]
Due to the significance of substituted furans as synthetic
Scheme 1. RCM/oxidation vs. RCM/deprotonation for the synthe-
sis of substituted furans.
intermediates and as structural elements in various drugs though numerous Diels–Alder reactions of furans have been
and drug candidates, we started to explore metathesis-based reported in the literature,[23] the number of examples using
routes for the synthesis of these aromatic heterocycles. Very masked furan-2-ols is rather limited.[24] For example, a
recently we disclosed a one-flask RCM/oxidation sequence [4 + 2] cycloaddition of a 2-(aryloxy)furan followed by acid-
for the synthesis of 2-substituted and 2,5-disubstituted fur- induced aromatization has been used in the synthesis of di-
ans 3 starting from diallyl ethers 1 that proceeds via dihy- aryl ethers,[25] which are important structural motifs in
drofurans 2.[10] Although this sequence requires oxidants many natural products and drugs.[26,27]
such as DDQ or chloranil for the aromatization, no oxi-
dation is necessary for the aromatization of lactones 5,
which result from the RCM of acrylates 4. Instead, depro-
tonation and subsequent trapping of the vinylogous enol-
ates should give 2-oxygenated furans 3 (Scheme 1).
The deprotonation of butenolides 5 and the subsequent
trapping as masked furan-2-ols 3 has mostly been limited
to unsubstituted 2(5H)-furanone[16] or simple 4-substituted
derivatives (Scheme 2).[17,18] In particular, the correspond-
ing 2-(silyloxy)furans (3, E1 = SiR3) have been used as vin-
ylogous nucleophiles in alkylation reactions with allyl bro-
mides[19,20] or organocatalytic vinylogous Michael[21] and
aldol reactions to give 5-substituted butenolides 6.[22] Al-
Scheme 2. Metallation/trapping sequence for the synthesis of
[a] Universität Potsdam, Institut für Chemie (Organische
masked furan-2-ols and prospective transformations.
Synthesechemie),
Karl-Liebknecht-Straße 24–25, Haus 25, 14476 Golm,
In this work we have investigated an olefin-metathesis-
based synthesis of masked 5-substituted furan-2-ols that re-
lies on the RCM of acrylates 4, their metallation and trap-
ping with an appropriate electrophile as well as their subse-
Germany
Fax: +49-331-9775059
E-mail: bernd.schmidt@uni-potsdam.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101078.
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Synthesis of Furans by RCM/Deprotonation/Phosphorylation
quent conversion into multiple-substituted benzenes by an 3aa was isolated in low yield along with a significant
acid-induced rearrangement of cycloadducts 7.
amount of the diacetylated furan 3ab. Unfortunately, the
combination of THF as solvent and acetyl bromide as trap-
ping reagent always led to the formation of significant
amounts of 1-acetoxy-4-bromobutane, a THF cleavage
product, even at –78 °C. We were surprised by this observa-
tion as the cleavage of THF with acetyl bromide had pre-
viously been reported to require ambient temperature and
Zeise’s salt as a catalyst.[30] In an attempt to improve the
selectivity of the reaction and to avoid the formation of the
THF cleavage product, we tested a combination of LDA
and acetic anhydride as acetylating agent (Entry 5). These
conditions resulted in the selective and quantitative forma-
Results and Discussion
Optimization of the Deprotonation/Trapping Sequence
The deprotonation/electrophilic trapping sequence was
optimized with lactone 5a as the test substrate, which was
synthesized by ring-closing metathesis of the corresponding
acrylate 4a under the optimized conditions previously dis-
closed by us.[28] Initially, we tested a combination of weak
amine bases and the strong and presumably hard acylating
agent, acetyl bromide, to achieve a selective O-acylation of
lactone 5a under concomitant aromatization to the 2-acet-
oxyfuran 3aa (Table 1).
1
tion of 3aa, based on the H NMR spectrum of the crude
reaction mixture. Unfortunately, the isolated yield never ex-
ceeded 30%, irrespective of the purification method. Even
more disappointing was the use of triflic anhydride, p-tolu-
enesulfonyl chloride and methanesulfonyl chloride as trap-
ping reagents (Entries 6–8). In all these cases, complete con-
sumption of the starting material and the formation of
Table 1. Optimization of the deprotonation/electrophilic trapping
sequence.
1
complex mixtures were observed. From the H NMR spec-
tra of the crude reaction mixtures, we could obtain no evi-
dence for the formation of the expected furans.
A breakthrough was eventually achieved with chloro-
phosphates. After deprotonation of 5a with a slight excess
of LDA and treatment of the reaction mixture with diethyl
or diphenyl chlorophosphate, the furan-2-yl phosphates 3ac
or 3ad, respectively, were isolated in acceptable yields of
between 46 and 60% (Entries 9 and 10). The yields of 3ad
could be further improved to 76–89% by replacing LDA by
NaHMDS in combination with diphenyl chlorophosphate
(Entry 11).
Entry
Base[a]
E1–X[a]
Products (yields [%])
[b]
1
2
NEt3
pyridine
BuLi
LDA
LDA
LDA
LDA
LDA
LDA
H3CC(O)Br
H3CC(O)Br
H3CC(O)Br
H3CC(O)Br
Ac2O
Tf2O
pTsCl
H3CSO2Cl
ClP(O)(OEt)2
ClP(O)(OPh)2
ClP(O)(OPh)2
–
–
[b]
Acetyl Bromide versus Acetic Anhydride as Trapping
Reagents
3
8 (51)
3aa (10), 3ab (31)
3aa (28)
4[c]
5
Although the isolated yields of the 2-acetoxyfurans were
disappointingly low in the test reactions (Table 1, Entries 4
and 5), we were intrigued by the distinctive reactivities of
acetyl bromide and acetic anhydride. Two mechanisms may
explain the formation of the 3-acetylated furan 3ab
(Scheme 3). The metallated butenolide A first reacts as an
[d]
6
7
8
9
10
11
–
–
–
[d]
[d]
3ac (46–54)
3ad (46–60)
3ad (76–89)
LDA
NaHMDS
[a] 1.1 equiv. of base and 1.1 equiv. of trapping reagent in THF
were used in all experiments unless otherwise stated. [b] No conver-
sion; only unreacted starting material was recovered. [c] 2.2 equiv.
of base and 2.0 equiv. of acetyl bromide were used. [d] Complex
1
mixture of products was detected by H NMR spectroscopy of the
crude reaction mixture.
Neither triethylamine nor pyridine led to a noticeable
conversion, as judged from the 1H NMR spectra of the
crude mixtures (Entries 1 and 2). It has previously been re-
ported that various organolithium reagents react with 3,5-
disubstituted butenolides under nucleophilic attack at the
2-position rather than deprotonation.[29] This was con-
firmed for 5a, which reacts with butyllithium after aqueous
workup to give the 2,5-dialkyl-substituted furan 8 in fair
yield (Entry 3). Next, an excess of in situ prepared LDA
was used as base with an excess of acetyl bromide in THF
Scheme 3. Proposed mechanism for the formation of diacetylated
(Entry 4). Under these conditions, the desired 2-acetoxyfur- furans.
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B. Schmidt, D. Geißler
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enolate by undergoing acetylation at the 3-position to give
B and its tautomer C, which then undergoes O-acetylation
to yield 3ab. Alternatively, A is first O-acetylated, and the
2-acetoxyfuran D (i.e., 3aa) then undergoes electrophilic 3-
acetylation to give 3ab, which proceeds via the σ complex
E. Although electrophilic substitution reactions of furans at
the 3-position are rare, we favour the latter scenario, be-
cause with a hard electrophile like acetyl bromide rapid O-
acylation of A appears to be more likely than C-acylation.
Furthermore, the oxygen atom at C-2 should enhance the
electron density at C-3, thereby facilitating electrophilic at-
tack at this position. This assumption is supported by the
observation that 2-methoxyfurans undergo electrophilic
bromination at C-3.[31] Also in line with this scenario is the
fact that no acetylation at C-3 was observed with the
weaker electrophile acetic anhydride.
Lactones 5b–d gave very similar results under these acyl-
ating conditions. With LDA and acetic anhydride, the cor-
responding 2-acetoxyfurans 3ba, 3ca and 3da were the only
products; however, purification by column chromatography
or Kugelrohr distillation resulted in extensive decomposi-
tion and rather low isolated yields of 20–30%. Similarly to
5a, the reactions of metallated 5b and 5c with acetyl bro-
mide gave mixtures of mono- and diacetylated products in
comparable isolated yields and product ratios. Lactone 5d
with an acetal-protected diol moiety underwent decomposi-
tion to a complex mixture of products. This observation
underlines the high Lewis acidity of acetyl bromide
(Table 2).
Figure 1. NOE interaction for 3bb.
2-Furanyl Phosphates: Synthesis and Diels–Alder Reactions
The optimized conditions for the aromatization of lac-
tone 5a (Table 1, Entry 11) were next applied to other lac-
1
tones. The H NMR spectra of all crude reaction mixtures
revealed a full conversion of the starting materials and the
highly selective formation of the expected 2-furanyl phos-
phates. Although the test compound 3ad could be isolated
after chromatography in yields varying between 76 and
89%, we were surprised that the isolated yields for the other
examples were greatly diminished due to hydrolysis upon
contact with silica. In some cases the starting material 5
was recovered, in others a complex mixture of products was
formed. For this reason we decided to characterize the
crude 2-furanyl phosphates obtained after aqueous workup
of the reaction mixture by NMR spectroscopy and convert
them directly into 7-oxanorbornadienes 7 by Diels–Alder
reaction with dimethyl acetylenedicarboxylate (DMAD).
These products turned out to be stable to chromatography
on silica and could be fully characterized. Not unexpec-
tedly, 7e was obtained as a mixture of diastereomers in a
ratio of approximately 3:1 (Table 3).
Table 2. Deprotonation/electrophilic trapping sequence for lactones
5a–d with acetic anhydride or acetyl bromide.
Lewis Acid Mediated Rearrangement of 7-
Oxanorbornadienes
Several ring-opening reactions to six-membered carba-
cycles have been reported for the Diels–Alder adducts of
furans. Base-induced rearrangement[32] or Rh-catalysed nu-
cleophilic ring-opening[33] gives functionalized cyclohexa-
dienes stereoselectively, whereas treatment of 7-oxanor-
bornadienes with Brønsted or Lewis acids normally results
in rearrangement to phenols.[34–36] The gold-catalysed[37] re-
arrangement of furans with a pendant alkyne side-chain
also gives phenols, but proceeds via an arene oxide rather
than a Diels–Alder adduct.[38,39]
A few examples of the Diels–Alder reactions of furans
with electron-donating substituents at the 2-position and
subsequent rearrangement to phenols have been reported.
For example, as shown in Scheme 4, 2-methoxyfuran (9)
was found to undergo a cycloaddition reaction with hexa-
fluorobutyne (10) to give 11, which rearranges thermally,
even in the absence of acid, to phenol 12.[40]
[a] Acetic anhydride as trapping reagent. [b] Acetyl bromide as
trapping reagent. [c] Complex mixture of products.
In this particular case, the rearrangement is facilitated by
The constitution of trisubstituted furans 3ab–3cb was not the electron-donating character of the 2-methoxy substitu-
obvious from routine NMR spectra, and therefore a 2D ent. The electron-withdrawing nature of the phosphate
NOE spectrum was recorded for 3bb, which revealed a group will most likely contribute to the stability of the cy-
strong NOE between 4-H and 2Ј-H of the 4-methoxyphenyl cloaddition products 7 described in this work. Equally im-
substituent (Figure 1).
portant for the stability of these cycloadducts should be the
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Synthesis of Furans by RCM/Deprotonation/Phosphorylation
Table 3. Synthesis of 2-furanyl phosphates 3#d and their Diels–Alder reactions to 7-oxanorbornadienes 7.
1
[a] Conversion of 5 into the corresponding furanyl phosphate 3 was quantitative based on H NMR spectroscopy of the crude reaction
mixtures. [b] Range of yields was obtained for three experiments, yields are calculated for the sequence starting from lactones 5. [c]
Isolated yields of analytically pure 3ad, purified by chromatography on silica, varied between 76 and 89%. [d] Isolated as a 3:1 mixture
of diastereomers.
16a were isolated in ratios of 1:4 to 1:2 in varying yields,
depending on the reaction time and the amount of Lewis
acid used (Table 4).
Table 4. BF3·OEt2-mediated cleavage of 7a.
Scheme 4. Diels–Alder reaction of 2-methoxyfuran and thermal re-
arrangement to a phenol.[40]
absence of a proton at C-5 of the furan precursor. It has,
for instance, been shown that Diels–Alder adducts 13 of 2-
(aryloxy)furans with a hydroxymethyl substituent at C-5 are
stable, but that in the presence of an acid the side-chain is
Entry
BF3·OEt2 [equiv.]
Time [h]
Yield [%]
cleaved to formaldehyde with concomitant rearrangement
to phenol 14 (Scheme 5).[25]
15
16a
1
1.5
1.5
2.5
1.1
24
5
18.5
18.5
12
23
20
27
58
55
77
63
2[a]
3
4[b]
[a] 14% of unreacted starting material was recovered. [b] 5% of
unreacted starting material was recovered.
Scheme 5. Fragmentation of hydroxymethyl-substituted Diels–
Alder adduct.[25]
Compound 15 was easily identified by the presence of a
pair of doublets in the aromatic region. It results from a
dealkylation reaction, presumably with the formation of
To investigate the effect of different C-5 side-chains on styrene as a byproduct, by a mechanism that involves Lewis
the course of acid-mediated ring-cleavage reactions, the bi- acid mediated cleavage of the bicyclic ring system to give
cyclic phosphates 7a,c,f,g were treated with BF3·OEt2 in the stabilized carbenium ion A, which then undergoes de-
dichloromethane. In the case of 7a, two products 15 and protonation at the benzylic position and cleavage of the C–
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B. Schmidt, D. Geißler
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C bond with concomitant reconstitution of aromaticity. The
formation of 16a can be explained by a competing pathway
resembling the NIH shift,[41] which was originally proposed
as a pathway to rationalize the oxidative metabolism of ar-
enes. Thus, the alkyl chain migrates to the ortho position to
give cyclohexadienone B, which rapidly tautomerizes to the
phenol 16a (Scheme 6).
Figure 2. HMBC experiments for 16c.
Conclusions
Metallation of α,β-unsaturated γ-butyrolactones and
trapping of the resulting vinylogous enolates with appropri-
ate electrophiles yielded 5-substituted furan-2-ol derivatives.
Chlorophosphates are particularly well suited as trapping
reagents, giving the corresponding furanyl phosphates.
These compounds readily underwent [4+2] cycloaddition
reactions to 7-oxanorbornadienes, which are remarkably
stable and can be isolated. Finally, the reactions of these
bicyclic products with Lewis acids were studied. Two com-
peting pathways, a rearrangement and an elimination, were
observed under the reaction conditions. Remarkably, the
phosphate remains intact in both cases. This is potentially
useful for synthetic applications such as Pd-catalysed aryl-
ation reactions.
Scheme 6. Mechanism for the competing formation of 15 and 16a
from 7a.
Experimental Section
We then investigated the reactions of 7c, 7f and 7g under
these conditions. Although for 7f a complex mixture of
products was obtained, treatment of the (benzyloxy)methyl-
substituted derivative 7g with BF3·OEt2 resulted in the ex-
clusive formation of the dealkylation product 15, which was
isolated in 77% yield. The rearrangement product resulting
from a 1,2-shift of the (benzyloxy)methyl substituent could
not even be detected in trace amounts (Scheme 7). Presum-
ably, a chelate C is formed that allows facile debenzylation
and subsequent fragmentation to formaldehyde and phenol
15.
General: All experiments were conducted in dry reaction vessels
under dry nitrogen. Solvents were purified by standard procedures.
1H NMR spectra were obtained with a Bruker DRX 300 spectrom-
eter at 300 MHz in CDCl3 with CHCl3 (δ = 7.26 ppm) as internal
standard. Coupling constants (J) are given in Hz. Signal assign-
ments refer to the numbering schemes detailed in the Supporting
Information. 13C NMR spectra were recorded with a Bruker DRX
300 spectrometer at 75 MHz in CDCl3 with CDCl3 (δ = 77.0 ppm)
as internal standard. IR spectra were recorded with a Nicolet Im-
pact 400 D spectrometer as films in NaCl or KBr plates or as KBr
discs. Wavenumbers (ν) are given in cm–1. EI mass spectra were
obtained at 70 eV with a GC TOF micromass spectrometer (Micro-
mass Manchester Waters Inc.). ESI mass spectra were obtained
with a Q-TOF micromass spectrometer (Micromass Manchester
Waters Inc.).
General Procedure for the Synthesis of 2-Furanyl Phosphates 3#d:
In a flame-dried and nitrogen-flushed reaction vessel, NaHMDS
(1.1 equiv.) was dissolved in dry THF and cooled to –78 °C. A solu-
tion of the appropriate lactone 5 (1.0 equiv.) was dissolved in dry
THF (5 mL/mmol) and added dropwise. The reaction mixture was
stirred at –78 °C for 15 min, and then diphenyl chlorophosphate
(1.1 equiv.) was added to the reaction mixture, which was stirred
for another 45 min. After completion of the reaction, the mixture
was quenched by the addition of water. After phase separation, the
aqueous phase was extracted with tert-butyl methyl ether
(3ϫ20 mL). The combined organic extracts were washed with
brine, dried with MgSO4, filtered and the solvents removed in
vacuo. The residue was suspended in a mixture of hexane and tert-
butyl methyl ether, filtered and the solvents were again removed in
vacuo. The resulting crude product was sufficiently pure for subse-
quent reactions without any further purification.
Scheme 7. BF3·OEt2-mediated cleavage of 7g.
Remarkably, the pentyl-substituted derivative 7c re-
arranges under otherwise identical conditions to 16c in 79%
yield. The dealkylation product 15 was observed only in
very minor amounts in all experiments starting from 7c.
For this derivative, a structural elucidation based on 2D
NMR techniques was achieved. Unfortunately, 2D NOE
experiments were ambiguous, and we therefore conducted
HMBC experiments. Relevant couplings between protons
and carbon atoms across two or three bonds are depicted
in Figure 2.
5-Phenethylfuran-2-yl Diphenyl Phosphate (3ad): By applying the
general procedure, the title compound was obtained from 5a
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Synthesis of Furans by RCM/Deprotonation/Phosphorylation
1
(500 mg, 2.7 mmol). H NMR spectroscopy of the crude reaction
Dimethyl 1-[(Diphenoxyphosphoryl)oxy]-4-phenethyl-7-oxabicyclo-
[2.2.1]hepta-2,5-diene-2,3-dicarboxylate (7a): By starting from puri-
fied 3ad (968 mg, 2.3 mmol), the title compound 7a (1.14 g,
2.0 mmol, 88%) was obtained by applying the general procedure
mixture indicated complete conversion into 3ad. For this particular
example, analytically pure 3ad (1.02 g, 2.4 mmol, 89%) was ob-
tained by column chromatography on silica with only a slightly
reduced yield. 1H NMR (300 MHz, CDCl3): δ = 7.42–7.33 (5 H, after purification by column chromatography on silica gel with a
1
Aryl), 7.31–7.14 (10 H, Aryl), 5.88 (d, J = 3.2 Hz, 1 H, 9-H), 5.63 mixture of hexane/tert-butyl methyl ether (3:1) as eluent. H NMR
(dd, J = 3.1, 2.3 Hz, 1 H, 8-H), 2.94–2.80 (4 H, 5-H, 6-H) ppm. (300 MHz, CDCl3): δ = 7.39–7.16 (16 H, Aryl, 9-H), 6.98 (dd, J =
13C NMR (75 MHz, CDCl3): δ = 150.2, 148.1, 148.0, 140.7, 129.8, 5.2, 1.0 Hz, 1 H, 8-H), 3.78 (s, 3 H, 14-H/16-H), 3.69 (s, 3 H, 16-
128.3, 128.2, 126.0, 125.8, 120.0, 106.5, 90.2, 34.0, 29.7 ppm. 31P
H/14-H), 2.69 (dd, J = 8.3, 8.1 Hz, 2 H, 5-H), 2.64–2.42 (2 H, 6-
NMR (121.5 MHz, CDCl3): δ = –17.7 ppm. HRMS (EI): calcd. for H) ppm. 13C NMR (75 MHz, CDCl3): δ = 163.2, 162.4, 153.1,
C24H21O5P [M]+ 420.1127; found 420.1113. C24H21O5P (420.39): 151.3, 150.3, 146.6, 142.5, 141.0, 129.6, 128.4, 126.1, 125.5, 120.3,
calcd. C 68.6, H 5.0; found C 68.4, H 4.9.
111.8, 91.4, 52.4, 52.2, 31.0, 30.9 ppm. 31P NMR (121.5 MHz,
CDCl ): δ = –16.1 ppm. IR (neat): ν = 1718, 1589, 1488, 1282,
˜
3
5-Pentylfuran-2-yl Diphenyl Phosphate (3cd): By applying the gene-
ral procedure, the title compound was obtained from 5c (82 mg,
0.5 mmol). 1H NMR spectroscopy of the crude reaction mixture
indicated complete conversion into 3cd. 1H NMR (300 MHz,
CDCl3): δ = 7.45–7.18 (10 H, Aryl), 5.88 (d, J = 3.1 Hz, 1 H, 8-
H), 5.62 (dd, J = 3.1, 2.4 Hz, 1 H, 7-H), 2.51 (t, J = 7.5 Hz, 2 H,
5-H), 1.63–1.52 (2 H, 4-H), 1.40–1.25 (4 H, 2-H, 3-H), 0.95–0.85
(3 H, 1-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 150.2, 149.8,
149.4, 147.9, 130.1, 129.9, 126.4, 125.9, 120.4, 120.1, 105.8, 90.1,
31.2, 27.8, 27.4, 22.3, 13.9 ppm. 31P NMR (121.5 MHz, CDCl3): δ
= –17.7 ppm.
1178, 1009, 957, 844, 754, 688 cm–1. HRMS (EI): calcd. for
C30H27O9P [M]+ 562.1387; found 562.1393. C30H27O9P (562.50):
calcd. C 64.1, H 4.8; found C 63.9, H 4.8.
Dimethyl
1-[(Diphenoxyphosphoryl)oxy]-4-pentyl-7-oxabicyclo-
[2.2.1]hepta-2,5-diene-2,3-dicarboxylate (7c): The title compound
was obtained from crude 3cd [synthesized from 5c (82 mg,
0.5 mmol) as described above] by applying the general procedure.
After purification by column chromatography on silica with hex-
ane/tert-butyl methyl ether mixtures (3:1 to 1:1) as eluent, 7c
(183 mg, 0.4 mmol, 82% based on 5c) was isolated. 1H NMR
(300 MHz, CDCl3): δ = 7.38–7.16 (11 H, Aryl, 8-H), 6.99 (d, J =
5.2 Hz, 1 H, 7-H), 3.79 (s, 3 H, 13-H/15-H), 3.66 (s, 3 H, 15-H/13-
H), 2.25–2.08 (2 H, 5-H), 1.47–1.20 (6 H, 2-H, 3-H, 4-H), 0.92–
0.84 (3 H, 1-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 163.3,
162.3, 153.9, 150.7, 150.3, 146.8, 142.1, 129.7, 125.4, 120.3, 111.7,
92.0, 52.4, 52.2, 31.8, 28.8, 24.5, 22.4, 13.9 ppm. 31P NMR
(R)-5-(2,2-Dimethyl-1,3-dioxolan-4-yl)furan-2-yl Diphenyl Phos-
phate (3ed): By applying the general procedure, the title compound
was obtained from 5e (98 mg, 0.5 mmol). 1H NMR spectroscopy
of the crude reaction mixture indicated complete conversion into
3ed. 1H NMR (300 MHz, CDCl3): δ = 7.45–7.19 (10 H, Aryl), 6.29
(d, J = 3.3 Hz, 1 H, 8-H), 5.72 (dd, J = 3.3, 2.2 Hz, 1 H, 7-H), 4.96
(dd, J = 7.1, 6.9 Hz, 1 H, 5-H), 4.18 (dd, J = 8.4, 6.5 Hz, 1 H, 4-
Ha), 4.01 (dd, J = 8.3, 7.5 Hz, 1 H, 4-Hb), 1.46 (s, 3 H, 1-H/2-H),
1.43 (s, 3 H, 2-H/1-H) ppm. 13C NMR (75 MHz, CDCl3): δ =
150.2, 149.9, 149.7, 144.7, 130.1, 129.9, 126.4, 125.9, 120.4, 120.1,
110.1, 90.7, 71.1, 67.6, 26.3, 25.9 ppm. 31P NMR (121.5 MHz,
CDCl3): δ = –18.1 ppm.
(121.5 MHz, CDCl ): δ = –16.1 ppm. IR (neat): ν = 1717, 1589,
˜
3
1488, 1435, 1282, 1179, 1162, 1009, 956, 883, 754, 687 cm–1. HRMS
(EI): calcd. for C27H29O9P [M]+ 528.1544; found 528.1555. HRMS
(ESI): calcd. for C27H29O9PNa [M + Na]+ 551.1447; found
551.0958. C27H29O9P (528.49): calcd. C 61.4, H 5.5; found C 61.1,
H 5.6.
Dimethyl 1-[(R)-2,2-Dimethyl-1,3-dioxolan-4-yl]-4-[(diphenoxyphos-
phoryl)oxy]-7-oxabicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate
(7e): The title compound was obtained from crude 3ed [synthesized
from 5e (98 mg, 0.5 mmol) as described above] by applying the ge-
neral procedure. After purification by column chromatography on
silica with hexane/tert-butyl methyl ether mixtures (2:1 to 1:1) as
eluent, 7e (104 mg, 0.2 mmol, 45% based on 5e) was isolated as a
1:1 mixture of diastereomers. Partial separation of the dia-
stereomers was achieved by careful chromatography. Analytical
data of the less polar diastereomer: [α]2D1 = –14.8 (c = 6, CH2Cl2).
1H NMR (300 MHz, CDCl3): δ = 7.38–7.16 (12 H, Aryl, 7-H, 8-
H), 4.93 (t, J = 6.2 Hz, 1 H, 4-H), 4.13 (dd, J = 8.6, 6.9 Hz, 1 H,
3-Ha), 3.97 (dd, J = 8.6, 5.7 Hz, 1 H, 3-Hb), 3.78 (s, 3 H, 13-H/
15-H), 3.67 (s, 3 H, 15-H/13-H), 1.39 (br. s, 3 H, 1-H/2-H], 1.38
(br. s, 3 H, 2-H/1-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 162.9,
161.8, 152.5, 150.2, 144.8, 142.3, 142.2, 129.7, 125.6, 120.4, 111.8,
110.5, 91.2, 72.4, 65.9, 52.6, 52.3, 25.9, 25.3 ppm. 31P NMR
Diphenyl 5-Phenylfuran-2-yl Phosphate (3fd): By applying the gene-
ral procedure, the title compound was obtained from 5f (85 mg,
0.5 mmol). 1H NMR spectroscopy of the crude reaction mixture
indicated complete conversion into 3fd. 1H NMR (300 MHz,
CDCl3): δ = 7.56–7.51 (2 H, Aryl), 7.46–7.21 (13 H, Aryl), 6.56 (d,
J = 3.4 Hz, 1 H, 7-H), 5.86 (dd, J = 3.4, 2.2 Hz, 1 H, 6-H) ppm.
13C NMR (75 MHz, CDCl3): δ = 150.2, 149.8, 149.3, 146.8, 130.1,
129.9, 129.7, 128.6, 127.3, 126.4, 125.9, 120.4, 120.1, 106.0,
92.1 ppm. 31P NMR (121.5 MHz, CDCl3): δ = –17.9 ppm.
5-[(Benzyloxy)methyl]furan-2-yl Diphenyl Phosphate (3gd): By ap-
plying the general procedure, the title compound was obtained
1
from 5g (108 mg, 0.5 mmol). H NMR spectroscopy of the crude
reaction mixture indicated complete conversion into 3gd. 1H NMR
(300 MHz, CDCl3): δ = 7.38–7.10 (15 H, Aryl), 6.19 (d, J = 3.3 Hz,
1 H, 9-H), 5.67 (dd, J = 3.3, 2.2 Hz, 1 H, 8-H), 4.46 (s, 2 H, 5-H),
4.31 (s, 2 H, 6-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 150.2,
149.7, 144.7, 131.7, 130.1, 129.9, 128.4, 127.9, 127.7, 126.4, 125.9,
120.4, 120.1, 111.1, 90.7, 71.8, 63.7 ppm. 31P NMR (121.5 MHz,
CDCl3): δ = –17.9 ppm.
(121.5 MHz, CDCl ): δ = –16.2 ppm. IR (neat): ν = 1720, 1589,
˜
3
1488, 1436, 1285, 1257, 1182, 1162, 1010, 961, 843, 770, 689 cm–1.
HRMS (EI): calcd. for C27H27O11PNa [M]+ 558.1286; found
General Procedure for the Diels–Alder Reactions of Furanyl Phos- 558.1278. C27H27O11P (558.47): calcd. C 58.1, H 4.9; found C 57.9,
1
phates 3#d: The appropriate crude or purified furanyl phosphate
3#d was dissolved in xylene (2 mL/mmol). DMAD (3.0 equiv.) was
added, and the reaction mixture was heated at 135 °C. After com-
plete consumption of the starting material, the solvent was re-
moved in vacuo. The residue was purified by column chromatog-
raphy on silica gel with a mixture of hexane and tert-butyl methyl
ether as eluent.
H 4.8. Analytical data for the more polar diastereomer of 7e: H
NMR (300 MHz, CDCl3): δ = 7.38–7.15 (10 H, Aryl, 8-H), 6.98
(br. d, J = 5.3 Hz, 1 H, 7-H), 4.94 (dd, J = 6.4, 6.4 Hz, 1 H, 5-H),
4.11 (dd, J = 8.6, 6.9 Hz, 1 H, 4-Ha), 3.96 (dd, J = 8.6, 6.0 Hz, 1
H, 4-Hb), 3.81 (s, 3 H, 13-H/15-H), 3.67 (s, 3 H, 15-H/13-H), 1.37
(br. s, 3 H, 1-H/2-H), 1.36 (br. s, 3 H, 2-H/1-H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 163.2, 161.9, 152.5, 150.3, 149.9, 144.8,
Eur. J. Org. Chem. 2011, 7140–7147
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7145

B. Schmidt, D. Geißler
FULL PAPER
143.2, 129.7, 125.6, 120.3, 111.9, 110.5, 91.6, 72.3, 65.5, 52.5, 52.3,
(121.5 MHz, CDCl ): δ = –16.7 ppm. IR (neat): ν = 1739, 1678,
˜
3
25.9, 25.4 ppm. 31P NMR (121.5 MHz, CDCl3): δ = –16.3 ppm.
1589, 1488, 1431, 1347, 1299, 1182, 1162, 1062, 1010, 947, 752,
688 cm–1. HRMS (ESI): calcd. for C30H28O9P [M + H]+ 563.1471;
found 563.1426. C30H27O9P (562.50): calcd. C 64.1, H 4.8; found
C 64.0, H 4.6.
Dimethyl 1-[(Diphenoxyphosphoryl)oxy]-4-phenyl-7-oxabicyclo-
[2.2.1]hepta-2,5-diene-2,3-dicarboxylate (7f): The title compound
was obtained from crude 3fd [synthesized from 5f (85 mg,
0.5 mmol) as described above] by applying the general procedure.
After purification by column chromatography on silica with hex-
ane/tert-butyl methyl ether mixtures (3:1 to 1:1) as eluent, 7f
(125 mg, 0.2 mmol, 52 % based on 5f) was isolated. 1H NMR
(300 MHz, CDCl3): δ = 7.48 (dd, J = 5.3, 1.1 Hz, 1 H, 6-H), 7.46–
7.16 (16 H, Aryl, 7-H), 3.68 (s, 3 H, 12-H/14-H), 3.62 (s, 3 H, 14-
H/12-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 163.6, 161.8,
156.8, 150.3, 147.6, 145.6, 142.4, 132.7, 129.6, 129.1, 128.5, 126.9,
125.6, 120.4, 111.9, 91.7, 52.3, 52.2 ppm. 31P NMR (121.5 MHz,
Dimethyl 6-[(Diphenoxyphosphoryl)oxy]-3-hydroxy-4-pentylphthal-
ate (16c): By applying the general procedure, 7c (94 mg, 0.2 mmol)
was converted into the title compound 16c. The crude product was
purified by column chromatography on silica gel using a hexane/
tert-butyl methyl ether mixture (5:1) as eluent. Yield of 16c: 74 mg
1
(0.1 mmol, 79%). H NMR (300 MHz, CDCl3): δ = 11.07 (s, 1 H,
20-H), 7.40–7.16 (11 H, Aryl), 3.89 (s, 3 H, 13-H/15-H), 3.69 (s, 3
H, 15-H/13-H), 2.61 (dd, J = 7.9, 7.5 Hz, 2 H, 5-H), 1.60–1.47 (2
H, 4-H), 1.36–1.25 (4 H, 2-H, 3-H), 0.87 (t, J = 6.7 Hz, 3 H, 1-H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 169.2, 165.9, 157.3, 150.4,
138.9, 134.9, 129.8, 127.1, 125.7, 120.2, 120.1, 108.8, 52.9, 52.4,
31.4, 29.7, 28.5, 22.4, 13.9 ppm. 31P NMR (121.5 MHz, CDCl3): δ
CDCl ): δ = –16.0 ppm. IR (neat): ν = 1721, 1589, 1488, 1435,
˜
3
1284, 1184, 1162, 1011, 951, 756, 688, 555 cm–1. HRMS (EI): calcd.
for C28H23O9P [M]+ 534.1074; found 534.1042. C28H23O9P
(534.45): calcd. C 62.9, H 4.3; found C 62.7, H 4.1.
= –16.6 ppm. IR (neat): ν = 1739, 1678, 1589, 1488, 1432, 1345,
˜
1299, 1247, 1205, 1182, 1161, 1060, 1009, 947, 878, 844, 804, 754,
687 cm–1. HRMS (ESI): calcd. for C27H30O9P [M + H]+ 529.1627;
found 529.1598. C27H29O9P (528.49): calcd. C 61.4, H 5.5; found
C 61.4, H 5.6.
Dimethyl 1-[(Benzyloxy)methyl]-4-[(diphenoxyphosphoryl)oxy]-7-
oxabicyclo[2.2.1]hepta-2,5-diene-2,3-dicarboxylate (7g): The title
compound was obtained from crude 3gd [synthesized from 5g
(108 mg, 0.5 mmol) as described above] by applying the general
procedure. After purification by column chromatography on silica
with hexane/tert-butyl methyl ether mixtures (1:1) as eluent, 7g
(168 mg, 0.3 mmol, 55 % based on 5g) was isolated. 1H NMR
(300 MHz, CDCl3): δ = 7.38–7.17 (16 H, Aryl, 9-H), 7.07 (dd, J =
5.3, 0.9 Hz, 1 H, 8-H), 4.60 (dd, J = 12.0, 8.3 Hz, 1 H, 5-Ha), 4.57
(dd, J = 12.0, 8.3 Hz, 1 H, 5-Hb), 4.19 (dd, J = 11.8, 9.4 Hz, 1 H,
6-Ha), 4.16 (dd, J = 11.8, 9.4 Hz, 1 H, 6-Hb), 3.74 (s, 3 H, 14-H/
16-H), 3.68 (s, 3 H, 16-H/14-H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 163.2, 162.0, 152.5, 150.3, 149.9, 144.5, 142.3, 137.5, 129.6,
128.3, 127.7, 125.6, 120.4, 112.1, 73.6, 66.0, 52.4, 52.2 ppm. 31P
Dimethyl 3-[(Diphenoxyphosphoryl)oxy]-6-hydroxyphthalate (15):
By applying the general procedure, 7g (303 mg, 0.5 mmol) was con-
verted into the title compound 15. The crude product was purified
by column chromatography on silica gel using hexane/tert-butyl
methyl ether mixtures (6:1 to 3:1) as eluent. Yield of 15: 184 mg
1
(0.4 mmol, 77%). H NMR (300 MHz, CDCl3): δ = 10.80 (s, 1 H,
15-H), 7.57 (d, J = 9.3 Hz, 1 H, Aryl), 7.40–7.18 (10 H, Aryl), 7.02
(d, J = 9.3 Hz, 1 H, Aryl), 3.91 (s, 2 H, 7-H/8-H), 3.71 (s, 3 H, 8-
H/7-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 168.6, 165.2, 158.9,
150.4, 139.5, 129.9, 127.6, 125.7, 120.1, 120.0, 115.3, 109.5, 53.1,
52.5 ppm. 31P NMR (121.5 MHz, CDCl3): δ = –16.6 ppm. IR
NMR (121.5 MHz, CDCl ): δ = –16.2 ppm. IR (neat): ν = 1720,
˜
3
(neat): ν = 1739, 1681, 1589, 1487, 1456, 1335, 1299, 1248, 1204,
˜
1589, 1488, 1436, 1283, 1183, 1162, 1010, 956, 844, 754, 688,
561 cm–1. HRMS (EI): calcd. for C30H27O10P [M]+ 578.1360; found
578.1363. C30H27O10P (578.50): calcd. C 62.3, H 4.7; found C 62.1,
H 4.6.
1182, 1161, 1118, 1023, 1009, 992, 952, 863, 754, 687 cm–1. HRMS
(ESI): calcd. for C22H19O9P [M]+ 458.0767; found 458.0750.
C22H19O9P (458.36): calcd. C 57.7, H 4.2; found C 57.9, H 4.2.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details and 1H and 13C NMR spectra for all new
compounds.
General Procedure for Lewis Acid Mediated Ring-Opening Reac-
tions of Diels–Alder Adducts 7: In a flame-dried and nitrogen-
flushed reaction vessel, the appropriate precursor 7 was dissolved
in dry CH2Cl2 and cooled to 0 °C. Then BF3·Et2O (1.5 equiv.) was
added, and the reaction mixture was stirred at 0 °C. After comple-
tion of the reaction, the mixture was quenched by the addition of
a solution of saturated aqueous NH4Cl. After phase separation,
the aqueous phase was extracted with CH2Cl2 (3ϫ20 mL). The
combined organic extracts were washed with brine, dried with
MgSO4, filtered, and the solvents removed with a rotary evapora-
tor. The residue was purified by column chromatography on silica
gel using a mixture of hexane/tert-butyl methyl ether as eluent.
Acknowledgments
This work was generously supported by the Deutsche Forschungs-
gemeinschaft. We thank Evonik Oxeno for the generous donation
of solvents.
[1] T. J. Donohoe, A. J. Orr, M. Bingham, Angew. Chem. 2006,
118, 2730; Angew. Chem. Int. Ed. 2006, 45, 2664–2670.
[2] W. A. L. van Otterlo, C. B. de Koning, Chem. Rev. 2009, 109,
3743–3782.
Dimethyl 6-[(Diphenoxyphosphoryl)oxy]-3-hydroxy-4-phenethyl-
phthalate (16a): By applying the general procedure, 7a (311 mg,
0.6 mmol) was converted into a mixture of 16a and 15 in a ratio of
approximately 4:1. The products were separated by column
chromatography on silica gel with a mixture of hexane/tert-butyl
methyl ether (5:1 to 3:1) as eluent. Yield of the less polar product
16a: 238 mg (0.4 mmol, 77%); yield of the more polar product 15:
55 mg (0.12 mmol, 20%). Analytical data for 16a: 1H NMR
(300 MHz, CDCl3): δ = 11.14 (s, 1 H, 21-H), 7.40–7.15 (16 H,
Aryl), 3.91 (s, 3 H, 14-H/16-H), 3.70 (s, 3 H, 16-H/14-H), 2.96–2.80
(4 H, 5-H, 6-H) ppm. 13C NMR (75 MHz, CDCl3): δ = 169.1,
165.8, 157.3, 150.2, 141.1, 138.9, 133.6, 129.8, 128.3, 127.2, 125.9,
125.6, 120.1, 120.0, 108.9, 53.0, 52.4, 34.9, 31.9 ppm. 31P NMR
[3] D. E. Fogg, E. N. dos Santos, Coord. Chem. Rev. 2004, 248,
2365–2379.
[4] P. Evans, R. Grigg, M. Monteith, Tetrahedron Lett. 1999, 40,
5247–5250.
[5] C. M. Yang, W. V. Murray, L. J. Wilson, Tetrahedron Lett.
2003, 44, 1783–1786.
[6] L. Evanno, B. Nay, B. Bodo, Synth. Commun. 2005, 35, 1559–
1565.
[7] N. Dieltiens, C. V. Stevens, D. De Vos, B. Allaert, R. Drozdzak,
F. Verpoort, Tetrahedron Lett. 2004, 45, 8995–8998.
[8] N. Dieltiens, C. V. Stevens, B. Allaert, F. Verpoort, ARKIVOC
2005, 1, 92–97.
7146
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 7140–7147

Synthesis of Furans by RCM/Deprotonation/Phosphorylation
[9] S. K. Chattopadhyay, K. Sarkar, S. Karmakar, Synlett 2005,
2083–2085.
[10] B. Schmidt, D. Geißler, Eur. J. Org. Chem. 2011, 4814–4822.
[11] T. J. Donohoe, A. J. Orr, K. Gosby, M. Bingham, Eur. J. Org.
Chem. 2005, 1969–1971.
[26] J. S. Sawyer, Tetrahedron 2000, 56, 5045–5065.
[27] R. Frlan, D. Kikelj, Synthesis 2006, 2271–2285.
[28] B. Schmidt, D. Geißler, ChemCatChem 2010, 2, 423–429.
[29] X. Zhang, E. U. Jackson, A. G. Schultz, J. Heterocycl. Chem.
2006, 43, 223–228.
[12] T. J. Donohoe, A. Ironmonger, N. M. Kershaw, Angew. Chem.
2008, 120, 7424; Angew. Chem. Int. Ed. 2008, 47, 7314–7316.
[13] T. J. Donohoe, L. P. Fishlock, A. R. Lacy, P. A. Procopiou,
Org. Lett. 2007, 9, 953–956.
[14] V. Declerck, P. Ribière, J. Martinez, F. Lamaty, J. Org. Chem.
2004, 69, 8372–8381.
[15] D. Banti, M. North, Tetrahedron Lett. 2002, 43, 1561–1564.
[16] O. E. O. Hormi, J. H. Näsman, Synth. Commun. 1986, 16, 69–
77.
[30] J. W. Fitch, W. G. Payne, D. Westmoreland, J. Org. Chem. 1983,
48, 751–753.
[31] D. G. Manly, E. D. Amstutz, J. Org. Chem. 1956, 21, 516–519.
[32] I. B. Masesane, A. S. Batsanov, J. A. K. Howard, R. Mondal,
P. G. Steel, Beilstein J. Org. Chem. 2006, 2, no. 9.
[33] T. D. Nguyen, R. Webster, M. Lautens, Org. Lett. 2011, 13,
1370–1373.
[34] A. Maggiani, A. Tubul, P. Brun, Chem. Commun. 1999, 2495–
2496.
[17] A. Pelter, R. Al-Bayati, W. Lewis, Tetrahedron Lett. 1982, 23,
[35] K. M. Guckian, E. Y.-S. Lin, L. Silvian, J. E. Friedman, D.
Chin, D. M. Scott, Bioorg. Med. Chem. Lett. 2008, 18, 5249–
5251.
353–356.
[18] F. Farina, M. D. Parellada, J. Org. Chem. 1988, 53, 3330–3333.
[19] G. Vassilikogiannakis, M. Stratakis, Angew. Chem. 2003, 115,
5623; Angew. Chem. Int. Ed. 2003, 42, 5465–5468.
[20] C. W. Jefford, J.-C. Rossier, J. Boukouvalas, A. W. Sledeski, P.-
Z. Huang, J. Nat. Prod. 2004, 67, 1383–1386.
[21] S. P. Brown, N. C. Goodwin, D. W. C. MacMillan, J. Am.
Chem. Soc. 2003, 125, 1192–1194.
[36] K. J. Procko, H. Li, S. F. Martin, Org. Lett. 2010, 12, 5632–
5635.
[37] A. S. K. Hashmi, M. Rudolph, Chem. Soc. Rev. 2008, 37, 1766–
1775.
[38] A. S. K. Hashmi, M. Rudolph, J. W. Bats, W. Frey, F. Rom-
inger, T. Oeser, Chem. Eur. J. 2008, 14, 6672–6678.
[39] A. S. K. Hashmi, M. Rudolph, H.-U. Siehl, M. Tanaka, J. W.
Bats, W. Frey, Chem. Eur. J. 2008, 14, 3703–3708.
[40] G.-D. Zhu, M. A. Staeger, S. A. Boyd, Org. Lett. 2000, 2, 3345–
3348.
[22] R. P. Singh, B. M. Foxman, L. Deng, J. Am. Chem. Soc. 2010,
132, 9558–9560.
[23] J. A. Joule, K. Mills, Heterocyclic Chemistry, 4th ed., Blackwell,
Oxford, 2000.
[24] J. Buck, N. G. Clemo, G. Pattenden, J. Chem. Soc. Perkin
Trans. 1 1985, 2399–2405.
[25] S. D. Carter, D. Thetford, M. Voyle, P. G. Sammes, J. Chem.
Soc. Perkin Trans. 1 1990, 1231–1233.
[41] G. Guroff, J. Renson, S. Udenfriend, J. W. Daly, D. M. Jerina,
B. Witkop, Science 1967, 157, 1524–1530.
Received: July 22, 2011
Published Online: October 13, 2011
Eur. J. Org. Chem. 2011, 7140–7147
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7147